sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e148, epub. 21 jan 15 submitted 3 oct 14 accepted 5 nov 14 رد: نتائج احلمل يف النساء اللوايت لديهن البيتا ثالسيميا املتماثلة جتربة مركز واحد من عمان re: pregnancy outcomes in women with homozygous beta thalassaemia a single-centre experience from oman sir, i have two comments on the interesting study by al-riyami et al. published in the squmj august 2014 issue.1 first, despite the small sample (n = 10) of studied pregnant women with homozygous beta thalassaemia (hbt), it was satisfying to read that all of them had conceived spontaneously, apart from one of the women with beta thalassaemia major (btm) who had conceived using hormonal therapy.1 the high rate of successful pregnancy outcomes (93%) observed among the studied hbt pregnant women is promising. the ability to have a family is an essential aspect of a patient’s quality of life. improvements in current treatments for btm, especially in the management of iron deposits and the prolongation of survival, have resulted in a remarkable increase in pregnancies among thalassaemic women.1 pregnancy is now a real possibility for these patients. although numerous complications can occur, vigilant monitoring by both experienced obstetricians and haematologists can lead to successful pregnancy outcomes, as was noted by gulino et al.2 second, al-riyami et al. stated in their study that all three women with btm underwent counselling before their pregnancies and had achieved low serum ferritin (sf) levels (236–522 ng/ml) with extensive chelation therapy before conception.1 moreover, they mentioned that all three btm women underwent t2* magnetic resonance imaging (mri) before and soon after their pregnancy in order to determine iron status. all three patients, and in particular the first two patients, had increased liver iron loads during their pregnancies. the third patient had undergone chelation therapy in her third trimester. however, the cardiac iron status of all the three patients remained normal.1 this observation is particularly interesting in view of the following two considerations. sf measurements are no longer believed to be precise in determining the iron content of body tissues. a moderate negative correlation was recently reported between sf and liver t2* mri relaxation time (r = -0.535) and a weak negative correlation was found between sf and heart t2* mri relaxation time (r = -0.361).3 as a result, t2* mri is the suggested method of evaluation of liver and heart iron content in order to more accurately evaluate haemosiderosis status in thalassaemic patients.3 moreover, t2* mri assessments have revealed that iron excess is not proportionally distributed among the organs; instead, it is stored in each organ at different concentrations.4 the distribution of iron is also different for each bτμ patient. kolnagou et al. have proposed that this variation in iron concentration among patients with bτμ may be due to chelation methods as well as genetic, dietary and pharmacological factors. it is therefore recommended that the individual iron load of all organs are monitored closely for patients with bτμ.4 mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al-riyami n, al-khaduri m, daar s. pregnancy outcomes in women with homozygous beta thalassaemia: a single-centre experience from oman. sultan qaboos univ med j 2014; 14:e337–41. 2. gulino fa, vitale sg, fauzia m, cianci s, pafumi c, palumbo ma. beta-thalassemia major and pregnancy. bratisl lek listy 2013; 114:523– 5. doi: 10.4149/bll_2013_109. 3. azarkeivan a, hashemieh m, akhlaghpoor s, shirkavand a, yaseri m, sheibani k. relation between serum ferritin and liver and heart mri t2* in beta thalassaemia major patients. east mediterr health j 2013; 19:727–32. 4. kolnagou a, natsiopoulos k, kleanthous m, ioannou a, kontoghiorghes gj. liver iron and serum ferritin levels are misleading for estimating cardiac, pancreatic, splenic and total body iron load in thalassemia patients: factors influencing the heterogenic distribution of excess storage iron in organs as identified by mri t2*. toxicol mech methods 2013; 23:48–56. doi: 10.3109/15376516.2012.727198. 148 | squ medical journal, february 2015, volume 15, issue 1 letter to the editor tomography (ct). the patient underwent an open pyelonephrolithotomy [figure 2] and a staghorn stone was extracted [figure 3]. the post-operative course was smooth and the residual stones were managed by extracorporeal shock wave lithotripsy (eswl). the horseshoe kidney is the most common of all renal fusion anomalies. it occurs in 0.25% of the population (1 in 400 persons). the horseshoe kidney, even though it produces no symptoms, is frequently found in association with other congenital anomalies including genital anomalies: hypospadias 4%, sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 534-536, epub. 20th nov 12 submitted 10th jan 12 revision req. 16th apr 12, revision recd. 22nd apr 12 accepted 8th may 12 department of surgery, sultan qaboos university hospital, muscat, oman e-mail: msalmarhoon@gmail.com حصاة مرجانية يف كلية حدوة احلصان حممد املرهون staghorn calculus in a horseshoe kidney mohammed s. al-marhoon interesting medical image a 52-year-old male patient presented with bilateral loin pain of four months’ duration. twenty years before, he had had surgery for kidney stone disease. an abdominal examination revealed a scar from the previous surgery on his left side. investigations showed microscopic haematuria with no growth on urine culture. his serum creatinine and haemoglobin were normal. a plain abdominal x-ray of the kidneys, ureter, and bladder (kub) [figure 1] showed bilateral renal stones. the detailed renal anatomy and the extent of renal stones were delineated by computed figure 1: plain x-ray showing staghorn calculus in a horseshoe kidney (black arrows). mohammed s. al-marhoon interesting medical image | 535 undescended testes 4%, bicornuate uterus 7% and septate vagina 7%; urinary collecting system anomalies: ureteral duplication 10%, ureteropelvic junction obstruction 20%, vesicoureteral reflux 50%; renal parenchymal abnormalities: multicystic dysplasia 1%, autosomal recessive polycystic kidney 1%, and metabolic derangements in patients with stones in 50%: hypercalciuria, hyperoxaluria, hypocitraturia, hypouricuria.1 the association of horseshoe kidneys with staghorn calculus formation is rare. the reported cases in the literature of a staghorn calculi in a horseshoe kidneys were 19,2 3,3 8,4 and 35 cases. percutaneous extraction of stones from horseshoe kidneys has been done safely and is considered the standard of care. prado et al. treated 8 patients with staghorn calculi in a horseshoe kidney by percutaneous nephrolithotomy (pcnl).4 complete stone clearance was achieved in all the patients. only one patient suffered a long-term urinary tract infection of three months’ duration, and temporary deterioration in renal function. it was concluded that pcnl, performed after an imaging study and careful assessment of the renal anatomy and related structures, can be a safe and effective monotherapy for patients with staghorn calculi in horseshoes kidney. liatsikos et al., in a study of 15 patients with 17 staghorn calculi in horseshoe kidneys who were treated by pcnl, reported an overall stone-free rate of 82%, with a major and minor complication rate of 20 and 46.6%, respectively.6 raj et al. used pcnl for the treatment of 37 patients with renal calculi in a horseshoe kidney (3 staghorn) and concluded that pcnl is an effective means of kidney stone management in this complex patient population.3 however, pcnl is technically challenging, usually requiring upper pole access and flexible nephroscopy due to the altered anatomical relationships of the fused renal units. the present case was managed by open surgery rather than pcnl due to the surgeon’s preference. in addition, it has been shown that staghorn calculi are associated with a lower stone-free rate after percutaneous nephrolithotomy.2 a patient with staghorn calculi in a horseshoe kidney was 45 times more likely to have a lower stone-free rate after percutaneous nephrolithotomy than a patient without staghorn calculi in the horseshoe kidney. therefore, open surgery still has a role in the treatment of horseshoe kidneys with staghorn calculus when indicated. references 1. boatman dl, kolln cp, flocks rh. congenital anomalies associated with horseshoe kidney. j urol 1972; 107:205–7. 2. skolarikos a, binbay m, bisas a, sari e, bourdoumis a, tefekli a, et al. percutaneous nephrolithotomy in horseshoe kidneys: factors affecting stone-free rate. j urol 2011; 186:1894–8. 3. raj gv, auge bk, weizer az, denstedt jd, watterson figure 3: the staghorn calculus extracted from the horseshoe kidney. figure 2: intra-operative view of the horseshoe kidney (vessel loop around renal artery). staghorn calculus in a horseshoe kidney 536 | squ medical journal, november 2012, volume 12, issue 4 jd, beiko dt, et al. percutaneous management of calculi within horseshoe kidneys. j urol 2003; 170:48–51. 4. prado n, ide e, batista aj. management of staghorn calculi in horshoes kidney. br j urol 1997; 80:332. 5. shokeir aa, el-nahas ar, shoma am, eraky i, el-kenawy m, mokhtar a, et al. percutaneous nephrolithotomy in treatment of large stones with horseshoe kidneys. urology 2004; 64:426–9. 6. liatsikos en, kallidonis p, stolzenburg ju, ost m, keeley f, traxer o, et al. percutaneous management of staghorn calculi in horseshoe kidneys: a multiinstitutional experience. j endourol 2010; 24:531–6. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 463-464, epub. 25th jun 13 submitted 25th jan 13 revision req. 12th mar 13; revision recd. 14th mar13 accepted 13th apr 13 department of cardiology, royal hospital, muscat, oman *corresponding author e-mail: prashanthp_69@yahoo.co.in تعفن بكتريي ضخم يف األذين األمين ملريض غسيل كلى بالقسطرة تعفن الدم بالستافيلوكوكاس متعلق بالقسطرة جيب إزالة أنبوب القسطرة عند عدم استعماله برا�شانث باندوراجنا و حممد املخيني large right atrial vegetation in a patient with tunnelled dialysis catheter-related staphylococcal sepsis remove the catheter if not in use *prashanth panduranga and mohammed al-mukhaini interesting medical image a 57-year-old woman who wasdiabetic and hypertensive, with a history of end-stage renal disease and on regular haemodialysis was referred from a regional hospital with fever and leucocytosis. she was receiving dialysis through an arteriovenous fistula (avf), initially created 8 months prior to the present admission. however, after 3 months, the patient developed recurrent haematoma and stenosis of the fistula, necessitating an angioplasty. at that time a tunnelled dialysis catheter (tdc) (quinton™ permcath™ dual lumen catheter, covidien, mansfield, massachusetts, usa) was inserted in the right internal jugular vein. dialysis was continued uneventfully using the tdc for approximately one month. for the following 3-month period the patient returned to using the avf. however, the tdc was left in situ. upon admission, 3 blood cultures drawn from the tdc and one from the peripheral blood were confirmed to be positive for methicillinsensitive staphylococcus aureus. a transthoracic echocardiogram showed multiple masses in the right atrium suggestive of vegetation. the tdc was removed as the tip of the catheter grew s. aureus. the patient was treated with flucloxacillin and vancomycin, with a trough vancomycin level figure 1 a & b: (a) transoesophageal echocardiogram demonstrating the presence of large vegetation attached to the right atrial wall in a patient with a tunnelled dialysis catheter-related staphylococcal sepsis (arrowheads); (b) multilobulations typical of staphylococcal bacteremia (arrowheads). ra = right atrium; la = left atrium; rv = right ventricle. prashanth panduranga and mohammed al-mukhaini interesting medical image | 457 of 18 µg/ml (target 15–20). the transoesophageal echocardiogram showed a large lobulated mobile mass in the right atrium, attached to the free wall just near the inferior vena cava. it measured 35 x 15 mm prolapsing into the tricuspid valve but with no significant obstruction [figure 1]. there were no vegetations on the valves. high-risk open heart surgery was offered to the patient but was refused. the patient subsequently went into a refractory sepsis and did not survive. the occurrence of a catheter-related bloodstream infection (crbi) in patients on haemodialysis has been found to beindependently associated with increased mortality.1 a report from the us renal data system (usrds) database states that infection is the second most common cause of mortality in end-stage renal disease (esrd), the first being cardiovascular events.2 a tdc-related infection can occur either at the exit site, within the tunnel and/or in the bloodstream (crbi). cases of crbi are reported to have a mortality rate of 12–25%.3 the centers for disease control and prevention (cdc) in the usa recommend that the primary prevention strategy is the avoidance of central lines in favor of avfs, for instance, as recommended in the fistula first breakthrough initiative.3 additionally, when catheters are used, the recommended interventions to improve central-line maintenance can reduce crbi in patients undergoing haemodialysis.3 furthermore, the cdc stress the need for the prompt removal of unused or unneeded central lines.3 tdcs have a reported infection rate of 1.6–5.5 cases every 1,000 days.4 the vascular access work group clinical practice guidelines for vascular access recommend important central-line maintenance measures: 1) staff manipulating catheters should wear masks and clean or sterile disposable gloves; 2) the need for meticulous skin preparation during the insertion and application of exit site cleaning solutions; 3) the application of non-occlusive dressings; 4) the application of topical antibiotic ointment at catheter exit sites; 5) the use of prophylactic antimicrobial locking solutions; 6) catheters should be coated with antimicrobial agents or heparin, and 7) the training of nurses and patient in the proper maintenance of central-lines.4 catheter exit-site infections should be treated with topical and oral antibiotics without the need for catheter replacement. however, crbi requires the administration of the appropriate systemic antibiotics (for a minimum of 3 weeks). the catheter should also either be removed with a delayed replacement (particularly for unstable patients, or those with a persistent fever lasting >48 hours), or the catheter should be exchanged over the wire, or it should be salvaged with antibiotic locking solutions, depending on the clinical situation. in the case of tunnel-tract infections, the appropriate response is the removal of the catheter. this case indicates that if a tdc is used in patients with end-stage renal disease, the catheter needs to be removed as soon as medically possible. in addition, national guidelines as initiated by the cdc3 or the vascular access work group4 need to be developed and employed in oman. references 1. raithatha a, mckane w, kendray d, evans c. catheter access for hemodialysis defines higher mortality in late-presenting dialysis patients. ren fail 2010; 32:1183–8. 2. patel pr, kallen aj, arduino mj. epidemiology, surveillance, and prevention of bloodstream infections in hemodialysis patients. am j kidney dis 2010; 56:566–77. 3. center for disease control and prevention (cdc). vital signs: central line–associated bloodstream infections united states, 2001, 2008, and 2009. mmwr 2011; 60:243–8. 4. vascular access work group. clinical practice guidelines for vascular access. am j kidney dis 2006; 48:s248–73. sir, i was most gratified to read the editorial by dr. ritu lakhtakia1 that accompanied my own contribution to the field of health professionsʼ education in oman.2 indeed, i felt validated in my strong belief in the ability of the health planners of oman to transform health professional education, following in the same tradition already demonstrated in the fundamental reforms of the past 42 years. i acknowledge the transformations already made in health professionsʼ education and applaud those planned for the future. however, i also agree with the theme of the editorial, which advocated the need for periodic reality checks. viewing the status of health professionsʼ education in oman within a global context, lakhtakia1 highlighted the impressive statistics concerning the improvement of physician-patient and nurse-patient ratios over the past four decades, and noted especially the rise in the representation of omanis in the overall health workforce. health service planners must not only be congratulated on this remarkable achievement but also commended for the current shift from an emphasis on the quantity of healthcare providers to a focus on the quality of healthcare provision. it is therefore expedient that such a dynamic shift is accompanied by a transformative learning process. as lakhtakia1 pointed out, transformational learning includes decisionmaking, core competencies for effective team work, and the adoption of creative educational models. these are supported by coordinated education strategies, networks, alliances, and consortia, as well as by interdependent education, and the sharing of knowledge, teaching resources and innovations. health professions have traditionally developed individual ʻsilosʼ of information, often with a deep distrust of each other in the name of ʻprofessional protectionismʼ. however, contemporary society now has its own access to medical information, and no longer believes in the omniscience of the medical and other health professions. therefore, physical, psychological, social, spiritual and ethical problem-solving in healthcare benefits from inter-disciplinary consultation (including the patient); thus, it would appear logical that quality healthcare is best provided through the development of inter-professional education, supported by instructional and institutional reform. paradoxically, as the number of medical practitioners and nurses choosing to specialise rises, the need for general and comprehensive teamwork increases, so that the patient’s voice does not get ‘lost’ within the system. learning together, and valuing different knowledge bases, acknowledges the contributions each profession makes in meeting the overall health objectives and the needs of individual patients. it is interesting that there is little evidence of assessments being made using inter-disciplinary teamwork scenarios, which is a vital competency for all health service providers. lakhtakia’s1 pride in the reforms achieved by the college of medicine & health sciences, sultan qaboos university (squ) is commendable. i look forward to feeling a similar pride in the reform of the nursing and allied health professions’ education that are governed by the ministry of health (moh). i am very optimistic that these changes will happen once the current individual competition over higher education scholarships (masters and doctorates) results in advanced knowledge and skills, and the provision of academic leadership and superior clinical supervision; this transcends individualism and promotes team development to benefit all the omani health professions and society as a whole. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 325-326, epub. 9th may 13 submitted 25th nov 12 accepted 29th dec 12 رد: تعليم املهن الصحية يف سلطنة عمان منظور معاصر re: health professions education in oman a contemporary perspective letter to editor 325 | squ medical journal, may 2013, volume 13, issue 2 326 | squ medical journal, may 2013, volume 13, issue 2 as an expert in health professions’ education, i have had the combined privilege and frustration of observing the achievements and the pitfalls in transforming this education in oman. i note a genuine desire for reform by some, and mere lip-service by many. as is happening in squ, i urge higher education healthcare institutes to embrace competency-based curricula (rather than adhering to the norm), to harness information technology and to develop simulation laboratories which can be effectively utilised to test inter-disciplinary case scenarios. educational specialists in the moh must 1) review the ‘currently required’ curriculum content against the curriculum which is ‘merely desired’; 2) provide students with appropriate electives to inspire and meet their individual interests; 3) encourage life-long learning through developing and rewarding self-learning strategies; 4) increase international exchange (for both teachers and students) and further create both regional and international networks and consortia to enhance this exchange; 5) commit greater resources to education through appropriate governance, and 6) build both research capability and capacity so that non-medical health professionals can have equitable access to research funding. it is no longer individual results that should take precedence; but the moh and its educational staff and students asking the right questions. of course, higher education does not stand alone. success depends on a seamless transition from primary to tertiary delivery systems, wherein the use of the english language is key. successful higher education results from linguistic competence for one main reason: a universal means of communication allows for scientific progress. as a native english speaker, i can only apologise that acts of history have decreed that the language of universal communication be my own. however, the past cannot be changed, and thus a concerted effort must be put into the pre-tertiary teaching of english in oman alongside arabic, and pride in the richness of a society that speaks at least two languages should be encouraged. as oman progresses further into its adulthood (having matured for over 40 years), greater responsibility is being placed upon its citizens to participate in the affairs of the gulf region, its arab alliances, and the world as a whole. oman has a role in the wider global community and its people will be well-prepared to play their part if the trajectory currently seen continues. well-educated health professionals with a positive attitude toward life-long patterns of learning, who are rewarded for their contributions and their willingness to serve all the regions of oman (whether as practitioners, administrators or in the academic field as teachers or researchers), will enhance the growing reputation of oman, ensure a healthy population and maintain its wealth. gillian white directorate of general education and training, muscat, oman e-mail: drgillianwhite@yahoo.co.nz references 1. lakhtakia r. health professions education in oman: a contemporary perspective. sultan qaboos univ med j 2012; 12:406–10. 2. white g. transforming education to strengthen health systems in the sultanate of oman. sultan qaboos univ med j 2012; 12:429–34. taurine levels in human aqueous humour medical sciences (2000), 2, 1-2 © 2000 sultan qaboos university *department of pharmacology, college of medicine, sultan qaboos university, p o box 35, al-khod, muscat 123, sultanate of oman. 1 thoughts for the future *tanira m o m رؤى للمستقبل تنيرة. م he three most significant health-related issues raised in the past year were, presumably, the introduction of drugs for ‘lifestyle improvement’, certain new medical interventions and a renewed interest in utilizing alternative medicine in medical care. these issues are expected to significantly influence medical practice in the future and contribute to modify its present pattern. ‘life-style improvement’ drugs this category of drugs is well represented by viagra (sildenafil citrate), about which little needs to be said. after little more than a year of its approval by the us food and drug administration (fda) in march 1998, it is difficult to find someone who does not know the name. in september 1998, less than six months of viagra’s approval, the fda cleared another drug called preven , indicated for emergency contraception in case of contraceptive failure or unprotected intercourse. nicknamed ‘morning-after kit’, preven consists of a patient information booklet, a urine pregnancy test and four emergency contraceptive pills, each containing a standard oral contraceptive combination (250 µg levonorgestrel and 50 µg ethinyloestradiol). the drug reduces the risk of pregnancy by about 75%.1 the public response generated by preven was similar to that of viagra, though this time confined to the west. preven and similar emergency contraception methods, were available for years.2 however, the fda approval and probably the opportune marketing of viagra, brought it in the spotlight. the implications of drugs such as viagra and preven may be two-fold. first, they represent a recent tendency to introduce more and more drugs to improve ‘lifestyle’ or quality of life. in the past (up to 1997), new drugs were introduced to make people live healthier. in the future, new drugs could be introduced also to make people live or look better and feel happier. second, the introduction of these drugs could be a response to public demand rather than to medical need. with either or both explanations, it is becoming likely that the patient would have a stronger say in deciding the pattern of future medical practice. new medical interventions the new medical interventions may be symbolised by more than one achievement. one is the approval of the first gene-based drug herceptin (trastuzumab; a humanised anti-her-2 monoclonal antibody).3 the second is the successful application of a chromosome-based technique of sperm separation that enables parents to choose the gender of their future child.4 these two achievements are harbingers of genetic applications in medical practice. expectedly, more genetics-based applications would be introduced in the near future. another advance is the successful culturing of embryonic stem cells from human blastocytes.5 embryonic stem cells can give rise to essentially all cell types in the body. this makes ‘cell and tissue replacement therapy’ a likely tool of the future with great potential applications in organ transplant, gene therapy and treating diseases such as diabetes mellitus, aids and neurodegenerative conditions such as parkinson’s disease. if the envisioned potential of this technique is materialised, then it would break new ground in medical practice.6 alternative medicine at the other extreme, ‘alternative medicine’, a collection of non-allopathic methods such as herbal medicine, acupuncture, homoeopathy and chiropractic, appears to pose as a healthcare frontier of the future. the popularity of alternative medicine in the developing countries is well known. it does not seem to be much different in the developed countries. in t t a n i r a m o m 2 the uk about 10% of the population visit alternative medicine practitioners and about 30% of the country’s general practices offer their patients access to alternative medicine services through the national health service.7 the journal of american medical association (jama) devoted almost all of its november 1998 issue to alternative medicine. one study in that issue estimated that 629 million visits worth us$ 27 billion were made in 1997 to alternative medicine practitioners in the us, a number that exceeded the total visits made to all primary care physicians.8 it also represented a 47.3% increase over the 1990 figure of 427 million. the study attributed this increase to a rise in the proportion of the population seeking alternative therapies, rather than to increased visits per patient. with these results, it is difficult to ignore that people want to use—and are using—alternative medical interventions alone or concurrently with allopathic medicine. the mainstream medical profession might eventually accept this shift and incorporate some ‘useful’ procedures from alternative medicine in their practice. conclusion if the above three issues progress as predicted, the present pattern of clinical practice might gradually be replaced with a future pattern, so far not fully envisioned. perhaps, with more technological applications and greater role for patients in health matters, the role of medical practitioner would also be redefined. in one scenario it was postulated that general practitioners of the future would be “highly skilled medical generalists and information specialists”.9 the author of this view expects that “general practitioners will have a key role in helping patients make complex decisions about diagnosis and treatment” and that everything else “will be done by nurses, technicians and robots”. those who are at present medical students (or just graduated) and in their early twenties are expected to practice more than 40 years in the new millennium. the above issues would probably be daily aspects of their practice. references 1. trussell j, rodriguez g, ellertson c. new estimates of the effectiveness of the yuzpe regimen of emergency contraception. contraception 1998, 57, 363–9. 2. yuzpe aa, lancee wj. ethinyloestradiol and dl– norgestrel as a postcoital contraceptive. fertil steril 1977, 28, 932–6. 3. tanira mom. viagra is not the last call: pharmacotherapy in the new millennium. (editorial) em med j 1998, 16, 77–9. 4. fugger ef, black sh, keyvanfar k, schulamn jd. births of normal daughters after microsort sperm separation and intrauterine insemination, in–vitro fertilisation and intracytoplasmic sperm injection. hum reprod 1998, 13, 2367–70. 5. thosmon ja, itskovitz-eldor j, shapiro ss, waknitz ma, fwiergiel jj, marshall vs, jones jm. embryonic stem cell lines derived from human blastocytes. science 1998, 282, 1145–7. 6. pedersen ra. embryonic stem cells for therapy. sci am april 1999, 68–73. 7. vickers a. use of complementary therapies. evidence-based medicine 1998, 3, 168–169. 8. eisenberg dm, davis rb, ettner sl, appel s, wilkey s, van rompay m, kessler rc. trends in alternative medicine use in the united states, 1990–1997: results of follow–up national survey. jama 1998, 280, 1569–75. 9. lipman t. is there a clinical future for the general practitioner? bmj 1999, 318, 1420. thoughts for the future *tanira m o m ??? ???????? ‘life-style improvement’ drugs new medical interventions alternative medicine conclusion references the round ligament extends from the uterus through the inguinal canal and terminates in the region of the mons pubis and labia majora. embryologically, it is the female equivalent of the gubernaculum testis. this structure is responsible for the descent of the ovary from the posterior abdominal wall to the uterus. it is mainly composed of smooth muscle fibres, connective tissue, vessels, and nerves with a mesothelial coating.1,2 leiomyoma of the round ligament is a rare condition occurring predominantly in premenopausal middle-aged women. abdominal, inguinal, and vulvar locations have been described.3 we report a case of smooth muscle tumour of the right inguinal area, presenting as a painless mass which increased gradually in size. the anatomic location was unique, as the clinical presentation closely resembled an inguinal hernia. case report a 38-year-old woman presented to the surgical outpatient department of sultan qaboos university hospital, oman, with painless swelling in the right inguinal region. it had been gradually increasing in size for the previous three months and was not reducible without skin changes. she denied any history of fever, weight loss, night sweats, or swelling in other part of her body. the round swelling measured measured 5 x 5 cm, was irreducible, and non-tender. the cough impulse was, however, equivocal. a working diagnosis of right-sided inguinal hernia was made and, after routine blood tests and without any imaging, surgical exploration of the inguinal region was accomplished under general anaesthesia. per-operatively, it was observed she had a rounded swelling arising within the superficial inguinal ring, which, on opening the inguinal canal, was found to be attached to the round ligament [figure 1]. no hernial sac was identified. squ med j, august 2012, vol. 12, iss. 3, pp. , epub. submitted 9th oct 11 revision req. 31st jan 12, revision recd. 3rd mar 12 accepted 14th mar 12 department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ali _2051@hotmail.com مت رصد حالة ومقارنتها بالدراسات السابقة اكتشاف ورم عضلي أملس يف الرباط املستدير بالرحم �سيد اأم علي ، كامران ك مالك ، هاين القا�سي ، حممد �سفيق امللخ�ص:تعد اأورام الع�سل الأمل�ض يف الرباط امل�ستدير بالرحم من احلالت النادرة وي�سبه الفتاق الأربي. ميكن احل�سول على الت�سخي�ض قبل اجراء العملية وذلك عن طريق ا�ستخدام الت�سوير املقطعي للبطن اأو عن طريق اجراء ا�ستق�ساء جراحي يف القناة الأربية. وتعترب العملية اجلراحية ل�ستئ�سال الورم هي الطريقة العالجية له. الكلمات: الرباط امل�ستدير ، ورم ع�سلي اأمل�ض ، ر�سد حالة ، �سلطنة عمان abstract: smooth muscle tumours of the round ligament of the uterus are rare and can mimic an inguinal hernia. preoperative diagnosis can be established by a computed tomography scan of the abdomen or an exploration of the inguinal canal. surgical excision is a curative treatment. keywords: round ligament; leiomyoma; case report; oman. leiomyoma of the round ligament of the uterus case report and review of literature *syed m ali, kamran a malik, hani al-qadhi, muhammad shafiq case report leiomyoma of the round ligament of the uterus case report and review of literature 364 | squ medical journal, may 2012, volume 12, issue 2 the mass was removed completely [figure 2] and the histopathology revealed encapsulated firm to hard grey tissue with well-defined spindle cell lesions arranged in interlacing fascicles. the mass was composed of bland cells with cigar-shaped nuclei and eosinophilic cytoplasm consistent with leiomyoma without mitotic figures, atypia, or necrosis. discussion tumours of the round ligament of the uterus are quite rare. the most commonly found tumours are leiomyomas, followed by endometriosis and mesothelial cysts.1,4–6,12 approximately, one-half to two-thirds of leiomyomas occur in the extraperitoneal portion of the round ligament and are more common on the right side for unknown reasons.1 the transformation of the myofibrous structure of the female genital tract to leiomyoma involves somatic mutations of normal smooth muscle and a complex interaction between sex steroids and local growth factors. estrogen is the major promoter of the myoma growth; however, the role of progesterone is still unclear,3,7as both receptors have been found in the round ligament.8 the differentiation between benign and malignant tumors can be difficult as the major criteria for malignancy are mitotic figures, nuclear atypia, and necrosis.4,9 in 50% of the reported cases, the lesions are associated with uterine leiomyomas.4 mass lesions that involve the extra-peritoneal portion of the round ligament as it passes through the inguinal ligament can mimic an incarcerated inguinal hernia or inguinal adenopathy. in our case, the mass presented like an inguinal hernia. preoperative imaging techniques such as computed tomography (ct) scans can be helpful in diagnosing the condition, but it is not usually employed before surgical exploration.10 leiomyoma presents as a circumscribed, heterogenous, dense mass in ct images.1,10,11 it may contain calcifications that may be mottled, whorled, streaked, and curvilinear.10 surgical excision of the tumour is adequate treatment as it would distinguish between the rare leiomyoma and an inguinal hernia or adenopathy.1 conclusion a smooth muscle tumour in the round ligament of the uterus in the inguinal region is a rare entity and can be mistaken for an incarcerated inguinal hernia. diagnosis can be established by a ct scan of the abdomen or surgical exploration. excision of the lesion provides symptomatic relief to the patient and enables a diagnosis of the exact nature of the swelling. references 1. david mw, stanley rm. leiomyoma of extraperitoneal round ligament: ct demonstration. clin imaging 1999; 23:375–6. 2. william pl, worwick r, dyson m, bannister lh, eds. grey’s anatomy. 37th ed. new york: churchill livingston, 1987. 3. alexander l, maria gha, christian k, gerhard b, johann l. leiomyoma of the round ligament in a post-menopausal woman. maturitas 1999; 31:133–5 4. breen jl, neubecker rd. tumors of the round figure 1: mass arising from right inguinal canal figure 2: exploration of inguinal canal syed m ali, kamran a malik, hani al-qadhi, muhammad shafiq case report | 365 ligament: a review of literature and a report of 25 cases. obstet gynecol 1962; 19:771–80. 5. candiani gb, vercellini p, fedele l, vendola n, carinelli s, scaglione v. inguinal endometriosis pathogenetic and clinical implications. obstet gynecol 1991; 78:191–4. 6. harper gb, jr, awbrey bj, thomas cg, jr, askin fb. mesothelial cysts of the round ligament simulating inguinal hernia: report of four cases and a review of the literature. am j surg 1986; 151:515–7. 7. rein ms, barbieri rl, freidman aj. progesterone: a critical role in the pathogenesis of uterine myomas. am j obstet gynecol 1995; 172:14–8. 8. smith p, heimer g, norgren a, ulmsten u. the round ligament: a target organ for steroid hormones. gynecol endocrinol 1993; 7:97–100. 9. bell sw, kempson rl, hendricson mr. problematic uterine smooth muscle neoplasms. am j surg pathol 1994; 18:535–58. 10. casillas j, joseph rc, guerra jj, jr. ct appearance of uterine leiomyomas. radiographics 1990; 10:999– 1007. 11. michel p, viola d. abdomino-pelvic leiomyoma of the round ligament: contribution of computed tomography and magnetic resonance imaging. j gynecol obstet biol reprod 2003; 32:571–4. 12. vignali m, bertulessi c, spreafico c, busacca m. a large symptomatic leiomyoma of the round ligament. j minim invasive gynecol 2006; 13:375–6 situs inversus can be either total or partial. total situs inversus is characterised by a heart on the right side of the midline, aorta turning to the right and reversed position of all cardiac chambers. the liver and the gall bladder are on the left side. the patients are usually asymptomatic and have a normal longevity, but at times this condition may be associated with other ailments, which may lead to its chance detection either preoperatively, or as an intraoperative surprise.1,2 laparoscopic cholecystectomy has become the standard operative procedure for gall bladder disease. it is associated with reduced hospital stay, fewer complications, less pain and a faster return to work.3 we report a patient with complete situs inversus who presented with biliary colic and underwent a difficult laparoscopic cholecystectomy that was completed by laparoscopy and not converted to open cholecystectomy. case report a 24 year-old single saudi female with situs inversus totalis presented to our general surgery clinic with a long history of pain in the left upper abdomen. the pain was colicky in nature, radiating to the back and this condition was aggravated by fatty meals. physical examination showed positive murphy's sign in the left hypochondrium. the patient was in good general condition apart from mild controlled bronchial asthma. examination of the cardiovascular system revealed the apex beat to be in the right fifth intercostal space. there was mild tenderness in the left hypochondrium and the adjoining epigastrium. haematological, biochemical and echocardiography parameters were within the normal range. ultrasound showed the location of gall bladder on the left side of the body and this was confirmed by a computed tomography (ct) scan of the abdomen squ med j, february 2012, vol. 12, iss. 1, pp. 113-115, epub. 7th feb 12. submitted 3rd may 11 revision req. 1st jun 11, revision recd. 23rd jul 11 accepted 27th aug 11 1general surgery department, khamis mushayt general hospital, aseer area, abha city, saudi arabia; 2general surgery department, faculty of medicine, mansoura university, egypt and khamis mushayt general hospital, aseer area, abha city, saudi arabia. *corresponding author e-mail: wghnnam@gmail.com استئصال املرارة العكسي باملنظار اجلراحي يف حالة انعكاس وضع األحشاء الكلي تركى معي�س الب�رصي، وجيه ممتاز غّنام امللخ�ص: انعكا�س و�سع الأح�ساء الكلي من العيوب نادرة احلدوث وتتميز بانعكا�س و�سع الأح�ساء اإىل اجلانب من اجل�سم، وهذا قد ي�سبب �سعوبة يف ت�سخي�س وعالج الأمرا�س التي ت�سيب الأح�ساء. نقدم هنا تقريرا لعالج حالة التهاب املرارة احل�سوي املزمن مت ا�ستئ�سالها باملنظار اجلراحي. مفتاح الكلمات: انعكا�س كلي لو�سع الأح�ساء، ح�سى املرارة، منظار البطن اجلراحي، ا�ستئ�سال املرارة، تقرير حالة، م�رص. abstract: situs i nversus totalis (sit) is an uncommon anomaly characterised by transposition of organs to the opposite side of the body in a mirror image of normal. it may cause difficulties in the diagnostic and therapeutic management of abdominal pathology due to the mirror-image anatomy. we report the management of a case of symptomatic cholilithiasis with emphasis on its surgical technique. keywords: situs inversus totalis; cholilithiasis; laparoscopy; cholecystectomy; case report; saudi arabia. retrograde (fundus first) laparoscopic cholecystectomy in situs inversus totalis turky maeed elbeshry1 and *wagih mommtaz ghnnam2 case report retrograde (fundus first) laparoscopic cholecystectomy in situs inversus totalis 114 | squ medical journal, february 2012, volume 12, issue 1 [figures 1 and 2]. she had been previously unaware of this anomaly. a laparoscopic cholecystectomy was performed on an elective basis. the patient was placed in the supine position with both the surgeon and cameraman on her right side and the assistant on the left side. laparoscopic cholecystectomy was undertaken using the 4-port technique. the video monitor was placed near the left side of the patient’s head. pneumoperitoneum was created to a pressure of 14 mm hg using an open technique through an umbilical incision and the 0-degree telescope was inserted through a 10mm umbilical (primary) port (port 1). a 5-mm port was placed about 10 cm just below the left costal cartilage in the anterior axillary line and a grasper was inserted to catch and retract the fundus of the gall bladder (port 2). a 10 mm port was inserted 4 cm below the xiphoid process, 1 cm left to midline (port 3) and another 5 mm port was inserted just 5 cm below the previous port (port 4) [figure 3]. being right-handed, it was difficult to dissect though port 3, as is routinely done, so we alternately used port 3 and port 4 for dissection. the dissection of calot’s triangle was difficult and the anatomy not clear so we dissected the gall bladder retrograde (fundus first) and applied an endoloop ® (autosuture, usa) ligature to the cystic duct and artery then division. the gall bladder was removed from port 3 and a suction tube drain was placed in the subhepatic space. the operation took nearly 2 hours and was completed successfully. the patient made an uneventful recovery and was discharged home the next day. discussion situs inversus occurs once in approximately 20,000 live births and has an autosomal recessive inheritance. the frequency of cholelithiasis in patients with situs inversus is similar to that in the general population; however, the condition may present diagnostic difficulty. the pain of biliary colic may be located in the epigastrium or in the left subcostal region and that of cholecystitis radiates to the left infrascapular region and the left shoulder.4 situs inversus usually remains undiagnosed, as exemplified by the present case, unless it is diagnosed accidentally while investigating for another associated problem. situs inversus totalis is an extremely rare condition and performing successful laparoscopic cholecystectomy in these patients is even rarer.5 in a medline search, only 38 cases were identified, one of these cases being from saudi arabia.6 in patients with situs inversus, the mirror image anatomy poses difficulty in orientation during laparoscopic cholecystectomy. first, various laparoscopy ports need to be positioned at sites that are mirror image of those in the usual patient. second, the surgeon needs to reorient visual images and surgical steps in an anatomical field that has undergone clockwise rotation. in the reports described previously, the surgeon dissected with his left hand, or asked for figure 1: computed tomography scan of the chest revealing heart mainly in the right side of the chest. figure 2: computed tomography scan of the abdomen revealing left-sided gall bladder with stone shadow inside. turky maeed elbeshry and wagih mommtaz ghnnam case report | 115 assistance to grasp the neck of the gall bladder while he dissected the calot’s triangle.7,8 in our case, both surgeons were right-handed; therefore the technique had to be adjusted. it is much easier for a left-handed surgeon to perform laparoscopic cholecystectomy in such patients. we performed the dissection alternatively from both cannulae of ports 3 and 4. retrograde ("fundus first") dissection is frequently used in open cholecystectomy and, although feasible in laparoscopic cholecystectomy (lc), it has not been widely practiced.9 the dissection was difficult as we could not dissect the calot’s triangle because of dense adhesions obscuring the anatomy so we started fundus first. it was a safe procedure and we could complete the procedure laparoscopically. though laparoscopic cholecystectomy in such patients is technically more demanding, an experienced laparoscopic surgeon can perform it safely. thus, situs inversus totalis does not appear to be a contraindication to laparoscopic cholecystectomy. conclusion we conclude from this case that retrograde laparoscopic cholecystectomy is the alternative choice instead of open cholecystectomy in difficult cases and can be carried out even in situs inversus totalis, but that these cases need a high degree of experience references 1. wood g, blalock a. situs inversus totalis and disease of the biliary tract. arch surg 1940; 40:885–96. 2. mcfarland sb. situs inversus with cholelithiasis. a case report. j tenn med assoc 1989; 82:69–70. 3. bedioui h, chebbi f, ayadi s, makni a, fteriche f, ksantini r, et al. laparoscopic cholecystectomy in a patient with situs inversus. ann chir 2006; 131:398– 400. 4. al jumaily m, hoche f. laparoscopic cholecystectomy in situs inversus totalis: is it safe? j laparoendosc adv sung tech a 2001; 11:229–31. 5. banerjee j, vyas f, jesudason m, govil s, muthusami j. laparoscopic cholecystectomy in a patient with situs inversus. indian j gastroenterol 2004; 23:79– 80. 6. hamdi j, abu hamdan o. laparoscopic cholecystectomy in situs inversus totalis. saudi j gastroenterol 2008; 14:31–2. 7. oms lm, badia jm. laparoscopic cholecystectomy in situs inversus totalis: the importance of being lefthanded. surg endosc2003; 17:1859–61. 8. mckay d, blake g. laparoscopic cholecystectomy in situs inversus totalis: a case report. bmc surg 2005; 5:5. 9. kelly m: laparoscopic retrograde (fundus first) cholecystectomy. bmc surg 2009; 9:19. figure 3: port sites after closure and before stitch removal sir, opioids have been used for decades and continue to be used to treat severe, acute, chronic non-cancer and cancer pain.1,2 they work mainly by inhibiting spinal cord neuronal transduction and the ascending pain signals at midbrain nuclei, and through the modulation of limbic system pain perception.3 the main opioids receptors are mu and kappa receptors.1–3 the use of opioids can be challenging and not without severe or life-threatening side-effects.1,2 the world health organization (who) has recommended the adoption of a three-step analgesic ladder to meet the therapeutic challenges of administering opioids and to reduce the incidence of these side-effects. this can be achieved by starting with non-opioid analgesics followed by weak opioids with adjuvants, reserving strong opioids for cases of severe pain.2,3 when we escalate the opioid dose without getting the expected clinical response, then we may face the dilemma of tolerance, which can be defined as a decrease in pharmacologic response following repeated or prolonged drug administration. in the case of opioids, patients may experience opioid-induced hyperalgesia (oih), which is a state of nociceptive sensitisation caused by exposure to opioids that leads to an increased response to a stimulus which is normally painful.1–4 in our practice, it is not uncommon to face this dilemma, especially during the management of patients who require long-term pain treatment with opioids.1,4 although tolerance is faced frequently, we should not fail to recognise oih by classifying all cases of poor response to escalating opioids as tolerance. in fact, much of the literature refers to the difficulty in differentiation between these two conditions.1,4 all patients with oih have some sort of tolerance but the reverse is not true.1,2 opioid-induced tolerance is rarely a limiting factor during opioid therapy in clinical practice and should not delay the start of treatment or dose escalation in patients with chronic pain.3 we should not refer to every pain-worsening during the course of therapy, as tolerance unless a detailed clinical evaluation fails to show any clear alternative cause.1,4 in oih, the pain can become more widespread, occur in areas beyond the original pain location, and may be associated with allodynia. it occurs with various routes of administration, happening more frequently in intermittent boluses with cessation in between, than with continuous infusion.1,4 oih is more evident with prolonged use of opioids. however, there is evidence of patients developing hyperalgesia after only short-term intraoperative opioids exposure.1,4,6 the degree or gradation of opioid tolerance is generally related to duration of exposure, daily dose requirement, and receptor association/disassociation kinetics. the mechanism of opioid-induced tolerance may include, among other things, the desensitisation to, or internalisation of opioid receptors. this is marked by a decrease in opioid binding sites that are available to provide pain relief.1–3 another cause of tolerance is an increase in spinal cord concentrations of dynorphin, which promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids.2,3 the sensitisation of n-methyl-d-aspartate (nmda)-sensitive glutamate receptors may play a role in opioid-induced tolerance. this is evident as nmda-antagonists like ketamine can attenuate tolerance development and decreases in dosage, which may delay the onset of tolerance.5 the mechanism of oih is complex and not always clear. usually more than one mechanism is involved.4 in oih, five possible mechanisms are involved, including activation of the central glutaminergic system; sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 185-187, epub. 27th feb 13 submitted 7th mar 12 revision req. 12th jun 12 revision recd. 16th jul 12 accepted 8th aug 12 معضلة فرط التأمل و حالة التحّمل الناتج عن العالج طويل األمد باألدوية )املسكنات( األفيونية the dilemma of opioid-induced hyperalgesia and tolerance in chronic opioid therapy letter to editor the dilemma of opioid-induced hyperalgesia and tolerance in chronic opioid therapy 186 | squ medical journal, february 2013, volume 13, issue 1 an increase in spinal dynorphins; activation of descending facilitation due to neuroplastic changes in rostroventral medulla; genetic mechanisms, and decreased reuptake of excitatory neurotransmitters and an enhanced nociceptive response. among these five mechanisms proposed to explain oih, the activation of nmda-sensitive glutamate receptors is the most common possibility.1,4 prostaglandins and cytokines might also be relevant to the development of oih.2 as a rule, when it comes to tolerance, the increase in pain should be overcome by increasing the dose, thus providing a mode of easy diagnosis.2,3 while the diagnosis of oih might not be straightforward, in general, if the opioids dose-reduction results in an improvement in pain control, oih is the most likely cause. if the pain worsens, then opioid tolerance is the most likely cause.1,3,4 quantitative sensory testing (qst), which is used to assess neurological function in chronic pain patients, can also be helpful in predicting oih. it is performed before the initiation of opioid treatment and then repeated at certain intervals. any changes in pain threshold upon qst can suggest oih if other causes have been excluded.1,4 tolerance can be treated by increasing the opioid dose. the addition of adjuvant medications like nonsteroidal anti-inflammatory drugs (nsaids), tricyclic antidepressant (tca), pregabalin and others may be effective in reduction of the required opioids and delay in occurrence of tolerance.2,3 ketamine has a dual action here as it can be used as an analgesic in low doses in addition to the nmda antagonist effect, which can attenuate receptor sensitisation and hence, the development of tolerance.3,5 oih treatment is much more complex and requires a specific strategy which may vary from one patient to another.1,4 this can be difficult, time-consuming ,and even impractical.1 practically speaking, opioid reduction might induce withdrawal symptoms, which can include an increase in pain.1,4 that increase in pain will mask the clinical picture and make the differentiation more difficult.2,4 the long course of weaning which is required for those patients can cause frustration and they may give up and stop the process. this type of treatment may also require special institutes.1 several drugs have been used to reduce the possibility of developing oih, especially when opioid dose-reduction is not accepted or tolerated by the patient.4,6 evidence showed that low-dose ketamine, an nmda-receptor blocker, can modulate oih.1,4–6 methadone, which is a weak nmda-receptor blocker and buprenorphine, which is a partial opioid mu agonist, can play roles in the treatment of chronic pain and oih.1,6 buprenorphine is an opioid partial agonist with a maximal effect which is less than that of full agonists. buprenorphine is efficacious for longer-term opioid maintenance with a lower risk of abuse, addiction, and side effects as compared to full opioid agonists. possible antihyperalgesics mechanisms include kappa-receptor antagonist properties and voltage-gated sodium channels blockade effects. it is an effective opioid detoxification agent with an equivalent or even better effect than methadone. formulations for opioid detoxification treatment are in the form of sublingual tablets as they have very poor bioavailability. transdermal patches are also available in europe and north america for treatment of chronic pain.1,6 other approaches may include adding nsaids (especially cox-2 inhibitors) as an adjuvant which may provide opioid-sparing effects in addition to modulating sensitised receptors by blocking prostaglandins.6 anti-epileptic therapy (gabapentin or pregabalin) and α-2 receptor agonists (clonidine) can also attenuate chronic pain and reduce oih.1,4,6 opioid rotation is another strategy that can be used to overcome oih.6 finally, we can conclude that although opioids are widely used in the treatment of pain, especially chronic pain, they cannot be free of side-effects, including serious ones. oih is one of these side-effects which may contribute to patient discomfort and carry harmful consequences if they are not diagnosed and treated. it is not uncommon to misdiagnose oih as opioid-induced tolerance, although the treatment modalities may be different. adding analgesic adjuvants like ketamine, cox-2 inhibitors, or gabapentinoids can reduce the required dose of opioids and attenuate both oih and tolerance. *qutaiba amir tawfic,1 ali s. faris,2 rohit r. date1 1department of anaesthesia & intensive care, sultan qaboos university hospital, muscat, oman; 2department of anaesthesia, the ottawa hospital, ottawa, canada *corresponding author e-mail: drqutaibaamir@yahoo.com qutaiba amir tawfic, ali s. faris and rohit r. date letter to editor | 187 references 1. lee m, silverman sm, hansen h, patel vb, manchikanti l. a comprehensive review of opioid-induced hyperalgesia. pain physician 2011; 14:145–61. 2. dumas eo, pollack gm. opioid tolerance development: a pharmacokinetic/ pharmacodynamic perspective. aaps j 2008; 10:537–51. 3. collett bj. opioid tolerance: the clinical perspective. br j anaesth 1998; 81:58–68. 4. tompkins da, campbell cm. opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? curr pain headache rep 2011; 15:129–36. 5. kapural l, kapural m, bensitel t, sessler di. opioid-sparing effect of intravenous outpatient ketamine infusions appears short-lived in chronic-pain patients with high opioid requirements. pain physician 2010; 13:389–94. 6. ramasubbu c, gupta a. pharmacological treatment of opioid-induced hyperalgesia: a review of the evidence. j pain palliat care pharmacother 2011; 25:219–30. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e294-296, epub. 24th jul 14 submitted 4th may 14 revision req. 18th may 14; revision recd. 19th may 14 accepted 20th may 14 obesity and cancer are regarded as two major epidemics of the 21st century.2 it has now been well established that obesity is a cause of several cancers, including cancers of the colon, post-menopausal breast, uterus, pancreas, gall bladder, liver, oesophagus and kidney.2 it has been estimated that as many as one-third of all cancers can be attributed to an unhealthy diet (such as high caloric intake, high intake of red and processed meat and low intake of fibre) lack of physical activity and obesity. as many as 3% of all the cancers in men and 9% of those in women can be attributed directly to obesity.3 as a result, the world cancer research fund and the american institute of cancer research (wcrf/ aicr) have issued guidance on the prevention of cancer in the form of 10 recommendations, one of them being: “be as lean as possible without becoming underweight”.3 in this issue of squmj, moten et al. have drawn attention to the very important question as to whether cancer survivors attempt to lose weight.4 according to globocan, 14.1 million cancer cases were diagnosed in 2012, there were 8.2 million deaths and 32.6 million cancer survivors; all these numbers were shown to be increasing.5 a cancer survivor is defined as an individual with a diagnosis of cancer, regardless of the course of illness, until the end of his/her life. epidemiological evidence suggests that cancer survivors who are obese and overweight are at an increased risk of cancer relapse/progression.3 hence, after the diagnosis of cancer, survivors maybe interested to learn how they could reduce the chances of cancer progression or relapse.6 clearly, if an exposure is associated with developing cancer and if that exposure continues, then the risk of subsequent cancer progression and/or relapse would be high.6 the wcrf/aicr recommend that cancer survivors follow the recommendations for cancer prevention including maintaining a healthy body weight. the question then arises—is there clear evidence that achieving and maintaining a lean body mass actually leads to a reduction in the incidence of cancer? although there is no evidence in the form of phase iii studies, epidemiological evidence is strong. robust data have emerged to suggest that the control of obesity and related lifestyle factors leads to the prevention of cancer. the european prospective investigation into cancer and nutrition (epic) study7 and the vitamins and life-style (vital) study8 are large prospective studies that have addressed the question. lifestyle modifications, including a reduction in body weight, actually lead to a reduction in the incidence of and mortality from cancer.9,10 more recently, a scientific rationale for this connection has begun to emerge as the biological mechanisms which suggest that obesity is a cause of cancer are beginning to be better understood.11 fat tissue is now considered to be an endocrine organ, which secretes adipokines, mainly leptin. leptin induces the upregulation of transcription factors through activation of pi3k, mapk and stat3 pathways. pro-inflammatory cytokines, such as tnf-α, il-2 and il-10 (secreted by the adipose tissue) lead to the activation of transcription factor nf-ĸb. adipose tissue also produces steroid hormones, such as oestrogens, progesterone and androgens; these are pro-inflammatory and lead to the activation of various transcription factors. importantly, insulin and insulin-like growth factor 1 (igf-1) which are elevated in people with obesity, signal through the akt/pi3k/mtor pathway, which in turn leads to the release of leptin and inflammatory cytokines [figure 1].11 as a result of the combined secretion of adipokines, 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: ikramburney@hotmail.com وبائيات السمنه والسرطان ال يوجد عالج بسيط موزه الكلبانية و اإكرام بريين editorial the epidemics of obesity and cancer no simple remedy moza al-kalbani1 and *ikram a. burney2 thou seest i have more flesh than another man, and therefore more frailty.1 moza al-kalbani and ikram a. burney editorial | e295 pro-inflammatory cytokines, steroid hormones, a state of persistent hyperinsulinemia, and the resultant continuous upregulation of transcription factors, the risk of cancer progression or its recurrence are higher amongst obese cancer survivors. furthermore, cancer survivors have an increased risk of morbidity and mortality, not only from cancer, but also from competing factors, such as heart disease, and psychological disturbances [figure 2].11 not only is the risk of recurrence and the morbidity and mortality higher among obese patients, but obesity also poses significant challenges in cases where subsequent treatment is needed. the challenges are present right through the stages of diagnosis and surgical and medical management, and even when trying to maintain good pain control. one of the surgeon’s nightmares is to operate on an obese patient. based on the concept that the aim of cancer surgery is to perform a radical excision, the accessibility of organs and the technicality of procedures for an obese patient present a major challenge for the course of the surgery. specific procedures like pelvic and para-aortic lymph node dissection are sometimes omitted which compromise the process of optimal treatment. post-operative complications such as ulnar neuropathy, deep vein thrombosis, right ventricular failure, atrial dysrhythmia and aspiration pneumonia are more frequent in obese patients.12,13 obese patients also present challenges to the anaesthesiologist while the pharmacokinetics of most drugs and the responses to some medications are altered by obesity. chemotherapy can therefore be underor overprescribed for obese patients. another question then arises, what can be done to curb obesity and its attendant complications in cancer survivors? the american society of clinical oncology (asco) has published guidance for cancer survivors on weight reduction strategies.14 while the main focus is still on ‘lifestyle modifications’, other strategies, such as weight loss drugs and bariatric surgery, are indicated for a selected few; however, the long term consequences of these treatments are not known. cancer survivors in moten et al.’s study did not demonstrate greater effort to lose weight compared to people with no history of cancer. this was despite having been through the ordeal of the diagnosis of cancer and the subsequent treatment.4 why? is it because of a lack of awareness and motivation amongst the survivors, or is it because the task is overwhelming and they feel it is too late to remedy the situation? the answer is probably all of the above. the authors of this editorial believe that just conducting a ‘fire-fighting campaign’ to treat obesity after the diagnosis of cancer may not be effective. the seeds of obesity are laid in childhood, or even before, and that is why obesity is turning into one of the epidemics of the 21st century.15 for example, it has been suggested that environmental influences during physical development increase the susceptibility to both obesity and cancer in adulthood by reprogramming of the epigenome.16 this is perhaps one of the many reasons that up to one-third of the children in developed countries such as the usa, and one-fifth of those in developing countries, like oman are obese—and the incidence is on the rise.17 this epidemic is assuming alarming proportions, especially since obesity can cause cancer in the first place, as well as increasing the risk of subsequent cancers in survivors. there is no simple remedy. serious efforts are required to modify not just individual lifestyles, but the overall environment to make it easier for individuals to make healthy choices in terms of food and physical activity. the provision of figure 1: biological explanation of increased risk of cancer amongst obese patients. figure 2: subsequent risks amongst cancer survivors. the epidemics of obesity and cancer no simple remedy e296 | squ medical journal, august 2014, volume 14, issue 3 healthy food in schools, offices and eating places, the availability of walking and cycling tracks and facilities for regular exercise, in addition to time allocation for physical activities during school and work, are only a few suggestions which can create an environment conducive to a healthy lifestyle and curb the dual menace of obesity and cancer. everybody should play a part—parents, curriculum designers, the media, the food industry, members of civil society, politicians and policy makers. references 1. shakespeare w. falstaff to prince hal, act 3, scene 3, henry iv part i. in: ds kastan, ed. arden shakespeare, 3rd series. london: bloomsbury publishing, 2002. 2. royal college of physicians. action on obesity: comprehensive care for all. report of a working party. london: royal college of physicians, 2013. 3. world cancer research fund/american institute for cancer research. food, nutrition, physical activity and the prevention of cancer: a global perspective. washington, dc: aicr, 2007. 4. moten a, jeffers k, larbi d, smith-white r, taylor t, wilson l, et al. obesity and weight loss attempts among subjects with a personal history of cancer. sultan qaboos univ med j 2014; 2014:301–7. 5. globocan 2012. estimated cancer incidence, mortality and prevalence worldwide in 2012. from: http://globocan.iarc.fr/ pages/fact_sheets_cancer.aspx# accessed: feb 2014. 6. meyenhardt ja. we are what we eat, or are we? j clin oncol 2013; 31: 2763–4. doi: 10.1200/jco.2013.50.7731. 7. gonzalez ca. the european prospective investigation into cancer and nutrition (epic). public health nutr 2006; 9:124–6. doi: http://dx.doi.org/10.1079/phn2005934. 8. white e, patterson re, kristal ar, thornquist m, king i, shattuck al, et al. vitamins and lifestyle cohort study: study design and characteristics of supplement users. am j epidemiol 2004; 159:83–93. doi: 10.1093/aje/kwh010. 9. romaguera d, vergnaud ac, peeters ph, van gils ch, chan ds, ferrari p, et al. is concordance with world cancer research fund/american institute for cancer research guidelines for cancer prevention related to subsequent risk of cancer? results from the epic study. am j clin nutr 2012; 96:150–63. doi: 10.3945/ajcn.111.031674. 10. vergnaud ac, romaguera d, peeters ph, van gils ch, chan ds, romieu i, et al. adherence to the world cancer research fund/american institute for cancer research guidelines and risk of death in europe: results from the european prospective investigation into nutrition and cancer cohort study. am j clin nutr 2013; 97:1107–20. doi: 10.3945/ajcn.112.049569. 11. vucenik i, stains jp. obesity and cancer risk: evidence, mechanisms, and recommendations. ann new york acad sci 2012; 1271:37–43. doi: 10.1111/j.1749-6632.2012.06750.x. 12. warner ma, warner do, harper cm, schroeder dr, maxson pm. ulnar neuropathy in medical patients. anesthesiology 2000; 92:613–15. 13. dority j, hassan z, chau d. anesthetic implications of obesity in the surgical patient. clin colon rectal surg 2011; 24:222–8. doi: 10.1055/s-0031-1295685. 14. american society of clinical oncology. obesity and cancer – a guide for oncology providers. from: www.asco.org/ sites/www.asco.org/files/obesity_provider_guide_final.pdf accessed: may 2014. 15. ludwig ds. childhood obesity: the shape of things to come. n engl j med 2007; 357:2325–7. doi: 10.1056/nejmp0706538. 16. walker cl, ho s-m. developmental reprogramming of cancer susceptibility. nat rev cancer 2012; 12:10.1038/nrc3220. doi: 10.1038/nrc3220. 17. lakhtakia r. conspicuous consumption and sedentary living: is this our legacy to our children? sultan qaboos univ med j 2013; 13:336–40. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 127-131, epub. 27th feb 13 submitted 9th jun 12 revision req. 7th aug 12, revision recd. 18th aug 12 accepted 2nd sep 12 departments of 1obstetrics & gynecology, 2radiology, 3pathology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mariamm1762@gmail.com الورم املخاطيين الغدي الكيسي عدمي األعراض يف املبيض املصحوب بورم عضلي أملس جداري صلب تقرير حالة مع مراجعة موجزة مرمي ماثيو، هازل جونزالفز، سنان العزاوي، سابارامادو امللخ�ض: ورم املبي�ض املخاطيني قد يت�صمن عقد جدارية حميدة اأو خبيثة. العقد اجلدارية احلاوية على الورم الع�صلي الأمل�ض هي علة حميدة نادرا ما ت�صاحب اأورام املبي�ض املخاطيني. نعر�ض هنا حالة عقدة جدارية حاوية على ورم ع�صلي اأمل�ض نا�صئة عن ورم خماطيني غدي كي�صي حميد لمراأة يف التا�صعة والع�رسين من العمر تعاين من كتلة كبرية غري متجان�صة يف البطن. بعد اإجراءات تقييم احلالة ما قبل احلميدة الطبيعة اأثبت املخربي الن�صيج فح�ض اخلبيث. املبي�ض ورم وجود يف ال�صك ب�صبب البطن فتح لعملية احلالة خ�صعت اجلراحة، للعقدة اجلدارية. مفتاح الكلمات: ورم املبي�ض، ورم غدي كي�صي خماطيني، الورم الع�صلي الأمل�ض اجلداري، الكيمياء املناعية لالأن�صجة، تقرير حالة، عمان. abstract: mucinous neoplasms of the ovary may have associated benign or malignant mural nodules. a leiomyomatous mural nodule is a rare, benign lesion associated with mucinous tumors of the ovary. we report a case of a mural leiomyomatous nodule arising in a benign mucinous cystadenoma in a 29-year-old woman who presented with a large heterogenous abdominal mass. after pre-operative evaluation, exploratory laparotomy was performed upon suspicion of ovarian malignancy. a pathological examination confirmed the benign nature of the mural nodule. keywords: ovarian tumor; mucinous cystadenoma; leiomyoma, mural; immunohistochemistry; case report; oman. asymptomatic ovarian mucinous cystadenoma with a solid mural leiomyoma case report and brief review *mariam mathew,1 hazel gonsalves,1 sinan al-azawi,2 saparamadu p.a.m3 case report cystic tumours of the ovary, whether benign or malignant, may be associated with mural nodules of various types. these mural nodules are composed of an epithelial or stromal component, or a mixture of both. sarcoma, sarcoma-like mural nodules (slmn), and anaplastic carcinomas in mucinous cystic tumours of the ovary have been well described.1 however, a leiomyomatous mural nodule within a mucinous cystic ovarian tumour is a rare, benign, spindle cell lesion and there have been only a few reported cases. we describe a case of large benign mucinous cystadenoma with a leiomyomatous mural nodule that clinically and radiologically raised the possibility of a malignant ovarian tumour. the benign nature of the nodule was confirmed by a microscopic and immunohistochemical examination. case report a 29-year-old unmarried woman with a large abdominal mass was referred to our hospital from a private institution. the abdominal mass was an incidental finding discovered when she sought medical advice for a 2 x 2 cm mobile mass in the right hypochondrium. she denied any recent weight loss or change in bowel habits. she had regular menstrual cycles with her last period three weeks prior to admission. there was no relevant medical or surgical history in the past. she had a family history of malignancy—an elder brother with a asymptomatic ovarian mucinous cystadenoma with a solid mural leiomyoma case report and brief review 128 | squ medical journal, february 2013, volume 13, issue 1 brain tumour and an uncle with hepatic cancer. on examination, her vital signs were normal with a body mass index (bmi) of 32. an abdominal examination revealed a smooth non-tender mobile mass arising from the pelvis corresponding to a uterine size distension of 28-weeks’ pregnancy. a 2 x 2 cm lipoma was felt below the right costal margin. an abdominal ultrasonogram showed a large, predominantly cystic mass with multiple locules and a solid area of about 4 x 4 cm in the right lower region. computed tomography (ct) and magnetic resonance imaging (mri) scans revealed a 22 x 19 x 10 cm multiloculated cystic mass arising from the left ovary. there was a solid component measuring 5 x 4 x 4 cm with homogenous enhancement in the right lower part of the tumour, raising the possibility of malignancy [figure 1]. the right ovary, uterus, and other abdominal organs looked normal with no ascites or lymphadenopathy. a chest x-ray was normal. the impression was ovarian cystadenoma/ cystadenocarcinoma. blood investigations showed hb 14 g/dl and a normal coagulation screen with normal renal and liver functions. tumour markers such as cancer antigen (ca) 125, carcinoembryonic antigen (cea), alpha-fetoprotein (afp) and beta-human chorionic gonadotropin (β hcg) were normal. the patient was scheduled for an exploratory laparotomy after arranging frozen sections. the laparotomy revealed a smooth-walled predominantly cystic mass of 22 x 18 x 10 cm in place of the left ovary with the left fallopian tube stretched over it. the uterus, right tube, and right ovary looked normal. there were no ascites, pelvic or para-aortic lymphadenopathy, or any other evidence of intra-abdominal metastasis. peritoneal washings for cytology, and left salpingo-oophorectomy and an omental biopsy were performed. the postoperative period was uneventful. the cystic ovarian mass submitted for frozen section weighed 2,400 grams and measured 22 x 18 x 8 cm. the surface of the cyst was intact with no papillary excretions; a solid whitish nodule measuring 4 x 3 x 3 cm was present on the wall of the cyst [figure 2]. sectioning revealed a multilocular cyst containing watery, non-haemorrhagic, mucinous fluid. there were small cystic spongy areas. the cyst wall thickness ranged from 0.2 to 0.4 cm. a cut section of the solid nodule on the wall of the cyst revealed a whitish whorled appearance. there were no haemorrhages or necroses in the cystic areas or in the solid nodule. haematoxilin and eosin (h & e) stained tissue sections from the cystic area showed large cystic areas lined by a single layered mucinous columnar epithelium with basally placed nuclei. sections of the solid area revealed a lesion consisting of interlacing bundles of spindle cells with elongated nuclei and eosinophylic cytoplasm [figure 3]. there was no nuclear pleomorphism and the mitosis was 2/10 hpf. the cystic and solid areas did not show any haemorrhages or necrosis. figure 1: computed tomography coronal re-formated image with contrast showing an enhanced solid component. figure 2: gross specimen of ovarian cystic mass with mural nodule (arrow). mariam mathew, hazel gonsalves, sinan al-azawi and saparamadu p.a.m case report | 129 these spindle cells stained positive with smooth muscle actin (sma) in immunohistochemistry [figure 4]. they were negative for monoclonal antibodies anti-cytokeratin ae1/ae3 and cd117. a diagnosis of mucinous cyst adenoma with mural leiomyoma was made. discussion the occurrence of mural nodules in serous or mucinous ovarian tumours is a rare but wellestablished entity. mural nodules can develop in benign, borderline, or malignant ovarian tumours. they are a heterogeneous group of lesions and can be benign, reactive, or neoplastic in nature.2 these mural nodules are seen as solid lesions on the wall of the tumour or project into the cyst lumen. being a part of a large cystic ovarian tumour, they can mimic malignancy both clinically and radiologically. reactive type mural nodules may mimic malignancy in histopathology as well. the benign and reactive mural nodules have a better prognosis; hence, it is important to differentiate them from the malignant mural nodules.2,3 reactive type mural nodules, also called sarcoma-like mural nodules (slmn), occur in younger females and are usually sharply demarcated small lesions. there are three histological types of slmns: epulis-like, the pleomorphic and spindle cell type, and the histiocytic type. malignant mural nodules are fibrosacromas and anaplastic carcinomas; they tend to occur in older females. when a mural nodule is composed of spindle cells, it needs careful evaluation to assess whether it represents a reactive spindle cell proliferation or a neoplastic process. low-grade spindle cell lesions could be underdiagnosed as benign spindle cell proliferations.1,4–6 immunohistochemistry will help to elucidate some of these diagnostic difficulties but awareness of the different types of mural nodules and a thorough assessment of morphology are still the key to the diagnosis.7,8 pathogenesis of mural nodules in ovarian tumours is not clear. more case studies are needed before the pathogenesis of this rare entity can be fully understood.2 to the best of our knowledge, this is the fourth report of a leiomyomatous mural nodule in a benign mucinous cystadenoma in english medical literature, and the youngest patient reported so far; size-wise this is the second largest tumour. the first case was described by lifschitz-mercer et al. in 1990, where the presence of a leiomyomatous mural nodule was confirmed by immunohistochemistry.9 the second report was one of the five cases of cystic ovarian mucinous tumours with mural nodules reported by nicholas et al.8 the third report of a mural leiomyomatous nodule in benign mucinous cystadenoma was published by hameed et al. in 1997.10 in their study of five cystic ovarian mucinous tumors with spindle cell mural nodules, nicholas et al. found that immunohistochemistry was useful in distinguishing the variant forms of spindle cell mural nodules in cystic ovarian mucinous tumours.8 they found that malignant spindle cell nodules co-expressed both cytokeratin and vimentin, whereas leiomyomatous nodules were negative for cytokeratin but positive for vimentin, desmin, and muscle-specific actin.7,8 the prognosis of each patient depends on the figure 3: haematoxylin & eosin stains. magnification x 20 showing mural nodule (arrow). figure 4: spindle cells of mural nodule stained with smooth muscle actin x 10. asymptomatic ovarian mucinous cystadenoma with a solid mural leiomyoma case report and brief review 130 | squ medical journal, february 2013, volume 13, issue 1 type of mural nodule associated with the tumour. malignant mural nodules have been reported to have a poor prognosis despite receiving postoperative adjuvant therapy, with 50% mortality within 5 years.1 several case reports have shown a poor prognosis, depending upon the international federation of gynecology and obstetrics (figo) staging associated with a sarcomatous/ carcinomatous nodule, as some tumours may behave in an aggressive manner. de rosa et al. stated that these tumours should be treated in the same way as high-grade conventional ovarian carcinoma despite a macroscopically favourable presentation.11 in contrast, those with leiomyomatous nodules or sarcoma-like mural nodules have an excellent prognosis and their presence does not influence the prognosis of the ovarian tumour associated with it, provided they are well-demarcated and lack invasion to the surrounding tissue or vascular spaces. the existence of sarcomatous nodules combined with the slmn is another rare entity that has been reported and necessitates a careful histologic analysis for treatment and the determination of prognosis.2 classification of these mural nodules is imperative in planning a patient’s postoperative therapy and follow-up, and has a general bearing on the overall prognosis of the ovarian tumour it is associated with.11,12 our patient did not require any postoperative treatment as the mural nodule was benign. on follow-up after 6 months, the patient was asymptomatic and a pelvic ultrasound was unremarkable. one of the criteria which differentiates a malignant cystic ovarian mass from that of a benign cystic ovarian mass is the presence of a solid component. the larger the solid component in a cystic mass, the higher is the likelihood of malignancy. this was of important relevance to our case since the patient was unmarried and in the reproductive age group; hence, a more conservative treatment was desirous, which would have been difficult had this mass been malignant. the presence of the solid nodule in this mass did raise a suspicion of malignancy, although other factors like the unilaterality, the presence of a cystic mass in the younger age group, its asymptomatic nature despite it being a large mass, and the absence of ascites and normal tumour markers were all indicators of the benign nature of this tumour. in such a scenario, modalities like a contrast ct/mri, histopathological analysis, and immunohistochemistry can play a useful role in management, as has been demonstrated in this case. conclusion mucinous neoplasms of the ovary may be associated with benign or malignant mural nodules. these nodules appear as solid lesions radiologically, raising the suspicion of malignancy. awareness of the heterogeneous nature of the mural nodules can help the clinician in planning the appropriate management of patients who have large cystic ovarian masses with solid nodules. references 1. chang wc, sheu bc, lin mc, chow sn, huang sc. carcinosarcoma-like mural nodule in intestinal-type mucinous ovarian of borderline malignancy: a case report. int j gynecol cancer 2005; 15:549–53. 2. gungor t, altinkaya so, akbay s, bilge u, mollamahmutoglu l. malignant mural nodules associated with serous ovarian tumor of borderline malignancy: a case report and literature review. arch gynecol obstet 2010; 281:485–90. 3. bague s, rodriguez im, prat j. sarcoma-like mural nodules in mucinous cystic tumors of the ovary revisited: a clinicopathologic analysis of 10 additional cases. am j surg pathol 2002; 26:1467–76. 4. prat j, young rh, scully re. ovarian mucinous tumors with foci of anaplastic carcinoma. cancer 1982; 50:300–4. 5. chakrabarti s, konar a, biswas s, das s. sarcoma-like mural nodules in ovarian mucinous cystadenomas-a report of two cases. indian j med sci 2005; 59:499– 502. 6. agarwal k, meenakshi, agarwal c, jain k. sarcoma-like mural nodule in an ovarian mucinous cystadenoma: a case report. indian j pathol microbiol 2004; 47:226–8. 7. mccluggage wg, young rh. immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumors. semin diagn pathol 2005; 22:3–32. 8. nicholas ge, mills se, ulbright tm, czernobilsky b, roth lm. spindle cell mural nodules in cystic ovarian mucinous tumors. a clinicopathologic and immunohistochemical study of five cases. am j surg pathol 1991; 15:1055–62. 9. lifschitz-mercer b, dgani r, jacob n, fogel m, czernobilsky b. ovarian mucinous cystadenoma with leiomyomatous mural nodule. int j gynecol pathol 1990; 9:80–5. mariam mathew, hazel gonsalves, sinan al-azawi and saparamadu p.a.m case report | 131 10. hameed a, ying aj, keyhani-rofagha s, xie d, copeland lj. ovarian mucinous cystadenoma associated with mural leiomyomatous nodule and massive ovarian edema. gynecol oncol 1997; 67:226–9. 11. de rosa g, donofrio v, de rosa n, fulciniti f, zeppa p. ovarian serous tumor with mural nodules of carcinomatous derivation (sarcomatoid carcinoma): report of a case. int j gynecol pathol 1991; 10:311– 8. 12. guilbeau c, soubeyrand ms, devillebichot c, sage m, collin f, arnold l. mural nodules of anaplastic carcinoma in bilateral ovarian borderline mucinous cystadenoma: a case report. ann pathol 2003; 23:340–4. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e149-151, epub. 7th apr 14 submitted 22nd feb 14 revision req. 9th mar 14; revision recd. 10th mar 14 accepted 11th mar 14 in this issue of squmj, hamadeh et al. report on the epidemiology of female breast cancer in the bahraini population with a total of 1,005 cases diagnosed over an 11-year period.1 the authors report the age-standardised incidence rate of 58.2 per 100,000 population in 2000 and 44.4 per 100,000 in 2010. the median age at diagnosis was 49 years and the five-year survival rate was 63%. this article raises a number of important issues. the incidence in bahrain is midway between that of developed and less-developed countries, while the mean age at diagnosis is lower than western countries, and survival is somewhat inferior to that reported from most developed countries. the incidence of cancer is rising across the globe. the international agency for research on cancer (iarc) publishes data in a series of reports called globocan. a comparison of the latest two versions (2008 and 2012) shows that the number of new cancer cases increased from 12.7 million in 2008 to 14.1 million in 2012.2,3 breast cancer remains the most common cancer among females and the second most common cancer overall, with an estimated 1.7 million new cases diagnosed in 2012. these account for more than a quarter of all the cases of cancer diagnosed in women. the incidence has increased by more than 20% since 2008.4 subsequent publication of the 2014 world cancer report confirmed that, regrettably, the earlier forecasts correspond to the actual numbers.5 if this trend were to continue, the total number of new cancers would increase to an alarming 22 million by the year 2025. the mortality is expected to increase to 13 million at that stage. a catastrophe is looming and urgent action is required. what is even more alarming is the fact that there is a palpable divide between regions with a high incidence or a low incidence of cancer, and this generally corresponds to their affluence. the agestandardised incidence rate of 268 cases per 100,000 population in the more developed regions, compares to 148 cases per 100,000 in the less developed regions.4 however, in terms of actual numbers, 43% of all cancers develop in resource-rich developed regions and 57% in resource-strapped less developed regions. while the increasing incidence of cancer in developed countries roughly corresponds to the increasing median age of population, the increasing numbers simply outgrow the median age in the less developed regions. this is also reflected in cancer-associated mortality. about 70% of cancer-associated deaths occur in less developed regions.4,5 the incidence of breast cancer reflects the overall cancer situation. in women, the overall age-standardised rate for breast cancer is 43.3 per 100,000, with 74.1 cases per 100,000 in developed countries, and 31.3 cases per 100,000 population in less developed countries.3 compared to the incidence rate of around 90 cases per 100,000 female population in the usa, hamadeh et al. reported an incidence rate of 44.4–58.2 cases per 100,000 women in bahrain.1 the current incidence rate in oman is 25.5 cases per 100,000 population.6 although the current incidence rate in oman is towards the lower end of the spectrum in the gulf cooperation council (gcc) countries, it is the increase in the incidence and the total number of cases which is of concern. for example, in oman, the age-standardised incidence rate of breast cancer has progressively increased from 13.8 in 1999, to 21.8 in 2005 and then to 25.5 in 2011. in 2011 alone, a total of 147 cases of breast cancer were diagnosed out of 573 new cases (25.6%). this is in comparison with 38/389 (14.9%) in 1999 and 95/422 (22.5%) in 2005.6 the reason for the increasing incidence remains unexplained. it could be either due to better detection and registration, e.g. the use of screening mammography, or an actual 1department of medicine, sultan qaboos university hospital; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: ikramburney@hotmail.com ما هي خياراتنا يف حربنا ضد معدالت وقوع سرطان الثدي املتزايدة؟ اإكرام بريين، حممد فروخ، من�صور املنذري editorial what are our options in the fight against breast cancer? *ikram a. burney,1 muhammad furrukh,1 mansour s. al-moundhri2 what are our options in the fight against breast cancer? e150 | squ medical journal, may 2014, volume 14, issue 2 increase in incidence. a total of 17 cases were detected using mammography over a four-year period between 2009 and 2012 in oman (personal communication with hon. ms. yuthar al-rawahia, chairperson, oman cancer association); however, it is not clear how many of these patients already had a palpable lump and used the mobile mammography unit for diagnosis. conversely, it is also not known how many patients may have travelled abroad for treatment and whose data therefore may not been captured by the national tumour registry. clearly, this small number of cases does not explain the increased number of breast cancer cases diagnosed in the last few years. the data from bahrain is in many ways similar to that reported from oman. hamadeh et al. reported a median age at diagnosis of 49 years, compared to 48.5 years reported by al moundhri et al.7 and 47.4 years reported by kumar et al.8 it should be noted that in the two studies from oman 50.7% and 60.4% patients presented with stage iii/iv disease, respectively.7,8 the problem of countries in the region is more or less similar: younger age, advanced stage, and hence compromised overall survival. so what can we do? like many other cancers, breast cancer can be tackled along the continuum of care at different stages—by the application of effective strategies for treatment and cure, early detection and prevention.9 the role of chemotherapy and hormone therapy (in the case of estrogen-receptor-positive tumours) is well established and the standard of care. however, a significant number of cancers still relapse. over the last decade, important advances have led to better cure rates with the use of monoclonal antibodies, tyrosine kinase inhibitors and more recently chemoimmunoconjugates. however, the treatment has become extremely expensive and out of reach for the vast majority of patients, especially in less developed countries. even in developed countries, the exploding cost of new agents is now causing problems. economists have questioned the sustainability of the model of evaluating and marketing new cancer drugs. early detection programmes using mammography have been in place for more than three decades. although an earlier meta-analysis of randomised controlled trials showed a relative reduction in death from breast cancer,10 more recently, the role of screening mammography has been questioned.11 while, a significantly higher number of early-stage breast cancers are diagnosed by this method, the advantage is offset by over-diagnosis and, in several instances, over-treatment. over-diagnosis may account for 20–30% of cancers detected,12 while screening has not been shown to decrease the rate of detection of advanced cancers.13 a recently concluded randomised trial showed that screening did not reduce mortality from breast cancer.11 furthermore, the cost-benefit ratio of screening mammography in low incidence countries augurs against its routine use.14 as a result, there has been a strong motion amongst the oncology community to reassess the need for breast cancer screening. overcoming the increasing incidence and subsequent mortality of breast cancer by prevention is a possible option. primary prevention by lifestyle modification is an attractive and, in many cases, an achievable target. the three major initiatives in this regard have been the european prospective investigation into cancer and nutrition (epic) study,15 the vitamins and lifestyle (vital) study16 and the recommendations of the world cancer research fund/american institute for cancer research (wcrf/ aicr).17 the epic is an ongoing prospective cohort study, initiated in 1992 in 10 european countries. dietary assessment is mainly carried out through a self-administered, semi-quantitative food frequency questionnaire and information on a wide range of lifestyle factors and anthropometric measurements are collected. in the vital study, the participants complete a detailed questionnaire on supplement use, diet and risk factors for cancers, and the cohort is prospectively followed-up for the incidence of cancers. in 2007, the wcrf/aicr released a set of recommendations on diet, physical activity and weight management for cancer prevention on the basis of the then available evidence.16 risk factors for breast cancer are different for the pre and postmenopausal population.4 for premenopausal breast cancer, there is convincing evidence that consuming alcohol increases the risk, whereas lactation protects against it. for postmenopausal breast cancer, there is convincing evidence that the consumption of alcohol, body fatness and adult-attained height increase the risk, whereas, lactation and physical activity protects against it. many of these factors are modifiable. however, the question is whether lifestyle modifications actually lead to a reduction in the incidence of breast cancer. more recently, answers have begun to emerge. the epic investigators have reported that a greater concordance with the wcrf/ aicr recommendations (for example: weight loss, physical activity and avoidance of sugar, salt, alcohol and red meat) was significantly associated with a decreased risk of cancer. a one-point increment was associated with a 5% risk reduction for all cancers.18 in the vital study, the breast cancer risk was found to be reduced by 60% in women who met at least ikram a burney, muhammad furrukh and mansour s. al-moundhri editorial | e151 five of the recommendations, compared with those who met only one.19 the reduction in mortality was demonstrated by the epic investigators, who reported that participants with maximum adherence to the wcrf recommendations had a 34% reduced risk of death compared with those who had least adherence to them.20 in conclusion, the incidence of breast cancer is on the increase worldwide. although the incidence is lower in less developed countries, it is rapidly increasing and so is mortality. early detection through screening is not widely available in many countries or may not be relevant. genetic studies may help to identify families with increased risk, who could then be offered early detection. however, these remain a small sub-set and account for no more than 5% of all breast cancer cases. the cost of the treatment has increased spectacularly and many patients or governments cannot or would not be able to afford it. primary prevention through lifestyle modification is an attractive cost-effective option. however, if primary prevention measures were to be adopted to combat the rising incidence and mortality, this would require a coordinated campaign. at the moment, cancer is not considered a major problem in less developed countries. there is an urgent need to remedy this opinion. future breast cancer outcomes will be determined by recognition of the problem; creating awareness not only by the advocacy groups, but also by the physicians; widespread dissemination of information through both print and electronic media, and the will of the policy-makers. references 1. hamadeh rr, abulfatih nm, fekri ma, al mehza he. epidemiology of female breast cancer among the bahraini population: bahrain cancer registry data. sultan qaboos univ med j 2014; 14:163–9. 2. international agency for research on cancer. globocan 2008 – cancer fact sheet. from: www.registrotumorivco.org/ download/iarc_globocan_word_2008.pdf accessed: jul 2013. 3. international agency for research on cancer. globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. from: www.globocan.iarc.fr/pages/fact_ sheets_cancer.aspx#. accessed: feb 2014. 4. world health organization, international agency for research on cancer. latest world cancer statistics: global cancer burden rises to 14.1 million new cases in 2012: marked increase in breast cancers must be addressed. from: www.iarc.fr/en/ media-centre/pr/2013/pdfs/pr223_e.pdf accessed: feb 2014 5. world health organization, international agency for research on cancer. global battle against cancer won’t be won with treatment alone effective prevention measures urgently needed to prevent cancer crisis. from: www.iarc.fr/en/mediacentre/pr/2014/pdfs/pr224_e.pdf accessed: feb 2014. 6. ministry of health oman. cancer incidence in oman 2011. from: www.moh.gov.om/en/reports/cancer2011-final. pdf accessed: feb 2014. 7. al-moundhri m, al-bahrani b, pervez i, ganguly ss, nirmala v, al-madhani a, et al. the outcome of treatment of breast cancer in a developing country--oman. breast 2004; 13:139– 45. doi: 10.1016/j.breast.2003.10.001. 8. kumar s, burney ia, al-ajmi a, al-moundhri ms. changing trends of breast cancer survival in sultanate of oman. j oncol 2011; 2011:316243. doi: 10.1155/2011/316243. 9. al moundhri m. the need for holistic cancer care framework: breast cancer care as an example. oman med j 2013; 28:300–1. doi: 10.5001/omj.2013.90. 10. kerlikowske k, grady d, rubin sm, sandrock c, ernster vl. efficacy of screening mammography. a meta-analysis. jama 1995; 273:149–54. doi:10.1001.jama.1995.03520260071035. 11. miller ab, wall c, baines cj, sun p, to t, narod sa. twenty five year follow-up for breast cancer incidence and mortality of the canadian national breast screening study: randomised screening trial. bmj 2014; 348. doi: http://dx.doi.org/10.1136/ bmj.g366 12. bleyer a, welch hg. effect of three decades of screening mammography on breast-cancer incidence. n engl j med 2012; 367:1998–2005. doi: 10.1056/nejmoa1206809. 13. gøtzsche pc, jørgensen kj, zahl p-h, mæhlen j. why mammography screening has not lived up to expectations from the randomised trials. cancer causes control 2012; 23:15–21. doi: 10.1007/s10552-011-9867-8. 14. brown ml, goldie sj, draisma g, harford j, lipscomb j. health service interventions for cancer control in developing countries. in: jamison dt, breman jg, measham ar, alleyne g, claeson m, evans db, et al., eds. disease control priorities in developing countries. 2nd ed. washington (dc): world bank; 2006. 15. gonzalez ca. the european prospective investigation into cancer and nutrition (epic). public health nutr 2006; 9:124–6. 16. white e, patterson re, kristal ar, thornquist m, king i, shattuck al, et al. vitamins and lifestyle cohort study: study design and characteristics of supplement users. am j epidemiol 2004; 159:83–93. doi: 10.1093/aje/kwh010. 17. world cancer research fund/american institute for cancer research (aicr). food, nutrition, physical activity and the prevention of cancer: a global perspective. washington, dc: aicr; 2007. 18. romaguera d, vergnaud ac, peeters ph, van gils ch, chan ds, ferrari p, et al. is concordance with world cancer research fund/american institute for cancer research guidelines for cancer prevention related to subsequent risk of cancer? results from the epic study. am j clin nutr 2012; 96:150–63. doi: 10.3945/ajcn.111.031674. 19. hastert ta, beresford sa, patterson re, kristal ar, white e. adherence to wcrf/aicr cancer prevention recommendations and risk of postmenopausal breast cancer. cancer epidemiol biomarkers prev 2013; 22:1498–508. doi: 10.1158/1055-9965.epi-13-0210. 20. vergnaud ac, romaguera d, peeters ph, van gils ch, chan ds, romieu i, et al. adherence to the world cancer research fund/american institute for cancer research guidelines and risk of death in europe: results from the european prospective investigation into nutrition and cancer cohort study. am j clin nutr 2013; 97:1107–20. doi: 10.3945/ajcn.112.049569. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. e601-605, epub. 8th oct 13 submitted 24th feb 13 revisions req. 5th apr & 27th may 13; revisions recd. 17th apr & 2nd jun 13 accepted 18th jun 13 department of 1family medicine & public health, 2medicine and 3radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: kawther@squ.edu.om خراج درين هائل يف العضالت الناصبة للظهر واألنسجة حتت اجللد عند رجل شاب كوثر طه �ل�سفيع, م�سطفى حممد �لهنائي, حمد�ن �أحمد �حلب�سي, حممد �سيف �لهطايل, �أ�سامة ح�سن, ر��سد �ل�سكيتي, �أ�سامه ح�سن, ر��سد �ل�سكيتي امللخ�ص: مر�ض �لدرن )tb( هوعدوى حبيبية مزمنة ميكن �أن تظهر على �سكل غريمنطي. �إ�سابته للع�سالت فقط �سيء نادر جد�. يف هذ� �ملقال نقدم تقرير� عن رجل يبلغ من �لعمر 25 عاما وجد عنده تورم كي�سي �سخم على �جلانب �لأمين من ظهره, ممتد من نهاية �ل�سدر �إىل �ملنطقة �لألوية من �لظهر. هذ� �لرجل تعر�ض لفرتة لأحد �أ�سدقائه �لذي كان ي�ستبه يف �إ�سابته بال�سل. �أظهر �لت�سوير بالرنني �ملغناطي�سي �ل�سائمة �حلم�ض ع�سيات �لكي�ض من �مل�سحوبة �ل�سو�ئل نتيجة و�أظهرت للظهر �لنا�سبة �لع�سالت من كان �لكي�ض �أ�سل �أن )mri( )بكرتيا �ل�سل(. �ختفى �لتورم بعد �لعالج بالأدوية �مل�سادة لل�سل. �إ�سابة �لع�سالت بال�سل هي حالة نادرة جد�. و يف مري�سنا هذ�, �أكدت تقارير �ملوجات فوق �ل�سوتية و�لت�سوير بالرنني �ملغناطي�سي �إ�سابة �لع�سالت و منطقة حتت �جللد دون �إ�سابة �لعظم. كتبت هذه �حلالة لزيادة وعي �لأطباء بخ�سو�ض �ل�سل �لذي ي�سيب �لأن�سجة �لرخوة. فعلى �لرغم من �أنه �أمر نادر �حلدوث, �ل �نه من �ملمكن روؤية و ت�سخي�ض حالت مماثلة يف �مل�ستقبل. مفتاح الكلمات: �لدرن؛ �لع�سالت؛ �خلر�ج؛ �لكي�ض؛ تقرير حالة؛ عمان. abstract: tuberculosis (tb) is a chronic granulomatous infection which can present in an atypical form. isolated muscle involvement is very rare. we report a 25-year-old man who presented with a massive cystic swelling on the right side of his back, extending from the lower thoracic to the gluteal region. he had a history of contact with a friend who was suspected of having tb. magnetic resonance imaging (mri) showed that the origin of the cyst was from the erector spinae muscles. the result of a fluid aspirate showed acid fast bacilli. the swelling disappeared after treatment with anti-tuberculous medications. muscular involvement in tb is very rare. in our patient, the reports of an ultrasound and mri confirmed isolated muscle and subcutaneous involvement without bony lesions. this case is reported to increase physician awareness regarding soft tissue tb. although it is rare, similar cases may be seen in the future. keywords: tuberculosis; muscle; abscess; cyst; case report; oman. a massive tuberculosis abscess at the erector spinae muscles and subcutaneous tissues in a young man *kawther t. elshafie,1 mustafa m. al-hinai,1 hamdan a. al-habsi,1 mohammed s. al-hattali,1 osama hassan,2 rashid al-sukaiti3 online case report tuberculosis (tb) is a chronic granulomatous infection caused by mycobacterium tuberculosis. it can present in atypical forms, such as a herniated intervertebral disc, granuloma that mimic a tumour, or a tb muscle abscess.1 occasionally these abscesses may appear in the supraclavicular, gluteal, psoas, or groin regions.1 isolated muscle involvement is very rare.2,3 we present a case of a massive tb abscess of the erector spinae muscles extending to the adjacent subcutaneous tissues without any underlying bone lesion. case report a 25-year-old male pharmacist presented to the clinic with an enlarging swelling of the right gluteal region which had lasted for two weeks. he had had a similar but painful swelling that had appeared three months before in the right subscapular region. the kawther t. elshafie, mustafa m. al-hinai, hamdan a. al-habsi, mohammed s. al-hattali, osama hassan and rashid al-sukaiti case report | 602 patient had sought the help of a traditional healer who managed the case with aggressive massage. the swelling had disappeared but two days later had reappeared in the right gluteal region. there was no fever or night sweating. he smoked, having consumed three cigarettes per day for the previous 5 years. prior to this problem, the patient had a history of chronic non-bloody diarrhoea of one year’s duration. it was associated with attacks of fever and he had lost about 15 kg in weight. he was suspected of having ulcerative colitis and was put on mesalazine but had shown no improvement and, accordingly, had discontinued the medication. the patient had not received other medications such as corticosteroids. the patient gave a history of contact with a friend who had a history of chronic cough, weight loss, fever and night sweating for 8 months, and was suspected of having pulmonary tb. on examination, the patient’s temperature, blood pressure and pulse were normal. there was no lymphadenopathy. a systemic examination including the chest was normal. on examination of his back, there was a right-sided swelling extending from the infrascapular to the right gluteal region. the swelling was maximal at the gluteal region and measured 20 cm x 15 cm x 10 cm. it was cystic and non-tender. there were no skin changes and no spinal tenderness [figure 1]. investigations showed normal haemoglobin of 12.8 mg/l with normal complete blood counts. c-reactive protein was 122 mg/l. human immunodeficiency virus (hiv) and hepatitis screens were negative. a rapid plasma reagin (rpr) test was negative. a mantoux test was 22 mm. a chest x-ray was normal. an ultrasound of the mass showed a fluid collection in the subcutaneous tissue of the right paraspinal region, extending from the ribs to the gluteal region and measuring 3.6 x 5.6 inches. it contained low level internal echoes. there were multiple areas of calcification noted in the posterior portion of the cyst. it was reported as a non-specific complicated cyst with the possibility of a chronic haematoma [figure 2]. a magnetic resonance imaging (mri) scan showed a large cyst extending from the level of the upper thoracic region to the gluteal region. it was predominately located posterior to the right erector spinae muscles. the proximal part of the cyst appeared to be intramuscular, whereas the lower lumber and gluteal region appeared to be subcutaneous. there was a thick rim of figure 1: a photo of the right side of the patient’s back showing the cold tuberculosis abscess extending from the thoracic to the gluteal region which is indicated by the arrow. figure 2: an ultrasound soft tissue study reveals complex fluid echoic lesion in the right paraspinal region, which is indicated by the arrow. figure 3: magnetic resonance imaging of the right paraspinal region shows an encysted, thick-walled fluid collection posterior to the paraspinal muscles and located predominantly in the subdermis region, which is indicated by the arrow. a massive tuberculosis abscess at the erector spinae muscles and subcutaneous tissues in a young man 603 | squ medical journal, november 2013, volume 13, issue 4 enhancement at the periphery of the lesions with multiple thick enhancing septations noted at the periphery of the lesion. there were also a few small thin nodular enlargements. on the t2-weighted images, there were a few low t2 hypotensive areas, likely representing calcifications. there was no involvement of the spine, intraspinal canal or peritoneum. the lesion measured 34 cm in the craniocaudal direction. it measured 12 cm x 4.4 cm in the gluteal region. the mri showed a large rim enhancing cystic lesion noted posterior to the right erector spinae muscles. it had enhancing septations and there were nodular changes. the lesion was reported as nonspecific and possibly representative of a chronic haematoma. however, a slow growing neoplastic cystic lesion could not be excluded [figure 3]. the patient was admitted. an aspirate of the cyst was done, which revealed a creamy turbid fluid that indicated an abscess. smears prepared from the fluid showed many neutrophils, some lymphocytes, and occasional macrophages. no malignant cells were seen. the abscess was evacuated under ultrasound guidance and a sample of the evacuated material of the lesion, as well as a blood sample, was sent for culture of bacteria and fungi. a ziehlneelsen stain was done to detect acid fast bacteria. the patient was started on empirical antibiotics (piperacillin/tazobactam and vancomycin) but he developed a reaction to one of the antibiotics, so they were stopped accordingly. the result of the microscopy showed two rods of one type of acid fast bacilli bacteria of tb. the culture was negative for other bacteria but was positive for acid fast bacilli bacteria of tb. accordingly, the patient was started on antituberclosis chemotherapy with isoniazid (inh), rifampin (rif), ethambutol (emb) and pyrazinamide (pza) for 9 months. the patient showed marked improvement and the swelling disappeared. the final diagnosis was a cold muscle and subcutaneous abscess caused by tb. table 1: previous case reports of primary muscular tuberculous abscesses report muscle involved predisposing factors methods of investigation involvement of other organs outcome of treatment mascarenhas s, et al.7 left masseter no history of contact with tbinfected patient. mri of the face. mycobacterium tuberculosis complex isolated from the drain of a facial abscess. acid-fast bacilli not identified. erosion of the lateral surface of the left ascending ramus of the mandible the patient responded to a 6-month course of anti-tb treatment ramakant d, et al.8 rectus abdominis no exposure to any known person with active tb. abdominal us. histology of the excised granulation tissue surrounding the abscess and infiltrating the muscle was suggestive of tuberculous. no bony or other organ involved the patient responded to a 6-month course of anti-tb treatment trikha v, et al.2 biceps brachii no family history of tb. mri of the limb us of the muscle.histopathology and culture of the tissue were positive for tb. the result of acid fast bacilli from the drained pus of the abscess was negative. no bony involvement was shown the patient respinded to a 4-month course of antitb treatment, with full range of elbow movement. perez-alonso aj, et al.3 right rectus femoris no history of contact with tbinfected patient. plain x-ray. us of the thigh. mri of the thigh. culture was positive for mycobacterium tuberculosis there was no bony involvement. the patient responded to anti-tb treatment. toda k, et al.9 gluteus maximus patient had a history of tb 20 years previously. ct scan of the muscle. mri imaging. open biopsy of the muscle showed chronic granulomatous tissue. ziehl-neelsen stain showed tuberculous bacilli. the tumour invaded the ischium bone. the patient responded to anti-tb treatment. harrigan ra, et al.6 psoas no history of contact with tbinfected patient. ct of the abdomen and pelvis. culture of the pus from the abscess was positive for mycobacterium tuberculosis. there was no bony or other organ involvement. the patient responded to anti-tb treatment. mri = magnetic resonance imaging ; us = ultrasound; tb = tuberculosis; ct = computed tomography. kawther t. elshafie, mustafa m. al-hinai, hamdan a. al-habsi, mohammed s. al-hattali, osama hassan and rashid al-sukaiti case report | 604 discussion the clinical picture of this patient pointed to the diagnosis of tb as the cause of his huge, cold abscess. the presenting symptom of a mild tender abscess without systemic features, the history of chronic diarrhoea with fever, weight loss and sweating, and the history of contact with a suspected tb patient with the typical symptoms of tb as well as the highly positive mantoux test and the confirmation of the diagnosis by isolation of the acid fast bacilli organisms from the needle aspirate were sufficient to prove the diagnosis. it seems that the origin of this abscess was the erector spinae muscles and, by application of massage, it drained through the adjacent subcutaneous tissues down to the buttock area. tb usually involves the lungs and the hilar lymph nodes. muscular involvement is very rare.4 the percentage of musculoskeletal tb is around 3% of all cases of tb.2 soft tissue involvement is usually associated with an underlying disorder such as those that present in immunosuppressed patients, during immunosuppression therapy or collagen vascular disease, or upon local injury.3,5 our patient was immnocompetent and not suffering from any other disease. tb of the soft tissue can present in the form of an abscess as in this patient, or as a tuberculoma. tuberculoma is a tumour-like mass resulting from the enlargement of a tuberculous lesion, while an abscess is a localised collection of pus. in most of the reported cases, muscle involvement coexists with adjacent bony or articular structures.2 in our patient, the reports of both the ultrasound and mri confirmed isolated muscle and subcutaneous involvement without bony lesions. isolated tubercles muscle abscesses have been reported in the following muscles: the biceps brachii,2 the right rectus femoris,3 the psoas,6 the rectus abdominis,7 and the gluteus maximus8 as well as the submasseteric space.9 there has been no report in the literature of the involvement of the erector spinae muscles together with the adjacent subcutaneous tissues; nor has there been a report of an abscess of such a large size [table 1]. we think that our patient was lucky that his tb was localised to the soft tissue and that it did not affect the spine. tb can affect any part of the spinal cord including the nerve roots; therefore, tb can present with upper or lower motor neuron involvement or a mixed clinical picture.10 it has been reported that tb that affects the skeletal muscles spreads either directly from the bone or by the synovial lining of the joints or tendon sheaths.8 it also has been reported that the primary focus of the disease is visceral (lungs, kidneys, lymph nodes), and musculoskeletal involvement occurs via haematogenous spread.11 however, primary muscle involvement, as occurred in our patient, is rare. the mechanism of muscle involvement by tb in our patient may be explained by haematogenous spread from an undetected occult primary focus (i.e. his friend). the reason for the skeletal muscle tb has been attributed to various causes such as high lactic acid content of muscles, the absence of lymphatic tissue, a rich blood supply and the highly differentiated state of muscle tissue.12 thankfully, our patient responded to the first line drugs (inh, rif, emb and pza) recommended by the american thoracic society, centers for disease control, and infectious diseases society of america.13 anti-tuberculous medications cannot penetrate an abscess; therefore, it is mandatory to drain the abscess for the medication to be effective. it seems that the outcome of pure muscle involvement with tb is better than during spinal involvement. in his review of two groups of patients (one with spine or lamina involvement and the other with pure muscle involvement), arora found that those with pure muscle involvement recovered completely in comparison to the ones in which the spine or the lamina were involved.14 conclusion the diagnosis of extrapulmonary tb is often difficult. this case has been reported to increase the awareness of physicians regarding soft tissue tb. although it is rare, physicians may come across similar cases in the future. references 1. ludwig b, lazarus a. musculoskeletal tuberculosis. dis mon 2007; 53:39–45. 2. trikha v, gupta v. isolated tuberculosis abscess in biceps brachii muscle of a young male. j infect 2002; 44:265–6. 3. perez-alonso aj, husein-elahmed h, duran cp, caballero-marcos l, ramon ja. isolated muscle a massive tuberculosis abscess at the erector spinae muscles and subcutaneous tissues in a young man 605 | squ medical journal, november 2013, volume 13, issue 4 tuberculosis. med mal infect 2011; 41:559–60. 4. kobayashi h, kotoura y, hosono m, tsuboyama t, sakahara h, konishi j. solitary muscular involvement by tuberculosis: ct, mri, and scintigraphic features. comput med imaging graph 1995; 19:237–40. 5. fitzgerald jm, grzybowski s, allen ea. the impact of human immunodeficiency virus infection on tuberculosis and its control. chest 1991; 100:191– 200. 6. harrigan ra, kauffman fh, love mb. tuberculosis psoas abscess. j emerg med 1995; 13:493–8. 7. ramakant d, kalpana d, hetal s, keyur s. tuberculosis abscess of rectus abdominis muscle. indian j tuberc 2004; 51:231–3. 8. toda k, yasunaga y, takemoto s, terada y. mr image and ct scan of a tuberculous abscess in the gluteus maximus muscle. comput med imaging graph 1998; 22:425–7. 9. mascarenhas s, tuffin jr, hassan i. tuberculous submasseteric abscess: case report. br j oral maxillofac surg 2009; 47:566–8. 10. thwaites g, fisher m, hemingway c, scott g, solomon t, innes j. british infection society. british infection society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. j infect 2009; 59:167– 87. 11. spiegel dg, ganley tj, flynn. jm. titanium elastic nailing of pediatric femur fractures. oper tech orthop 2005; 15:326–30. 12. abdelwahab if, kenan s. tuberculous abscess of the brachialis and biceps brachii muscles without osseous involvement: a case report. j bone joint surg am1998; 80:1521–4. 13. centers for disease control and prevention. treatment of tuberculosis. mmwr 2003; 52:1–77. 14. arora s, sabat d, maini l, sural s, kumar v, gupta a, dhal a. isolated involvement of the posterior elements in spinal tuberculosis: a review of twenty four cases. j bone joint surg am 2012; 94:151. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 534-538, epub. 8th oct 13 submitted 9th feb 13 revisions req. 14th may & 19th jun 13; revisions recd. 2nd jun & 23rd jun 13 accepted 27th jun 13 department of 1child health and 2student, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: munasa@squ.edu.om اخلروج ضد املشورة الطبية بني األطفال يف عمان جتربة مستشفى جامعي منى ال�سعدون, خالد ال�سمو�سي امللخ�ص: الهدف: يعترباخلروج �سد امل�سورة الطبية )dama( اأحد امل�ساكل الرئي�سية التي قد تزيد امل�ساكل ال�سحية التي يعاين منها كفاءة وتقييم عمان �سلطنة يف تعليمي م�ست�سفى يف الأطفال بني اخلروج عوامل فهم هو الدرا�سة هذه من الهدف كان تعقيدا. الأطفال عامني ملدة الطبية امل�سورة �سد خرجوا الذين للمر�سى الطبية لل�سجالت رجعي م�سح اإجراء مت الطريقة: الطبية. ال�سجالت يف توثيقها )2004-2006(. النتائج: من 11,802 حالة دخلت امل�ست�سفى يف فرتة الدرا�سة كانت هناك 38 حالة خروج �سد امل�سورة وذلك مبعدل انت�سار %0.32. يف %39.5 من احلالت حدث اخلروج �سد امل�سورة الطبية خالل 24 �ساعة من دخول امل�ست�سفى. كانت غالبية احلالت حالة و مبعدل %63.25(. الت�سخي�ص عند اخلروج ت�سمن م�ساكل خطرية قد تهدد احلياة يف بع�ص احلالت. مل تذكر من الر�سع )24 اأو توثق اأ�سباب اخلروج �سد امل�سورة يف ال�سجالت الطبية للعديد من للمر�سى )%57.9(. اخلال�صة: على الرغم من اأن نتائج هذه الدرا�سة اأ�سفرت عن معدل انت�سار منخف�ص مقارنة مع املعدلت يف درا�سات اأخرى, غري اأن جمرد حدوث خروج �سد امل�سورة لالأطفال يف م�ست�سفى من مزيد اإجراء وينبغي �سعيفا. الطبية امل�سورة �سد اخلروج اأ�سباب توثيق اأن الوا�سح من كان الأ�سى. على تبعث ظاهرة هو جامعي الأطفال بني الطبية امل�سورة �سد اخلروج تقليل حماولة اأجل من وتنفيذها �سيا�سات و�سع ينبغي كما امل�سكلة تفا�سيل لفهم الدرا�سات املر�سى وحمايتهم من عواقب تلك املمار�سات. مفتاح الكلمات: الأطفال؛ اخلروج �سد امل�سورة الطبية؛ امل�ست�سفيات؛ عمان. abstract: objectives: discharge against medical advice (dama) is a major problem in healthcare delivery as it can complicate the health problems from which patients are suffering. the aim of this study was to understand dama among children in a tertiary teaching hospital in oman and to evaluate the documentation of the events in the medical records. methods: a retrospective survey of the medical records of patients discharged against medical advice over a two-year interval was performed (2004–2006). results: of the 11,802 admissions, there were 38 cases of dama, giving a prevalence rate of 0.32%. in 39.5% of the cases, the discharge happened within 24 hours of hospital admission. the majority of the cases were infants (n = 24; 63.25%). the diagnosis at discharge in some cases included life-threatening conditions. however, in 57.9% of the cases, the reasons for dama were neither reported nor documented in the patients’ medical records. conclusion: although the results of this study yielded a low prevalence rate compared to the rates reported in other studies, the occurrence of dama for children in a tertiary hospital is a distressing phenomenon. it was evident that the documentation of the dama process was poor. more studies should be conducted to understand the details of the problem. policies should be established and implemented in order to attempt to reduce dama among child patients and to protect them from the consequences of such discharges. keywords: children; patient discharge; hospitals; oman. discharge against medical advice among children in oman a university hospital experience *muna al-sadoon1 and khalid al-shamousi2 clinical & basic research advances in knowledge this is the first study in oman that highlights discharge against medical advice (dama) among children. this study identified that, in oman, dama occurs more frequently among children younger than 3 years old and that the majority happens within a week of admission. it also reveals the seriousness of some of the health conditions that children are suspected of having at the time of dama. application to patient care this study highlights the need for proper documentation of the occurences of dama. the results of this study also indicate the need to implement policies to control dama, especially in children with life-threatening health conditions. discharge against medical advice among children in oman a university hospital experience 535 | squ medical journal, november 2013, volume 13, issue 4 discharge against medical advice (dama) happens when a patient (or the parents or caregivers, in the case of a young patient) decides the timing of the discharge without a treating doctor’s approval. the clinical, ethical and legal implications of dama are a major problem for doctors. dama is reported among adults and has also been reported in younger patients.1–6 in children, the decision to undertake dama is a liability for the care provider and can have immediate or long-term health consequences for the child. the prevalence rate of dama is estimated to be around 1% in most studies, but has been reported to reach up to 25.85% in other studies.3–5,7,8 in one study, dama was mainly reported among children aged under one year, followed by children aged 1–5 years.9 one alarming trend is that even critically ill children with life-threatening complications were reported to have been discharged against medical advice.3,5,10 perceived improvement, financial problems and the parents’ dissatisfaction with the care provided are some of the reasons that parents often claim to justify the dama of a child.11 dama can endanger the patient’s life and could further complicate the patient’s clinical outcome. it could also result in readmissions with longer hospital stays, prolonged illness and ultimately lead to higher costs of care.12‒14 the problem of dama has been reported in different countries worldwide.1–6 however, this subject has rarely been studied in arab countries, much less in oman. dama is an important issue to address; thus, the associated factors, reasons and outcomes of dama must be recognised and possible solutions must be determined. this study will describe the prevalence rate, and the clinical and sociodemographic factors of paediatric dama at sultan qaboos university hospital (squh), oman. methods this was a retrospective descriptive study on paediatric dama in squh, a tertiary teaching hospital attached to the college of medicine & health sciences at sultan qaboos university, muscat, oman. during the study period, squh was a 649bed hospital with 4 paediatric wards consisting of 115 beds, among other wards and specialties. the study was based on paediatric patients who left the hospital against medical advice over a two-year period (july 2004–june 2006). ethical approval for the study was obtained from the sultan qaboos university (squ) college of medicine & health sciences, medical ethics & research committee (mrec #259). cases were identified from the ward registry books which contain basic information about patient demographics and the modes of admission and discharge. all medical files and available discharge summaries of dama during the study period were reviewed. the following information was collected from patients’ medical records: date of birth, admission, dama, diagnosis at discharge and other social factors (age of parents, education and working status of parents, and number of siblings). the number of admissions and discharges in the paediatric wards during the study period were collected from the computerised hospital information system. due to the small number of cases, a simple descriptive analysis using the statistical package for the social sciences (spss), version 19 (ibm, corp., chicago, illinois, usa) was used to present the data (frequency tables and graphs, mean and median of continuous data). further statistical analysis was not possible; hence, no correlation could be construed. results a review of the ward registry books identified a total of 44 cases of dama during the study period. during the same interval, a total of 11,802 discharges were reported from all paediatric wards. after reviewing the medical records of the identified patients, only 38 cases had detailed information in their medical records about the cause of the dama. on the other hand, dama could not be confirmed from the medical records in the remaining 6 cases, and they were hence excluded from the study. thus, the rate of dama was 0.32%. female patients comprised 60.5% (n = 23) of the discharged patients, and almost all the study patients were omani (n = 35; 92.1%). the duration of admission ranged from a few hours to 36 days, with a median of two days (interquartile range = 4.25 days) [table 1]. the majority of cases of dama were infants (n = 24; 63.2%) with an age range of one day to 12 years, with the median age being one month (first quartile 6 days and third quartile 3 muna al-sadoon and khalid al-shamousi clinical and basic research | 536 years) [table 1]. other demographic factors concerning the parents were missing from the files for most of the patients, and thus were not reported. the diagnosis/symptoms varied among the study cases [table 2]. some of the patients were discharged against medical advice with life-threatening health conditions such as septicaemia, acute abdomen pain and inflammatory diseases of the central nervous system. while some patients exhibited a number of health problems, this was mainly observed among the neonatal group. furthermore, only two patients were known to have chronic diseases (rheumatoid arthritis and immunodeficiency), while 28 (73.7%) did not have any chronic diseases; however, it was not possible to confirm or exclude the presence of chronic diseases at the time of dama from the health records in 8 patients (21.1%). the data showed that 11 cases (28.9%) were admitted through the emergency room; two (5.3%) were admitted through the hospital’s outpatient clinic; 8 cases (21.1%) were referred from other health institutions; two (5.2%) were booked admissions, and 10 (26.3%) were referred from the squh postnatal ward. for 5 cases (13.2%), it was not possible to identify the source of admission from the medical records. the reasons for dama were not documented in 57.9% of the studied cases; for the rest of the cases however, the care provider reported alleged justifications for the dama in the patients’ hospital records, as illustrated in figure 1. discussion this was a descriptive study conducted to assess the number and types of cases of dama in a tertiary teaching hospital in oman. to our knowledge, this is the first study of this type highlighting dama among minors in oman. although this study presented retrospective data from approximately 6 years ago, this study constituted the groundwork for more comprehensive research utilising a prospective approach. dama is an existing problem among paediatric patients and it is more common among infants; this is a finding which has been similarly reported in other studies.9 the study shows that most dama patients were neonates; this is an alarming observation considering the possible complications and subtle symptoms that can affect this particular patient group. the diagnosis/symptoms at discharge were startling in some cases. table 1: age of patient and duration of admission before discharge against medical advice characteristics total (n = 38) n (%) age of child 1–30 days 19 (50) 1–12 months 5 (13.1) 13 months–3 years 8 (21) 4–6 years 2 (5.3) 7–10 years 2 (5.3) 11–12 years 2 (5.3) duration of admission in days 1 15 (39.5) 2–5 15 (39.5) 6–10 4 (10.5) 11–36 4 (10.5) table 2: diagnosis upon discharge against medical advice diagnosis n (%) life-threatening diseases septicaemia 6 (15.8) immunodeficiency 2 (5.3) hypoglycaemia 1 (2.6) inflammatory diseases of the central nervous system 4 (10.5) convulsion, cerebellar ataxia 2 (5.3) acute abdomen pain, inguinal hernia 3 (7.9) diarrhoea and gastroenteritis of presumed infectious origin 3 (7.9) poisoning by drugs 1 (2.6) other diseases acute bronchitis, bronchopneumonia 5 (13.2) failure to thrive 1 (2.6) jaundice 2 (5.3) urinary tract infection 1 (2.6) anaemia 2 (5.3) visceral leishmaniasis 1 (2.6) gastroesophageal reflex 1 (2.6) prematurity 6 (15.8) discharge against medical advice among children in oman a university hospital experience 537 | squ medical journal, november 2013, volume 13, issue 4 as with other studies, this study found a slightly higher rate of dama among female patients. it is difficult to explain this finding given the current study design.7 the issue of gender discrimination may be considered; however, it is unlikely to be the reason since gender discrimination is not so pervasive in oman, as for instance, there are no major differences in school enrolment between boys and girls.15 the majority of patients discharged against medical advice had acute problems but did not exhibit chronic diseases. whether the parents of children with chronic diseases are more adjusted and tolerant to hospitalisation needs to be considered. moreover, around two-thirds of the study’s patients were discharged against medical advice within 5 days (40% within 24 hrs) with a median of 2 days; this is slightly longer compared to other studies which reported the mean duration of hospital stay to be 3.1 days.7 healthcare is free for omani citizens; thus, it is less likely to contribute to the decision of dama. however, the financial burden of admissions (such as transportation, losing working days and the arrangement of alternative care for other children) should be considered as possible rationales for dama. the explanations that parents gave for the dama of a child was usually related to a medical management plan, such as the refusal of a procedure, while others stated “seeking a second opinion” to be the main reason. in such circumstances, it is important to consider the healthcare characteristics that could contribute to dama (for example, trust, communication barriers or satisfaction with the care provided). the fact that there are few other governmental tertiary care hospitals in oman makes the availability of local options for a second opinion very limited. there is a need to conduct prospective studies on dama to assess the reasons behind such discharges. other studies have reported financial problems, parents’ perceptions of a child’s medical improvement, a cultural belief in seeking traditional therapies and dissatisfaction with the care provided by the treating team as the main causes of dama.16,17 in 21.1% of the cases in this study, the documented reasons for dama were related to social factors without specifying the details. some of the possible reasons could be arranging care for other children at home, transportation from different regions and the work commitments of the parents. it would be useful to define such reasons and try to find solutions for such problems through the available governmental institutions, such as the ministry of social development. the fact that the reason for dama was not documented in the patients’ medical files in 57.9% of cases is of profound legal, ethical and medical importance. in many cases, the effort of the treating team to prevent such discharges was not documented. what is more worrying is that 6 cases were reported in the ward registry books as dama, but no other details pertaining to dama were recorded in the patients’ medical files. similar poor documentation practices on standardised dama forms have been reported in other studies.18 documentation in patients’ medical records is usually the responsibility of junior doctors, and assuring their proper documentation of dama is a necessity. due to the retrospective nature of this study, one of the limitations is that it was difficult to control for the quality of data collected and for missing data. the second limitation has to do with conducting the study in a single health institute, which resulted in a small sample size and an inability to generalise the results. the third limitation is that no information about the prognosis and eventual outcome of the patients was available. finally, it would be important to collect more recent data, and this obviously constitutes one of the important limitations of this study. therefore, a future study could expand the time period studied as well as include a more recent dataset. similarly, in order to circumvent the present limitation, a prospective study would be an added asset so that evidence-based groundwork for figure 1: reasons for discharge against medical advice. muna al-sadoon and khalid al-shamousi clinical and basic research | 538 informed policy might be contemplated. conclusion dama is an existing problem in tertiary care hospitals in oman, and infants are the most common victims. the discharge diagnoses in some patients were fatal and the children’s lives or health outcomes could have been placed at risk. it is also apparent that the amount of information reported in the medical records for the dama episodes in some cases was incomplete. it is a fundamental right of every child to receive healthcare; hence, dama deprives a child of this right. in cases of dama, suboptimal healthcare is provided instead. this is a violation of the child’s rights, and the parent’s authority over a child needs to be considered when a child’s welfare is at risk of being negatively affected. considering the size of this problem in a tertiary hospital, an assessment of the magnitude of the problem in secondary hospitals and primary health services should be considered. the impact of this problem on children and health services needs to be thoroughly examined. actions should be taken to control life-threatening dama, and serious efforts should be implemented as stated to ensure the child’s right to receive appropriate healthcare. we recommend ensuring that more details concerning dama be included in patients’ hospital records for medico-legal reasons. ideally, the discharging doctor should complete specific forms detailing the patient’s medical information, factors contributing to discharge, the process of counselling and an explanation of the risks involved in such a discharge. finally, we advocate a prospective study in more health institutes to evaluate and provide more information about the factors contributing to dama and the outcome of dama among children in oman. references 1. seaborn moyse h, osmun we. discharges against medical advice: a community hospital’s experience. can j rural med 2004; 9:148–53. 2. akpede go. presentation and outcome of sporadic acute bacterial meningitis in children in the african meningitis belt: recent experience from northern nigeria highlighting emergent factors in outcome. west afr j med 1995; 14:217–26. 3. okoromah cn, egri-qkwaji mt. profile of and control measures for paediatric discharges against medical advice. niger postgrad med j 2004; 11:21–5. 4. aliyu zy. discharge against medical advice: sociodemographic, clinical and financial perspectives. int j clin pract 2002; 56:325–7. 5. gloyd s, koné a, victor ae. pediatric discharge against medical advice in bouaké cote d’ivoire, 1980-1992. health policy plan 1995; 10:89–93. 6. ibrahim sa, kwoh ck, krishnan e. factors associated with patients who leave acute-care hospitals against medical advice. am j pub health 2007; 97:2204–8. 7. onyiriuka an. discharge of hospitalized under-fives against medical advice in benin city, nigeria. niger j clin pract 2007; 10:200–4. 8. parkash j, das n. pattern of admissions to neonatal unit. j coll physicians surg pak 2005; 15:341–4. 9. hong le, ling fc. discharges of children from hospital against medical advice. j singapore paediatr soc 1992; 34:34–8. 10. mahadi, pasaribu s, lubis m, lubis cp. acute hepatitis at the department of pediatrics, school of medicine, university of north sumatra/dr pirngadi hospital medan. paediatr indones 1991; 31:145–9. 11. roodpeyma s, hoseyni sae. discharge of children from hospital against medical advice. world j pediatr 2010; 6:353–6. 12. choi m, kim h, qian h, palepu a. readmission rates of patients discharged against medical advice: a matched cohort study. plos one 2011; 6:e24459. 13. glasgow jm, vaughn-sarrazin m, kaboli pj. leaving against medical advice (ama): risk of 30-day mortality and hospital readmission. j gen intern med 2010; 25:926–9. 14. pennycook ag, mcnaughton g, hogg f. irregular discharge against medical advice from the accident and emergency department--a cause for concern. arch emerg med 1992; 9:230–8. 15. united nations educational, scientific, and cultural organization institute for statistics. literacy statistics. from: http://stats.uis.unesco.org/unesco/ tableviewer/document.aspx?reportid=121&if_ l a n g u a g e = e n g & b r _ c o u n t r y = 5 8 0 0 & b r _ region=40525</eref> accessed: feb 2012. 16. onukwugha e, saunders e, mullins cd, pradel fg, zuckerman m, weir mr. reasons for discharges against medical advice: a qualitative study. qual saf health care 2010; 19:420–4. 17. macrohon bc. pediatrician’s perspectives on discharge against medical advice (dama) among pediatric patients: a qualitative study. bmc pediatr 2012; 18:12:75. 18. reinke da, walker m, boslaugh s, hodge d. predictors of pediatric emergency patients discharged against medical advice. clin pediatr (phila) 2009; 48:263–70. clinical & basic research sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 51-56, epub. 27th feb 13 submitted 17th jun 12 revision req. 6th aug 12, revision recd. 5th sep 12 accepted 6th oct 12 الوالدة املبتسرة الناجتة عن متزق أغشية اجلنيني املدقع قبل اكتمال 26 أسبوعا من احلمل نهال الريامي، فاطمة ال�صيزاوي ، انت�صار الرحيلي ، مرت�صى اخلابوري امللخ�ص: الهدف: متزق الأغ�صية قبل الأوان )prom( يعرف باأنه متزق الأغ�صية اجلنينية قبل اكتمال 37 اأ�صبوعا من احلمل، اأما متزق الفرتة يف والوفيات العتالل اإىل يوؤدي اأن وميكن احلمل، من اأ�صبوعا اكتمال 26 قبل يحدث باأنه يعرف فاإنه املدقع اجلنينية الأغ�صية املحيطة بالولدة. كان الهدف من هذه الدرا�صة هو تقييم نتائج الولدة لالأمهات الالآتي متزقت الأغ�صية اجلنينة لديهن قبل اكتمال 26 اأ�صبوعًا من احلمل. طرق الدرا�صة: اأجريت درا�صة ا�صتعادية على 44 امراأة حامال على التوايل ولدن مبت�رسين نتيجة متزق الأغ�صية املدقع قبل اكتمال 26 اأ�صبوعًا من احلمل، من يناير 2006 اإىل دي�صمرب 2011 يف م�صت�صفى جامعة ال�صلطان قابو�ض، �صلطنة عمان. وقد مت جمع املعلومات عن الأم والوليد من ال�صجالت الطبية، و�صجالت وحدة حديثي الولدة. مت ا�صتبعاد كل احلالت التي بها تعدد للحمل اأو ولدت بعد اإكمال 26 اأ�صبوعا من احلمل او اأي اأنواع اأخرى من الولدات قبل الأوان من الدرا�صة. النتائج: من بني منت�صبي الدرا�صة 24)%55( على قيد احلياة، 7)%16( تويف يف غ�صون 24 �صاعة من الولدة، �صقط 9)%20( و 4)%9( موت اجلنني داخل الرحم. كانت الإنتان الوليدي ونق�ض اكتمال الرئة هي الأ�صباب الرئي�صية التي اأدت للوفاة. و�صملت امل�صاعفات التي ت�صيب الولدان الر�صع على قيد احلياة من بني اخلدج معدل ارتبط )46%(11 يف الولدة عند الوزن وانخفا�ض ،)50%(12 والإنتان )79%(19 التنف�صية، ال�صائقة متالزمة ،)46%(11 البقاء على قيد احلياة مع عمر احلمل عند الولدة ولكن لي�ض مع عمر احلمل عند متزق الأغ�صية. اخلال�صة: نتائج هذه الدرا�صة قد ت�صاعد اأطباء التوليد و حديثي الولدة على ا�صداء الن�صح لالأزواج الذين عانوا من متزق الأغ�صية اجلنينية قبل اكتمال 26 اأ�صبوعًا من احلمل. نحتاج اىل العديد من الدرا�صات امل�صتقبلية على املدى الطويل ذات عينات اأكرب وت�صمل عدد اأكرب من امل�صت�صفيات. مفتاح الكلمات: املدقع؛ الولدان؛ الأمهات؛ النتيجة؛ عمان. abstract: objectives: preterm premature rupture of membranes (pprom) is defined as the rupture of fetal membranes before 37 weeks. extreme pprom occurs before 26 weeks’ gestation and can result in perinatal morbidity and mortality. the aim of this study was to study the perinatal outcomes of mothers with extreme pprom. methods: a retrospective cohort study of 44 consecutive pregnant women, presenting with pprom before 26 weeks’ gestation, was conducted from january 2006 to december 2011 at sultan qaboos university hospital, oman. maternal and neonatal information was collected from medical records, and delivery and neonatal unit registries. women with pprom presenting after 26 weeks’ gestation, those with multiple gestations, or other types of preterm deliveries were excluded from the study. results: of the 44 preterm infants admitted to the neonatal intensive care unit, 24 (55%) survived, 7 (16%) died within 24 hours of birth, 9 (20%) were miscarried, and 4 (9%) were stillbirths. neonatal sepsis and pulmonary hypoplasia were the major causes of death. neonatal complications among the surviving infants included prematurity in 11 (46%), respiratory distress syndrome in 19 (79%), sepsis in 12 (50%), and low birth weight in 11 (46%). the neonatal survival rate was significantly associated with the gestational age at delivery but not with the gestational age upon rupture of membranes. conclusion: extreme pprom was associated with adverse perinatal outcomes. the results of this study will help obstetricians and neonatologists in counselling couples experiencing pprom. future studies of long-term neonatal morbidity should have larger sample sizes and include more hospitals. keywords: extreme pprom; neonatal; maternal; outcome; oman. perinatal outcome in pregnancies with extreme preterm premature rupture of membranes (mid-trimester prom) *nihal al-riyami,1 fatma al-shezawi,2 intisar al-ruheili,2 tamima al-dughaishi,1 murtadha al-khabori3 clinical & basic research departments of 1obstetrics & gynecology and 3department of haematology, sultan qaboos university hospital, muscat, oman; 2college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: drriyami@hotmail.com advances in knowledge few studies have looked at extreme preterm premature rupture of membranes (pprom) or possible outcomes for mothers and fetuses. this complication carries a significant morbidity and mortality rate and affects the perinatal outcome. perinatal outcome in pregnancies with extreme preterm premature rupture of membranes (mid-trimester prom) 52 | squ medical journal, february 2013, volume 13, issue 1 the major cause of neonatal morbidity and mortality is preterm birth. it is divided into three categories: preterm premature rupture of membrane (pprom), preterm labour, and early delivery resulting from medical intervention. pprom is defined as a rupture of the amniotic membranes before 37 weeks’ gestation and before the onset of labour, while extreme pprom occurs before 26 weeks’ gestation. pprom is a serious condition leading to approximately onethird of preterm births and it complicates about 3% of pregnancies.1 it is associated with many perinatal complications including neonatal sepsis, respiratory distress syndrome (rds), placental abruption, and eventually fetal death, and carries a 1 to 2% risk of fetal death.2 in addition, pprom puts the mother at risk for infection (chorioamnionitis) and premature delivery, and increases the risk of caesarean section delivery. risk factors for pprom are trauma, smoking, bacterial infection, or inflammation. women with darker skin tone are at higher risk compared to women with lighter skin.3 other higher risk groups are those with a previous history of preterm delivery, those who are experiencing vaginal bleeding, or those with uterine distension. in addition, low socioeconomic status, a history of sexually transmitted infections, genetic and/or enzymatic abnormalities, nutritional deficiencies, an incompetent cervix, and placental abruption are known predisposing factors.4,5 procedures like amniocentesis and cerclage may result in pprom. pprom has been suggested to be due less to the collagen content of the amniotic membranes and is more likely a multifactorial phenomenon.6 proper evaluation and management are necessary in order to improve neonatal outcomes. corticosteroids are effective in reducing many neonatal complications, especially rds and intraventricular haemorrhage. antibiotics can be used effectively to increase the latency period. however, management of pprom varies according to the gestational age of the fetus. in the united states, approximately 1% of pregnancies are complicated by pprom between 16 and 26 weeks’ gestation, resulting in a potential risk of neonatal complications and death.7,8 extreme pprom has not been studied and little has been published in the literature. pprom, as far as we know, has not been studied in oman. studying our experience at squh will help in counselling parents, and allow us to compare our maternal and fetal outcomes with other institutions in the world. therefore, the purpose of this study was to look at maternal and fetal outcomes, including the survival rate of the neonates at the sultan qaboos university hospital (squh) neonatal intensive care unit (nicu) who were born to mothers with pprom before 26 weeks’ gestation. the results of the study will help obstetricians and neonatologists in counselling couples. methods after obtaining ethical approval from the sultan qaboos university hospital ethics committee, we started collecting the data and information needed. a retrospective cohort study with a sample size of 44 consecutive pregnant women was conducted from january 2006 to december 2011. all the participants were omani women who presented with pprom between 16 and 26 weeks’ gestation. they delivered and received medical care at squh and their data was available. the hospital database, including medical records, and labour ward and nicu registries were used to obtain the following information: 1) maternal demographics; 2) gestational age at pprom and at admission; 3) use of antibiotics and corticosteroids for fetal lung maturity; 4) gestational age at birth and mode of delivery (spontaneous vaginal or caesarean section delivery); 5) presence of chorioamnionitis; 6) 1 and 5-min apgar scores; 7) maternal and neonatal outcomes (morbidity and mortality rates), and 8) birth weight and sex of the baby. women who had pprom after 26 weeks’ gestation, who were pregnant with multiple gestation, or had a delivery due to medical intervention were excluded from the study. gestational age was determined by asking the application to patient care the results of this study will help in increasing awareness of pprom for both the obstetricians and neonatologists and encourage close follow-up, proper management and counselling for this high risk group. nihal al-riyami, fatma al-shezawi, intisar al-ruheili, tamima al-dughaishi and murtadha al-khabori clinical and basic research | 53 mother the date of her last menstrual period, if reliable, or by doing an ultrasound before 20 weeks gestation. diagnosis of pprom was based on history and vaginal examination. a history of sudden discharge of amniotic fluid from the vagina or feeling wet with a pooling of amniotic fluid in the posterior fornix on sterile speculum examination or ferning test confirmed the diagnosis. finally, ultrasonography was done to assess the amniotic fluid index level. the patients were managed conservatively in the obstetrical ward and monitored for signs of chorioamniotis or fetal compromise. all patients received oral erythromycin for 10 days and steroids for fetal lung maturity at gestational ages of 24 weeks and above. the diagnosis of clinical chorioamnionitis was based on the presence of two or more of the following symptoms: purulent vaginal discharge, maternal pyrexia with uterine tenderness, fetal tachycardia, or non-reassuring fetal heart tracing on the cardiotocogram. indications for delivery included clinical chorioamnionitis, fetal death, or advanced labour. viability was defined as a gestational age of 24 weeks and above, or an estimated fetal weight of 500 gr or above. patients who stopped leaking and had a normal amniotic fluid index were managed as outpatients with weekly complete blood count (cbc) and fetal ultrasound. they were asked to report to hospital for concerns such as fever, abdominal pains, foul smelling discharge, or reduced fetal movements. these patients were allowed to go to term. patients who continued to leak were managed as inpatients and delivered at 34 weeks’ gestation. a multivariate analysis was used to find the association between pprom and neonatal morbidities. microsoft excel (microsoft, redmond, washington, usa) and the statistical package for the social sciences (spss), version 19 (ibm, inc, chicago, illinois, usa) was used to do the data analysis. a p value of <0.05 was determined to be statistically significant. appropriate charts (e.g. pie and bar charts), depending on the type of variables, were drawn to illustrate the results. results forty-four consecutive pregnant women with pprom were included in this retrospective study. the median maternal age was 30 ± 5.4 years, while the median gravidity and parity were 3 and, 1 respectively. the mean gestational age at onset of pprom and at delivery/miscarriage was 20.7 weeks, (ranging from 16 to 26 weeks) and 29.7 weeks (ranging from 17 to 40 weeks), respectively. other maternal demographics are listed in table 1. among the 44 neonates delivered, 9 (20%) were miscarried, 4 (9%) were stillbirth, 24 (55%) survived, and 7 (16%) died within 24 hours of delivery. the cause of death was pulmonary hypoplasia in 4 of the neonates, with 3 complicated by neonatal sepsis. table 1: maternal demographics (n = 44) maternal age mean sd range 30 5.4 18-42 gravidity mean sd range 3.5 1.8 1-15 parity mean sd range 2 2.5 0-10 maternal bmi mean sd range 30 6.4 18-44 ga at pprom mean sd range 20.7 3.2 16-26 ga at delivery mean sd range 29.5 7.6 17-40 ga = gestational age; bmi = body mass index; pprom = preterm premature rupture of membranes. table 2: causes of neonatal deaths in newborns delivered after 24 weeks (n = 7) case no. ga at pprom ga at delivery cause of death 1 23 31 pulmonary hypoplasia 2 21 36 pulmonary hypoplasia/ neonatal sepsis 3 24 24 pulmonary hypoplasia 4 22 26 pulmonary hypoplasia 5 18 28 neonatal sepsis 6 23 25 neonatal sepsis 7 22 26 neonatal sepsis ga = gestational age; pprom = preterm premature rupture of membranes. perinatal outcome in pregnancies with extreme preterm premature rupture of membranes (mid-trimester prom) 54 | squ medical journal, february 2013, volume 13, issue 1 based on gestational age at the onset of pprom, the survival rate was 41.7% when the rupture occurred before 21 weeks of gestation and 8.3% at 21 weeks. a survival rate of 50% was found in the 22 to 26 weeks’ gestational age group [figure 1]. among the miscarried fetuses, the range of occurrence of pprom was between 17 and 21 weeks (miscarriage is defined as loss of pregnancy before 22 weeks). the fetal membranes for the majority of stillbirth fetus were ruptured at or before 21 weeks of gestation and all were born before 26 weeks. out of the neonatal deaths, 3 out of 7 were due to pulmonary hypoplasia, 3 were the result of neonatal sepsis, and one was complicated by both as shown in table 2. this study showed a significant association between death and gestational age at delivery (p = 0.001), but not with the gestational age at rupture of membranes (p = 0.541) this means that the earlier the gestational age at delivery, the higher the risk of perinatal death. a total of 24 (55%) live born infants survived. of these, 12 (50%) were boys and 12 (50%) were girls. eight (33%) neonates were delivered by caesarean section and 16 (67%) were delivered vaginally. the mean apgar scores at 1 and 5 minutes were 8.7 and 10, respectively. the birth weight showed a mean of 2.22 kg. eleven (46%) surviving neonates were preterm and were born with extreme low birth weight. diagnosis of rds was established in 19 (79%) babies; 12 (50%) newborns had neonatal sepsis; inguinal hernia occurred in 3 (13%). other significant neonatal complications are illustrated in table 3. the most common maternal complication noted was infection. out of 44 women with pprom, 20 mothers (45%) developed infection, 11 mothers (25%) had antepartum haemorrhage, and 12 mothers (27%) required caesarean section. one mother (3%) had no complications [table 4]. discussion about 1% of pprom pregnancies occur in the second trimester, leading to a significant level of morbidity among infants who survive. among the 44 patients, there were 4 stillbirths, 9 miscarriages, and 7 neonatal deaths. the major causes for the neonatal death were neonatal sepsis and pulmonary hypoplasia. thus, the perinatal survival rate was 55%—a number comparable with most previous studies.9,10 surprisingly, a survival rate of 41.7% was found when the ruptured membranes table 3: other neonatal complications among surviving infants (n = 24) conditions no. bronchiolitis 4 inguinal hernia 3 umbilical hernia 1 intestinal obstruction 1 pulmonary hypoplasia 1 umbilical cord compression 1 bronchopneumonia 2 omphalitis 2 conjunctivitis 1 congenital malformation 1 esophageal atresia 1 tracheoesophageal fistula 1 laryngomalacia 1 hyperbilirubinemia 1 osteopenia 1 clitromegaly 1 table 4: maternal complications outcome frequency (out of 44 mothers) 95% ci maternal infection 20 30‒61 cesarean section 12 15‒43 antepartum hemorrhage 11 13‒40 <21 wks 21 wks 22-26 wks 50% 8% 42% figure 1: survival rate based on ga at prom ga = gestational age; pprom = preterm premature rupture of membranes. nihal al-riyami, fatma al-shezawi, intisar al-ruheili, tamima al-dughaishi and murtadha al-khabori clinical and basic research | 55 occurred before 21 weeks of gestation. the 82% survival rate at 24 weeks of gestation might be due to the administration of antenatal antibiotics, corticosteroids, and improved antenatal care. such a high survival rate has been reported in very few studies among infants born at 24–26 weeks of gestation. in 1988, 118 cases of pprom were evaluated by moretti and sibai.9 they recorded 67.7% perinatal mortality. based on gestational age at the onset of pprom, the survival rate was 13% (8 of 60) at less than 23 weeks of gestation, and 50% (32 of 64) at 24–26 weeks of gestation. furthermore, taylor and garite reported a neonatal survival rate of 25%, and a 58.5% maternal morbidity rate.11 a study on 73 pregnant women, complicated with pprom between 16 and 26 weeks, suggested that gestational age at pprom is the main contributing factor for perinatal survival.12 this study revealed that neonatal complications and poor outcomes from pprom before 23 weeks of gestation are high. however, when the fetus is at the appropriate gestational age (24 weeks or above), the immediate perinatal survival rate was 100%. indeed, rds was noticed in 19 (79.2 %) surviving infants while 68.4% suffered from bronchopulmonary dysplasia. in the current study, the number of neonatal complications was higher compared to previous studies.12–14 the incidence of neonatal sepsis was 50% (12 of 24), which is higher than numbers reported elsewhere (2% to 19%). we can suggest that the complications and the high figures noticed in our study might be due to premature birth instead of the pprom. conclusion despite progress in medical services in oman, and especially those in obstetric and neonatal care, perinatal outcome in pregnancies with second trimester prom occurring between 16 and 26 weeks of gestation remains a difficult challenge. in our study, pprom was associated with adverse perinatal outcomes in deliveries between 16 and 26 weeks gestation. early use of antibiotics played a significant role in prolonging the latency period and minimised maternal and neonatal complications. thus, it is the physician’s responsibility to counsel the parents about the poor outcomes that may be expected in neonates after extreme pprom. however, this study was a small-scale retrospective study which had some limitations; therefore, the results should be interpretated with caution. indeed, further studies dealing with longterm neonatal morbidity, including larger sample sizes and covering more hospitals should be the focus of future studies. references 1. meis pj, ernest jm, moore ml. causes of low birth weight births in public and private patients. am j obstet gynecol 1987; 156:1165–8. 2. mercer bm, arheart kl. antimicrobial therapy in expectant management of preterm premature rupture of the membranes. lancet 1995; 346:1271–9. 3. savitz da, blackmore ca, thorp jm. epidemiologic characteristics of preterm delivery: etiologic heterogeneity. am j obstet gynecol 1991; 164:467– 71. 4. american college of obstetricians and gynecologists. prematurerupture of membranes. clinical management guidelines for obstetriciangynecologists. acog practice bulletin no. 1. int j gynaecol obstet 1998; 63:75–84. 5. bendon rw, faye-petersen o, pavlova z, qureshi f, mercer b, miodovnik m, et al. fetal membrane histology in preterm premature rupture of membranes: comparison to controls, and between antibiotic and placebo treatment. pediatr dev pathol 1999; 2:552–8. 6. stuart el, evans gs, lin ys, powers hj. reduced collagen and ascorbic acid concentrations and increased proteolytic susceptibility with prelabor fetal membrane rupture in women. biol reprod 2005; 72:230–5. 7. nourse cb, steer pa. perinatal outcome following conservative management of mid-trimester prelabor rupture of the membranes. j paediatr child health. 1997; 33:125–30. 8. taylor j, garite tj. premature rupture of membranes before fetal viability. obstet gynecol 1984; 64:615– 20. 9. moretti m, sibai bm. maternal and perinatal outcome of expectant management of premature rupture of membranes in the midtrimester. am j obstet gynecol 1988; 159:390–6. 10. beydoun sn, yasin sy. premature rupture of the membranes before 28 weeks: conservative management. am j obstet gynecol 1986; 155:471– 9. 11. taylor j, garite tj. premature rupture of membranes before fetal viability. obstet gynecol 1984; 64:615– 20. 12. yang lc, taylor dr, kaufman hh, hume r, calhoun b. maternal and fetal outcomes of spontaneous preterm premature rupture of membranes. obstet gynecol 2004; 104:537–41. perinatal outcome in pregnancies with extreme preterm premature rupture of membranes (mid-trimester prom) 56 | squ medical journal, february 2013, volume 13, issue 1 13. chapman sj, hauth jc, bottoms sf, iams jd, sibai bm, thom e, et al. benefits of maternal corticosteroid therapy in infants weighing 1000 grams at birth after preterm rupture of the amnion. am j obstet gynecol 1999; 180:677–82. 14. elimian a, verma u, beneck d, cipriano r, visintainer p, tejani n. histologic chorioamnionitis, antenatal steroids and perinatal outcomes. obstet gynecol 2000; 96:333–6. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 218-222, epub. 9th may 13 submitted 4th jun 12 revision req. 8th aug 12, revision recd. 30th aug 12 accepted 14th oct 12 departments of 1chest medicine, 2medicine, 3epidemiology & clinical research; royal hospital, muscat, oman *corresponding author e-mail: enhsa@hotmail.com التكلفة العالجية للربو يف عمان نا�رسحمد البو�شعيدي ذو الفقار حبيب اهلل . جوان �شوريانو على مبني التكلفة ح�شاب و الربو انت�شار مدى الطريقة: ال�شلطنة. يف الربو لعالج املبا�رسة التكلفة تقّيم الدرا�شة هذه الهدف: امللخ�ص: نتائج عن جمموعة من اخلرباء با�شتخدام تقنية "دلفي". هذه احل�شابات مت تتطبيقها على جمموع �شكان عمان فوق عمر خم�ض �شنوات للح�شول على عدد امل�شابني بالربو يف عمان ومن ثم اخذ العدد املح�شوب من تقنية "دلفي" و�رسبه بن�شبة املر�شى الذين ي�شتخدمون امل�شت�شفيات احلكومية وذلك لتقدير عدد مر�شى الربو العمانيني املعاجلني يف عمان. التكلفة العالجية مت ح�شابها با�شتخدام العدد الناجت من من تقنية" دلفي" و الدرا�شات ال�شابقة ملر�ض الربو يف عمان بعنوان نظره اإىل واقع الربو يف منطقة اخلليج وال�رسق الأدنى. وح�شبت بالريال العماين والدولر الأمريكي. النتائج مدى انت�شار الربو يف عمان هو %7.3 يف الكبار و%12.7 يف الأطفال و هذا ميثل 96,470 اأن الدرا�شة بينت كذلك احلكوميه. امل�شت�شفيات و ال�شحية املراكز على يرتددون %95منهم الأطفال. من الكبارو58,344 من مر�شى للعيادات 20% الطوارئ، ق�شم لزيارات 25% احلادة، الربو نوبات ب�شبب املنومني للمر�شى تعود للربو العالجية التكلفة من 55% ريال الأدوية 34,273,696 بدون الإجمالية التكلفة لالأدوية. العالجية التكلفة من من 0.2% اقل ميثل جداً �شئيل جزء و اخلارجية عماين 89,111,609( دولر اأمريكي( و27,014,735 ريال عماين 70,238,311( دولر اأمريكي( لالأطفال. و اإذا ما اأ�شفنا الأدوية امل�شتخدمة تقّدر التكلفة الإجمالية لعالج الربو يف عمان ما يزيد عن 61,500,294 ريال عماين 159,900,761( دولر اأمريكي(. اخلال�صة: بينت هذه الدرا�شة اأن التكلفة العالية لعالج الربو تعود اإىل الزيارات للطوارئ و للمر�شى املنومني ب�شبب حالت الربو احلادة مقارنه بالإنفاق الب�شيط لالأدوية، و لذا على املهتمني بهذا اجلانب النظر يف كيفية ال�شيطرة على اأعرا�ض الربو كاأولوية و لي�ض القت�شاد يف �رسف املبالغ اخلا�شة باأدوية الربو. مفتاح الكلمات: ربو؛ تكلفه الربو؛ اأدويه الربو؛ اقت�شاد؛ ا�شتخدام اخلدمات ال�شحية؛ عمان. abstract: objectives: this study evaluates the direct costs of treating asthma in oman. methods: asthma prevalence and unit cost estimates were based on results from a panel using the delphi technique, and were applied to the total omani population aged 5 and older to obtain the number of people diagnosed with asthma. the estimates from the delphi exercise were multiplied by the percentage of patients using government facilities to estimate the number of asthma patients managed in oman. treatment costs were also calculated using data from the delphi exercise and the asthma insights and reality for the gulf and near east study (reported in omani riyals [omr] and us dollars [usd]). results: the prevalence of asthma was estimated to be 7.3% of adults (n = 96,470) and 12.7% of children (n = 58,344). of these, 95% of both adults and children were estimated to be using government healthcare facilities. inpatient visits accounted for the largest proportion of total direct costs (55%), followed by emergency room and outpatient visits (25% and 20%, respectively) and medications (<0.2%). the annual cost of treatment excluding medications, was omr 34,273,696 (usd 89,111,609) for adults and omr 27,014,735 (usd 70,238,311) for children. including medications, the total annual direct cost of asthma treatment was estimated to be over omr 61,500,294 (usd 159,900,761). conclusion: given the high medical expenditures associated with facility visits relative to the lower medication costs, the focus of oman’s asthma cost savings should be on improving asthma control rather than reducing medication costs. keywords: asthma; cost of asthma; asthma medications; economy; health service utilization; oman. the asthma cost in oman *nasser h. al-busaidi,1 zulfikar habibullah,2 joan b. soriano3 clinical & basic research advances in knowledge this is the first study to address the cost of asthma in oman. this study presents comprehensive omani medical data. applications to patient care proper outpatient management will reduce the cost of inpatient and emergency visits. adequate management of asthma with proper medications will reduce the number of exacerbations and subsequent emergency room and inpatient visits. nasser h. al-busaidi, zulfikar habibullah and joan b. soriano clinical and basic research | 219 the world health organization (who) estimates that 300 million people suffer from asthma worldwide; it is the most common chronic illness among children, and one of the most frequent in adults.1 in the phase iii international study of asthma and allergies in children (isaac), 13.8% of school children aged 13–14 years worldwide reported that they had had asthma at some time in their lives, although with large regional variability.2 given the prevalence of the disease and its symptoms, asthma imposes a considerable economic burden on healthcare systems. one study found that the annual direct medical expenditure for asthma treatment in the usa in 2007 was us dollars (usd) 37.2 billion.3 in europe, the annual direct cost of asthma is estimated to be euros (eur) 7.9 billion.4 furthermore, another study in the usa found that the total incremental cost of asthma to society, also including indirect costs, was usd 56 billion in 2007.5 estimation of national expenditure for asthma treatment can provide useful information to guide clinicians and policymakers in improving the management of asthma through better treatment. to our knowledge, medical literature is lacking in studies that estimate the costs of asthma treatment in oman, although bazdawi et al. reported the prevalence rates of reported diagnoses of asthma in older children (13–14 years old) at 20.7%, and at 10.5% in younger children in oman (6–7 years old).6 al rawas and colleagues reported that asthma prevalence was increasing. the geographic variation in the prevalence of self-reported of asthma symptoms among omani school children still persisted with further increase in the sharqiya region. the findings also suggest under-diagnosis and/or poor recognition of asthma, which had not improved over time.7 the current study aims to evaluate the direct costs of treating asthma in oman, specifically focusing on omani nationals treated in government healthcare facilities in oman. these include costs of outpatient treatment, hospital emergency visits, inpatient treatment, medicines, and total direct costs of treatment for asthma. methods population figures were obtained from the 2009 census data from the omani ministry of economy.8 drug usage and costs were provided by the ministry of healths (moh) purchasing department.9 typical treatment profiles, including emergency visits, outpatient visits, inpatient stays, and pharmacological treatment use were obtained from the asthma insights and reality for the gulf and near east (airgne) study.10 due to a lack of published data on asthma prevalence and unit costs of asthma treatment, a modified delphi technique was used to gather consensus estimates of this data. one of the main advantages of using the delphi technique rather than a face-to-face group panel approach is its ability to obtain expert knowledge from each participant without the influence of others involved in the study.11–13 the delphi panel methodology consisted of consensus consultations with 10 leading physicians in asthma treatment in oman. two rounds of data collection from the panel were conducted to determine these estimates. currently available data on asthma prevalence and unit costs of asthma treatment were provided to each of the panel members. treatment costs included outpatient and emergency room (er) visits, and inpatient costs for both adults and children. each panel member provided their own expert estimates individually, including upper and lower estimates, in addition to a “best” estimate. an average of the combined estimates from the panel members in round one was calculated for each data input, and then used in round two. during round two, the panellists were given these mean values to consider, and were given the opportunity to revise their round one estimates where they thought it was appropriate. the revised estimates for prevalence and costs (for both adults and children) generated in this second round were used in the main calculations of the current study. costs are reported in omani riyals (omr) and usd, using the 2010 exchange rate of 1 omr = 2.60010 usd. the asthma prevalence determined in round two of the delphi exercise was applied to the total omani population aged 5 and over to obtain the percentage of individuals (both adults and children) diagnosed with asthma in oman. individuals aged 5 to 15 were categorised as children, and those aged 16 or older were categorised as adults. estimates from round two were then multiplied by the percentage of patients using government facilities the asthma cost in oman 220 | squ medical journal, may 2013, volume 13, issue 2 as reported in the airgne study to determine the total number of asthma patients managed in government healthcare facilities.10 to obtain an estimation of total outpatient treatment costs, the total number of asthma patients treated in government healthcare facilities was multiplied by the average number of outpatient visits per year as reported in the airgne study to determine the total number of outpatient visits per year which was then multiplied by the unit cost of an outpatient visit as determined in round two of the delphi panel exercise.10 figures were estimated for both adults and children. to obtain an estimation of the number of emergency room (er) visits and total inpatient treatment costs, the percentage of asthma sufferers visiting an er as reported in the airgne study was multiplied by the total number of asthma patients treated in government healthcare facilities. the result was then multiplied by the average number of er visits per year as reported in the airgne study and the asthma control in oman study to obtain the total number of er visits per year.12,14 the unit cost of an er visit as determined in round two of the delphi exercise was used to obtain the total cost of er visits. costs were estimated for both adults and children. the total inpatient treatment cost estimate was calculated in a similar manner using estimates from round two of the delphi exercise. to obtain an estimation of total direct treatment cost, the total direct costs for adults and children were estimated to be the sum of costs for outpatient and inpatient care, er visits, and the costs of asthma medications. all data were obtained from the moh purchasing department. a sensitivity analysis, according to the results from the delphi panel, was conducted based on the lowest 50% of the values collected in round one. results the best estimates of asthma prevalence in oman obtained from the delphi panel were 7.3% of adults and 12.7% of children, which corresponded to a total of 91,646 adults and 55,426 children, respectively. table 1: statistics on omani nationals suffering from asthma and using ministry of health facilities adults (16+) children (5+) population 2009 1,321,501 459,398 asthma prevalence 7.3% 12.7% subtotal number of asthma sufferers 96,470 58,344 percentage using government facilities 95% 95% total asthma sufferers using government facilities 91,646 55,426 table 2: calculations leading to total cost of inpatient treatments of asthma for omani nationals in omani riyals adults (16+) children (5+) total asthma sufferers using moh facilities 91,646 55,426 percentage hospitalised in past year 27% 42% number of sufferers hospitalised 24,744 23,279 number of hospital stays per patient 4.2 2.4 average nights hospitalised per patient per year 2.6 3.9 total hospital nights per year 270,209 217,892 cost of an overnight stay in omr 67 73 cost of inpatient visits in omr 18,104,026 15,906,126 moh = ministry of health; omr = omani riyals. table 3: calculations leading to the total cost of emergency room visits by omani nationals due to asthma in omani riyals adults (16+) children (5+) total number of asthma sufferers using moh 91,646 55,426 percentage making an emergency visit in past year 58% 55% total number of sufferers making er visits 53,155 30,485 average number of visits per patient per year 3.8 6.3 total number of visits per year 201,988 192,052 unit cost of an emergency visit 39 39 total cost of emergency visits in omr 7,877,532 7,490,042 moh = ministry of health; er = emergency room; omr = omani riyals. nasser h. al-busaidi, zulfikar habibullah and joan b. soriano clinical and basic research | 221 of these, 95% adults and the percentage of children were estimated to be using government healthcare facilities [table 1]. inpatient visits accounted for the largest portion of total direct costs for asthma treatment. the total number of nights that adult asthma patients spent in hospital per year was estimated to be 270,209, incurring a total cost of omr 18,104,026. the corresponding numbers for children were estimated to be 217,892 nights, at a total cost of omr 15,906,126 [table 2]. the second largest component of total direct costs was the cost of er visits at 25%. the total estimated number of er visits per year for adults with asthma was 53,155 at a total cost of omr 7,877,532. for children, the total number of er visits per year was 30,485 at a total cost of omr 7,490,042 [table 3]. there were 318,928 outpatient visits per year estimated for adults with asthma and 139,176 for children. the total cost of outpatient visits for adults was omr 8,292,139 and for children, omr 3,618,566, making up 20% of the total cost of asthma treatment [table 4]. the overall cost of asthma treatment is shown in table 5. the subtotal (before including the cost of medicines) for treatment visits for adults and children was omr 61,288,431. added together with the cost of medicine, the total direct cost of asthma treatment was over omr 61 million (omr 418 per patient). although the costs changed when using the lowest 50% of the values collected in round one of the delphi exercise, the inpatient and er treatment costs still made up the largest portion of the total direct costs, while the cost of medications was substantially smaller. discussion to our knowledge, the present study is the first to evaluate the cost burden of asthma in oman. we found that asthma treatment causes a substantial financial burden on the healthcare system with results showing that the direct cost of asthma treatment is estimated to be omr 61,500,293/ usd 159,900,762. this cost was primarily driven by inpatient stays and er visits, which made up approximately 80% of direct costs. compared to these costs, the cost of medications is minimal, less than 1% of the total direct costs. it should be noted that these estimates comprise only the costs incurred by omani nationals in government healthcare facilities, and do not include the private sector or the treatment of expatriates, the majority of whom are followed up in the private sector. this high proportion of costs is further emphasised when noting that the number of er visits and hospitalisations for asthma patients in oman are considerably higher than in europe. the airgne study reported that 21% of adults and children with asthma in oman reported visiting an er in the year preceding the study.14 in contrast, only 10% of asthma sufferers in europe reported table 4: calculations leading to the total cost of outpatient visits by omani nationals (omani riyals) adults (16+) children (5+) total number of asthma sufferers using moh 91,646 55,426 percentage needing outpatient treatment in a year 87% 81% asthma sufferers who are moh patients 79,732 44,895 outpatient visits per patient per year (airgne) 4.0 3.1 total number of outpatient visits per year 318,928 139,176 unit cost of an outpatient visit 26 26 total cost of outpatient visits 8,292,139 3,618,566 moh = ministry of health; airgne = asthma insights and reality for the gulf and near east. table 5: calculations leading to an estimate of the total direct cost of asthma treatment in oman (in omani riyals [omr]). total treatment costs adults (16+) children (5+) totals cost of outpatient visits 8,292,139 3,618,566 11,910,705 cost of emergency visits 7,877,532 7,490,042 15,367,574 cost of inpatient stays 18,104,026 15,906,126 34,010,152 total non-drug cost 34,273,696 27,014,735 61,288,431 cost of medicines 211,862 total direct cost of treatment 61,500,293 the asthma cost in oman 222 | squ medical journal, may 2013, volume 13, issue 2 visiting an er in the year preceding the study, as reported in the asthma insights and reality in europe (aire) study.14 in addition, the aire study reported that only 7% of sufferers required overnight hospitalisation in europe during the previous 12 months compared to 30% in oman as reported in the airgne study.15 inpatient stays and er visits are both correlated with a lower level of asthma control, leading to a potentially larger cost burden to the moh. in contrast to the distribution of costs in europe, of the eur 7.9 billion in annual direct costs 48% (eur 3.8 billion) was for outpatient care, 46% (eur 3.6 billion) was for drug costs and 6% (eur 0.5 billion) for inpatient care.4 in the usa, it was reported that prescription medications and physician office visits accounted for the largest share of total expenditures and comprised approximately 38% of the total incremental expenditures for asthma in children and approximately 49% among adults.5 comparatively, the higher proportion of expenditures on outpatient visits, inpatient stays, and er visits for asthma in oman could reflect a different level of disease control to that of asthma patients in the usa and europe. the strengths of this study include its novelty and the overall comprehensiveness of national omani data. however, there are some limitations to our research. asthma prevalence and unit cost estimates were based on results from an expert panel using the delphi technique. although the use of two rounds enhanced the reliability of the estimates, the results are still dependent on the individual opinions of the panel members which may result in the subjective estimation of costs and prevalence. conclusion the best method of controlling asthma is the regular use of controller medication and the education of patients, family, caregivers, school personnel, and so on. given the high medical expenditures associated with er and inpatient visits, and the relatively lower expenditure on medications in oman, it is reasonable to expect that improving levels of asthma control would correspond to a positive impact on total moh expenditure, even if this expenditure increases over time. cost-saving efforts should therefore be focused on improving asthma control rather than on reducing expenditures on medication procurement. references 1. bousquet j, kiley j, bateman ed, viegi g, cruz aa, khaltaev n, et al. prioritised research agenda for prevention and control of chronic respiratory diseases. eur respir j 2010; 36:995–1001. 2. pearce n, aït-khaled n, beasley r, mallol j, keil u, mitchell e, et al. the isaac phase three study group. worldwide trends in the prevalence of asthma symptoms: phase iii of the international study of asthma and allergies in childhood (isaac). thorax 2007; 62:758–66. 3. kamble s, bharmal m. incremental direct expenditure of treating asthma in the united states. j asthma 2009; 46:73–80. 4. european lung foundation. european lung white book. european respiratory society: geneva, 2003. 5. barnett sb, nurmagambetov ta. costs of asthma in the united states: 2002-2007. j allergy clin immunol 2011; 127:145–52. 6. al-riyami bm, alrawas oa, al-riyami a, jasim lg, mohammed aj. relatively high prevalence and severity of asthma, allergic rhinitis, and atopic eczema in school children in sultanate of oman. respirology 2003; 8:69–76. 7. al-rawas oa, al-riyami bm, al-kindy h, almaniri aa, al-riyami aa. regional variation in the prevalence of asthma symptoms among omani school children: comparisons from two nationwide cross-sectional surveys six years apart. sultan qaboos university med j 2008; 8:157–64. 8. directorate general, oman ministry of economy. omani population census 2009. muscat: ministry of economy, 2009. 9. purchasing department, directorate general of pharmaceutical affairs, ministry of health, oman. drug costs 2009. muscat: ministry of health, 2009. 10. khadadah m, mahboub b, al-busaidi nh, sliman n, soriano jb, bahous j. asthma insights and reality in the gulf and the near east. int j tuberc lung dis 2009; 13:1015–22. 11 rosengart mr, nathens ab, schiff ma. the identification of criteria to evaluate prehospital trauma care using the delphi technique. j trauma 2007; 62:708–13. 12. bramwell l, hykawy e. the delphi technique: a possible tool for predicting future events in nursing education. nurs pap 1974; 6:23–32. 13. kumaran km, lemieux m, satchell g. problem solving with the delphi technique. dimens health serv 1976; 53:34–5. 14. al busaidi n, soriano jb. asthma control in oman: nasser h. al-busaidi, zulfikar habibullah and joan b. soriano clinical and basic research | 223 national results within the asthma insights and reality in the gulf and the near east (airgne) study. sultan qaboos univ med j 2011; 11:45–51. 15. rabe kf, vermeire pa, soriano jb, maier wc. clinical management of asthma in 1999: the asthma insights and reality in europe (aire) study. eur respir j 2000; 16:802–7. pattern of viral infections among infants and children admitted to the paediatric intensive care unit at sultan qaboos university hospital, oman e546 | squ medical journal, november 2014, volume 14, issue 4 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e546−550, epub. 14th oct 14 submitted 2nd feb 14 revisions req. 19th mar & 12th may 14; revisions recd. 16th apr & 4th jun 14 accepted 19th jun 14 departments of 1child health and 2medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: anasalwogud@yahoo.com أمناط العدوى الفريوسية بني الرضع واألطفال املنومني يف وحدة العناية املركزة لألطفال يف مستشفى جامعة السلطان قابوس، سلطنة عمان اأن�س الوجود احمدعبد املغيث، ال�ضي حممد احمد الناير، عبد اهلل باخلري، اكرم حممد حممود، حممد عاطف النجاري abstract: objectives: the aim of this study was to describe the pattern of viral infections in infants and children admitted to the paediatric intensive care unit (picu) at sultan qaboos university hospital (squh) in muscat, oman. methods: a retrospective review of patient records was carried out on all patients admitted to the picu between january 2011 and december 2012. in order to detect viruses, polymerase chain reaction (pcr) technology was used to detect viruses in nasopharyngeal aspirates, tracheal aspirates, plasma, stool and urine samples. all infants and children below 13 years old, who were admitted to the picu at squh during the study period and with confirmed viral infections, were included in the study. results: a total of 373 infants and children were admitted to the picu during the study period. viruses were detected in 34 patients. the most frequently detected viruses were cytomegalovirus (cmv) in 29.4%; this virus was noted predominantly in immuncompromised patients (80%, p = 0.023) and was associated with increased mortality (50%, p = 0.031) and prolonged picu stay (70%, p = 0.045). fatalities before discharge were recorded in 23.5% of the patients. the most frequent risk factors for viral infections were an age of <12 months old (47.1%), assisted ventilation/intubation (52.9%) and a prolonged picu stay (55.9%). conclusion: the results of this study found that cmv was the most common viral infection among infants and children admitted to the picu in squh. cmv was also the leading cause of mortality. keywords: viral diseases; viruses; cytomegalovirus; respiratory syncytial viruses; infants; children; oman. املركزة العناية وحدة يف املنومني والأطفال الر�ضع لدى الفريو�ضية اللتهابات اأمناط و�ضف ايل الدرا�ضة هذه هدفت امللخ�ص: الهدف: لالطفال يف م�ضت�ضفى جامعة ال�ضلطان قابو�س مب�ضقط، �ضلطنة عمان. الطريقة: مت ادراج جميع املر�ضى الذين مت تنوميهم يف وحدة العناية البلعوم، من عينات يف الفريو�ضات عن للك�ضف البلمرة تفاعل �ضل�ضلة ا�ضتخدم مت .2012 ودي�ضمرب 2011 يناير بني لالطفال املركزة الق�ضبة الهوائية، البالزما، الرباز والبول. وقد مت إدراج جميع الر�ضع والأطفال اأقل من عمر 13 �ضنة والذين مت تنوميهم فى وحدة العناية املركزة مب�ضت�ضفي جامعة ال�ضلطان قابو�س خالل فرتة الدرا�ضة والذين ثبت وجود االتهابات فريو�ضية لديهم. النتائج: مت قبول عدد 373 مري�ضا من بينهم. كان طفل يف وحدة العناية املركزة لالأطفال خالل فرتة الدرا�ضة. وقد مت الك�ضف عن وجود التهاب فريو�ضي يف 34 الفريو�س امل�ضخم للخاليا هو الكرت �ضيوعاآ )%29.4(؛ وقد لوحظ وجود هذا الفريو�س ب�ضورة اأكرب يف املر�ضى ذوي املناعة املنخف�ضة )p = 0.023 ،80%( وكان وجودة مرتبطا مع زيادة معدل الوفيات )p = 0.031 ،50%( والإقامة لفرتات طويلة يف العناية املركزة )p = 0.045 ،70%(. و�ضجلت حالت الوفاة قبل اخلروج من الوحدة يف %23.5 من املر�ضى. لوحظ ان �ضغر ال�ضن يف الأطفال القل من 12 �ضهراآ هو اكرث العوامل ارتباطا بالعدوى الفريو�ضية )%47.1(، و الحتياج للتنف�س ال�ضطناعي )%52.9( والإقامة لفرتات طويلة يف العناية املركزة )%55.9(. اخلال�صة: اثبتت نتائج هذه الدرا�ضة اأن الفريو�س امل�ضخم للخاليا هو الأكرث �ضيوعا بني الر�ضع والأطفال املنومني يف العناية املركزة يف م�ضت�ضفى جامعة ال�ضلطان قابو�س وهو ميثل ال�ضبب الرئي�ضي للوفيات. مفتاح الكلمات: الأمرا�س الفريو�ضية؛ الفريو�ضات؛ الفريو�س امل�ضخم للخاليا؛ فريو�س اجلهاز التنف�ضي املخلوي؛ الر�ضع؛ الأطفال؛ عمان. pattern of viral infections among infants and children admitted to the paediatric intensive care unit at sultan qaboos university hospital, oman *anas-alwogud a. abdelmogheth,1 alddai m. a. al-nair,1 abdullah a. s. balkhair,2 akram m. mahmoud,1 mohamed el-naggari1 online brief communication viral infections are common among children and most cases are categorised as mild infections. however, some cases require hospital admission in intensive care or high dependency units. viral infections may be among the underlying causes for the high rates of morbidity among hospitalised children, especially in paediatric intensive care units (picus).1 nosocomial respiratory and systemic viral infections cause significant morbidity and mortality, particularly among hospitalised children with underlying cardiorespiratory diseases or immunodeficiencies.2,3 infections acquired in intensive care units (icus) account for high morbidity and mortality rates and cause considerable expense. infection and sepsis are the leading causes of death in non-cardiac icus and account for 40% of all icu expenditures.4 anas-alwogud a. abdelmogheth, alddai m. a. al-nair, abdullah a. s. balkhair, akram m. mahmoud and mohamed el-naggari online brief communication | e547 cytomegalovirus (cmv) infections have been shown to lead to significant disease in immunocompromised hosts.5,6 research has shown that critically ill patients, traditionally considered to be immunocompetent, may also be at risk of contracting cmv.5 septic insult as a result of bacterial or fungal infections has the potential to promote the release of immunomodulatory cytokines and lead to the reactivation of cmv.5,7–9 additionally, respiratory syncytial virus (rsv) infections are the leading cause of lower respiratory tract infections such as bronchiolitis and bronchopneumonia.10 rsv infections lead to the intermediate or intensive care admission of approximately 1–2% of each annual birth cohort in switzerland.11 understanding the pattern of viral infections is important as this knowledge will help improve infection control practices and limit the spread of disease within picus. the objective of this study was to characterise the pattern and risk factors of viral infections among infants and children admitted to the picu in sultan qaboos university hospital (squh), muscat, oman. methods patient records from the picu at squh were retrospectively reviewed to identify infants and children with viral infections admitted to the picu between january 2011 and december 2012. all patients below 13 years old who were admitted to the picu during the study period and who had confirmed viral infections were included in the study. these included immunodeficient patients (both primary and secondary immunodeficiencies), patients on steroids and haematological cases. patients with viruses that were not isolated and subjects known to have viral infections before admission were excluded from the study. data extracted from the records included demographic characteristics; clinical diagnosis; number and types of virus isolated; duration of assisted ventilation; duration of stay in the picu, and patient outcome. a stay of less than seven days was considered to be a short stay.12 viruses were isolated from nasopharyngeal aspirate (npa), tracheal aspirate (ta), plasma, stool or urine. viral studies were not taken routinely and were undertaken only on a clinical basis in patients suspected of viral infections. for the purpose of this study, the viruses were grouped into two major categories: respiratory viruses and systemic viruses. some patients underwent a respiratory virus panel while others underwent a systemic viral panel. respiratory system samples (npa and ta) were collected in disposable mucus extractors (vygon sa, écouen, france) and systemic samples (blood, urine and stool) were collected in plain containers. samples were processed by polymerase chain reaction (pcr) for viral detection using three kits (fast-track diagnostics ltd., sliema, malta). the pcr ftd® viral gastroenteritis kit was used to detect norovirus g1, norovirus g2, astrovirus, rotavirus, adenovirus and sapovirus. the ftd® ace kit was used to detect cmv, epstein-barr virus (ebv) and adenovirus. the ftd® respiratory pathogens 21 kit was used to detect influenza a; h1n1; influenza b; rhinovirus; coronaviruses nl63, 229e, hku1 and oc43; parainfluenza viruses 1, 2, 3 and 4; human metapneumoviruses a and b; rsv a and b; adenovirus; enterovirus; parechovirus; human bocavirus, and mycoplasma pneumoniae. data were analysed using the statistical package for social sciences (spss), version 19 (ibm corp., chicago, illinois, usa). fisher’s exact test was used to test the significance of the results at the 5% level. as this study was retrospective, it did not require ethical approval. results there were 373 infants and children admitted to the picu between january 2011 and december 2012. of these, a total of 34 (9.12%) were found to have confirmed viral infections. viral infections were identified among 47.1% of the infants below 12 months old. the most frequently isolated virus was cmv (n = 10; 29.4%) followed by rsv (n = 7; 23.3%), rotavirus (n = 7; 23.3%) and ebv (n = 6; 20.0%). the least frequently isolated viruses were the influenza b virus (n = 2; 5.9%), astrovirus (n = 2; 5.9%), rubella virus (n = 2; 5.9%), influenza a virus (n = 1; 2.9%) and norovirus (n = 1; 2.9%). dual or multiple co-infections were found in five cases (14.7%). respiratory viruses were identified in 29.4% of the cases. the most common was rsv, either in isolation (14.7%) or as a co-infection (5.9%) with cmv. ebv and cmv were also commonly identified as co-infections. other viruses, such as the influenza viruses and the rubella virus, were mostly detected as single infections. table 1 depicts the demographic characteristics and clinical parameters of infants and children with viral infections. the age of the patients ranged from two months to 13 years old with a mean of 2.6 ± 3.2 years. there were more males (61.8%) than females with a male to female ratio of 1.6:1. a substantial pattern of viral infections among infants and children admitted to the paediatric intensive care unit at sultan qaboos university hospital, oman e548 | squ medical journal, november 2014, volume 14, issue 4 proportion of the patients were immunocompromised (n = 16; 47.1%). more than half of the cases (n = 18; 52.9%) required assisted ventilation. a total of 12 patients (66.7%) required intubation for more than seven days with a mean duration of 10.5 ± 10.5 days. antiviral therapy was prescribed for 10 patients (29.4%). over half of the patients (n = 19; 55.9%) stayed in the picu for more than seven days with a mean duration of 10.6 ± 11.9 days. there were eight fatalities before discharge (23.5%). over the study period, the overall mortality rate in the picu was 2.97%. a high percentage of cmv cases (n = 8; 80.0%) were immunocompromised (p = 0.023). cmv infection was also significantly associated with a long stay in the picu (70%, p = 0.045) and mortality at discharge (50%, p = 0.031). out of the seven cases of rsv, four (57.1%) had a long picu stay and the majority (n = 6; 85.7%) were alive upon discharge [table 2]. table 1: demographic and clinical characteristics of paediatric intensive care unit-admitted infants and children with viral infections (n = 34) characteristics n % gender male 21 61.8 female 13 38.2 age <12 months 16 47.1 12 months – <5 years 12 35.3 ≥5 years 6 17.6 immunocompromised yes 16 47.1 no 18 52.9 intubated yes 18 52.9 no 16 47.1 duration of intubation <7 days 6 33.3 ≥7 days 12 66.7 duration of stay short stay (<7 days) 15 44.1 long stay (≥7 days) 19 55.9 number of viruses isolated 1 29 85.3 2 5 14.7 type of virus isolated respiratory 10 29.4 systemic 24 70.6 virus isolated* cmv 10 29.4 rsv 7 23.3 rotavirus 7 23.3 ebv 6 20 other** 8 23.5 management/antivirus therapy yes 10 29.4 no 24 70.6 outcome discharged alive 26 76.5 fatality 8 23.5 cmv = cytomegalovirus; rsv = respiratory syncytial virus; ebv = epstein-barr virus. *categories are not mutually exclusive. **influenza b virus (2, 5.9%), astrovirus (n = 2; 5.9%), rubella virus (n = 2; 5.9%), influenza a virus (n = 1; 2.9%) and norovirus (n = 1; 2.9%). table 2: clinical characteristics of paediatric intensive care unit-admitted infants and children with the four most frequently detected viral infections characteristics type of virus* n (%) rotavirus (n = 7) cmv (n = 10) ebv (n = 6) rsv (n = 7) immunocompromised yes 3 (42.9) 8 (80.0) 5 (83.3) 1 (14.3) no 4 (57.1) 2 (20.0) 1 (16.7) 6 (85.7) p value† 1.000 0.023 0.078 0.090 duration of stay <7 days 4 (57.1) 3 (30.0) 3 (50.0) 3 (42.9) ≥7 days 3 (42.9) 7 (70.0) 3 (50.0) 4 (57.1) p value† 0.067 0.045 1.000 1.000 type of virus isolated respiratory 0 (0.0) 1 (10.0) 1 (16.7) 7 (100.0) systemic 7 (100.0) 9 (90.0) 5 (83.3) 0 (0.0) p value† 0.078 0.215 0.644 0.000 outcome discharged alive 7 (100.0) 5 (50.0) 3 (50.0) 6 (85.7) fatality 0 (0.0) 5 (50.0) 3 (50.0) 1 (14.3) p value† 0.160 0.031 0.126 1.000 cmv = cytomegalovirus; ebv = epstein-barr virus; rsv = respiratory syncytial virus. *tests of significance were performed against other cases where the virus was not isolated. †p values were computed using fisher’s exact test. anas-alwogud a. abdelmogheth, alddai m. a. al-nair, abdullah a. s. balkhair, akram m. mahmoud and mohamed el-naggari online brief communication | e549 discussion the current study aimed to characterise the pattern of viral infections among infants and children admitted to the picu in squh over a two-year period. viral infections were identified among 9.12% of all admissions. it is unclear if the patients with isolated viruses were asymptomatic carriers. the most commonly isolated virus was cmv (29.4%), followed by rsv, rotavirus and ebv. this is comparable to the findings of ziemann et al. who observed cmv infections in 36% of the critically ill adult patients studied.9 risk factors for cmv infections in the current study included immunosuppression, mechanical ventilation and prolonged picu stay. however, systemic viral infections in cases requiring prolonged intubation may lead to ventilationassociated pneumonia, resulting in increased morbidity and mortality among these patients. cmv infection was also associated with increased mortality. these results were higher than those observed in a study by limaye et al., in which cmv infections were recorded in 35% of patients with a mortality rate of 28.6%.13 respiratory viruses were identified in 29.4% of the cases and the most commonly isolated virus was rsv, either alone or as a co-infection. similar results were found in previous studies which observed rates of infections between 11–15%.14,15 these rates are higher in comparison to a study by leung et al. which identified rsv in 117 rsv-associated picu admissions (2.4%).16 this low percentage may be attributable to the fact that the majority of rsv-infected children do not require picu support.16 a study performed in kenya by berkley et al. found a higher percentage of respiratory viruses in comparison to the current study. respiratory viruses were detected in 56% of participants, with rsv representing 34% of cases and other viruses showing similar percentages.17 the current study found co-infections in 14.7% of patients, which is similar to another local study in oman by khamis et al. which found dual or multiple infections in 18% of patients.18 of these, rsv infections were found in 22% of patients,18 which is again comparable to the results found in this study (23.3%). these high rates can be explained by the effect of winter seasonality on rsv-associated picu admissions. the deaths recorded as outcomes among eight patients were not attributable to a single factor; however viral infection was associated with increased mortality. this study has several limitations. as the data was collected retrospectively, there were some missing data and it was not possible to differentiate between nosocomial and community-acquired viral infections. future prospective studies are recommended to identify how many days post-admission viruses are isolated in order to determine if they are hospitalor community-acquired. additionally, specimens were not taken in a standardised manner among all children admitted to the picu. furthermore, the lack of a control group limits the interpretation of the results as it is not possible to establish the prevalence or generalise the results to the entire population of oman. future studies should investigate how many patients are negative for viral infections so as to determine the prevalence. by determining the baseline prevalence, improvements in infection control can be assessed. conclusion cmv was the most common virus among infants and children admitted to the picu in squh, followed by rsv, rotavirus and ebv. cmv infections were associated with increased mortality and prolonged picu stay. the most frequent risk factors for viral infection included an age of <12 months old, immune deficiencies and a prolonged picu stay. this is the first study in oman to focus on this emerging topic. more detailed studies are recommended to determine the prevalence of viral infections in oman. references 1. lichenstein r, king jc jr, lovchik j, keane v. respiratory viral infections in hospitalized children: implications for infection control. south med j 2002; 95:1022–5. 2. moler fw, khan as, meliones jn, custer jr, palmisano j, shope tc. respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. crit care med 1992; 20:1406–13. 3. hall cb, powell kr, macdonald ne, gala cl, menegus me, suffin sc, et al. respiratory syncytial viral infection with compromised immune function. n engl j med 1986; 315:77– 81. doi: 10.1056/nejm198607103150201. 4. vincent jl, rello j, marshall j, silva e, anzueto a, martin cd, et al. international study of the prevalence and outcomes of infection in intensive care units. jama 2009; 302:2323–9. doi: 10.1001/jama.2009.1754. 5. osawa r, singh n. cytomegalovirus infection in critically ill patients: a systematic review. crit care 2009; 13:r68. doi: 10.1186/cc7875. 6. kuppermann bd, petty jg, richman dd, mathews wc, fullerton sc, rickman ls, et al. correlation between cd4+ counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus-related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. am j ophthalmol 1993; 115:575–82. doi: 10.1097/00006982-199313030-00015. 7. döcke wd, prösch s, fietze e, kimel v, zuckermann h, klug c, et al. cytomegalovirus reactivation and tumour necrosis factor. lancet 1994; 343:268–9. doi: 10.1016/s0140-6736(94)91116-9. pattern of viral infections among infants and children admitted to the paediatric intensive care unit at sultan qaboos university hospital, oman e550 | squ medical journal, november 2014, volume 14, issue 4 8. kutza as, muhl e, hackstein h, kirchner h, bein g. high incidence of active cytomegalovirus infection among septic patients. clin infect dis 1998; 26:1076–82. doi: 10.1086/520307. 9. ziemann m, sedemund-adib b, reiland p, schmucker p, hennig h. increased mortality in long-term intensive care patients with active cytomegalovirus infection. crit care med 2008; 36:3145–50. doi: 10.1097/ccm.0b013e31818f3fc4. 10. nair h, nokes dj, gessner bd, dherani m, madhi sa, singleton rj, et al. global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. lancet 2010; 375:1545– 55. doi:10.1016/s0140-6736(11)61051-9. 11. berger tm, aebi c, duppenthaler a, stocker m; swiss pediatric surveillance unit. prospective population-based study of rsvrelated intermediate care and intensive care unit admissions in switzerland over a 4-year period (2001–2005). infection 2009; 37:109–16. doi: 10.1007/s15010-008-8130-z. 12. australian and new zealand intensive care society. anzpic registry. from: www.anzics.com.au/anzpicr accessed: jun 2014. 13. limaye ap, kirby ka, rubenfeld gd, leisenring wm, bulger em, neff mj, et al. cytomegalovirus reactivation in critically ill immunocompetent patients. jama 2008; 300:413–22. doi: 10.1001/jama.300.4.413. 14. chan pw, abdel-latif me. cost of hospitalization for respiratory syncytial virus chest infection and implications for passive immunization strategies in a developing nation. acta paediatr 2003; 92:481–5. doi: 10.1111/j.1651-2227.2003. tb00582.x. 15. ong mp, sam ic, azwa h, mohd zakaria ie, kamarulzaman a, wong mh, et al. high direct healthcare costs of patients hospitalised with pandemic (h1n1) 2009 influenza in malaysia. j infect 2010; 61:440–442. doi: 10.1016/j.jinf.2010.08.001. 16. leung tf, lam ds, miu ty, hon kl, chau cs, ku sw, et al. epidemiology and risk factors for severe respiratory syncytial virus infections requiring pediatric intensive care admission in hong kong children. infection 2014; 42:343–50. doi: 10.1007/ s15010-013-0557-1. 17. berkley ja, munywoki p, ngama m, kazungu s, abwao j, bett a, et al. viral etiology of severe pneumonia among kenyan infants and children. jama 2010; 303:2051–7. doi: 10.1001/ jama.2010.675. 18. khamis fa, al-kobaisi mf, al-areimi ws, al-kindi h, alzakwani i. epidemiology of respiratory virus infections among infants and young children admitted to hospital in oman. j med virol 2012; 84:1323–9. doi: 10.1002/jmv.23330. 1oral & maxillofacial surgery residency programme, oman medical specialty board, muscat, oman; 2department of oral health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: sunny6435@yahoo.com التهاب عظم الفك والنقي كمضاعفة ملرض فقر الدم املنجلي يف ثالثة مرضى عمانيني تقرير حاالت ومراجعه لألدبيات الطبية هالل االإ�ضماعيلي, عمر ن�ضيم, عبدالعزيز باكثري abstract: sickle cell anaemia (sca) is a common haemoglobinopathy among people from the middle east, the afro-caribbean region, the mediterranean and east india. while osteomyelitis of the long bones is a welldocumented complication of sca, there are few documented cases of sca patients presenting with jaw osteomyelitis. we report three sca patients with chronic jaw osteomyelitis who presented to the department of oral health, sultan qaboos university hospital, muscat, oman, between 2009 and 2013. two of the patients had osteomyelitis of the mandible and the third had osteomyelitis of the maxilla. in addition, a brief review of the literature is presented focusing on the clinical presentation, diagnosis and management of jaw osteomyelitis among patients with sca. keywords: sickle cell anemia; osteomyelitis; jaw; mandible; maxilla; case report; oman. امللخ�ص: يعترب فقر الدم املنجلي من اأمرا�ص اإعتالل الدم الهيم�غل�بيني املنت�رسة يف منطقة ال�رسق االأو�ضط ومنطقة الكاريبي وح��ص البحر االأبي�ص املت��ضط و�رسق الهند. يف حني يعترب التهاب العظام الط�يلة والنقي من امل�ضاعفات امل�ثقة يف مر�ضى فقر الدم املنجلي, حاالت ثالثة تقارير هنا نعر�ص والنقي. الفك عظم بالتهاب امل�ضابني املنجلي الدم فقر ملر�ضى امل�ثقة احلاالت من قليل عدد ي�جد ملر�ضى فقر الدم املنجلي م�ضابني بالتهاب عظم الفك والنقي املزمن والذين تقدم�ا للعالج يف ق�ضم �ضحة الفم مب�ضت�ضفى جامعة ال�ضلطان قاب��ص, م�ضقط, عمان بني عامي 2009 و 2013. اإثنان من املر�ضى كان لديهم التهاب عظم الفك والنقي ال�ضفلي, والثالث كان لديه التهاب عظم الفك العل�ي. اإ�ضافة اإىل ذلك, نعر�ص مراجعة م�جزة لالأدبيات الطبية مع الرتكيز على العر�ص ال�رسيري والت�ضخي�ص وعالج حاالت التهاب عظم الفك والنقي يف مر�ضى فقر الدم املنجلي. الكلمات املفتاحية: فقر الدم املنجلي؛ التهاب العظم والنقي؛ الفك؛ الفك ال�ضفلي؛ الفك العل�ي؛ تقرير احلالة؛ عمان. jaw osteomyelitis as a complication of sickle cell anaemia in three omani patients case reports and literature review *hilal al-ismaili,1 omar nasim,1 abdulaziz bakathir2 sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e93–97, epub. 30 mar 17 submitted 26 jun 16 revision req. 23 aug 16; revision recd. 26 sep 16 accepted 20 oct 16 doi: 10.18295/squmj.2016.17.01.016 case report sickle cell anaemia (sca) is an autosomal recessive haemoglobin disorder. the defective gene coded is haemoglobin s, which causes a deformation of the red blood cells (rbcs), making them sickle-shaped.1 in particular, sca commonly affects people originating from the middle east, the afro-caribbean region, the mediterranean and east india; in oman, the prevalence of sca is 0.2%.1,2 patients with sca have a wide spectrum of complications, of which vaso-oclusive crises (voc) are the most common.1 osteomyelitis is an infection of the bone and bone marrow and is a well-documented musculoskeletal complication of sca, especially in the long bones; sca patients have a 29–31% risk of experiencing osteomyelitis at least once in their lifetime.3–5 however, jaw osteomyelitis is extremely rare among sca patients, with a reported incidence of 3–5%.6,7 this report describes three cases of chronic jaw osteomyelitis among sca patients in oman. case 1 a 23-year-old man with sca presented to the department of oral health, sultan qaboos university hospital (squh), muscat, oman, in 2009 with pus discharge from the site of a recently extracted lower left third molar. he reported that the discharge had started soon after the extraction and did not abate, despite receiving multiple courses of oral antibiotics over the preceding two months. in addition, the patient reported numbness of the left side of his lower lip continuing throughout this period. the patient was known to have sca with frequent hospital admissions and was currently receiving hydroxyurea. three weeks prior to the dental extraction, the patient had been admitted due to a sickle cell crisis. a clinical examination revealed that the socket of tooth 38 was not healing and had pus discharge. additionally, pus discharge was observed in the interdental area between jaw osteomyelitis as a complication of sickle cell anaemia in three omani patients case reports and literature review e94 | squ medical journal, february 2017, volume 17, issue 1 teeth 35 and 36. the left submandibular lymph node was palpable and non-tender. an orthopantomogram (opg) showed an area of radiolucency related to the mesial root of tooth 36 [figure 1a]. mandibular osteomyelitis was suspected. the patient underwent removal of tooth 36, local socket curettage and a biopsy of the alveolar bone under local anaesthesia. subsequently, he was prescribed a two-week course of oral clindamycin. the biopsy revealed areas of necrotic bone and the presence of actinomyces spp. bacteria, confirming the diagnosis of chronic osteomyelitis [figure 1b]. a culture of the pus was positive for klebsiella pneumoniae and moraxella catarrhalis, which were sensitive to co-amoxiclav. following the diagnosis of jaw osteomyelitis, surgical curettage of the left mandible was performed with removal of the involved teeth while the patient was under general anaesthesia. extensive bone necrosis was observed in the medullary spaces affecting the left mandibular alveolar region around teeth 35 and 37. an extensive cancellous sequestrectomy was carried out to the level of the inferior alveolar nerve and the involved teeth were removed. following this, the surgical site was packed with bismuth iodine paraffin paste (bipp). the postoperative period was uneventful. the patient received oral co-amoxiclav for six weeks and the surgical site was repacked with bipp every two weeks until it was fully healed. at an eight-month follow-up, the oral wound had healed completely and the patient reported normal lip sensation. case 2 a 16-year-old male patient with known sca presented as an outpatient to the department of oral health at squh in 2013 with pus discharge of two months’ duration from the lower right posterior alveolus. he reported having had a voc episode two weeks prior to the start of his symptoms. initially, he was diagnosed with pericoronitis of the lower right third molar and was treated with multiple courses of oral antibiotics without improvement. a clinical examination indicated pus discharge from the buccal sinus and the gingiva surrounding tooth 46 [figure 2a]. tooth 48 was partially erupted and impacted and the patient had numbness on the right side of his lower lip. an opg revealed an ill-defined radiolucency in the region of tooth 46 [figure 2b]. a culture of the pus was positive for streptococcus anginosus. based on the clinical findings, chronic mandibular osteomyelitis was suspected. accordingly, the patient was admitted and intravenous (iv) coamoxiclav and metronidazole were administered. he figure 1: a: an orthopantomogram of a 23-year-old man with sickle cell anaemia showing a periapical radiolucent area related to the mesial root of tooth 36 (arrow) and obliterated pulp spaces in most teeth. b: haemotoxylin and eosin stain at x60 magnification showing bone necrosis (asterisk) in the left posterior mandible. figure 2: a: clinical photograph of a 16-year-old male with sickle cell anaemia showing chronic sinus buccal and gingival pus discharge near tooth 46. b: an orthopantomogram showing an ill-defined radiolucent area in the apical region of tooth 46. note the osteomyelitic appearance of the right body of the mandible (arrow). hilal al-ismaili, omar nasim and abdulaziz bakathir case report | e95 nonvital and root canal therapy was performed. two weeks later, the patient presented again with a small area of gingival buccal necrosis near tooth 17 with exposed necrotic bone. a small biopsy taken under local anaesthesia showed chronic inflammatory cells with bone necrosis and large colonies of actinomyces spp. bacteria. a diagnosis of chronic maxillary osteomyelitis was made and the patient underwent a sequestrectomy of the necrotic bone in the posterior maxilla up to the floor of the sinus with concurrent removal of teeth 16 and 17. the surgical site was packed with bipp, which was changed every two weeks. after six weeks, adequate healing was observed and the residual defect was closed using a small buccal advancement flap. discussion few cases of sickle cell jaw osteomyelitis (scjo) are reported in the literature [table 1].6–14 according to unpublished hospital data, only the three patients with scjo described in the present case report were seen at the department of oral health at squh over a 14-year period, despite the large number of sca patients seen at this institution on a regular basis. additionally, all three patients exhibited severe forms of sca. it is possible that the low number of scjo cases may be due to the prevalence of preserved splenic function in omani patients.15 in the largest published case series to date, olaitan et al. reported that jaw osteomyelitis occurred predominantly in men (81%) among 16 scjo patients.6 other reports have also noted a higher prevalence of scjo among men.7–9,11,12,14 moreover, the majority of scjo patients reportedly present at a young age, with most patients being between 20–39 years old.6–14 similarly, all three patients in the present case report were male and fell within this age group. sickled rbcs have a shorter life span in comparison to normal rbcs (5–15 days versus 120 days).16 subsequently underwent a sequestrectomy of the right mandible with removal of teeth 45 and 46 under general anaesthesia. as tooth 47 was deemed salvageable, a root canal treatment was also performed. following these procedures, the surgical site was packed with bipp. the patient had an uneventful postoperative recovery period and was discharged with a prescription for a 30-day course of oral coamoxiclav. regular follow-up appointments were scheduled every two weeks to repack the surgical site with bipp. during these sessions, the patient showed continued improvement with no pus discharge. after six months, the oral wound had healed significantly and the patient noted that sensation to his lower lip had returned. case 3 a 25-year-old male patient with sca was referred to the department of oral health at squh in 2013 with severe pain and swelling involving the right posterior maxilla following his admission to a local hospital due to a severe voc. he had a history of frequent hospital admissions, bilateral avascular necrosis of the femoral heads and was currently receiving oral hydroxyurea. a clinical examination showed swelling of the buccal and palatal mucosa with soft tissue buccal necrosis near teeth 17 and 18 [figure 3a]. however, an opg did not show any major pathological features other than a small area of bony infarction in the region of tooth 15 [figure 3b]. the patient underwent removal of tooth 18 with a soft tissue and bone biopsy. histopathology indicated normal bone and necrotic soft tissue with nonspecific chronic inflammatory cells. the patient was prescribed iv vancomycin and meropenem, with gradual improvement of the maxillary swelling. at a two-month follow-up, the intraoral swelling had subsided completely although the patient reported occasional pain in tooth 17. the tooth was found to be figure 3: a: clinical photograph of a 25-year-old male with sickle cell anaemia and swelling in the buccal and palatal aspects of the upper right posterior alveolus. b: a postoperative orthopantomogram following the removal of tooth 18 and resolution of the gingival swelling showing bony infarction (arrow) in the region of tooth 15. jaw osteomyelitis as a complication of sickle cell anaemia in three omani patients case reports and literature review e96 | squ medical journal, february 2017, volume 17, issue 1 at the end of their life, the rbcs are phagocytosed by macrophages. during a voc episode, the entanglement of sickled cells within the inferior alveolar artery causes blockage, infarction and pulpal necrosis.16 these ischaemic areas may become necrotic and infected secondarily via either the haematogenous route or by local invasion through the periodontal ligaments.16 among reported cases of scjo, the mandible is the most commonly involved part of the jaw, with the lower molar region being the most common mandibular site.6–9,11,12,14 this could be because the mandibular molar region is supplied by the ipsilateral inferior alveolar artery and periosteum; due to additional blood supply from the contralateral vessels, the anterior region is less vulnerable to ischaemia during a voc episode when the inferior alveolar artery is involved.6 borle et al. reported a single case of maxillary sickle cell osteomyelitis involving the molar region.13 to the best of the authors’ knowledge, this is the only case of maxillary scjo reported in the current literature, other than the third case described in the present report. shroyer et al. proposed two distinct hypotheses to explain the pathophysiology of scjo.12 first, a sickling crisis may cause bony infarctions, which become secondarily colonised by bacteria via haematogenous or local spread from the periodontal region. the second hypothesis suggests that a systemic infection may trigger voc, resulting in bony infarction.12 in keeping with the first hypothesis, the first two cases in the current report presented with a history of voc episodes with subsequent infarction and infection. however, the third case presented with a preceding infection which may have led to a voc episode and prompted maxillary infarction and osteomyelitis, thus supporting the method of pathogenesis described in the second hypothesis. patients with scjo may present with dental pain, pus discharge, necrosis or numbness in the perioral region, the latter of which is predominantly located in the lower lip in cases of inferior alveolar nerve involvement.17,18 in the present case report, the two patients with mandibular osteomyelitis presented with pus discharge in the molar region and were initially diagnosed with pericoronitis. olaitan et al. and shroyer et al. also reported pericoronitis to be a common cause of osteomyelitis among sca patients with mandi bular osteomyelitis.6,12 salmonella has been implicated as the most common causative microorganism of long bone table 1: literature review of cases of sickle cell jaw osteomyelitis6–14 author and year of case report number of cases age/gender site affected causative organism ryan et al.8 (1971) 1 36/m mandible normal flora plus staphylococcus aureus girasole et al.9 (1977) 3 22/m mandible staphylococcus aureus 34/f mandible streptococcus viridans 33/m mandible pseudomonas spp. daramola et al.7 (1982) 1 28/m mandible salmonella spp. iwu10 (1989) 3 16/f mandible negative culture 20/m mandible n/a 18/f mandible negative culture patton et al.11 (1990) 1 34/m mandible normal flora shroyer et al.12 (1991) 1 22/m mandible eikenella corrodens, bacteroides melaninogenicus, peptostreptococcus spp., mixed streptococcus spp. and staphylococcus spp. olaitan et al.6 (1997) 16 12–30/13:3* mandible mixed (n = 5), staphylococcus aureus (n = 4), none (n = 4) and others (n = 3) borle et al.13 (2001) 1 25/f maxilla pseudomonas aeruginosa araújo et al.14 (2015) 1 28/m mandible streptococcus viridans present cases (2009–2013) 3 23/m mandible actinomyces spp., klebsiella pneumoniae and moraxella catarrhalis 16/m mandible streptococcus anginosus 25/m maxilla actinomyces spp. f = female; m = male; n/a = not available. *male-to-female ratio. hilal al-ismaili, omar nasim and abdulaziz bakathir case report | e97 3. engh ca, hughes jl, abrams rc, bowerman jw. osteomyelitis in the patient with sickle-cell disease: diagnosis and management. j bone joint surg am 1971; 53:1–15. doi: 10.2106/00004623-197153010-00001. 4. balogun ra, obalum dc, giwa so, adekoya-cole to, ogo cn, enweluzo go. spectrum of musculo-skeletal disorders in sickle cell disease in lagos, nigeria. j orthop surg res 2010; 5:2. doi: 10.1186/1749-799x-5-2. 5. nwadiaro hc, ugwu bt, legbo jn. chronic osteomyelitis in patients with sickle cell disease. east afr med j 2000; 77:23–6. 6. olaitan aa, amuda jt, adekeye eo. osteomyelitis of the mandible in sickle cell disease. br j oral maxillofac surg 1997; 35:190–2. doi: 10.1016/s0266-4356(97)90562-3. 7. daramola jo, ajagbe ha. chronic osteomyelitis of the mandible in adults: a clinical study of 34 cases. br j oral surg 1982; 20:58–62. doi: 10.1016/0007-117x(82)90008-7. 8. ryan md. osteomyelitis associated with sickle-cell anemia: report of a case. oral surg oral med oral pathol 1971; 31:754–9. doi: 10.1016/0030-4220(71)90128-9. 9. girasole rv, lyon ed. sickle cell osteomyelitis of the mandible: report of three cases. j oral surg 1977; 35:231–4. 10. iwu co. osteomyelitis of the mandible in sickle cell homozygous patients in nigeria. br j oral maxillofac surg 1989; 27:429–34. doi: 10.1016/0266-4356(89)90085-5. 11. patton ll, brahim js, travis wd. mandibular osteomyelitis in a patient with sickle cell anemia: report of case. j am dent assoc 1990; 121:602–4. doi: 10.14219/jada.archive.1990.0224. 12. shroyer jv 3rd, lew d, abreo f, unhold gp. osteomyelitis of the mandible as a result of sickle cell disease: report and literature review. oral surg oral med oral pathol 1991; 72:25–8. doi: 10.1016/0030-4220(91)90184-e. 13. borle rm, prasant mc, badjate sj, patel ia. sickle cell osteomyelitis of the maxilla: a case report. j oral maxillofac surg 2001; 59:1371–3. doi: 10.1053/joms.2001.27540. 14. araújo jp, cadavid am, lemos ca, trierveiler m, alves fa. bilateral mandibular osteomyelitis mimicking periapical cysts in a patient with sickle cell anemia. autops case rep 2015; 5:55–60. doi: 10.4322/acr.2015.013. 15. wali ya, al-lamki z, hussein ss, bererhi h, kumar d, wasifuddin s, et al. splenic function in omani children with sickle cell disease: correlation with severity index, hemoglobin phenotype, iron status, and alpha-thalassemia trait. pediatr hematol oncol 2002; 19:491–500. doi: 10.1080/ 08880010290097314. 16. booth c, inusa b, obaro sk. infection in sickle cell disease: a review. int j infect dis 2010; 14:e2–12. doi: 10.1016/j.ijid. 2009.03.010. 17. kelleher m, bishop k, briggs p. oral complications associated with sickle cell anemia: a review and case report. oral surg oral med oral pathol oral radiol endod 1996; 82:225–8. doi: 10.1016/s1079-2104(96)80261-7. 18. podlesh sw, boyden dk. diagnosis of acute bone/bone marrow infarction of the mandible in sickle hemoglobinopathy: report of a case. oral surg oral med oral pathol oral radiol endod 1996; 81:547–9. doi: 10.1016/s1079-2104(96)80044-8. 19. burnett mw, bass jw, cook ba. etiology of osteomyelitis complicating sickle cell disease. pediatrics 1998; 101:296–7. doi: 10.1542/peds.101.2.296. osteomyelitis among sca patients.19 in comparison, staphylococcus aureus is most frequently reported in the literature as the cause of jaw osteomyelitis.6–9,12 however, other case reports have attributed the causative agents to be streptococcus spp., pseudomonas spp. and other mixed species.6,7,9,12–14 in the current case report, actinomyces spp. were isolated in the first and third cases, organisms which have not been reported previously in the literature in association with jaw osteomyelitis. however, streptococcus spp. and other mixed species were isolated in the second and first cases, respectively. early detection and prompt referral to a specialised centre for management with expert care is vital for scjo patients. as such, dental practitioners and oral and maxillofacial surgeons should have a high index of suspicion regarding this condition when treating sca patients. the treatment of chronic osteomyelitis involves a sequestrectomy with preservation of the cortices, removal of the involved teeth and the administration of antibiotics.7,8,10,14 however, antibiotics should only be used as an adjunct to surgical treatment, since their sole use is not sufficient to manage the condition.5,7 this was also evidenced by the first two patients presented in the current report. in order to guide the choice of antibiotics, it is essential to send samples of pus and tissue from the necrotic area for microbiological and histopathological evaluations. in the present cases, general anaesthesia was used to allow adequate access to ensure comprehensive debridement. this is supported by olaitan et al., although other researchers have recommended use of local anaesthesia instead.6,10 conclusion as scjo is an uncommon condition, it may be underdiagnosed. dental practitioners and oral and maxillofacial surgeons should be aware of this condition when treating sca patients. this case report describes three sca patients with chronic jaw osteomyelitis, in which two patients had osteomyelitis in the mandible and the third had osteomyelitis in the maxilla. references 1. craig ji, mcclelland db, watson hg. blood disease. in: colledge nr, walker br, ralston sh. davidson’s principles and practice of medicine, 21st ed. london, uk: churchill livingstone, 2010. pp. 985–1052. 2. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. https://doi.org/10.2106/00004623-197153010-00001 https://doi.org/10.1186/1749-799x-5-2 https://doi.org/10.1016/s0266-4356%2897%2990562-3 https://doi.org/10.1016/0007-117x%2882%2990008-7 https://doi.org/10.1016/0030-4220%2871%2990128-9 https://doi.org/10.1016/0266-4356%2889%2990085-5 https://doi.org/10.14219/jada.archive.1990.0224 https://doi.org/10.1016/0030-4220%2891%2990184-e https://doi.org/10.1053/joms.2001.27540 https://doi.org/10.4322/acr.2015.013 https://doi.org/10.1080/08880010290097314 https://doi.org/10.1080/08880010290097314 https://doi.org/10.1016/j.ijid.2009.03.010 https://doi.org/10.1016/j.ijid.2009.03.010 https://doi.org/10.1016/s1079-2104%2896%2980261-7 https://doi.org/10.1016/s1079-2104%2896%2980044-8 https://doi.org/10.1542/peds.101.2.296 clinical & basic research squ med j, may 2012, vol. 12, iss. 2, pp. 184-189, epub. 9th apr 2012 submitted 3rd may 11 revision req. 29th nov 11, revision recd. 19th dec 11 accepted 19th jan 12 تطبيق نتائج البحوث يف املمارسة السريرية جدوى املسارات املتكاملة للرعاية املبنية على األدلة يف ِطب األَْنِف واألُُذِن واحلَْنَجَرة وجراحة الرأس والرقبة مبستشفى جامعة السلطان قابوس، ُعمان ديبا بهارجافا، زينب اللواتية، را�سد العربي، كاملي�س بهارجافا امللخ�ص: الهدف: هناك ت�سور مفاده اأّن االأطباء يف ُعمان يرتددون يف تبني املمار�سة املبنية على الدليل. اأجريت هذه الدرا�سة التجريبية لدرا�سة جدوى ا�ستخدام املمار�سة املبنية على الدليل يف طب االأنف واالأذن واحلنجرة – جراحة الراأ�س والرقبة. وكان الهدف النهائي ت�سهيل الطريقة: ال�رضيرية. الرعاية يف املرتجمة االأبحاث / البحوث نتائج لتنفيذ جديد نظام و�سع احتمال مع الدليل على املبنية املمار�سة اأجريت هذه الدرا�سة املقطعية اال�ستباقية التجريبية با�ستعمال ا�ستبيان مت توزيعه على االأطباء يف م�ست�سفى جامعة ال�سلطان قابو�س يف ُعمان، وهو م�ست�سفى رعاية ثالثية. �سملت العينة 135 من االأطباء واجلراحني الذين ترتاوح خربتهم ال�رضيرية ما بني 3 اأ�سهر و25 عاما، بينهم متدربني وكبار اال�ست�ساريني يف جماالت الرعاية ال�سحية االأولية والرعاية املتخ�س�سة. النتائج: معظم الذين �سملهم اال�ستطالع )%90( )فرتة الثقة %95 بني 85 و %90( كانوا موافقني )�سواء كانت جمرد موافقة اأو موافقة بقوة(، على اأن بروتوكوالت املمار�سة املبنية على الدليل ميكن اأن ي�ساعد يف �سنع القرار. كما كان ما جمموعه %87.4 من امل�ساركني )فرتة الثقة %95 بني 81.8 و 93%( كانوا مواغفني اأي�سا )�سواء جمرد املوافقة اأو املوافقة بقوة( على اأن الرعاية املبنية على الدليل ميكن اأن حت�ّسن النتائج ال�رضيرية، و�رّضح اذا فيما الدليل على املبنية الرعاية ويطبقون �سي�ستخدمون باأنهم )96.4% و 87.2 بني 95% الثقة )فرتة امل�ساركني من 91.8% توفرت واأ�سبحت جزءا من نظام معلومات امل�ست�سفى. اخلال�صة: اإن االعتقاد باأن االأطباء يف م�ست�سفى جامعة ال�سلطان قابو�س يرتددون االأولية. ال�سحية الرعاية م�ستوى على جدا ممكن املمار�سة تلك م�سارات ا�ستحداث �سحيحة. غري الدليل على املبنية املمار�سة تبّني يف هناك حاجة اإىل الدعم املوؤ�س�سي لت�سمني تبّني املمار�سة املبنية على الدليل يف نظم معلومات امل�ست�سفى، ف�سال عن بحث نتائج اأخرى لتقييم التح�سن يف نوعية الرعاية. يف توجيهية مبادئ �رضيري، بروتوكول الدليل؛ على مبنية ممار�سة والرقبة، الراأ�س جراحة، واحلنجرة، واالأذن االأنف طب البحث: كلمات املمار�سة ال�رضيرية، اتخاذ القرار، ُعمان. abstract: objectives: a perception exists that clinicians in oman are reluctant to adopt evidence-based practice (ebp). this pilot study was undertaken to study the feasibility of using ebp pathways at the point of care in otorhinolaryngology head and neck surgery. the ultimate aim was to facilitate ebp with the probability of developing a new system for implementing research findings/translational research at the clinical point of care. methods: a cross-sectional prospective questionnaire pilot survey of clinicians at sultan qaboos university hospital (squh), oman, a tertiary care medical centre, was undertaken. respondents included 135 physicians and surgeons with between 3 months and 25 years of clinical experience and included personnel ranging from interns to senior consultants, in areas ranging from primary care to specialist care. results: of those polled, 90% (95% confidence interval (ci) 85–95%) either strongly agreed or agreed that evidence-based practice protocols (ebpp) could help in decision making. a total of 87.4% of participants (95% ci 81.8–93%) either strongly agreed or agreed that ebpps can improve clinical outcomes; 91.8% of participants (95% ci 87.2–96.4%) would use and apply ebpp in day-to-day care if they were available at the point of care and embedded in the hospital information system. conclusions: the perception that clinicians at squh are reluctant to adopt ebp is incorrect. the introduction of ebp pathways is very feasible at the primary care level. institutional support for embedding ebp in hospital information systems is needed as well as further outcome research to assess the improvement in quality of care. keywords: otorhinolaryngology; surgery, head and neck; evidence based practice; clinical protocol; clinical practice guidelines; decision making; oman. putting research findings into clinical practice feasibility of integrated evidence-based care pathways in otorhinolaryngology head and neck surgery at sultan qaboos university hospital, oman *deepa bhargava,1 zainab al-lawatia,1 rashid al-abri,1 kamlesh bhargava2 clinical & basic research departments of 1surgery and 2family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: deepaent@gmail,com deepa bhargava, zainab al-lawatia, rashid al-abri and kamlesh bhargava clinical and basic research | 185 as the volume of medical literature has expanded, the task of putting research findings into clinical practice has become increasingly overwhelming. practitioners of evidence-based medicine (ebm) claim that it frees clinicians from practicing medicine by rote, guesswork, and variable experience. it also ends their dependence on out-of-date authorities, and enables clinicians to work with the patient, using medical literature as a tool to solve the patient’s problems. it provides the clinicians with access to what is relevant, and gives them the ability to assess the validity and applicability of that information. in other words, it puts the clinicians in charge of information, the single most powerful resource in medicine.1 ebm integrates the best research and evidence with clinical expertise and patient values. when these three elements are integrated, clinicians and patients form a therapeutic alliance which optimises clinical outcomes and quality of life.2 although there are a vast number of translational clinical research findings in literature, not many are being applied in day-to-day clinical care. some barriers to practising ebm are information overload with literature of doubtful validity, lack of motivation, and lack of time. one of the methods of evidence-based practice (ebp) is implementation of the best current guidelines; however, there is also an overload of information pertaining to guidelines. integrated care pathways (icp) are predefined plans of patient care relating to a specific diagnosis, or intervention, with the aim of making the management more structured, consistent and efficient.3 the difference between icp and ebpp is that with ebpp the level of evidence and grade of recommendation is mentioned. a search of recent literature reveals that although icp are recent innovations, they are being adopted by clinicians in many specialties, like primary acute, cancer, and gynaecological care. research has shown that using icp, with a multidisciplinary team approach to care, significantly improves risk management, reduces health care costs and the length of hospital stays, and leads to increased patient and staff satisfaction.4–7 icp in one form or another has swept over the world largely as a grass roots movement of clinical professionals. the movement has been motivated by a search for a more efficient, economical, highquality tool that will improve the variations in patient care and outcomes.8 ebm is important in all areas of medicine, including otorhinolaryngology, and head and neck surgery (orl-hns). the aims of the present study were to test the feasibility of introducing ebp and icp into the orl-hns unit in the department of surgery at sultan qaboos university hospital (squh), oman; to gather facts from key personnel regarding changes and improvements they would like to see; to identify if we are being overly optimistic with regards to ebpp, and to determine the probability of developing a new system for improved quality of care. advances in knowledge the study demonstrates the willingness of clinicians in oman to adopt evidence-based practice (ebp) and evidence-based practice protocols (ebpp). the study demonstrates the feasibility of introducing ebpp and integrated care pathways (icp) at the point of care. this study has the potential to lead to the innovative development of a new system for implementing research findings/translational research in the clinical setting at the point of care. embedding ebpp and icp in hospital information systems has the potential to help clinicians make decisions and apply translational research findings to clinical care, thereby raising the quality of care. during the process of preparing the ebpp research, gaps in knowledge were identified. these could be the targets for future research. applications to patient care in the future, ebp will have far-reaching implications for patient care as embedding ebpp in the hospital information system will facilitate decision making and standardise patient care. since most clinicians polled believed ebpp can help in decision making and improve clinical care and outcomes, this study has demonstrated the potential for raising the standard of patient care. in the future, ebpp will facilitate the task of applying the latest, most accurate evidence to patient care. ebpp could potentially reduce wasteful spending by preventing unnecessary, outdated investigations and treatments. putting research findings into clinical practice feasibility of integrated evidence-based care pathways in otorhinolaryngology head and neck surgery at sultan qaboos university hospital, oman 186 | squ medical journal, may 2012, volume 12, issue 2 methods a questionnaire pilot survey was conducted to determine the attitude of clinicians to ebp, the relation of ebp to improved quality of care, and the prospects of introducing evidence-based practice protocols (ebpp) in oman. the main study on measuring outcomes of ebpp was submitted for approval to the medical ethics & research committee at squh. the subjects belonged to the following clinical specialties and departments: orlhns, general surgery, accident and emergency, and family and community medicine. the questionnaire was clearly designed with a concise one-page layout and clear focus, and was subjected to internal and external validity tests. internal validity was assessed by piloting the questionnaire with four experts who analysed it for validity of language, face, and content. following this, the questionnaire was edited and arranged in a logical, brief, unambiguous and user-friendly format. unnecessary and repetitive questions were detected and deleted. the external validity was carried out to determine whether the questionnaire measured what it was supposed to measure. its reliability was found to be satisfactory. random selections of doctors were invited to participate and the questionnaire was completed face-to-face. the aims of the study were clearly explained with a researcher on hand to answer questions and collect the completed questionnaire. the questionnaire included the following nine categories/queries: 1) number of years of clinical experience and 2) practice setting. questions 3 to 9 assessed different levels of agreement/disagreement regarding: 3) ebpp facilitating workflow; 4) the need of clinical protocols to be prepared based on best current evidence; 5) whether ebpp are preferable to routine protocols as they have a higher level of evidence and a higher grade of recommendation; 6) the respondent’s level of belief that ebpp could help in decision making; 7) the need of pathways to be problem specific since they change according to triage assessments; 8) the respondent’s feeling as to whether ebpp might improve clinical outcomes; and 9) the likelihood that the respondent would use ebpp, especially if embedded in the hospital information system. statistical analysis was done using the statistical package for the social sciences (spss, version 16, ibm, chicago, illinois, usa) and through a chi-square test. various correlations were studied (e.g. between ebpp from different points of view and number of years of clinical experience). the confidence intervals (cis) were calculated using the ci calculator for proportions. results the researchers distributed 150 questionnaires and 135 completed questionnaires were returned. the range of clinical experience of respondents ranged from 3 months to 25 years [figure 1]. overall, 71% of participants (95% confidence intervals [ci] 63.4−78.7%) agreed that ebpp are preferable to routine protocols as ebpp are prepared based on the best current research and include level of evidence and grade of recommendation. a total of 77% of respondents (95% ci 70−80%) agreed protocols change according to triage assessments, so they need to be problem-specific. overall, 90% (95% ci 85−95%) either strongly agreed or agreed that ebpp could help in decision making; however, 10% disagreed that ebpp could help in decision making. of those polled, 43% (95% ci 34.7−51.4%) strongly agreed and 44.4% (95% ci 36−52.8%) agreed that ebp protocols can improve clinical outcomes, while in total of 87.4% of respondents (95% ci 81.8−93%) expected an improvement in clinical outcomes by using ebpp [figure 2]. overall, a total of 91.8 % (95% ci 87.2– 96.4%) of the participants, (with 53.3% [95% ci 44.9−61.7%] having strongly agreed, and 38.5% [95% ci 30.3−46.7%] having agreed) would use ebpp and apply it in their day-to-day care if it were available at the point of care through the hospital information system [figure 3]. figures 2 and 3 also demonstrate the correlation between the number of years of experience with the expectation of clinical 49.63 29.63 20.74 0-5 years 6-10 years 11+ years figure 1: number of years of clinical experience of the respondents deepa bhargava, zainab al-lawatia, rashid al-abri and kamlesh bhargava clinical and basic research | 187 outcomes and a willingness to apply ebpp. discussion the present study tested the feasibility of introducing ebp and icp into the orl-hns unit in the department of surgery at squh, oman. a literature search revealed no similar survey on the feasibility of embedding ebm in care pathways; however, there have been a number of surveys of the behaviour of doctors, nurses and related professionals in regards to ebm. it was estimated in the 1970s in the usa that only around 10−20% of all health technologies then available (e.g. drugs, procedures, operations, etc.) were evidence-based; that figure improved to 21% in 1990, according to official us statistics. 9 when the ebm movement was still in its infancy, dave sackett emphasised that evidencebased practice was no threat to old-fashioned clinical experience or judgment.1 this perception is one of the barriers to the extension of ebm practice. greenhalgh wrote, “we clinicians would not be human if we ignored our personal clinical experiences, but we would be better off basing our decisions on the collective experience of thousands of clinicians treating millions of patients, rather than on what we as individuals have seen and felt.”10 however, in spite of high levels of clinical evidence, extensive grades of recommendations, and translational research, there is still a lack of evidence-based decisions being applied to patient care at the point of care. a pilot study for developing a model for implementing ebpp is being developed in the orl-hns unit in the department of surgery at squh. this model has multiple steps, starting from assessing the needs of ebpp, preparing the pathways, getting consensus from participating departments, implementing the pathways, and studying the outcomes by auditing the improvement in quality. one of the perceived barriers is the attitude of clinicians towards ebp; this has never been studied in oman. this feasibility study is important to determine the level of acceptance of ebpp prior to its implementation. the significance of the present study was that it aimed to identify barriers to ebp and is one step towards applying the above described model and implementing ebpp. the objectives of study have been met, as mentioned in the results, as 90% of participants strongly agreed or agreed that ebpp could help in decision making, and 87.4% of participants either strongly agreed or agreed that ebpp can improve clinical outcomes. the ultimate aim of this study is the introduction of ebpp and icp in orl-hns at the point of care by embedding the protocols into the hospitalelectronic patient records system. of special significance in the survey is the finding that 92% of the participants would use these protocols and apply them in their day-to-day care if available at point of care. a weakness of the study was that there was no control so it was difficult to assess if answers were correct or not. there are many advantages of using a strategy of implementing ebp and ebpp. in terms of medical education for health care professionals, 49.63 29.63 20.74 0-5 years 5-10 years 10-15 years 0 10 20 30 40 50 strongly agree agree equal disagree 48.8 50.0 35 49.3 39.3 40.0 6.0 10.7 22.5 0.0 2.5 0.0 figure 2: correlation of belief that evidence-based practice protocols can improve clinical outcomes to number of years of clinical experience putting research findings into clinical practice feasibility of integrated evidence-based care pathways in otorhinolaryngology head and neck surgery at sultan qaboos university hospital, oman 188 | squ medical journal, may 2012, volume 12, issue 2 self-directed, life-long learning can be achieved by ebp. information management in the current age is a challenge, but ebp clinicians are taught to be efficient information managers. introducing ebpp would enhance a collaborative learning strategy between the otolaryngologist and the primary care clinician. ebpp can also help improve the quality of care by solving clinical dilemmas at point of care, especially in the primary care setting. the users of ebpp, especially junior doctors, will be supported by the best evidence upon which to base their decisions rather than blindly following their seniors. there is the potential for ebpp to reduce wasteful expenditure that can occur when unnecessary or outdated investigations and treatments are ordered. in dealing with clinical problems, health professionals often differ in their approaches and opinions. there is a need for team work and a multidisciplinary approach to patient care which is facilitated by following ebpp. quality requires the maximisation of benefits and minimisation of risks for the patients. for these reasons, 90% of participants believe ebpp would improve the quality of care. finally, ebpp can lead to new research areas as, during the process of preparing the ebpp, research gaps could be identified and direct future research. however there are also disadvantages of ebpp. there can be a limited applicability of evidence. this is possible, especially in patients with comorbid conditions. the clinical expertise of the clinician should be relied on in these situations; however, working with the best knowledge available is usually better than having no idea at all. further disadvantages can be a lack of high-grade evidence, controversial evidence, inconsistent evidence, or incoherent evidence. in spite of this, based on unpublished research, we have found fairly good levels of evidence for common orl-hns conditions. a final disadvantage of ebpp would be the potential for limiting the learning for junior doctors. one of the participants, who was against ebpp, even mentioned that it is like “spoon-feeding residents”. we disagree with this statement. since most of the self-directed learning for residents is in order to pass examinations, they rarely find the time to ask the clinical questions which are vital to ebp. moreover, critical appraisal and ebm language is routinely taught in journal clubs. based on this questionnaire survey, our recommendations are: 1) ebpp are preferable to routine protocols as they provide a rigorous and acceptable framework for making complex decisions at the point of care; 2) embedding ebpp in hospital information systems would enhance ebp at the point of care and improve the quality of patient care for orl-hns conditions at the primary care level; 3) ebm requires institutional support by way of specialist skills, a supply of evidence, and embedding ebpp in hospital information systems, and 4) further outcome-based research is needed to study the degree of quality improvement after implementing the described ebpp. conclusion the perception that orl-hns doctors in oman are reluctant to adopt changes in ebp is incorrect. 49.63 29.63 20.74 0-5 years 5-10 years 10-15 years 0 10 20 30 40 50 60 strongly agree agree equal strongly disagree disagree 40.3 50.0 55.057.7 39.9 35.0 4.5 7.1 7.5 0.0 3.6 2.5 1.5 0.0 0.0 figure 3: correlation of belief that embedding protocols in hospital information systems will facilitate application of research at point of care to number of years of clinical experience. deepa bhargava, zainab al-lawatia, rashid al-abri and kamlesh bhargava clinical and basic research | 189 most clinicians, including otolaryngologists, believe ebpp can help in decision making and improve clinical outcomes. the feasibility of introducing otolaryngology ebpp for use at the primary care level is very high. embedding ebpp in hospital information systems would enhance ebp at point of care and help provide the benefit of research findings in the clinical care setting. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest. references 1. sackett dl, richardson ws, rosenberg wmc, haynes rb. evidence-based medicine: how to practice and teach ebm. 2nd ed. london: churchilllivingstone, 2000. pp. 7–12. 2. guyatt gh, rennie d. users’ guides to the medical literature. essentials of evidence-based clinical practice. evidence-based medicine working group. jama 2002. from: www.ama-assn.org accessed: feb 2011. 3. renholm m, leino kh, suominen t. critical pathways. a systematic review. j nurs adm 2002; 32:196−202. 4. latta g. evidence-based best practices at mater health services; a road map for integrated case management. prof case manag 2010; 15:159−63. 5. terra sm. an evidence-based approach to case management model selection for an acute care facility: is there really a preferred model? prof case manag 2007; 12:147−57. 6. cringles mc. developing an integrated care pathway to manage cancer patients across primary, secondary and tertiary care. int j palliat nurs 2002; 8:247−55. 7. julian s, naftain nj, clark m, szczepura a, rashid a, baker r, et al. an integrated care pathway for menorrhagia across the primary–secondary interface: patients experience clinical outcomes and service utilization. qual saf healthcare 2007; 1692:110−5. 8. zande k. integrated care pathways eleven international trends. int j care pathw 2002; 6:101−7. 9. dubinsky m, ferguson jh. analysis of the national institutes of health medicare coverage assessments. int j technol assess health care 1990; 6:480−8. 10. greenhalgh t. how to read a paper. the basics of evidence-based medicine. 4th ed. london: wileyblackwell, 2010. p. 5. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e231-235, epub. 7th apr 14 submitted 25th aug 13 revision req. 8th dec 13; revision recd. 2nd jan 14 accepted 16th jan 14 school of pharmacy, college of pharmacy & nursing, university of nizwa, nizwa, oman *corresponding author e-mails: jimmy_jose2001@yahoo.com and jimmy.jose@unizwa.edu.om االلتزام باألدوية بني مرضى السكري من النوع 2 يف ثالث واليات يف حمافظة الداخلية، عمان دراسة ارتيادية مستعرضة بينا جيمي، جيمي جو�س، زينب علي الهنائية، اإنت�صار خمي�س واداير، غالية حمد العامرية abstract: objectives: this pilot study aimed to assess the medication adherence of type 2 diabetes mellitus (t2dm) patients in three wilayats (districts) of the al dakhliyah governorate, oman, and to identify the probable reasons for medication non-adherence. methods: a cross-sectional questionnaire-based pilot survey was conducted among t2dm omani patients between february and june 2012 to assess their medication adherence and the relationship between their socio-demographic characteristics and adherence levels. results: a total of 158 patients participated in the survey. the majority of the participants were unemployed or were housewives (66.5%). forgetfulness was the most frequent reason for medication non-adherence (36.4%). participants demonstrated an excellent level of adherence to their medicines (median total score = 3). no significant difference in median total adherence scores was observed based on the evaluated parameters. conclusion: the medication adherence of t2dm patients in the area under study was good. a larger study in a wider population is warranted to obtain a more representative picture of this important factor which contributes to public health. keywords: diabetes mellitus, type 2; medication adherence; cross-sectional study; oman. امللخ�س: الهدف: تهدف هذه الدرا�صة التجريبية لتقييم مدى التزام مر�صى ال�صكري النوع 2 بالدواء يف ثلث وليات من حمافظة الداخلية ولتحديد الأ�صباب املحتملة لعدم التزام مر�صى ال�صكري النوع 2 باأخذ الدواء. الطريقة: مت القيام مب�صح جتريبي مقطعي عن طريق توزيع ا�صتبيان على مر�صى ال�صكري النوع 2 خلل الفرتة ما بني فرباير ويونيو 2012 لتقييم مدى التزامهم باأدويتهم والعلقة بني اخل�صائ�س الجتماعية الدميوغرافية ومدى اللتزام باأخذ الدواء. النتائج: من جمموع 158 مري�صًا �صاركو يف الدرا�صة، معظم امل�صاركني من العاطلني عن العمل و ربات بيوت)%66.5( .الن�صيان كان ال�صبب الأكرث تكرارا لعدم اللتزام بالدواء)%36.4(. امل�صاركون كانوا ملتزمني بدرجة عالية باأدويتهم )متو�صط الدرجة الكلية = 3(. مل يلحظ اأي فرق ملمو�س يف متو�صط درجات اللتزام بالن�صبة ملدة املر�س اأو عدد الأدوية. النتيجة: التزام مر�صى ال�صكري النوع 2 بالأدوية يف املناطق التي حتت الدرا�صة كان جيدا. من املهم اإجراء درا�صة مو�صعه ت�صمل عدد اأكرب من ال�صكان للح�صول على نتائج اأكرث متثيل وو�صوحا عن هذا العامل املهم الذي ي�صهم يف ال�صحة العامة. مفتاح الكلمات: مر�س ال�صكري؛ النوع 2؛ اللتزام بالدواء؛ درا�صة مقطعية م�صتعر�صة؛ عمان. adherence to medications among type 2 diabetes mellitus patients in three districts of al dakhliyah governorate, oman a cross-sectional pilot study beena jimmy, *jimmy jose, zainab a. al-hinai, intisar k. wadair, ghalia h. al-amri brief communication adherence to a medication regimen is generally defined as the extent to which patients take medications as prescribed by their healthcare providers.1 it is one of the major factors that determines therapeutic outcomes, especially in patients suffering from chronic illnesses. low medication adherence has become a key healthcare issue as it greatly affects the benefits of medical care and imposes a significant financial burden on the individual patient and healthcare system as a whole.2 it has been observed that the average adherence to long-term therapy for chronic illnesses in developed countries is only 50%.1 adherence rates for patients with type 2 diabetes mellitus (t2dm) range from 65–85% for oral agents and 60–80% for insulin.3 many factors are potentially related to adherence problems, including demographics, the psychological and social status of the patient, the type of healthcare provider and medical system and other disease and treatmentrelated factors.4 a study conducted by al moosa et al. in oman shows that rising rates of diabetes and associated risk factors have been observed in populations undergoing epidemiological transition and urbanisation.5 another study conducted in oman shows that the prevalence of diabetes mellitus (dm) is on the rise and that there adherence to medications among type 2 diabetes mellitus patients in three districts of al dakhliyah governorate, oman a cross-sectional pilot study e232 | squ medical journal, may 2014, volume 14, issue 2 are high rates of diabetes-related complications.6 more than 14% of people with dm in oman were found to have diabetic retinopathy and 27% of those with t2dm had microalbuminuria.7,8 although there have been some studies on the quality of diabetes care, there is a paucity of published data on medication adherence among the diabetic population in oman.9,10 of the studies conducted in the middle east, non-compliance with medications was reported by 10% of diabetic patients in the united arab emirates (uae).11 poor practices of taking medications in relation to meals and modifying doses when necessary were reported among qatari patients with dm12 and the level of diabetes knowledge among kuwaiti adults with t2dm was poor.12,13 hence, this cross-sectional pilot study was conducted to assess the medication adherence of t2dm patients in three wilayats (districts) of the al dakhliyah governorate of northern-central oman and to determine their opinions on the probable reasons for medication non-adherence. the association between sociodemographic characteristics and adherence levels was also investigated. methods a cross-sectional questionnaire-based pilot study was conducted during the period february to june 2012 in bid bid, nizwa and bahla, which are three wilayats of the al dakhliyah governorate of oman. the research committee of the college of pharmacy & nursing of the university of nizwa approved the study’s research and ethical components. a questionnaire was developed for the study based on the parameters to be evaluated and themes from previous studies.14,15 considering an omani population of 269,069 in the al dakhliyah governorate for the year 2011 and the prevalence of dm to be 12% in oman, a target population of 33,200 was assumed, the estimated population diagnosed with dm.16,17 based on this target population, an appropriate sample size of 150 was estimated with a confidence level of 95% and an interval of 8. three investigators visited houses in the study sites to enquire about residents potentially diagnosed with dm. these investigators were undergraduate students in pharmacy and co-authors of the study. all of them were involved in preparing the data collection tool and they were trained specifically in data collection by the two other co-authors, faculty members in pharmacy. the three investigators conducted the data collection independently in the three wilayats selected for the purpose of the study. potential participants were identified and, with the help of the study information sheet, asked if they were willing to participate in the study. those who were willing to participate and sign the informed consent form were enrolled for the study based on the inclusion and exclusion criteria. a convenience sampling method was adopted, taking into consideration the inherent difficulty in using other sampling methods to identify and enroll the diabetic patients from their households. potential participants were selected from households rather than from a healthcare setting so as to reduce the chance of exaggeration in self-reported adherence, which is common when patients are interviewed in a healthcare setting. t2dm patients between 35–70 years old and having been on anti-diabetic medication(s) for at least six months were included in the study. patients who were debilitated or had any disease affecting their cognition and those who were not willing to participate were excluded. the questionnaire was completed by the participant in most of the cases (158 out of 192) and the investigator was available for any clarification on the questionnaire. even though the majority of participants in the study had not received a formal education, they were not completely illiterate, having learnt to read and write from madrassa, the islamic school where the holy quran is learnt. the questionnaire was completed by the investigator or the patient’s relative for those few of the participants who had not received any education. the questionnaire consisted of three parts. the first part collected information on the participants’ knowledge of their prescribed anti-diabetes medications, such as its proper dosage and the frequency and time of administration with regard to food. it also had questions to evaluate patients’ adherence to their medications and their reasons for non-adherence. the second part was designed to obtain information on the duration of each patient’s dm and its management. the third part was designed to capture the demographic details of the participants. the questionnaire was prepared in english and translated into arabic. content validity was assessed by another expert who was not involved in the preparation of the data collection instrument. it was pre-tested with 10 prospective respondents. an arabic study information and informed consent form was also developed. the reported adherence to dose, frequency and administration of medicine with regard to food of the individual patients was compared with the instructions on the medication prescription or label from the healthcare provider. a score of 1 was given if adherence was observed and 0 if there was no adherence to these beena jimmy, jimmy jose, zainab a. al-hinai, intisar k. wadair and ghalia h. al-amri brief communication | e233 individual parameters. a total median adherence score was obtained by combining the individual scores for dose, frequency and administration. accordingly, a maximum score of 3 was obtained for patients who adhered to all three parameters of dose, frequency and administration with regard to food, and a minimum score of 0 was obtained if they did not adhere to any of the parameters. this total median score was related to the demographics of the patient and the disease and medication details. the results were analysed using the statistical package for the social sciences (spss), version 15 (ibm, corp., chicago, illinois, usa) while the mann-whitney u and kruskal-wallis tests were used for continuous variables for non-parametric data depending on the number of comparative groups. a p value of <0.05 was considered statistically significant. results a total of 158 completed questionnaires were obtained from the 192 questionnaires distributed, giving a response rate of 82.3%. most of the respondents were female (60.1%) and a slightly higher percentage of participants were 46–60 years old (38%) [table 1]. the majority of them had received no formal education (55.7%) and were unemployed or were housewives (66.5%). many of them had been diagnosed with dm approximately 2–15 years before the study period [table 2]. most of the participants were taking either one (54.4%) or two (43%) drugs to control their dm [table 2]. an evaluation of participants’ most likely reasons for non-adherence indicated that ‘forgetting to take’ their medication was the most frequent reason (36.4%) preventing optimal adherence to their prescribed drug regimen [table 3]. upon evaluation of the patients’ understanding of their medication regimen, it was observed that the vast majority of them (80%) understood their medication orders as instructed by their doctors. the median total score of adherence with regard to dose, frequency and taking medicine before or after food, was 3 out of the maximum score of 3, which demonstrates an excellent level of patient adherence to their medicines. upon evaluation of the association of the median total adherence score and demographics of participants, no significant difference was observed for gender, age, educational qualification or employment status. the median total adherence scores were evaluated to determine their relationship to other parameters such as number of years with dm and the number of diabetic medications prescribed. no significant difference was observed between median total adherence score and the number of years the patient had suffered from dm or the number of medications prescribed. table 1: relationship of median total adherence score with demographics of respondents demographics n (%) median total score (iqr) p value gender male 63 (39.9) 3 (1.0) 0.235 female 95 (60.1) 3 (0.5) age group in years 30–45 53 (33.5) 3 (1.0) 0.99146–60 60 (38.0) 3 (1.0) 61–75 45 (28.5) 3 (1.0) educational qualification no formal education 88 (55.7) 3 (1.0) 0.840 primary school 23 (14.6) 3 (0.5) secondary school 25 (15.8) 3 (0.0) higher secondary 17 (10.7) 3 (1.0) higher education 5 (3.2) 3 (1.0) employment status employed 34 (21.5) 3 (1.0) 0.263 self-employed 19 (12.0) 3 (1.5) unemployed/ housewife 105 (66.5) 3 (0.75) iqr = interquartile range. table 2: relationship of median total adherence score with disease and drug details demographics n (%) median total score (iqr) p value duration of diabetes 6 months–1 year 17 (10.8) 3 (0.0) 0.287 2–9 years 56 (35.4) 3 (1.0) 10–15 years 58 (36.7) 3 (1.0) ≥15 years 27 (17.1) 3 (1.0) number of anti-diabetic medications used 1 86 (54.4) 3 (1.0) 0.3462 68 (43.1) 3 (1.0) ≥3 4 (2.5) 3 (0.75) adherence to medications among type 2 diabetes mellitus patients in three districts of al dakhliyah governorate, oman a cross-sectional pilot study e234 | squ medical journal, may 2014, volume 14, issue 2 discussion medication adherence has a great impact on outcomes in chronic diseases. however, as many chronic disease patients often do not experience noticeable symptoms, following treatment recommendations can be difficult. presently, there is no single measure accepted as the gold standard to measure medication adherence as all of the commonly employed methods have disadvantages. patient interviews, while straightforward and inexpensive, are clearly limited by their subjective nature.18 this study was designed with the consideration that no previous published studies had assessed medication adherence among omani patients with dm. a total of 158 self-administered questionnaires from patients with t2dm were evaluated as a part of this study. the results showed that compliance levels were similar in male and female participants as well as among various age groups. a lack of significant association between compliance practice scores related to dm and gender and age was similarly observed in a study conducted in the uae.13 in contrast, studies conducted in uganda19 and saudi arabia20 showed a significant association of compliance with the female gender and education levels. one factor that might contribute to medication adherence is the influence of employment status since those who are working have a higher tendency towards nonadherence due to work schedules. the social norms in countries like oman mean that males are generally the primary income-earning members of the family. the majority of participants in this study were unemployed older men who were more likely to be retired. hence, the combined influence of gender and work status might not have a significant influence on adherence as reported by the study participants. the number of years since participants had been diagnosed with dm did not affect levels of adherence in the present study. similar results were found in a study in saudi arabia.20 this findings would seem to contradict the idea that patients with a longer history of the disease would be keener to adhere to their medications since complications would have developed, or that they would have a greater awareness and fear of developing them. unlike other studies where the cost of medication was reported as a reason for non-adherence, only a small proportion of patients in this study reported this as a reason for failing to follow medication guidelines.14,19 this is a reflection of oman’s healthcare system, which is dedicated to maintaining the health of all citizens and thereby improving their quality of life. the financial burden of the disease does not affect omani patients due to the availability of free medical care, including medications. this might also have influenced the absence of any significant relationship between the number of years since the diabetes diagnosis and the adherence level among participants in the study. as was found in a study by richard et al., the number of anti-diabetic drugs prescribed to a patient did not affect the participants’ medication adherence scores.21 forgetting to take medications was the most frequently given reason for failing to adhere to treatment guidelines. it is of note that a large percentage of participants believed that missing one dose would not cause any problem, which highlights the importance of the need for counselling by healthcare professionals. the study results reveal good patient adherence overall to the medication regimen in areas such as dose, frequency and following instructions as to administration. this positive reported adherence could be attributed to many factors, including good communication between patients and healthcare professionals; patients’ knowledge of the disease and awareness of its complications; the availability of medicines free of cost through government healthcare facilities, and the convenient availability and location of healthcare facilities. the current study has some limitations. the sample size was small, which makes it difficult to generalise the results. it was difficult to identify and enroll patients in the manner used here as compared to recruiting a study population within a healthcare facility; hence, the quota sampling was challenging. the use of convenience sampling has its own inherent disadvantages. further, the patients’ levels of adherence were self-reported, which needs to be taken into account when interpreting the results. however, to reduce any tendency to over-report adherence to the regimen, the potential participants were selected from households rather than from healthcare institutions, as exaggerated self-reported adherence is greatest when patients are interviewed in healthcare settings. table 3: most common reasons for patient medication non-adherence reason number of participants (%) forgetting to take 79 (36.4) missing one dose is not an issue 32 (14.7) i feel i am fine 23 (10.6) too many medicines 23 (10.6) side-effects 19 (8.7) beena jimmy, jimmy jose, zainab a. al-hinai, intisar k. wadair and ghalia h. al-amri brief communication | e235 conclusion overall, the findings from the present study indicate that the medication adherence of t2dm patients in the al dakhliyah governorate of oman is good. however, this finding should be interpreted with caution as the data is based on self-reported measures of adherence. nonetheless, this study gives insight into the various factors that affect patient adherence to medication guidelines among an omani patient population; these factors should be targeted by healthcare professionals. awareness of these factors will allow healthcare professionals to be more effective in their medication counselling and patients to become more selfresponsible in adhering to a medication regimen. a c k n o w l e d g e m e n t s we would like to thank the participants of the study for their time and efforts. references 1. osterberg l, blaschke t. adherence to medication. n engl j med 2005; 353:487–97. doi: 10.1056/nejmra050100. 2. mahesh pa, parthasarathi g. medication adherence. in: parthasarathi g, nyfort-hansen k, nahata mc (eds). a textbook of clinical pharmacy practice: essential concepts and skills. 1st ed. hyderabad, india: sangam books ltd, orient blackswan publishing, 2004. pp. 54–70. 3. rubin rr. adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. am j med 2005; 118:27s–34s. doi: 10.1016/j.amjmed.2005.04.012. 4. delamater am. improving patient adherence. clin diabetes 2006; 24:71–7. doi: 10.2337/diaclin.24.2.71. 5. al-moosa s, allin s, jemiai n, al-lawati j, mossialos e. diabetes and urbanization in the omani population: an analysis of national survey data. popul health metr 2006; 4:5. doi: 10.1186/1478-7954-4-5. 6. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. doi: 10.1046/j.1464-5491.2002.00818.x. 7. khandekar r, al lawatii j, mohammed aj, al raisi a. diabetic retinopathy in oman: a hospital based study. br j ophthalmol 2003; 87:1061–4. doi: 10.1136/bjo.87.9.1061. 8. al-futaisi a, al-zakwani i, almahrezi a, al-hajri r, alhashmi l, al-muniri a, et al. prevalence and predictors of microalbuminuria in patients with type 2 diabetes mellitus: a cross-sectional observational study in oman. diabetes res clin pract 2006; 72:212–5. doi: 10.1016/j.diabres.2005.10.001. 9. al-mandhari a, al-zakwani i, el-shafie o, al-shafaee m, woodhouse n. quality of diabetes care: a cross-sectional observational study in oman. sultan qaboos univ med j 2009; 9:32–6. 10. al-riyami aa, afifi m. distribution and correlates of total impaired fasting glucose in oman. east mediterr health j 2003; 9:377–89. 11. al-adsani am, moussa ma, al-jasem li, abdella na, alhamad nm. the level and determinants of diabetes knowledge in kuwaiti adults with type 2 diabetes. diabetes metab 2009; 35:121–8. doi: 10.1016/j.diabet.2008.09.005. 12. kheir n, greer w, yousif a, al geed h, al okkah r. knowledge, attitude and practices of qatari patients with type 2 diabetes mellitus. int j pharm pract 2011; 19:185–91. doi: 10.1111/j.2042-7174.2011.00118.x. 13. al-maskari f, el-sadig m, al-kaabi jm, afandi b, nagelkerke n, yeatts kb. knowledge, attitude and practices of diabetic patients in the united arab emirates. plos one 2013; 8:e52857. doi: 10.1371/journal.pone.0052857. 14. adisa r, fakeye to, fasanmade a. medication adherence among ambulatory patients with type 2 diabetes in a tertiary healthcare setting in southwestern nigeria. pharmacy pract 2011; 9:72–81. 15. tiv m, viel jf, mauny f, eschwège e, weill a, fournier c, et al. medication adherence in type 2 diabetes: the entred study 2007, a french population-based study. plos one 2012; 7:e32412. doi: 10.1371/journal.pone.0032412. 16. sultanate of oman national center for statistics & information. statistical yearbook 2011. from: www.ncsi.gov.om/ncsi_ website/book/syb2011/2-population.pdf accessed: jul 2012. 17. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 18. wabe nt, angamo mt, hussein s. medication adherence in diabetes mellitus and self management practices among type2 diabetics in ethiopia. n am j med sci 2011; 3:418–23. doi: 10.4297/najms.2011.3418. 19. kalyango jn, owino e, nambuya ap. non-adherence to diabetes treatment at mulago hospital in uganda: prevalence and associated factors. afr health sci 2008; 8:67–73. doi: 10.4314/ahs.v8i2.7052. 20. khan ar, al-abdul lateef zn, al aithan ma, bu-khamseen ma, al ibrahim i, khan sa. factors contributing to noncompliance among diabetics attending primary health centers in the al hasa district of saudi arabia. j family community med 2012; 19:26–32. doi: 10.4103/2230-8229.94008. 21. grant rw, devita ng, singer de, meigs jb. polypharmacy and medication adherence in patients with type 2 diabetes. diabetes care 2003; 26:1408–12. doi: 10.2337/diacare.26.5.1408. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e388-392, epub. 24th jul 14 submitted 3rd jun 13 revisions req. 28th jul & 13th nov 13; revisions recd. 28th oct 13 & 12th feb 14 accepted 4th mar 14 1department of oral health, sultan qaboos university hospital, muscat, oman; 2data management department, petroleum development oman; 3the research council, muscat, oman. *corresponding author e-mail: salanqoo@hotmail.com معدل انتشار و منط األضراس الثالثة املنحشرة دراسة استعادية للصور الشعاعية من عمان �سمرية مبارك العنقودية، �سامل م�سلم ال�سديري، اأحمد احلو�سني، عبداهلل املنريي abstract: objectives: the aim of this retrospective study was to investigate the prevalence and pattern of third molar impaction in patients between 19‒26 years old attending sultan qaboos university hospital (squh) in muscat, oman. methods: the study reviewed 1,000 orthopantomograms (opgs) of patients attending the oral health department of squh between october 2010 and april 2011. patients were evaluated to determine the prevalence of third molar impaction, angulation, level of eruption and associated pathological conditions. results: of the study population, 543 (54.3%) opgs showed at least one impacted third molar. the total number of impacted molars was 1,128. the most common number of impacted third molars was two (41%). the most common angulation of impaction in the mandible was the mesioangular (35%) and the most common level of impaction in the mandible was level a. of the 388 bilateral occurrences of impacted third molars, 377 were in the mandible. there was no significant difference in the frequency of impaction between the right and left sides of both jaws. pathological conditions associated with impacted lower third molars were found in 18%, of which 14% were associated with a radiographic radiolucency of more than 2.5 mm, and 4% of impacted lower third molars were associated with dental caries. conclusion: this study found that more than half of omani adult patients ranging in age from 19‒26 years had at least one impacted third molar. keywords: third molar; impacted teeth; mandible; prevalence; oman. الفئة من املر�سى عند املنح�رسة الثالثة الأ�رس�س ومنط انت�سار معدل بحث هو ال�ستعادية الدرا�سة هذه من الهدف الهدف: امللخ�ص: العمرية 26-19 عاما املراجعني مل�ست�سفى جامعة ال�سلطان قابو�س مب�سقط، عمان. الطريقة: مت فح�س 1,000 �سورة اإ�سعاعية للمر�سى املراجعني لعيادة �سحة الفم و الأ�سنان من اأكتوبر 2010 اإىل اأبريل 2011. وقد مت تقييم املر�سى ملعرفة معدل انت�سار الأ�رسا�س الثالثة املنح�رسة، ن�سبة التزوي، م�ستوى الظهور والآفات املر�سية امل�ساحبة. النتائج: من عينة الدرا�سة، تبني اأن عدد 543 )%54.3( من �سور اثنان عدد كان كانت 1,128. املنح�رسة الثالثة الأ�رسا�س عدد جملة منح�رسة. الثالثة الأ�رسا�س اأحد الأقل على وجود اأظهرت الأ�سعة )35%( ال�سفلي الفك يف �سيوعا التزوي حالت اأكرث الو�سطي التزوي كان �سيوعا. الأكرث هو املنح�رسة الثالثة الأ�رسا�س من )41%( وم�ستوى الظهور a هو الأكرث �سيوعا. من اأ�سل 388 حالة ثنائية النح�سار، وجد هناك 377 حالة يف الفك ال�سفلي. مل يوجد اأي فارق معتد يف تردد النح�سار بني اجلهتني اليمنى والي�رسى لكلى الفكني. امل�ساكل املر�سية امل�ساحبة لالأ�رسا�س املنح�رسة �سكلت %18، منها %14 كانت م�ساحبة لتغريات اإ�سعاعية وا�سحة و %4 من الأ�رسا�س الثالثة ال�سفلية املنح�رسة كانت م�سابة بالت�سو�س ال�سني. اخلال�صة: اأو�سحت هذه الدرا�سة اأن اأكرث من ن�سف املر�سى العمانيني البالغني من الفئة العمريةـ 26–19 عاما لديهم على الأقل واحد من الأ�رسا�س الثالثة منح�رسة. �سنان املنح�رسة؛ الفك ال�سفلي؛ معدل النت�سار؛ عمان. مفتاح الكلمات: الأ�رسا�س الثالثة؛ الأ prevalence and pattern of third molar impaction a retrospective study of radiographs in oman *samira m. al-anqudi,1 salim al-sudairy,1 ahmed al-hosni,2 abdullah al-maniri3 clinical & basic research advances in knowledge this study supports the available literature worldwide on the high prevalence of third molar impaction. to the best of the authors’ knowledge, the present study is the first of its kind to show the prevalence of third molar impaction in oman. application to patient care this study identifies the future need for health education targeted at patients with impacted third molars, particularly regarding possible complications, and the possible treatments and surgical interventions for this condition. the study also highlights the need for careful evaluation during routine dental examinations to identify third molar impaction and encourage specialist referral in cases requiring further management. teeth become impacted when they fail to erupt or develop in their proper functional location; of all teeth, mandibular third molars are the most frequently impacted.1 the cause of third molar impaction is due to inadequate space in the mandible; this may cause pericoronitis, dental caries and the development of cystic lesions.2,3 the angle of impaction can be measured using winter’s samira m. al-anqudi, salim al-sudairy, ahmed al-hosni and abdullah al-maniri clinical and basic research | e389 classification system, with reference to the angle formed between the intersected longitudinal axes of the second and third molars.4 the pell and gregory classification system is one of the common methods used to assess the level of third molar impaction where the impacted third molars are assessed in relation to the neighbouring second molars.5 the prevalence of third molar impaction ranges from 27‒68.6%.6‒9 a few studies from the gulf region have reported the prevalence of impacted third molars to be 32‒40.5%.7,8 the pattern of third molar impaction in an omani population has not been described in the literature to date; thus, the aim of this retrospective radiographic study was to investigate the prevalence and pattern of third molar impaction, angulation, level of eruption and associated pathological conditions among dental patients treated in the oral health department in sultan qaboos university hospital (squh) in muscat, oman. methods this retrospective study was conducted from october 2010 to april 2011 and reviewed 1,000 orthopantomograms (opgs) of patients who presented to the outpatient dental centre and were treated at the oral health department at squh, muscat, oman, between 2006‒2010. only patients 19‒26 years old were selected for the study as third molar eruption usually begins at this age. the data were collected retrospectively from clinical notes and opgs. for the purposes of this study, opg x-rays were selected randomly which meant that not all patients included in the study had attended the clinic for the management of impacted wisdom teeth. therefore, patients with any of the following conditions were excluded: any pathosis or trauma to the jaws that might have disrupted the dentition alignment; third molars presenting with incomplete root formation; absent adjacent second molars, and/or the presence of congenital diseases or facial syndromes. two pairs of examiners viewed the opgs using sidexis xg software, version 2005 (sirona dental systems gmbh, bensheim, germany). the presence, location, depth and angle of impaction of third molars were noted. for this study, impaction, and angulation and level of impaction were defined as follows. the third molar was considered impacted when it was not fully erupted to the assumed normal functional position in the occlusal plane. the angulation of impaction of the mandibular third molar was determined by the angle formed between the intersected longitudinal axes of the second and third molars. this angle was measured using tools available in the sidexis software (sirona dental systems gmbh). the angulation of the impacted third molar was recorded using winter’s classification with reference to the angle formed between the intersected longitudinal axes of the second and third molars.4 the angulation of impaction was measured using quek et al.’s classification system: mesioangular impaction at 11° to 79°; vertical impaction at 10° to ‒10°; distoangular impaction at ‒11° to ‒79°, and horizontal impaction at 80° to 100°.9 uncommon angulations such as buccolingual, mesioinverted, distoinverted and distohorizontal angulations were classified as ‘other’. maxillary third molars were recorded as impacted when the lowest portion of the crown of an impacted maxillary third molar was below the occlusal plane of the second molar.10 the level of impaction was determined using the pell and gregory classification as follows.5 position a was recorded if the highest portion of the impacted mandibular third molar was on a level with or above the occlusal plane, whereas position b was recorded if the highest portion of the impacted mandibular third molar was below the occlusal plane but above the cervical line of the second mandibular molar. position c was recorded if the highest portion of the impacted mandibular third molar was below the cervical line of the second mandibular molar.5 the pathological condition of the impacted mandibular third molar was determined from the patient’s opg based on the existence of lesions in which the widest area of the distal aspect of the mandibular third molar was >2.5 mm and the presence of caries in the impacted third molar.11 all assessments were done by a single examiner to measure the angulation of impaction. findings were recorded when both examiners agreed. from the pilot study, interexaminer and intraexaminer reproducibility was found to be 85%. data were analysed using the statistical package for the social sciences (spss), version 19.00 (ibm, corp., chicago, illinois, usa). the patient’s age, gender, number of impacted third molars, classification of impaction, level of impaction and pathological conditions associated with impacted mandibular third molars were displayed by frequency and percentage. the pearson’s chi-squared test was used to test the association between different variables. ethical approval was obtained from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university, (mrec #385). all data, including patient identification and x-rays, were kept confidential. prevalence and pattern of third molar impaction retrospective study of radiographs in oman e390 | squ medical journal, august 2014, volume 14, issue 3 results of the 1,000 patients, there were 435 male and 565 female patients. a total of 215 (40%) of the male patients and 328 (60%) of the female patients showed at least one impacted third molar on their opg, yielding a male to female ratio of 2:3. a total of 1,128 impacted third molars were found [figure 1]. table 1 presents the distribution of subjects according to the total number of impacted third molars. a total of 64 (12%) patients had all four third molars impacted, 81 (15%) had three third molars impacted and 226 (41%) had two third molars impacted, while 172 (32%) had only one third molar impacted. the total number of impacted third molars in an individual was significantly different between males and females (p <0.01). females were 1.73 times more likely to have three or more impacted teeth than males (95% confidence interval [ci]: 1.13–2.65; p <0.001). table 2 shows the distribution of impacted third molars by gender and arch (either upper or lower jaw, otherwise known as the maxilla and mandible). the prevalence of impacted mandibular third molars (n = 817) was significantly greater than that of impacted maxillary third molars (n = 311) which was statistically significant (48.7% versus 19.0%; p <0.01). the mandible accounted for 72.4% (n = 817) and the maxilla accounted for 27.6% (n = 311) of the impacted third molars. impacted third molars were 4.1 times more likely to occur in the mandible than in the maxilla (95% ci: 3.5‒4.76; p <0.001). in the maxilla, females (n = 218, 30.7%) had more impacted third molar teeth than males (n = 93, 22.1%) which was statistically significant (p <0.001). in the mandible, there was no statistically significant difference between gender and lower-third molar impaction. in addition, there was no statistically significant difference between the right and left impacted third molars within each arch; therefore, these data were pooled. table 3 shows the occurrence of the different angulations of impaction in the mandible. overall, mesioangular impaction was the most frequent (n = 282, 35%), followed by distoangular (n = 267, 33%), vertical (n = 247, 30%) and finally both horizontal and other types of impaction (n = 22, 2%). the distribution of the different angulations of impaction was significantly different between genders (p <0.01). mesioangular impaction (n = 147, 45%) was the most common form of impaction among males and distoangular impaction (n = 200, 41%) the most common among females. of the 1,128 teeth, 474 (58%) were positioned with the highest portion of the impacted mandibular third molar on a level with or table 1: distribution of subjects by total number of impacted third molars (n = 543) total number of impacted third molars female male total % 1 98 74 172 32 2 129 97 226 41 3 56 25 81 15 4 45 19 64 12 totals, n (%) 328 (60) 215 (40) 543 (100) 100 table 2: distribution of fully erupted and impacted third molars by arch and gender maxilla mandible total fully erupted female 724 465 1,189 male 606 394 1,000 totals 1,330 859 2,189 impacted female 218 491 709 male 93 326 419 totals 311 817 1,128 table 3: distribution of the angulation of impaction in the mandibular third molars (n = 817) angulation impacted mandibular third molars n (%) total n (%) females males mesioangular 135 (27) 147 (45) 282 (35) vertical 148 (30) 99 (30) 247 (30) distoangular 200 (41) 67 (21) 267 (33) horizontal 4 (1) 7 (2) 11 (1) other 4 (1) 6 (2) 10 (1) totals 491 (100) 326 (100) 817 (100) figure 1: an orthopantomogram showing an impacted third molar. samira m. al-anqudi, salim al-sudairy, ahmed al-hosni and abdullah al-maniri clinical and basic research | e391 above the occlusal plane (level a). level c eruption occurred least frequently compared to other levels (1%). there was no significant difference between the right and left sides when considering impacted mandibular third molars (p = 0.085). of the 543 radiographs with impacted third molars, 388 (71%) showed bilateral impacted third molars. a total of 377 opgs showed a bilateral impaction of third molars in the mandible, of which 60% had the same angulation of mandibular third molar impaction. bilateral impaction in the maxilla occurred in 75 opgs in 64 opgs all four third molars were impacted. the pathological changes associated with the impacted lower mandibular third molars, either the presence of caries in the impacted lower third molar and/or a radiolucency of more than 2.5 mm in the distal aspect, are presented in table 4. only 18% of the total impacted mandibular third molars were affected by at least one of the two pathological changes. around 116 (14%) impacted mandibular lower third molars were associated with a radiolucency of more than 2.5 mm and most of the radiolucencies were associated with mesioangular and distoangular impactions. only 33 (4%) impacted lower third molars were associated with caries, which were most common in mesioangular impacted lower third molars (n = 19, 58% of total caries). discussion this is the first study to evaluate the prevalence of third molar impaction in oman. a total of 543 opgs with 1,128 impacted upper and lower third molars were analysed. it was found that 54.3% of patients attending the oral health department of squh had at least one impacted third molar, indicating how common impaction is and the need to explore the possible aetiological factors of this condition. this will help determine whether this is an emerging problem or due to influences of the population’s ethnic background. the aetiology of third molar impaction has never been investigated in an omani population and there is a need to conduct future studies to assess the causes of this condition more extensively. the prevalence found from this study was lower than that observed by quek et al. who reported a frequency of 68.6% in singaporean chinese.9 on the other hand, studies by hassan,8 hattab et al.,2 and reddy et al.,6 reported lower frequencies in studies done on saudi arabians (40.5%), jordanian students (47.4%) and indians (27%), respectively. in the current study, the most common number of impacted third molars per patient was two (41%), which is in agreement with the findings of quek et al.9 but not with those of hassan,8 who reported that one was the most common number of impacted third molars per opg. in contrast, ma’aita reported that 40% of jordanian patients had all four third molars impacted.3 the most common numbers of impacted third molars in the present study by order of frequency were two (226, 41%), one (172, 32%), three (81, 15%) and four (64, 12%). this is in agreement with quek et al.’s study.9 radiological examination of the opgs revealed that mesioangular impaction was the most common type of angulation (35%). this is in agreement with many other studies where the frequency of mesioangular impaction ranged from 33.4–62%.3,8,9,12–15 however, the current study’s results differ from studies published by reddy et al.6 and haider et al.7 which found that vertical impaction was the most common type of third molar impaction. this could be due to the fact that a different method of classifying angulation was used in the current study. another study classified angulation according to visual impressions based on winter’s classification method.4 in the current study, vertical impaction was observed in 30%, which is less than the findings of byahatti et al. (38%)12 and sandhu et al. (42%) in libyan and asian-indian populations, respectively.16 an analysis of the level of impaction showed that level a was the most common level of impaction (58%). this disagrees with the results of other research which reported that level b was the most common level of impaction.8,9,16 the present study showed that bilateral third molar impaction was more common than unilateral impaction. bilateral impaction occurred in 388 (71%) of the 543 radiographs examined, which is higher than that reported by quek et al. (63%); however, this result is still in agreement with their conclusion that the majority of bilateral impacted third molars occur in the mandible.9 the prevalence of maxillary third molar impaction in the current study was 15%, which was higher than the 10% reported by reddy and prasad in table 4: distribution of pathology associated with impacted mandibular third molars angulation radiolucency >2.5 mm n (%) caries n (%) mesioangular 50 (43) 19 (58) distoangular 48 (42) 5 (15) vertical 12 (10) 7 (21) horizontal 4 (3) 1 (3) other 2 (2) 1 (3) total 116 (100) 33 (100) prevalence and pattern of third molar impaction retrospective study of radiographs in oman e392 | squ medical journal, august 2014, volume 14, issue 3 a study done on an urban population in south india.6 pathological changes associated with impacted third molars were found in 14% in the current study, which is higher than the 10% reported by polat et al. in a turkish population.11 however, celikoglu et al.17 reported that most pathological changes were associated with horizontally impacted third molars, in contrast with this retrospective study which found most changes in cases of mesioangular and vertical impaction. the prevalence of dental caries in impacted lower third molars was 4% in the current study, which is similar to that reported by polat et al. (5%)11 in a turkish population and ma’aita in a sample of jordanian adults (8%).3 however, this prevalence of dental caries was significantly lower than those reported in kenyan (46%)15 and jordanian populations (13.6%).18 this difference may be attributable to the wide age range in these respective study populations. conclusion this is the first retrospective radiographic study investigating the prevalence of third molar impaction in young omani patients aged 19‒26 years old. the high prevalence found, with more than half of these omani adult patients having at least one impacted third molar, underlines the need to increase awareness among dental professionals. further studies should also be conducted to determine how many patients with impacted third molars are symptomatic or actively seek treatment. further studies are also needed to assess the pattern of third molar impaction in other regions of oman. references 1. dimitroulis g. a synopsis of minor oral surgery, 4th ed. oxford, uk: butterworth-heinemann publishing, 1996. pp. 48‒57. 2. hattab fn, rawashdeh ma, fahmy ms. impaction status of third molars in jordanian students. oral surg oral med oral pathol oral radiol endod 1995; 79:24‒9. doi: 10.1016/s10792104(05)80068-x. 3. ma’aita jk. impacted third molars and associated pathology in jordanian patients. saudi dent j 2000; 12:16‒19. 4. winter gb. the principles of exodontia as applied to the impacted third molars: a complete treatise on the operative technic with clinical diagnoses and radiographic interpretations. st. louis, missouri: american medical book co., 1926. 5. pell gj, gregory gt. report on a ten year study of a tooth division technique for the removal of impacted teeth. am j orthod oral surg 1942; 28:b660‒6. doi: 10.1016/s00966347(42)90021-8. 6. reddy kvg, prasad kvv. prevalence of third molar impactions in urban population of age 22-30 years in south india: an epidemological study. j indian dent assoc 2011; 5:609‒11. 7. haidar z, shalhoub sy. the incidence of impacted wisdom teeth in a saudi community. int j oral maxillofac surg 1986; 15:569‒71. doi: 10.1016/s0300-9785(86)80060-6. 8. hassan ah. pattern of third molar impaction in a saudi population. clin cosmet investig dent 2010; 2:109‒13. doi: 10.2147/cciden.s12394. 9. quek sl, tay ck, tay kh, toh sl, lim kc. pattern of third molar impaction in a singapore chinese population: a retrospective radiographic survey. int j oral maxillofac surg 2003; 32:548‒52. doi: 10.1016/s0901-5027(03)90413-9. 10. archer wh. oral and maxillofacial surgery, 5th ed. philadelphia: wb saunders company, 1976. p. 311. 11. polat hb, ozan f, kara i, ozdemir h, ay s. prevalence of commonly found pathoses associated with mandibular impacted third molars based on panoramic radiographs in turkish population. oral surg oral med oral pathol oral radiol endod 2008; 105:e41‒7. doi: 10.1016/j.tripleo.2008.02.013. 12. byahatti s, ingafou msh. prevalence of eruption status in third molars in libyan students. dent res j (isfahan) 2012; 9:152‒7. 13. obiechina ae, arotiba jb, fasola ao. third molar impaction: evaluation of the symptoms and pattern of impaction of mandibular third molar teeth in nigerians. odontostomatol tropic 2001; 24:22‒5. 14. jaffar ro, tin-oo mm. impacted mandibular third molars among patients attending hospital universiti sains malaysia. arch orofac sci 2009; 4:7‒12. 15. mwaniki d, guthua sw. incidence of impacted mandibular third molars among dental patients in nairobi, kenya. odontostomatol tropic 1996; 19:17–19. 16. sandhu s, kaur t. radiographic evaluation of the status of third molars in the asian-indian students. j oral maxillofac surg 2005; 63:640‒5. doi: 10.1016/j.joms.2004.12.014. 17. celikoglu m, miloglu o, kazanci f. frequency of agenesis, impaction, angulation, and related pathologic changes of third molar teeth in orthodontic patients. j oral maxillofac surg 2010; 68:990‒5. doi: 10.1016/j.joms.2009.07.063. 18. al-khateeb th, bataineh a. pathology associated with impacted mandibular third molars in a group of jordanians. j oral maxillofac surg 2006; 64:1598‒602. doi: 10.1016/j. joms.2005.11.102. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 422-428, epub. 20th nov 12 submitted 1st mar 12 revision req. 1st may 12, revision recd. 28th may 12 accepted 4th jul 12 chronic myeloid leukaemia (cml) was first described as a distinct entity in 1845. j.h. bennett described a young man who died with an enormously enlarged spleen, and d. craigie published a case of disease of the spleen, in which death took place as a consequence of the presence of purulent matter in the blood.1,2 both of these cases were published in edinburgh. according to barnett and eaves, a further case was described in 1845 by r. virchow.3,4 however what makes cml such an interesting disease is that it is the first human cancer to be associated with a non-random chromosomal abnormality, the philadelphia chromosome.5,6 nowell and hungerford described the relatively small chromosome 22, which is present in all cases of cml. this was extremely important because, for the first time in humans, doctors and scientists were able to communicate with one another about a disease which had a specific chromosomal marker; in other words, there was a well-defined chromosomal marker which defined the disease. االبيضاض النخاعي املزمن منوذج لورم خبيث أو جمرد مرض غريب؟ �صون مكان امللخ�ص: حتول االبيضاض النخاعي املزمن من مرض مميت إىل مرض ميكن التعامل معه باألدوية عن طريق الفم. بدأ وصف املرض ألول مرة يف منتصف القرن 19، ومل يكن هناك أي عالج مقبول على نطاق واسع حىت ظهور زرع اخلاليا اجلذعية يف أواخر السبعينيات، وكان هذا العالج ذي قيمة حمدودة بسبب املشاكل الناجتة عن قلة املتربعني والُسّمية. لكن بعد اكتشاف صبغي فيالدلفيا وبعد معرفة مسؤولية النمط الظاهري للمرض اخلبيث من قبل املوّرث ) chimaeric abl / bcr( فُتحت األبواب لطرق عالجية أخرى هلذا املرض. تغريت حياة املرضى املصابني هبذا املرض بعد تطوير مثبطات أنزمي كاينيز التايروسني. وكان العالج ناجحا جدا مع العديد من املرضى يف َهْدأَة املرض السريرية واجلزيئية ألكثر من 10 سنوات، بعدها أصبح االمتثال للعالج مشكلة يف الوقت احلايل. تتجه املناقشات يف الوقت الراهن حنو االستخدام احملتمل للجيل الثاين ملثبطات أنزمي كاينيز التايروسني للمرضى الذين شخصوا حديثا لتجنب التكلفة العالية هلذه األدوية. وعلى الرغم من جناح مثبطات أنزمي كاينيز التايروسني يف عالج االبيضاض النخاعي املزمن ، مل تتحقق مثل هذه النتائج الناجحة يف عالج حاالت السرطان الشائعة، وبالتايل يطرح السؤال اآليت: هل يُعّد االبيضاض النخاعي املزمن منوذجا للخبث أو ُهَو جمّرد مرض غريب؟ مفتاح الكلمات: االبي�صا�ض النخاعي املزمن، �صبغي فيالدلفيا، مثبطات انزمي كاينيز التايرو�صني. abstract: chronic myeloid leukaemia (cml), previously a fatal illness, is now readily manageable with oral medication. first described in the 1840s, there was no widely accepted cure until the advent of allogeneic stem cell transplantation in the late 1970s. this treatment was of limited value because of donor availability and toxicity problems. discovering the philadelphia chromosome and demonstrating that the bcr-abl chimaeric gene was responsible for the malignant phenotype opened new avenues. the development of tyrosine kinase inhibitors (tkis) changed the lives of patients with cml. the treatment has been so successful that compliance is now a problem. currently under discussion is the possible use of more expensive second generation tkis for newly diagnosed patients. in spite of the success with tkis, treatment of common cancers has not been so successful. is cml therefore a paradigm for malignancy or just a strange disease? keywords: chronic myeloid leukaemia; philadelphia chromosome; tyrosine kinase inhibitor. special contribution chronic myeloid leukaemia a paradigm for malignancy or just a strange disease? shaun r. mccann european haematology association, training online unit, the hague, netherlands e-mail: shaunrmccann@gmail.com shaun r. mccann special contribution | 423 production of a p210 protein in 95% of patients and a p190 in the remaining 5%. this should be established at diagnosis as it may be used to measure response to treatment. this hybrid gene expresses a tyrosine kinase (tk) that is constitutively active and influences adhesion of cells to the bone marrow stroma and cell division, and probably most importantly it inhibits apoptosis. these experiments were seminal because they raised the possibility of a completely new approach to treatment. from the 1970s to the 1990s, there was no adequate chemotherapy for cml, although prognostic scores were developed.9,10 the average life expectancy was about three years and death was usually a result of accelerated disease, or a ‘blast crisis’. most patients were diagnosed in the first chronic phase (cp) but the disease inevitably progressed to an accelerated phase and blast crisis, simulating acute leukaemia and death. a blast crisis was initially thought to be a form of acute myeloid leukaemia, but the description by marks et al. of the presence of the enzyme terminal deoxynucleotidyl transferase (tdt) in the cells of some patients clearly showed that the acute leukaemic phase could be lymphoid or myeloid.11 treatment of 1cp consisted of busulfan, hydroxycarbamide, or recombinant interferon-α. the former two drugs reduced the white cell count and had some impact on symptoms but did little to halt the inexorable improvements in technology increased our understanding of the pathogenesis of cml the exploitation of discoveries is often limited by lack of technology. likewise with cml, it was not until the introduction of banding technology that rowley demonstrated that the philadelphia chromosome, instead of a small chromosome 22, was in fact a reciprocal translocation between a part of the long arm of chromosome 9 and the long arm of chromosome 22 [figure 1].7 current diagnostic methods include fluorescent in situ hybridisation (fish). interesting as these findings may have been to scientists, the real question for medical doctors was, ‘could these observations be the key to new treatments?’ to put it another way, was the reciprocal translocation an epiphenomenon or was the genetic abnormality the cause of the malignant phenotype? it took some time but eventually a number of scientists demonstrated that this was indeed the case. using animal models, daley, among others, clearly demonstrated that the malignant phenotype was caused by the bcr-abl hybrid gene on chromosome 22.8 the fusion of the 3’ segment of abl1 to the 5’ part of the bcr gene resulting in bcr-abl1 transcripts gave rise to the figure 1: a karyotype showing the philadelphia chromosome. mccann s, foá r, smith o, conneally e. haematology: clinical cases uncovered. oxford: wiley-blackwell, 2009.36 chronic myeloid leukaemia a paradigm for malignancy or just a strange disease? 424 | squ medical journal, november 2012, volume 12, issue 4 the patients were that the drug was available in an oral form and was relatively free of severe toxicity. this drug launched the term ‘targeted therapy’ into medicine. imatinib is a specific inhibitor of the tk domain in the abl gene (abelson is a protooncogene), c-kit, and platelet-derived growth factor receptor (pdgfr). tks have an active binding site for adenosine 5'-triphosphate (atp), which leads to phosphorylation of many intracellular substrates [figure 2]. glivec® binds close to the atp binding site and inhibits the enzyme activity. inhibition of bcr-abl by glivec® also stimulates its transfer into the cell nucleus where it ceases to act as an antiapoptotic agent.17 the drug is metabolised by the liver enzyme cyp34a. toxicity is minimal and consists of anaemia (probably secondary to inhibition of the c-kit), thrombocytopaenia, musculoskeletal pain, and skin rashes. most patients respond to a single daily dose of 400 mg. the best-known data demonstrating the efficacy of imatinib come from the international randomized study of interferon and sti571. a seven year follow-up showed a rate of event-free survival (efs) of 83% and, most importantly, freedom of progression to a blast crisis in 92%. patients who achieved a complete cytogenetic response (ccyr) at 12 months were less likely to progress to an advanced stage or a blast crisis (97%). thus, there was a high cytogenetic response rate and that was progress of the disease. there was no effect on the underlying chromosomal abnormality. interferon-α was accompanied by significant toxicity but was occasionally associated with the disappearance of the philadelphia chromosome.12 progression of the disease was associated with genetic instability manifest by +8, +ph, +19 and i(17q). the only curative therapy before the introduction of tk inhibitors (tkis) was allogeneic stem cell (mostly bone marrow) transplantation. a number of limiting factors, however, dictated the success of allografting: the availability of a matched sibling donor, expense, and access to an experienced transplant unit.13 the toxicity of stem cell transplantation is considerable and includes sterility.14 as the median age for presentation of cml is between 50 and 60 years (depending on the reference), allogeneic stem cell transplantation was not an option for older patients when classical myeloablative conditioning was used. however, despite these limitations, if allogeneic stem cell transplantation was carried out in the first chronic phase within a year of diagnosis, the survival rate was excellent.15 the world changed forever with the use of tkis and the initial publications by druker et al.16 the first drug that had significant activity against the chromosomal lesion in cml was a tki known initially as st-571 (imatinib mesylate) and marketed by novartis as glivec®. the important issues for figure 2: the mechanism of action of tyrosine kinase inhibitors. figure reproduced with the kind permission of professor junia melo, head of leukaemia research, division of haematology, centre for cancer biology, imvs pathology, adeliade, australia. shaun r. mccann special contribution | 425 seem strange that a relatively non-toxic oral drug which produces a dramatic effect in most patients would be associated with this problem. indeed, we know that patients on chronic medication for nonmalignant diseases have <50% compliance after 5 years. the incidence may not be as high in cml, but compliance is a problem. the measurement of plasma levels of imatinib was initially believed to overcome this problem as trough levels were shown to be associated with the degree of response.22 recent studies from the hammersmith hospital in the uk have shown that patients may fail to comply but take an extra dose the day before coming to the clinic, thus making plasma levels an unreliable indicator of compliance.23 continual reinforcement of patients with encouragement to take the drug together with a warning of the potential consequences of intermittent therapy should be given. it should also be noted that in a 5-year follow-up, 25% of newly diagnosed patients had discontinued imatinib because of failure to respond, or toxicity.24 another perhaps more serious cause of failure to respond to imatinib or loss of response may be due to mutations in the bcr-abl kinase domain (abl1 kd mutations). techniques to detect these mutations include direct sequencing, denaturing high-performance liquid associated with failure of progression of the disease.18 as well as documenting a cytogenetic response to imatinib, we are now able to apply the most modern technology to monitor patient response using a multiplex polymerase chain reaction (pcr).19 a three-log reduction in the number of transcripts is now taken as evidence reflecting an optimal patient response. the european leukemianet (eln) has published criteria for an optimal response to glivec® and recommendations for other therapies.20 although the outlook has changed dramatically for patients with cml since the advent of imatinib, not all patients respond to this drug, and some patients who respond initially subsequently lose their response. these observations stimulated the development of more potent, second generation tkis. these drugs are more potent than imatinib, more expensive, and have greater toxicity. however, druker still gives imatinib to all new patients with cml as an initial therapy.21 so what is the ideal response to glivec and who should receive second generation tkis? the eln recommendations for an optimal response include a complete cytogenetic response at 12 months and a major molecular response at 18 months. what should the doctor do if these milestones are not reached? one of the interesting new findings has been poor patient compliance. it may figure 3: the decrease in numbers of patients referred for allogeneic transplantation. figure reproduced with the kind permission of the center for international blood and marrow transplant research. www.cibmtr.org aml = acute myeloid leukaemia; all = acute lymphoblastic leukaemia; cml = chronic myeloid leukaemia; aa = aplastic anaemia; lym = lymphoma; mm = multiple myeloma; cll = chronic lymphoblastic leukaemia. chronic myeloid leukaemia a paradigm for malignancy or just a strange disease? 426 | squ medical journal, november 2012, volume 12, issue 4 allografting, which include chronic graft-versushost disease (gvhd) and death, far outweigh the risks of taking tkis, but the expense of taking tkis indefinitely may be prohibitive in some countries. it should also be remembered that relapse can occur many years after apparently successful allografting. it is clear that imatinib or other tkis have a role to play in such circumstances.34,35 perhaps patients under 25 years of age in cp1 with a fully matched sibling donor should be referred for allografting, but even this is controversial as fatal gvhd may occur in this setting. in the last 10 years, cml has gone from the most common indication for allogeneic stem cell transplantation to the least common because of the use of effective treatment with tkis. whether newly diagnosed patients should be given imatinib or a second-generation tki as initial therapy remains controversial. patients who relapse or do not respond to tkis should be investigated for compliance and/or abl-kd mutations. although second-generation tkis may play some role in the treatment of advanced disease or blast crisis (not discussed here), these clinical entities remain problematical and, if feasible, such patients should be referred for allogeneic transplantation. as mentioned by druker, one of the benefits of imatinib is that it reduces the chances of a patient progressing to blast crisis and thus makes it difficult to define optimal treatment for advanced disease.21 the fact that tkis may not cure cml but achieve a remission during which the disease remains undetectable at a molecular level seems a philosophical question that is not important for most patients. after all, most diseases, with the exception of infections, remain incurable, but many are treatable. for patients leading a virtually normal life 13 years after the initial diagnosis of cml, and taking tki medication orally, the issue of undetectable molecular disease may seem somewhat irrelevant. unfortunately, the success of the tkis has not been matched in common cancers such as that of the breast, bowel, or prostate so the question remains to be answered: ‘is cml a paradigm for malignancy, or just a strange disease?’ n o t e the author wishes to declare that the opinions expressed in this article are his own and do not chromatography, pyrosequencing, and allelespecific pcr; however, direct sequencing is the recommended technique.25,26 in some cases, the detection of a specific abl1 kd mutation will indicate appropriate therapy, whereas many mutations do not carry any prognostic significance. the presence of the t315i mutation is important, as patients with this abl1 kd mutation will not respond to any of the second generation tkis, although there is emerging evidence of possible response to an aurora kinase inhibitor, ponatinib.27–29 if a patient has a suitable donor, s/he should be referred for allogeneic stem cell transplantation. some mutations are more likely to respond to second line tkis. abl1 kd mutations e25k/v, f359c/v, and y253h seem sensitive to dasatinib, a second generation tki, whereas f317l and v299l respond to nitolinib.30 there are other mechanisms of resistance to imatinib not discussed here, including oct1 activity and multiple copies of the ph chromosome. multidrug resistance polymorphisms may also play a role. in a significant number of patients, the mechanism of resistance to tkis is still unknown. what is the place of second-generation tkis? this is controversial at present.31 two recent reports in the new england journal of medicine pointed out the efficacy of these agents.32,33 they both are associated with more rapid and deeper responses than imatinib, but toxicity is increased. some investigators claim that second-generation tkis should be used, therefore, for all newly diagnosed patients but, as mentioned earlier, druker still initiates therapy with imatnib in newly diagnosed patients. the other issue which has become and will be of increasing significance is cost. at present, imatinib costs €30,000 (c. $38,400) per patient per annum and the second-generation drugs are more expensive. as all of these drugs significantly delay the progression of cml, there will be increasing numbers of patients in 1cp. can patients with a three-log molecular response, which has been maintained for a number of years, discontinue therapy? unfortunately, the answer is not simple. a number of studies are currently examining this issue but, at present, patients are advised to continue tkis indefinitely. what is the current role of allografting? referring patients for allografting is certainly less frequent than 10 years ago [figure 3]. the risks associated with shaun r. mccann special contribution | 427 bn, battiwalla m, stratton p. female long-term survivors after allogeneic hematopoietic stem cell transplantation: evaluation and management. 2012; 43:83–93. 15. gratwohl a, brand r, apperley j, crawley c, ruutu t, corradini p, et al. allogeneic hematopoietic stem cell transplantation chronic myeloid leukemia in europe 2006. transplant activity and long-term data and current results; an analysis by the leukemia working party of the european group for blood and bone marrow transplantation. haematologica 2006; 91:513–21. 16. druker bj, talpaz m, resta dj, peng b, buchdunger e, ford jm, et al. efficacy and safety of a specific inhibitor of the bcr/abl tyrosine kinase in chronic myeloid leukemia. n engl j med 2001; 344:1031–7. 17. vigneri p, wang jy. induction of apoptosis in chronic myeloid leukemia cells through nuclear entrapment of bcr-abl tyrosine kinase. nat med 2001; 7:228– 34. 18. hughes tp, hochhaus a, bradford s, et al. longterm prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the international randomised study of interferon and st-571 (iris). blood 2010; 116:3758–65. 19. cross nc, melo jv, feng l, goldman jm. an optimized multiplex polymerase chain reaction (pcr) for detection of bcr/abl fusion mrnas in haematological disorders. leukemia 1994; 8:1901– 28. 20. baccarani m, cortes j, pane f, niederwieser d, saglio g, apperley j, et al. chronic myeloid leukemia: an update of concepts and management recommendations of european leukemianet. j clin oncol 2009; 27:6041–51. 21. interview with brian druker. from: ehaweb. org/e duc ations c ience/online-le ar ningto ols/ podcasts/?start=5. accessed: feb 2012. 22. picard s, titier k, etienne g, teilhet e, ducint d, bernard ma, et al. trough imatinib plasma levels are associated with both cytogenetic and molecular response to standard-dose imatinib in chronic myeloid leukemia. blood 2007; 109:3496–9. 23. marin d, bazeos a, mahon fx, eliasson l, milojkovic d, bua m, et al. adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. leukemia 2010; 28:2381–8. 24. de lavallade h, apperley j, khorashad js, milokovic d, reid ag, bua m, et al. imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained response in an intention-totreat analysis. j clin oncol 2008; 26:3358–63. 25. langabeer se, mccarron sl, kelly j, krawczyk j, mcpherson s, perera k, et al. chronic myeloid leukemia with e19a2 bcr-abl1 transcripts and necessarily reflect the views of the european hematology association. references 1. bennett jh. case of hypertrophy of the spleen and liver, in which death took place from suppuration of the blood. edinb med surg j 1845; 64:413. 2. craigie d. case of disease of the spleen, in which death took place in consequence of the presence of purulent matter in the blood. edinb med surg j 1845; 64:400. 3. barnett mj, eaves cj. chronic myeloid leukemia. in: henderson es, lister ta, greaves mf, saunders, eds. philadelphia: elsevier science, 2002. pp. 583– 600. 4. virchow r. weisses blut. frorieps notizen 1845; 36:151–6. 5. nowell pc, hungerford da. a minute chromosome in human chronic granulocytic leukemia. science 1960; 132:1497. 6. nowell pc, hungerford da. chromosome studies in human leukemia: chronic granulocytic leukemia. j natl cancer inst 1961; 27:1013. 7. rowley jd. a new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and giemsa staining. nature 1973; 243:290. 8. daley gq, van etten ra, baltimore d. induction of chronic myelogenous leukemia in mice by then p210bcr/abl gene of the philadelphia chromosome. science 1990; 247: 824–30. 9. sokal je, cox eb, baccarani m, tura s, gomez ga, robertson je, et al. prognostic discrimination in ‘good-risk’ chronic granulocytic leukemia. blood 1984; 63:789–99. 10. hasford j, pfirmannm, hehlmann r, et al. a new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alpha. j natl cancer inst 1998; 90:850–8. 11. marks sh, mccaffrey r, rosenthal ds, moloney wc. blastic transformation in chronic myelogenous leukemia; experience with 50 patients. pediatr blood cancer 1978; 4:159–67. 12. talpaz m, kantarjian hm, mccredie k, trujillo jm, keating mj, gutterman ju. hematologic remission and cytogenetic improvement induced by recombinant human α interferon in chronic myelogenous leukemia. n engl j med 1986; 314:1065–9. 13. gratwohl a, baldomeno h, fraudenorfer k and niederwieser d. why are there regional differences in stem cell transplantation activity? an ebmt analysis. bone marrow transplant 2008; 42:s7–10. 14. shanis d, merideth m, pulamic tk, savani chronic myeloid leukaemia a paradigm for malignancy or just a strange disease? 428 | squ medical journal, november 2012, volume 12, issue 4 30. radich jp. chronic myeloid leukemia 2010: where are we now and where can we go? clinical impact of targeted therapies in myeloproliferative neoplasms. american society of hematology. education program book 2010; pp. 122–8. 31. sawyers cl. even better kinase inhibitors for chronic myeloid leukemia. n engl j med 2010; 362:2314–5. 32. saglio g, kim dw, issaragrisil s, le coutre p, etienne g, lobo c, et al. nilotinib versus ifor newly diagnosed chromic myeloid leukemia. n engl j med 2010; 362:2251–9. 33. kantarjian h, shah n, hocchaus a, cortes j, shah s, ayala m, et al. dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. n engl j med 2010; 362:2260–70. 34. kantarjian hm, o’brien s, cortes je, giralt sa, rios mb, shan j, et al. imatinib mesylate for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. blood 2002; 100:1590–5. 35. mccann sr, gately k, conneally e, lawler m. molecular response to imatinib mesylate following sct for cml. blood 2003; 101:1200. 36. mccann s, foá r, smith o, conneally e. haematology: clinical cases uncovered. oxford: wiley-blackwell, 2009. p. 80. marked thrombocytosis: the role of molecular monitoring. case report hematol 2012; epub 2 jul 2012. doi:10.1155/2012/458716. 26. soverini s, hochhaus, nicolini fe, gruber f, lange t, saglio g, et al. bcr/abl kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of european leukemianet (eln). blood 2011; 118:1208–15. 27. gorre me, mohammed m, ellwood k, hsu n, paquette r, rao pn, et al. clinical resistance to sti-571 cancer therapy caused by bcr/abl gene mutation or amplification. science 2001; 293:876– 80. 28. manrique arechavaleta g, school v, pérez v, bittencourt r, moellmann a, hassan r, et al. rapid and sensitive allele-specific (as)-rt-pcr assay for detection of t315i mutation in chronic myeloid leukemia patients treated with tyrosine kinase inhibitor imatinib. clin exp med 2011; 11:55–9. 29. cortes j, talpaz m, bixby d, deininger m, shah n, flinn i, et al. a phase 1 trial of oral ponatinib (ap24534) in patients with refractory chronic myelogenous leukemia (cml) and other hematologic malignancies: emerging safety and clinical response findings. american society of hematology (ash) annual meeting; 4–7 december, 2010; orlando, fl, usa. abstract 210. blood 2010; 116:21. 327 | squ medical journal, may 2013, volume 13, issue 2 sir, i read with interest the article by dr. ritu lakhtakia,1 which appeared in your november 2012 issue. i would like to draw the attention of the author and other readers to a very important omission—the training in oman of pharmacists and clinical pharmacists. the first bachelor of pharmacy (bpharm) programme was started in the fall of 2003 by the oman medical college, a private college in bausher, muscat. this is a four-and-a-half-year programme, and its first graduates received their degrees in december 2007. the second educational institution to offer a bpharm degree was the school of pharmacy in the college of pharmacy & nursing of the university of nizwa, a private non-profit institution. this is a five-year programme; the first students were admitted in the fall of 2004 and graduated in march 2010. the fourth class of graduating students are due to collect their degree certificates in march 2013. in the fall of 2003, the college of medicine & health sciences in sultan qaboos university, which is a government institution, started a two-year graduate programme leading to a master of science degree (msc) in biomedical sciences, with a major in clinical pharmacy. i present these programmes to complete the information related to the education of healthcare professionals in oman. i would like to acknowledge that i have been involved in, or taught at, all three of these institutions during the course of my career. qasim a. al-riyami college of pharmacy & nursing, university of nizwa, nizwa, oman e-mail: qasim@unizwa.edu.om reference 1. lakhtakia r. health professions education in oman: a contemporary perspective. sultan qaboos univ med j 2012; 12:406–10. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 327, epub. 9th may 13 submitted 17th feb 13 accepted 20th mar 13 رد: تعليم املهن الصحية يف سلطنة عمان منظور معاصر re: health professions education in oman a contemporary perspective letter to editor sir, an 8-year-old girl presented with defective motor coordination, a speech delay, behavioural problems, and generalised hypotonia. on examination, she was found to have hypermobile joints; a cardiac anomaly (patent ductus arteriosus); facial dysmorphism, and irregularly spaced, overcrowded teeth. magnetic resonance imaging (mri) of the brain performed as part of the neurologic work-up showed generalised hypodense white matter with multiple widely distributed foci of high signal intensity on the t2 and flair sequences [ ]. on t1 sequences, these areas were hypointense. subsequent investigations confirmed an underlying rare chromosomal anomaly called tetrasomy x (48, xxxx). tetrasomy x is a rare chromosomal anomaly that was first reported in 1961 in two children with neurodisabilities.1–3 although early case reports suggest mental deficiency as an obligatory feature of the syndrome, more recent reports confirm considerable variability in the phenotypical expression, making it difficult to assess the exact prevalence of the disorder.4 in this 8-year-old girl, the presence of facial dysmorphism, a cardiac anomaly, and central hypotonia prompted the magnetic resonance imaging (mri) brain scan as well as subsequent investigations that uncovered an otherwise unsuspected underlying disorder. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 537-538, epub. 20th nov 12 submitted 24th dec 11 revision req. 18th apr 12, revision recd. 25th apr 12 accepted 5th jun 12 تغريات غري عادية يف الدماغ يف حالة شذوذ الرباع x الصبغي م�صيلبواال ، فينوجوباالن unusual brain changes in tetrasomy x chromosomal anomaly m. mshelbwala1 and *p. venugopalan2 letter to editor figure 1: magnetic resonance imaging of the brain in a child with tetrasomy x showing diffuse ill-defined areas of high density on a t2 weighted image (a) and an axial flare image (b). the corresponding areas were more lucent on the t1 weighted images. unusual brain changes in tetrasomy x chromosomal anomaly 538 | squ medical journal, november 2012, volume 12, issue 4 mri changes associated with sex chromosome aneuploidies were extensively reviewed in a recent australian publication.5 reported studies mostly involve children with klinefelter’s syndrome (47, xxy), and 47, xxy males. findings in 47, xxy males include decreased grey and white matter volumes, with most pronounced effects in the frontal and temporal lobes. functional studies have shown evidence of decreased lateralisation. it is widely believed that the severity of brain changes increases with the number of x chromosomes, as shown in children with klinefelter’s syndrome and varying numbers of x chromosomes. a report on 3 children with 49, xxxxy documented varying degrees of brain volume loss and white matter changes, and similar changes could be expected with 48, xxxx.2 however, our patient exhibited widespread focal increase in the cerebral white matter density, with a normal cerebellum and brain stem. although the exact relationship between the brain changes and neurobehavioural manifestations has not been elucidated, these changes are consistent with developmental aberrations, and could form the basis for the above manifestations in affected children.5 m. mshelbwala1 and *p. venugopalan2 1department of paediatrics, university hospitals of north tees & hartlepool, holdforth road, hartlepool, uk 2department of child health, brighton & sussex university hospitals, brighton, uk *corresponding author e-mail: pvenugopalan@gmail.com references 1. schoubben e, decaestecker k, quaegebeur k, danneels l, mortier g, cornette l. tetrasomy and pentasomy of the x chromosome. eur j pediatr 2011; 170:1325–7. 2. hoffman tl, vossough a, ficicioglu c, visootsak j. brain magnetic resonance imaging findings in 49, xxxxy syndrome. pediatr neurol 2008; 38:450–3. 3. carr d, barr ml, plunkett er. an xxxx sex chromosome complex in two mentally defective females. canad med ass j 1961; 84:131–7. 4. blackston rd, chen atl. a case of 48, xxxx female with normal intelligence. j med genet 1972; 9:230–2. 5. lenroot rk, lee nr, giedd jn. effects of sex chromosome aneuploidies on brain development: evidence from neuroimaging studies. dev disabil res rev 2009; 15:318–27. department of ear, nose & throat, university of siena, siena, italy *corresponding author e-mail: ishajacopo@hotmail.it توطني املصدر الصويت حتت املاء بني الغواصني املكفوفني واملبصرين دراسة مقارنة جاكوبو كامبي، لودوفيكا ليفي، والرت ليفي abstract: objectives: many blind individuals demonstrate enhanced auditory spatial discrimination or localisation of sound sources in comparison to sighted subjects. however, this hypothesis has not yet been confirmed with regards to underwater spatial localisation. this study therefore aimed to investigate underwater acoustic source localisation among blind and sighted scuba divers. methods: this study took place between february and june 2015 in elba, italy, and involved two experimental groups of divers with either acquired (n = 20) or congenital (n = 10) blindness and a control group of 30 sighted divers. each subject took part in five attempts at an under-water acoustic source localisation task, in which the divers were requested to swim to the source of a sound originating from one of 24 potential locations. the control group had their sight obscured during the task. results: the congenitally blind divers demonstrated significantly better underwater sound localisation compared to the control group or those with acquired blindness (p = 0.0007). in addition, there was a significant correlation between years of blindness and underwater sound localisation (p <0.0001). conclusion: congenital blindness was found to positively affect the ability of a diver to recognise the source of a sound in an underwater environment. as the correct localisation of sounds underwater may help individuals to avoid imminent danger, divers should perform sound localisation tests during training sessions. keywords: blindness; auditory perception; sound localization; spatial processing; diving. املب�رشين. من بنظرائهم مقارنة ال�سوت م�سادر لتحديد �سمعيا و مكانيا متيزا املكفوفني االأفراد من العديد يظهر الهدف: امللخ�ص: امل�سادر توطني يف البحث اإىل الدرا�سة هذه هدفت لذا، املاء. حتت املكاين بالتوطني يتعلق فيما الفر�سية هذه تاأكيد يتم مل ذلك، ومع 2015 وحزيران/يونيه �سباط/فرباير بني الدرا�سة هذه اأجريت وقد الطريقة: واملب�رشين. املكفوفني الغوا�سني بني املاء حتت ال�سوتية يف اإلبا باإيطاليا، و�سملت جمموعتني جتريبيتني من الغوا�سني امل�سابني اإما بعمى مكت�سب )n = 20( اأو عمى خلقي )n = 10( وجمموعة �سابطة من 30 من الغوا�سني املب�رشين. وقام كل م�سارك بخم�س حماوالت لتوطني م�سدر �سوتي حتت املاء، طلب فيها من الغوا�سني ال�سباحة اإىل م�سدر �سوتي واحد من 24 موقعا حمتمال. وقد حجبت املجموعة ال�سابطة الب�رش خالل املهمة. النتائج: اأظهرت النتائج اأن الغوا�سني امل�سابني بالعمى اخللقي اأف�سل بكثري يف توطني ال�سوت حتت املاء مقارنة مع املجموعة ال�سابطة اأو تلك امل�سابة بالعمى املكت�سب )p = 0.0007(. وباالإ�سافة اإىل ذلك، كان هناك ارتباط كبري بني عدد �سنوات االأ�سابة بالعمى وقدرة توطني ال�سوت حتت املاء اأن املاء. حتت ال�سوت م�سدر على التعرف على الغوا�س قدرة على اإيجابي ب�سكل يوؤثر اخللقي العمى اأن وجد p(. اخلال�صة: <0.0001( اختبارات باإجراء للغوا�سني ين�سح فاأنه ولذلك املخاطرالو�سيكة، جتنب على االأفراد ي�ساعد قد املاء حتت لالأ�سوات ال�سحيح التوطني توطني ال�سوت خالل الدورات التدريبية. الكلمات املفتاحية: العمى؛ االإدراك ال�سمعي؛ توطني ال�سوت؛ املعاجلة املكانية؛ الغو�س. underwater acoustic source localisation among blind and sighted scuba divers comparative study *jacopo cambi, ludovica livi, walter livi clinical & basic research advances in knowledge to the best of the authors’ knowledge, this study is the first to investigate the sound recognition capabilities of both blind and sighted subjects in an underwater environment. the findings of this study indicated that subjects who were congenitally blind demonstrated superior spatial discrimination of an underwater sound source. among individuals who are blind, sensory substitution in the cortex may explain enhanced localisation of an underwater sound source, which is an extremely difficult task for a person who is sighted. application to patient care the findings of this study indicated that congenitally blind subjects were significantly more able to locate underwater sound sources. as such, healthcare practitioners should encourage both sighted divers and those with acquired blindness to undertake additional sound localisation tests during training sessions. sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e168–173, epub. 20 jun 17 submitted 27 dec 16 revision req. 15 feb 17; revision recd. 26 feb 17 accepted 9 mar 17 doi: 10.18295/squmj.2016.17.02.006 jacopo cambi, ludovica livi and walter livi clinical and basic research | e169 sound waves travel through the air at a speed of approximately 300 m/second; however, since water is denser than air, sound waves travel at 1,471 m/second underwater.1 in addition, variations in salinity, temperature and pressure (i.e. depth) also influence the propagation of sound underwater.1 the human ear functions relatively poorly underwater because the external ear canal fills with water, the eardrum moves less and the resonant frequency shifts to the bass tones. in such circumstances, most individuals hear via bone conduction and scuba divers consequently are more able to perceive low-frequency sounds than high-frequency sounds; however, the water has an overall sound damping effect.2 another peculiarity of underwater hearing is the difficulty in establishing the precise location of a source of sound; this therefore has important safety implications for scuba divers in terms of hazard perception. the ability of the brain to learn or relearn to localise sounds does not necessitate visuomotor feedback as the neural paths assigned to spatial hearing can be set up in a vision-independent manner.3 previous research on sound localisation among people who are blind has been based on the theory of crossmodal compensatory plasticity in which increased cortical activity has been hypothesised to compensate or hypercompensate for the loss of visual calibration in spatial hearing by employing non-visual sensory signals.4 using neuroimaging techniques, several studies have suggested that posterior visual areas in subjects who are blind may be active during the performance of non-visual tasks such as auditory localisation.5,6 nevertheless, while some studies have reported that blind individuals show better auditory spatial discrimination or localisation of sound sources than sighted subjects, other studies have failed to demonstrate this gain.7–10 recently, finocchietti et al. reported that localisation of sound in the mid-sagittal plane was poorer among blind individuals than sighted controls, indicating a clear deficit in encoding the sound motion in the lower hemisphere of the spherical coordinate system; however, the researchers confirmed that no such deficit was observed among congenitally blind subjects.11 voss et al. confirmed that individuals who are blind demonstrated supernormal abilities in the recognition of sound sources both nearby and at a distance.12 however, several other researchers have reported inferior performances during experimental tasks of spatial sound recognition among subjects who were blind compared to those who were sighted.13,14 to the best of the authors’ knowledge, the localisation of spatial sounds underwater has never before been evaluated among both blind and sighted subjects. this is significant as, in water, sounds can arise from any point in a three-dimensional setting, including the vertical as well as horizontal planes. this study therefore aimed to evaluate underwater sound recognition among both blind and sighted scuba divers as well as to evaluate differences in sound recognition between subjects with acquired blindness and those with congenital blindness. methods this study took place between february and june 2015 in elba, italy. a total of 60 subjects were recruited to participate in the study, of which 30 participants had either acquired (n = 20) or congenital (n = 10) visual impairment and 30 had no visual impairment. subjects were considered congenitally blind if their visual acuity was below 1/300 within the first year of life, indicating that they were unable to detect hand movements at a distance of 1 m from their better eye. all participants had been scuba diving for at least a year before the beginning of the study; the sighted divers had a minimum of an advanced open water diver qualification and at least 20 underwater dives in the preceding two years. the blind subjects were recruited with the aid of blind scuba diver partnerships. an audiological and motor function examination was performed on all subjects, including otoscopy, pure tone audiometry, tympanometry and tubaric function tests. all of the subjects had normal hearing levels at ≤20 decibels (db) and no history of hearing disorders. sound localisation tasks were performed in the secca della torre, a bay with a rocky seabed located in marciana marina, elba. the tasks took place in an underwater test area of 10 m x 10 m in which the average depth was 22 m and the maximum depth was 38 m. each subject entered the water and moved to the centre of the test area at a depth of approximately 5 m. subsequently, a sound was produced approximately 5 m away from the diver by rhythmically hitting a metal screwdriver against the side of a diving tank at a frequency of 1 hz and a rate of 60 times per minute. the estimated sound pressure level was 90 db with a frequency band range of 2–8 khz. the sound originated from one of 24 possible locations with each location varying by 45° on three horizontal planes (either on the surface, at a depth of 5 m or at a depth of 10 m). each plane had eight possible origin points of the sound. the sound source was determined randomly by throwing a 24-sided polyhedral dice [figure 1]. each subject repeated the task five times. some of the individuals in the congenital blindness group had residual light perception and were underwater acoustic source localisation among blind and sighted scuba divers comparative study e170 | squ medical journal, may 2017, volume 17, issue 2 therefore required to perform the test with their eyes closed. subjects in the control group were requested to perform the tests with closed eyes while wearing a diving mask which obscured their vision. completion of the sound localisation task was scored as follows. subjects were assigned one point if they reached the sound source in less than a minute without changing course. half a point was awarded if they reached a position within 45° of the sound source on the horizontal plane and then corrected their route (e.g. if the sound source was at position nine and the diver initially swam towards positions 16 or 10) or if they reached a position deeper or shallower than the sound source and then corrected their route (e.g. if the sound source was at position nine and the diver initially swam towards position one). the participants were assigned zero points if they did not reach the sound source within one minute or swam more than 45° away from the sound source. the total number of points for the five task attempts was then summed up for each diver to constitute the total task score. data were analysed using the statistical package for the social sciences (spss), version 16.0 (ibm corp., armonk, new york, usa). the participants were divided into three groups for the purposes of the statistical analysis: the acquired blindness group, the congenital blindness group and the control group of sighted subjects. percentages of exact locali sation of the sound source were computed independently for each subject and each group. comparisons between groups were assessed using either a t-test, analysis of variance or spearman’s rank-correlation coefficient analysis, as appropriate. a p value of <0.0500 was considered statistically significant. this study was performed in accordance with the ethical guidelines of the declaration of helsinki. informed written consent was obtained from all of the participants prior to their inclusion in the study. results among the 60 divers included in the study, 20 were female and 40 were male. the mean age was 36.9 ± 10.1 years. the mean number of years of diving experience was 5.0 ± 1.4, while the mean figure 1: diagram showing the experimental set-up of an underwater sound localisation task for blind and sighted scuba divers. each task took place in an underwater test area of 10 m x 10 m with the diver located in the middle at a depth of 5 m. subsequently, sounds originated from one of 24 potential sources on three horizontal planes, with the diver required to reach the sound source within one minute in as direct a route as possible. table 1: demographic and clinical characteristics and test scores of blind and sighted scuba divers participating in an underwater sound localisation task (n = 60) characteristic mean ± sd acquired blindness group (n = 20) congenital blindness group (n = 10) control group (n = 30) total (n = 60) age in years 37.2 ± 9.1 37.1 ± 10.0 36.7 ± 10.4 36.9 ± 10.1 male-to-female ratio 15:5 7:3 18:12 40:20 years of blindness 14.6 ± 8.0 37.1 ± 10.0 years of diving experience 4.9 ± 8.0 5.5 ± 0.9 5.0 ± 1.4 5.0 ± 1.4 total task score* 2.6 ± 1.8 4.2 ± 0.8 1.8 ± 1.5 2.5 ± 1.5 time taken to perform task in seconds 46.0 ± 8.8 39.0 ± 6.5 46.6 ± 7.8 45.1 ± 7.8 number of perfect task scores† out of the total number of task attempts 33/100 36/50 36/150 105/300 sd = standard deviation. *total score after five attempts at the task. †perfect scores were awarded if subjects reached the sound source in less than a minute without changing course. jacopo cambi, ludovica livi and walter livi clinical and basic research | e171 number of years of blindness was 14.6 ± 8.0 and 37.1 ± 10.0 for the acquired blindness and congenital blindness groups, respectively [table 1]. among the acquired blindness group, 14 patients had retinitis pigmentosa, while three had glaucoma and one patient each had macular degeneration, a bilateral ocular injury or optic nerve atrophy. there were no significant differences in age, gender distribution or number of years of diving experience between the three groups. there was a statistically significant difference between the total task scores of the congenital blindness and acquired blindness groups as well as between the congenital blindness and control groups (p = 0.0007) [figure 2]. however, no significant difference was observed between the total scores of control subjects and those with acquired blindness. there was a significant positive association between the total sound localisation score and number of years of blindness (p <0.0001) and a significant negative correlation between the time taken to execute the task and number of years of blindness (p = 0.0452). however, no correlations were noted between age and years of diving experience or between time taken to execute the task and years of diving experience [table 2]. in an independent analysis of the acquired blindness group, there was a positive correlation between the number of years of blindness and the total task score (p = 0.0231). discussion while numerous studies have investigated sound localisation among sighted and blind subjects, most have focused on comparing sound localisation in two and three dimensions or on identifying mechanisms and conditions which favour individuals who are congenitally blind.3,15,16 to the best of the authors’ knowledge, the current study is the first to investigate the sound recognition capabilities of blind and sighted subjects in an underwater environment, comparing divers who were congenitally blind, those with acquired visual loss and a sighted control group whose vision was temporarily obscured. moreover, previous research has limited sound localisation experiments among blind individuals to one horizontal plane or to a small number of potential sound source positions.17 in the current study, a high number of potential sound source locations were included on three different horizontal planes; these experimental conditions therefore more accurately reflected the real-life experience of scuba diving in an open water environment. during auditory processing, a lag period of about 0.6 milliseconds—known as the interaural time difference (itd)—permits location of a sound source figure 2: bar chart showing the mean total task scores* of blind and sighted scuba divers participating in an underwater sound localisation task (n = 60). there was a significant difference between the scores of divers who were congenitally blind in comparison to sighted subjects and those with acquired blindness (p = 0.0007).† *total score after five attempts at the task. †using dunn’s multiple comparison test. table 2: correlation matrix* between demographic and clinical characteristics and test scores among blind and sighted scuba divers participating in an underwater sound localisation task (n = 60) correlation coefficient (p value) years of blindness years of diving experience time taken to perform task total task score† age years of blindness 0.1298 (0.3225) -0.2594 (0.0452)‡ 0.5145 (0.0001)‡ 0.0670 (0.6108) years of diving experience 0.1298 (0.3225) -0.0336 (0.7987) 0.1646 (0.2086) 0.1052 (0.4232) time taken to perform task -0.2594 (0.0452)‡ -0.0336 (0.7987) -0.1465 (0.2639) 0.0364 (0.7821) total task score† 0.5145 (0.0001)‡ 0.1646 (0.2086) -0.1465 (0.2639) 0.1585 (0.2261) age 0.0670 (0.6108) 0.1052 (0.4232) 0.0364 (0.7821) 0.1585 (0.2261) *using spearman’s rank-correlation coefficient. †total score after five attempts at the task. ‡statistically significant at p <0.0500. underwater acoustic source localisation among blind and sighted scuba divers comparative study e172 | squ medical journal, may 2017, volume 17, issue 2 in air, but does not occur under water due to the rapid propagation of sound.18 according to functional magnetic resonance imaging, four anatomical structures are involved during itd: the superior olivary complex in the pons, in which loudness is analysed by the medial nuclei and spatial laterality by the lateral nuclei; the midbrain inferior colliculus, which senses duration, loudness, frequency, spatial domain, amplitude modulation and bi-aural interactions; the medial geniculate body, which determines spatial localisation and differences in interaural intensity; and the posterior parietal and frontal cortexes.19,20 usually, a spherical coordinate scheme is used to express the origin of a sound relative to the position or orientation of the cranium, with sounds detectable on the frontal, horizontal and median planes. when a sound arrives at the ear, the auditory signal is successively transmitted by the neuronal nuclei in the auditory pathway in the brainstem until it reaches the auditory cortex. however, underwater sounds are perceived as if they originate symmetrically in front, behind and above the subject.21 in addition, the head shadow effect (i.e. a reduction in sound amplitude due to the volume of head) is missing underwater, so the discrimination of high-frequency (>3,000 hz) sound sources is difficult.22 recently, shupak et al. tested the use of masks with an air pocket around the ears as a method of improving underwater auditory perception; however, the authors concluded that the masks did not significantly improve underwater hearing.23 among scuba divers, poor sound localisation is a source of concern as certain sounds may indicate imminent danger, such as an approaching motorboat. in the current study, the results of the spatial localisation tasks among the sighted controls indicated that they could only immediately identify the source of sound at a rate of 24%; therefore, the task was feasible in only one out of four attempts. hypothetically, simply guessing the source of the sound using mathematical probability would result in seven correct answers, which is much lower than the actual rate of correct localisation. additionally, the average task execution time and rate of correction was relatively higher in the control group, with subjects making many changes in course. divers should therefore practice sound localisation during their training so as to more accurately perceive sources of potential hazards while underwater. as confirmed by wightman et al., it is easier to identify the source of a sound which originates closer to the subject than those which are more remote; therefore, sound localisation tasks become much easier during execution as the subjects move closer to the source.24 in accordance with existing scientific literature, the current researchers observed that many divers started their route more medially than ideal, as if exposing one ear towards the sound so as to aid understanding of where the sound was generated.25 in addition, interaural temporal and intensity differ ences are reduced in water; this explains why divers have difficulty in determining from which side a sound originates.2 the results of the current study agree with those of the existing literature in demonstrating enhanced spatial sound recognition among blind subjects in comparison to sighted controls.3,26 in particular, subjects who were blind from birth spent less time reaching the sound source and more often obtained perfect results; they also changed or adjusted their direction less frequently when moving towards the source of the sound. one theory to explain these findings is that certain auditory brain areas implicated in auditory motion perception may show greater activation among people who are blind; for example, neuroimaging has revealed that the posterior parietal cortex in blind subjects is more intensely activated during tasks of immobile sound localisation and motion discrimination than in sighted controls.6,27–29 another hypothesis focuses on compensatory plasticity in blindness, which may result in the recruitment of deafferented occipital cortical areas for the processing of auditory data; this theory is based on the strong extension and improvement of pre-existing neuronal pathways in the occipital cortex for processing auditory information.29,30 in the current study, a positive correlation was noted between number of years of blindness and task scores among subjects with acquired blindness; this finding indicates that, for two blind individuals of the same age, the individual who lost their sight earlier may have developed more effective spatial sound localisation abilities. a major limitation of the present study was that the sounds used in the sound localisation task were not studied with a hydrophone system to determine the exact frequency and intensity of the sound upon reaching the diver. however, all subjects had normal hearing levels and they all reported hearing the rhythmic sounds very clearly. another limitation is that, in seawater, different temperature levels can act as acoustic insulators;1 however, to counteract this, all tasks were conducted in the morning, when the sea was calm and at an average temperature of 20 ± 2 °c. conclusion subjects who were congenitally blind demonstrated superior spatial discrimination abilities in terms of locating an underwater sound source. these results jacopo cambi, ludovica livi and walter livi clinical and basic research | e173 therefore add to the growing body of evidence supporting sensory substitution or hypercompensation among individuals who are blind. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. lurton x. an introduction to underwater acoustics: principles and applications, 2nd ed. london, uk: springer, 2010. pp. 13–20. 2. hollien h. underwater sound localization in humans. j acoust soc am 1973; 53:1288–95. doi: 10.1121/1.1913466. 3. king aj. visual influences on auditory spatial learning. philos trans r soc lond b biol sci 2009; 364:331–9. doi: 10.1098/ rstb.2008.0230. 4. kujala t, alho k, huotilainen m, ilmoniemi rj, lehtokoski a, leinonen a, et al. electrophysiological evidence for crossmodal plasticity in humans with earlyand late-onset blindness. psychophysiology 1997; 34:213–16. doi: 10.1111/j.1469-8986. 1997.tb02134.x. 5. leclerc c, saint-amour d, lavoie me, lassonde m, lepore f. brain functional reorganization in early blind humans revealed by auditory event-related potentials. neuroreport 2000; 11:545–50. 6. weeks r, horwitz b, aziz-sultan a, tian b, wessinger cm, cohen lg, et al. a positron emission tomographic study of auditory localization in the congenitally blind. j neurosci 2000; 20:2664–72. 7. ashmead dh, wall rs, ebinger ka, eaton sb, snook-hill mm, yang x. spatial hearing in children with visual disabilities. perception 1998; 27:105–22. doi: 10.1068/p270105. 8. lessard n, paré m, lepore f, lassonde m. early-blind human subjects localize sound sources better than sighted subjects. nature 1998; 395:278–80. doi: 10.1038/26228. 9. muchnik c, efrati m, nemeth e, malin m, hildesheimer m. central auditory skills in blind and sighted subjects. scand audiol 1991; 20:19–23. doi: 10.3109/01050399109070785. 10. wanet mc, veraart c. processing of auditory information by the blind in spatial localization tasks. percept psychophys 1985; 38:91–6. doi: 10.3758/bf03202929. 11. finocchietti s, cappagli g, gori m. encoding audio motion: spatial impairment in early blind individuals. front psychol 2015; 6:1357. doi: 10.3389/fpsyg.2015.01357. 12. voss p, lassonde m, gougoux f, fortin m, guillemot jp, lepore f. earlyand late-onset blind individuals show supranormal auditory abilities in far-space. curr biol 2004; 14:1734–8. doi: 10.1016/j.cub.2004.09.051. 13. gori m, sandini g, martinoli c, burr dc. impairment of auditory spatial localization in congenitally blind human subjects. brain 2014; 137:288–93. doi: 10.1093/brain/awt311. 14. thinus-blanc c, gaunet f. representation of space in blind persons: vision as a spatial sense? psychol bull 1997; 121:20–42. doi: 10.1037/0033-2909.121.1.20. 15. lewald j. vertical sound localization in blind humans. neuropsychologia 2002; 40:1868–72. doi: 10.1016/s00283932(02)00071-4. 16. voss p, tabry v, zatorre rj. trade-off in the sound localization abilities of early blind individuals between the horizontal and vertical planes. j neurosci 2015; 35:6051–6. doi: 10.1523/jneu rosci.4544-14.2015. 17. zwiers mp, van opstal aj, cruysberg jr. two-dimensional sound-localization behavior of early-blind humans. exp brain res 2001; 140:206–22. doi: 10.1007/s002210100800. 18. bernstein lr. auditory processing of interaural timing information: new insights. j neurosci res 2001; 66:1035–46. doi: 10.1002/jnr.10103. 19. seifritz e, di salle f, esposito f, herdener m, neuhoff jg, scheffler k. enhancing bold response in the auditory system by neurophysiologically tuned fmri sequence. neuroimage 2006; 29:1013–22. doi: 10.1016/j.neuroimage.2005.08.029. 20. engel sa, rumelhart de, wandell ba, lee at, glover gh, chichilnisky ej, et al. fmri of human visual cortex. nature 1994; 369:525. doi: 10.1038/369525a0. 21. hernández-zamora e, poblano a. [the auditory pathway: levels of integration of information and principal neurotransmitters]. gac med mex 2014; 150:450–60. 22. rayleigh l. our perception of the direction of a source of sound. nature 1876; 14:32–3. doi: 10.1038/014032a0. 23. shupak a, sharoni z, yanir y, keynan y, alfie y, halpern p. underwater hearing and sound localization with and without an air interface. otol neurotol 2005; 26:127–30. 24. wightman fl, kistler dj. factors affecting the relative salience of sound localization cues. in: gilkey rh, anderson tr, eds. binaural and spatial hearing in real and virtual environments. new york, usa: lawrence erlbaum associates inc., 1997. pp. 1–24. 25. wells mj, ross he. distortion and adaptation in underwater sound localization. aviat space environ med 1980; 51:767–74. 26. röder b, teder-sälejärvi w, sterr a, rösler f, hillyard sa, neville hj. improved auditory spatial tuning in blind humans. nature 1999; 400:162–6. doi: 10.1038/22106. 27. gougoux f, zatorre rj, lassonde m, voss p, lepore f. a functional neuroimaging study of sound localization: visual cortex activity predicts performance in early-blind individuals. plos biol 2005; 3:e27. doi: 10.1371/journal.pbio.0030027. 28. poirier c, collignon o, scheiber c, renier l, vanlierde a, tranduy d, et al. auditory motion perception activates visual motion areas in early blind subjects. neuroimage 2006; 31:279–85. doi: 10.1016/j.neuroimage.2005.11.036. 29. lewald j. exceptional ability of blind humans to hear sound motion: implications for the emergence of auditory space. neuropsychologia 2013; 51:181–6. doi: 10.1016/j.neuropsycho logia.2012.11.017. 30. lewald j, meister ig, weidemann j, töpper r. involvement of the superior temporal cortex and the occipital cortex in spatial hearing: evidence from repetitive transcranial magnetic stimulation. j cogn neurosci 2004; 16:828–38. doi: 10.1162/089892904970834. https://doi.org/10.1121/1.1913466 https://doi.org/10.1098/rstb.2008.0230 https://doi.org/10.1098/rstb.2008.0230 https://doi.org/10.1111/j.1469-8986.1997.tb02134.x https://doi.org/10.1111/j.1469-8986.1997.tb02134.x https://doi.org/10.1068/p270105 https://doi.org/10.1038/26228 https://doi.org/10.3109/01050399109070785 https://doi.org/10.3758/bf03202929 https://doi.org/10.3389/fpsyg.2015.01357 https://doi.org/10.1016/j.cub.2004.09.051 https://doi.org/10.1093/brain/awt311 https://doi.org/10.1037/0033-2909.121.1.20 https://doi.org/10.1016/s0028-3932%2802%2900071-4 https://doi.org/10.1016/s0028-3932%2802%2900071-4 https://doi.org/10.1523/jneurosci.4544-14.2015 https://doi.org/10.1523/jneurosci.4544-14.2015 https://doi.org/10.1007/s002210100800 https://doi.org/10.1002/jnr.10103 https://doi.org/10.1016/j.neuroimage.2005.08.029 https://doi.org/10.1038/369525a0 https://doi.org/10.1038/014032a0 https://doi.org/10.1038/22106 https://doi.org/10.1371/journal.pbio.0030027 https://doi.org/10.1016/j.neuroimage.2005.11.036 https://doi.org/10.1016/j.neuropsychologia.2012.11.017 https://doi.org/10.1016/j.neuropsychologia.2012.11.017 https://doi.org/10.1162/089892904970834 sir, ashfaq et al.1 reported a significant correlation between circulating lipoprotein(a) [lp(a)] levels and the severity of coronary atherosclerosis (as assessed by the syntax score) in a north indian population. the authors suggested that lp(a) levels of >20 mg/dl predict the severity of coronary atherosclerosis. a few additional comments may be of interest to readers. studies have found a positive correlation between lp(a) and total cholesterol or low-density lipoprotein cholesterol (ldl-c) levels but an inverse association with triglyceride (tg) levels in patients with diabetes mellitus (dm).2 ashfaq et al.1 did not discuss the relationship between ldl-c and lp(a). in addition, the authors showed that lp(a) levels tended to be higher at raised tg levels.1 it would be useful to know how many patients in this study had dm. ashfaq et al.1 did not include the details of the kit used for the lp(a) measurement and the precision data at the different lp(a) levels. the problems with isoform specificity in lp(a) measurements, the sub-optimal performance of the different assays and the lack of commutability across lp(a) assay systems are well-known.3 population studies show that females after the age of 45 years tend to have higher lp(a) values than men of the same age.4 also, hormone replacement therapy can reduce the plasma concentration of lp(a).5 the authors did not describe the effect of gender on lp(a) nor show the numbers of females in the two groups and whether some of these women were on hrt. if there were more women in one group than the other, this may have influenced the distribution of lp(a) concentrations. lp(a) values are known not to be normally distributed.6 therefore, the preferred statistical evaluation is to use nonparametric tests and the data should be expressed in medians and ranges. in addition, the cut-off value (>20 mg/dl) proposed by ashfaq et al.1 could be influenced by the use of the mean ± standard deviation. by using a receiver operating characteristic curve analysis and calculating the area under the curve, the accuracy of a diagnostic test can be determined and used to predict the best cut-off value by showing the sensitivity and specificity of the test at a certain cut-off point. in our opinion, it would be interesting to carry out such a procedure for this particular study and to see the results. *khawla h. al-musalhi and devaki r. nair department of clinical biochemistry, royal free hospital, london, uk corresponding author e-mail: khawla.almusalhi@nhs.net references 1. ashfaq f, goel pk, moorthy n, rishi sethi, khan mi, idris mz. lipoprotein(a) and syntax score association with severity of coronary artery atherosclerosis in north india. sultan qaboos university med j 2012; 12:465–72. 2. hernández c, chacón p, garcía-pascual l, simó r. differential influence of ldl cholesterol and triglycerides on lipoprotein(a) concentrations in diabetic patients. diabetes care 2001; 24:350–5. 3. luc g, arveiler d, ferrieres j, evans a, amouyel p, fruchart jc, et al. lipoprotein (a) as a predictor of coronary heart disease: the prime study. atherosclerosis 2002; 163:377–84. 4. panteghini m, pagani f. pre-analytical, analytical and biological sources of variation of lipoprotein(a). eur j clin chem clin biochem 1993; 31:23–8. 5. kim cj, jang hc, cho dh and min yk. effects of hormone replacement therapy on lipoprotein(a) and lipids in postmenopausal women. arterioscler thromb 1994; 14:275–81. 6. nordestgaard bg, chapman mj, ray k, borén j, andreotti f, watts gf, et al. lipoprotein(a) as a cardiovascular risk factor: current status. eur heart j 2010; 31:2844–53. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 465, epub. 25th jun 13 submitted 11th feb 13 accepted 1st may 13 رد: الربوتني الدهين )أ( ومقياس syntax و ارتباطه مع شدة تصلب الشريان التاجي يف مشال اهلند re: lipoprotein(a) and syntax score association with severity of coronary artery atherosclerosis in north india letter to editor 458 | squ medical journal, august 2013, volume 13, issue 3 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e448−454, epub. 14th oct 14 submitted 14th mar 14 revision req. 14th apr; revision recd. 27th apr 14 accepted 8th may 14 currently, the optimal anticoagulant therapy to use during pregnancy in patients with mechanical prosthetic valves (mpvs) remains controversial, with the published international guidelines lacking a clear-cut consensus on the issue.1‒4 this is due to the fact that presently there is no anticoagulant available which results in both an excellent maternal outcome, defined by fewer thromboembolic events (tes), and minimal fetal damage, which is defined by the prevention of fetal loss or embryopathy. the case study that follows focuses on a pregnant patient with prosthetic valve thrombosis who was administered a fixed dose of lowmolecular-weight heparin (lmwh) throughout her first pregnancy. the leading international guidelines are then evaluated and a simplified approach to managing this type of patient is proposed. case study a 28-year-old omani pregnant woman was admitted to a regional hospital in oman in august 2009 for monitoring. she had received a st. jude medical™ standard bileaflet mpv (st. jude medical, inc., saint paul, minnesota, usa) for mitral regurgitation in the uk 15 years previously. the patient had been on regular warfarin (6 mg per day) since receiving the implant with good international normalised ratio (inr) control. when her pregnancy had become apparent in january 2009, the warfarin was stopped and she was begun on lmwh instead. she was prescribed dalteparin which was administered subcutaneously once daily at a dosage of 10,000 iu. she continued taking lmwh throughout her pregnancy without being monitored for her anti-factor xa levels as such monitoring was not available at the regional hospital. departments of 1cardiology and 2obstetrics & gynaecology, royal hospital, muscat, oman *corresponding author e-mail: prashanthp_69@yahoo.co.in صمامات القلب الصناعية واحلمل املعضلة العالجية ملنع ختثر الدم برا�شانت باندوراجنا، حممد الديب، �شيرتا جها abstract: choosing the best anticoagulant therapy for a pregnant patient with a mechanical prosthetic valve is controversial and the published international guidelines contain no clear-cut consensus on the best approach. this is due to the fact that there is presently no anticoagulant which can reliably decrease thromboembolic events while avoiding damage to the fetus. current treatments include either continuing oral warfarin or substituting warfarin for subcutaneous unfractionated heparin or low-molecular-weight heparin (lmwh) in the first trimester (6–12 weeks) or at any point throughout the pregnancy. however, lmwh, while widely-prescribed, requires close monitoring of the blood anti-factor xa levels. unfortunately, facilities for such monitoring are not universally available, such as within hospitals in developing countries. this review evaluates the leading international guidelines concerning anticoagulant therapy in pregnant patients with mechanical prosthetic valves as well as proposing a simplified guideline which may be more relevant to hospitals in this region. keywords: heart valve prosthesis; pregnancy; warfarin; low-molecular-weight heparin; thrombosis. امللخ�ش: ل يزال هختيار العالج الأمثل ملنع تخرث الدم على ال�شمامات ال�شناعية اأثناء احلمل حمل نقا�ش كما اأن الإر�شادات العالجية ويف الدم تخرث مينع الذي العالج توفر عدم هو لذلك الرئي�ش ال�شبب اأن واحلقيقة الأمثل. للعالج بالن�شبة وا�شحة توجيهات حتوي ل ذات الوقت ل ي�رض باجلنني. يف الوقت احلايل هناك طريقان للعالج: الأول يتمثل يف ا�شتمرار تعاطي دواء الوارفارين والآخر ا�شتبدال الوارفارين بحيث يتعاطى املري�شا لهيبارين غري املجزأ املعطى حتت اجللد اأو الهيبارين ذا الوزن اجلزيئي املنخف�ش من 12-6 اأ�شبوع من احلمل اأو خالل اأي فرتة اأثناء احلمل.ورغم اأن اأنواع الهيبارين ذات الوزن اجلزيئي املنخف�ش ت�شتعمل وبكرثة يف هذه احلالت اإل اأن متابعة العالج حتتاج اإىل فح�ش م�شتويات م�شاد العامل )xa( يف الدم، ولالأ�شف فإن هذا الفح�ش غري متوفر يف معظم م�شت�شفيات البالد النامية. اإن الغر�ش من هذا البحث يتمثل يف مراجعة الإر�شادات والتوجيهات الطبية العاملية التي ن�رضت بخ�شو�ش عالج تخرث الدم يف الن�شاء احلوامل وكذلك حماولة تقدمي طريقة مب�شطة للعالج الأمثل ملثل هذه احلالت يف هذه املنطقة. مفتاح الكلمات: �شمامات القلب ال�شناعية؛ احلمل؛ الوارفارين؛ الهيبارين ذا الوزن اجلزيئي املنخف�ش؛ تخرث الدم. review mechanical prosthetic valves and pregnancy a therapeutic dilemma of anticoagulation *prashanth panduranga,1 mohammed el-deeb,1 chitra jha2 prashanth panduranga, mohammed el-deeb and chitra jha review | e449 at 36 weeks, the patient underwent an emergency caesarean section due to fetal distress, with a resultant live birth. post-operatively, she developed acute pulmonary oedema which was managed with diuretics. the patient was then moved to the royal hospital, a tertiary hospital in muscat, oman, for further management. her inr was 1.0 and her activated partial thromboplastin time (aptt) was 30.1 seconds (range: 27.2–39.1 seconds). a transthoracic echocardiogram of the mpv showed a peak pressure gradient of 43 mmhg, a mean gradient of 25 mmhg (which had risen from a previously reported gradient of 16 mmhg at her regional hospital) and a calculated mitral valve area of 0.9 cm2. there was a loss of movement in one of the leaflets of the mpv. there was mild tricuspid regurgitation with a pulmonary artery systolic pressure of 85 mmhg and a left ventricular ejection fraction of 60%. transoesophageal echocardiography confirmed the presence of one immobile leaflet and detected a large soft immobile thrombus (1 cm2) towards the atrial side [figures 1a & b]. in view of the patient’s recent surgery, thrombolysis was contraindicated. after a week-long continuous infusion of unfractionated heparin (ufh) with aptt monitoring, the mean gradient on a repeat transthoracic echocardiogram was 16 mmhg. there were no embolic complications or bleeding. however, fluoroscopy showed that one of the leaflets was stuck in the closed position [figures 2a & b]. the patient underwent a successful redo mitral valve replacement surgery using a size 27 st. jude medical™ mpv (st. jude medical, inc.). at a oneyear follow-up, the patient was doing well and had a normally functioning mpv. international guidelines current management strategies for pregnant women figure 1 a & b: transoesophageal echocardiograms showing (a) a large, soft clot over the mechanical prosthetic bileaflet mitral valve on the atrial side (arrowheads) and (b) a thrombus with the immobile leaflet of a mechanical prosthetic bileaflet mitral valve in a closed position (arrowheads). the other leaflet can be seen to be opening well. la = left atrium. figure 2 a & b: fluoroscopy showing (a) the immobile leaflet of the mechanical prosthetic bileaflet mitral valve stuck in the closed position, while (b) the opposite leaflet opens well. mechanical prosthetic valves and pregnancy a therapeutic dilemma of anticoagulation e450 | squ medical journal, november 2014, volume 14, issue 4 acc/aha guidelines, the 2011 european society of cardiology (esc) guidelines for managing patients with valvular heart disease is very similar.3 these guidelines recommend that patients requiring less than 5 mg of warfarin per day should continue warfarin until 36 weeks of gestation (with an embryopathy risk of <3%), while those requiring more than 5 mg should switch to dose-adjusted iv ufh or lmwh between 6–12 gestational weeks.3 in addition, they specifically recommend that pregnant patients using lmwh should have their anti-factor xa levels monitored on a weekly basis; peak anti-factor xa levels should not exceed 0.8–1.2 u/ml approximately 4–6 hours after the dose was administered.3 a m e r i c a n c o l l e g e o f c h e s t p h y s i c i a n s the american college of chest physicians (accp) 2012 guidelines recommend the continuation of warfarin throughout pregnancy in high-risk patients, including patients with an older generation prosthesis, a mitral prosthesis or a history of te, atrial fibrillation or left ventricular dysfunction.4 in low-risk patients, the dosage should include subcutaneous ufh adjusted to attain mid-interval aptts of at least twice that of the control or anti-factor xa levels of 0.35–0.70 u/ ml.4 alternatively, lmwh may be given after 6–12 gestational weeks or throughout the entire pregnancy. the starting dose should be 100 u/kg of dalterparin and 1 mg/kg of enoxaparin. the patient should receive 12 hourly doses subcutaneously to achieve the correct peak anti-factor xa levels four hours post-injection and these levels should be checked every week. with lmwh, the guidelines suggest that physicians should consider additionally prescribing low-dose aspirin in high-risk women with mpvs.4 in women with a bileaflet aortic valve prosthesis who have been prescribed warfarin, the inr target can be 2–3 instead of 2.5–3.5.4 all of the above guidelines agree that lmwh should be given twice daily and that it is harmful to administer lmwh without regularly monitoring the patient’s anti-factor xa levels.1–4 g u i d e l i n e s f o r pat i e n t s a f t e r 36 g e s tat i o n a l w e e k s with regard to patient management after 36 gestational weeks, there is a vast disparity among the acc/aha, esc and acp guidelines. the acc/aha guidelines suggest stopping warfarin at 36 weeks and starting continuous iv ufh with aptt monitoring, which should be continued until approximately 2–3 weeks before the planned delivery.2 additionally, they recommend that ufh be discontinued 4–6 hours (up until 36–38 gestational weeks) with mpvs are varied. they include continuous oral warfarin; changing from warfarin to subcutaneous ufh or lmwh in the first trimester and then back to warfarin; continuous subcutaneous ufh, or continuous lmwh throughout the duration of the pregnancy.1‒4 in the absence of controlled clinical trials, most, if not all, of these recommendations are based on limited observational data. a m e r i c a n c o l l e g e o f c a r d i o l o g y/a m e r i c a n h e a r t a s s o c i at i o n in their 2008 and 2014 guidelines for the selection of an anticoagulation regimen in pregnant patients with mpvs, the american college of cardiology (acc) and american heart association (aha) suggest a detailed discussion with the patient regarding all of their anticoagulation therapeutic options during pregnancy.1,2 specifically, warfarin is strongly recommended in pregnant patients with a mpv to achieve a therapeutic inr in the second and third trimesters. however, recommendations regarding the subcutaneous use of lmwh and ufh throughout pregnancy, as well as the subcutaneous use of ufh in the first trimester, have been removed completely from these guidelines. according to the 2014 acc/aha guidelines, the main risk period for complications is within the first trimester.1,2 the continuation of warfarin during the first trimester is permissible if the dose of warfarin does not exceed 5 mg per day. for those who require stronger doses of warfarin in the first trimester or among those whose preferred treatment option is lmwh, the lmwh should be administered twice daily and the dose should be adjusted to attain peak anti-factor xa levels of 0.8–1.2 u/ml approximately 4–6 hours after the injection. alternatively, to achieve a therapeutic anticoagulation, dose-adjusted continuous intravenous (iv) ufh (with an aptt at least twice that of the control) during the first trimester is permissible if the dose of warfarin is greater than 5 mg per day. in addition, the guidelines recommend adding low-dose aspirin (75–100 mg per day) in the second and third trimesters. if warfarin is the preferred method of treatment throughout the pregnancy, the dose should be adjusted to attain a target inr of 3.0 (range: 2.5–3.5).1 however, the use of iv ufh in the first trimester is difficult from a practical standpoint, as a three-month hospital admission is required. e u r o p e a n s o c i e t y o f c a r d i o l o g y despite being released three years earlier than the prashanth panduranga, mohammed el-deeb and chitra jha review | e451 before the planned delivery and restarted 4–6 hours after delivery. in the absence of significant bleeding, oral warfarin should then be initiated 24 hours after the birth.2 esc guidelines suggest stopping warfarin at 36 weeks and starting dose-adjusted iv ufh or lmwh.3 this treatment should continue until 36 hours before delivery, when lmwh should be replaced by iv ufh.3 accp guidelines suggest continuing warfarin until the patient is close to term (although the word term is not specified, it is generally accepted to signify 48 hours before delivery). at this point, warfarin should be replaced by iv ufh or lmwh.4 if labour begins spontaneously while the patient is still undergoing oral anticoagulation therapy, a caesarean section is indicated due to the baby’s increased risk of intracranial bleeding in the case of a vaginal delivery or due to other obstetric-related causes. clinical trials in a retrospective systematic review, chan et al. reported that the use of warfarin in women between 6–12 gestational weeks resulted in fewer maternal te episodes (3.9%) at the cost of increased fetal loss and fetal anomalies (12% and 6.4%, respectively).5 as warfarin crosses the placenta, it is associated with a high incidence of fetal loss and an increased risk of embryopathy which mainly presents as skeletal abnormalities (nasal hypoplasia and stippling of the vertebrae or bony epiphyses of the extremities).4–7 the risk of warfarin-associated embryopathy is markedly reduced if warfarin is used after the first trimester, even though there are some reports of central nervous system structural anomalies such as microcephaly, hydrocephalus and eye abnormalities, including microphthalmia and optic atrophy.4–7 the overall rate of major bleeding in pregnant patients with mpvs is reported to be 2.5%; this rate does not change according to the type of anticoagulation therapy used.5 however, the risk of embryopathy is lower among patients whose warfarin doses do not exceed 5 mg per day.6 in a prospective cohort study of 250 pregnant patients with mpvs, 150 patients continued warfarin throughout their pregnancies; there were no incidences of valve thrombosis or coumarin-induced fetal malformations among this group in comparison to those receiving ufh.7 in another study of 196 pregnancies in 110 women, 142 women continued warfarin during their pregnancy, with an increased incidence of fetal loss (46% versus 14% for those in the ufh group).8 in contrast, the ufh group demonstrated a higher rate of valve thrombosis (13% versus 2.1%) when used during the first trimester.8 a study by chan et al. found that ufh (dose-adjusted so that the aptt is twice that of the control six hours after the injection) appears to demonstrate good fetal outcomes, with the treatment not crossing the placenta.5 however, this result came at the cost of an increased rate of te complications, with tes occurring in 33% of cases when ufh was used throughout the pregnancy and 9% of cases when it was used for the first trimester only.5 therapeutic doses of lmwh, which does not cross the placenta, are increasingly being used as an alternative option either in the first trimester or throughout the entire pregnancy, both with and without anti-factor xa monitoring, as seen in a singlecentre study by quinn et al.9 however, in a study of 81 patients, oran et al. found an overall incidence of prosthetic valve thrombosis in 8.6% and an overall te rate of 12.3%.10 of the 10 patients who suffered a te, nine had received a fixed dose of lmwh; in two of these, a low fixed dose was used without anti-factor xa monitoring.10 this was the same therapy option used for the 28-year-old woman in the aforementioned case study. in the same study, only one patient was reported to have had a te among 51 pregnancies where antifactor xa levels were monitored.10 thus, a careful review of previously reported cases of prosthetic valve thrombosis while on lmwh indicates that most of these cases were associated with an inadequate dosage, a lack of monitoring or sub-therapeutic anti-factor xa levels. another study observed te complications in seven out of 47 pregnancies, of which five were associated with the use of enoxaparin therapy.11 the predominant causative factors for these complications, which were identified in all cases, were poor compliance with the therapy requirements and sub-therapeutic peak anti-factor xa levels.11 there is evidence that, as lmwh undergoes renal clearance, there is an increase in the glomerular filtration rate and plasma volume expansion during pregnancy, which leads to a higher clearance of lmwh with lower plasma concentrations.12,13 in addition, there is increased activity of the placental heparinase, which means that an increased dose of lmwh is required in order to achieve therapeutic anti-factor xa levels.12,13 quinn et al. found that, in order to maintain adequate antifactor xa levels during pregnancy, the mean lmwh dose had to be increased over the initial dose by 54%.9 fixed-dose regimens or the administration of lmwh by weight alone have therefore proven to be inadequate; as a result, guidelines advise peak anti-factor xa level monitoring. however, even peak mechanical prosthetic valves and pregnancy a therapeutic dilemma of anticoagulation e452 | squ medical journal, november 2014, volume 14, issue 4 prosthetic valve replacements. the warfarin group had a higher incidence of spontaneous abortion than the heparin group, although this was not statistically significant.22 this study concluded that the role of warfarin in warfarin-associated embryopathy had been overstated.22 is there a role for prevention? of late, the surgical community has advocated against giving mechanical prostheses to women of a childbearing age.23 in addition, great progress has been made in valve-sparing surgeries.24 if a prosthesis is really necessary, the esc guidelines for valvular diseases outline the possibility of giving bioprostheses to younger patients who choose this option and have been informed of the risks (class i).25 bioprostheses should also be considered in young women contemplating pregnancy (class iia), with the understanding that they may have to undergo another operation in the future or a transcatheter valve-invalve implantation procedure.25 moreover, the ross procedure for aortic valve replacement surgery could be used in carefully selected patients.24 a simplified guideline based on the above review of the three major guidelines and large meta-analysis, the authors of this review recommend a simple approach with regards to anticoagulation therapy during pregnancy in patients with an mpv. this recommendation is easy for both patients and physicians to follow and takes into account the fact that anti-factor xa level monitoring may not be available in all centres. it is recommended that pregnant women with an mpv continue warfarin until 37 gestational weeks or one week prior to delivery. this recommendation is appropriate for patients who require warfarin at doses of either above or below 5 mg per day. however, it is important that practitioners discuss the significant maternal benefit and the fetal risk of this therapy option with their patient and advise them that fetal loss is more common than embryopathy. the patients’ inr should be measured on a monthly basis in order to maintain a target inr of 3.0 (range: 2.5–3.5). after 37 weeks’ gestation, or one week prior to a planned delivery, warfarin should be stopped and inr levels should be monitored on a daily outpatient basis. once the patient’s inr decreases to <2.5, a therapeutic dose of weight-based lmwh should be administered subcutaneously twice daily to attain peak antianti-factor xa levels may not reflect the adequacy of anticoagulation for periods between 12–24 hours.14–17 fan et al. studied the relationship between 177 paired peak and trough anti-factor xa levels during pregnancy.18 they found that that pregnant patients who received adjusted-dose enoxaparin (given every 12 hours with peak levels of 0.7–1.2 iu/ml) were associated with sub-therapeutic trough levels, with a pre-dose level of <0.6 iu/ml in >50% of the cases.18 thus, the previously mentioned guidelines ignore manufacturer recommendations to monitor both peak and trough levels.16,19 a large meta-analysis in a recent large meta-analysis of studies evaluating anticoagulation in pregnant patients with mechanical heart valves, malik et al. identified eight out of 281 articles that gave the best evidence towards answering the research question, is there a suitable method of anticoagulation in pregnant patients with mechanical prosthetic heart valves?20 malik et al. observed that while it is traditionally believed that oral anticoagulation in pregnancy can lead to warfarin embryopathy, only one study reported a higher incidence of fetal anomalies with warfarin use (6.4%), while two others reported no instances of embryopathy at all.20 fetal mortality with oral anticoagulation therapies ranged from 1.52–76% and all of the studies demonstrated excellent maternal outcomes with warfarin use, with te events ranging from 0–10% in comparison to 4–48% when heparin was used. thus, it was concluded that warfarin is a more durable anticoagulant with improved maternal outcomes, despite the increased fetal risk.20 this finding was confirmed in a study of 32 pregnancies by basude et al.21 while the rate of fetal loss in the warfarin group was high, all women in the lmwh group, and half of those who received lmwh in the first trimester and then subsequently received warfarin, had serious adverse maternal events, including valve thrombosis, maternal death and postpartum haemorrhage.21 in an omani study, al-lawati et al. reported on 63 pregnancies in 21 women with mechanical heart valves.22 the women received either warfarin throughout the entire duration of their pregnancy or subcutaneous heparin in their first trimester and oral warfarin for the rest of their pregnancy.22 no cases of warfarin-associated embryopathy were observed and there were no instances of maternal death. life-threatening valve thrombosis occurred in two patients, both of whom were in the heparin group and needed emergency prashanth panduranga, mohammed el-deeb and chitra jha review | e453 factor xa levels of 0.8–1.2 u/ml at 4–6 hours postadministration. at 36 hours before delivery, the patient should be admitted to the hospital. lmwh should be continued, with the last dose given 12 hours prior to the delivery and restarted six hours after the delivery. oral warfarin should be given after 24 hours, in the absence of any significant bleeding. in centres where anti-factor xa level monitoring is not available, the patient should be admitted to the hospital at 37 gestational weeks or one week prior to a planned delivery. at this point, warfarin should be stopped and the inr should be measured daily. once inr levels fall to <2.5, iv ufh therapy should commence, with six-hourly aptt monitoring in order to keep the aptt twice that of the control. the ufh should be discontinued 4–6 hours before delivery and restarted 4–6 hours after delivery. oral warfarin should be administered after 24 hours, in the absence of any significant bleeding. for patients who were receiving a very high prepregnancy dose of warfarin (>10 mg), practitioners should consider lmwh treatment in the first trimester with anti-factor xa level monitoring. if required, treating physicians should seek facilities to monitor anti-factor xa levels in such special cases. in all cases, the management and treatment of patients should follow a ‘team’ approach, with input from cardiologists, haematologists and obstetricians. additionally, these recommendations have been suggested for the management of patients in developing countries and regional hospitals without regular access to anti-factor xa level monitoring and in whom alternative treatments are difficult to apply. conclusion in summary, the best anticoagulant treatment for pregnant women with an mpv is dependent on the availability of anti-factor xa level monitoring facilities, the patient’s pre-pregnancy dose of warfarin and the type of anticoagulant preferred by the patient in relation to the maternal and fetal risks. regardless of the facilities available or previous treatment received, a pregnant woman who requires anticoagulants due to the presence of an mpv should be closely monitored by a team of healthcare practitioners, including cardiology, haematology and obstetric specialists. the simplified guidelines proposed in this review article are primarily for patients in hospitals that are not able to measure anti-factor xa levels regularly or those who are unable to consider alternative treatments. references 1. bonow ro, carabello ba, chatterjee k, de leon ac jr, faxon dp, freed md, et al. 2008 focused update incorporated into the acc/aha 2006 guidelines for the management of patients with valvular heart disease: a report of the american college of cardiology/american heart association task force on practice guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease): endorsed by the society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, and society of thoracic surgeons. j am coll cardiol 2008; 52:e1– 142. doi: 10.1016/j.jacc.2008.05.007. 2. nishimura ra, otto cm, bonow ro, carabello ba, erwin jp 3rd, guyton ra, et al. 2014 aha/acc guideline for the management of patients with valvular heart disease: a report of the american college of cardiology/american heart association task force on practice guidelines. circulation 2014; 129:2440–92. doi: 10.1161/cir.0000000000000029. 3. european society of gynecology (esg); association for european paediatric cardiology (aepc); german society for gender medicine (dgesgm), regitz-zagrosek v, blomstrom lundqvist c, borghi c, et al. esc guidelines on the management of cardiovascular diseases during pregnancy: the task force on the management of cardiovascular diseases during pregnancy of the european society of cardiology (esc). eur heart j 2011; 32:3147–97. doi: 10.1093/eurheartj/ehr218. 4. bates sm, greer ia, middeldorp s, veenstra dl, prabulos am, vandvik po; american college of chest physicians. vte, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. chest 2012; 141:e691s–736s. doi: 10.1378/ chest.11-2300. 5. chan ws, anand s, ginsberg js. anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. arch intern med 2000; 160:191–6. doi: 10.1001/ archinte.160.2.191. 6. vitale n, de feo m, de santo ls, pollice a, tedesco n, cotrufo m. dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. j am coll cardiol 1999; 33:1637–41. doi: 10.1016/s0735-1097(99)00044-3. 7. geelani ma, singh s, verma a, nagesh a, betigeri v, nigam m. anticoagulation in patients with mechanical valves during pregnancy. asian cardiovasc thorac ann 2005; 13:30–3. doi: 10.1177/021849230501300107. 8. khamooshi aj, kashfi f, hoseini s, tabatabaei mb, javadpour h, noohi f. anticoagulation for prosthetic heart valves in pregnancy: is there an answer? asian cardiovasc thorac ann 2007; 15:493–6. doi: 10.1177/021849230701500609. 9. quinn j, von klemperer k, brooks r, peebles d, walker f, cohen h. use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience. haematologica 2009; 94:1608–12. doi: 10.3324/haematol.2008.002840. 10. oran b, lee-parritz a, ansell j. low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. thromb haemost 2004; 92:747–51. doi: 10.1267/thro04040747. 11. mclintock c, mccowan lm, north ra. maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. bjog 2009; 116:1585–92. doi: 10.1111/j.1471-0528.2009.02299.x. 12. casele hl, laifer sa, woelkers da, venkataramanan r. changes in the pharmacokinetics of the low-molecular weight heparin enoxaparin sodium during pregnancy. am j obstet gynecol 1999; 181:1113–17. doi: 10.1016/s00029378(99)70091-8. 13. jeyabalan a, conrad kp. renal function during normal pregnancy and preeclampsia. front biosci 2007; 12:2425–37. doi: 10.2741/2244. mechanical prosthetic valves and pregnancy a therapeutic dilemma of anticoagulation e454 | squ medical journal, november 2014, volume 14, issue 4 20. malik ht, sepehripour ah, shipolini ar, mccormack dj. is there a suitable method of anticoagulation in pregnant patients with mechanical prosthetic heart valves? interact cardiovasc thorac surg 2012; 15:484–8. doi: 10.1093/icvts/ivs178. 21. basude s, hein c, curtis sl, clark a, trinder j. low-molecularweight heparin or warfarin for anticoagulation in pregnant women with mechanical heart valves: what are the risks? a retrospective observational study. bjog 2012; 119:1008–13. doi: 10.1111/j.1471-0528.2012.03359.x. 22. al-lawati aa, venkitraman m, al-delaime t, valliathu j. pregnancy and mechanical heart valves replacement: dilemma of anticoagulation. eur j cardiothorac surg 2002; 22:223–7. doi: 10.1016/s1010-7940(02)00302-0. 23. mihaljevic t, paul s, leacche m, rawn jd, cohn lh, byrne jg. valve replacement in women of childbearing age: influences on mother, fetus and neonate. j heart valve dis 2005; 14:151–7. 24. david te. surgical treatment of aortic valve disease. nat rev cardiol 2013; 10:375–86. doi: 10.1038/nrcardio.2013.72. 25. joint task force on the management of valvular heart disease of the european society of cardiology (esc); european association for cardio-thoracic surgery (eacts), vahanian a, alfieri o, andreotti f, antunes mj, et al. guidelines on the management of valvular heart disease (version 2012). eur heart j 2012; 33:2451–96. doi: 10.1093/eurheartj/ehs109. 14. elkayam u, singh h, irani a, akhter mw. anticoagulation in pregnant women with prosthetic heart valves. j cardiovasc pharmacol ther 2004; 9:107–15. doi: 10.1177/107424840400900206. 15. barbour la, oja jl, schultz lk. a prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. am j obstet gynecol 2004; 191:1024–9. doi: 10.1016/j. ajog.2004.05.050. 16. elkayam u, goland s. the search for a safe and effective anticoagulation regimen in pregnant women with mechanical prosthetic heart valves. j am coll cardiol 2012; 59:1116–18. doi: 10.1016/j.jacc.2011.12.018. 17. yinon y, siu sc, warshafsky c, maxwell c, mcleod a, colman jm, et al. use of low molecular weight heparin in pregnant women with mechanical heart valves. am j cardiol 2009; 1:1259–63. doi: 10.1016/j.amjcard.2009.06.040. 18. fan j, goland s, khatri n, elkayam u. abstract 18219: monitoring of anti-xa in pregnant patients with mechanical prosthetic valves receiving low molecular weight heparin: peak or trough levels? circulation 2010; 122:a18219. 19. mclintock c. anticoagulant choices in pregnant women with mechanical heart valves: balancing maternal and fetal risks the difference the dose makes. thromb res 2013; 131:s8–10. doi: 10.1016/s0049-3848(13)70010-0. clinical & basic research sultan qaboos university med j, february 2015, vol. 15, iss. 1 pp. e91–97, epub. 21 jan 15 submitted 14 apr 14 revision req. 29 may 14; revision recd. 12 jun 14 accepted 3 jul 14 departments of 1surgery and 2child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drkhalidmunirbhatti@yahoo.com أسباب البقاء لفرتات طويلة للحاالت اجلراحية من األطفال حديثي الوالدة يف وحدات العناية املركزة خالد بهاتي، زينب البلوشية، حممود �رضيف، �ضاريا ال�ضباعي، اأ�ضفق خان، مازن حممد، ماريا باتاكلن، �ضرييل مونتيمايور، حممد ف�ضل اهلل، م�ضعود اأحمد، ماثيو كريبايل، اأ�ضد الرحمن، زينايدا رئي�س، حممد عبد اللطيف abstract: objectives: the length of hospital stay (hs) for patients is a major concern due to its social, economic and administrative implications; this is particularly important for neonates admitted to intensive care units (icus). this study aimed to determine the factors responsible for prolonged hs in surgical neonates. methods: this retrospective study was conducted at sultan qaboos university hospital, in muscat, oman. the medical records of 95 neonates admitted to the neonatal icu who underwent general surgical procedures between july 2009 and june 2013 were reviewed. mann-whitney u and pearson’s chi-squared tests were used for non-parametric numerical and categorical variables, respectively. a multiple regression analysis was performed to find a relationship between the variables and to detect the most important factor responsible for prolonged hs. a p value of <0.05 was considered statistically significant. results: gestational age, birth weight, number of days on a ventilator and postoperative morbidity were associated with prolonged hs. furthermore, the age of neonates at first full enteral feed was associated with increased hs using both independent and multiple regression analyses. conclusion: prolonged hs can occur as a result of many factors. in this study, a number of factors were identified, including low gestational age, low birth weight, increased number of days on a ventilator and postoperative morbidity. additionally, neonate age at first full enteral feeds also correlated with increased hs. further research on this topic is suggested to explore this correlation in more detail and to inform future practices. keywords: neonates; neonatal intensive care units (nicu); length of stay; morbidity; oman. امللخ�س: الهدف: ي�ضكل طول مدة االإقامة يف امل�ضت�ضفى م�ضدر قلق كبري للمر�ضى وملا لها من اآثار اجتماعية واقت�ضادية واإدارية؛ وبخا�ضة للحاالت اإلقامة مدة طول عن امل�ضوؤولة العوامل حتديد اإىل الدرا�ضة هذه هدفت املركزة. العناية وحدة يف الوالدة حديثي االأطفال يف اجلراحية يف االأطفال حديثي الوالدة. الطريقة: اأجريت هذه الدرا�ضة اال�ضتعادية يف م�ضت�ضفى جامعة ال�ضلطان قابو�س ، يف م�ضقط، �ضلطنة عمان. متت مراجعة 95 حالة جراحية للطفال حديثي الوالدة من ال�ضجلت الطبية الذين أدخلو وحدة العناية املركزة و خ�ضعوا لعمليات جراحية عامة بني يوليو 2009 و يونيو 2013. ا�ضتخدم اختبار مان-ويتني u واختبار بري�ضون كاي للمتغريات العددية والفئوية ، على التوايل. اأجري حتليل االنحدار املتعدد الإيجاد العلقة بني املتغريات وللك�ضف عن اأهم عامل م�ضوؤول عن اإلقامة لفرتات طويلة. واعتربت قيمة من p >0.05 ذات داللة اإح�ضائية. النتائج: ارتبطت عوامل العمر احلملي، الوزن عند الوالدة، وعدد األيام على جهاز التنف�س ال�ضناعي واالعتلل بعد العملية اجلراحية مع طول مدة االإقامة. علوة على ذلك فإنه با�ضتخدام كل من حتليل االنحدار امل�ضتقل واملتعدد ،ثبت ارتباط �ضن الوليد عند حتقيقه التغذية املعوية الكاملة بطول مدة االإقامة. اخلال�صة: طول مدة االإقامة يف امل�ضت�ضفى ميكن اأن حتدث نتيجة لعوامل كثرية. يف هذه الدرا�ضة، مت حتديد عدد من العوامل، مبا يف ذلك انخفا�س العمر احلملي، وانخفا�س وزن املواليد، وزيادة عدد االأيام على جهاز التنف�س ال�ضناعي واالعتلل بعد العملية. باالإ�ضافة اإىل ذلك كان �ضن الوليد عند حتقيقه التغذية املعوية الكاملة مرتبطا بطول مدة االإقامة ويقرتح اإجراء املزيد من االأبحاث حول هذا املو�ضوع ال�ضتك�ضاف هذه العلقة مبزيد من التف�ضيل يف امل�ضتقبل. مفتاح الكلمات: حديثي الوالدة؛ وحدة العناية املركزة لألطفال حديثي الوالدة؛ طول مدة االإقامة؛ االإ�ضابة باالأمرا�س؛ عمان. factors responsible for the prolonged stay of surgical neonates in intensive care units *khalid m. bhatti,1 zainab n. al-balushi,1 mahmoud h. sherif,1 sareyah m. al-sibai,1 ashfaq a. khan,2 mazen a. mohammed,2 maria f. batacalan,2 cheryl c. montemayor,2 mohammad fazalullah,2 masood ahmed,2 mathew kripail,2 asad ur-rahman,2 zenaida reyes,2 mohamed abdellatif2 advances in knowledge the results of this study show that low gestational age, low birth weight, increased number of days on a ventilator and postoperative morbidity are factors affecting surgical neonates’ length of hospital stay (hs) in a neonatal intensive care unit (nicu). in addition, an infant’s age at first full enteral feed was shown to have a significant association with prolonged hs. this may encourage neonatologists to evaluate current neonatal feeding practices. application to patient care the results of this study may help to reduce the length of hs in surgical neonates by identifying certain modifiable factors that lead to prolonged nicu stays. factors responsible for the prolonged stay of surgical neonates in intensive care units e92 | squ medical journal, february 2015, volume 15, issue 1 the length of hospital stay (hs) for infants in neonatal intensive care units (nicus) is of interest for many reasons. studies have shown that prolonged hs leads to higher costs and greater morbidity.1,2 moreover, in smaller nicus with limited resources, bed availability and management can become a challenge. surgery in newborns is indicated either because of a primary surgical disease or other complications that have arisen in the neonatal period. many of the factors that prolong hs in non-surgical neonates have been well studied;1–3 however, the literature is scarce regarding the factors involved in prolonged hs among surgical neonates. identifying such factors may help to reduce the length of hs in surgical neonates admitted to nicus, in turn reducing related costs and improving the management and allocation of available resources. the purpose of this retrospective study was to determine the factors responsible for prolonged hs in surgical neonates admitted to the nicu of sultan qaboos university hospital (squh), in muscat, oman. methods this retrospective study was conducted at squh between july 2009 and june 2013. newborns who required general surgical procedures and were admitted to the nicu before four weeks of age were included in the study. the medical records of all included neonates admitted to the squh nicu for general surgical procedures during the study period were reviewed. prolonged hs was defined as a stay of more than 19 days, as this was the median stay in the cohort. patients were divided into two groups based on hs: group a included neonates hospitalised for >19 days, while group b included those hospitalised for ≤19 days. the following variables were determined as possible predictors for prolonged hs: gender; source of referral (at squh or elsewhere); maternal comorbidities; age at admission; gestational age; birth weight; associated anomalies; age at surgery; site of surgery (e.g. thorax, abdomen or other); need for and duration of ventilatory support; postoperative complications, and age at first attaining full enteral feeds. infants were identified as preterm if their gestational age was <37 weeks while low birth weight (lbw) was defined as a birth weight of less than 2,500 g. full enteral feeds were defined as the necessary amount of breast milk/formula fed orally based on an infant’s weight and energy requirements. data were analysed using the statistical package for the social sciences (spss), version 16 (ibm, corp., chicago, illinois, usa). the normality of numerical variables was determined using standard deviation, skewness and histograms. all variables had a skewed distribution. mann-whitney u and pearson’s chisquared tests were used for non-parametric and categorical variables to identify differences between the two groups. a multiple regression analysis was performed to determine the relationship of variables regarding length of hs. a p value of <0.05 was considered statistically significant. this study was approved by the medical research & ethics committee of sultan qaboos university (mrec #656). results a total of 102 surgical neonates were admitted to the nicu during the study period. however, seven cases were excluded as they were statistical outliers. these included five cases of necrotising enterocolitis (nec), one case of jejunoileal atresia and one case of intestinal malrotation. the patient with jejunoileal atresia and one of the patients with nec died. out of the remaining 95 patients, 52 were male and 43 were female. the number of neonates admitted to the nicu from other squh departments (n = 48) was almost equal to those transferred from other hospitals in oman (n = 47). the age of the neonates at admission ranged from 1–28 days, with a median age at admission of one day. the infants’ gestational ages varied from 26–42 weeks (mean: 36.38 ± 3.50 weeks; median: 38 weeks). of those included in the study, 64 neonates were considered term while 31 were preterm. the median birth weight was 2,770 g (range: 800–3,900 g). a total of 36 neonates (37.9%) were considered to have a lbw. there were 22 cases of maternal comorbidities, including gestational diabetes mellitus (n = 10), pregnancy-induced hypertension (n = 8), noninsulin-dependent diabetes mellitus (n = 1), twin pregnancy (n = 1), systemic lupus erythematosus (n = 1) and haemolysis/elevated liver enzymes/ low platelet (hellp) counts syndrome (n = 1). echocardiography was performed on 69 neonates, with 22 showing normal results. in the remaining 47 patients 58 anomalies were detected. patent ductus arteriosus in isolation or combined with other cardiac defects was the most common finding (n = 31; 66%). other cardiac anomalies included pulmonary hypertension (n = 8), atrial septal defects (n = 6), ventricular septal defects (n = 7), septal hypertrophy (n =2), dextrocardia (n = 2) and peripheral arterial hypertension (n = 2). the most common chromosomal anomaly was trisomy 21 (n = 5, 5.3%). khalid m. bhatti, zainab n. al-balushi, mahmoud h. sherif, sareyah m. al-sibai, ashfaq a. khan, mazen a. mohammed, maria f. batacalan, cheryl c. montemayor, mohammad fazalullah, masood ahmed, mathew kripail, asad ur-rahman, zenaida reyes and mohamed abdellatif clinical and basic research | e93 the neonates median age at surgery was three days (range: 1–45 days). surgical procedures included 51 abdominal, 29 thoracic and 15 other surgeries. the most common procedure was a tracheoesophageal fistula repair (n = 18). ventilatory support was required in 80 infants (85.3%) and was maintained for a median of four days (range: 1–40 days). postoperative morbidity was seen in 22 patients (23%) and included sepsis (n = 10), wound infections (n = 2), pneumothorax (n = 2), diarrhoea (n = 2), postoperative adhesions (n = 2), lung collapse (n = 1), disseminated intravascular coagulation (n = 1), bowel gangrene due to abdominal compartment syndrome (n = 1) and hypotension (n = 1). there were 10 fatalities (10.5%). the length of hs ranged from 3–79 days (median: 19 days). the maximum stay of 79 days was due to a case of gastroschisis repair while the mimimum stay of three days resulted from a case of an imperforated anus. neonates with nec had a median stay (53 days; range: 2–60 days) greater than that of neonates undergoing other types of surgery. neonates with anterior abdominal wall (awd) defects had a shorter hs (median: 35 days; range: 20–79 days). neonates with congenital diaphragmatic hernia had a median hs of 22 days (range: 6–48 days). regarding statistical analysis for responsible factors, table 1 shows the difference in medians, ranges, mean ranks, mann-whitney u values and p values of the two groups by duration of icu stay, i.e. group a (hs >19 days) and group b (hs ≤19 days). it is evident that low gestational age, lbw, prolonged ventilatory support and older age at first full feed were associated with increased hs. however, age at admission or age at surgery did not significantly affect the length of hs. among the categorical variables, preterm status, lbw and morbidity were associated with increased hs, while gender, maternal comorbidities, associated cardiac or non-cardiac anomalies and the site of surgery did not significantly affect hs [table 2]. all of the variables which were found to significantly increase hs were subjected to regression analysis. according to the multiple regression analysis, the infants’ age at first full feed was found to be the most important factor prolonging hs [table 3]. table 4 shows the neonate’s surgical conditions in relation to their median and maximum ages at full feeds and discharge, respectively. discussion this study aimed to identify possible factors responsible for prolonged hs in surgical neonates. the overall morbidity (23%) and mortality (10.5%) rates were higher than those mentioned in the western literature (6–13%)4,5 but lower than those reported from africa (up to 30%).6,7 regarding hs, neonates with nec had a greater median stay compared to those undergoing other types of surgery. this was shorter than that reported by moss et al. from a multicentre randomised clinical trial for perforated nec neonates who underwent laparotomies (116 ± 56 days).8 however, the neonates in the clinical trial all had birth weights of <1,500 g table 1: differences in the mean rank of numerical variables of the surgical neonates by duration of intensive care unit stay (n = 95) numerical variables groups a = >19 days (n=45) b = ≤19 days (n=50) median (range) mean rank* u-value* p value age at admission (days) a 1 (1–30) 45.02 991 0.27 b 2 (1–30) 50.68 gestational age (weeks) a 36 (26–42) 38.91 716 <0.001 b 38 (28–41) 56.18 birth weight (grams) a 2,400 (800–3,900) 3,734 645 <0.001 b 2,955 (990–3,900) 5,759 age at surgery (days) a 3 (1–45) 44.38 962 0.21 b 4 (1–37) 51.26 duration of ventilatory support (days) a 6 (0–40) 56.79 729 <0.001 b 2 (0–30) 40.09 age at full enteral feeds(days) a 20 (1–88) 65.29 347 <0.001 b 8 (0–17) 32.44 *test of significance using mann-whitney u. factors responsible for the prolonged stay of surgical neonates in intensive care units e94 | squ medical journal, february 2015, volume 15, issue 1 while birth weights varied from 700–2,500 g in the current study. similarly, the length of hs for neonates with congenital diaphragmatic hernia in the current study was shorter than that reported by skarsgard et al. (22 versus 36 days).9 however, the length of hs in this study was comparable to that of skarsgard et al.’s study with regards to cases of anterior awd (35 versus 39 days).9 preterm status and lbw were independent risk factors for prolonged hs. both are well-known risk factors for poor outcomes.10 surgery in such patients increases the duration of hs due to the time required for recovery and for the infant to gain weight, as the preterm infant’s weight should be similar to that of an infant born at term prior to discharge. the traditional approach to treating infants with nec is a laparotomy and resection of the necrotic bowel in addition to stoma formation.11 the resulting short bowel syndrome may increase hs due to the need for parenteral nutrition. moreover, neonates requiring subsequent surgeries (e.g. stoma reversals) are not discharged until after these procedures have been performed. similarly, mechanical ventilation appeared to prolong the duration of hs in the current study. a possible explanation for this could be due to morbidities associated with of ventilatory support, such as respiratory tract infections, lung barotrauma, brain injuries or cardiovascular instability.12 these conditions lead to delayed recovery from surgery and, therefore, prolonged hs. likewise, postoperative complications increased the duration of hs in the present study for obvious reasons. the most common complications found in the current study were table 3: multiple regression analysis of variables significantly increasing the duration of intensive care unit stay for surgical neonates (n = 95) variables b coefficient p value constant* 11.06 <0.001 age at first full enteral feed 0.91 <0.001 days of ventilatory support 0.65 0.71 gestational age† −5.02 0.13 birth weight‡ 0.11 0.97 morbidity§ 5.03 0.10 *predictors in combination; †term/pre-term; ‡ low birth weight/ normal birth weight; §present/absent. table 2: differences in the categorical variables of the surgical neonates by duration of intensive care unit stay* categorical variable duration of hospital stay or† p value >19 days ≤19 days total referral source internal 20 28 48 0.74 0.47 elsewhere 23 24 47 gender female 19 24 43 0.92 0.84 male 24 28 52 maternal comorbidities present 8 14 22 0.62 0.33 absent 35 38 73 gestational age preterm 23 8 31 6.32 <0.001 term 20 44 64 birth weight lbw 25 11 36 5.17 <0.001 nbw 18 41 59 associated non-cardiac anomalies present 5 7 12 0.84 0.78 absent 38 45 83 associated cardiac anomalies present 10 12 22 0.79 0.66 absent 24 23 47 site of surgery thorax 14 15 29 1.19 0.69 abdomen/other 29 37 66 postoperative complications present 14 8 22 2.94 0.02 absent 29 44 73 or = odds ratio; lbw = low birth weight; nbw = normal birth weight. *test of significance using pearson’s chi-squared test; †confidence interval = 95% khalid m. bhatti, zainab n. al-balushi, mahmoud h. sherif, sareyah m. al-sibai, ashfaq a. khan, mazen a. mohammed, maria f. batacalan, cheryl c. montemayor, mohammad fazalullah, masood ahmed, mathew kripail, asad ur-rahman, zenaida reyes and mohamed abdellatif clinical and basic research | e95 surgical site infections and sepsis. local and systemic infections in surgical patients tend to increase stress by shifting the balance towards a catabolic state, which leads to prolonged recovery time and an increase in the duration of hs.13 many factors were not found to affect length of hs in the current study. literature on these factors is either controversial, contradictory or scarce. the presence of cardiac anomalies as a risk factor is an example of the first. although studies such as that of kassa et al. have reported no association between cardiac anomalies and hs, berry et al. and payne et al. have both identified this factor as a predictor of longer hs.14–16 one possible reason that cardiac abnormalities were not observed to affect hs in the current study could be due to the minor nature of the cardiac anomalies observed, with no cases requiring surgical intervention. other factors that were determined to be contradictory to findings in the literature were gender, source of referral and the presence of maternal comorbidities. the male gender has been reported as a risk factor for poor outcomes in premature infants born at <27 gestational weeks.17 however, no significant difference was found in the duration of hs between male and female neonates in the present study. nevertheless, it is worth noting that the calculation of gender-based duration of hs in the current study did not include stratification of gestational age. another factor with contradictory evidence is the source of referral to the nicu. source of referral has been reported to affect outcomes in certain surgical neonate subgroups (e.g. neonates with congenital diaphragmatic hernias or gastroschisis).14,18 in the present study, there was no statistically significant difference in the duration of hs between neonates born at squh and those born elsewhere. it may be assumed that these findings differed from those of other researchers due to centre-specific referral and case acceptance practices and the individual nature table 4: surgical conditions of the neonates in relation to age at first full enteral feed and discharge from the intensive care unit surgical condition n age in days at first full enteral feed age in days at discharge median maximum median maximum nec 6 21 45 53 60 intestinal malrotation 3 30 70 41 73 anterior awd 6 13 39 35 79 congenital diaphragmatic hernia 14 14 42 22 48 duodenal atresia 9 11 29 19 37 tef 18 10 29 18 37 nad 3 15 20 15 51 hirschsprung’s disease 17 8 42 14 69 jejunoileal atresia 3 26 47 14 50 non-specific intestinal perforation 7 8 12 13 34 anorectal malformation 5 3 6 5 7 nec = necrotising entercolitis; awd = abdominal wall defect; tef = tracheoesophageal fistula; nad = no abnormality detected. table 5: protocol for neonatal minimal enteral feeds with expressed breast milk age of neonate in days required volume and schedule 1–2 0.5 ml every six hours 3–4 0.5 ml every four hours 5–6 0.5 ml every two hours 7 1.0 ml every two hours adapted from: sultan qaboos university hospital. neonatal protocols. muscat, oman: sultan qaboos university hospital, 2010. table 6: protocol for neonatal minimal enteral feeding and increases in feed volume length of gestation in weeks minimal enteral feeds feed volume <29 required increase by 20 ml/kg/day from day eight 29–32 may be required if health concerns are identified increase by 25 ml/kg/day 33–36 not required increase by 30 ml/kg/day adapted from: sultan qaboos university hospital. neonatal protocols. muscat, oman: sultan qaboos university hospital, 2010. factors responsible for the prolonged stay of surgical neonates in intensive care units e96 | squ medical journal, february 2015, volume 15, issue 1 of diseases requiring surgery. maternal comorbidity is another factor for which the current findings were not in accordance with the literature. many maternal comorbidities, including multiple gestation pregnancies, pregnancy-induced hypertension and gestational diabetes mellitus, have been identified as predictors of nicu admission and longer hs.19 however, no significant association between maternal comorbidities and length of hs was determined in this study. certain factors which have rarely been studied in the literature were investigated in the current study but were not found to affect the length of hs. for instance, the site of the surgery had no significant relationship with prolonged hs. possible reasons for this could include the low number of thoracic procedures among the studied infants, with tracheoesophageal fistula repairs being the only procedure done via thoracotomy. on the other hand, abdominal surgeries included both minor and major procedures. similarly, infant age at surgery did not appear to affect the duration of hs. while older age was expected to reduce hs by decreasing recovery time, it was in fact associated with an increased stay in most cases. this is because the duration of hs was calculated from the day of admission to the nicu and not from the day of surgery and most infants underwent surgery after admission. the age of neonates at first full enteral feed is of special concern. it is well documented that the early initiation and attainment of full feeds in postoperative neonates improves their outcome and decreases hs.20,21 it is usually recommended that postoperative neonates begin early enteral nutrition (5–20 ml of breast milk/kg/hour) within 12 hours of the surgery, even in cases of intestinal anastomosis after abdominal surgery.22 results of the current study found that an older age at first full feed was a risk factor for prolonged hs both through independent and multiple regression analyses. this may be because of variations in institutional feeding practices or intolerance to feeds due to the severity of the illness. at squh, feeding practices are based on recommended guidelines and the gestational age, health and operative status of the neonate. feeding procedures for postoperative patients are planned according to their gestational age.22 generally, the goal of neonatal nutrition is a weight gain of 15–20 g per day on full enteral feeds. expressed breast milk is the preferential option for enteral feeding. if this is not available, however, term formula is used for all babies until they reach full enteral feeds. at a later stage, preterm/highcalorie formula is used according to infants’ weightgain patterns. all neonates who are <32 weeks or <1.5 kg are started on total parenteral nutrition on their first day. the time-frame for the commencement of enteral feeding depends on the infants’ gestational age. all neonates who are <28 weeks or <32 weeks with health concerns are started on minimal enteral feeds according to neonatal feeding protocols [tables 5 and 6]. while neonate age at full feed was found to be the most important factor prolonging hs in the present study, it is difficult and potentially misleading to conclude that feeding practices are the only factor responsible for prolonged hs. the late attainment of full feeds could be attributable to illness severity or other variables. while this study suggests that a surgical neonate’s age at full feed prolongs their nicu stay, identifying the reasons behind the late attainment of full feeds, especially the severity of illness, should be assessed by future prospective studies. there were several limitations to this study. the first limitation was that the postoperative neonates who died were not excluded from the study. secondly, a severity score index was not used to classify the neonates. the major reason for this was the lack of a scoring system incorporating surgery as a factor in the score calculation. the third limitation was that most of the neonates were operated on using an open surgical technique. hence, the results are not applicable to infants who underwent minimal access surgery.23 the results of this study should therefore be interpreted in the light of the above limitations. conclusion prolonged icu stay in surgical neonates has major consequences in terms of morbidity, costs and bed management. a number of factors resulting in prolonged hs were identified through independent analysis, including low gestational age, lbw, number of days on a ventilator and postoperative morbidity. infant age at first full enteral feed was found to increase hs both through independent and multiple regression analyses. the implications of this finding require further research in order to determine if current neonate feeding practices should be revised. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. hintz sr, bann cm, ambalavanan n, cotten cm, das a, higgins rd, et al. predicting time to hospital discharge for extremely preterm infants. pediatrics 2010; 125:e146–54. doi: 10.1542/peds.2009-0810. khalid m. bhatti, zainab n. al-balushi, mahmoud h. sherif, sareyah m. al-sibai, ashfaq a. khan, mazen a. mohammed, maria f. batacalan, cheryl c. montemayor, mohammad fazalullah, masood ahmed, mathew kripail, asad ur-rahman, zenaida reyes and mohamed abdellatif clinical and basic research | e97 2. altman m, vanpée m, cnattingius s, norman m. moderately preterm infants and determinants of length of hospital stay. arch dis child fetal neonatal ed 2009; 94:f414–18. doi: 10.1136/adc.2008.153668. 3. pepler pt, uys dw, nel dg. predicting mortality and lengthof-stay for neonatal admissions to private hospital neonatal intensive care units: a southern african retrospective study. afr health sci 2012; 12:166–73. doi: 10.4314/ahs.v12i2.14. 4. rowe mi, rowe sa. the last fifty years of neonatal surgical management. am j surg 2000; 180:345–52. doi: 10.1016/s00029610(00)00545-6. 5. carachi r, hajivassiliou ca. preface. semin pediatr surg 2008; 17:219–21. doi: 10.1053/j.sempedsurg.2008.07.001. 6. chirdan lb, ngiloi pj, elhalaby ea. neonatal surgery in africa. semin pediatr surg 2012; 21:151–9. doi: 10.1053/j. sempedsurg.2012.01.007. 7. osifo do, oriaifo ia. factors affecting the management and outcome of neonatal surgery in benin city, nigeria. eur j pediatr surg 2008; 18:107–10. doi: 10.1055/s-2008-1038485. 8. moss rl, dimmitt ra, barnhart dc, sylvester kg, brown rl, powell dm et al. laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. n engl j med 2006; 354:2225–34. doi: 10.1056/nejmoa054605. 9. skarsgard ed, blair gk, lee sk. toward evidence-based best practices in neonatal surgical care-i: the canadian nicu network. j pediatr surg 2003; 38:672–7. doi: 10.1016/ jpsu.2003.50180. 10. cotten cm, oh w, mcdonald s, carlo w, fanaroff aa, duara s, et al. prolonged hospital stay for extremely premature infants: risk factors, center differences, and the impact of mortality on selecting a best-performing center. j perinatol 2005; 25:650–5. doi: 10.1038/sj.jp.7211369. 11. raval mv, moss rl. current concepts in the surgical approach to necrotising entercolitis pathophysiology. pathophysiology 2014; 21:105–10. doi: 10.1016/j.pathophys.2013.11.017. 12. mukhopadhyay k, louis d, mahajan r, kumar p. predictors of mortality and major morbidities in extremely low birth weight neonates. indian pediatr 2013; 50:1119–23. doi: 10.1007/s133 12-013-0305-8. 13. de luis pa, culebras jm, aller r, eiros-bouza jm. surgical infection and malnutrition. nutr hosp 2014; 30:509–13. doi: 10.3305/nh.2014.30.3.7702. 14. kassa am, lilja he. predictors of postnatal outcome in neonates with gastroschisis. j pediatr surg 2011; 46:2108–14. doi: 10.1016/j.jpedsurg.2011.07.012. 15. berry ma, shah ps, brouillette rt, hellmann j. predictors of mortality and length of stay for neonates admitted to children’s hospital neonatal intensive care units. j perinatol 2008; 28:297– 302. doi: 10.1038/sj.jp.7211904. 16. payne nr, pfleghaar k, assel b, johnson a, rich rh. predicting the outcome of newborns with gastroschisis. j pediatr surg 2009; 44:918–23. doi: 10.1016/j.jpedsurg.2009.01.036. 17. kent al, wright im, abdel-latif me; new south wales and australian capital territory neonatal intensive care units audit group. mortality and adverse neurologic outcomes are greater in preterm male infants. pediatrics 2012; 129:124–31. doi: 10.1542/peds.2011-1578. 18. nasr a, langer jc; canadian pediatric surgery network. influence of location of delivery on outcome in neonates with congenital diaphragmatic hernia. j pediatr surg 2011; 46:814– 16. doi: 10.1016/j.jpedsurg.2011.02.007. 19. ross mg, downey ca, bemis-heys r, nguyen m, jacques dl, stanziano g. prediction by maternal risk factors of neonatal intensive care admissions: evaluation of >59,000 women in national managed care programs. am j obstet gynecol 1999; 181:835–42. doi: 10.1016/s0002-9378(99)70310-8. 20. sharp m, bulsara m, gollow i, pemberton p. gastroschisis: early enteral feeds may improve outcome. j paediatr child health 2000; 36:472–6. doi: 10.1046/j.1440-1754.2000.00552.x. 21. lewis sj, egger m, sylvester pa, thomas s. early enteral feeding versus “nil by mouth” after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. bmj 2001; 323:773–6. doi: 10.1136/bmj.323.7316.773. 22. ekingen g, ceran c, guvenc bh, tuzlaci a, kahraman h. early enteral feeding in newborn surgical patients. nutrition 2005; 21:142–6. doi: 10.1016/j.nut.2004.10.003. 23. bhatti km, alsibai sm, albalushi zn, alisaee as, almasrouri sm. current status of pediatric minimal access surgery at sultan qaboos university hospital: a 3-year experience. ann pediatr surg 2013; 9:140–3. doi: 10.1097/01.xps.0000434487.93877.be. sultan qaboos university med j, may 2015, vol. 15, iss. , pp. e234–240, epub. 28 may 15 submitted 5 jun 14 revisions req. 17 aug & 27 oct 14; revisions recd. 28 sep & 26 dec 14 accepted 15 jan 14 1department of child health, sultan qaboos university hospital, muscat, oman; 2department of medicine, armed forces hospital, muscat, oman; 3department of pharmacology & clinical pharmacy, college of medicine & health sciences, sultan qaboos university, muscat, oman; 4oman medical speciality board, muscat, oman *corresponding author e-mail: siham_ss@hotmail.com عوامل و نسبة حدوث اإلصابة بالركود الصفراوي املرتبط بالتغذية الوريدية يف األطفال العمانيني حديثي الوالدة خربة مركز �رشيف �رشيف، �سهام ال�سنانية، خالد النعماين، اإبراهيم الزكواين، زنيدة �ض. ري�ض، هالل الريامي، اأ�سفق اأ. خان، وطفة املعمرية abstract: objectives: parenteral nutrition-associated cholestasis (pnac) is one of the most challenging complications of prolonged parenteral nutrition (pn) in neonates. there is a lack of research investigating its incidence in newborn infants in oman and the arab region. therefore, this study aimed to assess the incidence of pnac and its risk factors in omani neonates. methods: this retrospective study took place between january and april 2014. all neonates who received pn for ≥14 days during a four-year period (june 2009 to may 2013) at the neonatal intensive care unit (nicu) in sultan qaboos university hospital, muscat, oman, were enrolled. results: a total of 1,857 neonates were admitted to the nicu over the study period and 135 neonates (7.3%) received pn for ≥14 days. determining the incidence of pnac was only possible in 97 neonates; of these, 38 (39%) had pnac. the main risk factors associated with pnac were duration of pn, duration of enteral starvation, gastrointestinal surgeries, blood transfusions and sepsis. neonates with pnac had a slightly higher incidence of necrotising enterocolitis in comparison to those without pnac. conclusion: this study found a pnac incidence of 39% in omani neonates. there were several significant risk factors for pnac in omani neonates; however, after logistic regression analysis, only total pn duration remained statistically significant. preventive strategies should be implemented in nicus so as to avoid future chronic liver disease in this population. keywords: cholestasis; parenteral nutrition; neonates; incidence; risk factors; oman. امللخ�ص: الهدف: يعترب الركود ال�سفراوي من اأكرث م�ساعفات ا�ستخدام التغذية الوريدية لفرتات طويلة يف االأطفال حديثي الوالدة حتديا. ال توجد درا�سات تبحث ن�سبة ومعدالت حدوثه يف الدول العربية و�سلطنة عمان. هدفت هذة الدرا�سة اىل حتديد معدالت االإ�سابة بالركود ال�سفراوي املرتبط باالإ�ستخدام املطول للتغذية الوريدية وم�سبباته يف االأطفال العمانيني حديثي الوالدة. الطريقة: اأجريت هذه الدرا�سة االإ�سرتجاعية خالل الفرتة من �سهر يناير اىل اأبريل 2014. ومت ح�رش كل االأطفال العمانيني حديثي الوالدة والذين تلقوا التغذية الوريدية لفرتة اأطول من اأو ت�ساوي 14 يوم خالل فرتة 4 �سنوات بني يونيو 2009 وحتى مايو 2013 يف وحدة العناية املركزة لالأطفال حديثي الوالدة مب�ست�سفى جامعة ال�سلطان قابو�ض مب�سقط، �سلطنة عمان. النتائج: مت ح�رش عدد 1,857 طفال حديث الوالدة اأدخلوا الوحدة لتلقي العناية خالل فرتة احل�رش. تلقى135 منهم التغذية الوريدية لفرتة اأطول من اأو ت�ساوي 14 يوم بن�سبة مئوية تعادل %7.3. حتديد معدل بالركود االإ�سابة عوامل اأكرث كانت .)39% ( طفل 38 يف ال�سفراوي الركود حدث حيث فقط طفال 97 يف ممكنا كان ال�سفراوي الركود ال�سفراوي �سيوعا هي مدة تلقي التغذية الوريدية، مدة املجاعة املعوية، تعر�ض اجلهاز اله�سمي للعمليات اجلراحية ، نقل الدم وحدوث االمعاء باإلتهاب امل�سابني الوالدة حديثي ال�سفراوي، بالركود ي�سابوا مل والذين الوالدة حديثي لالأطفال وباملقارنة الدم. يف اإلتهاب والقولون الناخر كانوا اأكرث عر�سه حلدوث الركود ال�سفراوي املرتبط بالتغذية الوريدية. اخلال�صة: حددت هذة الدرا�سة حدوث الركود ال�سفراوي املرتبط بالتغذية الوريدية بن�سبة %39 يف االأطفال العمانيني حديثي الوالدة املتلقني للتغذية الوريدية وقد مت ح�رش العديد من عوامل االإ�سابة ولكن بعد اإ�ستخدام حتليل االإنحدار اللوج�ستي وجد اأن مدة التغذية الوريدية هو العامل الذي ظل له داللة اإح�سائية هامة. من املهم تنفيذ اإ�سرتاتيجيات وقائية يف وحدات العناية املركزة لالأطفال حديثي الوالدة لتجنب حدوث اأمرا�ض الكبد املزمنة م�ستقبال يف هذة الفئة. مفتاح الكلمات: الركود ال�سفراوي؛ التغذية الوريدية؛ حديثي الوالدة؛ معدل حدوث؛ عوامل االإ�سابة؛ عمان. incidence and risk factors of parenteral nutrition-associated cholestasis in omani neonates single centre experience sharef w. sharef,1 *siham al-sinani,1 khalid al-naamani,2 ibrahim al-zakwani,3 zenaida s. reyes,1 hilal al-ryiami,4 ashfaq a. khan,1 watfa al-mamari1 clinical & basic research sharef w. sharef, siham al-sinani, khalid al-naamani, ibrahim al-zakwani, zenaida s. reyes, hilal al-ryiami, ashfaq a. khan and watfa al-mamari clinical and basic research | e235 in oman, the use of parenteral nutrition (pn) in neonatal intensive care units (nicus) is increasingly practiced as preterm infants as young as 24 gestational weeks are resuscitated. pn has fundamentally changed the care of neonates who cannot achieve adequate growth through enteral feeding.1 today, many patients in different age groups depend on pn for their survival. parenteral nutrition-associated cholestasis (pnac) is one of the most challenging complications arising from the prolonged administration of pn and has long been recognised as a risk factor for neonatal cholestasis.2 pnac is defined as serum conjugated bilirubin levels of >2 mg/dl (34.2 μmol/l) associated with sustained exposure to pn for ≥14 days.3–5 other conditions which can potentially cause cholestasis in infants receiving pn and which must be ruled out include biliary atresia and infections as well as a variety of other metabolic, endocrine and genetic disorders.6,7 pnac is predominantly a paediatric disease, with premature neonates being the most predisposed age group with high morbidity and mortality rates.4 the incidence, severity and duration of cholestasis varies substantially among reports depending on the study population and duration of pn exposure;3 it can vary from 10–60% depending on the population studied and the criteria used.4,8 pnac remains a frequent and poorly understood complication of pn therapy in infants, despite improvements in the components of pn and neonatal intensive care measures.9 in addition, and despite an enhanced understanding of the molecular basis of neonatal cholestasis, the precise mechanism by which pn induces liver injury remains uncertain.10,11 several risk factors for pnac have been identified, including caloric overload, nutritional deficiencies, toxicity of specific pn constituents, oxidative stress and altered bile composition.12,13 in addition, intrauterine growth retardation, immaturity of the biliary excretory system, absence of enteral feeding, bacterial overgrowth, sepsis, hypotension or hypoxia, gastrointestinal (gi) surgeries, a cumulative high intake of amino acids and lipids and short bowel syndrome have been described as risk factors.9,14–21 nutritional deficiencies, including essential fatty acids, carnitine, choline, taurine, vitamin e and selenium, are also thought to contribute to pnac.22 histologically, pnac is associated with cholestasis, steatosis, steatohepatitis and, in severe cases, fibrosis and cirrhosis.3 the resolution of pnac and normalisation of liver enzymes may occur gradually after the alteration or withdrawal of pn and the initiation of enteral feeding. however, some infants may develop persistent or progressive liver disease or hepatic failure.12 pnac can lead to high morbidity and mortality rates.13,23 numerous studies have documented an association between pnac and risk of sepsis, liver failure and mortality.5,9 however, there is a lack of research investigating the incidence of pnac in newborn infants in the arab region. to the best of the authors’ knowledge, no studies of this kind have yet been undertaken in oman. hence, the aim of this study was to determine the incidence and risk factors of pnac in omani neonates for the first time. methods this four-year retrospective cohort study took place from january to april 2014. all neonates admitted to the nicu at sultan qaboos university hospital (squh) in muscat, oman, and who received pn for ≥14 days during the period from june 2009 to may 2013 were enrolled in the study. exclusion criteria included patients who died during their time in the nicu or those without conjugated bilirubin measurements (as the cause of cholestasis could not be determined retrospectively) as well as neonates with other causes of cholestasis. a diagnosis of pnac relied on a history of pn for ≥14 days, direct bilirubin of >2 mg/dl (34 μmol/l) and the exclusion of other causes of neonatal cholestasis. demographic and clinical data were obtained from hospital electronic records, including gestational age (ga); birth weight (bw); gender; evidence of advances in knowledge to the best of the authors’ knowledge, this study is the first to investigate the incidence and risk factors of parenteral nutrition-associated cholestasis (pnac) in an omani neonatal population. the risk factors for developing pnac in this population were similar to those reported elsewhere. significant risk factors for pnac in this population were related to the duration of parenteral nutrition (pn) and enteral starvation, as well as the presence of late-onset sepsis and the number of blood transfusions and gastrointestinal surgeries a neonate had undergone. application to patient care understanding the incidence of pnac and its risk factors in oman will aid in the implementation of preventive strategies. these could include reducing the duration of pn and promoting enteral feeds soon after birth by adopting appropriate early feeding protocols in neonatal intensive care units. these strategies may help minimise the incidence of pnac and prevent chronic liver disease in this age group. incidence and risk factors of parenteral nutrition-associated cholestasis in omani neonates single centre experience e236 | squ medical journal, may 2015, volume 15, issue 2 pnac; total duration and number of pn courses; ventilation; significant desaturation (oxygen saturation below 89%); morbidities such as respiratory distress syndrome (rds), bronchopulmonary dysplasia ([bpd] a form of chronic lung disease that develops in preterm neonates treated with oxygen and positive-pressure ventilation), hypotension, patent ductus arteriosus (pda) or necrotising enterocolitis (nec) of any stage, enteral starvation, gi surgeries and a history of blood transfusions. the presence of late-onset sepsis was determined by positive blood culture results which are routinely done if there is any fever or suspicion of clinical sepsis. the use of antibiotics and potential hepatotoxic medications (including acetaminophen, diuretics, ibuprofen, morphine, sildenafil, midazolam and caffeine) was also documented. descriptive statistics were calculated and compared between the pnac and non-pnac groups (the latter group included neonates in the study who did not develop pnac). for categorical variables, frequencies and percentages were reported. group comparisons were performed using the chi-squared test or fisher’s exact test where appropriate. means ± standard deviation or medians with interquartile range (iqr) were used to present the data where appropriate. comparisons of continuous data were performed using the student’s t-test for data with a normal distribution and the mann-whitney u test for continuous data without a normal distribution. furthermore, a multivariate logistic regression model was utilised to determine risk factors for pnac. the a priori two-tailed level of significance (p value) was set at 0.05. data were analysed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). ethical approval for this study was obtained from the medical research & ethics committee at the college of medicine & health sciences, sultan qaboos university, muscat, oman (mrec#622). results between june 2009 and may 2013, a total of 1,857 neonates were admitted to the squh nicu; of these, 244 (13%) received pn during their stay. nine neonates were excluded from the study either due to death (n = 8) or a diagnosis of cystic fibrosis (n = 1), which is known to cause cholestasis. among the remaining 235 figure 1: flowchart of omani neonates admitted to the sultan qaboos university hospital neonatal intensive care unit over a four-year period with regards to parenteral nutrition and parenteral nutrition-associated cholestasis. squh = sultan qaboos university hospital; nicu = neonatal intensive care unit; pn = parenteral nutrition; pnac= parenteral nutritionassociated cholestasis. table 1: demographic characteristics of omani neonates in a neonatal intensive care unit receiving parenteral nutrition for ≥14 days and evaluated for the presence of parenteral nutrition-associated cholestasis (n = 97) characteristic value gender male, n (%) 56 (58) female, n (%) 41 (42) ga in weeks, mean ± sd 29 ± 3 bw in g, mean ± sd 1,165 ± 495 small for ga, n (%) 36 (37) ga = gestational age; sd = standard deviation; bw = birth weight. sharef w. sharef, siham al-sinani, khalid al-naamani, ibrahim al-zakwani, zenaida s. reyes, hilal al-ryiami, ashfaq a. khan and watfa al-mamari clinical and basic research | e237 neonates, the median duration of pn was 14 days (iqr: 8–21 days). a total of 135 neonates (57%) received pn for ≥14 days and were evaluated for pnac. a total of 38 neonates were subsequently excluded from the study due to a lack of direct bilirubin measurements, resulting in a total number of 97 neonates [figure 1]. the demographic characteristics of these neonates are shown in table 1. out of the 97 neonates, 38 developed pnac, giving an incidence of 39% over four years. the details of yearly pnac incidence rates are shown in table 2. the duration of pn ranged from 14–120 days (mean: 30 ± 13 days). the majority of the neonates (34%) received pn for 2–3 weeks (14–21 days); these neonates demonstrated the lowest incidence of pnac (12%) [figure 2]. the incidence of pnac was higher in those who had received pn for a longer duration [table 2]. table 3 shows the comparison between the pnac and non-pnac groups. using a univariate analysis, the following significant risk factors for pnac were found: pn duration; enteral starvation; presence of late-onset sepsis; number of blood transfusions, and gi surgeries. the analysis showed that the pnac group had a longer median initial pn duration (30 versus 20 days; p <0.001), received pn more than once (24% versus 12%; p = 0.038) and had a longer median total pn duration (30 versus 21 days; p <0.001) in comparison to neonates in the non-pnac group. although the median duration of initial enteral starvation was not significantly different between the pnac and nonpnac groups (four and three days, respectively; p = 0.250), the number of neonates who underwent enteral starvation later on during the course of their nicu stay was higher (63% versus 32%; p = 0.003) and the median duration of total enteral starvation was longer in the pnac group (11 versus five days; p = 0.040) compared to the non-pnac group. neonates with pnac underwent more gi surgeries than those without pnac (21% versus 5%; p = 0.015). neonates in the pnac group underwent the following gi surgeries: laparotomies for stage 3 nec with intestinal resection (n = 3); exploratory laparotomies for stage 1 nec (n = 2); laparotomy for duodenal atresia (n = 1), and laparotomies for malrotation and gastroschisis (n = 2). the non-pnac group underwent the following gi surgeries: laparotomy for stage 1 nec (n = 1); laparotomy and intestinal resection for stage 3 nec (n = 1), and duodenal atresia repair (n = 1). in addition, neonates with pnac had a higher mean number of blood transfusions (six versus four; p = 0.037) and a greater frequency of late-onset sepsis (66% versus 41%; p = 0.016). although neonates with pnac had a higher incidence of nec in comparison to those without pnac (34% and 17% respectively), this difference was not significant (p = 0.051). additionally, there were no significant differences between the pnac and non-pnac groups with regards to ga, bw, weight for ga, rds, need for ventilation, presence table 2: yearly and total incidence of parenteral nutrition-associated cholestasis among a population of omani neonates in a neonatal intensive care unit receiving parenteral nutrition for ≥14 days (n = 97) year total june 2009–may 2010 june 2010–may 2011 june 2011–may 2012 june 2012–may 2013 patients on pn for ≥14 days, n 16 19 25 37 97 pn duration in days, mean ± sd 36 ± 26 29 ± 14 28 ± 12 28 ± 15 30 ± 17 patients with pnac, n 8 5 10 15 38 incidence of pnac, % 50 26 40 41 39 pn = parenteral nutrition; sd = standard deviation; pnac = parenteral nutrition-associated cholestasis. figure 2: the incidence of pnac in relation to the administration of pn for >14 days in a population of omani neonates in a neonatal intensive care unit (n = 97). pnac = parenteral nutrition-associated cholestasis; pn = parenteral nutrition. *range of pn duration in this group was 57–73 days for seven patients and 120 days for one patient. incidence and risk factors of parenteral nutrition-associated cholestasis in omani neonates single centre experience e238 | squ medical journal, may 2015, volume 15, issue 2 of significant desaturation/hypotension, bpd or pda (p >0.05) [table 3]. multivariate logistic regression revealed that only total pn duration was a statistically significant risk factor for developing pnac (p = 0.027; odds ratio = 1.41; 95% ci = 1.04–1.90; for each additional week of pn) [table 4]. discussion to the best of the authors’ knowledge, the present study is the first to investigate the incidence of and risk factors for pnac in an omani neonatal population at an nicu in a single tertiary centre. over the study period, the yearly incidence of pnac ranged from 26–50%, with an overall incidence of 39%. in general, the incidence of pnac reportedly ranges between 10– 60% depending on the population, criteria, duration table 3: demographic and clinical characteristics of omani neonates receiving pn for ≥14 days in a neonatal intensive care unit according to parenteral nutrition-associated cholestasis group (n = 97)* characteristic group p value pnac (n = 38; 39%) non-pnac (n = 59; 61%) demographic male gender, n (%) 26 (68) 30 (51) 0.087 ga in weeks, mean ± sd 29 ± 3.2 28.6 ± 3.4 0.410 bw in g, mean ± sd 1,180 ± 530 1150 ± 480 0.747 sga, n (%) 16 (42) 20 (34) 0.414 nicu finding/treatment rds, n (%) 33 (87) 56 (95) 0.158 ventilation, n (%) 34 (90) 54 (92) 0.734 significant desaturation, n (%) 25 (66) 36 (61) 0.635 significant hypotension, n (%) 7 (19) 12 (20) 0. 816 bpd, n (%) 15 (40) 24 (41) 0.853 pda, n (%) 2 (5) 6 (10) 0.475 nec, n (%) 13 (34) 10 (17) 0.051 initial pn received in days, median (iqr) 30 (23–39) 20 (15–26) <0.001* pn received more than once, n (%) 9 (24) 7 (12) 0.038* total pn received in days, median (iqr) 30 (24–42) 21 (16–31) <0.001* initial enteral starvation in days, median (iqr) 4 (2–9) 3 (2–6) 0.250 subsequent enteral starvation, n (%) 24 (63) 19 (32) 0.003* total enteral starvation duration in days, median (iqr) 11 (4–17) 5 (2–13) 0.040* gi surgery, n (%) 8 21) 3 (5) 0.015* blood transfusions, mean ± sd 6 ± 5 4 ± 3 0.037* infection late-onset sepsis, n (%) 25 (66) 24 (41) 0.016* late-onset g+ sepsis, n (%) 16 (42) 16 (27) 0.125 late-onset g sepsis, n (%) 13 (34) 11 (19) 0.083 uti, n (%) 1 (3) 5 (9) 0.399 ab use >7 days, n (%) 37 (97) 53 (90) 0.240 total ab in days, mean ± sd 21 ± 15 20 ± 14 0.623 hepatotoxic medication paracetamol, n (%) 4 (11) 2 (3) 0.206 diuretics, n (%) 12 (32) 19 (32) 0.712 ibuprofen, n (%) 6 (16) 5 (9) 0.276 morphine, n (%) 15 (40) 16 (27) 0.203 sildenafil, n (%) 2 (5) 4 (7) 1.000 midazolam, n (%) 5 (13) 6 (10) 0.650 caffeine, n (%) 32 (84) 52 (88) 0.580 pnac = parenteral nutrition associated cholestasis; ga = gestational age; sd = standard deviation; bw = birth weight; sga = small for gestational age; nicu = neonatal intensive care unit; rds = respiratory distress syndrome; bpd = bronchopulmonary dysplasia; pda= patent ductus arteriosus; nec = necrotising enterocolitis; pn = parenteral nutrition; iqr = interquartile range; gi = gastrointestinal; g+ = gram-positive; g-= gram-negative; uti = urinary tract infection; ab = antibiotics. *statistically significant. sharef w. sharef, siham al-sinani, khalid al-naamani, ibrahim al-zakwani, zenaida s. reyes, hilal al-ryiami, ashfaq a. khan and watfa al-mamari clinical and basic research | e239 of pn exposure and the components of pn.3,4,8,9 unfortunately, little is known regarding the incidence of pnac in arab populations. in saudi arabia, anabrees et al. reported an incidence of 10.7% among neonates with a very low bw.1 pnac has been associated with various risk factors, including pn duration, prematurity, low bw, enteral starvation, sepsis and gi surgeries. in the present study, the most significant risk factor for the development of pnac was pn duration, which remained significant after regression analysis. this is comparable with other studies.9,24–26 in this cohort, the lowest pnac incidence was observed in neonates who received pn for less than three weeks and the incidence of pnac increased dramatically beyond the third week of pn. a similar study reported an incidence of 14% among infants receiving pn for 2–4 weeks; this increased with total pn duration to 85% when pn was used for >14 weeks.9 in the current study, late-onset sepsis was an important risk factor for pnac. this finding has also been previously reported.16,18,24,25,27 another risk factor for pnac in the studied omani population was the total duration of enteral starvation; however, more importantly, undergoing enteral starvation later on during the course of the nicu stay was a significant risk factor. this was similarly reported in other studies.17,28 gi surgeries are a frequently reported risk factor for pnac. many earlier studies, as well as the present one, have clearly confirmed this relationship.9,24,25,28,29 a significant correlation between the number of blood transfusions and pnac was demonstrated in the current study. although there are currently no other published studies supporting this finding, it is assumed that blood transfusions in the current study were required for patients who were sick, septic and/ or possibly undergoing gi surgeries. future studies are needed to investigate the relationship between blood transfusions and pnac in order to determine its impact as an independent risk factor in the development of pnac. despite its strong indication as a major risk factor in many other studies,9,16,26,30 the association of nec with pnac in the present study was not significant. suita et al. also found no correlation between nec and pnac.28 while some studies have indicated that the incidence of pnac is higher in neonates with lower ga and bw,9,16,24,26 other studies, including the present study, found no causal relationship between these factors.25,28 in the present study, rds, ventilation, bpd and pda were not significant risk factors for pnac; this is contrary to other studies which have reported these factors to be associated with a higher risk of pnac.16,26 furthermore, the current study did not identify an association between the use of potentially hepatotoxic medications and increased pnac risk. understanding the incidence of pnac and its risk factors is important as it may aid in the implementation of preventive strategies so as to avoid future chronic liver disease and related complications in this age group. these strategies could include reducing the duration of pn and promoting enteral feeds soon after birth by adopting early feeding according to appropriate nicu protocols. these strategies may help minimise the incidence of pnac and prevent chronic liver disease among neonates. the present study had some limitations, including its retrospective nature as well as the exclusion of many neonates without direct bilirubin measurements due to the lack of laboratory monitoring or undetermined aetiology of the cholestasis. furthermore, the constitution of pn was not examined in this study. further studies are recommended to examine pn constituents among neonates in oman, as well as identifying the effect of pn components in the incidence and risk factors of pnac. conclusion in the studied omani neonatal population, the overall incidence of pnac was 39% over a four-year period. the duration of pn, sepsis, duration of enteral starvation, number of gi surgeries and number of blood transfusions were significant risk factors for developing pnac. however, only total pn duration remained a statistically significant risk factor after a logistic regression analysis. with these risk factors in mind, preventive strategies should be implemented in nicus so as to avoid future chronic liver disease and its complications in this age group. to the best of the authors’ knowledge, this study is the first to report the incidence of pnac and its risk factors among omani neonates. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. table 4: multivariate analysis for risk factors of parenteral nutrition-associated cholestasis among a population of omani neonates in a neonatal intensive care unit (n = 97) significant risk factors p value or 95% ci duration of pn 0.027 1.41 1.04–1.90 late-onset sepsis 0.132 2.01 0.81–4.98 duration of enteral starvation 0.458 1.02 0.97–1.07 pn = parenteral nutrition; or = odds ratio; ci = confidence interval. incidence and risk factors of parenteral nutrition-associated cholestasis in omani neonates single centre experience e240 | squ medical journal, may 2015, volume 15, issue 2 references 1. anabrees j, khan ms, alzahrani a. parenteral nutrition associated cholestatic jaundice in very low birth weight infants. early hum dev 2008; 84:s106. doi: 10.1016/j. earlhumdev.2008.09.275. 2. balistreri wf, bezerra ja. whatever happened to “neonatal hepatitis”? clin liver dis 2006; 10:27–53. doi: 10.1016/j. cld.2005.10.008. 3. baserga mc, sola a. intrauterine growth restriction impacts tolerance to total parenteral nutrition in extremely low birth weight infants. j perinatol 2004; 24:476–81. doi: 10.1038/ sj.jp.7211137. 4. beath sv, davies p, papadopoulou a, khan ar, buick rg, corkery jj, et al. parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. j pediatr surg 1996; 31:604–6. doi: 10.1016/s00223468(96)90507-2. 5. carter ba, shulman rj. mechanisms of disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis. nat clin pract gastroenterol hepatol 2007; 4:277–87. doi: 10.1038/ncpgasthep0796. 6. christensen rd, henry e, wiedmeier se, burnett j, lambert dk. identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease. j perinatol 2007; 27:284–90. doi: 10.1038/sj.jp.7211686. 7. cole cr, frem jc, schmotzer b, gewirtz at, meddings jb, gold bd, et al. the rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. j pediatr 2010; 156:941–7. doi: 10.1016/j.jpeds.2009.12.008. 8. costa s, maggio l, sindico p, cota f, de carolis mp, romagnoli c. preterm small for gestational age infants are not at higher risk for parenteral nutrition-associated cholestasis. j pediatr 2010; 156:575–9. doi: 10.1016/j.jpeds.2009.10.038. 9. diamanti a, basso ms, castro m, di ciommo v, bracci f, ferretti f, et al. irreversible intestinal failure: prevalence and prognostic factors. j pediatr gastroenterol nutr 2008; 47:450– 7. doi: 10.1097/mpg.0b013e31817af979. 10. emerick km, whitington pf. molecular basis of neonatal cholestasis. pediatr clin north am 2002; 49:221–35. doi: 10.1016/s0031-3955(03)00116-0. 11. emerick km, whitington pf. neonatal liver disease. pediatr ann 2006; 35:280–6. doi: 10.3928/0090-4481-20060401-13. 12. hagadorn ji, wolkoff l, esposito p, brumberg hl, emerick k, gerace jr. alterations in parenteral nutrition management for the treatment of parenteral nutrition-associated cholestasis in term and preterm infants (protocol). cochrane database syst rev 2009; 2:cd007833. doi: 10.1002/14651858.cd007833. 13. klein cj, revenis m, kusenda c, scavo l. parenteral nutritionassociated conjugated hyperbilirubinemia in hospitalized infants. j am diet assoc 2010; 110:1684–95. doi: 10.1016/j. jada.2010.08.012. 14. koseesirikul p, chotinaruemol s, ukarapol n. incidence and risk factors of parenteral nutrition-associated liver disease in newborn infants. pediatr int 2012; 54:434–6. doi: 10.1111/j.1442-200x.2012.03627.x. 15. lee sm, namgung r, park ms, eun hs, kim nh, park ki, et al. parenteral nutrition associated cholestasis is earlier, more prolonged and severe in small for gestational age compared with appropriate for gestational age very low birth weight infants. yonsei med j 2013; 54:839–44. doi: 10.3349/ymj.2013.54.4.839. 16. moss rl, amii la. new approaches to understanding the etiology and treatment of total parenteral nutrition-associated cholestasis. semin pediatr surg 1999; 8:140–7. doi: 10.1016/ s1055-8586(99)70015-6. 17. peden vh, witzleben cl, skelton ma. total parenteral nutrition. j pediatr 1971; 78:180–1. doi: 10.1016/s0022-3476(71)80289-5. 18. puligandla ps, janvier a, flageole h, bouchard s, mok e, laberge jm. the significance of intrauterine growth restriction is different from prematurity for the outcome of infants with gastroschisis. j pediatr surg 2004; 39:1200–4. doi: 10.1016/j. jpedsurg.2004.04.014. 19. robinson dt, ehrenkranz ra. parenteral nutrition-associated cholestasis in small for gestational age infants. j pediatr 2008; 152:59–62. doi: 10.1016/j.jpeds.2007.06.002. 20. shin ji, namgung r, park ms, lee c. could lipid infusion be a risk for parenteral nutrition-associated cholestasis in low birth weight neonates? eur j pediatr 2008; 167:197–202. doi: 10.1007/ s00431-007-0454-7. 21. slicker j, vermilyea s. pediatric parenteral nutrition: putting the microscope on macronutrients and micronutrients. nutr clin pract 2009; 24:481–6. doi: 10.1177/0884533609339073. 22. sondheimer jm, asturias e, cadnapaphornchai m. infection and cholestasis in neonates with intestinal resection and longterm parenteral nutrition. j pediatr gastroenterol nutr 1998; 27:131–7. 23. spencer au, yu s, tracy tf, aouthmany mm, llanos a, brown mb, et al. parenteral nutrition-associated cholestasis in neonates: multivariate analysis of the potential protective effect of taurine. jpen j parenter enteral nutr 2005; 29:337–43. doi: 10.1177/0148607105029005337. 24. teitelbaum dh. parenteral nutrition-associated cholestasis. curr opin pediatr 1997; 9:270–5. 25. teitelbaum dh, drongowski r, spivak d. rapid development of hyperbilirubinemia in infants with the short bowel syndrome as a correlate to mortality: possible indication for early small bowel transplantation. transplant proc 1996; 28:2699–700. 26. willis tc, carter ba, rogers sp, hawthorne km, hicks pd, abrams sa. high rates of mortality and morbidity occur in infants with parenteral nutrition-associated cholestasis. jpen j parenter enteral nutr 2010; 34:32–7. doi: 10.1177/0148607109332772. 27. steinbach m, clark rh, kelleher as, flores c, white r, chace dh, et al. demographic and nutritional factors associated with prolonged cholestatic jaundice in the premature infant. j perinatol 2008; 28:129–35. doi: 10.1038/sj.jp.7211889. 28. suita s, yamanouchi t, masumoto k, ogita k, nakamura m, taguchi s. changing profile of parenteral nutrition in pediatric surgery: a 30-year experience at one institute. surgery 2002; 131:s275–82. doi: 10.1067/msy.2002.119965. 29. wright k, ernst kd, gaylord ms, dawson jp, burnette tm. increased incidence of parenteral nutrition-associated cholestasis with aminosyn pf compared to trophamine. j perinatol 2003; 23:444–50. doi: 10.1038/sj.jp.7210965. 30. yang cf, lee m, valim c, hull ma, zhou j, jones ba, et al. persistent alanine aminotransferase elevations in children with parenteral nutrition-associated liver disease. j pediatr surg 2009; 44:1084–7. doi: 10.1016/j.jpedsurg.2009.02.011. sir, palmoplantar psoriasis is a condition characterised by erythema, infiltration, fissuring, and scaling, and is sometimes associated with recurrent crops of sterile pustules, occasionally presenting with hyperkeratosis. this chronic inflammatory skin disease can be disabling in cases where patients experience painful fissuring and may affect daily activities, possibly resulting in debilitating pain.1 smoking has been observed to be a trigger in the development of this form of psoriasis through oxidative, inflammatory, and genetic mechanisms. nicotine damages skin by increasing the reactive oxygen species and decreasing the expression of antioxidants. it also stimulates innate immune cells integral to the pathogenesis of psoriasis including macrophages, keratinocytes, and dendritic cells.2 a better understanding of palmoplantar psoriasis has disclosed some differences when compared to psoriasis vulgaris regarding age of onset, female predominance, and smoking influence.3 the impact of the cessation of smoking during the clinical course of the disease remains to be established. we present a case of refractory palmar psoriasis with clinical improvement after cessation of smoking. a 51-year-old male farmer presented to the department of dermatology at san cecilio university hospital, granada, spain, with palmoplantar psoriasis. he had been suffering this condition since the age of 34 with periods of remission and aggravation. his medical history showed that he had been a heavy smoker (3 packs per day) for the last 35 years. his lesions had become extremely painful and incapacitated him to the extent that he was unable to work. an examination revealed scaly hyperkeratotic plaques with fissures on both hands [figure 1]. his nails were also dramatically affected showing distal onycholysis, subungual hyperkeratosis, beau’s lines and oil spots [figure 2]. his feet were free of lesions. several therapies were used including topical steroids, psoralen and ultraviolet a (puva) light therapy, and methotrexate, but no improvement was observed. psoriasis on hands and feet is a disabling condition which highly impacts quality of life (qol). it is a particularly challenging form of psoriasis due to its resistance to treatment; topical therapies usually fail because of the thickened horny layer of epidermis in these areas, and systemic conventional therapies do sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 188-189, epub. 27th feb 13 submitted 31st mar 12 revision req. 13th jun 12, revision recd. 20th jul 12 accepted 25th sep 12 التحسن السريع من صدفّية الكف بعد التوقف عن التدخني rapid improvement of palmoplantar psoriasis after cessation of smoking letter to editor figure 1: tender scaly plaques on palmar side of the hands. the patient was unable to work. figure 2: nails were dramatically involved showing distal onycholysis, subungal hyperkeratosis, beau’s lines, and oil spot. husein h. el ahmed letter to editor | 189 not always give a therapeutic gain. many of these systemic therapies used in plaque psoriasis have been used in palmoplantar psoriasis, but none are generally accepted as being reliably effective. in addition, patients with this condition are excluded from most clinical trials of psoriasis, which leads to no evidence-based consensus regarding a therapeutic strategy for this disease. with all these considerations in mind, we also have to consider other environmental conditions that have an effect on the therapeutic results of smoking. patients with psoriasis are more likely to develop hypertension, obesity, depression, or psychiatric disorders, and become drinkers or smokers due to the impact of this disease on their qol.4,5 tobacco use is preventable, and has been shown to exacerbate pre-existing palmoplantar psoriasis, but its use has also been found among subjects with new onset of the disease.6 moreover, smoking has been suggested as an aggravating factor in the treatment outcomes and is believed to drive disease severity.6,7 the pathogenic mechanism is uncertain but may be linked to the products of smoking which induce oxidative stress, encouraging inflammatory cells to accumulate in the epidermis, altering the function of these cells and the extracellular matrix turnover.8 smoking enhances expression of genes known to confer an increased risk of psoriasis (hla-cw6, hla-dqa1*0201 and cyp1a1) and initiates the formation of free radicals that stimulate cell-signalling pathways active in psoriasis, including mitogen-activated protein kinase, nuclear factor-kb, and janus kinase/signal transducers and activators of transcription. nicotine stimulates cells associated with the pathogenesis of psoriasis such as dentritic cells, macrophages, and keratinocytes. these cells release cytokines which activate t-lymphocytes and perpetuate a cycle of chronic inflammation.3 improved understanding of the possible link between smoking and palmoplantar psoriasis may provide further insight into mechanisms underlying smoking, psoriasis, and its improvement after cessation of smoking. in a case series study, up to 95% of patients with psoriasis of the hands and feet were former or current smokers, but the impact of cessation in the clinical course of the disease has not been clarified yet.9 in our case, a satisfactory response to methotrexate (15 mg/week) and emollients was observed only after cessation of smoking. physicians should keep this in mind and carefully investigate the possibility of a patient being a smoker if that patient is refractory to conventional therapies. in unresponsive cases of psoriasis, smoking may be responsible for the refractoriness. discontinuation of smoking may lead to a satisfactory response, as was seen in our patient. husein h. elahmed san cecilio university hospital, granada, spain e-mail: huseinelahmed@hotmail.com references 1. pettey a, balkrishnan r, rapp s r, fleischer ab, feldman sr. patients with palmoplantar psoriasis have more physical disability and discomfort than patients with other forms of psoriasis: implications for clinical practice. j am acad dermatol 2003; 49:271–5. 2. armstrong aw, armstrong ej, fuller en, sockolov me, voyles sv. smoking and pathogenesis of psoriasis: a review of oxidative, inflammatory and genetic mechanisms. br j dermatol 2011; 165:1162–8. 3. miot ha, miot ld, lopes ps, haddad gr, marques sa. association between palmoplantar pustulosis and cigarette smoking in brazil: a case-control study. j eur acad dermatol venereol 2009; 23:1173–7. 4. schmitt j, ford de. psoriasis is independently associated with psychiatric morbidity and adverse cardiovascular risk factors, but not with cardiovascular events in a population-based sample. j eur acad dermatol venereol 2010; 24:885–92. 5. al-mutairi n, al-farag s, al-mutairi a, al-shiltawy m. comorbidities associated with psoriasis: an experience from the middle east. j dermatol 2010; 37:146–55. 6. naldi l. cigarette smoking and psoriasis. clin dermatol 1998; 16:571–4. 7. hayes j, koo j. psoriasis: depression, anxiety, smoking, and drinking habits. dermatol ther 2010; 23:174–80. 8. thomsen sf, sørensen lt. smoking and skin disease. skin therapy lett 2010; 15:4–7. 9. eriksson mo, hagforsen e, lundin ip, michaëlsson g. palmoplantar pustulosis: a clinical and immunohistological study. br j dermatol 1998; 138:390–8. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e149–151, epub. 28 may 15 submitted 26 feb 15 revision req. 23 mar 15; revision recd. 8 apr 15 accepted 16 apr 15 in the current issue of squmj, jose et al. reported that approximately 46% of the participants in their study (n = 618) held the erroneous notion that adverse effects occurred only when medications were consumed in high doses.1 approximately 60% of their cohort endorsed the view that medicines prescribed by doctors are completely safe. another most disheartening finding from the study was that the omani public appeared to hold the view that traditional medicines and over-thecounter medications were free of any side-effects.1 in a nutshell, these findings could be extrapolated to indicate that the general public harbours sub-optimal knowledge, belief and behaviour on issues pertinent to the usage of medicine. patient safety is an essential principle of healthcare. each phase of healthcare provision has the potential to trigger an error. this means that problems can occur in the practice, products, procedures or systems of healthcare provision which, in turn, could culminate in adverse events for the patients, including an adverse reaction to drugs. this reaction is defined by the world health organization (who) as “a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.2 although other terminologies have been used to describe unwanted effects of drugs, such as ‘toxic effect’ or ‘side-effect’, the term ‘adverse effect’ is currently the most preferred.3 pharmacovigilance is “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”.2 the importance of patient safety with regards to drug use has been translated into many policies and actions by the who, such as the initiation of the quality assurance and safety of medicines (qsm) team to address worldwide drug safety and drug utilisation. the qsm team function to encourage member states to participate in the who international drug monitoring programme.2 a second important milestone is the work of the who collaborating centre for international drug monitoring, located in uppsala, sweden, which maintains a database for reports of suspected adverse drug reactions from the member states.4 these initiatives strive to promote pharmacovigilance at national levels with the objectives of improving patient care and safety with regards to the use of medications. this aim is actioned by supporting public health programmes through “providing reliable, balanced information for the effective assessment of the risk-benefit profile of medicines”.4 the above-mentioned international and local level initiatives have the potential to safeguard the use of medications and indeed are vital for consumer safety and protection. however, jose et al.’s study suggests some significant gaps in the omani public’s awareness regarding the use of medication that need to be addressed. their study clearly indicates that the public harbour a view that runs counter to international best practice.1 therefore, concerted efforts are needed to increase public knowledge in alignment with the international best practice as stipulated by the who. jose et al.’s study found that the omani public believe that drug side-effects occur only with high doses, implying that the public would take the liberty to titrate dosage if deemed ‘high’.1 conversely, it is also possible that a perceived ‘low’ dosage would be deemed ‘safe’. such erroneous views could be a recipe for hindering compliance with treatment and observation for possible side-effects. the who reported a ‘‘50% phenomenon’’, indicating that half of patients do not follow treatment recommendations.5 indeed, according to the national department of child health, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: munasa@squ.edu.om اآلثار السلبية لألدوية هل الشعب العماين آمن؟ منى ال�سعدون editorial adverse effects of medicines is the omani population safe? muna al-saadoon adverse effects of medicines is the omani population safe? e150 | squ medical journal, may 2015, volume 15, issue 2 institute for health and clinical excellence, both high and low dosages are detrimental to health.6 in a systematic review, van gaalen et al. suggested that a failure to abide by the required dosage tends to put the patient at higher risk of an adverse drug reaction.7 according to the uk-based company, patient connect service limited, patients who take preventative medicines, such as those prescribed for an asymptomatic condition, are likely to fall prey to poor compliance as the preventative nature of the medication means they “do not feel immediately threatened”.8 if the patient has no overt symptoms, the chance of poor compliance increases or the concept of a ‘drug holiday’ comes to the forefront. in addition to the issue of an adverse drug reaction, jose et al.’s study indicated that the majority of the public in oman deemed traditional medicines to cause few or no adverse reactions. most disheartening was that, in another study, such a view was also endorsed by medical students in oman.9 this means that suboptimal knowledge not only exists among the general public, but also among those who are going to be the vanguard of health in the country–medical students. a major source of confusion is that traditional medicines are often parcelled as ‘food supplements’ which can evoke the ‘romance of a herbal elixir’. although there are studies that have reported the therapeutic effects of some herbal medications,10 other studies have revealed that traditional medicinal products contain banned pesticides, microbial contaminants, heavy metals, chemical toxins or orthodox drugs.11 in fact, the medical literature is rife with documentation on the toxic effects stemming from traditional medicine.12,13 there is a wide misconception that herbal medicines are derived from natural sources and are therefore nontoxic and safe. on this ground, there is a significant disjunction between what medical science has revealed about herbal medicine and public perception. there are a number of implicit implications behind the prevailing romance with herbal medicine, including potential delays in medical intervention and the abandonment of biomedical treatment. it has been found that a tendency to use both treatment modalities simultaneously has the potential to compromise the efficiency of medical treatment.14 in oman, traditional medicines are reportedly often consumed concurrently with prescription medication from a medical doctor.15,16 such ‘cocktails’ have the potential to do more harm than good. for this matter who recommends that all member states should: ‘a) establish, strengthen and implement an effective regulation of providers of herbal medicines in respect of their qualifications. b) establish, strengthen and effectively enforce regulations on herbal medicines. c) strengthen capacity-building efforts for providers, manufactures and regulators of herbal medicines in order to improve their capacity and expertise regarding assurance of safety and quality of herbal medicines. d) include safety monitoring of herbal medicines in pharmacovigilance systems and promote the awareness of consumers/patients on safety aspects of herbal medicines. e) provide technical support to member states in the implementation in particular regarding the safety of herbal medicines and of traditional and complementary medicine practices.17 due to the rise of chronic and lifestyle diseases in oman,12 emerging medical conditions require a more novel approach than the existing ‘cure-oriented’ healthcare system.18,19 by virtue of the chronic nature of a lifestyle disease, and as these diseases are often being impervious to available biomedical care, those afflicted by these diseases may be more inclined to utilise both allopathic medicine and alternative medicine. such ‘dual loyalty’ likely stems from emerging health education where patients are encouraged to work with their own doctor.20 with this emerging trend, a concerted effort is needed to impart to both the public and medical experts alike the pros and cons of both healthcare systems. health education in oman appears to represent a middle way between these two contesting parties. in the midst of such a predicament, perhaps we should take note of the words of t. s. eliot: “we shall not cease from exploration, and the end of all our exploring will be to arrive where we started and know the place for the first time”.21 references 1. jose j, jimmy b, al-mamari mns, al-hadrami tsn, al-zadjali hm. knowledge, beliefs and behaviours regarding the adverse effects of medicines in an omani population. sultan qaboos univ med j 2015; 15:234–40. 2. world health organization. international drug monitoring: the role of national centers. report of a who meeting. world health organ tech rep ser 1972; 498:1–25. 3. edwards ir, aronson jk. adverse drug reactions: definitions, diagnosis, and management. the lancet 2000; 356:1255‒1299. doi: 10.1016/s0140-6736(00)02799-9. 4. world health organization. essential medicines and health products: pharmacovigilance. from: www.who.int/medicines/ areas/quality_safety/safety_efficacy/pharmvigi/ accessed: feb 2015. 5. world health organization. adherence to long-term therapies: evidence for action. from: www.who.int/chp/ k n o w l e d g e / p u b l i c a t i o n s / a d h e r e n c e _ i n t r o d u c t i o n . p d f accessed: feb 2015. 6. national institute for health and clinical excellence. medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. from: www.nice.org.uk/ guidance/cg76/resources/guidance-medicines-adherence-pdf accessed: feb 2015. muna al-saadoon editorial | e151 7. van gaalen j, kerstens fg, maas rp, härmark l, van de warrenburg bp. drug-induced cerebellar ataxia: a systematic review. cns drugs 2014; 28:1139–53. doi: 10.1007/s40263014-0200-4. 8. patient connect uk. from: www.patientconnect.co.uk/ accessed: feb 2015. 9. al-saadoon m, al-jashemi rm, al-farsi am, al-suleimani sh, al-khayari hy. medical student attitude toward traditional, complementary and alternative medicine: cross-sectional study. j ethnobiol trad med 2014; 122:900–905. 10. eldeen im, elgorashi ee, van staden j. antibacterial, antiinflammatory, anti-cholinesterase and mutagenic effects of extracts obtained from some trees used in south african traditional medicine. j ethnopharmacol 2005; 102:457–64. doi: 10.1016/j.jep.2005.08.049. 11. chan k. some aspects of toxic contaminants in herbal medicines. chemosphere 2003; 52:1361–71. doi: 10.1016/s004 5-6535(03)00471-5. 12. al-lawati j, morsi m, al-riyami a, mabry r, el-sayed m, elaty ma, et al. trends in the risk for cardiovascular disease among adults with diabetes in oman. sultan qaboos univ med j 2015; 15:e39–45. 13. worthing ma, sutherland hh, al-riyami k. new information on the composition of bint al dhahab, a mixed lead monoxide used as a traditional medicine in oman and the united arab emirates. j trop pediatr 1995; 41:246–7. doi: 10.1093/ tropej/41.4.246. 14. al asmi a, al maniri a, al-farsi ym, burke dt, al asfoor fm, al busaidi i, et al. types and sociodemographic correlates of complementary and alternative medicine (cam) use among people with epilepsy in oman. epilepsy behav 2013; 29:361–6. doi: 10.1016/j.yebeh.2013.07.022. 15. al-kindi rm, al-mushrafi m, al-rabaani m, al-zakwani i. complementary and alternative medicine use among adults with diabetes in muscat region, oman. sultan qaboos univ med j 2011; 11:62–8. 16. al-lamki l. complementary and alternative medicine: where do we stand in the 21st century? sultan qaboos univ med j 2011; 11:161–4. 17. world health organization. regulatory harmonization: 16th international conference of drug regulatory authorities (icdra). from: www.who.int/medicines/publications/druginf ormation/who_di_28-3_regulator yharmonization.pdf accessed: feb 2015. 18. al-sinawi h, al-alawi m, al-lawati r, al-harrasi a, alshafaee m, al-adawi s. emerging burden of frail young and elderly persons in oman: for whom the bell tolls? sultan qaboos univ med j 2012; 12:169–76. 19. al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos univ med j 2006; 6:3–9. 20. al-adawi s, al-salmy h, martin rg, al-naamani a, prabhakar s, deleu d, et al. patient’s perspective on epilepsy: self-knowledge among omanis. seizure 2003; 12:11–8. doi: 10.1016/s1059131102001504. 21. eliot ts. four quartets. new york, usa: harcourt, 1943. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 360-363, epub. 15th jul 12 submitted 11th dec 11 revision req. 10th mar 12, revision recd. 14th mar 12 accepted 18th apr 12 departments of 1family medicine, 2anatomy, 4pathology and 3dermatology unit, medical faculty, universiti kebangsaan malaysia medical centre, kuala lumpur, malaysia. *corresponding author e-mail: drleelaraj@gmail.com َوَرٌم ميالنيينٌّ ُعْقِدّي حياكي ورم شائكي متقرن دروس للتعلم ليالفاثي موثوبالنيابني، �رسيجيت دا�ض، نورازيراه حممد نور، �سيتي علي امللخ�ص: قدم رجل عمره 67 عاما من اأ�سل �سيني مع اآفة عقدية غري موؤملة على ذراعه اليمنى خالل الأ�سهر الثالثة ال�سابقة. لوحظ وجود عقدة واحدة �سلبة وا�سحة املعامل على �سكل قبة ويف و�سطها فتحة من الكرياتني حماطة باحمرار. ا�ستبه بورم �سائكي متقرن مع اإنتان جرثومي ثانوي، وخ�سع املري�ض ل�ستئ�سال اخلزعة. مت تاأكيد ت�سخي�ض �رسطان اجللد اخلبيث العقدي بوا�سطة درا�سة خزعة العقدة واإجراء ال�سبغ املناعى الن�سيجي الكيمياوي . جتدر الإ�سارة اإىل اأن �رسطان اجللد العقدي اخلبيث قد يظهر بت�سكيلة وا�سعة من املظاهر ال�رسيرية، وباأن عدم وجود �سبغة امليالنني يف َوَرٌم ميالنينيٌّ ُعْقِدّي قد يعوق ت�سخي�ض هذه الأورام اخلبيثة. مفتاح الكلمات: امليالنوما، �رسطان اجللد اخلبيث، ورم �سائكي متقرن، تقرير احلالة، ماليزيا abstract: a 67-year-old man of chinese descent presented with a painless nodular lesion that had been present on his right forearm for the previous 3 months. a single, well-defined, dome-shaped, firm nodule with a central keratin plug surrounded by erythema was noted. keratoacanthoma with secondary bacterial infection was suspected and the patient underwent an excision biopsy. biopsy of the nodule and immunohistochemical staining supported a diagnosis of nodular malignant melanoma. it should be noted both that nodular malignant melanoma may present with a wide variety of clinical appearances, and that the lack of melanin pigment in nodular malignant melanoma may hinder the diagnosis of this aggressive tumour. keywords: melanoma; malignant melanoma; keratoacanthoma; case report; malaysia. nodular melanoma mimicking keratoacanthoma lessons to learn *leelavathi muthupalaniappen,1 srijit das,2 norazirah md nor,3 siti a. m. ali4 case report cutaneous malignancies are commonly classified as melanoma skin cancer (msc) and non-melanoma skin cancer (nmsc). among mscs, superficial spreading melanoma is the most common type, followed by nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. nodular melanoma accounts for 10 to 15% of all melanomas. it is a rapid growing, aggressive tumour observed mainly on sun-exposed areas, classically pigmented with a blue or black colour. however, some have been observed it to be hypoor amelanotic.1 it is postulated that during rapid growth the nodules lack pigmentation resulting in hypopigmented lesions.2 this poses a diagnostic challenge as it may be confused with nmsc. squamous cell carcinoma (scc), basal cell carcinoma (bcc), pilomatricoma, and fibroepethelial polyps have been commonly mistaken for keratoacanthoma. we report a rare case of a nodular malignant melanoma mimicking a keratoacanthoma. case report a 67-year-old man of chinese descent presented with a painless nodular lesion on the extensor surface of the right forearm. the lesion had grown from a pinpoint size to a lesion of 7 mm x 3 mm x 5 mm over the preceding 3 months. there was no history of trauma, discharge, pruritus, or bleeding from the lesion. examination revealed a single dome-shaped, pinkish nodule with a central keratin plug surrounded by erythema [figure 1]. an initial diagnosis of keratoacanthoma secondary leelavathi muthupalaniappen, srijit das, norazirah md nor and siti aishah mat ali case report | 361 to bacterial infection was made. the patient was prescribed a course of antibiotics prior to an excision biopsy. however, a week later, during the biopsy, the surrounding erythema was noted to be persistent. macroscopic examination of the biopsy specimen consisted of a piece of skin with a raised nodular lesion. the skin measured 20 x 10 x 5 mm and the nodule measured 10 x 10 x 10 mm. histopathology of the lesion showed a polypoid intradermal tumour with ulceration of the overlying epidermis composed of nests of epithelioid tumour cells which extended down to the mid-dermis [figures 2a and b]. the tumour cells had round to oval nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm with some clearing and a distinct cell border. some cells were large with pleomorphic nuclei and conspicuous nucleoli. both typical and atypical mitotic figures were observed. dense lymphoplasmacytic infiltrates were seen in the deep dermis; however, no lymphovascular invasion was noted. immunohistochemical (ihc) staining for tumour cells showed a strong and diffuse positivity for s-100 [figure 2c] and a few cells were positive for melan-a [figure 2d]. the melan-a test, repeated along with hmb45, revealed similar findings. the final diagnosis, based on the histopathology testing and the ihc stains was malignant melanoma, nodular type. the patient was subjected to a second excision biopsy to achieve a clear margin. histopathological examination of the margin representing the erythematous ring surrounding the lesion showed the presence of lymphocytes and plasma cells, suggesting an inflammatory reaction. a positron emission tomography (pet) scan was negative for any metastasis. discussion malignant melanoma presents with a wide range of clinical morphology. classically, it presents as a brown or black pigmented lesion. there are four types of melanomas: superficial spreading, nodular, lentigo maligna melanoma, and acral lentiginous melanoma. rarely, atypical presentations mimicking soft tissue malignancies have been reported.3 nodular melanoma usually presents as papules, nodules, plaques and occasionally as pedunculated lesions.1 it may present without the figure 1: nodular lesion with central keratin plug on the right forearm. erythema surrounding the lesion is also shown. nodular melanoma mimicking keratoacanthoma lessons to learn 362 | squ medical journal, august 2012, volume 12, issue 3 surrounding invasive melanoma have been described as an inflammatory reaction which in contrast is rarely encountered in benign pigmented lesions.10 the lack of melanin pigment with typical features of keratoacanthoma misled the diagnosis of a nodular melanoma in the present case. conclusion nodular melanoma may present with a multitude of clinical presentations. some may be atypical and totally unexpected. physicians should be aware of these various presentations, especially when attending to patients with skin lesions over sun-exposed areas. they should maintain a high index of suspicion for this condition, especially in managing hypoor non-pigmented nodular lesions. nodular lesions with surrounding erythema should be treated with more caution as this may provide a clue to an underlying malignancy. classical pigment and mimic the clinical appearance of other benign or malignant skin conditions; hence, they are likely to be misdiagnosed.4 the lack of the pigment and the variable ‘mindboggling’ presentations of melanoma often delay the diagnosis of this fairly aggressive malignant skin condition, resulting in increased morbidity such as amputation, distant metastasis, and even death.5 abnormal melanogenesis and loss of the functional capacity of tumour cells due to rapid proliferation have been postulated to cause the lack of pigment.6 keratoacanthomas are rapidly growing, dome-shaped nodules with a central grey-yellow coloured keratotic plug which often undergo spontaneous resolution over 2 to 6 months, leaving a residual scar.7 other lesions commonly mistaken for keratoacanthoma include scc, bcc, pilomatricoma, and fibroepethelial polyps.8 the presence of inflammation and tenderness surrounding scc and malignant melanoma have been described in an earlier article.9 histopathological features of the infiltrate figure 2: (a) intradermal neoplasm composed of large tumour cells with conspicuous nucleoli and eosinophilic cytoplasm is shown (haematoxylin & eosin [h&e] stain, x 100); (b) the lesion at higher magnification (h&e stain, x 400); (c) immunohistochemical stains of the tumour cells show diffuse, strong nuclear and cytoplasmic staining of s-100 (x 200); (d) cytoplasmic staining of melan-a (x 200) (arrows). leelavathi muthupalaniappen, srijit das, norazirah md nor and siti aishah mat ali case report | 363 a c k n o w l e d g e m e n t the authors would like thank prof. dr. thomas krausz of the university of chicago medical center for his contribution in the confirmation of the histological findings of this case. references 1. chamberlain aj, fritschi l, kelly jw. nodular melanoma: patients’ perceptions of presenting features and implications for earlier detection. j am acad dermatol 2003; 48:694–701. 2. chamberlain a. nodular melanoma: controversies and considerations for containment. dermatol surg 2005; 31:979. 3. sangüeza m, zelger b. melanoma simulating atypical fibroxanthoma. am j dermatopathol 2007; 29:551– 4. 4. koch se, lange jr. amelanotic melanoma: the great masquerader. j am acad dermatol 2000; 42:731–4. 5. rahbari h, nabai h, mehregan ah, mehregan da, mehregan dr, lipinski j. amelanotic lentigo maligna melanoma: a diagnostic conundrum-presentation of four new cases. cancer 1996; 77:2052–7. 6. roseeuw d. the invisible melanoma. j eur acad dermatol venereol 2001; 15:506–7. 7. trozak dj, tennenhouse dj, russel jj. dermatology skills for primary care. new jersey: humana press, 2006. pp. 293–7. 8. schwartz ra, tarlow mm, lambert wc. keratoacanthoma-like squamous cell carcinoma within the fibroepithelial polyp. dermatol surg 2004; 30:349–50. 9. hannon ra, pooler c, mattson porth c. pathophysiology: concepts of altered health states. philadelphia: lippincott williams & wilkins, 2009. p. 1521. 10. smoller br. histologic criteria for diagnosing primary cutaneous malignant melanoma. mod pathol 2006; 19:34–40. 1department of community medicine, gulf medical university, ajman, united arab emirates; 2al madina primary health care centre, ajman, united arab emirates *corresponding author e-mail: naila_kanwal@hotmail.com استخدام وسائل منع احلمل عند النساء يف مرحلة سن االجناب يف عجمان باإلمارات العربية املتحدة نائلة كنوال, جياك�ماري م�تاابليمايليل, شذى ال�رسباتي, اإميان اإ�ضماعيل abstract: objectives: this study aimed to determine contraceptive utilisation among mothers aged 18–49 years old in ajman, united arab emirates (uae). methods: this cross-sectional study was carried out from may to november 2013. a total of 400 participants were recruited from two primary healthcare centres and one private hospital in ajman. an interviewer-administered validated questionnaire was used for data collection. results: the frequency of previous and current contraceptive use was 68.0% and 61.8%, respectively. expatriates more frequently used contraceptives in comparison to emiratis (77.3% versus 54.3%, respectively). contraceptive use increased significantly with age (75.5% among >35-year-olds versus 57.3% among ≤25-year-olds; p <0.050) and education level (83.3% among postgraduates versus 60.0% among those with primary education; p <0.050). in addition, contraceptive use was significantly higher among those living in a nuclear family system (p <0.050). a univariate analysis indicated significant associations between contraceptive use and age, nationality, education level, type of family system, employment sector, parity, knowledge of birth control measures and source of birth control information (p <0.050 each). however, no significant associations were found via multivariate analysis. conclusion: healthcare practitioners can play a pivotal role in providing contraceptive advice which could lead to an improvement in contraceptive utilisation. efforts are recommended to raise awareness regarding newer forms of contraceptives among mothers of reproductive age in the uae. keywords: contraception; family planning services; reproductive health; women; united arab emirates. العربية باالإمارات عجمان يف االإجناب �ضن يف الن�ضاء عند احلمل منع و�ضائل ا�ضتخدام لتحديد الدرا�ضة هذه هدفت الهدف: امللخ�ص: املتحدة. الطريقة: اأجريت هذه الدرا�ضة املقطعية امل�ضتعر�ضة من ماي� اإىل ن�فمرب عام 2013. و�ضارك يف الدرا�ضة 400 امراأة مت اإدراجهن يف البحث من مركزين للرعاية ال�ضحية االأولية. ومن م�ضت�ضفى خا�ص يف عجمان. وجلمع املعل�مات, ا�ضتخدم ا�ضتبيان م�ثق امل�ضدوقية اأداره من اأجرى املقابالت مع الن�ضاء امل�ضاركات يف البحث. النتائج: بلغ تكرار اال�ضتخدام ال�ضابق واحلايل ل��ضائل منع احلمل %68.0 و %61.8, على الت�ايل. وكانت ال�افدات اأكرث ا�ضتخداما ل��ضائل منع احلمل من االأمارتيات )%77.3 مقابل %54.3, على الت�ايل(. واإزداد معدل ا�ضتخدام و�ضائل منع احلمل زيادة معن�ية اإح�ضائيا مع تقدم العمر )%75.5 عند الن�ضاء الل�اتي يزيد عمرهن عن 35> �ضنة, مقابل 57.3% عند الن�ضاء يف �ضن 25≥ �ضنة, p >0.050(. واإزداد معدل ا�ضتخدام و�ضائل منع احلمل كذلك مع عل� م�ضت�ى التعليم )%83.3 عند من نلن درا�ضات عليا, يف مقابل %60.0 عند من در�ضن اإىل حد امل�ضت�ى اجلامعي االأول اأو اأقل, p >0.050(. وباالإ�ضافة لذلك, كان معدل ا�ضتخدام و�ضائل منع احلمل اأعلى عند الن�ضاء الل�اتي يع�ضن يف نظام اأ�رسة ن�وية )p >0.050(. واأو�ضح حتليل اأحادي املتغري ترابطا معن�يا بني ا�ضتخدام و�ضائل منع احلمل والعمر, واجلن�ضية, وامل�ضت�ى التعليمي, ون�ع نظام االأ�رسة, وقطاع العمل, وعدد املرات التي ولدت فيها املراأة )رقم ال�الدة(, ومعرفة خمتلف و�ضائل منع احلمل, وم�ضادر املعل�مات عنها )p >0.050 يف كل حالة(. غري اأنه مل يكن هنالك اأي ترابط معن�ي بني ا�ضتخدام و�ضائل منع احلمل وتلك الع�امل عند ا�ضتخدام التحليل املتعدد. اخلال�صة: ميكن اأن ي�ؤدي ممار�ض� الرعاية ال�ضحية دورا مف�ضليا يف تقدمي الن�ضح واالإر�ضاد للن�ضاء بخ�ض��ص و�ضائل منع احلمل, مما �ضي�ؤدي لتح�ضني م�ضت�ى ا�ضتخدام تلك ال��ضائل. ونن�ضح برفع م�ضت�ى االإدراك العام بال��ضائل احلديثة ملنع احلمل عند الن�ضاء يف �ضن االإجناب يف االأمارات العربية املتحدة. الكلمات املفتاحية: منع احلمل؛ خدمات تنظيم االأ�رسة؛ ال�ضحة االإجنابية؛ الن�ضاء؛ االإمارات العربية املتحدة. contraceptive utilisation among mothers of reproductive age in ajman, united arab emirates *naila kanwal,1 jayakumary muttappallymyalil,1 shatha al-sharbatti,1 iman ismail2 clinical & basic research sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e50–58, epub. 30 mar 17 submitted 11 jun 16 revision req. 20 jul 16; revision recd. 18 aug 16 accepted 22 sep 16 doi: 10.18295/squmj.2016.17.01.010 advances in knowledge to the best of the authors’ knowledge, the current study is one of the first in the united arab emirates (uae) to carry out extensive research on contraceptive utilisation. among married mothers of reproductive age in ajman, uae, contraceptive use was significantly affected by various factors, including age, nationality, education level, type of family system and source of birth control information. application to patient care the findings of the current study indicate that there is a need to increase awareness of contraceptive availability and options among women of reproductive age in the uae, perhaps via appropriate community outreach awareness campaigns led by health care practitioners. naila kanwal, jayakumary muttappallymyalil, shatha al-sharbatti and iman ismail clinical and basic research | e51 a time period of two years is recomm-ended between births to prevent adverse pregnancy outcomes and to aid optimal child growth.1 contraceptives are family planning methods which can help individuals to control the timing, birth spacing and number of children they have, as necessary.1 different methods of contraception exist with various benefits and drawbacks to each; an ideal contraceptive method is considered safe, effective, non-permanent, easy to use and affordable.2–4 recently, high-quality family welfare programmes have been established in order to make contraception available, accessible, affordable and acceptable.5,6 at the world summit of 2005, various countries pledged their commitment to achieving universal access to reproductive healthcare by 2015; however, these goals are still far from being fully realised, with an estimated 143 million women worldwide still lacking access to contraception.7 population growth rates in less developed countries are greater than those of more developed countries, due in part to a lack of access to reproductive healthcare services.2 between 1970 and 2000, the worldwide fertility rate dropped from 4.7 to 2.6; this rapid decrease has been attributed to increased contraceptive usage in recent years.8 in 2011, it was estimated that 63% of women of reproductive age worldwide used various family planning methods.7 however, even in the usa, approximately 10–15% of all sexually active women do not use contraceptive measures, contributing to an unintentional pregnancy rate of ≈50%.2,9 a total of 830 women worldwide still die every day due to pregnancy-related complications; moreover, the risk of maternal mortality increases with each successive pregnancy and shorter intervals between births.10–12 as such, failures in adequate family planning measures can adversely affect the health of the mother and family as a whole.1,13 in the united arab emirates (uae), considerable improvements have been made with regards to the availability of contraceptive measures in both public and private sectors in response to growing consumer demand.14 in 1995, the estimated prevalence of contraceptive use in the uae among married women between 15–49 years old was 27.5%.7 other studies have reported rates of contraception use of 41.5% and 27% in 2001 and 2002, respectively.15,16 unfortunately, there are no recent empirical studies on contraceptive utilisation in the uae and previous findings are complicated by the existence of a diverse and multicultural society in which contraceptive use differs between population groups. this study therefore aimed to determine contraceptive utilisation among mothers of reproductive age in ajman, uae. methods this cross-sectional study was carried out from may to november 2013 at two primary healthcare centres and one private hospital in ajman. these locations were chosen so that the study participants would represent the diverse population of the uae, as primary health care centres generally cater to the local emirati population while expatriates typically seek healthcare services from private hospitals. the inclusion criteria consisted of married women between 18–49 years old who had given birth to at least one child previously, as women were considered less likely to use contraceptive measures immediately after marriage. women who were currently pregnant, had previously undergone a hysterectomy or who could not comprehend the questions were excluded. for this study, as contraceptive prevalence varies among different ethnicities, a contraceptive utilisation prevalence of 50% was assumed with a marginal error of 5%, resulting in a minimum required sample size of 400.15 as such, a total of 400 participants were recruited via a convenience sampling method from the department of obstetrics & gynaecology and the paediatric & immunization clinic of the gmc hospital and the female outpatient departments of the al madina primary health care centre and al mushrif primary health care centre. an interviewer-administered questionnaire was developed to collect information from the participants regarding their demographic characteristics (age, nationality, education level and duration of marriage), socioeconomic characteristics (employment status and sector as well as monthly income and type of family), reproductive history (number of pregnancies, live births and miscarriages) and contraceptive utilisation (current/previous use of contraceptives and preferred method of contraception). the questionnaire was originally developed in english before being translated into arabic using back translation methods. for the purposes of the study, current contraceptive utilisation was defined as the use of any modern or traditional method to delay or avoid pregnancy within the preceding 30 days.17 this period was chosen to minimise recall bias. the use of contraception more than one month beforehand was considered to denote previous use. family systems were categorised as either nuclear (i.e. a father, mother and their unmarried children), joint (i.e. a father, mother and their married sons or daughters, respective daughters-in-law or sons-in-law and any grandchildren in the same household) or threegeneration (i.e. a father, mother, only one married daughter or son, their respective daughter-in-law or son-in-law and their children) systems. contraceptive utilisation among mothers of reproductive age in ajman, united arab emirates e52 | squ medical journal, february 2017, volume 17, issue 1 in addition, the questionnaire also included items designed to assess factors influencing choice of contraceptive method (e.g. satisfaction with current contraceptive method, perceived vulnerability of becoming pregnant, concerns about side-effects, economic considerations, comfort with and access to contraceptives and associated embarrassment in discussing/buying contraceptives), reasons for using contraceptives (e.g. limiting family size, spacing pregnancies, financial or medical concerns, complications during previous pregnancies, genetic defects in older children and a desire to work outside of the home) and factors influencing discontinuation of birth control (e.g. hazards to health, refusal of the husband to cooperate in contraceptive use, secondary infertility, side-effects, cultural reasons, medical concerns and pressure from other family members not to use contraception). knowledge of birth control measures was assessed by whether the participants knew about the existence of different contraceptives and, if so, the source of their information regarding contraceptives. the content validity of the questionnaire was assessed by public health experts and a gynaecologist. a pilot study was subsequently carried out to finalise the questionnaire items, assess the time needed to complete the questionnaire and determine whether participants could easily understand the questions. as a result, questions regarding husbands’ age, education level and employment status were removed and a question assessing type of family system was included. the pilot study sample included five women recruited from the same study locations and using the same inclusion criteria as previously described; these women were not subsequently included in the full study. data were entered into a microsoft excel spreadsheet, version 2007 (microsoft corp., redmond, washington, usa) and transferred for analysis to the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). descriptive statistics, including frequencies and percentages, were used to describe the characteristics of the study population. a chi-squared test was used to assess associations between independent and dependent variables. significant variables were subsequently included in univariate and multivariate analyses. a p value of <0.050 was considered statistically significant. this study received ethical approval from the ethics & research committees of the gulf medical university, ajman, and the uae ministry of health (#57/2013-06-27). all of the women gave written informed consent before participating in the study. participants were assured of their anonymity and were informed that their responses would be kept confidential and used only for research purposes. table 1: sociodemographic characteristics of a cohort of married mothers of reproductive age in ajman, united arab emirates (n = 400) characteristic n (%) age in years ≤25 75 (18.8) >25–35 227 (56.8) >35 98 (24.5) nationality emirati 162 (40.5) non-emirati 238 (59.5) education level primary 45 (11.3) secondary 146 (36.5) graduate 173 (43.3) postgraduate 36 (9.0) employment status employed 104 (26.0) unemployed 296 (74.0) type of family system nuclear 281 (70.3) joint 69 (17.3) three-generation 50 (12.5) number of children 1 75 (18.8) 2 165 (41.3) 3 59 (14.8) 4 44 (11.0) 5 24 (6.0) ≥6 33 (8.3) current contraceptive use* yes 247 (61.8) no 153 (38.3) previous contraceptive use† yes 272 (68.0) no 128 (32.0) *defined as contraceptive use within the previous 30 days. †defined as contraceptive use before the preceding 30 days. naila kanwal, jayakumary muttappallymyalil, shatha al-sharbatti and iman ismail clinical and basic research | e53 results the mean age of the participants was 31.57 ± 6.88 years (range: 18–49 years old). the majority of the participants were 25–35 years old (56.8%), expatriates (59.5%), had a graduate level of education or higher (52.3%), were unemployed (74.0%), lived in a nuclear family system (70.3%) and had two children (41.3%). in terms of current contraceptive use, a total of 247 participants (61.8%) were current contraceptive users, while 153 (38.2%) had not used any method of contraception within the previous 30 days. a total of 272 women (68.0%) had previously used contraceptives before the preceding 30 days while 128 (32.0%) had never used contraceptives [table 1]. among previous contraceptive users, decisions relating to contraceptive choice (n = 141; 51.8%) figure 1: sources of contraceptive information among a cohort of married mothers of reproductive age in ajman, united arab emirates (n = 293). em = educational material. table 2: type of contraceptive used and preferred contraceptive method among current contraceptive users* in a cohort of married mothers of reproductive age in ajman, united arab emirates (n = 247) variable n (%) type of contraceptive used traditional† 83 (33.6) modern‡ 164 (66.4) preferred contraceptive method male condoms 78 (31.6) iud 55 (22.3) withdrawal method 50 (20.2) barrier and withdrawal method 3 (1.2) hormone injection 9 (3.6) ocp 40 (16.2) rhythm method 3 (1.2) tubal ligation 9 (3.6) iud = intrauterine device; ocp = oral contraceptive pill. *defined as contraceptive use within the previous 30 days. †including the withdrawal and rhythm methods. ‡including barriers (e.g. male condoms), intrauterine contraceptive devices, oral contraceptive pills, injections and tubal ligation. table 3: relationships between previous contraceptive use* and sociodemographic characteristics and source of contraceptive information in a cohort of married mothers of reproductive age in ajman, united arab emirates (n = 400) characteristic n (%) p value previous contraceptive use (n = 272) no previous contraceptive use (n = 128) age in years <0.050 ≤25 43 (57.3) 32 (42.7) >25–35 155 (68.3) 72 (31.7) >35 74 (75.5) 24 (24.5) nationality <0.001 emirati 88 (54.3) 74 (45.7) non-emirati 184 (77.3) 54 (22.7) education level <0.050 primary 27 (60.0) 18 (40.0) secondary 89 (61.0) 57 (39.0) graduate 126 (72.8) 47 (27.2) postgraduate 30 (83.3) 6 (16.7) employment status 0.075 employed 78 (75.0) 26 (25.0) unemployed 194 (65.5) 102 (34.5) type of family system <0.050 nuclear 203 (72.2) 78 (27.8) joint 43 (62.3) 26 (37.7) three-generation 26 (52.0) 24 (48.0) number of children <0.010 1 35 (46.7) 40 (53.3) 2 117 (70.9) 48 (29.1) 3 46 (78.0) 13 (22.0) 4 33 (75.0) 11 (25.0) 5 18 (75.0) 6 (25.0) ≥6 23 (69.7) 10 (30.3) *defined as contraceptive use before the preceding 30 days. contraceptive utilisation among mothers of reproductive age in ajman, united arab emirates e54 | squ medical journal, february 2017, volume 17, issue 1 and duration of use (n = 182; 66.9%) were most commonly made by both partners. when asked about their knowledge of birth control measures, 293 women (73.3%) knew about contraceptives, with doctors being reported as the most common source of contraceptive information (66.6%) [figure 1]. the majority of the participants (66.4%) used modern contraceptive methods, for instance male condoms, intrauterine devices (iuds), oral contraceptive pills or tubal ligation. fewer participants (33.6%) employed traditional contraceptive measures, such as the withdrawal or rhythm methods (i.e. engaging in sexual intercourse only during ‘safe’ non-ovulation periods). male condom use was reported to be the most commonly preferred method of contraception (31.6%) [table 2]. the use of contraceptives was significantly higher among expatriates in comparison to emiratis (77.3% versus 54.3%; p <0.001). contraceptive use also increased significantly with age (75.5% among >35-year-olds versus 57.3% among ≤25-year-olds; p <0.050), education level (83.3% among post graduates versus 60.0% among women with primary education only; p <0.050) and family system (72.2% table 4: relationships between previous contraceptive use* and source of contraceptive information in a cohort of married mothers of reproductive age in ajman, united arab emirates (n = 293) source n (%) p value previous contraceptive use (n = 262) no previous contraceptive use (n = 31) visual media 0.148 yes 100 (38.2) 16 (51.6) no 162 (61.8) 15 (48.4) doctors <0.050 yes 180 (68.7) 15 (48.4) no 82 (31.3) 16 (51.6) nurses 0.900 yes 40 (15.3) 5 (16.1) no 222 (84.7) 26 (83.9) em from hospitals 0.263 yes 32 (12.2) 6 (19.4) no 230 (87.8) 25 (80.6) friends 0.911 yes 124 (47.3) 15 (48.4) no 138 (52.7) 16 (51.6) family 0.477 yes 126 (48.1) 17 (54.8) no 136 (51.9) 14 (45.2) em = educational material. *defined as contraceptive use before the preceding 30 days. table 5: univariate analysis of relationships between significant variables and previous contraceptive use* in a cohort of married mothers of reproductive age in ajman, united arab emirates (n = 272) variable or (ci) p value age in years ≤25 1 >25–35 0.62 (0.37–1.07) 0.085 >35 0.44 (0.23–0.83) <0.050 nationality non-emirati 1 emirati 2.87 (1.86–4.42) <0.001 education level postgraduate 1 primary 3.33 (1.16–9.62) <0.050 secondary 3.20 (1.25–8.18) <0.050 graduate 1.87 (0.73–4.77) 0.191 type of family system nuclear 1 joint 1.57 (0.90–2.73) 0.103 three-generation 2.40 (1.30–4.43) <0.010 employment sector private 1 government 4.89 (1.90–12.56) <0.001 number of children ≥6 1 1 2.63 (1.10–6.27) <0.050 2 0.94 (0.42–2.13) 0.891 3 0.65 (0.25–1.70) 0.378 4 0.77 (0.28–2.10) 0.599 5 0.77 (0.23–2.50) 0.661 knowledge of birth control measures no 1 yes 0.01 (0.01–0.03) <0.001 doctors as source of contraceptive information no 1 yes 0.43 (0.20–0.91) <0.050 or = odds ratio; ci = confidence interval. *defined as contraceptive use before the preceding 30 days. naila kanwal, jayakumary muttappallymyalil, shatha al-sharbatti and iman ismail clinical and basic research | e55 among women with nuclear families versus 62.3% among those with joint families and 52.0% among those with three-generation families; p <0.050). a statistically significant positive association was observed between number of children and the use of contra ceptives (p <0.010). employment status was not significantly associated with the use of contraceptives [table 3]. in terms of associations between source of contraceptive knowledge and use of contraception, doctors were the only information source which showed a significant association with contraceptive use (p <0.050) [table 4]. a univariate analysis was conducted to determine factors affecting the probability of not using contraception. among women >35 years of age, there was a 56% lower chance of not using contraceptives in comparison to those ≤25 years old (odds ratio [or]: 0.44, confidence interval [ci]: 0.23–0.83). among emiratis, the likelihood of not using contraceptives was three times higher than for expatriates (or: 2.87, ci: 1.86–4.42). women with primarylevel education were three times more likely not to use contraception in comparison to postgraduates (or: 3.33, ci: 1.16–9.62). similarly, among women with a secondary education, the likelihood of not using contraceptives was 3.2 times higher compared to postgraduates (or: 3.20, ci: 1. 25–8.18). women from a three-generation family system had a 2.4 times higher chance of not using contraception compared to those with a nuclear family system (or: 2.40, ci: 1.30–4.43). working in the government sector resulted in a five times increased chance of not using contraceptives compared to the private sector (or: 4.89, ci: 1.90–12.56). women with one child were 2.6 times more likely to not use contraception as compared to those with ≥6 children (or: 2.63, ci: 1.10–6.27). women who knew about birth control measures were 99% more likely to use contraceptives (or: 0.01, ci: 0.01–0.03). among participants whose primary source of information about contraceptives was doctors, there was a 57% lower chance of not using contraceptives (or: 0.43, ci: 0.20–0.91) [table 5]. however, none of these variables were significantly associated with contraceptive use according to a multivariate analysis [table 6]. discussion preventing an unplanned pregnancy is an important global issue.17 effective contraceptives benefit both mothers and their children by decreasing morbidity and mortality rates and improving their social and economic status.18 in the uae, there is high parity and social acceptance of birth control is limited for cultural and religious reasons.15 the current study aimed to determine contraceptive utilisation among mothers table 6: multivariate analysis of relationships between significant variables and previous contraceptive use* in a cohort of married mothers of reproductive age in ajman, united arab emirates (n = 272) variables or (ci) p value age in years ≤25 1 >25–35 0.09 (0.00–4.88) 0.242 >35 0.19 (0.00–10.15) 0.421 nationality non-emirati 1 emirati 0.05 (0.00–7.93) 0.243 education level postgraduate 1 primary 0.00 >0.999 secondary 0.00 0.994 graduate 0.05 (0.00–3.89) 0.184 type of family system nuclear 1 joint 134.77 (0.62–1,942.37) 0.083 three-generation 0.00 0.993 employment sector private 1 government 2.07 (0.14–30.97) 0.588 number of children ≥6 1 1 0.00 >0.999 2 4,885.08 >0.999 3 0.00 >0.999 4 0.00 >0.999 5 0.00 0.994 knowledge of birth control measures no 1 yes 0.15 (0.01–3.96) 0.258 doctors as source of contraceptive information no 1 yes 96.71 0.333 or = odds ratio; ci = confidence interval. *defined as contraceptive use before the preceding 30 days. contraceptive utilisation among mothers of reproductive age in ajman, united arab emirates e56 | squ medical journal, february 2017, volume 17, issue 1 of reproductive age in ajman. according to the 2005 census, the total number of women of reproductive age in ajman was 47,191; of these, 10,687 were emiratis (22.6%) and 36,504 were expatriates (77.4%).19 rates of contraceptive use vary in arab countries. in the current study, the current and previous use of contraceptives was found to be 61.8% and 68.0%, respectively. use of contraceptives was noted to be 44.8% and 47.8% in saudi arabia and qatar, respectively.20,21 higher rates have been observed in bahrain (61.8%), syria (58.3%) and lebanon (58%), while lower rates have been reported from qatar (43.2%), oman (31.7%), yemen (27.7%) and saudi arabia (23.8%).7 this variation in findings could be attributed to differences in local cultural attitudes in these countries towards the use of contraceptives. in the current study, previous use of contraceptives was higher among expatriates than emiratis and the probability of not using contraceptives was three times higher among emiratis; this rate was higher than that reported in previous research.15 age was found to have a significant relationship with contraceptive use in the current study, with older women more likely to use contraceptives in comparison to younger women. this observation is in accordance with previous research conducted in saudi arabia and qatar.20,21 this finding may be due to the fact that older women are more likely to use contraceptives if their fertility goals have already been met or to ensure a greater amount of time between births to preserve their health. among women under 25 years old, contraceptive use was less frequent; this might be explained by an increased desire to have more children, as noted in previous studies conducted in the uae and saudi arabia.15,20 in addition, the current study found that contraceptive use increased with education level; this finding is similar to that of previous research conducted in the gulf region.15,20,21 however, studies conducted in india have found that education was not associated positively with contraceptive use.22,23 in general, improving women’s education has been reported as a method of increasing their status and autonomy, which in turn can help to improve contraceptive practices.24 it is possible that less educated women have fewer educational and career-oriented aspirations and have lower levels of understanding of their health as compared to more educated women.25 employment status and contraceptive use were not found to be significantly associated in the present study. this is contrary to findings from saudi arabia, where contraceptive use was reportedly four times higher among working women.20 however, mothers working in the private sector in the current study were five times more likely to use contraceptives compared to government sector workers. this may be because employment decisions among mothers often depend on family and child care responsibilities; as such, women may prefer government professions over those in the private sector due to increased job and income security, more desirable working conditions and shorter working hours.26 a significant association between type of family system and use of contraceptives was noted in the current study. women within a three-generation family system were less likely to use contraceptives compared to those within a nuclear family system. evidence from pakistan and india suggests that a joint family system may influence unsupportive or restrictive attitudes towards contraceptives.27–29 in addition, individuals in a joint family system often depend financially on the head of the family and therefore may not be limited by financial concerns when making family planning decisions.29 moreover, in a joint family system, a woman’s social position can be elevated after the birth of a child and they may not be solely responsible for making the decision to have more children.29 in general, most women prefer to use contraceptives after they have reached their ideal family size.20,30 however, the ideal family size differs according to culture and society. in the current study, women with one child were less likely to use contraception compared to those with six children or more. this finding is consistent with previous research from saudi arabia, which has similar religious and cultural characteristics to the uae; contraceptive usage was reportedly to be higher among women with higher parity.20 the majority of participants in the current study were aware of birth control measures; in addition, knowledge of birth control measures was significantly associated with contraceptive use. in contrast, research conducted in qatar indicated that the majority of participants were aware of contraceptives but had a negative attitude towards contraceptive use due to their sociocultural norms and religious beliefs.21 in saudi arabia and qatar, family members and friends were found to be the most common source of contraceptive information.20,21 however, in the current study, doctors were reported to be the main source of information about contraceptives; moreover, mothers who reported doctors as a source of contraceptive information had an increased probability of using contraceptives as compared to those who did not. this observation is in line with previously reported research in the region.15 this result clearly demonstrates the importance of doctors in providing advice to women about contra naila kanwal, jayakumary muttappallymyalil, shatha al-sharbatti and iman ismail clinical and basic research | e57 ceptives and influencing decisions to use contraceptives. therefore, sustained efforts to raise awareness of the proper use of contraceptives is highly recommended in the uae, for instance through the implementation of doctor-led community outreach/ awareness campaigns. in the present study, women who were currently using contraceptives primarily used modern methods of contraception. this is a key finding as previous research in the uae reported a greater frequency of use of traditional contraceptive methods, followed by the iud.15 however, the current study’s results were in accordance with research from qatar, where the practice of modern contraceptive methods was higher among current contraceptive users, probably due to the influence of economic development and the increased availability of information.21 in the current study, the most preferred birth control method was found to be male condoms followed by iuds and the withdrawal method. potentially, more women might prefer condoms as compared to other methods of contraception because of their easy availability without a prescription or due to concerns about the possible side-effects of other contraceptive methods. few women in the current study were aware of newer forms of contraceptives (e.g. transdermal patches, implants and rings); as such there is an urgent need to increase awareness of contraceptive availability and options among women of reproductive age in the uae. the current study is subject to certain limitations. the findings are not generalisable to all women in the uae due to the non-probability sampling method used to recruit participants. moreover, as the participants were recruited from women attending primary healthcare centres and private hospitals in ajman, the study cohort is not representative of the general population. in addition, the findings do not include contraceptive use among sexually-active single women as the aim of the study focused on contraceptive use among married women; however, it is important to note that extramarital relations are prohibited in predominantly islamic countries, such as the uae, and are henceforth not usually openly discussed.15 further research is recommended in order to compare the findings of the current study to those of the general population in the uae. conclusion the rates of current and previous contraceptive use among a cohort of married mothers of reproductive age in ajman were 61.8% and 68.0%, respectively. contraceptive use was higher among expatriates than emiratis. significant associations were observed between contraceptive use and age, nationality, education level, type of family system, employment sector, number of children, knowledge of birth control measures and source of contraceptive information. doctors were noted to have an important influence on contraceptive use. community outreach awareness campaigns on the availability and proper use of contraceptives are highly recommended. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. shaw d. the abc’s of family planning. from: www.who. int/pmnch/media/news/2010/20100322_d_shaw_oped/en/ accessed: aug 2016. 2. sonalkar s, schreiber ca, barnhart kt. contraception. in: de groot lj, chrousos g, dungan k, feingold kr, grossman a, hershman jm, et al., eds. from: www.ncbi.nlm.nih.gov/books/ nbk279148/ accessed: aug 2016. 3. world health organization. family planning: contraception fact sheet. from: http://who.int/mediacentre/factsheets/fs 351/en/ accessed: aug 2016. 4. world health organization. family planning: a global handbook for providers – 2011 update. from: http://apps.who. int/iris/bitstream/10665/44028/1/9780978856373_eng.pdf accessed: aug 2016. 5. cleland j, bernstein s, ezeh a, faundes a, glasier a, innis j. family planning: the unfinished agenda. lancet 2006; 368: 1810–27. doi: 10.1016/s0140-6736(06)69480-4. 6. united nations population fund. international conference on population and development: overview. from: www.unfpa. org/icpd accessed: aug 2016. 7. united nations department of economic and social affairs. world contraceptive patterns 2013. from: www. un.org/en/de velopment/desa/p opulation/public ations/ pdf/family/worldcontraceptivepatternswallchart2013.pdf accessed: aug 2016. 8. ahmed s, li q, liu l, tsui ao. maternal deaths averted by contraceptive use: an analysis of 172 countries. lancet 2012; 380:111–25. doi: 10.1016/s0140-6736(12)60478-4. 9. bonham ad. why are 50 percent of pregnancies in the u.s. unplanned? from: http://shriverreport.org/why-are-50-perc e nto f p re g n a n c i e s i n th e u s u np l a n n e d a d r i e n n e d bonham/ accessed: aug 2016. 10. world health organization. maternal mortality: fact sheet. from: www.who.int/mediacentre/factsheets/fs348/en/index.html accessed: aug 2016. 11. lassi zs, middleton pf, bhutta za, crowther c. strategies for improving health care seeking for maternal and newborn illnesses in lowand middle-income countries: a systematic review and meta-analysis. glob health action 2016; 9:31408. doi: 10.3402/gha.v9.31408. 12. smith r, ashford l, gribble j, clifton d; population reference bureau. family planning saves lives, 4th ed. from: www.prb. org/pdf09/familyplanningsaveslives.pdf accessed: aug 2016. https://doi.org/10.1016/s0140-6736%2806%2969480-4 https://doi.org/10.1016/s0140-6736%2812%2960478-4 https://doi.org/10.3402/gha.v9.31408 contraceptive utilisation among mothers of reproductive age in ajman, united arab emirates e58 | squ medical journal, february 2017, volume 17, issue 1 13. leke rj; geneva foundation for medical education and research. family planning in africa south of the sahara. from: www.gfmer.ch/books/reproductive_health/family_planning_ africa.html accessed: aug 2016. 14. united nations department of economic and social affairs. united arab emirates: abortion policy and reproductive health context. from: www.un.org/esa/population/publications/abor tion/doc/uae.doc accessed: aug 2016. 15. ghazal-aswad s, rizk de, al-khoori sm, shaheen h, thomas l. knowledge and practice of contraception in united arab emirates women. j fam plann reprod health care 2001; 27:212–16. doi: 10.1783/147118901101195786. 16. ghazal-aswad s, zaib-un-nisa s, rizk de, badrinath p, shaheen h, osman n. a study on the knowledge and practice of contraception among men in the united arab emirates. j fam plann reprod health care 2002; 28:196–200. doi: 10.1783/147118902101196559. 17. sarah p. the attack on planned parenthood: a historical analysis. ucla womens law j 2012; 19:165–211. 18. kaunitz am. the importance of contraception. from: www. glowm.com/section_view/heading/the%20importance%20 of%20contraception/item/373 accessed: aug 2016. 19. judy y. population and vital statistics, 1st ed. ajman, united arab emirates: ajman executive council, 2008. pp. 41–58. 20. al sheeha m. awareness and use of contraceptives among saudi women attending primary care centers in al-qassim, saudi arabia. int j health sci (qassim) 2010; 4:11–21. 21. arbab aa, bener a, abdulmalik m. prevalence, awareness and determinants of contraceptive use in qatari women. east mediterr health j 2011; 17:11–18. 22. pushpa s, venkatesh r, shivaswamy m. study of fertility pattern and contraceptive practices in a rural area: a crosssectional study. indian j sci technol 2011; 4:429–31. 23. chudasama r, godara n, moitra m. women’s position and their behavior towards family planning. internet j fam pract 2008; 7:1–5. 24. saleem s, bobak m. women’s autonomy, education and contraception use in pakistan: a national study. reprod health 2005; 2:8. doi: 10.1186/1742-4755-2-8. 25. ong j, temple-smith m, wong wc, mcnamee k, fairley c. contraception matters: indicators of poor usage of contraception in sexually active women attending family planning clinics in victoria, australia. bmc public health 2012; 12:1108. doi: 10.1186/1471-2458-12-1108. 26. narcisse da, state y. risky undertakings: the employment decision-making of women lawyers and accountants. forum qual soc res 2011; 12:3. 27. kazi k. a study of knowledge, attitude and practice (kap) of family planning among the women of rural karachi. thesis, 2008, university of karachi, karachi, pakistan. 28. fikree ff, khan a, kadir mm, sajan f, rahbar mh. what influences contraceptive use among young women in urban squatter settlements of karachi, pakistan? int fam plan perspect 2001; 27:130–6. doi: 10.2307/2673834. 29. murarkar sk, soundale s. epidemiological correlates of contraceptive prevalence in married women of reproductive age group in rural area. natl j community med 2011; 2:78–81. 30. population reference bureau. women’s need for family planning in arab countries. from: www.prb.org/publications/ reports/2012/family-planning-arab-countries.aspx accessed: aug 2016. https://doi.org/10.1783/147118901101195786 https://doi.org/10.1783/147118902101196559 https://doi.org/10.1186/1742-4755-2-8 https://doi.org/10.1186/1471-2458-12-1108 https://doi.org/10.2307/2673834 sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e390–397, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.014. submitted 30 dec 14 revision req. 9 feb 15; revision recd. 4 mar 15 accepted 31 mar 15 department of community medicine, college of medicine, hawler medical university, erbil, iraq *corresponding author e-mail: nazarshabila@gmail.com سلوكيات السياقة احملفوفة باملخاطر بني طالب الطب يف أربيل، العراق نزار بول�س �سابيله، كامران اأ�سماعيل، ابوبكر �سالح، طارق احلديثي abstract: objectives: this study aimed to assess risky driving behaviours among medical students in erbil, iraq, and to explore the relationship between risky driving behaviours and perceptions of risky driving. methods: this self-administered questionnaire-based survey was conducted from january to may 2014 among a random sample of 400 medical students at hawler medical university in erbil. the questionnaire was designed to assess the frequency of engagement in 21 risky driving behaviours, the perceived risk of each behaviour and the preference for each behaviour as ranked on a 5-point scale. results: a total of 386 students responded to the survey (response rate: 96.5%). of these, 211 reported that they currently drove a vehicle (54.7%). drivers most frequently engaged in the following behaviours: playing loud music (35.9%), speeding (30.4%), allowing front seat passengers to not wear seat belts (27.9%) and using mobile phones (27.7%). least frequent driving behaviours included not stopping at a red light (3.9%), driving while sleepy (4.4%), driving after a mild to moderate intake of alcohol (4.5%) and drunk driving (6.4%). mean risky driving behaviour scores were significantly higher among males (p <0.001) and those who owned a car (p = 0.002). the mean risk perception score was higher among >20-year-olds (p = 0.028). there was a significant positive relationship between the preference for risky behaviours and risky driving behaviours (beta = 0.44; p <0.001). conclusion: medical students in erbil reported high frequencies of several serious risky driving behaviours. the preference for risky behaviours was found to be an important predictor of risky driving behaviours among medical students in erbil. keywords: medical students; automobile driving; risk-taking; perception; risk assessment; iraq. وا�ستك�ساف العراق، اأربيل، يف الطب طالب بني ال�سياقة مبخاطر املحفوفة ال�سلوكيات تقييم اإىل الدرا�سة هذه هدفت الهدف: امللخ�ص: العالقة بني �سلوكيات القيادة اخلطرة وت�سوراتها. الطريقة: مت اإجراء هذه الدرا�سة بوا�سطة ال�ستبيان الذاتي من يناير اإىل مايو 2014 على عينة ع�سوائية من 400 طالب طب يف جامعة هولري الطبية يف أربيل. مت ت�سميم ا�ستبيان لتقييم وترية االرتباط يف 21 من �سلوكيات القيادة اخلطرة، واملخاطر املتوقعة من كل �سلوك وتف�سيل كل �سلوك على اآلخر ح�سب ت�سنيفها على مقيا�س من 5 نقاط. النتائج: ا�ستجاب ما جمموعه 386 طالبا للدرا�سة )معدل ال�ستجابة: %96.5(. مت ر�سد �سلوكيات ال�سياقة اخلطرة التالية الأكرث �سيوعا على ح�سب ترتيب حدوثها )27.9%( األمان حلزام الأمامي املقعد ركاب ارتداء بعدم ال�سماح ،)30.4%( والإ�رساع ،)35.9%( عال ب�سوت املو�سيقى ت�سغيل للطالب: احلمراء ال�سوئية اإل�سارة عند التوقف عدم مثل، انت�سارا اأقل اآلتية اخلطرة ال�سلوكيات كانت بينما .)27.7%( النقالة الهواتف وا�ستخدام )%3.9(، والقيادة اأثناء النعا�س )%4.4(، والقيادة حتت التاأثري اخلفيف واملتو�سط للكحول )%4.5( والقيادة يف حالة ال�سكر البني )6.4%(. .)p = 0.002( واأولئك الذين ميتلكون �سيارة )p >0.001( كانت �سلوكيات ال�سياقة املحفوفة باملخاطر اأعلى ب�سورة دالة إح�سائيا بني الذكور كان متو�سط درجة اإدراك خماطر اأعلى بني الذين اأكرب من �سن 20 عاما )p = 0.028(. كان هناك عالقة ذات دللة اإح�سائية اإيجابية بني تف�سيل ال�سلوكيات اخلطرة وممار�ستها الفعلية )p >0.001 ;0.44 = بيتا(. اخلال�صة: ينت�رس العديد من �سلوكيات ال�سياقة اخلطرة بني طالب الطب يف اأربيل. وجد اأن تف�سيل ال�سلوكيات اخلطرة هو موؤ�رس هام للتنبوؤ بهذه ال�سلوكيات بينهم. مفتاح الكلمات: طالب الطب؛ �سياقة ال�سيارات؛ املخاطرة؛ الت�سور؛ تقييم املخاطر؛ العراق. risky driving behaviours among medical students in erbil, iraq *nazar p. shabila, kamaran h. ismail, abubakir m. saleh, tariq s. al-hadithi clinical & basic research advances in knowledge risky driving behaviour was common among the studied group of medical students in erbil, iraq. students reported frequently engaging in dangerous driving behaviours. however, risky driving behaviour was more common among the male medical students than the female medical students. enjoyment of risky behaviours was found to be an important predictor of risky driving among this sample of medical students. application to patient care it is important that those employed in the medical profession be exemplary role models and advocates of safe driving. it is therefore concerning that many of the medical students, who will be in direct contact with the victims of road traffic accidents once they have graduated, are themselves frequently engaged in risky driving behaviour. the results of this study may inform future public health programmes targeted at this population. nazar p. shabila, kamaran h. ismail, abubakir m. saleh and tariq s. al-hadithi clinical and basic research | e391 road traffic injuries are a major public health problem around the world. an estimated 1.24 million people die on the road every year, with another 20–50 million sustaining non-fatal injuries as a result of road traffic crashes.1,2 human error is the most common factor for traffic accidents (~90%).2 risky driving behaviours are common amongst young people and are strongly linked to traffic accident risk.3 research worldwide has suggested different factors as important aspects and predictors of risky driving behaviour in young drivers. these include knowledge, beliefs and attitudes relating to risky driving, driving experience, personality factors and a lack of education regarding risky driving.4–7 risky driving behaviour is also attributed to a number of cognitive processes in young drivers, including underestimating the seriousness of the risk, overestimating driving skills and overconfidence in the ability to recognise hazards.8–11 commonly applied theoretical models generally assume that risky behaviour decision-making occurs through rational processes, such as risk perception and risk assessment of a specific behaviour. however, there is still no clear evidence that increased risk perception or risk awareness reduces risky driving behaviour and ultimately the rate of road traffic accidents.10,12 for many individuals, driving is characterised by positive emotions associated with the pleasures of driving.13 liking or enjoyment of (or positive feelings towards) specific driving behaviours, including risky behaviours, may be especially strong for young drivers.14 many medical students, once qualified, will have direct contact with patients who have engaged in risky driving behaviours and those suffering the consequences of road traffic accidents. those in the medical profession should be exemplary role models and advocates for safe driving. however, medical students, like many young people, are themselves frequently engaged in these risky behaviours.15 iraq is among the countries without available death registration data. according to the world health organization, the estimated road traffic death rate in iraq per 100,000 population was 31.5 in 2013, which was the highest in the eastern mediterranean region after iran.1 rapid economic growth in the iraqi kurdistan region, the open market economy and an increase in imported cars over the last decade has resulted in a substantial increase in the number of cars in the region, as well as a rapid increase in the number of teens and young people both driving and owning cars.16 road traffic injuries are an increasing public health concern in the region; however, there is limited research on the subject, particularly among the younger generation and medical students. therefore, this study was carried out in order to assess risky driving behaviours among a group of medical students in iraq and to explore the relationship between risky driving and the perception and enjoyment of risky driving. methods this self-administered questionnaire-based study was conducted from january to may 2014 among students from the college of medicine at hawler university in erbil, iraq. a simple random sample of medical students was selected from the list of all undergraduate medical students in the college of medicine. a sample size of 375 students was chosen from a total of 1,000 students, based on ± 4 precision with an estimated 50% of students driving a car and a 95% confidence interval. however, the sample size was increased to 400 students to adjust for non-response. an english-language questionnaire was designed to assess the self-reported frequency of engaging in a range of risky driving behaviours, the perceived risk of engaging in each of these actions and the enjoyment of or preference for each behaviour. questions were developed by reviewing the relevant literature.10,17–19 a total of 21 items covering different risk-taking behaviours formed the main questionnaire. for each item, participants indicated on a 5-point scale how frequently they usually engaged in the behaviour when driving (1 = never, 2 = rarely, 3 = sometimes, 4 = frequently and 5 = always), their perception of the risk associated with the behaviour (1 = not risky at all, 2 = slightly risky, 3 = fairly risky, 4 = very risky and 5 = extremely risky) and their enjoyment of the behaviour (1 = strongly dislike, 2 = dislike slightly, 3 = neutral, 4 = like slightly and 5 = strongly like). the order of the behaviours was randomised within each section. data were also obtained on the demographic characteristics of the participants, including whether they drove or owned a car. the survey instrument was tested to assess the comprehensiveness, adequacy, clarity and relevance of the items. this involved two cycles of modifications to the survey based on feedback from participants. the instrument’s internal consistency, measured by cronbach’s alpha, was 0.78 for the frequency component, 0.83 for the risk perception component and 0.82 for the enjoyment component. the questionnaire was disseminated directly to the selected sample of medical students. data were analysed using the statistical package for the social sciences (spss), version 18.0 (ibm corp., chicago, illinois, usa). the descriptive statistical analysis combined positive and negative ratings of engagement in behaviours using a 3-point risky driving behaviours among medical students in erbil, iraq e392 | squ medical journal, august 2015, volume 15, issue 3 table 1: frequency of risky driving behaviours among a group of medical student drivers in erbil, iraq (n = 211) behaviour frequency, % never/ rarely sometimes frequently/ always playing loud music while driving 40.2 23.9 35.9 driving faster than the speed limit 50.7 18.9 30.4 front seat passenger not wearing a seat belt 48.1 24 27.9 using a mobile phone without a hands-free device while driving 50 22.3 27.7 switching lanes frequently to get ahead of other cars 38 37.1 24.9 fast acceleration and braking 52.0 25.2 22.8 driving during rush hours 55.9 26.3 17.8 overtaking from the right-hand lane 56.9 25.5 17.6 lack of correct knowledge about speed limits in different areas 61.8 20.6 17.6 driver not wearing a seat belt 70.3 12.5 17.2 texting while driving 68.7 17.8 13.5 doing things that can be distracting while driving 62.9 23.9 13.2 racing with other cars 67.2 19.6 13.2 passengers doing things that can be distracting to the driver while driving 63.3 24.1 12.6 braking hard to stop in time 70.7 19.5 9.8 reading when the vehicle is in motion 68.5 22.2 9.3 driving fast on curving roads 70.7 20 9.3 drunk driving 89.6 4 6.4 driving after a mild to moderate intake of alcohol 89.1 6.4 4.5 driving while sleepy 81.5 14.1 4.4 driving through a red light 83.5 12.6 3.9 table 2: risk perception of risky driving behaviours among a group of medical student drivers in erbil, iraq (n = 211) behaviour perception, % not risky at all/slightly risky fairly risky very/ extremely risky driving after a mild to moderate intake of alcohol 14.9 5.0 80.1 driver not wearing a seat belt 13.2 10.8 76.0 drunk driving 15.0 12.5 72.5 racing with other cars 13.0 15.0 72.0 driving while sleepy 12.9 15.9 71.2 texting while driving 14.0 16.5 69.5 driving through a red light 13.6 17.7 68.7 doing things that can be distracting while driving 11.5 22.0 66.5 driving fast on curving roads 16.0 19.5 64.5 reading when the vehicle is in motion 13.1 23.1 63.8 driving faster than the speed limit 17.4 21.4 61.2 passengers doing things that can be distracting to the driver while driving 15.9 25.4 58.7 fast acceleration and braking 12.4 29.4 58.2 switching lanes frequently to get ahead of other cars 12.6 29.8 57.6 braking hard to stop in time 21.8 20.8 57.4 using a mobile phone without a hands-free device while driving 19.0 24.0 57.0 front seat passenger not wearing a seat belt 19.0 28.0 53.0 overtaking from the right-hand lane 13.2 34.0 52.8 driving during rush hour 20.1 31.7 48.2 lack of correct knowledge about speed limits in different areas 21.0 33.5 45.5 playing loud music while driving 39.4 27.3 33.3 nazar p. shabila, kamaran h. ismail, abubakir m. saleh and tariq s. al-hadithi clinical and basic research | e393 scale (frequently/always, sometimes or never/rarely). similar scales were used in reporting data from the risk perception and enjoyment components of the survey. as the internal consistency of the questionnaire was high, scores for all items in each component were summed to determine mean scores. a t-test was used to compare mean scores according to different demographic variables. a p value of ≤0.05 was considered statistically significant. the effect of risk perception and enjoyment of the risky behaviour with regards to driving behaviour was examined using linear regression. all participants were informed of the purpose of the study and assured of their anonymity. informed consent was obtained from all students before inclusion in the study. this study was approved by the research ethics committee of the college of medicine at hawler university in erbil, iraq (#412). results a total of 386 students completed the survey (response rate: 96.5%). the mean age of the respondents was 21.02 ± 1.87 years old (range: 17–26 years old; median and mode: 21 years old). of the participants, 211 (54.7%) reported that they were currently driving a car. the majority of drivers reported that they drove every day (66.4%). the mean age of the drivers was 21.37 ± 1.78 years old (range: 17–26 years old). there were 48.3% male drivers and 51.7% female drivers. of the drivers, 91.9% resided inside the city, only 89.6% had a driving licence and 66.4% owned a car. table 1 shows the frequency of each risky driving behaviour. the most frequent risky driving behaviours among the medical students were playing loud music (35.9%), speeding (30.4%), allowing the front seat passenger to not wear a seat belt (27.9%) and using a non-hands-free mobile phone (27.7%). the least frequent risky driving behaviours included not stopping at a red light (3.9%), driving while sleepy (4.4%) or after a mild to moderate intake of alcohol (4.5%) and drunk driving (6.4%). participants perceived that driving after a mild to moderate intake of alcohol (80.1%), not wearing a seat belt (76.0%), drunk driving (72.5%), racing with other cars (72.0%) and driving while sleepy (71.2%) were the most risky behaviours. in comparison, they perceived playing loud music (33.3%), a lack of correct knowledge about speed limits in different areas (45.5%) and driving during rush hour (48.3%) as the least risky behaviours [table 2]. the most preferred driving behaviours included playing loud music (37.4%), speeding (23.6%), racing (20.6%) and switching lanes frequently to get ahead of other cars (20.4%). the least enjoyed behaviours included reading when the vehicle was in motion (8.5%), drunk driving (8.7%) and driving during rush hour (9.8%) [table 3]. table 3: enjoyment of risky driving behaviours among a group of medical student drivers in erbil, iraq (n = 211) behaviour enjoyment, % strongly/ slightly dislike neutral strongly/ slightly like playing loud music while driving 40.4 22.2 37.4 driving faster than the speed limit 52.8 23.6 23.6 racing with other cars 62.3 17.1 20.6 switching lanes frequently to get ahead of other cars 54.1 25.5 20.4 front seat passenger not wearing a seat belt 55.6 24.7 19.7 driving fast on curving roads 64.6 18.2 17.2 overtaking from the right-hand lane 62.3 21.4 16.3 fast acceleration and braking 62.6 21.7 15.7 using a mobile phone without a hands-free device while driving 58.1 26.3 15.6 texting while driving 65.8 19.1 15.1 passengers doing things that can be distracting to the driver while driving 57.8 27.6 14.6 driving while sleepy 78.4 9.0 12.6 driving through a red light 76.4 11.0 12.6 braking hard to stop in time 66.0 21.5 12.5 driver not wearing a seat belt 71.3 16.6 12.1 lack of correct knowledge about speed limits in different areas 68.3 20.1 11.6 driving after a mild to moderate intake of alcohol 77.0 12.3 10.7 doing things that can be distracting while driving 73.3 16.4 10.3 driving during rush hour 64.4 25.8 9.8 drunk driving 79.1 12.2 8.7 reading when the vehicle is in motion 70.4 21.1 8.5 risky driving behaviours among medical students in erbil, iraq e394 | squ medical journal, august 2015, volume 15, issue 3 the mean frequency score of risky driving behaviour among the students was 2.17 ± 0.60, while the mean perception score was 3.73 ± 0.79 and the mean enjoyment score was 2.15 ± 0.82. the mean frequency score of risky driving behaviour was significantly higher among males (p <0.001) and those who owned a car (p = 0.002). the mean risk perception score was significantly higher for those over the age of 20 years old (p = 0.028). no significant associations were observed between the mean enjoyment score and gender, age, residence or car ownership [table 4]. there was a significant positive relationship between enjoyment of risky behaviours and the frequency of risky driving (beta = 0.44; r = 0.439; p <0.001). there was a very weak negative relationship between the perceived risk of driving behaviours and frequency of risky driving behaviours (beta = -0.12; r = 0.156; p = 0.026). discussion this study aimed to assess risky driving behaviour among a group of medical students in erbil. the medical students reported frequent engagement in a number of risky driving actions. this is unfortunate as these students may soon be treating patients who engage in risk driving behaviours, or perhaps comforting surviving family members in the event of road traffic accident-associated fatalities. it is therefore important that those in the medical profession do not engage in risky behaviours themselves. a study from brazil revealed that risky driving conduct was highly frequent among medical students and that this was directly related to involvement in accidents with casualties.15 sabbour et al. reported a number of common risky driving styles and behaviours, similar to the findings in this study, among medical students in egypt.20 these included driving at excessive speeds, driving without a licence, not wearing a seat belt and answering mobile phones while driving.20 similarly, a study from india revealed that 20% of medical students admitted to using hands-free mobile phones while driving and 68% revealed that they had surpassed speed limits on multiple occasions.18 some risky behaviours were more frequently undertaken by the students in the current study than others. however, the frequency of a specific action was not primarily related to its perceived risk. in addition to being involved in many less risky behaviours, students frequently engaged in a number of extremely risky behaviours, such as driving faster than the permitted speed limit and using a mobile phone. this could be attributed to specific cultural and environmental factors, as well as due to established road safety and disciplinary measures that can affect risk-taking behaviour. for example, less frequently carried out risky behaviours (e.g. not stopping at a red light or not wearing a seat belt) could be related to strict monitoring and disciplinary measures in the kurdistan region. these measures include the table 4: comparison of mean scores* for frequency, perceived risk and enjoyment of risky driving behaviours by gender, age, residence and car ownership among a group of medical student drivers in erbil, iraq (n = 211) variable n frequency perception enjoyment mean score ± sd p value mean score ± sd p value mean score ± sd p value gender male 102 2.34 ± 0.54 <0.001 3.66 ± 0.75 0.266 2.24 ± 0.83 0.116 female 109 2.02 ± 0.61 3.79 ± 0.83 2.06 ± 0.80 car owner yes 140 2.26 ± 0.60 0.002 3.73 ± 0.72 0.978 2.22 ± 0.82 0.110 no 71 1.99 ± 0.56 3.72 ± 0.92 2.01 ± 0.80 age group ≤20 years old 65 2.12 ± 0.53 0.367 3.54 ± 0.87 0.028 2.14 ± 0.71 0.973 >20 years old 146 2.14 ± 0.71 3.80 ± 0.74 2.15 ± 0.87 residence city 194 2.19 ± 0.61 0.105 3.74 ± 0.76 0.421 2.17 ± 0.81 0.285 outside the city 17 1.95 ± 0.50 2.17 ± 0.81 1.94 ± 0.94 * scores were rated on a 5-point scale for driving behaviour frequency (1 = never, 2 = rarely, 3 = sometimes, 4 = frequently and 5 = always), risk perception (1 = not risky at all, 2 = slightly risky, 3 = fairly risky, 4 = very risky and 5 = extremely risky) and enjoyment (1 = strongly dislike, 2 = dislike slightly, 3 = neutral, 4 = like slightly and 5 = strongly like). nazar p. shabila, kamaran h. ismail, abubakir m. saleh and tariq s. al-hadithi clinical and basic research | e395 presence of traffic police and speed cameras at most traffic intersections, as well as the implementation of strict fining measures. however, although there is an established fining system for exceeding the speed limit, the system for monitoring speeding is poor, as speed cameras are placed in known locations and are active only at specific times of the day. it is therefore easy and very common for drivers to breach the speed limits without being penalised. furthermore, there are either no established or poorly implemented disciplinary measures for a number of other risky behaviours (e.g. front passengers without seat belts, switching lanes or undertaking from the right lane). therefore, these types of behaviours are very common, particularly among young people. a number of other findings may be closely related to the distinctive culture and environment of erbil, such as the proportion of participants who reported driving after a mild or moderate intake of alcohol or driving whilst drunk. alcohol-related driving behaviour was reportedly low although there are no properly implemented measures to prevent these risky behaviours in this region. this could be attributed to the fact that drinking is restricted and socially unacceptable in this predominantly islamic society. in countries where alcohol is not as prohibited by religious and societal pressures, driving after consuming alcohol is substantially more common among young drivers. a study from india revealed that 25% of medical students had engaged in drunk driving in the previous year.18 similarly, colicchio et al. revealed that 59% of a sample of medical students in brazil had driven after drinking alcohol; of these, 21.5% reported driving after consuming large quantities of alcohol.15 research has suggested that the potential risks of driving while sleepy are at least as dangerous as the risks of driving under the influence of alcohol.21 it is therefore comforting that a low proportion of participants in the current study reported driving while tired. driving while drowsy is particularly common among long-distance drivers. mccartt et al. revealed that 47.1% of surveyed long-distance truck drivers in the usa had fallen asleep at the wheel of a truck and 25.4% had fallen asleep at the wheel in the past year.22 while drowsiness is not restricted to night-time driving, the low reported frequency of driving while sleepy among participants of the current study may be due to the fact that it is uncommon to drive long distances during the night in the kurdistan region. the mean frequency score of risky driving behaviour was significantly higher among male than female students and among those who owned a car compared to those who did not. in a study from the usa, male drivers similarly reported engaging in risky driving behaviours more frequently than female drivers (scores of 2.02 versus 1.93 out of 5, respectively).10 the same study also revealed that teenage drivers engaged in risky driving activities more frequently than adult drivers (scores of 2.04 versus 1.88 out of 5, respectively).10 the current study did not detect a significant difference between the two different age groups; however, this could be related to the relatively small sample size and/or the homogeneity in age of the sample. in the current study, over one-tenth of students who drove a car reported not having a driving licence. driving before obtaining a driving licence is a common problem in several countries. scott-parker et al. found that 12% of young people in australia reported prelicence driving and were significantly more risky drivers than learner and provisional drivers.23 sivak et al. showed a general reduced trend in the percentage of young persons with a driving licence in the usa; the percentage of licensed 19-year-olds dropped from 87.3% in 1983 to 75.5% in 2008 and 69.5% in 2010.24 it is not known if this trend also indicates an increased number of unlicensed young drivers. unlicensed drivers not only place themselves and other road users at risk at the time, but also usually continue to be risky drivers in the future.23 therefore, pre-licence driving should be discouraged and parents should be encouraged to monitor car use and the driving behaviour of their children.23 in this study, approximately half of the students drove a car, with the majority of these driving on a daily basis. this proportion could be reflected in the similarly high rate of car ownership. most young drivers in an australian study reported owning a vehicle and young drivers who had their own cars reported significantly greater mileage.25 for young drivers, car ownership is usually associated with more risky driving, which could be attributed to the lengthier time on the road and increased distance driven.25,26 in general, drivers who have their own cars usually report significantly more risky driving.25,27 therefore, researchers have recommended incorporating education on the dangers of risky driving—for parents as well as young drivers—as a requirement to holding a driving licence, particularly when the driver owns a vehicle. parents should be encouraged to delay exclusive access to a vehicle for their children.25,27 the mean risk perception score was higher among those above the age of 20 years old compared to those 20 years old or less, but there was no significant difference between males and females. this score is lower than that revealed by an american study which found higher risk perception scores for adults compared with teenagers.10 reang et al. reported that risky driving behaviours among medical students in erbil, iraq e396 | squ medical journal, august 2015, volume 15, issue 3 the majority of medical students in an indian sample knew the main risky behaviours that could result in road traffic accidents.28 overall knowledge of road safety measures was similarly high among participants in the current study. however, unlike the present study, males had significantly better knowledge compared to females in reang et al.’s study.28 another study from india showed that the overall awareness of medical students on road safety measures was slightly higher among females than males.18 nonetheless, participants demonstrated significantly less awareness of other risky diving behaviours, including consumption of alcohol (4.2%), not wearing seat belts (20%) and using mobile phones without a hands-free device (6.1%).18 no significant associations were observed between the mean enjoyment score and other variables (gender, age, residence and car ownership) in the current study. despite this, the mean score of liking risky driving behaviour was substantially higher than that revealed by a study from the usa.10 researchers found higher scores for teenagers compared to adults, although this was not significant, and significantly higher scores for males compared to females.10 in the sample of medical students from erbil, there was a weak negative relationship between perceived risk and risky driving and a significant positive relationship between liking risky behaviour and risky driving. a study from the usa showed that affect and risk perception were independent predictors of risky driving behaviours among young people and adults.10 a study of adolescents from new zealand reported a significant positive correlation between risk perception and driving behaviours with regards to exceeding posted speed limits and driving fast for pleasure or thrill.29 another study from australia revealed that poorer perception of safety was associated with an increased crash risk.17 according to the available literature, effective interventions to reduce risky driving behaviours among teenagers and young people include the implementation of educational programmes to effectively change behaviours and help risky drivers to temper positive emotions related to driving and more fully understand the associated risks.10,15 these interventions are in addition to more general measures targeting drivers, altering vehicle design and making the environment safer for road users.30 effective prevention strategies to reduce risky driving behaviours among teenagers and young people should also address the ways in which the socioeconomic environment of a community shapes individual behaviours. juarez et al. reported that multisectoral prevention strategies which are culturally appropriate and engage the target population are effective.31 in the context of the erbil community in iraq, prevention strategies could include the implementation of educational and awareness programmes for medical students. these programmes would aim to reduce enjoyment of risky driving behaviours, improve risk perception and remind students to act as role models for safe driving behaviour. in addition to stricter implementation of current traffic rules, these prevention strategies could represent promising methods of reducing risky driving behaviour. this study provided an insight into the risky driving behaviours of a group of young medical students in the iraqi kurdistan region and shed light on how perception and liking of risky driving behaviours can affect actual driving behaviours. however, further exploration of the attributes of and contributors to risky driving behaviours among teenagers and young adults is strongly suggested. the findings of this study were limited to a sample of medical students; the behaviours of non-students or students in other colleges or institutes, which might differ substantially, were not investigated. due to the lack of previous research on risky driving behaviours in the kurdistan region and iraq, particularly among young people, it was not possible to compare the findings of this study to other non-medical students in iraq in order to determine any differences. it would be very useful if a similar survey was conducted with other young people in iraq who are not students in order to determine ascertain more general implications of driving behaviours in this region. further research is needed to explore the attributes and causes of risky driving behaviours among teenagers and young adults. conclusion a high frequency of several serious risky driving behaviours were noted among this sample of medical students in erbil, including speeding, allowing the front seat passenger to not wear a seat belt and using a mobile phone. enjoyment of risky behaviours was an important predictor of risky driving behaviour. further research is recommended to shed light on this important public health issue in iraq, particularly regarding the driving behaviour of young people and teenagers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. nazar p. shabila, kamaran h. ismail, abubakir m. saleh and tariq s. al-hadithi clinical and basic research | e397 references 1. world health organization. global status report on road safety 2013: supporting a decade of action. from: www.who. int/violence_injury_prevention/road_safety_status/2013/en/ accessed: mar 2015. 2. world health organization. world report on road traffic injury prevention. from: www.whqlibdoc.who.int/publications /2004/9241562609.pdf accessed: mar 2015. 3. fergusson d, swain-campbell n, horwood j. risky driving behaviour in young people: prevalence, personal characteristics and traffic accidents. aust n z j public health 2003; 27:337–42. doi: 10.1111/j.1467-842x.2003.tb00404.x. 4. chen cf. personality, safety attitudes and risky driving behaviors: evidence from young taiwanese motorcyclists. accid anal prev 2009; 41:963–8. doi: 10.1016/j.aap.2009.05.013. 5. gulliver p, begg d. personality factors as predictors of persistent risky driving behavior and crash involvement among young adults. inj prev 2007; 13:376–81. doi: 10.1136/ip.2007.015925. 6. yilmaz v, çelik he. risky driving attitudes and self-reported traffic violations among turkish drivers: the case of eskişehir. doğuş üniversitesi dergisi 2006; 7:127–38. 7. hassen a, godesso a, abebe l, girma e. risky driving behaviors for road traffic accident among drivers in mekele city, northern ethiopia. bmc res notes 2011; 4:535. doi: 10.1186/1756-0500-4-535. 8. delhomme p, verlhiac j, martha c. are drivers’ comparative risk judgments about speeding realistic? j safety res 2009; 40:333–9. doi: 10.1016/j.jsr.2009.09.003. 9. harré n, foster s, o’neill m. self-enhancement, crashrisk optimism and the impact of safety advertisements on young drivers. br j psychol 2005; 96:215–30. doi: 10.13 48/000712605x36019. 10. rhodes n, pivik k. age and gender differences in risky driving: the roles of positive affect and risk perception. accid anal prev 2011; 43:923–31. doi: 10.1016/j.aap.2010.11.015. 11. teese r, bradley g. predicting recklessness in emerging adults: a test of a psychosocial model. j soc psychol 2008; 148:105–26. doi: 10.3200/socp.148.1.105-128. 12. mayhew dr. driver education and graduated licensing in north america: past, present, and future. j safety res 2007; 38:229–35. doi: 10.1016/j.jsr.2007.03.001. 13. sheller m. automotive emotions: feeling the car. theory cult soc 2004; 21:221–42. doi: 10.1177/0263276404046068. 14. winston fk, senserrick tm. competent independent driving as an archetypal task of adolescence. inj prev 2006; 1:i1–3. doi: 10.1136/ip.2006.012765. 15. colicchio d, passos ad. driving behavior among medical students. rev assoc med bras 2010; 56:535–40. doi: 10.1590/ s0104-42302010000500013. 16. nakshabandi mm. casualties and deaths from road traffic accidents in dohuk, iraq. duhok med j 2007; 1:15–22. 17. ivers r, senserrick t, boufous s, stevenson m, chen hy, woodward m, et al. novice drivers’ risky driving behavior, risk perception, and crash risk: findings from the drive study. am j public health 2009; 99:1638–44. doi: 10.2105/ ajph.2008.150367. 18. kulkarni v, kanchan t, palanivel c, papanna mk, kumar n, unnikrishnan b. awareness and practice of road safety measures among undergraduate medical students in a south indian state. j forensic leg med 2013; 20:226–9. doi: 10.1016/j. jflm.2012.09.022. 19. musselwhite c. attitudes towards vehicle driving behaviour: categorising and contextualising risk. accid anal prev 2006; 38:324–34. doi: 10.1016/j.aap.2005.10.003. 20. sabbour sm, ibrahim jm. driving behaviour, driver style and road traffic accidents among young medical group. inj prev 2010; 16:a33. doi: 10.1136/ip.2010.029215.120. 21. powell nb, schechtman kb, riley rw, li k, troell r, guilleminault c. the road to danger: the comparative risks of driving while sleepy. laryngoscope 2001; 111:887–93. doi: 10.1097/00005537-200105000-00024. 22. mccartt at, rohrbaugh jw, hammer mc, fuller sz. factors associated with falling asleep at the wheel among long-distance truck drivers. accid anal prev 2000; 32:493–504. doi: 10.1016/ s0001-4575(99)00067-6. 23. scott-parker b, watson b, king mj, hyde mk. young and unlicensed: risky driving before entering the licensing system. traffic inj prev 2012; 13:213–18. doi: 10.1080 /15389588.2011.638683. 24. sivak m, schoettle b. update: percentage of young persons with a driver’s license continues to drop. traffic inj prev 2012; 13:341. doi: 10.1080/15389588.2012.696755. 25. scott-parker b, watson b, king mj, hyde mk. mileage, car ownership, experience of punishment avoidance, and the risky driving of young drivers. traffic inj prev 2011; 12:559–67. doi: 10.1080/15389588.2011.621000. 26. twisk d, bos n, shope jt, kok g. changing mobility patterns and road mortality among pre-license teens in a late licensing country: an epidemiological study. bmc public health 2013; 13:333. doi: 10.1186/1471-2458-13-333. 27. garcía-españa jf, ginsburg kr, durbin dr, elliott mr, winston fk. primary access to vehicles increases risky teen driving behaviors and crashes: national perspective. pediatrics 2009; 124:1069–75. doi: 10.1542/peds.2008-3443. 28. reang t, tripura a. road safety: knowledge, practice and determinants among undergraduate medical students of agartala government medical college and govinda ballabh pant hospital. int j med sci public health 2014; 3:911–15. doi: 10.5455/ijmsph.2014.090420143. 29. brookland r, begg d, langley j, ameratunga s. risk perception and risky driving behaviours of adolescents and their parents: new zealand drivers study. inj prev 2010; 16:a170. doi: 10.11 36/ip.2010.029215.607. 30. khan aa, fatmi z. strategies for prevention of road traffic injuries (rtis) in pakistan: situational analysis. j coll physicians surg pak 2014; 24:356–60. doi: 04.2014/jcpsp.356360. 31. juarez p, schlundt dg, goldzweig i, stinson n jr. a conceptual framework for reducing risky teen driving behaviors among minority youth. inj prev 2006; 12:i49–55. doi: 10.1136/ip.20 06.012872. http://dx.doi.org/10.1111/j.1467-842x.2003.tb00404.x http://dx.doi.org/10.1016/j.aap.2009.05.013 http://dx.doi.org/10.1136/ip.2007.015925 http://dx.doi.org/10.1186/1756-0500-4-535 http://dx.doi.org/10.1016/j.jsr.2009.09.003 http://dx.doi.org/10.1348/000712605x36019 http://dx.doi.org/10.1348/000712605x36019 http://dx.doi.org/10.1016/j.aap.2010.11.015 http://dx.doi.org/10.3200/socp.148.1.105-128 http://dx.doi.org/10.1016/j.jsr.2007.03.001 http://dx.doi.org/10.1177/0263276404046068 http://dx.doi.org/10.1136/ip.2006.012765 http://dx.doi.org/10.1590/s0104-42302010000500013 http://dx.doi.org/10.1590/s0104-42302010000500013 http://dx.doi.org/10.2105/ajph.2008.150367 http://dx.doi.org/10.2105/ajph.2008.150367 http://dx.doi.org/10.1016/j.jflm.2012.09.022 http://dx.doi.org/10.1016/j.jflm.2012.09.022 http://dx.doi.org/10.1016/j.aap.2005.10.003 http://dx.doi.org/10.1136/ip.2010.029215.120 http://dx.doi.org/10.1097/00005537-200105000-00024 http://dx.doi.org/10.1016/s0001-4575%2899%2900067-6 http://dx.doi.org/10.1016/s0001-4575%2899%2900067-6 http://dx.doi.org/10.1080/15389588.2011.638683 http://dx.doi.org/10.1080/15389588.2011.638683 http://dx.doi.org/10.1080/15389588.2012.696755 http://dx.doi.org/10.1080/15389588.2011.621000 http://dx.doi.org/10.1186/1471-2458-13-333 http://dx.doi.org/10.1542/peds.2008-3443 http://dx.doi.org/10.5455/ijmsph.2014.090420143 http://dx.doi.org/10.1136/ip.2010.029215.607 http://dx.doi.org/10.1136/ip.2010.029215.607 http://dx.doi.org/04.2014/jcpsp.356360 http://dx.doi.org/10.1136/ip.2006.012872 http://dx.doi.org/10.1136/ip.2006.012872 clinical & basic research sultan qaboos university med j, feb 2014, vol. 14, iss. 1, pp. e80-87, epub. 27th jan 14 submitted 13th may 13 revision req. 25th sep 13; revision recd. 11th oct 13 accepted 31st oct 13 department of medical microbiology & immunology, faculty of medicine, sana’a university, sana’a, yemen *corresponding author e-mail: shmahe@yemen.net.ye األعراض السريرية و املخربية للمرضى اليمنيني املصابني مبرض الذئبة احلمراء اجلهازية ح�صن عبد �لوهاب �ل�صماحي, جنالء �صيف �هلل, يحيى �لعزي abstract: objectives: systemic lupus erythematosus (sle) is a chronic autoimmune disease characterised by multi-systemic involvement. this is the first study undertaken to determine the relationships between serological marker positivity and age, gender, signs and symptoms, risk factors and the treatment of sle in yemen. methods: we investigated the cases of 149 patients with sle admitted to al-thawra hospital in sana’a city between november 2009 and november 2010. of the 149 patients, females represented 75.2% and males, 24.8%. results: the most frequent presenting signs and symptoms were fatigue (84.6%), fever (81.9%), arthropathy (81.2%), anaemia (64.4%), photosensitivity (54.4%), renal involvement (53%), malar rash (52.3%), and alopecia (49%). antinuclear antibodies (ana) were detected in 95.3% of the patients and were associated significantly with most clinical presentations, except weight loss, hypertension and serositis. anti-ds deoxyribonucleic acid (anti-dsdna) was detected in 59.7% of the patients, and was associated significantly with fever and fatigue. anti-smith (anti-sm) antibodies were detected in 27.5% of the patients, but were not significantly associated with all clinical presentations. social stress was the most important risk factor for inducing sle, with an odds ratio (or) of 6.0, followed by common exposure to sunlight (or = 2.2). conclusion: in this study, sle was more prevalent among females and young adults. the clinical presentation was characterised by a high incidence of fatigue and fever, and a low incidence of oral ulcers and serositis. ana was associated with most clinical presentations except weight loss, hypertension, and serositis. antidsdna antibodies were most frequently associated with fever, fatigue and hypertension. there was no significant association of the anti-sm antibodies with any clinical presentations. keywords: systemic lupus erythematosus (sle); autoantibodies; antinuclear antibodies (ana); anti-ds dna; anti-smith antibodies (anti-sm); yemen. امللخ�ص: الهدف: مر�س �لذئبه �حلمر�ء هي عبارة عن مر�س مناعي ذ�تي مزمن يتميز باإ�صابة �أكرث من جهاز من �أجهزة ج�صم �الن�صان. تعترب هذه �لدر��صة هي �الأوىل يف �ليمن لتحديد �لعالقات بي �لعالمات �مل�صلية �الإيجابية و�ل�صن و�جلن�س وعالمات و�أعر��س هذ� �ملر�س وعو�مل �خلطر و�لعالج لهذ� �ملر�س. 24.8% و�لذكور 75.2% �الإناث مثلت �صنعاء؛ مدينة يف �لثورة مب�صت�صفى وذلك �حلمر�ء �لذئبة مر�س من يعانون مري�صا در��صة 149 متت �لطريقة: من كل �ملر�صى يف �لدر��صة. �لنتائج: كانت �لعالمات و�الأعر��س �الأكرث �صيوعا هي �لتعب )%84.6(، و�حلمى )%81.9(, �العتالل �ملف�صلي )81.2%(, �حل�صا�صية لل�صوء )%54.4(, تاأثر �لكلى )%53.0(, وطفح وجني )%52.3(، فقد�ن �لوزن وفقد�ن و ت�صاقط �ل�صعر )%49.0(. مت �لك�صف عن �الأج�صام �لتهاب و �لدم �صغط و�رتفاع �لوزن فقد�ن عد� فيما �ل�رشيرية �الأعر��س معظم مع كبري ب�صكل مرتبطة كانت و �ملر�صى من يف 95.3% للنو�ة �مل�صادة �مل�صلية. مت �لك�صف عن �الأج�صام �مل�صادة للحم�س �لنووي �لريبي يف نحو %59.7 من �ملر�صى, وكانت لديهم �أعر��س حمى وتعب وحمى. وجدت �أ�صد�د �صميث يف %27.5 من �ملر�صى, ولكنها مل تكن مرتبطة باأي مر�س. وكان �لتوتر �الجتماعي عامل �خلطر �الأكرث �أهمية يف �إحد�ث مر�س �لذئبة �حلمر�ء بن�صبة ترجيحية تبلغ %6.2 تليها �لتعر�س الأ�صعة �ل�صم�س بن�صبة ترجيحية تبلغ %2.2. �خلال�صة: كان مر�س �لذئبه �حلمر�ء �أكرث �نت�صار� بي �الإناث و�صغار �لبالغي. متيزت �الأعر��س �ل�رشيرية بن�صبة عالية من عر�صي �لتعب و�حلمى, وحدوث منخف�س لقرح �لفم و�اللتهاب �مل�صلي. �رتبطت �الأج�صام �مل�صادة للنو�ة مع معظم �الأعر��س �ل�رشيرية با�صتثناء فقد�ن �لوزن, �رتفاع �صغط �لدم, و �اللتهاب �مل�صلي. و�رتبطت �الأج�صام �مل�صادة للحم�س �لنووي �لريبي مع معظم �مل�صابي باحلمى, و�لتعب, و�رتفاع �صغط �لدم. ومل يكن هناك �رتباط كبري الأ�صد�د �صميث مع �أي من �الأعر��س �ل�رشيرية. مفتاح الكلمات: مر�س �لذئبه �حلمر�ء؛ �الأج�صام �مل�صادة للنو�ة؛ �الأج�صام �مل�صادة للحم�س �لنووي �لريبي؛ �أ�صد�د �صميث؛ �ليمن. clinical and laboratory manifestations of yemeni patients with systemic lupus erythematosus *hassan a. al-shamahy, najla h. m. dhaifallah, yahya m. al-ezzy advances in knowledge this study provides new information about systemic lupus erythematosus (sle) in yemen, including the ratio of males to females affected, as well as the antibody-marker association ratio with clinical manifestations, symptoms and signs. this study also highlights the potential risk factors that contribute to increasing a person’s likelihood of developing sle. such information is important in recommending a policy for the treatment and management of sle in yemen, especially as there are hassan a. al-shamahy, najla h. m. dhaifallah and yahya m. al-ezzy clinical and basic research | e81 systemic lupus erythematosus (sle) is an autoimmune disorder characterised by multisystem microvascular inflammation with the generation of numerous auto-antibodies, particularly antinuclear antibodies (ana). sle can affect persons of both sexes, all ages, and all ethnic groups. however, more than 90% of new patients presenting with sle are women in their childbearing years.1 sle is a disease that affects multiple systems and its symptoms vary widely. the multiple organ damage in sle is due to the production of auto-antibodies, which include auto-antibodies to antigens of the brain, renal and vascular tissues, ribosomes, nuclear antigens and phospholipids. intracranial vascular lesions (vasculitis and thrombosis) and inflammation have been related to the local release of cytokines.1 in addition, recent data have suggested that both renal and neuropsychiatric involvement negatively affects the overall five-year survival rate. however, the neuropsychiatric involvement did not change for the 10-year survival rate, in spite of the fact that the involvement of the nervous system in sle remains poorly understood.2 sle affects the immune system, thus reducing the body’s ability to prevent and fight infection. in addition, many of the drugs used to treat sle also impair the functioning of the immune system, thereby further reducing the patient’s ability to fight infection. the most common infections involve the respiratory tract, urinary tract and skin; these infections do not require hospitalisation if they are treated promptly. other opportunistic infections— particularly salmonella, herpes zoster and candida infections—are more common in patients with sle because of altered immune status.3‒5 fatigue in sle is probably multifactorial and has been related not only to disease activity, but also to complications such as anaemia or hypothyroidism. sle is known to differ among people with different racial, geographical and socioeconomic backgrounds. asia encompasses people of many sociocultural backgrounds with diverse ethnic groups—broadly orientals in east and southeast asia, indians in south asia and arabs in the middle east. it has been shown that race is a major predictor of the clinical manifestations of sle, laboratory and serological tests, and disease-related morbidity. comparative studies have shown that sle has a higher prevalence, and higher morbidity and mortality rates, in the oriental population than among caucasians.3‒5 due to a lack of national epidemiological research, the incidence and prevalence of sle in middle eastern and arab countries, have only recently been studied. there have been no previous studies on sle in yemen; therefore, this study aims to determine the relationships between serological marker positivity and age, gender, signs and symptoms, risk factors and the treatment of sle in yemen. methods this study was carried out over a period of one year from november 2009 to november 2010. the study was approved by the department of medical microbiology & clinical immunology of the faculty of medicine & health sciences at sana'a university, yemen. a consent form was completed by each participant. a total of 149 yemeni patients, admitted to medical wards and/or attending medical clinics at al-thawra hospital in sana’a city, were enrolled in this study. all patients fulfilled four or more of the revised american college of rheumatology (acr) criteria for the diagnosis of sle.6 the specifically-designed questionnaires were analysed retrospectively for relevant data such as patients’ age, sex, their clinical manifestation at presentation and during follow-up, and their exposure to possible risk factors of sle. the treatments, either initially or during their follow-up appointments, currently no other studies of this disease in yemen. moreover, sle is likely to be a growing problem in yemen that could go unrecognised if new information about the disease is not promoted within the national medical community. application to patient care the findings of this research could contribute to the formulation of a treatment and management policy for sle, including, ultimately, the management of its complications and sequelae. however, further studies are required to form a more comprehensive understanding of the risk factors and characteristics of sle in yemen. clinical and laboratory manifestations of yemeni patients with systemic lupus erythematosus e82 | squ medical journal, february 2014, volume 14, issue 1 were also recorded, as well as any complications. laboratory data include leukopaenia (white blood cells <4000/mm9), anaemia (haemoglobin <11 gm\ dl) and thrombocytopaenia (platelets <100,000/ mm9). laboratory data also included raised erythrocyte sedimentation rate, positive ana, positive rheumatoid factor, high anti-dna and antism antibody. ana was measured by two different methods: indirect immunofluorescence (iif) and enzyme-linked immunosorbent assay (elisa), anti-ds deoxyribonucleic acid (anti-dsdna) and anti-smith (anti-sm) antibodies were measured by the elisa method (inova diagnostics kits, san diego, california, usa). lupus nephritis was confirmed by renal biopsy, which was graded according to the world health organization classification of ii, iii, iv or v.6 photosensitivity was recognised by specific skin lesions induced by sunlight. the odds ratio (or) for the association of auto-antibody markers with clinical presentations of sle, and their cornfield 95% confidence limits, were calculated by the analysis of a single table (the simplest contingency table being the 2 x 2 table). furthermore, the chi-square (x2) value for statistical significance was calculated using yates’ continuity correction. however fisher's exact test was employed for small cell sizes with a two-tailed probability value (p), using the epi-info version 6 software (centers for disease control and prevention, atlanta, georgia, usa). the various medications used in patient treatment ranged from non-steroidal anti-inflammatory drugs (nsaids), hydroxychloroquine and steroids, to intermittent cyclophosphamide with intravenous methylprednisolone in lupus nephritis. warfarin was the anticoagulant used in the cases of venous thrombosis. results the mean age of patients was 28.8 years (range 11–57 years). females had a higher sle prevalence table 1: gender and age distribution among systemic lupus erythematosus patients attending al-thawra hospital in sana’a city, yemen age in years male female total n (%) n (%) n (%) <15 2 (5.4) 15 (13.4) 17 (11.4) 16–25 9 (24.3) 38 (33.9) 47 (1.5) 26–35 16 (43.2) 32 (28.6) 48 (32.2) 36–45 8 (21.6) 21 (18.8) 29 (19.5) >45 2 (5.4) 6 (5.3) 8 (5.4) total 37 (24.8) 112 (75.2) 149 (100) mean age years 30.2 28.3 28.8 variance years 69.9 127.8 113.5 standard deviation years 8.3 11.3 10.7 min years 12 11 11 max years 49 57 57 median years 30 26 29 mode years 30 45 25 table 2: the relationship between clinical manifestations and presence of antinuclear antibodies (ana) auto-antibodies among systemic lupus erythematosus patients signs and symptoms positive ana (n = 130) or ci χ2 p n (%) fever (n = 122) 114 (93.4) 9.8 3.1–32 20.2 <0.0001 fatigue (n = 126) 117 (92.8) 10 3.1–33.4 19.9 <0.0001 weight loss (n = 73) 67 (91.7) 2.3 0.75–7.3 1.9 0.16 arthropathy (n = 121) 112 (92.5) 6.9 2.2–21.9 13.9 0.0001 renal involvement (n = 79) 75 (94.9) 5.11 1.5–19.4 7.5 0.006 malar rash (n = 78) 75 (96.2) 7.3 1.86–33.2 10.1 0.001 alopecia (n = 73) 71 (97.2) 10.2 2.1–66.9 11.2 0.0008 photo sensitivity (n = 81) 78 (96.2) 8 2.1–36.5 11.34 0.0007 serositis (n = 14) 8 (57.1) 0.14 0.04–0.55 9.8 0.003* oral ulcers (n = 16) 7 (43.7) 0.06 0.02–0.24 26.3 <0.0001* hypertension (n = 55) 46 (83.6) 0.6 0.2–1.8 1.02 0.03* ana = antinuclear antibodies; or = odds ratio; ci = 95% confidence interval; *fisher's exact test p value; significant result χ2 ≥ 3.84, p <0.05. hassan a. al-shamahy, najla h. m. dhaifallah and yahya m. al-ezzy clinical and basic research | e83 than males, with a female to male ratio of 3:1. the prevalence of sle was greater in the 16–35 years age group [table 1]. the clinical presentation of sle was characterised by a high incidence of fatigue and fever, while there was a low incidence of oral ulcers and serositis [table 5]. the blood picture of the patients showed a low prevalence of leukopaenia and lymphopaenia, and a high prevalence of thrombocytopaenia [table 5]. tables 2, 3 and 4 show the relationship between the autoantibody positivity and the clinical symptoms. ana was statistically significant (χ2 >3.9 and p <0.05) and associated with most clinical presentations (or 5.1–10.2) except weight loss, hypertension and serositis [table 2]. anti-dsdna antibodies, which are a specific marker for sle, showed a statistically significant association with fever (or = 3.12; ci: 1.2–8.12; x2 = 5.9; p = 0.01); fatigue (or = 2.7; ci: 1–7.4; x2 = 3.84; p = 0.05), and hypertension (or = 2.15; ci: 1.0–4.6; χ2 = 3.84; p = 0.05) [table 3]. anti-sm antibodies, which are a highly specific marker for sle, were not significantly associated with any clinical presentations [table 4]. lupus nephritis was significantly associated with red blood cell (rbc) casts, proteinuria, hyaline casts, elevated creatinine levels and hypertension. the two main risk factors in yemeni sle patients were found to be frequent exposure to sunlight (or = 6.0; ci: 2.6–13.9; p <0.0001) and to social and mental stress (or = 2.8; ci: 0.4–9.6; p = 0.04), while the use of contraceptives by females was not a risk factor (or = 0.5; ci: 0.1–1.5; p = 0.17). similarly, chewing qat (plant containing an amphetaminelike stimulant native to the horn of africa and the arabian peninsula) was not found to be a risk factor for sle in this study (or = 0.5; ci: 0.2–0.9; p = 0.01) [table 6]. table 5 shows the frequencies of clinical and laboratory features of sle among different ethnicities compared with the present study. the table 3: the relationship between clinical manifestations and presence of ds deoxyribonucleic acid (dsdna) autoantibodies among systemic lupus erythematosus patients signs and symptoms positive antidsdna (n = 89) or ci χ2 p n (%) fever (n = 122) 79 (64.8) 3.1 1.2–8.12 5.96 0.01 fatigue (n = 126) 80 (63.5) 2.7 1–7.4 3.84 0.05 weight loss (n = 73) 49 (63.4) 1.8 0.9–3.7 2.68 0.1 arthropathy (n = 121) 77 (63.6) 2.3 0.94–5.85 3.3 0.07 renal involvement (n = 79) 51 (64.5) 1.5 0.75–3.13 1.23 0.26 malar rash (n = 78) 49 (62.8) 1.3 0.6–2.6 0.41 0.52 alopecia (n = 73) 46 (67.1) 1.3 0.64–2.7 0.4 0.52 photosensitivity (n = 81) 47 (58) 0.86 0.4–1.74 0.09 0.76 serositis (n = 14) 5 (35.7) 0.34 0.09–1.2 2.76 0.1* oral ulcers (n = 16) 5 (31.3) 0.34 0.09–1.18 2.69 0.1* hypertension (n = 55) 39 (71) 2.15 1–4.6 3.84 0.05 or = odds ratio; ci = 95% confidence interval; *fisher's exact test p value; significant result χ2 ≥ 3.84, p <0.05. table 4: the relationship between clinical manifestations and presence of anti-smith antibodies (anti-sm) autoantibodies among systemic lupus erythematosus patients signs and symptoms positive anti-sm (n = 41) or ci χ2 p n (%) fever (n = 122) 37 (30.3) 2.5 0.75–9.23 1.9 0.16 fatigue (n = 126) 38 (30.2) 2.9 0.75–12.9 2.06 0.15 weigh loss (n = 73) 22 (30.1) 1.3 0.6–2.8 0.27 0.6 arthropathy (n = 121) 35 (28.9) 1.5 0.5–4.5 0.32 0.57 renal involvement (n = 79) 20 (25.3) 0.8 0.36–1.7 0.21 0.64 malar rash (n = 78) 25 (32.1) 1.6 0.73–3.6 1.24 0.26 alopecia (n = 73) 24 (32.9) 1.7 0.77–3.7 1.57 0.2 photosensitivity (n = 81) 22 (27.2) 0.96 0.44–2.1 0.01 0.93 serositis (n = 14) 2 (14.3) 0.4 0.06–2.1 0.72 0.35* oral ulcers (n = 16) 4 (25) 0.86 0.2–3.1 0.00 1.0 hypertension (n = 55) 15 (27.3) 0.98 0.43–2.2 0.02 0.889 or = odds ratio; ci = 95% confidence interval; *fisher's exact test p value; significant result χ2 ≥ 3.84, p <0.05. clinical and laboratory manifestations of yemeni patients with systemic lupus erythematosus e84 | squ medical journal, february 2014, volume 14, issue 1 mortality rate in our study was 4.7%; the causes of death were pulmonary embolism (2%), septicaemia (2%) and disseminated intravascular coagulopathy with refractory heart failure (0.7%). discussion the ratio of male patients to female patients in the current study was 1:3. this result is in disagreement with the results of other studies which have reported an even higher prevalence of sle among females; these include male to female ratios of 1:7.2, 1:9 and 1:9.9.3,7,8 the mean patient age in the present study of 28.8 years was similar to that reported from dubai, united arab emirates (28.9 years)9 and spain (29 years).10 the majority of patients (88.6%) were adults, while 11.4% were children under 15 years. this is similar to the study by alballa whose patients were predominately above 15 years.11 the high rate among adults may be related to adult sex hormones which play an important role in triggering the disease.12 fatigue, the most common constitutional symptom associated with sle, could be caused by active sle, medications, lifestyle habits or concomitant fibromyalgia—or affective disorders. fatigue due to active sle generally occurs in concert with other clinical and laboratory markers.3 the most frequent clinical symptom among the sle patients in this study was fatigue (84.6%). this finding is in contrast to other studies performed in saudi arabia and iran, where the frequency of fatigue was reported as 9.2%13 and 30.2%,14 table 5: frequencies of clinical and laboratory features of systemic lupus erythematosus among studies of different ethnicities compared with the current study yemen saudi arabia7 uae9 kuwait18 lebanon17 tunis15 iran14 spain10 pakistan3 year 2010 2009 2008 1998 1999 2004 2008 2004 2004 number of patients 149 624 151 108 100 100 410 600 196 mean age 28.8 25.3 28.9 31.5 25 32 30.3 29 31 male:female ratio 1:3 1:9.8 1:20.5 1:9.8 1:6.1 1:11.5 1:6.6 1:8 1:7.1 signs and symptoms in % fatigue 84.6 42.5 30.2 fever 81.9 30.6 51.0 63.4 42 arthropathy 81.2 80.4 81.1 87 95 78 65.5 83 38 photosensitivity 54.4 30.6 43 48 16 53 54.5 41 6 renal involvement 53.0 47.9 51 37 50 43 47.8 34 33 malar rash 52.3 47.9 60.3 43 52 63 60.5 54 29 alopecia 49 44 23.0 81 22 oral ulcers 10.7 39.1 30.5 33 40 4 27.8 30 19.7 serositis 9.4 27.4 27.2 40 45 38 22 hemolytic anaemia 9.9 10 6 12.5 8 anaemia 64.4 63.1 44.3 74.6 19 leucopaenia 28.2 30 53.6 83 17 64.5 66 22 lymphopaenia 36.2 40.3 50 43.4 82 thrombocytopaenia 44.3 10.9 18.5 26 33 12 44.6 30 26 ana 95.3 99.7 88 94 87 100 93 99 86 anti-dsdna 59.7 80.1 88.7 58 50 56 83 90 74 anti-sm 27.5 19.7 13 61.2 12 50 uae = united arab emirates; ana = antinuclear antibodies; anti-dsdna = anti-ds deoxyribonucleic acid; anti-sm = anti-smith antibodies. hassan a. al-shamahy, najla h. m. dhaifallah and yahya m. al-ezzy clinical and basic research | e85 respectively. this could be explained by the fact that our questionnaire included fatigue as a potentially important symptom of sle, while questionnaires used in previous studies did not consider fatigue to be important. fever was also common in the patients int this study (81.9%), and their temperature usually showed diurnal variation—being high in the afternoon and evening. the frequency of fever was higher than that reported in other studies—in spain 42% of patients studied experienced fever, while in saudi arabia it was 30%.10,7 arthropathy was a common sign (81.2%) in this study, and this result is similar to findings reported from dubai (81.1%)9 and saudi arabia (80.4%).7 however, the rates of arthropathy in yemen were far higher than those experienced in pakistan (38%).3 photosensitivity occurred in 54.5% of the current study’s patients, which was similar to that reported in tunisia (53%)15 and iran (54.5%).14 however, lower prevalence rates have been reported from pakistan (6%),3 saudi arabia (22%)16 and europe (22.9%).8 this difference can be explained by the patients’ high exposure to sunlight in this study. in this study group, renal involvement of sle was variable in clinical presentation and prognosis, ranging from mild asymptomatic proteinuria to rapidly progressive glomerulonephritis (gn) leading to end-stage renal disease. renal involvement affected 53.3% of the patients. similar findings were reported by studies in lebanon (50%)17 and dubai (51%),8 but these are in contrast to the low frequencies reported in pakistan (33%)2 and european countries (27.9%).9 yemen’s findings of similar renal involvement to that of other arabic countries (lebanon and dubai) may be due to the shared factors (genetic, environmental and dietary) that could trigger or control the presentation of the disease. malar rash was present in 52.3% of the current study’s patients which is similar to findings in lebanon (52%)16 and spain (54%)9 but is in disagreement with the lower prevalence found in pakistan (29%).3 alopecia occurred in 49% of our patients, which is similar to the study in kuwait (44.0%) by al-jarallah et al,18 but lower than that of spain (81%), reported by font et al.10 oral ulcers were less frequent in our study (10.7%) and were of similar occurrence to findings from latin america (10.5%)19 but lower than those from lebanon (40%)17 and saudi arabia (39.1%).7 the present study had the lowest incidence of serositis (9.4%) compared to studies in lebanon (45%)17 and in iran (38%).14 this finding could be related to a failure of physicians to record the symptoms. the presence of ana is a hallmark of sle disease and one of the diagnostic criteria established by the acr. in the present study, the prevalence of ana was 95.3% [table 5]. similar findings have been reported from saudi arabia (95%)16 and european countries (96%),8 but an even higher prevalence was noted in tunisia (100%).15 however, our figure was slightly higher than those of india (71.4%),20 lebanon (87%)17 and pakistan (86%).3 in spite of its apparent importance, some researchers have not agreed that ana is a hallmark of sle disease. anti-dsdna antibodies are quite specific and diagnostically important for sle.21 the prevalence of circulating anti-dsdna antibodies in yemeni patients was 59.7% [table 5]. very similar results have been obtained from tunisia (56%)15 and kuwait (58%),18 but are in contrast to the higher frequency found in saudi arabia (93%),11 spain (90%)10 and dubai (88%).9 these differences may reflect a variable prevalence of anti-dsdna in the world. in the current study, the prevalence of antism antibodies was 27.5% [table 5] which indicates that anti-sm antibodies are highly specific and of considerable diagnostic value for sle as they appear table 6: the potential risk factors of systemic lupus erythematosus among the patients of the current study risk factors frequency or ci χ2 p n (%) type of stress** social mental financial 60 (40.2) 19 (12.8) 7 (4.7) 6.0 2.8 0.5 2.6–139 0.4–9.6 0.1–1.5 24.0 3.9 1.8 <0.0001* 0.04 0.17 exposure to sun light (at least 2 hours/ day) 42 (28.2) 2.2 1.1–4.7 5.0 0.02* qat chewing† 30 (20.1) 0.5 0.2–0.9 5.6 0.01* oral contraceptive use 14 (12.5) 0.8 0.4–2.0 0.17 0.68 or = odds ratio; ci = 95% confidence interval. *fisher's exact test p value; significant result χ2 ≥ 3.84, p <0.05. **the stress assessment was done by the psychiatrists at al-thawra hospital, sana’a city. †qat = plant containing amphetamine-like stimulant native to the horn of africa and the arabian peninsula. clinical and laboratory manifestations of yemeni patients with systemic lupus erythematosus e86 | squ medical journal, february 2014, volume 14, issue 1 almost exclusively in sle, as reported by tan et al.22 our prevalence is higher than that in spain (12%)10 but lower than that in tunisia (61.2%).15 the great diversity of clinical manifestations in sle, ranging, for example, from arthritis and serositis to life-threatening neuropsychiatric manifestations, is accompanied by a high titre of auto-antibodies.23 the current study found a strong statistical correlation between ana and most clinical manifestations except weight loss, serositis and hypertension [table 2]. there was also a significant correlation between anti-dsdna and clinical manifestations such as fever, fatigue and hypertension, but no significant correlation with weight loss, arthropathy, renal involvement, alopecia, malar rash, serositis, oral ulcer and photosensitivity [table 3]. the absence of a statistically significant correlation between antidsdna and renal involvement in our study, even though dsdna is known to be one of the main markers of lupus nephritis as described by raz et al.,24 may be related to unknown factors in yemen that need to be clarified. there was no significant association between anti-sm antibodies and most of the clinical manifestations in table 4, except fever, as has been confirmed by hitchon and peschken.25 patients with sle have a complex array of abnormalities involving their immune system. a history of multiple cytopaenias such as leukopaenia, lymphopaenia, anaemia or thrombocytopaenia may suggest sle, among other aetiologies.1,2 in our series, anaemia was the most frequently occurring haematological abnormality in our patients [table 5]. it occurred in about 64.4% of our patients, similar to the rate reported in saudi arabia (63.1%),7 but higher than that reported in spain (19%).10 lymphopaenia was present in 36.2% of our patients, the same as (30%) in saudi arabia,6 but lower than the 50% rate in tunisia15 and 82% rate in spain.10 the low incidence can probably be explained by the fact that the immunological response of our patients was not typical of the disease, in which the auto-antibodies in sle are directed against a wide variety of self-antigens. leukopaenia occurred in 28.2% of our patients. this is quite similar to other studies reported by agrawal et al.26 and al-arfaj and khalil,7 but much lower than the 83% reported by al-jarallah et al.18 and the 64.6% recorded by nazarinia et al.14 our study found a high prevalence of thrombocytopaenia (44.3%); a similar result was reported in iran by nazarinia et al.,14 while lower prevalence was reported from tunisia (12%),15 kuwait (26%)18 and saudi arabia (10.9%).9 erythrocyte sedimentation rate (esr) is one of the major monitoring tests for acute phase inflammation because it correlates with increased levels of acute phase reactants, in particular fibrinogen. in the present study, the frequency of esr was 89.9%. a similar finding was reported in a study on indian children (98.5%) by agrawal et al.,26 which is in contrast to studies with low frequency in iran(64.6%)14 and saudi arabia (54%).7 this difference may be due to many factors that affected the esr result, including the patient’s age, sex, red blood count morphology, haemoglobin concentration and serum levels of immunoglobulin.27 the mortality rate in our patients was low (4.7%) and was somewhat similar to the rates in three different studies from saudi arabia; 3%,13 4%,11 and 5.4%.7 this could be attributed to early diagnosis and effective treatment in controlling the disease. the second aim of this study was to examine the risk factors that could have influenced the occurrence of sle among our study group, this being the first study designed to determine the risk factors of contracting sle in yemen. frequent exposure to sunlight and stress (social and mental) were found to be risk factors in yemeni sle patients. this might be explained by the fact that psychological stress can activate an acute phase response, which is part of the innate immune inflammatory response; it is also evidence that the inflammatory response is contained within the stress response, and that stress can induce an inflammatory response.28 this study also indicates that sunlight, especially ultraviolet b light (290– 320 nm), plays an important role in inducing this systemic disease.29 oral contraceptive pills, especially those with high oestrogen doses, may provoke flares of sle.30 in the present study, however, no association was discovered between oral contraceptives and sle. conclusion sle was more prevalent among females and young adults. the clinical presentation was characterised by a high incidence of fatigue and fever, and a low incidence of oral ulcers and serositis. ana hassan a. al-shamahy, najla h. m. dhaifallah and yahya m. al-ezzy clinical and basic research | e87 was significantly associated with most clinical presentations except weight loss, hypertension and serositis. anti-dsdna antibodies were a specific marker and significantly associated with fever, serositis, oral ulcer, fatigue, hypertension and arthropathy. anti-sm antibodies were highly specific markers for sle and significantly associated with oral ulcers. references 1. verma j, arora v, marwaha v, kumar a, das n. association of leukocyte cr1 gene transcription with the disease severity and renal involvement in systemic lupus erythematosus. lupus 2005; 14:273–9. 2. alkhotani a. neuropsychiatric lupus. sultan qaboos univ med j 2013; 13:19–25. 3. rabbani ma, siddiqui bk, tahir mh, ahmad b, shamim a, majid s, et al. do clinical manifestations of systemic lupus erythematosus in pakistan correlate with rest of asia? j pak med assoc 2006; 56:222–7. 4. castro j, balada e, ordi-ros j, vilardell-tarrés m. the complex immunogenetic basis of systemic lupus erythematosus. autoimmun rev 2008; 7:345–51. 5. franchin g, peeva e, diamond b. pathogenesis of sle: implications for rational therapy. review. drug discov today dis mech 2004; 1:303–8. 6. d'cruz dp, khamashta ma, hughes gr. systemic lupus erythematosus. lancet 2007; 369:587–96. 7. al-arfaj as, khalil n. clinical and immunological manifestation in 624 sle patients in saudi arabia. lupus 2009; 18:456–73. 8. cervera r, khamashta ma, hughes grv. the euro-lupus project: epidemiology of systemic lupus erythematosus in europe. lupus 2009; 18:869–74. 9. al-saleh j, jassim v, el-sayed m, saleh n, harb d. clinical and immunological manifestations in 151 sle patients living in dubai. lupus 2008; 17:62–6. 10. font j, cervera r, ramos-casals m, garcía-carrasco m, sents j, herrero c, et al. clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center. semin arthritis rheum 2004; 33:217–30. 11. alballa sr. systemic lupus erythematosus in saudi patients. clin rheum 1995; 14:342–6. 12. hellmann db, stone jh. musculoskeletal disorders. in: tierney lm, mcphee sj, papadakis ma, eds. current medical diagnosis and treatment. 45th ed. new york: mcgraw-hill/appleton & lange, 2006. pp. 807–64. 13. qari fa. clinical pattern of systemic lupus erythematosus in western saudi arabia. saudi med j 2002; 23:1247–50. 14. nazarinia ma, ghaffarpasand f, shamsdin a, karimi aa, abbasi n, amiri a. systemic lupus erythematosus in the fars province of iran. lupus 2008; 17:221–7. 15. houman mh, smiti-khanfir m, ben ghorbell i, miled m. systemic lupus erythematosus in tunisia: demographic and clinical analysis of 100 patients. lupus 2004; 13:204–11. 16. heller t, ahmed m, siddiqqi a, wallrauch c, bahlas s. systemic lupus erythematosus in saudi arabia: morbidity and mortality in a multiethnic population. lupus 2007; 16:908–14. 17. uthman f, nasr f, kassak k, masri a-f. systemic lupus erythematosus in lebanon. lupus 1999; 8:713–15. 18. al-jarallah k, al-awadi a, siddiqui h, al-salim i, shehab d, umamaheswaran i, et al. systemic lupus erythematosus in a kuwait hospital-based study. lupus 1998; 7:434–8. 19. garcía tello a, villegas martínez a, gonzález fernández af. [hematological abnormalities in patients with systemic lupus erythematosus]. an med interna 2002; 19:539–43. 20. thumboo j, fong ky, chng hh, koh et, chia hp, leong kh, et al. the effects of ethnicity on disease patterns in 472 orientals with systemic lupus erythematosus. j rheumatol 1998; 25:1299–304. 21. rahman a. isenberg da. systemic lupus erythematosus. n engl j med 2008; 358:929–39. 22. asherson ra, cervera r, de groot pg erkan d, boffa mc, piette jc, et al. catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. lupus 2003; 12:530–4. 23. sherer y, gorstein a, fritzler mj, shoenfeld y. autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in sle patients. semin arthritis rheum 2004; 34:501–37. 24. general pathology images for immunopathology 2011. from:http://erl.pathology.iupui.edu/c603/gene607.htm accessed: apr 2013. 25. hitchon ca, peschken ca. sm antibodies increase risk of death in systemic lupus erythematosus. lupus 2007; 16:186–94. 26. agrawal i, kumar ts, ranjini k, kirubakaran c, danda d. clinical features and outcome of systemic lupus erythematosus. indian pediatr 2009; 46:711–15. 27. sox hc jr, liang mh. the erythrocyte sedimentation rate. ann intern med 1986; 104:515–23. 28. chida y, sudo n, kubo c. social isolation stress exacerbates autoimmune disease in mrl/lpr mice. j neuroimmunol 2005; 158:138–44. 29. wang gs, zhang m, li xp, zhang h, chen w, kan m, et al. ultraviolet b exposure of peripheral blood mononuclear cells of patients with systemic lupus erythematosus inhibits dna methylation. lupus 2009; 18:1037–44. 30. jungers p, dougados m, pélissier c, kuttenn f, tron f, lesavre p ,et al. influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. arthritis rheum 1982; 25:618–23. squ med j, february 2012, vol. 12, iss. 1, pp. 116-119, epub. 7th feb 12. submitted 6th jun 11 revision req. 2nd nov 11, revision recd. 6th nov 11 accepted 16th nov 11 discrepancies in palpable pulses are not uncommon in children, and could cause concern for the patient and parents, as well as physicians. when these are detected in an otherwise well child, a dilemma exists as to how extensive the medical investigation should be. we report the interesting case of a boy with a weak radial pulse which was detected during a routine follow-up visit to a paediatric clinic. this case emphasises the clinical importance in terms of knowing about unusual but normal variations in palpable pulses. case report ab, an 11-year old boy, was on follow up for hypokalaemic periodic paralysis. during one of the clinic visits, he was noted to have a weak radial pulse on the right side, and this prompted further investigation. there was no asymmetry in the limb size and there was no evidence of hypo-perfusion of the right arm or hand. other pulses were normally felt, including both femoral and left radial pulses. his cardiovascular system was essentially normal and there was no cardiac murmur. ab had not had any previous cardiac surgery, or intensive care admission in early infancy or during neonatal life. a vascular ultrasound scan of the arteries in the upper arms showed a number of features that explained the discrepancy in the pulses felt on each arm. on both sides, the radial artery was smaller than the ulnar artery, and the ulnar arteries provided the main source of blood flow to the arms (ulnar dominance). on the left side, the radial artery arose from the brachial artery at its upper end, well above the elbow, and then crossed over to the radial side of the forearm at the elbow [figure 1]. on the right side, the radial artery arose from the medial side of the brachial artery near the elbow and then looped across the distal end of the brachial artery to continue along the radial margin of the forearm. the loop was a very thin vessel, and continued to be thin in several places, especially at the wrist. 1department of child health, brighton & sussex university hospitals, brighton, uk; departments of 2child health and 3medical physics university hospital of hartlepool, hartlepool, uk; 3regional medical physics department, freeman hospital, newcastleupon-tyne, uk. corresponding author e-mail: pvenugopalan@gmail.com النبض الضعيف يف الشِّْرياُن الُكْعرُبِّي سبب َخلقي غري عادي بوثرييكوفيل فينوجوبالن، بوثوفال �سيفاكومار، روبرت ارديل، كري�سبيان اأوت�س ف التطبيق الناجح للموجات فوق امللخ�س: ُنقّدم هنا حالة طفل ُعُمره 11 عاما لديه �سعف النب�س يف ال�رصيان الكعربي الأمين ، وَن�سِ ال�سوتية لالأوعية الدموية لتحديد هيمنة ال�رصيان الزندي ورّقة ال�رصيان الكعربي الأمين مع �رصعة تدفق دوبلر الأدنى من الطبيعي والتي ميكن اأن ُتَف�رص هذا التناق�س. نناق�س اأي�سا الآثار املرتتبة على حتديد هذا الو�سع ال�ساذ. مفتاح الكلمات: �رصيان ُكعربي، نب�س، �سذوذ، الت�سوير باملوجات فوق ال�سوتية، تقرير حالة، اململكة املتحدة. abstract: we present an 11year-old boy with a weak right radial pulse, and describe the successful application of vascular ultrasound to identify the ulnar artery dominance and a thin right radial artery with below normal doppler flow velocity that could explain the discrepancy. the implications of identifying this anomaly are discussed. keywords: arterial anomalies; pulse, radial; congenital; embryology; ultrasonography; catheterization; case report; uk. weak radial artery pulse an unusual congenital cause *poothirikovil venugopalan,1 puthuval sivakumar,2 robert g. ardley,3 crispian oates4 case report poothirikovil venugopalan, puthuval sivakumar, robert g. ardley, crispian oates case report | 117 pulse-wave doppler signals showed normal flow velocity (30-50 cm/sec) along the ulnar arteries [figure 2]. the flow along the radial arteries was pulsatile, but with a below normal velocity, and more pronounced in the right radial artery (right 15 cm/sec; left 28 cm/sec). these variations explained the weak right radial pulse. we discussed with the family the role of magnetic resonance imaging (mri) to confirm the anomaly, but both the parents and the child were not happy to undergo any further tests. discussion congenital arterial anomalies of upper limbs have been reported in the literature, but each has its own thumbprint. upper limb abnormalities are sometimes encountered during transradial coronary procedures. such anomalies may contribute to procedure failure, or to vascular complications, and they may be a major reason to find alternative routes. arterial supply to the forearm and hand is by the radial and ulnar arteries. both are branches of the brachial artery, arising within or just distal to the cubital fossa from the bifurcation of the brachial artery. the radial artery is normally the dominant arterial supply to the hand.1 deviations from normal anatomy are not infrequent, occurring in 18.5% of 386 cadavers studied by mccormack et al.2 unilateral abnormalities were more common than bilateral (24.5% and 6.3%, respectively). similar findings have also been reported by fujii et al. and ziakas et al.3,4 rodriguez-baeza et al. have proposed 4 groups of anomalies: isolated persistence of the median artery; high origin of the ulnar artery; high origin of the radial artery, and duplication of the brachial artery, either with or without anastomosis at the cubital fossa.5 the most common anomaly is a high origin of the radial artery, either from the brachial or axillary artery, and has been shown in 14.27% of cadaveric samples and 9.75% in angiographic examinations.6 the majority of reported cases have a symmetrical distribution of the anomaly. the present case describes abnormal origins of radial arteries on both sides; however, the nature of the anomaly was different on each side. on the left side, the radial artery was proximal in its origin, and arose from the medial margin of the upper third of figure 1: diagramatic representation of upper limb arteries in an 11 year-old boy showing the radial artery anomalies detected by vascular ultrasound (r = right; l = left). the diagram is not drawn to scale and hence does not depict the smallness of the radial arteries, but does show the abnormal origins (arrows). weak radial artery pulse an unusual congenital cause 118 | squ medical journal, february 2012, volume 12, issue 1 the brachial artery. this is a common variant seen in 5˗10% of the population; however, the anomaly is usually seen symmetrically on both sides. in ab, the radial artery on the right side originated from the medial margin of the brachial artery, within the cubital fossa, and looped across the distal end of brachial artery, which is quite unusual. moreover, the right radial artery was thin and hypoplastic with a lower flow velocity, giving rise to a weak radial pulse on the right side. this pattern of malformation is very unusual. our case also describes the successful use of vascular ultrasound to identify a potentially important variation in the upper limb blood supply. recognition of anomalous anatomy was until recently possible only with arteriography or post-mortem examination. non-invasive imaging is emerging as a dependable means of identifying these variations, as described by yan et al.7 they published their study on 638 patients undergoing percutaneous coronary procedures, and defined normal values for adults with satisfactory interobserver agreement. more recently, mri has been employed to delineate the anomaly; however, our patient, as mentioned earlier, was not happy to undergo the procedure.8 the arterial anomalies are better understood with a description of the normal development of the arterial pattern in the upper limbs. the upper limb arteries arise from the seventh cervical inter-segmental artery. rodriguez-niedenfu et al. studied a total of 112 human embryos (224 upper limbs) between 3–5 weeks (developmental stages 12–23) of development, and observed that formation of the arterial system in the upper limb takes place as a dual process.9 an initial capillary plexus appears from the dorsal aorta during week 3 (stage 12) and develops at the same rate as the limb. subsequently, during the second stage, the capillary plexus begins a maturation process involving the enlargement and differentiation of selected parts. this remodelling process starts in the aorta and continues in a proximal to distal sequence, and parallels chronologically the development of the figure 2: pulse wave doppler pictures of arterial blood flow at the wrist in an 11 year-old boy showing reduced doppler flow velocity in the radial arteries compared to the ulnar arteries (left radial artery [a] 28 cm/sec; right radial artery [b] 15 cm/sec; left ulnar artery [c] 50 cm/sec; right ulnar artery [d] 38 cm/sec). poothirikovil venugopalan, puthuval sivakumar, robert g. ardley, crispian oates case report | 119 skeletal system. deviations are the result of the persistence, enlargement, and differentiation of parts of the initial network which would normally remain as capillaries, or even regress. these are generally detectable by 5 weeks (stage 23) as the brachial artery has already differentiated. most of the malformations can be explained by intussusceptive angiogenesis which occurs by internal division of pre-existing capillary beds by protrusion of capillary endothelial cells into the lumen, creating two new vessels from one vessel. a similar process has also been described in larger arteries in addition to the capillaries. four main embryologic groups of anomalies exist, namely: failure of the primitive artery to recede; failure of the primitive artery to form; aberrant origin of the native vessel, and ectopic location of an otherwise normal vessel. appreciation of variations in the upper extremity vasculature is essential to prevent injury, particularly in patients requiring dialysis or undergoing arteriography. inappropriate cannulation of these arteries due to aberrant locations in or near the antecubital fossa can result in thrombosis, gangrene, and even amputation of the limb.10 yan et al. have shown that percutaneous coronary procedures took longer and were associated with higher failure rates and artery occlusion when there were smaller than normal radial arteries.7 difficulties in palpable pulses in the limbs may act as a trigger to initiate a range of investigations including assessment of the heart and blood tests for thromboembolic disorders, and all these can be avoided if an ultrasound can quickly identify the congenital anomaly that underlies the discrepancy in the pulses. ab, as he was otherwise well, only underwent an echocardiogram to search for any underlying cardiovascular anomalies, followed by the vascular ultrasound which explained the pulse discrepancy. conclusion we have reported an 11 year-old boy with a weak radial pulse on the right hand, and the use of vascular ultrasound to explain the anomaly. clinical implications related to accidental arterial puncture and difficulties in any future cardiac catheterisations were discussed. references 1. ciervo a, kahn m, pangilinan aj, dardik h. absence of the brachial artery: report of a rare human variation and review of upper extremity arterial anomalies. j vasc surg 2001; 33:191−4. 2. mccormack l, cauldwell e, anson b. brachial and antebrachial patterns: a study of 750 extremities. surg gynecol obstet 1953; 96:43−54. 3. fujii t, masuda n, tamiya s, shima m, toda e, ito d, et al. angiographic evaluation of right upperlimb arterial anomalies: implications for transradial coronary interventions. j invasive cardiol 2010; 22:536−40. 4. ziakas ag, koskinas kc, gavrilidis s, giannoglou gd, hadjimiltiades s, gourassas i, et al. radial versus femoral access for orally anticoagulated patients. catheter cardiovasc interv 2010; 76:493−9. 5. baeza ra, nebot j, ferreira b, reina f, perez j, saundo jr, et al. an anatomical study and ontogenetic explanation of 23 cases with variations in the main pattern of the human brachio-antebrachial arteries. j. anal 1995; 187:473−9. 6. niedenfuhr rm, vazquez t, nearn l, ferreira b, parkin i, sanudo jr. variations of the arterial pattern in the upper limb revisited: a morphological and statistical study, with a review of the literature. j anat 2001; 199:547−66. 7. yan zx, zhou yj, zhao yx, zhou zm, yang sw, wang zj. anatomical study of forearm arteries with ultrasound for percutaneous coronary procedures. circ j 2010; 74:686−92. 8. claassen h, schmitt o, werner d, schareck w, kröger jc, wree a. superficial arm arteries revisited: brother and sister with absent radial pulse. ann anat 2010; 192:151−5. 9. docimo s jr, kornitsky de, hill rv, elkowitz de. arterio-arterial malformation between a high origin radial artery and brachial artery within the cubital fossa – its clinical and embryological significance: a case report. cases j 2009; 2:6836. 10. hazlett jw. the superficial ulnar artery with reference to accidental intra-arterial injection. cmaj 1949; 61:289−93. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 359-367, epub. 25th jun 13 submitted 2nd jan 13 revision req. 3rd feb 13; revision recd. 23rd feb 13 accepted 27th mar 13 urinary tract infections (utis) occur more often in women than in men, at a ratio of 8:1. approximately 50–60% of women report at least one uti in their lifetime, and one in three will have at least one symptomatic uti necessitating antibiotic treatment by age 24.1–3 normally, the urinary tract is sterile, but bacteria may rise from the perianal region, possibly leading to uti. pathogens in the bladder may stay silent or can cause irritative symptoms like urinary frequency and urgency, and 8% of women may have asymptomatic bacteriuria. if bacteria enter the blood stream, they could cause severe complications, including septicaemia, shock and, rarely, death.4,5 the definition of recurrent urinary tract infection (ruti) is three utis with three positive urine cultures during a 12-month period, or two infections during the previous 6 months.5–8 this article provides an up-to-date review of the epidemiology, pathophysiology, risk factors, diagnosis, management and prevention of rutis in women. classification of urinary tract infections utis are classified into 6 categories. the first category is an uncomplicated infection; this is when the urinary tract is normal, both structurally and physiologically, and there is no associated disorder that impairs the host defense mechanisms. the second category is an complicated infection; this is 1king fahad medical city, riyadh, saudi arabia; 2king saud university, king khalid university hospital, riyadh, saudi arabia *corresponding author e-mail: ahmed@albadr.com االلتهابات املتكررة للمسالك البولية عند النساء وطرق عالجها مراجعة اأحمد البدر و غدير ال ال�شيخ امللخ�ص: التهابات امل�شالك البولية )عدوى امل�شالك البولية( هي واحدة من االلتهابات البكتريية ال�رسيرية االأكرث �شيوعا لدى الن�شاء، وهو ما ميثل ما يقرب %25 من جميع حاالت العدوى. وحوايل %60-50 من الن�شاء ي�شنب بعدوى امل�شالك البولية يف حياتهن. بكترييا اي كوالى هي اأكرث كائن ي�شبب عدوى امل�شالك البولية يف معظم املر�شى. العدوى مرة اأخرى هي ال�شبب االأ�شا�شي يف االإ�شابة بعدوى امل�شالك البولية املتكررة من قبل نف�س املري�س. اجلماع املتكرر هو واحد من اأعظم عوامل اخلطر لعدوى امل�شالك البولية املتكررة. يف جمموعة االأفراد امل�شابني بظروف مر�شية اإ�شافية، ميكن لعدوى امل�شالك البولية املتكررة اأن توؤدي اإىل التهابات امل�شالك العلوية اأو انتان بويل. على الرغم من اأن العالج االأويل هو العالج امل�شاد للميكروبات، ا�شتخدام نظم وقائية خمتلفة و ا�شرتاتيجيات بديلة، هي طرق متاحة للحد من التعر�س للم�شادات احليوية. مفتاح الكلمات: عدوى امل�شالك البولية؛ العالج؛ الوقاية با�شتخدام امل�شادات احليوية؛ الوقاية. abstract: urinary tract infections (utis) are one of the most frequent clinical bacterial infections in women, accounting for nearly 25% of all infections. around 50–60% of women will develop utis in their lifetimes. escherichia coli is the organism that causes utis in most patients. recurrent utis (ruti) are mainly caused by reinfection by the same pathogen. having frequent sexual intercourse is one of the greatest risk factors for rutis. in a subgroup of individuals with coexisting morbid conditions, complicated rutis can lead to upper tract infections or urosepsis. although the initial treatment is antimicrobial therapy, use of different prophylactic regimens and alternative strategies are available to reduce exposure to antibiotics. keywords: urinary tract infection, therapy; antibiotic prophylaxis; prevention. review recurrent urinary tract infections management in women a review *ahmed al-badr1 and ghadeer al-shaikh2 recurrent urinary tract infections management in women a review 360 | squ medical journal, august 2013, volume 13, issue 3 when infection occurs within an abnormal urinary tract, such as when there is ureteric obstruction, renal calculi, or vesicoureteric reflux. the third category, an isolated infection, is when it is the first episode of uti, or the episodes are 6 months apart. isolated infections affect 25–40% of young females. the fourth category, an unresolved infection, is when therapy fails because of bacterial resistance or due to infection by two different bacteria with equally limited susceptibilities. the fifth category, reinfection, occurs where there has been no growth after a treated infection, but then the same organism regrows two weeks after therapy, or when a different microorganism grows during any period of time.9,10 this accounts for 95% of rutis in women. bacterial persistence happens when therapy is impaired by the accumulation of bacteria in a location that cannot be reached by antibiotics, such as infected stones, urethral diverticula and infected paraurethral glands. the sixth category, relapse, is when the same microorganism causes a uti within two weeks of therapy; however, it is usually difficult to distinguish a reinfection from a relapse.11 epidemiology and pathophysiology utis are one of the most frequent clinical bacterial infections in women, accounting for nearly 25% of all infections. around 50–60% of women will experience a uti in their lifetime.2,9 the estimated number of utis per person per year is 0.5 in young females.12 recurrences usually occur within three months of the original infection, and 80% of rutis are reinfections.13 the incidence of uti increases with age and sexual activity.14 post-menopausal women have higher rates of utis because of pelvic prolapse, lack of oestrogen, loss of lactobacilli in the vaginal flora, increased periurethral colonisation by escherichia coli (e. coli), and a higher incidence of medical illnesses such as diabetes mellitus (dm).15 the microorganism that causes rutis is similar, in most cases, to the sporadic infection. most uropathogens from the rectal flora ascend to the bladder after colonising the periurethral area and urethra. despite the fact that most e. coli are eradicated by the host defence mechanisms within days, only small clusters of intracellular e. coli are observed to persist for several months in an antibioticresistant state.16 reactivation of uropathogenic e. coli (upec), an intracellular bacteria, could cause rutis.17 other significant pathogens that can cause uti include proteus mirabilis, staphylococcus saprophyticus, staphylococcus epidermidis, and klebsiella pneumonia.18 in diabetic patients, klebsiella and group b streptococcus infections are more common. pseudomonas infections are more common in chronically-catheterised patients.18,19 risk factors for ruti in sexually-active premenopausal women are the onset of symptoms shortly after sexual intercourse, the use of spermicides for contraception, taking on new sexual partners, the age of the first uti, a maternal history of uti and voiding dysfunction.5,8,20,21 many other factors have been thought to predispose women to rutis, such as voiding patterns pre and post-coitus, wiping technique, wearing tight undergarments, deferred voiding habits and vaginal douching; nevertheless, there has been no proven association.22 medical conditions such as pregnancy, dm and immunosuppression increase a woman’s risk of ruti by facilitating the access of uropathogens overcoming normal host defense mechanisms.23 patients with dm have a higher risk of asymptomatic bacteriuria, rutis and pyelonephritis.24 clinical presentation and diagnosis common symptoms of a uti are dysuria, urinary frequency, urgency, suprapubic pain and possible haematuria. systemic symptoms are usually slight or absent. the urine may have an unpleasant odour and appear cloudy.23 diagnosis of ruti depends on the characteristic of clinical features, past history, three positive urinary cultures within the previous 12-month period in symptomatic patients and the presence of neutrophils in the urine (pyuria).7,8,21 irritative voiding symptoms are present in 25–30 % of women with rutis.25 the probability of finding a positive culture in the presence of the above symptoms and the absence of vaginal discharge is around 81%.26 in a complicated uti, such as pyelonephritis, the symptoms of a lower uti will persist for more than a week with systemic symptoms of persistent fever, chills, nausea and ahmed al-badr and ghadeer al-shaikh review | 361 saprophyticus lack that enzyme, which makes the nitrite test considerably less useful. dipstick analysis for leukocyte esterase (the enzyme produced by neutrophils) is indirect and is the least expensive test that detects pyuria with a sensitivity of 72–97% and a specificity of 41–86%, as organisms other than uropathogens can also produce leukocyte esterase.31 more advanced investigations, such as cystoscopy, are advised in women over the age of 50.32 ultrasound of the kidneys, an intravenous pyelogram (ivp) and a computed tomography (ct) scan can help in detecting congenital structural urogenital anomalies.9 management of recurrent urinary tract infections (rutis) c o u n s e l l i n g women with rutis should be educated about the characteristics of reinfection and relapse; the proper way to practice post-coital voiding; the importance of avoiding skin allergens, tight clothing and bubble baths; ways to ensure personal hygiene, and the choice of alternative forms of contraception rather than spermicides.21,33,34 g e n e r a l t h e r a p i e s patients should be advised and encouraged to drink plenty of fluids (two to three litres per day) and to urinate frequently to help flush bacteria from the bladder. holding urine for a long time allows bacteria to multiply within the urinary tract, resulting in cystitis. preventive measures related to sexual intercourse may reduce the recurrence rate. moreover, women are encouraged to clean the genital areas before and after sex and to wipe from front to back, which will reduce the spread of e. coli from the perigenital area to the urethra.35 avoiding multiple sexual partners will reduce the risk of both utis and sexually transmitted infections. women are encouraged to avoid spermicidal contraceptives, diaphragms and vaginal douching, which may irritate the vagina and urethra and facilitate the entry and colonisation of bacteria within the urinary tract. skin allergens introduced to the genital area, such as bubble bath liquids, bath oils, vaginal creams and lotions, deodorant sprays or soaps are better avoided as they could alter vaginal flora and vomiting.25 a recent study showed how to distinguish the clinical symptoms of a ruti from irritative voiding symptoms (urgency, dysuria and frequency) without infection. women with rutis were more likely to experience symptoms after intercourse, have a previous history of pyelonephritis, and experience rapid resolution of symptoms postantibiotic therapy than those women with irritative voiding symptoms.5,6 moreover, women with rutis were more unlikely to report nocturia and have symptoms between episodes of uti than women without infection. the presence of irritative voiding symptoms between perceived episodes of uti suggests a non-infectious cause as seen in interstitial cystitis, urethral syndrome or detrusor muscle overactivity.5,27 women with rutis should have an initial evaluation including a history-taking and a physical and pelvic examination; the latter is important to detect pelvic organ prolapse and to assess the status of the vaginal epithelium.28 urinalysis and urine culture with sensitivity are also valuable investigations. women with a positive family history of dm, obesity or ruti must be screened for dm.28,29 women with suspected urine retention need to be evaluated for high post-void residual urine volume. urine culture and sensitivity testing are the standard diagnostic investigations to detect the causative organism and to determine the type of antimicrobial therapy needed.8,21 a uti is defined as a positive urine culture with greater than 100,000 colony-forming units (cfu)/ml. in acute cystitis, even 1,000 cfu/ml and in acute pyelonephritis 10,000 cfu/ml may be sufficient for diagnosis in a symptomatic patient. a urine culture is recommended in a ruti or in the presence of complicating factors.9,21 a urine culture can remain positive for more than two weeks even after treatment in cases of chronic utis or rutis. a ‘clean-catch’ or midstream technique needs to be used when collecting the urine sample, which reduces the risk of vaginal and skin contamination to approximately 30%.30 urinalysis, either by dipstick or microscopy, for the detection of pyuria, as a method for predicting a uti has a sensitivity of 80–90% and a specificity of 50%, but it only detects those bacteria which reduce nitrates to nitrites in the urine. bacteria such as staphylococcus recurrent urinary tract infections management in women a review 362 | squ medical journal, august 2013, volume 13, issue 3 ultimately result in utis.36 a n t i m i c r o b i a l t h e r a p y antimicrobial therapy is the core treatment for utis, with the main objective being the eradication of bacteria growth in the urinary tract through an efficacious, safe and cost-effective antimicrobial agent. this can be achieved within hours if the antibiotics are maintained at sufficient urine levels.37 in order to ensure compliance and be patient-friendly, the drug should be given for a short period of time to prevent bacterial resistance. antimicrobial agents should be prescribed according to the susceptibility of the infecting bacteria, the concentrations of uropathogens in the urine and the urinary complaint. this is important to consider when there is septicaemia or parenchymal infection, as antimicrobials are usually at higher levels in the urine than in serum.33 dose modification is required for patients with renal insufficiency and in the case of other factors such as: age, pregnancy or lactation status, primary or recurrent infections, hospitalised patients, dm, liver disease, an immuncompromised state, hydration levels and psychiatric problems.34 a variety of antimicrobials are used for the prevention and management of rutis.6,15,24,29,33,38–41 a cochrane review has shown that antibiotics in comparison to a placebo are more effective in preventing recurrences in preand postmenopausal women with rutis.6 the criteria for the selection of the most effective antibiotic depend on a patient’s pattern of resistance, adverse effects, interaction with drugs and cost. ampicillin, amoxicillin, and sulfonamides are no longer the drugs of choice for empirical treatment because of the widespread emergence of resistance in 15–20% of e. coli in several areas of the usa and other countries.18,42–44 nitrofurantoin or amoxicillin/clavulanic acid remain effective in terms of bacterial sensitivity, but nitrofurantoin needs to be avoided in patients with pyelonephritis because of its poor serum and tissue levels. less than 5% of e. coli strains are resistant to nitrofurantoin, whereas other strains are often resistant to it. the rate of e. coli resistance to fluoroquinolones, even in uncomplicated utis, varies between countries with rates reported as 0.5–7.6% in europe,45 15% in korea,46 and up to 35% in some parts of india.47 penicillins and cephalosporins are considered safe during pregnancy, but trimethoprim, sulphonamides, and fluoroquinolones should be avoided. oral antibiotic therapy resolves 94% of uncomplicated utis, although recurrence is not uncommon. in the recently published international clinical practice guidelines for the treatment of acute cystitis, a 3-day regimen of trimethoprimsulfamethoxazole (tmp-smx) and a 5-day course of nitrofurantoin are recommended as a first-line therapy for the management of uncomplicated utis. a 5-day course of nitrofurantoin has an efficacy equivalent to a 3-day tmp-smx course.48,49 a 3to 7-day regimen of beta-lactams, such as cefaclor or amoxicillin/clavulanic acid, is appropriate when first-line therapies cannot be used.43,48 although a 3-day course of fluoroquinolones can be quite effective, it is not usually recommended as first-line therapy because of the emerging resistance to them and their potential side effects, as well as the high cost; nevertheless, fluoroquinolones are the drug of choice in women who are experiencing low tolerance or an allergic reaction after empirical therapy.48,50 in a meta-analysis, a single-dose regimen of fosfomycin trometamol has been shown to be a safe and effective alternative for the treatment of utis in both pregnant and non-pregnant women, as well as in elderly and paediatric patients, but it seems to be slightly less effective than the above mentioned therapies.43,48,51 pivmecillinam in a 3 to 7-day course is also effective, but not available in most regions. because of its poor efficacy, amoxicillin and ampicillin should not be used for the empirical treatment of utis.48 tmp-smx and fluoroquinolones prevent ruti by inhibiting the recovery rate of uropathogens (especially e. coli) from the faecal reservoir,52 while nitrofurantoin plays its role in the treatment of ruti by sterilising the urine and inhibiting bacterial attachment.24,53,54 a follow-up urinalysis and urine culture, also called the ‘test of cure’, is not indicated in women with uncomplicated utis, but should be performed in those women who are suffering from rutis or a complicated uti. different antibiotic prophylaxis regimens such as continuous prophylaxis, post-coital prophylaxis and acute self-treatment are important management strategies in preventing rutis. patient selftreatment is recommended in cases of those with ≤2 episodes of utis per year, whereas continuous ahmed al-badr and ghadeer al-shaikh review | 363 adjuvant measures o e s t r o g e n oestrogen use stimulates the proliferation of lactobacillus in the vaginal epithelium, reduces ph and avoids vaginal colonisation by uropathogens. after the menopause, oestrogen levels and lactobacilli numbers drop; this plays a significant role in the development of bacteriuria, and makes post-menopausal women susceptible to utis. vaginal oestrogen use reduces rutis by 36–75% and has minimal systemic absorption. based on a cochrane review in post-menopausal women with rutis, when compared to a placebo, vaginal oestrogens were found to prevent rutis, but oral oestrogen did not have the same effect.59,60 local oestrogen cream twice a week and an oestradiolreleasing vaginal ring are both effective in reducing ruti attacks.59,61,62 they restore vaginal flora, reduce ph and therefore reduce utis; however, the reappearance of vaginal lactobacilli takes at least 12 weeks when using an oestrogen vaginal ring.61– 63 although evidence does not support using a particular type or form of vaginal oestrogen topical creams are cheaper than an oestradiol-releasing vaginal ring but have more side effects.21,57,59,64 c r a n b e r r y j u i c e a n d ta b l e t s cranberry juice and tablets have been shown to reduce rutis as they contain a compound called tannin, or proanthocyanidin, which reduces e. coli vaginal colonisation.65,66 although earlier, smaller studies have shown that consuming cranberry juice or tablets can prevent rutis, an updated cochrane review showed that evidence for its benefit in preventing utis is small; therefore, cranberry juice cannot be recommended any longer for uti prevention.21,67–69 a c u p u n c t u r e recent studies indicate that the rate of cystitis among cystitis-prone women treated with acupuncture was one-third the rate of that among untreated women and half the rate among women treated by sham acupuncture. therefore, acupuncture may prevent rutis in healthy adult women.21,70,71 p r o b i o t i c s probiotics are beneficial microorganisms that could protect against utis. lactobacilli strains are the antimicrobial prophylaxis, low-dose prophylaxis, or post-coital prophylaxis is generally considered in ≥3 episodes of utis annually.24 c o n t i n u o u s a n t i b i o t i c p r o p h y l a x i s continuous prophylaxis is considered when simple measures fail. for this purpose, low-dose antibiotics can be given daily for 6 months or longer. some physicians advise prophylaxis on alternate nights or 3 nights per week. one study showed that prophylaxis given weekly was more effective than one given monthly, but there is no study comparing daily and weekly regimes.6,21,55 p o s t-c o i ta l a n t i b i o t i c p r o p h y l a x i s when a ruti is related to sexual activity, post-coital therapy is considered an effective alternative prophylactic approach.21,28,56 postintercourse prophylaxis has fewer side effects than daily prophylaxis, as antibiotic consumption is reduced to only one-third.53 after intercourse, a single dose of the most common antibiotics is used, such as nitrofurantoin, tmp-smx or a fluoroquinolone.21,54 studies have shown that women using continuous or post-coital prophylaxis will report about 1.2 to 1.3 utis per year within 6 months of stopping the treatment.6 a c u t e s e l f-t r e at m e n t the patient self-treatment management strategy is an ideal effort to decrease overall antibiotic consumption, and for women who are not suitable candidates for long-term daily prophylaxis. schaeffer showed that “self-start therapy” should be confined to those women who are self-motivated and have good compliance.57 a patient needs to consult a physician immediately if she becomes pregnant or if there is any change in symptoms, an increased recurrence of episodes of infection, or no change in symptoms within 48 hours of antimicrobial treatment. these patients can effectively self-treat rutis by initiating a standard 3 day course of recommended antimicrobials with minimum side effects.58 recurrent urinary tract infections management in women a review 364 | squ medical journal, august 2013, volume 13, issue 3 best-known probiotics and are found in fermented milk products, mainly yogurt. other probiotics include lactobacilli bifidobacteria, rhamnosus, casei, planetarium, bulgaricus and salivarius; streptococcus thermophiles and enterococcus faecium. reid et al. showed in vitro that lactobacillus can prevent uropathogen infections.72,73 other trials have showed that l. rhamnosus gr-1 and l. fermentum rc-14 can colonise the vagina, which could subsequently prevent utis. nevertheless, more clinical studies need be carried out to determine their role in ruti prevention.72–76 i m m u n o p r o p h y l a x i s immunoprophylaxis taken orally may prove an effective alternative to antibiotics in the prevention of rutis. a meta-analysis of 5 studies showed that oral immunoprophylaxis with the uro-vaxom® e. coli extract (terra-laba, zagreb, croatia) taken for a period of 3 months was effective in preventing rutis over a period of 6 months.77 another doubleblind study has confirmed that e. coli extracts are efficient and well-tolerated in the treatment of utis, reducing the need for antibiotics and preventing rutis.78 other therapies methenamine hippurate is used for prophylaxis and treatment of rutis. methenamine is hydrolysed to ammonia and formaldehyde when in acidic urine, which act as a bactericide to some strains of bacteria.79 they are well-tolerated and have mild adverse effects, such as gastrointestinal upsets, rashes, anorexia, and stomatitis. patients should be informed regarding adequate hydration, adverse effects and the need to avoid milk products and antacids to help keep the urine acidic. a recent cochrane review on the use of methenamine hippurate concluded that short-term use is effective in preventing rutis in patients with a normal renal tract. nevertheless, it is not effective in women who have urinary tract abnormalities or a neuropathic bladder.80,81 recurrent urinary tract infection in pregnancy uti is the most frequent medical complication of pregnancy. the risk factors of preterm delivery, low infant birth weight and abortions are most commonly associated with symptomatic and asymptomatic bacteriuria during pregnancy.77 in pregnancy, factors that contribute to uti risk are ureteric and renal pelvis dilation; increased urinary ph; decreased muscle tone of the ureters, and glycosuria, which promotes bacterial growth. treatment of asymptomatic bacteriuria in pregnancy reduces the risk of pyelonephritis. as rutis are common in pregnancy, they need prophylactic treatment if they occur. screening for bacteriuria is recommended in all pregnant women at their first prenatal visit and then in the third trimester.82,83 they should subsequently be treated with antibiotics such as nitrofurantoin, sulfisoxazole or cephalexin.21,24,82–84 antibiotic prophylaxis for ruti in pregnant women is effective using continuous or post-coital regimens. the causative organisms of uti in pregnancy are similar to those found in non-pregnant patients, with e. coli accounting for 80–90% of infections.85,86 urinary group b streptococcal infections in pregnant women need to be treated and followed by intrapartum prophylaxis.21 conclusion utis are some of the most frequent clinical bacterial infections in women. rutis are less common and are mainly caused by reinfection by the same pathogen. women with rutis need to be properly investigated by urinalysis, urine cultures and other radiological techniques in order to rule out causes of recurrence, as well as to assess possible anatomical or functional urinary tract abnormalities. although standard uti therapy starts with antimicrobial therapy, alternative strategies are available to reduce exposure to antibiotics, such as the use of methenamine salts, probiotics, cranberry juice, immunoprophylaxis and vaginal oestrogens in post-menopausal women. continuous antibiotic prophylaxis, postcoital prophylaxis, and acute selftreatment are cost-effective treatment strategies for reducing the number of rutis in some patients. ahmed al-badr and ghadeer al-shaikh review | 365 304:1062–6. 17. rosen da, hooten tm, stamm we, humphrey pa, hultgren sj. detection of intracellular bacterial communities in human urinary tract infection. plos med 2007; 4:e329. 18. gupta k, hooton tm, naber kg, wullt b, colgan r, miller lg, et al. infectious diseases society of america; european society for microbiology and infectious diseases. international clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the infectious diseases society of america and the european society for microbiology and infectious diseases. clin infect dis 2011; 52:e103–20. 19. ronald a. the etiology of urinary tract infection: traditional and emerging pathogens. am j med 2002; 113:14–19s. 20. scholes d, hooton tm, roberts pl, stapleton ae, gupta k, stamm we. risk factors for recurrent urinary tract infection in young women. j infect dis 2000; 182:1177–82. 21. epp a, larochelle a, lovatsis d, walter je, easton w, farrell sa, et al. recurrent urinary tract infection. j obstet gynaecol can 2010; 32:1082–101. 22. scholes d, hooton tm, roberts pl, stapleton ae, gupta k, stamm we. risk factors for recurrent urinary tract infection in young women. j infect dis 2000; 182:1177–82. 23. franco vma. recurrent urinary tract infections. best pract & research clinical obstet gynecol 2005; 19:861–73. 24. stapleton a, stamm we. prevention of urinary tract infection. infect dis clin north am 1997; 11:719– 33. 25. stamm we, wagner kf, amstel r. causes of acute urethral syndrome in women. n engl j med 1980; 303:409–15. 26. bent s, nallamothu bk, simel dl, fihn sd, saint s. does this woman have an acute urinary tract infection? jama 2002; 287:2701–10. 27. iosif cs, bekassy z. prevalence of genitourinary symptoms in the late menopause. acta obstet gynecol scand 1984; 63:257–60. 28. car j, sheikh a. recurrent urinary tract infection in women. bmj 2003; 327:1204. 29. hooton tm. recurrent urinary tract infection in women. int j antimicrobial agents 2001; 17:259–68. 30. lifshitz e, kramer l. outpatient urine culture. does collection technique matter? arch intern med 2000; 160:2537–40. 31. simerville ja, maxted wc, pahira jj. urinalysis: a comprehensive review. am fam physician 2005; 71:1153–62. 32. lawrentschuk n, ooi j, pang a, naidu ks, bolton dm. cystoscopy in women with recurrent urinary references 1. rahn dd. urinary tract infections: contemporary management. urol nurs 2008; 28:333–41. 2. foxman b, barlow r, d’arcy h, gillespie b, sobel jd. urinary tract infection: self-reported incidence and associated costs. ann epidemiol 2000; 10:509–15. 3. foxman b. epidemiology of urinary tract infections: incidence, morbidity, and economic costs. am j med 2002; 113:5–11s. 4. mignini l, carroli g, abalos e, widmer m, amigot s, nardin jm, et al. world health organization asymptomatic bacteriuria trial group. accuracy of diagnostic tests to detect asymptomatic bacteriuria during pregnancy. obstet gynecol 2009; 113:346– 52. 5. mohsin r, siddiqui km. recurrent urinary tract infections in females. j pak med assoc 2010; 60:55– 9. 6. albert x, huertas i, pereiro i, sanfelix j, gosalbes v, perrotta c. antibiotics for preventing recurrent urinary tract infection in non-pregnant women. cochrane database syst rev 2004; 3:cd001209. 7. gopal m, northington g, arya l. clinical symptoms predictive of recurrent urinary tract infections. am j obstet gynecol 2007; 197:74.e1–4. 8. foster rt sr. uncomplicated urinary tract infections in women. obstet gynecol clin north am 2008; 35:235–48. 9. american college of obstetricians and gynecologists. acog practice bulletin no. 91: treatment of urinary tract infections in nonpregnant women. obstet gynecol 2008; 111:785–94. 10. karram mm, mallipeddi pk. lower urinary tract infection. in: walters md, karram mm, eds. urogynecology & reconstructive pelvic surgery, 2nd ed. st louis: mosby, 1999. pp. 341–53. 11. o'reilly m. recurrent urinary tract infection. in: stanton sl, dwyer pl, eds. urinary tract infection in the female. london: martin dunitz, 2000. pp. 227–40. 12. hooton tm. a prospective study for risk factors for symptomatic urinary tract infection in young women. n engl j med 1996; 335:468. 13. gupta k, stamm we. pathogenesis and management of recurrent urinary tract infections in women. world j urol 1999; 17:415–20. 14. stapleton a. prevention of recurrent urinary-tract infections in women. lancet 1999; 353:7–8. 15. jackson sl, boyko ij, scholes d, abraham l, gupta k, fihn sd. predictors of urinary tract infection after menopause. am j med 2004; 117:903. 16. schaeffer aj, jones jm, dunn jk. association of vitro escherichia coli adherence to vaginal and buccal epithelial cells with susceptibility of women to recurrent urinary tract infection. n engl j med 1981; recurrent urinary tract infections management in women a review 366 | squ medical journal, august 2013, volume 13, issue 3 tract infection. int j urol 2006; 13:350–3. 33. jacobson sh. a five-year prospective follow-up of women with non-obstructive pyelonephritic renal scarring. scand j urol nephrol 1991; 25:51–3. 34. rocco f, franchini v. antimicrobial therapy for treatment of uti in the elderly. eur urol 1991; 19:7– 15. 35. hooton tm, scholes d, hughes jp, winter c, roberts pl, stapleton ae, et al. a prospective study of risk factors for symptomatic urinary tract infection in young women. n engl j med 1996; 335:468–74. 36. foxman b, chi jw. health behavior and urinary tract infection in college-aged women. j clin epidemiol 1990; 43:329–37. 37. hooton tm, stamm we. management of acute uncomplicated urinary tract infection in adults. med clin north am 1991; 75:339–57. 38. reid g. potential preventive strategies and therapies in urinary tract infection. world j urol 1999; 17:359– 63. 39. orenstein r, wong es. urinary tract infections in adults. am fam physician 1999; 59:1225–34, 1237. 40. dwyer pl, o’reilly m. recurrent urinary tract infection in the female. curr opin obstet gynecol 2002; 14:537–43. 41. nicolle le. urinary tract infection: traditional pharmacologic therapies. am j med 2002; 113:35– 44s. 42. drekonja dm, johnson jr. urinary tract infections. prim care 2008; 35:345–67. 43. hooton tm, stamm we. diagnosis and treatment of uncomplicated urinary tract infection. infect dis clin north am 1997; 11:551–81. 44. gupta k, scholes d, stamm we. increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis. j am med assoc 1999; 281:736–8. 45. kahlmeter g, poulsen ho. antimicrobial susceptibility of escherichia coli from communityacquired urinary tract infections in europe: the eco*sens study revisited. int j antimicrob agents 2012; 39:45–51. 46. shin j, kim j, wie sh, cho yk, lim sk, shin sy, et al. fluoroquinolone resistance in uncomplicated acute pyelonephritis: epidemiology and clinical impact. microb drug resist 2012; 18:169–75. 47. rizvi m, khan f, shukla i, malik a, shaheen. rising prevalence of antimicrobial resistance in urinary tract infections during pregnancy: necessity for exploring newer treatment options. j lab physicians 2011; 3:98–103. 48. warren jw, abrutyn e, hebel jr, johnson jr, schaeffer aj, stamm we. guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. clin infect dis 1999; 29:745–58. 49. gupta k, hooton tm, roberts ms, stamm we. short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women. arch intern med 2007; 167:2207–12. 50. wright sw, wrenn kd, haynes ml. trimethoprimsulfamethoxazole resistance among urinary coliform isolates. j gen intern med 1999; 14:606–9. 51. falagas me, vouloumanou ek, togias ag, karadima m, kapaskelis am, rafailidis p, et al. fosfomycin versus other antibiotics for the treatment of cystitis: a meta-analysis of randomized controlled trials. j antimicrob chemother 2010; 65:1862–77. 52. stamm we, counts gw, wagner k, martine d, gregory d, mckevitt m, et al. antimicrobial prophylaxis of recurrent urinary tract infections: a double-blind, placebo-controlled trial. ann intern med 1980; 92:770–5. 53. nicolle le. prophylaxis: recurrent urinary tract infections in women. infection 1992; 20:s203–5. 54. zhanel gg, nicolle le. effects of sub-inhibitory antimicrobial concentration (sub-mics) on invitro bacterial adherence to uroepithelial cells. j antimicrob chemother 1992; 29:617–27. 55. guibert j, humbert g, meyrier a, jardin a, vallancien g, piccoli s, et al. antibioprevention of recurrent cystitis. a randomized double-blind comparative trial of 2 dosages of pefloxacin. presse med 1995; 24:213–6. 56. stapleton a, latham rh, johnson c, stamm we. postcoital antimicrobial prophylaxis for recurrent urinary tract infection: a randomized, double-blind, placebo-controlled trial. jama 1990; 264:703–6. 57. schaeffer aj, stuppy ba. efficacy and safety of selfstart therapy in women with recurrent urinary tract infections. j urol 1999; 161:207–11. 58. engel jd, schaeffer aj. evaluation of and antimicrobial therapy for recurrent urinary tract infections in women. urol clin north am 1998; 25:685–701. 59. perrotta c, aznar m, mejia r, albert x, ng cw. oestrogens for preventing recurrent urinary tract infection in postmenopausal women. cochrane database syst rev 2008; 16:cd005131. 60. brown js, vittinghoff e, kanaya am, agarwal sk, hulley s, foxman b. heart and estrogen/progestin replacement study research group. urinary tract infections in postmenopausal women: effect of hormone therapy and risk factors. obstet gynecol 2001; 98:1045–52. 61. raz r, stamm we. a controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. n engl j med 1993; 329:753– 6. 62. eriksen b. a randomized, open, parallel-group study on the preventive effect of an estradiol-releasing ahmed al-badr and ghadeer al-shaikh review | 367 75. baerheim a, larsen e, digranes a. vaginal application of lactobacilli in the prophylaxis of recurrent urinary tract infection in women. scand j prim health care 1994; 12:239–43. 76. falagas me, betsi gi, tokas t, athanasiou s. probiotics for prevention of recurrent urinary tract infections in women. drugs 2006; 66:1253–61. 77. kul'chavenia ev, breusov aa. efficacy of uro-vaxom in recurrent infectious-inflammatory diseases of the urogenital system. urologia 2011; 4:7–11. 78. schulman cc, corbusier a, michiels h, taenzer hj. oral immunotherapy of recurrent urinary tract infections: a double-blind placebo-controlled multicenter study. j urol 1993; 150:917–21. 79. mayrer ar, andriole vt. urinary tract antiseptics. med clin north am 1982; 66:199–208. 80. mims malaysia. hiprex. from: http://www.mims. com/malaysia/drug/info/hiprex/. accessed dec 2012. 81. lee bs, bhuta t, simpson jm, craig jc. methenamine hippurate for preventing urinary tract infections. cochrane database syst rev 2012; 10:cd003265. 82. hooton tm, stamm we. urinary tract infections and asymptomatic bacteriuria in pregnancy. uptodate, 2007. from: http://obgyndo.com/ resources/rotating-residents/intern-uptodateuti-and-asymptomatic-bacteriuria-in-pregnancy. pdf accessed: dec 2012. 83. romero r, oyarzun e, mazor m, sirtori m, hobbins jc, bracken m. meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight. obstet gynecol 1989; 73:576–82. 84. pfau a, sacks tg. effective prophylaxis for recurrent urinary tract infections during pregnancy. clin infect dis 1992; 14:810–14. 85. smaill fm, vazquez jc. antibiotics for asymptomatic bacteriuria in pregnancy. cochrane database syst rev 2007; 2:cd000490. 86. sheiner e, maxor-drey e, levy a. asymptomatic bacteriuria during pregnancy. j matern fetal neonat med 2009; 22:423–7. vaginal ring (estring) on recurrent urinary tract infections in postmenopausal women. am j obstet gynecol 1999; 180:1072–9. 63. raz r. hormone replacement therapy or prophylaxis in postmenopausal women with recurrent urinary tract infection. j infect dis 2001; 183:s74–6. 64. cardozo l, lose g, mcclish d, versi e, de koning gans h. a systematic review of estrogens for recurrent urinary tract infections: third report of the hormones and urogenital therapy (hut) committee. int urogynecol j pelvic floor dysfunct 2001; 12:15– 20. 65. schmidt dr, sobota ae. an examination of the antiadherence activity of cranberry juice on urinary and non-urinary bacterial isolates. microbios 1988; 55:173–81. 66. zafriri d, ofek i, adar r, pocino m, sharon n. inhibitory activity of cranberry juice on adherence of type 1 and type p fimbriated escherichia coli to eucaryotic cells. antimicrob agents chemother 1989; 33:92–8. 67. jepson rg, craig jc. cranberries for preventing urinary tract infections. cochrane database syst rev 2008; 1:cd001321. 68. sen a. recurrent cystitis in non-pregnant women. clinical evidence 2006; 15:2558–64. 69. sheffield js, cunningham fg. urinary tract infection in women. obstet gynecol 2005; 106:1085–92. 70. aune a, alreak t, lihua h, baerheim a. acupuncture in the prophylaxis of recurrent lower urinary tract infection in adult women. scand j prim health care 1998; 16:37–9. 71. alraek t, soedal lif, fagerheim su, digranes a, baerheim a. acupuncture treatment in the prevention of uncomplicated recurrent lower urinary tract infections in adult women. am j public health 2002; 92:1609–11. 72. reid g, bruce aw. probiotics to prevent urinary tract infections: the rationale and evidence. world j urol 2006; 24:28–32. 73. reid g, bruce aw, taylor m. instillation of lactobacilli and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. microecol ther 1995; 23:32–45. 74. uehara s, monden k, nomoto k, seno y, kariyama r, kumon h. a pilot study evaluating the safety and effectiveness of lactobacillus vaginal suppositories in patients with recurrent urinary tract infection. int j antimicrob agents 2006; 28:s30–4. sir, eccrine syringofibroadenoma (es) was first described by mascaro in 19631 and is an uncommon tumour of the acrosyringium. several types of eccrine and apocrine tumours are observed in the eyelids, but es has not been reported previously on the eyelid. an 84-year-old man attended the eye clinic at rovereto hospital, trentino, italy, with a solitary, slowly growing, well-circumscribed, soft ovoid nodule mass (8 mm diameter) in the right upper eyelid. the overlying epithelium was intact. the lesion had been present for several years, and no recent change had been noticed. the tumour was removed. the lesion appeared to be arising at the eyelid margin, close to the mucocutaneous junction. the lesion was characterised by multiple downgrowths of squamoid or cuboidal epithelial cells which had anastomosed around a bland fibroblastic stroma. in many areas, there were appreciable formations of multiple small ductal structures by these epithelial downgrowths, as well as multifocally-scattered mucinous cells [figure 1]. no evidence of malignancy was found. a diagnosis of es was determined. the patient was free of disease 12 months after the excision. es usually affects the extremities of elderly individuals, either as a solitary or multiple tumours. multiple lesions have been reported in association with schöpf-schulz-passarge syndrome and clouston syndrome.2,3 in our patient, no features of these syndromes were found. the overall appearance of es incorporates aspects of mammary fibroadenoma as well as fibroepithelioma of pinkus (fibroepitheliomatous basal cell carcinoma). the stroma is likely ‘induced’ by the epithelial proliferation. it has been suggested that es is identical to the acrosyringeal nevus of weedon and lewis,4 but there do appear to be some clinicopathological differences. es is a benign lesion, and complete excision is the treatment of choice. *teresa pusiol, maria-grazia zorzi, alice morini institute of anatomic pathology, rovereto hospital, rovereto, trentino, italy *corresponding author e-mail: teresa.pusiol@apss.tn.it references 1. mascaro jm. considérations sur les tumeurs fibroépithéliales: le syringofibroadénome eccrine. ann derm syphiligr 1963; 90:146. 2. starink tm. eccrine syringofibroadenoma: multiple lesions representing a new cutaneous marker of the schöpf syndrome, and solitary nonhereditary tumors. j am acad dermatol 1997; 36:569–76. 3. clouston hr. a hereditary ectodermal dystrophy. can med assoc j 1929; 21:18–31. 4. weedon d, lewis j. acrosyringeal nevus. j cutan pathol 1977; 4:166–8. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 328, epub. 9th may 13 submitted 31st oct 12 accepted 10th nov 12 ورم غدي ليفي ناتح يف جفن العني eccrine syringofibroadenoma of the eyelid letter to editor figure 1: the neoplasm (under haematoxylin and eosin stain and x 40 magnification) was composed of elongated cords growing downward in a fenestrated pattern, embedded in the fibroblastic stroma. letter to editor | 328 sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e152-154, epub. 7th apr 14 submitted 20th nov 13 revision req. 13th feb 14; revision recd. 14th feb 14 accepted 16th feb 14 renal function is an indication of the state of the kidney and its role in renal physiology. various conditions, diseases and drugs can affect the function of the kidneys. in clinical practice, plasma concentrations of the waste substances of creatinine and urea as well as electrolytes are used by physicians to determine renal function. although these measures are adequate to determine whether a patient is suffering from kidney disease, blood urea nitrogen (bun) and creatinine will not be raised above the normal range until 50% of total kidney function is lost.1 hence, whenever renal disease is suspected or careful dosing of nephrotoxic drugs is required, the more accurate glomerular filtration rate (gfr), or its approximation by the creatinine clearance, is measured. the estimated glomerular filtration rate (egfr) does not diagnose any kidney disease but is a test to assess how well your kidneys are working. during last few decades, various equations have evolved in an attempt to precisely measure gfr. given squmj articles on gfr in this and the previous issue, this editorial will discuss the latest advances made in gfr estimation.2–4 the level of gfr is accepted as the most useful index of kidney function in both healthy and diseased states. the determination of the gfr is a cumbersome procedure, ideally involving inulin infusion and urine collection under very standardised conditions. gfr is also estimated by measuring the clearance of other exogenous filtration markers such as iothalamate, iohexol and 51chromium ethylene-diamine-tetra-acetic acid [51cr] edta or technetium-99m-diethylenetriaminepentacetic acid [99mtc] dpta. however, these methods are expensive and require exposure to radiation and compliance with strict regulatory guidelines, and thus have limited use in the routine laboratory settings. besides, these tests are performed only when accurate information on kidney function is mandatory. serum creatinine (cr), on the other hand, is freely filtered and has minimal tubular secretion and absorption. its estimation from random blood samples is simple and inexpensive. it has relatively good accuracy and, for precisely these reasons, it has become a valuable clinical tool for estimating gfr. in clinical practice, a rise in serum cr is used as a marker of reduced gfr, indicating it is inversely related with gfr. gfr can be estimated by measuring cr clearance using serum cr levels and a timed urine specimen. there are, however, limitations on the use of serum cr as an indirect filtration marker because of its biological variability, bias and non-specificity which affect cr measurement, medication effects, nutrition and the alterations in circulating serum cr produced by non-renal disease states. because of the differences in gfr range and cr production between the two populations—healthy people versus patients with chronic kidney disease (ckd)—the estimation of gfr by serum cr also differs between healthy people and patients with ckd. hence, there is a risk of overestimating the gfr as a result of these confounding factors; in addition, we know that the magnitude of the overestimation is not predictable.5 this proportional variation in the gfr is larger in populations with the disease than in populations without it. as a result, a larger proportion of the variation in serum cr levels among patients with the disease is due to a variation in the gfr, not to a variation in the other determinants as compared with healthy people. for example, among patients with the disease, a difference in levels of serum cr of 0.8 and 1.2 mg per decilitre (70.7 and 106.1 μmol per litre) probably reflects a difference in the gfr. in contrast, this same difference among healthy people more likely reflects a difference in muscle mass or protein intake rather than the gfr. when an estimating equation queen’s hospital, burton hospitals nhs foundation trust, burton upon trent, staffordshire, uk e-mail: anasrabbani@yahoo.com تطورات يف تقدير سرعة الرتشيح الكبييب اأن�س مالك الرباين editorial advances in glomerular filtration rate estimation malik a. rabbani malik a. rabbani editorial | e153 derived in a population with ckd is applied to a healthy population, the equation will overstate the strength of the relationship of the gfr with the level of serum cr. thus, in people with an unusually low or high estimated gfr, the measured gfr would tend to fall closer to the normal gfr of the population than the gfr estimates. despite these limitations, plasma cr is still measured as an estimate of the gfr in clinical practice, on the assumption that cr is completely filtered across the glomerulus and that cr production and excretion are constant. the limitations of cr clearance and inulin clearance have inspired researchers to seek out easy formulas to estimate gfr. the cockcroft and gault (c&g) formula is employed to measure cr clearance, using plasma cr concentration with a correction for age, sex and muscle mass.6 the c&g formula is effective only when plasma cr is in a steady state; it is also inaccurate in cases of liver disease, oedema and muscle wasting or extreme adiposity. it is important to remember that gfr estimation equations are mainly used for the systematic staging of ckd and should not be used in the setting of an acute rise in serum cr. the modification of diet in renal disease (mdrd) gfr equation is mostly used for the estimation of gfr. it often out-performs the c&g equation in populations with a low range of gfr.3 however, even this equation has several limitations, including age, disease state, and considerable variations in the standardisation of the serum cr assays. plasma cystatin c (cys c) was proposed some years ago as an alternative endogenous substance for serum cr in estimating the gfr because it has many properties of an ideal marker for gfr.7 cys c is claimed to be a promising marker to monitor glomerular dysfunction, having a higher sensitivity and specificity than serum cr and cr clearance for small changes in gfr.4 because of availability of immunonephelometric8 and immunoturbidimetric9 methods, which allow a rapid and precise routine measurement, cys c has become a subject of great interest. a number of studies comparing cys c with plasma cr have proved cystatin c is a more sensitive indicator of mild reductions of renal function than plasma cr.10 however, despite considerable evidence, its role as an alternate marker for estimating gfr is still limited in clinical practice. there are several reasons for this, for example, a general diffidence among clinicians, the absence of definitive cut-off values, conflicting results in clinical studies, no clear evidence on when and how to request the test, the poor commutability of results and no accurate examination of costs and of its routine use. despite these facts, there are certain cases where cr measurement is not appropriate; for example, cys c may be more reliable in cases with liver cirrhosis, beta thalassemia,4 morbid obesity and malnourished patients with a reduced muscle mass. this is true as we know that cys c is produced at a constant rate in all body cells, excreted by glomerular filtration and followed by catabolism in the tubular cells. besides, it is also now known that there are non-gfr determinants of its serum level11,12 and there are studies suggesting that cys c is less dependent upon muscle mass than cr, and therefore should provide more accurate estimate of gfr particularly in populations with differences in muscle mass.4,9–12 the more recent cr-based formula, the mayo clinic quadratic (mcq) equation13 and the chronic kidney disease epidemiology collaboration (ckd-epi) equation proposed in 200914 improve underestimation, a well-recognised fact seen with the mdrd formula in patients with preserved kidney function, as both mcq and ckd-epi were derived from populations that included subjects with normal renal function. the ckd-epi equation was developed in a pooled dataset from 10 studies that included participants of diverse clinical characteristics, with and without kidney disease, and validated in a separate dataset pooled from 16 additional studies.13 the ckd-epi equation was found to be more accurate than the mdrd study equation, in the 16 studies used for its validation, with lower bias especially at an estimated gfr greater than 60 ml/min per 1.73 m2; however, the precision was not substantially improved compared to the mdrd study equation.14 besides, there are weaknesses to this study, including relatively few participants older than 70 years of age and racial minorities other than black, incomplete data on diabetes type, immunosuppressive agents for transplantation, measures of muscle mass and other clinical conditions and medications that might affect serum cr independently from gfr. in addition, the ckd-epi equation does not overcome the limitations of serum cr as an endogenous filtration marker. moreover, a comparison between mdrd and mcq equations for gfr estimates provides significantly different results as the mcq estimate provides suspiciously high gfr values. however, only direct comparison using the costly and complex clearance of an exogenous marker could unequivocally confirm the superiority of one method over the other. despite these limitations, serum cr remains central at the present time for the evaluation of kidney function in clinical practice, and gfr estimates based on serum cr will continue to be used in clinical practice for the foreseeable future. advances in glomerular filtration rate estimation e154 | squ medical journal, may 2014, volume 14, issue 2 further research is necessary to improve gfr estimation. non-gfr determinants of cr seem to be responsible for imprecision in gfr estimation. measurement error in gfr also seems to contribute to this imprecision. research, therefore, should be directed not only towards improving gfr measurement but evaluating the novel filtration markers for gfr estimation, either alone or in combination with serum cr.15 moreover, studies in representative populations, especially the elderly and racial and ethnic minorities, are also necessary. in conclusion, significant advances have been made which have revolutionised our understanding of the performance and utilisation of gfr estimation in the current era. it is quite evident that a single equation will unlikely work equally well in all populations. however, given the current understanding, we believe, despite its limitations, that the new ckd-epi equation, which uses the same four variables as the mdrd study equation developed in people with and without kidney disease, has improved bias and risk prediction, without compromising the accuracy in people with ckd. it is an important step forward and should replace the mdrd study equation for routine clinical use. references 1. paige nm, nagami gt. the top 10 things nephrologists wish every primary care physician knew. mayo clin proc 2009; 84:180–6. doi: 10.1016/s0025-6196(11)60826-4. 2. al-maqbali srs, mula-abed w-as. comparison between three different equations for the estimation of glomerular filtration rate in omani patients with type 2 diabetes mellitus. sultan qaboos univ med j 2014; 14:184–90. 3. al-osali me, al-qassabi ss, al-harthi sm. assessment of glomerular filtration rates by cockcroft-gault and modification of diet in renal disease equations in a cohort of omani patients. sultan qaboos univ med j 2014; 14:70–7. 4. ali ba, mahmoud am. frequency of glomerular dysfunction in children with beta thalassaemia major. sultan qaboos univ med j 2014; 14:86–92. 5. mathew th, australasian creatinine consensus working group. chronic kidney disease and automatic reporting of estimated glomerular filtration rate: a position statement. med j aust 2005; 183:138–41. 6. jones gr, imam s. validation of the revised mdrd formula and the original cockcroft and gault formula for estimation of the glomerular filtration rate using australian data. pathology 2009; 41:379–82. doi: 10.1080/00313020902884980. 7. zhang z, lu b, sheng x, jin n. cystatin c in prediction of acute kidney injury: a systemic review and meta-analy. am j kidney dis 2011; 58:356–65. doi: 10.1053/j.ajkd.2011.02.389. 8. whicher jt, price cp, spencer k. immunonephelometric and immunoturbidimetric assays for proteins. crit rev clin lab sci 1983; 18:213–60. 9. schwartz gj, schneider mf, maier ps, moxey-mims m, dharnidharka vr, warady ba, et al. improved equations estimating gfr in children with chronic kidney disease using an immunonephelometric determination of cystatin c. kidney int 2012; 82:445–53. 10. madero m, sarnak mj, stevens la. serum cystatin c as a marker of glomerular filtration rate. curr opin nephrol hypertens 2006; 15:610–6. 11. stevens la, schmid ch, greene t, li l, beck gj, joffe mm, et al. factors other than glomerular filtration rate affect serum cystatin c levels. kidney int 2009; 75:652–60. doi: 10.1038/ ki.2008.638. 12. grubb a, bjork j, lindstrom v, sterner g, bondesson p, nyman u. a cystatin c-based formula without anthropometric variables estimates glomerular filtration rate better than creatinine clearance using the cockcroft-gault formula. scand j clin lab invest 2005; 65:153–62. 13. fontseré n, bonal j, salinas i, de arellano mr, rios j, torres f, et al. is the new mayo clinic quadratic equation useful for the estimation of glomerular filtration rate in type 2 diabetic patients? diabetes care 2008; 31:2265–7. doi: 10.2337/dc080958. 14. levey as, stevens la, schmid ch, zhang yl, castro af 3rd, feldman hi, et al. a new equation to estimate glomerular filtration rate. ann intern med 2009; 150:604–12. 15. lee d, levin a, roger sd, mcmahon lp. longitudinal analysis of performance of estimated glomerular filtration rate as renal function declines in chronic kidney disease. nephrol dial transplant 2009; 24:109–16. doi: 10.1093/ndt/gfn477. taurine levels in human aqueous humour medical sciences (2000), 2, 7−10 © 2000 sultan qaboos university 1department of microbiology and immunology, sultan qaboos university, p.o.box: 35, postal code: 123, muscat, sultanate of oman; 2department of tropical hygiene and public health and 3department of parasitology, university of heidelberg, im neuenheimer, feld 324, d – 69120 heidelberg, germany *to whom correspondence should be addressed. 7 antibodies against rickettsia in humans and potential vector ticks from dhofar, oman *idris m a1,2 , ruppel a2, petney t3 لها والقراد الناقل للريكتسياتاألجسام المضادة محافظة ظفارب بتني. روبل ، ت. إدريس ، أ. م تنتقل هذه الجرثوميات بواسطة أنواع مختلفة من المفصليات من بينها القراد مسببه أمراضًا مثل . واسعة أألنتشار تصيب أألنسان والحيوان عصيات بكتيرية الريكتسيات هي :الملخص آل من مصر ، سوريا ، باآستان ، إثيوبيا لقد تم إآتشاف اإلصابة بهذه الجرثوميات في منطقة الشرق األدنى في . ، حمى جبال الروآي البقعاء والحمى القرادية ) التيفوس(الحمى البقعاء عدوىلقد تم في هذه البحث مسح مصلى لألجسام المضادة. الريكتسيات بين األفراد في شبه الجزيرة العربية بما فيها سلطنة عمان عدوىحسب علمنا ال توجد معلومات عن . والصومال محافظة -ومراجعي العـيادة الخارجية بمدينة الحق ومزارعين بصاللة ) ، طوى إعتير ، ضلكوت و رخيوت بسدح( مصال تم جمعها من تالميذ المدارس 347الريكتسيات بفحص قرادة من 707أيضًا تم جمع ودراسة . الريكتسياتموجبة لألصابة ب من األمصال تحتوي أجسامًا % 59 البحث أن أثبتوقد تمت دراسة األجسام المضادة بطريقة التألق المناعي . ظفار ــوانًا 102 ــز ( حي ــ ـار وماعـ ـال ، أبقـ ــفار ) جمـ ـافظة ظـ ــن محـ ــواع . مــ ــمي ألن ــ ــراد وجد أنه ينـت ـيف الق دارســة وتصـن الحلميا ت المتغيرة الشكل، والقراد الزجاجي العين بأنواعه وـب .دل على إمكانية إنتشار اإلصابة بالريكتسيات بتلك المنطقةوجميع هذه األنواع من القراد يمكنها نقل العدوى مما ي. والقراد ذو الرأس المروحي abstract: ��������� to determine the extent of rickettsial infections prevalence of potential vector ticks in the rural population of dhofar, oman� ��� �� – human sera (n = 347) were obtained from six rural localities (school children, farmers, outpatients) in dhofar, sultanate of oman. sera were tested by immunofluorescence for the presence of antibodies reacting with rickettsia conorii antigen. ������� – more than half the samples (59%) gave positive reactions (titres of at least 1:64). ticks (n=707) were collected from cattle, camels and goats (n=102) and included amblyomma variegatum, hyalomma a. anatolicum, h. dromedarii, h. rufipes and rhipicephalus spp., all of which can potentially transmit rickettsiae to humans. ���������� – the results suggest that rickettsial infections are common among the rural population of dhofar. key words: rickettsia, antibodies, immunofluorescence, vector ticks, cattle, camels, goats, dhofar, oman ickettsial infections of man are widely distributed.1 they cause several forms of disease including spotted fevers, which are transmitted by ticks. in the near east, the presence of spotted fever rickettsiae as pathogens of man is well documented for israel and egypt2-5 and for somali refugees.6 however, no information is available for much of the arabian peninsula, including the sultanate of oman. the potential for the disease to occur in this area is high as a variety of tick species, which can transmit rickettsiae, has been recorded in yemen7, saudi arabia8 and oman.9 the present study was carried out in order to obtain an estimate of the prevalence of antibodies against rickettsia conorii in the dhofar province, which covers the southern part of the sultanate of oman. a detailed account of the environmental geography of dhofar region has been given by sale.10 except for the regional capital salalah, the population has a predominantly rural lifestyle where people live in close proximity to their animals. ticks were therefore collected from domestic stock in this region to investigate the presence of potential vectors of spotted fever rickettsiae. method the study localities were illustrated by idris11 except for shab al-saeeb, rakhyut, tawiattair and sudh all within 30 to 160 km from salalah, the capital of dhofar. blood was collected from volunteer school children (aged 8-16 years) in four localities in the dhofar province (sudh, dhalqut, tawiattair and rakhyut), from an outpatient clinic in madinat al-haq and from workers at the royal farm in salalah. sera were transported frozen to heidelberg where they were tested by the indirect fluorescent antibody r 7 i d r i s e t a l 8 test (ifa) using rickettsia conori-spot if (biomérieux deutschland gmbh, nürtingen, germany). principally, the serum is placed on a rickettsia conori-spot if antigen fixed slide. antibodies fixed to this antigen are revealed by a fluorescein labelled anti-human globulin. a positive reaction is indicated by fluorescence of r. conorii on the slide, visible under an ultravoilet (uv) microscope. sera were diluted in two-fold series from 1:16 to 1: 256 and applied to the slides. these were incubated in a moist chamber for 30 minutes at 37oc, washed twice for five minutes each time in tris (0.01m)-buffered (ph 7.2) saline (pbs) with 0.05% tween 20, dipped in distilled water and drained. they were then incubated as above in a moist chamber with fluorescein (fitc)conjugated goat antibodies against human igg (behringwerke, marburg, germany) diluted 1:100 in pbs with 0.01% evans blue. slides were washed as above and coverslips mounted with fluoprep (biomérieux). the results were read in a fluorescence microscope at ×400 magnification. according to the manufacturer, only fluorescent reactions with patient serum dilutions of at least 1:40 can be considered positive. in this study, fluorescent reactions obtained at dilutions of 1:64 or higher were taken as a positive reading. confirmatory determinations were done for some random samples of sera and yielded identical results. ticks were collected from livestock at dhalqut, madinat al-haq, tawiattair and shab al-saeeb areas through the cooperation from the animal’s owners and veterinary practioners. in addition, the skins of freshly slaughtered camels, cows and goats were searched for ticks at salalah municipality slaughter house, where animals are brought from various localities in dhofar. care was taken to obtain tick specimens from several sites including the ears, groin and anal area. ticks from each animal were stored separate and preserved in 70% ethanol. ticks were determined with respect to species, development stage and sex. results and discussion table 1 shows that between 42% and 66% of human sera from each locality gave a positive reaction. the results obtained from children were not detectably different from those obtained from adults. the data show that more than half (59%) of those individuals tested had antibodies against r. conorii. this suggests that rickettsial infections are common among the rural population of dhofar. the situation appears similar to that in the nile river delta of egypt, where up to 96%, 81% and 37% of the school age children were found seropositive for r. burnetii, r. typhi and r. conorii, respectively.4 in order to search conorii, the ticks, collec camels and goats), wer known ability to transm total of 707 adult ticks contribute to the natur conorii on the following use domestic stock as r stages in their life histo come into contact w variegatum and hyalomma conorii;12,13 immature stag and adults of h. rufipes (iii) h. anatolicum ssp. is and h. dromedarii was specimens) infected wit siae.5 both h. anatolicum humans.14 the genus rhipiceph of the main vectors of r been confused with r. attack humans, but the s for r. conorii, is un elucidated.16,17 rickettsia related to r. conorii, ha turanicus.18 in addition to prevalence of antibodies individuals from six population loca sudh dhalq tawia school children rakhy outpatients madinhaq farm workers salala total table 1. against rickettsia conorii among localities in dhofar, oman rickettsia conori spot i.f lity no. of sera tested no. of sera with positive reaction* 64 31 (48) ut 71 47 (66) ttair 54 34 (63) ut 67 41 (61) at al60 39 (65) h 31 13 (42) for potential vectors for r. ted from 102 animals (cows, e screened for species with a it this pathogen (table 2). a were identified, which might al epidemiological cycle of r. basis: (i) all these tick species egular hosts for one or more ry and are, therefore, likely to ith humans. (ii) amblyomma rufipes are known vectors of r. es of a. variegatum frequently, occasionally, attack humans.9,14 a known vector for r. conorii, reported to be (one out of 70 h spotted fever group rickett ssp and h. dromedarii attack alus includes r. sanguineus, one . conorii. this species has often turanicus which is known to tatus of r. turanicus as a vector certain15 and needs to be massiliae, a species closely s also been isolated from r. r. turanicus, r.camicasi belongs 347 205 (59) a n t i b o d i e s a g a i n s t r i c k e t t s i a to the r. sanguineus group of species and both are morphologically similar: it is difficult to distinguish their males and their engorged females are almost indistinguishable19 from each other. the involvement of r. camicasi in disease epidemiology is unknown.16 both r turanicus and r. camicasi are found in oman.9 in view of the problems encountered in identifying vectors of r. conorii in the r. sanguineus group, the identification of rhipicephalus to species level was not attempted. this report confirms the earlier records of tick species in oman by hoogstraal.9 it amply demonstrates the presence of ticks on domestic stock with the potential to transmit spotted fever group rickettsiae to humans. this, together with the rural life style of the local population,20,21 is compatible with a high prevalence of seropositivity in humans. however, the following three points deserve further investigation: first: whereas the serological data demonstrate a substantial prevalence of rickettsial infections, the cutoff titre set in immunofluorescence determines the sensitivity and specificity of the results as was suggested by comparative western blotting performed with specific protein antigen.22 thus, the true prevalence of r. conorii infections might be lower than the percentages of seropositivity. second: according to the manufacturer, the test antigen is not specific for r. conorii and the exact taxonomic status of the rickettsiae present in dhofar remains to be determined. r. conorii is antigenically diverse23 and, in addition to r. conorii, several new spotted fever group rickettsial strains have recently been described from ticks including a. variegatum and r. turanicus from the mediterranean and africa.24-26 we cannot also exclude the possibility that r. typhi or r. ticks collected from do in the transmission of r tick sp host (numbers sampled) amblyomma variegatum hyalomma a anatolicum hyalom drome cattle (77) 35 68 42 camels (21) 32 7 46 goats (4) 0 0 0 total 67 75 50 table 2 mestic stock and implicated ickettsia in dhofar, oman ecies (numbers collected) ma darii hyalomma rufipes rhipicephalus spp. total 8 16 169 3 15 0 517 0 21 21 5 23 37 707 9 prowazekii, which are not transmitted by ticks, might occur in dhofar and cross-react in the serologic test. third: it cannot be deduced from the mere presence of antibodies, whether infections with rickettsiae represent a significant source of disease in dhofar, as serology also detects asymptomatic cases of spotted fever as well as persisting antibodies.27-29 observation of the possible clinical spectrum of the disease should clarify this point. conclusion to our knowledge, this report is the first serological study of rickettsial infections in the oman and, together with the tick survey, demonstrates that transmission of such infection is possible and does occur. quantitative epidemiological aspects require further studies. the population of dhofar has appreciable seroprevalence rates for brucellosis20 and toxoplasmosis,21 which are also transmitted from domestic animals to humans. however, the recently improved living conditions and health services in dhofar should significantly reduce the prevalence of these pathogens, and the diseases transmitted from livestock to humans in this region should reduce correspondingly. acknowledgements we are grateful to the medical and veterinary practitioners and technical staff in the study localities, especially dr m. a. a. shaban, director of health affairs, dhofar and to all individuals who provided samples. we thank prof. j. e. keirans (u.s. national tick collection, statesboro, ga, u.s.a.) for confirming the identity of tick specimens, ms. angelika i d r i s e t a l 10 thomschke (department of infectious and tropical medicine, university of munich, germany) for the gift of a positive control serum. this study was supported in part by a travel grant from the faculty of theoretical medicine, university of heidelberg. references 1. who. global surveillance of rickettsial diseases: memorandum from a who meeting. bull world health orgn 1993, 71, 293-296. 2. yagupsky p, sarov b, naggan l, sarov i, avy k, goldwasser r. the prevalence of igg antibodies to spotted-fever group rickettsiae among urban and rural dwelling children in southern israel. scan j infect dis 1990, 22, 19-23. 3. yagupsky p, wolach b. fatal israeli spotted fever in children. clin infect dis 1993, 17, 850-3. 4. corwin a, habib m, olson j, scott d, ksiazek t, watts dm. the prevalence of arboviral, rickettsial and hantaan-like antibody among schoolchildren in the nile river delta of egypt. trans r soc trop med hyg 1992, 86, 677-9. 5. lange jv, el dessouky ag, manor e, merdan ai, azad af. spotted fever rickettsiae in ticks from the northern sinai governerate, egypt. am j trop med hyg 1992, 46, 546-51. 6. gray gc, rodier gr, matras-maslin vc, honein ma, ismail ea, botros bam, soliman ak, merrel br, wang sp, grayston jt. serologic evidence of respiratory and rickettsial infections among somali refugees. am j trop med hyg 1995, 52, 349-53. 7. pegram rg, hoogstraal h, wassef hy. ticks (acari: ixodoidea) of the yemen arab republic. i. species infesting livestock. bull entomol res 1982, 72, 215-27. 8. hoogstraal h, wassef hy, buttiker w.ticks (acarina) of saudi arabia fam. argasidae, ixodidae. fauna of saudia arabia 1981, 3, 25-110. 9. hoogstraal h. ticks (ixodoidea) from oman. journal of oman studies 1980, special reports 2, 265-72. 10. sale jb. the environment of the mountain region of dhofar. journal of oman studies 1980, 2, 17-23. 11. idris ma, ruppel a, de carneri i, shaban maa, alawfy sam, jayawardene cr, savioli l. high prevalence and intensity of hookworm infection in the dhofar governorate, oman. anna trop med parasitol, 1993a, 87, 421-4. 12. heisch rb, mc phee r, rickman lr. the epidemiology of tick-typhus in nairobi. east afr med j, 1957, 34, 459-77. 13. philip cb, hoogstraal h, reiss-gutfreund r, clifford cm. evidence of rickettsial disease agents in ticks from ethiopian cattle. bull world health organ, 1966, 35, 127-31. 14. hoogstraal h. african ixoidea. i. ticks of the sudan (with special reference to equatoria province and with preliminary reviews of the genera boophilus, margaropus and hyalomma). research report nm 005050.29.07. washington dc: department of navy, bureau of medicine and surgery, 1956, 1101. 15. pegram rg, clifford cm, walker jb, keirans je. clarification of the rhipicephalus sanguineus group (acari, ixodoidea, ixodidae). i. r. sulcatus neumann, 1908 and r. turanicus pomerantsev, 1936. sys parasitol, 1987, 10, 3-26. 16. pegram rg, keirans je, clifford cm, walker jb. clarification of the rhipicephalus sanguineus group (acari, ixodoidea, ixodidae) ii. r. sanguineus (latreille, 1806) and related species. sys parasitol 1987b, 10, 27-44. 17. rehacek j. rickettsiae and their ecology in the alpine region. acta virol 1993, 37, 290-301. 18. beati l, finidori jp, gilot b, raoult d. comparison of serologic typing, sodium dodecyl sulphate-polyacrylamide gel electrophoresis protein analysis, and genetic restriction fragment length polymorphism analysis for identification of rickettsiae: characterization of two new rickettsial strains. j clin microbiol 1992, 30, 1922-30. 19. pegram rg, zivkovic d, keirans je, wassef h, buttiker w. the rhipicephalus sanguineus group (acari: ixodidae) from saudi arabia. fauna of saudi arabia 1989, 10, 65-77. 20. idris ma, maiwald m, el-mauly kn, ruppel a. human brucellosis in dhofar, sultanate of oman. j trop med hyg 1993, 96, 46-50. 21. idris ma, ruppel a. prevalence of igg antibodies against toxoplasma gondii in human sera from dhofar, oman. ann trop med parasitol 1994, 88, 89-91. 22. babalis t, dupont ht, tselentis y, chatzichritodoulou c, raoult d. rickettsia conorii in greece: comparison of a microimmunoflourescence assays and western blotting for seroepidemiology. am j trop med hyg, 1993, 48, 784-92. 23. walker dh, liu qh, yu xj, li h, taylor c, feng hm. antigenic diversity of rickettsia conorii. am j trop med hyg, 1992, 47, 78-86. 24. manor e, ighbarieh j, sarov b, kassis i, regnery r. human and tick spotted fever group rickettsial isolates from israel: a genotypic analysis. j clin microbiol 1992, 30, 2653-6. 25. babalis t, tselentis y, roux v, psaroulaki a, raoult d. isolation and identification of a rickettsial strain related to rickettsia massiliae in greek ticks. am j trop med hyg 1994, 50, 365-72. 26. dupont ht, cornet jp, raoult d. identification of rickettsiae from ticks collected in the central african republic using the polymerase chain reaction. am j trop med hyg 1994, 50, 373-80. 27. mansueto s, vitale g, miceli md, tringali g, quartararo p, picone dm, occhino c. a seroepidemiological survey of asymptomatic cases of boutonneuse fever in western sicily. trans r soc trop med hyg, 1984, 78, 16-18. 28. sarov b, galil a, sikuler e, yagupsky p, saah a, gilad a, naggan l, sarov i. prospective study of symptomatic versus asymptomatic infections and serological response to spotted fever group rickettsiae in two rural sites in negev (southern israel). ann ny acad sci 1990, 590, 243-5. 29. raoult d, dupont ht, chicheportiche c, peter o, gilot b, drancourt m. mediterranean spotted fever in marseille, france: correlation between prevalence of hospitalized patients, seroepidemiology, and prevalence of infected ticks in three different areas. am j trop med hyg,1993, 48, 49-256. antibodies against rickettsia in humans and �potential vector ticks from dhofar, oman *idris m a1,2 , ruppel a2, petney t3 ??????? ??????? ?????????? ??????? ?????? ??? �??????? ???? ?. ????? ? ?. ???? ? ?. ???? method results and discussion conclusion acknowledgements references sir, drug-related phototoxic reaction is a well-established clinical entity. historically, antineoplastic cytotoxic agents such as actinomycin c, doxorubicin, and fluoroquinolones are the most common drugs to cause phototoxic reactions in humans.1 dopamine agonists, ropinirole, and pramipexole are considered the first line of treatment for restless legs syndrome (rls) in current evidenced-based guidelines, and to the best of our knowledge, no dermatological side-effects have been described in association with its use.2 we describe a case of a man with rls who developed a rare photosensitive rash due to pramipexole. a 57-year-old male presented to the department of dermatology at san cecilio university hospital, granada, spain, with a 3-day history of itchy, erythematous rash and swelling on his face and arms. other complaints included breathlessness and dysphonia. he had a past medical history of thyroidectomy and subsequent hypothyroidism, for which he took daily thyroxine. two weeks before the rash had started, he had been diagnosed with rls in the neurology department of our hospital, and a nightly dose of 0.3 mg of pramipexole had been prescribed. on clinical examination, patchy macular erythematous plaques were noted [figure 1]. the reaction was isolated to the photo-exposed aspects of his arms. maculopapular erythema with oedema was observed on his face [figure 2]. blood tests revealed high c-reactive protein levels, an elevated erythrocyte sedimentation rate, and eosinophilia. his level of immunoglobulin e was also elevated. biopsy of one lesion showed necrotic keratinocytes, an infiltration of lymphocyte associated with oedema, and vasodilation. a drug-induced phototoxic reaction was considered and pramipexole was discontinued. intravenous hydration, steroids, and antihistamines were started. symptoms and lesions cleared in the first 6 hours and resolved completely in 3 weeks with oral prednisone (1 mg/kg/day) and the use of strict photoprotection. prednisone was gradually sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 190-191, epub. 27th feb 13 submitted 31st mar 12 revision req. 7th aug 12, revision recd. 15th sep 12 accepted 6th oct 12 طفح عند التعرض لضوء الشمس خالل عالج املريض مبتالزمة متلمل الساقني phototoxic rash during therapy with pramipexole in a patient with restless legs syndrome letter to editor figure 1: phototoxic reaction involving arms in a patient under treatment with pramipexole for his restless legs syndrome. figure 2: maculo-papular erythema with oedema as observed on eyelids. husein h. elahmed letter to editor | 191 reduced and eventually discontinued. upon follow-up, the patient began treatment with gabapentin (200 mg/day) for the rls. he is free of lesions and no recurrence has been observed. drug-induced photosensitivity may be photoallergic or phototoxic. photoxic reactions do not require prior exposure and are dependent both on the drug dosage and the amount of the patient’s ultraviolet light (uvl) exposure. thus, a high dose of a photosensitising medication combined with prolonged and/or intense uvl exposure may result in erythema and oedema, resembling acute sunburn.3 pramipexole is a nonergoline dopamine agonist with a high selectivity for d2 and d3 receptors whose efficacy for rls has been confirmed in different studies.4–6 it is usually well tolerated. in all the studies examined, the discontinuation rate (~20%) was similar, and the incidence of adverse events was not clearly dose-related. the most frequent adverse reaction was nausea, followed by fatigue, dizziness, headache, diarrhoea, nasopharyngitis, orthostatic hypotension, and increased body weight. while uncommon, the dermatological side-effects are described by the makers of pramipexole in the drug manufacturers’ documents and on the european medicines agency’s website.7 according to this information, hypersensitive reactions like exanthema and pruritus have been associated with the use of pramipexole. however, no clinical reports regarding photosensivity or phototoxic reactions associated with pramipexole have been found. it is suggested that the prevalence of side-effects decreases significantly in long-term treatment (2.6%) as compared with early treatment.4–6 however, in our patient we decided to discontinue the therapy because of the severity of his rash. systemic re-exposition to the offending drug remains the gold standard for diagnosis, but that was not considered in this case due to the possibility of a life-threatening adverse reaction. instead, because our patient had been on pramipexole within the two weeks prior to the start of his rash, we suspected that pramipexole was the culprit in this patient’s skin reaction. a photo patch test was suggested to confirm our clinical suspicion, but it was declined by the patient. finally, while in our case there was a definite cause-effect correlation between the onset of rash and the initiation of pramipexole, we were not able to confirm this diagnosis; thus, our hypothesis is more probabilistic than direct. to the best of our knowledge, this is the first case of phototoxic reaction induced by pramipexole. husein h. elahmed department of dermatology, san cecilio university hospital, granada, spain e-mail: huseinelahmed@hotmail.com references 1. cunha jp. sun-sensitive drugs (photosensitivity to drugs). from: http://www.medicinenet.com/sun-sensitive_ drugs_photosensitivity_to_drugs/page6.htm accessed: jan 2013. 2. chesson al jr, wise m, davila d, johnson s, littner m, anderson wm, et al. practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder. an american academy of sleep medicine report. standards of practice committee of the american academy of sleep medicine. sleep 1999; 22:961–8. 3. stein kr, scheinfeld ns. drug-induced photoallergic and phototoxic reactions. expert opin drug saf 2007; 6:431– 43. 4. winkelman jw, sethi kd, kushida ca, becker pm, koester j, cappola jj, et al. efficacy and safety of pramipexole in restless legs syndrome. neurology 2006; 67:1034–9. 5. oertel wh, stiasny-kolster k, bergtholdt b, hallström y, albo j, leissner l, et al. pramipexole rls study group. efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study. mov disord 2007:213–19. 6. partinen m, hirvonen k, jama l, alakuijala a, hublin c, tamminen i, et al. open-label study of the long-term efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study. the prelude study. sleep med 2006; 7:407–17. 7. european public assessment reports: pramipexole accord. from: http://www.ema.europa. e u / e m a / i n d e x . j s p ? c u r l = p a g e s / m e d i c i n e s / l a n d i n g / e p a r _ s e a r c h .w c 0 b 0 1 a c 0 5 8 0 0 1 d 1 2 4 & s o u r c e =homemedsearch&keyword=pramipexole&category=human&isnewquery=true accessed: jan 2013. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e303–304, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.001. submitted 20 jun 15 revision req. 22 jul 15; revision recd. 23 jul 15 accepted 26 jul 15 diabetes mellitus is currently one of the most challenging public health problems worldwide. with a marked increase in its prevalence, it is reaching epidemic proportions in many countries.1 globally, the diabetes rate has risen by 45% over the past two decades.2 the international diabetes federation (idf) estimated that the number of adults affected by diabetes in 2013 was 387 million, with a projected increase of up to 592 million by 2035.3 in arab countries, the prevalence of type 2 diabetes mellitus has increased dramatically over the past 30 years.4 according to the idf, three arabian gulf countries are among the top 10 countries in the world with the highest prevalence of diabetes: saudi arabia (24%), kuwait (23.1%) and qatar (22.9%).5 in the may 2015 issue of squmj, al-lawati et al. showed that oman is following the same trend, with diabetes age-adjusted prevalence rates varying from 10.4% to 21.1%.6 al-lawati et al. also estimated that the number of patients diagnosed with diabetes in oman will rise to 350,000 by the year 2050; an increase of 174% compared to estimates for 2015.6 the study also found a remarkable proportion of undiagnosed diabetes cases in oman; this indicates that many individuals are living without treatment.6 the implications of these alarming statistics on the healthcare system in oman should be addressed and effective solutions to combat this trend be planned and implemented. the key risk factors for the development of diabetes include a genetic predisposition, poor dietary habits, a family history of the disease and a lack of physical activity.7 the prevalence of obesity among arab countries has increased rapidly in the last few decades.8 poor dietary habits and inadequate physical activity have contributed to large numbers of overweight and obese individuals, which will ultimately lead to increased cases of diabetes.9 research conducted by ng et al. showed that several countries in the middle east have had the largest increase in obesity rates globally, including bahrain, egypt, saudi arabia, oman and kuwait.10 in oman, the prevalence of overweight/ obese individuals was reported to be 54% among men and 73% among women.10 easy access to processed junk foods, cheap transportation methods and technologybased jobs that limit physical activity have resulted in a disturbance of metabolism leading to obesity and diabetes.11 it has been proposed that almost 80% of diabetes cases are preventable if individuals maintain a healthy body weight by taking part in regular physical activity and eating a well-balanced diet.12 the chronic nature of the disease, severity of its complications and means of controlling the condition makes diabetes a costly affair, not only for the affected individual and their families, but also for healthcare authorities.11 consequently, the globally increasing prevalence of diabetes has resulted in an increase in related healthcare costs, particularly in developing countries.2 a study carried out by the american diabetes association estimated that the total cost of diagnosed diabetes cases in the usa had risen from usd $174 billion in 2007 to usd $245 billion in 2012, which is a 40% increase over a five-year period.13 in india, the annual healthcare cost of diabetes cases has been reported as approximately usd $2.2 billion.14 in oman, no in-depth studies have yet evaluated the cost of diabetes to the healthcare system; however, the idf have reported that the mean diabetes-related health expenditure per diabetes patient in oman is approximately usd $500–1,500.5 in order to effectively control diabetes at a national level, it should be the responsibility of diabetes educators and physicians in oman to create public awareness about basic concepts of disease manage ment, such as glycated haemoglobin measurements, dietary control, sufficient exercise, carbohydrate department of child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: alyaarubica@gmail.com الوقاية من جائحة داء السكري يف سلطنة عمان �سيف اليعربي، عزه ال�سيذانية، �سمية حبيب editorial preventing the future pandemic of diabetes mellitus in oman *saif al-yaarubi, azza al-shidani, sumaya habib preventing the future pandemic of diabetes mellitus in oman e304 | squ medical journal, august 2015, volume 15, issue 3 counting and multiple daily injections.11 the secretariat of health in mexico implemented a structured diabetes education programme which aimed to provide better healthcare and improve quality of life for diabetic patients; it was subsequently found that the programme resulted in an increased number of people with well-controlled diabetes.15 in oman, not all primary healthcare facilities have diabetologists or the necessary equipment for the early detection of diabetes. therefore, most cases are attended by non-specialised primary healthcare physicians which affects the quality of care received by diabetic patients.11 the omani healthcare system needs to upgrade its existing healthcare policies to follow the current world health organization (who) chronic care model which has been implemented in the uk, australia, new zealand and canada.11 there should be more resources allocated to diabetes care in oman for better prevention, diagnostic infrastructure, convenience and affordability of treatment as well as skilled healthcare workers, as suggested by the who global strategy.16 the initiative of a national diabetes centre in oman in march 2013 was the first step towards creating an organisational body for awareness and diabetic care in the country; this centre should be further strengthened and expanded to provide better diabetic healthcare. this could be achieved by establishing regional diabetes centres in each governorate of oman. these centres should be equipped with all the necessary medications and resources needed for diabetic patients and have a diabetologist, diabetes nurse and dietician on staff. the role of these regional centres should not be limited solely to treating diabetic patients, but should also aim to prevent diabetes and its complications. this may be achieved by implementing health education campaigns in local communities and creating groups for peer support and patient empowerment. the presence of these centres in all regions of oman would facilitate patient compliance, help in lowering the number of undiagnosed diabetes cases and prevent a further increase in diabetes prevalence. a low-cost alternative to this would be to hold outreach clinics, where diabetic experts could travel to underprivileged areas and conduct educational, diagnostic and therapeutic campaigns. finally, the continuous training of primary healthcare professionals in diabetes care and prevention is an essential tool for improving the management of diabetes in oman. references 1. yoon kh, lee jh, kim jw, cho jh, choi yh, ko sh, et al. epidemic obesity and type 2 diabetes in asia. lancet 2006; 368:1681–8. doi: 10.1016/s0140-6736(06)69703-1. 2. global burden of disease study 2013 collaborators. global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the global burden of disease study 2013. lancet 2015; pii: s01406736(15)60692-4. doi: 10.1016/s0140-6736(15)60692-4. 3. international diabetes federation. international diabetes atlas sixth editon: key findings 2014. from: www.idf.org/ diabetesatlas/update-2014 accessed: jun 2015. 4. whiting dr, guariguata l, weil c, shaw j. idf diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. diabetes res clin pract 2011; 94:311–21. doi: 10.1016/j. diabres.2011.10.029. 5. international diabetes federation. international diabetes atlas sixth edition. from: www.idf.org/sites/default/files/en_6e_ atlas_full_0.pdf accessed: jun 2015. 6. al-lawati ja, panduranga p, al-shaikh ha, morsi m, mohsin n, khandekar rb, et al. epidemiology of diabetes mellitus in oman: results from two decades of research. sultan qaboos univ med j 2015; 15:e226–33. 7. botero d, wolfsdorf ji. diabetes mellitus in children and adolescents. arch med res 2005; 36:281–90. doi: 10.1016/j. arcmed.2004.12.002. 8. ng sw, zaghloul s, ali hi, harrison g, popkin bm. the prevalence and trends of overweight, obesity and nutritionrelated non-communicable diseases in the arabian gulf states. obes rev 2011; 12:1–13. doi: 10.1111/j.1467-789x. 2010.00750.x. 9. lobstein t, baur l, uauy r; iaso international obesity taskforce. obesity in children and young people: a crisis in public health. obes rev 2004; 5:4–104. doi: 10.1111/j.1467789x.2004.00133.x. 10. ng m, fleming t, robinson m, thomson b, graetz n, margono c, et al. global, regional, and national prevalence of overweight and obesity in children and adults during 1980– 2013: a systematic analysis for the global burden of disease study 2013. lancet 2014; 384:766–81. doi: 10.1016/s01406736(14)60460-8. 11. alyaarubi s. diabetes care in oman: obstacles and solutions. sultan qaboos univ med j 2011; 11:343–8. 12. bruno g, landi a. epidemiology and costs of diabetes. transplant proc 2011; 43:327–9. doi: 10.1016/j.transproceed.20 10.09.098. 13. american diabetes association. economic costs of diabetes in the u.s. in 2012. diabetes care 2013; 36:1033–46. doi: 10.2337/ dc12-2625. 14. siegel k, narayan km, kinra s. finding a policy solution to india’s diabetes epidemic. health aff (millwood) 2008; 27:1077–90. doi: 10.1377/hlthaff.27.4.1077. 15. deakin ta, cade je, williams r, greenwood dc. structured patient education: the diabetes x-pert programme makes a difference. diabet med 2006; 23:944–54. doi: 10.1111/j.14645491.2006.01906.x. 16. waxman a. why a global strategy on diet, physical activity and health? world rev nutr diet 2005; 95:162–6. doi: 10.1159/000088302. http://dx.doi.org/10.1016/s0140-6736%2806%2969703-1 http://dx.doi.org/10.1016/s0140-6736%2815%2960692-4 http://dx.doi.org/10.1016/s0140-6736%2815%2960692-4 http://dx.doi.org/10.1016/s0140-6736%2815%2960692-4 http://dx.doi.org/10.1016/j.arcmed.2004.12.002 http://dx.doi.org/10.1016/j.arcmed.2004.12.002 http://dx.doi.org/10.1111/j.1467-789x.2010.00750.x http://dx.doi.org/10.1111/j.1467-789x.2010.00750.x http://dx.doi.org/10.1111/j.1467-789x.2004.00133.x http://dx.doi.org/10.1111/j.1467-789x.2004.00133.x http://dx.doi.org/10.1016/s0140-6736%2814%2960460-8 http://dx.doi.org/10.1016/s0140-6736%2814%2960460-8 http://dx.doi.org/10.1016/j.transproceed.2010.09.098 http://dx.doi.org/10.1016/j.transproceed.2010.09.098 http://dx.doi.org/10.2337/dc12-2625 http://dx.doi.org/10.2337/dc12-2625 http://dx.doi.org/10.1377/hlthaff.27.4.1077 http://dx.doi.org/10.1111/j.1464-5491.2006.01906.x http://dx.doi.org/10.1111/j.1464-5491.2006.01906.x http://dx.doi.org/10.1159/000088302 sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. e606-610, epub. 8th oct 13 submitted 8th feb 13 revision req. 13th may 13; revision recd. 9th jun 13 accepted 18th jun 13 foreign body ingestion is a common complaint seen by practicing otolaryngologists. it occurs in both adults and children. children commonly ingest toys and small coins. the most common foreign bodies accidentally ingested by adults are bones, especially fish bones.1 complications due to foreign body ingestion are rare, although, if present, can cause significant morbidity and in some cases, mortality.2 the incidence of cervical abscess formation after foreign body migration in the literature is less than 1%.3,4 mortality following oesophageal perforation has been reported to be as high as 32%.3 advances in radiological techniques and the endoscopic management of foreign bodies have greatly improved the outcome of such cases; hence, impending complications of foreign body ingestion and cases of prolonged retention of foreign bodies have reduced over a period of years. however, migrating foreign bodies may make it difficult to diagnose the cause of worsening symptoms, especially after noting the absence of a foreign body on endoscopy. some complications of retained and migrating foreign bodies include oesophageal perforation, mediastinitis, vascular complications, various cervical abscesses and recurrent cervical infections.1,5,6 in our case, the patient’s consent was obtained for publication. case report a 58-year-old man with no comorbidities presented to the emergency triage of kasturba hospital, manipal, with his chief complaint being a swelling kasturba medical college, manipal, india *corresponding author e-mail: paimam08@gmail.com جسم غريب متنقل يف اجلهاز التنفسي اهلضمي العلوي مع حدوث صدمة انتانية تقرير حالة ومراجعة األدبيات كي�ساف باي, �سوري�ش بيلالي, اجاي بندركار, اي�سورايا اناند, هاري�ستا �سابهاهيت باخلطورة تت�سم فاإنها امل�ساعفات هذه من اأيا حدوث عند ولكن غريب ج�سم ابتالع عن الناجتة امل�ساعفات يف ندرة هناك امللخ�ص: ال�سديدة. واذا مامت اإغفالة فقد ينتج عنه الوفاة الطارئة.هذا تقرير حلالة اكت�ساف ج�سم غريب مبح�ش ال�سدفة وانتقالة اإىل الرقبة مع عمل خراج عنقي اأدى اإىل �سدمة انتانية. وقد احتاج املري�ش اإىل دعم ا�ستقرار حالته الطبية مع التدخل اجلراحي.وقد عادت عالمات املري�ش احليوية اإىل قيمها الطبيعية يف اليوم الثاين بعد التدخل اجلراحي, ومت خروج املري�ش يف اليوم التايل. مفتاح الكلمات: ج�سم غريب متنقل, �سدمة انتانية, خراج؛ تقرير حالة؛ الهند. abstract: complications due to foreign body ingestion are rare; however, if present, these can cause significant morbidity to the patient. an overlooked ingested foreign body could present as an emergency and may prove fatal. we present a case of an accidentally ingested foreign body with delayed presentation, which migrated to the neck and produced a cervical abscess presenting as septic shock. the patient required prompt stabilisation followed by surgical intervention. the patient’s vital signs returned to normal on the second post-operative day, and he was discharged the following day. keywords: foreign-body migration; septic shock; abscess; case report; india. migrating ingested foreign body of the upper aerodigestive tract with resultant septic shock case report and literature review *keshav pai, suresh pillai, ajay bhandarkar, aishwarya anand, harshita sabhahit online case report migrating ingested foreign body of the upper aerodigestive tract with resultant septic shock case report and literature review 607 | squ medical journal, november 2013, volume 13, issue 4 on the left side of the neck associated with pain for the previous 4 days. he claimed that a few days previously he had felt a pricking sensation in the throat upon having a vegetarian meal and said that he had probably swallowed a toothpick. pain and swelling followed this incident. as the pain increased in intensity and the swelling increased in size, he visited a local physician who performed an ultrasound of the neck which suggested a neck abscess. he also underwent an upper gastrointestinal (gi) endoscopy at that centre which revealed no foreign body. in the meantime, he developed a fever and became ill, at which time he was referred to our centre. on examination, the patient was ill, but conscious and coherent. his pulse was 110 beats per/ min, reduced in volume and feeble. blood pressure was 80/60 mmhg in a right arm supine position. respiratory rate was 22 breaths per/min and his temperature was 37 °c (99.5 °f). his extremities were cold and the oral mucosa was moist. the patient had no difficulty breathing and did not experience a change of voice. he only complained of pain around the area of swelling in the neck. on examination, a diffuse swelling approximately 3 x 3 cm was seen in the left side of the neck, in the region of the lower one-third of the left sternocleidomastoid muscle (scm) over the anterior aspect of the neck. the skin over the area of swelling appeared normal and there were no scars or sinuses present. on palpation, there was tenderness over the swelling and a local rise of temperature. the skin over the swelling was pinchable. the inspection findings were confirmed. no other swellings were seen in the neck. the patient was admitted and routine blood investigations were performed. the patient’s total white blood cell count was high and the differential count was high in neutrophils. serum creatinine level was 1.7 mg/dl, and a blood culture was ordered. x-rays of the neck (both an anteroposterior and lateral view) were done, showing a foreign body in the region of the lateral pharyngeal space on the left at the c5 level [figure 1]. a computed tomography (ct) scan of the neck with contrast was ordered. as he required intravenous contrast, the hydration protocol was followed. oral fluids were withheld and intravenous antibiotics along with parenteral hydration were started. a dopamine infusion (400 mg in 50 ml normal saline) at a rate of 4 ml/hr was begun. meanwhile, an emergency ct of the neck with contrast was obtained. the ct scan indicated a linear foreign body measuring approximately 5 cm extending anteroinferiorly in the deep cervical space close to the carotid space on the left side. the distance between the foreign body and the left common carotid artery was around 6 mm [figure 2]. a heterogeneously non-enhancing hypodense area with air pockets suggestive of an abscess was seen in the left visceral figure 1: x-ray of the neck (anterposterior and lateral views) showing the foreign body in the deep cervical space. figure 2: computed tomography axial scan showing the foreign body in the neck on the left side in close proximity to the carotid arteries (white arrow). keshav pai, suresh pillai, ajay bhandarkar, aishwarya anand and harshita sabhahit case report | 608 space of the neck [figure 3] extending from the hyoid bone to the region of the pyriform sinus. it was seen involving the strap muscles and scm. posteriorly, it reached the carotid space and inferiorly it extended to the thyroid gland. the patient was taken for emergency neck exploration under general anaesthesia. incision and drainage of the abscess was done. pus was evacuated and sent for culture and sensitivity. the foreign body was discovered in the neck abutting the left carotid artery. it was retrieved and found to be a 5.5 cm sewing needle [figure 4]. the wound was washed thoroughly. a corrugated rubber drain was placed in the wound and secured and a nasogastric tube was passed and secured. the wound was dressed, and the patient was moved to recovery and kept overnight for close monitoring. feeds were administered through the nasogastric tube. a blood culture was positive for methicillin-sensitive staphylococcus aureus after 48 hours of incubation. the patient’s vital signs returned to normal on the second post-operative day. the nasogastric tube and drain were removed on the third post-operative day, and the patient was discharged thereafter. an intraoperative endoscopy was not performed as the ct scan did not show a luminal foreign body. discussion migrating ingested foreign bodies cause significant morbidity. more often than not, cases of fish or chicken bone ingestion present to the otolaryngologist with sudden pharyngeal pain. other commonly ingested items include pins, coins and button batteries. it is possible that the sharp end of a foreign body such as bone inflicts mucosal injury on its way down, causing pain and anxiety to the patient. it may not be seen on flexible endoscopy or rigid angled telescopy of the larynx performed in the outpatient department. many such foreign bodies pass without alarm and the pain subsides over a day or two. however, if the pain persists or the patient develops respiratory compromise, haemoptysis, neck swelling or a fever, a second look may be necessary. diagnosis is more difficult in children and infants as compared to adults on account of their inability to provide an accurate history.6 the incidence of neck abscesses following foreign body ingestion has been assessed to be around 0.21% and 0.96% in two separate studies.3,4 lai et al. studied 29 cases of foreign body ingestion followed by complications to assess the risk factors which predict the occurrence of the latter.7 they included age, delayed presentation, comorbidities, cricopharyngeal impaction and radiographic identification. a case series demonstrated that oesophageal perforation may occur within 24 hours of ingestion whereas neck abscesses following ingestion may present after 4 or more days.3 therefore, the absence of an ingested foreign body on examination does not necessarily exclude the possibility of impending complications. figure 3: computed tomography coronal scan showing a neck abscess with air pockets on the left side (white arrow). the foreign body is partly seen. figure 4: the foreign body (a 5.5 cm sewing needle) retrieved from the neck. migrating ingested foreign body of the upper aerodigestive tract with resultant septic shock case report and literature review 609 | squ medical journal, november 2013, volume 13, issue 4 the most common site at which a foreign body could perforate the oesophagus to become extraluminal is at the cricopharynx, which is the narrowest part of the oesophagus.3 it has also been suggested that its orientation (horizontal with respect to the oesophageal lumen) along with strong muscular contractions at the cricopharynx facilitate perforation and extraluminal migration.8 in our case, this could have been the cause of migration as a horizontally-placed sewing needle could easily perforate the cricopharnyx. certain clues such as mucosal laceration or oedema seen during rigid endoscopy may suggest extraluminal migration at that site.9 loh et al. studied 273 cases of foreign bodies in the oesophagus.10 they reported a major complication rate of 7.3% in their study. according to them, foreign body impaction increases the risk of perforation 14 times. the most common clinical features of neck abscess following migrating ingested foreign body are fever, sore throat, odynophagia and leucocytosis.3 case reports have described a fish bone and also a tooth which lodged in the lobe of the thyroid gland.9,11 yadav et al. published a case in which an ingested foreign body burst through a neck swelling externally.12 other authors have described the development of a thyroid abscess and thyroid gland cutaneous fistula due to a migrating foreign body.13,14 joshi et al. described a case of foreign body ingestion which pierced the internal jugular vein.15 other case reports describe the migration of ingested foreign bodies to present as a mediastinal mass or a pulmonary mass, and another case report describes a patient who experienced cardiac tamponade due to a migrating foreign body.16–18 a rare case of the migration of a wooden toothpick into the liver, causing a pyogenic liver abscess has also been reported. however, this type of migration occurred through the anterior stomach wall.19 button batteries, usually ingested by infants and young children, can cause significant damage, such as oedema and ulceration at the region of foreign body impaction due to strong alkali leakage, possibly resulting in oesophageal perforation, pneumothorax or spondylodiscitis.20 other complications include periesophagitis, periesophageal abscess, mediastinitis, and upper gi haemmorhage.1,12,21 the most feared complications include aorto-oesophageal, subclavian-oesophageal fistula and carotid rupture.10,15,17 upon encountering a case of migrating foreign body with the development of other complications such as neck swelling, respiratory embarrassment, fever, chest pain or haemoptysis, a ct scan can help to identify the site and relationship of the foreign body in the neck, which is often missed by neck radiographs.22 studies have shown that a ct scan is highly accurate and has a high positive predictive value compared to a plain x-ray of the neck. however, a plain radiograph is the first-line investigation and a positive finding is enough to warrant an upper gi endoscopy, especially if an extraluminal foreign body is suspected. magnetic resonance imaging (mri) has also proven effective in diagnosing non-metallic migrated foreign bodies missed by a prior ct scan, but is contraindicated in suspected metallic foreign body ingestion. some authors have suggested using an intraoperative ultrasound to identify the location of a migrated foreign body in the neck.1 radiological features include the presence of a foreign body, free gas on a ct scan and air fluid levels on a lateral view of an x-ray of the neck.3 a contrast ct scan can be done if a vascular complication is suspected. the relation of the foreign body to the great vessels of the neck and chest should be studied prior to surgical exploration. a cervical abscess due to a migrated foreign body can be managed by draining the abscess, retrieving the foreign body and administering intravenous antibiotics along with nasogastric feedings. this treatment is sufficient in most cases. conclusion the inability to identify an ingested foreign body on clinical examination and endoscopy does not rule out its presence. the persistence of symptoms and the onset of ominous signs must direct the otolaryngologist to the possibility of a migrating foreign body. such cases could be easily mismanaged, wherein the physician might assume that the foreign body has passed to the stomach and therefore treat the patient conservatively, which could prove fatal. a high index of suspicion is necessary to rule out an overlooked foreign body. a ct scan of the neck is necessary to locate the same. we report this case because the patient presented with septic shock, which is an unusual presentation. keshav pai, suresh pillai, ajay bhandarkar, aishwarya anand and harshita sabhahit case report | 610 references 1. watanabe k, amano m, nakanome a, saito d, hashimoto s. the prolonged presence of a fish bone in the neck. tohoku j exp med 2012; 227:49–52. 2. kerschner je, beste dj, conley sf, kenna ma, lee d. mediastinitis associated with foreign body erosion of the esophagus in children. int j pediatr otorhinolaryngol 2001; 59:89–97. 3. lam hc, woo jk, van hasselt ca. esophageal perforation and neck abscess from ingested foreign bodies: treatment and outcomes. ear nose throat j 2003; 82:786–94. 4. nandi p, ong gb. foreign body in the oesophagus: review of 2394 cases. br j surg 1978; 65:5–9. 5. landis bm, giger r. an unusual foreign body migrating through time and tissues. head face med 2006; 2:30. 6. mclaughlin rt, morris jd, haight c. the morbid nature of migrating foreign body in the esophagus. j thorac cardiovasc surg 1968; 55:188–92. 7. lai at, chow tl, lee dt, kwok sp. risk factors predicting the development of complications after foreign body ingestion. br j surg 2003; 90:1531–5. 8. al-sebeih k, abu-shara ka, sobeih a. extraluminal perforation complicating foreign bodies in the upper aerodigestive tract. ann otol rhinol laryngol 2010; 119:284–8. 9. al-sebeih k, valvoda m, sobeih a, al-sihan m. perforating and migrating pharyngoesophageal foreign bodies: a series of 5 patients. ear nose throat j 2006; 85:600–3. 10. loh ks, tan lk, smith jd, yeoh kh, dong f. complications of foreign bodies in the oesophagus. otolaryngol head neck surg 2000; 123:613–6. 11. sreetharan ss, prepageran n, satwant s. unusual migratory foreign body in the neck. singapore med j 2004; 45:487–8. 12. yadav sp, chanda r, malik p, chanda s. ingested nail penetrating the neck in an infant. int j pediatr otorhinolaryngol 2002; 65:159–62. 13. chen cy, peng jp. esophageal fish bone migration induced thyroid abscess: case report and review of the literature. am j otolaryngol 2001; 32:253–5. 14. ohbuchi t, tabata t, nguyen kh, ohkubo ji, katoh a, suzuki h. thyroid gland cutaneous fistula secondary to a migratory fish bone: a case report. j med case rep 2012; 6:140. 15. joshi aa, bradoo r. a foreign body in the pharynx migrating through the internal jugular vein. am j otolaryngol 2003; 24:89–91. 16. radford pj, wells fc. perforation of the oesophagus by a swallowed foreign body presenting as mediastinal and pulmonary mass. thorax 1988; 43:416–7. 17. sinha a, shotton jc. an unusual foreign body migrating from pharynx to mediastinum. j laryngol otol 1996; 110:279–80. 18. sharland mg, mccaughan bc. perforation of the esophagus by a fish bone leading to cardiac tamponade. ann thorac surg 1993; 56:969–71. 19. stoica m, sãftoiu a, gheonea di, dumitrescu d, surlin v. pyogenic liver abscess caused by accidental ingestion of a wooden toothpick: role of preoperative imaging. j gastrointestin liver dis 2007; 16:221–2. 20. sudhakar pj, al dossary j, malik n. spondylodiscitis complicated by the ingestion of a button battery: a case report. korean j radiol 2008; 9:555–8. 21. huiping y, jian z, shixi l. esophageal foreign body as a cause of upper gastrointestinal hemorrhage: case report and review of the literature. eur arch otorhinolaryngol 2008; 265:247–9. 22. chung sm, kim hs, park eh. migrating pharyngeal foreign bodies: a series of four cases of saw-toothed fish bones. eur arch otorhinolaryngol 2008; 265:1125–9. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 132-136, epub. 27th feb 13 submitted 5th may 12 revision req. 7th jul 12, revision recd. 30th oct 12 accepted 24th nov 12 department of child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mnaggari@yahoo.com الغلوبيولني املناعي الوريدي يف عالج احنالل البشرة السمي الناتج عن الفانكوميسني حممد عاطف النجاري ، ها�صم جافاد ، الك�صندر �صاكو ، اأن�ض الوجود اأحمد عبد املغيث امللخ�ص: يت�صبب انحالل الب�رسة ال�صمي )ten( كثريا يف تفاعل الب�رسة ، التي من املحتمل اأن تهدد احلياة، عن طريق العقاقري. يتميز رد الفعل اجللدي املخاطي بانف�صال للب�رسه الفقاعية والأغ�صية املخاطية. نعر�ض حالة ذكر يباغ من العمر 9 �صهور يعاين من احم�صا�ض الدم امليثيل ارتخاء عام، وتاأخر يف النمو. ذات تاريخ مر�صى من احلمى، وال�صعال، و�صيق يف التنف�ض، والتقيوؤ ملدة 3 اأيام. ظهر طفح جلدي بعد 5 اأيام من العالج بالفانكوماي�صني. �صمل الطفح ما يقرب من %60 من م�صاحة �صطح اجل�صم الكلية وكلتا العينني. عولج بنجاح م�صاعفات مع التام ال�صفاء مت وقدم للجروح، املنا�صب العالج و احليوية، وامل�صادات ،)ivig( الوريدي املناعي الغلوبولني بوا�صطة ل تذكر على الرغم من �صدة مر�صه. العنا�رس الهامة يف جناح العالج ت�صمل التعرف املبكر والرعاية املركزة، الن�صحاب الفوري للعامل قد العدوى. على وال�صيطرة ال�صوائل، طريق عن الإنعا�ض ،)ivig( الوريدي املناعي الغلوبولني بوا�صطة املبكر العالج للمر�ض، امل�صبب لتقييم حاجة هناك ولكن ،)ten( ال�صمي الب�رسة انحالل عالج يف )ivig( الوريدي املناعي الغلوبولني ا�صتخدام املفيد من يكون الدرا�صات التى تقارن الغلوبولني املناعي الوريدي)ivig( بو�صائل اأخرى. مفتاح الكلمات: الغلوبيولني املناعي الوريدي، انحالل الب�رسة ال�صمي، العن�رس املّحفز خلاليا الدم البي�صاء، متالزمة �صتيفن-جون�صن، تقرير حالة، عمان. abstract: toxic epidermal necrolysis (ten), an uncommon but potentially life-threatening skin reaction, is frequently induced by drugs. the mucocutaneous reaction is characterised by bullous detachment of the epidermis and mucous membranes. we present a 9-month-old male with methylmalonic acidaemia, generalised hypotonia, and global developmental delay. he presented with a 3-day history of fever, cough, shortness of breath, and vomiting. eruption appeared after 5 days of vancomycin treatment. the eruption involved almost 60% of the total body surface area and both eyes. he was successfully treated with intravenous immunoglobulin (ivig), antibiotics, and appropriate wound management and made a full recovery with negligible sequelae despite the severity of his disease. important components of successful treatment include early recognition, intensive care, prompt withdrawal of the causative agent, early administration of ivig, appropriate fluid resuscitation, and control of infection. ivig might be beneficial in the treatment of ten; however, controlled studies are needed to evaluate ivig compared to other modalities. keywords: intravenous immunoglobulins; toxic epidermal necrolysis; granulocyte colony-stimulating factor; stevens-johnson syndrome; case report; oman. intravenous immunoglobulin in the treatment of vancomycin-induced toxic epidermal necrolysis *mohamed a. el-naggari, hashim javad, alexander p. chacko, anas a. abdelmogheth case report toxic epidermal necrolysis (ten) is a severe drug-induced life-threatening disease characterised by fulminant, widespread blisters which become responsible for epidermal sloughing. it is associated with high mortality and the majority of patients die from complications related to infection.1 supportive therapies and antiseptics are of paramount importance in the management of patients with ten. recently, a few cases have been treated successfully with intravenous immunoglobulin (ivig). case report this case features a 9-month-old male who had been diagnosed with methylmalonic acidaemia with generalised hypotonia and global mohamed a. el-naggari, hashim javad, alexander p. chacko and anas a. abdelmogheth case report | 133 developmental delay. he presented with a 3-day history of fever, cough, shortness of breath, and vomiting. at presentation, he was lethargic, tachypneic, tachycardic (heart rate range 150–160 beats/minute), and dehydrated. subsequently, he desaturated and was transferred to the paediatric intensive care unit (picu) with the diagnosis of severe metabolic crisis secondary to sepsis, and impending compensated shock. initial investigations showed a sodium level of 142 mmol/l (normal range [nr]: 135–145 mmol/l), potassium 4.6 mmol/l (nr: 2.5–5.1 mmol/l), creatinine 23 umol/l (nr: 15–31 umol/l), urea 9.3 mmol/l (nr: 2.1–7.1 mmol/l), bicarbonate 11 mmol/l (nr: 22–29 mmol/l), albumin 40 g/l (nr: 38–54 g/l), calcium 1.79 mmol/l (nr: 2.1–2.55 mmol/l), alkaline phosphatase 145 u/l (nr: <281 u/l), magnesium 1.1 mmol/l (nr: 0.7–1.05 mmol/l), phosphate 1.67 mmol/l (nr: 1.6–3.5 mmol/l), alanine transaminase (alt) 654 iu/l (nr: 0–41/ l), and aspartate aminotransferase (ast) 863 u/l (nr: 0–38 u/l). a complete blood count (cbc) showed haemoglobin (hb) at 9.6 g/dl (nr: 11.5– 15.5 g/dl), white blood count (wbc) 2.7 109/l (nr: 4.5–14.5 109/l), absolute neutrophilic count (anc) 1.9 109/l (nr: 1.4–9 109/l), and platelet count 284 (nr: 150–450 109/l). the c-reactive protein (crp) was elevated at 32 mg/l (normal range: 0–8 mg/l). initially, he received fluid resuscitation and the acidosis was corrected. careful fluid resuscitation was guided by central venous pressure (cvp) monitoring to avoid fluid overload. the ammonia level was 149 ummol/l (nr: 16–60 ummol/l). measures to lower the hyperammonemic state were begun as the patient was critically sick. a chest x-ray showed bilateral haziness. initially, the patient was treated empirically with cloxacillin and cefotaxime while we awaited the results of the cultures. on the second day, his condition started to deteriorate. he was electively ventilated using pressure-regulated volume control (prvc). we followed the directed goal therapy of management of shock, keeping the mean arterial blood pressure above normal for both age and sex. inotropic supports were escalated to dopamine 20 mcg/kg/min, dobutamine 20 mcg/kg/min, and noradrenaline 0.5 mcg/kg/min along with high doses of hydrocortisone. antibiotics were upgraded to vancomycin, meropenem, and metronidazole. a follow-up cbc showed hb 8.9 g/dl (nr: 11.5–15.5 g/dl), wbc 0.9 109/l (nr: 4.5–14.5 109/l), anc 0.2 109/l (nr: 1.4–9 109/l) and a platelet count of 17 109/l (nr: 150–450 109/l). granulocyte colony-stimulating factor (g-csf) was given for neutropaenia (10 mcg/kg once daily for two days) and then stopped when the neutropaenia resolved. his ammonia level increased to 495 ummol/l, so sodium benzoate and sodium phenyl butyrate were given again as bolus, and then continued as maintenance. his severe metabolic acidosis was corrected with sodium bicarbonate in a continuous infusion over 24 hours. his severe hyperglycaemia, with blood sugar reaching 20 mmol/l, was treated with an insulin infusion. he developed disseminated intravascular coagulopathy, a deranged coagulation profile, thrombocytopenia, haematuria, and bleeding from his stomach and endotracheal tubes. fresh frozen plasma and a platelet transfusion were administered. his vancomycin dose was adjusted on the third day, as the drug level was found to be high (pre-dose 23.1 mg/dl (nr: 5–15 mg/dl); post-dose 44.3 mg/dl (nr: 20–40 mg/dl)). in addition, the metronidazole was stopped. his ammonia level came down to 75 ummol/l. our aim was to keep his ammonia level below 100 ummol/l. the g-csf was restarted at a higher dose as the neutrophils dropped. the metabolic crisis then settled, with stable vital signs and clinical parameters, and no more metabolic acidosis or hyperammonemia. all blood, urine, and endotracheal tube secretion cultures were negative. on the sixth day, the patient started to have extensive diffuse erythematous skin lesions. these appeared 5 days after starting vancomycin. his fever ranged from 38.5 to 39.2o c as the rash evolved. the rash started on the left axilla and then extended to cover most of his trunk, front, back, and inguinal and perineal regions and, finally, the extremities. at its maximum coverage, the rash covered almost 60% of the total body surface area. the lesions were erythematous and hyperpigmented mainly on flexural sites and below the cardiac monitoring electrodes. there were spots and atypical targets leading to a confluent exanthema. on these lesions, blisters occurred with some of them becoming confluent. oral mucosal hyperaemia and erosions also appeared. these lesions were diagnosed as vancomycin-induced toxic epidermal necrolysis. experts in the paediatric field, and a drug reaction and consultant dermatologist confirmed our intravenous immunoglobulin in the treatment of vancomycin-induced toxic epidermal necrolysis 134 | squ medical journal, february 2013, volume 13, issue 1 clinical diagnosis. vancomycin was stopped and ivig (0.5 gm/kg) was started to treat the ten for 5 days. the skin lesions also involved both of the eyelids and interfered with the closing of the eyes. an ophthalmologic examination showed the ocular mucosa was affected by erosions, corneal abrasions, and abnormally directed lashes. the neutrophil count gradually increased and then stabilised. the entire skin fully recovered, although some pigmentation persisted. ophthalmological manifestations were managed medically with a good outcome. the diagnosis of ten in our patient was based on its classic presentation: 1) prodromal phase with fever and upper respiratory tract symptoms; 2) ophthalmological and oral mucous membrane involvement; 3) typical skin lesions involving more than 10% of the total surface area of the skin with positive nikolsky’s sign;2 4) exclusion of other differential diagnoses, including burns, pemphigus/ pemphigoid disease, erythema multiforme (their exclusion depended on which expert or illustrated medical atlas was consulted);3 5) superficial skin swabs and all septic work-ups were negative; the patient’s improvement after the withdrawal of vancomycin made toxic shock syndrome unlikely. a skin biopsy was not done as our patient was critically ill and immunocompromised. infection and sepsis are the main causes of death in patients with ten. it is recommended that all efforts should be made to reduce the risk of infection in order to improve survival.1 we depended on our clinical diagnosis in the management of the child.4 the patient’s score of toxic epidermal necrosis (scorten) should be calculated within the first 24 hours of admission and again on day 3. scorten is the sum of 7 measured clinical variables: age; heart rate; the presence of cancer or haematologic malignancy; the percentage of epidermal detachment; and blood, glucose, urea, and bicarbonate levels. our patient’s scorten was as follows: 1) age >40 years? no; 2) heart rate >120 beats per minute? yes; 3) presence of cancer or hematologic malignancy? no; 4) percentage of epidermal detachment involving body surface area >10% on day 1? yes; 5) blood urea nitrogen level >28 mg/dl? no, it was 10 mmol/l ; 6) glucose level >252 mg/dl? yes, it was 14 mmol/l; 7) bicarbonate level <20 meq/l? yes. one point is given for each positive variable and the mortality increases sharply with each additional point. our patient’s total score was 4. a scorten of 0 to 1 predicts 3.2% mortality; 2 predicts 12.1% mortality; 3 predicts 35.3% mortality; 4 predicts 58.3% mortality; 5 or greater predicts 90.0% mortality. scorten has proven to be extremely accurate in predicting mortality. discussion ten is also called lyell’s syndrome, after alan lyell who in 1956 described 4 cases of ten in patients who exhibited eruptions resembling a scalding of the skin.4 despite under-reporting, the incidence of ten in oman has been found to be two per million, with a total 4 patients and 5 episodes, figure 1: patient’s skin with positive nikolsky’s sign. figure 2: patient’s skin with target sign. mohamed a. el-naggari, hashim javad, alexander p. chacko and anas a. abdelmogheth case report | 135 which is just somewhat higher than the incidence reported in other studies (0.5 to 1.2 per million).6 ten is an acute onset, potentially life-threatening, idiosyncratic mucocutaneous reaction which usually occurs after commencement of a new medication. widespread full-thickness epidermal necrosis develops, producing erythema, large blisters, and detachment of large sheets of skin leaving a raw base.7 the skin develops an appearance similar to that which occurs upon receiving a scalding burn. it usually affects the trunk, face, and one or more mucous membranes. it is considered by some to be part of a spectrum of diseases including, in order of severity, erythema multiforme, stevens-johnson syndrome (sjs), and ten. however, others argue that as erythema multiforme is associated with infections such as herpes simplex virus and mycoplasma pneumonia, sjs and ten are necrolytic bullous reactions to certain drugs. therefore, erythema multiforme should not be classified as part of the same disease spectrum.7 regional reference in drug prescriptions, the genetic background of patients (e.g. human leukocyte antigen [hla] and metabolising enzymes), and the coexistence of other diseases can have an impact on the incidence of ten.7 another classification system is based on the fact that sjs and ten are related conditions which can be differentiated by the degree of skin involvement. less than 10% of the epidermis sloughs off in sjs as compared with >30% in ten.1,2,8 marcus proposed that a new medication will have been started shortly before the onset of symptoms in all children who develop ten. the mean duration of medication therapy until onset of symptoms in children with ten was 11 ± 2 days. ten occurred after starting antibiotics in 73% of patients in marcus’s study.9 an adverse drug reaction is defined as a response to a drug which is noxious and unintended that occurs at doses normally used for prophylaxis, diagnosis or therapy of disease, or for the modification of physiologic function.7 type a reactions are dose-dependent and predictable while type b reactions (idiosyncratic) are dose -independent. a severe cutaneous adverse drug reaction happens when such a response leads to changes in the structure and/or function of the skin, its appendages or mucous membrane, resulting in outcomes such as death, life-threatening events, hospitalisation, disability or interventions to prevent permanent impairment or damage.1,10 the pathogenesis of ten is still not fully understood. the widespread epidermal death is thought to be a consequence of keratinocyte apoptosis. a pivotal role of cytotoxic lymphocytes has been suggested.1,10 recent studies indicate that ten may be a major histocompatibility complex (mhc) class-i-restricted specific drug sensitivity resulting in clonal expansion of cd8+ cytotoxic lymphocytes with potential for cytolysis. the cytotoxicity is apparently mediated by granzymes, which are serine proteinases that are components of cytotoxic cells and natural killer cell granules.11 chung et al. found that granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme b, or soluble f as ligand concentrations, and depleting granulysin reduced the cytotoxicity. granulysin in the blister fluids was in a 15-kda secretory form, and injection of it into mouse skin resulted in features mimicking sjs/ten. these findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in sjs/ten.12 children with ten are best managed in burn units; however, as shown by prendiville et al., children with ten also can be treated successfully in picus. important strategies of success include meticulous wound care and prevention of all systemic and local infections.13 the optimal treatment of the blistering skin is a major issue discussed in the literature. most centres, including ours, follow recommendations made by prendiville et al., who advocated removal of only spontaneously blistering skin and did not recommend additional debridement. the group based this recommendation on the fact that the skin re-epithelialises under intact blisters. open areas were covered with topical antimicrobial agents and 0.5% silver nitrate dressing.13 as for adjuvant administration of mediator-neutralising effectors of keratinocyte apoptosis in the form of intravenous immunoglobulin, it has shown beneficial effects on survival in adult patients. however, most studies of this aspect of treatment in ten lack evidence or are based on prospective studies on large patient groups.1 intravenous immunoglobulin in the treatment of vancomycin-induced toxic epidermal necrolysis 136 | squ medical journal, february 2013, volume 13, issue 1 the use of ivig promotes inhibition of fasmediated keratinocyte apoptosis by fas-blocking antibodies contained in ivig preparations and it also decreases life-threatening infections. we used ivig in our patient 24 hours after the first appearance of skin lesions. three days later, epidermal detachment was interrupted and complete skin re-epithelisation was completed within two weeks. we think that poor prognostic factors delayed the skin re-epithelisation in our patient.14 neutropaenia is regarded as an important negative prognostic factor.14 in our case, neutropaenia was related to bone marrow suppression initially to methylmalonic acidaemia, and later to the development of ten. the neutrophilic count improved and reached normal levels within 10 days of g-csf administration. our patient made an excellent recovery despite poor prognostic factors due to the early introduction of ivig and the immediate removal of the medication thought to be the cause of ten (vancomycin). we believe that ivig played a significant role in the recovery of this child. our experience of using ivig in the treatment of ten with a favourable outcome could be useful to those in other arabian gulf countries, whose citizens’ genetic and environmental circumstances are similar to those of our patient.15 conclusion ten is an acute, life-threatening, exfoliative disorder with a high mortality rate. high clinical suspicion, prompt recognition, and initiation of supportive care are mandatory. we suspect that ivig was significantly responsible for this patient’s clinical improvement, despite the controversial efficacy of ivig in treatment of ten. a thorough investigation of the pathogenetic mechanisms is fundamental. optimal treatment guidelines are still unavailable. multi-institutional collaborative efforts to develop better treatment strategies are warranted. references 1. freiman a, borsuk d, sasseville d. dermatologic emergencies. cmaj 2005; 22, 173: 1317–19. 2. del pozzo-magana br, lazo-langner a, carleton b, castro-pastrana li, rieder mj. a systematic review of treatment of drug-induced stevens johnson syndrome and toxic epidermal necrolysis in children. j popul ther clin pharmacol 2011; 18:121–33. 3. bastuji-garin s, rzany b, stern rs, shear nh, naldi l, roujeau jc. clinical classification of cases of toxic epidermal necrolysis, stevens-johnson syndrome, and erythema multiforme. arch dermatol 1993; 129:92–6. 4. levi n, bastuji-garin s, mockenhaupt m, roujeau jc, flahault a, kelly jp, et al. medications as risk factors of stevens-johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. pediatrics 2009; 123:297–303. 5. lyell a. toxic epidermal necrolysis: an eruption resembling scalding of the skin. br j dermatol 1956; 68:355–61. 6. al-raaie f, banodkar dd. epidemiological study of cutaneous adverse drug reactions in oman. oman med j 2008; 23:21–7. 7. becker ds. toxic epidermal necrolysis. lancet 1998; 351:1417–20. 8. harr t, french le. toxic epidermal necrolysis and stevens-johnson syndrome. orphanet j rare dis 2010; 16:5–39. 9. spies m, sanford ap, aili low jf, wolf se, herndon dn. treatment of extensive toxic epidermal necrolysis in children. pediatrics 2001; 108:1162–8. 10. ofoma ur, chapnick ek. fluconazole induced toxic epidermal necrolysis: a case report. cases j 2009; 20:9071. 11. cohen s, billig a, ad-el d. ceftriaxone-induced toxic epidermal necrolysis mimicking burn: a case report. j med case rep 2009; 3:9323. 12. chung wh, hung si, yang jy, su sc, huang sp, wei cy, et al. granulysin is a key mediator for disseminated keratinocyte death in stevens-johnson syndrome and toxic epidermal necrolysis. nat med 2008; 14:1343–50. 13. prendiville js, hebert aa, greenwald mj, esterly nb. management of stevens-johnson syndrome and toxic epidermal necrolysis in children. j pediatr 1989; 115:881–7. 14. kayoncu m, cimsit g, cakir m, okten a. toxic epidermal necrolysis treated with intravenous immunoglobulin and granulocyte colony-stimulating factor. indian pediatr 2004; 41:392–5. 15. al-mutairi n, arun j, osama ne, amr z, mazen as, ibtesam el-a, et al. prospective, noncomparative open study from kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis. int j dermatol 2004; 43:847–51. editor’s note this is the first of what we hope will be a regular feature in the squmj. for each issue, we will scan the cochrane library for what is new and aim to select five or six reviews which we think will be of interest to readers. we hope you will find this a valuable resource. feedback and suggestions for topics to cover will be welcomed. the cochrane library of systematic reviews is published quarterly as a dvd and monthly online. the march 2012 on-line issue contained 5,010 complete reviews, 2,153 protocols for reviews in production and 16,773 short summaries of systematic reviews published in the general medical literature. in addition, there are citations of 670,000 randomized controlled trials, and 15,000 cited papers in the cochrane methodology register. the impact factor of the cochrane library stands at 6.186. introduction this article comments on six reviews covering a range of topics including childbirth, cancer care, pneumonia and the newborn. we describe the findings of these reviews and discuss implications for practice, draw out any learning points, and are critical where we feel that is justified. readers are encouraged to access the full report for any articles of interest as only a brief commentary is provided. medications for increasing milk supply in mothers expressing breast milk for their preterm hospitalised infants most authorities recognise that breast milk is the optimal form of nutrition for term and preterm infants. often mothers of preterm infants may have to express their breast milk which may prove difficult. this review looked for evidence of medicines that could be used to increase breast milk supply and the authors looked for randomised controlled trials (rcts) that might answer this question. they only found two trials with a total of 59 participants. both trials used domperidone at a dose of 10 mg for three times a day; it was used for seven days in one trial and fourteen days in the other. when the numbers were combined in meta-analysis, there was a small increase in milk volume expressed of just under 100 ml but with wide confidence intervals. there were no long term benefits but also no adverse effects. these studies are too small to be reliable and suggest any benefit may be small. more studies are needed to confirm the result. this is not an uncommon finding in cochrane reviews. this article should be cited as: donovan tj, buchanan k. medications for increasing milk supply in mothers expressing breast milk for their preterm hospitalized infants. cochrane database syst rev 2012, issue 3. art. no.: cd005544. doi: 10.1002/14651858.cd005544.pub2. oxygen therapy for pneumonia in adults the authors state that although oxygen therapy is widely used in lung diseases its effectiveness as a treatment for pneumonia is not well known. they looked for rcts of oxygen therapy in adults with community or hospital acquired pneumonia being treated in intensive care units. three rcts (151 participants) met the inclusion criteria. the results showed that non-invasive ventilation can reduce the risk of death in the intensive care unit (icu), with an odds ratio (or) 0.28, 95% confidence interval (ci) 0.09 to 0.88; lessen the need for endotracheal intubation, or 0.26, 95% ci 0.11 to 0.61; lower the rate of complications, or 0.23, 95% ci 0.08 to 0.70; and shorten icu length of stay. non-invasive ventilation and standard oxygen supplementation via a venturi mask were similar when measuring mortality in hospital (or 0.54, 95% ci 0.11 to 2.68); two-month survival (or 1.67, 95% ci 0.53 to 5.28); duration of hospital stay (mean duration [md] 1.00, 95% ci 2.05 to 0.05); and duration of mechanical ventilation, standard (md 0.26, 95% ci -0.66 to 0.14). some outcomes and complications of non-invasive ventilation varied according to different participant populations. what does this mean? خمتارات من مكتبة كوكرين فيل ويفني، مها اخل�صوري، خ�رصة جالل selections from the cochrane library *phil j. wiffen,1 maha al-khaduri,2 khadra galaal3 abstracts sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp., epub. 539-541, 20th nov 12 1pain research unit, churchill hospital, oxford, uk, and cochrane collaboration pain palliative and supportive care collaborative review group; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman; 3department of gynaecological oncology, queen elizabeth hospital, gateshead, uk, and cochrane gynaecological cancer group *corresponding author e-mail: phil.wiffen@ndcn.ox.ac.uk selections from the cochrane library 540 | squ medical journal, november 2012, volume 12, issue 4 the first figure above: odds ratio (or) 0.28, 95% confidence interval (ci) 0.09 to 0.88 means that the intervention reduced the risk of death by 72% (1 minus 0.28). however, the confidence intervals mean this could be as good as a 91% reduction or as poor as a 12% reduction. this result comes from one study of 52 patients. 10/26 died in the non-invasive group and 18/26 in the standard treatment group. this gives a relative risk of 56% which is not quite as impressive as 72%. based on this small amount of evidence, we can say that non-invasive ventilation can reduce the risk of death in the icu, lessen the need for endotracheal intubation, and shorten both the icu stay and length of intubation. this article should be cited as: zhang y, fang c, dong br, wu t, deng jl. oxygen therapy for pneumonia in adults. cochrane database syst rev 2012, issue 3. art. no.: cd006607. doi: 10.1002/14651858.cd006607.pub4. enteral iron supplementation in preterm and low birth weight infants the authors state that it is common practice to give enteral iron supplementation to preterm and low birth weight infants on order to prevent iron deficiency anaemia. we do not know whether such supplementation improves growth and neurodevelopment. it may in fact do more harm than good. rcts were sought that compared prophylactic iron supplementation by mouth with either no iron or with a different regime of iron in preterm and low birth weight infants. the authors found twenty-six studies (2,726 infants) for their analysis. the heterogeneity of participants, methods and results precluded an extensive quantitative synthesis. of the 21 studies comparing iron supplementation with controls, none evaluated neurodevelopmental status as an outcome. when looking at haematological outcomes, no benefit for iron supplementation was seen in the first 8.5 weeks of postnatal life (16 trials), except by two poor quality studies. after 8.5 weeks most studies reported higher mean haemoglobin in those given iron supplementation. despite the quantity of data, we can conclude that the results are uncertain. this article should be cited as: mills rj, davies mw. enteral iron supplementation in preterm and low birth weight infants. cochrane database syst rev 2012, issue 3. art. no.: cd005095. doi: 10.1002/14651858.cd005095.pub2. hyperbaric oxygenation for tumour sensitisation to radiotherapy cancer is a common disease and radiotherapy is one well-established treatment for some solid tumours. hyperbaric oxygenation (hbo) may improve the ability of radiotherapy to kill hypoxic cancer cells, so the administration of radiotherapy while breathing hbo may result in a reduction in mortality and recurrence. randomised and quasi-randomised studies comparing the outcome of malignant tumours following radiation therapy while breathing hbo versus air were sought. nineteen trials contributed to this review (2,286 patients). with hbo, there was a reduction in mortality for head and neck cancers at both one year and five years after therapy (relative risk (rr) 0.83, p = 0.03, and in the number needed to treat (nnt) = 11 and rr 0.82, p = 0.03, nnt = 5 respectively), as well as improved local tumour control at three months (rr with hbot 0.58, p = 0.006, nnt = 7). the effect of hbo varied with different fractionation schemes. we saw above the importance of cis, but unfortunately these are not reported in the abstract. the authors state that “there is some evidence that hbo improves local tumour control and mortality for cancers of the head and neck, and local tumour recurrence in cancers of the head and neck, and uterine cervix.” however, this needs to be put in context. hbo chambers cost around us $150,000 (c. omani riyals 57,750) per chamber supplied and installed. with an nnt of 11, eleven patients have to be exposed to hbo to see one more person alive at one year, or 5 patients have to be exposed to hbo to see one more person alive at 5 years. the upper ci is around 20 in which case 20 would need to be exposed to hbo for one to benefit at 5 years. in addition, with a number needed to harm of 8, for every 8 exposed to hbo, one more will suffer from severe radiation tissue injury compared to those not exposed. this article should be cited as: bennett mh, feldmeier j, smee r, milross c. hyperbaric oxygenation for tumour sensitisation to radiotherapy. cochrane database syst rev 2012, issue 4. art. no.: cd005007. doi: 10.1002/14651858.cd005007.pub3. centralisation of services for gynaecological cancer gynaecological cancers are the second most common cancers among women. it has been suggested that centralised care improves outcomes but consensus is lacking. this review aimed to assess the effectiveness of centralisation of care for patients with gynaecological cancer. they looked for rcts, quasi-rcts, controlled before-and-after studies, interrupted time series studies, and observational studies. five studies met the inclusion criteria but all were retrospective observational studies and therefore at high risk of bias. this type of study is not as reliable as an rct. when the authors combined three studies assessing over 9,000 women, it was found that institutions with gynaecological oncologists on site may prolong survival in women with ovarian cancer, compared to community or general hospitals: the hazard ratio (hr) of death was 0.90 (95% ci 0.82 to 0.99). this is only a modest improvement. by combining three other studies assessing over 50,000 women, it showed that teaching centres or regional cancer centres may prolong survival in women with any gynaecological cancer compared to community or general hospitals (hr 0.91; 95% ci 0.84 to 0.99) here is evidence, but of rather low quality, to suggest that women with gynaecological cancer who received treatment in specialised centres lived longer. this article should be cited as: woo yl, kyrgiou m, bryant a, everett t, dickinson ho. centralisation of services for gynaecological cancer. cochrane database syst rev 2012, issue 3. art. no.: cd007945. doi: 10.1002/14651858.cd007945.pub2. phil j. wiffen, maha al-khaduri and khadra galaal abstracts | 541 pain management for women in labour: an overview of systematic reviews this review is of a new type—an overview that summarises the evidence from other reviews. normally, this type of review is based on existing cochrane reviews but in this case the authors also included other published reviews. the authors looked at all pain management strategies include non-pharmacological interventions (coping with pain) and pharmacological interventions (pain relief ).to summarise the evidence from cochrane systematic reviews on the efficacy and safety of non-pharmacological and pharmacological interventions to manage pain in labour, the authors considered findings from non-cochrane systematic reviews if there was no relevant cochrane review. fifteen cochrane reviews (255 included trials) and three non-cochrane reviews (55 included trials) were included. the authors divided the results into 3 sections: what works? the authors state that epidural, combined spinal epidural (cse) and inhaled analgaesia effectively manage pain in labour, but may give rise to adverse effects. combined-spinal epidurals relieve pain more quickly than traditional or low dose epidurals. women receiving inhaled analgaesia were more likely to experience vomiting, nausea and dizziness. women receiving epidural analgaesia were more likely to experience hypotension, motor blockade, fever or urinary retention. less urinary retention was observed in women receiving cse than in women receiving traditional epidurals. what may work? there is some evidence to suggest that immersion in water, relaxation, acupuncture, massage and local anaesthetic nerve blocks or non-opioid drugs may improve management of labour pain, with few adverse effects. evidence was mainly limited to single trials. these interventions relieved pain and improved satisfaction with pain relief (immersion, relaxation, acupuncture, local anaesthetic nerve blocks, non-opioids) and childbirth experience (immersion, relaxation, non-opioids) when compared with placebo or standard care. relaxation was associated with fewer assisted vaginal births and acupuncture was associated with fewer assisted vaginal births and caesarean sections. insufficient evidence.the authors stated there was insufficient evidence to answer effectiveness questions for hypnosis, biofeedback, sterile water injection, or aromatherapy. the authors were hampered by the lack of standard assessment methods for pain and pain relief in these studies. this article should be cited as: jones l, othman m, dowswell t, alfirevic z, gates s, newburn m, jordan s, lavender t, neilson jp. pain management for women in labour: an overview of systematic reviews. cochrane database syst rev 2012, issue 3. art. no.: cd009234. doi: 10.1002/14651858.cd009234.pub2. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. e459-462, epub. 25th jun 13 submitted 17th aug 12 revision req. 7th oct 12; revision recd. 25th oct 12 accepted 19th dec 12 placental tumours are broadly divided into trophoblastic and non-trophoblastic tumours. the latter include chorioangiomas, teratomas, haemangiomas and haematomas. placental chorioangiomas are benign vascular tumours and are the most common placental tumours with a prevalence of 1%.1 large placental chorioangiomas are rare and may lead to pregnancy complications and poor perinatal outcomes, including fetal anaemia, hydrops fetalis, growth restriction, polyhydramnios and preterm delivery.1 we report a case of a large placental chorioangioma, the antenatal management and the maternal and fetal outcomes. case report a 36-year-old gravida 5 healthy woman was diagnosed with a vascular placental tumour on ultrasound at 25 weeks of gestation. the tumour was 1 x 1 cm in size, with mixed echogenicity and well-defined margins. until then, the patient had had an otherwise normal pregnancy with a negative serology for hepatitis and hiv and normal fetal anatomy scan. the woman had no significant past medical or surgical history. she had had two previous, full-term spontaneous vaginal deliveries and two spontaneous, first-trimester abortions. the initial scan evaluated in detail the placental function, characteristics of the tumour and the fetal anatomy. there were no fetal tumours or any other anomalies noted on that scan. follow-up scans during pregnancy showed an increase in the tumour size, with it reaching a maximum of 6 x 5 cm at 32 weeks of gestation. the tumour was within the centre of the umbilical cord insertion with a central feeding vessel [figures 1 & 2]. a provisional diagnosis of chorioangioma was made and the patient was assessed weekly in the high-risk clinic for any signs of maternal or fetal complications. the woman was well throughout the pregnancy with no antenatal complications such departments of 1obstetrics & gynaecology and 2pathology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drriyami@hotmail.com ورم املشيمة ماذا ميكن أن يكون؟ نهال الريامي، رحمه الهدابي، مروة الريامي امللخ�ص: ت�شمل اأورام امل�شيمة على اأورام وعائية م�شيمية، اأورام م�شخية، اأورام وعائية دموية واأورام دموية. الأورام الوعائية امل�شيمية هي اأورام دموية حميدة واأكرث اأورام امل�شيمة �شيوعاً، بواعق انت�شار %1. الأورام الوعائية امل�شيمية الكبرية تعترب نادرة وقد توؤدي اإىل م�شاعفات احلمل و�شوء نتائج الفرتة املحيطة بالولدة. وت�شمل هذه امل�شاعفات فقر الدم اجلنيني، ا�شت�شقاء اجلنني، تقييد منو اجلنني، موه ال�شلى والولدة قبل الأوان. نعر�ص هنا تقرير حالة ورم وعائي م�شيمي كبري، واإدارة الرعاية ال�شابقة للولدة، ونتائج الأمومة واجلنني. مفتاح الكلمات: امل�شيمة؛ ورم وعائي م�شيمي؛ فقر الدم؛ اجلنني؛ موه ال�شلى؛ تقرير حالة؛ ُعمان. abstract: placental tumours include placental chorioangiomas, teratomas, haemangiomas, and haematomas. placental chorioangiomas are benign vascular tumours and are the most common placental tumours, with a prevalence of 1%. large placental chorioangiomas are rare and may lead to pregnancy complications and poor perinatal outcomes. these complications include fetal anaemia, hydrops fetalis, fetal growth restriction, polyhydramnios, and preterm delivery. we report a case of a large placental chorioangioma, the antenatal management and the maternal and fetal outcomes. keywords: placenta; chorioangioma; anemia, fetal; polyhydramnios; case report; oman. placental tumour what could it be? *nihal al-riyami,1 rahma al-hadabi,1 tamima al-dughaishi,1 marwa al-riyami,2 online case report placental tumour what could it be? 460 | squ medical journal, august 2013, volume 13, issue 3 as pregnancy-induced hypertension or gestational diabetes. the fetus was monitored closely and the mother was also asked to monitor its movements. growth scans were performed every two weeks to exclude intrauterine growth restriction (iugr), and a weekly biophysical profile, done by doppler, included measurements of the middle cerebral artery peak systolic velocity (mca-psv). the cardiac function of the fetus was assessed and, fortunately, there were no signs of compromise such as cardiomegaly, abnormal ductus venosus (dv) waveforms, or signs of fetal hydrops. there was no evidence of polyhydramnios, iugr or fetal anaemia on follow-up scans. at 37 weeks and 3 days of gestation, the patient complained of reduced fetal movements; a scan showed a collapsed tumour 4 x 3 cm in size with less vascularity and irregular margins. there were no changes in the doppler measurement of mca-psv or in cardiac function. labour was induced and the patient had a spontaneous vaginal delivery of a healthy male baby of 2,730 g with apgar scores of 9 and 10 at 1 and 5 minutes, respectively. the postnatal assessment of the baby showed no evidence of anaemia or thrombocytopaenia. on macroscopic examination of the placenta, the umbilical cord was triplevesselled and unremarkable, and the extraplacental membranes were translucent. the placental disc was 19 cm x 16 cm x 4 cm with a trimmed weight of 666 g. beneath the insertion of the umbilical cord, a 2 cm pale-brown intraparenchymal lesion was noted adjacent to which was a cystic space; together, these measured 4.5 cm across. histopathological examination of the pale area showed an infracted chorangioma formed of a network of dilated cavernous type vessels lined by cd-31 positive endothelial cells with intervening collagenous stroma [figure 3]. the cystic space did not have a true lining and its wall was continuous with the chorionic plate. placental villi were appropriate for gestational age and were unremarkable. discussion placental chorioangiomas are the most common placental tumours, with a prevalence of 1%. they are thought to be hamartomatous lesions rather than true neoplasms and should be differentiated from other placental tumours.1–3 large placental chorioangiomas measuring more than 4 cm in size are rare, with an incidence of 1:500–1:16,000, and are associated with several perinatal complications including intrauterine fetal demise and premature birth.1–8 the main differential diagnoses include chorangiosis, chorangiomatosis and rare chorangiomas with trophoblastic proliferation. this case of a large placental chorioangioma was followed very closely during the antenatal period. fortunately, no complications occurred for either the mother or the fetus, except that the chorioangioma became infarcted at 37 weeks of gestation, requiring induction of labour. it is known that large tumours may produce degenerative phenomena like necrosis, calcifications, hyalinisation and infarction. the infarction usually occurs spontaneously, leading to a decrease in echogenicity, tumour volume and blood flow on colour doppler images, as observed in this case.9 figure 1: placental chorioangioma of 6 x 5 cm in size within the centre of the umbilical cord with a feeding vessel. figure 2: well-circumscribed lesion (arrow) within the placenta just beneath the insertion of the umbilical cord (asterisk). it had a pale tan cut surface. nihal al-riyami, rahma al-hadabi, tamima al-dughaishi and marwa al-riyami case report | 461 the recurrence risk of chorangiomas is rare, but there are occasional reports of such cases, suggesting some environmental or genetic predisposition.10 for example, there is a strong relationship between placental chorangiomas and gestation at high altitudes, suggesting the occurrence of vascular growth factors induced by hypoxia.11 fetal growth restriction has been reported in association with large placental tumours.12 the theory is not yet clear, but it could be due to these large vascular tumours acting as a physiological and functional dead space leading to placental insufficiency, chronic hypoxia, fetal compromise, fetal growth restriction and even death. fetal anaemia could also result from these large tumours.13 close monitoring with doppler measurement of mca-psv, and looking for early signs of hyperdynamic circulation, are essential actions as fetal cardiomegaly is important during the antenatal period. early detection could prevent subsequent major complications, such as fetal death by antenatal interventions like in utero fetal blood transfusion and early delivery at a reasonable gestational age. our patient was followed very closely with weekly scans looking for early signs of fetal anaemia and biweekly growth scans to rule out fetal growth restriction. a large series of 19 cases with giant placental chorioangiomas was reported recently. of those, 18 resulted in a variety of fetal complications, including fetal growth restriction in 6 cases and one with one stillbirth at 34 weeks’ gestation due to severe placental insufficiency and the mother's refusal of an early delivery.14 polyhydramnios was reported in three cases, out of which two required amnioreduction.14 this series also included the antenatal interventions performed in fetuses with evidence of hyperdynamic circulation to prevent the development of hydrops fetalis. the intervention included fetoscopic laser treatment in one case, preterm delivery in one case, and interstitial laser therapy in three cases.14 other possible interventions include fetoscopic devascularisation of the tumour by suture ligation of the arterial blood supply and alcohol ablation of the feeding vessel.15,16 another group in chile reported their experience with placental chorioangiomas, with 11 cases diagnosed over a 5-year period.17 polyhydramnios and preterm delivery were the most common complications. they concluded that amnioreduction in selected cases may improve the perinatal outcome; fetal hydrops carries the highest risk of perinatal death, and close follow-up of cases with no associated findings at the time of diagnosis is very important. conclusion large placental chorioangioma are rare and may lead to adverse perinatal outcomes. prenatal diagnosis of these tumours with close follow-up during the antenatal period and early intervention is crucial, and may result in a healthy mother and fetus. references 1. amer hz, heller ds. chorangioma and related vascular lesions of the placenta a review. fetal pediatr pathol 2010; 29:199–206. 2. sepulveda w, aviles g, carstens e, corral e, perez n. prenatal diagnosis of solid placental masses: the figure 3 a to c: (a & b) encapsulated lesion formed of variably-sized dilated and congested vessels. the lesion had undergone infarction. no chorionic villi were seen. (c) the cd-31 immunostain highlights the endothelial cells lining the vascular spaces. placental tumour what could it be? 462 | squ medical journal, august 2013, volume 13, issue 3 value of color flow imaging. ultrasound obstet gynecol 2000; 16:554–8. 3. zalwl y, weisz b, gamzu r, schiff e, shalmon b, achiron r. chorangiomas of the placenta: sonographic and doppler flow characteristics. j ultrasound med 2002; 21:909–13. 4. taori k, patil p, attarde v, et al. chorioangioma of placenta: sonographic features. j clin ultrasound 2008; 36:113–15. 5. wallenburg hcs. chorioangioma of the placenta: 13 new cases and a review of literature from 1939 to 1970 with special reference to the clinical complications. obstet gynecol surv 1971; 26:411–25. 6. kurt b. recent trends in chorangiomas, especially those of multiple and recurrent chorangiomas. pediatr dev pathol 1999; 2:264–9. 7. guschmann m, henrich w, entazami m, dudenhausen jw. chorioangioma new insights into a well-known problem. 1. results of a clinical and morphological study of 136 cases. j perinatal med 2003; 31:163–9. 8. hamid a, hadi jf, strickland d. placental chorioangioma: prenatal diagnosis and clinical significance. am j perinatol 1993; 10:146–9. 9. reshetnikova os, burton gj, milovanov ap, fokin ei. increased incidence of placental chorioangioma in high-altitude pregnancies: hypobaric hypoxia as a possible etiologic factor. am j obstet gynecol 1996; 174:557–61. 10. imdad a, sheikh l, malik a. a large chorioangioma causing intrauterine foetal demise. j pak med assoc 2009; 59:580–1. 11. kirkpatrick ad, podberesky dj, gray ae, mcdermott jh. best cases from the afip: placental chorioangioma. radiographics 2007; 27:1187–90. 12. mucitelli dr, charles ez, kraus ft. chorioangiomas of intermediate size and intrauterine growth restriction. pathol res pract 1990; 186:455–8. 13. haak mc, oosterhof h, mouw rj, oepkes d, vandenbussche fp. pathophysiology and treatment of fetal anemia due to placental chorioangioma. ultrasound obstet gynecol 1999; 14:68–70. 14. zanardini c, papageorghiou a, bhide a, thilaganathan b. giant placental chorioangioma: natural history and pregnancy outcome. ultrasound obstet gynecol 2010; 35:332–6. 15. quintero ra, reich h, romero r, johnson mp, gonzalves l, evans mi. in utero endoscopic devascularization of a large chorioangioma. ultrasound obstet gynecol 1996; 8:48–52. 16. wanapirak c, tongsong t, sirichotiyakul s, chanprapaph p. alcoholization: the choice of intrauterine treatment for chorioangioma. j obstet gynecol 2002; 28:71–5. 17. sepulveda w, alcalde jl, schnapp c, bravo m. perinatal outcome after prenatal diagnosis of placental chorioangioma. obstet gynecol 2003; 102:1028–33. مؤمتر علم الوراثة الثاين علم الوراثة يف البلدان النامية، حتديات فريدة وفرص جامعة ال�سلطان قابو�س، 9-11 مار�س 2014 2nd genetics conference genetics in developing countries, unique challenges and opportunities sultan qaboos university, 9–11 march 2014 online abstracts oral presentations quantitative genetic analysis of metabolic syndrome traits using extended families: a direction towards exome sequencing fahad al-zadjali department of biochemistry, sultan qaboos university, muscat, oman. e-mail: fahad.alzadjali@gmail.com the global disease pattern has shifted, with a more dominant prevalence of chronic disease such as type 2 diabetes, metabolic syndrome, cancer and cardiovascular diseases. the inter-population differences in the prevalence of these diseases support the role of genetics and biological factors in the aetiology of these diseases. most of the candidate gene and genome-wide association studies are conducted on large cohort of unrelated individuals. this has a major limitation due to the population subdivision and admixture that may lead to disease association even in the absence of linkage. recent studies have focused on the use of extended family pedigrees in the study of heritability and genetic associations of complex traits like metabolic syndrome. rapid developments in recent years with statistical methods have used family-based association designs to infer allelic association and linkage. in oman, each individual is traditionally genealogically well-defined within their family tribe. in addition, omani families have maintained homogeneity with extremely high levels of inbreeding due to the tradition of encouraging consanguineous marriages, mostly between first cousins. therefore, omani families in geographically-isolated regions like nizwa provide a unique ideal population to provide the statistical power required to study complex diseases with confidence. the oman family study consists of multigenerational pedigree subjects, descended from a small number of founders just a few generations ago, and with environmental homogeneity, restricted geographical distribution, detailed records, well-ascertained and validated pedigrees and a history of inbreeding. these families are used as a model to study the traits of metabolic syndrome: adiposity, hyperglycaemia, dyslipidaemia and hypertension. we have studied the heritability of these traits and the attributions of genetic loci for the adiponectin gene. further analysis was done on genetic and familial clustering in non-alcoholic fatty liver disease as a complication of metabolic syndrome. with the emerging roles of exome sequencing and dark inheritance from rare variants, we identified clusters of inheritance units within one family, in which there were different segregations of type 2 diabetes. these units provide an excellent model to identify rare variants that contribute to the genetics of type 2 diabetes. clinical and molecular genetic characteristics of primary open-angle glaucoma in oman *rayhanah a. al-mjeni,1 matthew n. bainbridge,2 nadiya al-kharousi,3 rana al-senawi,3 donna m. muzny,2 dalal al-mohammedawi,1 anuradha ganesh,3 richard a. gibbs,2 marie-claude gingras,2 said al-yahyaee1 departments of 1genetics and 3opthalmology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2human genome sequencing center, department of molecular & human genetics, baylor college of medicine, houston, texas, usa. *corresponding author e-mail: rayhanah@squ.edu.om glaucoma, an ocular neuropathy causing irreversible blindness, is both clinically and genetically diverse. deoxyribonucleic acid (dna) samples from nine families in oman were collected for the identification of potential causative genetic factors driving the disease. four of the families displayed primary congenital glaucoma (pcg) and three displayed juvenile open-angle glaucoma (joag). a combined phenotypic family displayed joag including pcg (joag-pcg) and one family displayed adult-onset primary open-angle glaucoma (ao-poag). single nucleotide polymorphism data were produced for a pcg family, yielding 14 chromosomal locations of interest, with four regions on chromosome 2 prioritised as a consequence of an influential pcg gene (cytochrome p450 subfamily i polypeptide 1 [cyp1b1]). however, sequencing of this gene did not reveal any mutations. whole exome sequencing data were generated for the remaining families. a total of 26 individuals were sequenced with 5,659 variants in 3,979 genes. sanger sequencing of 146 selected variants identified six co-segregating variants in four genes. cyp1b1 variants (p.g61e and p.d374n) were found in the pcg families and the p.e229k variant was identified in a joag family. novel variants in nitric oxide synthase 3 (nos3), p.g643s, and class ii major histocompatibility complex transactivator (ciita), p.l477i, were found separately in two pcg families co-segregating with cyp1b1 variants. in the joag-pcg family, a new chemotactic cytokine receptor 5 (ccr5) alteration, p.n48s, was identified. two variants (cyp1b1, p.e229k, and ccr5, p.n48s) in two individuals who were asymptomatic at the time of enrollment predicted the presence of the disease in the joag and joag-pcg families. cyp1b1 mutations are likely the primary cause of glaucoma in most families. however, the co-segregation of additional variants found in nos3 and ciita, along with the identification of a variant in the ccr5 gene, may indicate other genetic factors contributing to disease initiation and/or progression. as previously reported, the identity of the involved genes suggests autoimmune dysregulation, autoinflammatory events and oxidative stress in the disease pathophysiology. abstracts | 565 sultan qaboos university, 9−11 march 2014 this study also allowed for early diagnosis and identification of affected and at-risk individuals, enabling earlier medical intervention for the preservation of sight. the findings of this study warrant further investigation for improved clinical interventions with an aim to sight preservation. realising the potential of the role for nurses in genetics and genomic healthcare: a review of the literature jansirani natarajan college of nursing, sultan qaboos university, muscat, oman. email: jannat@squ.edu.om a literature review exploring the role of genetics in the nursing profession was undertaken. as nursing is the backbone of the healthcare system, the aim was to define the valuable contributions they could make to shape the delivery of genetic healthcare. advances in genetic science/technology have profound implications for healthcare and the growing importance and relevance of genetics in everyday nursing practice is increasingly being recognised. nurses are expected to have the necessary knowledge to interpret genetic information and technology into client care, integrate genomic healthcare into healthcare systems and address associated ethical challenges. a search was conducted in january 2014 using the cumulative index to nursing and allied health (cinahl) and google scholar databases with the following keywords: nurses’ role in genetics; genetics and nurses; genome, and genetics in nursing. papers were included in the review if they had been published in english between 2005–2013 and included empirical data about the role of genetics in nursing. findings indicated extensive agreement on the relevance of genetics in nursing practice. empirical evidence highlighted widespread deficits in knowledge/skills and low confidence levels. however, significant progress has been made in identifying learning outcomes for nurses. nurses expressed interest in educating and counselling patients. studies conducted worldwide assessed nurses’ perceived rather than actual genetic knowledge. genetic nursing education was limited and inadequate across many countries and was hampered by a lack of strategic development. research found that the delivery of genetics education was limited, although skill-based training, clinical scenarios and assessment have been identified as factors to promote learning. nurses’ knowledge of genetics was insufficient to provide comprehensive patient services; many studies identified gaps in professional competence/education. nurses are expected to play a significant role in caring for patients with genetic predispositions/disorders. they must be able to identify hereditary/familial or environmental/lifestyle characteristics that increase disease risk; facilitate informed decision-making; promote surveillance behaviours; prescribe appropriate management strategies, and advocate optimal genetic healthcare. as counsellors, technicians, care managers and teachers, nurses will create new leadership roles in healthcare. the development of university-level programmes to improve counselling skills, as well as a basic curriculum in genetic nursing, are essential. poster presentations griscelli syndrome type 2 in an omani child nashat al-sukaiti,1 nadia al-hashmi,1 *maryam al-shehhi,1 abdul h. al-rawas,1 yasser wali2 1department of child health, royal hospital; 2department of child health, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: drshihia@hotmail.com griscelli syndrome type 2 (gs2) is a rare autosomal recessive disorder caused by a mutation in the rab27a gene. it is characterised by partial albinism and cellular immune deficiency leading to an increased susceptibility to infections. patients go on to develop lifethreatening haemophagocytic lymphohistiocytosis (hlh) in the first few years of life. the prognosis is very poor unless allogenic haematopoietic stem cell transplantation is performed early. we report the case of a 2-year-old girl with a novel mutation in the rab27a gene presenting with silvery-grey hair and recurrent episodes of hlh. this case is reported so as to increase awareness about this condition; gs2 is often underdiagnosed, especially in regions with high rates of consanguinity. emphasising early diagnosis is crucial for successful treatment. mapping a new recessively inherited blindness disorder to chromosome 16q23.3-24.1 *musallam al-araimi,1,2 bishwanath pal,2 james a. poulter,2 maria m. van genderen,3 ian carr,2 tomas cudrnak,4 lawrence brown,5 eamonn sheridan,2 moin d. mohamed,2 john bradbury,4 manir ali,2 chris f. inglehearn,2 carmel toomes2 1national genetic centre, royal hospital, muscat, oman; 2leeds institute of molecular medicine, leeds, uk; 3bartiméus institute for the visually impaired, zeist, netherlands; 4bradford royal infirmary, bradford, uk; 5sheffield teaching hospitals nhs foundation trust, sheffield, uk. *corresponding author e-mail: musallam95@yahoo.com we previously described two families with unique phenotypes involving foveal hypoplasia. the first family (f1) presented with foveal hypoplasia and anterior segment dysgenesis and the second family (f2) presented with foveal hypoplasia and chiasmal misrouting without albinism. a genome-wide linkage search for f1 identified a 6.5 mb locus for this disorder on chromosome 16q23.2-24.1. the aim of this study was to determine if both families had the same disorder and to see if the presentation in f2 was also linked to the 16q locus. family members underwent routine clinical examinations. linkage was determined by genotyping microsatellite markers and calculating logarithm of the odds scores. locus refinement was undertaken with a single nucleotide polymorphism (snp) microarray analysis. the identification of chiasmal misrouting in f1 and anterior segment abnormalities in f2 suggested that both families had the same clinical phenotype. this was confirmed when linkage analysis showed that f2 also mapped to the 16q locus. the snp microarray analysis excluded a shared founder haplotype between the families and refined the locus to 3.1 mb. we therefore report a new recessively inherited syndrome consisting of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis, known as fhonda syndrome. the gene mutated in this disorder lies within a 3.1 mb interval containing 33 genes on chromosome 16q23.3-24.1 (chr16:83639061-86716445, hg19). 566 | squ medical journal, november 2014, volume 14, issue 4 2nd genetics conference genetics in developing countries, unique challenges and opportunities the identification of novel mutations in gucy2d causing leber’s congenital amaurosis in two unrelated pakistani families using the topo ta cloning method *musallam al-araimi,1,2 martin mckibbin,2 ian carr,2 adam booth,2 moin d. mohammed,2 hussain jafri,3 yasmin rashid,4 manir ali,2 chris f. inglehearn,2 carmel toomes2 1national genetic centre, royal hospital, muscat, oman; 2leeds institute of molecular medicine, leeds, uk; 3king edward medical university, lahore, pakistan; 4gene-tech laboratory 146/1, lahore, pakistan. *corresponding author e-mail: musallam95@yahoo.com leber’s congenital amaurosis (lca) is the name given to cases of severe early-onset inherited retinal dystrophy; however, it is clear that this term actually encompasses a group of diseases with different underlying pathologies. it is a rare form of retinal dystrophy that presents in the first year of life. studies of the molecular genetics of lca have revealed 14 different lca genes correlated to 70% of cases. determining the molecular defect underlying the disease in patients is becoming increasingly important and recent gene therapy clinical trials have been performed with lca patients. genetic studies have identified many genes which cause the lca phenotype but more have yet to be identified. this study aimed to map novel mutations in the gucy2d gene in two unrelated families using the topo ta cloning method. autozygosity mapping analysis was done on two pakistani lca families using the genome-wide human single nucleotide polymorphism array 5.0 (affymetrix, inc., santa clara, california, usa). a shared region of homozygosity was identified among all of the affected individuals. a potential region of homozygosity at the gucy2d locus (chr17:7,905,988-7,923,658, hg.19) was identified and confirmed. topo ta cloning was used to sequence the gucy2d gene in the affected patients. using unique methods, two novel homozygous missense mutations in the same gene were identified in both lca families (c.582g>c, p.w194c, and c.530 g>c, p.r177p). the genetic investigation of lca families may provide an ideal opportunity to identify other patients for phenotypegenotype analysis. this would identify new mutations to aid in the functional characterisation of lca proteins. genetic investigation of such families might also serve to molecularly characterise patients for future therapeutic clinical trials and identify families for future gene identification studies. inherited causes of chronic kidney disease in omani children: a tertiary hospital experience in oman between 2006–2012 *maryam al-shehhi, latifa al-maamari, thuraiya al-selaimi, mohammed al-riami department of child health, royal hospital, muscat, oman. *corresponding author e-mail: drshihia@hotmail.com this paper reports inherited and congenital causes of chronic kidney disease (ckd) in omani children. the study is part of a larger project currently studying the descriptive epidemiology of ckd in children at royal hospital, a tertiary centre in oman, where >80% of ckd patients in the nation are seen. this study is part of an initiative to establish local data on ckd to help plan possible preventative measures and strategies. a retrospective descriptive review of computerised medical records of all children aged <14 years diagnosed with ckd at the royal hospital, in muscat, oman, was undertaken from january 2006 to december 2012. there were 124 cases, of which 61% were male. the mean incidence of patients with advanced stages of ckd (glomerular filtration rate <60) was 18.2 per million of the age-related population. the mean age at diagnosis was three years. date were collected via a questionnaire and parents of patients were contacted to complete any missing data. the questionnaire collected information regarding patient demographics; consanguinity; family history; clinical, biochemical and imaging data; details of identified causes; treatment modalities, and overall outcomes. the preliminary results could be used for future research on related topics. congenital anomalies of the kidney and urinary tract (cakut) are the leading cause of ckd in children worldwide. in the current study, 48% of the patients had cakut. however, inherited causes were reported in 40% and consanguinity was observed in 40% of the patients. autosomal recessive polycystic kidney disease and primary hyperoxalurea were the most frequent inherited causes. mutations were also identified in consanguineous families. although the complete coverage of all centres treating paediatric ckd in oman was not achieved, the results of the current study may still reflect the actual condition nationwide. cakut and inherited renal diseases are the leading causes of ckd in children and the rate is even higher in countries with a high incidence of consanguinity. genetic polymorphism in mitochondrial deoxyribonucleic acid hypervariable regions i and ii in a sample omani population *aisha s. al-hosni, hilal al-shukili, aisha h. a. al-shehi department of biology, college of science, sultan qaboos university, muscat, oman. *corresponding author e-mail: aishaalhos@gmail.com the analysis of the mitochondrial deoxyribonucleic acid (mtdna) genome, in particular the control region of the genome, has been widely used in forensic analysis and population genetics to describe human variation, population substructure and migration patterns. this is due to the pattern of maternal inheritance, high mutation rate and lack of recombination. the mtdna sequence polymorphism of the hypervariable regions i and ii from 114 unrelated omanis were analysed using polymerase chain reaction and sanger sequencing. in order to identify polymorphic sites and their frequency and to determine the haplogroups’ incidence compared to neighbouring populations, dna sequences were aligned against the revised cambridge reference sequence. the haplogroups were scored using online software tools. the frequency of the haplogroups was determined using standard statistical tools. the samples covered nine governorates with 59 different maternal tribes. haplogroups j, h, u and r0 were highly prevalent. haplogroups were observed to be more diverse in the coastal regions. in the interior regions, haplogroups were observed to be less diverse. a new case of haemoglobin fontainebleau/haemoglobin bleuland compound heterozygote in oman *fatma al-mahrizi, nishath hamza, fatma al-lawati, s. al-lawati, ahmed al-aamri, shamsa al-hilali, ahmed al-aasmi, manal al-kharusi, anna rajab national genetic centre, royal hospital, muscat, oman. *corresponding author e-mail: fatmaalmahrizi@gmail.com initially reported in an italian family, haemoglobin (hb) fontainebleau (hba2: c.64g>c) is a clinically silent hb variant which exhibits a change from alanine to proline at codon 21 of the hba2 gene chain. no change in the stability or oxygen-binding properties of the hb molecule has been reported for this variant. hb bleuland is a clinically mild variant with an acc-->aac transversion and a threonine to asparagine change at codon 108 of the hba2 gene. understanding the consequence of a new hb variant has significant implications for abstracts | 567 sultan qaboos university, 9−11 march 2014 genetic counselling. the aim of this study was to predict the structural changes to the hb molecule as a result of the hb fontainebleau/ hb bleuland compound heterozygote variant. we analysed the hba2 deoxyribonucleic acid sequence from a 21-year-old female. her fetal hb was 0.4%, hb a2 was 3.4%, mean cell volume was 43.7 fl (normal range: 76–96 fl) and mean cell hb was 12.3 pg (normal range: 27–32 pg). the patient was a compound heterozygote for the hb fontainebleau/hb bleuland mutation. we conducted a protein structural bioinformatic analysis of the hb variants for hb fontainebleau and hb bleuland using the hope online tool (centre for molecular and biomolecular informatics, department of bioinformatics, radboud university, nijmegen, netherlands). hb variant comparisons were also confirmed using the national center for biotechnology information database and expasy tools (swiss institute of bioinformatics, lausanne, switzerland). in hb bleuland, the mutant asparagine residue is bigger and more hydrophobic than the wild-type threonine. the domain where the hb bleuland mutation occurs is associated with iron-ion binding and haeme-binding. in hb fontainebleau, the proline that is introduced by the mutation is a very rigid residue and may abolish the required flexibility of the protein at this position. however, phylogenetic analysis revealed other conserved protein sequences with residues similar to the variant residue in hb fontainebleau. according to the results, the hb bleuland variant is possibly damaging, which is reflected in the mean corpuscular volume and mean corpuscular hb data. the larger size of the asparagine molecule in the variant may also lead to steric hindrance. however, the hb fontainebleau variant was predicted to be acceptable and this is in concordance with experimental evidence reported in the literature. assessing the need for genetic testing in breast and ovarian cancer patients in oman *nishath hamza,1 taha al-lawati,2 thuria al-rawahi,3 manal al-kharusi,1 fatma al-lawati,4 anna rajab1 1national genetic centre and departments of 2surgery, 3obstetrics & gynaecology and 4pathology, royal hospital, muscat, oman. *corresponding author e-mail: nishahamz@yahoo.co.uk breast cancer (bc) is the most common cancer among omani females. ovarian cancer (oc) is also prevalent among omani women. according to the 2011 national cancer registry, 178 cases of bc (33.7% of all female cancers) and 21 cases of oc (4% of all female cancers) were reported in oman. since 10–15% of bc and oc cases may occur due to genetic mutations in, for example, the brca1 and brca2 genes, the national genetic centre was approached by clinicians and patients to start genetic testing services for bc and oc. the aim of this study was to assess the need for initiating genetic testing in bc and oc patients in oman. data on bc cases were obtained for the period of 2009–2013 from the medical records unit in royal hospital, muscat, oman. a list of oc patients from 2012–2013 was also obtained from the histology laboratory at the same hospital. we analysed the yearly incidence and age-specific trends for oc and bc. the data revealed that, in 2011 and 2012, the increase in bc cases was 17% and 12% compared to the previous year. in 2013, the number of bc cases rose dramatically by 148.7% (n = 475 cases) compared to 2012. combined data from 2009–2013 indicated that the majority of bc cases diagnosed were among patients under 50 years old. with regards to oc patients, 20 were diagnosed in 2012 and 28 in 2013. in 2012, the majority of oc patients were 41–50 years old, whereas this cancer was commonest in the 21–40-year-old age group in 2013. in conclusion, the number of bc and oc patients seen at royal hospital in 2013 was 2.5 and 1.4 times more, respectively, than the incidence reported in the 2011 national cancer registry. the increasing numbers and rising trends of these early-onset cancers strongly indicate the need to initiate genetic testing in oman as a major preventive strategy. genetic testing will help to reveal the risk for a second cancer in bc and oc patients and clarify the risk for bc and oc in unaffected individuals with pertinent family historie, thus enabling earlier cancer detection and prevention. retinal dysfunction in inborn errors of metabolism: ophthalmic findings may be crucial for diagnosis *beena harikrishna,1 sana al-zuhaibi,1 agha s. haider,1 khalid al-thihli,2 fathiya al-murshedi,2 amna al-futaisi,3 roshan l. koul,3 anuradha ganesh1 departments of 1ophthalmology, 2genetics and 3child health, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: beena.harikrishna@gmail.com inborn errors of metabolism (iem) are a heterogenous group of disorders that occur due to inherited enzymatic defects. they often pose a diagnostic dilemma. eye involvement is commonly encountered in iem and its detection could aid in the diagnosis of these complex disorders. early detection is extremely important in order to achieve appropriate therapeutic measures. the objective of this study was to highlight retinal findings that assisted in the diagnosis of iem in order to demonstrate that retinal abnormalities can help in the targeted evaluation of this group of patients. the sultan qaboos university hospital paediatric ophthalmology database was reviewed for children with retinal findings and confirmed/suspected iem. patient charts were retrospectively reviewed. data pertaining to systemic and ophthalmic evaluation, photographs and results of ophthalmic procedures were reviewed and recorded. institutional approval was sought. a total of 32 children were studied (19 male and 13 female). the age at presentation ranged from 2 months to 10 years old. all of the children had undergone a complete neurometabolic work-up but their diagnoses were still uncertain at the time of the ophthalmology consultations. all patients had undergone standard ophthalmic evaluations, including fundus photography. optical coherence tomography, intravenous fluorescein angiography and electrophysiological tests were performed when indicated. prompted by the findings of ophthalmic evaluation, appropriate biochemical, enzymatic or genetic investigations were undertaken, leading to a diagnosis. in some patients (n = 21), a diagnosis was confirmed, while 11 patients were evaluated for fundus findings, including maculopathy (n = 8), cherry-red spot (n = 6), bull’s eye maculopathy (n = 2), atypical pigmentary retinopathy (n = 10), chorioretinal lesions (n = 2) and lipaemia retinalis (n = 1). iem often present with non-specific signs and symptoms involving different systems. visual symptoms may or may not be present. a careful and detailed ophthalmic examination might reveal characteristic features that could lead to a targeted diagnostic evaluation and early diagnosis. certain retinal abnormalities strongly point towards a specific group of iem disorders. a prospective study is being planned to establish criteria for ophthalmic referrals in patients suspected of having iem. clinical and molecular characterisation of mucolipidosis type iv in omani patients *beena harikrishna,1 sana al-zuhaibi,1 agha s. haider,1 khalid al-thihli,2 fathiya al-murshedi,2 amna al-futaisi,3 roshan l. koul,3 anuradha ganesh1 departments of 1ophthalmology, 2genetics and 3child health, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: beena.harikrishna@gmail.com mucolipidosis type iv is a rare autosomal recessive lysosomal storage disorder with relatively high prevalence in the ashkenazic jewish population due to two founder mutations in the mcoln1 gene (19p13.3-p13.2). the aim of this study was to investigate the neuroophthalmic manifestations and molecular characteristics of mucolipidosis type iv in patients from oman and emphasise the need for 568 | squ medical journal, november 2014, volume 14, issue 4 2nd genetics conference genetics in developing countries, unique challenges and opportunities ophthalmic examinations in children with unexplained developmental delay and/or spasticity. in the first family, a three-year-old child presented with psychomotor delay, spasticity and photophobia. a family history was significant for consanguinity and also revealed a similarly affected brother and two affected cousins. in the second family, an eight-year-old child presented with psychomotor delay and spasticity. a family history revealed a similarly affected younger sister. all of the patients (n = 6) were under the care of neurologists for their developmental delay and underwent a complete ophthalmic examination. previously recorded neurological manifestations were reviewed. conjunctival biopsies and molecular genetic assessments were performed. informed consent was obtained from the parents and institutional approval was obtained. all of the children had been born at term. on examination, findings included minor dysmorphic features, developmental delay, spastic quadriparesis, photophobia, strabismus, nystagmus, poor vision, bilateral corneal haziness, cataracts and pigmentary retinopathy. high serum gastrin, low iron and ferritin, and microcytic hypochromic anaemia were detected. magnetic resonance imaging of the brain showed structural anomalies. molecular genetic testing showed a novel homozygous splice site variant in the mcoln1 gene (c.237 + 5g>a) in four of the six patients. conjunctival biopsies revealed typical intracytoplasmic inclusions consistent with mucolipidosis type iv. a novel homozygous splice site variant in the mcoln1 gene was found. mucolipidosis type iv is often underdiagnosed and mistaken either for cerebral palsy or a retinal dysfunction of unknown cause. spastic paraparesis or quadriparesis in combination with iron deficiency anaemia and corneal haziness should prompt consideration of mucolipidosis type iv. genetic diagnosis of lysosomal storage disease in iran *masoud houshmand1 and omid aryani2 1national institute for genetic engineering & biotechnology, tehran, iran; 2department of medical genetics, special medical center, tehran, iran. *corresponding author e-mail: massoudh@ nigeb.ac.ir lysosomes are subcellular organelles responsible for the physiological turnover of cell constituents. they contain catabolic enzymes which require a low-ph environment in order to function optimally. lysosomal storage diseases (lsds) describe a heterogeneous group of dozens of rare inherited disorders characterised by the accumulation of undigested or partially digested macromolecules, which ultimately results in cellular dysfunction and clinical abnormalities. organomegaly, connective-tissue and ocular pathology, and central nervous system dysfunction may result. classically, lsds encompassed only enzyme deficiencies of the lysosomal hydrolases. more recently, the group has been expanded to include deficiencies or defects in proteins necessary for the normal post-translational modification of lysosomal enzymes, activator proteins or proteins important for proper intracellular trafficking between the lysosome and other intracellular compartments. over 50 lsds have been described. the age of onset and clinical manifestations may vary widely among patients with a given lsd and significant phenotypic heterogeneity between family members carrying identical mutations has been reported. lsds are generally classified by the accumulated substrate and include sphingolipidoses, oligosaccharidoses, mucolipidoses, mucopolysaccharidoses, lipoprotein storage disorders, lysosomal transport defects, neuronal ceroid lipofuscinoses and others. a genetic diagnosis of some of the lsds diagnosed via genetic and prenatal diagnosis achieved through whole gene polymerase chain reaction sequencing methods is described. clinical and molecular study of niemann-pick type c disease in iran *masoud houshmand,1 seyed h. tonekaboni,2 omid aryani,3 parvaneh karimzadeh,2 talieh zaman,4 mahmoud r. ashrafi,4 shadab salehpour,2 manshadi dehghan,1 elham khalili1 1national institute for genetic engineering & biotechnology, tehran, iran; 2mofid children hospital, shahid beheshti university of medical sciences, tehran, iran; 3department of medical genetics, special medical center, tehran, iran; 4tehran university of medical sciences, tehran, iran. *corresponding author e-mail: massoudh@nigeb.ac.ir niemann-pick disease type c (npc) is a rare autosomal recessive neurovisceral disorder caused by mutations in the npc1 (95%) or npc2 (5%) genes. npc disease has a variable phenotype, whereby an alteration in cholesterol and glycolipid homeostasis leads to a broad spectrum of symptoms that include hepatosplenomegaly, liver dysfunction and neurological abnormalities such as progressive ataxia, cataplexy, vertical supranuclear gaze palsy, seizures and impairment of the swallowing reflexes. npc is rarely reported in iran. over a period of 18 months, 15 patients were diagnosed with npc by filipin staining in the medical school of tehran university. reverse transcription polymerase chain reaction and sequencing methods were used for molecular investigation of the npc1 and npc2 genes in five patients, two of who were female. all of these patients had the juvenile form of npc and had presented with ataxia gait. additionally, all five patients were the result of consanguineous marriages. case one was a 15-year-old boy who had hepatosplenomegaly and jaundice during his neonatal period. liver biopsy findings were compatible with a lipid storage disease. he had developed supra vertical gaze palsy at the age of 11 years and progressive ataxia, dystonia and gelastic cataplexy at the age of 13 years. magnetic resonance imaging (mri) of the brain was normal. case two was a 3.5-year-old boy; splenomegaly had been detected at the age of six months. he had psychomotor developmental delays, was unable to walk and had developed supra vertical gaze palsy one year previously. for the previous year he had also exhibited gelastic cataplexy even in a sitting position. a brain mri was normal. cases three and four were two sisters aged 13 and 17 years old, respectively. they were both products of a consanguineous marriage. case three presented with a complaint of progressive ataxia and dysarthria since the age of nine years. at the age of 11 years, progressive dysphagia had begun but its progression had plateaued. the patient’s cognitive state remained unchanged. she did not suffer from seizures or gelastic cataplexy, and lacked a history of neonatal jaundice or splenomegaly. upon a neurological examination, the patient was found to have supra vertical gaze palsy. a brain mri showed non-specific hypersignal changes in the white matter. the 17-year-old sister (case four) had been diagnosed with epistaxia when she was 6 years old. splenomegaly was detected in her work-up. progressive ataxia and dysphagia developed at seven years of age, leading to a wheelchair-bound state and nasogastric tube feeding at 14 years of age. a brain mri showed cerebellar atrophy. upon neurological examination she had supra vertical gaze palsy. she died a few months after the study. case five was a 13-year-old boy who presented primarily with neurological symptoms. he had started to develop ataxia and dysarthria at the age of eight years. dementia, dysphagia and seizures, in this sequence, followed within a couple of years. he was anarthric and bedridden four years after onset. supranuclear vertical gaze palsy was found at the time of the examination. however, no hepatosplenomegaly or other physical abnormalities were noted. whole transcribed exons of the npc1 genes were sequenced and four different unreported homozygous mutations were found: case one: (c.1069c>t) p.s357l; case two: (c.1180c>t) p.y394h; cases three and four: (c.1433a>c) p.n 478 t, and case five: (c.1192c>t) p.h398y. all of the mutations were analysed and found to be missense mutations. abstracts | 569 sultan qaboos university, 9−11 march 2014 genetic diagnosis of primary immunodeficiencies in iran *masoud houshmand,1 zahra pourpak,2 sepideh safaei,2 mohsen badalzadeh,2 zahra alizadeh,2 mohammad r. fazlollahi,2 mostafa moein2 1national institute for genetic engineering & biotechnology, tehran, iran; 2immunology, asthma & allergy research institute, tehran university, tehran, iran. *corresponding author e-mail: massoudh@nigeb.ac.ir primary immunodeficiencies (pids) are genetic disorders of the immune system comprising many different phenotypes. although previously considered rare, recent advances in clinical, epidemiological and molecular definitions have revealed that much remains to be learnt about these disorders. geographical and ethnic variations as well as the impact of certain practices influence their frequency and presentation, making it necessary to consider their study in terms of different regions. the genetic diagnosis of pid is very new in iran. in the past three years, more than 12 tests have been developed using polymerase chain reaction (pcr) sequencing methods. new mutations were found by the investigation of the il2rg, ada, rag1, rag2 and il7r genes in 62 patients with severe combined immunodeficiencies. investigations of the cybb, cyba, ncf1 and ncf2 genes in 58 patients with chronic granulomatous disease showed more autosomal recessive patterns than x-linked patterns in iran. patients with wiskott-aldrich syndrome (n = 28) were examined for the was gene and new mutations were found by sequencing methods. the hot spot exons, rab27a and myo5a, were investigated in 18 patients with griselli syndrome. additionally, 22 patients with bruton agammaglobulinaemia and 20 patients with haemophagocytic lymphohistiocytosis were studied for the spx11 and prs i genes. all results, including an investigation of neutropaenia, common variable immunodeficiencies and leukocyte adhesion deficiencies are presented in this seminar. molecular investigation of charcot-marie-tooth disorder for the pmp22, mpz, egr2, gjb1, mfn2 and gdap1 genes in some iranian patients *masoud houshmand,1 esmeel m. pargoo,2 omid aryani,3 seyed h. tonekaboni,4 parichehr yaghmaei2 1national institute for genetic engineering & biotechnology, tehran, iran; 2science & research branch, islamic azad university, tehran, iran; 3department of medical genetics, special medical center, tehran, iran; 4mofid children hospital, shahid beheshti university of medical sciences, tehran, iran. *corresponding author e-mail: massoudh@nigeb.ac.ir charcot-marie-tooth (cmt) disease is the commonest neurogenetic disorder with phenotypic and genotyping heterogeneity. both the phenotypic features and disease severity can either be consistent or vary widely within families. the affected individual typically has distal muscle weakness and atrophy often associated with mild to moderate sensory loss, diminished or absent deep tendon reflexes, high-arched feet and skeletal deformities such as pes cavus. cmt hereditary neuropathies are categorised by mode inheritance and causative gene or chromosomal locus. autosomal-dominant inherited cmt patients are usually classified according to demyelinating form, severely reduced nerve conduction velocities in type 1 (cmt1) and axonal form in type 2 (cmt2). an x-linked inheritance pattern is classified in the cmtx gene and an autosomal recessive inheritance pattern is classified in type 4. all patients (n = 142) were investigated for the pmp22 gene according to their electroclinical results, neurological examination and pedigree. polymerase chain reaction (pcr) restriction fragment length polymorphism and multiplex ligation-dependent probe amplification was undertaken for cmt1a patients. the mpz, egr2, mfn2, gjb1 and gdap1 genes were determined by a pcr sequencing method for all the exons and exon-intron boundaries. in order to show that these found novel mutations were pathogenetic, 50 genetically normal controls with no such mutations were sequenced for all of these genes. according to this study, the frequency of duplication in the pmp22 gene in comparison to other genes was very low. this is because of the high rate of consanguineous marriage in iran. it is believed that other unknown genes are involved in the development of cmt disease in these patients. there are limitations associated with the genetic diagnosis of cmt, including the fact that many genes are involved in the same phenotype and many phenotypes are caused by same gene. therefore, the cause of cmt should be clarified by an investigation of other genes associated with the disease. exploring the need for prenatal diagnosis and termination of pregnancy in oman: the unspoken challenges *zandre bruwer, amel al-foori, khalsa al-kharousi department of genetics, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: zandrebruwer@gmail.com genetic counselling and testing is an integral component in providing an effective clinical service for the management of families who are at-risk for or affected by a genetic disorder. where a causative mutation is identified, options aimed at reducing the genetic burden in that specific family become available, such as prenatal genetic diagnosis. this form of genetic testing can lead to the detection of an affected fetus; parents are subsequently faced with the decision to continue or terminate the pregnancy. the termination of the pregnancy raises ethical debate in all societies; addressing this topic is particularly difficult in islamic societies, where abortion is largely avoided. the increase in the number of requests for prenatal genetic diagnosis at the genetic and developmental medicine clinic of sultan qaboos university hospital (squh) calls for an open ethical and legal discussion of this topic. in the current study, conducted in 2013, descriptive data were gathered and interviews undertaken with individuals requesting prenatal diagnosis for a geneticallyconfirmed disorder following extensive genetic counselling. a total of 10 cases were identified and included in the study. patients most frequently requested testing for inherited metabolic disorders. test results were discussed together with the patient-driven outcomes following either a positive or negative result disclosure. interviews undertaken with each patient additionally provided data on the impact of the decision for the couple and their family. the effect of undertaking testing on future pregnancy-related decisions is also described in this study. these described experiences highlight the constellation of logistical, religious and psychosocial challenges faced by patients requesting the procedure in squh. awareness of the situation faced by patients accessing prenatal diagnosis will be extremely valuable in developing services according to patient needs. molecular analysis of inborn errors of metabolism in oman *lina al-mashhadani,1 surendranath joshi,2 aliya al-ansari,3 hussein al-kindy,2 allal ouhtit,1 bassam ali,4 said al-yahyaee1 departments of 1genetics and 2child health, college of medicine & health sciences, sultan qaboos university; 3department of biology, college of science, sultan qaboos university, muscat, oman; 4united arab emirates university, al-ain, uae. *corresponding author e-mail: lina@squ.edu.om inborn errors of metabolism (iem) are a group of inherited recessive disorders associated with amino acid metabolism, fatty acid oxidation and pyruvate and carbohydrate metabolism. many of the metabolic disorders carry serious clinical consequences to the affected neonates or young infants. these may include mild to severe irreversible mental retardation, physical handicaps or even fatality 570 | squ medical journal, november 2014, volume 14, issue 4 2nd genetics conference genetics in developing countries, unique challenges and opportunities if left untreated and results in a significant burden on the quality of life and socioeconomic status of affected individuals and their families. the investigation and recognition of iem is fairly new in oman, with the first cases being reported in 1998. in this study, patients from 56 families attending the metabolic clinic at sultan qaboos university hospital were recruited from 2010–2012. mutation analysis was carried out at the molecular genetic diagnostic laboratory using standard sequencing methods in the known genes associated with iem disorders. out of 56 families, 40 families displayed 24 homozygous mutations in 11 iem disorders. those include disturbances of amino acids, organic acids and carbohydrates as well as storage and fatty acid oxidation defects. from the identified mutations, 15 were novel mutations, including eight missense mutations, four premature stop codons and three frameshift mutations. mutations identified in omani patients will be further validated so that they can be integrated in the list of available molecular genetic laboratory tests. the availability of molecular testing for iem disorders in oman has important implications for families and genetic counselling. a case of jeune syndrome in oman: is this syndrome as rare as we think? *urooj t. sheikh, m. m. themalil, badriyah m. s. al-ghaithi, mohammed al-riyami, nadia al-hashmi department of child health, royal hospital, muscat, oman. *corresponding author e-mail: urooje@gmail.com asphyxiating thoracic dystrophy, also known as jeune syndrome, is an autosomal recessive multisystemic disorder and infants born with the disorder have an average life expectancy of approximately two years. it has an annual incidence of 1–5 in 100,000–130,000. there have been 250 reported cases of jeune syndrome in oman but the true incidence in the omani population has yet to be determined. in a country like oman, where consanguinity is rampant, one may ask whether jeune syndrome is as rare as it is commonly believed to be. a nine-year-old boy with disproportionate dwarfism was referred to hospital for evaluation of proteinuria. he had a history of repeated hospitalisations due to chest infections and had been diagnosed with nephrotic syndrome which had progressed to end-stage renal disease (with an estimated glomerular filtrartion rate of 5) which was resistant to steroids and tacrolimus. the child was suspected of having an undiagnosed skeletal dysplasia after he presented with one of its complications. jeune syndrome was confirmed by clinical findings, including short stature, triangular face, high arched palate, bell-shaped thorax and radiological findings of thanatophoric dysplasia. this case highlights the fact that investigations for rare conditions such as jeune syndrome should not be neglected. reviewed literature suggests that, in children with jeune syndrome who survive infancy, the thorax has the potential to grow. there is evidence of patients with this syndrome surviving beyond childhood. early diagnosis, aggressive management in the initial years and regular followup with a multidisciplinary approach may yield better outcomes for these patients. suspicion plays a major role in antenatal diagnosis and the need for awareness of this condition among medical practitioners is therefore essential. interventions such as titanium rib surgery and renal transplantation could make a significant difference to patients’ quality of life. mutational screening of the ptpn22 gene in an omani cohort affected with rheumatoid arthritis *aziza al-busaidi,1 buthaina al-hudar,1 mohammed al-kindi,1 batool hassan,2 yahya tamimi1 departments of 1biochemistry and 2medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: u085528@squ.edu.om rheumatoid arthritis (ra) is an autoimmune disease affecting 0.3–1.5% of the worldwide population. ra usually targets the synovial joints by initiating lymphocyte activation and immune complex deposition. genetic factors involved in the aetiology of ra are reported to be complex, diversified and poorly understood. among these, the protein tyrosine phosphate non-receptor type 22 (ptpn22) gene, seems to play a major role at different levels. in this study, ptpn22 mutations were screened in a cohort of omani patients with ra by targeting hot spot areas of the gene and matching the obtained results with available clinical data. deoxyribonucleic acid extracted from the blood samples of 30 patients (of whom 27 were female) and 14 controls was subjected to polymerase chain reaction amplification and sequencing of exons 13, 14, 15, and 18 of the ptpn22 gene. while no mutation or single nucleotide polymorphism was found in exon 15, one novel mutation and one insertion was recorded in exon 13, in addition to the novel mutation and reported polymorphism detected in exon 14. moreover, analysis of exon 18 revealed two reported mutations, three novel polymorphisms and 12 novel mutations. pearson’s chi-squared test showed no significance (p >0.1) between the number of mutations and different clinical parameters characterising ra. these findings suggest that a complex cocktail of events act independently in the formation of ra. clinical parameters did not reflect aberrations at the genomic levels such as in the ptpn22 mutations, deletions and polymorphisms involved in the pathogenesis of ra, at least in this omani population. genetic analysis of patients with neonatal diabetes in oman *aisha al-senani,1,2 nishath hamza,3 manal al-kharusi,3 hana al-azkawi,1 anna rajab3 1national diabetic centre, 2department of endocrinology, 3national genetic centre, royal hospital, muscat, oman. *corresponding author e-mail: amsalsenani@gmail.com neonatal diabetes mellitus (ndm) is rare, occurring in 1:300,000–400,000 births. ndm can be permanent (pndm) or transient (tndm). in pndm, the diabetes affects the patient throughout their entire life, while in tndm, the diabetes may disappear after the first few months of life but recur later in life. distinguishing tndm from pndm has significant implications for patient management and prognosis and in monitoring the recurrence. only genetic testing can make the distinction between pndm and tdnd. testing for mutations in specific genes can also guide therapy and affect clinical outcomes. for example, pndm patients with mutations in the kcnj11 or abcc8 genes can be transferred from insulin therapy to sulfonylureas. hence, it is important to establish comprehensive genetic testing for ndm syndromes in oman. the aim of this study was to identify the genotypes underlying ndm syndromes within the omani population. deoxyribonucleic acid from 23 patients with ndm who attended the diabetic clinic at the royal hospital from 2008–2013 were analysed for mutations in the gck, abcc8, kcnj11, ins, slc2a2, eif2ak3 and foxp3 genes using polymerase chain reaction and sanger sequencing. the 6q24 region was also investigated to rule out 6q24-related tndm. of the 23 patients analysed, three patients were diagnosed with pndm as they had homozygous mutations in the gck gene which encodes for glucokinase, a key enzyme responsible for regulating insulin secretion in pancreatic beta cells. two patients had mutations in the 6q24 locus and were determined to have tndm. another three patients were rediagnosed with fanconi-bickel syndrome due to mutations in the slc2a2 gene which encodes a protein that mediates bidirectional glucose transport. the other 15 patients did not exhibit any pathogenic mutations in the genes tested. among these 15 patients, two were later classified as having autoimmnune diabetes. of the 18 patients with actual ndm in this study, we were able to detect pathogenic mutations in only 28% (n = 5) of the patients. the lack of genetic test results in 72% of ndm patients supports the relevance of next-generation sequencing in genetic testing of monogenic diabetes syndromes. hence, the testing of monogenic diabetes syndromes will be initiated at the national genetic centre in oman. abstracts | 571 sultan qaboos university, 9−11 march 2014 evaluating the need for initiating colorectal cancer genetic testing in oman *manal al-kharusi,1 salim al-harthi,2 nishath hamza,1 anna rajab1 1national genetic centre and 2department of gastroenterology, royal hospital, muscat, oman. *corresponding author e-mail: mralkharusi@hotmail.com according to the 2011 national cancer registry, colorectal cancer (crc) is the second most common solid cancer in oman after breast cancer. crc has a low five-year survival rate (55%). this is mainly due to late clinical presentation, when the disease is already in an advanced stage and has metastasised to other tissues. this highlights the importance of identifying individuals at risk of developing crc. of all crc cases, 5–10% are due to genetic mutations in certain genes such as the apc gene. early onset of disease and a family history of cancer are two strong indicators of a genetic predisposition towards crc. clinicians from the royal hospital observed a high incidence of crc cases among young patients and hence approached the national genetic centre to initiate genetic testing for crc in oman. providing this service may help us to understand the contribution of genetics to the prevalence of crc in the omani population and may reduce the healthcare burden of crc cases by identifying high-risk individuals. it may also improve the management of crc patients by informing their treatment decisions. the aim of this study was to assess the need for initiating genetic testing for crc in oman. a list of patients who had been diagnosed with crc from 2009–2013 was obtained from medical records of the royal hospital and incidence data were analysed according to age and gender. the overall incidence of crc cases increased by 80% between 2009–2013. in that same period, 444 patients were diagnosed and treated for crc at the royal hospital clinics. of those patients, 169 (38%) were ≤50 years old and 279 (62%) were ≤60 years old. patients as young as 11 and 15 years old were diagnosed with crc in 2012. most crc cases in oman were found present at younger ages than those recorded in the western world. for example, in 2011, only 15.77% of the total number of crc cases in the uk occurred in those under the age of 60 years. during the same year, 60.9% of patients diagnosed with crc in oman were under the age of 60. therefore, genetic testing is strongly indicated for crc patients and their families in oman. frequently mutated/deleted hla-drb1 gene in omani patients affected with rheumatoid arthritis *buthaina al-hudar,1 aziza al-busaidi,1 mohammed al-kindi,1 yahya tamimi,1 batool hassan2 departments of 1biochemistry and 2medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: u085671@student.squ.edu. om rheumatoid arthritis (ra) is an autoimmune disease affecting the synovial joints, surrounding tissues and many other organs of the body. ra is considered a multifactorial disease that stems from both genetic and environmental factors. among the genes associated with ra, hla-drb1 plays a major role in the immune system by presenting peptides derived from extracellular proteins on antigenpresenting cells (including b lymphocytes, dendritic cells and macrophages). in this study, we screened for hla-drb1 mutations in omani patients affected with ra, with the ultimate goal of targeting hot spot areas of the gene and matching the obtained data with the clinical presentation and laboratory investigations for ra. in parallel with 14 samples from healthy subjects used as controls, 30 blood samples from affected patients were examined. patients’ hla-drb1 mutational statuses were examined using polymerase chain reaction and sequencing. among the 30 omani patients with ra and the 14 healthy controls, we found a total of 75 aberrations in the hla-drb1 gene, 15 of which were polymorphisms (20%). the remaining cases (68%) were scored as mutations, 25.49% of which were silent mutations. moreover, we identified six deletions and three insertions in 12% of the studied cases. the deletions occurred at amino acid position 101, introduced a stop codon at position 383 and were found in 10% of the affected population. statistical analysis showed no significance between the genetics aberrations in the hla-drb1 gene and the different clinical parameters used to assess ra (p >0.05). the hla-drb1 gene was found to be frequently targeted for mutation deletions in ra study cases and is, therefore, most likely involved in the pathogenesis of the disease. however, no significant correlation with clinical parameters was found. these findings suggest that hla-drb1 and clinical parameters act independently in promoting the pathogenesis of this disease. inhibition of breast cancer cell proliferation by novel boswellic acid derivative isolated from omani frankincense *somya shanmuganathan,1 allal ouhtit,1 ahmed al-harassi,2 lukmannul hakkim,2 amira al-hattali,1 ishita gupta,1 hamad al-riyami1 1department of genetics, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of biological sciences & chemistry, college of arts & sciences, university of nizwa, nizwa, oman. *corresponding author e-mail: somya.2003@gmail.com despite the rapid progress in technology and the availability of various cancer treatment modalities, conventional medicine still faces several challenges, including drug resistance. in contrast, complementary alternative medicine is increasingly being practiced worldwide due to its safety and effectiveness. boswellic acid (ba), the active ingredient in frankincense, is a well-known inhibitor of cancer cell growth. the aim of this study was to develop novel ba derivatives (bcl21 and bcl23) from omani frankincense and test their effect on the proliferation of the highly metastatic mda-mb-231 breast cancer cell line, using normal human skin fibroblasts and mcf10a breast epithelial cells as control cells. cell viability was examined using the alamarblue® assay (thermo fisher scientific corp., carlsbad, california, usa) and a dose-response curve was established. our results revealed that the ba derivative bcl21, even at a very low dose, induced the death of a higher number of mda-mb-231 breast cancer cells than either ba or bcl23, whereas the same concentrations of the compounds had no effect on the control cells. these results identified a novel ba derivative that not only can be produced in high quantities for commercial purposes but also appears to be a powerful agent for chemoprevention studies. genomics of breast cancer in oman *ishita gupta,1 somya shanmuganathan,1 allal ouhtit,1 hamad al-riyami,1 marwa al-riyami,2 adil al-ajmi3 1department of genetics, college of medicine & health sciences, sultan qaboos university; departments of 2pathology and 3surgery, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: ishugupta28@gmail.com breast cancer (bc), a heterogeneous disease, can invade locally or metastasise to the lymph nodes or other organs. despite advances in technology and research in bc, the complexity of the molecular basis of bc development and progression is still nascent. in the multistep process of bc metastasis, invasion is the recurring defining event, and elucidation of its molecular mechanisms is critical for understanding bc progression. previous studies have suggested that different breast tumour grades are associated with distinct gene expression signatures. this study aimed to test the following two hypotheses: (1) that a subset of specific genes is associated with the 572 | squ medical journal, november 2014, volume 14, issue 4 2nd genetics conference genetics in developing countries, unique challenges and opportunities transition from pre-invasive to invasive growth of breast tumours and (2) that the process of cell invasion involves specific anti-invasive and pro-invasive genes that interact to coordinate breast tumour cell migration/invasion. to test these hypotheses, ribonucleic acid was extracted from breast tumour tissues and a microarray analysis was performed. our results showed that the analysis of the microarray data revealed a set of genes that could potentially interplay with signaling the pathways that regulate the switch from the premalignant to malignant phenotype. further screening tests should be performed on these genes to identify and validate the candidate genes. consequently, this will pave the way towards the design of targeted anti-metastasis therapeutic strategies. novel leprechaunism mutation in an omani child *zaineb s. baqir, nadia al-hashmi, khoula al-said, aisha al-sinani, sunil k. bhatnagar, rawnaq al-said, hanan al-azkawi department of child health, royal hospital, muscat, oman. *corresponding author e-mail: zaineb.sadiq@gmail.com donohue syndrome (ds), also known as leprechaunism, is an extremely rare autosomal recessive disorder that was first described in 1948. it often results in early infantile or childhood death. it is characterised by severe insulin resistance, intrauterine growth restriction and postnatal growth retardation. common phenotypic features include a small elfin-like face with protuberant ears; thick lips; a broad ala nase; a distended abdomen; relatively large hands, feet and genitalia; abnormal skin with hypertrichosis; decreased subcutaneous fat levels, and acanthosis nigricans. biochemical evidence for insulin resistance has been found, including markedly elevated plasma insulin levels and impaired glucose haemostasis. the insulin resistance in ds is the result of a gene deletion in the insulin receptor which interferes with proper insulin receptor function. there is a paucity of genetic data about this syndrome in the arab population. there has been a report of a yemeni family in the united arab emirates where five children out of eight were affected with the disease due to a homozygous mutation in codon 119 of exon 2 of the insulin receptor (insr) gene. this paper focuses on the second reported case in the arab population with a novel mutation (insr homozygous variant c.671_685dup p.lys224_cys228dup) from oman. the patient was a four-month-old male infant born to consanguineous parents (first cousins) with the novel leprechaunism mutation cys807arg. the aim of this case presentation is to increase health professionals’ awareness of this extremely rare syndrome as it seems not to be as rare in the arab region as was previously thought. this syndrome is often misdiagnosed or underdiagnosed. the molecular genetics and genomics laboratory at sultan qaboos university hospital *mariam al-nabhani, sami al-kalbani, farida al-mamaari, feisal al-mahrizi, lina al-mashhadani, patrick scott department of genetics, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: nabhanim@squ.edu.om the laboratory section of the department of genetics at sultan qaboos university hospital (squh) involves the molecular-level study of disorders with a genetic basis. the investigations and studies are performed at the nucleic acid level. currently, the service is at an early stage of development, with staff being trained in various techniques, equipment being modernised and the available physical space retrofitted to accommodate the nature of the work being performed. when completed, the laboratory will provide comprehensive and specialised molecular diagnostic services, including teaching and research, in line with squh’s mission and vision. the laboratory has benefited from its proximity to research activities performed within the department of genetics as well as additional departments within the university. this has led to the translation of molecular-related findings into the development of routine diagnostic tests. it is anticipated that by the end of 2014, a basic menu of specific clinical tests will be available in support of the genetic and developmental clinic and other specialty clinics within squh and in the region. y-chromosome polymorphisms in an omani population using microsatellite markers khulood al-hinai and *aisha a. al-shehi department of biology, college of science, sultan qaboos university, muscat, oman. *corresponding author e-mail: alkhayat@squ.edu.om the y chromosome is one of the smaller human chromosomes, with an average size of 50 million base pairs. it contains different regions that can be detected to determine the variations among individuals and between different generations. in this project, short tandem repeat (str) genetic markers were used. due to their typing simplicity, high levels of diversity and tolerance of degraded deoxyribonucleic acid (dna) samples, they are usually used to study population genomes, as well as in forensic medicine to identify victims, and to test paternity and identify males and male lineages. to amplify dna from unrelated omani males, 17 polymorphic dna str markers were obtained using an ampflstr® yfiler® kit (thermo fisher scientific corp., carlsbad, california, usa). this kit uses polymerase chain reaction and fluorescently labeled primers to achieve identification. the genotypes and allele frequencies generated were analysed using the online y haplogroup prediction from y-str values program (www.hprg.com/hapest5/). in the studied omani sample, 12 haplogroups were found. males from the north al batinah region were found to belong to the j1, rla, t, e1b1a and e1b1b haplogroups. in south al batinah, males were determined to belong to the j1, t and l haplogroups. al dhakhiliya shows the most variable number of haplogroups, with males representing haplogroups t, q , j1, e1b1a and e1b1b; the group i2a (xi2a1) was also observed, which is a group found only in this region. similarly, the g2a haplogroup is only found in the al dhahirah and dhofar regions. additionally, haplogroups t, j1, e1b1a and e1b1b are also found in al dhahirah and dhofar. the group j2b was only found in dhofar. additionally, it was found that males from the muscat region carry a unique haplogroup not found in any of the other regions—the i2b1 haplogroup. the other haplogroups found in males from muscat were j1, t and e1b1b. males from ash sharqiyah males belonged to the same haplogroups that were found in north al batinah, with the exception of the e1b1a haplogroup, which was not found in north al batinah. finally, one male from the al buraimi region fell under the e1b1b haplogoup, which was also found in north al batinah. this may be attributable to the geographical proximity of the two regions. abstracts | 573 sultan qaboos university, 9−11 march 2014 utilisation of molecular genetic diagnosis by omani families with monogenic disorders: two years of experience *khalsa al-kharusi and zandre bruwer department of genetics, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: khalsakh@yahoo.co.uk the utilisation of molecular genetic diagnostic information is one of the core services offered at the genetic and developmental medicine clinic at sultan qaboos university hospital. the availability of molecular genetic testing is of particular importance to families with inherited genetic diseases as it offers the opportunity to reduce the risk of occurrence or recurrence. oman is an arab country where consanguineous marriage are culturally acceptable. this has been suggested as a contributing factor for the clustering of rare autosomal recessive disorders among families of the same descent in oman. molecular genetic testing can be utilised to provide these families with genetic information to facilitate family planning. access to premarital counselling and testing for candidates at high risk of being carriers has the potential to reduce the genetic burden within families. since the establishment of genetic services in august 2011, 1,104 samples have been sent for molecular genetic testing. of these, 112 (10%) were from families with a confirmed diagnosis of a genetic disorder who were undergoing carrier status testing for family planning purposes. a total of 36 (32%) of those who underwent testing did so as part of premarital counselling and testing for autosomal recessive disorders and 58 (51.7%) were utilising the molecular genetic information for prenatal or preimplantation genetic diagnosis. the remaining 18 patients (16.3%) were tested for carrier status confirmation. during 2012, a total of 322 samples were sent for molecular genetic testing. this number has since more than doubled, with 782 samples sent in 2013. considering that 56.4% of marriages in oman are consanguineous, as well as the fact that the majority of genetic disorders are autosomal recessive in nature, premarital counselling and testing can be extremely valuable to omani families. in this analysis, we present and discuss the utilisation of the molecular genetic diagnostic service with a focus on those families with a history of autosomal recessive disorders. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e393-396, epub. 24th jul 14 submitted 28th sep 13 revision req. 12th nov 13; revision recd. 8th mar 14 accepted 20th mar 14 1department of surgery, sultan qaboos university hospital; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: humaid44@gmail.com مقاومة االنسولني وارتباطها مع بعوامل االختطار لتطور مرض السكري يف 100 من طالب الطب العمانيني حميد حمود الفرعي، عي�سى العبودي، عزاء ال�سوافية، نورة البو�سعيدية، نيكول�س ودهاو�س abstract: objectives: the aim of this study was to assess the prevalence of insulin resistance (ir) in healthy young omanis and relate this with their body mass index (bmi) and family history (fh) of diabetes mellitus (dm). methods: this study was conducted between may 2009 and february 2010 at sultan qaboos university, muscat, oman. a detailed questionnaire was completed by 50 male and 50 female medical students between 20–25 years old. fasting blood samples were obtained for serum glucose and insulin measurements. ir was calculated using the homeostasis model assessment-estimated insulin resistance (homa-ir) formula (fasting insulin x fasting glucose/22.5) and a value above 2.5 was considered elevated. the results were analysed using the statistical package for the social sciences (spss). results: participants were classified into the following bmi categories: 59% were normal (18.5–24.9 kg/m2), 26% were overweight or obese (>24.9 kg/m2) and 15% were underweight (<18.5 kg/m2). a fh of dm was present in 74%. the homa-ir index was elevated in 16% and was directly correlated to the bmi (p = 0.003). there was no correlation between ir and a positive fh of dm. conclusion: there is a high prevalence of ir (16%) and obesity (26%) in healthy young omani medical students. counselling is recommended for all overweight and obese individuals in an attempt to prevent or delay the onset of dm in the future. keywords: insulin resistance; diabetes; body mass index; obesity; young adults; oman. مع ذلك عالقة و الأ�سحاء العمانيني ال�سباب عند )ir( الأن�سولني مقاومة انت�سار مدى تقييم هو الدرا�سة هذه من الهدف الهدف: امللخ�ص: وفرباير 2009 مايو بني الدرا�سة هذه اأجريت الطريقة: .)dm( ال�سكري داء بخ�سو�س لديهم العائلي والتاريخ )bmi( اجل�سم كتلة موؤ�رس الطب طالب من الإناث من 50 و الذكور من 50 قبل من مف�سل ا�ستبيان تعبئة مت عمان. �سلطنة م�سقط، يف قابو�س ال�سلطان جامعة يف 2010 با�ستخدام الأن�سولني مقاومة ح�ساب مت ال�سيام. حالة يف الأن�سولني و اجللوكوز لقيا�س الدم من عينات اأخذ مت �سنة. 25-20 اأعمارهم ترتاوح وقد لالأن�سولني. مقاوم اعتباره فيتم 2.5 من اأعلى القراءة كانت فاإذا الأن�سولني/22.5( x اجللوكوز ( ب�سيغة )homa ir( معادلة 59% كالتايل: )bmi( اجل�سم كتلة معامل ح�سب لفئات امل�ساركني ت�سنيف مت النتائج: .)spss( برنامج با�ستخدام النتائج حتليل مت الوزن نق�س من يعانون 15% و كجم/م2( 24.9 >( ال�سمنة اأو الوزن زيادة من يعانون 26% و كجم/م2(، 24.9-18.5( طبيعية كانت )< 18.5 كجم/م2(. وكانت ن�سبة وجود التاريخ العائلي ملر�س ال�سكري عند الأ�سخا�س امل�ساركني يف الدرا�سة %74. وكانت ن�سبة مقاومة الأن�سولني %16 وكان له ارتباط مبا�رس مع موؤ�رس كتلة اجل�سم )p = 0.003(. مل تكن هناك اأي عالقة بني مقاومة الأن�سولني ووجود التاريخ العائلي ملر�س ال�سكري. اخلال�صة: هناك ارتفاع يف معدل انت�سار مقاومة الأن�سولني )%16( والبدانة )%26( يف �سباب طالب الطب العماين. يو�سى بتقدمي الن�سح جلميع الأفراد امل�سابني بالبدانة يف حماولة ملنع اأو تاأخري ظهور مر�س ال�سكري يف امل�ستقبل. مفتاح الكلمات: مقاومة الأن�سولني؛ معامل كتلة اجل�سم؛ البدانة؛ ال�سباب؛ �سلطنة عمان. insulin resistance and its correlation with risk factors for developing diabetes mellitus in 100 omani medical students *humaid h. al-farai,1 issa al-aboodi,2 azza al-sawafi,2 noora al-busaidi,2 nicholas woodhouse2 brief communication in recent decades, diabetes mellitus (dm) has become one of the most challenging medical issues worldwide. the world health organization (who) estimates a 190% increase in the number of people living with dm in oman over the next 20 years, from 75,000 in 2000 to 217,000 in 2025.1 the distribution of chronic diseases and related risk factors among the omani general population is similar to that of industrialised nations: 12% of the population have diabetes, 30% are overweight, 20% are obese, 41% have high cholesterol and 21% have metabolic syndrome.1 insulin resistance (ir) is a major risk factor for developing metabolic syndrome. in clinical practice, ir refers to a state in which a given concentration of insulin is associated with a subnormal glucose response.2 in addition, ir is a precursor to the development of overt diabetes. it is therefore necessary to establish the magnitude of this problem in the omani society and, armed with this knowledge, develop measures to delay or prevent the onset of dm in affected individuals. insulin resistance and its correlation with risk factors for developing diabetes mellitus in 100 omani medical students e394 | squ medical journal, august 2014, volume 14, issue 3 the aim of this study was to establish the prevalence of ir in a group of healthy, young omani medical students and to correlate these findings with their body mass index (bmi) and the presence or absence of a positive family history (fh) of diabetes. methods omani students from the college of medicine & health sciences of sultan qaboos university (squ) in muscat, oman, were invited to participate in this study between may 2009 and february 2010. investigators visited the students’ classes and explained the nature, benefits, risks and anticipated outcomes of the study. smokers, diabetics, those taking regular medications and/or those with other medical problems were excluded from the study leaving 100 participants included in the study. the study group was comprised of 50 male and 50 female medical students between 20–25 years old in their fourth to sixth year of university and representing different regions of oman. most of the participants were from northern omani governorates (muscat, al-dakhliyah, al-batena, al-sharqiyah, aldahahira and musandam). although, the participants represented the overall population of young omanis in terms of geographical region, they did not give a fair representation of the overall young omani population in terms of educational level. each student anonymously filled out a questionnaire to determine the following: age; history of dm and other medical problems; regular medications taken; fh of dm with subtypes of first degree (mother, father, brother or sister) or second degree (grandfather, grandmother, uncle or aunt); smoking status, and weight, height and bmi measurements. participants then underwent investigations to determine their fasting serum insulin and glucose levels. insulin levels were measured with the access® 2 immunoassay system (beckman coulter, inc., brea, california, usa) using the chemiluminescence immunoassay principle while glucose levels were measured with the cobas integra® 800 analyser (roche diagnostics ltd., basel, switzerland) using the spectrophotometry principle. the clinical applications regarding the calculation of ir have not yet been standardised. however, the most reliable method to evaluate ir was chosen, the homeostasis model assessment-estimated insulin resistance (homair). the homa-ir is calculated using the following formula: fasting insulin in µu/ml is multiplied by fasting glucose in mmol/l and divided by 22.5. the cut-off rate for abnormal values is between ≥2.1–2.7.3 a homa-ir level of >2.5 was considered abnormal. this level was decided upon based on the current clinical evidence that suggests using 2.5 as a cutoff point for ir.4 bmi was calculated by assessing each participant’s weight and height. participants were then classified as either underweight (<18.5 kg/m2), normal (18.5–24.9 kg/m2) or overweight/obese (≥25 kg/m2). the data from the questionnaires and investigations were collected and analysed using the statistical package for the social sciences (spss), table 1: percentage of the sample of medical students according to insulin resistance, body mass index category and family history of diabetes (n = 100) category participants % male n = 50 female n = 50 total ir 10 6 16 underweight bmi 8 7 15 normal bmi 27 32 59 overweight or obese bmi 15 11 26 family history of dm 37 37 74 ir = insulin resistance; bmi = body mass index; dm = diabetes mellitus. figure 2: percentage of the sample of medical students by body mass index category (n = 100). figure 1: percentage of the sample of medical students by insulin group (n = 100). humaid h. al-farai, issa al-aboodi, azza al-sawafi, noora al-busaidi and nicholas woodhouse brief communication | e395 version 16 (ibm corp., chicago, illinois, usa), using the pearson’s chi-squared test, student’s t-test and pearson product-moment correlation coefficient. a p value of <0.05 was considered statistically significant and a 95% confidence interval (ci) was used. fully informed written consent was obtained from each participant. the study was approved by the medical research & ethics committee of the college of medicine & health sciences at squ. results the data showed a high prevalence of ir (16%) among the 100 healthy subjects [table 1 and figure 1]. the 95% ci for the ir of the students was 2.99–4.19 and the mean was 3.59. there was a high prevalence of obesity (26%) among the sample, while 59% of the participants had a normal bmi and 15% were underweight [figure 2]. ir was significantly associated with a high bmi (p = 0.003). obesity was the main determinant of the degree of ir, while all subjects with a bmi of ≤21kg/ m2 had no ir [figure 3]. a large majority students (74%) had a positive fh of dm at either the first degree, second degree or both [figure 4]. the results showed no correlation between ir and a positive fh of dm (p = 0.771). discussion the current study found a high prevalence (26%) of obese and overweight omani students. this finding strongly supports a recent study conducted among 202 omani students of both genders which found that approximately 28% were overweight or obese.5 in addition, 16% of the subjects was found to have ir. the association between ir and bmi was statistically significant and no student with a bmi of ≤21 kg/m2 had a raised ir.5 this finding is consistent with previous studies demonstrating that obesity is one of the most important risk factors for developing ir.6,7 out of the 16 students with ir and a mean bmi of 28.02 kg/m2, 10 were male and six were female. however, the significant association between ir and high bmi in terms of gender was biased due to the small sample size. a positive fh for dm is a controversial contributing risk factor for developing ir and dm. some research has demonstrated a significant association between a positive fh of dm and ir,8 whereas other studies strongly disagree.9,10 in the current study, 74% of participants had a fh of dm at either the first degree, second degree or both. however, the association between ir and a fh of dm was not statistically significant. it is difficult to conclude either the presence or absence of an association between ir and a positive fh of dm from the current study as almost two-thirds of the sample had a positive fh. this may have masked the significant association between these risk factors. awareness of ir and the associated risk of developing dm, as well as the strong association of these variables with obesity, will help improve oman’s healthcare and patient outcomes. the primary prevention of dm should occur through lifestyle modifications, including improvements in diet and levels of physical exercise. the data in this study underscore the need for public education and awareness of these issues. a genetic predisposition for type 2 (t2) dm is a very important contributing risk factor; there are increasing reports of several mutations associated with the development of t2dm, such as the pparg and capn10 genes.11,12 however, certain ethnic groups have specific genes that increase the risk of developing t2dm. for example, the chinese population exhibits figure 3: significant direct correlation between body mass index and insulin resistance among the sample of medical students (n = 100). figure 4: number of students with and without a family history of diabetes (n = 100). insulin resistance and its correlation with risk factors for developing diabetes mellitus in 100 omani medical students e396 | squ medical journal, august 2014, volume 14, issue 3 the presence of the tcf7l2 gene, which puts them at increased risk for dm.13 however, further studies with larger samples are needed, including studies to evaluate other factors like genetic determinants, especially in those who test positive for ir. the ir-positive individuals among the study population will continue to be followed-up in the coming years so as to measure the true likelihood of them developing dm. all of the volunteers’ data and contact detils have been preserved for future longitudinal studies. such studies would help healthcare professionals in the early identification and treatment of patients who are at risk of developing dm. conclusion the prevalence of ir in healthy omani medical students was found to be quite high in this study. obesity was also prevalent and there was a direct correlation between bmi and ir. significant ir was not seen in those with a bmi of 21 or less. the authors recommend efforts to reduce the prevalence of obesity, especially among young people, by promoting a healthy diet and physical exercise. this will reduce the prevalence of ir and the future risk of dm. references 1. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 2. moller de, flier js. insulin resistance: mechanisms, syndromes, and implications. n engl j med 1991; 325:938–48. doi: 10.1056/ nejm199109263251307. 3. lebovitz he. clinician’s manual on insulin resistance: the dysmetabolic syndrome. bejing, china: science press inc., 2002. p.5. 4. singh y, garg mk, tandon n, marwaha rk. a study of insulin resistance by homa-ir and its cut-off value to identify metabolic syndrome in urban indian adolescents. j clin res pediatr endocrinol 2013; 5:245–51. doi: 10.4274/jcrpe.1127. 5. al-kilani h, waly m, yousef r. trends of obesity and overweight among college students in oman: a cross sectional study. sultan qaboos univ med j 2012; 12:69–76. 6. arslanian s, suprasongsin c. insulin sensitivity, lipids, and body composition in childhood: is “syndrome x” present? j clin endocrinol metab 1996; 81:1058–62. doi: 10.1210/ jcem.81.3.8772576. 7. bacha f, saad r, gungor n, janosky j, arslanian sa. obesity, regional fat distribution, and syndrome x in obese black versus white adolescents: race differential in diabetogenic and atherogenic risk factors. j clin endocrinol metab 2003; 88:2534–40. doi: 10.1210/jc.2002-021267. 8. arslanian sa, bacha f, saad r, gungor n. family history of type 2 diabetes is associated with decreased insulin sensitivity and an impaired balance between insulin sensitivity and insulin secretion in white youth. diabetes care 2005; 28:115–19. doi: 10.2337/diacare.28.1.115. 9. goldfine ab, bouche c, parker ra, kim c, kerivan a, soeldner js, et al. insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease. proc natl acad sci u s a 2003; 100:2724–9. doi: 10.1073/pnas.0438009100. 10. goran mi, coronges k, bergman rn, cruz ml, gower ba. influence of family history of type 2 diabetes on insulin sensitivity in prepubertal children. j clin endocrinol metab 2003; 88:192–5. doi: 10.1210/jc.2002-020917. 11. lyssenko v, almgren p, anevski d, orho-melander m, sjögren m, saloranta c, et al. genetic prediction of future type 2 diabetes. plos med 2005; 2:e345. doi: 10.1371/journal. pmed.0020345. 12. cooper me, white mf, zick y, zimmet p. type 2 diabetes mellitus. from: www.nature.com/nrendo/posters/type2diabetes mellitus accessed: aug 2013. 13. wang j, hu f, feng t, zhao j, yin l, wang y, et al. meta-analysis of associations between tcf7l2 polymorphisms and risk of type 2 diabetes mellitus in the chinese population. bmc med genet 2013; 14:8. doi: 10.1186/1471-2350-14-8. verrucous hyperplasia (vh) is a pre-malignant exophytic oral mucosal lesion with a predominantly verrucous or papillary surface; this lesion can subsequently transform into verrucous carcinoma (vc), a well-established warty variant of squamous cell carcinoma (scc).1 among 324 taiwanese patients, hsue et al. found the malignant potential of vh to be 3.1% over an average of 54.6 months.2 as vh and vc may present with similar clinical features, these entities need to be distinguished histologically. in 1980, shear et al. first differentiated vh from vc based on the absence of endophytic growth in the former entity, wherein the verrucous and hyperplastic epithelium was completely superficial to the adjacent normal epithelium.3 therefore, it is crucial that biopsies of verrucous lesions include a lesional margin with adequate depth. case report an 80-year-old male patient presented to the outpatient department of the bapuji dental college & hospital, davangere, karanataka, india, in 2011 with a growth on the inside of his cheek. six months prior to presentation, the patient had noticed a pea-sized growth in his mouth which had continued to grow over time. he did not report any pain associated with the growth unless he accidentally bit it whilst chewing food. although the patient had not smoked or chewed tobacco for the previous 7–8 years, he reported a prior 40-year history of chewing tobacco 3–4 times per day and smoking 2–4 bidis (i.e. thin indian cigarettes made of unprocessed tobacco wrapped in leaves) per day. on clinical examination, a whitish-pink sessile oral mass of approximately 1.5 x 1.5 cm was observed with departments of 1oral & maxillofacial pathology, 3oral diagnosis & radiology and 7periodontics, christian dental college & hospital, ludhiana, punjab, india; 2department of pediatric & preventive dentistry, mahatma gandhi mission dental college & hospital, mumbai, maharashtra, india; 4department of oral medicine & radiology, shaheed kartar singh sarabha dental college & hospital, ludhiana, punjab, india; 5department of oral pathology & microbiology, asan memorial dental college & hospital, kanchipuram, tamil nadu, india; 6department of oral pathology & microbiology, anil neerukonda institute of dental sciences, visakhapatnam, andhra pradesh, india *corresponding author e-mail: sonalgrvr@yahoo.com فرط التنسج الثؤلويل تقرير حالة والتشخيص التفريقي �ض�نال جروفر, ميهر جا, ب��ضان �ضارما, �ضيكار كاب�ر, ك�مد ميتال, نيثان كافا�ضريي باراكات, اأنيل بنجل�ر �ضيفابا, رافلني ك�ر abstract: verrucous hyperplasia (vh) is a rare exophytic oral mucosal lesion which can transform into verrucous carcinoma (vc), its malignant but clinically similar counterpart. these entities can be distinguished by the lack of invasive growth in vh cases; as such, it is essential to include a margin with adequate depth when performing a biopsy of the epithelium of the lesion. we report an 80-year-old male patient who presented to the bapuji dental college & hospital, davangere, karanataka, india, in 2011 with a warty whitish-pink growth on the inside of his cheek. the patient was treated with wide surgical excision of the lesion and a diagnosis of vh was made based on histopathological features. there was no evidence of recurrence at a five-year follow-up. this report highlights the histological variations, pathogenesis and differential diagnosis of vh. keywords: hyperplasia; verrucous carcinoma; squamous cell carcinoma; histology, diagnosis; case report; india. امللخ�ص: فرط التن�ضج الث�ؤل�يل ه� اآفة غري �ضائعة ملخاطية الفم خارجية التنبت والتي قد تتح�ل اإىل �رسطان ث�ؤل�يل, وهي خبيثة ولكنها م�ضابهة اإكلينكيا لالآفة املقابلة. هذة الكيانات تفرق بعدم القدرة على النم� الغزوي يف حاالت فرط التن�ضج الث�ؤل�يل, لذا, من االأ�ضا�ضيات كلية اإىل تقدم عاما 80 عمرة ذكر ملري�ص حالة هنا نعر�ص منا�ضب. عمق ذو هام�ص على ت�ضمل اأن االآفة ظهارة من خزعة اأخذ عند عالج مت للخد. الداخلي اجلزء يف زهري اأبي�ص ث�ؤل�يل ب�رم 2011 عام يف الهند كارنتكا, دافاجنري, االأ�ضنان, لطب بابجي وم�ضت�ضفى اأي ي�جد ال االأن�ضجة. مر�ضيات مالمح على بناءا الث�ؤل�يل التن�ضج بفرط احلالة ت�ضخي�ص ومت لالآفة وا�ضع جراحي با�ضتئ�ضال املري�ص دليل على جتدد حدوث االآفة خالل فرتة اخلم�ضة �ضن�ات للمتابعة. هذا التقرير ي�ضلط ال�ض�ء على اختالفات مر�ضيات االأن�ضجة, االإمرا�ص والت�ضخي�ص التفريقي لفرط التن�ضج الث�ؤل�يل. الكلمات املفتاحية: فرط التن�ضج؛ �رسطانة ث�ؤل�لية؛ �رسطانة حر�ضفية اخلاليا؛ علم االأن�ضجة, الت�ضخي�ص؛ تقرير حالة؛ الهند. verrucous hyperplasia case report and differential diagnosis *sonal grover,1 mihir jha,2 bhushan sharma,1 shekhar kapoor,3 kumud mittal,4 nithin k. parakkat,5 anil b. shivappa,6 ravleen kaur7 case report sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e98–102, epub. 30 mar 17 submitted 9 jun 16 revision req. 7 aug 16; revision recd. 16 aug 16 accepted 1 sep 16 doi: 10.18295/squmj.2016.17.01.017 sonal grover, mihir jha, bhushan sharma, shekhar kapoor, kumud mittal, nithin k. parakkat, anil b. shivappa and ravleen kaur case report | e99 a warty/pebbly superficial surface and clearly defined margins [figure 1]. it was firm in consistency and non tender upon palpation. there was no evidence of discharge and no ulcerations were observed on the surface of the lesion, nor in the surrounding mucosa which appeared normal. an extraoral examination revealed an enlarged submandibular lymph node, which was mobile and non-tender upon palpation. the lesion was treated with wide surgical excision. histopathological examination of a biopsy specimen revealed a hyperplastic stratified squamous epithelium arranged in the form of exophytic papillary projections, with underlying fibrovascular connective tissue [figure 2a]. the epithelium exhibited hyperparakeratinisation with a few koilocytes seen in the superficial layers. the rete ridges had a broad ‘elephant’s foot’ shape and were at the same level as that of the adjoining normal epithelium [figure 2b]. some of the cells in the basal layer of the epithelium exhibited dysplastic features. in addition, the underlying connective tissue revealed dense chronic inflammatory cell infiltrates, chiefly concentrated in the juxta-epithelial areas. as a result of these features, a final diagnosis of vh was made. the patient was subsequently followed-up periodically over the next five years with no sign of recurrence [figure 3]. discussion clinically, vh presents as a warty or papillary fungating exophytic mucosal mass which can sometimes ulcerate and is predominantly pink in colour with a partly whitish surface.4 the average age at first presentation is between 30–60 years old.4,5 previous research has indicated the buccal mucosa to be the most common site for vh; this may potentially be correlated with usage of quid (i.e. clumps of chewing tobacco) which is usually placed in this region of the mouth.5,6 in contrast, shear et al. found that the gingiva and alveolar mucosa were the most common sites among 68 cases of vh.3 hazarey et al. reported that placement of tobacco-betel-lime quid (i.e. a mixture of slaked lime, chewing tobacco and betel leaf pieces) in the buccal vestibule was the most predominant habit associated with vh growth.6 wang et al. similarly observed that 91% of 60 patients with vh chewed areca nut quid (i.e. a mixture of areca nut, betel leaf pieces and chewing tobacco).5 smoking was reported to be the second most common aetiological factor in these two studies.5,6 shear et al. classified two histological patterns of vh, including the “sharp” variety (comprised of heavily keratinised, long and narrow verrucous processes) and the “blunt” variety (comprised of less heavily keratinised, broader and flatter verrucous processes).3 the former may potentially be referred to as verrucous leukoplakia due to its predominantly white colour resulting from the heavy keratinisation.3 however, no difference in prognosis has been reported according to these patterns. in contrast, wang et al. classified vh into plaque-type and mass-type lesions and identified significant differences in their malignant transformation rates.5 plaque-type vh was defined as horizontally-proliferating epithelial hyperplasia resulting in an elevated plaque-like lesion with a verrucous surface, while mass-type vh lesions displayed single or multiple protuberant masses of figure 2: photomicrographs of haematoxylin and eosin stains at x100 magnification showing (a) papillary projections (arrow) with keratin plugging (asterisk) in the clefts and (b) broad ‘elephant’s foot’ rete ridges (arrows) at the same level as that of the adjacent normal epithelium. figure 1: intraoral photograph showing a whitish-pink sessile exophytic lesion on the buccal mucosa of an 80-year-old male patient. verrucous hyperplasia case report and differential diagnosis e100 | squ medical journal, february 2017, volume 17, issue 1 to the adjacent normal epithelium; furthermore, the broadened epithelial ridges lie above the adjacent normal epithelium in vh, whereas similar rete ridges display an endophytic growth pattern in vc cases.6 in addition, the verrucous processes in vc often bring a margin of normal epithelium down with them into the underlying connective tissue.3 the histogenesis of vh as proposed by shear et al. is summarised in figure 4.3 it has been proposed that leukoplakia, if left untreated, may transform into vh or vc over time.3 moreover, vh can be confused with proliferative verrucous leukoplakia (pvl), a variant of non-homogenous leukoplakia in which the lesions eventually assume an exophytic verrucous appearance.8 while the term vh refers to both clinical and histopathological features, pvl is unequivocally accepted as a clinical term used to define a specific type of non-homogenous leukoplakia with a verrucous surface.4 histologically, pvl displays clinical foci of hyperkeratosis that progressively spread and become multifocal. many cases of pvl are extremely resistant to treatment and progress to invasive cancer.8 in cases of papillary squamous cell carcinoma (pscc), vc can be distinguished by its intact basement membrane which contrasts with the focal or early invasion seen in pscc; furthermore, the epithelium in pscc cases is significantly dysplastic when compared with the almost ‘bland’ cytological features of the epithelium of vc lesions.9 the clinicopathological spectrum of verrucous lesions as proposed by hansen et al. is shown in table 1.8 the malignant potential of vh is well established.1–3 slootweg et al. concluded that vh probably epithelial hyperplasia, with very little connective tissue at the core and a verrucous surface.5 histopathologically, all variants of vh exhibit verrucous projections of the hyperplastic epithelium which lie superficially to the adjacent epithelium.3,5 however, there are considerable similarities between vh and vc lesions. the latter is defined as a warty, papillary or fungating exophytic lesion with broad and intact intrusions of rete ridges.3 according to previous research, keratin plugging in the centre of epithelial invaginations is a histological hallmark of vc; however, slootweg et al. reported that the presence of keratin plugging is not obligatory for a vc diagnosis.4,7 although dysplasia is rarely seen, mitotic figures are more common.4 the distinction between vh and vc is histological, based on the location of the hyperplastic epithelium in relation figure 3: intraoral photograph of the buccal mucosa of an 85-year-old male patient showing no evidence of recurrence of verrucous hyperplasia five years after wide surgical excision of the lesion. figure 4: flowchart depicting the histogenesis of verrucous hyperplasia as proposed by shear et al.3 table 1: clinicopathological spectrum of verrucous lesions8 grade entity histopathological features 0 none normal oral mucosa 2 clinical leukoplakia hyperkeratosis with or without dysplasia 4 verrucous hyperplasia leukoplakia with papillary exophytic proliferation of the epithelium 6 verrucous carcinoma downgrowth of the welldifferentiated squamous epithelial blunt rete ridges with intact basement membrane 8 papillary carcinoma exophytic and invasive growth of the well-differentiated squamous epithelium with keratin formation and minimal dysplasia 10 scc loss of cohesion of moderately/ poorly-differentiated tumour cells with moderate to severe dysplasia and minimal keratin formation scc = squamous cell carcinoma. sonal grover, mihir jha, bhushan sharma, shekhar kapoor, kumud mittal, nithin k. parakkat, anil b. shivappa and ravleen kaur case report | e101 represents a morphological variant of vc after noting an association between vh and scc in 37% of 27 patients.4 chen et al. reported high expression of inducible nitric oxide synthase (inos) proteins and messenger ribonucleic acid in vh lesions and concluded that an inos-dependent mechanism may be involved in the malignant transformation of vh.10,11 additionally, the higher expression of interleukin-1β and glutathione s-transferase pi isoenzymes and the allelic loss at 19 loci on seven different chromosome arms may also play an important role in the malignant transformation of vh.12–14 tumour protein p53, epidermal growth factor receptor and human epidermal growth factor receptor 3 expression can also be used to differentiate vh from vc and scc.15,16 although greer jr et al. found an association between the human papilloma virus and vh, the role of the virus in the malignant transformation of vh has yet to be confirmed.17 in terms of treatment modality, surgery alone is the most common method of management for both vc and vh cases, due to their overlapping clinicopathological features.18,19 however, it is important to ensure wide surgical excision of the lesion with adequate soft tissue margins so as to avoid recurrence. although sporadic cases of cervical and distant metastasis have been reported, the overall rate of metastasis is insignificant.20 an incorrect histological diagnosis or the presence of occult foci indicating scc has been proposed to justify the metastatic nature of lesions otherwise characteristic of vc; as such, thorough sampling of the surgical specimen is highly recommended.20,21 conclusion distinction between vc and vh lesions can only be made histologically, by comparing the level of the rete ridges of the epithelium of the lesion with that of the adjacent normal epithelium. in addition, vh cases may also be confused with verrucous leukoplakia. thus, biopsies of verrucous lesions should include the adjacent normal epithelium in order to ensure correct diagnosis. as vh has the potential for malignant transformation, patients should be treated in a similar manner to those with vc. references 1. neville bw, damm dd, allen cm, bouquot je. epithelial pathology. in: oral and maxillofacial pathology, 3rd ed. philadelphia, pennsylvania, usa: saunders, 2008. pp. 388–97. 2. hsue ss, wang wc, chen ch, lin cc, chen yk, lin lm. malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: a follow-up study based in a taiwanese hospital. j oral pathol med 2007; 36:25–9. doi: 10.1111/j.1600-0714.2006.00491.x. 3. shear m, pindborg jj. verrucous hyperplasia of the oral mucosa. cancer 1980; 46:1855–62. doi: 10.1002/1097-0142(19801015)46:8< 1855::aid-cncr2820460825>3.0.co;2-#. 4. slootweg pj, müller h. verrucous hyperplasia or verrucous carcinoma: an analysis of 27 patients. j maxillofac surg 1983; 11:13–19. doi: 10.1016/s0301-0503(83)80006-x. 5. wang yp, chen hm, kuo rc, yu ch, sun a, liu by, et al. oral verrucous hyperplasia: histologic classification, prognosis, and clinical implications. j oral pathol med 2009; 38:651–6. doi: 10.1111/j.1600-0714.2009.00790.x. 6. hazarey vk, ganvir sm, bodhade as. verrucous hyperplasia: a clinico-pathological study. j oral maxillofac pathol 2011; 15:187–91. doi: 10.4103/0973-029x.84492. 7. rajendran r, sivapathasundaram b, eds. shafer’s textbook of oral pathology, 5th ed. new delhi, india: elsevier, 2005. pp. 164–5. 8. hansen ls, olson ja, silverman s jr. proliferative verrucous leukoplakia: a long-term study of thirty patients. oral surg oral med oral pathol 1985; 60:285–98. doi: 10.1016/00304220(85)90313-5. 9. ferlito a, devaney ko, rinaldo a, putzi mj. papillary squamous cell carcinoma versus verrucous squamous cell carcinoma of the head and neck. ann otol rhinol laryngol 1999; 108:318–22. doi: 10.1177/000348949910800318. 10. chen yk, hsuen ss, lin lm. increased expression of inducible nitric oxide synthase for human oral submucous fibrosis, verrucous hyperplasia, and verrucous carcinoma. int j oral maxillofac surg 2002; 31:419–22. doi: 10.1054/ijom.2002.0246. 11. chen yk, hsuen ss, lin lm. expression of inducible nitric oxide synthase in human oral premalignant epithelial lesions. arch oral biol 2002; 47:387–92. doi: 10.1016/s0003-9969(02)00011-0. 12. tsai cc, chen cc, lin cc, chen ch, lin ts, shieh ty. interleukin-1 beta in oral submucous fibrosis, verrucous hyperplasia and squamous cell carcinoma tissues. kaohsiung j med sci 1999; 15:513–19. 13. chen yk, lin lm. immunohistochemical demonstration of epithelial glutathione s-transferase isoenzymes in normal, benign, premalignant and malignant human oral mucosa. j oral pathol med 1995; 24:316–21. doi: 10.1111/j.1600-0714.1995. tb01192.x. 14. poh cf, zhang l, lam wl, zhang x, an d, chau c, et al. a high frequency of allelic loss in oral verrucous lesions may explain malignant risk. lab invest 2001; 81:629–34. doi: 10.1038/ labinvest.3780271. 15. sakurai k, urade m, takahashi y, kishimoto h, noguchi k, yasoshima h, et al. increased expression of c-erbb-3 protein and proliferating cell nuclear antigen during development of verrucous carcinoma of the oral mucosa. cancer 2000; 89:2597–605. doi: 10.1002/1097-0142(20001215)89:12<2597::a id-cncr12>3.0.co;2-n. 16. wu m, putti tc, bhuiya ta. comparative study in the expression of p53, egfr, tfg-alpha, and cyclin d1 in verrucous carcinoma, verrucous hyperplasia, and squamous cell carcinoma of head and neck region. appl immunohistochem mol morphol 2002; 10:351–6. doi: 10.1097/00129039-200212000-00011. 17. greer ro jr, eversole lr, crosby lk. detection of human papillomavirus-genomic dna in oral epithelial dysplasia, oral smokeless tobacco-associated leukoplakia and epithelial malignancies. j oral maxillofac surg 1990; 48:1201–5. doi: 10.10 16/0278-2391(90)90538-d. https://doi.org/10.1111/j.1600-0714.2006.00491.x https://doi.org/10.1002/1097-0142%2819801015%2946:8%3c1855::aid-cncr2820460825%3e3.0.co%3b2-%23 https://doi.org/10.1002/1097-0142%2819801015%2946:8%3c1855::aid-cncr2820460825%3e3.0.co%3b2-%23 https://doi.org/10.1016/s0301-0503%2883%2980006-x https://doi.org/10.1111/j.1600-0714.2009.00790.x https://doi.org/10.4103/0973-029x.84492 https://doi.org/10.1016/0030-4220%2885%2990313-5 https://doi.org/10.1016/0030-4220%2885%2990313-5 https://doi.org/10.1177/000348949910800318 https://doi.org/10.1054/ijom.2002.0246 https://doi.org/10.1016/s0003-9969%2802%2900011-0 https://doi.org/10.1111/j.1600-0714.1995.tb01192.x https://doi.org/10.1111/j.1600-0714.1995.tb01192.x https://doi.org/10.1038/labinvest.3780271 https://doi.org/10.1038/labinvest.3780271 https://doi.org/10.1002/1097-0142%2820001215%2989:12%3c2597::aid-cncr12%3e3.0.co%3b2-n https://doi.org/10.1002/1097-0142%2820001215%2989:12%3c2597::aid-cncr12%3e3.0.co%3b2-n https://doi.org/10.1097/00129039-200212000-00011 https://doi.org/10.1016/0278-2391%2890%2990538-d https://doi.org/10.1016/0278-2391%2890%2990538-d verrucous hyperplasia case report and differential diagnosis e102 | squ medical journal, february 2017, volume 17, issue 1 20. asproudis i, gorezis s, aspiotis m, tsanou e, kitsiou e, merminga e, et al. orbital metastasis from verrucous carcinoma of the oral cavity: case report and review of the literature. in vivo 2007; 21:909–12. 21. kallarakkal tg, ramanathan a, zain rb. verrucous papillary lesions: dilemmas in diagnosis and terminology. int j dent 2013; 2013:298249. doi: 10.1155/2013/298249. 18. kang cj, chang jt, chen tm, chen ih, liao ct. surgical treatment of oral verrucous carcinoma. chang gung med j 2003; 26:807–12. 19. mehrotra d, goel m, kumar s, pandey r, ram h. oral verrucous lesions: controversies in diagnosis and management. j oral biol craniofac res 2012; 2:163–9. doi: 10.1016/j.jobcr.2012.10.006. https://doi.org/10.1155/2013/298249 https://doi.org/10.1016/j.jobcr.2012.10.006 kadayam g. gomathi, syed i. shehnaz and nelofer khan online brief communication | e551 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e551−555, epub. 14th oct 14 submitted 30th mar 14 revision req. 4th may 14; revision recd. 28th may 14 accepted 23rd jun 14 departments of 1biochemistry and 2pharmacology, gulf medical university, ajman, united arab emirates *corresponding author e-mail: gomathikg@gmu.ac.ae and gomathikg@hotmail.com هل املزيد من تعليم التغذية مطلوب يف املناهج الطبية يف املرحلة اجلامعية؟ تصورات خرجيي إحدى اجلامعات الطبية يف دولة اإلمارات العربية املتحدة كادايام جورو�شوامي جوماثي، �شيد اليا�س �شهناز، نيلوفري خان abstract: objectives: the rise in lifestyle diseases has resulted in primary physicians advising more patients on the benefits of nutritional modifications. however, nutrition education has remained more or less unchanged in the undergraduate medical curriculum. this study aimed to assess the perceptions of medical graduates regarding nutrition education in their undergraduate curriculum. methods: a total of 125 medical graduates from the gulf medical university in ajman, united arab emirates, were invited to participate in an anonymous online survey from may to october 2012. the validated pilot-tested questionnaire was designed to assess perceptions regarding nutrition education in the undergraduate medical curriculum. results: a total of 65 medical graduates responded to the survey, of which 55% were female. of the respondents, 32% were general physicians and 68% were specialists in various disciplines. nutrition education was perceived to be very important by 80% of the respondents; however, 78.5% felt that they had not received adequate instruction in this field during their undergraduate medical curriculum. the major areas of deficit identified were in the categories of clinical nutrition, nutrition in primary care and evidence-based nutrition. conclusion: in this study, gulf medical university graduates perceived a need for more nutrition-related instruction in their undergraduate medical curriculum. the areas of deficit identified in this study could help in future curricular improvements. keywords: nutritional sciences; undergraduate medical education; curriculum; united arab emirates. عاداتهم تعديل بفوائد يتعلق فيما للمر�شى امل�شورة من للمزيد االطباء تقدمي اىل احلياة منط م�شتوى ارتفاع لقد اأدى امللخ�ص: الهدف: كلية خريجي ت�شورات تقييم اإىل الدرا�شة هذه هدفت تغيري. دون يزال ال الطب كلية منهج يف الغذائي التثقيف فان هذا، ومع الغذائية. الطب للتثقيف الغذائي يف املنهج الدرا�شي اجلامعي. الطريقة: متت دعوة 125 خريج من كلية الطب من جامعة اخلليج الطبية يف عجمان، االإمارات العربية املتحدة، للم�شاركة يف ا�شتطالع على االنرتنت من مايو اإىل اأكتوبر 2012. مت ت�شميم ا�شتبيان جتريبي للتحقق من تقييم 55% امل�شح، يف الطب كلية خريجي من 65 �شارك النتائج: اجلامعية. الطبية املناهج يف الغذائي التثقيف ب�شاأن اخلريجني ت�شورات منهم اإناث. %32 من االأطباء و %68 من التخ�ش�شات الطبيه املختلفه. وجد اأن التثقيف الغذائي"مهم جدا" عند %80 من امل�شتطلعني. وراأى %78.5 اأنهم مل يتلقوا معلومات كافية يف هذا املجال خالل درا�شتهم اجلامعية. وكانت جماالت العجز الرئي�شية حمددة يف فئات التغذية ال�رسيرية والتغذية يف الرعاية ال�شحية االأولية والتغذية القائمة على االأدلة. اخلال�صة: يف هذه الدرا�شة، يرى خريجي جامعة اخلليج الطبية احلاجة للمزيد من التثقيف الغذائي يف املناهج الطبية اجلامعية اخلا�شة بهم. ميكن للنقائ�س املحدده يف هذه الدرا�شة اأن ت�شاعد يف حت�شني املناهج الدرا�شية يف امل�شتقبل. مفتاح الكلمات: علوم التغذية؛ التعليم الطبي اجلامعي؛ املناهج الدرا�شية؛ االإمارات العربية املتحدة. is more nutrition education needed in the undergraduate medical curriculum? perceptions of graduates from a medical university in the united arab emirates *kadayam g. gomathi,1 syed i. shehnaz,2 nelofer khan1 in the past few decades, lifestyle and food habits in the united arab emirates (uae) and other arabian gulf countries have become more sedentary and westernised.1,2 while most communicable diseases are well managed in the uae, a dramatic rise in lifestyle-related diseases, including diabetes and cardiovascular disease, has been observed.3 physicians are treating more patients with lifestyle-related diseases and giving advice on beneficial nutritional modifications. the importance of increased nutrition education for health professionals has been recognised in both the usa and the uk, with the latter implementing a need for nutrition education programme.4,5 in the uae, there is also an increasing awareness about the rising incidence of lifestyle diseases and the role that good nutrition plays in preventing and managing these diseases.6 most medical schools across the world have nutrition-related topics on their curricula. however, a survey carried out in 2001 among 98 medical schools across the usa revealed inadequacies in the nutrition education being taught in the curricula.7 steps were online brief communication is more nutrition education needed in the undergraduate medical curriculum? perceptions of graduates from a medical university in the united arab emirates e552 | squ medical journal, november 2014, volume 14, issue 4 taken to increase nutrition-related instruction in medical schools; however, an updated study in 2010 showed that nutrition education continued to be inadequate.8 studies from canada and japan also indicated insufficient nutrition education in the medical curriculum.9,10 there are no studies, to the best of the authors’ knowledge, regarding the adequacy of nutrition education in the curricula of medical schools in the uae or other countries in the arabian gulf region. the objective of this study, therefore, was to assess the perceptions of medical graduates from a university in the uae regarding nutrition education in their undergraduate medical curriculum. methods a total of 178 doctors, of which 63% were female, graduated with a bachelor of medicine and a bachelor of surgery (mbbs) degree between 2008 and 2010 from the gulf medical university, an accredited medical school in ajman, uae. of these, 125 graduates with valid email addresses on the alumni database were invited by email to participate in an anonymous online survey using surveymonkey pro® software (surveymonkey, palo alto, california, usa) between may and october 2012. a questionnaire to assess the graduates’ perceptions regarding nutrition education in the undergraduate medical curriculum was designed with the help of medical education experts and faculty involved in nutrition education. the questionnaire included items related to the participants’ sociodemographic information; courses in which nutrition-related topics were taught and the teaching/learning methods used; importance of nutrition education for doctors; adequacy of nutrition instruction, and areas requiring more nutrition instruction. the respondents were asked to identify areas requiring more instruction from a list which included: basic nutrition concepts (energy balance, macro and micronutrients); nutrition and genetics; nutrition in primary care settings (primary care, community health and preventive medicine); clinical nutrition (nutrition in disease states and nutritional therapy), and evidence-based nutrition (applying evidence-based guidelines to nutrition). while questions related to sociodemographic information were close-ended, those regarding nutrition education had options for open-ended responses. the questionnaire was converted into an online survey with the help of information technology experts. it was validated and pilot-tested on five medical graduates before the alumni graduates were invited to participate. three reminders at one-month intervals were sent during the study period to the graduates who had not yet completed the survey. data were collected in microsoft excel, version 2007 (microsoft corp., redmond, washington, usa), and then transferred to the statistical package for social sciences (spss), version 19.0 software (ibm corp., chicago, illinois, usa) for analysis. the participants were divided into the following groups: male/female, general physicians/specialists and working in the uae/working outside the uae. pearson’s chi-squared test was used for comparisons between groups and the significance level was set at 0.05. figure 1: distribution of the survey respondents by country of present employment (n = 65). the respondents were all graduates of the gulf medical university in ajman, uae. uae = united arab emirates. kadayam g. gomathi, syed i. shehnaz and nelofer khan online brief communication | e553 ethical approval for the study was obtained from the research & ethics committee of the gulf medical university. results of the 125 medical graduates who were invited to participate, 65 completed the survey, giving a response rate of 52%. the respondents were aged between 27 and 32 years, with an average age of 29.3 years. a total of 55% of the respondents were female. as shown in figure 1, 32% of the respondents were based in the uae while the rest were in other countries. of all the respondents, 32% were working as general physicians and the rest were specialising within different disciplines. regarding nutrition education in their undergraduate medical curriculum, 80% of the respondents reported receiving nutrition-related instruction in their pre-clinical years, while 50% reported receiving nutrition-related instruction in their clinical years. the courses in which nutritionrelated topics were taught were community medicine (49%), biochemistry (49%), medicine (31%), paediatrics (25%), physiology (14%) and surgery (11%). the respondents reported that the main teaching/learning methods adopted were in a lecture and case-based discussion format. nutrition education for doctors was perceived as ‘very important’ by 80%, ‘fairly important’ by 18.5% and ‘not so important’ by 1.5% of the respondents [figure 2]. the respondents mentioned using nutritionrelated knowledge in their clinical practice ‘all the time’ (21.5%), ‘often’ (41.5%), ‘sometimes’ (20%) and ‘rarely’ (4.5%). most of the respondents (78.5%) felt that they had not received adequate nutrition instruction in relation to their past or present professional work [figure 3]. there were no significant differences in the perceptions reported between the different groups regarding the importance of nutrition education, the utilisation of nutrition-related knowledge or the adequacy of nutrition instruction received. the main areas where the respondents identified requiring more instruction were in the clinical nutrition (45%), nutrition in primary care settings (40%) and evidence-based nutrition (32%) categories [figure 4]. figure 2: distribution of the survey respondents regarding their perception of the importance of nutrition education for doctors (n = 65). the respondents were all graduates of the gulf medical university in ajman, united arab emirates. figure 3: distribution of the survey respondents regarding their perception of the adequacy of nutrition instruction in their undergraduate medical curriculum in relation to their past or present professional work (n = 65). the respondents were all graduates of the gulf medical university in ajman, united arab emirates. figure 4: categories of nutrition-related education identified by the survey respondents as requiring more instruction (n = 65). the respondents were all graduates of the gulf medical university in ajman, united arab emirates. is more nutrition education needed in the undergraduate medical curriculum? perceptions of graduates from a medical university in the united arab emirates e554 | squ medical journal, november 2014, volume 14, issue 4 there were only three open-ended responses within this section, all of which mentioned the importance of nutrition knowledge for the personal health of medical students during their training. discussion the emphasis on different aspects of education imparted to students is determined by each medical school’s curriculum. feedback from former students who are currently applying the knowledge and skills learnt in their programmes is valuable for improving curricula.11 this study attempted to study graduate perceptions regarding nutrition education in the curriculum of the gulf medical university in ajman. as the medical graduates were practicing in many different locations, it was necessary for the survey to be conducted online. although the response rate was low, this was expected since completing the survey was completely voluntary, anonymous and there was no incentive to participate other than goodwill. the disciplines and the teaching/learning methods identified by the respondents corresponded well with the courses and instructional methods that were used in their undergraduate medical curriculum. nutrition education in the medical curriculum was perceived as ‘very important’ by most of the respondents and the majority mentioned using nutrition-related knowledge ‘often’ or ‘all the time’. however, the majority of the respondents felt that they had not received adequate nutrition instruction in relation to their past or present work. this finding, though disturbing, is not unexpected. a study from the usa also found that a large number of resident physicians (62%) reported deficits in their nutrition knowledge, although they perceived nutrition counselling as a priority.12 a study by wynn et al. reported that 58.1% of the surveyed canadian physicians believed that more patients would benefit from nutrition counselling, even though 82.3% found that their formal nutrition training in medical school had been inadequate.13 in saudi arabia, 72.9% of physicians in one study had poor nutrition knowledge despite the fact that 77.8% perceived nutrition counselling and management to be important.14 as most respondents in the current study felt that nutrition education was very important and mentioned using their nutrition-related knowledge often or all the time, while also perceiving their instruction in medical school to be inadequate, it may be assumed that they made up for the deficits in their knowledge by selflearning.15 no differences in perceptions regarding the importance or adequacy of nutrition education were seen between the genders or the other groups (general physicians versus specialists and those working in the uae versus those elsewhere). this is similar to observations from a study carried out by mihalynuk et al. in the usa.16 the participants in the current survey had been taught in a traditional discipline-based undergraduate medical curriculum. the courses taught in the pre-clinical years included anatomy; physiology; biochemistry; pathology, microbiology; pharmacology; forensics, and community medicine. in their clinical years, participants took the following courses: medicine and allied specialties; surgery and allied specialties; paediatrics; obstetrics and gynaecology; otorhinolaryngology, and ophthalmology. the categories which were identified as requiring more instruction included clinical nutrition, nutrition in primary care settings and evidence-based nutrition. while clinical nutrition is taught mainly in the clinical years, nutrition in primary care and evidence-based nutrition are taught during the pre-clinical years in preventative medicine and subsequently reinforced during clinical postings. the categories identified in the current study as inadequate are similar to those reported by medical students in the usa, where the lowest self-reported proficiencies were in nutrition and disease management, micronutrients and alternative and complementary medicine.16 one probable reason for this inadequate instruction in nutrition topics could be the fact that most nutritionrelated teaching takes place in the pre-clinical years. suggestions for improving nutrition education in the undergraduate medical curriculum include vertical integration into the clinical years and an emphasis on nutritional assessment and support.17 this study is limited by the methodology, as data were gathered from an online survey and all conclusions were based on self-reported data. there may have been a selection bias among the respondents, with a greater number of responses from graduates who were more motivated to improve nutrition education, since the purpose of the survey was mentioned to be for medical education research and curriculum improvement. furthermore, this study was carried out among graduates from a single university and the results, though similar to those from other parts of the world, may not be representative of other medical schools in the uae or the region. similar studies in other uae or arabian gulf medical schools are warranted. conclusion most of the surveyed gulf medical university graduates perceived nutrition education to be very important for doctors and reported that more kadayam g. gomathi, syed i. shehnaz and nelofer khan online brief communication | e555 nutrition education is needed in the undergraduate medical curriculum. in particular, participants were of the opinion that further instruction is especially required in the areas of clinical nutrition, nutrition in primary care settings and evidence-based nutrition. feedback from graduates, who are now applying the knowledge and skills learnt during the curriculum, can be a valuable resource for identifying areas requiring curricular improvement. a c k n o w l e d g e m e n t s the authors would like to thank the medical graduates of gulf medical university for their cooperation. c o n f l i c t o f i n t e r e s t the authors report no conflicts of interest. references 1. musaiger ao, al-hazzaa hm. prevalence and risk factors associated with nutrition-related noncommunicable diseases in the eastern mediterranean region. int j gen med 2012; 5:199– 217. doi: 10.2147/ijgm.s29663. 2. ng sw, zaghloul s, ali h, harrison g, yeatts k, el sadig m, et al. nutrition transition in the united arab emirates. eur j clin nutr 2011; 65:1328–37. doi: 10.1038/ejcn.2011.135. 3. world health organization. countries: united arab emirates. from: www.who.int/countries/are/en/ accessed: jan 2014. 4. kris-etherton pm, akabas sr, bales cw, bistrian b, braun l, edwards ms, et al. the need to advance nutrition education in the training of health care professionals and recommended research to evaluate implementation and effectiveness. am j clin nutr 2014; 99:1153s–66s. doi: 10.3945/ajcn.113.073502. 5. need for nutrition education programme (nnedpro). five year update: the need for nutrition education programme. from: www.nnedpro.org.uk/wordpress/wp-content/uploads/ 2013/08/5yearupdate.pdf accessed: jan 2014. 6. hajat c, harrison o, shather z. a profile and approach to chronic disease in abu dhabi. global health 2012; 8:18. doi: 10.1186/1744-8603-8-18. 7. torti fm jr, adams km, edwards lj, lindell kc, zeisel sh. survey of nutrition education in u.s. medical schools: an instructor-based analysis. med educ online 2001; 6:8. 8. adams km, kohlmeier m, zeisel sh. nutrition education in u.s. medical schools: latest update of a national survey. acad med 2010; 85:1537–42. doi: 10.1097/acm.0b013e3181eab71b. 9. gramlich lm, olstad dl, nasser r, goonewardene l, raman m, innis s, et al. medical students’ perceptions of nutrition education in canadian universities. appl physiol nutr metab 2010; 35:336–43. doi: 10.1139/h10-016. 10. orimo h, ueno t, yoshida h, sone h, tanaka a, itakura h. nutrition education in japanese medical schools: a followup survey. asia pac j clin nutr 2013; 22:144–9. doi: 10.6133/ apjcn.2013.22.1.13. 11. goldacre mj, taylor k, lambert tw. views of junior doctors about whether their medical school prepared them well for work: questionnaire surveys. bmc med educ 2010; 10:78. doi: 10.1186/1472-6920-10-78. 12. vetter ml, herring sj, sood m, shah nr, kalet al. what do resident physicians know about nutrition? an evaluation of attitudes, self-perceived proficiency and knowledge. j am coll nutr 2008; 27:287–98. 13. wynn k, trudeau jd, taunton k, gowans m, scott i. nutrition in primary care: current practices, attitudes, and barriers. can fam physician 2010; 56:e109–16. 14. al-muammar mn. predictors of physicians’ practices related to nutritional counseling and management in riyadh city. alexandria j med 2012; 48:67–74. doi: 10.1016/j. ajme.2011.09.002. 15. van de wiel mw, van den bossche p, janssen s, jossberger h. exploring deliberate practice in medicine: how do physicians learn in the workplace? adv health sci educ theory pract 2011; 16:81–95. doi: 10.1007/s10459-010-9246-3. 16. mihalynuk tv, coombs jb, rosenfeld me, scott cs, knopp rh. survey correlations: proficiency and adequacy of nutrition training of medical students. j am coll nutr 2008; 27:59–64. 17. friedman g, kushner r, alger-mayer s, bistrian b, gramlich l, marik pe. proposal for medical school nutrition education: topics and recommendations. jpen j parenter enteral nutr 2010; 34:40s–6s. doi: 10.1177/0148607110376200. sir, the recent report on the spectrum of aids-defining opportunistic infections (ois) in hiv-infected patients is very interesting.1 balkhair et al. concluded that “a wide spectrum of ois are seen in hospitalised hivinfected patients in oman.”1 indeed, ois are common in hiv and can be seen elsewhere around the world. the concern with the present cohort study is the diagnostic approach. certainly, to identify the clinical spectrum, good, systematic and highly accurate tests must be implemented. some ois require special tests for detection. focusing on the present report, an interesting point is the low prevalence of intestinal ois. this might be due to these types of ois having been overlooked. in our experience, several intestinal parasites including ois are common and must be screened for in hiv-infected patients.2–3 *beuy joob1 and viroj wiwanitkit2 1department of sanitation, medical academic center, bangkok, thailand; 2department of tropical medicine, hainan medical university, china *corresponding author e-mail: beuyjoob@hotmail.com references 1. balkhair aa, al-muharrmi zk, ganguly s, al-jabri aa. spectrum of aids defining opportunistic infections in a series of 77 hospitalised hiv-infected omani patients. sultan qaboos univ med j 2012; 12:442–8. 2. wiwanitkit v. intestinal parasite infestation in hiv infected patients. curr hiv res 2006; 4:87–96. 3. wiwanitkit v. intestinal parasitic infections in thai hiv-infected patients with different immunity status. bmc gastroenterol 2001; 1:3. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 329, epub. 9th may 13 submitted 2nd jan 13 accepted 10th mar 13 رد: أنواع العدوى االنتهازية احملددة ملرض العوز املناعي الفريوسي املكتسب )اإليدز( يف جمموعة من 77 مريضا عمانيا مرقدا مصابا باإليدز re: spectrum of aids defining opportunistic infections in a series of 77 hospitalised hiv-infected omani patients letter to editor letter to editor | 329 sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 539-544, epub. 8th oct 13 submitted 22nd jun 12 revisions req. 5th jan, 24th mar & 5th may 13; revisions recd. 5th feb, 14th apr & 19th mar 13 accepted 5th jun 13 1college of nursing, sultan qaboos university, muscat, oman; 2department of sociology, college of arts, humanities & social sciences, university of sharjah, united arab emirates *corresponding author e-mail: raghda@squ.edu.om اجتاهات طلبة جامعة السلطان قابوس حنو مهنة التمريض رغدة خالد �سكري، بكار بكار، منذر �ل�سامن، �سمرية �أحمد امللخ�ص: الهدف: �لهدف من هذه �لدر��سة هو ��ستك�ساف �جتاهات طلبة جامعة �ل�سلطان قابو�ض نحو مهنة �لتمري�ض. الطريقة: مت �ختيار عينة مكونة من 377 طالبًا وطالبة من كليات خمتلفة من جامعة �ل�سلطان قابو�ض مبا يف ذلك كلية �لتمري�ض )�لذكور = 130 و�لإناث = 247( مت ت�سميم ��ستبيان و�لتحقق من م�سد�قيته لقيا�ض �جتاهات طلبة جامعة �ل�سلطان قابو�ض نحو مهنة �لتمري�ض. النتائج: �أظهرت �لنتائج �أن غالبية �لطلبة �لذكور و�لإناث من �ل�سنو�ت �لدر��سية و�لكليات �ملختلفة كانت �جتاهاتهم �إيجابية نحو مهنة �لتمري�ض. و�أظهرت �لنتائج كذلك �أن ل توجد �ختالفات ذ�ت دللة �إح�سائية ) α >0.05( بالن�سبة �إىل �جلن�ض و �مل�ستوى �لدر��سي بينما كان لنوع �لكلية باقي طلبة من �يجابية �أكرث �جتاهاتهم كانت حيث �لتمري�ض كلية طلبة �خل�سو�ض وجه على و �لجتاهات هذة على دللة ذي تاأثري �لكليات. اخلال�صة: �أ�سارت �لنتائج �إىل وجود �جتاهات �إيجابية لطلبة جامعة �ل�سلطان قابو�ض نحو مهنة �لتمري�ض و بخا�سة طلبه كلية �لتمري�ض مما يعني وجوب تكثيف �جلهود للنهو�ض مبهنة �لتمري�ض و �لتاأكيد على ��ستمر�رية �لنظرة �لإيجابية لها من جميع �لأطر�ف �ملعنية. مفتاح الكلمات: �جتاهات، طلبة، متري�ض،ُعمان abstract: objectives: the aim of this study was to explore the attitudes of sultan qaboos university (squ) students towards the nursing profession. methods: a sample of 377 students (male = 130; female = 247) were selected from different colleges of squ, including the college of nursing. a questionnaire was constructed and validated to assess the attitudes of squ students towards the nursing profession. results: findings revealed that both male and female students in all academic years and colleges had positive attitudes toward the nursing profession. the findings also revealed that gender and academic year created no significant differences (p <0.05) among the study participants, but that the students’ college affiliation did have a significant effect on their attitudes. in particular, nursing students had more positive attitudes than students of other colleges. conclusion: findings indicated that the attitudes of squ students towards the nursing profession were positive, especially those of the nursing students. this means that serious efforts should be made to continue to promote the nursing profession and so ensure that it remains positively regarded by all concerned. keywords: attitudes; students; nursing; oman. attitudes of students at sultan qaboos university towards the nursing profession *raghda k. shukri,1 bakkar s. bakkar,1 monther a. el-damen,2 samira m. ahmed1 advances in knowledge the findings of this study will provide the foundation for additional future research regarding the attitudes of nurses and community members in oman towards the nursing profession. applications to patient care the findings of this study will indirectly affect patient care in that nursing students with a positive attitude will provide better quality patient care. caring for patients who have a positive attitude towards the nursing profession will encourage nurses to provide better quality nursing services. clinical & basic research throughout its development, the nursing profession has faced different cultural challenges, including a negative image which may have resulted in discouraging people from joining the profession. several studies have been conducted in various countries to explore the image of nursing and attitudes towards the profession. a positive image was found to be a result of people understanding the meaning of nursing as a profession and also of nursing career planning.1 in other studies, the most common reasons for joining nursing were found to be an raghda k. shukri, bakkar s. bakkar, monther a. el-damen and samira m. ahmed clinical and basic research | 540 awareness of the humanitarian nature of nursing, the job opportunities and security it provides, a desire to help others and to work with people, and an interest in science.2–5 the results of these studies were varied. positive attitudes were reported among nursing students whose self-concepts were positive, and several studies found positive attitudes towards male nurses in the profession.6–10 one study found no relation between nursing students’ attitudes towards nursing and their demographic characteristics, while two others found that more positive attitudes were found among qualified and experienced persons in the profession than in those in an earlier academic year.11–13 oman, as one of the gulf countries in the middle east, has made great progress in the development of professional nursing, and its nursing programmes have grown rapidly since the country began to modernise its healthcare system in 1970. nursing has already overcome many challenges in the process of creating a more positive image. the government has encouraged students to study nursing by offering free education and increasing the number of educational institutions. in 2011, there were 12 nursing institutes which graduated nurses at diploma level and 3 universities offering bachelor’s degrees in nursing.14,15 the omanisation process in oman is also providing more opportunities for high school graduates to take up a nursing career. the number of nurses in oman has increased from 1,096 in 1980 to 14,238 in 2011.15,16 these figures may be seen as indicators of a positive attitude towards the nursing profession in oman as well as a reflection of healthcare needs. it was important to undertake this study in order to shed light on the attitudes of nursing and non-nursing students at sultan qaboos university (squ) towards the nursing profession. this is because the students’ attitudes may contribute to shaping the impression of the nursing profession among the wider population and also because a survey of these students’ attitudes might provide a clearer picture of the status of the nursing profession in omani society in general. there is still a shortage of omani nurses, a fact that may be due to the negative attitudes towards nursing that were held in omani society in the past. moreover, given that the image of nursing was enhanced by the creation of a bachelor’s degree level programme at squ in 2002, exploring the attitudes to nursing of squ students from different colleges is important because their opinions may play a significant role in making omani society more aware of the value of nursing as a career. the purpose of this study was to answer the following questions: first, what are squ students’ attitudes towards the nursing profession and, second, do any of the following factors affect squ students’ attitudes towards the nursing profession, and cause significant differences of opinion? these factors are: gender, academic year and type of college (arts, science, economics, education, agriculture, engineering, medicine or nursing). methods a convenience sample was selected by the following method. the list of elective courses offered in the semester was obtained from the office of the dean of admission & registration at squ. out of the 83 courses offered, 8 were chosen; this was done randomly by taking the courses numbered 10, 20, 30, 40, 50, 60, 70 and 80 on the admission and registration list. by chance, it turned out that the 8 courses selected were all from different squ colleges. the sample size was 377, i.e. the students who had chosen to study these 8 courses. to assess attitudes of squ students towards the nursing profession, the authors designed a questionnaire containing 50 items. the items were rated according to a 4-point likert scale (strongly agree = 4, agree = 3, disagree = 2, strongly disagree = 1). the maximum total score that could be obtained for all of the items was 200, while the minimum score was 50; the average score was thus 125. any score above 125 indicated a positive attitude, while any score below 125 indicated a negative attitude. the face validity of the questionnaire was assessed by submitting it to a panel of experts, each of whom had a ph.d. in either nursing or counselling. they were asked to indicate the extent to which each item was adequate or inadequate in terms of two factors—the construct (attitude to nursing), which was defined operationally, and the language of the items. inadequacy was determined by the inter-rater agreement (inter-rater reliability). the accepted range was from 0.7–1. if an item was deemed inadequate (below this range), it was attitudes of students at sultan qaboos university towards the nursing profession 541 | squ medical journal, november 2013, volume 13, issue 4 deleted or modified. the raters were also asked to add any item they believed to be missing. the original version of the questionnaire consisted of 60 items. most of these items (45) were judged to be highly adequate, but 5 items were modified and the other 10 items which were rated inadequate were deleted; this meant that the final version of the questionnaire consisted of 50 items. the reliability of the questionnaire was estimated using two methods: test-retest reliability and internal consistency. for the first method, a pilot study was conducted with 30 squ students, and the study was conducted twice with an interval of two weeks. the correlation coefficient between the first and second study was 0.743. internal consistency was calculated using cronbach’s alpha, which gave a total cronbach’s alpha coefficient of 0.925. these values indicated appreciable and stable reliability for the scale scores. after constructing the study scale and finding its psychometric characteristics, approval for conducting the study was gained from the research committee at the squ college of nursing. based on this approval, the researchers then gained approval for data collection from the directors of administration in each college involved in the study. ethical approval was also obtained, as it was decided that there would be no harm to participants except for the confidentiality issue, which was maintained by asking the participants not to write their names on the cover sheet of the questionnaire. no other ethical implications were present. all confidentiality issues were explained to participants in the cover sheet. each participant’s completion of the questionnaire was an indication of acceptance of participation in the study and was thus considered as informed consent to this study. table 1: distribution of participants according to gender and college college male female total arts 15 28 43 science 6 9 15 economics 7 18 25 education 31 63 94 agriculture 6 7 13 engineering 15 11 26 medicine 5 12 17 nursing 45 99 144 total 130 247 377 table 2: means and standard deviation of participants’ total scores male female total mean sd mean sd mean sd college arts 153.74 5.04 150.95 4.24 152.34 1.91 science 145.11 8.17 155.70 7.38 151.16 5.46 economics 159.67 7.92 156.18 5.71 157.92 4.88 education 142.94 3.65 145.23 2.84 144.09 2.31 agriculture 156.80 9.84 154.67 7.73 155.52 6.08 engineering 157.17 4.89 152.19 7.27 154.68 4.38 medicine 158.50 8.47 155.96 6.27 157.05 5.10 nursing 165.57 3.36 162.34 1.81 163.95 1.91 academic year first 160.39 5.82 145.36 6.22 152.87 4.26 second 153.07 4.04 155.21 3.11 154.21 2.51 third 153.08 3.13 155.35 3.25 154.21 2.25 fourth 157.83 5.17 156.63 4.29 157.19 3.33 fifth 131.00 10.37 145.25 10.04 140.50 7.53 sd = standard deviation. raghda k. shukri, bakkar s. bakkar, monther a. el-damen and samira m. ahmed clinical and basic research | 542 table 3: analysis of variance in sultan qaboos university students’ attitudes by gender, academic year and college source sum of squares df mean square f sig. corrected model 37119.42 54 687.40 2.13 0.0001* intercept 1832166.56 1 1832166.56 5680.24 0.0001* gender 9.54 1 9.54 0.03 0.87 academic year 742.31 4 185.58 0.58 0.68 college 11439.27 7 1634.19 5.07 0.0001* error 103861.44 322 322.55 total 9275449.00 377 corrected total 140980.86 376 *indicates α <0.05. df = degrees of freedom; f = f test; sig. = significance probability. after the approval of the research committee, the researchers obtained the consent of the faculty and went into each classroom to distribute the questionnaires to the students. students were asked to return them to the researcher in the next class. a total of 350 questionnaires were returned within 4 weeks and, after a reminder, the remaining 27 questionnaires were returned. in order to answer this study’s research questions, the researchers computed both the mean and standard deviation (sd) of items and also participants’ total scores. analysis of variance (two or more independent variables with one dependent variable) and post hoc comparisons were used as well. the statistical package for the social sciences (spss), version 18 (ibm, corp., chicago, illinois, usa) was used to analyse the data collected from the participants. results table 1 shows how the participants were distributed by gender and college. table 2 shows the results for the first research question, with results for the second research question being shown in table 3. table 2 illustrates the mean and sd of participants’ total scores. overall, both male and female squ students in all colleges and at all levels of study had positive attitudes towards the nursing profession [table 2]. male students had more positive attitudes than female students in all colleges except for the colleges of science and education, but they all held similar attitudes within the different academic years. understandably, perhaps, nursing students had the most positive attitudes towards nursing, with a mean of 163.95 compared to students from other colleges, while education students held the least positive attitudes, with a mean of 144.09. fourth year students, regardless of college affiliation, were most positive with a mean of 157.19; while fifth year students were least positive with a mean of 140.50. further results are shown in table 3. the findings revealed that neither the students’ gender (p = 0.87), nor their study year (p = 0.68) created any significant differences in attitude. however, there were significant differences in attitude depending on the student’s college (p = 0.0001), which means that the extent to which squ students held positive attitudes towards the nursing profession differed from one college to another. discussion the findings relating to the first research question indicated that both male and female squ students, in all academic years and in all colleges, had positive attitudes towards the nursing profession. their answers also showed that they viewed the nursing profession as humane, noble, ideal and ethical. they saw it as creating a climate of intimacy, with strong communication and dynamic interaction among people regardless of social class or ethnic group. they generally perceived nurses to be egalitarian and able to work cross-culturally, not recognising any limits in who they would work with or care for. they also characterised nurses as having human and professional power, because nursing mainly depends on offering care unconditionally and at all levels, and is based on interpersonal skills. when interviewing newly admitted squ nursing students, it was noticed that they (especially male attitudes of students at sultan qaboos university towards the nursing profession 543 | squ medical journal, november 2013, volume 13, issue 4 students), stated these same factors as their main reasons for selecting the college of nursing as their first choice. they also mentioned that they had been well-counselled by their school career counsellors. the students were motivated not only by the nature of nursing as described above, but also by the fact that it is a profession that would enable them to improve their standard of living in the future, which is a strong attraction. the findings emerging from this question are consistent with studies conducted by several researchers in other countries, which found that students held positive attitudes towards nursing.1–6,12,17 one study indicated that nonnursing majors were similar to nursing majors in their attitudes towards nursing, and would consider nursing as an alternative career.4 american and guatemalan nurses were also found to have positive attitudes towards nursing, because of its humanitarian nature and the job security it offered.4,5 nursing students of capella university in the usa viewed the public image of nursing as positive and also indicated that they had positive self-concepts, which is an interesting correlation.6 a study in china pointed out that nursing students’ perceptions of nursing were positive because of their understanding of the meaning of nursing as a profession, and also their career planning.1 two studies in qatar and canada showed that the most common reasons for joining the nursing profession were the humanitarian nature of nursing, job opportunity/security, helping others, working with people and an interest in science.2,3 the findings at squ are at odds with the results of only one study, which was done in turkey and showed that the turkish students surveyed had fewer positive perceptions about nursing, and more negative attitudes towards it.13 the findings related to the second research question revealed that neither gender nor academic year made a significant difference to squ students’ attitudes towards the nursing profession. the findings for this question were compared with those from studies in other countries which had varied results. in jordan, for instance, there was no significant correlation between gender and attitude towards nursing, and to the choice of nursing as a career.10 in comparison, a study in china yielded similar results to the one in oman, showing no statistically significant differences in attitudes towards nursing due to gender or other demographic variables.11 a study about male attitudes, however, had different results: showing that male university students’ attitudes were positive towards male nurses.7 in this study, there were significant differences in attitudes based on the college in which a student studied, with nursing students significantly more in favour of their own profession than students in other colleges. these results were consistent with the results of some studies, but not with those of others. for example, they were not consistent with the results of a study which showed that nonnursing and nursing majors had similar attitudes towards nursing.4 the findings of this study, in contrast, reflect the importance of the nursing profession for nursing students who have both theoretical and practical knowledge of nursing; their positive attitudes also reflect the fact that they chose to study nursing willingly, and emphasise the positive effects of qualification and experience on attitude. this is consistent with the results of a study conducted in west virginia, usa, which showed that a number of nursing students changed their perceptions about nursing after joining a college of nursing; this happened especially while they were gaining clinical experience.12 in turkey, too, nurses with a bachelor’s degree or higher had higher mean scores in attitudes towards nursing than nurses who had graduated from a health occupational high school.13 it appears then that although there are negative factors associated with the nursing profession, such as the nature of the work, the target people and the future of the profession, nursing students at squ have a positive attitude towards the profession. they may thus be able to a positive image of nursing and an awareness of its value to oman society. there are various limitations to this study. a larger sample size from each college would have enhanced its validity. a more equal proportion of male and female participants would also have been desirable. the choice of convenience sample reduced the validity of the study, introducing a bias that those who were most likely to respond were also the ones more likely to have positive attitudes. conclusion there is no doubt that the nursing profession is raghda k. shukri, bakkar s. bakkar, monther a. el-damen and samira m. ahmed clinical and basic research | 544 developing rapidly in oman. although there are still many negative perceptions that result in some people avoiding nursing as a profession, many students in omani high schools are motivated to choose nursing as a future profession, and are strongly attracted to it. the positive attitudes of omani students, especially nursing students, towards the profession reflect the importance of continuing to increase awareness of the positive value of nursing so that this specialty becomes as attractive as other fields. serious efforts should therefore be made to maintain and promote the positive image of nursing in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. references 1. songlan c, hui c, yun x. a study on education of professional attitude for nursing students. chinese nurs res 2005; 19:1704–170. from: http://en.cnki. com.cn/article_en/cjfdtotal-sxhz200519007. htm accessed: jan 2012. 2. okasha ms, ziady hh. joining the nursing profession in qatar: motives and perceptions. east mediterr health j 2001; 7:1025–33. 3. williams b, wertenberger dh, gushuliak t. why students choose nursing. j nurs educ 1997; 36:346– 8. 4. johnson m, goad s, canada b. attitudes toward nursing as expressed by nursing and non-nursing college males. j nurs educ 1984; 23:387–92. 5. coverston cr, harmon kr, keller er, malner aa. a comparison of guatemalan and usa nurses' attitudes towards nursing. int nurs rev 2004; 51:94– 103. 6. wallace cb. nursing students' perceptions of the public image of nursing. ph.d. thesis. capella university, mi, usa. proquest, umi dissertations publishing, 2007. 3274981. 7. horsmann r. attitudes of male undeclared university majors toward male nurses. master's thesis, 1991, san jose state university, california, usa. proquest, umi dissertations publishing, 1991. 8. ozdemir a, akansel n, tunk g. gender and career: female and male nursing student's perceptions of male nursing role in turkey. health sci j 2008; 2:153–61. 9. saritas s, karadag m, yildirim d. school for health sciences university students' opinions about male nurses. j prof nurs 2009; 25:279–84. 10. jrasat m, samawi o, wilson c. beliefs, attitudes and perceived practice among newly enrolled students at the jordanian ministry of health nursing colleges and institutes in 2003. educ health (abingdon) 2005; 18:145–56. 11. zhang mf, petrini ma. factors influencing chinese undergraduate nursing students' perceptions of the nursing profession. int nurs rev 2008; 55:274–80. 12. sand-jecklin ke and schaffer aj. nursing students' perceptions of their chosen profession. nursing educ perspect 2006; 27:130–5. 13. altuntas s, baykal u. exemplar: factors influencing turkish hospital nurses' attitudes towards their profession: a descriptive survey. contemp nurse 2010; 35: 114–27. 14. alghemini m, denham sa. professional nursing in oman 2013: minority nurse. from: http://www. minoritynurse.com/article/professional-nursingoman accessed: jan 2012. 15. department of health information & statistics directorate general of planning. 2011 health facts. muscat, oman: oman ministry of health, 2012. 16. ghosh b. health workforce development planning in the sultanate of oman: a case study. hum resour health 2009; 7:47. 17. bjorkstrom me, johansson is, hamrin ek, athlin ee. swedish nursing students' attitudes to and awareness of research and development within nursing. j adv nurs 2003; 41:393–402. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e236-240, epub. 7th apr 14 submitted 26th jul 13 revisions req. 24th sep, 21st nov & 31st dec 13; revisions recd. 22nd oct & 3rd dec 13 & 9th jan 14 accepted 16th jan 14 phaeochromocytoma is a neuro-endrocrine tumour (net) which presents multidimensional challenges during surgical resection in spite of our improved understanding of its physiological and clinical behaviour. the most common manifestations of this clinical condition include hypertension, headaches, palpitations, diaphoresis (episodic sweating) and feelings of doom. the incidence of phaeochromocytoma in the general population is 1–8/1,000,000.1 the triad of headaches, diaphoresis and palpitations is found in 20–40% of patients while 13% remain asymptomatic with high levels of catecholamines due to the downregulation of receptors.1 five types of genes are known to be important in hereditary phaeochromocytomas and paragangliomas; these are found in 25% of patients with phaeochromocytoma [table 1]. genes encoding succinate dehydrogenase subunits d (sdhd) and b (sdhb) are found to be implicated in familial nonsyndromic phaeochromocytomas.1,2 departments of 1anaesthesia & intensive care and 3medicine, sultan qaboos university hospital; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: sanathkumarbs@yahoo.com معاجلة ناجحة لورم القوامت باستخدام دواء البيتالول عن طريق الفم قبل العملية واستخدام كربيتات املغنيسيوم بالتسريب أثناء العملية اجلراحية تقرير أربعة حاالت �صاناث كومار٬ روهيت ديت٬ نيكول�س ودهاو�س٬ اأميمه ال�صافعي٬ كارن نولني abstract: phaeochromocytoma is a rare neuroendocrine catecholamine-secreting tumour. this type of tumour poses multidimensional anaesthetic challenges as it has an unpredictable clinical course during surgical resection. the alpha-blocking agent phenoxybenzamine remained the mainstay in preoperative preparation before the introduction of beta-blocking agents. we report four cases operated between 2009–2012 at sultan qaboos university hospital, muscat, oman. the cases were prepared with oral labetalol, as the alpha-blocking drug phenoxybenzamine was not immediately available. responses to simulated stress were tested in the theatre before surgery. anaesthesia was induced under invasive arterial pressure monitoring and magnesium sulphate infusion. rare intraoperative surges in blood pressure during tumour manipulation were treated with sodium nitroprusside infusions and phentolamine boluses. all of the patients had an uneventful postoperative recovery. preoperative treatment with labetalol has rarely been reported and can be considered as a potential therapeutic option with optimal patient monitoring if phenoxybenzamine is unavailable. keywords: pheochromocytoma; labetalol; phenoxybenzamine; phentolamine; magnesium sulfate; intraoperative care; case report; oman. امللخ�ص: ورم القوامت يف الغدة الكظرية حالة نادرة ت�صبب ارتفاع هرمون الأدرنالني. هذا النوع من الورم يفر�س حتديات متعددةعند عملية التخدير لأنه يوؤدي اإىل ارتفاع حاد يف �صغط الدم و م�صاعفات �رشيرية ل ميكن التنبوؤ بها اأثناءال�صتئ�صال اجلراحي. تبقى عقارات حا�رشات الألفا: فينوك�صي بنزامني العماد الول يف ال�صيطرة على ارتفاع �صغط الدم و التح�صري ملا قبل اجلراحة قبل ظهور عقارات حا�رشات البيتا. يف هذا التقرير ن�صتعر�س اأربع حالت اأجريت لهم عمليات جراحية بني 2012-2009 يف م�صت�صفى جامعة ال�صلطان قابو�س ، م�صقط، �صلطنة عمان. مت التح�صري لهذه احلالت باإعطاء لبيتالول عن طريق الفم لأن عقار فينوك�صي بنزامني مل يكن متوفرا يف الوقت املنا�صب. مت اختبار ال�صتجابه للإجهاد امل�صتحث يف غرفة العمليات قبل اجلراحة. مت التخدير حتت مراقبة ال�صغط ال�رشياين داخل ال�رشايني مع ت�رشيب كربيتات املغني�صيوم. ارتفاعات �صغط الدم نادرة اأثناء عمليه ا�صتئ�صال الورم وقد مت علجها بت�رشيب مادة �صوديوم نيرتوبرو�صيد وعقار فنتول امني. وقد تعافى جميع املر�صى املذكورين بدون م�صاعفات بعد العمليات التي اأجريت لهم. نادرا مامت الإبلغ عن ا�صتخدام علج لبيتالول قبل اجلراحة وميكن اعتباره خيارا علجيا حمتمل يف ظل عدم توافر عقار فينوك�صي بنزامني حتت املراقبة الطبية الأمثل للمري�س. مفتاح الكلمات: ورم القوامت؛ لبيتالول؛ فينوك�صي بنزامني؛ فينتولمني؛ كربيتات املغني�صيوم؛ رعاية جراحة داخلية؛ تقارير حالت؛ عمان. successful management of phaeochromocytoma using preoperative oral labetalol and intraoperative magnesium sulphate report of four cases *sanath kumar b. s.,1 rohit date,1 nicholas woodhouse,2 omayma el-shafie,3 karin nollain1 case report sanath kumar b. s., rohit date, nicholas woodhouse, omayma el-shafie and karin nollain case report | e237 different drugs and anaesthetic techniques are used for the perioperative management of patients with phaeochromocytoma.3–5 although α-adrenoceptor antagonists are the mainstay of perioperative blood pressure control, the use of various combinations of α and β-adrenoceptor antagonists has been reported.3–5 pretreatment with oral labetalol, as used in these cases, has rarely been reported, whereas intravenous labetalol and magnesium sulphate have been used for the rapid preparation of a patient with a phaeochromocytoma.6 the following four cases highlight the possibility of using oral labetalol for preoperative management. the findings indicate that labetalol may be used in the preoperative management of phaeochromocytoma as a therapeutic option, especially if phenoxybenzamine is not available. two of the four cases of phaeochromocytoma were siblings. one of the siblings presented with severe episodic hypertension (case 1) and the other with postural hypotension after standing for 30 minutes (case 2). however, when the latter was subjected to simulated stressful conditions in the anaesthesia induction room, he developed severe tachycardia and hypertension. the other two patients had long-established histories of serious classical phaeochromocytoma symptoms (cases 3 and 4). none of the cases had comorbidities. all underwent open adrenalectomies and were operated on between 2009–2012 at sultan qaboos university hospital, muscat, oman. case 1 a 13-year-old girl presented with a three-year history of headaches, sweating, palpitations and severe hypertension. on initial admission to a peripheral hospital, her blood pressure was 180/120 mmhg. the diagnosis of phaeochromocytoma was made based on a computed tomography (ct) scan of the abdomen, which showed bilateral adrenal masses. her plasma catecholamine and chromogranin a (cga) levels were high [table 2]. the initial echocardiogram (echo) showed a systolic dysfunction with global hypokinaesia and an ejection fraction (ef) of 46%. since phenoxybenzamine is not available in oman, she was treated with oral labetalol up to 400 mg twice a day (bd). after six weeks, the blood pressure was under control, the echo was normal and the ef was 64%. the haematocrit was 31 g/dl, indicating an expansion of the extracellular volume. before being scheduled for a bilateral adrenalectomy, she was taken to the induction room to undergo a simulated stress test while her blood pressure and heart rate were monitored. her haemodynamics remained within normal limits at this time as well as during subsequent postural changes. the night before the surgery, the patient received lorazepam, a fluid preloaded with ringer’s lactate solution, and midazolam as premedication. before inducing anaesthesia, a bolus of magnesium sulphate (50 mg/kg) was given followed by a maintenance dose of 15 mg/kg/hour. under invasive arterial pressure monitoring, the induction was done with fentanyl, propofol, cisatracurium and lidocaine (1.5 mg/kg) prior to intubation. during the manipulation of the tumour, hypertensive derangements with short spikes up to 200 mmhg systolic were controlled with an infusion of sodium nitroprusside (snp) and boluses of phentolamine, a potent α-adrenoceptor antagonist. under an adequate volume replacement and hydrocortisone supplementation, the patient remained haemodynamically stable after tumour table 1: genetic correlations in phaeochromocytomas genetic basis of phaeochromocytomas familial bilateral malignant multiple sdhd ret sdhb sdhd sdhb vhl vhl sdhb vhl sdhd vhl ret frequency of susceptibility genes in patients with phaeochromocytoma or paraganglioma in percent ret vhl nf1 sdh others 5 9 2 sdhd: 5 sdhc: 1 sdhb: 5 sdhaf2: <1 sdha: <1 tmem127: 2 max: <1 ret = roto-oncogene; vhl = von hippel-lindau disease tumour suppressor gene; nf1 = neurofibromatosistype 1 tumour suppressor gene; sdh = succinate dehydrogenase complex with subunit genes sdhb, sdhc and sdhd; max = myc-associated factor x gene. table 2: plasma levels of circulating catecholamine and chromogranin in the four patients case nadr in pmol/l adrenaline in pmol/l dopamine in pmol/l cga in µg/l 1 23,670 140 266 700 2 32,048 <54 3,012 300 3 38,400 1,104 4 3,294 240 64 1,233 normal ranges 650–2,433 <273 <475 27–94 nadr = noradrenaline; cga = plasma catecholamine and chromogranin a. successful management of phaeochromocytoma using preoperative oral labetalol and intraoperative magnesium sulphate report of four cases e238 | squ medical journal, may 2014, volume 14, issue 2 removal without any vasoactive drugs. case 2 a 16-year-old boy, the brother of the first case, was diagnosed with phaeochromocytoma by ct scan after elevated cga levels were found during family screening. he had a single right adrenal tumour but was asymptomatic apart from attacks of fainting during long periods of standing. his blood pressure and heart rate were normal despite high plasma noradrenaline levels [table 1]. the routine investigations, including electrocardiography (ecg) and echo, were normal. the patient’s response to simulated stressful conditions was cross-checked in the anaesthesia induction room; he developed severe tachycardia with 170 beats per minute and his blood pressure rose to 190/130 mmhg; this was associated with dizziness when in an upright position [figure 1]. as a result, the patient was treated preoperatively with labetalol (100 mg bd) for two weeks. after that time, he was exposed to simulated stress again without developing tachycardia or hypertension [figure 2]. the preoperative preparations and induction of anaesthesia were performed similarly to the first case. during the manipulation of the tumour, the blood pressure spikes were controlled with infusions of snp and boluses of phentolamine. after the removal of the tumour, the patient required a low dose of phenylephrine infusion for a short period. case 3 a 37-year-old woman presented with a three-year history of severe paroxysmal headaches, palpitations and hypertension. a ct scan of the abdomen showed a right adrenal tumour with elevated plasma catecholamine and cga levels [table 2]. the patient had been on labetalol (400 mg bd) during the previous month and her symptoms had mostly subsided with only short episodes of palpitations. the ecg and echo were normal. during the stress simulation, the haemodynamics parameters remained within normal limits with minimal postural changes and so the patient was admitted for an open right adrenalectomy. the preoperative preparations of hydration, anaesthesia induction and intraoperative management were similar to those of the previous two cases. the patient had more frequent hypertensive derangements during the tumour dissection, which were controlled by phentolamine boluses. she did not require any vasopressor support after the removal of the tumour. case 4 a 50-year-old woman presented with a more than three-year history of headaches, palpitations and sweating, and had a palpable painful mass in her upper left abdomen. the ct scan revealed an extensive infarction of a huge left adrenal tumour and only slightly increased plasma levels of noradrenaline [table 2]. although she was normotensive, a small dose of labetalol (25 mg bd) was given for 15 days prior to surgery and her symptoms subsided to only short episodes of palpitations. the ecg and echo were normal. during the stress simulation, her haemodynamics remained within normal limits with no postural changes. the patient was admitted for an open left adrenalectomy. the preoperative preparations and anaesthetic management were similar to those of the previous three cases. however, her blood pressure did not fluctuate much during the tumour dissection except for a mild hypertensive episode (170/90 mmhg) which was managed with a figure 1: marked postural fluctuations in heart rate, systolic blood pressure and diastolic blood pressure in case 2 before starting treatment with labetalol. sbp = systolic blood pressure; dbp = diastolic blood pressure; hr = heart rate. figure 2: after two weeks on labetalol, the haemodynamic variables of case 2 showed minimal postural fluctuations. sbp = systolic blood pressure; dbp = diastolic blood pressure; hr = heart rate. sanath kumar b. s., rohit date, nicholas woodhouse, omayma el-shafie and karin nollain case report | e239 phentolamine bolus. she did not require vasopressor support after the removal of the tumour. all four cases had uneventful postoperative periods and were extubated in the intensive care unit after a few hours of observation. discussion the problems surrounding the preand perioperative management of phaeochromocytoma have been well described in the literature.3,4 the main objective in the preoperative management of these patients is to control the blood pressure, heart rate and arrhythmias, and to allow restoration of blood volume.3,5 there is no consensus on the best pharmacological agent or optimal duration of therapy for the preparation of these patients for surgery. traditionally, phenoxybenzamine, a non-selective α-adrenergic antagonist, has been the mainstay of perioperative treatment.4,6–9 the greatest advantage of using phenoxybenzamine is its long duration of action. this is due to its non-competitive irreversible blockade which helps to avert the effects of surges of catecholamine release, particularly during the surgical manipulation of the tumour.4,10,11 after the removal of the tumour, the side-effects, such as postural hypotension and somnolence, may continue into the postoperative period; additionally, patients may require vasopressor support.4,12 however, phenoxybenzamine blocks α-2-adrenoreceptors, which may facilitate the noradrenaline release, resulting in undesirable chronotropic and inotropic effects.12 in some cases, these have been controlled with adjuvant β-adrenoreceptor antagonists.4,13 the other disadvantages of using phenoxybenzamine are its other side-effects—headaches and stuffy nose—which have been reported to reduce patient compliance with the medication regime.3,4 a variety of pharmacological agents, like prazocin, doxazocin and calcium channel blockers, have also been used in the preparation of patients with phaeochromocytoma.3,4,6 in the current case series, since phenoxybenzamine was not available, labetalol was used which is known to combine a selective competitive α-1and non-selective competitive β-adrenoreceptor antagonist with the ratio of α:β antagonism being 1:3 after oral and 1:7 after intravenous administration.14 cases have been reported where intravenous labetalol along with magnesium sulphate was used for the rapid preparation of patients with phaeochromocytoma without untoward effects.7 however, there is also a report in the literature of one incident of cardiovascular collapse where intravenous labetalol was used in an emergency to control blood pressure in a patient with an undiagnosed phaeochromocytoma.15 two additional reports of oral labetalol used for preoperative preparation have been recorded. one case displayed a hypertensive response while in the other report three patients were successfully prepared without untoward incidents.16–18 the administration of labetalol lowers systemic blood pressure by decreasing systemic vascular resistance due to the α-1-blockade where reflex tachycardia is attenuated by a simultaneous β-blockade.7 continued oral labetalol medication on the day of surgery has one advantage—the peak action of the drug occurs four hours after administration, acts during the operation on the active site and then wears off at the right time. this contributes to the patient’s circulatory stability after the removal of the tumour. two of the four patients in the current series, who responded normally to the simulated stress and were classically hypertensive, responded well to 100–400 mg of labetalol bd. one of the normotensive patients, case 2, had high noradrenaline levels. when exposed to simulated stress, he responded adversely with marked tachycardia and hypertension. however, two weeks after starting labetalol, a repeated stress test showed great improvement in the patient. given the history of this case, the authors support the recommendation to prepare normotensive phaeochromocytomas with an α-adrenergic blockade.3,19,20 case 4, who had an enormous infarcted adrenal mass with only slightly elevated noradrenaline levels, responded normally to a stress test after a small dose (25 mg) of labetalol bd. pacak explains the wide range of clinical presentations among patients with phaeochromocytoma as a “desensitisation” of the receptors. therefore, some patients will need significant amounts of adrenoreceptor blockers while others may not—despite high-circulating catecholamine concentrations.16 from the first use of magnesium sulphate in the anaesthetic management of phaeochromocytoma, there have been multiple case series which have confirmed its use during surgery. it has also been used in three patients with phaeochromocytoma, all of whom presented with severe cardiovascular instability.21–23 in the current cases series, magnesium sulphate was used in all cases as it inhibits the release of catecholamine from the adrenal medulla and adrenergic nerve endings; it has direct vasodilatory effects and anti-arrhythmic properties.21 since the patients in this series were on oral labetalol and the successful management of phaeochromocytoma using preoperative oral labetalol and intraoperative magnesium sulphate report of four cases e240 | squ medical journal, may 2014, volume 14, issue 2 severity of blood pressure derangements during surgery could not be anticipated, the potent alphablocker, phentolamine, was kept available and used during the tumour dissection. in addition, magnesium sulphate infusions were used in all of the patients— from the induction of anaesthesia until the final removal of the tumour. this may have contributed to the patients’ successful outcomes. in the postoperative period, especially after the removal of the tumour, there were no significant hypotensive episodes which required inotropic support. all patients were haemodynamically stable and extubated after a few hours of observation. conclusion the traditional view of a preoperative stabilisation phase with phenoxybenzamine has stood the test of time. although the use of labetalol is controversial as the first choice of treatment in the preparation of these types of patients, this pilot report of four cases has shown that oral labetalol, in combination with magnesium sulfate used intraoperatively, may be a potential therapeutic option in patients with phaeochromocytoma if phenoxybenzamine is not available. despite the fact that these patients were exposed to simulated stress, the authors do not recommend this as a routine practice; the roizen criteria should still be met if applicable. this case series encourages further study of the use of labetalol in order to collect and publish the necessary data and so establish a safe recommendation. references 1. subramaniam r. pheochromocytoma: current concepts in diagnosis and management. curr anaesth crit care 2011; 1:104–10. doi: 10.1016/j.tacc.2011.01.009. 2. galan sr, kann ph. genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. clin endocrinol (oxf ) 2013; 78:165–75. doi: 10.1111/cen.12071. 3. prys-roberts c. phaeochromocytoma: recent progress in its management. br j anaesth 2000; 85:44–57. doi: 10.1093/ bja/85.1.44. 4. hull cj. phaeochromocytoma: diagnosis, preoperative preparation and anaesthetic management. br j anaesth 1986; 58: 1453–68. doi: 10.1093/bja/58.12.1453. 5. bajwa s, bajwa sk. implications and considerations during pheochromocytoma resection: a challenge to the anesthesiologist. indian j endocrinol metab 2011; s337–44. doi: 10.4103/2230-8210.86977. 6. russell wj, metcalfe ir, tonkin al, frewin db. the preoperative management of phaeochromocytoma. anaesth intensive care 1998; 26:196–200. 7. poopalalingam r, chin ey. rapid preparation of a patient with pheochromocytoma with labetolol and magnesium sulfate. can j anaesth 2001; 48:876–80. doi: 10.1007/bf03017353. 8. stenstrom g, haljamae h, tisell le. influence of pre-operative treatment with phenoxybenzamine on the incidence of adverse cardiovascular reactions during anesthesia and surgery for phaeochromocytoma. acta anaesthesiol scand 1985; 29:797– 803. doi: 10.1111/j.1399-6576.1985.tb02303.x. 9. geoghegan jg, emberton m, bloom sr, lynn ja. changing trends in the management of phaeochromocytoma. br j surg 1998; 85:117–20. doi: 10.1046/j.1365-2168.1998.02875.x. 10. hoffman bb, lefkowitz rj. catecholamines, sympathomimetic drugs and adrenergic receptor antagonists. in: hardman jg, limbird le, molinoff pb, ruddon rw, gilman ag. eds. goodman & gilman’s the pharmacological basis of therapeutics. 9th ed. new york, usa: mcgraw-hill, 1996. pp. 199–248. 11. brown br jr. anaesthesia for phaeochromocytoma. in: roberts cp, brown br jr, nunn jf, eds. international practice of anaesthesia. 6th ed. oxford, uk: butterworth-heinemann, 1996. pp. 1/83/1–7. 12. langer sz. presynaptic regulation of the release of catecholamines. pharmacol rev 1980; 32:337–62. 13. manger wm, gifford jw jr. pheochromocytoma: a clinical overview. in: swales jd. ed. textbook of hypertension. oxford, uk: wiley-blackwell, 1994. pp. 941–58. 14. maccarthy ep, bloomfield ss. labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects. pharmacotherapy 1983; 3:193–219. doi: 10.1002/j.18759114.1983.tb03252.x. 15. kuok ch, yen cr, huang cs, ko yp, tsai ps. cardiovascular collapse after labetalol for hypertensive crisis in an undiagnosed pheochromocytoma during cesarean section. acta anaesthesiol taiwan 2011; 49:69–71. doi: 10.2165/00128415-20111366000075. 16. pacak k. preoperative management of the pheochromocytoma patient. j clin endocrinol metab 2007; 92:4069–72. doi: 10.1210/jc.2007-1720. 17. reach g, thibonnier m, chevillard c, corvol p, milliez p. effect of labetalol on blood pressure and plasma catecholamine concentrations in patients with phaeochromocytoma. br med j 1980; 280:1300–1. doi: 10.1136/bmj.280.6227. 18. briggs rs, birtwell aj, pohl je. hypertensive response to labetalol in phaeochromocytoma. lancet 1978; 311:1045–6. doi: 10.1016/s0140-6736(78)90772-9. 19. agarwal a, gupta s, mishra ak, singh n, mishra sk. normotensive pheochromocytoma: institutional experience. world j surg 2005; 29:1185–8. doi: 10.1007/s00268-005-78394. 20. gonzalez-pantaleon ad, simon b. nonclassic presentation of pheochromocytoma: difficulties in diagnosis and management of the normotensive patient. endocr pract 2008; 14:470–3. doi: 10.4158/ep.14.4.470. 21. james mf. use of magnesium sulphate in the anaesthetic management of phaeochromocytoma: a review of 17 anaesthetics. br j anaesth 1989; 62:616–23. doi: 10.1093/ bja/62.6.616. 22. james mf. use of magnesium sulphate in the anesthetic management of pheochromocytoma. anethesiology 1985; 62:188–90. 23. james mf, cronjé l. pheochromocytoma crisis: the use of magnesium sulphate. anesth analg 2004; 99:680–6. doi: 10.1213/01.ane.0000133136.01381.52. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 473-478, epub. 20th nov 12 submitted 19th feb 11 revision req. 25th apr 12, revision recd. 20th may 12 accepted 27th jun 12 departments of 1pathology and 2community medicine, gulf medical university, ajman, united arab emirates *corresponding author e-mail: ghaith_aleyd@yahoo.com معدل إجراء فحص التحري الظريف للطخة بابا نيكوال و منط الشذوذ يف اخَلالَيا الِظهارِيَّة يف لطخات بابا نيكوال عند النساء املراجعات يف مستشفى تعليمي يف عجمان، اإلمارات العربية املتحدة غيث ج العيد، رزوانة �صيخ امللخ�ص: الهدف: تقدير نسبة النساء اخلاضعات لفحص لطخة بابا نيكوال وتواتر الشذوذ يف اخَلالَيا الِظهارِيَّة يف لطخات عنق الرحم يف مستشفى تعليمي يف عجمان بدولة اإلمارات العربية املتحدة خالل مدة زمنية معينة. الطريقة: دراسة استعادية لسجالت 602 مريضة خالل املدة من يوليو 2007 اىل يوليو 2010 يف مستشفى تعليمي يف إمارة عجمان، اإلمارات العربية املتحدة. املتغريات اليت متت دراستها تشمل العمر والعرق وحالة انقطاع الطمث، وشذوذ لطخات بابا نيكوال. مت حتليل البيانات بواسطة برنامج اس يب اس اس – 19 ، ومت تقدمي البيانات بشكل نسب مئوية غالبا، كما استخدم اختبار مربع كاي لفحص مدى الرتابط النتائج: كان العدد الكلي للمريضات املراجعات لقسم األمراض النسائية والوالدات للفرتة من يوليو 2007 اىل يوليو 2010 هو 150,111 مريضة، خضعت 602 منهن فقط )0.4%( من اجملموع الكلي( لفحص لطخة بابا نيكوال لعنق الرحم. شّكلت النساء العربيات % 50.1من العينة، والبقية من جنسيات آسيوية أخرى. كان لدى 73% من املريضات شكاوى مرضية معينة، بينما كان 72% منهن يف زيارة روتينية للمستشفى إلجراء فحص مسح عنق الرحم. تبني أن 3.3 % من املريضات كّن يعانني من شذوذ يف اخلاليا الظهارية لعنق الرحم كما يلي: 1.8% خاليا حرشفية ال منطية غري حمددة األمهية، 1.2% آفة اخلاليا الظهارية احلرشفية منخفضة الدرجة، 0.3% آفة اخلاليا الظهارية احلرشفية عالية الدرجة. مل تكن هناك اي من حاالت سرطان اخلاليا احلرشفية. اخلال�صة: كان املسح الطوعي الروتيين بواسطة لطخة بابا نيكوال منخفضا جدا عند املريضات يف هذه الدراسة، وشكلت آفة اخلاليا احلرشفية الال منطية غري حمددة األمهية األكثر تشخيصا ضمن شذوذ اخلاليا الظهارية. ننصح بتعزيز التثقيف الصحي يف اجملتمع وإجراء املسح الظريف لسرطان عنق الرحم لكل النساء يف املنطقة، سواء كّن من املواطنات أو الوافدات. مفتاح الكلمات: لطخة بابا نيكوال، �رصطان عنق الرحم، التحري عن ال�رصطان، االإمارات العربية املتحدة. abstract: objectives: the aim of this study was to estimate the proportion of women undergoing papanicolaou (pap) smear examinations, and the frequency of epithelial cell abnormalities in a teaching hospital in one emirate of the united arab emirates (uae) during a three-year period. methods: a retrospective study of 602 patient records from july 2007 to july 2010 was done in a teaching hospital in ajman, uae. the variables studied were age, ethnicity, menopausal status, and abnormalities in the pap smear. data were analysed using the statistical package for the social sciences and presented mainly as percentages; to assess associations, the chi-square test was used. results: the total number of outpatients who attended the obstetrics & gynaecology department from july 2007 to july 2010 was 150,111 patients, of which 602 (0.4% of the total) had a pap smear test. the sample was 50.1% arabs and 49.9% other nationalities. while 73% of the outpatients had specific complaints, 27% came for a routine screening. epithelial cell abnormalities were seen in 3.3% of the sample, with atypical squamous cells of undetermined significance (ascus) found in 1.8%, low-grade squamous intraepithelial lesions (lsils) found in 1.2%, and high-grade squamous intraepithelial lesions (hsils) found in 0.3%. there were no cases of squamous cell carcinoma. conclusion: voluntary routine pap smear screening was remarkably low in the study group. ascus was the most common epithelial cell abnormality. community health education and opportunistic screening for cervical cancer are recommended for both national and expatriate women in the region. keywords: papanicolaou smear; cervix cancer; cancer screening; united arab emirates. rate of opportunistic pap smear screening and patterns of epithelial cell abnormalities in pap smears in ajman, united arab emirates *ghaith j. al eyd1 and rizwana b. shaik2 clinical & basic research rate of opportunistic pap smear screening and patterns of epithelial cell abnormalities in pap smears in ajman, united arab emirates 474 | squ medical journal, november 2012, volume 12, issue 4 cervical cancer is the second most common cancer in women worldwide, with about 500,000 new cases and 250,000 deaths each year.1 globally, it is estimated that over one million women currently have cervical cancer, most of whom have not been diagnosed, or have no access to treatment that could cure them or prolong their lives.2 cervical cancer is the third most common cancer in women—both in citizens and non-citizens—in the united arab emirates (uae).3 screening for cervical cancer is not mandatory in the uae. secondary prevention of cervical cancer goes beyond the laboratory test. it calls for the establishment of a comprehensive screening programme targeting appropriate age groups. this helps to identify asymptomatic women with precursor lesions of cervical cancer as well as to create effective links between all levels of care, including appropriate follow-up for definitive diagnosis and the treatment of women with positive screening results.2 cervicovaginal cytology screening with papanicolau (pap) smears has been used in many regions of the world since the last century. dr. papanicolau, the innovator of pap smear testing, emphasised the need for a simple inexpensive method that could be applied on a large scale for the early diagnosis of cancer. this test is crucial for the detection of early changes like dysplasia in the cervical cells which lead to cancer. over time, cervical dysplasia can gradually develop into squamous cell carcinoma of the cervix.2 in developed countries where cervical screening programmes are implemented and encouraged, new cases are not as advanced as those in developing countries.4 one possible explanation is that in countries with no screening programmes, women usually present to the clinic only when they have symptoms, such as pain, discharge, and/or abnormal bleeding. cervical cancer, being a slowgrowing cancer, can take up to 10 and sometimes 20 years for abnormal changes to develop into cancer.5 for this reason, cervical cancer is more frequent in women in their fourth, fifth or sixth decade of life.6,7 cervical screening can help save lives, and that is why many countries are encouraging and adopting cervical screening programmes. the world health organization (who) recommends that women should start screening for cervical cancer at 30 years or above, and include younger women only when the higher-risk groups have been covered. if a woman can be screened only once in her lifetime, then the best age is between 35 and 45 years. in 25–49 year olds, a three-year screening interval should be considered if resources are available. for women over 50 years, a five-year interval is appropriate, but for those over 65, it is not deemed necessary provided the two previous smears were negative.2 the incidence of cervical cancer in the uae would significantly decrease if we were to adopt such an effective screening programme. there is a shortage of studies in the arabian gulf region on the rates and results of pap smear testing. the present study addresses this issue with the aim of estimating the proportion of women undergoing pap smear examinations and the frequency of epithelial cell abnormalities in a teaching hospital in an emirate of the uae during a three year period. advances in knowledge this paper contributes to assessing current levels of cervical screening in the united arab emirates (uae). the rate of opportunistic screening with papanicolaou smear was only 0.4% in women attending the obstetrics & gynaecology department of a teaching hospital in the uae. the overall frequency of cervical intraepithelial abnormalities was 3.3%, out of which 1.8% had atypical squamous cells of undetermined significance (ascus), 1.2% had low-grade squamous intraepithelial lesion (lsils), and 0.3% had high-grade squamous intraepithelial lesions (hsils). application to patient care the proportion of women who underwent an opportunistic pap smear was very low. this indicates a major problem of missed opportunities for actively offering pap smear testing. educational efforts can be targeted toward gynaecologists, nurses, and other health care workers to play an active role in educating patients on the importance of pap smear testing, and to offer it whenever possible. community health awareness campaigns on the importance of cervical screening are recommended for women in the reproductive age group. organised, cost-effective cervical screening can be introduced to encourage more women to undergo pap smear testing. ghaith j. al eyd and rizwana b. shaik clinical and basic research | 475 methods a record-based study was conducted at the gulf medical college hospital and research center (gmchrc) in ajman, uae. gmchrc is a teaching hospital that caters not only to the patients of the emirate of ajman, whose adult female population is ~88,000, but also attracts patients from the neighbouring emirates because of its subsidised rates.8 access to the obstetrics & gynaecology clinic is by self-presentation. the clinic actively offers pap smear screening at the cost of ~$100 per test. the cytology unit of the histo/cytopathology laboratory of gmchrc is run by three pathologists and one cytotechnologist. thinprep liquid-based cytology was the method used for the collection and preparation of all pap smear test samples. all three pathologists were involved in interpreting the pap smear tests results with each slide double-checked by two different pathologists to verify the results. no mismatch was recorded during the verification of the results of this study. specimen adequacy and reporting was done according to the revised bethesda system 2001.9 the study sample included a series of pap smears taken from women attending the obstetrics & gynaecology clinic between july 2007 and july 2010. the information was entered in a proforma designed specifically for this study. variables selected for the study included abnormalities in the pap smear, age, ethnicity, and menopausal status. data were analysed using the statistical package for the social sciences, inc. (spss), version 19, (ibm, chicago, illinois, usa). tables and graphs were created using spss, microsoft (ms) excel, and ms word. data were presented mainly as percentages and, to verify associations, the chi-square test was used. all specimens with epithelial cell abnormalities were referred back to the obstetrics & gynaecology department for further followup. this follow-up was done according to the 2001 consensus guidelines for management of women with cervical cytological abnormalities, which recommends repeat cervical cytology, colposcopy, and human papilloma virus (hpv) testing for patients with atypical squamous cells of undetermined significance (ascus).10 results the total number of outpatients who attended the gmchrc obstetrics & gynaecology clinic from july 2007 to july 2010 was 150,111, of which 632 underwent a pap smear test. therefore the proportion of women who underwent this screening test at gmchrc was 0.4%. further analysis was done on 602 reports as 30 (4.9%) reports had to be excluded from the study due to inadequate or hypo-cellular smears. the age range of the women who underwent the pap smear test was 20–71 years (mean ± standard deviation (sd) = 37 ± 9). arabs constituted 50.1% of the study sample and 49.9% were from asian and other countries [figure 1]. of the 602 women who had a pap smear, 73% had specific complaints such as itching, vaginal discharge, pain, menorrhagia, and post-coital bleeding. the remaining 27% were asymptomatic and came for a routine screening. post-coital table 1: presenting symptoms in non-menopausal and menopausal women presenting symptoms nonmenopausal n (%) menopausal n (%) total n (%) routine pap smear (asymptomatic) 134 (25) 29 (41) 163 (27) menorrhagia 33 (6) 4 (6) 37 (6) vaginal discharge 152 (29) 13 (18) 165 (27) post-coital bleeding 102 (19) 6 (8) 108 (18) itching 21 (4) 6 (8) 27 (4) abdominal pain 43 (8) 6 (8) 49 (8) others 46 (9) 7 (10) 53 (9) total 531 (100) 71 (100) 602 (100) table 2: epithelial cell abnormality in non-menopausal and menopausal women epithelial cell abnormality nonmenopausal n (%) menopausal n (%) total n (%) negative for intraepithelial lesion/ malignancy 516 (97.2) 66 (93) 582 (96.7) positive for intra epithelial lesion 15 (2.8) 5 (7) 20 (3.3) total 531 (100) 71 (100) 602 (100) rate of opportunistic pap smear screening and patterns of epithelial cell abnormalities in pap smears in ajman, united arab emirates 476 | squ medical journal, november 2012, volume 12, issue 4 bleeding and discharge were the most common symptoms in non-menopausal women when compared to menopausal women, as seen in table 1. table 2 shows the results were positive for intraepithelial lesions in 3.3% of the total of 602 samples. intraepithelial lesions occurred in 7% of the menopausal and 2.8% of the non-menopausal women. the median age of patients with positive intra-epithelial lesions was 40 years with an age range of 24–56 years. figure 2 shows that out of the 20 samples positive for intra-epithelial lesions, 55% were ascus, 35% were low-grade squamous intraepithelial lesions (lsils), and 10% were high-grade intraepithelial lesions (hsil). out of the 602 samples, ascus represented 1.8% of the total; lsil 1.2%, and hsil 0.3%. discussion in this study, the proportion of women who underwent an opportunistic pap smear was very low. the rate of opportunistic screening with papanicolaou smear was only 0.4%. the overall frequency of cervical intraepithelial abnormalities was 3.3%, out of which 1.8% had atypical squamous cells of undetermined significance (ascus), 1.2% had low-grade squamous intraepithelial lesion (lsils), and 0.3% had high-grade squamous intraepithelial lesions (hsils). many reports have shown that mortality from cervical cancer occurs primarily in developing countries, reflecting the grim reality of the lack of effective control measures in the developing world.5,11,12 the high rate of incidence in these countries is mainly due to the lack of screening programmes, or their inefficacy.9 in this study, it was important to determine first the rates of opportunistic screening in the uae, where organised cervical screening programs are not in place, and second to assess the proportion of pap smears with epithelial cell abnormalities. the fact that merely 0.4% of the women underwent pap smear testing is worrisome because cervical dysplasia is an asymptomatic ongoing change in the cervical epithelium. it can go unnoticed for many years and progress to cancer. if a woman presents to the clinic only when she has a gynaecological problem and regular pap smears have not been done, the disease can easily take its natural course to full-blown cancer. the low number of pap smear tests in our study could be attributed to a lack of patient awareness, absence of a nationwide screening programme, or a lack of initiative from many of the insurance companies to cover pap smear testing in their basic packages. the latter results in patients having to pay for their own tests. there is a shortage of studies from the region regarding the practice of cervical screening. one study, done in kuwait among 300 married kuwaiti women, showed that only 23.8% of women underwent pap smear testing, and the main reason given among the rest of the women for not having the test was that it was not suggested by a doctor.13 asian asian asian african arab expats uae european others pe rc en ta ge 40 208 30 194 108 29 33 35 30 25 20 15 10 5 0 nationality of the study subjects (n = 602) figure 1: percentage distribution and number of subjects of the study according to location. uae = united arab emirates. ghaith j. al eyd and rizwana b. shaik clinical and basic research | 477 another study in qatar among 500 women showed that almost 40% of women had had a pap smear test at least once in their lifetime and the rest of them mentioned that they would have undergone the test if they were told that the procedure was painless and simple.14 in this context, educational efforts should be targeted toward gynaecologists, nurses, and other health care workers to encourage them to play an active role in educating the patients on the importance of pap smear testing and its convenience, and to offer this test whenever possible. research regarding risk factors and likelihoods of different minorities to develop invasive carcinoma has been studied extensively in western countries; however, few studies have been performed in the arabian gulf region to assess the effects of dysplasia on the development of carcinoma. studies regarding cervical dysplasia in the region show that the percentage of abnormal pap smears was 4.7% in a prospective study in saudi arabia, much higher than the 1.6% reported in the compounded literature by altaf.15 a 13-year study in kuwait examined the incidence of squamous cells abnormalities at one tertiary hospital. the results indicated that there was an increasing trend in younger women toward developing lsils and hsils. from these results it was determined that screening programmes for young women in kuwait is essential to preventing the disease.16 while the incidence of cervical cancer is generally low in the arab world, it is the third most common cancer in women in the uae.3 no published literature is available about the prevalence of cervical abnormalities in the northern emirates of the uae, the place where this study was performed. in our study, no cases of squamous cell carcinoma were detected and only 3.3% of the total cases were positive for intraepithelial lesions. this relatively low prevalence is similar to that reported in other studies done in the region. the reported prevalence was as follow: 4.3% in a tertiary hospital in kuwait,16 5% in a large referral hospital in saudi arabia,17 1.66% in the western region of saudi arabia,18 7.9% in southwestern saudi arabia, and 4.5% in a study in the eastern saudi arabia.19 a similar study done by the faculty of medicine & health science at uae university reported the prevalence of cervical abnormalities in the uae as 1.32%, and no cases of squamous cell carcinoma out of the total 2,013 smears were detected.20 the fact that only 20 out of the 602 women had cervical epithelial abnormalities, given that 108 women came with symptoms of post-coital bleeding, can be attributed to the fact that most of the those cases of post-coital bleeding could be due to other causes such as the use of intrauterine contraceptive device and cervicovaginal infections. conclusion voluntary routine screenings with pap smears was remarkably low in this study group. ascus was the most common epithelial cell abnormality detected. community health education and opportunistic screening for cervical cancer is recommended for both nationals and expatriate women in the region. references 1. sexual and reproductive health. cancer of the cervix. from: www.who.int/reproductivehealth/ topics/cancers/en/index.html. accessed: sep 2011. 2. world health organization. comprehensive cervical cancer control: a guide to essential practice 2006. from: www.who.int/reproductivehealth/ publications/cancers/9241547006/en/index.html. accessed: sep 2011. 3. ministry of health, united arab emirates, health policies sector. annual report. 2008. uae: ministry of health. 2008. pp. 22. 4. cervical cancer statistics. from: www. cervicalcancer.org/statistics.html. accessed: oct figure 2: distribution of pap smear according to abnormalities. ascus = atypical squamous cells of undetermined significance; lsil = low-grade squamous intraepithelial lesions; hsil = highgrade squamous intraepithelial lesions. rate of opportunistic pap smear screening and patterns of epithelial cell abnormalities in pap smears in ajman, united arab emirates 478 | squ medical journal, november 2012, volume 12, issue 4 2011. 5. peter b, bernard l. world cancer report. lyon: iarc press, 2008. pp. 418–23. 6. miller ab. cervical cancer screening programmes: managerial guidelines. geneva: world health organization, 1992. p. 17. 7. gustafsson l, adami ho. natural history of cervical neoplasia: consistent results obtained by an identification technique. br j cancer 1989; 60:132– 41. 8. national bureau of statistics. population and vital statistics: ajman in figures 2010. ajman: national bureau of statistics, 2011. p. 10. 9. solomon d, davey d, kurman r, moriarty a, o'connor d, prey m, et al.; forum group members; bethesda 2001 workshop. the 2001 bethesda system: terminology for reporting results of cervical cytology. jama 2002; 287:2114–9. 10. write tc jr, cox jt, massad ls, twiggs lb, wilkinson ej; asccp-sponsored consensus conference. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. jama 2002; 287:2120–9. 11. suba ej, raab ss. viet/american cervical cancer prevention project. papanicolaou screening in developing countries: an idea whose time has come. am j clin pathol 2004; 121:315–20. 12. suba ej, murphy sk, donnelly ad, furia lm, huynh ml, raab ss. systems analysis of real-world obstacles to successful cervical cancer prevention in developing countries. am j public health 2006; 96:480–7. 13. al sairafi m, mohamed fa. knowledge, attitudes, and practice related to cervical cancer screening among kuwaiti women. med princ pract 2009; 18:35–42. 14. al-meer fm, aseel mt, al-khalaf j, al-kuwari mg, ismail mfs. knowledge, attitude and practices regarding cervical cancer and screening among women visiting primary health care in qatar. east mediterr health j 2011; 17:855–61. 15. altaf f. cervical cancer screening with pattern of pap smear. saudi med j 2006; 27:1498–502. 16. kapila k, george ss, al-shaheen s, al-ottibi ms, pathan sk, sheikh za, et al. changing spectrum of squamous cell abnormalities observed on papanicolaou smears in mubarak al-kabeer hospital, kuwait, over a 13-year period. med princ pract 2006; 15:253–9. 17. abdullah ls. pattern of abnormal pap smears in developing countries: a report from a large referral hospital in saudi arabia using the revised 2001 bethesda system. ann saudi med 2007; 27:268–72. 18. jamal aa, al-maghrabi ja. profile of pap smear cytology in the western region of saudi arabia. saudi med j 2003; 24:1225–9. 19. balaha mh, al moghannum ms, al ghowinem n, al omran s. cytological pattern of cervical papanicolaou smear in eastern region of saudi arabia. j cytol 2011; 28:173–7. 20. ghazal-aswad s. cervical smear abnormalities in the united arab emirates: a pilot study in the arabian gulf. acta cytol 2006; 50:41–7. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e152–154, epub. 28 may 15 submitted 26 dec 14 revision req. 8 feb 15; revision recd. 13 feb 15 accepted 19 feb 15 colorectal cancer (crc) is the second most commonly diagnosed cancer in females and the third in males. more than 1.2 million cases around the globe are diagnosed every year and it is the estimated cause of death for more than half a million people each year. metastatic crc is the first presentation in approximately one-fourth of patients.1 another 30% of patients initially diagnosed with localised bowel cancer will subsequently develop liver metastases.1 the five-year survival rate for patients with stage iv crc with liver metastases is approximately 6%.2 however, if the liver is the only site involved and the metastases are amenable to surgical resection, then the five-year survival rate increases to 25–40%.2 the clinical evaluation of patients with crc requires multiple imaging modalities such as computed tomography (ct), contrast-enhanced ct, magnetic resonance imaging (mri), 18f-fluorodeoxyglucose (18f-fdg) positron emission tomography (pet) and pet/ct. all of these imaging modalities play a major role in the diagnosis and staging of crc. in the february 2015 issue of squmj, jafferbhoy et al. retrospectively evaluated the value of 18f-fdg-pet/ ct imaging in the management of patients with metastatic crc.3 18f-fdg-pet imaging has an important role in the diagnostic and staging algorithm. current evidence-based indications for 18f-fdg-pet in the uk recommend the use of this imaging modality in the staging of patients with synchronous crc and metastases at presentation, before considering surgical resection.4 this recommendation is similar to the north american national comprehensive cancer network guidelines for the initial staging of crc, which suggests the use of ct or mri of the chest, abdomen and pelvis; 18f-fdg-pet/ct imaging should be reserved for situations in which curative resection is being considered.5 the incorporation of 18f-fdg-pet scanning can facilitate the detection of extrahepatic disease and, therefore, can reduce the need for nontherapeutic laparotomies; however, we have to keep in mind that pet can be unreliable in certain settings where there is increased metabolic activity due to inflammation. in addition, mucinous adenocarcinomas may show a false-negative pet result.6,7 wiering et al. performed a systematic review of data looking at the superiority of pet imaging over ct alone in the detection of extrahepatic disease.6 for hepatic disease or metastases, pooled sensitivity and specificity for pet was 80% and 92%, respectively, in comparison to 91% and 98% for extrahepatic disease or metastases.6 corresponding values for ct imaging were 83% and 84% for hepatic metastases and 61% and 91% for extrahepatic metastatic disease. the use of pet imaging led to a 25% change in clinical management.6 a randomised trial demonstrated that combining pet with triphasic ct imaging reduced the number of unnecessary laparotomies from 34 (45%) in the control group to 21 (28%) in the experimental group. this combination of pet and triphasic ct imaging 1department of medicine, armed forces hospital, muscat, oman; 2oman medical specialty board, muscat, oman; 3department of child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: noumani73@gmail.com التصوير املقطعي باستخدام 18فلوروديوكسي جلوكوز البوزيرتون االنبعاثي/التصوير املقطعي يف تشخيص وعالج سرطان القولون واملستقيم املنتشر هل وصلنا؟ خالد النعمانى و �سهام ال�سنانية comment 18f-fluorodeoxyglucose-positron emission tomography/computed tomography in the management of metastatic colorectal cancer are we there yet? *khalid al-naamani1 and siham al-sinani2,3 khalid al-naamani and siham al-sinani comment | e153 prevented unnecessary surgery in one of six patients, with a relative risk reduction of 38%.7 similar findings were reported by jafferbhoy et al.3 18f-fdg-pet/ct imaging had a major impact on 72.7% of patients in the preoperative group; the intent of treatment was changed from curative to palliative due to the presence of inoperable disease in 36.3%, resectable metastases were identified after indeterminate ct scanning in 27.3% and 9.1% avoided unnecessary surgery after negative 18f-fdg-pet/ct results.3 the previously reported benefit of pet in reducing unnecessary laparotomies was disputed by moulton et al. in a recently published randomised trial in which 404 patients with potentially resectable isolated colorectal liver metastases (crlm) were randomly assigned to either undergo preoperative integrated pet/ct or forego pet/ct entirely.8 only 8% of those who had undergone preoperative pet/ct had a change in surgical management. the frequency of liver resections were similar in both groups (91% versus 92% in the experimental and control groups, respectively). additionally, there was no change in survival, with both groups demonstrating a two-year survival rate of 80%.8 due to the differences in outcomes of these studies, more data are required to evaluate the impact of 18f-fdgpet and pet/ct imaging on the clinical management of patients with crlm. several studies have investigated the role of 18f fdg-pet and pet/ct in patients with crlm undergoing selective internal radiation therapy (sirt) with yttrium-90 (90y) microspheres.9–12 radioembolisation using 90y resin or glass microspheres, also known as a palliative treatment, reduces the mass of a liver tumour, eventually permitting surgical resection.13 a recently published evidence-based review of the literature by annunziata et al. included 19 studies looking at the role of 18f-fdg-pet and pet/ct in patients with crlm undergoing sirt with 90y microspheres in 833 patients. the role of 18f-fdg-pet or pet/ct was evaluated in planning and assessing the response to treatment and evaluating pet as a prognostic tool.14 at present, the role of 18f-fdg-pet or pet/ct in planning sirt for crlm is still questionable. different studies have revealed different outcomes and therefore no strong conclusion can yet be drawn.11,15,16 further studies are needed to assess the role of 18f-fdg-pet or pet/ct in planning treatment before advising sirt for patients with crlm. a few recently published studies have investigated the role of 18f-fdg-pet or pet/ct imaging in the evaluation of patient response to sirt.9,17,18 all these studies confirmed the usefulness of 18f-fdg-pet and pet/ct imaging. furthermore, the role of 18f-fdg-pet or pet/ ct as a prognostic tool has been evaluated by a few recently published studies.10,18–20 gulec et al. looked at the relationship between functional tumour volume (ftv), total lesion glycolysis (tlg) and clinical outcomes. they demonstrated a correlation between semi-quantitative factors such as ftv and tlg with patient outcome and survival.19 similarly, fendler et al. reported the use of tlg in predicting survival in patients with crlm; ftv and tlg were found to correlate with outcome and survival in these patients using the response evaluation criteria in solid tumors.20 zerizer et al. investigated the role of early 18f-fdgpet/ct in predicting progression-free survival.18 early 18f-fdg-pet/ct was found to be superior to contrast-enhanced ct imaging in predicting progression-free survival in patients with crlm treated with 90y radioembolisation.18 18f-fdg-pet/ct is an emerging prognostic tool in patients with crlm undergoing sirt. however, this finding should be confirmed with larger prospective studies. unfortunately, pet technology is currently not available in oman at the present time and patients requiring pet scans are sent to nearby countries. with the establishment of an oncology service at the sultan qaboos university hospital and an oncology centre at the royal hospital in muscat, oman, pet imaging is becoming a necessity. according to personal sources, a pet scanning facility will be installed this year. this will definitely improve the oncology services available in oman and reduce the expenses required to send patients abroad. in summary, the role of integrated pet/ ct imaging in selecting optimal crlm surgical candidates and in the follow-up of surgical patients is uncertain. until additional data are available, 18f-fdgpet scans are recommended for crc staging and in selecting treatment options for patients, including the resection of metastases and sirt. at present, limited evidence supports the use of 18f-fdg-pet/ct as a tool for planning sirt, assessing treatment response and predicting progression-free survival. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin 2011; 61:69–90. doi: 10.3322/caac.20107. 2. cancer research uk. statistics and outlook for bowel cancer. from: www.cancerresearchuk.org/cancer-help/type/ bowel-cancer/treatment/statistics-and-outlook-for-bowelcancer accessed: feb 2015. 18f-fluorodeoxyglucose-positron emission tomography/computed tomography in the management of metastatic colorectal cancer are we there yet? e154 | squ medical journal, may 2015, volume 15, issue 2 3. jafferbhoy s, chambers a, mander j, paterson h. selective use of 18f-fluorodeoxyglucose-positron emission tomography and computed tomography in the management of metastatic disease from colorectal cancer: results from a regional centre. sultan qaboos univ med j 2015; 15:52–7. 4. royal college of physicians, royal college of radiologists. evidence based indications for the use of petct in the uk. from: www. rcplondon.ac.uk/sites/default/files/pet-ct_guidelines_2013.pdf accessed: dec 2014. 5. society of nuclear medicine & molecular imaging. 18f-fluorodeoxyglucose (fdg) pet and pet/ct practice guidelines in oncology: a summary of the recommendations and practice guidelines of professional groups. from: www.snm. org/docs/pet_pros/oncologypracticeguidelinesummary. pdf accessed: feb 2015. 6. wiering b, krabbe pf, jager gj, oyen wj, ruers tj. the impact of fluor-18-deoxyglucose-positron emission tomography in the management of colorectal liver metastases. cancer 2005; 104:2658–70. doi: 10.1002/cncr.21569. 7. ruers tj, wiering b, van der sijp jr, roumen rm, de jong kp, comans ef, et al. improved selection of patients for hepatic surgery of colorectal liver metastases with (18)f-fdg pet: a randomized study. j nucl med 2009; 50:1036–41. doi: 10.2967/ jnumed.109.063040. 8. moulton ca, gu cs, law ch, tandan vr, hart r, quan d, et al. effect of pet before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. jama 2014; 311:1863–9. doi: 10.1001/jama.2014.3740. 9. wong cy, salem r, qing f, wong kt, barker d, gates v, et al. metabolic response after intraarterial 90y-glass microsphere treatment for colorectal liver metastases: comparison of quantitative and visual analyses by 18f-fdg pet. j nucl med 2004; 45:1892–7. 10. wong cy, gates vl, tang b, campbell j, qing f, lewandowski rj, et al. fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography predicts extrahepatic metastatic potential of colorectal metastasis: a practical guide for yttrium-90 microsphere liver-directed therapy. cancer biother radiopharm 2010; 25:233–6. doi: 10.1089/ cbr.2009.0735. 11. bagni o, d’arienzo m, chiaramida p, chiacchiararelli l, cannas p, d’agostini a, et al. 90y-pet for the assessment of microsphere biodistribution after selective internal radiotherapy. nucl med commun 2012; 33:198–204. doi: 10.1097/mnm.0b013e32834dfa58. 12. tochetto sm, töre hg, chalian h, yaghmai v. colorectal liver metastasis after 90y radioembolization therapy: pilot study of change in mdct attenuation as a surrogate marker for future fdg pet response. ajr am j roentgenol 2012; 198:1093–9. doi: 10.2214/ajr.11.6622. 13. jakobs tf, hoffmann rt, poepperl g, schmitz a, lutz j, koch w, et al. mid-term results in otherwise treatment refractory primary or secondary liver confined tumours treated with selective internal radiation therapy (sirt) using (90)yttrium resin-microspheres. eur radiol 2007; 17:1320–30. doi: 10.1007/ s00330-006-0508-7. 14. annunziata s, treglia g, caldarella c, galiandro f. the role of 18f-fdg-pet and pet/ct in patients with colorectal liver metastases undergoing selective internal radiation therapy with yttrium-90: a first evidence-based review. scientificworld journal 2014; 2014:879469. doi: 10.1155/2014/879469. 15. denecke t, rühl r, hildebrandt b, stelter l, grieser c, stiepani h, et al. planning transarterial radioembolization of colorectal liver metastases with yttrium 90 microspheres: evaluation of a sequential diagnostic approach using radiologic and nuclear medicine imaging techniques. eur radiol 2008; 18:892–902. doi: 10.1007/s00330-007-0836-2. 16. campbell jm, wong co, muzik o, marples b, joiner m, burmeister j. early dose response to yttrium-90 microsphere treatment of metastatic liver cancer by a patient-specific method using single photon emission computed tomography and positron emission tomography. int j radiat oncol biol phys 2009; 74:313–20. doi: 10.1016/j.ijrobp.2008.12.058. 17. cianni r, urigo c, notarianni e, saltarelli a, salvatori r, pasqualini v, et al. selective internal radiation therapy with sirspheres for the treatment of unresectable colorectal hepatic metastases. cardiovasc intervent radiol 2009; 32:1179–86. doi: 10.1007/s00270-009-9658-8. 18. zerizer i, al-nahhas a, towey d, tait p, ariff b, wasan h, et al. the role of early 18ffdg pet/ct in prediction of progression-free survival after 90y radioembolization: comparison with recist and tumour density criteria. eur j nucl med mol imaging 2012; 39:1391–9. doi: 10.1007/s00259012-2149-1. 19. gulec sa, suthar rr, barot tc, pennington k. the prognostic value of functional tumor volume and total lesion glycolysis in patients with colorectal cancer liver metastases undergoing 90y selective internal radiation therapy plus chemotherapy. eur j nucl med mol imaging 2011; 38:1289–95. doi: 10.1007/ s00259-011-1758-4. 20. fendler wp, philippe tiega db, ilhan h, paprottka pm, heinemann v, jakobs tf, et al. validation of several suvbased parameters derived from 18f-fdg pet for prediction of survival after sirt of hepatic metastases from colorectal cancer. j nucl med 2013; 54:1202–8. doi: 10.2967/jnumed.112.116426. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 429-434, epub. 20th nov 12 submitted 16th jan 12 revision req. 16th apr 12, revision recd. 13th may 12 accepted 5th jun 12 education for health care professionals has evolved over many centuries through complex interactions between health and education. reforms have been propelled by new discoveries that affect health care delivery, health care expectations, and health professional education. however, medical wisdom has prevailed for centuries, emerging from early mesopotamian, egyptian, and greek thinkers including hammurabi, a mesopotamian physician who lived around 1700 bc; ibn sarabiyun, a 9th century syrian; muhammad ibn zakariya razi, a persian physician of the early 10th century; and avicenna or ibn sina, also persian, whose early 11th century books were standard medical texts.1 arabic medical literature between the 9th and 12th centuries ad provided some of the ideas and practices from which modern medicine arose. nursing was also valued in the early arab world and, according to ibn khaldun, nurse midwives were recognised in the 14th century as being one of the highest ranking professions.2 by the 19th and 20th centuries, scientific discovery had become the root of medical knowledge, and science-based curricula were developed. this was prefigured in the 11th century by ibn sina in the opening to his qanun fi al-tibb (canon of medicine), “medicine is a science from which one learns the states of the human body with respect to what is healthy and what is not, in order to preserve good health when it exists and restore it when it is lacking.”1 the growth and promotion of scientific technology has encouraged the creation of genuine حتويل التعليم لتعزيز الُنُظم الصحية يف ُعمان جيليان وايت امللخ�ص: ثغرات وا�صحة تثبت الف�صل العاملي يف الُنُظم ال�صحية وهم يحاولون عالج املطالب املعقدة واملكلفة. يف االآونة االأخرية قامت جلنة الن�صيت من خالل منظور عاملي متعدد التخ�ص�صات ونهج منتظم للنظر يف التحالفات بني املهنيني يف التعليم ال�صحي والُنُظم ال�صحية، وخل�صوا اإىل اأن النتائج االإيجابية تتطلب ت�صاميم تعليمية وموؤ�ص�صية جديدة. النتائج التي تو�صلت اإليها جلنة الن�صيت لها اآثار على تطوير التعليم املهني ال�صحي يف ُعمان وال �صيما يف الدعوة اإىل التعليم التكاملي والتحويلي للجيل القادم. يجب اأن يكون التعليم املهني يف القطاع ال�صحي الُعماين مواكبا للتحديات املتزايدة يف قطاعي ال�صحة والتعليم على حد �صواء. مفتاح الكلمات: تعليم، مهن طبية، تعّلم، مناهج، ُعمان. abstract: conspicuous gaps demonstrate a collective global failure in the world’s health systems as they struggle to manage complex and expensive demands. the lancet commission recently took a global interdisciplinary perspective and systematic approach to consider alliances between education for health professionals and health systems in order to address these problems. they concluded that positive outcomes require new instructional and institutional designs. findings from the lancet commission have implications for the development of health professional education in oman, particularly with regard to the call for integrative and transformative education for the next generation of health professionals. education in the omani health sector must keep up with increasing challenges in both the health and education sectors. keywords: education; health professions; learning; teaching; curriculum; oman. special contribution transforming education to strengthen health systems in the sultanate of oman gillian white directorate general education & training, ministry of health, muscat, oman email: drgillianwhite@yahoo.co.nz transforming education to strengthen health systems in the sultanate of oman 430 | squ medical journal, november 2012, volume 12, issue 4 human capital is essential in growing a knowledge economy, which in turn is crucial for economic competitiveness in developing countries. as a nation’s wealth depends on the health of its people, quality higher education of health professionals cannot be compromised, and developing effective and high-quality processes becomes a vital challenge for academic enhancement.4 in oman over the last 45 years, steps have been taken toward national development, global competitiveness, and fostering the flow of knowledge. oman is privileged to have debt-free health professional graduates with guaranteed jobs compared, for example, to the debt of american medical graduates which averages us$200,000 (c. omr 76,900). the ministry of health (moh) has made phenomenal strides in achieving exceptional outputs in health professional education while at the same time preparing omani academics as education providers (unpublished quality audit portfolio, directorate general of education & training, ministry of health, oman ). in this article, a century of global reforms will be described as the foundation for focusing on the future of health professional education and urging the development of transformative education that will strengthen oman’s health system. the vision outlined in the lancet commission’s report 2010 will be referred to extensively, and its implications for health professional education in oman will be discussed.5 lancet commision’s re-examination of health professional education the commission was launched in 2010 at the centennial of the flexner report6 to re-examine health professional education for the 21st century, and to ensure global quality and comprehensive services for advancing health equity.5 the need for the commission was fuelled by the systemic problems noted throughout the world concerning gaps in health services, new health challenges, and complex health systems that place excessive demands on health care professionals. twenty professional and academic leaders, supported by their own advisory bodies, were commissioned from countries as diverse as bangladesh, canada, open-minded enquiry and has encouraged the call for democracy, where citizens are adequately informed and able to make decisions according to their own best interests as they see them. through democracy, people have the opportunity to have their voices heard. the term is derived from the greek dēmokratiā, from dēmos (“people”) and kratos (“rule”) and, while normally associated with political ideology, the term can be applied to health and education in terms of access, affordability, and appropriateness for all.3 recent demonstrations have brought about an interest in democracy in the middle east. concurrently, there has been a backlash against consumerism in many western countries, including against the proliferation of medical ‘treatments’, illness ‘cures’, alternative health ‘strategies’, confusing dietary advice, fast ‘healthy’ food outlets, and medical tourism. in addition, the quest for quality has begun to supersede the demand for quantity in the ongoing search for excellence. thus, for different reasons, people all over the world are seeking greater selfdetermination and demanding equal rights to medical knowledge and high-quality health care. oman recognized its citizens’ rights through the establishment of a consultative assembly in 1981, which was replaced in 1991 by the majlis-al shura (consultative council). the an-nizam-al-assasilil-dawlah (basic charter), article 13, was adopted by royal decree in november 1996. article 13 contains “the rights and duties of the people” and a number of basic principles, including the right to education and to literacy, and the obligation of the state to produce a generation which is physically and morally strong, proud of its country and its cultural heritage and equipped with the knowledge of modern science and technology”.4 when qaboos bin said al said became sultan of oman in 1970, the country was struggling with endemic disease, illiteracy, and poverty. one of his first acts was to improve the country’s educational and health facilities. since then, oman has enjoyed prosperity and has not only progressed rapidly but with shrewd foresight. lessons from world history, however, show that economies change; thus, oman must look toward political and financial global transformations and capitalise on its human resources to grow knowledge and build capacity and capability for continuous development. gillian white special contribution | 431 supported by the rockefeller foundation, a 500page report on nursing and nursing education was authored which recommended university education for nurses, transforming them from technicians to professionals.8 second generation reforms accelerated medical and nursing education into graduate schools throughout the 20th century. mcmaster university pioneered problem-based learning in the 1960s, and integrated curricula were designed. patient surrogates were utilised and students were introduced to the needs of the wider community. oman was influenced by these two generations through the importation of foreign education programmes, notably from western systems of health professional education. even though the higher education sector is relatively young, the oman higher education admission centre lists 55 higher education institutes, including a number which are associated with ministries such as that of awqaf and religious affairs; higher education; manpower; health; the central bank, and 24 private institutions sanctioned by the ministry of higher education.9 health care education in oman sultan qaboos university (squ) is an omani public institution that has been offering ph.d. studies in medicine and health sciences, among others, since 2008. oman also offers programmes for the preparation of nurses and physicians at private universities. a number of health professional programmes for paramedics, nurses, specialist nurses and midwives, radiographers, assistant pharmacists, physiotherapists, medical technicians, dental assistants, and health information specialists are run under the auspices of the moh at both basic and post-basic levels. omanis aspiring to careers in the health professions have been sponsored or have taken up opportunities privately to undertake baccalaureate, masterate, and doctoral degrees overseas following a sensible plan of diversification and exposure to a variety of international institutions, both traditional and new. however, there has been concern in oman about the low level of english proficiency among students admitted to institutions of higher education. some enter at a zero level, and over 40% score below level china, the usa, pakistan, the uk, peru, south africa, india, uganda, and lebanon. the commission undertook research guided by an integrated conceptual framework aimed at understanding “the complex interactions between two systems: education and health”.5 in this framework, the population is endogenous to both education and health systems, being the supplier of the services and the recipient. the education system provides the educated workers to work in the health system and the health system meets the demands for a healthy labour workforce, both nationally and globally. interdependence is crucial for balance and equity in the respective services; however, the global reality is that there is imbalance and inequity within and between countries, and within and between populations. the commission aimed to develop a fresh vision with practical recommendations regarding the two interdependent systems. two generations of reforms during the 19th and 20th centuries were noted, and a call for a third generation in the 21st century was made. first and second generation reforms in the education of health professionals first generation reforms were ignited by developments in the biomedical sciences arising from 19th century discoveries in medical science and driven by the identification of microorganisms, or germ theory, leading to modern health care. science underpinned health professional education, and reforms were found in institutional design (i.e. university-based, academic medical hospitals) and instructional design (science-based curricula and research). the flexner report of 1910 informed a new medical curriculum that took medical education from apprenticeship to academic preparation (university-based science plus hospital clinical training).6 scientific research also informed public health, which was then connected to medical schools. the welch-rose report, a public health classic of 1915, initiated the education of public health workers who paralleled the medical profession and refined the interface of the curative and preventative.7 in the early 1900s, there was a movement to improve nursing education and, transforming education to strengthen health systems in the sultanate of oman 432 | squ medical journal, november 2012, volume 12, issue 4 reports recommend transdisciplinary approaches to life-long learning; integrating public health skills into nursing; engaging with local communities, and expanding funding for public health development.5 lastly, medical education reports agree that health professionals are not being adequately prepared to address the challenges of modern society, especially those of ageing populations, cultural diversity, chronic disease, and high public expectations.5 students of the 21st century have expectations for success that are not congruent with the effort they make in the classroom. price outlined five instructional strategies for engaging today’s students: research (active learning methods); relevance (connecting course content to current culture); rationale (the need to know the reason); informal interaction, and rapport (when teachers are perceived as on their side).12 easy access to google has led students to prefer non-authoritarian instructors who facilitate discovery, social interaction, and peer collaboration, and help with the application of knowledge, all in a laid back learning environment. the challenge of teaching 21st century students demands a transformation in widely-held beliefs about teaching. accepted wisdom and research suggests the concept of teaching is divided into teacher-centred/content-oriented, and studentcentred/learning-oriented categories, which are further divided into imparting knowledge and transmitting structured knowledge (teachercentred), and facilitating understanding and intellectual development (student-centred).11 integrating the two is the student-teacher interaction. upholding traditional competitive ideologies of the importance of getting high marks, for example, hinders teachers from encouraging students to value learning for the sake of deep lifelong learning rather than superficial learning for the sake of gaining marks on a particular test. outcome measures should not just focus on grades but rather on graduate employability; salary levels; student and staff satisfaction; student completion rates, and student engagement as valuable indicators of institute and programme effectiveness.13 thus the lancet commission recommends that reforms in institutional design (structure) and improvements in instructional design (process) will transport health professional education into the 21st century and build on the first and second generation 2 on the international english language testing system (ielts) test. given that students have had 12 years of english at the primary and secondary levels, and that they graduate with a general education diploma and a minimum general score of 70%, such low levels are unexpected.10 for basic health professionals, such a low level of education places an exceptional burden on teachers. students take a surface approach to learning and are more concerned about grades than the implications of what they are learning. in 2011, the moh higher education institutes commenced the new national general foundation course which comprises english language, mathematics, information technology (it), and general learning skills. prior to selection for entry into its health professional education programmes, students must achieve an ielts score >5.0. third generation reforms as oman builds its own capacity and capabilities in health professional practice and education, a third generation of reforms, benchmarked on global transformations in health and education, yet contextualised to oman’s unique needs, should be fashioned. this can be achieved by instituting strong measures of quality control and enhancement, ensuring social equity and access to the health professions, setting national standards, improving teaching methodologies (including establishing sound evaluation practices), and investing in resource materials. third generation reforms emphasise patient and population centredness, competency-based curricula, inter-professional and team-based education, it-empowered learning, policy formation, and management and leadership skills. the lancet commission identified four types of reports that initiated the call for third generation reforms in the education of health professionals: education and training of the workforce; nursing education; public health, and medical education.5 world-wide education and training reports draw attention to shortages, imbalances and maldistributions, inadequate rural coverage, unemployment, and international migration.5 nursing reports stress professional identity; bridging the theory-practice gap, and mainstreaming nursing into national service planning.5 public health gillian white special contribution | 433 from historical learning settings and will be cost effective as well. instructional design in oman while education research is abundant, there is little documentation about the impact of nursing or medical education innovations in oman.1 there is, therefore, vast potential for systematic research, from admission criteria to career pathways. research opportunities include the evaluation of foundation courses, teaching methodologies, student-centred learning, assessment strategies, competency-based curriculum development, developing knowledge and skills through simulation, life-long learning, and transformative education. third generation transformation does not negate first and second generation advances in health professional education. indeed, science remains the foundation of both transformation and integration while problem-based learning and the wider conceptualisation of health to society at large have produced valuable advances in health care. the difference is that while first and second generation transmission of knowledge was largely inert, objective, limiting, and reductive, the third generation style is richly relational, asserting the power of experience and imagination. the student has a relationship with the state of learning and its effects, and is affected by that relationship. in third generation reforms, the teacher facilitates the relationship, encouraging the student to explore phenomena from various perspectives. the teacher moves from the didactic (teacher-controlled) to the interactional (student-centred). if teachers do not engage and excite students through valuing their experiences and insights, then genuine solutions for the myriad of everyday problems will never be achieved. if education remains true to the human condition, then it “must reflect our nature in all its subtlety and complexity”.14 transformative education stimulates intellectual and emotional faculties—and increases relational, reflective, and physical knowing. it integrates values and respects the human soul. never has this been more important than in the education of health professionals in their pursuit of truth within an environment of compassion and social justice. reforms of the 20th century. the outcomes that depend on the configuration of structure and process will be competent practitioners. institutional design in oman in oman, most academic institutes are situated in urban areas, raising concerns about equity of access for students from rural and remote regions, as well as the resourcing for such institutes. moh students are supported through government allowances for transportation and accommodation to study in muscat or their nearest regional institute. when compared to countries where students pay for their own education and graduate with heavy debts, this is a privilege. however much the moh will pay, the problem of inequality of access still exists. online learning might be a possible solution for the teaching of theory subjects, but only if the delivering institutions were to be resourced and maintained in a supportive it environment and teachers were experienced with online teaching. the clinicalpractice nexus is also an issue for all institutes that deliver education to health professionals: it is vital that institutes are situated close to clinical practice facilities or have access to modern simulation laboratories, and that is not always a possibility in the case of many of oman’s potential health sciences students. currently, oman is progressing toward accreditation of higher education providers. this accreditation aims to reflect the aspirations of students, meet professional requirements, and embody the professionalism expected by society. the challenges to accreditation are the lack of institutional networking that would enhance interdisciplinary collegiality; a shortage of professional development opportunities, particularly in building faculty research capacities; leadership and management challenges; the need for a seamless integration of primary health care facilties, and the ongoing journey toward the transformation of the learning environment. the sharing of educational resources such as simulation laboratories, libraries, and it support for online learning between disciplines and across institutes; the exchange of faculty and students, and the establishment of multidisciplinary research will help break down the current silo mentality inherited transforming education to strengthen health systems in the sultanate of oman 434 | squ medical journal, november 2012, volume 12, issue 4 references 1. islamic culture and the medical arts. from: www. nlm.nih.gov/exhibition/islamic_medical index.html. accessed jul 2011. 2. khaldun i. the muqaddimah: an introduction to history (bollingen series xliii). princeton, nj: princeton university press, 1967. 3. encyclopædia britannica online. from: www. b r i t a n n i c a . c o m / e b c h e c k e d / t o p i c / 1 5 7 1 2 9 / democracy. accessed: jul 2011. 4. rassekh, s. education as a motor for development: recent education reforms in oman with particular reference to the status of women and girls. geneva: international bureau of education, 2004. p. 12. 5. frenk j, chen l, bhutta za, cohen j, crisp n, evans t, et al. health professionals for a new century: transforming education to strengthen health systems in an interdependent world. the lancet 2010; 376:1923–58. 6. flexner a. medical education in the united states and canada: a report to the carnegie foundation for the advancement of teaching. new york: the carnegie foundation for the advancement of teaching, 1910. 7. welch wh, rose w. institute of hygiene: a report to the general education board of the rockefeller foundation. new york: the rockefeller foundation, 1915. 8. the committee for the study of nursing education. nursing and nursing education in the united states. new york: the rockefeller foundation, 1923. 9. higher education admissions center of oman. from: heac.gov.om/index.php?lang=en. accessed: jul 2012. 10. al-mamari a. general foundation programme in higher education institutes in oman: presentation, regional conference on quality managament and quality enhancement in higher education. muscat: oman quality network in higher education. pp. 20–1. 11. devlin m. challenging accepted wisdom about the place of conceptions of teaching in university teaching improvement. int j teach learn high educ 2006; 18:112–9. 12. price c. why don’t my students think i’m groovy? teach prof 2009; 23:7. 13. jongbloed b, vossensteyn, h. keeping up performances: an international survey of performance based funding in higher education. j high educ manag 2001; 23:127–45. 14. parker pj, zajonc a. the heart of higher education: a call to renewal. hoboken, new jersey: josseybass, 2010. pp. 152. conclusion the rapid pace of change and the development of scientific theories that challenge existing knowledge demand an examination of any values concerning teaching and learning which continue to remain based in first and second generation ideologies. for example, quantum and relativity theories, discovered by scientists such as einstein, bohr, and schrödinger, are transformational, stressing relationships at the micro and macro levels rather than discrete units. similarly, transformational education allows students to have experiences, assess the reliability of those experiences, and reflect upon the hidden interrelationships and transfer of knowledge to new situations. thus education becomes expansive and life-long, merging philosophy and science, and art and logical reasoning. health professional education leaders in oman must look to reform both institutional and instructional designs to be able to find solutions for the challenges of the 21st century. health professional education reforms, however, do not belong only to teachers. the vision and innovative ideas of government and private employers, professional bodies, international health care agencies, experienced educators, and young aspiring omani academics and students who met at the international conference on health vision 2050 in oman in may 2012 must also be heard. finally, the lancet commission concluded their report with reference to pulitzer prize winner and harvard professor of english and american literature and language, louis menand: “…the pursuit, production, dissemination and preservation of knowledge are central activities of a civilization. knowledge is social memory, a connection to the past; and it is social hope, an investment in the future.” such wisdom is a good place to end this article. n o t e this topic was presented at the first international nursing conference at sultan qaboos university, oman, in november 2011. clinical & basic research squ med j, may 2012, vol. 12, iss. 2, pp. 190-196, epub. 9th apr 2012 submitted 21st sep 11 revision req. 11th dec 11, revision recd. 25th jan 12 accepted 29th feb 1department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman; 2department of obstetrics & gynaecology , college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: lovina1857@gmail.com عملية استئصال ورم الرحم العضلي أثناء إجراء العملية القيصرية: إمكانية إجراء العملية والسالمة لوفينا مات�سادو، فيدياناثان غوري، نهال الريامي، ملياء اخلرو�سي، حدوث من املخاوف ب�سبب القي�رضية العملية اإجراء اأثناء الع�سلي الرحم ورم ا�ستئ�سال تقبل عدم على العادة جرت الهدف: امللخ�ص: نزيف قد ي�سعب ال�سيطرة عليه اأثناء العملية اجلراحية وب�سبب امل�ساعفات املتوقعة بعد العملية. ومع ذلك، فقد ظهر موؤخرا يف العديد من االأبحاث اأن ا�ستئ�سال ورم الرحم الع�سلي اأثناء العملية القي�رضية اليزيد من خطر النزف اأو امل�ساعفات بعد العملية اجلراحية. الطريقة: نقدم هنا و�سفا لثمان حاالت من م�ست�سفى جامعة ال�سلطان قابو�س، ُعمان، حيث مت اإجراء ا�ستئ�سال اأورام ليفية يف اأ�سفل الرحم اأثناء مت والتي للرحم اخللفي اجلدار يف ليفي وورم االأمامي، الرحم جدار يف امل�ستاأ�سلة الليفية االأورام من �سبعة كانت القي�رضية. العملية ا�ستئ�ساله للتمكن من اإغالق �سق الرحم. النتائج: كان متو�سط عمر الن�ساء الالتي مت اإجراء العملية لهن 28.7 �سنة ومتو�سط عمر احلمل عند الوالدة 36.75 اأ�سبوعا. و فيما يتعلق بفقدان الدم اأثناء العملية، فقدت مري�سة واحدة 900 مل، وخم�س ن�ساء فقدن بني 1 – 1.5 لرتا، واثنتان فقدن بني 1.5 2 لرتا، وفقدت امراأة 3.2 لرتا من الدم حيث كان قيا�س الورم الليفي عندها 10×12 �سم. وعلى الرغم من كون اأغلبية االأورام الليفية كبرية )7 من االأورام الليفية كانت اأكرب من 5 �سم يف احلجم( و ٪50 منها �سنفت من �سمن التليفات الداخلة يف اجلدار الع�سلي للرحم، مل تكن هناك حاجة ال�ستئ�سال الرحم. وقد ا�ستدعت حالة واحدة لقطع التغذية الدموية، بينما ا�ستدعت حالة اأخرى للق�سطرة ببالون �رضيان الرحم قبل اإجراء العملية. مت التاأكد من حجم االأورام الليفية عن طريق فح�س الن�سيج املر�سي بعد عملية اال�ستئ�سال. عملية ا�سئ�سال الورم الليفي اأ�سافت 15 دقيقة اإىل الوقت الكلي املعتاد الإجراء العملية القي�رضية ويوما واحدا اآخرا للبقاء يف امل�ست�سفى ومل ت�سجل اأية م�ساعفات لالأمهات اأو اأطفالهن خالل املكوث يف امل�ست�سفى. اخلال�صة: ا�ستئ�سال اأورام الرحم الع�سلية اأثناء العملية القي�رضية يف ن�ساء خمتارات هو اإجراء اآمن وفّعال يف م�ست�سفيات الرعاية الثالثية بوجود جراحني ذوي خربة. مفتاح الكلمات: والدة قي�رضية، عملية ا�ستئ�سال ورم الرحم الع�سلي، اأورام ليفية، حمل، نزيف، ُعمان. abstract: objectives: caesarean myomectomy has traditionally been discouraged due to fears of intractable haemorrhage and increased postoperative morbidity. however, a number of authors have recently shown that myomectomy during caesarean section does not increase the risk of haemorrhage or postoperative morbidity. methods: we present a series of 8 cases from sultan qaboos university hospital, oman, where myomectomy was performed during caesarean section for large lower segment fibroids. seven were anterior lower segment fibroids, while one was a posterior lower uterine fibroid which interfered with closure of the uterine incision. the antenatal course, perioperative management, and postoperative morbidity are discussed. results: the average age of the women was 28.7 years and mean gestational age at delivery was 36.75 weeks. regarding intra-operative blood loss, 1 patient lost 900 ml, 5 patients lost 1–1.5 litres, 2 lost 1.5–2 l, and 1 patient with a 10 x 12 cm fibroid lost 3.2 l. despite the majority being large myomas (7 of the 8 patients had myomas >5 cm in size) and 50% being intramural, no hysterectomy was required. stepwise devascularisation was necessary in one case and preoperative placement of uterine balloon catheters was necessary in another. the size of the fibroids was confirmed by histopathology. myomectomy added 15 minutes to the operating time and 1 day to the hospital stay, but there was no significant postoperative morbidity. neonatal outcome was good in all patients. conclusion: in selected patients, myomectomy during caesarean section is a safe and effective procedure at tertiary centres with experienced surgeons. keywords: caesarean section; myomectomy; fibroids; pregnancy; haemorrhage; oman. caesarean myomectomy feasibility and safety *lovina sm machado,1 vaidyanathan gowri,2 nihal al-riyami,1 lamya al-kharusi,1 advances in knowledge this is the first study in oman addressing the controversial and important issue of performing myomectomy during caesarean section. this procedure is reported to be associated with intractable haemorrhage and postoperative morbidity by some authors while other authors advocate its safety. caesarean myomectomy is safe to perform in selected patients and results in no significant post-operative morbidity. the procedure can help younger patients avoid hysterectomy. lovina s m machado, vaidyanathan gowri, nihal al-riyami and lamya al-kharusi clinical and basic research | 191 the incidence of myoma associated with pregnancy is reported at 0.3–5%, with a majority of myomas not requiring surgical intervention during pregnancy or delivery.1–4 myomectomy at the time of a caesarean section has traditionally been discouraged due to fears of intractable haemorrhage and increased postoperative morbidity. however, a number of authors have recently shown that myomectomy at caesarean does not increase the risk of haemorrhage.2,10–21 we present a series of 8 cases where myomectomy was performed during caesarean section for large lower segment fibroids ranging in size from 4 to 12 cms. the antenatal course, perioperative management, and postoperative morbidity are discussed. methods we performed a retrospective cohort study of 8 patients with myomas which resulted in pregnancy complications. all 8 patients underwent myomectomy at the time of caesarean section at sultan qaboos university hospital (squh) between january 1999 and december 2010. ethical approval for the study was obtained from the university medical research and ethics committee (mrec #399). patients’ medical records were perused for demographic data, parity, and antenatal course, type of caesarean section, size and location of the fibroids, blood loss, postoperative morbidity, and neonatal outcome. all of the women in the study fulfilled the following five criteria: 1) documented fibroid during the index pregnancy by antenatal ultrasound or at surgery; 2) delivery by caesarean; 3) no evidence of antenatal bleeding; 4) no other procedure at caesarean apart from myomectomy, and 5) no pre-existing coagulopathy. informed consent was obtained from all patients preoperatively. of the 8 patients studied, 7 had anterior lower segment fibroids and one had a posterior lower uterine fibroid which interfered with closure of the uterine incision. adequate blood and blood products were arranged preoperatively. myomectomy was performed in the conventional fashion using an incision over the myoma, enucleating it, and obliterating the dead space in two to three layers using interrupted 1-0 vicryl sutures (ethicon inc., new jersey, usa). anterior lower segment myomas encroaching on the proposed incision line were excised prior to delivery of the baby while the others were removed after the baby had been delivered. the caesarean incision was closed in 2 layers with 1-0 vicryl sutures. high dose oxytocin was used intraoperatively and postoperatively, and some patients required additional uterotonic agents. blood loss was estimated from suction aspiration, and from weighing mops, swabs and drapes used during surgery. prophylactic antibiotics were administered to all the patients. a review of literature was performed using pubmed, medline, and google. results the average age of the women was 28.7 years. the age, parity, and associated risk factors of the patients; factors, size and location of the myomas; the operative findings and incisions used during surgery, and the complications and neonatal outcomes are summarised in table 1. of those in the study, 7 of the 8 patients had lower segment anterior wall fibroids at or close to the incision site, and one patient had a large posterior wall fibroid which projected through the uterine incision after delivery of the baby and needed removal to facilitate the article highlights various new techniques that effectively control haemorrhage during caesarean myomectomy, and has educational value for less experienced obstetricians. application to patient care caesarean myomectomy allows women to have a better obstetric outcome in future pregnancies, and to avoid hysterectomy. it relieves symptoms associated with fibroids and negates the need for later surgery or sonographic follow-ups for the fibroid after delivery. it is a safe procedure in selected patients when performed in tertiary care hospitals by experienced obstetricians with newer measures available to curtail haemorrhage. caesarean myomectomy feasibility and safety 192 | squ medical journal, may 2012, volume 12, issue 2 closure. in total, 4 were intramural fibroids (50%) and 4 were subserous. the size varied from 4–12 cm with 7 of them being larger than 5 cm in diameter. regarding intra-operative blood loss, 1 patient lost 900 ml, 5 patients lost 1–1.5 litres, 2 lost 1.5–2 l, and 1 patient with a 10 x 12 cm subserous fibroid lost 3.2 l. stepwise devascularisation was needed to control atonic postpartum haemorrhage (pph) in 1 patient. preoperative placement of uterine balloon catheters was used in another patient with a large posterior wall fibroid. the balloon was inflated intra-operatively after delivery of the baby, effectively controlling the haemorrhage. none of the patients required hysterectomy. neonatal outcome was good in all the patients. the mean gestational age at delivery was 36.75 weeks (range 33–38 weeks). the 5 minute apgar score was 9–10 in all the newborns with birth weights ranging from 2160 grams (preterm 33 weeks) to 3,000 grams. table 1: demographic and clinical profile, operative findings and outcome of the patients who underwent caesarean myomectomy at our institution age/parity g/p/a risk factors/ co-morbidities no. & location of fibroids size at start of pregnancy size at cs ga at cs in wks est. blood loss in ml baby details incision postoper ative morbidity 26 yrs g6/p1/a4 prev 1 cs intramural lus anterior wall + multiple small fibroids 6.2 x 4.3 cms 7 x 6 cms 38 1,100 female 2,660 gms apg 9/10 pfannenstiel utlower seg transverse none 19 yrs g1 essential ht pprom 32 w betamethasone x 2 doses lower segment left side. subserous 8.6 x9.1 cms 9 x 9 cms infarction 33 1,100 female 2,160 gms apg 8/9 vertical sumli ut-low vertical rop, deflexed head none 35 yrs g4/p3 none lower segment ant. wall intramural 9x10 cms 8 x 8 cms 38 1,500 2 u prbc uterine @ balloon catheter in situ male 2,830 gms apg 9/10 pfannenstiel ut-lower seg transverse blood transfusion 24 yrs g2/p1 breech, polyhydramnios. prev. multiple myomectomy (4). cavity not entered lower segment anterior wall intramural 6 x 7 cms 8 x 7 cms 38 1,100 atonic pph stepwise devascularisation female 2,790 gms apg 8/9 pfannenstiel ut-lower segment transverse none 28 yrs g2/p1 previous lscs pih lower segment posterior wall subserous 6.5 x 5.5 cms 6.5 x 6 cms 38 1,100 2 u prbc female 3,000 gms apg 9/10 pfannenstiel utlower segment transverse blood transfusion 38 yrs g5/p4 none lower segment rt side anterior subserous 9.8 x 7 cms 10 x 12 cms degen. 37 3,200 6 u prbc 4 ffp, uterotonics male 2,880 gms apg 5/9 vertical sumli uthigh lower segment transverse anaemia blood transfusion 28 yrs g1 pih lower segment anterior subserous 6 x 5 cms 7 x 5 cms haem. 37 900 female 2,690 gms apg 9/10 pfannenstiel utlower segment transverse none 32 yrs g9/p2/a6 previous 2 lscs upper part of lower segment anterior intramural 4 x 4 cms 4 x 4 cms calcified 35 2,000 2 u prbc female 2,530 gms apg 9/10 pfannenstiel utlower segment transverse blood transfusion legend: g/p/a = gravida/para/abortion; cs = caesarean section; ga =gestational age; lus = lower uterine segment; ht = hypertension; pprom = preterm premature rupture of membranes; sumli = subumbilical midline longitudinal incision; rop = right occipito-posterior position; ut = uterus; lscs = lower segment caesarean section; pih = pregnancy induced hypertension; pph = postpartum haemorrhage; prbc = packed red blood cells, ffp = fresh frozen plasma; apg = apgar score at 1 and 5 minutes lovina s m machado, vaidyanathan gowri, nihal al-riyami and lamya al-kharusi clinical and basic research | 193 discussion uterine myomas are found in approximately 0.3–5% of pregnant women, with the increasing incidence attributable to the fact that more and more women are delaying childbearing.1–4 one in ten of these women will have complications during pregnancy that are related to the myoma. a great majority of myomas associated with pregnancy remain asymptomatic and do not require treatment, with about 22–32% showing increased growth.5 larger fibroids (>5cm) are more likely to grow during pregnancy and can cause miscarriages, obstructed labour, malpresentations, pressure symptoms, pain due to red degeneration, preterm labour, preterm premature rupture of membranes, table 2: a comparison of various studies on cesarean myomectomy authors roman11 kwon15 kaymak2 ehigiegba16 ortac10 ahikari17 omar19 machado lsm year 2004 2003 2004 2001 1999 2006 1999 2011 no. and type of cases 368 88 120 25 22 14 2 8 111 cm 257 cs na 40 cm 80 cs na na na na na maternal age 37 35 32.5±4.4 31.9±4.5 30.8±3.1 30.8±3.8 na 25–35 yrs na 28.75 parity para 0 na na 84.1% 0.8±1.2 1.1±1.1 13 na 11 2 2 para 1-4 na na 16.9% na na 12 na 3 0 6 mean ga at cs 38 (27.3– 41.6) 39 (24– 42.6) 38±1.19 37.7±2.5 37.6±1.4 36.9 (29–42) na na na 36.75 (33–38) no. of fibroids single 91 67% 75% 10 na 12 2 7 multiple 20 33% 25% 15 na 2 0 1 location lower us na 50% 11 (27.5%) na na 6 2 7 upper us na 50% 22 (55%) na na 5 1 both na 7 (17.5%) na na 2 pedunculated na 0 na na 1 size <5 cms mean 3.5 (0.9–30) mean 3 (1 –20) na ≤3cm, 2 (5%) most 2–4 cms mean 22 (9.5±4.6) range 5–19 cm 5 na 1 5-10 cms 4–5cm, 14 (35%) 2 7 6 >10 cms ≥6cm, 24 (60%) 2 2 1 average operating time lscs 51 (20–07) na 44.4±6.7 35±3.28 na 1,500 ml cm 55 (25– 161) na 53.3±18.6 na 41.6±8 range 25–60 54.1±3.84 p >0.05 900– 3200ml blood loss blood loss 12.6% 12.8% 731.5 ml 12.5% 11.3% 876 ±312 ml 324.2 ml 472 ml na 1,500 ml range significant haem. significant haem. 400– 2500ml 400–1700ml 359–600ml 900– 3200ml postoperative morbidity blood transfusion 0.9% 1.2% 1 relap. for bleeding 4 (10%) 5 (6.3%) 5 na 1 na 4 fever 4.5% 4.7% 12 (13.6%) 3 (7.5%) 8 (10%) 2 (8%) na na na 0 anaemia na na na na na 60% na na na 2 hysterectomy postop hospital stay in days (range) 3.6 (2–7) 3.4 (2–12) na 3.3±0.8 2.7±0.6 7.4±2.2 (3–12) 3.7±0.9 (2–6) 6 na 5.0±0.8 (4-7) legend: ga = gestational age; us =uterine segment; cm = caesarean myomectomy; cs = caesarean section; lscs = lower segment caesarean section; na = not available or not specified; relap = relaparotomy caesarean myomectomy feasibility and safety 194 | squ medical journal, may 2012, volume 12, issue 2 retained placenta, postpartum haemorrhage and uterine torsion.5–7 katz et al. found that 10–30% of women with myomas associated with pregnancy had complications as listed above.7 caesarean section rates in women with myomas are higher, up to 73%, mainly due to obstructed labour and malpresentations.3 preservation of the uterus without loss of its function and compromising the mother’s ability to bear more children is definitely a greater surgical achievement than a hysterectomy; hence, caesarean myomectomy must be considered by experienced obstetricians wherever feasible. the orthodox view of one of the pioneers of myomectomy in non-pregnant women, bonney, is reflected in his writings: “it is tempting for the adventurous and sympathetic surgeon to condense the operation of lower segment caesarean section and myomectomy into one undertaking and save his patient the ordeal of a second admission to hospital. this kindly but misguided policy we heartily deprecate.” however, his pupils, hawkins and stallworthy, did advocate caesarean myomectomy in selected cases, as in the incidence of anterior lower segment myomas on the proposed incision line.8 exacoustos and rosetti reported that in their series of 9 cases of caesarean myomectomy, three were complicated by severe haemorrhage necessitating hysterectomy; hence, they recommended caution while making the decision to perform this procedure.9 some authors report a higher incidence of postpartum haemorrhage and puerperal sepsis if the fibroid is not removed at caesarean section.3,4 in addition, the uterus in the immediate postpartum phase is better adapted physiologically to control haemorrhage than at any other stage in a woman’s life; hence, it seems logical to perform caesarean myomectomy. the management of fibroids encountered at caesarean section remains a therapeutic dilemma. myomectomy during caesarean section has traditionally been discouraged due to the risk of uncontrollable haemorrhage, unless the myoma is pedunculated.11 recent studies have described techniques to minimise blood loss at caesarean myomectomy including uterine tourniquet, bilateral uterine artery ligation, and electrocautery.10,12,13 in our series, stepwise devascularisation was required to control atonic pph in one patient; in another patient uterine artery balloon catheters were placed preoperatively. several authors have now shown that in selected patients and in experienced hands, myomectomy at the time of caesarean section is a safe and effective procedure.2,10–21 the experience of different authors who have performed caesarean myomectomies is presented in table 2, including the present series. roman et al. compared the outcomes of 111 patients who had had myomectomy at caesarean with 257 patients who had undergone caesarean alone. no significant difference was found in the incidence of intraor postoperative complications between the 2 groups;11 however, accurate conclusions cannot be drawn from that study as only 22.7% of the patients had fibroids greater than 6 cm in diameter (median 3.5 cm). kaymak et al. compared 40 patients who underwent myomectomy at caesarean section with 80 patients with myomas who underwent caesarean section alone. the mean size of the fibroids removed was 8.1 cms compared to 5.7 cms in the controls. the authors found no significant difference in the incidence of haemorrhage (12.5% in the caesarean myomectomy group versus 11.3% in the controls), postoperative fever, or frequency of blood transfusions between the 2 groups, and concluded that myomectomy during caesarean section is not always a hazardous procedure and can be performed by experienced obstetricians without any complications.2 ortac et al. reported 22 myomectomies during caesarean for large fibroids (>5 cm) and advocate it to minimise postoperative sepsis.10 in another study by burton et al., of the reported 13 cases of myomectomy at caesarean section, only 1 case had intra-operative haemorrhage and they concluded it to be safe in selected patients.14 a large retrospective case-control study by li hui et al. assessed the effectiveness, safety, complications, and outcomes of myomectomy during caesarean section in chinese women with fibroids antedating pregnancy.20 the study group of 1,242 pregnant women with fibroids who underwent myomectomy during caesarean section was compared with 3 control groups: 200 pregnant women without fibroids (group a), 145 pregnant women with fibroids who underwent caesarean alone (group b), and 51 pregnant women who underwent caesarean hysterectomy (group c). no significant differences were noted between lovina s m machado, vaidyanathan gowri, nihal al-riyami and lamya al-kharusi clinical and basic research | 195 the groups in the mean haemoglobin change, the frequency of haemorrhage, postoperative fever, or the length of hospital stay. these findings corroborate the fact that myomectomy during caesarean section is a safe, effective procedure not associated with significant complications. further strengthening the increasing trend towards caesarean myomectomy is yet another case series by hassiakos et al.21 they compared 47 pregnant women with fibroids who underwent caesarean myomectomy with 94 pregnant women with fibroids who had caesarean section alone. myomectomy added a mean operating time of 15 minutes to the caesarean section. no patient had a hysterectomy, postpartum complications, or blood transfusion. the length of hospital stay was comparable in both groups; hence, these authors also generally recommended performing the procedure. yuddandi reported removal of a 33.3 × 28.8 × 15.6 cm fibroid at caesarean with an intraoperative blood loss of 1,860 ml, necessitating blood transfusion.22 leanza et al. and igwegbe et al. have also reported large myomas removed at caesarean section.23–24 in our series of 8 patients, 5 lost less than 1.5 l of blood and there was no significant postoperative morbidity. the patient with a blood loss of 3,200 ml had the largest myoma in this series (10 x 12 cm) which showed evidence of degeneration and also had atonicity of the uterus necessitating a higher dose of oxytocin, carboprost, and a blood transfusion. since the fibroid was on the right anterior lower segment, a low vertical incision was used. the large size of the fibroid and atonic uterus led to the increased haemorrhage. there were no postoperative complications. despite the majority of the patients having large myomas and 50% being intramurally located, no hysterectomy was required in any patient. stepwise devascularisation was necessary in one case. the size of the fibroids was confirmed by the pathology reports, and changes like haemorrhage, infarction, calcification, and hyaline degeneration were seen in 4 fibroids. myomectomy added 15 minutes to the operating time and 1 day to the hospital stay but there was no significant postoperative complication. none of the patients had postoperative sepsis. the limitations of this study are the small sample size and the retrospective nature of the study. conclusion in conclusion, patient selection is crucial in caesarean myomectomy. large fundal intramural fibroids should be intuitively avoided. intramural myomectomy should be performed with caution. fibroids obstructing the lower uterine segment or accessible subserosal or pedunculated fibroids in symptomatic patients can be safely removed by experienced surgeons. the message is that what was once considered taboo should now be reconsidered. measures to minimise blood loss, like preoperative placement of uterine artery, balloon catheters, uterotonic drugs, uterine artery ligation, uterine tourniquets, stepwise devascularisation, and post-caesarean uterine artery embolisation would optimise outcomes and significantly decrease the chance of hysterectomy. the time is right to recommend caesarean myomectomy in selected patients in well-equipped tertiary settings, which could also have a positive bearing on future reproductive outcomes. c o n f l i c t o f i n t e r e s t no funding was received for this study and the authors declared no conflict of interest. references 1. muram d, gillieson ms, walters jh. myomas of the uterus in pregnancy: ultrasonographic follow-up. am j obstet gynecol 1980; 138:16–9. 2. kaymak o, ustunyurt e, okyay re, kalyoncu s, mollamahmutoglu. myomectomy during cesarean section. int j gynecol obstet 2005; 89:90–3. 3. hasan f, armugam k, sivanesaratnam v. uterine leiomyomata in pregnancy. int j gynecol obstet 1990; 34:45–8. 4. davis jl, ray-mazumder s, hobel cj, baley k, sassoon d. uterine leiomyomas in pregnancy: a prospective study. obstet gynecol 1990; 75:41–4. 5. rosati p, exacoustas c, mancuso s. longitudinal evaluation of uterine myoma growth during pregnancy. j ultrasound med 1992; 11:511–5. 6. myerscough pr. pelvic tumors. other surgical complications in pregnancy, labor and the puerperium. in: munro kerr’s operative obstetrics. 10th ed. london: baillière tindall publications, 1982. pp. 203–411. 7. katz vl, dotters dj, droegemueller w. complications of uterine leiomyomas in pregnancy. obstet gynaecol 1989; 73:593–6. caesarean myomectomy feasibility and safety 196 | squ medical journal, may 2012, volume 12, issue 2 8. howkins j, stallworthy j. in: bonney’s gynaecological surgery. 8th ed. london: baillière tindall publications, 1974. p. 421. 9. exacoustos c, rosati p. ultrasound diagnosis of uterine myomas and complications in pregnancy. obstet gynecol 1993; 82:97–101. 10. ortac f, gungor m, sonmezer m. myomectomy during cesarean section. int j gynecol obstet 1999; 67:189–90. 11. roman as, tabsh kma. myomectomy at the time of cesarean delivery: retrospective cohort study. bmc pregnancy and childbirth 2004; 4:14. doi: 10.1186/1471-2393-4-14 12. sapmaz e, celik h, altungul a. bilateral ascending uterine artery ligation vs. tourniquet use for haemostasis in cesarean myomectomy: a comparison. j reprod med 2003; 48:950–4. 13. cobellis l, florio p, stradella l, lucia ed, messalli em, petraglia f, et al. electro-cautery of myomas during cesarean section: two case reports. eur j obstet gynecol reprod biol 2002; 102:98–9. 14. burton ca, grimes da, march cm. surgical management of leiomyoma during pregnancy. obstet gynecol 1989; 74:70. 15. kwon sy, kim th, jeong jh, lee cn. is myomectomy safe during cesarean section? korean j perinatol 2003; 14:154–9. 16. ehigiegba ae, ande ab, ojobo si. myomectomy during cesarean section. int j gynecol obstet 2001; 75:21–5. 17. ahikari s, goswami s. cesarean myomectomy: a study of 14 cases. j obstet gynecol india 2006; 56:486–8. 18. umezurike c, feyi-waboso p. successful myomectomy during pregnancy: a case report. reprod health 2005; 2:6. 19. omar sz, sivanesaratnam v, damodaran p. large lower segment myoma-myomectomy at lower segment cesarean section: a report of 2 cases. singapore med j 1999; 40:109–10. 20. li h, du j, jin l, shi z, liu m. myomectomy during cesarean section. acta obstet gynecol scand 2009; 88:183–6. 21. hassiakos d, christopoulos r, vitoratos n, xarchoulakou e, vaggos g, papadrias k. myomectomy during cesarean section: a safe procedure? ann n y acad sci 2006; 1092:408-13. doi:10.1196/annals.1365.038 22. yuddandi n. management of a massive caseous fibroid at cesarean section. j obstet gynaecol 2004; 24:455–6. 23. leanza v, fichera s, leanza g, cannizzaro ma. huge fibroid (g. 3,000) removed during cesarean section with uterus preservation. a case report. ann ital chir 2011; 82:75–7. 24. igwegbe ao, nwosu bo, ugboaja jo, monago en. inevitable cesarean myomectomy. niger j med 2010; 19:233–5. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e155-156, epub. 7th apr 14 submitted 16th feb 14 revision req. 18 feb 14; revision recd. 23rd feb 14 accepted 10th mar 14 department of ophthalmology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mujainisqu@hotmail.com متالزمة اسرتيج-فيرب دون حدوث ومحة الوجه انورادا جاني�س و عبد اهلل املجيني comment sturge-weber syndrome without facial nevus anuradha ganesh and *abdullah al-mujaini in this edition of squmj, koul et al. present a rare manifestation of sturge-weber syndrome (sws; online mendelian inheritance in man 185300) with parieto-occipital leptomeningeal angiomatosis and seizures, but without facial nevus or eye involvement.1 sws is a rare, sporadic, and congenital neurocutaneous disorder with an incidence of 1 in 50,000 live births.2 it is characterised by venouscapillary abnormalities which affect the skin in the distribution of the trigeminal nerve (nevus flammeus or port-wine stain [pws]), leptomeninges and the eye. for these reasons, it is often referred as encephalotrigeminal angiomatosis. the distinctive feature of sws is a facial cutaneous venous dilatation in the distribution of the ophthalmic (v1) and maxillary (v2) branches of the trigeminal nerve. they are present at birth and, in contrast to capillary haemangiomas, do not resolve with age. sws is referred to as complete or type i when both the central nervous system is affected and facial angiomas are present.3 a child born with a pws on the face has approximately a 6% chance of having sws;4 this risk increases to 26% when the pws is located in the distribution of the v1 division of the trigeminal nerve.4 reports of patients with sws and central nervous system (cns) manifestations but without a pws nevus do exist in literature but these are rare.5,6 between 5–15% of patients with sws have leptomeningeal angiomatosis without cutaneous lesion or ocular abnormalities, and are referred to as type iii encephalofacial angiomatosis.3 in the brain, the angiomas are typically unilateral and located in the pial vessels of the parieto-occipital lobes of the brain on the same side of the head as the port-wine birthmark. the slow flow of blood through these vessels leads to hypoxia, cortical atrophy and subsequent calcification resulting in the characteristic gyriform hyperdensity seen in neuroimaging. consequent neurological manifestations include seizures, local neurological deficits including contralateral stroke and hemianopsia, behavioural anomalies and progressive intellectual impairment. seizures are often the presenting neurological symptom secondary to facial angioma and occur in nearly 75% of patients, with 75% of the seizures appearing in the first year of life.7 in the eye, choroidal vascular malformations (haemangiomas) are common, and may lead to degenerative changes of the overlying retina and serous retinal detachment. however, the principal sight-threatening complication is glaucoma which occurs in 58–71% of cases.8 the proposed mechanisms for glaucoma in sws include mechanical obstruction of the angle of the eye, increased episcleral venous pressure caused by episcleral arteriovenous shunts or hypersecretion of fluid by either the choroidal angioma or a ciliary body. congenital glaucoma in sws is almost always associated with the involvement of both eyelids by the pws. it is worthwhile discussing the pathophysiology of the neurocutaneous manifestations of sws as this can shed light on the underlying basis of the development of sws with cns manifestations without skin lesions. this requires an understanding of the normal pattern of the primitive cephalic venous plexus in gestation. during the end of the first trimester, there is a division of the primitive vascular system into an external portion that feeds and drains the facial skin and scalp, a middle portion investing the meninges and a deep portion that feeds and drains the brain. the proximity of the ectoderm, destined to form the upper portion of facial skin, to the portion of the neural tube that will form the parieto-occipital area of the brain during this early stage of vascular development may explain the noted association between parieto-occipital leptomeningeal angioma and the facial pws in sws.9 spontaneous somatic mutations occurring during this period of embryonic development and disrupting vascular development offer an explanation of the association of facial angioma and the abnormal vascularity of the sturge-weber syndrome without facial nevus e156 | squ medical journal, may 2014, volume 14, issue 2 ipsilateral brain. it is likely that a smaller defect, involving only the developing pial vascular structures of the occipital lobe, can result in an occipital leptomeningeal angioma without the facial pws in a small subset of patients with this syndrome. there have been reports of sws patients without a facial nevus with a frontal location of the leptomeningeal angioma.6,10 the lack of a facial nevus may be attributed to the noncontiguous nature of the more anterior vascular plexus with the developing upper facial ectoderm.6 a recent development has been the discovery of a somatic mutation in patients with sws confirming a long-standing hypothesis about the pathogenesis of this condition. whole-genome sequencing of dna from three patients with sws, followed by targeted sequencing in skin samples from 50 patients with sws, revealed a somatic mosaic-activating mutation in gnaq,11 which encodes a g-protein receptor for endothelin that has important roles in vasculogenesis. a review of the literature revealed isolated case reports pertaining to sws from the middle east,12,13 and one study from saudi arabia investigating the characteristics of glaucoma in patients with sws.14 the interesting medical image in this issue of squmj is important in this respect as it brings to attention a rare presentation of sws in an omani patient. efforts to characterise the neurological, ophthalmic and cutaneous features of sws in the indigenous population of oman through larger studies is likely to provide additional insights into this rare disease and will have important implications. references 1. koul r, renjith m, hamid rs. three-year-old girl with sturgeweber syndrome without facial nevus. sultan qaboos univ med j 2014; 14:145–6. 2. thomas-sohl ka, vaslow df, maria bl. sturge-weber syndrome: a review. pediatr neurol 2004; 30:303–10. 3. roach es. neurocutaneous syndromes. pediatr clin north am 1992; 39:591–620. 4. ch’ng s, tan st. facial port-wine stains – clinical stratification and risks of neuro-ocular involvement. j plastic reconstr aesthet surg 2008; 61:889–93. 5. gururaj ak, sztriha l, johansen j, nork m. sturge-weber syndrome without facial nevus: a case report and review of the literature. acta paediatr 2000; 89:740–3. 6. comi am, fischer r, kossoff eh. encephalofacial angiomatosis sparing the occipital lobe and without facial nevus: on the spectrum of sturge-weber syndrome variants? j child neurol 2003; 18:35–8. 7. comi am. advances in sturge-weber syndrome. curr opin neurol 2006; 19:124–8. 8. sharan s, swamy b, taranath d, jamieson r, yu t, wargon o. port-wine vascular malformations and glaucoma risk in sturgeweber syndrome. j aapos 2009; 13:374–8. 9. maiuri f, gangemi m, iaconetta g, maiuri l. sturge-weber disease without facial nevus. j neurosurg sci 1989; 33:215–8. 10. dilber c, tasdemir ha, dagdemir a, incesu l, odaci e. sturgeweber syndrome involved frontoparietal region without facial nevus. pediatr neurol 2002; 26:387–90. 11. shirley md, tang h, gallione cj, baugher jd, frelin lp, cohen b, et al. sturge-weber syndrome and port-wine stains caused by somatic mutation in gnaq. n engl j med 2013; 368:1971–9. doi: 10.1056/nejmoa1213507. 12. nandhagopal r, al-asmi a. a young adult with seizure and visual field defect. neurosciences (riyadh) 2011; 16:389–90. 13. delvi mb, takrouri ms. anesthesia for encephalo-trigeminal angiomatosis (sturge-weber syndrome). middle east j anesthesiol 2006; 18:785–90. 14. awad ah, mullaney pb, al-mesfer s, zwaan jt. glaucoma in sturge-weber syndrome. j aapos 1999; 3:40–5. squ med j, february 2012, vol. 12, iss. 1, pp. 120-123, epub. 7th feb 12. submitted 4th jul 11 revision req. 10th sep 11, revision recd. 23rd nov 11 accepted 30th nov 11 department of medicine, sultan qaboos university hospital, muscat, oman. corresponding author e-mail: kowhassan@btinternet.com معاجلة اْلِتهاب الشَّغاِف الَعدوائّي للصّمام األهبر بالبكترييا الزائفة الزجنارية باألدوية عند مريض غسيل الكلى كوثر�سلمان ح�سن، داوؤود الريامي امللخ�ص: التهاب ال�سغاف العدوائي عند مر�سى غ�سيل الكلى عدوى خطرية حتمل ن�سبة وفاة مرتفعة. عادة ما ي�سبب هذا الإلتهاب البكترييا اإيجابية اجلرام ومن النادر اأن ت�سببه البكرتيا �سلبية اجلرام. غالبا ما يت�سمن العالج الناجع ا�ستبدال ال�سمام امل�ساب جراحيا، بالإ�سافة اإىل ال�ستخدام طويل الأجل للم�سادات احليوية، بينما ُيَعد جناح العالج بامل�سادات احليوية وحدها اأمر نادر احلدوث. يف هذا التقرير ن�سف حالة التهاب ال�سغاف الَعدوائي بالبكترييا الزائفة الزجنارية يف مري�س على غ�سيل الكلى عولج بامل�سادات احليوية لوحدها. مفتاح الكلمات: الزائفة الزجنارية، التهاب ال�سغاف الَعدوائي، غ�سيل الكلى، املعاجلة بامل�سادات احليوية، تقرير حالة، ُعمان. abstract: infective endocarditis (ie) in patients on dialysis is a serious infection with a high mortality rate. it is usually caused by gram positive bacteria with gram negative organisms being relatively rare as a cause. recommended treatment usually involves surgical valve replacement and the extended use of antibiotics. successful treatment with antibiotics alone is rare. we report a case of ie caused by pseudomonas aeruginosa in a patient on dialysis treated solely with antibiotics. keywords: pseudomonas aeruginosa; infective endocarditis; dialysis; treatment, antibiotic; case report; oman. infective endocarditis of the aortic valve caused by pseudomonas aeruginosa and treated medically in a patient on haemodialysis *kowthar s. hassan and dawood al-riyami case report infective endocarditis caused by pseudomonas aeruginosa is rarely seen in clinical practice. it has been reported mainly in intravenous (iv) drug abusers.1,2 p. aeruginosa is also an occasional cause of nosocomial endocarditis, accounting for 10% of cases in one small intensive care unit (icu) series.3 it carries a very high mortality rate of 80% necessitating, therefore, early diagnosis and intervention. the clinical outcome of right-sided endocarditis has improved with cure rates reaching 84% while that of the left side remains 33%.4 this sub optimal outcome is partly due to increasing resistance to beta-lactams and aminoglycosides.1,4,5 fluoroquinoloes, on the other hand, seem to be more potent against pseudomonas.6,7 numerous studies have shown significantly better outcomes with combined medical/surgical treatment.8-11 we report a haemodialysis patient who developed aortic regurgitation following catheter related p. aeruginosa endocarditis and describe her medical management and the outcome. case report a 49 year-old omani woman on dialysis with a past medical history of hypertension, diabetes, coronary artery disease, and end-stage renal disease presented to our hospital with uraemia. she was started on maintenance haemodialysis via a right internal jugular tunnelled cuffed catheter. a week later she had placement of an arteriovenous fistula (avf). kowthar s. hassan and dawood al-riyami case report | 121 two weeks following the insertion of the catheter she developed fever and generalised weakness. blood cultures taken from the central line grew p. aeruginosa. she was treated with ciprofloxacin and tazocin. she improved on this treatment and the tazocin was changed to amikacin after each dialysis. subsequent surveillance blood cultures after 4 and 6 weeks of the first blood culture were negative. she was investigated with transthoracic echocardiography which reported no evidence of thrombi or vegetations. given that her avf was maturing and could be potentially used for dialysis only a month after the bacteraemia, the central line was kept for dialysis. however, one week later, before the line was removed, she presented with fever, generalised weakness, sore throat and dry cough. her examination revealed a temperature of 37.9°c, blood pressure of 180/70 mmhg, mild pedal oedema and no signs of inflammation on the skin overlying the tunnelled catheter, but mild crusting at the exit site. her body weight was 65 kg. her systemic examination was remarkable for a new diastolic murmur. her investigations reported normal white blood cell (wbc) count and her chest x-ray reported no pneumonia. she continued to be sick and febrile despite initial management of presumed community-acquired pneumonia. at this stage, a catheter related infection was presumed and she was treated with vancomycin and amikacin. the tunnelled catheter was removed as her avf was ready to be used for dialysis. blood cultures grew p. aeruginosa. transthoracic echocardiography (tte) showed a well-circumscribed small mass attached to the non-coronary and right coronary cusp of the aortic valve suggestive of vegetation [figure 1]. transoesophageal echocardiography showed a huge vegetation of 2 cm on the left and non-coronary cusps of the aortic valve with no aortic root abscess. the cardiothoracic surgeon suggested valve replacement in addition to medical management with ceftazidime and amikacin. however, the patient strongly refused the surgery. on medical treatment alone she showed a remarkable improvement. tte was done one month post antibiotics commencement. it showed evidence of severe aortic regurgitation (ar) and mobile vegetation attached mostly to the right coronary cusp. the large vegetation on the non figure 1: apical view transthoracic echocardiography scan showing large vegetation seen on the aortic valve. figure 2: apical view transesophageal echocardiography scan showing decrease in the size of previous vegetation. figure 3: short axis, aortic view echocardiography scan showing total clearance of the vegetation. infective endocarditis of the aortic valve caused by pseudomonas aeruginosa and treated medically in a patient on haemodialysis 122 | squ medical journal, february 2012, volume 12, issue 1 coronary cusp was no longer seen and only small vegetation was seen on the left corornary cusp [figure 2]. a repeat echocardiography 2 weeks later showed a mildly thickened aortic valve, but no vegetation [figure 3]. in the last follow-up, one year later, the patient continued to do well clinically. discussion pseudomonas bacteraemia is a nosocomial problem being the third most frequent cause of gram negative bacteraemia.12 our patient had a central line which was the culprit for her bacteraemia and subsequent endocarditis. endocarditis caused by this pathogen is very serious with a very high mortality rate.13 patients with left-sided valvular infections, often develop rapidly progressive symptoms that are due to either congestive heart failure or an embolism of large or medium-sized arteries. ring and annular abscesses are also frequent complications. pseudomonas endocarditis is associated with high mortality. this is explained by the fact that beta-lactams have a slow bactericidal effect on the organism and resistance to the drugs develops rapidly. thus, treatment of p. aeruginosa endocarditis usually necessitates the combination of antibiotics and surgery to achieve a cure.14 valve replacement was offered to our patient, but she persistently refused any surgical interventions. she was managed with a combination of ceftazidime (1 g three times a day) and amikacin (500 mg once/ day, on three days of week with dialysis, to achieve trough levels below 5 mg/l and peak levels between 20–30 mg/l). after ten weeks the vegetation had completely disappeared. medical treatment alone in left-sided infective endocarditis caused by p. aeruginosa was previously reported to be successful.15 conclusion we reported the cure of a case of endocarditis caused by p. aeruginosa with ceftazidime and amikacin. in the case of catheter related bacteremia with pseudomonas, the line should be removed as soon as possible. a c k n o w l e d g e m e n t we thank dr. hatem l farhan for his effort in translating the abstract into arabic. references 1. reyes mp, lerner am. current problems in the treatment of infective endocarditis due to pseudomonas aeruginosa. rev inf dis 1983; 5:314-21. 2. reyes mp, ali a, mendes re, biedenbach dj. resurgence of pseudomonas endocarditis in detroit 2006-2008. medicine (baltimore) 2009; 88:294–301. 3. gouello jp, asfar p, brenet o, kouatchet a, berthelot g, alquier p. nosocomial endocarditis in the intensive care unit: an analysis of 22 cases. crit care med 2000; 28:377-82. 4. bayer as, norman d, kim ks. efficacy of amikacin and ceftazidime in experimental aortic valve endocarditis due to pseudomonas aeruginosa. antimicrob agent chemother 1985; 28:781-5. 5. jimenz-lucho ve, saravoltaz ld, medelros aa, pohlod d. failure of therapy in ps endocarditisselection of resistant mutants. j inf dis 1986; 154:648. 6. auckenthiler rn, michea-hamzehpour m, perchere jc. in vitro activity of newer quinolones against aerobic bacteria. j antimicrob chemother 1986; 17:29-39. 7. chalkley lj, koornhof hj. antimicrobial activity of ciprofloxacin against pseudomonas aeruginosa, escherichia coli, and staphylococcus aureus determined by the killing curve method: antibiotic comparisons and synergistic interactions. antimicrob agents chemother 1985; 28:331-42. 8. middlemost s,wisenbaugh t,meyerowitz c. a case for early surgery in native left-sided endocarditis complicated by heart failure: results in 203 patients. j am coll cardiol 1991; 18:663-7. 9. dinubile mj. surgery in subacute endocarditis. ann intern med 1982; 96:650-9. 10. daas h, abuhmaid f, zervos m. successful treatment of candidia parapsilosis and pseudomonas aeruginosa infection using medical and surgical management in an injecting drug user with mitral and aortic valve endocarditis: a case report. j med case reports 2009; 3:6598. 11. ahmed w. multidrug resistant pseudomonas endocarditis. internet j infect dis. from: http:// www.ispub.com/journal/the-internet-journal-ofinfectious-diseases/volume-1-number-2/multidrugr e s i s t a n tp s e u d o m o n a s e n d o c a r d i t i s 1 . h t m l accessed: nov 2011. 12. dawson nl, brumble lm, pritt bs, yao jd, echols jd, alvarez s. left-sided pseudomonas aeruginosa endocarditis in patients without injection drug use. kowthar s. hassan and dawood al-riyami case report | 123 medicine (baltimore) 2011; 90:250–5. 13. ordóñez km, hernández oa, cortés ja, lópez mj, alfonso g, junca a. left-sided infective endocarditis caused by pseudomonas aeruginosa treated medically. biomedia 2010; 30:164–9. 14. national nosocomial infections surveillance (nnis) system. national nosocomial infections surveillance (nnis) report; data summary october 1986 to april 1996, issued may 1996. am j infect control 1996; 24:380. 15. gavin pj, suseno mt, cook fv, peterson lr, thomson rb jr. left-sided endocarditis caused by pseudomonas aeruginosa: successful treatment with meropenem and tobramycin. diagn microbiol infect dis 2003; 47:427–30. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 364-368, epub. 15th jul 12 submitted 20th sep 11 revision req. 2nd apr 12, revision recd. 30th apr 12 accepted 14th may 12 departments of 1anesthesiology & icu and 2paediatrics, delma hospital, delma island, united arab emirates. *corresponding author e-mail: zmsaeed4@gmail.com عملية إنعاش ناجحة لطفل خديج ذي وزن والدي شديد االخنفاض يف مستشفى جزيرة دملا اجملتمعي،دولة اإلمارات العربية املتحدة زهراء حممد �سعيد، عماد اإبراهيم �سرب امللخ�ص: تعد عملية اإنعا�ض الأطفال اخلدج ذوي الأوزان الولدية �سديدة النخفا�ض مع�سلة كبرية تواجه ذوي الخت�سا�ض بهذا املجال حمدود بعيد، جمتمعي م�ست�سفى يف اأجريت لو فيما الطبية الرعاية ملانح اآخر حتديا هذه الإنعا�ض عملية ت�سيف وقد م�ست�سفى. اأي يف من حيث الإمكانات التقنية والب�رسية والكوادر ال�سحية. نعر�ض هنا حالة اإنعا�ض ناجحة لطفل خديج مولود يف الأ�سبوع 23 من احلياة اجلنينية وبوزن ولدي 650 غرام، مب�ست�سفى جزيرة دملا املجتمعي يف دولة الإمارات العربية املتحدة. وعلى الرغم من املحدودية الن�سبية يف الإمكانات لإجراء عملية اإنعا�ض كهذه، فاإن القرارات الأخالقية ال�رسيعة التي مت تخاذها عند النظر يف اإنعا�ض هذا اخلديج الذي كان يف حالة حرجة، كانت هي احلل الأمثل لتجنب امل�ساكل الع�سبية والرئوية التي من املمكن اأن حتدث على املدى البعيد، كما �ساهمت يف احل�سول على طفل يتمتع بال�سحة. مفتاح الكلمات: ر�سيع، وزن ولدي �سديد الإنخفا�ض، متالزمة �سيق التنف�ض، طفل وليد، ل�سيء عن طريق الفم، تقرير حالة، دولة الإمارات العربية املتحدة. abstract: because of their physical size and physiological immaturity, resuscitation of extremely very low birth weight premature infants is a big dilemma for neonatologists in any hospital. the resuscitation may present an additional challenge to the caregiver if it is undertaken in a remote community hospital with limited technical facilities and health personnel. we present the case of successful resuscitation of a 23-weekold premature infant, with a birth weight of 650 g, at delma island community hospital, united arab emirates. despite the comparatively limited facilities for such a resuscitation, the rapid ethical decisions made when considering the resuscitation of such a borderline viable fetus, were key in avoiding long term neurological and pulmonary problems and contributed to the outcome of a healthy infant. keywords: infant, extremely low birth weight; infant, very low birth weight; respiratory distress syndrome, newborn. successful resuscitation of an extremely low birth weight premature infant in delma island community hospital, united arab emirates *zahra’a mohamed saeed1 and imad ibrahim shubbar2 case report the decision to resuscitate extremely low birth weight (elbw) infants (birth weight of less than 1 kg) and extremely premature infants (born between 22 and 25 weeks gestation) presents difficult ethical issues for caregivers and parents. in recent years, survival of infants born weighing less than 1,000 g has improved dramatically. as mortality of elbw infants has significantly decreased, concern has been expressed as to whether morbidity has followed the same pattern of improvement.1 adequate care for newborn with elbw is essential so as to prevent asphyxial lesions, which cause neonatal death, and neurological sequelae in those who survive, impairing both their quality of life and that of their families. delma is a small island, belonging to the abu dhabi emirate, in the extreme west of the united arab emirates (uae). it is about 210 km distant from abu dhabi. the island has a population of around 6,000–7,000 people.2 there is only one zahra’a mohamed saeed and imad ibrahim shubbar case report | 365 hospital on the island, with a capacity of 29 beds. it provides emergency services as well as specialised medical care.3 we report the survival of an elbw premature infant (23 weeks gestational age, birth weight 650 g) at delma hospital. it was the youngest and smallest infant ever resuscitated there which survived. this was due to quick decision making and the strict resuscitation action in the initial hours of the infant’s life. in spite of the relatively limited facilities, these rapid actions, taken before transferring the infant to a tertiary hospital, contributed to the outcome of a healthy infant. at present time, the procedures carried out during neonatal resuscitation include: maintaining the body temperature by way of heat treatment; maintaining airway permeability through correct head and neck positioning; aspiration of the mouth, nose, pharynx and, if necessary, of the trachea; mechanical ventilation using positive airway pressure with a balloon and mask, or balloon and tracheal tube; maintaining circulation by applying cardiopulmonary resuscitation and administering drugs or fluids. all these procedures are performed based on integrated evaluation of three signs: breathing, heart rate and colour.4,5 the use of antenatal steroids and the administration of exogenous surfactant to infants with respiratory distress syndrome (rds) have had a significant impact on overall survival rates in very low birth weight (vlbw) infants. reports suggest improved survival in elbw infants ≤750 g birth weight in the postsurfactant era.6 the minimum age of viability has been proposed to be 23 weeks’ gestation.7 case report a 28-year-old primigravida, with a history of infertility for more than 12 years, was admitted to the delivery room at 23 weeks gestation, with lower abdominal pain (which had started 9 hours prior to admission), suspected rupture of membranes and uterine contractions. a cardiotocography (ctg) was done to monitor the uterine contractions and fetal heart rate. a vaginal examination revealed 6 cm cervical dilatation which was also fully effaced and a cephalic presentation. the patient was confirmed to be in preterm labour. she was administered 12 mg betamethasone by intramuscular injection (im) and was instructed for nothing by mouth. blood and urine investigations were requested and the results were normal. informed consent for resuscitation of the neonate was obtained from the parents after discussion of the possible complications. the patient was moved to the operating theatre for spontaneous normal vaginal delivery, which was followed by placental curettage under general anaesthesia. the amniotic fluid was meconium-stained. a male neonate with elbw (650 g) was thus born by a normal vaginal delivery. he had no congenital anomalies, but was apnoeic, cyanotic, and heart rate was below 100/minute. the apgar score was 4 at 1 and 5 minutes of life [figure 1]. he was intubated with a no. 2.5 endotracheal tube, cardiopulmonary resuscitation (cpr) was started with controlled manual ventilation with 60% figure 1: photograph of the baby taken at birth in march 2010. figure 2: photograph of the baby taken at 8 months old. successful resuscitation of an extremely low birth weight premature infant in delma island community hospital, united arab emirates 366 | squ medical journal, august 2012, volume 12, issue 3 oxygen by ambu bag, and adrenaline 0.1 mg/kg with 1/1000 concentration was administered through the endotracheal tube. then he received 100 mg/ kg (2.5 ml) surfactant endotracheally. intravenous umbilical catheterisation was done. the patient developed severe bradycardia and cyanosis twice for which cpr was resumed with assisted ventilation, external cardiac massage and adrenaline 0.01 mg/ kg of 1/10,000 concentration was administered intravenously. he was transferred to the neonatal intensive care unit (nicu) by portable incubator. the parents were informed about the patient’s condition and the necessity of transferring the neonate to a tertiary hospital for further management. a nasogastric tube was inserted to deflate the patient's stomach, a portable chest x-ray showed findings concomitant with rds. body warming measures were also undertaken. a dramatic improvement in the patient’s condition was noticed about 15 mins after the administration of the second dose of surfactant given in a dose of 100 mg/kg endotracheally 12 hours after the first dose. oxygen saturation (spo2) started to increase gradually reaching levels ranging from 91–100% on 2 l/min. the heart rate was 125–148/ min, blood pressure (bp) 48/20–51/21, and body temperature between 34.7° c and 35.9° c. random blood sugar (rbs) was between 140 and 200 mg/dl. such ranges continued for more than 3 hours until the patient was transferred by the helicopter to a tertiary hospital, on manual ventilation by ambu bag with 2 l/min, oxygen flow, and in the incubator. all these primary resuscitation measures were carried out at the remote delma island hospital for over 15 hours until the infant’s transfer. the efforts of doctors and the available nursing staff were able to keep the infant alive during that critical period. discussion the decision as to whether an elbw neonate should be resuscitated or not is one of the most distressing situations that pediatric care providers have to face. the decision is multifaceted taking into account the ethical, moral, religious and legal views of the parents, the resuscitation team, and the community. in our case study, the resuscitation of this elbw infant was accomplished successfully in a community hospital. given that the technical and personal facilities were relatively limited for such a type of resuscitation, and that the infant’s weight was 650 g and he was 23 weeks gestational age, the decision to resuscitate was a great dilemma. the decision was taken and informed consent obtained from the parents before delivery and after discussion of the possible potential complications, taking into consideration that the baby was precious since the mother had been infertile for 12 years. ethically, physicians have a duty to inform the parents of newborns about resuscitation procedures and the potential outcomes for their preterm infants as well as to obtain their consent to proceed with resuscitation and treatment. the process of informing is inherently flawed by the uncertainty of predicting outcomes and is often flawed by the urgency and tension of the potential parents’ situation.8 the other point of critical importance in the decision is that resuscitation should be undertaken urgently and aggressively second by second, because the care administered in the first critical hours of life can have a direct effect on the lifelong outcomes of the elbw infant. there may be a ‘golden hour’ (gh) of care for elbw infants that begins with delivery until admission to the nicu.6 the gh initiative goes beyond looking to change one clinical outcome. instead, it looks at a process for providing care to implement multiple evidencebased practice initiative “bundles” that could improve short and long term outcomes for elbw infants. during these initial hours, the clinician is faced with complex decisions based on multiple systems that require attention—knowing that a lack of care in these first minutes of life can translate into life-long medical problems. the promise of the gh in neonatal care lies not only in evidence-based treatment, but also in team structure, communication, and proficiency. health care providers are faced with a multitude of tasks (cognitive, procedural, communicative, and managerial) that must be completed in a relatively short time. neonatal resuscitation is complex and takes place in an extremely dynamic and complex environment.6 the pediatric profession has widely acknowledged that there exists a certain ‘grey zone’ of gestational ages, wherein it is not clear whether resuscitation should be attempted, because of the high likelihood of death or disability. within that zahra’a mohamed saeed and imad ibrahim shubbar case report | 367 grey zone, it has been recommended that informed parents be permitted to choose. there is some variation in opinion regarding the exact location of the margins of the grey zone, but in the united states and the united kingdom, at least, 23 weeks generally falls within it.9,10 literature data confirm that resuscitation should not be indicated for patients aged less than 23 weeks or weighing less than 400 g.4,7,11after this period, if time allows, parents should be informed about the implications of resuscitation procedures, including the possibility of sequelae from diseases associated with a specific gestational age.5 moreover, the previous outcome of newborns in the neonatal unit should also be included in resuscitation decisions.12 each clinical case must be analysed separately, always trying to establish adequate communication between parents, obstetricians and paediatricians in order to decide whether resuscitation is appropriate. most physicians agree that the delivery room is the proper place for life and death decision.13 some surveys of parents have indicated that the vast majority of parents prefer resuscitation to be initiated even when there is great uncertainty about the outcome.14 a recent survey of new england neonatologists sought to describe current practices of delivery room decision making and prenatal consultation at the border of viability. given a hypothetical scenario of impending delivery of a 23.5 to 24.5 week preterm infant of appropriate weight for gestational age, more than three-quarters of neonatologists believed that they and the parents should make the final decision together.6 it seems advisable to recommend that resuscitation should be performed if the diagnosis of gestational age has not been previously established. the “wait and see” strategy before starting resuscitation should be eliminated, since a delay in the procedures can cause cold stress injury, hypoglycemia, hypotension and hypoxaemia in newborn infants, increasing mortality and morbidity.13 the body temperature of premature infants drops precipitously after birth. hypothermia after admission is a risk factor for mortality in preterm infants and is associated with acid–base abnormalities, respiratory distress, necrotising enterocolitis, and intraventricular haemorrhages. cold stress in elbw infants, who are at increased risk for hypothermia, can be significantly reduced by controlling environmental temperature and using wraps. an early complication of extreme prematurity is respiratory distress caused by surfactant deficiency. the incidence of chronic lung disease can be significantly reduced by standardising practice, ensuring early administration of surfactant, and developing a ventilation protocol.15 another ethical aspect that should be considered is the time for discontinuation of resuscitation procedures in the delivery room. literature data reveal that the resuscitation of a newborn after 10 minutes of asystolic cardiac arrest resulting in survival, or survival without severe sequelae, is quite improbable.15,16 resuscitation should be suspended after 15 minutes of absent heart rate despite the appropriate use of all resuscitation procedures available.7,11 most clinicians agree that some infants are so immature that initiating resuscitation is futile, whereas others think that not initiating resuscitation is unacceptable. uncertainty exists, however, for infants between these 2 extremes, when it is unclear whether resuscitation is in the infant’s best interest.17 for these infants, selective resuscitation on the basis of parental preference is often considered to be an appropriate option, and general guidelines for decision-making are commonly based on estimated gestational age.7,18 a recent summary of international guidelines concluded that an individual approach consistent with parents’ wishes should be considered for infants born at 23 to 24 weeks’ gestation.15,19 circumstances are important, of course, e.g. additional morbidity, in particular severe malformations. conclusion in our case study we were able to prove that the rapid decision and action is very important to keep elbw infants alive, without long life neurological or pulmonary problems, even with relatively limited medical facilities. standardising care to ensure consistency in practice improves care to elbw infants. it is essential that we continue to work as health care teams to decrease morbidity and mortality among such infants. we should also take into consideration the importance of the golden initial hour of elbw successful resuscitation of an extremely low birth weight premature infant in delma island community hospital, united arab emirates 368 | squ medical journal, august 2012, volume 12, issue 3 infant resuscitation which should be undertaken aggressively and without delay. it provides a framework for training and team development that improves outcomes and care to some of our most vulnerable babies. the infant reported here is now over a year and a half old [figure 2]. he is developing normally without obvious neurological deficits. c o n s e n t informed consent had been obtained from the parents to publish this article and the photographs. references 1. al lamki z, hemani r, mathew m, rahman a, kumari r. the smallest miracle baby that survived in oman. sultan qaboos university med j 2003; 5:45– 8. 2. location of delma island. from: www.adias-uae. com/dalma.html accessed: october 2006 3. abu dhabi health services. from: http://www.seha. ae/seha/ar/pages/hospitalinfo.aspx. accessed: may 2012. 4. national institutes of health: national institute of child health and human development neonatal research network. extremely preterm birth outcome data. from: http://www.nichd.nih.gov/ about/org/cdbpm/pp/prog_epbo/). accessed: nov 2008. 5. hussain n, rosenkrantz ts. ethical considerations in the management of infants born at extremely low gestational age. semin perinatol 2003; 27:458–70. 6. bastek tk, richardson dk, zupancic jaf, burns jp. prenatal consultation practices at the border of viability: a regional survey. pediatrics 2005; 116:407– 413. 7. american academy of pediatrics. neonatal resuscitation textbook. elk grove village (il): american academy of pediatrics and american heart association, 2006. pp. 9-5–9-6. 8. higgins rd, delivoria-papadopoulos m, raju tnk. executive summary of the workshop on the border of viability. pediatrics 2005; 115:1392–6. 9. niermeyer s, kattwinkel j, van reempts p, nadkarni v, phillips b, zideman d, et al. international guidelines for neonatal resuscitation: an excerpt from the guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: international consensus on science. pediatrics 2000; 106:e29. 10. kattwinkel j. textbook of neonatal resuscitation. 4th ed. elk grove village (il): american academy of pediatrics, american heart association, 2000. 11. roberts d, dalziel s. antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth”. cochrane database systematic reviews 2006; 3: cd004454. pmid 16856047. 12. streiner dl, saigal s, burrows e, stoskopf b, rosenbaum p. attitudes of parents and health care professionals toward active treatment of extremely premature infants. pediatrics 2001; 108:152–7. 13. serenella m, donzelli g. perinatal care at the threshold of viability: an international comparison of practical guidelines for the treatment of extremely preterm births. pediatrics 2008; 121:70. 14. ginsberg hg, goldsmith jp. controversies in neonatal resuscitation. clin perinatol 1998; 25:1–15. 15. lee s, penner p, cox m. comparison of the attitudes of health care professionals and parents toward active treatment of very low birth weight infants. pediatrics 1991; 88:110–14. 16. jain l, ferre c, vidyasagar d, nath s, sheftel d. cardiopulmonary resuscitation of apparently stillborn infants: survival and long-term outcome. j pediatr 1991; 118:778–82. 17. nuffield council on bioethics. critical care and decisions in fetal and neonatal medicine: ethical issues. london: nuffield council on bioethics; 2006. from:www.nuffieldbioethics.org/go/ourwork/ neonatal/introduction. accessed: oct 2008. 18. yeo cl, tudelope dl. outcome of resuscitated apparently stillborn infants: a ten year review. j paediatr child health 1994; 30:129–33. 19. international liaison committee on resuscitation (ilcor). the international liaison committee on resuscitation (ilcor) consensus on science with treatment recommendations or pediatric and neonatal patients: neonatal resuscitation. pediatrics 2006; 117:e955-77. epub 2006 apr 17. from: www.pediatrics.org/cgi/content/full/117/5/e978 accessed: apr 2012. body image and self-esteem among female nursing students in three different arab countries nabila taha,1 essmat mansour,2 amal sobhy,3 entisar younis,4 1 assiut university, 2 tanta university, 3,4 port-said university, 3,4 egypt e-mail: dr.essmat@hotmail.com current western culture promotes standards of beauty and success which focus on physical attractiveness. these standards can create feelings of inadequacy and body dissatisfaction. traditionally, women have responded most strongly to cultural messages of bodily attractiveness, thereby experiencing greater body dissatisfaction than men. failure to achieve the ideal has been shown to lead to decreased self-esteem which compounds body dissatisfaction and body image disturbance. this study aimed to investigate the level of body image and self-esteem among three communitybased samples from riyadh, saudi arabia;, hadhramout, yemen, and assiut, egypt. 300 students were recruited, 100 per country. the study was carried out in three different faculties of nursing: riyadh female health science college in saudi arabia, hadhramout university of science and technology in yemen, and at assiut university in egypt. tools for data collection included the body image scale developed by el-desouki. this scale consists of 20 statements about positive and negative sensations of body image. also used was the rosenberg self-esteem scale which consists of 10 statements about positive and negative self-esteem. finally, an interview questionnaire, developed by the investigators, included information about students’ ages, residence, marital condition, economic condition, parents’ education level, number of brothers and sisters, and their sibling order. results of this study revealed that 86% of students in al-riyadh, 84% from assiut, and 73% from hadhramout had positive self-images. the majority of the subjects had high self-esteem (78% in alriyadh, 96% from assiut and 84% from hadhramout). it also found that 79.8% of the subjects with a positive body image had high self-esteem compared to only 20.2% of subjects with a negative body image had high self-esteem. in conclusion, a high level of self-esteem positively correlated with body image. age, parents’ level of education, marital status, and number of brothers and sisters significantly correlated to body image and self-esteem. this study recommended that the importance of developing a positive body image and healthy diet habits is crucial. nurses’ orientation towards lifelong learning: a case study of uganda’s national hospital jk muliira, c.etyang, ib kizza, rs muliira e-mail: jkmuliira@gmail.com the quality of nursing care in developing countries is poor and improvements via continuing education programmes are underway. nurses’ orientation towards lifelong learning (nolll) has not been explored despite its potential effect on the success of such programmes. the jefferson’s scale of physician lifelong learning (jsplll) was used to measure nolll among 200 nurses at uganda’s national hospital. most of the participants had fair orientation (52%) towards lifelong learning (lll), with a jsplll mean score = 36.8 ± 7.2, and rated their skills in self-directed learning as good or excellent (44%). reported barriers to lll were patient work-load, lack of mentors, library resources and computer skills. nolll was significantly associated with professional experience (p = 804; 0.05), age (p = 804; 0.05) and education level (p = 0.01). in uganda, nolll is still sub-optimal and this has implications for successful implementation of continuing education programmes for nurses. مؤمتر ُعمان الدويل األول للتمريض االبتكارات يف جمال تعليم التمريض واملمارسة اليت تؤدي اىل الرعاية اجليدة جامعة ال�سلطان قابو�س، �سلطنة ُعمان; 29-28 نوفمرب 2011 first international nursing conference oman innovations in nursing education and practice leading to quality care sultan qaboos university, oman, 28–29th november 2011 abstracts 250 | squ medical journal, may 2012, volume 12, issue 2 first international nursing conference oman innovations in nursing education and practice leading to quality care postnatal exercise programme on the health related fitness of omani primi postnatal women hashem kilani, raghda shukri, judith noronha, jothi clara sultan qaboos university, muscat, oman e-mail: hakilani@yahoo.com despite the fact that exercise is beneficial to the general population and pregnant women specifically, there is insufficient evidence regarding the effect of postnatal exercise on the well-being of omani women. it may be beneficial to test the hypothesis that postnatal participation in a well-designed exercise programme will enhance omani women’s health. however, there are vast differences between theory and practice in implementing such an experiment in oman. this paper aims to elaborate the limitations and obstacles facing this type of project. methods design is crucial to counteract the dilemma of omani women; they want to be fit but have no sustainable commitment to an exercise programme. the study used a randomised controlled trial design. 50 postnatal women were recruited to the exercise group and 50 to the control group. selection criteria were based on normal vaginal delivery, willingness to participate, and residence in the muscat region. health-related fitness components, both before and after implementation of the exercise programme, were to include handgrip and leg strength tests; aerobic stepping; lower trunk flexibility measurements; calculation of body mass index, and performance in push-up and sit-up tests. in addition, a standardised questionnaire was used to assess both psychological and social wellbeing in the subjects. an exercise programme was recorded and distributed to motivate subjects to work out in their homes. it was anticipated that the omani women who participated regularly in the exercise programme would have greater health benefits than those women who failed to participate in an exercise regime. however, the investigators found that cultural barriers, plus husband and family customs, may have impeded their participation. therefore we highlighted the difficulties and barriers faced in accomplishing a postnatal exercise programme. in conclusion, details of the project, its value, limitations, and the process will be presented. dietary intake of high school students and factors affecting the next generation of nurses in the united kingdom: findings from a qualitative study peter norrie, de montfort university, uk e-mail: pnorrie@dmu.ac.uk from september 2012, all students who study to obtain a registration in nursing in the uk will undertake degree level programmes. nursing in the uk is changing. first, there is a move to change health care, placing more emphasis on community-based care. second, funding is changing, with budget-holding general practitioners being given more power and freedom to source care within their communities. a recent government paper has also proposed that nurses will coordinate and lead teams in a range of settings. taken together these can be described as positive drivers for nursing education, allowing an expanded and developed nursing role. there are, however, also a number of negative drivers. in the uk it is likely that the number of students trained to full registration will decrease in the near future. this is worsened by between 25 and 30 percent of students not completing their studies, which is a significant financial drain. using a grounded theory methodology, a set of semi-structured interviews was conducted throughout the uk with academics who are involved in student selection (n = 14). enquiry focused on two main areas: personal qualities required for new student nurses and experiences of selection in comparison to procedures. interviews were recorded, transcribed, and analysed using a constant comparative technique. a number of common themes emerged, the most vivid being a pragmatic concept we have entitled ‘orientation for professionalism’. this is composed of a number of conceptual elements which can be explored and evaluated during the selection process. these findings have been used within de montfort university through a process of positive reflection to produce a new student selection process which allows sensitive and differentiated assessment of students at the selection phase. perspectives will be shared regarding the implementation of this into practice. serum lipid peroxides, lipids, antioxidant defence system of erythrocytes and antioxidant vitamins in plasma of urban and rural egyptian men yousif elhassaneen1 and amal el-badawy2 1minoufiya university, shebin el-kom, egypt; 2department of nutrition & food science, college of nursing, sultan qaboos university e-mail: yousif12@hotmail.com lipid peroxides, which are produced inevitably from polyunsaturated fatty acids, may damage cell membranes and might accelerate cellular ageing. research results to date indicate that increased levels of lipid peroxides are associated with premature ageing, atherosclerotic process, hypertension, and cancer. serum lipid peroxides, thiobarbituric acid reactive substances (tbars), lipids, enzymatic and vitamin antioxidants, blood pressure, body mass index, and dietary intake in 200 urban men were compared with the same number of rural men. the haematological analysis for all subjects indicated that significantly higher levels of tbars, serum cholesterol and triglycerides (tg) were seen in urban men when compared with the rural men. the opposite was observed for the activities of antioxidant enzymes, glutathione peroxidase, superoxide dismutase, and catalase measured in the erythrocytes and antioxidant vitamins measured in plasma including a, c, and e. also, significant correlations were observed between tbars, serum cholesterol, and tg in the urban men. all of these findings suggest that significant elevation of tbars and lipids and a decrease in antioxidant enzymes and vitamins in urban men may be the result of urbanisation, including exposure to environmental and food pollutants. abstracts | 251 sultan qaboos university, oman, 28–29th november 2011 a descriptive study to determine the relationship between stress coping skills and cognition angel david and dr. s. kadhiravan, aragonda apollo college of nursing, india e-mail: angeldanadavid@gmail.com can the cognition of students be influenced to help them cope with stress? nurses experience high rates of stress. college students, including nursing students, feel more overwhelmed and stressed than before. are they equipped with adequate coping skills? this study aimed to assess and compare cognitive styles of nursing students, evaluate and compare their coping skills, and to explore the relationship between cognitive styles and stress coping skills. a crosssectional descriptive correlational design was used with 443 students (214 first year and 229 final year students pursuing general nursing and midwifery [gnm]). stress-coping skills were evaluated in its seven dimensions with the coping skills inventory. six different styles of cognition were assessed with the personal style inventory (test-retest reliability). the difference between the intuitive mode of cognitive style used by the first-year and the logical mode of cognitive style used by the third-year (gnm) students was statistically significant. also a statistically significant difference exists between first-year and third-year gnm students in some dimensions of coping skills such as reactivity to stress, the ability to relax, and self-reliance. additionally, there is significant correlation between the cognitive styles and stresscoping skills of students. stress-coping skills can be positively strengthened and stress can indeed be managed by means of cognitive strengthening. teachers should try their best to innovatively strengthen the resilience of students. jordanian nurses’ attitudes towards organ donation from brain dead patients in the icu ashraf hussein, ammar aroury, alaa dalal, najwa safi, bilal abdel ghani nursing management and critical care department, saudi arabia e-mail: ashraf_hussain2003@yahoo.com intensive care unit (icu) nurses play a major role in the transplantation process, and it is important to study their attitudes as jordan is experiencing an increase in cadaveric organ donation. no research has been done to assess jordanian icu nurses’ attitudes which are influenced by cultural backgrounds, social norms, and religious beliefs. this study explored jordanian nurses’ attitudes regarding organ donation from brain dead patients in the icu. the researchers used a cross-sectional descriptive design with a self-report questionnaire, developed by kim, fisher & elliott (2006), with convenience sampling to collect data from 216 icu nurses from nine private hospitals in amman, jordan. the survey period was from march to april 2007. the majority of nurses in our sample (92.6%) accepted brain death as true death. nevertheless, an obvious decrement (66.2%) is seen when it was related to supporting the donation from the brain dead patients. but when it was related to donating their organs and their family members’ organs, just 55.1% and 36.6%, respectively, agreed with the procedure. icu experience positively affected nurses’ attitudes in the organ donation process. there is a misunderstanding of the islamic point of view and following the fatwa of forbiddance among nurses. this research finding provided new insight into jordanian icu nurses’ attitudes towards organ donation from brain dead patients. they have, in general, some positive attitudes toward organ donation, but with mixed feelings, especially regarding themselves and their families. these findings could be effectively used in further research. general social function for elderly in geriatric homes nazar ali sheren doski college of nursing, erbil, iraq the study aimed to assess general social factors for the elderly in geriatric homes in jordan.. a sample of 155 residents was selected. the older americans resource and services (oars) social resource scale was used for data collection. the questions focused on the facilities’ residents’ family structure, patterns of friends and visiting, availability of a confidant, satisfaction with the degree of social interaction, availability of a helper in the event of illness or disability, and outing programmes. the findings revealed that the life expectancy for women is greater than for men. in respect to marital status, 38.1% of those surveyed were widows. only 15.5% of them were visited by their family more than 5 times a year. of respondents, 61.3% trust the home’s staff and 25.1% have friends in the home. in regard to loneliness, 66.5% feel lonely and need outside assistance. in regard to clients’ help, 42% did not know how to answer this question. of those polled, 51.6% needed help from with bathing, eating, or taking medication. in relation to trips outside the home, 54.8% had opportunities to go outside for trips, mainly for visiting family, friends, or for religious purposes. the study recommended that the home managers must focus on increasing social relations within the facility through more communication, increase visiting times between residents and their families and friends, help residents get out of the house and meet other people, and find ways for residents to become more involved in activities. pressure ulcer project initiatives shadya hamyar al-yaarubi, directorate general of health services, oman e-mail: sh8687@hotmail.com this paper presents the pressure ulcers project initiatives at khoula hospital. it will highlight implementation of the evidence-based risk assessment tool used for the prevention of pressure ulcers. within the complex and rapidly 252 | squ medical journal, may 2012, volume 12, issue 2 first international nursing conference oman innovations in nursing education and practice leading to quality care changing health care environment, it is essential that the best available evidence is obtained to inform the practice. the european pressure ulcer advisory panel (epuap) definition is an area of localised damage to the skin and underlying tissue caused by pressure, shear, friction and or a combination of these. they can develop within 2–6 hours as a result of a local breakdown of soft tissue due to compression between a bony prominence and an external surface. this presents a huge burden for families and the health care institutions in any country. the project is located at khoula hospital, a national tertiary trauma centre with approximately 485 beds. there were reports of pressure ulcers in patients directly admitted from home, transferred from other institutions or had acquired them during the course of their treatment. treatment and prevention use significant resources—disposables, equipment, surgery and nursing time. the project group comprised the author, plastic surgeon, dietician, clinical nurses, infection control nurse, social worker and physiotherapist. the main objective was to create awareness and train staff to assess, prevent and manage pressure ulcers. quarterly workshops were conducted locally and then opened to for any interested institutions including private hospitals. pressure ulcers are globally considered a quality of care indicator. a comparative study to assess the knowledge of women in reproductive age group regarding urinary tract infections susan thomas blessy, nursing institue, ministry of health, muscat, oman e-mail: blessyvinu@yahoo.com urinary tract infections (utis) affect women more frequently than men, and are among the most common bacterial infections encountered by primary care physicians affecting 20% of women between 15 and 45. 1 woman in 5 develops a uti during her lifetime and 4 out of 5 women will experience a recurrence of uti. for women, utis are significant health challenges at all stages of life. the study assessed the knowledge of women in urban and rural areas regarding utis and compared it to that of women in rural and urban areas, to identify the relationship between this knowledge and selected socio-demographic variables, and to develop a uti health education module. a simple random sampling technique by lottery method was used. participants included 75 women from rural areas and 75 from urban areas. data were collected using a structured interview schedule and analysis done by using descriptive and inferential statistics. in urban areas, 36% of women were very knowledgeable, while in rural areas no women were highly knowledgeable. in urban areas, a significant relationship was found between women’s ages and their level of knowledge, education, occupation, religion, marital status and history of utis. in rural areas, there was a significant relationship between their knowledge and education, occupation, caste and marital status. this indicates the need for a health education module to support health awareness campaigns. it will focus on prevention, early detection, and management of utis and thus indirectly help reduce the incidence of utis. fear of death among drug addict patients fares dardakeh, hamdy meslehy, fatima college of health sciences, united arab emirates e-mail: faresdradkeh@yahoo.com the primary aim of this study was, to examine the level of death anxiety (thanatophobia) in drug-dependent individuals attending the outpatient clinic in a psychiatric hospital, and to examine the relationship of demographic variables to death anxiety. 85 patients were recruited from outpatients at the psychiatric hospital in bahrain. the death anxiety scale was administered to assess death anxiety, and a clinical psychiatric interview was used to assess psychopathology. the mean age of the sample was 36.8 years (sd 8.8). all subjects who participated in the study were arabic males; the majority of them were primary school educated (67%) and single (48; 56.5%). the total mean death anxiety score of the drug abusers was high (3.52 ±. 95). one-way analysis of variance (anova) showed that there was no significant difference among the scores the drug dependents received on the death anxiety scale related to different groups of age, education, type of drug used, or the number of times of taking drugs per day. however, there was a significant difference in the level of control of use, marital status, duration of use, cigarette smoking, and level of religiosity. the results of this study indicated that the level of death anxiety is high, in general, among drug abusers and that being divorced, not actively practicing a religious faith, having at least 1–10 years or more than 20 years history of drug abuse, and smoking at least 20 or more cigarettes per day significantly increased the level of death anxiety. evaluating the effectiveness of a clinical preceptorship program for rns in jordan mahmoud alhussami, mohammed saleh, muhammad darawad, university of jordan, ammam, jordan e-mail: m.alhussami@ju.edu.jo a shortage of clinical nursing instructors and an absence of hospital staff in clinical teaching may lead to incompetent graduates and poor quality of patient care. this study aimed to design and implement a programme to train registered nurses (rns) as preceptors, and to set up a nursing preceptorship education programme. true experimental design was utilised. the sample consisted of 68 rns recruited randomly from governmental, private, and university hospitals. a socio-demographic data form and a questionnaire concerning nurses’ knowledge of preceptorship were developed for self-administration. the study results indicated that the difference between experimental (n=30, m=33/41, sd=4.5) and control (n=38, m=26/41, sd=4.6) groups after implementing abstracts | 253 sultan qaboos university, oman, 28–29th november 2011 the preceptorship programmeme is statistically significant (t=5.5, df=66, p <0.001). these results suggest the usefulness of implementing preceptorship educational programmes to improve preceptors’ knowledge regarding teaching strategies. the preceptorship programme significantle improved knowledge of clinical teaching. transforming education to strengthen health systems: the lancet commission report gillian white, directorate general of education & training, ministry of health, oman e-mail: drgillianwhite@yahoo.co.nz in 1910, the flexner report led to a series of studies about the education of health professionals. today, conspicuous gaps demonstrate a collective global failure in health systems as they struggle to manage complex and expensive demands on health professionals. professional education in the health sector has not kept up with increasing challenges. deficits can be seen in the disparity of abilities to meet health consumer needs, health worker shortages, the incongruent theory-practice nexus, a focus on tertiary rather than primary care, imbalances in the labour market, and a failure to improve health systems. health professions resemble silos, often acting in isolation or even in competition with each other. remote areas are underserved, and mass migration of health professionals is common, both away from their own countries and from the specialties they trained for. the lancet commission (20 professional academic leaders from around the world) took a global, interdisciplinary perspective, and a systematic approach to consider alliances between education and health systems. the commission concluded that positive health outcomes require new instructional and institutional designs. this presentation discusses reforms in professional health education, as highlighted in the findings from the lancet commission’s report, with a specific focus on the impact for nurses, in order to develop a new vision to transform omani health education. preceptorship: a shared journey between practice and education amaal saad al sabbagh, college of health sciences, bahrain e-mail: a.khashaba@gmail.com clinical teaching is a purposeful facilitation of learning in the clinical setting that includes the identification of learning needs, the establishment of curricular outcomes, arranging and planning learning opportunities, planning and delivering learning experiences, assessment, and feedback and evaluation. preceptorship is an enabling process structured to support learners in clinical practice to achieve specified outcomes within a stated period of time. preceptors help students develop a knowledge base and clinical skills, and are described as experienced nurses who facilitate and evaluate student learning in clinical work over a predetermined amount of time, in addition to their regularly assigned nursing functions. serving as resource people and role models in one-to-one relationships, preceptors introduce students to the nursing role through direct involvement in the teaching-learning process. in 2004, the nursing division at the college of health sciences in bahrain developed a preceptor programme that provided opportunities for reflection, critical thinking, and discussions between preceptors and preceptees. it also helped to strengthen clinical learning experiences for students. this presentation summarises the benefits of preceptorship, outlines preceptor responsibilities and qualities, discusses the process of preceptor selection and role preparation, and details the evaluation system in the bahrain college of health sciences. first year student nurses experience a new beginning through problem based learning anne fahy, university of limerick, limerick, ireland e-mail: anne.fahy@ul.ie nursing education in ireland and internationally is increasingly under pressure to focus on developing nurses who are equipped to work in a rapidly changing, multicultural environment influenced by fiscal constraints and technological advances. the delivery of health care is becoming more complex and requires that professional nurses are proficient critical thinkers, problem solvers and self-directed learners. problem-based learning (pbl) is promoted as a means to nurture and facilitate critical thinking and self-directed learning skills among nursing students. the concept of pbl is well-established in the professions of medicine, engineering, law, and nursing in n. america and the uk, and is frequently referred to as a total approach to education. pbl is an innovative student-centred approach that teaches a multitude of strategies critical for success in the 21stcentury. nurse educators must develop the necessary skills and knowledge to integrate the theory of pbl into the curriculum, and evaluate teaching strategies that successfully prepare knowledgeable, competent, and professional graduates. these qualities are reflected as sound clinical judgements that result in quality care administered by skilled practitioners. this presentation shares lessons learnt from introducing a pbl approach for first-year student nurses. written case study scenarios presented to a class facilitated transformational learning as the students engaged in self-directed inquiry and critical thinking. small groups organised the information and identified relevant concepts as they analysed and evaluated all viewpoints. multiple perspectives from both personal experience and theory enhanced the discussion and students became actively involved with the case scenario, related to authentic professional practice. nurse education programmes should provide opportunities for students to develop 254 | squ medical journal, may 2012, volume 12, issue 2 first international nursing conference oman innovations in nursing education and practice leading to quality care these skills and abilities. application of cognitive critical thinking skills in the nursing process by nursing students chandrani isac, anandhi amirtharaj, anitha thanka, sheila melba d’souza, college of nursing, sultan qaboos university, oman e-mail: chandu@squ.edu.om evidence-based nursing practice focuses on the need for nurses to demonstrate orderliness, diligence, patience, reasonableness, persistence, willingness, flexibility, and precision when dealing with health care issues. student who aspire to become competent nurses are geared by nurse educators to overcome challenges and organise and implement patient care behaviours. knapp states that ‘it is in the application of nursing process that a nurse becomes proficient at critical thinking’. literature increasingly points at the need to infuse critical thinking into clinical education scenarios. in clinical nursing education the learner is able to marry the theoretical component with practice using the nursing process approach. this approach is a powerful scientific vehicle to facilitate critical thinking. this study was descriptive. data were collected using a tool, adapted from facione’s 1990 core ccts. the sub-skills investigated were inference, recognition of assumptions, deduction, interpretation, and evaluation. 60 nursing care plans were drafted by 2 levels of students. the results showed that there were significant differences in the use of ccts by nursing students. a major theme was that the nursing process compels students to apply ccts. there was a significant difference in the application of ccts between the 2 levels of nursing students. when nursing students are helped to identify and integrate ccts in nursing process, their critical thinking skills become functional and lead to sucessful implementation in clinical practice. the influence of academic nurse role ambiguity and role conflict on organisational claimant in saudi arabia nazik ma zakari, college of nursing, king saud university, saudi arabia e-mail: nzakari@ksu.edu.sa higher education in saudi arabia (ksa) was established to enhance the nation’s growth and well-being. the ksa’s nursing faculty’s mission covers teaching, research, and community service. the interaction of these factors may influence the academic setting and impact teaching nurses’ roles. this study aimed to examine the influence of academic nurses’ roles, and the ambiguity and role conflicts within institutions in ksa. a non-experimental, descriptive, crossaction correlation was conducted in the ksa’s three oldest and largest universities. full-time nursing instructors were recruited to participate in the study. all respondents completed the role conflict and role ambiguity scale. in addition, the organisational climate description questionnaire of higher education was used for data collection. selfreported survey procedures were used to collect the study data. descriptive procedures and pearson‘s product-moment correlation coefficients were used. the majority of participants were expatriates with a mean age of 36.86 years. the results revealed that the role ambiguity mean of nursing teachers = 29.88 while the role conflict mean = 35.26. in addition, the results showed that intimacy received the lowest mean score in the category of organisational climate. role ambiguity positively correlated with all dimensions of organisational climate. however, only role conflict positively correlated to disengagement. this result suggested that the nursing faculty faced role conflict and ambiguity. they also suggest that ksa’s nursing faculty have different perceptions of what their roles are compared to their colleagues or dean. faculty members experience deliberation, disengagement, and lack of intimacy in the academic setting. these findings have negative implications for a healthy workplace. deans should make an effort to match institutional and individual goals, and open discussions should take place between administrators and faculty about role expectations, criteria for promotion, and other institutional rewards. critical thinking: teaching for saliency and priority setting loucine m. huckabay, school of nursing, california state university long beach, california, usa e-mail: huckabay@csulb@edu implementation of critical thinking in caring for patients and their families comes through determining what the needs are, and then prioritising those needs based on saliency, meaning, and determining what is of most importance, or is most urgent now. setting priorities based on saliency is an acquired behaviour that teachers can teach and students can learn. teaching strategies that enable the acquisition of these behaviours include building upon prior knowledge, conducting guided inquiry, and reflecting on practice. this session is devoted to expanding and implementing these strategies through case studies and interactive small group discussions. perceptions of nursing science students regarding factors which hamper their motivation jacoba johanna van der colff, college of nursing, squ, muscat, oman e-mail: drjj@squ.edu.om this research originated from the observation that the motivation of nursing science students gradually declines during the course of their training. according to the literature, nursing science lecturers play a vital role in motivating their abstracts | 255 sultan qaboos university, oman, 28–29th november 2011 students. a qualitative research design was applied. purposeful voluntary samples were taken. the focus group technique was the research method. factors which hamper the motivation of nursing science students are presented: the overload of the nursing training programmes; unsatisfactory relationships with nursing science lecturers, and unsatisfactory relationships and circumstances in the clinical situations. recommendations regarding solutions are offered. the influence of a bsc. in nursing on professional practice dianne watkins, school of nursing and midwifery studies, cardiff university, wales, uk e-mail: watkinssd@cf.ac.uk cardiff university, the ministry of health in oman, and the oman specialised nursing institute developed a bachelor of science (bsc) in nursing studies for qualified nurses, delivered in oman. the first cohort commenced in may 2009; a second cohort in september 2010, and a third in september 2011. a longitudinal research study was established to explore nurses’ and managers’ perceptions of the effects of a bsc in nursing on professional development and practice, and to identify factors that influenced the implementation of new learning. preliminary findings from phase 1 are presented. this qualitative study collected data through focus groups and interviews. one focus group consisted of students nearly having completed the course. interviews with a random selection of ten students and ten managers took place six months later. data were transcribed using a ‘template approach’ and emerging themes and findings were agreed upon by a research team. early results indicate that the bsc has developed the evidence-based practitioner, who is able to search for evidence, critique research, and apply findings to practice. confidence, leadership, and change management skills improved and many nurses were promoted to senior positions. factors that inhibited the implementation of new learning were time, staff shortages, the culture of nursing, and resistance by other staff. facilitating factors included support of managers and a thirst by self and others to further professionalise nursing. nurses felt able to stand up for the profession and to talk with doctors on the same professional standing. educating nurses at degree level will develop the individual and further develop nursing as a profession in oman as well as improve care to patients by evidence-based practice. assessing clinical learning environment for baccalaureate nursing students in muscat melba sheila d’souza, ramesh venkatesaperumal, anandhi amirthraj, anitha thanka, chandrani isac, college of nursing, sultan qaboos university, muscat, oman e-mail: melba@squ.edu.com the quality of the clinical learning environment/placement is an essential factor in determining the quality of nursing students’ clinical experience/ learning. this paper reports an evaluation of the clinical learning environment for baccalaureate nursing students in oman based on the cognitive and socio-emotional aspects of the learning process. an exploratory study of nursing students’ perceptions of their learning environment was carried out using the clinical learning environment inventory (clei) derived from a comprehensive review of literature. after a pilot study, the instrument was administered to 100 undergraduate nursing students from 2 cohorts of the nursing programme in 2011 in sultan qaboos university. inferential statistics and multiple regressions were computed. the students perceived their clinical learning environment as good. some students were extremely satisfied (90%) with activities done on the ward, while others reported less satisfaction (80%). most of the students (92%) agreed that practical work experience was useful. providing an effective and productive clinical experience is vital in preparing nursing students to become competent clinicians. the clei offers a useful measure to explore nursing students’ satisfaction with 2 aspects of clinical experience: clinical facilitator support of learning and the clinical learning environment, and is considered useful for assessing learning environments in clinical settings. writing-to-learn as a learning strategy: attitude of omani nursing students clara jj, shreedevi b, venkatesaperumal r, shukri r college of nursing, sultan qaboos university, muscat, oman; e-mail: shreedev@squ.edu.om writing-to-learn (wtl) is considered an important learning strategy in all disciplines. the nursing curriculum requires documentation in clinical practice, expression of ideas in examination, completion of assignments and projects, and contributing to publications and presentations. the aim of this study was to assess the attitude of omani nursing students towards writing, and to investigate the relationship between certain demographic variables and attitudes towards writing. this study used a modified wtl attitude scale to generate data on sultan qaboos university nursing students’ attitudes towards writing. a convenience sampling technique was used. quantitative data was generated using a structured questionnaire. the scores on writing as a whole, the writing process, and self-efficacy were generated using spss. the results indicate that senior and junior students had a more positive attitude whereas middle level students had negative attitudes towards writing. although 52% of students had a negative attitude to the writing process, the median was higher in the writing process as compared to the median for self-efficacy. there was a positive co-relation between the scores for the writing process and self-efficacy. the findings of this study suggest that students have a negative attitude towards wtl. attitudes are learned or organised through experiences; hence, negative attitudes towards writing can be transformed with structured interventions. through wtl, faculty can help nursing students improve their writing skills and understand the course material, thus encouraging critical thinking. 256 | squ medical journal, may 2012, volume 12, issue 2 first international nursing conference oman innovations in nursing education and practice leading to quality care evidence and clinical decision making in nursing lubna hamed al-hasani, training and staff development, royal hospital, ministry of health, muscat, oman e-mail: lubna128@gmail.com evidence based practice (ebp) can be defined as “the practice of health care in which the practitioner systematically finds, appraises, and uses the most current and valid research findings as the basis for clinical decisions”. nursing is a challenging profession that requires the ability to make critical decisions every day while taking into consideration many factors, such as the patients’ values and beliefs along with the work environment, the current situation and time factors. integrating clinical decisions with evidence requires a lot of commitment by nurses. they should be aware of current research and this requires a lot of reading and updating. the majority of nurses have a positive attitude about ebp; however, not all of them are actually applying it for a variety of reasons. first, due to time constraints, nurses lack reading time and claim that they do not have the time to conduct research, or that they have not been provided with proper research resources such as internet or a library. second, research shows that nurses lack confidence and initiative. finally, although many nurses are aware of research related to specific information, they tend to follow old methods unless they have been informed to do otherwise by the nursing administration. portfolio in nurse education muna ramadhan baitsaad, oman specialized nursing institute, oman e-mail: mbaitsaad@hotmail.com recently, there has been an acceleration of changes in the nursing profession and so nurses find themselves confronted with an explosion of nursing knowledge and increasing complexities in their dynamic profession. therefore, a significant change is occurring in nursing education as institutions attempt to deal with these complexities. in response, nurses need to integrate theory and practice, and current nursing curricula do encourage self-directed learning, where nurses seek and analyse information that they use. naturally, portfolios are considered to be the device of choice to prove growing competency and encourage students to take an active role in their learning. the use of portfolios in nursing education is increasing and has become a transferable teaching and learning method that demonstrates students’ progress. this presentation will explore the current conceptualisation of the portfolio in nursing education, its advantages for students, and the challenges for nurse educators. paradigm shift in nursing education: an imperative change for the future jayanthi radhakrishnan and regina xavier, college of nursing, sultan qaboos university, oman e-mail: jayanthi@squ.edu.om innovation in nursing education entails nurse educators being challenged to think in new ways and explore new possibilities to prepare the future generation of nurses. in the past 25 years, reforms in nursing education have taken place without changing the substance of the curriculum or the educational paradigm. studies show evidence of nursing school graduates with limited inferential thinking skills and inadequately prepared in pharmacology, clinical practice, leadership, and the use of patient electronic medical records. often nurse educators are asked to teach more content, but this simple additive curriculum model that we have followed since the time of nightingale is not enough to ensure that learning has taken place. there is a strong urge to shift instructional emphasis from content coverage to student learning. the ‘curriculum revolution’ should change the way nursing is taught and learned. in short, a ‘paradigm shift’ is needed to prepare future nurses. transformations taking place in nursing and nursing education are driven by major socioeconomic factors, and by developments in health care delivery and professional issues unique to nursing. nurse educators need a deeper understanding of trends in health care and their impact on the nursing education/practice in order to facilitate the paradigm shift in nursing education. predictors of pain management satisfaction among jordanian icu patients: an exploratory study muhammd darawad, mahmoud al-hussami, ali saleh, manal al-sutari, school of nursing, university of jordan, amman, jordan e-mail: m.darawad@ju.edu.jo many studies have reported the problem of undertreating pain among hospitalised patients especially among icu patients who experience higher pain levels. despite patients’ pain management satisfaction receiving significant attention, it has not been fully explored among jordanian icu patients. the study aimed to: 1) assess jordanian icu patients’ pain characteristics (intensity and interference) and levels of pain management satisfaction, and 2) determine predictors of pain management satisfaction among icu patients. a descriptive cross-sectional design was utilised using the american pain society-patient outcome questionnaire to survey 139 jordanian icu patients from different health care sectors in jordan. higher levels of pain and pain interferences were reported. however, participants were relatively satisfied with pain management approaches. also, the results showed a predictive model of three predictors, which accounted for 41% of the variance in participants’ satisfaction with pain management. time needed to get analgaesia had the highest predictive power (beta = -.480, p = .000), followed by average pain interference (beta = .218, p = .02), and being told about the importance of reporting pain (beta = .198, p = .006). jordanian icu patients reported pain levels higher than those reported by previous studies in other countries, but comparable levels of pain management abstracts | 257 sultan qaboos university, oman, 28–29th november 2011 satisfaction. this supports the need for a caring attitude in managing patients’ pain reports. the study is among the first pain management studies in jordan aimed at setting the stage for future research studies. finally, results can be included in planning pain management strategies and protocols within jordanian hospitals. needs assessment of cancer patients and development of a standardised palliative care plan to improve quality of life nagwa elkateb, mona elshater, souad hashem, national cancer institute, cairo university, cairo, egypt e-mail: nelkateb@link.net palliative care is a concept of holistic care for patients who need symptom relief during their illness. it seeks to maximise quality of life for patients and families. perception and level of experience of health care professional may affect the continuity of care. nurses need written guidelines to enhance their performance and provide quality palliative care. the aim of this study was to develop a standardised care plan based on assessment of palliative needs of cancer patients and evaluate the impact of the implemented care on the quality of care. a convenient sample of adults and paediatric cancer patients were recruited from the palliative care unit and assessed before and after implementation of the care plan at the national cancer institute, cairo university, egypt. patients participated in a structured interview completed by the researchers, and were given problems assessment tools, and nursing guidelines and patient self-care instructions. the presentation describes the results of patients’ responses before and after implementation of the care plan, as well as the significant differences in the care provided after using the guidelines in spite of the shortage of staff and workload. palliative care is important and nursing guidelines and educational resources have a great impact on improving the quality of care provided during the various stages of illness. teaching tools for patients and families should be adapted to individuals’ needs. compliance with infection prevention and control protocols at governmental paediatric hospitals in the gaza governorates ashraf eljedi, shareef dalo, islamic university of gaza, palestine e-mail: ajedi@iugaza.edu.ps nosocomial infection is a significant burden for both patients and health systems. the palestinian ministry of health has adopted the national infection prevention and control (ipc) protocol in 2004, aiming to combat infections among health care providers, clients, and community. however, compliance with the ipc protocols has been poorly assessed. the aim of this study was to assess compliance of health care providers with the ipc protocols in the governmental paediatric hospitals in gaza in order to decrease childhood morbidity and mortality. the study is a descriptive crosssectional one that included a self-administered questionnaire for all doctors, nurses, and physiotherapists (n=334); an observation checklists for health care providers’ practices, and for the health facility. the reliability of the instruments was assured and the response rate was 92%.the study revealed the most important reasons for non-compliance with the ipc protocol were absence of education or training programmes (61.5%), lack of knowledge (52.4%), and scarcity of the required supplies (46.9%). only 2.3% of respondents had a copy of the ipc protocol, while 65.8% did not know about its existence. only 16.9% of respondents had participated in training sessions about ipc. of those polled, 66.1% had been exposed to an injury from used needles. the observation checklist for the respondents’ practices revealed lower levels of compliance in the areas of wearing uniforms (86.6%); hand washing (45.9%); wearing gloves (40.7%), and using antiseptic and disinfectant (49.16%). health facility checklists indicate a lack of some essential equipment and materials such as covered waste containers and heavy duty gloves. the study recommended making ipc protocols available in all hospital departments; intensifying education and training programmes by a highly qualified team, and providing the needed equipment and facilities. understanding the sexuality issues and queries of the adolescent students of pune rekha jaiprakash ogale, assistant professor, college of nursing, sultan qaboos university, muscat, oman email: the adolescent period is a most important phase, marked by various developmental changes. the adolescent becomes capable of reasoning and abstraction for the first time. this period is marked by rapid physical growth, social and emotional development, and a heightening of sexual and romantic interest in others. adolescents become more aware of themselves and the world around them. this phase is also marked by changes in the reproductive system, which makes them capable of reproduction. several studies have indicated that adolescents lack knowledge of sexuality and reproduction. how do adolescents address their own sexuality? what are the different issues that worry them and what type of questions really bother adolescent groups? the aims of this study were to assess the perception of the adolescent students about their sexuality and reproductive health, and to analyse the issues faced by the students about their own sexuality. the cluster random sampling method was used to select adolescent students from four schools in pune city. the sample selected was 119 students in the 8th standard and divided into 8 focus groups. the findings suggested that the majority of the boys (70%) ask more about sexuality than girls (30%). the issues identified by the students were related to understanding sex and its importance, problems related to sex, homosexuality, reproduction, menstruation, 258 | squ medical journal, may 2012, volume 12, issue 2 first international nursing conference oman innovations in nursing education and practice leading to quality care contraception, and problems related to them including hiv/aids and its prevention. there is a great need to address sexuality issues among adolescents to help promote their physical, social, emotional and mental health. pre-hospital delays, cognitive representations, and coping responses to symptoms of acute coronary syndrome in male and female patients of oman mousa al taani and jahara hayudini, college of nursing, sultan qaboos university, oman e-mail: hayudini@squ.edu.om although women in the arab gulf region have shown greater acute coronary symptoms (acs) events risk scores and hospital mortality than men, no research attention has been given to how men and women cognitively process and cope with symptoms of acs to make health care seeking decisions. the aim of this study was to examine differences between men and women in cognitive presentation and coping responses to symptoms of acs. data from 131 hospitalised patients for acs (81 men and 50 women) about pre-hospital delays, cognitive representations of and coping responses to the symptoms of acs were collected by structured interview. questions were developed based on the response to a symptoms questionnaire. women reported longer pre-hospital delays than men but the difference was not statistically significant. they were more likely to have hypertension, perceive themselves as less susceptible to acs and report a greater number of symptoms than men. the women were also more likely to report dyspnoea, nausea/vomiting, and stomach pain than men. coping responses used by women were similar to men’s. men who reported shorter pre-hospital delays were more likely to approach their symptoms in a “wait-and-see” fashion, be free from diabetes, experience neck pain and left arm pain, identify the symptoms as cardiac in origin, not use coping responses, and attempt to relax. in contrast, women who reported shorter pre-hospital delays were more likely to experience sweating, perceive greater overall intensity of symptoms, and report fear of diagnostic procedures as a barrier to early health care seeking. factors contributing to pre-hospital delays in men are thus different to women. counselling-educational approaches to shorten pre-hospital delays in women should focus on acs symptoms, and helping them explore their emotional reactions to the symptoms. leadership and its effect on institutional culture: the cornerstone of the changing context of nursing and midwifery in oman carol moss, college of nursing, royal hospital, ministry of health, oman e-mail: moss_squad@msn.com nurses in hospitals and health care institutions in oman are challenged like never before. there has been a seismic shift in the level of clinical experience at the staff nurse level, coupled with a rapid expansion of the outpatient sector, and a demand on hospitals to provide for growing numbers of higher acuity inpatients. the nursing leadership at all health care organisations has been placed under enormous pressure to resolve complex staffing issues, continue omanisation, and assure clinical competence. the nursing workforce in most institutions is close to 50% of total staff. this creates an opportunity to impact significantly the culture of the organisation. long standing research shows that leadership excellence has a a direct correlation with the institutional culture, employee satisfaction and achievement of high levels of patient safety. this presentation seeks to explore the major research findings and determine their applicability to the situation in oman. with properly planned and executed training and development, nursing leaders can significantly improve the culture of health care within oman’s institutions. with proper leadership, the transformation can lead to the highest levels of career satisfaction, clinical competence and patient safety. nursing staffing in oman: an approach for estimating the requirements of the 8th health system moeness moustafa alshishtawy, ministry of health, oman e-mail: drmoness@gmail.com at the beginning of the 21st century, it was found that conspicuous gaps and inequities in health still persisted despite the positive outcomes of patients and population health achieved in oman. new infectious, environmental, and behavioural risks, at a time of rapid demographic and epidemiological transitions, now threaten all the achievements of a health system which still has to struggle to keep up, placing additional demands on health workers. in light of this, health planners and decision makers have to ensure that an adequate number of suitably skilled medical professionals are in place to meet health needs. although the number of nurses working in health institutions in oman increased by about 27-fold within the last 35 years to reach 12,102 in 2009, the nursing profession still suffers from acute shortages, skill-mix imbalances, and misdistribution of personnel. this poses a new challenge for decision makers in oman, and the question of having the right number, the right skills and the right distribution of nurses to meet the requirements of the 8th 5-year plan for health development is one with which planners are struggling. various approaches have been proposed, all of which have different assumptions, data requirements, and costs. this paper gives an overview of various approaches for planning nursing staffing, with their advantages and limitations. moreover, it proposes an integrated approach to estimating nursing requirements in oman to achieve the goals of the 8th health plan, besides estimating several scenarios for future requirements, and identifying efficient ways of providing for them. abstracts | 259 sultan qaboos university, oman, 28–29th november 2011 job satisfaction among nurses working in the maternity hospital in judah, saudi arabia salma moawed, sahar m. yakout, king saud university, saudi arabia e-mail: saharyakout@yahoo.com saudi arabia (ksa) is a fast-developing country with a shortage of well-trained saudi health personnel, especially females. overcoming this shortage may take some time. nursing has traditionally been an unacceptable career option for saudi nationals. the reasons suggested are the low image/status of nurses, and traditional, cultural, and social values. there is no doubt that the present psycho-sociological conditions militate against the entry of young saudi women into nursing. this unfavourable situation can be ameliorated by improving the working conditions of nurses and increasing their job satisfaction. this research aimed to study the job satisfaction levels of maternity nurses in judah azizia, ksa. a descriptive study was undertaken on a convenience sample of 120 maternity nurses. data were collected through a self-administered questionnaire from december 2010 to march 2011. the questionnaire consisted of two parts. part i was comprised of five demographic items. part ii was the mueller-mccloskey satisfaction scale, providing information on job satisfaction among nurses and consisting of 31 items to measure the satisfaction of nurses with administrative services, and with their surrounding circumstances. the response rate was 83%.the maternity nurses were highly satisfied with following aspects: the head nurse, their co-workers, respect of their supervisors, and their capability to control the work. least satisfaction was expressed regarding maternity leave, writing, research, and publication opportunities, and childcare facilities. there was no statistically significant difference between the degree of satisfaction of nurses working in the maternity hospital and the variables of age, nationality, experience, education level, and marital status. the study concluded that maternity nurses are generally satisfied with nursing as a career choice and they are highly committed to the health care system, but some issues may lead to emotional exhaustion and, possibly, job dissatisfaction. dignity: the challenge for nurses in long stay older adult units jill murphy, department of nursing and midwifery, university of limerick, ireland e-mail: jill.murphy@ul.ie dignity is seen by health care professions and older people as a basic right. however, the literature highlights the effects of situations where the dignity of older people in long term care settings is compromised. from frequent news reports it would appear that older people suffer from poor care. all nurses who work with older people would claim that they treat them with dignity. why then does poor practice exist? the challenge of this study was to describe the maintenance and compromising of dignity in older adult long term care settings. although dignity is a central tenet of nursing, it has not been operationally defined and there is only one tool to measure dignity. evidence suggests that the health care system has failed to maintain dignity in long stay units for older adults, a factor attributed to the abstract concept of dignity and its precise definition. if nurses are to maintain a patient’s dignity, then nurses must have knowledge of the concept and an awareness of how to deliver care whilst maintaining an older adult’s dignity. the aim of this study was to describe how dignity is evidenced by nurses in older adult units. a quantitative descriptive study of 120 registered general nurses’ perceptions of dignity working in 8 long stay units for the older adult in ireland. the author completed a preliminary concept analysis resulting in three attributes of dignity being used to develop the questionnaire. the study was analysed using the spss package. nurses maintained patient’s dignity on long stay units for older adults. however, areas where nurses compromised older patient’s dignity were also highlighted, including dignity being compromised when administering medication, feeding, and toileting and maintaining hygiene. three intended learning outcomes were featured: 1) describe how dignity is evidenced by nurses in older adult units; 2) identify attributes of the concept of dignity; 3) demonstrate how dignity is maintained and compromised when administering medication, nutrition, and toilet care, and maintaining hygiene in older adult units. impact of in-service training program on operating room nurses for reducing incidence of infection nagwa mohamad ahmad, zeinab abdeltief, amal mohammed, hala ganam, faculty of nursing, assuit university, egypt e-mail: menah21@yahoo.com infection control nurses are qualified experienced nurses who have taken further courses on infection control. they are there to advise staff on how to prevent cross-infection, care for patients with infectious disease, and to assist in the interpretation of hospital policies and procedures dealing with infection control. they are involved in finding and implementing the latest research on infection control, advising on new products, and updating procedures. they work closely with the microbiology department and the health and safety officer. the aim of this study was to investigate the impact of in-service training programmes on operating room nurses in reducing the incidence of infection at elmbara hospital, egypt. a quasi-experimental research design was utilised in this study which was conducted over 2 months. data were collected from 200 nurses working in operating rooms. the following were used in data collection: 1) a questionnaire to assess nurses’ knowledge; 2) an observation checklist sheet for the nurses to assess their practice, and 3) a training programme. an improvement in mean knowledge and practice scores were found after implementing the training programme. a positive correlation between nurses’ knowledge and practice scores was found immediately and 2 months after implementation of the training programme (p <0.0). a significant relationship was found between complications and patients’ sociodemographic characteristics in regards to age and sex. implementation of an infection 260 | squ medical journal, may 2012, volume 12, issue 2 first international nursing conference oman innovations in nursing education and practice leading to quality care control training programme resulted in a significant improvement in nurses’ knowledge and practice. improving nurses’ knowledge and practice can favourably affect infections. continued nursing education and in-service training programmes should be organised at elmbara hospital. it should be equipped with the necessary educational facilities and materials to improve nurses’ knowledge and skills which will result in better patient services and outcomes. infection control: effect of a designed teaching protocol on nurses’ knowledge and practice regarding to haematemesis patients warda youssef mohamed, fatema abu-baker abdel’moez, samia youssef sayed, ghada thabet mohammed, faculty of nursing, assuit university, egypt e-mail: samia-yusuf2012@yahoo.com the aim of this study was 1) to design a teaching protocol for nurses working with patients with haematemesis, and 2) to evaluate the effect of implementing the protocol on nurses’ knowledge and practice regarding haematemesis patients. the study’s hypothesis was that 1) the post-mean knowledge scores of nurses who are exposed to a designed teaching protocol will be higher than their pre-mean knowledge scores; 2) the post-mean practice scores of nurses who are exposed to a designed teaching protocol will be higher than their pre-mean practice scores; 3) a positive relationship will exist between knowledge and practice scores obtained by nurses receiving the designed teaching protocol. the study was conducted at the emergency unit of assiut university hospital. data were collected from 50 nurses working in the emergency unit. tools utilised were a questionnaire sheet to assess nurses’ knowledge in addition to some sociodemographic data; an observation check list sheet to assess nurses’ skills, and a designed teaching protocol. the first and second hypotheses were supported by a sharp improvement in the mean knowledge and practice scores after the application of the teaching protocol. the third hypothesis was supported by a positive correlation between the nurses’ knowledge and practice scores immediately after and 2 months after application of the teaching protocol. patients with haematemesis and their nurses are at high risk for infection. effective measures to prevent and reduce infection are needed. improving nurses’ knowledge and practice can favourably affect the incidence and outcome of haematemesis. quality of life, stress, and coping of nurses working in selected hospitals of karnataka, india: a pilot study tessy treesa jose, college of nursing, manipal university, manipal, india e-mail: tejo1994@yahoo.com nurses make up the largest single group of health care professionals and are trained to consider patients’ quality of care and life, but seldom their own. they rarely consider that they themselves or others in the profession may need care. lerner found a significant association between job strain and components of health-related quality of life (qol). the aim of this study was to determine the qol, stress, and coping of nurses. instruments used in this study were a descriptive survey of 100 nurses, a demographic proforma, the whoqol-bref, and the nursing stress scale and ways of coping questionnaire. the majority (83%) were 21–30years. of those polled, 86% of the subjects were female, 69% were single, and 70% were from nuclear families. most subjects were working in intensive care units (17%). the majority (64%) had 1–5 years’ of experience while 85% had 1–3years’ experience in their current area of work. the environmental domain of qol obtained the highest score (26.61) while social domain obtained the lowest score (11.76). a total of 65% of the subjects had mild stress, while moderate stress was experienced by 34%. the mean stress score (6.87 + 3.09) was high for the nurses in the sub-area of death and dying, followed by workload (6.23 + 3.19). the lowest mean stress score was (2.7 + 1.63) in the area of inadequate preparation. the participants’ mean coping score was high (12.3) for positive reappraisal. no significant association was found between qol, stress, and selected variables. a significant association was found between stress and area of work, coping and marital status, and monthly income, and area of work. a weak but statistically significant negative relationship was found between qol and stress. a weak but significant relationship was found between stress and coping. no significant relationship was found between qol and coping of nurses. qol is affected by stress experienced by the nurses. application of infection control measures to reduce maternal sepsis & gynaecology in a teaching hospital, wad medani, sudan ietmad ibrahim abd. elrahman mohamed kambal, gazira university, sudan e-mail: ietimadkambal@yahoo.com this interventional study was conducted in the obstetrics and gynaecology teaching hospital in wad medani, sudan. this study assessed the effect of a programme targeting the application of infection prevention and control measure on the knowledge, attitudes, and practices of nursing staff, and on the occurrence of sepsis among patient admitted to the hospital between 2003 and 2007. hospital records were reviewed to identify the leading cause of maternal deaths. knowledge, attitude, and practices of nursing staff were identified through their standardised pre-test question and observation checklist. the results of the study identified that sepsis, a leading cause of maternal deaths, was responsible for 34% of maternal deaths. the knowledge of respondents related to the standard precautions of hospital infection prevention and control measures improved significantly after a training programme. prior to the training programme, 15% of respondents indicated having knowledge about hand washing techniques, whereas the percentage of those with proper knowledge about hand washing technique increased to 91% post-training. respondents’ attitudes towards abstracts | 261 sultan qaboos university, oman, 28–29th november 2011 infection control measures and their willingness to use them was positively changed. shortages of necessary supplies and equipment often impeded the achievement of safe levels of infection control. this shortage could also be due to the absence of supervision by an infection control committee. this study recommended periodic refreshers in the form of in-service training courses for nurses in order to update infection control knowledge and practices. blended teaching & learning mode a success story to address the critical shortage in the nursing industry vijaya kumaran k.k.nair and michelle zhong yi, university malaya, malaysia e-mail: vknair1@yahoo.com in most parts of the world, nursing education has progressed to higher education; nursing education in malaysia should head in the same direction. malaysia needs nurses with critical thinking abilities and the motivation for life-long learning, and with skills in technology, communication, management, collaboration and leadership. malaysia’s progress from hospital-based training to higher education has been rather slow compared with other countries. the ministry of health has mandated that in the future, 10% of nurses will have received tertiary education. higher education for nurses is not a luxury nowadays, but a necessity. nurses need to be educated at a higher level in order to equip themselves with the knowledge and skills that will empower them to practice innovatively, creatively, and autonomously. there is a need in malaysia to establish an institution of higher learning to address these issues. further there is a need to establish and develop a national capacity for retraining and upgrading registered nurses, medical assistants, and student nurses through blended learning, combining selfand face-to-face instruction delivered in a university-based learning environment supported by remote learning centres (rlc). this means establishing a new, distance education based mode for training/retraining registered nurses and medical assistants. apart from conventional teaching and training methodologies, the varied modes of distance education technology should be explored to ensure that the right match is found. to ensure success, the approach should bring the education/training to the clients rather than expecting clients to be on campus. the vehicle to ensure success will be the integration of conventional teaching-learning methodology with state of the art technology without compromising the quality of education/training provided. action learning, constructive learning, project-based learning and also problem-solving learning methods will be helpful. jigsaw – an innovative approach to teaching students about cancer in children lakshmi renganathan, oman nursing institute, ministry of health, oman e-mail: lakshmirenganathan@yahoo.com a trial study was conducted to teach students about paediatric cancer through the jigsaw method, a form of collaborative learning. the objective of the study was to incorporate an innovative approach to make the information more student-friendly. twenty-six 3rd year nursing students were divided into 5 groups of 5–6 members each. “cancer– essential concepts” was divided into 5 segments: a definition and general characteristics of cancer; classification of cancer; staging of cancer; assessment and lab diagnostic tests, and psychosocial implications. each group was assigned one segment. the level of knowledge on cancer concepts was assessed through a quiz. on average, 95% of the students scored more than 60% in the post test. they also expressed that this method was very useful, enabled decision making, encouraged group discussion, and that they benefited by sharing knowledge. the students also said that it inculcated in them critical thinking. therefore it can be concluded that this method is beneficial and can enhance the performance of nursing students. study to assess the prevalence and knowledge of diabetes and hypertension among adults suja karkada, navaneetha, ansuya, manipal college of nursing, manipal, india e-mail: suja77@yahoo.com the aim of this study was to assess the prevalence and knowledge of diabetes and hypertension among adults, and to find the association between knowledge level and variables were conducted in selected villages of udupi district. the study subjects were interviewed with a questionnaire tested for validity and reliability. blood pressure was measured by using a calibrated mercury sphygmomanometer and each individual was screened for diabetes mellitus through the benedict test. a total of 385 adults were selected by non-probability convenient sampling technique. data was analysed using descriptive and inferential statistics. of 385 adults, 27.8% were females and 72.2% had been educated up to the primary level. the majority (82.2%) of the adults were unskilled workers and 96% of them had exposure to mass media. the majority (50.4%) had average knowledge on diabetes mellitus and prevalence was found to be only 5%. the majority (50.6%) of the sample had an average level of knowledge about hypertension and the prevalence of hypertension was 19.5%. results show that there is no significant association between knowledge and selected variables. 262 | squ medical journal, may 2012, volume 12, issue 2 first international nursing conference oman innovations in nursing education and practice leading to quality care overweight and obesity and their correlates among jordanian adolescents shaher h. hamaideh, reham y. al-khateeb, ahmad b. al-rawashdeh, zarqa university, jordan e-mail: saharyakout@yahoo.com the aims of this study were to provide current estimates of the prevalence of overweight and obesity among jordanian adolescents 14 to 17 years of age living in irbid governorate, and to determine the factors that are associated with overweight and obesity by using a descriptive correlation cross-sectional design. body mass index, perceived stress, dietary habits, physical activity, and demographics of 824 jordanian adolescents living in irbid were measured through a multistage cluster sampling method. the overall prevalence of overweight and obesity was 19.1% and 6.3%, respectively. the prevalence of overweight and obesity among boys was 17.2% and 5.7%, respectively, and among girls was 21.0% and 7.0%, respectively. both overweight and obesity rates were higher among girls. physical activity, mother’s educational level, and number of family members were negatively correlated with overweight and obesity. on the other hand, eating breakfast regularly, mother’s weight, consumption of fried food, and perceived stress level were positively correlated with overweight and obesity. overweight and obesity are becoming a health problem among both boys and girls in jordan. detecting the prevalence and the associated factors of overweight and obesity among adolescents is the first step toward proposing intervention strategies developing an enquiry based learning template for higher education rasha ahmed, college of nursing, sultan qaboos university, oman e-mail: rasham@squ.edu.om there are no basic, clear guidelines for academics to realise criteria for enquiry-based learning (ebl). the aim of this study was to develop an ebl template in order to facilitate conversion from traditional didactic teaching to ebl. an extensive literature review was conducted to extract the critical key elements of a universal template. a qualitative approach of one-to-one interviews with experienced staff in developing/coordinating ebl modules at the university of manchester (um) was conducted. twenty-two staff representing different faculties across um were interviewed. the questions included: a) motivation for developing ebl (i.e. the decision to convert the course and the process of converting from conventional teaching to ebl); b) development and preparation (i.e. stimulating the students’ enquiry or trigger types); c) evaluation and feedback (i.e. maintaining good practice of the process), and d) the use of a universal template (i.e. what elements would make a useful template). all data was treated anonymously and subjected to content analysis. the template is an innovative approach to higher education teaching, and may enable academics to move easily and conveniently to ebl. additionally, it will aid the university’s major strategy of enabling ebl methods to be developed widely across higher education institutes. effectiveness of computer assisted patient education on knowledge and selfefficacy jayasree. r, suja karkad, mariamma, salalah nursing institute, ministry of health, oman e-mail: jayasreebibi@gmail.com the aim of this study was to describe how much patients know about rheumatoid arthritis (ra) and what kind of selfefficacy they undertake. the aim was also to evaluate the effectiveness of computer-assisted patient education in terms of knowledge and self-efficacy. an evaluative, one group pre-test/post-test design was used. data were collected from 76 patients who attended the rheumatology polyclinic at sultan qaboos hospital, salalah. the arabic version of the patient knowledge questionnaire (pkq) and the arthritis self-efficacy scale (ases) were used at baseline, and after 30 days of teaching. of the 76 patients studied, 90.8% were females, 29% were between 40 and 49 years, 41% were illiterate, and 79% were unemployed. the mean pre-test score of the pkq was 10.61 ± 4.16.tthe subscale of ra general knowledge had a better mean, at 3.58 ± 1.70 than that of the knowledge of drugs (1.74 ± 1.14). the mean pre-test scores of subscales exercise were 2.65 ± 1.28 and that of joint protection and energy conservation was 2.64 ± 1.75. 50% of the sample had average knowledge and 48.6% poor knowledge. the mean pre-test self-efficacy scores for pain, function, and other symptoms were 4.60 ±1.71, 4.99 ± 1.76, and 4.81 ± 2, respectively. the post-test score of knowledge was 21.69 ± 4.04 and selfefficacy was 7.25 ±1.46. the wilcoxon-matched pairs signed-rank test showed that knowledge and self -efficacy improved with patient education (z = -7.44, p <0.0001; z = -7.19, p <0.0001, respectively). correlation of knowledge and self-efficacy was significant (r = 0.31, p = 0.007). education helps patients become accustomed to living with ra. a systematic review regarding the effectiveness of high-fidelity computerised simulation in nursing education asiya said saif al-hasni, oman specialised nursing institute, oman e-mail: ondeal@hotmail.com despite the recent move towards the use of high-fidelity simulation (hfs) in nursing education, it has been available since 1960. the current interest in hfs is due to several factors. policies towards ‘fitness for practice’, advanced technology, nursing shortages, an increase in the number of nursing students, and patient safety concerns are motivating educators to look for new alternatives. therefore, the aim of this review is to identify the best evidence for the effectiveness of abstracts | 263 sultan qaboos university, oman, 28–29th november 2011 hfs on the knowledge, skill, confidence and critical thinking of preand post-registration nursing students. the review includes randomised and non-randomised controlled trials which investigated the effects of simulation on nursing students in their education and learning processes between 2000 and 2009. the participants included pre-registered and post-registered nursing students. the interventions included any study evaluating hfs, all of which were considered for inclusion in the review. the search strategy employed defined search and retrieval methods, with medline, cinahl, pubmed, british nursing index, psyc info and embase accessed for the period of 2000–2009. nine papers were assessed by two independent reviewers for methodological quality prior to inclusion in the review. for this purpose, the standardised critical appraisal instruments for evidence of effectiveness were used. differences of opinion were dealt with by consulting with a third reviewer. six papers were finally included in the review and were analysed using narrative analysis. hfs could significantly affect the knowledge, skill, and confidence of pre-registered nursing students. in addition, the systematic review indicated hfs can increase the confidence of post-registered nursing students. however, there was no evidence to show that hfs can significantly change the critical thinking of students. additionally, no evidence was found which investigated the effectiveness of hfs on the knowledge and skill of post-registered nursing students. q-methodology: a combination of qualitative and quantitative methods in nursing research noori akhtar-danesh, mcmaster university, canada e-mail: daneshn@mcmaster.ca q-methodology is a research method where qualitative data are analysed using quantitative techniques. although it was introduced by william stephenson in 1935, it is only now emerging as a widely used method in health research, mainly because of advances in its statistical analysis component. it has the strengths of both qualitative and quantitative methods and can be regarded as a bridge between these two approaches. q-methodology is usually used where the outcome variable involves assessment of subjectivity, including attitudes, perceptions, feelings and values, life experiences such as stress and quality of life, and intra-individual concerns such as self-esteem, body image, and satisfaction. it is used to identify unique and salient viewpoints as well as shared views, thereby providing unique insights into the richness of human subjectivity. in this workshop, different steps of q-methodology in health research are explained as applied to a research topic. participants will have the opportunity to participate actively in the different steps of the research process. also, some common issues in q-methodology such as sample size, reliability and validity, and interpretation of the statistical analysis will be discussed. the health research strategy at the research council ahmed al-shukaili, the research council, oman e-mail: ahmed.alshukaili@trc.gov.om the research council (trc) was established by a royal decree in june 2005. in november 2006, work began to prepare the organisational structure and develop a national research strategy for omani science and technology; this was accomplished in 2007. the objectives of trc are to build research capacity mechanisms, achieve research excellence, build knowledge transfer and value capture, and to provide an enabling environment for research and innovation. the trc’s overall health research mission is to build research capabilities in a responsive, evidence-based, cost-effective health care system that promotes healthy lifestyles, encourages preventive medicine, and ensures delivery to all citizens. also, trc strives to develop collaborative and multi-disciplinary research in genetics, nanotechnology and biotechnology. the health research strategy at trc is divided into 8 fields. the first, health care delivery systems research, covers health care systems management; primary, secondary and tertiary health care; pharmaceutical health care and nursing care; and quality assurance and patient care. the second covers human resource development research, while the third covers epidemiological research such as disease and injuries tracking; prevention and control; communicable and non-communicable diseases; environmental and occupational health; accidents and injuries, and public health. the remaining fields are health care financing and economic research, health policy research, medical sciences research, and health studies and medical science research. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e297-305, epub. 24th jul 14 submitted 8th jan 14 revision req. 9th feb 14; revision recd. 2nd apr 14 accepted 24th apr 14 young car drivers are five to 10 times more likely to experience injuries as a result of road crashes when compared to drivers among the safest age group. young males have a higher crash rate than young females.1 this elevated crash risk is not a new phenomenon and has been reported for at least the last 30 years. this risk falls rapidly during the first few months of driving and then declines more slowly for the next 18 months to two years.2–5 within the omani context, research suggests that the country has one of the highest rates of road crash mortality and morbidity in the world at 30.4 per 100,000 people compared to a global average of 19 per 100,00 people.6 although very recent data from the royal oman police indicate that fatalities from crashes decreased by 22% and injuries decreased by 13% in 2013 compared to the same period in 2012, the issue of young driver road crashes remains a constant concern regardless of changes in the overall data patterns.7 alreesi et al. found that young omani drivers reported higher levels of risky driving behaviours compared to wider international samples.8 furthermore, the same authors reported that young drivers are overrepresented in road crashes in oman.9 al-naamani et al., in a large-scale oman-based study of hospitalised road crash victims, found that the majority of patients were young with multiple injuries and that a significant number had resulting symptoms of acquired brain injuries.10 this review draws on international research evidence to identify the various factors that contribute to the elevated crash risk experienced by young drivers. while many risk-associated driving behaviours may be culturally specific, there is still much to be gained by examining wider international contexts and research to determine risks associated with young drivers.11 much of this literature may be relevant and appropriate to the omani context. furthermore, this review provides a foundation of knowledge which can be used to assist in planning future strategies targeting a reduction in road risk among young omani drivers. many factors influence young novice drivers’ behaviours [figure 1]. these factors include social and situational influences, exposure-related influences and the characteristics of young drivers. among the young driver characteristics influencing crash risk, there are several further factors, including core and modifiable attributes, situational assessment and decision-making skills as well as driver behaviour.12 while the model is not new, it comprehensively represents the factors that 1school of criminology & criminal justice, griffith university, mount gravatt, queensland, australia; 2centre for accident research & road safety, school of psychology & counselling, queensland university of technology, brisbane, queensland, australia *corresponding author e-mail: l.bates@griffith.edu.au العوامل املؤدية إىل احلوادث عند السائقني الصغار ليندل جوديث بيت�س، جريمي ديفي، باري واأت�سون، مارك كينج، كريي اأرم�سرتوجن abstract: young drivers are the group of drivers most likely to crash. there are a number of factors that contribute to the high crash risk experienced by these drivers. while some of these factors are intrinsic to the young driver, such as their age, gender or driving skill, others relate to social factors and when and how often they drive. this article reviews the factors that affect the risk of young drivers crashing to enable a fuller understanding of why this risk is so high in order to assist in developing effective countermeasures. keywords: traffic accidents; public health; accident prevention; safety; automobile driving; oman. امللخ�ص: ال�سائقني ال�سغار هم من فئة ال�سائقني الأكرث عر�سه للحوادث. توجد هناك عدة عوامل توؤدي اإىل زيادة احتمال احلوادث عند هذه الفئة من ال�سائقني. بينما جزء من هذه العوامل تعترب داخلية املن�ساأ ل�سغار ال�سائقني مثل العمر، اجلن�س اأو مهارة القيادة، الأخرى لها عالقة بالعوامل الإجتماعية و وقت وعدد مرات ال�سياقة. هذا املقال ي�ستعر�س العوامل التي توؤدي لزيادة ن�سبة احلوادث عند هذه الفئة من ال�سائقني من اأجل زيادة املعرفة وكذلك للتو�سل اإىل طرق فعالة للحد من هذه امل�سكلة. مفتاح الكلمات: حوادث الطرق؛ ال�سحة العامة؛ الوقاية من احلوادث؛ الأمان؛ �سياقة املركبات؛ عمان. review factors contributing to crashes among young drivers *lyndel j. bates,1,2 jeremy davey,2 barry watson,2 mark j. king,2 kerry armstrong2 factors contributing to crashes among young drivers e298 | squ medical journal, august 2014, volume 14, issue 3 influence novice driver behaviour. the original figure has been updated by the current authors to include socio-economic status, mobile phone use and fatigue in social and situational factors. social and situational factors influencing novice driver behaviour social and situational factors such as socio-economic status, passengers, impairment, mobile phone use, fatigue, social group and peers affect the crash risk of novice drivers.12 s o c i o-e c o n o m i c s tat u s drivers of all ages, including younger drivers who belong to lower socio-economic groups experience higher crash risks.13 a recent australian study found that young drivers from such backgrounds were twice as likely to be hospitalised as a result of a crash when compared with young drivers from higher socioeconomic backgrounds.14 this result occurred even after controlling for driver exposure and place of residence. the impact of socio-economic status on crash risk appears to persist over time.15 pa s s e n g e r s the presence of passengers similar in age to the young driver increases the risk of crashing. chen identified that young drivers between 16 and 19 years old were more likely to experience a fatal crash if they carried one or more passenger, and the more passengers that were carried in a vehicle, the higher the crash risk.16 there are a number of proposed reasons for this increased crash risk. it is possible that the presence of passengers may distract young drivers, leading to driving errors and thus increasing their crash risk.17–19 alternatively, passengers may encourage drivers to conform to the prevailing norms of their social group.20 while a driver may choose to drive in a risky manner on a given occasion, the support of their passengers will encourage this behaviour to continue. the gender of both the driver and the passengers plays an important role in the driver’s crash risk and driving behaviour in this effect. for instance, one study figure 1: factors relating to young driver safety. adapted from: williamson a. young drivers and crashes: why are young drivers over-represented in crashes? summary of the issues.12 lyndel j. bates, jeremy davey, barry watson, mark j. king and kerry armstrong review | e299 s o c i a l g r o u p a n d p e e r s a young driver’s social group may affect their driving behaviours by encouraging them to take greater risks.12 peers can affect a driver’s behaviour both directly and intentionally as well as indirectly and inadvertently. for instance, two studies found that peers could directly encourage drivers to engage in risky behaviours such as speeding.21,30 if a driver believes that driving in a certain way is expected by their peers, they may be more inclined to drive that way. it appears that young drivers who believe that their friends are unlikely to punish them if they drive in a risky manner, or who imitate the risky driving behaviour and attitudes of their friends, are more likely to drive in a risky manner. alternatively, young drivers who believe that their friends are not supportive of risky driving behaviour are less likely to drive in a risky manner.31 social factors such as a tolerance of breaking road rules also affect decision-making, with these factors more likely to affect younger than older drivers.32 younger drivers tend to drive safely because of a sense of legal obligation while older drivers consider the negative outcomes if they do not comply. however, younger drivers display more tolerance of those who commit violations. compared with older drivers, younger drivers believe more people commit violations.33 m o b i l e p h o n e u s e research has suggested that mobile phone use while driving reduces performance, with younger drivers more likely to use their mobile phones while driving.34,35 in addition, it has been found that young drivers are more likely to be severely injured if they are distracted by a mobile phone while driving.36 the involvement of mobile phones with driving has been found to reflect the level of cognitive and behavioural association that people have with their phones.37 studies have revealed that young people who are more involved with their mobile phones are more likely to indicate that they would use their mobile phones in some way while driving, including texting, and furthermore, that they would deliberately hide this behaviour.37,38 fat i g u e driving while fatigued appears to be a common behaviour, with younger drivers more strongly affected by sleepiness.39 within a sample of 17–25-year-old drivers, 67.3% reported driving while fatigued between one and 10 times in the previous month.26 a further 9.7% indicated that they had done so 11 or more times in the previous month.26 however, another study found that younger people are less likely than older identified that male drivers drove approximately five miles per hour faster with a male passenger in the vehicle than with a female passenger in the vehicle.21 drivers with only male passengers were more likely to crash when compared with drivers who only had female passengers. chen found that driver deaths per 1,000 crashes more than doubled when there were two or more male passengers and also doubled if there was a combination of male and female passengers. although female passengers also increased crash risk, they did so at a much lower rate.16 a l c o h o l a n d d r u g s alcohol increases the crash risk for all drivers, including young drivers.22,23 one study suggested that where alcohol or drug use was reported as a factor, adolescent drivers were 3.3 times more likely to sustain a severe injury.24 despite this, drunk driving may be limited to particular groups of young drivers.25 one australian study of drivers aged 17–25 years old found that 78.8% had not driven under the influence of alcohol in the previous month, 20% had driven under the influence of alcohol between one and 10 times and 1.2% had driven under the influence of alcohol more than 11 times in the previous month.26 morrison et al. found that the groups most likely to drive under the influence of alcohol included those dependent on alcohol and cannabis, males, those from lower socio-economic backgrounds, individuals with lower educational attainment and those who were unmarried.25 in addition, another study found that if an individual had travelled as a passenger with a drunk driver when they were an adolescent, the likelihood that they would drive a vehicle under the influence of alcohol when they were a young adult aged 18–24 years old increases by over 60%.27 there is a small but significant group of young drivers who report driving under the influence of drugs. researchers who studied a sample of university students found that 17% of the sample aged 18–21 years old reported having driven under the influence of drugs and that 13% of this group had done so in the past 12 months.28 research has suggested that driving under the influence of cannabis may be a more significant problem than driving under the influence of alcohol, even though more young people drink alcohol than smoke cannabis.29 participants who had driven under the influence of cannabis in the previous year had more than four times the crash risk compared to those who had never smoked cannabis.29 there was no increase in the crash risk for participants who smoked cannabis but did not drive under the influence of cannabis. factors contributing to crashes among young drivers e300 | squ medical journal, august 2014, volume 14, issue 3 drivers to drive while sleepy, but if they did attempt to drive while sleepy, they were also less likely to pull over and rest.40 driving while fatigued is a risky behaviour, with research suggesting that young drivers who are influenced by fatigue are a contributing factor for fatal crashes involving two vehicles.41 exposure factors influencing novice driver behaviour driving patterns that influence crash risks have been reported to be affected by the amount of time spent on the road, as well as by the time of day, the day of the week and the environment.12 young drivers have been found to have a higher crash rate than other age groups after controlling for their greater exposure.1 a m o u n t o f t i m e o n t h e r o a d using data from 1995, williams identified that 16–19-year-olds in the usa were involved in 17 crashes per million miles travelled.2 however, the crash risk fell rapidly among those aged 20–24; they were involved in nine crashes per million miles travelled. research using american mileage data from 2000–2001 identified that the crash risk per mile had fallen for 16-year-old drivers, although this age group still had the highest risk of being involved in a fatal and nonfatal crash per miles driven when compared with all but the very oldest drivers.42 t i m e o f d ay a n d w e e k it has been found that young drivers were more likely to crash at night and over the weekend.2 although older drivers also had an increased crash risk at these times, the crash risk for younger drivers increased at a disproportionate rate.12 a summary of studies from around the world evaluating night-time driving restrictions, and graduated driver licensing systems that include a night-time driving restriction, concluded that limiting driving at night reduced both the number of crashes and the rate of crash involvement at this time for young novice drivers.43 this finding was also corroborated by a more recent study.44 e n v i r o n m e n ta l fa c t o r s the weather is an important influence on the crash rates of all drivers, although these factors have been found to have a disproportionate impact on young drivers.45 for example, canadian research suggested that young drivers who drove above the speed limit in intemperate weather crashed more frequently.46 in addition, young drivers were also more likely to be involved in crashes when fog and smoke were present.47 the level of urbanisation is another factor that impacts crash rates. one australian study considered the various crash risks amongst young drivers who lived in urban, regional and rural settings.48 the study found that those who lived in urban areas had a higher crash risk, although no significant difference was found in terms of being involved in crashes that resulted in an injury. young drivers who lived in regional or rural areas were more likely to be involved in only a single vehicle crash.48 young driver attributes as depicted in figure 1, there are four categories of young driver factors that are relevant for explaining their heightened crash risk: (1) core attributes; (2) modifiable attributes; (3) situation assessment and decision-making characteristics, and (4) the types of driver behaviour.12 c o r e at t r i b u t e s the core attributes of the young driver are relatively fixed or enduring and are hence unlikely to change due to external influences.12,49 these attributes include age, gender, personality and clinical conditions. younger drivers have higher crash risks than older drivers, with research indicating that the youngest group of drivers have the highest risk.50 this higher crash risk has been found to be due to a lack of experience and a propensity to drive in highrisk situations.51 masten et al. found that younger drivers also lacked driving skill, were immature, lack risk perception abilities and overestimated their own driving skills.52 an australian study found that young drivers had lower risk aversion, higher risk propensity and stronger motives for risky driving.53 gender appears to be an important factor in young driver crash risk. young male drivers had a higher propensity to take risks than young female drivers.54 a study in jordan identified that male drivers travelled more kilometres per year than female drivers.55 the same study identified that males of all ages had higher crash rates than females. however, this difference was greatest among those aged 18–25 years.55 personality factors, such as sensation-seeking, aggressiveness and egocentrism, have also been found to affect the crash risk of a young driver.12,49,56 sensation-seeking is defined as the willingness to take physical and/or social risks to fulfil a need for varied, novel and complex sensations.57 when compared with older drivers, young drivers were more likely to demonstrate a greater propensity to take risks lyndel j. bates, jeremy davey, barry watson, mark j. king and kerry armstrong review | e301 driving skills tend to be overly reliant on formal traffic rules or laws, which can contribute to them failing to anticipate the mistakes of other road users. one study compared the novice driver’s assessment of their driving skills against the assessment of their driving examiner in both finland and sweden. the study identified that while a large proportion of the novice drivers accurately assessed or underestimated their driving skills, approximately 30% of the finnish and between 53–70% of the swedish sample overestimated their driving skill.72 however, it takes more than skill to drive safely. young people must be able to apply their skills and make judgements depending on the situation.12 driver training tends to focus on the development of driving skills and involves learning specific methods and techniques of driving and operating a vehicle.73 in contrast, driver education programmes tend to focus on teaching young drivers how to apply their skills. obtaining on-the-road experience is an important factor in reducing crashes. however, age and experience are highly correlated, making it difficult to identify if one is more important than the other in predicting the risk of crashing.50,74 mccartt et al. reviewed 11 studies that examined the effects of age and experience on crash risk.74 they concluded that teenage drivers had higher crash rates than older drivers, particularly those older than 25 years, after controlling for the length of time since receiving their license. they also concluded that crash risk was reduced when individuals had held their licences for a longer period of time.74 in the studies that attempted to distinguish the relative importance of age and experience, the effect of experience was stronger, with the exception of one study.74 research using a sample of students and staff from a major university in oman identified that both the age of the driver and years of driving experience were related to rates of selfreported crash involvement.8 research in sweden found that lowering the age requirement for obtaining a learner licence and increasing the amount of supervised driving practice time prior to obtaining a driver’s licence reduced the crash risk by approximately 40% once solo driving commenced.75 this research evaluated the introduction of a nation-wide initiative. for this reason, the study may have been confounded by factors such as age, socio-demographic variables and general crash rates. however, the study design attempted to estimate the effects of these factors.75 as well as stronger motives for drunk driving and speeding when compared with older drivers.53 highrisk young drivers tended to have a greater propensity for sensation-seeking.58 sensation-seeking has been linked to risky driving behaviours, including speeding, drunk driving and following the vehicle ahead too closely.59–61 however, more recent research, while identifying a link between thrill/adventure-seeking and not wearing a seatbelt, did not identify a link between drunk driving, speeding and driving while fatigued. these inconsistent results may be a result of cultural differences.62 a small group of younger drivers affected by clinical conditions may also have a higher crash risk.12 research has suggested that several conditions can increase a driver’s crash risk. these include stroke; myocardial infarction; underlying cardiovascular disease; affective or psychological disorders, including anxiety, depression and related conditions; sleep disturbances, and visual deficiencies.63 recent research in australia found a link between young drivers with psychological distress and risky driving, although the exact nature of the relationship was not discovered.64 conditions such as attention deficit hyperactivity disorder (adhd) have been found to impact the young driver’s behaviours and crash risk.65,66 for example, young drivers with adhd were more likely to speed and had a higher risk of injury.67 they were also more likely to crash. the effect of adhd on driving errors and crashes was found to decrease as the affected individual aged, as they were likely to develop more effective coping strategies that enabled them to decrease their risk.68 furthermore, young drivers who engaged in selfharming behaviours had an increased risk of being involved in a crash, with a high proportion of crashes involving multiple vehicles. this crash risk remained even after controlling for psychological distress and substance abuse.69 despite this finding, low levels of psychological distress, defined as poor mental health including symptoms of depression and anxiety, were identified as decreasing the crash risk.70 m o d i f i a b l e at t r i b u t e s the modifiable attributes of young drivers include skill and experience as well as the levels of education and training received. driving skill relates to the ability to operate a vehicle in traffic and reflects both an individual’s cognitive and psychomotor abilities.12 young drivers need to develop the ability to operate a motor vehicle with minimal cognitive resources. this allows them to free up cognitive space to concentrate on other aspects of driving, such as negotiating traffic.71 individuals still developing their cognitive factors contributing to crashes among young drivers e302 | squ medical journal, august 2014, volume 14, issue 3 s i t u at i o n a l a s s e s s m e n t, d e c i s i o n-m a k i n g a n d h a z a r d p e r c e p t i o n driving requires the driver to use a set of multifaceted, interconnected and simultaneous competencies, including psychomotor, cognitive and perceptual proficiencies.76 young drivers are asked to develop and use these skills during their teenage years when quick and radical physical, cognitive and psychosocial changes occur.49,76 a young driver’s skill in assessing the road environment as well as their motivations play a role in determining their on-the-road behaviours and related crash risk. the ability to detect, assess and react to developing traffic situations is known as hazard perception.77 this skill is important in reducing crash risk and may be one reason for the difference in crash risks between novice and more experienced drivers.78 novice drivers tend to focus on the lane and road markings close to their car. more experienced drivers look at the horizon and use their peripheral vision to maintain their position within the lane.79 an individual’s capacity to make decisions while driving also affects their crash risk. both internal and external factors affect the driver’s ability to make decisions. drivers with more developed skills have an increased cognitive capacity to make decisions. for instance, as the driving task becomes more automated, more cognitive capacity becomes available, allowing the driver to make more effective decisions.78 the ability to perceive potential hazards improves with driving experience.80 however, hazard perception skills may be affected by other factors such as sleepiness. one australian study identified that novice drivers were significantly slower at anticipating hazards at night in comparison to during the day, while experienced drivers did not differ in their ability to anticipate hazards at different times.81 as well as differences in hazard perception skills, inexperienced and more experienced drivers have been found to differ in their hazard anticipation abilities, particularly regarding vehicle and eye behaviours.82 research has indicated that it is possible to train a novice driver to anticipate hazards and that the effects of this training will persist for up to a week; in addition, it was found that this training could be generalised to the open road.82 d r i v e r b e h av i o u r the final factor that increases the crash risk of young novice drivers is their driving behaviour. the ways in which drivers behave on the road, including their violations of road rules, may increase their crash risk.12 self-reported risky driving behaviours by young drivers were linked with a 50% increased risk of crashing.83 young drivers were more likely to exceed the speed limit, drive too close to other vehicles and signal poorly.20 ‘hooning’ describes driving in a manner that is irresponsible and dangerous in public areas, and includes illegal street racing.84 research has suggested that ‘hoons’, are most likely to be young males aged 16 to 24 years;85 this group can be considered a risky group and their driving records are more likely to include traffic infringements, licence sanctions and crashes than other drivers.86 conclusion in many countries around the world young drivers have, over time, persistently had higher crash rates than older drivers and this is also the case in oman. these increased crash rates are due to a number of factors, including the amount of driving exposure, the time this driving takes place, social and peer factors, and factors that are intrinsic to the young driver. recent data has identified a number of characteristics associated with young driver crashes including variables associated with age, gender, passenger characteristics, the time of day, speed, type of vehicle, license status and nationality, amongst others. developing an understanding of these factors and how they increase crash risk is critical to developing appropriate countermeasures. most significantly, there is a large amount of data from around the world that identifies the vulnerability of young drivers, and the fact that much of this research is relevant to the omani context must not be forgotten. there is only a very small amount of research concerning young drivers within oman and the other gulf cooperation council countries. there is obviously a critical need for more research within oman if the country is to successfully respond to the pressing issue of crashrelated mortality and morbidity. while recognising the unique and cultural characteristics of young drivers within the omani context, the authors believe that valuable lessons can be learnt from international research. it is critical that effective countermeasures are adopted and implemented in order to reduce the crash rates experienced by young drivers. furthermore, if oman is to respond rapidly to this issue, international research in managing young drivers may provide useful insights and strategies that could be quickly assimilated, adopted and implemented in the current driving environment. lyndel j. bates, jeremy davey, barry watson, mark j. king and kerry armstrong review | e303 18. begg dj, stephenson s, alsop j, langley j. impact of graduated driver licensing restrictions on crashes involving young drivers in new zealand. inj prev 2001; 7:292–6. doi: 10.1136/ip.7.4.292. 19. lam lt, norton r, woodward m, connor j, ameratunga s. passenger carriage and car crash injury: a comparison between younger and older drivers. accid anal prev 2003; 35:861–7. doi: 10.1016/s0001-4575(02)00091-x. 20. baxter js, manstead asr, stradling sg, campbell ka, reason jt, parker d. social facilitation and driver behaviour. brit j psychol 1990; 81:351–60. doi: 10.1111/j.2044-8295.1990. tb02366.x. 21. simons-morton b, lerner n, singer j. the observed effects of teenage passengers on the risky driving behavior of teenage drivers. accid anal prev 2005; 37:973–82. doi: 10.1016/j. aap.2005.04.014. 22. begg dj, langley jd, stephenson s. identifying factors that predict persistent driving after drinking, unsafe driving after drinking, and driving after using cannabis among young adults. accid anal prev 2003; 35:669–75. doi: 10.1016/s00014575(02)00045-3. 23. voas rb, romano e, fell j, kelley-baker t. young impaired driver involvement in fatal crashes. in: transportation research board of the national academies. young impaired drivers: the nature of the problem and possible solutions. washington dc: transportation research board, 2009. pp. 9–17. 24. vachal k, malchose d; research faculty. what can we learn about north dakota’s youngest drivers from their crashes? accid anal prev 2009; 41:617–23. doi: 10.1016/j.aap.2009.02.014. 25. morrison l, begg dj, langley jd. personal and situational influences on drink driving and sober driving among a cohort of young adults. inj prev 2002; 8:111–5. doi: 10.1136/ip.8.2.111. 26. harbeck el, glendon ai. how reinforcement sensitivity and perceived risk influence young drivers’ reported engagement in risky driving behaviors. accid anal prev 2013; 54:73–80. doi: 10.1016/j.aap.2013.02.011. 27. evans-whipp tj, plenty sm, toumbourou jw, olsson c, rowland b, hemphill sa. adolescent exposure to drink driving as a predictor of young adults’ drink driving. accid anal prev 2013; 51:185–91. doi: 10.1016/j.aap.2012.11.016. 28. davey jd, davey t, obst pl. drug and drink driving by university students: an exploration of the influence of attitudes. traffic inj prev 2005; 6:44–52. doi: 10.1080/15389580590903168. 29. asbridge m, poulin c, donato a. motor vehicle collision risk and driving under the influence of cannabis: evidence from adolescents in atlantic canada. accid anal prev 2005; 37:1025–34. doi: 10.1016/j.aap.2005.05.006. 30. simons-morton bg, ouimet mc, chen r, klauer sg, lee se, wang j, et al. peer influence predicts speeding prevalence among teenage drivers. j safety res 2012; 43:397–403. doi: 10.1016/j.jsr.2012.10.002. 31. scott-parker b, watson b, king mj. “if they say go faster or something i’ll probably go faster”: peer influence upon the risky driving behaviour of young novices. in: australasian road safety research, policing and education conference, 28–30 august 2013, brisbane, queensland, australia. 32. delhomme p, meyer t. control motivation and young drivers decision making. ergonomics 1998; 41:373–93. doi: 10.1080/001401398187099. 33. yagil d. instrumental and normative motives for compliance with traffic laws among young and older drivers. accid anal prev 1998; 30:417–24. doi: 10.1016/s0001-4575(98)00003-7. 34. mccartt at, hellinga la, braitman ka. cell phones and driving: review of research. traffic inj prev 2006; 7:89–106. doi: 10.1080/15389580600651103. 35. walsh sp, white km, hyde mk, watson b. dialling and driving: factors influencing intentions to use a mobile phone while driving. accid anal prev 2008; 40:1893–900. doi: 10.1016/j. aap.2008.07.005. a c k n o w l e d g e m e n t s the authors appreciate the feedback provided by the anonymous reviewers and the editors as part of the peer-review process. references 1. elvik r. why some road safety problems are more difficult to solve than others. accid anal prev 2010; 42:1089–96. doi: 10.1016/j.aap.2009.12.020. 2. williams af. teenage drivers: patterns of risk. j safety res 2003; 34:5–15. doi: 10.1016/s0022-4375(02)00075-0. 3. lewis-evans b. crash involvement during the different phases of the new zealand graduated driver licensing system (gdls). j safety res 2010; 41:359–65. doi: 10.1016/j.jsr.2010.03.006. 4. mayhew dr, simpson hm, pak a. changes in collision rates among novice drivers during the first months of driving. accid anal prev 2003; 35:683–91. doi: 10.1016/s0001-4575(02)000477. 5. mccartt at, shabanova vi, leaf wa. driving experience, crashes and traffic citations of teenage beginning drivers. accid anal prev 2003; 35:311–20. doi: 10.1016/s0001-4575(02)000064. 6. world health organization. global status report on road safety 2013: supporting a decade of action. from: www.who. int/violence_injury_prevention/road_safety_status/2013/en/ accessed: may 2014. 7. directorate general of traffic, royal omani police. facts and figures. muscat: modern color press, 2014. 8. al reesi h, al maniri a, plankermann k, al hinai m, al adawi s, davey j, et al. risky driving behavior among university students and staff in the sultanate of oman. accid anal prev 2013; 58:1–9. doi: 10.1016/j.aap.2013.04.021. 9. al-maniri aa, al-reesi h, al-zakwani i, nasrullah m. road traffic fatalities in oman from 1995 to 2009: evidence from police reports. int j prev med 2013; 4:656–63. 10. al-naamani a, al-adawi s. ‘flying coffins’ and neglected neuropsychiatric syndromes in oman. sultan qaboos univ med j 2007; 7:75–81. 11. davey jd, freeman je. improving road safety through deterrence-based initiatives: a review of research. sultan qaboos univ med j 2011; 11:29–37. 12. williamson a. young drivers and crashes: why are young drivers over-represented in crashes? summary of the issues. sydney: university of new south wales, 1999. 13. males ma. poverty as a determinant of young drivers’ fatal crash risks. j safety res 2009; 40:443–8. doi: 10.1016/j. jsr.2009.10.001. 14. chen hy, ivers rq, martiniuk al, boufous s, senserrick tm, woodward m, et al. socioeconomic status and risk of car crash injury, independent of place of residence and driving exposure: results from the drive study. j epidemiol community health 2010; 64:998–1003. doi: 10.1136/jech.2009.091496. 15. chen hy, senserrick tm, martiniuk a, ivers rq, boufous s, chang hy, et al. fatal crash trends for australian young drivers 1997-2007: geographic and socioeconomic differentials. j safety res 2010; 41:123–8. doi: 10.1016/j.jsr.2009.12.006. 16. chen lh. teenage driver crash risk: the effect of passengers. baltimore, maryland: johns hopkins university, 1999. 17. preusser df, ferguson sa, williams af. the effect of teenage passengers on the fatal crash risk of teenage drivers. accid anal prev 1998; 30:217–22. doi: 10.1016/s0001-4575(97)00081-x. factors contributing to crashes among young drivers e304 | squ medical journal, august 2014, volume 14, issue 3 36. neyens dm, boyle ln. the influence of driver distraction on the severity of injuries sustained by teenage drivers and their passengers. accid anal prev 2008; 40:254–9. doi: 10.1016/j. aap.2007.06.005. 37. gauld cs, lewis i, white km. concealing their communication: exploring psychosocial predictors of young drivers’ intentions and engagement in concealed texting. accid anal prev 2014; 62:285–93. doi: 10.1016/j.aap.2013.10.016. 38. white km, walsh sp, hyde mk, watson bc. connection without caution? the role of mobile phone involvement in predicting young people’s intentions to use a mobile phone while driving. j australasian coll road safety 2012; 23:16–21. 39. watling cn, armstrong ka, smith ss. sleepiness: how a biological drive can influence other risky road user behaviours. in: proceedings of the 2013 australasian college of road safety (acrs) national conference, adelaide, south australia, australia. pp. 1–12. 40. watling cn. sleepy driving and pulling over for a rest: investigating individual factors that contribute to these driving behaviours. pers individ dif 2014; 56:105–10. doi: 10.1016/j. paid.2013.08.031. 41. weiss hb, kaplan s, prato cg. analysis of factors associated with injury severity in crashes involving young new zealand drivers. accid anal prev 2014; 65:142–55. doi: 10.1016/j. aap.2013.12.020. 42. ferguson sa, teoh er, mccartt at. progress in teenage crash risk during the last decade. j safety res 2007; 38:137–45. doi: 10.1016/j.jsr.2007.02.001. 43. lin ml, fearn kt. the provisional license: nighttime and passenger restrictions: a literature review. j safety res 2003; 34:51–61. doi: 10.1016/s0022-4375(02)00081-6. 44. fell jc, todd m, voas rb. a national evaluation of the nighttime and passenger restriction components of graduated driver licensing. j safety res 2011; 42:283–90. doi: 10.1016/j. jsr.2011.06.001. 45. nokhandan mh, bazrafshan j, ghorbani k. a quantitative analysis of risk based on climatic factors on the roads in iran. meteorol appl 2008; 15:347–57. doi:10.1002/met.77. 46. andrey j, hambly d, mills b, afrin s. insights into driver adaptation to inclement weather in canada. j transp geogr 2013; 28:192–203. doi: 10.1016/j.jtrangeo.2012.08.014. 47. abdel-aty m, ekram aa, huang h, choi k. a study on crashes related to visibility obstruction due to fog and smoke. accid anal prev 2011; 43:1730–7. doi: 10.1016/j.aap.2011.04.003. 48. chen hy, ivers rq, martiniuk al, boufous s, senserrick t, woodward m, et al. risk and type of crash among young drivers by rurality of residence: findings from the drive study. accid anal prev 2009; 41:676–82. doi: 10.1016/j.aap.2009.03.005. 49. shope jt. influences on youthful driving behavior and their potential for guiding interventions to reduce crashes. inj prev 2006; 12:i9–14. doi: 10.1136/ip.2006.011874. 50. mcknight aj, mcknight as. young novice drivers: careless or clueless? accid anal prev 2003; 35:921–5. doi: 10.1016/s00014575(02)00100-8. 51. wylie j. variation in relative safety of australian drivers with age. from: www.infrastructure.gov.au/roads/safety/ publications/1996/pdf/safe_age_1.pdf accessed: mar 2014. 52. masten sv, hagge ra. evaluation of california’s graduated driver licensing program. j safety res 2004; 35:523–35. doi: 10.1016/j.jsr.2004.08.006. 53. hatfield j, fernandes r. the role of risk-propensity in the risky driving of younger drivers. accid anal prev 2009; 41:25–35. doi: 10.1016/j.aap.2008.08.023. 54. prato cg, toledo t, lotan t, taubman-ben-ari o. modeling the behavior of novice young drivers during the first year after licensure. accid anal prev 2010; 42:480–6. doi: 10.1016/j. aap.2009.09.011. 55. al-balbissi ah. role of gender in road accidents. traffic inj prev 2003; 4:64–73. doi: 10.1080/15389580309857. 56. zakrajsek js, shope jt, ouimet mc, wang j, simons-morton bg. efficacy of a brief group parent-teen intervention in driver education to reduce teenage driver injury risk: a pilot study. fam community health 2009; 32:175–88. doi: 10.1097/ fch.0b013e318199482c. 57. arnett jj, offer d, fine ma. reckless driving in adolescence: ‘state’ and ‘trait’ factors. accid anal prev 1997; 29:57–63. doi: 10.1016/s0001-4575(97)87007-8. 58. scott-parker b, watson b, king mj, hyde mk. revisiting the concept of the ‘problem young driver’ within the context of the ‘young driver problem’: who are they? accid anal prev 2013; 59:144–52. doi: 10.1016/j.aap.2013.05.009. 59. arnett j. drunk driving, sensation seeking, and egocentrism among adolescents. pers individ dif 1990; 11:541–6. doi: 10.1016/0191-8869(90)90035-p. 60. jonah ba. sensation seeking and risky driving: a review and synthesis of the literature. accid anal prev 1997; 29:651–65. doi: 10.1016/s0001-4575(97)00017-1. 61. jonah ba, thiessen r, au-yeung e. sensation seeking, risky driving and behavioral adaptation. accid anal prev 2001; 33:679–84. doi: 10.1016/s0001-4575(00)00085-3. 62. hatfield j, fernandes r, job rf. thrill and adventure seeking as a modifier of the relationship of perceived risk with risky driving among young drivers. accid anal prev 2014; 62:223– 29. doi: 10.1016/j.aap.2013.09.028. 63. sagberg f. driver health and crash involvement: a casecontrol study. accid anal prev 2006; 38:28–34. doi: 10.1016/j. aap.2005.06.018. 64. scott-parker b, watson b, king mj, hyde mk. the psychological distress of the young driver: a brief report. inj prev 2011; 17:275–7. doi: 10.1136/ip.2010.031328. 65. rosenbloom t, wultz b. thirty-day self-reported risky driving behaviors of adhd and non-adhd drivers. accid anal prev 2011; 43:128–33. doi: 10.1016/j.aap.2010.08.002. 66. watson bc, mihovilovich s. motor smart: a driver education, judgement training and mentoring program for novice drivers with adhd. in: third national conference on injury prevention and control, may 1999, brisbane, queensland, australia. 67. barkley ra, murphy kr, kwasnik d. motor vehicle driving competencies and risks in teens and young adults with attention deficit hyperactivity disorder. pediatrics 1996; 98:1089–95. 68. reimer b, d’ambrosio la, gilbert j, coughlin jf, biederman j, surman c, et al. behavior differences in drivers with attention deficit hyperactivity disorder: the driving behavior questionnaire. accid anal prev 2005; 37:996–1004. doi: 10.1016/j.aap.2005.05.002. 69. martiniuk al, ivers rq, glozier n, patton gc, lam lt, boufous s, et al. self-harm and risk of motor vehicle crashes among young drivers: findings from the drive study. cmaj 2009; 181:807–12. doi: 10.1503/cmaj.090459. 70. martiniuk al, ivers rq, glozier n, patton gc, senserrick t, boufous s, et al. does psychological distress increase the risk for motor vehicle crashes in young people? findings from the drive study. j adolesc health 2010; 47:488–95. doi: 10.1016/j. jadohealth.2010.03.010. 71. mcdonald wa. young driver research program: a review of information on young driver performance characteristics and capacities. from: www.monash.edu.au/miri/research/reports/ atsb129.pdf accessed: mar 2014. 72. mynttinen s, sundström a, koivukoski m, hakuli k, keskinen e, henriksson w. are novice drivers overconfident? a comparison of self-assessed and examiner-assessed driver competences in a finnish and swedish sample. transp res part f traffic psychol behav 2009; 12:120–30. doi: 10.1016/j. trf.2008.09.002. lyndel j. bates, jeremy davey, barry watson, mark j. king and kerry armstrong review | e305 81. smith ss, horswill ms, chambers b, wetton m. hazard perception in novice and experienced drivers: the effects of sleepiness. accid anal prev 2009; 41:729–33. doi: 10.1016/j. aap.2009.03.016. 82. national highway traffic safety administration. evaluation of pc-based novice driver eisk awareness: final report. from: www.nhtsa.gov/dot/nhtsa/traffic%20injury%20control/ articles/associated%20files/810926.pdf accessed: may 2014. 83. ivers r, senserrick t, boufous s, stevenson m, chen hy, woodward m, et al. novice drivers’ risky driving behavior, risk perception, and crash risk: findings from the drive study. am j public health 2009; 99:1638–44. doi: 10.2105/ ajph.2008.150367. 84. leal nl, watson bc, armstrong ka. risky driving or risky drivers? exploring driving and crash histories of illegal street racing offenders. transportation res rec 2010; 2182:16–23. doi: 10.3141/2182-03. 85. palk g, freeman j, kee ag, steinhardt d, davey j. the prevalence and characteristics of self-reported dangerous driving behaviours among a young cohort. transp res part f traffic psychol behav 2011; 14:147–54. doi: 10.1016/j. trf.2010.11.004. 86. leal nl, watson bc. the road safety implications of illegal street racing and associated risky driving behaviours: an analysis of offences and offenders. accid anal prev 2011; 43:1547–54. doi: 10.1016/j.aap.2011.03.010. 73. langford j. using the research to reduce novice driver crashes. proceedings of the developing safer drivers and riders conference. brisbane: acrs and travelsafe committee, 2002. 74. mccartt at, mayhew dr, braitman ka, ferguson sa, simpson hm. effects of age and experience on young driver crashes: review of recent literature. traffic inj prev 2009; 10:209–19. doi: 10.1080/15389580802677807. 75. gregersen np, berg hy, engström i, nolén s, nyberg a, rimmö pa. sixteen years age limit for learner drivers in sweden: an evaluation of safety effects. accid anal prev 2000; 32:25–35. doi: 10.1016/s0001-4575(99)00045-7. 76. keating dp, halpern-felsher bl. adolescent drivers: a developmental perspective on risk, proficiency, and safety. am j prev med 2008; 35:s272–7. doi: 10.1016/j.amepre.2008.06.026. 77. vidotto g, bastianelli a, spoto a, sergeys f. enhancing hazard avoidance in teen-novice riders. accid anal prev 2011; 43:247– 52. doi: 10.1016/j.aap.2010.08.017. 78. sagberg f, bjørnskau t. hazard perception and driving experience among novice drivers. accid anal prev 2006; 38:407–14. doi: 10.1016/j.aap.2005.10.014. 79. leung s, starmer g. gap acceptance and risk-taking by young and mature drivers, both sober and alcohol-intoxicated, in a simulated driving task. accid anal prev 2005; 37:1056–65. doi: 10.1016/j.aap.2005.06.004. 80. borowsky a, oron-gilad t, parmet y. age and skill differences in classifying hazardous traffic scenes. transp res part f traffic psychol behav 2009; 12:277–87. doi: 10.1016/j.trf.2009.02.001. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 224-233, epub. 9th may 13 submitted 5th jul 12 revision req. 8th sept 12, revision recd. 13th oct 12 accepted 24th nov 12 department of 1biochemistry, college of medicine and health sciences, sultan qaboos university, muscat, oman; 2ministry of health, muscat, oman *corresponding author e-mail: clifab@gmail.com مستوى فيتامني )د( ومؤشرات القياسات البشرية يف دراسة على العمانيني كليفورد اأبياكا، ماريت ديلغاندي ، كاور مينو، حم�شن ال�شالح امللخ�ص: الهدف: تركيز 25هيدروك�شي فيتامني ]d ]25)oh(d يف م�شل الدم يعك�ض م�شتوى فيتامني د عند الأ�شخا�ض، حيث اأن نق�ض فيتامني د يت�شبب يف الكثري من الأمرا�ض. قّيمت هذه الدرا�شة م�شتوى فيتامني )د( عند العمانيني الأ�شحاء وعالقته مع موؤ�رسات القيا�ض الب�رسيه. الطريقة: مت قيا�ض oh(d(25 يف م�شل الدم عن طريق الكروماتوغرافيا ال�شائلة عالية الأداء يف 206 من العمانيني الأ�شحاء الذين ترتاوح اأعمارهم بني 55-18 �شنة )معدل الأعمار: الرجال 31.1، والن�شاء 26.8 �شنه( يف م�شقط،،�شلطنة عمان. %95 من هوؤلء الأ�شخا�ض مل ياأخذوا مكمالت فيتامني )د(. متت مقارنة النتائج مع القيم املن�شورة ل�شكان املناطق ال�شمالية. ا�شتخدمت الإجراءات املتعارف عليها عامليا لتحديد البدانة )موؤ�رس كتلة اجل�شم( ]bmi[ ، وال�شمنة املركزية ممثله مبحيط اخل�رس، ون�شبة قيا�ض اخل�رس اإىل الفخذ )whr(، ون�شبة قيا�ض اخل�رس اإىل الطول. النتائج: كان تركيز 25هيدروك�شي فيتامني )د( يف الن�شاء اأقل ب�شكل ملحوظ من الرجال. باعتبار القيمة الفا�شلة لعتبار م�شتوى oh(d(25 منخف�شا هي اأقل من 50 نانومول / لرت، فان ن�شبة انت�شار نق�ض فيتامني )د( يف هذه الدرا�شة %87.5. هذه القيمة اأعلى من املعدلت عند الربيطانيني، الأوروبييني، الالتينيني والأمريكيني من اأ�شل اأفريقي. و باعتبار القيمة الفا�شلة ملوؤ�رس ال�شمنة bmi اأكرث من30 كغم/مرت2، فقد كان معدل انت�شار ال�شمنة %14.6، وهذا اأقل من ن�شبة ال�شمنة whr 25 ن�شبة اإىل العمر وال�شمنة. وكان)oh(d عند الأوروبيني، الالتينيني والأمريكيني من اأ�شل اأفريقي. وقد ازدادت م�شتويات املوؤ�رس الرئي�شي مل�شتويات oh(d(25 يف م�شل الدم. اخلال�صة: نق�ض فيتامني )د( ال�شديد يف جمتمع الدرا�شة بالن�شبة ل�شكان املناطق ال�شمالية قد يكون ب�شبب جتنب اأ�شعة ال�شم�ض اأو عدم كفايته يف الغذاء، اأو لعدم تناول مكمالت فيتامني )د(. وم�شتوى فيتامني )د( وال�شمنة يتاأثران بالعمر والفوارق بني اجلن�شني بحيث يزداد عند الرجال. مفتاح الكلمات: فيتامني د؛ 25هيدروك�شي فيتامني )د(؛ الكروماتوغرافيا ال�شائلة عالية الأداء؛ موؤ�رسات القيا�شات الب�رسية؛ عمان. abstract: objectives: serum 25-hydroxyvitamin d [25(oh)d] concentrations reflect vitamin d status, with deficiency implicated as causative of many diseases. this study assessed vitamin d status and anthropometric indices in a sample of healthy omanis. methods: serum 25(oh)d concentrations were measured by high performance liquid chromatography in 206 healthy omanis, aged 18–55 years (mean age: men 31.1, women 26.8) in muscat, oman. of this number, 95% indicated that they had never taken vitamin d supplements. findings were compared with published values for populations domiciled in more northerly latitudes. classical procedures were used to determine global obesity (body mass index [bmi]), and central obesity determined by waist circumference, waist-to-hip ratio (whr), and waist-to-height ratio. results: women, as compared to men, had markedly lower concentrations of 25(oh)d. applying the cut-off point of serum 25(oh)d levels at 50 nmol/l, the prevalence of vitamin d deficiency in the study population was 87.5%; this was higher than the rates reported for the british, and european-, hispanic-, and african-americans. at a bmi cut-point of ≥30 kg/m2, the prevalence of obesity was 14.6%; this was lower than the rates reported for european-, hispanic-, and african-americans. levels of 25(oh) d increased relative to age and obesity. whr was the main predictor of 25(oh)d levels. conclusion: the striking vitamin d deficiency seen in the study population, relative to more northerly populations, may be linked to sun avoidance, inadequate dietary vitamin d, and virtual non-intake of supplemental vitamin d. age and male-gender determined the status of vitamin d and of obesity. keywords: vitamin d; 25-hydroxyvitamin d; high-performance liquid chromatography; anthropometric indices; oman. vitamin d status and anthropometric indices of an omani study population *clifford abiaka,1 marit delghandi,1 meenu kaur,2 mohsin al-saleh3 advances in knowledge the prevalence of vitamin d deficiency in this omani population was high at 87.5%. vitamin d provided by foods and supplements is inadequate compared to the amount generated by skin exposure to sunlight. vitamin d3 is more effective than vitamin d2 at raising and maintaining the vitamin d blood value. waist circumference, waist-to-hip ratio, and waist-to-height ratio are considered better determiners of the risk of cardiovascular disease than body mass index. clinical & basic research clifford abiaka, marit delghandi, meenu kaur and mohsin al-saleh clinical and basic research | 225 vitamin d consists of d2 (ergocalciferol) and d3 (cholecalciferol), the former is naturally synthesised from ergosterol by invertebrate fungi in response to ultraviolet b (uvb [280–315 nm]) irradiation, and the latter's synthesis is exclusively initiated in the skin of vertebrates also in response to the uvb irradiation. during sunlight exposure, uvb photons are absorbed by cutaneous 7-dehydrocholesterol, yielding pre-cholecalciferol, which rapidly rearranges to vitamin d3. 1 vitamin d3 synthesis reaches an equilibrium after several minutes, depending on numerous factors including conditions of sunlight (latitude, season, cloud cover, altitude), age, and skin pigmentation.2 vitamin d2 and d3 are also commercially synthesised and are used in fortified food and supplements. endogenously-produced vitamin d enters peripheral circulation where it binds to vitamin d-binding protein for transport to the liver. dietary vitamin d enters the peripheral circulation through the lymph bound to chylomicron remnants and is transported to the liver. both forms of vitamin d undergo hydroxylation in the liver on c-25 by the vitamin d-25-hydroxylase to 25-hydroxyvitamin d [25(oh)d]. further hydroxylation of 25(oh) d occurs in the kidneys by 25-hydroxyvitamin d-1-α-hydroxylase to 1,25-dihydroxyvitamin d [1,25(oh)2d], the biologically-active form of vitamin d.3 this enzyme is also present in a variety of extra-renal sites, including osteoclasts, and the skin, colon, brain and macrophages, which may be the cause of its broad-ranging effects.3 levels of 25(oh)d largely reflect the amount of vitamin d3 produced in the skin, or the vitamin d2 or d3 ingested.4 research has shown that 25(oh)d is also the major circulating form of vitamin d that is measured to determine a person’s vitamin d status because it has a half-life in circulation of 3 weeks and correlates with rickets, osteomalacia, and secondary hyperparathyroidism.5 vitamin d deficiency is implicated as a cause of osteoporosis, cancer, cardiovascular disease (cvd), diabetes mellitus, and multiple sclerosis (ms), among other conditions.6–9 vitamin d deficiency has been linked to obesity and central adiposity.10 body mass index (bmi), an indicator of relative weight for height, is frequently used to assess excess body fat, but does not adequately discriminate between body fat and lean body mass.11,12 visceral adiposity, or intra-abdominal obesity, reflects central body fat distribution and has been suggested as a better marker of obesity risk.11–14 anthropometric indices used as a substitute for evaluation of central body fat distribution are waist circumference (wc), waist-to-hip ratio (whr), and waist-to-height ratio (whtr).11–14 this baseline study aimed to measure serum concentrations of 25(oh)d to assess vitamin d status, and consequently to determine anthropometric indices to assess global obesity and central adiposity in a study population of healthy omani men and women. methods oman is situated in the northern hemisphere, 21° north of the equator. the study was carried out from november to march 2010, when the average temperature is 25° c and skies are mostly clear and sunny. the study population, 206 healthy omani volunteers aged 18–55 years (105 women [mean = 26.8 years] and 101 men [mean = 31.1 years]) was composed of university students, educators, administrators, office secretaries, and their relatives. they completed questionnaires about demographics (age, gender, educational attainment, social status) and their intake of natural and fortified vitamin d-containing foods and vitamin d supplements. the exclusion criteria were pregnancy and medications that raise blood levels, impact absorption, activity, and the activation of vitamin d. enrolment was voluntary, and participants signed applications to patient care the current upper safe limits set by the institute of medicine for vitamin d consumption for infants are 1,000 iu/day and 2,000 iu/day for children and adults. the current estimate is that the upper limit could be increased to 10,000 iu/ day. for repletion, intakes above the upper limit may, however, be required and necessary. the public should be encouraged to be proactive in protecting their health and have their vitamin d blood levels tested annually. women should be aware of their increased risk of vitamin d deficiency and postmenopausal osteoporosis. vitamin d status and anthropometric indices of an omani study population 226 | squ medical journal, may 2013, volume 13, issue 2 a consent form approved by the sultan qaboos university (squ) research review board’s ethics committee (#ec11) for the protection of human subjects in research. for anthropometric measurements, the participants wore light outfits and the means of triplicate measurements of height, weight, hip circumference (hc) and waist circumference (wc) were recorded. height was measured with a wallmounted stadiometer and recorded to the nearest millimetre. weight was measured with a balance beam scale with two sliding weights and recorded to the nearest 0.1 kg. bmi was obtained by dividing the weight by the square of the height. for hip circumference (hc), the participants stood erect with feet together. hc was then measured to the nearest 0.1 cm as the maximal circumference over the buttocks, with the tape position horizontal all around the body. wc was measured at a level midway between the lower rib margin and the iliac crest, with the measuring tape all around the body in a horizontal position and recorded to the nearest millimetre. whr and whtr were calculated and recorded as the ratio of the wc to the hc, and the ratio of wc to height, respectively. a bmi ≥30 kg/m2 was used as the cutoff point for determining global obesity in both genders. for central adiposity, the cut-off points were wc ≥94 cm in men and ≥80 cm for women, and a whr ≥0.90 in men and ≥0.85 in women.14 in both genders, a general cut-off point of ≥0.5 for whtr was used.12 the samples were taken as follows: venous blood samples were withdrawn into evacuated plain tubes and kept in the dark to clot. they were centrifuged and sera were separated into 1.0 ml capacity nalgene® cryogenic vials (nalge nunc international, rochester, new york, usa), capped, wrapped in aluminum foil to protect from light, and stored at -80° c, pending assay for 25(oh)d concentrations within a month. the serum concentrations were measure by high-performance liquid chromatography (hplc). the method used in the current study was modified from the method of turpeinen et al.15 duplicate samples that had been frozen only once were measured. briefly, 500 μl of serum or chromsystems 25(oh)-d3/d2 controls levels i and ii (chromsystems instruments and chemicals, gmbh, münchen, germany) were added to 350 μl of methanol-2-propanol (80:20 by volume) to precipitate protein. the tubes were mixed in a multi-tube vortex mixer for 30 seconds and 25(oh) d was extracted with 2 ml hexane after being mixed 3 times for 60 seconds each time. the phases were separated by centrifugation, and the upper hexane phase was transferred to a glass tube and dried under nitrogen at 40º c. the residue was dissolved in 100 μl of mobile phase (760 ml/l methanol in water), and dispensed in light-protected auto-sampler vials for injection of 25 μl volume. calibration curves were constructed using 4 concentrations of 25(oh)-d3 and 25(oh)-d2 (15–120 nmol/l) prepared in human serum albumin (50 g/l). shimadzu hplc class vp system with isocratic elution and separation of the vitamin d metabolites was performed on a lichrospher 60 reversed-phase select b column (4 mm i.d. x 250 mm long; 5 μm bead size) of ~25º c at a flow rate of 0.7 ml/min. the vitamin d metabolites photodiode array detection was at 265 nm with a sensitivity of 6 nmol/l and linearity 1,250 nmol/l. chromsystems controls were used for internal quality assessment. intra and inter-assay coefficients of variation (cv) (%) for 25(oh)-d2 level i were 3.8 and 4.0, respectively, and for 25(oh)-d3, 3.4 and 4.0, respectively. intra and inter-assay cv (%) for 25(oh)-d2 level ii were 7.8 and 9.9, respectively, and for 25(oh)-d3 10.2 and 11.4, respectively. the method was monitored by participation in the vitamin d external quality assessment scheme (deqas, uk). serum creatinine concentrations were measured by an enzymatic assay on a roche cobas c 111 system (roche diagnostics ltd., rotkreuz, switzerland). the intraand inter-assay cv (%) for biorad level i were 1.9 and 2.3, respectively; level ii were 0.7 and 1.1, respectively, and level iii were 1.2 and 1.5, respectively. statistical analyses were done as follows: the gaussian distribution of all data sets was confirmed by the one-sample kolmogorov-smirnoff test and by histogram plots, followed by presenting all data as mean ± standard deviation (sd). an independent sample t-test was used to differentiate between two mean groups. multiple comparison analyses were performed using scheffe post hoc tests to determine differences between the mean of 3 or more groups. the association between 25(oh)d concentrations and anthropometric measurements were assessed by pearson correlation. stepwise linear regression clifford abiaka, marit delghandi, meenu kaur and mohsin al-saleh clinical and basic research | 227 was used to determine which anthropometric index was the main predictor of serum 25(oh)d levels. probability values were two-tailed and p <0.05 was considered significant. all statistical analyses were performed using statistical package for the social sciences (spss), version 17.0 (ibm, inc., chicago, illinois, usa). results table 1 shows the participants’ responses to the questionnaire items on their intake of dietary and supplemental vitamin d. in decreasing order of intake were fish (51%), cheese (43.2%), laban (a salted yoghurt and water drink) (36.9%), milk (8.3%), and vitamin d supplements (5.3%). data comparison by gender for age, weight, anthropometric indices, 25(oh)d, and creatinine concentrations are detailed in table 2. all the values were significantly higher in men than in women. the prevalence of vitamin d deficiency, global obesity, and central adiposity calculated from the respective cut-off point values are represented in table 3. there was a higher percentage of low concentrations of 25(oh)d in women than in men at the 3 cut-off point values of <25, <50, and <75 nmol/l. global obesity at the bmi cut-off point value of ≥30 kg/m2 was more prevalent in men than in women. the prevalence of central adiposity at cut-off point values of a wc >102 in males (m) and >88 in females (f); a whr >0.9 m, >0.88 f, and a whtr >0.5 m/f were all significantly higher in men than in women. serum concentrations of 25(oh)d, performed in winter at different latitudes, are presented in table 4. the omani study population had lower 25(oh)d values relative to values for studies done in more northerly latitudes. the scatter plot [figure 1] shows that serum concentrations of 25(oh)d were associated moderately (p = 0.023) with bmi and markedly (p <0.0001) with wc, whr, and whtr. stepwise linear regression analysis revealed whr as the main predictor (r = 0.336; p <0.0001) of serum 25(oh)d concentrations. a scatter plot of age versus serum concentrations of 25(oh)d [figure 2] shows the two parameters were strongly correlated. discussion research suggests that vitamin d3, because it binds more tightly than d2 to vitamin d receptors, has a longer half-life and is more potent in raising and maintaining vitamin d blood levels.22 according to responses to the questionnaire [table 1], the omani study subjects ate a considerable amount of fish, including tuna and sardines, but not the table 1: participants' responses to the questionnaire on intake of dietary and supplemental vitamin d diet/supplement positive response (%) fish* 51 milk 8.3 laban** 36.9 cheese 43.2 yoghurt 17.5 vitamin supplement 5.3 *mainly tuna, sardines and other varieties of fish (no salmon, mackerel, or herring ) were consumed; ** laban is a drink produced by mixing an equal quantity of yogurt and water and adding salt to taste. table 2: data comparison (mean ± standard deviation) of various parameters by gender parameters total (n = 206) men (n = 101) women (n = 105) p value age (years) 28.8 ± 8.9 31.1 ± 8.6 26.8 ± 8.6 0.001 weight (kg) 68.1 ± 16.5 71.8 ± 16.5 64.8 ± 16.0 0.003 25(oh)d (nmol/l) 32.8 ± 15.4 36.8 ± 16.7 28.2 ± 12.6 <0.0001 wc (cm) 84.8 ± 15.2 94.7 ± 12.4 75.9 ± 11.1 <0.0001 whr 0.846 ± 0.1 0.914 ± 0.069 0.782 ± 0.076 <0.0001 whtr 0.514 ± .084 0.550 ± 0.074 0.481 ± 0.079 <0.0001 bmi (kg/m2) 24.9 ± 4.8 26.6 ± 4.8 23.5 ± 4.7 <0.0001 creatinine (μmol/l) 61.1 ± 13.5 72.2 ± 0.9 50.6 ± 0.7 <0.0001 statistical significance was considered at p <0.05; 25(oh)d = serum 25-hydroxyvitamin d; wc = waist circumference; whr = waist to hip ratio; whtr = waist to height ratio; bmi = body mass index. vitamin d status and anthropometric indices of an omani study population 228 | squ medical journal, may 2013, volume 13, issue 2 types richer in vitamin d3 such as salmon, herring, and mackerel.23,24 it is likely that because of lactose intolerance the intake of milk was much lower relative to the intake of laban. like milk, most laban drinks are fortified with vitamin d. a very small percentage of the participants indicated that they took vitamin d supplements. at the time of this study, vitamin d2/d3 capsules of the recommended daily allowance (rda) of 200 iu were sold overthe-counter in oman. an rda of ≥400 iu is more effective in boosting plasma levels of 25(oh)d3. 22 the current study utilised hplc to measure serum concentrations of 25(oh)d because the method isolates and quantifies the d2 and d3 metabolites when present in serum. for the purpose of this study, total 25(oh)d was reported. a comparative study of methods used to measure serum 25(oh)d found hplc values closest to the reference liquid chromatography/tandem mass spectrometry (lc-ms/ms ) defined target value.25 the mean serum 25(oh)d value (36.8 nmol/l) obtained for the omani study subjects [table 2] table 3: prevalence rates at cutoff points for vitamin d deficiency, global obesity, and central adiposity parameter cut-off point men n=101 % women n=105 % total n=206 % 25(oh)d (nmol/l) <25 23.8 52.4 39.0 ≤50 81.6 93.1 87.5 ≤75 97.0 100 98.5 bmi (kg/m2) ≥30 19.4 9.8 14.6 wc (cm) >102 m >88 f 24.5 13.7 19.1 whr >0.9 m >0.88 f 53.1 10.8 31.6 whtr >0.5 m/f 75.5 26.5 50.1 25(oh)d = serum 25-hydroxyvitamin d; bmi = body mass index; wc = waist circumference; whr = waist to hip ratio; whtr = waist to height ratio. table 4: reported serum mean serum 25-hydroxyvitamin d (nmol/l) performed at different latitudes location n latitude gender 25(oh)d oman* 101 21o n m 36.8 oman* 105 21o n f 28.2 oman* 206 21o n m, f 32.5 miami16 77 26o n m 62.3 miami16 135 26o n f 56.0 boston17 90 42o n f 60.0 calgary18 188 51o n m, f 57.3 britain19 7437 50–60o n m, f 41.1 denmark20 25 56o n m, f 56.4 norway21 309 68o n f 49.5 * = this study; 25(oh)d = serum 25-hydroxyvitamin d; f = female; m = male. figure 1: relationship between serum 25-hydroxyvitamin d and anthropometric indices (a, b, c, d). clifford abiaka, marit delghandi, meenu kaur and mohsin al-saleh clinical and basic research | 229 was lower than the mean (54.0 nmol/l) reported by a global meta-analysis of 394 studies.26 the mean serum 25(oh)d concentration (28.2 nmol/l) measured in the omani women was lower compared to the mean values (56.0, 60.0, and 49.5 nmol/l, respectively) reported for women in miami, boston, and norway [table 4].16,17,21 the mean serum creatinine values of the study population was normal, indicating unimpaired renal synthesis of 1,25(oh)2d. the current study determined the prevalence of vitamin d deficiency in the omani study population by applying 3 recommended cut-off point values of serum 25(oh)d. the first cut-off point was ≥25 nmol/l which is considered sufficient to prevent the severe hypovitaminosis d that leads to a softening of bone tissue, manifesting as rickets in children and osteomalacia in adults.27 the second is that an absolute minimum 25(oh)d of 50 nmol/l is necessary to support and maintain all the actions of vitamin d on bone and mineral health.3 the third is that newer data showing associations of vitamin d status and the prevalence of several diseases such as cvd, hypertension, colon and breast cancers, and ms, as well as involvement of vitamin d in muscle strength and immune functions, indicate that the target levels of 25(oh)d should be 75–100 nmol/l at the minimum.3 the prevalence of vitamin d deficiency at serum 25(oh)d at <25, <50, and <75 nmol/l were 39.0%, 87.5%, and 98.5% in the overall study sample; 23.8%, 81.6%, and 97% in the men, and 52.4%, 93.1%, and 100% in the women, respectively [table 3]. these values are higher than the prevalence of 15.5%, 46.6%, and 87.1% reported by a british study.19 the observed vitamin d deficiency in the omani study sample could be the consequence of sun avoidance habits, inadequate intake of dietary vitamin d, and the virtual absence of supplemental vitamin d tablets. the strikingly lower levels of 25(oh)d observed in the omani women could be attributed to the mentioned consequences and further compounded by the use of sunscreen and dressing in clothing that allows exposure of only the face. there were no veiled females in this study. clothing impedes cutaneous vitamin d3 photosynthesis; generally, the higher the thread per square inch, the more light attenuation produced.28 the higher the sun protection factor of sunscreen, the more blockage of solar uvb cutaneous synthesis of vitamin d3. 23 the current study evaluated anthropometric indices, noting that the men were heavier and had higher values of these indices than the women [table 2]. bmi is commonly used as an indicator for generalised or global obesity.29 the prevalence of global obesity at a bmi cut-off point of ≥30 kg/ m2 was 14.6% in this study population [table 3]; this was lower than the reported prevalence for whites (23.7%), hispanics (28.7%), and blacks (35.7%) in america.29 the indices of abdominal obesity (wc, whr, and whtr) are considered to be better determiners of the risk of cvd than bmi.12 the cut-off points used to determine the prevalence of central obesity in the omani study sample were wc >102 cm for men and >88 cm for women, a whr >0.9 for men and >0.85 for women, and a general cut-off point of >0.5 for whtr.12,14 central obesity synonymous with visceral adiposity or abdominal obesity (abnormal wc, whr, and whtr) was much more prevalent in men than in women [table 3]. visceral fat is located in the peritoneal cavity and is composed of adipose depots including mesenteric, epididymal white adipose tissue, and perirenal fat. excess visceral fat is a lipid overflow ensuing from a defect of adipose tissue to clear and store the excess triacylglycerols from over-eating and a lack of physical activity.12 the current study further observed that central adiposity indices and not bmi were strongly associated with serum 25(oh)d concentrations [figure 1], a finding inconsistent with previous reports that serum levels of 25(oh)d were inversely associated with wc and visceral adipose tissue.10,29,30 the discrepancy between the current figure 2: relationship between serum 25-hydroxyvitamin d and age. vitamin d status and anthropometric indices of an omani study population 230 | squ medical journal, may 2013, volume 13, issue 2 study and those studies may be linked to the size, age, and health status of the different study populations. the current omani study population was small, apparently healthy, and relatively young (≤55 years), which may not be the case for the populations of the previous studies.10,29,30 among the anthropometric indices evaluated in the current study, whr emerged by stepwise linear regression as the main predictor of serum 25(oh)d levels. there was an age-related increase of serum levels of 25(oh)d in the current study [figure 2], which was in accord with the global study’s findings.26 however, this study’s finding did not conform with suggestions that cutaneous vitamin d synthesis diminished with age (≥65 years), possibly because the omani study population was relatively young (≤55 years).4,27 as this study was done in the winter months of november to march, it was deemed fitting to compare serum 25(oh)d values of the study population domicile in oman (21° n) with summer values of 25(oh)d for populations dwelling in more northerly latitudes such as miami (26° n) and boston (42° n) in the usa, calgary (51° n) in canada, great britain (50–60° n), denmark (56° n), and norway (68° n), which experience summers similar to the omani winter.16–21 an omani winter is almost always cloudless and sunny with an average ambient temperature of 25° c. apart from miami, the other cities at the more northerly latitudes have more cloud cover, which impedes uvb cutaneous penetration for vitamin d3 synthesis. most uvb photons from the sun are absorbed by stratospheric ozone. an increase in the sun’s zenith angle results in an increased path length for the uvb photons to travel, and this explains why at higher latitudes (>~35° n), very little, if any, vitamin d3 is produced in the skin from november through march.2 ironically, the mean serum 25(oh)d values of this study population of omanis were lower than values reported for the populations domiciled in upper latitudes [table 4]. a possible explanation is that those populations were more likely to consume diets richer in vitamin d3 as well as regularly take supplemental vitamin d3. also, the dress habits of populations in more northerly latitudes allow more skin exposure to sunlight than those of omanis. overall, serum concentrations of 25(oh)d reported both for those from more northerly latitudes and omanis were deficient relative to the recommended cut-off point optimum of ≥75 nmol/l.3 conclusion in conclusion, the findings of this study are of great importance in, for example, later development of postmenopausal osteoporosis; particularly, the low level of vitamin d3 in women is worthy of attention. furthermore, correction of low plasma 25(oh)d concentrations can be attained only if people increase the safe, moderate exposure of skin to ultraviolet light; suitable increases in food fortification with vitamin d3, and the provision of higher prescribed amounts of vitamin d3 in supplements. references 1. slominski a, tobin dj, shibahara s, wortsman j. melanin pigmentation in mammalian skin and its hormonal regulation. physiol rev 2004; 84:1155– 228. 2. webb ar. who, what, where and when influences on cutaneous vitamin d synthesis. prog biophys molec biol 2006; 92:17–25. 3. henry hl, bouillon r, norman aw, gallagher jc, lips p, heaney rp, et al. 14th vitamin d workshop: consensus on vitamin d nutritional guidelines. j steroid biochem mol biol 2010; 121:4–6. 4. delucia hf. overview of physiological features and functions of vitamin d. am j clin nutr 2004; 80:1689–96s. 5. holick mf. resurrection of vitamin d deficiency and rickets. j clin invest 2006; 116:2062–72. 6. bischoff-ferrari ha, willett wc, wong jb, stuck ae, staehelin hb, orav ej, et al. prevention of non-vertebral fractures with oral vitamin d dose dependency. a meta-analysis of randomized control trials. arch intern med 2009; 169:551–61. 7. lappe jm, travers-gustafson d, davies km, recker rr, heaney rp. vitamin d and calcium supplementation reduces cancer risk: results of a randomized trial. am j clin nutr 2007; 85:1586–91. 8. baz-hecht m, goldfine ab. the impact of vitamin d deficiency on diabetes and cardiovascular risk. curr opin endocrinol diabetes obes 2010; 17:113– 9. 9. munger kl, levin li, hollis bw, howard ns, ascherio a. serum 25-hydroxyvitamin d levels and risk of multiple sclerosis. jama 2006; 296:2832–8. 10. young ka, engelman cd, langfeld cd, hairston kg, haffner sm, bryer-ash m, et al. association of clifford abiaka, marit delghandi, meenu kaur and mohsin al-saleh clinical and basic research | 231 plasma vitamin d levels with adiposity in hispanics and african americans. clin endocrinol metab 2009; 94:3306–13. 11. price gm, uauy r, breeze e, bulpitt cj, fletcher ae. weight, shape, and mortality risk in older persons: elevated waist-hip ratio, not high body mass index, is associated with a greater risk of death. am j clin nutr 2006; 84:449–60. 12. lee cm, huxley rr, wildman rp, woodward m. indices of abdominal obesity are better discriminator of cardiovascular risk factor than bmi: a metaanalysis. j clin epidemiol 2008; 61:646–53. 13. schneider hj, friedrich n, klotsche j, pieper l, nauck m, john u, et al. the predictive value of different measures of obesity for incident cardiovascular events and mortality. j endocrinol metab 2010; 95:1777–85. 14. ashwell m, hsieh sd. six reasons why the waist-toheight ratio is a rapid and effective global indicator for health risks of obesity and how its use could simplify the international public health message on obesity. int j food sci nutr 2005; 56:303–7. 15. turpeinen u, hohenthal u, stenman u-h. determination of 25-hydroxyvitamin d in serum by hplc and immunoassay. clin chem 2003; 49:1521– 34. 16. levis s, gomez a, jimenez c, vevas l, ma f, lai s, et al. vitamin d deficiency and seasonal variation in an adult south florida population. j clin endocrinol metab 2005; 90:1557–62. 17. harris ss, dawson-hughes b. seasonal changes in plasma 25-hydroxyvitamin d concentrations of young american black and white women. am j clin nutr 1998; 67:1232–6. 18. rucker d, allan ja, fick gh, hanley da. vitamin d insufficiency in a population of healthy western canadians. can med assoc j 2002; 166:1517–24. 19. hyppönen e, power c. hypovitaminosis d in british adults at age 45 years: nationwide cohort study of dietary and lifestyle predictors. am j clin nutr 2007; 85:860–8. 20. thieden e, philipsen pa, heydenreich j, wulf hc. vitamin d level in summer and winter related to measured uvr exposure and behavior. photochem photobiol 2009; 85:1480–4. 21. brustad m, alsaker e, engelsen o, aksenes l, lund e. vitamin d status of middle-aged women at 65–71o n in relation to dietary intake and exposure to ultraviolet radiation. public health nutr 2003; 7:327–35. 22. heaney rp, recker rr, grote j, horst rl, armas la. vitamin d3 is more potent than vitamin d2 in humans. j clin endocrinol metab 2011; 96:e447–52. 23. wolpowitz d, gilchrest ba. the vitamin d questions: how much do you need and how should you get it? j am acad dermatol 2006; 54:301–17. 24. national institutes of health (nih), office of dietary supplements. dietary supplement fact sheet: vitamin d. from: http://ods.od.nih.gov/factsheets/ vitamind.asp. accessed: jun 2008. 25. roth hg, schmidt-gayk h, weber h, nederau c. accuracy and clinical implications of seven 25-hydroxyvitamin d methods compared with liquid chromatography-tandem mass spectrometry as a reference. ann clin biochem 2008; 45:153–9. 26. hagenau t, vest r, gissel tn, poulsen cs, erlandsen m, mosekilde l, et al. global vitamin d level in relation to age, gender, skin pigmentation and latitude: an ecological meta-regression analysis. osteoporosis int 2009; 20:133–40. 27. souberbielle jc, friedlander g, kahan a, cormier c. evaluating vitamin d status. implication for preventing and managing osteoporosis and other chronic diseases. joint bone spine 2006; 73:249– 53. 28. salih fm. effect of clothing varieties on solar photosynthesis of pre-vitamin d3. photodermatol photoimmunol photomed 2004; 20:53–8. 29. pan l, galuska da, sherry b, hunter as, rutledge ge, dietz wh, et al. differences in prevalence of obesity among black, white and hispanic adults– united states, 2006–2008. mmwr 2009; 58:740–4. 30. cheng s, massaro jm, fox cs, larson mg, keyes mj, mccabe el, et al. adiposity, cardiometabolic risk, and vitamin d status: the framingham heart study. diabetes 2010; 59:242–8. صوم التطوع للتحكم بزيادة الوزن بعد شهر رمضان لدى زائدات الوزن والبدينات من النساء �ضورياين اإ�ضماعيل، خديجة �ضم�س الدين، غالب عبد اللطيف، حزيزي اأبو �ضعد، لطيفة عبد املجيد، ف�ضلن حممد عثمان abstract: objectives: this study aimed to examine the effectiveness of an islamic voluntary fasting intervention to control post-ramadan weight gain. methods: this study was conducted between july and november 2011. two weight loss intervention programmes were developed and implemented among groups of overweight or obese malay women living in the malaysian cities of putrajaya and seremban: a standard programme promoting control of food intake according to national dietary guidelines (group b) and a faith-based programme promoting voluntary fasting in addition to the standard programme (group a). participants’ dietary practices (i.e., voluntary fasting practices, frequency of fruit/vegetable consumption per week and quantity of carbohydrates/protein consumed per day), body mass index (bmi), blood pressure, fasting blood high-density lipoprotein cholesterol (hdl-c) and total cholesterol (tc):hdl-c ratio were assessed before ramadan and three months post-ramadan. results: voluntary fasting practices increased only in group a (p <0.01). additionally, the quantity of protein/carbohydrates consumed per day, mean diastolic pressure and tc:hdl-c ratio decreased only in group a (p <0.01, 0.05, 0.02 and <0.01, respectively). frequency of fruit/vegetable consumption per week, as well as hdl-c levels, increased only in group a (p = 0.03 and <0.01, respectively). although changes in bmi between the groups was not significant (p = 0.08), bmi decrease among participants in group a was significant (p <0.01). conclusion: control of post-ramadan weight gain was more evident in the faith-based intervention group. healthcare providers should consider faith-based interventions to encourage weight loss during ramadan and to prevent post-ramadan weight gain among patients. keywords: overweight; obesity; religion and medicine; fasting; weight gain; malaysia. امللخ�س:الهدف: تهدف هذه الدرا�ضة اإىل ختبارمدى فاعلية �ضوم التطوع االإ�ضلمي يف ال�ضيطرة على زيادة الوزن يف مرحلة ما بعد رم�ضان. الطريقة: اأجريت هذه الدرا�ضة بني يوليو اإىل نوفمرب 2011. مت تطوير وتطبيق برناجَمنْي لتقليل الوزن بني جمموعات من الن�ضاء املليو الزائدات الوزن اأو ال�ضمينات اللتي يع�ْضَن يف مدينتني من مدن ماليزيا هما بوتراجايا و�ضريميبان: اأحدهما برنامج معياري لرتويج ال�ضيطرة على تناول الطعام وفقا ملبادئ التوجيهات الغذائية الوطنية )املجموعة ب( والثاين برنامج ديني اإمياين لرتويج �ضيام التطوع باالإ�ضافة اإىل الربنامج املعياري )جمموعة اأ(. مت تقييم ن�ضبة املمار�ضات الغذائية للم�ضاركني )اأي ممار�ضات �ضيام التطوع، و تكرار ا�ضتهلك الفاكهة/ اخل�ضار يف االأ�ضبوع، وكمية ا�ضتهلك الربوتينات/الكربوهيدرات يوميا(، وموؤ�رض كتلة اجل�ضم )bmi(، و�ضغط الدم، والكولي�ضرتول املحمول على الربوتني الدهني عايل الكثافة )hdl-c( ون�ضبة الكولي�ضرتول الكلي إىل العايل الكثافة )hdl-c:)tc قبل رم�ضان وثلثة اأ�ضهر بعد رم�ضان. النتائج: ممار�ضات �ضيام التطوع زادت فقط يف جمموعة اأ مقارنة باملجموعة )ب( )p >0.01(. باالإ�ضافة اإىل ذلك، فاإن ن�ضبة ،0.02 ،0.05 ،p >0.01( )انخف�ضت فقط يف جمموعة)اأ hdl-c:tc كمية بروتني/الكربوهيدرات امل�ضتهلكة يوميا، وال�ضغط االنب�ضاطي و >0.01 ،p = 0.03( )اأ( ازدادت فقط يف جمموعة ،hdl-c تردد ا�ضتهلك الفاكهة/اخل�ضار يف االأ�ضبوع و م�ضتويات .)0.01< على التوايل على التوايل(. على الرغم من اأن التغريات يف موؤ�رض كتلة اجل�ضم بني املجموعات مل تكن موؤثرة اإح�ضائيا )p = 0.08(، فقد انخف�س موؤ�رض كتلة اجل�ضم بني امل�ضاركني يف جمموعة )اأ( ب�ضكل موؤثر )p >0.01(. النتيجة: كان التحكم يف زيادة الوزن يف مرحلة ما بعد رم�ضان اأكرث تاأثريا يف املجموعة التي تبنت التدخل االإمياين. لذا يجب على مقدمي الرعاية ال�ضحية اعتبار التدخلت ذات التاأثري اإلمياين لت�ضجيع فقدان الوزن خلل �ضهر رم�ضان والوقاية من زيادته يف مرحلة ما بعد رم�ضان بني املر�ضى. مفتاح الكلمات: الوزن الزائد؛ ال�ضمنة؛ الدين والطب؛ ال�ضوم؛ زيادة الوزن؛ ماليزيا. voluntary fasting to control post-ramadan weight gain among overweight and obese women *suriani ismail,1,2 khadijah shamsuddin,2 khalib a. latiff,2 hazizi a. saad,3 latifah a. majid,4 fadlan m. othman4 clinical & basic research sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e98–104, epub. 21 jan 15 submitted 15 may 14 revision req. 9 aug 14; revision recd. 9 sep 14 accepted 25 sep 14 departments of 1community health and 3nutrition & dietetics, faculty of medicine and health science, universiti putra malaysia, selangor, malaysia; 2department of community health, faculty of medicine and 4department of al-quran and sunnah, faculty of islamic studies, universiti kebangsaan malaysia, selangor, malaysia *corresponding author e-mail: si_suriani@upm.edu.my advances in knowledge the findings of this study suggest that the promotion of islamic teachings regarding voluntary fasting and the control of food consumption is useful for regulating food intake among overweight and obese women, helping them to prevent post-ramadan weight gain. applications to patient care the faith-based intervention proposed in this study could be implemented in other populations similar to those of malaysia in order to control post-ramadan weight gain. healthcare workers should consider using faith-based communications to control food intake among selected patients for the purposes of weight control. suriani ismail, khadijah shamsuddin, khalib a. latiff, hazizi a. saad, latifah a. majid and fadlan m. othman clinical and basic research | e99 overweightand nutrition-related non-communicable diseases are increasing globally. according to a systematic review of 38 nationally representative studies from six gulf countries, approximately two-thirds to three-quarters of adults were overweight or obese.1 in these countries, the prevalence of nutrition-related non-communicable diseases, such as hypertension and diabetes, was among the highest in the world, with a notably higher prevalence in women.1 obesity is a known health risk with critical implications in terms of related mortality.2 in malaysia, the third national health and morbidity survey (nhms) reported a 12.5% increase in overweight individuals and a 9.6% rise in obesity in 2006 compared with results from 1996.3 specifically, the most significant increase noted was in obesity rates among women, which had increased by 11.7%. the nhms 2006 report found that obesity among ethnic malays, who are predominantly muslim, was 29.8% (95% confidence interval [ci]: 29.1–30.5).3 in comparison, the nhms 2011 report revealed that this rate had increased to 31.1% (95% ci: 29.9–32.3).4 current epidemiological evidence indicates that the rise in the number of overweight individuals in islamic countries, including malaysia, is alarming.1,3,4 specific intervention models are therefore needed to target this high-risk group. diet control is acknowledged as an effective method of managing obesity.5 for certain individuals, dietary practices may be influenced by faith teachings; these teachings may therefore potentially aid the development of dietary interventions. voluntary fasting and control of food quantity are commendable acts according to islamic religious teachings.6,7 christian faith-based health and dietary interventions have reportedly been successful in reducing weight and health risks.8,9 a study by jaber et al. demonstrated that a culturally specific programme with both dietary and exercise components was more readily received than other dietary programmes and could be more effectively implemented to achieve weight loss among participants.10 among islamic followers, the most obvious dietary change occurs during ramadan, when muslims fast during the day for a period of one lunar month. while many studies report significant weight reduction during ramadan, the weight that was lost is typically regained within one month.11–13 the purpose of this study was to examine the effectiveness of an islamic faith-based dietary intervention to control postramadan weight gain. the intervention promoted post-ramadan voluntary fasting and encouraged individuals to control their food intake at all times. it was hypothesised that the control of food consumption and the retainment of ramadan-induced weight loss would be more pronounced in the faith-based intervention group than the control group. methods this study was conducted between july and november 2011 and included 140 muslim malay women working at selected government offices in the malaysian cities of putrajaya and seremban. the participants all had a body mass index (bmi) of >25 kg/m2. participants were excluded from the study if they were pregnant, taking cholesterol-lowering medications, following a commercial replacement diet to lose weight or if they had a medical condition that prevented them from fasting. a quasi-experimental design was followed and included an intervention group and a control group, with serial data collected preand post-intervention. a randomised cluster sampling method was used among consenting government offices [figure 1]. the head of each office gave administrative approval and participants were unaware of the allocation of the groups. the sample size was calculated using a mean difference formula based on a previous lifestyle intervention study conducted in malaysia that evaluated similar variables.14 after estimating a nonresponse rate of 10%, the appropriate sample size was calculated at 86 participants per group; however, only 56 and 84 respondents agreed to participate in the intervention and control groups, respectively. two dietary intervention programmes were developed. the first was a standard programme promo ting food quantity control, which consisted of a copy of national dietary guidelines developed by the malaysian ministry of health in 2010 as well as a food diary based on these guidelines.15 the second intervention included the same components as the standard programme, with additional faith-based components. the faith-based components took the form of four booklets containing relevant islamic information motivating participants to be healthy, control the quantity of food consumed, practice voluntary fasting and remain steadfast in their efforts. additionally, the food diary in the faith-based intervention was printed with religious quotations. participants in the intervention group (group a) received the faith-based intervention, prescribing post-ramadan voluntary fasting and dietary control, while those in the control group (group b) received the standard intervention only. all participants had the relevant dietary intervention programme explained to them thoroughly. in addition, all subjects were trained on methods of monitoring, estimating and reporting their food quantity intake (determined by the number of days per week during which vegetables voluntary fasting to control post-ramadan weight gain among overweight and obese women e100 | squ medical journal, february 2015, volume 15, issue 1 and fruit were consumed and the number of servings of carbohydrates and protein consumed per day). data were collected from the participants as follows. pre-intervention/baseline data were collected in the month before ramadan at the participants’ place of work and the follow-up data were collected three months post-ramadan using a validated selfadministered questionnaire. bmi was calculated using height and weight measurements determined via a tape measure and scale. blood pressure was also measured on-site and blood biochemistry was tested using fasting venous blood drawn for laboratory analysis on the same day. the respondents’ levels of physical activity were measured at baseline only using a malaysian version of the international physical activity questionnaire.16 statistical analysis of the data was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa). an intention-to-treat analysis technique was also applied [figure 1]. any missing values were replaced with baseline values, assuming that there was no change for that participant. basic characteristics between the groups were compared using a t-test. changes between baseline and post-intervention values were compared using a repeated measure analysis of variance test (time*group effect). behavioural changes within the groups were determined using mcnemar’s test for categorical data and a paired t-test for continuous data. appropriate covariate adjustments were performed for the relevant analysis (e.g. age and parity for the bmi analysis and physical activity scores for the blood biochemical analysis). this study was approved by the universiti kebangsaan malaysia medical centre research & ethics committee. written consent was obtained from all respondents and confidentiality was assured. results a total of 56 malay muslim women agreed to participate in group a (the faith-based intervention group) and 84 agreed to participate in group b (the control group). the characteristics of the two groups were similar at baseline, except that the mean parity and physical activity scores were significantly lower in group a than in group b [table 1]. the mean number of children was 1.79 ± 2.14 and 2.67 ± 1.89 (p <0.01) and the mean physical activity score was 1,204 ± 1,408 and 2,120 ± 2,787 metabolic equivalent of task-minutes/ week (p = 0.03), in groups a and b, respectively. the follow-up rate at three months post-ramadan was 85.7% in group a (n = 48) and 73.8% in group b (n = 62). table 2 shows the changes in voluntary fasting practices from baseline within the groups. assessments at three months post-ramadan showed an overall increase in voluntary fasting in group a (p <0.01) as well as an increase in all types of voluntary fasting, with a significant increase in fasting on mondays only, thursdays only and for six days in syawal, the month following ramadan (p = 0.01, 0.04 and 0.03, respectively). among the participants in table 1: baseline characteristics measured before ramadan among malay muslim women in a faith-based dietary intervention (group a) and those adhering to a standard dietary intervention (group b) characteristic group a (n = 56) group b (n = 84) p age in years, mean ± sd 36.65 ± 10.16 39.84 ± 10.28 0.07 parity, mean ± sd 1.79 ± 2.14 2.67 ± 1.89 0.01* monthly income in rm, mean ± sd 3,472 ± 1,979 3,369 ± 2,212 0.76 physical activity score in met-minutes/ week, mean ± sd 1,204 ± 1,408 2,120 ± 2,787 0.03* marital status, n (%) single 14 (25.0) 12 (14.3) 0.28 married 42 (75.0) 72 (85.7) education level, n (%) high school 36 (64.3) 57 (67.9) 0.23 tertiary 20 (35.7) 27 (32.1) employment position, n (%) managerial 17 (30.4) 18 (21.4) 0.23 clerical 39 (69.6) 66 (78.6) sd = standard deviation; rm = malaysian ringgit; met = metabolic equivalent of task. *significant at p ≤0.05. figure 1: flow chart detailing the study population sampling and analytical process. suriani ismail, khadijah shamsuddin, khalib a. latiff, hazizi a. saad, latifah a. majid and fadlan m. othman clinical and basic research | e101 group b, no increase was noted in overall voluntary fasting and there were no significant increases among specific types of voluntary fasting. table 3 shows that baseline dietary practices (i.e. voluntary fasting, the number of days per week during which fruit and vegetables were consumed and the number of servings of carbohydrates and protein consumed per day) were similar between groups a and b. however, significant differences were noted between the groups during post-ramadan assessments regarding the frequency of vegetable consumption per week (p = 0.03) and the number of servings of protein and carbohydrates consumed per day (p <0.01 and p = 0.05, respectively). the frequency of vegetable consumption per week increased in group a and decreased in group b, whereas the number of servings of protein and carbohydrates consumed per day decreased in group a and increased in group b. additionally, table 3 shows that the mean bmi in groups a and b were similar at baseline. at three months post-ramadan, mean bmi had decreased significantly in group a from 31.01 ± 4.07 kg/m2 to 30.52 ± 4.03 kg/m2 (p ≤0.01; ci: 0.22–0.75). in comparison, the decrease in mean bmi for group b was not statistically significant (31.14 ± 4.26 kg/ m2 to 30.98 ± 4.28 kg/m2; p = 0.16; ci: −0.06–0.38). however, changes in bmi between the groups was not significant (p = 0.08). the mean baseline diastolic blood pressure (dbp) in group b was lower than that of group a (p = 0.05). however, at three months post-ramadan, mean dbp had reduced significantly in group a (p <0.01) and a comparison of the changes between the two groups found a statistically significant differ ence (p = 0.02). baseline high-density lipoprotein cholesterol (hdl-c) levels were higher in group b (p <0.01) and the calculated total cholesterol (tc):hdl-c ratio was lower in group b (p <0.01). post-ramadan, hdl-c levels had increased in group a and decreased in group b; comparing the changes between the groups showed that the difference was statistically significant (p <0.01). the mean tc:hdl-c ratio decreased in group a and increased in group b with a statistically significant difference between the two groups (p <0.01). discussion in this study, a faith-based approach was used to develop a weight loss intervention. the treatment prescribed in this islamic faith-based programme was to practice voluntary fasting after ramadan and table 2: voluntary fasting practices at baseline and at three months post-ramadan follow-up among malay muslim women adhering to a faith-based dietary intervention (group a) or a standard dietary intervention (group b) practice group a (n = 56) group b (n = 84) baseline n (%) a follow-up n (%) b % difference b−a % change (b-a)/a x 100 p† baseline n (%) a follow-up n (%) b % difference b−a % change (b-a)/a x 100 p† overall 34 (80.7) 45 (80.4) 19.7 32.4 <0.01* 62 (73.8) 61 (72.6) −1.2 −1.6 1.00 specific mondays only 4 (7.1) 13 (23.2) 16.1 226.8 0.01* 23 (27.4) 19 (22.6) −4.8 −17.5 0.45 thursdays only 6 (10.7) 13 (23.2) 12.5 118.8 0.04* 17 (20.2) 18 (21.4) 1.2 5.9 1.00 mondays and thursdays 25 (44.6) 29 (51.8) 7.2 16.1 0.42 34 (40.5) 32 (38.1) −2.4 −5.9 0.77 three days in a month 4 (7.1) 7.1 (4) 0.0 0.0 1.00 10 (11.9) 7 (8.3) −3.6 −30.2 0.45 prophet david’s fasting 0 (0.0) 0 (0.0) 0.0 0.0 1 (1.2) 1 (1.2) 0.0 0.0 1.00 six days during syawal 19 (33.9) 29 (51.8) 17.9 50.1 0.03* 36 (42.9) 41 (48.8) 5.9 13.8 0.48 other‡ 2 (3.6) 6 (10.7) 7.1 213.9 0.22 15 (17.9) 8 (9.5) −8.4 −46.9 0.12 syawal = the month following ramadan. †mcnemar’s test. *significant at p ≤0.05. ‡including obligatory fasting to replace any fasting not performed during ramadan as well as fasting to fulfill a pledge. voluntary fasting to control post-ramadan weight gain among overweight and obese women e102 | squ medical journal, february 2015, volume 15, issue 1 to control food quantity consumption at all times. in the comparison between the control and fasting intervention groups of overweight or obese malay women, most baseline characteristics were similar. however, the control group appeared to be healthier as the respondents were more physically active and their mean hdl-c levels were higher than that of the fasting intervention groups. these differences could have resulted from unknown confounding variables among the groups associated with the local setting and could not be controlled in a study with a quasiexperimental design. the effect of the two weight loss programmes was investigated at a three month post-ramadan follow-up. control of food consumption and voluntary fasting practices were more pronounced in the faithbased intervention group than in the control group. decreased food consumption among the intervention group could have resulted from the practice of voluntary fasting; religious motivation may have caused subjects to exercise greater control. the overall percentage of participants practicing voluntary fasting increased only among those taking part in the faithbased intervention. when the dietary behaviour changes were quantified, a comparison between the groups showed that the number of servings of carbohydrates and protein consumed decreased in group a. a further positive dietary behaviour change observed among this group was the significantly increased frequency of vegetable consumption. this is important as several studies have shown that an increase in vegetable intake contributes to increased weight loss.14,17 the food quantity control demonstrated by participants taking part in the faith-based intervention could also be translated as reduced energy consumption. reduced consumption may have corrected an energy imbalance in the overweight and obese respondents, contributing to the successful retainment of ramadan weight loss. as a result, the participants’ mean bmi was significantly lower three months after ramadan than it had been before. additionally, mean dbp was table 3: changes in baseline dietary and weight loss variables among malay muslim women adhering to a faith-based dietary intervention (group a) or a standard dietary intervention (group b) before ramadan and at a three month post-ramadan follow-up variable group a (n = 56) group b (n = 84) comparison baseline, mean ± sd follow-up, mean ± sd p† baseline, mean ± sd follow-up, mean ± sd p† at baseline at follow-up t value p‡ f statistic (df ) p§ fasting in days/month 2.30 ± 2.62 2.34 ± 3.02 0.91 2.71 ± 2.62 2.27 ± 2.30 0.05* 0.91 0.37 1.61 (1,138) 0.21 vegetable consumption in days/week 4.63 ± 2.02 5.02 ± 1.80 0.06 4.86 ± 2.21 4.48 ± 2.21 0.13 0.64 0.53 4.95 (1,138) 0.03* fruit consumption in days/week 3.80 ± 1.86 4.13 ± 1.73 0.13 4.32 ± 2.05 4.12 ± 1.91 0.35 1.52 0.13 2.82 (1,138) 0.10 carbohydrates servings/day 3.17 ± 0.91 2.98 ± 0.95 0.11 3.14 ± 1.09 3.29 ± 1.05 0.18 0.17 0.87 4.00 (1,138) 0.05* protein servings/day 2.38 ± 1.15 2.20 ± 0.92 0.08 2.15 ± 0.83 2.42 ± 0.99 0.01* 1.36 0.18 8.70 (1,138) <0.01* bmi in kg/m2 31.01 ± 4.07 30.52 ± 4.03 <0.01* 31.14 ± 4.26 30.98 ± 4.28 0.16 0.17 0.86 3.12 (1,136) 0.08 sbp in mmhg 123.4 ± 12.3 122.0 ± 14.3 0.33 124.5 ± 18.1 124.0 ± 19.9 0.63 0.30 0.70 0.14 (1,137) 0.71 dbp in mmhg 79.8 ± 10.3 77.1 ± 10.5 <0.01* 76.4 ± 10.1 77.1 ± 11.0 0.44 1.96 0.05 6.09 (1,137) 0.02* hdl-c in mmol/l 0.73 ± 0.19 0.79 ± 0.22 0.01* 1.27 ± 0.36 0.90 ± 0.29 <0.01* 10.29 <0.01* 78.63 (1,131) <0.01* tc:hdl-c ratio 6.97 ± 1.73 6.82 ± 2.36 0.40 3.87 ± 1.06 4.87 ± 1.58 <0.01* 13.12 <0.01* 30.66 (1,131) <0.01* sd = standard deviation; df = degrees of freedom; bmi = body mass index; sbp = systolic blood pressure; dbp = diastolic blood pressure; hdl-c = high-density lipoprotein cholesterol; tc = total cholesterol. †paired t-test. ‡independent t-test. §repeated measure analysis of variance (time*group effect). *significant at p ≤0.05, adjusted to covariate age and parity. suriani ismail, khadijah shamsuddin, khalib a. latiff, hazizi a. saad, latifah a. majid and fadlan m. othman clinical and basic research | e103 observed to decrease in the intervention group and increase in the control group. generally, reduction in dbp may occur due to a corresponding decrease in weight, as weight loss has been shown to positively correlate with reduced blood pressure.18,19 the effect of the faith-based dietary intervention was more obviously observed in the participant’s dbp rather than systolic blood pressure. several studies have also shown that intermittent fasting and caloric restriction lowers blood pressure because it reduces oxidation damage and increases cellular resistance.20,21 as these fasting practices were more frequent among subjects in the faith-based intervention, this may further explain the reduction in mean bp. in the current study, biochemical changes in the blood were assessed in order to compare changes in health risk using the tc:hdl-c ratio, a measurement that indicates the risk of several diseases such as coronary heart disease.22 at baseline, mean tc:hdl-c ratio was significantly higher in the faithbased group. although the mean ratio remained high in this group even at the three month follow-up, there was a significant decrease in the mean ratio due to the increase in mean hdl-c. this may have resulted from the act of fasting as research has shown that hdl-c increases 20–30% after fasting.23,24 changes in the control group, however, showed the opposite result. this may have been due to several confounding factors that were not measured in this study, such as reduced physical activity, which is positively associated with hdl-c, or reduced consumption of hdl-cproducing foods such as fish.25,26 studies have shown that one of the best predictors of weight loss maintenance is adherence to the programme.27,28 women participating in the faithbased intervention may have been more successful in maintaining ramadan weight loss due to an improved adherence to the weight loss regime. the theory of planned behaviour (tpb) is used to explain the expected differences in behavioural changes; this theory states that behaviour intention predicts behaviour change.29 although material provided in the standard intervention was received by both groups, the faith-based intervention group received additional relevant religious information. this included, for example, reminders of the prohibition of overeating from a religious perspective. this additional information may have enhanced the motivation of these subjects to control their food consumption (behaviour intention). previous studies have shown that faith-related goals can strengthen behaviour intention and drive on-going pursuits with or without immediate tangible health outcomes.30,31 therefore, a faith-based approach to dietary control could prevent participants from giving up after failed weight loss attempts. the main limitations of this study include the quasi-experimental study design, as local environmental influences could not be controlled, and the loss of participants during the three month follow-up period. the limitation of the study design was minimised by using a control group and serial data collection. the effect of the loss of follow-up was minimised by using the intention-to-treat statistical principle. conclusion in this study, the control of post-ramadan weight gain was more evident among overweight and obese malay women undergoing an islamic faith-based intervention than among those undergoing a standard dietary intervention. these findings suggest that voluntary fasting during ramadan and at other times could serve as an excellent method to control food intake, while relevant islamic-based motivation and information could enhance these practices. healthcare providers should consider promoting faith-based dietary interventions by encouraging ramadan weight loss and the prevention of post-ramadan weight gain. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. ng sw, zaghloul s, ali hi, harison g, popkin bm. the prevalence and trends of overweight, obesity and nutritionrelated non-communicable diseases in the arabian gulf states obes rev 2011; 12:1–13. doi: 10.1111/j.1467-789x. 2010.00750.x. 2. flegal km, graubard bi, williamson df, gail mh. excess deaths associated with underweight, overweight and obesity. jama 2005; 293:1861–7. doi: 10.1001/jama.293.15.1861. 3. nor safiza mn, khor gl, suzana s, kee cc, jamaiyah h, geeta a, et al. the third national health and morbidity survey (nhms iii) 2006: nutritional status of adults aged 18 years and above. malays j nutr 2008; 14:1–87. 4. ministry of health malaysia. national health and morbidity survey 2011 fact sheet. from: www.moh.gov.my/index.php/file_manager/dl_ item/624746305a584e305833426b5a69394f51305176546b684 e5 53138794d44457858305a42513152665530684652565175634752 6d accessed: mar 2014. 5. astrup a. dietary management of obesity. jpen j parenter enteral nutr 2007; 32:575–7. doi: 10.1177/0148607108321707. 6. salleh ms. religiosity in development: a theoretical construct of an islamic-based development. int j humanit soc sci 2012; 2:266–74. 7. al-hilali mt, khan mm. the translation of the meanings of the noble quran. madina, saudia arabia: king fahd complex for printing the holy quran, 2005. verse 7:31. 8. dehaven mj, hunter ib, wilder l, walton jw, berry j. health programs in faith-based organizations: are they effective? am j public health 2004; 94:1030–6. doi: 10.2105/ajph.94.6.1030. voluntary fasting to control post-ramadan weight gain among overweight and obese women e104 | squ medical journal, february 2015, volume 15, issue 1 9. fitzgibbon ml, tussing-humphreys lm, porter js, martin ik, odoms-young a, sharp lk. weight loss and africanamerican women: a systematic review of the behavioural weight loss intervention literature. obes rev 2012; 13:193–213. doi: 10.1111/j.1467-789x.2011.00945.x. 10. jaber la, pinelli nr, brown mb, funnell mm, anderson r, hammad a, et al. feasibility of group lifestyle intervention for diabetes prevention in arab americans. diabetic res clin pract 2011; 91:307–15. doi: 10.1016/j.diabres.2010.11.032. 11. poh bk, zawiah h, ismail mn, henry c. changes in body weight, dietary intake and activity pattern of adolescents during ramadan. malays j nutr 1996; 2:1–10. 12. khaled bm, belbraouet s. effect of ramadan fasting on anthropometric parameters and food consumption in 276 type 2 diabetic obese women. int j diabetes dev ctries 2009; 29:62– 8. doi: 10.4103/0973-3930.53122. 13. hajek p, myers k, dhanji ar, west o, mcrobbie h. weight change during and after ramadan fasting. j public health (oxf ) 2012; 34:377–81. doi: 10.1093/pubmed/fdr087. 14. moy f, sallam aa, wong m. the results of a worksite health promotion programme in kuala lumpur, malaysia. health promot int 2006; 21:301–10. doi: 10.1093/heapro/dal031. 15. national coordinating committee on food and nutrition, ministry of health malaysia. malaysian dietary guidelines. from: dg.cnsoc.org/upload/affix/20140818104029708.pdf accessed: mar 2014. 16. unit for public health nutrition. international physical activity questionnaire, short format, language malay. from: www.ipaq. ki.se/questionnaires/malayipaqslself.pdf accessed: jan 2011. 17. whigham ld, valentine ar, johnson lk, zhang z, atkinson rl, tanumihardjo sa. increased vegetable and fruit consumption during weight loss effort correlates with increased weight and fat loss. nutr diabetes 2012; 2:e48. doi: 10.1038/ nutd.2012.22. 18. tesfaye f, nawi ng, van minh h, byass p, berhane y, bonita r, et al. association between body mass index and blood pressure across three populations in africa and asia. j hum hypertens 2007; 21:28–37. doi: 10.1038/sj.jhh.1002104. 19. lecheminant jd, kirk ep, hall ma, bailey bw, jacobsen dj, stewart e, et al. impact of different levels of weight loss on blood pressure in overweight and obese women. dis manag 2007; 10:83–90. doi: 10.1089/dis.2006.633. 20. mager de, wan r, brown m, cheng a, wareski p, abernethy dr, et al. caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats. faseb j 2006; 20:631–7. doi: 10.1096/fj.05-5263com. 21. mattson mp, wan r. beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. j nutr biochem 2005; 16:129–37. doi: 10.1016/j.jnutbio.2004.12.007. 22. linn s, fulwood r, caroll m, brook jg, johnson c, kalsbeek wd, et al. serum total cholesterol: hdl cholesterol ratios in us white and black adults by selected demographic and socioeconomic variable (hanes ii). am j public health 1991; 81:1038–43. doi: 10.2105/ajph.81.8.1038. 23. lamri-senhadji my, el kebir b, belleville j, bouchenak m. assessment of dietary consumption and time-course of changes in serum lipids and lipoproteins before, during and after ramadan in young algerian adults. singapore med j 2009; 50:288–94. 24. ibrahim o, kamaruddin n, wahab n, rahman m. ramadan fasting and cardiac biomarkers in patients with multiple cardiovascular disease risk factors. internet j cardiovasc res 2010; 7:1–11. 25. panagiotakos db, pitsavos c, chrysohoou c, skoumas j, zeimbekis a, papaioannou i, et al. effect of leisure time physical activity on blood lipid levels: the attica study. coron artery dis 2003; 8:533–9. 26. bulliyya g. influence of fish consumption on the distribution of serum cholesterol in lipoprotein fractions: comparative study among fish-consuming and non-fish-consuming population. asia pac j clin nutr 2002; 11:104–11. doi: 10.1046/j.14406047.2002.00256.x. 27. acharya sd, elci ou, sereika sm, music e, styn ma, turk, mw, et al. adherence to a behavioral weight loss treatment program enhances weight loss and improvements in biomarkers. patience prefer adherence 2009; 3:151–60. doi: 10.2147/ppa.s5802. 28. vogels n, diepvens k, westerterp-plantega ms. predictors of long-term weight maintenance. obes res 2005; 13:2162–8. doi: 10.1038/oby.2005.268. 29. armitage cj, conner m. efficacy of the theory of planned behavior: a meta-analytic review. br j soc psychol 2001; 40:471–99. doi: 10.1348/014466601164939. 30. baranowski t, cullen kw, nicklas t, thompson d, baranowski j. are current health behavioral changes models helpful in guiding prevention of weight gain efforts? obes res 2003; 11:23s–43s. doi: 10.1038/oby.2003.222. 31. omondi do, walingo mk, mbagaya gm, othuan loa. preintention mediators within the theory of planned behaviour applied to dietary practices among t6ype ii diabetics: what is the position of perceived dietary knowledge? asian j med sci 2010; 2:259–65. department of pediatrics, university children hospital, minia university, minia, egypt *corresponding author e-mail: basmaelmoez@yahoo.com تواتر اخللل الوظيفي الكبييب يف األطفال املصابني مبرض بيتا ثالسيميا الكربى يف ب�صمة عبد �ملعز علي و �أحمد حممد حممود abstract: objectives: this study investigated the frequency of glomerular dysfunction in children with beta thalassaemia major (β-tm) by using different markers and correlating them with serum ferritin and iron chelation therapy. methods: the study, carried out between august 2011 and may 2012, included 100 patients with β-tm, in two groups. group ia (n = 62) received chelation therapy (deferoxamine). group ib (n = 38) received followup care at the pediatric hematology outpatient clinic, minia university children’s hospital, egypt. group ii included 50 apparently healthy controls, ageand sex-matched to group i. all patients underwent a thorough history-taking, clinical examination and laboratory investigations. results: compared to group ii, groups ia and ib had significantly higher levels of cystatin c, serum creatinine and serum ferritin, and a higher albumin/ creatinine ratio in their urine, and a significantly lower estimated glomerular filtration rate (egfr) and creatinine clearance (p <0.05). moreover, group ιa had a significantly lower egfr and creatinine clearance than group ib. cystatin c had a highly significant strong negative correlation with egfr and creatinine clearance and a significantly strong positive correlation with serum ferritin, and a higher sensitivity and specificity than serum creatinine and creatinine clearance for small changes in gfr. conclusion: β-tm patients had a high frequency of glomerular dysfunction—possibly attributable to chronic anaemia, iron overload or chelation therapy. periodic renal assessment is mandatory to detect renal complications. cystatin c is a promising marker to monitor glomerular dysfunction, having a higher sensitivity and specificity than serum creatinine and creatinine clearance for small changes in gfr. keywords: abnormalities, glomerular; beta-thalassemia; cystatin c; chelation therapy; egypt. امللخ�ص: الهدف: هدفت هذه �لدر��صة �إىل �لتحقق من وترية حدوث �خللل �لوظيفي �لكبيبي يف �الأطفال �لذين يعانون من بيتا ثال�صيميا �لكربى با�صتخد�م موؤ�رش�ت خمتلفة و ربطها مع ن�صبة �لفرييتي و�لعالج �مل�صتخدم يف عملية �إز�لة �حلديد من �جل�صم. الطرق: �صملت �لدر��صة و�لتي �أجريت بي �أغ�صط�س 2011 ومايو 2012 مائة من �ملر�صى �لذين يعانون من بيتا ثال�صيميا, و ق�صمت �إيل جمموعتي. �ملجموعة �الأوىل �أ )عددها 62( وتاأخذ عقار ديفريوك�صامي الإز�لة �حلديد من �جل�صم �أما �ملجموعة �الأوىل ب )عددها 38( دون تناول ذلك �لعقار مع متابعة �لرعاية �ل�صحية يف �لعيادة �خلارجية الأمر��س �لدم يف م�صت�صفى جامعة �ملنيا لالأطفال, م�رش. �صملت �ملجموعة �لثانية 50 من �الأ�صحاء �ملتطابقي من حيث �لعمر و�جلن�س مع �ملجموعة �الأويل وخ�صع جميع �ملر�صى الأخذ تاريخ دقيق وفح�س �رشيري وخمتربي. النتائج: �أثبتت �ملقارنة بي �ملجموعة �الأويل )�أ( و )ب( مع �ملجموعة �لثانية �أن �ملجموعة �الأوىل )�أ ( و )ب( كان بها م�صتويات �ل�صي�صتاتي �صي, و م�صتوى �لكرياتيني و �لفرييتي يف م�صل �لدم, ومعدل ن�صبة �لزالل/ �لكرياتيني يف �لبول �أعلى بكثري من �ملجموعة �لثانية , وكذلك معدل �لرت�صيح �لكبيبي وت�صفية �لكرياتيني �أقل ب�صكل د�ل �إح�صائيا. وعالوة على ذلك وجد �أن معدل �لرت�صيح وت�صفية �لكرياتيني كان �أقل يف �ملجموعة �الأوىل )�أ ( عنه يف �ملجموعة �الأوىل )ب( ب�صكل د�ل �إح�صائيا ووجدت عالقة قويه عك�صية د�له �إح�صائيا بي �ل�صي�صتاتي �صي و معدل �لرت�صيح �لكبيبي وت�صفية �لكرياتيني و عالقة �إيجابية قوية ب�صكل ملحوظ بي م�صتوى �ل�صي�صتاتي �صى و م�صتوى �لفرييتي فى �مل�صل. وكانت ح�صا�صية وخ�صو�صية �ل�صي�صتاتي �صى فى �لتنبوؤ بالتغري�ت �ل�صغرية يف معدل �لرت�صيح �لكبيبي �أعلى من �لكرياتيني يف م�صل �لدم وت�صفية �لكرياتيني. و�خلال�صة: �ن مر�صى بيتا ثال�صيميا لديهم وترية عالية من �خللل �لكبيبي وقد يعزى ذلك �إىل فقر �لدم �ملزمن و �حلديد �لز�ئد �أو �لعالج �مل�صتخدم يف عملية �إز�لة �حلديد الإ�ستنتاج: �إن �لتقييم �لدوري للكلى �إلز�مي للك�صف عن �مل�صاعفات �لكلوية. �ل�صي�صتاتي �صي هو عالمة و�عدة لر�صد �خللل �لكبيبي, حل�صا�صيته وخ�صو�صيته �لعاليه للتغيري�ت �لب�صيطة يف �لرت�صيح �لكبيبي مقارنة مبوؤ�رش�ت �لكرياتيني و وت�صفية �لكرياتيني يف م�صل �لدم. مفتاح الكلمات: �خللل �لكبيبي؛ بيتا ثال�صيميا؛ �صي�صتاتي �صي؛ �لعالج الإز�لة �حلديد؛ م�رش. frequency of glomerular dysfunction in children with beta thalassaemia major *basma a. ali and ahmed m. mahmoud clinical & basic research advances in knowledge glomerular dysfunction in children with beta major thalassaemia (β-tm) may be subclinical and, as this dysfunction may not be detected by routine testing, the use of early markers is recommended. application to patient care in β-tm patients, a close follow-up of glomerular dysfunction is necessary as it is not a rare complication. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e88-94, epub. 27th jan 14 submitted 12th may 13 revision req. 14th aug 13; revision recd. 15th aug 13 accepted 5th sep 13 basma a. ali and ahmed m. mahmoud clinical and basic research | e89 beta thalassaemia (β-tm) is an inherited haemoglobin disorder characterised by the failure of the patient to produce beta haemoglobin chains, usually resulting in severe anaemia in its homozygous and compound heterozygous forms. the use of regular and frequent blood transfusions in patients with β-tm major has improved patients’ life spans and quality of life, but can lead to chronic iron overload.1 unlike other organs, it is unclear whether kidney damage results solely from intravascular haemolysis, chronic transfusion or as a complication of iron chelation therapy.2 patients with β-tm are known to have severe cardiopulmonary and reticuloendothelial dysfunction, but renal involvement has received little attention.3 cystatin c is a 122-amino acid non-glycosylated protein of low molecular weight (13 kilodaltons [kda]) that inhibits cysteine proteases. it is filtered by glomeruli and followed by tubular reabsorption and degradation, resulting in the excretion of a minute amount of cystatin c in the urine. it is not secreted by the renal tubules or reabsorbed back into the serum. therefore, its serum levels serve as an endogenous parameter of glomerular filtration rate (gfr).4 due to its small size, cystatin c is freely filtered by the glomerulus, and is not secreted but is fully reabsorbed and broken down by the renal tubules. this means that the primary determinate of blood cystatin c levels is the rate at which it is filtered at the glomerulus, making it an excellent marker of gfr. a recent meta-analysis demonstrated that serum cystatin c is a better marker for gfr than serum creatinine.4 therefore, this study aimed to investigate the frequency of glomerular dysfunction in children with β-tm by using different markers and correlating them with serum ferritin and iron chelation therapy. methods this cross-sectional study included an experimental group (group i) of 100 patients, 72 males (65.5%) and 28 females (34.5%) aged 8–16 years and recruited from august 2011 to may 2012. exclusion criteria included a patient history suggestive of recurrent urinary tract infections; the presence of systemic diseases affecting the kidney; the presence of rheumatic heart, thyroid, hepatic diseases, or diabetes mellitus; the intake of trimethoprim, corticosteroids or cephalosporin in the past seven days; a history of nephrotoxic drug use, and a family history of hereditary renal diseases. the control group included 50 apparently healthy volunteers who were ageand sex-matched to those in group i. the patients with β-tm were divided into two groups. group ia (n = 62) received regular chelation therapy consisting of deferoxamine (dfo) in doses of 20–40 mg/kg per day via subcutaneous pump infusions over 8–12 hours/night for five days a week. group ib (n = 38) did not receive chelation therapy. those in group ib underwent regular follow-up in the pediatric hematology outpatient’s clinic of the university children’s hospital of minia university, egypt. written consent was received from the patients’ caregivers after the approval of the study by the university’s ethical committee. both groups underwent a through historytaking and clinical examination. morning fasting blood samples and urine specimens were collected and tested for different biochemical function profiles, including simple urine analysis,5 an evaluation of the albumin/creatinine (a/c) ratio in the urine using the national kidney foundation’s level recommendations as a reference (female <3.5 mg/mmol, male <2.5 mg/mmol)6 and creatinine clearance.7 the estimated glomerular filtration rate (egfr) was calculated using the schwartz formula for children, where constants were 0.44 for children <2 years and 0.55 for children ≥2 years: renal dysfunction was defined as egfr <90 ml/ min per 1.73 m2.8 a complete blood count (cbc) was done using a sysmex complete blood count analyzer (sysmex corporation, kobe, hyogo, japan) and serum ferritin (ug/dl) was done by enzyme-linked immunosorbent assay (elisa) the use of alternative chelation therapy may decrease the possibility of renal damage by deferoxamine. increased awareness among patients and their parents about the benefits of compliance to chelation therapy is a necessity. egfr (ml/min per 1.73 m2) = height (cm) × constant/serum creatinine (mg/dl) frequency of glomerular dysfunction in children with beta thalassaemia major e90 | squ medical journal, february 2014, volume 14, issue 1 (r&d systems, minneapolis, usa).9 renal function tests include blood urea with a reference range of 3.0–6.0 mmol/l and serum creatinine with a reference value for females of 40–90 μmol/l and males of 50–100 μmol/l) by a creatinine-jaffe enzymatic assay using a spectrophotometer.10 finally, serum cystatin c level was measured by a quantikine® human cystatin c immunosorbent assay (elisa) kit (r&d systems) with a reference value of 0.80–0.90 mg/l.11,12 the data were coded and verified prior to data entry. the statistical package for the social sciences (spss), version 13 (ibm, corp., chicago, illinois, usa), was used for data entry and analysis. all numeric variables were expressed as mean ± standard deviation (sd). comparison of different variables in various groups was done using the student’s t-test and mann-whitney u test for normal and non-parametric variables, respectively. the chisquared test (χ2) was used to compare the frequency of qualitative variables among the different groups. pearson’s and spearman’s correlation tests were used for correlating parametric and non-parametric variables, respectively. multiple regression analysis was also performed to determine the effect of various factors on a dependent variable. a p value of >0.05 was determined as non-significant while a p value of <0.05 was significant. a z-test was used to compare proportions and correlations.13 a receiver operating characteristic (roc) analysis was done to determine the accuracy of serum cystatin c versus serum creatinine and creatinine clearance by plotting the sensitivity and specificity of the experimental and control groups. results in this study, the frequency of glomerular dysfunction in children with β-tm was investigated by using different markers and correlating them with serum ferritin and iron chelation therapy. a comparison of groups ιa and ib in regards to clinical findings showed that group ia had a significantly higher frequency of blood transfusions than group ιb (p = 0.02) [table 1]. concerning the laboratory parameters, table 2 shows that groups ιa and ib had statistically significant higher levels of serum cystatin c, serum creatinine and serum ferritin, and a higher albumin/creatinine (a/c) ratio of the urine than group ii where p <0.05. on the other hand, they had a significantly lower egfr as determined by schwartz and a lower creatinine clearance than group ii. a comparison between groups ia and ib demonstrated that group ιa had a significantly lower egfr and creatinine clearance than group ib (p = 0.004 for each). in regards to different correlations, there were statistically significant strong negative correlations between serum cystatin c with egfr and creatinine clearance where r = -0.91, p = 0.001 and r = -0.80, p = 0.005, respectively. moreover, there was an insignificant negative weak correlation with the frequency of blood transfusions (r = -0.14, p = 0.3) and a significant positive correlation with duration of chelation therapy, serum ferritin and a/c ratio in the urine (r = 0.29, p = 0.04; r = 0.9, p = 0.001; r = 0.82, p = 0.0001, respectively) [table 3]. a roc test was done for serum cystatin c and serum creatinine in β-tm patients and control groups, and it was found that the area under the curve (auc) for serum cystatin c was significantly higher than that for serum creatinine [figure 1]. moreover, serum cystatin c had higher sensitivity and specificity than serum creatinine (65% versus 27% and 91% versus 79%) [table 4]. table 5 and figure 2 show that the auc for serum cystatin c was significantly higher than that for creatinine clearance and serum cystatin c had higher sensitivity and specificity than creatinine clearance table 1: comparison between beta thalassaemia major patient subgroups by clinical characteristics parameter patient subgroups p value group ia with chelation (n = 62 ) group ib without chelation (n = 38) age in years, range (mean ± sd) 10–16 (9.6 ± 1.1) 8–14.5 (9.8 ± 1.7) 0.8 gender, n (%) male 40 (64.5) 24 (63.2) 0.5 female 22 (35.5) 14 (36.8) age of onset of transfusion in months, mean ± sd 7.8 ± 3.2 8.7 ± 2.6 0.07 frequency of blood transfusion per year, mean ± sd 11.3 ± 1.9 9.4 ± 4.03 0.02* splenectomy, n (%) positive 6 (9.7) 3 (7.9) 0.3 negative 56 (90.3) 35 (92.1) sd = standard deviation; *significant. basma a. ali and ahmed m. mahmoud clinical and basic research | e91 (67% versus 63% and 93% versus 66%, respectively). discussion in this study, it should be noted that less attention was paid to renal complications. koliakos et al. and others have conducted investigations of renal involvement in adult β-tm patients.14,15 the current study was designed to investigate glomerular dysfunction in children with β-tm by using different markers, including cystatin c, and to correlate those findings with serum ferritin and iron chelation therapy. the current study found that group ia had statistically significant higher frequencies of blood transfusion than group ib (p = 0.02) [table 1], this was perhaps due to the potential ignorance of the group ib parents and their failure to comply with treatment. concerning laboratory data, the current study found that β-tm patients, whether receiving chelation therapy or not, had statistically significant higher levels of serum cystatin c, serum creatinine and serum ferritin than those in the control group. on the other hand, they had a significantly lower egfr and creatinine clearance than the control group. this could be explained by the possibility that renal dysfunction in patients with β-tm was due to long-standing anaemia, chronic hypoxia and iron overload.14 in addition, the shortened life span of red blood cells with rapid iron turnover and dfo therapy may have proven nephrotoxic.15 these results were in agreement with the results obtained table 2: comparison between the beta thalassaemia major subgroups and the control group by laboratory findings parameter group ia with chelation (n = 31) group ib without chelation (n = 19) group ii control (n = 35) p value ia versus ii ib versus ii ia versus ib cystatin c in mg/dl, range (mean ± sd) 0.7–2 (1.9 ± 0.2) 0.5–1.8 (1.6 ± 0.3) 0.3–0.6 (0.6 ± 0.1) 0.01* 0.01* 0.1 serum creatinine in mg/ dl, range (mean ± sd) 0.7–1.5 (0.9 ± 0.1) 0.5–1.2 (0.7 ± 0.2) 0.5–0.8 (0.4 ± 0.08) 0.01* 0.01* 0.1 egfr by schwartz formula in ml/min per 1.73 m2, range (mean ± sd) 44–88.1 (77.4 ± 30.4) 56–99 (83.2 ± 36.4) 58.9–154 (102.9 ± 23.4) 0.01* 0.04* 0.04* creatinine clearance in ml/min, range (mean ± sd) 33–134 (34.2 ± 5.9) 40.3–140 (46.3 ± 6.05) 88–133 (89.7 ± 2.1) 0.001* 0.04* 0.04* serum ferritin in ng/ml, range (mean ± sd) 760–2500 (1120 ± 45.1) 98–1001 (995.09 ± 35.5) 12–76 (15.3 ± 2.5) 0.001* 0.001* 0.9 albumin/creatinine ratio in urine in mg/mmol, range (mean ± sd) 1.1–112.8 (75.5 ± 24.4) 0.6–101.4 (62.2 ± 30.1) 0.4–2.2 (1.3 ± 0.2) 0.001* 0.02* 0.5 sd = standard deviation; ; egfr = estimated glomerular filtration rate; *significant. figure 1: receiver operating characteristic curve for serum cystatin c and creatinine among beta thalassaemia major patients and the control group. figure 2: receiver operating characteristic curve for serum cystatin c and creatinine clearance among beta thalassaemia major patients and the control group. frequency of glomerular dysfunction in children with beta thalassaemia major e92 | squ medical journal, february 2014, volume 14, issue 1 by grundy et al.16 and hamed and elmelegy17 who reported higher serum levels of serum cystatin c and serum creatinine and lower levels creatinine clearance. in contrast to the current study’s findings, koliakos et al. found normal serum creatinine and creatinine clearance in β-tm patients who received subcutaneous dfo treatment.14 concerning the urinary findings, the current study found that groups ιa and ιb had statistically significant higher ratios of a/c in the urine than the control group. this albuminurea was attributed mainly to the destruction of the glomerular filtration membrane which may be due to massive iron deposition in the tissues, resulting in an increase of free radical production via the fenton reaction, leading to cell death by binding cell proteins and disturbing their production.18,19 in addition, albuminurea could result from prolonged hyperfiltration, prostaglandin secretion and chronic anaemia.20 a comparison between groups ia and ib in regard to some laboratory data showed that group ia had a significantly lower egfr and creatinine clearance than group ib. this might be due to the shortened red blood cell life span with rapid iron turnover and tissue deposition of excess iron and the deferoxamine (dfo) therapy that may have proven nephrotoxic.15 in addition, group ia had a higher frequency of blood transfusion than group ib, where each 1 ml of packed red cells increases the body’s iron load by 1 mg, resulting in iron overload. concerning different correlations, the current study found that serum cystatin c had a statistically higher, significantly strong negative correlation with egfr and creatinine clearance where r = -0.91, p = 0.001 and r = -0.80, p = 0.005, respectively [table 3]. because its biological variation is low, serum cystatin c gives a good assessment of gfr changes during follow-up.21 furthermore, cystatin c had a statistically higher, significantly strong positive correlation with ferritin where r = 0. 90 and p = 0.001. this may be due to increased iron deposition coming from multiple life-long transfusions and enhanced iron absorption, resulting in secondary haemosiderosis with secondary renal dysfunction.22 serum cystatin c had a statistically significant, fair positive correlation with a/c ratio in the urine where r = 0.82 and p = 0.001. this could be explained by the possibility that proteinuria and microalbuminuria could be related to prolonged glomerular hyperfiltration and glomerulosclerosis.23 also, serum cystatin c had a highly significant positive correlation with the duration of chelation therapy, where r = 0.29 and p = 0.04. in the present study, serum cystatin c and creatinine values were measured as markers of gfr in β-tm patients and a control group and therefore a roc test was done for serum cystatin c and serum creatinine to determine the accuracy of serum cystatin c versus serum creatinine by plotting the claimed sensitivity and specificity of the β-tm table 3: correlations between cystatin c and different parameters parameter r† p duration of chelation in months 0.29 0.04* frequency of transfusion per year -0.14 0.3 egfr in ml/min per 1.73 m2 -0.91 0.001* creatinine clearance in ml/min -0.80 0.005* serum ferritin in ng/ml 0.9 0.001* albumin/creatinine ratio 0.82 0.001* egfr = estimated glomerular filtration rate. *significant; †grades of r: 0.00–0.24 (weak or no association); 0.25–0.49 (fair association); 0.50– 0.74 (moderate association); >0.75 (strong association). table 4: diagnostic accuracy of reduced glomerular filtration rate from serum cystatine c and serum creatinine among beta thalassaemia major patients and the control group threshold value auc mean ± sd sensitivity % specificity % 95% ci cystatine c in mg/ dl 1.03 0.84 ± 0.03 65 91 0.75– 0.89 serum creatinine in mg/dl 0.6 0.71 ± 0.04 27 79 0.60– 0.82 auc = area under the curve; sd = standard deviation; ci = confidence interval. table 5: diagnostic accuracy of reduced glomerular filtration rate from serum cystatine c and creatinine clearance among beta thalassaemia major patients and the control group. threshold value auc, mean ± sd sensitivity % specificity % 95% ci cystatine c in mg/ ml 1.03 0.82 ± 0.02 67 93 0.75– 0.92 creatinine clearance in ml/min 112 0.36 ± 0.04 63 66 0.25– 0.46 auc = area under the curve; sd = standard deviation; ci = confidence interval. basma a. ali and ahmed m. mahmoud clinical and basic research | e93 and control patients. this test strongly suggested that serum cystatin c was indeed superior to serum creatinine for the detection of gfr as the auc was 0.85 ± 0.04 for cystatin c versus 0.73 ± 0.05 for serum creatinine with higher sensitivity and specificity (66% and 92% versus 64% and 75%) [table 4 and figure 1]. this finding was in agreement with the results obtained by larsson et al., who stated that plasma cystatin c provided a better indication of changes of gfr than serum creatinine.24 table 5 and figure 2 show that the auc for serum cystatin c was significantly higher than that for creatinine clearance (0.85 ± 0.04 versus 0.35 ±0.05) when comparing β-tm patients with the control group. also, the sensitivity and specificity of serum cystatin c were higher than creatinine clearance (66% and 92% versus 26% and 75%, respectively). this finding was in agreement with the findings obtained by finney et al., who demonstrated that, in contrast to creatinine clearance, serum cystatin c concentration was effectively constant by the first year of life, and remained constant throughout adulthood up to 50 years of age.25 they also suggested that serum cystatin c might offer a considerable advantage to paediatric nephrologists in the diagnosis of gfr due to its sensitivity in the detection and reduction of gfr. conclusion this study has shown that β-tm patients have a high frequency of glomerular dysfunction. this can be attributed to chronic anaemia, iron overload and dfo toxicity. periodic renal assessment of those patients is mandatory as they may be affected by hidden renal dysfunction. cystatin c is a promising marker to assist in monitoring glomerular dysfunction for small changes in gfr with higher sensitivity and specificity than serum creatinine and creatinine clearance. references 1. forget bg. b-thalassemia syndrome. in: hoffman r, benz ej jr, shattil sj, furie b, cohen hj, silberstein le, et al., eds. hematology: basic principles and practice, 3rd ed. new york: churchill livingstone, 2000. pp. 485–510. 2. tracz mj, alam j, nath k. physiology and pathophysiology of heme: implication for kidney disease. j am soc nephrol 2007; 18:414–20. 3. borgna-pignatti c, gamberini mr. complications of thalassemia major and their treatment. expert rev hematol 2011; 4:353–66. 4. tanaka a, suemaru k, araki h. a new approach for evaluating renal function and its practical application. j pharmacol sci 2007; 105:1–5. 5. ringsrud km, linne jj. urinalysis and body fluids: a color text and atlas, 1st ed. maryland heights, missouri: mosby inc., 1994. 6. national kidney foundation. k/doqi clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. am j kidney dis 2002; 39:s1–266. 7. mcclatchey kd. clinical laboratory medicine, 2nd ed. philadelphia: lippincott williams & wilkins, 2002. 8. schwartz gj, brion lp, spitzer a. the use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. pediatr clin north am 1987; 34:571–90. 9. young ds. effects of preanalytical variables on clinical laboratory tests, 2nd ed. washington dc: aacc press, 1977. pp. 152–4. 10. burtis ca, ashwood er, eds. tietz textbook of clinical chemistry, 3rd ed. philadelphia: w.b. saunders,1999. 11. galteau mm, guyon m, gueguen r, siest g. determination of serum cystatin c: biological variation and reference values. clin chem lab med 2001; 39:850–7. 12. filler g, bökenkamp a, hofmann w, le bricon t, martínez-brú c, grubb a. cystatin c as a marker of gfr -history, indications, and future research. clin biochem 2005; 38:1–8. 13. daniel ww. biostatistics: a foundation for analysis. in the health science, 6th ed. new york: john wiley & sons, inc., 1994. 14. koliakos g, papachristou f, koussi a, perifanis v, tsatra i, souliou e, et al. urine biochemical markers of early renal dysfunction are associated with iron overload in betathalassaemia. clin lab haematol 2003; 25:105–9. 15. cianciulli p, sollecito d, sorrentino f, forte l, gilardi e, massa a, et al. early detection of nephrotoxic effects in thalassemic patients receiving desferrioxamine therapy. kidney int 1994; 46:467–70. 16. grundy rg, woods ka, savage mo, evans jp. relationship of endocrinopathy to iron chelation status in young patients with thalassaemia major. arch dis child 1994; 71:128–32. 17. hamed ea, elmelegy nt. renal functions in pediatric patients with beta-thalassemia major: relation to chelation therapy: original prospective study. ital j pediatr 2010; 36:39. 18. thomas ce, morehouse la, aust sd. ferritin and superoxide-dependent lipid peroxidation. j biol chem 1985; 260:3275–80. 19. link g, athias p, grynberg a, pinson a, hershko c. effect of iron loading on transmembrane potential, contraction, and automaticity of rat ventricular muscle cells in culture. j lab clin med 1989; 113:103–11. 20. koren g, kochavi-atiya y, bentur y, olivieri n. the effects of subcutaneous deferoxamine administration on renal function in thalassemia major. int j hematol 1991; 54:371– 5. frequency of glomerular dysfunction in children with beta thalassaemia major e94 | squ medical journal, february 2014, volume 14, issue 1 21. hoek fj, kemperman fa, krediet rt. a comparison between cystatin c, plasma creatinine and the cockcroft and gault formula for the estimation of glomerular filtration rate. nephrol dial transplant 2003; 18:2024–31. 22. khalifa as, sheir s, el-magd la, el-tayeb h, el-lamie o, khalifa a, et al. the kidney in beta-thalassaemia major. acta haematol 1985; 74:60. 23. katopodis kp, elisaf ms, pappas ha, theodorou jc, milionis hj, bourantas kl, et al. renal abnormalities in patients with sickle cell-beta thalassemia. j nephrol 1997; 10:163–7. 24. larsson a, malm j, grubb a, hansson lo. calculation of glomerular filtration rate expressed in ml/min from plasma cystatin c values in mg/l. scand j clin lab invest 2004; 64:25–30. 25. finney h, newman d, thakkar h, fell jm, price cp. reference ranges for plasma cystatin c and creatinine measurements in premature infants, neonates, and older children. arch dis child 2000; 82:71–5. sir, leukoencephalopathies in children are a heterogeneous group of disorders affecting the white matter of the brain, and often pose a major challenge to the treating physician for the appropriate aetiological diagnosis and management. van der knapp and others described a peculiar form of leukoenchalopathy affecting the basal ganglia and cerebellum in children with extensive hypomyelination; however, since that publication, few cases have been reported in the literature.1 the patients described had normal births and early development followed by an extrapyramidal movement disorder in the form of dystonia, spasticity, and ataxia, with global developmental regression. magnetic resonance imaging (mri) of the brain showed characteristic hypomyelination with atrophy of basal ganglia and cerebellum; however, the thalamus and globus pallidus were spared. the molecular basis for the diagnosis has never been established for this disease.4 however, histopathologyhas been able to confirm extensive myelin loss in the aforementioned areas of the brain.2 we report a two-year-old nigerian boy with clinical and radiological features of hypomyelination, and mild atrophy of the basal ganglia and cerebellum. the boy was brought to our hospital by his parents due to abnormal movements of his trunk and limbs from 8 months of age. he was born full-term to non-consanguineous parents. he had a normal perinatal and postnatal history. the boy had been sent home two days after delivery and had had normal development until 8 months of age, when he had been able to sit with support and could hold objects in his hands. however, his mother noticed that, when he was crying, the boy would develop stiffness in both legs, with more stiffness on his left side. after a few months, he lost the ability to sit as the stiffness increased in severity and progressed to involve all 4 limbs. he was unable to interact with his parents and had orofacial dyskinesia which interfered with feeding. he was seen by doctors and was started on anti-epileptic drugs with no benefit. when he presented to us, he was severely malnourished and bed-ridden, with extensive orolingual dyskinesia movements. there was dystonia of both axial and appendicular integuments with intermittent opisthotonos posturing. his cognitive skills were severely compromised and he could not communicate with his parents. a neurological examination revealed normal cranial nerve function, rigidity of all four limbs including the trunk, few choreiform movements of the extremities, and normal deep tendon reflexes and flexor plantar responses. there were no kayser-fleischer rings, and other systemic examinations were unremarkable. a routine biochemistry and metabolic work-up, including a leukocyte enzymes estimation, an evaluation of serum copper and ceruloplasmin levels, and a human immunodeficiency virus (hiv) screening were normal. an mri brain study revealed severe cortical atrophy with hypomyelination and atrophy of the caudate and putamen nuclei as well as the cerebellum. [figure 1] he was treated with carbiodopa+levodopa (sinemet) and benzodiazepine after discontinuing all antiepileptic drugs. in the initial weeks, he showed symptomatic improvement, but the symptoms recurred despite adequate dosages of the above medications. our case clearly illustrates the importance of neuro-imaging in the diagnosis of hypomyelination with basal ganglia and cerebellar atrophy after ruling out other causes of dystonia with the available diagnostic tools. leukoencephalopathies have distinctive clinical and radiological findings, and aetiological confirmation could be established with an extensive molecular genetic work-up. this would help patients acquire appropriate genetic counselling and possibly a potential curative treatment. however, in reality, more than half of these disorders remain undiagnosed because of the lack of availability of neuroimaging tools and, in such conditions, specific mri findings could establish the correct diagnosis. recently described leukoencephalopathies, such sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 192-193, epub. 27th feb 13 submitted 22nd jan 12 revision req. 17th apr 12 revision recd. 28th jul 12 accepted 10th oct12 اعتالل بياض الدماغ بقلة تكون املايلني hypomyelinating leukoencephalopathy letter to editor riaz a. syed letter to editor | 193 as vanishing white matter disease, megalencephalic leukoencephalopathy with subcortical cysts, and adrenoleukodystrophy, deserve mention here for the importance of mri in achieving a diagnosis.5 in this context, van der knapp et al. identified seven unrelated patients with extensive extra pyramidal movement abnormalities, ataxia, and spasticity.2 an mri brain scan revealed atrophied cerebral white matter, neostriatum, and cerebellum. detailed metabolic work-ups were normal and none of the 7 had any history of perinatal insults. magnetic resonance spectroscopy (mrs) showed elevated myo-inositol in the white matter, which is an indicator of gliosis. n-acetyl aspartate and choline levels were normal, suggesting that neither axonal loss nor active demyelination had occurred. they named this a distinctive leukoencephalopathy “hypomyelination with atrophy of the basal ganglia and cerebellum” (h-abc) to indicate patients sharing these unique clinical and mr imaging features.2 our patient shared some of the above clinical and radiological features of h-abc, and we present this case to emphasise the role of neuro-imaging in the diagnosis of this recent and rare nosological entity. levodopa and cabiodopa were found to be effective in one patient with a similar condition.3 unfortunately, our patient did not improve much during this treatment, although the dystonic spasms were initially alleviated. riaz a. syed king fahad military hospital, jeddah, saudi arabia e-mail: paedbrain@yahoo.com references 1. van der knaap ms, naidu s, pouwels pj, bonavita s, van coster r, lagae l, et al. new syndrome characterized by hypomyelination with atrophy of basal ganglia and cerebellum. ajnr am j neuroradiol 2002; 23:1466–74. 2. van der knaap ms, linnankivi t, paetau md, feigenbaum a, wakusawa k, haginoya k, et al. hypomyelination with atrophy of basal ganglia and cerebellum: follow-up and pathology. neurology 2007; 69:166–71. 3. wakusawa k, haginoya k, kitamura t, togashi n, ishitobi m, yokoyama h, et al. effective treatment with levodopa and carbidopa for hypomyelination with atrophy of basal ganglia and cerebellum. tohoku j exp med 2006; 209:163–7. 4. mercimek-mahmutoqlu s, van der knaap ms, baric i, prayer d, stoeckler-ipsiroglu s. hypomyelination and atrophy of basal ganglia and cerebellum. report of a new case. neuropediatrics 2005; 35:223–6. 5. van der knaap ms, breiter sn, naidu s, hart aa, valk j. defining and categorizing leukoencephalopathies of unknown origin: mr imaging approach. radiology 1999; 213:121–33. figure 1: a magnetic resonance imaging brain scan revealing severe cortical atrophy with hypomyelination and atrophy of the caudate and putamen nuclei as well as the cerebellum. أم الدم الكاذب للشريان الكبدي أو الشريان املراري بعد إجراء عملية إزالة املرارة باملنظار مراجعة املنشورات الطبية ملسببات نشوء املرض وأعراضه وتشخيصه وعالجه نورمان اأونييل مات�سادو، عادل الزدجايل، اأنوبام كومار كاكاريا، �سهزاد يون�س، حممد عبدالرحيم، را�سد ال�سكيتي abstract: pseudoaneurysms (psas) of the hepatic and/or cystic artery are a rare complication following a laparoscopic cholecystectomy (lc). generally, psa cases present with haemobilia several weeks following the procedure. transarterial embolisation (tae) is considered the optimal management approach. we report a 70-year-old woman who presented to the sultan qaboos university hospital, muscat, oman, in 2016 with massive hemoperitoneum two weeks after undergoing a lc procedure in another hospital. she was successfully managed using coil tae. an extensive literature review revealed 101 cases of hepatic or cystic artery psas following a lc procedure. haemobilia was the main presentation (85.1%) and the mean time of postoperative presentation was 36 days. the hepatic artery was involved in most cases (88.1%), followed by the cystic artery (7.9%) and a combination of both (4.0%). most cases were managed with tae (72.3%), with a 94.5% success rate. the overall mortality rate was 2.0%. keywords: hepatic artery; pseudoaneurysm; hemoperitoneum; therapeutic embolization; laparoscopic cholecystectomy. امللخ�ص: تعترب اأم الدم الكاذب لل�رشيان الكبدي اأو ال�رشيان املراري من امل�ساعفات النادرة التي تعقب عملية اإزالة املرارة باملنظار. من اأ�سابيع عدة بعد ال�سفراء املجاري نزف �سكل على املراري ال�رشيان اأو الكبدي لل�رشيان الكاذب الدم اأم حاالت تظهر عام وب�سكل �سنة 70 العمر من تبلغ امراأة حالة هنا نن�رش احلاالت. هذه مثل يف االأمثل العالج هو ال�رشيان عرب االن�سمام ويعترب العملية. اإجراء اأتت اإىل م�ست�سفى جامعة ال�سلطان قابو�س، م�سقط، عمان يف 2016 بنزف هائل يف ال�سفاق بعد اأ�سبوعني من اإجراء عملية اإزالة املرارة باملنظار يف م�ست�سفى اآخر. و قد مت عالجها بنجاح باإ�ستخدام لفيفات االإن�سمام عرب ال�رشيان. وات�سح من البحث الوا�سع خالل املن�سورات ال�سفراء االأوعية نزف باملنظار. املرارة اإزالة عمليات عقب املراري اأو الكبدي لل�رشيان الكاذب الدم الأم حالة 101 هناك باأن الطبية من االأعرا�س ال�سائعة )%85.1( و متو�سط عر�س احلالة تكون بعد 36 يوما من اإجراء العملية و يكون ال�رشيان الكبدي م�سابا يف اأغلب احلاالت )%88.1( و يتبعه ال�رشيان املراري )%7.9( و ي�ساب ال�رشيانان معا بن�سبة )%4.0(. وتعالج اأغلب احلاالت بوا�سطة االإن�سمام عرب ال�رشيان )%72.3( بن�سبة جناح تبلغ %94.5 و ن�سبة الوفاة قد تبلغ 2.0%. الكلمات املفتاحية: ال�رشيان الكبدي؛ اأم دم كاذبة؛ تدمي ال�سفاق؛ االإن�سمام العالجي؛ ا�ستئ�سال املرارة باملنظار. hepatic or cystic artery pseudoaneurysms following a laparoscopic cholecystectomy literature review of aetiopathogenesis, presentation, diagnosis and management *norman o. machado,1 adil al-zadjali,1 anupam k. kakaria,2 shahzad younus,1 mohamed a. rahim,1 rashid al-sukaiti2 review sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e135–146, epub. 20 jun 17 submitted 25 jul 16 revision req. 5 oct 16; revision recd. 22 oct 16 accepted 22 oct 16 departments of 1surgery and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: oneilnorman@gmail.com doi: 10.18295/squmj.2016.17.02.002 a laparoscopic cholecystectomy (lc) is the gold standard of treatment for symptomatic cholelithiasis due to its distinct advan tages of reduced pain, early discharge and reduced wound complications.1,2 however, it is rarely associated with major complications, such as vascular comp lications (0.25%).1,2 these include intraoperative bleeding following injury to the cystic/hepatic artery or the portal vein as well as postoperative pseudoaneurysms (psas) of the cystic or hepatic arteries.2–5 the mechanisms involved in the formation of a psa may be multifactorial and include excessive use of cauterisation during the dissection of calot’s triangle, particularly if there are any abnormal anatomical variations of the vasculature.2,6 patients who present postoperatively with psas may develop hemoperitoneum or haemo bilia.3–9 this article describes a patient with a psa of the hepatic artery originating in the cystic artery and then presents an extensive review of the scientific literature regarding the aetiopathogenesis, presentation, diagnosis and management of psas following lc procedures. hepatic or cystic artery pseudoaneurysms following a laparoscopic cholecystectomy literature review of aetiopathogenesis, presentation, diagnosis and management e136 | squ medical journal, may 2017, volume 17, issue 2 case report a 70-year-old female with known hypertension presented to the emergency medicine department of the sultan qaboos university hospital, muscat, oman, in 2016 after collapsing due to sudden-onset abdominal pain. she had undergone a lc at another hospital 13 days previously and had had a prolonged fourday admission following the procedure for reasons unknown. the abdominal pain was diffuse, colicky in nature and associated with nausea and vomiting. there was no associated fever, haematemesis or melena. at presentation, the patient was hypotensive but responded to fluid resuscitation. she appeared pale and in severe pain. a physical examination revealed tenderness on the right side of the abdomen with abdominal guarding. laboratory investigations revealed a haemoglobin level of 6.7 g/dl, haematocrit level of 0.26 l/l and raised lactate levels, with all other measurements within normal limits. a computed tomography (ct) scan of the abdomen with intra venous contrast showed multiple collections of fluid in the abdomen and pelvis with some reactionary changes to the bowel wall and no evidence of mesenteric ischaemia [figures 1a and b]. after receiving a blood transfusion, the patient was transferred to the operating room for a diagnostic laparoscopy, which revealed 1,500 ml of blood and clots with small bleeding points in the liver bed around the clips from the initial lc surgery. these bleeding points were subsequently clipped. there was no evidence of bile leakage. following the procedure, detailed examination of the ct scans suggested a psa of the right hepatic artery (rha) at the point of origin of the cystic artery [figures 1c and d]. conventional angiography confirmed these findings and coil embolisation of the psa in the rha was carried out [figure 2]. the patient’s liver function test findings remained normal during the postoperative period. however, the postoperative figure 2: selective angiograms of the hepatic artery of a 70-year-old woman two weeks after a laparoscopic cholecystectomy showing (a) focal outpouching from the right hepatic artery (rha) at the site of origin of the cystic artery (arrow) and (b) complete obliteration of the pseudoaneurysm (arrow) following coil embolisation of the rha. figure 1: computed tomography (ct) images of a 70-year-old woman two weeks after a laparoscopic cholecystectomy. a: non-contrast ct scan of the pelvis showing hyper-dense pelvic fluid (arrow). b: non-contrast ct scan of the upper abdomen showing a small collection of fluid in the gallbladder fossa with layering hyper-dense contents (arrow). c: arterial-phase ct scan showing a slight irregularity (arrow) in the right hepatic artery (rha). d: three-dimensional ct reconstruction confirming the irregularity and focal dilatation of the rha (arrow). norman o. machado, adil al-zadjali, anupam k. kakaria, shahzad younus, mohamed a. rahim and rashid al-sukaiti review | e137 course was complicated by a hernia at the umbilical port site for which she underwent an open repair. she was discharged on the 12th postoperative day. six weeks later, during a follow-up appointment in the outpatient clinic, she appeared to be doing well. literature review m e t h o d s a literature search was carried out using the medline® database (national library of medicine, bethesda, maryland, usa) for all english-language articles on post-lc hepatic or cystic artery psas. in addition, references in articles were cross-checked to further identify potential articles on this topic. the inclusion criteria for articles encompassed all article types (including case reports and case series) published before april 2016. however, articles with inadequate data were excluded. r e s u lt s a total of 60 articles were identified during the literature search, including 101 cases of post-lc hepatic or cystic artery psas [table 1].3–62 among the cases which specified the gender or age of the patient, 45.2% were male and the age ranged from 12–81 years with a mean age of 49.8 years.4,5,9–13,15,17–21,24–31,33–35,37–43,46–48,51,57,58,60,62 the time of presentation following the lc procedure ranged from six days to five years with a mean of 36 days.3–5,7–13,15,17–21,23,24,26,28–31,33–44,46–53,55–62 the most common presentation was haemobilia (85.1%), followed by haematemesis (10.9%), jaundice (9.9%), abdominal pain (9.9%) anaemia (5.0%) and melena (5.0%).3–62 the commonest vessel involved was the rha (n = 88; 87.1%), the cystic artery (n = 8; 7.9%), both the cystic and hepatic arteries (n = 4; 4.0%) and the gastroduodenal artery (n = 1; 1.0%).3–62 in two cases, the rha arose from a replaced superior mesenteric artery and, in one case, it was an accessory artery.18,29,31 the size of the psas ranged from 13–200 mm, with a mean size of 43 mm.4,6,13,15,17,26,30,31,33,37,39,42,43,57 the modality of management was transarterial embolisation (tae) in 72.3%, endovascular stent placement in 4.0%, exploratory laparotomy and ligation of the hepatic artery in 5.0% and thrombin injection in 4.0% of cases.3–62 the tae procedure alone failed to control bleeding in four cases (5.5%), resulting in a 94.5% success rate.6,7,15,42 one of these cases was managed further using a percutaneous thrombin injection, while two cases were managed by exploratory laparotomy and ligation of vessels. reasons for tae failure included continuous growth of the psa over a period of two months, persistent bleeding and other associated injuries, including to the portal vein.6,7,42 among the cases treated with tae, complications included liver abscesses (n = 10; 13.7%), post-embolisation syndrome and hepatic ischaemia (n = 9; 12.3%),postoperative bleeding for a month (n = 1; 1.4%) and erosion of the stent into the common bile duct (cbd; n = 1; 1.4%).3,15,16,37,45 the overall mortality rate was 2.0% (n = 2).7,40 one fatality was due to severe haemorrhagic relapse following repair of the psa, resulting in irreversible hypovolaemic shock despite re-exploration and ligation.40 in the second case, the patient died from a concomitant injury to the portal vein.7 discussion i n c i d e n c e the true incidence of psas in the cystic/hepatic arteries is difficult to determine as many cases are asymptomatic and thus never detected.57 moreover, small subclinical psas may thrombose spontaneously or be too small to be observed, even on imaging.57 the reported incidence of psas involving the cystic or hepatic arteries following an lc procedure ranges from 0.06–0.6%.3,63 the incidence of haemobilia following an emergency lc for acute cholecystitis (within 72 hours) has been reported to be 0.001%, while it has been observed to be 0.0003% for those undergoing an elective lc.31 a higher incidence of psas involving the hepatic artery has been reported in patients with a concomitant bile duct injury (4.5%).4 however, the rha is usually the most commonly involved vessel.28,30,32,33,39–41,57 other involved sites include the cystic artery and, in some cases, the common hepatic and gastroduodenal arteries.4,9,37,38,44,47,58 a e t i o pat h o g e n e s i s a psa may arise due to multiple mechanisms of injury, including laceration, transection or occlusion of the blood vessels following a mechanical or thermal injury to the artery.6,37,51 this may occur when inappropriate energy (thermal/mechanical) is applied during dissection of the calot’s triangle or following dissection with a laser.5,37 a thermal injury could result from the direct transfer of heat to the vessel by cautery or indirectly via a metal clip in contact with the artery.3,18,31 injury of the vessel could also be due to clip intrusion, bile leakage or infection.4,9,31 in numerous cases, the psa has been found directly adjacent to a clip.31,43,46,51 bile acids are powerful solubilisers of membrane lipids due to their cytotoxic and amphipathic properties, causing cell death in hepatic or cystic artery pseudoaneurysms following a laparoscopic cholecystectomy literature review of aetiopathogenesis, presentation, diagnosis and management e138 | squ medical journal, may 2017, volume 17, issue 2 ta bl e 1: l it er at ur e re vi ew o f c as es o f p se ud oa ne ur ys m o f t he c ys ti c an d/ or h ep at ic a rt er ie s fo llo w in g a la pa ro sc op ic c ho le cy st ec to m y3 – 62 a ut ho r an d ye ar o f ar ti cl e n a ge in ye ar s/ ge n de r v es se l i nv ol ve d d et ai ls o f ch ol ec ys te ct om y t im e of pr es en ta ti on p re se nt at io n t re at m en t c om pl ic at io n s p at ie nt ou tc om e fe ng e t a l.1 6 2 01 7* 14 r h a (n = 1 4) •h m b t a e (c oi ls ) po st -e m bo lis at io n sy nd ro m e an d he pa tic is ch ae m ia (n = 9 ) g oo d h si ao e t a l.1 7 2 01 5 1 40 /m r h a (3 3 m m ) 2 w ee ks •j n •a b pa in t a e (c oi ls a nd p t c d ) n on e g oo d bi n t ra ik i e t a l.1 8 2 01 5 1 64 /m r h a a ri si ng fr om a re pl ac ed s m a a nd c bd in ju ry 4 w ee ks •f ev er •p ai n •j n st en t f ol lo w ed b y a re pe at s te nt a nd t a e (g el fo am ) b le ed in g fr om th e lh a a ft er p la ce m en t of th e in iti al s te nt g oo d a bd al la e t a l.1 9 2 01 5 1 40 /m r h a si ng le -p or t l c 2 w ee ks •j n •a b pa in t a e (c oi l) g oo d k um ar e t a l.6 2 01 4 1 c a b ra nc h (2 0 m m ) •h m b t a e (c oi ls ) f ol lo w ed b y pe rc ut an eo us t i fa ile d t a e r en cu zo gu lla ri e t a l.2 0 20 14 1 43 /m r h a (a nt /p os t bi fu rc at io n) 3 w ee ks •h m b •p ai n r h a li ga tio n an d t -t ub e pl ac em en t pa nd a et a l.2 1 2 01 4 1 29 /m r h a (r ig ht p os t se ct or al ar te ry p sa ) c a w as d iv id ed u si ng a ha rm on ic s ca lp el 2 w ee ks •a b pa in •a n la pa ro sc op ic r ep ai r (p ri ng le m an oe uv re ); t a e w as n ot c ar ri ed o ut as th e an eu ry sm w as c lo se to th e r h a fr om th e se ct or al b ra nc h g oo d m ur ug es an e t a l.2 2 2 01 4 3 r h a (n = 3 ) •h m b t a e g oo d k ir sc hb er g et a l.2 3 2 01 3 1 r h a 4 m on th s •h m b •m el en a •d iz zi ne ss •s w ea tin g t a e (m ic ro co il) g oo d m at e et a l.2 4 2 01 3 1 45 /m r h a 15 d ay s •h m b •d iz zi ne ss r h a li ga tio n an d lo op c ol os to m y g oo d pe tr ou e t a l.1 5 2 01 2 1 34 /f c a (1 3 m m ) 3 m on th s •h m b •h ae m at em es is •a b pa in t a e (m ic ro co il) fo llo w ed b y r h a lig at io n b le ed in g af te r a m on th fo llo w in g t a e as m ul tip le p re vi ou s co ils a ffe ct ed th e bi fu rc at io n g oo d b ut et e t a l.2 6 2 01 2 1 79 c a a nd r h a (3 5 m m ) 3 m on th s •j n •a b pa in r h a li ga tio n an d ps a e xc is io n im m ed ia te d ec om pr es si on o f c bd g oo d sa ns on na e t a l.3 1 2 01 1 1 55 /f r h a a ri si ng fr om a re pl ac ed s m a (2 0 m m ) a nd b ile le ak ag e fr om th e se gm en t v bi lia ry b ra nc h 3 w ee ks •h m b •h yp ot en si on •r ec ur re nt m el en a •h b le ve l o f 8 g /d l t a e (m ic ro co ils ) a nd n as ob ili ar y dr ai na ge fo r bi le le ak ag e n on e g oo d h ad j e t a l.3 0 2 01 1 1 32 /f r h a (4 0m m ) d iffi cu lt lc p ro ce du re w ith s om e bl ee di ng n ea r th e cy st ic d uc t w hi ch w as co nt ro lle d w ith c lip s 5 m on th s •h m b t a e (m ic ro co ils ) a nd e r c p re m ov al o f bl oo d cl ot s n on e g oo d k ha n et a l.2 8 2 01 1 1 54 /f r h a 5 m on th s •h m b •h ae m at em es is •h b le ve l o f 5 g /d l t a e (m ic ro co ils ) n on e g oo d norman o. machado, adil al-zadjali, anupam k. kakaria, shahzad younus, mohamed a. rahim and rashid al-sukaiti review | e139 k am an i e t a l.2 9 2 01 1 1 60 /m a cc es so ry r h a 4 m on th s •h m b t a e (m ic ro co ils ) n on e g oo d g an dh i e t a l.2 5 2 01 1 3 39 † / 16 :6 ‡ r h a (n = 3 ) •h m b t a e (m ic ro co ils ) n on e g oo d c am in iti et a l.2 7 2 01 1 1 r h a •h m b t a e (m ic ro co ils ) n on e g oo d h yl to n et a l.3 3 2 01 0 1 53 /f r h a (3 2 x 20 m m ) 1 ye ar •h m b •s te no si s o f r h a w ith p sa (9 0% ) st en t c ov er n on e g oo d ya o et a l.3 4 2 01 0 1 54 /m r h a 6 w ee ks •a b pa in •a n (h b le ve l o f 7 .6 g /d l) •g an gr en ou s ch ol ec ys tit is t a e (m ic ro co ils ) n on e g oo d m al ik e t a l.5 7 2 01 0 1 35 /f r h a (3 5 x 35 m m ) a nd m as seff ec t p ar tia l c bd c om pr es si on 1 m on th •f ev er •a b pa in •v om iti ng •a n (h b le ve l o f 7 .5 g /d l) ex pl or at or y la pa ro to m y an d r h a tr an sfi xa tio n lig at ur e h yp ot en si on a nd c ol la ps e up on m an ip ul at io n on th e op er at in g ta bl e; pa tie nt w as g iv en 7 u ni ts o f b lo od in th e ic u fo r a m on th g oo d b od dy e t a l.3 2 2 01 0 1 r h a •h m b st en t a nd t i f or s m al l r es id ua l p sa n on e g oo d c he n et a l.3 5 2 00 9 1 67 /m r h a 2 m on th s •h m b •h ae m at em es is •h b le ve l o f 9 .3 g /d l t a e n on e g oo d m os es e t a l.5 8 2 00 8 1 26 /m c a s tu m p ps a w ith no a ct iv e bl ee di ng 3 m on th s •u pp er g i h m b t a e (m ic ro co ils ) n on e g oo d m as an na t e t a l.4 1 2 00 8 1 71 /f m ul tip le r h a p sa s an d c a a dh es io ns a nt to th e co m m on h a th e lc w as c on ve rt ed to an o pe n pr oc ed ur e 6 da ys •a b pa in •d ro p in h b le ve l ( 9 gm /d l) t a e (m ic ro co il) n on e g oo d sr in iv as ai ah e t a l.3 9 2 00 8 1 57 /f r h a (6 9 m m ) 4 w ee ks •h m b •h ae m at em es is •a cu te c ho le cy st iti s t a e (m ic ro co il) n on e g oo d se ba st iá n et a l.4 0 2 00 8 1 66 /m r h a 1 m on th •h m b •h ae m at em es is •f or m at io n of a fi st ul a fr om th e r h a to th e du od en um la pa ro st om y an d r h a s ut ur in g fo llo w ed b y a re pe at la pa ro st om y du e to b le ed in g se ve re h ae m or rh ag ic r el ap se pa tie nt de at h n ak as e et a l.3 7 2 00 8 1 63 /f c a (3 0 m m ) m on op ol ar h oo k di ss ec tio n 11 d ay s •h m b •m el en a •h ae m at em es is (h b le ve l o f 7. 4 g/ dl ) •a cu te c ho le cy st iti s t a e w ith n b c a (n or m al a ng io gr am ) fo llo w ed b y m ic ro co ils to tr ea t t he ot he r ps a li ve r ab sc es s an d a se co nd p sa s ee n on r ep ea t c t 2 7 da ys a ft er th e fir st su rg er y g oo d k um ar e t a l.3 6 2 00 8 6 •r h a (n = 3 ) •a nt b ra nc h r h a (n = 1 ) •r h a w ith c om m on he pa tic d uc t i nj ur y (n = 2 ) 18 – 98 d ay s • h m b t a e (m ic ro co ils ) n on e g oo d m ad an ur e t a l.4 2 00 7 4 57 – 64 ; 3: 1‡ •r h a (n = 3 ; 19 – 30 m m ) •c a (n = 1 ) •c om m on h ep at ic du ct in ju ry (n = 4 ) 2– 5 w ee ks •h m b (n = 4 ) •h ae m at em es is (n = 2 ) •h m b an d m el en a (n = 2 ) •t a e w ith m ic ro co ils (n = 3 ) •s te nt (n = 1 ) •r h a li ga tio n (n = 1 ) •h ep at ic oj ej un os to m y (n = 3 ) in tr aab do m in al b ile c ol le ct io n (n = 1 ) g oo d hepatic or cystic artery pseudoaneurysms following a laparoscopic cholecystectomy literature review of aetiopathogenesis, presentation, diagnosis and management e140 | squ medical journal, may 2017, volume 17, issue 2 r oc he -n ag le e t a l.4 2 20 06 1 58 /f r h a b ra nc h (3 0 m m ) 5 da ys •i nt ra pe ri to ne al b le ed in g (h b le ve l o f 6 .1 g /d l) •a b pa in •f ev er •a cu te c ho le cy st iti s t a e (m ul tip le c oi ls ) f ol lo w ed b y an ex pl or at or y la pa ro to m y, li ga tio n of fe ed in g ve ss el in to p sa a nd c lo su re of s ac fa ile d t a e w ith g ro w th o f p sa o ve r 2 m on th s g oo d d e m ol la n et o et a l.3 8 20 06 1 31 /f c a 50 d ay s •p al e •j n r h a li ga tio n as s tu m p w as in fla m m at or y n on e g oo d h ey n et a l.6 2 2 00 6 1 78 /m c a 1 ye ar •h m b •r ec ur re nt m el en a •h ae m at em es is ex pl or at or y la pa ro to m y, p sa r es ec tio n of p sa , c bd r ep ai r an d t -t ub e pl ac em en t n on e g oo d jo ur né e t a l.1 4 2 00 4 1 r h a a nd c a •h m b t a e (c oi l/ na so bi lia ry d ra in ag e) n on e g oo d c hi go t e t a l.4 3 2 00 3 1 12 /f r h a a nt b ra nc h (2 0 x 20 m m ) a nd b le ed in g fr om in fe ri or r h a br an ch d iffi cu lt lc d ue to o ed em a an d in fla m m at io n 28 d ay s •h m b •a b pa in t a e (c ya no ac ry la te ) v ia tr an sh ep at ic ro ut e un de r flu or os co py n on e g oo d ya hc ho uc hy -c ho ui lla rd et a l.1 3 2 00 3 2 68 /f 81 /f •r h a (2 00 m m ) •r h a •3 w ee ks •3 m on th s •h m b, fe ve r, a n , n au se a an d h b le ve ls o f 8 .2 g /d l •j n , p ai n, m el en a an d h b le ve ls of 8 .4 g /d l t a e (m ic ro co il; n = 2 ) n on e g oo d sa ld in ge r et a l.9 2 00 2 1 50 /f in te rc on ne ct ed r h a an d c a 3 w ee ks •h m b •h ae m at em es is •m el en a t a e (m ic ro co ils ) n on e g oo d o zk an e t a l.4 5 2 00 2 1 r h a •h m b t a e (g ug lie lm i d et ac ha bl e co il) er os io n of c oi l i nt o c bd p re se nt in g as pa nc re at iti s 2 ye ar s la te r g oo d b ul ut e t a l.7 2 00 2 3 •r h a (s m al l p sa ) •r h a (i nt ra he pa tic ps a ) w ith c bd / pv in ju ry •r h a w ith r up tu re in to li ve r pa re nc hy m a w ee ks – 5 ye ar s •h m b •t a e (n = 1 ) •s ur gi ca l l ig at io n (n = 1 ) •t a e fo llo w ed b y su rg er y (n = 1 ) fa ile d t a e •g oo d •g oo d •p at ie nt de at h ja in e t a l.4 4 2 00 2 2 •h a •g d a •1 m on th •2 m on th s •h m b t a e w ith h om em ad e co ils (n = 2 ) n on e g oo d n ic ho ls on e t a l.3 1 99 9 9 r h a (n = 9 ) 9– 43 d ay s •h m b t a e c an di da li ve r ab sc es s g oo d h al be e t a l.4 6 1 99 9 1 32 /f r h a 3 w ee ks •h m b •m el en a •h ae m at em es is t a e (m ic ro co il) n on e g oo d k w au k et a l.4 7 1 99 8 1 35 /f r h a 3 w ee ks •h m b t a e n on e g oo d b al as ar a et a l.8 1 99 8 2 r h a (n = 2 ) •7 d ay s •4 m on th s •h em op er ito ne um a nd b ile le ak ag e •j n a nd h m b ex pl or at or y la pa ro to m y an d lig at io n (n = 2 ) n on e g oo d r ib ei ro e t a l.4 8 1 99 8 1 57 /f r h a 13 m on th s •h m b ex pl or at or y la pa ro to m y an d lig at io n n on e g oo d en gl an d et a l.5 9 1 99 8 1 r h a 4 w ee ks •h m b t a e n on e g oo d norman o. machado, adil al-zadjali, anupam k. kakaria, shahzad younus, mohamed a. rahim and rashid al-sukaiti review | e141 d oc to r et a l.6 0 1 99 8 1 49 /f r h a 6 w ee ks •r ec ur re nt h m b t a e n on e g oo d ib ra ru lla h et a l.1 2 1 99 7 1 r h a 2 w ee ks •h m b •m as si ve h ae m at em es is la pa ro to m y an d r h a li ga tio n n on e g oo d k ap oo r et a l.5 0 1 99 7 1 r h a 7 w ee ks •h m b t a e n on e g oo d h al pe rn 49 1 99 7 1 r h a 6 w ee ks •h m b t a e n on e g oo d ye lle e t a l.5 1 1 99 6 1 49 /f r h a a nd r ig ht h ep at ic du ct in ju ry 3 w ee ks •h m b •b ile fi st ul a ex pl or at or y la pa ro to m y an d su tu ri ng o f r h a te ar fo llo w ed b y re pe at la pa ro to m y an d su tu ri ng r ec ur re nc e of b le ed in g 3 w ee ks la te r g oo d si ab lis e t a l.1 1 1 99 6 1 29 /m r h a 1 m on th •h m b •p ai n •j n t a e n on e g oo d r iv itz et a l.5 3 1 99 6 1 r h a 1 m on th •h m b t a e n on e g oo d po rt e et a l.5 2 1 99 6 1 r h a 11 d ay s •h m b t a e n on e g oo d st ew ar t et a l.5 4 1 99 5 4 r h a ( n = 4) •h m b t a e (n = 4 ) n on e g oo d b er ge y et a l.1 0 1 99 5 1 39 /m r h a 3 w ee ks •h m b t a e n on e g oo d z ilb er st ei n et a l.6 1 1 99 4 1 c a w ee ks – 4 m on th s •h m b t a e n on e g oo d m or an et a l.5 6 1 99 4 1 r h a 3– 5 da ys •h m b t a e n on e g oo d g en yk et a l.5 1 99 4 1 57 /f r h a 2 w ee ks •h m b •j n •a b pa in •u pp er g i b le ed in g t a e an d di re ct t i t o ps a n on e g oo d b lo ch et a l.5 5 1 99 4 1 r h a 28 d ay s •h m b t a e (p la tin um c oi ls ) n on e g oo d to ta l 10 1 49 .8 † / 19 :2 3‡ r h a : 8 8 c a : 8 c om bi ne d r h a /c a : 4 g d a : 1 32 d ay s† h m b : 8 6 h ae m at em es is : 1 1 a b pa in : 1 0 jn : 1 0 a n : 5 m el en a: 5 fe ve r: 4 pa in : 4 o th er : 2 5 ta e: 7 3 la pa ro to m y: 1 2 li ga ti on : 8 st en t: 4 t i: 4 o th er : 1 6 n on e: 4 7 li ve r a bs ce ss : 1 0 po st -e m bo lis at io n sy nd ro m e an d he pa ti c is ch ae m ia : 9 b le ed in g: 4 p sa re cu rr en ce : 2 o th er : 8 g oo d: 9 7 pa ti en t de at h: 2 u nk no w n: 2 rh a = ri gh t h ep at ic a rt er y; h m b = ha em ob ili a; t a e = tr an sa rt er ia l e m bo lis at io n; m = m al e; jn = ja un di ce ; a b = ab do m in al ; p t c d = p er cu ta ne ou s t ra ns he pa tic ch ol an gi og ra ph y an d dr ai na ge ; s m a = su pe ri or m es en te ri c a rt er y; c bd = co m m on b ile d uc t; lh a = le ft he pa tic a rt er y; l c = la pa ro sc op ic ch ol ec ys te ct om y; c a = c ys tic a rt er y; t i = th ro m bi n in je ct io n; a nt = a nt er io r; po st = p os te ri or ; p sa = p se ud oa ne ur ys m ; a n = a na em ia ; f = fe m al e; h b = ha em og lo bi n; e rc p = en do sc op ic re tr og ra de ch ol an gi op an cr ea to gr ap hy ; i c u = in te ns iv e ca re u ni t; g i = g as tr oi nt es tin al ; h a = h ep at ic a rt er y; n bc a = n -b ut yl c ya no ac ry la te ; c t = co m pu te d to m og ra ph y; p v = p or ta l v ei n; g d a = g as tr od uo de na l a rt er y. *f ir st p ub lis he d on lin e i n m ar ch 2 01 6. † m ea n. ‡ m al eto -fe m al e r at io . hepatic or cystic artery pseudoaneurysms following a laparoscopic cholecystectomy literature review of aetiopathogenesis, presentation, diagnosis and management e142 | squ medical journal, may 2017, volume 17, issue 2 patients with bile leaks; this has been postulated to cause direct weakening and erosion of the vascular wall, leading to a psa.4,18 in patients with bilomas, the resulting secondary infection may precipitate the development of a psa.4 associations have also been reported between psas and intraoperative adhesions and anatomical variations of the ducts and cystic artery.16,41,57 major anatomical variations include a doubled cystic artery (20%), a “caterpillar hump” formation of the rha and the unusual course of the cystic artery anterior to the cbd or common hepatic artery.41,57 during a lc procedure, vessel injury can be avoided by adhering to basic surgical tenets, including performing the dissection in the plane closest to the gallbladder wall, retaining adequate view of the cystic artery and the duct entering the gallbladder before applying an energy source, freeing the infundibulum inferiorly to widen calot’s triangle (i.e. pediculisation) and ensuring meticulous dissection without bleeding so as to identify structures before applying the clips.1,57 in the event of bleeding, the blind application of clips or use of cautery may also enhance the risk of vascular injury.1 some researchers have recommended the use of bipolar cautery or ultrasonic dissection for a thickwalled gallbladder, particularly when the dissection penetrates deep into the liver—as in a buried gallbladder—because the potential carbonisation with the use of these tools is minimal in comparison to laser or monopolar cautery.31 the risk of a psa rupture is related to its size, with a greater than 10-fold risk when the aneurysm is more than 5 cm.7 in cases of rupture, bleeding can be either minimal or heavy, particularly in those presenting late.7,15 in such cases, a lc carried out for acute cholecystitis or concomitant ductal injury may be a difficult and prolonged procedure.4,6,18,30,31,37,41 p r e s e n tat i o n a psa may present either in the initial days following a cholecystectomy or be delayed over weeks, months or, on rare occasions, years.31,41 a delay in presentation following a thermal injury could be due to charring of a vessel which gets detached weeks later, particularly in the presence of bile.31 patients may present with gastrointestinal (gi) bleeding (i.e. haemobilia) and/or hemoperitoneum, particularly when the psa is large; in contrast, smaller psas may occasionally present with minimal abdominal discomfort.7 haemobilia has been reported to be the most frequent presentation (90%), while abdominal pain (70%) and jaundice (60%) are other common presentations.3,31 the classical presentation of quincke’s triad (jaundice, abdominal pain and gi bleeding) may be seen in less than 40% of haemobilia cases.64 rarely, an abdominal mass with a bruit may be noted.42 gi bleeding may present as haematemesis or melena, based on the rate of bleeding.63 during its natural course, a psa will progressively grow in size before rupturing in 21–80% of cases.30 the rupture of a psa into the peritoneal cavity may present with hypovolaemic shock or may be contained temporarily by the surrounding tissue—often referred to as “double rupture phenomenon”, as the initial contained bleeding may be followed by secondary bleeding which is more severe.7 erosion of a psa into the cystic duct stump or gi tract forming a fistula between the two structures has been previously reported.5,9,23,24,35,40 this could involve the duodenum, leading to haematemesis, the jejunum, for example in a patient presenting with lower gi bleeding who had previously undergone roux-en-y reconstruction following a stomach carcinoma, or hepatic flexure in a patient presenting with hematochezia.23,24,35,40 in most patients (80%), the psa usually presents approximately one month following the lc surgery; however, delayed psa presentation as late as five years after the surgery has been reported.6,7 d i a g n o s t i c a n d t h e r a p e u t i c i n v e s t i g at i o n s the diagnosis of a psa can be confirmed by a combination of history-taking (i.e. checking the patient’s surgical history), an upper gi endoscopy, regular or doppler ultrasonography, a contrast ct scan and/or an angiogram.6,9,13,18,20,23,29,33–35,37,53 ultrasonography may lead to the detection of an aneurysm or fluid consistent with haemorrhage; however, the diagnostic accuracy of this option is directly related to the size of the psa and the operator’s experience.13,16,25 three-dimensional (3d) ct reconstruction or catheter angiography can also help to define the aneurysm and its feeding vessels. with the advent of multidetector ct scans and advancements in 3d imaging software in the form of volume determination, ct is the preferred technique for primary vascular imaging among patients with suspected psas.20 recent reports have discussed features of haemobilia on a ct scan, including the presence of a haematoma within the abdominal cavity and gallbladder fossae, high attenuation of blood clots within the bile duct, biliary dilatation, a psa of the rha, contrast extravasation, enhancement of the bile duct wall and hypoperfusion of the right lobe of the liver.16,65 catheter angiography can be both diagnostic and therapeutic.18,20,29,31 indications of a dilated cystic artery stump on an angiogram are considered ominous and may warrant embolisation, despite a lack of active bleeding during other investigations.58 nevertheless, angiography has certain diagnostic norman o. machado, adil al-zadjali, anupam k. kakaria, shahzad younus, mohamed a. rahim and rashid al-sukaiti review | e143 limitations which may be influenced by variable flow rate, intermittent bleeding at the time of investigation and hepatic artery abnormalities.15 previous research has indicated that coeliac angiography can fail to identify psas subsequently detected via selective rha angiography.6,18 however, angiography has been reported to detect vascular abnormalities in 90% of patients with significant haemobilia.66 t r e at m e n t a diagnosis of psa is considered an acute emergency and requires immediate and aggressive intervention, as a rupture could lead to life-threatening exsanguination; the rupture of a psa in the hepatic artery has been associated with a mortality rate of 21–43%.17,18,22,33 historically, psas were principally managed via surgery, which involved resectioning of the psa and ligation of the cystic artery stump or rha.6 however, due to significant advances in catheter-based therapies, psas are now primarily treated with tae by occluding the sac or the feeding vessel with a variety of embolic agents, including gel foam, coils, n-butyl cyanoacrylate and thrombin, before ideally embolising the vessel distal and proximal to the psa in order to prevent collateral filling of the psa.5,6,15–19,22,23,25,37,43 when coils are used, they can induce thrombosis; hence, in patients with significant coagulopathies, the vessel may still remain patent despite embolisation and the procedure may be ineffective in controlling bleeding. in small psas, glue may be used instead as the adhesive conforms to the shape of psa.43,64 in addition, coil placement may be difficult in patients with a small psa.25 in some cases, both approaches may be used.25 distinct advantages of tae include the reduced risk of parenchymal injury, the use of local rather than general anaesthesia and rapid patient recovery following the procedure. however, in some instances, tae may fail initially and the patient may require a further attempt at embolisation.6 failure may be due to the difficulty in approaching the psa in the presence of a thrombosed proximal vessel, such as the coeliac or tortuous hepatic arteries.5,11,24,36,48,55 in patients where cannulation is feasible, embolisation failure could be related to an inability to isolate the bleeding vessel, misidentification of the bleeding vessel or incomplete occlusion despite the disappearance of the sac or feeding vessel on post-embolisation angiography.6,22 in addition, smaller vessels may feed the psa and contribute to rebleeding, which may not be easily detected during angiography.42 moreover, loosely packed coils can lead to recanalisation of the aneurysm.6 failure to successfully embolise a psa may require nonselective embolisation of the rha or direct surgical exploration of the psa. nonselective embolisation of the rha may also be required if there is bleeding from multiple sites.39 recently, several researchers have reported the successful management of psas by injecting thrombin directly into the hepatic artery aneurysm.5,6,32 however, embolisation using this technique may be nonselective, resulting in potentially serious complications such as liver and bowel infarctions; injecting small aliquots of thrombin with real-time ultrasound and doppler guidance may reduce this risk.6 on the other hand, angiographic embolisation may be associated with serious risks, including rupture of the psa during coil embolisation, an extension of the thrombosis in the rha, hepatobiliary necrosis, bleeding, abscess formation and cbd stricture due to ischaemia.3,4,22,37 a recent report found that post-embolisation syndrome occurred in nine out of 14 patients and was associated with the age of the patient and the time interval between the lc and tae.16 in patients with liver cirrhosis or abscesses, some researchers have recommended assessment of adequate arterial and collateral flow prior to hepatic artery embolisation to avoid the risk of ischaemia.37 others have advised use of a covered stent while treating the psa in order to maintain blood flow to the liver and prevent complications related to reduced flow.33 stents may also be used for patients with concomitant hepatic artery stenosis and psas.33 for small visceral vessels, the choice of stent is limited; one option is the jostent® graftmaster® graft (abbott vascular inc., chicago, illinois, usa), which is 3–5 mm in diameter and 12–26 mm long. the placement of a stent for a psa of the rha is con sidered technically challenging due its distant location, smaller diameter and often complex or altered anatomy.33 the patency of the graft is generally better in arteries with larger diameters and high flow rates. even though the hepatic artery has a smaller diameter, its high flow rate ensures good patency in most cases.33 in patients where an intra-arterial approach to the hepatic artery is not feasible, successful embo lisation via a transhepatic approach has been reported.43 in one case, erosion of the tae coil into the cbd was observed in a patient who presented two years after the lc procedure with acute pancreatitis.45 surgical intervention is required if embolisation fails, for patients who lack the necessary haemodynamic stability to undergo a tae procedure and for those with concomitant bile duct compression or injuries.4,15,22,57 the latter patient group may also require simultaneous biliodigestive anastomosis, although surgical repair can generally be delayed if the duct injury is detected later.2,8,12,19 surgical intervention may also be mandatory when endovascular hepatic or cystic artery pseudoaneurysms following a laparoscopic cholecystectomy literature review of aetiopathogenesis, presentation, diagnosis and management e144 | squ medical journal, may 2017, volume 17, issue 2 intervention facilities are not available and the patient is not stable enough to be transferred to a tertiary hospital.25,40 in cases whereby the psa has continued to expand after initial control with tae, subsequent surgical control has been reported in which an exploratory laparotomy and ligation of the feeding vessel resulted in a complete recovery.42 surgical interventions for psas may involve excision of the psa and ligation of the rha, removal of a biliary obstruction or, in exceptional cases, a hepatectomy.4,6,20 excision ensures that a psa will not grow due to sustained arterial blood pressure; moreover, failure to excise the psa may lead to its rupture as the aneurysm is often infected. infection could also lead to a high risk of vascular suture rupture following ligation of the artery; in one report, a patient died 48 hours after having undergone surgical repair of a psa due to fatal gi bleeding.40 although in most cases a psa is surgically treated using an open method, a recent report described the successful laparoscopic suture ligation of a psa in the right posterior sector of the hepatic artery.21 the initial inspection and manipulation of the psa led to severe bleeding, which was adequately controlled with a vascular clamp using the laparoscopic pringle manoeuvre. with a clearer view of the surrounding anatomy, laparoscopic ligation was performed by taking some of the periarterial tissue to prevent ligature slippage.21 following ligation of the rha, the risk of a liver infarction is generally limited as blood flow is maintained by portal circulation.26 in addition, revascularisation of the right liver lobe occurs due to the rapid development within the hilar plate of an omega-shaped collateral arterial circulatory system, originating from the preserved branch of the hepatic artery.26 some patients who present with haemobilia and obstructive jaundice may also require endoscopic retrograde cholangiopancreatography, transhepatic biliary drainage or cbd exploration to evacuate the clot if the jaundice does not improve.17,30,64 embolisation has been reported as generally successful in 82% of cases, with surgery required for the remaining 18% of patients.7 surgical management of massive haemobilia is reportedly successful for 90% of patients, with rebleeding and mortality rates of <5% and 10%, respectively.22 however, there have been reports of higher operative mortality rates (27–50%), particularly among haemodynamically unstable patients.36,67,68 conclusion a hepatic and/or cystic artery psa following a lc procedure is an uncommon yet potentially lifethreatening complication. the often delayed presen tation of this condition, which can occur weeks or months after the surgery, and its common manifestation with gi bleeding can easily result in misdiagnosis or delayed treatment. hence, a high index of clinical suspicion is required for patients with unexplained gi bleeding following a lc procedure. a contrast ct scan or angiogram usually confirms the diagnosis and tae is considered the gold standard of management, with a high success rate. however, surgical intervention is required for cases in which tae is unfeasible or fails. precautions should be taken to avoid vascular injury while performing a lc in order to reduce the risk of a psa, particularly when the cholecystectomy procedure is difficult. references 1. machado no. biliary complications post laparoscopic cholecystectomy: mechanism, preventive measures, and approach to management a review. diagn ther endosc 2011; 2011:967017. doi: 10.1155/2011/967017. 2. strasberg sm, helton ws. an analytical review of vasculobiliary injury in laparoscopic and open cholecystectomy. hpb (oxford) 2011; 13:1–14. doi: 10.1111/j.1477-2574.2010.00225.x. 3. nicholson t, travis s, ettles d, dyet j, sedman p, wedgewood k, et al. hepatic artery angiography and embolization for hemobilia following laparoscopic cholecystectomy. cardiovasc intervent radiol 1999; 22:20–4. doi: 10.1007/s002709900323. 4. madanur ma, battula n, sethi h, deshpande r, heaton n, rela m. pseudoaneurysm following laparoscopic cholecystectomy. hepatobiliary pancreat dis int 2007; 6:294–8. 5. genyk ys, keller fs, halpern nb. hepatic artery pseudoaneurysm and hemobilia following laser laparoscopic cholecystectomy: a case report. surg endosc 1994; 8:201–4. doi: 10.1007/bf00591830. 6. kumar a, sheikh a, partyka l, contractor s. cystic artery pseudoaneurysm presenting as a complication of laparoscopic cholecystectomy treated with percutaneous thrombin injection. clin imaging 2014; 38:522–5. doi: 10.1016/j.clinimag. 2014.03.002. 7. bulut t, yamaner s, bugra d, akyuz a, acarli k, poyanli a. false aneurysm of the hepatic artery after laparoscopic cholecystectomy. acta chir belg 2002; 102:459–63. doi: 10.10 80/00015458.2002.11679352. 8. balsara kp, dubash c, shah cr. pseudoaneurysm of the hepatic artery along with common bile duct injury following laparoscopic cholecystectomy: a report of two cases. surg endosc 1998; 12:276–7. doi: 10.1007/s004649900651. 9. saldinger pf, wang jy, boyd c, lang e. cystic artery stump pseudoaneurysm following laparoscopic cholecystectomy. surgery 2002; 131:585–6. doi: 10.1067/msy.2002.115353. 10. bergey e, einstein dm, herts br. cystic artery pseudoaneurysm as a complication of laparoscopic cholecystectomy. abdom imaging 1995; 20:75–7. doi: 10.1007/bf00199652. 11. siablis d, tepetes k, vasiou k, karnabatidis d, perifanos s, tzorakoleftherakis e. hepatic artery pseudoaneurysm following laparoscopic cholecystectomy: transcatheter intraarterial embolization. hepatogastroenterology 1996; 43:1343–6. 12. ibrarullah m, singh b, mehrotra p, kaushik sp. right hepatic artery pseudoaneurysm after laparoscopic cholecystectomy. am j gastroenterol 1997; 92:528–9. https://doi.org/10.1155/2011/967017 https://doi.org/10.1111/j.1477-2574.2010.00225.x https://doi.org/10.1007/s002709900323 https://doi.org/10.1007/bf00591830 https://doi.org/10.1016/j.clinimag.2014.03.002 https://doi.org/10.1016/j.clinimag.2014.03.002 https://doi.org/10.1080/00015458.2002.11679352 https://doi.org/10.1080/00015458.2002.11679352 https://doi.org/10.1007/s004649900651 https://doi.org/10.1067/msy.2002.115353 https://doi.org/10.1007/bf00199652 norman o. machado, adil al-zadjali, anupam k. kakaria, shahzad younus, mohamed a. rahim and rashid al-sukaiti review | e145 13. yahchouchy-chouillard e, limot o, ghiles e, etienne jc, de baer t, picone o, et al. embolization for right hepatic artery pseudoaneurysm following laparoscopic cholecystectomy. anz j surg 2003; 73:82–4. doi: 10.1046/j.1445-2197.2003.02625.x. 14. journé s, de simone p, laureys m, le moine o, gelin m, closset j. right hepatic artery pseudoaneurysm and cystic duct leak after laparoscopic cholecystectomy. surg endosc 2004; 18:554–6. doi: 10.1007/s00464-003-4262-5. 15. petrou a, brennan n, soonawalla z, silva ma. hemobilia due to cystic artery stump pseudoaneurysm following laparoscopic cholecystectomy: case presentation and literature review. int surg 2012; 97:140–4. doi: 10.9738/cc52.1. 16. feng w, yue d, zaiming l, zhaoyu l, wei l, qiyong g. hemobilia following laparoscopic cholecystectomy: computed tomography findings and clinical outcome of transcatheter arterial embolization. acta radiol 2017; 58:46–52. doi: 10.1177/ 0284185116638570. 17. hsiao cy, kuo tc, lai hs, yang cy, tien yw. obstructive jaundice as a complication of a right hepatic artery pseudoaneurysm after laparoscopic cholecystectomy. j minim access surg 2015; 11:163–4. doi: 10.4103/0972-9941.144097. 18. bin traiki ta, madkhali aa, hassanain mm. hemobilia post laparoscopic cholecystectomy. j surg case rep 2015; 2015:rju159. doi: 10.1093/jscr/rju159. 19. abdalla s, thome a, reslinger v, atanasiu c, pellerin o, sapoval m, et al. compressive hematoma due to pseudoaneurysm of the right hepatic artery: a rare cause of obstructive jaundice after single-port cholecystectomy. surg laparosc endosc percutan tech 2015; 25:e42–4. doi: 10.1097/ sle.0000000000000024. 20. rencuzogullari a, okoh ak, akcam ta, roach ec, dalci k, ulku a. hemobilia as a result of right hepatic artery pseudoaneurysm rupture: an unusual complication of laparoscopic cholecystectomy. int j surg case rep 2014; 5:142–4. doi: 10.1016/j.ijscr.2014.01.005. 21. panda n, narasimhan m, gunaraj a, ardhanari r. laparoscopic management of post-cholecystectomy sectoral artery pseudoaneurysm. j minim access surg 2014; 10:37–9. doi: 10.4103/0972-9941.124471. 22. murugesan sd, sathyanesan j, lakshmanan a, ramaswami s, perumal s, perumal su, et al. massive hemobilia: a diagnostic and therapeutic challenge. world j surg 2014; 38:1755–62. doi: 10.1007/s00268-013-2435-5. 23. kirschberg o, scheding a, saers t, krakamp b. detection and treatment of an aneurysma spurium of the arteria hepatica dextra after laparoscopic cholecystectomy. bmc gastroenterol 2013; 25;13:121. doi: 10.1186/1471-230x-13-121. 24. mate ad, surnare kr, deolekar ss, gvalani ak. lower gastrointestinal bleeding due to hepatic artery pseudoaneurysm following laparoscopic cholecystectomy. j minim access surg 2013; 9:31–3. doi: 10.4103/0972-9941.107135. 25. gandhi v, doctor n, marar s, nagral a, nagral s. major hemobilia: experience from a specialist unit in a developing country. trop gastroenterol 2011; 32:214–18. 26. butet y, bouras af, truant s, pruvot fr. pseudoaneurysm of the cystic artery as a complication of laparoscopic cholecystectomy. dig liver dis 2012; 44:449–50. doi: 10.1016/j.dld.2011.11.012. 27. caminiti r, rossitto m, ciccolo a. pseudoaneurysm of the hepatic artery and hemobilia: a rare complication of laparoscopic cholecystectomy clinical case and literature review. acta chir belg 2011; 111:400–3. doi: 10.1080/00015458.2011.11680782. 28. khan mr, raza r, salam b. leaking pseudoaneurysm of hepatic artery: a potentially life-threatening complication of a common procedure. j pak med assoc 2011; 61:504–6. 29. kamani l, mosharraf sm, tanveer-ul-haq, shah ha. haemobilia: a rare cause of gastrointestinal bleeding. j coll physicians surg pak 2011; 21:766–8. 30. hadj ak, goodwin m, schwalb h, nikfarjam m. pseudoaneurysm of the hepatic artery. j gastrointest surg 2011; 15:1899–901. doi: 10.1007/s11605-011-1535-5. 31. sansonna f, boati s, sguinzi r, migliorisi c, pugliese f, pugliese r. severe hemobilia from hepatic artery pseudoaneurysm. case rep gastrointest med 2011; 2011:925142. doi: 10.1155/ 2011/925142. 32. boddy a, macanovic m, thompson j, watkinson a. use of an endovascular stent graft and percutaneous thrombin injection to treat an iatrogenic hepatic artery pseudoaneurysm. ann r coll surg engl 2010 [epub ahead of print]. doi: 10.1308/147870 810x12822015504806. 33. hylton jr, pevec wc. successful treatment of an iatrogenic right hepatic artery pseudoaneurysm and stenosis with a stent graft. j vasc surg 2010; 51:1510–13. doi: 10.1016/j.jvs.2009. 12.061. 34. yao ca, arnell td. hepatic artery pseudoaneurysm following laparoscopic cholecystectomy. am j surg 2010; 199:e10–11. doi: 10.1016/j.amjsurg.2009.03.014. 35. chen cc, chen bb, wang hp. upper gastrointestinal bleeding owing to right hepatic artery pseudoaneurysm after laparoscopic cholecystectomy. gastroenterology 2009; 137:e5–6. doi: 10.1053/j.gastro.2009.02.083. 36. kumar m, gupta s, soin a, nundy s. management of massive haemobilia in an indian hospital. indian j surg 2008; 70:288–95. doi: 10.1007/s12262-008-0085-x. 37. nakase y, takagi t, fukumoto k, kassai k, yamagami t, itani k, et al. hemobilia and cystic artery stump pseudoaneurysm associated with liver abscess after laparoscopic cholecystectomy: report of a case. surg today 2008; 38:567–71. doi: 10.1007/ s00595-007-3663-9. 38. de molla neto ol, ribeiro ma, saad wa. pseudoaneurysm of cystic artery after laparoscopic cholecystectomy. hpb (oxford) 2006; 8:318–19. doi: 10.1080/13651820600869628. 39. srinivasaiah n, bhojak m, jackson r, woodcock s. vascular emergencies in cholelithiasis and cholecystectomy: our experience with two cases and literature review. hepatobiliary pancreat dis int 2008; 7:217–20. 40. sebastián jj, peña e, blas jm, ceña g. fatal upper gastrointestinal bleeding due to hepatic artery pseudoaneurysm diagnosed by endoscopy. dig dis sci 2008; 53:1152–3. doi: 10.1007/s10620007-9971-5. 41. masannat ya, al-naser s, al-tal y, al-koteesh j, sharaf ui. a rare complication of a common operation: hepatic artery pseudo aneurysm following cholecystectomy report of a case. ir j med sci 2008; 177:397–8. doi: 10.1007/s11845-007-0053-7. 42. roche-nagle g, maceneaney, harte p. pseudo-aneurysm of the hepatic artery after laparoscopic cholecystectomy: a case report. j minim access surg 2006; 2:73–5. doi: 10.4103/09729941.26652. 43. chigot v, lallier m, alvarez f, dubois j. hepatic artery pseudoaneurysm following laparoscopic cholecystectomy. pediatr radiol 2003; 33:24–6. doi: 10.1007/s00247-002-0772-x. 44. jain r, batra y, acharya sk. post cholecystectomy hemobilia: transcatheter embolization of pseudoaneurysms with homemade steel coils. indian j gastroenterol 2002; 21:161–2. 45. ozkan os, walser em, akinci d, nealon w, goodacre b. guglielmi detachable coil erosion into the common bile duct after embolization of iatrogenic hepatic artery pseudoaneurysm. j vasc interv radiol 2002; 13:935–8. doi: 10.1016/s10510443(07)61778-3. 46. halbe s, ahmed ni, sundar k, sathyakumar c. pseudoaneurysm in gall bladder fossa following laparoscopic cholecystectomy. indian j gastroenterol 1999; 18:122. https://doi.org/10.1046/j.1445-2197.2003.02625.x https://doi.org/10.1007/s00464-003-4262-5 https://doi.org/10.9738/cc52.1 https://doi.org/10.1177/0284185116638570 https://doi.org/10.1177/0284185116638570 https://doi.org/10.4103/0972-9941.144097 https://doi.org/10.1093/jscr/rju159 https://doi.org/10.1097/sle.0000000000000024 https://doi.org/10.1097/sle.0000000000000024 https://doi.org/10.1016/j.ijscr.2014.01.005 https://doi.org/10.4103/0972-9941.124471 https://doi.org/10.1007/s00268-013-2435-5 https://doi.org/10.1186/1471-230x-13-121 https://doi.org/10.4103/0972-9941.107135 https://doi.org/10.1016/j.dld.2011.11.012 https://doi.org/10.1080/00015458.2011.11680782 https://doi.org/10.1007/s11605-011-1535-5 https://doi.org/10.1155/2011/925142 https://doi.org/10.1155/2011/925142 https://doi.org/10.1308/147870810x12822015504806 https://doi.org/10.1308/147870810x12822015504806 https://doi.org/10.1016/j.jvs.2009.12.061 https://doi.org/10.1016/j.jvs.2009.12.061 https://doi.org/10.1016/j.amjsurg.2009.03.014 https://doi.org/10.1053/j.gastro.2009.02.083 https://doi.org/10.1007/s12262-008-0085-x https://doi.org/10.1007/s00595-007-3663-9 https://doi.org/10.1007/s00595-007-3663-9 https://doi.org/10.1080/13651820600869628 https://doi.org/10.1007/s10620-007-9971-5 https://doi.org/10.1007/s10620-007-9971-5 https://doi.org/10.1007/s11845-007-0053-7 https://doi.org/10.4103/0972-9941.26652 https://doi.org/10.4103/0972-9941.26652 https://doi.org/10.1007/s00247-002-0772-x https://doi.org/10.1016/s1051-0443%2807%2961778-3 https://doi.org/10.1016/s1051-0443%2807%2961778-3 hepatic or cystic artery pseudoaneurysms following a laparoscopic cholecystectomy literature review of aetiopathogenesis, presentation, diagnosis and management e146 | squ medical journal, may 2017, volume 17, issue 2 47. kwauk st, cameron r, burbridge b, keith rg. traumatic pseudoaneurysm of the hepatic artery after percutaneous liver biopsy and laparoscopic cholecystectomy in a patient with biliary cirrhosis: a case report. can j surg 1998; 41:316–20. 48. ribeiro a, williams h, may g, fulmer jt, spivey jr. hemobilia due to hepatic artery pseudoaneurysm thirteen months after laparoscopic cholecystectomy. j clin gastroenterol 1998; 26:50–3. doi: 10.1097/00004836-199801000-00013. 49. halpern nb. false aneurysm of a hepatic artery branch. surg endosc 1997; 11:402–3. doi: 10.1007/s004649900375. 50. kapoor r, agarwal s, calton r, pawar g. hepatic artery pseudoaneurysm and hemobilia following laparoscopic cholecystectomy. indian j gastroenterol 1997; 16:32–3. 51. yelle jd, fairfull-smith r, rasuli p, lorimer jw. hemobilia complicating elective laparoscopic cholecystectomy: a case report. can j surg 1996; 39:240–2. 52. porte rj, coerkamp eg, koumans rk. false aneurysm of a hepatic artery branch and a recurrent subphrenic abscess: two unusual complications after laparoscopic cholecystectomy. surg endosc 1996; 10:161–3. doi: 10.1007/bf00188363. 53. rivitz sm, waltman ac, kelsey pb. embolisation of an hepatic artery pseudoaneurysm following laparoscopic cholecystectomy. cardiovasc intervent radiol 1996; 19:43–6. doi: 10.10 07/bf02560147. 54. stewart bt, abraham rj, thomson kr, collier na. postcholecystectomy haemobilia: enjoying a renaissance in the laparoscopic era? aust n z j surg 1995; 65:185–8. doi: 10.1111/ j.1445-2197.1995.tb00604.x. 55. bloch p, modiano p, foster d, bouhot f, gompel h. recurrent hemobilia after laparoscopic cholecystectomy. surg laparosc endosc 1994; 4:375–7. 56. moran j, del grosso e, wills js, hagy ja, baker r. laparoscopic cholecystectomy: imaging of complications and normal postoperative ct appearance. abdom imaging 1994; 19:143–6. doi: 10.1007/bf00203489. 57. malik ka, muneeb md, jawaid m, khan ml. post laparoscopic cholecystectomy hepatic artery pseudo-aneurysm. pak j surg 2010; 26:89–91. 58. moses v, keshava sn, wann vc, joseph p, sitaram v. cystic artery pseudoaneurysm after laparoscopic cholecystectomy presenting as haemobilia: a case report. trop gastroenetrol 2008; 29:107–9. 59. england re, marsh pj, ashleigh r, martin df. case report: pseudoaneurysm of the cystic artery a rare cause of haemo bilia. clin radiol 1998; 53:72–5. doi: 10.1016/s0009-9260 (98)80041-x. 60. doctor n, dooley js, dick r, watkinson a, rolles k, davidson br. multidisciplinary approach to biliary complications of laparoscopic cholecystectomy. br j surg 1998; 85:627–32. doi: 10.1046/j.1365-2168.1998.00662.x. 61. zilberstein b, cecconello i, ramos ac, sallet ja, pinheiro ea. hemobilia as a complication of laparoscopic cholecystectomy. surg laparosc endosc 1994; 4:301–3. 62. heyn j, sommerey s, schmid r, hallfeldt k, schmidbauer s. fistula between cystic artery pseudoaneurysm and cystic bile duct cause of acute anemia one year after laparoscopic cholecystectomy. j laparoendosc adv surg tech a 2006; 16:609–12. doi: 10.1089/lap.2006.16.609. 63. deziel dj, millikan kw, economou sg, doolas a, ko st, airan mc. complications of laparoscopic cholecystectomy: a national survey of 4,292 hospitals and an analysis of 77,604 cases. am j surg 1993; 165:9–14. doi: 10.1016/s00029610(05)80397-6. 64. machado no. hemobilia post liver biopsy: mechanism, presentation, complications and management. j gastroenterol pancreatol liver disord 2015; 2:1–14. doi: 10.15226/2374815x/2/3/00142. 65. wen f, dong y, lu zm, liu zy, li w, guo qy. hemobilia after laparoscopic cholecystectomy: imaging features and management of an unusual complication. surg laparosc endosc percutan tech 2016; 26:e18–24. doi: 10.1097/sle.000 0000000000241. 66. merrell sw, schneider pd. hemobilia: evolution of current diagnosis and treatment. west j med 1991; 155:621–5. 67. hsu kl, ko sf, chou ff, sheen-chen sm, lee ty. massive hemobilia. hepatogastroenterology 2002; 49:306–10. 68. mohil r, narayan n, narayan a, kerketta z, jain s, bhatnagar d. life-threatening lower gastrointestinal haemorrhage from an aneurysm of the right hepatic artery: a rare case presentation due to delayed rupture. internet j surg 2009; 24:1. https://doi.org/10.1097/00004836-199801000-00013 https://doi.org/10.1007/s004649900375 https://doi.org/10.1007/bf00188363 https://doi.org/10.1007/bf02560147 https://doi.org/10.1007/bf02560147 https://doi.org/10.1111/j.1445-2197.1995.tb00604.x https://doi.org/10.1111/j.1445-2197.1995.tb00604.x https://doi.org/10.1007/bf00203489 https://doi.org/10.1016/s0009-9260%2898%2980041-x https://doi.org/10.1016/s0009-9260%2898%2980041-x https://doi.org/10.1046/j.1365-2168.1998.00662.x https://doi.org/10.1089/lap.2006.16.609 https://doi.org/10.1016/s0002-9610%2805%2980397-6 https://doi.org/10.1016/s0002-9610%2805%2980397-6 https://doi.org/10.15226/2374-815x/2/3/00142 https://doi.org/10.15226/2374-815x/2/3/00142 https://doi.org/10.1097/sle.0000000000000241 https://doi.org/10.1097/sle.0000000000000241 clinical & basic research sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e460−467, epub. 14th oct 14 submitted 8th jan 14 revision req. 17th feb 14 revision recd. 20th mar 14 accepted 17th apr 14 departments of 1research & studies and 4information & statistics, directorate general of planning and 3non-communicable diseases surveillance & control, directorate general of health affairs, ministry of health; 2office of the world health organization, muscat, oman *corresponding author e-mail: rmmabry@gmail.com املتالزمة األيضية ومكوناهتا حتليل ثانوي للمسح الصحي العاملي يف عمان حممود عطيه عبد العاطي، روث مابري، جمدي مر�سي، جواد اللواتي، اآ�سيا الريامية، مدحت ال�سيد abstract: objectives: the study aimed to describe the prevalence of metabolic syndrome (ms) and its components among omani adults. methods: the 2008 oman world health survey dataset was used to determine the national prevalence of ms. logistic regression using all key sociodemographic, clinical and behavioural variables was used to identify the associations of independent variables with ms. results: the age-adjusted prevalence of ms was 23.6%. ms was significantly associated with age, marital and work status and wealth level. ms was more common for people aged 50 years and older compared to the youngest cohort (or 3.6, ci: 2.4–5.3; p <0.001) and in people who were married or employed (or 1.6, ci: 1.3–2.1; p <0.001 and or 1.3, ci: 1.1–1.8; p = 0.043, respectively) compared to their unmarried and unemployed counterparts. ms was also more common in people in the second lowest wealth quintile (or 1.6, ci: 1.2–2.2; p = 0.05) compared to the lowest quintile and in those who sat for more than six hours per day (or 1.3, ci: 1.1-1.7; p = 0.035). conclusion: one in four adults had ms in oman. this may fuel the epidemic of non-communicable diseases (ncds) in oman, particularly given the increasingly elderly population. urgent action is required to ensure quality patient care at all levels of the healthcare system. further research on behavioural risk factors is needed. developing and implementing a multisectoral strategy to prevent ncds should be at the top of the current health agenda for oman. keywords: metabolic syndrome x; chronic diseases; epidemiology; public health; oman. امللخ�ص: الهدف: هدفت الدرا�سة اإىل و�سف معدل انت�سار املتالزمة الأي�سية ومكوناتها بني العمانيني البالغني. الطريقة: مت ا�ستخدام قاعدة بيانات امل�سح ال�سحي العاملي بال�سلطنة لعام 2008 لتحديد املعدل الوطني لنت�سار املتالزمة الأي�سية، ومت ا�ستخدام معادلة النحدار للمتغريات امل�ستقلة العالقة على للتعرف وال�سلوكيات وال�رسيرية ال�سكانية الجتماعية للعوامل الأ�سا�سية املتغريات لكل اللوج�ستي امل�ستقلة مع املتالزمة الأي�سية. النتائج: وجد اأن معدل انت�سار املتالزمة الأي�سية املعدل ح�سب ال�سن يبلغ %23.6. ووجد اأي�سا ارتباط ذو دللة اإح�سائية مع العمر واحلالة الزواجية والعمل والرثوة. وكانت املتالزمة اأكرث انت�سارا بني الأفراد البالغني من العمر 50 عاما فاأكرث باملقارنة مع الفئة العمرية الأ�سغر )الحتمال املرجح: 3.6 وحدود الثقة p>0.001 ،2.4-5.3(. ووجد اأي�سا اأن املتالزمة الأي�سية اأكرث �سيوعا بني املتزوجني والعاملني ) الحتمال املرجح: 1.6 حدود الثقة p>0.001 ،1.3–2.1 والحتمال املرجح1.3 وحدود الثقة p = 0.043 ،1.1-1.8 على التوايل( مقارنة بغري املتزوجني والعاطلني عن العمل. كما وجد اأن املتالزمة اأكرث انت�سارا بني امل�ستوى الثاين الأقل من ترتيب اأخما�س الرثوة )الحتمال املرجح:1.6 وحدود الثقة p = 0.05 ،1.2-2.2) مقارنة بالفئة الأدنى. واأظهر اأي�سا الأفراد الذين يجل�سون لأكرث من 6 �ساعات يوميا عالقة ذات دللة معنوية مع املتالزمة الأي�سية )الحتمال املرجح: 1.3 وحدود الثقة p = 0.035 ،1.1-1.7(. اخلال�صة: وجد اأنه من بني كل اأربعة بالغني يف عمان يوجد �سخ�س واحد م�ساب باملتالزمة الأي�سية. وهذا مما يزيد من وبائية الأمرا�س غري املعدية، خا�سة مع زيادة عدد امل�سنني. ويتطلب الأمر عمال عاجال ل�سمان توفري رعاية ذات جودة عالية للمر�سى على كل م�ستويات النظام ال�سحي، واجراء بحوث اأخرى على عوامل ال�سلوكيات الخاطئة ويجب تبني ا�سرتاتيجية متعددة القطاعات للوقاية من الأمرا�س غري املعدية وتنفيذها لتكون يف مقدمة الأجندة ال�سحية يف عمان. مفتاح الكلمات: املتالزمة الي�سية x؛ األمرا�س املزمنة؛ الوبائيات؛ ال�سحة العامة؛ عمان. metabolic syndrome and its components secondary analysis of the world health survey, oman mahmoud abd el-aty,1 *ruth mabry,2 magdi morsi,1 jawad al-lawati,3 asya al-riyami,1 medhat el-sayed4 advances in knowledge this is the first descriptive study at the national level in oman of metabolic syndrome (ms), a precursor of cardiovascular disease and type 2 diabetes. one in four omani adults was found to have ms. furthermore, older adults, people who were married and those who were employed were observed to be some of the key high-risk groups for ms. from the results of this study, it was found that a large portion of omani adults did not achieve the recommended amount of daily physical activity and did not consume the recommended amount of fruits and vegetables. application to patient care the results of this study, which observed a high proportion of omani adults with ms and its components, highlight the need for appropriate measures to ensure that the healthcare system can provide quality care, including prevention, screening for early diagnosis and management. mahmoud abd el-aty, ruth mabry, magdi morsi, jawad al-lawati, asya al-riyami and medhat el-sayed clinical and basic research | e461 metabolic syndrome (ms) includes a cluster of cardiovascular and diabetes risk factors.1,2 people with this syndrome are at higher risk of developing diabetes and cardiovascular disease as well as premature mortality.1 ms also increases the risk of other diseases, including cancer, kidney disease and mental illness.3–5 thus, ms is widely used as a marker for evaluating outcomes of population-based strategies aimed at preventing noncommunicable diseases.6 the first internationally recognised working definition for ms was proposed at a world health organization (who) consultation in 1988 and numerous attempts have been made since then to develop a standard definition. most identified a person with ms as one who had at least three of the following: central obesity, high fasting blood glucose levels, elevated blood pressure (bp), high cholesterol and high triglycerides, with the main difference between definitions being the cut-off points for each of these clinical indicators.7 non-communicable diseases account for 83% of all deaths in oman.8 despite the increasing rates of overweight/obesity, hypertension and type 2 diabetes, limited information is known about ms in oman.9–11 a community-based study conducted in 2001 in nizwa, oman, reported an age-adjusted prevalence of 19.5% in men and 23.0% in women aged 20 years and older.12,13 a more recent survey in sur, oman, found the age-adjusted prevalence of ms to be 24.2% in men and 29.8% in women aged 20 years and above.14 despite the differences in age groups and definitions for ms, these studies demonstrate a clear gender difference, with a higher prevalence of ms in women, which is a trend that has been identified in other countries of the region as well.15 this study aimed to provide for the first time a descriptive epidemiology of ms and its components at the national level in oman. methods the world health survey was developed by the who more than 10 years ago to obtain comprehensive information on the health of a population using a standard methodology.16 the oman world health survey (owhs) was a population-based household survey conducted in 2008 to obtain a wide range of reliable and comparable information on the population’s health and healthcare system in oman. the prevalence of non-communicable diseases and associated risk factors were captured by the survey. the owhs used the who stepwise approach.17 a multi-stage stratified cluster sampling design was used to select respondents aged 18 years and above. data were collected at the household level and included the following variables: gender, age, marital status (never married, currently married, separated/ divorced or widowed), education level (illiterate, primary/preparatory, secondary or post-secondary), work status (currently working, previously worked or never worked) and wealth (in quintiles, with quintile 1 being the lowest and quintile 5 being the wealthiest). respondents were asked to identify if they had ever been diagnosed with hypertension or diabetes and if so, whether they were taking medication or other treatments. respondents were also asked about their health risk behaviours (tobacco use, physical inactivity, sitting time and fruit and vegetable intake). an individual who was a current user of any tobacco product was defined as a current smoker. physical activity was assessed according to intensity, duration and frequency in three domains (work, transport and leisure); the total metabolic equivalent of task (met) in minutes per day was calculated according to the who guidelines to estimate the total minutes of moderate physical activity per week for each individual. a person was determined as doing sufficient physical activity if they had performed the equivalent of at least 150 minutes of moderate physical activity per week. one survey item assessed the number of hours the participant sat per day. fruit and vegetable intake was assessed by totalling the numbers of each item consumed on a typical day. in addition, the anthropometrics (height, weight and waist circumference) of the respondents were assessed and three bp measurements were taken. blood samples were collected after 8–14 hours of fasting to determine fasting blood glucose levels, total cholesterol levels, high-density lipoprotein (hdl) and low-density lipoprotein (ldl) cholesterol and triglyceride levels. the samples were labelled and transferred immediately in cold boxes filled with ice to a laboratory in a regional hospital. samples for measuring blood glucose levels were collected in 2 ml sodium fluoride oxalate anticoagulant containers and samples for measuring cholesterol were collected in 2 ml lithium heparin anticoagulant containers. after plasma separation by centrifuge, the blood glucose and lipid levels were estimated using a hitachi 911 automated clinical chemistry analyser (roche diagnostics, basel, switzerland) by the enzymatic colourimetric method.18 out of the 5,465 individuals who were invited, a total of 4,717 individuals successfully completed the interviews with a response rate of 86.3%. biomarkers were successfully analysed from 3,686 individuals (78.3%).9 details of the study methodology have been published elsewhere.9 metabolic syndrome and its components secondary analysis of the world health survey, oman e462 | squ medical journal, november 2014, volume 14, issue 4 among the participants, ms was identified using the national cholesterol education program’s revised adult treatment panel iii (atpiii) definition.7 this identified individuals as having ms if they were taking medication for or had at least three of the following: central obesity with a waist circumference of ≥102 cm for men or ≥88 cm for women; raised triglycerides of ≥1.7 mmol/l; reduced hdl cholesterol of <1.03 mmol/l for men or <1.3 mmol/l for women; raised systolic bp of ≥130 mm hg or diastolic bp of ≥85 mm, and raised fasting plasma glucose of ≥5.6 mmol/l.7 in addition to central obesity, obesity was also assessed using body mass index (bmi) calculated in kg/m2. the prevalence of ms was examined according to sociodemographic and behavioural risk factors for omani participants with complete information for all adults aged 20 years and above. data were entered on microcomputers using the census and survey processing (cspro) system (united states census bureau, washington, d.c., usa). survey data were cleaned using cspro as well as stata, version 13 (statacorp lp, college station, texas, usa). the statistical package for the social sciences (spss), version 18 (ibm corp., chicago, illinois, usa) was used for statistical analysis. logistic regression using all key sociodemographic, clinical and behavioural variables determined the associations of independent variables with ms. models were ageadjusted to the population of oman using national 2008 population statistics. results were reported as percentages, means with standard deviations (sd) and odds ratios (or) with 95% confidence intervals (ci). this secondary analysis of the owhs for chronic non-communicable diseases and associated risk factors was approved by the research and ethical review and approval committee of the ministry of health (moh). results a total of 3,137 omani participants had complete information for all of the variables and were included in this study (85%). the sample was relatively young (39.4 ± 15.8 years) and 46.5% were men. nearly twothirds (63.4%) of the participants were married [table 1]. approximately half of the men (49.5%) had received at least a secondary school education compared to only 34.7% of the women, and a larger proportion of men (60.3%) were employed compared to women (10.7%). the mean bmi and systolic bp measurements of the sample were higher than normal at 26.1 ± 6.5 kg/ m2 and 131.8 ± 21.9 mm hg, respectively. elevated means were observed among men for bmi, systolic bp, table 1: distribution of selected sociodemographic, metabolic and lifestyle characteristics by gender of the omani population sample using the 2008 oman world health survey data (n = 3,137)* men n = 1,459 women n = 1,678 total sociodemographic characteristics age group in years 20–29 36.5 32.1 34.2 30–39 23.7 27.0 25.5 40–49 14.8 13.6 14.1 50–59 10.0 14.5 12.4 ≥60 15.1 12.8 13.8 mean ± sd 39.4 ± 16.6 39.5 ± 15.1 39.4 ± 15.8 marital status married 63.6 63.2 63.4 education level no formal education 29.0 48.1 39.2 primary or preparatory 21.5 17.2 19.2 secondary 32.8 24.3 28.3 postsecondary 16.7 10.4 13.3 work status employed 60.3 10.7 33.8 wealth status† q1 16.5 17.7 17.1 q2 23.1 25.0 24.1 q3 22.1 22.6 22.4 q4 18.6 20.4 19.6 q5 19.7 14.2 16.8 metabolic components bmi in kg/m2 25.9 ± 6.3 26.3 ± 6.6 26.1 ± 6.5 wc in cm 90.5 ± 15.8 89.6 ± 17.8 90.0 ± 16.9 sbp in mm hg 138.4 ± 21.4 126.0 ± 20.8 131.8 ± 21.9 dbp in mm hg 84.9 ± 14.3 77.0 ± 13.4 80.7 ± 14.4 fbg in mmol/l 5.7 ± 2.2 5.4 ± 1.9 5.5 ± 2.1 triglycerides in mmol/l 1.40 ± 1.1 1.17 ± 0.8 1.30 ± 0.9 hdl cholesterol in mmol/l 1.18 ± 0.3 1.36 ± 0.4 1.26 ± 0.4 lifestyle characteristics current smoker 15.1 0.3 7.2 <150 minutes of moderate physical activity/week 32.0 40.5 36.6 >6 hours sitting per day 21.5 25.6 23.7 median sitting time in hours/ day 3.0 4.0 3.0 <5 servings of fruit/ vegetables per day 84.6 80.9 82.6 servings of fruit/vegetables per day 3.0 ± 2.3 3.2 ± 2.7 3.1 ± 2.5 q = quintile; sd = standard deviation; bmi = body mass index; wc = waist circumference; sbp = systolic blood pressure; dbp = diastolic blood pressure; fbg = fasting blood glucose; hdl = high-density lipoprotein.*data is expressed as unweighted percentages or mean ± sd. †wealth status was divided into quintiles, with q1 being the lowest and q5 being the wealthiest. mahmoud abd el-aty, ruth mabry, magdi morsi, jawad al-lawati, asya al-riyami and medhat el-sayed clinical and basic research | e463 blood glucose and triglycerides levels in comparison to women, where these variables were within normal ranges. however, women’s obesity measurements were outside these normal ranges. the mean waist circumferences of women (89.6 ± 17.8 cm) were above the normal range and similar to those of men (90.5 ± 15.8 cm). a high percentage of the sample ate less than the recommended five servings of fruit and vegetables per day (82.6%) and did less than 150 minutes of moderate physical activity per week (36.6%). tobacco use was relatively common among men (15.1%) but rare among women (0.3%). overall, the age-adjusted prevalence of ms was 23.6%; it was slightly higher in women (24.4%) than men (22.8%), but this difference was not statistically significant [table 2]. the age-adjusted prevalence of ms was particularly high in adults aged 40–49 years (33.4%), those aged 50 years and above (39.5%) and those with no formal education (33.7%). the prevalence of the various components of ms varied according to gender [figure 1]. the components with the highest prevalence for women were central obesity and low hdl cholesterol (73.7% and 59.8%, respectively). for men, the components with the highest prevalence were high bp, high triglycerides and impaired fasting glucose levels (60.1%, 56.4% and 53.0%, respectively). the gender difference in prevalence rates were highly significant for all components (p <0.001). table 2 presents the results of the logistic regression analysis using all key sociodemographic, clinical and behavioural variables. ms was significantly associated with age, wealth and marital and work status. ms was more common for people aged 50 years table 2: adjusted prevalence and odds ratio of demographic and behavioural risk factors for metabolic syndrome* in the omani population using the 2008 oman world health survey data (n = 3,137) metabolic syndrome or (95% ci) p value n ageadjusted prevalence % sociodemographic characteristics gender women 1,678 24.4 1 men 1,459 22.8 0.9 (0.7–1.2) 0.539 age group in years 20–29 30–39 40–49 >50 1,072 799 444 823 13.5 25.3 33.4 39.5 1 1.5 (1.2–2.1) 2.2 (1.5–3.1) 3.6 (2.4–5.3) 0.004 <0.001 <0.001 marital status other married 1,148 1,989 16.5 27.9 1 1.6 (1.3–2.1) <0.001 education level illiterate primary/ preparatory secondary postsecondary 1,229 603 886 419 33.7 24.3 16.4 18.1 1 0.98 (0.7–1.4) 0.84 (0.6–1.2) 0.76 (0.5–1.2) 0.945 0.314 0.199 work status not employed employed 2,077 1,059 23.2 24.4 1 1.3 (1.1–1.8) 0.043 wealth status† q1 q2 q3 q4 q5 537 756 703 615 526 23.4 29.9 18.6 21.6 23.6 1 1.6 (1.2–2.2) 0.8 (0.6–1.2) 1.0 (0.7–1.4) 1.2 (0.8–1.7) 0.005 0.308 0.859 0.439 behavioural risk factors smoking not a current smoker current smoker 2,910 226 23.4 26.1 1 0.9 (0.6–1.3) 0.500 moderate physical activity per week ≥150 minutes <150 minutes 1,990 1147 23.4 24.0 1 0.9 (0.7–1.1) 0.143 sitting time per day ≤6 hours >6 hours 2,395 742 22.8 26.5 1 1.3 (1.1-1.7) 0.035 servings of fruits and vegetables per day ≥5 <5 829 2,308 23.5 24.1 1 1.0 (0.7–1.3) 0.870 total 3,173 23.6 or = odds ratio; ci = confidence interval; q = quintile. *metabolic syndrome was identified according to the national cholesterol education program’s revised adult treatment panel iii definition. †wealth status was divided into quintiles, with q1 being the lowest and q5 being the wealthiest. metabolic syndrome and its components secondary analysis of the world health survey, oman e464 | squ medical journal, november 2014, volume 14, issue 4 and over compared to the youngest cohort (or 3.6, ci: 2.4–5.3; p <0.001). it was more common in people who were married or employed (or 1.6, ci: 1.3–2.1; p <0.001 and or 1.3, ci: 1.1–1.8; p = 0.043, respectively) compared to their unmarried and unemployed counterparts. ms was also more common in people in the second lowest wealth quintile (or 1.6, ci: 1.2– 2.2; p = 0.005) compared to the lowest quintile. of the behavioural risk factors examined (smoking, physical activity, sitting time and dietary intake), only sitting time showed a significant association with ms. the syndrome was more common in people who sat more than six hours per day in comparison to those who sat less (or 1.3, ci: 1.1–1.7; p = 0.035). discussion the results of this study showed a high national prevalence of ms (23.6%). this prevalence differed from other prevalences recorded in oman—it was slightly higher than that seen in nizwa in 2001 (21.0%) but lower than that seen in sur (27.3%).12,14 these differences could be due to the definition of ms that was used in these studies. the prevalence found was also slightly lower than in qatar (26.5%), but much lower than prevalences recorded among other countries of the gulf cooperation council (gcc) region, like saudi arabia (39.3%) and the united arab emirates (uae) (39.6%).15 like oman, other countries of the gcc region reported a higher prevalence of ms among women, with gender differences ranging between 4.8% in saudi arabia using the atpiii definition to 13% in the uae using the international diabetes federation definition.15 the prevalence rates in oman were lower than in the usa, where the rates were 35.1% and 32.6% for men and women, respectively.19 however, the rates for men and women were higher than those found in australia (15.7% and 14.4%, respectively)20 and european countries such as italy (15% and 18%, respectively)21 and france (16% and 11%, respectively).22 the lower prevalence seen in oman compared to neighbouring countries is likely due to the lower rates of obesity and possibly also a reflection of the relatively lower gross domestic product (gdp) per capita.23 it is concerning that despite having a young population compared to developed countries, one in four omani adults in the 2008 owhs were found to have ms. the prevalence of non-communicable diseases and their risk factors, such as obesity and high bp, are on the increase.9–11 evidence indicates that the omani population is genetically susceptible to some components of ms such as obesity, high cholesterol levels and elevated bp.24 in addition, evidence indicates that malnutrition in utero, a likely scenario for the current generation of adults, is linked to ms in adults.25 given the population’s increased vulnerability to ms, extensive efforts should be made by the government of oman to implement multisectoral, cost-effective, population-wide interventions such as the actions outlined in the united nations’ political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases.8,26 interestingly, of the behavioural risk factors examined (smoking, physical inactivity, sitting time figure 1: the age-adjusted prevalence of various components of metabolic syndrome among men and women using the 2008 oman world health survey. metabolic syndrome was defined according to the national cholesterol education program’s revised adult treatment panel iii criteria. the error bars denote 95% confidence intervals. hdl = high-density lipoproteins. ***significance was p <.001. mahmoud abd el-aty, ruth mabry, magdi morsi, jawad al-lawati, asya al-riyami and medhat el-sayed clinical and basic research | e465 and dietary intake), only sitting time was found to be associated with ms in this study. evidence clearly demonstrates that these behaviours can prevent ms and its components.8,14,27,28 thus, it is concerning that a large portion of omani adults do not meet the recommended amount of physical activity, sit for long periods of time and do not consume the recommended amount of fruit and vegetables.8,29 successful interventions within the gcc region, including the nizwa healthy lifestyle project, demonstrate how community-based activities can bring about behavioural changes.30,31 a more strategic approach to promoting physical activity and healthy eating involves changes in policies which are largely outside the health sector, such as agriculture, commerce, education, media, sports, transportation and urban planning.32 the high proportion of adults suffering from ms and its components is likely to increase in the near future given the increase in life expectancy and the high susceptibility of the population. despite the existence of well-defined clinical management guidelines and a national screening programme for non-communicable diseases,33–35 several studies have raised concerns regarding the quality of care for people with diabetes.31,36,37 improving the delivery of care, patient education and training for health workers at the primary care level have been identified as key areas for improvement.36,37 the significant associations of ms with older age and lower education are similar to the findings of other studies in oman and other gcc countries.12,15,38,39 the positive association with age is also commonly found in other parts of the world.40 however, the association with education and income varies internationally.40 given the significant associations with age and education in oman, the growth of the elderly population and a high proportion of older adults with ms, extensive efforts are required to ensure that prevention and disease management messages can be clearly understood and followed by all, including those with limited literacy skills.41 improving the quality of care by emphasising a patient-centred approach is a key way to address this particular issue.36,37 the main strength of this study is that it was a population-based study with a large sample. by obtaining information and collecting clinical measurements and blood at the household level, participants were not obligated to visit a health centre. on the other hand, the long questionnaire, which required an average of 2.25 hours to complete, may have wearied respondents and potentially lead to inaccuracy, particularly among self-reported items such as the questions regarding health risk behaviours. in addition, as a cross-sectional study, the associations identified do not necessarily denote causality. four main recommendations can be made based on the findings of this study. first, greater efforts should be made by the moh to advocate for an all-government approach to promoting healthy behaviours as part of a national strategy to prevent non-communicable diseases and their precursor, ms. given the vast amount of evidence demonstrating that physical activity and healthy dietary behaviours can prevent ms and its components, further research is recommended to better understand these behaviours and to test interventions. additionally, a patientcentred approach that ensures the provision of quality primary healthcare interventions to prevent, screen for and manage ms and its components is required in order to prevent complications and reduce hospitalisation and mortality. prevention and disease management messages need to be developed so that they can be easily understood and followed, particularly by older adults who may have limited literacy skills. conclusion in conclusion, one in four omani adults was found to have ms, which is a proximal precursor to cardiovascular disease and diabetes. this prevalence rate is higher than in many developed countries despite the much younger population in oman. an enormous amount of effort by various sectors is needed to reduce the prevalence of ms and its components in order to build on the health gains of the past and to meet the country’s united nations commitments to addressing non-communicable diseases. acknowledgements the authors would like to thank the moh for providing the raw data as well as the who regional office for the eastern mediterranean region for technical support and the relevant gcc authorities for their coordination with the original owhs. the views expressed in this paper are those of the authors and do not necessarily reflect those of the who. references 1. alberti kg, zimmet p, shaw j. metabolic syndrome: a new world-wide definition. a consensus statement from the international diabetes federation. diabet med 2006; 23:469– 80. doi: 10.1111/j.1464-5491.2006.01858.x. 2. zimmet p, alberti g, shaw j. a new idf worldwide definition of the metabolic syndrome: the rationale and the results. diabetes voice 2005; 50:31–3. metabolic syndrome and its components secondary analysis of the world health survey, oman e466 | squ medical journal, november 2014, volume 14, issue 4 3. borena w, edlinger m, bjørge t, häggström c, lindkvist b, nagel g, et al. a prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (me-can) collaborative study. plos one 2014; 9:e89368. doi: 10.1371/journal.pone.0089368. 4. pan a, keum n, okereke oi, sun q, kivimaki m, rubin rr, et al. bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. diabetes care 2012; 35:1171–80. doi: 10.2337/dc11-2055. 5. thomas g, sehgal ar, kashyap sr, srinivas tr, kirwan jp, navaneethan sd. metabolic syndrome and kidney disease: a systematic review and meta-analysis. clin j am soc nephrol 2011; 6:2364–73. doi: 10.2215/cjn.02180311. 6. simmons rk, alberti kg, gale ea, colagiuri s, tuomilehto j, qiao q, et al. the metabolic syndrome: useful concept or clinical tool? report of a who expert consultation. diabetologia 2010; 53:600–5. doi: 10.1007/s00125-009-1620-4. 7. kassi e, pervanidou p, kaltsas g, chrousos g. metabolic syndrome: definitions and controversies. bmc med 2011; 9:48. doi: 10.1186/1741-7015-9-48. 8. world health organization. global status report on noncommunicable disease: 2010. from: www.whqlibdoc. who.int/publications/2011/9789240686458_eng.pdf?ua=1 accessed: may 2014. 9. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1 methodology, sociodemographic profile and epidemiology of noncommunicable diseases in oman. oman med j 2012; 27:425– 43. 10. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. doi: 10.1046/j.1464-5491.2002.00818.x. 11. al riyami aa, afifi mm. hypertension in oman: distribution and correlates. j egypt public health assoc 2002; 77:383–407. 12. al-lawati ja, mohammed aj, al-hinai hq, jousilahti p. prevalence of the metabolic syndrome among omani adults. diabetes care 2003; 26:1781–5. doi: 10.2337/diacare.26.6.1781. 13. al-lawati ja, jousilahti p. prevalence of metabolic syndrome in oman using the international diabetes federation’s criteria. saudi med j 2006; 27:1925–6. 14. mabry rm, winkler ea, reeves mm, eakin eg, owen n. associations of physical activity and sitting time with the metabolic syndrome among omani adults. obesity (silver spring) 2012; 20:2290–5. doi: 10.1038/oby.2012.26. 15. mabry rm, reeves mm, eakin eg, owen n. gender differences in prevalence of the metabolic syndrome in gulf cooperation council countries: a systematic review. diabet med 2010; 27:593–7. doi: 10.1111/j.1464-5491.2010.02998.x. 16. world health organization. who world health survey. from: www.who.int/healthinfo/survey/en/ accessed: may 2014. 17. world health organization. chronic diseases and health promotion: stepwise approach to chronic disease risk factor surveillance (steps). from: www.who.int/chp/steps/ riskfactor/en/ accessed: may 2014. 18. oman ministry of health. world health survey oman. from: www.moh.gov.om/en/reports/whssurvey2008(1).pdf and www.moh.gov.om/en/reports/whssurvey2008(2).pdf accessed: may 2014. 19. ervin rb. prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: united states, 2003–2006. natl health stat report 2009; 5:1–7. 20. adams rj, appleton s, wilson dh, taylor aw, dal grande e, chittleborough c, et al. population comparison of two clinical approaches to the metabolic syndrome: implications of the new international diabetes federation consensus definition. diabetes care 2005; 28:2777–9. doi: 10.2337/ diacare.28.11.2777. 21. miccoli r, bianchi c, odoguardi l, penno g, caricato f, giovannitti mg, et al. prevalence of the metabolic syndrome among italian adults according to atp iii definition. nutr metab cardiovasc dis 2005; 15:250–4. doi: 10.1016/j. numecd.2004.09.002. 22. balkau b, vernay m, mhamdi l, novak m, arondel d, vol s, et al. the incidence and persistence of the ncep (national cholesterol education program) metabolic syndrome: the french d.e.s.i.r. study. diabetes metab 2003 29:526–32. doi: 10.1016/s1262-3636(07)70067-8. 23. ng sw, zaghloul s, ali hi, harrison g, popkin bm. the prevalence and trends of overweight, obesity and nutritionrelated non-communicable diseases in the arabian gulf states. obes rev 2011; 12:1–13. doi: 10.1111/j.1467-789x. 2010.00750.x. 24. bayoumi ra, al-yahyaee sa, albarwani sa, rizvi sg, alhadabi s, al-ubaidi ff, et al. heritability of determinants of the metabolic syndrome among healthy arabs of the oman family study. obesity (silver spring) 2007; 15:551–6. doi: 10.1038/ oby.2007.555. 25. wang j, wu z, li d, li n, dindot sv, satterfield mc, et al. nutrition, epigenetics, and metabolic syndrome. antioxid redox signal 2012; 17:282–301. doi: 10.1089/ars.2011.4381. 26. united nations general assembly. political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases. from: www.who. int/nmh/events/un_ncd_summit2011/political_declaration_ en.pdf?ua=1 accessed: may 2014. 27. edwardson cl, gorely t, davies mj, gray lj, khunti k, wilmot eg, et al. association of sedentary behaviour with metabolic syndrome: a meta-analysis. plos one 2012; 7:e34916. doi: 10.1371/journal.pone.0034916. 28. healy gn, matthews ce, dunstan d, winkler ea, owen n. sedentary time and cardio-metabolic biomarkers in us adults: nhanes 2003–06. eur heart j 2011; 32:590–7. doi: 10.1093/ eurheartj/ehq451. 29. alasfoor d, rajab h, al-rassasi b. food based dietary guidelines: technical background and description. from: www.fao.org/ag/humannutrition/19542-0561250979706400b7 cc8ca7366cc07c0.pdf accessed: may 2014. 30. midhet fm, sharaf fk. impact of health education on lifestyles in central saudi arabia. saudi med j 2011; 32:71–6. 31. al-sinani m, min y, ghebremeskel k, qazaq hs. effectiveness of and adherence to dietary and lifestyle counselling: effect on metabolic control in type 2 diabetic omani patients. sultan qaboos univ med j 2011; 10:341–9. 32. gortmaker sl, swinburn ba, levy d, carter r, mabry pl, finegood dt, et al. changing the future of obesity: science, policy, and action. lancet 2011; 378:838–47. doi: 10.1016/ s0140-6736(11)60815-5. 33. oman ministry of health. a manual for the management of hypertension in primary health care. from: www.moh.gov.om/ en/stat/2010/index_eng.htm accessed: may 2014. 34. oman ministry of health. diabetes mellitus: management guidelines for primary health care. from: www.moh.gov. om/en/reports/diabetesaftercorrection1.pdf accessed: may 2014. 35. oman ministry of health. operational and management guidelines for the national non-communicable diseases screening program. from: www.moh.gov.om/en/reports/ guidelines_manual_for_the_national_n c d_scre ening_ program.pdf accessed: may 2014. 36. elliott ja, abdulhadi nn, al-maniri aa, al-shafaee ma, wahlström r. diabetes self-management and education of people living with diabetes: a survey in primary health care in muscat oman. plos one 2013; 8:e57400. doi: 10.1371/journal. pone.0057400. mahmoud abd el-aty, ruth mabry, magdi morsi, jawad al-lawati, asya al-riyami and medhat el-sayed clinical and basic research | e467 37. al-shookri a, khor gl, chan ym, loke sc, al-maskari m. effectiveness of medical nutrition treatment delivered by dietitians on glycaemic outcomes and lipid profiles of arab, omani patients with type 2 diabetes. diabet med 2012; 29:236– 44. doi: 10.1111/j.1464-5491.2011.03405.x. 38. al rashdan i, al nesef y. prevalence of overweight, obesity, and metabolic syndrome among adult kuwaitis: results from community-based national survey. angiology 2010; 61:42–8. doi: 10.1177/0003319709333226. 39. bener a, zirie m, musallam m, khader ys, al-hamaq ao. prevalence of metabolic syndrome according to adult treatment panel iii and international diabetes federation criteria: a population-based study. metab syndr relat disord 2009; 7:221–9. doi: 10.1089/met.2008.0077. 40. cameron aj, shaw je, zimmet pz. the metabolic syndrome: prevalence in worldwide populations. endocrinol metab clin north am 2004; 33:351–75. doi: 10.1016/j.ecl.2004.03.005. 41. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. taurine levels in human aqueous humour medical sciences (2000), 2, 11−14 © 2000 sultan qaboos university department of biochemistry, sultan qaboos university, p.o.box: 35, postal code: 123, muscat, sultanate of oman *to whom correspondence should be addressed. 11 effect of single mismatches at 3′– e nd of primers on polymerase chain reaction *simsek m, adnan h تأثير عدم التوافق االحادي عند نقطة األنتنهاء الثالثي للمواد التمهيدية في )حافز البلمرة(سلسلة تفاعل البوليمارز .عدنان. سمسك ، ح. م ظهر أن االرتباط : الطريقة والنتائج . وقواعد االنتهاء الثالثي للمحفز ) بيتاجين الهيموجلوبين ( بين قواعد الحمض النووي توافق ال عدم مدى تأثير ثالثة أنواع من معرفة: الهدف: الملخص مض ا قاعدة ح268، وهي منطقة تحتوي على )الهدف( الهيموجلوبين ساعد في عملية التكاثر السريع للمنطقة المنشودة في جين بيتا) ج/ج،أ/ج،ت/ج(الذي حدث بين زوجي القواعد الثالث آان ) ج/ت(تالحم قاعدتي المحفز والهدف . درجة مئوية، وهي ما تعرف بدرجة حرارة التالحم المتماثل65 و 45نووي مزدوج، وذلك باستخدام سلسلة من درجات الحرارة تراوحت بين أي تفاعل يذآر ) ج/أأو ج/ج ( التحام القواعد األخرى لم ينتج من . هذا التالحم في آل درجات الحرارة المذآورة سلفا حدث )ج/س(قاعدتي قويا مثل التالحم الطبيعي الذي يحدث بين . درجة مئوية50 و 45 عند درجتي حرارة ج/جسوى التفاعل الضعيف للقاعدة . وقد تم التفاعل مع المنطقة المنشودة من جين بيتا الهيموجلوبين)ج /ج و ج/أ (ان المحفزين اللذين أمكنهما التفاعل هما زوجى القواعد : الخالصة abstract: objective and method – to investigate the effect of three different mismatches (g/t, g/a or g/g) at the 3•– end of a primer to amplify a 268 bp (base pair) region of the human •–globin gene using different annealing temperatures (45 to 65•c). results – the primer with the g/t mismatch was as efficient as the normal primer (g/c match) in the amplification of a 268 bp product at all temperatures tested. however, the primers having g/a or g/g mismatches at the 3'end did not produce any specific polymerase chain reaction (pcr) fragment at all the annealing temperatures used, except a barely detectable 268 bp product for the g/g mismatch at 45 and 50•c. conclusion – we conclude that our pcr system was refractory to amplification when one of the primers contained a g/a or g/g mismatch at the 3•–end with template dna. key words: pcr, mismatched primers, β−globin gene olymerase chain reaction (pcr) is a sensitive and powerful method by which specific sequences of template dna can be amplified more than a million fold using 20�30 cycles of dna synthesis.1 each cycle requires three stages: first, denaturation of dna at high temperature (90�94ºc), second, annealing of oligonucleotide primers at a lower temperature (usually at 40 to 60ºc), and finally, extension of primers at 72ûc by taq dna polymerase, a heat stable enzyme. most of the dna polymerases used in pcr lack an intrinsic 3' to 5' exonuclease activity.2 thus, oligonucleotides with a mismatch at the 3'�end may be extended and serve as primers in the polymerase chain reaction (pcr). the efficiency of such primers would depend on many factors, including the nature of the mismatch, the kinetics of association and dissociation of primer-template dna duplex at the annealing and extension temperatures, and the effect of a mismatch on the stability of the duplex dna formed. several investigators have begun to evaluate the possible effects of mismatches in their primers.3-5 it has been shown that a single mismatch at or near the terminal 3′ base of a primer affects pcr more dramatically than those single mismatches located internally or at 5′ end.6 using primers with one or more mismatches near the 3′ end, allele specific amplification (asa) has been developed7 for the detection of mutations in genetic diseases. in this study, we have evaluated the effect on pcr, of three different mismatches (g/t, g/a and g/g) located at the 3′ �terminal end of primers which were used to amplify a small region in the human βglobin gene. method dna isolation miller�s salting-out procedure8 was used to isolate genomic dna from whole blood with ethylenediamine tetra acetic acid (edta) as anticoagulant. the p 11 s i m s e k e t a l 12 nuclei of white blood cells were isolated after lysis of cells with a non-ionic detergent. the isolated cell nuclei were suspended in a buffer containing an ionic detergent (sds) and proteinase k which digests the proteins associated with chromosomal dna. all the proteins were precipitated using high salt concentration (salting out) and the dna in the supernatant was recovered by precipitation with ethanol. the amount of dna obtained was around 5�10 µg per 0.5 ml whole blood. dna amplification by polymerase chain reaction. a small region (286 bp) of human β�globin gene was amplified using a pair of primers which were either completely complementary to the globin gene, or had a single mismatch at the 3′ �end. genomic dna was amplified in 50 µl reaction volumes with 25 pmoles of each primer, 1 unit of amplitaq dna polymerase (perkin-elmer cetus inc.), 200 µm each of the four deoxynucleoside triphosphates, and a buffer containing 10 mm tris ph 8.3, 50 mm kcl, 0.01% gelatin, and 1 mm mgcl2 (unless otherwise mentioned). all amplifications were started by the addition of the taq dna polymerase at 94ûc (hot start) and continued for 30 cycles in a dna thermal cycler (hybaid inc.) each cycle of amplification contained the following steps: dna denaturation: 2 minutes at 94ûc, primer annealing: 2 minutes at 50ûc, and primer extension: 3 minutes at 72ûc. the pcr products were separated by electrophoresis on 2.5% agarose gels and detected by staining with ethidium bromide (0.5 µg/ml) for 15 minutes in electrophoresis buffer (40 mm tris acetate ph 8.0 and 1mm edta). a polaroid land camera (mp4 kodak) was used to take pictures of the gels over a uv trans-illuminator in dark room. synthesis of dna primers two sets of oligonucleotide primers were synthesised using a dna synthesizer (pharmacia, gene assembler special 4). one set completely matched the template dna while the other had an upstream primer with a mismatch at its 3′ �end. if the a residue in the atg initiation codon is taken as position 1 in the human globin gene, the down�stream primer (hg� p2) was complementary to the sense strand (positions 54 through 73), and had the following sequence: 5′ � caacttcatccacgttcacc�3′ . the upstream primer (hg�p1) complemented the anti-sense strand of the β�globin gene (from position �195 to �176) with the following sequence: 5′ �aagagccaaggacaggtac�3′ . the three different upstream primers (hg�p1a, hg�p1g, hg�p1t) with a single mismatch were identical to the sequence of the hg� p1, except that they had an a, g or t residues, respectively replacing the terminal c at their 3′ �end. results the primers used in this work specified the amplification of a 268 bp region of the human β�globin gene. before studying the effect of mismatches at the 3′ �end of primers, an optimization for mgcl2 was carried out since any pcr amplification is known to be very sensitive to magnesium ion concentration.9 using the normal primers, it was found that a detectable 268 bp pcr product was amplified at different mg+2 ion concentrations ranging from 0.5 to 4.0 mm in 0.5 mm increments (data not shown). however, above 1.5 mm concentration, there were too many nonspecific products, and furthermore, the desired 268 bp product decreased in quantity with increased mg+2 ion con figure 1. the effect of magnesium concentration on pcr. the reaction conditions were as described in the ‘methods’ section, using normal primers, except the variation in mg 2+ concentration. after 30 cycles of amplification, the pcr products were separated by electrophoresis on a 2.5% agarose gel (at 90 volts for 60 minutes) and detected by staining with ethidium bromide. the arrow shows the position of a specific pcr product (268 bp). lane m contained dna size markers. lane 1 was negative control (without any template dna added) in the pcr amplification. the reactions in lanes 2 to 6 contained different concentrations of mg 2+ ions: lanes 2 & 3 (0.5 mm), e f f e c t o f s i n g l e m i s m a t c h e s o n p c r 13 centration. figure 1 shows a duplicate titration of magnesium ions at 0.5 to 1.0 mm range. there were no detectable non-specific products and the best amplificaton of the 268 bp product was achieved at 1.0 mm mgcl2 concentration (figure 1, lanes 6 &7). to study the effect of mismatches at the 3′ �end of primers, we attempted to amplify the 268 bp dna fragment at different annealing temperatures, from 45 to 65ºc using a normal downstream primer (hg�p2) together with a single mismatch containing upstream primer (hg�p1a, hgp1t or hg�p1g). having a g residue in the template dna at the corresponding position, each of these primers would normally form 19 normal base pairs with the template, but in this case, resulted in a mismatch of g/a, g/t or g/g at the 3′ terminal end, respectively. figure 2 shows some representative results obtained with different primers at 50 and 65ºc. at both annealing temperatures, when normal primer pairs were used (figure 2, lane 5) the desired 268 bp dna fragment was amplified satisfactorily without any detectable non-specific products. interestingly, the primer with a g/t mismatch produced similar results (figure 2, lane 3). however, the results obtained with the primers containing either a g/a or g/g mismatch were entirely different. the primer with the g/a mismatch (figure 2b, lane 2) showed no detectable 268 bp product at 65ºc, a fairly distinct but a smaller pcr product than 268 bp at 50ºc, but was undetectable at 65ºc (lanes 4 in figure 2b and 2a respectively). discussion we have studied here the priming efficiency of a 20 nucleotide long primer set which provided three different single mismatches (g/t, g/a and g/g) with the template dna used. the g residue was located in the template (β-globin gene) while t, a or g were at the 3′ �end of the primers. our results showed that the g/t mismatch primed the synthesis of a 268 pb specific pcr product, almost as efficiently as the normal primer (hg�p1) which contained a g/c match at the 3′ �end. however, the priming efficiency of the primers with g/a or g/g mismatches was extremely poor, and resulted in the production of no specific pcr fragment that was detectable by staining with ethidium bromide. the results obtained with all three mismatches were essentially the same as in figure 2 at different annealing temperatures tested (45 to 65ºc) except that the specific pcr product (268 bp) was barely detectable for the g/g mismatch at 45, 50 and 55ºc but for the g/a mismatch, no specific product was detectable figure 2. the effect, on pcr, of single mismatches between the 3’ base of a primer and template dna at two temperatures the arrows indicate the position of the specific 268 bp pcr product. in both panels, lane m contained dna sized markers. lane 1 was negative control and lane 5 the positive control containing normal pair of primers. lanes 2, 3 and 4 contained the mismatched primers, ending with g/a, g/t and g/g, respectively. s i m s e k e t a l 14 at all at any of the tested annealing temperatures. the g/a mismatch, however, produced a fairly strong and distinct product at 45ºc, sized <200 bp and was not produced at all at higher annealing temperatures (figure 2b, lane 2). we concluded that it must be a non-specific pcr product formed possibly due to dimerization of the primers.2 the priming efficiency of mismatched primers has already been studied by various groups. our result with g/t mismatch agrees with that of kwok11 who showed that a single mismatch of t/t, t/c or t/g at 3′ �end had no effect on the priming efficiency of their primers. the same group also studied a a/g mismatch, and our results agree with theirs. however, our results with the g/g mismatched primer (figure 2, lane 4) contradict some of the published work. for example, newton10 reported that a single g/g mismatch had very little effect on the priming efficiency of their primers, while we could get only a barely detectable specific pcr product at 45�55ºc, and none at 60 or 65ºc. one potential application of mismatched primers has been towards identification of point mutations in genetic diseases. using asa primers which differed only by one base at 3′ �end, like ours, okayama7 was able to detect three different point mutations in patients with an α1-antitrypsin deficiency. however, their results were contradictory to ours, as well as many other studies reported10,11 in that 10 of the 12 possible mismatches, including a g/t mismatched primer, were all refractory to any detectable amplification. however, it is difficult to make a direct comparison of the results reported with various 3′ mismatched primers, due to differences in the pcr amplification conditions, especially the length and concentration of primers. in some studies, the primers were too short (12�16 bases)12 and hence a 3′ �mismatch may have more dramatic effects both on the stability of primertemplate dublex and the extension of mismatched primer by dna polymerase. on the other hand, if the primers are too long, like 30 bases used by ehlen and dubeau,13 the effect of 3′ �mismatch on pcr may be minimal. the primers used in this work were intermediate in size (20 bases long), a size commonly used by many research groups. conclusion in summary, our upstream primers resulting in an a/g or g/g mismatch at the 3′ �end with template dna were refractory to amplification. but the same primer, when ended with a t/g mismatch, showed no refractoriness, and was as efficient as the normal primer for the amplification of a 268 bp dna of the human β-globin gene. references 1. saiki rk, gelfand dh, stoffel s, scharf sj, higuchi r, horn gt, mullis kb, erlich ha. primer-directed enzymatic amplification of dna by a thermostable dna polymerase. science 1988, 239, 487–91. 2. newton cr, graham a., enzyme choice in pcr. introduction to biotechniques, bios scientific publishers, 1994, pp: 12–21. 3. gibbs ra, nguyen pn, caskey ct. detection of single base differences by competitive oligonucleotide priming. nucleic acids res 1989, 17, 2437–48. 4. eiken hg, odland e, boman h, skjelkvale l, engebretsen lf, apold j. applications of natural and amplification created sites for the diagnosis of pku mutations. nucleic acids res 1991, 19, 427–30. 5. tsai my, hanson nq, copeland kr, beheshti i, garg u. determination of a t/g polymorphism at nucleotide 3206 of the apolipoprotein ciii gene by amplification refractory mutation system. clin chem 1994, 40, 2235–39. 6. lindeman r, hu sp, volpato f, trent rj. pcr mutagenesis enabling rapid non-radioactive detection of common •-thalassemia mutations in mediterraneans. br j haematol 1991, 78, 100–4. 7. okayama h, curiel dt, brantly ml, holmes md, crystal rg. rapid, nonradioactive detection of mutations in the human genome by allele-specific amplification. j clin med 1989, 144, 105–13. 8. miller sa, dykes dd, polesky hf. a simple salting out procedure for extracting dna from human nucleated cells. nucleic acids res 1988, 1215–18. 9. saiki rk, scharf s, faloona f, mullis kb, horn gt, erlich ha, arnheim n. enzymatic amplification of β−globin genomic sequences and restriction site analysis for diagnosis of sickle cell anaemia. science 1985, 230, 1350–54. 10. newton cr, graham a, heptinstall le, powell sj, summers c, kalshekar n, smith jc, markham af. analysis of any point mutation in dna; the amplification refractory mutation system (arms). nucleic acids res 1989, 17, 2503–16. 11. kwok s, kellogg de, mckinney n, spasic d, goda l, levenson c, sninsky jj. effects of primer-template mismatches on the polymerase chain reaction. nucleic acids res, 1990, 18, 999– 1005. 12. wu dy, ugozzoli l, pal bk, wallace rb. allele specific enzymatic amplification of β-globin genomic dna for diagnosis of sickle cell anaemia. proc natl acad sci usa 1989, 86, 2757–60. 13. ehlen t, dubeau l. detection of ras point mutations by pcr using mutations-specific, inosine containing oligonucleotide primers. biochem biophys res commun 160, 441. effect of single mismatches at 3(–end of primers �on polymerase chain reaction method dna isolation dna amplification by polymerase chain reaction. synthesis of dna primers sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e241–249, epub. 28 may 15 submitted 27 may 14 revisions req. 10 aug & 30 sep 14; revisions recd. 18 aug & 3 oct 14 accepted 19 oct 14 1department of clinical pathology & immunology, faculty of medical sciences, university of sciences & technology, sana’a, yemen; 2department of medical microbiology & clinical immunology, faculty of medicine & health sciences, sana’a university, sana’a, yemen; 3department of clinical immunology, al-thorah university hospital, sana’a, yemen; 4yemen ministry of public health, sana’a, yemen *corresponding author e-mail: shmahe@yemen.net.ye العالقة بني انواع ُمْسَتِضدَّاُت الُكَريَّاِت البيِض الَبَشرِيَّة يف مرض املرحلة االخرية من الفشل الكلوي املصاحب الرتفاع ضغط الدم بني املرضى اليمنيني جماهد يحى ن�سار، ح�سن عبدالوهاب ال�سماحي، هيثم م�سعود abstract: objectives: many studies have attempted to locate a connection between various genetic factors and the pathogenesis of certain diseases. a number of these have found human leukocyte antigens (hlas) to be the most significant genetic factors affecting the susceptibility of an individual to a certain disease. the present casecontrol study aimed to determine the connection between class i and class ii hlas and cases of hypertensive end-stage renal failure (hesrf), as contrasted with healthy controls, in yemen. methods: the study was carried out between march 2013 and march 2014 and included 50 hesrf patients attending the urology & nephrology center at al-thawra university hospital in sana’a, yemen, and 50 healthy controls visiting the same centre for kidney donation. among both patients and controls, hla class i (a, b and c) and class ii (drb1) genotypes were determined by polymerase chain reactions. results: there was an association (odds ratio: 4.0) with hla-a9(24) and hesrf, although this was not statistically significant. a significant protective function was found for the hlacw3 and drb1-8 genes against the development of hesrf. although hla-b14 was present in some patients (0.06) and not in the controls, this difference was not statistically significant enough to conclude that hla-b14 plays a role in the genetic predisposition for end-stage renal disease development. there was a high frequency of hla-a2, b5, cw6, drb1-3, drb1-4 and drb1-13 in both patients and controls. conclusion: although no hlas were found to play a highly significant role in genetic predisposition to hesrf, certain hla genes could be considered as protective genes against hesrf development. keywords: hypertension; renal failure, end-stage; hla antigens; case-control study; yemen. امللخ�ص: الهدف: حاولْت العديد ِمْن الِدرا�ساِت حَتديد العالقة بني العوامِل الوراثيِة امُلْخَتِلفِة وحدوث َبْع�ض االأمرا�ِض. َوجد عدد ِمْن هذه هّدفْت االمرا�ض. ببع�ض لال�سابة اأكرب ب�سورة االفراد بع�ض وتعر�ض ة الَب�رَشِيَّ البي�ِض اِت الُكَريَّ دَّاُت ُم�ْسَت�سِ انواع بني عالقة الدرا�ساَت ة وحدوث الف�سل الكلوي امل�ساحب ارتفاع اِت البي�ِض الَب�رَشِيَّ دَّاُت الُكَريَّ الدرا�سُة لَتْقرير العالقِة بني ال�سنِف االول وال�سنِف الّثاين من ُم�ْسَت�سِ دَّاُت بني اال�سحاء كعينة للمقارنة. الطريقة: ُنّفذْت الدرا�سة بني مار�ض2013 �سغط الدم بني املر�سى و مقارنة ذلك بانت�سار هذه امُل�ْسَت�سِ واآذاِر 2014 وَت�سّمنْت 50 من مر�سى الف�سل الكلوي امل�ساحب الرتفاع �سغط الدم الذين و�سلوا اىل مركَز طّب الِكلى وطّب املجاري البوليَة يف م�ست�سفى الثورِة اجلامعي يف �سنعاء، اليمن، و 50 من اال�سحاء الذين راجعو نف�ض املركِز للترّبِع بالكلِى. مت ت�سنيف جينات ال�سنِف املت�سل�سلِة. ُبوليمرِياز تفاعالت بطريقة واال�سحاء املر�سى من كال بني ة الَب�رَشِيَّ البي�ِض اِت الُكَريَّ دَّاُت ُم�ْسَت�سِ من الّثاين وال�سنِف االول الَنتائِج: كان هناك عالقة )َلي�َست ذو داللة اإح�سائيةُ( بن�سبة اإحتماالِت: 4.0 بني )hla-a9)24 و hesrf، كما وجدت و ظيفة و قائية يف موجَد يكن ومَل املر�سى )0.06( َبْع�ض يف موجود َكاَن جني hla-b14 اأن من وبالرغم .drb1-8 و hla-cw3 جلينات هاّمة اال�سحاء اال ان هذا االإختالِف ملا يَكَن هامَّ ب�سكل اإح�سائي مبا فيه الكفاية الإ�ْسِتْنتاج امليِل الوراثِي لتطويِر املر�ِض الكلوِي النهائِي ب�سبب وجود هذا اجلني. كان هناك تكرار اإت�ض اإل اأي اأي-hla-a2( 2(، اإت�ض اإل اأي بي )hla-b5(، اإت�ض اإل اأي �سي دبليو )hla-cw6( واإت�ض اإل اأي دي اآر بي )hla-drb1-3, hla-drb1-4 و hla-drb1-13( يف كال من املر�سى و عينة املقارنة من اال�سحاء. اخلامتة: ة اال اننا اِت البي�ِض الَب�رَشِيَّ دَّاُت الُكَريَّ بالرغم من اأن الِدرا�سة مل تثبت وجود عالقة ذات اهمية بني ن�سوء الف�سل الكلوي وبع�ض انواع ُم�ْسَت�سِ ِكُن اأَْن ُتعَترَب اأن بع�ض اجلينات من اللمكن ان تكون لها وظيفة وقائية �سّد ن�سوء الف�سل الكلوي امل�ساحب الرتفاع �سغط الدم. مُيْ ة؛ درا�سة مقارنة؛ اليمن. اِت البي�ِض الَب�رَشِيَّ دَّاُت الُكَريَّ مفتاح الكلمات: اإرتفاع �سغط الدم؛ الف�سل الكلوي، مرحلة نهائيِة؛ ُم�ْسَت�سِ the association between human leukocyte antigens and hypertensive end-stage renal failure among yemeni patients mogahid y. nassar,1 *hassan a. al-shamahy,2 haitham a. a. masood3,4 clinical & basic research advances in knowledge this study gives information about human leukocyte antigens (hla) in individuals from yemen and investigates the relationship between hlas and hypertensive end-stage renal failure (hesrf). this study provides important information as it is the first time that the frequency of hla genes in the general yemeni population and in hesrf yemeni patients has been investigated. the association between human leukocyte antigens and hypertensive end-stage renal failure among yemeni patients e242 | squ medical journal, may 2015, volume 15, issue 2 the progression of chronic renal failure (crf) usually leads to end-stage renal disease (esrd), at which point renal replacement therapy is the only option. since the mid-1980s, there has been a noticeable rise in the incidence and prevalence of esrd around the world.1–4 gender, genetic profile, ethnicity, lipids, hypertension and smoking have been identified as factors which can influence the development of esrd.4,5 however, there is a need for further research to be carried out on the role of the immune system in renal diseases, as this could be the origin or cause of the disease and its progression.6 this theory is the outcome of investigations into positive relations between human leukocyte antigens (hlas) and a broad variety of renal diseases.6 studies have illustrated some significant associations between hla class i and ii alleles with renal diseases. methods for associating hlas with renal disease have been developed since the late 1980s, mostly as a result of more detailed knowledge of class i and ii molecules and their structure and function. hla phenotypes are interrelated, with an increased or reduced risk of alloantibody sensitisation in esrd candidates for first or repeat kidney transplantation.6 the incidence and prevalence of esrd and its relationship with class i and ii hla alleles in patients from yemen and other middle eastern and arab countries has only recently been studied due to deficiencies in national epidemiological research. prior to this study, no information was available on the frequency of class i and ii hlas, either in the yemeni population in general or in hypertensive end-stage renal failure (hesrf) patients. as such, this casecontrol study aimed first to determine the relationship between hla class i (a, b and c) and class ii (drb1) with hesrf. second, it aimed to compare the hlas found to have a relationship with hesrf with those from other races or national groups outside of yemen in a literature review. third, this study was designed to determine the potential genes that might give protection from hesrf development. methods this case-control study was carried out over a 12-month period between march 2013 and march 2014. a total of 100 individuals were enrolled in the study; the patient group comprised 50 adults with hesrf while the control group consisted of 50 healthy adult individuals. all patients and controls originated from sana’a, yemen. the patient group consisted of 40 males and 10 females (aged from 18 to 57 years) who had attended the urology & nephrology center at al-thawra university hospital in sana’a for a kidney transplant. hypertension was the cause of renal failure in all of these patients. all of the patients showed proteinuria and underwent a kidney biopsy to exclude an extensive focal and global glomerulosclerosis association with the apol1 gene. all hesrf patients in the study were on haemodialysis before they underwent kidney transplantation. the control group consisted of 32 males and 18 females (aged from 18 to 57 years) who had visited the urology & nephrology center at al-thawra university hospital for a kidney donation. they were confirmed to be healthy following a clinical examination by specialist physicians. as age and gender does not influence an individual’s hla frequency profile, the control group was not ageand gender-matched with the patient group. both the patients and controls were required to undergo certain tests, including blood pressure, abdominal ultrasound, complete blood count, blood sugar, kidney and liver function tests. in addition, a general urine examination and a 24-hour urine examination for protein detection and creatinine clearance were carried out. results for all of the aforementioned tests were normal in the control group. hla genotyping was completed for each individual in the patient and control groups. blood specimens were collected and treated with ethylenediaminetetraacetic acid. as the time of blood collection has no effect on genotyping results, blood specimens were collected whenever patients arrived at the hospital. blood specimens from both groups were used for hla class i (a, b and c) and class ii (drb1) genotyping. the typing of all of the subjects’ hla-a, -b, -c and -drb1 alleles were identified using low-resolution bagene sequence specific primers polymerase chain reaction kits (bag health care gmbh, lich, germany). the tests were carried out according to the manufacturer’s instructions. the genomic dna of each the findings revealed an association between hla-a9(24) and hesrf and a highly significant protective function for the hla-cw3 and drb1-8 genes against hesrf development. application to patient care research in the hla field is still in its early stages in yemen. it is therefore necessary to study the relationship between hlas and various diseases in yemen in order to improve treatment options for affected patients. the incidence and social burden of end-stage renal disease is growing. slowing or preventing the progression of this disease to renal failure is an important public health priority. mogahid y. nassar,hassan a. al-shamahy and haitham a. a. masood clinical and basic research | e243 sample was purified using the spin columns method of the qiagen dna purification kit (qiagen, hilden, germany). allele frequencies in hesrf patients and controls were calculated by direct counting.7 the association of hesrf with hla-i alleles was analysed by comparing the frequency of hla-a and -b alleles in the hesrf patients with those in the 50 healthy controls. the maximum likelihood method was used to evaluate the haplotype frequencies for the two loci of hla. the chi-squared test for two-way tables after yates correction for continuity was used to define the differences between allele frequencies in patients and controls, using the epi info™ programme, version 6 (centers for disease control and prevention, atlanta, usa). the odds ratios (or) with 95% confidence intervals (ci) were calculated. a p value of <0.05 was considered significant. the study was approved by the department of medical microbiology & clinical immunology in the faculty of medicine & health sciences at sana'a university, yemen. written consent was obtained from all of the participants in the study. results the age and gender of the subjects in the patient and control groups are shown in table 1. the hesrf patients’ mean age was 38.03 ± 10.9 years and that of the controls was 35.15 ± 8.9 years (range: 18–57 years for both groups). a total of 40 patients (80%) were male and the remaining 10 patients (20%) were female. there were 32 male (64%) and 18 female (36%) controls [table 1]. the results showed that hla-a2 and a9 had the highest frequency among hla-a alleles in the patients (0.48 and 0.18); hla-a2 and a3 were most frequent among the controls (0.48 and 0.16). hla-a28 and a1 were the next most frequent alleles in the patient group, whereas hla-a28 and a9 were the next most frequent alleles in the controls. a comparison of the frequency of hla-a alleles in the patients and controls showed higher frequencies of hla-a9(24) (or = 4.0, 95% ci = 0.42–103.9; p = 0.16) and a9 (or = 1.98; p = 0.24) and lower frequencies of hla-a19(30) (or = 0.0; p = 0.04) and a19(33) (or = 0.23; p = 0.16) in the hesrf patients [table 2]. the most numerous hla-b allele in the patients was hla-b5. this allele was articulated in the hesrf patients at a higher frequency in comparison to the controls (0.26 versus 0.18; or = 1.65; p = 0.33). on the other hand, the hla-b16(38), 21(49), 70 and 73 alleles were among the least expressed hla-b alleles in the patients. a total of 10 alleles were not found at all in the control group (b14, 21[44], 21[45], 27, 40, 40[60], 50, 51, 53, 62 and 78). the most frequent alleles expressed in the control subjects was hla-b5 (or = 1.65; p = 0.33) and b35 (or = 0.46; p = 0.21). hla-b21 and 21(50) were also observed at a lower frequency in the patients compared to the controls (or = 0.47; p = 0.29 each) [table 3]. the results showed that hla-cw6 and cw7 had the highest frequency among hla-cw alleles in the patients (0.44 and 0.38, respectively) and the controls (0.52 and 0.38, respectively). hla-cw4 and cw2 were the next most frequent alleles in the patients (0.28 and 0.12, respectively); hla-cw4 and cw3 were next most frequent in the controls (0.26 and 0.14, respectively). in comparison, the hla-cw3 allele was not found among the patients (p = 0.006), indicating a probable protective function [table 4]. the results showed that drb1-4 and 13 had the highest frequency among drb1 alleles in the patients (0.32 and 0.34, respectively) and controls (0.42 and 0.30, respectively). drb1-3 was the next most frequent allele in the patients and controls (0.26 each). a comparison of the frequency of drb1 alleles among those in the patient and control groups showed higher frequencies of drb1-8 in the controls (0.12), while in the patients it was 0.02 (or = 0.15; p = 0.05), indicating a probable protective function. in addition, a comparison of the frequency of drb1 alleles between both groups showed higher frequencies of drb1-10 (or = 2.3, 95% ci = 0.71–7.8; p = 0.11) and 15 (or = 2.3, 95% ci = 0.63–8.4; p = 0.16) and lower frequencies of 8 (or = 0.15; p = 0.05) in the hesrf patients [table 5]. discussion renal failure is mainly caused by a patient suffering from chronic high blood pressure over a period of table 1: age and gender of yemeni hypertensive-end stage renal failure cases and controls characteristic patient group control group total n % n % n % age in years 18–27 35 70 31 62 66 66 28–37 8 16 12 24 20 20 38–47 5 10 6 12 11 11 48–57 2 4 1 2 3 3 gender male 40 80 32 64 72 72 female 10 20 18 36 28 28 total 50 100 50 100 100 100 the association between human leukocyte antigens and hypertensive end-stage renal failure among yemeni patients e244 | squ medical journal, may 2015, volume 15, issue 2 many years. hypertension is also the second main cause, after diabetes, of esrd and is accountable for 25–30% of all reported cases.8 hypertension is an important risk factor for the progression of esrd in women as well as men.9 certain ethnicities, such as those of black african origin, have a high prevalence of the more severe form of hypertension; in addition, these patients have a higher prevalence of hypertension occurring at an earlier age than patients of white caucasian origin.10 essentially, hypertension suggests that at least one of the genes to blame for the genetic susceptibility to esrd is to be found in or close to the hla complex.11,12 many studies have been performed worldwide on the hla complex and disease, including in various arab countries, but this type of research is still in its infancy in yemen. indeed, to the best of the authors’ knowledge, the current study was the first in yemen on hla typing. the annual incidence of esrd in yemen is 120 per million which is comparable to the incidence reported in other countries of the same region.13 this study aimed mainly to investigate the association table 2: human leukocyte antigen-a (hla-a) and gene frequency in yemeni hypertensive-end stage renal disease patients and healthy controls (n = 100) hla-a patients controls odds ratio (95% confidence interval) p value* n antigen frequency gene frequency n antigen frequency gene frequency 1 7 0.14 0.072 4 0.08 0.040 1.9 (0.5–8.3 0.33 2 24 0.48 0.279 24 0.48 0.279 1 (0.4–2.4) 0.84 3 3 0.06 0.030 8 0.16 0.083 0.34 (0.1–1.5) 0.11 9 9 0.18 0.094 5 0.10 0.051 1.98 (0.54–7.5) 0.24 9(23) 5 0.10 0.051 3 0.06 0.030 1.74 (0.3–9.8) 0.48 9(24) 4 0.08 0.040 1 0.02 0.010 4.0 (0.42–103.9) 0.16 10 1 0.02 0.010 4 0.08 0.040 0.23 (0.01–2.3) 0.18 10(25) 1 0.02 0.010 0 0.00 0.000 undefined 0.3 10(26) 1 0.02 0.010 0 0.00 0.000 undefined 0.3 11 2 0.04 0.020 3 0.06 0.030 0.65 (0.1–5.1) 0.6 19 3 0.06 0.015 5 0.10 0.051 0.6 (0.1–2.99) 0.46 19(24) 1 0.02 0.010 0 0.00 0.000 undefined 0.31 19(29) 1 0.02 0.010 1 0.02 0.010 1 (0.0–37.8) 0.84 19(30) 0 0.00 0.000 4 0.08 0.040 0.0 (0.0–1.5) 0.04 19(31) 0 0.00 0.000 2 0.04 0.020 0.0 (0.0–4.1) 0.15 19(32) 3 0.06 0.030 2 0.04 0.020 1.5 (0.2–13.8) 0.64 19(33) 1 0.02 0.010 4 0.08 0.040 0.23 (0.01–2.37) 0.16 23 0 0.00 0.000 2 0.04 0.020 0.0 (0.0–4.1) 0.15 24 0 0.00 0.000 2 0.04 0.020 0.0 (0.0–4.1) 0.15 28 8 0.16 0.083 6 0.12 0.062 1.4 (0.4–5.03) 0.56 29 2 0.04 0.020 0 0.00 0.000 undefined 0.15 30 2 0.04 0.020 4 0.08 0.04 0.48 (0.06–3.2) 0.4 31 1 0.02 0.010 0 0.00 0.000 undefined 0.31 32 2 0.04 0.020 1 0.02 0.010 2.04 (0.14–58.9) 0.55 33 3 0.06 0.030 5 0.10 0.051 0.6 (0.1–2.99) 0.46 36 0 0.00 0.000 1 0.02 0.010 0.0 (0.0–17.6) 0.31 80 0 0.00 0.000 1 0.02 0.010 0.0 (0.0–17.8) 0.31 *p <0.05 was considered statistically significant. mogahid y. nassar,hassan a. al-shamahy and haitham a. a. masood clinical and basic research | e245 table 3: human leukocyte antigen-b (hla-b) and gene frequency in yemeni hypertensive end-stage renal disease patients and healthy controls (n = 100) hla-b patients controls odds ration (95% confidence interval) p value* n antigen frequency gene frequency n antigen frequency gene frequency 5 13 0.26 0.139 9 0.18 0.094 1.65 (0.6–4.6) 0.33 5(51) 4 0.08 0.040 4 0.08 0.040 1.0 (0.2–5.1) 0.84 5(52) 2 0.04 0.020 1 0.02 0.010 2 (0.14–5.8) 0.55 7 3 0.06 0.030 5 0.10 0.051 0.6 (0.1–2.99) 0.46 8 4 0.08 0.040 3 0.06 0.030 1.4 (0.24–8.2) 0.7 12 1 0.02 0.010 2 0.04 0.020 0.49 (0.02–7.23) 0.55 12(44) 7 0.14 0.073 5 0.10 0.051 1.47 (0.38–5.8) 0.53 13 2 0.04 0.020 1 0.02 0.010 2.04 (0.14–5.8) 0.55 14 3 0.06 0.030 0 0.00 0.000 undefined 0.07 16 1 0.02 0.010 3 0.06 0.030 0.32 (0.01–3.6) 0.3 16(38) 0 0.00 0.000 1 0.02 0.010 0 (0.0–17.5) 0.31 16(39) 1 0.02 0.010 2 0.04 0.020 0.49 (0.02–7.2) 0.55 17 6 0.12 0.062 6 0.12 0.062 1 (0.26–3.1) 0.84 17(57) 2 0.04 0.020 5 0.10 0.051 0.38 (0.05–2.3) 0.23 17(58) 1 0.02 0.010 1 0.02 0.012 1 (0.0–37.8) 0.84 18 5 0.10 0.051 3 0.06 0.030 1.7 (0.3–9.8) 0.46 21 3 0.06 0.030 6 0.10 0.060 0.47 (0.1–2.3) 0.29 21(44) 1 0.02 0.010 0 0.00 0.000 undefined 0.31 21(45) 1 0.02 0.010 0 0.00 0.000 undefined 0.31 21(49) 0 00.00 0.000 2 0.04 0.020 0.0 (0.0–4.1) 0.15 21(50) 3 0.06 0.030 6 0.12 0.062 0.47 (0.09–2.3) 0.29 22 1 0.02 0.010 1 0.02 0.010 1 (0.0–37) 0.84 27 1 0.02 0.010 0 0.00 0.000 undefined 0.31 35 4 0.08 0.041 8 0.16 0.083 0.46 (0.11–1.8) 0.21 37 2 0.04 0.020 2 0.04 0.020 1 (0.1–10.5) 0.84 40 1 0.02 0.010 0 0.00 0.000 undefined 0.31 40(60) 1 0.02 0.010 0 0.00 0.000 undefined 0.31 41 4 0.08 0.041 4 0.08 0.041 1 (0.19–5.14) 0.84 50 1 0.02 0.010 0 0.00 0.000 undefined 0.31 51 2 0.04 0.020 0 0.00 0.000 undefined 0.15 52 1 0.02 0.010 0 0.00 0.000 undefined 0.31 53 6 0.12 0.062 4 0.08 0.041 1.6 (0.4–7.2) 0.5 62 1 0.02 0.010 0 0.00 0.000 undefined 0.31 70 0 0.00 0.000 1 0.02 0.010 0.0 (0.0–17.5) 0.31 72 1 0.02 0.010 2 0.04 0.020 0.49 (0.02–7.2) 0.55 73 0 0.00 0.000 1 0.02 0.010 0.0 (0.0–17.5) 0.31 78 2 0.04 0.020 0 0.00 0.000 undefined 0.15 *p <0.05 was considered statistically significant. the association between human leukocyte antigens and hypertensive end-stage renal failure among yemeni patients e246 | squ medical journal, may 2015, volume 15, issue 2 between hlas (a, b, cw and drb1) and hesrf in comparison with healthy individuals. in this study, the male-to-female patient ratio was 4:1. the high prevalence of renal disease among males might be due to physiological differences between the genders as well as the higher susceptibility of males to hypertension, which can lead to renal failure. the higher prevalence of hypertension among males in this study was in agreement with the findings of another study, which reported a male-to-female ratio of 2:1.14 the present study also concurred with that of hsu et al., who reported that the male gender was a risk factor for esrd.15 another possible reason could be the statistically small sample size of females in the current study, partly due to the fact that yemeni females have less access than males to medical services due to social and cultural reasons.16 the findings of this study revealed the phenotypic and gene frequencies of the hla-a, hla-b, hla-cw and hla-drb1 genes in 100 yemenis (50 patients and 50 controls). hla-b14 was found in three patients, but was not identified in the controls. the patients, as compared to the controls, had lower frequencies of certain hla genes such as hla-a19(30), cw3 and drb1-8. these genes were found in the controls but not in the patients, apart from drb1-8 which was found in one patient. on the other hand, there was no statistically significant difference between the renal failure table 4: human leukocyte antigen-cw (hla-cw) and gene frequency in yemeni hypertensive end-stage renal disease patients and healthy controls (n = 100) hla-cw patients controls odds ratio (95% confidence interval) p value* n antigen frequency gene frequency n antigen frequency gene frequency 1 1 0.02 0.010 1 0.02 0.010 1 (0.0–3.7) 0.84 2 6 0.12 0.062 6 0.12 0.062 1 (0.26–3.9) 0.84 3 0 0.00 0.000 7 0.14 0.072 0 (0.0–0.72) 0.006 4 14 0.28 0.151 13 0.26 0.139 1.1 (0.42–2.9) 0.82 5 1 0.02 0.010 3 0.06 0.030 0.3 (0.01–3.6) 0.30 6 22 0.44 0.252 26 0.52 0.307 0.73 (0.3–1.7) 0.42 7 19 0.38 0.213 19 0.38 0.213 1 (0.41–2.4) 0.84 *p <0.05 was considered statistically significant. table 5: human leukocyte antigen-drb1 (hla-drb1) and gene frequency in yemeni hypertensive end-stage renal disease patients and healthy controls (n = 100) hladrb1 patients controls odds ratio (95% confidence interval) p value* n antigen frequency gene frequency n antigen frequency gene frequency 1 7 0.14 0.072 9 0.18 0.094 0.74 (0.22–2.4) 0.58 3 13 0.26 0.139 13 0.26 0.139 1 (0.37–2.7) 0.84 4 16 0.32 0.175 21 0.42 0.238 0.65 (0.26–1.6) 0.3 7 7 0.14 0.073 9 0.18 0.094 0.74 (0.22–2.4) 0.58 8 1 0.02 0.010 6 0.12 0.060 0.15 (0.01–1.3) 0.05 10 12 0.24 0.128 6 0.12 0.060 2.3 (0.71–7.8) 0.11 11 5 0.10 0.051 3 0.06 0.030 1.74 (0.33–9.9) 0.46 12 0 0.00 0.000 1 0.02 0.010 0.0 (0.0–176) 0.31 13 17 0.34 0.188 15 0.30 0.163 1.2 (0.48–3.0) 0.66 14 3 0.06 0.030 1 0.02 0.010 3.13 (0.3–80.9) 0.30 15 10 0.20 0.106 5 0.10 0.051 2.3 (0.63–8.4) 0.16 16 4 0.08 0.040 5 0.10 0.051 0.78 (0.16–3.7) 0.72 *p <0.05 was considered statistically significant. mogahid y. nassar,hassan a. al-shamahy and haitham a. a. masood clinical and basic research | e247 patients and the controls; this suggests that there are no hla genes predisposing to esrd. this result was in agreement with those of agrawal et al. and prasanavar et al. who determined that hla and haplotype frequencies were not significantly different in renal transplant patients and healthy donors.17,18 this contrasts sharply with another study that compared race-matched controls of white caucasian and black african ethnicity and showed how genetic differences associated with the hla system accounted for racial differences in hypertensive renal failure.19 a comparison between patients of white caucasian and black african ethnicity with hypertensive renal failure demonstrated that the patients of black african origin had an increased frequency of hla-dr3 alleles, which was greater than that normally known to exist among healthy individuals.19 these outcomes differ from the results of the current study which found no statistically significant differences between the patients and controls. however, this might be due to the fact that patients and healthy controls in this study were genetically similar; in fact, some of the patients and controls were related by family. however, the authors of the current study were of the opinion that it can be helpful to compare relatives; if there is a higher frequency of similar genes it is easier to indicate susceptibility to the disease rather than to race. it may also be the case that patients and controls were subjected to similar racial, genetic and environmental factors that may contribute to the development of esrd. zachary et al. also found that frequencies of hla alleles and their distribution among donors and renal patients in the united network for organ sharing (unos) registry varied between races.20 however, no difference was found in disease susceptibility; this was in agreement with the current study. similarly, several studies have indicated racial differences in hlas and their relationships with many diseases.4 the results of the current study were similar to those of crispim et al. who described associations of class i and ii hlas with esrd, independent of other factors, among crf patients with a variety of diagnoses.21 crispim et al. found that the antigens positively associated with esrd were hla-a78 and hla-dr11.21 in a previous study among mapuche and nonmapuche people in chile, hla-b8 alleles were found significantly more frequently in mapuche recipients than in non-mapuche recipients and mapuche donors.22 this result differs to that of the current study, in which hla-b8 alleles were roughly similar in both the patients and the controls. on the other hand, there was no positive association of hla-a2 alleles with esrd in the current study; this is similar to the findings reported among the zulian population in venezuela, in which hla-a2 alleles were also not associated with esrd.6 the most numerous hla-b allele in patients was hla-b5. this allele was articulated in the hesrf patients at a higher frequency in comparison to the controls (0.26 versus 0.18). this result is different from that reported among the zulian population in venezuela, in which hla-b5 was less frequent in both esrf patients and controls (3.9% and 2.4%, respectively).6 in the current study, a comparison of the frequency of hla-cw alleles showed considerably higher frequencies of hla-cw3 among the controls than the patients (p = 0.006), indicating the protective function of hla-cw3. this result is different from that reported in thyrotoxicosis patients, in whom hlacw3 was found to be significantly increased in patients with endocrine ophthalmopathy (eop) compared to thyrotoxic patients without eop.23 however, as yet, there have been no reported findings regarding the protective function of hla-cw3 alleles in renal diseases. a comparison of the frequency of drb1 alleles in the patients and controls showed higher frequencies of drb1-8 in the control group than the patient group (p = 0.05), indicating the protective function of drb18. this result is different to that reported among hispanic renal recipient patients, in which drb18 was found to be significantly increased in patients with renal failure compared with healthy donors (15% versus 0%).17 the results of this study demonstrate that hla-a2, a9, b5, cw6, cw7, drb1-4 and drb1-13 have very high frequencies among the hla alleles in both patients and controls in the studied population. this result matches those of studies performed on the frequency of hlas in iraqi, emirati and lebanese populations.24–26 in addition, comparing the antigen frequencies in the current study to those from kidney recipients and donors of other ethnic groups (i.e. african-americans, caucasians, asians and hispanics) included in the unos renal registry data on hla-a, b and dr loci showed that, while the population in the current study differed from the other groups in certain respects, there was a similarity with hispanics and caucasians in the highest frequencies of hla alleles.17 the diversity of the findings of different researchers may be due to the considerable irregularity in the frequency of hla alleles present in different populations or ethnic groups. a further cause may be the unequal relationship between these hla alleles and other nearby genes involved in accommodating the immune response. an example of this is reported by ranganath et al.; they stated that polymorphisms the association between human leukocyte antigens and hypertensive end-stage renal failure among yemeni patients e248 | squ medical journal, may 2015, volume 15, issue 2 in genes encoding certain cytokines, including interleukin (il)-6, il-4 and tumour necrosis factor, may be affected in the progression to esrd.27 this study had the limitation of being underpowered as only 50 patients were studied. however, it has laid the groundwork for future case-control studies in yemen with larger sample sizes of cases and controls. these future studies should aim to confirm the connection between class i and ii hlas and cases of hesrf as compared with healthy controls. conclusion this study found a high association between hla-a9(24) and hesrf and a highly significant protective function for the hla-cw3 and drb1-8 genes against hesrf development. at the same time, the findings showed no significant role for other hla molecules in the predisposition to developing esrd among yemeni patients. although the hla-b14 gene was found only in the patients and not in the control group, this difference was not statistically significant enough to conclude that the b14 gene is involved in a genetic predisposition to esrd development. certain hla genes, such as hla-a2, b5, cw6 and drb13, drb1-4 and drb1-13, were found to have a high frequency in both the patients and the controls. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. national kidney foundation. k/doqi clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. am j kidney dis 2002; 39:s1–266. doi: 10.1016/s0272-6386(02)70084-x. 2. national institutes of health. united states renal data system, usrds 2010 annual data report: atlas of chronic kidney disease and end-stage renal disease in the united states. bethesda, maryland, usa: national institute of diabetes and digestive and kidney diseases, 2010. 3. national institutes of health. united states renal data system. usrds 2013 annual data report: atlas of chronic kidney disease and end-stage renal disease in the united states. bethesda, maryland, usa: national institute of diabetes and digestive and kidney diseases, 2013. 4. centers for disease control and prevention (cdc). prevalence of chronic kidney disease and associated risk factors: united states, 1999-2004. mmwr morb mortal wkly rep 2007; 56:161–5. 5. de menthon m, lavalley mp, maldini c, guillevin l, mahr a. hla–b51/b5 and the risk of behçet's disease: a systematic review and meta-analysis of case-control genetic association studies. arthritis rheum 2009; 61:1287–96. doi: 10.1002/ art.24642. 6. sergio rp, marquez g, cipriani am, hassanhi m, villalobos cc, fuenmayor a, et al. hla class i association with progression to end-stage renal disease in patients from zulia, venezuela. inmunologia 2012; 31:37–42. doi:10.1016/j.inmuno.2011.12.001. 7. excoffier l, laval g, schneider s. arlequin (version 3.0): an integrated software package for population genetics data analysis. evol bioinform online 2005; 1:47–50. 8. narins b, ed. the gale encyclopedia of genetic disorders. 2nd ed. farmington hills, michigan, usa: thomas gale, 2005. 9. tozawa m, iseki k, iseki c, kinjo k, ikemiya y, takishita s. blood pressure predicts risk of developing end-stage renal disease in men and women. hypertension 2003; 41:1341–5. doi: 10.1161/01.hyp.0000069699.92349.8c. 10. lackland dt, orchard tj, keil je, saunders de jr, wheeler fc, adams-campbell ll, et al. are race differences in the prevalence of hypertension explained by body mass and fat distribution? a survey in a biracial population. int j epidemiol 1992; 21:236–45. doi: 10.1093/ije/21.2.236. 11. gerbase-delima m, ladalardo ma, delima jj, silva hb, bellotti g, pileggi f. essential hypertension and histocompatibility antigens: an association study. hypertension 1992; 19:400–2. doi: 10.1161/01.hyp.19.4.400. 12. frei u, schindler r, wieters d, grouven u, brunkhorst r, koch km. pre-transplant hypertension: a major risk factor for chronic progressive renal allograft dysfunction? nephrol dial transplant 1995; 10:1206–11. 13. el-nono ih, al-ba'adani th, ghilan am, asba nw, al alimy gm, al-massani mm, et al. adult-to-adult living related donor renal transplantation in yemen: the first experience. saudi j kidney dis transpl 2007; 18:265–9. 14. roderick pj, raleigh vs, hallam l, mallick np. the need and demand for renal replacement therapy in ethnic minorities in england. j epidemiol community health 1996; 50:334–9. doi: 10.1136/jech.50.3.334. 15. hsu cy, iribarren c, mcculloch ce, darbinian j, go as. risk factors for end-stage renal disease: 25-year followup. arch intern med 2009; 169:342–50. doi: 10.1001/ archinternmed.2008.605. 16. hennekens ch, buring je. analysis of epidemiologic studies. in: mayrent sl, ed. epidemiology in medicine. philadelphia: lippincott, williams & wilkins, 1987. pp. 272–82. 17. agrawal s, singh ak, sharma rk. hla gene and haplotype frequency in renal transplant recipients and donors of uttar pradesh (north india). indian j nephrol 2001; 11:88–97. 18. prasanavar d, shankarkumar u. hla-antigen and haplotype frequencies in renal transplant recipients and donors of maharashtra (western india). int j hum genet 2004; 4:155–9. 19. freedman bi, espeland ma, heise er, adams pl, buckalew vm jr, canzanello vj. racial differences in hla antigen frequency and hypertensive renal failure. am j hypertens 1991; 4:393–8. doi: 10.1093/ajh/4.5.393. 20. zachary aa, steinberg ag, bias wb, leffell ms. the frequencies of hla alleles and haplotypes and their distribution among donors and renal patients in the unos registry. transplant 1996; 62:272–83. 21. crispim j, mendes-júnior c, wastowski ij, palomino gm, saber lt, rassi dm, et al. hla polymorphisms as incidence factor in the progression to end-stage renal disease in brazilian patients awaiting kidney transplant. transplant proc 2008; 40:1333–6. doi: 10.1016/j.transproceed.2008.02.086. 22. droguett ma, beltran r, ardiles r, raddatz n, labraña c, arenas a, et al. ethnic differences in hla antigens in chilean donors and recipients: data from the national renal transplantation program. translplant proc 2008; 40:3247–50. doi: 10.1016/j.transproceed.2008.03.065. mogahid y. nassar,hassan a. al-shamahy and haitham a. a. masood clinical and basic research | e249 23. mayr wr, ludwig h, schernthaner g, höfer r. hla cw3 in thyrotoxicosis patients with and without endocrine ophthalmopathy. tissue antigens 1976; 7:243–6. doi: 10.1111/ j.1399-0039.1976.tb01062.x. 24. nuwayri-salti n, shaya m. major histocompatibility class i antigens in the lebanese population. east mediterr health j 1997; 3:101–7. 25. al-hassan aaa, al-naseri s, al-ghurabi bh, al-faham m, al-nnema aj, shereef sm. distribution of hla antigens class i and ii in iraqi arab population. iraqi j gastroenterol 2005; 5:2–9. 26. valluri v, mustafa m, santhosh a, middleton d, alvares m, el haj e, et al. frequencies of hla-a, hla-b, hla-dr, and hla-dq phenotypes in the united arab emirates population. tissue antigens 2005; 66:107–13. doi: 10.1111/j.1399-0039. 2005.00441.x. 27. ranganath p, tripathi g, sharma rk, sankhwar sn, agrawal s. role of non-hla genetic variants in end-stage renal disease. tissue antigens 2009; 74:147–55. doi: 10.1111/j.13990039.2009.01276.x. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e1–3, epub. 21 jan 15 submitted 14 oct 14 revision req. 2 nov 14; revision recd. 8 nov 14 accepted 11 nov 14 in this issue of squmj, jafferbhoy et al. have shared their regional experience about the impact of adding positron emission tomography (pet)/computed tomography (ct) to conventional ct in the preoperative work-up and follow-up of a select group of patients with colorectal cancer.1 in their retrospective study, pet/ct had a major impact in the preoperative and follow-up groups, altering the management of 73% and 64% of cases, respectively. according to the authors, they selected colorectal cancer as the focus of their investigation as it is one of the most common cancers in the uk;1 indeed, the survival rates of breast, colorectal and cervical cancer have more than doubled in the last six decades.2 the situation is similar in oman, with colon cancer among the top 10 most common cancers for both genders.3 therefore, the utilisation of pet/ ct for colorectal cancer patients in oman may also lead to a change in management for the majority of these patients. in colorectal cancer, surgery is the potential curative treatment for localised disease in addition to chemoradiotherapy in selected cases. salvage surgeries are usually performed for patients with recurrent disease and metastasectomies are an option for distant metastasis in some patients. in oman, there is a lack of national screening programmes for common cancers such as breast, colorectal and prostate cancers; this may result in the late presentation of some cases. as such, it is very important to establish accurate preoperative staging of the disease. furthermore, close monitoring and regular follow-up is essential in the postoperative period, as more than 85% of distant metastasis cases will appear within the first three years and all cases of metastasis in the first five years.4 identifying cases of disease recurrence and managing them as early as possible improves the overall survival rate—it is at this point that pet/ct can play a significant role.3 pet/ct can not only aid in the early detection of recurrence but can also accurately determine recurrence when ct alone cannot identify the lesion, as shown by jafferbhoy et al.1 in their study, jafferbhoy et al. used 18f-fluorodeoxyglucose (18f-fdg)-pet/ct to evaluate patients preoperatively and during follow-up in order to detect early recurrence;1 this method is also recommended in the literature.5,6 the main indication for using pet/ct in this cohort was either as a problem-solving measure, in cases where conventional ct was equivocal or patients had rising carcinogenic embryonic antigen levels with negative ct results, or as a confirmatory tool, for patients who had resectable metastatic disease or evidence of disease recurrence on conventional ct. in the latter group, pet/ct was used to confirm the ct findings prior to surgery.1 in oman, other stateof-the-art modalities are used in the staging and follow-up of oncological patients, including 64-slice ct and 3tesla magnetic resonance imaging machines, as well as trained and well-equipped surgical teams. nevertheless, pet/ct can be a major contributor and aid in more effective utilisation of this expensive equipment and accompanying human resources. this technology will confirm findings in some cases as well as potentially identify recurrent disease that may be missed by other modalities. in an extensive review of all published randomised clinical trials and systematic reviews, fletcher et al. proposed a number of recommendations for the utilisation of pet/ct in oncological patients.6 primarily, the authors recommended that 18f-fdgpet/ct be used for the diagnosis of lung, pancreas and head and neck cancers as well as cancers of unknown department of nuclear medicine, national oncology centre, royal hospital, muscat, oman e-mail: nkd004@hotmail.com التصوير املقطعي باإلصدار البوزيرتوين املصاحب للتصوير املقطعي احملوسب خيار أم ضرورة؟ نعيمة خمي�س البلوشية editorial combined positron emission tomography and computed tomography option or necessity? naima k. al-bulushi combined positron emission tomography and computed tomography option or necessity? e2 | squ medical journal, february 2015, volume 15, issue 1 primary. in addition, 18f-fdg-pet/ct should be utilised for staging breast, colon, oesophageal, lung, head and neck lymphomas and melanomas. fletcher et al. also advocated that this modality be used for detecting the recurrence of colorectal, breast, head, neck and thyroid cancers and lymphomas.6 apart from using pet/ct in staging, restaging and the evaluation of distant metastatic disease and local recurrence, it has a very important role in monitoring treatment. traditionally, pet/ct has been used to assess the treatment response at the end of chemotherapy cycles as well as the overall response at the end of therapy.7 however, more recent literature has shown that evaluating the response mid-treatment is useful to assess the response to that particular regime, as the waiting until the end of treatment to determine the patient’s response might be too late in some cases.8,9 to this end, combined pet/ct can help in ensuring the cost-effective utilisation of expensive chemotherapy treatments. in their retrospective analysis of the costeffectiveness of mid-treatment pet/ct, moulinromsee et al. reported that performing pet/ct after three chemotherapy cycles in patients with nonhodgkin’s lymphoma saved an average of €1,879 per patient.10 oman may potentially be an even better beneficiary than some european countries. until a specific tumour-targeted therapy is readily available for oncologists and cancer patients in this country, pet/ ct is the best option. further research has confirmed its efficiency in evaluating the early response to treatment—one such study noted that it could be used even as early as a week after a cycle of chemotherapy.11 fdg-pet/ct is invaluable for more than just the above-described oncological indications. an interesting emerging application of fdg-pet is for thrombus imaging; this was initially discovered incidentally in aneurysms with thrombi.12 another novel and fascinating aspect of fdg-pet/ct was discovered by figueroa et al.; the imaging modality did not just predict the occurrence of cardiovascular disease (cvd) but also the potential timeframe of cvd events.13 in oman, the incidence of cvd is the highest among all communicable and non-communicable diseases, with the proportional mortality due to cvd at 33%.14 in comparison, proportional mortality due to either diabetes or cancer were 10% each.14 thus, introducing this modality in oman will certainly have a considerable supplemental benefit to the health and welfare of omani citizens—not only in the oncological context, but also in terms of the early detection of cardiac events and the reduction of cardiovascularrelated mortality. nonetheless, it is important to consider a few limitations to pet/ct imaging. as mentioned by benhaim et al., high blood glucose reduces the overall quality of pet/ct images.2 abnormal lesions may therefore be missed in diabetics without controlled glucose levels. however, this problem may be overcome by using other non-fdg-pet/ct radiotracers (e.g. choline or methionine) which are not affected by high blood glucose levels. the other limitation of fdgpet/ct is the increased uptake of the tracer in cases of infection which can mimic that of tumours. while this can be considered a disadvantage of the modality, this feature of fdg-pet/ct has actually been utilised to image and evaluate patients with osteomyelitis, sarcoidosis and inflammatory bowel disease, where it showed high sensitivity in detecting the site of the lesions.15 it was also used for imaging purposes in patients with fever of unknown origin; due to the high affinity of fdg uptake at the sites of infection and inflammation, the modality was found to have a high sensitivity in detecting abnormalities.16 an additional limitation to the pet/ct modality, one which is probably unique to oman, is its current non-availability within the country. currently, only a small group of patients selected by a number of committees are able to benefit from pet/ct imaging abroad. so far it has been used as a problem-solving modality in cases where both other imaging modalities and tissue biopsies have proved inconclusive. data analysis has clearly shown that the number of cancer patients in oman is increasing, as it is globally.17 thousands of potential patients would benefit from this service if it was made available inhouse. the fact that patients have to be sent abroad for pet/ct scans creates many logistic impediments as well as significantly underutilising one of the most effective and state-of-the-art modalities for oncological patients—not to mention the fact that it is uneconomical to send patients abroad to receive this service.17 one of the fundamental human rights is the right to health. this necessarily involves the creation of a well-governed, financially secure, responsive and innovative health system that delivers services freely according to need.18 unsurprisingly, we are currently facing an increase in the global incidence of cancer. according to the worldwide globocan project, there were 14.1 million new cancer cases and 8.2 million deaths due to cancer in 2012.19 those numbers are expected to increase, with 22.2 million new cancer cases predicted for 2030.20 with such an immense surge in cancer patients expected within the next few decades, health services will face the significant challenge of coping with healthcare-related expenses. the optimisation and cost-effective utilisation of naima k. al-bulushi editorial | e3 available resources would be the most effective method to ensure the burden is not too great. this is particularly true for countries where healthcare is provided free to citizens by the government, such as in oman. when it comes to managing oncological patients, pet/ct has proven without a doubt to be the leading modality. over the last four decades, oman has borne witness to vast improvements in health services with health providers continuing to pursue excellence; however, this excellence cannot be achieved without the establishment of a national pet/ ct service in oman. references 1. jafferbhoy s, chambers a, mander j, paterson h. selective use of 18f-fluorodeoxyglucose-positron emission tomography and computed tomography in the management of metastatic disease from colorectal cancer: results from a regional centre. sultan qaboos univ med j 2015; 15:52–57. 2. ben-haim s, ell p. 18f-fdg pet and pet/ct in the evaluation of cancer treatment response. j nucl med 2009; 50:88–99. doi: 10.2967/jnumed.108.054205. 3. ministry of health oman, oman national cancer registry. cancer incidence in oman: report of 2010. muscat, oman: ministry of health, 2010. 4. casciato da. manual of clinical oncology. 5th ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2004. p. 207. 5. herbertson ra, scarsbrook af, lee st, tebbutt n, scott am. established, emerging and future roles of pet/ct in the management of colorectal cancer. clin radiol 2009; 64:225–37. doi: 10.1016/j.crad.2008.08.008. 6. fletcher jw, djulbegovic b, soares hp, siegel ba, lowe vj, lyman gh, et al. recommendations on the use of 18f-fdg pet in oncology. j nucl med 2008; 49:480–508. doi: 10.2967/ jnumed.107.047787. 7. ueda s, saeki t. early prediction of tumor response: a future strategy for optimizing cancer treatment. in: misciagna s, ed. positron emission tomography: recent developments in instrumentation, research and clinical oncological practice. rijeka, croatia: intech open access co., 2013. pp. 257–74. 8. skougaard k, nielsen d, jensen b, hendel h. comparison of eortc criteria and percist for pet/ct response evaluation of patients with metastatic colorectal cancer treated with irinotecan and cetuximab. j nucl med 2013; 54:1026–31. doi: 10.2967/jnumed.112.111757. 9. khong pl, huang b, phin lee ey, sum chan w, kwong yl. mid-treatment 18f-fdg pet/ct scan for early response assessment of smile therapy in natural killer/t-cell lymphoma: a prospective study from a single center. j nucl med 2014; 55:911–16. doi: 10.2967/jnumed.113.131946. 10. moulin-romsee g, spaepen k, stroobants s, mortelmans l. non-hodgkin lymphoma: retrospective study on the costeffectiveness of early treatment response assessment by fdgpet. eur j nucl med mol imaging 2008; 35:1074–80. doi: 10.1007/s00259-007-0690-0. 11. guo j, guo n, lang l, kiesewetter d, xie q, li q, et al. (18) f-alfatide ii and (18)f-fdg dual-tracer dynamic pet for parametric, early prediction of tumor response to therapy. j nucl med 2014; 55:154–60. doi: 10.2967/jnumed.113.122069. 12. muzaffar r, kudva g, nguyen nc, osman mm. incidental diagnosis of thrombus within an aneurysm on 18f-fdg pet/ ct: frequency in 926 patients. j nucl med 2011; 52:1408–11. doi: 10.2967/jnumed.111.091264. 13. figueroa al, abdelbaky a, truong qa, corsini e, macnabb mh, lavender zr, et al. measurement of arterial activity on routine fdg pet/ct images improves prediction of risk of future cv events. jacc cardiovasc imaging 2013; 6:1250–9. doi: 10.1016/j.jcmg.2013.08.006. 14. world health organization. noncommunicable diseases (ncd) country profiles, 2014: oman. from: www.who.int/ nmh/countries/omn_en.pdf?ua=1 accessed: oct 2014. 15. gotthardt m, bleeker-rovers cp, boerman oc, oyen wj. imaging of inflammation by pet, conventional scintigraphy, and other imaging techniques. j nucl med 2010; 51:1937–49. doi: 10.2967/jnumed.110.076232. 16. keidar z, gurman-balbir a, gaitini d, israel o. fever of unknown origin: the role of 18f-fdg pet/ct. j nucl med 2008; 49:1980–5. doi: 10.2967/jnumed.108.054692. 17. al-bulushi nk, bailey d, mariani g. the medical case for a positron emission tomography and x-ray computed tomography combined service in oman. sultan qaboos univ med j 2013; 13:491–501. 18. horton r. what does a national health service mean in the 21st century? lancet 2008; 371:2213–18. doi: 10.1016/s01406736(08)60956-3. 19. international agency for research on cancer and world health organization. globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012 all cancers (excluding non-melanoma skin cancer). from: globocan.iarc.fr/pages/fact_sheets_cancer.aspx accessed: oct 2014. 20. bray f, jemal a, grey n, ferlay j, forman d. global cancer transitions according to the human development index (20082030): a population-based study. lancet oncol 2012; 13:790– 801. doi: 10.1016/s1470-2045(12)70211-5. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. e611-615, epub. 8th oct 13 submitted 6th feb 13 revision req. 20th mar 13; revision recd. 15th jun 13 accepted 16th jun 13 1department of radiology, oman medical specialty board; 2khoula hospital, muscat, oman *corresponding author e-mail: albrashdi.yhs@gmail.com االخنفاض التلقائي للضغط داخل اجلمجمة مع أشعة الرنني املغناطيسي لتحديد تسريب السائل الشوكي يف العمود الفقري يحيى حمد الربا�شدي، �شمري رانيجا، �شارما رامان ريفاتي الرنني اأ�شعة الوقوف. اأو اجللو�س اأثناء حدته زادت م�شتع�شي �شداع من ا�شتكت العمر منت�شف يف ل�شيدة حالة تقرير هذا امللخ�ص: املغناطي�شي للعمود الفقري ت�رسب ال�شائل ال�شوكي يف م�شتوى العمود الفقري العنقي بالإ�شافة اإىل املظاهر ال�رسيرية املميزة للمر�س مثل جتمع ال�شائل حتت اجلافية وتعزيز حميطي للجافية وترهل الدماغ املتو�شط. خ�شعت املري�شة لت�شحيح جراحي لت�رسب ال�شائل ال�شوكي والذي اأدى اإىل حت�شن �رسيع وملحوظ يف الأعرا�س والذي مت تاأكيدة عن طريق املتابعة بالأ�شعة. مفتاح الكلمات: انخفا�س ال�شغط، تلقائي داخل القحف، ورم دموي، حتت اجلافية، تقرير حالة، عمان. abstract: to increase the awareness of spontaneous intracranial hypotension (sih), we report in this paper a middle-aged woman who presented with an intractable headache that worsened in sitting and standing positions (a postural headache). magnetic resonance imaging (mri) of the spine demonstrated a cerebrospinal fluid (csf) leak at the level of the cervical spine, in addition to typical features in a brain mri, including symmetrical subdural collections, circumferential dural enhancement and features of midbrain sagging. the patient underwent a surgical repair of the cervical csf leak which resulted in a dramatic symptomatic improvement that was confirmed by follow-up imaging. keywords: hypotension, spontaneous intracranial; cerebrospinal fluid; hematoma, subdural; case report; oman. spontaneous intracranial hypotension with magnetic resonance localisation of spinal cerebrospinal fluid leak *yahya h. al-brashdi,1 sameer raniga,2 sharma r. revati2 spontaneous intracranial hypotension (sih) is a syndrome of reduced cerebrospinal fluid (csf) pressure that occurs due to a spontaneous csf leak in the absence of a history of dural puncture, surgery or trauma. in an appropriate clinical setting, orthostatic headache is the main presenting feature to diagnose sih in the presence of classical imaging findings. recently reported cases have concentrated on identifying the typical brain magnetic resonance imaging (mri) features of sih; however, rabin et al. demonstrated spinal findings in 1998.1 mri, fluid-attenuated inversion recovery (flair) and post-contrast studies are the most important imaging sequences for diagnosis of sih. in addition to mri, imaging modalities such as conventional myelography, computed tomography (ct) and nuclear medicine have also been used to diagnose sih. we present in this case report a patient who had the clinical and radiological features of sih with of an occult csf leak upon an mri of the spine. surgical interventions can be attempted to secure radiologically obvious csf leaks, although an epidural blood patch and other conservative measures have been used in the past as the first line of treatment. case report a middle-aged, 50-year-old woman, with no previous medical complaints, presented with a three-month history of headaches that were aggravated while sitting or standing but relieved by lying down. the headaches increased in severity one month prior to presentation, during which time it was associated with nausea and vomiting. she gave no history of other symptoms such as neck pain or online case report yahya h. al-brashdi, sameer raniga and sharma r. revati case report | 612 visual complications. a neurological examination was completely normal. an mri of the brain showed small bilateral cerebral subdural collections which were more conspicuous in flair images [figure 1a]. postcontrast images showed bilateral circumferential pachymeningeal dural enhancement even involving the tentorium cerebelli [figure 1b]. mri features of brain sagging were also noted, including a closed pontomesencephalic angle, a reduced space between the dorsum sella and the mammillary body, and squaring and fattening of the midbrain. reduction of the space between the sella turcica and the optic chiasm, abnormal positioning of the pituitary stalk (so that it was almost covering the sella) and buckling of the medulla were also seen [figure 1c]. an mri of the whole spine was also done, including a deep three-dimensional constructive interference in steady state (3d-ciss) sequence which showed a left-sided cervical csf leak and accumulation at the level of the c2 vertebral body [figure 1d]. no spinal subdural collection or other spinal csf leaks were noticed. on the basis of these mr findings, sih was diagnosed, and no additional imaging modalities were required to confirm the diagnosis.l due to unavailable local expertise in performing an epidural blood patch, surgical exploration of the cervical spine at the c1, c2 and c3 levels was performed. it revealed a tiny area of csf leak at the 3 o’clock position at the level of the c2 vertebral body. tissue glue was applied with absorbable gelatin powder (gelfoam®, pfizer, inc., new york, usa) placed over it. dramatic improvement in the patient's symptoms was noticed after surgery. a follow-up mri of the brain and spine was done after two months, which showed an interval size reduction of the subdural collections and dural enhancement, except for a small residual subdural collection in the right hemisphere [figure 2a]. a 3d-ciss sequence of the cervical spine was repeated in the follow-up series showing the absence of a cervical csf leak [figure 2b]. discussion sih is defined as a syndrome characterised by reduced csf pressure that occurs in the absence of dural puncture, surgery, or trauma. it has been postulated that the most likely pathogenesis is an occult csf leak leading to a decrease in csf figure 1 a to d. a: coronal fluid-attenuated inversion recovery image showing bilateral subdural collections with high signal intensity. b: coronal post-contrast t1-weighted image shows circumferential dural enhancement also involving the tentorium cerebelli. c: sagittal t1-weighted image pre-contrast shows features of brain sagging. d: 3-d constructive interference in steady state sequence of the whole spine shows the csf leak at the c2 level of the cervical spine. spontaneous intracranial hypotension with magnetic resonance localisation of spinal cerebrospinal fluid leak 613 | squ medical journal, november 2013, volume 13, issue 4 pressure.1 the main presenting feature in those patients is headache, which is aggravated by sitting or standing, and relieved by lying down.1–3 there might be associated symptoms including nausea, vomiting or neck stiffness, with other features suggestive of cranial nerve neuropathies including vertigo and photophobia. arterial cerebral infarcts are rare but potentially life-threatening complications of sih.4 a lumbar puncture usually reveals a low opening pressure of less than 60 mm h2o, or the measurement of pressure may not be possible.1 the typical mri findings of sih are wellestablished in the literature, including symmetrical bilateral subdural collections/effusions which are isointense to csf in standard mr sequences.1 these collections show high signal intensity in flair images which can be attributed to dural thickening.1,3,5 the most important intracranial mri finding is diffuse pachymeningeal enhancement in t1-weighted post-contrast images.1,3,6 differential diagnoses include meningitis, meningeal metastasis, chronic subdural haematoma, post-surgical dural thickening and dural sinus thrombosis.7 the patient in this study showed bilateral subdural collections with evidence of a similar pattern of meningeal enhancement [figures 1a and 1b]. the cause of this dural enhancement is believed to be related to vascular dilatation, mainly venous congestion, as has been described by fishman and dillon.1–3 according to the monro-kellie rule, the csf volume fluctuates with intracranial blood volume in an intact skull.1,3 features of downward brain displacement can be seen upon mri, including a closed pontomesencephalic angle, reduction of the space between the dorsum sella and mammillary body, the sella almost being covered by the pituitary stalk, and fattening of the midbrain with buckling of the medulla. other imaging findings are enlargement of the pituitary gland, prominence of the spinal epidural venous plexus, engorgement of the cerebral venous sinuses (venous distension sign, etc.), venous sinus thrombosis and isolated cortical vein thrombosis.3 our patient demonstrated all the features of brain sagging, indicating the presence of intracranial hypotension. in 2008, schievink et al. described three criteria for diagnosing sih.8 criterion a is considered when spinal csf leak is demonstrated in any imaging modality by the presence of extrathecal csf. our patient met this criterion according to her spinal mri results. if no spinal csf leak can be shown, criterion b can be considered if the patient has brain features of intracranial hypotension in addition to a low opening pressure (<60 mmhg), spinal meningeal diverticulum or improvement of symptoms by epidural blood patch. if criteria a and b are not met, criterion c can be considered in the presence of all or at least two of the following if the typical orthostatic headache is present: low opening pressure, spinal meningeal diverticulum and symptomatic improvement following epidural blood patch. an mri of the spine can also be helpful, although it is not necessary in the diagnosis of sih. it can figure 2 a & b: follow-up images of the same patient two months after surgery. a: a coronal fluid-attenuated inversion recovery image shows resolving bilateral subdural collections with a remaining thin rim seen in the right side. b: a coronal constructive interference in steady state sequence shows no residual spinal leak at the level of the cervical spine. yahya h. al-brashdi, sameer raniga and sharma r. revati case report | 614 demonstrate the presence of subdural collections with the ability to localise the site of the csf leak in some cases. in this case report, a deep 3d-ciss sequence was very beneficial in pinpointing the level of the csf leak at the c2 cervical spine, with it being more obvious in the left side. intrathecal contrastenhanced mr cisternography has increased both the sensitivity and specificity for detecting cranial and spinal csf leaks with other clinical entities. despite these clinical values, intrathecal injection of gadolinium has not yet been approved by the united states food and drug administration, due to the risk of behavioural and neurological disturbances.9 a new developing mri technique in evaluating a spinal csf leak is the use of a spinal subtraction mri, in which the t1-weighted scan is subtracted from the t2-weighted scan to reveal the extradural csf collection. bonetto et al. were able to show the extradual csf collection in all of the sih-included patients in their study in 2011.10 in cases where the mri of the spine is negative in regard to the site of csf leak, conventional and digital subtraction myelography, ct myelography or rc can be used. digital subtraction myelography has been described as a valuable diagnostic tool to demonstrate rapid spinal csf leak.11 hoxworth et al. included 11 patients in their study in 2012; 6 were diagnosed with sih and 5 with superficial siderosis. the site of the leak was demonstrated in 9 of the 11 patients (82%) using subtraction myelography. however, in addition to the radiation exposure, a few limitations were encountered with the digital subtraction myelography. these included the possibility of motion artifacts, limited assessment of csf leaks at the level of the cervical and upper thoracic spine and reduced sensitivity in locating slow csf leaks. in rc, a delay in radionuclide upward movement is usually seen, indicating low csf pressure.1 however, low spatial resolution and the lack of cross-sectional images in rc make it less sensitive for spinal csf leaks.9 in spite of their diagnostic values, these imaging modalities all use ionising radiation, except for the mri. in addition, an mri has better soft tissue differentiation with no radiation issues. most cases of sih resolve spontaneously;7 however, in cases where treatment is required, management consists mainly of an epidural blood patch with other conservative measures.1–3 a ct-guided epidural blood patch is considered the most effective tool for treating patients with sih after which dramatic improvement is usually observed.1,3,4 conservative management includes bed rest, analgesics, use of sedatives and oral caffeine, and intravenous hydration.1–4 mohammed et al. reported a young male diagnosed with sih who became symptom-free after conservative treatment only. surgical intervention is sometimes required when a blood patch fails or if subdural haematomas present with acute clinical deterioration.7 a patient is considered improved after the procedure when the patient’s symptoms disappear and by the resolution or near-resolution of subdural collections, or by pachymeningeal enhancement.5 it was noted that our patient improved significantly after surgery, when a follow-up mri scan revealed the almost near-resolution of the previously noted imaging features. conclusion intracranial hypotension can be caused by previous lumbar punctures, trauma and previous spinal surgeries leading, in some cases, to life-threatening complications. however, sih has no precipitating factors, with postural headache as the main presenting symptom. although ct myelography or rc can be used in the diagnosis of sih, mri has the advantage of being a non-invasive modality with no ionising radiation involved. despite the fact that a good number of mri studies done for sih turn out to be normal, our patient’s mri clearly demonstrated the site of the spinal csf leak in addition to the intracranial manifestations. conservative measures and epidural blood patch should be the primary treatment strategies used in such patients prior to any surgical procedures. references 1. rabin bm, roychowdhury s, meyer jr, cohen ba, lapat kd, russell ej. spontaneous intracranial hypotension: spinal mr findings. ajnr am j neuroradiol 1998; 19:1034–9. 2. smirniotopoulos jm, murphy fm, rushing ej, rees jh, shroeder jw. patterns of contrast enhancement in the brain and meninges. radiographics 2007; 27:525–51. 3. tosaka m, sato n, fujimaki h, tanaka y, kagoshima k, takahashi a, et al. diffuse pachymeningeal hyperintensity and subdural effusion/hematoma spontaneous intracranial hypotension with magnetic resonance localisation of spinal cerebrospinal fluid leak 615 | squ medical journal, november 2013, volume 13, issue 4 detected by fluidattenuated inversion recovery mr imaging in patients with spontaneous intracranial hypotension. ajnr am j neuroradiol 2008; 29:1164–70. 4. schievink wi. stroke and death due to spontaneous intracranial hypotension. neurocrit care 2013; 18:248–51. 5. kranz pg, gray l, taylor jn. ct-guided epidural blood patching of directly observed or potential leak sites for the targeted treatment of spontaneous intracranial hypotension. ajnr am j neuroradiol 2011; 32:832–8. 6. quiñones d. dural hyperintensity on fluidattenuated inversion recovery in spontaneous intracranial hypotension. ajnr am j neuroradiol 2009; 30:e41 . 7. schievink wi, maya mm, louy c, moser fg, tourje j. diagnostic criteria for spinal csf leak and intracranial hypotension. ajnr am j neuroradiol 2008; 29:853–6. 8. osborn ag, blaser s, salzman kl. intracranial hypotension. in: diagnostic imaging: brain. 1st ed. salt lake city: amirsys, 2004. pp. ii-4–22 10 9. algin o, turkbey b. intrathecal gadoliniumenhanced mr cisternography: a comprehensive review. ajnr am j neuroradiol 2013; 34:14–22. 10. hoxworth jm, trentman tl, kotsenas al, thielen kr, nelson kd, dodick dw. the role of digital subtraction myelography in the diagnosis and localization of spontaneous spinal csf leaks. ajr am j roentgenol 2012; 199:649–53. 11. bonetto n, manara r, citton v, cagnin a. spinal subtraction mri for diagnosis of epidural leakage in sih. neurology 2011; 77:1873–6. burns, whether intentional or non-intentional, are increasingly emerging as a worldwide problem. the world health organization (who) states that 195,000 deaths annually are caused by fire alone, and many more people are left disabled or permanently injured.1 however, the who also notes that there is not enough data to determine the number of deaths caused from other types of burns such as scalding, electrical burns and other burns, thus indicating that the true figure is much higher.2 chandran et al. found that the burden of intentional injuries is disproportionately higher in low and middle income countries. data analysis of the global burden of diseases (gbd) project shows that 9% of the deaths in the middle eastern region were caused by fire; whereas the rate of disability-adjusted life years (dalys) was 2,825 per 100,000 life years, comparable to that of southeast asia and africa, and almost double the dalys caused by injuries in developed countries. the analysis provides an indication of the magnitude of the problem, although it does not classify burns specifically.3 understanding the magnitude of burns as a public health problem, its distribution in the community and the risk factors that accompany it, is an important step in establishing intervention strategies. such interventions could include raising awareness, improved legislation, and the careful engineering and planning of work places and houses in order to reduce the incidence of burns, the severity of burn-related injuries and their consequences.4 it is important to recognise burns as a public health problem, both in urban and rural settings. rapid urbanisation, and the increased reliance on electrical appliances in urban settings, combined with a lack of legislation regarding electrical household wiring, are among the factors that may contribute to injuries caused by burns. the epidemiology of burns in oman in oman, as in other parts of the world, burns have been given low priority in public health prevention policy as road traffic accidents (rta) are considered more important cause of death and disability. this has been reflected in the omani ministry of health’s 5-year plan which has 30 domains including one on injuries; however, there is no mention of burns management or prevention in this domain. this is possibly due to the lack of information regarding the magnitude and severity of the problem in oman.5 a recent publication in the journal burns by al-shaqsi et al. could contribute to filling the information gap in this area as it describes, for the first time, the burden of severe burns in oman. this article is of great significance, not only because of the scarcity of peer-reviewed publications from oman in the medical literature, but also because it highlights a critical issue that is not currently on the top priority list of health issues in the country. the article illustrates the value of longitudinal institution-based data in generating evidence for public health policy.6 there are two main issues to 1department of preventive & social medicine, dunedin school of medicine, university of otago, dunedin, new zealand; 2department of nutrition, ministry of health, muscat, oman *corresponding author e-mail: dhalasfoor@gmail.com احلروق وباء مهمل يف عمان �صلطان ال�صق�صي و دينا الع�صفور editorial burns the neglected epidemic in oman sultan al-shaqsi1 and *deena alasfoor2 sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 465-468, epub. 8th oct 13 submitted 31st jul 13 peer-reviewed accepted 2nd sep 13 sultan al-shaqsi and deena alasfoor editorial | 466 be learnt from such a publication: first, that burns are a hidden epidemic in oman, and second, that local scientific research ought to be the driving force behind national policies on healthcare quality. the article is based on a national burns register that was originally initiated by thomas and prasana in 1981, and hosted by the national burns unit at khoula hospital, muscat, oman. in 1986, thomas described the first case of severe burns admitted to the national burn unit in oman and recorded in this register. subsequently, in an article published in 2000, the process of coordinating emergency care for severe burns across the whole of oman was described. despite the multiple data gaps from which this national register suffers, it is still an important source of longitudinal health information that helps to highlight trends and assess the determinants of burns in oman.7 the register is probably the first of its kind in oman, but unfortunately it has been neglected for years because of the lack of research interest and the necessary funding to maintain such a rich resource of health information. the register itself includes data on all patients admitted to the national burns unit but lacks information regarding the patients’ long-term follow-up. there is a need at this stage to evaluate the accuracy and completeness of the register. while it is admirable that the register has been initiated and maintained by the efforts of individuals, it is time for healthcare policy-makers to invest in good quality healthcare databases in oman in order to formulate robust context-specific policies. additionally, it is important to integrate the register into a national health data bank with longitudinal health data. data on individual patients and system performance indicators could then be gathered, analysed and utilised to inform health policies and improve the quality of care in oman.8 another interesting point highlighted by this project is that local data can be used by omani researchers to conduct international research of a high standard with negligible costs. for years, policy-makers in oman have turned to external researchers to conduct studies who sometimes do not understand the national context; furthermore, such studies can be very expensive. perhaps it is time to invest in building a national research capacity, for example by encouraging and funding database formation and providing research training for clinicians. quality healthcare is driven by evidence; the era of healthcare being steered by clinical experience is now past. according to the data analysed by al-shaqsi et al., admissions rates to the national burns unit increased from 1994 onwards. the average annual admission rate during the study period was estimated to be 7 per 10,000 people per year.6 this steady increase in the admission rate could possibly be due to the increased detection and implementation of referral protocols. during the period 1995 to 2000, the number of physicians per 10,000 people increased from 11.8 to 13.6, and the number of specialists also increased from 3.7 to 4.5. this coincided with the opening of two new regional hospitals, adding an additional 626 beds to the 4,564 beds which already existed nationwide. thus this increase may possibly have arisen from an improvement in the detection of burn cases, better management in regions away from the capital area, and thus an increased number of referrals.9 international research suggests that only around 5% of the total burns requiring hospitalisation are severe enough to be admitted to a tertiary-level care institution.10 therefore, the annual incidence of burns requiring hospitalisation in oman is estimated to be around 4,000 patients per year. this is half the number of people injured in car crashes per year in oman; however, as mentioned earlier in this article, the issue of burns receives little attention compared to rta. another finding of al-shaqsi et al. was that the majority of severe burns in oman were in children aged between 1 and 10 years old. this is consistent with the data in the gbd project, which found that the dalys of fire casualties among children between 1 and 4 years old accounted for only 0.8% of the total dalys. in contrast, the contribution of fire to the years of potential life lost (yll) was highest among the same age group, at 1.8%; this is almost twice the contribution of the next highest age group. these findings raise questions regarding childcare and the need for prevention programmes.11 the comparison of the number of burns reported in the gbd project to the global estimates is noteworthy. the reported contribution of fire casualties globally is 2.4 % of yll and 2.1% of dalys—almost triple the estimates of oman. it is important to conduct an in-depth study to assess the true magnitude and risk factors for burns in oman. children are the most affected population group, and this may be the tip of the iceberg that warrants a careful investigation burns the neglected epidemic in oman 467 | squ medical journal, november 2013, volume 13, issue 4 of child rights in oman. furthermore, al-shaqsi et al. highlight the direct cost of severe burns in oman. for each patient admitted to the national burns unit, the estimated cost was around 16,000–30,000 omani riyals per patient.6 this cost does not take into account the intangible toll of the psychological and societal trauma, particularly in children, that may result from burns injuries. public health policy and evidence rapid social and economic transition in the span in the past decade, the number and complexity of health problems have increased significantly, and so have the decision-making tools and methods. generally, health authorities do not have enough resources to tackle each public health issue individually; therefore, a sound evaluation of each problem, and its relative contribution to the mortality and morbidity in a country, ought to be carried out in order to prioritise the allocation of resources. to that end, policy-makers and researchers need to employ all possible methods to improve the scientific quality and validity of medical research, and integrate available resources to reduce the financial and human resources burden on the system.12 the authors of the aforementioned article demonstrate a prime example of the feasibility of utilising available data for research. starting from a manual register, a computerised database with 25 years’ worth of cases was created and analysed. this is a tremendous effort, and it provides invaluable information that could not be otherwise obtained; furthermore, this data-set could subsequently be built on to monitor programme effectiveness and the trends of severe burns in oman over time. longitudinal data, generated from electronic medical records (emr), are becoming increasingly important to researchers and physicians. quality of care and patient outcome indicators could potentially be generated from emr; however, there are user satisfaction and data quality issues that should not be ignored. because of the wide utility of emr, it is important to develop these in consultation with all stakeholders.13,14 such a system is currently lacking in oman. instituting a national data-collection initiative in different areas of healthcare would enhance the overall quality of care provided to all of the country's residents. conclusion in summary, al-shaqsi et al.’s paper is a landmark in public health in oman. for a long time, the public health focus has been on communicable diseases and prevention strategies that include vaccinations and nutritional supplementation. it is now time to think beyond the box, and to be alert to what the data are telling us. researchers in oman are capable of using national data to influence national decisionmaking, particularly as context and evidence matter in healthcare policies. we are hopeful that articles like this will pave the way to further utilisation of emr and institutional data in oman to inform national health policies. furthermore, al-shaqsi et al. showed that burns are an expensive but preventable healthcare problem in oman—and one which disproportionately impacts our children. issues such as the adequacy of regional burn healthcare services and long term rehabilitation facilities for burn victims are yet to be addressed in oman. in conclusion, to tackle burns effectively and efficiently as a public health problem, it is important to establish a national programme that includes adequate surveillance and monitoring, assessment of risk factors, and public health interventions, as well as evidenced-based management guidelines. references 1. world health organization. burns fact sheet. from: http://www.who.int/mediacentre/factsheets/fs365/ en/ accessed: aug 2013. 2. world health organization. burns: violence and injury prevention. from: http://www.who.int/ violence_injury_prevention/other_injury/burns/en/ accessed: jul 2013. 3. chandran a, hyder aa, peek-asa c. the global burden of unintentional injuries and an agenda for progress. epidemiol rev 2010; 32:110–20. 4. world health organization. burn prevention: success stories and lessons learned. geneva: world health organization, 2011. pp. xii–8. 5. oman ministry of health. five-year plan of action 2010–2014. muscat: ministry of health, 2012. 6. al-shaqsi s, al-kashmiri a, al-bulushi t. epidemiology of burns undergoing hospitalization to the national burns unit in the sultanate of oman: a 25-year review. burns 2013; sultan al-shaqsi and deena alasfoor editorial | 468 pii:s0305–4179(13)00114-9. doi: 10.1016/j. burns.2013.04.012. epub ahead of print. 7. thomas c, prasanna m. the role of a 'satelliteservice' in the national organisation of burn care in the sultanate of oman. burns 2000; 26:181–5. 8. fung ch, lim yw, mattke s, damberg c, shekelle pg. systematic review: the evidence that publishing patient care performance data improves quality of care. ann intern med 2008; 148:111–23. 9. oman ministry of health. annual health report 2010. muscat: ministry of health, 2012. 10. burd a, yuen c. a global study of hospitalized paediatric burn patients. burns 2005; 31:432–8. 11. institute for health metrics and evaluation (ihme). data visualizations. from: http://www. h e a l t h m e t r i c s a n d e v a l u a t i o n . o r g / t o o l s / d a t a visualizations accessed: june 2013. 12. brownson rc, fielding je, maylahn cm. evidencebased public health: a fundamental concept for public health practice. annu rev public health 2009; 30:175–201. 13. ambinder ep. electronic health records. j oncol pract 2005; 1:57–63. 14. viner g, parush a. electronic medical records. cmaj 2008; 179:54. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e155–156, epub. submitted 14 feb 15 revision req. 19 mar 15; revision recd. 26 mar 15 accepted 29 mar 15 hepatoblastoma (hb), despite being rare, is the most common malignant hepatic tumour in children. it is debatable whether adult hb occurs as an entity. several features of the tumours described in adults are strikingly different from hb in the paediatric age group.1 in the february 2015 issue of squmj, rabah et al. described oman’s experience of hb over the last 21 years.2 hb is extremely rare in adults aged between 19 and 84 years, with only 40 reported cases of adult hb from 1958 to 2013.3,4 it is presumed that the majority of adult hb cases are, in fact, misdiagnosed hepatocellular carcinoma (hcc), combined hcccholangiocarcinoma or carcinosarcoma.5 adult hb usually presents with abdominal pain, weight loss and a palpable liver mass on physical examination. similarly, rabah et al. found that the main symptom in the omani children with hb was a palpable mass in the abdomen.2 hb affects both hepatic lobes and commonly presents as a unifocal large mass ranging from 5–25 cm.3,4 according to rougemont et al., liver fibrosis or cirrhosis was diagnosed in 30% of reported adult hb cases, in contrast to paediatric hb which appeared nearly always in children with no primary hepatic disease.1 the main differential diagnosis of adult hb is hcc.1 unfortunately, there are no typical features of hb that are visible on ultrasound, computed tomography (ct) or magnetic resonance imaging (mri) of the liver. kishimoto et al. suggested that intramural classification is helpful in the diagnosis of hb.6 other radiological features suggestive of hb are hypervascularity and cystic changes. however, none of the previously mentioned radiological features are specific for hb and all of these radiological features can be found in all types of liver tumours. postoperative pathological examination is the gold standard for diagnosing hb. hb and hcc usually display remarkable gross, histological and immunohistochemistry similarities.1,6 in addition, mixed features of hb and hcc can coexist in one tumour,7 and successive occurrence of hb and hcc in the same patient has been described.8,9 the use of chemotherapy in hb may lead to architectural and cytological changes resembling hcc.10 another differential diagnosis of hb in an adult would be the coexistence of hepatocellular-cholangiocarcinoma with stem cell characteristics. ishak et al. proposed a histological classification that classifies hb into epithelial and mixed epithelial types, which are most common, and the mesenchymal type, which is less common.11 molecular progress has enabled the recognition of different gene expression patterns in liver tumours.12 molecular overlap and coexistence of hb and hcc in adult cases support the hypothesis that these tumours may originate from a common progenitor cell.12 surgical resection, if feasible, remains the main method of hb management. neoadjuvant chemotherapy has been used to shrink the tumour, prevent intraoperative blood loss and delineate the tumour from the surrounding tissue, therefore facilitating easy resection.13 rabah et al. used three to four cycles of neoadjuvant chemotherapy in their study, followed by surgical resection in patients with pretreatment extent of disease stage ii, iii and iv who were deemed to have resectable disease.2 postoperative chemotherapy was also used by rabah et al. as two to five cycles of chemotherapy were given to 11 out of 15 patients.2 other local ablative procedures used in the treatment of hcc, such as ethanol ablation and radiofrequency ablation (rfa), have been tried mainly for the treatment of recurrent 1oman medical specialty board, muscat, oman; 2department of child health, sultan qaboos university hospital, muscat, oman; 3department of internal medicine, division of gastroenterology & hepatology, armed forces hospital, muscat, oman *corresponding author e-mail: noumani73@gmail.com االورام الكبدية ىف الكبار ماذا نعرف؟ �سهام ال�سنانية و خالد النعماين online comment adult hepatoblastoma what do we know? siham al-sinani1,2 and *khalid al-naamani3 adult hepatoblastoma what do we know? e156 | squ medical journal, may 2015, volume 15, issue 2 tumours post surgical resection.14,15 randomised trials comparing local ablative therapy, such as rfa, versus surgical resection for a small tumour of less than 3 cm are required to assess the efficacy of such treatments in hb. other methods used in the treatment of advanced hcc, such as transarterial chemotherapy and transarterial radioembolisation, need to be evaluated, especially in adults with advanced hb who are not surgical candidates. based on paediatric experience, liver transplantation has been associated with marked survival improvement, especially in those with an unresectable tumour. one of the 15 children described by rabah et al. had a liver transplantation due to multi-lobar involvement.2 generally, the milan criteria are used to assess which patients with hcc are suitable for liver transplantation.16 these criteria, which are also valued for assessing transplantation in hb patients, need further investigation. the survival rate of children who receive transplants due to hb is close to 80%. this percentage is based on results from the international society of paediatric oncology and a review of the global experience of hb and liver transplantation.17 rabah et al. presented a survival rate of 91% in their study, despite many obstacles faced by the treating paediatricians.2 this is comparable to other recently published studies.18–20 hb prognosis has improved since 1995 and this is most likely due to early diagnosis, improvement in surgical techniques, postoperative care and the use of neo-adjuvant and adjuvant chemotherapy.1,3 in conclusion, the results of rabah et al.’s study and the experience gained over many years should guide oncologists in treating patients diagnosed with hb and encourage all parents of such paediatric patients to address their treatment as soon as possible. in addition, the application of paediatric hb protocols in the treatment of adult hb may prove beneficial. references 1. rougemont al, mclin va, toso c, wildhaber be. adult hepatoblastoma: learning from children. j hepatol 2012; 56:1392–403. doi: 10.1016/j.jhep.2011.10.028. 2. rabah f, el-banna n, bhuyan d, al-ghaithi i, al-hinai m, alsabahi a, et al. hepatoblastomas in oman: unveiling success. sultan qaboos univ med j 2015; 15:81–6. 3. wang yx, liu h. adult hepaoblastoma: systemic review of the english literature. dig surg 2012; 29:323–30. doi: 10.1159/000342910. 4. zheng mh, zhang l, gu dn, shi hq, zeng qq, chen yp. hepatoblastoma in adult: review of the literature. j of clin med res 2009; 1:13–16. doi: 10.4021/jocmr2009.01.1222. 5. ishak kg, goodman zd, stocker jt. hepatoblastoma. in: tumors of the liver and intrahepatic bile ducts: atlas of tumor pathology. 2nd ed. washington dc, usa: american registry of pathology, 2001. 6. kishimoto y, hijiya s, nagasako r. malignant mixed tumor of the liver in adults. am j gastroenterol 1984; 79:229–35. 7. lopez-terrada d, finegold mj. tumors of the liver. in: suchy fj, sokol rj, balistreri wf, eds. liver disease in children. cambridge, uk: cambridge university press, 2007. pp. 943–74. 8. masuda t, beppu t, horino k, komori h, hayashi h, okabe h, et al. occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis c virus. hepatol res 2009; 39:525–30. doi: 10.1111/j.1872034x.2008.00471.x. 9. basile j, caldwell s, nolan n, hammerle c. clear cell hepatocellular carcinoma arising 25 years after the successful treatment of an infantile hepatoblastoma. ann hepatol 2010; 9:465–7. 10. wang ll, filippi rz, zurakowski d, archibald t, vargas so, voss sd, et al. effects of neoadjuvant chemotherapy on hepatoblastoma: a morphologic and immunohistochemical study. am j surg pathol 2010; 34:287–99. doi: 10.1097/ pas.0b013e3181ce5f1e. 11. ishak kg, glunz pr. hepatoblastoma and hepatocarcinoma in infancy and childhood: report of 47 cases. cancer 1967; 20:396–422. doi: 10.1002/1097-0142(1967)20:3<396::aid-cn cr2820200308>3.0.co;2-o. 12. luo jh, ren b, keryanov s, tseng gc, rao un, monga sp, et al. transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. hepatology 2006; 44:1012–24. doi: 10.1002/hep.21328. 13. pimpalwar ap, sharif k, ramani p, stevens m, grundy r, morland b, et al. strategy for hepatoblastoma management: transplant versus nontransplant surgery. j pediatr surg 2002; 37:240–5. doi: 10.1053/jpsu.2002.30264. 14. bortolasi l, marchiori l, dal dosso i, colombari r, nicoli n. hepatoblastoma in adult age: a report of two cases. hepatogastroenterology 1996; 43:1073–8. 15. ke hy, chen jh, jen ym, yu jc, hsieh cb, chen cj, et al. ruptured hepatoblastoma with massive internal bleeding in an adult. world j gastroenterol 2005; 11:6235–7. 16. mazzaferro v, chun ys, poon rt, schwartz me, yao fy, marsh jw, et al. liver transplantation for hepatocellular carcinoma. ann surg oncol 2008; 15:1001–7. doi: 10.1245/s10434-0079559-5. 17. otte jb, pritchard j, aronson dc, brown j, czauderna p, maibach r, et al. liver transplantation for hepatoblastoma: results from the international society of pediatric oncology (siop) study siopel-1 and review of the world experience. pediatr blood cancer 2004; 42:74–83. doi: 10.1002/pbc.10376. 18. moon sb, shin hb, seo jm, lee sk. hepatoblastoma: 15-year experience and role of surgical treatment. j korean surg soc 2011; 81:134–40. doi: 10.4174/jkss.2011.81.2.134. 19. zsíros j, maibach r, shafford e, brugieres l, brock p, czauderna p, et al. successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the siopel-3hr study. j clin oncol 2010; 28:2584–90. doi: 10.1200/jco.2009.22.4857. 20. otte jb. progress in the surgical treatment of malignant liver tumors in children. cancer treat rev 2010; 36:360–71. doi: 10.1016/j.ctrv.2010.02.013. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. e463-466, epub. 25th jun 13 submitted 15th aug 12 revision req. 18th nov 12; revision recd. 2nd dec 12 accepted 8th jan 13 departments of 1child health and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mnaggari@squ.edu.om; mnaggari@yahoo.com إْندماج مقدَّم الدِّماغ نصف الفصي مع زيادة صوديوم الدم العصيب املنشأ حالتان جديدتان ها�شم جافاد، �شيف اليعروبي، الك�شندر �شاكو، ديليب �شانكال، اأمنه الفطي�شي، اأن�س الوجود عبد املغيث، حممد النجاري امللخ�ص: اندماج مقدم الدماغ ن�شف الف�شي )hpe( هو عيب النمو يف مقدمة املخ اجلنيني و منت�شف الوجه. ذلك يرجع اإىل عدم انق�شام لكل 1.31 ايل اأنت�شار معدل ي�شل للنا�شف. املجاورة لالأجزاء املكتمل غري والتطور املخية الكرة ن�شفي اإىل اجلنيني الدماغ مقدمة 10,000 والدة. ميكن اأن تكون م�شببات املر�س وراثية، بيئية، اأو كليهما. ي�شنف hpe اإىل ف�شى ، ن�شف ف�شي ، ال ف�شي واأنواع فرعية اأخرى بناء على درجة انف�شال ن�شفي الكرة املخية. نحن نقدم تقريرا عن حالتني جديدتني م�شابني باأْندماج مقدَّم الدِّماغ ن�شف الف�شي مع زيادة �شوديوم الدم الع�شبي املن�شاأ. يعترب نق�س االأح�شا�س بالعط�س املرتبط بزيادة �شوديوم الدم املزمن يف املر�شى الذين يعانون من اأْندماج مقدَّم الدِّماغ ن�شف الف�شي موؤ�رسا قويا على وجود "زيادة �شوديوم الدم الع�شبي املن�شاأ". التعرف املبكر على زيادة �شوديوم الدم الع�شبي املن�شاأ مهم الأنه يتح�شن مع العالج الق�رسي بال�شوائل و ال يتطلب اأي دواء. مفتاح الكلمات: اندماج مقدم الدماغ، ن�شف الف�شي، زيادة �شوديوم الدم، ع�شبي املن�شاأ، نق�س االأح�شا�س بالعط�س، النا�شف، ت�شوهات، تقرير حالة، عمان. abstract: holoprosencephaly (hpe) is a developmental defect of the embryonic forebrain and midface. it is due to the non-cleavage of the embryonic forebrain into two cerebral hemispheres and the incomplete development of the paramedian structures. the overall prevalence is 1.31 per 10,000 births. the aetiology could be genetic, environmental, or both. hpe is classified into alobar, semilobar, and lobar subtypes based on the degree of separation of the cerebral hemispheres. we report two new cases of semilobar hpe with neurogenic hypernatraemia. lack of thirst and hypodypsia associated with chronic hypernatraemia in patients with hpe is highly suggestive of neurogenic hypernatraemia. early identification of neurogenic hypernatraemia is important as it improves with forced fluid therapy and does not require any medication. keywords: holoprosencephaly; semilobar holoprosencephaly; hypernatremia, neurogenic; hypodipsia; midline; malformations; case report; oman. semilobar holoprosencephaly with neurogenic hypernatraemia two new cases hashim javad,1 saif al-yarubi,1 alexander p. chacko,1 dilip sankhla,2 amna al-futasi,1 anas a. abdelmogheth,1 *mohamed el-naggari1 online case report we report two new cases of semi lobar holoprosencephaly (hpe) complicated by neurogenic hypernatraemia without signs of dehydration. case one a two-year-old female first presented at the age of one year with global developmental delay. she is the sixth child of consanguineous parents. she was born normally after an uneventful pregnancy and had good apgar scores. anthropometric parameters were suggestive of intrauterine growth restriction (iugr). she was discharged on the second postnatal day. at the age of 10 months, she was evaluated in a peripheral hospital for delayed growth and development, and investigations revealed persistent hypernatraemia. she was referred to sultan qaboos university hospital (squh), muscat, oman, for further evaluation of hypernatraemia and developmental delay. there was no history of excessive fluid loss or high salt intake. on examination, her vital signs were stable and there were no signs of significant dehydration. all her semilobar holoprosencephaly with neurogenic hypernatraemia two new cases 464 | squ medical journal, august 2013, volume 13, issue 3 growth parameters were below the third percentile, with a developmental age of 2 to 3 months. she had dysmorphic features (i.e. microcephaly, closely spaced eyes, and depressed infantile nose and synophrys). a neurological examination revealed microcephaly with spastic quadriplaegia. other systemic examinations were unremarkable. a blood work-up revealed persistent hypernatraemia (159–167 mmol/l). renal functions were normal (serum urea: 3.4–7 mmol/l; creatinine: 18–25 umol/l). the serum biochemistry revealed potassium levels at 4.1–4.4 mmol/l, chloride at 126–131 mmol/l, bicarbonate at 24–28 mmol/l, and the anion gap ranging from 11–13 mmol/l. her plasma anti-diuretic hormone (adh) level was low (<0.5 pmol/l) for the serum osmolality (331 mmol/kg). there was no change in urine osmolality following subcutaneous administration via injection of desmopressin. urine osmolality before and after desmopressin administration was almost the same, at 300 mmol/kg. a serum hormonal assay revealed a cortisol level of 301 nmol/l at 9 am (range: 185–624), a t4 level of 15.1 pmol/l, a thyroid stimulating hormone level of 1.96 μ/l, and growth hormone levels at 3.88 μ/l (range: 0.01–3.60 μ/l). urine output was 4–4.5 ml/kg/hr. a magnetic resonance imaging (mri) brain scan revealed a partially-formed inter-hemispheric fissure situated posteriorly. the frontal lobes were fused, but the thalami were partially separated. there was a single lateral ventricle with indication of the third ventricle. the corpus callosum was partially formed with normal orbits and optic nerves. there was a large posterior cranial fossa cystic lesion. these findings were consistent with semilobar hpe [figure 1]. the infant was not thirsty and did not demand feeding. she required nasogastric tube feeding to maintain a normal hydration level as her parents refused a gastrostomy. she is currently undergoing regular follow-up and, with fluid management, her serum sodium levels have been maintained at levels between 142–148 mmol/l for the last year. there have been no complications of hypernatraemia, and she is undergoing physiotherapy for her spasticity. case two an 8-month-old male infant born normally was admitted for evaluation of stridor, microcephaly and developmental delay. an examination revealed tachycardia and tachypnoea with normal temperature and blood pressure. as in the first case, the infant was not thirsty and did not demand feeding. hydration status and urine output were satisfactory. all growth parameters were below the third percentile. dysmorphic features like microcephaly, depressed infantile nose and closely spaced eyes were obvious. the serum biochemistry revealed persistent hypernatraemia (152–164 mmol/l). renal functions were normal (serum creatinine: 28 umol/l). there was hypodypsia even figure 1: sagittal t1 fluid attenuation inversion recovery (flair) image shows corpus callosum dysgenesis and hypoplasia of the frontal lobe with thick gyri. figure 1: axial t2wi magnetic resonance image shows fused basal nuclei, absent septum pellucidum, and a small third ventricle. hashim javad, saif al-yarubi, alexander p. chacko, dilip sankhla, amna al-futasi, anas a. abdelmogheth and mohamed el-naggari case report | 465 when the serum osmolality was above 310 mmol/kg. the serum electrolytes, urine and serum osmolality were similar to the first case. there were no associated endocrinopathies like hypothyroidism, hypocorticism or growth hormone deficiency. there was no change in the urine osmolality following administration of desmopressin. a serum adh level assessment was not requested in the second case as the history, dysmorphic features, and investigations were suggestive of semilobar hpe associated with neurogenic hypernatraemia. an mri brain scan revealed normal-sized third ventricles in the midline. both lateral ventricles are fused across the midline as a monoventricle. the thalami, the heads of the caudate nuclei, and the frontal lobes are also fused across the midline with an absent falx cerebri and an interhemispheric fissure consistent with semilobar hpe [figure 2]. the infant was managed with nasogastric feeds as the parents were not willing for the baby to undergo a gastrostomy. the hypernatraemia improved with appropriate fluid management (serum sodium: 144–147 mmol). the child is undergoing regular follow-up, gaining weight and undergoing physiotherapy for spasticity. discussion hpe is a developmental defect caused by the failure of the prosencephalon (the embryonic forebrain) to divide into the two lobes of the cerebral hemispheres. the incidence is 1.31 per 100,000 live births.1 the aetiology can be genetic, environmental, or both.2 numerous genes have been linked to hpe, including sonic hedgehog, zig2, six3, tgif, and others.3 environmental factors, such as maternal diabetes, retinoic acid, and drugs and alcohol abuse during early pregnancy have also been implicated.4,5 chromosomal anomalies like trisomy-13 18p deletion, 13p-deletion, and the meckel-gruber syndrome can be associated with hpe.6 the defect is also associated with chromosomes 2, 3, 7, 13 and 18. de myer divided hpe into three categories: alobar, semilobar and lobar, depending upon the severity of the defect.7 alobar is the most severe form, marked by the formation of only one cerebral hemisphere and one ventricle.8 the semilobar and lobar forms may be associated with mild facial dysmorphism, like abnormal upper labial frenulum, the formation of just a single incisor or a cleft palate.7–10 lobar hpe usually presents with developmental delay, and/or hypothalamic and pituitary dysfunctions. the distinction between semilobar and lobar hpe is poorly defined.7 hpe is frequently associated with endocrinopathies such as diabetes insipidus, hypocorticism, hypothyroidism and growth hormone deficiency because of midline defects.11 seizures may occur. there are reports of neurogenic hypernatraemia associated with hpe.11 neurogenic hypernatraemia is a rare complication of semilobar hpe. the commonest cause of hypernatraemia in hpe is central diabetes insipidus, which occurs in 70% of patients with classic hpe.11 neurogenic hypernatraemia is marked by a defective thirst mechanism, either alone or in combination with impaired osmoregulation and adh release.11 it is characterised by chronic hypernatraemia with adipsia, or hypodipsia polyuria with no sign of dehydration. in diabetes insipidus, hypernatraemia is associated with polydipsia, polyuria, and signs of dehydration.8,12,13 a central osmoregulatory defect is due to hypodipsia with normal levels of serum adh, even if there is plasmatic increase in osmolality.14,15 these findings suggest that hpe may be associated with a defect in the hypothalamic osmoreceptors that control thirst and vasopressin secretion, probably due to a defect of embryonic development. both of our cases had dysmorphic features such as closely-spaced eyes, a depressed infantile nose, synophrys, microcephaly and spastic quadriplegia; all of these are suggestive of a structural anomaly of the brain. mri brain scan findings were consistent with semilobar hpe in both of these cases. chronic hypernatraemia without signs of dehydration is usually seen in patients with neurogenic hypernatraemia. this is similar to the findings in our patients. causes of hypernatraemia, like excessive fluid loss and increased salt intake, were excluded in both patients. there were no vascular, neoplastic or degenerative causes for chronic hypernatraemia in either patient. neither of them was thirsty at all, even when their serum osmolality levels were high (≥331 mmol/kg). serum adh was only done in the first patient and it was within the normal reference range (<0.5 pmol/l), but was low for the serum osmolality (331 mmol/ kg). this can be explained by the disturbance of semilobar holoprosencephaly with neurogenic hypernatraemia two new cases 466 | squ medical journal, august 2013, volume 13, issue 3 the hypothalamic osmoreceptors, which govern vasopressin as seen in patients with neurogenic hypernatraemia.12 there was no change in either patient in urine osmolality upon the exogenous administration of desmopressin, ruling out central diabetes insipidus. low serum adh levels and normal renal functions, as observed in the first patient, are counter-indicative of nephrogenic diabetes insipidus. in nephrogenic diabetes insipidus, the serum adh levels are usually high. in spite of extensive investigations, a definite aetiology for hypernatraemia other than neurogenic hypernatraemia was not detected in our patients. the chronic hypernatraemia in both patients improved with forced nasogastric feeds, as has been observed in other cases of neurogenic hypernatraemia. both patients are now gaining weight and maintaining acceptable serum sodium levels with proper hydration, which also rules in favour of neurogenic hypernatraemia. conclusion in children with hpe, chronic hypernatraemia is usually due to central diabetes insipidus. neurogenic hypernatraemia should be considered in children with hpe presenting with chronic hypernatraemia without signs of dehydration, and who lack thirst and have adipsia. it improves with fluid management as the defect is in the central osmoregulation. the association of hpe with central diabetes insipidus has to be considered in all cases of hpe with chronic hypernatraemia, as it is the commonest cause. the presence of thirst, a poor response to fluid management alone, and an improvement with desmopressin would rule in favour of central diabetes insipidus, whereas the reverse is true for neurogenic hypernatraemia. early identification and management of neurogenic hypernatraemia with appropriate fluid management avoids extensive investigations and complications secondary to exogenously-administered adh. references 1. blaas hg, eriksson ag, salvesen ka, isaksen cv, christensen b, møllerløkken g, et al. brains and faces in holoprosencephaly: preand postnatal description of 30 cases. ultrasound obstet gynecol 2002; 19:24–38. 2. nanni l, schelper rl, muenke mt. molecular genetics of holoprosencephaly. front biosci 2000; 5:334–42. 3. arnold wh, meiselbach v. 3-d reconstruction of a human fetus with combined holoprosencephaly and cyclopia. head face med 2009; 5:14. 4. de wals p, bloch d, calabro a, calzolari e, cornel mc, johnson z, et al. association between holoprosencephaly and exposure to topical retinoids: results of the eurocat survey. paediatr perinat epidemiol 1991; 5:445–7. 5. croen la, shaw gm, lammer ej. risk factors for cytogenetically normal holoprosencephaly in california: a population-based case-control study. am j med genet 2000; 90:320–5. 6. capobianco g, cherchi pl, ambrosini g, cosmi e, andrisani a, dessole s. alobar holoprosencephaly, mobile proboscisand trisomy 13 in a fetus with maternal gestational diabetes mellitus: a 2d ultrasound diagnosis and review of the literature. arch gynecol obstet 2007; 275:385–7. 7. simon em, barkovich aj. holoprosencephaly: new concepts. magn reson imaging clin n am 2001; 9:149–64. 8. cuisset jm, cuvellier jc, vallee l, ryckewaert p, soto-ares g, nuyts jp. holoprosencephaly with neurogenic hypernatremia. arch pediatr 1999; 6:43– 5. 9. siddell ep, longobucco db. holoprosencephaly: a case presentation. neonatal netw 1995; 14:21–6. 10. thakur s, singh r, pradhan m, phadke sr. spectrum of holoprosencephaly. indian j pediatr 2004; 71:593–7. 11. savasta s, chiapedi s, borali e, perrini s, sepe v, caimmi s, et al. holoprosencephaly with neurogenic hypernatremia: a new case. childs nerv syst 2008; 24:139–42. 12. arrants gomez j, vidal sampedro j, herrantz fernandez jl, arteaga manjon-cabeza r, lozanode la torre mj. semilobar holoprosencephaly associated with central diabetes insipidus. an esp pediatr 1987; 27:385–9. 13. sarnat hb, flores-sarnat l. neuropathologic research strategies in holoprosencephaly. j child neurol 2001; 16:918–31. 14. karabay-bayazit a, hergüner o, altunbaşak s, noyan a, yükel b, anarat a. hypodipsiahypernatremia syndrome associated with holoprosencephaly in a child: a case report. turk j pediatr 2002; 44:263–6. 15. hasegawa y, hasegawa t, yokoyama t, kotoh s, tsuchiya y. holoprosencephaly associated with diabetes insipidus and syndrome of inappropriate secretion of antidiuretic hormone. j pediatr 1990; 117:756–8. the cubital fossa is a depression on the anterior aspect of the elbow containing the median nerve, the brachial artery, the tendon of the biceps brachii (bb) and the radial nerve; the roof of the cubital fossa is formed by the continuity of brachial and antebrachial fascia and reinforced by bicipital aponeurosis (ba), subcutaneous tissue and skin.1 the bb forms a flattened tendon at the elbow joint and then inserts the radial tuberosity; close to the insertion point, the tendon provides an expansion which is broad and extends medially (i.e. the ba). the ba passes across the brachial artery and deep to the median cubital vein (mcv) and fuses with the deep fascia of the forearm.1 due to its insertion away from the tendon of the bb, the ba disperses some of the power in a different direction and thus helps in the dual action of the bb as both a supinator and flexor muscle of the forearm.2 the ba reinforces the fascia of the cubital fossa and protects the underlying median nerve and brachial artery, which is important during venepuncture of the mcv.1 the muscles of the superficial flexor compartment of the forearm—the pronator teres (pt), flexor carpi radialis (fcr), palmaris longus, flexor digitorum superficialis and flexor carpi ulnaris muscles—arise from the medial epicondyle of the humerus by a common tendon. these muscles have an additional attachment to the antebrachial fascia near the elbow and the septa that passes from this fascia between individual muscles.1 however, these muscles may sometimes arise from the ba; such variable attachments to the ba can lead to an entrapment syndrome of the median nerve or ischaemic contracture due to compression of the brachial artery.2,3 the ba normally forms a support for the overlying mcv and aids in its identification and palpation for diagnostic purposes.2 the mcv connects the cephalic and basilic veins distal to the elbow and lies in the 1department of anatomy, kasturba medical college, manipal, karnataka, india; 2department of anatomy, college of medical sciences, ras al-khaimah medical & health sciences university, ras al-khaimah, united arab emirates *corresponding author e-mail: sushma.rk@manipal.edu جزء إضايف لصفاق العضلة العضدية ذات الرأسني و عالقته الشاذة تشرحييا مع الوريد الوسيط املرفقي نانديني بهات, ك�مار بهات, اأنت�ين �ضيلفانديسوزا, �ض��ضما ك�تيان abstract: the cubital region of the arm is a common site for recording blood pressure, taking blood for analysis and administering intravenous therapy and blood transfusions. during the routine dissection of a 70-year-old male cadaver at the kasturba medical college, manipal, karnataka, india, in 2015, it was observed that the aponeurotic insertion of the biceps brachii muscle divided into two slips. the medial slip fused normally with the deep fascia of the forearm, while flexor carpi radialis muscle fibres originated from the lateral slip. there was also a single vein in the forearm, the cephalic vein, which bifurcated to form the median cubital vein and the cephalic vein proper. the median cubital vein, further reinforced by the radial vein, passed deep to the two slips of the bicipital aponeurosis and then continued as the basilic vein. during venepuncture, medical practitioners should be aware of potential cubital fossa variations which could lead to nerve entrapment syndromes. keywords: anatomic variation; elbow; aponeurosis, abnormalities; case report; india. امللخ�ص: تعترب املنطقة املرفقية للذراع هي امل�قع امل�ضرتك لت�ضجيل �ضغط الدم و�ضحب الدم للتحليل وحقن العالج ال�ريدي ونقل الدم. عند اأجراء الت�رسيح الروتيني جلثة ذكر بالغ من العمر 70 عاما يف كلية كا�ضت�ربا الطبية, مانيبال, كارناتاكا, الهند يف عام 2015, ل�حظ اأن اإدراج �ضفاق الع�ضلة الع�ضدية ذات الراأ�ضني ينق�ضم اىل جزئني. جزء اأن�ضي طبيعي مدرج يف اللفافة العميقة يف ال�ضاعد, بينما ن�ضاأت األياف الع�ضالت الكعربية القاب�ضة لل�ضاعد من اجلزء ال�ح�ضي لل�ضفاق. وكان هناك اأي�ضا وريد واحد يف ال�ضاعد, ال�ريد الراأ�ضي, الذي انق�ضم اإىل ت�ضكيل ال�ريد ال��ضيط املرفقي وال�ريد الراأ�ضي االأ�ضيل. مت تعزيز ال�ريد ال��ضيط املرفقي, عن طريق ال�ريد الكعربي ثم مر من حتت جزئي �ضفاق الع�ضلة الع�ضدية ذات الراأ�ضني ثم وا�ضل م�ضاره كال�ريد البازيل. ينبغي اأن يك�ن االأطباء على علم باالختالفات املحتملة يف احلفرة املرفقية اأثناء بزل ال�ريد, والتي من املمكن اأن ت�ؤدي اإىل متالزمة انحبا�ص الع�ضب. الكلمات املفتاحية: التغري الت�رسيحي؛ ك�ع؛ �ضفاق, ت�ض�هات؛ تقرير احلالة؛ الهند. additional muscle slip of bicipital aponeurosis and its anomalous relationship with the median cubital vein nandini bhat,1 kumar m. r. bhat,2 antony s. d’souza,1 *sushma r. kotian1 sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e103–105, epub. 30 mar 17 submitted 12 jul 16 revision req. 21 aug 16; revision recd. 17 sep 16 accepted 6 oct 16 doi: 10.18295/squmj.2016.17.01.018 case report additional muscle slip of bicipital aponeurosis and its anomalous relationship with the median cubital vein e104 | squ medical journal, february 2017, volume 17, issue 1 superficial fascia of the cubital fossa, which is always superficial to the ba.1 many adverse effects can occur following venous mispuncture, such as bruising, haematomas and sensory changes.4 in clinical practice, knowledge of the anatomy of the mcv is important as this vein is frequently used for venepuncture during blood withdrawal and transfusion procedures, cardiac catheterisation, insertion of peripheral vascular grafts and for the creation of arteriovenous fistulae.5 knowledge of any variations in the cubital region is therefore helpful to avoid unwanted complications during routine cubital fossa procedures. case report a routine undergraduate dissection session of the right cubital fossa of a 70-year-old male cadaver was undertaken at the kasturba medical college, manipal, karnataka, india, in 2015. it was observed that the ba arose from the tendon of the bb, just proximal to the intercondylar line of the humerus. this aponeurosis then divided to form a broad thin medial slip and a thick slender lateral slip. the medial slip was superficial to the cubital structures and merged with the deep fascia of the forearm, while the lateral slip passed vertically downwards towards the forearm, medial to the tendon of the bb. in the forearm, this thick extension of the bicipital tendon provided an additional origin to the muscular slips of the fcr. these fleshy muscular fibres then fused with the rest of the fcr muscle, which originated from the medial epicondyle along with the other flexor muscles of the forearm. no abnormalities were observed in the dorsal venous network. the cephalic vein was the only vein present in the lateral side of the forearm and it continued as a single vein. there was a complete absence of the basilic vein. instead, many smaller veins from the medial side of the forearm joined the cephalic vein. as the cephalic vein reached the cubital fossa, it bifurcated with the lateral branch, continuing into the arm as the cephalic vein proper while the medial branch passed obliquely under both ba slips towards the medial side of the arm. in the cubital region, the medial branch (i.e. the mcv) was reinforced by a deep vein accompanying the radial artery and continued as the basilic vein in the medial side of the arm [figure 1]. discussion in humans, the muscles of the upper limbs develop from the mesenchyme of the paraxial mesoderm during the fifth week of fetal development.6 myoblasts are stimulated to migrate into the developing limb buds by several growth factors produced by cells in the proximal limb bud. these pre-muscle cells express adhesion molecules that are essential to their adequate distribution throughout the limb.7 the presence of additional slips from the ba and the variant origin of the fcr from the ba may indicate changes in the formation and structure of the myotome of a somite or in the distribution of cell adhesion molecules on pre-muscle cells.6,7 several anomalous anatomic variations of the cubital region of the arm have been previously described in the literature. bhat et al. reported an additional muscular slip from the ba to the fcr and pt.8 similarly, trivedi et al. described a case wherein additional muscle slips originated from the belly of the bb and were connected to the fcr and pt.9 however, in the present case, only fleshy fcr muscle fibres originated from the lateral slip of the ba, without any accompanying pt fibres. nayak et al. reported a case of ba bifurcation into a larger medial slip and a small lateral slip.3 the medial slip, instead of fusing with the deep fascia on the medial side of the forearm, merged with the common flexor muscles. a few fleshy fibres of the pt and fcr arose from this slip and the lateral slip merged with the brachioradialis muscle.3 deopujari et al. reported three ba variants, including thickened tendinous slips bordering the aponeurosis, a third head of the bb muscle forming the aponeurosis and the aponeurosis giving rise to some muscle fibres joining the fcr muscle.10 figure 1: photograph of the dissected right cubital fossa of a 70-year-old male cadaver showing an additional muscle slip from the bicipital aponeurosis (ba) to the flexor carpi radialis. the median cubital vein can be observed located deep to the ba (arrow). cv = cephalic vein; cvp = cephalic vein proper; ra = radial artery; dv = deep vein accompanying the ra; bb = biceps brachii; lat = lateral ba slip; ba = bicipital aponeurosis; bra = brachial artery; fcr = flexor carpi radialis; mcv = median cubital vein; mn = median nerve; med = medial ba slip; pt = pronator teres; bv = basilic vein. nandini bhat, kumar m. r. bhat, antony s. d’souza and sushma r. kotian case report | e105 conclusion the present case report described a rare anomaly in which the fcr originated from the ba and the mcv lay deep to the aponeurosis. these findings may be helpful for medical practitioners to encourage awareness of potential variations in the cubital region which may have an impact on diagnostic and therapeutic procedures. references 1. standring s. gray’s anatomy: the anatomical basis of clinical practice, 40th ed. london, uk: churchill livingstone-elsevier, 2008. pp. 825−6. 2. joshi sd, yogesh as, mittal ps, joshi ss. morphology of the bicipital aponeurosis: a cadaveric study. folia morphol (warsz) 2014; 73:79−83. doi: 10.5603/fm.2014.0011. 3. nayak sb, swamy rs, shetty p, maloor pa, dsouza mr. bifurcated bicipital aponeurosis giving origin to flexor and extensor muscles of the forearm: a case report. j clin diagn res 2016; 10:ad01−02. doi: 10.7860/jcdr/2016/17714.7215. 4. newman bh, pichette s, pichette d, dzaka e. adverse effects in blood donors after whole-blood donation: a study of 1000 blood donors interviewed 3 weeks after whole-blood donation. transfusion 2003; 43:598−603. doi: 10.1046/j.15372995.2003.00368.x. 5. ukoha uu, oranusi ck, okafor ji, ogugua pc, obiaduo ao. patterns of superficial venous arrangement in the cubital fossa of adult nigerians. niger j clin pract 2013; 16:104−9. doi: 10.41 03/1119-3077.106777. 6. larsen wj. human embryology, 2nd ed. philadelphia, pennsylvania, usa: saunders, 1997. pp. 311–39. 7. carlson bm. human embryology and developmental biology, 3rd ed. maryland heights, missouri, usa: mosby, 2004. pp. 224–5. 8. bhat km, kulakarni v, gupta c. additional muscle slips from the bicipital aponeurosis and a long communicating branch between the musculocutaneous and the median nerves. int j anat var 2012; 5:41–3. 9. trivedi s, sinha mb, sharma dk, rathore m, siddiqui au. abnormal musculotendinous slip from biceps brachii to pronator teres: a case report. int j biomed adv res 2015; 6:64−6. doi: 10.7469/ijbar.v6i1.1527. 10. deopujari r, quadir n, athavale s, gajbhiye v, kotgirwar s. variant bicipital aponeurosis: a cadaveric study. peoples j sci res 2014; 7:43−6. 11. paval j, mathew jg. a rare variation of the biceps brachi muscle. indian j plast surg 2006; 39:65–7. doi: 10.4103/09700358.26907. 12. jain t, yadav sk. case study: variation of superficial veins pattern of upper limb found in dissection. int ayurvedic med j 2015; 3:2223−5. 13. vasudha tk. a study on superficial veins of upper limb. natl j clin anat 2013; 2:204−8. 14. lee h, lee sh, kim sj, choi wi, lee jh, choi ij. variations of the cubital superficial vein investigated by using the intravenous illuminator. anat cell biol 2015; 48:62–5. doi: 10.51 15/acb.2015.48.1.62. 15. yamada k, yamada k, katsuda i, hida t. cubital fossa venipuncture sites based on anatomical variations and relationships of cutaneous veins and nerves. clin anat 2008; 21:307–13. doi: 10.1002/ca.20622. paval et al. described a case with a bb with a normal origin and course, but with a variant insertion.11 at the insertion, most of the fibres were inserted as a rounded tendon into the radial tuberosity; however, a few fibres from the medial side formed a tendinous slip which further bifurcated, with the brachial artery and median nerve passing between the two slips. the lateral slip merged with the fascia covering the flexor carpi ulnaris muscle, while the medial slip inserted into the medial supracondylar ridge.11 such variations of the ba may lead to neurovascular symptoms due to entrapment of the underlying vessels and nerves.2,3 extra slips from the ba may function independently and result in stress concentration on the bony areas of the attachment.11 variations are common in the superficial veins of the upper limb. jain et al. reported the absence of the mcv with the existence of an accessory cephalic vein.12 in a study of variations of the superficial veins of the upper limbs of 169 living caucasian individuals, nine patterns of venous drainage were observed.13 in another study of the cubital fossa venous arrangements of 135 living nigerian adults, the most common pattern was the separation of the median antebrachial vein into the median cephalic and median basilic veins which connect to the cephalic and basilic veins.5 in the present case, only the cephalic vein was present in the forearm while the basilic vein was absent; the former then bifurcated into the cephalic vein proper and the mcv, which subsequently continued as the basilic vein. using a venous illuminator, lee et al. classified the pattern of superficial veins in the cubital fossa of 200 korean patients into four types according to the presence of the mcv; in all cases, the mcv was superficial in the cubital fossa.14 previous research has described variations in the superficial veins of the upper limbs in relation to nearby structures and also the absence of some of the usual veins.5,14,15 interestingly, in the present case, the mcv was located deep to both ba slips. this finding is unusual and, to the best of the author’s knowledge, has not yet been reported in the liter ature. routine venepuncture procedures in individuals with deeply located mcvs would be difficult and painful. therefore, awareness of the possible existence of such a variation is essential when carrying out procedures involving the mcv in the cubital fossa. in these cases, the use of a venous illuminator during venepuncture procedures may be beneficial.14,15 https://doi.org/10.5603/fm.2014.0011 https://doi.org/10.7860/jcdr/2016/17714.7215 https://doi.org/10.1046/j.1537-2995.2003.00368.x https://doi.org/10.1046/j.1537-2995.2003.00368.x https://doi.org/10.4103/1119-3077.106777 https://doi.org/10.4103/1119-3077.106777 https://doi.org/10.7469/ijbar.v6i1.1527 https://doi.org/10.4103/0970-0358.26907 https://doi.org/10.4103/0970-0358.26907 https://doi.org/10.5115/acb.2015.48.1.62 https://doi.org/10.5115/acb.2015.48.1.62 https://doi.org/10.1002/ca.20622 figures 1a to d: brain magnetic resonance imaging (t2 weighted image) [1a and c] and susceptibility weighted image [b] demonstrating recent ischaemic infarction (bright signal) with sparing of motor cortex [c] in the left fronto-parietotemporal region along with haemorrhagic conversion (dark signal) in the basal ganglia [b]. the infarction spares the left motor cortex. note that there is no significant occlusion of the proximal portion of the left middle cerebral artery in magnetic resonance angiography (time of flight sequence, [d]). a 28 year-old man, while on aversion therapy for alcohol abuse with disulfiram, consumed an alcoholic beverage and developed a sudden onset of difficulty in speaking. neurologically, he demonstrated global aphasia and right homonymous hemianopia. right squ med j, february 2012, vol. 12, iss. 1, pp. 124-125, epub. 7th feb 12. submitted 17th may 11 revision req. 19th jul 11, revision recd. 25th jul 11 accepted 24th aug 11 department of medicine, college of medicine & health sciences, muscat, oman. corresponding author email: rnandagopal@yahoo.com ُحْبَسٌة شاِمَلة بدون َخَزل ِشقِّّي ترابط عصيب-ُشعاِعّي رامات�سانديران نانداجوبال global aphasia without hemiparesis a neuroradiologic correlation ramachandiran nandhagopal interesting medical image ramachandiran nandhagopal interesting medical image | 125 hemiparesis was conspicuously absent. he had transient atrial fibrillation, but no structural cardiac lesions or other vascular/thrombophilic risk factors. cranial magnetic resonance imaging (mri) [figure 1a] demonstrated recent infarction involving the perisylvian language areas with haemorrhagic transformation in the basal ganglia [figure 1b] in the distribution of the left middle cerebral artery. the ischaemic infarction spared the motor cortex [figure 1c], the adjacent subcortical area and the posterior limb of the internal capsule. a magnetic resonance angiogram of the cerebral arteries [figure 1d] did not reveal any major vessel occlusion. in view of the large infarct and mild haemorrhagic transformation, he was treated with low dose aspirin only. subsequent cardiac monitoring did not disclose any persistent atrial fibrillation or other arrhythmia. at follow-up, he made a good recovery with significant improvement in auditory comprehension and verbal expression. hemiparesis typically accompanies global aphasia. there are only rare cases of global aphasia without hemiparesis and the language outcome is quite variable at follow-up.1-3 in our patient, the lesion distribution in the perisylvian language areas with sparing of the motor cortex and posterior limb of internal capsule accounted for this unusual syndrome of global aphasia without hemiparesis. the most common aetiology of the syndrome is embolic infarction.1-3 disulfiram-alcohol interaction has been associated with cardiac events.4,5 in our patient, this interaction resulted in transient cardiac arrhythmia (atrial fibrillation) and subsequent embolic infarction. to the best of my knowledge, this is the first report of stroke in the unusual setting of disulfiram-alcohol interaction. caution should be exercised while prescribing drugs that would elicit disulfiram-like reaction in subjects who lack strong motivation for alcohol de-addiction. references 1. hanlon re, lux we, dromerick aw. global aphasia without hemiparesis: language profiles and lesion distribution. j neurol neurosurg psychiatry 1999; 66:365-9. 2. legatt ad, rubin mj, kaplan lr, healton eb, brust jc. global aphasia without hemiparesis: multiple etiologies. neurology 1987; 37:201–5. 3. van horn g, hawes a. global aphasia without hemiparesis: a sign of embolic encephalopathy. neurology 1982; 32:403–6. 4. tayyareci y, acarel e. acute myocardial infarction associated with disulfiram-alcohol interaction in a young man with normal coronary arteries. turk kardiyol dern ars 2009; 37:48–50. 5. altun g, altun a, erdogan o. acute myocardial infarction due to disulfiram (antabuse)-alcohol interaction. cardiovasc drugs ther 2006; 20:391–2. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 371-379, epub. 25th jun 13 submitted 25th aug 12 revisions req. 2nd jan & 5th feb 13; revisions recd. 5th jan & 11th mar 13 accepted 30th mar 13 departments of 1child health and 3radiology & molecular imaging, sultan qaboos university hospital; 2department of genetics, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: koul@squ.edu.om الطيف السريري للشلل السفلي التشنجي الوراثي يف األطفال دراسة 74 حالة رو�شان كول، فتحية املر�شدي، في�شل العزري ، راجنيت ماين، رنا عبد الرحيم ، فيفيك كول، اآمنة الفطي�شية الطريقة: عمان. �شلطنة يف االأطفال يف الوراثي الت�شنجي ال�شفلي ال�شلل ا�شتك�شاف هو الدرا�شة هذه من الهدف كان الهدف: امللخ�ص: اأجريت هذه الدرا�شة باأثر رجعي من الفرتة ما بني يناير 1994 و اأغ�شط�س 2011 على االأطفال الذين يعانون من تاأخر التطور النمائي، يف مبا اًل، مف�شّ واالأ�رسة الوالدة تاريخ ت�شجيل مت الهرمي. ال�شبيل متناظرة عالمات وجود مع احلركة ومعوقات امل�شية، وا�شطرابات ذلك �شن ظهور االأعرا�س. و�شفت اإ�شابات االأطفال باأنها اإما نقية اأو معقدة من طيف ال�شلل ال�شفلي الت�شنجي الوراثي ا�شتنادا اإىل معايري مت الدرا�شة، خالل االأ�شقاء. النتائج: وجميع االآباء فح�س اأي�شا مت ، اأكرث اأو واحد م�شاب طفل لديها التي االأ�رس يف املتبعة. الت�شخي�س من احلاالت، 44 طفاًل ت�شخي�س 74 طفال من 31 عائلة لديها ال�شلل ال�شفلي الت�شنجي الوراثي. وجدت ن�شبة القرابة االأبوية يف 91% )%59.4( يعانون من ظهور املر�س يف اإطار عام واحد من العمر. كان معقد النوع االأكرث �شيوعا ووجد يف %81.1. وكان اكتناف الكالم والتخلف العقلي، وال�رسع والت�شوهات املرتبطة االأكرث �شيوعا. لوحظت تغيريات غري حمددة للمادة البي�شاء وت�شوهات اجل�شم الثفني يف %24.3 من احلاالت يف الت�شوير بالرنني املغناطي�شي. اال�ستنتاج: و�شفت الدرا�شة املظاهر ال�رسيرية يف 74 طفال مع ظهورال�شلل ال�شفلي الت�شنجي متنحي الوراثة يف 81.1%. مفتاح الكلمات: �شلل �شفلي ت�شنجي؛ �شلل �شفلي ت�شنجي وراثي؛ وراثي متنحي؛ االأطفال ذوي االحتياجات اخلا�شة؛ عمان. abstract: objectives: the aim of the study was to explore the spectrum of hereditary spastic paraplegia (hsp) in children in oman. methods: this retrospective study was carried out between january 1994 and august 2011 on children with delayed development, gait disorders and motor handicaps, with signs of symmetrical pyramidal tract involvement. a detailed perinatal and family history, including the age of onset of symptoms, was recorded. the children were labelled as having either the pure or complicated form of hsp based on the established diagnostic criteria. in families with more than one affected child, parents and all other siblings were also examined. results: within the study, 74 children from 31 families were diagnosed with hsp. parental consanguinity was seen in 91% of cases, with 44 children (59.4%) experiencing onset of the disease under one year of age. complicated hsp was the most common type, seen in 81.1%. speech involvement, mental retardation, and epilepsy were the most common associated abnormalities. nonspecific white matter changes and corpus callosum abnormalities were noted in 24.3% of cases on magnetic resonance imaging. conclusion: the study described clinical features of 74 children with hsp. autosomal recessive complicated hsp was seen in 81.1% of cases. keywords: spastic paraplegia, hereditary; spastic paraplegia, autosomal recessive; disabled children; oman. clinical spectrum of hereditary spastic paraplegia in children a study of 74 cases *roshan koul,1 fathiya m. al-murshedi,2 faisal m. al-azri,3 ranjit mani,1 rana a. abdelrahim,1 vivek koul,1 amna m. alfutaisi1 advances in knowledge this study examined the largest series of hereditary spastic paraplegia (hsp) in children in oman. an autosomal recessive pattern of inheritance was seen in all cases in the study. early onset of symptoms was seen in the majority of patients (~60%). microcephaly was often seen in the children in this study. magnetic resonance imaging showed white matter abnormalities in 24.3% of cases. a differential diagnosis of hsp should be considered if the history and clinical features do not suggest cerebral palsy. application to patient care early diagnosis is essential in cases of hsp in children. multidisciplinary care should be implemented as soon as the initial diagnosis is made in order to prevent handicaps. support groups should be set up in oman for children afflicted with hsp. clinical & basic research clinical spectrum of hereditary spastic paraplegia in children a study of 74 cases 372 | squ medical journal, august 2013, volume 13, issue 3 hereditary spastic paraplegia (hsp) is defined as a neurological disorder characterised by progressive symmetrical pyramidal tract dysfunction with onset in the lower limbs resulting in weakness, mainly of the lower extremities.1 the onset of the disease can be from early childhood up to 70 years of age.2 childhoodonset hsp needs to be differentiated from more common conditions like cerebral palsy and other mimicking neurodegenerative disorders that particularly affect the white matter of the brain.3 hsp is classified as either pure or complicated based on well-established criteria.4,5 the disease is mainly reported in adults and there have been only a few studies in children.5,6 autosomal dominant, x-linked and autosomal recessive modes of inheritance have been described.7 the autosomal dominant variety is the most common type, reported in 70–80% of all cases of hsp seen so far.5,8 previous data from oman were limited to two reports of two large families involving 16 children with novel genetic mutations.9,10 the present study describes clinical features of hsp in 74 children, including the previous study of 16 children in which a genetic work-up has already been done. methods this work was carried out from january 1994 to august 2011 at the sultan qaboos university hospital (squh), muscat, oman, which is one of oman’s tertiary referral hospitals. children with delayed development, gait disorders and motor handicaps, who had signs of symmetrical pyramidal tract involvement, were included. children who had been diagnosed with cerebral palsy at another hospital or had been referred for neurological opinion were also included if the features were suggestive of hsp. a detailed history was taken for all cases regarding perinatal events, the age of onset of symptoms and the family history. all children were examined independently by two child neurologists and their hsp was classified as pure or complicated based on the established diagnostic criteria.4,5 in families with more than one affected child, the parents and all other siblings were examined for abnormal neurological signs. affected cousins could not be examined as they refused to come for a check-up. an intelligence quotient (iq) assessment was done only in one child as the majority of the children in the study (60%) were under one year of age. cognitive impairment (mental retardation) was assessed based on the achievement of mental and social milestones and on a developmental assessment test administered at the time of clinical examination. ophthalmological check-ups were performed in all cases. besides baseline blood tests and tandem mass spectrometry, an assessment of lactate, ammonia and creatine kinase levels was also performed for all cases. when indicated, lysosomal enzymes, very long chain fatty acids, plasma amino acids, and urine organic acids were also estimated. oman’s population has a large number of metabolic and neurodegenerative disorders; however, these were excluded on clinical features and appropriate laboratory investigations. vitamin b12 levels were also tested if a deficiency was suspected. magnetic resonance imaging (mri) scans of the brain and spinal cord were done in all cases at the time of presentation and in 12 others on follow-up. the progression of the disease was based on the clinical criteria of worsening spasticity and gait, deterioration of muscle power and declining school performance. nerve conduction studies, brainstem auditory evoked potentials (baeps) and visual evoked potentials (veps) were performed in all cases. an electroencephalograph was recorded if there had been a history of seizures. a genetic workup was done in the two large families who had been studied and reported earlier.9,10 a second study, to define the underlying genetic changes for the rest of the children, is planned in the near future. the basis for the diagnosis of pure hsp was drawn from already-established criteria.1,4,5 first, children were considered developmentally delayed based on slow development or walking gait abnormalities with a static or slowly progressive course, and examination findings of symmetrical genetic diagnosis should be undertaken for the families, and an antenatal diagnosis made, in order to prevent further cases of hsp in future pregnancies. genetic counselling should be made available to affected families. roshan koul, fathiya m. al-murshedi, faisal m. al-azri, ranjit mani, rana a. abdelrahim, vivek koul and amna m. alfutaisi clinical and basic research | 373 pyramidal tract features (weakness, hypertonia, hyperreflexia, upgoing plantars, plantar flexion of the feet and contractures at a later stage) mainly affecting lower limbs, with normal or minimal involvement of the upper limbs. second, a family history of a sibling or a cousin with a similar illness was an important indicator of the condition. third, mris of the brain and spinal cord that were normal or had nonspecific white matter changes (white matter hyperintensities) in the brain at the time of initial presentation or on follow-up were also included if clinical features were suggestive of hsp. the basis for the diagnosis of complicated hsp was the presence of one or more features such as microcephaly, seizures, mental retardation, delayed language development, dysarthria, abnormal eye findings, progressive course and abnormal imaging, in addition to the features of pure hsp. exclusion criteria included: 1) children with static encephalopathies (cerebral palsy) related to perinatal complications; 2) those with diseases affecting the grey/white matter of the brain (gangliosidoses, leukodystrophies) and 3) the presence of basal ganglia disorders, hereditary neuropathies, vitamin b12 deficiencies, spinal cord trauma or demyelinating diseases. this study was approved by the ethical committee of the college of medicine & health sciences at sultan qaboos university. results in the course of our study, 74 children with hsp were seen (42 males [56.8%] and 32 [43.2%] females). at the time of initial diagnosis, 42 were labelled as complicated hsp; 18 others progressed on followup and 14 were determined to have the pure form of hsp. the age of onset was under one year in 44 (59.4%) children. the children diagnosed in the initial years are adults now and have experienced progression of the disease. in 30 families, there was more than one child affected. only one family had a single case, which was presumed to be sporadic. on having more children, the chance of having another child affected with the disease is possible. the age of initial presentation ranged from 7 months to 15 years, 5 months, with a mean of 5 years, 8 months. all children had normal perinatal histories. parental consanguinity was seen in 91% of the children. there was an additional family history of affected cousins in 6 of the families. however, the cousins were not examined as they were reluctant to visit the hospital; hence, they were not included in the study. cognitive impairment (mental retardation) was seen in 17 children (23%). speech-related problems, mainly delayed language and dysarthria, were seen in 27 (36.5%). ophthalmologic examinations showed retinal pigmentary changes in four cases, table 1: various clinical features in children with hereditary spastic paraplegia feature n % age of onset birth 15 20.27 less than 6 months 12 16.21 6 months–1 year 17 22.97 1–4 years 12 16.21 4–10 years 15 20.27 10 years and above 3 4.05 speech abnormalities dysarthria 16 21.60 language delay 6 8.10 developmental aphasia 5 6.75 normal 47 63.50 mental retardation 17 22.97 epilepsy 13 17.56 cerebellar features 9 12.16 microcephaly 8 10.80 extra pyramidal features 6 8.10 simple febrile fit 1 1.35 eye changes 6 8.10 pigmentary retinopathy 4 5.40 anterior dystrophy 1 1.35 optic disc pallor 1 1.35 abnormal mri findings 18 24.32 nonspecific white matter changes 12 16.21 corpus callosum thin/agenesis 10 13.50 cerebellar volume reduction 1 1.35 neurophysiology nerve conduction abnormal 1 1.35 baep abnormal (delayed/flat) 5/3 6.75/4.05 vep poor waveform 1 1.35 mri = magnetic resonance imaging ; baep = brainstem auditory evoked potential; vep = visual evoked potential. clinical spectrum of hereditary spastic paraplegia in children a study of 74 cases 374 | squ medical journal, august 2013, volume 13, issue 3 anterior dystrophy in one, and optic disc pallor in one. the details of other features are given in table 1. neurometabolic disorders were initially suspected in a few children, but the disorders were excluded by performing tandem mass spectrometry, or by estimating lysosomal enzymes, very long chain fatty acids or urine organic acids. the vitamin b12 levels assessed in 6 children were normal. one child with hsp, who was suspected of having myopathy, underwent a muscle biopsy outside the country; the results were normal. brain abnormalities, detected upon mri, were noted in 18 cases. these abnormalities were noted at the first presentation or later on follow-up. mri changes that were not noted initially in 12 children eventually appeared in 3 on follow-up examinations performed after the children’s symptoms worsened clinically. overall, twelve children had nonspecific white matter changes (white matter hyperintensities) [figures 1b and 2b]. a total of 10 children had corpus callosum changes ranging from thin to absent, in addition to white matter changes [figures 1a and 2a]. basal ganglia and spinal cord abnormalities were not seen in any children. entire brain volume reduction was noted in one child and another had cerebellar atrophy. nerve conduction studies were normal in all except one. this patient had features of hereditary demyelinating motor sensory neuropathy. brainstem aeps were delayed in 5 children, while two had no response. veps were normal in all except one, who had poor waveform. there are approximately 45,000 live births per year in oman. as 74 children were seen over 18 years, this gave an approximate incidence of 1 in 11,000 live births. the incidence could be higher than this as patients of other tertiary care hospitals were not included in this study. all the children in this study were managed by supportive therapy, including muscle relaxants, physiotherapy and occupational therapy. some children received botox and a few had corrective orthopaedic surgery. one child underwent selective dorsal rhizotomy in the usa. discussion reaching a diagnosis of hsp is relatively challenging in the first two years of a child’s life when all investigations are normal and there is no relevant perinatal history indicating brain insult suggestive of cerebral palsy. a slowly progressing gait disorder with dominant pyramidal signs in the lower limbs and none or few sensory symptoms favour a diagnosis of hsp.1,2,7 various other neurodegenerative disorders affecting the neuroaxis at this age need to be differentiated if the typical clinical features of a particular disease are not present.6 a detailed algorithm for the diagnosis of hsp in children must be followed.6 the differential diagnosis in paediatric-onset hsp is different from the adult-onset type, as many figure 1 a&b: magnetic resonance imaging scan of the brain of a 13-year-old girl. (a) sagittal t1w view showing moderate hypoplasia of the corpus callosum (arrows). (b) axial t2w view showing non-specific hyperintense signal abnormalities in the periventricular white matter (arrows). roshan koul, fathiya m. al-murshedi, faisal m. al-azri, ranjit mani, rana a. abdelrahim, vivek koul and amna m. alfutaisi clinical and basic research | 375 children are misdiagnosed with cerebral palsy.6,7 hsp should be considered a diagnosis of exclusion in children.5 important diagnostic alerts against it are bulbar signs, early amyotrophy, asymmetric pyramidal tract lesions, extra pyramidal signs and peripheral neuropathy.5 the presence of more than one affected child in a family or affected cousins was very helpful in making the hsp diagnosis. following strict diagnostic criteria, we were able to give a detailed description of hsp in the children in our study, most of whom are still being followed-up at squh to look for progression of the disease and manifestations of any other disorders developing over time. as oman has a large number of metabolic and neurodegenerative disorders, doctors must watch for the presence or development of other neurological disorders; however, none of our children have yet developed features of other neurological disorders. hsp is mainly reported in adults; there have been only a few studies in children.5,6 the autosomal dominant variety is the most common type reported, constituting 70–80% of all cases.5,8 we did not encounter cases with an autosomal dominant or x-linked inheritance pattern. an examination of siblings and parents was important for excluding this pattern of inheritance. all children in this study had an autosomal recessive inheritance pattern. consanguinity may be the main underlying factor as consanguineous marriages are common in oman. depending upon the disease entity, consanguinity has been reported in 56.3–87.50% of cases.11,12 two forms of hsp were described initially: pure and complicated.2 mainly pyramidal features and mild sensory abnormalities were noted in the pure form. other neurological and non-neurological features were seen in the complicated form. recently, diagnostic criteria for pure and complicated hsp have been suggested.5 the differentiation between the pure and complicated forms was evident upon presentation in 42 cases, while 18 were seen to progress over time. by their second decade, many of the children in this study had developed speech impairments, dysarthria, a decline of intellect, cerebellar disorders and a loss of ambulatory function. these features suggested the complicated form of hsp. the majority (81.1%) of the children in our study had complicated hsp which also comprised 65% of cases in an earlier study.13 in another series of 72 children, autosomal recessive hsp was seen in 17%, and 25% of these cases had complicated hsp.6 this wide variability in the pure and complicated forms in our study may be related to the particular cohort of patients, the geographical location, patient genetics and the possibility of consanguinity in the population. other than these factors, the accuracy of a diagnosis of pure hsp has been questioned in the past.14 observations of the children in this study lend further evidence to the hypothesis that the pure form of hsp is rare in children, in contrast to adult-onset autosomal dominant hsp. over time, most patients invariably figure 2 a&b: magnetic resonance imaging scan of the brain of a four-year-old boy. (a) sagittal t1w view demonstrating marked hypoplasia of the corpus callosum (arrows). (b) axial t2w view showing hyperintense signal abnormalities in the periventricular trigon white matter (arrows). clinical spectrum of hereditary spastic paraplegia in children a study of 74 cases 376 | squ medical journal, august 2013, volume 13, issue 3 fall into the group of complicated hsp. a large number of the children in this study (59.45%) presented with symptoms at under one year of age, and the majority (56/74, 75.67%) presented at under 4 years. it was found that 20% had onset from birth, and 16% at around 6 months of age. this observation was based on the history taken from the parents. it was observed that the children with onset at under one year continued to achieve milestones, although with delays, up to the age of about 4 years and that subsequently progressive weakness started. this could be related to a growth spurt overtaking the disease process in this age group, as observed in many neurodegenerative diseases. this was not noted in the children with onset after 4 years of age. these children continued a downhill course after the onset of weakness. speech involvement was noted in 27 children (36.5%), dysarthria being the most common (16, 21.6%), while 6 (8.1%) had delayed language development. mental retardation was noted in 17 (23%) cases of complicated hsp in the current study. cognitive impairment over time has been reported in all types of hsp.5 mental retardation in hsp has been reported in several previous studies.5,7,15–19 some of our patients experienced a worsening of cognitive functions with disease progression, as noted previously.19,20 however, in this cohort, this observation could not be substantiated by an appropriate iq assessment. epilepsy is not a common feature of hsp; however, there are case reports and families with special genetic abnormalities associated with epilepsy.21 epilepsy was noted in 13 (17.5%) of our patients; 3 of them had a thin corpus callosum.9,10 different types of seizures have been associated with hsp.5,21 in the current study, tonic-clonic seizures were found in 7 children, myoclonic in 4, and partial in two. cerebellar features may be seen at the onset of the disease or later on after progression of the disease.5,9,10,17,20,22 in severe cases with spasticity and contractures, cerebellar features may be difficult to recognise. cerebellar features were seen in 9 children (12.1%), although mri scanning showed cerebellar atrophy in only one. microcephaly is an uncommon feature in adultonset cases of hsp and has been reported only in a few studies.5,15,23 it was noted in 8 (10.8%) of our patients; this is suggestive of early onset illness affecting brain growth and development. those with adult-onset hsp initially had normal brain growth and development—hence the normal head size. extrapyramidal features, mainly in the form of dystonia, were noted in 6 (8.1%) of our patients although no imaging changes in the basal ganglia were seen, except generalised atrophy (decreased brain volume) in one child. this may be a part of the global atrophy of the brain noted in some of these patients.5 eye abnormalities in the form of pigmentary retinopathy and disc pallor were noted in 6 (8.1%) patients. eye abnormalities like macular changes, pigment migration, and atrophy have been reported previously in other studies.5,17,24,25 the majority of children with hsp have normal mri results, as was seen in 75.6% of our patients. abnormal mri images were seen in 18 (24.3%) patients in the white matter, corpus callosum or both. nonspecific white matter changes in the brain, namely leukoencephalopathy or white matter hyperintensities, were the most common findings in these children, and were noted in 12 out of 18 (66.7%). these white matter changes have been reported before in the literature.9,10,17,20 loss of volume (thinning) and agenesis of the corpus callosum were seen in 10 out of 18 (55.5%) patients. involvement of the corpus callosum was the second most common abnormality found by mri in our patients. there are several reports in the literature of white matter hyperintensities (diffuse or patchy) and corpus callosum abnormalities in association with hsp.9,10,17,19,20,26–30 thinning of the cervical and thoracic spinal cord has been noted in hsp.31 volume loss is an expected finding as there is a degeneration of the longer corticospinal tracts to the spinal cord (mainly to the lower limbs) and dorsal column pathway within the spinal cord.5,32 however, this has not been noted in our patients to date. this study noted abnormalities at initial presentation or on follow-up in the brain mris only, but no changes were seen on follow-up in the spinal cord in the few children who underwent repeat mris. it may be possible to see these changes in the spinal cord at a later stage. in most cases of pure hsp, nerve conduction studies are normal.2 sensory impairment has been reported in 10–65% of cases of pure hsp; however, nerve conductions have been found to be normal.5,17,25,33 sensory abnormalities on clinical examination in children are the most difficult ones roshan koul, fathiya m. al-murshedi, faisal m. al-azri, ranjit mani, rana a. abdelrahim, vivek koul and amna m. alfutaisi clinical and basic research | 377 to detect. in this study, all children had normal nerve conduction velocities except in one whose abnormality was associated with hereditary motor sensory neuropathy. abnormalities of the central motor conduction times have also been reported. abnormalities of somatosensory evoked potentials in the form of low amplitudes also have been reported.34 similarly, abnormal baeps and veps have been reported previously. these are rare manifestations in hsp.34–36 we found abnormal baeps in 5 patients (6.7%) and veps in one (1.3%). the most common genes associated with recessive hsp are spg5a, spg7, spg11, and spg15.2 the pure form with variable age of onset and slow progression is located in the spg5a gene.22 in the two previous studies from oman on 16 children, 9 children with complicated hsp were genetically mapped to a new locus on 8p12-p11.21 and 7 children with the spg35 gene were mapped to 16q21-q23.1,9,10 in the rest of the children, genetic studies are expected to be undertaken in the future. specific molecular genetic tests will help in easy and early diagnosis and help patients to avoid invasive and costly work-ups.2 in over 50% of cases of autosomal dominant hsp, a molecular diagnosis is possible.2 the loci of at least 44 spastic paraplegia genes have been mapped, and 20 genes have been identified to date.2,20 a systematic review of clinical features and genetic studies from 1985 to 2008 was reported in a recent study.2 there are several hypotheses to explain the pathophysiologic mechanism of hsp. malfunction of the axonal transport and membrane trafficking are emerging as likely mechanisms.2,37 interference in the axonal transport of macromolecules, organelles and their cargoes to the longest neurons in the spinal cord result in hsp.37,38 mitochondrial dysfunction could also affect the efficient transport of signals, molecules, and organelles to and from the nerve terminals.20 mutation of fatty acid 2-hydroxylase (fa2h) was reported as the underlying mechanism of the complicated form of hsp in spg35.20 management of these hsp-affected children is a challenge. multidisciplinary approaches involving several specialties can help them and their families. locating the responsible genes and understanding the disease mechanism, and then translating these findings into therapies is a long term undertaking.38,39 the goal for the future is to prevent such severe forms of autosomal recessive hsp. genetic studies will help in the accurate diagnosis of patients, the detection of asymptomatic cases and prenatal diagnosis in families. this will eventually prevent the disease. life expectancy in those with adult-onset hsp is mostly normal.5,7 this may not be true in children as we have seen children become wheelchair-bound by their teens. the oldest survivor in this study is a 23-year-old male who is bedridden and severely handicapped. this study had the limitation that there was no supportive genetic study on 58 of the patients. it is possible that some rare neurometabolic disorder may be detected in some of them on long-term follow-up. conclusion autosomal recessive complicated hsp is the main form of hsp seen in children in the arabian peninsula, with an approximate incidence of 1 in 11,000 live births. the majority of children experience onset at under 4 years of age. in the initial few years, they do not show deterioration in motor functions but then show progressive weakness. speech involvement, mental retardation, epilepsy and microcephaly were commonly associated features in this study. future genetic studies should reveal whether these children are experiencing a different genetic mutation from the previously identified genes involved in hsp or have totally novel mutations. d e c l a r at i o n the authors declare no conflict of interest in this study, and that no financial help was received for the study from squh or any private party. references 1. harding ae. hereditary spastic paraplegia. semin neurol 1993; 13:333–6. 2. salinas s, proukakis c, crosby a, warner tt. hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. lancet neurology 2008; 7:1127–37. 3. rainier s, sher c, reish o, thomas d, fink jk. de novo occurrence of novel spg 3a/atlastin mutation presenting as cerebral palsy. arch neurol 2006; 63:445–7. 4. harding ae. classification of hereditary ataxias and clinical spectrum of hereditary spastic paraplegia in children a study of 74 cases 378 | squ medical journal, august 2013, volume 13, issue 3 paraplegias. lancet 1983; 1:1151–5. 5. mcdermott cj, white k, bushby k, shaw pj. hereditary spastic paraparesis: a review of new developments. j neurol neurosurg psychiatry 2000; 69:150–60. 6. debot st, van de warrenburg bpc, kremer hph, willemsen maap. child neurology: hereditary spastic paraplegia in children. neurology 2010; 75:e75–9. 7. mcdermott cj, shaw pj. hereditary spastic paraparesis. in: aa eisen, pj shaw, eds. handbook of clinical neurology series, motor neuron disorders and related diseases. 3rd ed. amsterdam: elsevier, 2007. pp. 327–52. 8. depienne c, stevanin g, brice a, durr a. hereditary spastic paraplegias: an update. curr opin neurol 2007; 20:674–80. 9. al-yahyaee s, al-gazali li, de jonghe p, albarwany h, al-kindi m, deyriedt e, et al. a novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy. neurology 2006; 66:1230–4. 10. dick kj, al-mjeni r, bashir w, koul r, simpson ma, patton ma, et al. a novel locus for an autosomal recessive hereditary spastic paraplegia (spg35) maps to 16q21-q23. neurology 2008; 71:248–52. 11. rajab a, patton ma. a study of consanguinity in the sultanate of oman. ann hum biol 2000; 27:321–6. 12. al-maawali aa, joshi sn, koul rl, al-maawali aa, al-sedari hs, al-amri bm, et al. spectrum of paediatric lysosomal storage disorders in oman. sultan qaboos univ med j; 2012: 12:295–9. 13. appleton re, farrel k, dunn hg. ‘pure’ and ‘complicated’ forms of hsp presenting in childhood. dev med child neurol 1991; 33:304–12. 14. figlewicz da, bird td. ‘pure’ hereditary spastic paraplegias. the story becomes complicated. neurology 1999; 53:5–7. 15. farah s, sabry ma, al-shubaili af, anim jt, hussain jm, montaser ma, et al. hereditary spastic paraparesis with distal muscle wasting, microcephaly, mental retardation, arachnodactyly, and tremors: new entity? clin neurol neurosurg 1997; 99:66–70. 16. wilkinson pa, crosby ah, turner c, bradley lj, ginsberge l, wood nw, et al. a clinical genetic and biochemical study of spg7 mutations in hereditary spastic paraplegia. brain 2004; 127:973–80. 17. stevanin g, santorelli fm, azzedine h, countinho p, chomilier j, denova ps, et al. mutations in spg 11 encoding spastascin are a major cause of spastic paraplegia with thin corpus callosum. nat genet 2007; 39:366–72. 18. dursun u, koroglu c, kocasoy orhan e, ugur sa, tolun a. autosomal recessive spastic paraplegia (spg45) with mental retardation maps to 10q24.3-q25.1 neurogenetics 2009; 10:325–31. 19. stevanin g, azzedine h, denora p, boukhris a, tazir m, lossos a, et al. mutations in spg11 are frequent in autosomal recessive spastic paraplegia with this corpus callosum, cognitive decline and lower motor neuron degeneration. brain 2008; 131:772–84. 20. dick kj, eckhardt m, paisán-ruiz c, alshehhi a, proukakis c, sibtain na, et al. mutation of fa2h underlies a complicated form of hereditary spastic paraplegia (spg35). hum mutat 2010; 4:e1251–60. 21. webb s, flanagan n, callaghan n, hutchinson m. a family with hereditary spastic paraparesis and epilepsy. epilepsia 1977; 38:495–9. 22. hentati a, pericak-vance ma, hung wy, belal s, laing n, boustany rm, et al. linkage of pure autosomal recessive spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. hum mol genet 1994; 3:1263– 7. 23. teebi as, miller s, ostrer h, eydoux p, colombbrockmann c, oudjhane k, et al. spastic paraplegia, optic atrophy, microcephaly with normal intelligence and xy sex reversal: a new autosomal recessive syndrome? j med genet 1998; 35:759–62. 24. leys a, gilbert hd, van de sompel w, verougstraete c, devriendt k, lagae l, et al. familial spastic paraplegia and maculopathy with juxtrafoveolar retinal telengiectasias and subretinal neovascularisation. retina 2000; 20:184–9. 25. hanein s, martin e, boukhris a, byrne p, goizet c, hamri a, et al. identification of the spg15 gene, encoding spastizin, as a frequent cause of complicated autosomal recessive spastic paraplegia, including kjellin syndrome. am j hum genet 2008; 82:992–1002. 26. shibasaki y, tanaka h, iwabuchi k, kawasaki s, kondo h, uekawa k et al. linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15a13-15. ann neurol 2000; 48:108– 12. 27. casali c, valente em, bertini e, montagna g, criscuolo c, di michele g, et al. clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum. neurology 2004; 27:262–8. 28. orlacchio a, kawarai t, totaro a, errico a, st george-hyslop ph, rugarli ei, et al. hereditary spastic paraplegia: clinical genetic study of 15 families. arch neurol 2004; 61:849–55. 29. winner b, uyanik g, gross c, lange m, schultemattler w, schuierer g, et al. clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (spg11). arch neurol 2004; 61:117–21. 30. goizet c, boukhris a, durr a, beetz c, truchetto j, tesson c, et al. cyp7b1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. brain 2009; 132:1589–1600. 31. hedera p, eldevik op, maly p, rainier s, fink jk. roshan koul, fathiya m. al-murshedi, faisal m. al-azri, ranjit mani, rana a. abdelrahim, vivek koul and amna m. alfutaisi clinical and basic research | 379 spinal cord mri in autosomal dominant hereditary spastic paraplegia. neuroradiology 2005; 47:730–4. 32. bruyn rpm. the neuropathology of hereditary spastic paraplegia. clin neurol neurosurg 1992; 94:s16–18. 33. schady w, smith cml. sensory neuropathy in hereditary spastic paraplegia. j neurol neurosurg psychiatry 1994; 57:693–8. 34. sartucci f, tavani s, murri l, saggliocco l. motor and somatosensory evoked potentials in autosomal dominant hereditary spastic paraplegia linked to chromosome 2pspg4. brain res bull 2007; 74:243– 9. 35. rossini pm, cracco jb. somatosensory and brainstem auditory evoked potentials in neurodegenerative system disorders. eur neurol 1987; 26:176–88. 36. happel lt, rothschild h, garcia c. visual evoked potentials in two forms of hereditary spastic paraplegia. electroencephalogr clin neurophysiol 1980; 48:233–6. 37. crosby ah, proukakis c. is the transportation highway the right road for hereditary spastic paraplegias? am j hum genet 2000; 71:1009–16. 38. tarrade a, fassier c, courageot s, charvin d, vitte j, peris l, et al. a mutation of spastin is responsible for swelling and impairment of transport in a region of axon characterized by changes in microtubule composition. hum mol genet 2006; 15:3544–58. 39. alexandra d. genetic testing for spastic paraplegia. neurology 2008; 71:236–8. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 137-142, epub. 27th feb 13 submitted 12th may 12 revision reqd. 7th jul 12, revision recd. 16th oct 12 accepted 24th nov 12 departments of 1ophthalmology, 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: msalabri@squ.edu.om ثنائية متالزمة العني الدماغية مضاعفات نادرة ناجتة عن داء الفطرية املخاطية يف مريض عماين تقرير حالة ومراجعة األدبيات �صامية اجلابري، حممد العربي، اأحمد الهنائي، في�صل العزري امللخ�ص: تعترب متالزمة العني الدماغية من احلالت غري ال�صائعة ن�صبيا. تزامن الثنائية يف وقت واحد، تعد اأقل �صيوعا وذكرت فقط يف %22 من جميع احلالت. يوجد العديد من الأعرا�ض ال�رسيرية، لكن يعترب فقدان الب�رس واآلم العني من اأكرثها �صيوعا. هذه املتالزمة حتدث عندما يكون هناك ان�صداد يف ال�رسيان ال�صباتي بن�صبة %90 اأو اأكرث، ومن املعروف جيدا اأنها ترتافق مع عدد من الأمرا�ض مبا يف ذلك مر�ض ال�صكري، ارتفاع �صغط الدم واأمرا�ض ال�رسايني التاجية والدماغية. يعد حدوث متالزمة العني الدماغية كم�صاعفات ناجتة عن داء الفطرية املخاطية من احلالت النادرة. يف هذا التقرير نوثق حالة نادرة من ثنائية متالزمة العني الدماغية ناجتة عن ت�صيق ال�رسيان ال�صباتي ب�صبب م�صاعفات داء الفطرية املخاطية. بالإ�صافة ي�صتعر�ض هذا التقرير الأدبيات الطبية املن�صورة عن هذه املتالزمة من حيث الأعرا�ض ال�رسيرية ، وطرق الت�صخي�ض املتبعة واخليارات العالجية. مفتاح الكلمات: متالزمة العني الدماغية، داء الفطرية املخاطية، ت�صيق ال�رسيان ال�صباتي، ت�صوير نظام ال�رسيان ال�صباتي، تقرير حالة، عمان abstract: ocular ischaemic syndrome (ois) is a relatively uncommon condition. simultaneous bilateral involvement is even less common and has been reported in only 22% of all cases of ois. it has variable clinical presentations, of which visual loss and ocular pain are the most common. it is believed to occur when there is a 90% or greater carotid artery obstruction. this syndrome is often associated with a number of systemic diseases including diabetes mellitus, hypertension, coronary artery disease, and cerebrovascular disease. only occasionally has it been described as a complication of rhinocerebral mucormycosis. we report an unusual case of bilateral ois secondary to bilateral internal carotid artery thrombosis as a complication of invasive rhinocerebral mucormycosis. in addition, a review of clinical presentation, diagnostic work-up and treatment options for ois is provided. keywords: ocular ischemic syndrome; mucormycosis; carotid stenosis; carotid system imaging; case report; oman. bilateral ocular ischaemic syndrome—rare complication of rhinocerebral mucormycosis in an omani patient case report and literature review samiya al-jabri,1 *mohamed al-abri,1 ahmed al-hinai,1 faisal al-azri2 case report mucormycosis is the most invasive and rapidly progressive fungal infection in humans, of which rhino-orbito-cerebral involvement is a common manifestation.1 affected individuals invariably have underlying disorders like diabetes mellitus, renal failure, liver cirrhosis, leukaemia, lymphoma, or other immunocompromised states.1,2,3 ocular involvement in mucormycosis is usually in the form of orbital cellulitis. the pathway of spread begins with inoculation of the nasal mucosa with the mucor pathogen followed by invasion of the paranasal sinuses. the pathogen then moves to the inferior orbital fissure leading to thrombosis of regional blood vessels. this results in acute ocular symptoms of the eyelid, including oedema and chemosis. extension of the infection into the orbital apex causes proptosis. visual loss may develop secondary to invasion into the optic nerve or thrombosis of the retinal artery.1 intracranial spread of the infection is believed to occur through the cribriform plate or orbital apex. in addition, bilateral ocular ischaemic syndrome—rare complication of rhinocerebral mucormycosis in an omani patient case report and literature review 138 | squ medical journal, february 2013, volume 13, issue 1 the organism spreads along the meninges, nerves, and vessels. hyphae can erode through the vascular endothelium leading to thrombosis, brain infarction, and necrosis. vascular thrombosis in this mechanism may involve cavernous sinuses or the carotid artery.2 ocular ischaemic syndrome results from severe and chronic hypoperfusion to ocular structures commonly due to severe atherosclerosis of the carotid vascular system with insufficient collateral circulation. there are few case reports in the literature of carotid vascular system thrombosis in association with invasive mucormycosis with secondary ocular involvement and severe visual loss. most of these patients had a direct orbital involvement with signs of orbital cellulitis.2,4 in this article we report a case of rhinocerebral mucormycosis with no evidence of direct spread through the orbit. the patient developed cavernous sinuses and bilateral internal carotid artery thrombosis leading to bilateral ois, which resulted in severe visual loss. case report in january 2010, a 57-year-old omani woman who was a known diabetic and had been receiving treatment for hypertension for many years developed right cavernous sinus thrombosis. in may 2010, she was diagnosed with chronic invasive rhinocerebral mucormycosis for which she was started on amphotericin and voriconazole and underwent multiple sinus debridement surgeries. in february 2011, she developed a right middle cerebral artery and anterior cerebral artery stroke and renal failure. she had a partial recovery with residual dysarthria for which she was treated with aspirin and clopidogrel. amphotericin was substituted for caspofungin and posaconazole due to renal failure. during one of her recent admissions for another sinus debridement surgery, she complained of bilateral sudden visual loss associated with right eye pain. her past ocular history revealed a bilateral cataract extraction with an intraocular lens figure 1: (a&b) color fundus photographs of the right and left eyes respectively, shows pale discs, attenuated retinal arteries, microaneurysms, no neovascularisation of discs or elsewhere and no macular oedema in both eyes. scattered exudates were noted over the macula of the right eye. (c) fundus fluorescein angiography (ffa) of the left eye at 07 seconds shows delayed choroidal filling. (d) ffa of the left eye at 3:36 seconds shows widespread of retinal ischaemia and prominent staining of retinal arterioles. samiya al-jabri, mohamed al-abri, ahmed al-hinai and faisal al-azri case report | 139 implantation, bilateral non-proliferative diabetic retinopathy, and diabetic macular oedema. her right eye was treated with a focal laser. her baseline visual acuity was 0.3 in the right eye and 0.8 in the left eye. an ophthalmic examination on the day of referral revealed no light perception in either eye. however, after one hour her perception improved to 0.2 in the right eye and 0.1 in the left eye at a distance of one metre. an anterior segment examination for both eyes (ou) was unremarkable except for middilated poorly reactive pupils and pseudophakia. her intraocular pressure (iop) ou was normal. there was no proptosis, and ocular motility was normal for ou. a dilated fundus examination revealed bilateral multiple microaneurysms; dot and blot retinal haemorrhages at the posterior pole and to some extent at the mid-periphery; pale optic discs, and attenuated retinal arteries. there was no neovascularisation of the disc or elsewhere, and there was no macular oedema ou [figures 1a and b]. fundus fluorescein angiography (ffa) revealed a bilateral delayed choroidal filling with evidence of widespread retinal ischaemia [figures 1c and d]. a magnetic resonance imaging (mri) scan showed diffuse inflammatory changes in the paranasal sinuses. there was a loss of the normal signal void within both internal carotid arteries at the level of the cavernous sinuses in keeping with thrombosis of the internal carotid arteries (icas). a mri angiogram showed complete absence of flow in the icas [figures 3a and b]. this was confirmed by conventional digital subtraction angiography (dsa) of the icas as well as by cerebral angiography, which revealed bilateral abrupt occlusion of the internal carotid arteries. however, there were good collaterals with opacification of the internal carotid arteries distal to cavernous sinuses through dural and meningeal collateral arteries [figures 3a and b]. electroretinograghy showed a decrease in the amplitude of both aand b-waves. no neovascularisation of anterior or posterior segments were detected throughout the followup period. however, the patient developed open angle glaucoma with poorly controlled iop, optic nerve cupping with further deterioration in vision to light perception in the right eye, and no light perception in the left eye. in april 2012, she was still attending hospital follow-up visits to monitor her rhinocerebral mucormycosis for which oral posaconazole was prescribed. discussion the incidence of ois is estimated to be 7.5 cases per million persons per year.5 this figure could be underestimating the true incidence, probably due to figure 2: (a) axial t2w magnetic resonance (mr) image through the cavernous sinus showing loss of normal signal void in the internal carotid arteries (arrow), in keeping with thrombus within the ica. (b) a time-of-flight mr angiography reformat image shows absence of both internal carotid arteries. the middle cerebral arteries (white arrows), basilar artery are with in normal limits (yellow arrow). bilateral ocular ischaemic syndrome—rare complication of rhinocerebral mucormycosis in an omani patient case report and literature review 140 | squ medical journal, february 2013, volume 13, issue 1 the overlap between ois in its clinical presentation and other ocular vascular diseases such as retinal vein occlusions and diabetic retinopathy.5,6 the fact that atherosclerotic vascular disease is the major cause of ois explains why it is twice as common in males and why it typically occurs at a mean age of 65 years.5 this also contributes to the close association of ois with vasculopathic conditions such as diabetes, hypertension, and hypercholesterolaemia, and the increased risk for ois among patients with a previous history of stroke and myocardial infarction. severe carotid artery occlusion by atherosclerosis with poor collateral circulation is evident in the majority of patients with ois who present with the above risk factors. on the other hand, in a large randomised prospective study, around 26% of affected eyes with ois were found to have no or mild ipsilateral carotid stenosis. this was explained by a possible vascular occlusion at the level of the aortic arch, and at the ophthalmic, central retinal, or ciliary arteries.7 other aetiological factors leading to ois include giant cell arteritis, aortic arch syndrome, takayasu arteritis, and hypercysteinemia.5–8,9 moreover, there have been several reported cases in the literature of carotid artery thrombosis secondary to invasion with mucormycosis, making mucormycosis another risk factor for ois.1–3 our patient had multiple atherosclerotic risk factors in addition to mucormycosis, which might together have contributed to the ica occlusion. her initial visual presentation was probably due to transient embolisation of the central retinal artery, or its branches or vasospasm.5,4 visual loss in ois is the most common symptom and it could be transient, sudden, or, most commonly, gradual.10,11 ocular pain is the second most common symptom and it is a result of either an increase in intraocular pressure or ischaemia to the globe or ipsilateral dura.6 our patient had ocular pain at presentation in the absence of neovascular glaucoma which might suggest ischaemia was the likely cause. anterior segment signs of ocular ischaemia include corneal oedema with descemet’s folds, scleral melting, iris atrophy and neovascularisation, fixed semi-dilated or poorly reactive pupils, peripheral anterior synechia with angle closure, mild iritis, and cataracts. among these signs, neovascularisation of the iris (nvi) is the most common (90%) and when seen at presentation it is an indicator of a poor prognosis.10 our patient did not have iris atrophy or nvi; however, she had poorly reactive pupils, probably due to retinal ischaemia and/or ischaemic optic neuropathy or iris ischaemia. figure 3: (a) lateral left carotid conventional angiogram demonstrating complete occlusion of the proximal left internal carotid artery (ica) (white arrow). there is opacification of the supra-clinoid ica (yellow arrow). (b) lateral right carotid angiogram demonstrating similar findings as the left side. samiya al-jabri, mohamed al-abri, ahmed al-hinai and faisal al-azri case report | 141 generally, in ois, intraocular pressure may be raised if fibrovascular tissue develops in the angle causing angle closure, or it may be normal or even low if aqueous production is reduced due to ciliary body ischaemia. also, normal tension glaucoma is described as occurring in conjunction with ois due to a chronic reduction of the retrobulbar blood flow.5 our patient developed limited peripheral anterior synechiae (pas) probably secondary to undetected fine angle neovascularisation, but the angles remained open. during subsequent followup visits, our patient was found to have high intraocular pressure ou with optic nerve cupping due to uncontrolled open angle glaucoma probably not directly related to ois. posterior segment signs in ois include attenuated retinal arteries; dilated but not tortuous retinal veins; mid-peripheral and posterior pole dot and blot retinal haemorrhages; microaneurysms; macular oedema; cherry red spots; cotton wool spots; anterior ischaemic optic neuropathy; neovascularisation of the disc or less commonly of the retina, and vitreous haemorrhage.5 our patient had attenuated retinal arteries and pale optic discs, possibly due to anterior ischaemic optic neuropathy. this latter sign is seen in up to 18% of eyes affected by ois.5 anterior ischaemic optic neuropathy can result from chronic iop elevation in the presence of compromised ocular perfusion.10 diagnosis of ois is made based on high clinical suspicion and confirmed by ancillary tests including ffa, indocyanine green angiography (icg), electroretinograghy, carotid system studies. ffa is useful in ois not only for diagnosis but also for planning treatment. if it reveals significant retinal ischaemia with the presence of retinal neovascularisation, then panretinal photocoagulation (prp) laser treatment is indicated.10 the most specific angiographic sign in ois is delayed or patchy choroidal filling, which is found in 60% of cases. a highly sensitive sign is prolonged retinal arteriovenous time (95%).5 other angiographic signs are prolonged retinal circulation time, staining of retinal vessels (85%), welldemarcated fluoresce in the dye edge, and retinal capillary non-perfusion.5 computed tomography (ct) angiography and mri angiography have gradually replaced the digital subtraction angiography (dsa) method for studying carotid occlusive disease with high sensitivity and specificity reaching 97% and 99%, respectively.5 icg typically shows prolonged choroidal filling.5 moreover, electroretinograghy in ois will typically show a decrease in the amplitude of both aand b-waves reflecting ischaemia of both the outer and inner retinas.5,6 the aim of ois treatment is to control anterior segment inflammation, ablate retinal ischaemia with prp, and control neovascular glaucoma.5,10 anterior segment inflammation is treated with regular topical steroids and long-acting cycloplegic agents to stabilise the blood-aqueous barrier. our patient had no anterior segment inflammation. prp is generally recommended in cases of established retina ischaemia with presence of iris or angle neovascularisation.10 prp can result in regression of anterior segment neovascularisation in only 36% of eyes.12 there is no role for prp if no retinal ischaemia is found with anterior segment neovascularisation as the latter may result from uveal ischaemia alone.13 our patient did not develop iris or angle neovascularisation; therefore, prp was not required. intravitreal injection of antivascular endothelial growth factor and steroids have been used in some eyes with ois with nvi or macular oedema which resulted in reasonable regression of neovascularisation and improvement in macular oedema but no change in visual acuity.5,14 in eyes with useful vision or that have potential for visual recovery and uncontrolled iop, trabeculectomy with antimetabolites, or aqueous shunt implants may be indicated. in painful blind eyes, cycloablation or even enucleation or evisceration are considered.10 the management of ois requires a multidisciplinary approach to assess and optimise treatment of underlying systemic conditions. the 5-year mortality rate in ois is around 40%, mostly due to cardiac disease.10 risk of stroke is also significantly increased (4% per year in patients with ois as compared to 0.49% per year in the control group).5 carotid artery surgery, either endarterectomy or bypass surgery, may relieve ois and also reduce the risk of stroke.10 surgery has to be considered in cases of carotid artery stenosis and occlusion with atherosclerosis. in cases of carotid artery thrombosis, thrombolytic therapy may be considered along with bilateral ocular ischaemic syndrome—rare complication of rhinocerebral mucormycosis in an omani patient case report and literature review 142 | squ medical journal, february 2013, volume 13, issue 1 treatment of the underlying cause. gelston et al. and simmons et al. reported successful treatment of a diabetic child with rhino-orbital mucormycosis with orbital compromise and evidence of ipsilateral carotid artery and cavernous sinus thrombosis. the child was treated with systemic posaconazole, amphotericin b, granulocyte colony-stimulating factor, interferon gamma, and low-molecular weight heparin. she showed clinical improvement with partial recovery of her vision.2,4 conclusion we presented a case of bilateral ois which is one of the rare ocular complications of rhinocerebral mucormycosis. ois has variable clinical presentations and can be masked by other ocular vascular conditions; therefore, it is probably underdiagnosed. various ocular tests and carotid system studies are useful in diagnosis and planning treatment. the mainstay of treatment is iop control, prp if indicated, and medical treatment of underlying conditions. references 1. hosseini s, borghei p. rhinocerebral mucormycosis: pathways of spread. eur arch otorhinolaryngol 2005; 262:932–83. 2. simmons j, zeitler p, fenton l, abzug m, fialloscharer r, klingensmith g. rhinocerebral mucormycosis complicated by internal carotid artery thrombosis in a pediatric patient with type 1 diabetes mellitus: a case report and review of the literature. pediatr diabetes 2005; 6:234–8. 3. sundaram c. rhinocerebral zygomycosis—a clinicopathological study. neurol india 1998; 46:126–9. 4. gelston c, durairaj v, simoes e. rhino-orbital mucormycosis causing cavernous and internal carotid thrombosis treated with posaconazole: case report. arch ophthalmol 2007; 125:848–9. 5. mendrinos e, machinis t, pournaras c. ocular ischemic syndrome: major review. surv ophthalmol 2010; 55:1. 6. de graeve c, van de sompel w, claes c. ocular ischemic syndrome: two case reports of bilateral involvement. bull soc belge ophthalmol 1999; 273:69–74. 7. imrie fr, hammer hm, jay jl. bilateral ocular ischemic syndrome in association with hyperhomocysteinaemia: case report. eye 2002; 16:497–500. 8. koz o, ates a, alp m, gultan e, karaasaln y, kural g. bilateral ocular ischemic syndrome as an initial manifestation of takayasu’s arteritis associated with carotid steal syndrome: case report. rheumatol internat clin experiment investig 2006; 27:299–302. 9. hwang j, girkin ca, perry jd, lai jc, miller nr, hellmann db. bilateral ocular ischemic syndrome secondary to giant cell arteritis progressing despite corticosteroid treatment. am j ophthalmol 1999; 127:102–4. 10. malhotra r. management of ocular ischemic syndrome: perspective. br j ophthalmol 2000; 84:1428– 31. 11. cohen r, padilla j, light d, diller r. carotid artery occlusive disease and ocular manifestations: importance of identifying patients at risk. optometry 2010; 81:359–63. 12. sivalingam a, brown gc, magargal le. the ocular ischemic syndrome, iii. visual prognosis and the effect of treatment. int ophthalmol 1991; 15:15–20. 13. hayreh ss, baines ja. occlusion of the vortex veins. an experimental study. br j ophthalmol 1973; 57:217–38. 14. luis a, javier m, manuel dl, jose sp, sophie jb, paula p, et al. intravitreal bevacizumab (avastin) injection in ocular ischemic syndrome. am j ophthalmol 2007; 144:122–4. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. e330-333, epub. 9th may 13 submitted 13th sep 12 revision. 11th nov 12, revision recd. 16th nov 12 accepted 12th dec 12 departments of 1surgery and 2pathology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drkhalidmunirbhatti@yahoo.com أورام شوان اللفائفّية غري املصحوبة بأعراض تعرض كورم مساريقي تقرير حالة ومراجعة األدبيات �شاهزاد يونا�ض خان، خالد منري بهاتي، �رسيدهاران كوليدان امللخ�ص: ورم �شوان اللفائفي هو ورم حميد ين�شاأ من خاليا �شوان يف اجلهاز الع�شبي املركزي اأو الطريف. املواقع الأكرث�شيوعا ت�شمل الراأ�ض والأطراف. من النادر اأن ين�شاأ هذا الورم من ال�شفرية الع�شبية للقناة اله�شمية. ومن الأندر اأن يكون موقع املن�شاأ هو دقاق الأمعاء الدقيقة. نقدم يف هذا التقرير حالة مري�ض لديه كتلة مركزية يف البطن كان قد مت ت�شخي�شها قبل اجلراحة كورم م�شاريقي. ومع ذلك، اأثبت ت�شخي�ض الِكيْمياُء الن�شيجية امَلناِعَيّة للعينة امل�شتاأ�شلة جراحيا باأن الورم هو ورم �شوان اللفائفي. مفتاح الكلمات: خاليا �شوان؛ حالت �شاذة؛ ورم غمد الليف الع�شبي؛ كي�ض م�شاريقي؛ الأورام اللفائفية؛ البطن تقرير حالة؛ عمان. abstract: a schwannoma is a benign tumour which arises from the schwann cells of the central or peripheral nervous system. common sites include the head and limbs; it is rare that this tumour arises from the gastrointestinal tract’s neural plexus. it is even rarer to find the ileum as the site of origin. we report a patient who presented with a central abdominal mass which was preoperatively diagnosed as a mesenteric tumour. however, immunohistochemistry of the surgically-removed specimen proved it to be a benign ileal schwannoma. keywords: schwann cells, abnormalities; neurilemmoma; mesenteric cyst; ileal neoplasms; abdomen; case report; oman. asymptomatic ileal schwannoma presenting as a mesenteric tumour case report and review of literature shahzad y. khan,1 *khalid m. bhatti,1 sreedharan v. koliyadan,1 marwa al riyami2 online case report a schwannoma is usually a benign, encapsulated neoplasm which arises from the schwann cells of the peripheral, autonomic or cranial nerves. the most common site for presentation is the 8th cranial nerve.1 schwannomas of the gastrointestinal (gi) tract are rare; even if present within the abdomen, the most common site is the stomach.2 only a few cases of benign ileal schwannomma have been reported in the literature.3–14 we report a case of ileal schwannoma where the patient presented with an abdominal mass and discomfort. case report a 37-year-old male presented with an abdominal mass which had arisen the previous week. there were no obstructive or other associated symptoms. his past medical and surgical history included a laparoscopic hernia repair 7 years previously; his family history was unremarkable. an abdominal examination revealed an 18 x 16 cm non-tender mass in the umbilical region, firm in consistency and dull on percussion, with no visceromegaly or ascites. the external genitalia, per rectal examination and the rest of the systemic examination were normal. a mesenteric or a retroperitoneal tumour was considered clinically as the initial diagnosis. the patient’s haemoglobin level was 14.4 g/ dl. he had a normal coagulation profile and a total leukocyte count. his blood sugar level was 4.5 mmol/l, blood urea was 3.1 mmol/l, serum creatinine was 79 µmol/l and his liver function tests were normal (alt [alanine aminotransferase] 48 iu/l, ast [aspartate aminotransferase] 24 u/l, total bilirubin 4 µmol/l). an ultrasound scan showed a large heterogeneous mass of unidentified origin with internal vascularity. a computed tomography (ct) scan of the abdomen with intravenous and oral contrast showed a mesenteric shahzad y. khan,khalid m. bhatti, sreedharan v. koliyadan and marwa al riyami case report | 331 mass of 15 x 14 x 11 cm, with faint enhancement, and central necrosis with no calcification [figure 1]. the mass was abutting the ascending colon and the hepatic flexure. there was no vascular enhancement or lymph node involvement. an ultrasound-guided true-cut biopsy was performed and showed a lowgrade spindle cell lesion suggestive of fibromatosis, myofibromatosis, a solitary fibrous tumour or a benign nerve sheath tumour. exploratory laparotomy findings revealed a well-encapsulated 2 kg tumour in the mesentery of the ileum, with an adherent ileocaecal junction and the appendix stretched over the tumour [figure 2]. no retroperitoneal infiltration or mesenteric lymph adenopathy was seen. the liver, spleen and the rest of the viscera were normal. a resection of the tumour, along with a limited right hemicolectomy and an end-to-end ileocolic anastomosis, were performed. his recovery was uneventful. histopathological examination showed a segment of the small bowel with an un-encapsulated neoplasm present within the muscularis propria of the ileum, and extending outwards into the serosa. the neoplasm was composed of bland spindle cells with tapered elongated nuclei, and a scattering of plumper nuclei with pale chromatin and small distinct nucleoli [figure 3]. immunohistochemical markers showed a diffuse positivity of s-100, with variable intensity, ranging from moderate to focally strong, highlighting the areas of neural differentiation. the cells were also strongly positive for neurospecific enolase (nse). the diffuse positivity of s-100 favoured the diagnosis of schwannoma. the recovery of the patient was uneventful, and he was discharged on the 7th postoperative day. the one year follow-up showed no recurrence. discussion ileal schwannomas usually present with abdominal pain,11 but may also present with other complications; melena,9,11 degeneration,4,6 and intussusception5,10,13 having also been reported [table 1]. this case presented with an abdominal mass without obstructive symptoms. a review of the limited available literature showed that it was the first case to present asymptomatically. a preoperative diagnosis is quite difficult.11 an ultrasound (us) may show a mass of variable echogenicity. there is no consensus on the ct findings of ileal schwannomas, as, in reported cases, ct was non-diagnostic and showed only a mass.11 magnetic resonance imaging (mri), as reported by nagi,11 may show a submucosal tumour; however, the findings were again nonspecific. in cases figure 1 a&b: computerised tomography scans, from the axial (a) and coronal (b) view, of the mass in the ileocaecal region without obstruction. figure 2: the mass in the ileocaecal region. figure 3: the top images show an unencapsulated spindle cell neoplasm involving the muscularis propria of the bowel wall (arrow). under high magnification, it is formed of fascicles of bland spindle cells. the tumour cells are positive for s-100 (lower left image) with darker staining nerve bundles highlighted. neurospecific enolase is also positive (lower right image). asymptomatic ileal schwannoma presenting as a mesenteric tumour case report and review of literature 332 | squ medical journal, may 2013, volume 13, issue 2 presenting with melena blood, a scintigraphy11 or angiography may be of help. in these cases, upper or lower gi endoscopies may rule out other causes of gi haemorrhage. in the present case, an usguided biopsy was supposed to assist in making a decision; however, the results were inconclusive. nevertheless, an us-guided biopsy may rule out lymphomas, in which case surgery could be avoided. spilling, a rupture of the mass, or seeding of the malignant tumour are a few of the theoretical risks associated with a us-guided biopsy of any intraabdominal mass. the preoperative differentiation between a benign or malignant schwannoma by a flourodeoxyglucose positron emission tomography (fdg-pet) scan15 has been proposed by some authors, but its application in diagnosing an ileal schwannoma has not yet been established. the gold standard is a histopathological examination of the surgically-removed specimen. with electron microscopy, spindle-shaped cells are characteristic, with areas of hyperand pauci-cellularity). immunohistochemistry confirms a schwannoma if the staining for s-100 protein is positive. the mainstay of treatment is a surgical resection and an end-to-end anastomosis. the extent of the resection will depend upon the location of the tumour. if, after the ileal resection, a sufficient length of the dista ileum is available for ileo-ileal anastomosis, continuity should be restored by anastomosing the two ends. in our case, location was so distal in the ileum that we had to proceed with a limited right hemicolectomy. histopathological analysis has a major role in the further management of such cases. in cases of benign ileal schwannomas, no recurrence has yet been reported;11 however, lifelong surveillance will be required in cases of malignant ileal schwannomas. conclusion the ileal schwannoma is a rare entity with variable presentation, and arriving at a preoperative diagnosis is usually challenging. in cases presenting without complication, a resection and an anastomosis of the ileal is the treatment of choice. references 1. darrouzet v, martel j, enée v, bébéar jp, guérin j. vestibular schwannoma surgery outcomes: our multidisciplinary experience in 400 cases over 17 years. laryngoscope 2004; 114:681–8. table 1: a review of the literature on schwannomas name of study year of publication origin of study no. of cases reported/reviewed presentation cornette de st-cyr m, et al.** 1958 france 1 poulat r, et al.** 1963 france 1 degeneration intraperitoneal bleeding maison e.** 1969 france 1 ileo-ileal invagination filimon c, et al.** 1974 romania 1 degeneration ilieve h.** 1977 croatia 1 gourtsoyiannis nc, et al.* 1993 greece 1 jadhav rn, et al.* 1996 mumbai (india) 1 bleeding per rectum insegno w, et al. 1996 genova 1 intussception in pregnancy nagal t, et al. 2003 beppu (japan) 5 adbominal pain = 3 melena = 2 rangiah ds, et al.* 2004 australia 1 hirasaki s, et al. 2008 japan 1 ileocolic intussception târcoveanu e, et al.* 2011 romania 1 * = abstract only; ** = no abstract. shahzad y. khan,khalid m. bhatti, sreedharan v. koliyadan and marwa al riyami case report | 333 2. voltaggio l, murray r, lasota j, miettinen m. gastric schwannoma: a clinicopathologic study of 51 cases and critical review of the literature. hum pathol 2012; 43:650–9. 3. cornette de st-cyr m, callens c. enormous abdominal tumor having as starting point the termination of the ileum (neurinoma). maroc med 1958; 37:1034–5. 4. poulat r, grandmottet p. intraperitoneal hemorrhage caused by rupture of a degenerated schwannoma of the ileum. resection, recovery. arch mal appar dig mal nutr 1963; 52:359–61. 5. maison e. schwannoma of the small intestine and ileo-ileal invagination. sem hop 1969; 45:1210–11. 6. filimon c, vanţă m. degenerated schwannoma of the ileum. chirurgia (bucur) 1974; 23:37–41. 7. iliev h. neurinoma of the small intestine. acta chir iugosl 1977; 24:297–302. 8. gourtsoyiannis nc, bays d, papaioannou n, theotokas j, barouxis g, karabelas t. benign tumors of the small intestine: preoperative evaluation with a barium infusion technique. eur j radiol 1993; 16:115–25. 9. jadhav rn, bapat rd, rohondia os, joshi as, bhatt p. bleeding ileal schwannoma. indian j gastroenterol 1996; 15:149. 10. insegno w, fiorone e, castrati g, turtulici g, palladino m. intestinal intussusception in pregnancy with obstruction, caused by benign neurilemmoma. role of abdominal echocardiography in the preoperative diagnosis. minerva ginecol 1996; 48:505–9. 11. nagai t, fujiyoshi k, takahashi k, torishima r, nakashima h, uchida am, et al. ileal schwannoma in which blood loss scintigraphy was useful for diagnosis. intern med 2003; 42:1178–82. 12. rangiah ds, cox m, richardson m, tompsett e, crawford m. small bowel tumours: a 10 year experience in four sydney teaching hospitals. anz j surg 2004; 74:788–92. 13. hirasaki s, kanzaki h, fujita k, suzuki s, kobayashi k, suzuki h, et al. schwannoma developing into ileocolic intussusception. world j gastroenterol 2008; 14:638–40. 14. târcoveanu e, georgescu s, vasilescu a, dănilă n, lupaşcu c, dimofte g, et al. small bowel tumours from barium meal to capsule endoscopy and from open to laparoscopic approach. chirurgia 2011; 106:451–64. 15. beaulieu s, rubin b, djang d, conrad e, turcotte e, janet f. early positron emission tomography of schwannomas: emphasizing its potential in preoperative planning. ajr 2004; 182:971–4. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e397-400, epub. 24th jul 14 submitted 20th oct 13 revision req. 16th dec 13; revision recd. 19th jan 14 accepted 6th feb 14 tyrosine hydroxylase (th) deficiency is a rare autosomal recessive neurometabolic disorder with variable phenotypes. it is almost exclusively caused by missense mutations in the th gene and its promoter region on chromosome 11p15.5. in 1971, castaigne et al. was the first to report this condition in two brothers.1 since then, it has been reported in 50 patients from 41 families worldwide.2 the only reported cases of th deficiency in the arab world were from lebanon; the onset of hypokinaesia, rigidity and dystonia was observed in patients under 12 months old. in these cases, all the patients showed a good clinical response to therapy with levodopa (l-dopa).3,4 this case is the first instance of th deficiency among the middle eastern population in an infant carrying a novel mutation in the th gene. the patient subsequently demonstrated an excellent response to treatment with l-dopa. informed consent was obtained from the patient’s parents for all tests and written consent was obtained for the publication of this case report. case report a 10-month-old boy was referred to the department of clinical neurosciences at salmaniya medical complex in manama, bahrain, with a three-month history of global developmental delay and excessive sleepiness. the mother’s pregnancy had been uneventful. he was born at term with a birth weight of 3.4 kg (within the 25th percentile), a head circumference of 34 cm (within the 10th percentile) and a length of 50 cm (within the 25th percentile). his apgar scores were 8 and 9 at one and five min, respectively. the postnatal period was uneventful. the patient was the first child of healthy consanguineous parents. there was no family history of neurological disorders. a visual examination of the patient showed an alert infant who was able to fix, follow and smile responsively. he showed reduced facial expression but no ptosis. full extra-ocular movements, normal saccades and no signs of nystagmus were observed. his optic fundi were normal. the patient had occasional episodes of uprolling of the eyes with head extension. department of clinical neurosciences, salmaniya medical complex, manama, bahrain *corresponding author e-mail: aalmuslamani@gmail.com منط جيين جديد للتريوسني هيدروكسيليز مع خلل حركي فموي وجهي عهود امل�سلماين، فوؤاد علي، فاطمة حممود abstract: tyrosine hydroxylase (th) deficiency is a rare autosomal recessive and often treatable neurometabolic disorder with variable phenotypes. more than 20 pathological mutations have been identified in patients with th deficiency. we report the case of a 10-month-old male patient who presented with developmental delay, hypotonia and oculogyric crises to the salmaniya medical complex in manama, bahrain. at a later stage, he developed orofacial dyskinaesia and tremors with hyper-reflexia and clonus. a magnetic resonance imaging scan of the brain showed mild atrophy with widened ventricles and genetic testing revealed a novel homozygous mutation (c.938g>t; p.arg313leu) in exon 9 of the th gene. the patient showed a remarkable response to treatment using combined levodopa-carbidopa. in this case, the orofacial dyskinaesia may be a specific clinical association unique to this novel mutation, which is the first to be described in bahrain and the middle east. keywords: tyrosine hydroxylase; dopa-responsive dystonia; case report; bahrain. مت ومتعددة متغرية �رسيرية ظواهر وله عالجه، ميكن ما غالبا" نادر، وراثي ع�سبي ا�ستقالبي اعتالل هو هايدروك�سيليز التايرو�سني نق�س امللخ�ص: اكت�ساف اأكرث من 20 طفرة وراثية مر�سية منوطة بهذه احلالت. يف هذا التقرير نناق�س حالة مري�س قدم اإلينا يف �سن الع�رسة �سهور باأعرا�س �سملت تاأخر يف النمو، رخاوة يف توتر الع�سالت مع اأزمات �سخو�س الب�رس. بعد ذلك، ظهرت عليه اأعرا�س احلركات الالإرادية يف الفم والوجه مع اهتزازات و فرط يف املنعك�سات الع�سبية. اأظهر ت�سوير الرنني املغناطي�سي للدماغ �سمور خفيف مع ات�ساع يف البطينني، و ك�سفت الختبارات اجلينية عن وجود طفرة جينية ملحوظة ا�ستجابة املري�س ا�ستجاب هايدروك�سايليز. التايرو�سني جني على ٩ اأك�سون يف )c.938g>t;p.arg313leu( متماثل تغري مع جديدة للعالج املركب بعقاري ال ل-دوبا/ الكاربي دوبا. يف هذه احلالة ،حدث عر�س اخللل احلركي الفموي الوجهي والذي قد يكون موؤ�رسا فريدا من نوعه لهذا التحوراجليني اجلديد، و تعترب هذه احلالة الأوىل من نوعها يف البحرين وال�رسق الأو�سط. مفتاح الكلمات: التايرو�سني هايدروك�سايليز؛ اخللل التوتري امل�ستجيب للدوبا؛ تقرير حالة؛ البحرين. a new tyrosine hydroxylase genotype with orofacial dyskinaesia *ahood m. al-muslamani, fouad ali, fatima mahmood case report a new tyrosine hydroxylase genotype with orofacial dyskinaesia e398 | squ medical journal, august 2014, volume 14, issue 3 this occurred without a change in his sensorium, which is consistent with oculogyric crises. he was able to lift his head to 45 degrees while lying in a prone position. he had increased muscle tone in his four limbs, generally with brisk, deep tendon reflexes. the remainder of the examination was unremarkable. laboratory investigations showed normal serum amino acids, tandem mass spectrometry, urine organic acids, lysosomal enzymes and very long chain fatty acids. renal, bone and liver function tests were also performed. computed tomography (ct) and magnetic resonance imaging (mri) scans showed signs of mild brain atrophy. an electroencephalogram (eeg) revealed intermittent bursts of sharp waves over the frontal regions. in spite of ongoing rehabilitation therapy, the patient continued to regress; he became more hypotonic and developed tremors with clonus in both ankles. his speech and cognition progressed slowly. a physical examination at one-and-a-half years of age revealed prominent orofacial dyskinaesia with drooling and, accordingly, he was started on a trial of combined l-dopa-carbidopa. after three months of treatment, the muscle tone in his limbs improved and he began to walk with support. he also began to put words together to form short sentences. by the age of two, he was walking independently. dopa-responsive dystonia (drd) was suspected clinically and this was subsequently confirmed by genetic analysis. genomic deoxyribonucleic acid (dna) from the patient and the mother was amplified for the gene encoding th (national center for biotechnology information reference sequence nm_199292.2) by means of a polymerase chain reaction (pcr). a pcr was performed using the amplitaq gold® 360 master mix (applied biosystems®, thermo fisher scientific inc., carlsbad, california, usa) as described by the manufacturer. forward and reverse primers are available in table 1. the fragments that were obtained, including the individual exons, the splice donor site, and the splice acceptor site, were subjected to double-stranded dna sequencing analysis on a 3730xl dna analyzer (applied biosystems®). the sequence analysis was performed using sequencher dna sequencing software,version 4.8 (gene codes corp., ann arbor, michigan, usa) and seqpilot version 3.2.1.0 (jsi medical systems gmbh, kippenheim, germany) software. the sequence analysis primers are recorded in table 2. the sequence analysis identified a homozygous mutation, c.938g>t (p.arg313leu), in exon 9 of the th gene in the proband; the patient’s mother was heterozygous [figures 1 a, b & c]. this change was predicted to be possibly pathogenic by the mutation prediction software, the sorting intolerant from tolerant (sift) tool version 1.03 (j. craig venter institute, rockville, maryland, usa). a substitution at position 313 from r to l was predicted to affect the protein function with a score of 0.01. the polyphen-2 mutation prediction software polyphen-2 showed that this amino acid change is probably damaging, giving a score of 0.987 (sensitivity 0.73, specificity table 1: forward and reverse primers for amplifying the coding exons of the tyrosine hydroxylase gene exon forward primer (5'→3') reverse primer (5'→3') 1 tgtaaaacgacggccagttggggagtgaaggcaattag caggaaacagctatgaccccaacagggactcaaacacc 2 tgtaaaacgacggccagtcttgggcactcagaaccttg caggaaacagctatgacccagcttcatcctgagcttcca 3 tgtaaaacgacggccagtctcaaaaacgtgctctcatcc caggaaacagctatgaccagctgaggcctgagactcc 4 tgtaaaacgacggccagtaagaacgggatctgtgtgct caggaaacagctatgaccctcccctacaagacttccgg 5 tgtaaaacgacggccagttgcttcaaggtgggtgacaca caggaaacagctatgaccggctaagggtaggggatgtg 6 tgtaaaacgacggccagtctgcccctgatcacatcc caggaaacagctatgacctggtgacaagatgggtcctc 7 tgtaaaacgacggccagtcttgtcaccagcatcagtgc caggaaacagctatgacccctgcaagtccctcttcttc 8 tgtaaaacgacggccagtctaaagccaccagcaaaagc caggaaacagctatgacctactgggtgcactggaacac 9 + 10 tgtaaaacgacggccagtgctaccgggaagacaatatcc caggaaacagctatgaccagcaggcagcacacttcac 11 + 12 tgtaaaacgacggccagtcttctcccaaacagagcctga caggaaacagctatgacccctggaggggctgctgaca 13 tgtaaaacgacggccagtcttgtctctgcccagtcctc caggaaacagctatgaccctcaaggccagaaggaagg 14 tgtaaaacgacggccagtaccagttggctcagaaaagc caggaaacagctatgaccaggacaggacctcaccacag table 2: sequence analysis primer primer m13_forward tgtaaaacgacggccagt m13_reverse caggaaacagctatgacc ahood m. al-muslamani, fouad ali and fatima mahmood case report | e399 0.96). the testing score of the align-gvgd program (international agency for research on cancer, lyon, france) was c35; this score lies midway in the spectrum of output prediction classes (c0, c15, c25, c35, c45, c55, c65), with c65 being the most likely to interfere with function and c0 being the least likely. this mutation has not been reported in the single nucleotide polymorphism database, the exome variant server or the human gene mutation database. at a later stage, the father was also screened and found to be a carrier of this novel mutation. discussion drd is largely caused by autosomal dominant mutations in the gtp cyclohydrolase1 (gch1) gene and, more rarely, by autosomal recessive mutations in the th or sepiapterin reductase (spr) genes.5 it was considered unlikely that the current patient had drd caused by mutations in the gch1 gene, as drd is an autosomal dominant disorder that presents in childhood at around six years of age.6–8 the current patient presented in infancy with delayed development and hypotonia that later became more pronounced. he developed fine tremors with orofacial dyskinaesia in the second year of life which alerted the treating physicians to the more common diagnosis of th deficiency. th-deficient drd may present as pure dystonia or as a dystonia-plus syndrome, featuring oculogyric crises, mental retardation, parkinsonism and other clinical features.9 th deficiency has been divided into two phenotypes. the first is a progressive, hypokineticrigid syndrome with dystonia and an infantile onset, known as type a, and the second is a complex encephalopathy with a neonatal/early infancy onset, known as type b.2 generally, there is an overlap of clinical features between the two types and a variable response to treatment with l-dopa.10 the patient’s presentation, clinical course and response to combined l-dopa-carbidopa was in keeping with a diagnosis of th-deficient drd type a.2 hypokinaesia, bradykinaesia and rigidity have typically dominated the neurological presentation in reported cases with dystonia often being less prominent,2 as was the case for the current patient. however, other features, including ataxia, chorea, ptosis and symptoms of dysautonomia, were absent. the cognitive function of patients is reported to be improved in those who develop symptoms after their first year of life.2 in addition, tremors and oculogyric crises are reported to be mild and rare.11–13 oculogyric crises are present in cases of th-deficient drd type b and in the other drd-plus syndromes caused by mutations in the spr gene.5 excessive sleepiness has been described in patients with th-deficient drd types a and b as well as in individuals with spr gene mutations.2,14 dyskinaesia, on the other hand, has been reported mainly in th-deficient drd type b cases and is usually severe and unresponsive to treatment.2 there has been no mention in the literature of orofacial dyskinaesia in patients with th-deficient drd type a. dyskinaesias are generally reported as l-dopainduced side-effects when the dosage is increased rapidly or the drug is prescribed for long periods. therefore, the presence of orofacial dyskinaesia in this case, prior to the patient’s l-dopa treatment, may represent a mutation-specific phenotype that has not been described previously. the differential diagnosis for psychomotor regression and dystonia includes early onset primary dystonia, early onset parkinsonism and various other genetic and acquired disorders. the patient did not undergo a lumbar puncture to assess the major metabolites of dopamine or homovanillic acid (hva). in addition, tests for the urine pterins concentration and the dihydropteridine reductase activity in the blood were not performed. while these investigations help support the diagnosis of th deficiency, they are not diagnostic. although the current patient had a mild form of th deficiency, brain imaging revealed mild brain atrophy figure 1 panel a, b & c: sequence profiles showing the c.938g>t mutation in exon 9 of the tyrosine hydroxylase (th) gene. panel a shows the normal genomic sequence, while panels b and c show the electropherograms corresponding to the genomic sequence of the proband and his mother, respectively. the vertical arrows point to the normal guanine nucleotide (a) and the variant thiamine nucleotide which was homozygous for the proband (b) and heterozygous for the mother (c). a new tyrosine hydroxylase genotype with orofacial dyskinaesia e400 | squ medical journal, august 2014, volume 14, issue 3 with prominent cerebrospinal fluid spaces throughout the ventricular system. similarly, a previous case report observed cerebral and cerebellar atrophy in an individual severely affected by th deficiency.15 more than 20 pathological mutations (including a point mutation in the th gene promoter region) have been reported in patients with th deficiency. all of these individuals have been homozygous or compound heterozygous for th gene mutations. most mutations have been single nucleotide substitutions, the most common of which are c.698g>a (p.arg233his) and c.707t>c (p.leu236pro).3,4,12,15–20 single nucleotide deletions, resulting in frameshift mutations and protein truncation, have also been reported.18–20 mutations in the highly conserved cyclic adenosine monophosphate (camp) response element, within the th gene promoter region, have been found in six families with th deficiency.3,15 both parents of the patient in this case report were found to be carriers of this mutation. they were subsequently offered genetic counselling to explain the ramifications of this genetic disorder. conclusion orofacial dyskinaesia is an uncommon presentation, especially for the hypokinetic-rigid syndrome of th deficiency. it may be specific to the novel homozygous mutation (c.938g>t; p.arg313leu) in exon 9 of the th gene; this mutation is potentially unique to the middle eastern population. a c k n o w l e d g e m e n t s the authors wish to thank professor joe mcmenamin, from the royal college of surgeons in ireland-medical university of bahrain for his support and advice and the bioscientia institut für medizinische diagnostik (ingelheim am rhein, germany) for performing the genetic test. references 1. castaigne p, rondot p, ribadeau-dumas jl, saïd g. [progressive extra-pyramidal disorder in 2 young brothers: remarkable effects of treatment with l-dopa]. rev neurol (paris) 1971; 124:162‒6. 2. willemsen ma, verbeek mm, kamsteeg ej, de rijk-van andel jf, aeby a, blau n, et al. tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. brain 2010; 133:1810‒22. doi: 10.1093/brain/awq087. 3. verbeek mm, steenbergen-spanjers gc, willemsen ma, hol fa, smeitink j, seeger j, et al. mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. ann neurol 2007; 62:422–6. doi: 10.1002/ana.21199. 4. grattan-smith pj, wevers ra, steenbergen-spanjers gc, fung vs, earl j, wilcken b. tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy. mov disord 2002; 17:354‒9. doi: 10.1002/mds.10095. 5. clot f, grabli d, cazeneuve c, roze e, castelnau p, chabrol b, et al. exhaustive analysis of bh4 and dopamine biosynthesis genes in patients with dopa-responsive dystonia. brain 2009; 132:1753–63. doi: 10.1093/brain/awp084. 6. nygaard tg, snow bj, fahn s, calne db. dopa-responsive dystonia: clinical characteristics and definition. in: segawa m, ed. hereditary progressive dystonia with marked diurnal fluctuation. new york, usa: parthenon publishing, 1993. pp. 21‒35. 7. segawa m, nomura y. hereditary progressive dystonia with marked diurnal fluctuation. in: segawa m, ed. hereditary progressive dystonia with marked diurnal fluctuation. new york, usa: parthenon publishing, 1993. pp. 3‒19. 8. furukawa y, guttman m, kish sj. dopa-responsive dystonia. in: frucht sj, fahn s, eds. movement disorder emergencies: diagnosis and treatment. totowa, new jersey, usa: humana press, 2005. pp. 209‒29. 9. casper c, kalliolia e, warner tt. recent advances in the molecular pathogenesis of dystonia-plus syndromes and heredodegenerative dystonias. curr neuropharmacol 2013; 11:30‒40. doi: 10.2174/157015913804999432. 10. brashear a, dobyns wb, de carvalho aguiar p, borg m, frijns cj, gollamudi s, et al. the phenotypic spectrum of rapid-onset dystonia-parkinsonism (rdp) and mutations in the atp1a3 gene. brain 2007; 130:828–35. doi: 10.1093/brain/awl340. 11. furukawa y. genetics and biochemistry of dopa-responsive dystonia: significance of striatal tyrosine hydroxylase protein loss. adv neurol 2003; 91:401–10. 12. hoffmann gf, assmann b, bräutigam c, dionisi-vici c, häussler m, de klerk jb, et al. tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia. ann neurol 2003; 54:56–65. doi: 10.1002/ana.10632. 13. furukawa y. update on dopa-responsive dystonia: locus heterogeneity and biochemical features. adv neurol 2004; 94:127–38. 14. leu-semenescu s, arnulf i, decaix c, moussa f, clot f, boniol c, et al. sleep and rhythm consequences of a genetically induced loss of serotonin. sleep 2010; 33:307–14. 15. ribasés m, serrano m, fernández-alvarez e, pahisa s, ormazabal a, garcía-cazorla a, et al. a homozygous tyrosine hydroxylase gene promoter mutation in a patient with doparesponsive encephalopathy: clinical, biochemical and genetic analysis. mol genet metab 2007; 92:274–7. doi: 10.1016/j. ymgme.2007.07.004. 16. lüdecke b, knappskog pm, clayton pt, surtees ra, clelland jd, heales sj, et al. recessively inherited l-dopa-responsive parkinsonism in infancy caused by a point mutation (l205p) in the tyrosine hydroxylase gene. hum mol genet1996; 5:1023–8. doi: 10.1093/hmg/5.7.1023. 17. wevers ra, de rijk-van andel jf, bräutigam c, geurtz b, van den heuvel lp, steenbergen-spanjers gc, et al. a review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delc). j inherit metab dis 1999; 22:364–73. doi: 10.1023/a:1005539803576. 18. de lonlay p, nassogne mc, van gennip ah, van cruchten ac, billatte de villemeur t, cretz m, et al. tyrosine hydroxylase deficiency unresponsive to l-dopa treatment with unusual clinical and biochemical presentation. j inherit metab dis 2000; 23:819–25. doi: 10.1023/a:1026760602577. 19. de rijk-van andel jf, gabreëls fj, geurtz b, steenbergenspanjers gc, van den heuvel lp, smeitink ja, et al. l-doparesponsive infantile hypokinetic rigid parkinsonism due to tyrosine hydroxylase deficiency. neurology 2000; 55:1926–8. doi: 10.1212/wnl.55.12.1926. 20. furukawa y, graf wd, wong h, shimadzu m, kish sj. doparesponsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (th) gene mutations. neurology 2001; 56:260–3. fournier’s gangrene (fg) is a life-threatening, necrotising, soft tissue infection which affects the perineum and the perianal and genital areas. the patient rapidly progresses to a debilitated state and may also have underlying systemic diseases such as diabetes mellitus (dm), uraemia, and immunodeficiency disorders. fg is commonest in men aged ≥60 years.1,2 early diagnosis and aggressive surgical debridement can save the patients’ lives. computed tomography (ct) can be used to determine the cause of fg and the tissues involved, but radiographic diagnosis is a more practical approach during initial evaluation, provided the film is carefully examined. a 56-yearold man with a history of dm was admitted to the emergency department of the mackay memorial hospital, taipei, taiwan. he had had nausea, dysuria, and progressive perianal and scrotal pain for 5 days. his vital signs at admission were as follows: body temperature, 36.5° c; pulse rate 87 beats/ min; respiratory rate 20/min; and blood pressure 105/67 mmhg. the scrotum appeared swollen and palpation indicated tenderness and crepitus. laboratory results showed leukocytosis with left sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 369-370, epub. 15th jul 12 submitted 30th oct 11 revision req. 18th feb 12, revision recd. 18th feb 12 accepted 29th feb 12 departments of 1emergency medicine and 4family medicine, mackay memorial hospital, taipei, taiwan; 2department of emergency medicine, taipei city hospital, zhongxing branch, taipei, taiwan; 3department of oral hygiene, college of oral medicine, taipei medical university, taipei, taiwan. *corresponding author e-mail: yjsu@ms1.mmh.org.tw كشف شعاعي لغرغرينة فورنييه يو هاجن يه، يوجاجن �سو، لو �سيه كوجن، يو�سياه �سني radiographic disclosure of fournier’s gangrene yu-hang yeh,1,2 *yu-jang su,1,3 lu-chih kung,1 yu-chia lin4 interesting medical image figure 1: radiography of the kidney, ureter, and bladder (kub) shows a mottled gas pattern in the subcutaneous tissue over the right scrotal area (white arrows). figure 2: computed tomography shows emphysema of the right side of the scrotum (white arrows). radiographic disclosure of fournier’s gangrene 370 | squ medical journal, august 2012, volume 12, issue 3 shift, and pyuria. radiography of the kidney, ureter, and bladder (kub) showed a mottled gas pattern in the subcutaneous tissues over the right scrotal area [figure 1, white arrows]. the ct scan showed emphysema of the right side of the scrotum [figure 2, white arrows]. broad-spectrum antibiotics (piperacillin/tazobactam 4.5 g) were administered every 8 hours. emergency surgical intervention, including debridement and local flap repair, were performed later by a proctologist, urologist, and plastic surgeon for a total of 5 surgeries. deep wound culture yielded peptostreptococcus species and bacteroides fragilis. the patient was discharged after 41 days. fg, which is one of the most important lifethreatening surgical emergencies, is a type of necrotising fasciitis that progresses rapidly, and involves the perineal, perianal, and genital regions3. fg is often clinically diagnosed. the disease occurs predominantly in men (96%), and dm was found in 80% of fg patients3. the leading origin sites of infection were the scrotum (52%) and the perineum (38%)3. both aerobic and anaerobic bacteria were found, and the most common pathogens were escherichia coli and enterococcus faecalis (48% and 28%, respectively).3 in 2007, a ten-year report from northern taiwan described the most common isolated pathogens involving fg as being e. coli, b. fragilis, klebsiella pneumoniae, enterococcus spp., and proteus mirabilis.4 compared with radiography and ultrasonography, ct plays a superior role in diagnosing fg and evaluating the extent of the disease.5 important ct findings include asymmetric fascial thickening, emphysema of the soft tissue, fluid collection, and abscess formation. broad-spectrum antibiotics and aggressive surgical debridement are essential for treatment. although early diagnosis of fg by radiography is a practical approach, ct is important for determining the extent of the disease. it is important that emergency physicians consider the possibility of fg among other genital infections if discoloured skin, bullalike lesions, emphysema, or swelling are noted. ct is imperative for prompt diagnosis of fg, and for effective planning of treatment. references 1. kabay s, yucel m, yaylak f, algin mc, hacioglu a, kabay b, et al. the clinical features of fournier's gangrene and the predictivity of the fournier's gangrene severity index on the outcomes. int urol nephrol 2008; 40:997–1004. 2. chen sy, fu jp, wang ch, lee tp, chen sg. fournier gangrene: a review of 41 patients and strategies for reconstruction. ann plast surg 2010; 64:765–9. 3. morua ag, lopez ja, garcia jd, montelongo rm, guerra ls. fournier's gangrene: our experience in 5 years, bibliographic review and assessment of the fournier’s gangrene severity index. arch esp urol 2009; 62:532–40. 4. kuo cf, wang ws, lee cm, liu cp, tseng hk. fournier's gangrene: ten-year experience in a medical center in northern taiwan. j microbiol immunol infect 2007; 40:500–6. 5. levenson rb, singh ak, novelline ra. fournier gangrene: role of imaging. radiographics 2008; 28:519–28. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e398–404, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.015. submitted 24 sept 14 revisions req. 24 nov 14 & 16 feb 15; revisions recd. 11 jan 15 & 4 mar 15 accepted 15 mar 15 department of 1public health, college of public health & informatics, university of hail, hail, saudi arabia; departments of 2community & environmental health and 3epidemiology & biostatistics, college of public health & health informatics, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia *corresponding author e-mail: bawazir56@hotmail.com املعتقدات الصحية للمراهقني يف اململكة العربية السعودية جتاه الوقاية من النوع الثاين لداء السكري رمي املطريي، اأمني باوزير، اأنور اأحمد، هدى اجلرادي abstract: objectives: the incidence of type 2 diabetes mellitus (t2dm) is growing rapidly in the saudi population. the purpose of this study was to assess the constructs of the health belief model (hbm) as they relate to t2dm lifestyle and prevention behaviours among adolescents. methods: a cross-sectional study was conducted between may and october 2013 among 426 non-diabetic secondary school students from randomly selected schools in riyadh, saudi arabia. an arabic version of an adapted english language questionnaire was used to assess knowledge and attitudes related to the severity and prevention of t2dm. a preventative behaviour assessment was also conducted to assess physical activity and dietary habits. results: the majority of the students (63.4%) had at least one diabetic family member. obesity was more frequent in males compared to females (p = 0.013). awareness about the importance of maintaining a healthy body weight to prevent t2dm was lower in males than females (p = 0.037), although males engaged in routine exercise more often (p = 0.001). males were less likely than females to recognise the risks for t2dm, including obesity (p = 0.030), heredity (p = 0.013) and high fat intake (p = 0.001). conclusion: an alarmingly high number of saudi students were unaware of t2dm severity and associated risk factors. female students were more aware of the benefits of t2dm preventative lifestyle behaviours than males, although males engaged in routine exercise more often. raising adolescents’ awareness about the primary prevention strategies for t2dm should be a public health priority in saudi arabia. the hbm could inform further research on diabetes prevention among saudi adolescents. keywords: adolescents; diabetes mellitus; knowledge; lifestyle risk reduction; saudi arabia. امللخ�ص: الهدف: اإن معدل الإ�سابة بالنوع الثاين من داء ال�سكري )t2dm( يف تزايد م�سطرد بني اأفراد املجتمع ال�سعودي تهدف هذه يف املراهقني بني ال�سكري داء من الثاين للنوع وقائي و�سلوك �سحي حياتي منط تبنى اجتاه ال�سحية املعتقدات قيا�س اإىل الدرا�سة اململكة العربية ال�سعودية با�ستخدام منوذج املعتقدات ال�سحية )hbm(. كما تهدف الدرا�سة إىل قيا�س التباين بني اجلن�سني يف املعلومات واملعتقدات ال�سحية للنوع الثاين من ال�سكري. الطريقة: اأجريت درا�سة م�ستعر�سة بني �سهري مايو إىل اأكتوبر 2013 �سملت 426 طالبا غري م�سابني بداء ال�سكري من مدار�س ثانوية مت اختيارها ع�سوائيا يف مدينة الريا�س باململكة العربية ال�سعودية. مت ا�ستخدام ا�ستبيان باللغة داء من الثاين النمط من بالوقاية ال�سلة ذات واملواقف املعارف لتقييم ا�ستخدامها مت حيث الإجنليزية الن�سخة من واملقتب�س العربية ال�سكري. كما �سمل ال�ستبيان بع�س اجلوانب اخلا�سة بتقييم �سلوك الفرد الوقائي من خالل تقييم الن�ساط البدين والعادات الغذائية. النتائج: اأظهرت الدرا�سة اأن %63.4 من الطالب لهم عالقة مب�ساب واحد بال�سكري على الأقل من اأفراد العائلة. وكانت ال�سمنة اأكرث تواترا عند الذكور مقارنة بالإناث )p = 0.013(. كما اأن الوعي حول اأهمية احلفاظ على وزن �سحي للج�سم للوقاية من النوع الثاين من داء ال�سكري اأقل يف الذكور عنه من الإناث )p = 0.037(، برغم قيامهم مبمار�سة الريا�سة ب�سكل روتيني اأكرث من الإناث )p = 0.001(. كما اأن الذكور اأقل اإدراكا )p = 0.013( والوراثة ،)p = 0.030( من الإناث اإىل التعرف على املخاطر التي تنجم عن النوع الثاين من داء ال�سكري، مبا يف ذلك ال�سمنة وارتفاع ن�سبة تناول الدهون )p = 0.001(. اخلال�صة: أن عددا كبريا من الطالب ال�سعوديني يجهل املعلومات الأ�سا�سية حول النوع الثاين من داء ال�سكري وعوامل اخلطر املرتبطة به بينما اأظهرت الطالبات اأنهن اأكرث وعيا بذلك وعلى اطالع بال�سلوكيات الفعالة يف منط احلياة ال�سحية وكيفية الوقائية منه.وعليه فاإن توعية املراهقني حول ا�سرتاتيجيات الوقاية الأولية من النوع الثاين من داء ال�سكري يجب اأن تكون من اأولويات ال�سحة العامة يف اململكة العربية ال�سعودية بالإ�سافة إىل اأهمية اإجراء درا�سات اأعمق بني املراهقني ال�سعوديني يف اجتاه الوقاية من مر�س ال�سكري. مفتاح الكلمات: املراهقني؛ داء ال�سكري؛ املعرفة؛ احلد من خماطر منط احلياة؛ اململكة العربية ال�سعودية. health beliefs related to diabetes mellitus prevention among adolescents in saudi arabia reem l. al-mutairi,1 *amen a. bawazir,2 anwar e. ahmed,3 hoda jradi2 clinical & basic research advances in knowledge the study demonstrated the effectiveness of using the health belief model in assessing knowledge and attitudes of diabetes among a sample of saudi adolescents. results of the study showed that a high percentage of saudi adolescents were unaware of the severity of type 2 diabetes mellitus (t2dm) and its associated risk factors. reem l. al-mutairi, amen a. bawazir, anwar e. ahmed and hoda jradi clinical and basic research | e399 type 2 diabetes mellitus (t2dm) is fast becoming a global epidemic and the number of individuals with diabetes in the world is expected to reach 330 million by 2030, with the majority residing in developing countries.1,2 the rate of t2dm is rapidly increasing in developing countries, particularly among younger age groups.1 in some countries in the middle east, t2dm contributes to one in four deaths of adults between 35–64 years old.2 although it is a debilitating and life-threatening disease with severe complications, t2dm can be prevented with lifestyle modifications.3 saudi arabia is a developing country with a young population (53% ≤24 years old).4 saudi adolescents are at a high risk of developing diabetes as many suffer from obesity, a sedentary lifestyle and hereditary diabetes.5 in 2004, almost a quarter (23.7%) of the saudi population was diagnosed with t2dm; this was 10 times the number of diabetic individuals in 1980.6 the occurrence of t2dm has been linked to the high rate of overweight adults (35.5%) in the saudi population and the number of overweight and obese saudi adolescents is high among both genders.7,8 a study of both obese and non-obese saudi women found that 75% did not exercise or did so infrequently.9 in saudi arabia, diabetic patients suffer from neuropathy (56%), neuroarthropathy requiring amputation (0.7%) or nephropathy requiring dialysis (30.4%).10–12 low levels of awareness of t2dm and its risk factors have been reported in saudi adults, with awareness varying significantly according to education level.13 the same study found that a low percentage of the saudi population believed that obesity (35.8%) and a lack of physical activity (32.3%) were risk factors for t2dm.13 mohieldein et al. found that almost 68.7% of the non-diabetic population in saudi arabia believed that t2dm was a curable disease.14 a cross-sectional study indicated that saudi adolescents exhibited more health-related knowledge than the older population; the majority of the adolescents believed that obesity was dangerous and that regular exercise was beneficial for their health.15 nevertheless, sedentary lifestyles and high obesity rates among saudi youth are still reported, placing them at a high risk of developing t2dm and raising the need for theoreticallygrounded interventions targeting this segment of the population.7,16,17 rather than a call for public health education programmes concerning t2dm risk factors, the above findings could be interpreted as a need among healthcare workers for knowledge of the psychosocial factors that affect engagement in preventative behaviours and avoidance of harmful actions. the health belief model (hbm) provides systematically defined variables that can be used to measure the impact of various psychosocial constructs upon a person’s willingness to engage in and maintain healthrelated behaviours.18 the model hypothesises that individuals will generally not seek preventative care or health screening unless they possess minimal levels of health-related motivation and knowledge; view themselves as potentially vulnerable and threatened by the condition; are convinced of the efficacy of intervention; and see few difficulties in undertaking the recommended actions.18,19 the use of the hbm has been established as a reliable research tool in preventative health behaviours, sick-role behaviours and clinical utilis ation.19 several studies have assessed the effectiveness and application of the hbm in diabetes care, patient compliance with treatment plans and in designing prevention programmes.20,21 the model enhances the understanding of outcomes after the implementation of a prevention programme, predicts health-related behaviours and is recommended as a part of any health education programme.19 however, this is the first study using this model to investigate t2dm knowledge and beliefs among adolescents in saudi arabia. the current study aims to determine the level of knowledge of t2dm and the health beliefs influencing healthy lifestyle behaviours associated with t2dm prevention among saudi adolescents living in riyadh, saudi arabia. methods this cross-sectional study was carried out in randomly selected public and private secondary schools in riyadh between may and october 2013. a total of 426 male and female adolescents from four second ary schools (a male-only private school, male-only public school, female-only public school and femaleonly private school) participated in the study. these schools were randomly selected from a list of schools application to patient care adolescents should be able to recognise the risk factors for developing t2dm so as to ensure preventative measures and lifestyle modifications can be implemented before the disease progresses. this may aid in reducing the future burden of diabetes on the healthcare system. the results of this study may help tailor diabetes prevention and education programmes targeting saudi adolescents. health beliefs related to diabetes mellitus prevention among adolescents in saudi arabia e400 | squ medical journal, august 2015, volume 15, issue 3 in riyadh. each secondary school had three class levels (levels 1–3). one classroom was randomly selected from each level in each school to cover the calculated sample size. all students present in the selected classrooms during the data collection period were asked to participate in the study. data collection included demographics such as age, gender, grade and current health status (i.e. presence of other chronic diseases). knowledge of and attitudes towards t2dm prevention behaviours and healthy lifestyle behaviours were assessed using an adapted version of whitford et al.’s hbm-based questionnaire.22 questions were adapted to take into account cultural and social variations in saudi arabia. the first part of the survey assessed knowledge of t2dm in four categories (nature, risk factors, complications and prevention methods) using 15 questionnaire items, each with three possible responses: “true,” “false” or “unsure”. the second part of the questionnaire aimed to determine cognitive factors from the hbm in five categories. the first category covered perceived susceptibility to t2dm while the second covered severity of t2dm in comparison with other chronic and acute diseases. in this section, participants were asked to rank the severity of various diseases or conditions (t2dm, hypertension, acquired immune deficiency syndrome, cancer, influenza and asthma) on a 5-point scale using a score of 1 (not serious) to 5 (critically serious). the third and fourth sections, respectively, were dedicated to assessing the perceived benefits of and barriers to healthy lifestyle behaviours. for the analysis of the cognitive factors related to susceptibility to the development of diabetes and benefits of and barriers to adopting a healthy lifestyle, only correct responses were considered in the analysis. a quantitative measure was also included in the survey instrument to assess t2dm prevention behaviours (regular physical activity and healthy dietary habits), to indicate whether participants were making a conscious effort to modify their lifestyle habits. for instance, in the first category, students were asked whether or not they exercised regularly and to identify the type and duration of sports or exercises usually performed. with regards to their dietary habits, students were asked if they were in the habit of having infrequent meals, skipping breakfast or consuming a large quantity of sugary or sweetened beverages. data were entered and analysed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa). demographic characteristics in relation to gender were examined using either the chi-squared test or t-test as appropriate. students’ knowledge of t2dm by gender was examined using the chi-squared test. attitudes and perceptions regarding t2dm susceptibility, disease severity and the advantages/ drawbacks of lifestyle choices in relation to gender were also examined using the chi-squared test. percentages were used to determine the frequency distribution of t2dm and other chronic and non-chronic diseases by perceived severity. the level of significance for all analyses was set at α <0.05. ethical approval for this study was obtained from the institutional review board at king saud bin abdul-aziz university for health sciences and king abdullah international medical research center (#irbc/070/13). verbal consent was received from all participants before inclusion in the study. results a total of 426 students participated in the study, including 224 (52.6%) from public and 202 (47.4%) from private schools. there were 205 females (48.1%) and 221 males (51.9%). of the total sample, 6.8% were smokers while 41.1% were from families with at least one smoker. the mean age of the students was 17.0 ± 1.0 years old (range: 15–22 years old) and mean weight was 64.5 ± 20.4 kg. none of the participants had t2dm; however, 63.4% had at least one family member with diabetes, while 10% had another type of chronic disease, including asthma, heart disease, gastrointestinal diseases, sickle cell anaemia and epilepsy. among the students, 68.1% reported that they exercised regularly. the demographic characteristics of the sample are shown in table 1. the number of participants with saudi nationality was higher for females than males (92.7% versus 81.9%; p = 0.001). obesity (23.7% versus 10.7%; p = 0.013) and smoking (10.4% versus 2.9%; p = 0.002) was more common among males than females. a family history of t2dm was higher among females than males (68.8% versus 58.4%; p = 0.026). more male students engaged in routine exercise or physical activity compared to the female students (77.4% versus 58.0%; p = 0.001). males also tended to weigh more than females (72.3 ± 23.1 kg versus 57.0 ± 14.0 kg; p = 0.001). the average age was similar for both genders (16.9 ± 0.9 years old in the female group versus 17.1 ± 1 years old in the male group; p = 0.086). no significant relationships were observed between gender and grade level, school sector or a family history of smoking. table 2 presents the associations between gender and knowledge of t2dm among the students. in response to the questionnaire item, 93.2% of females and 80.1% of males incorrectly stated that t2dm was an infectious disease (p = 0.001). awareness of high sugar intake, genetic factors, obesity and physical inactivity as risk factors for t2dm was high (88.3%, reem l. al-mutairi, amen a. bawazir, anwar e. ahmed and hoda jradi clinical and basic research | e401 83.1%, 82.2% and 68.1%, respectively). obesity (86.3% versus 78.3%; p = 0.030), genetic factors (87.8% versus 78.7%; p = 0.013) and high fat intake (52.7% versus 36.2%; p = 0.001) were more frequently recognised as risk factors for t2dm by female students than male students. inversely, males were more aware that physical inactivity was a risk factor of t2dm in comparison to females (72.4% versus 63.4%; p = 0.047). only 36.2% and 25.1% of students, respectively, were aware that blindness and renal failure were complications of t2dm. for the latter, awareness of the relationship between renal failure and t2dm was higher among females than males (32.2% versus 18.6%; p = 0.001). awareness of eye complications caused by t2dm was also higher among females than table 2: levels of accurate* awareness and knowledge of diabetes by gender among surveyed adolescents in saudi arabia (n = 426) item n (%) p value total female (n = 205) male (n = 221) disease type infectious 368 (86.4) 191 (93.2) 177 (80.1) 0.001† chronic 266 (62.6) 131 (63.9) 135 (61.4) 0.589 curable 138 (32.4) 71 (34.6) 67 (30.3) 0.341 risk factors obesity 350 (82.2) 177 (86.3) 173 (78.3) 0.030† heredity 354 (83.1) 180 (87.8) 174 (78.7) 0.013† smoker 80 (18.8) 39 (19.0) 41 (18.6) 0.901 physical inactivity 290 (68.1) 130 (63.4) 160 (72.4) 0.047† high sugar intake 376 (88.3) 183 (89.3) 193 (87.3) 0.535 high fat intake 188 (44.1) 108 (52.7) 80 (36.2) 0.001† complications blindness 154 (36.2) 96 (46.8) 58 (26.2) 0.001† kidney failure 107 (25.1) 66 (32.2) 41 (18.6) 0.001† prevention methods healthy diet 384 (90.1) 188 (91.7) 196 (88.7) 0.296 regular physical activity 380 (89.2) 184 (89.8) 196 (88.7) 0.723 control of body weight 344 (80.8) 174 (84.9) 170 (76.9) 0.037† cessation of smoking 143 (33.6) 74 (36.1) 69 (31.2) 0.287 *using correct responses only. †chi-squared test significance was set at α <0.05. table 1: demographic characteristics by gender among surveyed adolescents in saudi arabia (n = 426) characteristic n (%) p value total female (n = 205) male (n = 221) nationality saudi 371 (87.1) 190 (92.7) 181 (81.9) 0.001* non-saudi 55 (12.9) 15 (7.3) 40 (18.1) mean age in years ± sd 17.0 ± 1.0 16.9 ± 0.9 17.1 ± 1.0 0.086 grade level 1 143 (33.6) 64 (31.2) 79 (35.7) 0.585 2 125 (29.3) 61 (29.8) 64 (29.0) 3 158 (37.1) 80 (39.0) 78 (35.3) school sector public 224 (52.6) 103 (50.2) 121 (54.8) 0.352 private 202 (47.4) 102 (49.8) 100 (45.2) chronic disease no 383 (89.9) 187 (91.2) 196 (88.7) 0.386 yes 43 (10.1) 18 (8.8) 25 (11.3) bmi category underweight 41 (16.7) 23 (17.6) 18 (15.8) 0.013* normal 123 (50.2) 76 (58.0) 47 (41.2) overweight 40(16.3) 18 (13.7) 22 (19.3) obese 41 (16.7) 14 (10.7) 27 (23.7) family history of diabetes no 156 (36.6) 64 (31.2) 92 (41.6) 0.026* yes 270 (63.4) 141 (68.8) 129 (58.4) smoker no 397 (93.2) 199 (97.1) 198 (89.6) 0.002* yes 29 (6.8) 6 (2.9) 23 (10.4) family history of smoking no 251 (58.9) 124 (60.5) 127 (57.5) 0.526 yes 175 (41.1) 81 (39.5) 94 (42.5) regular physical exercise no 136 (31.9) 86 (42.0) 50 (22.6) 0.001* yes 290 (68.1) 119 (58.0) 171 (77.4) mean weight in kg ± sd 64.5 ± 20.4 57.0 ± 14.0 72.3 ± 23.1 0.001† sd = standard deviation; bmi = body mass index. *chi-squared test significance was set at α <0.05. †independent t-test significance was set at α <0.05. health beliefs related to diabetes mellitus prevention among adolescents in saudi arabia e402 | squ medical journal, august 2015, volume 15, issue 3 males (46.8% versus 26.2%; p = 0.001). a significantly higher percentage of females reported that controlling body weight could prevent t2dm (84.9% versus 76.9%; p = 0.037). table 3 displays the associations between gender and attitudes towards t2dm susceptibility and healthy lifestyle habits. perceived susceptibility to developing t2dm within the next 10–15 years (26.8% versus 15.5%; p = 0.008), or at any time in the future (32.7% versus 21.9%; p = 0.017) was significantly higher among females than males. the perception of t2dm as a serious disease was similar between males and females (33.5% versus 23.9%; p = 0.084). the belief that healthy habits were advantageous in maintaining a normal body weight was more common among females than males (88.8% versus 80.5%, p = 0.047). almost half of the students identified lack of time and hot weather as barriers to engaging in physical activity (46.5% and 42.7%, respectively), although 49.5% were confident that they could nevertheless maintain a routine of regular exercise. females were more inclined than males to view lack of time (53.7% versus 39.7%; p = 0.009) and hot weather (46.3% versus 39.3%; p = 0.005) as barriers to physical activity, whereas males were more confident that they would be able to maintain an exercise regimen (56.6% versus 42%; p = 0.003). the frequency distribution of selected diseases by perceived severity is presented in table 4. of the participants, 28.9% perceived t2dm as being either extremely or critically serious and more than half (56.3%) perceived it to be moderately serious. however, 14.8% believed that t2dm was either minimally serious or not serious at all. discussion this study aimed to characterise the knowledge, preventative behaviours and health beliefs regarding t2dm among a sample of secondary school students in saudi arabia. the perceived threat of developing t2dm in the future was low among the study sample. less than a quarter of the students believed that they might develop t2dm within the next 10–15 years. despite the fact that a high proportion of the participants reported a first-degree relative with diabetes, many did not perceive themselves as table 3: gender differences in accurate* perceptions of diabetes susceptibility and healthy lifestyle habits among surveyed adolescents in saudi arabia (n = 426) item n (%) p value total female (n = 205) male (n = 221) dm susceptibility in 10–15 years 89 (21.0) 55 (26.8) 34 (15.5) 0.008† in 20–30 years 129 (30.4) 67 (32.7) 62 (28.3) 0.572 in the future 115 (27.1) 67 (32.7) 48 (21.9) 0.017† disease severity‡ aids 415 (97.5) 204 (99.5) 211 (95.5) 0.010† htn 141 (33.1) 74 (36.1) 67 (30.3) 0.131 t2dm 123 (28.9) 49 (23.9) 74 (33.5) 0.084 cancer 410 (96.2) 199 (97.1) 211 (95.5) 0.201 influenza 15 (3.5) 8 (3.9) 7 (3.2) 0.200 asthma 44 (10.3) 14 (6.8) 30 (13.6) 0.048† advantage of healthy habits prevent diabetes in the future 389 (91.5) 193 (94.1) 196 (89.1) 0.116 prevent other chronic diseases 369 (86.8) 183 (89.3) 186 (84.5) 0.288 increase physical fitness 378 (88.9) 185 (90.2) 193 (87.7) 0.601 help maintain a normal body weight 359 (84.5) 182 (88.8) 177 (80.5) 0.047† barriers to a healthy lifestyle lack of time to exercise 197 (46.5) 110 (53.7) 87 (39.7) 0.009† unappetising taste of lowcalorie foods 196 (46.2) 95 (46.3) 101 (46.1) 0.991 difficulty finding lowcalorie foods 148 (34.9) 61 (29.8) 87 (39.7) 0.083 hot weather impedes exercise 181 (42.7) 95 (46.3) 86 (39.3) 0.005† ability to maintain healthy habits avoid smoking 400 (94.3) 197 (96.1) 203 (92.7) 0.130 eat low-fat meals 221 (52.1) 102 (49.8) 119 (54.3) 0.345 exercise regularly 210 (49.5) 86 (42.0) 124 (56.6) 0.003† eat lowsugar snacks 244 (57.5) 116 (56.6) 128 (58.4) 0.698 dm = diabetes mellitus; aids = acquired immune deficiency syndrome; htn = hypertension; t2dm = type 2 diabetes mellitus. *using correct responses only. †chi-squared test significance was set at α <0.05. ‡percentage of students indicating a disease severity score of 4 (extremely serious) or 5 (critically serious). reem l. al-mutairi, amen a. bawazir, anwar e. ahmed and hoda jradi clinical and basic research | e403 susceptible to developing the disease at any point in the future. this could be due to the low level of knowledge related to t2dm and its complications among this group of adolescents. in contrast, whitford et al. reported that people with a family history of t2dm had a high awareness level of their susceptibility to the same disease.22 alarmingly, results from the national health & nutrition examination survey in the usa have indicated that individuals with one or two first-degree relatives with t2dm are 2–5 times more susceptible to developing t2dm than those with none.23 approximately one-third of the students in the present study described t2dm as a serious disease compared to other chronic and acute diseases, while another third falsely believed that t2dm was a simple curable disease. similarly, in a study conducted among 2,007 non-diabetic adult subjects in al-qaseem, saudi arabia, two-thirds (67%) of the participants believed that t2dm was curable.14 such findings in both studies are most likely due to poor knowledge of t2dm risk factors or methods of t2dm prevention. a study conducted among high school students in mexico showed an association between gender and t2dm knowledge, with female students demonstrating higher levels of knowledge than males.24 in the current research, a greater number of female students perceived the benefits of adopting a healthy lifestyle. this indicates that the majority of females believed that prevention behaviours were key to preventing t2dm. gender differences could be driven by higher levels of awareness among females, especially with regards to obesity and maintaining a normal body weight, as reported by memish et al.25 according to the current study’s findings, females were less likely than males to be obese. however, they were also more likely to perceive barriers to engaging in t2dm prevention behaviours. almost half of the participants identified hot weather and lack of time as restrictions to exercise. female students were significantly more affected than male students by these two barriers. walking is a cost-effective physical activity that can improve health; however, findings from another study conducted in saudi arabia indicated that participants did not regard walking as exercise—the saudi population was noted to associate physical activity, and its associated health benefits, exclusively with sports and activities conducted in fitness clubs.26 additional factors that have been described as barriers to routine exercise include time limitations and a reliance on cars for transportation.27,28 previous studies have also reported lack of time as a barrier to exercise.22,29,30 one such study reported that 80% of college students in dammam, saudi arabia, felt that lack of time restricted their ability to partake in physical activity.29 in another study, conducted among people with a family history of t2dm, half of the subjects identified lack of time as a challenge to exercising.22 however, al-hazzaa et al. determined via logistic regression analysis that saudi adolescents had an increased chance of being overweight or obese if they did not engage in sufficient amounts of vigorous physical activity.30 the use of the hbm as a theoretical framework is controversial. some meta-analyses indicate that the theory of reasoned action is a substantially more effective predictor of health behaviours than the hbm as a value-expectancy theory-based model.31 however, relationships between the four fundamental dimensions of the hbm (perceived susceptibility and severity of a disease and perceived barriers and benefits of the preventative action) indicate that the model is a useful theoretical framework in describing attitudes toward diabetes prevention behaviours. the authors of the current study remain convinced of the value of this model in providing a relatively comprehensive understanding of the influence of social, economic and environmental factors on health behaviours, in addition to cognitive factors, in evaluating knowledge and behaviours among this group of students. therefore, a further nationwide study based on this framework is recommended to help develop more effective t2dm prevention interventions among adolescents in saudi arabia. this study should be interpreted within the context of its limitations. first, the use of a unique sample from riyadh may limit the generalisability of the findings to other regions in saudi arabia. in addition, this study was conducted among a sample of secondary school students who may have limited knowledge of the benefits of some health interventions. table 4: frequency distribution of selected diseases by perceived severity* among surveyed adolescents in saudi arabia (n = 426) disease severity ranking, % 1 2 3 4 5 t2dm 3.5 11.3 56.3 17.6 11.3 htn 0.4 8.7 54.2 17.8 15.3 aids 0.2 0 2.3 3.8 93.7 cancer 0.5 0.2 3.1 12.4 83.8 influenza 48.4 30 18.1 1.6 1.9 asthma 14.8 32.9 42 7.7 2.6 t2dm = type 2 diabetes mellitus; htn = hypertension; aids = acquired immune deficiency syndrome. *severity was ranked as follows: 1 = not serious, 2 = minimally serious, 3 = moderately serious, 4 = extremely serious and 5 = critically serious. health beliefs related to diabetes mellitus prevention among adolescents in saudi arabia e404 | squ medical journal, august 2015, volume 15, issue 3 conclusion although almost two-thirds of the students had at least one family member with diabetes, the current study revealed poor recognition of t2dm risk factors and the importance of adopting a healthy lifestyle among this saudi arabian population. furthermore, many students were unaware of the severity of this chronic disease. female students perceived the benefits of effective lifestyle behaviours more frequently than male students, although the latter reported engaging in physical activity more often. raising awareness of t2dm and its primary prevention strategies should be a priority in the saudi arabian public health agenda. the use of the hbm, as in this study, could form the framework for further research on diabetes prevention among saudi adolescents. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. tarin sma. global ‘epidemic’ of diabetes. nishtar med j 2010; 2:56–60. 2. rawal lb, tapp rj, williams ed, chan c, yasin s, oldenburg b. prevention of type 2 diabetes and its complications in developing countries: a review. int j behav med 2012; 19:121–33. doi: 10.1007/ s12529-011-9162-9. 3. knowler wc, barrett-connor e, fowler se, hamman rf, lachin jm, walker ea, et al. reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. n engl j med 2002; 346:393–403. doi: 10.1056/nejmoa012512. 4. department of economic & social affairs, united nations. world population prospects: the 2012 revision. from: www.esa.un.org/ wpp/unpp/panel_population.htm accessed: mar 2015. 5. elhadd ta, al-amoudi aa, alzahrani as. epidemiology, clinical and complications profile of diabetes in saudi arabia: a review. ann saudi med 2007; 27:241–50. doi: 10.4103/0256-4947.51484. 6. al-nozha mm, al-maatouq ma, al-mazrou yy, al-harthi ss, arafah mr, khalil mz, et al. diabetes mellitus in saudi arabia. saudi med j 2004; 25:1603–10. 7. al-nozha mm, al-mazrou yy, al-maatouq ma, arafah mr, khalil mz, khan nb, et al. obesity in saudi arabia. saudi med j 2005; 26:824–9. 8. al-almaie sm. prevalence of obesity and overweight among saudi adolescents in eastern saudi arabia. saudi med j 2005; 26:607–11. 9. rasheed p. perception of body weight and self-reported eating and exercise behaviour among obese and non-obese women in saudi arabia. public health 1998; 112:409–14. doi: 10.1038/sj.ph.1900479. 10. akbar dh, mira sa, zawawi th, malibary hm. subclinical diabetic neuropathy: a common complication in saudi diabetics. saudi med j 2000; 21:433–7. 11. qidwai sa, khan ma, hussain sr, malik ms. diabetic neuroarthropathy. saudi med j 2001; 22:142–5. 12. mitwalli ah, al-swailem ar, aziz k, paul tt, aswad s, shaheen fa, et al. etiology of end-stage renal disease in two regions of saudi arabia. saudi j kidney dis transpl 1997; 8:16–20. 13. aljoudi as, taha az. knowledge of diabetes risk factors and preventive measures among attendees of a primary care center in eastern saudi arabia. ann saudi med 2009; 29:15–19. doi: 10.41 03/0256-4947.51813. 14. mohieldein ah, alzohairy ma, hasan m. awareness of diabetes mellitus among saudi non-diabetic population in al-qassim region, saudi arabia. j diabetes endocrinol 2011; 2:14–19. 15. al-rukban mo. obesity among saudi male adolescents in riyadh, saudi arabia. saudi med j 2003; 24:27–33. 16. al-nakeeb y, lyons m, collins p, al-nuaim a, al-hazzaa h, duncan mj, et al. obesity, physical activity and sedentary behavior amongst british and saudi youth: a cross-cultural study. int j environ res public health 2012; 9:1490–506. doi: 10.3390/ijerph9041490. 17. sabra aa, taha az, al-sebiany am, al-kurashi ny, al-zubier ag. coronary heart disease risk factors: prevalence and behavior among male university students in dammam city, saudi arabia. j egypt public health assoc 2007; 82:21–42. 18. rosenstock im, strecher vj, becker mh. social learning theory and the health belief model. health educ q 1988; 15:175–83. doi: 10.1177/109019818801500203. 19. glanz k, rimer bk, viswanath k. health behavior and health education: theory, research, and practice. 4th ed. san francisco, california, usa: jossey-bass, 2008. p.46. 20. janz nk, becker mh. the health belief model: a decade later. health educ q 1984; 11:1–47. doi: 10.1177/109019818401100101. 21. tan my. the relationship of health beliefs and complication prevention behaviors of chinese individuals with type 2 diabetes mellitus. diabetes res clin pract 2004; 66:71–7. doi: 10.1016/j. diabres.2004.02.021. 22. whitford dl, mcgee h, o’sullivan b. reducing health risk in family members of patients with type 2 diabetes: views of first degree relatives. bmc public health. 2009; 9:455. doi: 10.1186/1471-2458-9-455. 23. valdez r, yoon pw, liu t, khoury mj. family history and prevalence of diabetes in the us population: 6-year results from the national health and nutrition examination survey (nhanes, 1999-2004). diabetes care 2007; 30:2517–22. doi: 10.2337/dc07-0720. 24. angeles-llerenas a, carbajal-sánchez n, allen b, zamora-muñoz s, lazcano-ponce e. gender, body mass index and socio-demographic variables associated with knowledge about type 2 diabetes mellitus among 13,293 mexican students. acta diabetol 2005; 42:36–45. doi: 10.1007/s00592-005-0172-4. 25. memish za, el bcheraoui c, tuffaha m, robinson m, daoud f, jaber s, et al. obesity and associated factors: kingdom of saudi arabia, 2013. prev chronic dis 2014; 11:e174. doi: 10.5888/pcd11. 140236. 26. amin tt, suleman w, ali a, gamal a, al wehedy a. pattern, prevalence, and perceived personal barriers toward physical activity among adult saudis in al-hassa, ksa. j phys act health 2011; 8:775–84. 27. al-eisa es, al-sobayel hi. physical activity and health beliefs among saudi women. j nutr metab 2012; 2012:642187. doi: 10.1155 /2012/642187. 28. awadalla nj, aboelyazed ae, hassanein ma, khalil sn, aftab r, gaballa ii, et al. assessment of physical inactivity and perceived barriers to physical activity among health college students, southwestern saudi arabia. east mediterr health j 2014; 20:596–604. 29. rasheed p. overweight status: body image and weight control beleifs and practices among female college students. ann saudi med 1999; 19:365–9. 30. al-hazzaa hm, abahussain na, al-sobayel hi, qahwaji dm, musaiger ao. lifestyle factors associated with overweight and obesity among saudi adolescents. bmc public health 2012; 12:1–11. doi: 10.1186/1471-2458-12-354. 31. taylor d, bury m, campling n, carter s, garfied s, newbould j, et al. a review of the use of the health belief model (hbm), the theory of reasoned action (tra), the theory of planned behaviour (tpb) and the trans-theoretical model (ttm) to study and predict health related behaviour change. from: www.nice.org. uk/guidance/ph6/resources/behaviour-change-taylor-et-al-modelsreview2 accessed: mar 2015. http://dx.doi.org/10.1007/s12529-011-9162-9 http://dx.doi.org/10.1007/s12529-011-9162-9 http://dx.doi.org/10.1056/nejmoa012512 http://dx.doi.org/10.4103/0256-4947.51484 http://dx.doi.org/10.1038/sj.ph.1900479 http://dx.doi.org/10.4103/0256-4947.51813 http://dx.doi.org/10.4103/0256-4947.51813 http://dx.doi.org/10.3390/ijerph9041490 http://dx.doi.org/10.1177/109019818801500203 http://dx.doi.org/10.1177/109019818401100101 http://dx.doi.org/10.1016/j.diabres.2004.02.021 http://dx.doi.org/10.1016/j.diabres.2004.02.021 http://dx.doi.org/10.1186/1471-2458-9-455 http://dx.doi.org/10.2337/dc07-0720 http://dx.doi.org/10.1007/s00592-005-0172-4 http://dx.doi.org/10.5888/pcd11.140236 http://dx.doi.org/10.1155/2012/642187 http://dx.doi.org/10.1155/2012/642187 http://dx.doi.org/10.1186/1471-2458-12-354 departments of 1child health, 2microbiology, 3surgery, 4pathology and 5radiology, royal hospital, muscat, oman; 6department of pediatrics, king faisal specialist hospital & research centre, riyadh, saudi arabia *corresponding author e-mail: amalalmaani@yahoo.com basidiobolomycosis is a known fungal infection of the skin and soft tissue in otherwise healthy individuals. gastrointestinal basidiobolomycosis (gib) is an uncommon infection in childhood. few cases have been reported in the literature.1,2 the disease commonly manifests with fever, nausea, vomiting, abdominal pain, diarrhoea and/or an abdominal mass. its non-specific presentation and unknown risk factors make it difficult to diagnose. in most reported cases the initial diagnosis is malignant neoplasm, tuberculosis or inflammatory bowel disease.3–5 a definite diagnosis of basidiobolomycosis requires a microbial culture of basidiobolus ranarum from fresh aspiration or surgical specimens. histopathological examinations reveal a characteristic appearance of the culture.6 a favourable outcome depends on early diagnosis, the institution of appropriate antifungal therapy and surgical debulking.1 in the middle east, the largest series of paediatric gib cases was seen in saudi arabia, with 11 reported in 2012.1,7,8 this paper reports the first case of laboratoryconfirmed abdominal basidiobolomycosis in a child from oman. case report a 5-year-old omani female was referred to the royal hospital, muscat, oman, in july 2012 with a twoweek history of nausea, vomiting, abdominal pain and low-grade fever. the child had been diagnosed with acute appendicitis in a regional hospital and had had an appendectomy. the intraoperative findings suggested a normal appendix with a paracaecal mass. the subsequent histopathological examination also showed that the appendix and regional lymph nodes had no significant morphological abnormalities. the postoperative course was eventful with high fever and the slow return of bowel functions. an ultrasound of the abdomen revealed a hypoechoic circumferential mural thickening involving the caecum and ascending colon with luminal effacement suggestive of colitis or typhilitis. a computed tomography (ct) scan of the abdomen showed a large mass of heterogeneous sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e241-244, epub. 7th apr 14 submitted 2nd sep 13 revision req. 27th oct 13; revision recd. 26th nov 13 accepted 5th jan 14 الفطريات الدعامية )باسيديومايكوسيس( يف اجلهاز اهلضمي أول حالة يتم تشخيصها يف سلطنة عمان مع مراجعة لألدبيات اأمل املعنية، جورج بول، اأمينة اجلردانية، مدافن ناير، فاطمه اللواتية، �صيخه البلو�صية، اإبراهيم ح�صني abstract: gastrointestinal basidiobolomycosis (gib) is a rare fungal infection with few reported cases worldwide. we report here the first case diagnosed in oman in a previously healthy 5-year-old omani female child who had been thought initially to have an abdominal malignancy. the case was referred to the royal hospital, muscat, oman, in july 2012. she was treated successfully with surgical resection and prolonged antifungal therapy (voriconazole). physicians, including clinicians, radiologists and pathologists, should have a high index of suspicion for gib when a patient presents with an abdominal mass and fever. keywords: mycoses; zygomycosis; entomophthorales; gastrointestinal diseases; child; case report; oman. امللخ�ص: تعترب عدوى فطر با�صيديومايكو�صي�س يف اجلهاز اله�صمي من احلالت النادرة على م�صتوى العامل. ندرج هنا احلالة الأوىل من نوعها يف �صلطنة عمان اأ�صابت طفلة كانت ب�صحة جيدة يف ال�صابق، و�صخ�صت مبدئيا على اإنها ورم خبيث يف البطن. وحولت احلالة اإىل امل�صت�صفي ال�صلطاين مب�صقط يف يوليو من عام 2012م. عوجلت احلالة بنجاح عن طريق التدخل اجلراحي وم�صاد الفطريات فوريكونازول. يجب على الأطباء مبا فيهم املمار�صون واأخ�صائيو )با�صيديومايكو�صي�س( الدعامية الفطريات عدوى يف ال�صك من عالية درجة على يكونوا اأن اله�صمي اجلهاز واأطباء واجلراحون الأمرا�س وعلم الأ�صعة كت�صخي�س حمتمل للمر�صى امل�صابني بحمى وورم يف اجلهاز اله�صمي. مفتاح الكلمات: فطار؛ فطار عفني؛ احلا�صوراوات؛ اجلهاز اله�صمي؛ طفل؛ تقرير حالة؛ عمان. gastrointestinal basidiobolomycosis first case report from oman and literature review *amal s. al-maani,1 george paul,1 amina jardani,2 madhavan nayar,3 fatma al-lawati,4 sheikha al-baluishi,5 ibrahim b. hussain6 case report gastrointestinal basidiobolomycosis first case report from oman and literature review e242 | squ medical journal, may 2014, volume 14, issue 2 density in the right iliac fossa inseparable from the bowel loops, with a markedly thickened irregular bowel wall involving the caecum and ascending colon and, to a lesser extent, the terminal ileum, probably suggestive of non-hodgkins lymphoma, typhilitis or adenocarcinoma [figure 1]. the parents noticed that the child had lost a significant amount of weight (2.5 kg) in a month even though she had previously been healthy and had had no blood-stained stools, constipation or pica. she had no history of recent travel abroad or contact with sick people. the child attended school regularly and had no history of previous hospital admissions. the family, who lived in the al-dakhiliyah region of oman, an area with many arable farms surrounded by large areas of desert, used the government water supply for drinking. her past medical and family histories were insignificant and she was fully immunised for her age. the physical examination on admission revealed a sick, febrile child with a few palpable discrete and nontender lymph nodes in the neck. no skin rashes or oral thrush was noted. the abdomen was soft with a tender large mass in the right iliac fossa. the liver and spleen were not palpable. at this stage, the differential diagnoses were abdominal malignancy, lymphoma, inflammatory bowel disease, tuberculosis or infected fluid collection. hence, an urgent ultrasound-guided aspiration and biopsy of the abdominal mass were done. the aspiration showed purulent fluid which was sent for both culture and cytological examinations. in addition, a true-cut biopsy specimen was sent for histological examination. the child was then started on piperacillin-tazobactam, gentamicin and metronidazole. the complete blood count (cbc) highlighted a remarkable increase in eosinophils (6.2 x 109/l) with a total white blood count (wbc) of 14.2 x 109/l. the peripheral blood film showed no significant morphological abnormalities other than eosinophilia. her erythrocyte sedimentation rate, lactate dehydrogenase amounts, uric acid levels and chest x-ray were all normal. on the third day of admission, the cytology report of the mass aspirate showed fungal filaments resembling mucormycosis. liposomal amphotericin b was added to the existing course of antibiotics. she continued with intermittent high-grade fevers up to 39 °c. she also had nausea and colicky abdominal pain which were suggestive of a partial obstruction. the patient underwent an exploratory laparotomy which revealed a large, inflamed, necrotic mass arising from the caecum and ascending colon. the mesentery adjacent to the mass was found to be thickened. a small ulceration was seen in the colonic mucosa close to the resection margin. a few slightly enlarged mesenteric lymph nodes were present. the liver and spleen appeared normal. a right hemicolectomy was performed and the bowel continuity was restored by an ileocolic anastomosis. posaconazole was added to the antifungal regimen and after two days the patient’s temperature started to lower and her abdominal pain improved significantly. the surgical wound still showed redness and induration despite the child being on liposomal amphotericin b and posaconazole. therefore, she underwent extensive debridement of the abdominal wall and swabs were sent for bacterial and fungal cultures. the histopathological examination of the resected mass showed numerous scattered broad pauciseptate fungal hyphae embedded in eosinophilic material rich in eosinophils and some neutrophils representing the splendore-hoeppli phenomenon [figure 2]. the special stains showed no acid fast bacilli and there was no evidence of malignancy. a subculture on sabouraud’s dextrose agar yielded basidiobolus spp. on the third day of inoculation, the figure 1: a large mass of heterogeneous density (arrow) in the right iliac fossa inseparable from the bowel loops with a markedly thickened irregular bowel wall involving the caecum, ascending colon and, to a lesser extent, the terminal ilium. figure 2: fungal hyphae surrounded by the splendorehoeppli phenomenon (white arrow) and dense eosinophil infiltrates (black arrows) at x 40 magnification with haematoxylin and eosin stain. amal s. al-maani, george paul, amina jardani, madhavan nayar, fatma al-lawati, sheikha al-baluishi and ibrahim b. hussain case report | e243 colonies were initially white and radially-folded with short aerial hyphae. with age, the colonies turned cream to yellow-brown in colour. the microscopic examination revealed pauciseptated hyphae measuring 5–20 μm wide. some of the hyphae fragmented into short hyphal bodies. zygospores with two beakshaped remnants of the copulation tube established this organism as basidiobolus spp. [figures 3 a and b]. another sample from the infected surgical wound also grew the basidiobolus species. the antifungal therapy was modified after isolating the basidiobolus spp. liposomal amphotericin b and posaconazole were discontinued and intravenous voriconazole was started at a dose of 8–15 mg/kg/ day, divided into two 12-hourly doses. the abdominal wound was closed when repeated cultures showed no fungal growth. on the 28th day, the patient was discharged with a three-month course of oral voriconazole (15 mg/kg/day, divided into two 12-hourly doses). when she visited the outpatient clinic a month later, the patient showed a dramatic improvement in her general condition. she had started gaining weight and the wound was healing well. her cbc showed a normal eosinophil count and the abdominal ultrasound showed no masses or thickening of the bowel. it was decided to keep her on antifungal treatment for a year with follow-up visits at three-month intervals. it was also decided to perform abdominal ct/magnetic resonance imaging scans a week prior to the end of therapy, or sooner if she became symptomatic again. discussion zygomycosis is caused by the mucorales and entomophthorales orders of fungi. entomophthoromycosis consists of both basidiobolomycosis and conidiobolomycosis. basidiobolus ranarum, as a causative species of basidiobolomycosis, was first isolated in 1955 in the usa from decaying plants and was later found in soil and vegetation worldwide.9 it can be found in the faeces of amphibians, reptiles and insectivorous bats and is known to cause skin and soft tissue infections in otherwise healthy individuals. recently, basidiobolomycosis has emerged primarily as a systemic infection of the alimentary tract; however, as it generally does not invade the blood vessels, it rarely disseminates.10 vikram et al. reported the worldwide occurrence of gib between 1964 and 2010 as 44 cases.1 of those, a total of 19 cases were reported from the usa, of which 17 were from arizona alone. a probable environmental link to the desert climate was suggested. saudi arabia had the second highest prevalence with a total of 11 cases. the youngest patient was 2 years old and the oldest 81 years old. the majority of patients presented with abdominal pain, an abdominal mass, fever, weight loss, constipation and/or diarrhoea. most of the patients had peripheral eosinophilia (76%) and the culture was positive in 71% of the cases. the colon and rectum were the most commonly involved organs, but it can also infect the small bowel, liver and stomach.1,8 predicting potential risk factors that predispose a person to gib is limited in these different case series by the small number of patients, incomplete patient information and variations in the follow-up period. a six-patient case-control study from 2001 suggested that male gender, a history of diabetes mellitus, peptic ulcer disease and pica could be risk factors, but these were hard to confirm in a later larger cohort.1,11 on histopathological examination, the fungal hyphae are irregularly branched, thin-walled and occasionally septate. in most reported cases, the fungal hyphae were surrounded by a thick eosinophilic cuff—the splendore-hoeppli phenomenon.12 this figure 3 a & b: microscopic morphology of basidiobolus spp showing globose one-celled conidia that are forcibly discharged from a sporophore (arrow) at x 100 magnification with lactophenol blue stain (a). microscopic morphology of basidiobolus spp showing numerous round smooth thick-walled zygospores (arrow) at x 100 magnification (b). gastrointestinal basidiobolomycosis first case report from oman and literature review e244 | squ medical journal, may 2014, volume 14, issue 2 phenomenon is not specific to gib and can also be seen around other fungi, helminths or their ova, bacterial colonies or, rarely, around suture material in tissues.3 the treatment for gib combines both surgical resection and appropriate antifungal therapy. the possibility of eradicating the infection using only antifungal therapy without surgical resection remains theoretical as there have not been many opportunities to follow this treatment method. the importance of early surgical intervention for paediatric gib was emphasised in a retrospective review of nine paediatric cases managed at the king faisal specialist hospital & research centre, riyad, saudi arabia.13 the azole antifungal group is considered the best for treating gib, including ketoconazole, itraconazole and voriconazole. there is concern about the resistance of b. ranarum to amphotericin b products and some reported mortality in patients treated with them.10,14 almost all previously reported cases were initially misdiagnosed as inflammatory bowel disease, malignancy, diverticulitis, appendicitis and gastrointestinal tuberculosis, among others.1,3–5,9,15 in the current case, the patient was initially thought to have appendicitis and then was referred to the royal hospital in order to rule out lymphoma. limited awareness about the histopathological findings in such an infection led to a misleading report that suggested mucormycosis in the patient. this resulted in the delay in instituting the proper antifungal course of treatment earlier in the course of the illness. the previously healthy child reported in this report presented with abdominal pain, abdominal mass, fever and weight loss. she had caecal and colonic involvement. her cbc showed peripheral eosinophilia. the histopathology of the biopsy showed typical fungal hyphae surrounded by the splendorehoeppli phenomenon, which together with the clinical input met the definition of probable gib. the fungal culture later confirmed the diagnosis. this case highlights the crucial importance of performing appropriate cultures to confirm the diagnosis of gib. she had a successful outcome with surgical resection and prolonged antifungal treatment. this is the first reported and diagnosed case of gib in oman; however, some cases may have been missed previously, especially those with atypical presentations and/or no request for microbial cultures. conclusion gib is an invasive fungal infection that should be among the differential diagnoses for children presenting with abdominal masses and fever. an awareness of this condition among paediatricians, paediatric surgeons and pathologists may lead to the discovery of more cases and help the treating physician to arrive at a diagnosis earlier and manage the case appropriately. a worldwide collection of case studies is needed to identify risk factors for gib. references 1. vikram hr, smilack jd, leighton ja, crowell md, de petris g. emergence of gastrointestinal basidiobolomycosis in the united states, with a review of worldwide cases. clin infect dis 2012; 54:1685–91. doi: 10.1093/cid/cis250. 2. el-shabrawi mh, kamal nm. gastrointestinal basidiobolomycosis in children: an overlooked emerging infection. j med microbiol 2011; 60:871–80. doi: 10.1099/ jmm.0.028670-0. 3. nemenqani d, yaqoob n, khoja h, al saif o, amra nk, amr ss. gastrointestinal basidiobolomycosis: an unusual fungal infection mimicking colon cancer. arch pathol lab med 2009; 133:1938–42. doi: 10.1043/1543-2165-133.12.1938. 4. van den berk ge, noorduyn la, van ketel rj, van leeuwen j, bemelman wa, prins jm. a fatal pseudo-tumour: disseminated basidiobolomycosis. bmc infect dis 2006: 6:140. doi: 10.1186/1471-2334-6-140. 5. zavasky dm, samowitz w, loftus t, segal h, carroll k. gastrointestinal zygomycotic infection caused by basidiobolus ranarum: case report and review. clin infect dis 1999; 28:1244–8. doi: 10.1086/514781. 6. yousef om, smilack jd, kerr dm, ramsey r, rosati l, colby tv. gastrointestinal basidiobolomycosis. morphologic findings in a cluster of six cases. am j clin pathol 1999; 112:610–6. 7. al jarie a, al-mohsen i, al jumaah s, al hazmi m, al zamil f, al zahrani m, et al. pediatric gastrointestinal basidiobolomycosis. pediatr infect dis j 2003; 22:1007–14. 8. khan zu, khoursheed m, makar r, al-waheeb s, al-bader i, al-muzaini a, et al. basidiobolus ranarum as an etiologic agent of gastrointestinal zygomycosis. j clin microbiol 2001; 39:2360–3. doi: 10.1128/jcm.39.6.2360-2363.2001. 9. drechsler c. a southern basidiobolus forming many sporangia from globose and from elongated adhesive conidia. j wash acad sci 1955; 45:49–56. 10. pasha tm, leighton ja, smilack jd, heppell j, colby tv, kaufman l. basidiobolomycosis: an unusual infection mimicking inflammatory bowel disease. gastroenterology 1997; 112:250–4. doi: 10.1016/s0016-5085(97)70242-7. 11. lyon gm, smilack jd, komatsu kk, pasha tm, leighton ja, guarner j, et al. gastrointestinal basidiobolomycosis in arizona: clinical and epidemiological characteristics and review of the literature. clin infect dis 2001; 32:1448–55. doi: 10.1086/320161. 12. hussein mr, musalam ao, assiry mh, eid ra, el motawa am, gamel am. histological and ultrastructural features of gastrointestinal basidiobolomycosis. mycol res 2007; 111:926– 30. doi: 10.1016/j.mycres.2007.06.009. 13. al-shanafey s, alrobean f, bin hussain i. surgical management of gastrointestinal basidiobolomycosis in pediatric patients. j pediatr surg 2012; 47:949–51. doi: 10.1016/j. jpedsurg.2012.01.053. 14. yangco bg, okafor ji, testrake d. in vitro susceptibilities of human and wild-type isolates of basidiobolus and conidiobolus species. antimicrob agents chemother 1984; 25:413–6. doi: 10.1128/aac.25.4.413. 15. saadah oi, farouq mf, daajani na, kamal js, ghanem at. gastrointestinal basidiobolomycosis in a child: an unusual fungal infection mimicking fistulising crohn’s disease. j crohns colitis 2012; 6:368–72. doi: 10.1016/j.crohns.2011.10.008. clinical & basic research sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 545-550, epub. 8th oct 13 submitted 19th mar 13 revision req. 2nd jun 13; revision recd. 2nd jul 13 accepted 25th aug 13 departments of 1obstetrics & gynecology, 2nursing, 3paediatrics, 4statistics, nizwa hospital, oman *corresponding author e-mail: pranjal07ochani@outlook.com معّدل وفيات ما حول الوالدة كمؤشر على جودة الرعاية الصحية يف حمافظة الداخلية يف سلطنة عمان اآ�سا �سانتو�ش، جيتا زجنارواد، اإلهام حمدي، جميلة اأحمد النبهانية، بهاء الدين �رشقاوي، ابراهيم هالل البو�سعيدي اأف�سل وحتديد املبكرة الوالدة حديثي ووفيات االإمال�ش وفيات اأ�سباب عن روؤية توفري اإىل الدرا�سة هذه تهدف الهدف: امللخ�ص: اإ�سرتاتيجيات للتدخل. الطريقة: كانت هذه الدرا�سة باأثر رجعي خالل فرتة 7 �سنوات )يناير 2003 اإىل دي�سمرب 2009( جلميع حاالت وفيات االإمال�ش ووفيات حديثي الوالدة املبكرة يف امل�ست�سفي املرجعي ملحافظة الداخلية �سلطنة عمان ) م�ست�سفى نزوى(. النتائج: من جمموع عدد الوالدات 27,668 والدة، كانت هناك 244 حالة وفيات االإمال�ش و 157 حالة وفيات حديثي الوالدة املبكرة. كان معدل 18.33/1,000 عام 2003، يف والدة املعدل 17.23/1,000 كان حيث والدة بالوالدة 14.49/1,000 املحيطة الفرتة وفيات يف والدة 12.46/1,000 عام 2006، يف والدة 12.20/1,000 عام 2005، يف والدة 15.20/1,000 عام 2004، يف والدة عام 2007 و12.09/1,000 والدة يف عام 2008. وكان االنخفا�ش يف معدل الوفيات ح�سب ال�سنوات معتد به اإح�سائيا 0.005<= p(.واأرتفع املعدل يف عام 2009 اإىل 15.63/1,000 والدة كانت معظم الزيادة يف وفيات حديثي الوالدة املبكرة )الت�سوهات اخللقية(. وكان ال�سبب االأكرث �سيوعا لوفيات االإمال�ش الت�سوهات اخللقية )%18.82(، وكان ال�سبب االأكرث �سيوعا من بني الت�سوهات اخللقية هو النمو وتقييد )12%( ال�رشي احلبل وحوادث )13%( الباكر امل�سيمة انف�سال االأخرى االأ�سباب وت�سمل الع�سبي. اجلهاز مركزية �سذوذ داخل الرحم، يف حني ظلت الوفيات جمهولة ال�سبب يف %22.59. �سكلت الت�سوهات اخللقية %53.50 من وفيات حديثي الوالدة املبكرة وفيات معدالت بزيادة مرتبطا كان �سغريا اأو كبريا املتطرف االأم عمر .)5.73%( الوالدة اأثناء واالختناق اخلداج )23.56%( تليها الفرتة املحيطة بالوالدة . اخلال�سة: هناك حت�سن ب�سكل عام يف معدالت وفيات االإمال�ش ووفيات حديثي الوالدة. ومع ذلك هناك حاجة لالإ�سابة املعر�سات للن�ساء اإ�سافية رعاية لتوفري حاجة هناك واجلنني. االأم لها يتعر�ش التي اخلطر عوامل لتجنب التدخل لتح�سني ب�سكري احلمل و ارتفاع �سغط الدم الناجت عن احلمل، وتقييد النمو داخل الرحم. مفتاح الكلمات: وفيات الفرتة املحيطة بالوالدة، االإمال�ش، موؤ�رشات اجلودة، والرعاية ال�سحية، عمر االأمهات، عمان abstract: objectives: this study aimed to provide insight into the causes of stillbirths and early neonatal deaths and identify better intervention strategies. methods: this was a retrospective study during a 7-year period (january 2003 to december 2009) of all stillbirths and early neonatal deaths at the nizwa regional referral hospital in aldakhiliyah region, oman. results: of a total 27,668 births, there were 244 stillbirths and 157 early neonatal deaths. the perinatal mortality rate (pmr) was 14.49/1,000 births. the period-specific rates were 17.23/1,000 in 2003, 18.33/1,000 in 2004, 15.20/1,000 in 2005, 12.20/1,000 in 2006, 12.46/1,000 in 2007 and 12.09/1000 in 2008. this decline in the death rate was significant (p = <0.005). the rate rose in 2009 to 15.63/1,000, mostly from an increase in early neonatal deaths (congenital anomalies). the most common identifiable cause of stillbirth was congenital anomalies (18.82%), in which central nervous system anomalies were most common. other causes include abruptio placentae (13%), cord accidents (12%), and intrauterine growth restriction (iugr), while the cause remained unknown in 22.59%. congenital anomalies accounted for 53.50% of early neonatal deaths followed by prematurity (23.56%) and birth asphyxia (5.73%). extremes of maternal age were related to higher pmrs. conclusion: an overall improvement in the stillbirths and neonatal death rates was witnessed; however, further improvement is warranted for common avoidable fetal and maternal risk factors. extra care needs to be provided for women who are at risk of developing complications such as gestational diabetes, pregnancy-induced hypertension, iugr, etc. keywords: perinatal mortality; stillbirth; quality indicators; health care; maternal age; oman. perinatal mortality rate as a quality indicator of healthcare in al-dakhiliyah region, oman *asha santosh,1 geeta zunjarwad,1 ilham hamdi,1 jamila a. al-nabhani,2 bahaa e. sherkawy,3 ibrahim h. al-busaidi4 advances in knowledge this retrospective study in oman reveals the following contributing factors to high perinatal mortality rate: comorbidity during the pregnancy, especially diabetes (mainly uncontrolled)., pregnancy at later ages (>35 years). lack of knowledge among treating physicians of risk factors for high perinatal mortality. asha santosh, geeta zunjarwad, ilham hamdi, jamila a. al-nabhani, bahaa e. sherkawy and ibrahim h. al-busaidi clinical and basic research | 546 the perinatal mortality rate (pmr) is defined as the number of stillbirths and early neonatal deaths for every 1,000 births, while stillbirth is defined as a baby born dead after the 24th week of gestation.1 maternal care is assessed by pmr as it is a very useful and comprehensive quality indicator. the pmr is much higher than the maternal death rate; hence, the pmr is more relevant in daily practice and also provides a clearer picture of the problems encountered.2 the extended wigglesworth classification mentions four main categories (congenital malformations, antepartum stillbirths, intrapartum stillbirths and prematurity) and has the potential to provide information which may lead to further reduction in perinatal mortality.2 congenital malformations are considered the most common cause of perinatal mortality, with cardiac anomalies being the commonest reason as cardiac deformities can be missed on a routine anomaly scan. in addition, detection of in utero cardiac abnormalities not only requires expertise but also expensive equipment. the majority of antepartum stillbirths, or fetal deaths taking place prior to the onset of labour, are classified as “unexplained” by the confidential enquiry into maternal and child health (cemach), and are also considered as unavoidable by most professionals.3 a recent study in the uk reported intrauterine growth restriction (iugr) in >50% of unexplained stillbirths.4 better screening for iugr was recommended by the 8th confidential enquiry into stillbirths and deaths in infancy (cesdi). it reported that 45% of all stillbirths were found to be related to suboptimal care and failure to recognise women at high risk for such events. a change in the frequency or strength of fetal movements are also often noticed by many mothers; therefore, prompt check-ups are required for concerns regarding fetal movement.5 the main problems in antepartum and intrapartum care, and the main risk factors in intrapartum stillbirths are suboptimal fetal assessment (heart rate monitoring and fetal blood sampling) and non-perception of risk factors. adherence to the guidelines of the royal college of obstetricians & gynaecologists for improved standards of care in labour, and for electronic fetal monitoring in labour will overcome these problems.6 in the usa, prematurity, or preterm birth, accounts for 12% of all births and 75% of all neonatal mortality.7 the immediate causes of neonatal death include respiratory distress syndrome (rds), infection, neurological causes and gastrointestinal causes. the survival of neonates has improved due to the administration of antenatal rds prophylaxis and better neonatal care. currently, the quality of antenatal and perinatal care is best judged by the pmr. this aim of this study was to highlight the risk factors causing perinatal mortality in oman and how these can be prevented. methods this was a retrospective study on all stillbirths (n = 244) and early neonatal deaths (n = 157) from january 2003 to december 2009 at nizwa hospital, a regional referral centre providing secondary-level antenatal and neonatal care in the al-dakhliyah central region of oman. data were collected from the hospital’s computer system and the records of the identified cases were scrutinised. apart from the cases of stillbirths and early neonatal deaths, 3,258 mothers of live births were selected randomly from a total of 27,668 for the analysis of maternal age and adequacy of antenatal care (anc), which was defined as >6 anc visits. additionally, a birth interval of 2 or >2 years was considered to see the effect of these contributory factors on perinatal mortality. in addition to the general health profile of the mother, any illnesses or factors known to predispose to perinatal loss were carefully analysed. the same procedure was performed on the neonates’ records. the date of the mother’s last menstrual period, application to patient care a background knowledge of identified risk factors for the omani population may contribute to decreasing the perinatal mortality through: education regarding strict control of sugar levels during the pregnancy. timely interventions during pregnancy and close monitoring of sick neonates. more emphasis on prenatal screening and possible termination of pregnancy—if socially and religiously acceptable—when lethal congenital anomalies are detected. perinatal mortality rate as a quality indicator of healthcare in al-dakhiliyah region, oman 547 | squ medical journal, november 2013, volume 13, issue 4 early antenatal ultrasound scans, and neonatal examination (where feasible) were used to estimate the gestational age of each baby. maternal age and parity, and the infants’ birth weight and gestational age were used to analyse the perinatal deaths. wigglesworth’s classification was used to determine the cause of perinatal deaths. a similar earlier study, carried out at nizwa hospital before 2002, was used a comparison to highlight the improvements achieved over the last 7 years.8 data were analysed using the statistical package for the social sciences (spss, ibm, corp., chicago, illinois, usa) version 16. the chi square test was used to evaluate the hypothesis with a level of significance of >0.05. this study was approved by the research & ethics committee of nizwa hospital. results out of all 27,668 deliveries which took place during the study period, there were 244 stillbirths and 157 early neonatal deaths. this figure includes all the referral cases from the al-dakhliyah region. if the neonate was delivered at ≥26 weeks’ gestation or at a birth weight of ≥800 g, then resuscitation was started. in cases of precious pregnancy such as infertility treatment or a poor obstetric history, then the threshold was 700 g. the pmr was 14.49/1,000 births. the period-specific rate showed an improving trend, descending from 17.23/1,000 in 2003 to 12.09/1,000 in 2008, which is statistically significant (p ≤0.005). however, the rate was 15.63/1,000 in 2009 due to an unusual increase in early neonatal deaths (congenital anomalies) [figure 1]. the most common identifiable cause of stillbirth was congenital anomalies (18.82%), in which central nervous system anomalies were the most common. other causes included abruptio placentae (13%) and cord accidents (12%), while in 22.59% of cases, the cause remained unknown [figures 2 and 3]. congenital anomalies accounted for the highest percentage of early neonatal deaths (53.5%) followed by prematurity (23.56%) and birth asphyxia (5.73%) [figures 4 and 5]. two-thirds (66%) of stillbirths occurred between 28 and 40 weeks’ gestation and 34% were before 28 weeks’ gestation. the results from the analysis of the 3,258 randomly selected women from a total of 27,668 mothers of births other than stillborn and early neonatal deaths are shown in table 1. we found that the perinatal mortality was 19% in women over 35 years of age compared to 14.7% live births table 1: effect of contributory factors on perinatal mortality factors survival rate n (%) perinatal mortality rate n (%) total p value (comparing survival and pmr) maternal age in years <20 220 (6.8) 40 (10) 260 (7.1) 0.00321–35 2,558 (78.5) 285 (71.1) 2,843 (77.7) >35 480 (14.7) 76 (19) 556 (15.2) total 3,258 401 3,659 anc visits ≤6 1,128 (34.6) 157 (39.2) 1,286 (35.1) 0.069 >6 2,130 (65.4) 244 (60.8) 2,374 (64.9) total 3,258 401 3,659 birth interval ≤2 years 1,186 (36.4) 89 (36.5) 1275 (36.4) 0.987 >2 years 2,072 (63.6) 155 (63.5) 2,227 (63.6) total 3,258 *244 3,503 *data not available for early neonatal deaths. pmr = perinatal mortality rates; anc = antenatal care. figure 1: incidence of perinatal mortality at nizwa hospital, oman. asha santosh, geeta zunjarwad, ilham hamdi, jamila a. al-nabhani, bahaa e. sherkawy and ibrahim h. al-busaidi clinical and basic research | 548 in the younger age group (p = 0.003). in women who had less than 6 antenatal visits, the pmr was 39.2%, which was higher than those having live births (34.6%; p = 0.069). there was no association between perinatal mortality and birth interval (p = 0.987). discussion the pmr is a sensitive indicator of the quality of care provided to women in pregnancy, during and after child birth and to the newborns in the first week of life.9 this study of a 7-year period showed an aggregate pmr of 14.49/1,000 births which is better than the rate of 19.1/1,000 births reported in a study from nepal.9 the period-specific rate declined from 17.23/1,000 in 2003 to 12.00/1,000 in 2008, followed by a rise to 15.63/1,000 in 2009, mostly from increased early neonatal deaths (congenital anomalies). it was 21.06/1,000 births in the last study at nizwa hospital carried out prior to 2002.8 the main reason for the decrease in the pmr was the improvement of both mother and newborn care. worthy of note is that despite a significant increase in the number of births in the last 7 years, there was no concurrent increase in perinatal death. despite this success, the pmr in oman is higher than in the uk. for example, in 2007 it was 14.7/1,000 births in oman, whereas in the uk it was 7.7/1,000 births.3,10 this was partially due to differences in patient compliance; for example, in figure 4: causes of early neonatal deaths at nizwa hospital, oman. figure 5: causes of early neonatal death in infants weighing >2.5 kg (n = 31) at nizwa hospital, oman. mas = myconium aspiration syndrome. figure 3: causes of death in stillbirth fetuses weighing >2.5 kg (n = 76) at nizwa hospital, oman. figure 2: causes of stillbirths at nizwa hospital, oman. iugr = intrauterine growth restriction; dm = diabetes mellitus; gdm = gestational diabetes mellitus; iufd = intrauterine fetal death. perinatal mortality rate as a quality indicator of healthcare in al-dakhiliyah region, oman 549 | squ medical journal, november 2013, volume 13, issue 4 oman there may be a higher frequency of cases of diabetic patients not willing to be admitted for blood glucose profile testing or to start taking insulin, or there may be a reluctant toward induction of labour where indicated, or pregnancy termination may be declined, due to religious and cultural customs, in cases of lethal congenital anomalies. this 7-year study in oman revealed a 22% unexplained stillbirth rate whereas studies from the uk and kathmandu, nepal, showed 33% and 36% rates, respectively.1,9 the most common identifiable cause of stillbirths in oman was congenital anomalies (19%), which is much lower than the number reported from nepal (63.6%) but higher than that in the cemach study in the uk (4%).3,9 abruptio placentae and cord accidents were responsible for 13% and 12% of cases, respectively as a cause of stillbirths, which is similar to the study from nepal (13.6% abruptio placentae and 17.9% cord accidents).9 in our study, iugr was responsible for 11% of stillbirths, which is lower than the figure given in the royal college of obstetricians & gynaecologists 2010 guidelines on late intrauterine fetal death and stillbirth, where one-third (33.3%) of stillbirths were due to the fetus being small-for-gestational-age.11 because of strict hospital protocols, including early identification of iugr fetuses, appropriate monitoring and timely intervention, the perinatal mortality from iugr was reduced in our study. other causes of stillbirth in our study were prolonged pregnancy, pregnancy associated with diabetes (dm), and hydrops fetalis. more recent studies have shown an increased risk of stillbirth in prolonged pregnancies, pregnancies associated with dm and hydrops fetalis.12-14 different ethnic backgrounds and methodologies, plus improved obstetrics and neonatal care, might be the reason for differences observed in various studies. during the study period, there were 157 early neonatal deaths at nizwa hospital (5.64/1,000 live births). these rates were comparable with overall national rates.15 the rate of early neonatal deaths was higher than that reported from other gulf countries. in qatar, the early neonatal death rate was 2.3/1,000 live births.16 in saudi arabia it was 3.14/1,000 live births.17 out of the 157 babies that died in the first week of life, 84 (54%) died from lethal malformations, making this the most common cause of neonatal death. prematurity (n = 37; 24%), neonatal sepsis (n = 16; 11%), birth asphyxia (n = 9; 6%), hydrops fetalis (3%) and inborn error of metabolism (2.2%) were seen in early neonatal deaths. mothers over 35 years of age have been found to have an increased risk of stillbirth and neonatal death compared to younger mothers, with the magnitude of the risk increasing from 40 years of age onwards.18 in the current study, 2.1/1,000 births were intrapartum stillbirths, which was a rate higher than the 1.1/1,000 stillbirths in an american study.18 the cause of the higher rate in our study was the increased incidence of congenital anomalies. in our study, nearly two-thirds (61%) of stillbirths and 69% of early neonatal death occurred at <37 weeks’ gestation which is a rate similar to the cemach 2007 results in the uk (66% and 74%, respectively).3 of all documented stillbirths in our study, 46.7 % weighed 1–2.5 kg, compared to 54.5% in the nepalese study. the same study reported 10% of cases weighing <1 kg while in our study, 40.7% weighed <1 kg.9 overall, the feedback showed that individualised perinatal mortality reports have been well documented and are being used locally to discuss and review perinatal deaths. the results of this retrospective study reveal that the contributing factors for high pmr are comorbidities during pregnancy, especially dm (mainly uncontrolled), pregnancy at later ages (>35 years), and a lack of knowledge of risk factors in treating physicians. this knowledge of identified risk factors for the omani population may contribute to decreasing oman’s pmr. this could be achieved by education regarding proper follow-up and strict control of sugar levels during pregnancy; timely intervention during the pregnancy; close monitoring of sick neonates; more emphasis on prenatal screening, and possible termination of pregnancy if this is socially and religiously acceptable to the family concerned. as the data were collected retrospectively, some records were not complete. in particular, the rate of anaemia in mothers, and information on maternal malnutrition and cephalopelvic disproportion were not available. prolonged labour could not be correlated with perinatal mortality. autopsy was not performed in these cases due to social and cultural beliefs. it is a known fact that to reach accurate diagnoses, especially in cases where there asha santosh, geeta zunjarwad, ilham hamdi, jamila a. al-nabhani, bahaa e. sherkawy and ibrahim h. al-busaidi clinical and basic research | 550 was no obvious cause of death, perinatal autopsy provides important information. conclusion our findings show an improvement in stillbirth and neonatal death rates at nizwa hospital, oman, but more vigilance is required to prevent common avoidable fetal and maternal risk factors, especially in women who need extra support and care. the pmr is a major marker to assess the quality of health care delivery. early interventions, high-quality antenatal care, proper care of sick neonates, prevention of preterm births, intensive care of low birth weight babies, and the implementation of a policy of standard intrapartum care, including appropriate and timely interventions, are important factors in reducing perinatal deaths. improving access to prenatal screening for congenital abnormalities and early termination of pregnancy for lethal congenital anomalies may help further in the reduction of the pmr. references 1. drife j. can we reduce perinatal mortality in the uk? expert rev obstet gynecol 2008; 3:1–3. 2. baker pn, johnson i, jones g, kean l, kenny lc, mires g, et al. maternal and perinatal mortality: the confidential enquiries. in: baker p, ed. obstetrics by ten teachers. 18th ed. london: hodder arnold, 2006. pp. 20–33. 3. cox s, golightly s, sullivan a. perinatal mortality 2007. united kingdom: confidential enquiry into maternal and child health (cemach), 2009. 4. gardosi j, kady sm, mcgeown p, francis a, tonks a. classification of stillbirth by relevant condition at death (recode): population based cohort study. brit med j 2005; 331:1113–7. 5. confidential enquiry into stillbirths and deaths in infancy report, 2001. from: www.dhsspsni.gov.uk/ cesdi_report.pdf accessed: feb 2013. 6. royal college of obstetricians and gynaecologists. standards for maternity care. report of a working party. from: www.rcm.org.uk/easysiteweb/ gatewaylink.aspx?alld=130242 accessed: feb 2013. 7. alvarez jr, apuzzio jj. controversies in the management of preterm premature rupture of membranes. in: studd j, tan sl, chervenak f, eds. progress in obstetrics and gynaecology. 18th ed. edinburgh: elsevier, 2008. pp. 203–22. 8. pandey b, hamdi i, george s, pandey r. perinatal mortality in nizwa hospital. oman med j 2002; 19:52–5. 9. shrestha m, manandhar d, dhakal s, nepal n. two year audit of perinatal mortality at kathmandu medical college teaching hospital. kathmandu univ med j (kumj) 2006; 4:176–81. 10. ministry of health of oman. status of health programmes and morbidity and mortality. muscat: ministry of health 2007. pp. 8.15, 8.6, 9.45. 11. royal college of obstetricians and gynaecologists. late intrauterine fetal death and stillbirth (greentop 55), 2010. from www.rcog.org.uk/womenshealth/clinical-guidance/late-intrauterine-fetaldeath-and-stillbirth-green-top-55 accessed: feb 2013. 12. crowley p. prolonged pregnancy. in: edmonds dk, ed. dewhurst’s textbook of obstetrics and gynaecology. 7th ed. london: blackwell, 2007. pp. 192–204. 13. tower cl. diabetes mellitus. in: luesley dm, baker pn, eds. obstetrics and gynaecology: an evidencebased text for mrcog. 2nd ed. london: edward arnold, 2010. pp. 49–58. 14. smoleniec js. fetal hydrops. in: james dk, ed. high risk pregnancy management options. 4th ed. london: elsevier saunders, 2011. pp. 437–48. 15. ministry of health of oman. health domains, morbidity and mortality. muscat: department of health information & statistics, ministry of health. 16. salameh k, rahman s, al-rifai h, masoud a, lutfi s, abdouh g, et al. an analytic study of the trends in perinatal and neonatal mortality rates in the state of qatar over a 30-year period (1977 to 2007): a comparative study with regional and developed countries. j perinatol 2009; 29:765–70. 17. majeed-saidan ma, kashlan ft, al-zahrani aa, ezzedeen fy, ammari an. pattern of neonatal and postneonatal deaths over a decade (1995-2004) at a military hospital in saudi arabia. saudi med j 2008; 29:879–83. 18. getahun d, ananth cv, kinzler wl. risk factors for antepartum and intrapartum stillbirth: a population-based study. am j obstet gynecol 2007; 196:499–507. clinical & basic research sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 479-484, epub. 20th nov 12 submitted 31st jan 12 revision req. 24th apr 12, revision recd. 23rd jul 12 accepted 19th sep 12 العالقة بني اخلاليا القيحية ومعامل السائل املنوي عند الذكور الباكستانيني املصابني بالعقم حممد �صعيب خان، �صيد ح�صنني حممد، فريال ديبا، فهيم طاهر امللخص: الهدف: تقييم العالقة بني اخلاليا القيحية ومعامل السائل املنوي عند الذكور الباكستانيني املصابني بالعقم. الطريقة: أجريت هذه الدراسة الوصفية املقطعية يف قسم وظائف األعضاء التناسلية / الصحة ويف املعهد الوطين للصحة، إسالم أباد من عام 2004 إىل عام 2009. مت حتليل السائل املنوي عند 1521 شخصا، مع عينة ضابطة مكونة من 97 من اآلباء. النتائج: كان املتوسط )االحنراف املعياري( للخاليا القيحية 7.43 ± 0.43، 4.35 ± 0.34 و 4.26 ± 0.17 لكل ساَحُة تَّْكبرِي عايل يف النطاف املمسوخة والنطاف الواهنة قليلة العدد والنطاف الواهنة على التوايل، يف حني كانت 3.25 ± 0.26، 3.10 ± 0.19 و 2.98 ± 0.04 لكل ساَحُة تَّْكبرِي عايل يف جمموعات قليلي ومعدومي النطاف وجمموعة اآلباء على التوايل. وقد لوحظ أقل عدد من اخلاليا القيحية بني اآلباء، واليت مل تكن ذات أمهية إحصائية ملحوظة )p<0.05( مع مجيع احلاالت، ما عدا حاالت النطاف املمسوخة، وقليلي النطاف والنطاف الواهنة قليلة العدد. وأظهرت اخلاليا القيحية عالقة عكسية مع حركة احليوانات املنوية وعددها إال يف حاالت فـَْقُد النِّطاف. وكذلك لوحظ أقل عدد من اخلاليا القيحية بني اجملموعات اليت لديها أعداد كبرية من األشكال الطبيعية )p>0.05 (، يف حني لوحظت خاليا القيح أكثر يف احلاالت اليت يكون الرتكيز واحلركة أو الشكل غري طبيعي. ومن جهة أخرى كانت خاليا القيح منخفضة يف احلاالت اليت تكون فيها عيوب الرأس والرقبة أقل. ولوحظ أن مجيع أنواع عيوب احليوانات املنوية ال ختتلف بشكل ملحوظ )p>0.05 ( بني اآلباء واحلاالت كان تركيز اخلاليا طبيعيا. اخلال�صة: لوحظ وجود أعداد كبرية من اخلاليا القيحية يف خمتلف فئات املرضى الذين يعانون من العقم. عدم االكرتاث هبذا العامل سيجعل املرضى املصابني بتقيح املين كاألشخاص الطبيعيني، ولذلك جيب النظر بوجود تقيح املين من قبل األطباء كعامل العقم عند الذكور. مفتاح الكلمات: تقّيح املني، ُعقم الذكور، باك�صتان. abstract: objectives: this study evaluated the association between pus cells and semen parameters in infertile pakistani males. methods: a cross-sectional descriptive study was carried out in the department of reproductive physiology/health, national institute of health, islamabad, pakistan, from 2004 to 2009. a total of 1,521 subjects were analysed, along with 97 proven fathers as controls. results: the mean of pus cells was 7.43 ± 0.43, 4.35 ± 0.34, and 4.26 ± 0.17 per high field in teratozoospermic, oligoasthenozoospermic, and asthenozoospermic groups, respectively, while it was 3.25 ± 0.26, 3.10 ± 0.19, and 2.98 ± 0.04 per high field in azoospermic, oligozoospermic and the proven father groups, respectively. the fewest pus cells were observed among proven fathers, which varied nonsignificantly (p >0.05) with all cases, except with teratozoospermic, oligozoospermic, and oligoasthenozoospermic cases. pus cells showed an inverse relationship to sperm motility and count, except in azoospemia cases. similarly, the fewest pus cells were observed among groups where normal forms where significantly more frequent (p <0.05). more pus cells were observed in cases where motility, and concentration or morphology was compromised. similarly, low pus cell counts were seen in cases where sperm had the fewest head and neck defects. all kinds of sperm defects varied non-significantly (p >0.05) between proven fathers and normal concentration cases. conclusion: high pus cell counts were observed in various subclasses of infertile patients. ignorance of this pyospermic factor will make pyospermic patients to be misdiagnosed as normozoospermic. therefore, the presence of pyospermia must be considered by physicians as a male infertility factor. keywords: pyospermia; male infertility; pakistan. association between pus cells and semen parameters in infertile pakistani males *mohammad s. khan,1 syed h. mohammad,2 fariyal deepa,3 fahim tahir3 advances in knowledge sperm infection is a classic cause of infertility. ignorance of the pyospermic factor would have rendered the “pyospermia only” patients as normozoospermic, and the rest azoo-, oligo-, asthenoor oligoasthenozoospermic. in such an instance, the pyospermic males would not be treated for pyospermia, and hence their state of infertility would persist. therefore, it is suggested that presence of wbc in the semen should not be ignored by the treating physician and must be considered as a male fertility limiting factor. 1department of biochemistry, bannu medical college, khyber pakhtunkhwa, pakistan; 2department of biochemistry, federal medical college, islamabad, pakistan; 3department of reproductive physiology/health, national institute of health, islamabad, pakistan *corresponding author e-mail: mshaoibkhan2003@yahoo.com association between pus cells and semen parameters in infertile pakistani males 480 | squ medical journal, november 2012, volume 12, issue 4 high white blood cell (wbc) concentrations within semen are an indicator of infection; this condition, marked by pus in the semen, is termed pyospermia. although small numbers of wbcs are a normal constituent of the semen, patients are only considered non-pyospermic as long as the wbc concentration remains below 5 per high power field (hpf).1 however, wbcs may have a valuable effect on sperm function when leukocyte levels range from 1–3 x 106/ml.2 the association of pyospermia with male infertility has been pointed out by many researchers.3–4 infections may affect male fertility in different ways. possible consequences are impairment of the spermatogenesis, the induction of an autoimmune mechanism, spematodysfunction, and inflammatory occlusion of the ejaculatory duct. reduced motility of spermatozoa has been found in semen samples which contain high concentrations of bacteria.5 similarly, 43% of pyospermic patients showed spontaneous downward variation in the absence of treatment.6 antisperm antibodies play a significant role in male factor infertility. the prevalence of antisperm antibodies in the infertile population is approximately 10%. earlier studies found that a higher prevalence of antisperm antibodies among infertile men with a history of bacterial prostitits or urethritis were pyospermic.7 moreover, the sperm motile efficiency index (smei) was found to be significantly lower in pyospermic patients when compared with that of non-pyospermic men.1 in a 1997 study, the relationship between semen quality, pyospermia, and microbiology were studied in 201 semen isolates, which showed reduced fertility in 43% of patients who were pyospermic. the most common organisms detected were enterobacteriaceae (2.8%), gardnerella vaginalis (9.6%), chlamydia trachomatis (1.6%), mycoplasma genitalium (0.9%), and ureaplasma urealyticum (11.85%).8 male infertility is a serious global problem. although the problem is mainly due to sperm defects, other factors are also responsible for male infertility, of which only one is pyospermia. with this in mind, the present study was designed to evaluate the association between pus cells and semen parameters in infertile pakistani male patients. methods this cross-sectional descriptive study of a nonprobability sampling was carried out in the department of reproductive physiology/health of the public health laboratories division of the national institute of health in islamabad, pakistan, over a 5-year period, from 2004 to 2009. the participants included 1,521 infertile males and 97 proven fathers. semen and seminal pus cell analysis and an assessment of various seminal parameters were carried out to determine pus levels. after obtaining approval from the ethics committee of the institute and taking informed consent from the patients, semen examinations of the patient and control groups were carried out according to the standardised method of the world health organization.9 patients who had never received infertility treatments and who had no cause of infertility were included in the study. semen samples were obtained through masturbation. subjects who had undergone pelvic surgery or hernia repair, had diseases such as diabetes mellitus or thyroid disease, or were recreational drug users were not included in this study. after fulfilling the protocols in standard operation procedures (sops) of the department, well mixed and homogenised semen samples were thoroughly checked by two trained senior technicians for concentration, activity, and morphology. samples were rechecked by a pathologist/laboratory scientist and then documented. finally, a report was issued. pus cells were confirmed by the giemsa staining technique. participants were divided into six groups on the basis of sperm concentration, motility, and morphology: azoospermic, oligozoospermic, polyzoospermic, or normozoospermic on the basis of their sperm concentrations, and asthenozoospermic or teratozoospermic on the application to patient care this study will be helpful for clinicians, infertility specialists and andrologists in treating and managing patients with pyospermia. mohammad s. khan, syed h. mohammad,fariyal deepa and fahim tahir clinical and basic research | 481 basis of sperm motility and morphology. men who had successfully impregnated their wives without medical intervention during the last six months were placed in the proven fathers’ seventh group. persons having no spermatozoa in their semen were classified as azoospermic and those having less than 15 million/ml were categorised as oligozoospermic. in cases where sperm concentrations were more than 250 million/ml, the subjects were placed in the polyzoospermic group, while those with counts ranging between 20–250 million/ml represented the normozoospermic group. similarly, persons having an overall impaired sperm motility of less than 50% or less than 25% of active motility were categorised as asthenozoospermic. sperm with a disturbed morphology of more than 70% of normal were considered teratozoospermic.10 the results obtained were subjected to statistical analysis by using statistical package for the social sciences (spss), version 14, (ibm, chicago, il, usa). the results of the various pyospermic groups were compared with the control group by applying a t-test and the level of significance was determined. values less than 0.05 were considered significant. results the mean number (%) of pus cells was 7.43 ± 0.43, 4.35 ± 0.34, and 4.26 ± 0.17 per hpf in the teratozoospermic, oligoasthenozoospermic and asthenozoospermic groups, while it was 3.25 ± 0.26, 3.10 ± 0.19 and 2.98 ± 0.04 per hpf in azoospermic, oligozoospermic, and proven father figure 1: individual and combined incidence of categories of pyospermia in 1,521 male partners of infertile couples. 1 = oligopyospermia; 2 = oligoasthenopyospermia; 3 = asthenopyospermia; 4 = azoopyospermia; 5 = pyospermia; 6 = teratopyospermia. table 1: pus cells with seminal morphology, including abnormal forms, and head, neck and tail defects in various groups. means sharing a common letter do not differ significantly. others differ significantly (p <0.05). group n pus cells/hpf abnormal forms (%) head defects (%) neck defects (%) tail defects (%) az* 203 3.25 ± 0.26 a 0.00 (0.00) a 0.00 (0.00) a 0.00 (0.00) a 0.00 (0.00) a ol† 353 3.10 ± 0.19 ab 38.54 (1.22) b 26.42 (0.97) b 6.64 (0.41) b 6.60 (0.35) b as‡ 535 4.26 ± 0.17 c 36.46 (1.00) bc 23.40 (0.86) c 4.86 (0.29) c 8.89 (0.49) c oas§ 159 4.35 ± 0.34 cd 47.79 (1.76) d 31.69 (1.47) d 10.82 (0.73) d 8.49 (0.62) cd t¦ 37 7.43 ± 0.43 e 89.84 (1.29) e 75.43 (2.99) e 4.32 (0.89) ce 10.08 (1.39) cde n** 221 3.29 ± 0.28 abf 20.92 (1.04) f 12.93 (0.68) f 2.90 (0.27) ef 5.28 (0.53) f p†† 13 3.85 ± 1.44 abcdfg 14.46 (2.58) g 6.31 (0.88) g 0.77 (0.30) g 7.38 (2.51) bcdefg f‡‡ 97 2.98 ± 0.04 abfg 17.46 (0.00) h 11.32 (0.87) f 1.92 (0.23) h 4.24 (0.62) fg hpf = high power field; az* = azoospermic; ol†= oligozoospermic; as ‡ = asthenozoospermic; oas§ = oligoasthenozoospermic; t ¦ = teratozoospermic; n** = normozoospermic; p † †= polyzoospermic; f ‡‡ = proven fathers association between pus cells and semen parameters in infertile pakistani males 482 | squ medical journal, november 2012, volume 12, issue 4 groups. the fewest pus cells were observed among proven fathers, which varied non-significantly (p >0.05) in all cases, except with teratozoospermic, oligozoospermic, and oligoasthenozoospermic cases [tables 1 & 2, figure 1]. table 1 shows that fewer pus cells were observed in cases where the sperm displayed the fewest head and neck defects, such as in polyzoospermic subjects, followed by normal count cases and proven fathers, while tail defects were fewest in proven fathers. all kinds of defects varied nonsignificantly (p >0.05) between proven fathers and normal concentration cases. similarly, table 2 shows an inverse relationship between pus cells sperm motility and count, except in azoospemic patients. the results show that pus cells are in decline when motility and count increases in the semen ejaculates. similarly, the fewest pus cells were observed among groups (i.e. proven fathers and polyzoospermic cases) where normal forms where significantly higher (p <0.05). more pus cells were observed in cases where motility and concentration or morphology was compromised. discussion high pus cell counts were observed in various subclasses of infertile patients. the fewest pus cells were observed among proven fathers. pus cells showed an inverse relationship to sperm motility and count, except in azoospemia cases. similarly, the fewest pus cells were observed among groups where normal forms where significantly more frequent. more pus cells were observed in cases where motility, and concentration or morphology was compromised. similarly, low pus cell counts were seen in cases where sperm had the fewest head and neck defects. all kinds of sperm defects varied non-significantly between proven fathers and normal concentration cases. pyospermia is one of the most important causes of male infertility, but the distribution, origin, and role of pus cells in semen is still controversial. researchers have reported pyospermia’s negative effects on semen parameters and even on in vitro fertilisation (ivf). this negative effect stems from the fact that pyospermia increases reactive oxygen species (ros) which may cause sperm damage, leading to significantly increased male infertility.11 aspects of factors affecting male infertility need to be addressed specifically in order to treat the patient effectively. in the present study, although 36% of the examined patients exhibited pyospermia, only 10% had isolated pyospermia; while 26% were pyospermic in addition to having concentration and motility disturbances [figure 1]. in a similar study, pyospermia was found in the semen samples of up to 23% of infertile men.12 pyospermia has been reported to affect negatively sperm penetration assays, count, and motility.13 the highest incidence reported in the present investigation was that in teratopyospermic and oligoasthenopyospermic patients [table 2]. the probable cause of impaired semen motility appears to be that the leukocytes have a negative effect on semen parameters.1,13–14 table 2: seminal parameters (i.e. concentrations, active motility, sluggish, immotile, or containing pus cells) in various groups. means sharing a common letter do not differ significantly. others differ significantly (p <0.05). group n pus cells/hpf sperm concentration active motility (%) sluggish motility (%) immotile (%) az* 203 3.25 (0.26) a 0.00 (0.00) a 0.00 (0.00) a 0.00 (0.00) a 0.00 (0.00) a ol† 353 3.10 (0.19) ab 6.99 (0.35) b 29.16 (0.96) b 15.25 (0.51) b 55.59 (1.07) b as‡ 535 4.26 (0.17) c 50.11 (2.12) c 17.77 (0.49) c 11.67 (0.29) c 70.57 (0.61) c oas§ 159 4.35 (0.34) cd 4.45 (0.42) d 14.50 (0.86) d 12.14 (0.56) cd 73.36 (1.18) d t¦ 37 7.43 (0.43) e 5.64 (1.15) bde 17.73 (3.22) cde 10.73 (1.27) cde 71.54 (4.08) cde n** 221 3.29 (0.28) abf 87.49 (3.51) f 46.61 (1.27) f 11.29 (0.41) cdef 42.10 (1.28) f p†† 13 3.85 (1.44) abcdfg 402.23 (39.70) g 55.92 (4.19) g 8.85 (1.62) cdefg 35.23 (3.07) g f‡‡ 97 2.98 (0.04) abfg 102.12 (1.34) h 60.01 (0.58) g 10.94 (1.38) cdefg 28.85 (0.28) h hpf = high power field; az* = azoospermic; ol†= oligozoospermic; as ‡ = asthenozoospermic; oas§ = oligoasthenozoospermic; t ¦ = teratozoospermic; n** = normozoospermic; p † †= polyzoospermic; f ‡‡ = proven fathers. mohammad s. khan, syed h. mohammad,fariyal deepa and fahim tahir clinical and basic research | 483 the presence of significant numbers of wbc in the semen correlates with altered sperm parameters and diminished fertility. however, it is not known with certainty whether these changes are because of increased leukocyte concentrations or due to an underlying cause that may cause both pyospermia and altered sperm function.12 leukocytes represent the main source of ros both in seminal plasma and in sperm suspensions, and have a negative influence on sperm function and fertilisation rates.15 the sperm deformity index (sdi) is calculated by dividing the total number of deformities observed by the number of sperm selected. the score is a novel expression of the quality of sperm morphology, which has been shown to be a more powerful predictor of male fertility and of in vitro fertilisation outcomes as opposed to an assessment of the proportion of sperm with normal morphology.16 it also has been reported that a significant positive correlation exists between pyospermia and compromised sperm morphology, including tail defects, acrosomal damage, and high sdi scores.17 in another study, the findings suggest that leukocytes had a positive association with normal morphology and progressive motility.18 the same finding was also observed in our study. table 1 shows that pus cells were found high in teratozoospermic cases where morphology was compromised (89.84%). the altered morphology exhibited is mainly that of head defects (75.43%), which was in agreement with the previous study cited. some studies have shown a disassociation between bacteria growing in semen and pyospermia.12 this disassociation was noted in our study. of all of the patients who were found to be pyospermic, only a few samples yielded bacterial growths in semen cultures. other studies in the west, have observed that pyospermia may not necessarily be linked to microbial activity.4,13 the low percentage of positive bacterial cultures in our population may be due to our sociocultural practices, along with the frequent inappropriate and indiscriminate use of antibiotics. finally, in the present study, pyospermia was detected in 36% of males. only 10% of these were pyospermic, while 26% combined with it other semen disturbances. by ignoring pyospermia, the 10% of purely pyospermic cases would otherwise be classified together with patients free of male factor infertility, causing a decrease in male factor contribution towards infertility. similarly, and in other conditions as well, the remaining factors alone could be considered the cause of infertility for therapeutic purposes. many studies have shown that pyospermia reduces male fertility, and unless the state of pyospermia is corrected, the fertility of these patients will remain affected.3,4,12 conclusion high pus cell counts were observed in various subclasses of infertile patients, confirming that semen infection is a classic cause of male infertility. our study results showed that pyospermia is associated either with reduced sperm motility or altered normal morphology. if not properly treated, infertility will persist in such patients. therefore, it is suggested that the presence of pus cells in the semen should not be ignored by the treating physician and must be considered as a factor limiting male fertility. references 1. satoh s, satoh k, orikasa s, maehar i, takahashi m, hiramatsu m. studies on pyospermia in male infertility. nippon hinyokika gakkai zasshi 1990; 81:170–2. 2. kaleli s, ocer f, irez t, budak e, aksu mf. does leukocytospermia associate with poor semen parameters and sperm functions in male infertility? the role of different seminal leukocyte concentrations. eur j obstet gynecol reprod biol 2000; 89:185–91. 3. maruyama h. studies on the usefulness of a longterm high dose of methylcobalamin in-patients with oligozoospermia. hin kiyo 1985; 33:151–6. 4. matthews gj, goldstein m, henry jm, schlegel pn. non-bacterial pyospermia: a consequence of clomiphene citrate therapy. int j fertil menopausal stud 1995; 40:187–91. 5. krause w, weidner w. sexually transmitted diseases as causes of disorders of male fertility. z hautkr 1989; 64:596, 599–601. 6. lackner je, lakovic e, waldhor t, schatzl g, marberger m. spontaneous variation of leukocytospermia in asymptomatic infertile males. fertil steril 2008; 90:1757–60. 7. jarow jp, kirkland ja jr, assimos dg. association of antisperm antibodies with chronic non-bacterial prostates. urology 1990; 36:154–6. 8. kjaergaard n, kristensen b, hansen es, farholt s, association between pus cells and semen parameters in infertile pakistani males 484 | squ medical journal, november 2012, volume 12, issue 4 schonheyder hc, uldbjerg n, et al. microbiology of semen specimens from males attending a fertility clinic. apmis 1997; 105:566–70. 9. world health organization. who laboratory biosafety manual. 3rd ed. geneva: world health organization, 2004. 10. schirren c. textbook of practical andrology. hamburg: schireng ag., 1983. pp. 17–31. 11. li j, liu rz. progress in leukocytospermia research. zhonghusa nan ke xue 2006; 12:730–2, 736. 12. jarvi k, noss mb. pyospermia and male infertility. can j urol 1994; 1:25–30. 13. berger re, karp le, williamson ra, koehler j, moore de, holmes kk. the relationship of pyospermia and seminal fluid bacteriology to sperm function as reflected in the sperm penetration assay. fertil steril 1982; 37:557–64. 14. corradi g, jaszovszky i. a pyospermia hatasa a fertilitasra. vizsgalatok szelektiv feherversejt festessel, elasztaz meghatarozassal es hagyomanyos ondoparameterekkel. (effect of pyospermia on fertility. studies by selective leukocyte staining, elastase determination and routine sperm parameters). orv hetil 1994; 135:573–76. 15. ricci g, perticarari s, boscolo r, simeone r, martinelli m, fischer-tamaro l, et al. leukocytospermia and sperm preparation: a flow cytometric study. reprod biol endocrinol 2009; 19:128. 16. aziz n, buchan i, taylor c, kingsland cr, lewisjones i. the sperm deformity index: a reliable predictor of the outcome of oocyte fertilization in vitro. fertil steril 1996; 66:1000–8. 17. aziz n, agarwal a, lewis-jones i, sharma rk, thomas aj, jr. novel associations between specific sperm morphological defects and leukocytospermia. fertil steril 2004; 82:621–7. 18. lackner je, agarwal a, mahfouz r, du plessis ss, schatzl g. the association between leukocytes and sperm quality is concentration dependent. reprod biol endocrinol 2010; 5:12. hepatobiliary complications of sickle cell disease among children admitted to al wahda teaching hospital, aden, yemen e556 | squ medical journal, november 2014, volume 14, issue 4 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e556−560, epub. 14th oct 14 submitted 3rd sep 13 revisions req. 18th nov 13, 20th feb & 12th jun 14; revisions recd. 18th dec 13, 17th apr & 19th jun 14 accepted 19th jun 14 1department of paediatrics, faculty of medicine, aden university, aden, yemen; 2paediatric haematology & oncology unit, al wahda teaching hospital, aden, yemen *corresponding author e-mail: gamal_zain@hotmail.com املضاعفات الكبدية الصفراوية عند األطفال املصابني مبرض فقر الدم املنجلي مبستشفى الوحدة التعليمي يف عدن باليمن حنان علوي غالب و جمال ح�سني زين abstract: objectives: this study aimed to describe the pattern of hepatobiliary complications among patients with sickle cell disease (scd) and to assess their correlation with age, gender and other risk factors. methods: this cross-sectional study assessed 106 patients with scd who were admitted to al wahda teaching hospital in aden, yemen, between january and june 2009. a full history, thorough examination, essential laboratory investigations (including a complete blood count, liver function test and viral markers test) and an abdominal ultrasound were performed on all patients. the clinicopathological characteristics of the hepatobiliary complications were analysed for their correlation to different risk factors such as age and gender. results: it was found that 46.2% of the patients with scd had hepatobiliary complications. of these, 36.7% had viral hepatitis, 26.0% had cholecystitis and 20% had gallstones. a total of 60.4% of the affected patients were male. the mean levels of alanine aminotransferase (59.4 and 56.0 u/l) and aspartate transaminase (40.1 and 38.3 u/l) were significantly elevated in patients with viral hepatitis and cholecystitis, respectively. hepatitis b virus surface antigen showed higher positivity (10.4%) than anti-hepatitis a and anti-hepatitis c antibodies. hepatobiliary complications increased significantly with age and were notably higher among those who were often admitted to hospital and/or underwent frequent blood transfusions. conclusion: this study suggests that hepatobiliary complications are common among scd patients and the likelihood of developing such complications increases as patients age. thus, regular clinical follow-ups, abdominal ultrasound studies and periodic liver function tests, as well as serological tests for viral hepatitis, are strongly recommended. these can help in the early detection of these complications and allow opportunities for their management and prevention. keywords: sickle cell disease; digestive system; biliary tract; children; yemen. املنجلي، الدم فقر مبر�ض امل�سابني املر�سى عند ال�سفراوية الكبدية امل�ساعفات منط لو�سف الدرا�سة هذه تهدف الهدف: امللخ�ص: ولتقييم مدى ترابطها مع العمر واجلن�ض وعوامل الختطار الأخرى. الطريقة: مت يف هذه الدرا�سة املقطعية تقييم 106 مري�سا بفقر الدم املنجلي اأدخلوا مل�ست�سفى الوحدة التعليمي يف عدن باليمن بني يناير و يونيو 2009م. وبعد اأخذ التاريخ املر�سي والفح�ض ال�سامل وعمل فح�ض مت بالفريو�سات( الإ�سابة وموؤ�رشات الكبد وظائف واختبارات الكاملة الدم �سورة �سملت ال�رشورية )والتي املختربية الفحو�ض مدى لتقييم ال�سفراوية الكبدية للم�ساعفات الإمرا�سية ال�رشيرية اخلوا�ض حتليل ومت املر�سى. لكل ال�سوتية فوق باملوجات البطن ترابطها بعوامل الختطار املختلفة كالعمر واجلن�ض. النتائج: وجد اأن نحو %46.2 من مر�سى فقر الدم املنجلي يف هذه الدرا�سة اأعرا�سا نحو 26.0% عند كان بينما الفريو�سي، الكبد مر�ض اأعرا�ض هوؤلء من نحو 36.7% واأظهر �سفراوية. كبدية – م�ساعفات على دالة وترواحت .60.4% تبلغ امل�سابني املر�سى بني الذكور ن�سبة وكانت التوايل. على �سفراوية، وح�سوات مرارة التهاب منهم و20% متو�سطات ن�ساط انزميي ناقل اأمني الأللني وناقل اأمني ال�سبريتات بني 56.0 و 59.4 وحدة دولية و 38.3 و 40.1 وحدة دولية، على التوايل، وكانت ن�سبها اأعلى عند امل�سابني بالتهاب الكبد الفريو�سي و التهاب املرارة. واأظهرت م�ست�سدات ال�سطح يف فريو�ض التهاب الكبد الوبائي ب اإيجابية اأكرث )%10.4( من اأ�سداد التهاب الكبد الوبائي اأ و ج. ووجد اأن معدلت امل�ساعفات الكبديةال�سفراوية تزداد مع العمر، وكانت اأكرث حدوثا يف املر�سي الأكرث دخول للم�ست�سفى و / اأو الذين اأجريت لهم عمليات نقل دم ب�سورة متكررة. اخلال�صة: وجد العمر. تقدم مع حدوثها معدلت وتزداد املنجلي، الدم فقر مبر�ض امل�سابني الأطفال عند �سائعة ال�سفراوية الكبدية امل�ساعفات اأن وظائف واختبارات ال�سوتية فوق باملوجات البطن فح�ض درا�سات وعمل دورية ب�سورة �رشيرا املر�سى هوؤلء مبتابعة فين�سح ولذا الكبد وال�سريولوجيا للكشف عن التهاب الكبد الفريو�سي. وهذا من �ساأنه امل�ساعدة يف الكت�ساف املبكر عن هذه امل�ساعفات ويوفر فر�سا لعالجها والوقاية منها. مفتاح الكلمات: مر�ض فقر الدم املنجلي؛ اجلهاز اله�سمي؛ ال�سبيل ال�سفراوي؛ الأطفال؛ اليمن. hepatobiliary complications of sickle cell disease among children admitted to al wahda teaching hospital, aden, yemen hana a. qhalib1 and *gamal h. zain1,2 online brief communication hana a. qhalib and gamal h. zain online brief communication | e557 sickle cell disease (scd) is an inherited blood disease characterised by chronic haemolytic anaemia. the frequency of the hbs gene in yemen is estimated to be 0.04, with an expected birth incidence of 20/10,000 per year.1 scd is a multisystem disease with a variable range and degree of complications. the hepatobiliary system is often involved in scd complications and can be affected in various ways, ranging from benign liver function abnormalities to dramatic clinical crises marked by acute hepatic failure.2,3 the liver is frequently affected, with a complex pathophysiology involving interrelated causative factors such as haemolysis, iron overload, transfusion complications, sickling consequences, vaso-occlusion and cholelithiasis.4 since the 1950s, it has been theorised that hepatitis may cause liver disease in scd patients.5 the global prevalence of viral hepatitis is 30–40%, 2–8% and 1.45% for hepatitis a, b and c strains, respectively.6 a study by al-ghonaim et al. found that hepatitis virus a (hav) is the most common cause of viral hepatitis among children in saudi arabia.7 gallstones are a common complication of scd and their development is closely related to the disease’s severity and the intensity of haemolysis. gallstone prevalence often increases in scd patients over the age of five years.8 to the best of the authors’ knowledge, no previous studies have been done to characterise hepatobiliary complications among scd patients in yemen. the al wahda teaching hospital, one of the major tertiary hospitals in yemen, admits many scd patients with varied complications, including hepatobiliary system diseases. however, treating physicians have at times not recognised these diseases and, consequently, they have been left undiagnosed. the main objectives of this study, therefore, were to highlight the different patterns of hepatobiliary complications in yemeni patients with scd and to assess the relationship with age, gender and other risk factors. methods this cross-sectional descriptive study was conducted between 1 january and 30 june 2009 at al wahda teaching hospital in aden, yemen. the inclusion criteria comprised children of both genders between the ages of six months and 14 years with scd confirmed by haemoglobin (hb) electrophoresis. patients who did not have electrophoresis-confirmed scd, those with combined haemoglobinopathies, those who had not completed the required investigations and those who had abandoned the treatment were excluded from the study. the parents of the patients were instructed to fill out a predesigned questionnaire, which included questions on demographic characteristics, current medical information, past medical history and previous hospital admissions and blood transfusions. following this, a thorough physical examination, specifically designed to assess signs of hepatobiliary system disease was carried out for each patient. all subjects underwent laboratory investigations to assess their hb levels, white blood cell count, albumin, bilirubin (total and direct), alkaline phosphatase (alp), alanine aminotransferase (alt) and aspartate aminotransferase (ast) levels. the normal ranges for these tests are indicated as follows: total bilirubin = 1.12 mg/dl; direct bilirubin = 0.6 mg/dl; alt ≤12 u/l; ast ≤14 u/l, and alp ≥200 u/l. serological tests for viral hepatitis were performed, using the enzyme-linked immunosorbent assay maxmat kit (maxmat s.a, montpellier, france) to detect antihav antibodies, hepatitis b (hbv) surface antigen and anti-hepatitis c (hcv) antibodies. an abdominal ultrasound was performed on all of the studied patients using a doppler colour ultrasound machine with a 3.5 megahertz frequency. the patients were instructed to fast overnight and the ultrasound was conducted the following morning. standard views were obtained in the transverse and sagittal plains with the subjects in supine, right lateral and left lateral decubitus positions. the ultrasound results were used to assess the standard features of scd, such as the surface, edge and size of the liver; the echogenicity of the liver parenchyma; the dilatation of the bile ducts; the status of the pancreas; evidence of gallbladder disease, and other diagnostic features of disease processes, if they were present in the patient. liver biopsies were not performed on the subjects due to the expense and time required. in suspected cases of salmonella, patients underwent stool and blood culture tests. other investigations were carried out according to clinical indications. the data were processed and analysed using the statistical package for the social sciences (spss), version 16.0 (ibm corp., new york, usa). the statistical analysis included a quantitative descriptive analysis and summary statistics consisting of the mean, percentages and standard deviations with a confidence interval of 95%. the analysis was based on the chisquared test, fisher’s exact test, odds ratio, student-t test and univariate analysis of variance. a p value of <0.05 was considered statistically significant. this study was approved by the ethical committee at the faculty of medicine & health sciences of aden university in aden, yemen. all of the patients’ parents gave permission for their inclusion in the study. hepatobiliary complications of sickle cell disease among children admitted to al wahda teaching hospital, aden, yemen e558 | squ medical journal, november 2014, volume 14, issue 4 results a total of 106 scd patients were included in the study, of which 49 (46.2%) had hepatobiliary complications. the male to female ratio was 1.5:1 with scd complications occurring more commonly in male patients (55.1%). the main complications reported were viral hepatitis (36.7%), cholecystitis (26.0%) and gallstones (20.0%). the prevalence of cholecystitis was substantially higher among the male patients, as 76.9% of those affected were male [table 1]. there was a significant connection between age and the different forms of hepatobiliary complications [table 1]. of the patients with cholecystitis, 92.3% were found to be five years of age or older, while 44.4% of the patients with viral hepatitis were 5.1–10 years old. of the patients who had previously been admitted to hospital more than 10 times (n = 20), six (30.0%) had cholecystitis, four (20.0%) had gallstones and three (15.0%) had biliary sludge. the frequency of blood transfusions among the patients was related to the varying forms of hepatobiliary complications [table 2]. of the patients who had previously had more than three blood transfusions, 62.5% presented with biliary sludge and 60% had gallstones. hepatobiliary complications increased significantly with age and were notably higher among those who were often admitted to hospital and/or underwent frequent blood transfusions. the mean hb levels of the patients with viral hepatitis, cholecystitis and gallstones were 5.3, 6.2 and 6.0 g/l respectively. the mean total bilirubin and indirect bilirubin levels (9.5 and 7.1 mg/dl, respectively) were high in viral hepatitis cases, while the mean alt (59.4 and 56.0 u/l) and ast (40.1 and 38.3 u/l) levels were significantly higher in those patients with viral hepatitis and cholecystitis, respectively. discussion the hepatobiliary tract of a patient with scd may be affected by the disease in various ways. of the 106 patients observed in this study, 49 had hepatobiliary complications. a higher proportion of males were affected in comparison to female patients. similar studies performed in yemen by bamahraz et al. and in saudi arabia by mulik et al.9,10 also found a male predominance among their affected subjects. the authors of this study therefore theorise that male patients have a higher prevalence of hepatobiliary complications due to their greater exposure to certain precipitating factors of scd crises. these factors include frequent infections as well as regular outdoor physical activities that may lead to an elevated metabolic process and increased sweating. this may cause some degree of dehydration, increased blood viscosity and increased oxygen consumption, leaving male patients more susceptible to developing scd crises.11 table 1: types of hepatobiliary complications by gender and age among patients with sickle cell disease (n = 49) variable type of hepatobiliary complication n (%) viral hepatitis n = 18 cholecystitis n = 13 gallstones n = 10 other n = 8 gender male 8 (44.4) 10 (76.9) 5 (50.0) 4 (50.0)* female 10 (55.6) 3 (23.1) 5 (50.0) 4 (50.0)** age group 6 months–2 years 0 (0.0) 0 (0.0) 0 (0.0) 1 (12.5)† 2.1–5 years 5 (27.8) 1 (7.7) 0 (0.0) 2 (25.0)† 5.1–10 years 8 (44.4) 3 (23.1) 6 (60.0) 2 (25.0)‡ >10 years 5 (27.8) 9 (69.2) 4 (40.0) 3 (37.5)§ *three patients with biliary sludge and one with periportal fibrosis; **three patients with biliary sludge and one with liver cirrhosis; †one patient with biliary sludge; ‡one patient with biliary sludge and one with liver cirrhosis; §two patients with biliary sludge and one with periportal fibrosis. table 2: frequency of hospital admissions and blood transfusions among sickle cell disease patients with hepatobiliary complications (n = 49) variable type of hepatobiliary complication n (%) viral hepatitis n = 18 cholecystitis n = 13 gallstone n = 10 other n = 8 frequency of previous hospital admissions 0 1 (5.6) 1 (7.7) 1 (10.0) 1 (12.5)* 1–3 6 (33.3) 5 (38.5) 3 (30.0) 1 (12.5)** 4–9 7 (38.9) 1 (7.7) 2 (20.0) 3 (37.5)† ≥10 4 (22.2) 6 (46.2) 4 (40.0) 3 (37.5)* frequency of previous blood transfusions per year 0 1 (5.6) 2 (15.4) 1 (10.0) 1 (12.5) 1 3 (16.7) 2 (15.4) 1 (10.0) 1 (12.5) 2 4 (22.2) 2 (15.4) 2 (20.0) 1 (12.5) ≥3 10 (55.6) 7 (53.8) 6 (60.0) 5 (62.5)* *one patient with biliary sludge; **one patient with periportal fibrosis; †two patients with biliary sludge and one with liver cirrhosis. hana a. qhalib and gamal h. zain online brief communication | e559 the results of this study also show that hepatobiliary complications are significantly correlated to a patient’s age and the prevalence of such complications significantly increases in patients aged five years and older. in addition, it was observed that a higher proportion of patients with previous histories of hospital admissions and blood transfusions were more commonly affected by hepatobiliary complications, mainly viral hepatitis, cholecystitis and gallstones. this could be explained by the fact that patients who were exposed to a higher frequency of hospital admissions had a greater likelihood of presenting with frequent crises associated with haemolysis. this in turn likely increased their opportunity for further blood transfusions, raising the likelihood of gallstone formation. in addition, it is possible that the blood transfusions predisposed patients to acquiring viral hepatitis from infected blood. hence, there is a connection between frequent blood transfusions, gallstone formation and viral hepatitis. the current study’s findings, with regards to the correlation between hospital admissions, blood transfusions and gallstone formation, were comparable to those reported in a study by darko et al.12 a high proportion of the patients with hepatitis in the current study had had at least one previous blood transfusion and 5% had had at least three. this result was similar to findings noted by ocak et al.13 cholecystitis is considered one of the most common hepatobiliary complications in patients with scd, often occurring due to a gallstone obstruction or infections. this complication was observed in approximately one-fifth of those with hepatobiliary complications in the current study, while similar results were found in a comparable study performed in india.14 it is likely that cholecystitis developed in the affected patients due to an infectious process. however, it may alternatively have been caused by an obstructive gallbladder stone, or as a hepatobiliary crisis due to the sickling process. in the current study, the frequency of developing cholecystitis increased with a patient’s age, as a high proportion of cholecystitis patients were over 10 years old. this could be explained by the fact that cholecystitis is largely attributed to gallstone formation, which requires time for development. there was also a higher prevalence of cholecystitis among the male subjects. this result is in contrast to a similar study performed in the congo that did not see a gender difference in cholecystitis prevalence.15 these opposing results may be due to the differences in the sample size, time frame and the methods used for cholecystitis detection between the studies. biliary sludge is one of the most intriguing complications of scd.3 it is a mixture of calcium bilirubinate and cholesterol crystals found within viscous bile, containing a high concentration of mucus and proteins.16 in the current study, biliary sludge was found in nine patients (18.3%). this was similar to findings from a saudi arabian study (16.4%),10 but exceeded that of studies performed in the congo (2.1%)15 and india (8%).14 these variations may have occurred because the sludge formation and evaporation is a dynamic process caused by frequent intermittent haemolysis, biliary tract infections and fluctuations in the inflammation levels which can differ from one scd population to another.8 patients with biliary sludge need regular follow-up as most are prone to gallstone formation. therefore, regular examinations are important for the early prevention and proper management of predisposing factors.17 the formation of pigmented gallstones in scd patients is the result of an excessive production of bilirubin due to red cell haemolysis. its prevalence depends on age, gender and methods of detection, in addition to the patient’s geographical location and, in some cases, dietary habits.18 in this study, only a few patients were found to have gallstones (20.4%). a study performed in western orissa, india, had similar results.14 however, a study from turkey reported a much higher prevalence,8 while studies from yemen19 and ghana12 noted lower prevalences of 4.49% and 4%, respectively. several factors appear to cause these significant variations in the reported prevalence of gallstones, including the patient’s age, type of imaging equipment used and the standard and sophistication of this equipment.20 the reason for the comparatively low prevalence of gallstones among scd patients in some areas is not clear. however, it may be related to the general low incidence of gallstones in some populations, such as certain african countries.12 in this study, 22.4% of all subjects presented with hbv. this result may reflect the lack of necessary vaccinations available to individuals in yemen. the authors recommend that yemeni scd patients undergo an annual screening for hbv and that patients with an hbv surface antibody titre of <10 should be revaccinated. the mean hb values of patients with gallstones were not significantly different from those patients without gallstones; this result is consistent with a study by sarnaik et al.21 white blood cell counts were high among patients who had gallstones and biliary sludge, which is similar to a study by longo-mbenza et al.15 the majority of the current patients had elevated mean total bilirubin, direct bilirubin, ast, alt and alp levels, with a significant elevation of ast and alt in those patients with viral hepatitis and cholecystitis. this is comparable with a study from brazil.22 hepatobiliary complications of sickle cell disease among children admitted to al wahda teaching hospital, aden, yemen e560 | squ medical journal, november 2014, volume 14, issue 4 based on the results of the current study, the authors recommend that thorough family education and genetic counselling be offered to all those affected by scd. in addition, the regular and continuous follow-up of patients with scd should be emphasised. these follow-ups should include routine vaccinations, additional abdominal ultrasounds, periodic liver function tests, serological tests for viral hepatitis and serum ferritin level tests to help in the early diagnosis and management of common scd complications. conclusion hepatobiliary complications in scd patients are common and their prevalence increases as patients age, with the exception of gallstones which can occur from an early age. among the group of studied patients, the most frequent complications were viral hepatitis, cholecystitis and gallstones. there was a strong correlation between the occurrence of these complications and the frequency of previous blood transfusions and hospital admissions. based on the findings of this study, genetic counselling and education about the potential complications linked to this condition are recommended for scd patients and their families. in addition, follow-up appointments and examinations must be prioritised in order to preempt the development of scd complications and to monitor existing symptoms. references 1. al-nood h, al-ismail s, king l, may a. prevalence of the sickle cell gene in yemen: a pilot study. hemoglobin 2004; 28:305–15. doi: 10.1081/hem-200037708. 2. costa db, miksad ra, buff ms, wang y, dezube bj. case of fatal sickle cell intrahepatic cholestasis despite use of exchange transfusion in an african-american patient. j natl med assoc 2006; 98:1183–86. 3. banerjee s, owen c, chopra s. sickle cell hepatopathy. hepatology 2001; 33:1021–28. doi: 10.1053/jhep.2001.24114. 4. traina f, jorge sg, yamanaka a, de meirelles lr, costa ff, saad st. chronic liver abnormalities in sickle cell disease: a clinicopathological study in 70 living patients. acta haematol 2007; 118:129–35. doi: 10.1159/000107744. 5. torres mc, pereira lm, ximenes ra, araújo as, secaf m, rodrigues ss, et al. hepatitis c virus infection in a brazilian population with sickle-cell anemia. braz j med biol res 2003; 36:323–9. doi: 10.1590/s0100-879x2003000300006. 6. rook m, rosenthal p. hepatitis a in children. in: jonas mm, ed. viral hepatitis in children: unique features and opportunities. new york, usa: humana press, 2010. pp. 1–12. 7. al-ghonaim mi, abdel-ghaffar mh, alnomasy sf, thalji mr, khan fr. prevalence of viral hepatitis among population of al-quwayiyah governorate, saudi arabia. wordl j pharm res 2012; 4:1212–22. 8. gürkan e, ergun y, zorludemir s, başlamişli f, koçak r. liver involvement in sickle cell disease. turk j gastroenterol 2005; 16:194–8. 9. bamahraz a. clinical spectrum and hematological investigations of sca among children in al-wahda teaching hospital. master dissertation, medical college, university of aden, aden, yemen, 2009. 10. mulik r, butikofer a, aramouni g, munshi n, iliff p. a clinicoepidemiological study of sickle cell anaemia in saudi arabia. j trop pediatr 1991; 37:100–5. doi: 10.1093/tropej/37.3.100. 11. wang wc. sickle cell anemia and other sickling syndromes. in: greer jp, foerster j, rodgers gm, paraskevas f, glader be, arber da, et al., eds. wintrobe’s clinical hematology. 12th ed. philadelphia, pennsylvania, usa: lippincott william & wilkins, 2008. pp. 1038–82. 12. darko r, rodrigues op, oliver-commey jo, kotei cn. gallstones in ghanaian children with sickle cell disease. west afr j med 2005; 24:295–8. doi: 10.4314/wajm.v24i4.28088. 13. ocak s, kaya h, cetin m, gali e, ozturk m. seroprevalence of hepatitis b and hepatitis c in patients with thalassemia and sickle cell anemia in a long-term follow-up. arch med res 2006; 37:895–8. doi: 10.1016/j.arcmed.2006.04.007. 14. mohanty j, narayan jvs, bhagat s, panda bb, satpathi g, saha n. sonological evaluation of abdominal organs in sickle cell crisis in western orissa. indian j radiol imaging 2004; 14:247– 51. 15. longo-mbenza b, ngiyulu r, kizunda p, kaluila m, bikangi n. gallbladder disease in young congolese with sickle cell anemia: an ultrasound survey. j trop pediatr 2004; 50:73–7. doi: 10.1093/tropej/50.2.73. 16. al-salem ah, qaisruddin s. the significance of biliary sludge in children with sickle cell disease. pediatr surg int 1998;13:14– 6. doi: 10.1007/s003830050233. 17. issa h, al-salem ah. hepatobiliary manifestations of sickle cell anemia. gastroenterol res 2010; 3:1–8. doi: 10.4021/ gr2010.01.1332. 18. ahmed s, shahid rk, russo la. unusual causes of abdominal pain: sickle cell anemia. best pract res clin gastroenterol 2005; 19:297–310. doi: 10.1016/j.bpg.2004.11.007. 19. al-saqladi aw, delpisheh a, bin-gadeem h, brabin bj. clinical profile of sickle cell disease in yemeni children. ann trop paediatr 2007; 27:253–9. 20. balci a, karazincir s, sangün o, gali e, daplan t, cingiz c, et al. prevalence of abdominal ultrasonographic abnormalities in patients with sickle cell disease. diagn interv radiol 2008; 14:133–7. 21. sarnaik s, slovis tl, corbett dp, emami a, whitten cf. incidence of cholelithiasis in sickle cell anemia using the ultrasonic gray-scale technique. j pediatr 1980; 96:1005–8. doi: 10.1016/s0022-3476(80)80626-3. 22. teixeira al, viana mb, roquete ml, toppa nh. sickle cell disease: a clinical and histopathologic study of the liver in living children. j pediatr hematol oncol 2002; 24:125–9. 1department of family medicine & public health, 2college of medicine and health sciences, sultan qaboos university, muscat, oman; 3department of research, oman medical specialty board, muscat, oman *corresponding author’s e-mail: mhalazri@squ.edu.om معرفة عوامل اخلطر واألعراض واحلواجز اليت حتول دون طلب املساعدة الطبية لسرطان عنق الرحم بني النساء العمانيات احلاضرات اىل مستشفى جامعة السلطان قابوس حممد العزري، ميثاء ال�شعيدية، اميان املطريية، �شاثيا مورثي بان�شات�رشام abstract: objectives: this study aimed to assess knowledge and attitudes among omani woman regarding cervical cancer risk factors and symptoms as well as barriers to them seeking medical help. methods: this cross-sectional study was conducted between december 2017 and march 2018 at the sultan qaboos university hospital (squh) in muscat, oman. a validated arabic-language version of the cervical cancer awareness measure questionnaire was used to collect data from 550 omani women visiting squh during the study period. results: a total of 490 women participated (response rate: 89.1%) in this study. overall, the women demonstrated low levels of knowledge of cervical cancer risk factors and symptoms (28.5% and 45.0%, respectively). the most frequently recognised risk factor was having many children (36.1%), while the most recognised symptom was unexplained vaginal bleeding (69.8%). women reported that being too scared was the greatest barrier to seeking medical help (68.0%). various factors were significantly associated with greater knowledge of cervical cancer signs and symptoms including education level (odds ratio [or] = 2.85; 95% confidence interval [ci]: 1.0–8.22; p <0.05), income (or = 4.34; 95% ci: 1.70–11.12; p <0.05), parity (or = 3.59; 95% ci: 1.38–9.36; p <0.05) and a family history of cancer (or = 1.71; ci: 1.0–2.90; p <0.05). conclusion: overall, omani women demonstrated poor knowledge with regards to cervical cancer; in addition, they identified several emotional barriers to seeking medical help. healthcare practitioners should reassure female patients to encourage care-seeking behaviour. a national screening programme is also recommended to increase awareness and early diagnosis of cervical cancer in oman. keywords: cervical cancer; knowledge; awareness; risk factors; health care seeking behavior; women; oman. املرتبطة والأعرا�ض اخلطر بعوامل يتعلق فيما العمانية املراأة لدى واملواقف املعرفة تقييم اإىل الدرا�شة هذه هدفت الهدف: امللخ�ص: دي�شمرب بني املقطعية الدرا�شة هذه اأجريت الطبية. الطريقة: امل�شاعدة طلب دون حتول التي العوائق اإىل بالإ�شافة الرحم عنق ب�رشطان ا�شتبيان من العربية باللغة معتمده ن�شخة ا�شتخدام مت عمان. م�شقط، يف قابو�ض ال�شلطان جامعة م�شت�شفى يف 2018 ومار�ض 2017 الدرا�شة. فرتة خالل قابو�ض ال�شلطان جامعة م�شت�شفى زارت عمانية امراأة 550 من بيانات جلمع الرحم عنق ب�رشطان الوعي قيا�ض بعوامل املعرفة من منخف�شة م�شتويات الن�شاء اأظهرت عام، ب�شكل .)89.1% ال�شتجابة: امراأة )معدل 490 جمموعه ما �شاركت النتائج: من العديد اإجناب هو �شيوًعا الأكرث اخلطر عامل كان التوايل(. على 45.0% و 28.5%( واأعرا�شه الرحم عنق ب�رشطان الإ�شابة خطر كان ال�شديد اخلوف اأن الن�شاء ذكرت .)69.8%( املربر غري املهبلي النزيف كان املعروفة الأعرا�ض اأكرث اأن حني يف ،)36.1% الأطفال �رشطان واأعرا�ض بعالمات اأكرب مبعرفة اإح�شائية دللة ذات خمتلفة عوامل ارتبطت .)68.0%( الطبية امل�شاعدة طلب اأمام عائق اأكرب عنق الرحم، مبا يف ذلك م�شتوى التعليم )p > 0.05؛ ci[: 1.0-8.22[ فا�شل الثقة %95؛ 2.85= ]or[ ن�شبة الأرجحية( ، الدخل املادي )p >0.05؛ ci: 1.70-11.12 %95؛ or = 4.34(، عدد مرات احلمل )p >0.05؛ ci: 1.38-9.36 %95؛ or = 3.59( والتاريخ العائلي يتعلق فيما املعرفة �شعف العمانيات الن�شاء اأظهرت ، عام ب�شكل اخلال�صة: .)or = 1.71 %95؛ ci: 1.0-2.90 p؛ >0.05( لل�رشطان ب�رشطان عنق الرحم. بالإ�شافة اإىل ذلك ، حددت الن�شاء العمانيات العديد من احلواجز النف�شيه لطلب امل�شاعدة الطبية. يجب على ممار�شي ا ب�رشورة وجود برنامج واطباء الرعاية ال�شحية طماأنة املري�شات وحماولة ت�شجيع �شلوك طلب الرعاية ال�شحيه. تو�شى الدرا�شه اأي�شً فح�ض وطني ل�رشطان عنق الرحم يف عمان وذالك لزيادة الوعي والت�شخي�ض املبكر ل�رشطان عنق الرحم يف �شلطنة عمان. الكلمات املفتاحية: �رشطان عنق الرحم ؛املعرفه؛ الوعي؛ عوامل اخلطر؛ �شلوك البحث عن الرعاية ال�شحية؛ ن�شاء؛ ُعمان. knowledge of risk factors, symptoms and barriers to seeking medical help for cervical cancer among omani women attending sultan qaboos university hospital *mohammed h. al-azri,1 maytha al-saidi,2 eman al-mutairi,2 sathiya m. panchatcharam3 clinical & basic research sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e301–309, epub. 5 oct 20 submitted21 oct 19 revisions req. 22 dec 19 & 2 feb 20; revisions recd. 8 jan & 6 feb 20 accepted 17 mar 20 https://doi.org/10.18295/squmj.2020.20.03.009 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ knowledge of risk factors, symptoms and barriers to seeking medical help for cervical cancer among omani women attending sultan qaboos university hospital e302 | squ medical journal, august 2020, volume 20, issue 3 cervical cancer is the fourth most common cancer affecting women worldwide. with an estimated 570,000 new cases diagnosed in 2018, cervical cancer represents 6.6% of all cancers affecting women.1 the majority of deaths (90%) from cervical cancer occur in lowand middleincome countries, largely due to a lack of cancer screening programmes, poor health infrastructure and delays in diagnosis.1,2 most women diagnosed with cervical cancer in lowand middle-income countries are aged between 15–49 years old.3 the main risk factor for cervical cancer is human papillomavirus (hpv) infection, particularly type 16.4 the virus can be detected in approximately 96.6% of women with cervical cancer; as such, prophylactic hpv vaccines could prevent up to 70–80% of cervical cancer cases.5 other risk factors include having a history of sexually-transmitted diseases (stds) or immunosuppression, engaging in sex at an early age (i.e. before 17 years old) or with multiple partners and using oral contraceptives or smoking cigarettes.6,7 knowledge of cancer symptoms among members of the public can prompt early medical help-seeking behaviours, thereby leading to earlier diagnosis and improved survival rates and prognosis.8 however, studies conducted in both developed and developing countries have shown that women have poor knowledge regarding cervical cancer risk factors and symptoms, which leads to many patients being diagnosed at later stages of the disease.9,10 in middle eastern countries, previous studies have reported several barriers to cervical cancer screening including poor knowledge of and negative attitudes towards risk factors (particularly hpv infection), physicians not referring or encouraging patients to take part in screening, fear of the results and concern regarding the gender of the doctor performing the test.11–13 although government-funded cervical screening services are currently available in oman, they are only performed at the patient’s request or if ordered by a doctor; moreover, as in other middle eastern countries, there is no national programme to promote cervical cancer screening or hpv vaccination.14,15 a recent study of female medical staff, university graduate students and gynaecology outpatients in oman revealed low levels of cervical cancer-related knowledge and awareness of cervical cancer screening.16 therefore, the aim of this study was to identify levels of knowledge among omani women regarding cervical cancer-related risk factors, symptoms and barriers to seeking medical help. methods this cross-sectional study was conducted between december 2017 and march 2018 at the sultan qaboos university hospital (squh), a tertiary care teaching hospital located in muscat, oman, which receives patients referred from primary healthcare centres located in muscat governorate and governmental hospitals throughout the country. this institution was selected for the study due to the high likelihood of recruiting a heterogeneous group of women originating from different regions of oman and for the sake of convenience in collecting data. a convenience sample was recruited of adult omani female patients of >18 years of age attending squh as well as those accompanying them. the required sample size was calculated to be 400 based on the assumption that omani women would have moderate knowledge of cervical cancer (50%), with a precision of 5% and a confidence level of 95%. however, in order to allow for missing responses, a total of 550 women were recruited. seriously ill women or those who were in pain were excluded from the study. a validated arabic-language version of the cervical cancer awareness measure (ccam) questionnaire was developed to collect data from the participants. the original ccam is an englishlanguage questionnaire that includes questions to measure awareness of cervical cancer risk factors (11 items), warning symptoms and anticipated time before seeking medical help for each symptom (12 items) and barriers to seeking medical help (10 items). the survey has been validated in multiple forms (i.e. by telephone, during face-to-face interviews and when self-completed) with high validity and test-retest reliability.17–19 in order to be relevant to the omani population, the sociodemographic section of the ccam was advances in knowledge omani women have low levels of knowledge regarding cervical cancer. omani women reported several emotional barriers to seeking early medical attention for signs and symptoms of cervical cancer. application to patient care healthcare workers in oman should try to educate female patients regarding cervical cancer. decision-makers should be aware of potential emotional barriers affecting care-seeking behaviours when raising awareness about cervical cancer. mohammed h. al-azri, maytha al-saidi, eman al-mutairi and sathiya m. panchatcharam clinical and basic research | e303 modified and the entire questionnaire was translated to arabic using forwards-backwards translation methods. a pilot study of 50 women was conducted to assess the clarity, cultural validity and reliability of the translated questionnaire. based on a standardised item analysis, the internal consistency of the arabic ccam questionnaire was high (cronbach’s α = 0.90). subsequently, two female medical students were trained to distribute and collect the translated ccam questionnaires from the participants. women who were literate were asked to complete the survey themselves, whereas the questionnaire was administered to illiterate participants by the medical students via face-to-face interviews. the survey was conducted either in the waiting areas of the outpatient clinic or in the external resting area outside squh. data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). for the descriptive analysis, findings were presented as numbers and percentages. a chi-square test was used to determine associations between demographic factors and knowledge of cervical cancer signs and symptoms. a multinomial analysis was conducted to adjust for various factors. a p value of <0.05 was considered statistically significant. this study was approved by the medical research and ethics committee of the college of medicine and health sciences of sultan qaboos university in muscat, oman (mrec#1190). all women provided written informed consent before participating in the study, following a detailed explanation of the study’s purposes and nature. women who did not agree to participate in the study were informed that this decision would not affect their medical care. results a total of 490 women participated in the study (response rate: 89.1%). the mean age was 30.3 ± 7.6 years old (range: 18–68 years). the majority of women table 1: sociodemographic characteristics and awareness of cervical cancer among omani women attending sultan qaboos university hospital (n = 490) variable n (%) age in years (n = 490) 18–30 276 (56.3) >30 214 (43.7) marital status (n = 490) single 110 (22.5) married 370 (75.5) divorced/widowed 10 (2.0) education level (n = 490) none 33 (6.8) secondary 127 (25.9) university 302 (61.6) postgraduate and above 28 (5.7) monthly income in omr (n = 471) <500 73 (15.5) 500–1,000 202 (42.9) 1,000–2,000 147 (31.2) >2,000 49 (10.4) number of marriages (n = 484) 0 146 (30.2) 1 328 (67.8) 2 7 (1.4) >2 3 (0.6) duration of marriage in years (n = 355) 1–5 144 (40.6) 6–11 96 (27.0) 16–20 67 (18.9) >20 48 (13.5) number of pregnancies (n = 416) 0 94 (22.6) 1 80 (19.2) 2–4 139 (33.4) >4 103 (24.8) do you know about cervical cancer? (n = 488) yes 181 (37.1) no 307 (62.9) if yes, what was the source of your knowledge? (n = 263) media (e.g. tv, newspapers or lectures) 137 (52.1) obgyn doctor 72 (27.4) relatives/friends 18 (6.9) family doctor 9 (3.4) social media 8 (3.0) other 19 (7.2) how common is cervical cancer in oman? (n = 484) common 112 (23.1) not common 80 (16.5) i don’t know 292 (60.4) do you think that cervical cancer can be cured if it is detected earlier? (n = 487) yes 390 (80.1) no 4 (0.8) i don’t know 93 (19.1) omr = omani rials; tv = television; obgyn = obstetrics and gynaecology. knowledge of risk factors, symptoms and barriers to seeking medical help for cervical cancer among omani women attending sultan qaboos university hospital e304 | squ medical journal, august 2020, volume 20, issue 3 figure 1: awareness of cervical cancer risk factors among omani women attending sultan qaboos university hospital (n = 490). hpv = human papillomavirus. figure 2: recognition of cervical cancer symptoms among omani women attending sultan qaboos university hospital (n = 490). table 2: anticipated time to seek medical help in response to possible cervical cancer symptoms among omani women attending sultan qaboos university hospital (n = 490) risk factor time before seeking help in percentage within two weeks within a month within six months after six months never unexplained vaginal bleeding 88.8 5.1 1.8 0.6 3.7 blood in stool or urine 85.0 6.2 3.5 1.2 4.1 vaginal bleeding during or after sex 77.6 6.8 6.2 2.1 7.3 persistent vaginal discharge 76.6 10.3 5.7 1.6 5.7 postmenopausal bleeding 76.6 8.4 8.0 2.5 4.5 persistent diarrhoea 72.2 6.2 6.0 2.7 13.0 pelvic pain 70.8 11.3 107 1.0 6.2 bleeding between periods 67.7 10.7 13.8 1.6 6.2 discomfort or pain during sex 64.3 8.5 11.6 2.9 12.7 lower back pain 58.5 13.7 15.1 3.1 9.6 disturbance in menstrual cycle 48.9 12.1 24.6 4.9 9.4 unexplained weight loss 48.2 10.9 16.0 6.1 18.9 figure 3: reported barriers to seeking medical help for cervical cancer symptoms among omani women attending sultan qaboos university hospital (n = 490). mohammed h. al-azri, maytha al-saidi, eman al-mutairi and sathiya m. panchatcharam clinical and basic research | e305 ta bl e 3: a ss oc ia ti on s be tw ee n so ci od em og ra ph ic v ar ia bl es a nd k no w le dg e re ga rd in g ce rv ic al c an ce r si gn s an d sy m pt om s am on g o m an i w om en a tt en di ng s ul ta n q ab oo s u ni ve rs it y h os pi ta l ( n = 4 90 ) v ar ia bl e si gn o r sy m pt om o r (9 5% c i) u ne xp la in ed va gi na l bl ee di ng pe rs is te nt va gi na l di sc ha rg e pe lv ic p ai n lo w er b ac k pa in d is co m fo rt or p ai n du ri ng s ex b lo od in st oo l o r u ri ne po st m en op au sa l bl ee di ng u ne xp la in ed w ei gh t l os s d is tu rb an ce in m en st ru al cy cl e pe rs is te nt di ar rh oe a b le ed in g be tw ee n pe ri od s v ag in al bl ee di ng du ri ng o r af te r s ex a ge in y ea rs ≤3 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 >3 0 0. 84 (0 .4 7– 1. 48 ) 0. 89 (0 .5 3– 1. 48 ) 1. 57 (0 .9 4– 2. 61 ) 1. 14 (0 .6 9– 1. 90 ) 1. 05 (0 .6 3– 1. 75 ) 1. 60 (0 .5 6– 4. 53 ) 0. 85 (0 .5 1– 1. 42 ) 0. 95 (0 .5 6– 1. 62 ) 0. 57 (0 .3 4– 0. 94 )* 1. 64 (0 .7 2– 3. 75 ) 1. 19 (0 .7 1– 1. 99 ) 1. 24 (0 .7 4– 2. 10 ) ed uc at io n le ve l n on e 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 se co nd ar y 2. 67 (0 .9 4– 7. 5) 0. 76 (0 .2 9– 2. 0) 1. 48 (0 .5 5– 4. 01 ) 2. 03 (0 .7 3– 5. 66 ) 1. 30 (0 .4 9– 3. 47 ) 1. 60 (0 .5 6– 4. 53 ) 2. 60 (0 .9 4– 7. 19 ) 1. 10 (0 .3 8– 3. 20 ) 1. 92 (0 .7 1– 5. 23 ) 0. 72 (0 .1 7– 3. 40 ) 1. 99 (0 .7 2– 5. 53 ) 1. 86 (0 .6 5– 5. 34 ) u ni ve rs ity / po st gr ad ua te 2. 84 (0 .9 5– 8. 49 ) 0. 98 (0 .3 5– 2. 71 ) 2. 33 (0 .8 3– 6. 54 ) 2. 12 (0 .7 3– 6. 17 ) 2. 03 (0 .7 2– 5. 68 ) 2. 34 (0 .7 9– 6. 93 ) 2. 85 (1 .0 – 8. 22 )* 1. 22 (0 .4 1– 3. 69 ) 2. 2 (0 .8 0– 6. 38 ) 0. 69 (0 .1 5– 3. 26 ) 2. 78 (0 .9 6– 8. 03 ) 2. 23 (0 .7 5– 6. 68 ) m ar it al st at us si ng le 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 m ar ri ed 1. 04 (0 .4 2– 2. 61 ) 1. 03 (0 .4 2– 2. 52 ) 0. 98 (0 .4 1– 2. 37 ) 1. 14 (0 .4 6– 2. 81 ) 2. 21 (0 .8 9– 5. 50 ) 1. 09 (0 .4 6– 2. 63 ) 1. 18 (0 .4 9– 2. 86 ) 1. 52 (0 .7 2– 3. 20 ) 0. 66 (0 .2 7– 1. 60 ) 9. 36 (1 .1 8– 49 .3 9) * 2. 58 (1 .0 5– 6. 35 )* 2. 89 (1 .0 6– 7. 87 )* m on th ly in co m e in o m r <5 00 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 50 0– 1, 00 0 2. 58 (1 .3 – 5. 08 )* 2. 24 (1 .1 5– 4. 34 )* 1. 19 (0 .6 2– 2. 29 ) 0. 72 (0 .3 7– 1. 40 ) 1. 16 (0 .5 9– 2. 28 ) 0. 81 (0 .4 1– 1. 60 ) 1. 59 (0 .8 2– 3. 09 ) 1. 52 (0 .7 2– 3. 20 ) 1. 21 (0 .6 3– 2. 34 ) 1. 16 (0 .3 8– 3. 54 ) 1. 84 (0 .9 3– 3. 65 ) 1. 53 (0 .7 5– 3. 15 ) 1, 00 0– 2, 00 0 2. 43 (1 .1 1– 5. 31 )* 2. 0 (0 .9 5– 4. 2) 1. 08 (0 .5 2– 2. 27 ) 0. 99 (0 .4 7– 2. 07 ) 1. 23 (0 .5 8– 2. 62 ) 0. 94 (0 .4 4– 2. 02 ) 1. 63 (0 .7 7– 3. 44 ) 2. 33 (1 .0 3– 5. 27 )* 1. 14 (0 .5 5– 2. 39 ) 1. 13 (0 .3 1– 4. 09 ) 1. 91 (0 .8 9– 4. 09 ) 2. 13 (0 .9 6– 4. 72 ) >2 ,0 00 4. 09 (1 .4 9– 11 .2 )* 2. 42 (1 .0 1– 5. 83 )* 1. 28 (0 .5 4– 3. 04 ) 1. 45 (0 .6 1– 3. 47 ) 1. 97 (0 .8 2– 4. 77 ) 1. 03 (0 .4 2– 2. 50 ) 2. 82 (1 .1 6– 6. 90 )* 3. 43 (1 .3 6– 8. 65 )* 1. 86 (0 .7 8– 4. 44 ) 4. 79 (1 .3 0– 17 .6 1) * 4. 37 (1 .7 5– 10 .9 2) * 4. 34 (1 .7 0– 11 .1 2) * n um be r o f p re gn an ci es 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1 1. 13 (0 .4 9– 2. 59 ) 0. 81 (0 .3 6– 1. 79 ) 0. 91 (0 .4 1– 2. 0) 1. 03 (0 .4 6– 2. 30 ) 0. 73 (0 .3 3– 1. 61 ) 0. 78 (0 .3 5– 1. 72 ) 1. 07 (0 .4 9– 2. 36 ) 0. 64 (0 .2 8– 1. 46 ) 1. 05 (0 .4 8– 2. 31 ) 0. 29 (0 .1 0– 0. 82 )* 0. 67 (0 .3 1– 1. 48 ) 1. 37 (0 .6 1– 3. 05 ) 2– 4 1. 55 (0 .7 1– 3. 38 ) 0. 87 (0 .4 1– 1. 84 ) 0. 92 (0 .4 4– 1. 94 ) 1. 14 (0 .5 4– 2. 41 ) 0. 80 (0 .3 8– 1. 69 ) 0. 49 (0 .2 3– 1. 04 ) 1. 48 (0 .7 0– 3. 11 ) 0. 79 (0 .3 7– 1. 69 ) 1. 12 (0 .5 3– 2. 34 ) 0. 17 (0 .0 6– 0. 47 )* 0. 63 (0 .3 0– 1. 31 ) 1. 07 (0 .5 0– 2. 27 ) >4 3. 59 (1 .3 8– 9. 36 )* 1. 40 (0 .6 0– 3. 28 ) 0. 62 (0 .2 7– 1. 43 ) 0. 82 (0 .3 5– 1. 90 ) 1. 51 (0 .6 6– 3. 49 ) 1. 01 (0 .4 4– 2. 33 ) 2. 39 (1 .0 2– 5. 58 )* 0. 89 (0 .3 8– 2. 09 ) 1. 63 (0 .7 1– 3. 75 ) 0. 16 (0 .0 5– 0. 50 )* 0. 78 (1 .1 3– 0. 49 ) 1. 28 (0 .5 5– 2. 96 ) fa m ily h is to ry o f c an ce r n o 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 ye s 1. 02 (0 .5 6– 1. 88 ) 1. 33 (0 .7 7– 2. 28 ) 1. 07 (0 .6 3– 1. 81 ) 1. 01 (0 .6 0– 1. 72 ) 1. 12 (0 .6 6– 1. 90 ) 0. 84 (0 .4 8– 1. 46 ) 1. 21 (0 .7 1– 2. 07 ) 1. 71 (1 .0 – 2. 90 )* 1. 26 (0 .7 4– 2. 15 ) 0. 94 (0 .4 1– 2. 14 ) 0. 78 (0 .4 6– 1. 34 ) 1. 23 (0 .7 1– 2. 11 ) o r = od ds ra tio ; c i = co nfi de nc e i nt er va l; o m r = o m an i r ia ls . *s ig ni fic an t a t p < 0. 05 . knowledge of risk factors, symptoms and barriers to seeking medical help for cervical cancer among omani women attending sultan qaboos university hospital e306 | squ medical journal, august 2020, volume 20, issue 3 were married (75.5%), with 40.6% having been married for five years or less. most women had been educated to a university or postgraduate level (67.3%) and the majority (99.8%) were non-smokers. few women (20.3%) had a family history of cancer; of these, 30.3% knew someone with breast cancer [table 1]. a bivariate analysis showed that average overall awareness of cervical cancer risk factors was low (28.5%). the most recognised risk was having many children (36.1%) while the least recognised was having sex at a young age (23.3%) [figure 1]. in addition, average overall awareness of cervical symptoms was low (45.0%). the most commonly recognised symptom was unexplained vaginal bleeding (69.8%); in contrast, persistent diarrhoea was least frequently recognised (10.6%) [figure 2]. most participants stated that they would seek medical help within two weeks when faced with each cervical cancer sign or symptom (48.2– 88.8%) [table 2]. overall, the most commonly reported barriers to seeking medical help were emotional barriers (i.e. being too scared or embarrassed to seek medical help or being afraid of the doctor’s findings), while service-related barriers (i.e. difficulty making an appointment or relating their concerns to the doctor) were infrequently noted [figure 3]. after adjusting for other variables, a multivariate analysis showed that older women were significantly less likely than their younger counterparts to recognise menstrual cycle disturbances as a symptom of cervical cancer (odds ratio [or] = 0.57; 95% confidence interval [ci]: 0.34–0.94; p <0.05). however, women with a university or postgraduate degree were significantly more likely than women with no formal education to be aware of postmenopausal bleeding as a symptom of cervical cancer (or = 2.85; 95% ci: 1.0–8.22; p <0.05). married women were significantly more likely than single women to recognise persistent diarrhoea (or = 9.36; 95% ci: 1.18–49.39; p <0.05), bleeding between periods (or = 2.58; 95% ci: 1.05–6.35; p <0.05) and vaginal bleeding during or after sex (or = 2.89; 95% ci: 1.06–7.87; p <0.05) as symptoms of cervical cancer [table 3]. participants in a higher income bracket were significantly more likely than women with lower incomes to demonstrate awareness of various symptoms of cervical cancer including unexplained vaginal bleeding (or = 4.09; 95% ci: 1.49–11.2; p <0.05), persistent vaginal discharge (or = 2.42; 95% ci: 1.01–5.83; p <0.05), postmenopausal bleeding (or = 2.82; 95% ci: 1.16–6.90; p <0.05), unexplained weight loss (or = 3.43; 95% ci: 1.36–8.65; p <0.05), persistent diarrhoea (or = 4.79; 95% ci: 1.30–17.61; p <0.05), bleeding between periods (or = 4.37; 95% ci: 1.75–10.92; p <0.05) and vaginal bleeding during or after sex (or = 4.34; 95% ci= 1.70–11.12; p <0.05) [table 3]. parity was also found to be a significant factor for awareness with multiparous women significantly more likely than nulliparous women to recognise unexplained vaginal bleeding (or = 3.59; 95% ci: 1.38–9.36; p <0.05) and postmenopausal bleeding (or = 2.39; 95% ci: 1.02–5.58; p <0.05) as symptoms of cervical cancer. however, the reverse was true when it came to awareness of persistent diarrhoea as a symptom of cervical cancer (or = 0.16; 95% ci: 0.05–0.50; p <0.05). finally, women with a family history of cancer were significantly more likely than those without to recognise unexplained weight loss as a symptom of cervical cancer (or = 1.71; ci: 1.0–2.90; p <0.05) [table 3]. discussion after breast and thyroid cancer, cervical cancer is the third most common type of cancer affecting women in oman, with an annual incidence of 26.2 per 100,000 individuals.20 as in other developing countries, cancer patients in oman usually present at a later stage and younger age.21 in the current study, only 37.1% of omani women knew of cervical cancer and the average level of awareness regarding cervical cancer-related risk factors was low (28.5%). these findings support those of a previous study observing that knowledge levels of cervical cancer and cervical cancer screening were low among omani women.16 other studies from developing countries, however, have reported conflicting results. a study conducted in uganda found that recognition of cervical cancer-related risk factors among women was high, particularly for risk factors such as having multiple sexual partners or hpv infection and engaging in sexual activity at a young age.10 greater knowledge levels in african countries such as uganda and cameroon might be due to the existence of preventative campaigns to stop the spread of stds such as hiv and hpv.10,22 even in western countries such as the uk, most women are not aware that hpv is sexually transmitted and can cause cervical cancer.23 low levels of knowledge among omani women regarding cervical cancer risk factors might be due to the unavailability of a national policy or programme for cervical cancer screening or hpv vaccination.14,15 although arab countries traditionally have lower rates of hpv infection due to social and cultural factors which encourage more conservative sexual behaviour, the prevalence of hpv infection is increasing at an alarming rate as a result of increased levels of sexual activity by younger members of the population (i.e. mohammed h. al-azri, maytha al-saidi, eman al-mutairi and sathiya m. panchatcharam clinical and basic research | e307 10–24 years old).24 furthermore, the majority of women in these countries are either not aware of the availability of the hpv vaccination or do not wish to be vaccinated.15,25 a fear of potential side-effects, the absence of clear benefits and objections from religious authorities have been cited as reasons for not accepting the hpv vaccine.24,25 the present study noted low overall recognition of cervical cancer symptoms (45.0%); this frequency of recognition supports previous research conducted in the uk, in which 75.0% of participants were unable to recall any key cervical cancer symptoms.9 women in oman have also previously shown low levels of knowledge regarding other gynaecological cancers such as ovarian and breast cancer.26,27 however, higher levels of recognition were observed for more visible cervical cancer symptoms such as vaginal bleeding or persistent vaginal discharge; this difference in levels of recognition is to be expected, as people usually tend to be more cognisant of and alarmed by visible symptoms, thereby influencing them to seek medical help.28 nevertheless, the key issue is not only recognition of cervical cancer symptoms themselves, but also whether such symptoms are perceived by women as a serious concern.26 for example, less than 50% of the women in the present study reported that they would seek early medical help (i.e. within two weeks) for unexplained weight loss, which is often not perceived to be a specific symptom of cervical cancer. in the current study, various emotional barriers— such as fear, anxiety about what the doctor might find, embarrassment and a lack of confidence in speaking with the doctor—were frequently reported as reasons for not seeking medical help. fear of a cancer diagnosis is a common factor influencing delays in seeking medical help.8 in a conservative society such as oman, many women may feel embarrassed to talk to or be examined internally by a male doctor, particularly when dealing with sensitive or gynaecological symptoms. although both omani and expatriate female physicians are employed at all local healthcare centres and government hospitals in oman, female muslim patients often report delays in seeking care due to a perceived lack of female clinicians, particularly among those with higher self-rated levels of modesty and religious belief.29 several factors were found to be associated with awareness of various cervical cancer signs and symptoms in the current study including age, education level, income, parity and a family history of cancer. older omani women were significantly less likely than younger women to recognise menstrual cycle disturbances as a symptom of cervical cancer; in contrast, younger participants in the uk have been reported to demonstrate lower levels of knowledge regarding cervical cancer risk factors.9 this difference in findings may be because younger omani women tend to have higher education levels than older women, as formal education was only established 50 years ago in oman, thus explaining why they were able to recognise more risk factors and symptoms than their older counterparts.26 in addition, both multiparous women and women with a family history of cancer were significantly more likely to recognise cervical cancer symptoms compared to nulliparous women or those without a family history of cancer. these findings support those reported in a previous study conducted in oman.16 multiparous women are more likely to be exposed to sources of health-related knowledge such as through information leaflets or when visiting healthcare professionals for check-ups. the distribution of tailored information leaflets at hospitals or local healthcare centres has been found to be an effective measure for increasing cancer-related knowledge levels.28 moreover, having close family members with cancer would presumably also increase one’s knowledge of cancer, as such women would receive information from healthcare providers and might also be involved in treatment decision-making and caring for the patient.30,31 this study was subject to certain limitations. first, the study was conducted at a single teaching hospital in muscat, which could affect the generalisability of the results. however, the authors believe that this is not a major issue, as many patients attending this hospital are originally from other regions in oman. second, some women had a family history of cancer and may therefore have introduced the possibility of bias when answering the survey. nevertheless, the questionnaire was specifically tailored to cervical symptoms; moreover, the authors of the original ccam questionnaire do not recommend excluding participants with a family history of cancer.17 third, although the ccam questionnaire was translated to arabic, some cultural differences may have affected the results. finally, although the medical students were trained to remain neutral while administering the questionnaire to illiterate women, some disparity may have been present in the meaning of some translated statements. results from the pilot study, however, indicated that the internal consistency of the arabic version of the ccam questionnaire was high. conclusion overall awareness of cervical cancer-related risk factors and symptoms among omani women was low. educating members of the public, perhaps by knowledge of risk factors, symptoms and barriers to seeking medical help for cervical cancer among omani women attending sultan qaboos university hospital e308 | squ medical journal, august 2020, volume 20, issue 3 distributing information leaflets at local healthcare centres and government hospitals in oman or via collaboration with the omani women’s association, is recommended to increase knowledge of signs and symptoms of cancer and hopefully encourage early diagnosis and treatment. healthcare practitioners should reassure patients regarding the availability of female doctors for consultations of a gynaecological or sensitive nature to try to decrease emotional barriers to seeking early medical help. finally, as it is likely that acceptance of hpv vaccinations in oman might be limited due to local cultural and religious stigma, further research is needed to explore attitudes towards the introduction of a national cervical cancer screening and hpv vaccination programme. a c k n o w l e d g e m e n t s the authors are grateful to all of the women who agreed to take part in this study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. cervical cancer. from: www.who. int/cancer/prevention/diagnosis-screening/cervical-cancer/ en/ accessed: feb 2020. 2. torre la, siegel rl, ward em, jemal a. global cancer inci dence and mortality rates and trends: an update. cancer epid emiol biomarkers prev 2016; 25:16–27. https://doi.org/10.1158 /1055-9965.epi-15-0578. 3. joint united nations programme on hiv/aids. cervical cancer. from: www.unaids.org/en/cervical_cancer accessed: feb 2020. 4. dunne ef, unger er, sternberg m, mcquillan g, swan dc, patel ss, et al. prevalence of hpv infection among females in the united states. jama 2007; 297:813–9. https://doi. org/10.1001/jama.297.8.813. 5. crosbie ej, einstein mh, franceschi s, kitchener hc. human papillomavirus and cervical cancer. lancet 2013; 382:889–99. https://doi.org/10.1016/s0140-6736(13)60022-7. 6. international collaboration of epidemiological studies of cervical cancer; appleby p, beral v, berrington de gonzález a, colin d, franceschi s, et al. carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. int j cancer 2016; 118:1481–95. https://doi.org/10.1002/ijc.21493. 7. schiffman m. cervical cancer screening: epidemiology as the necessary but not sufficient basis of public health practice. prev med 2017; 98:3–4. https://doi.org/10.1016/j.ypmed.2016.12.028. 8. macleod u, mitchell ed, burgess c, macdonald s, ramirez aj. risk factors for delayed presentation and referral of symptomatic cancer: evidence for common cancers. br j cancer 2009; 101:s92–101. https://doi.org/10.1038/sj.bjc.6605398. 9. low el, simon ae, lyons j, romney-alexander d, waller j. what do british women know about cervical cancer symptoms and risk factors? eur j cancer 2012; 48:3001–8. https://doi. org/10.1016/j.ejca.2012.05.004. 10. mwaka ad, orach cg, were em, lyratzopoulos g, wabinga h, roland m. awareness of cervical cancer risk factors and symptoms: cross-sectional community survey in post-conflict northern uganda. health expect 2016; 19:854–67. https://doi. org/10.1111/hex.12382. 11. al sairafi m, mohamed fa. knowledge, attitudes, and practice related to cervical cancer screening among kuwaiti women. med princ pract 2009; 18:35–42. https://doi. org/10.1159/000163044. 12. sait kh. attitudes, knowledge, and practices in relation to cervical cancer and its screening among women in saudi arabia. saudi med j 2009; 30:1208–12. 13. amarin zo, badria lf, obeidat br. attitudes and beliefs about cervical smear testing in ever-married jordanian women. east mediterr health j 2008; 4:389–97. 14. alsaad ma, shamsuddin k, fadzil f. knowledge towards hpv infection and hpv vaccines among syrian mothers. asian pac j cancer prev 2012; 13:879–83. https://doi.org/1010.7314/ apjcp.2012.13.3.879. 15. ortashi o, raheel h, shalal m, osman n. awareness and knowledge about human papillomavirus infection and vaccination among women in uae. asian pac j cancer prev 2013; 14:6077–80. https://doi.org/10.7314/apjcp.2013.14.10.6077. 16. alwahaibi n, alsalami w, alramadhani n, alzaabi a. factors influencing knowledge and practice regarding cervical cancer and pap smear testing among omani women. asian pac j cancer prev 2018; 19:3367–74. https://doi.org/10.31557/apjcp.2018.1 9.12.3367. 17. cancer research uk. cervical cancer awareness measure (cervical cam): toolkit. from: www.cancerresearchuk. org/sites/default/files/health_professional_cervical_cancer_ aw a re n e s s _ m e a s u re _ to o l k i t _ v e r s i o n _ 2 . 1 _ 0 9 . 0 2 . 1 1 . p d f accessed: feb 2020. 18. al-azri m, al-rasbi k, al-hinai m, davidson r, al-maniri a. awareness of risk factors for cancer among omani adults: a community based study. asian pac j cancer prev 2014; 15:5401–6. https://doi.org/10.7314/apjcp.2014.15.13.5401. 19. simon ae, wardle j, grimmett c, power e, corker e, menon u, et al. ovarian and cervical cancer awareness: development of two validated measurement tools. j fam plann reprod health care 2012; 38:167–74. https://doi.org/10.1136/jfprhc-2011-100118. 20. al-lawati na, al-bahrani bj, al-raisi ss, al-lawati ja. twenty-year trends of cancer incidence in omanis, 1996-2015. oman med j 2019; 34:361–87. 21. kumar s, burney ia, al-ajmi a, al-moundhri ms. changing trends of breast cancer survival in sultanate of oman. j oncol 2011; 2011:316243. https://doi.org/10.1155/2011/316243. 22. wamai rg, ayissi ca, oduwo go, perlman s, welty e, manga s, et al. assessing the effectiveness of a communitybased sensitization strategy in creating awareness about hpv, cervical cancer and hpv vaccine among parents in north west cameroon. j community health 2012; 37:917–26. https://doi. org/10.1007/s10900-012-9540-5. 23. marlow la, waller j, wardle j. public awareness that hpv is a risk factor for cervical cancer. br j cancer 2007; 97:691–4. https://10.1038/sj.bjc.6603927. 24. ortashi o, raheel h, khamis j. acceptability of human papillomavirus vaccination among male university students in the united arab emirates. vaccine 2013; 31:5141–4. https:// doi.org/10.1016/j.vaccine.2013.08.016. 25. ortashi o, raheel h, shalal m. acceptability of human papilloma virus vaccination among women in the united arab emirates. asian pac j cancer prev 2014; 15:2007–11. https:// doi.org/10.7314/apjcp.2014.15.5.2007. https://doi.org/10.1158/1055-9965.epi-15-0578 https://doi.org/10.1158/1055-9965.epi-15-0578 https://doi.org/10.1001/jama.297.8.813 https://doi.org/10.1001/jama.297.8.813 https://doi.org/10.1016/s0140-6736%2813%2960022-7 https://doi.org/10.1002/ijc.21493 https://doi.org/10.1016/j.ypmed.2016.12.028 https://doi.org/10.1038/sj.bjc.6605398 https://doi.org/10.1016/j.ejca.2012.05.004 https://doi.org/10.1016/j.ejca.2012.05.004 https://doi.org/10.1111/hex.12382 https://doi.org/10.1111/hex.12382 https://doi.org/10.1159/000163044 https://doi.org/10.1159/000163044 https://doi.org/1010.7314/apjcp.2012.13.3.879 https://doi.org/1010.7314/apjcp.2012.13.3.879 https://doi.org/10.7314/apjcp.2013.14.10.6077 https://doi.org/10.31557/apjcp.2018.19.12.3367 https://doi.org/10.31557/apjcp.2018.19.12.3367 https://doi.org/10.7314/apjcp.2014.15.13.5401 https://doi.org/10.1136/jfprhc-2011-100118 https://doi.org/10.1155/2011/316243 https://doi.org/10.1007/s10900-012-9540-5 https://doi.org/10.1007/s10900-012-9540-5 https://10.1038/sj.bjc.6603927 https://doi.org/10.1016/j.vaccine.2013.08.016 https://doi.org/10.1016/j.vaccine.2013.08.016 https://doi.org/10.7314/apjcp.2014.15.5.2007 https://doi.org/10.7314/apjcp.2014.15.5.2007 mohammed h. al-azri, maytha al-saidi, eman al-mutairi and sathiya m. panchatcharam clinical and basic research | e309 26. al-azri m, al-saidi m, al-mutair e, panchatcharam sm. awareness of risk factors, symptoms and time to seek medical help of ovarian cancer amongst omani women attending teaching hospital in muscat governorate, oman. asian pac j cancer prev 2018; 19:1833–43. https://doi.org/10.22034/ apjcp.2018.19.7.1833. 27. renganathan l, ramasubramaniam s, al-touby s, seshan v, al-balushi a, al-amri w, et al. what do omani women know about breast cancer symptoms? oman med j 2014; 29:408–13. https://doi.org/10.5001/omj.2014.110. 28. austoker j, bankhead c, forbes lj, atkins l, martin f, robb k, et al. interventions to promote cancer awareness and early presentation: systematic review. br j cancer 2009; 101:s31–9. https://doi.org/10.1038/sj.bjc.6605388. 29. vu m, azmat a, radejko t, padela ai. predictors of delayed healthcare seeking among american muslim women. j womens health (larchmt) 2016; 25:586–93. https://doi.org/10.1089/ jwh.2015.5517. 30. al-bahri a, al-moundhri m, al-mandhari z, al-azri m. the role of patients’ families in treatment decision-making among adult cancer patients in the sultanate of oman. eur j cancer care (engl) 2018; 27:e12845. https://doi.org/10.1111/ ecc.12845. 31. quaife sl, forbes lj, ramirez aj, brain ke, donnelly c, simon ae, et al. recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the uk. br j cancer 2014; 110:12–8. https://doi.org/10.1038/bjc.2013.684. https://doi.org/10.22034/apjcp.2018.19.7.1833 https://doi.org/10.22034/apjcp.2018.19.7.1833 https://doi.org/10.5001/omj.2014.110 https://doi.org/10.1038/sj.bjc.6605388 https://doi.org/10.1089/jwh.2015.5517 https://doi.org/10.1089/jwh.2015.5517 https://doi.org/10.1111/ecc.12845 https://doi.org/10.1111/ecc.12845 https://doi.org/10.1038/bjc.2013.684 sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 435-441, epub. 20th nov 12 submitted 26th nov 11 revision req. 31st jan 12, revision recd. 8th feb 12 accepted 25th may 12 department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ibrahim1@squ.edu.om فعالية التعليم املشرتك بني طالب العلوم الصحية يف جامعة السلطان قابوس آن األوان لتطبيقه اآلن! اإبراهيم حممد انوا امللخ�ض: تاريخيا، يتم تعليم املهنيني ال�صحيني يف مهنة حمددة االآفاق والتي توفر بدورها فر�صا حمدودة الكت�صاب خمتلف املهارات عرب التعلم امل�صرتك بني الطلبة. اأ�صبح الكثري تبعا لذلكمن املمار�صني املوؤهلني، ولكّنهم غري مهيئني ملواجهة التحديات التي تخ�ض املمار�صة امل�صرتكة. لدى املر�صى هذه االأيام احتياجات معقدة وتتطلب عادة اأكرث من مهني متخ�ص�ض، وتعتمد الرعاية الفعالة امل�صرتكة على قدرات املتخ�ص�صني يف الرعاية ال�صحية ومدى التوا�صل مع بع�صهم البع�ض. اإن التوا�صل اجليد يعمل على حت�صني نوعية الرعاية، وحت�صني نتائج العالج. الهدف من التعليم امل�صرتك يتمّثل يف اإعداد الطالب لتقدمي الرعاية امل�صرتكة يف امل�صتقبل. تقوم كليتا الطب والعلوم فر�صة الطالب لدى لي�ض ذلك، ومع ُعمان. يف امل�صتقبلية ال�صحية العاملة القوى بتدريب قابو�ض ال�صلطان بجامعة والتمري�ض ال�صحية للتعلم امل�صرتك فيما بينهم. وهنا ال بد من اأن يتم خلق فر�ض بحيث يتعلم الطالب فيما بينهم وذلك بهدف حت�صني نوعية الرعاية التي من امُلحتمل اأن ُتقّدم يف امل�صتقبل. مفتاح الكلمات: طالب الطب، تعليم طبي، تعاون، عالقات مهنية،متعدد التخ�ص�صات، رعاية �صحية، ُعمان. abstract: historically, health professionals have been educated in profession-specific institutions which provide limited opportunities for learning interprofessional (ip) skills. many qualified practitioners are therefore poorly prepared for the challenges of ip practice (ipp). patients today have complex needs and typically require more than one professional to address their medical issues and effective ip care relies upon health care professionals’ abilities to communicate with one another. competent communication improves the quality of care, thus enhancing patient outcomes. the objective of ip education (ipe) is to prepare students to deliver ip care in the future. sultan qaboos university’s medical and nursing colleges train the future health workforce for oman. however, students have no opportunities for collaborative learning. it is imperative that opportunities be created where students learn with, about, and from each other with the aim of improving the quality of care they are likely to deliver in the future. keywords: students, medical; education, medical; collaboration; interdisciplinary; interprofessional relations; healthcare; oman. interprofessional education (ipe) activity amongst health sciences students at sultan qaboos university the time is now! ibrahim m. inuwa sounding board the purpose of all health care education is to prepare students to become professionals who can competently deliver high quality care. however, although health care professionals share common core values, their respective education programmes have traditionally been conducted separately, with students in one programme rarely meeting those in other programmes. teachers from each specialty educate and instruct their students to develop profession-specific knowledge, skills, and attitudes. simultaneously, teachers transfer their opinions of other medical professions. as a result, subsequent difficulties in teamwork are often encountered due to a lack of awareness, understanding and respect of the roles or knowledge of other health professionals.1–2 as a result of this situation, the world health interprofessional education (ipe) activity amongst health sciences students at sultan qaboos university the time is now! 436 | squ medical journal, november 2012, volume 12, issue 4 and decrease costs.8 however, moving to an ipcp model of health care service delivery first requires changing the educational experiences of health care providers during and after their qualification programmes. the rationale behind interprofessional education ipe was first introduced into the health and social care sectors over four decades ago through sporadic initiatives first implemented in north america and later in europe. the first statement hinting at the concept of ipe has been credited to dr. john f. mccreary, dean of medicine at the university of british columbia (ubc), who published an article in the canadian medical association journal (cmaj) in 1964 and stated, “all of these diverse members of the health team should be brought together during their undergraduate years, taught by the same teachers, in the same classrooms, and on the same patients.”9 this was to be followed a few years later by the emergence of ip approaches to education and collaborative care in both the usa and the uk. some examples of medical schools with distinct programmes in ipe include mcmaster in canada and linköping in sweden. these initiatives initially took place between 1975 and 1980.10 as a summary of these experiences, and to establish the underlying philosophy of ipe, a who working group followed up with a publication on the topic.10 this gave the impetus to promote ipe programmes and collaborative practices to many national and international organisations, including the australasian interprofessional practice and education network (aippen), the canadian interprofessional health collaborative (cihc), the european interprofessional education network (eipen), and the uk centre for the advancement of interprofessional education (caipe). it was the active involvement of these organisations that culminated in the publication by the who in 2010 of the framework for action on interprofessional education & collaborative practice, which serves as a blueprint for developing ipe and collaborative practice in health care.11 currently in many institutions, health care education, especially at the pre-qualification stage, is uniprofessional with students learning together in organization (who) has now firmly fixed interprofessional education (ipe) on the global health agenda, where it is recognised as a necessary component of every health professional’s education.3 according to the who, ipe refers to the process by which a group of students (or workers) from healthrelated occupations with different educational backgrounds learn together during certain periods of their education. in this phase, interaction is an important goal, and the participants learn to collaborate in providing supportive, preventive, curative, rehabilitative and other health-related services.3 the result of this training is that such professionals learn with, from, and about each other in order to improve collaboration and the quality of care. through ipe activities, participants are likely to become mutually respectful, maximise the use of collective resources, develop an awareness of individual accountabilities, and acquire competence and capabilities within respective scopes of practice. in contemporary medical practice, medical problems are often complex and are best addressed by interprofessional (ip) teams working collaboratively.4 this process, referred to as interprofessional collaborative practice (ipcp), includes effective communication and decision making which enables a synergy of group knowledge and skills with the aim of improving patient outcomes.5 for ipe to be effective, learning activities should include the following critical elements: 1) active interaction between two or more students from different health care programmes; 2) a process by which participants learn with, from, and about one another, both within and across disciplines via the experience itself, and 3) acknowledgment, but setting aside, of the differences in power and status between professions.6 numerous reports and policy documents over many years have emphasised the importance of wellarticulated teamwork in the health care setting. for example, the commission on education of health professionals for the 21st century, in a published analysis on health professions education, global health, and health workforce needs, suggested an emphasis on “the promotion of inter-professional education that breaks down professional silos while enhancing collaborative and non-hierarchical relationships.”7 meads et al. suggested that health care teams working interprofessionally have the potential to improve the quality of health care ibrahim m. inuwa sounding board | 437 information defining the types of competencies that may be required of health professionals who work collaboratively [table 1]. the who ipe and collaborative practice study group has developed a global framework for action.3 in this framework, the goal of ipe [figure 1] is envisaged as a process of preparation of a “collaborative practice-ready” work force, driven by local health needs and local health systems designed to respond to those needs. requiring students to achieve these competencies as part of the learning process ensures that they are likely to enter the workforce ready to practice effective teamwork and team-based care.15 potential benefits of interprofessional education there are a number of potential benefits to be derived from creating opportunities for ipe.17 learning in the ipe context is an important element of preparation for working in multiprofessional teams. in such a setting, prior exposure to ipe and the adoption of an attitude of interprofessional practice (ipp) could potentially improve the quality of care. this is because professionals realise that no one profession working in isolation has the expertise to respond adequately and effectively to the complexity of many service users’ needs. therefore, to ensure that care is safe, seamless, and holistic and delivered to the highest possible standard, ipp has to be adopted by all involved. ipe also allows for comparative, collaborative, and interactive learning, taking into homogenous groups (e.g. medical students learning with medical students, student nurses with other student nurses, etc.). although uniprofessional education is necessary for students to develop knowledge, skills, and attitudes relating to their own professional group, in many instances it does not allow the students to learn how to function within ip or interdisciplinary teams. contemporary health care practice, however, recognises the shifting boundaries in relation to roles and responsibilities between health care professionals. it recognises that patient needs are best met by multiskilled and collaborative health care providers.12 ipe can therefore reflect what happens in real clinical practice. it has been suggested that health care professionals who work in ip teams can best communicate and address these complex and challenging needs.13 this ip approach may also allow the sharing of expertise and perspectives in order to form a common goal of restoring or maintaining an individual’s health and improving outcomes while combining resources.14 content and competencies of interprofessional education although the need for ipe is widely recognised, there were arguments in the past as to whether or not ipc is ‘caught’ indirectly or should be taught explicitly through ipe activities. what should an ipe activity include? what competencies should be achieved? the literature provides a wealth of table 1: suggested collaborative competencies guiding interprofessional education (ipe) activities collaborative competencies 1. describe one’s roles and responsibilities clearly to other professions 2. recognise and observe the constraints of one’s role, responsibilities, and competence, yet perceive patient needs in a wider framework 3. recognise and respect the roles, responsibilities, and competence of other professions in relation to one’s own 4. work with other professions to effect change and resolve conflict in the provision of care and treatment 5. work with others to assess, plan, provide, and review care for individual patients 6. tolerate differences, misunderstandings, and shortcomings in other professions 7. facilitate ip case conferences, team meetings, etc. 8. enter into interdependent relationships with other professions ip = interprofessional adapted from: barr h. competent to collaborate: towards a competency-based model for interprofessional education.16 interprofessional education (ipe) activity amongst health sciences students at sultan qaboos university the time is now! 438 | squ medical journal, november 2012, volume 12, issue 4 during health care training include: 1) improved relationships among team members; 2) increased trust between team members; 3) opportunity to dispel negative stereotypes, and 4) improved attitudes towards other professional groups.19–22 health care literature provides multiple examples of successful teamwork and collaboration following ipe activities. parsell et al. demonstrated altered attitudes towards interprofessional work through collaborative teaching, whilst wake-dyster found that through ipe team members came to value the ip perspective stating that they felt better suited to meet the challenges of everyday work life and respond to consumer needs.23–24 although the suggestion that learning together may help people to work together more effectively seems instinctively reasonable, what evidence might indicate that the students’ experience will carry over into working practice? generally, an evaluation of ipe [figure 2] could be divided into four broad categories, with learner reaction (a measure of satisfaction with the activity) as the most basic and benefit to patients or clients (the activity resulting in better patient outcomes) being the most advanced outcome.25 clearly, the level of evaluation possible will largely depend on the setting where the ipe activity is conducted. for example, ipe based in the early stages of training will largely focus on learners’ account respective roles and responsibilities; skills and knowledge; powers and duties; value systems and codes of conduct, and opportunities and constraints. this cultivates mutual trust and respect by acknowledging differences, dispelling prejudice and rivalry, and confronting misconceptions and stereotypes. the concept of ipe is grounded in mutual respect. participants, whatever the differences in their future status in the workplace, are equal as learners. they celebrate and utilise the distinctive experiences and expertise that participants bring from their respective professional fields. this engenders respect of contributions from each profession.18 through ipe, participants can gain a deeper understanding of their own practice and how they can complement and reinforce the professional practice of others. therefore, learners within ip contexts could potentially improve their practice within their own professions. because ipe cultivates collaborative practice, there is a potential for increased professional satisfaction where mutual support eases occupational stress, either by setting limits on the demands made on any one profession or by ensuring that cross-professional support and guidance are provided if and when added responsibilities are shouldered. some of the other potential benefits of interprofessional learning (ipl) figure 1: the objective of interprofessional education is to prepare a collaborative practice-ready health workforce able to deliver optimal health services through collaborative practice in a strengthened health system, thus improving health outcomes. ibrahim m. inuwa sounding board | 439 underpin and inform the practice of ipe. students in our undergraduate medical, nursing, and allied health sciences programs spend years developing attitudes, beliefs, and insights that conform to their respective professions. however, students often complete these programmes with insufficient knowledge of the skills that facilitate working with other professional groups. as a result, many students enter the workforce poorly prepared for the challenges associated with ipp. the literature supports the introduction of ipe at a time when pre-licensure learners have integrated health-profession-specific role identity.22 several studies indicate that improved ipp in emergency response leads to better client outcomes.1,30 it is therefore logical to suggest that if people are expected to work interprofessionally, they should be educated in ipp.31 research has suggested that the way to improve team work and the quality of patient care is to develop shared learning programmes at undergraduate level.32 the educational system has a major impact on ipp because it is during professional training that such values are instilled in students.33 previous studies indicated that in some settings medical students enter educational programmes perceiving nurses as less competent and academically weaker than doctors, and with lower social status. such attitudes and perceptions have been identified as influential factors in determining the success of ipe and how both groups interact with each other in practice.34,35 learning in ip teams is increasingly an reactions, attitudes, perceptions, knowledge, and skills because the emphasis at that stage is on consciousness raising and preparation for future practice. interprofessional education and sultan qaboos university ipe has never been carried out at sultan qaboos university amongst health profession students. this is despite the fact that the current approach to health care education in many institutions is to produce professionals who are good communicators as well as adaptable, flexible team players who can collaborate with and share the same goals as other health care professionals.23 there is an assumption that this will happen automatically in the workplace, although structural, organisational and attitudinal factors may inhibit team development. structural and organisational barriers could be difficult to overcome and may reflect in large part the attitudes of individuals within such organisations.23 ipe can, however, help to change attitudes by increasing knowledge and understanding of other professionals' potential contributions towards patient care. such understanding can improve relationships, increase trust and dispel stereotypes.26 numerous educational theories inform the practice of ipe including theories of adult learning, the ‘reflective practitioner’, and social group behaviour.27–29 each of these theoretical approaches figure 2: classification of interprofessional education outcomes. interprofessional education (ipe) activity amongst health sciences students at sultan qaboos university the time is now! 440 | squ medical journal, november 2012, volume 12, issue 4 med educ online 2011; 16. 6. olenick m, allen l, smego r. interprofessional education: a concept analysis. adv med educ pract 2010; 1:75–84. 7. frenk j, chen l, bhutta z, cohen j, crisp n, evans t. health professionals for a new century: transforming education to strengthen health systems in an interdependent world. lancet 2010; 376:1923–58. 8. meads g, ashcroft j, barr h, scott r, wild a. the case for interprofessional collaboration in health and social care. oxford: blackwell publishing ltd, 2005. pp. 1–184. 9. mccreary j. the education of physicians in canada. can med assoc j 1964:1215–21. 10. world health organization. learning together to work together for health. report of a who study group on multiprofessional education of health personnel: the team approach. geneva: world health organization. technical report series who, 1988. pp. 769–74. 11. world health organization. framework for action on interprofessional education and collaborative practice. geneva: world health organization, 2010. pp. 10–11. 12. nolan m. towards an ethos of interdisciplinary practice. bmj 1995; 311:305–7. 13. lumague m, morgan a, mak d, hanna m, kwong j, cameron c, et al. interprofessional education: the student perspective. j interprof care 2006; 20:246– 53. 14. barker kk, oandasan i. interprofessional care review with medical residents: lessons learned, tensions aired--a pilot study. j interprof care 2005; 19:207–14. 15. interprofessional education collaborative expert panel. core competencies for interprofessional collaborative practice: report of an expert panel. washington, dc: interprofessional education collaborative expert panel, 2011. 16. barr h. competent to collaborate: towards a competency-based model for interprofessional education. j interprof care 1998; 12:181–7. 17. illingworth p, chelvanayagam s. benefits of interprofessional education in health care. br j nurs 2007; 16:121–4. 18. mires g, williams f, harden r, howie p, mccarey m, robertson a. multiprofessional education in undergraduate curricula can work. med teach 1999; 21:281–5. 19. wackerhausen s. collaboration, professional identity and reflection across boundaries. j interprof care 2009; 23:455–73. 20. williams a, mostyn a, fyson r. nursing and social work students' perceptions of lecturing by non-university practitioners. j interprof care 2009; 23:98–100. important part of the learning experience for students of health and social care sciences during their initial education and training and in their post-registration programmes and continuing professional development (cpd). as barr et al.36 and hammick et al.37 have shown, there is now evidence to indicate that this type of learning is an effective means of enabling practitioners to understand each other better and work more collaboratively, and thus to enhance patient and client care, and service delivery. although there are three professional programmes in the college of medicine & health sciences (comhs) and college of nursing (con) with new courses in speech therapy and radiography being planned, ipe is not anticipated as a feature in the curricula of these programmes. given global trends in this direction, it is vital that ipe be introduced in our medical and allied health sciences curricula. conclusion currently at sultan qaboos university, there are three courses for health professionals, with more courses being planned for the future. considering the multiprofessional nature of health care delivery, it is crucial that ipe activities be created where students in all health professions learn with, about, and from each other. a future article on this subject will focus on practical suggestions as to how ipe activities might be implemented. references 1. mcnair rp. the case for educating health care students in professionalism as the core content of interprofessional education. med educ 2005; 39:456–4. 2. kvarnstrom s. difficulties in collaboration: a critical incident study of interprofessional healthcare teamwork. j interprof care 2008; 22:191–203. 3. world health organization. aiecp framework for action on interprofessional education & collaborative practice. geneva: world health organization, 2010. p. 13 4. institute of medicine. pebq health professions education: a bridge to quality. washington, dc: national academies press, 2003. pp. 2–3. 5. bridges dr, davidson ra, odegard ps, maki iv, tomkowiak j. interprofessional collaboration: three best practice models of interprofessional education. ibrahim m. inuwa sounding board | 441 30. d'amour d, oandasan i. interprofessionality as the field of interprofessional practice and interprofessional education: an emerging concept. j interprof care 2005; 19 s1:8–20. 31. borrill c, west m, shapiro d, rees a. teamworking and effectiveness in the nhs. brit j healthc manage 2000; 6:364–71. 32. kyrkjebo jm, brattebo g, smith-strom h. improving patient safety by using interprofessional simulation training in health professional education. j interprof care 2006; 20:507–16. 33. san martin-rodriguez l, beaulieu md, d'amour d, ferrada-videla m. the determinants of successful collaboration: a review of theoretical and empirical studies. j interprof care 2005; 19 s1:132–47. 34. hall p. interprofessional teamwork: professional cultures as barriers. j interprof care 2005; 19 s1:188–96. 35. rudland jr, mires gj. characteristics of doctors and nurses as perceived by students entering medical school: implications for shared teaching. med educ 2005; 39:448–55. 36. barr h, koppel i, reeves s, hammick m, freeth d. effective interprofessional education: argument, assumption and evidence. oxford: blackwell publishing, 2005. pp. 25–56 37. hammick m, freeth d, koppel i, reeves s, barr h. a best evidence systematic review of interprofessional education: beme guide no. 9. med teach 2007; 29:735–51. 21. young l, baker p, waller s, hodgson l, moor m. knowing your allies: medical education and interprofessional exposure. j interprof care 2007; 21:155–63. 22. zwarenstein m, reeves s, perrier l. effectiveness of pre-licensure interprofessional education and postlicensure collaborative interventions. j interprof care 2005; 19 s1:148–65. 23. parsell g, spalding r, bligh j. shared goals, shared learning: evaluation of a multiprofessional course for undergraduate students. med educ 1998; 32:304–11. 24. wake-dyster w. designing teams that work. aust health rev 2001; 24:34–41. 25. freeth d, hammick m, koppel i, reeves s, barr h. a critical review of evaluations of interprofessional education. london: higher education academy, london, 2002. pp. 1–63. 26. jacobsen f, lindqvist s. a two-week stay in an interprofessional training unit changes students' attitudes to health professionals. j interprof care 2009; 23:242–50. 27. knowles m. the adult learner: a neglected species. hoston, texas: gulf publishing, 1980. pp. 27–31 28. schon d. the reflective practitioner: how pt professionals think in action. new york: basic books, 1983. pp. 128–167. 29. bandura a. social foundations of thought and action: sct: a social cognitive theory. englewoods cliffs, nj: prentice hall, 1986. p. xii. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 269-272 , epub. 15th jul 12 submitted 23rd may 12 accepted 26th may 12 in this issue of squmj, there is a very good review article on dyslexia by drs. shidhani and arora.1 they describe the different types of dyslexia, the various aetiological causes and also its management. perhaps the next major question to be discussed is its social impact. how does dyslexia impact the child, the parents and society in general? what does dyslexia do to the sufferer? dyslexia typically is clinically manifested when the child first goes to school and has to cope with learning how to read. the child then discovers his/her disability, but unfortunately, the degree of the trauma varies according to initial interpretation and hence the translation of the trauma into symptoms may also vary significantly. in addition, as described in dr. shidhani’s article, the precise nature and the degree of disability will vary from individual to individual. the child with dyslexia, even though often of average or above-average intelligence, may have difficulty in grasping abstract concepts and in retelling a story. they may be slow at word recall and have difficulty in reading because of reversing or inverting letters or reading a whole word backwards. the unfortunate consequence is that a sufferer may have to read a paragraph 3 or 4 times before they can grasp its content. often this happens as a result of poor recall and fluctuating performance— when reading a particular sentence, they may have no difficulty with the first few words, but then get mixed up with the last few words, and then a different problem when they read it again in an effort to try understand the sentence. spelling is the second major problem in the classroom. children with dyslexia may spell the same word differently even in the same essay. all these difficulties lead to frustration and delays necessitating an extra time for reading, writing and other scholarly activities.2 because they have to work much harder in school to catch up with their classmates, their self-esteem drops, sometimes to a seriously low level. such children come to believe that they are “stupid” with the serious consequences of that attitude. these problems can by exacerbated by teasing from classmate with all consequences this may entail. what other emotions do children challenged with dyslexia feel? they can become so frustrated with words, sentences, meanings and recall that they remain anxious throughout school age and into adulthood. they can thus often develop severe anxiety disorder, which is the most frequent emotional symptom that dyslexic children experience,3 and this adverse disposition can be lifelong. another emotional symptom from which dyslexics suffer is anger arising from their frustrations in schools. social scientists point out that the greater the frustration the more it breeds anger.3 poor self-image is a another problem for such individuals despite their often superior intellectual capacity. in fact, the diagnosis of dyslexia, generally, includes the consideration that the intellect and iq has to be at least average.2,4,5 poor self-image can lead to low self-esteem; this is characterised by negative thoughts which, in turn, tend to worsen editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, oman. *e-mail: mjournal@squ.edu.om عسر القراءة تأثريها على الفرد والوالدين واجملتمع ملك اللمكي editorial dyslexia its impact on the individual, parents and society lamk al-lamki dyslexia its impact on the individual, parents and society 270 | squ medical journal, august 2012, volume 12, issue 3 self-image and can lead to clinical depression.6,7 next to the individual distress occasioned by dyslexia, come the problems encountered by the family. dyslexia impacts the family in variety of ways and can often result in sibling rivalry. the dyslexic child needs special attention from parents and relatives, while the non-dyslexic siblings may be jealous of this extra attention. this can lead to family quarrels, which can create a further psychological burden for the afflicted individual. there is some indication that dyslexia runs in families meaning that some parents maybe anxious about the possibility of their offspring also suffering from dyslexia. some caregivers may not accept that the child has a learning disorder, instead simply defining the problem as laziness. such a scenario is likely to trigger frustration not only for the affected individual but also for the caregiver. another predicament of people with dyslexia is the perception that they have a cognitive impairment such as poor memory since they may not readily remember what they read or recall a specific word. this can then lead to a struggle with the teacher, with the parents and with themselves. the result can be a child deemed to be “incorrigible”, a judgment which can further traumatise the individual.8 other problems from which children with dyslexia may suffer are the setting of realistic and attainable goals, or the lack of opportunity to rejoice over their achievements and success. learning to set attainable goals should be part of the rehabilitation of people with dyslexia. it is well known that children with dyslexia who achieve success in athletics or in artistic endeavours are likely to have high self-esteem. the above discussion has dwelt on children with dyslexia and their caregivers. the next question is in what diverse ways dyslexia can impact society in general.6,8,9–12 typically, dyslexia incidence is 5–10% of school children.8 unfortunately, it is not uncommon for children with dyslexia to have other impairments or disability. the most common among these are attention deficit disorder (add) and attention deficit hyper-active disorder (adhd). the school drop-out rate of dyslexics can be a high as 35%, twice as the national average school drop-out rate of many countries;4,5,13 in the united states, 27% of the high school drop-outs have learning disabilities.14 it has been estimated that barely 2% of dyslexics enrolled in undergraduate programmes in the usa complete the requisite 4 years of study. in the workplace, up to 20% of the workers may have dyslexia.15 a survey-based exploration of the impact of dyslexia on the career progression of uk registered nurses explored the effects of dyslexia on the practice and career progression of the uk registered nurses.15 the study concluded that dyslexia appears to have “a negative impact on working practices and career progression but remains a poorly understood and often, hidden disability.” functional illiteracy is a major problem in some societies; in the usa, the estimated rate is about 20%11 and, of these people, 50% have dyslexia. a total of 80% of all people diagnosed learning disabilities are dyslexic. when one looks at the high prison figures of people with dyslexia, one wonders why, but part of the answer is embodied in the fact that 85% of juvenile offenders have reading disabilities.14 it can thus be seen that dyslexia can cause various social and psychological problems for the individual, the family and society. the question now is what needs to be done. there is a dearth of empirical information on the prevalence of such learning disorders in oman. unfortunately, there is also no provision for remedial services and rehabilitation for children with dyslexia in oman, nor even culture-specific tools for diagnosing dyslexia. however, there is a significant amount that can still be done and some measures can be implemented with minimum effort. some shining initiatives have emerged from private schools. anecdotal reports suggest special education teachers are available in some private schools in oman. they are able to give special attention to dyslexic pupils, helping them to compensate for or cope with their learning disorder. these children are given more time to do tests, typically 20 extra minutes more per hour. we need to implement these actions in the ministry of education’s (moe) public schools. it is generally accepted by the experts in dyslexia that the answer to managing dyslexia is not to have special schools, as the disabilities are subtle and often mild, but to get these children accommodated in the mainstream schools, with special support. the children need to believe that they are not stupid but have a disability that can be overcome once it is properly understood. there are several specific evidence-based lamk al-lamki editorial | 271 therapeutic measures that are commonly employed for people with dyslexia. some of these remedial measures have been shown to mitigate the severity of dyslexia. these include the use of coloured overlays to avoid the problem of reading black print on white paper, and the use of computers to help in reading and spelling.16also a test may be read out to the individual. these and many other remedial measures that can be used by teachers and caregivers often have to be individualised. while much can be done in school by the teachers, as described above, much needs to be done by the parents at home.13 empowering caregivers should be an integral part of devising mechanisms for remedial intervention. expert advice is available to support caregivers. parents can specifically help the dyslexic child by listening to them, not overpressuring them, by talking about their disability, pointing out specific problems and helping them, and by giving them plenty of praise and encouragement. they can also inspire them by giving examples of famous international figures that had dyslexia such as alexander graham bell, albert einstein, mozart, and john f. kennedy. in oman, we need to take steps to educate the parents and the public. the moe has to be commended for recognising the lack of facilities in its own schools and giving special permission for omani children to go to private schools. however, what we really need is specially trained teachers in moe schools. the moe, perhaps together with the ministry of health, needs to recognise officially that dyslexia is a condition requiring special attention and to provide resources for rehabilitation as has been done for other children with special needs. this is important since dyslexia is a disability affecting around 10% of the population, both children and adults. it is less obvious among adults, because they have learned how to compensate for their disability, while some lucky ones have also had good help from their parents and teachers. there are signs that oman is starting to deal with the problem of learning disability.17 many of the solutions discussed above can, in fact, be fairly easily handled if the appropriate infrastructure is in place. thus, we urge the moe to focus more attention on this very common disability and build appropriate and required infrastructure to deal with the problem. we need specialised teachers and we need education of parents and the community as a whole. educated communities might then form the all-important non-governmental organisations (ngos) as is happening in neighbouring countries.18 we need more psychologists trained in diagnosing learning disorders, and they will need special and appropriate diagnostic tools.19 researchers from the college of education and the college of medicine at squ have recently been given a grant from his majesty’s strategic research fund to study dyslexia, specifically the authentication of diagnostic tests for dyslexia—an area where improvement is needed. we need to do more in oman so that the challenges of dyslexia can be surmounted. this is eminently possible if appropriate efforts are made by all parties concerned. references 1. shidhani ta, arora v. understanding dyslexia in children through human development theories. sultan qaboos university med j 2012; 12:287–94. 2. developmental reading disorders. from: http://www. ncbi.nlm.nih.gov/pubmedhealth/ pmh0002379/ accessed may 12. 3. ryan m and international dyslexia association. social and emotional problems related to dyslexia (2004). from: http://www.ldonline.org/ article/19296/ accessed may 12. 4. international dyslexia association. from: http:// www.dyslexia-usa.com/ accessed may 12. 5. american dyslexia association. from: http://www. american-dyslexia-association.com/dyslexia.html accessed may 12. 6. the behavioral and emotional impact of dyslexia dyslexia takes a toll on your child’s self-esteem and self-concept. from: http://toni-d-anna-hernandez. s u i te 1 0 1 . co m / th e b eh av i o r a l a n d e m o t i o n a l impact-of-dyslexia-a161374 accessed may 12. 7. glazzard j. the impact of dyslexia on pupils’ selfesteem. supprt learning 2010; 25:63–9. 8. samuelsson s, lundberg i. the impact of environmental factors on components of reading and dyslexia. ann dyslexia 2003; 53: 201–17. 9. impact of dyslexia on society. from: http://www. guardian.co.uk/society/joepublic/2009/nov/03/ dyslexia-awareness-week-blog accessed may 12. 10. ingesson sg. growing up with dyslexia interviews with teenagers and young adults. from: http://spi. sagepub.com/content/28/5/574.short accessed may 12. 11. dyslexia facts. from: http://www.headstrongnation. org/dyslexia-facts accessed may 12. dyslexia its impact on the individual, parents and society 272 | squ medical journal, august 2012, volume 12, issue 3 12. what are the effects of dyslexia? from: http://www. uread.org/index.php/dyslexia-is/83-what-are-theeffects-of-dyslexia accessed may 12. 13. dyslexic dropout rates. from: http://www. the australian.com.au/ne ws/nation/only -ns w makes-rightsounds-on-learning-to-read/stor ye6frg6nf-1225780651581 accessed may 12. 14. silver l. learning disabilities & attention deficit hyperactivity disorder. from: http:// www.ldworldwide.org/pdf/silver-dr-ooklethttp:// www.ldworldwide.org/pdf/silverdr-booklet.pdf. p df http://w w w.ldworldwide.org/p df/silver-drbooklet.pdf=accessed may 12. 15. morris d, turnbull p. a survey-based exploration of the impact of dyslexia on career progression of uk registered nurses. j nurs manag 2007; 97–106. 16. alsuwaidan a, alzahrani a, meldah e, alnukhilan h, alismail s. designing software for cognitive training of children with learning difficulties: the memory challenge project. in: proceedings of world conference on educational multimedia, hypermedia and telecommunications, 2010. pp. 737–40. from: http://www.editlib.org/p/34717. accessed may 12. 17. al-ghafri sh. the effectiveness of the learning difficulties programme in basic education cycle 1 schools. from: http://www.moe.gov.om/portal/ sitebuilder/sites/eps/ arabic/ips/importa/tesol/5/ the%20effectiveness%20of%20the%20learning%20 difficulties%20programme%20in%20.pdf accessed may 12. 18. kuwait dyslexia association. from: http://www. q8da.com/kw/en/index.php? option=com_content& view=article&id=53&itemid=61 accessed may 12. 19. helping people with dyslexia: a national action. from: http://www.dest.gov.au/nitl/ accessed may 12. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e1-3, epub. 27th jan 14 submitted 29th sep 13 revision req. 27th oct 13; revision recd. 30th oct 13 accepted 31st oct 13 nutrigenomics, a term derived from ‘nutrition’ and ‘genomics’, analyses the interactions of nutrients/dietary bioactive components with the genome. the purpose of nutrigenomics is to comprehend the body’s response to various diets and food through various high-throughput ‘omics’ techniques— including genomics, transcriptomics, proteomics and metabolomics.1 genomics makes use of techniques such as recombinant deoxyribonucleic acid (dna) and dna sequencing methods to sequence, assemble and analyse the structure and function of genomes. transcriptomics, also known as ‘gene expression profiling’ is the study of the transcriptome encoded by the genome in a given cell population using dna microarray technology.2 proteomics is the study of the structure and function of proteins and is a vital component of functional genomics. apart from being used in the analysis of gene expression in tissues, proteomics can also be used for the identification of new protein biomarkers that can be detected in plasma.3 metabolomics is an emerging field of ‘omics’ research that studies metabolite levels in the metabolome (a set of smallmolecule metabolites) and their changes over time in response to stimuli. metabolic abnormalities could be detected in individuals by the quantitative non-invasive analysis of human body fluids (such as urine, blood and saliva) to detect physiological alterations in response to the toxic effects of chemicals, visible in the form of lesions in the liver or kidneys.4 transcriptomics has, however, helped in understanding the complex interactions between genetic and environmental factors in order to design nutritional interventions.5 the ‘omics’ applied to nutrition will ultimately lead to the discovery of biomarkers for early diagnosis as well as to the design of personalised diets that encompass bioactive food components of great health benefit.2 with the success of the human genome project and advances in technologies, a significant amount of information has been amassed related to human genes and their mechanisms. in turn, nutrigenomics is a new and evolving field which forms a junction between health, diet and genomics to analyse patterns of gene expression, protein expression and metabolite production triggered by nutrients.6 it examines the characteristic behaviour of cells towards a particular nutrient and its influence on homeostasis. nutrigenomics is also involved in the discovery of certain genes and markers during the initial-stages of diet-related diseases. nutrigenomics increases our knowledge about the mechanisms by which nutrition affects the metabolic pathways underlying homeostatic control. subsequently, this can be used to determine naturally occurring chemical agents in food that could prevent the onset of diseases such as obesity, type-2 diabetes and cancer. the nutrients present in the diet are received as signals by the sensory system of the various cells in the body which are interpreted by the cells to gene expression, protein expression and metabolite production. hence, different diet patterns elicit a variety of gene and protein expression and metabolite production. such diet-induced patterns and their effects are described by nutrigenomics as “signature dietary patterns”. micronutrients and macronutrients are department of genetics, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: aouhtit@squ.edu.om علم املورثات التغذوي من الوعد إىل التطبيق عالل �أوهتيت editorial nutrigenomics from promise to practice allal ouhtit nutrigenomics from promise to practice e2 | squ medical journal, february 2014, volume 14, issue 1 potent dietary signals that influence the metabolic programming of cells that play a crucial role in the control of homeostasis. nutrigenomics, which studies the interactions between different types of food and the genome, can aid in selecting foodstuffs that are vital to health. one of the emerging fields of research to use nutrigenomics is complementary alternative medicine (cam). cam is defined as a method of treatment that is used together with (complementary) or instead of (alternative) traditional medicine and includes meditation, spiritual healing, energy therapy (magnet therapy and light therapy), massage therapy, acupuncture, herbal preparations (ayurveda), dietary supplements, yoga, acupressure, movement therapies, naturopathy and homeopathy.7–8 cam research has identified a number of active compounds from various herbal and dietary products and evaluated their anti-disease (e.g. anti-cancer) properties; these include polyphenols from green tea, resveratrol from grape seed/ skin, anthocyanin and pigments from numerous flowers, algae, fruits and vegetables. the common property of these compounds is their anti-oxidant/ free radical scavenging ability. our previous study demonstrated that some of these compounds induce high free-radical formation, prevent cell growth and cause apoptosis selectively in cancer cells, but not in normal cells.9 a number of cam studies have focused on the effects of individual compounds derived from herbs/plants used at ‘bioavailable’ concentrations. however, only a few studies, including our own work, have explored the effects (synergistic, additive or antagonistic) of the combination of these compounds in diseases.9 interestingly, each of these individual compounds, when used in combination, have been found to target multiple signalling pathways in the cell.9 oral administration of cam natural medications has shown to have the great advantage of low toxicity and positive effects on various diseases.10—11 in oman, with high rates of consanguinity, the risk of developing genetic disorders, including inborn errors of metabolism is widespread.12 the rapid advances in nutrigenomic technology will ultimately lead to breakthroughs in the treatment of various genetic disorders. inherited mutations in specific genes can predispose the individual to diseases. the risk of developing cancer can be markedly increased if there is a gene-diet interaction. twin studies showed that the probability of identical twins developing the same cancer is less than 10%, indicating that the environment is an important factor in cancer susceptibility. for example, studies have shown that familial susceptibility is only responsible for relatively rare cancer variants.13 in addition, most twin studies make the assumption that both twins are exposed to the same environment and the absence of any environmentgenotype interaction.13 differences in epigenetic modifications between twins can also explain the differences in susceptibility between twins.14 as nutrition is a major component of the environmental conditions which can putatively interact with the genotype to bring about a phenotypical change, any disease or condition that is associated with genetic and/or nutritional components can be targeted for nutrigenomic studies in order to test whether dietary intervention can affect the outcome. differences in genetic makeup (genotype), as well as nutrient deficiencies, are factors in various diseases, including cancer, cardiovascular, digestive and inflammatory diseases. nutrigenomics is addressing why some people can control disease with diet, whereas others require drugs. therefore, nutrigenomics is expected to significantly contribute to personalised medicine. the expected benefits from nutrigenomics are tremendous and encompass: (1) a better understanding of the toxicity and safety profile of macroand micronutrients; (2) the prevention of certain diet-associated diseases; (3) the enjoyment of otherwise less healthy food by individuals whose health is not likely to be affected; (4) the avoidance of unhelpful dietary supplements that are routinely used by certain people, and (5) the prevention of diseases and an increase in life expectancy. despite its recognised future potential benefits, nutrigenomics nevertheless raises a number of ethical issues and risks that are similar to ‘genethics’ or ethics in genetics: (1) a predisposition to develop a disease might trigger anxiety and stress in the individual; (2) the privacy of the patient might be jeopardised (for instance in deciding who should know the results); (3) potential discrimination against affected individuals by employers, health insurance companies, family, etc.; (4) the crucial need for well-qualified physicians to interpret nutrigenomic reports and make the appropriate allal ouhtit editorial | e3 decisions, and (5) other unrecognised risks. despite its early positive impact and the very few diet-gene interactions that have been well characterised to yield useful information (e.g. obesity), far more research is needed before nutrigenomic expectations become a reality. understanding the mechanisms by which some components in food interact with certain genes that can predispose to metabolic diseases would help people to avoid certain types of food; this can subsequently lead to the prevention of certain diseases. furthermore, knowing the right amount and the type of specific nutrients that our body requires would positively impact the management of our health. although studies conducted in this field have been costly and difficult, the results are deemed to be helpful for the advancement of medical technologies pertaining to health care (personalised medicine) and weight management. ongoing nutrigenomic studies in our laboratory aim to establish the relationship between various combinations of powerful specific natural compounds that can target specific diseases (e.g. a combination of phytochemicals specific to treat cancer). more interestingly, in addition to understanding the basic molecular mechanisms of action of certain compounds in cancer, functional nutrigenomics will ultimately lead to the identification and validation of candidate gene targets that can pave the way towards the design of anti-cancer therapeutic strategies. references 1. kato h. nutrigenomics: the cutting edge and asian perspectives. asia pac j clin nutr 2008; 17:12–15. 2. lau fc, bagchi m, sen c, roy s, bagchi d. nutrigenomic analysis of diet-gene interactions on functional supplements for weight management. current genomics 2008; 9:239– 51. 3. omenn gs, states dj, adamski m, blackwell tw, menon r, hermjakob h, et al. overview of the hupo plasma proteome project: results from the pilot phase with 35 collaborating laboratories and multiple analytical groups, generating a core dataset of 3,020 proteins and a publicly available database. proteomics 2005; 5:3226–45. 4. robertson dg. metabonomics in toxicology: a review. toxicol sci 2005; 85:809–22. 5. hocquette jf. where are we in genomics? j physiol pharmacol 2005; 56:37–70. 6. afman l, muller m. nutrigenomics: from molecular nutrition to prevention of disease. j am diet assoc 2006; 106:569–76. 7. national centre for complementary and alternative medicine. complementary, alternative, or integrative health: what’s in a name? from: http://nccam.nih.gov/ health/whatiscam accessed: mar 2012. 8. richardson ma, sanders t, palmer jl, greisinger a, singletary se. complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. j clin oncol 2000; 18:2505–14. 9. raj mh, abd elmageed zy, zhou j, gaur rl, nguyen l, azam ga, et al. synergistic action of dietary phytooxidants on survival and proliferation of ovarian cancer cells. gynecol oncol 2008; 110:432–8. 10. ismail mf, ali da, fernando a, abdraboh me, gaur rl, ibrahim wm, et al. chemoprevention of rat liver toxicity and carcinogenesis by spirulina. int j biol sci 2009; 5:377– 87. 11. hassan ha, el-agmy sm, gaur rl, fernando a, raj mh, ouhtit a. in vivo evidence of hepatoand reno-protective effect of garlic oil against sodium nitrite-induced oxidative stress. int j biol sci 2009; 5:249–55. 12. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32–42. 13. wallace hm. a model of gene-gene and geneenvironmental interactions and its implications for targeting environmental interventions by genotype. theor biol med model 2006; 3:35. 14. heyn h, carmona fj, gomez a, ferreira hj, bell jt, sayols s, et al. dna methylation profiling in breast cancer discordant identical twins identifies dok7 as novel epigenetic biomarker. carcinogenesis 2013; 34:102–8. department of anatomy, all india institute of medical sciences, new delhi, india *corresponding author e-mail: seemahkg@gmail.com شذوذ تعصيب العصب الناصف بالعضد مع غياب للعصب العضلي اجللدي خ�ر�ضيد رازا, �ضيما �ضينق, نريجا راين, راقف مي�رسا, كاماك�ضي ميهتا, �ضارج� كالر abstract: the brachial plexus innervates the upper extremities. while variations in the formation of the brachial plexus and its terminal branches are quite common, it is uncommon for the median nerve to innervate the muscles of the arm. during the dissection of an elderly male cadaver at the department of anatomy, all india institute of medical sciences, new delhi, india, in 2016, the coracobrachialis muscle was found to be supplied by a direct branch from the lateral root of the median nerve and the musculocutaneous nerve was absent. the branches of the median nerve supplied the biceps brachii and brachialis muscles and the last branch continued as the lateral cutaneous nerve of the forearm. these variations may present atypically in cases of arm flexor paralysis or sensory loss on the lateral forearm. knowledge of these variations is important in surgeries and during the administration of regional anaesthesia near the shoulder joint and upper arm. keywords: anatomic variation; dissection; median nerve; musculocutaneous nerve; case report; india. امللخ�ص: تغذي ال�ضفرية الع�ضدية ع�ضبيا االأطراف العليا. ومن ال�ضائع وج�د بع�ص االإختالفات يف تك�ين ال�ضفرية الع�ضدية غري اأن تغذية الع�ضب النا�ضف لع�ضالت الع�ضد لي�ص اأمرا كثري احلدوث. ففي غ�ض�ن ت�رسيحنا جلثة رجل م�ضن يف ق�ضم الت�رسيح الب�رسي مبعهد عم�م الهند للعل�م الطبية يف ني�دلهي عام 2016 وجدنا اأن الع�ضلة الغرابية الع�ضدية تع�ضب ب�ا�ضطة فرع مبا�رس من اجلذع ال�ح�ضي للع�ضب النا�ضف, يف غياب الع�ضب الع�ضلي اجللدي. ووجد اأن اأفرع الع�ضب النا�ضف تع�ضب الع�ضلة الع�ضدية وع�ضلة "ذات الراأ�ضني الع�ضدية", وتت�ا�ضل كع�ضب جلدي وح�ضي �ضاعدي. وقد تظهر تلك االختالفات ب�ض�رة غري معتادة يف حاالت �ضلل الع�ضلة املثنية يف الع�ضد, اأو فقدان احل�ص يف ال�ضاعد ال�ح�ضي. ومن املهم اإدراك مثل تلك االختالفات يف اجلراحات, ويف اأثناء اإعطاء اأدوية التخدير الناحي بقرب مف�ضل الكتف والع�ضد العل�ي. الكلمات املفتاحية: االختالفات الت�رسيحية؛ الت�رسيح؛ الع�ضب النا�ضف؛ الع�ضب الع�ضلي اجللدي؛ تقرير حالة؛ الهند. anomalous innervation of the median nerve in the arm in the absence of the musculocutaneous nerve khursheed raza, *seema singh, neerja rani, raghav mishra, kamakshi mehta, saroj kaler case report sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e106–108, epub. 30 mar 17 submitted 21 jun 16 revision req. 1 aug 16; revision recd. 22 aug 16 accepted 22 sep 16 doi: 10.18295/squmj.2016.17.01.019 the brachial plexus innervates the upper extremities and is a complex network of nerves formed by the union of the ventral primary rami of the spinal nerves—from the cervical (c) 5 to c8 vertebrae and the thoracic (t) 1 vertebra—with a small contribution from the c4 or t2 vertebrae.1–3 variations in the formation of the brachial plexus and its terminal branches are quite common; however, it is uncommon that the median nerve innervates the muscles of the arm.4 case report an upper limb dissection of an elderly male cadaver was performed during a routine educational dissection at the department of anatomy of the all india institute of medical sciences, new delhi, india, in 2016. during the dissection, the brachial plexus was observed to have a unilateral anomalous branching pattern. all of the usual branches of the medial and posterior cords were present; however, branches from the lateral cord were unusual in the left axilla. the left lateral cord gave rise to a lateral pectoral nerve and, distal to this branch, it continued as the lateral root of the median nerve around the third part of the axillary artery. the musculocutaneous nerve was absent. a branch originated from the lateral root of the median nerve and supplied the coracobrachialis muscle. the median nerve was formed by the union of the medial and lateral roots from the respective medial and lateral cords of the brachial plexus, anterior to the axillary artery. the branches from the median nerve supplied the flexor muscles of the left arm, except the coracobrachialis muscle, and the last branch continued as the lateral cutaneous nerve of the forearm. the first branch from the left median nerve supplied the two heads of the biceps brachii muscle and another branch supplied the brachialis muscle approximately 3.5 cm below the first branch. after that, a third branch arose and passed deep to the biceps brachii muscle from khursheed raza, seema singh, neerja rani, raghav mishra, kamakshi mehta and saroj kaler case report | e107 the medial to lateral side, piercing the deep fascia and continuing as the lateral cutaneous nerve of the forearm, superficial to the brachioradialis muscle [figure 1]. the variation was present unilaterally without any communication between the nerves. no other variations were found in relation to the other vessels and muscles. discussion branching pattern variations of the brachial plexus can be explained embryologically. during the fifth gestational week, the fetus develops forelimb muscles due to regional expression of the homeobox d genes in the mesenchyme of the paraxial mesoderm.5 the growth cones of the motor axons arrive at the base of the limb bud to form the brachial plexus and continue into the limb bud. the growth cones are guided by many chemoattractants and chemorepulsants—such as brain-derived nerve growth factor, c-kit ligand, neutrin-1, neutrin-2, slits, semaphorins and ephrins—which work in a highly coordinated manner so that the correct growth cones reach their target before halting and forming synapses. somatic motor and sensory fibres synapse directly with their target organs.5 any deviation in this phenomenon can lead to variations. variations in the formation, branching patterns and communications of the median nerve are well documented [table 1].2,6–10 in the present case, all of the flexor muscles were innervated by the median nerve proper, except for the coracobrachialis muscle which was innervated directly by a branch from the lateral root of the median nerve, while the lateral cutaneous nerve of the left forearm arose from the median nerve. the variation was present unilaterally without any communication between the nerves. the flexors of the arm and the lateral aspect of the forearm are generally innervated by the musculocutaneous nerve, a branch of the lateral cord, which was absent in the present case.4 a previous case report noted a single branch arising from the lateral root of the median nerve, supplying the two head of the biceps brachii.7 the coracobrachialis muscle was innervated by a nerve originating from the lateral cord of the brachial plexus while the rest of the flexor muscles were innervated by branches from the median nerve. the lateral cutaneous branch of the forearm also arose from the median nerve, along with a communication between the median and lateral cutaneous nerves of the forearm.7 gümüsburun et al. observed a case wherein the coracobrachialis muscle was innervated by two direct branches from the lateral cord and that the variation was present bilaterally.2 le minor categorised communications between the median and musculocutaneous nerves; in type v cases, the musculocutaneous nerve is absent and all of the flexor muscles of the arm are innervated by the median nerve.6 nakatani et al. reported three anomalies in which all of the flexor muscles were innervated by branches from the lateral cord and the lateral cutaneous nerve of the forearm arose from the lateral and medial roots of the brachial plexus.8 pacholczak et al. described a case in which the lateral cord pierced and innervated figure 1: photograph of the anteromedial aspect of the dissected left axilla and arm of an elderly male cadaver showing branches to the flexor muscles and lateral cutaneous nerve of the forearm from the median nerve. the coracobrachialis muscle was innervated by the branch from the lateral root of the median nerve. bb = biceps brachii; lcn = lateral cutaneous nerve of the forearm; bbn = nerve into the biceps brachii; cm = coracobrachialis; brn = nerve into the brachialis; br = brachialis; cmb = branch to the coracobrachialis; lr = lateral root of the median nerve; mr = medial root of the median nerve; mn = median nerve; aa = axillary artery; un = ulnar nerve; rn = radial nerve; av = axillary vein; t = triceps; mcn = medial cutaneous nerve of the forearm. table 1: literature review of anomalous anatomical variations of the median nerve2,6–10 author and year of case report source of innervation arm flexor muscles coracobrachialis muscle beheiry7 (2004) lateral root of the median nerve branch from the lateral cord gümüsburun et al.2 (2000) median nerve branch from the lateral cord le minor6 (1990) median nerve median nerve nakatani et al.8 (1997) median nerve median nerve pacholczak et al.9 (2011) lateral root of the median nerve lateral cord shinde et al.10 (2015) lateral root of the median nerve lateral root of the median nerve present case (2016) median nerve lateral root of the median nerve anomalous innervation of the median nerve in the arm in the absence of the musculocutaneous nerve e108 | squ medical journal, february 2017, volume 17, issue 1 conclusion this case report describes the dissection of a cadaver in which the left median nerve was found to supply the lateral aspect of the forearm as well as the flexor muscles of the arm, except for the coracobrachialis muscle. this rare variation may result in unexpected clinical presentations in cases of traumatic injuries or paralysis. knowledge of such variations is therefore of clinical and surgical importance. references 1. ibrahim c, adnan e, cem d. variation between median and musculocutaneous nerves. internet j surg 2004; 6:1−3. 2. gümüsburun e, adigüzel e. a variation of the brachial plexus characterized by the absence of the musculocutaneous nerve: a case report. surg radiol anat 2000; 22:63−5. doi: 10.1007/ s00276-000-0063-x. 3. singh s, rani n, kaushal p, kumar h, sharrif a, roy ts. anomalous cutaneous branch of median nerve in arm: a report of anatomical variation with clinical implications. anat cell biol 2014; 47:138−40. doi: 10.5115/acb.2014.47.2.138. 4. jamuna m, amudha g. a cadaveric study on the anatomic variations of the musculocutaneous nerve in the infra clavicular part of the brachial plexus. j clin diagn res 2011; 5:1144−7. 5. schoenwolf gc, bleyl sb, brauer pr, francis-west ph. larsen’s human embryology, 4th ed. london, uk: churchill livingstone, 2008. pp. 311−12. 6. le minor jm. [a rare variation of the median and musculocutaneous nerves in man]. arch anat histol embryol 1990; 73:33−42. 7. beheiry ee. anatomical variations of the median nerve distribution and communication in the arm. folia morphol (warsz) 2004; 63:313−18. 8. nakatani t, mizukami s, tanaka s. three cases of the musculocutaneous nerve not perforating the coracobrachialis muscle. kaibogaku zasshi 1997; 72:191−4. 9. pacholczak r, klimek-piotrowska w, walocha ja. absence of the musculocutaneous nerve associated with a super numerary head of biceps brachii: a case report. surg radiol anat 2011; 33:551−4. doi: 10.1007/s00276-010-0771-9. 10. shinde cd, mane r. median nerve as a nerve of anterior compartment of arm with its variant formation. int j anat res 2015; 3:1008−10. doi: 10.16965/ijar.2015.146. 11. budhiraja v, rastogi r, asthana ak, sinha p, krishna a, trivedi v. concurrent variations of median and musculocutaneous nerves and their clinical correlation: a cadaveric study. ital j anat embryol 2011; 116:67−72. doi: 10.13128/ijae10335. the coracobrachialis muscle without any substantial branching and continued as the lateral root of the median nerve; this subsequently led to two branches supplying the rest of the flexor muscles and one branch continuing as the lateral cutaneous nerve of the forearm.9 the lateral root joined the medial root of the median nerve at the mid-arm and continued as the median nerve proper.9 variations in lateral cord branching patterns have been associated with other anomalies, such as the splitting of the median nerve into medial and lateral branches wherein the medial branch forms the median nerve proper and the lateral branch innervates the muscles, communication between the median nerve and other nerves or formation of the median nerve in the middle of the arm.6,9–11 in addition, it has been reported that the lateral root of the median nerve can bifurcate into two branches, one supplying the coracobrachialis muscle and the other branch functioning as the common trunk supplying the rest of the muscles of the arm and continuing as the lateral cutaneous nerve of the forearm.10 in the present case, no such variations were associated with the anomaly. variations of the median nerve and its distribution patterns have important clinical and surgical implications, especially when dealing with traumatic injuries of the shoulder, upper arms or axillae.1,4 knowledge of these variations is also important during the administration of regional anaesthesia. in addition, pre-existing median nerve variations may present atypically in cases of paralysis.1,4 https://doi.org/10.1007/s00276-000-0063-x https://doi.org/10.1007/s00276-000-0063-x https://doi.org/10.5115/acb.2014.47.2.138 https://doi.org/10.1007/s00276-010-0771-9 https://doi.org/10.16965/ijar.2015.146 https://doi.org/10.13128/ijae-10335 https://doi.org/10.13128/ijae-10335 sir, i read, with great interest, the editorial article written by prof. lamk al-lamki in the august 2011 issue of squmj, on acute coronary syndrome, diabetes and hypertension.1 dr. al-lamki reported in his article that the ministry of health (moh), oman, needs to sort out its priorities and give more attention to the management of chronic non-communicable diseases (ncd's). he imperatively called the ministry to invest a significant portion of its finance and manpower to control and reduce the prevalence of diabetes mellitus and hypertension (htn) as well as other chronic ncd's. as he indicated, three other articles in the same issue of the journal showed that diabetes and htn, the two major factors predisposing to acute coronary syndrome, were clearly being sub-optimally managed in oman.2–4 i am afraid to say that these articles, collectively, have participated in giving squmj readers the erroneous impression that the moh is reluctant in fulfilling its duty to reduce the magnitude of ncd's in oman. moreover, in the last few years, other published reports have conveyed the same picture and mentioned a drastic increase in the prevalence of diabetes and htn in oman.5–7 nonetheless, in the light of the available valid statistical information collected over the last 15–20 years from hospitals and the community, the moh's continuous efforts to face the double burden of both communicable diseases and ncd's in oman have been proven, so the picture is not as black as many may think. table 1 contains some data from moh institutions that show that outpatient morbidity due to ncd's has shown instability in the period 1996 to 2010. they represented 42.5% of total outpatient morbidity in 1996, then increased to 53.2% in 2000, and rose again to 54.6% in 2005, before it dropping sharply to 39.5% in 2010. regarding inpatient morbidity, ncd's have represented a more or less a stable proportion of cases during the last 15 years; however, there was an overall decline from 37.4% in 1995 to 36.8% in 2010. data from different successive national surveys conducted in oman in the last two decades are shown in table 2 and reveal a marginal increase (2.3%) in the prevalence of diabetes over the last 18 years (1991– 2008). during the same period, the prevalence of htn increased from 27% in the year 1991 to 40.3% in 2008, with a rate of increase of 2.25% annually. however, the rate of increase of htn prevalence during the period 2000–2008 was only 0.57% per annum. such a remarkable reduction in the rate of increase of htn prevalence indicates that successful preventive measures have been adopted during the last decade. in addition, it should be remembered that in the 1990s and early 2000s, a large proportion of the people with high blood glucose levels and high blood pressure were not known about. accordingly, the statistics likely reflect more the success in case detection than an increase in the prevalence of diabetes and htn. this success in control of the two most important ncd's in the country should be attributed largely to the efforts of moh in increasing public awareness about various causes of these health sapping diseases and engaging health-related sectors and the entire community in activities that ocver all the various aspects necessary for squ med j, february 2012, vol. 12, iss. 1, pp. 126-128, epub. 7th feb 12. submitted 10th dec 11 internally reviewed accepted 15th jan 12 رد على: متالزمة الشريان التاجي ومرض السكري وارتفاع ضغط الدم على عمان أن تويل اهتماماً أكرب لألمراض املزمنة غري املعدية re: acute coronary syndrome, diabetes and hypertension oman must pay more attention to chronic non-communicable diseases letter to editor moeness moustafa alshishtawy letter to editor | 127 the nurturing of a healthy community. there is no doubt that prof. al-lamki's call for more and better specialised centres and modern medications and equipment should be supported and advocated by all. the moh, if it has the financial resources to respond to these demands, should do so immediately. however, management of chronic cases is costly, especially at the advanced stages, and that is why preventive strategies, including primary prevention, early diagnosis and treatment, are always given priority. the challenge faced by the moh in oman, was to deliver interventions which could promote behavioural changes in the population, and to disseminate such changes nationally. accordingly, the moh has focused heavily, since 1991, on health promotion activities through the various health programmes incorporated in its successive five-year health development plans. health planners have focused on meeting public demand for specialised health facilities and services by providing curative clinical services to all governorates of oman at the health centre level. mini diabetes clinics, run by family physicians on specific days of the week, have now been established in most health centres. the ministry of health has ensured the availability of arabic-speaking diabetes specialists in every governorate of oman. diabetes and hypertension management guidelines for doctors and nurses have been developed by the moh and distributed to all doctors and nurses. most of these activities were planned in harmony with international and regional policies and strategies such as the who global strategy for the prevention and control of chronic diseases (2000), the eastern mediterranean approach to non-communicable diseases – eman (2001), the framework convention for tobacco control (2003), and the global strategy on diet, physical activity, and health (2004). it is worth mentioning that the moh started to encourage the implementation of various communitybased activities and projects planned by community volunteers and wilayat (district) health committees starting from 1991 and 1998 respectively. the community-based projects focused mainly on health promotion activities to raise awareness among healthy people of the risk factors for chronic diseases including diabetes and htn. efforts were specially exerted to impart health promotion among school students as well as throughout adulthood. these projects also included campaigns for the early detection of both diseases, as many people are unaware that they have a high blood glucose level or high blood pressure and thus remained undiagnosed for too long. through such projects, the benefits of medication and lifestyle modification were directly communicated to patients and the public, in order to prevent diabetes and htn, or to manage them as early and effectively as possible. all of these activities are documented, advocated and appreciated by all concerned inside and outside oman. what is really lacking in order to convey the bright picture to the public of the moh’s efforts in combatting ncds is a proper studying of oman’s health status during the period of “epidemiologic transition” table 1: outpatient and inpatient morbidity due to communicable and non-communicable diseases in oman (1995– 2010)8 percentage of total outpatient morbidity percentage of total inpatient morbidity 1996 2000 2005 2010 1995 2000 2005 2010 communicable diseases 43.2 34.2 35.1 30.4 22.6 20.9 17.3 18.0 non-communicable diseases 42.5 53.2 54.6 39.5 37.4 40.5 39.8 36.8 table 2: prevalence of diabetes mellitus and hypertension in oman survey/year prevalence of diabetes mellitus prevalence of hypertension national diabetes mellitus survey, 1991 10%9 national blood pressure survey, 1991 27%10 national health survey, 2000 11.6%11 38.3%12 (age-adjusted prevalence) world health survey, 2008 12.3%13 40.3%13 re: acute coronary syndrome, diabetes and hypertension oman must pay more attention to chronic non-communicable diseases 128 | squ medical journal, february 2012, volume 12, issue 1 that started in oman 20 years ago. clearly, what we need now is more foundational information about the epidemiology of ncd's, their distribution, and the consequences of them in the community. such information must be used not only to plan, but also to properly manage and evaluate past and current national health programmes and community-based projects. obviously, the epidemiological surveillance and response capacity of the moh in oman must be further strengthened, by the provision of a sufficient number of trained epidemiologists, the support of modern and efficient public health laboratories and use of information technology. also, a greater level of interaction is needed between moh epidemiologists and social researchers for uncovering, in a multi-disciplinary way, social, cultural, economic, environmental, and ecological health determinants in the omani community. such an approach will enable us move beyond health problems per se to a new set of complex social and human developmental challenges, and then, through the use of the principles of epidemiology and of social sciences, we can together formulate effective national strategies and health programmes. moeness moustafa alshishtawy department of community medicine & public health, faculty of medicine. tanta university, egypt; consultant, health planning, ministry of health, oman e-mail: drmoness@gmail.com references 1. al-lamki l. acute coronary syndrome, diabetes and hypertension: oman must pay more attention to chronic noncommunicable diseases, sultan qaboos university med j, august 2011; 11:318–21. 2. panduranga p, sulaiman k, al-zakwani i. acute coronary syndrome in oman: results from the gulf registry of acute coronary events. sultan qaboos university med j 2011; 11:338–42. 3. alyaarubi s. diabetes care in oman: obstacles and solutions. sultan qaboos university med j 2011; 11:343–8. 4. al-saadi r, al-shukaili s, al-mahrazi s, al-busaidi z. prevalence of uncontrolled hypertension in primary care settings in al seeb wilayat, oman. sultan qaboos university med j 2011; 11:349–56. 5. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. 6. al shafaee ma, al-shukaili s, rizvi sg, al farsi y, khan ma, ganguly ss, et al. knowledge and perceptions of diabetes in a semi-urban omani population. bmc public health 2008; 8:249. 7. al-riyami a. type 2 diabetes in oman: can we learn from the lancet editorial? oman med j 2010; 25:153–4. 8. ministry of health. annual health report 2010. muscat: ministry of health, oman, 2012 (in press). 9. asfour mg, lambourne a, soliman a, al-behlani s, al-asfoor d, bold a, mahtab h, king h. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabetic med 1995; 12:1122–5. 10. hasab aa, jaffer a, hallaj z. blood pressure patterns among the omani population. east mediterr health j 1999; 5:46–54. 11. al shafaee ma, al-shukaili s, rizvi sg, al farsi y, khan ma, ganguly ss, et al. knowledge and perceptions of diabetes in a semi-urban omani population. bmc public health 2008; 8:249. 12. al riyami aa, afifi mm. hypertension in oman: distribution and correlates. j egypt public health assoc 2002; 77:383–407. 13. ministry of health. world health survey oman 2008. muscat: ministry of health, oman, 2012 (in press). sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e4–6, epub. 21 jan 15 submitted 27 oct 14 revision req. 10 nov 14; revision recd. 15 nov 14 accepted 18 nov 14 in this issue of squmj, al-maddah et al. reported a significant association between sleep deprivation among medical trainees and depressive indices using the beck depression inventory-2.1 using a cross-sectional study design, the authors found that depressive symptoms were more profound with acute rather than chronic sleep deprivation. they attributed the emerging depressive symptoms among medical residents to the acute lack of sleep because of long working hours, but not to the number of on-call nights per week.1 however, there was no follow-up to ascertain the cause-and-effect relationship between chronic sleep deprivation and depressive indices. sleep occupies about a third of our lives and is vital to fulfil physiological needs, particularly in terms of cognitive function and mood. disrupted sleep is very distressing for most individuals and may have a negative impact on their quality of life. sleep deprivation has been shown to alter performance among medical professionals and shift workers, with several studies addressing its association with depressive symptoms.2–4 residents and medical interns often suffer from reduced sleep which may lead to neurobehavioural impairment. rosen et al. reported that medical interns with chronic sleep deprivation displayed high levels of depression and burnout over a period of one working year.5 in another study, papp et al. found that chronic sleep loss had a negative impact on residents’ personal lives and their ability to perform their work.6 this supports the idea that chronic rather than acute sleep deprivation may result in depression, contrary to the findings of al-maddah et al.1 night shift work is a well-known cause of daytime sleepiness and mood disorders among workers. these results might also be attributable to chronic sleep loss and changes in circadian rhythm.7 however, one night of fragmented sleep was shown to cause normal subjects to feel sleepier during the day, impair subjective assessments of their mood and decrease mental flexibility and sustained attention.8 therefore, clinical depression might result from the accumulative effect of chronic sleep fragmentation, deprivation and disturbance.8 there is a strong bi-directional relationship between sleep deprivation/disturbance and depression. although disturbed sleep is associated with psychiatric disorders and is traditionally considered to be a symptom of depression,9 research suggests that the relationship between sleep changes and mood disorders may work in the other direction as well.10 in addition to being a symptom, disrupted or a lack of sleep may also be a causal factor that contributes to the development of mood disorders.10,11 chronic insomnia was found to increase the odds ratio of developing depression in several longitudinal studies.9,12 alterations in sleep patterns are associated with depression, a fact which has been reported in the literature for over three decades.11,12 additionally, certain sleep breathing disorders have a strong association with depression. obstructive sleep apnoea syndrome is significantly associated with an impairment in cognitive function due to sleep disturbance and subsequent daytime sleepiness.13 peppard et al. found a dose-response association between sleep-related breathing disorders and depression.14 this finding might be attributed to frequent awakening due to the sleep apnoea, in addition to repeated hypoxic stress to the brain as a result of desaturation.14 contrarily, acute sleep deprivation has been long reported to be beneficial in treating depression. an early study revealed that a single night of sleep deprivation had an antidepressive effect.15 therapeutic sleep deprivation was performed either as total sleep department of clinical physiology, sultan qaboos university hospital, muscat, oman e-mail: malabri@squ.edu.om احلرمان من النوم واالكتئاب ارتباط ثنائي االجتاه حممد عبد اهلل العربي editorial sleep deprivation and depression a bi-directional association mohammed a. al-abri mohammed a. al-abri editorial |e5 deprivation or with selective non-rapid eye movement (rem) sleep deprivation.16,17 the efficacy of either method has not yet been well investigated, although the impression received suggests that total sleep deprivation is superior to the selective technique.15 nonetheless, therapeutic sleep deprivation is not free of side-effects. depressed individuals may experience increases in impulsiveness and drive.17 in addition, they would also suffer from excessive daytime sleepiness, which might be difficult to distinguish, especially in non-responders, with a worsening of the depressive symptoms.17 two processes mainly regulate sleep. firstly, the circadian process regulates the daily rhythms of the body and brain.18 the circadian pacemaker is found in a group of cells in the suprachiasmatic nucleus of the hypothalamus.18,19 these cells provide an oscillatory pattern of activity that drives rhythms such as sleepwake activity and endocrine secretions. they are markedly affected by light and darkness and, to some extent, by temperature.19 bright light in the evening will delay the ‘clock’ and bright light in the morning is necessary to synchronise individuals to a 24-hour rhythm. all animals have a form of this process and the specific period and timing appear to be dependent on particular genes, which are similar in fruit flies and mammals.20 there is strong evidence to support the role of the sleep-wake cycle and circadian rhythm in the pathogenesis of major psychiatric disorders, particularly depression.18 melatonin, a peptide synthesised by the pineal gland, has been shown to play a role in the modulation of the circadian rhythm.21 disrupted melatonin secretion and abnormal circadian rhythms have been reported among depressed subjects and the elderly; this could be the cause of sleep-phase shifts and consequent daytime sleepiness among these groups.22,23 as part of the circadian clock, the drive to sleep in normal sleepers slowly begins to increase a few hours after sunset and gradually reaches a peak in the early morning. the timing of rem sleep is linked to the circadian rhythm, closely mirroring the core temperature of the body. thus, the maximum propensity for rem sleep is usually in the second half of the night with the onset of slow-wave sleep at the beginning of the night.24,25 the occurrence of rem sleep during daytime naps indicates a patho logical daytime sleepiness, as can be observed in cases of narcolepsy.24 secondly, the homeostatic process is the other important regulatory factor for sleep. it increases via sleep deprivation and peaks 16 hours after morning awakening and then decreases again during sleep. when there is a lack of sleep or the duration of sleep is shorter than usual, there is an increase in the homeostatic process. consequently, this works to ensure that the sleep deprivation is made up for during the next sleep period, by accelerating the time before sleep and by possibly increasing sleep depth and duration.25 in animal models, chronic sleep restriction for more than a week was shown to lead to alterations in the neurotransmitter receptor systems (serotonin-1a receptor and corticotropin-releasing hormone receptor systems) and neuroendocrine stress systems (hypothalamic-pituitary-adrenal axis).26 these changes are similar to those reported for major depression. the link between sleep and depression occurs through the serotoninergic system, which is active during wakefulness and inactive during sleep. serotonin release is very much inhibited during slowwave and rem sleep.22 endogenous depression is associated with the functional impairment of several neurotransmitter systems, particularly monaminergic neurotransmission. likewise, evidence of decreased serotoninergic activity was observed in the brains of depressed patients.27 in conclusion, chronic sleep deprivation rather than acute sleep loss may lead to depression that is potentially attributable to the neurochemical changes that occur in the brain. on the other hand, depression may lead to disturbed sleep which could manifest as a symptom of a mood disorder. short sleep duration has been shown to be increasing in prevalence worldwide with a concurrent increase in depressive symptoms, mainly among the younger population.28 further epidemiological studies are required to ascertain the prevalence of such an association among the local population in oman. references 1. al-maddah em, al-dabal bk, khalil ms. prevalence of sleep deprivation and relation with depressive symptoms among medical residents in king fahd university hospital, saudi arabia. sultan qaboos univ med j 2015; 15:78–84. 2. veasey s, rosen r, barzansky b, rosen i, owens j. sleep loss and fatigue in residency training: a reappraisal. jama 2002; 228:1116–24. doi: 10.1001/jama.288.9.1116. 3. dinges df, pack f, williams k, gillen ka, powell jw, ott ge, et al. cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. sleep 1997; 20:267–77. 4. shanafelt td, bradley ka, wipf je, back al. burnout and self-reported patient care in an internal medicine residency program. ann intern med 2002; 136:358–67. doi: 10.7326/00034819-136-5-200203050-00008. 5. rosen im, gimotty pa, shea ja, bellini lm. evolution of sleep quantity, sleep deprivation, mood disturbances, empathy, and burnout among interns. acad med 2006; 81:82–5. sleep deprivation and depression a bi-directional association e6 | squ medical journal, february 2015, volume 15, issue 1 6. papp kk, stoller ep, sage p, aikens je, owens j, avidan a, et al. the effects of sleep loss and fatigue on resident-physicians: a multi-institutional, mixed-method study. acad med 2004; 79:394–406. 7. drake cl, roehrs t, richardson g, walsh jk, roth t. shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. sleep 2004; 27:1453–62. 8. martin se, engleman hm, deary ij, douglas nj. the effect of sleep fragmentation on daytime function. am j respir crit care med 1996; 153:1328–32. doi: 10.1164/ajrccm.153.4.8616562. 9. breslau n, roth t, rosenthal l, andreski p. sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. biol psychiatry 1996; 39:411–18. doi: 10.1016/0006-3223(95)00188-3. 10. ng th, chung kf, ho fy, yeung wf, yung kp, lam th. sleepwake disturbance in interepisode bipolar disorder and highrisk individuals: a systematic review and meta-analysis. sleep med rev 2014; pii:s1087-0792(14)00070-7. doi: 10.1016/j. smrv.2014.06.006. 11. adrien j. neurobiological bases for the relation between sleep and depression. sleep med rev 2002; 6:341–51. doi: 10.1053/ smrv.2001.0200. 12. perlis ml, giles de, buysse dj, tu x, kupfer dj. self-reported sleep disturbance as a prodromal symptom in recurrent depression. j affect disord 1997; 42:209–12. doi: 10.1016/ s0165-0327(96)01411-5. 13. institute of medicine united states committee on sleep medicine and research. functional and economic impact of sleep loss and sleep-related disorders. in: colten hr, altevogt bm, eds. sleep disorders and sleep deprivation: an unmet public health problem. washington d.c., usa: national academies press, 2006. pp. 137–72. 14. peppard pe, szklo-coxe m, hla km, young t. longitudinal association of sleep-related breathing disorder and depression. arch intern med 2006; 166:1709–15. doi: 10.1001/arch inte.166.16.1709. 15. wu jc, bunney we. the biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. am j psychiatry 1990; 147:14–21. 16. vogel gw, vogel f, mcabee rs, thurmond aj. improvement of depression by rem sleep deprivation: new findings and a theory. arch gen psychiatry 1980; 37:247–53. doi: 10.1001/ archpsyc.1980.01780160017001. 17. adrien j, maudhuit c, martin p. antidepressant-like effects of paradoxical sleep deprivation in the learned helplessness paradigm. j sleep res 1992; 1:s2. 18. nutt d, wilson s, paterson l. sleep disorders as core symptoms of depression. dialogues clin neurosci 2008; 10:329–36. 19. steriade m, mccarley r. rem sleep as a biological rhythm. in: steriade m, mccarley r, eds. brainstem control of wakefulness and sleep. new york, usa: springer, 1990. pp. 363–93. 20. gervasoni d, peyron c, rampon c, barbagli b, chouvet g, urbain n, et al. role and origin of the gabaergic innervation of dorsal raphe serotoninergic neurons. j neurosci 2000; 20:4217–25. 21. binkley sa. circadian rhythms of pineal function in rats. endocr rev 1983; 4:255–70. doi: 10.1210/edrv-4-3-255. 22. bouwmans me, bos eh, booij sh, van faassen m, oldehinkel aj, de jonge p. intraand inter-individual variability of longitudinal daytime melatonin secretion patterns in depressed and non-depressed individuals. chronobiol int 2014; 27:1–6. doi: 10.3109/07420528.2014.973114. 23. campos costa i, nogueira carvalho h, fernandes l. aging, circadian rhythms and depressive disorders: a review. am j neurodegener dis 2013; 2:228–46. 24. siegel jm. rem sleep: a biological and psychological paradox. sleep med rev 2011; 15:139–42. doi: 10.1016/j. smrv.2011.01.001. 25. borbély aa, achermann p. sleep homeostasis and models of sleep regulation. j biol rhythms 1999; 14:557–68. doi: 10.1177/074873099129000894. 26. novati a, roman v, cetin t, hagewoud r, den boer ja, luiten pg, et al. chronically restricted sleep leads to depressionlike changes in neurotransmitter receptor sensitivity and neuroendocrine stress reactivity in rats. sleep 2008; 31:1579–85. 27. ursin r. serotonin and sleep. sleep med rev 2002; 6:55–69. doi: 10.1053/smrv.2001.0174. 28. matsushita m, koyama a, ushijima h, mikami a, katsumata y, kikuchi y, et al. sleep duration and its association with sleepiness and depression in “ronin-sei” preparatory school students. asian j psychiatr 2014; 9:61–6. doi: 10.1016/j. ajp.2014.01.006. a 56-year-old male patient with a rare dermatofibrosarcoma protuberans and fibrosarcomatous change (dfspfs) presented with a solitary fluorodeoxyglucose (fdg)-avid tumour with no evidence of metastasis in the left upper extremity [figure 1a]. this initial presentation was treated with wide excision, and then again at its recurrence 8 months later. at admission, the patient had symptoms of gastritis and underwent an oesophago-gastroduodenoscopy, which was normal. almost 3 years after the initial presentation, the patient presented with a retroperitoneal mass measuring 1.4 x 0.8 cm. investigation revealed the tumour, which was avid on fdg-pet/ct (standardised uptake value [suv] max 11.3) and new compared to the previous study [figure 2b]. mild fdg uptake was also noted in a new pulmonary nodule (suv max 1.9) and sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 371-374, epub. 15th jul 12 submitted 30th jun 11 revision req. 1st nov 11, revisions recd. 7th dec 11th & 27th mar 12 accepted 11th apr 12 departments of 1nuclear medicine & pet, 2general surgery, 4pathology, singapore general hospital, singapore; 3radlink pet & cardiac imaging, paragon medical, singapore. *corresponding author e-mail: he77@hotmail.com ساركوما ليفية جلدية متكررة يف الكتف مع انتشار نادر للبطن اكتشف عن طريق التصوير املقطعي باالصدار البوزيرتوين عماد التميمي، �سمبل زاهر، بيري�ض ت�ساو، �سربي عثماين، كي�سافان �سيتمبالم recurrent dermatofibrosarcoma protuberans of the shoulder with rare distant abdominal metastasis detected by fluorodeoxyglucosepositron emission tomography/computed tomography (fdg-pet/ct) *ammad al-tamimi,1 sumbul zaheer,1 chow kah hoe pierce,2 saabry osmany,3 kesavan sittampalam4 interesting medical image figure 1: fluorodeoxyglucose (fdg) positron emission tomography (pet)/computed tomography (ct) scans at the same trans-axial levels, showing mildly fdg-avid local recurrence in the shoulder (a), with no lesion subsequently identified in the same region (b). recurrent dermatofibrosarcoma protuberans of the shoulder with rare distant abdominal metastasis detected by fluorodeoxyglucose-positron emission tomography/computed tomography (fdg-pet/ct) 372 | squ medical journal, august 2012, volume 12, issue 3 appeared malignant [figure 3b]. figure 4 shows the maximum intensity projection (mip) images from the two studies. the retroperitoneal tumour was found to be dermatofibrosarcoma protuberans with extensive fibrosarcomatous transformation, histology grade 3 [figures 5a and 5b]. dfsp is a rare cutaneous tumour of low malignant grade characterised by a pattern of slow, infiltrative growth and a marked tendency to recur locally after surgical excision.1 dfsp is commonly found on the trunk (42–72%), occasionally in the proximal extremities (16–30%), and infrequently above the neck (10–16%).7 rare distant metastases (in less than 5% of cases) may occur many years after the onset of disease and are limited mostly to the lungs, followed by regional lymph nodes, while the visceral organs and bones are rarely affected.2 metastases are more likely with repeated incomplete surgical excisions and by tumour de-differentiation to higher grades.6 metastases are associated with local recurrence and poor prognosis. the 5-year survival rate is estimated at 99.2%.7 dfsp is a fibrosarcoma originating from dermal fibroblasts.6 the genetic abnormalities in dfsp include a supernumerary ring chromosome related to the low amplification of sequences of chromosomes 17 and 22 which is a form of balanced reciprocal translocation.8 this rearrangement will cause fusion of alpha chain type a (col1a1) located on 17q22 to the platelet-derived growth factor beta (pdgfb) located on 22q13. as a result, the col1a1-pdgfb gene formation will result in up regulation of pdgfb expression, resulting in continuous autocrine activation of pdgf receptor beta (pdgfr-b) and propagation of the mitotic signal by formation of autocrine and paracrine loops.9 these transformed cells are inhibited by the tyrosine kinase inhibitor imatinib mesylate with figure 2: fluorodeoxyglucose (fdg) positron emission tomography (pet)/ computed tomography (ct) scan at the same trans-axial level comparing the two scans at the time of local recurrence in 2006, when there was no retroperitoneal lesion (a) and subsequently at the time of 1.4 x 0.8 cm heterogeneous, left retro-peritoneal distant metastasis in 2009 (b). figure 3: fluorodeoxyglucose (fdg) positron emission tomography (pet)/computed tomography (ct) scan at the same trans-axial level comparing the two scans at the time of local recurrence in 2006 when there was no pulmonary lesion (a) and subsequently at the time of retro-peritoneal distant metastasis in 2009, when a mildly fdg-avid pulmonary nodule was detected (b). ammad al-tamimi, sumbul zaheer, chow kah hoe pierce, saabry osmany and kesavan sittampalam interesting medical image | 373 reported cases of response often documented with fdg.10 the surgical objective in dfsp is complete tumour excision with maximal normal tissue preservation. hence, a wide local excision with lateral margins of at least 3 cm and including the underlying fascia is recommended. in addition, micrographic controlled excision (mce) showed favourable outcomes in treating dfsp.6 fdgpet/ct findings in a case of recurrence of dermatofibrosarcoma in the surgical scar have been reported.3 fdg-pet/ct has also been used to monitor response to imatinib mesylate in 2 reported cases of unresectable metastatic dfsp, with a decrease in tumour uptake of fdg after treatment documented in both cases.4–5 in the former case, this decrease in uptake coincided with clinical improvement as early as 2 weeks after commencement of the therapy. 4 in contrast to our case, where a fdg-avid pulmonary lesion was noted on pet/ct, a previous case reported a pulmonary nodule which was noted on ct but not on fdg-pet. it was thought this may have been due to the size (8 mm). a case has also been reported where dfsp response to imatinib was noted on fdg-pet but not on ct.10 this is similar to findings in other malignancies. dfsp is a rare cutaneous tumour of low malignant grade. fdg-pet/ct has been reported to be useful in dfsp imaging for delineating disease extent, both in staging and recurrence, which can be useful in planning surgery. fdg has also been documented as assessing dfsp response to imatinib, showing response when none was noted on ct. given the rarity of the disease there are no large studies to date but the existing data appears promising. we suggest that fdg pet/ct be considered as an important component of the treatment plan of patients with dfsp. figure 4: maximum intensity projection of the fluorodeoxyglucose (fdg) positron emission tomography (pet)/ computed tomography (ct) scans at the time of the first presentation in 2006 with (a) a mildly fdg-avid local recurrence, and (b) subsequently, in 2009, with an intensely fdg-avid retro-peritoneal metastasis. recurrent dermatofibrosarcoma protuberans of the shoulder with rare distant abdominal metastasis detected by fluorodeoxyglucose-positron emission tomography/computed tomography (fdg-pet/ct) 374 | squ medical journal, august 2012, volume 12, issue 3 references 1. mcarthur g. dermatofibrosarcoma protuberans: recent clinical progress. ann surg oncol 2007; 14:2876–86. 2. yilmaz a, cenesizoglu e, egilmez e, onel s, mustu m, cennet a. dermatofibrosarcoma protuberans: a case report of a rare, bulky tumor that was managed with surgical therapy. int j shoulder surg 2009; 3:16– 20. 3. basu s, baghel ns. recurrence of dermatofibrosarcoma protuberans in post-surgical scar detected by (18) f-fdg-pet imaging. hell j nucl med 2009; 12:68. 4. rubin bp, schuetze sm, eary jf, norwood th, mirza s, conrad eu, et al. molecular targeting of plateletderived growth factor b by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. j clin oncol 2002; 20:3586–91. 5. mizutani k, tamada y, hara k, tsuzuki t, saeki h, tamaki k. imatinib mesylate inhibits the growth of metastatic lung lesions in a patient with dermatofibrosarcoma protuberance. brit j dermatol 2004; 151:232–57. 6. ah-weng a, marsden jr, sanders dsa, waters r. dermatofibrosarcoma protuberans treated by micrographic surgery. brit j cancer 2002; 87:1386–9. 7. dragoumis dm, katsohi la, amplianitis ik, tsiftsoglou ap. late local recurrence of dermatofibrosarcoma protuberans in the skin of female breast. world j surg oncol 2010; 8:48. 8. cottier o, fiche m, meuwly j-y, delaloye j-f. dermatofibrosarcoma presenting as a nodule in the breast of a 75-year-old woman: a case report. j med case reports 2011; 5:503. 9. rutkowski p, wozniak a, switaj t. advances in molecular characterization and targeted therapy in dermatofibrosarcoma protuberans. sarcoma 2011; 959132. 10. labropoulos sv, razis ed. imatinib in the treatment of dermatofibrosarcoma protuberans, biologics 2007; 1:347–53. figure 5: (a) pathology slide of low-powered view of fibrosarcoma with herring-bone pattern; (b) pathology slide showing areas of viable tumor fascicles with adjacent necrosis sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 275-279, epub. 9th may 13 submitted 30th jul 12 revision req. 6th jan 13, revision recd. 7th jan 13 accepted 21st jan 13 مقارنة بني تكلفة عمليات استئصال الزائدة عن طريق فتح البطن واملناظري عند األطفال �شازاد يون�ض خان، زينب نا�رس البلو�شي، خالد منري باتي، توفيق اإح�شان، براكا�ض مندان امللخ�ص: الهدف: . ا�شتئ�شال الزائدة عن طريق املناظري عند الأطفال تعترب من العمليات املنت�رسة والتي متار�ض روتينيا يف معظم مراكز اإىل الدرا�شة هذه تهدف ال�شحية. اخلدمات ومقدمي للمر�شى بالن�شبة مهم يعد اجلراحية العمليات تكلفة العامل. حول ال�شحية الرعاية ب�شبب الزائدة لال�شتئ�شال بحاجة كانوا الذين لالأطفال املناظري وبا�شتخدام املفتوحة الزائدة ا�شتئ�شال بني الإجمالية التكلفة مقارنة التهاب الزائدة احلاد. مت البحث عن الطرق املنا�شبة والآمنة ذات التكلفة الفعالة خلف�ض ن�شبة هذه العمليات. الطريقة: مت ا�شتعرا�ض امللفات الطبية جلميع الأطفال ) من �شن 0 اإىل 12�شنة( مب�شت�شفى جامعة ال�شلطان قابو�ض بعمان الذين احتاجوا لإجراء عمليات ا�شتئ�شال الزائدة عن طريق فتح البطن واملناظري من يونيو 2009 اإىل يوليو 2011. النتائج: كان ا�شتئ�شال الزائدة باملناظري فى 75 مري�شا بينما كان ال�شتئ�شال طريق فتح البطن يف 34 مري�شا. مت مطابقة العمر واجلن�ض ملر�شى عمليات ا�شتئ�شال الزائدة بالفتح واملناظري. كان متو�شط وقت العملية 76 دقيقة بالن�شبة ل�شتئ�شال الزائدة باملناظري مقارنة مع 49 دقيقة ل�شتئ�شال بالفتح )p >0.001( بينما كان متو�شط الإقامة بامل�شت�شفى 3.14 بالن�شبة ل�شتئ�شال الزائدة باملناظري و 2.15 يوما بال�شتئ�شال بالفتح )p = 0.08( كان متو�شط التكلفة للعمليتني بالريال العماين 534 بالن�شبة ل�شتئ�شال باملناظري و 343 ل�شتئ�شال بالفتح )p = 0.00(. معدل امل�شاعفات بعد العملية ا�شتئ�شال مقارنة %8 باملناظري )ا�شتئ�شال اإح�شائيا معرب يكن مل الفرق هذا اأن غري باملناظري، الزائدة ل�شتئ�شال بالن�شبة اأقل كان ن�شبة من يزيد ول بالفتح بال�شتئ�شال باملقارنة تكلفة اأكرث باملناظري الزائدة ا�شتئ�شال اخلال�صة: .)p = 0.32 ،11.7% بالفتح املرا�شة اأو طول فرتة الإقامة بامل�شت�شفى. مفتاح الكلمات: التهاب الزائدة؛ ا�شتئ�شال الزائدة؛ التكلفة وحتليل التكلفة؛ عمان. abstract: objectives: laparoscopic appendectomy (la) for children has become very popular and is routinely performed in most health care centres around the world. the cost of surgical procedures is always a concern for patients and health care providers. this study compares, the total cost of open appendectomy (oa) with la in children who required an appendectomy for acute appendicitis. suitable and safe cost-effective techniques were also explored to reduce the cost of these procedures. methods: the medical records of all the children (ranging between 0 and 12 years) at sultan qaboos university hospital in oman, who required oa or la from june 2009 to july 2011, were reviewed. results: la were performed in 75 patients while oa were done in 34. patients from the oa and la groups were ageand gender-matched. the average operative time was 76 minutes for la and 49 minutes for oa (p <0.001) while the average hospital stay was 3.14 days for la and 2.15 days for oa (p = 0.08). the average cost of the two procedures was omani riyals (omr) 534 for la and omr 343 for oa (p = 0.00). the complication rate following procedures was lower in the case of la, however this was not statistically significant (la = 8% versus oa = 11.7 %, p = 0.32). conclusion: la are costlier procedures than oa, however they are as safe as oa, and do not increase morbidity or the duration of hospital stay. keywords: appendicitis; appendectomy; costs and cost analysis; oman. cost comparison between laparoscopic and open appendectomies in children shahzad y. khan, zainab n. al-balushi, *khalid m. bhatti, toufique ehsan, prakash mandhan department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drkhalidmunirbhatti@yahoo.com advances in knowledge the insight into the factors responsible for the comparatively higher cost within the laparoscopic appendectomy group is expected to highlight techniques to reduce the cost of laparoscopic appendectomies. application to patient care this study demonstrates that laparoscopic appendectomy (la) is as safe as open appendectomy. it establishes that the cost of la can be reduced by certain modifications which will help in reducing health-related costs. therefore, this study encourages the use of this technique in patients requiring an appendectomy. clinical & basic research cost comparison between laparoscopic and open appendectomies in children 276 | squ medical journal, may 2013, volume 13, issue 2 pain in the right iliac fossa is one of the most common complaints in the accident and emergency departments of most hospitals.1 in the paediatric age group, about 50% of such patients undergo an appendectomy with a working diagnosis of acute appendicitis.2 therefore, this makes the appendectomy, either laparoscopic appendectomy (la) or open appendectomy (oa), the most commonly performed emergency procedure in children. for children, the conventional oa has been a gold standard; however, in the last two decades, la for children has become very popular and routine in most healthcare centres around the world.1–4 in the current economic circumstances, the cost of surgical procedures is always a concern for patients and healthcare providers. it has been previously shown that laparoscopic surgery in general is more expensive than the open procedure for the same disease.1-6 similarly, there has been debate about the total cost of la versus oa in children in order to analyse the cost differences between the two techniques.7,8 although la for adults has been practised for the last 7 years at sultan qaboos university hospital (squh), it has only become routine for the paediatric age group within the last 3 years, after the paediatric surgery unit was established. while a quantity of western literature is available on cost comparisons between the two techniques, there has been no such study in the middle eastern region to date. in the present study, we compared the total cost of oa and la in children who required an appendectomy for acute appendicitis, as well as searching for suitable and safe cost-effective techniques to reduce the cost of the procedures in our set-up. methods this retrospective study was conducted in squh, muscat, oman. the medical records of all the children (ranging in age between 0 and 12 years) who required oa or la, from june 2009 to july 2011, were reviewed after receiving approval from the medical ethics research committee of sultan qaboos university’s college of medicine & health sciences. demographic data, such as age, weight and gender, were collected from the electronic patient database of squh. other variables recorded were the date of admission, the date and time of surgery, the technique of surgery, the experience level of the operating surgeon, the total theatre time utilised during each technique, the operating time duration, the use of reusable or disposable instruments, the use of postoperative analgaesics and the duration of hospital stay. the cost of individual consumables used in both techniques was obtained from squh’s medical supply department. first, we calculated the common costs for oa and la, based on the cost of the consumables which were the same for each procedure of the same type. for instance, the common costs for oa included the theatre charges and the cost of sutures. for la, it included the theatre charges, the cost of one endoloop® ligature (ethicon, johnson & johnson, new jersey, usa) and the cost of disposable instruments. this last cost varied depending on how many times a disposable instrument was used per appendectomy. the cost of disposable endo scissors and graspers was obtained by dividing the total cost of these items by 3, as they were used up to 3 times a session after sterilisation. however, the cost of disposable trocars was added in full. after obtaining the common costs for each type of procedure, the total cost for each patient was calculated. for oa, the total cost included the oa common cost, the cost of analgaesics and hospital stay [table 1a]. for la, the total cost included the la common cost as well as various other costs where applicable, for instance the cost of co2 used, any extra loops or side bags utilised, the use of harmonic scalpels (for the division of the mesoappendix, instead of cauterisation using maryland forceps), intravenous (iv) analgaesics and the cost of the hospital stay [table 1b]. the lifespan of reusable instruments for the two techniques is variable, and hence this was not counted in this study. data analysis was performed using the statistical package for the social sciences (spss), version 16 (ibm, chicago, illinois, usa). chi-squared (χ2) tests were used to compare the difference in frequencies of categorical variables. to compare the means of two independent samples, t-tests (for weight, total theatre time and operative time) and non-parametric tests (mann-whitney u tests for age, duration of hospital stay and total cost) were used, depending upon the normality of distribution curves. a p value of <0.05 was considered significant. shahzad y. khan, zainab n. al-balushi, khalid m. bhatti, toufique ehsan and prakash mandhan clinical and basic research | 277 results in total, 109 patients underwent appendectomies between june 2009 and july 2011; of these, 75 patients were in the la group and 34 were in the oa group. the male to female ratio of patients was 2:1, and the average age ranged from 6 to 144 months, with a mean of 110.57 ± (standard deviation [sd]) 28.83 months. the average weight was 29.78 ± 11.0 kg. preoperative evaluation was done by historytaking, clinical examination, routine full blood count (fbc) and urinalysis for both groups. further evaluation was done by ultrasonography (usg) and computed tomography (ct) of the abdomen, if the previous evaluation’s findings were equivocal. patients from the oa and la groups were age-(oa = 105.15 ± 32.70 months versus la 113.47± 26.34 months, p = 0.232) and gender-matched (oa = 70% males versus la 64 % males, χ2 = 0.45, p = 0.50). the average weight of children in the la group was significantly higher than of those in the oa group (31.59 kg versus 26.3, p = 0.01). the calculated common cost for oa was omani riyals (omr) 317 (1 omr = 2.6 usd) while that for la was omr 479. the total costs for individual patients varied depending on the doses of analgesia used (omr 1.01/1 g of paracetamol) and the duration of their stay in hospital (omr 12/day). however, the total cost for la included not only the cost of the analgesia and hospital stay, but also the cost of the extra equipment used (side bags, extra endoloops®, harmonic scalpels and co2 per litre). the cost for oa ranged from omr 328 to 381, while that for la ranged from omr 491 to 693. the average cost for la was significantly higher than for oa (la = 535 ± 42.17; oa = 344 ± 15.12; p = 0.00) [table 2]. the comparison between the two techniques, regarding other important factors, showed that the total theatre time utilised (in minutes) was 110.38 ± 35.99 for la and 76.38 ± 17.18 for oa (p <0.001) while actual operative time (in minutes) was 76.53 ± 31.99 for la and 49.23 ± 16.18 for oa (p <0.001) [table 2]. as the total operative/theatre time increases, the costs also increase due to factors such as the cost of labour, electricity and equipment. there was no statistically significant difference between the two techniques in terms of the duration of iv analgaesics used (la = 0.89 ± 1.44; oa = 0.88 ± 1.34; p = 0.97); postoperative morbidity (la = 8% [6 patients], oa = 11.7% [4 patients], p = 0.32), and duration of hospital stay (la = 3.14 ± 2.70; oa = 2.15 ± 1.23; p = 0.08). the complications in the la group included a bladder injury (n = 1); postoperative fever table 1a: cost breakdown of open appendectomies in omani riyals* cost in omr to ta l c os t o f o a common cost theatre charge 312 suture material •1 monocryl 3/0 •1 vicryl 2/0 •1 vicryl 3/0 4.67 analgaesics cost (per 1 g paracetamol) 1.01 hospital stay cost (per day) 12 oa= open appendectomy; omr = omani riyals; g = grams. *in 2012, 1 omr = 2.59 usd. table 1b: cost breakdown of laparoscopic appendectomies in omani riyals* cost in omr t ot al c os t of l a common cost theatre charge 312 suction tube 0.91 gas tube 3.2 camera tube cover 1.616 catherisation cost 6.035 trocar 11mm 38.4 5mm† 36.8 x 2 endograsper‡ 34.5 / 3 endodissector‡ 29.83 / 3 endoloop® 16.833 1 vicryl j-needle 1.824 1 monocryl 3/0 2.99 additional costs side bag 0.615 extra endoloop® 16 harmonic scalpel‡ 218.25 / 3 co2 (per litre) 0.262 analgaesics cost (per 1 g paracetamol) 1.01 hospital stay cost (per day) 12 la = laparoscopic appendectomies; omr = omani riyals; mm = millimetres; co 2 = carbon dioxide; g = grams. *in 2012, 1 omr= 2.6 usd; †two 5mm ports were used; ‡price was divided by 3. cost comparison between laparoscopic and open appendectomies in children 278 | squ medical journal, may 2013, volume 13, issue 2 (n = 1); intestinal intussusception requiring a laparotomy (n = 1); postoperative ileus (n = 1); adhesion obstruction ( n= 1), and lower respiratory tract infection (lrti) (n = 1). in the oa group, complications included postoperative diarrhoea (n = 2); postoperative ileus (n = 1), and lrti (n = 1). discussion the cost of a laparoscopic appendectomy is an area of great interest in most published literature on the subject.7,9–11 although the safety of la is well documented, the superiority of la over oa has not yet been established. this is in contrast to laparoscopic cholecystectomies, which have clear advantages over open cholecystectomies.12 in this study, we found that la was more costly than oa. however, the average hospital stay was comparable in both the la and oa groups, and to those mentioned in the literature.13,14 moreover, the duration of iv analgaesics used in the procedures and the rate of postoperative morbidity were similar in both groups. therefore, the causes of the higher cost in the la were other than those mentioned above. significantly longer theatre/operative times [table 2], and higher common costs (la = 316.67 versus oa = 479.04, p <0.001) are probably the causes of the significantly higher cost of la. accordingly, an overall reduction in operative time, through utilising more experienced surgeons and by modifying the instruments used, may reduce the cost of la. another point worth mentioning is that although the higher cost of la is well-established,10,15 this study found that costs varied considerably within the la group (omr 491–693). the cheapest procedure was performed using 3 ports and a single loop on the base of the appendix. in this procedure, the patient in question did not receive iv analgaesics, developed no complications and stayed in the hospital for only one day. in contrast, in another la procedure, the cost was higher as two loops were used at the request of the surgeon, and the patient suffered a preoperative complication (a urinary bladder injury) and therefore had to stay in the hospital for 14 days. to evaluate the factors responsible for relatively higher cost within the la group, the analysis was done using a cut-off value of omr 535 (the mean cost value). the analysis revealed that the factors which significantly increased the cost of the procedure were the use of harmonic scalpels (χ2 = 10.01; p = 0.002), longer operative times (>80 minutes, χ2= 9.87; p = 0.002), and duration of hospital stay (>2 days, χ2 = 25.24, p <0.001). as mentioned previously, longer operative times increase the cost of the procedure due to the increased cost of labour. the use of harmonic scalpels in la is also expensive; division of the mesoappendix can be performed less expensively by cauterising using maryland forceps. a longer hospital stay increases the cost for the same reason as longer operative times. in this study, one of the reasons for longer hospital stays was the set protocol of giving iv antibiotics for 5 days to patients who had complicated appendicitis; this set protocol has currently been modified to reduce the length of hospital stays. recently, the paediatric surgery unit at squh has improved current practices in many ways. the average operative time (in minutes) has been reduced from 85 in the first year to 76 in the second year. additionally, almost all of the patients are now started on oral analgaesics once they are fit to take analgaesics orally. moreover, most of the patients, barring any complications, are currently discharged from the hospital on their first postoperative day. table 2: comparison of laparoscopic appendectomies with open appendectomies variables technique of surgery statistics la oa p value total theatre time utilised (mins) 110.38 ± 35.99 (sd) 76.38 ± 17.18 (sd) <0.001 operative time (mins) 76.53 ± 31.99 (sd) 49.23 ± 16.18 (sd) <0.001 iv analgaesics (days) 0.89 ± 1.44 (sd) 0.88 ± 1.34 (sd) 0.97 postoperative morbidity 8% (χ2 = 9.25) 11.7% 0.32 hospital stay (days) 3.14 ± 2.70 (sd) 2.15 ± 1.23 (sd) 0.08 total cost for procedure (omr) 535 ± 42.17 (sd) 344 ± 15.12 (sd) 0.00 la = laparoscopic appendectomy; oa = open appendectomy; mins = minutes; iv = intravenous; sd = standard deviation; omr = omani riyals. shahzad y. khan, zainab n. al-balushi, khalid m. bhatti, toufique ehsan and prakash mandhan clinical and basic research | 279 although the above mentioned measures are expected to decrease the cost of la in the near future, we feel that certain other modifications are still needed to make the existing techniques of la more cost-effective. for example, the results of two ports15,16 or a single ‘all-in-one’ port appendectomies are promising, as reported by visnjic et al. and stylianos et al.11,17 as these studies demonstrate, the cost of a single port appendectomy is less than that of an appendectomy using 3 ports. similarly, the use of a single endoloop® or endo stapler,18 and avoiding the use of harmonic scalpels, are other possible ways to reduce the cost of la. the use of an endo stapler with polymeric clips has been shown to be safe, as well as reducing operative time.18 appropriate patient evaluations and same day discharges may also help to reduce the duration and cost of hospital stays.19,20 conclusion an la is a costlier procedure than an open appendectomy, however it is as safe as an open appendectomy, and does not increase patient morbidity or the duration of hospital stay. certain modifications to the standard existing technique, such as equipment substitution or economy, should be undertaken in order to reduce the overall cost of la. references 1. cariati a, brignole e, tonelli e, filippi m, guasone f, de negri a. laparoscopic or open appendectomy. critical review of the literature and personal experience. g chir 2001; 22:353–7. 2. esposito c, borzi p, valla js, mekki m, nouri a, becmeur f. laparoscopic versus open appendectomy in children: a retrospective comparative study of 2,332 cases. world j surg 2007; 31:750–5. 3. li x, zhang j, sang l, zhang w, chu z, li x, et al. laparoscopic versus conventional appendectomy--a meta-analysis of randomized controlled trials. bmc gastroenterol 2010; 10:129. 4. masoomi h, mills s, dolich mo, ketana n, carmichael jc, nguyen nt. comparison of outcomes of laparoscopic versus open appendectomy in children: data from the nationwide inpatient sample (nis), 2006–2008. world j surg 2012; 36:573–8. 5. douglas cd, macpherson ne, davidson dm, gani js. randomized controlled trial of ultrasonography in diagnosis of acute appendicitis incorporating alvarado’s score. bmj 2000; 321:919–22. 6. shareef ks, waly ah, abd-elrahman s, abd elhafez ma. alvarado score as an admission criterion in children with pain in right iliac fossa. afr j paediatr surg 2010; 7:163–5. 7. lintula h, kokki h, vanamo k, valtonen h, mattila m, eskelinen m. the costs and effects of laparoscopic appendectomy in children. arch pediatr adolesc med 2004; 158:34–7. 8. oka t, kurkchubasche ag, bussey jg, wesselhoeft cw, tracy tf, luks fi. open and laparoscopic appendectomy are equally safe and acceptable in children. surg endosc 2004; 18:242–5. 9. little dc, custer md, may bh, blalock se, cooney dr. laparoscopic appendectomy: an unnecessary and expensive procedure in children? j pediatr surg 2002; 37:310–7. 10. mcgrath b, buckius mt, grim r, bell t, ahuja v. economics of appendicitis: cost trend analysis of laparoscopic versus open appendectomy from 1998 to 2008. j surg res 2011; 171:161–8. 11. visnjic s. transumbilical laparoscopically assisted appendectomy in children: high-tech low-budget surgery. surg endosc 2008; 22:1667–71. 12. litwin de, cahan ma. laparoscopic cholecystectomy. surg clin north am 2008; 88:1295–313. 13. panteli c, desai a, manoharan s, bouhadiba n, singh s, tsang t. emergency laparoscopic appendicectomy in children: the results in trainees hands. j pediatr surg spec 2010; 4:1–66. 14. thambidorai cr, aman fuad y. laparoscopic appendicectomy for complicated appendicitis in children. singapore med j 2008; 49:994–7. 15. needham pj, laughlan ka, botterill id, ambrose ns. laparoscopic appendicectomy: calculating the cost. ann r coll surg engl 2009; 91:606–8. 16. khan ar, al-bassam a. two-port versus threeport laparoscopic appendectomy in children with uncomplicated appendicitis. pediatr endosurg innov tech 2002; 6:255–60. 17. stylianos s, nichols l, ventura n, malvezzi l, knight c, burnweit c. the "all-in-one" appendectomy: quick, scarless, and less costly. j pediatr surg 2011; 46:2336–41. 18. safavi a, langer m, skarsgard ed. endoloop versus endostapler closure of the appendiceal stump in pediatric laparoscopic appendectomy. can j surg 2012; 55:37–40. 19. grewal h, sweat j, vazquez wd. laparoscopic appendectomy in children can be done as a fast-track or same-day surgery. jsls 2004; 8:151–4. 20. alkhoury f, burnweit c, malvezzi l, knight c, diana j, pasaron r, et al. a prospective study of safety and satisfaction with same-day discharge after laparoscopic appendectomy for acute appendicitis. j pediatr surg 2012; 47:313–6. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e468−472, epub. 14th oct 14 submitted 30th mar 14 revision req. 11th may 14; revision recd. 3rd jun 14 accepted 19th jun 14 departments of 1haematology, 2medicine, 3anaesthesia & intensive care and 5emergency medicine, sultan qaboos university hospital; 4department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: khabori@squ.edu.om تقدير مستوى تركيز اهليموجلوبني بطريقة غري تداخلية يف مرضى الثالسيميا الكربى مرت�شى خمي�س اخلابوري، اأروى الريامية، خليل الفار�شي، حممد احلنيني، عبداحلكيم الها�شم، نا�رص الكمياين، عي�شى القر�شوبي، حماد خان، خلفان العمراين، �شاهينا داعر abstract: objectives: this study aimed to validate pulse co-oximetry-based haemoglobin (hb) estimation in children and adults with thalassaemia major (tm) and to determine the impact of different baseline variables on the accuracy of the estimation. methods: this observational study was conducted over a five-week period from march to april 2012. a total of 108 patients with tm attending the daycare thalassaemia centre of a tertiary care hospital in muscat, oman, were enrolled. spot (sp) hb measurements were estimated using a pronto-7® pulse co-oximetry device (masimo corp., irvine, california, usa). these were compared to venous samples of hb using the cell-dyn sapphire hematology analyzer (abbott diagnostics, abbott park, illinois, usa) to determine the reference (ref ) hb levels. a multivariable linear regression model was used to assess the impact of baseline variables such as age, gender, weight, height, ref hb and blood pressure on the hb estimations. results: of the 108 enrolled patients, there were 54 males and 54 females with a mean age of 21.6 years (standard deviation [sd] = 7.3 years; range: 2.5–38 years). the mean ref hb and sp hb were 9.4 g/dl (sd = 0.9 g/dl; range: 7.5–12.3 g/dl) and 11.1 g/dl (sd = 1.2 g/dl; range: 7.5–14.7 g/dl), respectively. the coefficient of determination (r2) was 21% with a mean difference of 1.7 g/dl (sd = 1.1 g/dl; range: −0.9–4.3 g/dl). in the multivariable model, the ref hb level (p = 0.001) was the only statistically significant predictor. conclusion: the pronto-7® pulse co-oximetry device was found to overestimate hb levels in patients with tm and therefore cannot be recommended. further larger studies are needed to confirm these results. keywords: beta thalassemia; validation studies; hemoglobin; pulse oximetry. لدى النب�شي التاأك�شج قيا�س بطريقة الهيموجلوبني تركيز م�شتوى تقدير �شحة من التحقق اإىل الدرا�شة هذه تهدف الهدف: امللخ�ص: الأطفال والبالغني امل�شابني مبر�س الثال�شيميا الكربى. الطريقة: اأجريت هذه الدرا�شة الو�شفية على مدى خم�شة اأ�شابيع خالل الفرتة من مار�س اإىل اأبريل 2012. و�شملت الدرا�شة 108 مر�شى بالثال�شيميا الكربى املراجعني للعيادة النهارية مبركز الثال�شيميا يف م�شت�شفى pronto-7® مرجعي مب�شقط، �شلطنة عمان. مت قيا�س م�شتوى تركيز الهيموجلوبني لكل مري�س بطريقة التاأك�شج النب�شي بوا�شطة جهاز )�رصكة ما�شيمو، اإرفني، كاليفورنيا، الوليات املتحدة الأمريكية( ثم مقارنتها بقيا�س الهيموجلوبني يف عينة دم وريدي بوا�شطة جهاز cell-dyn sapphire hematology analyzer )�رصكة اأبوت، اأبوت بارك، اإلينوي�س، الوليات املتحدة الأمريكية( لتحديد الهيموجلوبني املرجعي. ا�شتمل منوذج النحدار اخلطي متعدد املتغريات لتوقع تقدير الختالفات على املتغريات التالية: العمر واجلن�س والوزن والطول وقيا�س �شغط الدم والهيموجلوبني املرجعي. النتائج: �شملت الدرا�شة 108 مر�شى ن�شفهم من الذكور والن�شف الآخر من الإناث وكان متو�شط العمر 21.6 �شنة )النحراف املعياري 7.3 �شنة؛ النطاق 38-2.5 �شنة(. وكان متو�شط تركيزالهيموجلوبني املرجعي تركيزالهيموجلوبني متو�شط اأما غرام/دي�شيليرت( 7.5-12.3 النطاق غرام/دي�شيليرت؛ 0.9 املعياري )النحراف غرام/دي�شيليرت 9.4 بطريقة التاأك�شج النب�شي فكان 11.1 غرام/دي�شيليرت )النحراف املعياري 1.2 غرام/دي�شيليرت؛ النطاق 14.7-7.5 غرام/دي�شيليرت(. واأما معامل التعيني )r2( فكان %21 مع متو�شط فارق وقدره 1.7 غرام/دي�شيليرت )النحراف املعياري 1.1 غرام/دي�شيليرت؛ النطاق 4.3-0.9 غرام/دي�شيليرت(. ويف منوذج متعدد املتغريات كان م�شتوى تركيز الهيموجلوبني )p = 0.001( هو العامل املتنبئ الوحيد ذو دللة اإح�شائية معنوية. اخلال�صة: يبالغ جهاز التاأك�شج النب�شي ®pronto-7 يف قيا�س م�شتوى تركيز الهيموجلوبني ملر�شى الثال�شيميا الكربى. ولذا ل نن�شح با�شتخدامه يف هذه ال�رصيحة من املر�شى. ونن�شح باإجراء درا�شات اأكرب للتثبت من هذه النتائج. مفتاح الكلمات: الثال�شيميا الكربى؛ درا�شات التحقق؛ هيموجلوبني؛ التاأك�شج النب�شي. non-invasive haemoglobin estimation in patients with thalassaemia major *murtadha k. al khabori,1 arwa z. al-riyami,1 khalil al-farsi,1 mohammed al-huneini,1 abdulhakeem al-hashim,2 nasser al-kemyani,3 issa al-qarshoubi,2 hammad khan,4 khalfan al-amrani,5 shahina daar4 clinical & basic research advances in knowledge this study found that the investigated co-oximetry device (pronto-7® pulse, masimo corp., irvine, california, usa) overestimates haemoglobin levels in patients with thalassaemia major (tm). murtadha k. al khabori, arwa z. al-riyami, khalil al-farsi, mohammed al-huneini, abdulhakeem al-hashim, nasser al-kemyani, issa al-qarshoubi, hammad khan, khalfan al-amrani and shahina daar clinical and basic research | e469 thalassemia major (tm) is a relatively common inherited blood disorder that is prevalent among the population of oman. it results from the homozygous loss of beta-globin gene expression and presents in childhood with impaired growth and a failure to thrive.1,2 those affected need regular, adequate blood transfusions in order to maintain normal growth and to prevent extramedullary haematopoiesis which leads to the skeletal abnormalities typically seen in tm-affected individuals.3–5 patients with tm are able to tolerate low haemoglobin (hb) levels without showing the typical symptoms of anaemia and, as a result, the parents of young tm patients do not always realise the importance of maintaining adequate hb levels. it was hypothesised that regular non-invasive spot (sp) hb measurements would improve transfusion planning for tm patients and optimise the prevention of extramedullary haematopoiesis, along with the related skeletal abnormalities of this condition. the portable pronto-7® device (masimo corp., irvine, california, usa) has been previously evaluated as a non-invasive method for assessing hb levels via pulse co-oximetry hb estimation.6‒9 additionally, a former study validated the use of sp hb measurements in patients with sickle cell disease (scd) and in normal blood donors.10,11 research has also shown that the pronto-7® device, which is based on spectrophotometry,12 could be used effectively as a continuous hb monitor to assess trends in hb levels among patients in intensive care settings.8 however, the use of this device in tm patients with lower hb levels has not previously been examined and the ability of the device to accurately estimate sp hb levels in this patient group has yet to be validated. the aim of this study, therefore, was to validate the pulse cooximetry-based method of hb estimation in patients with tm and to assess the impact of different baseline variables on the accuracy of the estimation. methods this observational study involved 108 patients with tm from the thalassaemia daycare unit of the sultan qaboos university hospital (squh) in muscat, oman. the study was conducted over a five-week period from march to april 2012 and included participants of all ages and both genders. the diagnosis of tm was based on the absence of hb a via high-performance liquid chromatography in patients requiring regular blood transfusions. two spot hb measurements (sp1 hb and sp2 hb) were taken 10 minutes apart using small, medium and large rainbow® reusable spot check sensors (masimo corp.), for patients weighing 10 to 50 kg. these were connected to the pronto-7® pulse co-oximetry device according to the manufacturer’s recommendations. in addition, a venous sample was taken in order to make a laboratory-based hb estimation and determine the patients’ reference (ref ) hb levels. for this purpose, the cell-dyn sapphire hematology analyzer (abbott laboratories, abbot park, illinois, usa), was used, as this is considered the gold standard for accurately recording hb levels.13 continuous variables were presented as means with standard deviations and ranges, while categorical variables were shown as frequencies and percentages. scatter plots were used to compare the continuous variables (ref hb versus sp1 hb and sp1 hb versus sp2 hb). a linear regression model was used to estimate the intercept, the beta coefficients and the coefficient of determination (r2). the r2 value was used as an estimate of goodness-of-fit and the two methods of hb estimation were compared using a bland-altman plot. multivariable linear regression was used to assess the impact of selected baseline characteristics (age, gender, weight, height, ref hb and blood pressure) on the difference between the sp1 hb and ref hb levels. an alpha error threshold of 0.05 was considered for statistical significance. the statistical software stata, version 11 (statacorp lp, college station, texas, usa) was used for all descriptive statistics, graphs and analytical tests. the study protocol was reviewed and approved by the medical research & ethics committee at the college of medicine & health sciences, sultan qaboos university (mrec#506). all patients gave informed consent after being briefed by a trained medical officer or nurse. results a total of 108 patients (54 male and 54 female) with tm were enrolled in this study, with a mean age of 21.6 ± 7.3 years (range: 2.5–38 years). only 10% of application to patient care the results of this study indicate that this pulse co-oximetry device should not be used for the purpose of haemoglobin estimation in tm patients as it was found to overestimate haemoglobin levels among this patient population. non-invasive haemoglobin estimation in patients with thalassaemia major e470 | squ medical journal, november 2014, volume 14, issue 4 the patients were aged 11 years or younger. the mean ref hb, sp1 hb and sp2 hb levels were 9.4 ± 0.9 g/ dl (range: 7.5–12.3 g/dl), 11.1 ± 1.2 g/dl (range: 7.5–14.7 g/dl) and 10.8 ± 1.2 g/dl (range: 7.5–14.2 g/ dl), respectively. the mean weight and height of the participants were 52.4 ± 16.4 kg (range: 12.8–100.7 kg) and 154 ± 15 cm (range: 88–184 cm), respectively. the mean blood pressure of the patients was 111/66 ± 13/9 mmhg (range: 80/47–138/100 mmhg) [table 1]. the scatter plot of sp1 hb versus ref hb is shown in figure 1, with an r2 of 21%. the mean difference between sp1 hb and ref hb was 1.7 ± 1.1 g/dl (range: −0.9–4.3 g/dl). a bland-altman plot of the differences in estimation between sp hb and ref hb levels indicated that most of the variations were greater than 1 g/dl [figure 2], indicating that the pronto-7® pulse co-oximetry device overestimated the patients’ hb levels. the upper and lower limits of agreement were 3.8 and −0.4 g/dl, respectively. in the multivariable model, ref hb level was the only statistically significant predictor of the difference (p = 0.001). the r2 of the two co-oximetry hb measurements, which were taken 10 minutes apart, was 46% [figure 3]. discussion the pronto-7® pulse co-oximetry device was found to overestimate the hb level in tm patients by a mean of 1.7 g/dl, with clinically unacceptable limits of agreement. the use of this device in estimating hb levels, therefore, cannot be recommended for this group of patients. the only significant predictor for this discrepancy in estimation was the ref hb level, which was assessed using a gold standard method. the reproducibility of the estimation remained high when figure 1: scatter plot showing reference haemoglobin (hb) versus spot hb levels estimated by a pulse cooximetry device among patients with thalassaemia major (n = 108). ref hb = reference haemoglobin; sp hb = spot haemoglobin; ci = confidence interval. figure 2: distribution of the differences between spot (sp) haemoglobin (hb) levels estimated by a pulse cooximetry device and reference (ref ) hb levels among patients with thalassaemia major (n = 108). the y-axis shows the difference between sp hb and ref hb (sp hb – ref hb) and the x-axis shows the value of the ref hb. the three continuous lines represent the differences at +1, 0 and -1 (starting from the top). ref hb = reference haemoglobin; sp hb = spot haemoglobin. figure 3: scatter plot of two spot haemoglobin measurements by the co-oximetry device among patients with thalassaemia major (n = 108). sp hb = spot haemoglobin; ci = confidence interval. table 1: baseline characteristics among patients with thalassaemia major (n = 108) variable mean value age in years 21.6 ± 7.3 male: female ratio* 54:54 ref hb in g/dl 9.4 ± 0.9 spot 1 hb in g/dl 11.1 ± 1.2 spot 2 hb in g/dl 10.8 ± 1.2 weight in kg 52.4 ± 16.4 height in cm 154 ± 15 bp in mmhg 111/66 ± 13/9 ref = reference; hb = haemoglobin; bp = blood pressure. *this value is not expressed as mean ± standard deviation. murtadha k. al khabori, arwa z. al-riyami, khalil al-farsi, mohammed al-huneini, abdulhakeem al-hashim, nasser al-kemyani, issa al-qarshoubi, hammad khan, khalfan al-amrani and shahina daar clinical and basic research | e471 the test was repeated after a short interval. a spectrum bias is a common problem in diagnostic studies, leading to a false increase in the sensitivity and specificity of new diagnostic tests.14 previous studies have demonstrated the validity of the pronto-7® pulse co-oximetry device for use in normal blood donors and in patients with scd.10,11 in contrast, the current study observed that the same device overestimates hb levels in tm patients by a clinically significant margin. the difference in the validation results may potentially be due to the lower hb levels commonly seen in patients with tm; these lower hb levels are not frequently observed among patients with scd or in normal blood donors. the use of this device is therefore not recommended in patients with low hb levels, for instance among those suspected of being anaemic. another reason why different validation results were observed in the current study may be due to variations within the chosen patient populations. the present study included paediatric patients, whereas the previous studies investigating blood donors and patients with scd did not.10,11 in the study investigating blood donors, differences in height may have been partially responsible for the different estimates.10 this is because the three different sizes of sensor may not have been optimal in terms of fit for certain patients with different heights. in the two previous studies, as well as the current study, the same sized sensors were used.10,11 however, if the fit of the sensor was not optimal on all patients, this could have affected the accuracy of the estimates produced, leading to a larger difference between estimates. in the current study, the age and height of the participants were not found to be statistically significant enough to explain the difference in estimates. it is possible that modelling the interaction between patients’ heights or ages and differing hb estimates may shed further light on the issue; this was not carried out in the present study due to the complexity of such modelling and the relatively small sample size. although different conclusions were drawn with regards to the validity of the pulse co-oximetry device, it is interesting to note that similar findings were noted between the current study and the previous studies in the numerical estimates of the studied subjects, when comparing the r2.10,11 in validation studies, it is important that any conclusions drawn should not be based on a single parameter, but instead take into consideration all available parameters, the limitations of each and the fact that these complement each other. in the current study, the bland-altman plot showed the distribution of the difference between estimations and revealed the bias of overestimation in the sp hb levels compared with the ref hb levels. the standard methodology of the present study has many merits and is frequently utilised in diagnostic studies.15 in light of its limitations, the results of this study should be interpreted with caution. there was a limited supply of sensor sizes, although every attempt was made among individual patients to choose the finger with the best physical fit for the sensor used. the fact that only three sizes of sensors were available for use (small, medium or large), without taking into consideration the need for other sizes among the patients, likely biased the difference between estimations to be larger than the true value. moreover, the inclusion of both children and adults in one study may have increased the variance and decreased the power, making it difficult to truly show the validity of the device. high levels of fetal hb in children may have interfered with the measurement accuracy of the device.16 additionally, as the majority of the patients in the study were adults, the conclusions drawn from this study cannot be generalised to paediatric patients, although the authors would still caution the use of this device in children. paediatric patients were included in this study so as to assess this device among the age group that may potentially benefit the most from its use. furthermore, it should be noted that previous research has indicated that the pronto-7®’s performance was satisfactory when used as a continuous monitor, rather than a single spot measurement as in the present study.8 finally, the study was also limited by its relatively small sample size, which decreased the power to detect significant factors to predict the discrepancy in hb estimates. the study has a number of strengths despite the above limitations. foremost, this is the first and only study to specifically address the population of tm patients. this study included patients with hb levels as low as 7.5 g/dl, although patients with tm can have levels lower than this. in addition, the biased estimate found in this evaluation of the pronto-7® device calls for caution in the interpretation of diagnostic studies with potential spectrum bias. conclusion the results of this study demonstrate that the pronto-7® pulse co-oximetry device overestimates the haemoglobin level in patients with tm, and therefore cannot be recommended for use with this group. the authors further caution the use of this device in children and in patients suspected of being anaemic. studies with larger patient populations are needed to confirm these results. non-invasive haemoglobin estimation in patients with thalassaemia major e472 | squ medical journal, november 2014, volume 14, issue 4 c o n f l i c t o f i n t e r e s t the pronto-77® pulse co-oximetry device and the reusable sensors were provided free of charge by muscat pharmacy, oman. muscat pharmacy had no access to the data and had no input in the analysis or the writing of the manuscript. a c k n o w l e d g e m e n t s the authors of this study would like to thank muscat pharmacy for providing the pulse co-oximetry device and the reusable sensors. the authors would also like to thank the nurses in the squh daycare thalassaemia unit for their great contribution and help during this study. this study was presented in abstract form in december 2012 at the 54th annual meeting of the american society of hematology in atlanta, georgia, usa. the abstract was previously published in blood journal in november 2012 (vol. 120, iss. 21, abstract 5179). references 1. alkindi s, al zadjali s, al madhani a, daar s, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. doi: 10.3109/03630261003677213. 2. higgs dr, engel jd, stamatoyannopoulos g. thalassaemia. lancet 2012; 379:373–83. doi: 10.1016/s0140–6736(11)60283– 3. 3. al-khabori m, bhandari s, al-huneini m, al-farsi k, panjwani v, daar s. side effects of deferasirox iron chelation in patients with beta thalassemia major or intermedia. oman med j 2013; 28:121–4. doi: 10.5001/omj.2013.31. 4. borgna-pignatti c, gamberini mr. complications of thalassemia major and their treatment. expert rev hematol 2011; 4:353–66. doi: 10.1586/ehm.11.29. 5. sleem ga, al-zakwani is, almuslahi m. hypoparathyroidism in adult patients with beta-thalassemia major. sultan qaboos univ med j 2007; 7:215–18. 6. gayat e, aulagnier j, matthieu e, boisson m, fischler m. noninvasive measurement of hemoglobin: assessment of two different point-of-care technologies. plos one 2012; 7:e30065. doi: 10.1371/journal.pone.0030065. 7. nguyen bv, vincent jl, nowak e, coat m, paleiron n, gouny p, et al. the accuracy of noninvasive hemoglobin measurement by multiwavelength pulse oximetry after cardiac surgery. anesth analg 2011; 113:1052–57. doi: 10.1213/ ane.0b013e31822c9679. 8. frasca d, dahyot-fizelier c, catherine k, levrat q, debaene b, mimoz o. accuracy of a continuous noninvasive hemoglobin monitor in intensive care unit patients. crit care med 2011; 39:2277–82. doi: 10.1097/ccm.0b013e3182227e2d. 9. berkow l, rotolo s, mirski e. continuous noninvasive hemoglobin monitoring during complex spine surgery. anesth analg 2011; 113:1396–402. doi: 10.1213/ane.0b013e 318230b425. 10. al-khabori m, al-riyami az, al-farsi k, al-huneini m, alhashim a, al-kemyani n, et al. validation of a non-invasive pulse co-oximetry based hemoglobin estimation in normal blood donors. transfus apher sci 2014; 50:95–8. doi: 10.1016/j. transci.2013.10.007. 11. al-khabori m, al-hashim a, jabeen z, al-farsi k, al-huneini m, al-riyami a, et al. validation of a noninvasive pulse cooximetry-based hemoglobin estimation in patients with sickle cell disease. int j lab hematol 2013; 35:e21–3. doi: 10.1111/ ijlh.12056. 12. barker sj, tremper kk. pulse oximetry: applications and limitations. int anesthesiol clin 1987; 25:155–75. 13. hedberg p, lehto t. aging stability of complete blood count and white blood cell differential parameters analyzed by abbott cell-dyn sapphire hematology analyzer. int j lab hematol 2009; 31:87–96. doi: 10.1111/j.1751–553x.2007.01009.x. 14. willis bh. spectrum bias: why clinicians need to be cautious when applying diagnostic test studies. fam pract 2008; 25:390– 6. doi: 10.1093/fampra/cmn051. 15. dewitte k, fierens c, stöckl d, thienpont lm. application of the bland-altman plot for interpretation of methodcomparison studies: a critical investigation of its practice. clin chem 2002; 48:799–801. 16. fouzas s, priftis kn, anthracopoulos mb. pulse oximetry in pediatric practice. paediatrics 2011; 128:740–52. doi: 10.1542/ peds.2011–0271. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 143-146, epub. 27th feb 13 submitted 10th jun 12 revision req. 7th aug 12, revision recd. 8th sep12 accepted 6th oct 12 departments of 1general surgery and 2pathology, barnsley district general hospital, barnsley, uk *corresponding author e-mail: sjafferbhoy@doctors.org.uk تدفق سري مزمن عرض غري عادي لالنتباذ البطاين الرمحي �صدف جافربوي، بانا�ض �صيمونيد�ض، حنيف �صيواين، ميالين ليفي. امللخ�ص: يعترب النتباذ البطاين الرحمي اأحد الت�صخي�صات التفريقية لأية اإ�صابة �رسية. هذا تقرير حلالة مري�صة عمرها 35 عاما م�صابة بداء البول ال�صكري النوع 2 ح�رست اإىل امل�صت�صفى ب�صبب اإفراز �رسي مزمن مل ي�صتجب لعدة م�صادات حيوية. مل يظهر امل�صح باملوجات فوق ال�صوتية ول الرنني املغناطي�صي اأي اعتاللت ظاهرة. مت ا�صتئ�صال ال�رسة باأكملها واأظهر فح�ض الأن�صجة وجود انتباذ بطاين رحمي. كان هذا ال�صتئ�صال اجلراحي كافيا لتاأكيد الت�صخي�ض و�صفاء املري�صة. مفتاح الكلمات: الأنتباذ البطاين الرحمي، اإفراز مزمن، �رسي، تقرير حالة، اململكة املتحدة. abstract: umbilical endometriosis is an important differential diagnosis of any umbilical lesion. a 35-yearold type 2 diabetic woman presented with intermittent umbilical discharge which failed to respond to various antibiotics. an ultrasound scan and mri scan failed to show any obvious abnormality. the umbilicus was excised and histology confirmed endometriosis. surgical excision provides a definitive diagnosis and curative treatment for isolated endometriosis. keywords: endometriosis; discharge, umbilical; case report; great britain. chronic umbilical discharge an unusual presentation of endometriosis *sadaf jafferbhoy,1 panas symeonides,1 melanie levy2, muhammad h. shiwani,1 case report endometriosis, a common gynae-cological disorder, is characterised by the proliferation of endometrial glands and stroma outside the uterine cavity, and affects 5–10% of fertile women.1 extrapelvic endometriosis refers to endometriosis found at body sites other than the pelvis and can involve almost every organ in the human body, with a reported incidence of 8.9%.2 cutaneous endometriosis is a subtype of extrapelvic endometriosis and can present with various non-specific symptoms to a variety of specialist outpatient clinics, ranging from dermatology to gynaecology to general surgery. this sometimes makes the diagnosis more challenging. we present the case of a woman with solitary umbilical endometriosis who presented with intermittent umbilical discharge. case report a 35-year-old caucasian woman presented to the surgical outpatient clinic at barnsley district general hospital, uk, with a 3-year history of intermittent umbilical discharge. she described an uncomfortable feeling in the umbilicus preceding her menses and a cyclical bloody discharge from its raised centre. this discharge was associated with her menstrual cycle and resolved spontaneously a couple of days after her menses ceased. she also admitted having occasional dysmenorrhoea and menorrhagia but there was no history of intermenstrual or postcoital bleeding. she was a type-ii diabetic and had had two previous normal vaginal deliveries. there was no past surgical history of note. she was treated in the community clinic with multiple courses of antibiotics for presumed umbilical infections. a physical examination was normal and an abdominal examination did not reveal any masses. on closer inspection of the chronic umbilical discharge an unusual presentation of endometriosis 144 | squ medical journal, february 2013, volume 13, issue 1 umbilicus, a non-tender indurated skin lesion of normal flesh colour was noted. a pelvic ultrasound and a magnetic resonance imaging (mri) scan revealed a normal uterus and ovaries with no evidence of adnexal masses. a tiny enhancement at the umbilicus with no underlying soft tissue abnormality was noted on the mri scan. due to the inconclusive investigations, the decision was made to proceed to an excision biopsy of the umbilicus. the exploration of the umbilical cavity under general anaesthesia revealed abnormal growth at the cicatrix and a wide excision of the umbilicus was performed [figure 1]. the histology revealed the presence of endometrial tissue with no evidence of malignancy [figure 2]. discussion endometriosis is the presence of endometrial stroma and glands outside the boundaries of the uterus which responds to the cyclical hormonal fluctuation.3 it affects 7% of women of childbearing age, with mean presentation at 34 years, and is most commonly found in other pelvic structures like the ovaries, fallopian tubes, and pelvic ligaments. the literature includes reports of extrapelvic endometriosis of nearly all other body tissues including the intestinal tract, urinary tract, and lungs, and surgical scars.4 pelvic disease usually presents with pain that worsens around the time of menstruation and a history of menorrhagia, dysmenorrhoea, and infertility. extrapelvic disease is more difficult to diagnose due to the variety of symptoms that result from the different tissue involvement. in addition, 44% of all women with endometriosis are asymptomatic and the diagnosis is incidental at the time of a laparoscopy for unrelated symptoms.5 solitary umbilical lesions occur in 0.5–1% of women with endometriosis. they were first reported by villar in 1886; hence, the lesions are sometimes called villar’s nodules.6 villar’s nodules can present spontaneously or in the scar tissue following abdominal or pelvic procedures.7 although the exact pathogenesis is not known, a number of hypotheses have been suggested to explain endometriosis. the theory of endometrial tissue implantation in the pelvic structures due to retrograde menstruation is most widely accepted. for extrapelvic endometriosis, transport of endometrial cells occurring at the time of surgery or via lymphatic and vascular routes has been suggested. scars seem to have a tendency to attract endometrial tissue and the umbilicus behaves as a physiological scar, making this site susceptible to developing endometriosis. another theory refers to the potential of coelomic cells to differentiate into peritoneal and endometrial cells.4,6,8 malignant degeneration of endometriosis has been reported in patients with long-standing and recurrent endometriosis.9 umbilical endometriosis can present, like in our case, with a history of cyclical bleeding from a slightly tender nodule which self-resolves.10 this can occur in isolation, but other gynaecological figure 1: gross appearances of specimen with raised nodule slightly visible in centre. figure 2: immunohistochemical staining with cd-10 (x 20 magnification showing the presence of endometrial glands and stroma. sadaf jafferbhoy, panas symeonides, melanie levy and muhammad h. shiwani case report | 145 symptoms, like menorrhagia and dysmenorrhagia, should prompt further investigations to exclude pelvic disease.11 the diagnosis can be difficult and a high index of suspicion and awareness of the condition is necessary by the clinician. a study by douglas et al. revealed that out of 34 cases of extrapelvic endometriosis, a high percentage presented to general surgical clinics with symptoms ranging from a change in bowel habits to palpable abdominal masses.2 in our case, the patient was misdiagnosed and treated with multiple courses of antibiotics in community medical centres before being referred to a secondary care centre. the differential diagnoses of an umbilical swelling are malignant melanoma or other intraabdominal malignancies, granulomas, umbilical hernias, urachal or simple cysts, and lipomas. a number of tools have been suggested in the literature to investigate umbilical endometriosis including fine-needle aspiration, pelvic ultrasound scans, computed tomography (ct) scans, mri scans, dermoscopy, and, more recently, high-frequency doppler sonographic imaging.6 ultrasound findings are often non-specific and a wide spectrum of disorders presenting as a mass in the abdominal wall should be considered in the differential diagnosis.12 in a series, ultrasound-guided fine needle aspiration (fna) was found to be inconclusive in 75% of cases.13 the use of dermoscopy can be helpful in the pre-operative evaluation of such lesions. de giorgi et al. described specific dermoscopic features of endometriosis as homogenous reddish pigmentation with small globules called red atolls and may be a useful modality in getting a preoperative diagnosis.14 another report by wu et al. emphasised the usefulness of high-frequency doppler scans for diagnosing subcutaneous endometriomas.15 mri is particularly helpful in studying the extent and biological behaviour of lesions, and in planning operative resectioning accurately and safely, particularly in cases where extensive lesions infiltrate deeper layers of the abdominal wall.16 in our case, neither an ultrasound nor an mri scan showed any conclusive evidence of endometriosis; therefore, we proceeded to an excision biopsy of the umbilicus. although medical treatment with antigonadotrophin agents can be used, this provides only temporary relief.2,4,5,7 the treatment for cutaneous endometriosis is mainly surgical, preferably performed at the end of the menstrual cycle when the lesions are small in order to achieve a minimal excision.6 the surgical technique may vary depending on the size and extent of the lesions, ranging from a simple excision with wide margins to an en bloc excision of the umbilicus. a gynaecological examination and hormonal evaluation is recommended after excision of the cutaneous endometriosis but whether systematic laparoscopy should be performed is a debatable issue.17,18 the prognosis for cutaneous endometriosis is good. recurrence is rare following a surgical excision, and is usually attributed to inadequate excision.11 however, malignant transformation, including histological subtypes such as endometrioid carcinoma, clear cell carcinoma, adenosarcomas, and serous carcinomas has been reported and should be suspected in recurrent or rapidly growing lesions.19 conclusion solitary umbilical endometriosis is rare but can present to primary and secondary care centres. awareness of the condition is paramount for clinicians, who should consider endometriosis in the differential diagnosis of umbilical lesions. surgical excision is the treatment of choice and provides a histological diagnosis. gynaecological evaluation is recommended after excision, especially if the patient is symptomatic for pelvic endometriosis. references 1. bulun se. endometriosis. n engl j med 2009; 360:268–79. 2. douglas c, rotimi o. extragenital endometriosis: a clinicopathological review of a glasgow hospital experience with case illustrations. j obstet gynaecol 2004; 24:804–8. 3. techapongsatorn s, techapongsatorn s. primary umbilical endometriosis. j med assoc thai 2006; 89:1753–5. 4. majeski j, craggie j. scar endometriosis developing after an umbilical hernia repair with mesh. south med j 2004; 97:532–4. 5. seleem mi, al hashemy am, obeid ma. umbilical endometriosis: a diagnostic dilemma. kuwait med j 2002; 34: 303–5. 6. chatzikokkinou p, thorfinn j, angelidis k, papa chronic umbilical discharge an unusual presentation of endometriosis 146 | squ medical journal, february 2013, volume 13, issue 1 g, trevisan g. spontaneous endometriosis in an umbilical skin lesion. acta dermatoven apa 2009; 18:126–130. 7. al-saad s, al-shinawi ha, ashok m. extra-gonadal endometriosis: unusual presentation. bahrain med bull 2007; 29:1–11. 8. zollner u, girschick g, steck t, dietl j. umbilical endometriosis without previous pelvic surgery: a case report. arch gynecol obstet 2003; 267: 258–60. 9. obata k, ikoma n, oomura g, inoue y. clear cell adenocarcinoma arising from umbilical endometriosis. j obstet gynaecol res 2013; 39:455– 61. 10. lee a, tran ht, walters rf yee h, rosenman k, sanchez mr. cutaneous umbilical endometriosis. dermatol online j 2008; 14:23. 11. kerr oa, mowbray m, tidman mj. an umbilical nodule due to endometriosis. acta derm venereol 2006; 86:277–8. 12. hensen jh, van b v, pulyeart jb. abdominal wall endometriosis: clinical imaging and imaging with emphasis on sonography. ajr am j roentgenol 2006; 186:616–20. 13. singh m, sivinasen k, ghani r, granger k. caesarean scar endometriosis. arch gynecol obstet 2009; 279:217–9. 14. de giorgi v, massi d, mannone f, stante m, carli p. cutaneous endometriosis: non –invasive analysis by epiluminescence endometriosis. clin exp dermatol 2003; 28:315–17. 15. wu yc, tsui kh, hung jh, yuan cc, ng ht. highfrequency power doppler angiographic appearance and microvascular flow velocity in recurrent scar endometriosis. ultrasound obstet genecol 2003;21:96–7. 16. busard mp, mijatovic v, van kuijk c, hompes pg, van waesberghe jh. appearance of abdominal wall endometriosis on mr imaging. eur radiol 2010; 20:1267–76. 17. agarwal a, fong yf. cutaneous endometriosis. singapore med j 2008; 49:704–9. 18. fedele l, frontino g, biachi s, borruto f, ciappina n. umbilical endometriosis: a radical excision with laparoscopic assistance. int j surg 2010; 8:109–11. 19. modesitt sc, tortolero-luna g, robinson jb, gershenson dm, wolf jk. ovarian and extraovarian endometriosis-associated cancer. obstet gynecol 2002; 100:788–95. squ med j, may 2012, vol. 12, iss. 2, pp. 197-205, epub. 9th apr 2012 submitted 17th aug 11 revision req. 12th dec 11, revision recd. 2nd jan 12 accepted 22nd feb 12 1college of medicine, university of mosul, mosul, iraq; 2neurosurgery unit, iben seena hospital, mosul, iraq; 3sharkat general hospital, salah al-din health institute, salah al-din, iraq. *corresponding author e-mail: imadpharma@yahoo.com, and ithanoon.63@gmail.com جهد األكسدة والربوتني التفاعلي )ج( يف مرضى احلوادث الوعائية الدماغية ) السكتة االقفارية ( تأثري خالصة اجلنكوبالوبا عماد ذنون، حلمي عبد اجلبار، �سياء طه م�ستوى بقيا�س االقفارية ال�سكتة مر�سى دم م�سل يف االلتهابية واال�ستجابة االأك�سدة جهد عالمات وجود من التاأكد الهدف: امللخ�ص: املالونديليهايد وحالة م�سادات االأك�سدة الكلّية والربوتني التفاعلي عايل احل�سا�سية )ج( يف م�سل دم املر�سى يف املرحلة املبكرة التالية لل�سكتة االقفارية وحتديد دور العالج بخال�سة اجلنكوبالوبا يف ت�سحيح عالمات جهد االأك�سدة واال�ستجابة االلتهابية. الطريقة: اأجريت وثالثني االقفارية بال�سكتة مري�سا وثالثني واحداً الدرا�سة هذه �سّمت بالعراق. املو�سل مدينة يف �سينا ابن م�ست�سفى يف الدرا�سة هذه �سخ�سا من االأ�سحاء كمجموعة �سابطة. مت تق�سيم املر�سى اإىل جمموعتني: املجموعة االأوىل )15 مري�سا( مّت عالجهم بالطريقة التقليدية، واملجموعة الثانية )16 مري�سا( عوجلوا بالطريقة التقليدية اإ�سافة اإىل اجلنكوبالوبا ) 1500 ملغم/ يوميا( ملده �سهر. مّت قيا�س م�ستوى ال�سابطة واملجموعة املر�سى دم عينات من )ج( احل�سا�سية عايل التفاعلي والربوتني الكلّية االأك�سدة م�سادات وحالة املالونديليهايد قبل العالج وبعده. النتائج . هناك زيادة معتّدة يف م�ستوى املالونديليهايد والربوتني التفاعلي عايل احل�سا�سية )ج( عند املر�سى مقارنة االأوىل املجموعة اأظهرت كما املر�سى. يف الكلّية االأك�سدة م�سادات م�ستوى يف معنّدا وانخفا�سا ،)p ≤0.001( ال�سابطة باملجموعة والثانية من املر�سى انخفا�سا معتّدا يف م�ستوى املالونديليهايد والربوتني التفاعلي عايل احل�سا�سية )ج(، مع ارتفاع معتّد يف م�ستوى حالة م�سادات االأك�سدة الكلّية باملقارنة مع م�ستويات ما قبل العالج. مل يكن هنالك اختالفا معتّدا يف م�ستوى املالونديايهايد يف م�سل الدم بني مر�سى املجموعة االأوىل والثانية بينما كان هناك ارتفاعا معتّدا يف حالة م�سادات االأك�سدة الكلّية وانخفا�سا معتّدا يف م�ستوى مع اأك�سدة جهد احلادة االقفارية ال�سكتة ُي�ساحب اخلال�صة: الثانية. املجموعة مر�سى يف )ج( نوع احل�سا�سية علي التفاعلي الربوتني ا�ستجابة التهابية يف الفرتة املبكرة التالية للحالة االقفارية،، واجلنكوبالوبا كان له دور فعال يف تقليل �رضر جهد االأك�سدة واال�ستجابة االلتهابية. مفتاح الكلمات: حادثة وعائية دماغية، الربوتني التفاعلي )ج(، اجلنكوبالوبا، حالة اقفارية، ،�سكتة، مالوندليهايد، جهد االأك�سدة ،حالة م�سادات االأك�سدة، العراق. abstract: objectives: this study aimed to investigate the presence of oxidative stress and inflammation in ischaemic stroke patients by measuring malondialdehyde (mda), total antioxidant status (tas), and highlysensitivity c-reactive protein (hscrp) in the early post-ischaemic period, and to determine the role of ginkgo biloba therapy in correcting the markers of oxidative stress and inflammation. methods: this study was conducted at ibn seena hospital, mosul city, iraq and included 31 cerebrovascular accident (cva) patients and 30 healthy controls. ischaemic stroke patients were divided into two groups: group i (n = 15) received conventional therapy; group ii (n = 16) received conventional therapy with g. biloba (1500 mg/day) for 30 days. blood samples were obtained from patients and controls before treatment and assays done of serum levels of mda, tas, and hscrp. for cva patients, a post-treatment blood sample was taken and the same parameters reassessed. results: compared with the controls, patients’ serum levels of mda, and hscrp were significantly higher (p ≤0.001) and tas significantly lower. group i and ii patients reported a significant reduction in serum levels of mda and hscrp and a significant increase in serum levels of tas, in comparison with pre-treatment levels. there was no significant difference (p = 0.19) in serum mda levels between groups i and ii, whereas, serum tas levels were significantly higher (p ≤0.01) and hscrp significantly lower (p ≤0.01) in group ii. conclusion: acute stroke is associated with oxidative stress and inflammatory response in the early period. g. biloba plays a potential role in reducing oxidative damage and oxidative stress and c-reactive protein in patients with cerebrovascular accident (ischaemic stroke) the role of ginkgo biloba extract *imad a-j thanoon,1 hilmy as abdul-jabbar,2 dhia a taha3 clinical & basic research oxidative stress and c-reactive protein in patients with cerebrovascular accident (ischaemic stroke) the role of ginkgo biloba extract 198 | squ medical journal, may 2012, volume 12, issue 2 stroke, or cerebrovascular accident (cva), is the third leading cause of death after cardiovascular diseases and cancer.1 in fact, it is the second-leading cause of mortality and disease among adults over 60 years of age worldwide.2 approximately 80% of strokes are ischaemic in origin, since they result either from thrombus in situ or an embolism of distant origin.3 cerebral ischaemia initiates a cascade of cellular and molecular events that lead to brain damage, with one such event being post-ischaemic inflammation.4 focal cerebral ischaemia is associated with a local inflammatory reaction that contributes to tissue damage.5 microglial cells in particular become activated and provoke tissue injury by releasing pro-inflammatory mediators and reactive oxygen species (ros).6,7 when oxygen supply is limited during ischaemia, a calcium influx may activate phospholipase c, which results in a breakdown of membrane phospholipids, or may convert xanthine dehydrogenase to xanthine oxidase in the cerebral blood vessels leading to the formation of superoxide radicals and hydrogen peroxide.8 ros causes oxidative damage that may affect lipids, proteins, nucleic acids and other molecules. quantification of lipid peroxidation end products is considered to be a measure of whole-body oxidative damage. serum malondialdehyde (mda), a marker of lipid peroxidation, is the most abundant aldehyde generated by the attack of free radicals on polyunsaturated fatty acids of cell membranes; its measurement provides information of oxidative injury in vivo.9 the impact of free radicals may also be obtained by comparisons of antioxidant concentrations, because serious damage by free radicals implies insufficiency of the body’s multilevel defence systems against radicals.10measurement of the total antioxidant capacity (tac) of biological fluids, however, is regarded as more physiologically representative in certain settings than individual antioxidants, and is believed to be a useful measure of how much the antioxidants present can protect against oxidative damage to membranes and other cellular components.11 c-reactive protein (crp) has been the most extensively studied marker of inflammation. it is a novel plasma marker of atherothrombotic disease.12 c-reactive protein (crp) is produced not only by the liver but also in atherosclerotic lesions by vascular smooth muscle cells and macrophages in response to stimulation by the ‘pro-inflammatory’ cytokine interleukin-6 (il-6).13,14 elevated plasma levels of crp are not disease specific but are sensitive markers which are produced in response to tissue injury, infectious agents, and inflammation.12 various cross-sectional studies support the notion that crp may be a marker for stroke and poststroke status.15,16 several studies support the role of crp in the prediction of ischaemic stroke risk and outcome, as well as the possible role of inflammation before and after stroke.17,18as the methods traditionally employed to measure crp do not have good sensitivity, measurement of highly-sensitivity c-reactive protein (hscrp) is recommended to evaluate atherothrombotic disease, which usually presents with lower crp levels than the other inflammatory processes.14 ginkgo biloba extract (egb 761) is known to have neuroprotective properties in diseases associated with free radical generation. extensive studies on g. biloba extracts showed their ability to protect brain neurons from oxidative stress19 and to inhibit apoptosis in cell culture.20 the g. biloba extracts that are currently used for medicinal purposes contain 24% flavonoid glycosides (quercetin, kaempferol, isorhamnetin) and 6% terpene lactones (ginkgolides a, b, c, m, j and bilobalides).21 the egb 761 components eliminate free radicals advances in knowledge ischaemic stroke is associated with oxidative stress and inflammatory responses in the early post-ischaemic period. applications to patient care ginkgo biloba therapy plays a potential role in reducing oxidative damage and inflammatory response in early post-ischaemic stroke patients. inflammatory response. keywords: cerebrovascular accident; c-reactive protein; ginkgo biloba; ischaemia; stroke; malondialdehyde; oxidative stress; antioxidant; iraq. imad a-j thanoon, hilmy as abdul-jabbar and dhia a taha clinical and basic research | 199 such as the hydroxyl radical and the superoxide anion.22 quercetin is a powerful antioxidant in the flavonoid family due to its molecular configuration, which is capable of eliminating free radicals.23 the pharmacologically active terpene lactones selectively inhibit the platelet-activating factor, preventing thrombus formation. bilobalide is reported to possess neuroprotective properties.24 the aim of the present study was to investigate the presence of oxidative stress and inflammation in serum samples of ischaemic stroke patients by measuring mda concentrations, total antioxidant status (tas), and hscrp in the early post-ischaemic period, and to determine the role of g. biloba therapy in correcting the markers of oxidative stress and inflammation in question. methods this double-blind randomised study was conducted in the ibn seena hospital, department of neurology, in mosul city, from january 2009 to april 2011. approval was obtained from the ethical committee of the main health centre in nineveh in mosul city and the college of medicine university of mosul, iraq. our study included 31 cva hypertensive patients (26 males and 5 females) suffering from ischaemic stroke, aged 69.03 ± 2.96 years and 30 healthy control subjects aged 69.40 ± 2.69 years. all patients included in this study were initially diagnosed as having cva, or acute ischaemic stroke. all had problems with anterior circulation, a diagnosis made on the basis of full physical and neurological examinations by a neurologist. the diagnoses were then confirmed by either a magnetic resonance imaging (mri) or computed tomography (ct) scan of the brain. vascular risk factors including hypertension or diabetes mellitus, and smoking and alcohol habits were recorded. patients with haemorrhagic stroke, intracranial tumour, or other neurological diseases, infection, inflammation, liver disease, and renal failure were excluded. for controls, the criteria were as follows: age ≥60 years, healthy subjects, non-smokers, and not taking vitamin supplements. ischaemic stroke patients were divided into two groups: group i (n = 15 of a possible 18 patients) included patients with ischaemic stroke who received conventional therapy (aspirin, rosuvastatin and lisinopril), and group ii (n = 16 of a possible 28 patients) included patients who received conventional therapy with g. biloba (1500 mg/ day) for 30 days. the dose was decided as a safe increment after previous promising results with 500 and 1000 mg/day. blood samples were initially obtained from all cva patients within 48–120 hours of their accidents, and before starting treatment. they were also taken from the controls. assays of the serums mda, tas and hscrp were done at the department of pharmacology in the college of medicine at the university of mosul. for the patient group, another blood sample was taken after treatment with either conventional therapy or conventional therapy with g. biloba, and the parameters reassessed. mda was measured by the method outlined by buege and aust where mda reacts with thiobarbituric acid (tba) to yield a red-coloured product.25 the absorbance of a 3 ml coloured layer was measured at 535 nm spectrophotometrically. tas was measured by peroxidase/h2o2/abts colorimetric assay using commercial kits from randox laboratories, belfast, uk. crp was measured using the biocheck hscrp elisa kit (biocheck, inc., foster city, california, usa). data were expressed as means ± standard deviation (sd). statistical comparisons were performed using the student’s t-test between patients before therapy and controls, and the oneway analysis of variance (anova). the dunnett test was used to compare groups of patients. linear regression analysis and pearson correlation coefficients (r) were performed to determine the relationships between parameters. all statistical analyses were performed using the statistical package for the social sciences (spss) for windows (version 11.5, chicago, illinois, usa). a p value of table 1: concentrations of malondialdehyde (mda), total antioxidant status (tas), and highly-sensitivity c-reactive protein (hscrp) in patients with acute ischaemic stroke before therapy and in healthy controls parameters control (n = 30) ischaemic stroke patients before therapy(n = 31) mda (µmol/l) 1.03 ± 0.17 2.11 ± 0.28*** tas (mmol/l) 1.85 ± 0.12 1.06 ± 0.13*** hscrp (mg/l) 0.53± 0.09 1.79 ± 0.18*** notes: results are expressed as mean ± sd; *** significant difference from control at p ≤0.001 oxidative stress and c-reactive protein in patients with cerebrovascular accident (ischaemic stroke) the role of ginkgo biloba extract 200 | squ medical journal, may 2012, volume 12, issue 2 <0.05 was considered statistically significant. results the serum levels of mda, tas and hscrp from healthy subjects and patients with acute ischaemic stroke before starting drug therapy are shown in table 1. the serum levels of mda and hscrp were found to be significantly higher (p ≤0.001) and tas were significantly lower in ischaemic stroke patients in the early post-ischaemic period (before starting therapy) in comparison to the controls [table 1]. table 2 shows the serum levels of mda, tas, and hscrp in the two groups of ischaemic stroke patients before and after therapy. patients in group i reported a significant reduction in serum levels of mda (p ≤0.001) and hscrp (p ≤0.01), and a significant increase (p ≤0.01) in serum levels of tas after treatment with conventional therapy in comparison with their levels before therapy. also, patients in group ii reported a significant reduction in serum levels of mda (p ≤0.001) and hscrp (p ≤0.001) and a significant increase in serum levels of tas (p ≤0.001) after treatment with g. biloba together with conventional therapy in comparison with their levels before therapy. by comparing the serum levels of mda, tas, and hscrp between the two groups of ischaemic stroke patients after therapy, no significant differences (p = 0.19) were reported in serum mda levels between group i, who received conventional therapy, and group ii, who received g. biloba with conventional therapy, whereas the serum levels of tas were found to be significantly higher (p ≤0.01) and hscrp were significantly lower (p ≤0.01) in group ii who received g. biloba with conventional therapy in comparison with group i who received conventional therapy alone [table 2]. regarding correlations between different biochemical parameters, figures 1 to 3 show the relationships between mda, tas, and hscrp in patients with acute ischaemic stroke. a significant negative correlation (r = -0.418, p = 0.001) was observed between mda and tas in the serum samples of patients with acute ischaemic stroke. mda had a significant positive correlation with hscrp (r = 0.729, p ≤0.001), and there was a significant negative correlation (r = -0.602, p = <0.001) between tas and hscrp in the serum samples of ischaemic stroke patients. discussion there is strong indirect evidence that free radical production appears to be an important mechanism of brain injury after exposure to ischaemia and reperfusion.26 free radicals in biological samples are difficult to measure because they are extremely reactive and have a short half-life. therefore, particularly in human studies, indirect approaches have been used to demonstrate free radical production during cerebral ischaemia by measuring the products of free radical reaction with other molecules, such as lipids, proteins, and deoxyribonucleic acid (dna), and the level or activity of antioxidant molecules.27,28 ros causes impairment of cellular membrane stability and cell death by lipid peroxidation.29 mda is the end product of the lipid peroxidation process.30 an increase in free radicals causes overproduction of mda, which is commonly known as a marker of oxidative stress.31 table 2: concentrations of malondialdehyde (mda), total antioxidant status (tas), and highly-sensitivity c-reactive protein (hscrp) in patients with acute ischaemic stroke before therapy and after therapy parameters group i (n = 15) group ii (n = 16) before therapy after conventional therapy before therapy after ginkgo biloba+ conventional therapy (n = 16) mda (µmol/l) 2.12 ± 0.26 1.98 ± 0.24*** 2.10 ± 0.31 1.86 ± 0.23*** tas (mmol/l) 1.07 ± 0.12 1.15 ± 0.12** 1.05 ± 0.14 1.31 ± 0.15*** δδ hscrp (mg/l) 1.80 ± 0.17 1.69 ± 0.20** 1.78 ± 0.19 1.42 ±0.24*** δδ notes: results are expressed as mean ± sd; ** significant difference compared to before therapy at p ≤0.01 and *** at p ≤ 0.001; δδ significant difference compared to after conventional therapy at p ≤0.01 imad a-j thanoon, hilmy as abdul-jabbar and dhia a taha clinical and basic research | 201 in the present study, it was observed that ischaemic stroke patients in the early post ischaemic period (before starting therapy) had significantly higher levels of serum mda and hscrp, and significantly lower tas than controls. these findings provide evidence for the presence of oxidative stress and inflammation in ischaemic stroke patients. there are several possible reasons for increased lipid peroxidation in cases of ischaemic stroke. first, the brain’s cellular membranes are very rich in polyunsaturated fatty acid side chains, which are especially sensitive to free radical attack. additionally, they have a low content of antioxidant enzymes, such as catalase and glutathione peroxidase, while the brain contains a significant amount of iron, despite the fact that its iron binding capacity is not very high. iron ions are known to stimulate free radical generation.32,33 lower tas was accounted for by an increased use of endogenous antioxidants to fight free radicals and oxidative stress during ischaemic stroke.34 our findings are in accordance with several studies which have been done to evaluate oxidative stress, antioxidant status, and markers of inflammation in ischaemic stroke patients.5-8 most of these studies have shown enhanced levels of oxidative stress which are markers of inflammation, and reduced levels of antioxidants;5,10 however, some studies have reported controversial and conflicting results with regard to the levels of antioxidant enzymes.35 studies evaluating markers of oxidative stress in patients in the early period of ischaemic stroke revealed an increase in the blood, cerebrospinal fluid, or salivary concentrations of lipid peroxides, protein carbonyl, homocysteine, nitric oxide, and of mda, conjugated dienes, and other tbareactive molecules at the onset of stroke.8,10,33,36–39 some studies showed persistently elevated mda concentrations 6 months after strokes.40 evaluations of antioxidants in blood, urine, or cerebrospinal fluid of ischaemic stroke patients revealed lower plasma vitamin c, e, vitamin a, and uric acid, lower glutathione peroxidase (gpx) activity, decreased glutathione (gsh) concentration, and a decreased total plasma antioxidant capacity.8,10,32,34,35,37,41 data associated with superoxide dismutase (sod) activity after acute ischaemic stroke are controversial. sod activity of patients with acute ischaemic stroke was reported to be reduced in the serum and increased in the cerebrospinal fluid (csf), increased in both csf and serum, or remained unchanged.32,24,43 several prospective studies have shown that an elevated serum crp concentration is a strong predictor of cardiovascular events, including stroke. crp plays an important role as a marker of outcome and may determine the degree of recovery for stroke patients. in their study, sánchez-moreno et al. found that ischaemic stroke patients had significantly 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 6 8 1.0 1.2 1.4 1.6 1.8 tas mmol/l m d a um ol /l figure 1: the relationship between malondialdehyde (mda) and total antioxidant status (tas) in patients with acute ischaemic stroke (r = -0.418, p = 0.001) oxidative stress and c-reactive protein in patients with cerebrovascular accident (ischaemic stroke) the role of ginkgo biloba extract 202 | squ medical journal, may 2012, volume 12, issue 2 elevated markers of inflammation, marked by crp, intracellular adhesion molecule-1 (icam-1), and chemokine monocyte chemottractant protein-1 (mcp-1), and that elevated crp concentrations were associated with a two-fold increase in the risk of ischaemic stroke. winbeck et al. observed that an increase in crp levels between 12 and 24 hours after the onset of symptoms predicts an unfavorable outcome and is associated with an increase in the incidence of cerebrovascular events. mishra et al. observed an increase in hscrp levels in stroke patients and that the increased levels were correlated with larger infarct, severe neurological deficit, and worse outcomes.12 our study showed a highly significant negative correlation between serum mda levels and tas in ischaemic stroke patients, which suggests increased utilisation by ros as an important contributing factor to the lower concentrations of antioxidants in ischaemic stroke patients. in the present study, we have investigated the relationship between markers of oxidative stress and markers of inflammation in ischaemic stroke patients. ischaemic stroke patients with higher serum hscrp concentrations, indicative of greater inflammatory response, also had higher serum mda levels and lower tas than those with lower serum hscrp concentrations. this can be observed in the figures, which show that serum hscrp levels positively correlate with lipid peroxidation products and negatively correlate with tas. our findings are in accordance with sánchezmoreno et al.’s results in which they found that crp were inversely associated with concentrations of antioxidant vitamins c and e, and positively associated with markers of oxidative stress (8-isoprostanes).41 this study also showed that patients in groups i and ii reported a significant reduction in serum levels of mda and hscrp and a significant increase in serum levels of tas after treatment in comparison with their levels before therapy. interestingly, we did not observe any statistically significant differences in serum mda levels between group i, who received conventional therapy, and group ii, who received g. biloba with conventional therapy. in fact, the serum levels of tas were found to be significantly higher, while those of hscrp were significantly lower in group ii who received g. biloba with conventional therapy, in comparison with group i who received conventional therapy alone. higher tas in the serum of ischaemic stroke patients who received g. biloba together with conventional therapy (group ii) was most likely caused by a lower use of endogenous antioxidants because of supplementary antioxidant effects of flavonoids glycosides.23. antioxidant treatment may be an efficient therapeutic option for cardiac embolisms and macroangiopathic strokes, contributing to an improvement of neurological deficits and the functional status of the patients through the reduction of oxidative stress following ischaemia 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 6 8 1.0 1.2 1.4 1.6 1.8 hscrp mg/l m d a um ol /l figure 2: the relationship between malondialdehyde (mda) and highly-sensitivity c-reactive protein (hscrp) in patients with acute ischaemic stroke (r = 0.729, p = <0.001) imad a-j thanoon, hilmy as abdul-jabbar and dhia a taha clinical and basic research | 203 and/or reperfusion.48 it has been reported in many studies that g. biloba improved tissue damage in various organs through its antioxidant effect. zeybek et al. reported that g. biloba significantly decreased mda levels and histopathological scores of the pancreatitis in rats.49 bridi et al. reported that g. biloba had antioxidant activity in the hippocampus, striatum, and substantia nigra of rats.50 egb 761 has an antioxidant effect as a free radical scavenger, a relaxing effect on vascular walls, an ameliorating effect on blood flow and microcirculation, and a stimulating effect on neurotransmitters. besides a direct scavenging effect on ros, g. biloba exerts an anti-inflammatory effect on inflammatory cells by suppressing the production of ros and nitrogen species.51 several studies have shown that egb 761 could protect cultured neurons against damage induced by peroxynitrate and hydrogen peroxide.19,51 zhang et al. demonstrated that total ginkgolides (tg) (a terpenoid constituent of egb 761) protected cultured rat cortical neurons from oxidative damages induced by hydrogen peroxide (h2o2). 52 egb 761 extract, with free radical scavenging activity, has been shown to reduce the size of cerebral infarction and improve neurological behaviour in rats with permanent and transient mid-cerebral artery occlusion (mcao).53,54 saleem et al. showed that the standardised egb761 significantly improved the outcome in mice after cerebral ischaemia and reperfusion in terms of neurobehavioral function and infarct size without affecting physiological parameters.55 our findings suggest a potential role of g. biloba in acute ischaemic stroke, and the findings are important in view of the fact that stroke is, at present, the third leading cause of death worldwide.1 the mechanisms by which g. biloba normalise the cerebral damage, and reduce oxidative stress and inflammation, can probably be attributed to the antioxidant effects of flavonoids combined with the anti-inflammatory properties of the terpenoids bilobalide and ginkgolides a, b, c, m, j, and the terpenoids antagonists of platelet-activating factor (paf), making this natural extract plausible to use in the treatment of ischaemic stroke, which is characterised by both oxidative damage and inflammation.56 one of the limitations of this study is that it does not relate the biochemical changes to the clinical evaluation and outcome prognosis. conclusion from this study, we conclude that acute ischaemic stroke is associated with oxidative stress and inflammatory response as indicated by increased lipid peroxidation products (mda), reduced tas and elevated levels of hscrp in the early postischaemic period, and that g. biloba therapy has a potential role in reducing oxidative damage and inflammatory response in ischaemic stroke patients. 1.8 1.6 1.4 1.2 1.0 0.8 0.6 1.0 1.2 1.4 1.6 1.8 2.0 2.2 hscrp mmol/l ta s m m ol /l figure 3: the relationship between total antioxidant status (tas) and highly-sensitivity c-reactive protein (hscrp) in patients with acute ischaemic stroke (r = 0.602, p = <0.001) oxidative stress and c-reactive protein in patients with cerebrovascular accident (ischaemic stroke) the role of ginkgo biloba extract 204 | squ medical journal, may 2012, volume 12, issue 2 c o n f l i c t o f i n t e r e s t no funding was received for this study and the authors declared no conflict of interest. references 1. thorvaldsen p, kuulasmaa k, rajakangas a, rastenyte d, sarti c, wilhelmsen l. stroke trends in the who monica project. stroke 1997; 28:500–6. 2. world health organization. the world health report (2003): shaping the future. geneva: world health organization, 2003. 3. kidd pm. integrated brain restoration after ischemic stroke – medical management, risk factors, nutrients, and other interventions for managing inflammation and enhancing brain plasticity. altern med rev 2009; 14:14–35. 4. lo eh, dalkara t, moskowitz ma. mechanisms, challenges and opportunities in stroke. nat rev neurosci 2003; 4:399–415. 5. iadecola c, cho s, feuerstein gz, hallenbeck j. cerebral ischemia and inflammation. in: wolf p, ed. stroke: pathophysiology, diagnosis, and management. new york: churchill livingstone, 2004. pp. 883–94. 6. giulian d. reactive microglia and ischemic injury. in: weir, b, ed. primer on cerebrovascular diseases. san diego: academic, 1997. pp. 117–124. 7. schwartz m. macrophages and microglia in central nervous system injury: are they helpful or harmful? j cereb blood flow metab 2003; 23:385–94. 8. sudha k, rao av, rao sn, rao a. oxidative damage and plasma antioxidants in cerebrovascular accident. indian j physiol pharmacol 2004; 48:489–92. 9. lópez e, illnait j, molina v, oyárzabal a, fernández l, pérez y, et al. effects of d-002 (beeswax alcohols) on lipid peroxidation in middle-aged and older subjects. lat am j pharm 2008; 27:695–703. 10. gariballa se, hutchin tp, sinclair aj. antioxidant capacity after acute ischemic stroke. 2002; 95:685– 90. 11. ryan m, grayson l, clarke dj. the total antioxidant capacity of human serum measured using enhanced chemiluminescence is almost completely accounted for by urate. ann clin biochem 1997; 34:688–9. 12. mishra pt, chandra r, saxena sk, verma s, jain r, bhuyan a. h sensitivity c-reactive protein (hscrp) level in cerebrovascular accident (stroke). jiacm 2010; 11:204–7. 13. elkind ms. inflammation, atherosclerosis, and stroke. neurologist 2006; 12:140–8. 14. ramos am, pellanda lc, gus i, portal vl. inflammatory markers of cardiovascular disease in the elderly. arq bras cardiol 2009; 92:221–8. 15. di napoli m, di gianfilippa g, sollecito a, bocola v. c-reactive protein and outcome after first-ever ischemic stroke. stroke 2000; 31:238–9. 16. ford es, giles wh. serum c-reactive protein and self-reported stroke: findings from the third national health and nutrition examination survey. arterioscler thromb vasc biol 2000; 20:1052–6. 17. ridker pm, hennekens ch, buring je, rifai n. c-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. n engl j med 2000; 342:836–43. 18. winbeck k, kukla c, poppert h, klingelhofer j, conrad b, sander d. elevated c-reactive protein is associated with an increased intima to media thickness of the common carotid artery. cerebrovasc dis 2002; 13:57–63. 19. oyama y, chikahisa l, ueha t, kanemaru k, noda k. ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. brain res 1996; 712:349–52. 20. xin w, wei t, chen c, ni y, zhao b, hou j. mechanisms of apoptosis in rat cerebellar granule cells induced by hydroxyl radicals and the effect of egb761 and its constituents. toxicology 2000; 148:103–10. 21. da silva ggp, zanoni jn, buttow nc. neuroprotective action of ginkgo biloba on the enteric nervous system of diabetic rats. world j gastroenterol 2011; 17: 898–905. 22. ni y, zhao b, hou j, xin w. preventive effect of ginkgo biloba extract on apoptosis in rat cerebellar neuronal cells induced by hydroxyl radicals. neurosci lett 1996; 214:115–8. 23. boots aw, haenen gr, bast a. health effects of quercetin: from antioxidant to nutraceutical. eur j pharmacol 2008; 585:325–37. 24. smith pf, maclennan cl, darlington j. the neuroprotective properties of the ginkgo biloba leaf: a review of the possible relationship to plateletactivating factor (paf). j ethnopharmacol 1996; 50:131–9. 25. buege ja, aust sd. thiobarbuturic acid assay. methods enzymol 1978; 52:306–7. 26. traystamn rj, kirsch jr, koehler rc. oxygen radical mechanism of brain injury following ischaemia and reperfusion. j appl physiol 1991; 71:1185–95. 27. white bc, daya a, degracia dj, o’neil bj, skjaerlund jm, trumble s. fluorescent histochemical localization of lipid peroxidation during brain reperfusion following cardiac arrest. acta neuropathol (berl) 1993; 86:1–9. 28. alexandrova ml, bochev pg. oxidative stress during the chronic phase after stroke. free radic biol med 2005; 39:297–316. 29. flohe l, beckmann r, giertz h, loschen g. oxygencentered free radicals as mediators of inflammation. imad a-j thanoon, hilmy as abdul-jabbar and dhia a taha clinical and basic research | 205 in: sies h, ed. oxidative stress. london: academic press, 1985. pp. 403–36. 30. marnett lj. oxy radicals, lipid peroxidation and dna damage. toxicology 2002; 27:181–2, 219–22. 31. gawel s, wardas m, niedworok e, wardas p. malondialdehyde (mda) as a lipid peroxidation marker. wiad lek 2004; 57:453–5. 32. yildirim a, kotan d, yildirim s, aygûl r, akçay f. increased lipid peroxidation and decreased antioxidant response in serum and cerebrospinal fluid in acute ischemic stroke. turk j med sci 2007; 37:75–81. 33. aygül r, kotan d, yıldırım a, ulvi h, akçay f. plasma and cerebrospinal fluid homocysteine, nitric oxide and malondialdehyde in acute ischemic stroke: possible role of free radicals in the development of brain injury. eur j gen med 2008; 5:57–63. 34. leionen js, ahonen jp, lonrot k, jehkonen m, dastidar p, molnar g, alho h. low plasma antioxidant activity is associated with high lesion volume and neurological impairment in stroke. stroke 2000; 31:33–9. 35. cherubini a, polidori mc, bregnachi m, pezzuto s, cecchetti rbs, ingegni t, et al. antioxidant profile and early outcome in stroke patients. stroke 2000; 31:2295-2300. 36. santos md, valles j, aznar j, vilches j. determination of plasma malondialdehyde-like material and its clinical application in stroke patients. j clin pathol 1980; 33:973–6. 37. el kossi mmh, zakhary mm. oxidative stress in the context of acute cerebrovascular stroke. stroke 2000; 31:1889–92. 38. al-rawi nh. salivary lipid peroxidation and lipid profile levels in patients with recent ischemic stroke. j int dent med res 2010; 3:57–64. 39. jawalekar sl, kulkarni uj, surve vt, deshmukh ya. status of lipid profile, mda and protein carbonyl in patients with cardiovascular diseases. arch appl sci res 2010; 2:8–14. 40. bir ls, demir s, rota s, koseoglu m. increased serum malodialdehyde levels in chronic stage of ischemic stroke. tohoku j exp med 2006; 208:33–9. 41. sánchez-moreno c, dashe jf, scott t, thaler d, folstein mf, martin a. decreased levels of plasma vitamin c and increased concentrations of inflammatory and oxidative stress markers after stroke. stroke 2004; 35:163–8. 42. gruener n, gross b, gozlan o, barak m. increase in superoxide dismutase after cerebrovascular accident. life sci 1994; 54:711–13. 43. adachi t, nakamura m, yamada h, futenma a, kato k, hirano k. quantitative and qualitative changes of extracellular-superoxide dismutase in patients with various diseases. clin chim acta 1994; 229:123–31. 44. ridker pm, cushman m, stampfer mj, tracy rp, hennekens ch. inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. n engl j med 1997; 336:973–9. 45. koenig w, pepys mb. c-reactive protein risk prediction: low specificity, high sensitivity. ann intern med 2002; 136:550–2. 46. barone fc, feuerstein gz. inflammatory mediators and stroke: new opportunities for novel therapeutics. j cereb blood flow metab 1999; 19:819–34. 47. winbeck k, poppert h, etgen t, conrad b, sander d. prognostic relevance of early serial c-reactive protein measurements after first ischemic stroke. stroke 2002; 33:2459–64. 48. jurcau a. the role of antioxidant treatment in acute ischemic stroke: a clinical study. romanian j neurol 2007; 6:181–8. 49. zeybek n, gorgulu s, yagci g, serdar m, simsek a, kaymakcioglu n, et al. the effect of gingko biloba extract (egb 761) on experimental acute pancreatitis. j surg res 2003; 15:286–93. 50. bridi r, crosseti fp, steffen vm, henriques at. the antioxidant activity of standardized extract of gingko biloba (egb 761) in rats. phytother res 2001; 15:449. 51. chen c, wei tt, gao zh, zhao bl, hou jw, xu hb, et al. different effects of the constituents of egb 761 on apoptosis in rat cerebellar granule cells induced by hydroxyl radicals. biochem mol biol int 1999; 47:397–405. 52. zhang y, yu q, you s, sheng l. ginkgolies protects the cultured rat cortical cells against metabolic, excitotoxic and oxidative insults. j health sci 2004; 50:348–55. 53. morioka t, kalehua an, streit wj. the microglial reaction in the rat dorsal hippocampus following transient forebrain. j cereb blood flow metab 1991; 11:966–73. 54. korematsu k, goto s, nagahiro s, ushio y. microglial response to transient focal cerebral ischemia: an immunochemical study on the rat cerebral cortex using anti-phosphotysine antibody. j cereb blood flow metab 1994; 14:825–30. 55. saleem s, zhuang h, biswal s. ginkgo biloba extract neuroprotective action is dependent on heme oxygenase 1 in ischemic reperfusion brain injury. stroke 2008; 39:3389–96. 56. butterfield da, castegna a, pocernich cb, drake j, scapagnini g, calabrese v. nutritional approaches to combat oxidative stress in alzeimer’s disease. j nutr biochem 2002; 13:444–61. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. e334-338, epub. 9th may 13 submitted 12th may 12 revision req. 8th aug 12, revision recd. 2nd oct 12 accepted 13th oct 12 departments of 1surgery and 4pathology, sultan qaboos university hospital; 2department of surgery, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3oman medical specialty board, muscat, oman *corresponding author e-mail: sureshkannan18@gmail.com ورم اونكوسايتوما للغدة الكظرية ذات السلوك اخلبيث غري املؤكد �شوري�ض كنان، موؤيد علي اأحمد، زيد روؤوف، �رسيدهاران كوليديان، كر�شتوفر جرانت، اأحمد احلب�شي، �شابرامادو، �شحى ال�شاجي امللخ�ص: هي جمموعة من الأورام النادرة التي ت�شيب الغدة الكظرية غري معلومة التاريخ املر�شي و ال�شلوك امل�شتقبلي. من �شتة واأربعني اخلبيث ال�شلوك ذات اأورام باأنها املجهري الت�رسيحي الفح�ض على بناء �شنفت فقط حالت �شتة احلا�رس، الوقت حتى �شجلت قد حالة الكامن. بدورنا نقدم حالة ا�شتثنائية ملري�ض ذكر يبلغ من العمر خم�شة وثالثني �شنة م�شاب بورم الغدة الكظرية احلميد ظاهريا مع بع�ض اخل�شائ�ض الدالة على ال�شلوك اخلبيث الكامن مفتاح الكلمات: اأورام الغدة الكظرية؛ انكو�شايتوما؛ ادرينال ان�شدانتالوما؛ عر�ض حاله؛ عمان. abstract: adrenal oncocytic neoplasms (aons) are a rare group of tumours with a somewhat uncertain natural history and clinical behaviour. out of 46 cases of aon reported to date, 6 cases were histologically classified as neoplasms with uncertain malignant potential. we report the case of a 35-year-old male with an incidentallydetected large aon with mostly benign morphology and some characteristics which would make its behaviour uncertain. keywords: adrenal tumors; oncocytoma; adrenal incidentaloma; case report; oman. adrenal oncocytic neoplasm with uncertain malignant potential mooyad a. ahmed,1 *sureshkannan k. s.,1 zaid r. raouf,1 sreedharan v. koliyadan,1 christopher s. grant,2 ahmed h. al-habsi,3 p. a. m saparamadu,4 dhuha al-sajee4 online case report oncocytic neoplasms are rare, predominantly benign neoplasms. they have been discovered in the kidneys, thyroid, parathyroid, salivary and pituitary glands, ovaries, and lungs. adrenal oncocytic neoplasms (aon) are extremely rare. oncocytomas are epithelial neoplasms composed of cells with abundant eosinophilic granular cytoplasm. ultrastructurally, the component cells are packed with swollen mitochondria. they have non-functional neoplasm and, hence, are usually detected incidentally. however, one case exhibiting secretion of cortisol and testosterone was reported recently.1 case report a 35-year-old male presented having experienced chronic upper abdominal pain for a year and reported a history of headache, excessive sweating, and sleep disturbance. a physical examination was unremarkable except for high blood pressure. an abdominal computed tomography (ct) scan showed a 12 x 9 x 5 cm left adrenal mass [figures 1a & b]. his serum electrolytes, blood urea nitrogen, serum creatinine, and complete blood counts were all normal. his plasma normatanephrine level was 0.31 nmol/l (normal range [nr] ≥0.94), plasma metanephrine 0.17 nmol/l (nr ≤0.37), 24 hours urinary adrenalin >41 nmol/24h (nr = 3–109), urine noradrenaline 150 nmol/24h (nr = 89–473), and urine dopamine was 1260 nmol/24h (nr = 424–2612). plasma rennin was 3.8 ng/l (nr = 3–16), aldosterone 219 pmol/l (nr = 21–413), serum prolactin 235 miu/l (nr = 56– 278), and serum chromogranin a was 2 ug/l (nr = 27–94). a metaiodobenzylguanidine (mibg) scan showed no abnormal uptake. a diagnosis of a nonfunctioning left adrenal tumour was made. open trans-peritoneal exploration showed a well circumscribed 12 x 9 x 3 cm left adrenal tumour [figure 2]. there were no enlarged lymph nodes and no other evidence of metastasis to suggest adrenal carcinoma. the right adrenal gland mooyad a. ahmed, sureshkannan k. s., zaid r. raouf, sreedharan v. koliyadan, christopher s. grant, ahmed h. al-habsi, p. a. m saparamadu and dhuha al-sajee case report | 335 was normal. a left adrenalectomy was carried out. grossly, the outer surface of the 320 g tumour was smooth with intact capsule. the cut surface showed a solid grey-brown appearance with areas of haemorrhage. sections of the tumour revealed a lesion that was mainly composed of spheroidal cells having granular eosinophilic cytoplasm and large vesicular nuclei [figure 3]. these nuclei showed marked variation in size but no increase of mitosis. the cells also contained lipid vacuoles and eosinophilic globules. some showed intra-nuclear and cytoplasmic vacuoles. the stroma showed focal oedema and myxoid changes with small areas of necrosis. there was no capsular or vascular invasion. the mitotic count was low and the tumour showed no overt malignant features morphologically. immunohistochemical staining was positive for calretinin and inhibin [figures 4a & b]. focally, the tumour cells were positive for neuron-specific enolase but negative for chromogranin, ae1/ae3, s-100, and epithelial membrane antigens. an electron microscopic examination showed that the tumour cells contained mitochondria and scattered cytoplasmic vacuoles. the ki-67 tumour marker test showed occasional mitotic figures. a morphological diagnosis of adrenal oncocytoma (ao) was made. however, the tumour exceeded 10 cm and weighed over 200 g, making this an aon with uncertain malignant potential (aonump). the patient was discharged 4 days after surgery with no further treatment recommendations. the patient’s follow-up included a physical examination and abdominal ultrasound every 6 months, for 24 months in total. there was no evidence or symptoms of recurrence. the patient was advised to continue with long term follow-up because of the possible malignant potential of the tumour. discussion aons are extremely rare with only 46 reported cases, including 24 aos, 16 malignant oncocytic tumours, and 6 tumours with uncertain malignant potential.2 most of these tumours were detected incidentally upon imaging done to evaluate unrelated symptoms. recent literature showed that the detection of "adrenal incidentalomas" (including adenomas, myelolipomas, cysts, ganglioneuromas, pheochromocytomas, carcinomas, or metastasis) had increased by 5% with use of high-resolution imaging.3 most aons are well-circumscribed, ranging from 2.2–15 cm, and weighing from 8–860 g (mean = 281 g). studies have shown a female predominance (7:4) with a mean age of 43.5 years (range = 27–72 years).4 with the exception of two cases with heterotropic supra figure 1 a & b: abdominal computed tomography scans showing a 12 x 9 x 5 cm left adrenal mass (arrows). figure 2: a well-circumscribed 12 x 9 x 3 cm left adrenal tumour. the outer surface was smooth with an intact capsule. the cut surface showed a solid grey-brown appearance with areas of haemorrhage. figure 3: tumour cells showing an abundant eosinophilic and granular cytoplasm with vesicular nuclei (haematoxylin and eosin stain; magnification x 400). adrenal oncocytic neoplasm with uncertain malignant potential 336 | squ medical journal, may 2013, volume 13, issue 2 adrenal retroperitoneal tissue, and 6 symptomatic intraspinal oncocytic adrenocortical adenomas, all aons were located in the adrenal glands with a left side predominance (7:5).5 most of these tumours were non-functioning with the exception of one case which presented with cushing’s syndrome.4 aons are mostly benign and generally small (<5 cm diameter and weighing <50 g). in 22 reported cases, no evidence of recurrence or metastasis was recorded after a follow-up period ranging from 1 to 99 months. borderline aons also seem to have benign clinical behaviours. basceglia et al. reported 4 patients with aons with uncertain malignant potential, with a mean follow up of 38.75 months 10–61 months) with no evidence of recurrence.6 lin et al. also reported two patients with a mean follow-up of 15.5 months (12–19 months).4 however, some cases showed malignant potential which might not correlate with histological appearance.6 one locally invasive malignant case was reported with metastasis in the liver that invaded the inferior vena cava, although the microscopic appearance was that of a benign lesion with the absence of mitosis and nuclear pleomorphism.7 benign adrenal cortical tumours are differentiated from malignant ones by examining macroscopic and microscopic features, as no other criteria seem to be predictive of their behaviour. several histological systems have been proposed to predict the biological behaviours of adrenocortical tumours. the weiss system uses histological criteria to differentiate benign adrenocortical tumours from malignant ones. if 3 or more of these features are present (nuclear grade iii–iv; a mitotic rate of more than 5 per high-power field; atypical mitosis; a clear cell tumour composition of less than 25%; diffuse architecture; the presence of necrosis, and venous, sinusoidal or capsular invasion), the tumour is regarded as malignant.8 the weiss system recently was revised by bisceglia et al. to define clearly the terms adrenal oncocytic carcinoma (aoc), aonump, and ao.6 if the oncocytic tumour shows one or more major criteria (a mitotic figure of more than 5 mitoses per 50 high-power fields, any atypical mitosis, or any venous invasion), it is an aoc. if the tumour exhibits one or more minor criteria (a size of more than 10 cm and/or more than 200 g, necrosis, or capsular or sinusoidal invasion), it is aonump. if none of the described features is present, the tumour is ao. in our case, the tumour was considered borderline because of its size and weight. proliferative activity tests by ki-67 and oncoprotein p53 have been used to predict the behaviour of adrenocortical tumours. the results of basceglia et al. concerning the ki-67 expression of aoc were almost in accordance with other studies for conventional adrenocarcinoma.6 other studies showed that ki-67 and p53 cannot be reliably used to predict the biology of aons.4,9,10 currently, morphological assessment remains the cornerstone of diagnosis and assessment of biological behaviour of adrenal cortical neoplasms.10 to our knowledge, the radiological features of aons have been described in only 5 case reports in english medical literature.11–13 the findings were mostly homogeneous attenuation on nonenhanced ct. however, one case demonstrated a homogeneous mass with a central hyperdense area owing to haemorrhage, or central necrosis resulting in fibrous scarring which gave the appearance of a spoke wheel pattern. contrast ct demonstrated mostly heterogeneous masses. magnetic resonance imaging (mri) demonstrated homogeneous and intermediate signal intensity on t1and t2weighted images with heterogeneous enhancement following gadolinium administration.12 recently, 18f-fluorodeoxyglucose positron emission tomography (18f-fdg-pet) has shown great potential in differentiating malignant from benign adrenal lesions, and was used to evaluate an adrenal lesion in a patient known to have a hepatocellular carcinoma.9,14 the scan images showed intense hypermetabolism in the adrenal mass, which was diagnosed initially as a metastatic figure 4 a & b: (a) tumor cells show cytoplasmic and nuclear immunohistochemical staining for calretinin. (magnification x 400). (b) tumour cells showing a positive immunoreactivity for inhibin (magnification x 200). mooyad a. ahmed, sureshkannan k. s., zaid r. raouf, sreedharan v. koliyadan, christopher s. grant, ahmed h. al-habsi, p. a. m saparamadu and dhuha al-sajee case report | 337 lesion from hepatocelluar carcinoma. however, the histopathological report was of an ao. tumours known to have a false high uptake are pheochromocytomas and adenomas.9 therefore, aos might also result in a false-positive 18f-fdgpet scan. interestingly, renal oncocytomas also revealed an intense uptake on 18f-fdg-pet as they also have the presence of numerous intracellular mitochondria.15 the surgical approaches for excision of adrenocortical tumours are controversial. indeed, there is evidence that laparoscopic excision has an advantage as a minimally invasive procedure, allowing quick recovery, low postoperative discomfort, and a short hospital stay.16 a retroperitoneal laparoscopic approach for large or potentially malignant adrenal masses can be performed safely by highly skilled laparoscopic surgeons and a conversion to open adrenalectomy should be considered if local invasion is observed during surgery.11,16 oncological outcomes suggest that in the setting of adequate surgical resection, recurrence patterns relate more to diseaseprocess biology rather than the surgical approach. some authors contend that size, suspicion of malignancy, and locally invasive disease should not be considered an absolute contraindication to laparoscopic adrenalectomy.17 however, there is still controversy regarding the appropriateness of laparoscopy for the resection of large adrenal tumours (>6 cm), or oncocytic tumours of uncertain malignant potential, because of the high risk of complications and incomplete resections. this is partly attributed to a lack of experience with the high rate of loco-regional recurrence.18 whereas some authors reported the feasibility of laparoscopic adrenalectomy for all benign tumours irrespective of size, in difficult cases, hand-assisted laparoscopic adrenalectomy is a good alternative.19,20 conclusion because of the low incidence of aonump, little is known in terms of the long-term behaviour of ao tumors. hence, long-term clinical follow-up of the patient is required. there is an increasing trend toward the laparoscopic approach, even for large or potentially malignant adrenal tumours. references 1. logasundaram r, parkinson c, donaldson p, coode pe. co-secretion of testosterone and cortisol by a functional adrenocortical oncocytoma. histopathology 2007; 51:418–20. 2. kabayegit oy, soysal d, oruk g, ustaoglu b, kosan u, solmaz s, et al. adrenocortical oncocytic neoplasm presenting with cushing’s syndrome: a case report. j med case reports 2008; 2:228–9. 3. stewart pm. the adrenal cortex. in: larsen pr, kronenberg hm, melmed s, polonsky ks, eds. williams textbook of endocrinology. 10th ed. philadelphia: saunders, 2003. pp. 491–551. 4. lin bt, bonsib sm, mierau gw, weiss lm, medeiros lj. oncocytic adrenocortical neoplasms. a report of seven cases and review of the literature. am j surg pathol 1998; 22:603–14. 5. nguyen gk, vriend r, ronagham d, lakey wh. heterotopic adrenocortical oncocytoma. a case report with light and electron microscopic studies. cancer 1992; 70:2681–4. 6. bisceglia m, ludovico o, di mattia a, ben-dor d, sandbank j, pasquinelli g, et al. adrenocortical oncocytic tumors: report of 10 cases and review of the literature. int j sur pathol 2004; 12:231–43. 7. winston js, mompoint a, wang h, crossland d. the utility of ki-67 in the evaluation of adrenocortical neoplasms [abstract]. mod pathol 1997; 10:52a. 8. weiss lm, medeiros lj, vickery al, jr. pathologic features of prognostic significance in adrenocortical carcinoma. am j surg pathol 1989; 13:202–6. 9. kumar r, xiu y, yu jq, takalkar a, el-haddad g, potenta s, et al. 18f-fdg pet in evaluation of adrenal lesions in patients with lung cancer. j nucl med 2004; 45:2058–62. 10. hoang mp, ayala ag, albores-saavedra j. oncocytic adrenocortical carcinoma: a morphologic, immunohistochemical, and ultrastructural study of four cases. mod pathol 2002; 15:973–8. 11. shah rk, oto a, ozkan os, ernst rd, hernandez ja, chaudhary hb, et al. adrenal oncocytoma: us and ct findings. jbr-btr 2004; 87:180–2. 12. gandras ej, schwartz lh, panicek dm, levi g. case report: adrenocortical oncocytoma: ct and mri findings. j comput assist tomogr 1996; 20:407–9. 13. kitching pa, patel v, harach hr. adrenocortical oncocytoma. j clin pathol 1999; 52:151–3. 14. maurea s, mainolfi c, bazzicalupo l, panico mr, imparato c, alfano b, et al. imaging of adrenal tumors using fdg pet: comparison of benign and malignant lesions. am j roentgenol 1999; 173:25–9. 15. aide n, cappele o, bottet p, bensadoun h, regeasse a, comoz f, et al. metastases: a comparison with ct. eur j nucl med mol imaging 2003; 30:1236–45. 16. henry jf, sebag f, iacobone m, mirallie e. results of adrenal oncocytic neoplasm with uncertain malignant potential 338 | squ medical journal, may 2013, volume 13, issue 2 laparoscopic adrenalectomy for large and potentially malignant tumors. world j surg 2002; 26:1043–7. 17. kercher kw, novitsky yw, park a, matthews bd, litwin de, heniford bt. laparoscopic curative resection of pheochromocytomas. ann surg 2005; 241:919–26. 18. kebebew e, siperstein ae, clark oh, duh qy. results of laparoscopic adrenalectomy for suspected and unsuspected malignant adrenal neoplasms. arch surg 2002; 137:948–53. 19. zografos gn, farfaras a, vasiliadis g, pappa t, aggeli c, vasilatou e, et al. laparoscopic resection of large adrenal tumors. jsls 2010; 14:364–8. 20. parnaby cn, chong ps, chisholm l, farrow j, connell jm, o'dwyer pj. the role of laparoscopic adrenalectomy for adrenal tumours of 6 cm or greater. surg endosc 2008; 22:617–21. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e401-404, epub. 24th jul 14 submitted 25th sep 13 revisions req. 15th nov 13 & 2nd mar 14; revisions recd. 3rd feb & 19th mar 14 accepted 20th mar 14 departments of 1ophthalmology, 2genetics and 3child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: zuhaibi@hotmail.com عالمات جديده بالعني ملتالزمة سنجاد سكايت تقرير حالة من سلطنة عمان اغا �سهاب حيدر، انورادا جاني�س، عديله الكندية، اأحمد الهنائي، ناديه اخلرو�سية، �سيف اليعربي، �سنا الزهيبية abstract: sanjad-sakati syndrome (sss; online mendelian inheritance in man [omim] #241410), also known as hypoparathyroidism-retardation-dysmorphism (hrd) syndrome, is an autosomal recessive disorder in which prenatal-onset extreme growth retardation, congenital hypoparathyroidism and craniofacial dysmorphism result from mutations in the tubulin-specific chaperone e (tbce) gene on chromosome 1q42-43. we report unique ophthalmic findings in a two-year-old child with molecularly confirmed sss, who was admitted to sultan qaboos university hospital in oman at 11 weeks old with bilateral congenital corneal clouding. the ophthalmic findings in this patient were linked to faulty microtubule assembly in the brain, abnormal intracellular membrane transport and the resulting metabolic derangement seen in patients with sss. keywords: sanjad-sakati syndrome; tbce protein, human; corneal opacity, congenital; persistent fetal vasculature syndrome; nanophthalmos; hypoparathyroidism; case report; oman. واملعروفة اي�سا مبتالزمة ق�سور الدريقات-التخلف الذهني-العيوب اخللقية )sss; omim #241410( امللخ�ص: تعد متالزمة �سنجاد �سكاتي )hrd(، من الأمرا�س ذات ال�سفة املتنحية التي تظهريف فرتة ما قبل الولدة يف �سورة تاأخر �سديد يف النمو و ق�سور خلقي يف وظائف الدريقات وعيوب خلقية يف منطقة الوجه والراأ�س والذي ينتج عن طفرة وراثية يف اجلني اخلا�س بربوتني الأنابيب للم�ساحب �سيربون)e )tbce على كرمو�سوم 1 اجلزء 1q42-43. يف هذا البحث مت توثيق عالمات فريدة يف عني طفلة يف الثانية من العمر م�سابة مبتالزمة �سنجاد �سكاتي املثبتة علي امل�ستوى اجلزيئي الوراثي يف م�ست�سفي جامعة ال�سلطان قابو�س يف عمان. مت ربط هذه العالمات بخلل يف جتمع الأنابيب الدقيقه باملخ مع وجود خلل يف النقل عرب الأغ�سيه داخل اخللية وما ينتج عنه من اختالل يف عملية الي�س والذي يظهر يف مر�سى متالزمة �سنجاد �سكاتي. وظائف ق�سور العني؛ قزامة اجلنينية؛ الدموية الأوعيه ا�ستمرارية القرنيه،متالزمة عتامة بروتنيtbce؛ �سكاتي؛ �سنجاد متالزمة الكلمات: مفتاح الدريقات؛ تقرير حالة؛ عمان. new ocular associations in sanjad-sakati syndrome case report from oman agha s. haider,1 anuradha ganesh,1 adila al-kindi,2 ahmad al-hinai,1 nadia al-kharousi,1 saif al-yaroubi,3 *sana al-zuhaibi1 sanjad-sakati syndrome (sss; online mendelian inheritance in man [omim] #241410), also known as hypoparathyroidismretardation-dysmorphism (hrd) syndrome, is an autosomal recessive chaperone disorder that is reported almost exclusively in patients of arab ethnicity. first reported by sanjad et al. in 1988,1 sss is caused by mutations in the gene-encoding tubulinspecific chaperone e (tbce; refseq #nm_003193), located on chromosome 1q42.3.2,3 the disorder is characterised by congenital hypoparathyroidism leading to early onset hypocalcaemic seizures, prenatal onset of extreme growth retardation, mental retardation and craniofacial dysmorphism. patients have a distinctive facies comprising of a narrow face, deep-set eyes, a beaked nose, large floppy ears, a thin upper lip and micrognathia.1,4 various ocular anomalies, such as nanophthalmos, corneal opacification and retinal vascular tortuosity, have been reported in patients with sss.5–7 this case report highlights unique ophthalmic findings of spontaneously resolving corneal opacities and persistent fetal vasculature in a two-year-old child with molecularly-confirmed sss. a hypothesis is proposed that links the ophthalmic findings in this patient to faulty microtubule assembly, abnormal intracellular membrane transport and the resulting metabolic derangement distinctive to sss. case report an 11-week-old infant girl presented to the sultan qaboos university hospital, muscat, oman, with bilateral cloudy corneas which had been noted since birth. the infant’s past medical history was significant case report new ocular associations in sanjad-sakati syndrome case report from oman e402 | squ medical journal, august 2014, volume 14, issue 3 as she had severe growth retardation, with all growth parameters well below the third centile (weight: 4 kg; length: 48 cm; head circumference: 33 cm). the patient had had recurrent episodes of hypocalceamic seizures from the second week of life and recurrent hospital admissions for chest infections. she was the second child of consanguineous omani parents and was born at 37 gestational weeks. she had a low birth weight of 1,500 g and was delivered by elective caesarean section due to severe intrauterine growth retardation. a systemic review revealed a small-built infant with a beaked nose, long philtrum, thin upper lip, small pointed chin, large floppy ears and deep-set eyes. an ophthalmic examination of the patient showed normal vision at the light perception level, poor fixation and following in both eyes, with horizontal pendular, sensory nystagmus. an examination of the anterior segment showed diffuse, dense corneal opacification; however, no further symptoms were visible. on follow-up, the patient’s corneal opacification was found to have partially resolved, with an improvement in corneal clarity. at the age of three months, the infant was examined under general anesthaesia. this assessment revealed that she had bilateral nanophthalmos (the axial length of her right eye was 14 mm, while her left eye was 12 mm) and central, patchy corneal opacification, with peripheral scleralisation and 360 degree pannus [figure 1]. the anterior segments of the eyes were otherwise unremarkable. the pupillary reaction to light was difficult to determine due to her corneal opacity, but was believed to be sluggish in both eyes. an examination of the fundus revealed optic disc swelling and retinal vascular tortuosity in both eyes. the swelling was due to the presence of disc drusen in the right eye [figure 2a]. in the left eye, the disc was dysplastic with extensive peripapillary gliosis. a papilomacular fold with shallow retinal detachment was seen in the posterior pole of the left eye [figure 2b]. the intraocular pressure was 13 mmhg and 03 mmhg in the right and left eye, respectively. features in the left eye were thought to be consistent with findings of persistent fetal vasculature (pfv) syndrome. the child was later followed-up by clinical geneticists and paediatric endocrinologists. biochemical investigations revealed low levels of parathyroid hormone (<0.1 pmol/l), with a low level of total calcium (1.97 mmol/l) and high levels of alkaline phosphatase (513 u/l) and phosphate (9.38 mmol/l). a skeletal survey showed that the child had severe osteopenia. consequently, a supportive treatment plan, including vitamin d supplementation and growth hormones, was commenced. this clinical and biochemical phenotype appearing in a consanguineous omani family suggested the possibility of sss. thus, with the parents’ informed consent, molecular genetic testing (real-time polymerase chain reaction using the melting curve method) was carried out, using primers specific for the c.155-166 12 base pair deletion in the tbce gene on chromosome 1q42.3. the c.156-166 deletion in exon 3 was detected in both copies (homozygous) of the patient’s tbce gene. as yet, all cases of sss reported in the middle east have the same 12 base pair deletion, confirming its founder effect.2,4 discussion the tbce gene governs the synthesis of acytoskeleton-associated protein glycine-rich (capgly) domain at the n-terminus of the tubulin-folding cofactor e protein. this protein is required for microtubule assembly and stability and is ubiquitously figure 2 a & b: retcam (clarity medical systems, pleasanton, california, usa) images* of the (a) right and (b) left fundi. a: the right fundus shows a hyperemic elevated disc, tortuous retinal vessels and a tigroid appearance of the retina. b: the left fundus shows a large and dysplastic disc, peripapillary glial tissue extending temporaly from the disc and a papillomacular fold. *views are hazy due to residual corneal opacification. figure 1: image of the anterior segment of the patient’s left eye showing patchy corneal opacification with peripheral scelralisation and 360 degree pannus. a yellowish reflex can be seen in the pupil, indicating the presence of posterior segment anomalies. agha s. haider, anuradha ganesh, adila al-kindi, ahmad al-hinai, nadia al-kharousi, saif al-yaroubi and sana al-zuhaibi case report | e403 expressed in all cells of the body. the c.155-166 deletion seen in this patient resulted in a deletion of four amino acids (p.ser52-glyc55del) in the capgly domain of the tbce transcript. this eliminated the highly conserved glycine, which is adjacent to the essential residue for alpha-tubulin binding. this can result in a generalised aberration of microtubular polarity, intracellular transport signal transduction and cellular migration, which would explain the pleiotropic manifestations of sss.2 the homozygous deletions in the tbce gene have also been reported in patients with kenny-caffey syndrome (kcs) type 1 (omim #244460).2,6 this syndrome has a phenotype that resembles that of sss but is characterised by slightly different clinical features, including normal intelligence, macrocephaly and deranged cellmediated immunity [table 1]. it is likely that kcs type 1 and sss represent varying ends of the tbce gene expression spectrum.3 microphthalmia, nanophthalmos, hypermetropia, disk swelling and tortuous retinal vessels attributed to hypermetropia, pseudoduplication of the optic disc and strabismus have been reported in cases of sss.5,7,9 corneal opacities have been noted in individuals with sss.7 however, their spontaneous resolution, as seen in the current patient, has not been reported. other manifestations that have also not been previously described in sss patients include posterior segment anomalies of pfv, such as disc dysplasia, peripapillary gliosis, papillomacular folds and shallow retinal detachment. in one study of eight patients with sss, the predominant ocular finding was dense corneal opacities, abnormal retinal vessels and retinal vascular tortuosity.7 papilloedema was reported in one patient, but no details were provided as to its cause.7 similarly, no supporting figures were provided. previous studies have attributed the disc swelling, and other posterior segment abnormalities, to the nanophthalmos.5,6 the authors of this case report believe that the disc swelling and vessel tortuosity, as well as the other retinal findings seen in this patient, are features of pfv. this condition can influence, either primarily or secondarily, the appearance of the optic nerve head and macula. tractional deformation by the adherent fibroblastic or glial tissue can cause malformations of the optic nerve and macula,10 as was also seen in the current patient. the pleotrophic disease manifestations of sss and kcs are related to deranged tubulin physiology, which affects tissues with abundant microtubules, such as the brain.3 the ocular phenotype in sss can also be explained in light of this knowledge. the authors of this case report postulate that mutations in the tbce gene can cause a disturbance in microtubule function, which may explain the altered apoptosis and involution of the fetal vasculature. the tubulin microtubule system is known to play an important role in inducing the diverse signals responsible for the initiation of cell death.11 corneal opacities in patients with sss may be caused by corneal calcium deposition as a consequence of the metabolic abnormalities that are a hallmark of this disease. the transient nature and spontaneous partial resolution of the corneal opacification in the current patient may be attributed to the prompt initiation of therapy and the improved serum calcium and phosphate levels. table 1: a comparison of the characteristics of sanjad-sakati syndrome, kenny-caffey syndrome type 1 and the current case characteristic sanjad-sakati syndrome kenny-caffey syndrome type 1 present case growth retardation intrauterine and postnatal growth retardation postnatal growth retardation only intrauterine and post-natal growth retardation mental characteristics mental retardation intellectually normal mental retardation head circumference microcephaly macrocephaly microcephaly hypoparathyroidism and hypocalcaemia hypoparathyroidism and hypocalcaemia hypoparathyroidism and hypocalcaemia hypoparathyroidism and hypocalcaemia infections/immunology an increased susceptibility to infections in some patients due to hyposplenism and an impaired polymorphonuclear function8 deranged cell-mediated immunity with recurrent bacterial infections recurrent infections; normal immune studies; but no detailed studies of polymorphonuclear or splenic function were reported bone characteristics x-rays show demineralisation of bones; delayed bone age; there are reports of medullary stenosis and osteosclerosis in some patients osteosclerosis and thickening of long bones with medullary stenosis; absent diploic space in the skull bones demineralisation of bones; delayed bone age new ocular associations in sanjad-sakati syndrome case report from oman e404 | squ medical journal, august 2014, volume 14, issue 3 conclusion unique ophthalmic findings of spontaneously resolving corneal opacities and pfv were observed in a two-year-old child with molecularly-confirmed sss. a hypothesis is proposed to explain the pathogenesis of ocular anomalies seen in patients with sss—the ophthalmic findings are thought to be caused by faulty microtubule assembly in the brain, abnormal intracellular membrane transport and the metabolic irregularities that are often seen in individuals with sss. reports of ocular findings in sss patients are limited and the observations noted in this patient have not been previously reported. references 1. sanjad sa, sakati na, abu-osba yk, kaddoura r, milner rd. a new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features. arch dis child 1991; 66:193–6. doi: 10.1136/adc.66.2.193/. 2. parvari r, hershkovitz e, grossman n, gorodischer r, loeys b, zecic a, et al. mutation of tbce causes hypoparathyroidismretardation-dysmorphism and autosomal recessive kennycaffey syndrome. nat genet 2002; 32:448–52. doi: 10.1038/ ng1012. 3. kelly te, blanton s, saif r, sanjad sa, sakati na. confirmation of the assignment of the sanjad-sakati (congenital hypoparathyroidism) syndrome (omim 241410) locus to chromosome 1q42-43. j med genet 2000; 37:63–4. doi: 10.1136/jmg.37.1.63. 4. rafique b, al-yaarubi s. sanjad-sakati syndrome in omani children. oman med j 2010; 25:227–9. doi: 10.5001/ omj.2010.63. 5. khan ao, al-assiri a, al-mesfer s. ophthalmic features of hypoparathyroidism-retardation-dysmorphism. j aapos 2007; 11:288–90. doi: 10.1016/j.jaapos.2006.10.015. 6. al dhoyan n, al hemidan ai, ozand pt. ophthalmic manifestations of sanjad-sakati syndrome. ophthalmic genet 2006; 5:83–7. doi: 10.1080/13816810600862568. 7. albaramki j, akl k, al-muhtaseb a, al-shboul m, mahmoud t, el-khateeb m, et al. sanjad sakati syndrome: a case series from jordan. east mediterr health j 2012; 18:527–31. 8. hershkovitz e, rozin i, limony y, golan h, hadad n, gorodischer r, et al. hypoparathyroidism, retardation, and dysmorphism syndrome: impaired early growth and increased susceptibility to severe infections due to hyposplenism and impaired polymorphonuclear cell functions. pediatr res 2007; 62:505–9. doi: 10.1203/pdr.0b013e31813cbf2d. 9. diaz ga, khan kt, gelb bd. the autosomal recessive kennycaffey syndrome locus maps to chromosome 1q42-q43. genomics 1988; 54:13–18. doi: 10.1006/geno.1998.5530. 10. goldberg mf. persistent fetal vasculature (pfv): an integrated interpretation of signs and symptoms associated with persistent hyperplastic primary vitreous (phpv): liv edward jackson memorial lecture. am j ophthalmol 1997; 124:587–626. 11. estève ma, carré m, braguer d. microtubules in apoptosis induction: are they necessary? curr cancer drug targets 2007; 7:713–29. doi: 10.2174/156800907783220480. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. e467-471, epub. 25th jun 13 submitted 8th sep 12 revisions req. 11th nov & 9th jan 12; revisions recd. 9th dec 12 & 20th jan 13 accepted 10th mar 13 department of anaesthesia & intensive care, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: aravindn@squ.edu.om إدارة التخدير ملريض الوذمة الوعائية الوراثية مع إعطاء اجلرعة الوقائية من مثبط c1 اسرتيز تقرير حالة ومراجعة األدبيات اأرفيند نارايانان، روهيت ديت، �شاناث كومار بريور، براديبتا بهاكتا، �شينا كريو�شنان �رسينيفا�شان امللخ�ص: الوذمة الوعائية الوراثية هو ا�شطراب نادر ناجم عن عوز يف مثبط c1 ا�شرتيز. ال�شدمات الطفيفة وال�شغط النف�شي هي االأ�شباب وذمة لظهور يوؤدي مما هذا املن�شبط. غري املفرط للرباديكينني واالإفراز النظام لتفعيل االت�شال يف لل�رسوع توؤدي التي �شيوعا االأكرث وعائية، وهو رد فعل االأوعية الدموية يف الطبقات العميقة من اجللد واالأغ�شية املخاطية، مع تو�شع االأوعية وزيادة النفاذية مما يوؤدى اإىل تورم االأن�شجة. ميكن اأن حتدث الوذمة الوعائية احلادة يف الفرتة املحيطة باجلراحة، مما قد يوؤدى اإىل ان�شداد جمرى الهواء م�شببا الوفاة. يف هذه التادة تاأهيل االأ�شنان حلالة طفل م�شاب بالوذمة الوعائية الوراثية، مع مراجعة االأدبيات ذات ال�شلة. مفتاح الكلمات: التخدير، وذمة وعائية وراثية، عوز مثبط c1 ا�شرتيز، تقرير حالة ،عمان. abstract: hereditary angioedema (hae) is a rare disorder caused by a deficiency of c1 esterase inhibitor. minor trauma and emotional stress are the most common initiating events leading to contact system activation and excessive uncontrolled bradykinin release. this manifests as angioedema, a vascular reaction of the deeper layers of the skin and mucous membranes, with vasodilatation and increased permeability resulting in tissue swelling. severe angioedema can occur in the perioperative period, leading to fatal airway obstruction. we describe the anaesthetic management of a child with hae for dental rehabilitation and provide an review of the relevant literature. keywords: anesthesia; hereditary angioedema; c1 esterase inhibitor deficiency; case report; oman. anaesthesia management of a patient with hereditary angioedema with prophylactic administration of c1 esterase inhibitor case report and literature review *aravind narayanan, rohit r. date, sanathkumar birur, pradipta bhakta, sinnakirouchenane srinivasan online case report hereditary angioedema (hae) is caused by a deficiency of c1 esterase inhibitor (c1-inh). c1-inh is a serine protease which inhibits "activated factor xiia" and "kallikrein". deficiency of this key inhibitor leads to uncontrolled activation of the contact system thereby generating profuse amounts of bradykinin; which is a potent local vasodilator. trivial stressors can then lead to uncontrolled bradykinin production, with increased vascular permeability of deeper tissues. airway oedema and hypovolemic shock due to the tissue leak of fluids are especially significant in the perioperative period, challenging even the most experienced anaesthesiologist. case report a 6-year-old girl weighing 15 kg who had been diagnosed with c1-inh deficiency was admitted to sultan qaboos university hospital (squh), oman, for dental rehabilitation from multiple dental caries. from two years of age, there had been episodes of abdominal pain and facial swelling, which were self-limiting within 2 to 3 days. subsequently, there were more aggressive attacks with acute dyspnoea, dysphagia and diarrhoea combined with the progressive swelling of the right side of the neck for which she required admission to the intensive care unit (icu) for observation; however, no endotracheal intubation was required. anaesthesia management of a patient with hereditary angioedema with prophylactic administration of c1 esterase inhibitor case report and literature review 468 | squ medical journal, august 2013, volume 13, issue 3 at 3 years old, she was diagnosed by the squh immunology team with hae type ii and received 500 units of plasma-derived c1-inh concentrate (pdc1inh) (berinert p®, csl behring, marburg, germany) for the successful management of severe periorbital swelling and subacute intestinal obstruction. laboratory investigations revealed low complement 4 (c4) levels of 0.06 g/l (reference value: 0.16–0.38 g/l) and high c1-inh antigenic levels of 694 mg/l (reference value: 210–345 mg/l). however, the functional activity of c1-inh was only 22% at 4.9 u/ml (reference value: 17.2–27.4) and c1 inh-specific activity was 7.0 u/mg (reference value: 67.4–93.6). her pre-anaesthetic evaluation was otherwise unremarkable. the plasma-derived c1-inh (pdc1-inh) concentrate was administered prophylactically, one hour preoperatively. two additional doses of pdc1-inh and fresh frozen plasma (ffp) were kept ready. with difficult airway equipment, an emergency tracheostomy kit and an experienced otorhinolaryngologist present, the anaesthesia was induced with propofol with 2.5 mg/kg and fentanyl at 2 µg/kg. under neuromuscular blockade, cisatracurium 0.1 mg/kg, the airway was secured via the nasal route using a cuffed ringadair-elwyn (rae) endotracheal tube, and a throat pack was inserted using minimal manipulation of the oropharyngeal airway. a paracetamol (375mg) suppository was placed rectally. her intraoperative course was uneventful. residual muscle paralysis was reversed using neostigmine (0.05 mg/kg) and glycopyrolate (0.01 mg/kg). after ensuring a positive audible air leak with cuff deflation, the trachea was extubated when she became fully awake so as to rule out any airway oedema. she was transferred to the pediatric intensive care unit for further observation. apart from a mild lip swelling which persisted for a few hours post-operatively, there was no other complication. she was discharged after two days. discussion hae is an uncommon hereditary disorder (1:10,000–150,000) caused by the congenital deficiency of c1-inh, which inhibits function in three different pathways: the complement system, the fibrinolytic system and the contact activation system, in which c1-inh inhibits both activated factor xiia and kallikrein in the ultimate cascade to the production of bradykinin.1,2 the uncontrolled release of bradykinin (a vasoactive peptide) is central to the pathophysiology of hae.3,4 excessive bradykinin eventually leads to vasodilatation and microvascular fluid leakage with subcutaneous and mucosal oedema. hae has autosomal dominant inheritance with mutations of the hae-c1-inh gene on chromosome 11q12-q13.1.5 three forms of hae have been described: type i with low c1-inh antigenic protein and functional activity (85% of cases), type ii with normal or elevated protein but low c1-inh function (15% of cases), and type iii hae with normal c1-inh. type iii is further classified into two types: hae-xii, a familial oestrogen-dependent variety, described only in females and thought to be due to the mutation of coagulation factor xii, and hae-unknown, with an as yet unidentified genetic defect.5–7 most hae patients have a positive family history. the age of onset is variable with laryngeal attacks uncommon before the age of 3 and tending to occur later than other symptoms.8 hae can be precipitated or exacerbated by minor trauma (50% of cases), emotional upset (30–40% of cases), infection, menstruation, pregnancy, cold exposure, certain foods or drugs (angiotensin-convertingenzyme inhibitors or oestrogen oral contraceptives) or sometimes without any obvious trigger.9 surgical trauma and stress can be a potent trigger of hae and fatal attacks have been reported after dental surgeries.10,11 angioedema attacks typically involve the extremities, genitourinary tract, bowel, face, oropharynx or larynx. attacks may last for 72 to 96 hours, and are often severe and disabling. extremity and/or abdominal attacks account for almost 50% of all attacks, and more than 50% of patients experience at least one upper airway attack during their lifetime, which carries a risk of asphyxiation.10,12,13 prodromal symptoms such as fatigue, irritability, weakness, nausea and erythema marginatum precede an angioedema attack by several hours or even a whole day in up to 50% of hae patients.4 a prodromal serpiginous erythematous rash is sometimes seen, but pruritic urticaria usually makes the diagnosis of hae unlikely.14 airway obstruction can be fatal if left aravind narayanan, rohit r. date, sanathkumar birur, pradipta bhakta and sinnakirouchenane srinivasan case report | 469 untreated.13 unexplained episodic mucocutaneous oedema in a patient with recurrent abdominal pain, cramps, vomiting and a lack of fever should raise suspicion of hae. a diagnosis of c1-inh deficiency requires laboratory confirmation with measurement of the c4 level, c1-inh antigenic level and c1-inh functional level. c4 level assessment allows excellent rapid screening, with nearly 100% of patients having a reduced c4 level during attacks. a normal c4 level during an attack of angioedema strongly supports an alternative diagnosis, whereas decreased levels (less than 30% of normal levels) warrants an assay of c1-inh. childhood presentation, strong family history and a low serum level of antigenic c1-inh (<30% of normal levels) are diagnostic. if a patient’s c1-inh level is normal, or raised along with a low c4 level, a functional assay of c1-inh should be done to detect the possibility of the type ii defect.4 diagnostic uncertainty is higher in the paediatric age group because of age-related variations in the normal level of c1-inh.8 hae is especially important to anaesthesiologists because these patients are prone to develop massive upper aerodigestive tract swelling and life-threatening airway obstruction.15 airway trauma during intubation may rapidly progress to laryngotracheal oedema leading to a fatal airway obstruction, and is more prevalent in children who have narrow airways—a 1-mm thick oedema causes a 44% airway diameter reduction in children versus 27% in adults.16 the initial facial or labial oedema seen in 15–30% cases may mask the early indicators of airway oedema such as hoarseness, voice change, stridor and dyspnoea.16 mortality from acute laryngeal oedema is as high as 15–33% in undiagnosed versus 4–6% in diagnosed hae patients.13 considering the risk of airway compromise, all patients with hae should be carefully observed for at least 36 hours postoperatively as the onset time can vary between 60 minutes to 36 hours.10,17 management of hae consists of long-term prophylaxis, short-term prophylaxis and treatment of established acute attack. pharmacologic agents are considered in patients who experience more than one attack per month with recurrent abdominal symptoms or life-threatening laryngotracheal symptoms.18 in addition to being efficacious as an on-demand treatment of attacks, pdc1inh is also effective for long-term prophylaxis.16 treatment with oral 17a-alkylated androgens like methyltestosterone, danazol and stanozolol may be useful in long-term therapy as they stimulate the hepatic synthesis of c1-inh. however, their long-term use may produce serious steroid-related adverse events and hepatocellular tumours; hence, they should be avoided in children. antifibrinolytics like epsilon-aminocaproic acid and tranexamic acid are no longer employed because of their poor efficacy.16,4 short-term prophylaxis can be achieved with the administration of 10–25 u/kg of pdc1-inh (berinert p®) given one hour before the procedure. alternatively, an infusion of 10 ml/kg of solventtreated plasma or ffp can be administered up to 6 hours before a scheduled procedure. although ffp is a good source of c1-inh, it also contains kinins and uncleaved c2 and c4 which may exacerbate acute attacks, apart from its transfusionrelated hazards.19 ffp is less effective, having a shorter duration of action and requiring a longer time for administration. therefore, pdc1-inh concentrate has emerged as the most favoured option for prophylaxis before any provocative surgical procedure.20 high-dose androgens (danazol 6–10 mg/kg/day in 3 divided doses) taken for 5–7 days before and two days after the procedure is an alternative strategy. for emergency procedures and in pregnant patients, the administration of pdc1-inh is preferred.14,4 for acute attacks, standard angioedema treatment modalities, such as epinephrine, corticosteroids or antihistamines, do not have a salutary effect and are not recommended.5 ondemand treatment modalities include the replacement of c1-inhibitor with filtered pdc1-inh (berinert p®), bradykinin2-receptor inhibitor (icatibant: subcutaneous selfadministration possible; 10% recurrence after 16– 24 hours), kallikrein antagonists (ecallantide: 4–6% anaphylaxis chance) and a recombinant c1-inh, conestat alfa (rhucin®, pharming group nv, leiden, netherlands) with a half-life of 3 hours.18,14,21,22 after administration, most patients experience relief after 15–120 minutes but a major swelling might take up to 24 hours to resolve completely. swellings respond more quickly when treated early in the course of the attack. the pdc1-inh concentrate is preferred for acute attacks because of evidence of higher efficacy anaesthesia management of a patient with hereditary angioedema with prophylactic administration of c1 esterase inhibitor case report and literature review 470 | squ medical journal, august 2013, volume 13, issue 3 and safety.4,14,23 it has minimal to no transfusion hazards and can be safely used in paediatric as well as pregnant patients. it causes a partial resolution of symptoms within 30 minutes, and a complete resolution in 4–24 hours.21 the normalisation of laryngeal oedema occurs faster than any other manifestations. the pdc1-inh increases c1-inh levels by more than 50% within 30 minutes and the level remains above the baseline for 3–4 days. thus, it can be used to treat acute attacks as well as shortand long-term prophylaxis when other drugs are not effective. when injected slowly, pdc1-inh is free from any major adverse effects. its main disadvantages are the high cost, limited duration of activity, necessity of parenteral administration and the possible transmission of blood-borne infections.4 because of the rarity of occurrence, reports of perioperative management of hae are very limited in the literature.1,15,10 this makes it difficult to formulate any specific guidelines for anaesthetic or perioperative management. however international consensus guidelines have emerged in the last two years elucidating an algorithmic approach to the management of hae.4,5 the precipitating triggers mentioned earlier should be avoided. regional or general anaesthesia can be safely performed in such patients. regional anaesthesia is preferred wherever possible because of the better suppression of the stress response and the avoidance of airway manipulation.2,24 there is no known contraindication related to the use of any of the available intravenous or volatile anaesthetics and neuromuscular blocking agents, including succinylcholine. although tracheal intubation is not contraindicated, it is important to reduce airway manipulation to the minimum. the role of the laryngeal mask airway in hae patients is not completely clear, but it is reasonable to believe that the larger contact area may aggravate airway oedema. a dose of an on-demand shortterm treatment drug (pdc1-inh, ecallantide or icatibant) or ffp should be held ready, particularly for dental procedures or surgical procedures that require intubation.11,17 upper airway oedema is the most dangerous presentation of hae and is associated with high mortality.4,13,17 fatalities are most commonly seen after dental surgeries.11 intubation is always the first choice in the case of acute airway compromise and should be done as early as possible. while performing laryngoscopy and intubation, the presence of difficult airway equipment and a provision for urgent tracheostomy or cricothyroidotomy is mandatory. airway swelling may become so severe at times that even a tracheostomy may be ineffective in maintaining a patent airway.2 the presence of severe airway oedema, swelling and the demand for immediate intervention can greatly limit the usefulness of fiberoptic intubation.24 this patient had already been diagnosed with hae with a positive history of successful management with pdc1-inh concentrate. the case was managed successfully with a multidisciplinary team, using pdc1-inh prophylaxis as recommended and extubating the patient in a fully-awake condition in order to avoid any airway complications or subsequent precipitation of an acute attack. the absence of any airway oedema was confirmed by a cuff-leak test before the extubation and the patient was observed strictly for the recommended period for the development of any postoperative events.25 although the immediate postoperative period was uneventful, she developed an acute attack after two weeks. the acute relapse occurring two weeks after the operation is unlikely to have been related to perioperative events. conclusion a high index of suspicion for the early diagnosis and active management with pdc1-inh forms the cornerstone of the successful management of hae cases. successful perioperative management requires prophylactic pdc1-inh, diligent monitoring and measures to avoid airway oedema triggers. references 1. poppers pj. anaesthetic implications of hereditary angioneurotic oedema. can j anaesth 1987; 34:76–8. 2. jensen nf, weiler jm. c1 esterase inhibitor deficiency, airway compromise, and anesthesia. anesth analg 1998; 87:480–8. 3. cugno m, zanichelli a, foieni f, caccia s, cicardi m. c1-inhibitor deficiency and angioedema: molecular mechanism and clinical progress. trends mol med 2009; 15:69–78. 4. lang dm, aberer w, bernstein ja, chng hh, grumach as, hide m, et al. international consensus on hereditary and acquired angioedema. ann allergy aravind narayanan, rohit r. date, sanathkumar birur, pradipta bhakta and sinnakirouchenane srinivasan case report | 471 asthma immunol 2012; 109:395–402. 5. bowen t, cicardi m, bork k, zuraw b, frank m, ritchie b, et al. 2010 international consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. allergy asthma clin immunol 2010; 6:24. 6. frank mm. hereditary angioedema. j allergy clin immunol 2008; 121:s398–401. 7. zuraw bl. hereditary angioedema. new engl j med 2008; 359:1027–36. 8. farkas h, varga l, széplaki g, visy b, harmat g, bowen t. management of hereditary angioedema in pediatric patients. pediatrics 2007; 120:e713–22. 9. zuraw bl, christiansen sc. pathophysiology of hereditary angioedema. am j rhinol allergy 2011; 25:373–8. 10. bork k, barnstedt se. laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. j am dent assoc 2003; 134:1088–94. 11. van sickels nj, hunsaker rb, van sickels je. hereditary angioedema: treatment, management, and precautions in patients presenting for dental care. oral surg oral med oral pathol oral radiol endod 2010; 109:168–72. 12. bork k, hardt j, schicketanz kh, ressel n. clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to c1 esterase inhibitor deficiency. arch intern med 2003; 163:1229–35. 13. bork k, hardt j, witzke g. fatal laryngeal attacks and mortality in hereditary angioedema due to c1-inh deficiency. j allergy clin immunol 2012; 130:692–7. 14. longhurst h, cicardi m. hereditary angioedema. lancet 2012; 379:474–81. 15. bork k, barnstedt se. treatment of 193 episodes of laryngeal edema with c1 inhibitor concentrate in patients with hereditary angioedema. arch intern med 2001; 161:714–8. 16. farkas h. management of upper airway edema caused by hereditary angioedema. allergy asthma clin immunol 2010; 6:19. 17. bork k, hardt j, staubach-renz p, witzke g. risk of laryngeal edema and facial swellings after tooth extraction in patients with hereditary angioedema with and without prophylaxis with c1 inhibitor concentrate: a retrospective study. oral surg oral med oral pathol oral radiol endod 2011; 112:58– 64. 18. cicardi m, bork k, caballero t, craig t, li hh, longhurst h, et al. evidence-based recommendations for the therapeutic management of angioedema owing to hereditary c1 inhibitor deficiency: consensus report of an international working group (hawk hereditary angioedema international working group). allergy 2012; 67:147–57. 19. prematta m, gibbs jg, pratt el, stoughton tr, craig tj. fresh frozen plasma for the treatment of hereditary angioedema. ann allergy asthma immunol 2007; 98:383–8. 20. epstein tg, bernstein ja. current and emerging management options for hereditary angioedema in the us. drugs 2008; 68:2561–73. 21. zuraw bl, kalfus i. safety and efficacy of prophylactic nanofiltered c1-inhibitor in hereditary angioedema. am j med 2012; 125:938.e1–7. 22. farkas h, varga l. ecallantide is a novel treatment for attacks of hereditary angioedema due to c1 inhibitor deficiency. clin cosmet investig dermatol 2011; 4:61–8. 23. riedl m. hereditary angioedema therapies in the united states: movement toward an international treatment consensus. clin ther 2012; 34:623–30. 24. spyridonidou a, iatrou c, alexoudis a, vogiatzaki t, polychronidis a, simopoulos c. peri-operative management of a patient with hereditary angioedema undergoing laparoscopic cholecystectomy. anaesthesia 2010; 65:74–7. 25. christiansen sc, zuraw bl. hereditary angioedema: management of laryngeal attacks. am j rhinol allergy 2011; 25:379–82. clinical & basic research نظرة طلبة التمريض العمانيني إىل فوائد تدريب احملاكاة السريرية على خمرجات التعلم اإلكلينيكي جرييجا مادهافان برابهاكاران، اإ�رضاء اخل�ضاونة، الين ويتمان abstract: objectives: this study aimed to explore the benefits perceived by omani undergraduate maternity nursing students regarding the effect of pre-clinical simulation-based training (psbt) on clinical learning outcomes. methods: this non-experimental quantitative survey was conducted between august and december 2012 among third-year baccalaureate nursing students at sultan qaboos university in muscat, oman. voluntary participants were exposed to faculty-guided psbt sessions using lowand medium-fidelity manikins, standardised scenarios and skill checklists on antenatal, intranatal, postnatal and newborn care and assessment. participants answered a purposely designed self-administered questionnaire on the benefits of psbt in enhancing learning outcomes. items were categorised into six subscales: knowledge, skills, patient safety, academic safety, confidence and satisfaction. scores were rated on a four-point likert scale. results: of the 57 participants, the majority (95.2%) agreed that psbt enhanced their knowledge. most students (94.3%) felt that their patient safety practices improved and 86.5% rated psbt as beneficial for enhancing skill competencies. all male students and 97% of the female students agreed that psbt enhanced their confidence in the safe holding of newborns. moreover, 93% of participants were satisfied with psbt. conclusion: omani undergraduate nursing students perceived that psbt enhanced their knowledge, skills, patient safety practices and confidence levels in providing maternity care. these findings support the use of simulation training as a strategy to facilitate clinical learning outcomes in future nursing courses in oman, although further research is needed to explore the objective impact of psbt on learning outcomes. keywords: education; patient safety; nursing; maternal-child nursing; clinical competence; middle east; oman. امللخ�ص: الهدف: تهدف الدرا�ضة اإىل اكت�ضاف الفوائد التي يتوقعها طلب متري�س االأمومة العمانيون من تاأثري تدريب املحاكاة ال�رضيرية ال�ضنة يف التمري�س بكالوريو�س طلبة على اأُجري التجريبي غري الكمي امل�ضح هذا الطريقة: ال�رضيري. التعليم خمرجات على )psbt( من املعدة psbt جل�ضات املتطوعون امل�ضاركون ح�رض ولقد .2012 ودي�ضمرب اأغ�ضط�س �ضهري بني قابو�س ال�ضلطان جامعة يف الثالثة اأثناء الوالدة، قبل ما على املهارات وقوائم موحدة �ضيناريوهات الدقة، ومتو�ضطة منخف�ضة دمى با�ضتخدام التدري�س هيئة اأع�ضاء قبل لدرا�ضة خ�ضي�ضًا امل�ضممة اال�ضتبانة على باالإجابة امل�ضاركون قام لقد الوالدة. حديثي االأطفال وتقييم ورعاية الوالدة وبعد الوالدة، فوائد تدريب املحاكاة ال�رضيرية على خمرجات التعليم ال�رضيري. مت ت�ضنيف العنا�رض إىل �ضتة م�ضتويات فرعية وهي املعرفة واملهارات الدرا�ضة ا�ضتملت نقاط. النتائج: الأربع ليكرت مقيا�س على النتائج ت�ضنيف ومت والر�ضى. والثقة االأكادميية وال�ضلمة املر�ضى و�ضلمة م�ضاركًا حيث اأن الغالبية العظمى )%95.2( اتفقوا على اأن تدريب املحاكاة ال�رضيرية عزز املعرفة لديهم. كما اأن معظم الطلبة على 57 %94.3 ي�ضعرون باأن ممار�ضات �ضلمة املر�ضى تطورت عندهم و %86.5 �ضوتوا على اأن تدريب املحاكاة ال�رضيرية اأفادهم يف تعزيز كفاءة االآمنة باالإجراءات بالقيام ثقتهم عزز ال�رضيرية املحاكاة تدريب على أن وافقوا الطالبات من ون�ضبة 97% الذكور الطلبة كل مهاراتهم. حلديثي الوالدة. علوة على ذلك %93 من امل�ضاركني كانوا را�ضني عن تدريب املحاكاة ال�رضيرية. اخلال�صة: طلبة التمري�س العمانيون يعتربون اأن تدريب املحاكاة ال�رضيرية يعزز املعرفة واملهارات وممار�ضة �ضلمة املر�ضى والثقة يف توفري رعاية االمومة لديهم. وهذه النتائج تدعم ا�ضتخدام تدريب املحاكاة كا�ضرتاتيجية لتي�ضري خمرجات التعليم اإلكلينيكي يف مواد التمري�س م�ضتقبًل يف عمان، إىل جانب اأن هناك حاجة ملزيد من البحوث الكت�ضاف التاأثري املو�ضوعي لتدريب املحاكاة ال�رضيرية على خمرجات التعليم. مفتاح الكلمات: التعليم؛ �ضلمة املر�ضى؛ التمري�س؛ متري�س االأمومة والطفل؛ الكفاءة اإلكلينيكية؛ ال�رضق االأو�ضط؛ عمان. perceived benefits of pre-clinical simulation-based training on clinical learning outcomes among omani undergraduate nursing students *girija madhavanprabhakaran,1 esra al-khasawneh,1 lani wittmann2 sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e105–111, epub. 21 jan 15 submitted 14 apr 14 revisions req. 22 may & 20 jul 14; revisions recd. 5 jul & 4 aug 14 accepted 28 may 14 1department of maternal & child health, college of nursing, sultan qaboos university, muscat, oman; 2perinatal services british columbia, vancouver, british columbia, canada *corresponding author e-mail: girija@squ.edu.om and km_girija@yahoo.com perceived benefits of pre-clinical simulation-based training on clinical learning outcomes among omani undergraduate nursing students e106 | squ medical journal, february 2015, volume 15, issue 1 the ultimate goal of undergraduate clinical nursing education is to create competent and safe entry-level practitioners. in order to do this, educators must provide students with the opportunity to learn in a safe environment. the use of simulation as an effective educational methodology is well-recognised and its use is now widespread in the training of health professionals worldwide, including nursing.1–4 a recent systematic review and meta-analysis by cook et al. concluded that, when used among healthcare professionals, technology-enhanced simulation training yields consistently positive outcomes with regards to the improvement of knowledge, skills and behaviours.5 within the framework of nursing theory, benner’s novice to expert model and kolb’s experiential learning theory have provided support for the use of simulation in the nursing curriculum.6,7 jeffries developed a framework for designing, implementing and evaluating simulations used as teaching strategies for nursing students while highlighting the importance of understanding student factors, including their comfort level.8 well-structured simulation-based training (sbt) permits the creation of a safe, convenient and comfortable learning environ ment that is student-centred, promotes active learning and supports deliberate practice.8 simulation is a supportive non-threatening teaching strategy that allows students to master new skills sequentially and incrementally according to their stage of learning. it allows repetitive practice, debriefing and the correction of errors without risk to patient safety.4,5,9–11 since 2003, there has been an increased focus on sbt in nursing education due to a growing emphasis on patient safety and the increasing competition for student clinical placements.1,2,4,12,13 a blend of simulated and real-life clinical experiences allows nursing education programmes to prepare competent and safe practitioners. current research has shown that sbt in undergraduate nursing programmes consolidates knowledge, facilitates skill acquisition, reinforces safety habits and improves clinical judgment, interpersonal communication and collaboration.1,3,5,14–21 students have described increased self-confidence and satisfaction, as well as decreased anxiety with the sbt learning process.1,3,10,15,22–25 according to ganley et al., a friendly and supportive academic climate is critical to success-ful simulation, so that students can learn without fear of failure.10 traynor et al. reported that simulation aids understanding of the relationship between theory and practice and that students valued the experience as a means of improving their knowledge and enhancing their confidence for future clinical practice.24 research also indicates that sbt is effective for promoting team work and communication in emergency scenarios.26 in an era of highly complex patient care, educators can implement innovative teaching and learning strategies such as pre-clinical simulation-based training (psbt). the provision of psbt at the outset of nursing clinical courses can help students to gain requisite competencies prior to working with real patients. however, to the best of the authors’ knowledge, there is a lack of published research in this field from oman or the middle east. it is important to obtain an understanding of the perceptions of students from these areas in order to successfully integrate simulation as a teaching-learning strategy in the nursing curricula of this region. the purpose of this study was therefore to determine the perceived benefits of psbt on clinical learning outcomes by omani undergraduate nursing students enrolled in a maternal health clinical course in sultan qaboos university (squ), muscat, oman. specifically, the study’s objectives were to determine perceived benefits of psbt on enhancing knowledge, skills, patient safety and self-confidence among the nursing students, as well as to identify their overall level of satisfaction with psbt. advances in knowledge in order to effectively utilise simulations in education, the perspective of the learner must first be understood. this study addresses the perceptions of omani undergraduate nursing students with regards to the benefits of simulation. there is limited published literature on the usefulness of pre-clinical simulation-based training (psbt) in undergraduate maternity nursing education. to the best of the authors’ knowledge, this is the first study addressing the use of this strategy in a middle eastern nursing student population. the results of this study indicated that psbt enhances omani maternity nursing students’ knowledge, skills and confidence. application to patient care pre-clinical exposure to simulation provides a safe and supportive environment that allows students to develop knowledge, psychomotor skills, critical thinking and decision-making skills that aid the achievement of clinical learning outcomes. as was noted in this study, these improved the nursing students’ ability to provide safe and competent patient care. an added benefit of promoting simulation-based teaching in the arab world is the opportunity for male students to develop hands-on maternity clinical skills which otherwise might not be possible due to cultural reasons. girija madhavanprabhakaran, esra al-khasawneh and lani wittmann clinical and basic research | e107 methods this non-experimental quantitative study was carried out between august and december 2012. a convenience sample was used comprising all third-year baccalaureate nursing students who were registered for the maternal health clinical course in the college of nursing at squ (n = 57). these students were then invited to participate in a four-week course of psbt (phase one) as part of their preparation for clinical rotations. the psbt was then followed by 10 weeks of real clinical posting (phase two) and the objective structured clinical examination (osce). students voluntarily completed a survey questionnaire regarding the perceived benefits of psbt during their last week of clinical training, after their completion of the osce. the core clinical learning outcomes of the maternal health clinical course focus on the students’ ability to competently provide evidence-based nursing care to women and infants during the ante-, intraand postnatal periods. this includes the development of knowledge essential to the provision of maternal and newborn nursing care; the demonstration of skills in the clinical assessment and provision of nursing care to women and infants during the ante-, intra-, and postnatal periods; the provision of safe nursing care to both mother and newborn, and effective communication and collaboration with patients, their families and members of the healthcare team. during phase one, all students underwent an introductory session covering the main concepts of the course. this was followed by 36 hours of psbt divided into four sessions with students working in groups of 5–7. simulation sessions were conducted using lowand medium-fidelity manikins in standardised scenarios. the four simulation sessions included the following training activities: antenatal assessment and care (including leopold manoeuvres and gestational age assessment); conduct of delivery and placental examination; postnatal assessment and management of postpartum haemorrhages; and immediate newborn assessment, initial steps of resuscitation and newborn bathing techniques. skill checklists on the above practices were also used in psbt.27 after an initial 45 minutes of demonstration and discussion by faculty at each station, students were able to engage in repetitive hands-on practice of the necessary skills with faculty support. faculty guided the simulation exercises with direct demonstrations and debriefings, giving an opportunity for reflection at each station. this allowed faculty to correct misconceptions and reinforce clinical reasoning and concepts of safe care. study tasks and the opportunity to view related videos were also provided during this phase. during phase two, all students were exposed to the ante-, intra-, postnatal and gynaecology areas and the operating theatre of their assigned clinics for two weeks each. this was followed by one week of final summative assessment of clinical learning outcomes by the osce. the osce assessment focused on knowledge, skill competencies and patient safety practices. it is used almost exclusively for the assessment of learning outcomes through simulation and has been shown to satisfactorily evaluate the abilities of undergraduate midwifery students.28,29 after the examination, students completed a purposely-designed 50-item self-administered questionnaire on the benefits of psbt in enhancing clinical learning outcomes, which was developed based on the available literature.10,27 items in the questionnaire were categorised into six subscales representing knowledge (seven items), skills (four areas with 25 items), patient safety (five items), academic safety (five items), confidence (five items) and satisfaction (three items). each item on the questionnaire was rated on a four-point likert scale ranging from strongly disagree (one) to strongly agree (four). scores of one and two were categorised as ‘disagree’ and scores of three and four were categorised as ‘agree’. the content and face validity of the questionnaire were evaluated by experts and tested during a pilot study to determine the relevance of the items to the concepts. cronbach’s alpha reliability was 0.82, which ensured the reliability of the tool. gender and age were also noted. the questionnaire took approximately 10–15 minutes to complete. data analysis was carried out using the statistical package for the social sciences (spss), version 16 (ibm corp., chicago, illinois, usa). both descriptive and inferential statistics were used to analyse the data. this study was approved by the squ research & ethical review committee of (#nurs/kh/25/2012). the purpose and voluntary nature of the study was explained to all of the participants. participants were assured of data confidentiality and their freedom to withdraw from the study at any time without academic consequences. informed written consent was obtained from each participant. results all of the 57 third-year baccalaureate nursing students in the convenience sample elected to participate in the study, comprising 22 male and 35 female students. in the domain of perceived knowledge and skills, the majority (95.24%) of students agreed that psbt helped them to develop essential knowledge in perceived benefits of pre-clinical simulation-based training on clinical learning outcomes among omani undergraduate nursing students e108 | squ medical journal, february 2015, volume 15, issue 1 different aspects of maternity care. in addition, 86.48% of the participants were of the opinion that psbt provided an opportunity for them to practise their skills. more than 97% perceived psbt as beneficial for developing knowledge of antenatal, postnatal and newborn care; however, their self-rated knowledge of intranatal skills was relatively low (86.4% and 85.7% for males and females, respectively) [figure 1]. it is important to note that students’ perceived enhanced skill competency was significantly positively related to their corresponding improved knowledge (p = 0.400, 0.384, 0.513 and 0.646 for antenatal, postnatal, delivery and newborn skills, respectively) [figure 2]. most students (94.3%) reported that the use of psbt enhanced their patient safety practices [table 1]. furthermore, 96.4% agreed that psbt had helped increase their confidence in the care and assessment of patients, especially with regards to antenatal, postnatal and newborn care. however, only 67.8% of female students and 59.1% of male students reported confidence in intranatal care practices. all male students and 97% of the female students agreed that psbt enhanced their confidence in holding newborns and providing newborn care. with regards to learner satisfaction, psbt was rated as a safe academic environment by the majority of students (93.9%). almost all of the students (98%) rated psbt as an enjoyable opportunity to practice clinical skills and 95.8% reported that it provided a foundation for learning to work with less fear in a clinical environment. most students (92.5%) valued psbt as a convenient method to learn and practice patient care without fear of failure and with enhanced communication and collaboration. overall, 93% of the students were satisfied with psbt as it helped them develop antenatal, postnatal and newborn assessment and care skills. in contrast, however, the students’ satisfaction in the area of intranatal care was rated comparatively low (67%). the relationships between perceived knowledge and skills, safety practices and confidence is displayed in table 2. the findings demonstrated a statistitable 1: distribution of perceived safety practices by gender among omani undergraduate maternity nursing students undergoing pre-clinical simulation-based training (n = 57) safety practice percentage male (n = 22) female (n = 35) universal precautions 94.0 92.0 high-risk management 94.0 95.2 prevention of hypothermia in newborns 95.7 98.6 proper identification of patients 95.5 97.1 documentation and reporting 91.0 98.3 table 2: correlation between perceived knowledge and skills, safety practices and confidence among omani undergraduate maternity nursing students undergoing pre-clinical simulation-based training (n = 57) outcome r value safety practice confidence knowledge 0.514** 0.421** skills antenatal 0.527** 0.497** postnatal 0.620** 0.360** conduction of delivery 0.296* 0.336** newborn care 0.709** 0.477** safety practices 1.000 0.348** confidence 0.348** 1.000 *significant at p <0.05. **significant at p <0.01. figure 1: distribution of perceived knowledge acquisition by gender and learning domain among omani undergraduate maternity nursing students undergoing pre-clinical simulation-based training (n = 57). figure 2: comparison of perceived knowledge with skill acquisition by learning domain among omani undergraduate maternity nursing students undergoing pre-clinical simulation-based training (n = 57). girija madhavanprabhakaran, esra al-khasawneh and lani wittmann clinical and basic research | e109 cally significant correlation (p <0.05) between these variables, indicating that psbt was effective in enhancing students’ perceptions and the achievement of their clinical learning outcomes. discussion in light of limited clinical placements and the increasing complexities of safe patient care, innovative teaching-learning experiences like psbt have become essential. the provision of psbt at the outset of nursing clinical courses can help students gain the requisite competencies prior to their exposure to real patients, thereby increasing patient safety and decreasing the requisite learning time in the clinical environment.8,11,21,22,24 this study assessed the perceived benefits of a psbt teaching-learning strategy in enhancing knowledge, skills, patient safety practices and confidence among nursing students at squ. the results indicated that the students perceived psbt to be useful in developing and improving their knowledge, clinical skills and safety practices, which were the key clinical learning outcomes of their course. this finding is consistent with previous studies from other regions that have highlighted the benefits of simulation-based education.11,14,16,17,19–21,24,25 it is likely that the students’ perceived increase in confidence and competencies reflected their actual perceptions as the students completed the questionnaire following their exposure to real-life situations as encountered during a 10-week clinical posting. the positive correlation between perceived knowledge and skills with safety aspects and confidence indicates that psbt was beneficial in enhancing perceived patient safety practices and the achievement of the final clinical learning outcomes; this has also been observed in the literature.2,24 furthermore, the non-threatening learning environment of psbt allowed the students in this study to gain confidence in their ability to care safely for maternity patients and newborns prior to actual patient contact. overall, participants expressed that they appreciated psbt as a teaching strategy to facilitate achievement of clinical learning outcomes. in the current study, students reported that psbt sessions were enjoyable, safe, supportive, nonthreatening and less likely to cause anxiety. furthermore, the sessions allowed students the opportunity to learn from their mistakes. research has shown that students who engage in comfortable and enjoyable activities are more likely to be motivated to learn.10 students in the present study reported high levels of satisfaction with psbt and commented positively on its benefits in confidence-building and facilitating communication and collaboration between team members. these findings are congruent with previous research focusing on different student populations.10,20–22,24 it is noteworthy that the students in the current study reported lower scores for their knowledge, skills, confidence and satisfaction related to intrapartum care. despite these low scores, this observation is heartening as it indicates a degree of accurate critical reflection in the students’ evaluations of their own competencies. this may be because it takes considerably longer to develop the necessary knowledge and skills to feel competent in conducting a delivery, even at the novice level. adjustments to this specific skill competency expectation are therefore recommended in future maternity course outcomes. interestingly, male students reported equally high levels of satisfaction with the simulation experience as females, despite the fact that psbt exposed them to female reproductive anatomy, terminology and procedures that would normally be considered outside the comfort zone of an omani male. while male students do spend clinical time in maternity units, their hands-on skills are realistically limited to newborn care due to the cultural and ethical limitations in place in oman. despite these restrictions, they are nevertheless still expected to meet clinical learning outcomes. it is important for male students to develop competent maternity skills since, while they may never permanently work in a maternity unit, they may very well be faced with emergency situations where these skills are needed. in this instance, sbt provides male nurses with an opportunity to gain valuable maternity clinical competencies while remaining respectful of cultural barriers; this is an additional benefit of psbt in the arab world. despite its benefits as a learning strategy, laschinger et al. stress that simulation tools should only be used as an adjunct for clinical practice, not as a replacement.3 the results of the present study support this principle. the inclusion of psbt as an integral aspect of the entire clinical course was perceived as helpful by students to prepare them for safe practice in a real-life clinical environment. adopting simulation as a teaching strategy requires that standards and guidelines be developed, preferably by a professional organisation. while oman does not yet have a national regulating body for nursing, other international professional bodies have endorsed simulation as an effective instructional method in nursing.30–32 however, the ideal percentage of clinical time that should be allocated to simulation learning has yet to be determined. the national council of state boards of nursing in the usa is currently conducting a national multi-site longitudinal perceived benefits of pre-clinical simulation-based training on clinical learning outcomes among omani undergraduate nursing students e110 | squ medical journal, february 2015, volume 15, issue 1 study of simulation use in american pre-licensure nursing programmes.33 phase two of this study will take the form of a randomised controlled study examining the outcomes of various frequencies of simulation education (10%, 25% or 50%) to replace a portion of the hours spent in traditional clinical settings.33 the findings of the current study are restricted by its setting in a single institution using a small sample. furthermore, students were not given the option of reporting additional opportunities gained from psbt, as the questionnaire items extensively covered all aspects under each learning objective in the course. this may have limited the study. a two-group control experimental design would have been ideal; however, in the current context it was not feasible as the clinical course outlines were planned and implemented for the whole cohort. however, the results observed in this study were consistent with the aforementioned previously published studies in a variety of different countries. thus, in spite of its limitations, the current study’s findings serve to support the applicability of sbt research findings to middle eastern settings. the results of this study add to the body of research that supports the effectiveness of sbt learning in nursing education by documenting perceived benefits in a previously untested population of students. nevertheless, there is a need for future research to be conducted regarding the transferability of simulated learning to the practice environment. conclusion this study found that omani undergraduate nursing students in a maternity clinical course at a middle eastern university perceived that psbt enhanced their knowledge, skill acquisition and safety practices. they rated psbt as enjoyable and helpful in building their confidence and enhancing their communication and collaboration skills. the findings also suggest that psbt provides an opportunity for arab male nursing students to achieve clinical maternity skills which they may otherwise have limited opportunities to practise due to cultural barriers. the observed rate of student satisfaction with this teaching strategy supports the inclusion of simulation as an adjunct to clinical practice in future maternity nursing courses in the middle east. however, further research is needed to explore the objective impact of psbt on actual practice. a c k n o w l e d g e m e n t s the authors are grateful to the participating students, whose wholehearted input made this study possible. in addition, dr. jadevan sreedharan is sincerely thanked for his scholarly guidance and help in the statistical analysis of the data. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. cant rp, cooper sj. simulation-based learning in nurse education: systematic review. j adv nurs 2010; 66:3–15. doi: 10.1111/j.1365-2648.2009.05240.x. 2. cooper s, cant r, porter j, bogossian f, mckenna l, brady s, et al. simulation based learning in midwifery education: a systematic review. women birth 2012; 25:64–78. doi: 10.1016/j. wombi.2011.03.004. 3. laschinger s, medves j, pulling c, mcgraw dr, waytuck b, harrison mb, et al. effectiveness of simulation on health profession students’ knowledge, skills, confidence and satisfaction. int j evid based healthc 2008; 6:278–302. doi: 10.1111/j.1744-1609.2008.00108.x. 4. henneman ea, cunningham h, fisher dl, plotkin k, nathanson bh, roche jp, et al. eye tracking as a debriefing mechanism in the simulated setting improves patient safety practices. dimens crit care nurs 2014; 33:129–35. doi: 10.1097/dcc.0000000000000041. 5. cook da, hatala r, brydges r, zendejas b, szostek jh, wang at, et al. technology-enhanced simulation for health professions education: a systematic review and meta-analysis. jama 2011; 306:978–88. doi: 10.1001/jama.2011.1234. 6. larew c, lessans s, spunt d, foster d, covington bg. innovations in clinical simulation: application of benner’s theory in an interactive patient care simulation. nurs educ perspect 2006; 27:16–21. doi: 10.1043/1094-2831(2006)027[0016:iicsao]2.0.co;2. 7. waldner mh, olson jk. taking the patient to the classroom: applying theoretical frameworks to simulation in nursing education. int j nurs educ scholarsh 2007; 4:article18. doi: 10.2202/1548-923x.1317. 8. jeffries pr. a framework for designing, implementing, and evaluating simulations used as teaching strategies in nursing. nurs educ perspect 2005; 26:96–103. doi: 10.1043/1536-5026(2005)026<0096:afwfdi>2.0.co;2. 9. weller jm, nestel d, marshall sd, brooks pm, conn jj. simulation in clinical teaching and learning. med j aust 2012; 196:594. doi: 10.5694/mja10.11474. 10. ganley bj, linnard-palmer l. academic safety during nursing simulation: perceptions of nursing students and faculty. clin simul nurs 2012; 8:e49–57. doi: 10.1016/j.ecns.2010.06.004. 11. lewis dy, ciak ad. the impact of a simulation lab experience for nursing students. nurs educ perspect 2011; 32:256–8. doi: 10.5480/1536-5026-32.4.256. 12. institute of medicine of the national academies. health professions education: a bridge to quality. washington dc, usa: national academies press, 2003. pp. 1–18. 13. quality and safety education for nurses institute. teaching strategies: simulation. from: www.qsen.org/teaching-strategies/ simulation/ accessed: aug 2012. 14. alinier g, hunt b, gordon r, harwood c. effectiveness of intermediate-fidelity simulation training technology in undergraduate nursing education. j adv nurs 2006; 54:359–69. doi: 10.1111/j.1365-2648.2006.03810. 15. rhodes ml, curran c. use of the human patient simulator to teach clinical judgment skills in a baccalaureate nursing program. comput inform nurs 2005; 23:256–62. 16. ricketts b, merriman c, stayt l. simulated practice learning in a preregistration programme. br j nurs 2012; 21:435–40. girija madhavanprabhakaran, esra al-khasawneh and lani wittmann clinical and basic research | e111 17. lapkin s, levett-jones t, bellchambers h, fernandez r. effectiveness of patient simulation manikins in teaching clinical reasoning skills to undergraduate nursing students: a systematic review. clin simul nurs 2010; 6:e207–22. doi: 10.1016/j.ecns.2010.05.005. 18. robinson bk, dearmon v. evidence-based nursing education: effective use of instructional design and simulated learning environments to enhance knowledge transfer in undergraduate nursing students. j prof nurs 2013; 29:203–9. doi: 10.1016/j. profnurs.2012.04.022. 19. broussard l. simulation-based learning: how simulators help nurses improve clinical skills and preserve patient safety. nurs womens health 2008; 12:521–4. doi: 10.1111/j.1751486x.2008.00386.x. 20. clapper tc, kardong-edgren s. using deliberate practice and simulation to improve nursing skills. clin simul nurs 2012; 8:e109–13. doi: 10.1016/j.ecns.2010.12.001. 21. durham cf, alden kr. enhancing patient safety in nursing education through patient simulation. in: hughes rg, ed. source patient safety and quality: an evidence-based handbook for nurses. rockville, maryland, usa: agency for healthcare research and quality, usa department of health & human services, 2008. pp. 1364–4403. 22. bambini d, washburn j, perkins r. outcomes of clinical simulation for novice nursing students: communication, confidence, clinical judgment. nurs educ perspect 2009; 30:79– 82. doi: 10.1043/1536-5026-030.002.0079. 23. sportsman s, schumacker re, hamilton p. evaluating the impact of scenario-based high-fidelity patient simulation on academic metrics of student success. nurs educ perspect 2011; 32:259–65. doi: 10.5480/1536-5026-32.4.259. 24. traynor m, gallagher a, martin l, smyth s. from novice to expert: using simulators to enhance practical skill. br j nurs 2010; 19:1422–6. 25. weaver a. high-fidelity patient simulation in nursing education: an integrative review. nurs educ perspect 2011; 32:37–40. doi: 10.5480/1536-5026-32.1.37. 26. ennen cs, satin aj. training and assessment in obstetrics: the role of simulation. best pract res clin obstet gynaecol 2010; 24:747–58. doi: 10.1016/j.bpobgyn.2010.03.003. 27. lowdermilk dl, perry se, cashion mc. maternity nursing. 8th ed. st. louis, missouri: mosby-elsevier, 2010. 28. nulty dd, mitchell ml, jeffrey ca, henderson a, groves m. best practice guidelines for use of osces: maximising value for student learning. nurse educ today 2011; 31:145–51. doi: 10.1016/j.nedt.2010.05.006. 29. delavar ma, salmalian h, faramarzi m, pasha h, bakhtiari a, nikpour m, et al. using the objective structured clinical examinations in undergraduate midwifery students. j med life 2013; 6:76–9. 30. national league for nursing, simulation innovation resource center. history of the sirc. from: www.sirc.nln.org/mod/ page/view.php?id=347 accessed: jun 2014. 31. nursing & midwifery council. nmc circular 36/2007: supporting direct care through simulated practice learning in the pre-registration nursing program. from: www.nmc-uk.org/ documents/circulars/2007circulars/nmccircular36_2007.pdf accessed: jun 2014. 32. nursing & midwifery council. simulation and practice learning project: outcome of a pilot study to the test principles for auditing simulated practice learning environments in the pre-registration nursing programme. from: www.nmc-uk.org/ documents/consultations/nmc%20consultation%20-%20 simulated%20practice%20learning%20-%20final%20report.pdf accessed: jun 2014. 33. national council of state boards of nursing. simulation study. from: www.ncsbn.org/685.htm accessed: jun 2014. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 232-240, epub. 9th may 13 submitted 12th aug 12 revision req. 21th aug 12, revision recd. 22nd nov 12 accepted 19th dec 12 1college of nursing, sultan qaboos university, muscat, oman; 2school of social service administration, university of chicago, chicago, illinois, usa; 3social work institute, university of jordan, amman, jordan; 4school of social work, columbia university, new york, usa *corresponding author e-mail: esra@squ.edu.om قياس الوعي بفريوس نقص املناعة املكتسب بني الشباب األردين اإ�رساء من�شور اخل�شاونة، ليلى اإ�شماعيلونوفا، فيديا �شي�شان، عليمات حمود، نبيلة البا�شل امللخ�ص: الهدف: فهم العوامل امل�شاحبة مل�شتوى الوعي بفريو�ض نق�ض املناعة املكت�شبة احل�شول على مثل هذه البيانات مهم جدا من املكت�شبة. املناعة نق�ض بفريو�ض الأردين ال�شباب وعي ملدى املحدده العوامل الدرا�شة هذه تناق�ض لل�شباب. وقائية برامج و�شع اأجل الطريقه: هذه درا�شة مقطعيه على �رسيحة وا�شعة �شمت 8,129 �شابا و�شابة تراوحت اأعمارهم بني 14 و25 �شنة اأختريوا ع�شوائيا من مدار�ض خمتلفة من جميع املحافظات الأردنية الإثنى ع�رس. مثلت الإناث امل�شرتكات %50 ومعدل اأعمارهم 17 �شنة. وقام امل�شاركون املكت�شبة، املناعة نق�ض بفريو�ض العامة واملعرفة والدميوغرافية، الجتماعية اخل�شائ�ض على ا�شتملت والتي ذاتيا ال�شتبانة بتعبئة بفريو�ض املعرفة مدى لقيا�ض �شوؤال 13 ي�شم اختبار يف النتائج: للمجازفة. امليل اأو للمخاطر والتعر�ض اجلن�شني، بني الوعي ومدى نق�ض املناعة املكت�شبة، كان معدل ما اأجاب عنه امل�شاركون ب�شورة �شحيحة 7 اأ�شئلة )اأي 7.21، وبـ 2.63 انحراف معياري(. �شجلت الإناث يف املناطق الريفية م�شتوى متدن من املعرفة بالفريو�ض، بينما �شجل طالب الكليات واجلامعات م�شتويات اأعلى. كما يختلف الوعي بالفريو�ض باختالف م�شادر املعلومات، فقد كانت املعلومات املتلقاة من الرفاق اأكرث دقة، بينما �شجلت املعلومات املتلقاة من الوالدين واملراكز ال�شحية درجة اأقل. و�شجل ال�شباب املوؤمنون بامل�شاواة بني اجلن�شني درجات وعي اأكرب بالفريو�ض، وكانت درجة الوعي اأقل عند ال�شباب الذين يوافقون على تعاطي املخدرات. اخلال�صه: ركزت الربامج التثقيفية املتعلقة بالفريو�ض يف الأردن على ال�شباب والإناث يف املناطق الريفية. كما اأثبتت املوؤ�ش�شات التعليمية اأنها فاعلة يف توفري املعلومات الدقيقة للطالب، بينما يجب �شم اأولياء الأمور وخرباء ال�شحة يف الربامج التوعوية من اأجل جتنب املفاهيم اخلاطئة ورفع م�شتوى الوعي بفريو�ض نق�ض املناعة املكت�شبة بني ال�شباب الأردين. مفتاح الكلمات: املعرفة بفريو�ض نق�ض املناعة املكت�شب؛ ال�شباب؛ الأردن؛ ال�رسق الأو�شط. abstract: objectives: understanding factors associated with the level of human immunodeficiency virus (hiv) knowledge acquisition is crucial to inform preventative programmes for young people. this study examines predictors of hiv knowledge among jordanian youths. methods: a cross-sectional survey was conducted among 8,129 youths aged between 14 and 25 years randomly selected from schools representing each of the 12 governorates of jordan. a total of 50% of respondents were female and, on average, 17 years old. participants completed a self-administered questionnaire covering sociodemographic characteristics, hiv knowledge, gender awareness, exposure to and favourable attitudes toward risky behaviours. results: on a 13-item hiv knowledge test, participants answered an average of 7 questions correctly (mean = 7.21; standard deviation = 2.63). female respondents from rural areas demonstrated significantly lower levels of hiv knowledge, while college and university students demonstrated higher levels. hiv knowledge differed significantly by sources of information, with peeracquired information associated with more accuracy, while hiv information from parents or health centres was associated with a lower score. youths with more egalitarian gender views also demonstrated higher knowledge levels, whereas youths approving of drug use showed lower levels of hiv knowledge. conclusion: hiv education programmes in jordan should focus on females and youths living in rural areas. educational institutions have been shown to be effective in providing accurate information to students, while parents and health professionals should also be included in hiv prevention programmes in order to reduce misconceptions and raise the level of hiv knowledge among jordanian youths. keywords: hiv knowledge; youth; jordan; middle east. predictors of human immunodeficiency virus knowledge among jordanian youths *esra m. al-khasawneh,1 leyla ismayilova,2 vidya seshan,1 olimat hmoud,3 nabila el-bassel4 clinical & basic research advances in knowledge limited research on human immunodeficiency virus/acquired immunodeficiency syndrome (hiv/aids) has been conducted among young people in jordan. the findings of this study have significant implications for the practice and support of hiv education programmes for youth. adolescents need to be aware of hiv and methods that contribute to its prevention. teachers and lecturers can play a significant role in educating young people about risky sexual behaviours. esra m. al-khasawneh, leyla ismayilova, vidya seshan, olimat hmoud and nabila el-bassel clinical and basic research | 233 the united nations defines youth as persons between the ages of 15 and 24 years old. individuals under the age of 25 continue to account for more than half of new human immunodeficiency virus (hiv) cases around the world.1 the median age of the population in jordan is 22 years, and about three-quarters of jordan’s 6 million people are under the age of 25.2 countries with a large proportion of youth tend to have a high prevalence of hiv.3,4 by the end of 2009, jordan had 850 officially registered hiv cases, indicating a prevalence rate of less than 0.01%.5,6 other countries with traditional muslim cultures, such as algeria, tunisia and iran, previously had low rates of hiv but are currently experiencing an alarming increase in rates of hiv infection.7 globalisation, changes in sociocultural norms, poverty, and high levels of migration in jordan may increase youths’ exposure to high-risk behaviours, including unprotected sex. there has been limited research on hiv knowledge among youth in jordan. a descriptive study conducted among 1,013 university students in jordan further demonstrated a ‘knowledge-deficit’ and the presence of misconceptions with regards to hiv among jordanian youths.8 recent literature suggests that jordanian youths, like other arab youths, experience challenges in receiving accurate information about hiv/aids.9 the healthcare system does not offer hiv education programmes specifically targeting youth, and social norms do not encourage public discussions about sex.10 in families, parents avoid talking with their adolescents about sexuality; educational programmes about puberty and sexuality are nearly absent from school curricula.9,11 when a curriculum does contain information related to reproductive health in high school, teachers often avoid it.9,11 cultural taboos as well as traditional norms prevent health educators from informing young people publicly about condom use, or providing educational materials such as pamphlets or brochures.12 thus, the purpose of this study was to examine predictors of hiv knowledge among youths in jordan. more specifically, the study aimed to identify levels of hiv knowledge among youths in jordan; examine gender differences in the level of hiv knowledge among jordanian youth, and examine which demographic, socioeconomic, and cultural factors predict hiv knowledge among youths in jordan. methods the study used data from a cross-sectional survey conducted among 8,129 youths between the ages of 14 and 25 years. respondents from all schools and educational institutions representing each of the 12 governorates were randomly selected to participate in the survey. a total of 50% of the respondents were female and, on average, respondents were 17 years old. participants completed a self-administered questionnaire that collected information about sociodemographic characteristics, hiv knowledge, gender awareness, exposure to risky behaviours and favourable attitudes toward risky behaviours. students were recruited for the study from all public, private, military, and united nations relief and works agencies (unrwa) schools in jordan, including institutions of higher education (universities, community colleges) and vocational training centres (vtcs). the sampling process passed through several multistage levels. first, the sample size was set at 6,000 students in order to have sufficient numbers to meet statistical requirements. second, a list of all schools and institutions of higher education was compiled. third, samples of schools (male and female) were randomly selected from each district. fourth, all classes in the selected schools (grades 9 to 12) were taken as a unit for data collection. data were collected during class periods. sampling was conducted in several stages as a sample of each type of institution was selected and students were selected according to their college affiliation. it was decided that the selection should cover jordan’s three geographic regions—north, central, and south. the total sample size was 8,129, which exceeded the number originally decided upon application to patient care the knowledge obtained from this study can help adolescents to initiate a healthy lifestyle, thus preventing hiv. hiv knowledge among adolescents will help them to behave more responsibly in society. predictors of human immunodeficiency virus knowledge among jordanian youths 234 | squ medical journal, may 2013, volume 13, issue 2 because the class was the unit of data collection; all students in the selected classes were interviewed. the questionnaire used was designed in arabic to fulfill the multiple purposes of the research project. before embarking on the actual study, the questionnaire was piloted on several hundred students to check for any discrepancies, ambiguity, or sensitivity of questions or statements and was then revised based on the findings of this pilot test. the test of hiv knowledge included 13 questions that assessed students’ knowledge of hiv infection and hiv transmission modes (e.g. is there any effective cure for acquired immune deficiency syndrome (aids)? can hiv be transmitted by touching an infected person? can hiv be transmitted by having sex with a person infected with hiv?). correct answers were coded as 1 while incorrect and ‘don’t know’ answers were coded as 0. a composite score was computed by summing up all correctly answered items. the hiv knowledge score ranged from 0 to 13, with a higher score indicating a higher level of hiv knowledge. a steering committee was formed to oversee and facilitate the research project. it was comprised of physicians, educators, psychologists, a sociologist, pharmacists, a lawyer, a retired police general who had been head of the anti-drug department, statisticians, and united nations fund for population activities (unfpa) representatives and technical experts. the study was approved by this steering committee as well as research committees in the jordanian ministries of higher education and of education. the study purpose was explained to the students and written informed consent was obtained from consenting students. no financial incentives were provided to students who participated in the study. a number of variables were used to measure important predictors of hiv knowledge. respondents were asked to name the main sources of information on hiv and other sexually transmitted infections (stis). respondents could choose more than one source of information from the following list: parent/s, sibling/s, other relative/s, friends, teachers, educational materials (books, magazines, the internet), healthcare centres, and mass media (tv or radio). additionally, respondents were asked whether they had ever attended a lecture on hiv/aids, feared getting infected with hiv/ aids, or felt embarrassed to see a doctor if they experienced pain in the reproductive area. a permissive attitude toward drug use is an important predictor of risky behaviour among youth. a gauge of this attitude is commonly used in situations where it is difficult to assess risk-taking behaviour. the attitudes toward drug use scale included 18 questions (e.g. use of small amounts of drugs will cause no harm; smoking is a gateway to drugs; use of drugs brings pleasure and happiness; drinking alcohol leads to using drugs; drugs are no more dangerous than smoking). respondents used a 5-point likert scale to express their options about each statement (from 1 = strongly disagree to 5 = strongly agree). items disapproving of drug use were reverse coded (i avoid the company of drug users; drugs destroy human life; experimenting with drugs even once is dangerous). higher than average scores on the scale indicate attitudes justifying or in favour of/approving drug use. another attitudinal scale measured youths’ attitudes toward gender roles. a gender awareness scale assessed the respondents’ views on gender roles and gender equality in public and private lives and asked students to rate statements such as the acceptability of working in a job headed by a woman; a son sharing in household chores and childcare; offering males and females equal opportunities in education and employment, and women taking leadership positions in the public sector. each of the 6 statements were rated on a 4-point scale with possible responses being agree, hesitant, neutral, or disagree. an average composite score indicated a greater level of gender awareness and more supportive attitudes toward gender equality. sociodemographic variables included the respondents’ ages, genders, places of residence (urban, rural, the badia region (i.e. desert), or refugee camps), geographic regions (north, central, or south), paternal and maternal levels of educational attainment, number of siblings, and number of rooms in the household. data analysis was performed using the statistical package for the social sciences (spss), version 18 (ibm, inc., chicago, illinois, usa). first, descriptive statistics and gender differences for key sociodemographic and explanatory variables were examined. second, using a multiple linear regression approach, the factors associated with the higher levels of hiv knowledge were examined. about 13% of the data were missing for paternal and esra m. al-khasawneh, leyla ismayilova, vidya seshan, olimat hmoud and nabila el-bassel clinical and basic research | 235 maternal education variables. multiple imputation procedures were used to impute data for these two variables. the findings from the imputed dataset did not differ from the analysis conducted on the original data with missing cases. results the total sample consisted of 8,129 youths and was equally distributed by gender, with 4,064 male participants (50%) and 4,065 female participants (50%). the sociodemographic characteristics of the sample are presented in table 1. the sample included young people between 14 and 25 years of age, the mean age being 17.23 years (standard deviation [sd] = ± 1.88). participants reported having on average 7 other siblings (mean [m] = 7.18; standard deviation [sd] = ± 2.7) with some participants reporting as many as 20 siblings. the number of rooms, used as a proxy of household wealth, ranged from 1 to 11 rooms with the average apartment or house having 4 rooms (m = 4.84; sd = ± 2.07). out of 8,129 participants, the majority (69.3%) was from the central region of jordan, followed by participants from the northern (25.5%) and southern (10.3%) regions. at the time of the interview, over half of the participants (55.6%) were attending secondary school, 21.2% had achieved only a basic level of education, and 14.1% were studying at a university. about 15% of mothers and 7.5% of fathers of respondents had only basic education or no education at all. the overwhelming majority of respondents (97.2%) had heard of hiv/aids. as presented in table 1: socio-demographic characteristics of the sample variable total (n = 8,129) male (n = 4,064) female (n = 4,065) p value, χ², t-test frequency (%) level of education p <0.01 basic secondary vocational community college university 1,720 (21.2) 4,521 (55.6) 342 (4.2) 399 (4.9) 1,147 (14.1) 814 (20.0) 2,321 (57.1) 257 (6.3) 109 (2.7) 563 (13.9) 906 (22.3) 2,200 (54.1) 85 (2.1) 290 (7.1) 584 (14.4) residence p <0.01 city village badia and camps 5,632 (69.3) 2,122 (26.1) 375 (4.6) 2,830 (69.6) 909 (22.4) 325 (8.0) 2,802 (68.9) 1,213 (29.8) 50 (1.2) region p <0.01 central north south 5,217 (64.2) 2,071 (25.5) 841 (10.3) 2,793 (68.7) 923 (22.7) 348 (8.6) 2,424 (59.6) 1,148 (28.2) 493 (12.1) maternal education level χ² 2.52 illiterate basic secondary college or university 1,215 (15.0) 2,275 (28.0) 2,907 (35.8) 1,732 (21.3) 623 (15.3) 1,113 (31.0) 1,449 (35.7) 879 (21.6) 592 (14.6) 1,162 (28.6) 1,458 (35.9) 853 (21.0) paternal education level p <0.05 illiterate basic secondary college or university 609 (7.5) 1,912 (23.5) 2,409 (29.6) 3,199 (39.4) 333 (8.2) 981 (24.1) 1,136 (27.9) 1,615 (39.7) 277 (6.8) 931 (22.9) 1,273 (31.3) 1,584 (39.0) total male female mean (sd) age in years 17.23 (± 1.88) 17.25 (± 1.89) 17.21 (± 1.87) t-test 0.99 number of siblings 7.18 (± 2.7) 7.06 (± 2.75) 7.29 (± 2.66) p <0.01 number of rooms 4.84 (± 2.07) 4.89 (± 2.19) 4.8 (±1.94) p <0.1 sd = standard deviation. predictors of human immunodeficiency virus knowledge among jordanian youths 236 | squ medical journal, may 2013, volume 13, issue 2 table 2, the average score on the hiv knowledge test was 7.21 (sd = ± 2.63) demonstrating that respondents answered 7 out of 13 questions correctly. a third of respondents (32.4%) had attended lectures on hiv/aids. the most common sources of information about hiv were books, magazines, and the internet (85.4%), mass media (81.5%), and teachers (73.6%). significant gender differences were observed in regards to the sources of hiv information. as compared to male participants, more female participants received information about hiv within the family setting. a total of 50% of females mentioned parents as a source of information as compared to 33.5% of males, and the difference was statistically significant (χ2 = 238.11; p <0.001). similarly, more female respondents received information about hiv from their siblings (49.8%) as compared to their male counterparts (38.8%, χ2 = 99.41; p <0.001). participants primarily received information from a parent or sibling of the same gender. boys more than girls learned about hiv from their peers (χ2= 22.42; p <0.001) and other relatives (χ2 = 80.63; p <0.001). overall, respondents disapproved of the use of drugs and the average score on the 5-point favourable attitude toward drugs scale was 2.07 (sd = ± 0.5). male participants demonstrated more favourable attitudes toward drug use (m = 2.16; sd = ± 0.54) as compared to girls (m = 1.99; sd = ± 0.45; χ2 = 15.13; p <0.001). the gender awareness score measuring participants’ attitudes to the equal roles of men and women was 3.1 (sd = ± 0.7) out of 4. females demonstrated more supportive attitudes toward gender equality (m = 3.4; sd = ± 0.55) compared to male respondents (m = 2.8; sd = ± 0.71; χ2 = -42.57; p <0.001). the results of the regression analysis are presented in table 3. the analysis demonstrated that girls reported a significantly lower score on the hiv knowledge test (regression coefficient [b] = -0.51; p <0.001), while controlling for other important sociodemographic covariates. compared to respondents with a basic level of education, respondents pursuing a college or university education demonstrated significantly higher scores on the hiv knowledge test (b = 0.52; p <0.01 and b = 0.51; p <0.001, respectively). respondents attending secondary or vocational schools did not differ significantly in their level of hiv knowledge from respondents with basic education. compared to youth from the central region of jordan, youths from the north or south of jordan showed lower levels of hiv knowledge (b = -0.33; p <0.001 table 2: level of human immunodeficiency virus (hiv) knowledge among jordanian youth and gender differences hiv-related variables total (n = 8,129) male (n = 4,064) female (n = 4,065) p value hiv knowledge score mean (sd), (range 0–13) 7.21 (± 2.63) 7.39 (± 2.66) 7.03 (± 2.58) p >0.01 attended lectures on aids 2,631 (± 32.4) 1,200 (± 29.5) 1,431 (± 35.2) p >0.01 fear of getting aids 2,053 (± 25.3) 1,277 (± 31.4) 776 (± 19.1) p >0.01 feels hesitant or embarrassed to see a doctor if experiencing pain in reproductive area 4,492 (± 56.5) 1,733 (± 43.9) 2,759 (± 69.0) p >0.01 gender awareness mean (sd), (range 1–4) 3.1 (± .7) 2.8 (±0.71) 3.4 (± 0.55) p >0.01 favorable attitudes to drug use mean (sd), (range 1–5) 2.07 (± 0.5) 2.16 (± 0.54) 1.99 (± 0.45) p >0.01 sources of hiv information n (%) parent/s sibling/s friend/s relatives teachers books, magazines, or internet mass media (tv or radio) health centres 3,411 (42) 3,603 (44.3) 5,153 (63.4) 2,313 (28.5) 5,984 (73.6) 6,941 (85.4) 6,628 (81.5) 5,119 (63) 1,362 (33.5) 1,578 (38.8) 2,679 (65.9) 1,339 (32.9) 3,030 (74.6) 3,519 (86.6) 3,372 (83.0) 2,492 (61.3) 2,049 (50.4) 2,025 (49.8) 2,474 (60.9) 974 (24.0) 2,954 (72.7) 3,422 (84.2) 3,256 (80.1) 2,627 (64.6) p >0.01 p >0.01 p >0.01 p >0.01 t-test 3.73 p >0.05 p >0.01 p >0.05 currently smokes 1,312 (16.14) 1,113 (27.4) 199 (4.9) p >0.01 ever drank alcohol 2,296 (28.24) 1,500 (36.9) 796 (19.6) p >0.01 sd = standard deviation. esra m. al-khasawneh, leyla ismayilova, vidya seshan, olimat hmoud and nabila el-bassel clinical and basic research | 237 table 3: regression analysis of factors associated with human immunodeficiency virus knowledge among jordanian youth (n = 8,128) variables unstandardised coefficients p value/t-test b se (constant) 5.79 0.28 p >0.01 female -0.51 0.07 p >0.01 age ages 14–16 years (ref.) ages 17–19 years ages 20–25 years 1.0 0.09 0.11 0.08 0.14 1.14 0.78 level of education basic education (ref.) secondary education vocational education college education university education 1.0 -0.12 -0.13 0.52 0.51 0.09 0.17 0.18 0.14 -1.32 -0.79 p >0.05 p >0.01 number of rooms in home 0.06 0.01 p >0.01 number of siblings -0.05 0.01 p >0.01 region central (ref.) north south 1.0 -0.33 -0.41 0.07 0.1 p >0.01 p >0.01 place of residence city (ref.) village badia or camp 1.0 -0.35 -0.07 0.07 0.14 p >0.01 -0.47 maternal level of education illiterate basic secondary college or university 1.0 -0.18 -0.14 0.42 0.11 0.11 0.13 1.6 1.23 p >0.01 paternal level of education illiterate basic secondary college or university 1.0 -0.07 -0.05 0.14 0.15 0.15 0.16 -0.46 -0.32 0.89 favourable attitudes toward drug use -0.38 0.06 p >0.01 gender awareness 0.31 0.04 p >0.01 sources of hiv information parent/s -0.25 0.06 p >0.01 sibling/s 0.18 0.06 p >0.05 other relatives -0.03 0.06 -0.53 friend/s 0.28 0.07 p >0.01 teachers 0.48 0.07 p >0.01 tv or radio 0.35 0.09 p >0.01 books, magazines, or internet 0.74 0.10 p >0.01 health centres -0.18 0.06 p >0.05 attended lectures on aids 0.72 0.06 p >0.01 fear of getting aids -0.27 0.06 p >0.01 hesitation to see a doctor -0.001 0.06 -0.02 risk behaviours currently smokes cigarettes ever drank alcohol 0.2 0.01 0.08 0.07 p >0.1 0.09 b= regresion coefficient; se = standard error. predictors of human immunodeficiency virus knowledge among jordanian youths 238 | squ medical journal, may 2013, volume 13, issue 2 and b = -0.41; p <0.001). respondents living in villages demonstrated a lower level of knowledge (b = -0.35; p <0.001) as compared to respondents from cities. however, the residents of the badia or camps did not differ significantly from their urban counterparts in their levels of hiv knowledge. higher levels of maternal education, namely college or university education, were associated with an increased knowledge of hiv (b = 0.42; p <0.001). the level of paternal education did not demonstrate any significant relationships with the level of hiv knowledge. receiving information from parents (b = -0.25; p <0.001) or health centres (b = -0.18; p <0.01) was associated with a lower (or incorrect) level of hiv knowledge. the sources of information that showed the strongest contribution to accurate hiv knowledge were informational materials such as books, magazines, and the internet (b = 0.74; p <0.001) and teachers (b = 0.48; p <0.001). receiving information from peers, including siblings (b = 0.18; p <0.01) and friends (b = 0.28; p <0.001), also contributed to higher levels of hiv knowledge, but the effect was lower when compared to information derived from educational materials and teachers. attending lectures on hiv/aids was among the strongest predictors of a high level of hiv knowledge (b = 0.72; p <0.001). having more supportive attitudes toward gender equality was associated with high hiv knowledge (b = 0.31, p <0.001), whereas attitudes justifying drug use showed an inverse relationship with hiv knowledge (b = -0.38, p <0.001). discussion this is the first research study that examines hiv knowledge among a random sample of youths recruited from all administrative districts of jordan. using this national sample, this study described youths’ levels of hiv knowledge, identified the most commonly held perceptions and misperceptions regarding hiv, and identified significant predictors of hiv knowledge among young people in jordan. the findings of the present study suggest an improvement in the level of hiv knowledge over the past decade; however, the level of hiv knowledge is still insufficient. the low levels of hiv knowledge among jordanian youth in this study were similar to the results from other arab countries, including lebanon, yemen, and egypt.9,13–15 youths in the middle eastern region lack access to information on sexual health, including stis and hiv.9 a systematic review showed that behavioural research on hiv/ aids in jordan is limited, even when compared to other middle eastern countries.23 however, youth in other muslim countries in the region, such as iran, turkey and morocco, demonstrated a greater awareness of hiv, including more accurate knowledge about the method of hiv transmission and protection.3,16–20 analysis of a global school-based student health survey among 13to 15-year-old adolescents from the middle east and north africa between 2004 to 2008 showed that hiv/aids-related knowledge varied significantly according to countries and gender.24 such differences might exist for different reasons. despite the similar taboos on talking about sexuality within the family in these cultures, the hiv information provided through educational institutions and youth-friendly clinics created better access to information among youth in these countries.3,20 this study confirmed that the strongest predictor of accurate hiv knowledge among youths in jordan was attending lectures on hiv/aids and receiving information from teachers or books. these findings have significant implications for practice, and support the importance of conducting hiv education programmes for youth. moreover, our finding that a large percentage of youths regard receiving information from parents to be associated with incorrect hiv knowledge might be explained by barriers in communication between parents and their adolescents. additionally, a lack of parental knowledge of hiv and safe sexual behaviours may have contributed to youths’ low confidence in their parents’ information. finally, youths may be reluctant to ask questions that their parents may interpret as an indication that their children are sexually active. this last finding may be explained by looking into gender inequalities. in the literature, gender inequalities in middle eastern countries were reported as a barrier to acquiring information on sexual and reproductive health.9,21 our findings were consistent with the literature. first, females in this study demonstrated a significantly lower level of hiv knowledge, which might be the result of societal gender inequalities. women in the middle east are expected to be timid, and neither esra m. al-khasawneh, leyla ismayilova, vidya seshan, olimat hmoud and nabila el-bassel clinical and basic research | 239 to negotiate regarding their reproductive or sexual health, nor to be knowledgeable about sexual health or be sexually active.22 second, positive attitudes toward gender equality were associated with a higher level of hiv knowledge. the literature reports that gender inequalities undermine the status of women and reinforce the power imbalances associated with health vulnerabilities and increased risky sexual behaviours.21 our findings were consistent with the international literature, in which young people who have favourable gender attitudes have demonstrated better hiv knowledge. third, a higher level of maternal education was a significant factor associated with a higher level of hiv knowledge. the educational level of the father did not have a significant impact on his child’s level of hiv knowledge. conclusion this study’s findings have significant implications for the development of health education programmes in jordan. most hiv education programmes in jordan target youth at universities and colleges, and those who are living or studying in urban areas or camps. however, youth living in northern and southern regions, as well as those in vtcs usually do not receive enough attention from organisations that provide hiv education. poor hiv knowledge among these groups might contribute to higher risk sexual behaviours and increase youths’ risk of hiv. teachers and lecturers can play significant roles in educating young people about risky sexual behaviours. the benefits of sex education programmes can be enhanced by targeting parents and teachers. a governmental commitment to encouraging national programmes that provide equal healthcare and education to youth in different regions of the country is important. references 1. roudi-fahimi f, ashford l. sexual & reproductive health in the middle east and north africa: a guide for reporters. washington: population reference burea, 2008. 2. worldwide governance indicators. jordan, 19962010. from: http://info.worldbank.org/governance/ wgi/sc_chart.asp accessed: jul 2012. 3. assaad r, roudi-fahimi f. youth in the middle east and north africa: demographic opportunity or challenge. population reference bureau, mena policy brief, 2007. 4. unaids. global report. from: http://www.unaids. org/en/media/unaids/contentassets/documents/ epidemiology/2012/gr2012/20121120_unaids_ global_report_2012_en.pdf. accessed jul 2012. 5. ministry of health (moh), jordan. aids statistics 2009. amman: moh, 2009. 6. ministry of health & un general assembly special session. country progress report hashemite kingdom of jordan report to the secretary general of the united nations on the united nations general assembly special session on hiv/aids, january 2008–december 2009. new york: united nations, 2009. 7. roudi-fahimi f. time to intervene: preventing the spread of hiv/aids in the middle eastern and north african populations. washington, dc: population reference bureau, 2007. 8. petro-nustas w. university students' knowledge of aids. int j nurs stud 2000; 37:423–33. 9. dejong j, el-khoury g. reproductive health of arab young people. bmj 2006; 333:849. 10. kleffner n. understanding arabs: a guide for modern times. 4th ed. boston: intercultural press, 2010. 11. olimat h. jordanian youth and hiv/aids: knowledge, attitudes and vulnerability. report submitted to unesco office, amman, jordan, 2010. 12. hijawi b, rahhal a. surveillance of risk behavior in populations potentially at risk of sexually transmitted infections in jordan. amman: world health organization, jordan, 2008. 13. kahhaleh j, el-nakib m, jurjus a. knowledge, attitudes, beliefs and practices in lebanon concerning hiv/aids, 1996–2004. east mediterr health j 2009; 15:921. 14. al-serouri a, anaam m, al-iryani b, al-deram a, ramaroson s. aids awareness and attitudes among yemeni young people living in high-risk areas. east mediterr health j 2010; 16:242–50. 15. refaat a. practice and awareness of health risk behaviour among egyptian university students. east mediterr health j 2004; 10:72–81. 16. tavoosi a, zaferani a, enzevaei a, tajik p, ahmadinezhad z. knowledge and attitude towards hiv/aids among iranian students. bmc pub health 2004; 4:17. 17. tehrani f, malek-afzali h. knowledge, attitudes and practices concerning hiv/aids among iranian atrisk sub-populations. east mediterr health j 2008; 14:143. 18. yazdi c, aschbacher k, arvantaj a, naser h, abdollahi e, asadi a, et al. knowledge, attitudes and sources of information regarding hiv/aids in predictors of human immunodeficiency virus knowledge among jordanian youths 240 | squ medical journal, may 2013, volume 13, issue 2 iranian adolescents. aids care 2006; 18:1004–10. 19. koksal s, namal n, vehid s, yurtsever e. knowledge and attitude towards hiv/aids among turkish students. infec dis j pak 2005; 14:118–23. 20. ungan m, yaman h. aids knowledge and educational needs of technical university students in turkey. patient educ couns 2003; 51:163–7. 21. shawky s, soliman c, sawires s. gender and hiv in the middle east and north africa: lessons for low prevalence scenarios. j acquir immune defic syndr 2009; 51:s73–4. 22. remien r, chowdhury j, mokhbat j, soliman c, adawy m, el-sadr w. gender and care: access to hiv testing, care, and treatment. j acquir immune defic syndr 2009; 51:s106. 22. alkhasawneh e, ismayilova l, olimat h, el-bassel n. social and behavioural hiv/aids research in jordan: a systematic review. east mediterr health j 2012; 18:487–94. 23. boneberger a, ruckinger s, guthold r, kann l, riley l. hiv/aids related knowledge among schoolgoing adolescents from the middle east and north africa. sex health 2012; 9:196–8. أحباث السرطان يف العامل العريب استعراض منشورات من سبعة بلدان بني الفرتة 2000-2013 رندة ربحي حمادة، �سيف الربقان، عبلة ال�سباعي abstract: this review aimed to examine trends in cancer research in the arab world and identify existing research gaps. a search of the medline® database (national library of medicine, bethesda, maryland, usa) was undertaken for all cancer-related publications published between january 2000 and december 2013 from seven countries, including bahrain, kuwait, iraq, lebanon, morocco, palestine and sudan. a total of 1,773 articles were identified, with a significant increase in yearly publications over time (p <0.005). only 30.6% of the publications included subjects over the age of 50 years old. there was a dearth of cross-sectional/correlational studies (8.8%), randomised controlled trials (2.4%) and systematic reviews/meta-analyses (1.3%). research exploring cancer associations mainly considered social and structural determinants of health (27.1%), followed by behavioural risk factors (14.1%), particularly tobacco use. overall, more cancer research is needed in the arab world, particularly analytical studies with high-quality evidence and those focusing on older age groups and associations with physical activity and diet. keywords: chronic diseases; cancer; research; publications; arab world. امللخ�ص: يهدف هذا اال�ستعرا�س اإىل درا�سة توجهات اأبحاث ال�رشطان يف العامل العربي وحتديد الثغرات البحثية القائمة. مت اإجراء بحث ن�رشت والتي ال�رشطان ملطبوعات االأمريكية( املتحدة الواليات ماريالند، بيثي�سدا، الوطنية، الطب )مكتبة ميدالين بيانات قاعدة يف ما حتديد مت وال�سودان. وفل�سطني واملغرب ولبنان والعراق والكويت البحرين وهي بلدان، �سبعة من 2013 ودي�سمرب 2000 يناير بني جمموعه 1,773 مقالة، مع وجود زيادة ملحوظة يف املن�سورات ال�سنوية مبرور الوقت )p <0.005(. وجد اأن فقط %30.6 من املن�سورات )2.4%( الع�سوائية ال�رشيرية التجارب ،)8.8%( املقطعية/الرتابطية الدرا�سات يف نق�س هناك كان �سنة. 50 �سن فوق املر�سى �سملت ب�سفة ت�سمل والتي ال�رشطان ارتباطات ا�ستك�سفت التي البحوث ومثلت .)1.3%( التلوي التحليل املنهجية/ودرا�سات واال�ستعرا�سات اأ�سا�سية املحددات االجتماعية والهيكلية لل�سحة اكرب الن�سب )%27.1(، تليها تلك املرتبطة بعوامل اخلطر ال�سلوكي بن�سبة )%14.1(، وال �سيما تعاطي التبغ. وب�سفة عامة، فاأن هناك حاجة اإىل املزيد من البحوث حول ال�رشطان يف العامل العربي، وخا�سة الدرا�سات التحليلية ذات االأدلة عالية اجلودة وتلك التي تركز على الفئات العمرية االأكرب �سنا واأرتباط ال�رشطان مع الن�ساط البدين والنظام الغذائي. الكلمات املفتاحية: االأمرا�س املزمنة؛ �رشطان؛ بحوث؛ املن�سورات؛ العامل العربي. cancer research in the arab world a review of publications from seven countries between 2000–2013 *randah r. hamadeh,1 saif m. borgan,2 abla m. sibai3 review sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e147–154, epub. 20 jun 17 submitted 30 aug 16 revisions req. 7 nov 16 & 2 jan 17; revisions recd. 1 dec 16 & 12 jan 17 accepted 26 jan 17 doi: 10.18295/squmj.2016.17.02.003 cancer presents a global public health problem and extensively impacts healthcare costs.1–3 in 2013, there were 14.9 million new cancer cases and 8.2 million cancer-attributable deaths; in addition, global cancer mortality increased by 25.0% from 1990, with a projected incidence of 23.6 million cases/year by 2030.1,2,4 the burden of cancer is disproportionately greater in countries with a low-to-medium human development index, with approximately 70.0% of all cancer deaths and 60.0% of disability-adjusted life years occurring in developing countries.2–6 moreover, nine of the 10 countries with the highest age-standardised female cancer mortality rates worldwide are developing nations.3 although many western countries have rapidly established national and regional cancer control initiatives, the most vulnerable regions for cancer mortality—such as those in the arab world—have yet to institute clear or reliable cancer resources.7–9 for example, there are few population-based cancer registries in arab countries, with only 5.0% of asian populations and 2.0% of african populations reporting high-quality incidence data in comparison to cancer registries in australia and new zealand, which cover 100% of their total populations.10 additionally, while 80.0% of countries in the eastern mediterranean region have national cancer control policies, only 45.0% are operational.11 in general, healthcare systems in this region are inadequately equipped to deal with chronic diseases, such as cancer, which necessitate long and costly management facilities, especially in countries with political unrest. 1department of family & community medicine, college of medicine & medical sciences, arabian gulf university, manama, bahrain; 2department of pulmonary & critical care medicine, university of maryland, college park, maryland, usa; 3department of epidemiology & population health, american university of beirut, beirut, lebanon *corresponding author e-mails: randah@agu.edu.bh and randah.hamadeh@gmail.com cancer research in the arab world a review of publications from seven countries between 2000–2013 e148 | squ medical journal, may 2017, volume 17, issue 2 the commonest cancers worldwide for both genders are breast, lung, colorectal, prostate and stomach cancers.3,4,10 in the middle eastern and north african (mena) region, similar trends exist, although bladder and stomach cancers constitute the fifth and sixth most common forms of cancer, regardless of gender.3 among gulf cooperation council countries, the most frequent cancers among males are colorectal cancer, non-hodgkin’s lymphomas, lung cancer and liver cancer, while breast cancer is most common among females, followed by thyroid and colorectal cancers and non-hodgkin’s lymphomas.12,13 however, despite similar sociocultural environments, cancer incidence rates vary widely within and between arab populations.14 cancer research is vital for the development of effective, specific and sustainable healthcare policies. within this context, this article aimed to examine the landscape of cancer research in seven selected arab countries to identify publication trends as well as gaps and opportunities for future research. methods a scoping review methodology was used to analyse articles published on non-communicable diseases (ncds) from bahrain, kuwait, iraq, lebanon, morocco, palestine and sudan.15 these seven countries were selected to represent various stages of demographic and epidemiological transition as well as socioeconomic development. the selected countries were categorised into low-middle income countries (lmics), upper-middle income countries (umics) and high-income countries (hics) based on their gross domestic product (gdp); as such, sudan, palestine and morocco were classified as lmics while iraq and lebanon were designated as umics and bahrain and kuwait as hics.16 four conditions were defined as ncds, namely cardiovascular diseases, cancer, chronic obstructive pulmonary disease and type 2 diabetes mellitus. the medline® database (national library of medicine, bethesda, maryland, usa) was used to systematically search for all ncd-related articles published between january 2000 and december 2013. the search strategy consisted of a combination of key terms related to the four ncd conditions and their associated risk factors. further details on the search strategy have been published elsewhere using the same dataset.17 briefly, several reviewers independently assessed each article to determine whether it met the inclusion criteria and was relevant. articles were included if the content addressed ncds and/or ncd risk factors, was related to human health or health systems and if the article pertained to or originated from one of the seven selected arab countries. any discrepancies in the selection of articles were systematically addressed and discussed in a group before a communal decision was reached. during the initial database search, 9,162 publications were identified, of which 1,212 were duplicates and were removed. subsequently, 3,466 publications were excluded as they were deemed irrelevant based on screening of the abstract and title and another 708 papers were excluded as they did not meet the inclusion criteria upon reading the full text. finally, 2,003 other ncd-related articles were excluded as the main outcome was not cancer. this yielded a total of 1,773 cancer-related publications which were included in the final analysis. the full text and abstract of each article was downloaded, if available, including article-specific information (e.g. journal title, year of publication, authors’ names and first authors’ affiliation details). data regarding the research setting, design and content were independently extracted from each article using a standardised form. the research setting was described according to whether it was laboratory-, hospital/clinic-, patientor populationbased. publications were classified into four major types: descriptive (i.e. case reports, case series and correlational/cross-sectional studies), analytic (i.e. cohort studies, case-control studies and randomised control trials [rcts]), reviews (i.e. descriptive literature reviews and systematic reviews/metaanalyses) and laboratory studies (i.e. pathology/in vivo studies). studies with qualitative and/or mixed methods and commentary articles/letters to editors were given a separate grouping as there were very few of these types of articles. risk factors identified during a review of the content of each article were grouped into broad categories, including social/structural determinants of health (e.g. demographic/socioeconomic variables or access to care/health system research), behav ioural/lifestyle-related variables (e.g. tobacco and alcohol use, nutrition/diet, salt intake and physical activity) and physiological factors (e.g. anthropometric measurements, obesity, diabetes, hypertension or cholesterol). other information was also noted, including the age group of the subjects, whether the article had a public health focus as opposed to a clinical one, whether the authors’ affiliations indicated collaborations with non-academic individuals/institutions, such as governmental or nongovernmental organisations (ngos), and the scope of the journals (either local, regional or international). first authors’ affiliations were analysed according to randah r. hamadeh, saif m. borgan and abla m. sibai review | e149 whether the author was associated with a clinical or academic institution. in order to eliminate the effect of more populous countries, the publication rate per million people was estimated for each country. results were presented using numbers and percentages. the trends over time were first assessed for all publications and then stratified by country and article type. all data were recorded in a database before being transferred to the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa) for statistical analysis. correlation regression, chisquared and linear regression tests were used, as appropriate. a p value of <0.050 was considered statistically significant. results of the 1,773 publications identified, 1,611 (90.9%) were published in international journals, with 81 (4.6%) articles each published in regional and local journals, respectively. the proportion of international publications out of the total number of publications per country varied, with 98.6% in morocco, 93.1% in palestine, 89.8% in lebanon, 85.5% in kuwait, 85.3% in sudan, 83.8% in bahrain and 66.0% in iraq. the majority of the articles were published in english (n = 1,368; 77.2%). of the articles published in other languages, most were from morocco and were published in french (55.0%). a significant positive linear relationship was observed between year and total number of publications (r2 = 0.791; p <0.005), with a 132.9% increase in publications during the last seven years of the review period compared to the first seven years [figure 1a]. of the total number of publications, 723 were from morocco (40.8%), 449 were from lebanon (25.3%), 337 were from kuwait (19.0%), 103 were from iraq (5.8%), 95 were from sudan (5.4%), 37 were from bahrain (2.1%) and 29 were from palestine (1.6%). however, lebanon had the highest publication rate per million people (98.7), followed by kuwait (89.8), bahrain (27.2), morocco (21.3), palestine (6.8), iraq (3.0) and sudan (2.4), with a significant difference across countries (p <0.001) [figure 1b]. with the exception of iraq and sudan, the highest proportions of articles in all countries were published in 2013, with the greatest increase observed in palestine [figure 2]. in total, the most common types of research published were case reports (34.8%) and laboratory studies (15.5%), whereas very few systematic reviews/ meta-analyses (1.3%) were published. over half of all publications (51.0%) were descriptive in design, with morocco having the highest proportion of descriptive articles out of their total number of publications (72.3%). articles with an analytical research design formed 18.2% of the publication pool, with iraq having the highest proportion out of their total number of publications (29.1%). of the 43 rcts figure 1: number of cancer publications from selected arab countries between 2000–2013 (a) per year and (b) per million people per country (n = 1,773). figure 2: percentage of yearly publications out of the total number of cancer publications from selected arab countries between 2000–2013 (n = 1,773). cancer research in the arab world a review of publications from seven countries between 2000–2013 e150 | squ medical journal, may 2017, volume 17, issue 2 published (2.4%), 55.8% were from lebanon, 27.9% were from kuwait, 7.0% were from morocco and 4.7% each were from iraq and sudan. of the total publications per country, bahrain and palestine had the highest proportions of reviews (27.0% and 24.1%, respectively) while palestine had the highest proportion of laboratory studies (41.4%) [table 1]. a significant positive linear relationship was noted between the year and rct publications (r2 = 0.319; p = 0.035). when grouping countries by gdp category, lmics more frequently published descriptive research (68.7% versus 35.8%, respectively) and less frequently published laboratory studies (8.5% versus 25.9%, respectively) or analytical research (13.9% versus 22.7%, respectively) compared to hics (p <0.001). the majority of publications with ascertained settings were hospital-based (79.8%), followed by laboratory-based (14.1%) and population-based (5.1%) articles. according to the first author’s affiliations, there was an overall comparable proportion of associations with hospital (41.6%) and academic (40.3%) institutions. however, palestine and sudan had the highest proportions of first authors affiliated with universities (86.2% and 81.1%, respectively), while morocco had the lowest (16.3%); the corresponding percentages for iraq, kuwait, lebanon and bahrain were 77.7%, 54.6%, 48.8% and 32.4%, respectively. collaboration with non-academic ngo and governmental organisations was evident in 6.0% of all publications. articles published in collaboration with non-academic authors were most prevalent from sudan (22.1%), followed by bahrain (16.2%), iraq (7.8%), kuwait (7.1%), palestine (6.9%), lebanon (4.5%) and morocco (3.5%). of the total number of publications, 16.6% had a public health focus with 51.7% in palestine, 42.1% in sudan, 35.1% in bahrain, 21.1% in kuwait, 18.4% in iraq, 14.9% in lebanon and 9.7% in morocco. table 1: cancer publications from selected arab countries between 2000–2013 by research design and country (n = 1,773) research design n (%) bahrain iraq kuwait lebanon morocco palestine sudan total descriptive case reports 12 (32.4) 8 (7.8) 79 (23.4) 116 (25.8) 396 (54.8) 1 (3.4) 4 (4.3) 616 (34.8) case series 0 (0.0) 6 (5.8) 9 (2.7) 15 (3.3) 88 (12.2) 0 (0.0) 13 (13.8) 131 (7.4) cross-sectional/ correlational studies 5 (13.5) 19 (18.4) 29 (8.6) 28 (6.2) 38 (5.2) 4 (13.8) 33 (35.1) 156 (8.8) analytical case-control studies 1 (2.7) 11 (10.7) 17 (5.0) 13 (2.9) 26 (3.6) 1 (3.4) 16 (17.0) 85 (4.8) cohort studies 6 (16.2) 17 (16.5) 49 (14.5) 53 (11.8) 64 (8.9) 3 (10.3) 2 (2.1) 194 (11.0) rcts 0 (0.0) 2 (1.9) 12 (3.6) 24 (5.3) 3 (0.4) 0 (0.0) 2 (2.1) 43 (2.4) reviews systematic reviews/ meta-analyses 1 (2.7) 3 (2.9) 2 (0.6) 9 (2.0) 5 (0.7) 3 (10.3) 0 (0.0) 23 (1.3) descriptive literature reviews 9 (24.3) 4 (3.9) 42 (12.5) 90 (20.0) 39 (5.4) 4 (13.8) 12 (12.8) 200 (11.3) laboratory studies pathology/in vivo studies 3 (8.1) 27 (26.2) 94 (27.9) 80 (17.8) 49 (6.8) 12 (41.4) 10 (10.6) 275 (15.5) other commentaries/letters to the editor 0 (0.0) 6 (5.8) 4 (1.2) 14 (3.1) 9 (1.2) 1 (3.4) 2 (2.1) 36 (2.0) qualitative and/ or mixed methods studies 0 (0.0) 0 (0.0) 0 (0.0) 7 (1.6) 5 (0.7) 0 (0.0) 0 (0.0) 12 (0.7) total 37 (2.1) 103 (5.8) 337 (19.0) 449 (25.4) 722 (40.8) 29 (1.6) 94 (5.3) 1,771* rct = randomised control trial. *study design was not specified in two publications (one from morocco and one from sudan). randah r. hamadeh, saif m. borgan and abla m. sibai review | e151 out of 1,179 publications (66.5%) involving human subjects, 73.4% included adult participants aged ≥18 years old and 10.7% involved all age groups. the most commonly included age group was 18–50 years (37.6%), whereas only 30.6% of the articles examined older individuals (>50 years old). a total of 780 publications examined determinants of cancer, of which 211 publications (27.1%) investigated social/ structural determinants of health, 41 articles (5.3%) examined physiological risk factors and 110 identified behavioural risk factors (14.1%) [figure 3a]. among physiological risk factors, obesity was the most common (65.2%), followed by hypertension (34.8%), cholesterol (13.0%) and metabolic syndrome (4.3%). the most common behavioural risk factors studied were tobacco use (71.2%) and nutrition (29.7%) [figure 3b]. discussion although cancer poses a global healthcare burden, research efforts in this field remain limited in many developing countries. to the best of the authors’ knowledge, this is the first scoping review of cancer research in the arab world and sheds light on the paucity of cancer publications in this region as well as providing insight into research areas needing greater focus. a consistent increase was observed in cancer research in the selected arab countries from the beginning of the 21st century until 2013. however, the total number of publications was considerably lower than in other parts of the world; while the current review identified a total of 1,773 articles published in seven arab countries over 14 years, there was a yearly average of 10,293 cancer publications in the usa, 9,962 in europe and 2,225 in japan between 2000–2008.18 the vast difference in research publications from the arab region could be explained by several factors. first, there are fewer researchers in arab countries in comparison to western countries, with arab researchers in 2013 forming a mere 1.9% of all researchers worldwide, a decrease from 2.2% in 1996.19 second, national and regional spending on research and development is relatively modest; in 2013, the regional gross expenditure on research and development (gerd) by all arab states was usd $15.5 million, considerably lower than that of the european union and north america (usd $282.0 million and usd $427.0 million, respectively), and constituting only 1.0% of total global research expenditures.19 in 2011, the hic nations of bahrain and kuwait invested 0.04% and 0.1%, respectively, of their gdp on gerd, compared to 2.8% in the usa and 3.3% in japan.19 other reasons have also been proposed to explain low research output in the mena region. lages et al. reported that conducting research in this region could be challenging due to a lack of access to reliable and valid data, deficiencies in research support infrastructure, language barriers and a lack of networking among researchers.20 political instability has also been hypothesised to affect research publications, as demonstrated in uganda and kenya.21–23 unfortunately, political unrest may result in a reduction in funding, massive inand outmigration, strikes and violence. while no studies have yet systematically investigated the effect of political instability on research production in the arab world, output trends from the current review revealed a clear drop in cancer-related publications from iraq, sudan and bahrain coinciding with specific periods of civil unrest in these countries. more research is warranted to explore reasons for low cancer research output in the arab world and the possible effect of political unrest. while all types of research designs are vital in the field of oncology, the current review noted a scarcity of analytical studies and systematic reviews/ meta-analyses from the selected arab countries. in addition, it was observed that lmics were more likely to publish descriptive research, while hics were more likely to conduct laboratory and analytic research. high-evidence analytical research studies, such as figure 3: proportion of (a) overall risk factors and (b) behavioural risk factors identified in cancer publications from selected arab countries between 2000–2013.* *percentages do not add up to 100% as multiple factors were sometimes examined in a single article. cancer research in the arab world a review of publications from seven countries between 2000–2013 e152 | squ medical journal, may 2017, volume 17, issue 2 rcts, may be difficult to conduct in lmics due to weak infrastructure, low research spending and the cultural attitudes of physicians and patients towards clinical research.24–26 currently, rcts remain the gold standard for analysing healthcare interventions, especially for cancer treatments which are becoming more specific with varying efficacies and side-effect profiles across different ethnic populations.27,28 thus, it is vital that arab populations be included during drug research and development. furthermore, health ministries in the arab world should encourage and facilitate analytical cancer research. while the incidence of cancer increases with age and occurs predominately in older individuals, patients over the age of 65 years are rarely included in oncology clinical trials.29,30 in the current review, the most commonly included age group was 18–50 years, with those >50 years old comprising the minority of subjects. this lack of representation of older age groups may negatively impact cancer treatments for the elderly.31 a hesitancy to include older participants could be attributed to perceptions by physicians of a lack of tolerance on the part of older patients, varying drug metabolisms and a lack of evidence of treatment efficacy among this population.31 conducting geriatric specific studies in the arab world could therefore provide new insights regarding the diagnosis and treatment of cancer in this population. although cancer poses a major public health challenge, surprisingly few of the publications identified in the current review were found to be focused on public health.1,4 primary prevention of cancer through lifestyle modifications is important to reduce the global cancer burden, as an estimated 35% of cancer deaths may be attributable to modifiable risk factors such as smoking, alcohol use, diet, obesity and unprotected sexual activity.32 of note, the burden of a high body mass index has increased over the last 23 years and is currently the leading risk factor for cancer among women, especially in north and south america and the mena region.33 the prevalence of behavioural risk factors for ncds is alarmingly high in the arab region, with overall limited governmental response measures; for example, only bahrain, iraq, morocco and sudan of the countries included in the present review have established national cancer control policies.34,35 moreover, preventative cancer control policies targeting behavioural risk factors are only present in certain arab countries; for instance, only bahrain, iraq, lebanon, morocco and sudan have operational policies, strategies or action plans in place to reduce the tobacco burden, with bahrain, iraq and sudan also having primary prevention policies for obesity and physical inactivity.35 in the current review, behavioural risk factors for cancer were examined in only 14.1% of publications, with the majority focusing on tobacco use as a sole risk factor and very few examining physical inactivity and salt/sodium intake. future studies should therefore address diet, obesity and physical inactivity in cancer risk factor epidemiological studies of arab populations. academia is a highly competitive curiositydriven field that is privileged to have a large degree of research freedom, whereas non-academic research may be driven by other factors such as policies and market demands.34,36,37 nevertheless, both sectors are vital for the advancement of clinical research and, in many instances, are complementary.36 in the present review, very few research publications involved collaborative efforts between researchers from educational/academic settings and those from ngos and governmental institutions. while the ultimate responsibility for advancing medical knowledge through research lies on academic institutions, collaboration between academic researchers, the public sector and ngos is conducive and necessary for the translation of research into action, for instance in terms of national policies and programmes. the findings of this review need to be considered in the light of certain limitations. the search strategy was restricted to the medline® database (national library of medicine); as such, articles published in local and regional journals were likely excluded, particularly those written in arabic, which may have led to an underestimation of the total number of published studies from this region. additionally, electronic searches using specific search terms do not always identify all eligible publications; for example, in a cochrane review, hopewell et al. found that an electronic search in the medline® database (national library of medicine) identified only 55% of actual rcts compared to hand-searching, which identified 92–100%.38 it is also important to note that the present review drew on data from only seven arab countries and, while these countries were selected to represent a range of demographic characteristics, epidemiological transitions and political stability, the current findings therefore cannot be generalised to the entire arab region. conclusion cancer research is increasing in the arab world. however, the total research output remains low when compared to other regions. the current review identified several gaps in research, including a deficiency in research involving elderly populations and investigating specific risk factors such as diet randah r. hamadeh, saif m. borgan and abla m. sibai review | e153 and physical activity. in addition, there was a dearth of systematic reviews/meta-analyses and analytical studies; further studies are therefore recommended to identify reasons for the scarcity of these types of research in this region. furthermore, increased collaboration between ngos, governmental agencies and academic institutions is key for the implementation of national evidence-based healthcare policies specific to cancer control. cancer researchers and funding agencies are encouraged to consider the gaps identified in this review in order to better guide future cancer research. a c k n o w l e d g e m e n t s the authors wish to acknowledge the help of the ncd scoping review working group of the faculty of health sciences at the american university of beirut, beirut, lebanon. in particular, the authors thank dr. sawsan abdulrahim, dr. farah naja, dr. shadi saleh and dr. samer jabbour, as well as the various research assistants involved, especially mr. anthony rizk. f u n d i n g this work was funded with the aid of a grant from the international development research centre, ottawa, ontario, canada (grant #106981-00). references 1. ncd alliance. cancer burden. from: www.ncdalliance.org/ cancer accessed: jan 2017. 2. terzic a, waldman s. chronic diseases: the emerging pandemic. clin transl sci 2011; 4:225–6. doi: 10.1111/j.1752-8062.2011. 00295.x. 3. international agency for research on cancer. globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. from: http://globocan.iarc.fr/pages/fact_ sheets_population.aspx accessed: jan 2017. 4. global burden of disease collaboration; fitzmaurice c, dicker d, pain a, hamavid h, moradi-lakeh m, et al. the global burden of cancer 2013. jama oncol 2015; 1:505–27. doi: 10.1001/ jamaoncol.2015.0735. 5. bray f, jemal a, grey n, ferlay j, forman d. global cancer transitions according to the human development index (20082030): a population-based study. lancet oncol 2012; 13:790– 801. doi: 10.1016/s1470-2045(12)70211-5. 6. world health organization regional office for africa. building capacity in cancer registration. from: www.afro. who.int/en/clusters-a-programmes/dpc/non-communicabledis e a s e smanagementndm/np c-fe ature s/3221-buildingcapacity-in-cancer-registration.html accessed: jan 2017. 7. european commission. european partnership action against cancer: contribution of eu funded research. from: http:// e uropa .e u/rapid/pre ss -rele a s e_me mo-09-294_en.htm accessed: jan 2017. 8. the world bank. updated income classifications. from: http:// blogs.worldbank.org/opendata/updated-income-classifications accessed: jan 2017. 9. batouli a, jahanshahi p, gross cp, makarov dv, yu jb. the global cancer divide: relationships between national healthcare resources and cancer outcomes in high-income vs. middleand low-income countries. j epidemiol glob health 2014; 4:115–24. doi: 10.1016/j.jegh.2013.10.004. 10. ferlay j, soerjomataram i, dikshit r, eser s, mathers c, rebelo m, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012; int j cancer 2015; 136:e359–86. doi: 10.1002/ijc.29210. 11. world health organization. cancer control: a global snapshot in 2015. from: www.who.int/cancer/cancer_control_snapshot _in_2015.pdf?ua=1 accessed: jan 2017. 12. world health organization regional office for the eastern mediterranean. cancer registry in the region. from: www.emro. who.int/noncommunicable-diseases/information-resources/ cancer-registry.html accessed: jan 2017. 13. gulf center for cancer control & prevention. ten-year cancer incidence among nationals of the gcc states: 1998-2009. from: www.moh.gov.bh/content/files/publications/gcc%20 cancer%20incidence%202011.pdf accessed: jan 2017. 14. salim ei, moore ma, al-lawati ja, al-sayyad j, bazawir a, bener a, et al. cancer epidemiology and control in the arab world: past, present and future. asian pac j cancer prev 2009; 10:3–16. 15. arksey h, o’malley l. scoping studies: towards a methodological framework. int j soc res methodol 2005; 8:19–32. doi: 10.1080/1364557032000119616. 16. the world bank. population, total. from: data.worldbank.org/ indicator/sp.pop.totl accessed: jan 2017. 17. jamaluddine z, sibai am, othman s, yazbek s. mapping genetic research in non-communicable disease publications in selected arab countries: first step towards a guided research agenda. health res policy syst 2016; 14:81. doi: 10.1186/s129 61-016-0153-9. 18. micheli a, di salvo f, lombardo c, ugolini d, baili p, pierotti am. cancer research performance in the european union: a study of published output from 2000 to 2008. tumori 2011; 97:683–9. doi: 10.1700/1018.11081. 19. united nations educational, scientific and cultural organization instutute for statistics. science, technology and innovation: gross domestic expenditure on r&d (gerd), gerd as a percentage of gdp, gerd per capita and gerd per researcher. from: http://data.uis.unesco.org/?queryid=74 accessed: jan 2017. 20. lages cr, pfajfar g, shoham a. challenges in conducting and publishing research on the middle east and africa in leading journals. int mark rev 2015; 32:52–77. doi: 10.1108/imr-122014-0374. 21. mokdad ah, forouzanfar mh, daoud f, el bcheraoui c, moradi-lakeh m, khalil i, et al. health in times of uncertainty in the eastern mediterranean region, 1990-2013: a systematic analysis for the global burden of disease study 2013. lancet glob health 2016; 4:e704–13. doi: 10.1016/s2214109x(16)30168-1. 22. bakamanume bb. political instability and health services in uganda, 1972-1997. east afr geogr rev 1998; 20:58–71. doi: 10.1080/00707961.1998.9756267. 23. house dr, marete i, meslin em. to research (or not) that is the question: ethical issues in research when medical care is disrupted by political action a case study from eldoret, kenya. j med ethics 2016; 42:61–5. doi: 10.1136/medethics 2013-101490. 24. devasenapathy n, singh k, prabhakaran d. conduct of clinical trials in developing countries: a perspective. curr opin cardiol 2009; 24:295–300. doi: 10.1097/hco.0b013e32832af21b. https://doi.org/10.1111/j.1752-8062.2011.00295.x https://doi.org/10.1111/j.1752-8062.2011.00295.x https://doi.org/10.1001/jamaoncol.2015.0735 https://doi.org/10.1001/jamaoncol.2015.0735 https://doi.org/10.1016/s1470-2045%2812%2970211-5 https://doi.org/10.1016/j.jegh.2013.10.004 https://doi.org/10.1002/ijc.29210 https://doi.org/10.1080/1364557032000119616 https://doi.org/10.1186/s12961-016-0153-9 https://doi.org/10.1186/s12961-016-0153-9 https://doi.org/10.1700/1018.11081 https://doi.org/10.1108/imr-12-2014-0374 https://doi.org/10.1108/imr-12-2014-0374 https://doi.org/10.1016/s2214-109x%2816%2930168-1 https://doi.org/10.1016/s2214-109x%2816%2930168-1 https://doi.org/10.1080/00707961.1998.9756267 https://doi.org/10.1136/medethics-2013-101490 https://doi.org/10.1136/medethics-2013-101490 https://doi.org/10.1097/hco.0b013e32832af21b cancer research in the arab world a review of publications from seven countries between 2000–2013 e154 | squ medical journal, may 2017, volume 17, issue 2 25. lang ta, white nj, tran ht, farrar jj, day np, fitzpatrick r, et al. clinical research in resource-limited settings: enhancing research capacity and working together to make trials less complicated. plos negl trop dis 2010; 29:e619. doi: 10.1371/ journal.pntd.0000619. 26. mbuagbaw l, thabane l, ongolo-zogo p, lang t. the challenges and opportunities of conducting a clinical trial in a low resource setting: the case of the cameroon mobile phone sms (camps) trial, an investigator initiated trial. trials 2011; 12:145. doi: 10.1186/1745-6215-12-145. 27. domanski m, mckinlay s. successful randomized trials: a handbook for the 21st century. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2008. p. 13. 28. o’donnell ph, dolan me. cancer pharmacoethnicity: ethnic differences in susceptibility to the effects of chemotherapy. clin cancer res 2009; 15:4806–14. doi: 10.1158/1078-0432.ccr09-0344. 29. unger jm, coltman ca jr, crowley jj, hutchins lf, martino s, livingston rb, et al. impact of the year 2000 medicare policy change on older patient enrollment to cancer clinical trials. j clin oncol 2006; 24:141–4. doi: 10.1200/jco.2005.02.8928. 30. kimmick gg, peterson bl, kornblith ab, mandelblatt j, johnson jl, wheeler j, et al. improving accrual of older persons to cancer treatment trials: a randomized trial comparing an educational intervention with standard information calgb 360001. j clin oncol 2005; 23:2201–7. doi: 10.1200/jco.2005. 01.222. 31. denson ac, mahipal a. participation of the elderly population in clinical trials: barriers and solutions. cancer control 2014; 21:209–14. 32. danaei g, vander hoorn s, lopez ad, murray cj, ezzati m; comparative risk assessment collaborating group (cancers). causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. lancet 2005; 366:1784–93. doi: 10.1016/s0140-6736(05)67725-2. 33. gbd 2015 risk factors collaborators. global, regional, and national comparative risk assessment of 79 behavioral, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the global burden of disease study 2015. lancet 2016; 388:1659–1724. doi: 10.1016/s0140-6736(16)31679-8. 34. rahim hf, sibai a, khader y, hwalla n, fadhil i, alsiyabi h, et al. non-communicable diseases in the arab world. lancet 2014; 383:356–67. doi: 10.1016/s0140-6736(13)62383-1. 35. world health organization. cancer country profiles 2014. from: www.who.int/cancer/country-profiles/en/ accessed: jan 2017. 36. leung i. research in academic and non-academic institutions. from: www.cuhk.edu.hk/clear/rs/research_in_institutions.pdf accessed: jan 2017. 37. brew a, lucas l. academic research and researchers. berkshire, uk: open university press, 2009. pp. 13–14. 38. hopewell s, clarke m, lefebvre c, scherer r. handsearching versus electronic searching to identify reports of randomized trials. cochrane database syst rev 2007; 2:mr000001. doi: 10.1002/14651858.mr000001.pub2. https://doi.org/10.1371/journal.pntd.0000619 https://doi.org/10.1371/journal.pntd.0000619 https://doi.org/10.1186/1745-6215-12-145 https://doi.org/10.1158/1078-0432.ccr-09-0344 https://doi.org/10.1158/1078-0432.ccr-09-0344 https://doi.org/10.1200/jco.2005.02.8928 https://doi.org/10.1200/jco.2005.01.222 https://doi.org/10.1200/jco.2005.01.222 https://doi.org/10.1016/s0140-6736%2805%2967725-2 https://doi.org/10.1016/s0140-6736%2816%2931679-8 https://doi.org/10.1016/s0140-6736%2813%2962383-1 https://doi.org/10.1002/14651858.mr000001.pub2 sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e157-165, epub. 7th apr 14 submitted 21st aug 13 revision req. 1st oct 13; revision recd. 10th oct 13 accepted 31st oct 13 vitamin e is the collective term given to a group of fat-soluble compounds first discovered in 1922 by evans and bishop; these compounds have distinct antioxidant activities essential for health.1 vitamin e is present in fatcontaining foods2 and, as the fat-soluble property of the vitamin allows it to be stored within the fatty tissues of animals and humans, it does not have to be consumed every day. the vitamin e group (i.e. chroman-6-ols), collectively termed tocochromanols (divided into tocopherols and tocotrienols), includes all of the tocol and tocotrienol derivatives which qualitatively exhibit the biological activity of d-alpha-tocopherol. there are eight naturally occurring forms of vitamin e; namely, the alpha, beta, gamma and delta classes of tocopherol and tocotrienol, which are synthesised by plants from homogentisic acid. alpha and gamma-tocopherols are the two major forms of the vitamin, with the relative proportions of these depending on the source. the richest dietary sources of vitamin e are edible vegetable oils as they contain all the different homologues in varying proportions [table 1]. among the tocopherols, the alphaand gamma-tocopherols are found in the serum and the red blood cells, with alpha-tocopherol present in the highest concentration.3 betaand delta-tocopherols are found in the plasma in minute concentrations only. the preferential distribution of alpha-tocopherol in humans over the other forms of tocopherol stems from the faster metabolism of the other forms and from the alpha-tocopherol transfer protein (alpha-ttp). it is due to the binding affinity of alpha-tocopherol with alpha-ttp that most of the absorbed beta-, gamma and delta-tocopherols are secreted into the bile and excreted in the faeces, while alpha-tocopherol is largely excreted in the urine. the alpha-tocopherol form also accumulates in the non-hepatic tissues, particularly at sites where free radical production is greatest, such as in the membranes of the mitochondria and endoplasmic reticulum in the heart and lungs. this review mainly focuses on the current developments in vitamin e research in the context department of biochemistry, era’s lucknow medical college india, lucknow, india *corresponding author e-mail: tasleem24@gmail.com فيتامني هـ ودوره يف الصحة واملرض عند البشر �صاحلة ريزيف، �صيد ت�صليم ر�صا، في�صل اأحمد، اأب�صار اأحمد، �صانية عبا�س، فرزانة مهدي abstract: vitamin e is the major lipid-soluble component in the cell antioxidant defence system and is exclusively obtained from the diet. it has numerous important roles within the body because of its antioxidant activity. oxidation has been linked to numerous possible conditions and diseases, including cancer, ageing, arthritis and cataracts; vitamin e has been shown to be effective against these. platelet hyperaggregation, which can lead to atherosclerosis, may also be prevented by vitamin e; additionally, it also helps to reduce the production of prostaglandins such as thromboxane, which cause platelet clumping. the current literature review discusses the functions and roles of vitamin e in human health and some diseases as well as the consequences of vitamin e deficiency. the main focus of the review is on the tocopherol class of the vitamers. keywords: vitamin e; health; tocopherols; antioxidants. امللخ�ص: يعد فيتامني هـ املكون الرئي�صي الذائب يف الدهن يف اجلهاز الدفاعي امل�صاد للأك�صدة. يتح�صل الب�رش على هذا الفيتامني ب�صورة كاملة من الغذاء. للفيتامني وظائف مهمة عديدة يف داخل اجل�صم لكونه م�صادا للأك�صدة. ترتبط الأك�صدة بعدد من احلالت والأمرا�س مثل ال�رشطان والهرم والتهابات املفا�صل وال�صاد )كاتراكت(، و لفيتامني هـ فعالية �صد جميع هذه الأمرا�س واحلالت. مينع تناول فيتامني هـ التجلط املفرط لل�صفائح الدموية، والذي قد يوؤدي اإىل الت�صلب الع�صيدي، ويقوم اأي�صا الفيتامني بتقليل انتاج الربو�صتاغلدين مثل الرثومبوك�صني والذي ي�صبب تكد�س ال�صفائح الدموية. يناق�س هذا املقال ال�صتعرا�صي وظائف واأدوار فيتامني هـ يف حالتي ال�صحة واملر�س، والنتائج املرتتبة على نق�س الفيتامني. يركز املقال عن هذا الفيتامني على التوكوفريول مفتاح الكلمات: فيتامني هـ؛ ال�صحة؛ التوكوفريول؛ م�صادات الأك�صدة. review the role of vitamin e in human health and some diseases saliha rizvi, *syed t. raza, faizal ahmed, absar ahmad, shania abbas, farzana mahdi the role of vitamin e in human health and some diseases e158 | squ medical journal, may 2014, volume 14, issue 2 of their importance to human health and disease prevention. the data obtained from a survey of clinical trials or systematic reviews have been included here due to the difficulty of proving the efficacy of vitamin e supplementation, and in order to describe the evidence-based results. chemistry of vitamin e the term ‘tocopherol’ signifies the methyl-substituted derivatives of tocol and is not synonymous with the term ‘vitamin e’. natural tocochromanols comprise two homologous series: tocopherols with a saturated side chain and tocotrienols with an unsaturated side chain. tocopherols and tocotrienols have the same basic chemical structure, which is characterised by a long isoprenoid side chain attached at the 2 position of a 6-chromanol ring, as shown in figure 1. tocotrienols differ from tocopherols in that they possess a farnesyl rather than a saturated isoprenoid c16 side chain. natural tocopherols occur in the rrr-configuration while the synthetic form contains eight different stereoisomers and is called all-racalpha-tocopherol. tocotrienols possess only the chiral stereocenter at c-2 and naturally occurring tocotrienols exclusively possess the 2r,3’e,7’e configuration.5 the receptors and enzymes in the body are highly stereoselective and interact exclusively with one of the enantiomers of a chiral molecule in a process called chiral recognition. as a result, only one enantiomer has the desired effect on the body, while the others may have either no effect or an adverse effect.6 vitamin e isoforms are not interconvertible inside the human body.7 sources and recommended intakes vitamin e is found in various foods and oils. nuts, seeds and vegetable oils contain high amounts of alpha-tocopherol, and significant amounts are also available in green leafy vegetables and fortified cereals. some of the richest sources of vitamin e, along with their tocopherol content and percent daily values, are shown in tables 1 and 2. no specific recommendations regarding the intake of vitamin e have been made officially, and the optimal supplementation dosage of mixed tocopherols is still undetermined. when obtained from food sources alone, vitamin e has no documented evidence of toxicity. however, evidence of pro-oxidant damage has been found to be associated with supplements, but usually only at very high doses (for example at >1,000 mg/day).9 the recommended dietary allowances (rdas) for vitamin e (alpha-tocopherol) are shown in table 3. table 1: vitamin e content in vegetable oils oil alphatocopherol g tocopherol d tocopherol a tocotrienol in mg of tocopherol per 100 g coconut 0.5 0 0.6 0.5 maize (corn) 11.2 60.2 1.8 0 palm 25.6 31.6 7.0 14.3 olive 5.1 trace amounts 0 0 peanut 13.0 21.4 2.1 0 soybean 10.1 59.3 26.4 0 wheatgerm 133.0 26.0 27.1 2.6 sunflower 48.7 5.1 0.8 0 source: slover ht. tocopherols in foods and fats.4 table 2: selected dietary sources of vitamin e (alphatocopherol) food and recommended intake alphatocopherol content in mg per serving percent daily value wheat germ oil, 1 tablespoon 20.3 100 sunflower seeds, dry roasted, 1 ounce 7.4 37 almonds, dry roasted, 1 ounce 6.8 34 sunflower oil, 1 tablespoon 5.6 28 safflower oil, 1 tablespoon 4.6 25 hazelnuts, dry roasted, 1 ounce 4.3 22 peanut butter, 2 tablespoons 2.9 15 peanuts, dry roasted, 1 ounce 2.2 11 corn oil, 1 tablespoon 1.9 10 spinach, boiled, ½ cup 1.9 10 broccoli, chopped, boiled, ½ cup 1.2 6 soybean oil, 1 tablespoon 1.1 6 kiwifruit, 1 medium 1.1 6 mango, sliced, ½ cup 0.7 4 tomato, raw, 1 medium 0.7 4 spinach, raw, 1 cup 0.6 3 adapted from: united states department of agriculture (usda), agricultural research service. usda national nutrient database for standard reference, release 25.8 saliha rizvi, syed t. raza, faizal ahmed, absar ahmad, shania abbas and farzana mahdi review | e159 vitamin e supplements in humans were also seen to increase the under-carboxylation of prothrombin,13 suggesting that vitamin e decreases the vitamin k status in humans. functions of vitamin e p r e v e n t i o n o f o x i d at i v e s t r e s s vitamin e is a potent chain-breaking antioxidant that inhibits the production of reactive oxygen species molecules when fat undergoes oxidation and during the propagation of free radical reactions.14 it is primarily located in the cell and organelle membranes where it can exert its maximum protective effect, even when its concentration ratio may be only one molecule for every 2,000 phospholipid molecules. it acts as the first line of defence against lipid peroxidation, protecting the cell membranes from free radical attack [figure 2]. studies have shown that a mixture of tocopherols has a stronger inhibitory effect on lipid peroxidation induced in human erythrocytes compared to alphatocopherol alone.15 due to its peroxyl radicalscavenging activity, it also protects the polyunsaturated fatty acids present in membrane phospholipids and in plasma lipoproteins.16 the tocopheroxyl radicals formed can either: (1) oxidise other lipids; (2) undergo further oxidation producing tocopheryl quinones; (3) form non-reactive tocopherol dimers by reacting with another tocopheroxyl radical, or (4) be reduced by other antioxidants to tocopherol. it has been found that alpha-tocopherol mainly inhibits the production of new free radicals, while gamma-tocopherol traps and neutralises the existing free radicals. oxidation has been linked to numerous possible conditions/diseases including: cancer, ageing, arthritis and cataracts. thus, vitamin e might help prevent or delay the chronic diseases associated with interactions with dietary factors vitamin e is heavily dependent on vitamin c, vitamin b3, selenium and glutathione. a diet high in vitamin e cannot have an optimal effect unless it is also rich in foods that provide these other nutrients. it was found that a cooperative interaction between vitamin c and vitamin e is quite probable, while one between vitamin c and beta-carotene is improbable and one may exist between vitamin e and beta-carotene.10 interactions were also found between thiols, tocopherols and other compounds which enhance the effectiveness of the cellular antioxidant defence systems.11 in 2007, reports from the women’s health study (whs) demonstrated that vitamin e supplements decrease the risk of mortality from thromboembolism and that alpha-tocopherol decreases the tendency for clotting in normal healthy women.12 in addition, table 3: recommended dietary allowances for vitamin e (alpha-tocopherol) age rda in mg (iu) males females 0–6 months* 4 (6) 4 (6) 7–12 months* 5 (7.5) 5 (7.5) 1–3 years 6 (9) 6 (9) 4–8 years 7 (10.4) 7 (10.4) 9–13 years 11 (16.4) 11 (16.4) >14 years in pregnancy if lactating 15 (22.4) 15 (22.4) 15 (22.4) 19 (28.4) rda = recommended dietary allowances; iu = international units. *adequate intake. source: institute of medicine. food and nutrition board. dietary reference intakes: vitamin c, vitamin e, selenium, and carotenoids.63 figure 1: the structures of a tocopherol and tocotrienol. adapted from: colombo ml. an update on vitamin e, tocopherol and tocotrienol: perspectives.10 the role of vitamin e in human health and some diseases e160 | squ medical journal, may 2014, volume 14, issue 2 reactive oxygen species molecules. p r o t e c t i o n o f t h e c e l l m e m b r a n e s vitamin e increases the orderliness of the membrane lipid packaging, thus allowing for a tighter packing of the membrane and, in turn, greater stability to the cell. in 2011, howard et al. showed that vitamin e is necessary for maintaining proper skeletal muscle homeostasis and that the supplementation of cultured myocytes with alpha-tocopherol promotes plasma membrane repair.18 this occurs because the membrane phospholipids are prominent targets of oxidants and vitamin e efficiently prevents lipid peroxidation. conversely, in the absence of alpha-tocopherol supplementation, the exposure of the cultured cells to an oxidant challenge strikingly inhibits the repair. comparative measurements reveal that in order to promote the repair, an antioxidant must associate with the membranes, as alpha-tocopherol does, or be capable of alpha-tocopherol regeneration. thus, vitamin e promotes membrane repair by preventing the formation of oxidised phospholipids that theoretically might interfere with the membrane fusion events. r e g u l at i o n o f p l at e l e t a g g r e g at i o n a n d p r o t e i n k i n a s e c a c t i vat i o n an increase in the concentration of alpha-tocopherol in the endothelial cells has been found to inhibit platelet aggregation and to release prostacyclin from the endothelium. this effect was thought to occur because of the downregulation of the intracellular cell adhesion molecule (icam-1) and the vascular cell adhesion molecule (vcam-1), thereby decreasing the adhesion of blood cell components to the endothelium. also, due to their upregulation by vitamin e in the arachidonic acid cascade, the increase in the expression of cytosolic phospholipase a2,19 and cyclooxygenase-1,20 increases the release of prostacyclin, which is a potent vasodilator and inhibitor of platelet aggregation in humans.21 a few other studies suggest that tocopherols appear to inhibit platelet aggregation through the inhibition of protein kinase c (pkc)22 and the increased action of nitric oxide synthase.23 the natural rrr-configuration form of alphatocopherol has been shown to be twice as potent as the other all-racemic (synthetic) alpha-tocopherols in inhibiting pkc activity.24 this occurs because of the attenuating effect of alpha-tocopherol on the generation of membrane-derived diacylglycerol (a lipid which facilitates pkc translocation and thus increases its activity); additionally, alpha-tocopherol increases the activity of protein phosphatase type 2a, which inhibits pkc autophosphorylation and, consequently, its activity. mixed tocopherols are more effective than alpha-tocopherol in inhibiting platelet aggregation. adenosine diphosphate-induced platelet aggregation decreased significantly in healthy people who were given gamma-tocopherol-enriched vitamin e (100 mg of gamma-tocopherol, 40 mg of delta-tocopherol and 20 mg of alpha-tocopherol per day), but not in those receiving pure alpha-tocopherol alone (100 mg per day) or in the controls.25 vitamin e in disease prevention vitamin e has been found to be very effective in figure 2: the mechanism of vitamin e (alpha-tocopherol)-mediated low-density lipoprotein lipid peroxidation. adapted from: rathore gs, suthar m, pareek a, gupta rn. nutritional antioxidants: a battle for better health.17 saliha rizvi, syed t. raza, faizal ahmed, absar ahmad, shania abbas and farzana mahdi review | e161 delta-tocopherol has shown growth inhibitory activity against mouse mammary cancer cell lines.33 gamma-tocopherol inhibits the growth of cancer cells in cultures through a number of mechanisms. it traps free radicals, including the reactive nitrogen species molecules that cause mutations in the deoxyribonucleic acid strands and malignant transformations in the cells.34 it also downregulates the control molecules known as cyclins, stopping the cancerous cell cycle in the middle and thus preventing their proliferation.35 gamma-tocopherol has also been found to be superior to alpha-tocopherol in: inducing apoptosis; triggering a number of cell-death-inducing pathways;36 stimulating peroxisome proliferatoractivated receptor gamma activity, especially in colon cancer cells,37 and in reducing the formation of new blood vessels in tumours, thus depriving them of the nutrients they need to thrive.38 in this context, tocotrienols were also found to have antiproliferative and apoptotic activities on normal and cancerous cells in humans, which could be due to the induction of apoptosis by a mitochondria-mediated pathway, or due to the suppression of cyclin d which would therefore arrest the cell cycle.39 they also inhibit vascularisation and suppress 3-hydroxy-3-methyl coenzyme a (hmg-coa) reductase activity, thus preventing malignant proliferation. jiang et al. showed that, of the various forms of vitamin e, gamma-tocopherol, particularly in combination with delta-tocopherol, induced apoptosis in androgen-sensitive prostate cancer cells within three days of treatment, while alpha-tocopherol alone did not have the same effect.40 the gamma and delta e fractions appear to induce apoptosis by interrupting the synthesis of sphingolipid in the membranes of human prostate cancer cells.40 the fractions do this by inducing the release of cytochrome c, the activation of caspase-9 and caspase-3, the cleavage of polyadenosine diphosphate (adp)-ribose polymerase (parp) and the involvement of caspase-independent pathways. recently, chen reported that, of the tocopherols tested, the gamma form was the most potent anti-cancer form of the vitamin. they also found a novel anti-cancer mechanism of vitamin e: gamma-tocopherol, they created a new agent which was found to be 20-fold more effective. they did so by removing a string of chemical groups dangling from the head group of gamma-tocopherol which enhanced its anti-cancer effect. chen et al. said that gammatocopherol was more effective than other tocopherols because of its chemical structure which is more effective in attaching and thus shutting off the akt enzyme.38 these findings suggest that an agent based on the chemical structure of one form of vitamin e the prevention and reversal of various disease complications due to its function as an antioxidant, its role in anti-inflammatory processes, its inhibition of platelet aggregation and its immune-enhancing activity. c a r d i o va s c u l a r d i s e a s e s cardiovascular complications basically arise because of the oxidation of low-density lipoproteins present in the body and the consequent inflammation.26 gammatocopherol is found to improve cardiovascular functions by increasing the activity of nitric oxide synthase, which produces vessel-relaxing nitric oxide.27 it does this by trapping the reactive nitrogen species (peroxynitriten) molecules and thus enhancing the endothelial function. researchers have found that the supplementation of 100 mg per day of gammatocopherol in humans leads to a reduction in several risk factors for arterial clotting, such as platelet aggregation and cholesterol.28 in another study, mixed tocopherols were found to have a stronger inhibitory effect on lipid peroxidation and the inhibition of human platelet aggregation than individual tocopherols alone,25 suggesting a synergistic plateletinhibitory effect. apart from tocopherols, tocotrienols were also found to inhibit cholesterol biosynthesis by suppressing 3-hydroxy-3-methylglutaryl-coa (hmgcoa) reductase, resulting in less cholesterol being manufactured by the liver cells.29 contradictory to this, most of the recent large interventional clinical trials have not shown cardiovascular benefits from vitamin e supplementation and report that the use of vitamin e was associated with a significantly increased risk of a haemorrhagic stroke in the participants.30 thus, it was suggested that understanding the potential uses of vitamin e in preventing coronary heart disease might require longer studies with younger participants. c a n c e r vitamin e also possesses anti-cancer properties. this is possibly because of the various functions of vitamin e which include: the stimulation of the wild-type p53 tumor suppressor gene; the downregulation of mutant p53 proteins; the activation of heat shock proteins, and an anti-angiogenic effect mediated by the blockage of transforming growth factor alpha.31 alpha-, gamma and delta-tocopherols have emerged as vitamin e molecules with functions clearly distinct from each other in anti-cancer activity as well. alpha-tocopherol was found to inhibit the production of pkc and collagenase,32 which facilitate cancer cell growth. in this context gamma-tocopherol was found to be more effective than alpha-tocopherol in its growth inhibitory effect on human prostate cancer cell lines, whereas the role of vitamin e in human health and some diseases e162 | squ medical journal, may 2014, volume 14, issue 2 could help to prevent and treat numerous types of cancer—particularly those associated with a mutation in the pten gene, a fairly common cancer-related genetic defect that keeps protein kinase b (akt) active. chen studied both alpha and gamma forms of the vitamin e molecule; both inhibited the akt enzyme in very targeted ways, but the gamma structure emerged as the more powerful form of the vitamin. in effect, the vitamin halted akt activation by attracting akt and the phlpp1 protein to the same region of a cell where the vitamin was absorbed in the fat-rich cell membrane. the phlpp1 tumour suppressor protein then launched a chemical reaction that inactivated akt, rendering it unable to keep cancer cells alive. apart from these findings, the role of vitamin e in cancer prevention remains controversial. the reports from the cancer institute of new jersey show that gammaand delta-tocopherols can prevent colon, lung, breast and prostate cancers, while alphatocopherol had no such effect. in addition, human trials and surveys aiming to study the association between vitamin e intake and cancer have found that vitamin e is not beneficial in most cases. both the heart outcomes prevention evaluation—the ongoing outcomes (hope-too) trial and the whs study evaluated whether vitamin e supplements might protect people from cancer and found no significant reduction in the risk of developing cancer in individuals taking daily doses of 400 iu or 600 iu of vitamin e.41,42 c ata r a c t s cataracts are one of the commonest causes of significant vision loss in older people. they basically occur due to the accumulation of proteins damaged by free radicals. several observational studies have revealed a potential relationship between vitamin e supplements and the risk of cataract formation. leske et al. found that lens clarity was superior in participants who took vitamin e supplements and those with higher blood levels of the vitamin.43 in another study, a long-term supplementation of vitamin e was associated with the slower progression of age-related lens opacification.44 however, in the randomised age-related eye disease study (areds), vitamin e had no apparent effect on cataract development/progression over an average of 6.3 years.45 overall, the available evidence is insufficient to conclude that vitamin e supplements, taken alone or in combination with other antioxidants, can reduce the risk of cataract formation. a l z h e i m e r’s d i s e a s e alzheimer’s disease (ad) occurs as a result of protein oxidation and lipid peroxidation via a free radical mechanism, where the beta amyloid protein induces cytotoxicity through a mechanism involving oxidative stress and hydrogen peroxide, leading to neuronal cell death and, finally, ad. vitamin e can block the production of hydrogen peroxide and the resulting cytotoxicity. it reduces beta amyloid-induced cell death in rat hippocampal cell cultures46 and pc12 cells47 and attenuates the excitatory amino acid-induced toxicity in neuroblastoma cells.48 the alzheimer’s disease cooperative study in 1997 showed that vitamin e may slow disease progression in patients with moderately severe ad. high doses of vitamin e delayed the loss of the patient’s ability to carry out daily activities and their consequent placement in residential care for several months.49 in another study, it was found that subjects with ad had reduced concentrations of plasma antioxidant micronutrients, suggesting that inadequate antioxidant activity is a factor in this disease. high plasma levels of vitamin e are associated with a reduced risk of ad in older patients and this neuroprotective effect is related to the combination of different forms of vitamin e rather than to alphatocopherol alone.50 a study published in 2009 examined the effects of taking 2,000 iu of vitamin e with and without an ad drug on 847 people. it concluded that vitamin e plus a cholinesterase inhibitor may be more beneficial than taking either agent alone.51 at the biomarker level, mangialasche et al. demonstrated that plasma levels of tocopherols and tocotrienols together with automated magnetic resonance imaging (mri) measures can help to differentiate patients with ad and mild cognitive impairment (mci) from the control subjects, and prospectively predict the mci conversion into ad.49 this therefore suggests the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols as indirect indicators of ad pathology.52 however, researchers have recommended that patients should not take vitamin e to treat ad without the supervision of a physician, as in high doses it can interact negatively with other medications, including those prescribed to lower cholesterol. h u m a n i m m u n o d e f i c i e n c y v i r u s a n d a c q u i r e d i m m u n o d e f i c i e n c y s y n d r o m e vitamin e is an important anti-inflammatory agent that is often found to be deficient in human immunodeficiency virus (hiv)-positive individuals; however, it is not known whether vitamin e supplementation is beneficial either at every or any stage of hiv infection. at a dose of 400 iu, vitamin e was shown to restore delayed skin hypersensitivity reactions and interleukin-2 production, and at high doses it was shown to stimulate t helper cell (cd4 saliha rizvi, syed t. raza, faizal ahmed, absar ahmad, shania abbas and farzana mahdi review | e163 or acquired condition that impairs their ability to absorb the vitamin (for instance, cystic fibrosis, short bowel syndrome or bile duct obstruction) and in those who cannot absorb dietary fat or have rare disorders of fat metabolism. recent reports have shown that the alpha-ttp regulates the secretion of alpha-tocopherol from the liver cells and that missense mutations of some arginine residues at the surface of the alphattp can cause severe vitamin e deficiency in humans.63 the wild-type alpha-ttp was found to bind phosphatidylinositol phosphates (pips), whereas the arginine mutants did not—where the pips in the target membrane promoted the inter-membrane transfer of alpha-tocopherol by alpha-ttp. the resulting symptoms of vitamin e deficiency include muscle weakness, vision problems, immune system changes, numbness, difficulty in walking and tremors as well as a poor sense of balance. apart from these symptoms, deficiency can also lead to neuromuscular problems such as spinocerebellar ataxia and myopathies,24 dysarthria, an absence of deep tendon reflexes, the loss of both vibratory sensations and positive babinski reflexes.24 vitamin e deficiency can also cause anaemia due to the oxidative damage to the red blood cells,24 retinopathy64–67 and the impairment of the immune response.59–61 if untreated, vitamin e deficiency may result in blindness, heart disease, permanent nerve damage and impaired thinking. some reports also suggest that vitamin e deficiency can even result in male infertility.24 conclusion vitamin e was first used as a supplement in canada by the physicians shute and shute; based on the positive results it achieved, they began using it regularly in their practices. since then, well-designed experimental and clinical studies have progressed steadily and increased our knowledge of vitamin e. the antioxidative properties of vitamin e have been found to play a vital role in the battle against various diseases such as atherosclerosis, oxidative stress, cancer, cataract and ad, among others. this review focussed on the important functions of vitamin e in some diseases; in addition to these, this vitamin has been found to be effective against asthma, allergies and diabetes, among others. discussion of the dietary sources, rda and the interaction of vitamin e supplements with other dietary factors, has demonstrated the need for and significance of vitamin e in the human context. thus, raising public awareness of the role of dietary antioxidants in maintaining better health would benefit a number of lives. t-cell) proliferation.53 in 1997, tang et al. studied the association between serum vitamin a and e levels with hiv-1 disease progression. in this study, it was found that men with serum vitamin e levels above 23.5 µm/l had a significantly reduced risk of disease progression. a strong correlation was noted in this cohort between the intake of supplements containing vitamin e at the point of entry into the study and high blood levels of vitamin e.54 a study on murine acquired immunodeficiency syndrome (aids) using a 15-fold increase in dietary vitamin e showed the normalisation of immune parameters that are altered in hiv/aids.55 apart from this, an increase in dietary vitamin e has also been shown to protect against the side-effects of azidothymidine, such as bone marrow toxicity.56 related studies on bone marrow cultures from stage iv aids patients using d-alpha-tocopherol supplementation revealed similar results.57 nevertheless, it has also been reported that higher vitamin e levels pre-infection were found to be associated with increased mortality. thus, further research is needed to elucidate the role vitamin e plays in the pathogenesis of hiv-1.58 i m m u n i t y it has now been proven that vitamin e stimulates the body’s defences, enhances humoral and cell immune responses and increases phagocytic functions. it has a pronounced effect in infectious diseases where immune phagocytosis is involved, but is less effective in the case of cell-mediated immune defences. its supplementation significantly enhances both cellmediated and humoral immune functions in humans, especially in the elderly. a daily intake of 200 mg of vitamin e improved the antibody response to various vaccines in healthy subjects who showed no adverse side-effects to vitamin e supplementation.59 vitamin e also enhanced resistance to viral diseases in elderly subjects, where higher plasma vitamin e levels correlated with a reduced number of infections over a three-year period.60 a recent study by kutty et al. showed that a daily supplementation of vitamin e can enhance the immune response to a specific antigen.61 besides the above mentioned diseases, vitamin e has also been found to play a beneficial role in other diseases, such as photodermatitis, menstrual pain/ dysmenorrhoea, pre-eclampsia and tardive dyskinesia, when taken along with vitamin c.62 vitamin e deficiency vitamin e deficiency is quite rare in humans. it happens almost exclusively in people with an inherited the role of vitamin e in human health and some diseases e164 | squ medical journal, may 2014, volume 14, issue 2 apart from the enormous benefits reported, there has always been debate about the exact function of vitamin e and its role in various diseases. there are many conflicting reports of positive and negative results on the same biological activities in the literature. the primary hindrance in determining the roles of vitamin e in human health is the lack of validated biomarkers for vitamin e intake and status, which would help to relate intakes to possible clinical outcomes. in conclusion, although the data surrounding vitamin e is contradictory, the current literature appears to support the view that the benefits outweigh the side-effects. references 1. niki e, traber mg. a history of vitamin e. ann nutr metab 2012; 61:207–12. 2. zingg jm. vitamin e: an overview of major research directions. mol aspects med 2007; 28:400–422. 3. chow ck. distribution of tocopherols in human plasma and red blood cells. am j clin nutr. 1975; 28:756–60. 4. drotleff am, ternes w. determination of rs,e/z-tocotrienols by hplc. j chomatogr a 2001; 909:215–23. 5. zingg jm. molecular and cellular activities of vitamin e analogues. mini rev med chem 2007; 7:543–58. 6. ball gfm. vitamins in foods: analysis, bioavailability, and stability. boca raton, florida: crc press, 2006, pp. 119–36. 7. brown km, morrice pc, duthie gg. erythrocyte vitamin e and plasma ascorbate concentrations in relation to erythrocyte peroxidation in smokers and non-smokers: dose response to vitamin e supplementation. am j clin nutr 1997; 65:496–502. 8. niki e, noguchi n, tsuchihashi h, gotoh n. interaction among vitamin c, vitamin e, and beta-carotene. am j clin nutr 1995; 62:1322s–26s. 9. di mascio p, murphy me, sies h. antioxidant defense systems: the role of carotenoids, tocopherols, and thiols. am j clin nutr 1991; 53:194s–200s. 10. glynn rj, ridker pm, goldhaber sz, zee ry, buring je. effects of random allocation to vitamin e supplementation on the occurrence of venous thromboembolism: report from the women’s health study. circulation 2007; 116:1497–503. 11. booth sl, golly i, sacheck jm, roubenoff r, dallal ge, hamada k, et al. effect of vitamin e supplementation on vitamin k status in adults with normal coagulation status. am j clin nutr 2004; 80:143–8. 12. burton gw, ingold ku. autoxidation of biological molecules: 1. the antioxidant activity of vitamin e and related chainbreaking phenolic antioxidants in vitro. j am chem soc 1981; 103:6472–7. 13. liu m, wallin r, wallmon a, saldeen t. mixed tocopherols have a stronger inhibitory effect on lipid peroxidation than alpha-tocopherol alone. j cardiovasc pharmacol 2002; 39:714– 21. 14. burton gw, joyce a, ingold ku. is vitamin e the only lipidsoluble, chain-breaking antioxidant in human blood plasma and erythrocyte membranes? arch biochem biophys 1983; 221:281–90. 15. howard ac, anna k. mcneil ak, mcneil pl. promotion of plasma membrane repair by vitamin e. nat commun 2011; 20:597. 16. tran k, wong jt, lee e, chan ac, choy pc. vitamin e potentiates arachidonate release and phospholipase a2 activity in rat heart myoblastic cells. biochem j 1996; 319:385–91. 17. chan ac, wagner m, kennedy c, mroske c, proulx p, laneuville o, et al. vitamin e up-regulates phospholipase a2, arachidonic acid release and cyclooxygenasin endothelial cells. aktuel ernährungsmed 1998; 23:1–8. 18. szczeklik a, gryglewski rj, domagala b, dworski r, basista m. dietary supplementation with vitamin e in hyperlipoproteinemias: effects on plasma lipid peroxides, antioxidant activity, prostacyclin generation and platelet aggregability. thromb haemost 1985; 54:425–30. 19. freedman je, farhat jh, loscalzo j, keaney jf jr. alphatocopherol inhibits aggregation of human platelets by a protein kinase c-dependent mechanism. circulation 1996; 94:2434–40. 20. li d, saldeen t, romeo f, mehta jl. different isoforms of tocopherols enhance nitric oxide synthase phosphorylation and inhibit human platelet aggregation and lipid peroxidation: implications in therapy with vitamin e. j cardiovasc pharmacol ther 2001; 6:155–61. 21. brigelius-flohé r, traber mg. vitamin e: function and metabolism. faseb j 1999; 13:1145–55. 22. liu m, wallmon a, olsson-mortlock c, wallin r, saldeen t. mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms. am j clin nutr 2003; 77:700–6. 23. steinberg d, parthasarathy s, carew te, khoo jc, witztum jl. beyond cholesterol: modifications of low-density lipoprotein that increase its artherogenicity. n engl j med 1989; 320:915– 24. 24. li d, saldeen t, romeo f, mehta jl. relative effects of alpha and gamma-tocopherol on low-density lipoprotein oxidation and superoxide dismutase and nitric oxide synthase activity and protein expression in rats. j cardiovasc pharmacol ther 1999; 4:219–26. 25. singh i, turner ah, sinclair aj, li d, hawley ja. effects of gamma-tocopherol supplementation on thrombotic risk factors. asia pac j clin nutr 2007; 16:422–8. 26. mcanally ja, gupta j, sodhani, s, bravo l, mo h. tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. exp biol med (maywood) 2007; 232:523–31. 27. sesso hd, buring je, christen wg, kurth t, belanger c, macfadyen j, et al. vitamins e and c in the prevention of cardiovascular disease in men: the physicians’ health study ii randomized controlled trial. jama 2008; 300:2123–33. 28. shklar g, oh sk. experimental basis for cancer prevention by vitamin e. cancer invest 2000; 18:214–22. 29. ricciarelli r, maroni p, ozer n, zingg jm, azzi a. agedependent increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase c inhibition. free radic biol med 1999; 27:729–37. 30. mcintyre bs, briski kp, gapor a, sylvester pw. antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. proc soc exp biol med 2000; 224:292–301. 31. christen s, woodall aa, shigenaga mk, southwell-keely pt, duncan mw, ames bn. gamma-tocopherol traps mutagenic electrophiles such as no(x) and complements alphatocopherol: physiological implications. proc natl acad sci u s a 1997; 94:3217–22. 32. gysin r, azzi a, visarius t. gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. faseb j 2002; 16:1952–4. 33. takahashi s, takeshita k, seeni a, sugiura s, tang m, sato sy, et al. suppression of prostate cancer in a transgenic rat model via gamma-tocopherol activation of caspase signaling. prostate 2009; 69:644–51. saliha rizvi, syed t. raza, faizal ahmed, absar ahmad, shania abbas and farzana mahdi review | e165 50. meydani m. vitamin e. lancet 1995; 345:170–5. 51. tang am, graham nm, semba rd, saah aj. association between serum vitamin a and e levels and hiv-1 disease progression. aids 1997; 11:613–20. 52. wang y, huang ds, watson rr. vitamin e supplementation modulates cytokine production by thymocytes during murine aids. immunol res 1993; 12:358–66. 53. ganser a, greher j, volkers b, staszewski a, hoelzer d. azidothymidine in the treatment of atds. n engl j med 1988; 318:250–1. 54. geissler rg, ganser a, ottmann og, gute p, morawetz a, guba p, et al. in vitro improvement of bone marrow-derived hematopoietic colony formation in hiv-positive patients by alpha-d-tocopherol and erythropoietin. eur j haematol 1994; 53:201–6. 55. graham sm, baeten jm, richardson ba, bankson dd, lavreys l, ndinya-achola jo, et al. higher pre-infection vitamin e levels are associated with higher mortality in hiv-1-infected kenyan women: a prospective study. bmc infect dis 2007; 7:63. 56. meydani sn, meydani m, blumberg jb, leka ls, siber g, loszewski r, et al. vitamin e supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. jama 1997; 277:1380–6. 57. chavance m, herbeth b, fournier c, janot c, vernhes g. vitamin status, immunity and infections in an elderly population. eur j clin nutr 1989; 43:827–35. 58. radhakrishnan ak, mahalingam d, selvaduray kr, nesaretnam k. supplementation with natural forms of vitamin e augments antigen-specific th1-type immune response to tetanus toxoid. biomed res int 2013; 2013:782067. 59. university of maryland medical center. vitamin e. from: www.umm.edu/health/medical/altmed/supplement/vitamine#ixzz2c7gfq93r accessed: dec 2013. 60. kono n, ohto u, hiramatsu t, urabe m, uchida y, satow y, et al. impaired a-ttp-pips interaction underlies familial vitamin e deficiency. science 2013; 340:1106–10. 61. office of dietary supplements, national institutes of health. dietary supplement fact sheet: vitamin e.. from: www.ods. od.nih.gov/factsheets/vitamine.asp accessed: aug 2010. 62. food and nutrition board, institute of medicine. dietary reference intakes for vitamin c, vitamin e, selenium, and carotenoids. washington, dc: national academy press, 2000. 63. kowdley kv, mason jb, meydani sn, cornwall s, grand rj. "vitamin e deficiency and impaired cellular immunity related to intestinal fat malabsorption". gastroenterology. 1992;102(6):2139–42. 64. slover ht. tocopherols in foods and fats. lipids 1971; 6:291–6. 65. united states department of agriculture (usda), agricultural research service. usda national nutrient database for standard reference, release 25. from: www.ars.usda.gov/ sp2userfiles/place/12354500/data/sr25/nutrlist/sr25a323. pdf accessed: dec 2013. 66. colombo ml. an update on vitamin e, tocopherol and tocotrienol: perspectives. molecules 2010; 15:2103–13. 67. rathore gs, suthar m, pareek a, gupta rn. nutritional antioxidants: a battle for better health. j nat pharmaceuticals 2011; 2:2–14. 34. stone wl, krishnan k, campbell se, qui m, whaley sg, yang h. tocopherols and the treatment of colon cancer. ann n y acad sci 2004; 1031:223–33. 35. wells sr, jennings mh, rome c, hadjivassiliou v, papas ka, alexander js. alpha-, gammaand delta-tocopherols reduce inflammatory angiogenesis in human microvascular endothelial cells. j nutr biochem 2010; 21:589–97. 36. wada s. chemoprevention of tocotrienols: the mechanism of antiproliferative effects. forum nutr 2009; 61:204–16. 37. jiang q, wong j, fyrst h, saba jd, ames bn. gamma-tocopherol or combinations of vitamin e forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. proc natl acad sci u s a 2004; 101:17825–30. 38. chen cs. study shows how vitamin e can help prevent cancer. from: www.researchnews.osu.edu/archive/silenceakt. htm accessed: dec 2013. 39. lonn e, bosch j, yusuf s, sheridan p, pogue j, arnold jm, et al. effects of long-term vitamin e supplementation on cardiovascular events and cancer: a randomized controlled trial. jama 2005; 293:1338–47. 40. lee im, cook nr, gaziano jm, gordon d, ridker pm, manson je, et al. vitamin e in the primary prevention of cardiovascular disease and cancer: the women’s health study: a randomized controlled trial. jama 2005; 294:56–65. 41. jacques pf, taylor a, moeller s, hankinson se, rogers g, tung w, et al. long-term nutrient intake and 5-year change in nuclear lens opacities. arch ophthalmol 2005; 123:517–26. 42. age-related eye disease study research group. a randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins c and e and beta carotene for age-related cataract and vision loss: areds report no. 9. arch opthalmol 2001; 119:1439–52. 43. goodman y, mattson mp. secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. exp neurol 1994; 128:1–12. 44. behl c, davis j, cole gm, schubert d. vitamin e protects nerve cells from amyloid beta protein toxicity. biochem biophys res commun 1992; 186:944–50. 45. murphy th, schnaar rl, coyle jt. immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. faseb j 1990; 4:1624–33. 46. sano m, ernesto c, thomas rg, klauber mr, schafer k, grundman m, et al. a controlled trial of selegiline, alphatocopherol, or both as treatment for alzheimer’s disease. the alzheimer’s disease cooperative study. n engl j med 1997; 336:1216–22. 47. mangialasche f, kivipelto m, mecocci p, rizzuto d, palmer k, winblad b, et al. high plasma levels of vitamin e forms and reduced alzheimer’s disease risk in advanced age. j alzheimer’s dis 2010; 20:1029–37. 48. pavlik, vn, doody rs, rountree sd, darby ej. vitamin e use is associated with improved survival in an alzheimer’s disease cohort. dement geriatr cogn disord 2009; 28:536–40. 49. mangialasche f, westman e, kivipelto m, muehlboeck js, cecchetti r, baglioni m, et al. classification and prediction of clinical diagnosis of alzheimer’s disease based on mri and plasma measures of α-/γ-tocotrienols and γ-tocopherol. j intern med 2013; 273:602–21. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e250–256, epub. 28 may 15 submitted 24 oct 14 revision req. 2 nov 14; revision recd. 1 jan 15 accepted 29 jan 15 school of pharmacy, college of pharmacy & nursing, university of nizwa, nizwa, oman *corresponding author e-mail: jimmy_jose2001@yahoo.com and jimmy.jose@unizwa.edu.om املعرفة واملعتقدات والسلوكيات فيما يتعلق باآلثار الضارة لألدوية عند العمانيني دراسة مستعرضة جيمي خو�سيه، بينا جيمي، موزة املعمرية، ثريا احل�رشمية، حليمة الزدجايل abstract: objectives: this study aimed to assess the knowledge, beliefs and behaviours of an omani population with regards to the adverse effects of medicines. methods: this cross-sectional survey was conducted between february and june 2012. a 17-item questionnaire was designed to assess three aspects: knowledge, beliefs and behaviours related to medicine safety. a total of 740 questionnaires were distributed in three representative governorates of oman. median total scores for the three sections were estimated. associations with participants’ demographic variables and medication histories were also assessed. results: a total of 618 participants completed the survey (response rate: 83.5%). many participants (46.4%) believed that side-effects occurred only with high doses of medication and over 30% believed that they did not occur at all with traditional and over-the-counter medicines. the median total score was 19 (interquartile range: 6) out of a maximum of 30. inadequate knowledge, incorrect beliefs and good behaviours were observed among the participants. there was a significant association between certain demographic parameters (age, educational qualification, history of chronic use of medicines and employment status) and median total scores. participants reported obtaining additional information on medication safety from various sources, with doctors as the most widely used source. conclusion: inadequate knowledge and incorrect beliefs among this omani population indicate a need for interventions to improve public knowledge and address misconceptions regarding medication safety. these interventions could be initiated on both an individual and public scale, with patient interactions by healthcare professionals and mass education activities targeting the larger population. keywords: knowledge; beliefs; behavior; public health; drug side effects; adverse drug reactions; medication adherence; oman. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل تقييم معرفة ومعتقدات و�سلوكيات العمانيني مبا يتعلق باالآثار ال�سارة لالأدوية. الطريقة: اأجريت هذه الدرا�سة ب�سالمة املتعلقة وال�سلوكيات واملعتقدات املعرفة جوانب: ثالثة لتقييم ا�ستبيان يف مادة 17 ت�سميم مت حيث 2012 ويونيو فرباير بني امل�ستعر�سة الدميوغرافية املتغريات مع العالقة اأي�سا قيمت الثالثة. لالأق�سام الدرجات متو�سط وقدر عمان. يف حمافظات ثالث يف ا�ستبيان 740 توزيع مت الدواء. للم�ساركني وتناولهم للدواء. النتائج: اأكمل 618 من امل�ساركني يف اال�ستطالع مبعدل %83.5. اعتقد العديد من امل�ساركني )%46.4( اأن االآثار اجلانبية حتدث فقط نتيجةجرعات عالية من الدواء. اأكرث من %30 اعتقدوا اأناأنها مل حتدث على االإطالق مع االأدوية التقليدية وعلى و�سفة طبية، على التوايل. كانت النتيجة االإجمالية متو�سط 19 )املدى الربعي: 6( من اأ�سل 30 كحد اأق�سى. لوحظت حمدودية املعرفة، املعتقدات غري ال�سحيحة وال�سلوكيات احل�سنة بني امل�ساركني. كان هناك ارتباط كبري بني معايري دميوغرافية معينة )العمر، املوؤهل العلمي، وتاريخ اال�ستخدام املزمن لالأدوية والو�سع الوظيفي( و متو�سط جمموع الدرجات. اأفاد امل�ساركون اأنهم ح�سلوا على معلومات اإ�سافية عن �سالمة الدواء من م�سادر خمتلفة، وكان االأطباء امل�سدر االأكرث�سيوعا. اخلال�صة: حمدوديةاملعرفة واملعتقدات غري ال�سحيحة بني العمانيني امل�ساركني ت�سري اإىل احلاجة اإىل التدخل لتح�سني املعرفة العامة وت�سحيح املفاهيم اخلاطئة فيما يتعلق ب�سالمة الدواء. من املمكن اأن تبداأ هذه التدخالت على م�ستوى االأفراد وعلى النطاق العام عن طريق التفاعل بني املتخ�س�سني يف الرعاية ال�سحية واملر�سى واأن�سطة التثقيف اجلماعي الذي ي�ستهدف عدد اأكرب من ال�سكان. مفتاح الكلمات: املعرفة؛ املعتقدات؛ ال�سلوك؛ ال�سحة العامة؛ التفاعالت ال�سلبية؛ االآثاراجلانبية لالأدوية؛ االلتزام بالدواء؛ عمان. knowledge, beliefs and behaviours regarding the adverse effects of medicines in an omani population cross-sectional survey *jimmy jose, beena jimmy, moza n. s. al-mamari, thuraiya s. n. al-hadrami, halima m. al-zadjali advances in knowledge little is known regarding the knowledge, beliefs and behaviours of the omani public with regards to the adverse effects of medicines among populations in the wider middle eastern region. the results of the present study serve to add new data to the existing literature. application to patient care the results of this study revealed that members of the omani public had inadequate knowledge and incorrect beliefs regarding aspects of drug safety. this finding needs to be considered in daily healthcare delivery. misconceptions regarding the adverse effect of medicines identified in this study should be addressed both on an individual basis as well as through national campaigns. clinical & basic research jimmy jose, beena jimmy, moza n. s. al-mamari, thuraiya s. n. al-hadrami and halima m. al-zadjali clinical and basic research | e251 adverse drug reactions (adrs) are a significant cause of morbidity and mortality in all areas of healthcare. they can result in a significant financial burden as well as severely impacting patient quality of life.1 in terms of adverse drug events, a recently published study based on hospital data reported overall prevalence rates of 3.22%, 4.78% and 5.64% in england, germany and the usa, respectively.2 similarly, a prospective observational cohort study in a paediatric referral centre in the uk found that 17.7% of admitted patients had experienced at least one adr.3 in the united arab emirates (uae), saheb sharif-askari et al. reported that among patients with heart failure, adr-related cases accounted for 6.7% of admissions to cardiac units.4 in oman, a retrospective review reported a prevalence of 4.3% of statin-related hepatic effects among patients.5 patients are active participants in the drug therapy process; their knowledge greatly influences the way drugs are used and, in effect, the overall safety of drug use. patients’ misconceptions on drug safety can adversely affect the drug treatment process. in pharmacovigilance, the involvement of every stakeholder, including patients, is of the utmost importance.6 it is essential that patients have adequate knowledge and information about drug risks and efficacy in order to be able to make informed decisions about their medical treatment.7 patients are becoming more aware of the potential side-effects of drug therapies.8 moreover, patients and consumers often use a number of sources to obtain information about their medicines and other health-related topics.9,10 nevertheless, it is the responsibility of health practitioners to ensure that patients are informed users of the medicines prescribed to them.11,12 most patients expect their physicians to provide detailed information concerning the possible adverse effects of prescribed medication.13 as reported by cullen et al., patient knowledge of the risks associated with medications is frequently inaccurate and inconsistent.14 furthermore, poor knowledge and inadequate behaviours with regards to prescription, over-the-counter (otc) and complementary/alternative medicines (cam) have been widely reported among patients.9,15,16 a cross-sectional study among members of the public in ajman, uae, reported poor knowledge among participants regarding the interaction of otc and prescription medicines.17 khanderkar et al. reported a lack of modern scientific beliefs among omani participants and identified the male gender and illiteracy as predictors of non-scientific beliefs.18 minimising the impact of adverse-effects depends crucially on the early identification of possible drug reactions by patients and informed knowledge of actions to be taken in response.19 it is therefore to be expected that patients who are better informed are more likely to avoid adverse drug-related interactions, cope with predictable side-effects and recognise potential non-dose-related side-effects.7 with this in mind, it is essential to assess patient knowledge and practices regarding medication safety. understanding existing drug safety knowledge held by patients/ consumers benefits healthcare providers and helps to refine effective communications of drug safety.20 there are limited published studies from oman as well as the middle eastern region assessing the existing knowledge and practices with regards to drug use and safety among members of the public. hence, this study aimed to assess the knowledge, beliefs and behaviours of an omani population with regard to the adverse effects of medicines. methods this cross-sectional survey was conducted between february and june 2012 in three representative governorates (al dakhiliyah, al-batinah and muscat) of oman. the study population included members of the public from one wilayat of each of the three representative governorates. the estimated sample size used for the study was 600 with a confidence level of 99% and interval of four for an overall estimated omani population of 2.7 million.21 three investigators were involved in the distribution of 740 questionnaires. members of the public were approached at various places, including at schools, government offices and in their homes in the wilayats of samail (al-dakhiliyah), saham (al-batinah) and bawshar (muscat) by one investigator. participants were enrolled in the study using quota sampling by age and gender followed by convenience sampling methods. inclusion criteria included participants over the age of 21 years who were neither healthcare practitioners nor students in any medical or health-related field. a modified arabic version of a questionnaire from a similar study conducted in malaysia was used.15 the self-administered questionnaire had 17 items designed to assess three aspects of medication safety: while omanis claim to have good behaviours with regards to medication safety, it is important that healthcare professionals continue to share information regarding the potential adverse effects of drugs prescribed or taken by their patients. knowledge, beliefs and behaviours regarding the adverse effects of medicines in an omani population cross-sectional survey e252 | squ medical journal, may 2015, volume 15, issue 2 knowledge (n = 7), beliefs (n = 5) and behaviours (n = 5). additionally, the questionnaire included a section designed to obtain demographic information as well as details on history of medication usage and personal experience with side-effects. the initial english version of the questionnaire was translated into arabic. to ensure appropriate translation, it was further retranslated into english by another translator before being pilot tested on 30 participants. no difficulties in understanding or answering the questions were reported by the respondents of the pilot study. this arabic version of the questionnaire was then used without any further modifications. for a minority of participants, the questionnaire was filled in by the investigator (e.g. in cases of illiteracy). investigators remained on hand while participants were completing the survey for any required clarifications. the majority of the questionnaire responses were scored using a three-point likert scale (agree, unsure or disagree). two of the questions did not follow the likert scale. subsequently, responses to these questions, in the three sections of knowledge, beliefs and behaviours, were assessed by estimating the percentage of respondents choosing each response. scores of 2, 1 and 0 were used for correct, unsure and incorrect responses, respectively, following the likert scale.15 median scores were then estimated for each section, with a maximum score of 14, 8 and 8 for the knowledge, beliefs and behaviours sections, respectively, and a minimum score of 0. in addition, median total scores were estimated based on responses to all three sections, with a maximum score of 30 and a minimum score of 0. a score of >80% of the possible maximum score was considered good, 60–80% was considered moderate and <60% was considered poor. the median total scores of the participants were correlated with selected demographic variables in order to determine associations, including gender, age group, educational qualification, employment status, history of medication usage or previous experience with side-effects. statistical analysis of the data was conducted using the statistical package for the social sciences (spss), version 15 (ibm, corp., chicago, illinois, usa). the mann-whitney u test was used for analysing the difference in median total scores as well as median knowledge, belief and behaviour scores when evaluation was based on more than two groups (gender and chronic use of medicine status). similarly, the kruskal-wallis test was used when evaluation was based on more than two groups (age, educational status, history of experiencing side-effects and employment status). a p value of <0.05 was considered statistically significant. ethical approval for this study was obtained from the research committee of the college of pharmacy & nursing, university of nizwa, oman. results a total of 618 participants completed the survey, giving a response rate of 83.5%. the demographic characteristics of the participants and associations table 1: demographic variables and associations with median total scores assessing knowledge, beliefs and behaviours with regard to the adverse effects of medicines among an omani population (n = 618) demographic variable n (%) median total score (iqr) p value gender 0.311 male 293 (47.4) 18 (5.15) female 325 (52.6) 19 (5) age group in years <0.001 18–30 156 (25.2) 20 (4.75) 31–45 156 (25.2) 19 (95) 46–60 132 (21.4) 18 (5.75) 61–75 127 (20.6) 18 (4) >75 47 (7.6) 18 (4) educational qualification <0.001 no education 130 (21.0) 18 (4) primary 111 (17.9) 18 (5) secondary 135 (21.8) 19 (5) higher secondary 93 (15.0) 19 (5) higher education 149 (24.1) 22 (6) chronic use of medicines 0.001 yes 283 (45.8) 18 (5) no 335 (54.2) 19 (5) experienced side-effects 0.090 yes 161 (26.1) 18 (4) no 277 (44.8) 19 (5) unsure 180 (29.1) 18 (5) employment status <0.001 employed 228 (36.9) 19 (5) self-employed 106 (17.2) 18 (4.25) unemployed 183 (29.6) 18 (4) student 101 (16.3) 20 (4) iqr =interquartile range. jimmy jose, beena jimmy, moza n. s. al-mamari, thuraiya s. n. al-hadrami and halima m. al-zadjali clinical and basic research | e253 with median total scores assessing knowledge, beliefs and behaviours are shown in table 1. a total of 26.1% of participants reported previously experiencing adverse effects from medicines. the median total score based on the responses to all sections was 19 (interquartile range [iqr]: 6) out of a possible maximum score of 30, which constituted a moderate score. individual median scores in the knowledge, beliefs and behaviours sections were 8 (iqr: 4), 4 (iqr: 2) and 7 (iqr: 3), out of maximum scores of 14, 8 and 8, respectively. this indicated poor knowledge, poor beliefs and good behaviour scores among the participants. significant associations were observed between the median total score and age, educational qualification, history of chronic use of medicines and employment status [table 1]. participants’ responses to selected questionnaire items in the knowledge, beliefs and behaviours sections are presented in table 2. many participants (46.4%) were under the impression that side-effects occured only when using medication in high doses. furthermore, 34.3% and 37.3% of the participants believed that traditional and otc medicines, respectively, did not cause side-effects at all. the majority (59.9%) believed that medicines prescribed by doctors were completely safe. the vast majority (71.7%) of the participants claimed that they informed consulting doctors regarding any history of allergies or the use of traditional medicines [table 2]. almost all of the selected demographic variables were found to have a significant association with median knowledge scores, except gender. however, only educational qualification was significantly associated with median belief score, while the median behaviour score was influenced by educational qualification and a personal history of experiencing side-effects [table 3]. most of the participants (56.1%) reported that they expected healthcare professionals to provide comprehensive information regarding side-effects and medication safety. participants also reported obtaining additional information on medication safety and adverse effects from various sources, with consulting a doctor being the most widely used method (59.7%) followed by consulting a pharmacist (33.9%) [table 4]. discussion in recent years, ensuring that patients are active partners in drug therapies has become a priority. as demonstrated by jha et al., well-informed patients are more likely to play an active role in drug therapy, thereby influencing its outcome and practice.22 understanding the existing knowledge, beliefs and behaviours of the public regarding drug safetyrelated issues can therefore be beneficial in attaining safer drug utilisation among members of the public. in the present study, over a quarter of the omani participants reported having previously experienced adverse effects from medications. this was similar to results from a study conducted by hughes et al. in the uk which indicated that a number of patients had experienced adrs.9 alarmingly, a good number of participants in the current study were under the impression that both traditional and otc medicines could not cause adverse effects at all; a similar study conducted in malaysia by jose et al. also reported misconceptions regarding the safety of these agents.15 in the usa, wilcox et al. observed that 46% of exclusive otc users believed that these medications were safe.16 in contrast, a high level of awareness on the potential abuse, and the safety and effectiveness, of otc medicines was observed in tanzania.23 in the middle eastern region, a study conducted among the kuwaiti public found that 61.4% of participants considered natural herbal products to be safe due to the fact that they were made from natural ingredients.24 due to the wide-spread nature of these misconceptions, it is imperative that members table 2: responses to selected questionnaire items assessing knowledge, beliefs and behaviour on drug safety among an omani population (n = 618) questionnaire item response n (%) agree unsure disagree knowledge side-effects occur only with high doses of medicine 287 (46.4) 181 (29.3) 131 (21.2) traditional medicines do not cause any side-effects 212 (34.3) 254 (41.1) 152 (24.5) over-the-counter medicines* do not cause any side-effects 231 (37.3) 246 (39.8) 141 (22.8) beliefs medicines prescribed by a doctor are completely safe 370 (59.9) 140 (22.7) 108 (17.5) doctors are responsible for any side-effects caused by prescribed medicines 359 (58.1) 165 (26.7) 94 (15.2) behaviours i normally tell my doctor if i am using traditional medicines 443 (71.7) 97 (15.6) 78 (12.6) i try to obtain additional information before taking a new medication 484 (78.3) 68 (11.0) 66 (10.7) *medicines bought without a prescription. knowledge, beliefs and behaviours regarding the adverse effects of medicines in an omani population cross-sectional survey e254 | squ medical journal, may 2015, volume 15, issue 2 of the public be educated regarding otc medicines, the safety of these medications and potential adverse effects. necessary caution needs to be exercised while using traditional medicines with due consideration of potential interactions with other medications (e.g. interactions between traditional medicines and diseases and between traditional medicines and other drugs). in the current study, the majority of respondents believed that medicines prescribed by a doctor were completely safe, which suggests that members of the public put great confidence in physician management. furthermore, most respondents expected doctors and pharmacists to provide comprehensive safety-related information. this was similar to results observed in a canadian study by nair et al.25 additionally, these results corresponded with those of earlier studies with patients reporting that inadequate information about drugs and a lack of monitoring were important causes of adrs.19 the overall median knowledge score observed in the present study was low in contrast to a study in malaysia where a moderate knowledge score was observed.15 however, the median behaviour score of the participants was good. this is encouraging as it table 3: demographic variables and associations with median knowledge, belief and behaviour scores with regard to the adverse effects of medicines among an omani population (n = 618) demographic variable median knowledge score (iqr) p value median belief score (iqr) p value median behaviour score (iqr) p value gender 0.504 0.815 0.834 male 8 (4) 4 (2) 7 (3) female 8 (4) 4 (2) 7 (2) age group in years <0.001 0.601 0.258 18–30 9 (4) 5 (2) 7 (2) 31–45 8 (4) 4 (2) 7 (2) 46–60 7 (4) 4 (2) 7 (3) 61–75 7 (3) 5 (2) 6 (3) >75 6 (3) 4 (2) 8 (2) educational qualification <0.001 0.005 0.015 no education 7 (3) 4 (2) 7 (3) primary 7 (4) 4 (2) 6 (3) secondary 8 (3) 4 (2) 7 (3) higher secondary 8 (4) 4 (2) 7 (3) higher education 9 (4) 5 (2) 8 (2) chronic use of medicines <0.001 0.471 0.058 yes 7 (3) 4 (2) 7 (3) no 8 (4) 4 (2) 7 (2) experienced side-effects 0.001 0.410 0.013 yes 7 (3) 5 (2) 8 (3) no 8 (4) 4 (2) 7 (2) unsure 8 (4) 4 (2) 6 (3) employment status <0.001 0.706 0.421 employed 8 (4) 4 (2) 7 (2) self-employed 7 (3) 4 (2) 7 (3) unemployed 7 (3) 4 (2) 7 (3) student 9 (3) 5 (2) 7 (2) iqr =interquartile range. jimmy jose, beena jimmy, moza n. s. al-mamari, thuraiya s. n. al-hadrami and halima m. al-zadjali clinical and basic research | e255 shows that members of the omani public are aware of the importance of informing doctors about their allergy and side-effect history as well as informing them of any concomitant use of traditional and/or otc medicines. in contrast, the results observed in a study conducted in taiwan found that the majority of participants did not inform their doctor or pharmacist about their current medications.26 a study conducted among members of the public in saudi arabia observed that only a minor percentage of participants discussed cam use with their physicians.27 the majority of the participants in the present study reported that they expected to be informed of all possible adverse effects of medications; this was in line with other studies.13,25 moreover, most participants considered their doctor to be the primary source of their information on side-effects; pharmacists were considered to be the secondary source of information. this finding indicates that improving patient-pharmacist interactions is an important priority and should be given due consideration. patients should be more confident in interacting with pharmacists regarding drug-related information as these healthcare professionals have expertise in this field. nair et al. demonstrated that canadian patients considered pharmacists to be the most accessible source of drug-related information.25 based on a study conducted in abu dhabi, uae, fahmy et al. reported that pharmacists need more education on drug indications, interactions and adverse events as well as precautionary education on the use of herbal products.28 however, pharmacists in thailand recommended that drug safety education be provided directly to patients, especially those who are considered to be high-risk.29 in the uk, hughes et al. reported that patient information leaflets were rarely used by patients, despite their wide availability.9 significant associations were observed in the current study between median total scores and age, educational qualification, history of chronic use of medicines and employment status. younger participants (under 45 years old) were found to have a higher score in comparison to their older counterparts. furthermore, younger participants had greater knowledge and belief scores, although this did not extend to their behaviour scores. further, as might be expected, participants with a secondary school education or higher demonstrated better scores in all sections (knowledge, beliefs and behaviours), as those with a higher education qualification had the highest scores. however, no significant associations were observed between median belief scores and a history of experiencing side-effects; this was at odds with results observed by jose et al. in malaysia.15 this study had the following limitations. the use of a convenience sample instead of a random sample should be considered as a possible source of bias in the sample selection. in order to accommodate the general public and ensure the questionnaire was easy to answer, a 3-point likert scale was used instead of a more objective 5-point likert scale. additionally, even though the number of participants who required the interviewer to respond to the questionnaire on their behalf was limited, the possibility of interviewer bias among these cases needs to be considered. furthermore, caution needs to be exercised in interpreting the findings related to behaviours as questionnaire responses were self-assessed by participants and therefore may not always reflect real practices. finally, there were limited responses from members of the public who were over 75 years old. collecting data from individuals of this age group is important considering that this group is likely to use more medications. as such, further studies are recommended in this field. conclusion this study evaluated the knowledge, beliefs and behaviours regarding the adverse effects of medicines among an omani population. members of the public were found to underestimate the risk of side-effects when using traditional and otc medications. there is, therefore, a need for educational interventions to improve public knowledge and address misconceptions regarding medication safety. on the other hand, participants reported several encouraging table 4: responses to selected questionnaire items assessing expectations regarding side-effect-related information and sources of information among an omani population (n = 618) questionnaire item response n (%) i expect healthcare professionals to inform me regarding: all possible side-effects 347 (56.1) severe side-effects 263 (42.5) common side-effects 175 (28.3) patient identifiable side-effects 142 (22.9) predictable side-effects 184 (29.7) sources of information asking the doctor 369 (59.7) asking the pharmacist 210 (33.9) information leaflet 195 (31.5) internet 70 (11.3) family members or friends 145 (23.4) knowledge, beliefs and behaviours regarding the adverse effects of medicines in an omani population cross-sectional survey e256 | squ medical journal, may 2015, volume 15, issue 2 drug safety-related behaviours. however, these behaviours need to be objectively observed and assessed in actual drug use situations in order to verify self-reported findings. furthermore, this study found that participants expected comprehensive information regarding medication safety to be shared by healthcare professionals. effective communication on drug sideeffects between healthcare professionals and patients is recommended as well as obtaining patient histories on their use of alternative and otc medications. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. szymusiak-mutnick b. adverse drug reaction reporting. in: shargel l, mutnick ah, souney pf, swanson ln (eds). comprehensive pharmacy review. 6th edition. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2007. pp. 482–90. 2. stausberg j. international prevalence of adverse drug events in hospitals: an analysis of routine data from england, germany, and the usa. bmc health serv res 2014; 14:125. doi: 10.1186/1472-6963-14-125. 3. thiesen s, conroy ej, bellis jr, bracken le, mannix hl, bird ka, et al. incidence, characteristics and risk factors of adverse drug reactions in hospitalized children: a prospective observational cohort study of 6,601 admissions. bmc med 2013; 11:237. doi: 10.1186/1741-7015-11-237. 4. saheb sharif-askari n, syed sulaiman sa, saheb sharif-askari f, hussain aa. adverse drug reaction-related hospitalisations among patients with heart failure at two hospitals in the united arab emirates. int j clin pharm 2015; 37:105–12. doi: 10.1007/ s11096-014-0046-3. 5. jose j, al-tamimi fa, helal mm, jimmy b, al riyami q. statin associated hepatic adverse effects: a retrospective review from a regional hospital in sultanate of oman. oman med j 2014; 29:351–7. doi: 10.5001/omj.2014.93. 6. elkalmi r, hassali ma, al-lela oq, jawad awadh ai, al-shami ak, jamshed sq. adverse drug reactions reporting: knowledge and opinion of general public in penang, malaysia. j pharm bioallied sci 2013; 5:224–8. doi: 10.4103/0975-7406.116824. 7. brounéus f, macleod g, maclennan k, parkin l, paul c. drug safety awareness in new zealand: public knowledge and preferred sources for information. j prim health care 2012; 4:288–93. 8. krska j. adverse drug reaction. in: winfield ja, richards rme (eds). pharmaceutical practice. 3rd edition. philadelphia, pennsylvania, usa: elsevier limited, 2004. pp. 360–71. 9. hughes l,whittlesea c, luscombe d. patients’ knowledge and perceptions of the side-effects of otc medication. j clin pharm ther 2002; 27:243–8. doi: 10.1046/j.1365-2710.2002.00416.x. 10. eagle l, hawkins j, styles e, reid j. breaking through the invisible barrier of low functional health literacy: implications for health communication. stud commun sci 2006; 5:29–55. 11. university of the sciences in philadelphia. remington: the science and practice of pharmacy. 21st edition. philadelphia, pennsylvania, usa: lippincott wiliams & wilkins, 2005. 12. jimmy b, jose j, al-hinai za, wadair ik, al-amri gh. adherence to medications among type 2 diabetes mellitus patients in three districts of al dakhliyah governorate, oman: a cross-sectional pilot study. sultan qaboos univ med j 2014; 14:e231–5. 13. ziegler dk, mosier mc, buenaver m, okuyemi k. how much information about adverse effects of medication do patients want from physicians? arch intern med 2001; 161:706–13. doi: 10.1001/archinte.161.5.706. 14. cullen g, kelly e, murray fe. patients’ knowledge of adverse reactions to current medications. br j clin pharmacol 2006; 62:232–6. doi: 10.1111/j.1365-2125.2006.02642.x. 15. jose j, chong d, lynn ts, jye ge, jimmy b. a survey on the knowledge, beliefs and behaviour of a general adult population in malaysia with respect to the adverse effects of medicines. int j pharm pract 2011; 19:246–52. doi: 10.1111/j.20427174.2011.00113.x. 16. wilcox cm, cryer b, triadafilopoulos g. patterns of use and public perception of over-the counter pain relievers: focus on nonsteroidal antiinflammatory drugs. j rheumatol 2005; 32:2218–24. 17. hamoudi nm. drug interaction awareness among public attending gmch ajman/uae. asian j biomed pharm sci 2013; 3:17–20. doi: 10.15272/ajbps.v3i20.260. 18. khandekar r, p nv, kk k, mane p, hassan ar, niar r, a sf, et al. hearing health practices and beliefs among over 20 yearolds in the omani population. sultan qaboos univ med j 2010; 10:241–8. 19. bennett pn, brown mj. clinical pharmacology. 9th edition. philadelphia, pennsylvania, usa: elsevier health sciences, 2003. 20. bahri p. public pharmacovigilance communication: a process calling for evidence based objective-driven strategies. drug saf 2010; 33:1065–79. doi: 10.2165/11539040-000000000-00000. 21. national centre for statistics and information, oman. the statistical year book 2011. from: http://www.ncsi.gov.om/ncsi_ website/book/syb2011/2-population.pdf accessed: oct 2014. 22. jha n, bajracharya o, shankar pr. knowledge, attitude and practice towards medicines among school teachers in lalitpur district, nepal before and after an educational intervention. bmc public health 2013; 13:652. doi: 10.1186/1471-2458-13-652. 23. justin-temu m, mwambete dk, nyaki d. public knowledge, attitude and perception of over the counter medicines: case study in dar es salaam region, tanzania. east afr j public health 2010; 7:282–5. doi: 10.4314/eajph.v7i4.64743. 24. awad a, al-shaye d. public awareness, patterns of use and attitudes toward natural health products in kuwait: a crosssectional survey. bmc complement altern med 2014; 14:105. doi: 10.1186/1472-6882-14-105. 25. nair k, dolovich l, cassels a, mccormack j, levine m, gray j, et al. what patients want to know about their medications: focus group study of patient and clinician perspectives. can fam physician 2002; 48:104–10. 26. hsiao fy, lee ja, huang wf, chen sm, chen hy. survey of medication knowledge and behaviors among college students in taiwan. am j pharm educ 2006; 70:30. doi: 10.5688/aj700230. 27. elolemy at, albedah am. public knowledge, attitude and practice of complementary and alternative medicine in riyadh region, saudi arabia. oman med j 2012; 27:20–26. doi: 10.5001/omj.2012.04. 28. fahmy sa, abdu s, abuelkhair m. pharmacists’ attitude, perceptions and knowledge towards the use of herbal products in abu dhabi, united arab emirates. pharm pract 2010; 8:109–15. 29. phueanpinit p, jarernsiripornkul n, pongwecharak j, krska j. hospital pharmacists’ roles and attitudes in providing information on the safety of non-steroidal anti-inflammatory drugs in thailand. int j clin pharm 2014; 36:1205–12. doi: 10.1007/s11096-014-0018-7. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e245-248, epub. 7th apr 14 submitted 26th sep 13 revision req. 17th nov 13; revision recd. 30th dec 13 accepted 26th jan 14 department of child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mails: mnaggari@squ.edu.om and mnaggari@yahoo.com إدارة عالج ناجحة حلالة مهملة من اعتالل الداء السيستيين الكلوي حممد عاطف النجاري ، ابتسام النور، حسني الكندي، عامر الشهربلي، أنس الوجود عبد املغيث abstract: cystinosis is a rare metabolic disorder characterised by lysosomal cystine accumulation leading to multi-organ damage; clinically, the kidneys are the first organ affected. respiratory insufficiency caused by overall respiratory muscle myopathy is a life-threatening complication. treatment with cysteamine should be initiated rapidly and continued lifelong to prolong renal function and protect the extra-renal organs. we report the case of a four-year-old omani girl, diagnosed with infantile nephropathic cystinosis at 21 months. cysteamine was prescribed but with no compliance to medications. she presented to the child health department of sultan qaboos university hospital, oman, two years later with severe failure to thrive, electrolyte disturbance and respiratory failure. the hypoventilation and early respiratory dysfunction, due to intercostal and diaphragm myopathy, was treated by non-invasive positive-pressure ventilation. the patient was discharged after four months of intensive rehabilitation with no ventilator support. no standard treatment options have yet been established for respiratory dysfunction in cystinosis. keywords: cystinosis; cysteamine; continuous positive airway pressure; positive-pressure ventilation; failure to thrive; pediatric intensive care units; case report; oman. هي الكلى �رشيريا، متعددة. اأع�صاء �رشر اإىل يوؤدي مما احلال اجل�صيم يف ال�صي�صتني برتاكم يتميز نادر اأي�صي ا�صطراب هو ال�صي�صتيني الداء امللخ�ص: اأول الأع�صاء تاأثراً. الق�صور التنف�صي الناجم عن العتلل الع�صلي العام يف ع�صلت التنف�س، هو من امل�صاعفات التي تهدد احلياة . ال�رشوع يف بداأ علج "cysteamine" ب�رشعة وا�صتمرارة مدى احلياة يطيل بقاء وظيفة الكلى وحماية الأجهزة خارج الكلية. نعر�س هنا تقرير حلالة فتاة عمانية تبلغ من العمر 4 �صنوات، مت ت�صخي�صها باإعتلل الداء ال�صي�صتيني الكلوي الطفويل يف عمر 21 �صهرا. كان هناك عدم اأمتثال لأخذ دواء "cysteamine" الذي كان مقررا اأعطاءة. قدمت الطفلة اإىل ق�صم �صحة الطفل يف م�صت�صفى جامعة ال�صلطان قابو�س يف �صلطنة عمان ، و هي تعاين من ف�صل حاد يف النمو، و ا�صطرابات يف الأملح ، و ف�صل يف اجلهاز التنف�صي . مت علج نق�س التهوية و �صعف اجلهاز التنف�صي املبكر نتيجة اأعتلل الع�صلت الوربية و احلجاب احلاجز ، بوا�صطة جهاز تهوية اإيجابي ال�صغط غري غري با�صع )nippv(. خرجت املري�صة بعد اأربعة اأ�صهر من اإعادة التاأهيل املكثف مع عدم وجود دعم التنف�س ال�صناعي . مل يتم حتى الآن حتديد مقيا�س للخيارات العلجية يف حالت اختلل وظيفة اجلهاز التنف�صي يف الداء ال�صي�صتيني . مفتاح الكلمات: تهوية اإيجابية ال�صغط؛ غري با�صع؛ الف�صل يف النمو؛ الداء ال�صي�صتيني؛ �صغط اإيجابي م�صتمر ملجرى الهواء؛ وحدة العناية املركزة للأطفال؛ تقرير حالة، عمان. successful management of a neglected case of nephropathic cystinosis *mohamed a. el-naggari, ibtisam elnour, hussein al-kindy, aamir al-shahrabally, anas a. abdelmogheth case report cystinosis is an autosomal recessive disorder characterised by an accumulation of the amino acid cystine in lysosomes throughout the body. ctns, the responsible gene, is defective in this disease. usually, this gene encodes the lysosomal cystine carrier cystinosin, which is a lysosomal transport molecule needed to carry cystine out of the cells. it was cloned in 1998 and is located on the short arm of the chromosome 17p13.1,2 in virtually all tissues, cystine accumulation causes multi-organ damage, with the kidneys being clinically the first affected. cystinosis generally manifests in infancy as fanconi syndrome with severe renal proximal tubular dysfunction. end-stage disease develops around the age of 10 years without specific therapy using the cystine-depleting agent, cysteamine.2 cystine accumulation has also been detected in the muscular tissue; the first case of severe myopathy in cystinosis was reported in 1988.3 the association of nephropathic cystinosis with progressive distal vacuolar myopathy was described in more detail in 1994.4 anikster et al. studied the pulmonary function and myopathy of 12 patients with nephropathic cystinosis and concluded that restrictive pulmonary disease due to overall respiratory muscle dysfunction is characteristic of the disease.5 it usually develops after patients reach 10 years of age in the majority of those not treated with cysteamine.2 the aminothiol cysteamine depletes lysosomal cystine content by a disulfide exchange reaction with cystine, resulting in the formation of cysteinecysteamine mixed disulfide and cysteine. this exits successful management of a neglected case of nephropathic cystinosis e246 | squ medical journal, may 2014, volume 14, issue 2 the lysosomes via a system c transporter and the remaining cysteine via a cysteine carrier.6,7 the system c transporter was recently identified to be the pqlc2 transporter.8 we report a case of cystinosis with myopathy whose hypercapnic respiratory failure was treated with noninvasive positive-pressure ventilation (nippv). due to this treatment modality, the patient was moved from prolonged admission in the paediatric intensive care unit (picu) and gradually weaned from nippv to nocturnal ventilation. she was weaned off ventilation completely after approximately two months. case report this omani female child had been previously reported as the first case of nephropathic cystinosis in oman when she was 21 months old.9 at that time, the patient was started on cysteamine (30 mg/kg/day) but the family had poor compliance to medications and she was lost to follow-up for the following two years.9 subsequently, the patient presented to the child health department of sultan qaboos hospital, oman, at the age of four years with a severe failure to thrive (weighing 6.1 kg and below the third centile), pallor, metabolic acidosis, hypophosphataemia, hypokalaemia and a severe chest deformity with rachitic manifestations [figure 1]. additionally, she presented with bronchopneumonia with respiratory failure which required her to be admitted to the picu for respiratory support [figure 2]. during her three-month stay in the picu, she was ventilated using pressure-regulated volume control (prvc) mode. the patient was ventilated with high ventilator settings for a short period, but for most of the time in the picu she was ventilated with moderate ventilator settings. she remained on low ventilator settings after two failed attempts to extubate her to continuous positive airway pressure (cpap). the extubation failed because of respiratory dysfunction due to myopathy, the chest deformity, electrolyte disturbance, feeding intolerance and infections. a multidisciplinary team was involved in her treatment. it was decided to start the patient gradually on cysteamine until a good response was seen. during this time, efforts were made to increase her weight using total parenteral nutrition and a high-caloric formula through continuous nasogastric tube feeding; this was successful and the patient gained 3 kg in weight. additionally, her electrolytes were corrected and she spent time in physiotherapy and play therapy with familial support. cpap was begun after three months of conventional ventilation. whilst on cpap (at a flow of 12 and 40% fraction of inspired oxygen [fio2]), the patient was conscious, figure 1: a photograph of the child on presentation with severe failure to thrive and severe muscle wasting. note the small rachitic deformed chest. figure 2: chest x-ray on admission with extensive bilateral infiltration showing the hypoplastic chest and rachitic rosary. mohamed a. el-naggari, ibtisam elnour, hussein al-kindy, aamir al-shahrabally and anas a. abdelmogheth case report | e247 figure 3: a photograph of the patient after treatment. note the marked increase in weight and the improvement of the muscle wasting and rachitic rosary. a nasogastric tube was used for continuous feeding. figure 4: chest x-ray before discharge showing the almost completely clear bilateral lung fields with improvement of the rachitic rosary. alert, tachypnoeic (at 50 breaths/min), with subcostal recession and poor bilateral air entry. an arterial blood gas (abg) test showed partial compensated respiratory acidosis with a ph of 7.30; partial pressure of carbon dioxide (pco2) at 7 kilopascals (kpa); bicarbonate (hco3) of 25.2, and partial pressure of oxygen (po2) at 9.6 kpa. after 24 hours, the patient began ventilation using the bipap® vision® ventilatory support system (vvs, respironics, philips healthcare, andover, massachusetts, usa) at inspiratory positive airway pressure (ipap)/expiratory positive airway pressure (epap) setting of 16/7, rate of 25 and 40% fio2. clinically, the patient was conscious and alert with improvement in air entry. her abg test showed a ph of 7.42; pco2 at 6.9 kpa; hco3 of 31, and po2 at 10 kpa. after two weeks, the bipap® vss settings were changed to an ipap/epap setting of 12/6, a rate of 20 and 30% fio2. initially, her weight increased incrementally at a rate of almost 0.4 kg per day due to the effects of the high calorie intake, medication and electrolyte supplementation. on follow-up of her respiratory status, there was a significant improvement of respiratory stress and chest air entry with the abg test recording a ph of 7.35, pco2 at 5.4 kpa, a hco3 of 25 and po2 at 10.8 kpa. from that point, the patient was gradually weaned from the bipap® vss; within two weeks, she was only using the ventilation system during her sleep. during the day, the patient maintained saturation on room air. after a further two weeks, the patient had gained 0.6 kg and was weaned completely from the bipap® vss even while asleep. she displayed no early morning lethargy, cyanosis or tachypnoea [figure 3]. her abg test in the morning recorded a ph of 7.4; pco2 at 4.2 kpa; hco3 of 20.1, and po2 at 10.9 kpa. before she was discharged, a chest x-ray was performed which showed a marked improvement [figure 4]. the patient was discharged with no ventilator support after four months of intensive rehabilitation, repeated counselling and familal support. nutritional support was continued with a feeding tube at home. the patient was followed-up and her respiratory status was closely monitored; she continued to show improvement in her respiratory dysfunction with normal blood gas results. discussion cystinosis is a rare metabolic disorder and the respiratory insufficiency caused by the overall respiratory myopathy is a severely invalidating and sometimes life-threatening complication.5 the current patient, initially diagnosed at 21 months, presented—after two years of non-compliance to the cystine-depleting agent, cysteamine—with failure successful management of a neglected case of nephropathic cystinosis e248 | squ medical journal, may 2014, volume 14, issue 2 to thrive, myopathy, respiratory dysfunction and failure and other associated conditions. there was evidence of diaphragmatic myopathy as the patient was hypoventilating, as proven by the abg tests and clinical evidence of emaciated intercostals, paradoxical chest movements during the first few days of admission and the preference to remain in a sitting position even during sleep. this improved with cysteamine and other modalities of support. cysteamine is the only available treatment for cystinosis, slowing the deterioration of renal function and the occurrence of extra-renal complications. it can deplete cystine from the muscles and can stop or delay the myopathy; however, it should be started early and continued for the rest of the patient’s life. although no study has yet addressed the question of whether cysteamine is an effective treatment for cystinosisassociated myopathy, gahl et al. demonstrated that cysteamine is able to deplete muscular tissue of cystine.3 through multidisciplinary teamwork—with the reintroduction of cysteamine, the correction of the electrolyte disturbance, physiotherapy, play therapy, feeding supplementation of a high-caloric formula through a nasogastric tube and a change of respiratory support to bipap® vss—the patient’s general condition and respiratory function improved and she was discharged from the picu. the patient had been tachypnoeic and showing signs of distress even with cpap ventilator support and her blood ph was suboptimal due to a high carbon dioxide concentration. the patient initially awoke drowsy in the mornings due to carbon dioxide retention. after treatment, she was fully conscious and alert in the mornings with normal blood ph and carbon dioxide levels and no signs of respiratory distress despite no ventilator support. it was evident that her carbon dioxide levels had reduced by almost 20% even after the bipap® vss was discontinued. eden et al. reported the use of nocturnal nippv in a 38-year-old male suffering from respiratory dysfunction due to cystinosis. the diagnosis was initially made when the patient was 2 years old and treatment was started at the age of 25 years.10 although mostly used for other disease processes, nippv can improve the patient’s quality of life and reduce the hospital stay and expenses for cases of cystinosis and respiratory dysfunction, as can be evidenced from the current reported case. conclusion cysteamine is currently the only available treatment for cystinosis. it is assumed that cysteamine depletes the accumulation of cystine in the muscles. in cases of established respiratory dysfunction, no treatment options have so far been describe. as evidenced in the case of nephropathic cystinosis reported here, nippv can be used in cases of myopathy for the correction of hypoventilation and respiratory dysfunction. references 1. town m, jean g, cherqui s, attard m, forestier l, whitmore sa, et al. a novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. nat genet 1998; 18:319– 24. doi: 10.1038/ng0498-319. 2. gahl wa, thoene jg, schneider ja. cystinosis. n engl j med 2002; 347:111–21. doi: 10.1056/nejmra020552. 3. gahl wa, dalakas mc, charnas l, chen kt, pezeshkpour gh, kuwabara t, et al. myopathy and cystine storage in muscles in a patient with nephropathic cystinosis. n eng j med 1988; 319:1461–4. doi: 10.1056/nejm198812013192206. 4. charnas lr, luciano ca, dalakas m, gilliatt rw, bernadini i, ishak k, et al. distal vacuolar myopathy in nephropathic cystinosis. ann neurol 1994; 35:181–8. doi: 10.1002/ ana.410350209. 5. anikster y, lacbawan f, brantly m, gochuico bl, avila na, travis w, et al. pulmonary dysfunction in adults with nephropathic cystinosis. chest 2001; 119:394–401. doi: 10.1378/chest.119.2.394. 6. kimonis ve, troendle j, rose sr, yang ml, markello tc, gahl wa. effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis. j clin endocrinol metab 1995; 80:3257–61. doi: 10.1210/jcem.80.11.7593434. 7. kleta r, bernardini i, ueda m, varade ws, phornphutkul c, krasnewich d, et al. long-term follow-up of well-treated nephropathic cystinosis patients. j pediatr 2004; 145:555–60. 8. jézégou a, llinares e, anne c, kieffer-jaquinod s, o’regan s, aupetit j, et al. heptahelical protein pqlc2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. proc natl acad sci u s a 2012; 109:e3434–43. doi: 10.1073/pnas.1211198109. 9. al-nabhani d, el-naggari m, al-sinawi r, chacko ap, ganesh a, el nour i. nephropathic cystinosis: first reported case in oman. sultan qaboos univ med j 2011; 11:503–6. 10. edens ma, van son wj, de greef mh, levtchenko en, blijham t, wijkstra pj. successful treatment of respiratory dysfunction in cystinosis by nocturnal non-invasive positive pressure ventilation. clin nephrol 2006; 66:306–9. إزاحة الستار عن السرطان ريتو الكتاكيا، اإكرام بريين، عا�سم قرييش، �سنان العزاوي، حامد البادي، �سيخة الهاجرية abstract: this article narrates a multifaceted educational journey undertaken by a medical student through a weekly scraps (surgery, clinical disciplines, radiology, anatomy, psychiatry and laboratory sciences) clinicopathological meeting held in the college of medicine & health sciences at sultan qaboos university in muscat, oman. through a presentation titled ‘unveiling cancer’, the multidisciplinary and interprofessional audience witnessed a simulated interaction between a medical student, a technologist peer and tutors in medicine, pathology and radiology. the presentation was based on the complexities of presentation, diagnosis and management of a patient with anaplastic large cell lymphoma, a rare type of non-hodgkin lymphoma, in the aftermath of a bone marrow transplantation. after describing the case, the student shared with the audience a spectrum of learning objectives, which included integration in the complex world of contemporary medicine, insight into the triumphs and travails of technology (immunohistochemistry) and peer collaboration, communication and mentorship. keywords: clinico-pathological conference; anaplastic large-cell lymphoma; immunohistochemistry; medical education; oman. امللخ�ص: ي�سف هذا املقال رحلة علمية متعددة اجلوانب قام بها طالب طب يف ملتقى عيادي-باثولوجي يعقد اأ�سبوعيا يف كلية الطب العيادية واملواد اجلراحة علوم يف مر�سية وحالت حما�رسات لتقدمي بعمان م�سقط يف قابو�س ال�سلطان جامعة يف ال�سحية والعلوم والأ�سعة والت�رسيح والأمرا�س الع�سبية والنف�سية وعلوم املختربات )يعرف اخت�سارا بـ scraps(. ويف ذلك امللتقى قدم الطالب للح�سور )وهم من تخ�س�سات علمية ومهنية خمتلفة( حما�رسة بعنوان "اإزاحة ال�ستار عن ال�رسطان" اأتاحت فر�سة طيبة لإثارة تفاعل بني طالب طب واأحد الأقران من الفنيني واأ�ساتذة يف الطب والأ�سعة وعلم الأمرا�س. وكان اأ�سا�س املحا�رسة املقدمة يعتمد على التعقيدات يف عر�س احلالة وت�سخي�سها واأ�سلوب معاجلتها يف مري�س كان م�سابا برسطان الغدد اللمفاوية الكشمي الالهودجكيني كبرية اخللية )وهي نوع نادر احلدوث من اللمفوما الالهودجكينة( حدثت نتيجة لنقل نقي العظام. وبعد اأن قدم الطالب احلالة اأ�رسك الطالب احلا�رسين يف طيف من اأهداف التعلم والتي �سملت التكامل يف عامل معقد من الطب الع�رسي، وتب�رس نافذ يف انت�سارات وإخفاقات التقنية )الكيمياء الهي�ستولوجية املناعية(، والتعاون بني الزمالء والأقران والتوا�سل والإر�ساد. مفتاح الكلمات: ملتقى عيادي-باثولوجي؛ ملفومة ك�سمية لهودجكينة كبرية اخللية؛ الكيمياء الهي�ستولوجية املناعية؛ التعليم الطبي؛ عمان. unveiling cancer *ritu lakhtakia,1 ikram burney,2 asim qureshi,3 sinan al-azawi,4 hamid al-badi,5 shaikha al-hajri5 sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e405–410, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.016. submitted 22 aug 14 revision req. 19 nov 14; revision recd. 28 dec 14 accepted 15 jan 15 departments of 1pathology and 4radiology & molecular imaging, 5college of medicine & health sciences, sultan qaboos university; departments of 2medicine and 3pathology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: lakhtakiar@yahoo.com continuing medical education the acronym ‘scraps’ stands for surgery, clinical disciplines, radiology, anatomy, psychiatry and laboratory sciences and it is the name of a weekly clinico-pathological forum held at the college of medicine & health sciences (comhs) at sultan qaboos university (squ) in muscat, oman. the forum is a one-hour interdisciplinary presentation of clinical cases with educational value for faculty and clerkship students, usually steered by divisions of medicine and surgery with diagnostic input. in a significant diversion from this practice, a pathologyled scraps session was used to focus on a triumvirate that is the foundation of 21st century academic clinical practice, in a presentation called ‘unveiling cancer’. firstly, its educational objective aimed at unifying and dissecting the complexities and challenges of disease arising from advances in therapy and technology.1 secondly, it offered an insightful analysis of the triumphs and travails of technology, using immunohistochemistry (ihc) as an example. thirdly, it highlighted the interdependency and need for dialogue among interdisciplinary and interprofessional health providers. the whole exercise was designed to simulate the learning journey undertaken by a medical graduate in a clinical scenario, mentored by a team of educators, which unfolded in a staged format to engage the audience.2 at the bedside a junior clerkship student presented a patient’s clinical profile to his physician-educator. a 24-year-old male patient presented with a two-week history of shortness of breath on mild exertion. there was no history of cough, chest pain or palpitations, nor was there any recent history of fever or weight loss. however, he had noticed a mass in unveiling cancer e406 | squ medical journal, august 2015, volume 15, issue 3 the left thigh over the past one month. the patient had undergone an allogeneic bone marrow transplant (bmt) for thalassaemia major 12 years previously, using high doses of alkylating agents as conditioning chemotherapy. on examination, he was a fit young man, not pale or icteric and with no peripheral lymphadenopathy. a respiratory system examination revealed he had reduced chest movement, a dull percussion note, reduced breath sounds and an increased vocal fremitus on the right side in the lower third of the chest. he was not anaemic but had polymorphonuclear leucocytosis and thrombocytosis. the prothrombin time showed a mild increase in the international normalised ratio. shadows of disease the radiologist recounted the salient imaging findings for the audience. an x-ray of the chest revealed a right lower lobe collapse, confirmed via computerised tomography of the chest, abdomen and pelvis [figure 1]. a small soft tissue mass was seen projecting within the lumen of the right bronchus intermedius with no significant focal enhancement. there was no significant thoracic or abdominal lymphadenopathy. the right adrenal gland showed an irregular 2 x 3.4 cm well-defined internally degenerated mass with mural enhancement. a bronschoscopy revealed an endobronchial mass. magnetic resonance imaging of the left thigh revealed an oval solid mass (15.7 x 6.3 cm) in the medial aspect of the lower half of the thigh, engulfing the belly of the gracilis muscle, extending and splaying the adductor magnus and sartorius muscles; it showed heterogenous enhancement. the neurovascular bundle and bones were free. overlying skin and subcutaneous tissue were thickened. a diagnosis of sarcoma was suggested, requiring confirmation by biopsy [figure 2]. the student analysed the case and suggested to the tutor that the two masses probably had the same aetiology. the physician and student debated the biopsy diagnosis of the endobronchial mass and the thigh mass, which had been categorised as small round blue cell tumours (srct). following immunophenotyping, the former was diagnosed as a primitive neuroectodermal tumour (pnet) and the latter as an anaplastic large cell lymphoma (alcl). the student expressed uncertainty in comprehending the application of ihc that led to these divergent diagnoses. the physician suggested that the student solve this dilemma by going to the laboratory to acquire clarity on the concepts of usage and interpretation of ihc. a quest for knowledge the student approached his former pathology teachers to fill the gaps in his knowledge. the pathologist-educator was surprised and delighted with the young student’s sense of purpose in resolving clinical applications of laboratory techniques. she recommended a short ‘back to basics’ tutorial on the principles of ihc to the medical clerk, provided by the student’s biomedical sciences peer, in order to initiate his understanding of ihc. the technologist-student succinctly explained it as an application of the immunologic principle of antigenantibody reaction on tumour tissues. in tumours which are poorly differentiated on morphology, the antigenic figure 1a & b: chest imaging (a) x-ray and (b) computed tomography scan showing a right lower lobe collapse and endobronchial mass. ritu lakhtakia, ikram burney, asim qureshi, sinan al-azawi, hamid al-badi and shaikha al-hajri continuing medical education | e407 ewing’s sarcoma/pnet and small cell (neuroendocrine) carcinoma. he illustrated a ‘shopping cart’ of antibodies, from which a panel was selected to ‘unveil’ the poorly differentiated tumour in the patient [figure 3]. the first biopsy, in a small and crushed sample (bronchial mass), showed immunoreactivity to cluster of differentiation (cd) 99 and cd30 and was negative for leukocyte common antigen (lca; a commonly employed lymphoma marker); hence the pnet interpretation. the second larger and better preserved biopsy (the thigh mass) showed positivity for the previous two antigens as well as additional markers: anaplastic lymphoma kinase (alk)-1 and cd43 [figure 4]. this led to a final diagnosis of alcl. both masses represented alcl on final review. with this patient as an example, the pathologist listed several pitfalls in the contextual interpretation of ihc: small and poorly preserved tissue resulted in a challenge for interpretation; the primary site would have been the better and more reliable biopsy source for antigenic expression; antibodies like cd99 are cross-reactive with other tumours; and lca, which is usually expressed in lymphoid cells, is negative in alcl (a rare type of lymphoma).3–5 he also explained that alk immunohistochemical positivity in alcl was due to the abnormal accumulation of a chimeric protein due to a nucleophosmin (npm)1alk translocation t(2;5)(p23;35), which can be further confirmed by fluorescence in situ hybridisation. the student completed his laboratory search for the final diagnosis and returned to the physiciantutor to discuss this unusual and educative case and its management. fidelity in specific tumours could be identified in vitro by the application of the corresponding antibody on sections of the tumour tissue, thus ‘unveiling’ its histogenetic differentiation. this, in turn, would direct the choice of therapy or provide an insight into the tumour’s biological behaviour. armed with this knowledge the medical student proceeded to meet the reporting pathologist to demystify the two divergent diagnoses rendered in the patient. the ‘final’ diagnosis the reporting pathologist listed a short differential diagnosis for srct in this young adult including rhabdomyosarcoma, non-hodgkin lymphoma (nhl), figure 2a & b: a: computed tomography scan of the abdomen, showing an irregular mass in the right adrenal gland. b: magnetic resonance imaging of the thigh, showing a large oval solid soft tissue mass in the medial aspect of the lower thigh. figure 3: shopping cart illustrating the panel of antibodies used for immunophenotypic characterisation of the biopsies from the bronchial and thigh masses. lca = leukocyte common antigen; myod1 = myoblast determination protein 1; cd = cluster of differentiation. unveiling cancer e408 | squ medical journal, august 2015, volume 15, issue 3 figure 4a & b: haematoxylin and eosin stains of biopsies from the (a) bronchial mass and (b) thigh mass showing a malignant round blue cell tumour at x100 magnification. boxes display immunohistochemistry patterns in both biopsies: cd99, cd30 positive/lca negative. additional markers on the thigh biopsy clinched the diagnosis of anaplastic large cell lymphoma by immunoreactivity for alk and cd43. cd = cluster of differentiation; lca = leukocyte common antigen; alk = anaplastic lymphoma kinase. complexities of 21 st century cancer management after the student had recounted his learning experience, the physician outlined the two questions he should now consider as a medical student. first, in view of the past treatment for thalassaemia major with allogeneic bone marrow transplantation, could the alcl be regarded as a ‘secondary’ cancer? second, what was unique about alcl which justified the elaborate attempts made to accurately characterise this type of nhl? firstly, in 21st century practice of medicine, the success of a cancer cure comes with the downside of diagnosis and the treatment of ‘secondary’ cancers that arise on a background of immunosuppression. immunosuppression may be secondary to therapy (chemoradiotherapy or conditioning for bmt) or due to the first malignancy itself, such as haematolymphoid malignancies.6 the incidence increases with time and is approximately 15% at 15–20 years from the time of the first treatment.6 secondary cancers are usually acute non-lymphocytic leukaemia, nhl or solid tumours (especially in the field of radiation). amongst nhl, the most common sub-type is b-cell lymphoma; if immunosuppression-driven, it is associated with the epstein-barr virus. this patient received high doses of alkylating agents as part of the conditioning regimen for bmt and this may well have caused the alcl. the second question relates to understanding alcl; this is one of the several types of mature t/ natural killer (nk)-cell lymphomas, accounting for almost a quarter of all the t/nk-cell lymphomas in north america, around 6% of the t cell lymphomas in asia and 10% of all nhls in oman.7–9 alcl presents either with cutaneous involvement only (calcl) or with systemic involvement (salcl).10 the significant majority of patients with salcl have a translocation t(2;5) causing a npm-alk fusion gene, resulting in an 80 kilodalton protein. an ihc demonstration of this protein is helpful in several ways: in diagnosing difficult cases (as in this patient), defining the prognosis and as a predictive marker for treatment with a specific tyrosine kinase inhibitor (crizotinib).11 the presence of alk translocation is an independent favourable prognostic factor. alk-positive calcl usually presents in the first three decades of life and, despite the advanced stage at presentation, has a better prognosis (around 75% overall survival at five years).11 alk-negative salcl, on the other hand, usually occurs in the elderly with a poor overall survival rate of less than 25% at five years.11 as demonstrated in this patient, alcl also strongly expresses cd30 antigen, which promotes cell proliferation and survival, upregulates the susceptibility to apoptosis signalling and downregulates the immune response. all of these factors make cd30 antigen an attractive target for diagnosis and targeted treatment with brentuximab vedotin (the anti-cd30 antibody).12 thus, ihc detection of characteristic molecular alterations provide unprecedented targets for the management of alcl. the session concluded with the student acknowledging the unique patient-to-laboratory learning journey he had undertaken through this patient’s disease complexities; exhorting his peers in the audience to replicate such learning opportunities in their clinical years and beyond. ritu lakhtakia, ikram burney, asim qureshi, sinan al-azawi, hamid al-badi and shaikha al-hajri continuing medical education | e409 presenter-audience dialogue. it is a golden opportunity for the novice medical clerk to embark on a journey of exploration, confidence and communication. this scraps presentation serves to emphasise the significance of the physician-pathologist dialogue where balanced use and interpretation of sophisticated tests and imaginative educational methods extended beyond the curriculum to groom physicians-in the-making. references 1. epstein rj. learning from the problems of problem-based learning. bmc med educ 2004; 4:1. doi: 10.1186/1472-6920-4-1. 2. nestel d, groom j, eikeland-husebø s, o'donnell jm. simulation for learning and teaching procedural skills: the state of the science. simul healthc 2011; 6:s10–3. doi: 10.1097/ sih.0b013e318227ce96. 3. sung co, ko yh, park s, kim k, kim w. immunoreactivity of cd99 in non-hodgkin’s lymphoma: unexpected frequent expression in alk-positive anaplastic large cell lymphoma. j korean med sci 2005; 20:952–6. doi: 10.3346/ jkms.2005.20.6.952. 4. devoe k, weidner n. immunohistochemistry of small roundcell tumors. semin diagn pathol 2000; 17:216–24. 5. minoo p, wang hy. alk-immunoreactive neoplasms. int j clin exp pathol 2012; 5:397–410. 6. bhatia s, ramsay nk, steinbuch m, dusenbery ke, shapiro rs, weisdorf dj, et al. malignant neoplasms following bone marrow transplantation. blood 1996; 87:3633–9. 7. lim ms, de leval l, quintanilla-martinez l. commentary on the 2008 who classification of mature tand nk-cell neoplasms. j hematop 2009; 2:65–73. doi: 10.1007/s12308-0090034-z. 8. vose j, armitage j, weisenburger d; international t-cell lymphoma project. international peripheral t-cell and natural killer/t-cell lymphoma study: pathology findings and clinical outcomes. j clin oncol 2008; 26:4124–30. doi: 10.1200/ jco.2008.16.4558. 9. advanced general medicine conference: joint conference of the royal college of physicians uk, ministry of health, oman and sultan qaboos university, 20th–23rd february 2010. sultan qaboos univ med j 2010; 10:293. 10. stein h, foss hd, dürkop h, marafioti t, delsol g, pulford k, et al. cd30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. blood 2000; 96:3681–95. 11. eyre ta, khan d, hall gw, collins gp. anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease. eur j haematol 2014; 93:455–68. doi: 10.1111/ejh.12360. 12. pro b, advani r, brice p, bartlett nl, rosenblatt jd, illidge t, et al. brentuximab vedotin (sgn-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase ii study. j clin oncol 2012; 30:2190–6. doi: 10.1200/ jco.2011.38.0402. 13. nash jr. pathology in the new medical curriculum: what has replaced the subject courses? pathology oncol res 2000; 6:149–54. doi: 10.1007/bf03032367. 14. sadofsky m, knollmann-ritschel b, conran r, prystowsky mb. national standards in pathology education: developing competencies for integrated medical school curricula. arch pathol lab med 2014; 138:328–32. doi: 10.5858/arpa.20130404-ra. epilogue the narrative of this patient is evocative of secondary cancers (post-bmt lymphoproliferative disorders), iatrogenic outcomes (infectious predisposition), the challenges of technology (ihc), and cutting-edge personalised medicine (molecular targets in oncologic practice). all of these provide the learning content that the scraps arena aims for. however, in this interactive scraps presentation, one of an infinitesimal number of strategies medical educators can adopt was used to make the clinico-pathological session a simulated exercise in reality.2 integrated curricula in leading educational centres have introduced other methods like pathology special study modules or pathology-led problem-based learning to achieve this synthesis.13 a recent review from the usa recommended the inclusion of the vital competency of ‘diagnostic medicine’ overseen by the liaison committee on medical education to fulfil holistic integration of the laboratory with clinical practice.14 curricular time in clinical years often precludes allotting additional hours to revisit the laboratories. the concept that assessment drives learning has prompted uk educators to suggest that objective structured clinical examinations in clinical assessment should include pathologists in the design and evaluation process.15 a common phenomenon in medical students’ learning is emphasis on the concept and neglect of procedural knowledge of laboratory inputs, which can later lead to poor strategising when requesting and interpreting tests.16 this case presentation brings this issue to the fore and makes a case for finding more opportunities to reinforce laboratory education beyond the didactic curricular hours, perhaps in the format of interprofessional education.17 novel medical curricula, including the world federation for medical education-accredited integrated curriculum offered at the comhs of squ, abound in innovative strategies for improving the teaching skills of students.18–20 the scraps forum is one more arena where this can be effectively practiced. the art of problem-solving and the shaping of professional identity is an integral part of development for the budding physician;21 brain storming and in-depth discussions prior to such presentations identify grey areas in learning for the learner-presenter, the educator and the target audience; the outcome benefits all three. grounded in the grim environs of disease and its increasing complexities, learning and teaching can be made mutual and responsive. it can and should achieve a new dimension to the teacher-taught relationship; embed student-peer learning; integrate clinical, basic and diagnostic specialties; and forge http://dx.doi.org/10.1186/1472-6920-4-1 http://dx.doi.org/10.1097/sih.0b013e318227ce96 http://dx.doi.org/10.1097/sih.0b013e318227ce96 http://dx.doi.org/10.3346/jkms.2005.20.6.952 http://dx.doi.org/10.3346/jkms.2005.20.6.952 http://dx.doi.org/10.1007/s12308-009-0034-z http://dx.doi.org/10.1007/s12308-009-0034-z http://dx.doi.org/10.1200/jco.2008.16.4558 http://dx.doi.org/10.1200/jco.2008.16.4558 http://dx.doi.org/10.1111/ejh.12360 http://dx.doi.org/10.1200/jco.2011.38.0402 http://dx.doi.org/10.1200/jco.2011.38.0402 http://dx.doi.org/10.1007/bf03032367 http://dx.doi.org/10.5858/arpa.2013-0404-ra http://dx.doi.org/10.5858/arpa.2013-0404-ra unveiling cancer e410 | squ medical journal, august 2015, volume 15, issue 3 answers: 1: c; 2: c; 3: a; 4: d; 5: b; 6: a; 7: a; 8: c; 9: b; 10: a, d, e. 15. mcmahon r. pathology education: sy17-1 preserving pathology in an integrated curriculum in the uk. pathology 2014; 46 suppl 2:s31. doi: 10.1097/01.pat.0000454192.05043.96. 16. schmidmaier r, eiber s, ebersbach r, schiller m, hege i, holzer m, et al. learning the facts in medical school is not enough: which factors predict successful application of procedural knowledge in a laboratory setting? bmc med edu 2013; 13:28. doi: 10.11 86/1472-6920-13-28. 17. blue av, mitcham m, smith t, raymond j, greenberg r. changing the future of health professions: embedding interprofessional education within an academic health center. acad med 2010; 85:1290–5. doi: 10.1097/acm.0b 013e3181e53e07. 18. albarwani s, al-saadoon m, al-rawas o, al-yaarubi s, al-abri r, al-lamki l, et al. reflections on the academic accreditation of the md programme of the college of medicine & health sciences, sultan qaboos university, oman. sultan qaboos univ med j 2014; 14:e7–11. 19. lakhtakia r. health professions education in oman: a contemporary perspective. sultan qaboos univ med j 2012; 12:406–10. 20. erlich dr, shaughnessy af. student–teacher education programme (step) by step: transforming medical students into competent, confident teachers. med teach 2014; 36: 322–32. doi: 10.3109/0142159x.2014.887835. 21. lingard l, garwood k, schryer cf, spafford mm. a certain art of uncertainty: case presentation and the development of professional identity. soc sci med 2003; 56:603–16. doi: 10.1016/s0277-9536(02)00057-6. cme quiz questions 1. which of the following is classified as a small round blue cell tumour? a. adenocarcinoma b. hepatocellular carcinoma c. lymphoma d. squamous cell carcinoma 6. which second malignancy is most common after bone marrow transplantation? a. lymphoma/leukaemia b. carcinoid c. sarcoma d. glioma 2. a specialised histotechnique commonly used in identifying the cell lineage in a poorly differentiated tumour is: a. enzyme histochemistry b. electron microscopy c. immunohistochemistry d. mucin histochemistry 7. which one of the following groups of chemotherapy is most often associated with an increased risk of second malignancy? a. alkylating agents b. antimetabolites c. vinca alkaloids d. anthracyclines 3. which antibody is immunoreactive with the majority of alcl? a. alk-1 b. cd20 c. cd99 d. s-100 8. a total of 85% of alcl patients have a translocation, t(2;5) leading to npm-alk fusion gene, resulting in the translation of a 80 kilodalton protein. which one of the following agents is now being used as a targeted agent to treat alcl? a. imatinib b. gefitinib c. crizotinib d. sunitinib 4. which of the following cell lineages do most alcl belong to? a. b b. dendritic c. histiocytic d. t 9. brentuximab vedotin has been approved by the fda for the treatment of relapsed alcl. to which class of drugs does brentuximab vedotin belong? a. chemoradiotherapy b. chemo-immunotherapy c. monoclonal antibody d. tyrosine kinase inhibitor 5. which antigen expressed on the alcl cell also serves as a target for treatment with a therapeutic antibody? a. bcl-2 b. cd30 c. cd43 d. cd3 10. t(2;5) is present in 85% of alcl cases. if present, the marker could be used for which of the following purposes? check all correct answers. a. diagnosis b. staging c. grading d. prognosis e. predictive marker alcl = anaplastic large cell lymphoma; alk = anaplastic lymphoma kinase; bcl-2 = bacillus collagen-like antigen 2; cd = cluster of differentiation; npm = nucleophosmin; fda = food and drug administration. http://dx.doi.org/10.1097/01.pat.0000454192.05043.96 http://dx.doi.org/10.1186/1472-6920-13-28 http://dx.doi.org/10.1186/1472-6920-13-28 http://dx.doi.org/10.1097/acm.0b013e3181e53e07 http://dx.doi.org/10.1097/acm.0b013e3181e53e07 http://dx.doi.org/10.3109/0142159x.2014.887835 http://dx.doi.org/10.1016/s0277-9536%2802%2900057-6 sir, i read the recent on acute abdomen in dengue with great interest.1 i would like to share with your readers experience on this specific issue of dengue. indeed, the classical manifestation of dengue is high fever with haemorrhagic diathesis. the common laboratory triad of testing for thrombocytopenia and haemoconcentration and atypical lymphocytosis can be helpful in presumptive diagnosis;2 however, sometimes unusual clinical manifestations can be seen.3 gastrointestinal manifestations of dengue are not a rare manifestation, and cannot be overlooked. in a recent report from mexico, ramos-de la medina et al. noted that “close to 67% of patients with dengue fever have abdominal and gastrointestinal symptoms.”3 this rate is very high. any organs in the gastrointestinal tract can be involved in the infection. there are various gastrointestinal manifestations in dengue. bleeding in the gastrointestinal tract can also be seen although it is not common.4 thrombocytopenia is the main predisposing factor for gastrointestinal bleeding in dengue.5 if we now focus on hepatic involvement, hepatitis due to dengue is also a possibility and abnormal liver function tests are not uncommon.3 based on the author’s experience, about one-third of dengue cases have hepatitis and 8% of these cases can end up with severe complications such as hepatic encephalopathy.6 abdominal pain can also be the manifestation in dengue and this is classified as an atypical manifestation.7 indeed, abdominal pain is not uncommon and is accepted as an important warning sign in dengue.8,9 the severity of dengue is strongly relating to the presence of abdominal pain.10 in a recent article from india, it was reported as being seen in up to 70% of the paediatric cases.8 conclusively, acute abdomen can be a first presentation of dengue and conservative management can be used similar to general dengue cases. however, it should be noted that co-morbidity of the disorder that needs surgical management is possible. abdominal pain is an important warning sign that can be seen in either dengue or other acute febrile illness.11 nevertheless, mustafa et al. reported that abdominal pain is a more common presentation in dengue compared to other tropical acute febrile illness.12 in a recent report by shamim, many conditions can co-present with dengue. some co-morbidities can be serious and require surgical management. these include, for example, acute cholecystitis and acute appendicitis.13 it is suggested that dengue must be the differential diagnosis of any cases from the endemic area, south and southeast asia, which present with unexplained high fever.2 also, abdominal pain might be the main complaint and, if vital sign monitoring is not done adequately to detect the fever, the case of dengue can be missed. furthermore, although dengue infection can be confirmed in the case with acute abdomen, it is still necessary to rule out any possible co-morbidity. the use of abdominal ultrasonography can help determine the intrabdominal abnormalities in dengue and rule out other causes of abdominal pain.14 viroj wiwanitkit wiwanitkit house, bangkhae, bangkok, thailand e-mail: wviroj@yahoo.com squ med j, february 2012, vol. 12, iss. 1, pp. 680-681, epub. 7th feb 12 submitted 5th jun 11 accepted 14th sep 11 رد على: البطن احلادة كعرض حلمى الدنك النزفية re: dengue haemorrhagic fever presenting as acute abdomen letter to editor viroj wiwanitkit letter to editor | 681 references 1. al-araimi h, al-jabri a, mehmoud a, al-abri s. dengue haemorrhagic fever presenting as acute abdomen. sultan qaboos univ med j 2011; 11:265–8. 2. ramos-de la medina a, remes-troche jm, gonzález-medina mf, anitúa-valdovinos mdel m, cerón t, zamudio c, et al. abdominal and gastrointestinal symptoms of dengue fever. analysis of a cohort of 8559 patients. gastroenterol hepatol 2011; 34:243–7. 3. wiwanitkit v. dengue fever: diagnosis and treatment. expert rev anti infect ther 2010; 8:841–5. 4. wiwanitkit v. bleeding and other presentations in thai patients with dengue infection. clin appl thromb hemost 2004; 10:397–8. 5. wang jy, tseng cc, lee cs, cheng kp. clinical and upper gastroendoscopic features of patients with dengue virus infection. j gastroenterol hepatol 1990; 5:664–8. 6. wiwanitkit v. liver dysfunction in dengue infection: an analysis of the previously published thai cases. j ayub med coll abbottabad 2007; 19:10 –12. 7. gulati s, maheshwari a. atypical manifestations of dengue. trop med int health 2007; 12:1087–95. 8. mittal h, faridi mm, arora sk, patil r. clinicohematological profile and platelet trends in children with dengue during 2010 epidemic in north india. indian j pediatr 2011 oct 29. epub ahead of print. 9. narvaez f, gutierrez g, pérez ma, elizondo d, nuñez a, balmaseda a, et al. evaluation of the traditional and revised who classifications of dengue disease severity. plos negl trop dis 2011; 5:e1397. 10. giraldo d, sant’anna c, périssé ar, march mde f, souza ap, mendes a, et al. characteristics of children hospitalized with dengue fever in an outbreak in rio de janeiro, brazil. trans r soc trop med hyg 2011; 105:601–3. 11. kalayanarooj s. dengue classification: current who vs. the newly suggested classification for better clinical application? j med assoc thai 2011; 94:s74–84. 12. mustafa b, hani aw, chem yk, mariam m, khairul ah, abdul rasid k, et al. epidemiological and clinical features of dengue versus other acute febrile illnesses amongst patients seen at government polyclinics. med j malaysia 2010; 65:291–6. 13. shamim m. frequency, pattern and management of acute abdomen in dengue fever in karachi, pakistan. asian j surg 2010; 33:107–13. 14. wu kl, changchien cs, kuo ch, chiu kw, lu sn, kuo cm, et al. early abdominal sonographic findings in patients with dengue fever. j clin ultrasound 2004; 32:386–8. 1department of medicine, armed forces hospital, muscat, oman; 2department of medicine, oman medical specialty board, muscat, oman; 3department of child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: siham_ss@hotmail.com خصائص التهاب الكبد الوبائي ب يف عينة من املرضى العمانيني خالد النعماين، علي املقبايل، �شهام ال�شنانية امللخ�ص: الهدف: هدفت الدرا�شة لو�شف اخل�شائ�س الدميوغرافية والفريو�شية لفريو�س التهاب الكبدي الوبائي ب املزمن يف جمموعة من املر�شى العمانيني ولتقييم ب�شكل غري مبا�رس فعالية برامج التطعيم �شد فريو�س التهاب الكبدي الوبائي ب وا�شرتاتيجية اللحاق بالتطيعم. الطرق: درا�شة ا�شتعادية لكل املر�شى اللذين يعانون من التهاب الكبدي الوبائي ب املزمن ومتت معاينتهم وتقييمهم يف عيادة الكبد يف م�شت�شفى القوات امل�شلحة، م�شقط، �شلطنة عمان، بني يناير2009 واأبريل 2011. النتائج: �شملت الدرا�شة ما جمموعه 154 مري�شا ا�شتوفوا معايري اال�شتمال يف الدرا�شة. كان متو�شط عمر املر�شى امل�شابني 33 �شنة مع ن�شبة %72.7 منهم اأكرب من 27 عاما. �شكلت االإناث ن�شبة %47.7 من املر�شى. اأكرث من ن�شف املر�شى مت حتويلهم من عيادتي احلمل والوالدة )%29.2( وبنك الدم )%22.1( يف امل�شت�شفى. وجد تاريخ عائلي لالإ�شابة بالتهاب الكبدي الوبائي ب املزمن يف %70 من املر�شى. فح�س املولد امل�شاد ال�شطحي لفريو�س الكبدي الوبائي ب )hepatitis b surface antigens( كان اإيجابيا يف ما جمموعه %95 من املر�شى. وجدت امل�شادات اال�شا�شية للفريو�س negative( ب�شكل منفرد يف %5 من املر�شى فقط. كان فح�س مولد امل�شادات اي للفريو�س )hepatitis b core antibodies( hepatitis b e-antigen( �شلبيا عند معظم املر�شى )%96(. وجد اأن معدل م�شتوى احلم�س النووي للفريو�س كان منخفظا )اأقل من 2,000 وحدة دولية/مل( يف غالبية املر�شى )%77.9(. لوحظ وجود عالمات تليف الكبد من خالل فحو�شات االأ�شعة يف ن�شبة %5 من املر�شى. االأقلية من املر�شى اي ما ن�شبته %9 ا�شتدعت العالج. اخلال�سة: مايقارب من %50 من املر�شى امل�شابني من االإناث، غالبيتهم يف �شن االإجناب. يجب على ال�شلطات الطبية يف عمان اأن تدر�س �شيا�شة تطبيق فح�س جميع الن�شاء احلوامل باإ�شتخدام اختبارات التهاب الكبدي الوبائي ب يف امل�شل الكاملة. مفتاح الكلمات: االلتهاب الكبدي الوبائي ب املزمن؛ لقاحات التهاب الكبد الوبائي ب؛ الوقاية واملكافحة؛ املتربعون بالدم؛ عمان. abstract: objectives: this study aimed to describe the demographic and virological characteristics of chronic hepatitis b virus (hbv) infection in a sample of omani patients, and indirectly assess the efficacy of hepatitis b vaccination programmes and catch-up strategies. methods: a retrospective study was undertaken of all patients with chronic hbv infections evaluated and followed-up at the hepatology clinic of the armed forces hospital (afh), muscat, oman, between january 2009 and april 2011. results: a total of 154 patients met the inclusion criteria. the mean age of infected patients was 33 years with 72.7% being over 27 years. females constituted 47.7% of the patients. half of the cohort was referred either from the afh’s obstetric clinic (29.2%) or its blood bank (22.1%). a family history of chronic hbv infection was present in 70% of patients. a total of 95% had positive hepatitis b surface antigens, while only 5% had isolated total hepatitis b core antibodies. most patients (96%) were hepatitis b e-antigen-negative. the majority (77.9%) had low hbv dioribonucleic acid levels of <2,000 iu/ml. radiological features of liver cirrhosis were observed in 5%. patients requiring treatment were in the minority (9%). conclusion: almost 50% of the infected patients were female, the majority being of childbearing age. medical authorities in oman should consider enforcing a screening policy for all pregnant women using complete hepatitis b serological testing. keywords: hepatitis b, chronic; hepatitis b vaccines; hepatitis b, prevention and control; blood donors; oman. characteristics of hepatitis b infection in a sample of omani patients khalid al-naamani,1 ali al-maqbali,2 *siham al-sinani3 clinical & basic research advances in knowledge hepatitis b vaccination has led to a lower prevalence of hepatitis b infection in the younger omani population as compared to older age groups. the postulated vaccination failure rate determined by this study (4%) is in keeping with internationally-documented figures. almost 50% of the infected patients in this study were female, and the majority was of childbearing age. this could lead to a higher number of infected children in the future if these potential mothers are not identified by screening and then managed appropriately. most patients had chronic inactive hepatitis b virus infections while a minority had active infection requiring therapy. application to patient care this study recommends that prevention of hepatitis b virus (hbv) infection be enforced by obligatory antenatal screening of all pregnant women, regardless of a history of previous testing or vaccinations, using a complete hepatitis b serology (including hepatitis b core antibodies) as the standard of care. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 380-385, epub. 25th jun 13 submitted 16th sep 12 revisions req. 18th nov 12 & 10th mar 13; revisions recd. 17th jan & 18th mar 13 accepted 14th apr 13 khalid al-naamani, ali al-maqbali and siham al-sinani clinical and basic research | 381 despite the introduction of effective vaccinations in 1981, hepatitis b virus (hbv) infection is still a major health problem with approximately 350 to 400 million people infected worldwide.1 a total of 75% of those infected live in asia.2,3 chronic hbv infection is responsible for 60–80% of the cases of liver cancer around the world.4 in addition, 25–40% of infected patients are expected to die from hbv-related complications such as decompensated cirrhosis and hepatocellular carcinoma (hcc). this means that approximately one million people around the globe die each year from hbv infections and related complications. this high rate of mortality makes chronic hbv infection the ninth leading cause of death worldwide.5 the estimated prevalence of chronic hbv infection in oman is considered to be intermediate at 2–7%;6 however, there are no true prevalence data to substantiate this figure. only a few studies have been published concerning the prevalence of hbv infection in omani patients— those with sickle cell disease and renal disorders requiring dialysis or renal transplant—and these studies had small sample sizes.7,8 the prevalence of hepatitis b among pregnant omani women in 2006 was found to be 7.1%, with 0.5% being hepatitis b e-antigen (e-ag)-positive.9 in oman, hepatitis b vaccinations were carried out for all children born in the period from 1984 to 1990, with a procedure of three serial doses at 0, 1 and 6 months. the goal of this programme was to ensure that by the year 2005 everyone under 21 years of age would have been vaccinated against hbv.10 in addition to the above measures, blood bank screening for hbv, using hepatitis b surface antigens (hbsag) as the only marker, was started in 1990. in 2009, the screening of all blood units using hbsag as well as hepatitis b core antibodies (anti-hbc) was implemented. to date, however, routine screening of pregnant women is not yet the standard of care in ministry of health (moh) institutions.10 the primary aim of this study was to record the descriptive, demographic and virological characteristics of chronic hbv mono-infection among omani patients. the secondary aim was an indirect assessment of the efficacy of the hepatitis b vaccination programmes and the catch-up strategies in reducing the prevalence of chronic hbv within the age group targeted for vaccination. methods this was a retrospective study based on a review of the chart and computer data of all patients with chronic hbv infection, who attended and had regular follow-up at the hepatology clinic of the armed forces hospital (afh), oman, between january 2009 and april 2011. the afh is one of three tertiary hospitals located in the area of the capital city, muscat. almost one third of the omani population is entitled to receive medical services from the afh. entitled patients are referred from all over oman, and this study's sample is therefore representative of the omani population. any demographic data missing from the charts and computer data review were obtained by telephone. ethical approval for the study was obtained from the afh administration. the inclusion criteria for the study were all omani patients in the above-specified time period who were over 13 years old and had chronic hbv infection. non-omani patients and patients with missing data were excluded, as well as patients coinfected with hepatitis b and other viruses, such as hepatitis c or human immunodeficiency virus (hiv). these latter were excluded because coinfection with hiv and hepatitis c is known to change the natural history of hepatitis b. patients co-infected with hiv tend to have a higher rate of chronic hepatitis b, a high rate of replication and a low rate of hbsag and e-ag seroconversion. a total of 154 patients met the inclusion criteria. the following data were collected: patient demographic data [table 1], hbv serology using the architect i2000sr (abbott diagnostics, lake forest, illinois, usa) and molecular markers using the cobas® taqman® analyzer (roche diagnostics international ltd., rotkreuz, as 70% of the patients had a positive family history of hbv infection, and bearing in mind that hbv can be transmitted horizontally, unvaccinated or non-immune family members should also be vaccinated. patients should be educated that the traditional medical practice of cautery may increase the rate of virus transmission. characteristics of hepatitis b infection in a sample of omani patients 382 | squ medical journal, august 2013, volume 13, issue 3 switzerland) for amplification and detection. it has a lower limit of detection of 20 iu/ml and a linear dynamic range, with an upper limit of 1.7 × 108 iu/ml [table 2]. the markers of liver injury (liver enzymes and function) were detected using a cobas® 6000 (c501 module) clinical chemistry analyzer (roche diagnostics international ltd., rotkreuz, switzerland) and with liver radiological investigations. statistical analysis was performed using the statistical package for the social sciences (spss) version 16 (ibm corp., chicago, illinois, usa). data are presented as a mean or, when indicated, as an absolute number and a percentage. results a total of 170 patients were initially included in the study, with 16 patients subsequently excluded for the following reasons: one died, two were co-infected with hepatitis c and 13 patients had missing data. there were therefore 154 patients included in the final analysis. the mean age of the patients was 33 years, ranging from 13–78 years old. a total of 5 patients (3.2%) were 13–21 years old, 37 patients (24.1%) were 22–27 years old, and 112 patients (72.7%) were over 27 years old [figure 1]. almost half of the patients (47.4%) were female. half of the cohort was referred from obstetric clinics and blood banks, reflecting the efficiency of screening certain high-risk groups in identifying hbv-infected patients. a family history of chronic hepatitis b was present in 70% of the patients, with most having more than one family member infected with hbv. a total of 65% had undergone traditional therapy in the form of cautery (wasm in arabic), which is used by omani healers to treat patients with jaundice. this therapy entails applying the tip of a small hot rod to certain parts of the body, particularly the abdomen and the arms. a total of 40% of the females had ear and/or nose piercings that had been performed at home or by local dealers using nonsterile needles. a history of blood transfusions and surgeries was present in 15% and 6% of the patients, respectively. a total of 95% had positive hbsag while only 5% had isolated total anti-hbc. all of the isolated anti-hbc patients (negative hbsag and hepatitis b surface antibodies [anti-hbs]) had a low to undetectable viral load. a total of 5 patients had figure 1: the age distribution of the hepatitis b-infected omani patients. table 1: demographic data of the studied patients demographic characteristic n = 154 n (%) age (mean) 33 years gender female 73 (47.4) male 81 (52.6) referred from obstetric clinics 45 (29.2) blood bank 34 (22.1) history of family history of hepatitis b 108 (70) traditional cautery (wasm) 100 (65) body piercing(s) 62 (40) blood transfusion(s) 7 (4.5) surgery(ies) 28 (18.2) wasm = traditional medicine technique where the tip of a small hot rod is applied to certain parts of the body, particularly the abdomen and the arms, as a method of treating jaundice. table 2: viral, serological and molecular markers of hepatitis b infection marker n = 154 n (%) hbsag and anti-hbc 146 (94.8) isolated anti-hbc (obi) 8 (5.2) e-ag 6 (3.9) anti-e-ag 145 (94.2) hbv dna levels <2000 iu/ml 120 (77.9) 2000–20,000 iu/ml 23 (14.9) >20,000 iu/ml 11 (7.1) hbsag = hepatitis b surface antigen; anti-hbc = hepatitis b core antibodies; obi = occult hepatitis b infection; e-ag = hepatitis b e-antigen; anti-e-ag = hepatitis b e-antigen antibody; hbv dna = hepatitis b virus dioribonucleic acid. khalid al-naamani, ali al-maqbali and siham al-sinani clinical and basic research | 383 a repeatedly undetectable viral load (i.e. <20 iu/ ml) and did not exhibit any rise in hbsag after one dose of the hepatitis b vaccination. one patient had a viral load of 80 iu/ml and two patients had viral loads from 30–75 iu/ml. the age of these patients ranged from 30–60 years old. most of our patients (96%) were e-ag-negative. the hepatitis b dioribonucleic acid (hbv dna) level was >20,000 iu/ml in 7%, between 2,000 iu/ ml and 20,000 iu/ml in 15%, and the rest had low dna levels of <2,000 iu/ml. elevated liver enzymes were observed in all dna level categories and radiological features of liver cirrhosis were seen in 5% of the patients. a minority of our patients (9%) required treatment based on international criteria and guidelines. discussion the estimated prevalence of hbv infection in oman is between 2–7%.11,12 the most common source of hbv transmission in intermediateand high-prevalence areas is vertical transmutation.13–16 the majority of the patients in this study were hb e-ag-negative and had a family history of hbvinfected members. this illustrates that the majority of the infections were acquired during the early years of life through vertical, perior postnatal transmission. the introduction of hbv vaccinations in taiwan in 1984 reduced the rate of hbv infection among children from 10% in 1984 to only 1.3% in 1994.17 the reduction in hbv infection was also associated with a reduction in the incidence of hcc.17–19 the introduction of hbv vaccinations in oman in august 1990, using a procedure of three serial doses (at birth, one month and 6 months) as well as a catch-up strategy of school campaigns from 2001 to 2005, has undoubtedly reduced the number of new cases of hbv infection in the country.10,20 this study revealed that the prevalence of hbv infection among those born after 1991 is low (around 4%), which is in keeping with the 5–10% expected failure rate of hbv vaccinations.21,22 however, the rate of infection among those born before the introduction of the vaccination, but within the period of the catch-up campaigns, is high. this can be partly explained by the fact that many of the people targeted by the catch-up campaigns received the vaccination without being tested to determine if they were infected. the other major factor contributing to the high rate of infection among this group is the length of time the catch-up campaigns took to cover the entire country, thus increasing the risk of unvaccinated children contracting the infection from infected family members. the moh in oman does not currently support a policy of screening pregnant women for viral hepatitis.10 however, a substantial percentage of our patients (29.2%) were referred from obstetric clinics whereas 22.1% were referred from blood banks. jonas et al. demonstrated that if screening were only applied to high-risk pregnant women, 47% of infected women would not have been identified.23 cowan et al. confirmed this and showed that screening pregnant women for hbv in a low-prevalence area based on identifiable risk factors may miss up to 50% of infected pregnant women.24 the usa centers for disease control and prevention recommend that the screening of pregnant women for hepatitis b be the standard of care regardless of previous testing or vaccinations.25 this screening will identify those patients who might need treatment. the benefit of screening is not limited to pregnant women, but also helps to identify infants who require prophylaxis, and other individuals who are in contact with infected people and who would also benefit from testing, counselling, vaccination and, if indicated, therapy. therefore, we believe that the screening of pregnant women in oman is a necessity. the prevalence of occult hbv infection (obi)— which is defined as the presence of hbv dna in the liver of individuals testing hbsag-negative with currently available assays—varies from one country to another. it has been reported to be as low as 0.56% among blood donors in the uk, and as high as 76% among blood donors in ghana.26 kaminski et al. reported a prevalence of isolated anti-hbc (negative hbsag and negative anti-hbs) to be 2.8% among 200 random hbsag-negative omani blood donor samples.27 the current study revealed that 5% of patients had obi [table 2]. the presence of isolated antihbc in a low-endemic area can be due to falsepositive test results.28 however, an isolated antihbc in intermediate to high prevalence areas can be due to long-standing infections with a low level of replication.29 several possibilities have been suggested to explain the mechanisms of obi. these characteristics of hepatitis b infection in a sample of omani patients 384 | squ medical journal, august 2013, volume 13, issue 3 include, 1) a surface gene ‘escape’ mutation leading to decreased reactivity of the hbsag detection assay;30,31 2) a mutation within the polymerase domain that results in a lower production of hbv dna and hbsag expression;32 3) the formation of an hbv-containing immune complex;33 4) altered host immune response,34 and 5) co-infection with other viruses such as hepatitis c and the hepatitis delta virus that may decrease production of hbv dna and increase hbsag clearance.35–39 due to the high reported prevalence of obi in intermediateto high-prevalence areas, the screening of high-risk groups should not be restricted to hbsag alone but include total antihbc as well. in 2009, the central blood bank of oman introduced screening for anti-hbc as part of the routine screening of blood units for hepatitis b. this concept of combining hbsag with antihbc adds another protective measure against the accidental transfusion of infected blood units. the majority of the patients in this study were positive for hbsag and anti-e-ag with a low viral load, indicating a chronic inactive infection most likely acquired during the early years of life. the minority had an active hbv infection requiring treatment (9%). more than 50% of the patients had tried the traditional therapy of wasm before seeking medical attention. the belief by patients and community in the curative action of this traditional therapy has many serious implications. most of the patients who had tried this form of traditional therapy believed they were cured and had not sought further medical attention until the formal screening. individuals who undergo wasm and do not seek further medical advice may present later with hbv-related complications such as cirrhosis or hcc, and will additionally remain a continuous source of hbv infection. conclusion almost 50% of this study cohort was female and the most likely mode of transmission was vertical. it is therefore suggested that medical authorities in oman enforce a policy of screening all pregnant women, regardless of previous testing or vaccinations, using a complete hepatitis b serology (including anti-hbc) as the standard of care. transmission through horizontal infection is also illustrated in this study, and therefore newborn and non-immune family members in contact with an infected person must also be vaccinated. references 1. kao jh, chen ds. global control of hepatitis b virus infection. lancet infect dis 2002; 2:395–403. 2. lavanchy d. hepatitis b virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. j viral hepat 2004; 11:97–107. 3. lee wm. hepatitis b virus infection. n engl j med 1997; 337:1733–45. 4. mcmahon bj. the natural history of chronic hepatitis b virus infection. hepatology 2009; 49:s45–55. 5. perz jf, armstrong gl, farrington la, hutin yj, bell bp. the contributions of hepatitis b virus and hepatitis c virus infections to cirrhosis and primary liver cancer worldwide. j hepatol 2006; 45:529–38. 6. custer b, sullivan sd, hazlet k, iloeje u, veenstra dl, kowdley kv. global epidemiology of hepatitis b virus. j clin gastroenterol 2004; 38:s158–68. 7. al-dhahry ss, aghanashinikar pn, al-marhuby ha, buhl mr, daar as, al-hasani mk. hepatitis b, delta and human immunodeficiency virus infections among omani patients with renal diseases: a seroprevalence study. ann saudi med 1994; 14:312– 5. 8. soliman at, bassiouny mr, elbanna na. study of hepatic functions and prevalence of hepatitis-b surface antigenaemia in omani children with sickle cell disease. j trop pediatr 1995; 41:174–6. 9. al awaidy s, abu-elyazeed r, al hosani h, al mulla a, al busaiedy s, al amiry a, et al. seroepidemiology of hepatitis b infection in pregnant women in oman, qatar and the united arab emirates. j infect 2006; 52:202–6. 10. ministry of health, oman. oman viral hepatitis survey: 2005. in: community health & disease surveillance newsletter. muscat: ministry of health. from: www.moh.gov.om/en/reports/publications/ newsletter14-2.pdf accessed: jul 2012. 11. goldstein st, zhou f, hadler sc, bell bp, mast ee, margolis hs. a mathematical model to estimate global hepatitis b disease burden and vaccination impact. int j epidemiol 2005; 34:1329–39. 12. centers for disease control and prevention, usa. travelers’ health, yellow book 2008. atlanta: cdc, 2008. 13. ghendon y. perinatal transmission of hepatitis b virus in high-incidence countries. j virol methods 1987; 17:69–79. 14. schweitzer il, dunn ae, peters rl, spears rl. viral hepatitis b in neonates and infants. am j med 1973; 55:762–71. khalid al-naamani, ali al-maqbali and siham al-sinani clinical and basic research | 385 15. xu dz, yan yp, choi bc, xu jq, men k, zhang jx, et al. risk factors and mechanism of transplacental transmission of hepatitis b virus: a case-control study. j med virol 2002; 67:20–6. 16. lin hh, lee ty, chen ds, sung jl, ohto h, kawana t, et al. transplacental leakage of hbeag-positive maternal blood as the most likely route in causing intrauterine infection with hepatitis b virus. j pediatr 1987; 111:877–81. 17. chang mh, chen cj, lai ms, hsu hm, wu tc, kong ms, et al. universal hepatitis b vaccination in taiwan and the incidence of hepatocellular carcinoma in children. taiwan childhood hepatoma study group. n engl j of med 1997; 336:1855–9. 18. chang mh, chen th, hsu hm, wu tc, kong ms, liang dc, et al. prevention of hepatocellular carcinoma by universal vaccination against hepatitis b virus: the effect and problems. clin cancer res 2005; 11:7953–7. 19. ni yh, chen ds. hepatitis b vaccination in children: the taiwan experience. pathol biol 2010; 58:296– 300. 20. bhat sk, sachdeva vn, saleem hi. profile of viral hepatitis patients in dakhliya, oman. saudi med j 2005; 26:819–23. 21. dienstag jl, werner bg, polk bf, snydman dr, craven de, platt r, et al. hepatitis b vaccine in health care personnel: safety, immunogenicity, and indicators of efficacy. ann intern med 1984; 101:34– 40. 22. craven de, awdeh zl, kunches lm, yunis ej, dienstag jl,werner bg, et al. nonresponsiveness to hepatitis b vaccine in health care workers. results of revaccination and genetic typings. ann intern med 1986; 105:356–60. 23. jonas mm, schiff er, o'sullivan mj, de medina m, reddy kr, jeffers lj, et al. failure of the centers for disease control criteria to identify hepatitis b infection in a large municipal obstetrical population. ann intern med 1987; 107:335–7. 24. cowan sa, bagdonaite j, qureshi k. universal hepatitis b screening of pregnant women in denmark ascertains substantial additional infections: results from the first five months. euro surveill 2006; 11:e060608.3. 25. mast ee, margolis hs, flore ae, brink ew, goldstein st, wang sa, et al. a comprehensive immunization strategy to eliminate transmission of hepatitis b virus infection in the united states: recommendations of the advisory committee on immunization practices (acip) part 1: immunization of infants, children, and adolescents. mmwr recomm rep 2005; 54:1–31. 26. allain jp, candotti d, soldan k, sarkodie f, phelps b, giachetti c, et al. the risk of hepatitis b virus infection by transfusion in kumasi, ghana. blood 2003; 101:2419–25. 27. kaminski g, alnaqdy a, al-belushi i, nograles j, al-dhahry sh. evidence of occult hepatitis b virus infection among omani blood donors: a preliminary study. med princ pract 2006; 15:368–72. 28. lok as, lai cl, wu pc. prevalence of isolated antibody to hepatitis b-core antigen in an area endemic for hepatitis b virus infection: implications in hepatitis b vaccination programs. hepatology 1988; 8:766–70. 29. allain jp. occult hepatitis b virus infection. transfus clin biol 2004; 11:18–25. 30. el chaar m, candotti d, crowther ra, allain jp. impact of hepatitis b virus surface protein mutations on the diagnosis of occult hepatitis b virus infection. hepatology 2010; 52:1600–10. 31. gerlich wh, bremer c, saniewski m, schüttler cg, wend uc, willems wr, et al. occult hepatitis b virus infection: detection and significance. dig dis 2010; 28:116–25. 32. gutiérrez c, devesa m, loureiro cl, león g, liprandi f, pujol fh. molecular and serological evaluation of surface antigen negative hepatitis b virus infection in blood donors from venezuela. j med virol 2004; 73:200–7. 33. zhang jm, xu y, wang xy, yin yk, wu xh, weng xh, et al. coexistence of hepatitis b surface antigen (hbsag) and heterologous subtype-specific antibodies to hbsag among patients with chronic hepatitis b virus infection. clin infect dis 2007; 44:1161–9. 34. rehermann b, ferrari c, pasquinelli c, chisari fv. the hepatitis b virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic t-lymphocyte response. nat med 1996; 2:1104–8. 35. sheen is, liaw yf, lin dy, chu cm. role of hepatitis c and delta viruses in the termination of chronic hepatitis b surface antigen carrier state: a multivariate analysis in a longitudinal follow-up study. j infect dis 1994; 170:358–61. 36. guido m, thung sn, fattovich g, cusinato r, leandro g, cecchetto a, et al. intrahepatic expression of hepatitis b virus antigens: effect of hepatitis c virus infection. mod pathol 1999; 12:599–603. 37. sagnelli e, coppola n, scolastico c, filippini p, santantonio t, stroffolini t, et al. virologic and clinical expressions of reciprocal inhibitory effect of hepatitis b, c, and delta viruses in patients with chronic hepatitis. hepatology 2000; 32:1106–10. 38. chu cj, lee sd. hepatitis b virus/hepatitis c virus coinfection: epidemiology, clinical features, viral interactions and treatment. j gastroenterol hepatol 2008; 23:512–20. 39. alavian sm, miri sm, hollinger fb, jazayeri sm. occult hepatitis b (ohb) in clinical settings. hepat mon 2012; 12:e6126. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e95-103, epub. 27th jan14 submitted 9th apr 13 revisions req. 3rd jun & 18th aug 13; revisions recd. 29th jun & 26th aug 13 accepted 22nd sep 13 1department of biology, faculty of science, sabha university, sabha, libya; 2programme of biomedical sciences, school of diagnostic applied health sciences, universiti kebangsaan malaysia, kuala lumpur, malayasia; 3department of clinical oral biology, faculty of dentistry, universiti kebangsaan malaysia, kuala lumpur, malayasia; 4department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: jamaludinmohammed@yahoo.com التوكوتراينول املشتق من زيت النخيل مينع ضرر اإلجهاد التأكسدي يف اجلرذان املصابة بداء السكري فاطمة علي معتوق, �صيتي بلقي�س بودين, ز�ريانتي عبد�حلميد, مارياتي عبد �لرحمن, نا�رش �لوهيبي, جمال �لدين حممد abstract: objectives: this study was carried out to determine the effects of tocotrienol-rich fraction (trf) (200 mg/kg) on biomarkers of oxidative stress on erythrocyte membranes and leukocyte deoxyribonucleic acid (dna) damage in streptozotocin (stz)-induced diabetic rats. methods: male rats (n = 40) were divided randomly into four groups of 10: a normal group; a normal group with trf; a diabetic group, and a diabetic group with trf. following four weeks of treatment, fasting blood glucose (fbg) levels, oxidative stress markers and the antioxidant status of the erythrocytes were measured. results: fbg levels for the stz-induced diabetic rats were significantly increased (p <0.001) when compared to the normal group and erythrocyte malondialdehyde levels were also significantly higher (p <0.0001) in this group. decreased levels of reduced glutathione and increased levels of oxidised glutathione (p <0.001) were observed in stz-induced diabetic rats when compared to the control group and diabetic group with trf. the results of the superoxide dismutase and glutathione peroxidase activities were significantly lower in the stz-induced diabetic rats than in the normal group (p <0.001). the levels of dna damage, measured by the tail length and tail moment of the leukocyte, were significantly higher in stz-induced diabetic (p <0.0001). trf supplementation managed to normalise the level of dna damage in diabetic rats treated with trf. conclusion: daily supplementation with 200 mg/kg of trf for four weeks was found to reduce levels of oxidative stress markers by inhibiting lipid peroxidation and increasing the levels of antioxidant status in a prevention trial for stz-induced diabetic rats. keywords: antioxidants; diabetes mellitus; oxidative stress; tocotrienols. امللخ�ص: الهدف: تهدف هذه �لدر��صة �يل حتديد تاأثري فعالية �لتوكوتر�ينول )200 ملجم/كجم( على �ملوؤ�رش�ت �حليوية لالإجهاد �لتاأك�صدي فى �أغ�صية كريات �لدم �حلمر�ء وجزيئة �حلم�س �لنووي �لريبي منقو�س �الأك�صجي )dna( يف �جلرذ�ن �مل�صابة بد�ء �ل�صكري �ملحدث بو��صطة �ل�صرتيبتوزوتو�صي. الطريقة: مت تق�صيم 40 جرذ ذكر ع�صو�ئيا �يل �أربع جمموعات مت�صاوية كالتايل: جمموعة طبيعية وجمموعة طبيعية �أعطت توكوتر�ينول وجمموعة م�صابة بد�ء �ل�صكري وجمموعة م�صابة بد�ء �ل�صكري �أعطت توكوتر�ينول. بعد فرتة �أربع ��صابيع من �لعالج مت قيا�س م�صتوى �جللوكوز يف �لدم وم�صتويات �ملوؤ�رش�ت معنويا �زدياد� �ل�صكري بد�ء �مل�صابة �جلرذ�ن جمموعة �أظهرت النتائج: �حلمر�ء. �لدم لكريات �الأك�صدة م�صاد�ت وحالة �لتاأك�صدي لالأجهاد �حليوية �ح�صائيا يف م�صتوى �جللوكوز وم�صتوى �ملالونديليهايد مقارنة باملجموعة �لطبيعية. كما �أظهرت �لنتائج باأن هناك �نخفا�صا يف م�صتوى �حلالة �ملختزلة للجلوتاثيون وباملقابل �زدياد يف م�صتوى �حلالة �ملوؤك�صدة للجلوتاثيون يف �ملجموعة �مل�صابة بد�ء �ل�صكري مقارنة باملجموعة �لطبيعية. من جهة �أخرى كان هناك �نخفا�س معنوي �ح�صائي يف م�صتوى ن�صاط �نزميي �ل�صوبر �ك�صيد دي�صميوتيز و �جللتاثيون بريوك�صيديز يف �ملجموعة �مل�صابة بد�ء �ل�صكري. مقارنة �ل�صكري بد�ء �مل�صابة �ملجموعة يف �لبي�صاء �لدم لكريات )dna( جزيئة يف �ل�رشر م�صتوى يف �ح�صائي معنوي �رتفاع هناك كان �أي�صا باملجموعة �لطبيعية. لقد بينت �لنتائج باأن �لعالج بالتوكوتر�ينول كان فعاال يف معادلة �صمية و�رشر جزيئة )dna( يف جمموعة �جلرذ�ن �مل�صابة بد�ء �ل�صكري. اخلال�سة: وجد �أن تناول 200 ملجم / كجم يوميا ملدة �أربعة ��صابيع فعال يف تخفي�س م�صتويات �ملوؤ�رش�ت �حليوية لالإجهاد �لتاأك�صدي وذلك عن طريق تثبيط تاأك�صد �لدهون وزيادة يف م�صتويات م�صاد�ت �الأك�صدة يف �جلرذ�ن �مل�صابة بد�ء �ل�صكري. مفتاح الكلمات: م�صاد�ت �الأك�صدة؛ مر�س �ل�صكري؛ �الإجهاد �لتاأك�صدي؛ �لتوكوتر�ينول. tocotrienol-rich fraction from palm oil prevents oxidative damage in diabetic rats fatmah a. matough,1 siti b. budin,2 zariyantey a. hamid,2 mariati abdul-rahman,3 nasar al-wahaibi,4 *jamaludine mohammed2 clinical & basic research advances in knowledge the antioxidant potential of tocotrienols has been a focus of scientific interest in recent years. recent findings have shown that tocotrienols are responsible for the majority of the activity of vitamin e. this study shows that a tocotrienol-rich fraction (trf) from palm oil at 200 mg/kg of body weight for four weeks provides sufficient antioxidant activity to reduce oxidative stress, by inhibiting lipid peroxidation and reducing levels of deribonucleic acid (dna) damage, as well as increasing the status of the antioxidant system in a prevention trial for diabetic rats. tocotrienol-rich fraction from palm oil prevents oxidative damage in diabetic rats e96 | squ medical journal, february 2014, volume 14, issue 1 according to the world health organization (who), a total of 171 million people in all age groups worldwide (2.8% of the world’s population) have diabetes; this number is expected to rise to 366 million (4.4% of the world’s population) by 2030.1 a balance between the rate of free radical generation and the rate of radical elimination is important so that cellular radical generation is not harmful.2 however, if there is a significant increase in radical generation or a decrease in radical elimination of the cells, this balance is disrupted, resulting in the formation of oxidative stress.3 free radicals and oxidative stress are among the factors involved in the pathogenesis of diabetes; in particular, they appear to play a major role in the development of chronic complications from diabetes.4 vitamin e is widely accepted as the first line of defense against lipid peroxidation, protecting the polyunsaturated fatty acids in the cell membranes through its free radical-quenching activity in the biomembranes in the early stages of the free radical attack.5 palm oil contains a larger concentration of tocotrienols (70%) than any other natural source, except annatto (100%).6 tocotrienols and tocopherols act as potent antioxidants, serving to protect the cellular membranes from free radical-catalysed lipid peroxidation.7 a number of health-related biological properties of tocotrienols have been identified, including anticancer, anti-cholesterolemic, antihypertensive, antioxidant, immunomodulatory and neuroprotective properties.6 tocotrienol-rich fraction (trf) has unique biological properties that make it a potential neuroprotective dietary factor. in addition to its antioxidant activity, trf at micromolar concentrations displays cholesterol-lowering activities in cells, animal models and some, but not all, human subjects by means of the inhibition of the activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylgluta ryl coenzyme a reductase.8 furthermore, trf at lower concentrations (~10 nmol/l) modulates signalling pathways involved in neuronal cell death in cell culture experiments.8 currently, trf is addressed as an anti-apoptotic and antiinflammatory agent, and emerging findings suggest a role for nuclear factor kappa-b cells (nf-κb) as a mediator of the effects of dietary factors on neuronal plasticity.9 our previous study showed that the trf of palm oil (200 mg/kg of body weight) has some protective effects as it reduces lipid peroxidation and protein oxidation, and prevents the physical and morphological alterations of erythrocytes after four weeks.10 another study reported that the supplementation of trf reduced oxidative stress and blood glucose levels and had protective effects on diabetes-induced pancreatic damage in diabetic rats.11 the purpose of this study was to investigate the effects of trf on oxidative stress and antioxidant status on erythrocytes in streptozotocin (stz)-induced diabetic rats. methods for this study, male sprague-dawley rats were provided by the laboratory animal resources unit, faculty of medicine, universiti kebangsaan malaysia, kuala lumpur. the animals were 8–10 weeks old and weighed 200–250 g. during the study period, the rats had unrestricted access to food and tap water with a standard diet containing 22% crude protein, 5% crude fibre, 3% fat, 13% moisture, 8% ash, 0.85–1.2% calcium, 0.6–1% phosphorus and 49% nitrogen-free extract in the form of mouse pellet 702-p (gold coin holdings, kuala lumpur, malaysia). they were housed in pairs in plastic cages with wood chips for bedding (changed weekly for the normal groups and daily for the diabetic groups). the animals were acclimatised to standard laboratory conditions, with a temperature of 25 °c with standard light-darkness cycles of 12 hours for one week before experimentation. the study was approved by the universiti kebangsaan malaysia animal ethics committee. the experiment was designed with 40 rats, divided randomly into four groups of 10 rats: a normal group; a normal group supplemented application to patient care in terms of using tocotrienols for antioxidant agent activity in diabetic humans, the finding of this study suggests that trf at 200 mg/kg for four weeks may play an important role in reducing the complications of oxidative stress-mediated diabetes mellitus. fatmah a. matough, siti b. budin, zariyantey a. hamid, mariati a. rahman, nasar al-wahaibi and jamaludine mohammed clinical and basic research | e97 with trf; a diabetic group, and a diabetic group supplemented with trf. initially, all experimental groups had similar body weights (200–250 g). at the end of the study period, both diabetic groups (stz-induced diabetic rats and diabetic rats with trf) showed a significant loss of body weight (average weight 190 g) when compared to the normal groups (average weight 319 g). diabetes was induced after an overnight fast by a single intravenous injection of stz via the tail vein (45 mg/ kg of body weight), which was freshly dissolved in a normal saline solution (9 g/l of sodium chloride). three days later, blood was collected via the tail vein and the glucose concentration was measured by a strip-operated blood glucose sensor (companion 2, medisense ltd., birmingham, uk). rats with blood glucose levels of >7.0 mmol/l were included in the study. trf was obtained from the sime darby group (kuala lumpur, malaysia) as follows: α-tocopherol at 171.1 mg/g, α-tocotrienol at 190.4 mg/g, β-tocotrienol at 36.0 mg/g, γ-tocotrienol at 211.2 mg/g and δ-tocotrienol at 150 mg/g. it was administered orally at a dose of 200 mg/kg of body weight per day throughout the four-week feeding period, and supplementation was begun the same day. after four weeks of supplementation, all the rats underwent overnight fasting and were then euthanised by a cardiac puncture while under deep anaesthesia with diethyl ether. the biochemical investigation commenced while the rats were under deep anaesthesia. a blood sample was taken from each of the rats via a cardiac puncture using a 21 gauge needle with a 10 ml syringe. samples were then transferred into tubes containing a sodium fluoride plastic tube (fluoride oxalate tube, #x2230, teklab ltd., uk) for fasting blood glucose (fbg) analysis and ethylene diamine tetra acetic acid (edta) tubes (bd vacutainer® plus plastic k2edta tube #368589, becton, dickinson and company, franklin lakes, new jersey, usa) and kept on ice. plasma glucose levels were analysed on the same day using enzymatic glucose-oxidase kits (glucose oxidase reagent, # tr15103, fisher scientific ltd., loughborough, uk). erythrocyte pellets were separated from the plasma and the leukocyte layer by centrifugation at 4,000 rpm for 10 mins at 4 °c. the supernatant plasma was pipetted into 1.5 ml eppendorf tubes (eppendorf ag, hamburg, germany) and frozen at -80 °c until use. after the removal of the buffy coat, the erythrocyte pellets were prepared by being washed three times with a cold (4 °c) normal saline (9%) solution. these pellets were then stored at -80 °c for biochemical analyses. the amount of blood taken from each rat varied from 6–10 ml. erythrocyte malondialdehyde (mda) samples were measured using the high performance liquid chromatography (hplc) method with some modifications as described by pilz et al., based on the derivation with 2, 4-dinitrophenylhydrazine (dnph).12 the total mda was prepared from the erythrocytes by perchloric acid deproteinisation whereas an alkaline hydrolysation step for 30 mins at 60 °c was introduced prior to protein precipitation for the determination of the total (free and bound) mda. the standard and samples were processed under the same conditions as described in this section. the mda standard was prepared by dissolving 25 µl of 1,1, 3,3-tetraethoxypropane (tep) in 100 ml of 1% sulfuric acid to give a 1 mm stock solution and was kept at 4 °c overnight. the working standard was prepared by the hydrolysis of the 1 ml of tep stock solution in 50 ml of distilled water (dh2o) and incubated for two hours at room temperature.13 the concentration of 1, 2, 4, 6, 8, and 10 µmol was prepared from the working standard to get the standard curve for the estimation of total mda. a solution of 200 µl of sodium hydroxide (naoh) of 1.3 m was added to the 50 µl standard or sample. for the protein-bound alkaline hydrolysis step, the mixture was incubated in a 60 °c water bath for 30 mins and then cooled in ice for five mins. the hydrolysis samples were acidified with 100 µl of 35% (volume/volume [v/v]) perchloric acid. after centrifugation at 1,000 g for 10 mins, 300 µl of the supernatant were mixed with 12.5 µl of the dnph solution and incubated in the dark at room temperature for 30 mins. finally, 40 µl was injected into the hplc system. analytical hplc separations were performed with a 655a-12 liquid chromatography instrument (scl-10avp system controller, shimadzu scientific instruments, kyoto, japan) equipped with an auto injector (655a-40) and a variable-wavelength ultraviolet (uv) detector (655a) operated at 310 nm on a 125 × 3 mm nucleosil c18 column of 5 µm particle size on reversed-phase with an integrated precolumn (sepserv hpcl, separation service tocotrienol-rich fraction from palm oil prevents oxidative damage in diabetic rats e98 | squ medical journal, february 2014, volume 14, issue 1 berlin ohg, berlin, germany). the column was kept at 30 °c in a column oven with a mobile phase. the hplc mobile phase was prepared by mixing 380 ml acetonitrile with 620 ml of dh2o acidified with 0.2% (v/v) acetic acid and degassed under reduced pressure with a flow-rate of 1 ml/min. superoxide dismutase (sod) activity was determined according to fridovich and beyer’s method, based on the inhibition or reduction of nitroblue tetrazolium (nbt).14 a reaction mixture of a substrate solution containing l-methionine (30 mg/ml), tritone x-100 (1%) and nbt (1.14 mg/ ml) was added in a phosphate buffer saline (pbs) solution (ph 7.8). lyses erythrocytes (20 μl) were added to 0.1 ml of cold dh2o and were kept at 4 °c for 15 mins. the mixture (1 ml) was added to 20 μl of lyses erythrocyte or a pbs solution (8 g of sodium chloride [nacl], 0.2 g of potassium chloride, 1.44 g of disodium hydrogen phosphate and 0.24 g of monopotassium phosphate) (control), and 10 μl of riboflavin was then added. the samples were incubated for seven mins. the absorbance of the mixture at 560 nm was determined using a spectrophotometer uv-160a (shimadzu scientific instruments). the enzyme activities were calculated in u/g haemoglobin (hb). glutathione peroxidase (gpx) activity was determined according to the lawrence method, based on the principle that gpx catalyses the oxidation of glutaredoxin (grx) and nicotinamide adenine dinucleotide phosphate (nadph).15 the oxidised glutathione was immediately converted to the reduced form with a concomitant oxidation, nadph to nadp+. a 100 μl sample of lysed erythrocyte and 0.8 ml of a buffered solution (1 mm of sodium azide, 1 mm of edta, 0.2 mm of nadph, 50 units of grx1 mm of gsh and 50 mm of pbs; ph 7) were incubated at room temperature for 5 mins, then 100 μl (0.25 mm) of hydrogen peroxide was added. the absorbance of the mixture at 340 nm was determined using the shimadzu scientific instruments spectrophoto meter. activities of enzymes were calculated in u/g hb. a commercial glutathione detection kit (biovision, inc., milpitas, california, usa) was used to measure gsh, gssg and total glutathione. the readings for samples and the standard were determined using a fluorescence plate reader equipped with an excitation wavelength/emission wavelength (ex/em) of 340/420 nm (skanit software, thermo fisher scientific inc.). the concentration of vitamin e in the rat erythrocyte samples was measured by the hplc method with some modification of the procedures described by brandt et al.16 briefly, α-tocopherol and α-tocopheryl-acetate (the internal standard) in the samples were extracted into hexane. the hexane extract was dried under nitrogen and dissolved in the mobile phase for injection into the hplc for separation with detection by uv. the mobile phase used was composed of methanol and toluene of hplc grade (bdh merck ltd., poole, uk) in the ratio of 80:20. a stock standard of 10 mmol/l of α-tocopherol (bdh merck ltd.) was prepared by dissolving 0.0216 g of vitamin e in 5 ml of absolute ethanol. different standards concentrations of α-tocopherol (10, 20, 30, 40 and 50 umol/l) were prepared. the internal standard, α-tocopheryl acetate, was prepared by dissolving 0.0236 g of α-tocopheryl acetate in 5 ml of absolute ethanol and then pipetting 0.75 ml of this into 50 ml of absolute ethanol. the final concentration of α-tocopheryl acetate in every standard and sample was 150 µmol/l. lyphochek 1 and lyphochek 2 (bio-rad laboratories, hercules, california, usa) were used as the low and high precision controls, respectively, and treated as plasma samples. a 100 µl of sample or standard was added to 100 μl of ethanol together with 100 µl of α-tocopheryl acetate. hexane (200 µl) was added and centrifuged at 2,500 g (for 10 mins at 4 °c). then 120 µl of the upper layer (hexane extract) was evaporated. a total of 60 μl of the mobile phase were added to dissolve the extract, and this was immediately loaded for injection into the hplc system. analytical hplc separations were performed as previously described in this section. the running condition of hplc was seven mins per sample. the flow-rate was 1 ml/min. the injection volume was 20 μl and the detection wavelength was at 292 nm. the retention time was ~4.4 mins for vitamin e and ~5.3 mins for α-tocopheryl acetate. a calibration curve was constructed by plotting the peak area ratio of vitamin e and α-tocopherylacetate against the vitamin e standard values. the slope obtained from the calibration curve was used to determine the α-tocopherol concentration in the sample by the following calculation: the deoxyribonucleic acid (dna) oxida-tive fatmah a. matough, siti b. budin, zariyantey a. hamid, mariati a. rahman, nasar al-wahaibi and jamaludine mohammed clinical and basic research | e99 damage was then measured as follows. the alkaline single-cell gel electrophoresis assay procedure was performed according to the method described by singh et al.17 for slide preparation, 100 µl (0.5%) of normal melting agarose at about 121 °c in calcium ionand magnesium ion-free butylphthalate plasticised styrene, was immediately covered with a cover slip and kept on ice for 5 mins to allow the agarose to solidify. around 10 µl of whole blood was suspended in 80 µl (0.5%) of low melting agarose. the cell suspension was rapidly pipetted onto the first agarose layer and spread using a cover slip, and the slides were immersed in a lysis buffer solution (2.5 m of nacl, 100 mm of sodium edta, 10 mm of trisaminomethane hydrochloride (tris-hcl) and 1% of triton x-100), and 10% dimethyl sulfoxide was added just before use at 4 °c for a minimum of one hour. the slides were placed in a horizontal gel electrophoresis tank and filled with fresh cold electrophoresis solution (10 n of sodium hydroxide and 200 mm of sodium (in the form of na2) edta) and were left in the solution for 20 mins to allow the dna to unwind. electrophoresis was conducted at 4 °c for 20 mins. the slides were neutralised with a tris-hcl buffer (ph 7.5) three times for five mins and stained with ethidium-bromide (100 µg/ml) for 10 mins. slides were examined at x 20 magnification using a fluorescence microscope with 100 cells per slide analysed using image analysing software (comet assay software project (casplab), version 1.2.2xcap™ image processing software (version 1.1.1), casplabepix, inc., swietokrzyska academy, kielce, poland). all results were expressed as mean ± standard error of mean (sem). the data were analysed using the statistical package for the social sciences (spss), version 20.0 (ibm, corp., chicago, illinois, usa), and microsoft office excel 2007 (microsoft, inc., redmond, washington, usa) was used to draw the graphs. the shapiro-wilk test was used to check the normality of the variables. accordingly, a oneway analysis of variance (anova) test followed by a post hoc least significant difference (lsd) multiple comparison test to estimate the significance of difference between groups, and the kruskalwallis one-way anova test was used to analyse the data that followed non-normal behaviour of distribution patterns, respectively. the difference between groups was considered significant when p <0.05. results as far as plasma glucose levels are concerned, figure 1 shows that the levels of fbg were significantly increased (p <0.0001) in the stz-induced diabetic rats compared to the normal group. on the other hand, fbg levels were significantly lower in the diabetic group (p <0.001), which had been supplemented with trf, in comparison with the stz-induced diabetic rats; however, this improvement was not sufficient to have restored the blood glucose levels to their normal state. as to the mda erythrocyte membrane, the erythrocyte mda levels were statistically significantly higher in the stz-induced diabetic rats (76.69 ± 6.8) compared with the normal rats (1.9 ± 0.1; p <0.0001) [table 1]. on the other hand, the diabetic rats treated with trf showed significantly decreased (13.11 ± 0.3; p <0.001) mda levels compared with stz-induced diabetic rats. the results for the erythrocyte antioxidants status were as follows. in the diabetic group there was significantly decreased activity of sod, gpx table 1: effects of treatment with tocotrienol-rich fraction on antioxidant status and oxidative stress group sod in u/ghb gpx in u/ghb gsh in µmol/ghb gssg in nmol/ghb mda in nmol/ghb normal 3673 ± 182 71.6 ± 1.8 8.32 ± 0.66 73.34 ± 2.1 1.9 ± 0.13 normal with trf 4028 ± 161† 65.3 ± 4.7† 18.70 ± 0.7* 79.24 ± 1.9† 7.5 ± 0.6 diabetic 2916 ± 126* 39.3 ± 2.6* 4.91 ± 0.3* 92.75 ± 4.6* 76.6 ± 6.8* diabetic with trf 3364 ± 137† 46.5 ± 3.4 8.84 ± 0.4† 77.76 ± 1.4† 13.1 ± 0.3*† sod = superoxide dismutase; gpx = glutathione peroxidase; gsh = reduced glutathione; gssg = oxydised glutathione; mda = malondialdehyde; trf = tocotrienol-rich fraction. results are expressed as mean ± standard error of mean; *significantly different as compared to the control group (p <0.05); †significantly different as compared to the diabetic group (p <0.05). peak area ratio of the sample slope of the calibration curve μmol l( )= vitamin e concentration in tocotrienol-rich fraction from palm oil prevents oxidative damage in diabetic rats e100 | squ medical journal, february 2014, volume 14, issue 1 and levels of gsh (p values were 0.006, 0.0001 and 0.001, respectively). on the other hand, levels of gssg were significantly increased (p = 0.002) compared with the normal group. however, trf supplementation produced a significant increase in sod activity and levels of gsh, as well as a decreased level of gssg in the diabetic with trf group when compared to the stz-induced diabetic rats group [table 1 and figure 1]. as far as the vitamin e erythrocyte membrane was concerned, the concentration of vitamin e was significantly lower in the diabetic groups (stzinduced diabetic rats and diabetic rats with trf) compared with the normal group (0.33 ± 0.03 and 0.55 ± 0.05 versus 2.07 ± 0.29). p values were 0.01 and 0.04, respectively. on the other hand, vitamin e levels in the normal group supplemented with trf were significantly increased when compared to other groups (p = 0.0001) [figure 2]. the levels of dna damage were significantly higher in the stz-induced diabetic rats compared to normal rats [table 2]. trf supplementation was found to minimise the dna damage parameters in diabetic rats with trf. figure 3 shows the normal and damaged cells with long tails of dna migration. discussion this study shows that a daily supplementation of trf (200 mg/kg) reduced the levels of oxidative stress markers in stz-induced diabetic rats. the results of the fbg tests indicated increased plasma glucose levels in stz-induced diabetic rats, which could be due to the inhibition of insulin secretion resulting from the injection of stz. previous studies have demonstrated that injections of stz in experimental diabetic rats led to the degeneration of beta cells of the islets of langerhans, thereby increasing fbg levels.18 in this study, the supplementation of trf at 200 mg/kg for four weeks improved blood glucose levels. however, the improvement was not enough to restore blood glucose levels to a normal state. the mechanism through which tocotrienols reduce blood glucose levels in patients and in preclinical animal models was investigated by fang figure 1: the effect of treatment with tocotrienol-rich fraction (trf) on blood glucose in the experimental groups of rats. a = significantly different compared to the normal group (p <0.05); b = significantly different from the normal with trf group (p <0.05); c = significantly different from the diabetic group (p <0.05). figure 2: the effect of treatment with tocotrienol-rich fraction (trf) on the concentration of vitamin e in the experimental groups of rats. a = significantly different from the normal group (p <0.05); b = significantly different from the normal with trf group (p <0.05). table 2: effect of treatment with tocotrienol-rich fraction on the level of deoxyribonucleic acid (dna) damage (determined by tail length, tail moment and percentage of tail dna) of the leukocytes tl in µm tm in arbitrary units tail dna in % normal group 4.57 ± 0.23 0.015 ± 0.002 0.114 ± 0.016 normal with trf group 4.03 ± 0.15 0.0086 ± 0.001 0.084 ± 0.012 diabetic group 127.38 ± 3.17* 39.009 ± 1.45* 24.93 ± 0.66* diabetic with trf group 45.28 ± 0.75*† 3.93 ± 0.12† 7.93 ± 0.16*† tl = tail length; tm = tail moment; dna = deoxyribonucleic acid; trf = tocotrienol rich fraction. results are expressed as mean ± standard error of mean; *significantly different as compared to the control group (p <0.05); †significantly different as compared to the diabetic group (p <0.05). fatmah a. matough, siti b. budin, zariyantey a. hamid, mariati a. rahman, nasar al-wahaibi and jamaludine mohammed clinical and basic research | e101 figure 3: single-cell gel electrophoresis assay image of the deoxyribonucleic acid (dna) using rat whole blood (10 µl) directly for the assay. single-cell gel electrophoresis image of the dna in the (a) normal group; (b) normal with tocotrienol-rich fraction (trf) group; (c) diabetic group, and (d) diabetic with trf group. et al.19 they proposed that tocotrienols function as peroxisome proliferator-activated receptor (ppar) modulators. ppars are ligand-regulated transcription factors that play essential roles in energy metabolism. synthetic pparα and pparγ ligands have been used recently in the treatment of hyperlipidaemia and diabetes. both αand γ-tocotrienol activated pparα, while δ-tocotrienol alone activated pparα, pparγ and pparδ in reporter-based assays. several studies have shown an increased lipid peroxidation in clinical and experimental diabetes.20 in the first part of this study, we confirmed that oxidative stress is enhanced in stz-induced diabetic rats as demonstrated by the significant augmentation in diabetic erythrocyte mda. mda is a late-stage lipid oxidation by-product that can be formed non-enzymatically, or is a by-product of cyclooxygenase activity.21 previous studies have reported elevated levels of lipid peroxidation products in the erythrocytes, plasma and retinas of diabetic patients and animals.22 the findings of the present study showed elevated levels of lipid peroxidation in erythrocyte stz-induced diabetic rats, and this finding was in agreement with the reports documented in the literature.22–24 increased levels of lipid peroxide may cause oxidative injury to the erythrocytes and cross-linking in the membrane proteins and lipids.25 moreover, the levels of mda were slightly increased in the normal group treated with trf compared to the control group, although the difference was not statistically significant. this might be related to having exposed the rats to stressors during the force-feeding of the trf supplementation. in this study, four weeks of trf supplementation showed significantly lower erythrocyte lipid peroxidation in the diabetic with trf group compared to the stz-induced diabetic group. moreover, the normalisation of lipid peroxides in the stz-induced diabetic rats treated with trf was in agreement with sung et al., who found that vitamin e inhibited the thiobarbituric acid reactive substances in the erythrocyte membrane.26 also, the formation of lipid peroxidation products such as mda was prevented by vitamin e treatment. evidence from the present study suggests that trf supplementation may help prevent and protect against free radical production in diabetes. increased oxidative damage and changes in the antioxidant defense system have been reported in experimental diabetes and have been associated with the development of diabetic complications.27 previous studies have shown that the presence of oxidative stress in diabetes mellitus, and antioxidant enzymes such as sod, catalase (cat) and gpx as well as molecules such as gsh, vitamins e and c, and beta carotene, increase the response of the antioxidant defense system to oxidative stress in the body.28,29 in the present study, the levels of erythrocyte antioxidant enzymes, sod and gpx, were decreased in both the stz-induced diabetic rats and the diabetic with trf group in comparison to the normal group. these findings agree with other research showing that the presence of oxidative stress in rat erythrocytes was caused by stzinduced diabetes.28,30 in this study, supplementation with trf was found to augment the antioxidative system and increase the levels of antioxidant enzymes, such as sod, which catalytically converts superoxide anion radicals to hydrogen peroxide; this was especially remarkable in the diabetic with trf group. while gpx activity was not significantly different in the diabetic with trf group compared with the stz-induced diabetic group, these results agree with some previous studies which showed that gpx appears to be a relatively stable enzyme;31,32 thus, it may only be inactivated under conditions of severe oxidative stress.33 in addition, other previous tocotrienol-rich fraction from palm oil prevents oxidative damage in diabetic rats e102 | squ medical journal, february 2014, volume 14, issue 1 experimental animal studies have reported that high levels of glucose have no effect on gpx activity and its gene expression.34 decreased erythrocyte gsh together with significantly increased gssg was observed in stz-induced diabetic rats when compared with the normal rats. these findings are consistent with other studies.32 the current study found that the supplementation of trf significantly increased the levels of gsh and decreased gssg in the diabetic group treated with trf, and may indicate that high concentrations of trf can significantly reduce the levels of lipid peroxidation and the reduction of oxidative agents, thereby increasing levels of antioxidant gsh. the increased production of reactive oxygen species (ros) under diabetic conditions underlines the increased amount of oxidatively-damaged dna in different tissues. the presence of ros may lead to increased dna damage in peripheral blood lymphocytes that may be revealed by the singlecell gel electrophoresis assay. significant differences were detected between the control and stz-induced diabetic rats in terms of the frequency of damaged cells. the tail moment (tm) and tail length (tl) parameters for dna damage were significantly higher in the stz-induced diabetic rats than in the control rats, which might indicate that these cells are handling more oxidative damage on a regular basis. also, clear differences between the stz-induced diabetic rats and diabetic rats with four weeks of trf supplementation were observed on the basis of the extent of dna migration during single-cell gel electrophoresis, supporting the hypothesis that antioxidants protect cells from dna damage. a previous study showed that antioxidants such as vitamin e exhibited a protective effect against oxidative dna damage.35 conclusion this study showed that a daily oral supplementation of 200 mg/kg of trf of palm oil had the beneficial effect of reducing levels of oxidative stress markers by an inhibition of lipid peroxidation and an increase in the levels of antioxidant defense system. this was demonstrated through a significant increase in the sod activity, and the gsh levels in diabetic rats supplemented with trf. in contrast, gpx activity and vitamin e levels were not significantly affected following four weeks of trf supplementation. furthermore, the antioxidant properties of trf showed some protective effects in the reduction of the percentage of damaged dna in the tail. the dna tl and tm of the leukocyte single-cell gel electrophoresis assay were used as indicators of oxidative dna damage. additionally, trf was also found to have a beneficial effect in improving hyperglycaemic status, which resulted in a lowering of the plasma glucose levels after four weeks of supplementation. this study suggests that trf supplementation plays an important role in reducing oxidative stress-induced diabetes mellitus. a c k n o w l e d g e m e n t the study was financed by the government of libya (grant #nn-026-2010). references 1. wild s, roglic g, green a, sicree r, king h. global prevalence of diabetes: estimates for the year 2000 and projections for 2030. diabetes care 2004; 27:1047–53. 2. moussa sa. oxidative stress in diabetes mellitus. romanian j biophys 2008; 18:225–36. 3. valko m, leibfritz d, moncol j, cronin mt, mazur m, telser j. free radicals and antioxidants in normal physiological functions and human disease. int j biochem cell biol 2007; 39:44–84. 4. baynes jw. role of oxidative stress in development of complications in diabetes. diabetes 1991; 40:405–12. 5. fukuzawa k. dynamics of lipid peroxidation and antioxidion of alpha-tocopherol in membranes. j nutr sci vitaminol (tokyo) 2008; 54:273–85. 6. tan b, watson rr, preedy vr, eds. tocotrienols: vitamin e beyond tocopherols. 2nd ed. florida: crc press, taylor & francis group, 2013. 7. gapor ab, ong ash, kato a, watanabe h, kawada t. antioxidant activities of palm vitamin e with special reference to tocotrienols. j oil palm res 1989; 1:63–7. 8. frank j, chin xw, schrader c, eckert gp, rimbach g. do tocotrienols have potential as neuroprotective dietary factors? ageing res rev 2012; 11:163–80. 9. wilankar c, sharma d, checker r, khan nm, patwardhan r, patil a, et al. role of immunoregulatory transcription factors in differential immunomodulatory effects of tocotrienols. free radic biol med 2011; 51:129–43. 10. matough fa, budin sb, hamid za, louis sr, alwahaibi n, mohamed j. palm vitamin e reduces oxidative stress, and physical and morphological alterations of erythrocyte membranes in streptozotocin-induced diabetic rats. oxi antioxid med sci 2012; 1:59–68. 11. budin sb, yusof km, idris mhm, abd hamid z, mohamed j. tocotrienol-rich fraction of palm oil reduced pancreatic damage and oxidative stress in streptozotocin-induced diabetic rats. australian j basic appl sci 2011; 5:2367–74. fatmah a. matough, siti b. budin, zariyantey a. hamid, mariati a. rahman, nasar al-wahaibi and jamaludine mohammed clinical and basic research | e103 12. pilz j, meineke i, gleiter ch. measurement of free and bound malondialdehyde in plasma by high-performance liquid chromatography as the 2,4-dinitrophenylhydrazine derivative. j chromatogr b biomed sci appl 2000; 742:315– 25. 13. esterbauer h, lang j, zadravec s, slater tf. detection of malonaldehyde by high-performance liquid chromatography. methods enzymol 1984; 105:319–28. 14. beyer wf jr, fridovich i. assaying for superoxide dismutase ac¬tivity: some large consequences of minor changes in conditions. anal biochem 1987; 161:559–66. 15. lawrence ra, burk rf. glutathione peroxidase activity in selenium-deficient rat liver. biochem biophys res commun 1976; 71:952–8. 16. brandt rb, kaugars ge, riley wt, bei ra, silverman s jr, lovas jg, et al. evaluation of serum and tissue levels of alpha-tocopherol. biochem mol med 1996; 57:64–6. 17. singh np, mccoy mt, tice rr, schneider el. a simple technique for quantitation of low levels of dna damage in individual cells. exp cell res 1988; 175:184–91. 18. ikebukuro k, adachi y, yamada y, fujimoto s, seino y, oyaizu h., et al. treatment of streptozotocin-induced diabetes mellitus by transplantation of islet cells plus bone marrow cells via portal vein in rats. transplantation 2002; 73:512–8. 19. fang f, kang z, wong c. vitamin e tocotrienols improve insulin sensitivity through activating peroxisome proliferator-activated receptors. mol nutr food res 2010; 54:345–52. 20. kakkar r, mantha sv, radhi j, prasad k, kalra j. increased oxidative stress in rat liver and pancreas during progression of streptozotocin-induced diabetes. clin sci (lond) 1998; 94:623–32. 21. slatter da, bolton ch, bailey aj. the importance of lipidderived malondialdehyde in diabetes mellitus. diabetologia 2002; 43:550–7. 22. jain sk, mcvie r, duett j, herbst jj. erythrocyte membrane lipid peroxidation and glycosylated hemoglobin in diabetes. diabetes.1989; 38:1539–43. 23. sharpe pc, liu wh, yue kk, mcmaster d, catherwood ma, mcginty am, et al. glucose-induced oxidative stress in vascular contractile cells: comparison of aortic smooth muscle cells and retinal pericytes. diabetes 1998; 47:801–9. 24. nourooz-zadeh j, rahimi a, tajaddini-sarmadi j, tritschler h, rosen p, halliwell b, et al. relationships between plasma measures of oxidative stress and metabolic control in niddm. diabetologia 1997; 40:647–53. 25. parthibhan a, vijaylingam s, shanmughsundaram k, mohan r. oxidative stress and the development of diabetic complications: antioxidants and lipid peroxidation in erythrocytes and cell membrane. cell bio int 1995; 19:987– 93. 26. ihm sh, yoo hj, park sw, ihm j. effect of aminoguanidine on lipid peroxidation in streptozotocin-induced diabetic rats. metabolism 1999; 48:1141–5. 27. thompson kh, godin dv. micronutrient and antioxidants in the progression of diabetes. nutr res 1995; 15:1377–410. 28. vural h, sabuncu t, arslan so, aksoy n. melatonin inhibits lipid peroxidation and stimulates the antioxidant status of diabetic rats. j pineal res 2001; 31:193–8. 29. sabuncu t, vural h, harma m, harma m. oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease. clin biochem 2001; 34:407– 13. 30. aksoy n, vural h, sabuncu t, aksoy s. effects of melatonin on oxidative-antioxidative status of tissues in streptozotocin-induced diabetic rats. cell biochem funct 2003; 21:121–5. 31. bonnefont-rousselot d, bastard jp, jaudon mc, delattre j. consequences of the diabetic status on the oxidant/ antioxidant balance. diabetes metab 2000; 26:163–76. 32. firoozrai m, nourbakhsh m, razzaghy-azar m. erythrocyte susceptibility to oxidative stress and antioxidant status in patients with type 1 diabetes. diabetes res clin pract 2007; 77:427–32. 33. condell ra, tappel al. evidence for suitability of glutathione peroxidase as a protective enzyme: studies of oxidative damage, renaturation, and proteolysis. arch biochem biophys 1983; 223:407–16. 34. forsberg h, borg la, cagliero e, eriksson uj. altered levels of scavenging enzymes in embryos subjected to a diabetic environment. free radic res 1996; 24:451–9. 35. claycombe kj, meydani sn. vitamin e and genome stability. mutat res 2001; 475:37–44. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e7–8, epub. 21 jan 15 submitted 29 oct 14 revision req. 10 nov 14; revision recd. 18 nov 14 accepted 20 nov 14 sarcoidosis is a systemic granulomatous disease which principally involves the pulmonary and lymphatic systems. however, such a formal definition of sarcoidosis is simplistic since it can resemble many other diagnoses and may therefore have ‘a thousand faces’. in this issue of squmj, chappity et al. describe an atypical case of heerfordt’s syndrome and discuss findings from a systematic review of the literature over the last 10 years.1 heerfordt’s syndrome is an atypical manifestation of acute sarcoidosis presenting with fever, uveitis and swelling of the parotid glands and, most often, unilateral facial nerve palsy. because most patients with heerfordt’s syndrome present with atypical symptoms at onset, many are misdiagnosed or remain undiagnosed. in chappity et al.’s case report, a 52-year-old woman had recurrent facial nerve palsy on two different occasions four months apart; at first unilateral and, later, bilateral. the patient reported a recent history of swelling of the parotid region and low-grade fever. she reported no significant visual disturbances or other ophthalmological symptoms. however, upon examination, the patient was found to have anterior intermediate uveitis. she was subsequently diagnosed with heerfordt’s syndrome and treated with steroids.1 the authors present an interesting clinical example of an atypical presentation of heerfordt’s syndrome, emphasising the need for a careful comprehensive examination of patients presenting with facial nerve palsy.1 historically, a clear presentation of heerfordt’s syndrome involves the onset of unilateral facial nerve palsy, parotid gland swelling, fever, night sweats, weight loss and optical disturbances.2,3 however, as the authors observed in their review of published literature, most cases of heerfordt’s syndrome present with ambiguous manifestations and do not fall within the standard norms of diagnostic criteria.1 due to the fact that most cases of unilateral facial nerve palsy with an unknown aetiology are diagnosed as bell’s palsy, there is a considerable need for a systematic approach in the recognition and diagnosis of heerfordt’s syndrome. sudden onset of facial nerve palsy is common in 25–50% of patients with heerfordt’s syndrome and is normally preceded by enlargement of the parotid gland.1,4 other potential indications of the syndrome include sensorineural hearing loss, labyrinthine involvement with vestibular dysfunction, epistaxis, nasal pain or obstruction, low-grade nonspecific fever, night sweats and visual disturbances.1–3 in their systematic review, chappity et al. found that the most commonly documented features associated with heerfordt’s syndrome included symptoms or signs demonstrating the involvement of the seventh or fifth cranial nerves; the presence of parotid swelling; fever, and an array of ophthalmic anomalies.1 these anomalies included panuveitis, posterior and anterior uveitis, bilateral granulomatous uveitis, bilateral swelling of the eyelids and myodesopsia (floaters), with cytology demonstrating either parotid or preauricular lymph node nonceasing granulomas. other clinical features often associated with this syndrome, including night sweats and weight loss, were not commonly reported in the recent literature.1 the findings of chappity et al.’s case report and systematic literature review underline the importance of obtaining a comprehensive and current medical history from patients presenting with facial nerve palsy.1 for neurologists and other clinicians, recognising the significance of a patient’s self-reported symptomology within the past week is critical to the differential diagnosis and consideration of heerfordt’s syndrome.4 patients presenting with either unilateral or bilateral facial nerve palsy should be questioned department of neurology, louisiana state university health sciences center, shreveport, louisiana, usa *corresponding author e-mail: aminag@lsuhsc.edu متالزمة هريفورد ظاهرة من مظاهر الساركويد غري املألوفة و املثرية لالهتمام جيني ماغي وعلي ر�ضا ميناجار comment heerfordt’s syndrome an interesting and under-recognised manifestation of sarcoidosis jeanie mcgee and *alireza minagar heerfordt’s syndrome an interesting and under-recognised manifestation of sarcoidosis e8 | squ medical journal, february 2015, volume 15, issue 1 regarding and assessed for visual disturbances and an ophthalmology consultation should be secured immediately. the presence of fever, night sweats, a cough, throat swelling, difficulty swallowing or even headaches could indicate a potential case of heerfordt’s syndrome.5,6 in conclusion, the authors have done an excellent job in educating the clinician regarding the rare diagnosis of heerfordt’s syndrome and recognising the need for an updated awareness of its clinical features.1 early diagnosis and treatment with steroid therapy can prove effective in reducing morbidity and promoting recovery. the alert clinician may therefore need to pursue additional diagnostic work-up beyond the initial clinical assessment as well as seek to obtain a comprehensive medical history when evaluating patients with facial weakness.1,6–8 references 1. chappity p, kumar r, sahoo ak. heerfordt’s syndrome presenting with recurrent facial nerve palsy: case report and 10-year literature review. sultan qaboos univ med j 2015; 15:129. 2. denny mc, fotino ad. the heerfordt-waldenström syndrome as an initial presentation of sarcoidosis. proc (bayl univ med cent) 2013; 26:390–2. 3. tamme t, leibur e, kulla a. sarcoidosis (heerfordt syndrome): a case report. stomatologija 2007; 9:61–4. 4. joseph fg, scolding nj. sarcoidosis of the nervous system. pract neurol 2007; 7:234–44. doi: 10.1136/jnnp.2007.124263. 5. dua a, manadan a. images in clinical medicine: heerfordt’s syndrome, or uveoparotid fever. n engl j med 2013; 369:458. doi: 10.1056/nejmicm1303454. 6. sharma sk, soneja m, sharma a, sharma mc, hari s. rare manifestations of sarcoidosis in modern era of new diagnostic tools. indian j med res 2012; 135:621–9. 7. kimura j. electrodiagnosis of the cranial nerves. acta neurol taiwan 2006; 15:2–12. 8. sugawara y, sakayama k, sada e, kajihara m, semba t, higashino h, et al. heerfordt syndrome initially presenting with subcutaneous mass lesions: usefulness of gallium-67 scans before and after treatment. clin nucl med 2005; 30:732– 3. doi: 10.1097/01.rlu.0000182264.76461.74. mohammed al reesi, amal al-maani, george paul and sumaiah al-arimi online case report | e561 1department of paediatrics, sohar hospital, sohar; 2department of child health, royal hospital, muscat, oman *corresponding author e-mail: alreesimohammed@gmail.com eosinophilic pneumonia is a rare condition in the paediatric population.1,2 it usually presents with acute respiratory distress and eosinophilic pulmonary infiltrates. in most cases, the cause remains idiopathic although patients generally respond well to steroid therapy and do not experience recurrence.3,4 cytomegalovirus (cmv) infection has never been reported as a potential cause for this condition nor has it previously been associated with it. this case, to the best of the authors’ knowledge, is the first that suggests an association between cmv infection and eosinophilic pneumonia without peripheral eosinophilia. case report a three-year-old male child in the maintenance phase of chemotherapy for acute lymphoblastic leukaemia (all) presented to the emergency department of royal hospital, in muscat, oman, during november 2011. the patient had a low-grade fever which had been present for the previous two weeks. a systemic review revealed no other associated symptoms. he was not known to have suffered from bronchial asthma in the past and had no history of exposure to dust or secondhand smoke. one week prior to presentation he had received a course of chemotherapy consisting sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e561−565, epub. 14th oct 14 submitted 6th nov 13 revision req. 2nd feb 14; revision recd. 1st mar 14 accepted 3rd apr 14 االلتهاب الرئوي اإليزينوفيلي األويل املرتبط بالفريوس املضخم للخاليا يف طفل يبلغ من العمر ثالث سنوات , ومصاب بسرطان الدم الليمفاوي احلاد تقرير حالة ومراجعة األدبيات الطبية حممد الري�سي، اأمل املعني، جورج باول، �سمية العرميي abstract: a diagnosis of eosinophilic pneumonia (ep) is rare in patients with acute lymphoblastic leukaemia (all). we report a case of ep in association with a primary cytomegalovirus (cmv) infection in a three-yearold omani child with all. the patient presented with fever while undergoing maintenance chemotherapy. he was admitted to the child health department of royal hospital, in muscat, oman, in november 2011. he was initially thought to have sepsis but failed to respond to antibiotics. chest computed tomography showed diffuse ground glass lung opacification. bronchoalveolar lavage (bal) cytology was consistent with the diagnosis of ep. polymerase chain reaction tests for cmv were performed on the bal and blood samples and were both markedly elevated. the patient made a full recovery after treatment with prednisolone and ganciclovir. the association between cmv infection and ep as well as the management of this combination in immunocompromised patients has never been reported in the english literature. keywords: eosinophilic pneumonia; cytomegalovirus; lymphocytic leukemia; bronchoalveolar lavage; immunocompromised patients; case report; oman. امللخ�ص: يعترب ت�سخي�ص االلتهاب الرئوي االيزينوفيلي نادراً يف املر�سى امل�سابني ب�رسطان الدم الليمفاوي احلاد. نعرض حالة التهاب رئوي اإيزينوفيلي يل للفريو�ص امل�سخم للخاليا يف طفل يبلغ من العمر ثالث �سنوات ، وم�ساب ب�رسطان الدم الليمفاوي احلاد. اأ�سيب املري�ص بحمى اأثناء مقرتن بالتهاب اأوّ العالج الكيماوي املحافظ. مت تنومي املري�ص يف ق�سم �سحة الطفل بامل�ست�سفى ال�سلطاين مب�سقط، عمان يف �سهر نوفمرب 2011. يف البداية كان االعتقاد اأنه م�ساب مبيكروب يف الدم، ولكنه ف�سل يف اال�ستجابة للم�سادات احليوية. اأو�سحت االأ�سعة املقطعية لل�سدر ا�سابات على هيئة زجاج باهت يف الرئتني للفريو�ص املت�سل�سل البوليمرييز تفاعل اجراء مت االإيزينوفيلي. الرئوي االلتهاب ت�سخي�ص مع واالأ�سناخ الق�سبات منغ�سل اخلاليا درا�سة نتائج توافقت . امل�سخم للخاليا يف عينة الغ�سل الق�سبات واالأ�سناخ وعينة للدم ، وكان مرتفعًا ب�سكل وا�سح يف العينتني. تعافى املري�ص ب�سكل كامل بعد عالجه بعقاري الربيدنيزولون واجلان�سيكلوفري. الرتابط بني التهاب الفريو�ص امل�سخم للخاليا وااللتهاب الرئوي االإيزينوفيلي باالإ�سافة اإىل عالج هذا املزيج يف املر�سى منقو�سي املناعة مل يتم تقريره مطلقُا يف ااألدبيات الطبية اإلنكليزية. منقو�سو مر�سى واالأ�سناخ؛ الق�سبات غ�سل احلاد؛ الليمفاوي الدم �رسطان للخاليا؛ امل�سخم الفريو�ص االإيزينوفيلي؛ الرئوي االلتهاب الكلمات: مفتاح املناعة؛ تقرير حالة؛ عمان. primary cytomegalovirus-related eosinophilic pneumonia in a three-year-old child with acute lymphoblastic leukaemia case report and literature review *mohammed al reesi,1 amal al-maani,2 george paul,2 sumaiah al-arimi2 online case report primary cytomegalovirus-related eosinophilic pneumonia in a three-year-old child with acute lymphoblastic leukaemia case report and literature review e562 | squ medical journal, november 2014, volume 14, issue 4 of intravenous vincristine sulphate and methotrexate. he was then discharged and prescribed oral dexamethasone, mercaptopurine, methotrexate and co-trimoxazole. a physical examination showed that the child was active, haemodynamically stable, with no signs of breathing difficulties and no documented fever. a complete blood count (cbc) showed a haemoglobin (hb) level of 10.0 g/dl, a platelet count of 233 x 109/l, a white blood cell count (wcc) of 1.8 x 109/l and an absolute neutrophil count (anc) of 1.2 x 109/l. his c-reactive protein (crp) was 3.9 mg/l. a peripheral blood culture was taken and the patient was discharged with a prescription for oral amoxicillin and clavulanic acid. three days later, the patient’s blood culture grew gram-positive cocci and he was requested to return to the hospital. on arrival, he was febrile with a temperature of 38.0 °c, tachypnoeic with a respiratory rate of 40 breaths per minute and tachycardic with a heart rate of 140 beats per minute. his blood pressure was 100/64 mmhg and his oxygen saturation was 100% in room air. the rest of the systemic examination was normal. investigations showed a slight decrease in hb level (9.4 g/dl), wcc (1.4 x 109/l) and anc (1.0 x 109/l), while a chest radiograph (cxr) was normal. following blood and urine cultures, the patient was started on piperacillin-tazobactam and vancomycin. due to his persistent spiking fever, which ranged from 37.8–38.8 °c, he was also prescribed amikacin for superior antimicrobial coverage on the fourth day after admission. on the seventh day post-admission, amphotericin b was administered due to the possibility of a fungal infection. as the initial blood culture grew gram-positive micrococci of doubtful clinical significance (normal skin flora), further investigations were deemed necessary. a peripheral smear for malaria was negative and bone marrow aspiration did not show any evidence of relapse. abdominal magnetic resonance imaging did not reveal any deep tissue abscesses or enlarged lymph nodes and a transthoracic echocardiogram ruled out the presence of vegetations. in addition to the persistent fever, the patient began to develop other clinical signs. his oxygen saturation began to drop and crepitations and wheezing were heard during a chest examination. in addition, hepatomegaly (3 cm below the costal margin) and splenomegaly (2 cm) were identified, both of which had been absent at presentation. a cbc revealed that the anc had dropped to 0.7 x 109/l, while the crp had increased to 49.5 mg/l. a repeat cxr showed new pulmonary infiltrates [figure 1]. a computed tomography (ct) scan of the chest and sinuses was subsequently performed to delineate the lung pathology. it showed diffuse ground glass opacification in both lung fields in addition to a few pleural-based nodules possibly representing pleural tags. there were also mild atelectatic changes, mainly in the right middle lobe and lingula. no mediastinal lymphadenopathy, pleural effusions, interlobular septal thickening or bronchiectatic changes were noted [figure 2]. the sinuses were also normal. although non-specific, these findings were thought to be indicative of an acute process. in order to determine the specific aetiology of these radiological findings, a bronchoscopy and bronchoalveolar lavage (bal) were performed. the bal was negative for pneumocystis carinii pneumonia, bacterial and fungal cultures. the cytology of the bal showed a significant number of eosinophils (>30%), even though there was no peripheral eosinophilia on repeated blood investigations. based on this finding, a figure 1: chest x-ray showing poor inspiratory film, with a suspicious bilateral mild diffuse air-space consolidation (black arrows). r = right side; ap = anterior-posterior view. figure 2: axial computed tomography image through the lower lobes of the lungs in the lung window, showing areas of diffuse ground glass appearance in both lungs (arrows). mohammed al reesi, amal al-maani, george paul and sumaiah al-arimi online case report | e563 diagnosis of eosinophilic pneumonia was made and the patient was started on steroid therapy (2 mg/kg/ day of prednisolone). considering the evidence of hepatosplenomegaly and the fact that the child was immunocompromised, tests for cmv and epsteinbarr virus were also carried out. despite having previously been seronegative for cmv, the serology reported positive immunoglobulin m (igm) and negative immunoglobulin g (igg) results. the cmv polymerase chain reaction (pcr) in the bal was positive (1,300 copies/ml), while the blood pcr was highly positive (160,750 copies/ml). a repeat sample of blood for cmv pcr was taken and the patient was started on intravenous ganciclovir (5 mg/kg every 12 hours). after the patient had been on prednisolone for 48 hours, he became afebrile with an improvement in respiratory distress and chest findings. all other antimicrobial agents were discontinued. prednisolone was tapered off over the following two-week period. his cmv pcr was monitored on a weekly basis and his cbc was monitored twice weekly for cytopoenia. after two weeks of therapy, the cxr was normal and the patient remained afebrile, with a gradual disappearance of his respiratory signs. during the course of treatment, the patient’s chemotherapy was resumed and he required granulocyte colony-stimulating factor (g-csf) due to neutropaenia. he did not develop thrombocytopoenia and his hb levels remained within the normal range. his renal function was monitored for nephrotoxicity on a weekly basis but remained within normal limits. the child developed diaphoresis for a few days as a side-effect of ganciclovir; however, this resolved spontaneously. his cmv pcr decreased dramatically over the subsequent weeks [table 1]. the patient received a full course of parenteral ganciclovir for three weeks, followed by a maintenance phase of oral valganciclovir (15 mg/kg/day) for three weeks. he was discharged after completing the first week of the maintenance phase and was followed up in the outpatient department every two weeks. throughout this time he remained asymptomatic. a repeated cmv blood pcr was below detection level and he continued his scheduled chemotherapy course without complications. discussion paediatric cases of eosinophilic pneumonia are rare, especially in association with all.1,2 eosinophilic pneumonia is characterised by an acute onset of respiratory distress, radiological evidence of pulmonary infiltrates and significant eosinophilia (>25%) identified through bal and/or a lung biopsy.3,5 a physical examination will normally show fever, tachypnoea, bilateral inspiratory crepitations and wheezing.1,6 the patient described in this case report had an atypical presentation, as the respiratory signs took time to develop and fever was initially the only clinical sign. in an immunocompromised host, the presence of fever has a broad range of differential diagnoses, including infections by different organisms, disease relapse and drug reactions.7 therefore, an interventional approach, including any investigations and subsequent management, must be both extensive and aggressive, as they were in the case of the current patient. the radiological findings in the patient’s chest ct scan were consistent with those described in the literature for eosinophilic pneumonia. these can include diffuse areas of ground glass attenuation, alveolar infiltrates, poorly defined nodules and interlobular septal thickening.8 this diagnosis was confirmed by the bal cytology findings which determined a significant number of eosinophils (>30%). similar to previously reported cases, peripheral blood eosinophilia was not present in this patient.9,10 this may have been because other reported patients were already undergoing oral steroid therapies.5 correspondingly, the current patient had been on oral dexamethasone one week before presentation as part of a chemotherapy management plan. in the majority of cases, eosinophilic pneumonia is idiopathic. however, it can be present in association with different factors, including certain drugs and toxins, smoking, inhaled agents, infections (mainly parasitic), malignant infiltrates and systemic eosinophilic disorders.11 the current patient did not have a history of exposure to smoke or dust and he was not undergoing a relapse. among the various drugs he was taking, methotrexate and co-trimoxazole were the only ones which have been reported to cause pulmonary toxicities with eosinophilia.12,13 however, in addition to the respiratory signs, the patient had copies/ml before treatment 160,750 after treatment in days 1 855,088 6 3128 11 273 18 <10 25 <1* *below detection level. table 1: the patient’s blood cytomegalovirus polymerase chain reaction results over time primary cytomegalovirus-related eosinophilic pneumonia in a three-year-old child with acute lymphoblastic leukaemia case report and literature review e564 | squ medical journal, november 2014, volume 14, issue 4 also developed hepatosplenomegaly and experienced a sudden decrease in both his hb level and anc. the cmv seroconversion (from the negative igm and igg levels recorded two months prior to presentation to positive igm levels) indicates a primary infection of the virus rather than a reactivation. although the drop in his cbc parameters may have been primarily related to the chemotherapy, the hepatosplenomegaly, positive cmv serology and significantly high cmv pcr results strongly suggest that cmv infection was the primary aetiology of the eosinophilic pneumonia. it was difficult to establish cmv as the cause of eosinophilic pneumonia in this case due to the fact that a lung biopsy was not performed. however, the positive pcr from the bal fluid at a time when the patient was also viremic (as evidenced by the positive blood pcr), indicates that it was the likely cause, or at least that there was an association between the cmv infection and eosinophilic pneumonia. among the known causes of eosinophilic pneumonia, viruses are considered rare. nunoda et al. reported one case in an adult patient after allogeneic stem cell transplantation for all.14 the pcr for cmv and human herpes virus 6 were positive in both the bal and blood; these became undetectable after successful treatment with a high dose of methylprednisolone. as a result, nunoda et al. concluded that the eosinophilic pneumonia was an alloreactive response, rather than a condition related to a viral infection.14 in another reported case, influenza a virus was identified as the cause of eosinophilic pneumonia.15 park et al. also reported a case of eosinophilic pneumonia in a 14-month-old infant, from which they isolated human bocavirus (hbov) from nasopharyngeal aspirate by pcr. in this instance, however, they considered the case to be idiopathic as they did not measure the viral load and reported that previous hbov-related cases of respiratory infections were associated only with mild illness.1 it is not uncommon for cases of eosinophilic pneumonia to be misdiagnosed as microbial-related pneumonia or sepsis.2 this is evidenced by the patient in the current case report, who was empirically treated with antibiotics and antifungal medication before a diagnosis was made. most patients respond well to steroid therapy and recurrence is not usual.1,4 in the present case, there was debate among the treating physicians regarding whether steroid treatment alone would be sufficient or whether a specific antiviral agent for cmv infection should be prescribed. it is known that cmv infections in immunocompetent individuals are asymptomatic or cause only mild illness. in immunocompromised patients, however, these infections are associated with high morbiditiy and mortality.16 an antiviral agent was therefore preferable for this patient once the diagnosis had been established. ganciclovir has been shown to be effective in the prevention and treatment of cmv infections in immunocompromised patients, especially if it is given early.17 one of the challenges with using this drug, particularly for an immunocompromised host, is the occurrence of cytopoenia as a side-effect. in such cases, g-csf can be used as a prophylaxis and a treatment for neutropaenia.18 the neutropaenia in this patient was evident before starting ganciclovir and may have been the result of the cmv infection itself or the previous chemotherapy treatment. impaired renal function can also develop, especially in patients who are already on other nephrotoxic agents. it is therefore recommended that patients be monitored on a weekly basis during the induction phase of treatment and that pcr is monitored weekly to follow up the patient’s response to the antiviral therapy.19,20 conclusion eosinophilic pneumonia is a rare disease in children. the aetiology in most cases remains idiopathic. this paper reports a case of eosinophilic pneumonia in association with a cmv primary infection in a child with all. treatment with steroid and antiviral therapy resulted in a complete recovery. the association between eosinophilic pneumonia and cmv infection as well as the management of such a case has never previously been reported in the english literature. references 1. park hn, chung bh, pyun je, lee kc, choung jt, lim ch, et al. idiopathic acute eosinophilic pneumonia in a 14-monthold girl. korean j pediatr 2013; 56:37–41. doi: 10.3345/ kjp.2013.56.1.37. 2. oermann cm, panesar ks, langston c, larsen gl, menendez aa, schofield de, et al. pulmonary infiltrates with eosinophilia syndromes in children. j pediatr 2000; 136:351–8. doi: 10.1067/ mpd.2000.103350. 3. allen j. acute eosinophilic pneumonia. semin respir crit care med 2006; 27:142–7. doi: 10.1055/s-2006-939517. 4. sauvaget e, dellamonica j, arlaud k, sanfiorenzo c, bernardin g, padovani b, et al. idiopathic acute eosinophilic pneumonia requiring ecmo in a teenager smoking tobacco and cannabis. pediatr pulmonol 2010; 45:1246–9. doi: 10.1002/ppul.21314. 5. cottin v, cordier jf. eosinophilic pneumonias. allergy 2005; 60:841–57. doi: 10.1111/j.1398-9995.2005.00812.x. 6. rhee ck, min kh, yim ny, lee je, lee nr, chung mp, et al. clinical characteristics and corticosteroid treatment of acute eosinophilic pneumonia. eur respir j 2013; 41:402–9. doi: 10.1183/09031936.00221811. 7. peng lh, keng tc, sinniah d. fever in children with acute lymphoblastic leukemia. cancer 1981; 47:583–7. doi: mohammed al reesi, amal al-maani, george paul and sumaiah al-arimi online case report | e565 10.1002/1097-0142(19810201)47:3<583::aid-cncr2820470 326>3.0.co;2-k. 8. daimon t, johkoh t, sumikawa h, honda o, fujimoto k, koga t, et al. acute eosinophilic pneumonia: thin-section ct findings in 29 patients. eur j radiol 2008; 65:462–7. doi: 10.1016/j.ejrad.2007.04.012. 9. philit f, etienne-mastroïanni b, parrot a, guérin c, robert d, cordier jf. idiopathic acute eosinophilic pneumonia: a study of 22 patients. am j respir crit care med 2002; 166:1235–9. doi: 10.1164/rccm.2112056. 10. katz u, shoenfeld y. pulmonary eosinophilia. clin rev allergy immunol 2008; 34:367–71. doi: 10.1007/s12016-007-8053-y. 11. pope-harman al, davis wb, allen ed, christoforidis aj, allen jn. acute eosinophilic pneumonia: a summary of 15 cases and review of the literature. medicine (baltimore) 1996; 75:334–42. 12. imokawa s, colby tv, leslie ko, helmers ra. methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. eur respir j 2000; 15:373–81. 13. marchand e, cordier jf. idiopathic chronic eosinophilic pneumonia. orphanet j rare dis 2006; 1:11. doi: 10.1186/17501172-1-11. 14. nunoda k, sumi m, takaku t, tanaka y, akahane d, honda s, et al. [eosinophilic pneumonia after stem cell transplantation due to alloreactive response in acute lymphoblastic leukemia]. j tokyo med univ 2006; 64:585–9. 15. jeon ej, kim kh, min kh. acute eosinophilic pneumonia associated with 2009 influenza a (h1n1). thorax 2010; 65:268–70. doi: 10.1136/thx.2009.133025. 16. demmler-harrison gj. cytomegalovirus. in: feigin rd, cherry jd, demmler-harrison gj, kaplan sl. feigin and cherry’s textbook of pediatric infectious diseases. 6th ed. philadelphia, pennslyvania, usa: saunders elsevier, 2009. pp. 2022–42. 17. goodrich jm, boeckh m, bowden r. strategies for the prevention of cytomegalovirus disease after marrow transplantation. clin infect dis 1994; 19:287–98. doi: 10.1093/ clinids/19.2.287. 18. drugs for non-hiv viral infections. treat guidel med lett 2007; 5:59–70. 19. tice ad, rehm sj, dalovisio jr, bradley js, martinelli lp, graham dr, et al. practice guidelines for outpatient parenteral antimicrobial therapy: idsa guidelines. clin infect dis 2004; 38:1651–72. doi: 10.1086/420939. 20. weinberg a, hodges tn, li s, cai g, zamora mr. comparison of pcr, antigenemia assay, and rapid blood culture for detection and prevention of cytomegalovirus disease after lung transplantation. j clin microbiol 2000; 38:768–72. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 469-476, epub. 8th oct 13 submitted 3rd oct 12 revisions req. 6th jan & 20th mar 13; revisions recd. 3rd feb & 21st mar 13 accepted 31st may 13 college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mail: rhodam@squ.edu.om الصحة اجلنسية للنساء املسنات انعكاساهتا ممرضني واملمرضات ومقدمي الرعاية الصحية األخرى جو�ضوا مولريا ورو�ضة مولريا scopus ,medline من امل�ضنات للن�ضاء اجلن�ضية بال�ضحة املتعلقة الأدلة ا�ضتعرا�ض نتائج املقالة هذه تقدم امللخ�ص: واملوؤ�رش الرتاكمي لقواعد البيانات التمري�ضية وال�ضحية امل�ضاعدة )cinhal( وقد اأخذ يف العتبار 10 مقالت تعتمد على الدرا�ضة -2012 عامي بني ن�رشت والتي عام( ب�ضكل )وامل�ضنني للم�ضنات اجلن�ضية ال�ضحة اأو اجلن�ضية احلياة حول التقارير وتقدمي الأولية 2002 واعتربت منا�ضب. ت�ضري املو�ضوعات الرئي�ضية التي ظهرت من التقارير املتوفرة اإىل اأن ال�ضحة اجلن�ضية للم�ضنني تتاأثر بعوامل مثل التغريات اجل�ضدية وال�ضحة النف�ضية, والتغريات مع اأزواجهن, واعتالل ال�ضحة املزمن وحالت نف�ضية اأخرى. ن�ضتنتج من ذلك باأن للممر�ضني واملمر�ضات ومقدمي الرعاية ال�ضحية لديهم القدرة على اإجراء جمموعة من التدخالت والتي من املمكن ان ت�ضاهم يف تعزيز ال�ضحة اجلن�ضية بني امل�ضنات, قد تركز هذه التدخالت على حت�ضني تقييم امراأة م�ضنة يف جمال ال�ضحة اجلن�ضية, وزيادة الوعي املعريف حول احلياة اجلن�ضية يف وقت لحق؛ وحت�ضني العالجات الدوائية والعالج النف�ضي, وا�ضتخدام تقنيات بديلة لتحقيق اأداء جن�ضي اأف�ضل, ومعاجلة ق�ضايا العالقات الزوجية, والدعوة اإىل اأهمية ال�ضحة اجلن�ضية من خالل و�ضائل الإعالم و�ضيا�ضات التطوير. مفتاح الكلمات: اأنثى؛ م�ضّنة؛ ال�ضلوك اجلن�ضي؛ الرعاية التمري�ضية. abstract: this article presents findings from a review of the evidence regarding sexual health for older women from medline, scopus and the cumulative index to nursing and allied health (cinhal) databases. a total of 10 articles based on primary studies, reporting about the sexuality or sexual health of older women (and older people), and published between 2002–2012, were deemed suitable. the major themes that emerged from the available literature suggest that the sexual health of older people is affected by factors such as physical changes, mental health, changes to their relationship with their husband, chronic ill health and other psychosocial situations. it is concluded that nurses and other healthcare providers have a range of interventions that can be adopted to promote sexual health among older women. these interventions may focus on improving the older woman’s sexual health assessment; increasing awareness and knowledge about sexuality in later life; pharmacological and psychotherapeutic therapies; using alternative techniques to achieve better sexual functioning; addressing partner and relationship issues, and advocating the importance of sexual health through media and policy development. keywords: female; aged; sexual behaviour; nursing care. review sexual health for older women implications for nurses and other healthcare providers joshua k. muliira and *rhoda s. muliira the world health organization (who) defines sexual health as a state of physical, emotional, mental and social well-being in relation to sexuality, and not merely as the absence of disease, dysfunction or infirmity.1 it is also widely recognised that sexuality is a central aspect of being human; international organisations such as the who have reaffirmed this recognition by delineating human sexual rights. the who states that sexuality should be free of coercion, discrimination and violence, and that all humans have a right to access sexual and reproductive healthcare services; seek, receive and impart information related to sexuality; access sexual education; possess and retain sexual health of the highest possible standard; be respected and maintain dignity regarding their body; decide to be sexually active or not; consent to marriage, and to pursue a satisfying, safe and pleasurable sexual life.1 sexuality contributes to a human being’s dignity and social life. commentators on this subject also hold a very similar view of sexuality, and this is demonstrated through statements such as: “sexuality is an important component of health throughout the life span”,2 “being a sexual being and having sexual feelings is a part of being human” and joshua k. muliira and rhoda s. muliira review | 470 in initiating discussions regarding sexual matters even when their patients have sexual problems.8–12 a study of the sexual healthcare needs of older people found that 68% of the older women sampled had never disclosed their sexual problems to their healthcare provider;4 various factors have been identified which contribute to such a trend.7,10,11,13,14 given this background, the aim of the present discourse is to review the available literature on issues germane to the sexual health of the elderly population. given the increased standards of living and advances in medicine, the average lifespan of people in different parts of the world is likely to increase. therefore, evidence-based policies are needed to be contemplated for this growing population of elderly people. although the population structure in oman is generally ‘youthful’, recent affluence has increased the life expectancy for omanis to 72.61 years for men and 76.43 years for women.15 in order to lay the groundwork for meeting future challenges, this study reviews the available literature on sexual functioning among the elderly population. methods a strategy was formulated to identify articles reporting primary studies relevant to the subject of the sexual health of older women or older people. trial searches were conducted to finalise search terms, and this helped to maximise the number of relevant citations. the search terms used were “older women”, “female older adults”, “older people”, “sexual health”, “sexual well-being”, “care” and “nursing care”. these search terms were used both individually and in various combinations in order to locate articles concerning sexual health and older women or older people in the medline, scopus and the cumulative index to nursing and allied health (cinhal) databases. other databases were not searched as it was observed that several articles were already repeated in all three databases. a total of 10 articles based on primary studies, reporting on the sexuality or sexual health of older women (and older people), and published between 2002–2012, were used to formulate the foundation for this review. the 10 articles were included regardless of the methods and instruments used in each study. other literature on the subject— not necessarily primary studies—was used to “there are no age limits to enjoying a healthy sex life”.3 however, in order to maintain sexual health some individuals may require professional help. despite this, it is common for nurses and other healthcare providers to perceive sexuality and sexual health to be relevant only to those in the reproductive age group. they tend to neglect the fact that affection and sexual intimacy contribute to healthy relationships and individual well-being for people of all ages, and that sexuality may increase as humans get older. contrary to the commonlyheld belief, there is empirical evidence to suggest that sexual interest is not significantly impacted by ageing.4 studies conducted in the last decade confirm that sexual concerns are common among people as they age, and specifically show that more older women report problems with sexual function compared to older men.5 unfortunately, the sexual concerns of older women tend to receive less attention5 and be undermined by social misconceptions concerning older women as sexual beings.2 for instance, in some societies, older women are perceived to be asexual.6 other misconceptions related to the sexuality of older women include the belief that their sexual problems are part of the normal ageing process and therefore do not warrant serious attention.7 this pervasive perception of older women as asexual beings is not supported by the scientific literature,6 and may be indirectly propagating a denial of their sexual rights and of the healthcare necessary to maintain their sexual health. this issue appears to be global. epidemiological studies conducted in the usa show that sexual dysfunction is more prevalent among older women (43%) in comparison to older men (31%).5 the most prevalent sexual problems among old women are hypoactive sexual desire disorder (43%), vaginal dryness (39%) and anorgasmia (34%).8 the high prevalence of sexual health problems and the misconceptions about older women’s sexuality highlight a health need that should be addressed by nurses and other healthcare providers. this health need can be met through integrating appropriate interventions to promote sexual health into the regular healthcare provided to older women. however, some studies which have surveyed samples of healthcare providers have found that healthcare professionals frequently have difficulties sexual health for older women implications for nurses and other healthcare providers 471 | squ medical journal, november 2013, volume 13, issue 4 support the discussion of the main points. results the findings of the 10 studies reviewed [table 1] show that older women frequently engage in satisfying sexual activity but also frequently suffer from sexual dysfunctions such as low sexual desire, difficulty with vaginal lubrication and anorgasmia. very few older women discuss their sexual problems or concerns with healthcare providers, although some older women are willing to discuss their sexual problems. the barriers experienced by older women when seeking treatment for sexual problems include the gender of the healthcare provider; their own attitudes towards later-life sexuality; the attribution of sexual problems to the normal ageing process; shame or fear; the perception of older women’s sexual problems as ‘not serious’, and a lack of knowledge concerning sexual health-related services. the healthcare provider’s personal perceptions can be a barrier to addressing older women’s sexual health concerns as these may inhibit them from discussing sex-related matters with older female patients. the discussion below articulates the importance of sexual health, the factors affecting older women’s sexual health and some of the interventions that nurses and other healthcare providers can adopt to promote sexual health in this population. discussion sexual health for older women has been linked to positive health outcomes, and is associated with psychological health and quality of life.16,17 among women (regardless of age), aspects of sexual health such as sexual satisfaction are reported to be associated with high vitality scores and positive wellbeing.18,3 therefore, it is essential that the healthcare professional assist in safeguarding the sexual health of the elderly population and be vigilant on matters related to sex and sexuality among the elderly. politi et al. emphasise that communicating about sexual history may impact patients’ screening behaviours, their willingness to disclose relevant personal health information, and may help to develop a good relationship with their healthcare provider.11 on the other hand, the failure to recognise the importance of sexual health may impose barriers and devalue the sexuality of adults.2 therefore nurses and other healthcare providers should be constantly aware that older women, even those living with chronic illnesses or health problems, need to have their sexual health needs met and that sexual health has physical, physiological, psychological, emotional and spiritual benefits.3,19 fa c t o r s i n f l u e n c i n g t h e s e x u a l h e a lt h o f o l d e r w o m e n a variety of factors influence the sexual functioning and health of women as they age. the most commonly-encountered factors are the hormonal and physiological changes associated with the menopause, changes in physical or mental health, the adverse effects of medications or health interventions and the capability to engage in sexual activity.4,20 as women age, a decline in circulating oestrogen levels results in significant changes to their genitalia, such as the thinning of the uterine and vaginal walls, a shrinkage of the width and length of the vagina, a loss of vaginal wall elasticity and decreased or delayed vaginal lubrication.21,22 subsequently, changes in the vaginal mucus membranes increase the vulnerability to infections and may induce pain during intercourse.21,22 additionally, pain during sexual penetration can lead to sexual dysfunctions such as vaginismus and dyspareunia.23 in some women the labia (minora and majora) significantly atrophy with age, leaving the clitoris exposed to direct stimulation which can sometimes become painful.23 in other older women, the cervix may descend downwards into the vagina, and when this is combined with the loss of the fat pad over the symphysis pubis, it can lead to pain due to direct pressure over the bone during intercourse.21,22 the other major factor influencing the sexual health of older women is chronic ill health. chronic diseases tend to impede sexual functioning. health problems such as dementia, multiple sclerosis, spinal cord injuries, diabetes, hypothyroidism, renal failure and depression have been particularly reported to have an adverse effect on sexual health among the elderly population.22,24 the impact of chronic ill health on the sexual health of older women is further worsened by the treatments used to manage the multiple chronic health problems that can affect older people. the medications commonly used by older people, such joshua k. muliira and rhoda s. muliira review | 472 table 1: studies focusing on sexual health for older women author and year of study sample characteristics, design, instrument and location purpose of study main findings and conclusions gott et al. 7 2003 n = 45. female and male patients 50–92 years old. interview guides. to identify the barriers experienced by older people in seeking treatment for sexual problems. 1) the barriers identified included the gp’s gender, attitudes towards later life sexuality, the attribution of sexual problems to normal ageing, shame and fear, perception of sexual problems as ‘not serious’ and a lack of knowledge about appropriate services. 2) gps need to be more proactive in raising sexual health issues in consultations if the patient’s sexual needs are to be met. nusbaum et al.4 2004 n = 1,480. female patients aged 65 years and over. depts. family practice and obstetrics & gynecology, madigan army medical center, washington, usa. crosssectional survey. self-reported mailed questionnaires. to compare the prevalence and type of sexual concerns, and the interest in and experience with discussing these concerns with physicians for women aged 65 and over. 1) all women aged 65 and over reported having one or more sexual concerns, with a mean of 12 concerns per woman. 2) a total of 68% of the older women were less likely to have heard the topic of sexual health raised by their physicians. 3) a total of 97% of the older women would have discussed their sexual concerns if the physician had asked them. 4) the older women wanted physicians to inquire about their sexual health and partners sexual functioning. gott et al.12 2004 n = 57. female and male gps and nurses of all ages. diverse health practices in sheffield, uk. semi-structured interviews and interview guides. to identify barriers perceived by gps and practice nurses which inhibit discussion of sexual health issues in primary care and explore strategies to improve communication in this area. 1) barriers identified included patients’ gender and being an older or non-heterosexual patient. 2) potential strategies to improve communication included training, providing patients with information, and expanding the role of the practice nurse within sexual health management. addis et al.5 2006 n = 2,109. females, aged 40–69 years old, who were participants of the population-based rrisk study. kaiser permanente medical care program, northern california, usa. cross-sectional study. self-reported questionnaires and inperson interviews. to determine the prevalence of and risk factors for the frequency of sexual activity, satisfaction and sexual dysfunction among middle aged and older women. 1) older women engaged in frequent and satisfying sexual activity (33%) and also reported sexual dysfunction (45%). 2) sexual dysfunction was more common among older women who were not white by race, and had lower education levels and psychological stress. 3) healthcare providers need to be aware of older women’s continuing interest in sexual activity, and should screen for sexual dysfunction and treat any dysfunction with care and sensitivity. lindau et al.8 2007 n = 3,005. females and males aged 57–85 years. nationally representative probability sample of community-dwelling persons. usa. survey. self-reported questionnaires and inhome interviews. to describe the prevalence of sexual activity, behaviour and problems, and the association of these variables with age and health status. 1) sexual problems are frequent among older women and these include low desire (43%), difficulty with vaginal lubrication (39%) and the inability to climax (34%). 2) only 22% of participants reported having discussed sexual matters with their physician after the age of 50 years. 3) physicians’ knowledge about the sexual behaviour of older patients should be utilised to improve patients’ education, counselling, and their ability to identify sexual health problems. wang et al.25 2008 n = 616. female and male community-dwellers, aged 65 years and over, in taipei, taiwan. retrospective study. face-to-face interviews. sexuality knowledge and attitudes scale. to characterise the older population engaged in sexual activity and determine influencing factors, exploring aspects of sexuality that may influence elders’ health and quality of life. 1) most participants (93%) reported being satisfied with their sexual life. 2) lower stress and more daily activities among sexually active older people was associated with sexual activity and higher quality of life (or: 0.77, 95% ci: 0.60–0.99). 3) increased knowledge (or: 1.63, 95% ci: 1.07–2.50) and attitudes (or: 2.16, 95% ci: 1.41–3.31) about sexuality were likely to help people build healthier relationships and enhance their health and quality of life. 4) healthcare professionals’ understanding of older people’s sexuality may help increase their patient’s sexual knowledge, and help them foster healthier attitudes, relationships, overall health and quality of life. sexual health for older women implications for nurses and other healthcare providers 473 | squ medical journal, november 2013, volume 13, issue 4 as antidepressants, antipsychotics, antiepileptics and anticholinergics, have mechanisms of action which have an effect on neurotransmitter systems and can negatively impact sexual desire and sexual arousal; this can make older women unable to have or enjoy sex.22,24 the other classes of medication that have been noted to affect sexual health and function include antihypertensives, diuretics and steroids; alcohol abuse and illicit drug use have also shown to have a negative impact on sexual function.6 other specific factors which are a barrier to the achievement of sexual health among older women include chronic pain, cognitive impairment, environmental restrictions and poor body image.4,20 many older women living with a caregiver who is their child, or in long-term care settings such as nursing homes, experience limitations to their sexuality because of factors such as the disapproval of their caregivers or nurses, feelings that sexuality is inappropriate, and the lack of necessary privacy. nurses and other healthcare providers need to be aware of and address these factors during the assessment, planning and delivery of healthcare— not only to ensure sexual health promotion, but also to ensure the delivery of holistic quality healthcare to older women. i n t e r v e n t i o n s t o p r o m o t e t h e s e x u a l h e a lt h o f o l d e r w o m e n one of the critical interventions that nurses and other healthcare providers can implement to promote the sexual health of older women is to explore the barriers and factors affecting sexual health during health assessments.11,25 the discussion of sexual history with older people is an important part of physical and emotional health assessment.11 older women are interested in discussing sexual concerns with nurses and other healthcare providers, and most of those who discuss their sexual problems with a healthcare provider find these discussions to politi et al.11 2009 n = 40. female patients 40–75 years old. community setting, rhode island, usa. semi-structured interviews and interview guides. to describe experiences of middle-aged and older women in communicating about sexual health and intimate relationships with their healthcare providers. 1) not all women thought healthcare providers should ask about sexual issues unless the questions were directly related to a health problem. 2) women were not satisfied with the questions about sexual issues on medical forms. 3) healthcare providers should ask questions about sexual health in a way that is sensitive to the woman’s needs and in a non-judgmental manner. woloskiwruble et al.29 2010 n = 127. female patients, 45 years and over, of a midlife outpatient clinic affiliated with a teaching hospital, israel. descriptive correlation study. derogatis sexual functioning inventory. the life satisfaction index. to investigate the sexual activities of older women, their levels of sexual and life satisfaction, and to examine the relationship between sexual activity and sexual/life satisfaction. 1) sexual activity was positively associated with sexual satisfaction (r = 0.32, p <0.001). 2) older women were interested in continuing their sexual activity. 3) sexual activity was significantly associated with quality of life, but differed according to the experiences the women had had in the past. 4) healthcare professionals should deepen their knowledge about sexuality in older age, develop specific techniques of sexual assessment and initiate active communication with women about this sensitive issue. farrell et al.9 2012 n = 101. female and male residents (80 years and over) of retirement communities and participants in fitness classes. washington, usa. cross-sectional study. a 24-item investigatordeveloped survey. to ascertain whether older adults had unanswered questions about their sexuality and whether they were comfortable discussing sexual health with nurses. 1) most respondents were female (70.3%). 2) most respondents (47.1%) wanted to be asked about their sexual health during healthcare visits. 3) most respondents (86%) reported being comfortable discussing sexual health and not being embarrassed. 4) 56.9% of the women were willing to talk to physicians and nurses about sexual issues. 5) physicians and nurses have the potential to enhance communication with older adults regarding issues of sexual health that impact quality of life. trompeter et al.28 2012 n = 1,303. female participants, 40 years and over, from rancho bernardo study, usa. survey by postal questionnaire. to describe the prevalence and covariates of sexual activity and satisfaction in older community-dwelling women. 1) sexual activity with arousal (65%), lubrication (69%) and orgasms (67%) were maintained despite a low libido. 2) emotional and physical closeness to the partner was considered more important than experiencing orgasm. 3) sexual satisfaction increased with age and did not require sexual activity. 4) greater emphasis on specific sources of satisfaction may be more useful than focusing only on female sexual activity or dysfunction. gps = general practitioners; rrisk = reproductive risk factors for incontinence study; or = odds ratio; ci = confidence interval. joshua k. muliira and rhoda s. muliira review | 474 be helpful.4,20 although earlier reports showed that older women found communicating with healthcare providers about their personal sexual health to be particularly difficult,7,11 more recent studies show that this attitude is changing in some countries.9 nurses are especially suited to carrying out the health assessment of older women’s sexual health because they are routinely involved in patient and family health education, and spend the most time with patients in all healthcare settings. the other interventions that nurses and healthcare providers can implement to promote the sexual health of older women are those focusing on improving knowledge about sexuality. having knowledge about sexuality in later life is associated with a more positive attitude towards sexuality among older people.26 therefore sexual health education is very important in modifying older people’s attitudes towards sex.13 nurses and other healthcare providers need to know that it is crucial to teach patients about issues related to sexual performance and expectations because the knowledge gained from such interactions can help patients adapt to the bodily changes and changes in sexuality caused by the ageing of women and their husbands.27 educating older women about the typical bodily changes caused by ageing may also help to normalise their experiences and reduce distress about the meaning of certain symptoms and experiences.13,26 addressing and increasing older people’s knowledge about the impact of physical health problems on sexual health provides the opportunity to moderate their sexual performance expectations and improves their emotional wellbeing.14 another potential category of interventions are those that address partner and relationship issues. one of the most important factors affecting the sexual activities of older women is being in an intimate relationship with another person.27,28 the presence of a husband is very important and changes in the husband’s health condition or sexual functioning significantly affects the woman.29,30 therefore interventions that focus on supporting and improving older women’s relationships with their husbands and older women’s health are critical to sexual health promotion.20 depending on the care setting and environment, nurses can encourage the husbands of older women to visit more regularly, and talk or demonstrate affection in privacy. maintaining physical intimacy through cuddling and touching is central to to the sexual satisfaction and well-being of older people when penetrative sex is no longer possible.10 interventions focusing on the older woman’s husband should mainly aim at promoting positive intimate experiences, improving communication, dealing with negative emotions and harmonising sexual wishes and desires.22 social factors are very important, especially in the nursing care of older women, because after mid-life most women have limited social recognition and support for sexual relationships, and because most cultures and media are silent on the subject of sexuality in later life.32 this support and recognition can be given to older women by nurses during nursing care. nurses and other healthcare providers can also suggest to older women that they use alternative techniques to achieve better sexual function. some of the alternative techniques that can be adopted by older women who cannot tolerate penetrative sex for very long include asking their husbands to enjoy longer periods of foreplay, using techniques such as kissing, petting, embracing, stroking different body parts, or trying new sexual positions which may cause less pain.23,33 older women can also practise kegel exercises to increase vaginal muscle tone and use lubricating creams to compensate for and reduce vaginal dryness.23,30,32 older women usually describe intimacy in broader terms than simply sexual intercourse, and therefore alternative aspects of sexual expression are highly regarded and are most likely to lead to sexual satisfaction.28 there are also pharmacological and psychotherapeutic interventions that can be used to improve the sexual functioning of older women. the management of the physiological changes secondary to the reduced oestrogen levels that affect the appearance and functioning of the genital area of older women can be done using psychotherapy and supplementary hormonal treatment when symptoms are severe.21,22 however nurses and other healthcare providers should be extremely careful and vigilant when an older woman chooses to use supplemental hormonal treatments, because of the potential complications and risks such as embolism, cancer, stroke, etc. that are associated with these treatments. hormonal treatment can comprise oestrogen with or without testosterone. oestrogen is necessary for genital lubrication and testosterone sexual health for older women implications for nurses and other healthcare providers 475 | squ medical journal, november 2013, volume 13, issue 4 helps to increase sexual desire.23 a combination of oestrogen and testosterone seems to have a better effect on the various aspects of sexual functioning and psychological well-being than oestrogen therapy alone;22 however, the pharmacological facilitation of sexual arousal can only be successful when the treatment also focuses on psychological and social factors.22,33 psychotherapy techniques can be used when addressing physical health problems affecting the sexual functioning of older women.14 if the nurse or health care provider is not competent in psychotherapy techiques, he or she can refer the patient (or advocate referral) to a healthcare professional who can provide these intervetions. it is also important to note that psychotherapeutic interventions are most effective when both the woman and her husband are involved. some of the problems that are commonly managed using psychotherapy include low sexual desire, arousal problems, difficulties in climaxing and problems with sexual satisfaction.22 the referral of older women to other forms of psychological treatment such as sex therapy and cognitive interventions are recommended for those with low sexual desire, and those who need detailed education about how to achieve adequate stimulation.31,33 the technique of cognitive restructuring is used for patients with dysfuctional thoughts and those whose partners have behaviours that can inhibit sexual desire and arousal or cause insufficient physical stimulation.22,33 interventions to promote the sexual health of older women can also take the form of professional advocacy and policy development on issues related to sexual health. in most countries, the media and culture depict older people as asexual.20,31 this misconception can be corrected by delivering healthcare that values and addresses the sexual needs of older people. unfortunately, it is often considered inappropriate to use the media, scientific publications and other professional forums to encourage older women to engage in regular and appropriate activities that make them feel sexually attractive and aroused. at the policy level, the sexual health of older people is mostly neglected as it is assumed to be irrelevant and of no benefit to their quality of life.10 nurses and healthcare providers are generally more likely to be effective than any other group in advocating for policies that promote the sexual health of older people. such policies could, for example, include supporting and participating in policies that oblige the reimbursement of costs for nursing interventions that focus on sexual health or that support the integration of sexual health-related competencies in the training and curricula of the healthcare professions. therefore issues related to sexual health promotion for older women during patient care or at the level of policy development present a unique opportunity for healthcare providers to fulfill an important health need and subsequently enhance the well-being of older people.28 conclusion although the sexual health of the older generation is often neglected, a substantial proportion of older women remain interested and engaged in sexual activities. nurses and other healthcare providers have many interventions that can be adopted to promote sexual health among older women. these interventions may focus on improving the older woman’s sexual health assessment; increasing awareness and knowledge about sexuality in later life; pharmacological and psychotherapeutic therapies; using alternative techniques to achieve better sexual functioning; addressing partner and relationship issues; and advocating the importance of sexual health through media and policy development. this review has several implications for practice. first, older women expect nurses and other healthcare providers caring for them to address their sexual health needs. second, promoting and addressing the sexual health of older women enhances their general health and well-being. third, ensuring that interventions focusing on sexual health are integrated into care plans for older women will enhance the quality of their health care and ensure their right to sexual health. finally, nurses are better positioned to implement interventions focusing on sexual health for older women because of their regular and extensive contact with patients during healthcare. references 1. world health organization. defining sexual health. report of a technical consultation on sexual health. from: http://www.who.int/reproductivehealth/publi cations/sexual_health/defining_sexual_health.pdf accessed: feb 2012. joshua k. muliira and rhoda s. muliira review | 476 2. pagman vc, seguire m. sexuality and the chronically ill older adult: a social justice issue. sex disabil 2000; 18:49–59. 3. peate i. sexuality and sexual health promotion for the older person. br j nurs 2004; 13:188–93. 4. nusbaum mr, singh ar, pyles aa. sexual health care needs of women aged 65 and older. j am geriatr soc 2004; 52:117–22. 5. addis ib, van den eeden sk, wassel-fyr cl, vittinghoff e, brown js, thom dh. sexual activity and function in middle-aged and older women. obstet gynecol 2006; 107:755–64. 6. ambler dr, bieber ej, diamond mp. sexual function in elderly women: a review of current literature. rev obstet gynecol 2012; 5:16–27. 7. gott m, hinchliff s. barriers to seeking treatment for sexual problems in primary care: a qualitative study with older people. fam pract 2003; 20:690–5. 8. lindau st, schumm lp, laumann eo, levinson w, o’muircheartaigh ca, waite lj. a study of sexuality and health among older adults in the united states. n eng j med 2007; 375:762–74. 9. farrell j, belza b. are older patients comfortable discussing sexual health with nurses? nurs res 2012; 61:51–7. 10. gott m, hinchliff s, galena e. general practitioner attitudes to discussing sexual health issues with older people. soc sci med 2004; 58:2093–103. 11. politi mc, clark m a, armstrong g, mcgarry ka, sciamanna cn. patient-provider communication about sexual health among unmarried middle-aged and older women. j gen intern med 2009; 24:511–16. 12. gott m, galena e, hinchliff s, elford h. opening a can of worms: gp and practice nurse barriers to talking about sexual health in primary care. fam pract 2004; 21:528–36. 13. parish sj, rubio-aurioles e. education in sexual medicine: proceedings from the international consultation in sexual medicine, 2009. j sex med 2010; 7:3305–14. 14. barret cm. auditing organisational capacity to promote the sexual health of older people. e j appl psychol 2011; 7:31–36. 15. index mundi. oman life expectancy at birth. from: http://www.indexmundi.com/oman/life_expectancy_ at_birth.html accessed: may 2013. 16. kermode s, maclean d. a study of the relationship between quality of life, health and self-esteem. aust j adv nurs 2001; 19:33–40 17. langer n. late life love and intimacy. educ gerontol 2009; 35:752–64. 18. davison sl, bell rj, lachina m, holden sl, davis sr. the relationship between self-reported sexual satisfaction and general well-being in women. j sex med 2009; 6:2690–7. 19. brody s. the relative health benefits of different sexual activities. j sex med 2010; 7:1336–61. 20. huang aj, subak ll, thom dh, van den eeden sk, ragins ai, kuppermann m, et al. sexual function and aging in racially and ethnically diverse women. j am geriatr soc 2009; 57:1362–8. 21. basson r, althof s, davis s, fugl-meyer k, goldstein i, leiblum s, et al. summary of the recommendations on sexual dysfunctions in women. j sex med 2004; 1:24–34. 22. both s, laan e, schultz ww. disorders in sexual desire and sexual arousal in women, a 2010 state of the art. j psychosom obstet gynecol 2010; 31:207– 18. 23. trudel g, villeneuve l, préville m, boyer r, fréchette v. dyadic adjustment, sexuality and psychological distress in older couples. sex relation ther 2010; 25:306–15. 24. wang tf, lu ch, chen ij, yu s. sexual knowledge, attitudes and activity of older people in taipei, taiwan. j clin nurs 2008; 17:443–50. 25. määttä k, uusiautti s. how to learn to enjoy sexuality – the resources of human sexuality. adv psychol study 2012; 1:8–13. 26. bradford a, meston cm. senior sexual health: the effect of aging on sexuality. in: vandecreek l, peterson fl, bley jw, eds. innovations in clinical practice: focus on sexual health. 1st ed. florida: professional resources press, 2007. pp. 35–45. 27. trompeter se, bettencourt r, barrett-connor e. sexual activity and satisfaction in healthy communitydwelling older women. am j med 2012; 125:38–43. 28. woloski-wruble ac, oliel y, leefsma m, hochnercelnikier d. sexual activities, sexual and life satisfaction, and successful aging in women. j sex med 2010; 7:2401–10. 29. kingsberg sa. the impact of aging on sexual function in women and their partners. arch sex behav 2002; 31:431–7. 30. delamater jd, sill m. sexual desire in later life. j sex res 2005; 42:138–49. 31. laumann eo, waite lj. sexual dysfunction among older adults: prevalence and risk factors from a nationally representative u.s. probability sample of men and women 57-85 years of age. j sex med 2008; 5:2300–11. 32. glasier a, gülmezoglu am, schmid gp, moreno cg, van look pf. sexual and reproductive health: a matter of life and death. lancet 2006; 368:1595–607. 33. montgomery ka. sexual desire disorders. psychiatry (edgmont) 2008; 5:50–5. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e305–316, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.002. submitted 18 aug 14 revisions req. 20 oct 14 & 26 jan 15; revisions recd. 17 dec 14 & 9 feb 15 accepted 19 mar 15 alzheimer’s disease (ad) is a chronic neurodegenerative disease considered to be the most common cause of dementia.1 ad is characterised by visuospatial dysgnosia and memory, language, emotional, personality and complex cognition impairment. the primary sign of ad is the gradual deterioration in an individual’s ability to remember recent events, likely due to the perturbation of neuronal function in the temporal lobes.1,2 more than 44 million people worldwide were estimated to be suffering from ad in 2014 and this number is projected to double by 2030.3 there is a direct correlation between the incidence of dementia and ageing, with the highest rates of ad seen in the seventh and eighth decades of life. in addition, it is proposed that the incidence of ad may dramatically rise every five years after the age of 65 years.4 the most common neuropathological hallmarks of ad are deposition of amyloid β (aβ) in a compact structure outside the neurons, intracellular neurofibrillary tangles (nfts) and inflammatory processes. aβ is derived from the amyloid precursor protein (app) by processing enzymes (α-, βand γ-secretases). these altered proteins are deposited as extracellular plaques called senile plaques.5–7 intracellular nfts, which are composed of microtubule-associated protein tau, are another pathological aspect of adaffected brains. following chemical changes such as hyperphosphorylation, these aggregates often pair with other threads and accumulate inside the neurons, consequently causing microtubule destabilisation.5,8,9 histopathological evidence from patients with ad shows cerebral atrophy, deposition of aβ in plaques and neuritic changes, such as neuritic plaques and 1department of laboratory medicine, imam hassan mojtaba hospital, alborz university of medical sciences, karaj, iran; 2research center for immunodeficiencies, children’s medical center and 3department of immunology, school of public health, tehran university of medical sciences, tehran, iran; 4health & social services sector, the research council oman, muscat, oman; 5department of immunology, faculty of medicine, isfahan university of medical sciences, isfahan, iran *corresponding author e-mail: mirshafiey@tums.ac.ir دور وسائط االلتهاب يف اآللية املرضية لداء الزهامير غالمريزا عزيزي، �سادي �سادات نافابي، اأحمد ال�سكيلي، مري هادي �سيدزاده، ر�سا يزدين، عبا�س مري�سايف abstract: alzheimer’s disease (ad), a neurodegenerative disorder associated with advanced age, is the most common cause of dementia globally. ad is characterised by cognitive dysfunction, deposition of amyloid plaques, neurofibrillary tangles and neuro-inflammation. inflammation of the brain is a key pathological hallmark of ad. thus, clinical and immunopathological evidence of ad could be potentially supported by inflammatory mediators, including cytokines, chemokines, the complement system, acute phase proteins and oxidative mediators. in particular, oxidative mediators may actively contribute to the progression of ad and on-going inflammation in the brain. this review provides an overview of the functions and activities of inflammatory mediators in ad. an improved understanding of inflammatory processes and their role in ad is needed to improve therapeutic research aims in the field of ad and similar diseases. keywords: alzheimer’s disease; inflammation mediators; cytokines; chemokines; complement system proteins; acute phase proteins. امللخ�ص: داء الزهامير هو انتكا�سة ع�سبية حتدث مع التقدم يف العمر وهي اأكرث اأ�سباب خرف ال�سيخوخة �سيوعا. ويتميز املر�س بحدوث خلل إدراكي، وتر�سب لويحات اميلويدية، وت�سابك الألياف الع�سبية مع األتهاب ع�سبي. وال�سمة املميزة لداء الزهامير هي حدوث إلتهاب املخ. وبالتايل فاإن الأدلة ال�رسيرية واملناعية املر�سية قد يتم دعمها بالو�سائط اللتهابية، مثل ال�سيتوكينات والكيموكينات، ونظام الكومبليمنت )املتممة(، وعالمات اللتهاب احلاد، والو�سائط املوؤك�سدة. وعلى وجه اخل�سو�س فاإن الو�سائط املوؤك�سدة قد يكون لها دور داء يف اللتهاب و�سائط واأن�سطة وظائف على عامة ملحة يقدم ال�ستعرا�س وهذا اجلاري. املخ والتهاب الزهامير داء تفاقم يف ن�سط الزهامير. إن حت�سن فهمنا لدور الألتهاب يف حدوث داء الزهامير �سيوؤدي إيل تقدم البحث العلمي يف إمكانية عالج هذا املر�س وبالتايل اأمرا�س اأخرى م�سابهة. مفتاح الكلمات: داء الزهامير؛ و�سائط الألتهاب؛ ال�سيتوكينات؛ الكيموكينات؛ بروتينات نظام الكومبليمنت؛ عالمات اللتهاب احلاد. the role of inflammatory mediators in the pathogenesis of alzheimer’s disease gholamreza azizi,1,2 shadi s. navabi,3 ahmed al-shukaili,4 mir h. seyedzadeh,3 reza yazdani,2,5 *abbas mirshafiey3 review the role of inflammatory mediators in the pathogenesis of alzheimer’s disease e306 | squ medical journal, august 2015, volume 15, issue 3 nfts. although the brains of people diagnosed with ad have increased aβ deposition, these findings are not specific to ad alone and may be found in elderly people not suffering from dementia.10,11 although the amyloid cascade theory is the most widely accepted explanation for the aetiology of ad, other theories have also been described to illustrate the role of inflammation in actively contributing to the progression of the disease.12 it is often assumed that the accumulation of aβ in the brain results in the development of systemic inflammatory reactions by prompting immune responses.13,14 this article reviews the major role of inflammatory mediators in the immunopathogenesis of ad. immunopathology of alzheimer’s disease cells of the adaptive immune system can migrate to the brain through the blood-brain barrier (bbb), which is structurally different in people with ad in comparison to healthy individuals.15 based on electron microscope observation, most aβ plaques in the brains of ad patients are associated with activated microglial cells (central nervous system [cns]-resident macrophages). these cells seem to be responsible for on-going neuro-inflammatory processes in ad through the release of cytokines, chemokines and neurotoxins. moreover, microglial cells can produce several proand anti-inflammatory cytokines via direct inter-action with infiltrated t lymphocytes.15 interestingly, bromley et al. reported that some chemokines are able to restrain immunological synapse formation and t cell activation.16 they indicated that the immunosuppressive effect of chemokines occurred with c-x-c motif receptor (cxcr) 3 and c-c motif receptor (ccr) 7 chemokines, but not with ccr2, 4 and 5 or cxcr4 chemokines.16 inflammation commences when innate immune mediators detect damaged tissue or other molecules on the surface of cells. chemokines and other inflammatory mediators are responsible for the recruitment of immune cells to the damaged area.17,18 various inflammatory processes in ad contribute to the pathology of the disease [table 1]. degenerated cells and tissues, as well as an accumulation of abnormal insoluble materials, are the most common stimuli for inflammation. likewise, in the brain of ad patients, damaged neurons and neurites, along with nft and insoluble aβ peptide deposits, can act as potent triggers of inflammation.19 accordingly, inflammation may contribute to the pathogenesis of ad by two mechanisms. the first is a preliminary innate immune response to the alterations in the ad brain; inflammation is involved in the recruitment of immune cells to the site of injury as a result of the initial signalling of cytokines and chemokines and complement system activation. the second mechanism involves a minor amount of on-going inflammation in the brain, which can result in the pathogenesis of ad. this inflammation can be considered a sign of an impaired adaptive immune response and leads to chronic inflammation.19,20 g l i a l c e l l s a s a t r i g g e r o f i m m u n e r e s p o n s e s microglial cells have the ability to induce neuronal damage through the following processes: (1) phagocytosis; (2) the release of cytokines/chemokines/ prostaglandins and reactive oxygen species (ros); and (3) the expression of innate and adaptive immune function molecules such as toll-like receptors (tlrs), immunoglobulin fragment crystallisable gamma receptors, major histocompatibility complex class ii (mhc ii) molecules, complement receptors and purinergic receptors (e.g. p2x purinoceptor 7).21–23 the activation of microglia with aβ can occur either via the internalisation of soluble aβ through phagocytosis while fibrillary aβ binds to tlr2 and tlr4 or through the activation of a mitogen-activated protein kinase pathway, stimulating pro-inflammatory gene expression leading to the secretion of cytokines and chemokines.24 moreover, aβ may be presented by activated microglial cells to t lymphocytes, eventually causing aβ-specific t cells to enter the brain [figure 1]. it should be noted that while aβ-reactive t cells are present in healthy individuals, t cells are vital for protecting against ad pathogenesis by cooperating with and modulating the innate immune system.25 table 1: inflammatory components contributing to the pathology of alzheimer’s disease inflammatory component examples cns cells microglia, astrocytes and neurons cytokines tnf-α, il-1β, il-6, ifn-γ and il-18 chemokines mcp-1, cxcl8, cxcl12, cx3cl1 and mip complement system classical and alternative pathways acute phase proteins crp and saa oxidative mediators ros, rns, no, o2and onoocns = central nervous system; tnf-α = tumour necrosis factor-α; il = interleukin; ifn-γ = interferon-γ; mcp-1 = monocyte chemoattractant protein-1; cxcl = c-x-c motif ligand; cx3cl1= c-x3-c motif ligand 1; mip = macrophage inflammatory protein; crp = c-reactive protein; saa = serum amyloid a; ros = reactive oxygen species; rns = reactive nitrogen species; no = nitric oxide; o2= superoxide anion radical; onoo= peroxynitrite anions. gholamreza azizi,shadi s. navabi, ahmed al-shukaili, mir h. seyedzadeh, reza yazdani and abbas mirshafiey review | e307 however, t cells are more susceptible to ageing than innate immune components. fulop et al. demonstrated that adaptive immune responses in the elderly were less effective in eliminating aβ deposition than an innate immune response.25 therefore, once the immune system is overwhelmed with aβ deposition, inflammation becomes chronic and adverse, resulting in accelerated neurodegeneration.26 r o l e o f ly m p h o c y t e s several studies have evaluated the function of t cells in ad so as to determine ad-related abnormalities in the immune system.27,28 richartz-salzburger et al. reported the general decline of immune function among patients with ad due to a decreased number of t and b cells.27 in addition, another study noted the hyporesponsiveness of t cells to certain intrinsic functional defects in ad patients when compared with control subjects.29 some alterations, such as accelerated telomere shortening, can serve as an important factor in the impairment of normal lymphocyte activity in ad patients.30 this finding was confirmed by zhang et al.; their research indicated that the increase of telomerase activity in the lymphocytes of ad patients can lead to diminishing lymphocyte proliferation activity, consequently resulting in the loss of immune function.31 as yet, the precise mechanism regarding the activation, migration and survival of t cells in the brains of ad patients is not clear. as previously mentioned, antigen-presenting cells with a high expression of mhc іі molecules, which either differentiate from microglia in the brain or are recruited from the blood, can present aβ to t cells. in addition, interferon-γ (ifn-γ) plays a key role in facilitating t cell migration as well as promoting an immune regulatory process within the brain.32 the amount of ifn-γ in the brain determines its effect as it is adverse at high levels and beneficial at low levels.33 research has demonstrated the pathogenic reaction of both t and b cells against aβ as well as the risk of meningoencephalitis, caused by the entry of figure 1: the immunological function of microglia in alzheimer’s disease. aβ = amyloid β; tlr = toll-like receptors; cd = cluster of differentiation; rage = receptor for advanced glycation end-products; fcγr = fragment crystallisable gamma receptor; mhc ii = major histocompatibility complex class ii; cr = complement receptor. the role of inflammatory mediators in the pathogenesis of alzheimer’s disease e308 | squ medical journal, august 2015, volume 15, issue 3 cluster of differentiation (cd) 8 cytotoxic t cells to the brain followed by the secretion of pro-inflammatory cytokines by cd4 t cells.33,34 r o l e o f i n f l a m m at o r y c y t o k i n e s a n d c h e m o k i n e s there is growing evidence that inflammatory mediators in the cns contribute to cognitive impairment through cytokine-mediated interactions between glial cells and neurons. moreover, it has been demonstrated that ad is associated with the upregulation of proinflammatory cytokines, which can initiate plaque production and enhance nerve cell degeneration.6,15 some of these mediators—including tumour necrosis factor (tnf)-α, interleukin (il)-6, ifn-γ, inducible protein-10, monocyte chemoattractant protein (mcp)-1 and c-x-c motif ligand (cxcl) 8—increase in the prodromal stage of ad. elevation of these cytokines occurs during the initiation of ad. this may explain the failure of clinical trials using anti-inflammatory drugs against severe ad.35 this idea is supported by immunohistochemistry examinations performed by sokolova et al. which confirmed the increase of mcp-1, il-6 and cxcl8 in ad brains and determined that these mediators were localised in neurons (il-6, mcp-1 and cxcl8), astrocytes (il-6 and mcp-1) and plaques (cxcl8 and mcp-1).36 moreover, logistic linear regression modelling determined that, of the cytokines, mcp-1 was the most accurate for the prediction of ad.36 hence, these findings support the importance of il-6, mcp-1 and cxcl8 in ad and also show that mcp-1 may play an important role in the progression of chronic inflammation in ad. as a result of these observations, some cytokines (such as il-1, -4, -6, -10, -12 and -18, ifn-γ, tnf and transforming growth factor [tgf]-β) have been proposed as ad biomarkers.6 interleukin (il)-1ß, il-6 and tumour necrosis factor-α the elevation of il-1β, il-6 and tnf-α is widely recognised as a critical component of neuroinflammation and leukocyte recruitment to the cns.6 this response is characterised by promoting deposition of aβ in the brain and astrocytic and microglial activation. moreover, il-1β and tnf-α are potent stimuli for inducible nitric oxide (no) synthase (nos) expression and activity in the brain and no metabolite overflow into the cerebrospinal fluid.5 importantly, belkhelfa et al. revealed recently that a high level of no is associated with the rise of tnf-α levels in patients in the severe stages of ad.37 in response to numerous intrinsic and extrinsic stimuli, tnf-α is produced by microglia, astrocytes and neurons in the brain. in addition, genetic and epidemiological findings have implicated augmented levels of tnf-α in the brain as a risk factor for ad.37 tnf-α can mediate neuronal dysfunction as well as aβ-induced disruption of the molecular mechanisms involved in memory function. likewise, tnf-α can stimulate accumulation of the tau proteins in neurites through induction of ros.5 in another recent study, lin et al. observed a significant decrease of tnf-α, il-1α, -6 and -12 in sera after vaccinating transgenic mice.38 remarkably, the decrease in tnf-α and il-6 levels correlated with cognitive and behavioural improvements in the transgenic mouse model of ad.38 in contrast, it has been reported that some inflammatory cytokines, such as il-1β, il-6 and ifn-γ, have also had beneficial and protective effects against ad.6,39 overexpression of il-1 and il-6 in the brain results in extensive gliosis which may be beneficial in the disease process by stimulating increased amyloid phagocytosis rather than mediating a neurotoxic feedback loop. interleukin-18 and interferon-γ several studies have highlighted a critical role for il-18 in mediating neuro-inflammation and neurodegeneration in the brains of ad patients.40,41 notably, an imbalance of il-18 and its endogenous inhibitor, il-18 binding protein (il-18bp), has been shown in ad, with an elevated il-18:il18bp ratio that might be involved in the disease immunopathogenesis.42 in the brain, il-18 is produced by microglial, astrocyte and ependymal cells as well as by neurons of the medial habenular nucleus.43 through the induction of ifn-γ and expression of mhc іі molecules in microglial cells, il-18 can initiate a neural-immune cell interaction which may play a key role in the induction of autoimmunity in the cns environment.44 moreover, ifn-γ can enhance aβ deposition through β-secretase 1 expression as well as stimulate the upregulation of mhc ii molecules in a subpopulation of microglia and induce auto immune processes in the cns. importantly, significant ifn-γ levels are only detected in mild cases of ad. collectively, this suggests that no production is ifn-γ-dependent in ad.37 on the other hand, ifn-γ is a known inhibitor of app fragment production. ifn-γ can prevent amyloid deposition during inflammatory processes in both non-neuronal and neuronal tissues. furthermore, ifn-γ has a strong suppressive effect on the production and metabolism of app.5,45 transforming growth factor-ß recent data have implicated anti-inflammatory cyto kines as integral factors to the pathogenesis of ad.6 among them, tgf-β is emerging as a critical factor in regulating inflammatory responses. three known gholamreza azizi,shadi s. navabi, ahmed al-shukaili, mir h. seyedzadeh, reza yazdani and abbas mirshafiey review | e309 isoforms of tgf-β (tgf-β1, -β2 and -β3) are expressed in mammalian tissues. in ad, the expression of tgf-β2 is induced by toxic aβ in both glial and neuronal cells; increased levels of tgf-β2 trigger the cell death pathway due to alterations in the morphology and number of lysosomes in neurons.46 tgf-β2 causes lysosomal membranes to become unstable and leak and this effect is intensified with the accumulation of aβ, as tgf-β2 rapidly targets the aβ peptide in lysosomal compartments in cortical neurons, inducing cell death.47 as a neurotrophic factor, tgf-β1 initiates and maintains neuronal differentiation and synaptic plasticity. in ad animal models, it has been suggested that a deficiency of tgf-β1 signalling may correlate with aβ pathology and nft formation.48 c-c motif ligand 2 c-c motif ligand (ccl) 2, also known as mcp1, plays a significant role in ad pathogenesis. increased levels of ccl2 in the brain result in the recruitment of activated monocyte cells into the organ where they differentiate into macrophages and produce neurotoxic and inflammatory mediators.49–51 immunohistochemistry findings have confirmed this increase in ccl2 levels and have determined localisation of these factors in astrocytes, neurons and plaques via pathology.49 however, mononuclear phagocyte accumulation is regulated via the interaction of ccl2 with its receptor, ccr2; ccr2 deficiency in these cells therefore leads to diminished phagocyte cell recruitment to the brain which is associated with higher levels of aβ in the brain, particularly around the blood vessels. this suggests that monocytes are initially recruited and accumulate at aβ deposition sites in order to clear them and either halt or delay their associated neurotoxic effects. indeed, an increase of mononuclear phagocyte recruitment to the brain delays the progression of ad in its early stages.36,49 c-c motif ligand 5 the role of ccl5, also known as the rantes (regulates on activation, normal t cell expressed and secreted) protein, has been determined in neurodegenerative diseases such as ad and elevated levels of rantes protein are commonly observed in the microcirculatory system of ad-affected brains.52 the rantes protein, as well as several other chemokines in astrocytes, is upregulated as a response to a cytokine-mediated increase of ros.53 moreover, oxidative stress upregulates rantes protein expression in endothelial cells in the brain.52 in brain injury models, elevated levels of the rantes protein contributed to immune cell recruitment that occurred concurrently with increased rates of neuronal death.52,54,55 c-x-c motif ligand 8 cxcl8 (il-8) is a microglia-derived chemokine that is produced in response to pro-inflammatory signals such as aβ. cxcl8 could be important for the recruitment of activated microglia and neutrophils into areas of the damaged brain during the late stages of ad, suggesting a role for this chemokine in phases with prevalent neurodegeneration. in addition, cxcl8 is continually upregulated in neurons and plaques.19 c-x-c motif ligand 12 the chemokine cxcl12 has been associated with neurogenesis and the recruitment of brain-resident and non-resident circulating cells to sites of lesions in the cns.56 moreover, in tg2576 mouse models of ad, cxcl12 messenger ribonucleic acid (mrna) protein and its receptors were downregulated, with co-existing cognitive deficits.57 zhu et al. found that cxcl12 plasma levels in patients with early ad were low and that cxcr4 and cxcl12 had anti-inflammatory properties.58 an in vitro study demonstrated that neurons pre-treated with cxcl12 were significantly protected from antibody-induced dendritic regression and apoptosis via protein kinase b and extracellular signal-regulated kinases 1/2 activation, as well as maintenance of a disintegrin and metalloproteinase 17, especially with cxcl12.59 c-x3-c motif ligand 1 c-x3-c motif ligand (cx3cl) 1, also known as fractalkine, is produced and expressed constitutively by neurons. cx3cl1 suppresses microglial activation and the cx3cl1/c-x3-c motif receptor (cx3cr) 1 complex may control neurotoxicity. research has demonstrated that levels of plasma-soluble cx3cl1 are significantly greater in patients with mild to moderate ad than in those with severe ad.60 these findings and other data suggest that cx3cl1 has a neuroprotective function that may potentially have therapeutic applications for several neurodegenerative diseases, including ad and parkinson’s disease, in which inflammation also plays an important role.5,60 cho et al. identified cx3cl1/cx3cr1 signalling as a central microglial pathway in protecting against ad; this pathway was associated with the inhibition of aberrant microglial activation and inflammatory cytokine elevation.61 macrophage migration inhibitory factor the macrophage migration inhibitory factor (mif) is a pleiotropic pro-inflammatory cytokine which increases the production of other inflammatory cytokines, such as tnf-α, il-6 and ifn-γ, and has a pivotal regulatory role in the pathogenesis of numerous autoimmune and inflammatory disorders.62,63 cellular the role of inflammatory mediators in the pathogenesis of alzheimer’s disease e310 | squ medical journal, august 2015, volume 15, issue 3 sources for mif are neurons and activated microglia; the clustering of microglia at amyloid deposition sites implies that this cell migrates to these locations and undergoes attempted removal of the amyloid protein.64 in their study, oyama et al. found that mif was able to bind aβ in ad-affected brains and that aβ toxicity could thus be accredited directly to the increased expression of mif.65 however, microglial cells are seemingly unable to clear aβ due to its insoluble nature and the fact that it is present in substantial quantities. therefore, aβ deposits are not phagocytised and remain present while microglial cells continue to be attracted to the sites for long periods of time.66 macrophage inflammatory protein-1α macrophage inflammatory protein (mip)-1α is a chemokine present in humans which has a significant part in the pathogenesis of ad mainly via its expre ssion by astrocytes, microglia, neurons, infiltrated monocytes and t cells.67 it has been demonstrated that higher mip-1α expression in the peripheral t lymphocytes of ad patients results in ccr5 expression, a potential mip-1α receptor on microvascular endothelial cells in the human brain, which subsequently leads to increased t cell transendothelial migration from the blood to the brain.68 li et al. found that serum mip1α levels were significantly higher in patients with the ta6/6 genotype of the apolipoprotein e gene and that this genotype seems to be a genetic risk factor for ad.69 according to passos et al., the activation of the mip-1α/ccr5 signalling pathway was one of the initial events following aβ1–40 injections in ad mouse models; this seems to be a critical signal for activated glial cell accumulation, inflammatory responses, synaptic dysfunction and cognitive failure.70 c o n t r i b u t i o n o f t h e c o m p l e m e n t s y s t e m in the ad-affected brain, levels of complement mrnas and their protein products have been found to be significantly higher than those in the livers of healthy individuals; moreover, neurons of ad patients have been found to express complement proteins of the classical pathway to an increased degree in comparison to neurons in brains which were not affected by ad.9 at the very first stages of amyloid deposition in ad, integral complement protein components of amyloid plaques and cerebral vascular amyloid material can be found; their activation occurs simultaneously with the clinical expression of ad.71 aβ can activate the classic and alternative complement pathways in areas of the brain associated with ad pathology, even in the absence of antibodies.72 moreover, it has been demonstrated that tau protein is an antibody-independent activator of the classical complement pathway.9 this activation of the complement cascade not only causes substantial damage to the neurons, but can also lead to increased phosphorylation of tau proteins and formation of nfts, resulting in elevated levels of membrane attack complex in ad brains.9 nevertheless, the complement cascade has both positive and negative aspects; although it is essential to maintaining the health of the brain, it may have adverse effects when unregulated and often exacerbates ad. the complement protein c1q is induced in the brain in response to ad and blocks fibrillary aβ neurotoxicity in vitro.73 c1q binds to β-sheet fibrillary aβ plaques and, when associated with c1r and c1s as in the c1 complex, activates the complement cascade that can have detrimental inflammatory consequences via production of the chemotactic factor c5a and following recruitment and activation of microglial cells to the site of injury. it also has a protective effect by increasing the clearance of aβ through c1qand c3-dependent opsonisation.74 benoit et al. showed that c1q protected both immature and mature primary neurons against fibrillary aβ toxicity and prevented oligomeric aβ toxicity.75 in addition, gene expression analysis revealed that c1q-induced lowdensity lipoprotein receptor-related protein 1b and g protein-coupled receptor 6 expressed early in ad mouse models were vital for c1q-mediated protection against aβ neurotoxicity.75,76 loeffler et al. noted that c3b and ic3b (a cleavage product of c3b) are also deposited on ad-affected neurons, much like c1q.77 f u n c t i o n o f a c u t e p h a s e p r o t e i n s several prospective epidemiological studies have found that increased acute phase mediator serum levels can serve as a risk factor for ad, as detailed in a review article by eikelenboom et al.78 in addition, other clinical studies compiled in the review have suggested that increased peripheral inflammation is associated with a greater risk of dementia, mainly in patients with pre-existing cognitive impairments, and accelerates subsequent deterioration in patients with dementia.78 higher levels of serum c-reactive protein (crp) in middle-aged patients are also associated with an increased risk of ad and vascular dementia, which may indicate that inflammatory factors are a reflection of both dementia-related peripheral disease and cerebral mechanisms.78 of note is the fact that these processes can be measured long before manifestations of dementia begin to be observed. follow-up studies in the elderly have also revealed a correlation between serum crp levels and an increased incidence of dementia and ad.4 kravitz et al. reported that high crp levels were related to the increased likelihood of gholamreza azizi,shadi s. navabi, ahmed al-shukaili, mir h. seyedzadeh, reza yazdani and abbas mirshafiey review | e311 all-cause dementia occurring in the elderly, particularly for females.79 moreover, komulainen et al. found that elevated high-sensitivity crp (hscrp) serum concentrations were a predictor of poorer memory function in women 12 years after the measurements had been taken.80 therefore, hscrp may be a useful biomarker to identify individuals with an increased risk for cognitive decline. strang et al. discussed the fact that no pathomechanistic link has yet been established between circulating pentameric crp (pcrp) and ad, despite reports of an association between the two.81 their hypothesis was that aβ plaques induce the dissociation of pcrp to single monomers, which have more potent pro-inflammatory properties than pcrp, and the inflammation is subsequently localised to the ad plaques.81 helmy et al. presented evidence that serum levels of il-6 and crp were significantly elevated among patients with vascular and alzheimer’s dementia in comparison to elderly subjects in good health.82 although il-6 levels were higher in ad patients in comparison to those with vascular dementia, the difference was not found to be significant. furthermore, α₁and α₂-globulins were significantly higher in ad patients and researchers were able to distinguish vascular from alzheimer’s dementia.82 elevations in crp in middle-aged patients have been associated with an increased risk of ad development. o’bryant et al. reported decreased crp levels in ad patients; in fact, mean crp levels were found to be significantly reduced in ad patients versus controls (2.9 versus 4.9 μg/ml, respectively).83 however, sundelöf et al. reported contradictory findings which indicated that hscrp and serum amyloid a levels were not associated with ad risk in elderly men.84 o x i d at i v e s t r e s s cellular oxidative stress—including enhanced protein oxidation and nitration, glycoloxidation, lipid peroxidation and aβ accumulation—is associated with ad.85 the deposition of aβ generates ros, which is involved in the inflammatory and neurodegenerative pathology of ad. oxidative stress can therefore exacerbate the progression of ad. when repair attempts are made by the brain to remedy oxidative damage, characterised by app overexpression, adenosine triphosphate (atp)binding cassette sub-family g member 2 (abcg2) is upregulated and activator protein-1 is activated. not only do these proteins stop blood aβ from entering the brain via the bbb but they also protect against oxidative stress by decreasing ros production, boosting antioxidant activity and inhibiting the inflammatory response through the inhibition of the nuclear factor-κb signalling pathway in brain tissue. as a result, abcg2 may have a protective function in the neuroinflammatory response of ad.85–87 additionally, the apparent end-product of app, the formation and accumulation of aβ, appears to be initiated by abcg2. this process can lead to increased free radical production—mainly superoxide anions via the mitochondria—which induces the interruption of oxidative phosphorylation and engenders a decrease in atp levels. the mitochondrial dysfunction and damage that occurs with ageing correlates with the augmented intracellular production of oxidants and pro-oxidants. the extended oxidative stress in brain tissue, and the resultant hypoperfusion, stimulates the expression of nos which subsequently drives the formation of ros and reactive nitrogen species (rns). ros contributes to the dysfunction of the bbb and damage to the brain’s parenchymal cells. moreover, it has been shown that ros is potentially toxic and may damage the proteins, lipids and nucleic acids of brain cells and mitochondria, including neurons and oligodendrocytes that may mediate toxicity.88,89 generation of ros is controlled by sensitive genes called vitagenes. these genes encode proteins such as heat shock proteins, nutritional antioxidants which play a neuroprotective role.90 oxidative stress could also lead to further damage in ad-affected brains through inducible nos overexpression and constitutive neuronal nos activity, which increases the production of no and its derivative rns. in an ad-affected brain, no and superoxide anion radicals (o2-) are produced by reactive astrocytes and microglia in response to aβ.91–93 formed from no and o2-, peroxynitrite anions are another component of oxidative stress. these extremely reactive oxidising and nitrating agents lead to the oxidisation of cellular components, increased aβ aggregation and a stimulated inflammatory response.94 in the early stages of ad, the pathology shows that inducible neuron-specific cyclooxygenase-2 (cox-2) enzymes are expressed and upregulated by neuronal cells which are closely linked with the aβ-bearing cells. it has been suggested that aβ can stimulate activity of cox-2 oxygenase and peroxidase in a cell-free system—this stimulation of the two-step action of cox-2 leads to the production of ros and prostaglandin e2. 85,95–97 in addition, recent findings in mouse models suggest a role for cox/prostaglandin e2 signalling in the development of ad. 98 treatment and immunotherapy for alzheimer’s disease there is currently no cure available for ad; however, drug and non-drug treatments may help with both the role of inflammatory mediators in the pathogenesis of alzheimer’s disease e312 | squ medical journal, august 2015, volume 15, issue 3 cognitive and behavioural symptoms of the disease. two types of medications designed to treat the cognitive manifestations of ad have been approved by the food and drug administration in the usa: cholinesterase inhibitors and a new n-methyl-daspartate receptor antagonist, memantine.99 three forms of cholinesterase inhibitor drugs are commonly prescribed: donepezil (approved to treat all stages of ad), rivastigmine and galantamine (both approved to treat only mild to moderate cases of ad).100 inflammation is one of numerous hypotheses that have been proposed for the multifactorial aetiology of ad; indeed, inflammation may interact with other triggers in several ways. this network of mechanisms makes it difficult to identify any specific inflammatory process, causal factor or cell in order to determine their individual role in ad.101 risk factors for ad, which may include genetic, biological and environmental factors, contribute to neuro-inflammation and to subsequent neurodegeneration in the later stages of ad. however, they may have fewer effects on the early pathogenesis of the disease.102,103 therefore, due to the distinctive role of inflammation in the early versus late stages of ad, anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (nsaids), may potentially be a treatment option for ad patients, although this would be dependent on the stage of the disease. researchers have reported a decrease in ad development among subjects taking nsaids for long periods of time; thus, it has been proposed that nsaids could directly reduce the production of aβ through several mechanisms.9,104 unfortunately, conflicting results have been reported in the literature and related clinical trials have not yet yielded promising findings. the toxic effects of nsaid treatments also prevent their widespread use.9,104 additionally, anti-inflammatory medications may have no effect on patients in later stages of the disease. this is because the most important aetiological factors for early-onset ad are the mismetabolism of app along with the increased production of aβ followed by the deposition of fibrillary aβ, which can activate the innate immunity receptors leading to activation of microglia and reactive astrocytes. this exacerbates neurodegeneration through the release of inflammatory cytokines, ros and other factors. modifications of these factors can occur very early during the development of the disease; trials with anti-inflammatory agents may therefore be ineffective in patients with severe ad.6 furthermore, the efficacy of anti-inflammatory drugs such as aspirin, steroids and other traditional nsaids and cox-2 inhibitors in ad patients has not yet been proven; thus, these drugs cannot be recommended for ad treatment.105 immunotherapy has been proposed as a potential candidate for the treatment of ad. both active and passive aβ immunotherapies have been developed to decrease the load of aβ by enhancing its rate of elimination. vaccinations, in the form of active immunisation with aβ42 (the common form of aβ in amyloid plaques) or other synthetic peptides, have been successfully assessed in transgenic animal models of ad.106 the basis of this approach is the priming of t, b and microglial cells, which provoke immune responses. one type of passive immunotherapy, administering monoclonal antibodies against the aβ fragment, diminishes the need for patients to mount immunity against aβ peptides. an on-going clinical trial in the usa sponsored by a pharmaceutical company (eli lilly & co., indianapolis, indiana, usa) is currently testing to see if treatment with solanezumab, a monoclonal antibody against aβ, significantly slows the loss of awareness and cognitive and functional decline in patients with mild ad.107 however, concerns exist regarding the use of related monoclonal antibodies as a therapeutic option. firstly, new approaches are needed due to the poor penetration of antibodies into the brain and, secondly, recognition of the clearance pathways of aβ/anti-aβ immune complexes is essential to circumvent obstruction of these pathways during treatment.106 recent advances in alzheimer’s disease a prospective longitudinal study by bateman et al. has indicated that aβ deposition in the brain is detectable more than 20 years prior to the onset of ad symptoms.108 in addition, although the production of aβ in ad patients is similar to that of cognitively normal individuals, clearance of aβ in the brain of ad patients is significantly reduced in comparison to control subjects.109 immunotherapy and the involvement of antibodies could therefore be a successful approach to facilitating this clearance process. active immunisation with the dna aβ42 vaccination may be effective in accomplishing this; the method involves injecting dna encoding aβ42 where it is subsequently translated in the immunised individual to express aβ peptide which then stimulates the respective immune responses against aβ42. qu et al. found a 50% reduction in the level of aβ42 plaques in transgenic mouse models when using this approach; this reduction was later confirmed by another study.110,111 currently, other approaches for ad therapy focus on clearance of aβ fragments by different pathways, including chaperone-mediated and autophagocytic gholamreza azizi,shadi s. navabi, ahmed al-shukaili, mir h. seyedzadeh, reza yazdani and abbas mirshafiey review | e313 clearance.112 chaperones are a specific cluster of proteins which can correct or prevent the misfolding of proteins. autophagy is a normal cellular process in the body which preserves homeostasis or normal functioning through protein destruction and turnover of destroyed cell organelles for new cell formation. several studies have noted the occurrence of autophagocytic vacuoles in the brains of patients with ad.113,114 caccamo et al. reported that the level of beclin 1, a protein involved in the formation of the autophagosome, is diminished in the brains of ad patients.115 moreover, martorana et al. found an augmented subset of b cells with a memory doublenegative phenotype in elderly people.116 interestingly, colonna-romano et al. reported that b cells are late memory or exhausted cells, which may be a manifestation of ageing or a dysregulation of the immune system.117 conclusion numerous hypotheses have been proposed for the multifactorial aetiology of ad, including inflammation. current evidence supports the potential role of inflammation in ad, although this factor may interact with other genetic, biological and environmental triggers in several ways. immunotherapy and the use of antibodies could have applications for patients with ad. in order to improve the range and efficacy of therapeutic options for ad patients and those with similar neurodegenerative disorders, further research is recommended to advance the current knowledge of inflammatory processes with regards to this form of dementia. references 1. alzheimer’s association. 2012 alzheimer’s disease facts and figures. alzheimers dement 2012; 8:131–68. doi: 10.1016/j. jalz.2012.02.001. 2. oda h, yamamoto y, maeda k. the neuropsychological profile in dementia with lewy bodies and alzheimer’s disease. int j geriatr psychiatry 2009; 24:125–31. doi: 10.1002/gps.2078. 3. alzheimer’s disease international. world alzheimer report 2014: dementia and risk reduction an analysis of protective and modifiable factors. from: www.alz.co.uk/research/ worldalzheimerreport2014.pdf accessed: feb 2015. 4. qiu c, kivipelto m, von strauss e. epidemiology of alzheimer’s disease: occurrence, determinants, and strategies toward intervention. dialogues clin neurosci 2009; 11:111–28. 5. gorlovoy p, larionov s, pham tt, neumann h. accumulation of tau induced in neurites by microglial proinflammatory mediators. faseb j 2009; 23:2502–13. doi: 10.1096/fj.08123877. 6. azizi g, mirshafiey a. the potential role of proinflammatory and antiinflammatory cytokines in alzheimer disease pathogen esis. immunopharmacol immunotoxicol 2012; 34:881–95. doi: 10.3109/08923973.2012.705292. 7. mirshafiey a, asghari b, ghalamfarsa g, jadidi-niaragh f, azizi g. the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis. sultan qaboos univ med j 2014; 14:e13–25. 8. reitz c, brayne c, mayeux r. epidemiology of alzheimer disease. nat rev neurol 2011; 7:137–52. doi: 10.1038/ nrneurol.2011.2. 9. tuppo ee, arias hr. the role of inflammation in alzheimer’s disease. int j biochem cell biol 2005; 37:289–305. doi: 10. 1016/j.biocel.2004.07.009. 10. serrano-pozo a, frosch mp, masliah e, hyman bt. neuropathological alterations in alzheimer disease. cold spring harb perspect med 2011; 1:a006189. doi: 10.1101/ cshperspect.a006189. 11. jellinger ka, bancher c. neuropathology of alzheimer’s disease: a critical update. j neural transm suppl 1998; 54:77– 95. doi: 10.1007/978-3-7091-7508-8_8. 12. mcgeer pl, mcgeer eg. the amyloid cascade-inflammatory hypothesis of alzheimer disease: implications for therapy. acta neuropathol 2013; 126:479–97. doi: 10.1007/s00401-013-1177-7. 13. orsini f, de blasio d, zangari r, zanier er, de simoni mg. versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. front cell neurosci 2014; 8:380. doi: 10.3389/fncel.2014.00380. 14. blach-olszewska z, leszek j. mechanisms of over-activated innate immune system regulation in autoimmune and neurodegenerative disorders. neuropsychiatr dis treat 2007; 3:365–72. 15. azizi g, khannazer n, mirshafiey a. the potential role of chemokines in alzheimer’s disease pathogenesis. am j alzheimers dis other demen 2014: 29:415–25. doi: 10.1177/1533317513518651. 16. bromley sk, peterson da, gunn md, dustin ml. cutting edge: hierarchy of chemokine receptor and tcr signals regulating t cell migration and proliferation. j immunol 2000; 165:15–19. doi: 10.4049/jimmunol.165.1.15. 17. heneka mt, o’banion mk, terwel d, kummer mp. neuroinflammatory processes in alzheimer’s disease. j neural transm 2010; 117:919–47. doi: 10.1007/s00702-010-0438-z. 18. rubio-perez jm, morillas-ruiz jm. a review: inflammatory process in alzheimer’s disease, role of cytokines. scientificworldjournal 2012; 2012:756357. doi: 10.1100/2012/756357. 19. akiyama h, barger s, barnum s, bradt b, bauer j, cole gm, et al. inflammation and alzheimer’s disease. neurobiol aging 2000; 21:383–421. doi: 10.1016/s0197-4580(00)00124-x. 20. zotova e, nicoll ja, kalaria r, holmes c, boche d. inflammation in alzheimer’s disease: relevance to pathogenesis and therapy. alzheimers res ther 2010; 2:1. doi: 10.1186/alzrt24. 21. brown gc, neher jj. microglial phagocytosis of live neurons. nat rev neurosci 2014; 15:209–16. doi: 10.1038/nrn3710. 22. li xq, wang j, fang b, tan wf, ma h. intrathecal antagonism of microglial tlr4 reduces inflammatory damage to bloodspinal cord barrier following ischemia/reperfusion injury in rats. mol brain 2014; 7:28. doi: 10.1186/1756-6606-7-28. 23. lee hg, won sm, gwag bj, lee yb. microglial p2x7 receptor expression is accompanied by neuronal damage in the cerebral cortex of the appswe/ps1de9 mouse model of alzheimer’s disease. exp mol med 2011; 43:7–14. doi: 10.3858/ emm.2011.43.1.001. 24. ho gj, drego r, hakimian e, masliah e. mechanisms of cell signaling and inflammation in alzheimer’s disease. curr drug targets inflamm allergy 2005; 4:247–56. doi: 10.2174/1568010053586237. 25. fulop t, lacombe g, cunnane s, le page a, dupuis g, frost eh, et al. elusive alzheimer’s disease: can immune signatures help our understanding of this challenging disease? part 2: new immune paradigm. discov med 2013; 15:33–42. http://dx.doi.org/10.1016/j.jalz.2012.02.001 http://dx.doi.org/10.1016/j.jalz.2012.02.001 http://dx.doi.org/10.1002/gps.2078 http://dx.doi.org/10.1096/fj.08-123877 http://dx.doi.org/10.1096/fj.08-123877 http://dx.doi.org/10.3109/08923973.2012.705292 http://dx.doi.org/10.1038/nrneurol.2011.2 http://dx.doi.org/10.1038/nrneurol.2011.2 http://dx.doi.org/10.1016/j.biocel.2004.07.009 http://dx.doi.org/10.1016/j.biocel.2004.07.009 http://dx.doi.org/10.1101/cshperspect.a006189 http://dx.doi.org/10.1101/cshperspect.a006189 http://dx.doi.org/10.1007/978-3-7091-7508-8_8 http://dx.doi.org/10.1007/s00401-013-1177-7 http://dx.doi.org/10.3389/fncel.2014.00380 http://dx.doi.org/10.1177/1533317513518651 http://dx.doi.org/10.4049/jimmunol.165.1.15 http://dx.doi.org/10.1007/s00702-010-0438-z http://dx.doi.org/10.1100/2012/756357 http://dx.doi.org/10.1016/s0197-4580%2800%2900124-x http://dx.doi.org/10.1186/alzrt24 http://dx.doi.org/10.1038/nrn3710 http://dx.doi.org/10.1186/1756-6606-7-28 http://dx.doi.org/10.3858/emm.2011.43.1.001 http://dx.doi.org/10.3858/emm.2011.43.1.001 http://dx.doi.org/10.2174/1568010053586237 the role of inflammatory mediators in the pathogenesis of alzheimer’s disease e314 | squ medical journal, august 2015, volume 15, issue 3 26. querfurth hw, laferla fm. alzheimer’s disease. n engl j med 2010; 362:329–44. doi: 10.1056/nejmra0909142. 27. richartz-salzburger e, batra a, stransky e, laske c, kohler n, bartels m, et al. altered lymphocyte distribution in alzheimer’s disease. j psychiatr res 2007; 41:174–8. doi: 10.1016/j. jpsychires.2006.01.010. 28. skias d, bania m, reder at, luchins d, antel jp. senile dementia of alzheimer’s type (sdat): reduced t8+-cellmediated suppressor activity. neurology 1985; 35:1635–8. doi: 10.1212/wnl.35.11.1635. 29. giubilei f, antonini g, montesperelli c, sepe-monti m, cannoni s, pichi a, et al. t cell response to amyloid-beta and to mitochondrial antigens in alzheimer’s disease. dement geriatr cogn disord 2003; 16:35–8. doi: 10.1159/000069991. 30. panossian la, porter vr, valenzuela hf, zhu x, reback e, masterman d, et al. telomere shortening in t cells correlates with alzheimer’s disease status. neurobiol aging 2003; 24:77– 84. doi: 10.1016/s0197-4580(02)00043-x. 31. zhang j, kong q, zhang z, ge p, ba d, he w. telomere dysfunction of lymphocytes in patients with alzheimer disease. cogn behav neurol 2003,16:170–6. doi: 10.1097/00146965200309000-00004. 32. pierson e, simmons sb, castelli l, goverman jm. mechanisms regulating regional localization of inflammation during cns autoimmunity. immunol rev 2012; 248:205–15. doi: 10.1111/j.1600-065x.2012.01126.x. 33. monsonego a, nemirovsky a, harpaz i. cd4 t cells in immunity and immunotherapy of alzheimer’s disease. immunology 2013; 139:438–46. doi: 10.1111/imm.12103. 34. racke mm, boone li, hepburn dl, parsadainian m, bryan mt, ness dk, et al. exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. j neurosci 2005; 25:629–36. doi: 10.1523/jneurosci.4337-04.2005. 35. galimberti d, scarpini e. inflammation and oxidative damage in alzheimer’s disease: friend or foe? front biosci (schol ed) 2011; 3:252–66. doi: 10.2741/s149. 36. sokolova a, hill md, rahimi f, warden la, halliday gm, shepherd ce. monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in alzheimer’s disease. brain pathol 2009; 19:392–8. doi: 10.1111/j.1750-3639.2008.00188.x. 37. belkhelfa m, rafa h, medjeber o, arroul-lammali a, behairi n, abada-bendib m, et al. ifn-γ and tnf-α are involved during alzheimer disease progression and correlate with nitric oxide production: a study in algerian patients. j interferon cytokine res 2014; 34:839–47. doi: 10.1089/ jir.2013.0085. 38. lin x, bai g, lin l, wu h, cai j, ugen ke, et al. vaccination induced changes in pro-inflammatory cytokine levels as an early putative biomarker for cognitive improvement in a transgenic mouse model for alzheimer disease. hum vaccin immunother 2014; 10:2024–31. doi: 10.4161/hv.28735. 39. chakrabarty p, jansen-west k, beccard a, ceballos-diaz c, levites y, verbeeck c, et al. massive gliosis induced by interleukin-6 suppresses abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. faseb j 2010; 24:548–59. doi: 10.1096/fj.09-141754. 40. yu jt, tan l, song jh, sun yp, chen w, miao d, et al. interleukin-18 promoter polymorphisms and risk of late onset alzheimer’s disease. brain res 2009; 1253:169–75. doi: 10.1016/j.brainres.2008.11.083. 41. felderhoff-mueser u, schmidt oi, oberholzer a, bührer c, stahel pf. il-18: a key player in neuroinflammation and neurodegeneration? trends neurosci 2005; 28:487–93. doi: 10.1016/j.tins.2005.06.008. 42. reale m, kamal ma, velluto l, gambi d, di nicola m, greig nh. relationship between inflammatory mediators, aβ levels and apoe genotype in alzheimer disease. curr alzheimer res 2012; 9:447–57. doi: 10.2174/156720512800492549. 43. conti b, park lc, calingasan ny, kim y, kim h, bae y, et al. cultures of astrocytes and microglia express interleukin 18. brain res mol brain res 1999; 67:46–52. doi: 10.1016/s0169328x(99)00034-0. 44. kawanokuchi j, mizuno t, takeuchi h, kato h, wang j, mitsuma n, et al. production of interferon-gamma by microglia. mult scler 2006; 12:558–64. doi: 10.1177/1352458506070763. 45. schmitt tl, steiner e, klinger p, sztankay a, grubeckloebenstein b. the production of an amyloidogenic metabolite of the alzheimer amyloid beta precursor protein (app) in thyroid cells is stimulated by interleukin 1 beta, but inhibited by interferon gamma. j clin endocrinol metab 1996; 81:1666–9. doi: 10.1210/jcem.81.4.8636387. 46. noguchi a, nawa m, aiso s, okamoto k, matsuoka m. transforming growth factor beta2 level is elevated in neurons of alzheimer’s disease brains. int j neurosci 2010; 120:168–75. doi: 10.3109/00207450903139689. 47. eslami p, johnson mf, terzakaryan e, chew c, harris-white me. tgf beta2-induced changes in lrp-1/t beta r-v and the impact on lysosomal a beta uptake and neurotoxicity. brain res 2008; 1241:176–87. doi: 10.1016/j.brainres.2008.08.086. 48. caraci f, spampinato s, sortino ma, bosco p, battaglia g, bruno v, et al. dysfunction of tgf-beta1 signaling in alzheimer’s disease: perspectives for neuroprotection. cell tissue res 2012; 347:291–301. doi: 10.1007/s00441-011-1230-6. 49. hickman se, el khoury j. mechanisms of mononuclear phagocyte recruitment in alzheimer’s disease. cns neurol disord drug targets 2010; 9:168–73. doi: 10.2174/ 187152710791011982. 50. d’mello c, le t, swain mg. cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor alpha signaling during peripheral organ inflammation. j neurosci 2009; 29:2089–102. doi: 10.1523/jneurosci.3567-08.2009. 51. selenica ml, alvarez ja, nash kr, lee dc, cao c, lin x, et al. diverse activation of microglia by chemokine (c-c motif ) ligand 2 overexpression in brain. j neuroinflammation 2013; 10:86. doi: 10.1186/1742-2094-10-86. 52. tripathy d, thirumangalakudi l, grammas p. rantes upregulation in the alzheimer’s disease brain: a possible neuroprotective role. neurobiol aging 2010; 31:8–16. doi: 10.1016/j.neurobiolaging.2008.03.009. 53. sharma v, mishra m, ghosh s, tewari r, basu a, seth p, et al. modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. brain res bull 2007; 73:55–63. doi: 10.1016/j. brainresbull.2007.01.016. 54. lumpkins k, bochicchio gv, zagol b, ulloa k, simard jm, schaub s, et al. plasma levels of the beta chemokine regulated upon activation, normal t cell expressed, and secreted (rantes) correlate with severe brain injury. j trauma 2008; 64:358–61. doi: 10.1097/ta.0b013e318160df9b. 55. vago l, nebuloni m, bonetto s, pellegrinelli a, zerbi p, ferri a, et al. rantes distribution and cellular localization in the brain of hiv-infected patients. clin neuropathol 2001; 20:139–45. 56. laske c, stellos k, eschweiler gw, leyhe t, gawaz m. decreased cxcl12 (sdf-1) plasma levels in early alzheimer’s disease: a contribution to a deficient hematopoietic brain support? j alzheimers dis 2008; 15:83–95. 57. li m, hale js, rich jn, ransohoff rm, lathia jd. chemokine cxcl12 in neurodegenerative diseases: an sos signal for stem cell-based repair. trends neurosci 2012; 35:619–28. doi: 10.1016/j.tins.2012.06.003. http://dx.doi.org/10.1056/nejmra0909142 http://dx.doi.org/10.1016/j.jpsychires.2006.01.010 http://dx.doi.org/10.1016/j.jpsychires.2006.01.010 http://dx.doi.org/10.1212/wnl.35.11.1635 http://dx.doi.org/10.1159/000069991 http://dx.doi.org/10.1016/s0197-4580%2802%2900043-x http://dx.doi.org/10.1097/00146965-200309000-00004 http://dx.doi.org/10.1097/00146965-200309000-00004 http://dx.doi.org/10.1111/j.1600-065x.2012.01126.x http://dx.doi.org/10.1111/imm.12103 http://dx.doi.org/10.1523/jneurosci.4337-04.2005 http://dx.doi.org/10.2741/s149 http://dx.doi.org/10.1111/j.1750-3639.2008.00188.x http://dx.doi.org/10.1089/jir.2013.0085 http://dx.doi.org/10.1089/jir.2013.0085 http://dx.doi.org/10.4161/hv.28735 http://dx.doi.org/10.1096/fj.09-141754 http://dx.doi.org/10.1016/j.brainres.2008.11.083 http://dx.doi.org/10.1016/j.tins.2005.06.008 http://dx.doi.org/10.1016/j.tins.2005.06.008 http://dx.doi.org/10.2174/156720512800492549 http://dx.doi.org/10.1016/s0169-328x%2899%2900034-0 http://dx.doi.org/10.1016/s0169-328x%2899%2900034-0 http://dx.doi.org/10.1177/1352458506070763 http://dx.doi.org/10.1210/jcem.81.4.8636387 http://dx.doi.org/10.3109/00207450903139689 http://dx.doi.org/10.1016/j.brainres.2008.08.086 http://dx.doi.org/10.1007/s00441-011-1230-6 http://dx.doi.org/10.2174/187152710791011982 http://dx.doi.org/10.2174/187152710791011982 http://dx.doi.org/10.1523/jneurosci.3567-08.2009 http://dx.doi.org/10.1186/1742-2094-10-86 http://dx.doi.org/10.1016/j.neurobiolaging.2008.03.009 http://dx.doi.org/10.1016/j.brainresbull.2007.01.016 http://dx.doi.org/10.1016/j.brainresbull.2007.01.016 http://dx.doi.org/10.1097/ta.0b013e318160df9b http://dx.doi.org/10.1016/j.tins.2012.06.003 gholamreza azizi,shadi s. navabi, ahmed al-shukaili, mir h. seyedzadeh, reza yazdani and abbas mirshafiey review | e315 58. zhu b, xu d, deng x, chen q, huang y, peng h, et al. cxcl12 enhances human neural progenitor cell survival through a cxcr7and cxcr4-mediated endocytotic signaling pathway. stem cells 2012; 30:2571–83. doi: 10.1002/stem.1239. 59. raman d, milatovic sz, milatovic d, splittgerber r, fan gh, richmond a. chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity. toxicol appl pharmacol 2011; 256:300–13. doi: 10.1016/j.taap.2011.06.006. 60. kim ts, lim hk, lee jy, kim dj, park s, lee c, et al. changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and alzheimer’s disease. neurosci lett 2008; 436:196–200. doi: 10.1016/j.neulet.2008.03.019. 61. cho sh, sun b, zhou y, kauppinen tm, halabisky b, wes p, et al. cx3cr1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of alzheimer disease. j biol chem 2011; 286:32713–22. doi: 10.1074/jbc.m111.254268. 62. popp j, bacher m, kölsch h, noelker c, deuster o, dodel r, et al. macrophage migration inhibitory factor in mild cognitive impairment and alzheimer’s disease. j psychiatr res 2009; 43:749–53. doi: 10.1016/j.jpsychires.2008.10.006. 63. al-abed y, vanpatten s. mif as a disease target: iso-1 as a proof-of-concept therapeutic. future med chem 2011; 3: 45–63. doi: 10.4155/fmc.10.281. 64. bacher m, deuster o, aljabari b, egensperger r, neff f, jessen f, et al. the role of macrophage migration inhibitory factor in alzheimer’s disease. mol med 2010; 16:116–21. doi: 10.2119/molmed.2009.00123. 65. oyama r, yamamoto h, titani k. glutamine synthetase, hemoglobin alpha-chain, and macrophage migration inhibitory factor binding to amyloid beta-protein: their identification in rat brain by a novel affinity chromatography and in alzheimer’s disease brain by immunoprecipitation. biochim biophys acta 2000; 1479:91–102. doi: 10.1016/s0167-4838(00)00057-1. 66. lashuel ha, aljabari b, sigurdsson em, metz cn, leng l, callaway dj, et al. amyloid fibril formation by macrophage migration inhibitory factor. biochem biophys res commun 2005; 338:973–80. doi: 10.1016/j.bbrc.2005.10.040. 67. xia mq, qin sx, wu lj, mackay cr, hyman bt. immunohistochemical study of the beta-chemokine receptors ccr3 and ccr5 and their ligands in normal and alzheimer’s disease brains. am j pathol 1998; 153:31–7. 68. man sm, ma yr, shang ds, zhao wd, li b, guo dw, et al. peripheral t cells overexpress mip-1alpha to enhance its transendothelial migration in alzheimer’s disease. neurobiol aging 2007; 28:485–96. doi: 10.1016/j. neurobiolaging.2006.02.013. 69. li k, dai d, yao l, gu x, luan k, tian w, et al. association between the macrophage inflammatory protein-l alpha gene polymorphism and alzheimer’s disease in the chinese population. neurosci lett 2008; 433:125–8. doi: 10.1016/j. neulet.2008.01.002. 70. passos gf, figueiredo cp, prediger rd, pandolfo p, duarte fs, medeiros r, et al. role of the macrophage inflammatory protein-1alpha/cc chemokine receptor 5 signaling pathway in the neuroinflammatory response and cognitive deficits induced by beta-amyloid peptide. am j pathol 2009; 175:1586–97. doi: 10.2353/ajpath.2009.081113. 71. kolev mv, ruseva mm, harris cl, morgan bp, donev rm. implication of complement system and its regulators in alzheimer’s disease. curr neuropharmacol 2009; 7:1–8. doi: 10.2174/157015909787602805. 72. shen y, yang l, li r. what does complement do in alzheimer’s disease? old molecules with new insights. transl neurodegener 2013; 2:21. doi: 10.1186/2047-9158-2-21. 73. fraser da, pisalyaput k, tenner aj. c1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. j neurochem 2010; 112:733–43. doi: 10.1111/j.1471-4159.2009.06494.x. 74. alexander jj, anderson aj, barnum sr, stevens b, tenner aj. the complement cascade: yin-yang in neuroinflammationneuro-protection and -degeneration. j neurochem 2008; 107:1169–87. doi: 10.1111/j.1471-4159.2008.05668.x. 75. benoit me, hernandez mx, dinh ml, benavente f, vasquez o, tenner aj. c1q-induced lrp1b and gpr6 proteins expressed early in alzheimer disease mouse models, are essential for the c1q-mediated protection against amyloid-beta neurotoxicity. j biol chem 2013; 288:654–65. doi: 10.1074/jbc.m112.400168. 76. benoit me, tenner aj. complement protein c1q-mediated neuroprotection is correlated with regulation of neuronal gene and microrna expression. j neurosci 2011; 31:3459–69. doi: 10.1523/jneurosci.3932-10.2011. 77. loeffler da, camp dm, bennett da. plaque complement activation and cognitive loss in alzheimer’s disease. j neuroinflammation 2008; 5:9. doi: 10.1186/1742-2094-5-9. 78. eikelenboom p, hoozemans jj, veerhuis r, van exel e, rozemuller aj, van gool wa. whether, when and how chronic inflammation increases the risk of developing lateonset alzheimer’s disease. alzheimers res ther 2012; 4:15. doi: 10.1186/alzrt118. 79. kravitz ba, corrada mm, kawas ch. elevated c-reactive protein levels are associated with prevalent dementia in the oldest-old. alzheimers dement 2009; 5:318–23. doi: 10.1016/j. jalz.2009.04.1230. 80. komulainen p, lakka ta, kivipelto m, hassinen m, penttilä im, helkala el, et al. serum high sensitivity c-reactive protein and cognitive function in elderly women. age ageing 2007; 36:443–8. doi: 10.1093/ageing/afm051. 81. strang f, scheichl a, chen yc, wang x, htun nm, bassler n, et al. amyloid plaques dissociate pentameric to monomeric c-reactive protein: a novel pathomechanism driving cortical inflammation in alzheimer’s disease? brain pathol 2012; 22:337–46. doi: 10.1111/j.1750-3639.2011.00539.x. 82. helmy aa, naseer mm, shafie se, nada ma. role of interleukin 6 and alpha-globulins in differentiating alzheimer and vascular dementias. neurodegener dis 2012; 9:81–6. doi: 10.1159/000329568. 83. o’bryant se, waring sc, hobson v, hall jr, moore cb, bottiglieri t, et al. decreased c-reactive protein levels in alzheimer disease. j geriatr psychiatry neurol 2010; 23:49–53. doi: 10.1177/0891988709351832. 84. sundelöf j, kilander l, helmersson j, larsson a, rönnemaa e, degerman-gunnarsson m, et al. systemic inflammation and the risk of alzheimer’s disease and dementia: a prospective population-based study. j alzheimers dis 2009; 18:79–87. doi: 10.3233/jad-2009-1126. 85. mohsenzadegan m, mirshafiey a. the immunopathogenic role of reactive oxygen species in alzheimer disease. iran j allergy asthma immunol 2012; 11:203–16. doi: 011.03/ijaai.203216. 86. shen s, callaghan d, juzwik c, xiong h, huang p, zhang w. abcg2 reduces ros-mediated toxicity and inflammation: a potential role in alzheimer’s disease. j neurochem 2010; 114:1590–1604. doi: 10.1111/j.1471-4159.2010.06887.x. 87. xiong h, callaghan d, jones a, bai j, rasquinha i, smith c, et al. abcg2 is upregulated in alzheimer’s brain with cerebral amyloid angiopathy and may act as a gatekeeper at the bloodbrain barrier for abeta(1-40) peptides. j neurosci 2009; 29:5463–75. doi: 10.1523/jneurosci.5103-08.2009. 88. vladimirova o, lu fm, shawver l, kalman b. the activation of protein kinase c induces higher production of reactive oxygen species by mononuclear cells in patients with multiple sclerosis than in controls. inflamm res 1999; 48:412–16. doi: 10.1007/ s000110050480. http://dx.doi.org/10.1002/stem.1239 http://dx.doi.org/10.1016/j.taap.2011.06.006 http://dx.doi.org/10.1016/j.neulet.2008.03.019 http://dx.doi.org/10.1074/jbc.m111.254268 http://dx.doi.org/10.1016/j.jpsychires.2008.10.006 http://dx.doi.org/10.4155/fmc.10.281 http://dx.doi.org/10.2119/molmed.2009.00123 http://dx.doi.org/10.2119/molmed.2009.00123 http://dx.doi.org/10.1016/s0167-4838%2800%2900057-1 http://dx.doi.org/10.1016/j.bbrc.2005.10.040 http://dx.doi.org/10.1016/j.neurobiolaging.2006.02.013 http://dx.doi.org/10.1016/j.neurobiolaging.2006.02.013 http://dx.doi.org/10.1016/j.neulet.2008.01.002 http://dx.doi.org/10.1016/j.neulet.2008.01.002 http://dx.doi.org/10.2353/ajpath.2009.081113 http://dx.doi.org/10.2174/157015909787602805 http://dx.doi.org/10.1186/2047-9158-2-21 http://dx.doi.org/10.1111/j.1471-4159.2009.06494.x http://dx.doi.org/10.1111/j.1471-4159.2008.05668.x http://dx.doi.org/10.1074/jbc.m112.400168 http://dx.doi.org/10.1523/jneurosci.3932-10.2011 http://dx.doi.org/10.1186/1742-2094-5-9 http://dx.doi.org/10.1186/alzrt118 http://dx.doi.org/10.1016/j.jalz.2009.04.1230 http://dx.doi.org/10.1016/j.jalz.2009.04.1230 http://dx.doi.org/10.1093/ageing/afm051 http://dx.doi.org/10.1111/j.1750-3639.2011.00539.x http://dx.doi.org/10.1159/000329568 http://dx.doi.org/10.1177/0891988709351832 http://dx.doi.org/10.3233/jad-2009-1126 http://dx.doi.org/011.03/ijaai.203216 http://dx.doi.org/10.1111/j.1471-4159.2010.06887.x http://dx.doi.org/10.1523/jneurosci.5103-08.2009 http://dx.doi.org/10.1007/s000110050480 http://dx.doi.org/10.1007/s000110050480 the role of inflammatory mediators in the pathogenesis of alzheimer’s disease e316 | squ medical journal, august 2015, volume 15, issue 3 89. aliev g, priyadarshini m, reddy vp, grieg nh, kaminsky y, cacabelos r, et al. oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of alzheimer disease. curr med chem 2014; 21:2208–17. doi: 10.2174/09298 67321666131227161303. 90. cornelius c, koverech g, crupi r, di paola r, koverech a, lodato f, et al. osteoporosis and alzheimer pathology: role of cellular stress response and hormetic redox signaling in aging and bone remodeling. front pharmacol 2014; 5:120. doi: 10.3389/fphar.2014.00120. 91. sarti p, arese m, giuffre a. the molecular mechanisms by which nitric oxide controls mitochondrial complex iv. ital j biochem 2003; 52:37–42. 92. sheng b, gong k, niu y, liu l, yan y, lu g, et al. inhibition of gamma-secretase activity reduces abeta production, reduces oxidative stress, increases mitochondrial activity and leads to reduced vulnerability to apoptosis: implications for the treatment of alzheimer’s disease. free radic biol med 2009; 46:1362–75. doi: 10.1016/j.freeradbiomed.2009.02.018. 93. bodovitz s, klein wl. cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. j biol chem 1996; 271:4436–40. 94. mirshafiey a, mohsenzadegan m. the role of reactive oxygen species in immunopathogenesis of rheumatoid arthritis. iran j allergy asthma immunol 2008; 7:195–202. doi: 07.04/ ijaai.195202. 95. ferretti mt, bruno ma, ducatenzeiler a, klein wl, cuello ac. intracellular aβ-oligomers and early inflammation in a model of alzheimer’s disease. neurobiol aging 2012; 33:1329–42. doi: 10.1016/j.neurobiolaging.2011.01.007. 96. ferrera p, arias c. differential effects of cox inhibitors against beta-amyloid-induced neurotoxicity in human neuroblastoma cells. neurochem int 2005; 47:589–96. doi: 10.1016/j.neuint.200 5.06.012. 97. lee m, sparatore a, del soldato p, mcgeer e, mcgeer pl. hydrogen sulfide-releasing nsaids attenuate neuroinflammation induced by microglial and astrocytic activation. glia 2010; 58:103–13. doi: 10.1002/glia.20905. 98. shi j, wang q, johansson ju, liang x, woodling ns, priyam p, et al. inflammatory prostaglandin e2 signaling in a mouse model of alzheimer disease. ann neurol 2012; 72:788–98. doi: 10.1002/ana.23677. 99. alzheimer’s association. fda-approved treatments for alzheimer’s. from: www.alz.org/national/documents/topicsheet_ treatments.pdf accessed: feb 2015. 100. zemek f, drtinova l, nepovimova e, sepsova v, korabecny j, klimes j, et al. outcomes of alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. expert opin drug saf 2014; 13:759–74. doi: 10.1517/14740338.2014.914168. 101. wyss-coray t, rogers j. inflammation in alzheimer disease: a brief review of the basic science and clinical literature. cold spring harb perspect med 2012; 2:a006346. doi: 10.1101/ cshperspect.a006346. 102. mcnaull bb, todd s, mcguinness b, passmore ap. inflammation and anti-inflammatory strategies for alzheimer’s disease: a mini-review. gerontology 2010; 56:3–14. doi: 10.1 159/000237873. 103. yu d, corbett b, yan y, zhang gx, reinhart p, cho sj, et al. early cerebrovascular inflammation in a transgenic mouse model of alzheimer’s disease. neurobiol aging 2012; 33:2942–7. doi: 10.1016/j.neurobiolaging.2012.02.023. 104. leoutsakos jm, muthen bo, breitner jc, lyketsos cg; adapt research team. effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of preclinical alzheimer disease: findings from the randomized controlled alzheimer’s disease anti-inflammatory prevention trial. int j geriatr psychiatry 2012; 27:364–74. doi: 10.1002/ gps.2723. 105. jaturapatporn d, isaac mg, mccleery j, tabet n. aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of alzheimer’s disease. cochrane database syst rev 2012; 2:cd006378. doi: 10.1002/14651858.cd006378.pub2. 106. lemere ca. immunotherapy for alzheimer’s disease: hoops and hurdles. mol neurodegener 2013; 8:36. doi: 10.1186/17501326-8-36. 107. clinical trials, usa national institutes of health. progress of mild alzheimer’s disease in participants on solanezumab versus placebo (expedition 3). from: https://clinicaltrials.gov/ct2/ show/nct01900665 accessed: feb 2015. 108. bateman rj, xiong c, benzinger tl, fagan am, goate a, fox nc, et al. clinical and biomarker changes in dominantly inherited alzheimer’s disease. n engl j med 2012; 367:795–804. doi: 10.1056/nejmoa1202753. 109. lambracht-washington d, rosenberg rn. advances in the development of vaccines for alzheimer’s disease. discov med 2013; 15:319–26. 110. qu b, boyer pj, johnston sa, hynan ls, rosenberg rn. abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice. j neurol sci 2006; 244:151–8. 111. dasilva ka, brown me, mclaurin j. reduced oligomeric and vascular amyloid-beta following immunization of tgcrnd8 mice with an alzheimer’s dna vaccine. vaccine 2009; 27:1365–76. doi: 10.1016/j.vaccine.2008.12.044. 112. ubhi k, masliah e. alzheimer’s disease: recent advances and future perspectives. j alzheimers dis 2013; 33:s185–94. doi: 10. 3233/jad-2012-129028. 113. nixon ra, wegiel j, kumar a, yu wh, peterhoff c, cataldo a, et al. extensive involvement of autophagy in alzheimer disease: an immuno-electron microscopy study. j neuropathol exp neurol 2005; 64:113–22. 114. yu wh, cuervo am, kumar a, peterhoff cm, schmidt sd, lee jh, et al. macroautophagy: a novel beta-amyloid peptidegenerating pathway activated in alzheimer’s disease. j cell biol 2005; 171:87–98. doi: 10.1083/jcb.200505082. 115. caccamo a, majumder s, richardson a, strong r, oddo s. molecular interplay between mammalian target of rapamycin (mtor), amyloid-beta, and tau: effects on cognitive impairments. j biol chem 2010; 285:13107–20. doi: 10.1074/ jbc.m110.100420. 116. martorana a, balistreri cr, bulati m, buffa s, azzarello dm, camarda c, et al. double negative (cd19+igg+igd-cd27-) b lymphocytes: a new insight from telomerase in healthy elderly, in centenarian offspring and in alzheimer’s disease patients. immunol lett 2014; 162:303–9. doi: 10.1016/j. imlet.2014.06.003. 117. colonna-romano g, bulati m, aquino a, pellicanò m, vitello s, lio d, et al. a double-negative (igd-cd27-) b cell population is increased in the peripheral blood of elderly people. mech ageing dev 2009; 130:681–90. doi: 10.1016/j. mad.2009.08.003. http://dx.doi.org/10.2174/0929867321666131227161303 http://dx.doi.org/10.2174/0929867321666131227161303 http://dx.doi.org/10.3389/fphar.2014.00120 http://dx.doi.org/10.1016/j.freeradbiomed.2009.02.018 http://dx.doi.org/10.1016/j.neurobiolaging.2011.01.007 http://dx.doi.org/10.1016/j.neuint.2005.06.012 http://dx.doi.org/10.1016/j.neuint.2005.06.012 http://dx.doi.org/10.1002/glia.20905 http://dx.doi.org/10.1002/ana.23677 http://dx.doi.org/10.1517/14740338.2014.914168 http://dx.doi.org/10.1101/cshperspect.a006346 http://dx.doi.org/10.1101/cshperspect.a006346 http://dx.doi.org/10.1159/000237873 http://dx.doi.org/10.1159/000237873 http://dx.doi.org/10.1016/j.neurobiolaging.2012.02.023 http://dx.doi.org/10.1002/gps.2723 http://dx.doi.org/10.1002/gps.2723 http://dx.doi.org/10.1002/14651858.cd006378.pub2 http://dx.doi.org/10.1186/1750-1326-8-36 http://dx.doi.org/10.1186/1750-1326-8-36 http://dx.doi.org/10.1056/nejmoa1202753 http://dx.doi.org/10.1016/j.vaccine.2008.12.044 http://dx.doi.org/10.3233/jad-2012-129028 http://dx.doi.org/10.3233/jad-2012-129028 http://dx.doi.org/10.1083/jcb.200505082 http://dx.doi.org/10.1074/jbc.m110.100420 http://dx.doi.org/10.1074/jbc.m110.100420 http://dx.doi.org/10.1016/j.imlet.2014.06.003 http://dx.doi.org/10.1016/j.imlet.2014.06.003 http://dx.doi.org/10.1016/j.mad.2009.08.003 http://dx.doi.org/10.1016/j.mad.2009.08.003 taurine levels in human aqueous humour medical sciences (2000), 2, 15−24 © 2000 sultan qaboos university 1department of anatomy, college of medicine, sultan qaboos university, p.o.box: 35, postal code: 123, muscat, sultanate of oman. 2department of cell and structural biology, division of anatomy, medical school, university of manchester, manchester, u.k. 3department of anatomy, faculty of medicine, jordan university of science & technology, irbid, jordan. *to whom correspondence should be addressed. 15 thymic proliferative response during different physiological states: a comparative study * habbal o a1, mclean i m2, abu-hijleh m f3 ة وظيفيفي حاالت) الثيموسية(االستجابة التكاثرية لخاليا الغدة السعترية ةدراسة مقارن : مختلفة)فسيولوجية( أبو حجله. ما آلين ، م. لحّبال ، جا. ع ت هرمونا خgالل حgاالت فسgيولوجية مختgلفة وذلgك للgتمييز بيgن التغيرات التي تحدث نتيجة إفراز ) الثيموسgية ( دراسgة االسgتجابة الgتكاثرية لخاليgا الغgدة السgعترية :اله9دف : الم9لخص .ين المبكر في الجهاز التناسلي لألنثىالستيرويد عن تلك الناتجة بسبب وجود الحيوانات المنوية أو الجن ولقد احتوت آل . ao (rt1u) تمgت مgتابعة الgتغيرات يوميgًا خgالل فgترات الطمgث والحمgل الكgاذب والحمgل المgتماثل جيgنيًا ، وذلgك باسgتخدام جgرذان ناضgجة مgن فصgيلة :الط9ريقة مgتكررًا فgي االسgتجابة الgتكاثرية لخاليا الغدة السعترية في اليوم الثاني لفترة الطمث ، والذي لربما آان لوحgظ أن هgناك ارتفاعgا :الن9تائج . جgرذان عgلى األقgل 6مجموعgة يوميgة عgلى ومع استحثاث الحمل . ذلgك إلى وجgود هرمون األستروجين المعروف بتواجده بصورة مرتفعة خالل هذه الفترة جgاع ويمكgن إر . لgتهيئ األنgثى للgتحديات المgناعية الgناتجة عgن الجمgاع ومع . الكgاذب ، تgم الحصgول عgلى نgتائج مماثgلة السgتجابة الغgدة السgعترية خgالل اليgوم الgثالث والgذي يتصgادف مgع االرتفاع المعروف عنه في إفرازات اإلستروجين خالل هذه الفترة : الخالصة. خالل اليوم الخامس مقارنة بنفس الفترة للحمل الكاذب حgدوث هgبوط مgناعي مgلحوظ خالل اليوم الثالث والذي تبعه إرتفاع ملحوظ لوحgظ حgدوث الحمgل المgتماثل جيgنيًا ، تgبعًا لذلgك فإنgه مgن المعgتقد أن الهgبوط المgبدأي في االستجابة التكاثرية لخاليا الغدة السعترية يمكن أن يكون نتيجة الخواص المناعية المحبطة للسائل المنوي وذلك بقصد حماية الجنين . وأما الزيادة الملحوظة في اإلستجابة التكاثرية لخاليا الغدة ، فإنه من المقترح بأنها إستجابة مناعية لعملية الغرس الجيني نفسها. لغرس في الرحمالمبكر خالل فترة ما قبل ا abstract:�������� � –to study the thymic proliferative response during different physiological states to distinguish those changes due to alterations in steroid hormone secretion from those resulting from the presence of spermatozoa and/or early conceptual products in the female reproductive tract. ���� �� using mature female rats of an inbred ao(rt1u) strain, observations on the thymus were made at 24 hour intervals during the oestrous cycle, early pseudopregnancy and early syngeneic pregnancy. each daily group contained a minimum of 6 animals. ������� – during the oestrous cycle, a significant mid-cycle increase of thymocyte proliferation occurred during dioestrus which peaked on day 2, and as a repetitive response may be a preparation for a coital challenge. this response may be oestrogen-dependent since oestrogen levels begin to increase during early dioestrus. the induction of pseudopregnancy generates a comparable but delayed increase in thymic proliferative activity. since thymocyte proliferation and oestrogen secretion both peak on day 3 of pseudopregnancy, such a response may indeed also be oestrogen-dependent. after syngeneic mating, there was a significant depression in thymic proliferative activity on day 3 followed by a significant increase on day 5 compared with the same days of pseudopregnancy. ���������� – this initial depression of proliferative activity may be induced by the immunosuppressive action of seminal plasma, to safeguard the preimplantation conceptus while the day 5 increase in cellular proliferation suggests a response to implantation. key words: oestrous cycle, pseudopregnancy, implantation, seminal fluid, thymus or a number of years it has been apparent that manipulations of the maternal immune system can have both positive and negative effects on fertility. for example, abortion can be induced by immunisation of experimental animals with sperm1 or tumour cells,2 whereas recurrent abortions in certain strain combinations of mice can be dramatically reduced by immunisation with cells carrying paternal major histocompatibility complex (mhc).3 striking thymic changes are evident after adrenalectomy4 and gonadectomy5 in murine laboratory animals. the presence of high affinity oestrogen receptors, confined to thymic epithelial cells indicates that the thymus is a target organ for oestrogen.6 dynamic remodelling of its structure occurs after oestradiol treatment7, and varying oestrogen levels can alter thymic hormone f 15 h a b b a l e t a l 16 output.8 serum levels of progesterone vary during the ovarian cycle but progesterone is apparently the only hormone essential for the maintenance of pregnancy in every species studied.9 however, the effects of sex steroids on immunity and the lymphoid tissues remain controversial.10 sterile coitus and experimental stimulation of the uterine cervix induce a state of pseudopregnancy in which the oestrous cycle is interrupted and a dioestrous state persists as confirmed by daily vaginal smears. the classical response of the early pseudopregnant uterus to an appropriate stimulus is the formation of deciduomata.12 these are well-defined areas of endometrial reaction made up of decidual cells similar to those occurring during early pregnancy, and this response cannot be elicited during the normal oestrous cycle. during pseudopregnancy, progesterone level reaches that of the pro-oestrous phase by the fourth or sixth day13 and are sustained at that level until the ninth or tenth day.14 thereafter, the progesterone level falls steadily until the twelfth day.15 although progesterone priming alone is sufficient to induce the cellular changes associated with the decidual reaction, the addition of oestrogen influences the uterine response, since it increases the size of the deciduoma and regulates the length of time during which the stimulus is effective in rats.16 serum assays of oestrogen during pseudopregnancy indicate a surge on the third and fourth day.17 there is considerable evidence to suggest that spermatozoa possess surface alloantigens,18,19 whereas secretions from the prostate and other parts of the male reproductive tract probably constitute another antigen system.20 during the first 5 days of pregnancy, the female reproductive tract is exposed to an ejaculate of spermatozoa in seminal fluid and a number of preimplantation embryos. in the latter part of this preimplantation period, the embryo sheds its zona pellucida preparatory to implantation. since the conceptus expresses paternal alloantigens,21 any immune response, particularly a cell-mediated one, generated by non-fertilising spermatozoa could hazard the survival of the preimplantation embryo. the zona pellucida provides the initial protection, but with its dissolution, some other mechanism must operate to safeguard the implanting conceptus from immunological attack. central to the allograft reaction is cell proliferation within the t-cell population of the regional lymph nodes, where it is associated with weight gain.22 in the rat, the regional lymph node response to subcutaneous challenge with spermatozoa is unequivocal23 and includes the generation of specific anti-male strain cytolytic t-cells.24 in addition to its role as the suspensory agent for spermatozoa, seminal fluid contains a number of immunosuppressive factors which may protect spermatozoa from immunological damage and prevent sensitization of the female to spermatozoal antigens following coitus.20 seminal fluid can interfere directly or indirectly with the function of t-cells,25 bcells,26 natural killer cells (nk cells),27 antibody28 and complement.29 it also affects cell-mediated immunity as it limits the duration of an effective cytolytic t-cell response to ejaculated spermatozoa.30 the ejaculate therefore contains highly immunogenic cells and a number of factors, which appear capable of modifying an immune response. the response of the thymus during pregnancy is generally considered one of involution. in the mouse, observations are of continuous involution from the onset of pregnancy31 or involution beginning later during pregnancy.32 in the rat, this variability in the onset of thymic involution during pregnancy has been shown to be strain-dependent33 and this presumably explains the conflicting results found in mice. the gestational thymus of the rat has also been observed to be associated with increased levels of thymocyte proliferation following allogeneic pregnancy.33 such an immunological effect upon the thymus is also demonstrable in analyses of thymic responses during syngeneic and allogeneic pregnancy in mice34 and rats.35 these changes in the thymus associated with pregnancy are presumably the result of hormonal changes as well as the presence of the ejaculate and the products of conception. neonatal thymectomy in mice delays vaginal opening, an effect that may be due to a thymic-ovarian interaction.36 this study primarily collates and compares the changes in the thymus during the oestrous cycle, early pseudopregnancy and early syngeneic pregnancy. the study was done in an attempt to distinguish those changes induced by the presence of spermatozoa and/ or the early zygote from those occurring as a result of alterations in levels of steroid hormone secretions. the authors’ previous work35,37 looked broadly into the lymphoid tissue changes that occur during each of the three hormonal states. methods the animals a highly inbred strain of rat, ao(rt1u/agb2), was used in this investigation. the sexually mature female animals were bred from a specially maintained stock fed on a standard diet with a 12 hours light cycle. at the time of sacrifice, the rats had body weights of 160–200 g, and were between 13 and 15 weeks of age. t h y m i c p r o l i f e r a t i v e r e s p o n s e 17 the latter choice minimised age-related changes in the lymphoid tissues. determination of oestrous cycle stage in the sexually mature rat, the various stages of the oestrous cycle were determined by low-power (×40) microscopic observation of the unstained smear taken daily with a wire loop from the lower vagina.38 although the rat cycle is subject to individual variations, the oestrous phase recurs every 4–5 days in the absence of mating.39 in the present study, vaginal smears were prepared from the virgin rats at 10.00 hrs each day. the oestrous phase animals, designated group 0, were sacrificed at approximately 11.00 hrs on the day oestrus was identified in the vaginal smear. the remaining groups, designated 1–4, were sacrificed at 24–hour intervals, when the vaginal smears confirmed the appropriate phase of the cycle. all groups contained at least 6 animals each and these were sacrificed without cervical stimulation or mating over the period of the oestrous cycle. induction of pseudopregnancy pseudopregnancy was induced in virgin rats by mechanical cervical stimulation during oestrus. an electrical vibrator was used for this purpose and the stimulation was maintained for a minimum of 30 seconds in the restrained animal.40 this method was chosen because of its simplicity and effectiveness.40 the day following cervical stimulation was designated the first day of pseudopregnancy. groups of animals, designated 1–5, were sacrificed at 24–hour intervals as successive daily smears confirmed the presence of a dioestrous-like vaginal smear characteristic of pseudopregnancy. mated animals in the mated (pregnant) animals, 1 to 3 virgin female rats in oestrus were caged late in the afternoon with a male rat of proven fertility. vaginal smears were prepared from the rats at 10.00 hrs each day. the day spermatozoa were noted in the smear was designated day 1 of pregnancy. the remaining groups designated days 2 to 5 were sacrificed at 24-hour intervals following day 1 of pregnancy. removal of the thymus and preparation of cell suspensions on the day of sacrifice, all the animals were sacrificed at approximately 11.00 hrs after verification of the vaginal smear. each animal was anaesthetised with ether and subsequently given an i.p. injection of 12 mg of veterinary nembutal ('sagatal': may & baker ltd., dagenham). the weight of the animal was recorded and after exsanguination, the thymus was removed and cleaned, weighed and placed in 199 tissue culture medium (wellcome reagents ltd., beckenham) adjusted to ph 7.2. a cell suspension from each thymus was prepared by repeated squashing with a plastic pestle. this cell suspension was subsequently filtered through a stainless steel mesh (144 holes/cm2) and made up to a final volume of 10 ml. from this, 1 ml was taken and used for cell counting, with a coulter zb counting instrument. radiolabelling and preparation of cell smears after removal of aliquots for the cell counts, 10 µl of [6–3h] thymidine (amersham international plc., aylesbury) at an activity of 100 µci/ml were added for each 1 ml of cell suspension. after mixing, the suspensions were incubated in a water bath at 37°c for 1 hour with occasional shaking. the suspensions were then centrifuged at 2000 rpm (700 g) for 10 minutes and the resultant pellets resuspended in phosphate buffered saline (pbs) at a concentration of 5 × 106 cells/ml. previous work has shown that at this dilution the cell suspension requires no further washing. this cell concentration is also optimal for preparing smears in the shandon-elliot cytocentrifuge. after radiolabelling, six smears were prepared from each thymocyte suspension. the smears were prepared on slides previously coated with gelatin/chrome alum41 to prevent peeling of the nuclear emulsion used in the autoradiography. the smears were dried in air and fixed in methanol, dipped in diluted ilford k2 nuclear emulsion (ilford ltd., knutsford) and stored at 4°c in the dark for three weeks. after this period, when a trial slide showed clear labelling, the remaining slides were developed in kodak d19 developer, fixed in acidhardening fixer, stained with haematoxylin and eosin and mounted. radiolabelled cell counts a non-random strip counting method was used to assay, at ×400 magnification, the number of labelled and unlabelled cells and thus the percentage of cells labelled. total labelled cell counts were then calculated from the total thymocyte counts. only cells in the dna-synthesis ‘s’ phase of mitosis incorporate thymidine.42 assuming a random distribution of mitotic phases, a constant proportion of the actively proliferating cells, approaching 50%,43 will be in the ‘s’ phase. the consistency and low standard errors of the results obtained from each group in this study support this assumption. consequently, it seemed reasonable to use the figures for percentage labelling and total labelled cell counts as a measure of proliferative activity; not an absolute measure but an accurate reflection of the relative differences between groups. h a b b a l e t a l statistical analysis the data were analysed in two ways. comparisons were made between the different time points of animals in the same hormonal state and comparisons were made between the same time point, of animals in different hormonal states. where a one-factor analysis of variance gave a significant result, this was further analysed by a comparison of individual group means using the least significant difference method. two group means differing by more than the least significant difference value indicates a significant difference at the 0.05 level or less. results in this study, a number of observations were made on the thymus. these observations were recorded at 24-hour intervals throughout the oestrous cycle and during the first five days of pseudopregnancy and syngeneic pregnancy (tables 1–3). the time interval between the observations and the limitation of the observation period allowed the results obtained on different days in each of the three physiological states, and those obtained on comparable days in any two states, to be compared. the observations made on oestrous phase virgin animals, day 0 of the oestrous cycle, provided base-line data for the pseudopregnant and pregnant animals since the induction of pseudopregnancy and the initiation of pregnancy took place on that day. the results obtained during days 1–4 of pseudopregnancy and pregnancy were compared with those of days 1–4 of the oestrous cycle while the day 5 results from the stimulated animals were considered comparable with the oestrous phase results of the unstimulated animals since in such animals the oestrous phase recurs every fifth day. each group contained at least 6 animals and each animal yielded figures for body weight, thymic weight, total thymocyte content both absolute and relative to thymic weight, percentage of labelled cells and total labelled cell counts. although body weight rose to a maximum value on day 2 of the oestrous cycle, it had returned to its oestrous phase value on day 4. no significant changes were observed during either of the other two physiological states or between any of the three states. no significant changes in thymic weight were observed during the oestrous cycle, early pseudopregnancy or early syngeneic pregnancy. however, the thymus was significantly heavier on day 4 of pseudopregnancy and syngeneic pregnancy than on the comparable day of the oestrous cycle. observations of the total thymocyte counts (figure 1) within each of the three physiological states again showed no significant differences. however, on comparing these physiological states, the total thymocyte counts on day 4 of pseudopregnancy and days 2, 3 and 4 of syngeneic pregnancy, were significantly greater than those on the comparable days of the oestrous cycle, while the count on day 2 of syngeneic pregnancy was significantly greater than that on the same day of pseudopregnancy. the only significant differences in thymic cell densities (figure 2) day of oestrous cycle thymic weight total thymocyte content x106 cell density x 106/100 mg tissue % cell proliferation (size) % labelled (proliferating) cells total labelled cells x 106 tables indicating the means of thymic results table 1 oestrous cycle 0 1 2 3 4 5 292.00 252.00 282.00 268.00 227.00 292.00 +/14.14 18.93 18.70 11.81 18.04 14.14 893.00 779.00 759.00 785.00 682.00 893.00 +/53.50 89.23 75.14 64.01 70.72 53.50 308.00 304.00 269.00 291.00 299.00 308.00 +/22.59 13.13 18.59 17.69 14.78 22.59 8.44 7.65 12.22 11.14 7.65 8.44 +/0.70 0.18 0.78 0.62 0.48 0.70 8.23 6.27 13.17 10.50 6.24 8.23 +/1.14 0.43 1.84 0.56 0.78 1.14 74.34 48.13 95.44 81.95 40.55 74.34 +/13.10 5.42 13.67 7.04 2.95 13.10 18 t h y m i c p r o l i f e r a t i v e r e s p o n s e 19 wererecorded on day 2 when the density observed during syngeneic pregnancy was significantly greater than that on the same day of pseudopregnancy and the oestrous cycle. during the oestrous cycle, thymocyte proliferation (figure 3) peaked on day 2 and was significantly greater on days 2 and 3 than on day 0 (oestrus), 1 and 4. after the induction of pseudopregnancy, proliferative activity was significantly greater on day 3 than on any other day, and on days 2 and 4 was significantly greater than that on day 5. following syngeneic mating, thymocyte proliferation was significantly greater on days 3 and 4 than on post-coital days 1 and 2. when comparing thymocyte proliferation during the oestrous cycle with that during pseudopregnancy, there was significantly greater mitotic activity on days 3 and 4 of pseudopregnancy than on the same days of the oestrous cycle. when comparing the levels of thymocyte proliferation during the oestrous cycle with those after syngeneic mating, the post-coital level on day 4 was significantly greater than that on the comparable day of the oestrous cycle. a comparison of the results obtained during pseudopregnancy with those after syngeneic mating demonstrated a significantly greater level of thymocyte proliferation on the fifth post-coital day than on the same day of pseudopregnancy. table 2 pseudopregnancy day of pseudopregnancy 0 1 2 3 4 5 thymic weight mg 293.00 397.00 273.00 262.00 275.00 279.00 +/14.14 39.68 18.46 15.00 22.03 8.71 total thymocyte content x106 893.00 962.00 816.00 931.00 955.00 903.00 +/53.50 125.83 65.65 69.66 133.47 35.86 cell density x 106/100 mg tissue 308.00 320.00 297.00 329.00 339.00 334.00 +/22.59 20.23 9.39 16.68 21.72 9.85 % cell proliferation (size) 8.44 9.39 10.67 12.96 8.56 7.36 +/0.70 0.55 0.54 1.66 0.51 0.17 % labelled (proliferating) cells 8.23 7.04 8.96 12.82 8.88 5.19 +/1.14 0.47 0.87 0.85 1.16 1.28 total labelled cells x 106 74.34 56.89 71.48 118.31 80.12 44.74 +/13.10 7.01 7.17 10.04 10.31 9.28 table 3 syngeneic pregnancy day of syngenic pregnancy 0 1 2 3 4 5 thymic weight 292.00 281.00 289.00 298.00 311.00 291.00 +/14.14 21.25 10.54 10.57 16.57 21.99 total thymocyte content x106 893.00 961.00 1008.00 942.00 973.00 977.00 +/53.50 98.04 64.37 61.89 63.64 99.26 cell density x 106/100 mg tissue 308.00 339.00 349.00 315.00 312.00 333.00 +/22.59 14.33 15.13 11.92 8.06 14.98 % cell proliferation (size) 8.44 7.47 7.84 10.24 9.58 7.36 +/0.70 0.22 0.58 0.21 0.61 0.19 % labelled (proliferating) cells 8.23 7.18 7.64 10.80 10.92 8.80 +/1.14 0.45 0.40 0.64 0.75 0.31 total labelled cells x 106 74.34 70.60 77.56 100.63 105.70 86.45 +/13.10 10.96 7.59 6.04 9.09 10.06 h a b b a l e t a l 0 200 400 600 800 1000 1200 0 1 2 3 4 5 d a y ce lls x 1 06 oestrous cycle pseudopregnancy syngeneic pregnancy 0 100 200 300 400 0ce lls x 1 06 / 1 0 0 m g tis su e 0 20 40 60 80 100 120 140 0 la be lle d ce lls x 1 06 figure 1. total thymocyte counts 1 2 3 4 5 oestrous cycle pseudopregnancy syngeneic pregnancy d a y figure 2. thymic cell density 1 2 3 4 5 d a y oestrous cycle pseudopregnancy syngeneic pregnancy figure 3. total proliferating thymocyte counts 20 t h y m i c p r o l i f e r a t i v e r e s p o n s e 21 discussion the thymus is a primary lymphoid organ and its central role in the immune system, as the source of t cells, was demonstrated over 30 years ago.44 recent research suggests that all immunoregulatory processes are part of an integrated response involving neural, endocrinal and immune systems.45 given the central role of the thymus in the immune system and the complex neuroendocrinological events involved in the initiation and continuance of pregnancy in eutherian mammals, it is not surprising that the gestational thymus has been the focus of much research46 concerning the immunological paradox of pregnancy. this study, however, had more limited objectives and was confined to observations on the rat thymus during the oestrous cycle and for five days following interruption of the oestrous cycle by either mechanically induced pseudopregnancy or fertile mating. the observations of thymic weights, thymocyte counts and thymic cell densities yielded few statistically significant differences, but those observed may be biologically important. on day 4 of both pseudopregnancy and syngeneic pregnancy, the thymic weights and thymocyte counts were significantly greater than those on the same day of the oestrous cycle. furthermore, despite the absence of significant weight changes, the thymocyte counts on days 2 and 3 of pregnancy were significantly greater than those on the comparable days of the oestrous cycle, and on day 2 of pregnancy significantly greater than on the same day of pseudopregnancy. these observations were reflected in the significantly greater thymic cell density on day 2 of pregnancy compared with those of the same day of pseudopregnancy and the oestrous cycle. the significant drop in thymic weight and cell counts on day 4 of oestrous cycle, when compared with the same days of pseudopregnancy and pregnancy, indicate that the hormonal events associated with the interruption of the oestrous cycle have an influence on the thymus and modify the toxic effects of sex steroids on the thymus, while the earlier differences in thymocyte counts and thymic cell densities observed during pregnancy compared with the oestrous cycle and pseudopregnancy indicate that some factor associated with mating has an additional effect upon the thymus. these observations of tissue weight, cell content and cell density include significant differences between the thymic responses to the physiological events characteristic of each state. by extending these observations to include daily levels of thymocyte proliferation, it was anticipated that these differences might be confirmed. during the oestrous cycle, thymocyte proliferation peaked on day 2 and was significantly greater on days 2 and 3 than on any other day of the cycle. having observed no significant changes in the thymic weight, cell content or cell density during the oestrous cycle, this significant mid-cycle increase in thymocyte proliferation was unexpected. the most feasible explanation of these unchanging thymic parameters in the presence of increased thymocyte proliferation is a comparable increase in the export of t-lymphocytes from the thymus to secondary lymphoid tissues. the mid-cycle increase in thymocyte proliferation is almost certainly caused by ovarian hormones. unless there is a significant delay between increased hormone secretion and increased thymocyte proliferation, this increased mitotic activity within the thymus is possibly oestrogen-dependent since oestrogen levels begin to increase during early dioestrus while progesterone levels remain very low until midway through prooestrus.47 it is known that oestrogen stimulates mitotic activity in endometrial epithelium and stroma during the preovulatory phase of the human menstrual cycle.48 since there are oestrogen receptors in the thymus,49 this hormone may indeed be responsible for the increased thymocyte proliferation observed during the oestrous cycle. a repetitive oestrogen-dependent mid-cycle increase in thymocyte proliferation would appear to be a preparation for the coital challenge, which the female rat will allow only during the oestrous phase of the ovarian cycle. after mechanical induction of pseudopregnancy, thymocyte proliferation was significantly greater on day 3 than on any other day during the observation period. on days 2, 3 and 4, it was significantly greater than on day 5. since there are no significant changes in thymic weights, thymocyte counts or thymic cell densities during the first five days of pseudopregnancy, it would seem that, as in the case of the oestrous cycle, thymocyte proliferation during early pseudopregnancy is accompanied by an equivalent outflow of t-cells to the secondary lymphoid tissues. this peak of proliferative activity during pseudopregnancy, however, occurred on day 3, some 24 hours later than the peak of proliferative activity during the oestrous cycle. since thymocyte proliferation and oestrogen secretion both peak on day 3 of pseudopregnancy, it would seem reasonable to conclude that, as during the oestrous cycle, thymocyte proliferation during early pseudopregnancy is oestrogen-dependent.36 the significantly lower level of thymocyte proliferation on day 5 of pseudopregnancy compared with those on days 2, 3 and 4 suggests that this is a response to increasing levels of progesterone secretion which begin between days 4 and 6 of pseudopregnancy and are sustained until day 9 or 10. since mechanical induction of h a b b a l e t a l 22 pseudopregnancy does not expose the female reproductive tract to either the ejaculate or the products of conception, the thymic events of early pseudopregnancy are probably controlled solely by the neuroendocrine system. following syngeneic mating, thymocyte proliferation was significantly greater on days 3 and 4 than on any other post-coital day. again the absence of significant changes in the other thymic results during the first 5 days of pregnancy suggests either an equivalent exodus of t-cells to the secondary lymphoid tissues or some immunological mechanism operating within the thymus to achieve clonal deletion during t-cell development.50 the peak proliferative response during early pregnancy occurred on day 3, as it did during early pseudopregnancy, but following mating this level of proliferation was sustained until day 4 before it fell to the control oestrous phase level on day 5. since the profiles of ovarian hormone secretion are identical during the 5 days following mechanical induction of pseudopregnancy and syngeneic mating, this altered pattern of thymocyte proliferation in early pregnancy compared with pseudopregnancy suggests that factors other than ovarian hormone secretion, influence the early gestational thymus. when comparing thymocyte proliferation during the oestrous cycle with that during early pseudopregnancy, there was significantly greater mitotic activity on days 3 and 4 of pseudopregnancy than during the oestrous cycle. furthermore, during the oestrous phase of the cycle, which in the unstimulated female rat recurs every 5 days, thymocyte proliferation was significantly greater than on day 5 of pseudopregnancy. these significant differences between thymocyte proliferation during the oestrous cycle and early pseudopregnancy confirm the observations already made when considering each of these two physiological states separately. in addition, they may validate the assumption that while thymocyte proliferation is oestrogen-dependent, it can be suppressed by increasing levels of progesterone secretion. such a validation would certainly require further studies on foetal thymic organ culture where oestrogen-dependency can be elucidated. given the assumption that any physiological interruption of the oestrous cycle will produce comparable changes in ovarian hormone secretion, it might be expected that, should thymic proliferation be determined solely or principally by endocrine factors, a comparison of thymocyte proliferation during the oestrous cycle with that during either early pseudopregnancy or early syngeneic pregnancy would present the same pattern of significant differences. while this is true for days 2, 3 and 4, it is not so for day 5 when, contrary to the comparison with early pseudopregnancy, no significant differences between the levels of thymocyte proliferation during the oestrous cycle and early pregnancy were observed on this day. this suggests that thymocyte proliferation during early pregnancy is influenced by other factors apart from ovarian hormones. this was confirmed by comparing thymocyte proliferation during early pseudopregnancy with that during early pregnancy, which demonstrated a significantly greater level of mitotic activity on day 3 of pseudopregnancy and on day 5 of pregnancy. the absence of significant differences between the daily observations of thymic weights, cell counts and cell densities despite significant increases in thymocyte proliferation during each of the three physiological states suggests either an equivalent exodus of t-cells or some intrathymic mechanism of cell deletion. the significant differences in thymocyte proliferation between the three states suggest a principal role for oestrogen in effecting increased mitotic activity within the thymus. however, the significant increase in both total thymocyte count and thymic cell density on the second post-coital day, the significant depression of thymocyte proliferation on the third post-coital day and the significant increase in thymocyte proliferation on the fifth post-coital day relative to the values recorded on the comparable days of pseudopregnancy, suggest that other factors apart from oestrogen influence the early gestational thymus. the probable cause of the differences observed on days 3, 4 and 5 is the presence of the ejaculate and/or conceptual products in the upper female reproductive tract, since certain components of seminal plasma are known to have a direct immunosuppressive effect. early mammalian embryos also produce immunosuppressive factors.51,52 the increased thymocyte proliferation on the fifth post-coital day not only coincides with the onset of implantation but occurs during a period of increasing progesterone secretion. this suggests either a programmed thymic response to ejaculated spermatozoa, initially rendered non-immunogenic by their suspension in seminal plasma, or a response to the process of implantation. at coitus, large numbers of spermatozoa invade the endometrial glands.53 while it has been shown that a specific anti-male strain cytolytic t-cell response in the regional lymph nodes continues for 5 days after subcutaneous challenge or artificial insemination of epididymal spermatozoa,24,30 the comparable post-coital response is limited to the second and third days and is no longer detectable at the time of implantation on day 5.30 this ‘switch-off’ of the cytolytic t-cell rest h y m i c p r o l i f e r a t i v e r e s p o n s e 23 ponse to mating during the pre-implantation period suggests that some factor in the seminal fluid exerts a suppressive function on the female host’s immune response to spermatozoal antigens. a limited cytolytic t-cell response to coitus resulting from the effects of seminal fluid is clearly beneficial in reproduction, but may have adverse effects for the host when exposed to virally infected ejaculate. since the host’s defence against viral infection is predominantly a cell–mediated response, it is particularly relevant, for there is now a well established aetiological link between human papilloma viral infection and cervical neoplasia.54 conclusion it seems reasonable to suggest that proliferative activity in the female thymus is hormonally driven and that the timing of this proliferative activity seems to be programmed to reflect the needs of the immune system in its putative response to mating and implantation. the depression of intrathymic proliferative response consequent to pregnancy is perhaps induced by seminal plasma and may safeguard the implanting conceptus. acknowledgement we would like to express our deep gratitude to professor anjali saha, dept. of epidemiology and medical statistics, college of medicine, sultan qaboos university, for her help and advice on the statistical analyses. references 1. tung ks, goldberg gh, goldberg e. 1979 immunobiological consequences of immunization of female mice with homologous spermatozoa: induction of infertility. j reprod immunol 1979, 1, 145–58. 2. tartakovsky b, gorelik e. immunisation with syngeneic regressor tumour causes resorption in allopregnant mice. j reprod immunol 1988, 31, 113–22. 3. wegmann tg. maternal t cells promote placental growth and preventspontaneous abortion. immunol lett 1988, 17, 297–302. 4. la pushin rw, de harven e. a study of gluco– corticosteroid induced pyknosis in the thymus and lymph node of adrenalectomised rat. j cell biol 1971, 50, 583–97. 5. calzolari a effect of castration on the thymic gland. arch ital biol 1898, 30, 71–89. 6. luster mi, hays ht, korach k, tucker an, dean j, greenlee w, boomrman g oestrogen immunosuppression is regulated through estrogen responses in the thymus. j immunol, 1984, 133, 110–16. 7. sandberg g, hagelin m lymphatic vessels and kurloff cells in the thymus of oestradiol-treated guinea pigs. cell tiss res 1990, 259, 361–9. 8. low tlk, thurman gb, zatz mm, hu sk, goldstein al in: advances in immunopharmacology (hadden j ed.), new york: pergamon press 1981. 9. siiteri pk, febers f, clemens le, chang rj, gondos b, stites d progesterone and maintenance of pregnancy: is progesterone nature's immunosuppressive? ann ny acad sci 1977, 286, 384. 10. grossman cj. regulation of the immune system by sex steroids. endocrinol rev 1984, 5, 435–55. 11. michael sd, chapman jc. the influence of the endocrine system on the immune system. immunol aller clin n am 1990, 10, 215–34. 12. defeo vj. decidualisation. in: cellular biology of the uterus (wynn rm ed.pp. new york: appleton-century-crofts.1967, 192–290. 13. fajer ab, arraclough ca. ovarian secretion of progesterone and 20-a-hydroxy pregn-4-en-3-one during pseudopregnancy and pregnancy in rats. endocrinol 1967, 7, 622–5. 14. pepe gj, rothchild i. a comparative study of serum progesterone levels in pregnancy and in various types of pseudopregnancy in rat. endocrinol 1974, 95, 275–9. 15. hashimoto i, hendricks dm, anderson l, melampy rm (1968) progesterone and pregn-4-en-20a-ol-3-one in ovarian venous blood during various reproductive states in the rat. endocrinology 1968, 82, 333-4. 16. yochim jm, defeo vj hormonal control of the onset, magnitude and duration of uterine sensitivity in the rat by steroid hormones of the ovary. endocrinol 1963, 72, 317– 26. 17. shelesnyak mc, kraicer pf, zeilmaker gh. studies on the mechanism of decidualisation. i. the oestrogen surge of pseudopregnancy and progravidity and its role in the process of decidualisation. acta endocrinol 1963, 42, 225-6. 18. mori t, gou mw, mori e, shindo y, mori n, fukuda i, mori t. expression of class ii mhc antigen on mouse spermatozoa and its roles in fertilisation. am j reprod immunol 1990, 24, 9–14. 19. ohashi k, saji f, kato m, wakimoto a, tanizawa o. hla expression on human ejaculated sperm. am j reprod immunol 1990, 23, 29–32. 20. quayle a, james k. immunosuppression by seminal plasma and its biological significance. arch immunol ther exp 1990, 38, 87–100. 21. warner cm, spannaus dj. demonstration of h2antigens on preimplantation mouse embryos using conventional antisera and monoclonalantibodies. j exp zool 1984, 230, 37–52. 22. parrott dm. the response of draining lymph nodes to immunological stimulation in intact and thymectomised animals: in symposium on tissue and organ transplantation. j clin exp path (suppl) 1967, 20, 456–65. 23. willetts ie. the effect of allogeneic spermatozoa on the thymus of the rat. bsc thesis, 1985, 317–26. 24. thomas ik, leeming g, gibbs acc, mclean jm. a specific cytolytic cell response induced by subcutaneous challenge with allogeneic rat epididymal spermatozoa. j reprod immunol 1981, 3, 157–164. 25. prakash c, lang rw. studies on immune infertility: a hypothesis on the aetiology of immune infertility based on the aetiological role of seminal plasma immune response inhibition. mount sinai j med 1980, 47, 491–510. h a b b a l e t a l 24 26. lewis wr, whalen jj, shrines rj. mixed cultures of sperm and leucocytes as a measure of histocompatibility in man. science 1976, 191, 302–4. 27. schopf re, schramm p, benes p, morsches b. seminal plasma-induced immunosuppression of the respiratory burst of polymorphnuclear leucocytes and monocytes. androlo 1984, 16, 124–8. 28. witkin ss, richards jm, bongiovanni m, zelikousky g. an igg-fc binding protein in seminal fluid. am j reprod immunol 1983, 3, 23–27. 29. anderson dj and tarter th. immunosuppressive effects of mouse seminal plasma components in vivo and in vitro. j immunol 1982, 182, 535–9. 30. thomas ik, mclean jm. seminal plasma abrogates the post-coital t-cell response to spermatozoa histocompatibility antigens. j reprod immunol 1984, 6, 185–189. 31. phuc lh, papiernik m, dardenne m. thymic involution in pregnant mice. ii. functional aspects of the remaining thymocytes. clin exp immunol 1981, 44, 253– 61. 32. chatterjee-hasrouni s, santer v, lala pk. characterisation on maternal small lymphocyte subsets during allogeneic pregnancy in the mouse. cell immunol 1980, 50, 290–304. 33. leeming g, mclean jm, gibbs acc. thymic and body weight changes during first syngeneic and allogeneic pregnancy in the rat and the effect of strain differences. thymus 1984, 8, 153–65. 34. chaouat g, fowlkes bj, leiserson wl, asofsky r. modification of thymocyte subsets during pregnancy analysed by microfluorometry: role of alloantigenic status of the conceptus. thymus 1982, 4, 299–308. 35. habbal o, mclean jm. lymphoid tissue changes during early syngeneic pregnancy in the rtiu rat. acta anat 1992, 144, 363–70. 36. allen ls, mclure je, goldstein al, barkley ms, michael sd. delayed vaginal opening in thymectomised mice: a possible pituitary-thymic-ovarian axis. j reprod immunol 1984, 6, 25–31. 37. habbal o, mclean jm. an increase in thymocyte proliferation during pseudopregnancy in two inbred strains of rat. acta anat 1992, 144, 296–303. 38. stockard cr, papanicolau gn. the existence of a typical oestrous cycle in the guinea pig with a study of its histological and physiological changes. am j anat 1917, 22, 225–83. 39. long ja and evans hm. oestrous cycle in the rat and its associated phenomena. mem univ calif 1922, 6, 1–14. 40. defeo vj. vaginal-cervical vibration a simple effective method for the induction of pseudopregnancy in the rat. endocrinol 1966, 79, 440–2. 41. rogers aw. in: techniques of autoradiography (rogers aw ed.), 1969, new york: elsevier publishing co. p. 211. 42. ford wl. the preparation and labelling of lymphocytes; in: handbook of experimental immunology (weir dm ed.), 1978, blackwell scientific publications, oxford. 2315. 43. wagner hp, cottier h, cronkite ep, cunningham l, janzen cr, rai k. studies on lymphocytes v: short in vivo dna synthesis and generation time of lymphoid cells in the calf thoracic duct after simulated or effective extracorporal irradiation of circulating blood. exp cell res 1967, 46, 441–51. 44. miller jfap, marshall ahe, white rg. the immunological significance of the thymus. adv immunol 1962, 2, 111–62. 45. ader r, cohen n, felten d. psychoneuroimmunology: interactions between the nervous system and the immune system. lancet 1995, 345, 99–103. 46. kendall md, clarke ag. the female thymus and reproduction in mammals. oxford reviews of reproductive biology 1994, 16, 165–213. 47. butcher rl, collins we, fugo nw. plasma concentration of lh, fsh, prolactin, progesterone and oestradiol-17ß throughout the 4–day oestrous cycleof the rat. endocrinol 1974, 94, 1704–8. 48. ross gt, van de weile rl. the ovaries: in: textbook of endocrinology, 1981 williams rh ed., philadelphia: saunders. p: 355. 49. franks cr, perkins ft, bishop d. the effects of sex hormones on the growth of hcla tumour nodules in male and females mice. brit j cancer 1975, 31, 100–10. 50. jones la, chin lt, merriam gr, nelson lm, kruisbeck am. failure of clonal deletion in neonatally thymectomised mice: tolerance is preserved through clonal anergy. j exp immunol 1990, 172, 1277–85. 51. van vlasselaer p, van de putte m. immunosuppressive properties of murine trophoblast. cell immunol 1984, 83, 422–32. 52. daya s, clarke da. production of immunosuppressive factors by reimplantation human embryos. am j reprod immunol microbiol 1986, 11, 98–101. 53. hafez ese transport and survival of spermatozoa in the female reproductive tract. (hafez ese ed). st. louis: cv mosby co 1976, pp. 107–129. 54. reid bl. papilloma virus and cervical neoplasia. colposcopy gynaecol laser surg 1984, 1, 3–24. thymic proliferative response during different �physiological states: a comparative study methods the animals determination of oestrous cycle stage induction of pseudopregnancy mated animals removal of the thymus and �pre˜˜pa˜ration of cell suspensions radiolabelling and prepara˜tion of cell smears radiolabelled cell counts statistical analysis results discussion conclusion acknowledgement references sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e4-6, epub. 27th jan 14 submitted 24th nov 13 revision req. 16th dec 13; revision recd. 16th dec 13 accepted 18th dec 13 academia demands of its dons a life of ideals, commitment, striving and timelessness in fulfilling intellectual self-actualisation and imbuing the same spirit in the students they serve. the hallowed portals of academic medicine bring the additional, inbuilt mandate of patient care with the onerous responsibility of handling life and death on a regular basis. opting for a career in contemporary medical education demands a balanced contribution to teaching, clinical service and research. somewhere in the prioritisation of these roles there appears to be a worrying diminution of a fourth dimension: the vital need for mentoring that a medical teacher can and should offer to a medical student.1 a brief introspection on the compelling arguments for mentoring and the opportunities that exist to achieve this maverick role is made in the succeeding paragraphs. mentoring the recorded wisdom of the preceding centuries provides innumerable examples of the real meaning of the word ‘guru’. students entering higher education may be driven by various motivations: achievement, affluence, love of learning, parental pressure, etc. those who choose to become physicians are pre-aware that the common theme that will make this goal a reality is unrelenting hard work. within and beyond the didactic ‘instruction’ in the art and science of medicine lies a unique opportunity to groom, motivate and develop personalities that will place these healthcare givers into society imbued with the right values, ethics and empathy. achieving entry into a medical school is a far cry from deciding the direction of your chosen vocation for the rest of your years. the once sought after disciplines like surgery have seen a significant drop in career aspirants, at least in part due to the lack of role models and mentorship in clerkship years.2 some medical students are fortunate in being influenced by iconic and charismatic teachers while a majority merely drift into careers with little thought for matching their inherent talent and aptitude with their choices. within the middle east, a study from kuwait found that 62.8% of medical students were undecided about future choices with lack of mentoring as a leading cause of this.3 the stresses that adaptation to the intense learning experience and chosen lifestyle impose on medical students constitute a recurrent theme of scientific research.4,5 the appointment of ‘academic advisers’ needs to be complemented with an innate zeal and passion in mentors to nurture, inspire, guide and comfort in this period of medical adolescence. they can raise the bar of achievement, instill values, provide support during periods of despondency and even encourage a change of direction for those unequal to the task ahead. formal training programmes provide real value to bolster mentoring skills.6 department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ritu@squ.edu.om هل سينهض املعلم الطيب احلقيقي وينال االهتمام؟ ريتو لكتاكيا editorial will the real medical teacher stand up and be counted? ritu lakhtakia the teacher who is indeed wise does not bid you to enter the house of his wisdom but rather leads you to the threshold of your mind. kahlil gibran (the prophet, 1923). ritu lakhtakia editorial | e5 mentoring through the instructional process the last hundred years have been witness to remarkable efforts by educationists to define and refine the processes involved in medical instruction and medical education. oman is at the forefront of this educational revolution.7 intense research has resulted in novel instructional and assessment methods that claim and exhibit focus and objectivity.8 student-centricity and student learning methods have become buzzwords in the classroom. team-based learning, comprehensively addressed in the current and previous issues of this journal, is illustrative of a brave new world where the science of medical education has provided solutions for ground realities.9–11 yet, there is a reluctance on the part of many to join this movement. factors like student numbers, lack of resources or simply the comfort of sticking to the ‘good old ways’ slow the transformation process. each golden hour in the classroom sets the stage, through these innovations, for a dynamic instructor-student interaction where factual knowledge is wrapped in unlimited opportunities for personality growth and confidence-building for the student mentees. there are now objective ways to grade educators’ quality of delivery in this arena.12 mentoring in patient care all medical graduates take the hippocratic oath and commit themselves to be teachers (latin docere [to teach] = doctor). in varying degrees they will all teach as physicians—their patients, healthcare support workers and the community. however, those who consciously adopt an academic career must live it: for every word and action in their professional practice will influence a young learner. the ‘generation gap’, on which every disappointment is heaped when students fail to respond, is merely a reflection of the older educator’s failure to present knowledge and experience in the right format and context. the failure to point out lapses in the mentee by using the excuse of populism, is a death blow to the rights of passage for a budding young physician. mentoring in patient care is merely to ‘walk the talk’ through self-example and selfcritique. the integration of arts courses into the study of medicine has by no means been relegated to the era of dinosaurs; top-ranked universities such as harvard, yale and weil-cornell consider the study of classical painting a valuable innovation to improve medical students’ observation and diagnostic skills.13 well-rounded teachers with varied extracurricular interests can transmit that joie de vivre to the student-physician that ultimately translates into better patient care. mentoring in the world of ‘publish or perish’ we all live with the trials and tribulations, and yes, the competitive environment of the limited resources and opportunities of our times. opting for an academic medical career comes with the challenge of proving one’s contribution to scientific knowledge through publications. these mustdo ‘rules of the game’ have compromised the amount of time that could be apportioned to the teaching and mentoring arenas in all their facets as outlined above. research and publications uplift individual and institutional rankings, job prospects and, indeed, are a cog in the wheel of scientific progress.14 however, it is a fact that a fair number of these writings do not even dent the advancement of science, beyond passing the reviewers’ and editors’ approval and inking the pages of high impact journals.15 publication quality is judged in the narrow, purist, scientific context while equally worthy paedagogic contributions to the humanities in medicine and educational advancement are ignored. professionals with academic potential and intent are lost to alternative medical careers when faced with the genie of snail-paced promotions heavily skewed towards research output. much more could be achieved if the research-based ranking of a medical scientist’s worth encompassed demonstrable mentoring of student research. this would provide real value by taking ‘scorers’ and creating ‘learners and thinkers’. time is of the essence a single factor is the bedrock of the academic medical professional’s life: time. it is a life choice where the clock has to stand still when fulfilling the requirements of love for teaching, passion for mentoring, skilful and compassionate patient care and laborious basic or translational research. it will the real medical teacher stand up and be counted? e6 | squ medical journal, february 2014, volume 14, issue 1 5. pagnin d, de queiroz v, de oliveira filho ma, gonzalez nv, salgado ae, cordeiro e oliveira b, et al. burnout and career choice motivation in medical students. med teach 2013; 35:388–94. 6. connor mp, bynoe ag, redfern n, pokora j, clarke j. developing senior doctors as mentors: a form of continuing professional development. report of an initiative to develop a network of senior doctors as mentors: 1994-99. med educ 2000; 34:747–53. 7. lakhtakia r. health professions education in oman: a contemporary perspective. sultan qaboos univ med j 2012; 12:406–10. 8. al-wardy nm. medical education units: history, functions, and organisation. sultan qaboos univ med j 2008; 8:149– 56. 9. ghorbani n, karbalay-doust s, noorafshan a. is a teambased learning approach to anatomy teaching superior compared to didactic lecturing? sultan qaboos univ med j 2014; 14:120–125. 10. inuwa im. perceptions and attitudes of first-year medical students on a modified team-based learning (tbl) strategy in anatomy. sultan qaboos univ med j 2012; 12:336–43. 11. masters k. student response to team-based learning and mixed gender teams in an undergraduate medical informatics course. sultan qaboos univ med j 2012; 12:344–51. 12. lamki n, marchand m. the medical educator teaching portfolio: its compilation and potential utility. sultan qaboos univ med j 2006; 6:7–12. 13. class helping future doctors learn the art of observation. from: http://news.yale.edu/2009/04/10/ cla ss -helping-f uture-do ctors -le ar n-ar t-ob s er v ation accessed: dec 2013. 14. reich es. the golden club. nature 2013;502:291–3. 15. schoenwolf gc. getting published well requires fulfilling editors’ and reviewers’ needs and desires. dev growth differ 2013. e-pub 10 oct. doi: 10.1111/dgd.12092. 16. obituary, professor christopher grant. sultan qaboos univ med j 2014; 14:12. would need extraordinary talent to excel in all these roles. there is a vital need for academic medical institutions to develop an organisational policy and perceptive leadership that recognises and accords credit to educationists who may lead the uninitiated through one or more of the many roles listed above. one might even go a step further and consider removing or penalising those who are negative role models. quod erat demonstrandum the obituary in this issue to prof. christopher grant, who walked tall among his peers and whose professional and human qualities left their mark on generations of omani surgeons, is an apt illustration of the magical legacy of mentoring.16 yeoman contributions to medical student development have a beneficial domino effect on the society. the dwindling entry into the life of academia from among today’s budding physicians demands action by inspiring role models who can recognise and motivate individuals with capability and commitment. mentorship should not be just the voluntary, evangelistic zeal of an individual but a quality characteristic for employment and annual evaluation. the exemplars who don the mantle of the medical teacher, in all its multidimensional capacity, must remember that they are entrusted with launching generations of young people empowered as life-givers—by inspiring, initiating and instructing them to be healers in every sense of the word. references 1. frei e, stamm m, buddeberg-fischer b. mentoring programs for medical students a review of the pubmed literature 2000-2008 bmc medical education 2010; 10:1– 14. 2. quillin rc, pritts ta, davis br, hanseman d, collins jm, athota kp, et al. surgeons underestimate their influence on medical students entering surgery. j surg res 2012; 177:201–6. 3. al-fouzan r, al-ajlan s, marwan y, al-saleh m. factors affecting future specialty choice among medical students in kuwait. med educ online 2012; 17:19587. from: http:// dx.doi.org/10.3402/meo.v17i0.19587 accessed oct 2013. 4. al-lamki l. stress in the medical profession and its roots in medical school. sultan qaboos university med j 2010; 10:156–9. a human tail is a benign congenital anomaly resulting in a vestigial lumbosacral dorsal cutaneous appendage which can be categorised as either a ‘true tail’ or a ‘pseudotail’ by clinical, radiological and histopathological examination.1,2 unlike a true tail, a pseudotail indicates possible underlying spinal dysraphism and accurate distinction between these two entities is vital as both management and outcomes can vary.1–3 true human tails are very rare, with fewer than 40 cases reported to date.4 this case report describes an otherwise healthy neonate who was born with a true human tail. case report a one-day-old male neonate was referred to the bharath hospital, kottayam, kerala, india, in 2014 with a cutaneous appendage arising from the lumbosacral region which had been present at birth. he was the second child born to non-consanguineous parents and his sibling was clinically normal. the neonate had been born by vaginal delivery and the mother had had no history of illness, radiation exposure or drug intake other than vitamin supplementation during the antenatal period. in addition, there was no history of congenital anomalies in any of the family members. apart from the appendage, the male newborn was otherwise healthy. on examination, the neonate was observed to have a 6.5 cm-long club-shaped soft tissue appendage arising and hanging down from the mid-sacral region, which was completely covered by skin and had no spontaneous movement [figure 1]. the mass of the appendage was fleshy but firm and was not translucent. during palpation of the mass, the neonate cried when the appendage was pressed and cried even more loudly when it was pricked with a pin. the anal muscle tone was normal and the neonate had active movement in both lower limbs. a detailed examination revealed no other associated anomalies. 1department of surgery, sultan qaboos university hospital, muscat, oman; 2department of surgery, bharath hospital, kottayam, kerala, india; 3department of general surgery, armed forces hospital, muscat, oman *corresponding author e-mail: kaniyampadikkal@yahoo.co.in ذيل بشري حقيقي يف طفل حديث الوالدة تسجيل حالة واستعراض لألدبيات العلمية ماهي�ص كري�ضنا بيالي و�ضميثا ثانكابان ناير abstract: a true human tail is a benign vestigial caudal cutaneous structure composed of adipose, connective tissue, muscle, vessels, nerves and mechanoreceptors. a true human tail can be distinguished from a pseudotail as the latter is commonly associated with underlying spinal dysraphism, which requires specialised management. true human tails are very rare, with fewer than 40 cases reported to date. we report a healthy one-day-old male new born who was referred to the bharath hospital, kottayam, kerala, india, in 2014 with a cutaneous appendage arising from the lumbosacral region. magnetic resonance imaging of the spine ruled out spinal dysraphism. the appendage was removed by simple surgical excision. clinicians should emphasise use of ‘true tail’ and ‘pseudotail’ as specific disparate terms as the clinical, radiological and histological findings of these conditions differ significantly, along with management strategies and outcomes. keywords: tail; newborn; magnetic resonance imaging; spinal dysraphism; case report; india. دم�ية واأوعية وع�ضل دهنية, واأن�ضجة �ضامة اأن�ضجة من تتك�ن حميدة, جلدية ذنبية اأثارية بنية احلقيقي الب�رسي الذيل يعد امللخ�ص: واأع�ضاب وم�ضتقبالت ميكانيكية. وميكن التفريق بني الذيل الب�رسي احلقيقي وغري احلقيقي باأن الذيل غري احلقيقي يرتبط عادة ب�ج�د خلل الرفاء ال�ض�كي امل�ضتبطن, الذي يتطلب معاجلة متخ�ض�ضة. ويعد وج�د ذنب ب�رسي حقيقي اأمرا نادرا, حيث اأن احلاالت امل�ضجلة عن وج�ده اإىل االآن اأقل من 40 حالة. ون�ضجل هنا حالة طفل �ضحيح حديث ال�الدة مت حت�يله اإىل م�ضت�ضفى باهراث بك�تيام يف كلريا بالهند يف عام 2014م ب�ضبب وج�د زائدة جلدية نا�ضئة من املنطقة القطنية العجزية. ومت ا�ضتبعاد وج�د خلل الرفاء ال�ض�كي عن طريق ت�ض�ير العم�د الفقري بالرنني املغنطي�ضي. ومتت اإزالة تلك الزائدة با�ضتئ�ضال جراحي ب�ضيط. ينبغي على املمار�ضني التفريق بني "الذيل احلقيقي" و"الذيل خمتلفة, وهي�ضت�ل�جية وا�ضعاعية �رسيرية خ�ا�ضا لهما اأن اإذ منف�ضلتني, وحالتني خمتلفني, م�ضطلحني واعتبارهما احلقيقي", غري ويتطلبان ا�ضرتاتيجيات عالجية خمتلفة, ويف�ضيان اإىل نتائج متباينة. الكلمات املفتاحية: ذيل؛ حديث ال�الدة؛ الت�ض�ير بالرنني املغناطي�ضي؛ خلل الرفاء ال�ض�كي؛ تقرير حالة؛ الهند. a true human tail in a neonate case report and literature review *mahesh k. pillai1,2 and smitha t. nair2,3 case report sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e109–111, epub. 30 mar 17 submitted 6 sep 16 revision req. 12 oct 16; revision recd. 17 oct16 accepted 25 oct 16 doi: 10.18295/squmj.2016.17.01.020 a true human tail in a neonate case report and literature review e110 | squ medical journal, february 2017, volume 17, issue 1 elements project outwards temporarily, before disappearing completely via apoptosis by the end of the eighth gestational week.2,5–9 according to lu et al., the presence of a human tail is an abnormality in embryonic development, rather than a regression in the evolutionary process.2 in mice and other vertebrates, the genes that control the development of tails are the wnt family member 3a (wnt3a) and caudal type homeobox 1 genes; the downregulation of the wnt3a gene has been observed to induce apoptosis of the tail cells in mice.10–13 therefore, it is possible that mutations resulting in increased upregulation of the wnt3a gene may result in retention of the embryonic tail in human newborns. however, further genetic research on this topic is necessary. the presence of cutaneous midline congenital lesions in the lumbosacral region—such as vascular naevi, tufts of hair, dermal sinuses, subcutaneous lipomas, deviated gluteal furrows or a human tail—may indicate the presence of occult spinal dysraphism.1 a congenital cutaneous appendix arising from the lumbosacral region is referred to as a human tail.14 on histopathological examination, human tails can be classified into either true tails or pseudotails.1,15 a true human tail is a distal skin-covered boneless midline protrusion which is a remnant of the embryonic tail, composed of a core of striated muscle, adipose and connective tissue and containing blood vessels, nerve fibres, ganglion cells and mechanoreceptors, such as pacinian corpuscles.4,15,16 true tails are commonly attached to the skin of the lumbosacral region; the skin which completely envelopes the mass is deficient in hair follicles and sweat and sebaceous glands.4,15,17 however, there is one case in the literature of a neonate born with a true tail which contained bone.18 true human tails are sometimes capable of spontaneous or reflexive motion, while voluntary contractmagnetic resonance imaging (mri) of the spine showed no evidence of spinal dysraphism, confirming the diagnosis of a true human tail [figures 2 and 3]. the tail was excised by making an elliptical incision at the base. the wound was examined to rule out any connections between the tail and deeper structures which might not have been evident on the mri scans. microscopy of the excised tail showed that the tissue was lined by a squamous epithelium containing adipose tissue, muscle bundles, blood vessels and nerve bundles. the postoperative period was uneventful. at a one-month follow-up, the wound had healed well and a neurological examination was normal. discussion in developing human embryos, a tail bud starts to develop during the fourth gestational week and grows unevenly for the next two weeks, extending and curling behind the hindgut.2,5–9 the proximal portion of the tail bud has 10–12 vertebrae, whereas the distal portion is composed of mesodermal elements without vertebrae. during the seventh and eighth gestational weeks, the proximal mesodermal elements retract into the soft tissue and the distal mesodermal figure 1: clinical photographs of a male newborn showing a cutaneous appendage arising from the sacral region from the (a) frontal and (b) side views. figure 3: a: sagittal t1-weighted magnetic resonance imaging (mri) scan of a male newborn showing the thickened filum terminale with fat intensity (arrow). axial (b) t1and (c) t2-weighted mri scans showing the origin of the appendage in the midline at the sacral level. figure 2: a–c: sagittal t2-weighted magnetic resonance imaging (mri) scans of a male newborn showing a pedunculated appendage (arrows) with fat intensity at the sacral region. d: sagittal t2-weighted mri scan showing the conus located at the level of the third lumbar vertebra (arrow). mahesh k. pillai and smitha t. nair case report | e111 ions are rare.15,19 true human tails are not inherited; however, a single report has been published in which three female generations within one family were born with true human tails.20 the incidence rate of true human tails is twice as high among males in comparison to females.15 unlike true tails, a pseudotail is a caudal protrusion composed of other normal and abnormal tissue such as bone, cartilage and remnants of notochord.3,15 during neurulation, non-fusion of the neural tube due to focal premature dysfunction can lead to the formation of a pseudotail.1 the non-fused neural tube exposes the paraxial mesoderm to the dorsal aspect of the neural ectoderm and induces the formation of fatty elements. this prevents neural tube fusion and the attachment of these fatty elements to the neural structures, which leads to a tethering cord and tethered cord syndrome.2 early untethering of the cord is essential to prevent the development of catastrophic neurological sequelae.9,14,21 the incidence of cutaneous lesions along the craniospinal axis in the general population is approximately 3% and the most common lesions are deep dimples.22 however, cutaneous signs are present in 76% of patients with occult spinal dysraphism, including tails, dermal sinuses, lumbar lipomas, port wine stains, deviated gluteal furrows, hypertrichosis, haemangiomas and hamartomas.1 lu et al. reviewed 59 patients with human tails and noted that 49% of cases had spinal dysraphism and 20% had tethered cords.2 conclusion the current case describes a neonate who was found to have a true human tail as evidenced by the absence of bony elements or underlying spinal dysraphism. it is very important that clinicians differentiate true tails from pseudotails as the latter entity is associated with underlying spinal lesions. accordingly, mri of the spine is crucial as it outlines the underlying pathology and helps in surgical planning. a true human tail is a benign condition and can be treated via simple surgical excision. references 1. guggisberg d, hadj-rabia s, viney c, bodemer c, brunelle f, zerah m, et al. skin markers of occult spinal dysraphism in children: a review of 54 cases. arch dermatol 2004; 140:1109–15. doi: 10.1001/archderm.140.9.1109. 2. lu fl, wang pj, teng rj, yau ki. the human tail. pediatr neurol 1998; 19:230–3. doi: 10.1016/s0887-8994(98)00046-0. 3. liaqat n, sandhu ai, khan fa, ehmed e, dar sh. child with a tail. apsp j case rep 2013; 4:42. doi: 10.21699/ajcr.v4i3.69. 4. shad j, biswas r. an infant with caudal appendage. bmj case rep 2012; 2012:bcr1120115160. doi: 10.1136/bcr.11.2011.5160. 5. ledley fd. evolution and the human tail: a case report. n engl j med 1982; 306:1212–15. doi: 10.1056/nejm198205203062006. 6. zimmer ez, bronshtein m. early sonographic findings suggestive of the human fetal tail. prenat diagn 1996; 16:360–2. doi: 10.1002/(sici)1097-0223(199604)16:4<360::aid-pd857> 3.0.co;2-u. 7. hughes af, freeman rb. comparative remarks on the development of the tail cord among higher vertebrates. j embryol exp morphol 1974; 32:355–63. 8. fallon jf, simandl bk. evidence of a role for cell death in the disappearance of the embryonic human tail. am j anat 1978; 152:111–29. doi: 10.1002/aja.1001520108. 9. cai c, shi o, shen c. surgical treatment of a patient with human tail and multiple abnormalities of the spinal cord and column. adv orthop 2011; 2011:153797. doi: 10.4061/2011/153797. 10. greco tl, takada s, newhouse mm, mcmahon ja, mcmahon ap, camper sa. analysis of the vestigial tail mutation demonstrates that wnt-3a gene dosage regulates mouse axial development. genes dev 1996; 10:313–24. doi: 10.1101/gad.10.3.313. 11. prinos p, joseph s, oh k, meyer bi, gruss p, lohnes d. multiple pathways governing cdx1 expression during murine development. dev biol 2001; 239:257–69. doi: 10.1006/dbio. 2001.0446. 12. schubert m, holland lz, stokes md, holland nd. three amphioxus wnt genes (amphiwnt3, amphiwnt5, and amphiwnt6) associated with the tail bud: the evolution of somitogenesis in chordates. dev biol 2001; 240:262–73. doi: 10.1006/dbio.2001.0460. 13. takada s, stark kl, shea mj, vassileva g, mcmahon ja, mcmahon ap. wnt-3a regulates somite and tailbud formation in the mouse embryo. genes dev 1994; 8:174–89. doi: 10.1101/ gad.8.2.174. 14. kumar d, kapoor a. human tail: nature’s aberration. jj child neurol 2012; 27:924–6. doi: 10.1177/0883073811428006. 15. dao ah, netsky mg. human tails and pseudotails. hum pathol 1984; 15:449–53. doi: 10.1016/s0046-8177(84)80079-9. 16. mukhopadhyay b, shukla rm, mukhopadhyay m, mandal kc, haldar p, benare a. spectrum of human tails: a report of six cases. j indian assoc pediatr surg 2012; 17:23–5. doi: 10.41 03/0971-9261.91082. 17. belzberg aj, myles st, trevenen cl. the human tail and spinal dysraphism. j pediatr surg; 26:1243–5. doi: 10.1016/0022-3468 (91)90343-r. 18. kabra ns, srinivasan g, udani rh. true tail in a neonate. indian pediatr 1999; 36:712–3. 19. lundberg gd, parsons rw. a case of a human tail. am j dis child 1962; 104:72–3. doi: 10.1001/archpedi.1962.020800300 74010. 20. standfast al. the human tail. n y state j med 1992; 92:116. 21. amirjamshidi a, abbassioun k, shirani bidabadi m. skincovered midline spinal anomalies: a report of four rare cases with a discussion on their genesis and milestones in surgical management. childs nerv syst 2006; 22:460–5. doi: 10.1007/ s00381-005-0014-2. 22. powell kr, cherry jd, hougen tj, blinderman ee, dunn mc. a prospective search for congenital dermal abnormalities of the craniospinal axis. j pediatr 1975; 87:744–50. doi: 10.1016/ s0022-3476(75)80298-8. https://doi.org/10.1001/archderm.140.9.1109 https://doi.org/10.1016/s0887-8994%2898%2900046-0 https://doi.org/10.21699/ajcr.v4i3.69 https://doi.org/10.1136/bcr.11.2011.5160 https://doi.org/10.1056/nejm198205203062006 https://doi.org/10.1002/%28sici%291097-0223%28199604%2916:4%3c360::aid-pd857%3e3.0.co%3b2-u https://doi.org/10.1002/%28sici%291097-0223%28199604%2916:4%3c360::aid-pd857%3e3.0.co%3b2-u https://doi.org/10.1002/aja.1001520108 https://doi.org/10.4061/2011/153797 https://doi.org/10.1101/gad.10.3.313 https://doi.org/10.1006/dbio.2001.0446 https://doi.org/10.1006/dbio.2001.0446 https://doi.org/10.1006/dbio.2001.0460 https://doi.org/10.1101/gad.8.2.174 https://doi.org/10.1101/gad.8.2.174 https://doi.org/10.1177/0883073811428006 https://doi.org/10.1016/s0046-8177%2884%2980079-9 https://doi.org/10.4103/0971-9261.91082 https://doi.org/10.4103/0971-9261.91082 https://doi.org/10.1016/0022-3468%2891%2990343-r https://doi.org/10.1016/0022-3468%2891%2990343-r https://doi.org/10.1001/archpedi.1962.02080030074010 https://doi.org/10.1001/archpedi.1962.02080030074010 https://doi.org/10.1007/s00381-005-0014-2 https://doi.org/10.1007/s00381-005-0014-2 https://doi.org/10.1016/s0022-3476%2875%2980298-8 https://doi.org/10.1016/s0022-3476%2875%2980298-8 sir, i write in response to the important editorial article of dr. al-lamki on that appeared in the february 2012 issue of squmj,1 as well as to the other pioneer study written by al-saadoon et al. on child maltreatment, published in the same issue.2 these cases of violence to children reported in oman, although few, add to other accumulating data on cases of child abuse and neglect. they reflect the statutory response to these problems bearing in mind that oman has still not established a child law. as a pragmatic compromise, an integrated child protection system should include the following basic elements: a legal framework to protect and prevent children from all forms of maltreatment; a proactive child protection agency with statutory powers to coordinate multi-sectoral policy and multi-agency work and to ensure presence of operating community-based protection mechanisms in both rural and urban areas; a coordinated service statutorily empowered and directed to act on and for violations of child protection rights, and a competent service empowered to monitor, inspect and take appropriate action on quality of practice in child protection service and provision. as stated in al-lamki’s article, it is true that oman cares a lot about children and gives them its full attention. since the convention on the rights of the child (crc) was signed in 1996, oman’s government has been working hard to demonstrate its commitment to the care and protection of children. however, the efficacy of such efforts has been questioned by a recent unicef report.3 the report stated that the expenditure on child rights has been huge, but the results remained unsatisfactory. in fact, little attention is being paid to the broad range of circumstances and experiences that constitute vulnerabilities and risks for children. furthermore, as the social and economic context changes over time, so new strands of vulnerability appear, or the emphasis shifts. accordingly, it is very important now to understand what children need to be protected from, and why and how children come to be in need of protection services. ultimately, vulnerability needs to be defined and analysed locally, because circumstances vary, as do local ideas of childhood. while a behaviour like abuse of children is never acceptable, the forms of abuse, how children become vulnerable and what places them at risk, vary.4 it is also noted that the omani child protection system understandably prioritises very young children as being in most need of protection due to their greater vulnerability. however this results in a lack of attention by society to the needs of older children (7–18 years), especially in big families; as a result, some of their developmental needs are remaining unmet. accordingly, there is an urgent need for oman's government to inform the general population why the crc defines a child as anyone under 18 years old rather than a lower age limit. in order to ensure compliance with article 4 of the crc, oman must adopt a child rights-based approach to policy development. in recognition that the child rights-based approach consists of a holistic package of requirements needed for the implementation of the crc, oman is confronted with the challenge of ensuring that its efforts should be accompanied by policy reforms, institutional development, effective co-ordination, data collection, training, dissemination and appropriate budgetary allocation. the budgetary allocation should be directed towards the key implementers and more priority concern should be given to the implementation of the crc, the children statute and relevant developments in the social sector which ensure sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 375-377, epub. 15th jul 12 submitted 15th apr 12 revision req. 22nd apr 12, revision recd. 29th apr 12 accepted 5th may رد على: حقوق الطفل ماذا نستطيع عمله يف عمان؟ re: child rights what can we do in oman? letter to editor re: child rights what can we do in oman? 376 | squ medical journal, august 2012, volume 12, issue 3 enjoyment of the rights by children. without such an approach, oman’s commitment to providing support for children will remain based on the conventional political formula that providing economic benefits to the family is generally sufficient to allow children to be raised in a supportive environment. the key measure oman has to take in relation to prevention of child abuse and neglect is the development of a national strategy or framework for protecting children. the strategy should set out the roles and responsibilities of different organisations involved in safeguarding and promoting the welfare of children and identify actions that can be taken to prevent and reduce child abuse and maltreatment. preventative interventions are described as either: primary, secondary, or tertiary interventions. primary or universal interventions are strategies that target whole communities in order to build public resources and attend to the factors that contribute to child maltreatment. the general media awareness campaigns represent an example of a primary intervention. these campaigns usually use television, radio and print material to educate the community in relation to the importance of a child’s early years and the need for a child to have a safe and secure home environment. other examples of primary interventions include the range of support and services provided through maternal and child health clinics, and the provision of high quality child care services. the strategy should focus on providing timely and universal support to all families (not just those deemed ‘at risk’), in line with articles 2 and 19 of the crc. where families are “at risk” for child maltreatment, secondary approaches, (e.g. early screening to detect children who are most “at risk”, home visiting, parent education, assertiveness training for “at risk” children, and targeted media campaigns in “at risk” communities) prioritise early intervention. these interventions aim to address the risk factors for child maltreatment. tertiary interventions (for example, therapeutic and specific rehabilitative services for abused children) operate once child maltreatment has occurred or is believed to have occurred, so they have been termed as “reactive approaches”. however, primary and secondary interventions have gained increasing attention as government and non-government bodies have recognised the importance of “proactive strategies”, which intervene before maltreatment occurs. to make these strategies a reality, there is a compelling need for oman to create an independent national children’s council (ncc) tasked with: establishing an integrated vision for child rights and strategic directions for evidence-based policy development; monitoring the extent to which omani children are enjoying their rights; promoting those rights; promoting children’s participation as full citizens in omani society, and closely monitoring the use of public services and facilities as regards family support and child protection. if an ncc is not established, then the omani crc follow-up committee should be adequately resourced to undertake these tasks. “vulnerable” children are typically at the highest risk of abuse, including children with disabilities, children in care, children with drug-related problems, those who are socially deprived and those who have already experienced abuse. children with special medical, developmental, or mental health needs should be placed in the least restrictive environment possible. this means that social workers must make every effort to provide the treatment services that children require while allowing them to remain in their normal family settings. treatment foster care, whereby specially trained foster parents provide active and structured treatment in the context of a family setting,5 was suggested as an appropriate placement for such children.6 prospective foster parents should be visited in advance of placement, and periodically afterwards, to check that they are in good health and in a position to take proper care of the child. if the child has problems adapting to a family, another foster family should be found.7 compared to traditional foster parents, treatment foster parents have been found to display more appropriate parenting behaviours toward such demanding children, including better monitoring, consistent discipline, and the use of appropriate positive reinforcement.8 sometimes, however, a child needs more intensive treatment or supervision than even treatment foster care can provide. under such circumstances, it may be necessary to place him or her in a congregate care setting, a non-family placement where a large number of children receive specialised care and/or treatment. emergency shelters are also considered a form of congregate care, but they do not provide any therapeutic services and are normally used when no other placement can be found.6 it is true that placing children in family settings removes a number of risks that are associated with group moeness moustafa alshishtawy letter to editor | 377 care.9 limiting children’s ability to develop lasting relationships with adults is an obvious disadvantage of living in congregate care facilities. also, the intense structure of group settings hinders normal adolescent development.6 despite this, congregate care is an important part of the foster care continuum because some children in foster care may express difficult behaviours due to the extreme physical and mental trauma they suffer as a result of abuse or neglect. when used appropriately, congregate care can provide the level of specialised service that these high-need children require.6 however, congregate care should never be considered a long-term placement for any child; rather, it should be used to deliver critical, time-limited therapeutic services while social workers plan for the child’s early reintegration into the family setting.10 consequently, the protection of children is a shared responsibility requiring the development of active and robust community partnerships. therefore, a national social advisory center should be established in oman to provide expert legal, medical and other advice to children and families with problems, as well as rehabilitation and counselling programmes for the victims and perpetrators of child abuse and neglect. in order to facilitate the programmes for children, the government should also give support to nongovernmental organisations (ngos) to operate in such fields as an adjunct to governmental programmes. both the government and ngos should expand their educational and legal aid programmes to cover all governorates, particularly to meet the needs of people at the grassroots where lack of knowledge and access combined with fear of litigation continue to deprive children of enjoyment of their rights and legal protection. moeness moustafa alshishtawy department of community medicine & public health, tanta university, egypt and department of health planning, ministry of health, muscat, oman. e-mail: drmoness@gmail.com references 1. al-lamki l. child rights: what can we do in oman? squ med j 2012; 12:1–4. 2. al-saadoon m, al-sharbati m, el nour i, al-said b. child maltreatment, types and effects: series of six cases from a university hospital in oman. squ med j 2012; 12:97–102. 3. muscat daily. oman needs to track spending on child rights: unicef, 17 may 2011. from: http://www.muscatdaily. com/archive/stories-files/oman-needs-to-track-spending-on-child-rights-unicef accessed: mar 2012. 4. west a. a child protection system in mongolia: review report. save the children (uk), ulaanbaatar, 2006. from: http://cfsc.trunky.net/_uploads/publications/2_a_child_protection_system.pdf accessed: mar 2012. 5. foster family-based treatment association. what is treatment foster care? (2004) from: http://www.ffta.org/ whatis.html accessed: mar 2012. 6. children’s rights. what works in child welfare reform: reducing reliance on congregate care in tennessee: executive summary, jul 2011. from: http://www.childrensrights.org/congregatecare accessed: mar 2012. 7. united nations, convention on the rights of the child. summary record of the 728th meeting, 28th session. geneva, sep 2001. from: http://www.unhchr.ch/tbs/doc.nsf/0/219275c560d0b03ec1256ae3004b0af8?opendocum ent accessed: mar 2012. 8. fischer pa, gunnar mr, chamberlain p, reid jb. preventive intervention for maltreated preschool children: impact on children’s behavior, neuroendocrine activity, and foster parent functioning. j am acad child adolesc psychiatry 2000; 39:1356–65. 9. lee br, bright cl, svoboda db, fakunmoju s, barth rp. outcomes of group care for youth: a review of comparative studies. res soc work pract 2011; 21:177–89. 10. child welfare league of america. position statement on residential services. washington, dc, 2005. from: http:// www.cwla.org/programs/groupcare/rgcpositionstatement.pdf accessed: mar 2012. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 485-492, epub. 20th nov 12 submitted 10th dec 11 revision req. 2nd apr 12, revision recd. 2nd may 12 accepted 5th jun 12 1oman medical college, sohar, oman; 2foundation program, oman medical college, muscat, oman *corresponding author e-mail: theming@omc.edu.om صعوبات املقارنة بني املفردات غري العلمية العامة واملصطلحات العلمية / الطبية يف اللغة اإلجنليزية كلغة ثانية لطالب الطب توما�ض هيمنج، �صوبها نانداجوبال امللخ�ص: الهدف: التعليم الطبي يتطلب ا�صتيعاب الطالب لكل من املفردات التقنية )العلمية / الطبية( وغري التقنية )العامة( على حد �صواء. وجدنا من خالل جتربتنا مع اللغة االإجنليزية كلغة ثانية اأن الطالب العرب يعانون عادة من م�صاكل يف فهم البيانات العلمية ب�صبب �صعف فهمهم للمفردات غري العلمية. تهدف هذه الدرا�صة لتحديد ما اإذا كان الطالب يجدون �صعوبة يف اللغة االإجنليزية كلغة ثانية مع املفردات العامة التي قد تعوق فهمهم للن�صو�ض العلمية / الطبية. الطريقة: قمنا بدرا�صة م�صحية بتوزيع ن�ض للغة االإجنليزية لطالب طب يف بلد عربي يف �صنوات التعليم االأ�صا�صي الذي ي�صبق التعليم الطبي. تتاألف الدرا�صة من عينة من االأ�صئلة التي ُتعطى يف اختبار القبول بكليات الطب بالواليات املتحدة االأمريكية. طلبنا من الطالب حتديد جميع الكلمات غري املعروفة يف الن�ض. النتائج: بداأ الطالب املذكورين الدرا�صات االأ�صا�صية التي ت�صبق الدرا�صة الطبية مع نق�ض جوهري يف املفردات الإجنليزية: وكان الطالب الذين يدر�صون اللغة االإجنليزية باملدار�ض الثانوية كلغة اأولية يعانون من نق�ض انتقائي يف امل�صطلحات العلمية / الطبية الذي اختفى مع مرور الوقت. بينما كان الطالب الذين يدر�صون باللغة العربية باملدار�ض الثانوية يجدون �صعوبة يف كال من املفردات العامة اإ�صافة اإىل املفردات العلمية / الطبية. لوحظ اأن تلك ال�صعوبات تت�صاءل مع الوقت، ولكنها ما تزال موجودة حتى بعد ثالث �صنوات من التعليم اجلامعي باللغة االإجنليزية. اخلال�صة: ب�صكل عام، عند تدري�ض املواد الفنية لطالب الطب غري الناطقني باالجنليزية، يتم الرتكيز على املفردات التقنية اخلا�صة باملو�صوع واملرتبطة بها. تلقي هذه الدرا�صة ال�صوء على اأن الطالب غري الناطقني باالإجنليزية يواجهون اأي�صا �صعوبات مع املفردات العامة امل�صتخدمة يف بناء عبارات ت�صتخدم الكلمات التقنية. وميكن ملثل هوؤالء الطالب اال�صتفادة من زيادة معرفة امل�صطلحات العامة. مفتاح الكلمات: التعليم الطبي، تعليم ما قبل الطب، ُلغة، اجنليزية، طالب الطب، التعليم، ُعمان. abstract: objectives: medical education requires student comprehension of both technical (scientific/ medical) and non-technical (general) vocabulary. our experience with “english as a second language” (esl) arab students suggested they often have problems comprehending scientific statements because of weaknesses in their understanding of non-scientific vocabulary. this study aimed to determine whether esl students have difficulties with general vocabulary that could hinder their understanding of scientific/medical texts. methods: a survey containing english text was given to esl students in the premedical years of an english-medium medical school in an arabic country. the survey consisted of sample questions from the medical college admission test (usa). students were instructed to identify all unknown words in the text. results: esl students commenced premedical studies with substantial deficiencies in english vocabulary. students from english-medium secondary schools had a selective deficiency in scientific/medical terminology which disappeared with time. students from arabicmedium secondary schools had equal difficulty with general and scientific/medical vocabulary. deficiencies in both areas diminished with time but remained even after three years of english-medium higher education. conclusion: typically, when teaching technical subjects to esl students, attention is focused on subject-unique vocabulary and associated modifiers. this study highlights that esl students also face difficulties with the general vocabulary used to construct statements employing technical words. such students would benefit from increases in general vocabulary knowledge. keywords: medical education; premedical education; language; english; medical students; teaching; oman. comparative difficulties with non-scientific general vocabulary and scientific/medical terminology in english as a second language (esl) medical students *thomas a. heming1 and shobha nandagopal2 clinical & basic research comparative difficulties with non-scientific general vocabulary and scientific/medical terminology in english as a second language (esl) medical students 486 | squ medical journal, november 2012, volume 12, issue 4 advances in knowledge “english as a second language” (esl) students commencing premedical studies had difficulties with english vocabulary, including both scientific/medical and general terms. the magnitude and persistence of these difficulties, specifically in general vocabulary, differed markedly between students from arabicmedium secondary schools versus those from english-medium secondary schools. difficulties with general vocabulary might hinder understanding of scientific/medical information for esl medical students, depending on the students’ prior exposure to english. application to patient care english is the de facto language of international medicine, and english proficiency is a prerequisite for success in undergraduate and postgraduate examinations. the ideal goal of english-medium medical schools in non-english-speaking countries is to produce graduates who are competent in english as well as the first language of their patients in order to support academic success, effective physician-patient communication, and for virtually all aspects of workplace professional communication in the country, as well as the in the globalised medical world. the present article suggests this is an achievable goal for arab esl medical students and discusses strategies to facilitate their english proficiency. there is a sizeable body of literature about the education of “english as a second language” (esl) students in health sciences;1–4 however, much of this information addresses esl students in english speaking countries. there is less information about the challenges faced by esl students studying health sciences in english in non-english speaking countries. these students may encounter english only during academic activities; consequently, they will have fewer opportunities to develop their english language skills. moreover, since clinical training in such environments involves interaction with nonenglish-speaking patients, it necessarily requires switching back and forth between english and the local language. this requirement emphasises the advantage for such students to become competent in english as well as the local language. oman medical college (omc) is a private medical school in oman, an arabic-speaking country. education at omc is conducted exclusively in english. omc’s curriculum includes a one-year foundation program, followed by a sixyear doctor of medicine (md) programme. the md programme consists of two years of premedical studies followed by four years of medical studies. students receive approximately 22 hours per week of english-language instruction in the foundation program. before advancing to the md programme, students must achieve a score approaching 500 on the externally-benchmarked “test of english as a foreign language” (toefl). students receive an additional 6 credit hours of english-language instruction during their premedical studies. success in medical studies requires an understanding of both technical (scientific/ medical) and non-technical (general) vocabulary. technical words are often perceived as harder to understand than non-technical words. however, our experience suggested that arab esl students often have difficulty comprehending scientific/ medical statements because of weaknesses in their understanding of general vocabulary. the present study aimed to determine if this is indeed the case. methods a survey was conducted at the beginning of the academic year, during regularly-scheduled classes, with students in years 2, 3 and 4 of the medical curriculum. in this way, students in year 2 had completed the foundation programme, students in year 3 had completed the first premedical year, and students in year 4 had completed the two premedical years. students were informed that the survey’s purpose was to obtain information about their english vocabulary skills. the survey was completed voluntarily and anonymously. it was approved by the institutional review board. the survey consisted of sample questions from the medical college admission test (mcat).5 the survey comprised approximately 2.5 pages of text. students were instructed to read the text and circle the words they did not know. the survey contained 310 different words, of which 87 were judged to be scientific/medical terms and 223 were general terms. a word was classified as a scientific/medical term if it met the following criteria: it was listed in dorland’s illustrated medical dictionary, or it had no meaning outside its scientific context.6 thomas a. heming and shobha nandagopal clinical and basic research | 487 students also provided the first two digits of their student identification number and the language of instruction at their secondary schools. the first two digits of the student number indicate the year of initial enrollment. this information allowed the responders to be classified as on-time (groups 1 and 2: students who had progressed along the expected timeline) or delayed (groups 3 and 4: students who were delayed because of unsatisfactory performance). students identified as advanced placement (who had been exempted from the one-year foundation programme) were excluded from the study. the tagged words (words identified as unknown) in completed surveys were compiled. data for delayed students from english-medium secondary school (group 4) were omitted from further analyses because the sample size was insufficient to provide meaningful information [table 1]. finally, the same survey was distributed to instructors of year 2–4 courses. the instructors were asked to identify the words they believed students did not know. in total, 10 faculty members (response rate = 45%) volunteered to participate. the tagged words (words predicted to be unknown to students) were compiled. statistical treatment of the data included oneway analysis of variance (anova). a p value of ≤0.05 was considered statistically significant. the data are shown as an arithmetic mean ± standard error of the mean (sem), unless stated otherwise. results table 1 shows the number of responding students by group. esl students in year 2 had substantial deficiencies in english vocabulary. the deficiency was particularly acute for students from arabicmedium secondary schools. figure 1a shows the number of different tagged words per student for on-time students (groups 1 and 2). in year 2, ontime students from arabic-medium secondary schools (group 1) tagged an average of 28.2 ± 1.4 (n = 71) different words per student. in contrast, on-time year 2 students from english-medium secondary schools (group 2) tagged less than half that number (12.8 ± 2.0, n = 20). the same trend was observed when the data were analysed to obtain the total number of different tagged words. however, a comparison of the total number of different tagged words between groups is complicated by differences in the number of students in each group. for example, if each student tagged only one word but tagged a different word than classmates, the total number of different tagged words would reflect group size and not student vocabulary skills. to reduce this bias, the data were analysed to obtain the total number of different words tagged by more than one student. these data [figure 1b] show that group 1 tagged approximately twice as many words as did group 2. there was a dramatic improvement in vocabulary skills as students advanced through the curriculum [figure 1]. for group 1, there was an 85% reduction in the incidence of tagged words between years 2 and 4. likewise for group 1, there was a 71% reduction in the total number of words tagged by more than one student between years 2 and 4. the vocabulary skills of group 2 also improved with time. by year 4, group 2 knew every word in the survey. figure 1c shows the distribution of tagged words between science and general vocabulary for on-time students. group 1 had difficulty with both science and general vocabulary. the vocabulary skills of group 1 improved with time, but the number of tagged words in any specific year was almost equally split between science and general terms. in contrast, group 2 students began premedical studies with a table 1: characteristics of student responders (number of students per group) group curriculum year year 2 year 3 year 4 group 1 on-time students from arabic-medium secondary schools 71 61 39 group 2 on-time students from english-medium secondary schools 20 24 15 group 3 delayed students from arabic-medium secondary schools 4 5 19 group 4 delayed students from english-medium secondary schools 1 1 3 total number of student responders (response rate) 96 (94%) 91 (89%) 76 (86%) comparative difficulties with non-scientific general vocabulary and scientific/medical terminology in english as a second language (esl) medical students 488 | squ medical journal, november 2012, volume 12, issue 4 selective deficiency in science vocabulary but little difficulty with general vocabulary. the deficiency in science vocabulary for group 2 disappeared incrementally with time. to examine the retention of vocabulary skills from foundation to advanced level, the tagged words were compared with the foundation course’s academic word list.7 of the 310 different words in the survey, 38 were on the academic word list. figure 2 shows the number of foundation words tagged by more than one student. group 1 tagged a substantial number of foundation words in each year. in contrast, group 2 students tagged a small number of foundation words in year 2 and, thereafter, knew every foundation word in the survey. another analytical approach evaluated the persistence of specific vocabulary deficiencies by determining the total number of different words that were tagged by students across academic years. in other words, it identified the specific words that table 2: ability of faculty to predict vocabulary difficulties of group 1 students (on-time students from arabicmedium secondary schools) number of different words unknown to students in only one year unknown to students in any two years unknown to students in all three years general terms (n = 32 words) science terms (n = 32 words) general terms (n = 21 words) science terms (n = 17 words) general terms (n = 17 words) science terms (n = 19 words) number of matching words, predicted by faculty to be unknown to students 9 12 13 12 13 15 accuracy of faculty prediction 28% 38% 62% 71% 76% 79% n u m b er o f d iff er en t ta g g ed w or d s p er s tu d en t 35 30 25 20 15 10 5 0 year 2 year 3 year 4 group 1 group 2 * * * a n u m b er o f d iff er en t w or d s ta g g ed b y m or e th an o n e st u d en t 100 180 60 40 20 0 120 year 2 year 3 year 4 group 1 group 2 b n um be r of d iff er en t w or ds t ag ge d by m or e th an o ne s tu de nt 60 50 40 20 30 10 0 year 2 year 3 year 4 grp 1 general vocab grp 2 general vocab grp 1 science vocab grp 2 science vocab c figures 1: vocabulary difficulties of on-time students from arabic-language secondary schools (group 1) or englishlanguage secondary schools (group 2). (a) average number of different words per student identified as unknown. mean values ±sem (see table 1 for sample sizes). (b) total number of different words identified as unknown by more than one student. (c) specific difficulties with general and scientific/medical vocabulary. * = significant difference between groups (p <0.05); sem = standard error of the mean. thomas a. heming and shobha nandagopal clinical and basic research | 489 were tagged in more than one year. the analysis was confined to group 1. the data [figure 3] emphasise that group 1 had substantial deficiencies in general vocabulary, similar to their deficiencies in scientific/ medical terminology. delayed students had greater difficulty with the text than did on-time students. this can be seen by comparing the incidence of unknown words for group 3 with group 1 after taking into account the additional time that delayed students had spent in higher education [figure 4]. this adjustment was necessary because delayed students had repeated an academic year. where there was overlap between the two data sets, group 3 tagged about twice as many words as did group 1. instructors were aware of student difficulties with vocabulary. the faculty predicted 60–80% of the “persistently-tagged” words, (i.e. words tagged by group 1 in more than one year [table 2]). this applied to both general and scientific/medical vocabulary. discussion on entry to premedical studies, esl students in this study exhibited considerable deficiencies in both general and scientific/medical vocabulary. their vocabulary skills improved with time; however, for some students, the deficiencies remained even after three years of higher education. the students with poorer performance had attended arabicmedium secondary schools. our past experience indicates that many of these students are effectively monolingual (arabic only) on entry to higher education. these students had poor retention of vocabulary from foundation studies to more advanced years. they commenced their premedical courses with sizable deficiencies in general and science vocabulary, which did not disappear over the subsequent two premedical years. not surprisingly, they constituted the bulk of students whose academic progression was delayed due to unsatisfactory performance. in contrast, esl students from englishmedium secondary schools fared much better. they demonstrated good retention of foundation vocabulary. they commenced premedical studies with a deficiency in science terminology, but relatively good knowledge of general vocabulary. for these students, vocabulary deficiencies disappeared during their premedical studies. few were delayed in their academic progression. our past experience indicates that these students are, to some degree, competent in multiple languages (arabic and/or another language, as well as english) on entry to medical school. n um be r of d iff er en t fo un da tio n w or ds t ag ge d as u nk no w n 20 18 16 14 12 10 8 6 2 4 0 year 2 year 3 year 4 group 1 group 2 figure 2: retention of vocabulary knowledge from foundation to more advanced levels. n u m b er o f d iff er en t ta g g ed w or d s 35 30 25 20 15 10 5 0 tagged 2 yrs tagged 3 yrstagged 1 yr general vocab science vocab figure 3: persistence of specific vocabulary difficulties for group 1. number of specific words tagged as unknown by one or more students in only one year, in any two years, or in all three years. figure 4: comparison of vocabulary difficulties for ontime (group 1) and delayed (group 3) students. mean values ± sem (see table 1 for sample sizes). * = significant difference between groups (p <0.05); sem = standard error of the mean. comparative difficulties with non-scientific general vocabulary and scientific/medical terminology in english as a second language (esl) medical students 490 | squ medical journal, november 2012, volume 12, issue 4 past studies of second language acquisition have proposed two dimensions to language proficiency: basic interpersonal communication skills (bics) and cognitive academic language proficiency (calp).8–10 bics are the language skills involved in the development of conversational fluency, whereas calp describes the use of language in decontextualised academic situations. it takes learners about 2 years of immersion in a second language to achieve conversational fluency but significantly longer, perhaps 5–7 years, to achieve academic linguistic proficiency to the level of peers who are native speakers.8–10 a number of factors probably explain the difficulty with general vocabulary exhibited by some arab esl students. it seems obvious that esl students with limited exposure to secondary school english would have poorer vocabulary skills than students from english-medium secondary school. basically, the students are at different stages in bics/calp development. a more subtle influence relates to the inherent interest in esl. arabic is the principal language of instruction at public schools in oman. in order to obtain a secondary education conducted in english, one must attend a private school which entails a financial burden. thus, one can assume that esl students from englishlanguage secondary schools had a family interest in english fluency that was acted upon years before medical school enrollment. it is possible for esl students in a non-englishspeaking country to function in an effective monolingual environment using the local language or a mixed-language (local language/english) environment. the authors’ impression is that many arab esl students with poor english skills function in a largely monolingual-arabic environment. these students have minimal interactions with english-speaking peers and little exposure to english outside their studies. as a result, they have minimal opportunity to develop bics during casual interactions with peers. this effectively negates the distinction between bics and calp. for these students, all second language acquisition (both general and scientific vocabulary) is part of the development of their “medical english” calp. on the other hand, in our experience, arab esl students with good english skills function in a mixed arabic-english environment. they practice and expand their bics during non-academic interactions with english-speaking peers. this allows them to focus in their studies on adding scientific/medical terms to their calp. a number of strategies could facilitate the development of english proficiency in arab esl students, including increased exposure to english, fostering interest in becoming competent in english, and providing increased opportunities for interactions with english-speaking peers. as noted previously, esl students benefit from using english outside their classroom activities.11 it also follows that a diverse student population with englishspeaking peers is beneficial. for example, european esl students prefer informal, interactive learning methods (e.g. direct contact with english-speaking peers) over theory-oriented, classroom-based methods of second language acquisition.12 further, since proficiency in a second language develops incrementally over years, it is important that esl students remain in the curriculum long enough to develop their calp.8–10 thus, it would be beneficial to adopt pedagogic approaches during the early curriculum years that are specifically designed to support students with underdeveloped english proficiency. such methods could include linguist/ cultural adaptation of examination questions, providing extra time during examinations, and using teaching methods that address the unique difficulties that arab esl students face in reading english text.13–16 these “crutches” could be discarded incrementally in later curriculum years as students improve their english proficiency. given that faculty understand the students’ vocabulary deficiencies, faculty input would be valuable to determine how much support to give students entering medical school and how quickly students could be weaned from that support. it also is important to foster students’ interest in becoming competent in english, which involves a degree of acculturation with english. englishlanguage acculturation is a reliable predictor of academic performance for esl students.17 if nothing else, students should recognise the utility of english competence in an increasinglyglobalised healthcare environment. this could be accomplished by exposing students to bilingual arabic-english faculty and clinicians as role models. finally, it cannot be forgotten that learning is driven by testing. undoubtedly, esl students will attach increased importance to english skills if they are thomas a. heming and shobha nandagopal clinical and basic research | 491 assessed for english proficiency in their science and clinical courses. previous work has suggested that during the process of learning one language the learner acquires a set of metalinguistic skills and knowledge that are utilised when learning a second language.8–10 this is the theoretical basis of the common underlying proficiency (cup) model of second language acquisition.8,10 according to this model, there is enough cognitive overlap between a person’s first and second languages that enhancing the firstlanguage proficiency of an esl student will benefit the student’s acquisition of english. indeed, there is evidence of cognitive crosstalk across linguistic boundaries in arab esl medical students.18 thus, instruction in arabic communication skills is another strategy for enhancing english proficiency in arab esl students. as a bonus, instruction in arabic communication skills will enhance the ability of students to communicate with arab patients.19 esl students who were delayed in their academic advancement had poorer vocabulary skills than did on-time peers. other studies with arab esl medical students have found a similar correlation between english proficiency and student performance.20,21 still, the present data are not sufficient to determine a cause-and-effect relationship, i.e., whether poor academic performance was due to weak vocabulary skills or merely that vocabulary skills and academic performance were indirectly related to each other via another factor (e.g., inadequate study skills). nonetheless, for delayed students, the difficulty with general vocabulary was an additional challenge to academic success. thus, it would be helpful to provide additional english instruction to esl students who perform poorly in preclinical/clinical courses. conclusion english is the de facto language of international medicine. fluency in english is necessary for access to an array of medical/scientific information and for success in many postgraduate medical examinations. however, english is not the first language of most of the world’s population. the implication for english-language medical schools, whose graduates will treat non-english-speaking patients, is that graduates should be competent in both the first language of patients and english. the present data suggest this is an achievable goal for arab esl students. by the end of premedical studies, students from english-language secondary schools had no difficulties with the survey text. students from arabic-language secondary schools had difficulties with both general and scientific/medical vocabulary. nonetheless, they showed incremental improvements during premedical studies. such students would benefit from more time and support, as well as further coaching in academic study skills (e.g. help in paraphrasing to avoid plagiarism), to develop their english proficiency. references 1. choi ll. literature review: issues surrounding education of english-as-a-second language (esl) nursing students. j transcult nurs 2005; 16:263–8. 2. scheele th, pruitt r, johnson a, xu y. what do we know about educating asian esl nursing students? a literature review. nurs educ perspect 2011; 32:244–9. 3. mohanna k. supporting learners who are studying or training using a second language: preventing problems and maximizing potential. ann acad med singapore 2008; 37:1034–7. 4. shaw gp, molnar d. non-native english language speakers benefit most from the use of lecture capture in medical school. biochem mol biol educ 2011; 39:416–20. 5. kaplan, inc. mcat® practice tests, 6th ed. new york: kaplan publishing, 2007. 6. dorland’s illustrated medical dictionary, 30th ed. philadelphia: w.b. saunders, 2003. 7. coxhead a. a new academic word list. tesol quart 2000; 34:213–38. 8. cummins j. bilingual education and special education: issues in assessment and pedagogy. san diego: college-hill press, 1984. 9. cummins j. the acquisition of english as a second language. in: pritchard k, spangenberg-urbschat k, eds. kids come in all languages. newark, delaware: international reading association, 1994. pp. 36–62. 10. cummins j. language, power and pedagogy: bilingual children in the crossfire. clevedon, england: multilingual matters, 2000. 11. hays rb, pearse p, cooper cw, sanderson l. language background and communication skills of medical students. ethn health 1996; 1:383–8. 12. sumskas l, czabanowski k, bruneviciūte r, kregzdyte r, krikstaponyte z, ziomkiewicz a. specialist english as a foreign language for european public health: evaluation of competencies and needs comparative difficulties with non-scientific general vocabulary and scientific/medical terminology in english as a second language (esl) medical students 492 | squ medical journal, november 2012, volume 12, issue 4 among polish and lithuanian students. medicina (kaunas) 2010; 46:51–60. 13. bosher s, bowles m. the effects of linguistic modification on esl students’ comprehension of nursing course test items. nurs educ perspect 2008; 29:165–72. 14. lujan j. linguistic and cultural adaptation needs of mexican american nursing students related to multiple-choice tests. j nurs educ 2008; 47:327–30. 15. klisch ml. guidelines for reducing bias in nursing examinations. nurse educ 1994; 19:35–9. 16. fender m. spelling knowledge and reading development: insights from arab esl learners. reading in foreign lang 2008; 20:19–42. 17. salmonson y, everett b, koch j, andrew s, davidson pm. english-language acculturation predicts academic performance in nursing students who speak english as a second language. res nurs health 2008; 31:86–94. 18. ypinazar va, margolis sa. western medical ethics taught to junior medical students can cross cultural and linguistic boundaries. bmc med ethics 2004; 30:5. 19. mirza dm, hashim mj. communication skills training in english alone can leave arab medical students unconfident with patient communication in their native language. educ health (abingdon) 2010; 23:450. 20. mpofu dj, lanphear j, stewart t, das m, ridding p, dunn e. facility with the english language and problem-based learning group interaction: findings from an arabic setting. med educ 1998; 32:479–85. 21. ahmed b, ahmed lb, al-jouhari mm. factors determining the performance of medical students of the faculty of medicine, university of kuwait. med educ 2009; 22:506–8. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e306-318, epub. 24th jul 14 submitted 18th jan 14 revisions req. 19th feb & 24th mar 14; revisions recd. 10th & 26th mar 14 accepted 3rd apr 14 تشخيص وفحص وعالج العواقب السلبية لعمليات نقل الدم املبادئ التوجيهية اجملمع عليها لعمان اأروى الرياميه، �شربيه الها�شميه، زينب العرمييه، لوي�س واد�شورث، عبد احلكيم الروا�س، مرت�شى اخلابوري، �شاهينا دار abstract: the recognition and management of transfusion reactions (trs) are critical to ensure patient safety during and after a blood transfusion. transfusion reactions are classified into acute transfusion reactions (atrs) or delayed transfusion reactions, and each category includes different subtypes. different atrs share common signs and symptoms which can make categorisation difficult at the beginning of the reaction. moreover, trs are often under-recognised and under-reported. to ensure uniform practice and safety, it is necessary to implement a national haemovigilance system and a set of national guidelines establishing policies for blood transfusion and for the detection and management of trs. in oman, there are currently no local tr guidelines to guide physicians and hospital blood banks. this paper summarises the available literature and provides consensus guidelines to be used in the recognition, management and reporting of atrs. keywords: blood transfusion; blood safety; transfusion reactions; health planning guidelines; oman. امللخ�ص: إن لتشخيص وفحص وعالج العواقب السلبية لعمليات نقل الدم دورا حامسا يف احلفاظ على سالمة املريض يف أثناء عملية نقل الدم وبعدها. تقسم العواقب السلبية لنقل الدم إىل نوعني: نوع مبكر وأخر متأخر، ولكل نوع منهما أنواع فرعية خمتلفة. وتشرتك العواقب السلبية يف بعض األعراض مما قد جيعل تصنيفها عسريا عند بداية ظهورها. باإلضافة لذلك فان من الغالب عدم التعرف عليها واإلبالغ عنها بالصورة املطلوبة. ويف سبيل ارساء قواعد ممارسة آمنة وموحدة لعمليات نقل الدم فانه من الضروري تطبيق نظام وطين للمراقبة والتيقظ يف املستشفيات وبنوك الدم، ووضع مبادئ توجيهية جممع عليها لسياسات نقل الدم والكشف عن األعراض السلبية اليت قد تنتج عنها وطرق معاجلتها. وال يتواجد يف الوقت احلايل يف عمان قواعد ممارسة حملية يف هذا اجملال إلرشاد األطباء واملستشفيات وبنوك الدم. تلخص هذه الورقة األدبيات العلمية والطبية املنشورة يف هذا اجلانب، وتقرتح جمموعة من املبادئ التوجيهية اجملمع عليها لتستخدم يف متييز العواقب السلبية لنقل الدم وفحصها وعالجها واإلبالغ عنها. مفتاح الكلمات: نقل الدم؛ سالمة الدم؛ ردود فعل نقل الدم؛ املبادئ التوجيهية للتخطيط الصحي؛ عمان. recognition, investigation and management of acute transfusion reactions consensus guidelines for oman *arwa z. al-riyami,1 sabria al-hashmi,2 zainab al-arimi,3 louis d. wadsworth,4 abdulhakim al-rawas,5 murtadha al-khabori,1 shahina daar6 departments of 1haematology and 5child health, sultan qaboos university hospital, muscat, oman; 2department of haematology & blood transfusion, royal hospital, muscat, oman; 3directorate of blood services, ministry of health, muscat, oman; 4centre for blood research, university of british columbia, vancouver, british columbia, canada; 6department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: arwa.alriyami@gmail.com a key aspect of patient safety during blood transfusions is to ensure that patients are monitored by staff trained in transfusion medicine and the recognition and management of transfusion reactions (trs). each organisation should have a local transfusion programme and guidelines for the administration of blood components and for reporting trs. the true incidence of trs is uncertain due to the wide variation in reporting rates.1 reports from the serious hazard of transfusion (shot) haemovigilance scheme in the uk suggest an incidence of serious trs of 14/100,000 components transfused.2 transfusion in oman takes place at the secondary and tertiary healthcare settings. blood is collected and prepared in the central blood bank and the hospitals. pre-storage leukoreduction has not yet been universally implemented, although some institutions have introduced pre-storage and bedside leukoreduction. the lack of universal leukoreduction can result in an increased risk of a febrile non-haemolytic transfusion reaction (fnhtr), human leukocyte antigen (hla) alloimmunisation, platelet refractoriness and possibly transfusion-related acute lung injury (trali).3 a uniform tr reporting form was implemented in 2007 in oman. however, there are no national guidelines, and the incidence of serious trs remains unknown. this article aims to provide a guide on the diagnosis, investigation, management and reporting of acute transfusion reactions (atrs). these guidelines were produced by a working group of experts from four different institutions, including two haematopathologists, one pediatric haematologist, special contribution arwa z. al-riyami, sabria al-hashmi, zainab al-arimi, louis d. wadsworth, abdulhakim al-rawas, murtadha al-khabori and shahina daar special contribution | e307 from hospital, should also be instructed to report any symptoms that develop within the following 24-hour period of completion of the transfusion.4,5 different atrs share common manifestations [table 2], and some features can be obscured by the patient’s underlying condition or treatment. for example, fever is common in atrs, but can represent febrile neutropaenia in a patient receiving chemotherapy. scant data exist regarding the frequency of trs in children, which may reflect the under-recognition or under-reporting of these reactions.6 some researchers have observed increased adverse reactions in children over two years of age, who presented with allergic reactions more frequently than adults, while fnhtrs were more common in children aged 1–2 years.7,8 it is necessary to monitor the patients closely and to treat any manifestations (e.g. skin rashes, tachycardia, tachypnoea and irritability) that develop during a transfusion as an alert to a potential tr. initial clinical assessment and management the main aim of the initial clinical assessment of atrs is to identify patients with serious or life-threatening atrs so as to provide timely and appropriate management. the management of atrs should be guided by the manifestation and severity of the reaction, and be based on the most probable reaction subtype.1 the first step to approaching any atr is to stop the transfusion. the venous access needs to be maintained with normal saline while the patient is being assessed. the patient’s airway, breathing and circulation (abc) need to be assessed next. if dyspnoea is present, the patient’s airway patency needs to be ensured and high-flow oxygen should be started. if the patient is wheezing without an upper airway obstruction being present, a physician should be informed immediately and the patient needs to be given a short-acting beta-2 agonist (e.g. salbutamol). if the patient is hypotensive, they should be positioned in a recumbent position with their legs elevated. the patient’s details on their identity band should then be verified to ensure that they correspond exactly with those on the blood component compatibility label. finally, the unit undergoing transfusion needs to be examined for its colour and for the presence of any unusual clumps, particulate matter or discolouration suggestive of bacterial contamination. after these steps have been undertaken, an initial assessment is made. the save acronym summarises these common steps taken in the three adult haematologists, and an external reviewer with expertise in the field of transfusion medicine. available literature and international guidelines on atrs were reviewed and summarised. these guidelines were then customised to the local processes and to the therapeutic options available in oman, including available laboratory investigations and medications. classification of transfusion reactions the general classification of trs is based on the time between the transfusion and the onset of the reaction. the uk shot group has defined two types of trs— atrs and delayed transfusion reactions (dtrs).1 atrs occur within 24 hours of the commencement of the transfusion while dtrs occur afterwards. trs have various subtypes and further classification is based on the manifestations and the results of the investigations of the reaction. table 1 describes the general classification and subtypes of trs. atrs will be reviewed in detail in these guidelines. recognition of transfusion reactions it is critical to monitor patients throughout a transfusion episode. the recognition of trs may be improved by asking patients to report any signs and symptoms if these develop during the transfusion. as atrs can present just hours after completing a transfusion, all patients, including those discharged table 1: classifications and subtypes of transfusion reactions acute delayed febrile non-haemolytic transfusion reactions delayed haemolytic transfusion reactions acute haemolytic transfusion reactions post-transfusion purpura minor allergic reactions transfusion-associated graft versus host disease anaphylactic reactions alloimmunisation septic reactions (bacterial contamination) transfusion-transmitted infections hypotensive reactions* immunomodulation transfusion-related acute lung injury transfusion-associated circulatory overload transfusion-associated dyspnoea* *diagnosis of exclusion. recognition, investigation and management of acute transfusion reactions consensus guidelines for oman e308 | squ medical journal, august 2014, volume 14, issue 3 initial assessment and management of any tr [figure 1]. subsequent decisions follow based on the severity of the atr. it is very important to determine the severity of the reaction upon its onset in order to call for immediate medical help. in addition, any suspicion of abo blood group incompatibility or bacterial contamination upon visual assessment of the unit or by the patient’s symptoms and manifestations should prompt an immediate call to the hospital blood bank. this step is undertaken so as to quarantine and possibly recall related components that may pose a risk to other recipients. once initial measures have been undertaken, additional therapies may be given and a decision needs to be made on whether to resume or discontinue the transfusion. patients with mild febrile and allergic reactions, with no or limited changes in their vital signs and who are lacking other clinical symptoms, can have their transfusion resumed at a slower rate and under direct observation. however, if symptoms recur, the transfusion must be discontinued. transfusions should not be resumed in patients with other types of atr. subsequent management depends on the patient’s signs and symptoms. all trs must be reported to the hospital blood bank regardless of the severity. a tr form should be completed and sent to the blood bank along with the implicated unit and post-transfusion samples. units that were transfused within 24 hours prior to table 2: signs and symptoms of acute transfusion reactions sign/symptom type of reaction comments fever* fnhtr, ahtr, trali (with respiratory symptoms) or a septic reaction (bacterial contamination). this could also be unrelated to the blood transfusion. can coexist with other symptoms such as chills, rigors, myalgia, nausea or vomiting, dyspnoea, hypotension (≥30 mmhg below the baseline) and tachycardia (heart rate of >40 bpm above the baseline).8 urticaria, hives or pruritus allergic tr or anaphylaxis. can be mild and localised or more severe with generalised urticaria. angioedema allergic tr or anaphylaxis. may be preceded by a tingling sensation around the face and lips. dyspnoea or hypoxia trali, taco, tad or a severe allergic tr. severe dyspnoea without shock may occur in trali or taco. tad is a diagnosis of exclusion. therefore patients should be assessed for other causes of dyspnoea before making this diagnosis. stridor or bronchospasms allergic tr/anaphylaxis or taco. pulmonary oedema taco or trali. hypotension† ahtr, severe allergic tr, anaphylaxis, septic reaction (bacterial contamination), trali, taco, tad or a hypotensive reaction (bradykinin-mediated hypotension). this could also be unrelated to the transfusion. isolated hypotensive reactions are a diagnosis of exclusion and occur within an hour of transfusion, in the absence of allergic or anaphylactic symptoms. these reactions usually require no or only minor interventions.1 patients on ace inhibitors are at risk. the risk is higher with bedside leukofiltration. pain fnhtr (generalised aches), ahtr (pain at the infusion site, abdomen, chest or loins) or an anaphylactic reaction (chest pain). severe anxiety or feelings of impending doom ahtr or a septic reaction (bacterial contamination). mild anxiety is common in patients undergoing transfusions, especially for the first time. however, patients should be assessed for any trs if anxiety develops. acute onset of bleeding dic can be associated with ahtr or a septic reaction (bacterial contamination). fnhtr = febrile non-haemolytic transfusion reaction; ahtr = acute haemolytic transfusion reaction; trali = transfusion-related acute lung injury; tr = transfusion reaction; taco = transfusion-associated circulatory overload; tad = transfusion-associated dyspnoea; dic = disseminated intravascular coagulation. *defined as a temperature of ≥38 °c and a rise of 1–2 °c from the baseline;1 †defined as a drop in systolic and/or diastolic blood pressure by >30 mmhg and a systolic blood pressure of ≤80 mm.1 arwa z. al-riyami, sabria al-hashmi, zainab al-arimi, louis d. wadsworth, abdulhakim al-rawas, murtadha al-khabori and shahina daar special contribution | e309 fnhtrs are characterised by an oral temperature ≥38 °c and a rise of ≥1 °c from the baseline without systemic symptoms. on the other hand, moderate/ severe reactions are defined by an oral temperature ≥39 °c or a rise of ≥2 °c from the baseline and/or any rise in temperature accompanied with systemic signs or symptoms (e.g. chills, rigors, myalgia, nausea or vomiting). if the patient has anxiety, tachycardia, dyspnoea, back/chest pain, haemoglobinuria, oliguria or bleeding from the intravenous (iv) site, other differential diagnoses should be considered, including bacterial contamination, an acute haemolytic transfusion reaction (ahtr) and trali. management classic fnhtrs are transient, resolving with symptomatic intervention including the administration of antipyretics (such as paracetamol/ acetaminophen) or non-steroidal anti-inflammatory the reaction can be associated with the reaction, and should be retained if possible and sent to the blood bank. if there is suspicion of a septic reaction, bacterial cultures should be requested. figure 1 summarises the steps to be undertaken in the event of an atr and table 3 details the steps to be undertaken after the initial assessment is performed. subtypes of acute transfusion reactions f e b r i l e n o n-h a e m o ly t i c t r a n s f u s i o n r e a c t i o n s fnhtrs result from the patient’s reaction to donor white blood cells or to biological response modifiers in the component.9 pre-storage leukoreduction reduces the rate of fnhtrs.10 patients may present with either mild, moderate or severe reactions.1,11 mild figure 1: approach to acute transfusion reactions. abc = airway, breathing and circulation; bp = blood pressure; trali = transfusion-related acute lung injury; taco = transfusion-associated circulatory overload; tad = transfusion-associated dyspnoea; tr = transfusion reaction; edta = ethylene-diamine-tetra-acetic acid. recognition, investigation and management of acute transfusion reactions consensus guidelines for oman e310 | squ medical journal, august 2014, volume 14, issue 3 drugs (nsaids). pethidine may be effective for patients with severe rigors. if the fnhtr is mild, the transfusion can be resumed after management and under direct observation of the patient.1,12 the tr needs to be reported to the blood bank, but post-transfusion samples and the implicated unit do not need to be sent. if the symptoms recur after restarting the transfusion in a mild fnhtr, or if the fnhtr is moderate to severe, the transfusion has to be discontinued. the tr must be reported to the blood bank by sending the tr reporting form along with the post-transfusion samples and the implicated unit(s). prevention patients with significant and recurrent fnhtrs may benefit from oral paracetamol (acetaminophen) given one hour prior to subsequent transfusions.1 however, there is no firm evidence supporting this practice. if the fever persists despite premedication, leukoreduced red blood cells (rbcs) should be considered for future transfusions, if the implicated unit was not leukoreduced and if leukoreduction is locally available. if the fever persists or leukoreduction is unavailable, washed rbcs may be considered.1 a l l e r g i c t r a n s f u s i o n r e a c t i o n s allergic trs are more frequently seen with platelets and plasma than with rbcs.2 the cause of the majority of allergic reactions remains unexplained and it is not easy to identify the allergens causing the reaction. evidence suggests that a history of allergies may predispose a patient to an allergic tr. however, both immunoglobulin a (iga) and haptoglobin (hp) deficiency should be suspected in the event of recurrent and/or severe allergic trs. igadeficient patients have a tendency to develop anti-iga antibodies, which may cause severe and potentially fatal anaphylactic reactions if high titres of anti-iga antibodies are present. these reactions occur early and can be fatal if not managed appropriately.13 hpdeficient individuals may experience anaphylaxis upon exposure to hp in transfused products. there are data suggesting racial differences in the incidence of iga and hp-deficiency.14 however, the incidence in oman table 3: subsequent actions and procedures to be followed with acute transfusion reactions action procedure notification • if the presumed atr is severe or life-threatening, a doctor should be called immediately to assess the patient. the patient should be under direct observation until clinical improvments are noted. reactions that fall under this category include:1 life-threatening reactions that cause the airway, breathing and/or circulatory system to become compromised. mismatched transfusion due to abo blood group incompatibility identified by evidence of unit mislabelling or intravascular haemolysis. septic reactions identified by evidence of bacterial contamination seen in the visual assessment of the unit. • if there is evidence of abo blood group incompatibility or bacterial contamination, the hospital blood bank should be contacted immediately as other patients may be at risk. specific management • this should be provided based on the physician’s orders. decision to resume or discontinue the transfusion • in patients with mild reactions, the transfusion may be continued after appropriate treatment at a slower infusion rate and direct observation. mild reactions are defined as an atr with no or limited changes in the vital signs or other clinical symptoms of the patient. the two reactions that can be categorised this way are: mild febrile reactions with a temperature ≥38 °c and a rise of 1–2 °c from baseline, without other changes in vital signs. transient urticaria, pruritus and/or flushing, without other systemic symptoms. • in patients with all other tr types, the transfusion should be discontinued. reporting* • fill out a tr reporting form and send it to the blood bank. • send the implicated component in a sealed plastic envelope to the laboratory with the transfusion set and clamped tubing. do not send the bag with the infusion needle attached. attach the tr reporting form to the outside of the sealed envelope. • retrieve all bags of products transfused whenever possible and send them to the blood bank. products transfused anytime within the 24 hours preceding the onset of symptoms may be related to the tr symptoms encountered and should be retrieved and sent whenever possible. • send the following patient samples to the blood bank (except in the case of mild reactions): one edta sample first voided post-transfusion urine sample (whenever feasible). • if a septic reaction (bacterial contamination) is suspected, blood cultures should be sent before starting the patient on any antibiotics. atr = acute transfusion reaction; tr = transfusion reaction; edta = ethylene-diamine-tetra-acetic acid. *all trs must be reported to the hospital blood bank, regardless of severity. arwa z. al-riyami, sabria al-hashmi, zainab al-arimi, louis d. wadsworth, abdulhakim al-rawas, murtadha al-khabori and shahina daar special contribution | e311 or prednisolone should be considered.14 finally, a bronchodilator or nebulised beta-2 agonist (e.g. salbutamol) should be considered if bronchospasm develops. if a blood transfusion is still urgently needed and cannot be postponed, a different unit should be requested and infused as slowly as possible. patients with moderate/severe or recurrent allergic trs should be tested for iga defiency. iga deficiency is defined as the selective deficiency of iga (<0.05 mg/ dl) in patients older than four years of age with other causes of hypogammaglobulinaemia having been excluded.15 the results should be interpreted with caution if a post-transfusion sample is tested. isolated low iga levels warrant testing for iga antibodies. prevention there is no evidence to support routine prophylaxis with antihistamines in patients with a previous history of mild allergic trs and no studies have assessed the use of steroids.16 patients with a previous mild allergic tr may receive further transfusions without premedication, and subsequent mild reactions can be managed by using systemic antihistamines and reducing the rate of the transfusion.1 however, it might be justifiable to premedicate patients with moderate to severe reactions with antihistamines. moreover, subsequent transfusions must be performed in settings where patients can be directly observed by trained staff and where resuscitation facilities are available.1 washed rbcs are indicated in patients with severe or recurrent allergic trs. however, washing platelet units has its own limitations and is not available in oman.13 iga-deficient patients with iga antibodies and a history of trs should receive rbc units donated by iga-deficient donors as the first choice of treatment, or thoroughly washed rbcs as a second choice whenever feasible. plasma and platelets should also be from iga-deficient donors.1,17 in view of the lack of an igadeficient donor database in oman, thoroughly washed components should be requested as the most feasible option. however, urgent transfusions should not be withheld if washed components are not immediately available. that being said, the facilities and skills to manage severe allergic trs must be present.1 a n a p h y l a x i s anaphylaxis is a severe life-threatening systemic hypersensitivity characterised by rapidly developing airway, breathing and/or circulation compromises, usually associated with skin and mucosal changes.1 patients may have bronchospasms, stridor, angioedema, urticaria, hypotension or other symptoms. this reaction shares a common pathophysiology with allergic trs. anaphylactic shock has rarely been is unknown. allergic reactions are subclassified as mild or moderate to severe. mild reactions are defined as localised mild skin rashes/urticaria in the absence of other symptoms. moderate to severe reactions are defined as severe urticarial reactions with widespread lesions and/or bronchospasms, angioedema or respiratory compromise. another possible sign is hypotension which, if present, should suggest the possibility of impending anaphylactic shock. urticarial rashes may also be associated with pruritus, erythema, flushing, nausea/vomiting, abdominal cramps or diarrhoea. management the management of allergic trs depends on the severity of the reaction. as for all trs, the first step is to stop the transfusion. for mild allergic trs, practitioners should consider systemic antihistamines such as chlorphenamine.1 if symptoms improve with these initial measures, and in the absence of other symptoms, the transfusion may be resumed at a lower infusion rate after consultation with the physician and under direct observation.1,11 if the symptoms persist or recur despite the above measures, the transfusion must be terminated. the tr should still be reported to the blood bank, whether the transfusion was continued or terminated. however, post-transfusion samples and the implicated unit do not need to be sent. in cases of moderate to severe allergic trs, the transfusion should be halted immediately and a physician notified urgently. the patient’s abc should be assessed and, if necessary, interventions should commence. adrenaline (1:1000 dilution) should be administered immediately. although both intramuscular (im) and iv injections can be given, im injections are more effective and circumvent any delay in establishing venous access. adrenaline should not be withheld in thrombocytopenic patients or patients with coagulopathy. the dose can be repeated if needed at 5-min intervals depending on the patient’s blood pressure, pulse and respiratory status. after administration of the adrenaline, the patient should be placed in a recumbent position with the lower extremities elevated. oxygen (o2) should be administered via facemask at 8–10 l/min. two largebore iv cannulae should be inserted (14–16 gauges for adults and 20–22 gauges for paediatric patients). patients should be given chlorphenamine via im or slow iv injection. if the patient is hypotensive, a normal saline bolus of 10–20 ml/kg (500–1,000 ml in adults) should be administered over 15 mins. repeated boluses may be required to maintain the blood pressure. if the symptoms are severe, methylprednisolone recognition, investigation and management of acute transfusion reactions consensus guidelines for oman e312 | squ medical journal, august 2014, volume 14, issue 3 reported in complement component 4 (c4)-deficient patients after blood transfusions.18,19 management the management of anaphylactic reactions is the same as for moderate to severe allergic reactions as outlined above. prevention premedication with steroids and antihistamines should be considered to prevent recurrence in patients with a history of anaphylactic reactions. subsequent transfusions should only be carried out where patients can be observed directly and where staff trained in managing anaphylaxis are available.1 s e p t i c r e a c t i o n s (b a c t e r i a l c o n ta m i n at i o n) bacterial contamination of a blood component can occur either at the time of donation (due to subclinical donor bacteremia or non-adherence to aseptic techniques during the phlebotomy) or during blood component preparation, storage or handling. this can cause a septic atr when the component is tranfused to a recipient. both gram-negative and -positive bacteria have been implicated.12 although these reactions can occur with any blood component, platelets are the most commonly implicated since they are stored at room temperature which allows faster bacterial growth.4 when the implicated unit is transfused, the patient rapidly develops acute manifestations.20 bacterial contamination should be considered if the patient presents with a moderate or severe fever defined as a temperature ≥39 °c or a temperature rise of ≥2 °c from baseline. bacterial contamination should also be suspected if any fever is accompanied with systemic symptoms such as chills, rigors, severe hypotension, shock, dyspnoea, myalgia, nausea or vomiting.1 bacterial contamination should also be considered if the fever is persistent or unresponsive to symptomatic measures. patients may also present with isolated hypotension. other symptoms, such as pain in the chest, back, abdomen or transfusion site, may confuse this reaction with an ahtr.21 symptoms may develop rapidly or within four hours of the transfusion.21 the severity of the reaction is influenced by the type of bacteria involved, bacterial load and the recipient’s clinical status. shock and disseminated intravascular coagulation (dic) can occur if a gram-negative bacterially infected unit with high levels of endotoxin was transfused. there should be increased caution in patients receiving blood transfusions while under anaesthesia (where manifestations may be masked) in patients with underlying fevers and in those who have been pre-medicated with antipyretics, as they may not develop a high-grade temperature as a warning sign. management the management of patients suspected of a septic reaction begins with halting the transfusion. the implicated unit should be inspected for any discolouration, abnormal particles, clumps or signs of leakage. if any of these are present, the hospital blood bank must be notified immediately so its staff may recall and quarantine any other components from the implicated donation. a tr form must be sent to the blood bank along with the patient’s posttransfusion samples and the implicated unit(s). the implicated unit should be cultured for aerobic and anaerobic organisms. in addition, blood cultures should be drawn from the patient and broad-spectrum iv antibiotics should be started. blood cultures from the implicated unit should be examined for aerobic and anaerobic organisms. if the cultures are positive, all related components must be discarded and further antibiotic coverage should be determined based on the organism identified. prevention future transfusions do not require any precautions. however, if there is a high frequency of these reactions, then a critical review of the blood collection process and storage facilities is indicated. the routine visual inspection of any unit at the time of laboratory processing and at the bedside prior to blood transfusion is crucial. all personnel must be trained to perform these visual assessments. the normal appearance of a unit does not exclude bacterial contamination.1 therefore, if this type of reaction is clinically suspected, action must be undertaken as detailed above. t r a n s f u s i o n-r e l at e d a c u t e l u n g i n j u r y trali is defined as noncardiogenic pulmonary oedema following blood transfusion. although all blood components have been implicated in trali, frozen plasma is the most common.22 however, small volumes of plasma (e.g. in rbc units) can cause trali if there are high levels of hla or human neutrophil antigen (hna) antibodies in the implicated unit and the patient has susceptible risk factors. the diagnosis of trali must fulfill the following criteria: (1) acute respiratory distress during the transfusion or within six hours of completing the transfusion; (2) hypoxaemia, defined by partial pressure of o2 (pao2) in arterial blood divided by the fraction of inspired o2 (fio2) ≤300 mmhg, blood oxygen saturation (spo2) <90% on room air or other clinical evidence of hypoxaemia; (3) bilateral arwa z. al-riyami, sabria al-hashmi, zainab al-arimi, louis d. wadsworth, abdulhakim al-rawas, murtadha al-khabori and shahina daar special contribution | e313 pressure ≤18 mmhg or central venous pressure ≤15 mmhg; (5) no pre-existing acute lung injury (ali), and (6) no temporal relationship to an alternative risk factor of ali, including aspiration, severe sepsis, pneumonia, multiple fractures, pancreatitis, shock, cardiopulmonary bypass, burn injuries, toxic inhalation, lung contusion, drug overdose or near drowning.24 if the first five criteria are met but there is a temporal association with another risk factor for ali, the case is categorised as possible trali. the primary mechanism of trali is the accumulation and activation of neutrophils within the pulmonary vascular endothelium. there are two existing models of trali. the two-hit model supports the hypothesis that trali occurs due to the interaction of two factors. the first factor is an underlying condition (e.g. critical illness, surgery, mechanical ventilation or severe sepsis) that may result in neutrophil priming and adherence to the pulmonary endothelium.25 the second factor is a mediator within the transfused component which activates the primed neutrophils and endothelial cells, inducing capillary leakage and pulmonary oedema.23,26 this can be caused by donor hla or hna antibodies that target recipient antigens, or bioactive lipids and soluble cd40 ligands that accumulate during the storage of cellular components.27 the second model, known as the threshold model, is based on the hypothesis that both the recipient and transfusion factors act together to overcome a particular recipient’s threshold and induce trali.24,27 manifestations of trali can occur during the transfusion or in the six hours after completion of the transfusion, although they usually occur within two hours.1,28 dyspnoea with acute hypoxia usually dominates the clinical picture. other features include tachycardia, rigors, fever, hypothermia and hypotension.28 trali remains a clinical diagnosis.29 although taco is in the differential diagnosis, certain features help to differentiate trali from taco [table 4]. a clinical examination and cxr are crucial to rule out any evidence of cardiac overload. the severity of trali can range from mild, requiring supplemental o2, to severe, necessitating mechanical ventilation. with respiratory support, most patients with trali recover in 24–72 hours, however 5–25% of cases are fatal.30,31 management the management of suspected trali requires immediate cessation of the transfusion. the patient’s airway should be ensured, the arterial o2 saturation level obtained and high-flow o2 should be begun. mechanical ventilation should be considered. the patient should be assessed clinically for cardiac pulmonary infiltrates on a frontal chest x-ray (cxr); (4) no evidence of transfusion-associated circulatory overload (taco) with pulmonary arterial wedge table 4: helpful features in differentiating transfusionrelated acute lung injury from transfusion-associated circulatory overload feature trali taco patient characteristics may occur in any patient but are more frequently reported in haematological and surgical patients may occur at any age, but characteristically occurs at >70 years type of component usually plasma or platelets any speed of onset during the transfusion or within six hours of completion, usually within the first two hours during the transfusion or within six hours of completion of the transfusion dyspnoea present present fever present usually absent blood pressure usually hypotension usually hypertension oxygen saturation reduced reduced jvp normal raised full blood count leukopenia with neutropenia and monocytopenia followed by neutrophil leukocytosis and thrombocytopenia no specific changes cxr pulmonary oedema with normal heart size pulmonary oedema with cardiomegaly echo normal left ventricular function* normal or decreased left ventricular function pulmonary wedge pressure low raised other tests normal bnp levels raised bnp levels response to fluid load improves worsens response to diuretics worsens improves trali = transfusion-related acute lung injury; taco = transfusionassociated circulatory overload; jvp = jugular venous pressure; cxr = chest x-ray; echo = echocardiogram; bnp = b-natriuretic peptide. *decreased left ventricular function does not exclude trali. adapted from: tinegate h, birchall j, gray a, haggas r, massey e, norfolk d, et al. guideline on the investigation and management of acute transfusion reactions: prepared by the bcsh blood transfusion task force.1 and vlaar ap, juffermans np. transfusion-related acute lung injury: a clinical review.23 recognition, investigation and management of acute transfusion reactions consensus guidelines for oman e314 | squ medical journal, august 2014, volume 14, issue 3 overload and a cxr should be obtained. the rest of the management should be supportive. although some case reports advocate the use of steroids, no evidence supports their use.16 the reaction must be reported to the blood bank to quarantine or recall the rest of components from the implicated donor and to make decisions regarding donor deferral. the donor deferral decision must be made by an expert in transfusion medicine. currently, tests to investigate an implicated donor are not available in oman, but should be considered whenever made available. prevention no precautions are needed for future transfusions, providing that taco has been ruled out. there are two groups of donors likely to be implicated in antibody-mediated trali: multiparous females and donors with a history of transfusions. in the light of this, some countries have undertaken policies which only accept male donors for plasma and platelet donations in order to minimise the risk of trali.11 t r a n s f u s i o n-a s s o c i at e d c i r c u l at o r y o v e r l o a d taco is a condition characterised by left ventricular failure and pulmonary oedema due to fluid overload. this occurs either during transfusion or within the following six hours, in transfusions with a rapid infusion rate or a high volume of transfused products. risk factors include extremes of age (patients >60 years or <3 years), pre-existing cardiac and/or renal dysfunction, transfusions after an acute myocardial infarction, plasma transfusions, pre-existing positive fluid balances in the 24 hours prior to the transfusion and large-volume transfusions.32,33 patients present with acute respiratory distress, dyspnoea, cyanosis, orthopnea, hypoxia, increase in systolic blood pressure (>20 mmhg above the baseline) and signs of cardiac overload (jugular venous pressure elevation and bilateral crepitation).1 patients tend to respond to diuretics and worsen with fluid boluses. a cxr will show pulmonary oedema and cardiomegaly and an echocardiogram will be abnormal. there is some evidence suggesting that b-type natriuretic peptide (bnp) is a sensitive and specific marker of taco.30 until further evidence is available, bnp levels should be used as an adjunct marker to other features of volume overload in confirming the diagnosis of taco. management in suspected cases of taco, management should begin by stopping the transfusion. practitioners should ensure a patent airway, obtain the arterial o2 saturation level and start high-flow o2. mechanical ventilation should be considered. in addition, cardiac overload should be assessed and a cxr obtained. diuretics should be administered, such as furosemide via the iv route. prevention in order to prevent recurrence, preor mid-transfusion diuretics should be considered in patients with a prior history or risk factors of taco. transfusion should recommence one unit at a time, with the patient being assessed after each unit. in high-risk patients, the transfusion can be performed at a slow rate. in patients with congestive heart failure (chf), the transfusion should be postponed if possible until the chf is deemed to be under control. when a transfusion is needed during an episode of chf, it is important to request a split rbc unit to reduce the volume of infused blood in the four-hour time frame.33 t r a n s f u s i o n-a s s o c i at e d d y s p n o e a transfusion-associated dyspnoea (tad) is defined as any respiratory distress within 24 hours of transfusion that does not meet the criteria of trali, taco or an allergic reaction and that cannot be explained by an underlying condition or any other known cause.34 tad remains a clinical diagnosis and a diagnosis of exclusion. management tad should be managed by stopping the transfusion immediately. management is supportive, after the patient has been assessed for potential causes of dyspnoea, including an ahtr, allergic tr, trali or taco. prevention no precautions are needed for future transfusions, provided that other transfusion-related causes of dyspnoea have been ruled out. a c u t e h a e m o ly t i c t r a n s f u s i o n r e a c t i o n s an ahtr occurs secondarily to a mismatched transfusion due to abo incompatibility. this can occur as a result of clerical error, improper sample labelling or an error in patient testing or identification. it can also occur as an anamnestic response caused by non-abo antibodies in alloimmuised patients due to a prior pregnancy or transfusion. the latter can occur in alloimmunised patients with sickle cell disease, among others, who develop an anamnestic response of pre-existing antibodies following the transfusion of non-phenotype-matched rbc unit(s), leading to acute haemolysis. the binding of the antibodies to donor arwa z. al-riyami, sabria al-hashmi, zainab al-arimi, louis d. wadsworth, abdulhakim al-rawas, murtadha al-khabori and shahina daar special contribution | e315 testing in the blood bank must include an antibody screen. if the antibody screen is positive, antibody identification should be carried out. units selected for the transfusion should be antigen-negative for the implicated antibody and must be serologically crossmatch compatible with the patient’s plasma using an indirect antiglobulin method. h y p o t e n s i v e r e a c t i o n s hypotensive reactions are defined as hypotensive episodes with an isolated fall in systolic blood pressure of ≥30 mm occurring during or within one hour of completing the transfusion and a systolic blood pressure ≤80 mm, without any symptoms to suggest an allergic or anaphylactic reaction, other types of atrs or other causes hypotension (e.g. blood loss).1 this reaction has been associated with bradykinin release upon exposure to filtered blood and a history of angiotensin-converting enzyme (ace) inhibitors should therefore be checked. management in cases of hypotensive reactions, the transfusion should be stopped. the patient should be placed in a recumbent position with their legs elevated, or in the recovery position if they are unconscious or nauseated. normal saline boluses should be administered via an iv route. the transfusion should not be restarted. the reaction should be reported and the patient should be investigated as per the tr reporting format. prevention in order to prevent further recurrence, patients should be given a trial of washed rbcs. in cases where ace inhibitors have been implicated, halting the ace inhibitors before a blood transfusion should be considered if clinically safe, otherwise alternative antihypertensives should be considered.1,12 reporting transfusion reactions the reporting of trs to hospital blood banks is essential. it directs immediate action when haemolytic trs, trali or septic reactions are suspected, and also contributes to the haemovigilance system. reporting instances of trs may prompt recall of related components from the same donation and may result in donor deferrals. for some reactions, action should be undertaken immediately so as to prevent harming other patients. the two classic reactions are haemolytic trs and septic reactions. the process of reporting trs to the blood bank should follow the local procedures within an rbcs leads to rbc lysis, activation of complement and coagulation pathways and cytokine release. complement activation induces haemolysis, while activation of the coagulation cascade and thrombin generation predisposes the patient to dic. the most common presentation of an ahtr is significant fever and chills, defined as a sustained fever ≥39 °c or a rise of ≥2 °c from baseline and/or a fever accompanied by systemic symptoms such as chills, rigors, myalgia, nausea or vomiting. alternatively, fevers which are unresponsive to symptomatic measures should be considered as a sign of a possible ahtr. the classic presenting features are intravascular haemolysis (e.g. a falling haemoglobin level with a positive direct antiglobulin test (dat), a rise in serum lactate dehydrogenase and haemoglobinurea), pain at the infusion site, flank pain, feelings of impending doom, anxiety and facial flushing. patients may also present with isolated hypotension. if this reaction is not recognised, patients can progress to acute renal failure, dic and death. management the management of suspected ahtrs should begin by stopping the transfusion immediately, establishing a new iv line and starting 0.9% normal saline. saline boluses should be given to maintain urine output. the attending physician should be notified immediately and urine alkalinisation should be considered in the event of renal failure. as soon as a reaction is suspected, the hospital blood bank should be immediately informed by telephone as well as via the regular reaction reporting procedures. this is crucial in order to quarantine and recall other components that could have been issued to other patients. a post-transfusion blood sample and the first voided urine sample should be collected and sent to the blood bank, along with the implicated unit and the tr report. coagulation, renal and liver function tests should be considered. prevention prevention of ahtrs is heavily related to adherence to clinical and laboratory policies with regards to patient identification and testing. at the time of the blood order/request proper patient identification and bedside sample labelling is a necessity to avoid sample mislabelling. in addition, and prior to commencing the transfusion, proper verification of the patient’s identity, the unit compatibility label and the request details is critical to detect errors and any abo incompatibility. this should be performed at the patient’s bedside and in the presence of two nurses. however, it is also crucial to remember that non-abo antibodies can be implicated in an ahtr. therefore, pre-transfusion recognition, investigation and management of acute transfusion reactions consensus guidelines for oman e316 | squ medical journal, august 2014, volume 14, issue 3 institution. however, there must be a standardised procedure in the blood banks on how to handle tr investigations. reports should be reviewed by an expert in transfusion medicine in order to ensure a proper evaluation, management and the final classification of the reaction type. laboratory investigations the primary work-up for samples suspected of causing a tr is standardised. all units returned to the blood bank should undergo a second visual check for labelling, integrity and any evidence of haemolysis or bacterial contamination. in the event of a suspected haemolytic or septic reaction, the blood bank should recall and quarantine any associated components. reports of moderate or severe trs should prompt testing to rule out ahtrs. this includes repeat abo and rhesus (d) grouping of both the patient sample and the returned unit; repeat antibody screening of the preand post-transfusion samples; repeat crossmatching of both samples with the returned unit, and the performance of a dat on the post-transfusion blood sample.1 in addition, the first voided posttransfusion urine sample should be assessed for the presence of haemoglobinuria. in addition to the above, and if there is any suspicion of bacterial contamination, blood cultures should be obtained from the patient and the implicated unit. a protocol should be established regarding the aseptic sampling of the components for cultures to minimise the risk of contamination. other basic investigations to be considered for moderate and severe trs include a complete blood count, a coagulation profile and renal and liver function tests. haemovigilance a haemovigilance scheme is a monitoring programme which ensure the safety of transfusions. it allows the evaluation of trends, identification of any practice concerns or training needs, the introduction of guidelines and the evaluation of corrective actions taken to reduce transfusion risks. haemovigilance programmes have been developed in many countries and include either mandatory or voluntary reporting schemes. as part of a haemovigilance programme, a uniform and systematic method for the reporting and evaluation of trs should be implemented. haemovigilance programmes should be overseen locally within individual institutions by the hospital transfusion committees. in addition, a haemovigilance programme needs to exist at a national level and all reported trs should be reviewed by a national haemovigilance committee. conclusion the prompt recognition, management and reporting of trs are important aspects in ensuring patient safety during and after transfusions. trs may have overlapping manifestations and it is therefore imperative that medical personnel be aware of the different types of reactions that can occur. this requires the continuous education of all healthcare professionals involved in the transfusion process as well as the development of standardised procedures. this paper has summarised the available literature on the recognition and management of different atrs in order to provide local consensus guidelines for oman. a national haemovigilance programme is required to set standards as well as ensuring training requirements on the proper handling and management of these reactions. once such a programme has been developed in oman, these guidelines may be used as a comprehensive source of information and guidance. a p p e n d i x a list of common medications that can be used for the management of different atrs is available in the appendix after the references. this appendix should be used as a reference only. references 1. tinegate h, birchall j, gray a, haggas r, massey e, norfolk d, et al. guideline on the investigation and management of acute transfusion reactions: prepared by the bcsh blood transfusion task force. br j haematol 2012; 159:143–53. doi: 10.1111/bjh.12017. 2. knowles s, cohen h, watt a, poles d, jones h, davies t, et al. serious hazards of transfusion (shot): annual report 2010. from: www.shotuk.org/wp-content/uploads/2011/07/shot2010-report.pdf accessed: jan 2014. 3. hillyer cd, silberstein md, ness pm, anderson kn. blood banking and transfusion medicine: basic principles and practice. 1st ed. oxford, uk: churchill livingstone. pp. 265– 361. 4. taylor c, cohen h, mold d, jones h, asher d, cawley c, et al. serious hazards of transfusion (shot): annual 2009 report. from: www.shotuk.org/wp-content/uploads/2010/03/shotreport-2008.pdf accessed: jan 2014. 5. british committee for standards in haematology. guideline on the administration of blood components. from: www. bcshguidelines.com/documents/admin_blood_components_ bcsh_05012010.pdf accessed: mar 2014. 6. gauvin f, lacroix j, robillard p, lapointe h, hume h. acute transfusion reactions in the pediatric intensive care unit. transfusion 2006; 46:1899–908. doi: 10.1111/j.15372995.2006.00995.x. 7. slonim ad, joseph jg, turenne wm, sharangpani a, luban nl. blood transfusions in children: a multi-institutional analysis of practices and complications. transfusion 2008; arwa z. al-riyami, sabria al-hashmi, zainab al-arimi, louis d. wadsworth, abdulhakim al-rawas, murtadha al-khabori and shahina daar special contribution | e317 pp. 870–84. 23. vlaar ap, juffermans np. transfusion-related acute lung injury: a clinical review. lancet 2013; 382:984–94. doi: 10.1016/s01406736(12)62197-7. 24. kleinman s, caulfield t, chan p, davenport r, mcfarland j, mcphedran s, et al. toward an understanding of transfusion related acute lung injury: statement of a consensus panel. transfusion 2004; 44:1774–89. doi: 10.1111/j.00411132.2004.04347.x. 25. bux j, sachs uj. the pathogenesis of transfusion-related acute lung injury (trali). brit j haematol 2007; 136:788–99. doi: 10.1111/j.1365-2141.2007.06492.x. 26. silliman cc. the two-event model of transfusion-related acute lung injury. crit care med 2006; 34:s124–31. doi: 10.1097/01. ccm.0000214292.62276.8e. 27. sachs uj. recent insights into the mechanism of transfusionrelated acute lung injury. curr opin hematol 2011; 18:436–42. doi: 10.1097/moh.0b013e32834bab01. 28. skeate rc, eastlund t. distinguishing between transfusion related acute lung injury and transfusion associated circulatory overload. curr opin hematol 2007; 14:682–7. doi: 10.1097/ moh.0b013e3282ef195a. 29. li g, daniels ce, kojicic m, krpata t, wilson ga, winters jl, et al. the accuracy of natriuretic peptides (brain natriuretic peptide and n-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically ill. transfusion 2009; 49:13–20. doi: 10.1111/j.15372995.2008.01941.x. 30. silliman cc, mclaughlin nj. transfusion-related acute lung injury. blood rev 2006; 20:139–59. doi: 10.1016/j. blre.2005.11.001. 31. sheppard ca, lögdberg le, zimring jc, hillyer cd. transfusion-related acute lung injury. hematol oncol clin north am 2007; 21:163–76. doi: 10.1016/j.hoc.2006.11.011. 32. growe gh, petraszko tr, bigham m. the approach taken to reducing the risk of transfusion related acute lung injury in canada. asian j transfus sci 2008; 2:84–6. doi: 10.4103/09736247.42696. 33. alam a, lin y, lima a, hansen m, callum jl. the prevention of transfusion-associated circulatory overload. transfusion med rev 2013; 27:105–12. doi: 10.1016/j.tmrv.2013.02.001. 34. international haemovigilance network/international society for blood transfusion. proposed standard definitions for surveillance of non-infectious adverse transfusion reactions. from: www.ihn-org.com/wp-content/uploads/2011 /06/isbt-definitions-for-non-infectious-transfusion-reactions. pdf accessed: mar 2014. 35. british medical association, royal pharmaceutical society of great britain. british national formulary. 66th ed. london: pharmaceutical press, 2013. 36. british medical association, royal pharmaceutical society, royal college of paediatrics & child health, neonatal & paediatric pharmacists group. british national formulary for children, 2014–2015. london: pharmaceutical press, 2014. 48:73–80. doi: 10.1111/j.1537-2995.2007.01484.x. 8. pedrosa ak, pinto fj, lins ld, deus gm. blood transfusion reactions in children: associated factors. j pediatr (rio j) 2013; 89:400–6. doi: 10.1016/j.jped.2012.12.009. 9. heddle nm, klama l, meyer r, walker i, boshkov l, roberts r, et al. a randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets. transfusion 1999; 39:231–8. doi: 10.1046/j.15372995.1999.39399219278.x. 10. paglino jc, pomper gj, fisch gs, champion mh, snyder el. reduction of febrile but not allergic reactions to rbcs and platelets after conversion to universal prestorage leukoreduction. transfusion 2004; 44:16–24. doi: 10.1046/j.0041-1132.2004.00608.x. 11. british columbia provincial blood coordinating office, provincial health services authority. transfusion medicine medical policy manual. from: www.pbco.ca/index. php?option=com_content&task=category&id=58&itemid=96 accessed: may 2014. 12. callum jl, lin y, pinkerton ph. bloody easy 3: blood transfusions, blood alternatives and transfusion reactions: a guide to transfusion medicine. 3rd ed. toronto, canada: ontario regional blood coordinating network, 2011. 13. lerner nb, refaai ma, blumberg n. red cell transfusion. in: kaushansky k, lichtman ma, beutler e, kipps tj, seligsohn u, prchal jt, eds. williams hematology. 8th ed. columbus, ohio: mcgraw hill professional, 2010. pp. 2287–300. 14. hirayama f. current understanding of allergic transfusion reactions: incidence, pathogenesis, laboratory tests, prevention and treatment. brit j haematol 2013; 160:434–44. doi: 10.1111/ bjh.12150. 15. european society for immunodeficiencies. definition of iga deficiency. from: www.esid.org/content/download/198/910/ file/iga%20deficiency.doc accessed: mar 2014. 16. kennedy ld, case ld, hurd dd, cruz jm, pomper gj. a prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine pretransfusion medication versus placebo for the prevention of transfusion reactions. transfusion 2008; 48:2285–91. doi: 10.1111/j.15372995.2008.01858.x. 17. sandler sg. how i manage patients suspected of having had an iga anaphylactic transfusion reaction. transfusion 2006; 46:10–13. doi: 10.1111/j.1537-2995.2006.00686.x. 18. lambin p, le pennec py, hauptmann g, desaint o, habibi b, salmon c. adverse transfusion reactions associated with a precipitating anti-c4 antibody of anti-rodgers specificity. vox sang 1984; 47:242–9. doi: 10.1111/j.1423-0410.1984.tb01592.x. 19. westhoff cm, sipherd bd, wylie de, toalson ld. severe anaphylactic reactions following transfusions of platelets to a patient with anti-ch. transfusion 1992; 32:576–9. doi: 10.1046/j.1537-2995.1992.32692367205.x. 20. blajchman m, goldman m. bacterial contamination of platelet concentrates: incidence, significance, and prevention. semin hematol 2011; 38:20–6. doi: 10.1016/s0037-1963(01)90120-9. 21. hewitt p. bacterial contamination. in: murphy mf, pamphilon dh, eds. practical transfusion medicine. 3rd ed. oxford, uk: wiley-blackwell, 2009. pp. 146–52. 22. wallis jp, sachs ujh. transfusion-related acute lung injury. in: simon tl, snyder el, solheim bg, stowell cp, strauss rg, solheim bg, et al., eds. rossi’s principles of transfusion medicine. 4th ed. bethesda, maryland: wiley-blackwell, 2009. recognition, investigation and management of acute transfusion reactions consensus guidelines for oman e318 | squ medical journal, august 2014, volume 14, issue 3 appendix: list of common medications that can be used for the management of different acute transfusion reactions medication adult doses35 paediatric and adolescent doses36 adrenaline, im [1:1000 dilution, 1 mg/ml] 0.5 ml (500 mcg)* <6 years: 0.15 ml (150 mcg)* 6–12 years: 0.3 ml (300 mcg)* 12–18 years: 0.5 ml (500 mcg)* only 0.3 ml (300 mcg) should be given if the adolescent is small or pre-pubertal chlorphenamine, po 4 mg† maximum of 24 mg daily for adults and 12 mg daily for the elderly 1 month–2 years: 1 mg‡ 2–6 years: 1 mg† maximum of 6 mg daily 6–12 years: 2 mg† maximum of 12 mg daily 12–18 years: 4 mg† maximum of 24 mg daily chlorphenamine, im or slow iv 10 mg† maximum of 40 mg daily 1-6 months: 250 mcg/kg/dose§ maximum of 2.5 mg per dose 6 months–6 years: 2.5 mg§ 6–12 years: 5 mg§ 12–18 years: 10 mg§ furosemide 20–50 mg, via im or slow iv 0.5–1.0 mg/kg, via iv only hydrocortisone, im/iv 100–500 mg¶ <6 months: 25 mg¶ 6 months–6 years: 50 mg¶ 6–12 years: 100 mg¶ 12–18 years: 200 mg¶ paracetamol/acetaminophen, po 500–1,000 mg† maximum of 4 g daily 10–15 mg/kg† maximum of 60 mg/kg/day daily paracetamol/acetaminophen, iv <50 kg: 10–15 mg/kg/dose† maximum of 60 mg/kg daily >50 kg: 1,000 mg† maximum of 4 g daily <10 kg: 7.5 mg/kg/dose† maximum of 30 mg/kg daily 10–50 kg: 10–15 mg/kg/dose† maximum of 60 mg/kg daily pethidine, slow iv 25–50 mg not recommended salbutamol, nebulised 5 mg†† <5 years: 2.5 mg†† 6–12 years: 2.5–5 mg†† 12–18 years: 5 mg†† im = intramuscular; po = per os; iv = intravenous. *doses may be repeated if necessary at 5-min intervals according to the patient’s blood pressure, pulse and respiratory function.†doses may be repeated every 4–6 hours.‡doses may be repeated if required up to two times in 24 hours.§doses may be repeated if required up to four times in 24 hours.¶doses may be repeated if required up to three times in 24 hours and adjusted as per the response.††repeat at 20–30 min intervals as necessary. 1medical skills & simulation centre and 2department of family & community medicine, arabian gulf university, manama, bahrain *corresponding author’s e-mail: salmanr@agu.edu.bh خمرجات التعليم الطيب اجلامعي ابستخدام احملاكاة الطبية وفًقا ملالحظات الطالب �سلمان ريا�ض، اأحمد عبد الكرمي جرادات، رويل جوترييز، تي�سري �سعيد جرادة abstract: objectives: this study aimed to determine students’ overall satisfaction with clinical simulation sessions and compare the satisfaction levels of obstetrics/gynaecology (obgyn) students (group one) and internal medicine students (group two). methods: this study was conducted from january to june 2019 at the arabian gulf university, manama, bahrain. students from year five were included and offered sessions that used simulations to support clinical skill development. data were collected using a five-point likert scale (i.e. strongly agree, agree, neutral, disagree, strongly disagree) via feedback forms. results: a total of 150 students were included in this study (response rate: 99.07%). in groups of seven, the students attended five cycles of simulations with two sessions per cycle in each specialty over six months. the mean percentage of responses of “strongly agree” and “agree” was 97.8 ± 2.3% in group one and 95.7 ± 2.7% in group two. the satisfaction scores of group one were higher than those from group two for all statements. significant differences were found between groups one and two in their responses to the statement of whether the simulation session was relevant to clinical practice (100% versus 92.9%; p <0.001) and whether the debriefing session was useful (98.1% versus 94.8%; p = 0.015). conclusion: students indicated high satisfaction after attending the simulation sessions; however, obgyn students were more satisfied compared to those studying internal medicine. keywords: simulation training; patient simulation; high fidelity simulation training; undergraduate medical education; bahrain. ر�سا م�ستويات ومقارنة ال�رسيرية املحاكاة جل�سات عن عام ب�سكل الطالب ر�سا مدى حتديد اإىل الدرا�سة هذه هدفت امللخ�ص: الهدف: يناير من الدرا�سة هذه اأجريت الطريقة: الثانية(. )املجموعة الباطني الطب وطالب الأوىل( )املجموعة واالتوليد الن�ساء اأمرا�ض طالب املحاكاة ت�ستخدم جل�سات وتقدمي اخلام�سة ال�سنة من طالب ت�سمني مت البحرين. املنامة، العربي، اخلليج جامعة يف 2019 يونيو اإىل غري حمايد، موافق، ب�سدة، )موافق نقاط خم�ض من املكون ليكرت مقيا�ض با�ستخدام البيانات جمع مت ال�رسيرية. املهارات تنمية لدعم موافق، ل اأوافق ب�سدة( عرب مناذج املالحظات. النتائج: مت ت�سمني ما جمموعه 150 طالًبا يف هذه الدرا�سة )معدل ال�ستجابة: 99.07%(. يف جمموعات من �سبعة، ح�رس الطالب خم�ض دورات من املحاكاة مع جل�ستني يف كل دورة يف كل تخ�س�ض على مدى �ستة اأ�سهر. كان متو�سط الن�سبة املئوية لالإجابات "اأوافق ب�سدة" و "موافق" %2.3 ± 97.8 يف املجموعة الأوىل و %2.7 ± 95.7 يف املجموعة الثانية. كانت درجات الر�سا للمجموعة الأوىل اأعلى من تلك اخلا�سة باملجموعة الثانية جلميع الإفادات. مت العثور على فروق ذات دللة اإح�سائية بني املجموعتني الأوىل والثانية يف ا�ستجاباتهم لبيان ما اإذا كانت جل�سة املحاكاة ذات �سلة باملمار�سة ال�رسيرية )p >0.001؛ %92.9 مقابل %100( وما اإذا كانت جل�سة ا�ستخال�ض املعلومات مفيدة )p = 0.015؛ %94.8 مقابل %98.1(. اخلال�صة: اأبدى الطالب ر�ساهم العايل بعد ح�سور جل�سات املحاكاة. ومع ذلك، كان طالب اأمرا�ض الن�ساء واالتوليد اأكرث ر�سا مقارنة باأولئك الذين يدر�سون الطب الباطني. الكلمات املفتاحية: تدريب املحاكاة؛ حماكاة املري�ض؛ تدريب حماكاة عايل الدقة؛ التعليم الطبي يف املرحلة اجلامعية؛ البحرين. outcome of undergraduate medical education using medical simulation according to students’ feedback *salman riaz,1 ahmed a. k. jaradat,2 ruel gutierrez,1 taysir s. garadah1 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e310–315, epub. 5 oct 20 submitted 13 nov 19 revision req. 27 jan 20; revisions recd. 18 feb 20 accepted 10 mar 20 https://doi.org/10.18295/squmj.2020.20.03.010 clinical & basic research advances in knowledge students from obstetrics/gynaecology (obgyn) and internal medicine specialities found simulation-based learning helpful for improving their clinical skills. obgyn students were more satisfied with the clinical simulation sessions than internal medicine students because they were able to practice cases they would not normally be able to work with in ward-based teaching due to reasons such as patient privacy and discomfort. application to patient care simulation can be especially useful for improving clinical skills in specialties that require hands-on practice, but fewer opportunities are given to practice the procedures due to the critical nature of cases or patient concerns. undergraduates can be trained in both technical and non-technical skills using simulation-based education, as it fosters higher retention of knowledge and improves students’ future practice. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ salman riaz, ahmed a. k. jaradat, ruel gutierrez and taysir s. garadah clinical and basic research | 311 clinical skills training is an important part of medical education because it plays a key role in training medical students to become qualified clinicians.1 developing clinical skills requires a systematic approach for solving problems and providing skills appropriate for working with a team of clinicians; however, developing these skills is a major challenge for undergraduate medical students.2 to address this challenge, simulation has been incorporated in undergraduate medical curricula as it provides real experience to students without harming patients.3 research has suggested that simulationbased learning better improves clinical skills and undergraduate comprehension compared to casebased discussions.4 issues such as patient safety, the busy schedules of consultants/specialist doctors, limited availability of real patients for training purposes and other related factors have led to the introduction of simulation laboratories and clinical skills practice centres to train medical students.5 medical simulation is an increasingly familiar tool in many countries and is becoming progressively dominant in medical and surgical training.6–9 research and advancements are needed to develop methods which can be used to address the issue of training undergraduates for clinical skills in the best possible ways. a literature review was conducted and studies from 2006–2016 showed that concern about patient safety is not new, as it is recognised in many countries with global awareness fostered by world health organisation’s world alliance for patient safety which started in 2004.10 however, there is very little literature comparing the usefulness of simulation-based teaching between certain specialities. the medical skills and simulation centre (mssc) at arabian gulf university (agu), manama, bahrain, was launched in january 2018. the aim of the centre is to incorporate medical simulation in the undergraduate medical curriculum, providing a platform for undergraduate medical students to improve their clinical, communication and nontechnical skills (i.e. human factors) so that their practice can contribute to an improved healthcare system. the centre consists of clinical simulation rooms with high-fidelity manikins and part-task trainers which are used along with standardised patients and debriefing rooms. part-task trainers are used to improve skills and high-fidelity simulators are used to improve competencies with full clinical immersion. both provide the opportunity to practice different clinical cases and scenarios. currently, medical simulation is introduced to students in the clinical year (year five) for obgyn and internal medicine specialties. this study aimed to determine the overall satisfaction levels of students at the end of every clinical simulation session and compare these levels between obgyn and internal medicine students. in addition, this study aimed to evaluate the usefulness of high-fidelity manikins and part-task trainers in simulation-based teaching for undergraduate medical students in these two specialties. methods this prospective observational cross-sectional study was conducted from january to june 2019 at agu, manama, bahrain. students in the clinical year (year five) of the doctor of medicine (md) programme were offered five simulation cycles and each cycle had two sessions for a total of 10 sessions in each specialty; these cycles were offered during their rotation in the obgyn (group one) and internal medicine (group two) specialties. the scenarios for simulated sessions were prepared by faculty members, all of whom were experienced doctors with clinical teaching experience. the scenarios were developed in accordance with the curricula of both specialties and were validated by the simulation expert of the mssc. training on the basics of medical simulation, facilitating sessions and using high/low-fidelity manikins was provided to the faculty members by relevant experts before teaching started in the centre. clinical simulation instructors facilitated the sessions, starting with pre-briefing followed by clinical immersion, hands-on clinical practice and debriefing. the instructors were aware that student feedback would be collected at the end of the sessions. the students were divided into groups of seven for each simulation activity; each simulation activity was two hours long. this rotation was repeated on different days to accommodate all the students/groups. in the simulation sessions, two of the students were assigned the role of active participants while other students were observers. jobs were distributed among the observers to closely monitor the active participants for aspects of clinical immersion, such as approaching the patient, taking patient history, conducting clinical examinations, carrying out investigations, undertaking patient management, assessing patient concerns/comfort, communicating with the patient and colleagues and corresponding with a consultant/senior doctor via the phone to present the case for further advice. to maximise the efficacy of the sessions, the observers were also asked to note the strengths and deficiencies of the active participants’ performances for discussion during the debriefing. outcome of undergraduate medical education using medical simulation according to students’ feedback 312 | squ medical journal, august 2020, volume 20, issue 3 istan (cae healthcare, inc., florida, united states), a high-fidelity manikin, was used for the internal medicine sessions. the part-task trainers for this specialty included: (1) a lumbar puncture trainer, (2) opthosim (otosim, inc., toronto, canada) for practicing fundoscopy including retinal pathologies; (3) an abdominal examination trainer with different pathology options including organomegalies, aortic/ renal artery bruit and ascites and (4) other training aids. for obgyn sessions, the high-fidelity manikin, lucina (cae healthcare inc., florida, united states), was used along with part-task trainers that allowed for practicing pertinent skills, such as identifying cervical abnormalities and taking specimens for a cervical smear. at the end of each two-session cycle, student feedback was collected through a five-point likert scale and included eight statements regarding the session, with responses ranging from “strongly agree” to “strongly disagree” [table 1]. the data were stored and analysed using statistical package for the social sciences (spss), version 14.0 (spss, inc., chicago, illinois, usa). descriptive statistical measurements of percentage and mean were used to analyse the data. the students’ overall satisfaction with the simulation sessions was estimated by calculating the percentage of the “strongly agree” and “agree” fields for each item. the “strongly agree” and “agree” responses were assigned a numerical value of one while the remainder of the responses were assigned a numerical value of zero. an independent samples t-test was conducted to compare significant differences in the satisfaction levels between the two groups. a p value <0.05 was considered statistically significant. data collection was halted after six months of offering the sessions, once 75 students had completed their obgyn cycle and the other 75 had completed the internal medicine cycle. this study was approved by the ethics and research committee of agu (e007-pi-04/18). as personal views were required, respect for participants’ rights, anonymity and dignity was given constant consideration. the forms did not collect student names, gender or identification numbers and were kept anonymous. an information sheet stating the purpose and aim of the study was attached to each form. results a total of 150 students participated in this study (response rate: 99.07%). as all students present for the sessions were offered feedback forms at the end of each cycle and there were a total of five different cycles, the potential total feedback was 375 forms. in total, 373 and 370 forms were received from groups one and two, respectively. all forms with incomplete responses were excluded. finally, a total of 371 and 367 forms from groups one and two were used for analyses. the average percentage demonstrating the satisfaction of students was 97.8 ± 2.3% in group one and 95.7 ± 2.7% in group two [table 2]. of the students, 93.3% in group one and 92.4% in group two responded that the prebriefing session was easy to understand (statement one; p = 0.639). moreover, 96.2% and 94.3% of students from groups one and two, respectively, indicated satisfaction that the learning outcomes of the simulation sessions were easy to understand (statement two; p = 0.213). all the students from group one agreed that the simulation sessions were relevant to their clinical practice (statement three); however, only 92.9% of the students in group two found them to be relevant; this finding showed a statistically significant difference between the groups (p <0.001). concerning the opportunity to discuss the sessions during debriefing (statement four), 97% of the students from group one and 95.1% of the students from group two demonstrated satisfaction (p = 0.175). with regard to the usefulness of the debriefing sessions after the simulation experience (statement five), 98.1% and 94.8% of the students from groups one and two, respectively, agreed that they were useful; this finding indicated a significant difference between the two groups (p = 0.015). the competency of the facilitators and staff (statement six) received high levels of satisfaction; 100% from group one and 99.5% from group two (p = 0.154). of the students, 98.4% table 1: statements used to determine students’ satisf action with clinical simulation sessions at the arabian gulf university, manama, bahrain statement number statement* 1 the pre-briefing was easy to understand 2 the learning outcome of the session were easy to understand 3 the session was relevant to your clinical practice 4 you were given the opportunity to discuss this session in the debriefing 5 the debriefing session was useful 6 facilitator/staff in this session were competent 7 the session was useful to you 8 overall, today’s session was good and well organised *a five-point likert scale was used (“strongly agree”, “agree”, “neutral”, “disagree” and “strongly disagree”) salman riaz, ahmed a. k. jaradat, ruel gutierrez and taysir s. garadah clinical and basic research | 313 from group one and 97% from group two found the sessions useful (statement seven; p = 0.211). finally, the percentage of overall satisfaction (statement eight) in both groups was similar; 99.5% and 99.2% in groups one and two, respectively (p = 0.645) [table 3]. discussion the fundamental aim of healthcare education is to produce doctors who not only possess a good level of knowledge but are also capable of practically applying that knowledge.11 applying such knowledge during medical practice means possessing clinical and patient management skills; however, developing these skills is a major challenge for future doctors.5 many international bodies and institutions have universally agreed that, although clinical skills are key to medical practice, most undergraduate students who complete their programmes have theoretical knowledge but lack competence in clinical skills due to inadequate resources and opportunities.5 this persistent issue suggests the need to revise medical curricula and include simulation-based teaching, which provides an opportunity for students to apply their knowledge before beginning clinical practice.11 the findings of this study suggest that students involved in simulation-based training were highly satisfied overall with the sessions, finding them beneficial for practicing what they had previously theoretically learnt. these results are in accordance with a study conducted by agha et al., in which undergraduate medical students reported that simulation-based learning is useful for improving knowledge retention and enhancing decision-making skills.12 moreover, the results agreed with the findings of a study in which medical students found that clinical simulation sessions were a unique opportunity to learn by practicing and the students received feedback on their practice.2 medical education using simulation, therefore, might be used to train doctors who possess the confidence and skills to handle problems in reallife cases at their workplace.11 researchers have demonstrated that competence is directly related table 2: mean scores of participants in the specialties of obstetrics/gynaecology and internal medicine who strongly agreed or agreed with the questionnaire’s statements statement number speciality mean score (%) 1 obgyn 0.932 (93.3) internal medicine 0.923 (92.4) 2 obgyn 0.962 (96.2) internal medicine 0.942 (94.3) 3 obgyn 1 (100) internal medicine 0.929 (92.9) 4 obgyn 0.97 (97) internal medicine 0.95 (95.1) 5 obgyn 0.981 (98.1) internal medicine 0.948 (94.8) 6 obgyn 1 (100) internal medicine 0.994 (99.5) 7 obgyn 0.983 (98.4) internal medicine 0.97 (97) 8 obgyn 0.994 (99.5) internal medicine 0.991 (99.2) overall mean score (mean percentage ± sd) obgyn 0.98 (97.8 ± 2.3) internal medicine 0.96 (95.7 ± 2.7) obgyn = obstetrics and gynaecology; sd = standard deviation. table 3: summary of results by statement response acc ording to specialty statement number specialty n (%)* p value not satisfied satisfied 1 obgyn 25 (6.7) 346 (93.3) 0.639 internal medicine 28 (7.6) 339 (92.4) 2 obgyn 14 (3.8) 357 (96.2) 0.213 internal medicine 21 (5.7) 346 (94.3) 3 obgyn 0 (0) 371 (100) < 0.001 internal medicine 26 (7.1) 341 (92.9) 4 obgyn 11 (3.0) 360 (97.0) 0.175 internal medicine 18 (4.9) 349 (95.1) 5 obgyn 7 (1.9) 364 (98.1) 0.015 internal medicine 19 (5.2) 348 (94.8) 6 obgyn 0 (0) 371 (100) 0.154 internal medicine 2 (0.5) 365 (99.5) 7 obgyn 6 (1.6) 365 (98.4) 0.211 internal medicine 11 (3.0) 356 (97.0) 8 obgyn 2 (0.5) 369 (99.5) 0.645 internal medicine 3 (0.8) 364 (99.2) *internal medicine total response = 367; obgyn total response = 371 obgyn = obstetrics and gynaecology. outcome of undergraduate medical education using medical simulation according to students’ feedback 314 | squ medical journal, august 2020, volume 20, issue 3 to confidence, and simulation-based education can be used to build confidence because it provides opportunities to practice difficult cases without fear of errors.11,13 high-fidelity simulators were used in the mssc to train students from two specialties; the students’ satisfaction demonstrated that, when the high-fidelity simulation was facilitated in the form of small groups, it was preferred to any other laboratory experience.14 the noticeable difference in mean values showed that students in group one were more satisfied than students in group two after attending the simulation sessions. also, results with a low standard deviation in both groups showed that there was little variation among the students’ opinions; most of the students attending the simulation sessions were satisfied. however, two major statements about relevance to clinical practice and usefulness of the debriefing sessions received a significantly different response from both groups. the students in group one felt that the sessions were more relevant to their clinical practice than the students in group two. this finding suggests that group one learners found simulation-based sessions helpful in acquiring specific medical skills required in the obgyn specialty. similarly, group one scored higher than group two on the statement concerning the debriefing sessions’ usefulness. although both groups’ sessions were conducted similarly, using related techniques, resources, high-fidelity manikins, part-task trainers and standardised patients, group one indicated a higher percentage of satisfaction than group two students for every statement. students usually do not receive opportunities to practice certain clinical cases in the obgyn specialty due to the risk of complications and the critical nature of some cases. also contributing to this shortage of opportunities is the desire to prevent patient discomfort, maintain patient privacy and remain culturally sensitive. furthermore, opportunities are not often available in real-time learning in this specialty due to patient safety issues, which is an important consideration. in agu, teaching in this specialty was previously done using traditional medical education methods in which theoretical knowledge was given in didactic sessions and students later observed some cases or practiced on patients.15 although teaching in internal medicine was done in the same way, there are generally fewer privacy and cultural issues restraining students from practicing in ward-based teaching. ultimately, medical simulation is similar to real-time cases, but it provides increased accuracy and no fear of errors.16 the students in group one, therefore, might have found the sessions to be closer to the reality of clinical practice, in addition to providing training in an area otherwise not available to them. the results demonstrated that the students found combining the simulation with traditional medical education methods in the obgyn specialty useful for reducing the shortcomings of medical errors due to lack of practice.17 although this study did not aim to compare simulation-based teaching with clinical placements, previous studies have recommended that simulated sessions should only be an addition to medical curricula and should not replace clinical placements.18 the present study found high satisfaction levels of students in simulation sessions, suggesting that more sessions should be planned for various specialties such as anaesthesia, intensive care medicine, radiology and emergency medicine and for paramedics, nurses and respiratory therapists.19–21 expanding exposure to simulations would provide learning experiences that can improve healthcare practices broadly. simulationbased training might also play a vital role in increasing the competence of undergraduates and junior doctors, especially in acute clinical cases which are difficult to practice because of their rarity and life-threatening nature.22 although the outcomes showed that students were satisfied with the sessions overall, this study faced some limitations. open-ended comments or suggestions were not gathered on the feedback forms; adding them might yield qualitative information about how students understood the scenarios or might present more informed differences between the groups. although information on participants’ genders were not collected, having that data would have been helpful in analysing the results, particularly for the obgyn speciality where male students receive fewer chances to practice with real cases due to patient preferences. future studies, therefore, should enquire about the participants’ gender for more clarity in the analyses. this study was conducted with a small sample size and only two specialties; hence, the findings cannot be generalised. another study with an increased sample size could be planned after one or two years so that there is sufficient time for the courses offered at the centre to be evaluated and improved if necessary. moreover, longitudinal studies could also be conducted to detect changes in responses over time. the findings of the study will be utilised to plan advancements in the centre and future simulation training. although simulation-based learning in this study was specific to two specialties only, the study’s findings can be modified to design courses applicable to more specialties. salman riaz, ahmed a. k. jaradat, ruel gutierrez and taysir s. garadah clinical and basic research | 315 conclusion this study found a high student satisfaction of simulation sessions, indicating that they found simulation-based learning helpful for improving their skills. obgyn students were more satisfied with the sessions compared to internal medicine students. these results were probably due to the fact that simulations are useful for improving clinical skills that require hands-on practice but are difficult to perform. relatively few opportunities to perform these skills are available due to the critical nature of some cases, patient privacy concerns and a desire to avoid patient discomfort in specialties such as gynaecology. concrete, real-life encounters produce higher knowledge and skill retention and help improve the future practices of students. similarly, undergraduates can learn both technical and non-technical skills using simulation-based training including managing rare cases, developing appropriate knowledge, attitudes, and communication skills and directing teams and resources. this study will help university curriculum planners and stakeholders add further simulation sessions for different specialities and improve educational experiences. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s we acknowledge the contribution of misbah tabassum in the preparation, editing, proofreading and review of the manuscript. references 1. wang z, liu q, wang h. medical simulation-based education improves medicos’ clinical skills. j biomed res 2013; 27:81–4. https://doi.org/10.7555/jbr.27.20120131. 2. weller jm. simulation in undergraduate medical education: bridging the gap between theory and practice. med educ 2004; 38:32–8. https://doi.org/10.1111/j.1365-2923.2004.01739.x. 3. vattanavanit v, kawla-ied j, bhurayanontachai r. highfidelity medical simulation training improves medical students’ knowledge and confidence levels in septic shock resuscitation. open access emerg med 2016; 9:1–7. https://doi.org/10.2147/ oaem.s122525. 4. littlewood ke, shilling am, stemland cj, wright eb, kirk ma. high-fidelity simulation is superior to case-based discussion in teaching the management of shock. med teach 2013; 35:e1003–10. https://doi.org/10.3109/0142159x.2012.733043. 5. al-elq ah. simulation-based medical teaching and learning. j family community med 2010; 17:35–40. https://doi. org/10.4103/1319-1683.68787. 6. okuda y, bond w, bonfante g, mclaughlin s, spillane l, wang e, et al. national growth in simulation training within emergency medicine residency programs, 2003-2008. acad emerg med 2008; 15:1113–16. https://doi.org/10.1111/j.15532712.2008.00195.x. 7. leblanc v, bould md, mcnaughton n, brydges r, piquette d, sharma b. 18 simulation in postgraduate medical educ ation co-leads. from: https://pdfs.semanticscholar.org/2f18/0f6 0927d2265145b4e280481d61daf569d16.pdf accessed: feb 2020. 8. issenberg sb, mcgaghie wc, petrusa er, lee gordon d, scalese rj. features and uses of high-fidelity medical simul ations that lead to effective learning: a beme systematic review. med teach 2005; 27:10–28. https://doi.org/10.1080/01421590500046924. 9. mcgaghie wc, issenberg sb, petrusa er, scalese rj. a critical review of simulation based medical education research: 20032009. med educ 2010; 44:50–63. https://doi.org/10.1111/ j.1365-2923.2009.03547.x. 10. emanuel l, berwick d, conway j, et al. what exactly is patient safety? in: henrisken k, battles jb, keyes ma, et al., editors. advances in patient safety: new directions and alternative approaches (vol. 1: assessment). rockvile (md): agency for healthcare research and quality; 2008. available from: https:// www.ncbi.nlm.nih.gov/books/nbk43629. 11. abas t, juma fz. benefits of simulation training in medical education. adv med educ pract 2016; 7:399–400. https://doi. org/10.2147/amep.s110386. 12. agha s, alhamrani ay, khan ma. satisfaction of medical students with simulation-based learning. saudi med j 2015; 36:731–6. https://doi.org/10.15537/smj.2015.6.11501. 13. hecimovich m, volet s. development of professional confidence in health education: research evidence of the impact of guided practice into the profession. health educ 2011; 111:177–97. https://doi.org/10.1108/09654281111123475. 14. euliano ty. small group teaching: clinical correlation with a human patient simulator. adv physiol educ 2001; 25:36–43. https://doi.org/10.1152/advances.2001.25.1.36. 15. zhang my, cheng x, xu ad, luo lp, yang x. clinical simulation training improves the clinical performance of chinese medical students. med educ online 2015; 20:28796. https://doi.org/10.3402/meo.v20.28796. 16. jang hw, kim kj. use of online clinical videos for clinical skills training for medical students: benefits and challenges. bmc med educ 2014; 14:56. https://doi.org/10.1186/1472-6920-14-56. 17. back da, haberstroh n, antolic a, sostmann k, schmidmaier g, hoff e. blended learning approach improves teaching in a problem-based learning environment in orthopedics a pilot study. bmc med educ 2014; 14:17. https://doi.org/10.1186/14 72-6920-14-17. 18. levett-jones t, mccoy m, lapkin s, noble d, hoffman k, dempsey j, et al. the development and psychometric testing of the satisfaction with simulation experience scale. nurse educ today 2011; 31:705–10. https://doi.org/10.1016/j.nedt.2011.0 1.004. 19. flanagan b, nestel d, joseph m. making patient safety the focus: crisis resource management in the undergraduate curriculum. med educ 2004; 38:56–66. https://doi.org/10.1111/j.1365-2923.2 004.01701.x. 20. cherry ra, ali j. current concepts in simulation-based trauma education. j trauma 2008; 65:1186–93. https://doi.org/10.1097/ ta.0b013e318170a75e. 21. jeffries pr. a framework for designing, implementing, and evaluating simulation used as teaching strategies in nursing. nurs educ perspect 2005; 26:96–103. 22. ayres-de-campos d. simulation-based training in obstetrics and gynaecology. from: www.fvvo.be/assets/247/07-ayres-decampos.pdf accessed: feb 2020. https://doi.org/10.7555/jbr.27.20120131 https://doi.org/10.1111/j.1365-2923.2004.01739.x https://doi.org/10.2147/oaem.s122525 https://doi.org/10.2147/oaem.s122525 https://doi.org/10.3109/0142159x.2012.733043 https://doi.org/10.4103/1319-1683.68787 https://doi.org/10.4103/1319-1683.68787 https://doi.org/10.1111/j.1553-2712.2008.00195.x https://doi.org/10.1111/j.1553-2712.2008.00195.x https://doi.org/10.1080/01421590500046924 https://doi.org/10.1111/j.1365-2923.2009.03547.x https://doi.org/10.1111/j.1365-2923.2009.03547.x https://doi.org/10.2147/amep.s110386 https://doi.org/10.2147/amep.s110386 https://doi.org/10.15537/smj.2015.6.11501 https://doi.org/10.1108/09654281111123475 https://doi.org/10.1152/advances.2001.25.1.36 https://doi.org/10.3402/meo.v20.28796 https://doi.org/10.1186/1472-6920-14-56 https://doi.org/10.1186/1472-6920-14-17 https://doi.org/10.1186/1472-6920-14-17 https://doi.org/10.1016/j.nedt.2011.01.004 https://doi.org/10.1016/j.nedt.2011.01.004 https://doi.org/10.1111/j.1365-2923.2004.01701.x https://doi.org/10.1111/j.1365-2923.2004.01701.x https://doi.org/10.1097/ta.0b013e318170a75e https://doi.org/10.1097/ta.0b013e318170a75e sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 442-448, epub. 20th nov 12 submitted 28th jan 12 revision req. 17th apr 12, revision recd. 16th may 12 accepted 4th jul 12 1department of medicine, sultan qaboos university hospital, muscat, oman; departments of 2microbiology & immunology and 3family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: balkhair2000@hotmail.com أنواع العدوى االنتهازية احملددة ملرض العوز املناعي الفريوسي املكتسب )اإليدز( يف جمموعة من 77 مريضا عمانيا مرّقدا مصابا باإليدز )اأ اأ( باخلري، )ز ك( امُلحّرمي، �صيام جاجنويل، علي اجلابري امللخ�ص: الهدف: معظم املضاعفات والوفيات الناجتة عن مرض العوز املناعي الفريوسي املكتسب تنتج من العدوى االنتهازية، يف حني أن نسبة مثل هذه العدوى يف الدول املتقدمة قد مت نشرها، تظل املعلومات من العامل العريب قليلة فيما خيص تارخيه الطبيعي وأعراضه وشفاء املرضى املرّقدين. متت دراسة أنواع ونسبة العدوى االنتهازية بطريقة استعادية يف لفيف من املرضى العمانيني املصابني مبرض العوز املناعي املكتسب املرّقدين يف مستشفى جامعي. الطريقة: مشلت الدراسة 77 مريضا عمانيا مصابا باملرض، مت ترقيدهم يف مستشفى تعليمي ثالثي يف مسقط، ُعمان، يف الفرتة من يناير 1999 إىل ديسمرب 2008. وقد مت التشخيص أثناء الرتقيد األول، حيث مل يتم البدء بالعالج باألدوية املضادة لفريوس العوز املناعي املكتسب. وقد مت حتليل خمتلف النتائج السريرية واملخربية لكل نوع من العدوى االنتهازية. النتائج: كان لدى 45 مريضا )%58( واحدة او أكثر من العدوى االنتهازية احملددة ملرض العوز املناعي الفريوسي املكتسب. كان االلتهاب الرئوي الطفيلي األكثر شيوعا )%25(، تاله التهاب السحايا الفطري )اْلِتهاُب السَّحايا )داُء الدماغي والطفيلي ،)15%( املنتشر والسّل ،)17%( للَخالَيا( َضخُِّم ُ امل )الَفريوُس الفريوسي الشبكية التهاب مث ،)22%( سَتْخِفيات( ُ بامل تـََفطَِّرُة الطَّرْيِيَّة اخللوية، بينما عاىن مريض آخر من داُء اللِّيْشمانِيَّاِت احَلَشِوّي. كان لدى ُ َُقوَّسات( )%12.5(. عاىن مريض واحد فقط من بكترييا امل امل ُمعظم املرضى )%77( خاليا مناعية )سي دي 4( < 200 خلية/ ميكروليرت. تُويف عشرة مرضى )%22( أثناء ترقديهم، مخسة منهم )%50( نتيجة انتشار فريوس تضخم اخلاليا. اخلال�صة: كان هناك طيفا كبريا من أنواع العدوى االنتهازية لدى مرضى العوز املناعي الفريوسي املكتسب املرقدين يف سَتْخِفيات( مها األكثر انتشارا، بينما كان انتشار فريوس تضخم اخلاليا أهم سبب للوفاة. ُ ُعمان. التهاب الطفيل الرئوي والتهاب السحايا الدماغي )بامل نتمىن أن تكون هذه النتائج وسيلة إىل إثراء معرفة املختصني املعاجلني ملرضى فريوس العوز املناعي املكتسب يف ُعمان ومنطقة اخلليج. مفتاح الكلمات: فريو�ض العوز املناعي املكت�صب، مر�ض العوز املناعي املكت�صب، العدوى االنتهازية، ُعمان. abstract: objectives: most of the morbidity and mortality in human immunodeficiency virus/acquired immune deficiency syndrome (hiv/aids) result from opportunistic infections (ois). although the spectrum of ois in hiv infected patients from developing countries has been reported, there is a paucity of data on the natural history, pattern of disease, and survival of hospitalised patients with hiv/aids, particularly in arab countries. the aim of this study was to study retrospectively the spectrum and frequency of various ois in a cohort of hospitalised hiv-infected omani patients. methods: included in the study were 77 hiv-infected omani patients admitted to a tertiary care teaching hospital in muscat, oman, between january 1999 and december 2008. they were diagnosed on their first admission and hence were not on highly active antiretroviral therapy (haart) at presentation. the frequency of various clinical and laboratory findings and individual ois were analysed. results: in total, 45 patients (58%) had one or more aids-defining ois. pneumocystis jiroveci pneumonia (pcp) was commonest (25%), followed by cryptococcal meningitis (22%), cytomegalovirus (cmv), retinitis (17%), disseminated tuberculosis (15%), and cerebral toxoplasmosis (12.5%). only one patient with mycobacterium avium-intracellulare (mai) was identified and one patient had disseminated visceral leishmaniasis. the majority of patients (77%) had cd4+ counts <200 cells/μl. ten patients (22%) died during hospital stays, with five deaths (50%) being caused by disseminated cmv infection. conclusion: a wide spectrum of ois is seen in hospitalised hiv-infected patients in oman. p. jiroveci pneumonia and cryptococcal meningitis were the commonest ois, while disseminated cmv was the commonest cause of death. we hope these results will advance the knowledge of specialists treating hiv in oman and the gulf region. keywords: hiv; aids; opportunistic infections; oman. spectrum of aids defining opportunistic infections in a series of 77 hospitalised hiv-infected omani patients *abdullah a. balkhair,1 zakariya k. al-muharrmi,2 shyam ganguly,3 ali a. al-jabri2 clinical & basic research abdullah a. balkhair, zakariya k. al-muharrmi, shyam ganguly and ali a. al-jabri clinical and basic research | 443 the emergence and pandemic spread of human immunodeficiency virus/acquired immune deficiency syndrome (hiv/aids) constitutes the greatest health challenge in modern times. according to estimates by the world health organization and the joint united nations programme on hiv/aids (unaids), 34 million people were living with hiv at the end of 2010. that same year, some 2.7 million people became newly infected, and 1.8 million died of aids.1 infections associated with severe immunodeficiency are known as opportunistic infections (ois) because they take advantage of a weakened immune system. some of these ois are used to mark the stages of hiv/aids.2 before the widespread use of potent combination antiretroviral therapy (art), ois were the principal cause of morbidity and mortality in hiv-infected patients worldwide. in one study, the mortality rate among individuals with a history of preventable ois was 66.7 per 100 people per year compared with 2.3 per 100 people per year for those without a history of preventable ois.3 the first case of hiv/aids in oman was reported in 1984.4 as of 31st december 2009, 1,119 omanis were living with hiv/aids with more than 50% of them between 15 and 35 years of age. around 100 new cases of hiv/aids are diagnosed annually in oman.5 during 2009, 116 new cases of hiv infection were reported by the ministry of health in oman, which makes it the highest annual number reported since 1995.5 many organisms responsible for ois in patients with hiv/aids have similar clinical presentation and the type of pathogen responsible for morbidity and mortality can vary from region to region. the identification of such pathogens in oman is essential for clinicians providing care for these patients. hence, the present retrospective study was performed to evaluate the spectrum of various ois and determine their relative frequencies in a cohort of hospitalised hiv-infected omani patients. methods this was a retrospective chart review study. a total of 77 omani patients with hiv/aids who were admitted to sultan qaboos university (squ) hospital, muscat, oman, between january 1999 and december 2008 were investigated for a variety of aids-defining ois at the time of their hiv diagnosis. all patients were diagnosed on their first admission and hence were not on highly active antiretroviral therapy (haart) at presentation. appropriate clinical samples, including sputum, bronchoalveolar lavage (bal), cerebrospinal fluid (csf), and bone marrow aspirates, as indicated by the clinical presentation, were collected. computed tomography (ct) and magnetic resonance imaging (mri) scans of the brain, and high resolution ct chest scans were performed as per symptoms and clinical presentations. the following criteria were used to define an oi concern. in the case of cryptococcal meningitis, oi was defined by the demonstration of cryptococcus sp. yeast cells in the csf by india ink staining, antigen presence by latex agglutination, or growth of cells in a culture. in the case of cerebral toxoplasmosis, oi was defined by the demonstration of multiple ring-enhancing cerebral parenchymal lesions on contrast-enhanced ct or mri scans in the presence of anti-toxoplasma antibody in serum and clinical response to antitoxoplasma therapy. in the case of pneumocystis jiroveci pneumonia (pcp), oi was proven through bilateral, diffuse, interstitial infiltrates on chest radiograph or high-resolution ct, with hypoxaemia (pao2 <12 kpa) and/or demonstration of p. jiroveci in induced sputum. in the case of disseminated tuberculosis, oi was defined by clinical features advances in knowledge this study provides a scientific account of the epidemiology of aids defining opportunistic infections (ois) and their burden on omani hiv-infected patients. application to patient care this study provides guidance for developing local guidelines on prophylaxis and management of these infections. the results can be used to guide the hiv/aids programme in oman on future directions in hiv care and how to address the issues relating to late diagnoses. recommendations for primary prophylaxis for aids-defining ois can be made on the basis of these findings, which may be different from those used in industrialised countries. spectrum of aids defining opportunistic infections in a series of 77 hospitalised hiv-infected omani patients 444 | squ medical journal, november 2012, volume 12, issue 4 suggestive of tuberculosis (tb) with concurrent involvement of at least two non-contiguous organs, in the presence of bacteriological and/or histopathological evidence of tb and improvement with anti-tuberculosis therapy. entry and analysis of all available data were performed using the statistical package for the social sciences (spss), version 16.0, (ibm, chicago, il, usa). entered data were double-checked for discrepancies. the frequency of various clinical and laboratory findings and the frequencies of individual ois are expressed as percentages. ethical approval was obtained from the squ ethics and research committee before starting this study. patients’ consent was not required as the study was retrospective. results a total of 77 hiv-positive omani patients were included. their demographic data is presented in table 1. of those participating in the study, 45 patients (58%) (38 ± 12 years, males = 62%) presented with one or more aids-defining ois. in these patients, 72 episodes of aids-defining ois were diagnosed (1.6 oi episodes/patient). during the same hospitalisation period, 24 patients (53%) presented with two or more aids-defining ois. of the patients who presented with one or more oi, 73% were male. as shown in table 2, pcp was the commonest aids-defining oi (25%), followed by cryptococcal meningitis (22%), invasive cmv disease/retinitis (17%), disseminated tb (15%), and cerebral toxoplasmosis (12.5%). only one patient suffered infection with mycobacterium avium-intracellulare (mai). cryptosporidiosis, microsporidiosis, and invasive candida infections presented in 3%, 1.5% and 1.5% of cases, respectively. in addition, one patient had disseminated visceral leishmaniasis. cd4+ cell counts were performed in all 77 patients. the majority of patients (77%) had cd4+ counts of <200 cells/μl at their initial presentation to the hospital. the mean cd4+ cell count was 72 cells/μl in those with aids-defining ois versus 301 cells/μl in the group not suffering from an aidsdefining oi. figure 1 shows mean cd4+ cell counts at the time of diagnosis of each aids-defining oi. a total of 10 patients with aids-defining ois (22%) died during their hospital stays. five deaths (50%) were caused by disseminated cmv infections. the remaining 5 deaths were caused by cryptococcal meningitis (2 patients), cerebral toxoplasmosis (2 patients), and disseminated mai (1 patient). although pcp was the commonest aids-defining oi, no death was attributed to this infection in our cohort. discussion before the widespread use of potent combination art, ois were the principal cause of morbidity and mortality in this population. in the early 1990s, table 1: demographic characteristics of hiv-infected patients total number of patients 77 age in years, mean (range) 37.5 (13–66) male gender, number (%) 48 (62%) cd4 at diagnosis of hiv infection, mean (range) 167 cells/mm3 (1 cell/ mm3–1200 cells/mm3 viral load at diagnosis of hiv infection, mean (range) 330,000 rna copies/ml (60 rna copies/ml–5,000,000 rna copies/ml) rna = ribonucleic acid; hiv = human immunodeficiency virus table 2: aids-defining opportunistic infections (ois) and their frequencies aids-defining oi number of oi events % out of all oi events pcp 18 25 cryptococcal meningitis 16 22 cmv (retinitis/ disseminated) 12 17 tuberculosis (disseminated) 11 15 toxoplasmosis (cerebral) 9 12.5 cryptosporidiosis 2 3 microsporidiosis 1 1.5 candidiasis (invasive/ gastrointestinal) 1 1.5 mai 1 1.5 leishmaniasis (visceral/ disseminated) 1 1.5 total 72 100 aids = acquired immune deficiency syndrome; oi = opportunistic infection; pcp = pneumocystis jiroveci pneumonia; cmv = cytomegalovirus; mai = mycobacterium avium-intracellulare. abdullah a. balkhair, zakariya k. al-muharrmi, shyam ganguly and ali a. al-jabri clinical and basic research | 445 the use of chemoprophylaxis and better strategies for managing acute ois contributed to improved quality of life and patient survival.6 however, the widespread use of art starting in the mid-1990s has had the most profound influence on reducing oi-related mortality in hiv-infected persons in countries where therapies are accessible and affordable.6–8 combination art was offered to <10% of hiv-infected individuals in oman in 2004.9 an estimated 500 omani patients received art in 2008.10 despite the availability of art in oman, ois continue to cause considerable morbidity and mortality for three primary reasons: 1) many patients are unaware of their hiv infection and seek medical care when an oi becomes the initial indicator of their disease; 2) certain patients are aware of their hiv infection, but do not take art, and 3) some patients are prescribed art, but fail to attain adequate virologic and immunologic response because of factors related to adherence, pharmacokinetics, or other unexplained biologic factors.11 thus, although hospitalisation and death from ois have decreased in those countries in which art is accessible and affordable, ois remain a leading cause of morbidity and mortality in hivinfected persons.12 clinicians should be aware of the epidemiology of such infections in oman in order to provide comprehensive high-quality care for these patients. a wide variety of these infections are encountered in the hiv/aids population, including bacteria, fungi, viruses, and protozoa. very often, these represent not new infections but the reactivation of an old infection. in this study, 58% of people who were diagnosed with hiv presented with an aids-defining oi and more than half of them (53%) had two or more ois. the proportion of persons with a cd4+ cell count of <200 cells/μl at the time of hiv infection diagnosis was 77%. this finding is consistent with data from india where 83.4% of patients were late presenters.13 however, data from europe show that only one-third of patients were defined as late hiv presenters.14 both the above findings were interesting. whatever the underlying causes, reducing the number of late-stage diagnoses of hiv infection through earlier and more widespread testing, and promoting early introduction and adherence to art will substantially reduce the burden of ois. as mentioned earlier, 73% of the omani patients who presented with one or more ois were male; this warrants a second mention in order to reference the national percentage and its association with the epidemiology of hiv infections in oman, where males accounted for 74% of all reported hiv/aids cases in 2008.10 figure 1: mean cd4 counts at time of diagnosis of each aids-defining oi. aids = acquired immune deficiency syndrome; oi = opportunistic infection; tb = tuberculosis; pcp = pneumocystis jiroveci pneumonia; cmv = cytomegalovirus; mac/mai = mycobacterium avium complex/mycobacterium avium-intracellulare spectrum of aids defining opportunistic infections in a series of 77 hospitalised hiv-infected omani patients 446 | squ medical journal, november 2012, volume 12, issue 4 pcp was the commonest aids-defining oi, accounting for 25% of all diagnosed oi events in our study. a total of 18 patients (23%) with hiv/ aids had pcp as an aids-defining oi at their first presentation. the prevalence of pcp in our cohort was higher than that reported in lebanon (10.9%), and is very much higher than in europe where only 2–3% of pcp cases were reported among hiv/ aids patients.15,16 before the widespread use of primary pcp prophylaxis and art, pcp occurred in 70–80% of patients with aids.17 all cases in this cohort occurred among patients with cd4+ counts of <200 cells/µl.17 a definitive diagnosis of pcp with a demonstration of organisms in induced sputum samples or bal fluid was made in 11 patients. a presumptive diagnosis of pcp was made in the remaining 7 patients. oral candidiasis was the most common oi (59%) and our finding is similar to that reported in nepal by sharma et al.18 some investigators from india, have reported oral candidiasis as the second most common infection in aids patients, while others have reported very low incidence of candidiasis (27.7%).19,20 mycobacterium tb was the commonest isolate reported in a few studies from hong kong21 and india.22 pulmonary tb was observed in 35% and extra-pulmonary tb in 21% of omani cases. this is similar to data from brazil where pulmonary tb was the commonest oi (52.9%).23 hiv infection is a strong risk factor for active tb in persons with latent m. tuberculosis infection. disseminated tb accounts for 15% of all oi events (14% of all hiv patients). disseminated tb, on the other hand, was reported in 7.8% of the cohort from lebanon.15 in 2008, there were an estimated 1.5 million new cases of tuberculosis among persons with hiv infection, and tb accounted for 26% of aids-related deaths.24 in the same year, 1.4 million patients with tb were tested globally for hiv, and 81 countries tested more than half of their patients with tb for hiv. only 4% of all persons infected with hiv were screened for tb in the same year.25 tb is endemic in some countries like india, and is the commonest cause of death in aids patients.26 hiv patients are at increased risk of developing active tb because of the high rate of reactivation of latent infection and the high degree of susceptibility to new infection.27 cryptosporidium infection was observed in only 3% of omani cases. this is in contrast to data from ethiopia where 21% of hiv patients had cryptosporidium.28 cryptosporidium parvum is an enteric pathogen and a common cause of gastroenteritis in humans. in patients with hiv, cryptosporidiosis may cause potentially fatal complications, including bile duct damage.29 the rate of infection among individuals with hiv/ aids in many countries has subsided considerably because of the use of art.30 cryptococcus neoformans is the most important cause of invasive fungal disease in patients with hiv worldwide. meningitis is the commonest clinical manifestation of invasive cryptococcosis in patients with hiv. in our study, cryptococcus meningitis accounted for 22% of oi events (21% of all hiv patients). indian reports show the incidence of cryptococcal infection (including meningitis) to be only 6–8%, whereas it is about 5–11% in the usa, 33% in africa, and 28.5% in thailand.31 interestingly, none of the patients in the lebanese cohort developed cryptococcal meningitis.15 the exact explanation for such high incidence in oman is unclear. as a result, primary prophylaxis for invasive cryptococcal disease is widely practised by many physicians caring for hiv-infected patients in oman. toxoplasmosis, caused by the protozoon toxoplasma gondii, is one of the major ois afflicting hiv patients. serological tests play a crucial role in the diagnosis of toxoplasmosis in immunecompetent persons.32 the prevalence rate of latent toxoplasmosis in hiv/aids vary from 3–97% based on ethnicity and other factors.33 cerebral toxoplasmosis is the most common cause of focal neurological disorders in hiv patients. in our cohort, cerebral toxoplasmosis accounted for 12.5% of all aids-defining ois (12% of all hiv patients). in a study from lebanon, neurotoxoplasmosis was reported in 21.9% of the hiv-infected patients.15 this striking difference probably reflects differences in social behaviour between the two populations. in our cohort, all patients with cerebral toxoplasmosis had positive igg for toxoplasmosis, ct/mri evidence of compatible brain lesions, and clinical and radiological response to therapy for toxoplasmosis. both mai and leishmaniasis were uncommon in our cohort, accounting for only 1.5% of all aids-associated ois (1.3% of the cohort). primary prophylaxis for mai is not routinely practised in oman. abdullah a. balkhair, zakariya k. al-muharrmi, shyam ganguly and ali a. al-jabri clinical and basic research | 447 conclusion this study shows clearly the necessity of specific measures to prevent ois. although many patients benefit from art, not all patients are willing to take it. many patients cannot tolerate or adhere to the complex drug regimes that constitute this therapy, and immunity may not be restored to a level that substantially reduces the risk of ois in all patients. with better knowledge and diagnosis of ois in hiv patients, clinicians and health planners can tackle the aids epidemic in a more effective manner. specific antimicrobial prophylaxis by itself or in combination with art can reduce the substantial morbidity and mortality caused by ois in patients with hiv infections. early diagnosis of ois and prompt treatment definitely contributes to increased life expectancy among infected patients, thus delaying the progression to aids. references 1. joint united nations programme on hiv/aids (unaids). unaids world aids day report. from: www.unaids.org/en/media/unaids/contentassets/ d o c u m e nt s / u n a i d s p u b l i c at i o n / 2 0 1 1 / j c 2 2 1 6 _ worldaidsday_report_2011_en.pdf. accessed: may 2012. 2. centers for disease control. revised surveillance case definitions for hiv infection among adults, adolescents, and children aged <18 months and for hiv infection and aids among children aged 18 months to <13 years—united states, 2008. mmwr 2008; 57:rr-10. 3. seage gr 3rd, losina e, goldie sj, paltiel ad, kimmel ad, freedberg ka. the relationship of preventable opportunistic infections, hiv-1 rna, and cd4 cell counts to chronic mortality. j acquir immune defic syndr 2002; 30:421–8. 4. ministry of health, oman. community health and disease surveillance newsletter. vol. 17, iss. 1, muscat: ministry of health. from: www.unaids. org/.../2010progressreportssubmittedbycountries/ oman_2010_countr y_prog re ss_re p or t_en.p df. accessed: jul 2010. 5. walensky rp, paltiel ad, losina e, mercincavage lm, schackman br, sax pe, et al. the survival benefits of aids treatment in the united states. j infect dis 2006; 194:11–9. 6. mocroft a, vella s, benfield tl, chiesi a, miller v, gargalianos p, et al. changing patterns of mortality across europe in patients infected with hiv-1. eurosida study group. lancet 1998; 352:1725–30. 7. mcnaghten ad, hanson dl, jones jl, dworkin ms, ward jw. effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after aids diagnosis. adult/adolescent spectrum of disease group. aids 1999; 13:1687– 95. 8. al dhahry sh, scrimgeour em, al suwaid ar, al lawati mr, el khatim hs, al kobaisi mf, et al. human immunodeficiency virus type 1 infection in oman: antiretroviral therapy and frequencies of drug resistance mutations. aids res hum retroviruses 2004; 20:1166–72. 9. kaiser family foundation. reported number of people receiving antiretroviral therapy. from:http:// www.globalhealthfacts.org/topic.jsp?i=10&dsp=c. accessed: jul 2010. 10. perbost i, malafronte b, pradier c, santo ld, dunais b, counillon e, et al. in the era of highly active antiretroviral therapy, why are hiv-infected patients still admitted to hospital for an inaugural opportunistic infection? hiv med 2005; 6:232–9. 11. bonnet f, lewden c, may t, heripret l, jougla e, bevilacqua s, et al. opportunistic infections as causes of death in hiv-infected patients in the haart era in france. scand j infect dis 2005; 37:482–7. 12. mojumdar k, vajpayee m, chauhan nk, mendiratta s. late presenters to hiv care and treatment, identification of associated risk factors in hiv-1 infected indian population. bmc public health 2010; 10:416. 13. antinori a, coenen t, costagiola d, dedes n, ellefson m, gatell j, et al. late presentation of hiv infection: a consensus definition. hiv med 2011; 12:61–4. 14. naba mr, kanafani za, awar gn, kanj ss. profile of opportunistic infections in hiv-infected patients at a tertiary care center in lebanon. j infect public health 2010; 3:130–3. 15. furrer h, egger m, opravil m, bernasconi e, hirschel b, battegay m, et al. discontinuation of primary prophylaxis against pneumocystis carinii pneumonia in hiv-1-infected adults treated with combination antiretroviral therapy. swiss hiv cohort study. n engl j med 1999; 340:1301–6. 16. phair j, munoz a, detels r, kaslow r, rinaldo c, saah a, et al. the risk of pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. multicenter aids cohort study group. n engl j med 1990; 322:161–5. 17. sharma s, dhungana gp, pokhrel bm, rijal bp. opportunistic infections in relation to cd4 level among hiv seropositive patients from central nepal. nepal med coll j 2010; 12:1–4. 18. kaur a, babu pg, jacob m, narasimhan c, ganesh a, saraswathi nk, et al. clinical and laboratory profile of aids in india. j acquir defic synd 1992; 5:883–9. 19. ayyagari a, sharma ak, prasad kn, dhole tn, kishore j, chaudhary g. spectrum of opportunistic spectrum of aids defining opportunistic infections in a series of 77 hospitalised hiv-infected omani patients 448 | squ medical journal, november 2012, volume 12, issue 4 infections in hiv infected cases in a tertiary care hospital. indian j med microbiol 1999; 17:78–80. 20. chan ck, alvarez bognar f, wong kh, leung cc, tam cm, chan kc, et al. the epidemiology and clinical manifestations of human immunodeficiency virus-associated tuberculosis in hong kong. hong kong med j 2010; 16:192–8. 21. kumaraswamy n, solomon s. spectrum of opportunistic infections among aids patient in tamil nadu, india. int j std aids 1995; 6:447–9. 22. santos mde l, ponce ma, vendramini sh, villa tc, santos ns, wysocki ad, et al. the epidemiological dimension of tb/hiv co-infection. rev lat am enfermagem 2009; 17:683–8. 23. harrington m. from hiv to tuberculosis and back again: a tale of activism in 2 pandemics. clin infect dis 2010; 50:s260–6. 24. getahun h, gunneberg c, granich r, nunn p. hiv infection-associated tuberculosis: the epidemiology and the response. clin infect dis 2010; 50:s201–7. 25. swaminathan s, nagendran g. hiv and tuberculosis in india. j biosci 2008; 33:527–37. 26. cruciani m, malena m, bosco o, gatti g, serpelloni g. the impact of human immunodeficiency virus type 1 on infectiousness of tuberculosis: a metaanalysis. clin infect dis 2001; 33:1922–30. 27. assefa s, erko b, medhin g, assefa z, shimelis t. intestinal parasitic infections in relation to hiv/ aids status, diarrhea and cd4 t-cell count. bmc infect dis 2009 9:155. 28. o'hara sp, small aj, gajdos gb, badley ad, chen xm, larusso nf. hiv-1 tat protein suppresses cholangiocyte toll-like receptor 4 expression and defense against cryptosporidium parvum. j infect dis 2009; 199:1195–204. 29. tzipori s, widmer g. a hundred-year retrospective on cryptosporidiosis. trends parasitol 2008; 24:184– 9. 30. satishchandra p, nalini a, gourie-devi m, khanna n, santosh v, ravi v, et al. profile of neurological disorders associated with hiv/aids from bangalore, south india (1986-96). indian j med res 2000; 111:14–23. 31. machala l, malý m, hrdá s, rozsypal h, stanková m, kodym p. antibody response of hiv-infected patients to latent, cerebral and recently acquired toxoplasmosis. eur j clin microbiol infect dis 2009; 28:179–82. 32. nissapatorn v. toxoplasmosis in hiv/aids: a living legacy. southeast asian j trop med public health 2009; 40:1158–78. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. e339-341, epub. 9th may 13 submitted 9th sep 12 revision req. 11th nov 12, reviison recd. 19th nov 12 accepted 12th dec 12 department of family medicine & public health, sultan qaboos university hospital, muscat, oman e-mail: kawther@squ.edu.om خفقان بسبب نوبة صرع العصب الالإرادي د. كوثر طه ال�شفيع امل�شاكل بع�ض و القلب، �رسبات انتظام عدم ب�شبب عادة تنتج و ، الطبية املمار�شة يف ال�شائعة الأعرا�ض من القلب خفقان امللخ�ص: النف�شية اأو اأ�شباب اأخرى متنوعة، مثل فقر الدم اأو خلل الغدد ال�شماء. نادرا ما تكون ب�شبب النوبات ال�رسعية الع�شبية الالاإرادية. نن�رس يف هذا التقرير حالة امراأة تبلغ خم�شة وخم�شني عاما جاءت اإىل م�شت�شفى جامعة ال�شلطان قابو�ض ب�شلطنة عمان ت�شكو من نوبات متكررة من اخلفقان. و�شملت الأعرا�ض املرتبطة بها �شيقًا يف التنف�ض وتعرقًا، يليها الح�شا�ض بالدوار. ويف فرتة لحقة، بداأت ت�شكو من اأعرا�ض اأخرى مثل اآلم يف البطن ثم ترتفع اإىل ال�شدر ويتبعها فقدان للوعي. وقد اأ�شارت نتيجة تخطيط الدماغ اإىل وجود زيادة يف الن�شاط الكهربي باملخ ) �رسع(، وقد ا�شتجابت حالة املري�شة اإىل الأدوية امل�شادة لل�رسع، مما ي�شري بقوة اإىل اأن الت�شخي�ض هو �رسع الف�ض ال�شدغي. لقد اأظهر تخطيط القلب بني النوبات ال�رسعية نتائج طبيعة مما يوؤكد اأن حالة اخلفقان كانت ب�شبب النوبات ال�رسعية الع�شبية الالاإرادية وبناء عليه ينبغي اعتبار ال�رسع �شمن اأحد اأ�شباب زيادة خفقان القلب وب�شفة خا�شة اإذا حدثت اأعرا�ض اخلفقان ب�شورة دورية. مفتاح الكلمات: ا�شطراب �رسبات القلب؛ ال�رسع؛ الف�ض ال�شدغي؛ نوبات؛ تقرير حالة؛ عمان. abstract: palpitations are a common symptom of presentation in medical practice. they are usually caused by cardiac arrhythmias, psychiatric problems or other miscellaneous causes, such as anaemia or endocrine causes. they are rarely due to autonomic seizures. we report a 55-year-old woman who presented at sultan qaboos university hospital, oman, with recurrent episodes of palpitations. her associated symptoms included breathlessness and excessive sweating, followed by a sensation of dizziness. during subsequent episodes, she experienced symptoms of rising abdominal pain followed by a loss of consciousness. positive electroencephalogram findings, as well as the response of the symptoms to antiepileptic drugs, were strongly suggestive of temporal lobe epilepsy as the possible diagnosis. the fact that the cardiac investigations, performed during an interictal period, were unremarkable also supports the hypothesis that the palpitations were linked to seizures. epilepsy should be considered as a differential diagnosis of palpitations, especially if the palpitations are episodic. keywords: arrhythmias, cardiac; epilepsy, temporal lobe; seizures; case report; oman. palpitations caused by a seizure with autonomic features kawther t. el-shafie online case report palpitations are usually caused by cardiac arrhythmias (43%), psychiatric problems (31%), no specific cause (16%) or miscellaneous causes (thyrotoxicosis, anemia, medications or caffeine [10%]).1 palpitations can also be related to neurological problems; they may result from seizures involving the autonomic system, such as complex partial seizures, generalised tonicclonic seizures or simple partial seizures.2 if these are associated with respiratory dysfunction, they may lead to sudden unexpected death in epilepsy (sudep).3 a case of a middle-aged woman presenting with episodes of palpitations, dizziness, breathlessness, increased sweating and presyncope is reported, in which the diagnosis of temporal lobe epilepsy was initially missed. case report a 55-year-old housewife presented to the family medicine & public health clinic of sultan qaboos university hospital, having had recurrent episodes of palpitations over a period of one year. on further exploration of the history, she admitted that these symptoms were associated with breathlessness and increased sweating, followed by a sensation of dizziness and generalised weakness. during these episodes she had a sensation of presyncope, but experienced no loss of consciousness. she palpitations caused by a seizure with autonomic features 340 | squ medical journal, may 2013, volume 13, issue 2 experienced approximately 3 to 4 episodes per day, with each episode lasting a few minutes and unrelated to psychological effort or emotional stress. the patient had sought medical help at different hospitals without success. her past medical, family and social history was unremarkable. she was a non-smoker and there was no family history of epilepsy. on examination, her pulse and blood pressure were normal. blood tests, including a complete blood count, erythrocyte sedimentation rate, electrolytes, glucose, renal and thyroid function tests were all normal. an electrocardiogram (ecg) showed normal sinus rhythm, and a holter ecg did not reveal any cardiac arrhythmia. an electroencephalogram (eeg) was abnormal and showed features of temporal lobe epilepsy (tle). the patient responded to carbamazepine therapy, which controlled her symptoms; she noticed that the symptoms recurred only upon stopping the medication. one year later, the patient presented with episodic symptoms of rising abdominal pain, which started at the epigastric region, radiated upwards to the head and were followed by a loss of consciousness. they were also associated with the palpitations. again, the patient commented that these symptoms also occurred only upon stopping the antiepileptic medication. discussion the clinical features in this case, along with the positive eeg findings, as well as the response of the symptoms to antiepileptic drugs, were strongly suggestive of tle as the possible diagnosis. the recurrence of the symptoms whenever the patient stopped the antiepileptic drugs, and their disappearance after resuming the medication, confirmed this diagnosis. the initial presentation of her tle seemed typical of a simple partial seizure, which can include symptoms of strange or unpleasant sensations in the stomach, chest, or head; changes in heart rate or breathing; sweating, or goose bumps.4 the symptoms of rising abdominal pain which the patient experienced one year later, after stopping the medication, also confirms the diagnosis; this is a symptom known to be related to tle, as has been observed for many decades.5 during this one-year period, the patient experienced losses of consciousness, which indicates the progression of her seizures to complex partial seizures.6 it is difficult in this case to establish the exact link between the palpitations and the tle seizures, because we have no data concerning the cardiac rhythm abnormality, or its relationship to the epileptic event, since the episodes occurred in an unmonitored environment. however, the unremarkable results of the cardiac investigations, which were performed during an interictal period, indicate that our patient’s palpitations were most probably linked to the seizures. it is reported that the ictal autonomic symptoms of complex partial seizures include a variety of symptoms which are related to cardiovascular, respiratory, gastrointestinal, cutaneous, papillary, urinary, genital, and sexual manifestations.7 most of these symptoms manifested in our patient. ictal tachycardia is the most common ecg finding, and accounts for 73–99% of seizures.8 there are additional reports of other types of arrythmias related to epilepsy, such as ictal bradycardia,9 and atrial fibrillation.10 the mechanism behind these ictal autonomic symptoms is believed to be related to the involvement of the central autonomic network. they may accompany other ictal symptoms or may be the predominant seizure.11 it is postulated that seizures originating from the right temporal lobe usually cause tachycardia when there is sympathetic overactivity, while the ones originating from the left side cause bradycardia due to the predominance of parasympathetic activity.12 a c k n o w l e d g e m e n t i am grateful to dr p. c. jacob, neurologist in the department of medicine, college of medicine & health sciences, sultan qaboos universtiy, who also managed this patient and reviewed this article. conclusion this report contributes the case of another subject to the recently growing literature on autonomic dysregulation during epileptic seizures. although cardiac, endocrine and psychiatric disorders are the most common causes of palpitations, seizures should be considered as a possible cause, particularly if the seizures are episodic, and accompanied by kawther t. el-shafie case report | 341 other autonomic symptoms, such as dizziness, sweating, breathlessness, and confusion. references 1. mayou r, sprigings d, birkhead j, price j. characteristics of patients presenting to a cardiac clinic with palpitation. qjm 2003; 96:115–23. 2. gandelman-marton r, segev y, theitler j, rabey j, pollak l. palpitations: could they be neurogenic? a case report. neurologist 2006; 12:160–2. 3. tomson t, nashel l, ryvlin p. sudden unexpected death in epilepsy: current knowledge and future directions. lancet neurol 2008; 7:1021–31. 4. bancaud j, henriksen o, donnadieu f, seino m, dreifuss f, penry j. proposal for revised classification of epilepsies and epileptic syndromes: commission on classification and terminology of the international league against epilepsy. epilepsia 1989; 30:389–99. 5. van buren jm. the abdominal aura: a study of abdominal sensations occurring in epilepsy and produced by depth stimulation. electroencephalogr clin neurophysiol 1963; 15:1–19. 6. bancaud j, henriksen o, rubio f, seino m, dreifuss f, penry j. proposal for revised clinical and electroencephalographic classification of epileptic seizures: from the commission on classification and terminology of the international league against epilepsy. epilepsia 1981; 22:489–501. 7. panayiotopoulos cp. autonomic seizures and autonomic status epilepticus peculiar to childhood: diagnosis and management. epilepsy behav 2004; 5:286–95. 8. nei m, ho rt, sperling mr. ekg abnormalities during partial seizures in refractory epilepsy. epilepsia 2000; 41:542–8. 9. almansori m, ijaz m, ahmed s. cerebral arrhythmia influencing cardiac rhythm: a case of ictal bradycardia. seizure 2006; 15: 459–61. 10. vedovello m, baldacci f, nuti a, cipriani g, ulivi m, vergallo a, et al. peri-ictal prolonged atrial fibrillation after generalized seizures: description of a case and etiopathological considerations. epilepsy behav 2012; 23:377–8. 11. baumgartner c, lurger s, leutmezer f. autonomic symptoms during epileptic seizures. epileptic disord 2001; 3:103–16. 12. oppenheimer sm, gelb a, girvin jp, hachinski vc. cardiovascular effects of human insular cortex stimulation. neurology 1992; 42:1727–32. femoral artery pseudoaneurysms (psa) typically result from percutaneous access for the purpose of angiography and other interventions. psas can be asymptomatic or manifest as a pulsatile mass or thrill. rarely, they rupture leading to a life-threatening shock.1 operative repair has been largely replaced by image-guided occlusion for iatrogenic femoral psas.2 spontaneous femoral psas are extremely rare, and only a few cases have been described in medical literature. we report a large spontaneous psa of the distal part of a superficial femoral artery (sfa) which was successfully treated with covered stents. case report a 62-year-old woman with diabetes, hypertension, and dyslipidemia presented with a one-month history of a painless, gradually enlarging left thigh mass. there was no history of trauma, anticoagulation or interventions. on physical examination, a large pulsatile mass was felt in the posterior aspect of the distal part of the left thigh. the distal pulses were normal with good capillary refilling. a complete blood count, coagulation profile, erythrocyte sedimentation rate, c-reactive protein and other vasculitis screening tests were within normal limits. a duplex ultrasound (us) study revealed a large hypoechoic mass with turbulent flow communicating with the distal part of the sfa via a wide neck, and demonstrating a ‘to-and-fro’ flow pattern [figure 1a]. these findings, typical of a psa, were confirmed by a magnetic resonance imaging (mri) scan [figure 1b]. after discussing the therapeutic options, including operative and endovascular repair, the consensus was to obliterate the psa endovascularly. informed consent was obtained following a discussion with the patient of treatment options, and of the endovascular procedure with its risk and benefits. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. e472-475 epub. 25th jun 13 submitted 27th jun 12 revision req. 4th nov 12; revision recd. 2nd dec 12 accepted 19th dec 12 department of 1radiology & nuclear medicine, university of jordan hospital, amman, jordan; 2department of interventional radiology, boston children’s hospital/harvard medical school, boston, massachusetts, usa; 3department of general surgery, division of cardiothoracic & vascular surgery, university of jordan, amman, jordan *corresponding author e-mail: bestdoctorlolo@yahoo.com ام دم كاذبة تلقائية عمالقة بشريان الفخذ مت عالجه بالدعامات املغطاة تقرير حالة نادرة ومراجعة لألدبيات اأ�شامة �شماره، اآالء �شالح، اأحمد العمري، ن�شيبه الرياالت، عزمي احلديدي، معاذ ال�شمادي امللخ�ص: نعر�س يف هذا التقرير حالة المراأه عمرها 62 �شنة، تقدمت ب�شكوى من كتلة ناب�شة ملدة �شهر بدون �شابق اإ�شابة اأو تداخل. اأظهر الت�شوير اأم دم كاذبة يف اجلزء البعيد لل�رسيان الفخذي ال�شطحي والتي مت عالجها بنجاح با�شتخدام الدعامات املغطاة عن طريق التداخل الوعائي. مفتاح الكلمات: اأم دم كاذبة؛ ال�رسيان الفخذي؛ التداخل الوعائي؛ الدعامات؛ تقرير حالة؛ االأردن. abstract: we report the case of a 62-year-old woman who presented with a one-month history of a pulsatile mass, with no antecedent trauma or intervention. imaging showed a large pseudoaneurysm (psa) of the distal portion of the left superficial femoral artery. the psa was treated successfully with endovascular placement of covered stents. keywords: pseudoaneurysm; femoral artery; endovascular technique; stents; case report; jordan. giant spontaneous femoral artery pseudoaneurysm treated with covered stents report of a rare presentation and review of literature osama samara,1 *alaa i. saleh,1 ahmad alomari,2 nosaiba al ryalat,1 azmy hadidy,1 moaath alsmady3 online case report osama samara, alaa i. saleh, ahmad alomari, nosaiba al ryalat, azmy hadidy and moaath alsmady case report | 473 under local anaesthesia, an antegrade puncture of the left common femoral artery was performed and a 7 french vascular sheath was inserted. an angiography showed an eccentric sac measuring 7 × 6 cm, with a 3 cm wide neck originating from the distal part of the left sfa [figures 2a and b]. no thrombus or contrast extravasation was noted. the rest of the extremity angiogram was normal with no signs of atherosclerosis or vasculitis. intra-arterially, 5000 iu of heparin was instilled. an 8 mm × 10 cm self-expanding gore® viabahn® covered stent (w. l. gore & associates, inc., flagstaff, arizona, usa) was deployed over a 0.035'' j-wire across the neck of the psa under fluoroscopic guidance. however, during the stent deployment, the guide wire was inadvertently retracted, resulting in partial coverage of the psa with part of the covered stent protruding into the psa sac [figure 2c]. the covered stent was pulled out of the sac, the wire was repositioned and the stent was then fully deployed. nonetheless, the sac was only partially excluded [figure 2d]. another 8 mm × 10 cm viabahn® stent was deployed to cover the distal aspect of the psa, which successfully obliterated the neck, restoring normal flow via the stents and distally [figure 2e]. there were no complications. clinical examinations and duplex us studies done at 1 day and 1 week post-procedure, as well as at 1, 2 and 3 months post-procedure, and every 6 months thereafter for 2 years confirmed normal flow and pulses of the stent graft and lower limb with no flow into the psa. discussion a psa is a focal enlargement of the vascular lumen due to the partial or complete disruption of the arterial wall and a contained bleed.3,4 the leaking blood is either contained by the surrounding tissue or by the intact layers of the media or tunica adventitia.5 the aetiology of a psa includes trauma, iatrogenic causes, infection, behçet’s disease, ehlersdanlos syndrome (type iv) and other connective tissue disorders.3–10 a femoral psa is commonly figure 1 a & b: a pseudoaneurysm of the distal superficial femoral artery, depicted in (a) a colour doppler ultrasound image and (b) in a gadoliniumenhanced magnetic resonance angiography. figure 2 a to e: (a & b) arteriograms of the left superficial femoral artery depict the large pseudoaneurysm with a wide neck (between the calibers); (c) the first covered stent is deployed with partial herniation into the pseudoaneurysm (long arrow). note the inadvertent retraction of the guide wire (short arrow); (d & e) completion images of the overlapping covered stents, effectively excluding the pseudoaneurysm. giant spontaneous femoral artery pseudoaneurysm treated with covered stents report of a rare presentation and review of literature 474 | squ medical journal, august 2013, volume 13, issue 3 caused by arterial access for invasive cardiovascular procedures.6 spontaneous femoral psas are extremely rare with a limited number of published reports [table 1]. although origuchi et al. reported a high incidence of spontaneous psa (5.9%), those patients were most likely predisposed to this by atherosclerotic changes.7 similarly, siana et al. reviewed the 5 published reports in english medical literature and found that all of those cases of spontaneous psas had atherosclerotic disease.3 spontaneous psa of the sfa was reported in behçet’s disease.9,10 as in our case, goh et al. reported bilateral psas in a 15-year-old boy which affected the small muscular branches of normal superficial femoral arteries.8 the region around the knee is one of the most common sites for a psa typically related to previous surgical intervention and trauma.4 in the current case, the psa was spontaneous and giant, which is a very rare occurrence. psa occurring in unusual sites or occurring spontaneously, especially in young people, should raise the possibility of vasculitis or connective tissue diseases. however, our patient had no clinical or laboratory evidence of any of these disorders. open surgical repair has traditionally been considered the standard treatment for psas, particularly for large iatrogenic ones.11 since the psa had caused no significant haemodynamic or neurological effects in our patient, a less invasive approach was deemed more desirable. femoral psa secondary to arterial access can be treated with ultrasound-guided compression with 70–100% efficacy.12 there is a better outcome if the psa is slow growing, less than 6 cm, located below the inguinal ligament and has a narrow neck.12 the thrombin injections guided by us have become the treatment of choice for iatrogenic femoral artery psas, with the success rates ranging from 93–100%.13 in our patient, we opted to use a covered stent to exclude the psa in order to avoid early recanalisation of the large lesion. unfortunately, local experience with and literature on thrombin injections for this particular type of lesion were lacking. using coils to embolise the psa was a possible alternative. however, the neck was wide and many coils would have been needed to occlude the psa, which might have left table 1: literature review of spontaneous pseudoaneurysms of the femoral artery report age in years, gender laterality, location size imaging modalities treatment present patient 62, f left sfa, distal 7 x 6 cm us, mra, ca covered stent kouvelas et al.17 (2011) 71, f right sfa, proximal 10 cm cta stent graft siani et al.3 (2008) 86, f left sfa, middle 4 cm us, cta, mra, ca covered stent ramus et al.14 (2007) 74, m left sfa, proximal 4 & 5 cm (bilobed) us, mra, ca covered stent goh et al.8 (2004) 15, m bilateral muscular sfa branches n/a mri, us, ca embolisation & operation origuchi et al.7 (1996) 71, m left common femoral artery 2 cm cta, ca operation lossef et al.15 (2008) 70, m right sfa muscular branch 2.5 mm ca spontaneous obliteration lenartova et al.6 (2003) 82, f right sfa muscular branch n/a ca operation cadir et al.10 (1993) 37, m left common femoral artery n/a ca operation king et al.16 (1994) 72, m left sfa, proximal 2.5 x 2 cm ca operation sfa = superficial femoral artery; us = ultrasound; mri/a: magnetic resonance imaging/angiography; ca = conventional angiography; cta = computed tomography angiography; n/a = not available. osama samara, alaa i. saleh, ahmad alomari, nosaiba al ryalat, azmy hadidy and moaath alsmady case report | 475 a solid mass in a superficial area of the limb. the literature on the use of covered stents for treating spontaneous psas is limited. siana et al. reported an 86-year-old woman with atherosclerosis and an acute spontaneous psa of the superficial femoral artery measuring 4 cm in diameter with a large surrounding haematoma.3 that psa was treated successfully with a viabahn® covered stent. the authors advocated surgical treatment for young patients and endovascular therapy in elderly or unstable patients, and in diffuse atherosclerosis. ramus et al. reported the use of a fluency® plus vascular stent graft (c. r. bard, inc., murray hill, new jersey, usa) for the successful treatment of a superficial femoral psa in a 74-year-old man.14 the patient had several risk factors, including a history of stroke, chronic renal impairment, hypertension, smoking and atrial fibrillation, and was on oral anticoagulation and antihypertensive medications. in addition, he had advanced atherosclerotic changes. the authors provided no long-term follow-up. conclusion in conclusion, we believe the endovascular approach with covered stent placement for the treatment of a rare spontaneous psas may offer a safe and less invasive therapeutic alternative. the long-term outcome of this relatively new approach is still to be validated. references 1. saad ne, saad we, davies mg, waldman dl, fultz pj, rubens dj. pseudoaneurysm and the role of minimally invasive techniques in their management. radiographics 2005; 25:s173–89. 2. morgan r, belli am. current treatment methods for postcatheterization of pseudoaneurysms. j vasc interv radiol 2003; 14:697–710. 3. siani a, flishman i, siani l, mounayergi f, zaccaria a, schioppa a, et al. spontaneous rupture of the superficial femoral artery treated via an endovascular approach. tex heart inst j 2008; 35:66–8. 4. dhillon ms, mccafferty i, davies am, tillman rm. intra-osseous pseudoaneurysm following curettage of an aneurysmal bone cyst. skeletal radiol 2007; 36:s46–9. 5. burli p, winterbottom ap, cousins c, appelton ds, see tc. imaging appearances and endovascular management of uncommon pseudoaneurysms. clin radiol 2008; 63:1254–64. 6. lenartova m, tak t. iatrogenic pseudoaneurysm of femoral artery: case report and literature review. clin med res 2003; 1:243–7. 7. origuchi n, shigematsu h, nunokawa m, yasuhura h, muto t. spontaneous perforation of a nonaneurysmal atherosclerotic abdominal aorta or femoral artery. cardiovasc surg 1996; 4:351–5. 8. goh bk, chen cy, hoe mn. bilateral spontaneous rupture of the muscular branch of the superficial femoral artery with pseudoaneurysm formation. ann vasc surg 2004; 18:736–9. 9. kanko m, ciftci e. spontaneous pseudoaneurysm of the superficial femoral artery in behcet’s disease— endovascular stent graft treatment combined with percutaneous drainage: a case report. heart surg forum 2007; 10:e84–6. 10. cadier ma, watkin g, pope fm, marston a. spontaneous rupture of the femoral arteries. j r soc med 1993; 86:54. 11. henderiks jm, dieleman p, delrue f, d'archambeau o, lauwers p, van schil p. spontaneous pseudoaneurysm of the deep femoral artery treated by a covered stent. acta chir belg 2007; 107:412–5. 12. latic a, delibegovic m, pudic i, latic f, samardzic j, karmela r. non-invasive ultrasound guided compression repair of post puncture femoral pseudoaneurysm. med arh 2011; 65:113–4. 13. vlachou pa, karkos cd, bains s, mccarthy mj, fishwick g, bolia a. percutaneous ultrasoundguided thrombin injection for the treatment of iatrogenic femoral artery pseudoaneurysms. eur j radiol 2011; 77:172–4. 14. ramus jr, gibson m, magee t, torrie p. spontaneous rupture of the superficial femoral artery treated with endovascular stent grafting. cardiovasc intervent radiol 2007; 30:1016–9. 15. king jn, kaupp ha. spontaneuos rupture of the superficial artery with formation of a false aneurysm. j cardiovasc surg (torino) 1970; 11:398–400. 16. lossef sv, gomes mn, barth kh. hemorrhage from spontaneous rupture of muscular branches of the superficial femoral artery. j vasc interv radiol 1994; 5:147–8. 17. kouvelos gn, papa n, matsagkas mi. spontaneous superficial femoral artery giant false aneurysm. anz j surg 2011; 81:655–6. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 147-151, epub. 27th feb 13 submitted 12th jun 12 revision reqd. 6th aug 12, revision recd. 4th sep 12 accepted 6th oct 12 department of child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: anasalwogud@yahoo.com فرط كلس الدم الناتج عن فصل البالزما اأن�ض الوجود عبد املغيث، اإ�صالم البارودى، �صيف اليعربي امللخ�ص: متالزمة جيالن باريه هي مر�ض ي�صيب الأع�صاب واجلذورالع�صبية بالتهاب حاد مما قد يوؤدى اإىل �صلل حركي كلي فىبع�ض احلالت ال�صديدة. ونادرا ما مت ت�صجيل ارتفاع م�صتوى الكال�صيوم بالدم فى هذه املتالزمة. حتتاج هذه اإىل متالزمة اإىل العالج عن طريق ف�صل البالزما وهو اإجراء يتبع لتنقية الدم من ال�صوائب ذات الوزن اجلزيئي الكبري. من الناحية النظرية فاإن ارتفاع الكال�صيوم بالدم مل يو�صف كم�صكلة متعلقة بف�صل البالزما اإل اإذا كان هناك م�صبب اخر اإل اأن ذلك ل مينع اأنها �صجلت بالفعل يف بع�ض احلالت النادرة. نحن نتعر�ض بالدرا�صة حلالة نادرة من متالزمة جيالن باريه وهى طفل يبلغ من العمر 8 �صنوات، اإذ اإنه اإىل جانب الأعرا�ض املعتادة للمر�ض و التي تتلخ�ض يف ال�صداع، وازدواج الروؤية، واحلول متبوعة بفقدان الوعى وال�صلل الكلي بعد مرور اأ�صبوع اإل اأنه وبعد ا�صتجابة الطفل للعالج الذي يتمثل فى اإعطاء الأج�صام امل�صادة عن طريق الوريد وف�صل البالزما مت مالحظة ارتفاع حاد مب�صتوى الكال�صيوم بالدم عن طريق الفح�ض املعملي .كما وجد اأن هذا الرتفاع مرتبط ب�صكل وثيق بجل�صات ف�صل البالزما دون العثور على اأى م�صبب اآخر. مما دعانا اإىل ا�صتعرا�ض مثل تلك احلالت النادرة يف املراجع الطبية يف حماولة لإيجاد تف�صري معقول لها. مفتاح الكلمات: ف�صل البالزما، فرط كال�صيوم الدم، متالزمة جيالن باري،تقرير حالة،عمان. abstract: guillain-barré syndrome (gbs) is an acute inflammatory polyradiculoneuropathy that can cause total motor paralysis in severe cases. reports of hypercalcaemia in patients with gbs are rare. plasmapheresis, an extracorporeal blood purification procedure for the removal of large molecular weight substances, is a wellestablished therapy for ventilated gbs patients. although it has been observed in a few reported cases, theoretically, hypercalcaemia is not described as a plasmapheresis-related problem unless there is an underlying cause. we present a rare case of an 8-year-old child presenting with headache, diplopia, and squint, followed by disturbed conscious levels and paralysis. he was treated with both intravenous immunoglobulin and plasmapheresis, with a favourable outcome. we made a laboratory observation of hypercalcaemia which was associated with the plasmapheresis therapy without any related underlying cause. this raises the need for similar observations and the gathering of other possible acceptable explanations. keywords: plasmapheresis; hypercalcemia; guillain-barré syndrome; case report; oman. plasmapheresis-induced hypercalcaemia *anas-alwogud abdelmogheth, islam el-baroudy, saif al-yaaruby case report guillain–barré syndrome (gbs) is characterised by acute areflexic paralysis with albuminocytologic dissociation (i.e. high levels of protein in the cerebrospinal fluid and normal cell counts). since poliomyelitis has nearly been eliminated, gbs is currently the most frequent cause of acute flaccid paralysis worldwide and constitutes one of the serious emergencies in neurology. a common misconception is that the gbs has a good prognosis, but up to 20% of patients remain severely disabled and approximately 5% die, despite immunotherapy.1 plasmapheresis is a procedure for the removal, treatment, and return of blood plasma or its components to blood circulation. it is also known as therapeutic plasma exchange and is increasingly used in critically ill patients.2 it has been used effectively and safely in the treatment of gbs in children weighing more than 10 kg. the treatment protocol is to perform plasmapheresis 4–6 times on an alternate-day schedule.3 the basic procedure consists of removing blood, separating blood cells from plasma, and then returning those blood cells, which are diluted with fresh plasma substitute, to the body’s circulation. fresh plasma is not routinely used because of concerns over viral contamination or allergic reactions. the most common substitute is a saline solution with sterilised human albumin protein. plasmapheresis requires the insertion of a venous catheter, either in a limb or central vein. the discontinuous flow centrifugation method needs only one venous catheter line. using this, plasmapheresis-induced hypercalcaemia 148 | squ medical journal, february 2013, volume 13, issue 1 approximately 300 ml of blood is removed at a time and centrifuged to separate plasma from blood cells. when blood is outside the body, a citratebased anticoagulant is given to prevent it from clotting—most commonly trisodium citrate or acid citrate dextrose (acd) formula a, the latter being the one that is used in our institute. it has become popular as a regional anticoagulant for these procedures as it minimises the risk of haemorrhage or thrombocytopaenia, which is associated with the use of heparin.4 non-critical hypocalcaemia and metabolic alkalosis have been associated with such treatment. to prevent this complication, calcium is infused intravenously while the patient is undergoing the plasmapheresis.5 hypercalcaemia, although reported anecdotally, is not a common complication of plasmapheresis.6 case report a previously healthy 8-year-old boy was referred to our paediatric ward from the ophthalmology department (opd) of sultan qaboos university hospital, muscat, oman, for evaluation of persistent severe headaches. his history was unremarkable until a few days before presentation when he suddenly had an episode of severe headache followed by diplopia and a convergent squint. the clinical examination revealed normal temperature (36.8° c), a pulse rate of 55–65 beats/minute, a respiratory rate of 30 breaths/minute, and an o2 saturation of 96–98% on room air with good peripheral perfusion. there were no signs of dehydration. the initial neurological examination and the rest of the clinical examinations were unremarkable. an urgent computerised tomography (ct) scan of the brain followed by a magnetic resonance imaging (mri) scan were both completely normal. he was labelled as pseudotumor cerebri and was started on intravenous (iv) methylprednisolone and mannitol. initial laboratory tests showed the following results: haemoglobin 11 g/dl; platelets 338 x 109/l; white blood cells 11.9 x 109; absolute neutrophilic count 9.5 x 109 and lymphocytes 1.8 x 109; haematocrit 0.34 l/l; c-reactive protein (crp) 1 mg/l; erythrocytes sedimentation rate 10 mm/h; sodium (na) 132; potassium (k) 4; creatinine 35; urea 6.8 mmol/l; total calcium (ca) 2.1 mmol/l; ionised ca 1.1; po4 1.1 mmol/l; alkaline phosphatase 247 u/l; albumin 35 g/l, and total protein 69 g/l. arterial blood gas was normal (ph 7.38, pco2 37.8, po2 88.3, hco3 23, be -1.6), and urinalysis , urine culture, and blood cultures were normal until discharge. a coagulation profile was normal with a prothrombin time (pt) of 11.9 seconds, an activated partial thromboplastin time (aptt) of 38 seconds, and an international normalised ratio (inr) of 1.13. on day 6 of admission, the child had a rapid clinical deterioration of consciousness level with severe hypertension and bradycardia, and was moved to the paediatric intensive care unit (picu) where he was ventilated. a repeat ct brain scan and a spinal tap revealed no evidence of increased intracranial tension; it was decided to discontinue the steroids and mannitol. a subsequent set of investigations revealed a positive serum polymerase chain reaction (pcr) for epstein-barr virus (ebv) and a delayed nerve conduction study (ncs). a fluoroscopy-guided lumbar puncture revealed clear cerebral spinal fluid (csf), no white blood cells (wbcs), red blood cells (rbcs) at 450, protein levels at 1.3 g/l, and glucose levels at 3.4 mmol/l. the child then was diagnosed with an atypical presentation of gbs and treated with a two-day course of iv immunoglobulin (2 gm/kg). his blood pressure (b/p) and heart rate were fluctuating, reflecting a severe autonomic labiality that was subsequently controlled by a labetalol infusion. a course of plasmapheresis was tried every other day, for a total of 5 sessions, and the child achieved a dramatic improvement. in accordance with our guidelines, plasmapheresis was initiated with acd formula a, an anticoagulant, in combination with a calciumfree, alkali-free dialysate. however, a cacl2 infusion was held to assess the response following the session. surprisingly, both the total serum ca and the albumin-adjusted ca were high (3.33 and 3.38 mmol/l, respectively). moreover, the ionised ca level was high (1.5 mmol/l). a quick revision for the infused fluid and hydration status, and urine output before and after the procedure was unremarkable as reflected by the following laboratory results: albumin 38 g/l, po4 1.4 mmol/l, na 139, k 3.4, cl 102, bicarbonate 26, creatinine 19, urea 6.5, haematocrit 0.32 l/l, anion gap 11, ph 7.37, and alkaline phosphatase was slightly high (483 u/l). other specific investigations related to hypercalcaemia included normal 25-hydroxy anas-alwogud abdelmogheth, islam el-baroudy and saif al-yaaruby case report | 149 vitamin d 1,25-dihydroxy vitamin d and a normally suppressed parathyroid hormone level of 0.8 pmol/l, free thyroxin 18 pmol/l (10–28 pmol/l), thyroid stimulating hormone (tsh) 3.9 miu/l (0.7–6.4 miu/l) and a cortisol level of 354 nmol/l at 8:00 hrs. frusemide (2 mg/kg/dose) was given after the first session of plasmapheresis and both total ca and albumin-adjusted ca levels normalised before the next session. hypercalcaemia followed by normal calcium levels occurred in all the subsequent sessions of plasmapheresis [figure 1] and the whole set of initial investigations was done following each session [table 1]. interestingly, there were no clinical signs of hypercalcaemia such as headache, irritability, ileus, epigastric pain, bone pains, conjunctivitis, respiratory distress syndrome (rds), or arrhythmia. the episodes were not treated by frusemide and the hypercalcaemia disappeared spontaneously. an electrocardiogram (ecg) was normal after each session. serum ca levels returned to normal after the cessation of the sessions and continued to be normal during one month of follow-up after discharge. intensive physiotherapy was continued over a period of 6 months until the patient experienced a complete recovery. discussion we report a very rare presentation of hypercalcaemia induced by plasmapheresis in a child with gbs. hypocalcaemia is a common side -effect in children exposed to plasmapheresis as the anticoagulant used commonly combines with serum calcium. of interest, the hypercalcaemia was not persistent and occurred only immediately after the plasmapheresis sessions, even though it was normal before, during, and after the sessions. the aetiology of hypercalcaemia falls into two major categories: parathyroid and non-parathyroid. in children and adolescents, hypercalcaemia is most often related to primary hyperparathyroidism. primary hyperparathyroidism is characterised by an excessive secretion of parathyroid hormone (pth) from the parathyroid glands.7 the diagnosis is best confirmed by demonstrating persistent hypercalcaemia in the presence of pth concentrations above the reference interval.8 this diagnosis was ruled out in our case as the hypercalcaemia was transient, with a normal pth value. non-parathyroid causes of hypercalcaemia, including vitamin d toxicity, malignancy, fungal infection, thyrotoxicosis, and addison's disease were ruled out as their clinical manifestations and the laboratory findings (normal levels of thyroid-stimulating hormone [tsh], total and table 1: significant laboratory investigation results before, during, and after the plasmapheresis sessions timing parameter before the sessions 1st session 2nd session 3rd session 4th session 5th session after the sessions after 1 month before after before after before after before after before after ca (albumin adjusted) (2.1-2.55 mmol/l) 2.23 2.3 3.38 2.3 2.94 2.52 3.29 2.59 2.87 2.59 2.64 2.55 2.19 free ca (0.9-1.1 mmol/l) 1.07 1 1.5 1.1 1.38 1.02 1.4 1.1 1.37 1.06 1.34 1.03 1.08 ph (7.35-7.45) 7.37 7.33 7.43 7.38 7.41 7.36 7.41 7.39 7.41 7.33 7.36 7.37 7.39 creatinine (30-47 umol/l) 22 20 19 21 17 18 29 21 21 18 19 18 20 alkaline phosphatase (145-420 u/l) 247 205 483 395 441 405 469 392 436 381 427 308 226 plasmapheresis-induced hypercalcaemia 150 | squ medical journal, february 2013, volume 13, issue 1 free thyroxine, and cortisol, and normal negative cultures and complete blood count [cbc]) did not fit in our case.9 iatrogenic causes such as total parenteral nutrition (tpn) and medications were also reviewed. tpn initially started with 0.5 mmol/ kg/day maintenance calcium on the first day and was discontinued immediately after the first high calcium level. subsequent tpns were calcium-free. vitamin a, thiazide, and theophylline were not used at any time. the hydration status of the patient was observed daily for clinical signs and on a laboratory basis. the patient was found to be euvolemic throughout his illness; we targeted a zero balance daily, especially during the plasmapheresis sessions. moreover, the child did not show any evidence of metabolic acidosis which is commonly associated with hypercalcaemia.9 pseudohypercalcaemia was also excluded in our case as both the total and ionised calcium levels were high.9 more recently, a lot of interest has been directed toward the calcium-sensing receptor (casr) as a regulator of ca metabolism. it is primarily expressed by the kidneys and parathyroid gland controlling pth secretion, and ca reabsorption is performed in the renal tubules based on the extracellular calcium level. inactivation of this receptor can cause hypercalcaemia.10 calcium-citrate complex may affect the bone resorption mechanism leading to calcium efflux from the bone to the blood stream, elevating both total and ionised ca.11 the mildly elevated alkaline phosphatase in our case after each session was indirect evidence that bone resorption had occurred [table 1]. plasmapheresis in some unusual settings, such as in the case of atypical gbs, may affect the extracellular ca balance, therefore inactivating the casrs resulting in hypercalcaemia with an increase in both total and ionised ca. this inactivation is related to the plasmapheresis period; hence, the hypercalcaemia is transient. moreover, there may be a mild and transient ineffective removal by the kidneys of the ca-citrate complex which would also lead to hypercalcaemia. additonally, it is possible that atypical gbs affects the casr as part of the neuropathy; however, we failed to find any association in the literature. conclusion in conclusion, we want to highlight the importance of monitoring changes in plasma ca concentrations during plasmapheresis in order to avoid the routine administration of unnecessary and even dangerous iv ca to patients who may be prone to hypercalcaemia in certain situations. references 1. yuki n, hartung hp. guillain-barré syndrome. n engl j med 2012; 366:2294–304. 2. kaplan aa. therapeutic plasma exchange: core curriculum 2008. american j kidney dis 2008: 52:1180–1219. 3. ryan mm. guillian-barré syndrome in childhood. j paediatr child health 2005; 41:237–41. 4. haupt wf, rosenow f, van der ven c, birkmann c. sequential treatment of guillain-barré syndrome with extracorporeal elimination and intravenous immunoglobulin. j neurol sci 1996; 137:145–9. figure 1: changes in calcium levels before starting and in between the plasmapheresis sessions. anas-alwogud abdelmogheth, islam el-baroudy and saif al-yaaruby case report | 151 5. roberts wh, domen re, walters mi. changes in calcium distribution during therapeutic plasmapheresis. arch pathol lab med 1984;108:881– 3. 6. meythaler jm, korko ab, nanda t, kumar na, fallon m. immobolization hypercalcemia associated with landry-guillian-barré syndrome: successful therapy with combined calcitonin and etidronate. arch intern med 1986; 146:1567–71. 7. kollars j, zarroug ae, van heerden j, lteif a, stavlo p, suarez l, et al. primary hyperparathyroidism in pediatric patients. pediatrics 2005; 115:974–80. 8. davies m, fraser wd, hosking dj. the management of primary hyperparathyroidism. clin endocrinol (oxf ) 2002; 57:145–55. 9. jacobs tp and bilezikian jp. rare causes of hypercalcemia. j clin endocrinol metab (jcem). 2005; 90:6316–22. 10. claudius ia, nakamoto j, fattal o. pediatric hypercalcemia. from: www.emedicine.medscape. com accessed: apr 2012. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. , epub. 8th oct 13 submitted 6th jan 13 revision req. 11th mar 13; revision recd. 1st may 13 accepted 2nd jun 13 1medical center, universiti kebangsaan malaysia, bangi, selangor, malaysia; 2hospital universiti kebangsaan malaysia (hukm), kuala lumpur, malaysia *corresponding author e-mail: dr_faida@hotmail.com الوظيفة االنقباضية وخلل التزامن امليكانيكي داخل البطني متابعة بتقنية التنقيط باملوجات الصوتيه للقلب مع بروهرمون ناتريوتك ببتايد للتنبؤ بالنتائج ملرضى فشل القلب املزمن فايدة اأحمد عبيد، اأوتيه م�ضكون، ف�ضيلة عبدالواحد امللخ�ص: الهدف: هدف هذه الدرا�ضة هو تقييم الوظيفة االنقبا�ضية الطولية و التزامن امليكانيكي داخل البطني و ذلك با�ضتخدام دالئل -probnp( م�ضتقة من تقنية حديثة جلهاز املوجات ال�ضوتيه للقلب وعالقتها برتكيز ال�ضطر االأميني من بروهرمون الناتريوتك ببتايد nt( ولدرا�ضة تـاأثريها على االأحداث امل�ضتقبلية لف�ضل ع�ضلة القلب بعد �ضنة من املتابعة االإكلينيكية و التي مل تو�ضح بعد يف درا�ضات اأخرى. الطريقة: مت ا�ضتخدام التقنية احلديثة جلهاز املوجات ال�ضوتية للقلب من �ضهر اأغ�ضط�ض 2009 اإىل يناير 2012 لفح�ض 103مري�ض والتزامن الطولية االنقبا�ضية القلب وظيفة لتقييم الطبي ماليزيا كبانغ�ضان جامعة مركز يف املزمن القلب ف�ضل مر�ض من يعانون اجلزئي٬ القلب ت�ضارع ٬ الطويل القلب ت�ضارع النتائج: الوقت. نف�ض يف nt-probnp تركيز قيا�ض ومت البطني داخل امليكانيكي االنقبا�ضي ال�ضغط �رسعة ذروة اإىل الوقت من )sd( املعياري االنحراف على باالعتماد البطني داخل امليكانيكي التزامن و االإزاحة متعدد التحليل على باالعتماد القلب. ف�ضل باأحداث ارتبطت )as-p( للخلفي االأمامي احلاجز انقبا�ض وتاأخر واالإزاحة )tsr-sd( ٬nt-probnp ب�ضكل م�ضتقل باأحداث ف�ضل القلب ووجد ارتباط ملمو�ض بني as -pو nt-probnp للمتغريات تنباأت عوامل ت�ضارع القلب الطويل ٬االإزاحة٬ معدل ال�ضغط االنقبا�ضي و ت�ضارع القلب اجلزئي. لوغاريثمnt-probnp ارتبطت ب�ضكل معتدل مع االنحراف املعياري )sd( من الوقت اإىل ذروة االإزاحة وذروة ال�ضغط االنقبا�ضي وارتبطت ب�ضكل ب�ضيط مع الفروق الق�ضوى و )sd( من الوقت اإىل ذروة �رسعة ال�ضغط االنقبا�ضي وباالعتماد على التحليل متعدد للمتغريات و جد اأن تركيز nt-probnp اإرتبطت ب�ضكل ملمو�ض ب�ضن املري�ض و ت�ضارع القلب اجلزئي. اخلال�صة: تقنية متابعة التنقيط باملوجات ال�ضوتية للقلب طريقة واعدة لت�رسيع التطبيق ال�رسيري لتقدير حجم وظيفة ع�ضلة القلب و التزامن امليكانيكي داخل البطني. وهذه التقنية مع زيادة تركيز nt-probnp لديها املقدرة على حتديد املر�ضى االأكرث عر�ضة للوفاه واحلاجة للرتقيد يف امل�ضت�ضفى. مفتاح الكلمات: ف�ضل القلب ٬ تخطيط �ضدى القلب ٬ اختالل البطني االأي�رس ٬ الناتريوتك ببتايد abstract: objectives: the aim of this study was to assess longitudinal systolic function and mechanical synchrony parameters derived from advanced speckle tracking echocardiography (ste) and to determine their correlation with n-terminal prohormone of brain natriuretic peptide (nt-probnp). their influence on heart failure (hf) outcomes at a one-year follow-up, not clarified in previous studies, was also examined. methods: advanced ste was performed from august 2009 to january 2012 in 103 chronic hf patients at the university kebangsaan malaysia medical center to assess their longitudinal systolic function and synchrony parameters; nt-probnp blood measurement was taken at the same time. results: longitudinal cardiac velocity; strain; strain rate; displacement; intraventricular mechanical dyssynchrony based on the standard deviation (sd) of time to peak systolic strain rate (tsr-sd); displacement, and antero-septal to posterior (as-p) delay were associated with cardiac events. in multivariate analysis, nt-probnp and as-p delay were identified as independent predictors for cardiac events. significant correlations were found between nt-probnp and longitudinal velocity; displacement; strain; strain rate, and ejection fraction. log nt-probnp levels correlated moderately with the sd of time to peak displacement and to peak strain, and there was a small correlation with maximal differences and sd of time to peak velocity. a multiple linear analysis revealed that nt-probnp levels significantly correlated to age, ejection fraction and velocity. conclusion: advanced ste is a promising technique which accelerates the clinical application of the quantification of myocardial function and synchrony. ste parameters and nt-probnp have the ability to identify patients at higher risk of death and hospitalisation. keywords: heart failure; echocardiography; left ventricular dysfunction; n-terminal pro-bnp. systolic function and intraventricular mechanical dyssynchrony assessed by advanced speckle tracking imaging with n-terminal prohormone of brain natriuretic peptide for outcome prediction in chronic heart failure patients *faida a. obaid,1 oteh maskon,2 fadillah abdolwahid1 clinical & basic research faida a. obaid, oteh maskon and fadillah abdolwahid clinical and basic research | 552 heart failure (hf) constitutes a major world health problem. despite therapeutic progress, the prognosis for patients with hf remains poor.1,2 one possibility to improve hf management would be early detection and treatment of left ventricular (lv) dysfunction, which has traditionally been evaluated as left ventricular ejection fraction (lvef) and lv endsystolic volume, both regarded as the simplest and most widely used parameters for global assessment of lv function.3 recently, new echocardiographic techniques have been introduced to evaluate myocardial mechanics. tissue doppler imaging (tdi) and two-dimensional (2d) speckle tracking echocardiography (ste) allow more objective quantification of myocardial mechanics in the form of tissue velocities, displacement, strain, strain rate and mechanical dyssynchrony assessment. the tdi technique is limited by angledependency such that only deformation along the ultrasound beam can be derived from velocities while the myocardium deforms simultaneously in three dimensions. ste is a more recent technique that provides a global approach to lv myocardial mechanics, giving information about the three spatial dimensions of cardiac deformation. systolic asynchrony is a relatively common finding in patients with systolic hf and is believed to indicate a more severe form of hf which is prognostically independent of qrs duration.4–9 although systolic asynchrony often exists in patients with systolic hf who commonly have wide qrs complexes, recent studies observed that it also exists in about 30–40% of patients with a normal qrs duration and is related to increased morbidity and mortality.4–8,10 in addition, the correction of dyssynchrony has been shown to improve the immediate haemodynamic effects, symptoms of hf, quality of life, exercise tolerance and survival in patients with chronic heart failure (chf).11–14 chf is currently recognised as a clinical syndrome occurring not only as a result of mechanical dysfunction of the ventricles, but also due to complex molecular, endocrine, neuro-endocrine and inflammatory changes.15 neurohormonal activation plays a fundamental role in the onset and progression of hf, and the use of biochemical markers as prognostic indicators of hf have expanded in the last decade. n-terminal prohormone of brain natriuretic peptide (nt-probnp) has been studied as a biomarker of severity and prognosis of chf in small studies and has shown to be very reliable.16–19 the level of nt-probnp remained predictive of death and of the combined endpoint of death and hospitalisation. we performed this study to assess the prognostic value of multiple parameters of longitudinal systolic function and intraventricular synchrony derived from ste, also considering nt-probnp levels for predicting adverse cardiac events in patients with chf and examined the utility of nt-probnp levels compared to multiple 2d-strain tool ste parameters. methods the study enrolled 150 chf patients who presented to the cardiology unit of the university kebangsaan malaysia (ukm) medical center between august 2009 and january 2012 with signs and symptoms matching the european society of cardiology clinical practice guidelines for heart failure.2 advances in knowledge this is the first study of its kind in malaysia and the middle east that uses multiple parameters derived from the advanced twodimensional strain tool speckle tracking echocardiography (ste) supplemented by n-terminal prohormone of brain natriuretic peptide to predict cardiac events. ste is breaking new ground in heart failure (hf) monitoring and therapy so that treatment can be administrated earlier to high-risk patients as part of a hf management programme. application to patient care: hf management programmes have been developed to reduce the frequency and severity of these clinical events, but their effectiveness may be limited by physicians’ difficulty in identifying patients at imminent risk. reliable prediction may afford physicians the opportunity to intervene aggressively, potentially minimising the need for hospitalisation or the risk of a serious adverse outcome. the study emphasises the importance of promoting and improving cardiac services to hf patients. systolic function and intraventricular mechanical dyssynchrony assessed by advanced speckle tracking imaging with n-terminal prohormone of brain natriuretic peptide for prediction of outcome in chronic heart failure patients 553 | squ medical journal, november 2013, volume 13, issue 4 patients of either gender were recruited according to the following inclusion criteria: ≥20 years old, and chf documented in medical notes. all patients gave written informed consent to take part in the study. patients with severe renal failure (serum creatinine >5 mg/dl), no sinus rhythm, myocardial infarction within the previous 3 months, hf caused by cor pulmonale, congenital heart disease, constrictive pericarditis, hypertrophic or restrictive cardiomyopathy, or ventricular thrombus were excluded. among the 150 patients initially enrolled in the study, 47 were disqualified, leaving 103 patients eligible for analysis. the study was approved by the local ethics committee of ukm. during the health examination, hypertension (ht) was defined by systolic blood pressure ≥140 mmhg, diastolic blood pressure ≥90 mmhg or the use of antihypertensive medication. diabetes mellitus (dm) was defined by a plasma glucose concentration ≥11.1 mmol/l, the use of insulin or other anti-diabetic medicine, self-reported disease or haemoglobin a1c levels ≥6.5%. coronary artery disease (cad) was defined by a history of hospital admission for acute coronary artery syndrome, percutaneous coronary intervention or coronary artery bypass grafting or major ischaemic alterations. lv systolic dysfunction was defined by a lvef <50%. primary endpoints included death or hospitalisation due to the deterioration of hf. hospitalisation for hf was defined as unplanned intravenous treatment of new or worsening hf with inotropic agents, diuretics, or vasodilators requiring an overnight stay in or admission to any healthcare facility. cardiovascular death was defined as sudden cardiac death, or death attributed to hf, a cardiovascular procedure or another cardiovascular cause. all patients were followed-up at the end of 12 months for the occurrence of hf-adverse cardiac events, which was prospectively defined as death, hospitalisation or an outpatient visit for worsening hf that required intensification of treatment. at the time of echocardiographic examination, a blood sample was collected into tubes containing separating gel, processed, and frozen at -80 °c for later measurement of nt-probnp using the cobas e 411 analyzer (roche diagnostics, pleasanton, california, usa). baseline echocardiographic studies were performed in the left lateral decubitus position using a vingmed vivid i ultrasound machine (general electric healthcare, fairfield, connecticut, usa). data acquisition was performed with a 3s transducer and apical views were obtained during breath hold and stored in a cineloop format from 6 consecutive beats. the lv eject was assessed by the biplane simpson’s rule.20,21 for ste analysis, tissue velocity imaging (tvi) 2d images were acquired in apical 2-, 3and 4-chamber views. all of the images were recorded with a frame rate of ≥50 frames per sec (fps) to allow for the reliable operation of the software with the use of vivid e9/echopac for pc, version 110 software (general electric, fairfield, connecticut, usa). from an end-systolic single frame, a region of interest was traced on the endocardial cavity; an automated tracking algorithm followed the endocardium throughout the cardiac cycle. further adjustment of the region of interest was performed to ensure that all of the myocardial regions were included. the so-called ‘speckles’ which were equally distributed in the region of interest could then be followed throughout the entire cardiac cycle. the distance between the speckles was measured as a function of time, and parameters of lv function and myocardial deformation could be calculated. finally, the myocardium was divided into 6 segments that were colour-coded as previously described and displayed into 6 segmental times to peak longitudinal systolic velocity, displacement, strain and strain rate curves.22 for longitudinal analysis, two different parameters for dyssynchrony were obtained: the maximal time delay between two segments in the septum and lateral, antero-septal and posterior walls of the lv. the basal and mid segments, were subjected to the measurement for longitudinal velocity, strain, strain-rate and displacement. apical segments were prospectively excluded because of the relatively low velocity movement of the lv apex. the asynchrony index of the lv was also calculated through the standard deviation (sd) of time-to-peak systolic velocity (tv-sd), strain (tstsd), strain-rate (tsr-sd) and displacement (td-sd), for 12 lv segments.20,23,24 dyssynchrony was defined as the maximal difference in peak longitudinal velocity at the basal and mid segments in opposing walls per view and time to regional peak velocity, strain, strain rate faida a. obaid, oteh maskon and fadillah abdolwahid clinical and basic research | 554 and displacement. these were measured during the ejection phase, and the sd between all 12 segments was used as a measure of dyssynchrony.25,26 data were analysed using the statistical package for the social sciences (spss), version 20 (ibm, corp., chicago, illinois, usa). categorical data were expressed as numbers and percentages, and compared with the chi-square test. data were tested for normality. parametric data were expressed as mean ± sd and compared using the two-tailed student’s t-test. non-parametric data were reported as median and at 25th and 75th percentiles and compared by the mann-whitney u test. log-transformation and square were used to achieve normality in distribution. univariable simple linear regression analysis was used to determine the correlation between echocardiographic parameters and age as independent variables with log nt-probnp levels as a dependent variable. a multivariable linear regression analysis model was used to determine correlations between variables. a logistic regression analysis model was used to determine independent predictors of primary end points at the end of one year. a receiver-operating characteristic (roc) curve was performed to calculate the optimal cut-off values with its sensitivity and specificity for predicting the primary endpoints. a p value of <0.05 was considered statistically significant. results the mean age of the 103 patients in the study (n = 18 female; n = 85 male was 59 ± 10.6 years (range 31–81 years). of these patients, 70 (68%) were hypertensive, 44 (42.7%) were diabetic, 81 (78.6%) had a history of cad and 74 (71.8%) had dyslipidemia. the mean lvef was 37.86 ± 13.23. baseline clinical data of the patients are summarised in table 1. the median nt-probnp level among the 103 patients with systolic and diastolic hf in this study was 711.70 pg/ml (range 5–17,100 pg/ml; inter-quartile range (iqr) = 189.91–2125 pg/ml). simple linear regression analysis was performed between log nt-probnp levels as a dependent parameter and age and other independent parameters of cardiac function and lv intraventricular mechanical dyssynchrony indices derived from advanced ste. these are shown in table 2. there was a strong, negative and highly significant correlation between ef and log nt-probnp levels (r = -0.828, p <0.0001, r2 = 0.65), which implies that 65% of nt-probnp variations can be explained by ef. no correlation was found between age and log nt-probnp levels. the correlation between the parameters derived from the ste average and log nt-probnp levels were strong, negative and table 1: baseline clinical and advanced speckle tracking echocardiography parameters of the study population clinical variables study sample (n = 103) n (%) age in years 59 (± 10.60) male 85 (82.5) female 18 (17.5) ht 70 (68) dm 44 (42.7) cad 81(78.6) dyslipidemia 74 (71.8) nt-probnp level, median (pg/ ml; iqr) 711.70 (189.91‒212.5) echocardiographic variables lvef (%) 37.86 (13.23) average systolic velocity (cm/s) 2.34 (1.36) average strain (%) -9.19 (5.18) average strain rate (s-1) -0.76 (0.27) average displacement (cm) 5.38 (3.37) tv-sd (mins) 71.37 (3.37) tv-diff (mins) 236.26 (69.61) tst-sd (mins) 64.93 (36.76) tstr-sd (mins) 80.51 (24.45) td-sd (mins) 54.85 (33.89) s-l delay, mins (median/iqr) 71 (30‒124) as-p delay, mins (median/iqr) 69 (26‒133) results are presented as mean (standard deviation) for normally distributed parameters and median with inter-quartile range (iqr) 25th and 75th percentiles for non-normally distributed parameters. ht = hypertension; dm = diabetes mellitus; cad = coronary artery disease; nt-probnp = n-terminal prohormone of brain natriuretic peptide; iqr = inter-quartile range; lvef = left ventricular ejection fraction; tv-sd = time to peak systolic velocity; tv-diff = maximal temporal difference of tv; tst-sd = time to peak systolic strain; tsrsd = time to peak systolic strain rate; td-sd = time to peak systolic displacement; s-l = septal to lateral; as-p = antero-septal to posterior. systolic function and intraventricular mechanical dyssynchrony assessed by advanced speckle tracking imaging with n-terminal prohormone of brain natriuretic peptide for prediction of outcome in chronic heart failure patients 555 | squ medical journal, november 2013, volume 13, issue 4 highly significant (r = -0.633, p <0.0001 and r = -0.625, p <0.0001, respectively). additionally, r2 = 0.400 and 0.391, which implies that 40% and 39% of nt-probnp variations can be explained by the longitudinal velocity and displacement, respectively. there was also a strong and highly significant correlation between average and log nt-probnp levels (r = 0.661, p <0.0001 and r = 0.623, p <0.0001, respectively, and r2 = 0.437, 0.388). this implies that 43.7% and 38.8% of nt-probnp variations can be explained by the longitudinal strain and strain rate, respectively. additionally, log nt-probnp levels correlated moderately but significantly with systolic dyssynchrony based on tst-sd and tdsd (r = 0.313, p <0.001 and r = 0.343, p <0.0001, respectively). there was also a small correlation with systolic dyssynchrony based on tv-sd, tsr-s and maximal time difference between 12 segments (tv-diff ) which was statistically significant (r = 0.243, p = 0.01 and r = 0.264, p <0.007, respectively) [figure 1]. this study revealed that there was no relation between nt-probnp levels and age, septal to lateral (s-l) delay, or as-p delay. analyses with a multiple linear regression model to confirm the important variables correlating with nt-probnp, revealed that nt-probnp levels were independently related to age, ef and longitudinal systolic velocity, and were significantly correlated to nt-pro bnp levels [table 2]. adjusted, these statistics can be expressed as r2 = 0.72, p <0.0001, which implies that 72% of the variability in nt-probnp levels can be explained by independent variables, and the ef was the strongest predictor of nt-probnp levels (β = 0.774, p <0.0001). after 12 months, 35 of 103 patients (33.98%) had reached the primary endpoint; there were 22 (21.36%) hospitalisations for hf deterioration and 13 (12.62%) cardiac deaths. the significant characteristics of all patients are listed in table 3. patients with high baseline nt-probnp levels were more prone to cardiac events than those with low nt-probnp levels. figure 1 a & b. scatter plots showing the correlation between log n-terminal prohormone of brain natriuretic peptide level and a: ejection fraction and b: longitudinal strain. table 2: linear regressions in univariate and multivariate analyses correlation of log n-terminal prohormone of brain natriuretic peptide levels to age and advanced speckle tracking echocardiography parameters univariate linear regression multiple linear regression r r2 p β p age -0.002 0 0.987 0.176 0.001 lvef -0.828 0.685 0.0001 0.774 0.0001 strain 0.661 0.437 0.0001 strain rate 0.623 0.388 0.0001 displacement -0.625 0.391 0.0001 average velocity -0.633 0.4 0.0001 -0.141 0.045 s-l delay 0.011 0 0.913 as-p delay 0.041 0.002 0.679 tv-sd 0.243 0.059 0.014 tv-diff 0.264 0.07 0.007 0.124 0.026 tst-sd 0.313 0.098 0.001 tsr-sd 0.285 0.081 0.004 td-sd 0.343 0.118 0.0001 correlation is significant at < 0.05 level. lvef = left ventricular ejection fraction; s-l = septal to lateral; as-p = antero-septal to posterior; tv-sd = time to peak systolic velocity; tv-diff = maximal temporal difference of tv; tst-sd = time to peak systolic strain; tsr-sd = time to peak systolic strain rate; td-sd = time to peak systolic displacement. faida a. obaid, oteh maskon and fadillah abdolwahid clinical and basic research | 556 multivariate logistic regression analysis demonstrated that independent predictors for cardiac events were nt-probnp levels and as-p delay (p <0.0001 and 0.049, respectively). the overall accuracy of this model to predict subjects prone to clinical events was 76.7% with 51.43% sensitivity and 89.70% specificity. positive predictive value (ppv) was 72% and negative predictive value (npv) was 78.2%. in the receiver-operating characteristic curve (roc) curve analysis, a 948.5 pg/ml nt-probnp cut-off value revealed a sensitivity of 74.3% and specificity of 71% for the prediction of cardiac events. the area under the roc in predicting cardiac events was found to be 0.780 (95% ci, 0.681–0.880) for nt-probnp [figure 2]. the results of cardiac function and mechanical lv dyssynchrony indices assessed by ste are displayed in table 3. parameters were measured from 12 segments obtained from apical 4-, 2and 3-chamber views and then averaged according to longitudinal velocity, strain, strain rate and displacement. there were significant differences (p 0.0001) in these parameters between the two groups of clinical events. the lv intraventricular delay, as measured by the sd of 12 segments derived from the 2d strain tool ste through measurement of tsr-sd: p 0.022; td-sd: p 0.028 and the as-p delay (p 0.035) were prolonged and provided significant differences between the two groups of clinical events. however, the lv intraventricular delay (as measured by the sd of a 12-segment tst-sd, tv-sd, maximal tv-diff between 12 segments and s-l delay) were prolonged figure 2. receiver-operating characteristic curve analysis to determine the optimal cut-off value of n-terminal prohormone of brain natriuretic peptide (nt-pro bnp) for prediction of cardiac events at the end of 12 months in 103 patients. parameters: nt-pro bnp; cut-off: 948.5; area under the curve: 0.780; sensitivity: 74.3%; specificity: 71%. table 3: clinical and advanced speckle tracking echocardiography parameters between two groups of cardiac events clinical events no n = 68 yes n = 35 p value clinical variables age in years 59 (11) 57 (9) 0.352 female gender, n (%) 13 (19) 5 (14) male gender, n (%) 55 (81) 30 (85.7) 0.541 cad, n (%) 52 (76.5) 29 (83) 0.454 dm, n (%) 27 (39.7) 17 (48.6) 0.389 ht, n (%) 47 (69) 23 (65.7) 0.726 dyslipidemia, n (%) 48 (70.6) 26 (74.3) 0.693 nt-probnp, n (iqr) 428 (118.9‒1195.5) 2125 (936‒4307) 0.0001 echocardiographic variables n (%) lvef, mean (sd) 42 (12) 29.8 (11) 0.0001 average velocity in cm/sec, mean (sd) 2.7 (1) 1.5 (1) 0.0001 average strain, mean (sd) -10.42 (5) -6.8 (4.8) 0.0001 average strain rate s-1, mean (sd) -0.82 (28) 0.6 (0.23) 0.001 average displacement in cm, mean (sd) 6.2 (3.4) 3.79 (2.81) 0.001 tv-sd in mins, mean (sd) 71.7 (23.3) 79.50 (26.7) 0.147 tv-diff in mins, mean (sd) 228 (65.7) 252.40 (75) 0.108 tst-sd in mins, mean (sd) 61.54 (36.6) 71.50 (36.7) 0.196 tstr-sd in mins, mean (sd) 76.6 (23.7) 88.3 (21.5) 0.022 td-sd in mins, median (iqr) 50.13 (33.3) 64 (33.6) 0.028 s-l delay in mins, median (iqr) 74 (30‒130) 86 (30‒160) 0.126 as-p delay in mins, median (iqr) 49 (21‒100) 110 (47‒181) 0.035 cad = coronary artery disease; dm = diabetes mellitus; ht = hypertension; nt-probnp = n-terminal prohormone of brain natriuretic peptide; lvef = left ventricular ejection fraction; sd = standard deviation; tv-sd = time to peak systolic velocity; tv-diff = maximal temporal difference of tv; tst-sd = time to peak systolic strain; tsr-sd = time to peak systolic strain rate; td-sd = time to peak systolic displacement; s-l = septal to lateral; as-p = antero-septal to posterior. systolic function and intraventricular mechanical dyssynchrony assessed by advanced speckle tracking imaging with n-terminal prohormone of brain natriuretic peptide for prediction of outcome in chronic heart failure patients 557 | squ medical journal, november 2013, volume 13, issue 4 and statistically provided no significant differences between the two groups of clinical events. clinical and echocardiographic data for the two groups are summarised in table 3. clinical and echocardiographic parameters were investigated for their predictive value for clinical events by bivariate and multivariate analyses. in bivariate analysis, there was a higher prevalence of cad (83%) and dyslipidemia (75%) among patients who developed cardiac events. on the other hand, ht (66.7%) and dm (50%) were less prevalent in this group. however, the p value was not significant. longitudinal cardiac function, average ef, nt-probnp and intra-ventricular mechanical dyssynchrony were significantly associated with the development of clinical events [table 3]. nt-probnp and as-p delay were identified as the independent predictors of cardiac events (p 0.0001 and 0.035, respectively). the overall accuracy of this model to predict subjects having clinical events was 76.7% with 51.4% sensitivity and 89.7% specificity. the positive predictive value was 72% and the negative predictive value 78.2%. we constructed the roc curve to determine the optimal, average strain, average strain rate, tsr-sd and as-p delay cut-off value for predicting clinical events. discussion ste is a novel method of quantifying global and regional cardiac longitudinal function from routine b-mode grey-scale images.27,28 tracking patterns of speckles quantifies tissue deformation without the directionality constraints of doppler techniques. image degradation and throughplane motion both compromise ste. temporal resolution is lower than that obtained through tdi techniques. conventionally, defining the region of interest remains user-dependent. the endocardial and epicardial borders are manually traced and fine-tuned to include all segments throughout the cardiac cycle.27,28 further adjustment is undertaken to optimise the tracking stability score.27 in this study, the more advanced 2d-strain tool was applied by using tvi scans in which the 2d-strain tool optimally combines tvi for a more comprehensive analysis and increased sensitivity. it has a built-in quality assurance that automatically evaluates the reliability of the results by looking at the variability of velocities in small tissue areas. it then chooses which acoustic markers to track, making the tool more robust than traditional ste. this is the first study of its kind in malaysia and the middle east that uses multiple parameters derived from the advanced ste and biomarkers to predict cardiac outcome of patients with chf by determining lv dysfunction and intraventricular dyssynchrony parameters. considering the high worldwide cardiac death rate, we need to identify high-risk patients to reduce morbidity and mortality. in this study, there was a higher prevalence of cad (83%) and dyslipidemia (74.3%) among patients who developed cardiac events. on the other hand, ht (65.7%) and dm (48.6%) were less prevalent but not significant. there were significant correlations between nt-probnp and some echocardiographic parameters; on the other hand, there was a correlation with advanced clinical cardiac outcome. our findings are in accordance with other studies which showed that nt-probnp levels are important in predicting cardiac events in hf patients. this study emphasised that some echocardiography parameters and nt-probnp levels provide a powerful incremental assessment of lv function and the prediction of adverse cardiac outcome. elevated nt-probnp levels correlated with several important echocardiographic parameters of systolic and diastolic hf. the clinical applications of ste-derived myocardial velocity, displacement, strain and strain rate measurements are very promising for the assessment of lv function and the prediction of cardiac events at one-year follow-up; however, further refinement is required. advanced ste has an advantage of ease of application and analysis. numerous echocardiographic techniques have been proposed for the assessment of lv function and intraventricular dyssynchrony, and echocardiographic dyssynchrony has been the subject of numerous publications. the currently observed differences between the results provided by different echocardiographic modalities is not entirely surprising since the methods represent independent approaches to the assessment of lv function and dyssynchrony. the lack of standardisation of imaging planes and different speckle tracking algorithms among vendors make comparisons or the establishment of normal values faida a. obaid, oteh maskon and fadillah abdolwahid clinical and basic research | 558 with high levels of confidence difficult. the recently published prospect trial tested 12 different techniques to describe dyssynchrony and concluded that no single technique can be recommended as a standard.29 echocardiographic parameters have largely been studied in small, non-randomised studies with surrogate endpoints. however, prospect identified that, outside of expert centres, reduced test reproducibility and marked intra-observer variability limited the clinical utility of many echocardiographic techniques.29,30 in particular, the automated processing algorithm reduces the impact of operator skill and improves reproducibility while reducing analysis time. the most recent expert consensus reported that there is a lack of scientifically verified data and all the statements and recommendations are primarily based on the opinions of experts and cannot provide an evidence base for potential clinical applications of this technique in multiple clinical scenarios. they therefore concluded that this methodology is not yet ready for routine clinical use.31 the present study demonstrates that evaluation of lv function and intra-ventricular dyssynchrony using advanced 2d strain tool speckle tracking analysis is feasible and predicts the cardiac outcome in heart failure patients. no data exist on this advanced 2d strain tool as a comprehensive tool. the implications of these research findings are ground-breaking in hf monitoring and therapy, allowing earlier treatment and hf management to be administrated to high-risk patients. this study emphasises the importance of promoting and improving cardiac services to hf patients. the limitations of this technique include the significant time required for post-processing; differences among vendors, driven by the fact that ste analysis is performed on data stored in a proprietary scan line format which cannot be analysed by other vendors’ software; limited experience in cross-comparing data from different vendors’ images, and the need for further investigation. all echocardiography measurements in this study were obtained by a single cardiologist without intraor inter-observer variability. this study did not compare circumferential or radial fibres function with longitudinal fibres function. conclusion the advanced 2d-strain tool ste is a promising technique which is accelerating the clinical application of the quantification of myocardial velocity and deformation. one important advantage is based on its tvi and grey-scale images, with their comprehensive analyses which are independent of angle of incidence and less dependent on image quality, making it the most robust technique. ste is a reliable and feasible tool for evaluating longitudinal myocardial function and synchrony, and also allows the further identification of patients at higher risk of death and hospitalisation. it appears more trustworthy than conventional ste and tdi; however, further studies need to be done before it is implemented widely in clinical practice. references 1. cleland jg, swedberg k, follath f. the euroheart failure survey programme: a survey on the quality of care among patients with heart failure in europe. part 1: patient characteristics and diagnosis. eur heart j 2003; 24:442–63. 2. swedberg k, cleland j, dargie h, drexler h, follath f, komajda m, et al. guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the task force for the diagnosis and treatment of chronic heart failure of the european society of cardiology. eur heart j 2005; 26:1115–40. 3. edvardsen t, helle-valle t, smiseth o. systolic dysfunction in heart failure with normal ejection fraction: speckle-tracking echocardiography. prog cardiov diseases 2006; 49:207–14. 4. yu cm, lin h, zhang q, sanderson je. high prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal qrs duration. heart 2003; 89:54–60. 5. ghio s, constantin c, klersy c, serio a, fontana a, campana c, et al. interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of qrs duration. eur heart j 2004; 25:571–8. 6. bleeker gb, schali j, martin j, molhoek sg, verwey hf, holman er, et al. relationship between qrs duration and left ventricular dyssynchrony in patients with endstage heart failure. j cardiovasc electrophysiol 2004; 15:544–9. 7. sade le, kanzaki h, severyn d, dohi k, gorcsan j, iii. quantification of radial mechanical dyssynchrony in patients with left bundle branch block and idiopathic dilated cardiomyopathy without conduction delay by tissue displacement imaging. am j cardiol 2004; 94:514–18. 8. bader h, garrigue s, lafitte s, reuter s, jais systolic function and intraventricular mechanical dyssynchrony assessed by advanced speckle tracking imaging with n-terminal prohormone of brain natriuretic peptide for prediction of outcome in chronic heart failure patients 559 | squ medical journal, november 2013, volume 13, issue 4 p, haissaguerre m, et al. intra-left ventricular electromechanical asynchrony. a new independent predictor of severe cardiac events in heart failure patients. j am coll cardiol 2004; 43:248–56. 9. cho gy, song jk, park wj, han sw, choi sh, doo yc, et al. mechanical dyssynchrony assessed by tissue doppler imaging is a powerful predictor of mortality in congestive heart failure with normal qrs duration. j am coll cardiol 2005; 46:2237–43. 10. fauchier l, marie o, casset-senon d, babuty d, cosnay p, fauchier jp. interventricular and intraventricular dyssynchrony in idiopathic dilated cardiomyopathy. j am coll cardiol 2002; 40:2022–30. 11. abraham wt, fisher wg, smith al, delurgio db, leon ar, loh e, et al. multicenter insync randomized clinical evaluation. cardiac resynchronization in chronic heart failure. n engl j med 2002; 24:1845–53. 12. bristow mr, saxon la, boehmer j, krueger s, kass da, de marco t, et al. cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. n engl j med 2004; 350:2140–50. 13. cleland jg, daubert jc, erdmann e, freemantle n, gras d, kappenberger l, et al. the effect of cardiac resynchronization on morbidity and mortality in heart failure. n engl j med 2005; 352:1539–49. 14. yu cm, chau e, sanderson je, fan k, tang mo, fung wh, et al. tissue doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. circulation 2002; 105:438–45. 15. buunwald e, bristow mr. congestive heart failure: fifty years of progress. circulation 2000; 102:iv14–23. 16. hartmann f, packer m, coats ajs, fowler mb, krum h, mohacsi p, et al. prognostic impact of plasma n-terminal pro-brain natriuretic peptide in severe chronic conges¬tive heart failure: a substudy of the carvedilol prospective randomised cumulative survival (copernicus) trial. circulation 2004; 110:1780–6. 17. gardner rs, ozalp f, murday aj, robb sd, mcdonagh ta. n-terminal pro-brain natriuretic peptide: a new gold standard in predicting mortality in patients with advanced heart failure. eur heart fail 2003; 24:1735–43. 18. song bg, jeon es, kim yh, kang mk, doh jh, kim ph, et al. correlation between levels of pro-btype natriuretic peptide and degrees of heart failure. korean j inter med 2005; 20:26–32. 19. weber t, auer j, eber b. the diagnostic and prognostic value of brain natriuretic peptide and aminoterminal (nt)-pro brain natriuretic peptide. curr pharm des 2005; 11:511–25. 20. gorcsan j, kanzaki h, bazaz r, dohi k, schwartzman d. usefulness of echocardiographic tissue synchronization imaging to predict acute response to cardiac resynchronization therapy. am j cardiol 2004; 93:1178–81. 21. dohi k, suffoletto ms, schwartzman d, ganz l, pinsky mr, gorcsan, j. utility of echocardiographic radial strain imaging to quantify left ventricular dyssynchrony and predict acute response to cardiac resynchronization therapy. am j cardiol 2005; 96:112–16. 22. perk g, tunick pa, kronzon i. non-doppler twodimensional strain imaging by echocardiography— from technical considerations to clinical applications. j am soc echocardiogr 2007; 20:234–43. 23. yu cm, chau e, sanderson je, fan k, tang mo, fung wh, et al. tissue doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. circulation 2002; 105:438–45. 24. sutton mg, plappert t, abraham wt, smith al, delurgio db, leon ar, et al. multicenter insync randomized clinical evaluation (miracle) study group. effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. circulation 2003; 107:1985–90. 25. yu cm, fung jw, zhang q, chan ck, chan ys, lin h, et al. tissue doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. circulation 2004; 110:66–73. 26. yu cm, bax jj, gorcsan j. critical appraisal of methods to assess mechanical dyssynchrony. curr opin cardiol 2009; 24:18–28. 27. gorcsan j, tanabe m, bleeker gb, suffoletto ms, thomas nc, saba s, et al. combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization therapy. j am coll cardiol 2007; 50:1476–83. 28. suffoletto ms, dohi k, cannesson m, saba s, gorcsan j. novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. circulation 2006; 113:960– 8. 29. chung es, leon ar, tavazzi l, sun jp, nihoyannopoulos p, merlino j, abraham wt, et al. results of the predictors of response to crt (prospect) trial. circulation 2008; 117:2608–16. 30. bax jj, gorcsan j iii. echocardiography and noninvasive imaging in cardiac resynchronization therapy: results of the prospect (predictors of response to cardiac resynchronization therapy) study in perspective. j am coll cardiol 2009; 53:1933–43. 31. mor-avi v, lang rm, badano lp, belohlavek m, cardim nm, derumeaux g, et al. current and evolving echocardiographic techniques for quantitative evaluation of cardiac mechanics: ase/eae consensus statement on methodology and indications: endorsed by the japanese society of echocardiography. j am soc echocardiogr 2011; 24:277–313. jyoti burad, sonali deoskar, pradipta bhakta, rohit date and pradeep sharma case report | e405 department of anaesthesia & intensive care, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: jyotiburad@yahoo.com the insertion of a gastric tube (gt) is a common day-to-day procedure in medical practice.1‒4 a gt is usually inserted to provide a patient with enteral nutrition, to administer medicines and, in some cases, to decompress the stomach.1‒5 normally, a gt is inserted usually inserted blindly in a patient. it is a seemingly simple procedure but can sometimes result in serious complications in unconscious patients.1,2,6 this case report highlights an incident where a patient experienced laryngeal injuries due to the blind insertion of an orogastric tube (ogt). as the patient was anaesthetised, she could not respond to the impact on her larynx. the authors propose a simple solution to make this procedure less traumatic for unconscious patients. consent for the write-up and publication of this paper was obtained from the patient. case report a 52-year-old woman was referred to the sultan qaboos university hospital in muscat, oman, for the coiling of a right carotico-ophthalmic aneurysm. she had been diagnosed with bronchial asthma as well as renal calculi (there were two calculi on the right side measuring approximately 10 x 5 mm and 4 x 7 mm in size). she was taking salbutamol (two puffs twice daily) which she had been prescribed for bronchial asthma. she was also on several other medications which could have predisposed her to gastrointestinal (gi) bleeding, such as clopidogrel (75 mg twice daily), aspirin (81 mg once daily), nimodipine (30 mg every four hours) and diclofenac (75 mg as required). there were no signs or symptoms suggestive of reflux oesophagitis, such as heartburn, dyspepsia, chest pain, hoarseness, sore throat, cough or the onset of asthma by heartburn. moreover, there were no positive risk factors for reflux oesophagitis, including obesity, smoking, alcohol consumption, specific food habits, pregnancy, diabetes, a prior vagotomy or surgery, or an intake of anticholinergic, nitrate and bisphosphonate medications. the patient took diclofenac infrequently for knee pain. she had bronchial asthma but it was seasonal and was not sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e405-408, epub. 24th jul 14 submitted 5th dec 13 revision req. 12th feb 14; revision recd. 14th mar 14 accepted 24th apr 14 جتنب إصابة احلنجرة عند إدخال األنبوب الغذائي إىل املعدة جيوتي بوراد، �سونايل ديو�سكار، براديبتا بهاكتا، روهيت ديت، براديب �سارما abstract: gastric intubation is a common and simple procedure that is often performed on patients who are sedated or anaesthetised. if the gastric tube (gt) is inserted blindly while the patient is unconscious, this procedure may result in easily preventable complications such as laryngeal trauma. we present an interesting case where the blind placement of a orogastric tube (ogt) in an anesthetised 52-year-old female patient at sultan qaboos university hospital in oman resulted in significant arytenoid trauma. this led to delayed tracheal extubation. the movement of the gt from the oropharyngeal area to the upper oesophageal sphincter can be visualised and controlled with the use of magill forceps and a laryngoscope. therefore, this report highlights the need for gt insertion procedures to be performed under direct vision in patients who are unconscious (due to sedation, anaesthesia or an inherent condition) in order to prevent trauma to the laryngeal structures. keywords: gastrointestinal intubation; laryngoscopy, complications; case report; oman. امللخ�ص: اإدخال اأنبوب اإىل املعدة هو اإجراء �سائع و غري معقد و غالبا ما يتم تنفيذه على املر�سى حتت التخدير اأو حتت تاأثري امل�سكنات. اإدخال الأنبوب حالة هنا نقدم احلنجرة. اإ�سابة مثل ب�سهولة منها الوقاية ميكن م�ساعفات اإىل يوؤدي اأن ممكن الوعي عن غائبا املري�س يكون عندما عمياء بطريقة مثرية لالهتمام حيث مت اإدخال اأنبوب اأنفي-معوي بطريقة عمياء اإىل معدة مري�سة حتت التخدير تبلغ 52 عاما مما اأدى اإىل اإ�سابة كبريه يف الغ�رسوف الطرجهايل قيء دموي وتاأخر نزع الأنبوب الرغامي. من املمكن متابعة حركة اجلهاز اله�سمي من منطقة الفم والبلعوم اإىل الع�سلة العا�رسة املريئية العليا و ال�سيطرة عليها مع ا�ستخدام ملقط ميجل و املنظار. لهذا نربز يف هذا التقرير احلاجة اإىل اإدخال اأنابيب اجلهاز اله�سمي حتت الروؤية املبا�رسة باملنظار للمر�سى الغائبني عن الوعي )ب�سبب التخدير اأو امل�سكنات اأو اأ�سباب اأخرى( ملنع اإ�سابات احلنجرة. مفتاح الكلمات: تنبيب اجلهاز اله�سمي؛ تنظري احلنجرة؛ م�ساعفات؛ تقرير احلالة؛ �سلطنة عمان. avoidance of laryngeal injuries during gastric intubation *jyoti burad, sonali deoskar, pradipta bhakta, rohit date, pradeep sharma case report avoidance of laryngeal injuries during gastric intubation e406 | squ medical journal, august 2014, volume 14, issue 3 precipitated by heartburn. routine investigations for this patient, such as a complete blood count, renal function test and coagulation profile, were found to be within the normal limits. the aneurysm coiling was scheduled in the catheterisation laboratory under general anaesthesia. the patient’s airway was graded as class 1 using the mallampati score with normal neck movements, a thyromental distance of more than 6 cm and normal teeth. the anaesthesia was induced with propofol (2.5 mg/kg), fentanyl (2 mcg/kg) and rocuronium (0.8 mg/kg). the laryngeal view via the laryngoscopy was considered to be grade 1 using the cormack-lehane classification system. all of the laryngeal structures appeared normal without any oedema or bruising. the laryngoscopy was done in a smooth manner. the oral, cuffed endotracheal size 7 tube was placed in a single attempt which took approximately 10 seconds. the anaesthesia was maintained with an air-oxygen mixture of sevoflurane and morphine (0.15 mg/kg). while the patient was on the operating table, it was noted that she had not taken her usual medication that morning or the day before. this omission occurred while she was being transferred from her previous hospital to the sultan qaboos university hospital. consequently, the radiologist decided to administer aspirin and clopidogrel to facilitate the coiling procedure, after the induction of anaesthesia through the gt. on the first placement attempt, the gt (tube size 18 fg, pennine healthcare, derby, uk) was lubricated and inserted through the oral cavity. the gt was manoeuvered beyond the tongue but encountered resistance further on. the tube was rotated 60‒90 degrees and further insertion was attempted with external pressure on the lateral side of the patient’s neck. however, the gt could not be inserted any further. as the gt had not been frozen prior to insertion, it became more malleable when it was inserted in the patient’s oral cavity which meant that further insertion was not possible. hence, the tube was removed and replaced by another gt of the same type. on this second attempt, the blind insertion of the gt was successful. the placement of the ogt was confirmed by a fluoroscopy and the procedure was completed uneventfully. however, while suctioning the oral cavity, fresh blood was aspirated and a laryngoscopy was consequently done to determine the cause. oedema and swelling of the laryngeal inlet and laryngopharynx was noted, but the source of bleeding could not be identified. the patient was started on intravenous dexamethasone (8 mg three times daily). at the end of the procedure, it was decided to postpone the extubation and the patient was transferred to the intensive care unit (icu) for a planned extubation. this was performed after a few hours of steroid administration and a leak test. following the extubation, the patient had two episodes of haematemesis in the icu, losing approximately 100 ml of blood each time. she did not experience any episodes of epistaxis. blood grouping and cross-matching were done. a gastroenterologist was immediately consulted and an omeprazole infusion (8 mg/hour) was started as a preliminary measure. an upper gi endoscopy was performed twice to diagnose the cause of the bleeding. the gi endoscopy revealed an oedematous, bruised pharyngeal mucosa and an oedematous upper airway [figure 1], multiple superficial erosions in the oesophageal wall [figure 2] and a superficial ulcer just below the upper oesophageal sphincter. there was a small ulcer with an adherent clot on the gastric wall [figure 3], which was dislodged through flushing and suctioning. figure 1: an arytenoid oedema with normal vocal cords. figure 2: superficial erosion of the patient’s upper oesophagus. jyoti burad, sonali deoskar, pradipta bhakta, rohit date and pradeep sharma case report | e407 the patient’s clinical condition and routine chest and abdominal x-rays were within normal limits and did not reveal any features indicating perforation of the gi passage. the patient was kept nil per os (fasting) and under observation in the icu for the following 24 hours. within this period, her respiratory status did not worsen and there were no more episodes of haematemesis. her vital signs remained stable during her stay in the icu. the patient experienced no swelling of the neck, fever, stridor or dysphagia during the postoperative period. she did not require a blood transfusion, although her serial complete blood count showed a slight decrease in haemoglobin percentage (from 12% to 11.2%). after some time, the patient was transferred to the general ward and subsequently discharged to her referring primary care hospital. discussion the placement of a gt is an invasive procedure that is routinely performed blindly by many healthcare workers,2 although there are several reports of serious complications caused by blind insertion.1,6,7 blind gt insertion is a simple procedure when performed in conscious patients because muscle tone and swallowing guides the tube to the appropriate path with the patient’s cooperation. in anaesthetised patients, no resistance is offered by the adjacent tissues for guidance and therefore, there is a high chance of deviation from the desired path.1 the predisposing factors for such a complication include repeated attempts at insertion, a difficult insertion, abnormal anatomy, altered mental status and an insertion in anaesthetised patients.1,2,4 the following complications have been reported due to gt placement: trauma to the pharynx and larynx;3‒5 oesophageal and gastric perforation;4,7 broncho-pulmonary placement; pneumothoraxic placement,4,6 and placement in the brain parenchyma.1,2,4 gentle force can also cause the accidental iatrogenic insertion of a foreign body between the muscle layers, with the formation of a false passage along the line of insertion.8 in a case series of 57 patients, 32% of the patients had oedema of the arytenoids following a gt insertion.5 this highlights the high incidence of this uncommonly reported entity. the patient very rapidly developed arytenoid oedema, indicating that this was the result of a direct trauma rather than due to pressure from the gt against her adjacent laryngeal structures. however, a laryngoscopy can also cause its own complications if it is not performed correctly such as sympathetic stimulation if the patient is not sufficiently sedated.9 nevertheless, these problems can occur with any invasive procedure that causes pain; even trauma to the larynx by the blind insertion of a gastric tube can cause pain and sympathetic stimulation. in addition, laryngoscopies may also result in injuries to the tongue and teeth. a large retrospective study found a 0.04–0.05% incidence of dental trauma during the perianaesthetic period in unconscious patients who had had at least one laryngoscopy for an endotracheal intubation.10 moreover, there are fewer requirements for lifting the larynx in order to visualise the oesophageal opening when it is lying posterior. as such, it is more easily visualised than the larynx which is anterior. in the case of the current patient, the arytenoid oedema [figure 1] can be explained by trauma during the ogt placement.2,3,7 the haematemesis was also believed to have been caused by an injury to the upper gi tract during the ogt placement.2 the patient was predisposed to bleeding diathesis as a result of her medications which included clopidogrel (75 mg twice daily) and aspirin (81 mg once daily). yamada et al. observed that dual antiplatelet medications can reduce the rate of thromboembolic complications during a coil embolisation for an unruptured cerebral aneurysm.11 dual antiplatelets could have predisposed the current patient to a gi bleed although evidence shows that the incidence of gi bleeds with dual antiplatelets is low (2.7%).11 a previous history of gi bleeding is the most important and independent predictor for a patient’s likelihood of gi bleeding while on antiplatelets.12 the patient was also prescribed nimodipine due to the cerebral vasodilaory action of this medication. as per the us food and drug administration, the incidence of a gi bleeding in patients taking nimodipine is less than 1%.13 in addition, the patient was prescribed diclofenac, which she was taking infrequently for knee pain. this may have predisposed the patient to figure 3: a small gastric ulcer with an adherent clot. avoidance of laryngeal injuries during gastric intubation e408 | squ medical journal, august 2014, volume 14, issue 3 gi bleeding in a dose-dependent manner as the risk increases with a higher dosage and sustained-release preparations. a recent meta-analysis has shown that diclofenac’s relative risk for causing an upper gi bleed is between 3 to 3.6.14 although the patient had missed her final dose of antiplatelet medication the night before the procedure, she still should have been considered a high-risk case for blind insertion of an ogt. this is because anti-platelet medications, especially clopidogrel, have a long duration of action and the time elapsed was not sufficient to prevent bleeding in case of trauma. in the case of this patient, the gt should have been inserted under direct vision, using a laryngoscope and magill forceps to minimise any trauma. the endotracheal intubation was performed in the first attempt. the laryngoscopic view was scored as grade 1 using the cormack-lehane classification system and there was no evidence of trauma. therefore, the possibility of laryngeal trauma secondary to intubation was ruled out. as such, the only possible cause of the laryngeal oedema and upper gi tract injuries was direct trauma from the ogt insertion.7 arytenoid dislocation can occur even with an atraumatic intubation, but was ruled out by the absence of painful swallowing, hoarseness of voice or any other respiratory problems. episodes of trauma to the upper airway during insertion often go unrecognised, as tests are geared only to confirm the final position of the gt. trauma to the airway increases the chances of a delayed tracheal extubation. furthermore, prolonged periods of tracheal intubation and ventilation increase the chances of related complications, such as ventilatorassociated pneumonia, hypoxia, deep vein thrombosis and icu delirium. morbidity due to an airway trauma is an unnecessary and preventable consequence of the blind placement of a gt. conclusion the insertion of a gt should be attempted orally under direct laryngoscopic vision in sedated or anaesthetised patients. this is especially true for high-risk patients who are on antiplatelet or antithrombotic medications as they have a greater likelihood of bleeding. to maintain quality of care, the utmost precautions should be taken while performing such minor interventions. consequently, it is recommended that this procedure be performed under the guidance of a gentle laryngoscopy in order to minimise the chances of airway trauma. references 1. halloran o, grecu b, sinha a. methods and complication of nasoenteral intubation. jpen j parenter enteral nutr 2011; 35:61‒6. doi: 10.1177/0148607110370976. 2. prabhakaran s, doraiswamy va, nagaraja v, cipolla j, ofurum u, evans dc, et al. nasoenteric tube complications. scand j surg 2012; 101:147‒55. doi: 10.1177/145749691210100302. 3. friedman m, baim h, shelton v, stobnicki m, chilis t, ferrara t, et al. laryngeal injuries secondary to nasogastric tubes. ann otol rhinol laryngol 1981; 90:469‒74. 4. boyes rj, kruse ja. nasogastric and nasoenteric intubation. crit care clin 1992; 8:865‒78. 5. sofferman ra, hubbell rn. laryngeal complication of nasogastric tubes. ann otol rhinol laryngol 1981; 90:465‒8. 6. krenitsky j. blind bedside placement of feeding tubes: treatment or threat? from: www.medicine.virginia. edu/clinical/departments/medicine/divisions/digestiveh e a l t h / n u t r i t i o n s u p p o r t t e a m / n u t r i t i o n a r t i c l e s / krenitsky0311article.pdf accessed: aug 2013. 7. brand jb, emerson cw, wilson rs. acute laryngeal edema 24 hours after passage of a nasogastric tube. anesthesiology 1976; 45:555‒7. 8. shelton jh, mallat db, spechler sj. esophageal obstruction due to extensive intramural esophageal dissection: diagnosis and treatment using an endoscopic ‘rendezvous’ technique. dis esophagus 2007; 20:274–7. 9. shribman aj, smith g, achola kj. cardiovascular and catecholamine responses to laryngoscopy with and without tracheal intubation. br j anaesth 1987; 59:295–9. doi: 10.1093/ bja/59.3.295. 10. warner me, benenfeld sm, warner ma, schroeder dr, maxson pm. perianaesthetic dental injuries: frequency, outcomes and risk factors. anesthesiology 1999; 90:1302–5. 11. yamada nk, cross dt 3rd, pilgram tk, moran cj, derdeyn cp, dacey rg jr. effect of antiplatelet therapy on thromboembolic complications of elective coil embolization of cerebral aneurysms. ajnr am j neuroradiol 2007; 28:1778‒82. doi: 10.3174/ajnr.a0641. 12. alli o, smith c, hoffman m, amanullah s, katz p, amanullah am. incidence, predictors, and outcomes of gastrointestinal bleeding in patients on dual antiplatelet therapy with aspirin and clopidogrel. j clin gastroenterol 2011; 45:410‒4. doi: 10.1097/mcg.0b013e3181faec3c. 13. bayer pharmaceuticals corporation. nimotop® (nimodipine) capsules for oral use: fda approved labeling text. from: www. accessdata.fda.gov/drugsatfda_docs/label/2006/018869s014lbl. pdf accessed: jun 2014. 14. castellsague j, riera-guardia n, calingaert b, varas-lorenzo c, fourrier-reglat a, nicotra f, et al. individual nsaids and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the sos project). drug saf 2012; 35:1127–46. doi: 10.2165/11633470-00000000000000. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e112–115, epub. 21 jan 15 submitted 22 may 14 revision req. 14 aug 14; revision recd. 21 aug 14 accepted 2 oct 14 1department of pathology and 2health science centre, faculty of medicine and 4faculty of allied health sciences & nursing, kuwait university, safat, kuwait; 3cytopathology laboratory, mubarak al-kabeer hospital, safat, kuwait *corresponding author e-mail: kkapila@gmail.com االجتاهات احملّددة يف تشّوهات اخلاليا الظهارية احملّددة عند إجراء املسحات الُعنقّية ملدة 21 سنة يف مستشفى للرعاية العالية االختصاص يف الكويت كو�ضوم كابيل، برمي ن. �ضارما، �ضاره �س.جورج، عّزة ال�ضاهني، اأحلم اجلوي�رض، رنا العو�ضي abstract: objectives: this study aimed to analyse trends in epithelial cell abnormalities (ecas) in cervical cytology at a tertiary care hospital in kuwait. methods: ecas in 135,766 reports were compared over three seven-year periods between 1992 and 2012. conventional papanicolaou (pap) smear tests were used in the first two periods and thinprep (hologic corp., bedford, massachusetts, usa) tests were used in the third. results: significant increases in satisfactory smears, atypical squamous cells of undetermined significance (ascus) and atypical glandular cells of undetermined significance/atypical glandular cells (agus/agcs) were seen in the second and third periods (p <0.001). no significant increases were observed among low-grade squamous intraepithelial lesions (lsils) or high-grade squamous intraepithelial lesions (hsils) (p >0.05). an increase was noted in carcinomas between the first and second periods although a significant decline was seen in the third (p <0.014). conclusion: satisfactory smears, ascus and agus/agc increased during the study period although no significant increases in lsils, hsils or carcinomas were observed. keywords: cytological techniques; papanicolaou smear; epithelial cells; retrospective study; kuwait. داخل العنقّية اخلليا فح�س يف )اإي.�ضي.اإيي( الظهارية اخلليا ت�ضّوهات اجتاهات حتليل اإىل الدرا�ضة هذه تهدف الهدف: امللخ�ص: يف الواردة )اإي.�ضي.اإيي( الظهارية اخلليا ت�ضّوهات اجتاهات مقارنة مّتت الطريقة: الكويت. يف االخت�ضا�س العالية للرعاية م�ضت�ضفى 135,766 حالة فيما بينها على مّر واحٍد وع�رضين �ضنة بني الفرتة املمتدة من العام 1992 وحتى العام 2102م. وقد ا�ضتخِدَمت فحو�ضات لطاخة عنق الرحم بابا نيكوالو التقليدّية يف الفرتتني االأوىل والثانية ثم مّتت اال�ضتعانة باختبارات عنق الرحم )هولوجيك كوربوري�ضن، بيدفورد، م�ضات�ضو�ضت�س، الواليات املتحدة االأمريكية( يف الفرتة الثالثة. النتائج: اأظهرت هذه االختبارات زيادًة كبرية يف امل�ضحات العنقية /agus( اإ�ضافة اإىل خليا ُغّدية �ضاذة وغري حمّددة/خليا غدّية �ضاذة )ascus( وارتفاًعا يف اخلليا ال�ضاذة ال�ضدفّية غري املحّددة الظهارة داخل احلرف�ضية االآفات �ضعيد على ُتذَكر زيادة اأية ل ُت�ضجَّ مل .)p >0.001( والثالثة الثانية الفرتتني يف حتديدها مّت )agcs منخف�ضة الدرجة )lsils( اأو االآفات احلرف�ضية داخل الظهارة املرتفعة الدرجة )p <0.05 )hsils(. مت ت�ضجيل ارتفاع يف ال�رضطان الغّدي بني الفرتتني االأوىل والثانية على الرغم من ت�ضجيل انخفا�س هام خلل الفرتة الثالثة )p >0.014(. اخلال�صة: �ضّجلت امل�ضحات العنقية نتيجة ُمر�ضية ومقبولة مع زيادة يف ascus و agc/agus طوال مدة الدرا�ضة على الرغم من عدم ت�ضجيل اأية زيادة ملحوظة بالن�ضبة اإىل lsils و hsils اأو حتى ظهور اأّي �رضطان غدّي. مفتاح الكلمات: تقنيات فح�س اخلليا؛ لطاخة عنق الرحم؛ خاليا ظهارية؛ دراسة استعادية؛ الكويت. trends in epithelial cell abnormalities observed on cervical smears over a 21-year period in a tertiary care hospital in kuwait *kusum kapila,1 prem n. sharma,2 sara s. george,1 azza al-shaheen,3 ahlam al-juwaiser,3 rana al-awadhi4 cervical cancer is the fourth most frequently occurring cancer affecting women worldwide after breast, colorectal and lung cancers; it is also the seventh most common form of cancer overall, with an estimated 528,000 new cases worldwide in 2012.1 approximately 70% of the global burden of cancer falls on less developed countries, with more than one-fifth of all new diagnosed cases from india.1 in developing areas, the highest agestandardised rates (asrs) of cancer per 100,000 are in south and central america (33.5), sub-saharan africa (31.0) and south central and southeast asia (26.5).2 the lowest rates of cancer are reported in china (6.8) and in developed regions such as north america, japan and europe, which has an asr of 4.5. low incidences have also been observed in some developing areas, such as the middle east, including iran and turkey.2 cancer of the uterine cervix is the fifth most common cancer in kuwaiti females (4.6%), with an asr of 6.8.3 invasive cervical cancer is preceded by a spectrum of heterogeneous epithelial cell abnormalities (ecas) over a long period. identification of the relevant risk factors and prompt management of the precancerous lesions are important in the brief communication kusum kapila, prem n. sharma, sara s. george, azza al-shaheen, ahlam al-juwaiser and rana al-awadhi brief communication | e113 prevention of invasive cancer of the uterine cervix. several studies from saudi arabia, including a study of sub-fertile saudi females, showed a low prevalence of ecas; however, there was still a wide range of distribution (2.9–17.3%).4,5 this range strongly correlates with the actual difference in the distribution of invasive carcinomas of the cervix in saudi arabia.6 other studies from the arab world have also reported a significant variation in the rate of ecas: 3.3–3.6% in the united arab emirates,7,8 4.2% in kuwait,9 7.8% in egypt10 and 11.9% in nablus, palestine.11 most of these studies were completed using conventional papanicolaou (pap) smear tests, where the cervical smears were reclassified according to the revised 2001 bethesda system.12 mubarak al-kabeer hospital is a tertiary care hospital which provides cytological diagnostic services to 15 hospitals, 17 clinics and practitioners both in the hawally area and elsewhere in kuwait. the aim of this study was to analyse the changing trends of ecas observed in cervical smears at this hospital over a period of 21 years compared in three periods of seven years each. methods this retrospective study was designed to review cervical cytology reports performed in the cytology laboratory of mubarak al-kabeer hospital over a 21-year period from january 1992 to december 2012. the first two seven-year periods (1992–2005) used conventional pap smear tests whereas the third period (2006–2012) used thinprep (hologic corp., bedford, massachusetts, usa) smear tests. a comparison was made between the trends of ecas seen in the three seven-year periods (1992–1998, 1999–2005 and 2006–2012). unsatisfactory cytology reports were excluded from the study. these included smears with very few epithelial cells or those where the morphology of the cells was obscured by blood or severe inflammation. smears were categorised as “satisfactory” when an adequate number of epithelial cells were clearly visualised, as per the guidelines of the bethesda system.12 cytological diagnoses were changed where required to the modified bethesda classification system.12 the following categories were used: normal/ negative for intraepithelial lesions or malignancy (nilm); atypical squamous cells of undetermined significance (ascus); atypical glandular cells of undetermined significance/atypical glandular cells (agus/agcs); low-grade squamous intraepithelial lesions (lsils), including changes induced by human papillomavirus (hpv) infection; high-grade squamous intraepithelial lesions (hsils), which included ascus results with possible hsil (asc-h), and carcinomas. epithelial cell abnormalities comprising of ascs, lsils, hsils were considered as cervical precursor lesions. data management, analysis and graphical presentation were completed using the statistical table 1: spectrum of cervical cytology smear diagnoses during three seven-year periods between 1992 and 2012 (n = 135,766) period p value 1 1992–1998 2 1999–2005 3 2006–2012 total 1992–2012 period 1 versus 2 period 2 versus 3 period 1 versus 3 total, n 40,806 52,728 46,870 140,404 satisfactory smears, n (%) 38,079 (93.3) 51,990 (98.6) 45,697 (97.5) 135,766 (96.7) 0.001 0.001 0.001 cytological diagnosis, n (%) ascus 587 (1.54) 1,363 (2.62) 1,262 (2.76) 3,212 (2.37) 0.001 0.183 0.001 agus/agc 160 (0.42) 543 (1.04) 389 (0.85) 1,092 (0.80) 0.001 0.002 0.001 lsil 400 (1.05) 487 (0.94) 410 (0.90) 1,297 (0.95) 0.094 0.540 0.026 hsil 92 (0.24) 106 (0.20) 96 (0.21) 294 (0.22) 0.262 0.887 0.375 carcinoma 28 (0.07) 60 (0.12) 30 (0.07) 118 (0.09) 0.060 0.014 0.764 ascus = atypical squamous cells of undetermined significance; agus = atypical glandular cells of undetermined significance; agcs = atypical glandular cells; lsil = low-grade squamous intraepithelial lesion; hsil = high-grade squamous intraepithelial lesion. italics indicate percentages from satisfactory smear tests. trends in epithelial cell abnormalities observed on cervical smears over a 21-year period in a tertiary care hospital in kuwait e114 | squ medical journal, february 2015, volume 15, issue 1 package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa). descriptive statistics were presented as numbers, percentages and means ± standard deviations. the normal z-test was used to test the difference in proportions and the chi-squared test was used to determine if there was any trend in the proportion of cases over the 21-year period. the two-tailed probability value p <0.05 was considered statistically significant. this study was performed according to the guidelines of the combined ethics committee of the faculty of medicine, health science centre and ministry of health in kuwait, which conforms to the world medical association declaration of helsinki. results during the 21-year period, a total of 140,404 cervical cytology smears were analysed in the cytology laboratory of mubarak al-kabeer hospital. of these, 135,766 (96.7%) were found satisfactory for reporting [table 1]. overall, ecas were observed in 4.43% of satisfactory smears; ecas from the first, second and third seven-year periods were present in 3.32%, 4.92% and 4.79% of the smears, respectively. ascus were seen in 3,212 cases (2.37%), agus/agcs in 1,092 cases (0.80%), lsils in 1,297 cases (0.97%), hsils in 294 cases (0.22%) and carcinomas in 118 cases (0.09%). a significant increase (p <0.001) was noted in the proportion of satisfactory smears in the second and third period compared to the first (98.6% and 97.5% versus 93.3%, respectively) [table 1]. additionally, a significant increase was also observed between the first two combined periods (1992–2005) of conventional pap smears in comparison to the third period (2006–2012) of thinprep smears (96.3% versus 97.5%, respectively). with regard to cytological diagnoses, a significant increasing trend (p <0.001) was found among ascus and agus/agc cases in the later periods compared to the first; agus/agc cases were found to be more accurately identified using thinprep smears than with conventional pap smears. no significant increase was observed among the number of lsils and hsils during the study (p >0.05). in carcinoma cases, an increase was observed between the first and second periods but a significant decline (p <0.014) was noted between the second and third periods [figure 1]. discussion the distribution of ecas in 140,404 cervical cytology smears analysed over a 21-year period did not show any significant change in lsil, hsil or carcinoma cases. the introduction of liquid-based cytology (lbc) during the final seven-year period (2006–2012) showed an increasing trend in satisfactory smears and the detection of ascus and agus/agc cases. in a population-based cervical cancer screening programme in japan, disease detection rates were compared between specimens prepared by lbc and those prepared by conventional methods.13 with the lbc method, the researchers found a significantly lower percentage of unsatisfactory specimens and a significantly higher positive rate of detection of tumour lesions.13 however, siebers et al. demonstrated in a large randomised controlled trial that the most common lbc method was not more effective in detecting cervical cancer precursors than wellperformed conventional pap smears; the prevalence of cervical intraepithelial neoplasms was equal in both study groups.14 in a systematic review and metaanalysis comparing the two techniques, no incremental improvement in accuracy was demonstrated for the detection of high-grade cervical intraepithelial neoplasms using lbc versus conventional methods.15 this was also observed in the current study as no statistically significant changes were observed for cervical precursors between cytology performed using conventional pap smear tests and those performed using thinprep tests. furthermore, schiffmann et al. reported that both cytology methods provided similar risk stratification in predicting cervical cancer precursors.16 they concluded that the choice of figure 1: trends in cervical cytology smear diagnoses in a tertiary care hospital in kuwait between 1992 and 2012 (n = 135,766). ascus = atypical squamous cells of undetermined significance; agus = atypical glandular cells of undetermined significance; agcs= atypical glandular cells; lsil = low-grade squamous intraepithelial lesion; hsil = high-grade squamous intraepithelial lesion. kusum kapila, prem n. sharma, sara s. george, azza al-shaheen, ahlam al-juwaiser and rana al-awadhi brief communication | e115 cervical cancer screening method should be chosen on the basis of cost-effectiveness related to laboratory productivity, slide adequacy and the ease of ancillary molecular testing.16 conclusion overall, ecas were observed in 4.43% of cervical cytology smears analysed in a tertiary care hospital in kuwait over a 21-year period. satisfactory smears and the detection of ascus and agus/agc cases were significantly increased during the seven-year period when thinprep smears were used. there were no statistically significant changes in the detection of lsils, hsils and carcinomas when lbc preparations were used as compared to conventional pap smears. references 1. international agency for research on cancer and world health organization. globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. from: globocan. iarc.fr accessed: aug 2014. 2. altaf fj, mufti st. pattern of cervical smear abnormalities using the revised bethesda system in a tertiary care hospital in western saudi arabia. saudi med j 2012; 33:634–9. 3. kuwait cancer registry. annual report 2001. kuwait: ministry of health, 2001. p. 30,85. 4. altaf fj. cervical cancer screening with pattern of pap smear: review of multicenter studies. saudi med j 2006; 27:1498–502. 5. al-jaroudi d, hussain tz. prevalence of abnormal cervical cytology among subfertile saudi women. ann saudi med 2010; 30:397–400. doi: 10.4103/0256-4947.68550. 6. al-eid hs, manalo ms. cancer incidence report in saudi arabia. riyadh, saudi arabia: national cancer registry, ministry of health, 2007. pp. 91–6. 7. al eyd gj, shaik rb. rate of opportunistic pap smear screening and patterns of epithelial cell abnormalities in pap smears in ajman, united arab emirates. sultan qaboos univ med j 2012; 12:473–8. 8. ghazal-aswad s, gargash h, badrinath p, al-sharhan ma, sidky i, osman n, et al. cervical smear abnormalities in the united arab emirates: a pilot study in the arabian gulf. acta cytol 2006; 50:41–7. 9. kapila k, george ss, al-shaheen a, al-ottibi ms, pathan sk, sheikh za, et al. changing spectrum of squamous cell abnormalities observed on papanicolaou smears in mubarak al-kabeer hospital, kuwait, over a 13-year period. med princ pract 2006; 15:253–9. doi: 10.1159/000092986. 10. el-all hs, refaat a, dandash k. prevalence of cervical neoplastic lesions and human papilloma virus infection in egypt: national cervical cancer screening project. infect agent cancer 2007; 2:12. doi: 10.1186/1750-9378-2-12. 11. musmar gs. pattern and factors affecting pap smear test in nablus: a retrospective study. middle east j family med 2004; 2:7–12. 12. solomon d, davey d, kurman r, moriarty a, o’connor d, prey m, et al. the 2001 bethesda system: terminology for reporting results of cervical cytology. jama 2002; 287:2114– 19. doi: 10.1001/jama.287.16.2114. 13. akamatsu s, kodama s, himeji y, ikuta n, shimagaki n. a comparison of liquid-based cytology with conventional cytology in cervical cancer screening. acta cytol 2012; 56:370– 4. doi: 10.1159/000337641 14. siebers ag, klinkhamer pj, grefte jm, massuger lf, vedder je, beijers-broos a, et al. comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. jama 2009; 302:1757–64. doi: 10.1001/jama.2009.1569. 15. arbyn m, bergeron c, klinkhamer p, martin-hirsch p, siebers ag, bulten j. liquid compared with conventional cervical cytology: a systematic review and meta-analysis. obstet gynecol 2008; 111:167–77. doi: 10.1097/01.aog.0000296 488.85807.b3. 16. schiffman m, solomon d. screening and prevention methods for cervical cancer. jama 2009; 302:1809–10. doi: 10.1001/ jama.2009.1573. clinical & basic research sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e473−477, epub. 14th oct 14 submitted 9th jan 14 revisions req. 12th mar & 30th apr 14; revisions recd. 9th apr & 12th may 14 accepted 15th may 14 1department of clinical physiology, sultan qaboos university hospital; 2department of mathematics & statistics, college of science, sultan qaboos university, muscat, oman; 3department of neurology, institute of epileptology, king’s college hospital, london, uk *corresponding author e-mail: farah@squ.edu.om العالقة بني مدى التخطيط الدماغي والدالئل الكهربية غري الطبيعية للتشنجات دراسة مراجعة �سامي فارح الروا�ش, راجي�ش بوثريكوفيل, خ�رضعبدالبا�سط, روبرت ديالمونت abstract: objectives: the aim of this study was to establish the relationship between background amplitude and interictal abnormalities in routine electroencephalography (eeg). methods: this retrospective audit was conducted between july 2006 and december 2009 at the department of clinical physiology at sultan qaboos university hospital (squh) in muscat, oman. a total of 1,718 electroencephalograms (eegs) were reviewed. all eegs were from patients who had been referred due to epilepsy, syncope or headaches. eegs were divided into four groups based on their amplitude: group one ≤20 μv; group two 21–35 μv; group three 36–50 μv, and group four >50 μv. interictal abnormalities were defined as epileptiform discharges with or without associated slow waves. abnormalities were identified during periods of resting, hyperventilation and photic stimulation in each group. results: the mean age ± standard deviation of the patients was 27 ± 12.5 years. of the 1,718 eegs, 542 (31.5%) were abnormal. interictal abnormalities increased with amplitude in all four categories and demonstrated a significant association (p <0.05). a total of 56 eegs (3.3%) had amplitudes that were ≤20 μv and none of these showed interictal epileptiform abnormalities. conclusion: eeg amplitude is an important factor in determining the presence of interictal epileptiform abnormalities in routine eegs. this should be taken into account when investigating patients for epilepsy. a strong argument is made for considering long-term eeg monitoring in order to identify unexplained seizures which may be secondary to epilepsy. it is recommended that all tertiary institutions provide eeg telemetry services. keywords: electroencephalography, abnormalities; epilepsy. امللخ�ص: الهدف: تهدف هذه الدرا�سة اإىل تقريرالعالقة بني مدى اجلهد الكهربي يف خلفية التخطيط الكهربي الروتيني للدماغ و الدالئل الكهربية غري الطبيعية بني الت�سنجات. الطريقة: مت اإجراء هذه املراجعة البحثية يف ق�سم علم وظائف االأع�ساء الرسيري مب�ست�سفى جامعة ال�سلطان قابو�ش, م�سقط, عمان. جمموع 1,718 تخطيطا لكهربية الدماغ يف الفرتة ما بني يوليو 2006 وديسمرب 2009 مت مراجعتها. جميع هذه التخطيطات كانت ملر�سى حمولني الأ�سباب تتعلق مبر�ش ال�رضع, االإغماء, اأو ال�سداع. مت تق�سيم التخطيطات الكهربية للدماغ الثالثة: املجموعة ,20–35 μv الثانية: املجموعة ,≤20 μv :االأوىل املجموعة الكهربي: اجلهد مدى على بناء جمموعات اأربع اإىل μv 50–36, املجموعة الرابعة: μv 50>. مت تعريف الدالئل الكهربية غريالطبيعية بني الت�سنجات على اأنها نب�سات كهربية م�ساحبة ملر�ش ال�رضع �سواء كانت مرتابطة مع اأو بدون موجات كهربية بطيئة. الدالئل غريالطبيعية مت التعرف عليها خالل فرتات الراحة, تنفس من �سنوات. 27 ± هو 12.5 للمر�سى املعياري العمر ± االنحراف معدل جمموعة. النتائج: كل يف ال�سوئي التنبيه التهوية,و فرط مع الطبيعية غري الدالئل اأن الدرا�سة اأظهرت طبيعي. غري تخطيطا )31.5%( 542 هناك كان الدماغ لكهربية تخطيطا 1,718 جمموع لتخطيط الدماغ تزداد مع مدى اجلهد الكهربي للتخطيط يف جميع املجموعات االأربع مع وجود عالقة معتدة اإح�سائيا )p >0.05(. كذلك تبني اأن هناك 56 )%3.3( تخطيطا دماغى مدى اجلهد الكهربي فيها μv 20≥ و جميعها مل تظهر اأي موؤ�رض على دالئل غري طبيعية يف تخطيط الدماغ. اخلال�صة: يعترب مدى اجلهد الكهربي لتخطيط الدماغ عامال مهما يف حتديد ظهور الدالئل غري الطبيعية يف تخطيط الدماغ الروتيني. هذه النتيجة يجب اأن توؤخذ يف االعتبارعند فح�ش مر�سى ال�رضع. توؤكد الدرا�سة يف مناق�سة قوية على اأهمية االأخذ يف االعتبار ا�ستخدام التخطيط الكهربي للدماغ طويل املدى للتو�سل اإىل تف�سري للت�سنجات التي ميكن اأن تكون ثانوية ملر�ش ال�رضع. تو�سي هذه الدرا�سة بتوفري تخطيط الدماغ طويل املدى يف كل امل�ست�سفيات املرجعية. مفتاح الكلمات: تخطيط كهربية الدماغ، ت�سوهات؛ ال�رضع. the correlation between electroencephalography amplitude and interictal abnormalities audit study *sami f. al-rawas,1 rajesh p. poothrikovil,1 khidir m. abdelbasit,2 robert s. delamont3 advances in knowledge this audit investigates and establishes electroencephalography (eeg) amplitude as an important factor that limits eeg outcomes. the data collected from this study sheds light on current eeg practices. the correlation between electroencephalography amplitude and interictal abnormalities audit study e474 | squ medical journal, november 2014, volume 14, issue 4 electroencephalography (eeg) is a well-established and essential investigation for evaluating cortical function. abnormal waveforms such as epileptiform discharges seen on electroencephalograms (eegs) may have a significant impact on the diagnosis of episodic disorders of consciousness such as epilepsy. epilepsy affects 65 million people worldwide, with an incidence of 50/100,000 and a prevalence of 700/100,000 in developing countries.1 eeg remains an essential laboratory investigation that can support clinical diagnoses.2 however, the sensitivity of eeg in demonstrating interictal epileptiform discharges is limited. the initial eeg may show epileptiform abnormalities in only 29– 50% of cases.3 therefore, the use of eeg during periods of hyperventilation, photic stimulation and sleep deprivation was introduced to increase the chance of finding abnormalities.4 most eegs are performed in an outpatient setting, utilising surface scalp electrodes which are positioned using the 10/20 international system or the modified maudsley system.5 rhythmic activity derived from the surface of the scalp is identified by its configuration, frequency, amplitude and location.2,4 these rhythms are not uniform and vary between and within individuals over time. for example, frequency is strongly influenced by the level of consciousness and underlying pathology. slow activity (less than 3 hertz [hz]) is commonly seen when individuals are in a deep sleep, as well as in those with organic disorders such as encephalopathies.6 the eeg amplitude represents the vector sum of the cortical potential differences at 90° to the surface in real time.7,8 these signals are recorded through the skull and can be influenced by the structures between the cortex and the recording electrodes,9,10 as well as age11 and genetics.12 these eeg signals are modulated during periods of sleep13 and hyperventilation14 and also change with inter-electrode distance,14–16 variations in skull thickness17,18 and in the presence of underlying pathologies, such as a tumour or hydrocephalus. these pathologies can impede signals or affect conductivity, resulting in a reduction of the eeg voltage.9,10 when the eeg amplitude is less than 20 μv, it becomes difficult to identify small abnormalities against a bland and relatively featureless background; this is defined as a low amplitude eeg.19 such low amplitude eegs have been described in individuals from certain ethnic groups, such as african americans,20 and in those who have specific pathological conditions such as huntington’s disease21 or alcoholism.20 they have also been reported in normal subjects during periods of increased attention and vigilance22 and when under general anaesthesia.23 to the best of the authors’ knowledge, no studies in the literature have thus far quantified the ability of low voltage eeg recordings to detect clinically relevant eeg abnormalities. this audit explored the relationship between eeg amplitude and the detection of interictal abnormalities by professionals in a busy clinical neurophysiology department. methods this retrospective audit was conducted between july 2006 and december 2009 in the department of clinical physiology at sultan qaboos university hospital (squh) in muscat, oman. all of the eegs reviewed were performed during the study period on non-homogenous patients over 13 years old. participants of various ethnic groups were included in the audit, representing a composite of omani society. the participants had attended the eeg laboratory for various reasons including epilepsy, syncope and headaches. the eegs of patients in the intensive care unit or those with brain pathologies that could influence eeg amplitudes (such as a ventriculoperitoneal shunt, recent brain surgery or tumours) were excluded from the study. the eegs were recorded and analysed using the comet series’ model cmxle-230 (grass technologies, warwick, rhode island, usa) with 16 recording channels, using silver/silver chloride or gold-plated disc electrodes placed on the scalp according to the 10/20 international system. the highpass filter was set to 1 hz and the low-pass filter was set to 70 hz. the notch filter was off in all cases. after the application of the electrodes and impedance correction, each subject was requested to lie in a supine position. after 20–25 minutes in a relaxed wakeful state, an eeg recording was obtained. activation procedures such as hyperventilation and photic stimulation were then carried out. if a subject felt drowsy, then a sleep recording was obtained after application to patient care the results of this audit will alert clinical neurophysiologists and neurologists to the impact of eeg amplitude on eeg interpretation. furthermore, these results indicate the need to prolong eeg recordings and minimise the possibility of false-negative outcomes, particularly in patients with epilepsy. sami f. al-rawas, rajesh p. poothrikovil, khidir m. abdelbasit and robert s. delamont clinical and basic research | e475 a further 10–20 minute interval. no sedatives were given at any time to any of the subjects included in this study. each record was then interpreted by a qualified clinical neurophysiologist. in order to determine the eeg amplitude, a standard approach was followed.24 an area of not less than two seconds of maximum voltage, recorded over the occipital regions of the head with alpha activity during periods of quiet resting and with the patient’s eyes closed, was determined visually and then highlighted. the amplitude was calculated as the peak-to-peak alpha activity in the bipolar double banana montage. interictal epileptiform and slow wave abnormalities were identified in each eeg during periods of resting, hyperventilation and photic stimulation. the eegs were subsequently labelled as normal or abnormal. the amplitudes obtained were operationalised and classified into four categories with the following low voltages: group one ≤20 μv;19 group two 20–35 μv; group three 36–50 μv, and group four >50 μv. the relationship between eeg amplitudes and reported abnormalities was analysed using the statistical package for the social sciences (spss), version 18 (ibm, corp., chicago, illinois, usa). this study was approved by the medical research & ethics committee at the sultan qaboos university college of medicine & health sciences (mrec #297). results a total of 1,718 eegs were reviewed in this audit. patients were aged 13–85 years old, with 75% of this patient population below 32 years of age (mean: 27 ± 12.5 years). figure 1 shows the distribution of the 1,718 eegs according to amplitude categories, with 56 (3%) in group one, 266 (16%) in group two, 294 (17%) in group three and 1,102 (64%) in group four. the overall results of the abnormal eegs are displayed in figure 2. of the 1,718 eegs, a total of 542 (31.5%) were abnormal. the percentage of eeg abnormalities increased steadily with amplitude, as shown in figure 2. to test whether this observed increase was significant (i.e. evidence of a trend in the population), pearson’s chisquared test was performed (χ2 = 56.20; p <0.001). this demonstrated strong evidence of an association between amplitude and the detected abnormalities, particularly given that no abnormalities were detected in group one (≤20 μv). all of the 1,718 patients underwent eegs during periods of resting. while resting, a similar rise was observed in the percentage of abnormal eegs with an increase in eeg amplitude [figure 3]. these results are almost identical to those found overall [figure 2]. there was also an association between amplitude and the frequency of abnormal eegs during periods of resting (χ2 = 49.366; p <0.001). hyperventilation was initiated in 1,310 patients [figure 4]. the same steady increase in the percentage of abnormal eegs with increasing amplitude was observed, although the percentages were lower than those seen while patients were resting. pearson’s chisquared test indicated a strong association between amplitude and the percentage of eeg-detected abnormalities during hyperventilation (χ2 = 15.20; p = 0.002). figure 1: distribution of all electroencephalograms by amplitude group (n = 1,718). figure 2: percentage of all abnormal electroencephalograms (eegs) by amplitude group (n = 542). figure 3: percentage of abnormal electroencephalograms (eegs) by amplitude group while resting (n = 1,718). the correlation between electroencephalography amplitude and interictal abnormalities audit study e476 | squ medical journal, november 2014, volume 14, issue 4 figure 5 shows the percentage of abnormal eegs by amplitude range in those who underwent photic stimulation (n = 1,570). the same upward trend in the percentage of abnormalities was observed (χ2 = 11.05; p value = 0.011). this further indicates a highly significant association between amplitude and the percentage of abnormalities detected. discussion the variability in eeg amplitudes among individuals has long been noted; however, this has never been correlated with the presence of interictal abnormalities. this audit identified eeg voltage/ amplitude as an essential factor that influences the likelihood of finding an abnormality in eegs carried out in a clinical service. to the best of the authors’ knowledge, this is the first time that the importance of eeg amplitude has been demonstrated in both resting and activated eeg recordings (i.e. during periods of hyperventilation and photic stimulation). this audit supports anecdotal observations related to the level of eeg amplitude and the sensitivity of recognising abnormal discharges. this was most marked in patients with very low voltage eegs of ≤20 μv (3.3%), none of whom were found to have interictal abnormalities. consequently, such an eeg is unlikely to demonstrate interictal abnormalities even if the patient were to have a significant disorder, such as epilepsy. for these patients, an alternative means of identifying abnormalities needs to be considered. the significance of failing to find interictal abnormalities was illustrated by one of the authors’ patients who had had a bland low amplitude recording (≤20 μv) and then suffered a seizure during the latter part of the recording. upon review, the eeg showed only ictal discharges. this suggests that patients with low amplitude eegs will require prolonged eeg video-telemetry recordings if epilepsy is still suspected, despite an apparently normal interictal low-amplitude recording. the authors recommend that clinical neurophysiologists undertake a prospective study of all patients referred to them for testing. the patients’ ultimate clinical diagnosis should be identified and subsequently correlated with their eeg amplitude and the observed abnormalities. it is also worth noting that this audit provides information on the overall contribution of the provocative tests that are routinely performed as part of the standard eeg test, including hyperventilation and photic stimulation. in this audit, these tests showed a relatively modest contribution in identifying abnormalities, although the results could still be important clinically. further studies are essential to identify the significance of these activation procedures in arriving at an ultimate diagnosis. furthermore, while this audit may have limitations, it has highlighted some of the drawbacks of only using a standard eeg to identify potential abnormalities. in order to identify patients with clinically important syndromes such as epilepsy, prolonged eeg recordings with videotelemetry should be undertaken. this is particularly important for regional clinical neurophysiology departments, such as that of squh in oman. this study has a number of limitations. the study investigated the clinical practice of a single laboratory with an unselected patient population. as a result, only 56 records with mean voltages of ≤20 μv were obtained from the total population. despite the low number of these records, the statistical analysis suggested that the association between amplitude and the detection of abnormalities was significant. the sample was also skewed towards a young population, with 75% under 32 years of age. future studies are recommended to study the correlation between age, eeg amplitude and identified abnormalities. figure 5: percentage of abnormal electroencephalograms (eegs) by amplitude group during a period of photic stimulation (n = 1,570). figure 4: percentage of abnormal electroencephalograms (eegs) by amplitude group during a period of hyperventilation (n = 1,310). sami f. al-rawas, rajesh p. poothrikovil, khidir m. abdelbasit and robert s. delamont clinical and basic research | e477 conclusion a significant association was found between eeg amplitude and interictal abnormalities in this audit. this association may limit the likelihood of detecting abnormalities in eeg recordings, as was clearly seen among participants with low voltage eegs. such an effect would have ramifications on eeg reporting and could potentially impact patient care, particularly for those with epilepsy. therefore, prolonged eeg recordings should be undertaken to minimise the risks of false-negative eeg outcomes. references 1. thurman dj, beghi e, begley ce, berg at, buchhalter jr, ding d, et al. standards for epidemiologic studies and surveillance of epilepsy. epilepsia 2011; 52:2–26. doi: 10.1111/j.15281167.2011.03121.x. 2. markand on. pearls, perils, and pitfalls in the use of the electroencephalogram. semin neurol 2003; 23:7–46. doi: 10.1055/s-2003-40750. 3. pedley ta, mendiratta a, walczak ts. seizures and epilepsy. in: ebersole js, pedley ta, eds. current practice of clinical electroencephalography. 3rd ed. philadelphia, pennsylvania: lippincott williams & wilkins, 2002. pp. 506–87. 4. gilmore rl. american electroencephalographic society guidelines in electroencephalography, evoked potentials, and polysomnography. j clin neurophysiol 1994; 11:1–147. 5. pampiglione g. some anatomical considerations upon electrode placement in routine eeg. proc electrophysiol technol ass 1956; 7:20–30. 6. liscombe mp, hoffmann rf, trivedi mh, parker mk, rush aj, armitage r. quantitative eeg amplitude across rem sleep periods in depression: preliminary report. j psychiatry neurosci 2002; 27:40–6. 7. subha dp, joseph pk, acharya ur, lim cm. eeg signal analysis: a survey. j med syst 2010; 34:195–212. doi: 10.1007/ s10916-008-9231-z. 8. ruiz y, li g, freeman wj, gonzalez e. detecting stable phase structures in eeg signals to classify brain activity amplitude patterns. j zhejiang univ sci a 2009; 10:1483–91. doi: 10.1631/ jzus.a0820690. 9. myslobodsky ms, coppola r, bar-ziv j, karson c, daniel d, van praag h, et al. eeg asymmetries may be affected by cranial and brain parenchymal asymmetries. brain topogr 1989; 1:221–8. doi: 10.1007/bf01129599. 10. jochmann t, güllmar d, haueisen j, reichenbach jr. influence of tissue conductivity changes on the eeg signal in the human brain: a simulation study. z med phys 2011; 21:102–12. doi: 10.1016/j.zemedi.2010.07.004. 11. vysata o, kukal j, prochazka a, pazdera l, simko j, valis m. age-related changes in eeg coherence. neurol neurochir pol 2014; 48:35–8. doi: 10.1016/j.pjnns.2013.09.001. 12. tang y, chorlian db, rangaswamy m, porjesz b, bauer l, kuperman s, et al. genetic influences on bipolar eeg power spectra. int j psychophysiol 2007; 65:2–9. doi: 10.1016/j. ijpsycho.2007.02.004. 13. coenen am. neuronal phenomena associated with vigilance and consciousness: from cellular mechanisms to electroencephalographic patterns. conscious cogn 1998; 7:42– 53. doi: 10.1006/ccog.1997.0324. 14. lum lm, connolly mb, farrell k, wong pk. hyperventilationinduced high-amplitude rhythmic slowing with altered awareness: a video-eeg comparison with absence seizures. epilepsia 2002; 43:1372–8. doi: 10.1046/j.1528-1157.2002. 35101.x. 15. barry rj, clarke ar, mccarthy r, selikowitz m, johnstone sj. eeg coherence adjusted for inter-electrode distance in children with attention-deficit/hyperactivity disorder. int j psychophysiol 2005; 58:12–20. doi: 10.1016/j.ijpsycho.2005.03.005. 16. vaisanen j, ryynanen o, hyttinen j, malmivuo j. analysing specificity of a bipolar eeg measurement. conf proc ieee eng med biol soc 2006; 1:1102–5. doi: 10.1109/iembs.2006.260015. 17. leissner p, lindholm le, petersen i. alpha amplitude dependence on skull thickness as measured by ultrasound technique. electroencephalogr clin neurophysiol 1970; 29:392–9. doi: 10.1016/0013-4694(70)90047-7. 18. hagemann d, hewig j, walter c, naumann e. skull thickness and magnitude of eeg alpha activity. clin neurophysiol 2008; 119:1271–80. doi: 10.1016/j.clinph.2008.02.010. 19. enoch ma, white kv, harris cr, robin rw, ross j, rohrbaugh jw, goldman d. association of low-voltage alpha eeg with a subtype of alcohol use disorders. alcohol clin exp res 1999; 23:1312–19. doi: 10.1111/j.1530-0277.1999.tb04352.x. 20. ehlers cl, phillips e. eeg low-voltage alpha and alpha power in african american young adults: relation to family history of alcoholism. alcohol clin exp res 2003; 27:765–72. doi: 10.1097/01.alc.0000065439.09492.67. 21. scott df, heathfield kw, toone b, margerison jh. the eeg in huntington’s chorea: a clinical and neuropathological study. j neurol neurosurg psychiatry 1972; 35:97–102. doi: 10.1136/ jnnp.35.1.97. 22. oken bs, salinsky mc, elsas sm. vigilance, alertness, or sustained attention: physiological basis and measurement. clin neurophysiol 2006; 117:1885–901. doi: 10.1016/j. clinph.2006.01.017. 23. sloan tb. anesthetic effects on electrophysiologic recordings. clin neurophysiol 1998; 15:217–26. 24. niedermeyer e. the normal eeg of the waking adult. in: niedermeyer e, lopes da silva f, eds. electroencephalography: basic principles, clinical application and related fields. 4th ed. baltimore, maryland: lippincott williams & wilkins, 1999. pp. 149–73. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 280-286, epub. 9th may 13 submitted 10th aug 12 revision req. 20th oct 12, revision recd. 27th oct 12 accepted 26th nov 12 department of radiology, king hussein medical center, amman, jordan e-mail: ahiari@hotmail.com دور الرنني املغناطيسي امللون ملفصل املعصم يف تشخيص متزق اجملمع الغضرويف املثلث جتربة مدينة احلسني الطبية األردن عا�شم احمد احلياري امللخ�ص: الهدف: هتدف هذه الدراسة هي تقييم دور التصوير بالرنني املغناطيسي امللون ملفصل املعصم يف الكشف عن متزق كامل السمك للمجمع الغضرويف املثلث ومقارنة نتائج الفحص بالرنني املغناطيسي مع النتائج باملنظار. الطريقة: مت إجراء الدراسة يف مدينة احلسني الطبية، عمان، األردن، خالل الفرتة من يناير2008 إىل ديسمرب2011. اثنني وأربعني مريضا )35 من الذكورو7 من اإلناث( أدرجوا يف الدراسة ممن كانوا يعانوا من امل يف اجلانب الزندي من املعصم مع احتمال سريري بإصابتهم بتمزق يف اجملمع الغضرويف املثلث. خضع مجيع املرضى لفحص الرنني املغناطيسي امللون ملفصل املعصم وبعد ذلك تنظري املعصم. متت مقارنة نتائج الرنني املغناطيسي امللون ملفصل املعصم مع نتائج املنظار. النتائج: بعد املقارنة مع النتائج باملنظار كان لفحص الرنني املغناطيسي امللون ثالث نتائج سلبية كاذبة )احلساسية = %93( وليس هناك أي نتائج إجيابية كاذبة. تسعة وثالثون مريضا استطاعوا العودة لعملهم. نسبة الرضا كانت عالية يف 38 من أصل 42 مريضا و 33 كان لديهم حتسن مقبول يف مستوى األمل. كانت حساسية الرنني املغناطيسي امللون ملفصل املعصم يف الكشف عن التمزق كامل السمك للمجمع الغضروف املثلث هي %93 )42/39(، وكانت اخلصوصية 80% )20/16(. كانت الدقة العامة لتنظري املعصم يف الكشف عن التمزق كامل السمك للمجمع الغضرويف املثلث يف دراستنا هي 85% )34/29(. اخلال�صة: هذه النتائج توضح دور الرنني املغناطيسي امللون ملفصل املعصم يف تقييم متزق اجملمع الغضرويف املثلث مع االقرتاح باستخدامها كتقنية التصوير األوىل، بعد صورة األشعة السينية يف تقييم املرضى الذين يعانون من امل مزمن يف اجلانب الزندي من الرسغ مع احتمال سريري بإصابتهم بتمزق يف اجملمع الغضرويف املثلث. مفتاح الكلمات: املجمع الغ�رسوف املثلث؛ مف�شل املع�شم؛ ت�شوير الرنني املغناطي�شي امللون. abstract: objectives: the aims of the study were to evaluate the role of magnetic resonance arthrography (mra) of the wrist in detecting full-thickness tears of the triangular fibrocartilage complex (tfcc) and to compare the results of the magnetic resonance arthrography (mra) with the gold standard arthroscopic findings. methods:the study was performed at king hussein medical center, amman, jordan, between january 2008 and december 2011. a total of 42 patients (35 males and 7 females) who had ulnar-sided wrist pain and clinical suspicions of tfcc tears were included in the study. all patients underwent wrist magnetic resonance arthrography (mra) and then a wrist arthroscopy. the results of mra were compared with the arthroscopic findings. results: after comparison with the arthroscopic findings, the mra had three false-negative results (sensitivity = 93%) and no false-positive results. a total of 39 patients were able to return to work. satisfaction was high in 38 of the patients and 33 had satisfactory pain relief. the sensitivity of the wrist mra in detecting tfcc full-thickness tears was 93% (39), and specificity was 80% (16/20). the overall accuracy of wrist arthroscopy in detecting a full-thickness tear of the tfcc in our study was 85% (29/34). conclusion: these results illustrate the role of wrist mra in assessing the tfcc pathology and suggest its use as the first imaging technique, following a plain x-ray, in evaluating patients with chronic ulnar side wrist pain with suspected tfcc injuries. keywords: triangular fibrocartilage complex; wrist; magnetic resonance imaging; arthrography. the role of wrist magnetic resonance arthrography in diagnosing triangular fibrocartilage complex tears experience at king hussein medical center, jordan asem a. al-hiari clinical & basic research advances in knowledge this was the first study in jordan to use intra-articular injection magnetic resonance arthrography (mra) for evaluating injuries of the triangular fibrocartilage complex (tfcc) in the wrist. although the procedure is invasive, in a normal setting it carries no major complications. asem a. al-hiari clinical and basic research | 281 wrist pain is always a challenging presenting complaint, particularly when it occurs on the ulnar side. determining the exact cause of ulnar-sided wrist pain is difficult due to the complexity of the anatomic and biomechanical properties of the ulnar side of the wrist.1 lesions of the triangular fibrocartilage complex (tfcc) are a common source of ulnar-sided wrist pain.2,3 the tfcc consists of the articular disk, dorsal and palmar radioulnar ligaments, the meniscal homologue, the dorsal and palmar ulnocarpal ligaments, the ulnar collateral ligament, the sheath of the extensor carpi ulnaris tendon, and the capsule of the distal radioulnar joint (druj).5 there are two attachments for the tfcc—the radial and ulnar sides. the radial side is attached to the medial surface of the distal radius at the distal margin of the sigmoid notch, while the ulnar side is either a single broad band that is attached to the ulnar styloid or two separate bands that insert into the styloid process and fovea.2,6 the ulnar portion of the tfcc is vascularised by the ulnar and posterior interosseous artery braches; on the other hand, the central and radial aspects of the complex are avascular.6 ulnar-sided wrist pain may be due to a tear or perforation in the tfcc. the tear can be detected radiologically in many ways, including through arthrography, magnetic resonance imaging (mri), or magnetic resonance arthrography (mra).4 arthroscopy is considered the gold standard to which all other modalities are compared. radial side tears or perforations tend to be traumatic and occur more in younger age groups. on the other hand, central and ulnar side lesions are more often degenerative and are more commonly seen in older patients.2 a carefully investigated medical history and a physical examination often lead to a correct diagnosis. however, a search for whether the wrist pain was caused by an acute injury, or brought on by repetitive minor trauma of the wrist, is essential in reaching a diagnosis of the patient’s complaint. the aim of this study was to compare the findings of mra of the tfcc with the findings of the gold standard, arthroscopy. methods this study was performed at king hussein medical center, amman, jordan, between january 2008 and december 2011. approval of the ethical committee was obtained before starting the study. patient consent was obtained before examination. the study included 42 consecutive patients who had ulnar-sided wrist pain and clinical suspicions of tfcc tear. the sample consisted of 35 males and 7 females, with an average age of 27.5 years. all 42 patients underwent a wrist arthrogram before they were sent for a wrist mri study. the arthrogram was done with the wrist in a prone semi-flexed position to allow the distal articular surface of the radius to be nearly perpendicular to the tabletop. using a complete aseptic technique to avoid infection, local anaesthetic was given. a 23–24 gauge needle was then introduced and guided fluoroscopically into the radioscaphoid joint. the needle tip position was confirmed with an injection of a few drops of water-soluble contrast material. then 4–6 ml of a prepared solution of 50% normal saline and 50% water soluble contrast with gadolinium in a concentration of 2.5 mmol/l was injected [figure 1]. the mri was initiated within 10–15 minutes of the contrast injection, using the same mri machine for all patients (1.5t syngo mri scanner, symphonytm, siemens medical solutions, erlangen germany). a small joint coil was used with the wrist in a neutral position. the following sequences were performed: coronal t1weighted (t1-w); coronal t1-w fat-saturated; coronal t2-w fat-saturated; axial proton densityweighted, and sagittal t1-w fat-saturated sequences [figure 2]. an additional 3-d coronal gradientrecalled acquisition was taken in a few cases when the aim was to visualise the small ligaments or structures [figure 3]. all scans were interpreted by the same radiologist; the site and type of tear were applications to patient care mra of the wrist is a valuable tool in the diagnostic evaluation and detection of full-thickness tears of the tfcc. it is a safe procedure when performed by an expert radiologist and in the presence of a new magnetic resonance imaging machine with retracted small joint coils. the role of wrist magnetic resonance arthrography in diagnosing triangular fibrocartilage complex tears experience at king hussein medical center, jordan 282 | squ medical journal, may 2013, volume 13, issue 2 specified. all patients underwent a wrist mra and then were referred to the orthopaedic hand surgeon for a wrist arthroscopy. the arthroscopy was done within 18 weeks of the mra (mean time = 46 days) and the results of wrist mra were compared with the arthroscopic findings. results a wrist arthroscopy was carried out regardless of mra findings, and the decision for an arthroscopy was based purely on clinical findings. tfcc tears were classified according to their locations, and were classified as site 1 if they were at the cartilage attachment to the radius; site 2 if they were pararadial (2–3 mm from the radius); site 3 if they were at the mid-portion; site 4 if they were paraulnar (2–3 mm from the ulnar insertion point of the tfcc); or site 5 if they were at the ulnar insertion point [figure 4].4 of the 42 patients who underwent an mra, 25 had a radiological criterium of tfcc tears. the tears were classified as: 15 central (site 3), 6 radial (site 1), 3 ulnar (site 5), and 1 paraulnar (site 4) [figures 5–7]. after a comparison with the arthroscopic findings, the wrist mra had 3 false-negative results (sensitivity = 93%) and no false-positive results. the 3 false-negative cases included a 28-year-old male patient with a complete vertical tear at the ulnar attachment of the tfcc which was seen clearly in arthroscopy, but not shown on the mra. it was reported as an increase in signal intensity in the t1-w sequence at the ulnar attachment side and the finding was considered non-specific. in two male patients, a 35-year-old and a 19-year-old, ulnar detachment tears in the most dorsal aspects of the tfcc were recognised retrospectively. the sensitivity of a wrist mra in detecting tfcc fullthickness tears was 93% (39/42), and specificity was 80% (16/20). the overall accuracy of a wrist arthroscopy in detecting a full-thickness tear of the figure 1: normal wrist arthrogram after injecting a water soluble contrast in the radioscaphoid joint. figure 2: coronal fat-saturated t1-weighted image from a magnetic resonance arthrography demonstrates a normal triangular fibrocartilage complex (arrow). figure 3: coronal fat-saturated three-dimensional gradient echo (3-d gre) image from a magnetic resonance arthrography shows the triangular fibrocartilage complex very clearly, particularly the radial side attachment (arrow). 3-d gre is excellent for the imaging of small structures of the wrist and evaluation of the cartilage. asem a. al-hiari clinical and basic research | 283 tfcc in this study was 85% (29/34). on a long term follow-up, 39 of the 42 patients were able to return to work, and 31 of the patients were able to return to their previous level of activity. patient satisfaction was high in 38 of 42 patients, and 33 had satisfactory pain relief. discussion this study revealed an overall accuracy of a wrist arthroscopy in detecting a full-thickness tear of the tfcc of 85%. many studies have shown evidence of central degenerative disc changes after age 40, which is often asymptomatic. this degeneration results in abnormal increased signal intensity within the material of the tfcc upon mri. this disc degeneration may also cause non-traumatic communication between the distal radioulnar and radiocarpal joints which is reported in up to 7% of patients who are over 40 years of age.5,7 detecting peripheral tears of the ulnar attachment of the tfcc is an imaging challenge. they are clinically important because they may be associated with instability of the druj.4,6,8 although tears of the tfcc in the radial or central aspect are easily seen, tears at the ulnar attachment are frequently difficult to evaluate and may be missed. this difficulty in detection is clearly evident by the three false-negative ulnar side tears in this study. standard mri plays a limited role in the evaluation figure 4: coronal drawing of the wrist showing the location of triangular fibrocartilage complex tears. figure 5: coronal t1w fat-saturated sequence showing a relatively big communicating tear (arrow head) close to the radial attachment of the triangular fibrocartilage complex. figure 6: (a) radiocarpal wrist arthrography showing a tear at the pararadial part of the triangular fibrocartilage complex (site 2); (b) coronal t1-weighted fat-saturated sequence confirming the arthrogram finding and clearly showing the tear (arrow). the role of wrist magnetic resonance arthrography in diagnosing triangular fibrocartilage complex tears experience at king hussein medical center, jordan 284 | squ medical journal, may 2013, volume 13, issue 2 of peripheral ulnar side tears, so an mri arthrogram is the examination of choice in such cases.8 the peripheral and central tears of the tfcc must be differentiated as the mode of treatment is different in each condition. peripheral tears have a good vascular supply and are repaired; however, central tears are avascular and are commonly managed with debridement.6 the most widely-adapted classification of the appearance of tfcc tears upon mri is the palmer classification [table 1]. however, in this study, tears are described as radial, central, or ulnar because this classification plays a major role in the clinical evaluation and management of patients. at king hussein medical center, the ulnar side tears are repaired and sutured. on the other hand, radial and central tears are debrided. this information allows improved preoperative patient consent and planning. in this study, the radiological evaluation of the tfcc included a plain x-ray, a computed tomography (ct) and mri scans, and an arthrogram or mra. a simple, plain x-ray should include posterioranterior (pa) and lateral views of the wrist, and is essential as it could illustrate joint arthrosis, ulnar styloid process fractures, and ulna variance (positive or negative). about 60–70% of the tfcc tears are associated with ulnar styloid fracture.5,9 a ct scan is a more detailed mode of investigation, particularly if 3-d reconstruction images are needed. the overall alignment of the carpal bones can be clearly evaluated. if ct arthrography is used, it can be helpful in detecting tfcc or an interosseous ligament defect. no research has mentioned the superiority of a ct scan over mra in diagnosing tfcc tears.9–12 figure 7: (a) coronal t2-weighted fat-saturated sequence; (b) coronal t1-weighted image; (c) coronal t1w fatsaturated sequences showing clearly a small, full thickness tear of the triangular fibrocartilage complex at the radial end (arrow). table 1: magnetic resonance imaging appearance of triangular fibrocartilage complex tears (palmer classification) commentsmri featurescategory 1. traumatic avascular portion, may not heal linear increase signal intensity (t2w) a. central perforation may have ulnar base fracture increase signal at ulnar attachment (t2w) b. ulnar avulsion may lead to ulnar translation increase signal at ulnar attachment and ulnolunate and ulnotriquetral ligament attachment (t2w) c. distal avulsion may be associated with radial fractures increase signal at radial attachment (t2w) d. radial avulsion 2. degenerative intermediate signal in pd and t2w sequence a. tfcc central degeneration same as a with thinning or increase signal in lunate articular cartilage. b. tfcc perforation with lunate chondromalacia signal increase on t2w and lunate cartilage changes c. tfcc perforation and chondromalacia same as 2c plus increased signal in lunotriquetral ligament d. tfcc perforation, chondromalacia and lunotriquetral tear same as 2d plus osteophytes in ulnocarpal and radioulnar joints e. features of 2d plus ulnocarpal and radioulnar arthritis. mri = magnetic resonance imaging ; t2w = t2-weighted image; tfcc = triangular fibrocartilage complex asem a. al-hiari clinical and basic research | 285 an mri evaluation is usually done by using spin-echo t1-w and t2-w sequences along with a pd-weighted gradient-echo and a t1-weighted fat saturation technique. recently, high-resolution 3-d gradient-echo, with thin cut sequence, has been used and could increase the detection rate of tfcc tears.3,13 the tfcc appears very similar to the knee meniscus upon mri.14 mri has been proposed as a non-invasive alternative diagnostic test but it did not approach the accuracy of mra in this sort of pathology.3 besides information about the tfcc and interosseous ligaments, mri will give additional information regarding bone oedema, cartilage lesions, neuropathy, and bone and muscle injuries. using arthroscopy as the gold standard, mri has been shown to have an accuracy of 64–75% for perforations or tears.2 the inhomogeneous signal intensity and the striated appearance of the tfcc, especially of the ulnar side, may make these disruptions more difficult to detect.2,8 an arthrogram may be used to confirm the diagnosis when a clinical history and physical examination suggest a tfcc defect or interosseous ligament instability. water-soluble contrast material is injected into one of the 3 non-communicating spaces of the carpus: the distal radioulnar joint, the radiocarpal joint, and the midcarpal joint. the decision to obtain a single-injection versus a tripleinjection arthrogram must be based on specific clinical findings.1 this method will show abnormal connections between the radiocarpal, distal radioulnar, and midcarpal joints. with the addition of video recording during the injection of contrast material, the arthrogram can determine the specific site of abnormal communication.7 mra is involved in the controversial question of the appropriate technique to use in the diagnosis of tfcc tears. shionova et al. reported arthrograms to be superior to mri scanning.10 however, it is important to keep in mind that the mri technique described in that study used relatively thick sections and a wide interslice gap, which may be considered suboptimal. some authors would agree that the two techniques may be equivalent.4 however, it is generally accepted that a combination of mri and mra is currently the method of choice in tfcc tear diagnosis, and at our institute the protocol was to perform this investigation in all patients who were sent to evaluate the tfcc for possible injuries or rupture. the mra procedure is the same as arthrography; however, the contrast injected is a prepared solution of 50% normal saline and 50% water soluble contrast with gadolinium in a concentration of 2.5 mmol/l [figure 5–7]. the mri sequences also remain the same but with more fatsaturated sequences, as required. there were some limitations to this study. the study group did not include asymptomatic patients with expected normal tfccs. a second limitation was the delay of up to 18 weeks between the mra and the arthroscopy. during such a delay, an incomplete tear can turn into a complete one, or a tear seen through mra can fill in with healing reaction tissue, making such a tear undetectable upon arthroscopy. the small number of patients included in the study precluded statistical inference, but the results, if taken as those of a prospective pilot study, are promising. a c k n o w l e d g e m e n t s the author wishes to thank dr issam dahabreh and dr ayman borghol, hand surgeons from the orthopedic department, king hussein medical center, jordan for their contribution and help with this research. conclusion these results illustrate the useful role of wrist mra in assessing tfcc pathology and suggest its use as the first imaging technique, after a plain x-ray, in evaluating patients with chronic ulnar side wrist pain with suspected tfcc injuries. mra of the wrist is a valuable tool in a diagnostic evaluation to detect full-thickness tears of the tfcc. references 1. haims ah, schweitzer me, morrison wb, deely d, lange r, osterman al, et al. limitations of mr imaging in the diagnosis of peripheral tears of the triangular fibrocartilage of the wrist. am j roentgenol 2002; 178:419–22. 2. mcalinden ps, teh j. imaging of the wrist. imaging 2003; 15:180–92. 3. blazar pe, chan psh, kneeland jb, leatherwood d, bozentka dj, kowalchick r. the effect of observer experience on magnetic resonance imaging: interpretation and localization of triangular fibrocartilage. hand surg 2001; 26a:742–48. the role of wrist magnetic resonance arthrography in diagnosing triangular fibrocartilage complex tears experience at king hussein medical center, jordan 286 | squ medical journal, may 2013, volume 13, issue 2 4. rüegger c, schmid mr, pfirrmann cwa, nagy l, gilula la, zanetti m. peripheral tear of the triangular fibrocartilage: depiction with mr arthrography of the distal radioulnar joint. am j roentgenol 2007; 188:187–92. 5. hobby jl, tom bd, bearcroft pw, dixon ak. magnetic resonance imaging of the wrist: diagnostic performance statistics. clin radiol 2001; 56:50–7. 6. zanetti m, linkous d, gilula la, hodler j. characteristics of triangular fibrocartilage defects in symptomatic and contralateral asymptomatic wrists. radiology 2000; 216:840–5. 7. moser t, dosch jc, moussaoui a, dietemann jl. wrist ligament tears: evaluation of mri and combined mdct and mr arthrography. ajr am j roentgenol 2007; 188:1278–86. 8. schmid mr, schertler t, pfirrmann cw, saupe n, manestar m, wildermuth s, et al. interosseous ligament tears of the wrist: comparison of multidetector row ct arthrography and mr imaging. radiology 2005; 237:1008–13. 9. magee t. comparison of 3-t mri and arthroscopy of intrinsic wrist ligament and tfcc tears. ajr am j roentgenol 2009; 192:80–5. 10. shionova k, nakamura r, imaeda t, makino n. arthrography is superior to magnetic resonance imaging for diagnosing injuries of the triangular fibrocartilage. j hand surg br 1998; 23:402–5. 11. haims ah, schweitzer me, morrison wb, deely d, lange rc, osterman al, et al. internal derangement of the wrist: indirect mr arthrography versus unenhanced mr imaging. radiology 2003; 227:701– 7. 12. saupe n, prussmann kp, luechinger r. mr imaging of the wrist: comparison between 1.5and 3-t mr imaging—preliminary experience. radiology 2005; 234:256–64. 13. schweitzer me, brahme sk, hodler j, hanker gj, lynch tp, flannigan bd, et al. chronic wrist pain: spin-echo and short tau inversion recovery mr imaging and conventional mr arthrography. radiology 1992; 182:205–11. 14. oneson sr, timins me, scales lm, erickson sj, chamoy l. mr imaging diagnosis of triangular fibrocartilage pathology with arthroscopic correlation. ajr am j roentgenol 1997; 168:1513– 18. the mucoepidermoid carcinoma (mec) was originally described by volkmann in 1895. mec has since emerged in most series as the most commonly diagnosed primary malignancy of the major salivary glands. histologically, mec is composed of various combinations of epidermoid, mucous and intermediate cells; the latter cell is presumed to be the precursor of the former. mec occasionally displays morphological variations with a minimum or complete absence of more typical morphological features. the presence of clear cells, a focal spindlecell pattern, sebaceous-like differentiation, areas mimicking thyroid follicles, a predominantly oncocytic appearance and an intense sclerosing pattern may complicate the diagnosis.1–4 what distinguishes the sclerosing variant of a mec from the other variants is a dense, hyalinised, sclerotic tumour stroma that surrounds, compresses and sometimes even obliterates the nests of tumour cells. since not many cases have been reported, its behaviour is yet to be determined. the sclerosis associated with these tumours may overshadow the typical histopathological features and result in diagnostic confusion.2,5 we report the case of a sclerosing mucoepidermoid carcinoma (smec) that was diagnosed in a 32-yearold male and include a brief review of the literature. case report a male patient aged 32 years reported to a private hospital with the chief complaint of an asymptomatic swelling over the right parotid region for the previous 2 years and 6 months. on clinical examination, a multilobulated swelling of the right parotid region was noted; it measured approximately 6 x 8 cm with a slight erythema of the overlying skin. the swelling also caused a lifting of the ear lobe [figure 1]. palpation of the swelling showed that it was firm in consistency with fixity to the deeper tissues. no lymphadenopathy was present on clinical examination and the facial nerve function was not altered. the results of routine blood tests were within normal limits. the investigations performed prior to an incisional vydehi institute of dental sciences, bangalore, karnataka, india *corresponding author e-mail: kooks85@gmail.com سرطان خماطي بشروي متصلب حالة فريدة كي�صافا بات، بافنا باندي، ب�صباراجا �صيتي، فيديا مانور، �رشثيلك�صمي، مدهفيكا فاتيدار abstract: sclerosing mucoepidermoid carcinoma is an unusual type of mucoepidermoid carcinoma with special histological features which differ from those of the classic type of mucoepidermoid carcinoma. we report the case of a 32-year-old male, who reported to the vydehi institute of dental sciences, bangalore, india, with an asymptomatic swelling over the right parotid region which had been present for the previous two and a half years. histopathological sections of the tumour mass showed mucous and epidermoid cell nests in a dense, hyalinised, sclerotic stroma. a diagnosis of sclerosing mucoepidermoid carcinoma was made. a superficial parotidectomy was performed on the patient and he has remained disease free to date. keywords: mucoepidermoid carcinoma; salivary gland neoplasms; case report; india. امللخ�ص: يعترب ال�رشطان املخاطي الب�رشوي املت�صلب من الأنواع غري العتيادية من ال�رشطانات املخاطية الب�رشوية مع وجود ملمح ه�صتولوجية خا�صة تفرقها عن الأنواع املعهودة من ال�رشطانات املخاطية الب�رشوية. نعر�س هنا تقريراً حلالة ذكر عمره 32 عاما، والذي عر�س نف�صه ملركز فيدهي لعلوم طب الأ�صنان يف بنجلور بالهند، ب�صكوى لتورم عدمي الأعرا�س يف املنطقة اليمني للغد النكفية، والذي كان موجوداً منذ �صنتني ون�صف. مقاطع من مر�صيات الأن�صجة لكتلة التورم اأظهرت وجود اأع�صا�س خلليا خماطية وب�رشانية �صمن تزجج كثيف من ال�صدودية املت�صلبة. مت اإجراء ا�صتئ�صال �صطحي للغدة النكفية للمري�س مع خلو املري�س من املر�س حتى اليوم. كلمات البحث: �رشطان؛ خماطي ب�رشوي؛ مت�صلب؛ اأورام الغدد اللعابية؛ تقرير حالة؛ الهند. sclerosing mucoepidermoid carcinoma a unique case keshava bhat, *bhavna pandey, pushparaja shetty, vidya manohar, shruthilaxmi m. k., madhvika patidar sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e249-252, epub. 7th apr 14 submitted 11th oct 13 revision req. 8th dec 13; revision recd. 7th jan 14 accepted 19th feb 14 case report sclerosing mucoepidermoid carcinoma a unique case e250 | squ medical journal, may 2014, volume 14, issue 2 biopsy included fine needle aspiration cytology (fnac) and a computed tomography (ct) scan. the fnac findings were inconclusive due to the paucity of cells. the ct scan revealed a well-defined soft-tissue density lesion [figure 2]. a provisional diagnosis of a benign salivary gland tumour was considered due to the lack of adenopathy, a lack of nerve dysfunction, the ct findings and the duration of the tumour mass. an incisional biopsy of the tumour was performed under local anaesthesia. this procedure was done prior to surgery to provide an accurate histological diagnosis. gross examination revealed a specimen measuring around 4.5 x 3.0 x 2.5 cm, grayish-white in colour and of a very firm consistency. the histopathological haematoxylin and eosin stained sections revealed a tumour mass consisting of mucous and epidermoid cells forming microcysts in a dense fibrinous stroma. the mucous cells were large, pale, columnar to polygonal in shape and seen to be lining the cystic areas. epidermoid cells were formed solid masses in a few other areas. several darklystained intermediate cells were also seen. throughout the tumour mass connective tissue stroma was noted which consisted of dense hyalinised fibrous tissue made up of thick collagen fibres encircling the cellular nests and islands with scant inflammatory infiltrate [figure 3]. a diagnosis of smec was made. following an incisional biopsy, a superficial parotidectomy was performed on the patient under general anaesthesia in consideration of the lack of facial nerve involvement and the absence of both fixity and lymphadenopathy. the tumour was completely excised with negative margins. a modified blair incision was used to raise the skin flap covering the gland at face-lift level, i.e. in the layer of fat between the skin and the gland beyond the apparent margin of the tumour. the facial nerve was identified at the proximal end as it emerged from the stylomastoid foramen before entering the substance of the gland. all the salivary tissue superficial to the facial nerve was removed and the skin flap was closed in layers. the patient continues to be on routine six-month followup and has remained disease free to date [figure 4]. the facial nerve function has remained unaffected. discussion smec was first reported in 1987 by chan and saw, who described a case of parotid involvement.6 the distinctive feature of the smec is an extreme sclerotic stroma that is present in the tumour mass. the sclerosis associated with these tumours may be so intense that it can confuse even experienced pathologists. extensive desmoplastic stroma is observed in many salivary gland tumours like the pleomorphic adenoma and the carcinoma ex-pleomorphic adenoma, but is not commonly seen in the mec. it is also seen in inflammatory salivary gland disease such as chronic figure 1: multilobulated swelling of the right parotid region with slight erythema of the overlying skin. figure 3: scanner view of cellular nests and islands surrounded by dense hyalinised connective tissue stroma (haematoxylin and eosin stained sections, x 40 magnification). figure 2: computed tomography scans showing a welldefined soft tissue density lesion. keshava bhat, bhavna pandey, pushparaja shetty, vidya manohar, shruthilaxmi m. k. and madhvika patidar case report | e251 sclerosing sialadenitis.2,5 the possible pathogenetic mechanisms causing this type of sclerosis are tumour infarction and mucin extravasation.5 the mucin acts as a foreign material, resulting in fibrosis that forms as an attempt to wall-off the mucin. as seen in this case, a smec represents a potential diagnostic pitfall on fnac samples due to the intense sclerosis and low cellularity; the fnac can therefore often prove to be inconclusive. histologically, the sclerosing variant of the mec is characterised by some exclusive features: areas of dense sclerosis (almost resembling that of a keloid) with distributed solid or cystic nests of mucoepidermoid tumour cells. in 1990, batsakis and luna mentioned stromal desmoplasia as a feature of high-grade mecs.7 according to fadare et al., the sclerosing morphological variant of this tumour is extremely rare, with only six reported cases. out of these, two showed metastasis but this could have been because of their larger tumour size rather than the sclerotic stroma.5 analyses with larger number of cases are required to evaluate whether the sclerosis appears as a self-determining prognostic factor. comparing the tumours reported in the past, most of them have been put into the low-grade category; they were observed with a few mitotic figures and minimal anaplasia.5 perineural invasion, another factor that determines prognosis of salivary gland tumours, is generally absent in these sclerotic tumours. it was reported in only three of the previous cases.5–14 negative prognostic factors included the high grade of the tumour, increasing patient age, tumour size, extraparenchymal extension, nodal metastases and distant metastases.15,16 the histological differential diagnoses of salivary gland smec include sclerosing polycystic adenosis, chronic sclerosing sialadenitis, lowgrade cystadenocarcinoma and necrotising sialometaplasia.10,11,15–17 the treatment recommended for these cases is total surgical excision with marginal resection. the facial nerve should be preserved if it is not involved. if complete marginal resection is not possible, postoperative radiation therapy is recommended to prevent tumour spread, recurrence and distant disease. patients should be routinely investigated with magnetic resonance and ct imaging studies of the tumour, with thorough evaluation of the regional lymph nodes, to ensure there is no recurrence or metastasis.10 conclusion the present case of smec that was diagnosed in a 32-year-old male was found to have unique histological features, causing its recognition and diagnosis to be challenging. moreover, in view of both its distinctive pathology and its rarity, no clear treatment strategy has been formulated. it was treated by superficial parotidectomy. the patient is on long-term review, having undergone clinical and ultrasonographic evaluation for the past six years and the prognosis has so far been favourable. references 1. ellis gl, auclair pl, gnepp dr. mucoepidermoid carcinoma. in: mitchell j, ed. surgical pathology of the salivary glands. major problems in pathology series.vol. 25. philadelphia: w. b. saunders co., 1991. pp. 269–95. 2. rajendran r. sivapathasundharam b. tumors of the salivary glands. in: rajendran r. sivapathasundharam b, eds. shafer's textbook of oral pathology. 6th ed. new delhi: elsevier health sciences, indian reprint, 2009. pp. 235–6. 3. neville bw. salivary gland tumors. in: neville bw, damm dd, allen cm, bouquot je, eds. oral & maxillofacial pathology. 3rd ed. philadelphia: saunders/elsevier, indian reprint, 2009. pp. 487–90. 4. regezi ja, sciubba jj, jordan ckr. salivary gland diseases. in: regezi ja, sciubba jj, jordan ckr, eds. oral pathology, clinical pathologic correlations. 5th ed. philadelphia: saunders/ elsevier. indian reprint, 2009. pp. 203–4. 5. fadare o, hileeto d, gruddin yl, mariappan mr. sclerosing mucoepidermoid carcinoma of the parotid gland. arch pathol lab med 2004; 128:1046–9. 6. chan jk, saw d. sclerosing mucoepidermoid tumour of the parotid gland: report of a case. histopathology 1987; 11:203–7. 7. batsakis jg, luna ma. histopathologic grading of salivary gland neoplasms: i. mucoepidermoid carcinomas. ann otol rhinol laryngol 1990; 99:835–8. 8. hamper k, schimmelpenning h, caselitz j, arps h, berger j, askensten u, et al. mucoepidermoid tumors of the salivary glands. correlation of the cytophotometrical data and prognosis. cancer 1989; 63:708–17. 9. muller s, barnes l, goodurn wj jr. sclerosing mucoepidermoid carcinoma of the parotid. oral surg oral med oral pathol oral radiol endod 1997; 83:685–90. 10. sinha sk, keogh ij, russell jd, o'keane jc. sclerosing mucoepidermoid carcinoma of minor salivary glands: a case report [letter]. histopathology 1999; 35:283–4. figure 4: post-surgical photograph of the patient. sclerosing mucoepidermoid carcinoma a unique case e252 | squ medical journal, may 2014, volume 14, issue 2 11. urano m, abe m, horibe y, kuroda m, mizoguchi y, sakurai k, et al. sclerosing mucoepidermoid carcinoma with eosinophilia of the salivary glands. pathol res pract 2002; 198:305–10. 12. heavner sb, shah rb, moyer js. sclerosing mucoepidermoid carcinoma of the parotid gland. eur arch otorhinolaryngol 2006; 263:955–9. 13. veras ef, sturgis e, luna ma. sclerosing mucoepidermoid carcinoma of the salivary glands. ann diagn pathol 2007; 11:407–12. 14. aguiar mc, bernardes vf, cardoso sv, barbosa aa, mesquita ra, carmo ma. a rare case of sclerosing mucoepidermoid carcinoma arising in minor salivary glands with immunohistochemical evaluation. minerva stomatol 2008; 57:453–7. 15. mendelson aa, al-macki k, chauvin p, kost km. sclerosing mucoepidermoid carcinoma of the salivary gland: case report and literature review. ear nose throat j 2010; 89:600–3. 16. chen mm, roman sa, sosa ja, judson bl. histologic grade as prognostic indicator for mucoepidermoid carcinoma: a population-level analysis of 2400 patients. head neck 2013; 36:158–63. doi: 10.1002/hed.23256. 17. shinhar sy. sclerosing mucoepidermoid carcinoma of the parotid gland: case report. ear nose throat j 2009; 88:e29–31. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e411–414, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.017. submitted 23 dec 14 revision req. 8 feb 15; revision recd. 10 mar 15 accepted 30 apr 15 follicular dendritic cell sarcoma (fdcs) is a rare neoplasm; although it is classified under histiocytic and dendritic cell neoplasms, fdcs is typically nodal, with extranodal involvement occurring in approximately 30% of cases.1 the major hurdle in treating fdcs cases is misdiagnosis, due to similarities in presentation to lymphoma. cytogenetic data on fdcs are very scarce, with the first description appearing in 2008.2,3 this report presents a fdcs patient with a complex karyotype and pathological findings. case report a 39-year-old woman presented to the sultan qaboos university hospital in muscat, oman, in february 2013 with a swelling on the right side of her neck. on examination, a firm, non-mobile, nontender supraclavicular swelling was found. magnetic resonance imaging showed a mass involving the sternocleidomastoid muscle and the compression of the internal jugular vein with an intact carotid [figure 1a].surgical excision of the tumour revealed a globular nodular firm grey mass measuring 7 x 6 x 2.8 cm [figure 1b]. for the cytogenetic analysis, a fine needle aspirate (fna) was collected under sterile conditions. the fna was distributed into three culture flasks and cultured in roswell park memorial institute media at 37 °c with 5% carbon dioxide. both 24-hour and long-term cultures were set up. when sufficient growth was observed under an inverted microscope 1department of genetics, college of medicine & health sciences, sultan qaboos university; departments of 2pathology and 3medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: uday.achandira@gmail.com ساركومة اخللية التغصنية اجلريبية الوراثة اخللوية و النتائج املرضية اكانديرا موتابا اوداي كومار، مايا البحرية، اكرام علي برين، اإبراهيم الهدابي abstract: follicular dendritic cell sarcoma (fdcs) is a rare neoplasm with a non-specific and insidious presentation further complicated by the difficult diagnostic and therapeutic assessment. it has a low to intermediate risk of recurrence and metastasis. unlike other soft tissue sarcomas or histiocytic and dendritic cell neoplasms, cytogenetic studies are very limited in fdcs cases. although no specific chromosomal marker has yet been established, complex aberrations and different ploidy types have been documented. we report the case of a 39-yearold woman with fdcs who presented to the sultan qaboos university hospital in muscat, oman, in february 2013. ultrastructural, immunophenotypical and histological findings are reported. in addition, karyotypic findings showed deletions of the chromosomes 1p, 3q, 6q, 7q, 8q and 11q. to the best of the authors’ knowledge, these have not been reported previously in this tumour. techniques such as spectral karyotyping may help to better characterise chromosomal abnormalities in this type of tumour. keywords: chromosomal aberrations; cytogenetics; follicular dendritic cell sarcoma; fine needle aspiration; karyotyping; case report; oman. امللخ�ص: �ساركومة اخللية التغ�سنية اجلريبية هو ورم نادر تكون اأعرا�سه غري وا�سحة وظهوره قد يكون ب�سورة غري متوقعة. ت�سخي�س املر�س يكون �سعبا جدا لعدم وجود طفرة وراثية حمددة ميكن الك�سف عنها عن طريق التنميط النووي و الفحو�سات اجلينية األخرى. يحمل هذا املر�س ن�سبة اختطار ب�سيطة اإىل متو�سطة من رجوعه والنقيلة. يختلف هذا الورم عن بقية اأنواع �ساركومة الأن�سجة الرخوية و الأورام الن�سيجية والتغ�سنية بقلة فحو�سات الوراثة اخللوية فيه ولكن مت ت�سجيل عدد من الزيغ املعقد و اأنواع خمتلفة من ال�سيغة ال�سبغية لهذا املر�س. نعر�س هنا حالة امراأة عمرها 39 عاما مت ت�سخي�سها ب�ساركومة اخللية التغ�سنية اجلريبية يف م�ست�سفى جامعة ال�سلطان قابو�س مب�سقط، �سلطنة عمان يف �سهر فرباير من عام 2013، حيث مت االعتماد على التحليل اجلزيئي والفح�س با�ستخدام امل�سادات والت�سخي�س مل للموؤلفني معرفة اأف�سل ح�سب .1q ،3q ،6q ،7q ،8q و 11q ال�سبغيات، يف حذف وجود اخللوية الوراثة فحو�سات بينت الن�سيجي. هذة يف للتغريات الدقيق الت�سخي�س من متكن قد الطيفي النووي التنميط مثل التقنية الفحو�سات الورم. هذا يف �سابقا هذا عر�س يتم ال�سبغيات. مفتاح الكلمات: زيغ ال�سبغي؛ الوراثيات اخللوية؛ �ساركومة اخللية التغ�سنية اجلريبية؛ خزعة م�سفوطة بالإبرة؛ التنميط النووي؛ تقرير حالة؛ �سلطنة عمان. follicular dendritic cell sarcoma cytogenetics and pathological findings *achandira m. udayakumar,1 maiya al-bahri,2 ikram a. burney,3 ibrahim al-haddabi2 online case report follicular dendritic cell sarcoma cytogenetics and pathological findings e412 | squ medical journal, august 2015, volume 15, issue 3 on the fourth day, 50 µl of colcemid at 10 µl/ml of gibco™ (life technologies, thermo fisher scientific corp., carlsbad, california, usa) was added for 30 minutes, followed by hypotonic treatment (0.075 m of potassium chloride) for 45 minutes. the cell pellet was fixed using carnoy’s fixative solution and slides were prepared and g-banded the following day. microscopic findings showed a relatively well encapsulated neoplasm, composed of nodules separated by thick fibrous septae which contained multiple foci of lymphoid aggregates. the nodules were composed of sheets of pleomorphic spindle cells and epithelioid cells with indistinct cytoplasmic borders; the nodules exhibited a moderate amount of acidophilic cytoplasm, vesicular nuclei and prominent nucleoli. these cells were arranged in short fascicles or whorls or exhibited a storiform pattern. abundant mitotic figures (24 mitoses/10 high-power fields) and apoptotic bodies were present and foci of necrosis and haemorrhage were also noted [figure 2a]. immunohistochemical staining showed strong positivity of neoplastic cells for clusters of differentiation (cd) 23, cd35 and cd21 via membranous staining [figure 2b] and focal positivity for cd99. markers for cd34, human melanoma black 45 and cd68 were negative. the ki-67 protein cell proliferation index was high (80%). electron microscopy findings showed elongated nuclei with cytoplasmic invagination. abundant desmosomes with no evidence of birbeck granules were also observed [figure 2c], favouring a diagnosis of fdcs. intranuclear pseudo-inclusions were not visible on morphology. the nodular grey tumour mass on the sternocleidomastoid muscle compressed the internal jugular vein. of the 20 karyotypes, 19 showed complex abnormal karyotypes and one showed a normal karyotype. the chromosome numbers ranged from 72 to 80. structural aberrations, such as deletions, were observed on chromosomes 1p, 3q, 6q, 7q, 8q and 11q. additional material of unknown origin was observed on both copies of 16q and 19q. the loss of chromosome 21 was obvious in the majority of the metaphases. other common missing chromosomes were 8, 9, 13, 14 and 22. various marker chromosomes were present in all of the abnormal metaphases. as the range of chromosomes were in the hypertriploid category, a composite karyotype was interpreted as per the international system for human cytogenetic nomenclature (2013).4 these were as follows: 72~80<3n+>,xxxx,-1,del(1) (p32)x2,-3,del(3)(q24),-4,del(6)(q13)x2,-7,del(7)(q11) x2,-8,-8,del(8)(q22)x2,-9-9-9,del(11)(q13),-12,-13,13,-14,-14,-14,add(16)(q24)x2,-18,add(19)(q13)x2,20,-21,-21,-21,-21,-22,-22,-22,+mar1,+mar2,+mar3,+ mar4,+mar5[19][cp11]/46,xx[1] [figure 3]. discussion figure 1a & b: a: magnetic resonance image showing the follicular dendritic cell sarcoma tumour mass involving the sternocleidomastoid muscle. b: photograph showing a gross specimen of the globular nodular tumour after excision (7 x 6 x 2.8 cm). figure 2a–c: haematoxylin and eosin histopathology section showing (a) neoplastic nodules composed of sheaths of spindle cells exhibiting vesicular nuclei, prominent nucleoli and indistinct cytoplasmic borders at x40 magnification, (b) tumour cells showing strong membranous positive staining for cluster of differentiation 21 at x400 magnification and (c) several well-formed desmosomes firmly joining the cytoplasmic process of contiguous neoplastic cells at x25,000 magnification. this favoured a diagnosis of follicular dendritic cell sarcoma. achandira m. udayakumar, maiya al-bahri, ikram a. burney and ibrahim al-haddabi online case report | e413 current and past experiences with soft tissue sarcomas.8 immunophenotypic comparisons of the positivity of cd21 and cd35 markers vary among patients. in the current case, cd21 was strongly positive and the tumour cells were also positive for cd23 and cd35; similar results were reported by wang et al. in a previous report.6 however, in another report of fdcs by jones et al., all these markers were negative.5 the current patient had hypertriploidy in all of the abnormal metaphases ranging from 72 to 80. earlier reports of fdcs have shown hypodiploidy and diploidy in two cases;3,7 furthermore, two cases had hyperdiploidy along with pseudodiploidy.5,7 della porta et al. reported a patient with hypotriploidy and jones et al. reported a patient with hypertetraploidy.5,9 notably, two reported cases showed the involvement of chromosome xp.5,7 no involvement of chromosome x was observed in the current patient. add(16q) has been reported in previous cases and the current patient had similar additional material of unknown origin on 16q.3 add(21q), add(21p), add(15p) and add(17p) were reported by suzuki et al., perry et al. and jones et al.2,3,5 the patient in the current report study also had add(19q) and did not have any involvement of chromosomes 14, 15, 17 or 21. marker chromosomes were seen in two earlier cases reported by perry et al., which were also observed in the patient in the current report in all of the abnormal metaphases.3 cytogenetic observations in the current patient showed novel aberrations, such as the deletion of chromosomes 1p, 3q, 6q, 7q, 8q and 11q, which were not reported earlier [table 1]. these novel findings are an addition to the literature already available on fdcs. material of unknown origin was observed in both copies of chromosome 16 and 19 in the current patient, in contrast to the gains observed in earlier reports although fdcs is pathologically well characterised, there are very few cases described cytogenetically. thus far, only six case reports are available in the literature with chromosomal findings.2,3–7 to the best of the authors’ knowledge, this is the first report from a middle eastern arab population. the results of the current case yielded a good mitotic index and morphology of chromosomes by culturing the fna of the tumour, which is often difficult to obtain. in sarcomas, even though the cytology of fna material may not be of much diagnostic use, the cytogenetic benefits are substantial.6 hence, the authors of this report endorse fna as the best technique for obtaining ideal samples for solid tumour cytogenetics, as per figure 3a & b: representative complex karyotypes showing structural abnormalities such as del(1p), del(3q), del(6q), del(7q), del(8q), del(11q), add(16q) and marker chromosomes in a patient with follicular dendritic cell sarcoma. table 1: comparative analysis of the ploidy status, frequently involved chromosomes and structural aberrations in follicular dendritic sarcoma cases in the literature author and year of case report ploidy status (chromosomes involved) structural aberrations jones et al.5 2001 hypertetraploidy (93–103)/hyperdiploidy (47–57)/pseudodiploidy xp-, 21p+ della porta et al.9 2003 hypotriploidy (62–71) 14q+, 15qsander et al.7 2007 hypodiploidy (35–45_/ pseudodiploidy 3q+,7p+, 8p-, 8q+, 9p-, 9q+, 10p-, xpsuzuki et al.2 2008 diploidy (46) 21q+ wang et al.6 2010 diploidy (46) normal karyotype perry et al.3 2013 hypodiploidy 15p+, 16q+, 17p+ present case hypertriploidy (72–80) 1p-,3q-, 6q-, 7q-, 11q-, 16q+, 19q+ follicular dendritic cell sarcoma cytogenetics and pathological findings e414 | squ medical journal, august 2015, volume 15, issue 3 for chromosomes 3, 7, 8 and 9.7 hence, observations from the current patient confirm the heterogeneity of chromosomal findings in fdcs proposed by perry et al. in their two cases.3 great variation has been observed among the ploidy statuses and structural alterations in fdcs cases. use of the latest technologies, such as spectral karyotyping, is recommended for the complete characterisation of chromosomes. single nucleotide polymorphism arrays and next generation sequencing should also be utilised in future studies investigating the genes responsible for fdcs. conclusion fdcs is a rare tumour which is difficult to diagnose based on its non-specific presentation. unlike other soft tissue sarcomas, cytogenetic studies are very limited in fdcs cases. cytogenetic observations of the current patient with fdcs showed novel aberrations, such as the deletion of chromosomes 1p, 3q, 6q, 7q, 8q and 11q; to the best of the authors’ knowledge, these have not yet been reported. the cytogenetic characterisation of rare tumours is important so as to establish chromosomal markers. this aids in the diagnosis of patients and enables a precise classification in order to predict prognosis. however, further research is needed before a conclusion can be drawn. spectral karyotyping is recommended for the complete characterisation of chromosomes for this type of tumour. moreover, fna is deemed the best technique for obtaining samples for cytogenetic analyses of solid tumours. references 1. pizzi m, ludwig k, palazzolo g, busatto g, rettore c, altavilla g. cervical follicular dendritic cell sarcoma: a case report and review of the literature. int j immunopathol pharmacol 2011; 24:539–44. doi: 10.1177/039463201102400231. 2. suzuki n, katsusihma h, takeuchi k, nakamura s, ishizawa k, ishii s, et al. cytogenetic abnormality 46,xx,add(21) (q11.2) in a patient with follicular dendritic cell sarcoma. cancer genet cytogenet 2008; 186:54–7. doi: 10.1016/j. cancergencyto.2008.06.002. 3. perry am, nelson m, sanger wg, bridge ja, greiner tc. cytogenetic abnormalities in follicular dendritic cell sarcoma: report of two cases and literature review. in vivo 2013; 27:211–14. 4. shaffer lg, mcgowan-jordan j, schmid m, eds. iscn 2013: an international system for human cytogenetic nomenclature. 1st ed. basel, switzerland: karger publishers, 2013. 5. jones d, amin m, ordonez ng, glassman ab, hayes kj, medeiros lj. reticulum cell sarcoma of lymph node with mixed dendritic and fibroblastic features. mod pathol 2001; 14:1059–67. doi: 10.1038/modpathol.3880436. 6. wang xi, zhang s, thomas jo, adegboyega pa. cytomorphology, ultrastructural, and cytogenetic findings in follicular dendritic cell sarcoma: a case report. acta cytol 2010; 54:759–63. 7. sander b, middel p, gunawan b, schulten hj, baum f, golas mm, et al. follicular dendritic cell sarcoma of the spleen. hum pathol 2007; 38:668–72. doi: 10.1016/j.humpath.2006.08.030. 8. udayakumar am, sundareshan ts, goud tm, devi mg, biswas s, appaji l, et al. cytogenetic characterization of ewing tumors using fine needle aspiration samples: a 10-year experience and review of the literature. cancer genet cytogenet 2001; 127:42–8. doi: 10.1016/s0165-4608(00)00417-9. 9. della porta m, rigolin gm, bugli am, bardi a, bragotti lz, bigoni r, et al. differentiation of follicular dendritic sarcoma cells into functional myeloid-dendritic cell-like elements. eur j haematol 2003; 70:315–18. doi: 10.1034/j.1600-0609. 2003.00042.x. http://dx.doi.org/10.1177/039463201102400231 http://dx.doi.org/10.1016/j.cancergencyto.2008.06.002 http://dx.doi.org/10.1016/j.cancergencyto.2008.06.002 http://dx.doi.org/10.1038/modpathol.3880436 http://dx.doi.org/10.1016/j.humpath.2006.08.030 http://dx.doi.org/10.1016/s0165-4608%2800%2900417-9 http://dx.doi.org/10.1034/j.1600-0609.2003.00042.x http://dx.doi.org/10.1034/j.1600-0609.2003.00042.x sir, i congratulate al-maawali et al.1 for their efforts to identify the factors that influence the publication record of the gulf cooperation council (gcc) countries. this analysis will help plan ways to improve the current situation. as a colleague who has lectured in all the gcc countries and who strongly believes that they can improve their scores i would like to make a few comments. first, one indicator of research output can be monitored with very little effort. the institute for scientific information’s (isi) essential science indicators provides a list of ranking by country. the results listed below represent the status on 1st march 2012 in the field of clinical medicine. these “metrics” are updated every 2 months and reflect performance over the past 11 years. greece is added for comparison being a small and relatively poor country when compared with the gcc members. the population of greece is 11.3 million (2010 census).2 this is less than one third of the population of the gcc countries combined (2010 censuses).3-8 second, as al-maawali and colleagues1 correctly state many factors influence research performance as can be clearly seen from the results listed above. additional factors are experience in research. possibly, this can be acquired by collaboration with established groups. several decades ago there may have been a need to import clinical expertise to the region and to export trainees. i do not think that there is now much need to improve clinical expertise because of the high local standards. in contrast, it may be time to expand and improve research performance. third, it is regrettably necessary to mention that the performance of some gcc countries, in terms of citations, is lower than that of several thousand individual researchers listed in the isi’s essential science indicators. this observation confirms the need for progress as stated by al-maawali et al.1 fourth, al-maawali et al.1 make several perceptive comments concerning local journals and the recognition of work carried out in gcc countries. for local journals, an extensive international editorial board is mandatory. for recognition, collaborative research would compensate for the inappropriate negative bias shown by some editors/reviewers based in other countries. this suggestion can include joint supervision of doctoral degrees and even conjoint awards with universities abroad. i would also recommend a thesis squ med j, august 2012, vol. 12, iss. 3, pp. , epub. submitted 12th feb 12 accepted 22nd feb 12 رد على: شاكلة املنشورات الطبية احليوية وإجتاهاهتا يف ُدَول جملس الّتعاون اخلليجي re: biomedical publications profile and trends in gulf cooperation council countries letter to editor rank country publications citations citations/publication 44 saudi arabia 6,505 32,150 4.94 68 kuwait 1,995 12,441 6.24 72 uae 1,348 9,659 7.17 103 oman 741 3,287 4.44 105 qatar 616 3,058 4.96 25 greece 25,702 271,094 10.55 dimitri p mikhailidis letter to editor | 385 programme based on publications to ensure high standards.2 such theses would be based on peer reviewed published work and would therefore stand firm against any international scrutiny. a key factor determining success is enthusiasm. this factor is already present because i met many colleagues in the region who share my enthusiasm! dimitri p mikhailidis department of clinical biochemistry, royal free hospital, london, uk e-mail: mikhailidis@aol.com references 1. al-maawali a, al busadi a, al-adawi s. biomedical publications profile and trends in gulf cooperation council countries. sultan qaboos univ med j 2012; 12:41–7. epub 2012 feb 7. pubmed pmid: 22375257; pubmed central pmcid: pmc3286715. 2. census information greece. from: http://en.wikipedia.org/wiki/greece. accessed may 2012. 3. census information saudi arabia. from: http://en.wikipedia.org/wiki/saudi_arabia. accessed may 2012. 4. census information kuwait. from: http://en.wikipedia.org/wiki/kuwait. accessed may 2012. 5. census information united arab emirates. from: http://en.wikipedia.org/wiki/united_arab_emirates. accessed may 2012. 6. census information oman. from: http://en.wikipedia.org/wiki/oman. accessed may 2012. 7. census information qatar. from: http://en.wikipedia.org/wiki/qatar. accessed may 2012. 8. census information bahrain. from: http://en.wikipedia.org/wiki/bahrain. accessed may 2012. 9. breimer lh, mikhailidis dp. a thesis for all seasons. nature 1991; 353:789–90. primary extradural meningioma presenting as frontal sinusitis with extensive bony changes case report e566 | squ medical journal, november 2014, volume 14, issue 4 departments of 1surgery and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: rajeevkariyattil@gmail.com meningiomas comprise between 15–18% of all intracranial tumours.1 besides the typical intracranial location, meningiomas are also known to occur in the calvaria, scalp, orbit, paranasal sinuses, skin, neck, mediastinum and lungs. as these meningiomas have a non-dural origin, they are referred to as primary extradural meningiomas (pems).2 pems account for 2% of all meningiomas.3 of these, intraosseous or calvarial account for two-thirds of all extradural meningiomas.2 this report discusses the management of a calvarial meningioma with extensive bony changes and extracalvarial extension presenting as frontal sinusitis in a 40-year-old woman. case report a 40-year-old female presented to the otorhinolaryngologist at sultan qaboos university hospital in muscat, oman, in october 2013 with a history of chronic headaches and recurrent sinusitis. she also had a painless swelling on the left side of her forehead which she had noticed over the past year. with a clinical diagnosis of sinusitis, a computed tomography (ct) scan of her paranasal sinuses was performed, revealing a soft tissue lesion in the left frontal sinus. the lesion was eroding the lateral sinus margins, extending into the diploic space of the adjacent part of the left frontal bone. it was associated with erosion and irregularity of the inner table and marked thickening and sclerosis of the outer table. the bony changes were quite extensive, involving the entire frontal bone on the left side and sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e566−570, epub. 14th oct 14 submitted 24th mar 14 revision req. 5th may 14; revision recd. 18th may 14 accepted 4th jun 14 ورم األغشية السحائية االبتدائية خارج اجلافية للجهاز العصيب تظهر كالتهاب للجيوب األنفية األمامية مع تغيريات عظمية واسعة النطاق تقرير حالة راجيف كارياتل, فنكات�ش جوفيندراجو, رنا �شعيب حميد, موثوكوتيبارامبيل يونيكر�شنان abstract: primary extradural meningiomas are rare tumours and calvarial meningiomas with extensive bony changes and frontal sinusitis are rarer still. we report a 40-year-old female patient who presented to the otorhinolaryngologist at the sultan qaboos university hospital in muscat, oman, in october 2013 with headaches and frontal swelling. she was diagnosed with frontal sinusitis complicated by osteomyelitis. further clinical examination and imaging revealed a left frontal calvarial meningioma with extensive bony changes and extracalvarial extension into the frontal sinus. she underwent a left frontal craniotomy during which the tumour was removed. the postoperative period was uneventful and a follow-up computed tomography scan after three months showed only postoperative changes. this report discusses the radiological differential diagnosis and management of this type of lesion. keywords: meningioma; calvarial hyperostosis; neoplasm invasiveness; case report; oman. امللخ�ص: ورم الأغ�شية ال�شحائية االبتدائية خارج اجلافية تعترب من الأورام النادرة والأندر من ذلك الورم ال�شحائي لقبة القحف امل�شحوب بالتهاب اجليوب م�شت�شفى يف واحلنجرة, والأذن الأنف عيادة يف مثلت العمر من الأربعني يف �شيدة حالة عر�ش نود النطاق. وا�شعة عظمية تغيريات مع الأمامية الأنفية جامعة ال�شلطان قابو�ش يف م�شقط, �شلطنة عمان, يف اأكتوبر2013, وكانت تعاين من ال�شداع وتورم اجلبهة الأمامية. كانت الت�شخي�ش هوالتهاب اجليوب الأنفية الأمامية وزاد تعقيدا بااللتهاب العظمي. مزيد من الفح�ش ال�رسيري والت�شوير ك�شف ورم �شحائي للجبهة الي�رسى مع تغريات عظمية وا�شعة يف قبة القحف يف اجليب الأمامي. اأجريت للمري�شة عملية َحجُّ الِقْحف ل�شتئ�شال الورم املكت�شف, ولقد ظلت حالة املري�شة م�شتقرة يف مرحلة ما بعد العملية, ومت اإعادة الأ�شعة بعد اأ�شهر من العملية وظهرت التغريات املتوقعة بعد العملية , هذا التقرير يناق�ش الت�شخي�ش املتفاوت للأ�شعة وكيفية التعامل مع هذه الأورام. مفتاح الكلمات: الورم ال�شحائي؛ داخل العظم؛ قبي؛ تقرير حالة؛ عمان. primary extradural meningioma presenting as frontal sinusitis with extensive bony changes case report *rajeev kariyattil,1 venkatesh govindaraju,1 rana s. hamid,2 muthukuttiparambil unnikrishnan1 online case report rajeev kariyattil, venkatesh govindaraju, rana s. hamid and muthukuttiparambil unnikrishnan online case report | e567 reaching the coronal suture posteriorly, as well as extending into the orbital roof inferiorly. in addition, there was opacification of the left frontal sinus and bilateral ethmoid sinuses [figures 1a & b]. a neurosurgical opinion was sought for the case as the patient was believed to have frontal sinusitis with osteomyelitis. on examination, the patient was conscious and alert with no constitutional symptoms. a neurological examination was normal. there was a diffuse bony swelling on the left side of her forehead which was smooth and non-tender with no signs of inflammation. magnetic resonance imaging (mri) of the brain revealed an expansile mass lesion with its epicentre in the left frontal bone, with thickening of the outer table and erosion of the inner table. the lesion was isointense to the brain on t1-weighted images and hyperintense on t2-weighted and fluid-attenuated inversion recovery images with intense post-contrast enhancement. there was also a thickening and an enhancement of the underlying frontal convexity dura, extending to the parietal area [figures 2a & b]. the mri findings were in favour of a meningioma, mainly due to the contrast enhancement and dural involvement; however, due to the ct scan findings showing extensive bony involvement, other possibilities including primary bone tumours or chronic inflammatory disease were also considered. further investigations including technetium-99m bone scintigraphy and a biopsy were considered. as the clinical and mri findings indicated that the lesion was a meningioma and because a wide excision would be required in either case, it was decided to proceed with the surgery. following routine blood investigations, which were found to be within normal limits, the patient figure 1 a & b: plain computed tomography scan of the paranasal sinuses in the (a) axial and (b) coronal views, showing the partial soft tissue opacification of the left frontal sinus with areas of hyperdensity within the sinus (black arrows). the soft tissue extends into the diploic space of the adjacent frontal bone on the left side, with associated thickening of the outer table and erosion of the inner table (black arrow head). note the chronic sinusitis in the bilateral ethmoid sinuses and right frontal sinus (white arrow). figure 2 a & b: pre-operative magnetic resonance t1-weighted axial images of the brain (a) before and (b) after contrast, showing a soft lesion in the diploic space of the left frontal bone which is isointense to the brain on the precontrast image. the post-contrast t1-weighted image shows the enhancement of the lesion. note the thickening and enhancement of the underlying dura, extending posteriorly to the parietal area. primary extradural meningioma presenting as frontal sinusitis with extensive bony changes case report e568 | squ medical journal, november 2014, volume 14, issue 4 underwent a left frontal craniotomy. the bone was found to be grossly thickened with an intact outer table and tumour tissue eroding the inner table, infiltrating the underlying dura. a frozen section confirmed the diagnosis of a meningioma. the tumour was found extending into the frontal sinus and was easily removed. as the large bony defect was close to the open air sinuses, neither an autologous bonemarrow cell transfer nor an acrylic cranioplasty were considered ideal. given that the outer table of the bone flap was intact, the diseased sections were thoroughly drilled away and re-implanted. the histopathology was consistent with a diagnosis of meningothelial meningioma (world health organization grade 1). the post-operative period was uneventful. a follow-up ct scan after three months showed postoperative changes only [figures 3a & b]. the patient was advised to adhere to a careful follow-up plan with six-monthly mri scans in view of the extensive bony changes and the replaced bone flap. discussion although the generally reported incidence of meningiomas is between 15–18% of all brain tumours,1 the central brain tumour registry of the united states has reported the incidence to be as high as 35%.4 only 2% of all meningiomas are pems, with two-thirds of these being calvarial meningiomas.2,3 unlike intradural meningiomas, which have a female preponderance, pems occur at almost the same frequency in both genders.5 these tumours have a bimodal incidence, with the first peak occurring in the second decade of life and the second peak from the fifth to seventh decade.2 the origin of pem remains speculative with various theories as to its aetiology. pems may form as a result of ectopic arachnoid cap cell transformation, the trapping of arachnoid cells in the cranial suture site during head moulding at birth and trauma to the skull causing trapping of the dura and arachnoid cells at the fracture site.5 meningiomas of the paranasal sinuses are very rare and occur due to the extension of the tumour from the cranial cavity or calvarium.6 these account for less than 0.1% of all sinonasal tumours.6 the clinical presentation of a pem depends on the location of the tumour. the most common type, the calvarial meningioma, usually presents in the form of a painless mass (52.1%), focal pain (22.7%) or cranial nerve deficit (18.4%).7 tumours involving the paranasal sinuses usually present with a nasal obstruction or epistaxis.2 the current patient had had a painless bony swelling for at least a year before presenting with symptoms of sinusitis. this was probably caused by the blocked frontal sinuses. a number of different terminologies have been used to describe these lesions, leading to confusion in the nomenclature. lang et al. described the following classification system: extracalvarial lesions are known as type 1; calvarial lesions are known as type 2, and calvarial lesions with an extracalvarial extension are classified as type 3. types 2 and 3 are further subdivided into either convexity (c) or skull base (b) lesions.2 utilising this classification system, the patient in this report was observed to have a type 3b lesion. there are also some differences in scientific opinion regarding the significance of dural involvement in the diagnosis of pem. while some authors completely exclude any kind of dural involvement,8 others consider these cases to denote pem, provided that the figure 3 a & b: postoperative contrast-enhanced computed tomography scans performed three months after a craniotomy in the left frontal region. the scans show (a) the re-implanted outer table and (b) that there is no abnormal soft tissue lesion within the bone and no abnormal dural enhancement. rajeev kariyattil, venkatesh govindaraju, rana s. hamid and muthukuttiparambil unnikrishnan online case report | e569 epicentre of the tumour seems to be outside the dura.2 while the patient described in this report displayed dural involvement both clinically and radiologically, the bulk of the tumour was located within the bone. based on ct findings, calvarial meningiomas are either osteoblastic, osteolytic or both. osteoblastic meningiomas cause hyperostosis, with the ct scan showing a thickening of the bone. osteolytic lesions, on the other hand, cause erosion of the inner and outer table of the skull. on mri scans, with intense contrast enhancement after the injection of gadolinium, the lesion appears hypointense on t1-weighted images and hyperintense on t2-weighted images.5 the current patient displayed both osteolytic and osteoblastic features on her ct scan. a notable component in this case was the extensive bony sclerotic and lytic changes. these changes involved the entire frontal bone as well as the orbital roof, causing the destruction of the lateral wall of the frontal sinus with an extension of the mass into the sinus. this extensive involvement, along with the mucosal thickening in the nearby paranasal sinuses, explains the initial radiological impression of chronic sinusitis complicated by osteomyelitis. the differential diagnoses that need to be considered in cases such as this include osteolytic lesions like osteomyelitis (based on clinical features); haemangiomas (non-enhancement on ct/ mri); eosinophilic granulomas (non-enhancement on ct/mri); aneurysmal bone cysts (multiloculated with fluid levels on ct/mri); epidermoid/dermoid lesions (sclerotic margins on ct and fat content on mri); plasmacytoma (immunoglobulin g kappa band on serum electrophoresis), and metastatic cancer (multiple ragged margins on ct). osteoblastic lesions include meningioma en plaque (hyperostosis on ct), fibrous dysplasia (in pre-pubertal patients), paget’s disease (heterogeneous non-enhancing lesions on ct with elevated serum alkaline phosphatase), osteoma (non-enhancing on ct) and osteosarcoma (irregular margins with heterogeneous enhancement on ct/ mri).5 histopathology results reveal that pem tumours are predominantly benign (87.7%); however, 5.5% are atypical and 6.8% are malignant.7 there is a higher incidence of atypical and malignant cases with osteolytic lesions.7 the most common histopathological subtype remains the meningothelial meningioma, as was observed in the current case. a recurrence rate of 22% and a mortality rate of 4.8% was reported in patients with benign pems by lang et al.; all of these patients were found to have involvement of the skull base (types 2b and 3b).2 in comparison, all patients with malignant pathologies were found to show recurrence and have a mortality rate of 29%.2 the preferred method of treatment is a wide surgical excision of the tumour.7 the use of intraoperative adjuncts, such as neuronavigation, can help in planning a more complete excision. certain tumours that originate in the frontal bone or orbital wall and extend into the nasal cavity may require transcranial or transnasal approaches.9 usually the entire section of the involved bone is removed as completely as possible and a primary cranioplasty is performed.7 however, if there is a large defect in a cosmetically or functionally critical area (such as the forehead), or the tumour is close to the open air sinuses, cranioplasties with split autologous grafts or synthetic materials are not ideal. in such cases, the replacement of an uninvolved part of the bone, after thorough removal of the diseased section via drilling, may be performed after careful consideration. tumours with a world health organization grade of 1 and removed via gross total resection do not need adjuvant radiotherapy; however, this therapeutic option may be considered in cases where there is an incomplete resection or recurrence of the tumour.7 close follow-up is recommended for patients with this tumour, with mri scans performed immediately after surgery and then subsequently ever year for five years. after this, follow-up mri scans are advised every two years for up to 10 years after the surgery.7 conclusion calvarial meningiomas are the most common subtype of pems. these lesions are slow-growing and can extend into the air sinuses. a menigioma should be considered in the differential diagnosis of patients presenting with osteoblastic or osteolytic skull lesions. a proper pre-operative surgical plan is necessary in managing these lesions. since the chance of recurrence after surgery is high, regular follow-up of the patient is advised. references 1. bassiouni h, asgari s, hübschen u, könig hj, stolke d. dural involvement in primary extradural meningiomas of the cranial vault. j neurosurg 2006; 105:51–9. doi: 10.3171/ jns.2006.105.1.51. 2. lang ff, macdonald ok, fuller gn, demonte f. primary extradural meningiomas: a report on nine cases and review of the literature from the era of computerized tomography scanning. j neurosurg 2000; 93:940–50. doi: 10.3171/ jns.2000.93.6.0940. 3. muzumdar dp, vengsarkar us, bhatjiwale mg, goel a. diffuse calvarial meningioma: a case report. j postgrad med 2001; 47:116–18. primary extradural meningioma presenting as frontal sinusitis with extensive bony changes case report e570 | squ medical journal, november 2014, volume 14, issue 4 4. central brain tumor registry of the united states. cbtrus statistical report: primary brain and central nervous system tumors diagnosed in the united states in 20042008. from: www.cbtrus.org/2012-npcr-seer/cbtrus_ report_2004-2008_3-23-2012.pdf accessed: may 2014. 5. elder jb, atkinson r, zee cs, chen tc. primary intraosseous meningioma. neurosurg focus 2007; 23:e13. doi: 10.3171/ foc-07/10/e13. 6. aiyer rg, prashanth v, ambani k, bhat vs, soni gb. primary extracranial meningioma of paranasal sinuses. indian j otolaryngol head neck surg 2013; 65:384–7. doi: 10.1007/ s12070-012-0565-y. 7. mattox a, hughes b, oleson j, reardon d, mclendon r, adamson c. treatment recommendations for primary extradural meningiomas. cancer 2011; 117:24–38. doi: 10.1002/ cncr.25384. 8. crawford ts, kleinschmidt-demasters bk, lillehei ko. primary intraosseous meningioma: case report. j neurosurg 1995; 83:912–15. doi: 10.3171/jns.1995.83.5.0912. 9. cirak b, guven mb, ugras s, kutluhan a, unal o. frontoorbitonasal intradiploic meningioma in a child. pediatr neurosurg 2000; 32:48–51. doi: 10.1159/000028897. squ med j, may 2012, vol. 12, iss. 2, pp. 206-213, epub. 9th apr 2012 submitted 9th oct 11 revision req. 8th jan 12, revision recd. 29th jan 12 accepted 15th feb 12 1department of biochemistry, 2department of physiology, 3research division, gulf medical university, ajman, uae *corresponding author e-mail: gomathikg@gmu.ac.ae الصحة النفسية لطالب السنة األوىل للمهن الصحية يف جامعة طبية باإلمارات العربية املتحدة كادايام ج كوماثي، �سوفيا اأحمد، جاياديفان �سريدهاران دعوة متت الطريقة: ال�صحية. للمهن االأوىل ال�صنة لطالب االإجهاد ودرا�صة م�صادر النف�صية ال�صحة تقييم الهدف: امللخ�ص: جميع طالب ال�صنة االأوىل )125 طالبا( من جامعة اخلليج الطبية يف عجمان باالإمارات العربية املتحدة للم�صاركة يف م�صح ا�صتبياين ذاتي مت كما بندا، 12 يت�صمن عام �صحي ا�صتبيان ا�صتخدام على الدرا�صة يف النف�صية ال�صحة تقييم اعتمد .2011 عام يناير يف تطوعي ا�صتخدام ا�صتبيانا اآخر ي�صمل 24 بندا »مرتبطا« باملجاالت ال�صحية والتعليمية والنف�صية للتعرف على م�صادر االإجهاد. ا�صتخدمنا يف هذه الدرا�صة نوعني من االختبارات االإح�صائية وهما مرّبع كاي بري�صون واختبار مان ويتني يو الختبار االرتباط بني م�صادر االإجهاد و النف�صي االعتالل انت�صار ن�صبة اأن النتائج واأظهرت الدرا�صة هذه يف النتائج: �صارك 112 طالبا )89.6%( االعتالل النف�صي. و«تنظيم االأكادميي« و«ال�صغط االختبارات« »تعدد ت�صمل للقلق الرئي�صية االأكادميية امل�صادر اأن وظهر كانت 33.6%. الطلبة بني مع و»التعامل و»القلق« الوالدين« و»توقعات امل�صتقبل« من »اخلوف ف�صملت االجتماعية االأخرى ال�صغوطات النف�صية اأما الوقت«. ممار�صة و»قلة الطعام« مواعيد تنظيم »عدم �صملت فقد النف�صي لالعتالل امل�صببة ال�صحية بامل�صادر يخت�ض وفيما االآخر«. اجلن�ض الريا�صة« و»امل�صاكل املتعلقة بالنوم«. مل يرتبط املر�ض النف�صي باأي من العوامل الدميوغرافية التي �صملتها الدرا�صة، غري اأنه ارتبط بن�صبة القلق النف�صي وجمموع التح�صيل االأكادميي. اخلال�صة: يعاين من االعتالل النف�صي واحد من كل ثالث طالب من طلبة ال�صنة االأوىل يف االعتالل اأما الطالب، من كبري لعدد القلق م�صادر من الوالدين وتوقعات بامل�صتقبل املرتبطة املخاوف كانت الطبية. اخلليج جامعة النف�صي فقد ارتبط ب�صكل ملحوظ بال�صغط الكلي وجمموع التح�صيل االأكادميي. مفتاح الكلمات: االإجهاد النف�صي، طالب طب، مهن �صحية، تعليم طبي جامعي، االإمارات العربية املتحدة. abstract: objectives: the aim of this study was to assess the psychological health of first-year health professional students and to study sources of student stress. methods: all first-year students (n = 125) of the gulf medical university (gmu) in ajman, united arab emirates (uae), were invited to participate in a voluntary, anonymous, self-administered, questionnaire-based survey in january 2011. psychological health was assessed using the 12-item general health questionnaire. a 24-item questionnaire, with items related to academic, psychosocial and health domains was used to identify sources of stress. pearson’s chi-squared test and the mann-whitney u-test were used for testing the association between psychological morbidity and sources of stress. results: a total of 112 students (89.6%) completed the survey and the overall prevalence of psychological morbidity was found to be 33.6%. the main academic-related sources of stress were ‘frequency of exams’, ‘academic workload’, and ‘time management’. major psychosocial stressors were ‘worries regarding future’, ‘high parental expectations’, ‘anxiety’, and ‘dealing with members of the opposite sex’. health-related issues were ‘irregular eating habits’, ‘lack of exercise’, and ‘sleep-related problems’. psychological morbidity was not significantly associated with any of the demographic factors studied. however, total stress scores and academics-related domain scores were significantly associated with psychological morbidity. conclusion: psychological morbidity was seen in one in three first-year students attending gmu. while worries regarding the future and parental expectations were sources of stress for many students, psychological morbidity was found to be significantly associated with only the total stress and the academic-related domain scores. keywords: psychological stress; medical student; health professions; undergraduate medical education; united arab emirates. psychological health of first-year health professional students in a medical university in the united arab emirates *kadayam g gomathi,1 soofia ahmed,2 jayadevan sreedharan3 clinical & basic research kadayam g gomathi, soofia ahmed and jayadevan sreedharan clinical and basic research | 207 a university student’s life is subject to many different kinds of stress. sources of student stress can be academic pressures, social or personal issues, and financial problems. in recent years, there has been a growing appreciation of the stresses involved in the training of health professionals. several studies have shown stress among medical students and qualified doctors to be higher than that of the general population and other college students.1,2 health professional students not only have to face the challenge of a rigorous curriculum, but also have to learn to deal with emotionally difficult experiences. the pressures put on students by academics, an obligation to succeed, the difficulties of integrating into the system, and social, emotional and family problems are all potential stressors which can affect learning ability and academic performance.3,4 high stress levels have been reported in not only medical, but also in dental, pharmacy and physiotherapy students from various parts of the world.1,2,5–7 studies from arab countries also indicate high stress levels in medical and dental students.8–13 the gulf medical university (gmu) in ajman, united arab emirates (uae), is a 13-year-old international university where students from different cultures, educational backgrounds, and parts of the world study together. a large number of students are in the uae for the first time. many first-year students are adjusting not only to a new learning environment but also to a new culture during their training in gmu. our objective was to assess the psychological health of the firstyear health professional students and to study the various sources of psychological stress. methods a cross-sectional survey using a voluntary, anonymous, self-administered questionnaire was carried out in january and february 2011, about five months after the first-year students had joined gmu. all 125 first year undergraduate students were contacted for the survey. this study was approved by the ethics committee of gmu. participants were informed about the study, verbal consent was taken, and participation was voluntary and anonymous. the questionnaire had three parts. the first part obtained demographic details. the second part of the questionnaire was the well-validated 12-item general health questionnaire (ghq-12).14,15 the ghq-12 method of scoring (0-0-1-1) was used.16 scores were summed up to give a total score for each student, with a maximum possible score being 12. based on the mean and median values, a cutoff score of 4/5 was considered appropriate. students with scores of 0–4 were coded as having no or very few signs of possible mental health problems (i.e. were in normal psychological health [n]), while students with scores of 5 and above were determined to be ghq-12 cases and to have psychological morbidity (pm).17 sources of stress were identified in the third part of the questionnaire, which was based on the studies by sreeramareddy et al. and el-gilany et al.18,9 it had 24 items grouped into three domains: academic-related, psychosocial, and health-related. it was developed with the help of experts in the field, checked for validity, and pilot tested before use. students were asked to rate the frequency of occurrence of the stressor on the scale ‘never/rarely’, ‘sometimes’, or ‘often/always’. ‘never/rarely’ and ‘sometimes’ were given a score of 0 and responses of ‘often/always’ were scored as 1. negatively worded questions were reverse scored. data were entered into the predictive analytics software (pasw) advances in knowledge this study investigates psychological morbidity in health professional students in the arab region. the association of psychological morbidity with total stress levels highlights the importance of addressing sources of stress in health professional students. while a number of stressors are similar to those experienced by medical students in other parts of the world, some sources unique to the region have also been found. application to patient care this study showed that early detection of psychological morbidity; appropriate support in the form of career counselling ; teaching techniques to reduce stress and resolve conflicts; sessions with parents, if necessary, and creating sports and recreational opportunities on campus may help in improving the psychological health of the health professional students. psychological health of first-year health professional students in a medical university in the united arab emirates 208 | squ medical journal, may 2012, volume 12, issue 2 statistics software (version 18, spss-ibm, chicago, illinois, usa) and analysed. pearson’s chi-squared test and the mann-whitney u-test were used for testing significance. results all 125 first year undergraduate students were contacted for the survey. of that number, 112 students completed the survey, giving a response rate of 89.6%. the characteristics of the participants are given in table 1. the students’ psychological health is shown by the distribution of the ghq-12 scores in figure 1. the mean ± standard deviation (sd) of the ghq-12 score was 3.53 ± 2.57, while the median ghq-12 score was 3.0. using the ghq-12 and a cutoff of 4/5, the prevalence of psychological morbidity was found to be 33.6% in the first-year undergraduate students at gmu. as shown in table 1, more psychological morbidity was seen in female students (36.6%) as compared to male students (30.8%). psychological morbidity was also found to vary among students in the different programs. morbidity was higher (40.6%) in students with other languages of instruction in high school compared to those who had been taught in english (31%). however, psychological morbidity was not found to be significantly associated (p >0.05) with any of the demographic groups studied. table 1: demographic variables and psychological health of the students variable* group normal number (%) psychological morbidity number (%) total number gender female 46 (63.4) 27 (36.6) 73 male 27 (69.2) 12 (30.8) 39 programme mbbs 28 (60.9) 18 (39.1) 46 dmd 20 (69) 9 (31) 29 pharm d 14 (73.7) 5 (26.3) 19 bpt 12 (66.7) 6 (33.3) 18 marital status unmarried 64 (66) 33 (34) 97 married 10 (66.7) 5(33.3) 15 language of instruction in high school english 55 (68.8) 25 (31.3) 80 other 19 (59.4) 13 (40.6) 32 accommodation living alone (hostel/ apartment) 37 (69.8) 16 (30.2) 53 living at home 37 (62.7) 22 (37.3) 59 family details parents living together 60 (64.5) 33 (35.5) 93 parents separated/ divorced 14 (73.7) 5 (26.3) 19 parent(s) in a healthrelated profession yes 21 (67.7) 10 (32.3) 31 no 53 (65.4) 28 (34.6) 81 on financial aid/ scholarship yes 7 (87.5) 1 (12.5) 8 no 67 (64.4) 37 (35.6) 104 self-reported academic performance satisfactory 27 (67.5) 13 (32.5) 40 unsatisfactory 47 (32.5) 25 (67.5) 72 legend: mbbs = bachelor of medicine, bachelor of surgery; dmd = doctor of dental medicine; pharm d = doctorate in pharmacy; bpt = bachelor of physiotherapy *none of the variables were found to be significantly associated with psychological morbidity kadayam g gomathi, soofia ahmed and jayadevan sreedharan clinical and basic research | 209 the stressors were classified into three domains: academic-related, psychosocial and health-related. in the academic-related domain, the total student population identified the following as ‘often’ or ‘always stressful’: ‘frequency of exams’ (22%), ‘academic workload’ (19%), and ‘time management’ (19%). in the psychosocial domain, the main concerns were ‘worries regarding future’ (50.5%), ‘high parental expectations’ (45%), ‘anxiety’ (21%) and ‘dealing with members of the opposite sex’ (18%). getting along with peers, loneliness, and financial or family problems were identified as stressors by less than 10% of the students. among the health-related issues, ‘irregular eating habits’, ‘lack of exercise’, and ‘lack of a healthy diet’ were reported as ‘often’ or ‘always stressful by 39%, 35% and 22.5% of the total student population, respectively. sleep-related problems were a concern for 25% of the students. illness and tobacco/alcohol abuse were identified as stressors by only 6 and 4 students, respectively. table 2 compares the percentage of students in the normal and psychologically morbid groups reporting academic-related, psychosocial, and health-related stressors. within the academicrelated domain, only ‘satisfaction with lectures/ classes’ and ‘ability to concentrate’ were negatively associated with psychological morbidity (p <0.05). in the psychosocial domain, ‘family problems’ were found to be significantly associated with psychological morbidity, while in the health-related domain, ‘lack of regular eating habits’ was associated with significantly more students in normal health compared to those with psychological morbidity. between the two groups, none of the other stressors were found to be statistically different. a total stress score and stress scores in each of the three domains were generated for each student. the median total stress score of the psychological morbidity group was 5 while that of the normal group was 4. this difference was statistically significant (p <0.05). among the three domains, only the median academic-related domain score was significantly different (p <0.05) between the students in normal psychological health (0) as compared to those having psychological morbidity (2). discussion stress is a physical, mental, or emotional response to events that causes bodily or mental tension. in small amounts, stress is normal and can help us be more active and productive. however, very high levels of stress experienced over a prolonged period can cause significant mental and physical problems. gmu has a very diverse student population with students of 35 different nationalities coming from 15 different educational systems studying in the university. adjusting to a new country, culture, educational system, along with being away from home for the first time, can cause significant amounts of stress. since students join gmu after high school, most of the students in the first year are very young, with 92% being less than 21 years old. female students outnumber male students; this is a trend that can be seen in all healthcare-related programmes at all universities in the uae. about 29% of first-year students have studied science in a language other than english in high school, usually in arabic or persian. none of the students work part-time due to uae laws. very few students receive financial aid or scholarships, with most supported by their families. using the ghq-12, the prevalence of psychological morbidity was determined to be 33.6% in first-year students. this prevalence, although high, is lower than that seen in medical students from the uk (36%), iran (40%), or malaysia (46%);19– 21 however, it is higher than that reported from nepal (20.9%),18and lower than that reported in dentistry figure 1: distribution of general health questionnaire-12 scores of the first-year undergraduate students (n = 112) psychological health of first-year health professional students in a medical university in the united arab emirates 210 | squ medical journal, may 2012, volume 12, issue 2 students from jordan (70%) and iraq (51%).12,13 we could not find any statistically significant difference in the prevalence of psychological morbidity between the genders [table 1]. conflicting reports are available in the literature, with some reporting a higher prevalence of psychological distress in females while others have reported no gender differences.1,2 there was no significant difference in the prevalence of psychological morbidity among students studying in different programmes at gmu. some studies have reported higher stress levels in dentistry students compared to medical students while others have found higher levels of stress in medical students as compared to other health-related professions.22–23 the prevalence of psychological morbidity was higher in students who had studied in a language other than english at school compared to those who had studied in english [table 1]. this observation, though not found to be statistically significant, correlates well with the higher percentage of students reporting ‘difficulty in reading textbooks’ in the psychological table 2: percentage of students identifying stressors in the normal health and psychological morbidity group type of stressor percentage of students normal health (n = 73) psychological morbidity (n = 39) academic academic workload too much 15.1 26.3 satisfied with classes 97.3 *76.3 too frequent examinations 17.8 28.9 satisfied with performance in examination 87.7 73.7 learning material available 90.4 84.2 difficulty reading textbooks 12.3 21.1 able to manage time 84.9 73.7 able to concentrate 94.5 *81.6 psychosocial anxiety 17.8 26.3 parental expectations too high 42.5 50 worries about future 52.1 47.4 problems adjusting to classmates 9.6 10.5 loneliness 8.2 7.9 financial problems 4.1 10.5 family problems 1.4 *13.2 difficulty getting along with members of the opposite sex 20.5 13.2 lack of recreation 30.1 23.7 health-related lack of healthy diet 23.3 21.1 irregular eating habits 45.2 *26.3 sleep problems 21.9 31.6 illness/health problems 2.7 10.5 tobacco/alcohol/substance abuse 1.4 7.9 lack of exercise 39.7 26.3 *significant difference between the two groups (p <0.05) kadayam g gomathi, soofia ahmed and jayadevan sreedharan clinical and basic research | 211 morbidity group [table 2]. even though the test of english as a foreign language (toefl) is a mandatory requirement for admission into gmu, students who have studied in arabic or persian in high school often find it difficult to keep up with reading assignments in the first year. these findings are similar to the difficulty in reading textbooks and the translation of english terms reported by 44.8% of students from a medical college in egypt where most of the students had studied in arabic in high school, as well as the anecdotal references in a study from saudi arabia.24,8 the total stress score was found to be significantly associated with psychological morbidity. though academic-related stressors were concerns for fewer students than psychosocial or health-related issues, a significant difference was found between the median academics-related domain stress scores of normal students and those with psychological morbidity. this also correlates well with the finding that significantly more students with psychological morbidity were dissatisfied with lectures/classes and were unable to concentrate in classes [table 2]. these findings are similar to those reported in literature where stress in medical students was found related to academic training rather than personal factors.8,25 while similar proportions of self-reported unsatisfactory academic performance were found in healthy students and those having psychological morbidity [table 1], it is interesting to note that among those with self-reported unsatisfactory academic performance, 67.5% had psychological morbidity, which correlates well with the significantly higher academic domain stress scores in students with psychological morbidity. in the psychosocial domain, about half the student population reported often or always worrying about the future. this was surprising considering that these students had just entered the university and joined a professional programme. ‘high parental expectations’’ was also a cause of stress for 45% of the student population. this finding is similar to that reported from asian countries like nepal and pakistan where ‘high parental expectations’ were a cause of stress for 52 and 63% students, respectively.18,26 in this context, it is also interesting to note that there was a significant association between family problems and psychological morbidity [table 2]. dealing with members of the opposite sex was reported as stressful by 18% of the students. this was not unexpected since gmu is one of the few universities in the uae with mixed gender classes. most high school students in arab countries study in single gender schools and young people do not have much interaction with members of the opposite sex in academic or social settings. similar findings have been reported in a recent study from australia where saudi international students transitioning from a single gender to a mixed gender environment experienced stress.27 anxiety is an issue for many students (21%), but making friends at gmu does not seem to be a problem for most students as difficulty in getting along with peers and loneliness were concerns for less than 10% of the students. this is very encouraging since adjusting to a new environment is much easier if students can make friends. since most of our students are supported by their families, financial problems were identified as a concern by less than 10% of the students. lack of recreation was identified as a stressor by 25% of the students. gmu is located in a small emirate in the uae and affords few avenues for entertainment. further, most students do not find time or opportunities to pursue their hobbies as is true for students in health-related professional training around the world.2,5 in the health-related domain, the lack of a healthy diet and irregular meals were reported by many students. young adults, especially those living away from home, often do not eat at regular times or eat healthily, so this is not unexpected. it is encouraging to note that they are aware that they are not practicing healthy lifestyles. sleep-related problems were a concern for 1 in 4 students. this is significant and is similar to reports in literature regarding sleep problems in medical students and needs to be addressed.28–30 illnesses and tobacco/ alcohol abuse were reported by only 6 and 4 students, respectively. this is a small percentage of the student population, but is not unexpected since the uae is an islamic country with strict rules regarding alcohol consumption, and most of the first-year students are very young. this study has some limitations. all data obtained was self-reported, including academic performance, so the results need to be interpreted with care. it is possible that some students might have been in denial about certain issues or, due to psychological health of first-year health professional students in a medical university in the united arab emirates 212 | squ medical journal, may 2012, volume 12, issue 2 cultural reasons, were not able to answer certain questions truthfully. the study was a crosssectional survey taken midway through the first year and may not be representative of student behaviours over time. the conclusions drawn are based on the data obtained from gmu and may not be applicable to other universities. we did not study the psychological health of other university students in the uae for comparison. conclusion in the first year of undergraduate studies at gmu, one in three students had psychological morbidity when screened using the ghq-12. there was no significant difference in psychological morbidity between the genders. high parental expectations and worries about the future were sources of stress for about half the students. anxiety, sleep-related issues, lack of recreation, and poor eating habits were also reported by many students. total stress was significantly associated with psychological morbidity, highlighting the need for measures to reduce stress in students. while academic-related sources of stress were significantly associated with psychological morbidity, no such associations were seen for the psychosocial or health-related sources of stress. a c k n o w l e d g e m e n t s we thank the students and the gmu authorities for their cooperation. we also wish to thank dr. sondus al omar, of the department of physiology at gmu, and mrs hina aman, career counsellor, for their valuable suggestions during questionnaire preparation. we thank gl assessment, uk, for permission to use the ghq-12. c o n f l i c t o f i n t e r e s t this study was carried out in the gulf medical university, ajman, uae, in january-february 2011 and was a non-funded study. none of the authors has any conflict of interest. references 1. dyrbye ln, thomas mr, shanafelt td. systematic review of depression, anxiety, and other indicators of psychological distress among us and canadian medical students. acad med 2006; 81:354–73. 2. firth j. levels and sources of stress in medical students. br med j (clin res ed) 1986; 292:1177–80. 3. stewart sm, lam th, betson cl, wong cm, wong am. a prospective analysis of stress and academic performance in the first two years of medical school. med educ 1999; 33:243–50. 4. willcock sm, daly mg, tennant cc, allard bj. burnout and psychiatric morbidity in new medical graduates. med j aust 2004; 181:357–60. 5. polychronopoulou a. perceived sources of stress among greek dental students. j dent educ 2005; 69:687–92. 6. frick lj, frick jl, coffman re, dey s. student stress in a three-year doctor of pharmacy program using a mastery learning educational model. am j pharm educ 2011; 75:64. 7. tucker b, jones s, mandy a, gupta r. physiotherapy students’ sources of stress, perceived course difficulty, and paid employment: comparison between western australia and united kingdom. physiother theory pract 2006; 22:317–28. 8. al-dabal bk, koura mr, rasheed p, al-sowielem l, makki sm. a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia. sultan qaboos univ med j 2010; 10:231–40. 9. el-gilany ah, amr m, hammad s. perceived stress among male medical students in egypt and saudi arabia: effects of sociodemographic factors. ann saudi med 2008; 28:442–8. 10. ahmadi j, kamel m, ahmed mg, bayoumi fa, moneenum aa. dubai medical college students’ scores on the beck depression inventory. iran red crescent med j 2008; 10:169–72. 11. elzubeir ma, elzubeir ke, magzoub me. stress and coping strategies among arab medical students: towards a research agenda. educ health 2010; 23:355. 12. abu-ghazaleh sb, rajab ld, sonbol hn. psychological stress among dental students at the university of jordan. j dent educ 2011; 75:1107–14. 13. al-nimer ms. measuring mental health following the 6-year american invasion of iraq. a general health questionnaire analysis of iraqi medical and dentistry students. neurosci 2010; 15:27–32. 14. goldberg dp, blackwell b. psychiatric illness in general practice: a detailed study using a new method of case identification. br med j 1970; 2:439–43. 15. goldberg dp, gater r, sartorius n, ustun tb, piccinelli m, gureje o, et al. the validity of two versions of the ghq in the who study of mental illness in general health care. psychol med 1997; 27:191–7. 16. goldberg d, williams p. a user’s guide to the general health questionnaire. windsor, uk: nfernelson, 1988. kadayam g gomathi, soofia ahmed and jayadevan sreedharan clinical and basic research | 213 17. goldberg dp, oldhinkel t, ormel j. why ghq threshold varies from one place to another. psychol med 1998; 28:915–21. 18. sreeramareddy ct, shankar pr, binu vs, mukhopadhyay c, ray b, menezes rg. psychological morbidity, sources of stress and coping strategies among undergraduate medical students of nepal. bmc med educ 2007; 7:26. 19. guthrie e, black d, bagalkote h, shaw c, campbell m, creed f. psychological stress and burnout in medical students: a five-year prospective longitudinal study. j r soc med 1998; 91:237–43. 20. shariati m, yunesian m, vash jh. mental health of medical students: a cross-sectional study in tehran. psychol rep 2007; 100:346–54. 21. al-dubai sa, al-naggar ra, alshagga ma, rampal kg. stress and coping strategies of students in a medical faculty in malaysia. malays j med sci 2011; 18:57–64. 22. murphy rj, gray sa, sterling g, reeves k, ducette j. a comparative study of professional student stress. j dent educ 2009; 73:328–7. 23. dutta ap, pyles ma, miederhoff pa. stress in health professions students: myth or reality? a review of the existing literature. j natl black nurses assoc 2005; 16:63–8. 24. sabbour sm, dewedar sa, kandil sk. language barriers in medical education and attitudes towards arabization of medicine: student and staff perspectives. east mediterr health j 2010; 16:1263– 71. 25. moffat kj, mcconnachie a, ross s, morrison jm. first year medical student stress and coping in a problem-based learning medical curriculum. med educ 2004; 38:482–91. 26. shah m, hasan s, malik s, sreeramareddy ct. perceived stress, sources and severity of stress among medical undergraduates in a pakistani medical school. bmc med educ 2010; 10:2. 27. alhazmi a. saudi international students in australia and intercultural engagement: a study of transitioning from a gender segregated culture to a mixed gender environment. from: http:// www.cdesign.com.au/proceedings_isana2010/pdf/ doctoral_paper_%20alhazmi.pdf?id=254&file=p:/ eventwin/docs/pdf/isana2010abstract00026.pdf accessed: sep 2011. 28. veldi m, aluoja a, vasar v. sleep quality and more common sleep-related problems in medical students. sleep med 2005; 6:269–75. 29. ball s, bax a. self-care in medical education: effectiveness of health-habits interventions for firstyear medical students. acad med 2002; 77:911–7. 30. zailinawati ah, teng cl, chung yc, teow tl, lee pn, jagmohni ks. daytime sleepiness and sleep quality among malaysian medical students. med j malaysia 2009; 64:108–10. squ med j, may 2012, vol. 12, iss. 2, pp.133-136 , epub. 9th apr 2012 submitted 14th jan 12 accepted 17th jan 12 in this issue of the journal, dr. qutaiba tawfic and his colleagues report their experience with sickle cell disease patients (scd) who were admitted to the intensive care unit (icu) at sultan qaboos university hospital, oman, with various complications of sickle cell disease. they studied 49 patients who were admitted 56 times in the icu between the years 2005 and 2009.1 this is an important study which has several points worthy of reflection. there is very little literature specifically discussing the subject of scd patients who are admitted to an icu for any scd related complication. the literature typically deals with specific complications of scd, like the acute chest syndrome (acs), vaso-occlusive disorder and stroke in these patients, as well as their precipitating factors and their management.2–5 the mortality among tawfic et al.’s, patients admitted to the icu was 16%. they pointed out that this figure was lower than the general mortality rate of 21.1% in that icu. 1 however, this is not much of a consolation, and it is far from being a reason to rejoice. a typical patient admitted to an adult icu, for problems other than scd, is generally older than the patients who were the subject of this study. patients in this study had a median age of only 27 years and the oldest patient was 52 years old. therefore, the mortality of these patients cannot be compared to the mortality of the general adult icu patients. the 16% mortality rate is indeed alarming for such a young population and should not be readily accepted. it should be a wake-up call as here we are dealing with a hereditary blood disorder, a killer disease of young adults. the situation is probably much worse than that if we include the number of children dying from complications of scd in paediatric icus across this country, and in the general medical and paediatric wards. child statistics were not included in this study, which only investigated adults scd sufferers admitted to the icu. the number of children who die in oman from scd is not clear and needs further studies. how many other children and adults die from scd in their homes in oman? we truly need to exert a more concerted effort to find out the basic facts about this disease in oman. medical researchers need to stop and ponder about the impact of this devastating disease on our society. this needs the full attention of the government in general, the health services in particular and more expectations from patients and non-governmental organisations (ngos). we need answers! unfortunately, in the western world, scd is relatively rare and, hence, there is limited interest in research into this disorder. as a result of the low incidence, it has neither drawn the attention of researchers nor stimulated pharmaceutical companies to fund scd research. there were editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, oman. *e-mail: mjournal@squ.edu.om الوفيات النامجة عن مرض فقر الدم املنجلي يف وحدات العناية املركزة هل نستطيع عمل ما هو أفضل؟ ملك اللمكي editorial deaths from sickle cell disease in intensive care units can we do better? lamk al-lamki deaths from sickle cell disease in intensive care units can we do better? 134 | squ medical journal, may 2012, volume 12, issue 2 a number of clinical research studies on scd published from the united states in the 1990s, many of them in reputable journals like new england journal of medicine,4,5 and other western journals, but there were very few basic research studies into this disease. this was followed by a relative lull in the 2000s, when there was even less research published on the subject. interest had probably waned for above-mentioned reasons. earlier clinical research on scd was into the major complications such as acs, vaso-occlusive disorder, fat embolism, etc. and how to manage them. unfortunately, these studies, though worthwhile, contributed little to the basic understanding that is needed to reduce scd mortality in countries such as oman where it is prevalent. thus, oman and the other arab countries need to be more proactive and themselves undertake research into inherited blood disorders such as scd. this would ultimately reduce not only mortality and morbidity, but also lessen the social and cultural impact of these diseases. for example, relationships can be disrupted and marriage plans destroyed because of the fear that a potential partner has the sickle cell trait or disease. tawfic et al. have shown that acs is the most common cause of death in their group of patients. this is not an altogether new finding, but nonetheless interesting. it is well known that acs is the second commonest cause of scd admissions after painful crisis, and it is the prime cause of death killing around 30% of scd patients. even though acs was described approximately 20 years ago,2 and repeatedly studied by others,3,4 we have not advanced much in either managing this condition, preventing it or dramatically reduce its effect, at least not in arab countries. an aetiological contributing factor to acs is fat embolism, yet little research is gone into preventing or combating that condition, although there is some evidence that hydroxyurea can reduce the recurrence of acs, and reduce its severity.6 other patients die of acute stroke, commonly a result of vaso-occlusive disease. again, we physicians as the health guardians of our communities have failed our societies by allowing ourselves to remain in the dark with respect to the disorders that lead to fat embolism, vaso-occlusive disorders, acute stroke and acs, or other complications of scd. we have achieved some progress in infection control, which is another major contributing factor to the mortality of scd, and we do use the current preventative treatment with hydroxyurea.7 all these complications were present in the patients studied by tawfic et al. in the usa, the prevalence of heterozygous carriers of the sickle cell trait is 8% among the african americans.8 this has lead bruce mitchell to summarise the frustration on the current lack of relevant scd research in usa very concisely: “that is where we are: inconclusive data have been accepted; inconsistent messages about screening, prevention and precaution have been relayed; and research into sickle cell trait-associated sudden death has not advanced. for many physicians, the story stops there.”8 typically, patients with sickle cell trait have about 40% of their haemoglobin as haemoglobin-s, but they do not have anaemia and so are able to live a normal life. unfortunately, that is not always the case in africa where life expectancy of the 6 million people with sickle cell anaemia is only half the normal life expectancy.9 the world health organization (who) has declared scd a public health priority. “the who estimates that 70% of sickle cell anemia deaths in africa are preventable with simple, cost-effective interventions, such as early identification of sickle cell anemia patients by new born screening and subsequent provision of comprehensive care such as giving regular prophylaxis such as penicillin v and vaccinations. implementation of comprehensive care for scd patients could lead to improved survival through these targeted interventions.”9 if 70% of scd deaths are preventable in africa with simple interventions, then we should be able to achieve a higher percentage in oman with all the resources and potential that we have in oman. if the who has declared sickle cell disease a public health priority in africa, then why is it not one here in oman? certainly, we need to pause and ponder— what do we need to do in oman for this public health priority and to reduce the mortality? to start with we need early detection of the trait and of the symptoms of the disease. in africa, haemoglobin-s trait is protective against malaria, morbidity and mortality, and hence, to some extent, it may protect some people from that disease.10 although it may be that the sickle cell gene has come to oman for the same reason, this country no longer has a major problem with malaria and therefore we can afford to rid of scd. the prevalence of scd in lamk al-lamki editorial | 135 oman is generally accepted as 6%.11,12 the incidence of the sickle cell disease itself has been reported at both 0.2%.12 clearly, we need much more research to obtain more accurate statistics on both, the trait and the disease. recent prospective data from our university hospital and sohar hospital by alkindi et al. indicates the incidence of scd is about 0.3%.13 the oman hereditary blood disorder association was established with the aim of improving services provided to patients with haemoglobin disorders in oman, including on psychological and social levels.11 they raise awareness about hereditary blood disorders, including scd, and their effects on the community. this association involves both health professionals and patients and, while they are doing a commendable job, they need to be more active in lobbying for legislation on widespread testing and screening for hereditary blood disorders, and in calling for more research. the research council (trc) of oman is currently supporting one on-going research project on scd. however, as we have seen, with a mortality rate of over 16% from scd in one omani icu, we need much more basic research on the aetiology and management and, specifically, prevention of all the complications. the association needs to work in concert with the research council and the ministry of health to reduce this mortality. western countries such as usa and uk have managed to lower their overall mortality from scd (not only in the icu) from 3% to 0.13 per 100 person years of observation.9 surely, we need to do even better because of the impact this condition has on our society. our doctors have the knowhow but we need more support from the ngos, the public and the ministry of health. oman is spending one of the lowest percentages of gross domestic product (gdp) on health care, compared to most of the world—only just over 2% of gdp, compared to 6–12% in other countries and 17.4% in the usa.14,15 oman needs to invest more money to support and improve our health system and reduce mortality from scd and other hereditary blood disorders. our health care investment levels should not remain at about the lowest in the gulf region, and much lower than most other countries. so what is the effect of this low health care expenditure on scd? to start with, if we had more icu beds, then we might be able to admit patients earlier and therefore, reduce mortality. as indicated above, because there is very little in the world literature on icu patients with scd, we have no statistics to compare with our figure of 16% mortality, but general medical logic tells us that we should be able to lower this rate by earlier intervention and better preventative measures. not only should doctors and the ministry be more vigilant, but also, the patients need to be better educated about the disease, e.g. by presenting themselves early to the doctor, as soon as they have symptoms that may suggest acs, such as fever, shortness of breath or cough. the paper published in the new england journal of medicine in 1994 studied 538 patients with scd and acs.4 their mortality was lower with only 18 out of their 538 patients dying from acs (3.3%). certainly, this would indicate that mortality from acs can be reduced with adequate and early medical intervention which implies greater expenditure and investment in our health services. in 1999, the national institutes of health in the usa published suggestions for preventing morbidity and mortality from scd, from which we could learn several lessons and develop more research.16 likewise, the harvard study17 and the sultan qaboos university studies18,19 also offer some ideas which, hopefully, could stimulate the oman hereditary blood disorder association and the research council to get together and do some similar research on scd. overall, we need much more research on this genetic disorder, like many other genetic disorders in oman and in the arab world.20 we have to shoulder this responsibility ourselves as we cannot wait for, or rely on, pharmaceutical companies or western countries to do this research for us. yes, we can, and we must do better in oman. references 1. tawfic qa, kausalya r, alwan dm, burad j, mohamed ak, narayanan a. adult sickle cell disease: a five-year experience of intensive care management in a university hospital in oman. sultan qaboos university med j 2012; 12:177-83. 2. sc davies, aa win, pj luce, jf riordan, m brozovic. acute chest syndrome in sickle-cell disease. lancet 1984; 323:36–8. doi: 10.1016/s01406736(84)90193-4 3. maitre b, habibi a, roudot-thoraval f, bachir d, belghiti dd, galacteros f, et al. therapeutic approach, outcome, and results of bal in a deaths from sickle cell disease in intensive care units can we do better? 136 | squ medical journal, may 2012, volume 12, issue 2 monocentric series of 107 episodes. chest 2000; 117:1386–92. doi: 10.1378/chest.117.5.1386 4. vichinsky ep, neumayr ld, earles an, williams r, lennette et, dean d, et al. causes and outcomes of the acute chest syndrome in sickle cell disease. national acute chest syndrome study group. n engl j med 2000; 342:1855–65. 5. steinberg mh. management of sickle cell disease. n engl j med 1999; 340:1021–30. 6. ware re, aygun. advances in the use of hydroxyurea. hematology am soc hematol educ prog 2009:62–9. 7. steinberg mh, barton f, castro o, pegelow ch, ballas sk, kutlar a, et al. effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia; risks and benefits up to 9 years of treatment. jama 2003; 289:1645–51. doi: 10.1001/jama.289.13.1645. 8. mitchell b. sickle cell trait and sudden death - bringing it home. j natl med assoc 2007; 99:300–5. 9. makani j, cox se, soka d, komba an, oruo j, mwantemi h, et al. mortality in sickle cell anemia in africa: a prospective cohort study in tanzania. plosone 2011; 6:e14699. 10. aidoo m, terlouw dj, kolczak ms, mcelroy pd, ter kuile fo, kariuki s, et al. protective effects of the sickle cell gene against malaria morbidity and mortality. lancet 2002; 359:1311–12. doi:10.1016/ s0140-6736(02)08273-9 11. oman hereditary blood disorder association. f r o m : h t t p : / / w w w. o n l i n e d o n a t i o n s . o r g . o m / d o n at i o n s p o r t a l / p a g e s / p a g e . a s px ? n i d = 4 8 3 6 accessed mar 2012. 12. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 13. alkindi s, pathare a, al-madhani a, al-zadjali s, al-haddabi h, al-abri q, et al. neonatal screening: mean haemoglobin and red cell indices in cord blood from omani neonates. sultan qaboos univ med j 2011; 11:462–9. 14. world bank. health expenditure as total % of gdp. from: http://data.worldbank.org/indicator/sh.xpd. totl.zs accessed mar 2012. 15. list of countries by total health expenditure (ppp) per capita. from: http://en.wikipedia.org/wiki/list_ of_countries_by_total_health_expenditure(ppp)_ per_capita accessed mar 2012. 16. olney rs. preventing morbidity and mortality from sickle cell disease: a public health perspective. am j prev med 1999; 16:116–21 17. management of patients with sickle cell disease: an overview. from: http://sickle.bwh.har vard.edu/scdmanage.html accessed mar 2012. 18. al-lamki z, wali ya, shah w, zachariah m, rafique b, ahmed s. natural history of sickle hemoglobinopathies in omani children. intern j ped hemat/oncol 2001; 7:101–7. 19. wali y, almaskari s. avascular necrosis of the hip in sickle cell diseases in oman. sultan qaboos univ med j 2011; 11:127–8. 20. al ali mt. centre for arab genomic studies. genetic disorders in the arab world – oman. editorial. from: http://www.cags.org.ae/cb33for.pdf accessed mar 2012. paget’s disease of bone (pdb) is characterised by the disruption of bone formation and resorption which leads to bone deformities. it is considered to be a relatively benign bone disease in most cases. the most commonly affected sites are the pelvis [figure 1], femur, tibia, lumbar spine and skull; thus, abdominal radiographs are often performed to diagnose pdb in people over the age of 55 years.1 the disease is more prevalent among northern european populations, including scandinavians, and is considered to be uncommon in non-caucasians.1 randomised trials have shown that antiresorptive therapy decreases bone pain and lowers alkaline phosphatase levels, which helps to assess the extent and severity of the disease in affected patients.2 the aetiology of pdb is not yet fully understood. however, genetics are thought to play a part in the disease’s development, with more than 20% of pdb patients reporting a first-degree relative with the same condition.3 studies have shown the involvement of specific genetic loci, including the colony stimulating factor 1, optineurin, transmembrane 7 superfamily member 4 and ras and rab interactor 3 genes.3,4 heterozygous mutations affecting the sequestosome 1 (sqstm1) gene, which are clustered in the ubiquitinbinding domain encoded by exon 7 and 8, have been commonly reported among pdb patients.5 the other type of mutation is less common and includes domain-specific defects within valosincontaining protein which can lead to pdb in a rare syndrome associated with dementia and late-onset inclusion body myopathy.6 a viral aetiology remains controversial, since these observations have not always been replicated and thus far, viruses have not been isolated from pagetoid tissue.7 as the prevalence of pdb has decreased in certain countries over the past 25 years, it has been suggested that environmental factors may be important in the development of pdb.8 however, additional research addressing the environmental impact on the development of pdb is required. the highest prevalences of pdb are found in britain, australia, new zealand, north america, western europe and among caucasians over the age of 50 years.9,10 department of rheumatology, mile end hospital, london, uk *corresponding author e-mail: ali.jawad@bartshealth.nhs.uk مرض باجيت )paget's disease( الذي يصيب العظام ضمن اجملموعات العرقية املختلفة مريا مرع�ضلي و علي جواد abstract: paget’s disease of bone (pdb) is a relatively benign disease common among many european populations, including those in the uk, italy and spain. however, it appears to be rare among scandinavians and non-european immigrants living in europe. the prevalence among asian populations may be underestimated because a large number of reported cases were discovered incidentally. there is a need for surveys addressing the prevalence rate and consequences of pdb to be carried out in various parts of the world, particularly asia. keywords: paget’s disease of bone; ethnic groups; epidemiology. ومن االأوروبية، املناطق �ضكان بني �ضائع وهو ن�ضبيًا الحميدة األمر�س من )pdb( العظام ي�ضيب الذي باجيت مر�س يعد امللخ�ص: �ضمنها �ضكان اململكة املتحدة واإيطاليا واإ�ضبانيا. ومع ذلك فهو نادراً ما يظهر بني اال�ضكندنافيني واملهاجرين من اأ�ضول غري اأوروبية الذين يعي�ضون يف اأوروبا. وقد يكون تقدير انت�ضار هذا املر�س بني �ضكان اآ�ضيا اأقل كثريا مما هو يف الواقع ب�ضبب اأن عددا كبريا من احلاالت امل�ضجلة كان اكت�ضافها م�ضادفة. اإن هنالك حاجة الإجراء درا�ضات ا�ضتق�ضائية لدرا�ضة معدل انت�ضار ونتائج االإ�ضابة مبر�س باجيت التي ال بد من معرفتها واالأخذ بها يف اأجزاء خمتلفة من العامل، وخا�ضة اآ�ضيا. مفتاح الكلمات: مر�س باجيت الذي ي�ضيب العظام؛ املجموعات العرقية؛ علم االأوبئة. review paget’s disease of bone among various ethnic groups mira merashli and *ali jawad sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e22–26, epub. 21 jan 15 submitted 9 mar 14 revision req. 22 apr 14; revision recd. 14 jun 14 accepted 21 aug 14 mira merashli and ali jawad review | e23 although this disease is generally not seen in non-european populations, a case series reported eight non-caucasian pdb patients in east london in the uk.14 two of the patients were of bangladeshi origin and both died of complications; one had an angiosarcoma and the other had an osteosarcoma. both patients were male and relatively young (63 and 58 years old).15 similar pdb prevalence rates were found in a survey of 13 different european towns across nine countries (2–3%), except for sweden which showed a much lower prevalence (0.4%) [table 1].16 in italy, the overall rate of pdb was found to range between 0.7–2.4%.17 a recent study demonstrated that the incidence of pdb in two regions of spain had stayed the same over the past 24 years, although the severity of the disease had declined.18 campagnia, italy, and vitigudino, spain, are also known to have a high prevalence of pdb.19 n o r t h a m e r i c a in the usa, approximately 1% of the population are affected by pdb, with the north-eastern region of the usa showing the highest prevalence.20 although the disease is thought to be rare in non-caucasian populations, research has indicated that there is no difference in prevalence between caucasians and african-americans.21 a survey carried out in new york city, new york, and atlanta, georgia, revealed that while there was a different prevalence between the two cities, there was a similar prevalence between the two ethnic groups [table 2].20 a u s t r a l i a a n d n e w z e a l a n d pdb is also common in australia and new zealand, with a prevalence of approximately 4%.21,22 in one study, the prevalence was found to be higher among british migrants coming to australia than among the australian residents.21 recent evidence suggests a decrease in the prevalence rate and severity of the disease in new zealand.22 a study of the asian population in auckland, new zealand, showed nearly the same prevalence of pdb as in people of european origin.23 this finding suggests that the low prevalence prevalence in various regions e u r o p e pdb is common in caucasians, although the disease rarely occurs among individuals below 50 years old.1 it has been found that the rate of pdb increases significantly in those over 90 years of age.11 within the uk, the prevalence of this condition appears to have decreased over recent years. in a study conducted in 1980, it was found that the north-western lancashire towns of preston, bolton, wigan, burnley and blackburn had an average pdb prevalence of 6.8%, while lancaster had the highest prevalence rate at 8.3%.12 however, a more recent study conducted in england and wales revealed a total prevalence of 0.3% among men and women aged 55 years and above.13 this suggests a dramatic decline in the pdb prevalence in the uk. table 1: ageand sex-standardised prevalence of paget’s disease of bone among hospital patients aged ≥55 years in various european towns16 town prevalence in % uk* 4.6 bordeaux, france 2.7 rennes, france 2.4 nancy, france 2.0 dublin, ireland 1.7 valencia, spain 1.3 essen, germany 1.3 palermo, italy 1.0 porto, portugal 0.9 galloway, ireland 0.7 athens, greece 0.5 crete, greece 0.5 malmo, sweden 0.4 *prevalence calculated from 31 towns in the uk. table 2: age-standardised prevalence of paget’s disease of bone in african-american and caucasian residents in two cities in the usa20 city ethnic group prevalence in % men women both new york african 3.3 2.0 2.6 new york caucasian 5.2 2.5 3.9 atlanta african 1.9 0.6 1.2 atlanta caucasian 0.9 0.8 0.9 figure 1: radiograph of the pelvis of a 73-year-old patient originally from sierra leone with widespread paget’s disease of the bone. paget’s disease of bone among various ethnic groups e24 | squ medical journal, february 2015, volume 15, issue 1 of pdb in asia, as discussed later on in this review, might be underestimated due to a lack of awareness among physicians. a f r i c a pdb is also common in south africa. a survey of abdominal radiographs from 1,003 south africans of european descent and 1,355 south africans of african descent who were 55 years or older, showed prevalence rates of 2.4% and 1.3%, respectively.24 the disease prevalence varies in other regions of africa; however, it is generally rare. a study of 82,000 radiographs collected over four years in freetown, sierra leone, revealed only 14 cases of pdb, while no documented case was detected over the same period and number of radiographs in northern nigeria.25 research has shown that this disease is also rare in sub-saharan africa.25 a s i a in asia, pdb is known to be rare; however, there are reported cases among chinese patients.26–28 in singapore, five cases of pdb were found over an eightyear period.29 this series included a 72-year-old indian patient whose diagnosis of pdb was made incidentally after he had suffered an ischaemic stroke. a computed tomography scan of the head revealed bony changes in the skull consistent with pdb and his serum alkaline phosphatase levels were also elevated.29 there have been other reported cases of pdb among indians, although its true prevalence in the indian population is suspected to be higher, as most cases are discovered incidentally.30,31 as mentioned previously, research has indicated a similar prevalence of pdb between individuals of asian and those of european origin,23 indicating that this disease is under-recognised in asia. furthermore, a review of pdb among the ethnic thai population theorised that the prevalence of this disorder will increase in the future due to the increasing number of asian-european intermarriages.32 thus, it is imperative that healthcare workers in asia increase their awareness of pdb and its symptoms in order to provide effective care for their patients. s o u t h a m e r i c a in south america, pdb is generally present among those of european descent, with research demonstrating that the disease is not present within the indigenous population.33 the incidence is relatively high in argentina, especially around buenos aires, which has a large population of spanish and italian immigrants. it occurs less frequently in chile and venezuela, both of which have fewer citizens of european descent.33 however, a pilot epidemiological study conducted in the city of recife, in north-east brazil, found a similar pdb prevalence (6.8 per 1,000 people) and incidence (50.3 per 10,000 person-years) as that noted in southern europe.34 t h e m i d d l e e a s t a survey conducted in southern israel from 1968– 1993 yielded 61 cases of pdb and indicated a prevalence of approximately 1%, which is close to that found in southern europe.35 the majority of these cases were patients of afro-asian descent (56%), with the remaining 44% of afro-asian origin. israel was the country of origin for few of the identified pdb patients; romania, tunisia, australia and argentina were the most frequent countries of origin. all of the patients were jewish with the exception of one bedouin arab.35 in another study carried out between 1961 and 1985 in four medical centres in israel, 278 cases of pdb were identified in jewish patients.36 only six of these patients were immigrants, of which 74% were originally from eastern europe. there were no patients of arab ethnicity included in the 278 studied pdb cases.36 there have been isolated cases of pdb reported in saudi arabia, iran, iraq and turkey.37–40 although, to the best of the authors’ knowledge, no cases of pdb in egypt, lebanon or syria have been published, there are verbal reports from rheumatologists in these countries about isolated cases of pdb in the local arab populations. recommendations for future research it is difficult to be certain of the exact prevalence of pdb among various ethnic groups due to the small sample sizes used in many studies. based on the available research, pdb appears to be comparatively rare in asian and african populations. however, it is very likely that this disease is under-reported in these populations, especially given the lack of prevalence studies in asian and african countries. there is no clear explanation for the high pdb prevalence in lancashire, uk, but the fact that this area has a high proportion of immigrants who are asian in origin may be significant.12 therefore, there is a need to conduct epidemiological studies aimed at estimating the prevalence of the disease among asians and caucasians. further studies should seek to investigate the true prevalence and incidence of pdb in various regions of the world. the overall prevalence of this disease has decreased by 36% over the last 19 years.41 this decline mira merashli and ali jawad review | e25 10. cooper c, schafheutle k, dennison e, kellingray s, guyer p, barker d. the epidemiology of paget’s disease in britain: is the prevalence decreasing? j bone miner res 1999; 14:192–7. doi: 10.1359/jbmr.1999.14.2.192. 11. bastin s, bird h, gamble g, cundy t. paget’s disease of bone: becoming a rarity? rheumatology (oxford) 2009; 48:1232–5. doi: 10.1093/rheumatology/kep212. 12. barker dj, chamberlain at, guyer pb, gardner mj. paget’s disease of bone: the lancashire focus. br med j 1980; 280:1105–7. doi: 10.1136/bmj.280.6222.1105. 13. barker dj. the epidemiology of paget’s disease of bone. br med bull 1984; 40:396–400. 14. van staa tp, selby p, leufkens hg, lyles k, sprafka jm, cooper c. incidence and natural history of paget’s disease of bone in england and wales. j bone miner res 2002; 17:465–71. doi: 10.1359/jbmr.2002.17.3.465. 15. soo j, arif s, kidd bl, jawad as. pyrexia, pelvic pain and thrombocytopenia in an asian man with paget’s disease of bone. rheumatology (oxford) 2004; 43:110–1. doi: 10.1093/ rheumatology/keg431. 16. detheridge fm, guyer pb, barker dj. european distribution of paget’s disease of bone. br med j (clin res ed) 1982; 285:1005– 8. doi: 10.1136/bmj.285.6347.1005. 17. gennari l, merlotti d, martini g, nuti r. paget’s disease of bone in italy. j bone miner res 2006; 21:p14–21. doi: 10.1359/ jbmr.06s203. 18. corral-gudino l, garcía-aparicio j, sánchez-gonzález md, mirón-canelo ja, blanco jf, ralston sh, et al. secular changes in paget’s disease: contrasting changes in the number of new referrals and in disease severity in two neighboring regions of spain. osteoporos int 2013; 24:443–50. doi: 10.1007/s00198012-1954-5. 19. merlotti d, gennari l, galli b, martini g, calabrò a, de paola v, et al. characteristics and familial aggregation of paget’s disease of bone in italy. j bone miner res 2005; 20:1356–64. doi: 10.1359/jbmr.050322. 20. altman rd, bloch da, hochberg mc, murphy wa. prevalence of pelvic paget’s disease of bone in the united states. j bone miner res 2000; 15:461–5. doi: 10.1359/jbmr.2000.15.3.461. 21. gardner mj, guyer pb, barker dj. radiological prevalence of paget’s disease of bone in british migrants to australia. br med j 1978; 1:1655–7. doi: 10.1136/bmj.1.6128.1655. 22. cundy hr, gamble g, wattie d, rutland m, cundy t. paget’s disease of bone in new zealand: continued decline in disease severity. calcif tissue int 2004; 75:358–64. doi: 10.1007/s00223 -004-0281-z. 23. sankaran s, naot d, grey a, cundy t. paget’s disease in patients of asian descent in new zealand. j bone miner res 2012; 27:223–6. doi: 10.1002/jbmr.507. 24. guyer pb, chamberlain at. paget’s disease of bone in south africa. clin radiol 1988; 39:51–2. doi: 10.1016/s0009-9260(88) 80341-6. 25. dahniya mh. paget’s disease of bone in africans. br j radiol 1987; 60:113–16. doi: 10.1259/0007-1285-60-710-113. 26. yip km, lee yl, kumta sm, lin j. the second case of paget’s disease (osteitis deformans) in a chinese lady. singapore med j 1996; 37:665–7. 27. chen wt, shih tt, shih ls, lo sy, chen rc, tu hy. paget’s disease of the bone: a case report. j formos med assoc 2001; 100:137–41. 28. wat wz, cheung ws, lau tw. a case series of paget’s disease of bone in chinese. hong kong med j 2013; 19:242–8. doi: 10.128 09/hkmj133661. is mostly attributed to environmental rather than genetic factors.41 however, while significant progress has been made in the identification of the exact genetic mutations associated with pdb, further research is needed to determine the precise environmental factors involved. conclusion pdb appears to be more common among europeans and rare among asian and african populations. however, cases of pdb in africa and asia are likely under-reported, resulting in a need for further epidemiological studies to assess the true incidence of this disease in both caucasian and non-caucasian populations. considerable progress has been made regarding the genetic factors associated with pdb. however, it is theorised that environmental factors contribute greatly to the development of this condition. future research is therefore recommended in this area. references 1. ankrom ma, shapiro jr. paget’s disease of bone (osteitis deformans). j am geriatr soc 1998; 46:1025–33. 2. selby pl, davie mw, ralston sh, stone md; bone and tooth society of great britain; national association for the relief of paget’s disease. guidelines on the management of paget’s disease of bone. bone 2002; 31:366–73. doi: 10.1016/s87563282(02)00817-7. 3. albagha om, visconti mr, alonso n, langston al, cundy t, dargie r, et al. genome-wide association study identifies variants at csf1, optn and tnfrsf11a as genetic risk factors for paget’s disease of bone. nat genet 2010; 42:520–4. doi: 10.1038/ng.562. 4. albagha om, wani se, visconti mr, alonso n, goodman k, brandi ml, et al. genome-wide association identifies three new susceptibility loci for paget’s disease of bone. nat genet 2011; 43:685–9. doi: 10.1038/ng.845. 5. cavey jr, ralston sh, hocking lj, sheppard pw, ciani b, searle ms, et al. loss of ubiquitin-binding associated with paget’s disease of bone p62 (sqstm1) mutations. j bone miner res 2005; 20:619–24. doi: 10.1359/jbmr.041205. 6. watts gd, wymer j, kovach mj, mehta sg, mumm s, darvish d, et al. inclusion body myopathy associated with paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. nat genet 2004; 36:377–81. doi: 10.1038/ng1332. 7. helfrich mh, hobson rp, grabowski ps, zurbriggen a, cosby sl, dickson gr, et al. a negative search for a paramyxoviral etiology of paget’s disease of bone: molecular, immunological, and ultrastructural studies in uk patients. j bone miner res 2000; 15:2315–29. doi: 10.1359/jbmr.2000.15.12.2315. 8. bolland mj, cundy t. paget’s disease of bone: clinical review and update. j clin pathol 2013; 66:924–7. doi:10.1136/ jclinpath-2013-201688. 9. ralston sh. clinical practice: paget’s disease of bone. n engl j med 2013; 368:644–50. doi: 10.1056/nejmcp1204713. paget’s disease of bone among various ethnic groups e26 | squ medical journal, february 2015, volume 15, issue 1 29. hsu lf, rajasoorya c. a case series of paget’s disease of bone: diagnosing a rather uncommon condition in singapore. ann acad med singapore 1998; 27:289–93. 30. sridhar gr. paget’s disease in india: is it truly rare? natl med j india 1994; 7:101. 31. zargar ah, laway ba, masoodi sr, wani ai, bashir mi, tramboo na, et al. paget’s disease of the bone. saudi med j 1999; 20:629–32. 32. sirikulchayanonta v, jaovisidha s, subhadrabandhu t, rajatanavin r. asymptomatic paget’s bone disease in ethnic thais: a series of four case reports and a review of the literature. j bone miner metab 2012; 30:485–92. doi: 10.1007/s00774011-0330-4. 33. mautalen c, pumarino h, blanco mc, gonzález d, ghiringhelli g, fromm g. paget’s disease: the south american experience. semin arthritis rheum 1994; 23:226–7. doi: 10.1016/00490172(94)90038-8. 34. reis rl, poncell mf, diniz et, bandeira f. epidemiology of paget’s disease of bone in the city of recife, brazil. rheumatol int 2012; 32:3087–91. doi: 10.1007/s00296-011-2092-7. 35. magen h, liel y, bearman je, lowenthal mn. demographic aspects of paget’s disease of bone in the negev of southern israel. calcif tissue int 1994; 55:353–5. doi: 10.1007/bf00299314. 36. dolev e, samuel r, foldes j, brickman m, assia a, liberman ua. some epidemiological aspects of paget’s disease of bone in israel. semin arthritis rheum 1994; 23:228. doi: 10.1016/00490172(94)90039-6. 37. alshaikh om, almanea h, alzahrani as. paget disease of the bone: does it exist in saudi arabia? ann saudi med 2011; 31:305–10. doi: 10.4103/0256-4947.75588. 38. etemadi j, bagheri n, falaknazi k, ardalan m, rahbar k, nobakht haghighi a, et al. paget’s disease of bone in a patient on hemodialysis. iran j kidney dis 2008; 2:105–7. 39. uthman aa, al-shawaff m. paget’s disease of the mandible: report of a case. oral surg oral med oral pathol 1969; 28:866– 70. doi: 10.1016/0030-4220(69)90341-7. 40. karaoğlan a, akdemir o, erdoğan h, colak a. a rare emergency condition in neurosurgery: foot drop due to paget’s disease. turk neurosurg 2009; 19:208–10. 41. corral-gudino l, borao-cengotita-bengoa m, del pinomontes j, ralston s. epidemiology of paget’s disease of bone: a systematic review and meta-analysis of secular changes. bone 2013; 55:347–52. doi: 10.1016/j.bone.2013.04.024. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e157–170, epub. 28 may 15 submitted 18 jun 14 revision req. 30 sep 14; revision recd. 5 oct 14 accepted 30 oct 14 in part i of this review, the role ofdamage-associated molecular patterns (damps) in mounting inflammation and shaping adaptive immunity was briefly described by defining various classes of damps that activate and orchestrate several innate immune machineries including inflammasomes and the unfolded protein response (upr).1 in brief, damps are intracellularly sequestered molecules and are hidden from recognition by the immune system under normal physiological conditions. however, under conditions of cellular stress/tissue injury, these molecules can either be actively secreted by stressed immune cells; exposed on stressed cells, for example, in terms of neo-antigens binding to natural immunoglobulin m (igm) antibodies, or they can be passively released into the extracellular environment from dying cells or the damaged extracellular matrix.2–6 damps are recognised by pattern recognition receptor (prr)-bearing cells of the innate immune system, including macrophages, leukocytes and dendritic cells (dcs) as well as vascular cells, fibroblasts and epithelial cells, to promote pro-inflammatory and profibrotic pathways. various definitions and interpretations of damps can be found in the literature and may confuse a new reader in this field. thus, in this article, for didactic reasons only and without covering all possible damps, they are divided into five partially overlapping classes. laboratoire d’immunorhumatologie moléculaire, inserm umr_s1109, labex transplantex, centre de recherche d’immunologie et d’hématologie, université de strasbourg, strasbourg, france e-mail: gottliebland@gmail.com دور األضرار املرتبطة باألمناط اجلزيئية يف أمراض البشر اجلزء الثاين: الدور التشخيصي، اإلنذاري واملداواة يف الطب السريري والرت الند abstract: this article is the second part of a review that addresses the role of damage-associated molecular patterns (damps) in human diseases by presenting examples of traumatic (systemic inflammatory response syndrome), cardiovascular (myocardial infarction), metabolic (type 2 diabetes mellitus), neurodegenerative (alzheimer’s disease), malignant and infectious diseases. various damps are involved in the pathogenesis of all these diseases as they activate innate immune machineries including the unfolded protein response and inflammasomes. these subsequently promote sterile autoinflammation accompanied, at least in part, by subsequent adaptive autoimmune processes. this review article discusses the future role of damps in routine practical medicine by highlighting the possibility of harnessing and deploying damps either as biomarkers for the appropriate diagnosis and prognosis of diseases, as therapeutics in the treatment of tumours or as vaccine adjuncts for the prophylaxis of infections. in addition, this article examines the potential for developing strategies aimed at mitigating damps-mediated hyperinflammatory responses, such as those seen in systemic inflammatory response syndrome associated with multiple organ failure. keywords: innate immunity; receptors, pattern recognition; inflammation; adaptive immunity; autoimmunity. امللخ�ض: هذا املقال هو اجلزء الثاين من املراجعة التى تركز على دور االأ�رشار املرتبطة باالأمناط اجلزيئية يف اأمرا�ض الب�رش عن طريق عر�ض اأمثلة من الر�سحية )متالزمة ا�ستجابة االلتهاب املجموعي(، القلبية )اأحت�ساء ع�سل القلب(، االأي�سي )النوع الثاين من ال�سكري(، النها االأمرا�ض هذه جميع مر�سية يف معنية املتعددة االأمناط هذه واملعدية. اخلبيثة االأمرا�ض و الزهامير( الع�سبي )مر�ض التنك�ض تقوم بتن�سيط اآليات املناعة الطبيعية مبا فيها ك�سف ا�ستجابة الربوتني وااللتهابية. وهذه الحقا تعزز االلتهابات الذاتية املرافقة، على االأقل جزئيا عن طريق تالوؤم عمليات املناعة الذاتية. يناق�ض مقال املراجعة هذا م�ستقبل دور االأ�رشار املرتبطة باالأمناط اجلزيئية يف والتنبوؤ املنا�سب للت�سخي�ض بيولوجية كعالمات اإما االأمناط هذة ون�رش ت�سخري امكانية اإبراز طريق عن الروتينية الطبية املمار�سات باالأمرا�ض، اأو عالجية لعالج االأورام اأو كلقاح م�ساعد الإتقاء االلتهابات. اي�سا، يدر�ض هذا املقال جهد تطوير ا�سرتاتيجيات تهدف اإىل التخفيف من اآثار جهد فرط االلتهاب امل�ساحب لهذه االإمناط، مثل ماميكن م�ساهدته يف متالزمة ا�ستجابة االلتهاب املجموعي املرتبطة مع ف�سل االأع�ساء املتعدد. مفتاح الكلمات: املناعة الطبيعية؛ امل�ستقبالت، تعرف النمط؛ التهاب؛ مناعة متالئمة؛ مناعة ذاتية. the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine walter g. land review the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine e158 | squ medical journal, may 2015, volume 15, issue 2 in the current article only three classes are covered: classes i, ii and v. class i damps are recognised by physically binding to prrs, while class ii damps are those sensed without directly binding to prrs. particularly addressed in this article are class v damps, or dyshomeostasis-associated molecular patterns (see part i).1 class v damps, in terms of homeostatic danger signals, have recently been reported as an emerging class of damps in terms of defining an altered pattern of molecules reflecting perturbations in the steady state of the intracellular and/or extracellular microenvironment.3 such homeostatic damps, when associated with endoplasmic reticulum (er) stress, may be sensed by three sensor molecules of the upr: the protein kinase-like eukaryotic initiation factor 2α kinase (perk), the inositol-requiring transmembrane kinase/endoribonuclease 1α (ire1α) and the activating transcription factor 6 (atf6).7–9 the various classes of sterile inflammationpromoting damps, as true for infectious inflamma tion-evoking pathogen-associated molecular patterns (pamps), are sensed by a variety of distinct prrs, thereby promoting an inflammatory response. they are not reviewed here since prrs and their triggered signalling pathways have recently been the subjects of excellent review articles, including those covering toll-like receptors (tlrs),10 receptors for advanced glycation end-products (rage),11 nucleotide-binding oligomerization domain (nod)-like receptors (nlrs),11 c-type lectin receptors (clrs),12 retonic acid inducible gene-i (rig-i)-like receptors (rlrs)13–15 and dna sensors, including absent in melanoma 2 protein (aim2)-like receptors (alrs). the recently discovered cyclic guanosine monophosphate-adenosine monophosphate (cgamp) synthase (cgas) has also been covered in recent reviews.15–17 in part i of this review, the five classes of damps were shown to synergistically operate in instigating (auto)inflammatory and adaptive (auto)immune pathologies as manifested by many human diseases.1 two examples of autoimmune diseases, systemic lupus erythematosus (sle) and rheumatoid arthritis, were discussed in order to represent a typical paradigm of the intimate interplay between innate and adaptive immune responses. this second part of the review addresses the role of damps in human diseases where the involvement of immune processes (in terms of adaptive immune processes) were almost unconsidered in the past but are now clearly recognised in terms of dysregulated innate immune processes. traumatic diseases the field of trauma impressively reflects the inherently ambivalent role of injury-induced damps in medicine as their controlled beneficial function instigates the whole machinery of inflammation/fibrosis-mediated wound healing following any kind of small or moderate trauma.18 on the other hand, their uncontrolled detrimental action in the case of severe trauma/ polytrauma can lead to the catastrophe of a systemic inflammatory response syndrome (sirs) associated with multiple organ failure (mof).19,20 typically, the generation of damps correlates with the degree of severity of accidental insults in traumatic diseases ranging from small cuts to blunt-force trauma and bone fractures or severe large-scale physical or thermal injuries.21 following all these injurious lesions, damps, such as high-mobility group box 1 (hmgb1) and heat shock proteins (hsps), not only induce an acute inflammatory response but are also responsible for subsequent tissue repair. inflammation after tissue injury is certainly a critical component of wound repair. innate immune inflammatory cells migrate to the wound and promote tissue regeneration by removing cellular debris, killing and phagocytosing potential invading pathogens, and producing cytokines that promote collagen production, cellular migration, wound epithelialization and angiogenesis. in fact, any post-injury profibrotic and angiogenic response, for example after surgery or accidental trauma, is mediated by damps-activated prrsexpressing innate immune cells such as fibroblasts, epithelial cells, macrophages and vascular cells.18,22,23 it is the damps and their triggered pathways, together with the surrounding cytokine and growth factor milieu, that ultimately determine whether or not these post-injury innate cellular responses cause mild acute inflammation and wound healing,22,24 or subchronicly on-going inflammation and fibrosis.25 in very severe trauma, when damps are produced in very high concentrations and systemically released, they can cause acutely occurring sirs that may be accompanied by mof.25 in severe trauma in humans, hmgb1 has been found to be systemically released within 30–60 minutes, peaking two to six hours after injury. remarkably, patients who develop organ dysfunction and nonsurvivors of severe trauma have been observed to have very high levels of this damp. moreover, hmgb1 levels were found to be predictive of outcome of traumatic lesions as shown, for example, in patients with traumatic brain injury.26–28 moreover, in extensive trauma, increasing attention has been devoted to the crucial role of mitochondria-derived damps, since they have been shown to be markedly elevated in severely injured patients.29 this category of damps mainly includes circular dna strands containing walter g. land review | e159 c-phosphate-g (cpg) dna repeats, n-formylated peptides and mitochondrial dna (mtdna) itself.30 interestingly, it has been found that mtdna, observed to directly activate neutrophils after binding to tlr9, are released under various traumatic conditions including shock and severe traumatic brain injury.31,32 recent clinical studies in massively injured human subjects provided the first observational evidence that plasma mtdna damps are associated with the evolution of sirs, mof and mortality.33 one of the most interesting reported findings was that a determination of mtdna damps levels made within eight hours of hospital admission allowed a differentiation between survivors and non-survivors.33 interestingly, the humoral part of the innate immune system, which is likely to be induced by class iv damps in terms of injury-induced neo-antigens, namely the complement system, is activated immediately after trauma as well. in fact, severe, sterile, injury-induced, systemic intravascular activation of the complement cascade (in particular, the mannose-binding lectinmediated pathway) reportedly can promote mof by contributing to a fulminant inflammatory response associated with disseminated intravascular coagulation and comprised microcirculation.34 cardiovascular diseases most cardiovascular diseases (cvds) develop on the basis of atherosclerosis. for many years, atherosclerosis was simply regarded as a consequence of the accumulation of lipids in the vessel walls. today, the picture has completely changed. current notions in vascular biology hold that vessel wall injury-induced damps elicit pro-inflammatory, profibrotic and adaptive autoimmune responses to promote atherogenesis as the underlying disorder of cvds, the most common being coronary artery and cerebrovascular diseases.35–37 atherosclerosis a large variety of stressful stimuli and inciting events to the arterial wall, including hypertension, diabetes, hyperlipidaemia, drugs and chemical toxins, can lead to vascular injury associated with the creation of various damps. remarkably, most of these injuries are mediated by the generation of reactive oxygen species (ros), a typical example being hypertension, an insult-mediating injurious factor that has been already described for sle.1,38 accordingly, numerous studies have identified oxidative stress-induced damps as the major activators of innate immune-mediated vascular inflammation promoting atherosclerosis.35–37 low-density lipoprotein (ldl) is a key damp that accumulates in the subendothelium in the form of oxidised ldl (oxldl) and minimally oxidised ldl. both damps activate vascular cells via recognition of their cognate receptors, lectin-like oxldl receptor 1 (lox-1) and tlr4. further oxidation-specific epitopes, for example those derived from oxldl, appear to play a prominent atherogenic role by forming a distinct family of damps consisting of various categories of oxidative reactions. other injuryinduced damps, such as hsps and hmgb1, known to bind to tlr2, tlr4 and rage on vascular cells, in particular on vascular macrophages, are also involved in establishing a vascular pro-inflammatory/profibrotic cascade contributing to atherogenesis.35–37,39–41 more recently, other types of damps released from severely damaged cells, such as s100a8/a9, sensed by tlr4 and rage, and mtdna, sensed by tlr9, have increasingly been recognised to contribute to vascular innate immunity-mediated inflammatory pathways involved in atherogenesis.1,42 of note, the nlr-containing pyrin domains (nlrp3) inflammasome, located in vascular macrophages and smooth muscle cells (smcs), is reportedly also involved in atherogenesis via promotion of pro-inflammatory and profibrotic responses. in particular, studies on murine and human phagocytes and in in vivo settings revealed that crystals of cholesterol, operating as damps, activate the nlrp3 inflammasome required for atherogenesis [figure 1].36,43 at a later stage of the disease, immunostimulatory dcs in the arterial wall, activated after recognition of damps through prrs, engulf and process stress/ injury-induced neo-antigens in terms of altered/ modified self-proteins generated in early atherosclerotic lesions such as the oxidatively modified apolipoprotein b100 component of ldl, hsps and others. the vascular autostimulatory dcs then present these altered self-proteins as peptide/major histocompatibility complex (mhc) complexes to naïve autoreactive t cells in secondary lymphoid tissues of the host, leading to an adaptive t cell autoimmune response. in a vicious cycle, cytotoxic effector t cells then migrate into arterial lesions where they cause further vascular injury, leading to the induction of damps that again initiate pro-inflammatory and/or profibrotic innate immune pathways [figure 1].35–37 it is of note that homeostatic danger signals, denoted here as class v damps, can initiate an upr in endothelial cells (ecs), smcs and vascular macrophages. in fact, multiple local stressors in the arterial wall, including to the presence of ros and oxidised lipids, shear stress and increa sed homocysteine-/cholesterol-mediated stress, have the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine e160 | squ medical journal, may 2015, volume 15, issue 2 been shown to cause er stress in vessel cells during the initiation and progression of atherosclerosis. as highlighted in a recent review, the activation of the various upr signalling pathways displays a temporal pattern of activation at different stages of the disease.44 thus, the atf6 and ire1α pathways are activated in ecs in athero-susceptible regions of pre-lesional arteries whereas the perk pathway is activated in smcs and macrophages in early lesions.1 with the progression of atherosclerosis, the extended duration and increased intensity of er stress in lesions lead to prolonged and enhanced upr signalling. under this circumstance, the perk pathway induces the expression of death effectors and, possibly, ire1α activates apoptosis signalling pathways. this leads to the apoptosis of macrophages, ecs and smcs in advanced lesions. the subsequent unavoidable elicitation of other classes of damps, then, may promote what is now upr-independent vascular inflammation. it is likely this occurs in terms of a crosstalk with the nlrp3 inflammasomes located in macrophages, thereby contributing to the clinical progression of atherosclerosis.45 myocardial infarction in regard to cvds, a myocardial infarction (mi) is a classic example of an atherosclerosis-associated acute disease. its pathophysiology is a typical example of consequences in the course of ischaemia plus postischaemic reperfusion injury (iri), here to the myocardium mediated by a burst of ros—in particular, mitochondria-derived ros.46,47 notably, experimental data suggest that up to 50% of the final infarct size may be related to iri.48 again, damps are predominantly involved in this pathogenetic scenario.49 induced by iri and subsequently recognised by prrbearing cells (for example, neutrophils), damps elicit a sterile inflammatory response following primary coronary artery occlusion. thus, damps such as hmgb1, adenosine triphosphate (atp) and s100a8/ a9 have been shown to be locally released following a mi. recognition of these damps by prrs such as tlrs (e.g. tlr3 and tlr4) trigger innate immune pathways to evoke an inflammatory response that aggravates the primary iri to the myocardium.42,50–53 of note, activation of the nlrp3 inflammasome by damps, such as atp, plays an eminent role in the creation of a myocardial inflammatory response that, as stressed above, increases the infarction size.53–55 moreover, the patient’s long-term outcome after a mi event is influenced by innate immune responses as well. thus, post-mi, a controlled inflammatory/ fibrotic innate immune response can lead to the clearance of injured tissue, angiogenesis and the proliferation of fibroblasts, eventually resulting in scar figure 1: scenario model of vascular damps-induced innate and adaptive immune responses involved in atherogenesis. damps = damage-associated molecular patterns; neoag = neo-antigens (altered-self antigens); oxldl = oxidised low-density lipoprotein; hsp60 = heat shock protein 60; th1 = t helper 1 subset of cd4+ cells; th17 = t helper 17 subset of cd4+ cells; prrs = pattern recognition receptors; il-1r = interleukin-1 receptor; nlrp3 = nucleotide-binding oligomerization domain (nod)-like receptor-containing pyrin domain 3; nf-κb = nuclear factor kappa b; mapks = mitogen-activated protein kinases; proil-1β = prointerleukin-1-beta; il-1β = interleukin-1-beta; tgf-β = transforming growth factor-beta; dc = dendritic cell; mø = macrophage; vsmc = vascular smooth muscle cell; ucm = upregulation of costimulatory molecules; mhc = major histocompatibility complex; ecm = extracellular matrix; tcr = t cell receptor. walter g. land review | e161 formation and infarct healing. however, uncontrolled dysregulation of the response, as shown in mice, and under involvement of the nlrp3 inflammasome may result in damps-driven continued cardiomyocyte loss. this results in the overshooting of fibrosis beyond the limits of the infarcted area, reactive hypertrophy and chamber dilatation. this process is termed adverse cardiac remodelling and is known to lead to functional compromise and heart failure.54,56 metabolic diseases in the case of metabolic diseases, class v damps play a crucial role. as mentioned above, this class of damps can be generated by intracellular stress in nondying cells. this can occur by the slightest metabolic perturbations of the homeostasis within the intra/ extracellular microenvironment. such a scenario can be observed in diseases such as type 2 diabetes (t2d) and metabolic syndrome. additionally, in obesity, as in t2d, primary perturbations of the er provoke a chain of different classes of damps that, via recognition by prr-bearing cells, promote innate immune tissue inflammation resulting in cell/organ dysfunction. that metabolism and innate immunity are linked is perhaps not surprising as both systems involve recognition of exogenous stressors. but proper handling, in general, leads to the maintenance of homeostasis. in fact, recent studies have revealed intriguing molecular associations between these two processes which could give rise to substantial new insights into the pathogenesis of inflammatory diseases, as briefly described below using the example of t2d.57 t2d represents a prototypical innate immune disease where damps-induced, prr-triggered sterile autoinflammatory processes lead to β cell dysfunction and ultimately cell death (pyroptosis).58–61 current notions hold that metabolic insults such as insulin resistance, prolonged hyperglycaemia and increased free fatty acid levels (mechanistically explained by depleting er calcium levels) leads to excessive stimulation of insulin production in the β cells that are associated with protein (proinsulin) accumulation in the er.1 the increasing protein (proinsulin) overload, however, leads to a disruption of er homeostasis which results in the accumulation of newly synthesised unfolded/misfolded proteins in the er lumen, which can be regarded as class v damps.62–64 this scenario elicits a metabolic perturbation of the er, which becomes exhausted, thereby causing er stress that is usually associated with oxidative stress.65,66 as noted in part one of this review, this kind of er stress/oxidative stress activates signalling pathways of the upr whereby the three branches of the upr—perk, ire1α and atf6—sense those accumulating misfolded proteins via their function as recognition receptors.1 consequently, it is the prolonged or excessive function of the β cell upr that provokes a local inflammatory response in terms of a crosstalk with other members of the innate immune system that, via aggravation of insulitis, finally contributes to β cell dysfunction and death in t2d.1,59,63,67 at this point, class i and ii damps come into play by activating, in islet cells and resident islet macrophages, the nlrp3 inflammasome as well as other nlrp3-related and nlrp6-dependent pathways.60,61,68–73 the priming step of nlrp3 inflammasome activation is reportedly believed to be instigated by systemic and/or islet tissue-derived class i damps, including hmgb1, hsp70, fatty acids (palmitate) and islet amyloid polypeptide; the last of these is also discussed as an nlrp3 activator. these damps can stimulate tlr2 and tlr4 expressed in islets and pancreatic macrophages to trigger transcriptional pathways, leading to the activation of nuclear factor kappa β (nf-kβ) and mitogenactivated protein kinases (mapks).59–61,72,74,75 of note, for the first time, upr-derived class ii damps, namely thioredoxin-interacting protein (txnip), have been found to initiate the post-translational activation step of the nlrp3 inflammasome in t2d. in fact, recent evidence suggests that txnip is a critical link between er stress, nlrp3 inflammasome activation, islet inflammation and programmed β cell death. in the course of hyperactivation of the upr to irremediable er stress, txnip becomes rapidly activated by er stressors via induction by the perk and ire1α pathway to trigger interleukin(il)-1β (il1β) production, thereby contributing to local sterile islet inflammation [figure 2].64,75,76 of note, as also discussed elsewhere, intersection and crosstalk between the two tools of the innate immune system, the er stress/upr-signalling and the inflammasome machinery, appear to regulate the quality, intensity and duration of innate immune proinflammatory and proapoptotic responses.77,78 this reflects a new quality of damps’ role in terms of a ‘damps axis’—the consecutively operating ‘damps axis’ composed of class v damps (misfolded proteins in the er) → class i damps (for example, hsps) → class ii damps (txnip) which leads to islet inflammation in t2d and contributes to β cell failure. clearly, future studies are needed to determine if the proposal of such a ‘damps axis’ reflects an innate immune pathway that, in principle, contributes to the pathogenesis of metabolic inflammatory diseases or even neurodegenerative diseases. the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine e162 | squ medical journal, may 2015, volume 15, issue 2 neurodegenerative diseases the phenomenon of er stress in association with inflammasome-mediated inflammation is also encountered in neurodegenerative diseases such as alzheimer’s disease (ad), parkinson’s disease, huntington’s disease, amyotrophic lateral sclerosis and prion-related diseases. all of these have diverse clinical manifestations but all involve, besides neuroinflammation, the scenario of a ‘perturbed proteostasis’, or the accumulation of misfolded pathological proteins. notably, this fact has led to their classification as protein misfolding disorders.79 for example, the hallmark lesions in the pathology of ad, which are extracellular deposits of amyloid β (aβ) peptides derived from cleavage of the amyloid precursor protein (app) as well as neurofibrillary tangles composed of the hyperphosphorylated tau protein, both arise from protein misfolding in the form of oligomers.80 on the other hand, neuroinflammatory processes characterised by the activation of astrocytes and microglia and the release of pro-inflammatory mediator substances are also recognised as aetiologic events in ad evolution. in fact, ad represents a prototypical neurodegenerative disease where damp-induced prr-triggered sterile autoinflammatory processes are associated with neuronal cell dysfunction finally leading to neuron death (apoptosis/pyroptosis). to date, there are several competing hypotheses that attempt to explain which comes first, and what drives what in governing ad pathogenesis, including the aβ cascade, tau protein, oxidative stress and inflammation hypotheses.81 however, according to the danger/injury model, any stress activates the innate immune system which then reacts with an inflammatory response. thus, in the current review article, oxidative stress due to the overproduction of ros caused by a genetically determined age-dependent decline in mitochondrial function is here proposed to be the ‘head of the snake’ of the ad-typical pathologic cascade, phrased here as the ‘mitochondrial cascade hypothesis’. in fact, increasing evidence suggests that dysfunctioning mitochondria mutually cause oxidative stress that is associated with the production of accumulating app-derived aβ peptide and hyperphosphorylated tau proteins.81 in addition, it is the intraneuronal overload of these proteins that, as similarly discussed in t2d, leads to er stress. in fact, er stress with a subsequent upr may also play a direct role in the aetiopathogenesis of sporadic ad.82–84 thus, intraneuronal er stress in ad is well documented and is proposed to be primarily caused by mitochondrial dysfunction-mediated production of ros leading to the accumulation of aβ and tau proteins. a reverse causality is also hypothesised as er stress is primarily caused by accumulating aβ, subsequently promoting oxidative stress [figure 3].81,85–88 further, figure 2: simplified illustration of a scenario modelling the role of damps in upr-mediated and nlrp3 inflammasomepromoted islet inflammation and programmed β cell death in type 2 diabetes mellitus. damps = damage-associated molecular pattern molecules; upr = unfolded protein response; nlrp3 = (nod)-like receptor (nlr)-containing pyrin domain 3; hmgb1 = high-mobility group box 1; er = endoplasmic reticulum; ros = reactive oxygen species; iapp = islet amyloid polypeptide; tlr = toll-like receptor; perk = protein kinase-like eukaryotic initiation factor 2α kinase; ire1α = inositol-requiring transmembrane kinase/endoribonuclease 1α; txnip = thioredoxin-interacting protein; pro-il-1β = pro-interleukin-1β; nf-κβ = nuclear factor kappa β; mpks = mitogen-activated protein kinases; il-1β = interleukin-1β; il-1r = interleukin 1 receptor. walter g. land review | e163 as has been discussed elsewhere, the additional promotion of er stress in ad is provided by ongoing chronic mitochondrial dysfunction, resulting in continuously greater oxidative stress associated with accumulating aβ oligomers, as well as contributing to calcium dyshomeostasis and dna alterations in the form of oxidised mtdna.83,87,89,90 finally, all of these intraneuronally accumulating molecules induce permanent er stress, promoting an upr which reportedly has been activated in postmortem brain samples from ad patients.82–84,91,92 in other words, these er stress-inducing molecules operate as class v damps that are recognised by the three stress sensors: perk, ire1 and atf6. this promotes the upr signalling network. interestingly, a growing body of evidence suggests that damps-induced upr signalling events may actually control the expression of diverse ad-related proteins as well as early steps of app maturation and processing.82,83 again, as has been similarly proposed for t2d, a damps-driven innate immune crosstalk between erstress/upr and nlrp3 activation can be discussed for ad that may contribute to pro-inflammatory and proapoptotic responses, as pathognomonically observed in ad. according to current notions, however, this crosstalk does not take place in a single cell but between two cell types: neurons (er stress-upr) and microglia/ astrocytes (nlrp3 inflammasome) [figure 3]. in fact, inflammasome-dependent pathways appear to play an emerging role in the pathogenesis of neuroinflammation, including ad.93 in particular, the nlrp3 inflammasome has recently gained increasing attention.94 in vivo studies, cell experiments and investigations on transgenic app/ps1 mice have shown that fibrillar aβ, obviously acting as a class ii damp, activates the nlrp3 inflammasome to produce microglial il-1β. phagocytosis of aβ and subsequent lysosomal damage associated with the release of cathepsin b were identified to initiate nlrp3 inflammasome activation promoting neuroinflammation.1,95,96 it is conceivable that stressor apoptosis-derived class i damps may promote priming of the nlrp3 inflammasome as transcriptionally triggered by tlrs. thus, class i damps, such as neuronal stress-induced hsp72 as well as tlrs of the microglia including tlr2, 4 and 9, have been discussed and reported to be involved in ad-associated neuroinflammation.80,97–100 in turn, microglial nlrp3 inflammasome products, such as il-1β, promote ad pathology via contributions to intraneuronal amyloidogenesis and the formation of neurofibrillary tangles. this results in an innate vicious immune circle of pathogenic pathways in ad [figure 3].93,94,96,101 taken all together, a wealth of information has recently emerged that links er stress/upr and figure 3: simplified illustration of a scenario modelling the role of damps in er stress/upr-mediated, nlrp3-promoted neuroinflammation and neuronal cell death in alzheimer’s disease. er = endoplasmic reticulum; upr = unfolded protein response; nlrp3 = nucleotide binding oligomerization domain (nod)-like receptor (nlr)-containing pyrin domain 3; ros = reactive oxygen species; il-1β = interleukin-1β; aβ = amyloid β; tau = tau protein; ca2+ = calcium ion; perk = protein kinase-like eukaryotic initiation factor 2-alpha kinase; ire1α = inositol-requiring transmembrane kinase/endoribonuclease 1α; atf6 = activating transcription factor 6; proil-1β = prointerleukin-1β; tlrs = toll-like receptors; hmgb1 = high-mobility group box 1; hsps = heat shock proteins. the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine e164 | squ medical journal, may 2015, volume 15, issue 2 nlrp3 inflammasome signalling to ad pathogenesis. however, the precise roles of these innate immune pathways in promoting and modulating ad remain elusive. still, ad must be regarded as a complex neurodegenerative disease with an unclear aetiology. malignant diseases: anticancer therapy the role of damps in malignant diseases is a therapeutic one—to attempt to eradicate tumours via the elicitation of damps. notably, the field of anticancer therapy has recently experienced a significant paradigm shift. an expanding body of evidence now indicates that antineoplastic agents do not mediate their therapeutic effects due to their capacity to directly kill malignant cells but rather actively stimulate adaptive anti-tumour immune responses via the induction of damps. in general, apoptotic cell death, as characterised by a morphologically homogenous entity, has been considered essentially non-immunogenic—that is, intrinsically tolerogenic. thus, cancer cells undergoing a kind of physiological apoptosis cause an induction of tolerance towards cancer antigens. the already low immunogenic cancer cells are further cleared up ‘silently’ by phagocytes without evoking inflammation and anti-tumour immunity, a phenomenon called tolerogenic cell death. however, growing evidence indicates that certain chemotherapeutics, radiotherapy and photodynamic therapy can induce a functionally distinct type of apoptosis in cancer cells that is associated with the generation of immunogenicity-promoting damps. notably, these damps assist in initiating an adaptive anti-tumour immune response, which is a phenomenon called immunogenic cell death (icd) induced by icd inducers.102–104 of note, it is the spatiotemporallydefined generation of those damps—the pre-, early-, midor late apoptotic emission of damps—that are sensed by prr-bearing cells of the innate immune system, thereby keeping the immune system alert in a pro-inflammatory state.102,105 key damps generated, trafficked and emitted by dying cancer cells that are found to be crucial for cancer immunogenicity include er-derived calreticulin (crt) and hsp70 exposed at the cell surface. additionally, atp extracellularly secreted in a complex mechanistic manner, nucleic acids and hmgb1 in a special redox modification are released from dying cells. 103,105–107 for example, during icd, secreted extracellular atp (eatp) mainly binds the p2x purinoceptor 7 receptors causing activation of the nlrp3 inflammasome which in turn leads to caspase-1-mediated processing and secretion of active il-1β.1,108 interestingly, the phenomenon described above is also at work in all scenarios of icd; emerging molecular links between ros-based er stress, upr signalling, damps and anti-tumour immunity have recently been revealed.102,105 in fact, the efficient emission of damps from dying cancer cells relies on the joint induction of ros and er stress, which governs the trafficking of those damps. for example, chemotherapy-induced pre-apoptotic crt translocation to the cell surface has been found to be mediated by co-interaction with perk-induced eukaryotic initiation factor 2α phosphorylation, er-togolgi transport and the classical secretory pathway.1 similarly, the pre-apoptotic secretion of the class ii damp eatp is mediated by secretory pathways including the classical and perk-regulated proximal secretory pathway [figure 4].1,97,106,109,110 hence, a robust er stress response, preferably accompanied by or induced by ros production, is a salient biochemical prerequisite for the generation of homeostatic danger signals/class v damps that are sensed by branches of the upr, thereby activating the upr in the scenario of icd. in other words, the induction of as-yet-unknown class v damps, via a complex interplay between er stress and ros production, initiate signalling pathways to emit secondary class i and ii damps such as pre-apoptotic crt, early apoptotic eatp, and mid/late apoptotic hmgb1 and hsps, leading to an icd-induced adaptive anti-tumour immune response [figure 4]. in fact, these class i and ii damps in the company of cancer cell antigens cause maturation of dcs, which ultimately activate an anti-tumour cluster of differentiation (cd) 4+/cd8+ t cell immune response.1,105 indeed, it currently appears that the immunogenic characteristics of dying cells (in the form of apoptotic, autophagic, necroptotic and pyroptotic cell death) are mainly mediated by damps. the damps, via induction of immunostimulatory tumour antigen-presenting dcs, elicit pathways leading to the development of an innate/adaptive immune defense response against tumours. this occurs following icd induction, thereby contributing to the immunemediated eradication of tumours.102,105,111 infectious diseases the dominating role of damps in human diseases is strikingly, but perhaps unexpectedly, reflected by their participation in infectious disorders. in fact, their inflammation-amplifying effect in infectious diseases walter g. land review | e165 is already well known. however, there is growing evidence in support of the notion that damps are the real players in instigating and mounting a vigorous injurious inflammatory response against invading pathogens, resulting in an adaptive anti-pathogen immune response.112–115 in particular, overwhelming evidence in support of this theory has come from recent insights into the function of the mammalian gut’s innate immune system’s ability to discriminate, under the control of dcs and regulated by innate immune prrs, between harmless commensal bacteria to induce immune tolerance and harmful pathogenic bacteria to induce inflammation and immunity.112–115 in other words, commensals, although possessing pamps, do not cause inflammation and adaptive immunity. this is a notion that has led to the creation of the more precise term, microbe-associated molecular patterns (mamps), given the fact that the microbial ligands sensed by prrs are not necessarily confined to pathogens, but are also present in commensal bacteria. in fact, on a molecular level, it appears unlikely that the innate immune system possesses the ability to distinctly discriminate between the myriads of nonpathogenic commensals within the gut microbiota and those that operate as injuring pathogenic microbes. rather, this function may be achieved by recognising pathogen-induced damps in addition to mamps, which do not emit a danger signal per se, that is, by sensing altered patterns of molecules associated with cell/tissue damage caused by pathogenic microbes [figure 5]. in the following section, a few examples of the role of damps in cooperation with mamps in pathogen-induced infectious inflammation are briefly touched upon. as mentioned above, any perturbation of physical or homeostatic conditions within the cell reflects the presence of class v damps. this seems also to be true for cell stress as provoked by viral or bacterial infection, as has been discussed elsewhere.116 for example, virus entry requires membrane and cytoskeletal perturbation/disruption, and both membrane fusion or actin-depolymerising agents alone are able to activate antiviral genes. accordingly, recent studies using virus-like particles have supported this hypothesis.117 in addition, viruses cause cellular stress and change the cellular environment. in particular, viruses provoke oxidative stress or er stress accompanied with oxidative stress, thereby inducing ‘homeostatic’ class v damps. even simpler, both viruses and intracellular bacteria cause cell stress through their replication alone. broad changes to the cellular environment, including host translational inhibition and overexpression of viral proteins could cause er stress associated with the generation of damps. collectively, these damps-induced pathways lead to ampification of prr-triggered antiviral signalling, converging, for example, on the activation of the transcription factor interferon regulatory factor 3.85,116 figure 4: simplified diagram of a schematic illustration of the role of damps in the elicitation of adaptive anti-tumour immune responses. compare also figure 4 in part 1 of this review.1 damps = damage-associated molecular patterns; icd = immunogenic cell death; ros = reactive oxygen species; er = endoplasmic reticulum; crt = calreticulin; hmgb1 = high-mobility group box 1; hsps = heat shock proteins; perk = protein kinase-like eukaryotic initiation factor 2α kinase; upr = unfolded protein response; eatp = extracellular adenosine triphosphate; mdc = mature dendritic cell. the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine e166 | squ medical journal, may 2015, volume 15, issue 2 in addition to er stress-provoked class v damps, class i and ii damps can be exposed or released from bacteriaor virus-infected cells. thus, in studies on mice, the damp, s100a9, was identified as an activator of tlr signalling during influenza a virus (iav) infection.118 s100a9 was found to be released from undamaged iav-infected cells and extracellular s100a9 acted as a critical host-derived molecular pattern to regulate inflammatory response outcomes and disease during infection by exaggerating the pro-inflammatory response, cell death and virus pathogenesis. furthermore, the inflammatory activity of extracellular s100a9 was mediated by activation of the tlr4-myd88 pathway.118 in accordance with these observations in mice are studies on a bacterial high-grade sepsis model in nonhuman primates that allowed quantification of damps and pamps after bacterial challenges of increasing clinical severity.119 these studies allowed a definition for the contribution of bacterial pamps and endogenous damps to clinical organ dysfunction in septic and sterile sirs.119 interestingly, the experiments showed that the degree of clinical severity of the bacterial sepsis reflecting the tissue/organ injury correlated with the concentration of the circulating mtdna damp better than with bacterial dna acting as a pamp. this indicates that damps from septic injury, rather than pamps, determine the clinical course of bacterial sepsis. in particular, the study showed that following a lethal bacterial challenge, bacterial dna only transiently increased while mtdna levels remained elevated until death, suggesting on-going tissue damage long after the bacteria were cleared. it is of note that the clinical relevance of the role of damps, as assessed by findings from this non-human primate sepsis model, has been stressed by a recently performed clinical study showing that the mtdna damp was elevated in the blood of patients suffering from severe sepsis.120 outlook without a doubt, damps will have a considerate impact on routine practical medicine in the future. they could be used as either biomarkers for the proper diagnosis and prognosis of diseases, or as therapeutics in the treatment of tumours or in vaccines for prophylaxis of infections. the use of damps as biomarkers is indeed emerging; thus, in view of the possibility of three different types of injury-induced innate immune responses, clinicians are eager to know at an early stage what pathogenic pathways will be induced by a given injury in a patient.will the injury have a controlled response, leading to smooth wound healing and scar formation? will the injury undergo symptomless infarct healing after a mi? or will the injury result in a catastrophically uncontrolled acute hyperinflammatory/chronic overshooting repara tive response? will sirs follow polytrauma or cardiac dilative remodelling after a mi, leading to figure 5: this model shows commensal microbes expressing mamps which are protected by immunotolerance. pathogenic microbes, expressing mamps and causing injury-induced damps, are eliminated by inflammation and immunity. mamps = microbe-associated molecular patterns; damps = damage-associated molecular pattern molecules; prrs = pattern recognition receptors. walter g. land review | e167 functional compromise and heart failure? indeed, the measurement of damps in terms of biomarkers in such situations will be helpful in assessing the degree of the underlying lesions, ensuring the right diagnosis, making personalised damps-based therapeutic decisions and assigning valid outcome prognoses. for example, interfering with damps-induced innate immune pathways such as nlrp3-mediated pathways may be a good treatment option to prevent sirs or dilative cardiac remodelling. in addition, the induction of damps by special treatment modalities to eradicate tumours is also emerging. in fact, the new insights into the role of damps in successfully eliciting anti-tumour immune responses have opened modern perspectives for the development of treatment modalities aiming to cure cancer. accordingly, it would be desirable to identify class v damps evoked by er stress or other processes such as autophagy that instigate upr signalling in cancer cells leading to exposure and/or secretion of class i and ii damps, thereby eliciting adaptive antitumour t cell immunity. in contrast to such treatment of tumours, namely to promote er stress-associated class v damp formation to instigate an upr, future treatment strategies in metabolic and neurodegenerative diseases should include efforts to interfere with the er stress-associated generation of dyshomeostatic class v damps. in regard to elucidating mechanisms involved in both pathways, future research will have to concentrate on efforts to explore the precise mechanism involved in the network of er stress ↔ generation of class v damps → upr signalling ↔ induction of class i and ii damps. finally, with respect to the detrimental role of damps in amplifying infectious or sterile injury-induced inflammation, another attractive therapeutic modality emerges at the horizon—to develop strategies which specifically inhibit or at least mitigate damps-mediated hyperinflammatory responses without compro mising the anti-pathogen innate/adaptive immune response. in fact, such a possibility may help to improve the clinical management of infectionor injury-evoked hyperinflammatory diseases such as sirs. conclusion this article is part ii of a review addressing the role of damps in human diseases, focusing on traumatic, cardiovascular, metabolic, neurodegenerative, malignant and infectious diseases. available research in this area shows that there is certainly a future role for damps in routine practical medicine as they could be used as either biomarkers for the proper diagnosis and prognosis of diseases, as therapeutics in the treatment of tumours or in vaccines for prophylaxis of infections. using damps as biomarkers would be advantageous in assessing the degree of underlying lesions, ensuring the right diagnosis and assigning valid outcome prognoses. in addition, the ‘dampening’ of damps could also help to improve the clinical management of infectionor injury-evoked hyperinflammatory diseases such as sirs. research has also shown there is a plausible role for damps in eliciting antitumour immune responses, which could lead to groundbreaking developments in treatment modalities aiming to cure cancer. references 1. land wg. the role of damage associated molecular patterns in human diseases: part i: promoting inflammation and immunity. sultan qaboos univ med j 2015; 15:9–21. 2. land wg. emerging role of innate immunity in organ transplantation part ii: potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells. transplant rev (orlando) 2012; 26:73–87. doi: 10.1016/j. trre.2011.02.003. 3. gallo pm, gallucci s. the dendritic cell response to classic, emerging, and homeostatic danger signals: implications for autoimmunity. front immunol 2013; 4:138. doi: 10.3389/ fimmu.2013.00138. 4. wenceslau cf, mccarthy cg, szasz t, spitler k, goulopoulou s, webb rc; working group on damps in cardiovascular disease, et al. mitochondrial damage-associated molecular patterns and vascular function. eur heart j 2014; 35:1172–7. doi: 10.1093/eurheartj/ehu047. 5. zhang m, carroll mc. natural igm-mediated innate autoimmunity: a new target for early intervention of ischemiareperfusion injury. expert opin biol ther 2007: 7:1575–82. doi: 10.1517/14712598.7.10.1575. 6. binder cj. naturally occurring igm antibodies to oxidationspecific epitopes. adv exp med biol 2012; 750:2–13. doi: 10.1007/978-1-4614-3461-0_1. 7. uchida k. natural antibodies as a sensor of electronegative damage-associated molecular patterns (damps). free radic biol med 2014; 72:156–61. doi: 10.1016/j.freeradbiomed.2014.03.016. 8. schröder m, kaufman rj. the mammalian unfolded protein response. annu rev biochem 2005; 74:739–89. doi: 10.1146/ annurev.biochem.73.011303.074134. 9. wang s, kaufman rj. the impact of the unfolded protein response on human disease. j cell biol 2012; 197:857–67. doi: 10.1083/jcb.201110131. 10. kawai t, akira s. the role of pattern-recognition receptors in innate immunity: update on toll-like receptors. nat immunol 2010; 11:373–84. doi: 10.1038/ni.1863. 11. lee ej, park jh. receptor for advanced glycation endproducts (rage), its ligands, and soluble rage: potential biomarkers for diagnosis and therapeutic targets for human renal diseases. genomics inform 2013; 11:224–9. doi: 10.5808/ gi.2013.11.4.224. 12. zhong y, kinio a, saleh m. functions of nod-like receptors in human diseases. front immunol 2013; 4:333. doi: 10.3389/ fimmu.2013.00333. 13. drummond ra, brown gd. signalling c-type lectins in antimicrobial immunity. plos pathog 2013; 9:e1003417. doi: 10.1371/journal.ppat.1003417. the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine e168 | squ medical journal, may 2015, volume 15, issue 2 14. jounai n, kobiyama k, takeshita f, ishii kj. recognition of damage-associated molecular patterns related to nucleic acids during inflammation and vaccination. front cell infect microbiol 2013; 2:168. doi: 10.3389/fcimb.2012.00168. 15. wu j, chen zj. innate immune sensing and signaling of cytosolic nucleic acids. annu rev immunol 2014; 32:461–88. doi: 10.1146/annurev-immunol-032713-120156. 16. unterholzner l. the interferon response to intracellular dna: why so many receptors? immunobiology 2013; 218:1312–21. doi: 10.1016/j.imbio.2013.07.007. 17. ratsimandresy ra, dorfleutner a, stehlik c. an update on pyrin domain-containing pattern recognition receptors: from immunity to pathology. front immunol 2013; 4:440. doi: 10.3389/fimmu.2013.00440. 18. wynn ta, ramalingam tr. mechanisms of fibrosis: therapeutic translation for fibrotic disease. nat med 2012; 18:1028–40. doi: 10.1038/nm.2807. 19. dewar d, moore fa, moore ee, balogh z. postinjury multiple organ failure. injury 2009; 40:912–8. doi: 10.1016/j. injury.2009.05.024. 20. hirsiger s, simmen hp, werner cm, wanner ga, rittirsch d. danger signals activating the immune response after trauma. mediators inflamm 2012; 2012:315941. doi: 10.1155/2012/315941. 21. stoecklein vm, osuka a, lederer ja. trauma equals dangerdamage control by the immune system. j leukoc biol 2012; 92:539–51. doi: 10.1189/jlb.0212072. 22. straino s, di carlo a, mangoni a, de mori r, guerra l, maurelli r, et al. high-mobility group box 1 protein in human and murine skin: involvement in wound healing. j invest dermatol 2008; 128:1545–53. doi: 10.1038/sj.jid.5701212. 23. yang s, xu l, yang t, wang f. high-mobility group box-1 and its role in angiogenesis. j leukoc biol 2014; 95:563–74. doi: 10.1189/jlb.0713412. 24. zampell jc, yan a, avraham t, andrade v, malliaris s, aschen s, et al. temporal and spatial patterns of endogenous danger signal expression after wound healing and in response to lymphedema. am j physiol cell physiol 2011; 300:c1107–21. doi: 10.1152/ajpcell.00378.2010. 25. duffield js, lupher m, thannickal vj, wynn ta. host responses in tissue repair and fibrosis. annu rev pathol 2013; 8:241–76. doi: 10.1146/annurev-pathol-020712-163930. 26. cohen mj, brohi k, calfee cs, rahn p, chesebro bb, christiaans sc, et al. early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. crit care 2009; 13:r174. doi: 10.1186/cc8152. 27. peltz ed, moore ee, eckels pc, damle ss, tsuruta y, johnson jl, et al. hmgb1 is markedly elevated within 6 hours of mechanical trauma in humans. shock 2009; 32:17–22. doi: 10.1097/shk.0b013e3181997173. 28. wang ky, yu gf, zhang zy, huang q, dong xq. plasma high-mobility group box 1 levels and prediction of outcome in patients with traumatic brain injury. clin chim acta 2012; 413:1737–41. doi: 10.1016/j.cca.2012.07.002. 29. zhang q, raoof m, chen y, sumi y, sursal t, junger w, et al. circulating mitochondrial damps cause inflammatory responses to injury. nature 2010; 464:104–7. doi: 10.1038/ nature08780. 30. krysko dv, agostinis p, krysko o, garg ad, bachert c, lambrecht bn, vandenabeele p. emerging role of damageassociated molecular patterns derived from mitochondria in inflammation. trends immunol 2011; 32:157–64. doi: 10.1016/j.it.2011.01.005. 31. zhang q, itagaki k, hauser cj. mitochondrial dna is released by shock and activates neutrophils via p38 map kinase. shock 2010; 34:55–9. doi: 10.1097/shk.0b013e3181cd8c08. 32. walko td 3rd, bola ra, hong jd, au ak, bell mj, kochanek pm, et al. cerebrospinal fluid mitochondrial dna: a novel damp in pediatric traumatic brain injury. shock 2014; 41:499– 503. doi: 10.1097/shk.0000000000000160. 33. simmons jd, lee yl, mulekar s, kuck jl, brevard sb, gonzalez rp, et al. elevated levels of plasma mitochondrial dna damps are linked to clinical outcome in severely injured human subjects. ann surg 2013; 258:591–6. doi: 10.1097/ sla.0b013e3182a4ea46. 34. huber-lang m, kovtun a, ignatius a. the role of complement in trauma and fracture healing. semin immunol 2013; 25:73–8. doi: 10.1016/j.smim.2013.05.006. 35. hansson gk, hermansson a. the immune system in atherosclerosis. nat immunol 2011; 12:204–12. doi: 10.1038/ ni.2001. 36. land wg. chronic allograft dysfunction: a model disorder of innate immunity. biomed j 2013; 36:209–28. doi: 10.4103/23194170.117622. 37. witztum jl, lichtman ah. the influence of innate and adaptive immune responses on atherosclerosis. annu rev pathol 2014; 9:73–102. doi: 10.1146/annurev-pathol-020712-163936. 38. dobrin pb. mechanical factors associated with the development of intimal and medial thickening in vein grafts subjected to arterial pressure. a model of arteries exposed to hypertension. hypertension 1995; 26:38–43. doi: 10.1161/01.hyp.26.1.38. 39. land wg. interaction of damage-associated molecular patterns and pathogen-associated molecular patterns with pattern recognition receptor-bearing vascular cells and myofibroblasts and its consequences for the development of chronic allograft dysfunction. in: land wg, ed. innate alloimmunity. part ii. innate immunity and rejection. ankara, lengerich: başkent university-pabst science publishers, 2011. pp. 518–65. 40. weismann d, binder cj. the innate immune response to products of phospholipid peroxidation. biochim biophys acta 2012; 1818:2465–75. doi: 10.1016/j.bbamem.2012.01.018. 41. de souza aw, westra j, limburg pc, bijl m, kallenberg cg. hmgb1 in vascular diseases: its role in vascular inflammation and atherosclerosis. autoimmun rev 2012; 11:909–17. doi: 10.1016/j.autrev.2012.03.007. 42. schiopu a, cotoi os. s100a8 and s100a9: damps at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. mediators inflamm 2013; 2013:828354. doi: 10.1155/2013/828354. 43. ding z, liu s, wang x, dai y, khaidakov m, deng x, et al. lox-1, mtdna damage and nlrp3 inflammasome activation in macrophages: implications in atherogenesis. cardiovasc res 2014; 103:619–28. doi: 10.1093/cvr/cvu114. 44. zhou ax, tabas i. the upr in atherosclerosis. semin immunopathol 2013; 35:321–32. doi: 10.1007/s00281-0130372-x. 45. menu p, mayor a, zhou r, tardivel a, ichijo h, mori k, tschopp j. er stress activates the nlrp3 inflammasome via an upr-independent pathway. cell death dis 2012; 3:e261. doi: 10.1038/cddis.2011.132. 46. chen yr, zweier jl. cardiac mitochondria and reactive oxygen species generation. circ res 2014; 114:524–37. doi: 10.1161/ circresaha.114.300559. 47. ouyang yb, stary cm, white re, giffard rg. the use of micrornas to modulate redox and immune response to stroke. antioxid redox signal 2015; 22:187–202. doi: 10.1089/ ars.2013.5757. 48. yellon dm, hausenloy dj. myocardial reperfusion injury. n engl j med 2007; 357:1121–35. doi: 10.1056/nejmra071667. 49. de haan jj, smeets mb, pasterkamp g, arslan f. danger signals in the initiation of the inflammatory response after myocardial infarction. mediators inflamm 2013; 2013:206039. doi: 10.1155/2013/206039. walter g. land review | e169 50. ding hs, yang j, chen p, yang j, bo sq, ding jw, et al. the hmgb1-tlr4 axis contributes to myocardial ischemia/ reperfusion injury via regulation of cardiomyocyte apoptosis. gene 2013; 527:389–93. doi: 10.1016/j.gene.2013.05.041. 51. lu c, ren d, wang x, ha t, liu l, lee ej, et al. toll-like receptor 3 plays a role in myocardial infarction and ischemia/ reperfusion injury. biochim biophys acta 2014; 1842:22–31. doi: 1016/j.bbadis.2013.10.006. 52. sandanger ø, ranheim t, vinge le, bliksøen m, alfsnes k, finsen av, et al. the nlrp3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia reperfusion injury. cardiovasc res 2013; 99:164–74. doi: 10.1093/cvr/cvt091. 53. takahashi m. nlrp3 inflammasome as a novel player in myocardial infarction. int heart j 2014; 55:101–5. doi: 10.1536/ ihj.13-388. 54. mezzaroma e, toldo s, farkas d, seropian im, van tassell bw, salloum fn, et al. the inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. proc natl acad sci u s a 2011; 108:19725–30. doi: 10.1073/ pnas.1108586108. 55. mezzaroma e, marchetti c, toldo s. letter by mezzaroma, et al regarding article, "nlrp3 inflammasome as a therapeutic target in myocardial infarction". int heart j 2014; 55:379. doi: 10.1536/ihj.14-140. 56. liaudet l, rosenblatt-velin n. role of innate immunity in cardiac inflammation after myocardial infarction. front biosci (schol ed) 2013; 5:86–104. doi: 10.2741/s359. 57. cheng sc, joosten la, netea mg. the interplay between central metabolism and innate immune responses. cytokine growth factor rev 2014; 25:707‒13. doi: 10.1016/j.cytogfr.2014.06.008. 58. donath my, böni-schnetzler m, ellingsgaard h, ehses ja. islet inflammation impairs the pancreatic beta-cell in type 2 diabetes. physiology (bethesda) 2009; 24:325–31. doi: 10.1152/ physiol.00032.2009. 59. eizirik dl, miani m, cardozo ak. signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. diabetologia 2013; 56:234–41. doi: 10.1007/s00125-012-2762-3. 60. jin c, flavell ra. innate sensors of pathogen and stress: linking inflammation to obesity. j allergy clin immunol 2013; 132:287–94. doi: 10.1016/j.jaci.2013.06.022. 61. westwell-roper c, nackiewicz d, dan m, ehses ja. toll-like receptors and nlrp3 as central regulators of pancreatic islet inflammation in type 2 diabetes. immunol cell biol 2014; 92:314–23. doi: 10.1038/icb.2014.4. 62. hotamisligil gs. endoplasmic reticulum stress and the inflammatory basis of metabolic disease. cell 2010; 140:900– 17. doi: 10.1016/j.cell.2010.02.034. 63. oslowski cm, urano f. the binary switch that controls the life and death decisions of er stressed β cells. curr opin cell biol 2011; 23:207–15. doi: 10.1016/j.ceb.2010.11.005. 64. lerner ag, upton jp, praveen pv, ghosh r, nakagawa y, igbaria a, et al. ire1α induces thioredoxin-interacting protein to activate the nlrp3 inflammasome and promote programmed cell death under irremediable er stress. cell metab 2012; 16:250–64. doi: 10.1016/j.cmet.2012.07.007. 65. landau g, kodali vk, malhotra jd, kaufman rj. detection of oxidative damage in response to protein misfolding in the endoplasmic reticulum. methods enzymol 2013; 526:231–50. doi: 10.1016/b978-0-12-405883-5.00014-4. 66. lu j, holmgren a. the thioredoxin superfamily in oxidative protein folding. antioxid redox signal 2014; 21:457–70. doi: 10.1089/ars.2014.5849. 67. liu yp, zeng l, tian a, bomkamp a, rivera d, gutman d, et al. endoplasmic reticulum stress regulates the innate immunity critical transcription factor irf3. j immunol 2012; 189:4630–9. doi: 10.4049/jimmunol.1102737. 68. lee hm, kim jj, kim hj, shong m, ku bj, jo ek. upregulated nlrp3 inflammasome activation in patients with type 2 diabetes. diabetes 2013; 62:194–204. doi: 10.2337/db12-0420. 69. kim s, joe y, jeong so, zheng m, back sh, park sw, et al. endoplasmic reticulum stress is sufficient for the induction of il-1β production via activation of the nf-κb and inflammasome pathways. innate immun 2014; 20:799–815. doi: 10.1177/1753425913508593. 70. grant rw, dixit vd. mechanisms of disease: inflammasome activation and the development of type 2 diabetes. front immunol 2013; 4:50. doi: 10.3389/fimmu.2013.00050. 71. fernandes-alnemri t, kang s, anderson c, sagara j, fitzgerald ka, alnemri es. cutting edge: tlr signaling licenses irak1 for rapid activation of the nlrp3 inflammasome. j immunol 2013; 191:3995–9. doi: 10.4049/jimmunol.1301681. 72. masters sl. specific inflammasomes in complex diseases. clin immunol 2013; 147:223–8. doi: 10.1016/j.clim.2012.12.006. 73. shenderov k, riteau n, yip r, mayer-barber kd, oland s, hieny s, et al. cutting edge: endoplasmic reticulum stress licenses macrophages to produce mature il-1β in response to tlr4 stimulation through a caspase-8and trif-dependent pathway. j immunol 2014; 192:2029–33. doi: 10.4049/jimmunol.1302549. 74. eguchi k, manabe i, oishi-tanaka y, ohsugi m, kono n, ogata f, et al. saturated fatty acid and tlr signaling link β cell dysfunction and islet inflammation. cell metab 2012; 15:518–33. doi: 10.1016/j.cmet.2012.01.023. 75. oslowski cm, hara t, o'sullivan-murphy b, kanekura k, lu s, hara m, et al. thioredoxininteracting protein mediates er stress-induced β cell death through initiation of the inflammasome. cell metab 2012; 16:265–73. doi: 10.1016/j. cmet.2012.07.005. 76. anthony tg, wek rc. txnip switches tracks toward a terminal upr. cell metab 2012; 16:135–7. doi: 10.1016/j.cmet.2012.07.012. 77. martinon f, glimcher lh. regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. curr opin immunol 2011; 23:35–40. doi: 10.1016/j. coi.2010.10.016. 78. tabas i, ron d. integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. nat cell biol 2011; 13:184–90. doi: 10.1038/ncb0311-184. 79. soto c. unfolding the role of protein misfolding in neurodegenerative diseases. nat rev neurosci 2003; 4:49–60. doi: 10.1038/nrn1007. 80. guillot-sestier mv, town t. innate immunity in alzheimer's disease: a complex affair. cns neurol disord drug targets 2013; 12:593–607. 81. swerdlow rh. alzheimer's disease pathologic cascades: who comes first, what drives what. neurotox res 2012; 22:182–94. doi: 10.1007/s12640-011-9272-9. 82. cornejo vh, hetz c. the unfolded protein response in alzheimer's disease. semin immunopathol 2013; 35:277–92. doi: 10.1007/s00281-013-0373-9. 83. hetz c, mollereau b. disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. nat rev neurosci 2014; 15:233–49. doi: 10.1038/nrn3689. 84. li jq, yu jt, jiang t, tan l. endoplasmic reticulum dysfunction in alzheimer's disease. mol neurobiol 2015; 51:383–95. doi: 10.1007/s12035-014-8695-8. 85. cao ss, kaufman rj. endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. antioxid redox signal 2014; 21:396–413. doi: 10.1089/ars.2014.5851. 86. sutherland gt, chami b, youssef p, witting pk. oxidative stress in alzheimer's disease: primary villain or physiological by-product? redox rep 2013; 18:134–41. doi: 10.1179/1351000213y.0000000052. the role of damage-associated molecular patterns (damps) in human diseases part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine e170 | squ medical journal, may 2015, volume 15, issue 2 87. wang x, wang w, li l, perry g, lee hg, zhu x. oxidative stress and mitochondrial dysfunction in alzheimer's disease. biochim biophys acta 2014; 1842:1240–7. doi: 10.1016/j. bbadis.2013.10.015. 88. chen z, zhong c. oxidative stress in alzheimer's disease. neurosci bull 2014; 30:271–81. doi: 10.1007/s12264-0131423-y. 89. gibson ge, chen hl, xu h, qiu l, xu z, denton tt, shi q. deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to alzheimer's disease-like calcium dysregulation. neurobiol aging 2012; 33:e13–24. doi: 10.1016/j. neurobiolaging.2011.11.003. 90. bradley-whitman ma, timmons md, beckett tl, murphy mp, lynn bc, lovell ma. nucleic acid oxidation: an early feature of alzheimer's disease. j neurochem 2014; 128:294– 304. doi: 10.1111/jnc.12444. 91. hoozemans jj, van haastert es, nijholt da, rozemuller aj, scheper w. activation of the unfolded protein response is an early event in alzheimer's and parkinson's disease. neurodegener dis 2012; 10:212–5. doi: 10.1159/000334536. 92. abisambra jf, jinwal uk, blair lj, o'leary jc 3rd, li q, brady s, et al. tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. j neurosci 2013; 33:9498–507. doi: 10.1523/ jneurosci.5397-12.2013. 93. liu l, chan c. the role of inflammasome in alzheimer's disease. ageing res rev 2014; 15:6–15. doi: 10.1016/j.arr.2013.12.007. 94. tan ms, yu jt, jiang t, zhu xc, tan l. the nlrp3 inflammasome in alzheimer's disease. mol neurobiol 2013; 48:875–82. doi: 10.1007/s12035-013-8475-x. 95. halle a, hornung v, petzold gc, stewart cr, monks bg, reinheckel t, et al. the nalp3 inflammasome is involved in the innate immune response to amyloid-beta. nat immunol 2008; 9:857–65. doi: 10.1038/ni.1636. 96. heneka mt, kummer mp, stutz a, delekate a, schwartz s, saecker a, et al. nlrp3 is activated in alzheimer's disease and contributes to pathology in app/ps1 mice. nature 2013; 493:674–8. doi: 10.1038/nature11729. 97. hamos je, oblas b, pulaski-salo d, welch wj, bole dg, drachman da. expression of heat shock proteins in alzheimer's disease. neurology 1991; 41:345–50. doi: 10.1212/ wnl.41.3.345. 98. salminen a, ojala j, kauppinen a, kaarniranta k, suuronen t. inflammation in alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. prog neurobiol 2009; 87:181–94. 99. liu s, liu y, hao w, wolf l, kiliaan aj, penke b, et al. tlr2 is a primary receptor for alzheimer's amyloid β peptide to trigger neuroinflammatory activation. j immunol 2012; 188:1098–107. doi: 10.4049/jimmunol.1101121. 100. trotta t, porro c, calvello r, panaro ma. biological role of toll-like receptor-4 in the brain. j neuroimmunol 2014; 268:1– 12. doi: 10.1016/j.jneuroim.2014.01.014. 101. shi jq, zhang cc, sun xl, cheng xx, wang jb, zhang yd, et al. antimalarial drug artemisinin extenuates amyloidogenesis and neuroinflammation in appswe/ps1de9 transgenic mice via inhibition of nuclear factor-κb and nlrp3 inflammasome activation. cns neurosci ther 2013; 19:262–8. doi: 10.1111/ cns.12066. 102. kroemer g, galluzzi l, kepp o, zitvogel l. immunogenic cell death in cancer therapy. annu rev immunol 2013; 31:51–72. doi: 10.1146/annurev-immunol-032712-100008. 103. krysko o, løve aaes t, bachert c, vandenabeele p, krysko dv. many faces of damps in cancer therapy. cell death dis 2013; 4:e631. doi: 10.1038/cddis.2013.156. 104. garg ad, dudek am, agostinis p. cancer immunogenicity, danger signals, and damps: what, when, and how? biofactors 2013; 39:355–67. doi: 10.1002/biof.1125. 105. garg ad, martin s, golab j, agostinis p. danger signalling during cancer cell death: origins, plasticity and regulation. cell death differ 2014; 21:26–38. doi: 10.1038/cdd.2013.48. 106. inoue h, tani k. multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments. cell death differ 2014; 21:39–49. doi: 10.1038/cdd.2013.84. 107. dodd k, nance s, quezada m, janke l, morrison jb, williams rt, beere hm. tumorderived inducible heat-shock protein 70 (hsp70) is an essential component of anti-tumor immunity. oncogene 2015. 34:1312–22. doi: 10.1038/onc.2014.63. 108. ghiringhelli f, apetoh l, tesniere a, aymeric l, ma y, ortiz c, et al. activation of the nlrp3 inflammasome in dendritic cells induces il-1beta-dependent adaptive immunity against tumors. nat med 2009; 15:1170–8. doi: 10.1038/nm.2028. 109. panaretakis t, joza n, modjtahedi n, tesniere a, vitale i, durchschlag m, et al. the co-translocation of erp57 and calreticulin determines the immunogenicity of cell death. cell death differ 2008; 15:1499–509. doi: 10.1038/cdd.2008.67. 110. verfaillie t, rubio n, garg ad, bultynck g, rizzuto r, decuypere jp, et al. perk is required at the er-mitochondrial contact sites to convey apoptosis after ros-based er stress. cell death differ 2012; 19:1880–91. doi: 10.1038/cdd.2012.74. 111. hou w, zhang q, yan z, chen r, zeh iii hj, kang r, et al. strange attractors: damps and autophagy link tumor cell death and immunity. cell death dis 2013; 4:e966. doi: 10.1038/ cddis.2013.493. 112. carvalho fa, aitken jd, vijay-kumar m, gewirtz at. tolllike receptor-gut microbiota interactions: perturb at your own risk! annu rev physiol 2012; 74:177. doi: 10.1146/annurevphysiol-020911-153330. 113. kamada n, seo su, chen gy, núñez g. role of the gut microbiota in immunity and inflammatory disease. nat rev immunol 2013; 13:321–35. doi: 10.1038/nri3430. 114. kamdar k, nguyen v, depaolo rw. toll-like receptor signaling and regulation of intestinal immunity. virulence 2013; 4:207– 12. doi: 10.4161/viru.23354. 115. strober w. the impact of the gut microbiome on mucosal inflammation. trends immunol 2013; 34:423–30. doi: 10.1016/j. it.2013.07.001. 116. collins se, mossman kl. danger, diversity and priming in innate antiviral immunity. cytokine growth factor rev 2014; 25:525–31. doi: 10.1016/j.cytogfr.2014.07.002. 117. roberts ap, abaitua f, o'hare p, mcnab d, rixon fj, pasdeloup d. differing roles of inner tegument proteins pul36 and pul37 during entry of herpes simplex virus type 1. j virol 2009; 83:105–16. doi: 10.1128/jvi.01032-08. 118. tsai sy, segovia ja, chang th, morris ir, berton mt, tessier pa, et al. damp molecule s100a9 acts as a molecular pattern to enhance inflammation during influenza a virus infection: role of ddx21-trif-tlr4-myd88 pathway. plos pathog 2014; 10:e1003848. doi: 10.1371/journal.ppat.1003848. 119. sursal t, stearns-kurosawa dj, itagaki k, oh sy, sun s, kurosawa s, hauser cj. plasma bacterial and mitochondrial dna distinguish bacterial sepsis from sterile systemic inflammatory response syndrome and quantify inflammatory tissue injury in nonhuman primates. shock 2013; 39:55–62. doi: 10.1097/shk.0b013e318276f4ca. 120. yamanouchi s, kudo d, yamada m, miyagawa n, furukawa h, kushimoto s. plasma mitochondrial dna levels in patients with trauma and severe sepsis: time course and the association with clinical status. j crit care 2013; 28:1027–31. doi: 10.1016/j. jcrc.2013.05.006. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 241-247, epub. 9th may 13 submitted 27th aug 12 revision reqd. 12th nov 12, revision recd. 9th dec 12 accepted 30th dec 12 departments of 1surgery and 4radiology & molecular imaging, sultan qaboos university hospital; departments of 2human & clinical anatomy and 3pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman note: all authors are members of the breast unit at sultan qaboos uiversity hospital. *corresponding author e-mail: varna@squ.edu.om; seenuvarna@gmail.com التهاب الثدي احلبييب خطط التشخيص و التطبيقات العالجية للمرضى العمانيني عادل اجلراح ، فارنا تارانيكانتي، ريتو لكتاكيا، ا�شماء اجلابري، �شكبال �شوهني امللخ�ص: الهدف: يعترب اإلتهاب الثدي احلبيبي مر�ض حميد ونادر ي�شيب الثدي لأ�شباب جمهوله، وعادة ما يتم ت�شخي�شه ب�شكل خاطىء �رسيريا واإ�شعاعيا على اأنه ورم خبيث يف الثدي، ونتيجة لذلك قد تتم معاجلته ب�شكل خاطىء. وعلى الرغم من عدم وجود طريقة ثابته لعالج هذا املر�ض املزمن، اإل انه قد متت جتربة العالج باجلراحة اأو باإ�شتخدام اأو )كورتيكو�شتريويد( اأو العالج الكيمياوي. وقد ظهرت نتائج مثرية للجدل يف اأغلب الدرا�شات. الطريقة: قد قامت وحدة اأمرا�ض الثدي مب�شت�شفي جامعة ال�شلطان قابو�ض بعمل درا�شة �رسيريه اأنه على ت�شخي�شه مت وقد خبيث، املر�ض اأن والإ�شعاعية ال�رسيرية الفحو�شات اأثبتت حيث الثدي بورم م�شابة مري�شة ع�رسون �شملت اإلتهاب ثدي حبيبي فقط من خالل الت�رسيح الن�شيجي. يف هذه الدرا�شة �شنناق�ض البيانات ال�رسيرية، والت�شخي�ض ومتابعة حالة املر�ض، و فر�ض عودة املر�ض وبيانات املتابعة للمري�شات مع مراجعة املراجع العلمية ذات ال�شلة بهذا املو�شوع. النتائج: اإن غالبية احلالت ملر�شانا هي حالت فردية لأ�شباب غري معروفة وقد ظهرت على �شكل كتلة يف اأحدى الثديني. وقد ظهر لبع�ض املري�شات كتلة يف الثدي مع خراج ي�شاحبه ت�شخم يف العقد اللمفاوية. لقد ثبت اإ�شعاعيا اإ�شابة اأربع من املري�شات بورم خبيث. اأر�شل ال�شديد للزراعة. وكانت النتيجة عدم وجود بكترييا. وقد اأظهر الفح�ض املجهري ال�شفات املميزة للتهاب الثدي احلبيبي. وقد خ�شعت جميع املري�شات للعالج جميع اأظهرت وقد �شهرا(. 33-11( �شهرا 15 ملدة املري�شات متابعة متو�شط كان و اأ�شابيع �شتة ملدة احليوية امل�شادات با�شتخدام املري�شات تقل�ض تام مع عدم ظهور جديد للمر�ض. وقد اأظهرت واحدة من املري�شات رجوع للمر�ض ولكنها ا�شتجابت للعالج مبزيد من امل�شاد احليوي. اخلال�شة: اأن هذه الدرا�شة املو�شعة واملفردة على حالت اإلتهاب الثدي احلبيبي يف عمان قد �شلطت ال�شوء على الأخطاء يف ت�شخي�ض هذا النوع غري الورمي وغري معروف الأ�شباب . وقد اأكدت الدرا�شة على الإ�شتجابة املمتازة للعالج بامل�شادات احليوية لإلتهاب الثدي احلبيبي الذي طاملا اأعترب مر�شا ي�شعب عالجه ومثارا للجدل. مفتاح الكلمات: التهاب الثدي احلبيبي؛ الت�رسيح الن�شيجي؛ املناعة الكيميائية؛ اأ�شعة الثدي؛ الأ�شعة التلفزيونية؛ الت�شخي�ض؛ م�شادات حيوية. abstract: objectives: idiopathic granulomatous mastitis (igm) is a rare benign disorder of the breast whose aetiology is controversial, and is often misdiagnosed clinically and radiologically as mammary malignancy; as a result, it may be incorrectly treated. although no standard treatment is available for this chronic disease, surgery with or without corticosteroids has been tried with controversial results. this study discusses the clinical presentation, diagnosis, management, recurrence, and follow-up data of igm with a review of relevant literature. methods: from 2009–2012, the breast unit at sultan qaboos university hospital, oman, conducted a clinical study on 20 patients with breast lumps. their clinical and radiological examinations were indeterminate, and a diagnosis of granulomatous mastitis was established only by histopathology. results: the majority of the patients were cases of unknown aetiology, who presented with a unilateral breast mass. a few patients had a mass with an abscess, along with axillary lymphadenopathy. a total of 4 patients were suspected of malignancy using radiology. in all patients, sterilised pus was sent for culture and sensitivity. microscopy showed the characteristic pattern of granulomatous inflammation. all patients were treated with antibiotics for 6 weeks, and the mean follow-up period was 15 months (11–33 months). all patients had complete remission with no further recurrence. conclusion: this single largest study of cases of igm in oman highlights the pitfalls in diagnosing this non-neoplastic disease of unknown aetiology and uncertain pathogenesis. it emphasises igm’s excellent response to antibiotics, which is crucial, as igm is a disease which is notoriously difficult and controversial to treat. keywords: breast; granulomatous mastitis; pathology; immunohistochemistry; mammography; ultrasonography; diagnosis; antibiotics; oman. idiopathic granulomatous mastitis diagnostic strategy and therapeutic implications in omani patients adil al-jarrah,1 *varna taranikanti,2 ritu lakhtakia,3 asma al-jabri,1 sukhpal sawhney4 clinical & basic research advances in knowledge idiopathic granulomatous mastitis can mimic a breast carcinoma; it is hence vital, when treating patients, not to ignore the clinical, radiological and histopathological findings of this rare, though benign, challenging disease. idiopathic granulomatous mastitis diagnostic strategy and therapeutic implications in omani patients 242 | squ medical journal, may 2013, volume 13, issue 2 idiopathic granulomatous mastitis (igm) is a rare benign disorder of the breast first described in 1972 by kessler and wolloch.1 most patients are women of childbearing age with a recent history of pregnancy and lactation.2 patients present with a unilateral painful breast lump, with no predilection to a particular quadrant. in most cases, there is no axillary lymph node involvement. although the exact aetiology of igm remains unclear, associations with autoimmune disorders, oral contraceptive use, pregnancy, hyperprolactinaemia and alpha-1 antitrypsin deficiency have been suggested.3 diagnosis of igm is also very challenging as the clinical and radiological features often mimic a carcinoma.4 the definitive diagnosis is usually established by histopathology. although there is no clear clinical consensus regarding the ideal therapeutic management of igm, wide local excision and corticosteroids are commonly used to treat this condition, albeit with a very high local recurrence rate.5 this article discusses the clinical presentation, diagnosis and management of 20 cases of igm at sultan qaboos university hospital (squh), a secondary care teaching hospital in oman. methods a prospective study was undertaken of 20 patients diagnosed with igm and treated in squh from 2009 to 2012. female patients of all ages presenting with clinical features of breast lumps, with or without primary breast abscesses, were included in the study. the diagnosis of igm was based on core biopsy using a bard® disposable 14 gauge core biopsy needle (bard biopsy systems, tempe, arizona, usa). the biopsy was sent for immunohistochemistry, for pancytokeratin and epithelial cadherin (e-cadherin) staining, and the pus was sent for microscopy, culture and antibiotic sensitivity. all patients diagnosed with igm were managed conservatively with systemic antibiotics consisting of augmentin (1 gm twice a day) for 6 weeks and metronidazole (400 mg three times a day) for two weeks. patients who developed secondary breast abscesses had fine needle aspiration (fnac) and a further course of antibiotics for another two weeks. patients with previous surgery or medical treatment for chronic diseases, chronic mastitis, non-granulomatous mastitis, immunocompromised patients, and those allergic to the penicillin group of drugs were excluded from the study. ethical clearance was obtained from the squh ethics committee. the data were entered into a predesigned proforma with the following variables: clinical presentation, radiological imaging, microbiological findings, histopathological assessment, treatment modalities, recurrence, and follow-up. the data were analysed using descriptive statistics. results this study reports 20 patients who presented with a breast lump at the breast unit of sultan qaboos university hospital (squh); all patients underwent triple assessment (clinical, radiological and histopathological) to establish the diagnosis of gm. the clinical characteristics of the cases were as follows: 20 patients presented with a breast lump, ranging from 2−10 cm (mean size 5.6 cm), and manifesting as firm, tender, ill-defined and indurated. the lesions were unilateral. the right breast was affected in 12 cases (60%) and the left breast in 8 cases (40%), with most of the lumps centrally located around the areola. only one patient developed a lump in the contralateral breast 5 months after treatment, and the biopsy from the lump was suggestive of gm. three of the patients (15%) presented with primary breast abscesses and 6 patients (30%) presented with secondary abscesses. a total of 13 of our patients (65%) had axillary lymphadenopathy, where the lymph nodes were firm and fixed with a mean size of 1.8 cm. two patients (10%) had nipple retraction, two patients (10%) presented with nipple discharge the use of broad-spectrum antibiotics may provide gratifying results in selected groups of patients, thus obviating the need for surgery and immunosuppressive drugs. application to patient care this study shows that conservative management of idiopathic granulomatous mastitis can prevent needless surgeries and the use of immunosuppressive agents, thereby decreasing morbidity. adil al-jarrah, varna taranikanti, ritu lakhtakia, asma al-jabri and sukhpal sawhney clinical and basic research | 243 and one patient presented with peau d’orange, a pitted or dimpled appearance of the skin which is characteristic of some types of breast cancer. the majority of our patients were of childbearing age (25–54 years), with a mean age of 37.5 years, and all of them were multiparous (mean = 4 children) and had breastfed their children. two of them (10%) had a history of taking hormonal contraceptives [table 1]. the radiological features of the cases were determined through ultrasound and mammography. an ultrasound was performed in all 20 cases, with both a mammogram and an ultrasound done in the 7 cases (35%) which showed dilated ducts with thick debris, or cystic lesions with debris, or severe inflammatory changes [figure 1]. the lesions ranged from 1–7cm. in 4 of the patients (20%), a hypoechoic mass was seen on the ultrasound. the majority of the masses under mammography did not show any calcification, spiculation or changes involving the skin or nipple. however, in one case some skin-thickening was seen in the region of the skin and areola, and the nipple was retracted. in 4 patients (20%), radiological findings were suspicious of malignancy. several patients were graded using the breast imaging reporting and data system (birads); three patients were graded as bi-rads v and one patient as bi-rads iv.6 the histological and cytological characteristics of the cases were determined by fnac, which was suggestive of igm in 5 patients (25%), and was inconclusive for the others. all patients underwent core biopsy regardless of fnac-confirmed igm. in one patient, core biopsy was inconclusive for igm, so an open biopsy was done which, by cytology, was suggestive of igm. the sensitivity of core biopsy was 95%. all other cases on histopathology showed table 1: clinicopathological characteristics of patients characteristic number of cases 20 (%) age (years) <40 14 (70) >40 6 (30) parity nulliparous 0 multiparous 20 (100) breastfeeding yes 20 (100) no 0 oral contraceptives yes 2 (10) no 18 (90) clinical presentation pain 20 (100) right breast lump 12 (60) left breast lump 8 (40) nipple retraction 2 (10) nipple discharge 2 (10) peau d’orange 1 (5) axillary lymph nodes 13 (65) radiological imaging bi-rad iv 1 (5) bi-rad v 3 (15) microbiology organisms absent 20 (100) histopathology igm 19 (95) indeterminate 1 (5) treatment antibiotics 19 (95) surgery 1 (5) recurrence 0 follow-up <1 year 6 (30) >1 year 14 (70) bi-rads = breast imaging reporting and data system; igm = idiopathic granulomatous mastitis. figure 1: ultrasound showing an irregular mass with both solid and cystic components. idiopathic granulomatous mastitis diagnostic strategy and therapeutic implications in omani patients 244 | squ medical journal, may 2013, volume 13, issue 2 moderate to severe lobule-centric non-caseating granulomatous inflammation, involving most of the lobules in a global fashion, with a sparing of the ducts and the absence of fat necrosis in all of the biopsies. the necrotising granulomas comprised collections of granulocytes (predominantly neutrophils), lymphocytes and plasma cells, palisaded by sheets of epithelioid cells and foreign body giant cells with intact acini, or acini showing destruction [figure 2]. pancytokeratin and e-cadherin staining confirmed the lobular localisation of the granulomas and the progressive destruction of the acini. in one case, the severely inflamed lobule showed ectatic acini containing necrotic inspissated material. two of the cases were suggestive of duct ectasia with gm. none of the cases showed caseating granulomas suggestive of tuberculosis. gram, periodic acidschiff, ziehl-neelsen and giemsa stains did not reveal any microorganisms (bacteria, mycobacteria, fungi and parasites). in the subsequent treatment and follow-up of the cases, there was significant improvement in 17 out of 20 patients (85%) treated conservatively with antibiotics. surgical treatment with wide local excision was performed in one patient where the diagnosis could not be confirmed either radiologically or by core biopsy. two patients were lost to follow-up after the initial treatment. posttreatment response was monitored both clinically and radiologically with a breast ultrasound every 3 months. a total of 6 patients had secondary abscess formation (initially presenting with a hard mass) within the first 3 months, and these patients had fnac of the abscess and were given antibiotics for a further two weeks. after a mean follow-up at 15 months (11−33 months), there was no recurrence in 18 out of the 20 patients and all of them are in complete remission to date. discussion igm is an uncommon clinical condition involving the breast. though the exact aetiology of this condition is not known, an autoimmune reaction to the protein secretions from the mammary ducts is implicated in its causation.7 histologically, igm is characterised by the presence of non-necrotic granulomas confined to breast lobules. as the radiological and clinical features closely mimic a carcinoma in most instances, igm often poses a diagnostic and therapeutic dilemma. igm has been reported to occur commonly in women of reproductive age,8 and this has been seen in our study, wherein the mean age of the patients was 37.4 years. typically, igm presents as a breast mass; pain, skin-thickening, abscess formation, sinus or regional lymphadenopathy may be associated features.8 thus, when women with igm present with a hard unilateral mass, axillary lymphadenopathy, nipple retraction or peau d’orange, igm can be mistaken for a carcinoma.5 in our study, all of the patients presented with a unilateral mass, which was most often situated in the periphery of the breast. only one patient developed a de novo mass in the contralateral breast a few months after the diagnosis of igm in the other breast. however, the de novo mass was suggestive of igm when using core biopsy. similar to other studies, our patients also commonly presented with cellulitis, axillary lymphadenopathy, abscesses, skin-thickening and nipple retraction. mammographic features of igm are essentially nonspecific, with focal asymmetric density being the most common feature.7–11 our study showed that the most common radiological findings observed were dilated ducts with inflammatory changes, with some patients (15%) showing cystic lesions with thick debris. using mammography, 20% of our patients displayed asymmetric diffuse density of fibroglandular tissue and with ultrasound, 20% of the patients showed hypoechoic ill-defined lesions. figure 2: breast lobule under haematoxylin and eosin stain and x 100 magnification, showing expansion due to a granulomatous inflammation. adil al-jarrah, varna taranikanti, ritu lakhtakia, asma al-jabri and sukhpal sawhney clinical and basic research | 245 with these nonspecific clinical and radiological findings, histopathology played a crucial role in diagnosing the cases of granulomatous lobular mastitis. fnac for pus aspiration and culture was done in 6 patients (30%) who presented with an abscess, because igm can mimic an abscess, and fnac gives faster results than core biopsy. in our study, core biopsy was more accurate than fnac in diagnosing igm, as the characteristic features of igm were more obvious with histopathology. as in the study done by larsen et al., core biopsy was more accurate as it showed the tissue architecture.8 core biopsy was diagnostic in 19 patients (95%), and was indeterminate in only one patient. granulomatous lobular mastitis is characterised histologically by the presence of non-necrotising granulomas, usually admixed with neutrophils originating in the breast lobules.8 the other conditions that can mimic igm are mammary duct ectasia and chronic inflammatory conditions like plasma cell mastitis, tuberculosis, histoplasmosis, sarcoidosis and wegener’s granuloma.11 hence, a biopsy is useful to distinguish igm from other granulomatous conditions, as well as establishing malignancy. in our study, the cases were characterised by chronic lobulitis with granulomatous inflammation. the granulomas comprised collections of granulocytes (predominantly polymorphs), palisaded by sheets of epithelioid cells and foreign body giant cells. pancytokeratin and e-cadherin staining confirmed the lobular localisation of the granulomas and the progressive destruction of the acini. the exact causes of igm are still unknown. keller and wolloch proposed an autoimmune pathogenesis.1 it has been postulated that as most women presenting with igm are in the reproductive age group, and since many patients had previously given birth or were lactating at the time of the initial symptoms, a localised immune response to extravasated secretions from lobules may occur. miliauskas et al. reported a case in which they showed that immunohistochemical staining of the lesion contained predominantly stromal t lymphocytes.12 this might be due to a local cellular response to injury as there has been no evidence of systemic immune abnormalities such as the formation of autoantibodies or antigenantibody complexes. furthermore, in our study, no microorganisms (bacteria, mycobacteria, fungi and parasites) were demonstrated by gram, periodic acid-schiff, ziehlneelsen or giemsa stains. going et al. emphasised the importance of use of appropriate swabs and appropriate transport media to recover these organisms.13 miles et al. reported that immediate inoculation into robertson's cooked meat broth has been shown to increase the recovery and range of organisms from wound swabs.14 the treatment of igm remains contentious, and there is no clear clinical consensus regarding the ideal therapeutic management of igm. although several studies have reported different approaches for the management of igm, many of these treatment algorithms were formulated without a definitive initial diagnosis.15 the treatment plan for igm followed at most centres is to perform a complete resection or an open biopsy with corticosteroid therapy.16 however, surgery can be complicated by abscess formation, fistulas, scarring and chronic suppuration. chronic mastitis after excisional biopsies has also been reported.17 imoto et al. followed 29 patients with igm, of which 11 (38%) showed relapse, and thus patients must be followed carefully after treatment by excision.18 bani-hani et al. reported 24 patients with histologically-confirmed igm who were treated by wide local excision. their analysis of patients over a period of 8 years showed a 16% recurrence after a mean follow-up period of 31.2 months.11 as some studies have implicated an immune aetiology for igm, many centres have used prednisolone as a common regimen especially with clinically advanced diseases or more severe symptoms. however, high-dose steroids, in addition to their potential side effects, have been linked with a recurrence rate as high as 50%, as seen in one study by azlina et al.19 immunosuppressive agents, like methotrexate or azathioprine, have also been utilised, with variable responses, in cases refractory to the above therapies.20–21 akbulut et al. retrospectively analysed 541 igm cases treated with steroids and/or methotrexate between 1972 and 2010. they found a high recurrence rate in patients using steroids, and also the occurrence of adverse side effects such as steroid-induced diabetes mellitus. however, in 4 cases exhibiting recurrence, when methotrexate was used instead of steroids, it was found to be more effective in preventing idiopathic granulomatous mastitis diagnostic strategy and therapeutic implications in omani patients 246 | squ medical journal, may 2013, volume 13, issue 2 complications, resolving the inflammatory process, and limiting the side effects of corticosteroids.22 conservative management has been tried by various centres due to the variable responses to different therapeutic strategies. in a study by lai et al., 8 patients were treated conservatively, with no surgery performed or medication given, and were monitored with close regular surveillance. a total of 50% of the patients had spontaneous complete resolution of disease after a mean interval of 14.5 months.23 based on the clinical presentation of the cases and the presence of acute inflammatory cells, the breast unit at squh developed a diagnostic and treatment algorithm by conservatively managing histopathologically proven cases of igm [figure 3]. with this mode of management, all women with igm showed improvement, excluding the two patients who were lost to follow-up. based on the results of our study, the breast unit team at squh implemented the following treatment plan for women diagnosed with granulomatous lobular mastitis. initially, a course of antibiotics is prescribed for 6 weeks, with assessment of the patient every 3 months. if there is recurrence, a second course of antibiotics is given. if treatment fails, or if minimal or no improvement is seen after the second course of antibiotics, other options are considered. at squh, patients are examined by the breast surgeon at least every two weeks for the first month, then on a monthly basis for the next 3 months. a follow-up ultrasound is performed 6 months after the symptoms have resolved. thereafter, if the patient is asymptomatic, and imaging does not show any recurrence, the patient is advised to undergo annual screening following the national screening guidelines.24 conclusion igm is an enigma because of its nonspecific clinical and radiological characteristics, and poses a diagnostic and therapeutic dilemma to the treating surgeon. nevertheless, the ultimate diagnosis of this chronic inflammatory disease rests on core biopsy. in our series, treatment with antibiotics produced excellent responses and patients did not require any other forms of treatment. as the course of the disease is unpredictable with a strong tendency towards persistence and recurrence, a conservative approach seems to be the best option in the management of this disease. greater awareness of the rare entity of igm is mandatory to avoid unnecessary mastectomies and to reduce morbidity among patients. references 1. kessler e, wolloch y. granulomatous mastitis: a lesion clinically simulating carcinoma. am j clin pathol 1972; 58:642–6. 2. davies jd, burton pa. post-partum lobular granulomatous mastitis. j clin pathol 1983; 36:363. 3. rowe ph. granulomatous mastitis associated with a pituitary prolactinoma. br j clin pract 1984; 38:32– 4. 4. milward tm, gough mh. granulomatous lesions in the breast presenting as carcinoma. surg gynaecol obstet 1970; 130:478–82. 5. dehertogh da, rossof ah, harris aa, economou sg. prednisone management of granulomatous mastitis. n eng j med 1980; 308:799–800. figure 3: diagnostic and therapeutic algorithm for patients suspected of granulomatous mastitis at sultan qaboos university hospital, oman. gm = granulomatous mastitis. adil al-jarrah, varna taranikanti, ritu lakhtakia, asma al-jabri and sukhpal sawhney clinical and basic research | 247 6. breast imaging reporting and data system (birads). from: www.birads.at/info.html accessed: jul 2012. 7. han bk, choe yh, park jm, moon wk, ko yh, yang jh, et al. granulomatous mastitis: mammographic and sonographic appearances. ajr 1999; 173:317– 20. 8. larsen ljh, peyvandi b, klipfel n, grant e, iyengar g. granulomatous lobular mastitis: imaging, diagnosis, and treatment. ajr am j roentgenol 2009; 193:574–81. 9. yilmaz e, lebe b, usal c, balci p. mammographic and sonographic findings in the diagnosis of idiopathic granulomatous mastitis. eur radiol 2001; 11:2236– 40. 10. lee jh, oh kk, kim ek, kwack ks, jung wh, lee hk. radiologic and clinical features of idiopathic granulomatous lobular mastitis mimicking advanced breast cancer. yonsei med j 2006; 47:78–84. 11. bani-hani ke, yaghan rj, matalka ii, shatnawi nj. idiopathic granulomatous mastitis: time to avoid unnecessary mastectomies. breast j 2004; 10:318– 22. 12. miliauskas jr, pieterse as, williams rs. granulomatous lobular mastitis. aust n z j surg 1995; 65:139–41. 13. going jj, anderson tj, wilkinson s, chetty u. granulomatous lobular mastitis. j clin pathol 1987; 40:535–40. 14. miles rs, hood j, bundred nj, jeffrey rj, davies gc, collee jg. the role of robertson's cooked-meat broth in the bacteriological evaluation of surgical specimens. j med microbiol 1985; 20:373–8. 15. tuli r, o'hara bj, hines j, rosenberg al. idiopathic granulomatous mastitis masquerading as carcinoma of the breast: a case report and review of the literature. int semin surg oncol 2007; 4:22. 16. salam im, alhomsi mf, daniel mf, sim aj. diagnosis and treatment of granulomatous mastitis. br j surg 1995; 82:214. 17. asoglu o, ozmen v, karanlik h, tunaci m, cabioglu n, igci a, et al. feasibility of surgical management in patients with granulomatous mastitis. breast j 2005; 11:108–14. 18. imoto s, kitaya t, kodama t, hasebe t, mukai k. idiopathic granulomatous mastitis: case report and review of the literature. jpn j clin oncol 2002; 27:274–7. 19. azlina af, ariza z, arni t, hisham an: chronic granulomatous mastitis: diagnostic and therapeutic considerations. world j surg 2003; 27:515–18. 20. kim j, tymms ke, buckingham jm: methotrexate in the management of granulomatous mastitis. aust n z j surg 2003; 73:247–9. 21. raj n, macmillan rd, ellis io, deighton cm. rheumatologists and breasts: immunosuppressive therapy for granulomatous mastitis. rheumatology (oxford) 2004; 43:1055–6. 22. akbulut s, arikanoglu z, sogutcu n, basbug m, yeniaras e, yagmur y. is methotrexate an acceptable treatment in the management of idiopathic granulomatous mastitis? arch gynecol obstet 2011; 284:1189–95. 23. lai ec, chan wc, ma tk, tang ap, poon cs, leong ht. the role of conservative treatment in idiopathic granulomatous mastitis. breast j 2005; 11:454–6. 24. ministry of health oman and united nations population fund. early detection & screening for breat cancer. 1st ed. muscat: directorate general of health affairs, ministry of health, 2010. إجتاهات وحمددات الرضاعة الطبيعية التأثريات و التوصيات لدول جملس التعاون اخلليجي ن�رشين النعيمي، جودفري كاتندا، جودي اأروالبان abstract: optimal breastfeeding practices entail the early initiation of breastfeeding soon after delivery of the baby, exclusive breastfeeding for the first six months of life and the continuation of breastfeeding complemented by solid food up until two years of age. breastfeeding has wide-ranging health benefits for both the mother and her child; however, many factors contribute to low rates of exclusive breastfeeding. this article highlights the benefits of optimal breastfeeding as well as trends and determinants associated with breastfeeding both worldwide and in gulf cooperation council (gcc) countries. strategies to optimise breastfeeding and overcome breastfeeding barriers in the gcc region are recommended, including community health and education programmes and ‘baby-friendly’ hospital initiatives. advocates of breastfeeding are needed at the national, community and family levels. in addition, more systematic research should be conducted to examine breastfeeding practices and the best strategies to promote breastfeeding in this region. keywords: breastfeeding; trends; maternal-child health services; health planning recommendations; arab world. الطبيعية والر�ساعة الوالدة، بعد مبا�رشة الطبيعية بالر�ساعة املبكر بالبدء املثلى الطبيعية الر�ساعة ممار�سات تتمثل امللخ�ص: احل�رشية خالل االأ�سهر ال�ستة االأوىل من احلياة، مع ا�ستمرارية توا�سل الر�ساعة الطبيعية التي تكملها االأغذية ال�سلبة حتى �سن �سنتني. وعلى الرغم من الفوائد ال�سحية وا�سعة النطاق لكل من االأم وطفلها املرتبطة بالر�ساعة الطبيعية اال اأن هنالك العديد من العوامل التي واملحددات املثلى الطبيعية الر�ساعة فوائد على ال�سوء املقال هذا وي�سلط احل�رشية. الطبيعية الر�ساعة معدالت انخفا�س يف ت�سهم املرتبطة بها يف جميع اأنحاء العامل ويف دول جمل�س التعاون اخلليجي. وتو�سي باال�سرتاتيجيات الالزمة لتح�سني الر�ساعة الطبيعية للطفل. ال�سديقة امل�ست�سفى ومبادرات ال�سحي التثقيف برامج مثل العربي، اخلليج منطقة يف فيها املرتبطة املعوقات على والتغلب ان دعم الر�ساعة الطبيعية مطلوب على امل�ستوى الوطني واملجتمعي واالأ�رشي وهنالك حاجة الأعمال بحثية تهدف لدرا�سة ممار�سات الر�ساعة الطبيعية ودرا�سة اأف�سل اال�سرتاتيجيات الالزمة لتعزيزها يف املنطقة. الكلمات املفتاحية: الر�ساعة الطبيعية؛ االجتاهات؛ خدمات �سحة االأم والطفل؛ تو�سيات التخطيط ال�سحي؛ العامل العربي. breastfeeding trends and determinants implications and recommendations for gulf cooperation council countries *nisreen al-nuaimi,1 godfrey katende,2 judie arulappan1 special contribution sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e155–161, epub. 20 jun 17 submitted 20 oct 16 revisions req. 8 dec 16, 29 jan & 23 feb 17; revisions recd. 6 jan, 14 feb & 6 mar 17 accepted 9 mar 17 departments of 1maternal & child health and 2adult health & critical care, college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mail: nalnuaimi@squ.edu.om doi: 10.18295/squmj.2016.17.02.004 breast milk is a natural, renewable and complete source of food during the first six months of life, fulfilling all of an infant’s nutri tional requirements.1 the united nations international children’s emergency fund (unicef) defines optimal breastfeeding as the practice of exclusively breastfeeding during the first six months, followed by breastfeeding with the appropriate addition of complementary food thereafter up until two years of age.2 the early initiation of breastfeeding—defined as breastfeeding within an hour of delivery—is considered an indicator of best practice.3 the beneficial effects of breastfeeding on maternal and child health are well recognised. due to its excellent immunological and anti-inflammatory properties, breast milk can protect both mothers and children against various illnesses and diseases.4 in addition, breastfeeding also improves bonding between a mother and her newborn as well as avoiding the cost of purchasing infant formula.5,6 by 2025, the world health organization (who) aims to achieve a 50% universal exclusive breastfeeding rate which will significantly reduce maternal, neonatal, infant and childhood mortality.7–9 according to unicef, improving breastfeeding practices worldwide could save the lives of an estimated 1.5 million children annually.2 furthermore, the risk of mortality before the age of five years is expected to decrease from 13% to 11.6% if optimal breastfeeding practices are followed.10 while both the who and unicef have made tremendous efforts to encourage universal exclusive breastfeeding, this goal has been achieved only at a suboptimal level, with some children not breastfed at all.2,7 breastfeeding trends and determinants implications and recommendations for gulf cooperation council countries e156 | squ medical journal, may 2017, volume 17, issue 2 a recent report indicated that the rate of exclusive breastfeeding among infants of 4–6 months of age increased from 32% in 1995 to 40% in 2013.11 however, as per rates reported by unicef for the middle east in 2016, exclusive breastfeeding rates for infants at 6 months of age in this region have declined.12 this article aimed to highlight the benefits of exclusive breastfeeding, analyse existing breastfeeding trends and determinants and identify strategies and recommendations to improve breastfeeding rates in gulf cooperation council (gcc) countries. benefits of optimal breastfeeding breast milk is the ideal source of nutrition for infants, as it contains the appropriate proportion and quantity of vitamins, protein and fat.1 a recent meta-analysis indicated that breastfeeding protects infants against diarrhoea, otitis media and respiratory infections, thus reducing related hospital admissions.9 moreover, intelligence quotient (iq) has been found to correlate positively with breastfeeding practices for both mother and child.9 a 30-year prospective birth cohort study conducted in brazil also showed a positive correlation between mean breastfeeding duration and iq and educational attainment; in addition, breastfeeding was to found to improve an infant’s immune system as well as have a significant positive influence on long-term economic and social outcomes.13 in the gcc region, a case-control study conducted in 2012 reported that autism spectrum disorder (asd) was significantly correlated with suboptimal breastfeeding practices in oman.14 the risk of asd was related to the late initiation of breastfeeding and insufficient intake of colostrum, whereas longer periods of continued breastfeeding lowered the risk of asd. moreover, the risk of asd was linked with premature delivery; this may be because premature babies are often separated from their mothers and may therefore not receive sufficient quantities of breast milk.14 for breastfeeding mothers, both exclusive and continued breastfeeding practices are strongly linked with maternal amenorrhoea, which is considered a natural birth spacing method.9 in addition, mothers who do not breastfeed have an increased risk of premenopausal breast cancer, ovarian cancer, retained gestational weight gain, type 2 diabetes, myocardial infarctions and metabolic syndrome.15 figure 1 shows the extent to which breastfeeding can reduce the risk of various maternal and child health problems.9 breastfeeding trends in gulf cooperation council countries in the middle east, universal breastfeeding rates are low and do not achieve the target set by the who, with breastfeeding rates decreasing from 30% in 1990 to 26% in 2006.10,14 in saudi arabia, a study reported that exclusive breastfeeding practices were suboptimal in abha city, despite most participants demonstrating either good (55.3%) or excellent (30.7%) levels of knowledge regarding breastfeeding practices and 62.2% reporting positive attitudes towards breastfeeding; in contrast, unsatisfactory levels of knowledge were found in only 14% of mothers overall.16 in bahrain, exclusive and continued breastfeeding rates in 2010 among children <6 and 20–23 months old were 34% and 41%, respectively.17 moreover, two-thirds of bahraini mothers supplemented breastfeeding with other forms of nutrition before their babies were six months old.17 in oman, breastfeeding rates are reportedly still suboptimal despite implementation of a ‘baby-friendly’ hospital initiative (bfhi) in 1990 to promote exclusive breastfeeding for the first six months of a baby’s life.18 the rate of exclusive breastfeeding at birth was 97.5% in 2005 but decreased to 94.9% in 2012; in addition, only 31.3% of children were exclusively breastfed at six months in 2005, with this rate decreasing to 9.1% in 2012. overall, the majority of omani children received infant formula at six months of age in both 2005 and 2012 (60.7% and 90.1%, respectively).18 in kuwait, exclusive breastfeeding rates at birth and six months of age in 2011 were 81.8% and 15.2%, respectively.19 overall, 45.3% of women reported food supplementation at six months, although the rate of continued breastfeeding at 12–15 months was not reported. the average duration of breastfeeding was 2.7 months.19 figure 1: chart showing percentage reductions attributable to breastfeeding of various maternal and child health problems.9 nisreen al-nuaimi, godfrey katende and judie arulappan special contribution | e157 in the united arab emirates (uae), mixed feeding and complementary food and fluid addition to breastfeeding is a common practice reported to start as early as one month after birth.20 in qatar, a cross-sectional study conducted among 770 mothers with children under 24 months old indicated that breastfeeding practices did not align with the recommendations of the who and unicef.21 while 49.9% of infants were reportedly breastfed for up to one year after birth, the percentage of those breastfed up until two years dropped to 45.4%.21 figure 2 shows recent breastfeeding trends in gcc countries based on data reported by the unicef.12 global determinants of breastfeeding practices the who has identified several factors which contribute to a low rate of universal exclusive breastfeeding, including sociocultural, health systemrelated, marketing, environmental and knowledgerelated factors.5 common inaccurate societal beliefs cast doubt on the nutritional sufficiency of breast milk and falsely indicate the need for additional supplementation of liquids and solids while a baby is being breastfed. moreover, existing policies at hospitals and birth centres may be inadequate and perceived as neither supportive nor encouraging of breastfeeding.5 there is also a shortage of adequately trained health professionals to aid and advocate for breastfeeding. increased marketing and promotion of high-quality breast milk substitutes and non-supportive work environments and employment conditions have also been observed to negatively impact breast feeding rates.5,22 similarly, rates of early and continued breastfeeding are significantly affected by individual attributes of the mother and infant and the mother-infant relationship in general.22 method of delivery, parity, alcohol consumption, breast-related problems (i.e. breast engorgement or nipple soreness), occupation and education level are considered influential maternal factors affecting successful breastfeeding.23 overall, members of the global community at all levels—including individuals, families, healthcare professionals and policy-makers—lack appropriate knowledge of the risks and negative outcomes of suboptimal breastfeeding practices.22 determinants of breastfeeding practices in gulf cooperation council countries in saudi arabia, an analysis of 70 studies revealed that increased maternal age, low levels of education, rural residency, low income, increased parity and nonadherence to contraceptive use were contributing factors to a higher rate and longer duration of breastfeeding, whereas insufficient breast milk production, breastfeeding problems, sickness and getting pregnant again were identified as common barriers to breastfeeding.24 another study among saudi arabian employed mothers who had undergone caesarean deliveries and did not receive breastfeeding education noted that the main factors which doubled the risk of failing to breastfeed were work-related problems, insufficient breast milk and maternal and neonatal health problems.16 in oman, suboptimal breastfeeding practices have reportedly been linked to a lack of continuity of support, inadequate healthcare staff training/education and increased marketing of infant formula.18,25 fortunately, in order to revitalise the bfhi campaign, oman has recently adopted the who international guidelines for the marketing of breast milk substitutes.18,26 in the uae, maternal age, education level and parity, the practice of ‘rooming-in’ (i.e. placing the infant with the mother immediately after delivery), nipple problems and the use of contraceptives were significantly related to breastfeeding practices.20 furthermore, getting pregnant again, insufficient breast milk and selfweaning on the part of the infant were reported as the main reasons for breastfeeding cessation.20 the uae figure 2: chart showing breastfeeding trends in gulf cooperation council countries according to recent data* reported by the united international children’s emergency fund.12 uae = united arab emirates. *data sourced from the following years: 2014 (oman), 2012 (qatar), 1996 (saudi arabia and kuwait; national surveys) and 1995 (uae and bahrain; national surveys). breastfeeding trends and determinants implications and recommendations for gulf cooperation council countries e158 | squ medical journal, may 2017, volume 17, issue 2 ministry of health (moh) recommends six months of exclusive breastfeeding; however, to achieve this target, breastfeeding promotion strategies and programmes need to be implemented and supported.20 in kuwait, identified determinants of suboptimal breastfeeding rates include a lack of/inadequate antenatal breastfeeding education and support polices, with only three out of 11 non-governmental hospitals expressing an interest in bfhi practices and none as yet implementing any bfhi activities or procedures.19 women have also reported a lack of postnatal breastfeeding support at the community level; this finding is not surprising as there are only 35 certified lactation specialists currently available in kuwait.19 decreased rates of breastfeeding in both kuwait and bahrain have also been associated with the early addition of complementary food.17,19 in addition, a short maternity leave period of 45 days was reported by bahraini mothers to be the main factor inhibiting breastfeeding intentions after giving birth.17 table 1 summarises the main determinants of breastfeeding practices in gcc countries.16–21,24,25 global strategies and recommendations to promote breastfeeding in 2014, the who published recommendations to promote breastfeeding with the aim of achieving a target universal exclusive breastfeeding rate of 50% by 2025.7 all hospitals and birth centres are encouraged to provide the maximum level of breastfeeding support possible, for example by implementing optimal bfhi breastfeeding policies, hiring specialised healthcare professionals and, at the institutional level, maintaining breastfeeding certifications and birth records.7 these recommendations are important to ensure continuity of support for breastfeeding mothers during the postnatal period. another recommendation is the implementation of community projects and special strategies under the supervision of community leaders to support breastfeeding mothers at home once they have been discharged after delivery.7 as such, effective channels of communication and the media should be utilised to increase community knowledge and awareness of breastfeeding. individualised and group counselling by a trained health professional would also be helpful in improving rates of exclusive breastfeeding.7 the who also recommends strict adherence to marketing legislation for breast milk substitutes, with any violations to be observed and controlled by legal regulations.7,26 governmentimplemented improvements in working conditions are highly recommended to encourage breastfeeding; for example, by ensuring a mandatory six-month paid maternity leave period for all new mothers.7 finally, the who recommends additional training for healthcare professionals focusing on problem-solving abilities and efficient counselling of breastfeeding mothers so as to promote optimal breastfeeding practices.7 according to joint who and unicef guidelines, all hospitals and birthing facilities should have a written breastfeeding policy which should be regularly distributed to all healthcare staff.27 in addition, special training sessions for healthcare personnel should be routinely implemented to enhance the skills necessary to implement the policy.27 pregnant women should be informed of the benefits of breastfeeding and new mothers encouraged to initiate early breastfeeding, for example by allowing ‘rooming-in’ practices.22,27 in addition, practical education regarding breastfeeding should also be provided, instructing mothers on how to continue breastfeeding in a variety of scenarios (e.g. after discharge, on demand or if they have been separated from their infant) and reminding them not to give their infants pacifiers or supplement breast milk with any other kind of food or drink unless medically advised to do so.27 the recommendations also stress the need to maintain hospital links with breastfeeding support groups to which new mothers can be referred after discharge.27 strategies to promote breastfeeding in gulf cooperation council countries according to the available literature, breastfeeding rates in gcc countries are suboptimal and achievement table 1: breastfeeding determinants in gulf cooperation council countries16–21,24,25 high breastfeeding rates low breastfeeding rates •increased maternal age •low education level •rural residency •low income level •multiparity •lack of use of contraceptives •employment •marketing of breast milk substitutes •inadequate teaching, support and guidance from healthcare providers •inadequate breast milk •health problems and sickness (both maternal and infant) •breastfeeding problems •getting pregnant again •contraceptive use •shyness/reticence over breastfeeding in public places •early addition of complementary food before six months of age nisreen al-nuaimi, godfrey katende and judie arulappan special contribution | e159 of the 50% universal exclusive breastfeeding goal set by the who poses a challenge in this region.7,10,12 breastfeeding practices in gcc countries can be improved by adopting universal breastfeeding recomm endations and integrating and implementing them using breastfeeding interventions and programmes with the support of policy-makers and community stakeholders. in order to achieve an increase in exclusive breastfeeding rates, it is essential that gcc countries look to one another’s experiences with breastfeeding promotion strategies.28 this regional collaboration should then be maintained while planning and implementing country-specific breastfeeding community programmes and initiatives. in saudi arabia, the world breastfeeding trends initiative has recommended government-led organisation of breastfeeding awareness campaigns targeting different populations in the community as well as the integration of breastfeeding education in the curricula of secondary schools and universities.29 breastfeeding counselling was also advised, as well as the creation of breastfeeding-conducive spaces in public and at work to increase social acceptance of breastfeeding, perhaps through the establishment of ‘breastfeeding rooms’. moreover, saudi arabian policymakers were encouraged to increase the number of days of paid maternity leave for new mothers and to introduce legislative controls over the marketing of formula/breast milk substitutes.30 additionally, community awareness should be raised on the benefits of breast milk as compared to breast milk substitutes. in oman, the moh has set an exclusive breastfeeding target rate of >90% to be achieved by 2025.18 in pursuit of this goal, it has been recommended that cultural and social barriers to breastfeeding specific to oman should be taken into consideration during development and implementation of community breastfeeding programmes.28 for such programmes to be successful, researchers have stressed the importance of promoting awareness and knowledge of breastfeeding policies among omani healthcare providers.28 in addition, the omani moh aims to introduce marketing regulations for formula and breast milk substitutes during the planning of a future exclusive breastfeeding initiative.18 in 2006, the bahraini breastfeeding committee reported that the national decree implemented in 1995 regarding the marketing of breast milk substitutes had been violated.17,26 the bahraini moh subsequently took necessary action by ensuring all health centres were committed to the decree and increasing awareness of the importance of breastfeeding among healthcare practitioners by conducting lectures and regular meetings.17 this approach can be adopted by other gcc countries to control adherence to the who international guidelines for the marketing of breast milk substitutes.26 in the uae, a community intervention plan has been identified as essential to promote breastfeeding in the country.20 similarly, a health policy revision has been recommended in kuwait to enable adequate breastfeeding training for healthcare providers, as well as to discourage use of formula feeding at hospitals.30 in addition, the quality of postnatal education should be improved, with breastfeeding support maintained after delivery and the current maternity leave period of 18 weeks extended so as to facilitate maternal commitment to continued breastfeeding practices.19 another recommendation for improving exclusive breastfeeding rates in the gcc region is the promotion of bfhi-certified hospitals. in 2002, only six of 28 hospitals and birth institutions in bahrain were certified as ‘baby-friendly’; recommendations were subsequently made to increase the number of bfhi hospitals in the ountry.17 similarly, only six hospitals in the uae have embraced bfhi policies.31 as in bahrain, emirati policy-makers have been encouraged to commit to universal breastfeeding recommendations by setting up a comprehensive national breastfeeding promotion plan.20 implementation of bfhi policies needs to be encouraged throughout the gcc region. recommendations for future research in gulf cooperation council countries there are several areas of potential research which should be conducted in the gcc region, such as the actual economic cost of suboptimal breastfeeding practices at the individual and national levels. in addition, there is currently a lack of comprehensive information regarding the determinants and indicators of breastfeeding practices in gcc countries. the majority of the current data describing breastfeeding practices and its determinants have not recently been updated and originate from individualised countryspecific studies with a wide variety of methodologies. in addition, there is a lack of knowledge regarding detailed applications of recommendations to improve breastfeeding practices in gcc countries. further in-depth cohort-driven research is needed to explore breastfeeding practices in this region.24 future research should aim to identify variables associated with exclusive breastfeeding and assess knowledge among members of the public and health professionals regarding the benefits of breastfeeding and the risks associated with breast milk substitutes. breastfeeding trends and determinants implications and recommendations for gulf cooperation council countries e160 | squ medical journal, may 2017, volume 17, issue 2 moreover, more studies are necessary to describe actual breastfeeding practices in gcc countries in relation to international recommendations. in this regard, an assessment of common contributing barriers and facilitators of exclusive breastfeeding practices would be of great benefit. in addition, special attention should be given to correlations between infant morbidity and mortality rates and breastfeeding practices. national surveys should be carried out on a regular basis to provide current updates of indicators of breastfeeding and infant feeding statuses in each gcc country. conclusion exclusive breastfeeding for the first six months of life has wide-ranging health benefits for both the infant and mother. however, universal breastfeeding rates are suboptimal in gcc countries and many barriers to breastfeeding exist, including individual factors (e.g. maternal age, education level and getting pregnant again), sociocultural factors (e.g. negative perceptions of insufficient breast milk or breastfeeding in public), healthcare-related factors (e.g. a lack of well-trained specialists to provide breastfeeding support to new mothers) and workplace-related factors (e.g. short maternity leave allowances). as such, breastfeeding practices in this region can be enhanced by implementing policies that are supportive of optimal breastfeeding practices at the individual, family, community and governmental levels, as per the who and unicef recommendations. references 1. gartner lm, morton j, lawrence ra, naylor aj, o’hare d, schanler rj, et al. breastfeeding and the use of human milk. pediatrics 2005; 115:496–506. doi: 10.1542/peds.2004-2491. 2. united nations international children’s emergency fund. the challenge. from: www.unicef.org/programme/breastfeeding/ challenge.htm accessed: mar 2017. 3. world health organization. indicators for assessing infant and young child feeding practices: part 1 definition. from: w w w. w h o . i nt / m ate r n a l _ ch i l d _ a d o l e s ce nt / d o c u m e nt s / 9789241596664/en/ accessed: mar 2017. 4. lawrence ra, lawrence rm. breastfeeding: a guide for the medical profession, 7th ed. philadelphia, pennsylvania, usa: saunders, 2010. p. 19. 5. bai yk, middlestadt se, peng cy, fly ad. psychosocial factors underlying the mother’s decision to continue exclusive breastfeeding for 6 months: an elicitation study. j hum nutr diet 2009; 22:134–40. doi: 10.1111/j.1365-277x.2009.00950.x. 6. ball tm, wright al. health care costs of formula-feeding in the first year of life. pediatrics 1999; 103:870–6. 7. world health organization. global nutrition targets 2025: policy brief series. from: www.who.int/nutrition/publications/ globaltargets2025_policybrief_overview/en/ accessed: mar 2017. 8. sankar mj, sinha b, chowdhury r, bhandari n, taneja s, martines j, et al. optimal breastfeeding practices and infant and child mortality: a systematic review and meta-analysis. acta paediatr 2015; 104:3–13. doi: 10.1111/apa.13147. 9. victoria cg, bahl r, barros aj, frança gv, horton s, kaseverc j, et al. breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. lancet 2016; 387:457–90. doi: 10.1016/s0140-6736(15)01024-7. 10. black re, victora cg, walker sp, bhutta za, christian p, de onis m, et al. maternal and child undernutrition and overweight in low-income and middle-income countries. lancet 2013; 382:427–51. doi: 10.1016/s0140-6736(13)60937-x. 11. oot l, sethuraman k, ross j, sommerfelt ae. the effect of suboptimal breastfeeding on preschool overweight/obesity: a model in profiles for country-level advocacy. from: http:// pdf.usaid.gov/pdf_docs/pa00mnt3.pdf accessed: mar 2017. 12. united nations international children’s emergency fund. nutrition: current status and progress. from: data.unicef.org/ topic/nutrition/infant-and-young-child-feeding/# accessed: mar 2017. 13. victora cg, horta bl, loret de mola c, quevendo l, pinheiro rt, gigante dp, et al. association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from brazil. lancet glob health 2015; 3:e199–205. doi: 10.1016/s2214-109x(15)70002-1. 14. al-farsi ym, al-sharbati mm, waly mi, al-farsi oa, alshafaee ma, al-khaduri mm, et al. effect of suboptimal breast-feeding on occurrence of autism: a case-control study. nutrition 2012; 28:e27–e32. doi: 10.1016/j.nut.2012.01.007. 15. stuebe a. the risks of not breastfeeding for mothers and infants. rev obstet gynecol 2009; 2:222–31. 16. ayed aa. knowledge, attitude and practice regarding exclusive breastfeeding among mothers attending primary health care centers in abha city. int j med sci public health 2014; 3:1355–63. doi: 10.5455/ijmsph.2014.140820141. 17. international baby food action network. the convention on the rights of the child: report on the situation of infant and young child feeding in bahrain. from: www.ibfan.org/art/ ibfan_crc57-2011bahrein.pdf accessed: mar 2017. 18. al-ghannami s, atwood sj. national nutrition strategy: strategic study 2014–2025. from: https://extranet.who.int/nutrition /g ina/sites/default/files/omn%202014%20national%20 nutrition%20startegy.pdf accessed: mar 2017. 19. international baby food action network. the convention on the rights of the child: report on the situation of infant and young child feeding in kuwait. from: www.ibfan.org/ crc/ibfan%20report%20_%2064_crc%202013_kuwait.pdf accessed: mar 2017. 20. radwan h. patterns and determinants of breastfeeding and complementary feeding practices of emirati mothers in the united arab emirates. bmc pub health 2013; 13:171. doi: 10.1186/1471-2458-13-171. 21. al-kohji s, said ha, selim na. breastfeeding practice and determinants among arab mothers in qatar. saudi med j 2012; 33:436–43. 22. rollins nc, bhandari n, hajeebhoy n, horton s, lutter ck, martines jc, et al. why invest, and what it will take to improve breastfeeding practices? lancet 2016; 387:491–504. doi: 10.10 16/s0140-6736(15)01044-2. 23. motee a, ramasawmy d, pugo-gunsam p, jeewon r. an assessment of the breastfeeding practices and infant feeding pattern among mothers in mauritius. j nutr metab 2013; 2013:243852. doi: 10.1155/2013/243852. 24. al juaid da, binns cw, giglia rc. breastfeeding in saudi arabia: a review. int breastfeed j 2014; 9:1. doi: 10.1186/17464358-9-1. https://doi.org/10.1542/peds.2004-2491 https://doi.org/10.1111/j.1365-277x.2009.00950.x https://doi.org/10.1111/apa.13147 https://doi.org/10.1016/s0140-6736%2815%2901024-7 https://doi.org/10.1016/s0140-6736%2813%2960937-x https://doi.org/10.1016/s2214-109x%2815%2970002-1 https://doi.org/10.1016/j.nut.2012.01.007 https://doi.org/10.5455/ijmsph.2014.140820141 https://doi.org/10.1186/1471-2458-13-171 https://doi.org/10.1016/s0140-6736%2815%2901044-2 https://doi.org/10.1016/s0140-6736%2815%2901044-2 https://doi.org/10.1155/2013/243852 https://doi.org/10.1186/1746-4358-9-1 https://doi.org/10.1186/1746-4358-9-1 nisreen al-nuaimi, godfrey katende and judie arulappan special contribution | e161 25. oman ministry of health. the second national pem survey. from: www.cdscoman.org/uploads/cdscoman/newsletter%20 17-9.pdf accessed: mar 2017. 26. world health organization. international code of marketing of breast-milk substitutes. from: www.who.int/nutrition/ publications/code_english.pdf accessed: mar 2017. 27. world health organization, united nations international children’s emergency fund. protecting, promoting and supporting breastfeeding: the special role of maternity services. from: www.who.int/nutrition/publications/infantfeeding/924 1561300/en/ accessed: mar 2017. 28. sinai ma. breastfeeding in oman: the way forward. oman med j 2008; 23:236–40. 29. world breastfeeding trends initiative. kingdom of saudi arabia: 2012. from: www.worldbreastfeedingtrends.org/gene ratereports/report/wbti-ksa-2012.pdf accessed: mar 2017. 30. dashti m, scott ja, edwards ca, al-sughayer m. determinants of breastfeeding initiation among mothers in kuwait. int breastfeed j 2010; 5:7. doi: 10.1186/1746-4358-5-7. 31. radwan h. influences and determinants of breastfeeding and weaning practices of emirati mothers. thesis, 2013, teesside university, middlesbrough, uk. https://doi.org/10.1186/1746-4358-5-7 sultan qaboos university med j, may 2013, vol. 13, iss. 3, pp. 386-391, epub. 25th jun 13 submitted 14th aug 12 revisions req. 26th nov 12 & 3rd feb 13; revisions recd. 24th dec 12 & 12th feb 13 accepted 30th mar 13 department of 1family medicine & public health, sultan qaboos university hospital; 2department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: almaniri@gmail.com تأثري مؤشر كتلة اجلسم قبل احلمل وزيادة الوزن أثناء احلمل على املواليد قليلي الوزن يف عمان دراسة مقارنة م�شطفى الهنائي ، ماجد املقبايل ، عائ�شة املقبالية ، فايدياناثان جاوري ، عبد اهلل املنريي امللخ�ص: الهدف: يهدف هذا البحث اىل درا�شة االرتباط بني موؤ�رس كتلة ج�شم االأم قبل احلمل وزيادة الوزن اأثناء احلمل واملواليد منخف�شي الوزن يف عينة من الن�شاء العمانيات من م�شت�شفى جامعة ال�شلطان قابو�س. الطريقة: درا�شة مقارنة اأجريت بني حاالت الوالدة امل�شجلة بني 1 مايو 2010 و30 اأبريل 2011. عرفت احلالة غري الطبيعية على اأنها: املراأة التي و�شعت طفل منخف�س الوزن ) اأقل من 2,500 جم ( و احلالة الطبيعيه التي �شيتم املقارنة بها هي: املراأة التي و�شعت طفل وزنه بني 2,500 و 4,000 جم. مت االختيار الع�شوائي لعدد 150 حالة و300 حالة مقارنة با�شتخدام البيانات امل�شجلة بامل�شت�شفى. مت ا�شتخراج املعلومات املتعلقة باالأمهات احلوامل و ما قبل الوالدة وبعد الوالدة من بطاقات املتابعة اخلا�شة باملراأة احلامل. مت فح�س حتليل االنحدار اللوج�شتي ذا ال�شقنّي؛ �شق ذا متغريين و�شق ذات عدة متغريات، لبحث االرتباط بني موؤ�رس كتلة اجل�شم اأثناء احلمل واملواليد منخف�شي الوزن. النتائج: ن�شبة االأمهات ذوات الوزن املنخف�س ) )p >0.001 ،6% موؤ�رس كتلة اجل�شم اأقل من 18.5<( كانت اأعلى بني احلاالت غري الطبيعية مقارنًة باحلاالت املقارنة ) %17.3 مقابل مقارنًة طبيعيه الغري احلاالت يف اأعلى اأي�شا كانت به املو�شى املعدل من اأقل لديهن الوزن زيادة معدل كان الالئي االأمهات ن�شبة و عر�شة فاإن النتائج، دقة مع تتعار�س اأن يحتمل التي العوامل �شبط بعد .)p >0.001 مقابل 33%، 57.7%( املقارنة باحلاالت 95% ،or = 2.27 )مواليد االأمهات ذوات الوزن املنخف�س لنق�شان الوزن هو ال�شعف مقارنة مبواليد االأمهات ذوات الوزن الطبيعي ,ci 1.09–4.71( اخلال�سة: الن�شاء العمانيات ذوات الوزن املنخف�س وكذلك الن�شاء الالئي كان معدل زيادة الوزن اأثناء احلمل لديهن اأقل من املعدل املو�شى به كان خطر والدة اأطفال منخف�شي الوزن لديهن اأعلى. يجب اأن توجه برامج رفع امل�شتوى ال�شحي لالأمهات يف اجتاه حت�شني تغذية االأمهات قبل واأثناء احلمل. مفتاح الكلمات: موؤ�رس كتلة اجل�شم؛ احلمل؛ عمر احلمل؛ وزن الطفل عند الوالدة؛ عمان. abstract: objectives: this study aimed to investigate the association between pre-pregnancy maternal body mass index (bmi), gestational weight gain and low birth weight (lbw) in babies born to a sample population of omani women. methods: a case-control study was carried out among deliveries registered between 1st may 2010 and 30th april 2011 at sultan qaboos university hospital, muscat, oman. a case was defined as a woman who delivered a low birth weight baby (<2,500 g); a control was a woman delivering a baby weighing between 2,500 and 4,000 g. a random selection of 150 cases and 300 controls was carried out using the hospital information system. maternal, pre-natal, and delivery data were extracted from the mothers’ follow-up cards. bivariate and multivariate logistic regression analyses were executed to examine the association between pre-pregnancy maternal bmi and lbw. results: the percentage of underweight mothers (bmi <18.5) was higher among the cases compared to the controls (17.3% versus 6%; p <0.001). the proportion of mothers with less-than-recommended weight gain was also higher among the cases compared to the controls (57.7% versus 33%; p <0.001). after adjustment for potential confounders, infants of underweight mothers had more than twice the risk of lbw compared to those of mothers with normal weight (odds ratio = 2.27; 95% confidence interval 1.09–4.71). conclusion: underweight omani women as well as women with less-than-recommended gestational weight gain were at higher risk of delivering lbw babies. maternal health promotion programmes should be directed towards improving mothers’ nutrition before and during pregnancies. keywords: body mass index; pregnancy; gestational age; birth weight; oman. effects of pre-pregnancy body mass index and gestational weight gain on low birth weight in omani infants a case-control study mustafa al-hinai,1 majid al-muqbali,2 aisha al-moqbali,2 vaidyanathan gowri,2 *abdullah al-maniri1 clinical & basic research advances in knowledge a mother's weight before and during pregnancy influences her baby’s birth weight. mustafa al-hinai, majid al-muqbali, aisha al-moqbali, vaidyanathan gowri and abdullah al-maniri clinical and basic research | 387 the world health organization (who) defines low birth weight (lbw) as weight at birth of less than 2,500 g. infants with lbw are approximately 20 times more likely to die than heavier babies.¹ lbw affects a person throughout life and is associated with poor growth in childhood and, subsequently, a higher incidence of adult diseases, such as type 2 diabetes (dm), hypertension (htn) and cardiovascular disease.² at the population level, lbw is an indicator of numerous public health problems, such as longterm maternal malnutrition, ill health, overwork and poor care during pregnancy. at the individual level, lbw is a predictor of newborn health and survival. furthermore, in healthcare scenarios, the success of a maternal-child health programme can be evaluated and monitored using the incidence of lbw babies as a key indicator.³ in developing countries, 19 million babies (16%) per year are born with lbw. asia has the highest incidence of low birthweight, with 18% of all babies weighing under 2,500 grams at birth. mauritania, pakistan, the sudan and yemen all have an estimated low birthweight incidence of more than 30%. however, the figures may be much higher since 60% newborns in developing countries are not weighed at birth.2 lbw can result from prematurity, fetal growth restriction or fetal pathology, or it can be constitutional. the nutritional status of women plays a crucial role for the well-being of both the mother and their developing fetuses. two independent factors— pre-maternal body mass index (bmi) and weight gain during pregnancy—play important roles in determining the outcome of the pregnancy for both the mother and fetus.4 various reports have documented the significant effect of these two factors and their impact on the outcomes of pregnancy, especially in developing countries.5–7 oman is a developing nation on the arabian peninsula, with a population of around 3 million, but the omanis constitute only 65% of the population according to recent statistics.8 in oman, the incidence of lbw was estimated to be around 9.2% in 2009 compared to 8.1% in 2000.9 omani children with lbw are at a higher risk of being underweight when they grow up.10 this study aimed to evaluate the association of maternal bmi before pregnancy and gestational weight gain on lbw babies in a cohort of omani women at sultan qaboos university hospital (squh), a tertiary teaching hospital in muscat, oman. methods a case-control study was carried out among omani women who delivered at squh from the 1st may 2010 to 30th april 2011. both the cases and the controls were identified using the computerised hospital information system. a list of deliveries at squh during the study period was generated and organised into two groups: cases and controls. a case was defined as a woman who delivered a lbw baby (<2,500 g) and a control as a woman delivering a baby weighing 2,500–4,000 g. a total of 150 cases and 300 controls were selected based on an expected prevalence of maternal underweight among lbw babies (15%) being two times higher than the prevalence of maternal underweight among normal weight babies, with a power of 80% and an error (a) of 5%.10 the allocation ratio was 1:2. subjects were selected using systematic sampling of every fifth case and of every ninth control. medical record numbers (mrn) of cases and controls were used to extract maternal, prenatal and delivery data from the mothers’ follow-up cards. variables included in the data collection were maternal age, pre-pregnancy bmi, gravidity, gestational age and weight gain, past medical history, antenatal complications, the baby’s gender and mode of delivery. the pre-pregnancy weights of mothers were obtained from the mothers’ health cards if their first prenatal visit was before 13 weeks’ gestation, as weight does not change in the first trimester. pregnant women with a first visit made after 13 weeks’ gestation were excluded to avoid errors in the measurement of weight and height. then, prepregnancy bmi was calculated as pre-pregnancy weight in kg divided by measured height in metres squared.11 the who definitions of bmi for the omani population were used as follows: application to patient care prenatal and antenatal nutritional counselling is essential to minimise the risk of women delivering low birth weight babies. effects of pre-pregnancy body mass index and gestational weight gain on low birth weight in omani infants a case-control study 388 | squ medical journal, august 2013, volume 13, issue 3 underweight (bmi <18.5), normal (bmi ≥18.5 and <25), overweight (bmi ≥25 and <30), and obese (bmi ≥30).11 the classifications of the us institute of medicine (iom) for recommended gestational weight gain were used according to specific bmi.12 means and standard deviations for parametric variables and frequencies and percentages for categorical data were described. the two sample proportions were tested with the chi-square test. both bivariate and multivariate logistic regression analyses were carried out using statistical package for the social sciences (spss), version 19 (ibm corp., chicago, illinois, usa) to examine the association between lbw, maternal bmi and gestational weight gain with adjustment of potential confounders such as pregnancy-induced htn or prematurity. all high-risk pregnancies, for example those complicated by preeclampsia, systemic lupus erythematosus (sle) and htn were followed-up with fetal doppler scans. the study was approved by the ethics committee of the college of medicine & health sciences at sultan qaboos university. results table 1 shows the distribution of cases and controls according to the demographic and clinical characteristics of the mothers. the mean age among the cases was 27.8 ± 5.7 years compared to 29.3 ± 5.3 years in the control group (p = 0.004). the average gestational age was 37.6 ± 2.1 weeks and the average weight of the babies was 2,773.3 ± 595.6 g. there were more primiparous women in the case group (33.3%) and more multiparous women in the control group (74.7%). the average number of women with pregnancies complicated by pregnancy-induced htn and premature rupture of membrane (prom) was higher among the cases (9.3 and 5.3%, respectively) than the controls (1.7 and 0.3%, respectively; p ≤0.001). neither the mode of delivery nor the gender of the babies was found table 1: distribution of cases and controls according to demographic and clinical characteristics description cases n = 150 controls n = 300 p value mean maternal age (years ± sd) 27.8 ± 5.7 29.3 ± 5.3 0.004 mean gestational age (weeks ± sd) 36.2 ± 2.66 38.5 ±1.25 <0.001 mean birth weight (g ± sd) 2110.3 ± 367.4 3104.9 ± 366.9 <0.001 mean bmi (± sd) 24.4 ± 6.3 26.4 ± 6.0 0.001 age groups, n (%) <20 years 9 (6) 6 (2) 0.047 20–24 years 36 (24) 54 (18) 25–29 years 54 (36) 105 (35) 30–34 years 32 (21.3) 82 (27.3) >34 years 19 (12.7) 53 (17.4) gravidity, n (%) primiparae 50 (33.3) 77 (25.7) 0.088 multiparae 100 (66.7) 223 (74.3) gestational age at delivery, n (%) preterm 41 (27.3) 19 (6.3) <0.001 full term 109 (72.7) 281 (93.7) past maternal history, n (%) chronic dm 2 (1.3) 4 (1.3) 1.000 chronic htn 3 (2.0) 6 (2) 1.000 hypothyroidism 2 (1.3) 3 (1) 0.750 scd 4 (2.7) 4 (1.3) 0.313 sle 1 (0.7) 3 (1) 0.722 antenatal complication, n (%) preeclampsia 1 (0.7) 1 (0.3) 0.616 pih 14 (9.3) 5 (1.7) <0.001 gdm 20 (13.3) 37 (12.3) 0.764 prom 8 (5.3) 1 (0.3) <0.001 gender of baby, n (%) male 70 (46.7) 137 (45.7) 0.841 female 80 (53.3) 163 (54.3) mode of delivery, n (%) svd 103 (68.7) 225 (75) 0.154 cs 47 (31.3) 75 (25) sd = standard deviation; bmi = body mass index; dm = diabetes mellitus; htn = hypertension; scd = sickle cell disease; sle = systemic lupus erythematosus; pih = pregnancy-induced hypertension; gdm = gestational diabetes mellitus; prom = premature rupture of membrane; svd = spontaneous vaginal delivery; cs = caesarean section. mustafa al-hinai, majid al-muqbali, aisha al-moqbali, vaidyanathan gowri and abdullah al-maniri clinical and basic research | 389 to be associated with lbw (p = 0.154 and p = 0.841, respectively). figure 1 shows the distribution of bmi groups in both cases and controls. the percentage of underweight mothers (bmi <18.5) was higher among the cases compared to the controls (17.3% versus 6%, p <0.001). on the other hand, mothers with normal weight babies were more often overweight or obese compared to mothers with lbw babies. figure 2 shows the distribution of recommended weight gain groups according to bmi. the percentage of cases with less-thanrecommended weight gain was higher among the cases compared to the controls (57.7% versus 33%; p <0.001). table 2 presents the adjusted odds ratio (or) with 95% confidence interval (ci) for bmi groups, using normal bmi as the reference category, and gestational weight gain groups, with recommended gestational weight gain as the reference category. adjustments were made for the effect of maternal age, gravidity, gestational age at delivery, pregnancyinduced htn and premature rupture of membrane (prom). the or of lbw was 2.27 times higher among underweight mothers compared to 0.83 among overweight and 0.75 among obese mothers. furthermore, the or of lbw was 2.67 times higher in women who gained less than the recommended gestational weight compared to women who gained the recommended weight. discussion this study was the first to examine the relationship between pre-pregnancy bmi, gestational weight gain and lbw babies in oman. the negative health consequences of a high incidence of lbw babies in a country puts considerable strain on its healthcare resources, facilities and future plans.2 therefore, many international organisations, such as who have expended considerable effort towards improving the global burden of lbw. this study specifically highlights the effects of pre-pregnancy bmi and gestational weight gain on lbw deliveries. several maternal factors may contribute to lbw babies. some of these factors, such as weight, gestational weight gain, smoking and socioeconomic status, are modifiable; however, others, such as age, height and inherited diseases, are not modifiable. the age of the mother can play both harmful and protective roles in relation to lbw. this study found that most women younger than 20 years gave birth to lbw babies whereas most who were over table 2: adjusted odds ratio with 95% confidence interval for body mass index and gestational weight gain groups adjusted or* percentage ci p value bmi groups normal bmi group used as a reference underweight 2.27 1.09–4.71 0.02 overweight 0.83 0.47–1.47 0.53 obese 0.75 0.38–1.47 0.41 weight gain normal weight gain group used as a reference less than recommended 2.67 1.57–4.52 <0.001 above recommended 0.97 0.51–1.86 0.94 *adjusted for maternal age, gravidity, gestational age at delivery, pregnancy induced hypertension, premature rupture of membrane. or = odds ratio; ci = confidence interval; bmi = body mass index . figure 1: distribution of bmi groups among cases and controls. p value = 0.001. figure 2: distribution of gestational weight gain among cases and controls. p value <0.001. effects of pre-pregnancy body mass index and gestational weight gain on low birth weight in omani infants a case-control study 390 | squ medical journal, august 2013, volume 13, issue 3 35 years gave birth to normal weight babies. this fact has been shown in previous studies in which youth counts as a risk factor for lbw and older age as a protector. the latter may be attributed mainly to the higher parity in older women.13 in the current sample, about 36% of cases and 35% of controls were between 25 and 29 years of age, which demonstrates the fact that the age at which women get married in oman has increased due to lifestyle changes and increasing levels of education.5 delivering before the expected due date (preterm <37 weeks) has a significant impact on the weight of the baby and acts as a risk factor for intellectual and physical development in future life. the factors influencing birth weight and prematurity included smoking, htn (both pre-pregnancy or pregnancyinduced), dm, anaemia, the weight of mothers before pregnancy, preterm prom, and gestational weight gain.14–16 in this study, it was found that those women who gave birth before 37 weeks were at about a 27.3% higher risk of delivering lbw babies [table 1]; the major factors influencing this situation were pregnancy-induced htn and preterm prom. even after adjusting for preterm deliveries, there was a significant relationship between maternal weight gain, bmi and lbw in the current study. several studies have shown a direct relationship between a mother’s health status before and during pregnancy, and lbw.17–19 in this study, a medical history including all possible diseases that mothers suffered before pregnancy was analysed, but there was no significant difference between the cases and controls. the diseases that mothers may have had during pregnancy, especially pregnancy-induced htn and prom, were associated with lbw of newborns. there were no pathologies, such as abnormal cord insertions, in either the case or control groups. the nutritional status of the mother prior to, during, or after pregnancy directly influences the health status of the fetus. pre-pregnancy bmi and gestational weight gain have been studied and found to have an important impact on the birth weight and future health of babies.20,21 in the current study, underweight mothers or those who gained less weight than recommended had a two times greater risk of giving birth to lbw babies compared to women with a normal bmi. this finding is consistent with the results of other studies.22–24 as with many other observational studies, this study was prone to errors, including selection bias, misclassification and confounding. first, selection bias may have occurred because women delivering at a tertiary hospital may already have a higher prevalence of risk factors compared to women delivering at other types of hospitals. therefore, because the controls were selected from the same hospital, such bias may have led to an underestimation of the or. in addition, the exclusion of mothers who had their first prenatal visit after 13 weeks’ gestation may have introduced a potential selection bias into the estimates. an underestimation of the or is likely if those who were excluded were likely to be mothers who were underweight. secondly, because the data was gathered from patient files, information bias or misclassification may have also influenced the study. however, due to the fact that all the exposure data were measured before the delivery of the babies, such misclassification would most likely be non-differential and may not have influenced the estimates. finally, unmeasured confounders such as socioeconomic factors and the educational levels of mothers may also have affected the findings of this study. smoking was not adjusted for because it is extremely rare in oman (only three cases in this study). conclusion this study showed that underweight women, as well as women with less-than-recommended gestational weight gain, were at higher risk of delivering lbw babies. thus, it is recommended that the issue of appropriate weight gain in relation to pre-pregnancy bmi should be included during prenatal consultations with women of childbearing age as well as pregnant women. accordingly, more attention needs to be given to nutrition-related consultations offered by health providers during prenatal visits. further research is needed to explore possible relevant interventions pertaining to improving weight gain during pregnancy. mustafa al-hinai, majid al-muqbali, aisha al-moqbali, vaidyanathan gowri and abdullah al-maniri clinical and basic research | 391 references 1. kramer ms. determinants of low birth weight: methodological assessment and meta-analysis. bull world health organ 1987; 65:663–737. 2. united nations children’s fund (unicef). tracking progress on child and maternal nutrition: a survival and development priority. new york: unicef, nov 2009. p. 22 from: http://www.childinfo.org/ files/tracking_progress_on_child_and_maternal_ nutrition_en.pdf accessed: feb 2013. 3. goldenberg rl, rouse dj. prevention of premature birth. n engl j med 1998; 30:313–20. 4. choi sk, park iy, shin jc. the effects of prepregnancy body mass index and gestational weight gain on perinatal outcomes in korean women: a retrospective cohort study. reprod biol endocrinol 2011; 18:6. 5. united nations children's fund and world health organization. low birthweight: country, regional and global estimates. unicef, new york, 2004. from: http://www.childinfo.org/files/low_ birthweight_from_ey.pdf accessed: aug 2011. 6. badshah s, mason l, mckelvie k, payne r, lisboa pj. risk factors for low birthweight in the publichospitals at peshawar, nwfp-pakistan. bmc public health 2008; 4:197. 7. valero de bernabé j, soriano t, albaladejo r, juarranz m, calle me, martínez d, et al. risk factors for low birth weight: a review. eur j obstet gynecol reprod biol 2004; 116:3–15. 8. ministry of national economy. statistical yearly report. ministry of national economy, muscat, oman, 2010. 9. ministry of health. annual report, health status indicators related to mortality indicators, 2008. from http://www.moh.gov.om/stat/2008/chapters/ ch02y08.pdf accessed: aug 2011. 10. alasfoor d, traissac p, gartner a, delpeuch f. determinants of persistent underweight among children, aged 6–35 months, after huge economic development and improvements in health services in oman. j health popul nutr 2007; 25:359–69. 11. world health organization. global database on body mass index (bmi)/detailed data section. from: http://apps.who.int/bmi/index.jsp accessed: aug 2011. 12. institute of medicine (us) and national research council (us) committee to reexamine iom pregnancy weight guidelines. weight gain during pregnancy: reexamining the guidelines. rasmussen km, yaktine al, eds. washington, dc: national academies press, 2009. 13. borga jb, adair ls. assessing the net effect young maternal age on birth weight. am j hum biol 2003; 15:733–40. 14. villar j, belizan j. the relative contribution of prematurity and fetal growth retardation to low birth weight in developing countries. am j obstet gynecol 1982; 143:793–8. 15. wilcox aj. on the importance and the unimportance of birthweight. int j epidemiol 2001; 30:1233–41. 16. borkowski w, mielniczuk h. the influence of social and health factors including pregnancy weight gain rate and pre-pregnancy body mass on low birth weight of the infant. ginekol pol 2008; 79:415–21. 17. ganesh kumar s, harsha kumar hn, jayaram s, kotian ms. determinants of low birth weight: a case control study in a district hospital in karnataka. indian j pediatr 2010; 77:87–9. 18. alfadhli am, hajia am, mohammed fak, alfadhli ha, el shazly mk. incidence and potential risk factors of low birth weight among full term deliveries. bull alex fac med 2010; 46:152–64. 19. rafati s, borna h, akhavirad mb, fallah n. maternal determinants of giving birth to low-birth-weight neonates. arch iran med 2005; 4:277–81. 20. yekta z, ayatollahi h, porali r, farzin a. the effect of pre-pregnancy body mass index and gestational weight gain on pregnancy outcomes in urban care settings in urmia, iran. bmc pregnancy childbirth 2006; 20:15. 21. yazdanpanahi z, forouhari s, parsanezhad me. prepregnancy body mass index and gestational weight gain and their association with some pregnancy outcomes. iran red crescent med j 2008; 10:326–31. 22. ronnenberg ag, wang x, xing h, chen c, chen d, guang w, et al. low preconception body mass index is associated with birth outcome in a prospective cohort of chinese women. j nutr 2003; 133:3449–55. 23. han z, mulla s, beyene j, liao g, mcdonald sd. knowledge synthesis group. maternal underweight and the risk of preterm birth and low birth weight. int j epidemiol 2011; 40:65–101. 24. frederick io, williams ma, sales ae, martin dp, killien m. pre-pregnancy body mass index, gestational weight gain, and other maternal characteristics in relation to infant birth weight. matern child health j 2008; 12:557–67. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 273-285 , epub. 15th jul 12 submitted 30th nov 11 revision req. 10th mar 12, revision recd. 12th apr 12 accepted 2nd may 12 in the past ten years, much progress has been made in enlarging the treatment options for b-cell neoplasms due mainly to surface targeted therapies. particularly, the greatest impact has been made with monoclonal antibodies (mabs), which bind therapeutically to the relevant target antigens causing cell death via several mechanisms. given their success in treating refractory or relapsed b-cell neoplasms, mabs are now included in first-line therapy during the induction phase or intensification period, as well as during maintenance therapy in the post-remission phase of treatment.1,2 however, as for chemotherapeutic drugs, resistance to monoclonal antibody therapy has emerged as a limiting factor for the effectiveness of these compounds in the treatment of b-cell neoplasms. to 1division of hematology, royal victoria hospital, mcgill university health centre, montreal, quebec, canada; 2department of haematology, college of medicine & health sciences, sultan qaboos university hospital, muscat, oman; 3division of hematology, department of medicine, university of saskatchewan, saskatoon saskatchewan, canada. *corresponding author e-mail: boulassel@squ.edu.om and medrachidb@yahoo.com العالج املناعي ألورام اخلاليا )b( باستخدام اخلاليا )t(املبلورة ملستقبالت هجينة مولدة للمضادات من مرحلة اختيار مولد املضاد إىل التطبيقات السريرية حممد ر�سيد بولع�سل واأحمد جالل لأورام حمتمل كعالج للم�سادات مولدة هجينة مل�ستقبالت املبلورة )t( اخلاليا با�ستخدام املناعي العالج تقييم يتم امللخ�ص: اخلاليا)b(. اأظهرت التجارب ال�رسيرية الأخرية نتائج واعدة. وكلما زاد عدد امل�سادات املحتملة للرت�سح، اأ�سبح اختيار امل�ساد املنا�سب اأكرث حتديا لت�سميم الدرا�سات ولتقييم اأمثل لفعالية اخلاليا )t( املبلورة للم�ستقبالت الهجينة. املطلوب تقييم دقيق للم�سادات للتاأكد من اأن اخلاليا )t( املبلورة للم�ستقبالت الهجينة �سوف تق�سي على اخلاليا اخلبيثة ب�سكل تف�سيلي مع �سمان اأدنى م�ستوى �سمية �سد )t( اخلاليا لت�سميم كاأهداف نظريا ت�ستعمل اأن ميكن التي امل�سادات ملولدات حمددا �سطحا )b( اخلاليا ُتبلور الطبيعية. الأن�سجة املبلورة للم�ستقبالت الهجينة. على الرغم من اأن العديد من هذه امل�سادات ميكن اأن حتفز ا�ستجابات خلوية مناعية فعالة داخل اجل�سم )cd19( احلي، فاإن تطبيقاتها ال�رسيرية ماتزال متثل حتديا اإذ اإن امل�سادات الوحيدة التي مت اختبارها يف التطبيقات ال�رسيرية هي و )cd20(. ن�ستعر�ض هنا مولدات امل�سادات للخاليا )b( لت�سميم امل�ستقبالت الهجينة كما نذكر العقبات التي ميكن اأن تتخلل عملية التعرف على الأهداف اخللوية التي ميكن اأن تكون مفيدة. مفتاح الكلمات: العالج املناعي، خاليا )b(، خاليا )t(، الأورام، امل�ستقبالت الهجينة املولدة للم�سادات. abstract: immunotherapy with t cells expressing chimeric antigen receptors (car) is being evaluated as a potential treatment for b-cell neoplasms. in recent clinical trials it has shown promising results. as the number of potential candidate antigens expands, the choice of suitable target antigens becomes more challenging to design studies and to assess optimal efficacy of car. careful evaluation of candidate target antigens is required to ensure that t cells expressing car will preferentially kill malignant cells with a minimal toxicity against normal tissues. b cells express specific surface antigens that can theoretically act as targets for car design. although many of these antigens can stimulate effective cellular immune responses in vivo, their implementation in clinical settings remains a challenge. only targeted b-cell antigens cd19 and cd20 have been tested in clinical trials. this article reviews exploitable b cell surface antigens for car design and examines obstacles that could interfere with the identification of potentially useful cellular targets. keywords: immunotherapy; b cells; t cells; neoplasms; chimeric antigen receptors. review immunotherapy for b-cell neoplasms using t cells expressing chimeric antigen receptors from antigen choice to clinical implementation *mohamed-rachid boulassel1,2 and ahmed galal3 immunotherapy for b-cell neoplasms using t cells expressing chimeric antigen receptors from antigen choice to clinical implementation 274 | squ medical journal, august 2012, volume 12, issue 3 overcome these limitations, a variety of approaches are being developed to augment the ways by which antibodies kill malignant cells.3 an interesting approach to enforce tumour antigen recognition is to generate genetically engineered t cells to express highly active chimeric antigen receptors (car) to kill leukaemic cells without the requirement for restriction of the major histocompatibility complex (mhc) molecules. these genetically engineered t-cell constructs combine the antibody-derived antigen-binding motif, known as a single-chain fragment of variable regions (scfv) that recognises the target antigen, with the intracellular functional domains of t-cell receptor (tcr)-related signalling molecules, the cd3ζ-chain, and t-cell costimulatory molecules such as cd28, cd134, and cd137.4,5 using lentiviral transduction or electroporation, the genetic constructs are introduced into the autologous peripheral t cells collected by leukapheresis procedures [figure 1]. when expressed on t cells, car redirects t-cell specificity and cytotoxic immunoreactivity against the cells expressing the targeted antigen epitope.6–8 generally, before an infusion of genetically engineered t cells, patients receive lymphodepleting chemotherapy to eliminate immunosuppressive cells and other lymphoid immune cells that produce growth factors such as inteleukin-7 (il-7) and il-15.9,10 current protocols suggest that lymphodepletion is required to enhance the clinical efficacy of genetically engineered t cells.11–13 it has been reported that the day of adoptive t-cell transfers in relation to preconditioning regimens is critical as t cells given at day two after stem cell transplantation show superior persistence as compared to those given in later days.14 until recently, development of this personalised t-cell-based therapy was limited due to the lack of gene transfer techniques and efficient t-cell culture systems. therefore, previous clinical applications with t cells expressing car showed modest clinical activities, as these engineered t cells demonstrated a limited expansion in vivo and rapidly disappeared from circulation.6,7,15,16 with the most recent wave of genomic technology, great progress has been made in improving gene transfer technology and in developing methods to enhance t-cell effector functions. these advances have made possible the creation of secondand third-generation t cells expressing car, which are endowed with potent effector functions.4–8 thus, several groups have evaluated these second generations of car as a potential treatment to kill leukaemic cells in patients with b-cell neoplasms.17-22 as for any targeted immunotherapy, the success of novel genetically engineered t cells relies heavily on the characteristics of the target cell surface antigen. since the list of potential candidate antigens is expanding, the choice of a suitable target becomes more crucial for both the design and optimal efficacy of car. in addition, a critical evaluation of candidate target antigens is required to ensure that t cells expressing car will preferentially kill malignant cells with little toxicity against normal tissues. therefore, this article will briefly review the b-cell surface antigens, which may be exploited as targets for car design to treat b-cell neoplasms. it will also examine potential obstacles that could interfere with the identification of these cellular targets, which might be useful for car immunotherapy. characteristics of an ideal target antigen an important step in designing a car is the selection of a good candidate antigen. the target antigen should possess certain characteristics to justify scientifically its clinical applicability. first, the suitable antigen should ideally be expressed by malignant cells but not on normal cells. while this seems to be a reasonable criterion for antigen selection, it may not be a prerequisite in every case, especially for b-cell neoplasms where most potential targets are also expressed by some cells of normal tissues. in these cases, the target antigen should be expressed in higher amounts on malignant cells relative to normal cells. second, the target antigen should be expressed on the surface of the malignant cells. this reasonable cell surface expression is important to avoid immune escape of malignant cells, which are endowed with a strong predilection to down-regulate antigen expression.23 third, beside its immunogenicity, the target antigen should not be internalised by malignant cells to ensure the induction of immune effector cell functions. fourth, an ideal antigen should exhibit negligible shedding and only a small amount of secretion with a limited potential for mutation to avoid compromising its mohamed-rachid boulassel and ahmed galal review | 275 surface molecule exclusively expressed by b cells and follicular dendritic cells among cells of the hematopoietic system.25,26 of interest, its expression is lost during terminal b-cell differentiation into plasma cells. cd19 is involved in growth regulation of b cells through the b-cell antigen receptor. it is also required for the development of marginal zone b cells, germinal centre formation, t-dependent antibody response, and b-cell memory maintenance.26 compared to other b-cell surface molecules, cd19 is expressed at high levels on essentially all b-lineage leukaemias and lymphomas, making this antigen an excellent tumour-associated antigen for car development. cd20 antigen following the identification of surface immunoglobulin, cd20 was the first cell surface differentiation antigen of human b cells to be identified by a monoclonal antibody. cd20 is a 33-37-kda integral membrane protein with four transmembrane domains and an extracellular disulfide bond.27 it is expressed on pre-b and mature naïve b cells but not on plasma cells or early pro-b cells. at the primary sequence level, cd20 shows little sequence homology with cd19 but therapeutic utility. finally, the antigen of interest should preferentially be involved in key functions of the target cell such as growth-regulating signalling, immune recognition, or apoptosis. potential candidate antigens for car design in b-cell neoplasms b cells express a variety of specific surface antigens that can theoretically act as targets for car design. although many of these antigens showed the ability to stimulate effective cellular immune responses in vivo, their implementation in clinical settings remains a big challenge. the ones with the most promise in b-cell neoplasms are summarised in figure 2, and their characteristics are briefly described in table 1. cd19 antigen because of its promising proprieties in b-cell development, pioneering work in car design focused on the cd19 antigen. this molecule was first identified as the b4 antigen on normal and malignant human b lymphocytes.24 this 95kda type i transmembrane glycoprotein is a cell figure 1: clinical application of t cells expressing chimeric antigen receptors. following a leukapheresis procedure, autologous t cells are isolated, transduced with a lentiviral vector and re-infused to patient after lymphodepletion with chemotherapy. immunotherapy for b-cell neoplasms using t cells expressing chimeric antigen receptors from antigen choice to clinical implementation 276 | squ medical journal, august 2012, volume 12, issue 3 both antigens interact with mhc class ii molecules on b cells. current studies suggest that cd20 is a component of a signal transduction complex that is involved in the growth regulation of b lymphocytes following activation.28 in addition to its restricted b-lineage expression, cd20 is present on the majority of b-cell lymphomas, providing a strong rationale for car design. cd22 antigen the cd22 antigen was originally identified as a b-cell-associated adhesion molecule that appears to function in the regulation of b-cell activation. it is a member of the sialic-acid binding immunoglobulinlike lectin (siglec) family. siglec proteins are a subset of the immunoglobulin super-family of cell recognition molecules that bind to sialic acidcontaining glycans of the cell surface.29 cd22 is a 135-140-kda b-cell-specific transmembrane sialoglycoprotein, expressed on all b cells except on memory b cells and plasma cells.30 it regulates multiple b-cell functions including the cellular activation thresholds and survival. in this role, cd22 modulates b-cell dependent immune responses, prevents autoimmunity, and controls the homing of b cells back to the bone marrow. it also modulates t-cell signalling upon binding to its ligand on t cells.31 cd22 is strongly expressed by many b-cell lymphomas and leukaemias, particularly hairy cell leukaemia, where it is universally highly expressed.32 given that cd22 is found on normal b cells at low levels but not on plasma cells, these table 1: characteristic features of potential target b-cell antigens for chimeric antigen receptor design. potential antigens structural features b-cell expression in vitro and in vivo studies clinical trials usage references cd19 95-kda glycoprotein all b cells except plasma cells raji and daudi b cell lines scid/ beige mice nod/ scid mice cll fl smzl b-all 18, 19, 20, 21, 22 cd20 33-37-kda nonglycosylated phosphoprotein all b cells except plasma cells and early pro-b cells mb185 cell line scid/beige mice balb/c mice mcl fl 17 cd22 135-140-kda sialoglycoprotein all b cells except plasma cells and memory b cells raji, daudi and ramos b cell lines nd 57 cd23 45-kda glycoprotein all b cells except immature bone marrow b cells mec-1 cll, bjab and jeko-1 cell lines rag2 mice nd 58 cd30 102-120-kda glycoprotein activated b cells nd nd 37 cd40 54-50-kda glycosylated phosphoprotein all stages of b-cell development nd nd 39 cd52 21-28kda glycoprotein all b cells nd nd 41 cd70 50-kda glycoprotein activated b cells raji, daudi, cll120, 239t, u266 and k562 cell lines scid mice nd 59 cd74 31-41-kda glycoprotein all b cells nd nd 44 cd80 60-kda glycoprotein activated b cells nd nd 47 igκ light chain 25-kda glycoprotein all b cells raji, daudi, bjab cll-120, sp-53 and k562 cell lines scid mice nd 60 legend: raji, daudi and ramos = human burkitt's lymphoma cell line; scid = severe combined immunodeficient; nod = non-obese diabetic; mb185 = mouse pre-b cell lymphoma cell line; mec-1 cll and cll-120 = chronic lymphocytic leukemia cell line; blab = b-lymphoblastoid cell line; jeko-1 = mantle cell lymphoma cell line; 293t = human embryonic kidney cell line; u266 = myeloma cell line; k562= human erythroleukaemic cell line; sp-53 = lymphoma cell line; cll = chronic lymphocytic leukaemia; fl = follicular lymphoma; smzl = splenic marginal zone lymphoma; b-all = b-cell acute lymphoblastic leukaemia; mcl = mantle cell lymphoma; nd = not determined. mohamed-rachid boulassel and ahmed galal review | 277 on activated monocytes and eosinophils. the expression of cd30 is highly induced on b cells by mitogen activators, or as a result of viral infection with human t-cell lymphotropic viruses (htlv), human immunodeficiency virus (hiv), or ebv.37 of interest is the finding that cd30 expression is absent on most cells outside the immune system. interaction of cd30 with its ligand cd153 induces the recruitment of signalling proteins, which leads to the transduction of several biological signals such as cell death, proliferation, activation, and differentiation depending on the cellular context.37 in addition to the malignant disorders cited above, cd30 is also expressed on 20% of b-cell lymphomas and some multiple myeloma cells. thus, because of its restricted profile expression in normal conditions, the cd30 antigen appears to be an attractive target for car development. cd40 antigen like cd30, the cd40 antigen belongs to the tnfr superfamily and is a surface receptor of 45-50kda, playing a central role in t-cell-dependent b-cell activation and proliferation36 cd40 is expressed during all stages of b-cell development and differentiation, whereas its ligand (cd40l or cd154) is mainly expressed on activated t cells. in addition to its expression on all antigenpresenting cells such as dendritic cells, follicular dendritic cells, and monocytes, cd40 is also expressed on non-haematopoietic cells including endothelial cells, fibroblasts, and epithelial cells.38 in fact, cd40 is involved in the amplification and regulation of inflammatory responses by providing critical signals required for the optimal activation of immune cells. these key signals resulted in optimal antigen presentation, expansion of antigen-specific memory and effector t cells, proliferation of b-cell responses, immunoglobulin class switching, and secretion of cytokines.39 currently, the cd40cd40l immunostimulatory effect is used to enhance antigen presentation in gene transfer protocols. high levels of cd40 expression were detected on a wide range of malignant cells including b-cell neoplasms, bladder cells, and carcinoma cell types, among others. it has been reported that in hodgkin’s lymphoma, hairy cell leukaemia, chronic lymphocytic leukaemia, and follicular lymphomas, cd40 activation contributed to tumour survival and resistance to chemotherapy. in hiv-related characteristics make cd22 an attractive target for car development. cd23 antigen the cd23 antigen was initially defined as the low-affinity receptor for immunoglobulin (ig)-e, also known as fcεrii. it is a 45-kda type ii transmembrane glycoprotein expressed on b cells but not on immature bone marrow b lymphocytes. its expression was also reported on various cell types including monocytes, eosinophils, and platelets.33 cd23 participates in multiple regulatory functions either as a membrane-bound glycoprotein or as a freely soluble protein. among these functions, cd23 regulates the production of immunoglobulin-e, the antibody that mediates the allergic reactions, and b-cell growth, as underlined by its overexpression and abnormal regulation in two b-cell neoplasms resulting from the clonal expansion of mature b cells (i.e. chronic lymphocytic leukaemia and small cell lymphocytic lymphoma).34 in addition, the epstein-barr virus (ebv)-transformed b cells express high levels of cd23 and its expression is used to delineate classical hodgkin’s lymphoma from mediastinal diffuse large lymphoma.34 in combination, these properties support cd23 credibility as an interesting target for car design in b-cell neoplasms. cd30 antigen based on its presence on reed-sternberg cells, which are characteristic of hodgkin’s lymphoma, cd30 was identified by means of the monoclonal antibody ki-1 in 1982. since then, cd30 has been used as a diagnostic marker for hodgkin’s lymphoma and allowed the description of a new group of malignant disorders named cd30-positive lymphoproliferative disorders.35 the cd30 antigen is a member of the tumour necrosis factor receptor (tnfr) superfamily which includes cd40, cd70, cd95, and cd134, among others.36 cd30 is a type i glycoprotein with a molecular weight of 102-120-kda. structurally, an 85-kda form, which is a product of the proteolytic cleavage of the cd30 antigen, could be detected in the blood of patients with cd30-positive lymphoproliferative disorders or autoimmune diseases.37 under normal conditions, cd30 expression is detected in activated b, t and natural killer cells. in addition, lower levels of expression were reported immunotherapy for b-cell neoplasms using t cells expressing chimeric antigen receptors from antigen choice to clinical implementation 278 | squ medical journal, august 2012, volume 12, issue 3 lymphomas, cd40 binding triggered the growth of b cells via the activation of the nuclear factorkappa-b (nf-κb) pathway that in turn stimulated hiv replication.38,39 because of the key role of cd40 in mediating growth of b-cell neoplasms, this antigen could be a promising target for car development. cd52 antigen the cd52 antigen, also known as the cambridge pathology (campath)-1 antigen, is a surface glycoprotein with a molecular weight of 21-28kda. cd52 comprises a short peptide sequence of twelve amino acids and a large complex n-linked oligosaccharide, and is attached to the cellular membrane by a glycosylphosphatidylinositol (gpi) anchor.40 it is abundantly expressed on virtually all b and t lymphocytes and, to a lesser degree, on monocytes and natural killer cells. it is also expresses on a large proportion of lymphoid b-cell malignancies including lymphomas and chronic lymphocytic leukaemia.41 the response of b lymphocytes, following its activation via the cd52 antigen, varies according to both the state of cellular maturation and the way the antigen is presented to cells and results in clonal expansion, differentiation, anergy, or deletion by apoptosis. it has been reported that the cross-linking of cd52 on b-cell lines resulted in profound growth inhibition, corroborating the notion that this antigen might be used as a target for car design. cd70 antigen the cd70 antigen is a member of the tnfr superfamily, like the cd30 and cd40 antigens.36 cd70 is a type ii transmembrane glycoprotein with a molecular weight of 50-kda. it is transiently expressed by activated t and b lymphocytes, monocytes, and dendritic cells. it is also expressed on stromal thymic cells of the medulla, but not on other normal cells or tissues.42 the interaction of cd70 with its ligand cd27 regulates the expansion and differentiation of memory and effector t cells whereas in b cells, cd70-cd27 co-stimulation promotes b-cell expansion through several signalling pathways including spleen tyrosine kinase, phosphoinositide 3-kinase, and nf-κb.43 of interest, cd70 expression is documented in many different types of lymphomas, leukaemias, and carcinomas. cd70 is abundantly expressed by b-cell derived non-hodgkin lymphoma including diffuse large b-cell lymphoma, follicular lymphoma, burkitt’s and mantle cell lymphomas, and b-cell lymphocytic leukaemia as well as waldenström macroglobulinaemia, multiple myeloma, and chronic lymphocytic leukaemia.42 it is also highly figure 2: b-cell surface antigens that may be exploited as potential targets for chimeric antigen receptor design. mohamed-rachid boulassel and ahmed galal review | 279 includes cd80-, cd86-, b7-h3, b7-h4, the inducible costimulator ligand, and the programmed death-1 and death-2 ligands.46 these molecules are transmembrane, or glycosyl-phosphatidylinositol (gpi)-linked proteins, playing key roles in immune responses by providing co-stimulatory or coinhibitory signals upon binding their receptor. in addition to its well-known role in regulating t-cell activity, recent studies suggest that cd80 also regulates b-cell functions.47 cross-linking of cd80 on lymphoma cell lines resulted in growth inhibition and up-regulation of pro-apoptotic molecules.48 cd80 is transiently expressed on the surface of activated b cells but is constitutively expressed on a variety of non-hodgkin lymphomas, including follicular lymphoma, making it a good target for car design. immunoglobulin light chains another potential antigen for car design is the kappa (κ) light chain (lc) of the ig molecules. ig is formed by two identical heavy chains and two identical lcs, lambda (λ) and κ. b lymphocytes express surface monoclonal igs with either κ or λ light chains. since expression of λ/κ lcs is clonally restricted, and b-cell neoplasms such as low-grade non-hodgkin lymphoma and chronic lymphocytic leukaemia are themselves clonal, the malignant cells in a given patient will express either κ or λ lc.49 therefore, targeting the lc expressed by malignant b-cells should spare the normal population of b lymphocytes that express the reciprocal lc. thus, lc λ or κ may be considered an attractive antigen for car development. improving the clinical applicability of targeted antigens for designing car as discussed above, several candidate antigens can be targeted for designing car. these antigens are typically normal cell constituents that are over-expressed in b-cell neoplasms. the potential contribution of each antigen to car development and implementation is still debated. for instance, what determines which antigens should be first targeted? an additional question expressed on reed-sternberg cells in hodgkin’s lymphoma and other non-lymphoid tumour cells such as nasopharyngeal carcinoma, astrocytoma, glioblastoma, and renal cell carcinoma (rcc) as well as in ebvand htlv-associated malignancies.42 given the differential expression pattern of cd70 in leukaemic cells as compared to normal b cells, this antigen represents a prominent target for car development. cd74 antigen the cd74 antigen, also known as an invariant chain (ii), is a conserved type ii membrane glycoprotein with a molecular weight of 31-41-kda. the ii on the cell surface is present in four isoforms and controls several aspects of the immune system.44 in addition to its role as a chaperone molecule for mhc class ii molecules, cd74 is involved in several signalling pathways. cd74 is fundamental to the correct folding and transport of mhc class ii molecules to endosomes and lysosomes as well as in antigen loading. it is directly involved in the maturation of b cells through the nf-κb pathway.44 it also serves as the high-affinity receptor for the proinflammatory cytokine known as the macrophage migration inhibitory factor, which activates innate immune cells such as macrophages and monocytes through kinase signalling pathways.44 under normal conditions, cd74 is expressed on mhc class ii positive cells such as b cells, monocytes, macrophages, thymic epithelium, langerhans cells, activated t cells and dendritic cells. under the inflammatory processes, cd74 is also detected in high levels on endothelial and epithelial cells as well as on a variety of malignant cells.45 its overexpression is observed in several forms of cancer and many b-cell neoplasms, including non-hodgkin lymphoma, chronic lymphocytic leukaemia, multiple myeloma, and follicular lymphoma. in many of these cancers, increased cd74 expression is associated with tumour progression and poor clinical outcomes.45 compared to normal tissue, the relatively high expression of cd74 combined with the rapid internalisation of cd74 on ligation makes it an attractive target for car design. cd80 antigen among other potential antigens for car design is cd80, a 60-kda transmembrane glycoprotein. this antigen is a member of the b-family that immunotherapy for b-cell neoplasms using t cells expressing chimeric antigen receptors from antigen choice to clinical implementation 280 | squ medical journal, august 2012, volume 12, issue 3 is which b-cell neoplasms should be studied first? in this regard, defining shared features of target antigens is of paramount importance in designing and implementing car in b-cell neoplasms. car targeting cd19 (cart19) and cd20 (cart20) antigens were the first molecules to be used in b-cell malignancies. in early ex vivo studies, both t cells expressing car19 (cart19) and cart20 efficiently lysed a wide panel of tumour cell lines expressing cd19 and cd20 antigens, respectively, as well as b cells freshly isolated from patients with b-cell neoplasms.50–56 in animal models, cart19 and cart20 also eradicated systemic cell tumours established in severe combined immunodeficient (scid) mice that were expressing cd19 or cd20.51,52 these preclinical experiments have supported the notion that under appropriate conditions, t cells can be therapeutically redirected to eliminate malignant b cells and have justified the translation of these genetically engineered t cells to clinical settings. recently, in proof of principle studies, adoptive transfer of cart19 or cart20 to patients with chemotherapy-refractory chronic lymphocytic leukaemia or follicular lymphoma demonstrate encouraging results in terms of reducing the leukaemic b-cell burden.17–22 taken together, cart19and cart20-based clinical trials are at the advanced planning stage in several centres around the world, and the results of these will be of importance to further establish the clinical efficacy of this therapeutic approach. other cartargeting cd22 (cart22), cd23 (cart23), and cd70 (cart70) antigens as well as κ lc (cartκ) were also developed showing promising results in in vitro and in vivo mouse tumour models.57–60 with respect to the therapeutic potential of tested car, it is worthwhile to note that suboptimal cytotoxic effects of these genetically engineered t cells vary among targeted antigens. although several explanations may be proposed, one possible reason is the difference in expression levels of the targeted antigens in malignant and normal b cells. for example, it has been reported that normal b cells express high levels of cd20 when compared to cd22, with copy numbers per cell of approximately 150 x 103 and 30 x 103, respectively.61,62 this high antigen intensity of cd20 on b cells may lead to anergy or deletion of engineered t cells, as demonstrated in adoptively transferred antigenspecific t cells in transgenic mice.63 malignant b cells also showed a substantial variability over time in the expression intensity of different targeted antigens. the expression levels of targeted antigens on b cells may vary according to type of b-cell neoplasms, stage of the disease, and also from patient to patient.61,62,64 thus, it is of importance that optimisation of car design benefits from the quantification of information about expression levels of targeted antigens on malignant b cells for each patient to increase anti-tumour activities. therefore, the challenge now is to develop methods that can precisely measure the expression levels of targeted antigens on malignant and normal b cells in an accurate and reproducible way. additionally, these standardised methods should be suited to clinical settings, easy to run, and non-invasive. one such method is flow cytometry, a robust and well-established technique that is regarded as an excellent immunophenotyping tool, as multiple molecules and surface antigens can be detected in individual cells.65 at present, it is not known to what extent heterogeneous antigen expression by individual malignant b cells represents a problem for car immunotherapy. however, it is quite likely that malignant b cells with low levels of targeted antigens may escape immunotherapy with engineered t cells. since the targeted antigens are distinct molecules, the possibility exists for combining cart19 or cart20 with cart22, cart23, cart70, or cartκ potentially to yield additive or synergistic activities against malignant b cells. in addition, to eliminate completely all malignant b cells, effective immunotherapy with car requires targeting surface antigens, which are expressed with great specificity by the earliest leukaemic progenitor. in this regard, engineered t cells should successfully penetrate deeper into the tissue and home to the sites with residual leukaemic b cells. besides their capacity to proliferate and survive in vivo, the efficacy of engineered t cells to eradicate residual leukaemic b cells may also be dependent on the choice of the epitope targeted by the potential antigens. clearly, the position of the targeted epitope itself, particularly its position within the antigen, has a major impact on the efficacy of engineered t cells activation independent of the scfv binding efficiency.66 mohamed-rachid boulassel and ahmed galal review | 281 long term potential toxicities of targeted b cell antigens in order to establish t cells expressing car as an effective immunotherapy for b-cell neoplasms, several issues still need to be overcome. some of these issues include the long-term potential toxicity to normal cells, long half-life, potential crossreactivity, immuno-toxicity, and genotoxicity of car. toxicity to normal cells an important concern with t cells expressing car is the long-term toxicity resulting from the depletion of normal human cells, which are important for homeostatic functions. this toxicity depends mainly on the distribution of the targeted antigens in normal tissues, as recently demonstrated in a clinical trial using t cells expressing carg250 (cartg250), a prominent rcc antigen.67 in early studies, monoclonal antibodies against this antigen showed a good safety profile in patients with rcc, but when scfv specificity was tested in cartg250, severe hepatotoxicity occurred due to the reactivity of engineered t cells against the g250 antigen expressed at very low levels on the biliary epithelium. similarly, based on the widely used humanised mab trastuzumab in cancer patients, a third generation of t cells expressing car was developed against the tumour antigen erbb2. the genetically engineered t cells displayed a robust anti-tumour activity in animal models, but strongly reacted with the erbb2 antigen expressed at low levels on lung epithelial cells, resulting in sudden death of the patient five days after treatment.68 collectively, these results demonstrate that the safety of targeted antigens with mabs does not translate into the safety of t cells expressing car because these engineered t cells with high-avidity receptors can respond to cells expressing their targeted antigens at levels too low to be detected with conventional means. although in b cell neoplasms, depletion of normal b cells following an engineered t-cell infusion could be medically managed by ig transfer and antiviral drugs, the potential risk of a negative impact on other organ functions due to low levels of antigen expression should be carefully evaluated. long half-life the issue of the long half-life of t cells expressing car remains a major problem. unlike mabs, which have defined half-lives, engineered t cells may potentially survive and function for years. therefore, the risks versus benefits should be clearly balanced for any given patient and a given car design. as a cautionary note, early therapy with cart19 resulted in the death of a patient who was suffering from chronic lymphocytic leukaemia with a cytokine storm, supporting further the direct cytotoxic potency of these engineered t cells.69 potential crossreactivity the possibility of unwanted cross-reactivity is becoming increasingly important in car design. engineered t cells may react with more than one antigenic determinant if some modifications occur when transfecting these t cells with viral vectors. this cross-reactivity may arise because the targeted antigens share an epitope with other tissue antigens, or because they have an epitope which is structurally similar to one used for designing car. it may also result from an epitope or antigen spreading, a process in which engineered t cells may expand their immune responses beyond the primary epitope to target other epitopes on normal cells. while these cross-reactivities are difficult to predict, they may lead to severe toxicity, especially since new targeted antigens are being evaluated with second or third generations of car. these latter are endowed with potent cytotoxic activities by killing cells which express just a few antigen molecules. potential immunotoxicity a key issue for the use of engineered t cells is the potential immunotoxicity of car. it has recently been reported that immune responses against both viral vector and scfv binding epitopes can be detected in patients receiving engineered t cells.70,71as a consequence, these immune responses may compromise the persistence of engineered t cells and also limit their anti-tumour activities. it is therefore essential to monitor carefully a host’s immune responses against all transgene products, including vectors themselves in order to increase the efficacy of engineered t cells. immunotherapy for b-cell neoplasms using t cells expressing chimeric antigen receptors from antigen choice to clinical implementation 282 | squ medical journal, august 2012, volume 12, issue 3 potential genotoxicity insertion of suicide genes into the protein constructs could be envisaged to further limit long-term car toxicities. however, introduction of genetic material may lead to genotoxicity; that considered, so far there has been no reported evidence that retrovirally engineered mature t cells induce mutagenesis.72,73 since their first description, engineered t cells have been used in more than one hundred patients with no malignant transformation reported in any case, contrasting with what was observed with genetically modified haematopoietic stem cells.74 to mitigate car toxicities, approaches such as a dose-escalating strategy or splitting t-cell doses over two or more days may be applied, particularly when new targeted antigens are first evaluated.8,75another approach is to administer high-dose corticosteroids, which could effectively eliminate engineered t cells as was demonstrated in rcc patients receiving cartg250.67 conclusion as engineered t-cell designs continue to improve, the selection of therapeutic targeted antigens has become crucial to the development of car. lessons learned so far from pilot clinical trials in patients treated with t cells expressing car clearly emphasise the importance of the choice of the right antigen. intense investigation is underway to discover more candidate antigens not only to expand the repertoire of potential targets for car design but also to identify those antigens that will provide selected killing of malignant b cells while sparing normal lymphocytes. a critical issue remains in identifying those targeted antigens that could be specifically expressed on b cells in individual neoplasms but not necessarily be used across all categories of patients with b cell malignancies. by further understanding the characteristics of potential targeted antigens, it may be possible to identify key epitopes that will help design new car with the goal of providing maximal clinical efficacy of engineered t cells. it might also be expected that multiple antigenic epitopes could be combined and targeted to further improve the killing properties of car therapy. equally important, research should also focus on identifying subsets of patients who are likely to respond to a specific target antigen. this will provide a rational basis for target antigens to be exploited in well-designed multicentre studies to establish engineered t-cell immunotherapy as a viable option in the treatment of b-cell neoplasms. one might also argue that the selection of t-cell populations that could be used for car design, conditioning regimens, and infused t-cell doses may be different for each targeted antigen. thus, it is quite possible that the only improvements in all these aspects will lead to significant progress that will ultimately advance the field of car therapy. this will require collaboration across different academic groups representing different disciplines in order to provide faster information that could be quickly translated into the car design. in the meantime, it is hoped that ongoing clinical trials will continue to generate increasing enthusiasm for the application of this personalised t-cell-based immunotherapy in b-cell neoplasms. a c k n o w l e d g m e n t the authors are grateful to rhyan pineda for technical assistance in drawing the figures. c o n f l i c t o f i n t e r e s t none. references 1. chamuleau me, van de loosdrecht aa, huijgens pc. monoclonal antibody therapy in haematological malignancies. curr clin pharmacol 2010; 5:148–59. 2. cartron g, watier h, golay j, solal-celigny p. from the bench to the bedside: ways to improve rituximab efficacy. blood 2004; 104:2635–42. 3. quintás-cardama a, wierda w, o’brien s. investigational immunotherapeutics for b-cell malignancies. j clin oncol 2010; 28:884–92. 4. cartellieri m, bachmann m, feldmann a, bippes c, stamova s, wehner r, et al. chimeric antigen receptor-engineered t-cells for immunotherapy of cancer. j biomed biotechnol 2010; 2010:956304. 5. kohn db, dotti g, brentjens r, savoldo b, jensen m, cooper lj, et al. cars on track in the clinic. mol ther 2011; 19:432–8. 6. jena b, dotti g, cooper lj. redirecting t-cell specificity by introducing a tumor-specific chimeric antigen receptor. blood 2010; 116:1035–44. 7. sadelain m, brentjens r, rivière i. the promise and potential pitfalls of chimeric antigen receptors. curr opin immunol 2009; 21:215–23. mohamed-rachid boulassel and ahmed galal review | 283 8. ertl hc, zaia j, rosenberg sa, june ch, dotti g, kahn j, et al. considerations for the clinical application of chimeric antigen receptor t cells: observations from a recombinant dna advisory committee symposium held june 15, 2010. cancer res 2011; 71:3175–81. 9. gattinoni l, finkelstein se, klebanoff ca, antony pa, palmer dc, spiess pj, et al. removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific cd8+ t cells. j exp med 2005; 202:907–12. 10. dudley me, yang jc, sherry r, hughes ms, royal r, kammula u, et al. adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. j clin oncol 2008; 26:5233–9. 11. cui y, zhang h, meadors j, poon r, guimond m, mackall cl. harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts. blood 2009; 114:3831–40. 12. wrzesinski c, paulos cm, kaiser a, muranski p, palmer dc, gattinoni l, et al. increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific t cells. j immunother 2010; 33:1–7. 13. muranski p, boni a, wrzesinski c, citrin de, rosenberg sa, childs r, et al. increased intensity lymphodepletion and adoptive immunotherapy-how far can we go? nat clin pract oncol 2006; 3:668–81. 14. rapoport ap, stadtmauer ea, aqui n, vogl d, chew a, fang hb, et al. rapid immune recovery and graftversus-host disease-like engraftment syndrome following adoptive transfer of costimulated autologous t cells. clin cancer res 2009; 15:4499– 507. 15. brocker t, karjalainen k. signals through t-cell receptor-zeta chain alone are insufficient to prime resting t lymphocytes. j exp med 1995; 181:1653–9. 16. brocker t. chimeric fv-zeta or fv-epsilon receptors are not sufficient to induce activation or cytokine production in peripheral t cells. blood 2000; 96:1999–2001. 17. till bg, jensen mc, wang j, chen ey, wood bl, greisman ha, et al. adoptive immunotherapy for indolent non-hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous cd20-specific t cells. blood 2008; 112:2261–71. 18. kochenderfer jn, wilson wh, janik je, dudley me, stetler-stevenson m, feldman sa, et al. eradication of b-lineage cells and regression of lymphoma in a patient treated with autologous t cells genetically engineered to recognise cd19. blood 2010; 116:4099–102. 19. porter dl, levine bl, kalos m, bagg a, june ch. chimeric antigen receptor-modified t cells in chronic lymphoid leukemia. n engl j med 2011; 365:725–33. 20. kalos m, levine bl, porter dl, katz s, grupp sa, bagg a, et al. t cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. sci transl med 2011; 3:95ra73. 21. brentjens rj, rivière i, park jh, davila ml, wang x, stefanski j, et al. safety and persistence of adoptively transferred autologous cd19-targeted t cells in patients with relapsed or chemotherapy refractory b-cell leukemias. blood 2011; 118:4817–28. 22. kochenderfer jn, dudley me, feldman sa, wilson wh, spaner de, maric i, et al. b-cell depletion and remissions of malignancy along with cytokineassociated toxicity in a clinical trial of anti-cd19 chimeric-antigen-receptor-transduced t cells. blood 2012; 119:2709–20. 23. lollini pl, forni g. cancer immunoprevention: tracking down persistent tumor antigens. trends immunol 2003; 24:62–6. 24. nadler lm, anderson kc, marti g, bates m, park e, daley jf, et al. b4, a human b lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant b lymphocytes. j immunol 1983; 131:244–50. 25. schriever f, freedman as, freeman g, messner e, lee g, daley j, et al. isolated human follicular dendritic cells display a unique antigenic phenotype. j exp med 1989; 169:2043–58. 26. tedder tf. cd19: a promising b cell target for rheumatoid arthritis. nat rev rheumatol 2009; 5:572–7. 27. tedder tf, engel p. cd20: a regulator of cell-cycle progression of b lymphocytes. immunol today 1994; 15:450–4. 28. ernst ja, li h, kim hs, nakamura gr, yansura dg, vandlen rl. isolation and characterisation of the b-cell marker cd20. biochemistry 2005; 44:15150– 8. 29. crocker pr, paulson jc, varki a. siglecs and their roles in the immune system. nat rev immunol 2007; 7:255–66. 30. tedder tf, tuscano j, sato s, kehrl jh. cd22, a b lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. annu rev immunol 1997; 15:481–504. 31. walker ja, smith kg. cd22: an inhibitory enigma. j immunol 2008; 123:314–25. 32. robbins ba, ellison dj, spinosa jc, carey ca, lukes rj, poppema s, et al. diagnostic application of two-color flow cytometry in 161 cases of hairy cell leukemia. blood 1993; 82:1277–87. 33. bonnefoy jy, lecoanet-henchoz s, gauchat jf, graber p, aubry jp, jeannin p, et al. structure and functions of cd23. int rev immunol 1997; 16:113– 28. immunotherapy for b-cell neoplasms using t cells expressing chimeric antigen receptors from antigen choice to clinical implementation 284 | squ medical journal, august 2012, volume 12, issue 3 34. acharya m, borland g, edkins al, maclellan lm, matheson j, ozanne bw, et al. cd23/fcεrii: molecular multi-tasking. clin exp immunol 2010; 162:12–23. 35. pinter-brown lc. sgn-30: a basis for the effective treatment of cd30 positive hematopoietic malignancies. expert opin investig drugs 2008; 17:1883–7. 36. rickert rc, jellusova j, miletic av. signaling by the tumor necrosis factor receptor superfamily in b-cell biology and disease. immunol rev 2011; 244:115–33. 37. gerber hp. emerging immunotherapies targeting cd30 in hodgkin‘s lymphoma. biochem pharmacol 2010; 79:1544–52. 38. van kooten c, banchereau j. cd40-cd40 ligand. j leukoc biol 2000; 67:2–17 39. tong aw, stone mj. prospects for cd40-directed experimental therapy of human cancer. cancer gene ther 2003; 10:1–13. 40. treumann a, lifely mr, schneider p, ferguson ma. primary structure of cd52. j biol chem 1995; 270:6088–99. 41. gilleece mh, dexter tm. effect of campath-1h antibody on human hematopoietic progenitors in vitro. blood 1993; 82:807–12. 42. boursalian te, mcearchern ja, law cl, grewal is. targeting cd70 for human therapeutic use. adv exp med biol 2009; 647:108–19. 43. borst j, hendriks j, xiao y. cd27 and cd70 in t cell and b cell activation. curr opin immunol 2005; 17:275–81. 44. borghese f, clanchy fi. cd74: an emerging opportunity as a therapeutic target in cancer and autoimmune disease. expert opin ther targets 2011; 15:237–51. 45. stein r, mattes mj, cardillo tm, hansen hj, chang ch, burton j, et al. cd74: a new candidate target for the immunotherapy of b-cell neoplasms. clin cancer res 2007; 13:5556–63s. 46. collins m, ling v, carreno bm. the b7 family of immune-regulatory ligands. genome biol 2005; 6:223. 47. suvas s, singh v, sahdev s, vohra h, agrewala jn. distinct role of cd80 and cd86 in the regulation of the activation of b cell and b cell lymphoma. j biol chem 2002; 277:7766–75. 48. vyth-dreese fa, boot h, dellemijn ta, majoor dm, oomen lc, laman jd, et al. localisation in situ of costimulatory molecules and cytokines in b-cell nonhodgkin’s lymphoma. immunology 1998; 94:580–6. 49. walsh sh, rosenquist r. immunoglobulin gene analysis of mature b-cell malignancies: reconsideration of cellular origin and potential antigen involvement in pathogenesis. med oncol 2005; 22:327–41. 50. jensen m, tan g, forman s, wu am, raubitschek a. cd20 is a molecular target for scfvfc:zeta receptor redirected t cells: implications for cellular immunotherapy of cd20+ malignancy. biol blood marrow transplant 1998; 4:75–83. 51. brentjens rj, latouche jb, santos e, marti f, gong mc, lyddane c, et al. eradication of systemic b-cell tumors by genetically targeted human t lymphocytes co-stimulated by cd80 and interleukin-15. nat med 2003; 9:279–86. 52. chen ey, press ow, jensen mc. cd8 immunomagnetic selection and interleukin-15 (il-15) facilitate the isolation of human cd8 cytotoxic t-lymphocytes (ctl) genetically engineered to express an anti-cd20 chimeric t-cell receptor (ctcr). j clin oncol 2004; 22:2542. 53. wang j, press ow, lindgren cg, greenberg p, riddell s, qian x, et al. cellular immunotherapy for follicular lymphoma using genetically modified cd20-specific cd8+ cytotoxic t lymphocytes. mol ther 2004; 9:577–86. 54. kowolik cm, topp ms, gonzalez s, pfeiffer t, olivares s, gonzalez n, et al. cd28 costimulation provided through a cd19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred t cells. cancer res 2006; 66:10995–11004. 55. wang j, jensen m, lin y, sui x, chen e, lindgren cg, et al. optimising adoptive polyclonal t cell immunotherapy of lymphomas, using a chimeric t cell receptor possessing cd28 and cd137 costimulatory domains. hum gene ther 2007; 18:712–25. 56. milone mc, fish jd, carpenito c, carroll rg, binder gk, teachey d, et al. chimeric receptors containing cd137 signal transduction domains mediate enhanced survival of t cells and increased antileukemic efficacy in vivo. mol ther 2009; 17:1453–64. 57. james se, greenberg pd, jensen mc, lin y, wang j, till bg, et al. antigen sensitivity of cd22-specific chimeric tcr is modulated by target epitope distance from the cell membrane. j immunol 2008; 180:7028–38. 58. giordano attianese gm, marin v, hoyos v, savoldo b, piszitola i, tettamanti s, agostoni v, et al. in vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-cd23 chimeric antigen receptor. blood 2011; 117:4736–45. 59. shaffer dr, savoldo b, yi z, chow kk, kakarla s, spencer dm, et al. t cells redirected against cd70 for the immunotherapy of cd70-positive malignancies. blood 2011; 117:4304–14. 60. vera j, savoldo b, vigouroux s, biagi e, pule m, rossig c, et al. t lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature b lymphocyte-derived malignant cells. blood mohamed-rachid boulassel and ahmed galal review | 285 2006; 108:3890–7. 61. wang l, abbasi f, gaigalas ak, vogt rf, marti ge. comparison of fluorescein and phycoerythrin conjugates for quantifying cd20 expression on normal and leukemic b-cells. cytometry b clin cytom 2006; 70:410–15. 62. rossmann ed, lundin j, lenkei r, mellstedt h, osterborg a. variability in b-cell antigen expression: implications for the treatment of b-cell lymphomas and leukemias with monoclonal antibodies. hematol j 2001; 2:300–6. 63. rocha b, grandien a, freitas aa. anergy and exhaustion are independent mechanisms of peripheral t cell tolerance. j exp med 1995; 181:993– 1003. 64. bataille r, jégo g, robillard n, barillé-nion s, harousseau jl, moreau p, et al. the phenotype of normal, reactive and malignant plasma cells. identification of «many and multiple myelomas» and of new targets for myeloma therapy. haematologica 2006; 91:1234–340. 65. moloney m, shreffler wg. basic science for the practicing physician: flow cytometry and cell sorting. ann allergy asthma immunol 2008; 101:544–9. 66. hombach aa, schildgen v, heuser c, finnern r, gilham de, abken h. t cell activation by antibodylike immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected t cells. j immunol 2007; 178:4650–7. 67. lamers ch, sleijfer s, vulto ag, kruit wh, kliffen m, debets r, et al. treatment of metastatic renal cell carcinoma with autologous t-lymphocytes genetically retargeted against carbonic anhydrase ix: first clinical experience. j clin oncol 2006; 24:e20– 2. 68. morgan ra, yang jc, kitano m, dudley me, laurencot cm, rosenberg sa. case report of a serious adverse event following the administration of t cells transduced with a chimeric antigen receptor recognising erbb2. mol ther 2010; 18:843–51. 69. brentjens r, yeh r, bernal y, riviere i, sadelain m. treatment of chronic lymphocytic leukemia with genetically targeted autologous t cells: case report of an unforeseen adverse event in a phase i clinical trial. mol ther 2010; 18:666–8. 70. lamers ch, willemsen r, van elzakker p, van steenbergen-langeveld s, broertjes m, oosterwijkwakka j, et al. immune responses to transgene and retroviral vector in patients treated with ex vivoengineered t cells. blood 2011; 117:72–82. 71. jensen mc, popplewell l, cooper lj, digiusto d, kalos m, ostberg jr, et al. antitransgene rejection responses contribute to attenuated persistence of adoptively transferred cd20/cd19-specific chimeric antigen receptor redirected t cells in humans. biol blood marrow transplant 2010; 16:1245–56. 72. van lunzen j, glaunsinger t, stahmer i, von baehr v, baum c, schilz a, et al. transfer of autologous gene-modified t cells in hiv-infected patients with advanced immunodeficiency and drug-resistant virus. mol ther 2007; 15:1024–33. 73. newrzela s, cornils k, li z, baum c, brugman mh, hartmann m, et al. resistance of mature t cells to oncogene transformation. blood 2008; 112:2278–86. 74. hacein-bey-abina s, hauer j, lim a, picard c, wang gp, berry cc, et al. efficacy of gene therapy for x-linked severe combined immunodeficiency. n engl j med 2010; 363:355–64. 75. junghans, rp. strategy escalation: an emerging paradigm for safe clinical development of t cell gene therapies. j transl med 2010; 8:55. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e7-11, epub. 27th jan 14 accepted 1st jan 14 in november 2013, the college of medicine and health sciences (comhs) at sultan qaboos university (squ) was “fully accredited” for a ten-year period (on its first attempt) by the association for medical education in the eastern mediterranean region (ameemr) in association with and in accordance with the standards of the world federation for medical education (wfme).the accreditation decision was made on the basis that the md programme complies with the wfme’s “basic and quality development standards”.1 it is notable that comhs’ “quality development standards” are considered by the wfme as “best practice” thus conferring distinguished status on the comhs’ md programme. this article describes the actions taken by the comhs which led to this success. the achievement of accreditation was neither a sudden nor an unsystematic accomplishment. it was the result of a lengthy and extensive process of continuous improvement of the comhs’ abilities and capacities that started long before the accreditation endeavour per se began in 2008. the process began by the construction of the “new” curriculum—an exercise that was accompanied and followed by other complementary measures. only after that was the accreditation process initiated. before explaining the process in more detail, a description of squ and the comhs might be helpful. sultan qaboos university and the college of medicine & health sciences squ was established in 1986 with five colleges (including the comhs). it offered only undergraduate programmes with an annual intake of 557 students. it now has nine colleges, four deanships, six support centres, three libraries, nine research centres, the squ hospital (squh), and offers 61 undergraduate, 59 master’s and 30 ph.d. programmes. in 2012–13, it admitted 4,221 students (3,441 undergraduates); and 2,689 students graduated in 2012 (2,345 undergraduates). in 2012– 13, squ employed 5,733 staff: 948 academics; 222 in the language center; 571 technical; 1,131 administrative; 232 support staff, plus 2,629 employees in squh. the university council (uc) is the supreme governing body of the university. the vice chancellor (vc) is the chief executive officer of the uc, aided by three deputy vice chancellors (dvcs) and various administrative units. the academic council, the top academic body of the university, is chaired by the vc. the comhs is managed by the college board (cb) and the dean (chief executive officer of the cb) who is aided by four assistant deans and the administration directorship. the college has a medical education unit (meu), an accreditation departments of 1physiology, 2child health, 3medicine, 4surgery, 5radiology & molecular imaging, 6pharmacology & clinical pharmacy, college of medicine & health sciences, sultan qaboos university, muscat, oman corresponding author e-mail: tanira@squ.edu.om تأمالت يف مسار اإلعتماد األكادميي لربنامج "دكتور يف الطب" بكلية الطب و العلوم الصحية جامعة السلطان قابوس �صليمه �لربو�ين, منى �ل�صعدون, عمر �لرو��س, �صيف �ليعربي, ر��صد �لعربي, ملك �للمكي, م�صباح تنرية editorial reflections on the academic accreditation of the md programme of the college of medicine & health sciences, sultan qaboos university, oman sulayma albarwani,1 muna al-saadoon,2 omar al-rawas,3 saif al-yaarubi,2 rashid al-abri,4 lamk al-lamki,5 *musbah o. tanira6 reflections on the academic accreditation of the md programme of the college of medicine & health sciences, sultan qaboos university, oman e8 | squ medical journal, february 2014, volume 14, issue 1 contemporary demands, of which accreditation was one. hence, accreditation was targeted during the construction of the new curriculum. this awareness of international standards led many other actions that proved to be of immense value to the comhs’ pursuit of accreditation. parallel to the curriculum restructuring, the comhs actively built its educational capacity to comply with international standards. the dean, in concert with the cc, planned a new annex building to house the nuclei of the skills laboratory, the computer laboratories, the medical informatics section and later the meu. these facilities were considered instrumental elements to the implementation of the new mep. in 2008, the new curriculum was initiated and all the new facilities put into use. in 2009, the cb approved the assessment policy, an important step towards developing the mep. one of the key features of the new curriculum was its management system, where the cc, not the departments, held the academic leadership of the comhs’ educational affairs. this, together with the close cooperation between the cc, the college examination committee and the meu greatly benefitted the mep implementation process. in particular, it helped align tutor development activities and the use of medical informatics with the requisites of the new curriculum. synergistically, all these factors meant that the college satisfied the most fundamental accreditation standards. however, ‘teething problems’ and the need for continuous development continued (and still continue) to pose on-going challenges. s ta g e 2: s e l f s t u d y c o m p i l at i o n simultaneously with the implementation of the new curriculum, the comhs focused on accreditation by establishing the accreditation and quality management committee (aqmc). the composition of the aqmc was critical to the pursuit of accreditation, as was fully realised at the end of the whole process. its members were accomplished basic or clinical scientists with a comprehensive knowledge of the mep, clinical teaching and assessment policy, etc., and enjoyed the respect of comhs and university staff as well as forming a cohesive and technically expert working group. it was imperative that all aqmc members gain and quality management unit, a curriculum office, an examination office, a publications office, the medical library and 19 departments (six basic and 13 clinical science). it employs 75 academics (25 clinical) with 329 clinical tutors who share the responsibility of delivering the md programme together with 41 administrative and 49 technical staff and eight research associates. the college changed its name from the college of medicine to the college of medicine & health sciences in june 2002. currently, it offers md, b.sc. health sciences and biomedical laboratory sciences programmes, a master’s in biomedical sciences (since 2001) and a ph.d. programme (since 2008). the annual md programme intake is 120– 130 students. the comhs graduated its first 48 doctors in 1993 and 128 in 2012; since its inception, the comhs has graduated a total of 1,640 doctors. the college’s pursuit of accreditation the accreditation process took place in three distinct stages: (1) pre-accreditation (preparing for accreditation); (2) self study compilation (self evaluation), and (3) receiving the site visit team (external evaluation). s ta g e 1: p r e-a c c r e d i tat i o n a c t i v i t i e s in september 2000, the cb decided to reform its md degree medical educational programme (mep) and, thus, reformulated its curriculum committee (cc) with the mission “to recommend changes to improve the alignment of the mep with evolving practice pattern, scientific development and social needs.” from this mission, the cc drew a number of objectives and principles, communicated to the cb in its first progress report. a principle stated “… that curriculum development should not be restricted to reforming contents and pedagogic strategy; but also cover areas such as tutor/student development, improving educational resources, adopting an assessment policy that complies with curricular reform and forging an administrative structure to optimize management of the curriculum. in addition, it was made explicit that the committee perceives the process of curriculum development as a continuum.” in accordance to this principle, it was indispensable for the cc to meet sulayma albarwani, muna al-sadoon, omar al-rawas, saif al-yaarubi, rashid al-abri, lamk al-lamki and musbah o. tanira editorial | e9 an in-depth understanding of the accreditation standards and process and that they should be fully knowledgeable of the requirements for achieving their mission. initially, the aqmc investigated the international accrediting agencies for medical educational programmes and identified the lcme (liaison committee on medical education – usa) and the world federation for medical education (wfme). both agencies were contacted and visited; the wfme was selected as lcme does not evaluate non-usa-based md programmes. this decision was followed by a focus on mastering the wfme’s standards and process of accreditation. first, key publications on accreditation were obtained and discussed. second, aqmc members attended international events organised by international accrediting agencies in the arab world and beyond. third, face-to-face meetings were held with officials of all the accreditation agencies to discuss comhsrelated issues and obtain their feedback. these activities acquainted the aqmc with accreditation processes, standards and requirements and supplied the inspiration and confidence to begin and complete the accreditation process. then each member of the aqmc was assigned as a comhs focal point for one or more areas of the wfme standards. the effort was now directed towards the comhs staff so that they would take ‘ownership’ of the accreditation process. the aqmc regularly disseminated their acquired knowledge, not only to staff, but also to students and other stakeholders via: (1) periodical reporting to the cb; (2) distributing of the “basic medical education: wfme global standards for quality improvement” to heads of department (hods) and members of the cb; (3) conducting a “knowledge sharing day” workshop for faculty, staff, clinical tutors, students and other stakeholders to discuss the wfme standards where the vc and the dvcs were invited to discuss relevant issues; (4) inviting wfme advisors to the comhs so that all faculty, staff, clinical tutors and students could interact with them, and (5) arranging a discussion meeting for hods and wfme advisors. concurrent to the above activities, the arduous and challenging task of collecting the information for compiling the self study of the md programme was begun. as it was being done for the first time, the process was cumbersome—collecting a voluminous amount of information that was neither always available nor complete. yet, there was an utter and patient determination that the information in the self study should be supported by documents and evidence. after interactions with the ‘sources of information’, a more ‘closely-interactive’ strategy was developed to optimise the data collection: (1) identify the most appropriate source/s of information; (2) assign the most suitable member of the aqmc to act as the representative, contact the identified source/s, plan with them how to retrieve and verify the required information and, when appropriate, submit the information to the aqmc; (3) periodic meetings of the aqmc to ensure that the required information was complete and up-todate, and (4) continual contact between the aqmc representative and the ‘sources of information’ to resolve any queries. in addition to the above, it was realised that some areas of the standards, namely, educational programme, student assessment and programme evaluation, were central to the portrayal of the md prorgramme and warranted additional preparation efforts. on receipt of the information from each aqmc member, the information was discussed and verified. progressively, a preliminary information document was constructed; the comhs history and other contextual information were added to form the initial draft of the self study document. this was circulated to cb members to be disseminated to comhs staff for their feedback. their comments/ modifications were iteratively reviewed, verified, discussed and sanctioned by the aqmc until an ‘acceptable-to-all’ first draft of the self study document was compiled. it was unequivocally accepted that the final self study document should be a comprehensive record of the comhs and the md programme for future reference.2 therefore, its production was a rigorous operation and an admirable collaborative effort shared by the aqmc, a number of faculty and the medical informatics section of the meu. from the start until the end of the accreditation process, all decisions were reached by consensus; this approach later proved to be invaluable to accentuating the college-at-large ownership of the accreditation process and led to the comhs’ motto “together towards accreditation” which dominated the working environment, as well as eliciting student support, during the later stages of the accreditation process. reflections on the academic accreditation of the md programme of the college of medicine & health sciences, sultan qaboos university, oman e10 | squ medical journal, february 2014, volume 14, issue 1 casual interactions in the comhs and squh—so that everyone would share in this event and make it their own. although the aqmc had assiduously collected the required documentation, it became apparent as the site visit approached that this process needed further work. a detailed audit was conducted to review the documentation and to identify, collect and prepare all other potentially useful documentation that might be requested by the visiting panel, e.g., even lists of students, faculty and staff compiled. each document was saved on a dedicated computer; cds of this information were also made available for the site visit panel members in case they needed to browse during their free time. indexing systems for the hard and soft copies were made: one by subject (using keywords) and the other according to wfme areas/subareas. it was important that the visit schedule be arranged with the utmost care since it would be the ‘presentation’ of all our work and the impression it left should be representative of the amount of effort the comhs had devoted to the whole process. therefore, arrangements for escorting and transporting the panel, the induction of interviewees, and the choice of venues for interviews and the selection of sites to be visited were all made in good time. meetings were held with those involved to ensure that every item of the schedule would be completed in the most satisfactory way. an aqmc representative was selected to accompany the site visit panel and attend the interviews in order to facilitate their work and answer any queries. this member was the person in-charge of indexing the documentation. another member oversaw the task of alerting interviewees to their time slot in the schedule, handling id cards, and ensuring the sites were ready for viewing, etc. thus, every item, minor or major, in the site visit schedule was closely monitored and managed. conclusion after all the intense and diligent work of obtaining the accreditation of the md programme ended in success, there was time to analyse and reflect, but not to forget to celebrate. actually and more importantly, it was time to decide what was next! the answer to this question lies in what the accreditation pursuit has yielded. on the one hand, it has helped s ta g e 3: r e c e i v i n g t h e e x t e r n a l e va l u at i o n t e a m the literature related to accreditation, and our own experience, underlines the key role of top management in any successful accreditation process. indeed, without top management ‘champions’ the process will be hindered and the likelihood of success be distant—especially during the final stages of external evaluation. in our endeavor, the part played by the comhs top management was commendable. once the dates of the site visit were announced and the college received the agenda details, the aqmc declared a ‘state of alert’ marked by frequent meetings and additional work with one person assigned to oversee the attainment of each task. a number of specific measures were taken: (1) an awareness raising campaign was run for all stakeholders appropriate to their level of involvement; (2) completion and categorisation of all the documentation and its cross-indexing by subject and in accordance to the standards numbering system; (3) identification and categorisation of people to be interviewed by the site visit team; (4) ensuring the site visit schedule was executed as planned, and (5) ensuring full coordination between the aqmc, the comhs top management and its directorship of administration. the awareness raising campaign had the objective that every individual in the comhs and every stakeholder should be aware and fully knowledgeable of the event, its details and their specific role, if any. for this purpose, many measures were undertaken, for example: (1) printing sufficient copies (3,000) of the self study for every student, faculty, clinical tutor, administrative staff, and all stakeholders; (2) the ‘campaign motto’ was a routine stamp on all the deanery’s correspondence and appeared on 2,500 badges to be worn by all comhs and squh affiliates; (3) danglers and banners in halls and walkways marked the occasion and encouraged people to become involved; (4) videos of students and staff explaining their views on the accreditation process were run on the comhs closed circuit television; (5) an aqmc member attended all levels of comhs meetings to explain the details and significance of the site visit, and (6) every opportunity was taken to make the accreditation the “talk-of-the-time”—even during sulayma albarwani, muna al-sadoon, omar al-rawas, saif al-yaarubi, rashid al-abri, lamk al-lamki and musbah o. tanira editorial | e11 the comhs to identify areas of improvement. on the other hand, it has brought out an amazing spirit of loyalty and solidarity among its community (faculty, staff and students). the challenge now is how the comhs can accelerate the momentum that it gained during the accreditation endeavour and couple it with the unique spirit of cohesion and loyalty generated in its community so as to create a continuum for development and progress. a c k n o w l e d g e m e n t s the comhs acknowledges the significant contribution of all its staff and students, the staff of squh and the ministry of health, particularly its hospitals, that contribute to the delivery of the medical educational programme. references 1. world foundation for medical education. global standards for quality improvement in basic medical education. from: www.wfme.org/standards/bme accessed: nov 2013. 2. college of medicine and health sciences, sultan qaboos university. md programme self study. from: http://web. squ.edu.om/med/accreditation/selfstudy2012_2013.pdf accessed: nov 2013. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e170-175, epub. 7th apr 14 submitted 30th sep 13 revision req. 12th nov 13; revision recd. 5th dec 13 accepted 9th jan 14 the escalating burden of chronic disease in oman—primarily type 2 diabetes and cardiovascular disease—is a major public health challenge. the political declaration of the united nations (un) general assembly on the prevention and control of non-communicable diseases, adopted in 2011, asserted that population-based strategies to prevent chronic disease require an all-of-government approach targeting modifiable risk factors, particularly tobacco use, unhealthy diets and physical inactivity.1 with a focus on one particular risk factor, physical inactivity, this article aims to operationalise these lofty goals by proposing a framework for a national strategy designed to encourage physical activity. physical activity encompasses “recreational or leisure-time physical activity, transportation (e.g. walking or cycling), occupational (i.e. work), household chores, play, games, sports or planned exercise, in the context of daily, family, and community activities”.2 physical inactivity is the fourth leading risk factor for chronic disease globally.3 the world health organization (who) and the american college of sports medicine recommend that adults do at least 150 minutes of moderate-intensity activity a week and strength training at least twice a week.3,4 this aerobic activity recommendation is also used by the ministry of health (moh) of oman.5 for adults, the available evidence on the prevalence of physical inactivity in oman shows that it occurs in 33% of men and 41% of women. for college students, the prevalence is 43% in men and 57.8% in women; for adolescents, who are recommended to do at least 60 minutes of moderate-intensity physical activity per day,2 the prevalence is 70.1% in boys and 84.6% in girls.6–8 these data underscore the vital importance of public health efforts to reduce physical inactivity 1office of the world health organization, muscat, oman; 2behavioral epidemiology laboratory, baker idi heart & diabetes institute, melbourne, australia; 3cancer prevention research centre, school of population health, university of queensland, brisbane, australia *corresponding author e-mail: rmmabry@gmail.com اسرتاتيجية وطنية لتشجيع النشاط البدين يف سلطنة عمان دعوة للعمل روث مابري ، نيفيل اأوين ، اليزابيث اإيكني abstract: the increasing prevalence of chronic disease in oman is a public health challenge. available evidence in oman on physical inactivity, the fourth leading risk factor for chronic disease, calls for urgent action to reduce physical inactivity as part of a key strategy to address chronic disease in oman. the public health implications of this evidence for oman are considered in light of recommendations outlined in the toronto charter for physical activity. the charter provides a systematic approach of physical activity and outlines an action plan that could be adapted to the omani context. urgent intersectoral action focusing on a shared goal and a more deliberate public health response addressing physical inactivity is required. further research is needed on the determinants of physical inactivity and culturally appropriate interventions in order to guide future public health actions. keywords: epidemiology; public health; physical activity; health policy; oman. امللخ�ص: تزايد انت�صار الأمرا�س املزمنة يف عمان ميثل حتديا لل�صحة العامة. الأدلة املتاحة يف �صلطنة عمان على اخلمول البدين ، والذي هو رابع عامل يف املزمنة الأمرا�س معاجلة ل�صرتاتيجية اأ�صا�صي كجزء البدين الن�صاط قلة من للحد عاجلة اإجراءات اتخاذ اإىل يدعو ، املزمنة للأمرا�س رئي�صي خطر �صلطنة عمان. من هذه الأدلة توؤخذ الآثار ال�صحية العامة ل�صلطنة عمان بالعتبار يف �صوء التو�صيات الواردة يف ميثاق تورونتو للن�صاط البدين. ين�س امليثاق على طريقه ممنهجة للن�صاط البدين و ي�صع اخلطوط العري�صة خلطة عمل ميكن تكييفها مع احلالة العمانية. العمل امل�صرتك العاجل بني القطاعات والذي يركز على هدف م�صرتك وال�صتجابة املدرو�صة ملعاجلة اخلمول البدين مطلوب. و هناك حاجة اإىل املزيد من البحوث لتحديد العوامل امل�صببة يف اخلمول البدين و التدخلت املنا�صبة ثقافيا للمجتمع العماين من اأجل توجيه الإجراءات ال�صحية العامة يف امل�صتقبل . مفتاح الكلمات: علم الأوبئة؛ وال�صحة العامة؛ الن�صاط البدين؛ ال�صيا�صة ال�صحية؛ عمان. sounding board a national strategy for promoting physical activity in oman a call for action *ruth mabry,1 neville owen,2 elizabeth eakin3 ruth mabry, neville owen and elizabeth eakin sounding board | e171 20–29 years and men who were married.16 the only commonly-identified high-risk sub-group across all physical activity domains was the unemployed group. this group included students, retirees, housewives and people looking for work. factors associated with physical inactivity among the unemployed could include conservative cultural norms as well as limited options for entertainment and volunteer work.17 this varied pattern of physical activity by gender and domain implies that policies and programmes need to target women and men separately and according to behaviour domains. for example, establishing womenonly exercise locations could reduce leisure inactivity among women and building walker-friendly residential areas could reduce transport inactivity in men. p o l i c y a n d p r o g r a m m at i c o p t i o n s t o a d d r e s s p h y s i c a l i n a c t i v i t y in a qualitative study, mid-level public health managers were asked to reflect upon the implications of the evidence described above to identify relevant policy interventions to increase physical activity in oman.17 the key suggestion made by the respondents was to create activity-supportive and culturally-sensitive environments through relevant changes to the physical environment and to public policy. this recommendation was in response to the following key barriers identified by the participants: personal (lack of motivation, awareness and time); social (norms restricting women’s participation in outdoor activities and the low value placed on physical activity); environmental (lack of places to be active and unfavourable weather), and policy (ineffective health communication and limited resources). studies from gcc countries have examined the constraints and opportunities for physical activity and have made similar recommendations.18,19 n e e d f o r f u r t h e r r e s e a r c h given the rising prevalence of chronic disease in oman, further research and on-going surveillance is required to gather context-specific evidence regarding the level of physical inactivity in the country.20,21 there is great potential to inform public health approaches through building on the initial research findings presented in this paper. population-based survey datasets at the national and local level provide a wealth of data to improve the understanding of physical inactivity and to develop and monitor the outcomes of evidence-based policies and public health programmes.7,8,22,23 based on the behavioral epidemiology framework proposed by sallis et al., an in-depth analysis of these datasets could be carried out to explore the associations of physical as part of a multisectoral strategy to address the burden of chronic disease in oman. e p i d e m i o l o g y o f p h y s i c a l a c t i v i t y i n o m a n in addition to the previously mentioned studies reporting on the national prevalence, seven studies utilising a similar definition for physical activity have been published, with five focusing on young people9–13 and two on adults.14,15 all the studies carried out among young people focused on secondary school students living in the capital region of muscat. only one study examined the association of physical activity with health outcomes; it reported a significant inverse association of vigorous physical activity with body mass index among both boys and girls.12 all studies explored the prevalence and distribution of physical activity. the key findings included a high prevalence of physical inactivity in this age group (ranging from 33.3–61.2% in boys and 76.9–90.2% in girls).12,13 boys were significantly more physically active than girls9,10,12,13 and students living in rural areas were significantly more active than their urban counterparts.9 in addition, a larger percentage of girls were reported to be in the earlier stages of behaviour change compared to boys (i.e. pre-contemplation: 5.8% versus 4.7% and contemplation: 26.7% versus 10.3% respectively) and girls identified a significantly higher number of internal and external barriers to physical activity than boys.13 the two peer-reviewed studies among adults in oman relate to the adult population of the city of sur. one study demonstrated a significant association of physical inactivity, particularly in the work domain, with the metabolic syndrome, which is a clustering of risk factors for type 2 diabetes and cardiovascular disease.14 the study also found a higher prevalence of the metabolic syndrome among women across all domains of activity (work, transport and leisure) when compared to men. this pattern of higher prevalence of the metabolic syndrome among women in comparison to men is similar to other countries in the gulf cooperation council (gcc).15 the second study found that the lowest level of physical activity was in the leisure domain.16 in general, men were more inactive in the work domain compared to women and women were more inactive in the transport and leisure domains, a pattern seen in many developing countries. this same study also reported that demographic, anthropometric and behavioural correlates varied by gender and by the domain of activity. high-risk groups for physical inactivity included men and women who were unemployed, women aged 40 years and older, men aged a national strategy for promoting physical activity in oman a call for action e172 | squ medical journal, may 2014, volume 14, issue 2 inactivity and health outcomes and to determine the prevalence (and variations among population sub-groups) and correlates of physical inactivity.24 in addition, documenting and evaluating existing interventions, some of which are mentioned below, as well as testing interventions aimed at promoting physical activity, could provide practical approaches to addressing physical activity in oman. this population-health approach is vital to understanding and addressing the increasing prevalence of chronic disease and its risk factors in oman.25 public health implications for oman public health experts in oman have emphasised that a more deliberate and coordinated multisectoral approach needs to be implemented to promote physical activity.17 the health sector needs to coordinate with other sectors—such as the municipalities, and the transportation and urban planning sectors that are involved in shaping the built environment and the education, sports and tourism sectors that promote recreational physical activity and competitive sports— to ensure that policies supportive of physical activity are established. evidence from around the world reiterates the importance of taking a comprehensive approach to the promotion of physical activity.1,3,26,27 the nizwa healthy lifestyle project (nhlp) is a community-based initiative focusing on the promotion of healthy lifestyles and the primary prevention of chronic diseases. an evaluation of the nhlp has provided helpful initial evidence on physical activity interventions for informing public health initiatives in oman; this has been the only well-documented population-level physical activity intervention project in the country to date. the settings-based approaches used to address physical inactivity as part of a broader strategy to address cardiovascular disease appeared to succeed in increasing the prevalence of physical activity in both men and women.23 helpful further guidance is now available to inform population strategies designed to promote physical activity. the toronto charter for physical activity is an advocacy tool developed by physical activity experts and launched at the 3rd international congress on physical activity and public health held in may 2010, in toronto, canada.28 it summarises the evidence on the benefits of physical activity and outlines four key action points: (1) implement a national policy and action plan; (2) introduce policies that support physical activity; (3) reorient services and funding to prioritise physical activity, and (4) develop partnerships for action. the following paragraphs discuss the public health implications of the available evidence in oman around these four overlapping priority areas. i m p l e m e n t a n at i o n a l p o l i c y a n d a c t i o n p l a n the toronto charter emphasises the unifying role of a national policy and action plan.28 promoting physical activity requires the involvement of numerous stakeholders, many of whom are not within the health sector. integrated action beyond the health sector is not a new approach in oman. the health-promoting school (hps) initiative introduced in 2004 brought together the moh and the ministry of education.29 the national strategic response to hiv/aids launched in 2005 involves several government entities and civil society as well as international agencies,30 while the nhlp involves more than 22 sectors.27 oman can build on these national intersectoral experiences to develop and implement a national policy and plan of action on physical activity. i n t r o d u c e p o l i c i e s t h at s u p p o r t p h y s i c a l a c t i v i t y the toronto charter stresses the importance of a supportive policy framework for physical activity.28 the creation of communities that make physical activity an easier choice is determined by numerous policy decisions that influence where people live and work, their means of transport, the availability of schools and health services and their options for recreation.31,32 creating a supportive policy environment has been a key solution suggested by programme managers in oman.17 given that the prevalence of the metabolic syndrome was higher in women across all domains of physical activity, and that demographic correlates varied by gender and physical activity domains (work, transport and leisure), it is imperative that policies be gender-relevant and domain-specific. r e o r i e n t s e r v i c e s a n d f u n d i n g t o p r i o r i t i s e p h y s i c a l a c t i v i t y according to the toronto charter, for policies to be successful, services and funding need to prioritise physical activity.28 the following paragraphs provide a brief overview of services that could promote physical activity based on the suggestions made in the toronto charter. school settings have the potential to reach a large number of young people as nearly a quarter of the omani population is school-aged and over 90% attend school.33,34 several existing initiatives targeting schoolaged children promote physical activity, including the national hps initiative31 and the move for health ruth mabry, neville owen and elizabeth eakin sounding board | e173 segregated facilities and/or scheduling.53 promoting women-only venues could involve collaborating with other government and private institutions, such as with the omani women’s association under the ministry of social development. in addition, since many adults are neither athletic nor interested in participating in competitive sports, the scope of the ministry of sports affairs could be broadened to promote and support informal recreational sports like walking, hiking, biking and swimming, in addition to the women’s aerobics classes recently initiated in government sports facilities in the capital area. d e v e l o p pa r t n e r s h i p s f o r a c t i o n increasing a population’s participation in physical activity, as the toronto charter states, requires partnership and intersectoral collaboration.28 given that the moh bears the cost of managing chronic disease patients, the health sector needs to take a strong leadership role in galvanising support from other sectors to promote physical activity. this whole-of-government approach is perhaps the most challenging aspect of promoting physical activity; however, it is also the most vital in terms of prevention of chronic disease in oman.54 among the most successful examples of intersectoral collaboration for health in oman are the community-based initiatives and the school health programme.23,29 partnership efforts now need to be taken to the next level so that policy-makers can adhere to the commitments that were made at the united nations general assembly on non-communicable diseases.1 the toronto charter, which emphasises inclusiveness by avoiding “health-centric” language28 and the accompanying document, investments that work for physical activity,39 are excellent advocacy tools for this process. conclusion given the rising prevalence of chronic disease and the ageing of both the omani population and those in neighbouring countries, public health priorities must address the well-known behavioural risk factors of chronic disease. promoting physical activity involves creating a supportive physical environment and building a more proactive public policy response in the omani context as identified by key public health experts. the toronto charter provides a useful framework for developing a national strategy on physical activity. concerted intersectoral action focused on a shared national goal and a more deliberate public health response addressing physical inactivity are key strategies for the prevention of initiative in nizwa.23 examining the effectiveness of these initiatives and developing and testing multicomponent school-based interventions based on available evidence could help shape appropriate policies and behaviour change interventions targeting young people in schools.35–39 given the gender differences in physical activity among young people and adults, a special focus on approaches to increasing physical activity among girls at an early age is vital. using both a cross-sectional survey and focus group discussions with members of the community, an evaluation of the nhlp suggests that the introduction of gender-segregated walkways has led to an increase in the prevalence of physical activity.23 in addition, anecdotal evidence suggests a general appreciation for recent initiatives to build sidewalks and neighbourhood parks in the capital area. research indicates that landuse mix, population density, transport connectivity, parking and neighbourhood aesthetics (walkways and green areas) influence physical activity in developed countries.31,32 the evidence on transportation and urban design in relation to physical activity is sparse for gcc countries. thus, research from within the region is required to identify neighbourhood environmental characteristics that are gender-relevant, supportive of walking and cycling activities and appropriate for the hot arid climate. primary healthcare is the backbone of the health system in oman.40 evidence, largely from developed countries, demonstrates the effectiveness of promoting physical activity in primary care.26 existing patient-focussed interventions, addressing diabetes and hypertension management and the adult screening programme for people 40 years and older, could benefit from the inclusion of detailed physical activity counselling guidelines within their protocols.41–43 routine screening of physical activity for all adults visiting primary care facilities could be introduced through the adoption of simple assessment tools and complemented with relevant counselling that targets high-risk groups, such as women and the unemployed.44–46 the introduction of more intensive behaviour change interventions modelled from available programmes could be complemented by reorienting the training of healthcare workers and strengthening the healthcare system to include preventive health services. this is a need that has been identified both within the region and globally.23,26,47–52 the ministry of sports affairs advocates sports for all; however, a key solution is to ensure that government facilities provide a variety of sporting options and are accessible for men and women of all ages. this could be implemented by having gendera national strategy for promoting physical activity in oman a call for action e174 | squ medical journal, may 2014, volume 14, issue 2 chronic disease. given that the moh bears the cost of managing chronic disease, policy-makers within the health sector need to advocate for multisectoral interventions. a c k n o w l e d g e m e n t s an earlier version of this paper was presented at the moh's directorate general of health affairs continuing professional development workshop held on 14th march 2013 and the 1st national public health symposium held on 15th april 2013. the views expressed in this article are those of the authors and do not necessarily reflect those of the who. references 1. united nations general assembly. political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases. from: www.who. int/nmh/events/un_ncd_summit2011/political_declaration_ en.pdf?ua=1 accessed: aug 2013. 2. world health organization. global recommendations on physical activity for health. from: www.whqlibdoc.who.int/ publications/2010/9789241599979_eng.pdf accessed: aug 2013. 3. world health organization. global status report on noncommunicable diseases 2010: description of the global burden of ncds, their risk factors and determinants. from: www. whqlibdoc.who.int/publications/2011/9789240686458_eng.pdf accessed: aug 2013. 4. haskell wl, lee im, pate rr, powell ke, blair sn, franklin ba, et al. physical activity and public health: updated recommendation for adults from the american college of sports medicine and the american heart association. circulation 2007; 116:1081–93. doi: 10.1161/ circulationaha.107.185649. 5. alasfoor d, rajab h, al-rassasi b. task force for the development and implementation of the omani food based dietary guidelines. food based dietary guidelines: technical background and description. from: www.fao.org/ ag/humannutrition/19542-0561250979706400b7cc8ca7366cc0 7c0.pdf accessed: aug 2013. 6. directorate of research & studies, ministry of health oman. world health survey, oman, 2008. from: www.moh.gov.om/ en/reports/whssurvey2008(1).pdf accessed: aug 2013. 7. abdou sah, al-muzahmi sn. oman global school-based student health survey 2010: gshs country report. from: w w w.who.int/chp/gshs/2010_countr y_report_om an_ gshs_en.pdf accessed: aug 2013. 8. ministry of health. community health and disease surveillance newsletter, vol. 17, iss. 6. from: www.moh.gov.om/en/reports/ publications/newsletter17-6.pdf accessed: aug 2013. 9. albarwani s, al-hashmi k, al-abri m, jaju d, hassan mo. effects of overweight and leisure-time activities on aerobic fitness in urban and rural adolescents. metab syndr relat disord 2009; 7:369–74. doi: 10.1089/met.2008.0052. 10. al barwani s, al abri m, al hashmi k, al shukeiry m, tahlilkar k, al zuheibi t, et al. assessment of aerobic fitness and its correlates in omani adolescents using the 20-metre shuttle run test: a pilot study. j sci res med sci 2001; 3:77–80. 11. hassan mo, al-kharusy w. physical fitness and fatness among omani schoolboys: a pilot study. j sci res med sci 2000; 2:37– 41. 12. kilani h, al-hazzaa h, waly mi, musaiger a. lifestyle habits: diet, physical activity and sleep duration among omani adolescents. sultan qaboos univ med j 2013; 13:510–19. 13. youssef rm, al shafie k, al-mukhaini m, al-balushi h. physical activity and perceived barriers among high-school students in muscat, oman. east mediterr health j 2013; 19:759–68. 14. mabry rm, winkler ea, reeves mm, eakin eg, owen n. associations of physical activity and sitting time with the metabolic syndrome among omani adults. obesity (silver spring) 2012; 20:2290–5. doi: 10.1038/oby.2012.26. 15. mabry rm, winkler ea, reeves mm, eakin eg, owen n. correlates of omani adults’ physical inactivity and sitting time. public health nutr 2013; 16:65–72. doi: 10.1017/ s1368980012002844. 16. mabry rm, reeves mm, eakin eg, owen n. gender differences in prevalence of the metabolic syndrome in gulf cooperation council countries: a systematic review. diabet med 2010; 27:593–7. doi: 10.1111/j.1464-5491.2010.02998.x. 17. mabry rm, al-busaidi zq, reeves mm, owen n, eakin eg. addressing physical inactivity in omani adults: perceptions of public health managers. public health nutr 2013; 17:674–81. doi:10.1017/s1368980012005678. 18. ali hi, baynouna lm, bernsen rm. barriers and facilitators of weight management: perspectives of arab women at risk for type 2 diabetes. health soc care community 2010; 18:219–28. doi: 10.1111/j.1365-2524.2009.00896.x. 19. berger g, peerson a. giving young emirati women a voice: participatory action research on physical activity. health place 2009; 15:117–24. doi: 10.1016/j.healthplace.2008.03.003. 20. al-kilani h, waly m, yousef r. trends of obesity and overweight among college students in oman: a cross sectional study. sultan qaboos univ med j 2012; 12:69–76. 21. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 22. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1—methodology, sociodemographic profile and epidemiology of noncommunicable diseases in oman. oman med j 2012; 27:425– 43. 23. ministry of health oman. nizwa healthy lifestyle evaluation report. muscat, oman: ministry of health, 2012. 24. sallis jf, owen n, fotheringham mj. behavioral epidemiology: a systematic framework to classify phases of research on health promotion and disease prevention. ann behav med 2000; 22:294–8. doi: 10.1007/bf02895665. 25. al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos univ med j 2006; 6:3–9. 26. marcus bh, williams dm, dubbert pm, sallis jf, king ac, yancey ak, et al. physical activity intervention studies: what we know and what we need to know: a scientific statement from the american heart association council on nutrition, physical activity, and metabolism (subcommittee on physical activity); council on cardiovascular disease in the young; and the interdisciplinary working group on quality of care and outcomes research. circulation 2006; 114:2739–52. doi: 10.1161/circulationaha.106.179683. 27. yancey ak, fielding je, flores gr, sallis jf, mccarthy wj, breslow l. creating a robust public health infrastructure for physical activity promotion. am j prev med 2007; 32:68–78. doi: 10.1016/j.amepre.2006.08.029. 28. bull fc. global advocacy for physical activity—development and progress of the toronto charter for physical activity: a global call for action. res exerc epidemiol 2011; 13:1–10. 29. whitman cv, aldinger ce, eds. case studies in global school health promotion: from research to practice. new york, usa: springer science+business media, llc, 2009. ruth mabry, neville owen and elizabeth eakin sounding board | e175 42. ministry of health oman. diabetes mellitus: management guidelines for primary health care. 2nd ed. from: www.moh. gov.om/en/mgl/manual/diabetesmoh.pdf accessed: aug 2013. 43. ministry of health oman. operational and management guidelines for the national non-communicable diseases screening program. 1st ed. from: www.moh.gov.om/en/ r e p o r t s / g u i d e l i n e s _ m a n u a l _ f o r _ t h e _ n a t i o n a l _ n c d _ screening_program.pdf accessed: aug 2013. 44. smith bj, marshall al, huang n. screening for physical activity in family practice: evaluation of two brief assessment tools. am j prev med 2005; 29:256–64. doi: 10.1016/j.amepre.2006.01.008. 45. milton k, clemes s, bull f. can a single question provide an accurate measure of physical activity? br j sports med 2013; 47:44–8. doi: 10.1136/bjsports-2011-090899. 46. milton k, bull fc, bauman a. reliability and validity testing of a single-item physical activity measure. br j sports med 2011; 45:203–8. doi: 10.1136/bjsm.2009.068395. 47. al-ghafri t. al-amirat women’s health. muscat, oman: ministry of health (unpublished report). 48. midhet fm, sharaf fk. impact of health education on lifestyles in central saudi arabia. saudi med j 2011; 32:71–6. 49. kalter-leibovici o, younis-zeidan n, atamna a, lubin f, alpert g, chetrit a, et al. lifestyle intervention in obese arab women: a randomized controlled trial. arch intern med 2010; 170:970–6. doi: 10.1001/archinternmed.2010.103. 50. al-ghawi a, uauy r. study of the knowledge, attitudes and practices of physicians towards obesity management in primary health care in bahrain. public health nutr 2009; 12:1791–8. doi: 10.1017/s1368980008004564. 51. al-doghether m, al-tuwijri a, khan a. obstacles to preventive intervention: do physicians’ health habits and mind-set towards preventive care play any role? saudi med j 2007; 28:1269–74. 52. ali hi, bernsen rm, baynouna lm. barriers to weight management among emirati women: a qualitative investigation of health professionals’ perspectives. int q community health educ 2008–2009; 29:143–59. doi: 10.2190/iq.29.2.d. 53. ministry of sports affairs oman. annual report 2010 [in arabic]. muscat, oman: ministry of sports affairs, 2011. 54. bull fc, bauman ae. physical inactivity: the “cinderella” risk factor for noncommunicable disease prevention. j health commun 2011; 16:13–26. doi: 10.1080/10810730.2011.601226. 30. joint united nations programme on hiv/aids (unaids). global aids response progress report 2012: country progress report sultanate of oman. from: w w w. u n a i d s . o r g / e n / d a t a a n a l y s i s / k n o w y o u r r e s p o n s e / countryprogressreports/2012countries/ce_om_narrative_ report[1].pdf accessed: aug 2013. 31. saelens be, sallis jf, black jb, chen d. neighborhoodbased differences in physical activity: an environment scale evaluation. am j public health 2003; 93:1552–8. doi: 10.2105/ ajph.93.9.1552. 32. saelens be, sallis jf, frank ld. environmental correlates of walking and cycling: findings from the transportation, urban design, and planning literatures. ann behav med 2003; 25:80– 91. doi: 10.1207/s15324796abm2502_03. 33. ministry of national economy oman. statistical yearbook 2011. muscat, oman: ministry of national economy, 2011. 34. world health organization regional office for the eastern mediterranean. the work of who in the eastern mediterranean region: annual report of the regional director 1 january–31 december 2010. from: www.emro.who.int/about-who/annualreports/annual-report-2010.html accessed: aug 2013. 35. mehana m, kilani h. enhancing physical education in omani basic education curriculum: rationale and implications. int j cross-discip sub educ 2010; 1:27. 36. van sluijs em, mcminn am, griffin sj. effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials. br j sports med 2008; 42:653–7. doi: 10.1136/bmj.39320.843947.be. 37. kriemler s, meyer u, martin e, van sluijs em, andersen lb, martin bw. effect of school-based interventions on physical activity and fitness in children and adolescents: a review of reviews and systematic update. br j sports med 2011; 45:923– 30. doi: 10.1136/bjsports-2011-090186. 38. faulkner ge, buliung rn, flora pk, fusco c. active school transport, physical activity levels and body weight of children and youth: a systematic review. prev med 2009; 48:3–8. doi: 10.1016/j.ypmed.2008.10.017. 39. global advocacy for physical activity (gapa). non communicable disease prevention: investments that work for physical activity. from: www.globalpa.org.uk/pdf/investmentswork.pdf accessed: aug 2013, 40. world health organization regional office for the eastern mediterranean. country cooperation strategy for who and oman: 2010–2015. em/ard/036/e. from: www.who. int/countr yfocus/cooperation_strateg y/ccs_omn_en.pdf accessed: aug 2013. 41. ministry of health oman and world health organization regional office for the eastern mediterranean. a manual for the management of hypertension in primary health care. 1st ed. from: www.moh.gov.om/en/mgl/manual/htn.pdf accessed: aug 2013. department of anatomy, vardhman mahavir medical college & safdarjung hospital, new delhi, india *corresponding author e-mail: drhitendra3@gmail.com تفرع غري طبيعي للحبل الفرعي للضفرية العضدية مصاحبة لإلنضغاط العصيب الوعائي تقرير احلالة هتندرة ك�مار ل�ه, �ضيخا �ضينغ, راجي�ص ك�مار �ض�ري abstract: the brachial plexus consists of a network of nerves that innervates the upper limbs and its musculature. we report a rare formation of the lateral cord of the brachial plexus observed during the dissection of a 47-year-old male cadaver at the department of anatomy, vardhman mahavir medical college, new delhi, india, in 2016. the lateral cord was exceptionally long with twin lateral pectoral nerves and twin lateral roots of the median nerve. the proximal lateral root of the median nerve was thin in comparison to the medial root of the median nerve. the distal lateral root of the median nerve was thicker and followed an unusual course through the coracobrachialis muscle. in the lower third of the arm, the median nerve and the brachial artery—along with its vena comitans—spanned through the brachialis muscle. surgeons, anaesthesiologists, radiologists and anatomists should be aware of such anatomical variations as they may result in neurovascular compression. keywords: anatomic variation; dissection; brachial plexus; pectoral nerves; median nerve; musculocutaneous nerve; case report; india. من نادر لت�ضكل حالة هنا نعر�ص الع�ضلي. وجهازها العل�ية االأطراف تتخلل ع�ضبية �ضبكة من الع�ضدية ال�ضفرية تتك�ن امللخ�ص: ماهافري فاردمن كلية يف الت�رسيح, ق�ضم يف عاما العمر 47 من يبلغ رجل جلثة ت�رسيح اأثناء ل�حظت الع�ضدية لل�ضفرية الفرعي احلبل الطبية, ني�دلهي, الهند, عام 2016. كان احلبل اجلانبي ال�ح�ضي ط�يل ب�ضكل ا�ضتثنائي مع ت�ضكل اأع�ضاب مزدوجة �ضدرية وح�ضية وجذور الع�ضب. لهذا االأن�ضي اجلذر مع باملقارنة رقيقا النا�ضف للع�ضب االأدنى ال�ح�ضي اجلذر كان النا�ضف, للع�ضب ال�ح�ضي للفرع مزدوجة كان اجلذر الفرعي االأدنى من الع�ضب املت��ضط رقيقا باملقارنة مع اجلذر االأو�ضط من الع�ضب املت��ضط. وكان اجلذر الفرعي القا�ضي من الع�ضب املت��ضط �ضميكا ويتبع م�ضارغري طبيعي من خالل الع�ضالت الغرابية الع�ضدية. يف الثلث ال�ضفلي من الذراع, تخلل الع�ضب املت��ضط بهذه الت�رسيح وعلماء االأ�ضعة اأطباء التخديرو واأطباء اجلراحني يعلم اأن ينبغي الع�ضدية. الع�ضلة املرافق وال�ريد الع�ضدي وال�رسيان االختالفات الت�رسيحية الأنها قد ت�ؤدي اإىل �ضغط وعائي ع�ضبي. الكلمات املفتاحية: اإختالفات ت�رسيحية؛ ت�رسيح؛ ال�ضفرية الع�ضدية؛ االأع�ضاب ال�ضدرية؛ الع�ضب املت��ضط؛ الع�ضب الع�ضلي اجللدي؛ تقرير حالة؛ الهند. unusual branching pattern of the lateral cord of the brachial plexus associated with neurovascular compression case report *hitendra k. loh, shikha singh, rajesh k. suri sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e112–115, epub. 30 mar 17 submitted 2 sep 16 revision req. 12 oct 16; revision recd. 10 nov 16 accepted 17 nov 16 doi: 10.18295/squmj.2016.17.01.021 case report the brachial plexus is a network ofmultiple nerves which innervates the upper arm and the muscles which control movement of the shoulder girdle.1 the union of the anterior divisions of the upper and middle trunk in the infraclavicular part of the brachial plexus forms the lateral cord (lc). the first branch of the lc, the lateral pectoral nerve (lpn), pierces the clavipectoral fascia to supply the pectoralis major muscle.1 in addition, the lpn gives rise to a communicating twig to the medial pectoral nerve across the axillary artery, through which it supplies the pectoralis minor muscle. the next branch, the musculocutaneous nerve (mcn), runs obliquely downwards to pierce and supply the coracobrachialis (cb) muscle.1 inferiorly, the mcn also supplies the biceps brachii (bb) and the brach ialis muscles before forming the lateral cutaneous nerve of the forearm. the third branch is the lateral root of the median nerve (mn), which is a continuation of the lc; this joins the medial root to enfold the axillary artery and forms the mn.1 clavicular and sternal attachments of the pectoralis major muscle are supplied by the medial pectoral nerve, whereas the inferior third and costo-abdominal insertions of the pectoralis major muscle are innervated by the lpn.2 various arterial, neural and muscular variations in the upper limbs have been described in the literature.3–5 however, anatomical variations in the course hitendra k. loh, shikha singh and rajesh k. suri case report | e113 and branching patterns of the distal part of the brachial artery are extremely rare. these may include variations in the course beneath the supracondylar process, through the brachialis or pronator teres muscles or a low division under the pronator teres muscle.4,6 awareness of neural variations in the brachial plexus region is essential for surgeons, anaesthesiologists, radiologists and anatomists. the presence of anatomic variations in the peripheral nervous system may also explain unusual clinical findings or symptoms.7 this case describes an interesting and rare variant of the lc of the brachial plexus with a duplication of the lpn, twinning of the lateral root of the mn, the absence of the medial pectoral nerve, an atypical formation of the mn and an abnormal course of the mcn. case report a routine undergraduate medical dissection of an embalmed 47-year-old male indian cadaver took place at the department of anatomy, vardhman mahavir medical college, new delhi, india, in 2016. during the dissection, an unusual variation of the left brachial plexus was noted [figure 1]. the lc was unusually long at 8.9 cm and gave rise to a double lpn. the proximal lpn (lp1) was thicker, pierced the clavipectoral fascia and entered the superficial surface of the pectoralis major muscle. the distal lpn (lp2) was slender, branched one centimetre away from the lp1 and entered the pectoralis minor muscle from its deeper aspect. the lc also supplied double lateral roots of the mn. the proximal lateral root of the mn (lrm1) was slender and originated 3.7 cm from the formation of the lc. the distal lateral root of the mn (lrm2) measured 9.2 cm in length, was significantly thicker and arose 9 cm from the formation of the lc [figure 2]. upon reaching the cb, the lrm2 pierced the muscle belly and joined the mn in the mid-arm. at the formation of the mn, the lrm1 was very thin in comparison to its medial root, whereas the lrm2 was significantly thicker. the proximal course of the mcn passed between the bb and cb muscles and traversed between the bb and brachialis muscles distally to continue as the lateral cutaneous nerve of the forearm. the mn and the brachial artery, flanked by its vena comitans, were wrapped in a common fascial sheath and traversed through the brachialis muscle in the lower third of the arm. the intramuscular course of this neurovascular bundle was 5.9 cm in length and the medial pectoral nerve was absent. the anatomy of the brachial plexus on the right side of the cadaver was normal. all measurements were recorded using a thread to follow the course of the nerves. figure 1: photograph from the anterior view of the dissected axillary fossa and the upper arm of an embalmed 47-year-old male indian cadaver showing an unusual variation of the left brachial plexus. the biceps brachii has been cut and reflected. lp2 = distal lateral pectoral nerve; pmi = pectoralis minor; pma = pectoralis major; lp1 = proximal lateral pectoral nerve; lc = lateral cord; lrm1 = proximal lateral root of the median nerve; aa = axillary artery; cb = coracobrachialis; bb = biceps brachii; mn = median nerve; mcn = musculocutaneous nerve; ba = brachial artery; lrm2 = distal lateral root of the median nerve. figure 2: photograph from the anterior view of the dissected axillary fossa and the upper arm of an embalmed 47-year-old male indian cadaver. the coracobrachialis muscle has been partially removed to expose the distal lateral root of the median nerve. the biceps brachii has been cut and reflected. pma = pectoralis major; pmi = pectoralis minor; lp2 = distal lateral pectoral nerve; lp1 = proximal lateral pectoral nerve; bb = biceps brachii; lc = lateral cord; lrm1 = proximal lateral root of the median nerve; aa = axillary artery; cb = coracobrachialis; mcn = musculocutaneous nerve; mn = median nerve; lrm2 = distal lateral root of the median nerve; ba = brachial artery; br = brachialis; nvb = lower part of the neurovascular bundle. unusual branching pattern of the lateral cord of the brachial plexus associated with neurovascular compression case report e114 | squ medical journal, february 2017, volume 17, issue 1 nerves is established. communication between the mcn and the mn can therefore be attributed to their common embryological derivation during the development of the brachial plexus.15 altered signalling amongst mesenchymal cells and neuronal growth cones during the union of the brachial plexus cords has been previously found to result in variations in neural anatomy.16 in the current case, there were two potential sites which may have resulted in neurovascular compression in the arm: the entrapment of the lrm2 through the cb muscle or a potential injury to the lrm2 in the middle arm and the irregular course of the mn and the brachial artery through the brachialis muscle in the lower arm.17 entrapment injuries in the arm may lead to paresthaesia along the preaxial border of the forearm, weak elbow flexion and other manifestations of a mn injury.17 entrapment of the mn and brachial artery is widely studied.18 however, it is rare for anatomical variations to occur in the distal part of the brachial artery in the muscles of the arm and forearm.4,6 the mn and the brachial artery cross the mid and lower arm as the main neurovascular complex.19 however, their proximity to the medial intermuscular septum and the medial side of the bb and brachialis muscles make them vulnerable to various entrapment syndromes; moreover, while mn entrapment can occur at several sites from the upper arm to the carpal tunnel, it is especially common at sites below the elbow.20 the mn and brachial artery can also be compressed by the lacertus fibrosus in the lower arm.21 this is critical as the nerve can lose its suppleness and become stretched by joint movement when it becomes attached to adjacent structures. although nerve compression is easily managed and can be resolved by releasing the neurovascular structure from the entrapment, clinicians should be aware of potential entrapment injuries as they can lead to neuropathy, loss of muscle strength and atrophy.22 conclusion this case describes the unusual occurrence of a double lpn, double lateral roots of the mn and an anomalous course of the mcn. these rare variations are potential sites for neural or neurovascular compression in the middle and distal arm, respectively. radiologists, neurovascular surgeons, anaesthesiologists and anatomists should consider such potential variations when dealing with the brachial plexus region. discussion the current report describes a case in which there were two lpns present: the lp1, which supplied the pectoralis major muscle after piercing the clavipectoral fascia, and the lp2, which supplied the pectoralis minor directly. the occurrence of a duplicate lpn arising from the anterior division of the upper and middle trunk instead of the lc has been previously reported in the literature.8 a common trunk of origin of the medial pectoral nerve and the lpn from the middle trunk of the brachial plexus has also been documented.9 awareness of variations in the anatomy and course of the pectoral nerves is crucial during surgery; for example, when using pectoral muscle flaps during breast surgeries or when the brachial plexus pectoral nerves are transferred to supply a paralysed arm during traction injury repairs.10,11 cases in which the lc of the brachial plexus pierces the cb muscle and divides into the mcn and the lateral root of the mn are very rare.4 in the present case, the lc was longer than usual and gave rise to the lp1, lp2 and lrm1 before dividing into the mcn and the lrm2 upon reaching the cb muscle. the mcn then continued between the bb and cb muscles in the arm instead of piercing the cb muscle; hence, the mn presented with double lateral roots (the lrm1 and lrm2). moreover, the lrm1 was very thin compared to the lrm2 which joined the mn in the mid-arm. this difference in thickness, along with the abnormal course of the lrm2 through the cb, is clinically significant. durgesh et al. reported a case in which the mcn passed along the medial edge of the cb muscle without penetrating it.12 jamuna et al. reported a case whereby the mcn joined the mn after piercing the cb muscle and abhaya et al. reported a rare case in which the lc directly pierced the cb before dividing into the mcn and the lateral root of the mn.3,13 abnormal variations in the formation and course of the mcn are important as they may affect the outcomes of surgical interventions for shoulder joint trauma, flap dissections, explorative procedures, axillary blocks and post-traumatic evaluations.14 anatomical variations in the brachial plexus arise during embryonic development. in a developing embryo, the upper limb bud appears by the 27th gestational day.15 after the fifth gestational week, motor axons originating from the spinal cord enter the limb buds and the brachial plexus forms as a single radicular cone by the 34–35th gestational day. following this, the brachial plexus splits into ventral and dorsal segments and the roots of the mn and ulnar nerve are derived from the ventral segments.15 by the 48th gestational day, the localisation of the upper limb hitendra k. loh, shikha singh and rajesh k. suri case report | e115 references 1. mcminn rm. last’s anatomy: regional and applied, 8th ed. london, uk: churchill livingstone, 1990. pp. 68–9. 2. cunningham dj, romanes gj. cunningham’s textbook of regional anatomy, 11th ed. london, uk: oxford university press, 1972. p. 308. 3. abhaya a, khanna j, prakash r. variation of the lateral cord of brachial plexus piercing coracobrachialis muscle. j anat soc india 2003; 52:168–70. 4. bergman ra, afifi ak, myiauchi r. illustrated encyclopedia of human anatomic variation. from: www.anatomyatlases.org/ anatomicvariants/anatomyhp.shtml accessed: nov 2016. 5. vollala vr, nagabhooshana s, bhat sm, potu bk, rodrigues v, pamidi n. multiple arterial, neural and muscular variations in upper limb of a single cadaver. rom j morphol embryol 2009; 50:129–35. 6. wysiadecki g, polguj m, haładaj r, topol m. low origin of the radial artery: a case study including a review of literature and proposal of an embryological explanation. anat sci int 2016. doi: 10.1007/s12565-016-0371-9. 7. thwin ss, zaini f, than m, lwin s, myint m. unusual variations of the lateral and posterior cords in a female cadaver. singapore med j 2012; 53:e128–30. 8. bhanu sp, sankar dk, susan pj. formation of median nerve without the medial root of medial cord and associated variations of the brachial plexus. int j anat var 2010; 3:27–9. 9. khullar m, sharma s, khullar s. multiple bilateral neuroanatomical variations of the nerves of the arm: a case report. int j med health sci 2012; 1:75–84. 10. david s, balaguer t, baque p, de peretti f, valla m, lebreton e, et al. the anatomy of the pectoral nerves and its significance in breast augmentation, axillary dissection and pectoral muscle flaps. j plast reconstr aesthet surg 2012; 65:1193–8. doi: 10.1016/j.bjps.2012.03.032. 11. samardzic m, rasulic lg, grujicic dm, bacetic dt, milicic br. nerve transfers using collateral branches of the brachial plexus as donors in patients with upper palsy: thirty years’ experience. acta neurochir (wien) 2011; 153:2009–19. doi: 10.1007/ s00701-011-1108-0. 12. durgesh v, rao rr. musculocutaneous nerve revisited. int j basic appl med sci 2013; 3:34–6. 13. jamuna m, amudha g. a cadaveric study on the anatomic variations of the musculocutaneous nerve in the infraclavicular part of the branchial plexus. j clin diagn res 2011; 5:1144–7. 14. mavishettar sm, iddalagave s. musculocutaneous nerve and its variations. int j gen med pharm 2013; 2:53–64. 15. uyaroğlu fg, kayalioğlu g, ertürk m. anastomotic branch from the median nerve to the musculocutaneous nerve: a case report. anat 2008; 2:63–6. doi: 10.2399/ana.08.063. 16. sanes dh, reh ta, harris wa. axon growth and guidance. in: development of the nervous system, 3rd ed. san diego, california, usa: academic press; 2011. pp. 105–42. doi: 10.10 16/b978-0-12-374539-2.00009-4. 17. neal s, fields kb. peripheral nerve entrapment and injury in the upper extremity. am fam physician 2010; 81:147–55. 18. bilecenoglu b, uz a, karalezli n. possible anatomic structures causing entrapment neuropathies of the median nerve: an anatomic study. acta orthop belg 2005; 71:169–76. 19. mcnamara b. clinical anatomy of the median nerve. adv clin neurosci rehabil 2003; 2:19–20. 20. birch r. operating on peripheral nerves. in: surgical disorders of the peripheral nerves, 2nd ed. london, uk: churchill livingstone, 2011. pp. 231–302. doi: 10.1007/978-1-84882 108-8_7. 21. kumar h, das s, gaur s. case report: entrapment of the median nerve and the brachial artery by the lacertus fibrosus. arch med sci 2007; 3:284–6. 22. green dp, hotchkiss rn, pederson wc. green’s operative hand surgery, 4th ed. philadelphia, pennsylvania, usa: churchill livingstone, 1999. pp. 1417–22. https://doi.org/10.1007/s12565-016-0371-9 https://doi.org/10.1016/j.bjps.2012.03.032 https://doi.org/10.1007/s00701-011-1108-0 https://doi.org/10.1007/s00701-011-1108-0 https://doi.org/10.2399/ana.08.063 https://doi.org/10.1016/b978-0-12-374539-2.00009-4 https://doi.org/10.1016/b978-0-12-374539-2.00009-4 https://doi.org/10.1007/978-1-84882-108-8_7 https://doi.org/10.1007/978-1-84882-108-8_7 taurine levels in human aqueous humour medical sciences (2000), 2, 25−31 © 2000 sultan qaboos university department of microbiology, college of medicine, sultan qaboos university, p.o.box: 35, postal code: 123, muscat, sultanate of oman 25 in-vitro activity of synercid and related drugs against streptococcus oralis isolated from septicaemia and endocarditis cases * rafay a m فاعلية عقار السنرسيد وأمثاله ضد المكورات السبحية الفمية المعزولة من )ن الدم وعفونتهانتا( حاالت التهاب بطانة القلب واألنتانية رافع. أ تمت معمليًا :الطريقة. ا موجبة الصبغة وشدة خطورة التهاب بطانة القلب أصبح من الضرورة النظر الى طرق بديلة للعالج لبكيتري مع زيادة المقاومة ل :الهدف: الملخص القلب البكتيري، وأثنين من مرضى تسمم الدم ، واثنين من أفواه أشخاص أصحاء ، ثم دراسة منحنى اإلبادة لســتة من المكورات السبحية تم عزلها من مرضى التهاب بطانة آانت الفاعلية التثبيطية الصغرى للسنرسيد :النتائج. مقارنة فاعلية السنرسيد مع البنسلين، األموآسسلين، التيكوبالنين، الفنكومايسين، الكليندمايسين واإلرثرومايسين في المختبر 0.5 (الفاعلية التثبيطية الكبرىو) لتر/ملغ0.25 (الفاعلية التثبيطية الصغرى وقد وجد فرق بسيط بين . لتر/ملغ0.25وآانت قيمة القراءتين لتر/ ملغ 0.5-0.06بين ضيقة وتتراوح بكل من البنسلينن، آليندمايسين، ارثرومايسين وبالرغم من أن الفاعلية الصغرى للسنرسيد ضد المكورات السبحية من نوع أوراليس آانت نسبيًا أعلى مقارنة ). لتر/ملغ لتر لمعظم المعزوالت ماعدا /ملغ4وجد أن الترآيزات القاتلة للسنرسيد مساوية أو أدنى من . وتيكوبالنين إال أن مقدرة السنرسيد على إبادة الباآتريا في المختبر آانت أآبر بكثير أظهر السنرسيد فاعلية إبادة عالية متفوقًا على آل من البنسلين والفانكومايسين، بالنسبة لكل المعزوالت :الخالصة. لتر/ملغ 64لتر واألخرى أآبر من /ملغ16إثنتين واحدة آانت .خالل ستة ساعات من المالمسة% 99.9العشرة من المكورات السبحية بنسبة abstract: ��������� – the increase in resistance to gram positive organisms and seriousness of infective endocarditis, makes it necessary to look for an alternate treatment. �� �� – in-vitro activity of synercid was compared with penicillin, amoxycillin, teicoplanin, vancomycin, clindamycin and erythromycin. ������ – synercid showed minimum inhibitory concentrations (mic) within the narrow range of 0.06 – 0.5 mg/l. mic50 and mode values were both 0.25 mg/l. there was just two-fold difference between the mic50 (0.25 mg/l) and the mic90, (0.5 mg/l). although the mics of synercid for s. oralis were relatively high compared to penicillin, clindamycin, erythromycin and teicoplanin, the in-vitro bactericidal activity of synercid was much greater. synercid mbc values were < 4 mg/l for most of the isolates, except for one of 16 mg/l and the other >64 mg/l. killing curve was performed on six isolates of s. oralis from infective endocarditis, two from septicaemia patients and two from the oral flora of normal individuals. ���������� – synercid showed superior bactericidal activity when compared to penicillin and vancomycin against all ten isolates of s. oralis tested. synercid was bactericidal (99.9% kill) against all ten isolates of s. oralis within six hours of contact. key words: streptococcus oralis, synercid, penicillin, amoxycillin, erythromycin, vancomycin, teicoplanin, clindamycin iridans streptococci are among the commonest causes of infective endocarditis, except in intravenous drug abusers where staphylococcus epidermidis is frequently isolated.1 bayliss found that streptococci or enterococci were the causative organisms in 63% of infective endocarditis cases and that 48% of these cases were viridans streptococci.2 these findings were also supported by young.3 with newer identification methods viridans streptococci have been further classified to its species level and it has been shown that s. oralis, s. sanguis, and s. gordonii are the most frequently isolated species in patients with infective endocarditis.4,5 owing to an increasing resistance to β-lactam antibiotics, the treatment of infective endocarditis has become more complicated.6 keeping these in mind, a range of antibiotics was considered, where antibiotic sensitivity, bactericidal kill and killing curve were tested to estimate their potential for the treatment of infective endocarditis caused by s. oralis. synercid (rp59500), like pristinamycin, is a streptogramin antibiotic. it is a semi-synthetic modification of the two major constituents of pristinamycin: pristinamycin ia and pristinamycin iia. synercid consists of a quinuclidinylthiomethyl pristinamycin ia derivative and a diethlyaminoethyl-sulphonyl pristinamycin iia derivative in a ratio of 30:70 weight for weight.7 its several novel properties have excited the interest of infectious diseases researchers.7,8,9 one of these is the activity of synercid against a number of resistant gram-positive pathogens.10 because of its v 25 r a f a y 26 bactericidal activity against oral streptococci, its role in the treatment of infective endocarditis is indicated. method a total of sixty clinical isolates of s. oralis were collected from patients either with endocarditis, neutropenia and from the normal oral flora of healthy individuals. strains from blood culture were primarily isolated using bactec nr850 and identified using api 20 strep (bio merieux, la balme les grottes, france), and were further identified using laboratory-devised method.11 determination of mic the isolates were tested for their susceptibility to penicillin (glaxo), amoxycillin (sigma), erythromycin (abbot), vancomycin (sigma), teicoplanin (merrel dow), clindamycin (upjohn) and synercid, a new injectable streptogramin. isolates grown on columbia agar (ca) were used to inoculate 10 ml of iso-sensitest broth (oxoid cm473) supplemented with 2% horse serum (wellcome no. 5) and incubated for 4 hours at 37°c in air. broth suspensions were adjusted by making a standard dilution in iso-sensitest broth in order to obtain a final inoculum on antibiotic containing agar plates of approximately 104 colony-forming units (cfu). doubling dilutions of the antibiotics were prepared in 0.1m phosphate buffer of ph 7 to provide final concentrations in iso-sensitest agar (oxoid cm471) over the range 0.003–128 mg/l. a multipoint inoculator (denley instruments ltd) was used to inoculate the isolates, which were then incubated aerobically at 37°c for 18 hours. the mic was defined as the lowest antibiotic concentration that completely suppressed visible growth (one colony being ignored). standard strain of s. oralis (a6) was inoculated with each batch of susceptibility tests to serve as control (mic 0.12 mg/l for penicillin). determination of minimum bactericidal concentrations (mbc) a total of 15 clinical isolates of s. oralis were used. isolates ar3, ar12, ar13, ar19, ar40 were from patients with endocarditis, 92c17, 93c87, t8-2-12 from patients with neutropenia, 23, 24, a26, n4-1-4 from those with normal oral flora and a6, a10, a 9 from those with septicaemia. mic/mbc values were determined for synercid, penicillin, vancomycin, clindamycin, erythromycin and teicoplanin against 15 strains of s. oralis using a microtitre method, with antibiotic concentrations ranging from 0.003–64 mg/ml. doubling dilutions of antibiotics were prepared in iso-sensitest broth and these were inoculated with 5 hour broth cultures, diluted to give a final concentration of 104 cfu/ml. after 18 hours of incubation at 37°c, mbcs were determined by subculture of all wells with no visible growth. mic was recorded as the highest antibiotic dilution showing no turbidity. mbcs were determined by transferring 100µl from wells showing no growth to ca plates. the inoculum was allowed to dry before spreading and incubated for 18 hours at 37°c in air. the mbc was taken as the lowest antibiotic concentrations of antimicrobial that reduced the number of viable organisms by 99.9% kill after 18 hours incubation. time kill curves. the in-vitro bactericidal activities of penicillin, vancomycin and synercid were compared against ten isolates of s. oralis. organisms were grown in brain heart infusion (bhi) for 18 hours at 37°c in air and 100 µl added to 100 ml of freshly prepared pre-warmed bhi. after one hour incubation at 37°c on an aerobic shaker, solutions of antibiotics were added to the culture to provide final concentrations of 4 times the previously determined mics for s. oralis under investigation and an antibiotic-free growth control. viable counts were performed at one, two, four, six and twenty-four hours by the miles and misra12 method. the counts were converted to log10 and the mean of the duplicate determination calculated. the counts did not differ by more than 10% and the majority of the counts differed by less than 5%. results table 1 demonstrates the relative activities of penicillin, amoxycillin, erythromycin, clindamycin, vancomycin, teicoplanin and synercid against 60 isolates of s. oralis isolated from infective endocarditis, neutropneic and normal oral flora patients. table 2 shows the mic50, mic90 and mode mic values for each of the antibiotics tested. synercid was the most active of all the agents tested, except with clindamycin and for some strains with erythromycin. one distinct population of isolates could be distinguished with synercid, all of which were inhibited within a narrow 0.06–0.5 mg/l range. the mic50 and mode values were both at 0.25 mg/l, with two-fold difference between the mic50 and mic90, at 0.25 mg/l and 0.5 mg/l respectively. synercid was four fold more active compared with penicillin and amoxycillin. mics for penicillin and amoxycillin were similar, with a range of 0.015–16.0 mg/l. the mode and mic50 values for penicillin and amoxycillin were 0.03 mg/l and 0.125 mg/l respectively, while mic90 values were 2 and 8 mg/l, respectively. the distribution of isolates according to their susceptibility to erythromycin showed one population with an mic range of 0.015 – 2 mg/l, in an approximate normal distribution with 6% strains requiring mic 8 mg/l and 2% requiring 64 mg/l. i n v i t r o a c t i v i t y o f s y n e r c i d two very distinct populations of isolates could distinguished for clindamycin with no isolates showin intermediate susceptibility. clindamycin was the mo active of the antibiotics tested against these isolates wi mic50 value of 0.00375 mg/l, with a sensitive pop lation in mic range of < 0.00375 – 0.06 mg/l. t majority of isolates were clustered within this narro band at 0.00375 – 0.06 mg/l and 14% isolates showed higher range of mics of 2–8 mg/l. the distribution isolates according to their susceptibility to teicoplan was uni-modal with mics range of 0.06–1 mg/l, show percentage of s. oralis (n=60) isolate erythromycin, , teicoplanin antibiotics 0.0037 0.0075 0.015 0.03 0.06 penicillin 3 21 14 amoxycillin 3 24 14 clindamycin 43 14 13 13 3 erythromycin 2 24 8 teicoplanin 14 vancomycin synercid 5 mic (mg/l) of the 7 antibiotic against 6 antibiotic mode penicillin 0.03 amoxycillin 0.03 clindamycin 0.00375 erythromycin 0.03 teicoplanin 0.125 vancomycin 0.5 syncercid 0.125 table 1. s susceptible to penicillin, amoxycillin, clindamycin, , vancomycin, synercid, (mic, mg/l). 0.12 0.25 0.50 1 2 4 8 16 32 64 20 14 5 11 3 6 3 9 18 3 13 3 5 8 2 7 5 14 14 10 14 6 6 2 40 41 2 2 1 2 60 36 2 25 52 18 be g st th uhe w a of in ing a normal distribution curve, and only 1% strain with an mic of 4 mg/l fell outside this range. vancomycin showed narrow mic range of 0.25–2 mg/l, in an approximate normal distribution curve. for teicoplanin, the values for mic50, mode and mic90 were generally two fold lower than those for vancomycin. synercid was four fold more active than vancomycin. in-vitro mbcs with six antibiotics to s. oralis. table 3 shows the comparative in-vitro bactericidal activity of synercid, penicillin, vancomycin, clindamycin, erythromycin and teicoplanin against fifteen isolates of . oralis, using a microdilution broth technique. hree strains showed moderate penicillin esistance (>0.25 mg/l), but all fifteen isolates ere inhibited by < 2 mg/l penicillin. seven of hese were penicillin tolerant (mic/mbc ratio 1:8) and required >2 mg/l of penicillin for a 9.9% kill. the mic's for teicoplanin (range .03–0.5 mg/l) against these isolates were lower han those of vancomycin (range 0.5–2 mg/l); he bactericidal activity of teicoplanin was also ower than that of vancomycin recorded over he 24 hour period. an mbc range of 16– >32 g/l teicoplanin was needed for 14 strains; the bc for one isolate was 4 mg/l. all isolates howed a high tolerance to teicoplanin with ic/mbc ratio of >32. with vancomycin, bc values for ten of the fifteen isolates anged from 16 to 128 mg/l and from 1 to 4 g/l for four isolates. the majority (10/14) of he isolates showed a high tolerance to ancomycin with an mic/mbc ratio >8. ynercid achieved a >99.9% kill against ten of s t r w t > 9 0 t t l t m m s m m r m t v s table 2 s tested exhibiting mode, mic50 and mic90 0 isolates of s.oralis mic50 mic90 % of strains sensitive % of strains outside normal range 0.125 2 72 28 0.125 8 84 16 0.0075 4 86 14 0.25 2 92 8 0.125 0.25 99 1 0.5 0.5 100 0 0.125 0.125 100 0 27 r a f a y the fifteen isolates at a concentration of < 2 mg/l. of the five remaining isolates, three required 4 mg/l, one 16 mg/l and the remaining one 64 mg/l of synercid for a 99.9% kill. the mbc 99.9% values for synercid were within the 1–4 times mic range for all but two of the isolates. the majority of the isolates showed a relatively low tolerance to synercid (87% mic/mbc ratio of < 4). although the isolates were inhibited by lower concentrations of erythromycin than of synercid erythromycin showed much lower bactericidal activity than synercid. clindamycin also demonstrated lower mic values than those for synercid, but the mbc values for ten of the fifteen isolates were between 1–4 mg/l of clindamycin, for a 99.9% kill, five isolates required >4 mg/l. all isolates showed a relatively high tolerance to clindamycin with 12/15 mic/mbc ratio of > 8. two comparative mic/mbc values (mg/l) for synercid, penicill strains syncercid penicillin erythromycin mic mbc mic mbc mic mbc ar3 0.5 >64 0.12 0.12 0.06 >16 ar12 1 1 0.12 16 0.06 4 ar13 1 2 0.12 0.12 0.12 >16 ar19 1 4 0.25 2 0.5 >16 ar40 0.5 16 1 >16 0.5 >16 23 1 2 0.25 >16 0.25 >16 n4-1-4 1 1 0.25 0.25 2 4 a9 1 1 0.25 0.5 0.03 >16 24 1 4 0.06 <0.06 0.25 >16 26 1 1 0.06 8 0.12 1 a6 1 2 0.06 <0.06 0.12 0.12 a10 0.5 0.5 2 >2 0.12 0.5 92c17 1 2 0.06 4 0.12 >16 93c87 1 2 0.5 0.5 0.12 0.5 t8-2-12 1 4 0.25 >8 0.12 0.5 strains were tolerant to synercid show tolerance to all table 3 in, erythromycin, teicoplanin, vanomycin and clindamycin against s.oralis vanomycin teicoplanin clindamycin mic mbc mic mbc mic mbc 0.5 64 0.03 32 0.12 >4 2 >64 0.06 32 0.12 >4 2 16 0.12 4 0.12 >4 2 16 0.25 >32 0.25 4 2 >64 0.03 >32 0.12 >4 4 >64 0 >32 0.25 >4 2 1 0.03 >32 0.25 2 2 >128 0.06 >16 0.06 >1 1 4 0.12 >16 0.12 >1 2 32 0.12 >16 0.06 0.25 2 0.5 >16 0.12 0.12 2 >128 0.25 >16 0.06 0.5 2 4 0.5 >16 0.12 >1 2 2 0.25 >16 0.12 >1 2 >128 0.5 >16 0.12 >1 28 , the antibiotics as well. killing curve killing curve was performed on ten isolates from endocarditis, neutropenic and normal oral flora strains. the pattern of kill was similar within these different sources of strains. figures 1 and 2 show the comparative bactericidal activity at 4x mic of synercid, vancomycin and penicillin against s. oralis (ar12 & ar13) from a patient with endocarditis. a three-log reduction in viable count was achieved within two hours of the organism coming into contact with synercid. figure 3 shows the comparative bactericidal activity at 4x mic of synercid, vancomycin and penicillin against an isolate of s. oralis (23) from the i n v i t r o a c t i v i t y o f s y n e r c i d 29 1 2 3 4 5 6 7 8 9 10 0 2 4 6 8 10 12 14 16 18 20 22 24 time (hour) lo g1 0 cf u control vancomycin synercid penicillin 1 2 3 4 5 6 7 8 9 10 0 2 4 6 8 10 12 14 16 18 20 22 24 time (hour) lo g1 0 cf u control vancomycin synercid penicillin 1 2 3 4 5 6 7 8 9 10 0 2 4 6 8 10 12 14 16 18 20 22 24 time (hour) lo g1 0 cf u control vancomycin synercid penicillin figure 1. bacterial activity of synercid (rp 595,00), vancomycin and penicillin at 4 x mic against s.oralis from endocarditis patient. figure 2. bacterial activity of synercid (rp 595,00), vancomycin and penicillin at 4xmic against s.oralis from endocaridtis patient. figure 3. bacterial activity of synercid (rp 595,00), vancomycin and penicillin at 4xmic against s.oralis from normal oral flora. r a f a y 30 normal oral flora. synercid reduced the viable count of this isolate by three-log10 after 1.5 hour's exposure; a five-log10 reduction was achieved within six hours. discussion susceptibility studies demonstrated that both penicillin and amoxycillin exerted similar activities against 60 isolates of s. oralis. these strains showed a wide range of susceptibilities but the mic50 and the mode mic values for both antibiotics were 0.125 mg/l and 0.03 mg/l respectively. synercid, a streptogramin, demonstrated a relatively high mic50 against s. oralis when compared with the macrolides and clindamycin. similar findings were observed in a study reported by williams.13 the result of this study regarding synercid activity against s. oralis correlates well with the observations of fass14 who tested 30 viridans streptococci and found mic50 of synercid to be 1 mg/l. mic90 against these isolates was 2 mg/l and all isolates were inhibited by < 4 mg/l synercid. these findings were also supported by separate studies.14-16 there was a two-fold difference between the mic50 of 0.25 mg/l and the mic90 of 0.5 mg/l, compared to mic90 values for clindamycin and erythromycin between 2–4 mg/l. these findings correlate well with other studies.17-19 however, 14 % isolates required >2 mg/l clindamycin for inhibition and 28% isolates required >1 mg/l erythromycin for inhibition. maskell20,21 performed in-vitro susceptibility testing on 50 isolates of oral streptococci and obtained similar results for pristinamycin: all isolates were inhibited by < 1 mg/l pristinamycin. susceptibility testing showed that teicoplanin demonstrated greater in-vitro activity than vancomycin, although it is not used as frequently as the latter. mics of synercid for s. oralis were relatively high compared to all antibiotics tested; mbc values were < 4 mg/l for most of the isolates, except for one at 16 mg/l and the other at > 64 mg/l. from these findings it was clear that synercid has superior bactericidal activity against s. oralis compared to penicillin, erythromycin, vancomycin, teicoplanin and clindamycin. none of the s. oralis strains tested was tolerant to synercid. similar findings have been demonstrated elsewhere.16, 19 synercid was bactericidal (99.9% kill) against all ten isolates of s. oralis within six hours of contact. this correlates with the previous killing curve studies performed using synercid against oral streptococci.19-20 interestingly, in this study, 99.9% kill was achieved with nine out of the ten isolates within four hours of contact. the isolates from infective endocarditis cases required two to six hours of contact with synercid for 99.9% kill, whereas for isolates from neutropenic cases and the normal oral flora, 2.5 and 1.5 hours respectively were sufficient. these results also showed that none of the ten isolates tested were tolerant to synercid. this finding correlates well with the other studies.15,16,18 with penicillin, only four of the six infective endocarditis isolates showed a three-log10 reduction in viable colony count within 6 –24 hours. vanomycin achieved a three-log10 reduction with only three out of the ten isolates. conclusion there is concern about the increasing prevalence of methicillin resistant s. aureus (mrsa) s. epidermidis21-23 and reduced vancomycin susceptibility.24 there is great need for an agent with excellent activity against macrolide resistant strains of gram-positive organisms and the recently reported strains of enterococcus faecium which are resistant to both vancomycin and gentamicin.25 thus synercid offers a potentially new agent for use in the treatment of infections caused by mrsa and other gram-positive bacteria.15 synercid might be useful against most viridans streptococci for the treatment of complicated cases of infective endocarditis. references 1. skehan, jd, murray, m, mills pg. infective endocarditis: incidence and mortality in the north thames region. brit heart j 1988, 59, 62–68. 2. bayliss r, clarke c, oakley cm, somerville w, young je. the microbiology and pathogenesis of endocarditis. br heart j 1983, 50, 513–519. 3. young je, susan. aetiology and epidemiology of infective endocarditis in england and wales. j antimicrob chemother 1987, 20, 7–14. 4. bouvet a, durand a, devine c, etienne j, leport c, and the group d'enquete sur l'endocardite en france en 1990–1991. in vitro susceptibility to antibiotics of 200 strains of streptococci and enterococci isolated during infective endocarditis. lancer publication st.petersburg, russia 1994,72–3. 5. douglas cwi, heath j, hampton kk, preston fe. identity of viridans streptococci isolated from cases of infective endocarditis. j med microbiol 1993, 39, 179–82. 6. parker mt, ball lc. streptococci and aerococci associated with systemic infections in man. j med microbiol 1976, 9, 275–302. 7. barriere jc, bouanchaud dh, harris nv, paris jm, rolin o, smith c. the design synthesis and properties of rp59500 and related semi-synthetic streptogramin antibiotics. in: program and abstract of the 30th conference on antimicrobial agents and chemotherapy. atlanta. american society for microbiology, washington, dc, 1990, 768a. 8. barriere jc, bouanchaud dh, paris jm, rolin o, harris nv, smith c. antimicrobial activity against staphylococcus aureus of semi synthetic injectable streptogramin: rp 59500 and related compounds. j antimicrob chemother 1992, 30, 1–8. 9. aumercier m, bouhallab s, capmau m, goffic fl. rp 59500: a proposed mechanism for its bacterial activity. j antimicrob chemother 1992, 30, 9–14. i n v i t r o a c t i v i t y o f s y n e r c i d 31 10. baquero f gram-positive resistance: a challenge for the development of new antibiotics. 19th icc montreal, 1995. 11. beighton d, hardie jm, whiley ra. a scheme for the identification of viridans streptococci. j med microbiol 1991, 35, 367–72. 12. miles aa, misra ssk, irwin jo. the estimation of the bactericidal power of the blood. j hygiene 1938, 38, 732– 49. 13. williams jd, maskell jp, shain h, chrysos g, sefton am, fraser hy, hardie jm. comparative in– vitro activity of azithromycin, macrolides (erythromycin, clarithromycin and spiramycin) and streptogramin rp 59500 against oral organisms. j antimicrob chemother 1992, 30, 27–37. 14. fass rj. in vitro activity of rp59500, a semi-synthetic injectable prestinamycin, against staphylococci, streptococci and enterococci. antimicrob agents chemother 1991, 35, 553–9. 15. verbist l, verhaegen j. comparative in-vitro activity of rp59500. j antimicrob chemother 1992, 30, 39–44. 16. neu c harold chin, nai-xun, gu, jain-wei. the invitro activity of new streptogramin, rp 59500, rp 57667 and rp 54476, alone and in combination. j antimicrob chemother 1992, 30, 83–94. 17. soussy cj, acar jf, cluzel r, courvalin p, duval j, fleurette j, megraoud f, meryaan m, thabaut a. a collaborative study of the in-vitro sensitivity to rp 59500 of bacteria isolated in seven hospitals in france. j antimicrob chemother 1992, 30, 53–8. 18. pankuch ga, jacobs mr, appelbaum pc. study of comparative anti pneumococcal activities of penicillin g, rp59500, erythromycin, sparfloxacin, ciprofloxacin and vancomycin by using the time-kill methodology. antimicrob agents chemother 1994, 38, 2065–72. 19. pechere jc. in-vitro activity of rp 59500, a semi synthetic streptogramin, against staphylococci and streptococci. j antimicrob chemother 1992, 30, 15–18. 20. maskell jp, willams jd. in-vitro susceptibility of oral streptococci to pristinamycin. j antimicrob chemother 1987, 19, 585–90. 21. hoban dj, weshnoweski b, palatnick l. in–vitro activity of rp59500, a new semi-synthetic streptogramin antibiotic against staphylococcus species. in program an abstract of the thirteenth international conference on antimicrobial agents and chemotherapy, atlanta, georgia. american society for microbiology, washington, dc 1990, 770, 214. 22. boyce jm. methicillin resistant staphylococcus aureus. detection, epidemiology and control measures. infect dis clin north am 1989, 3, 901–13. 23. nafziger dj, wenzel rp. coagulase-negative staphylococci epidimiology evaluation and therapy. infect dis clin north am 1989, 3, 915–29. 24. hiramatsu k, hanaki h, ino t, yabutta k, oguri t, tenover fc. methicillin-resistant staphylococcus aureus clinical strains with reduced vancomycin susceptibility. j antimicrob chemother 1997, 40, 135–6 25. cassewell mw, seyed-akhavani m, wade j. in vitro activity of rp 59500 against vancomycin resistant enterococcus faecium also resistant to >512 mg/l of gentamicin. 33rd icaac, new orleans 1993, poster presentation. in-vitro activity of synercid and related drugs �against streptococcus oralis isolated from �septicaemia and endocarditis cases intro method determination of mic determination of minimum bactericidal �concen˜trations (mbc) time kill curves. results in-vitro mbcs with six antibiotics to s. oralis. killing curve discussion conclusion references sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 493-497, epub. 20th nov 12 submitted 27th dec 11 revision req. 24th apr 12, revision recd. 5th jun and 24th aug 12 accepted 29th aug 12 1department of medicine, sultan qaboos university hospital, muscat, oman; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: omayma0@hotmail.com مرض كوشينج االستجابة الكاملة واملستمرة للعالج بواسطة عقار الكابرجولني اأميمة ال�صفيع، اأجنم عثمان، فاطمة عامر، علي املعمري، نيكوال�ض وودهاو�ض امللخ�ض: ُندرج هنا و�صفا خلم�ض حاالت م�صابة مبر�ض كو�صينج يف م�صت�صفى جامعة ال�صلطان قابو�ض عوجلت الأول مرة با�صتخدام دواء مرتفعة، الُكْظر لِق�رْصِ ُه امُلَوجِّ والُهْرُموُن وامل�صاء( ال�صباح )يف الكورتيزول هرمون م�صتويات كانت فعاليته. مدى ملعرفة الكابرجولني ُه لِق�رْصِ الُكْظر واأثبت الرنني املغناطي�صي وجود ورم يف الغدة النخامية عند ثالثة مر�صى فقط، ومل يثبت وجود ورم فارز للُهْرُموُن امُلَوجِّ عند كاملة ا�صتجابة هناك وكانت يوميا، ملجم 1 بجرعة الكابرجولني دواء ا�صتخدم مت االآخرين. املري�صني عند النخامية الغدة خارج اأربعة مر�صى حيث انخف�ض م�صتوى هرمون الكورتيزول اإىل احلد الطبيعي، واأثبتت زيارات املتابعة ا�صتقرار احلالة ال�رصيرية والكيميائية احلياتية عندهم بعد 14 و28 و44 و378 يوما على التوايل. اأما املري�ض اخلام�ض فلم ي�صتجب للعالج. نو�صي بعالج كل حاالت مر�ض الكو�صينج بدواء الكابرجولني حتى يرجع الهرمون ملعدله الطبيعي قبل اإجراء العملية، اأو ميكن تفادي العملية وا�صتخدامه على املدى البعيد. ُه لِق�رْصِ الُكْظر، م�صتقبالت دوبامني، دواء كابرجولني، تقرير حالة، ُعمان. مفتاح الكلمات: مر�ض كو�صينج، الُهْرُموُن امُلَوجِّ abstract: we report five cases of cushing’s disease where the patients were given a therapeutic trial of cabergoline. morning serum cortisol, adrenocorticotrophic hormone (acth), and sleeping cortisol concentrations were significantly raised. magnetic resonance imaging (mri) scans revealed pituitary microadenomas in 3 patients but were normal in the others. ectopic acth production was excluded in the 2 patients with normal mri scans. all were given a therapeutic trial of cabergoline (1 mg daily). four patients responded with a prompt fall in serum cortisol levels and had a sustained clinical and biochemical remission for 378, 44, 28 and 14 days, respectively. one patient failed to respond. in conclusion, we suggest that all patients with cushing’s disease should undergo a therapeutic trial of cabergoline. responders can then be prepared for surgery or, if needed, treated medically in the long term. keywords: cushing’s disease; adrenocorticotrophic hormone; dopamine receptors; cabergoline; case report; oman. cushing’s disease sustained remission in five cases induced by medical therapy with the dopamine agonist cabergoline *omayma elshafie,1 anjum osman,1 fatima aamer,1 ali al-mamari,1 njy woodhouse2 case series cushing’s disease due to pituitary adenoma is the most common cause of adrenocorticotrophic hormone-(acth) dependent cushing’s syndrome. magnetic resonance imaging (mri) may show the adenoma, but the scan may be normal in up to 40% of patients.1 the remaining 15% of cases of acth-dependent cushing’s syndrome are due to ectopic acth secretion, usually from bronchial, pancreatic, or neuroendocrine tumours (nets) or, rarely, due to tumours that produce corticotropin releasing hormones (crh).2 most nets express somatostatin receptors, mainly types 2 and 5, and thus are amenable to inhibition by somatostatin analogues such as octreotide as opposed to acth-producing adenomas which usually do not respond due to lack of expression or down regulation of somatostatin receptors.3 we report a series of five cases of cushing’s disease, four of which responded successfully to cabergoline, which has been used sporadically in cushing’s disease, but is not yet the standard of care. the patients and their families were all made aware cushing’s disease sustained remission in five cases induced by medical therapy with the dopamine agonist cabergoline 494 | squ medical journal, november 2012, volume 12, issue 4 that this drug is not yet the standard of care and consented to its use. we suggest that a therapeutic trial of cabergoline should be given to all patients in preparation for surgery, as well as to those who are not candidates for surgery. case one a 32-year-old married omani woman with three children was admitted to our hospital with a recurrent thigh abscesses which required surgical drainage and antibiotics. four years previously, she had presented with type 2 diabetes mellitus (dm) and hypertension. she had been amenorrhoeic for the previous year. she was on 90 daily units of insulin mixtard and 10 mg daily of lisinopril. on examination, she was severely cushingoid with central obesity, a moon face, male pattern baldness, hirsutism, thin skin, and easy bruising. the patient's blood pressure was 185/104 and fasting blood sugar was 14 mmol/l with a hba1c of 10.9%. liver, bone, renal, and thyroid profiles were within normal limits. the patient's serum cortisol and acth levels, both fasting and sleeping, were in keeping with acth-dependent cushing’s syndrome [table 1]. the pituitary mri, chest and abdominal computed tomography (ct) scans, and the serum chromogranin a levels were normal (56 µg/l, normal range 27–94). a therapeutic trial of somatostatin analogue octreotide 100 µg three times daily was carried out for three days but failed to lower serum cortisol levels [table 2]. a laparoscopic bilateral adrenalectomy was offered but the patient refused; thus, treatment with the dopamine agonist cabergoline was attempted at a dose of 1 mg/day. the response was dramatic, with normalisation of serum cortisol levels within one week of the treatment. levels subsequently remained normal for up to 378 days in this case [table 3]. after 4 months, there was a complete disappearance of the patient's cushingoid features, resumption of normal menses, normalisation of blood pressure to 123/86, and a hba1c of 5.7% without any antihypertensive or diabetic medications. after 52 weeks, the cabergoline was reduced to 0.5 mg daily. two weeks later, she remained in biochemical remission with normal cortisol values [table 3]. she currently remains in remission and is taking 0.5 mg of cabergoline 3 times a week and is now pregnant after 10 years of secondary infertility. case two a 28-year-old woman presented with hypothyroidism, hypertension, mild type 2 dm, obesity, irregular periods, and hirsutism. she was taking thyroxine 75 µg daily for central hypothyroidism, and irbesartan/hydrochlorthiazide 150/12.5. examination revealed central obesity and a small buffalo hump. the patient's blood pressure was controlled at 125/70 and the fasting blood sugar was 6.3 mmol/l on diet alone. hba1c was 6.5% (n <6.0) with normal bone, liver, electrolyte and table 1: serum cortisol and adrenocorticotrophic hormone (acth) data on admission case number 1 2 3 4 5 cortisol (nmol/l) fasting level (morning) (n = 184–580) 752 612 961 933 751 sleeping level (n <128) 458 430 398 704 -post 1 mg dexamethasone (n <50) 523 317 660 ---acth (pmol/l) fasting level (n = 1.6–13.9) 14.4 12.9 37 24 27 acth = adrenocorticotrophic hormone table 2: serum cortisol levels before and during the administration of octreotide (100 mcg) subcutaneously fasting cortisol levels (nmol/l) time/hours 0 24 48 72 case 1 650 590 680 920 case 2 752 750 omayma elshafie, anjum osman, fatima aamer, ali al mamari and njy woodhouse case series | 495 osteomyelitis of the foot. cushing’s disease was confirmed by raised serum cortisol and acth levels, and sleeping and post-dexamethasone cortisol levels [table 1]. a pituitary mri revealed a 6 x 4 mm microadenoma. a ct scan of the abdomen revealed normal adrenal glands. she failed to respond to a one-week trial of cabergoline [table 3]. surgery was advised but the patient discharged herself against medical advice. she later underwent transsphenoidal surgery in india and was cured. case four a 45-year-old omani woman was admitted to our hospital for assessment and possible adrenalectomy. she presented with type 2 dm and hypertension thyroid profiles. serum chromogranin a was 43 ug/l (normal range 27–94). a pituitary mri and adrenal ct scan revealed a microadenoma and nodular enlargement of the left adrenal gland. fasting serum cortisol, acth and sleeping cortisol concentrations were in keeping with acthdependent cushing’s syndrome [table 1]. a 72-hour therapeutic trial of octreotide failed to lower serum cortisol levels [table 2]. a trial of cabergoline, however, produced a rapid and sustained fall in serum cortisol levels [table 3]. case three a 46-year-old female patient presented with clinically severe cushing’s syndrome with hypertension, dm, recurrent abscesses, and 1000 500 0 0 0 1 2 10 50 84 90 weeks co rt iso l nm ol/ l cabergoline trial in cushing’s disease 3 4 5 2 1 figure 1: response to cabergoline therapy in 5 patients with cushing’s disease. the normal range is shaded. table 3: cabergoline trial serum cortisol levels before and during the daily administration of cabergoline fasting cortisol levels (nmol/l) (n = 184–580) days 0 7 14 21 28 44 196 364 378 case 1 752 284 276 415 513 303 case 2 612 392 541 414 case 3 736 914 case 4 789 578 561 case 5 751 406 274 250 cushing’s disease sustained remission in five cases induced by medical therapy with the dopamine agonist cabergoline 496 | squ medical journal, november 2012, volume 12, issue 4 and was taking 2 mg of glimipride and 150 mg/12.5 mg of valsartan and hydrochlorothiazide (novartis pharmaceuticals uk ltd.) daily. the ct scan initially revealed a right-sided 8 x 8 mm adrenal nodule. on examination, she was severely cushingoid, with hyperpigmentation, a moon face, supraclavicular fat pad, and central obesity. the patient's blood pressure was 170/85 and fasting blood glucose level was 6.4 mmol/dl with a hb1ac level of 7.5%. liver, bone, renal, and thyroid profiles were within normal limits. fasting serum cortisol levels, and sleeping acth levels were in keeping with acth-dependent cushing’s syndrome [table 1]. a pituitary mri scan showed a 10 x 10 mm microadenoma. a therapeutic trial of cabergoline was carried out for 2 weeks [table 3]. the response was dramatic, with normalisation of serum cortisol levels within a week of treatment [table 3]. she subsequently underwent successful transsphenoidal pituitary surgery. case five a 19-year-old female presented to the emergency department with severe psychosis. eight months earlier she had presented with cushing’s syndrome and was found to have an acth-secreting pituitary tumor and had undergone transsphenoidal surgery. she remained well for one year but relapsed and presented with amenorrhoea and all the clinical features of acth-induced cushing’s syndrome. she was normotensive and not diabetic. morning serum cortisol and acth levels were in keeping with this diagnosis [table 1]. treatment was started with 1 mg of cabergoline daily. the response was dramatic, with a reversal of the psychotic state within a week, associated with a progressive reduction of serum cortisol levels over the following month [table 3]. discussion five patients with cushing’s disease and raised acth levels were given a therapeutic trial of cabergoline. four of them responded with a prompt fall in serum cortisol levels [figure 1]. in cases 1 and 2, their normal menses resumed and associated comorbidities, namely dm and hypertension, were reversed. pituitary mris were normal in two of the patients as may be the case in up to 40% of all cushing’s disease patients.1 in these circumstances, the diagnosis of cushing’s disease should ideally be confirmed by inferior petrosal sinus sampling with acth measurements. since this technique is not yet available in oman, we used indirect methods to exclude ectopic acth production and as a result are confident that both had cushing’s disease. nets almost invariably express somatostatin receptors 2 and 5 and respond to treatment with octreotide.4,5 as noted, there was no fall in serum cortisol levels during the therapeutic trial of ocreotide in either patient, and no evidence of ectopic tumours was seen on ct scans of the neck, chest, or abdomen. furthermore, serum chromogranin-a levels, which are frequently elevated in patients with nets, were also normal.2 high dose dexamethasone suppression can also be used to differentiate pituitary from ectopic diseases. since this test was considered potentially harmful, it was not performed. one patient was septacaemic with several abscesses (case 1) and the other had a steroid psychosis (case 5). somatostatin receptors are also expressed on normal pituitary acth-producing cells, but their expression is down-regulated by elevated glucocorticoid levels which explains why octreotide is not useful therapeutically in the majority of patients with cushing’s disease.3 so why is cabergoline effective? up to 80% of acth-secreting pituitary adenomas express dopamine receptors and many respond well to treatment with dopamine agonists.6 a sustained response to bromocriptine is unusual but so far cabergoline has been shown to induce clinical and biochemical remission in 20– 50% of cases.7,8 the beneficial effect of cabergoline was first demonstrated in a patient with nelson’s syndrome in 1999, which resulted in normalisation of the patient’s acth levels and disappearance of the tumour.9 because of these observations, we have started to give a therapeutic trial of 1 mg of cabergoline daily to all patients with cushing’s disease. four of the five patients treated so far responded with a rapid normalisation of serum cortisol levels, and a reversal of associated comorbidities in the two patients treated for one or more months. indeed, the patient refusing surgery has elected to remain on medical treatment and is still in complete omayma elshafie, anjum osman, fatima aamer, ali al mamari and njy woodhouse case series | 497 references 1. kaye tb, crapo l. the cushing syndrome: an update on diagnostic tests. ann intern med 1990; 112:434–44. 2. jameson j. harrison’s endocrinology. 2nd ed. new york: mcgraw-hill, 2010. pp. 348–67. 3. schonbrunn a. glucocorticoids down-regulate somatostatin receptors on pituitary cells in culture. endocrinology 1982; 110:1147–54. 4. hearn pr, reynolds cl, johansen k, woodhouse njy. lung carcinoid with cushing’s syndrome: control of serum acth and cortisol levels using sms 201-995 (sandostatin). clin endocrinol (oxf ) 1988; 28:181–5. 5. woodhouse njy, dagogo-jack s, ahmed m, judzewitsch r. acute and long-term effects of octreotide in patients with acth-dependent cushing’s syndrome. am j med 1983; 305. 6. pivonello r, ferone d, de herder ww, kros jm, de caro ml, arvigo m, et al. dopamine receptor expression and function in corticotroph pituitary tumors. j clin endocrinol metab 2004; 89:2452–62. 7. mancini t, porcelli t, giustina a. treatment of cushing disease: overview and recent findings. ther clin risk manag 2010; 6:505–16. 8. illouz f, dubois-ginouves s, laboureau s, rohmer v, rodien p. use of cabergoline in persisting cushing’s disease. ann endocrinol (paris) 2006; 67:353–6. 9. pivonello r, faggiano a, di salle f, filippella m, lombardi g, colao a. complete remission of nelson’s syndrome after one year treatment with cabergoline. j endocrinol invest dec 1999; 22:860–5. 10. pivonello r, de martino mc, cappabianca p, de leo m, faggiano a, lombardi g, et al. the medical treatment of cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. j clin endocrinol metab 2009; 94:223–30. 11. godbout a, manavela m, danilowicz k, beauregard h, bruno od, lacroix a. cabergoline monotherapy in the long-term treatment of cushing's disease. eur j endocrinol 2010; 163:709–16. remission after 378 days, having reduced the dose of cabergoline to 0.5 mg three times per week. we have so far studied only 5 patients and were pleasantly surprised to find that four of them responded to cabergoline [figure 1]. this may be because we used a higher dose than reported earlier—usually not more than 0.5 mg daily.7 further studies need to be carried out to find the optimal cabergoline dose required for treatment of this disease. other medical therapies have been used in the medical management of cushing’s disease in preparation for surgery. these act either by inhibiting the release of acth or by inhibiting cortisol secretions.7 however, many have unpleasant side effects and are frequently ineffective, unlike cabergoline which has few short-term side effects even in large doses.7 lightheadedness on the first day of treatment was the only reported side effect in these patients. conclusion in conclusion, we recommend that a therapeutic trial of cabergoline, starting at 1 mg daily, be carried out in every patient with cushing’s disease and, if successful, can then be used to induce a remission prior to surgery or, if indicated, taken long term, as in case 1. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e409-411, epub. 24th jul 14 submitted 30th aug 13 revisions req. 26th sep 13 & 15th jan 14; revisions recd. 16th dec 13 & 23rd jan 14 accepted 30th jan 14 departments of 1child health, 2radiology & molecular imaging and 3genetics, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: koul@squ.edu.om and roshankoul@hotmail.com التهاب الدماغ احلاد املنتشر مشابه ملرض حثل املادة البيضاء الطِّْفِلي اآمنة الفطي�سية، في�سل العزري، اأن�س الوجود عبد املغيث، فتحية املر�سدية، رو�سان كول severe acute disseminated encephalomyelitis mimicking leukodystrophy in a child amna al-futaisi,1 faisal al-azri,2 anas a. abdelmogheth,1 fathiya al-murshedi,3 *roshan koul1 interesting medical image figure 1 a & b: an initial axial t2-weighted magnetic resonance image (mri) at the level of the (a) centrum semiovale, and a coronal image (b) at the level of the third ventricle show diffuse hyperintense t2 signal abnormalities involving the periventricular white matter (white arrows). on the coronal image, the signal abnormalities are present bilaterally towards the temporal lobes and the corpus callosum (black arrows). there is no significant mass effect. there were no restrictions on diffusion-weighted images or abnormal enhancements (images not shown). acute disseminated encephalomyelitis (adem) is a monophasic, inflammatory central nervous system (cns) demyelinating disease that usually affects children more than adults.1 the international pediatric multiple sclerosis (ms) study group defines adem as the “first clinical event with a presumed inflammatory or demyelinating cause, with acute or sub acute onset that affects multifocal areas of the cns”.2 a polysymptomatic presentation, along with evidence of encephalopathy, such as behavioural changes or lethargy, must be present for the diagnosis.3 clinical, biological and radiographic delineation are important to differentiate monophasic illnesses like adem from chronic and recurrent diseases.3 the clinical features vary from mild forms to the severe catastrophic haemorrhagic type, also known as haemorrhagic leukoencephalopathy.3 a favourable outcome is often described for children with adem, as various studies have shown that more than 50–60% of patients experience a full recovery.1,4 a similar case of adem mimicking leukodystrophy was recorded in turkey.5 the current case reports a girl with catastrophic severe adem, who recovered completely within six months. an eight-year-old girl suspected of having dysmorphism, suggestive but not typical of noonan syndrome, presented to a peripheral hospital in oman with progressive lethargy and a disturbed level of consciousness. this had been preceded by a threeday history of upper respiratory tract symptoms severe acute disseminated encephalomyelitis mimicking leukodystrophy in a child e410 | squ medical journal, august 2014, volume 14, issue 3 and mild fever. due to her low score of 6/14 on the glasgow coma scale, she was immediately intubated and ventilated. the patient had a generalised tonicclonic seizure and was consequently given regular doses of phenytoin. an urgent computed tomography (ct) scan of the brain was performed and suggested potential brain oedema. an ophthalmological examination showed papilloedema. the patient was started on acyclovir and ceftriaxone as an empirical treatment for viral encephalitis/bacterial meningitis. anti-cerebral oedema measures were also instituted. she was transferred on a ventilator to the sultan qaboos university hospital (squh), muscat, oman, for further management. an examination on admission showed dysmorphism with mild exophthalmos, without apparent hypertelorism. the assessment also showed coarseness of the skin, neck webbing, widely spaced nipples and pectus excavatum with a bulging middle sternum. these features did not fit any specific syndrome. she was deeply comatose with minimal response to painful stimuli, a poor gag reflex and small and constricted pupils. signs of a meningeal infection were negative. she had spastic quadriparesis with hypertonia, hyper-reflexia and upgoing plantar reflexes. magnetic resonance imaging (mri) of the brain showed extensive diffuse, bilateral, symmetrical t2 hyperintensity with an involvement of the corpus callosum and the supra and infratentorial regions of the brain [figure 1a & b]. there were extensive, nearly symmetrical, bilateral white matter lesions with a mild asymmetric involvement of the right frontal region. this extensive, diffuse and bilaterally symmetric demyelination raised the possibility of an underlying leukodystrophy triggered by the intercurrent febrile illness. adem is characterised by multifocal white matter lesions, which are not symmetrical and may involve the deep grey matter as well. in order to treat the adem, treatment with steroids was initiated (methylprednisolone at 30 mg/day per kg intravenously for five days followed by 2 mg/day per kg for six weeks). this was administered in conjunction with intravenous immunoglobulins (ivig), at a dose of 1 g/day per kg over two days, given the patient’s severe presentation. her blood lactate, creatine kinase and ammonia levels were normal. the cerebrospinal fluid (csf) had no white blood cells, although there were 8,000 red blood cells (reported as traumatic). her sugar and protein levels were normal at 3.9 mmol/l and 0.18 g/l, respectively. viral screening of the blood and csf were normal. the serum was screened and found negative for the herpes, varicella, epstein-barr, paravovirus, n1h1 and influenza viruses. the csf was reported as negative for herpes simplex, enteroviruses, varicella and mumps. the serum antinuclear antibodies (ana) were weakly-positive while the anti n-deoxyribonucleic acid (dna) was negative. the arylsulphatase level was normal and a urine organic acids test gave a negative result. the plasma amino acids and tandem mass spectrometry were normal and figure 2 a & b: a follow-up axial t2-weighted magnetic resonance image (mri) at the level of (a) the centrum semiovale, and a coronal image (b) at the level of the third ventricle show mild residual diffuse hyperintense t2 signal abnormalities involving the periventricular white matter. the coronal image shows the signal abnormalities present bilaterally towards the temporal lobes and the corpus callosum (black arrows). however, there is evidence of moderate brain atrophy with a dilatation of the lateral ventricles (white arrows). overall, there is a marked improvement. amna al-futaisi, faisal al-azri, anas a. abdelmogheth, fathiya al-murshedi and roshan koul interesting medical image | e411 brucella and borrelia antibodies were negative. an electroencephalogram (eeg) showed bihemispheric slowing, with no epileptiform discharges. an ophthalmology review showed bilateral disc oedema with exposure keratitis of both eyes. the child was extubated after approximately 10 days. following a 25-day stay in squh, she was transferred to her local hospital in a quadriparetic state with nasogastric tube feeding and inability to speak. on evaluation, three months later, she had remarkably improved and returned to a baseline neurological state. her improvement was demonstrated by an mri that showed a resolution of the lesions [figure 2a & b]. comment the child health department of squh sees about two to three cases of adem in a year.6 the majority of these cases are the mild to moderate type. this patient, however, had a severe catastrophic form of adem and mri results that were not typical of this condition. the uniform symmetrical imaging features were suggestive of a leukodystrophy. different childhood leukodystrophies have classic radiological features. metachromatic leukodystrophy is more commonly seen in this age group. it is well known that any infection can precipitate an acute presentation in these leukodystrophies. despite the atypical mri appearance, the decision to treat the patient for adem was made. this condition is a severe demyelinating illness of the cns and its severity prompts an aggressive treatment, which is of paramount importance to hasten recovery and improve a patient’s outcome.7 unusual mri findings should not preclude the diagnosis and empirical treatment should be instituted rapidly. fortunately, this patient responded to a combination of steroids and ivig with a complete recovery. in refractory cases, other modalities of treatment such as plasmapheresis and cytotoxic and immunomodulating agents are advised. references 1. anlar b, basaran c, kose g, guven a, haspolat s, yakut a, et al. acute disseminated encephalomyelitis in children: outcome and prognosis. neuropediatrics 2003; 34:194–9. doi: 10.1055/s2003-42208. 2. tenembaum s, chitnis t, ness j, hahn js; international pediatric ms study group. acute disseminated encephalomyelitis. neurology 2007; 68:s23–36. doi: 10.1212/01. wnl.0000259404.51352.7f. 3. krupp lb, banwell b, tenembaum s; international pediatric ms study group. consensus definitions proposed for pediatric multiple sclerosis and related disorders. neurology 2007; 68:s7–12. doi: 10.1212/01.wnl.0000259422.44235.a8. 4. tenembaum s, chamoles n, fejerman n. acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. neurology 2002; 59:1224–31. doi: 10.1212/ wnl.59.8.1224. 5. kaya a, acikgoz m, ustyol l, avcu s, sal e, okur m, et al. a case of acute disseminated encephalomyelitis mimicking leukodystrophy. kurume med j 2010; 57:85–9. doi: 10.2739/ kurumemedj.57.85. 6. al-futaisi a, al-busaidi m, al-abdwani r, javad h, koul r. acute disseminated encephalomyelitis in arabian peninsula: a retrospective study from oman. j pediatr neurol 2007; 5:295– 9. 7. absoud m, parslow rc, wassmer e, hemingway c, duncan hp, cummins c, lim mj; uk & ireland childhood cns inflammatory demyelination working group and the pediatric intensive care audit network. severe acute disseminated encephalomyelitis: a paediatric intensive care population-based study. mult scler 2011; 17:1258–61. doi: 10.1177/1352458510382554. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. e476-478, epub. 25th jun 13 submitted 4th may 12 revision req 25th nov 12; revision recd. 22nd dec 12 accepted 21st jan 13 departments of 1internal medicine and 2family medicine, federal medical centre, ido-ekiti, nigeria *corresponding author e-mail: olubusari@yahoo.com تفاعل خلل التوتُّر العضلي احلاد بعد جرعة قياسية للكلوروكني لعالج املالريا غري املعقدة اأولو�شيجون بو�شاري، جوزيف فادير، �شيغان اجبوال، اولو�شيجون جربائيل، اأواليد اليجبيد، يو�شف اأوالدو�شو ر الع�شلي احلاد هو من االآثار خارج الهرمية التي حتدث عادة بعد ا�شتخدام جمموعة متنوعة من االأدوية اأو امللخ�س: تفاعل خلل التوتُّ العوامل املثرية للتوتر غري اأدوية الذهان.هنا نعر�س حالة رجل يبلغ من العمر 54 عاما نقل اإىل امل�شت�شفى بعد 10 �شاعات من ارتعا�س الع�شالت حول العينني والوجه والرقبة بعد تناول اجلرعة االأوىل عن طريق الفم من فو�شفات الكلوروكني )1غم ] 600 ملغ]( و�شفت لعالج املالريا الغري معقدة. اأعطي املري�س الديازيبام يف الوريد )10 ملغ( تلتها 10 ملغ من الديازيبام عن طريق الفم 3 مرات يف اليوم. حت�ّشنت االأعرا�س يف غ�شون 30 دقيقة من العالج، وخرج املري�س بعد 14 �شاعة بعد ال�شفاء الكامل. ر الع�شلي احلاد؛ املال ريا؛ الكلوروكني؛ التناول عن طريق الفم؛ تقرير حالة؛ نيجرييا. مفتاح الكلمات: رد فعل؛ خلل التوتُّ abstract: acute dystonic reactions (adr) are extrapyramidal effects that usually occur after the initiation of a wide variety of drugs or triggering factors besides neuroleptics. we report the case of a 54-year-old man who was admitted with an approximately 10-hour history of muscle twitching around the eyes, face and neck after he took the first dose of oral chloroquine phosphate (1 g [600 mg base]) prescribed for uncomplicated malaria. he was given intravenous diazepam (10 mg statum) followed by 10 mg of oral diazepam 3 times a day. the symptoms improved within 30 minutes of treatment, and he was discharged 14 hours later after a complete recovery. keywords: dystonia; reactions, acute; malaria; chloroquine; administration, oral; case report; nigeria. chloroquine-induced acute dystonic reactions after a standard therapeutic dose for uncomplicated malaria *olusegun a. busari,1 joseph fadare,1 segun agboola,2 olusegun gabriel,2 olayide elegbede,2 yusuf oladosu2 online case report acute dystonic reactions (adr) are extrapyramidal side effects (epse) that usually occur after the initiation or a rapid increase in the dose of neuroleptic drugs.1 however, the reactions may occur with a wide variety of drugs or triggering factors besides neuroleptics.2,3 adrs are characterised by the intermittent spasmodic or sustained involuntary contractions of muscles in the face, neck, trunk, pelvis and extremities.4 they are often not life-threatening, but can cause great discomfort, producing significant anxiety and distress for patients, and may seriously disturb the relationship between the doctor and the patient.5 chloroquine (cq), a 4-aminoquinoline drug used for both the prevention and treatment of malaria, was discovered in 1934 and introduced into clinical practice in 1947.5 it has been largely replaced by the newer artemisinin-based combination therapy (act) as the first line of treatment for uncomplicated malaria due to plasmodium falciparum. this is because of the emergence and spread of resistant strains through east and west africa, southeast asia, and south america.5–8 however, in some african countries there have been reports of a rapid decline in the frequency of resistance to cq after its withdrawal, to the point where the drug is now once again considered to be effective.9–11 thus, cq still remains a frequently used drug in the treatment of uncomplicated malaria in sub-saharan africa. given its low cost and wide availability, its occasional use in some autoimmune disorders, and current evaluation for new potential utilisations, cq may remain in clinical use for a long time.12–14 extrapyramidal syndrome (eps) following cq therapy has been reported in the past.15,16 however, olusegun a. busari, joseph fadare, segun agboola, olusegun gabriel, olayide elegbede and yusuf oladosu case report | 477 in our setting, cq-induced adr is very rare. this case report describes an occurrence of adr in a middle-aged man after commencing a standard dose of oral cq phosphate for parasitologicallyconfirmed uncomplicated malaria. case report a 54-year old man was brought to the emergency room (er) of the federal medical centre, idoekiti, nigeria, with a complaint of involuntary muscle twitching around the eyes, face and neck which had started approximately 10 hours prior to presentation. he was experiencing difficulty in speaking and an abnormal posturing of the neck. there was no fever, dizziness, altered consciousness, photophobia or weakness of the limbs. he had been diagnosed with parasitologically-confirmed uncomplicated malaria about 18 hours previously and had immediately been given oral cq phosphate bp (1 g cq phosphate [600 mg base]) to be followed by 500 mg (300 mg base) at 6, 24 and 48 hours. the presenting complaint had started within 8 hours of the first dose of cq. he was not on any other drugs, food or herbal preparations. there was no past history of similar complaints or of any transient ischaemic attack, and he had neither a family history of dystonia nor a history of alcohol ingestion, cigarette smoking or use of illicit drugs such as cocaine. a general examination revealed an anxious middle-aged man with facial muscle twitching and facial grimace. other aspects of the general examination were unremarkable. a central nervous system examination showed a fully-conscious man who was well-oriented in time, place and person. there were neither signs of meningeal irritation nor asterixis. there was no cognitive impairment and no cranial nerve palsy. deep tendon reflexes and tones were also normal. all other systems were grossly normal. all baseline investigations, which included complete blood counts, serum electrolytes, urea and basic urea nitrogen, liver enzymes and function tests, random and fasting blood glucose, and a serum lipid profile, were within normal limits. his resting electrocardiogram was also normal. a peripheral blood smear study for malaria parasites by light microscopy of thick and thin stained blood showed trophozoite and schizont forms of p. falciparum. a clinical diagnosis of adr secondary to cq was made. the drug was discontinued and the patient was treated with intravenous diazepam (10 mg statum followed by 10 mg oral diazepam three times a day). an intravenous access line was also secured and a maintenance dose of an intravenous infusion of isotonic saline was administered. the symptoms improved rapidly within 30 minutes of commencing treatment and the patient was discharged after about 14 hours of admission with complete recovery. he remained well at follow-up one week later. discussion the therapeutic index for cq is small.17 however, at a standard dose for malaria treatment, the common adverse effects include gastrointestinal problems, headaches, nightmares, blurring of vision and itching. an adr due to the use of cq is very rare and there is a paucity of data on it in the literature.18 achumba et al. reported a case of adr after a single dose of cq in a postoperative patient and in the presence of metronidazole.19 the reported case suggested that the adr might have been an idiosyncratic reaction and probably potentiated by the metronidazole. in our case, the adr also occurred after a single dose of cq but in the absence of any other medications. although adrs occasionally are dose-related, they are more often idiosyncratic and unpredictable.19 for most drugs that often cause adr, particularly the neuroleptics, the pathophysiology is a drug-induced alteration of dopaminergiccholinergic balance in the nigrostriatum. they produce adr by a nigrostriatal dopamine d2 receptor blockade, which results in an excess of striatal cholinergic output.20 the pathophysiological mechanism underlying cq-associated adr is not well-known. however, it has been linked to a reduction in forebrain catecholamine levels and an inhibition of neuronal calcium uptake.19 this hypothesis could be supported in part by the effectiveness of benzodiazepines in the reversal of cq-associated adr. a normal balance between dopamine and acetylcholine in the basal ganglia involves modulation from gamma aminobutyric acid (gaba)-containing striatonigral neurons. gaba-ergic neurons are inhibitory and antagonise excitatory dopaminergic neurons. stimulation of chloroquine-induced acute dystonic reactions after a standard therapeutic dose for uncomplicated malaria 478 | squ medical journal, august 2013, volume 13, issue 3 the benzodiazepine receptors coupled to gaba receptors via the chloride ion channel in the central nervous system facilitate gaba transmission with a consequent inhibitory effect of muscle hypertonia and tremors.19–22 conclusion although cq-induced adr is a very rare adverse effect, it can be confused with other medical conditions in the er such as a seizure disorder or a transient ischaemic attack. a detailed historytaking remains pivotal, particularly the medication history, which should be obtained from others if the patient is not able to speak. adrs occur very rarely in cq use; thus, its prophylaxis is unnecessary and also not feasible. however, the treatment is usually straightforward and nearly always effective. references 1. american psychiatric association. diagnostic and statistical manual of mental disorders. 9th ed. washington, dc: american psychiatric association, 1991. 2. oo mt. acute dystonic reactions in a lady presenting with repetitive involuntary muscle twitching: a case report. cases j 2009; 2:186. 3. fadare jo, owolabi lf. carbamazepine-induced dystonia. a case report. neurol asia 2009; 14:160–5. 4. fahn s. the varied clinical expression of dystonia. neurol clin 1984; 2:541–54. 5. casey de. neuroleptic induced acute dystonia. in: lang ae, weiner wj, eds. drug-induced movement disorder. mount kisco, new york: futura pub. co., 1992. pp. 21–40. 6. centre for disease control and prevention. malaria. from: www.cdc.gov/malaria accessed: aug 2011. 7. martin re, marchetti rv, cowan al, howitt sm, broer sa, kirk k. chloroquine transport via the malaria parasite’s chloroquine resistance transporter. science 2009; 325:1680–2. 8. tripathi kd. essentials of medical pharmacology. 5th ed. delhi: jaypee medical publishers, 2003. pp. 739–40. 9. mwai l, ochong e, abdirahman a, kiara sm, ward s, kokwaro g, et al. chloroquine resistance before and after its withdrawal in kenya. malaria j 2009; 8:106. 10. kublin jg, cortese jf, njunju em, mukadam ra, wirima jj, kazembe pn, et al. re-emergence of chloroquine sensitive plasmodium falciparum malaria after cessation of chloroquine use in malawi. j infect dis 2003; 187:1870–5. 11. lacifer mk, thesing pc, eddington no, masonga r, dzinjalamala fk, takala sl, et al. return of chloroquine antimalaria efficacy in malawi. n engl j med 2006; 355:1959–66. 12. savarino a, boelaert jr, cassone a, majori g, cauda r. effects of chloroquine on viral infections: an old drug against today’s diseases? lancet infect dis 2003; 3:722–7. 13. savarino a, lucia mb, giordano f, cauda r. risks and benefits of chloroquine use in anticancer strategies. lancet oncol 2006; 7:792–3. 14. sotelo j, briceno e, lopez-gonzalez ma. adding chloroquine to conventional treatment for glioblastoma multiforme: a randomised, double blind, placebo controlled trial. ann intern med 2006; 144:337–43. 15. singhi s, singhi p, singhi m. extrapyramidal syndrome following chloroquine therapy. indian j paediatr 1979; 46:58–60. 16. joseph v, varma m, vidhyasagar s, mathew a. comparison of the clinical profile and complications of mixed malarial infections of plasmodium falciparum and plasmodium vivax versus plasmodium falciparum mono-infection. sultan qaboos univ med j 2011; 11:377–82. 17. cann hm, verhulst hl. fatal acute chloroquine poisoning in children. paediatrics 1961; 27:95–102. 18. lange ae. miscellaneous drug induced movement disorders. in: lange ae, weiner wj, eds. druginduced movement disorders. mount kisco, new york: futura pub. co., 1992. pp. 339–81. 19. achumba ji, ette ei, thomas wo, essien ee. chloroquine-induced acute dystonic reactions in the presence of metronidazole. drug intell pharma 1988; 22:308–10. 20. marsden cd, jenner p. the pathophysiology of extrapyramidal side effects of neuroleptic drugs. psychol med 1980; 10:55–72. 21. adjei go, goka bq, rodrigues op, hoegberg lcg, alifrangis m, kurtzhals jal. amodiaquineassociated adverse effects after inadvertent overdose and after a standard therapeutic dose. ghana med j 2009; 43:135–8. 22. mccormick ma, manoguerra as. dystonic reaction. in: harwood-nuss a, linden ch, luten rc, et al, eds. clinical practice of emergency medicine. philadelphia: lippincott williams & wilkins, 1991. pp. 510–11. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e322–326, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.004. submitted 11 nov 14 revision req. 23 dec 14; revision recd. 22 jan 15 accepted 19 feb 15 over the last 40 years, oman hasundergone demographic, economic and social changes that have led to new epidemiological trends and a dramatic transformation of its health status over a short period of time.1 the healthcare needs of the expanding population are rapidly evolving, thus creating demands on the nursing workforce to offer commensurate healthcare services. currently, the omani population has an average life expectancy of 71.6 years, with 75% of the national disease burden due to non-communicable diseases (ncds) and cardiovascular disease as the leading cause of death.1 similar to other industrialised nations, common ncds and risk factors in oman include diabetes mellitus (12%), being overweight (30%) or obese (20%), high cholesterol (41%) and metabolic syndrome (21%).2 primary healthcare (phc) is the backbone of healthcare delivery and the national ministry of health (moh) considers it the main entry point for all levels of care.3 phc is part of the national health policy based on the following principles: provision of comprehensive health services; equal distribution of health services among different population groups in line with their needs; involvement of the community in healthcare planning/implementation; and intersectorial collaboration with other health-related institutions to ensure a positive impact on community health. individual phc systems are based in wilayats (districts) or units of local administration and are key to ensuring free healthcare provision for all omani nationals.1,3 district healthcare centres serve a local population of approximately 10–15 thousand with a team of doctors, nurses and support staff.4 department of adult & critical care, college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mail: joyk@squ.edu.om دعوة للممرضات اللوايت حيملن مؤهل الدبلوم لنيل درجة البكالوريوس النهوض مبهنة التمريض يف عمان جوي كابا�سيندي كمانيار و �سوزان اكورا abstract: the healthcare needs of the omani population are evolving, particularly with regards to changes in disease complexity, advances in technology and the enhanced delivery of healthcare services. nurses now need to adapt to a fundamental shift in the provision of patient-centred care. in line with lifelong learning goals, registered nurses in oman at the diploma level should seek to obtain a more advanced qualification, for instance a bachelor of science in nursing, to ensure they possess the requisite skills and knowledge to keep abreast of new developments in healthcare management. challenges involved in this transition and suggestions to overcome these potential obstacles are discussed in this article in order to inform nursing education stakeholders. recommendations to ensure the success of bridging programmes are also suggested. keywords: nursing; clinical competence; patient care; baccalaureate nursing education; nursing diploma program; nursing licensure; oman. على تطراأ التي بالتغريات يتعلق مبا وبخا�سة ملحوظة ب�سورة العمانيني للمواطنني ال�سحية الرعاية احتياجات تتغري امللخ�ص: تعقيدات الأمرا�س، التقدم يف التقنيات، و تعزيز تقدمي خدمات الرعاية ال�سحية. حتتاج املمر�سات الآن للتكيف مع التحولت الأ�سا�سية يف توفري الرعاية املتمحورة حول املري�س. ومتا�سيا مع اأهداف التعلم مدى احلياة، يجب على املمر�سات امل�سجالت يف �سلطنة عمان ممن يحملن درجة الدبلوم اأن ي�سعني للح�سول على موؤهل اأكرث تقدما على �سبيل املثال على درجة البكالوريو�س يف علوم التمري�س، وذلك للتاأكد من اأنها متتلك املهارات واملعارف املطلوبة ملواكبة التطورات اجلديدة يف جمال اإدارة الرعاية ال�سحية. تناق�س هذه املقالة التحديات التي ينطوي عليها هذا التحول واملقرتحات للتغلب على هذه العقبات املحتملة وذلك من اأجل اإبالغ اجلهات املخت�سة بتعليم التمري�س. ي�ستمل املقال اي�سا على تو�سيات ل�سمان جناح هذه الربامج. الرتخي�س التمري�س؛ دبلوم برنامج التمري�س؛ تعليم البكالوريو�س؛ درجة املر�سى؛ رعاية ال�رسيرية؛ الكفاءة التمري�س؛ الكلمات: مفتاح املهني للمر�سات؛ �سلطنة عمان. sounding board a call for more diploma nurses to attain a baccalaureate degree advancing the nursing profession in oman *joy k. kamanyire and susan achora joy k. kamanyire and susan achora sounding board | e323 oman is faced with an increasing population of young and elderly people.3 epidemiological, demographical and environmental health challenges necessitate changes to phc implementation strategies, thereby requiring stronger links between regional health centres, the community and higher levels of care. wider preventive and curative interventions are needed, with greater emphasis on injuries, mental health diseases, cancer, diabetes mellitus, human immunodeficiency virus/acquired immune deficiency syndrome, hypertension and lifestyle diseases like tobacco or drug abuse and obesity.3 these developments demand a review of the basic and continued training of phc workers in their ability to manage complex ncds.2 nursing in oman the moh is the largest employer of nurses in oman, with approximately 10,394 registered nurses (rns) in 2007; of these, 65% were omani nationals.5 the majority (72%) of these nurses were diploma holders providing general nursing care.5 however, the moh began implementing post-basic education programmes in selected nursing specialties in 1977 and opened the oman specialised nursing institute in 2001 to increase the number of nurses with specialised skills.6 by 2007, there were a total of 3,164 specialty nurses.5 overall, few clinical nurses have a bachelor of science in nursing (bsn) degree or an advanced degree. to date, oman still faces a 30% shortage of omani nurses which is countered by employing expatriates on a fixed-term contractual basis.6 however, these nurses have short-term employment agreements with a subsequent high rate of staff turnover. this high turnover can lead to a shortage of nurses, further crippling the workforce and affecting healthcare delivery. the government of oman has begun to support the nursing profession and ensure a sustainable human resource supply through the establishment and funding of nursing institutions and by offering free education to those pursuing nursing as a profession.6 there are 12 nursing institutions in oman offering a three-year diploma programme and three universities offering a four-year bsn. two universities offer rnto-bsn bridging programmes. in addition, the moh sends nurses abroad to study for graduate degrees.5,6 by 2011, oman had a total of 14,238 nurses serving a population of more than three million people.7 despite this progress, there is still tremendous pressure for additional manpower due to the changing healthcare needs of the population and expansion of healthcare services in both public and private sectors. additional health workers should encompass a larger scope of specialties and possess different skills, with expertise in counselling, health promotion, communication and community and home-based care.3 shipman et al. reported that diploma holders may lack the necessary training to provide increasingly complex healthcare delivery due to their hospitalbased education in basic patient care.8 in a study of 414 nurses recruited from the four national referral hospitals in oman, ammouri et al. found that academic qualifications had a significant impact on evidence-based practice, with bsn nurses reporting fewer barriers to evidence-based research than diploma holders (34.6% versus 65.4%, respectively).9 furthermore, only 34.6% of nurses in this study held a baccalaureate degree in nursing;9 this distribution of academic qualifications among nurses appears to be typical for most hospitals in oman. demand for a baccalaureate degree in the nursing profession nursing continues to lag behind other professions with lower qualifications on average compared to other healthcare disciplines.10 multiple entry points into the profession have further weakened its standing in a society that expects certain standards of the healthcare sector.11 professionalism demands long-term and intensive academic preparation; compared to the fouryear bsn programme, the associate degree in nursing (adn) and similar diploma nursing programmes take only three years to complete.11,12 a crucial step in rebuilding the image of nursing professionalism would be to standardise the baccalaureate bsn degree as the only permissible entry point to a nursing career.11 nursing has undergone a paradigm shift; the rapidly changing healthcare environment, increasingly complex diseases, advances in technology and a shift of care from hospital to community settings all require well-prepared nurses.8 the american association of colleges of nursing (aacn) postulated that the massive shortage of nurses in the usa was due to a shortage of nurse educators.12,13 in 2013, approximately 78,089 qualified applicants for baccalaureate and graduate degrees in the usa were turned away, largely due to faculty shortages.13 there is a great need for baccalaureateand graduate degree-educated nurses.11 the aacn recommends that all new nurses should complete a bsn degree within 10 years of licensure.12 a call for more diploma nurses to attain a baccalaureate degree advancing the nursing profession in oman e324 | squ medical journal, august 2015, volume 15, issue 3 upgrading diploma-level education the world health organization reported that the provision of healthcare services continues to shift from hospital settings to focus on preventive care in the community.14 nurses are now engaged in health promotion, disease prevention and case management, as well as traditional bedside nursing.15 inevitably, there is a need for more qualified nurses and an education system that better prepares nurses to meet the complex demands of today’s healthcare.16,17 nursing baccalaureate programmes have been reported to equip nurses with critical thinking, leadership, care management and health promotion skills as well as the ability to work in a variety of inpatient and outpatient settings.11 bsn education covers all of the information provided in adn and diploma courses, as well as in-depth courses in physical and social sciences, nursing research, public and community health and nursing management. these additional courses enrich the students’ professional development and prepare nurses for a broader scope of practice with an improved understanding of the cultural, political and social issues that affect patients and influence healthcare delivery.12 concerns have been raised that eliminating adn and diploma level programmes will further worsen the already critical shortage of nurses.11 nevertheless, the benefits of a baccalaureate education outweigh these concerns in terms of ensuring high-quality patient care.11 studies have reported that baccalaureate nurses are associated with reduced patient mortality rates (e.g. approximately 3.6 deaths per 1,000 surgical patients) and shorter lengths of patient stay.18–20 these findings demonstrate that the level of nurse education directly influences patient outcomes. as lane et al. observed, baccalaureate education can change the characteristics of the nursing workforce.11 however, not all rns can meet the financial requirements of a baccalaureate education.11 the aacn encourages healthcare providers and employers to foster practice environments that embrace lifelong learning by offering incentives to rns to pursue a bsn and higher degree qualifications.12 in addition, the lack of differentiation between various nursing qualifications in terms of acknowledgement, job description or salary was reported as a barrier for rns to undertake bsn education.21 hospitals and employers need to demonstrate their willingness to support baccalaureate nurses with clinical career ladders and financial incentives upon educational advancement.11 baccalaureate nurses have been encouraged to seek out employers who recognise and value their level of education and distinct competencies.12 additionally, employers should affirm their readiness to retain nurses upon completion of their bsn as a form of job security. bridging programmes adn and diploma programmes are said to prepare ‘technical’ nurses, while the bsn programme prepares ‘professional’ nurses.22 rn-to-bsn bridging programmes are transitional programmes with additional courses designed to enhance upon the education offered in adn or diploma programmes.23 three critical elements that could help to foster this transition include: (1) an environment that promotes seamless academic progression; (2) teaching models that meet different learning needs; and (3) relevant content that prepares graduate nurses for practice.24 the national league for nursing strongly advocates that rn-to-bsn bridging programmes provide different pathways for academic progression.25 there should be no additional prerequisite courses, but rather new courses that build on previous competencies and which are accessible and flexible, allowing for uninterrupted, individualised and independent learning. c u r r i c u l u m m o d e l rn-to-bsn bridging curricula should be developed in response to emerging healthcare needs; the model should build on concepts from the adn/diploma programmes, be student-centred and faculty-facilitated and emphasise principles of adult learning.26 the core content in a bsn education should include health promotion, disease prevention, public health and health policy, with core competencies like evidencebased practice, leadership and professionalism.17 rnto-bsn bridging programmes should seek to prepare nurses to work both in hospital and community settings, applying evidence-based research to practice and managing resources efficiently and effectively. c h a l l e n g e s higher institutions of learning have been advised to offer “efficient, academically sound, cost-effective and convenient” bridging programmes in order to encourage student enrolment and reduce attrition.27 retaining students in these programmes is a challenge, as mature students may drop out if they cannot balance school and their career with home and family life.22 boylston et al. found that rn-to-bsn students strongly believed that their families were their top priority and were willing to leave the programme when faced with a family crisis.27 attrition rates of more joy k. kamanyire and susan achora sounding board | e325 than 25% have been reported in some institutions.28 factors such as considerable tuition payments, lack of time to study, fear of failing, lack of recognition for past accomplishments, equal treatment of bsn and adn or diploma nurses in the workplace and negative past educational experiences were reported to hinder rns from pursuing a bsn education.21 o v e r c o m i n g r e c r u i t m e n t a n d at t r i t i o n c h a l l e n g e s education providers must develop innovative educational methods that foster career mobility, improve satisfaction and increase retention. flexibility has been raised as a fundamental component to the success of bridging programmes, allowing students to study alongside other obligations.22 however, providing a flexible and comprehensive degree education has been reported as a challenge for faculty at some institutions.22 specific acceleration bridging programmes have been developed for rns and these have resulted in increased enrolment, decreased attrition rates and higher completion rates; online programmes have also been initiated to deal with accessibility and flexibility challenges.22 furthermore, students have been reported to appreciate faculty support when educators acknowledge past experience, provide a caring environment and empower their students.29 in particular, rn students felt empowered when the faculty treated them as mature colleagues in the profession and acknowledged and built on past clinical experience during learning sessions. they also wished to be treated with empathy, especially when faced with family and social obligations.29 it has been found that rns are more receptive to programmes that acknowledge them as working adults with multiple roles.25 according to boylston et al., students reported greater satisfaction in bridging programmes with accessible services, flexible curricula and supportive faculties.22 motivation to enrol in a bridging programme is paramount to the programme’s success. rns return to school for personal and professional development.30 however, this process can be perceived as both challenging and demotivating. a previous negative academic experience during the diploma programme may have a lasting traumatic effect on the decision to attain a bsn.21 incorporating experiences from faculty who have gone through this programme would be beneficial to its restructuring. urgent research is also needed to identify specific reasons why diploma nurses with more than 10 years of experience do not seek to attain bsn degrees. b r i d g i n g p r o g r a m m e s i n o m a n in the omani setting, cultural and social factors may also play a role in the success of bridging programmes. as the ratio of female to male nurses in oman is 7:1,6 most bridging students would be female. according to boylston et al., most rns in their study were mature adult learners who were married with children and had numerous family obligations.22 in oman, wives may need consent and the approval of their spouses to enrol or complete a programme. omani women have been reported to have less social empowerment and autonomy in decision-making than men.31,32 experiences of graduates at the two universities which offer rn-bsn bridging programmes need to be explored. bridging programmes implemented in oman should be tailored to their unique social and cultural setting. advancing the nursing profession in oman although oman has made significant economic developments over the last four decades, the population has doubled in the span of 30 years with an increased prevalence of chronic diseases and an ageing population.3 these factors may jeopardise the quality of healthcare services. quality improvements in nursing care can be realised by improving the academic standards of practising nurses. greater emphasis on nursing qualifications, evidence-based practice and research and strategic leadership positions will improve the image of nursing in oman. it seems inevitable that all rns will eventually be required to upgrade to a bsn degree and that entry into the nursing workforce will stipulate a baccalaureate degree as a minimum requirement. the most recent five-year strategic plan by the moh in oman has proposed that the bsn should be the minimum entry level for nursing practice.33 oman plans to develop human resources in nursing and midwifery by focusing on leadership, continuous education and the provision of a safe and effective working environment.33 providing diploma nurses with the necessary support to achieve a baccalaureate education would be one fundamental step towards helping omani nurses pursue lifelong learning.11 salary increments for bsn nurses and differentiation between nursing qualifications are also recommended. efforts should be made to cultivate and promote nurse leaders who can join stakeholders in other health professions as full partners on advisory boards and in the planning of health policies and reforms to advance health systems and improve patient care.17 a call for more diploma nurses to attain a baccalaureate degree advancing the nursing profession in oman e326 | squ medical journal, august 2015, volume 15, issue 3 conclusion due to recent changes in the health needs of the omani population, diploma nurses should be encouraged to obtain a baccalaureate degree as part of their lifelong learning goals. this will help rns maintain clinical competencies and meet the demands of a dynamic healthcare system. education incentives for rns to pursue a bsn should include differentiation of baccalaureate nurses from diploma nurses in terms of salary and job description. furthermore, having a bsn degree should be the minimum entry point into the nursing profession. seamless rn-tobsn transition programmes will improve the overall quality of nursing care and the image of the nursing profession in oman. however, understanding the unique academic, cultural and social needs of omani rn-to-bsn bridging students is crucial. references 1. alshishtawy mm. four decades of progress: evolution of the health system in oman. sultan qaboos univ med j 2010; 10:12–22. 2. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 3. world health organization. country cooperation strategy for who and oman 2010–2015. from: www.applications.emro.who. int/docs/ccs_oman_2010_en_14485.pdf accessed: jan 2015. 4. world health organization. health system profile: oman. from: www.apps.who.int/medicinedocs/en/d/js17304e accessed: jan 2015. 5. ghosh b. health workforce development planning in the sultanate of oman: a case study. hum resour health 2009; 7:47. doi: 10.1186/1478-4491-7-47. 6. minority nurse. professional nursing in oman. from: www. minoritynurse.com/professional-nursing-in-oman/ accessed: jan 2015. 7. oman ministry of health. health facts report 2011. from: www. moh.gov.om/en/web/statistics/-/health-facts-report-2011 accessed: jan 2015. 8. shipman d, hooten j. employers prefer bsn nurses: but where’s the financial compensation? nurse educ today 2010; 30:105–6. doi: 10.1016/j.nedt.2009.09.015. 9. ammouri aa, raddaha aa, dsouza p, geethakrishnan r, noronha ja, obeidat aa, et al. evidence-based practice: knowledge, attitudes, practice and perceived barriers among nurses in oman. sultan qaboos univ med j 2014; 14:e537–45. 10. nelson ma. education for professional nursing practice: looking backward into the future. online j issues nurs 2002; 7:4. 11. lane sh, kohlenberg e. the future of baccalaureate degrees for nurses. nurs forum 2010; 45:218–27. doi: 10.1111/j.17446198.2010.00194.x. 12. american association of colleges of nursing. fact sheet: the impact of education on nursing practice. from: www.aacn. nche.edu/media-relations/edimpact.pdf accessed: jan 2015. 13. american association of colleges of nursing. enrollment growth slows at u.s. nursing colleges and universities in 2007 despite calls for more registered nurses. from: www.aacn.nche. edu/news/articles/2007/enrl accessed: jan 2015. 14. world health organization. who nursing and midwifery progress report 2008–2012. from: www.who.int/hrh/nursing_midwifery/ nursingmidwiferyprogressreport.pdf accessed: jan 2015. 15. american association of colleges of nursing. the baccalaureate degree in nursing as minimal preparation for professional practice. j prof nurs 2001; 17:267–9. doi: 10.1053/ jpnu.2001.26300. 16. institute of medicine. the future of nursing: leading change, advancing health. washington dc, usa: the national academic press, 2011. pp. 163–219. 17. orsolini-hain l. mixed messages: hospital practices that serve as disincentives for associate degree-prepared nurses to return to school. nurs outlook 2012; 60:81–90. doi: 10.1016/j. outlook.2011.05.007. 18. aiken lh, clarke sp, cheung rb, sloane dm, silber jh. educational levels of hospital nurses and surgical patient mortality. jama 2003; 290:1617–23. doi: 10.1001/ jama.290.12.1617. 19. friese cr, lake et, aiken lh, siber jh, sochalski j. hospital nurse practice environments and outcomes for surgical oncology patients. health serv res 2008; 43:1145–63. doi: 10.1111/j.1475-6773.2007.00825.x. 20. blegen ma, goode cj, park sh, vaughn t, spetz j. baccalaureate education in nursing and patient outcomes. j nurs adm 2013; 43:89–94. doi: 10.1097/nna.0b013e31827f2028. 21. megginson la. rn-bsn education: 21st century barriers and incentives. j nurs manag 2008; 16:47–55. doi: 10.1111/j.13652934.2007.00784.x. 22. boylston mt, peters ma, lacey m. adult student satisfaction in traditional and accelerated rn-to-bsn programs. j prof nurs 2004; 20:23–32. doi: 10.1016/j.profnurs.2003.12.008. 23. mcewen m, white mj, pullis br, krawtz s. essential content in rn-bsn programs. j prof nurs 2014; 30:333–40. doi: 10.1016/j. profnurs.2013.10.003. 24. conner ne, thielemann pa. rn-bsn completion programs: equipping nurses for the future. nurs outlook 2013; 61:458– 65. doi: 10.1016/j.outlook.2013.03.003. 25. national league for nursing board of governors. academic progression in nursing education: a living document from the national league for nursing. from: www.nln.org/docs/ default-source/about/nln-vision-series-(position-statements)/ nlnvision_1.pdf?sfvrsn=4 accessed: jan 2015. 26. allen pe, armstrong ml. rn-bsn curricula: designed for transition, not repetition. j prof nurs 2013; 29:e37–42. doi: 10.1016/j.profnurs.2013.06.001. 27. boylston mt, jackson c. adult student satisfaction in an accelerated rn-to-bsn program: a follow-up study. j prof nurs 2008; 24:285–95. doi: 10.1016/j.profnurs.2007.10.006. 28. robertson s, canary cw, orr m, herberg p, rutledge dn. factors related to progression and graduation rates for rn-tobachelor of science in nursing programs: searching for realistic benchmarks. j prof nurs 2010; 26:99–107. doi: 10.1016/j. profnurs.2009.09.003. 29. cangelosi pr. the tact of teaching rn-to-bsn students. j prof nurs 2004; 20:267–73. doi: 10.1016/j.profnurs.2004.04.002. 30. delaney c, piscopo b. there really is a difference: nurses’ experience with transitioning from rns to bsns. j prof nurs 2007; 23:167–73. doi: 10.1016/j.profnurs.2007.01.011. 31. al-riyami aa, afifi m. determinants of women’s fertility in oman. saudi med j 2003; 24:748–53. 32. varghese t. women empowerment in oman: a study based on women empowerment index. far east j psychol bus 2011; 2:37–53. 33. oman ministry of health. the 8th five-year plan for health development (2011–2015). from: www.nationalplanningcycles. org/sites/default/files/country_docs/oman/five_year_plan_ for_health_development_2011-2015.pdf accessed: jan 2015. http://dx.doi.org/10.1186/1478-4491-7-47 http://dx.doi.org/10.1016/j.nedt.2009.09.015 http://dx.doi.org/10.1111/j.1744-6198.2010.00194.x http://dx.doi.org/10.1111/j.1744-6198.2010.00194.x http://dx.doi.org/10.1053/jpnu.2001.26300 http://dx.doi.org/10.1053/jpnu.2001.26300 http://dx.doi.org/10.1016/j.outlook.2011.05.007 http://dx.doi.org/10.1016/j.outlook.2011.05.007 http://dx.doi.org/10.1001/jama.290.12.1617 http://dx.doi.org/10.1001/jama.290.12.1617 http://dx.doi.org/10.1111/j.1475-6773.2007.00825.x http://dx.doi.org/10.1097/nna.0b013e31827f2028 http://dx.doi.org/10.1111/j.1365-2934.2007.00784.x http://dx.doi.org/10.1111/j.1365-2934.2007.00784.x http://dx.doi.org/10.1016/j.profnurs.2003.12.008 http://dx.doi.org/10.1016/j.profnurs.2013.10.003 http://dx.doi.org/10.1016/j.profnurs.2013.10.003 http://dx.doi.org/10.1016/j.outlook.2013.03.003 http://dx.doi.org/10.1016/j.profnurs.2013.06.001 http://dx.doi.org/10.1016/j.profnurs.2007.10.006 http://dx.doi.org/10.1016/j.profnurs.2009.09.003 http://dx.doi.org/10.1016/j.profnurs.2009.09.003 http://dx.doi.org/10.1016/j.profnurs.2004.04.002 http://dx.doi.org/10.1016/j.profnurs.2007.01.011 sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 152-155, epub. 27th feb 13 submitted 27th mar 12 revision req. 15th may 12, revision recd. 28th may 12 accepted 30th jul 12 departments of 1cardiology, 2emergency medicine, royal hospital, muscat, oman *corresponding author e mail: prashanthp_69@yahoo.co.in األسباب املتعددة اللتواء ختطيط القلب حول النقطة يف مريض جراحي داخل املستشفى بر�صانث باندوراجنا، حممد املخيني، مامثا راجاراو امللخ�ص: رجل يف ال55 من العمر معروف باإدمان الكحول وم�صاب بفريو�ض نق�ض املناعة الب�رسية مت اإدخاله اإىل جناح اجلراحة بعد ت�رسيف خراج العجان. مت اكت�صاف وجود بطء يف اجليب القلبي، جممعات البطني املبكرة وانخفا�ض �صغط الدم اخلفيف. النتائج املخربية بينت وجود نق�ض خفيف ببوتا�صيوم الدم. املري�ض كان م�صطرب ب�صكل متقطع ومت ت�صخي�صه مبتالزمة �صحب الكحول. بعد اجلراحة ح�صل املري�ض عن طريق احلقن الوريدي علي البيربا�صيلني/تازوباكتام واملرتانيدزول بالإظافة اىل جرعة �صغرية من الدوبامني. اأظهر حتليل جهاز مراقبة هولرت 24 �صاعة )ecg( على فا�صل qt مطول مع حالتني لإلتواء تخطيط القلب حول النقطة ذاتية الإنتهاء. مت عالج متالزمة �صحب الكحول، ت�صحيح نق�ض بوتا�صيم الدم و�صحب الدوبامني وامل�صادات احليوية. مل يكن هناك تكرار لإ�صطراب النظم القلبي. هذه احلالة �صلطت ال�صوء على اأهمية جتنب الأدوية التي ت�صبب اإطالة فا�صل qt يف املر�صى املدخلني للم�صت�صفيات اإذ اإنه غالبا ما يكون املر�صى لديهم عوامل خطر متعددة ل�صطراب النظم املحر�ض. نق�ض بفريو�ض الكحول، �صحب متالزمة ،qt اإطالة اأدوية ، qt اإطالة ، qt فا�صل النقطة، حول القلب تخطيط التواء الكلمات: مفتاح املناعة الب�رسية، عمان. abstract: a 55-year-old chronic alcoholic male known to be positive for human immunodeficiency virus (hiv) was admitted to a surgical ward following perianal abscess drainage. he was noted to have sinus bradycardia, ventricular premature complexes, and mild hypotension. his laboratory investigations revealed mild hypokalaemia. he was intermittently agitated and alcohol withdrawal syndrome (aws) was diagnosed. postoperatively, he received intravenous piperacillin/tazobactam and metronidazole infusions along with a small dose of dopamine. analysis of a 24-hour holter monitor (ecg) showed a prolonged qt interval with two episodes of self-terminating torsade de pointes. his aws was treated, hypokalaemia was corrected, and dopamine, along with antibiotics, was withdrawn. there was no recurrence of arrhythmias. this case highlights the importance of avoiding qt-prolonging drugs in hospitalised patients, since hospitalised patients often have multiple risk factors for a proarrhythmic response. keywords: torsade de pointes; qt interval; qt prolongation; qt-prolonging drugs; alcohol withdrawal syndrome; human immunodeficiency virus; case report; oman. multi-factorial causes of torsade de pointes in a hospitalised surgical patient *prashanth panduranga,1 mohammed al-mukhaini,1 mamatha p. rajarao2 case report drug-induced qt prolongation and torsade de pointes (tdp) with cardiac arrest is a rare but potentially fatal event in hospital settings.1 we present a patient with tdp in whom the aetiology was multifactorial. case report a 55-year-old non-diabetic, non-hypertensive male was admitted to the surgical ward at the royal hospital, muscat, oman, following perianal abscess drainage surgery. he was referred to a cardiologist for sinus bradycardia, ventricular premature complexes (vpcs), and mild hypotension, which were not present pre-operatively. he was not on any regular medications but was receiving regular doses of piperacillin/tazobactam and metronidazole infusions as antibiotics along with a dopamine infusion of 5 μg/kg/minute postoperatively. no cardiovascular symptoms were described. his past medical history had included chronic alcoholism and human immunodeficiency virus (hiv) positivity but he was without any history of substance abuse. an examination prashanth panduranga, mohammed al-mukhaini and mamatha p. rajarao case report | 153 demonstrated anxiety, agitation, tremors, and excessive sweating, but no cardiovascular issues or other abnormalities. there were no episodes of seizure, hallucination, or delirium tremens. his serum potassium level was 2.9 mmol/l. other routine blood tests, including amylase, troponin t, calcium, sodium, and magnesium were normal. his baseline electrocardiogram (ecg) showed a sinus rhythm of 60 beats/minute, and narrow normal qrs complexes with few uniform vpcs, and a normal corrected qt interval (qtc). a diagnosis of alcohol withdrawal syndrome (aws) was made and treated with oral diazepam. he was also given intravenous (iv) fluids with potassium supplementation. his transthoracic echocardiography was normal. a 24-hour ambulatory holter monitor ecg showed an intermittently prolonged qtc interval (qtc, bazett’s correction = 470 ms) along with two episodes of selfterminating non-sustained torsade de pointe (tdp) ventricular tachycardia [figure 1]. the first episode lasted 6 seconds and the second episode lasted 11 seconds. there were no st-segment changes noted. the nursing staff on the ward were unaware of these arrhythmias. his dopamine and antibiotics were withdrawn. the patient's symptoms settled within 72 hours and the rest of his stay was uneventful. his discharge serum potassium level was 4.9 mmol/l with no vpcs or tdp on telemetry monitoring. the patient also had a normal qtc interval. discussion the role of alcohol in causing heart failure (alcoholic cardiomyopathy) and supraventricular arrhythmias, especially atrial fibrillation (holiday heart syndrome) is well-known.2 tdp is a form of polymorphic ventricular tachycardia associated with a prolonged qt interval (either congenital or acquired). qt prolongation is known to occur in aws.3,4 otero-anton et al. documented a prolonged qtc interval in 46% of patients studied and cuculi et al. in 63% of patients who had aws, with two patients developing tdp, but without any pre-treatment with qt-prolonging drugs.3,4 however, our patient was treated with piperacillin/ tazobactam and metronidazole, which have recently been discovered to cause tdp.5 cuculi et al. opined that qt prolongation may be due to autonomous system disturbances in aws.3 this was demonstrated in recent experimental studies involving rats.6,7 abrupt termination of the chronic ethanol intake in rats increased heart rate variability and qt interval dispersion, suggesting impaired homogeneity of myocardial repolarisation and a shift of the cardiac sympathovagal balance toward sympathetic predominance and reduced vagal tone. the mechanism for most qt-prolonging drugs is inhibition of the kcnh2-encoded human etherà-go-go related gene (herg) potassium channel which mediates ikr (rapid component of the delayed rectifier potassium current), although some drugs mainly modify sodium channels.8 inhibition of this current results in prolongation of myocardial repolarisation/action potential duration along with a prolonged qt interval as well as changes in t-u wave morphology. there is a graded increase in the risk for tdp as the qtc increases. specifically, each 10-millisecond (msec) increase in qtc leads to an approximate 5–7% increase in a patient’s risk for developing tdp.1 there is no threshold of qtc prolongation at which tdp is certain to occur. in this patient, tdp occurred at a mildly prolonged figure 1: electrocardiogram rhythm strips from a 24-hour ecg (holter monitor) showing selfterminating non-sustained torsade de pointes in a patient with alcohol withdrawal syndrome and human immunodeficiency virus infection receiving dopamine and qt-prolonging antibiotics. multi-factorial causes of torsade de pointes in a hospitalised surgical patient 154 | squ medical journal, february 2013, volume 13, issue 1 qtc interval. however, small studies of druginduced tdp have shown an increased risk when the threshold of qtc >500 msec is exceeded.1 the onset of tdp is pause-dependent and is precipitated by either bradycardia, in which sudden long cycles may lead to arrhythmogenic early afterdepolarisations, or by premature beats that lead to short-longshort cycles.1 both these factors were seen in this patient. the trigger for tdp is a vpc that results from an early afterdepolarisation generated during the abnormally prolonged repolarisation phase of the affected myocardium.1 because of the extreme delay of repolarisation in certain regions of the myocardium, conduction of the vpc is blocked initially in some directions but not in others, which sets up re-entry that perpetuates tdp. although in the majority of cases prolonged myocardial repolarisation caused by drugs is clinically silent, when prescribed in the setting of other risk factors, it may lead to tdp as seen in this patient. in-hospital risk factors for tdp include female gender, advanced age, electrolyte derangements (hypokalaemia, hypomagnesaemia, hypocalcaemia), treatment with diuretics, underlying heart disease, rapid iv infusion, use of more than one qt-prolonging drug (including various antipsychotics, antidepressants, antibiotics, antiemetics, antihistaminics, inotropes, and class ia and iii antiarrhythmics), hepatic and/ or renal failure, pharmacokinetic/pharmaco dynamic interactions, occult congenital long qt syndrome, genetic polymorphisms, and bradycardia.1,8 this patient had five risk factors for tdp. these included acute aws, hiv infection, bradycardia, hypokalaemia, and treatment with three qt-prolonging drugs (dopamine, piperacillin/ tazobactam, and metronidazole). hiv infection has been shown to be an independent risk factor for qt prolongation. kocheril et al. reported a prevalence of qt prolongation in 28% of hospitalised hiv patients.9 in the recent hiv-infection and heart disease (hiv-heart) study, the prevalence was 20%.10 yang et al. have demonstrated that the ikrblocking properties of certain drugs is directly dependent on extracellular potassium.11 they showed anincreasing drug block of the potassium current precipitated by hypokalaemia. this was an important mechanism to explain the link between hypokalaemia and tdp.11 analysing data from the united states food and drug administration (usfda) adverse event reporting system, poluzzi et al. reported additional drugs that can cause qt prolongation and tdp, which included piperacillin/ tazobactam and metronidazole.5 management of tdp includes correction of any predisposing factors, such as hypokalaemia, and cessation of any predisposing medication. acute treatment includes electrical (dc) cardioversion if haemodynamically compromised, defibrillation if tdp degenerates into ventricular fibrillation, iv magnesium (first-line therapy), and isoprenaline or temporary ventricular overdrive pacing to augment the heart rate. conclusion in conclusion, this case highlights the importance of avoiding qt-prolonging drugs in hospitalised patients, since hospitalised patients often have multiple risk factors for a proarrhythmic response. in addition, this case reiterates the recent american heart association/american college of cardiology foundation (aha/accf) scientific statement to raise awareness among acute care physicians, managing such patients in hospital units, about the multiple risk factors, ecg monitoring, and management of drug-induced long qt syndrome (lqts).1 references 1. drew bj, ackerman mj, funk m, gibler wb, kligfield p, menon v, et al. american heart association acute cardiac care committee of the council on clinical cardiology; council on cardiovascular nursing; american college of cardiology foundation. prevention of torsade de pointes in hospital settings: a scientific statement from the american heart association and the american college of cardiology foundation. j am coll cardiol 2010; 55:934–47. 2. laonigro i, correale m, di biase m, altomare e. alcohol abuse and heart failure. eur j heart fail 2009; 11:453–62. 3. cuculi f, kobza r, ehmann t, erne p. ecg changes amongst patients with alcohol withdrawal seizures and delirium tremens. swiss med wkly 2006; 136: 223–7. 4. otero-anton e, gonzalez-quintela a, saborido j, torre ja, virgos a, barrio e. prolongation of the qtc interval during alcohol withdrawal syndrome. acta cardiol 1997; 52:285–94. 5. poluzzi e, raschi e, motola d, moretti u, de ponti f. antimicrobials and the risk of torsade de pointes: the contribution from data mining of the usfda prashanth panduranga, mohammed al-mukhaini and mamatha p. rajarao case report | 155 adverse event reporting system. drug saf 2010; 33:303–14. 6. shirafuji s, liu j, okamura n, hamada k, fujimiya t. qt interval dispersion and cardiac sympathovagal balance shift in rats with acute ethanol withdrawal. alcohol clin exp res 2010; 34:223–30. 7. liu j, fujimiya t. abrupt termination of an ethanol regimen provokes ventricular arrhythmia and enhances susceptibility to the arrhythmogenic effects of epinephrine in rats. alcohol clin exp res 2010; 34:s45–53. 8. van noord c, eijgelsheim m, stricker bh. drugand non-drug-associated qt interval prolongation. br j clin pharmacol 2010; 70:16–23. 9. kocheril ag, bokhari sa, batsford wp, sinusas aj. long qtc and torsade de pointes in human immunodeficiency virus disease. pacing clin electrophysiol 1997; 20:2810–16. 10. reinsch n, buhr c, krings p, kaelsch h, neuhaus k, wieneke h, et al. german heart failure network. prevalence and risk factors of prolonged qtc interval in hiv-infected patients: results of the hiv-heart study. hiv clin trials 2009; 10:261–8. 11. yang t, roden dm. extracellular potassium modulation of drug block of ikr. implications for torsade de pointes and reverse use-dependence. circulation 1996; 93:407–11. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 477-485, epub. 8th oct 13 submitted 16th feb 13 revisions req. 21st apr & 8th jul 13; revisions recd. 3rd jun & 20th jul 13 accepted 25th jul 13 1department of child health, royal hospital, muscat, oman; 2directorate general of health services, ministry of health, muscat, oman *corresponding author e-mail: geepaul1@gmail.com معاجلة الرضع و األطفال املخالطني للمرضى املصابني مبرض السل املعدي جورج بول، اأمل �سيف املعنية، بادماموهان جاناردانا كوروب حاالت تعد التي البلدان يف املر�ض هذا مكافحة مفتاح ي�سكل )الدرن( ال�سل ملر�سى املخالطني االأ�سخا�ض وعالج التحقيق امللخ�ص: االإ�سابة فيها منخف�سة. �سلطنة عمان كاأحدى الدول املعروفة بانخفا�ض حاالت وقوع ال�سل، اعتمدت تطبيق التحقيق ومعاجلة االأ�سخا�ض املت�سلني باملر�سى امل�سابني بهذه العدوى كاإحدى اال�سرتاتيجيات املهمة ملكافحة ال�سل. على الرغم من ذلك، ال توجد مبادئ توجيهية وا�سحة للتحقيق واملعاجلة ال �سيما فيما يتعلق باالأطفال املخالطني ملر�سى ال�سل. اإن الف�سل يف معاجلة مثل هذا االت�سال عند االأطفال يعد فر�سة �سائعة للحد من انت�سار املر�ض بني ال�سكان الذي قد يعر�سهم خلطر التقدم ال�رسيع للمر�ض وم�ساعفاته. هذا املقال يحاول توفري نهج موجز عن عملية التحقيق وعالج الر�سع واالأطفال املخالطني ملر�سى ال�سل ويناق�ض باإيجاز اخلطوات اال�سا�سية يف جمموعة من ال�سيناريوهات املحتملة. مفتاح الكلمات: ال�سل؛ االأطفال؛ عدوى �سل خاف؛ اختبار التوبركولني؛ ُعمان. abstract: contact investigation and management form the key for tuberculosis (tb) control in countries with a low tuberculosis incidence. oman, with a low tb incidence, has implemented contact investigation and management as one important strategy to control tb. however there is a lack of clear guidelines for the investigation and treatment of contacts, especially with regard to children who are contacts of tb cases. the failure to manage children in contact with infectious tb cases indicates a missed opportunity to prevent tb disease in a population which is prone to progress rapidly to severe and complicated illness. this article attempts to provide a concise and practical approach for managing infants and children who are in contact with tb patients. essential steps in a variety of possible scenarios are briefly discussed. keywords: tuberculoses; children; latent tuberculosis infection; tuberculin tests; oman. special contribution management of infants and children who are contacts of contagious tuberculous patients *george paul,1 amal s. al-maani,1 padmamohan j. kurup2 investigation of people exposed to cases of infectious tuberculosis (tb), also called contact investigation, is the key to tb control, especially in countries with a low incidence of tb. recent literature suggests that contact investigation also merits serious consideration as a means to improve early case detection and decrease the transmission of mycobacterium tuberculosis (mtb) even in high-incidence areas.1 oman, with a low tb incidence and high bacillus calmette-guérin (bcg) vaccine coverage at birth, has implemented contact investigation and management as an important strategy for the control of tb.2 the incidence of sputum smear-positive tb in oman was 5.1 per 100,000 omanis in 2011. incidence rates of tb as well as sputum smear-positive tb has shown an almost static trend over the past decade [figure 1].3 contact investigation and the management of children who are exposed to an infectious adult source case are considered the most efficient ways to prevent paediatric tb disease. missed opportunities to prevent cases of tb disease in children can be due to a delay in the diagnosis or management of the adult source case, a delay in the reporting of a source case to the local public health/ tb control authority, a failure to identify a child during contact investigations, or lack of knowledge on how to manage and follow-up paediatric contact cases.4 although contact management is an important strategy, there is a lack of clear guidelines for the investigation and treatment of contacts, especially george paul, amal s. al-maani and padmamohan j. kurup special contribution | 478 children who are in contact with tb patients that would be helpful in the omani context. the manifestations of tb infection, after exposure to a person with active infectious tb, are very different in infants and children. therefore, the management should vary from that of an adult who is exposed to the same. children pose three unique challenges to tb control. first, the diagnosis of tb disease in children under 5 years of age can be difficult because they often have nonspecific signs and symptoms and a paucity of mycobacteria. second, tb in children is considered a sentinel event usually indicating recent transmission. finally, children, especially infants, are at an increased risk of progressing from latent tb infection (ltbi) to active and sometimes severe tb disease. infection with mtb is usually the result of inhaling into the lungs infected droplets produced by someone who has laryngeal tb or pulmonary tb and is coughing. the source of infection for most children is thus an infectious adult in their close environment, usually the household. this exposure leads to the development of a primary parenchymal lesion (ghon’s focus) in the lung which spreads to the regional lymph node(s).6 the immune response (delayed hypersensitivity and cellular immunity) develops about 4–6 weeks after the primary infection. in most cases, the immune when it comes to children. this is primarily due to a lack of awareness regarding the various aspects of childhood tb. in addition, tb contact investigations typically require interdependent decisions which sometimes are based on incomplete data. simple decision trees are often not applicable and the decision making is often a complex process.5 in oman, these challenges are more prominent in the primary care setting where most of the contact screening and management of tb cases are undertaken. due to these factors, although an outline for managing paediatric contacts of contagious tb is provided in the tb manual published by the omani ministry of health, the authors have noted that a significant proportion of formal and informal consultations are done in this regard.2 thus, there is an obvious need to provide the essential principles and approach to such cases in a clear and concise manner for the primary healthcare setting in oman. this outline is derived from current practice in a tertiary care setting in oman which is essentially based on the latest guidelines issued by the world health organization (who) and the centers for disease control and prevention (cdc) in atlanta, georgia, usa. this is not an exhaustive review of all the relevant publications nor is it a national tb programme guideline. our objective is to provide a practical approach for managing infants and figure 1: annual tuberculosis incidence among the omani population (per 100,000). tb = tuberculosis. adapted from: annual statistical reports, ministry of health, muscat, oman. management of infants and children who are contacts of contagious tuberculous patients 479 | squ medical journal, november 2013, volume 13, issue 4 response stops the multiplication of tb bacilli at this stage. however, a few dormant bacilli may persist. the primary infection may be associated with complications, especially in children under 5 years of age.7,8 the parenchymal lesion may enlarge and caseate, or nodes may enlarge and compress or erode through a bronchus, causing wheezing, segmental pneumonia or atelectasis. the occult subclinical bacteremia that usually accompanies primary infection may result in severe tb diseases such as disseminated tb or central nervous system tb. the risk of tb disease and severe forms of it after exposure is inversely related to age [table 1].7 children living in close contact with a source case of smear-positive pulmonary tb or laryngeal tb are at particular risk of tb infection and disease. no safe exposure time to airborne mtb has been established. if a single bacterium can initiate an infection leading to tb disease, then even the briefest exposure entails a theoretical risk. the risk of infection is greatest in the case of close and prolonged contact, such as the contact an infant or toddler has with the mother or other caregivers in the household. the risk of developing disease after infection is much greater for infants and young children under 5 years of age than it is for children aged 5 years or above. the risk of progression gradually decreases through childhood.7 also, infants and younger children are more likely to develop life-threatening forms of tb, especially meningeal and disseminated disease, compared to older children and adults.9 if disease does develop, it usually does so within two years of infection, but in infants the time-lag can be as short as a few weeks. isoniazid (inh) preventive therapy for young children with infection who have not yet developed disease will greatly reduce the likelihood of tb during childhood with a risk reduction of 70–90%.10 a tuberculin skin test (tst), interferon gamma release assay (igra), or chest x-ray (cxr) is the best method to screen for tb disease among contacts.6,9 terminology some of the terminologies used in this article need explanation.2,9 • close contact: a child living in the same household as a source case (e.g. the child’s caregiver) or who is in frequent contact with a source case. • contagious or infectious tb: pulmonary tb or laryngeal tb. • exposure: a situation in which a child has significant contact with an adult infected with a contagious form of tb. a child exposed to mtb does not necessarily become infected. the recommended minimum period between the most recent exposure and tuberculin skin testing should be 8–10 weeks. • exposure history and time frame: the start of infectious period for an index case cannot be determined with precision through the available methods. however, on the basis of expert opinion, a date three months prior to the date of diagnosis is to be assigned as the starting date for infection and this duration should be considered as the infectious period.9 in those circumstances where there is a longer duration of symptoms or protracted illness, it is wiser to have an earlier start based on the duration of the illness. • ltbi: a condition in which mtb has entered the body and typically has elicited immune responses. ltbi is an asymptomatic condition that follows the initial infection; the infection is still present but is dormant and believed not to be currently progressive or invasive. the only sign of tb infection is a positive reaction to the tst table 1: average age-specific risk for disease development after untreated primary infection age at primary infection manifestations of disease risk of disease (%) <12 months no disease 50 pulmonary disease 30–40 tb meningitis or miliary disease 10–20 12–23 months no disease 70–80 pulmonary disease 10–20 tb meningitis or miliary disease 2–5 2–4 years no disease 95 pulmonary disease 5 tb meningitis or miliary disease 0.5 5–10 years no disease 98 pulmonary disease 2 tb meningitis or miliary disease <0.5 >10 years no disease 80–90 pulmonary disease 10–20 tb meningitis or miliary disease 0.5 tb = tuberculosis. adapted from marais et al.7 george paul, amal s. al-maani and padmamohan j. kurup special contribution | 480 for one month or more) and anti-neoplastic agents. when the induration following a tst (mantoux test) is ≥10 mm, it should be considered as positive in the following situations: children with frequent exposure to adults at high risk; birth in or recent immigration (<5 years) from a high-prevalence country; children who had travelled or been exposed to visitors from high-prevalence countries, or children with malnutrition, chronic renal failure, diabetes mellitus or lymphoma. in the case of children exposed to contagious tb, the management should be adapted according to the age of the child and his/her immune status.5,9 the investigations and management of newborns and children who are contacts of tb cases would differ; thus, the discussion should focus on the following settings: (1) a newborn whose mother or other household contact has a contagious form of tb or ltbi; (2) children less than 5 years of age with exposure to a contagious case of tb or more than 5 years of age with exposure to a contagious case of tb; (3) children with exposure to a non-contagious case of tb, another child with tb disease, or an adult with mdrtb, or (4) a child who has a contact who is known to be hiv-infected. management of newborns in a newborn whose mother or other household contact has a contagious form of tb, the management should also vary according to the situation. if the mother is known or suspected of having tb disease, a maternal evaluation to rule out pulmonary or extra pulmonary disease including uterine tb needs to be done. an hiv serology should be undertaken if her prenatal screening is not done or is unavailable. a bcg vaccine should not be given to a newborn. however, an evaluation for congenital tb should be carried out if the newborn is symptomatic or in the cases where the mother is still acid fast bacilli (afb)-positive or has disseminated disease that was not treated or was partially treated. an evaluation should also be carried out in cases of maternal endometrial tb regardless of treatment status with cxr, gastric aspirates for afb and a tb culture of 3 early morning consecutive samples, an abdominal ultrasound or a lumbar puncture followed by submitting cerebrospinal fluid for afb and tb cultures.9 if the or a positive result with the currently available blood test—the igra. for practical purposes, a child with ltbi is someone with a positive tst, no clinical evidence of disease, and a cxr that is either normal or demonstrates evidence of remote infection, such as a calcified parenchymal nodule and/or a calcified intrathoracic lymph node. although these abnormal cxr findings do not strictly come under the definition of ltbi, it is also not considered an active disease and it is prudent to treat it as ltbi. people with a latent tb infection are not infectious; however, some of them develop tb disease depending on their immune status and the presence of other risk factors.8 • tb disease: the diagnosis is based on symptoms, radiological changes and microscopy. positive culture results for mtb are typically interpreted as both the indication and the confirmation of tb disease. for persons whose immune systems are weak, especially those with human immunodeficiency virus (hiv) infection, the risk of developing tb disease is significantly higher than it is for persons with normal immune systems. • multidrug resistant tb (mdrtb): this is defined as tb caused by mtb resistant in vitro to the effects of isoniazid and rifampicin, with or without resistance to any other drugs.11 diagnosis the definition used here for a positive tst is based on the cdc guidelines.9 oman is a country with a low prevalence of tb and high bcg coverage at birth; thus, the interpretation of a positive test has to be done cautiously. there is neither a compelling need to adopt a lower cut-off for positivity, nor is it advisable to use a higher cut-off. therefore, a special cut-off seems warranted in the context of tb control in oman. when the induration following a tst (mantoux test) is ≥5 mm, it should be considered as positive in the following situations: children in close contact with known/suspected contagious cases of tb; children suspected to have tb disease; findings in cxr consistent with active/previously active tb; clinical evidence of tb disease; children with hiv infection or immune deficiency states; children receiving immune suppressive therapy including immunosuppressive doses of corticosteroids (>15 mg prednisolone/day management of infants and children who are contacts of contagious tuberculous patients 481 | squ medical journal, november 2013, volume 13, issue 4 newborn is found to have tb disease, then treatment should be initiated promptly with the appropriate regimen in consultation with a paediatric infectious diseases specialist. if congenital tb is excluded, treatment for ltbi with inh (10 mg/kg/day) should be administered until the infant is at least 3 months of age and then a tst should be performed. if the repeated tst is positive, the child should be reassessed for active tb. if the disease is absent, a full course of treatment for ltbi should be given based on the sensitivities of the index strain. if the tst is negative and tb disease is ruled out, and the mother or the household contact has become noncontagious, then the inh should be stopped and a bcg vaccine administered to the baby who should then be followed-up on a monthly basis.9 for infection control, the newborn should be separated from any active tb case in the household including his/her mother during the evaluation period and any mother/adult contact should wear a facemask while handling the baby while following the isolation precautions. once the baby is on inh and the mother or adult source is on full treatment, there is no need to separate the baby, and the mother can again breastfeed the baby.9,12 management is different if the mother has mdrtb, as is described later in this article. in a newborn whose mother or other household contact has ltbi, the mother or household contact should be treated for ltbi. since a positive tst result could be a marker for an unrecognised case of contagious tb within the household, other household members should be investigated for tb disease/ltbi. the newborn needs no special evaluation, and a bcg vaccine can be given if no infectious case of tb disease is identified in the household.9 management of children under 5 years in the management of children under 5 years of age with exposure to a contagious case of tuberculosis, the investigation for tb disease should include a tst (gastric juice for afb is required only if the cxr is abnormal or the child is symptomatic). if a child has tb disease, the child should be started on a regimen of 3–4 anti-tb drugs in consultation with a paediatric infectious disease specialist and followed up. if tb disease is ruled out, all children in this category should be started on inh. further follow-up depends on the child’s tst status. if tb disease is ruled out, but the child has a positive tst, inh should be continued for 9 months. these children should be followed-up closely and reinvestigated for tb disease after 3 months. if the reinvestigation rules out tb disease, inh should be continued for 9 months and, if the child has impaired immunity, inh should be continued for 12 months. there is no need to repeat the tst at 3 months while reinvestigating for tb disease. if tb disease is ruled out and the tst is negative, inh should be continued and the child reinvestigated after three months. if the reinvestigation rules out tb disease, and if the repeat tst is negative, then inh should be stopped and the child followed-up [figure 2].5,9 management of children over 5 years in children above 5 years of age with exposure to a contagious case of tb, the child needs to be investigated for tb disease; however, gastric juice for afb or sputum examination is required only if the cxr is abnormal or if the child is symptomatic. if tb disease is ruled out and tst is found to be negative, there is no need for any treatment in the case of a child with a normal immune status. however, if the child has impaired immunity, then s/he should be started on inh prophylaxis. these children should be followed-up and reinvestigated for tb disease after three months.5,9 if tb disease is ruled out again but the repeat tst is positive, inh should be started and the case treated as ltbi. the duration of treatment should be decided on the basis of the child’s immune status. if the tst is negative, there is no need for any treatment or follow-up.5 if the child is hiv-positive, inh should be continued for one year [figure 3].2 in children with exposure to a non-contagious case of tb, an investigation is required because there could be an unrecognised contagious case in the household.5,9 if the tst is positive, they should be managed as a case of ltbi.2 in a child exposed to another child with tb disease, the tb disease in children need not be considered contagious unless the child has a cavitating adult form of pulmonary tb or has laryngeal tb. both these conditions are very rare george paul, amal s. al-maani and padmamohan j. kurup special contribution | 482 figure 2: flowchart showing the proposed management of children of less than 5 years of age with exposure to a contagious case of tuberculosis. tb = tuberculosis; tst = tuberculin skin test; cxr = chest x-ray; inh = isoniazid; hiv = human immunodeficiency virus. children and multidrug resistant tuberculosis in a child with exposure to an adult with mdrtb, the optimal therapy for those with ltbi caused by an organism resistant to inh and rifampicin is not known. in these circumstances, multidrug regimens have been used. drugs that are considered for these regimens include pyrazinamide, fluroquinolone, and ethambutol depending on the susceptibility of the isolated organisms. consultation of infectious disease experts for the management of such children is recommended.11,12 and so there is no contraindication for children with these types of tb disease to attend schools or play with normal children.5,9 for the same reason, when children are admitted for the investigation of tb, there is no need to keep them in isolation rooms unless there is some uncertainty regarding the status of attendants who are quite often the source of tb transmission in paediatrics wards. children with tb are rarely contagious, but that is not necessarily the case with their caregivers.12,13 management of infants and children who are contacts of contagious tuberculous patients 483 | squ medical journal, november 2013, volume 13, issue 4 hiv-infected children if the child contact is hiv-infected and asymptomatic, then inh therapy should be considered for all ages, including those who are 5 years and older. as with other contacts, active disease should be ruled out before providing hivinfected children with inh treatment. hiv-infected children who have symptoms should be carefully evaluated for tb disease as they are at an increased risk of developing active disease after tb exposure/ infection; therefore, the use of inh is justified once active tb has been excluded.12 therapies inh is widely used as the drug of choice for ltbi treatment with the standard recommended dose being 10–15 mg/kg/day (maximum dose: 300 mg/ day). young children eliminate inh faster than older children and adults and, consequently, require a higher dosage to achieve similar levels. the drug is well absorbed orally and is best absorbed when consumed on an empty stomach. the primary possible adverse reactions include hepatitis (agerelated), peripheral neuropathy and hypersensitivity reactions. other reactions include optic neuritis, figure 3: flowchart showing the proposed management of children over 5 years of age with exposure to a contagious case of tuberculosis. tb = tuberculosis; tst = tuberculin skin test; cxr = chest x-ray; inh = isoniazid; hiv = human immunodeficiency virus. george paul, amal s. al-maani and padmamohan j. kurup special contribution | 484 number of studies have shown that igras perform well in immunocompetent children of 4 years of age and older.15 implementation of igra testing in children can be done with less caution for those who are ≥5 years old. this is because they are less likely to develop active tb or severe forms of it compared to children who are under 5 years old and in them it is logistically easier (e.g. in the ability to draw sufficient quantities of blood).16 evaluation of this test has been hampered by the lack of a gold standard for ltbi, and limited paediatric data on their use. it appears that it is more specific than the tst and may be useful for evaluating tst-positive patients at low risk of true ltbi. moreover, it may provide valuable information on sensitivity if used in addition to the tst in immunocompromised patients, very young children, and those in close contact with infectious adults.17 additional larger studies are needed to evaluate the performance of igras in children.16 conclusion in countries with low tb incidence, such as oman, that are working towards tb elimination, there is an emphasis on contact investigation and management. the process of investigation and management for children who are contacts of contagious tb have been described and simple algorithms provided for easy application in the primary care setting. the importance of mantoux testing and its timing have been highlighted, along with a brief summary of interferon testing and latent tb infection treatment. we have provided a concise and practical approach aimed at enhancing contact investigation effectiveness and management of infants and children who are in contact with a contagious case of tb. references 1. morrison j, pai m, hopewell pc. tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis. lancet infect dis 2008; 8:359–68. 2. ministry of health. childhood tuberculosis. stop tb—manual of tb control programme, 4th ed. muscat: national tuberculosis control program, department of communicable disease surveillance & control, directorate general of health affairs, oman. pp. 24–32. arthralgia, nervous system changes, drug-induced lupus, diarrhoea and cramping with liquid product. routine laboratory monitoring is not recommended for children receiving inh monotherapy.9,14 for patients receiving multiple tb drugs or other hepatotoxic drugs and for those with underlying liver disease (including viral hepatitis), baseline liver function testing is recommended. follow-up liver function testing is determined by baseline concerns and symptoms of hepatotoxicity.2,9,12 laboratory testing should be obtained upon the first sign or symptom of a possible adverse event. in 10–20% of patients, aminotransferase levels will elevate 2–3 times during the first months of therapy; these levels will usually return to normal despite the continuance of the drug. in the absence of symptoms, inh should be discontinued if aminotransferase values are 5 times the upper limit of normal. in the presence of symptoms, inh should be discontinued if aminotransferase values are 3 times the upper limit of normal. inh therapy may be reinstituted when liver function tests return to baseline and symptoms of toxicity resolve. vitamin b6 should be used in situations where high-dose inh is employed, and in the case of children with diabetes, uraemia, hiv infection, malnutrition, or peripheral neuropathy. additionally, exclusively breastfed infants should receive vitamin b6 while taking inh. for persons who cannot tolerate inh or have been exposed to inh-resistant tb, an alternative treatment regimen constitutes 4 months of rifampicin (10–20 mg/kg/ day).9,14 igra detects the release of interferon-gamma (ifn-γ) in fresh heparinised whole blood from sensitised persons when it is incubated with mixtures of synthetic peptides representing two proteins present in mtb: early secretory antigenic target-6 (esat-6) and culture filtrate protein-10 (cfp-10). in direct comparisons, the sensitivity of igra was statistically similar to that of the tst for detecting infection in persons with untreated culture-confirmed tb, and the cdc recommends that igra may be used in all circumstances in which the tst is currently used, including contact investigations. the specificity of igra is higher than that of tsts because the antigen used is not found in bcg or most pathogenic non-tuberculous mycobacteria. experience with testing in children with igras is less extensive than adults, but a management of infants and children who are contacts of contagious tuberculous patients 485 | squ medical journal, november 2013, volume 13, issue 4 3. ministry of health. annual health report, 2010. muscat: directorate general of planning, ministry of health. pp. 8–42. 4. lobato mn, mohle-boetani jc, royce se. missed opportunities forpreventing tuberculosis among children younger than five years of age. pediatrics 2000; 106:e75. 5. national tuberculosis controllers association; centers for disease control and prevention (cdc). guidelines for the investigation of contacts of persons with infectious tuberculosis. recommendations from the national tuberculosis controllers association and cdc. mmwr recomm rep 2005; 54:1‒47. 6. cruz at, starke jr. pediatric tuberculosis. pediatr rev 2010; 31:13–26. 7. marais bj, gie rp, schaaf hs, hesseling ac, obihara cc, starke jj, et al. the natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. int j tuberc lung dis 2004; 8:392–402. 8. jasmer rm, nahid p, hopewell pc. clinical practice: latent tuberculosis infection. n engl j med 2002; 347:1860–6. 9. pickering lj, baker cj, kimberlin dw, long ss, eds. tuberculosis. in: red book. 28th ed. elk grove village, illinois: american academy of pediatrics. 2009. pp. 680–701. 10. piessens wf, nardell ea. pathogenesis of tuberculosis. in: reichman lb, hershfield es, eds. tuberculosis: a comprehensive international approach. 2nd ed. new york: marcel dekker, inc., 2000. pp.241–60. 11. world health organization. guidelines for the programmatic management of drug-resistant tuberculosis. emergency update 2008. geneva: world health organization, 2008. 12. world health organization. guidance for national tuberculosis programmeson the management of tuberculosis in children. geneva: world health organization who/htm/tb/2006. p. 371. 13. cruz at, medina d, whaley em, ware km, koy th, starke jr, et al. tuberculosis among families of children with suspected tuberculosis. infect control hosp epidemiol 2011; 32:188–90. 14. centers for disease control and prevention. severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection united states, 2004–2008. mmwr morb mortal wkly rep 2009; 59:224–9. 15. mazurek gh, jereb j, lobue p, iademarco mf, metchock b, vernon a; division of tuberculosis elimination, national center for hiv, std, and tb prevention, centers for disease control and prevention (cdc). guidelines for using the quantiferon®-tb gold test for detecting mycobacterium tuberculosis infection, united states. mmwr recomm rep 2005; 54:49–55. 16. mazurek gh, jereb j, vernon a, lobue p, goldberg s, castro k; igra expert committee; centers for disease control and prevention (cdc). updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection, united states, 2010. mmwr recomm rep 2010; 59:1–25. 17. kakkar f, allen ud, ling d, pai m, kitai ic. tuberculosis in children: new diagnostic blood tests. canadian paediatric society, infectious diseases and immunization committee. paediatr child health 2010; 15:8. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. e342-345, epub. 9th may 13 submitted 4th jun 12 revision req. 8th aug 12, revision recd. 30th aug 12 accepted 14th oct 12 1a. b. shetty memorial institute of dental sciences, nitte university, mangalore, karnataka, india; 2oxford dental college, hospital & research centre, bangalore, karnataka, india *corresponding author e-mail: audreydcruz@yahoo.co.in ورم سين مركب كبري عرض حلالة نادرة اأودري ديكروز، �شو�شميني هدج، اأرفا�شي �شيتي، اأي بي �شيتي امللخ�ص: الأورام ال�شنية تعترب من اأمرا�ض الورم العابي والتي تتكون من مركبات نا�شجة من امليناء والعاج واللب ال�شني وتنق�شم اإىل املن�شاأ، �شنية احلميدة الأورام اأكرث من تعترب الأورام هذه الطبيعي. ال�شن مع الت�شابه اأو ال�شكلي التمايز اإىل ن�شبة معقدة اأو مركبة اأورام وت�شكل%22 من جميع الأورام �شنية املن�شاأ يف الفك. عادة تعترب هذه الأورام ذات طبيعة غري عدوانية وبطيئة النمو ويتم ت�شخي�شها عادة عن طريق فحو�شات الأ�شعة العتيادية يف العقد الثاين من العمر. نعر�ض هنا تقريراً حلالة ا�شتثنائية لورم �شني مركب كبري غري موؤمل. كان موقع الورم يف اجلهة اخللفية الي�رسى من الفك ال�شفلي وكان متعلق بفقدان الرحى الأويل والثانية من الفك ال�شفلي. مت تاأكيد الت�شخي�ض بعد الإزالة اجلراحية للورم وفح�ض اأمرا�ض الأن�شجة. مفتاح الكلمات: ورم �شني؛ عتامة �شعاعية؛ ورم �شني املن�شاأ؛ الهند؛ تقرير حالة. abstract: odontomas are hamartomatous lesions composed of mature enamel, dentin, and pulp, and may be compound or complex depending on the extent of morphodifferentiation or on their resemblance to normal teeth. they are the most common benign odontogenic tumours, constituting 22% of all odontogenic tumours of the jaw. they are often non-aggressive and slow growing in nature, and are usually diagnosed on routine radiological examinations in the second decade of life. we report the case of an unusually large, painless, complex odontoma, which is a rare entity. it was located in the left posterior mandible and was associated with missing 1st and 2nd left mandibular molars. the diagnosis was confirmed following surgical excision and histopathological analysis of the lesion. keywords: odontoma; radiopacity; odontogenic tumor; cysts; case report; india. large complex odontoma a report of a rare entity *audrey m. d'cruz,1 sushmini hegde,2 urvashi a. shetty1 online case report the term odontoma has been used to describe any tumour of odontogenic origin. they are known as mixed odontogenic tumours because they are composed of both epithelial and ectomesenchymal components.1 the enamel and dentin are laid down in an abnormal pattern because the organisation of the odontogenic cells fails to reach a normal state of morphodifferentiation.2 broca was the first to coin the term odontoma in 1867.3 although the aetiology of the condition is unknown, several theories have been proposed, including local trauma or infection. it has also been proposed that odontomas are inherited from a mutant gene or possible postnatal interference with the genetic control of tooth development.4 odontomas are often non-aggressive and slow growing in nature. the world health organization (who) classifies odontomas into compound and complex odontomas. in a compound odontoma, all the dental tissue is in a more orderly pattern so that the lesion consists of many tooth-like structures. when this calcified dental tissue is simply an irregular mass, bearing no morphologic similarity even to rudimentary teeth, it is termed a composite complex odontoma.2,3 odontomas have also been classified as central or intraosseous, which present inside the bone; peripheral or extraosseous, which occur in the soft tissue covering the tooth-bearing portions of the jaws, and erupted odontomas according to clinical presentation.5,6 audrey m. d'cruz, sushmini hegde and urvashi a. shetty case report | 343 case report a male patient aged 18 years reported to a private dental clinic in bangalore, india, with a complaint of swelling in the lower left side of his face. a medical history revealed the presence of a painless swelling which had gradually increased in size over the previous two years. the patient had undergone an uneventful extraction of two teeth in that region 4 years before. on extra oral examination, there was a solitary, ill-defined swelling measuring 4.5 x 5.5 cm, extending 2.5 cm from the midline anteriorly to the angle of the mandible posteriorly and superioinferiorly one cm above and below the border of the mandible. there were no secondary changes on the skin. an intraoral examination revealed a well-defined lesion extending from the lower left second premolar region to the retromolar area. laterally, the lesion extended into the buccal vestibule causing vestibular obliteration. the mandibular left first and second permanent molars (36 and 37) were missing. the 1st and 2nd mandibular left premolars were displaced but the teeth were firm and non-mobile. the overlying mucosa appeared smooth and erythematous. on palpation, the swelling was non-tender and bony, hard in consistency, associated with buccal and lingual cortical plate expansion. considering the above clinical findings, a provisional diagnosis of a residual cyst in the mandibular left molar region was made, with a differential diagnosis of ameloblastoma and periapical cemental dysplasia. the patient was advised to undergo an orthopantomograph (opg) and cross-sectional occlusal x-ray of the mandible. the opg revealed a well-defined, radiodense, multilocular lesion in the lower left molar region extending from the mandibular left 2nd premolar to the angle of the mandible. the lesion was surrounded by a radiolucent border, which was ill-defined superiorly [figure 1]. on the occlusal radiograph, the expansion of buccal and lingual cortical plates could be clearly seen. on the basis of the radiological features, a differential diagnosis of calcifying epithelial odontogenic cyst, cementossifying fibroma, and complex odontoma was made. surgical excision via an intraoral approach was done under general anaesthesia at a private hospital and the specimen was sent for histopathological examination. grossly, the specimen showed a lobulated, yellowish-white, large, hard tissue mass, measuring 4.5 x 3 x 3 cm. an additional brownish-yellow soft tissue mass measuring 2.5 x 3 x 2.5 cm was attached to this hard tissue mass [figure 2]. the ground section of the tissue showed the presence of enamel and cemental globules with irregularly arranged dentinal tubules around a pulp-like tissue [figure 3]. on histological examination, decalcified sections showed the presence of eosinophilic masses of haphazardly arranged dentine and pulplike tissues [figure 4]. an area of fibrous connective tissue capsule was also noted. irregular empty spaces representing the enamel space lost due to decalcification were also seen. a histopathological examination of the soft tissue mass that was attached to the hard tissue showed the presence of connective tissue, comprised mainly of acute and chronic inflammatory cells, and numerous dilated figure 1: orthopantomograph showing a well-defined radiodense, multilocular lesion in the lower left molar region extending from mandibular left second premolar to the angle of the mandible. figure 2: gross specimen showing a hard mass (left) along with the soft tissue (right) attached to it. large complex odontoma a report of a rare entity 344 | squ medical journal, may 2013, volume 13, issue 2 vascular spaces with red blood cells interspersed between mature collagen fibres. some odontogenic islands with cohesive cells and hyperchromatic cells were also seen. the histopathological diagnosis was of a complex odontoma. discussion odontomas are hamartomatous lesions or malformations rather than true neoplasms. they are the most common benign odontogenic tumours, constituting 22% of all odontogenic tumours of the jaw.7,8 the occurrence of complex odontomas is rare, with a prevalence of 5–30%.9 most of the complex odontomas reported in the literature usually measure 1–2 cm in diameter. however, a large complex odontoma such as the one in the present case, measuring 4.5 x 5.5 cm, is very rare. compound odontomas show a predilection for the anterior maxilla, while complex odontomas are typically found in the posterior mandibular region as seen in the present case. complex odontomas are frequently found in the right side of the jaw.10 however, in this case, in contrast to the usual reported findings, the complex odontoma was seen on the left side of the jaw. complex odontoma are less common compared to the compound variety in a ratio of 1:2. there is no gender predilection and odontomas can occur at any age, but most are found in the second decade of life, as in the present case.9 the aetiology of complex odontomas is unknown. several theories have been proposed, including local trauma, infection, family history, and genetic mutation. it has also been suggested that odontomas are inherited from a mutant gene or interference, possibly postnatally, with the genetic control of tooth development.11 odontomas are commonly asymptomatic and are usually detected on routine radiography. a clinical indication of odontomas may include retention of deciduous teeth, non-eruption of permanent teeth, pain, expansion of the cortical bone, and tooth displacement. other symptoms that may be present include numbness in the lower lip, frontal headaches, and swelling in the affected areas.4 pain is a rare symptom and is usually caused by a secondary infection due to the invasion of oral microorganisms between the bone and odontoma. the infection is likely to occur due to the absence of the periodontal ligament and lack of adequate adhesion between them. in the present case, the patient presented with swelling and expansion of the bucco-lingual cortical plate. the radiological appearance of complex odontomas depends on their stage of development and degree of mineralisation. the first stage is characterised by radiolucency due to the lack of dental tissue calcification, followed by an intermediate stage characterised by partial calcification of odontogenic tissue. this stage is characterised by radiolucent-radiopaque images. in the third stage, the lesion usually appears radiopaque with amorphous masses of dental hard tissue surrounded by a thin radiolucent zone figure 3: ground section showing presence of enamel and cemental globules with irregularly arranged dentinal tubules around a pulp-like tissue (x 40 magnification). figure 4: decalcified hematoxylin & eosin stained section showing irregularly-arranged dental tissues, principally dentine (solid arrows) and pulp (dash arrows) (x 40 magnification). audrey m. d'cruz, sushmini hegde and urvashi a. shetty case report | 345 corresponding histologically to the connective capsule.12 since the present case had a mixed radiodense radiolucent lesion, we considered the present lesion to be not completely mature—that is, at the intermediate stage. histopathologically, complex odontomas are often spherical in shape and consist primarily of a disordered mixture of odontogenic tissues. cementum or cementum-like substances are often admixed with dentinoid structures. small spaces with pulp tissue, enamel matrix, and epithelial remnants may be observed within the calcified mineralised masses of dentin of different qualities. a thin fibrous capsule or, occasionally, a cyst wall is seen surrounding the lesion.1 similar histological findings were noted in the present case. the present case should be differentiated from periapical cemental dysplasia. periapical cemental dysplasia occurs at the periapical region of the mandibular anteriors, whereas odontomas are commonly found in the posterior mandible occlusal to the tooth, although some may be located periapically. also, the presence of a radiolucent border is not a constant feature in periapical cemental dysplasia and, when present, it is surrounded by sclerotic margins, whereas a radiolucent rim is a constant finding with odontomas. periapical cemental dysplasia is uniformly radiopaque whereas an odontoma has mixed radiopaque-radiolucent features. mixed radiolucencies can also occur in adenomatoid odontogenic tumours, calcifying epithelial odontogenic tumours, or odontoameloblastomas. the presence of disorderly-arranged, well-formed, odontogenic tissues on histopathological examination will confirm the diagnosis of complex odontoma. the treatment of complex odontomas varies depending on the clinical situation. the treatment options comprise surgical extraction, fenestration, and posterior orthodontic traction, or simple observation with periodic clinical and radiological controls.13 most often, the treatment of choice is surgical excision of the odontoma followed by histological analysis. conclusion the authors present a case report of a complex odontoma that was painless, unusually large, and associated with missing 1st and 2nd left mandibular molars. although rare in occurrence, it is important to diagnose complex odontomas that form in association with missing teeth. the use of panoramic radiography will aid in the early detection of such dental lesions, followed by surgical excision and histopathological analysis, will prevent complications. the prognosis of these tumours is very favourable, with a minimal tendency towards relapse. references 1. regezi ja, sciubba jj, jordan rc. odontogenic tumors. in: rudolf p, ed. oral pathology, clinical pathologic correlations. 4th ed. st. louis: w. b. saunders, 2003. pp. 286–8. 2. shafer wg, hine mk, levy bm. odontogenic tumors. in: rajendra r, ed. a textbook of oral pathology, 6th ed. philadelphia: elsevier noida, 2009. pp. 287–90. 3. cohen dm, bhattacharyya i. ameloblastic fibroma, ameloblastic fibro-odontoma, and odontoma. oral maxillofac surg clin north am 2004; 16:375–84. 4. preetha a, balikai bs, sujatha d, pai a, ganapathy ks. complex odontoma. gen dent 2010; 58:e100–2. 5. junquera l, de vicente jc, roig p, olay s, rodriguezrecio o. intraosseus odontoma erupted into the oral cavity: an unusual pathology. med oral patol oral cir bucal 2005; 10:248–51. 6. singh v, dhasmana s, mohammad s, singh n. the odontomes: report of five cases. natl j maxillofac surg 2010; 1:157–60. 7. lakshmi kavitha n, venkateswarlu m, geetha p. radiological evaluation of a large complex odontoma by computed tomography. j clin diagnostic res 2011; 5:1307–30. 8. amado cs, gargallo aj, berini al, gay ec. review of 61 cases of odontoma: presentation of an erupted complex odontoma. med oral 2003; 8:366–73. 9. nisha d, rishabh k, ashwarya t, sukriti m, gupta sd. an unusual case of erupted composite complex odontoma. j dent sci res 2011; 2:59–61. 10. magnur vs, prabhadevi c, sharma r. odontoma. a brief overview. int j clin ped dent 2011; 4:177–85. 11. kodali rm, suresh bv, raju pr, vor sk. an unusual complex odontoma. j maxillofac oral surg 2010; 9:314–7. 12. reichart ap, philipsen hp. odontogenic tumors and allied lesions. london: quintessence, 2004. 13. serra-serra g, berini-aytés l, gay-escoda c. erupted odontomas: a report of three cases and review of the literature. med oral patol oral cir bucal 2009; 14:e299–303. sir, in the last four decades there has been tremendous growth in the number of hospitals and doctors in oman.1 it is also heartening to see the increasing number of female students in omani medical colleges leading to a concomitant increase in women in the medical labour force.2 it would seem that omani women think that the health sector is a suitable place for women to play an important role in society. this growth and feminisation of the medical profession has taken place since the accession in 1970 of his majesty sultan qaboos bin said. his vision and leadership have overseen major growth and transformation in omani health care; he draws on islamic teachings to underscore the expanded role that women should play in omani society and to emphasise his support for women’s rights. omani women are thus encouraged by their monarch’s commitment to national welfare, and are eager to participate in all aspects of their nation’s growth. the oman medical college, a private medical university run in partnership with west virginia university, usa, opened in 2001 with only 69 students, 68 of them girls.3 by 2010, out of a total of 866 students spread over in its bausher and sohar campuses, 744 (86%) of them were girls. also the available omani ministry of health (moh) statistical data shows that, in 2009, 57% of moh doctors were women.2 this feminisation of the omani medical profession could be attributed to many factors such as encouragement from his majesty, and favourable conditions in the country: a low crime rate, availability of transport, safe accommodation, schools and institutions of higher education. it is also possible that certain qualities inherent in women, which make them better doctors, could be another factor in the growing feminisation of this profession. there is a new and growing appreciation of those traits that women use to keep families together and to organise volunteers to unite and make changes in the shared life of communities. these newly admired leadership qualities of shared leadership, nurturance and doing good to others are today not only sought after, but also needed to make a difference in the world. a feminine way of leading includes helping the world to understand and be principled about values that really matter.4 these factors have helped women to achieve career success despite the multiple roles they are required to play. this is maybe precisely why women have had career success; they are used to multi-tasking and prioritising. evidence suggests that women doctors typically adopt a democratic style of communication that fosters collaborative relationships. they discuss treatment options, elicit patient’s preferences and engage patients in making decisions.5 female doctors’ communication style tends to be sensitive and they offer more emotional support and encouragement and reassurance to their patients than their male counterparts.6 the strengths that women demonstrate in patient-centered care may lead to important improvements in the effectiveness and outcomes of care. studies have demonstrated that patient-centered communication between physicians and patients can enhance outcomes of care, including patient adherence to treatment recommendations, biological outcomes in chronic disease, and patient satisfaction.7 the accreditation sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 380-381, epub. 15th jul 12 submitted 1st dec 11 revision req. 2nd apr 12, revision recd. 25th apr 12 accepted 8th may 12 إزدياد عدد األطباء اإلناث يف ُعمان ماهي األسباب؟ growth in the number of female medical doctors in oman what are the reasons? letter to editor srilekha goveas letter to editor | 381 council for graduate medical education (acgme) in the usa now requires that physicians demonstrate effective communication skills and female doctors are likely to meet or exceed these standards.8 the acgme also requires physicians to have the ability to work effectively with others in a health care team or medical professional group. several recent studies of leadership style indicate that women empower other team members to develop their potential, act as role models by gaining the trust and confidence of colleagues and take an interest in the personal needs of their staff.5 the institute of medicine in the usa articulated the importance of striving to provide patient-centered care that “encompasses qualities of compassion, empathy, and responsiveness to the needs, values, and expressed preferences of the individual patient”. two dimensions are inherent in this definition: physicians should engage each patient in a process of making health care decisions, and they should demonstrate emotional sensitivity toward each patient’s circumstances. evidence suggests that women are well-equipped to satisfy both of these elements of patient-centered care in their one-on-one relationships with patients.9 several studies by swiss and american researchers have shown that female doctors tend to be more encouraging and reassuring, use shared decision making, ask more psychosocial questions and spend more time (up to 10% more) with patients than male doctors. it was seen that the female patients were most satisfied with their women doctors since they expressed concern and empathy and were extremely reassuring.5 more and more medical schools are offering courses that teach young doctors how to offer better counselling and prevention advice, implement shared decision-making and pay increased attention to how an illness and its treatment are affecting a patient. these skills have been found to be present more often in female physicians.10 since certain inherently female qualities, such as empathy, sensitivity, encouragement, caring, nurturing, and reassurance, seem to make women better doctors, more and more women are entering and being successful in the medical profession. feminisation of the profession will positively affect patient care and health care systems, as well as the profession itself. srilekha goveas department of management, waljat college of applied sciences, muscat, oman e-mail: srilekha_goveas@yahoo.com references 1. oman news agency. sultanate’s achievements in 40 years. from: http://www.omannews.gov.om/ona/english/ national4.jsp accessed apr 2012. 2. kamoonpuri h. women excel in medicine. oman daily observer, may 1, 2010. 3. oman medical college. history of college. from: http://www.omc.edu.om/omchistory.html accessed: may 2012 4. women are superior. learning management system news, august 31 2011. from: http://www.trainingforce.com/ blog/ accessed: apr 2012. 5. levinson w, lurie n. when most doctors are women: what lies ahead? ann intern med 2004; 141:471–4. 6. hall ja, roster dl. medical communication and gender: a summary of research. j gend specif med 1998; 1:39–42. 7. greenfield s, kaplan s, ware je jr. expanding patient involvement in care. effects on patient outcomes. ann intern med. 1985 8. kaplan sh, greenfield s, ware je jr. assessing the effects of physician patient interactions on the outcomes of chronic disease. med care 1989;27: s110–27 9. institute of medicine, committee on the quality of health care in america. crossing the quality chasm: a new health system for the 21st century. washington, dc: the national academy press, 2001. pp. 39–60. 10. chen pw. do women make better doctors? new york times, may 6, 2010. from: http://www.nytimes. com/2010/05/06/health/06chen.html accessed: apr 2012. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e257–265, epub. 28 may 15 submitted 2 jun 14 revisions req. 16 jul & 1 sep 14; revisions recd. 18 aug & 10 sep 14 accepted 30 oct 14 1department of female sport activities, deanship of student affairs and 2department of physical education, college of education, sultan qaboos university, muscat, oman; 3health and recreation department, faculty of physical education, university of jordan *corresponding author e-mail: hashemkilani@gmail.com أمناط حياة املرأة العمانية دراسة مستعرضة للنشاط البدين والسلوك اخلامل عزة احلب�سية و ها�سم الكيالين abstract: objectives: this study aimed to investigate the lifestyles of adult omani women with regards to physical activity (pa) levels and sedentary behaviour (sb). methods: the study was carried out between may and june 2013 and included a total of 277 healthy women aged 18–48 years from five governorates in oman. total, moderate and vigorous pa levels and walking were self-reported by participants using the short form of the international physical activity questionnaire. sb (total sitting time and different types of sitting time) was self-reported using the domainspecific sitting time questionnaire on both working and non-working days. pa levels and sb were also objectively measured among 86 of the participants using an accelerometer. results: the self-reported median ± interquartile range (iqr) total pa was 1,516 ± 3,392 metabolic equivalent of task minutes/week. the self-reported median ± iqr total sitting time was 433 ± 323 minutes/day and 470 ± 423 minutes/day for working and non-working days, respectively. sitting at work on working days and sitting during leisure activities on non-working days formed the greatest proportion of total sitting time. overall, accelerometer results indicated that participants spent 62% of their time involved in sb, 35% in light pa and only 3% in moderate to vigorous pa. conclusion: sedentary lifestyles were common among the adult omani women studied. lack of pa and increased sb is known to increase the risk of metabolic syndrome and obesity. the use of accelerometers to monitor pa and sb among different groups in oman is highly recommended in order to accurately assess the lifestyle risks of this population. keywords: lifestyle; adult; women; physical activity; sedentary lifestyle; oman. .)sb( وال�سلوك اخلامل )pa( امللخ�ص: الهدف: هدفت الدرا�سة اإىل البحث يف اأ�ساليب حياة املراأة العمانية املتعلقة مب�ستويات الن�ساط البدين الطريقة: اأجريت الدرا�سة يف الفرتة ما بني �سهري مايو ويونيو 2013 و�سملت ما جمموعه )277( امراأة �سليمة ترتاوح اأعمارهن بني 48–18 عامًا من خم�ض حمافظات ب�سلطنة عمان. مت التحقق من م�ستويات الن�ساط البدين االإجمالية، املعتدلة واملرتفعة ال�سدة اإ�سافة اإىل امل�سي اخلامل )اجمايل ال�سلوك م�ستوى قيا�ض مت البدين. الن�ساط م�ستوى لقيا�ض ذاتيا املعبئة الدولية الق�سرية اال�ستبانة بوا�سطة للم�ساركات اأوقات اجللو�ض واأوقات اجللو�ض لالأمناط املختلفة للجلو�ض( بوا�سطة ا�ستبيان االأوقات اخلا�سة باجللو�ض املعبىء ذاتيًا لكل من اأيام العمل واأيام غري العمل. كذلك مت قيا�ض م�ستوى الن�ساط البدين وال�سلوك اخلامل مبو�سوعية بوا�سطة ا�ستخدام اأجهزة الت�سارع لعدد )86( م�ساركة دقيقة/ met )1,516 ± 3,392( ذاتيًا عنه املخرب البدين للن�ساط الربعية النطاقات ± متو�سط اإجمايل كان النتائج: الدرا�سة. عينة من االأ�سبوع. وكان اجمايل متو�سط ± النطاقات الربعية الأوقات اجللو�ض املخرب عنه ذاتيًا )323 ± 433( دقيقة/اليوم و )423 ± 470( دقيقة/ اليوم الأيام العمل واأيام غري العمل بالتتابع. �سكل اجللو�ض يف العمل خالل اأيام العمل واجللو�ض خالل اأوقات الفراغ يف غري اأيام العمل الن�سبة االأكرب من اإجمايل اأوقات اجللو�ض. اإجمااًل بينت نتائج اأجهزة الت�سارع اأن امل�ساركات يق�سني %62 من وقتهن يف منط احلياة اخلامل و %35 يف اأن�سطة بدنية خفيفة و %3 فقط يف اأن�سطة بدنية معتدلة اإىل مرتفعة ال�سدة. اخلال�صة: منط احلياة اخلامل هو ال�سائدا لدى الن�ساء العمانيات امل�ساركات بالدرا�سة ومن املعروف باأن قلة الن�ساط البدين و زيادة الن�ساط اخلامل يزيدان من خماطر متالزمة االي�ض والبدانة. نو�سي ب�رشورة ا�ستخدام اأجهزة الت�سارع ملتابعة الن�ساط البدين و ال�سلوك اخلامل لدى املجموعات املختلفة للن�ساء ب�سلطنة عمان للح�سول على تقييم دقيق عن خماطر االأمناط احلياتية لل�سكان. مفتاح الكلمات: اأمناط احلياة؛ الكبار؛ املراأة؛ الن�ساط البدين؛ منط احلياة اخلامل؛ عمان. lifestyles of adult omani women cross-sectional study on physical activity and sedentary behaviour azza al-habsi1 and *hashem kilani2,3 advances in knowledge there is a lack of information in the literature regarding the physical activity (pa) and sedentary behaviour (sb) of adult omani women. this is the first time pa and sb have been objectively measured using accelerometers in a group of adult omani women. application to patient care as demonstrated in this study, accelerometers can be used as a tool to remotely and accurately monitor the pa and sb of different population groups in oman. the results of this study indicate that an awareness promotion programme, with regards to lifestyle behavioural changes, aimed at the adult female population is urgently needed in oman. clinical & basic research lifestyles of adult omani women cross-sectional study on physical activity and sedentary behaviour e258 | squ medical journal, may 2015, volume 15, issue 2 unlike inactivity, sedentary behaviour (sb) can be defined as actions which have low energy expenditure, typically between 1–1.5 metabolic equivalent of task (mets), such as sitting.1 like many countries in the gulf region, oman has experienced recent socioeconomic growth. the technological innovations and advances in automation related to this socioeconomic change may affect aspects of an individual’s daily life. as such, lifestyles of the omani population are evolving to reflect a more sedentary way of living. a recent study in oman revealed an increase in lifestyle-related metabolic syndrome and the prevalence of associated risk factors, such as type 2 diabetes (the frequency of which was ranked among the 10 highest prevalences reported worldwide), cardiovascular disease (cvd) and being overweight or obese.2 mabry et al. also demonstrated an association between low physical activity (pa), frequent sitting time and metabolic syndrome, suggesting that low pa levels increase the risk of developing metabolic syndrome.3 the populationwide surveillance of pa levels and sb is both a national and international priority, as measurement of these indicators enable a better understanding of their associated health risks. in oman, women may be at greater risk of associated health concerns due to their low pa levels and high sb. a report by the omani ministry of health in 2011 revealed that, out of 5,006 new cases of type 2 diabetes, 51.5% were female.4 furthermore, nearly 53.6% of omani women were reported to be overweight or obese.5 despite this, studies measuring pa levels and sb among omani women are rare. a study of omani college students showed that male students spent significantly more time exercising weekly (6.84 ± 1.04 hours) than female students (3.36 ± 0.70 hours).6 another recent study found that 32.5% of female omani university students had low pa levels.7 data from the world health survey in oman demonstrated that only 59% of women were undertaking sufficient exercise compared to 67% of men.5 the majority of the above mentioned studies were found to have assessed pa levels using subjective measures. to the best of the authors’ knowledge, no studies which objectively measure pa levels and sb in adult omani women have yet been published. therefore, the aim of this study was to assess pa levels and sb among a cohort of adult omani women using both subjective and objective tools. additionally, this study aimed to describe the differences in pa levels and sitting time between various demographic groups. methods a cross-sectional study was undertaken between may and june 2013 in five out of 11 governorates in oman (including the governorates of muscat, north al-batinah, south al-batinah, north ash sharqiyah and south ash sharqiyah). a total of 277 healthy adult omani women aged 18–48 years with no physical illnesses or disabilities that could affect their normal daily activities were included in the study. all participants were recruited through word-of-mouth advertising in several different workplaces, higher education institutions, committees and sports organisations. participants were initially visited either in the workplace or in other institutions. at this time, the following were measured: weight (seca 875 electronic flat scale, seca gmbh, hamburg, germany), height (seca 217 mobile stadiometer, seca gmbh) and waist and hip circumferences (seca 203 ergonomic circumference measuring tape, seca gmbh). body mass index (bmi) was calculated and participants were categorised according to the world health organization (who) as underweight (<18.5 kg/ m2), normal weight (18.5–24.9 kg/m2), overweight (>25.0–29.9 kg/m2) or obese (≥30.0 kg/m2).8 waistto-hip ratio (whr) was calculated by dividing waist circumference by hip circumference and participants were subsequently classified as having a low (<0.80), moderate (0.80–0.85) or high (>0.85) risk of developing a non-communicable disease.9 demographic characteristics were elicited using an arabic-language questionnaire that was specifically designed for this study. participants were classified according to age as young adults or adults (18–29 or 30–48 years old, respectively), marital status; level of education; employment status, and income level. participants completed two questionnaires assessing their pa and sb. both questionnaires were back-translated into arabic for use in this study. participants reported their estimated total pa levels using the self-administered short form of the international physical activity questionnaire (ipaq).10 it has been shown that the ipaq is a valid and reliable measure of pa.11 results from this questionnaire were scored using the ipaq scoring protocol.10 light pa, moderate to vigorous pa (mvpa), walking and total pa levels were calculated in mets minutes/week. sb was self-assessed by participants using the domainspecific sitting time questionnaire (d-sstq), which has been validated for use by adults.1,12 minutes spent sitting were calculated for both working and nonworking days by domain (sitting during transportation, azza al-habsi and hashem kilani clinical and basic research | e259 at work, while watching television, while using the computer or during another type of leisure activity). total daily sitting times were then calculated by adding up the minutes spent sitting across each domain. of the 277 participants, 86 women volunteered to take part in the further objective measurement of their pa levels. after baseline measurements were obtained, participants were provided with and asked to wear a gt3x accelerometer (actigraph, pensacola, florida, usa) which is a small device of 4.6 x 3.3 x 1.5 cm, weighing 19 g.13 this device has been shown to be a valid and reliable measure of pa levels and sb.14 participants wore the accelerometer for seven consecutive days while continuing with their normal daily activities and were instructed to wear the device at all times during waking hours, only removing the device to sleep or during water-based activities. the accelerometer epoch interval was set at one minute.12,14 data from the accelerometer were downloaded and summarised using actilife software, version 6.5.3 (actigraph). data were considered to be valid if the device had recorded a minimum of 600 minutes per day (excluding continuous strings of zero counts for 60 minutes or longer) for four days, including at least one non-working day on a weekend. a cut-off value of <100 counts per minute (cpm) was considered to indicate sb, while values of 100–1,951 cpm and ≥1,952 cpm indicated time spent engaged in light pa and mvpa, respectively.15,16 the frequency of time spent in either sb, light pa or mvpa per week was obtained by dividing the time spent in each activity by the mean wearing time per week. accelerometer data were obtained for weekdays and weekend days separately. statistical analysis was conducted using the statistical package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa). a p value of ≤0.05 was considered significant. data from the ipaq and d-sstq were checked for normality using the one-sample kolmogorov-smirnov test. non-parametric analyses were also carried out. medians and interquartile ranges (iqrs) were used to describe the data descriptively throughout. to examine differences in self-reported pa levels and sb among the different demographic groups, the mannwhitney u and the kruskal-wallis tests were used for non-parametric data and the independent t-test and the one-way analysis of variance were used for parametric data. the procedures of the study were approved by all participating institutions (including universities, schools and committees). all participants gave written informed consent. ethical approval for the study was obtained from the office of the advisor for academic affairs at sultan qaboos university, muscat, oman. results table 1 shows the descriptive demographics of the participants by the instrument used to measure pa levels and sb (ipaq, d-sstq and accelerometer). table 2 shows the participants’ self-reported pa levels by demographic group. of the 277 participants enrolled in the study, only 229 provided complete responses to the ipaq. according to their responses, 34% of the participants were categorised as minimally active, 32% were classified as moderately active and 34% were classified as highly active. women reported that they spent a median of 75 ± 249 minutes/ week engaged in moderate pa, 0 ± 80 minutes/ week on vigorous pa and 120 ± 330 minutes/week walking. in addition, the self-reported median ± iqr total sitting time was 433 ± 323 minutes/day and 470 ± 423 minutes/day for working and non-working days, respectively. there was a significant difference in time spent in self-reported moderate pa between age groups (z = −1.96; p ≤0.05), with adults reporting more moderate pa than young adults. however, neither age group differed significantly in terms of vigorous pa or walking. based on education level, the high school education or lower group reported significantly higher levels of vigorous pa compared to those with a degree or postgraduate qualification (χ2 = 20.51; p ≤0.001). nevertheless, these groups did not differ in terms of moderate pa or walking. married women reported more moderate pa than those who were single (z = −2.2; p ≤0.03), but no differences were reported in vigorous pa or walking. unemployed participants reported significantly more vigorous pa (z = −3.81; p ≤0.001) compared with those women who were table 1: descriptive characteristics of a sample of adult omani women by instrument characteristic instrument mean ± sd ipaq* (n = 229) d-sstq** (n = 191) accelerometer (n = 80) age in years 29.6 ± 7.3 31.0 ± 7.1 29.0 ± 8.0 weight in kg 64.0 ± 16.0 65.1 ± 15.0 61.0 ± 15.0 height in cm 161.0 ± 66.0 156.2 ± 4.9 156.0 ± 5.0 bmi in kg/m2 25.9 ± 6.3 26.7 ± 5.9 25.1 ± 6.1 sd = standard deviation; ipaq = international physical activity questionnaire; d-sstq = domain-specific sitting time questionnaire; bmi = body mass index. *data collected using the international physical activity questionnaire.10,11 **data collected using the domain-specific sitting time questionnaire.1,12 lifestyles of adult omani women cross-sectional study on physical activity and sedentary behaviour e260 | squ medical journal, may 2015, volume 15, issue 2 employed. women in rural areas spent significantly more time in moderate pa in comparison to those living in urban areas (z = −2.52; p ≤0.05). however, no significant differences were noted among any form of pa when participants were grouped according to income. moreover, there were no differences in pa between bmi and whr groups (p >0.05). pa ranged from 945 ± 2,997 mets minutes/week in the underweight group to 1,800 ± 4,961 mets minutes/ week in the obese group. table 3 presents the self-reported sitting times among different domains for the sample by demographic table 2: self-reported physical activity levels* among a sample of adult omani women by demographic group (n = 229) demographic group n (%) median physical activity by types ± iqr in mets minutes/week vigorous moderate walking total total 0 ± 640 300 ± 1,176 396 ± 1,089 1,516 ± 3,392 age in years 18–29 113 (49.3) 0 ± 560 160 ± 960† 462 ± 295 1,584 ± 3,478 30–48 116 (50.7) 0 ± 720 480± 1,440† 396 ± 974 1,478 ± 3,512 level of education high school or lower 50 (22.3) 720 ± 1,680** 600 ± 1,080 396 ± 891 2,316 ± 2,460 degree 164 (73.2) 0 ± 260** 240 ± 1,182 462 ± 245 1,431 ± 3,671 postgraduate qualification 10 (4.5) 0 ± 330** 240 ± 795 272 ± 2,186 1,473 ± 2,363 marital status single 111 (48.9) 0 ± 960 180 ± 960† 495 ± 1,254 1,638 ± 4,263 married 116 (51) 0 ± 480 480 ± 1,438† 371 ± 924 1,431 ± 3,209 employment status employed 133 (58.6) 0 ± 280** 360 ± 1,440 396 ± 1,320 1,314 ± 2,873 unemployed 94 (41.4) 0 ± 1,920** 300 ± 690 396 ± 929 2,168 ± 5,072 location urban 132 (58.7) 0 ± 720 240 ± 840** 371 ± 1,287 1,440 ± 2,866 rural 93 (41.3) 0 ± 480 480 ± 1,680** 396 ± 817 1,638 ± 4,167 monthly income low 56 (25.9) 0 ± 1,620 380 ± 1,050 445 ± 795 2,249 ± 4,320 moderate 70 (32.4) 0 ± 480 540 ±1,434 396 ± 1,320 1,584 ± 3,088 high 90 (41.7) 0 ± 480 2,020 ± 765 462 ± 1,254 1,350 ± 3,823 bmi underweight 18 (7.9) 0 ± 60 40 ± 1,080 289 ± 1,411 945 ± 2,997 normal 90 (39.3) 0 ± 630 240 ± 1,182 478.5 ± 1,320 1,440 ± 3,417 overweight 68 (29.7) 0 ± 960 240 ± 960 445.5 ± 1,139 1,611 ± 2,616 obese 53 (23.1) 0 ±1,440 480 ± 1,440 297 ± 685 1,800 ± 4,961 whr low risk 142 (62) 0 ± 480 330 ± 1,440 495 ± 1,188 1,550 ± 3,353 moderate risk 44 (14.7) 0 ± 960 220 ± 840 396 ± 1,341 1,584 ± 3,820 high risk 43 (18.8) 0 ± 1,440 360 ± 1,200 198 ± 792 792 ± 3,804 iqr = interquartile range; met = metabolic equivalent of task; bmi = body mass index; whr = waist-to-hip ratio. *data collected using the international physical activity questionnaire.10,11 †p <0.05. **p <0.001. azza al-habsi and hashem kilani clinical and basic research | e261 group for both a weekday (working) and weekend (nonworking) day. out of the total 277 participants, only 191 completed the d-sstq. the mean self-reported sitting time by domain is shown in figure 1 for both a working and non-working day. there were significant differences in sitting time spent watching television (z = −3.6; p <0.001) during a working day between age groups, with adults reporting more time spent sitting watching television than young adults. in contrast, young adults reported significantly more time using table 3: self-reported sitting time* among a sample of adult omani women by demographic group and domain per weekday/weekend day (n = 191) demographic group n (%) median sitting time by domain ± iqr in minutes/day weekday weekend day transport work tv comp other la trans port work tv comp other la total 30 ± 50 120 ± 210 30 ± 60 60 ± 150 60 ± 92.5 60 ± 120 0 ± 120 60 ± 120 60 ± 180 120 ± 123.5 age in years 18–29 73 (39.7) 30 ± 80 120 ± 210 150 ± 60** 120 ± 120** 60 ± 105 60 ± 135 0 ± 70 60 ± 120 120 ± 180 120 ± 180 30–48 111 (60.3) 30 ± 60 120 ± 210 60 ± 75** 60 ± 90** 60 ± 105 60 ± 120 0 ± 120 60 ± 120 60 ± 180 120 ± 120 level of education high school or lower 43 (24.0) 50 ± 111 105 ± 180** 60 ± 120 90 ± 175 60 ± 120 0 ± 58** 0 ± 64** 37 ± 120** 10.5 ± 23** 120 ± 180 degree 128 (71.5) 30 ± 50 120 ± 199** 30 ± 60 60 ± 131 60 ± 90 120 ± 120** 20 ± 120** 60 ± 118** 120 ± 150** 120 ± 120 postgraduate qualification 8 (4.5) 25 ± 29 270 ± 150** 30 ± 98 87 ± 128 30 ± 48 90 ± 134** 0 ± 28** 60 ± 68** 30 ± 148** 90 ± 128 marital status single 73 (39.9) 30 ± 80 180 ± 248** 2 ± 60** 120 ± 120** 60 ± 90 60 ± 120 0 ± 60 60 ± 120 60 ± 193 120 ± 128 married 110 (60.1) 20 ± 50 120 ± 150** 60 ± 83** 60 ± 90** 60 ± 100 60 ± 108 0 ± 120 60 ± 120 60 ± 179 120 ± 143 employment status employed 119 (66.1) 30 ± 50** 120 ± 195** 30 ± 50 60 ± 90 60 ± 100 90 ± 105 10 ± 120 60 ± 110 60 ± 178 120 ± 120 unemployed 61 (33.9) 35 ± 95** 120 ± 240** 30 ± 60 120 ± 150 60 ± 120 40 ± 120 0 ± 29 60 ± 120 60 ± 193 120 ± 178 location urban 106 (58.9) 30 ± 49 120 ± 210 30 ± 52 60 ± 120 60 ± 100 60 ± 105 0 ± 60 60 ± 120 60 ± 180 120 ± 128 rural 74 (41.1) 30 ± 74 120 ± 195 30 ± 60 120 ± 150 60 ± 90 67.5 ± 150 0 ± 120 60 ± 120 60 ± 180 120 ± 136 monthly income low 43 (25.3) 40 ± 110 120 ± 240 30 ± 60 120 ± 150 60 ± 90 30 ± 75** 0 ± 60 60 ± 120 60 ± 180 120 ± 180 moderate 51 (30.0) 20 ± 40 120 ± 200 25 ± 120 60 ± 110 60 ± 100 120 ± 85** 0 ± 120 60 ± 105 120 ± 165 120 ± 150 high 76 (44.7) 30 ± 60 120 ± 199 60 ± 49 60 ± 120 60 ± 90 115 ± 153** 5 ± 120 60 ± 118 60 ± 168 120 ± 120 bmi underweight 9 (4.9) 20 ± 88 120 ± 257 20 ± 60 180 ± 150 60 ± 155 60 ± 125 40 ± 120 45 ± 120 60 ± 195 180 ± 190 normal 67 (36.4) 20 ± 52 120 ± 205 20 ± 60 120 ± 135 60 ± 90 75 ± 100 0 ± 120 60 ± 105 120 ± 178 90 ± 150 overweight 59 (32.0) 40 ± 55 120 ± 195 60 ± 110 60 ± 150 60 ± 90 60 ± 105 0 ± 120 60 ± 120 60 ± 165 120 ± 120 obese 49 (26.6) 30 ± 80 120 ± 228 30 ± 120 60 ± 120 60 ± 120 30 ± 130 0 ± 23 60 ± 120 30 ± 120 120 ± 180 whr low risk 104 (56.5) 30 ± 60 120 ± 210 30 ± 60 120 ± 131† 60 ± 90 75 ± 98 0 ± 120 60 ± 120 105.3 ± 169 120 ± 120 moderate risk 44 (23.9) 25 ± 50 120 ± 210 30 ± 56 60 ± 90† 60 ± 180 60 ± 124 0 ± 60 60 ± 114 60 ± 120 120 ± 135 high risk 36 (19.6) 30 ± 90 120 ± 150 60 ± 110 60 ± 123† 60 ± 105 60 ± 120 0 ± 120 60 ± 120 35 ± 180 68 ± 180 iqr = interquartile range; tv = television; comp = computer; la = leisure activity; bmi = body mass index; whr = waist-to-hip ratio. *data collected using the domain-specific sitting time questionnaire.1,12 †p <0.05. **p <0.001. lifestyles of adult omani women cross-sectional study on physical activity and sedentary behaviour e262 | squ medical journal, may 2015, volume 15, issue 2 the computer (z = −2.5; p ≤0.01). individuals with a high school education or lower, college degree or postgraduate qualification differed significantly in time spent sitting at work on a working day (χ2 = 0.57; p ≤0.001), with postgraduate qualification holders reporting more sitting time than the other two groups. additionally, these groups differed significantly in the sitting time reported on a non-working day in the domains of transportation (χ2 = 33.41; p ≤0.001), work (as a number of working women reported carrying out work-related tasks during non-working days) (χ2 =18.91; p ≤0.001) and the use of a computer (χ2 = 9.9; p ≤0.001); degree holders spent more time sitting in all of these domains. single women reported significantly more time spent sitting at work (z = −3.0; p ≤0.004) and using a computer (z = −3.0; p ≤0.006), while married women spent more time sitting while watching television (z = −4.0; p ≤0.001). employed women spent more time sitting on a non-working day while travelling (z = −2.3; p ≤0.02) and working (z = −2.7; p ≤0.01), compared with unemployed women. participants in the moderate monthly income group reported significantly more sitting time while travelling on a non-working day than the other income groups (χ2 = 14.21; p ≤0.001). however, there were no significant differences between sitting time among women in terms of their location and bmi categories. demographic groups were compared in terms of total sitting time on a working day versus that of a non-working day. there were significant differences found between the two age groups (t = 2.02; p = 0.04) with young adults reporting more sitting than adults on working days. however, no differences were observed between the groups on non-working days. the same results were found with regards to marital status (t = 2.75; p = 0.007) with single women reporting more time spent sitting on working days in comparison to married women. in contrast, no significant differences were observed on non-working days. significant differences were noted among education groups (f = 11.86; p = 0.001), with degree holders spending more time sitting on non-working days. no significant differences were found between the groups on working days. in addition, no significant differences were observed in total sitting time between the other demographic groups (employment status, location, income, bmi and whr) on working and non-working days. generally, participants spent the greatest proportion of sitting time at work on working days (31% of the total sitting time) and while doing other leisure activities during non-working days (26% of the total sitting time). of the 86 women who agreed to wear the accelerometers, only 80 participants provided usable data according to the study’s criteria. the mean time spent wearing the accelerometer was 813.7 ± 101.6 minutes/day. figure 2 shows the mean accelerometerrecorded pa levels and sb among the sample for the seven day period. these objective measurements revealed that the participants spent 62% of their time engaged in sb, 35% of their time taking part in light pa and only 3% of their time engaged in mvpa. discussion the results of this study suggest that further research on the determinants of physical inactivity or activity is needed in oman; mabry et al. recommended several strategies to this effect.17 sitting time is also a major concern; the deleterious effects of sb suggest that excessive sitting carries a serious health hazard when it is not balanced by a corresponding increase in figure 1: mean self-reported sitting time among a sample of adult omani women by domain and by weekday (working) or weekend (non-working) day (n = 191). participants assessed their sitting time using the domain-specific sitting time questionnaire.1,12 the mean total sitting time calculated across all domains was 450 minutes on a weekday and 448 minutes on a weekend day. azza al-habsi and hashem kilani clinical and basic research | e263 pa.18 a physiological study has identified unique and hazardous mechanisms in sb that are distinct from the biological benefits of exercising.18 unfortunately, according to objective measurements from an accelerometer, the participants in the current study were observed to spend the majority of their time engaged in sb. this therefore indicates that urgent action is needed in oman to increase awareness of the health risks of low pa and increased sb as well as to create public health interventions and programmes aiming to change the lifestyle behaviours of omani women. among the sample of adult omani women, selfreported pa levels from the ipaq revealed that women between 30–48 years old reported more moderate pa than their younger counterparts. although some research indicates that pa levels decrease with age,19 the results from the current study showed that adults reported increased levels of moderate pa compared with young adults. this finding is supported by a study by al-hazzaa, in which a slight increase in pa levels was observed between 15–29-year-olds and 30–44-year-olds (from 28.4% to 29.1%, respectively).20 additionally, women living in rural areas reported engaging in increased levels of moderate pa in the current study. this finding is in line with another study which also indicated that rural women were more active in terms of moderate pa in comparison to those in urban areas.21 in oman, this association could be explained by the fact that small towns and villages which are less built-up and have less infrastructure may afford opportunities to engage in increased pa, such as walking, as local residents in these rural environments do not have to rely as much on transportation.22 moreover, women in rural areas are more likely to be involved in physically demanding work, such as farming, raising livestock or creating handicrafts. in the current study, married women were also found to engage in more moderate pa. while this finding is supported by a study by al-hazzaa et al.,23 jacoby et al. found discordant results.24 cleaning, cooking and looking after children are typical activities that may constitute moderate pa in the daily routine of a married omani woman. in the current study, those with a high school education or lower reported more vigorous pa compared to participants with a degree or postgraduate qualification. in line with this, padrão et al. observed that vigorous pa decreased in inverse proportion to the level of education.25 these findings are additionally supported by a study by cohen et al. in the usa, which investigated pa and sb in african american and white adults.26 cohen et al. observed that participants reported lower overall pa levels as their level of education increased.26 in the current study, omani women with higher levels of education may have had jobs which demanded less pa as compared to the women who were less educated. research supports the observation that pa levels decrease as bmi and whr increase; in a study describing pa patterns in french adults, researchers found that pa decreased by 1.31–1.67 mets minutes/ week in women with an increased bmi.27 in contrast, the current study did not find a significant difference between bmi groups with respect to measured variables, although there was a small difference in total pa between the underweight and obese groups, as those who were obese reported increased levels of pa. this increase is probably due to an increasing trend among overweight and obese women to try to reduce their body fat. al-kilani et al. found that female omani students were less likely to be obese than male students.6 to date, only a few studies have examined pa levels and sb among adult women in oman. these studies have shown that increased pa results in a corresponding increase in fitness and thus helps to reduce excessive weight gain.28,29 another lifestyle study investigating pa and sb in under-18-year figure 2: mean time spent engaged in sedentary behaviour, light physical activity and moderate to vigorous physical activity over a seven day period among a sample of adult omani women who wore an accelerometer for a minimum of four days (n = 80). sb = sedentary behaviour; pa = physical activity; mvpa = moderate to vigorous pa. lifestyles of adult omani women cross-sectional study on physical activity and sedentary behaviour e264 | squ medical journal, may 2015, volume 15, issue 2 old omanis found a significant association between low levels of fitness and obesity.30 the results of the current study found that walking was considered the main contributor to the total pa levels among the participants. for omani women, walking is a common, accessible and inexpensive form of pa and is considered culturally acceptable. in terms of the proportion of women classified as inactive, moderately active and highly active, the results of the present study were found to differ from those of the world health survey in oman, which observed that 59% of omani women were getting sufficient exercise.5 this disparity could be due to differences between study designs, measurement tools and sample sizes. however, a comparison of the omani women’s activity levels with those of women in other gulf countries showed similar results. in a saudi arabian study, 40.6% of the studied men and women living in riyadh exhibited low activity, 34.3% were minimally active and 25.1% were highly active.20 studies in both australia and the uk reported similar results in terms of sitting time at work.1,12 furthermore, both studies found that sitting at work contributed to 50% of the total daily sitting time and that watching television was the major contributor to non-working day activities. in the present study, married adult women seemed to spend more time sitting while watching television, as compared to single young adults who spent more time using the computer, which may potentially be explained by a desire for socialisation among the latter. to the best of the authors’ knowledge, this study was the first to use accelerometers in order to objectively measure pa and sb among an omani population. the use of this tool is recommended for future studies to monitor pa and sb in order to accurately assess the lifestyles of different population groups in oman. one of the limitations of this study was that the data were collected during the summer months. furthermore, 33.9% of the participants were unemployed and the majority were students who participated in the study during their final exams. all of these factors may have affected the daily pa routines of the participants and could potentially have increased their sitting times. in addition, this study sought to examine pa levels and sb among young and middle-aged women only. a small sample size was used and the volunteers who wore the accelerometers were recruited exclusively from the governorate of muscat; these factors may have limited the generalisability of the results. further research with a larger sample and multivariate analysis is recommended to enhance understanding of the associations between demographic variables and indicators of pa and sb. conclusion investigation of the lifestyles of the studied adult omani women revealed a lack of pa and a high level of sb. leisure activities during non-working days and sitting at work on working days contributed the majority of sitting time. lifestyle-related factors such as low pa levels, increased sb and being overweight or obese can result in an increased risk of metabolic syndrome and other non-communicable diseases. the use of objective measuring tools, such as accelerometers, is highly recommended in future studies to accurately monitor pa and sb among population groups. public awareness of the health concerns associated with low levels of pa and increased sb is urgently needed along with public health interventions aimed at changing lifestyle behaviours among omani women. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. marshall al, miller yd, burton nw, brown wj. measuring total and domainspecific sitting: a study of reliability and validity. med sci sports exerc 2010; 42:1094–102. doi: 10.1249/ mss.0b013e3181c5ec18. 2. mabry rm, reeves mm, eakin eg, owen n. evidence of physical activity participation among men and women in the countries of the gulf cooperation council: a review. obes rev 2010; 11:457–464. doi: 10.1111/j.1467-789x.2009.00655.x. 3. mabry rm, winkler ea, reeves mm, eakin eg, owen n. associations of physical activity and sitting time with the metabolic syndrome among omani adults. obesity (silver spring) 2012; 20:2290–5. doi: 10.1038/oby.2012.26. 4. department of health information & statistics, oman ministry of health. annual health report 2011. muscat, oman: ministry of health, 2012. pp. 8–74. 5. al-riyami a, abd el aty ma, jaju s, morsi m, al-kharusi h, al-shekaili w. world health survey 2008. muscat, oman: oman ministry of health, 2012. p. 54. 6. al-kilani h, waly m, yousef r. trends of obesity and overweight among college students in oman: a cross sectional study. sultan qaboos univ med j 2012; 12:69–76. 7. waly mi, ali a, kilani ha. effects of dietary patterns, dietary glycemic load and physical activity level on the weight status of healthy female omani university students. asian j clin nutr 2014; 6:59–66. doi: 10.3923/ajcn.2014.59.66. 8. kilani h, al-hazzaa h, waly mi, musaiger a. lifestyle habits: diet, physical activity and sleep duration among omani adolescents. sultan qaboos univ med j 2013; 13:510–19. 9. world health organization. obesity: preventing and managing the global epidemic. from: www.who.int/nutrition/ publications/obesity/who_trs_894/en/ accessed: jul 2013. 10. international physical activity questionnaire group. international physical activity questionnaire. from: www. sites.google.com/site/theipaq/ accessed: jul 2013. 11. craig cl, marshall al, sjöström m, bauman ae, booth ml, ainsworth be, et al. international physical activity questionnaire: 12-country reliability and validity. med sci sports exerc 2003; 35:1381–95. doi: 10.1249/01.mss.0000078924.61453.fb. azza al-habsi and hashem kilani clinical and basic research | e265 12. clemes sa, david bm, zhao y, han x, brown w. validity of two self-report measures of sitting time. j phys act health 2012; 9:533–9. 13. garcía-massó x, serra-añó p, garcía-raffi lm, sánchezpérez ea, lópez-pascual j, gonzalez lm. validation of the use of actigraph gt3x accelerometers to estimate energy expenditure in full time manual wheelchair users with spinal cord injury. spinal cord 2013; 51:898–903. doi: 10.1038/ sc.2013.85. 14. ried-larsen m, brønd jc, brage s, hansen bh, grydeland m, andersen lb, et al. mechanical and free living comparisons of four generations of the actigraph activity monitor. int j behav nutr phys act 2012; 9:113. doi: 10.1186/1479-5868-9-113. 15. atkin aj, gorely t, clemes sa, yates t, edwardson c, brage s, et al. methods of measurement in epidemiology: sedentary behaviour. int j epidemiol 2012; 41:1460–71. doi: 10.1093/ije/ dys118. 16. freedson ps, melanson e, sirard j. calibration of the computer science and applications, inc. accelerometer. med sci sports exerc 1998; 30:777–81. 17. mabry r, owen n, eakin e. a national strategy for promoting physical activity in oman: a call for action. sultan qaboos univ med j 2014; 14:e170–5. 18. hamilton mt, healy gn, dunstan dw, zderic tw, owen n. too little exercise and too much sitting: inactivity physiology and the need for new recommendations on sedentary behavior. curr cardiovasc risk rep 2008; 2:292–8. doi: 10.1007/s12170008-0054-8. 19. hagstromer m, ainsworth be, oja p, sjostrom m. comparison of a subjective and an objective measure of physical activity in a population sample. j phys act health 2010; 7:541–50. 20. al-hazzaa hm. health-enhancing physical activity among saudi adults using the international physical activity questionnaire (ipaq). public health nutr 2007; 10:59–64. doi: 10.1017/s1368980007184299. 21. sjöström m, oja p, hagströmer m, smith bj, bauman a. health-enhancing physical activity across european union countries: the eurobarometer study. j public health 2006; 14:291–300. doi: 10.007/s10389-006-0031-y. 22. mehana m, kilani h. enhancing physical education in omani basic education curriculum: rationale and implications. int j cross dis sub edu 2010; 1:99‒104. 23. al-hazzaa hm, musaiger ao, atls research group. arab teens lifestyle study (atls): objectives, design, methodology and implications. diabetes metab syndr obes 2011; 4:417–26. doi: 10.2147/dmso.s26676. 24. jacoby e, goldstein j, lópez a, núñez e, lópez t. social class, family, and life-style factors associated with overweight and obesity among adults in peruvian cities. prev med 2003; 37:396–405. doi: 10.1016/s0091-7435(03)00159-2. 25. padrão p, damasceno a, silva-matos c, prista a, lunet n. physical activity patterns in mozambique: urban/rural differences during epidemiological transition. prev med 2012; 55:444–9. doi: 10.1016/j.ypmed.2012.08.006. 26. cohen ss, matthews cs, signorello lb, schlundt dg, blot wj, buchowski ms. sedentary and physically active behavior patterns among low-income african-american and white adults living in the southeastern united states. plos one 2013; 8:e59975. doi: 10.1371/journal.pone.0059975. 27. bertrais s, preziosi p, mennen l, galan p, hercberg s, oppert jm. sociodemographic and geographic correlates of meeting current recommendations for physical activity in middle-aged french adults: the supplémentation en vitamins et minéraux antioxydants (suvimax) study. am j public health 2004; 94:1560–6. doi: 10.2105/ajph.94.9.1560. 28. kilani h, kitani m, shaheen m. body composition, physical activity and dietary intake among omani adults: a populationbased study. can j clin nutr 2014; 2:41‒49. 29. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 30. kilani h, alyaarubi s, zayed k, alzakwani i, bererhi h, shukri r, et al. physical fitness attributes, vitamin d, depression, and bmd in omani’s children. eur sci j 2013; 9:156–73. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e104-112, epub. 27th jan 14 submitted 17th apr 13 revisions req. 2nd jun & 28th jul 13; revisions recd. 3rd jul & 2ndaug 13 accepted 25th aug 13 1department of public health, manipal university, manipal, india; 2indian institute of public health, public health foundation of india, odisha, india; 3district surveillance unit, udupi district, karnataka, india; 4state health resource center, chhattishgarh, india; 5jhpiego, jharkhand, india *corresponding author e-mail: subhashisaswain11@gmail.com معدل انتشار استهالك الكحول، عادة التبغ والسلوك اجلنسي لدى املراهقني يف املناطق احلضرية مبقاطعة أدويب، كرنتكا، اهلند بدما موهانن, �صوبها�صي�صا �صوين, نوري �صناه, فيكر�م �صارما, ديبوبورنا جو�س abstract: objectives: the aim of this study was to assess the prevalence of alcohol consumption, tobacco use and risky sexual behaviour among adolescents, and to evaluate the socioeconomic factors potentially influencing these behaviours. methods: this cross-sectional study was conducted from january to april 2011 among 376 adolescents (15–19 years old) studying in different schools and colleges in udupi, india. the youth risk behavior survey questionnaire and guidelines were followed for data collection. participants’ alcohol consumption, smoking habits and sexual behaviour patterns were explored. univariate analysis followed by multivariate logistic regression was done. results: the prevalence of alcohol consumption, tobacco use and sexual activity was found to occur in 5.7%, 7.2% and 5.5% of participants, respectively. the mean age of the participants’ first sexual activity, consumption of alcohol and tobacco use was reported to be approximately 16.8 years. multivariate analysis showed that males were more likely to have used alcohol and tobacco. other factors, such as religion and tobacco use among family members, were found to be influential. conclusion: the potential coexistence of multiple risk behaviours in a student demands an integrated approach. emphasis should be placed on health education in schools and an increased awareness among parents in order to prevent adolescents’ behaviours from becoming a risk to their health. keywords: adolescents; risk behaviors; tobacco; alcoholic beverages; sexual behavior; india. امللخ�ص: الهدف: تهدف هذه �لدر��صة �إىل تقييم معدل �نت�صار ��صتهالك �لكحول, ��صتخد�م �لتبغ و�ل�صلوك �جلن�صي لدى �ملر�هقي, وكذلك تقييم �لعو�مل �الجتماعية-�القت�صادية �ملوؤثرة يف هذه �ل�صلوكيات. الطريقة: �أجريت هذه �لدر��صة �مل�صتعر�صة على عينة من 376 مر�هقا )1915 �صنة( يدر�صون يف عدة مد�ر�س وكليات خمتلفة يف �أدوبي بالهند. مت ��صتخد�م ��صتبيان و�إر�صاد�ت م�صح �صلوكيات �الختطار عند �ل�صباب جلمع �لبيانات. مت عمل حتليل �أحادي �ملتغري�ت وبعد ذلك �النحد�ر �للوج�صتي متعدد �ملتغري�ت. النتائج: معدل �نت�صار ��صتهالك �لكحول, ��صتخد�م �لتبغ و�ملمار�صة �جلن�صية لدى �مل�صاركي كانت %5.7، %7.2، %5.5 على �لتو�يل. متو�صط عمر �مل�صاركي عند �أول ممار�صة ال�صتخد�م عر�صة �أكرث كانو� �لذكور �أن بي �ملتغري�ت متعدد حتليل �صنة. 16.8 تقريبا كان �لتبغ و��صتخد�م للكحول ��صتهالك جن�صية, �لكحول و�لتبغ. �لعو�مل �الأخرى, مثل �لديانة و��صتخد�م �لتبغ من قبل �أفر�د �لعائلة وجد �أن لها تاأثري. اخلال�سة: �حتمال تو�جد عدة عو�مل �ختطار لل�صلوكيات عند �لطلبة يحتم ��صتخد�م �أ�صلوب متكامل. يجب �لرتكيز على �لتعليم �ل�صحي يف �ملد�ر�س وزيادة �إدر�ك �الأهل من �أجل �حلد من حتول �صلوكيات �ملر�هقي �إىل عو�مل �ختطار على �صحتهم. مفتاح الكلمات: �ملر�هقون؛ �صلوكيات �الختطار؛ �لتبغ؛ م�رشوبات كحولية؛ �ل�صلوك �جلن�صي؛ �لهند. a study on the prevalence of alcohol consumption, tobacco use and sexual behaviour among adolescents in urban areas of the udupi district, karnataka, india padma mohanan,1 *subhashisa swain,2 noore sanah,3 vikram sharma,4 deboporna ghosh5 clinical & basic research advances in knowledge this study, the first of its kind, investigated the clustering of at-risk behaviours which might appear at an early stage among indian adolescents. even though this study did not target a particular risk group, it can still give a proxy image of the existence of behavioural patterns. applications to patient care determining the current prevalence of at-risk behaviours among indian adolesents and their correlates could help in strengthening adolescent health programmes and health promotion activities targeting this age group. the results of this study can be used to help tailor a targeted information programme. padma mohanan, subhashisa swain, noore sanah, vikram sharma and deboporna ghosh clinical and basic research | e105 the development of healthy behaviours, attitudes and lifestyles during adolescence can contribute significantly to a person’s current and future physical wellbeing. youth risk behaviours (yrb) are described as adverse health behaviours adopted in childhood or adolescence and are one of several indicators of the health of young people. yrb serve as a basis for measuring adolescent health over time as well as for the improved targeting of health policies and programmes.1 the importance of this measure is based on its association with several mortality and morbidity outcomes, chronic disease resulting from substance use and misuse, sexually transmitted diseases and undesirable social outcomes such as unintended teenage pregnancies.2 according to the world health organization (who), 67% of premature deaths and 33% of the disease burden among adults is due to behavioural patterns that emerge during adolescence. this also includes unintended pregnancies due to unprotected sex, 11% of which occur in 15–19 year olds, with a prevalence of approximately 16 million girls.3 the aim of this study was to assess the prevalence of alcohol consumption, tobacco use and risky sexual behaviour among indian adolescents, and to evaluate the socioeconomic factors potentially influencing these behaviours. like other cities in the developing world, cities in india are reporting a higher prevalence of risky behaviours among their young people.4,5 due to globalisation, the country’s improved economic status and possibly the effect of the media, the frequency of risky behaviours among india’s urban adolescents is approaching that of developed countries.6 a recent study revealed that the high prevalence of tobacco use among indians may contribute to 13.3% of total deaths by 2020.7 a number of studies from different parts of india have also independently highlighted the frequencies of tobacco use, alcohol consumption and sexual behaviour.8–10 studies from udupi have shown that nearly 17.8% of literate individuals above 15 years of age are tobacco users.11 another study from southern karnataka documented that nearly 38.1% of men between 16–49 years of age had an alcohol habit and 9.5% had human immunodeficiency virus/acquired immune deficiency syndrome (hiv/aids)-related risk behaviours.9 in both of these studies, the prevalence of risky behaviours was found to be high among individuals over 15 years of age. however, there is limited information available on the prevalence of tobacco use, alcohol consumption and sexual risk behaviours among the adolescent population in this area. behaviours which put the adolescent at risk usually coexist with other risk behaviours; however, very few studies have attempted to investigate all of the identified risk factors together on a large scale. despite the link between health and behaviour, there is a lack of studies on the basic prevalence of risky behaviours in the indian youth population, particularly in karnataka. to this end, the present study investigated risky behaviours among adolescents of the udupi district as well as to understand the underlying factors determining these behaviours. methods this cross-sectional study was carried out from january to april 2011 among 376 adolescents aged 15–19 years old studying in various schools and colleges in udupi, karnataka. udupi is one of the most developed cities of southern karnataka, with a literacy rate of 93.89%.12 it has a population of only 125,350 and a gender ratio of 1,019 females to 1,000 males.12 the city is divided into three administrative areas; however, sampling was only considered in the urban area of udupi. all schools and colleges, except professional colleges, were included in the sampling frame. the large number of professional colleges and their students were not included in the sampling process because of time and resource constraints. two-stage cluster sampling was used to assemble a representative sample of students studying in high school grades 9–12 and the first year of college. a total of 14 high schools, six pre-university colleges (pucs) and four degree-granting colleges identifying at-risk behaviours and potential risk groups at an early stage of life may help in estimating the future burden of diseases expected among adolescents. therefore, there is a need for preventive care and health education activities to be tailored according to the target population which, in the long term, could help limit adverse health consequences in later life. a study on the prevalence of alcohol consumption, tobacco use and sexual behaviour among adolescents in urban areas of the udupi district, karnataka, india e106 | squ medical journal, february 2014, volume 14, issue 1 in udupi city’s main urban area were included in the study, including both public and private schools. in total, four high schools, two pucs and one degree-granting college were selected randomly in the first stage of sampling. in the second stage, students from each grade division were enrolled using a systematic sampling method. students younger than 15 years or older than 19 years were excluded from the study. an extensive literature review was done to explore studies documenting risk behaviours among adolescents in south karnataka, karnataka, south india and india.4,11,13 all of the prevalent behaviours in these studies were noted, and those with the highest frequency were considered for the sample size calculation. with an expected prevalence of 49.1% (for an 80% power and a 5% margin of error) the sample size was estimated to be 384. a pre-tested, validated youth risk behavior survey (yrbs) questionnaire from the centers for disease control and prevention (cdc) was used to collect the information. a pilot survey was carried out among 30 students in the study, establishing consistent reliability (cronbach’s α = 0.70) for the final sample size (n = 384). the yrbs is widely used and accepted in countries across the world, including india.2 among the nine identified risk areas (safety; violence-related activities; tobacco use; alcohol consumption; sexual behaviour; physical activity; weight; drug use, and suicide and health-related topics), only six areas (safety; violence-related activities; tobacco use; alcohol consumption; sexual behaviour, and suicide and health-related topics) were chosen as the focus of this study. data on these six identified risk behaviours as well as basic sociodemographic information were collected. the self-administered yrbs consisted of semi-structured open-ended questions with dichotomous and ordinal responses to determine the health behaviours of the adolescents. only three of these six domains were analysed and discussed in this article. questions about sociodemographic characteristics included information about each student’s age; gender; place of residence; type of family (either nuclear or joint, which was defined as a family staying with the families of either parent); number of family members, and father’s occupation. the latter was classified according to the type of employment during analysis. questions on alcohol consumption sought to ascertain the drinking habits of the student during the previous six-month period; the age of initiation of drinking; the reason for drinking; the location for obtaining alcohol, and the drinking habits of the student’s family members. the section on tobacco use in the questionnaire sought to identify: the students’ tobacco use during the previous six-month period, for both smoking and smokeless tobacco; the age of initiation of smoking; the reason for tobacco use; the location for obtaining tobacco; the method of acquiring the money required to buy tobacco, and the tobacco use habits in the student’s family. similarly, in the domain of sexual behaviour, questions were asked about the students’ sexual relationships in the previous six months or earlier; the reason for the relationship, and the use of contraceptive measures such as condoms during the last sexual encounter. the yrbs 2010 guidelines were strictly followed during the data collection stage. selected students were made to sit separately and separate locations used for male and female participants. before beginning the questionnaires, the students were given a verbal explanation of the questions. each student received individual attention and was free to discuss any questions during the survey, with both female and male representatives assisting. the information obtained was analysed using the statistical package for the social sciences (spss), version 15 (ibm corp., chicago, illinois, usa). an analysis was performed to describe the adolescents’ sociodemographic characteristics and the prevalence of the risk factors. a chi-squared test and univariate analysis was done to estimate the unadjusted odds ratio (or) with a 95% confidence interval (ci). multivariate analysis was done for significant variables to identify the associated factors and reported with the adjusted or and a 95% ci. during the univariate analysis only, in order to select variables for multiple regression, the p value was kept at <0.25, considering the increased chance of biased responses from the students. in multivariate regression, a p value of <0.05 was considered significant. permission for the study was obtained from the deputy director of public instruction and written consent was obtained from all of the concerned school/college authorities as well as the students. padma mohanan, subhashisa swain, noore sanah, vikram sharma and deboporna ghosh clinical and basic research | e107 for students below 18 years of age, consent was obtained from their guardians/parents before their inclusion in the study. students participated in the study voluntarily and anonymously. the utmost care was taken to make the study participants feel free and comfortable, with personal communications arranged separately for each gender. the study was reviewed and approved by the institutional ethical committee of manipal university. results out of the 384 students selected by the sampling process, a total of 376 agreed to participate in the study. of these 376 students, the ratio of male participants (n = 201) to female participants (n = 175) was 1:1.1. the mean age of the female and male participants was 17.09 years and 16.09 years, respectively. the majority of the students were hindu (82.18%; n = 309). most students (87%; n = 330) lived with their parents and 75% lived within nuclear families. nearly equal numbers of the respondents’ fathers were professional compared to unskilled, with 31% in a professional occupation and 43.6% unskilled [table 1]. out of the 201 male participants, 9.5% revealed their drinking status compared to 1.7% of female participants. the median age of the student at first consumption of alcohol was 16.82 years (95% ci; 16.44–17.2 years). a total of 12 (54.5%) out of 22 respondents revealed that at least one of their family members had an alcohol habit [table 2]. in total, about 27 students (7.1%) had smoked in the previous six months. the mean age of the student at first tobacco use was found to be 16.8 years. when asked about their reasons for smoking, 14 (51.84%) students claimed a desire to look stylish and a relief from stress as their motivators. nearly 41% of students smoked daily whereas 16 students (59.26%) smoked once to thrice a week. out of 27 students, 55% obtained their cigarettes from a shop and 20 of those students (74.1%) spent their pocket money to get them. only eight students (30%) smoked an average of one cigarette per day. it was interesting to note that 55.6% of students with a smoking habit had tried to quit smoking at least once before. only two students (7.4%) mentioned the use of chewing tobacco [table 3]. questions were also asked about whether the students had had sexual intercourse within the sixmonth period prior to the study; their age upon first initiation of sexual intercourse; reasons for the behaviour, and usage of any contraceptive measures. out of 376 students, 368 answered questions regarding sexual behaviour. of them, 21 (5.5%) students responded that they had had at least one incidence of sexual intercourse within the previous six months. the median age at initiation was 16.71 years old (range 16.28–17.15). nearly half of these 21 respondents had had sexual intercourse after 17 years of age; 18 of them lived with their parents compared to three who were staying with friends. the majority of students (52.38%) mentioned that table 1: sociodemographic characteristics of the participants (n = 376) variables frequency (95% ci) gender male 53.45 (48.42–58.40) female 46.55 (41.50–51.65) age <16 years 35.37 (30.66–40.31) ≥16 years 64.63 (59.69–69.34) religion hindu 82.18 (78.00–85.80) muslim 11.42 (08.50–14.09) christian 8.50 (6.00–11.60) father’s occupation professional 31.38 (26.80–36.20) skilled 16.75 (13.30–20.80) semi-skilled 7.10 (4.90–10.14) unskilled 43.60 (38.60–48.60) currently staying with parents 86.90 (83.20–90.09) relatives 5.85 (3.80–5.70) friend 3.90 (2.30–6.30) others 3.19 (1.74–5.36) type of family nuclear 75.00 (70.40–79.10) joint 25.00 (20.80–29.56) alcohol/tobacco habits among any current family members yes 25.80 (21.30–31.70) tobacco use among students yes 7.10 (4.80–10.10) alcohol use among students yes 5.85 (3.80–8.50) sexual relationship within last 6 months [n = 368] yes 5.70 (3.60–8.40) ci = confidence interval. a study on the prevalence of alcohol consumption, tobacco use and sexual behaviour among adolescents in urban areas of the udupi district, karnataka, india e108 | squ medical journal, february 2014, volume 14, issue 1 having fun was the main motivating factor for having sexual intercourse with 76.2% answering that they had had a sexual relationship with their boyfriend or girlfriend. out of 21 students, 13 (62%) had not used any kind of contraception during their last sexual encounter. univariate analysis showed that gender (p = 0.001), religion (p = 0.014) and having current family members with alcohol habits (p = 0.001) were strongly associated with alcohol consumption among the students. considering a p value of 0.25 as a margin for selecting variables for multivariate analysis, gender, religion, father’s occupations, a family habit of alcohol and smoking habits were considered for binary logistic regression analysis. binary logistic regression showed that there was a strong association with gender (or 4.8; 95% ci: 1.3–17.5). christians were more at risk for having or developing an alcohol habit (or = 2.45; ci: 1.1–8.7), and the alcohol habits of family members strongly influenced the drinking habits of the cohabitating adolescents living at home (or = 6.23; 95% ci: 3.45–8.95) [table 2]. after the univariate analysis, gender, religion, type of family and smoking habits of family memebers and the alcohol habits of students were included in a multivariate analysis. binary logistic regression showed that gender (or = 4.29; 95% ci: 1.42–13.43), age over 16 years (or = 5.3: 95% ci: 3.6–9.71) the smoking habits of family members (or = 5.1; 95% ci: 2.1–12.21) and having an alcohol habit (or = 6.4; 95% ci: 1.72–22.6) were identified risk factors for the development of smoking habits in students [table 3]. binary logistic regression showed that students of both genders who had alcohol and smoking habits were more likely to be involved in sexual activities. males were more likely (or 2.6; 95% ci: 1.37–17.8) than females to form or have a sexual relationship. students with alcohol habits (or = 11.3; 95% ci: 3.17–40.25) were also more likely to participate in sexual activities than students who did not consume alcohol [table 4]. table 2: adolescents having an alcohol habit across sociodemographic variables (n = 22) variables frequency n (%) univariate analysis† (p value) adjusted or (95% ci) gender male 19 (86.36) <0.001* 4.82 (1.3–17.5)* female 03 (13.64) 1 age <16 years 08 (36.36) 0.920 ≥16 years 14 (63.64) religion hindu 15 (68.18) 0.014* 1 muslim 01 (4.54) 0.01 christians 06 (27.28) 2.45 (1.1–8.7)* father’s occupation professional 06 (27.28) 0.295 skilled 05 (22.72) semi-skilled 02 (9.10) unskilled 09 (40.9) currently staying with parents 17 (77.26) 0.490 relatives 01 (4.54) friends 02 (9.10) others 02 (9.10) type of family nuclear 17 (77.26) 0.490 joint 05 (22.74) alcohol habit among any current family members yes 12 (54.54) <0.001* 6.23 (3.45–8.95)* no 10 (45.46) 1 age at sexual initiation <14 years 05 (22.74) -15–16 years 05 (22.74) >16 years 12 (54.54) reason for sexual initiation stylish 02 [9.10] curiosity and peer pressure 07 [31.81] media (tv) 10 [45.45] stress relief 03 [13.64] frequency daily 01 [4.54] 1–2 times per week 07 [31.81] 3–4 times per week 14 [63.65] place of acquisition shop 05 [22.74] friends 02 [9.10] family members 08 [36.35] party/ function 07 [31.81] tobacco use yes 16 [72.72] no 06 [27.38] † = chi-squared test; or = odds ratio; ci = confidence interval; n/a = not applicable;*p value <0.05. padma mohanan, subhashisa swain, noore sanah, vikram sharma and deboporna ghosh clinical and basic research | e109 discussion in the present study, the mean age of the respondents was 16.09 and 17.09 years old for males and females, respectively. this study found that 5.1% of the respondents had consumed alcohol in the previous six months. among female participants, the prevalence of alcohol consumption was 1.4% and among male participants it was 4.9%. similar results were also documented in the indian national family health survey-3 (nfhs-3), where the prevalence among 15–19 year old girls was 1%.14 a higher prevalence was reported in the nfhs-3 among boys, which could be due to intercultural variation between the different states of india. the mean age of the participants upon first consuming alcohol was 16.82 ± 0.38 years which was lower than a study done in kolkata which reported the mean age upon initiation as 20.8 ± 5.9 years.13 a study in mexico noted the mean age upon initial consumption of alcohol as 15.6 years.15 in this study, it was found that risky behaviours such as alcohol use were 4.8 times higher among males in comparison to females. univariate analysis showed there was a positive association (or = 2.25) between the alcohol consumption habits of parents and those of their offspring. one study done in kerala showed similar results (or = 2.9) among fathers’ and children’s alcohol consumption habits.16 it was also noted that religion might be a factor contributing to alcohol use among students. christian students were 2.4 times more likely to have consumed alcohol than non-christians. this could be because of cultural habits seen in some christian families, where drinking is a custom during social functions or gatherings; in fact, 78% of students mentioned ‘home’ or ‘parties’ as a source of obtaining or consuming alcohol. a large numbers of studies have been carried out to investigate tobacco use among adolescents in india. this study showed that the prevalence of smoking among students within the previous six months was 7.1%. among male students, the prevalence was found to be 11.8% and among female students it was found to be 2.2%. this number was comparable to the nfhs-3 study, which showed that 12.8% of males and 3.5% of those in the 15– 19 year old age group smoked cigarettes or bidi (a thin, indian cigarette filled with tobacco flake and wrapped in a tendu leaf ).14 this included males table 3: adolescents reporting a tobacco habit across sociodemographic variables (n = 27) variables categories frequency n (%) univariate analysis (p value) adjusted or (95% ci) gender male 23 (85.18) <0.001* 4.29 (1.42–13.4)* female 04 (14.82) 1 age <16 years 09 (33.33) 0.057 1 ≥16 years 18 (66.67) 5.3 (3.6–9.71)* religion hindu 21 (77.78) 0.084 1 muslim 06 (22.22) 0.545 (0.193–1.54) christian father’s occupation professional 06 (22.22) 2.97 skilled 05 (18.52) semiskilled 11 (40.74) unskilled 05 (18.52) currently staying with parents 24 (88.90) 0.490 others 03 (11.10) type of family nuclear 18 (66.67) 0.080 3.2 (0.72–12.56) joint 09 (33.33) 1 tobacco habit among any current family members yes 17 (62.96) <0.001* 5.07 (2.1–12.21)* no 10 (37.04) 1 age at initiation <14 years 04 (14.81) 15–16years 10 (37.04) >16 years 13 (48.15) reason for initiation style 07 (25.925) curiosity and peer pressure 07 (25.925) media (tv) 06 (22.221) stress relief 07 (25.925) frequency daily 11 (40.74) 1–2 times per week 06 (22.22) 3–4 times per week 10 (37.04) place of acquisition shop 15 (55.55) friends 10 (37.04) family members 2 (7.41) alcohol habit yes 20 (74.07) <0.001 6.4 (1.72–22.6)no 07 (25.93) or = odds ratio; ci = confidence interval; *p value <0.05. a study on the prevalence of alcohol consumption, tobacco use and sexual behaviour among adolescents in urban areas of the udupi district, karnataka, india e110 | squ medical journal, february 2014, volume 14, issue 1 from both urban and rural areas of india. another study done in noida by narain et al. reported a prevalence of 11.2% of tobacco use in any form.17 in a south indian study done in tamil nadu, the prevalence of tobacco use among 13–15 year olds was 10%.10 the mean age of the user at first tobacco use was 16.8 years compared to 12.4 years in the narain et al. study. one study done in nepal showed the age of the user at initiation of tobacco use was 15.7 years.18 reasons for smoking, influenced by the media, were identified as a desire to look stylish and curiosity. a study of schoolchildren in new delhi also described the influence of the media and celebrities as factors which contributed to smoking.4 the majority of students reported acquiring cigarettes from shops near their homes. a study done in dhakishna kannda by shenoy et al. also identified easy access to tobacco as a factor for smoking.19 furthermore, the use of pocket money to buy tobacco products was extremely common among all respondents in this study.19 of all smokers in this study, 40.7% had tried to quit smoking; similar results were found in a study in nepal.18 this indicates that the students knew that they should quit but their attempts to do so were unsuccessful. the presence of other family members using tobacco increases by five-fold the student’s likelihood of using tobacco. this study showed a higher risk of using tobacco than a study done by chopra et al. (or = 1.5).16 there is a verified genetic association between parental habits of tobacco use and alcohol consumption and the habits of tobacco use and alcohol consumption among their offspring.20 in the current study, 5.5% of students responded that they had had sexual intercourse at least once in the previous six months. studies on premarital sex and risky sexual behaviours among adolescents are still unexplored in india. results showed that fewer students in this study were engaging in sexual intercourse compared to a study done over 15 years ago in mumbai (participants between 15–24 years old).21 nearly 10% of the male students in the current study reported having had a sexual relationship, which was comparable to the alexander et al. study in maharashtra.22 the median age of the adolescents at their first sexual encounter was 16.71 years and the majority of the students identified fun and curiosity as the reason for having sex. a large college-based study in gujarat noted similar experiences and attitudes among students.23 however, social taboos in indian society associated with issues regarding sexuality, as well as gender-biased reporting, does not give a clear picture of the actual incidence of premarital sexual activity among adolescents and youth. in addition, 76.2% of the students in this study reported that they had had sex with a girlfriend or boyfriend, table 4: adolescents demonstrating sexual behaviours across sociodemographic variables (n = 21) variables frequency n (%) univariate analysis (p value) adjusted or (95% ci) gender male 20 (95.23) <0.001 2.6 (1.37–17.8)* female 1 (4.77) 1 age <16 years 10 (47.62) 0.890 ≥16 years 11 (52.38) religion hindu 14 (66.67) 0.072 1 muslim 05 (23.81) 0.599 (0.105–2.32) christian 1 (04.76) 0.18 (0.13–10.28) not mentioned 1 (04.76) father’s occupation professional 06 (28.57) 0.392 skilled 03 (14.29) unskilled 12 (57.14) currently staying with parents 18 (85.71) 0.898 friends 03 (14.29) type of family nuclear 18 (85.71) 0.20 3.2 (0.72–12.56)* joint 03 (14.29) 1 alcohol habit yes 08 (38.09) <0.001 11.3 (3.2–40.2)* no 13 (61.91) 1 tobacco use yes 11 (52.38) <0.001 3.23 (0.81–12.82) no 10 (47.62) age of sexual initiation <14 years 05 (23.81) 15–16 years 06 (28.57) >16 years 10 (47.62) reason for sexual initiation curiosity and peer pressure 9 (42.86) earning purposes 1 (4.76) fun 11 (52.38) or = odds ratio; ci = confidence interval;*p value <0.05. padma mohanan, subhashisa swain, noore sanah, vikram sharma and deboporna ghosh clinical and basic research | e111 which is similar to results seen in other gujarat studies.23 nearly 62% of the respondents who had had a sexual relationship did not use any kind of contraceptive during their last sexual encounter. this prevalence of unprotected sex leads to a great risk of spreading sexually transmitted diseases (std) and hiv/aids in addition to pregnancy. a report in delhi found that unprotected sex puts this age group at a high risk of contracting stds.23,24 this study had a number of limitations, including the fact that self-reporting by the students could have biased the results. underreporting to sensitive questions could also not be ruled out. furthermore, as this was a cross-sectional study, causal relationships could not be established. additionally, no further questions were asked in this study about alcohol, tobacco and sexual habits among students, as the aim was to determine the prevalence of these behaviours; however, further enquiries might have uncovered details regarding other risk factors. for example, mutual masturbation was not included as an option in the sexual behaviour section of the questionnaire, which could have given more insight into sexual activity amongst adolescents. the sample size was also not large enough to deduce any other risk factors. finally, the trends of at-risk behaviours among the population could not be determined, so a longitudinal follow-up study might provide useful insights. conclusion risk behaviours among adolescents in udupi are comparable to the findings of studies from other urban areas in india. behavioural patterns of family members were found to influence the behaviours of adolescents, which highlights the importance of the role of family on adolescent risk-taking. the coexistence and development of multiple risky behaviours such as alcohol consumption, tobacco use and sexual activities indicates the dangerous interconnection between such behaviours among adolescents. thus there is an urgent need to initiate programmes at various levels to generate awareness regarding the potential health hazards of tobacco, alcohol and premature sexual relationships. the incorporation of educational material regarding the ill effects of risky behaviours in the syllabi of schools and colleges might be helpful. a focus on an increased awareness among school students through health and peer education and counselling might influence the target population in adopting and supporting health promotion activities. references 1. united nations population fund. adolescents in india: a profile. from: www.scribd.com/doc/77136294/adolescenthealth-and-development-ahd-unfpa-country-report accessed: nov 2013. 2. kann l, kinchen sa, williams bi, ross jg, lowry r, grunbaum ja, et al. youth risk behavior surveillance-united states, 1999. mmwr cdc surveill summ 2000; 49:1–32. 3. world health organization. young people: health risks and solutions. from: www.who.int/mediacentre/factsheets/ fs345/en/index.html accessed: nov 2013. 4. sharma r, grover vl, chaturvedi s. risk behaviors related to inter-personal violence among school and college-going adolescents in south delhi. indian j community med 2008; 33:85–8. 5. stigler mh, perry cl, arora m, reddy ks. why are urban indian 6th graders using more tobacco than 8th graders? findings from project mytri. tob control 2006; 15:i54– 60. 6. gidley j. globalization and its impact on youth. from: http://www.academia.edu/302381/globalization_and_its_ impact_on_youth accessed: nov 2013. 7. srinath reddy k, shah b, varghese c, ramadoss a. responding to the threat of chronic diseases in india. lancet 2005; 366:1744–9. 8. srinath reddy k, perry cl, stigler mh, arora m. differences in tobacco use among young people in urban india by sex, socioeconomic status, age, and school grade: assessment of baseline survey data. lancet 2006; 367;589– 94. 9. nayak mb, korcha ra, benegal v. alcohol use, mental health, and hiv-related risk behaviors among adult men in karnataka. aids behav 2010; 14:s61–73. 10. gajalakshmi v, asma s, warren cw. tobacco survey among youth in south india. asia pac j cancer prev 2004; 5:273–8. 11. daniel ab, nagaraj k, kamath r. prevalence and determinants of tobacco use in a highly literate rural community in southern india. nat med j india 2008; 21:163–5. 12. census organization of india. udupi city census 2011 data. from: www.census2011.co.in/census/city/445-udupi. html accessed: nov 2013. 13. ghosh s, samanta a, mukherjee s. patterns of alcohol consumption among male adults at a slum in kolkata, india. j health popul nutr 2012; 30:73–81. 14. ministry of health and family welfare government of india. india: national family health survey (nfhs-3) 2005-06 key findings. from: www.measuredhs.com/pubs/ pdf/sr128/sr128.pdf accessed nov 2013. 15. mancha be, rojas vc, latimer ww. alcohol use, alcohol problems, and problem behavior engagement among students at two schools in northern mexico. alcohol 2012; 46:695–701. a study on the prevalence of alcohol consumption, tobacco use and sexual behaviour among adolescents in urban areas of the udupi district, karnataka, india e112 | squ medical journal, february 2014, volume 14, issue 1 16. chopra a, dhawan a, sethi h, mohan d. association between parental and offspring’s alcohol use--population data from india. j indian assoc child adolesc ment health 2008; 4:38–43. 17. narain r, sardana s, gupta s, sehgal a. age at initiation & prevalence of tobacco use among school children in noida, india: a cross-sectional questionnaire based survey. indian j med res 2011; 133:300–7. 18. subba sh, binu vs, menezes rg, ninan j, rana ms. tobacco chewing and associated factors among youth of western nepal: a cross-sectional study. indian j community med 2011; 36:128–32. 19. shenoy rp, shenai pk, panchmal gs, kotian sm. tobacco use among rural schoolchildren of 13-15 years age group: a cross-sectional study. indian j community med 2010; 35:433–5. 20. schuckit ma. an overview of genetic influences in alcoholism. j subst abuse treat 2009; 36:s5–14. 21. abraham l, kumar ka. sexual experiences and their correlates among college students in mumbai city, india. int fam plan perspect 1999; 25:139–46. 22. alexander m, garda l, kanade s, jejeebhoy s, ganatra b. formation of partnerships among young women and men in pune district, maharashtra. new delhi: population council, 2006. 23. sujay r. premarital sexual behavior among unmarried college students of gujarat, india. from: www.popcouncil. org/pdfs/wp/india_hpif/009.pdf accessed: nov 2013. 24. mehra s, savithri r, coutinho l. sexual behavior among unmarried adolescents in delhi, india: opportunities despite parental controls. mamta-health institute for mother and child. paper presentation, international union for the scientific study of population (iussp) regional population conference on southeast asia's population in a changing asian context, bangkok, thailand, 10–13 jun 2002. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e253-256, epub. 7th apr 14 submitted 24th sep 13 revisions req. 4th nov 13 & 5th jan 14; revisions recd. 11th dec 13 & 15th jan 14 accepted 16th jan 14 department of urology, sohar hospital, sohar, oman *corresponding author e-mail: joseph.maliakal@gmail.com تضخم بروستات عمالق رابع أكرب بروستات سجل يف األدب الطيب جوزيف مالياكال، عماد الدين مو�صى، فارنا مينون abstract: a giant prostatic hyperplasia (gph) weighing more than 700 g is a rare entity. it is believed that only eight such cases have been previously reported in the medical literature. this case report concerns a patient with a gph weighing 740 g which was successfully removed by suprapubic prostatectomy. to our knowledge, this is the fourth largest benign prostatic enlargement ever reported in the literature. keywords: benign prostatic hyperplasia; prostatectomy, suprapubic; case report; oman. امللخ�ص: ت�صخم الربو�صتات العملق ليزن اأكرث من 700 غرام ميثل حاله نادرة للغاية. ويعتقد باأنه مت ت�صجيل ثمانية حالت مماثلة فقط عمان �صلطنة يف �صحار م�صت�صفى يف البولية امل�صالك جراحة ق�صم اإىل حتويله مت مري�س حالة ي�صتعر�س التقرير هذا الطبي. الأدب يف عنده �صخامة برو�صتات عملق يزن 740 غرام ا�صتوؤ�صل بنجاح عن طريق �صق فوق العانة. على حد علمنا هذا رابع اأكرب ت�صخم حميد للربو�صتات �صجل يف الأدب الطبي مفتاح الكلمات: ت�صخم الربو�صتات احلميد؛ ا�صتئ�صال برو�صتات فوق العانة؛ تقرير حالة؛ عمان. giant prostatic hyperplasia fourth largest prostate reported in medical literature *joseph maliakal, emad e. mousa, varna menon case report benign prostatic hyperplasia (bph) in males is commonly associated with the ageing process. as a man ages, the enlarged prostate usually produces progressive lower urinary tract symptoms. in some people, the prostate enlarges massively, eventually weighing more than 500 g; this is defined as giant prostatic hyperplasia (gph).1 researchers have not identified to date any specific cause for this massive enlargement of the prostate.2 the case under discussion is a patient whose only symptom was frequent urination yet who had a massive prostate enlargement (740 g). the prostate’s large size and the relative lack of symptoms in the patient further underline the fact that symptoms do not necessarily correlate with the size of the prostate. case report an 89-year-old man of medium stature, weighing 65 kg and with a height of 162 cm attended the urology clinic at sohar hospital, oman, with a long history of frequent day and night urination that had worsened during the previous three months. he claimed that his urinary stream was satisfactory. a clinical examination revealed a non-tender dull mass in the suprapubic area. on digital rectal examination, the anal tone was found to be normal, but the prostate was very large with a rubbery consistency and no palpable hard nodules. the upper border of the prostate could not be reached. an ultrasound scan revealed a huge prostatic enlargement bulging into the bladder. renal function tests and urine investigations were within normal range. the patient’s preoperative haemoglobin level was 13 g/dl. his prostate specific antigen (psa) level was 85.7 ng/ml. a computed tomography (ct) scan revealed normal kidneys but a prostate which was abnormally large in size, measuring 14 x 13 x 9 cm and occupying the whole bladder [figure 1]. in view of the patient’s severe urinary frequency, catheterisation was carried out. the catheter went in easily but drained only 100 ml of clear urine and the suprapubic mass persisted after catheterisation. after the detailed examination and investigations, the patient underwent a suprapubic prostatectomy. the surgical procedure revealed a massively enlarged prostate with a median lobe occupying the entire bladder, with large dilated and tortuous veins over it [figure 2]. the enlarged gland was enucleated completely in the classical transvesical method. the enucleation caused excessive bleeding from the prostatic bed due to the large size and increased giant prostatic hyperplasia fourth largest prostate reported in medical literature e254 | squ medical journal, may 2014, volume 14, issue 2 vasularity of the gland and the patient became haemodynamically unstable with hypotension and tachycardia, which was managed by blood transfusion and fluid replacement. the estimated blood loss was about 1,800 ml and three units of blood were transfused during surgery. when routine methods failed to control the bleeding, the technique of pursestring partition closure of the bladder neck, described by malament in 1965, was applied.3 the bladder neck was closed with a number one prolene purse-string suture after inserting a 24fr foley catheter via the urethra into the bladder. the ends of the suture were brought outside the abdominal wall and tied. the bladder was closed in layers after the insertion of a 22fr foley catheter as a suprapubic catheter. the patient’s postoperative haemoglobin was 11.8 g/dl. no significant bleeding occurred in the postoperative period. the urine was clear from the first postoperative day. the prolene suture was removed after 48 hours and no bleeding was encountered. the urethral catheter was removed after seven days with clamping of the suprapubic catheter and the patient could pass urine with a good stream. the suprapubic catheter was removed on the ninth postoperative day and the patient was discharged the next day. at the two-month follow-up visit, the patient was voiding satisfactorily and was continent. the excised specimen was submitted for histopathological examination. the specimen measured 14 x 13 cm and weighed 740 g [figure 3]. on gross examination, there was no evidence of induration or necrosis. a microscopic examination revealed glandular and fibromuscular stromal proliferation in varying proportions [figure 4]. findings were compatible with bph. there was no evidence of prostatitis or carcinoma. discussion bph is a common disorder of the prostate affecting most males above the age of 40 years. prostatic hyperplasia is considered to be due to the proliferation of epithelial and stromal cells, impairment of programmed cell death (apoptosis) or both and is endocrine controlled.4 autopsy data indicate that over 90% of men older than 80 years have histological evidence of bph.5 prostates weighing more than 100 g have been recorded in only 4% of men above the age of 70 years.5 bph with the prostate weighing more than 500 g is rarely seen and is defined as gph.1 only eight cases of bph where the prostate weighed more than 700 g have been reported in the literature to date [table 1]. the genesis of gph is not known; however, an exaggerated over-expression of growth factors combined with the absence or reduction of inhibitory figure 1: computed tomography scan showing the huge prostate filling the bladder. figure 2: the median lobe of the prostate after opening the bladder, with dilated veins over it (arrow). figure 3: the removed prostatic specimen weighed 740 g. joseph maliakal, emad e. mousa and varna menon case report | e255 factors have been proposed as possible mechanisms.6 the mutation of certain proto-oncogenes such as ras and c-erbb-2 may also be involved, developing a continuous cellular proliferation signal or the loss of influence of the p53 suppressor gene through its mutation or deletion, which would allow for abnormal cell proliferation.6 transurethral surgical techniques or other minimally invasive procedures are performed for patients with smallto medium-sized prostates. however open surgery is recommended for bigger prostates. most surgeons prefer suprapubic prostatectomy. rapid removal of the enlarged gland with immediate effective haemostatic techniques is essential to decrease blood loss. the measures suggested to stop bleeding include applying pressure in the prostatic fossa with gauze pads; applying one or two plicating sutures to reduce both the bleeding and the prostatic fossa volume;7 suturing of the bladder neck at the 5 and 7 o’clock positions;8 taping both internal iliac arteries before surgery; ligation during surgery if bleeding is excessive;9 compressing the bladder neck with a catheter balloon to control rebleeding,10 and a purse-string partition closure.3 of the eight patients in whom the prostate weighed more than 700 g, three died as a consequence of haemorrhage.11 the application of a purse-string partition closure of the bladder neck gave an excellent result in our patient; other measures used in this case, like packing, plication of the prostatic fossa and suturing of the bladder neck, could not stop the bleeding. the authors recommend purse-string partition closure of the bladder neck as the first step to stop the bleeding during the surgical enucleation of massively enlarged prostates in order to avoid a potentially fatal excessive blood loss. conclusion the case report presented here constitutes the fourth heaviest prostate reported in medical literature to date. more importantly, in certain cases surgical treatment of gph ended fatally due to the aftereffects of haemorrhage. in order to tackle the risk of haemorrhage effectively, the authors recommend the technique of purse-string partition closure of the bladder neck to stop bleeding in large and vascular prostates. this technique was applied effectively in this case and yielded an excellent result for the patient. references 1. fishman jr, merrill dc. a case of giant prostatic hyperplasia. urology 1993; 42:336–7. 2. soichiro o, masahiko m, michihiro y, yoshinobu k, masaaki y, yuichi s, et al. a giant prostatic hyperplasia treated by open surgery. int j gen med 2012; 5:1009–12. doi: 10.2147/ijgm. s38238. 3. malament m. maximal haemostasis in suprapubic prostatectomy. surg gynecol obstet 1965; 120:1307. doi: 10.1016/j.eeus.2006.07.002. 4. joseph cp. neoplasms of the prostate gland. in: tanagho ea, mcaninch jw, smith’s general urology, 15th ed. new york: lange medical books/mcgraw-hill, 2000. p. 399. 5. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol 1984; 132:474–9. 6. silva-gutierrez a, perez-evia ca, alcocer-gaxiola b, martinez-mendez me. giant prostatic hyperplasia: a case report and literature review. rev mex urol 2010; 70:183–6. 7. o’conor vj, jr. an aid for hemostasis in open prostatectomy: capsular plication. j urol 1982; 127:448. 8. wadstein t. the largest surgically removed hypertrophied prostate. jama 1938; 110:509. 9. sood r, jain v, chauhan d. giant prostatic hyperplasia. j postgrad med 2006; 52:232–3. 10. shahapurkar w, khare n, deshmukh av. modified technique in freyer’s prostatectomy to achieve hemostasis. indian j urol 2009; 25:332–4. doi: 10.4103/0979-1591.56189. figure 4: microscopic examination of the prostatic specimen. table 1: giant prostates exceeding 700 g in medical literature author weight in g result 1. medina-peres et al.12 2,410 survival not mentioned 2. tolley da et al.13 1,058 recovered 3. ockerblad14 820 died 4. current case 740 recovered 5. ucer et al.15 734 recovered 6. nelson16 720 died 7. gilbert17 713 died 8. wadstein8 705 recovered 9. lantzius-beninga18 705 recovered giant prostatic hyperplasia fourth largest prostate reported in medical literature e256 | squ medical journal, may 2014, volume 14, issue 2 11. klinger me, dimartini j. massive prostatic hypertrophy. urology 1975; 6:618–9. 12. medina pm, valero pj, valpuesta fi. giant hypertrophy of the prostate: 2410 grams of weight and 24 cm in diameter. arch esp urol 1997; 50:79–97. 13. tolley da, english pj, grigor km. massive benign prostatic hyperplasia. j r soc med 1987; 80:777–8. 14. ockerblad nf. giant prostate: the largest recorded. j urol 1946; 56:81–2. 15. üçer o, başer o, gümüş b. giant prostatic hyperplasia: case report and literature review. dicle med j 2011; 38:489–91. doi: 10.5798/diclemedj.0921.2011.04.0072. 16. nelson oa. largest recorded prostate. urol cutan rev 1940; 44:454–5. 17. gilbert jb. one-stage suprapubic prostatectomy for a gland weighing 713 grams (one and one-half pounds). urol cutan rev 1939; 43:309–10. 18. lantzius-beninga f. prostate of world record size. j urol nephrol 1966; 59:77–9. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e116–119, epub. 21 jan 15 submitted 6 jun 14 revisions req. 13 jul & 18 aug 14; revisions recd. 4 aug & 21 aug 14 accepted 27 aug 14 3department of family & community medicine, 1school of medicine, royal college of surgeons in ireland medical university of bahrain, busaiteen, bahrain; 2department of haematology, royal albert edward infirmary, wrightington, wigan & leigh nhs foundation trust, uk *corresponding author e-mail: a.abdulnabi@live.com هل حيمي مرض فقر الدم املنجلي من اإلصابة بداء السكري؟ دراسة مقطعية علي عبدالنبي حممد، فتحية القر�ضي، ديفيد ويتفورد abstract: objectives: the co-existence of diabetes mellitus (dm) and sickle cell disease (scd) is rare. this study aimed to explore whether scd patients have the same dm prevalence as the general population in a country with a high prevalence of dm. methods: this cross-sectional study included all scd adult patients admitted to salmaniya medical complex, bahrain, between 2003 and 2010 (n = 2,204). a random sample (n = 520) was taken to establish the prevalence of dm. laboratory records were examined to determine the presence of dm. results: there were 376 scd patients with complete records; of these, 24 (6.4%) had dm. the ageand sex-standardised prevalence of dm was 8.3%. conclusion: while the prevalence of dm in scd patients in bahrain was high, it was lower than expected in this population. scd may have a protective effect towards dm development. however, the impact of these two conditions on vascular diseases suggest a need for screening and aggressive treatment in this population. keywords: diabetes mellitus; sickle cell disease; prevalence; epidemiology; comorbidity; vascular diseases; bahrain. امللخ�ص: الهدف: من النادر ح�ضول مر�س فقر الدم املنجلي وداء ال�ضكري يف نف�س املري�س معا. هذه الدرا�ضة تبحث يف ن�ضبة انت�ضار داء ال�ضكري يف املر�ضى امل�ضابني بفقر الدم املنجلي يف بلد ينت�رض فيه مر�س ال�ضكري بن�ضبة عالية. الطريقة: ا�ضتملت هذه الدرا�ضة املقطعية على كل مر�ضى فقر الدم املنجلي البالغني الذين اأدخلوا اإىل م�ضت�ضفى ال�ضلمانية الطبي يف البحرين، من �ضنة 2003 اإىل �ضنة 2010 )2,204 مري�ضا(. مت اأخذ عينة ع�ضوائية من 520 مري�ضا لدرا�ضة معدل انت�ضار مر�س ال�ضكري بينهم. متت درا�ضة النتائج املختربية لفح�س ال�ضكري لتحديد وجود املر�س. النتائج: مت إدراج 376 مري�ضا بفقر الدم املنجلي وكانت �ضجلتهم الطبية كاملة يف الدرا�ضة. وجد أن24 مريضا منهم %6.4 م�ضابون بال�ضكري. كان معدل انت�ضار داء ال�ضكري يف مر�ضى فقر الدم املنجلي بعد �ضبط النتائج بناء على العمر واجلن�س هو8.3%. اخلال�صة: يف حني اأّن معدل انت�ضار داء ال�ضكري يف املر�ضى امل�ضابني بفقر الدم املنجلي يف البحرين و�ضل إيل ن�ضبة عالية، اإاّل اأنها اأقل من املتوقع يف هذه الفئة ال�ضكانية. هذا ي�ضري اإىل احتمالية وجود تاأثري وقائي ملر�س فقر الدم املنجلي نحو االإ�ضابة بداء ال�ضكري. ولكن مع ذلك، فاإّن تاأثري هذين املر�ضني ال�ضلبي على االإ�ضابة باأمرا�س االأوعية الدموية ي�ضري اإىل اأهمية الفح�س املربمج والعلج الوقائي لهذه العوامل يف هذه الفئة من املر�ضى. ِرّي؛ مر�س فقر الدم املنجلي؛ مدى االْنِت�ضار؛ الَوباِئيَّات؛ املرا�ضة امل�ضرتكة؛ اأمرا�س االأوعية الدموية؛ البحرين. كَّ مفتاح الكلمات: ال�ضُّ does sickle cell disease protect against diabetes mellitus? cross-sectional study *ali a. mohamed,1 fathia al-qurashi,2 david l. whitford3 sickle cell disease (scd) is one of the most common inherited haemoglobinopathies.1 the leading cause of death among patients with scd has changed from infections to chronic cardiopulmonary complications.2 diabetes mellitus (dm) is a major risk factor for cardiovascular diseases, accounting for an increased risk of myocardial infarctions or strokes.3 in addition, dm patients are predisposed to complications that are also associated with scd, including infections, renal failure and retinopathy. fortunately, research has indicated that the co-existence of type 1 and type 2 dm with scd is rare; several studies have found no cases of dm at all among scd patients.4,5 a large multi-centre study, carried out in 31 centres in the usa, canada and the uk, revealed that only 2% of blood-transfused scd patients also had dm.6 bahrain has a population of approximately 1.2 million, although around 50% are expatriates.7 the country has a high prevalence of both dm and scd, ranking fifth in the world for dm at 15.8%.8 the prevalence of scd in bahrain was 2.1% in 1987,9 but this prevalence had decreased by 1.3% in 2008.10 both diseases present considerable challenges to the national healthcare system.11,12 the co-existence of these two conditions in a population where both are highly prevalent has not been previously studied. therefore, this preliminary study aimed to explore whether patients with scd have the same prevalence of dm as the general population in bahrain. brief communication ali a. mohamed, fathia al-qurashi and david l. whitford brief communication | e117 methods the medical records of all patients with scd aged 18 years and over who were admitted to the salmaniya medical complex in manama, bahrain, between january 2003 and december 2010 were included in this study (n = 2,204). the salmaniya medical complex is the single government sickle cell service available in the country. the majority of patients attending this clinic are of arab descent. based on the population size, a random sample of 327 patients was calculated as the minimum sample required to establish the prevalence of dm with a 5% margin of error. in order to allow for missing medical records and data, a computer-generated random sample of 520 subjects was taken. however, 26 patients (5%) were subsequently found not to have scd based on their haemoglobin electrophoresis results. these patients were therefore removed from the sample (n = 494). data from the patients’ medical records were collected, including age, gender, fasting blood sugar levels, random blood sugar levels, glucose tolerance test results and haemoglobin electrophoresis (haemoglobin s and fetal haemoglobin percentages). laboratory data from other governmental health centres and hospitals in bahrain were accessed through a centralised repository. patients were categorised into the following four groups according to the world health organization’s (who) diagnostic criteria for dm: diagnosed or undiagnosed dm; impaired fasting glucose and/ or impaired glucose tolerance (also known as prediabetes); no dm, or unknown dm status due to insufficient or missing blood results.13 among the patients included in the study, dm was ruled out by two normal readings of fasting or random blood glucose levels on two separate days. haemoglobin a1c levels were not used to either establish or rule out a diagnosis of dm, as these measurements are unreliable in patients with haemoglobinopathies such as scd.14 a total of 118 patients (22.7%) had insufficient data in their medical records to establish their diabetic status. these patients were therefore excluded from the analysis, resulting in a final sample of 376. the study sample was statistically compared to data from the 2010 census of the bahraini population in order to establish the ageand sex-standardised prevalence of dm in the sample.7 data were analysed using jmp-in®, version 9 (sas institute inc., cary, north carolina, usa) with descriptive statistics and non-parametric tests of association. ethical approval for this study was granted by the research ethics committee of the royal college of surgeons in ireland (rcsi) medical university of bahrain, as well as the research technical support team of the bahraini ministry of health and the research committee of salmaniya medical complex. results there were 376 scd patients with complete records. the mean age was 33.5 ± 11.2 years (range: 18–79 years). there were 196 male patients (52.1%) among the cohort, which was consistent with the gender ratio of the general bahraini population (1.07 versus 1.01, respectively; p = 0.47).7 however, the sample had a lower proportion of individuals aged >55 years in comparison to the general bahraini population (4.4% versus 9.8%, respectively; p <0.001). the mean number of hospital admissions was 14.5 ± 24.4 with a range of 1–195 admissions. of the final sample, 24 scd patients (6.4%) were determined to have either type 1 or type 2 dm. a total of 11 patients had previously been diagnosed with dm and their diagnosis was confirmed by recent glucose measurements. a further 13 patients had sufficiently raised blood glucose levels to establish a diagnosis of dm according to who criteria. in addition, 32 patients (8.5%) were found to have impaired fasting glucose or impaired glucose tolerance. as expected, the prevalence of dm rose with age (χ2 = 42.9; degrees of freedom [df ] = 2; p <0.0001). the prevalence of dm in patients aged ≥40 years was 16.4% (17 out of 103 patients). the ageand sex-standardised prevalence of dm was 8.3% while impaired glucose tolerance/impaired fasting glucose was 11.0%. no association was found between dm and gender (χ2 = 1.5; df = 2; p = 0.47) or number of hospital admissions (χ2 = 2.2; df = 2; p = 0.34). discussion previous studies have found low or non-existent rates of dm in patients with scd.4‒6 this has led to the hypothesis that scd may inhibit the inheritance or the development of dm through a genetic mechanism.15 alternative explanations include the lowered life expectancy of scd patients, which reduces the likelihood of overt dm developing over time,15 or the increased frequency of illnesses among scd patients population, which leads to an underweight population with a lower predisposition to dm.16 a high ageand sex-standardised prevalence of dm was found among the studied bahraini patients with scd (8.3%). however, this was still lower than the expected prevalence (15.4%) among the general does sickle cell disease protect against diabetes mellitus? cross-sectional study e118 | squ medical journal, february 2015, volume 15, issue 1 population of bahrain [figure 1].8,17 despite this, the prevalence of dm among the studied cohort was not as uncommon as other studies based outside of bahrain have indicated.4–6 the prevalence of dm in the general bahraini population aged ≥40 years is approximately 30%,17 as can be seen in figure 1, this is almost double the rate of dm that was observed among scd patients of the same age category in the current study. lower life expectancy was excluded as an explanation for the lower prevalence of dm in these scd patients by statistical adjustments of age. however, decreased rates of obesity in the scd population may be responsible for the low observed prevalence of dm. subsequent matched case-control or cohort studies are recommended in order to establish an age-, sex and body mass index-adjusted prevalence for dm in patients with scd in bahrain and the gulf. although the prevalence of dm among the studied cohort was lower than expected, the rate of dm found among the studied scd patients is still high enough to raise concerns about the potential impact of these two co-existing conditions on the development of cardiovascular disease. to the best of the authors’ knowledge, no published studies have yet observed that the occurrence of scd alongside dm leads to poorer outcomes; however, the coexistence of vascular risk factors (e.g. hypertension or smoking) could theoretically lead to further increased vascular risk. as a result, there may be a need for both structured screening programmes and the aggressive treatment of vascular risk factors in this population. furthermore, additional research is recommended to identify the potential factors of scd which may have a protective effect against the development of dm. this study was undertaken as a preliminary study to determine whether the lower prevalence of dm in patients with scd established in several previous studies would be reflected in this highly prevalent bahraini population.4–6 the results of this rapid and costeffective study shed light on the potential protective effect of scd over dm. nonetheless, the results should be interpreted in light of several limitations. while the selection of a nationally-representative sample was assured due to the existence of a single centre in bahrain serving all patients with scd, the study was retrospective in nature and therefore limited to patients with hospital admissions—however, it is probable that most adults with scd would have been admitted at least once during the seven-year study period. as a result, a portion of the population with milder scd may have been excluded, leading to a selection bias. this bias may have led to an underestimation of the dm prevalence. in addition, this study was also dependent on available laboratory glucose results; any recently developed symptoms of dm may have been missed, thereby potentially resulting in an underestimation of the prevalence. furthermore, since it was not possible to obtain sufficient data to establish patients’ body mass indexes, a link between lower rates of obesity and a lower prevalence of dm among the scd could not be excluded. data regarding any medications were also not obtained and this may have led to an additional underestimation of the dm prevalence. moreover, other confounding factors, including ethnicity, were not accounted for. it would be of interest to establish whether other cardiovascular risk factors, such as hypertension and hyperlipidaemia, are less prevalent in patients with scd. in spite of these limitations, this is the first study of its kind in a population with a high prevalence of both dm and scd and adds to the existing literature that suggests a lower prevalence of dm among patients with scd. conclusion while the prevalence of dm among the studied scd patients in bahrain was high (8.3%), it was lower than expected among this population. lower rates of obesity in this population may be responsible for the low observed prevalence of dm. alternatively, there may be a genetic or epigenetic protective effect of scd towards the development of dm. nevertheless, the impact of these two conditions on the development of vascular disease suggests a need for screening and the aggressive treatment of vascular risk factors in this population. figure 1: comparison of the ageand sex-adjusted prevalence of diabetes found among the studied sickle cell disease cohort in bahrain (n = 376) with the prevalence of diabetes among the general population in bahrain. *data sourced from international diabetes federation. idf diabetes atlas: fourth edition8 and al-mahroos, mckeigue pm. high prevalence of diabetes in bahrainis: associations with ethnicity and raised plasma cholesterol.17 ali a. mohamed, fathia al-qurashi and david l. whitford brief communication | e119 a c k n o w l e d g e m e n t s this study was presented in abstract form as a poster at the international diabetes federation world diabetes congress in melbourne, australia, in december 2013 (p-1860). the abstract was also presented orally at the international conference on sickle cell disease management & prevention in manama, bahrain, in february 2013. this study received the rcsi alumni research award in july 2010. the authors would like to thank the departments of medical records and laboratory services at salmaniya medical complex for access to and help in retrieving patients’ records. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. steinberg mh. in the clinic: sickle cell disease. ann intern med 2011; 155:itc31–15. doi: 10.7326/0003-4819-155-5-201109 060-01003. 2. fitzhugh cd, lauder n, jonassaint jc, telen mj, zhao x, wright ec, et al. cardiopulmonary complications leading to premature deaths in adult patients with sickle cell disease. am j hematol 2010; 85:36–40. doi: 10.1002/ajh.21569. 3. almdal t, scharling h, jensen js, vestergaard h. the independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. arch intern med 2004; 164:1422–6. doi: 10.1001/archinte.164.13.1422. 4. morrison jc, schneider jm, kraus ap, kitabchi ae. the prevalence of diabetes mellitus in sickle cell hemoglobinopathies. j clin endocrinol metab 1979; 48:192–5. doi: 10.1210/jcem-482-192. 5. reid hl, photiades dp, oli jm, kaine w. concurrent sickle cell disease and diabetes mellitus. trop geogr med 1988; 40:201–4. 6. fung eb, harmatz pr, lee pd, milet m, bellevue r, jeng mr, et al. increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. br j haematol 2006; 135:574–82. doi: 10.1111/j.1365-2141.200 6.06332.x. 7. bahrain census department. 2010 census. from: www. census2010.gov.bh/results_en.php accessed: aug 2014. 8. international diabetes federation. idf diabetes atlas: fourth edition. from: www.idf.org/sites/default/files/idf-diabetesatlas-4th-edition.pdf accessed: apr 2014. 9. al arrayed ss, haites n. features of sickle-cell disease in bahrain. east mediterr health j 1995; 1:112–19. 10. al arrayed ss. prevalence of abnormal hemoglobins among students in bahrain: a ten-year study. bahrain med bull 2011; 33:19–21. 11. al-baharna mm, whitford dl. clinical audit of diabetes care in the bahrain defence forces hospital. sultan qaboos univ med j 2013; 13:520–6. 12. tawfic qa, kausalya r, al-sajee d, burad j, mohammed ak, narayanan a. adult sickle cell disease: a five-year experience of intensive care management in a university hospital in oman. sultan qaboos univ med j 2012; 12:177–83. 13. alberti kg, zimmet pz. definition, diagnosis and classification of diabetes mellitus and its complications: part 1: diagnosis and classification of diabetes mellitus, provisional report of a who consultation. diabet med 1998; 15:539–53. doi: 10.1002/ (sici)1096-9136(199807)15:7<539::aid-dia668>3.0.co;2-s. 14. world health organization. use of glycated haemoglobin (hba1c) in the diagnosis of diabetes mellitus. from: www. who.int/diabetes/publications/diagnosis_diabetes2011/en/ accessed: apr 2014. 15. mohapatra mk. type 1 diabetes mellitus in homozygous sickle cell anaemia. j assoc physicians india 2005; 53:895–6. 16. bays he, chapman rh, grandy s; shield investigators’ group. the relationship of body mass index to diabetes mellitus, hypertension and dyslipidaemia: comparison of data from two national surveys. int j clin pract 2007; 61:737–47. doi: 10.1111/j.1742-1241.2007.01336.x. 17. al-mahroos f, mckeigue pm. high prevalence of diabetes in bahrainis: associations with ethnicity and raised plasma cholesterol. diabetes care 1998; 21:936–42. doi: 10.2337/ diacare.21.6.936. squ med j, may 2012, vol. 12, iss. 2, pp. 137-152, epub. 9th apr 2012 submitted 29th nov 11 revision req. 21st feb 12, revision recd. 27th feb 12 accepted 13th mar 12 over the past decade substantial advances have been made in understanding the biological and molecular mechanisms of chronic lymphocytic leukaemia (cll). the evaluation of new chemotherapeutic combinations has led to an increase in the rate of complete remission in patients with cll. in addition, the use of monoclonal antibodies such as rituximab and alemtuzumab has added substantial benefit when combined with chemotherapy.1,2 however, the ability to eradicate disease at a molecular level, and improve clinically relevant patient outcome measures, continue to pose difficult challenges. regardless of the stage of the disease, most patients will relapse after initial treatment and become refractory to salvage chemotherapy with median overall survival ranging from 10 to 19 months.3,4 thus, the need to develop alternative therapies to kill leukaemic cells, or to fight relapse, remains a hot topic under intense investigation. targeting cell-surface molecules present on leukaemic b-cells with t-cells transfected with chimeric antigen receptors (car) may be an attractive immunotherapeutic strategy to reduce the leukaemic cell burden. car can be engineered by combining an antigen-specific monoclonal antibody using its variable chain fragments with a t-cell activating signalling receptor in a single fusion protein.5 once this modified protein is expressed on the surface of a t-cell, and binds to its specific antigen, an activation signal is transmitted into the t-cell. this latter will trigger its effector functions to lyse the target cell. typically, t-cells expressing car react like conventional t-cells, but attach to the target antigen by the variable chain fragments of the monoclonal antibody, and so are named t-bodies. since its first description, car design has evolved over the years with the goal of enhancing t-cell signalling functions [figure 1]. the first generation of car consisted of heavy and light chain immunoglobulin variable regions fused in a single chain and coupled to signalling modules, which are normally present in the t-cell receptor complex such as the cd3zeta-chain.6 this first generation of car effectively redirected t-cell cytotoxicity, but failed to enable t-cell proliferation and survival upon repeated antigen exposure, and anti-tumour responses were limited.7 the second generation of car incorporated another signalling receptor from co-stimulatory molecules such as cd28, cd134 or cd137 to reduce activation-induced cell death and improve t-cell survival. the third generation of car incorporated two co-stimulatory molecules: cd28, cd134 or cd137 in a sequence fused to cd3-zeta chain and were designed to further enhance killing functions, proliferation capacities and production of survival cytokines such as interleukin-2.7,8 compared to classical t-cell-based immunotherapies, t-cells expressing-car present several attractive advantages including obviating the need for recognising peptide presentation by major histocompatibility complex, the ability to target a range of tumour surface antigens, and relatively division of hematology, royal victoria hospital, mcgill university health centre e-mail: rachid.boulass@muhc.mcgill.ca سالح ُخلوي جديد لقتل خاليا "ب" املسّببة البيضاض الدم حممد ر�سيد بولع�سل editorial a new cellular weapon to kill leukaemic b-cells mohamed-rachid boulassel a new cellular weapon to kill leukaemic b-cells 138 | squ medical journal, may 2012, volume 12, issue 2 rapid generation within one to four weeks.5,7,8 although the clinical value of genetically engineered t-cells is still to be validated, recent data from two studies reported that car targeting cd19 (cart19) was able to kill leukaemic b-cells expressing this surface antigen and that tumour control was sustained for 10 months following this therapy.9,10 the cart19 was designed to express a single chain variable fragment derived from an anti-cd19 specific antibody along with a cd137 signalling domain and the cd3zeta-chain. t-cells expressing-cart19 were generated by transfecting autologous t-cells from each cll patient with a lentiviral vector, which express the cart19 construct. prior to receiving a low dose of cart19, patients received lymphodepleting chemotherapy with pentostatin and cyclophosphamide and, 4 days later, 1.42 x 107 of engineered cart19 cells were administrated without additional cytokines or monoclonal antibodies. two to three weeks after cart19 immunotherapy, patients developed a tumour lysis syndrome, which correlated positively with an increase in the number of circulating t-cells expressing cart19. three to four days later the tumour lysis syndrome subsided without evidence of disease on physical examination. there was no palpable adenopathy and no evidence of cll in the bone marrow. in addition, computed tomography (ct) scans showed a resolution of adenopathies. six to 10 months following cart19 infusion, two of three subjects showed a complete remission with no residual cll found by means of physical examination, ct scans, flowcytometry and cytogenetic analyses. normal b cells however continued to be lacking. of note, each infused cart19 cell eradicated on average about 1,000 malignant cells. t-cell expressing cart19 underwent robust expansion, persisted at high levels in both circulating blood and bone marrow for at least 6 months and, most importantly, a proportion of these t-cells expressed memory markers and retained anti-cd19 effector functions. as expected the most frequent side effects, in addition to the tumour lysis syndrome, were b-cell lymphopenia and hypogammaglobulinaemia but these undesirable conditions should be manageable in cll patients. overall, these small pilot, prospective, singlecentre studies yielded very encouraging results as two of the three patients enrolled in the clinical trial had p53 gene deletion, which predicts poor survival, non-response to therapy and rapid progression. it also provides a proof of principle that car represents a promising approach to treat cll patients and possibly other b-cell malignancies.11,12 indeed, this therapy resulted in partial remission figure 1: simplified representation of chimeric antigen receptors (car) design. generally, t-cells expressing-car consist of a single chain variable fragments (scfv) from a monoclonal antibody, a transmembrane region (tm) and signaling receptors such as cd3zeta-chain domain (first generation), two signaling domains (second generation) or three signaling domains (third generation). mohamed-rachid boulassel editorial | 139 in a patient with follicular lymphoma for up to 32 weeks.11 in a more recent study, three patients with bulky cll and one patient with b-cell acute lymphoblastic exhibited a response to cart19 containing cd28 as a co-stimulatory molecule 12. accordingly, cart19 is generating substantial enthusiasm and its clinical value will probably be evaluated in large clinical trials. however, one potential concern is that co-stimulatory signals may lead to uncontrolled car t-cell proliferation thereby increasing the long term risk of toxicity by depleting non-tumour cells, which are important for homeostatic functions. it remains to be seen whether the long term side effects of cart19 will be acceptable or not. another major safety issue is the theoretical risk of inducing oncogenic mutations after dna integration of the vector. previous reports have shown the occurrence of t-cell acute lymphoblastic leukaemia in four children treated with gene-transfer stem cells to correct their x-linked severe combined immunodeficiency.13 however, in contrast to haematopoietic stem cells, retroviral vector integration to mature t-cells has been found to be a safe strategy as demonstrated by long-term engraftment of donor lymphocytes genetically engineered with the suicide gene thymidine kinase of herpes simplex virus after allogeneic stem cell transplantation.14,15 treatment with cart19 is an innovative immunotherapeutic approach to target leukaemic b-cells in patients with advanced chemotherapy-resistant cll. certainly, this approach is still in its infancy for clinical use, but it constitutes a new weapon against b-cell neoplasms and potentially a model to further improve the curative potential of cellular therapies in patients for whom conventional therapies have failed. references 1. ahmadi t, maniar t, schuster s, stadtmauer e. chronic lymphocytic leukemia: new concepts and emerging therapies. curr treat options oncol 2009; 10:16–32. 2. quintás-cardama a, wierda w, o’brien s. investigational immunotherapeutics for b-cell malignancies. j clin oncol 2010; 28:884–92. 3. keating mj, o’brien s, kontoyiannis d, plunkett w, koller c, beran m, et al. results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. leuk lymphoma. 2002; 43:1755–62. 4. stilgenbauer s, zenz t, winkler d, bühler a, schlenk rf, groner s, et al. subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the cll2h study of the german chronic lymphocytic leukemia study group. j clin oncol 2009; 27:3994–4001. 5. kohn db, dotti g, brentjens r, savoldo b, jensen m, cooper lj, et al. cars on track in the clinic. mol ther 2011; 19:432–8. 6. gross g, waks t, eshhar z. expression of immunoglobulin-t-cell receptor chimeric molecules as functional receptors with antibody-type specificity. proc natl acad sci u s a 1989; 86:10024–8. 7. sadelain m, brentjens r, rivière i. the promise and potential pitfalls of chimeric antigen receptors. curr opin immunol 2009; 21:215–23. 8. cartellieri m, bachmann m, feldmann a, bippes c, stamova s, wehner r, et al. chimeric antigen receptor-engineered t cells for immunotherapy of cancer. j biomed biotechnol 2010; 2010:956304. 9. porter dl, levine bl, kalos m, bagg a, june ch. chimeric antigen receptor-modified t cells in chronic lymphoid leukemia. n engl j med 2011; 365:725–33. 10. kalos m, levine bl, porter dl, katz s, grupp sa, bagg a, et al. t cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. sci transl med 2011; 3:95–73. 11. kochenderfer jn, wilson wh, janik je, dudley me, stetler-stevenson m, feldman sa, et al. eradication of b-lineage cells and regression of lymphoma in a patient treated with autologous t cells genetically engineered to recognize cd19. blood 2010; 116:4099–102. 12. brentjens rj, rivière i, park jh, davila ml, wang x, stefanski j, et al. safety and persistence of adoptively transferred autologous cd19-targeted t cells in patients with relapsed or chemotherapy refractory b-cell leukemias. blood 2011; 118:4817–28. 13. hacein-bey-abina s, hauer j, lim a, picard c, wang gp, berry cc, et al. efficacy of gene therapy for x-linked severe combined immunodeficiency. n engl j med 2010; 363:355–64. 14. ciceri f, bonini c, marktel s, zappone e, servida p, bernardi m, et al. antitumor effects of hsv-tkengineered donor lymphocytes after allogeneic stem-cell transplantation. blood 2007; 109:4698– 707. 15. recchia a, bonini c, magnani z, urbinati f, sartori d, muraro s, et al. retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted t cells. proc natl acad sci u s a 2006; 103:1457–62. department of physics, college of education, university of mosul, mosul, ninevah, iraq *corresponding author e-mail: faikaazooz@yahoo.com معادلة لوغارمتية لوصف العالقة بني زيادة احلساسية اإلشعاعية عند اجلرع املنخفضة والبقاء عند 2 غراي فائقة عبد الكرمي عزوز و �شوزان خالد ها�شم امللخ�ص: الهدف: تتاأثر احل�شا�شية ال�شعاعية داخلية املن�شاأ امل�شتخدمة عند اجلرع املعتمدة يف العالج الإ�شعاعي بفرط احل�شا�شية الإ�شعاعية و زيادة املقاومة الإ�شعاعية )hrs/irr(عند اجلرع املنخف�شة. يهدف هذا العمل اىل ا�شتك�شاف هذه العالقة. الطريقة: مت حتليل منحنيات البقاء لثمانية ع�رش خط خلوي من خاليا الأورام الب�رشية و ذلك با�شتخدام منوذجني لعملية املالءمة للنقاط العملية من اأجل احل�شول على املوؤ�رشات ال�رشورية ذات العالقة بهذه الدرا�شة. النتائج: ميكن و�شف ن�شبة زيادة املقاومة ال�شعاعية αs/αr مقابل البقاء عند 2 غراي بعالقة لوغارمتية توؤدي اإىل �شل�شة من امل�شتقيمات. اخلال�صة: العالقة امل�شتخل�شة تبني وجود عالقة مبا�رشة بني فرط التح�ش�سزيادة املقاومة الإ�شعاعية والبقاء عند اجلرع املعتمدة �رشيريا وهي 2 غراي. مفتاح الكلمات: فرط التح�ش�س، العالج بالأ�شعة، خط خلوي، ورم، حتليل. abstract: objectives: intrinsic radiosensitivity at doses used in radiotherapy is linked to hypersensitivity (hrs) and increased radio resistance (irr) at low doses. the aim of this study was to explore this relationship. methods: survival curves for 18 human tumour cell lines were analysed, using two models to fit the data points in order to extract the necessary parameters relevant for this study. results: the irr ratio αs/αr versus the survival at 2 gray (gy) can be described by a logarithmic relation which leads to a series of straight lines. conclusion: the relationship obtained implies that there is a direct link between hrs/irr and survival at clinically relevant doses of 2 gy. keywords: hypersensitivity, radiotherapy; cell line; tumor; analysis. a logarithmic formula to describe the relationship between the increased radiosensitivity at low doses and the survival at 2 gray *faika a. azooz and suzan k. hashim clinical & basic research advances in knowledge for the first time, the relationship between the increased radio resistance (irr) αs/αr and the survival at 2 gray (gy) (sf2) has been described by a series of straight lines. this study uses the repairable-conditionally repairable (rcr) model for the first time to extract αs in addition to the inducible repair (ir) model, which is usually applied for this purpose. since the rcr model is statistical in nature, special analysis had to be done in order to extract the hypersensitivity (hrs) parameters αs. to have good fits, the survival curve data points were separated into two parts. the hypersensitivity region part (<1 gy) was fitted to the ir or the rcr model, and the conventional survival curve region (>1gy with the 0 gy point) was fitted to the linear quadratic model. application to patient care the influence of hrs/irr on clinically relevant doses is of great importance in radiation therapy. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 560-566, epub. 8th oct 13 submitted 15th jan 13 revision req. 5th may 13; revision recd. 20th may 13 accepted 4th jul 13 over the last two decades, much attention has been focused on the existence of a hypersensitivity region in the survival curves for many mammalian cells at doses below 0.5 gray (gy). this makes the linear-quadratic (lq) equation inappropriate for use at low doses. this phenomenon, termed hypersensitivity (hrs), precedes the occurrence of relative resistance per unit dose to cell killing by radiation over the dose range ~0.5–1 gy. this latter phenomenon is increased radioresistance (irr). the ratio of the initial slope of the survival curve associated with the hypersensitivity region (αs) to the slope in the shoulder region (αr) is usually a logarithmic formula to describe the relationship between the increased radiosensitivity at low doses and the survival at 2 gray 561 | squ medical journal, november 2013, volume 13, issue 4 used as a metric in the analysis of the hrs/irr phenomenon. the hrs/irr phenomenon has been found in different types of cell lines, both in vivo and in vitro. the former includes cell lines from plants, bacteria and mammals. the latter mostly involve human tumour cell lines.1–5 many researchers have tried to explain this phenomenon depending on the analysis of cell phase or gene structure, while others have tried to study the influence of this phenomenon on dose fractionation in radiotherapy by analysing survival curve parameters.1,6,8,10–14 explanations of this phenomenon are still regarded as matters of controversy. the use of mathematical equations to extract useful parameters to be applied in radiotherapy procedures is very important. in the case of hrs/ irr curves, there is always a need to establish a relation between αs/αr and the survival at 2 gy (sf2), which is clinically relevant. those attempting to develop a standard equation to be used in such a procedure have been faced with difficulties related to an inadequate or poorly fitting equation, colony assays being unreliable at low doses, and the difference in the new technology methods that are used to identify the position of the plated cells such as the fluorescence-activated cell sorting method (facs) and the dynamic microscope image processing scanner method (dmips).12 in order to make it possible to fit the hypersensitivity survival curves to a model and extract useful parameters for the analysis, the lq model was modified by joiner and johns.15 this new model, the inducible repair (ir) model, involves two new parameters in addition to α and β in the original lq model. these parameters are αs which is a measure of the initial slope in the low dose region and the dc parameter which represents the dose at which the inflexion occurs from hrs to irr. the α parameter in the lq model, termed αr in this model, defines the slope in the shoulder region. the most common inducible repair (ir) model equation is given by: s = exp (– αr 1 + (α / αr -) e –d/dc) d – βd2) [equation 1] where s is the survival fraction, d is the dose and αs, αr and dc as defined above. 12 equation 1 has been used extensively to fit the hrs/irr curves, with varying goodness of fit results. another equation based on statistical analysis has been put forward to describe hrs/irr data. this equation does not give αs and αr directly. consequently, it is not used as commonly in αs/αr analysis. the model that adopts this equation is called the repairable-conditionally repairable (rcr) model and is described by: s(d) = e – ad + bde – cd [equation 2]16 to overcome some of the obstacles that prevent obtaining reliable values for αs/αr and for sf2 to be used in establishing the relationship between them, we have chosen to fit a set of survival curves that belong to human tumour cell lines to equations 1 and 2 in order to obtain smooth curves that reasonably describe all survival data with the aim of finding a relation between αs/αr and sf2. methods a set of 18 survival curves related to various kinds of human tumour cell lines were compiled from the literature.7,17–25 data points and their error bars were obtained using programming techniques described in previous work.26 each survival data set for a given cell line were fitted to the ir model and the rcr model using all data points on the curve. the fit results did not prove to be satisfactory in most cases. this was particularly evident in the case of the ir model. however, fits carried out using the hrs/ irr part of the survival curve produced acceptable results. this part is represented by the region of 0–1 gy or slightly higher in very few cases. the other part of the survival curve (>1 gy) together with the 0 gy dose represents the conventional survival curve with no hrs/irr region. this was fitted to the lq equation. the criteria used for considering the fit acceptable involved having the fitted curve as close as possible to data points with small residuals values. in addition, the residuals distribution should be of the random type narrowly centred near zero. the fulfillment of these criteria was checked by having the sum of squares error (sse) and the root mean square error (rmse) being close to zero, and r2 and the adjusted r2 (ajr) are very close to 1. a problem arises when handling cases with survival curves data points which are randomly distributed. these cannot be described by a smooth curve. such cases are usually associated faika a. azooz and suzan k. hashim clinical and basic research | 562 with small fractional doses arising from the difficulty in measuring small changes in survival. in these cases, the curve-fitting procedure becomes fruitless. in order to overcome this problem, some data treatment becomes necessary. the treatment employed involves constrained data smoothing. this is performed using the matlab library routine “smooth”, which uses a successive averaging method. in addition, one constraint was added on the smoothing process. the constraint was that no smoothed data point was to move during the smoothing process beyond its error-bar boundaries. this process was similar to weighting the data points, but it was found that the smoothing method gave better results. the other problem was that the rcr model is statistical in nature; thus, it does not give the required physical parameters directly as is the case with the the ir model. this problem was solved by finding the first derivative on the survival curve at the initial slope which represents αs, and the first minimum value of the survival followed by increase of survival defined as dc. the α parameter from the lq fit was used as αr. whether one is using either the ir model or the rcr model, this treatment is considered justified since the ir model is not efficient enough to control the hrs/irr region and the conventional part of the survival curve at the same time. the same argument applies in the case of the rcr model, which is better at describing the data than the former in spite of its statistical nature. results the fitting results from the models ir, rcr, and lq for various cell lines are shown in table 1. the first column in table 1 gives the cell lines. columns 2, 3 and 4 represent the αs, αr and dc parameters that were obtained by selecting the best fits to the region 0–1 gy when using the ir model. columns 5 and 6 represent the αs and dc parameters that were derived from the best fits to the rcr model table 1: best fits parameters from inducible repair, repairable-conditionally repairable and linear-quadratic models cell lines parameters obtained from best fits to the ir model derived parameters from best fits to the rcr model parameters obtained from best fits to the lq model αr (gy -1) αs (gy -1) dc (gy) αs (gy -1) dc (gy) α (gy-1) sf2 derived rt112 (18) 0.27 ± 0.00 1.07 ±0.21 0.29 ± 0.06 0.99 0.47 0.17 ± 0.50 0.62 ags (19) 0.24 ± 0.00 1.30 ± 0.19 0.39 ± 0.07 1.19 0.5 0.42 ± 0.05 0.45 pc3 (19) 0.77 ± 0.00 0.68 ± 0.17 0.44 ± 0.12 0.66 0.51 0.27 ±0.07 0.52 t98g (20) 0.39 ±0.00 0.84 ±0.34 0.45 ± 0.29 0.74 0.56 0.15 ± 0.02 0.69 be11 (7) 0.16 ± 0.00 1.37 ± 0.19 0.25 ± 0.04 1.294 0.39 0.16 ± 0.03 0.68 a549 (19) 0.82 ± 0.00 1.26 ± 1.32 0.16 ± 0.12 1.02 0.32 0.20 ± 0.06 0.71 bmg1 (21) 5 19.55 ± 7.36 0.08 ± 0.02 14.27 0.09 0.10 ± 0.10 0.81 du145 (22) 0.38 ± 0.00 0.54 ± 0.19 0.32 ± 0.12 0.49 0.4 0.17 ± 0.01 0.64 t98g (17) 0.29 ± 0.00 1.28 ± 0.62 0.13 ± 0.04 0.89 0.18 0.08± 0.03 0.73 ht-29 (23) 0.21 ±0.00 0.98 ± 0.11 0.23 ± 0.02 0.88 0.28 0.07 ± 0.01 0.71 mewo (23) 0.38 ± 0.00 1.00 ± 0.97 0.46 ± 0.68 0.83 0.63 0.25 ± 0.02 0.27 peca4197 (21) 0.29 ± 0.00 4.61 ± 0.87 0.35 ± 0.06 4.16 0.32 0.12 ± 0.00 0.64 peca4451 (21) 0.30 ± 0.00 2.93 ± 0.09 0.37 ± 0.12 2.63 0.38 0.40± 0.0624 0.65 bj (24) 0.31 ± 0.00 1.28 ± 0.73 0.85 ± 0.50 1.18 1.1 0.28 ± 0.09 0.57 scc-61 (25) 0.1 ± 0.00 1.41 ± 0.61 0.8 fixed 0.87 0.8 0.47 ± 0.09 0.30 sq20b (25) 0.5 fixed 0.69 ± 0.21 0.63 ± 0.17 0.51 0.65 0.03 ± 0.01 0.88 u1 (22) 0.70 ± 0.00 0.18 ± 0.04 0.11 ± 0.02 0.061 0.32 0.001 ± 0.011 0.92 u87 (21) 0.20 ± 0.00 10.35 ± 3.06 0.22 ± 0.05 9.211 0.19 0.70 ± 0.40 0.57 ir = inducible repair; rcr = repairable-conditionally repairable; lq = linear-quadratic; gy = gray. a logarithmic formula to describe the relationship between the increased radiosensitivity at low doses and the survival at 2 gray 563 | squ medical journal, november 2013, volume 13, issue 4 in the region of 0–1 gy using the first derivative method mentioned above to obtain αs and the first minimum point on the curve to get dc. the last two columns in this table represent the αr and the sf2 values that were obtained from fitting the survival curve data in the region >1 gy together with the 0 gy to the lq model. figure 1 shows an example of the fit for the three models for the cell line rt112. when αs/αr against sf2 are plotted on a linear scale, the data points are distributed randomly. however, when the αs/αr for the best fit results from the rcr model and the lq model are plotted on a logarithmic scale against sf2, the data points become grouped in three straight lines intersecting at one point. good straight line fits for all three lines are obtained by fitting the data to the equation: log (y) = ax + b [equation 3] the results of such fits are shown in figure 2a with the dashed blue line representing the cells ags, u87, peca4197, bmgi; the solid red line representing the cells pc3, bj, rt112, peca4451, ht-29, u1, gt98, be11, and the dotted green line representing the cells du145, t98g, a549, sq20b. only two cell lines did not fit to any of these lines. these are the mewo and scc61 data. one possible explanation is that they could perhaps belong to other lines. furthermore, the survival data points for t98g were taken from two experiments and there seems to be significant differences between the two.17,20 one group fitted well with the solid red line while the other group fitted well to the dotted green line.17,20 figure 1. survival curve fits for rt112 cell line to the lq, ir, and rcr models.18 the upper right figure is a magnified portion for ir and rcr fits in the hypersensitivity region. lq = linear-quadratic; rcr = repairable-conditionally repairable; ir = inducible repair; gy = gray. figure 2 a & b. fitted lines to equation 3. a: using αs from best fits to the repairable-conditionally repairable (rcr) model and αr from best fits to the linear-quadratic (lq) model, and b: using αs derived from fitting smoothed and non-smoothed data to the rcr model and αr from fitting smoothed and non-smoothed data to the lq model. faika a. azooz and suzan k. hashim clinical and basic research | 564 in order to exclude the possibility that the data points were not biased by the smoothing process, we plotted the combined data values of αs/αr from both the rcr model and the lq model. in this case, a set of 4 values of αs/αr for each sf2 value was obtained. these were αs smoothed/αr smoothed, αs non-smoothed/αr non-smoothed, αs smoothed/αrnon-smoothed and αs non-smoothed/ αr smoothed. similar results were obtained, as seen in figure 2b. the procedure was repeated for the case of the ir model (i.e. αs was taken from the ir model fits and αr values were taken from the lq model fits). the results that correspond to figures 2a and b in the rcr model are shown as figures 3a and b for the ir model case. the three straight lines obtained were also fitted to equation 3. the results of fits indicate that the values of the parameters a and b in the case of the ir model are slightly higher than those in the case of the rcr model. the final cross-check employed involved plotting all the data points from both models (8 values of αs/ αr for each sf2 value). self-consistent results were obtained as shown in figure 4. the fitted a and b parameters obtained by fitting equation 3 to the lines shown in figures 2–4 are shown in table 2, with columns 2 and 3 represent the dashed blue line (line 1) parameters, columns 4 and 5 represent the solid red line (line 2) parameters and columns 6 and 7 represent the dotted green line (line 3) parameters. discussion as seen from table 2, all fits gave very close results for the a and b parameters. this was independent of whether the αs was taken from the ir model fits or the rcr model fits, or when the αs from the ir and the rcr fits were amalgamated. in all cases, the a figure 3 a & b. fitted lines to equation 3. a: using αs from best fits to the inducible repair (ir) model and αr from best fits to the linear-quadratic (lq) model, and b: using αs derived from fitting smoothed and non-smoothed data to the ir model and αr from fitting smoothed and non-smoothed data to the lq model. table 2: the a and b parameters obtained from fitting lines 1–3 to the equation ± standard deviation data type fitting parameters for line 1 fitting parameters for line 2 fitting parameters for line 3 a b a b a b αs from best rcr fit/αr from best lq fit 4.30 ± 0.85 -1.32 ± 0.53 3.20 ± 0.25 -1.26 ± 0.17 2.85 ± 0.62 -1.33 ± 0.45 αs from all rcr fit/αr from all lq fit 4.60 ± 0.19 -1.52 ± 0.12 3.53 ± 0.21 -1.47 ± 0.14 3.15 ± 0.26 -1.53 ± 0.19 αs from best ir fit /αr from best lq fit 4.76 ± 0.64 -1.55 ± 0.40 4.09 ± 0.39 -1.74 ± 0.26 3.04 ± 0.69 -1.37 ± 0.51 αs from all ir fit/αr from all lq fit 4.99 ± 0.36 -1.77 ± 0.23 4.06 ± 0.31 -1.75 ± 0.20 3.02 ± 0.32 -1.35 ± 0.23 αs from all data fit/αr from all lq fit 4.73 ± 0.23 -1.58 ± 0.15 3.81 ± 0.18 -1.60 ± 0.12 2.97 ± 0.36 -1.35 ± 0.26 rcr = repairable-conditionally repairable; lq = linear-quadratic; ir = inducible repair. a logarithmic formula to describe the relationship between the increased radiosensitivity at low doses and the survival at 2 gray 565 | squ medical journal, november 2013, volume 13, issue 4 and b values obtained proved to be consistent. the results confirmed the log-linear relation between αs/αr and sf2. this represents a diversion from the method suggested by dasu and kamp which involved plotting αs/αr on a linear scale. 12 in their work, an attempt to find a linear relation resulted in inadequate fits. it may be worth mentioning, however, that their work involved the use of data for different cell lines while only human tumour cell lines were used in the present work. furthermore, the procedure used by dasu and kamp depended on the ir model which fits the hrs/irr part of the survival curve only but fails to fit the conventional part (>1gy) in a one-fit process. the present work involved fitting each part separately, helping to give more precise values for the fit parameters. also, joiner et al. used published data to find a relation between αs/αr and sf2. 1 their results showed some kind of logarithmic linear relationship but no fitting was provided. this may be due to the interference between the human tumour cell lines and other cell lines which makes the picture less clear. it may thus be argued that the use of logarithmic procedure can be important in radiotherapy. this is due to the fact that the intrinsic radiosensitivity at clinically relevant doses is directly linked to the cell’s ability to mount an adaptive response as a result of exposure to very low doses of radiation. the survival at 2 gy doses, which is usually used in dose fractionation, is believed to be affected by the hrs/irr phenomenon. it may cause the tumour to grow again. so, a revision of dose fractionation is required with the need to study each cell line separately. conclusion precisely fitting parameters that describe the hrs at low doses of radiation αs and the survival in the shoulder region αr are obtained by dividing the survival curve data points into two groups. the first group (<1 gy) fits well to the ir and the rcr models. the second group (>1 gy plus 0 gy point) fits well to the lq model. the αs/αr ratio plotted on a logarithmic scale against the survival at 2 gy as a linear scale displays a series of straight lines. the lines are well-fitted to a logarithmic-linear relation with two parameters a and b with good quality fits. the relations obtained imply that there is a direct link between the hrs/irr ratio and the survival at the clinically relevant dose of 2 gy. references 1. joiner mc, marples b. low-dose hypersensitivity current status and possible mechanism. int j radiat oncl biol phys 2001; 49:379–89. 2. joiner mc, johns h. renal damage in the mouse: the response to very small doses per fraction. radiat res 1988; 114:385–98. 3. marples b, skov ka, joiner mc. the effect of oxygen on low-dose hypersensitivity and increased radio resistance in chinese hamster v79-379 a cells. radiat res 1994; 198:s17–20. 4. böhrnsen g, weber kj, scholz m. low dose hypersensitivity and resistance of v97 cells after charge particle irradiation using 100µev/u carbon ions. radiat prot dosimetry 2002; 99:255–6. 5. schettino g, folkard m, prise km, vojnovic b, bowey ag, michael bd. low-dose hypersensitivity in chinese hamster v79 cells target with counted protons using a charged-particle microbeam. radiat res 2001; 156:526–34. 6. zhao yx, cui ys, han j, ren jh, wu g, cheng j. cell division cycle 25 homolog c effects on low-dose hyperradiosensitivity and induced radioresistance at elevated dosage in a549 cells. j radiat res 2012; 53:686–94. 7. lambin p, fertil b, malaise ep, joiner mc. mutiphasic survival curves for cells of human tumor cell lines: induced repair or hypersensitivity subpopulation? radiat res 1994; 138:s32–6. 8. nakayama m, kaida a, deguchi s, sakaguchi k. figure 4: fitted lines to equation 3 using αs from smoothed and non-smoothed fits to the inducible repair (ir) model and the repairable-conditionally repairable (rcr) model and αr from smoothed and non-smoothed fits to the linear-quadratic (lq) model. faika a. azooz and suzan k. hashim clinical and basic research | 566 radiosensitivity of early and late m-phase hela cells isolated by a combination of fluorescent ubiquitination-based cell cycle indicator (fucci) and mitotic shake-off. radiat res 2011; 176:407–11. 9. marples b, woutersb bg, joiner mc. an association between the radiation–induced arrest of g2-phase cells and low–dose hypersensitivity: plausible underlying mechanism? radiat res 2003; 160:38–45. 10. agui t, miyamoto t, jung cg, masuda k, manabe t. genetic linkage analysis of x-ray hypersensitivity in the lec mutant rat. mamm genome 2000; 11:862– 5. 11. joiner mc, wilson gd, mccullough w, price me, logana i, jones h, et al. a novel human stress response-related gene with a potential role in induced radio resistance. radiat res 1999; 152:451– 61. 12. dasu a, kamp jd. inducible repair and intrinsic radiosensitivity: a complex but predictable relationship. radiat res 2000; 153:279–88. 13. smith lg, miller rc, richards m, brenner dj, hall ej. investigation of hypersensitivity to fractionated low-dose radiation exposure. int j radiat oncol biol phys 1999; 45:187–91. 14. gupta s, koru-segul t, arnold sm, devi gr, mohiuddin m, ahmed mm. low-dose fractionated radiation potentiates the effects of cisplatin independent of the hyper-radiation sensitivity in human lung cancer cells. mol cancer ther 2011; 10:292–302. 15. joiner mc, johns h. renal damage in the mouse: the response to very small doses per fraction. radiat res 1988; 114:385–98. 16. linda bk, persson lm, edgren mr, hedlof i, brahame a. repairable conditionally repairable damage model based on dual poisson processes. radiat res 2003; 160:366–75. 17. short sc, bourne s, martindale c, woodcock m, jackson p. dna damage responses at low radiation doses. radiat res 2005; 164:292–302. 18. joiner mc, lambin p, malaise ep, robson t, arrand je, skov ka, et al. hypersensitivity to very-low single radiation doses: its relationship to the adaptive response and induced redioresistance. mutat res 1996; 358:171–83. 19. balcer-kubiczek ek, attarpour m, wang jz, regine wf. the effect of docetaxel (taxotere ®) on human gastric cancer cells exhibiting low-dose radiation hypersensitivity. clin med oncol 2008; 2:301–11. 20. short s, mayes c, woodcock m. low dose hypersensitivity in the t98g human glioblastoma cell line. int j radiat biol 1999; 75:847–55. 21. chandna s, dwarakanuth bs, khaitan d, mathew lt, jain v. low-dose radiation hypersensitivity in human tumor cell lines: effect of cell-cell contact and nutritional deprivation. radiat res 2002; 157:516– 25. 22. wouters bg, sy am, skarsgard ld. low-dose hypersensitivity and increased radioresistance in a panel of human tumor cell lines with different radiosensitivity. radiat res 1996; 146:399–413. 23. lambin p, coco-martin j, legal jd, begg ac, parmentier c, joiner mc, et al. intrinsic radiosensitivity and chromosome aberration analysis using fluorescence in situ hybridization in cells of two human tumor cell lines. radiat res 1994; 138:s40–3. 24. nuta o, darroudi f. the impact of the bystander on the low-dose hypersensitivity phenomenon. radiat environ biophys 2008; 47:265–74. 25. dey s, spring pm, arnold sm, valentino j, chendil d, regine wf, et al. low dose fractionated radiation potentiates the effects of paclitaxel in wild-type and mutant p53 head and neck tumor cell line. clin cancer res 2003; 9:1557–65. 26. azooz f, meerkhan s. phenomenological explanation of cell inactivation cross section in terms of direct and indirect action. squmj 2010; 10:319–23. omayma t. el-shafie, samir hussain, dilip sankhla and nicholas woodhouse online case report | e571 departments of 1medicine and 2radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: omayma0@hotmail.com in 1869, hickman reported the first case of lingual ectopic thyroid, which is the most common type of thyroid ectopia and accounts for 90% of all reported cases.1 thyroid tissue originates at the foramen caecum, which is situated in the midline of the tongue at the junction between the anterior two-thirds and posterior third. it grows downward, bifurcating to form the lateral lobes and isthmus of the normal thyroid gland. a failure to migrate from the foramen caecum may leave part or all of the thyroid tissue at the base of the tongue or along the thyroglossal duct.2–4 of all ectopic thyroids, 90% are found in the lingual dorsum;1 these are known as lingual thyroid or ectopic lingual thyroid. in rare cases, parathyroid glands are associated with ectopic thyroid tissue.5 other sites of ectopic thyroid deposition include the cervical lymph nodes, the submandibular glands and the trachea. approximately two-thirds of patients with a lingual thyroid lack thyroid tissue in the neck.6 this paper presents a rare case of a large (8 x 6 cm) submental ectopic thyroid mass and includes a discussion of the clinical presentation, diagnosis and treatment of this condition. case report a 27-year-old female presented to the sultan qaboos university hospital (squh) in muscat, oman, in october 2011 with a long-standing swelling at the base of the tongue, which had been gradually increasing in size over the past 11 years. her speech was adversely affected and she reported a feeling of heaviness in the tongue. over the previous four years, a submental sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e571−574, epub. 14th oct 14 submitted 9th feb 14 revision req. 2nd apr 14; revision recd. 15th apr 14 accepted 1st may 14 العالج بأستخدام األيودين 131 املشع حلالة وجود نسيج للغدة درقية خارج مكاهنا اأميمه طه ال�سافعي, �سامر ح�سن, ديليب �سانكال, نيكوال�س وودهاو�س abstract: the occurrence of ectopic lingual thyroid tissue was first reported over 100 years ago. we report an unusual presentation of ectopic thyroid tissue occurring in the submental area. a 27-year-old female presented to the sultan qaboos university hospital in muscat, oman, in october 2011 with an 8 x 6 cm mass which caused difficulty in talking and a feeling of heaviness in the jaw. she was clinically and biochemically euthyroid upon presentation. the clinical diagnosis was confirmed by a technetium-99m thyroid scan, magnetic resonance imaging and fine needle aspiration. a single dose of 976 megabecquerels of radioactive iodine-131 resulted in hypothyroidism after three months and the complete disappearance of the swelling and associated symptoms. at a two-year follow-up, the patient was healthy and continuing lifelong replacement therapy with thyroxine. keywords: thyroid, abnormalities; ectopic thyroid; iodine radioisotopes, therapeutic use; fine needle aspiration; thyroglossal cyst; case report; oman. امللخ�ص: لقد مت ر�سد حاالت وجود ن�سيج الغدة الدرقية يف الل�سان منذ اأكرث من مائة عام. هذا تقرير حالة نادرة لوجود ن�سيج للغدة الدرقية يف منطقة حتت الذقن. قدمت �سيدة عمرها 27 عاما ايل م�ست�سفي جامعة ال�سلطان قابو�س مب�سقط, �سلطنة عمان يف اكتوبر عام 2011 ت�سكو من �سعوبة يف الننطق واالأح�سا�س بثقل يف منطقة الفك نتيجة لوجود ورم حجمه x 6 8 �سم. وبالفحو�سات املختلفة االأكلينيكية و الكيميائية احليوية وجد اأن هورمون الغدة الدرقية يف معدله الطبيعي. مت اثبات الت�سخي�س بوا�سطة مت م�سح التيكني�سيوم 99 امل�سع, وا�سعة الرنني املغناطي�سي واأي�سا باأخذ عينة من الن�سيج باأ�ستخدام االأبرة الدقيقة. مت ا�ستخدام جرعة واحدة من االأيودين 131 امل�سع مقدارها 976 ميجابيكريل ونتج عنها اأختفاء كامل للورم واالأعرا�س بينما حدث نق�س يف افراز الغدة الدرقية. بعد مرور �سنتني من متابعة احلالة كانت املري�سه يف حاله �سحيه جيدة ولكنها حتتاج ايل العالج با�ستخدام عقار الثريوك�سني مدى احلياة. مفتاح الكلمات: الغدة الدرقية؛ وجود ن�سيج للغدة الدرقية خارج مكانها؛ النظائر امل�سعة, االأ�ستخدام العالجي؛ ال�سحب با�ستخدام االأبرة الدقيقة؛ الكي�س الدرقي الل�ساين؛ تقرير حالة؛ عمان. radioactive iodine-131 therapy in the management of ectopic thyroid tissue *omayma t. el-shafie,1 samir hussain,2 dilip sankhla,2 nicholas woodhouse1 online case report radioactive iodine-131 therapy in the management of ectopic thyroid tissue e572 | squ medical journal, november 2014, volume 14, issue 4 mass had developed and was slowly increasing in size. there was no history of difficulty in swallowing or breathing and no history of palpitations, haemoptysis or changes in weight. the past medical history of the patient was insignificant and she was not currently taking any medication. she had two children and her youngest child was three years old. a clinical examination revealed a large non-tender submental spherical swelling extending from the mental front of the trachea to the chin, approximately 8 x 6 cm in size. the swelling was firm in consistency, with a smooth regular surface and no bruit or thrill. it moved when the patient swallowed but not when she protruded her tongue. the overlying skin was scarred due to previous cautery attempts. there were no palpable lymph nodes [figure 1]. an oropharyngeal examination revealed a rounded mass at the base of the tongue, which was the result of the upward enlargement of the submental thyroid tissue. she was euthyroid on clinical examination, with a pulse rate of 72 beats per minute, sinus rhythm and blood pressure of 120/80 mmhg, with no palpable thyroid in the neck. the systemic examination was unremarkable. due to these findings, a clinical diagnosis of ectopic thyroid tissue was suspected. laboratory investigations revealed a normal thyroid function test with the following results: free thyroxine (ft4) of 9.9 pmol/l (normal range: 7–14 pmol/l); thyroid stimulating hormone (tsh) of 2.27 miu/l (normal range: 0.3–5.5 miu/l), and thyroglobulin (tg) of 481 μg/l (normal range: 0–35 μg/l). in addition, thyroid peroxidase antibodies were negative. the technetium (tc)-99m thyroid scan showed an uptake of 1.2% in the submental area; however, there was no uptake in the normal thyroid location, which is a feature consistent with a diagnosis of ectopic thyroid [figure 2]. magnetic resonance imaging (mri) revealed a single distinct ectopic submental thyroid mass without any discrete nodules [figure 3]. an ultrasound-guided fine needle aspiration (fna) revealed changes compatible with nodular hyperplasia without evidence of malignancy. the patient was treated with a single dose of iodine-131 (976 megabecquerels). three months later she became hypothyroid with a tsh level of >100 miu/l and an ft4 result of <3.2 pmol/l. additionally, both the swellings at the base of the tongue and the submental area, as well all other associated symptoms, disappeared completely [figure 4]. the patient was prescribed lifelong thyroxine replacement medication (100 mcg daily) and the adverse symptoms resulting from her hypothyroid state were soon resolved. at a two-year follow-up, she remained clinically and biochemically euthyroid, with undetectable tg levels, and was also referred to a dermatologist to treat her keloid scars. figure 1: lateral view of the patient’s face showing a large submental ectopic thyroid mass. figure 2: technetium-99m thyroid scan showing a large abnormal uptake of 1.2% at the submental area and no uptake in the normal thyroid location. figure 3: magnetic resonance image showing a single distinct submental ectopic thyroid mass. omayma t. el-shafie, samir hussain, dilip sankhla and nicholas woodhouse online case report | e573 discussion thyroid ectopia is defined as functioning thyroid tissue found anywhere other than the usual anatomic location of the thyroid gland. ectopic thyroid is usually located along the normal path of the thyroid gland descent; however, on rare occasions it can also be found in the mediastinum, heart, oesophagus or diaphragm. ectopic thyroid tissue is derived from abnormalities in the migration of the medial anlage and it therefore does not typically contain parafollicular cells.7,8 a failure of the thyroid gland to descend correctly from the foramen caecum occurs in approximately one in 200,000 normal subjects and one in 6,000 patients with thyroid disease.7,8 it is four times more prevalent among females. the true incidence of thyroid ectopia is not known due to the asymptomatic nature of some cases of ectopic thyroid tissue.7,8 in patients with ectopic thyroid tissue, 70% will present with hypothyroidism, due to an enlargement of the ectopic tissue resulting from the elevated tsh levels.6 many of these patients will respond to thyroxine suppression treatment, which results in the shrinkage of the tumour as the tsh levels return to normal. the patient in the current case report was considered unusual in that her tumour continued to grow despite normal ft4 and tsh levels. fortunately, she had relatively few associated symptoms. however, the patient reported experiencing a rapid increase in the submental swelling during her last pregnancy; as a result she became symptomatic, experiencing a change in speech and a feeling of heaviness in the jaw. the gland became hypertropic as a response to the increased demand for the thyroid hormone during pregnancy. a similar response can occur during other conditions of metabolic stress, such as puberty, upper respiratory infections (due to the associated lymphoid tissue), trauma or menopause.1,7–9 this may then lead to regional symptoms such as dysphagia, dysphonia, dyspnoea or haemoptysis.2,7,10,11 in patients presenting with a lingual thyroid, over 70% have no thyroid tissue in the normal location.1,7–9 in the present case, the patient’s tc-99m thyroid scan revealed that there was no thyroid uptake in the normal location. in situations where a tc-99m thyroid scan is not available, ectopic lingual thyroid tissue can be demonstrated using computed tomographic scanning. normal thyroid tissue gives the appearance of enhancement without a contrast injection due to the presence of iodine in the thyroid.2,10,11 the treatment of ectopic thyroid tissue depends on the size of the tissue as well as the presence or absence of symptoms and complicating factors such as ulceration, haemorrhage or malignancy. the recommendation for asymptomatic lingual thyroid patients is to prescribe lifelong thyroxine suppression treatment in order to prevent subsequent enlargement of the tissue, diminish the risk of malignancy and prevent the onset of hypothyroidism.2 fortunately, carcinoma in ectopic thyroid tissue is rare, with fewer than 30 cases reported in the literature.12 before iodine-131 therapy was established as a viable treatment option for such cases, surgery was the only option available for severely symptomatic patients who failed to respond to t4 suppression. in the current case, there was concern regarding the potential for further growth of the tumour and whether t4 suppression alone would result in a complete regression of the ectopic tissue. this was doubted because the tumour had continued to grow despite normal tsh levels and because the fna had revealed nodular hyperplasia. following discussions with the surgical team at squh, a surgical approach was deemed too risky in view of the extensive exposure required to remove such a large vascular mass. it was therefore decided that the best course of action would be to use iodine-131 therapy, which had previously proven to be extremely effective.2,13–17 however, surgery is still the preferred treatment option in many countries today. in view of the current case, the authors recommend that patients with ectopic thyroid tissue who are unlikely to respond to thyroxine suppression treatment should be prescribed iodine-131 therapy, except in cases where the patient has developed cancer in the ectopic thyroid tissue.17 conclusion this case report presents a patient with a large vascular ectopic submental thyroid tissue and associated figure 4: lateral view of the patient’s face and neck three months after iodine-131 therapy. as can be observed, the swelling has completely disappeared. radioactive iodine-131 therapy in the management of ectopic thyroid tissue e574 | squ medical journal, november 2014, volume 14, issue 4 symptoms. this case was unusual as the tissue continued to increase in size despite normal ft4 and tsh levels. the patient was subsequently treated with iodine-131 therapy which successfully resulted in the disappearance of both swellings and all associated symptoms. the authors therefore suggest that any patient requiring therapy who is unlikely to respond to thyroxine suppression treatment should initially be treated with iodine-131, unless the ectopic thyroid tissue is determined to be cancerous. references 1. mussak en, kacker a. surgical and medical management of midline ectopic thyroid. otolaryngol head neck surg 2007; 136:870–2. doi: 10.1016/j.otohns.2007.01.008. 2. kansal p, sakati n, rifai a, woodhouse n. lingual thyroid: diagnosis and treatment. arch intern med 1987; 147:2046–8. doi: 10.1001/archinte.1987.00370110174028. 3. aalaa m, mohajeri-tehrani mr. images in clinical medicine: ectopic thyroid gland. n engl j med 2012; 366:943. doi: 10.1056/nejmicm1106077. 4. yu ty, chang tc. images in clinical medicine: lingual thyroid. n engl j med 2012; 366:e15. doi: 10.1056/nejmicm1112306. 5. salain s, rodrigues g, kumar s. sublingual thyroid: a case report with literature review. internet j surgery 2006; 11:1. 6. basaria s. images in medicine: lingual thyroid. postgrad med j 2000; 76:419. doi: 10.1136/pmj.76.897.419. 7. amani mel a, benabadji n, benzian z, amani s. ectopic lingual thyroid. indian j nucl med 2012; 27:124–6. doi: 10.4103/0972-3919.110718. 8. di benedetto v. ectopic thyroid gland in the submandibular region simulating a thyroglossal duct cyst: a case report. j pediatr surg 1997; 32:1745–6. doi: 10.1016/s00223468(97)90522-4. 9. leung ak. ectopic thyroid gland and thyroxine-binding globulin excess. acta paediatr scand 1986; 75:872–4. doi: 10.1111/j.1651-2227.1986.tb10308.x. 10. wolf bs, nakagawa h, yeh hc. visualization of the thyroid gland with computed tomography. radiology 1977; 123:368. doi: 10.1148/123.2.368. 11. al-hindawi ay, mohammed kh, baba wi, al-hiti t. the clinical presentation of ectopic thyroid gland with results of radioiodine studies. br j clin pract 1969; 23:372–3. 12. massine re, durning sj, koroscil tm. lingual thyroid carcinoma: a case report and review of the literature. thyroid 2001; 11:1191–6. doi: 10.1089/10507250152741055. 13. schilling ja, karr jw, hursh jb. the treatment of a lingual thyroid with radioactive iodine. surgery 1950; 27:130–8. doi: 10.1016/0030-4220(51)90557-9. 14. danner c, bodenner d, breau r. lingual thyroid: iodine 131: a viable treatment modality revisited. am j otolaryngol 2001; 22:276–81. doi: 10.1053/ajot.2001.24819. 15. ibrahim na, fadeyibi io. ectopic thyroid: etiology, pathology and management. hormones (athens) 2011; 10:261–9. 16. patel z, johnson l. iodine 131 ablation of an obstructive lingual thyroid. j radiol case rep 2009; 3:3–6. doi: 10.3941/ jrcr.v3i2.70. 17. noussios g, anagnostis p, goulis dg, lappas d, natsis k. ectopic thyroid tissue: anatomical, clinical, and surgical implications of a rare entity. eur j endocrinol 2011; 165:375– 82. doi: 10.1530/eje-11-0461. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e412-413, epub. 24th jul 14 submitted 1st aug 13 revision req. 18th sep 13; revision recd. 26th oct 13 accepted 14th nov 13 1department of medicine, sultan qaboos university hospital; 2department of gastroenterology, armed forces hospital, muscat, oman *corresponding author e-mail: z.alhashami@gmail.com التحكم بأنبوب التغذية املتنقل زمزم �سالم اله�سامية، خالد النعماين و عبداهلل الكلباين management of a migrating feeding tube *zamzam s. al-hashami,1 khalid al-naamani,2 abdullah al-kalbani2 interesting medical image a 67-year-old male with dementia presented with a locally advanced inoperable obstructive gastric adenocarcinoma. a jejunostomy (js) was perfomed to insert a jejunal feeding tube; however, it was pulled out one month later by the patient. in order to keep the js tract accessible, a size 20 fr foley catheter was placed which included an inflatable balloon filled with 10 cc of water. unfortunately, the foley catheter slipped internally a few days later with no symptoms or signs of an intestinal obstruction. an abdominal radiograph showed the tip of the catheter in the right upper quadrant [figure 1a]. there were no radiological signs of an intestinal obstruction and it was not clear if the catheter was intraluminal or if it was in the peritoneal cavity. a computed tomography (ct) scan of the patient’s abdomen confirmed its intraluminal position with the inflated catheter balloon at the ileocecal valve [figure 1b]. initially, the clinical team opted to keep the patient under observation for 48 hours, hoping that the catheter would pass through the ileocecal valve; however, the catheter did not pass through. a colonoscopy was performed to remove the catheter [figures 2a & b]. multiple attempts to puncture the catheter balloon were unsuccessful. finally, the catheter tip was held by a snare and pulled gently through the ileocecal valve and the colon. an expandable metallic stent was inserted across the obstruction point of the gastric outlet under fluoroscopic guidance. the patient’s feeding was restarted orally and he was later discharged home with a tolerated oral diet. comment intestinal obstructions due to an inflated foley catheter balloon inserted into a js tract have rarely been reported.1–3 there were many challenges in this case. the first challenge was in determining if the feeding foley catheter was intraluminal or whether it had moved figure 1 a & b: plain radiograph of the abdomen showing (a) the foley catheter tip in the right upper quadrant (black arrow) and (b) axial image of computed tomography scan showing foley catheter with the inflated balloon positioned at the ileocecal valve (white arrow). zamzam s. al-hashami, khalid al-naamani and abdullah al-kalbani interesting medical image | e413 into the peritoneal cavity. this form of catheter is made of rubber and therefore was not seen on the plain x-ray. however, a spiral metallic piece, proximal to the catheter’s tip, was used to reinforce the tip and prevent collapse during suctioning; this piece was fortunately visible via x-ray [figure 1a]. there was concern, however, that the catheter might dislodge into the peritoneal cavity, leading to peritonitis. a ct scan of the abdomen clearly showed the catheter’s exact position at the level of the ileocecal valve. there were no radiological signs of an intestinal obstruction [figure 1b]. the exact mechanism that led to the intraluminal migration of the foley catheter is unknown. in this case, it is likely that the patient experienced wound dehiscence at the insertion site, secondary to a gastric and pancreatic fluid leak. the weight of the water-filled balloon, in addition to the distal bowel, propagated waves that may have caused an internal migration of the feeding tube. the second challenge was the best way to manage a patient with multiple comorbidities. thompson et al. described an ultrasound (us) puncture of a catheter balloon that had obstructed a 53-year-old patient’s bowel.4 however puncturing the catheter balloon using us guidance would have been difficult in the current patient. the patient had kyphoscoliosis, which resulted in a poor window for us imaging, and it was difficult to keep the patient in one position due to frequent movements secondary to dementia. since there were no signs of an intestinal obstruction, and to avoid the morbidities associated with surgery, the decision was made to perform a colonoscopy and an intubation of the terminal ileum. the inflated balloon was clearly seen during the colonoscopy at the ileocecal valve [figures 2a & b]. o’keefe et al. reported a successful endoscopic removal of an inflated foley catheter balloon obstructing the duodenum which was achieved by rupturing the balloon.5 unfortunately, multiple attempts to puncture the catheter balloon using different techniques and instruments, such as endoscopic needles, an endoscopic snare, a needle knife, biopsy forceps and the sharp edges of an endoscopic tripod retriever, were unsuccessful. this was most likely due to the stiffness of the balloon, as a result of its direct contact with bile and bowel content. caregivers responsible for patients with feeding catheters should be informed about and made aware of the risk of catheter migration, which could cause a small bowel obstruction. therefore, feeding tubes must be well fixed to the patient’s skin and regularly checked by the caregiver. references 1. hussien m, fawzy m, carey d. percutaneous endoscopic gastroscopy tube migration: a rare cause of a common surgical problem. int j clin pract 2001; 55:557–9. 2. sato y, frey e, foderaro a, pringle kc. small-bowel obstruction due to an intestinal ballon: treatment by percutaneous needle puncture. ajr am j roentgenol 1986; 147:1019–20. doi: 10.2214/ajr.147.5.1019. 3. ozben v, karataş a, atasoy d, sımşek a, sarigül r, tortum ob. a rare complication of jejunostomy tube: enteral migration. turk j gastroenterol 2011; 22:83–5. doi: 10.4318/tjg.2011.0162. 4. thompson zm, lebowitz ea. ultrasound-guided puncture of an obstructing migratory jejunostomy tube. j vasc interv radiol 2009; 20:137–8. doi: 10.1016/j.jvir.2008.10.003. 5. o’keefe kp, dula dj, varano v. duodenal obstruction by a non deflating foley catheter gastrostomy tube. ann emerg med 1990; 19:1454–7. doi: 10.1016/s0196-0644(05)82620-4. figure 2 a & b: the foley catheter with the inflated balloon at the ileocecal valve during the colonoscopy (a) and after its removal from the patient (b). sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e323-329, epub. 24th jul 14 submitted 14th nov 13 revisions req. 31st dec 13 & 24th feb 14; revisions recd. 29th jan & 10th mar 14 accepted 23rd mar 14 1department of biochemistry & genetics, oman medical college, sohar, oman; 2laboratoire d’excellence ion channel science andtherapeutics, lp2m, umr 7370 cnrs, faculté de médecine, université nice-sophia antipolis, nice, france; departments of 3pediatrics and 4physiotherapy, sohar regional teaching hospital, sohar, oman *corresponding author e-mail: uwfass@omc.edu.om حتديُد قائمٍة للطفراِت الوراثيِة وتقديُر انتشاِر الَتليُِّف الكيسيِّ يف ُعمان اأويف وارنر فا�س، ماجد ال�سلماين، �سعيد بندحو، جاجني �سيفالنجام، كاثرين نور�س، كالي�س هيببال، فيونا كالرك، توما�س هيمنج، �سالح اخل�سيبي abstract: objectives: cystic fibrosis transmembrane conductance regulator (cftr) mutations form distinct mutational panels in different populations and subgroups. the frequency of cystic fibrosis (cf) mutations and prevalence are unknown in oman. this study aimed to elucidate the mutational panel and prevalence of cf for the north al batinah (nab) region in oman and to estimate the national prevalence of cf based on the carrier screening of unrelated volunteers. methods: the study included retrospective and prospective analyses of cf cases in the nab region for 1998–2012. genetic analysis of disease-causing mutations was conducted by screening of the entire coding sequence and exon-intron borders. the obtained mutational panel was used for the carrier screening of 408 alleles of unrelated and unaffected omani individuals. results: s549r and f508del were the major mutations, accounting for 89% of mutations in the patient population. two private mutations, c.1733-1734delta and c.1175t>g, were identified in the patient cohort. two carriers, one for f508del and another for s549r, were identified by screening of the volunteer cohort, resulting in a predicted prevalence for oman of 1 in 8,264. the estimated carrier frequency of cf in oman was 1 in 94. the carrier frequency in the nab region was 3.9 times higher. conclusion: the mutational panel for the nab region and the high proportion of s549r mutations emphasises the need for specific screening for cf in oman. the different distribution of allele frequencies suggests a spatial clustering of cf in the nab region. keywords: cystic fibrosis; prevalence; mutations; oman. ال�ّسعوِب يف حمددة قوائمًا )cftr( الكي�سيِّ التليُِّف مِلر�ِس الِغ�سائيٍّ َعرْبَ للّتو�سيِل ِم املنظِّ للربوتنِي الوراثيُة الطفراُت ُت�سّكُل الهدف: امللخ�ص: واملجموعاِت املختلفة. ل ُتعَرُف ِن�سبُة الطفراِت الوراثيِة للتليُِّف الكي�سيِّ يف عمان. َهَدَفْت هذه الدرا�سُة لتحديد قائمِة الطفراِت الوراثيِة ون�سبِة انت�ساِر التليُِّف الكي�سيِّ يف حمافظِة �سماِل الباطنِة بُعمان، وكذلَك تقديُر ن�سبِة انت�ساِر التليُِّف الكي�سيِّ على امل�ستوى الوطنيِّ عن طريِق امل�سِح ال�ستق�سائيِّ عِن احلاملنَي للخلِل َلُة قرابٍة ببع�سهم. الطريقة: ت�سمنت الدرا�سة حتلياًل رجعّيًا وتتابعّيًا حلالِت مر�ِس التليُِّف الكي�سيِّ يف �سمال الوراثيِّ من املتطوعنَي الذيَن ل ترِبطهم �سِ الباطنة خالل الفرتة من 1998 اإىل 2012 ميالدي. متَّ عمل التحليُل اجلينيُّ للطفراِت الوراثيَِّة امل�سببِة للمر�ِس عن طريِق امل�سِح الكامِل لل�ِسل�ِسلِة اجلينيَِّة احلاملني عن الإ�ستق�سائيِّ البحِث يف الوراثيَِّة للطفراِت امل�ستخل�سُة القائمُة ا�سُتْخِدَمْت والإْنرْتوناِت. الإْك�سوناِت اأطراِف يف وال�سال�سِل للربوتنِي امُلنِتَجِة f508del و s549r لهذه الطفرات يف عدد 408 األيالٍت من اأ�سخا�ٍس غري متاأثريَن باملر�ِس ول تربطهم �سلُة قرابٍة ببع�سهم. النتائج: كانت الطفرتان ِ c.1733ال�سائدتني، ومثَّلتا ن�سبَة %89 من الطفراِت الوراثّيِة يف جمموعِة املر�سى. كما ُوِجَدْت طفرتان وراثيَّتاِن منعزلَتاِن يف جمموعِة املر�سى؛ وهما 1734delta و c.1175t>g. وجدت الطفرتني s545rِ و f508del يف عدد اثننٍي من جمموعِة املتطوعنَي، معطيًا بذلَك ن�سبًة لالإنت�ساِر تقدُر بـ 1 من ُة حلاملي التليُِّف الكي�سيِّ يف عمان 1 من 94. كانت ن�سبة احلاملني يف حمافظِة �سماِل الباطنِة اأعلى بـ 3.9 مّراٍت من 8,264 بينما بلغت الن�سبة التقديريَّ داِن احلاجَة لعمل م�سٍح ا�ستق�سائيٍّ s545r يف حمافظِة �سماِل الباطنِة وعدد الطفرات الأخرى يوؤكِّ باقي ال�سلطنة. اخُلال�صة: املقدار الكبري للطفرة الوراثية ِ حُمّدٍد للتليُِّف الكي�سيِّ يف ُعمان. اختالُف توزيِع ن�سبِة الأليالِت يف عمان ُي�سرُي لتمرُكٍز جغرايف اأكرب للتليُِّف الكي�سيِّ يف حمافظِة �سماِل الباطنِة. مفتاح الكلمات: التليف الكي�سي؛ معدل انت�سار؛ طفرات وراثية؛ عمان. defining a mutational panel and predicting the prevalence of cystic fibrosis in oman *uwe w. fass,1 majid al-salmani,1 said bendahhou,2 ganji shivalingam,3 catherine norrish,1 kallesh hebal,3 fiona clark,4 thomas heming,1 saleh al-khusaiby1 clinical & basic research advances in knowledge this study defines a mutational panel for cystic fibrosis (cf) in oman. s549r is the predominant disease-causing mutation. the combined epidemiological and molecular-genetic analysis of cf mutations in patients and unaffected volunteers resulted in a predicted prevalence of cf in the north al batinah (nab) region of oman. the study confirms that cf is a major genetic disease in the nab region, comparable with the incidence and prevalence in the caucasian population. application to patient care the predominance of only two major disease-causing cf mutations in the population (s549r and f508del) allows for economically efficient detection methods and a fast confirmation of a clinical cf diagnosis in 89% of cases. defining a mutational panel and predicting the prevalence of cystic fibrosis in oman e324 | squ medical journal, august 2014, volume 14, issue 3 cystic fibrosis (cf) is an autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (cftr) gene.1–3 pathophysiological changes of cftr chloride conductance affect the mucus-producing organs and result in pulmonary, pancreatic and gastrointestinal disease, or contribute to cf-related disorders such as a congenital bilateral absence of the vas deferens, idiopathic pancreatitis and bronchiectasis.4–8 cf affects approximately 1 in 2,500 individuals in the caucasian population and has a reported average carrier frequency of 1:25.9 epidemiological data about birth prevalence and carrier frequencies vary in the arab population.10–12 for instance, the predicted cf prevalence is 1:4,243 in saudi arabia,10 1:15,876 in the united arab emirates (uae)11 and 1:1,680 to 1:4,150 in morocco.12 the population and/or birth prevalence of cf in oman is still unknown. recent conservative estimations based on retrospective data for the north al batinah (nab) region, the second most populated administrative area of oman, predicted a carrier frequency of 1:25 and a birth prevalence similar to the caucasian population.13 however, most previous estimations of the prevalence in arabic populations are based on a relatively small number of analysed chromosomes,14 whereas the analysis of thousands of chromosomes is available for molecular epidemiological estimations in the caucasian populations.9 the major disease-causing mutation for cf in caucasians is f508del, a mutation in exon 10 (legacy nomenclature) with an overall frequency of approximately 70%. other mutations are less frequent and only four, g542x, n1303k, g551d and w1282x, have allele frequencies above 1% in caucasian patients.15 nonetheless, regional and geographical differences of common caucasian mutations exist in various ethnic subpopulations.15 similarly comprehensive molecular epidemiological data about cf in arab populations are missing. as a disease, cf was under-recognised in arab and asian populations for decades, even after the cloning of the gene.16 with the advent of accessible advanced healthcare, such as clinical and laboratorybased deoxyribonucleic acid (dna) diagnoses, the situation is changing.10–12 the establishment of a mutational panel, and consequently the estimation of prevalence and carrier frequencies, are impacted by a high degree of consanguinity in arab populations in general and in oman in particular.17 intra-marriage occurs within kabilahs (large extended families), which can encompass thousands of individuals. furthermore, cultural traditions and interrelated geographical and territorial factors result in the limited migration patterns of individuals and subpopulations. these factors might explain the observed regionally-defined geographical differences of specific cf mutations that are typical for one arab subpopulation but not present in other arab populations.18,19 therefore, defining the specific mutation patterns and panels within arab populations are important for the molecular genetic diagnosis and eventual screening of cf. the first aim of the present study was to establish a cf mutational panel for the investigated population in the nab region of oman. the second aim focused on predicting cf prevalence in the nab region and oman through the carrier screening of unrelated omani volunteers. methods in total, 47 cf patients were identified in the nab region by retrospective and prospective analysis for 1998–2012. all patients met the clinical diagnostic criteria for cf.20 four families had more than one child with cf. the cf cohort consisted of 24 kabilahs; two families in the cf cohort had derived from the same kabilah and were related to each other. of the unrelated cf cases, 37 patients were alive at the end of the observation period. from these patients, 14 gave consent for the mutational analysis of their underlying genetic defects. a total of 204 volunteer samples were collected from medical students and employees of the oman medical college in sohar, a city in the nab region, in february and september 2012. only individuals who completed a comprehensive questionnaire were included in the volunteer cohort. the questionnaire ensured that none of the volunteers were related to each other by enquiring about the geographical origin of the participants’ parents and maternal and paternal grandparents over three generations. genomic dna was isolated from ethylenediamine-tetra-acetic acid (edta)-buffered blood using the wizard® genomic dna purification kit (promega corp., madison, wisconsin, usa) according to the manufacturer’s instructions. an initial screening for potential cf-causing mutations was conducted by amplifying the entire coding sequence and exonintron borders of the cftr gene using polymerase chain reaction (pcr) conditions for exon 10 as described by fanen et al.21 all other exons and their flanking intronic regions were amplified using primers and pcr conditions described by zielinsky et al.22 the pcr products were subsequently sequenced for the identification of disease-causing mutations. the cftr wide screening for individual patient samples uwe w. fass, majid al-salmani, said bendahhou, ganji shivalingam, catherine norrish, kallesh hebal, fiona clark, thomas heming and saleh al-khusaiby clinical and basic research | e325 was discontinued as soon as two disease-causing mutations were identified. for identified mutations in the patient cohort, alternative mutation detection methods were established. these methods allowed high through-put and cost-effective carrier screening in the volunteer samples. identified differences in volunteer samples versus the control samples were sequenced to confirm the potential cf carrier status. the mutation f508del and the newly identified mutation c.1733_1734delta were analysed by heteroduplex (hd) analysis using a modified standard protocol.23 briefly, the amplified pcr product mixtures from the wild type (wt) and the f508del or c.1733-1734delta mutations, serving as the heterozygote control, were denatured at 95 °c and hd formation was initiated by maintaining a temperature of 65 °c for 10 min. electrophoresis was conducted using 16 cm x 18 cm x 0.75 mm of 10% polyacrylamide gel electrophoresis (page) in one trisborate-edta (tbe) buffer at 500 volts for 10 hours with three μl of either the sample or the heterozygote control. the page gels were incubated in 100 ml of fixative containing 20% ethanol and 5% acetic acid for one hour. following incubation of the page gels with 0.2% silver nitrate and 100 μl of formaldehyde, the dna banding pattern was developed with a solution of 0.2% sodium thiosulfate, 0.15% sodium carbonate and 100 μl of formaldehyde. screening for the mutation c.1175t>g was performed by single strand conformation polymorphism analysis. the 10 µl of amplified pcr products were ethanol precipitated and directly rehydrated in an equal volume of denaturing mixture, consisting of 100 mm of sodium hydroxide in formamide with loading dyes bromophenol blue and xylenol orange. denaturing was achieved by maintaining a temperature of 95 °c for five min. samples were immediately placed on ice and loaded after five min on 16 cm x 18 cm x 0.75 mm of 10% page containing 20% glycerol in 1 x tbe buffer. electrophoresis was conducted with 0.5 x tbe buffer at 500 volts for 24 hours. silver staining was applied according to the above protocol. restriction digest analysis was used for the screening of the substitution s549r in the volunteer cohort. briefly, 10 µl of amplification product was digested utilising four units of the restriction enzyme draiii-hf® (new england biolabs inc., ipswich, massachusetts, usa) in a total volume of 15 µl for three hours. the restriction digest was separated in 3% agarose gels at 90 volts for 20–30 min. to determine the allele prevalence, incidence proportion and carrier frequency of cf (ipcf) in the nab region, the quotient of observed and confirmed genetically independent cf cases (ncf) during the observation period (1998–2012) was divided by the average number of births in the nab region during the same period (nbirth), according to the following formula: ipcf = ncf/nbirth. volunteer samples were screened for all of the identified mutations in the nab region mutational panel [table 1]. subsequently, the carrier frequency and allelic prevalence (p[a2]) of cf-causing mutations was determined by counting confirmed mutated alleles. cultural factors contribute to a high rate of consanguinity within arab populations which consequently result in deviation from the hardyweinberg law.24,25 consanguinity with an inbreeding factor (f) of 0.0176 was reported in oman recently.17 therefore, genotype frequencies were determined as below:26 formula 1a: p(a2a2) = q 2 + pqf = q2(1-f) + qf formula 1b: p(a1a2) = 2pq 2pqf = 2pq(1-f) in the above formulae, p is the frequency of allele a1, q is the frequency of allele a2, 2pq is the frequency of the heterozygote a1 a2 genotype and q2 is the frequency of the homozygote a2 a2 genotype. for the estimation of cf prevalence, the allele table 1: mutational panel of cystic fibrosis transmembrane conductance regulator (cftr) mutations of unrelated patients in the north al batinah region (n = 14) cdna name protein name legacy name location at exon # (legacy nomenclature exon #) number of alleles allelic frequency c.1647t>g p.ser549arg s549r (t>g) 12 (11) 21 0.75 c.1521-1523delctt p.phe508del f508del 11 (10) 4 0.14 †c.1733-1734delta p.leu578argfs*10 13 (12) 2 0.07 c.1175t>g p.val392gly v392g 9 (8) 1 0.04 cdna = complementary deoxyribonucleic acid. †this mutation was novel and has not been reported previously. defining a mutational panel and predicting the prevalence of cystic fibrosis in oman e326 | squ medical journal, august 2014, volume 14, issue 3 frequency of disease-causing mutations in the whole population of oman is required. this information is unknown. however, detailed information about cf allele frequencies are available for the nab region, as determined by the current study, as well as in the neighbouring uae.11 these findings allow the prediction of cf prevalence in oman based on the most commonly observed mutations, s549r and f508del. this study was approved by the institutional review board of oman medical college and the ethical committee of the ministry of health of oman. patient and volunteer consent was taken according to the approved protocol. results a total of 47 patients were diagnosed with cf during the period of 1998–2012. with an average annual birth rate of 7,473, approximately 3.1 observed cases of cf were born per year, resulting in an annual incidence of 1/2,410 affected newborns in the nab region. consanguinity within extended families is culturally common in oman.17 in 10 cases, cf patients were born either into the same core or extended family; therefore, only 37 cases were considered independent. this resulted in 2.4 non-related cf cases and 1/3,114 newborns with cf per year. the incidence proportion of cf cases per year allowed the calculation of the frequency of mutated cf alleles to be 1/56, using p(a2) = q. consequently, by applying formula 1b with q + p = 1, the carrier frequency for cf in the patient cohort was calculated to be 1:29 for independent cf cases. the carrier frequency was higher and accounted for 1:25.5 when all of the observed cf cases were included in the calculation. the substitution s549r and the three base pair deletion f508del mutations accounted for 89.2% of all disease-causing mutations in the patient cohort [table 1]. s549r was the predominant mutation followed by f508del, with an allele frequency of 0.75 and 0.14, respectively [table 1]. one individual was a compound heterozygote with s549r on one allele and the reported but not yet clinically described alteration c.1175t>g (p.val392gly) at exon 9 (or exon 8 using legacy nomenclature) on the other allele.27 the substitution of thymine to guanine results in the amino acid valine being changed to glycine at the position 392. no other genetic alteration was found by analysing all of the cftr exons and their exon-intron borders. the possibility that the identified mutations were in cis and that another potential cftr modifier gene mutation may contribute to the cf symptoms of the individuals cannot be dismissed. another patient was homozygous for a deletion of two base pairs (thymine and adenine) at position 1733 in exon 13 (or exon 12 using legacy nomenclature). the deletion resulted in a frame shift in amino acids from leucine to arginine and the formation of a premature stop codon at position 587 (c.1733-1734delta; p.leu578argfs*10). the screening of 204 unrelated omani volunteers did not reveal any carrier status for either c.1175t>g or c.1733-1734delta mutations. from these results, the prediction of cf prevalence in the nab region and oman could be estimated. the joined allele frequency for f508del and s549r in the nab region was 0.89, which is very similar to the reported allele frequency of 0.95 for these two mutations in the uae.11 the total cf allele frequency for f508del and s549r for the whole of oman is unknown. however, the geographical proximity and similarities in culture between the emirati and omani populations implies that an average of 0.92 for the allele frequencies can be used to estimate cf prevalence in the omani population. furthermore, by screening 204 non-related omani volunteers with the mutational panel [table 1], two carriers were identified. one individual was identified as a carrier for f508del and another individual as a carrier for s549r. applying the average allele frequency for f508del and s549r, the identified mutations accounted for 92% of cf mutations in the population. the resulting carrier frequency was 1:94 using the formula (2 x 100/92)/204. consequently, the allele frequency of the mutated p(a2) could be obtained and was 1/188 by using formula 1b with p(a2)<<p(a1). furthermore, the genotype frequency under the condition of consanguinity was derived by utilising formula 1a; this resulted in a frequency of 1/8,264 for oman. however, the two carriers were identified within the 44 samples from the volunteer subgroup of the nab region, resulting in a theoretical carrier frequency of 1/20.4 for this particular region of oman. the estimations above were conducted with the same preconditions as for the volunteer population. in comparing the volunteer-based estimation of the carrier frequency with the independent cf casebased estimated carrier frequency (i.e. 1:29), the similarity of both values appears confirmative and is similar to the cf carrier frequency of 1:25 in the caucasian population. however, the carrier frequency for cf in the nab regions appears 3.9 times higher in comparison to the carrier frequency of cf in the total omani population. uwe w. fass, majid al-salmani, said bendahhou, ganji shivalingam, catherine norrish, kallesh hebal, fiona clark, thomas heming and saleh al-khusaiby clinical and basic research | e327 discussion the substitution s549r and three base pair deletion f508del were found to be the two most common cf mutations in the nab region of oman. together these mutations covered 89.2% of the disease-causing mutations in the cf cohort. the clinical characteristics were in accordance with recorded homozygote mutations of s549r and f508del in cftr2, including sweat chloride concentrations above 100 mmol/l, pancreatic insufficiency and diminished pulmonary function.27 the disease liability of s549r was recently confirmed.28 the predominant and characteristic mutation of the current cf cohort was the substitution s549r with an allele frequency of 0.75 [table 1]. the high coverage of cf cases by only two mutations was similar to findings in the uae, where s549r and f508del were reported to be disease-causing in 95% of the investigated cf cases.27 concordantly, in all investigated alleles of cf patients in the uae, the substitution s549r occurred with the highest allele frequency (0.68).29 an explanation for the observed similarity might be the territorial proximity of the two countries and the cultural and historical ties between extended families which may go beyond administrative borders. the allele frequency of s549r in an analysis of 27,177 chromosomes from 23 european and three north african countries only accounts for 12 identified chromosomes with s549r, resulting in an allele frequency of 4.4 x 10-4.15 in addition, to the best of the authors’ knowledge, s549r has been reported in six chromosomes of cf patients of moroccan descent in israel but in no other arab epidemiological study of cf.29–31 therefore, the high allele frequency of s549r in oman and the uae might suggest a specific geographical cluster for this substitution. furthermore, since all investigated cf individuals were unrelated by pedigree analysis and consideration of kabilah names, the high frequency might point towards a founder effect of the mutation in the region, a notion which has been expressed previously.26 the low allele frequency of f508del (0.14) in the current study parallels other molecular epidemiological cf data for f508del in arab populations.18,19 it appears that the allele frequencies for f508del in the uae and oman are among the lowest reported in comparison to other arab populations. in addition, the low allele frequency of f508del in this region stands in sharp contrast to the predominance of this mutation in caucasians and white european-derived populations.15 however, differences for the allele frequency of f508del are observed in those populations depending on geographical regions.15 on the contrary, allele frequencies for the cf mutation f508del in saudi arabia18 and libya,19 for instance, were reported as 0.15 and 0.30, respectively. other regional mutations occur with higher frequencies, such as 1548delg in saudi arabia18 and e1104x in libya.19 the observed frequency for s549r in oman follows exactly this pattern. screening for other disease-causing mutations in the current patient cohort revealed two additional mutations: c.1175t>g and c.1733-1734delat [table 1]. both mutations were considered private. the patient with the c.1175t>g mutation was reported and described as pancreatic-sufficient.32 however, detailed information about this mutation and the resulting clinical consequences were not yet available. the cf patient in the cohort who was compound heterozygote for c.1175g>t and s549r had mild pancreatic insufficiency and sweat chloride levels of above 100 mmol/l. the mutation c.1733-1734delat was novel and reported for the first time in this investigation. the observed severity of the disease and nutritional failure in this patient might be explained by the formation of a truncated cftr protein due to the formation of a stop codon at position 582. it is significant to note that the mutational panel established in this study, with the predominance of the mutations s549r and f508del, emphasises the need for the development of regional laboratory strategies for fast and effective cf mutational screening and molecular genetic diagnoses. for s549r, the disruption of the restriction site of the draiii enzyme can be considered a fast and costefficient screening tool. cost-effective screening tools are of significant importance for clinical laboratories in developing countries with limited resources. the strategy of screening for potential s549r carrier status in volunteer samples was successfully applied in this study and can be readily adapted for clinical use. in addition, this strategy does not exclude other private mutations which might be identified during the screening of future cf patients. however, it appears unlikely that the predominance of s549r identified in the omani mutational panel of this study, with an allele frequency of 0.75, will be replaced by another as yet unidentified mutation because of the very close similarity to the s549r frequency reported in the uae. the estimation of cf prevalence in oman was approached using two independent strategies. the first strategy focused on the analysis of the cf carrier frequency in the nab region, the second largest populated administrative district of oman, by retrospective analysis and prospective clinical diagnoses of cf cases over a 15-year period. in the second strategy, the carrier frequency for the total defining a mutational panel and predicting the prevalence of cystic fibrosis in oman e328 | squ medical journal, august 2014, volume 14, issue 3 population and the population of the nab region was estimated by screening 204 volunteers for all of the identified mutations in the mutational panel. the structured recruitment of volunteers from medical students and the implementation of a comprehensive questionnaire ensured that individuals were unrelated to each other in the volunteer cohort, which is essential for genetic studies in a highly consanguineous population. the clinically observed carrier frequency for cf in the nab region was similar to the estimated carrier frequency from the volunteer cohort, at 1:29 and 1:20, respectively. however, in comparison to the estimated cf carrier frequency of the total omani population of 1/94, the carrier frequency in the nab region was found to be 3.9 times higher. it is possible to argue that 44 samples from the subpopulation of the nab region are not representative for population genetic estimations. however, the similarity of the carrier frequencies is unlikely to have been the result of chance and this is supported by the following arguments. first, the families of the identified carriers had lived for over three generations in the nab region. second, none of the volunteers were related to each other which meant that the volunteer cohort was a random representation of the omani population. third, the cf mutations s549r and f508del were the major mutations in the area and have also been reported in the uae which shares a border with the nab region. therefore, the identification of two carriers in the nab region but not in any other sample might indicate an increased allele frequency for the cf mutations s549r and f508del in the area. the 3.9-fold difference in the carrier frequency between the population of the nab region and the screened omani volunteers supports the notion of a spatial distribution of these mutations within the overall omani population. from these results, it appears that the major cftr mutations s549r and f508del follow a spatial north-to-south pattern within the omani population. the formation of geographical clusters of specific mutations within a population appears likely under the conditions of consanguinity present within this population. for instance, the most common saudi mutations 1548delg and i1234v are reported mainly in the central region of the country whereas the mutation 3120+1g→a appears to be more predominant in the east.18 furthermore, the mutation i1234v has been described in 17 families of the same kabilah in qatar.33 the estimated carrier frequency for cf in oman of 1/94 appears lower than the reported carrier frequency for the uae of 1/64.11 however, the context of mutational clusters with increased cf allele frequencies in subpopulations might be an explanation for this difference. the samples in the current study are representative for a random selection of volunteers in the omani population. in contrast, the volunteer samples in the uae were collected in one hospital and might therefore represent a specific regional collection of cf carriers similar to the identified higher carrier frequency in the nab region recorded in the present study. conclusion the two predominant cf mutations of s549r and f508del define the mutational panel in oman. the mutation s549r appears to be clustered in one region and occurs with a higher prevalence in the nab region of oman. two other physiologically as yet uncharacterised mutations were identified in the study: c.1733-1734delta and c.1175t>g. the mutation c.1175t>g has been reported previously whereas c.1733-1734delta was novel. these results illustrate that cf is a frequent genetic disease in oman which requires further attention. there is a need to develop regional laboratory strategies for fast and effective cf mutational screening and molecular genetic diagnoses. a c k n o w l e d g e m e n t s this research was funded by a grant from the oman research council (trc grant #org omc hss 10 008) and a grant from the association française contre les myopathies (afm grant #15725). the authors would like to express their deep appreciation for the insightful clinical discussions with dr. a. rodney, head of the department of pediatrics at sohar regional teaching hospital, as well as the unconditional support of all his colleagues. the authors would also like to express their gratitude to all students of the oman medical college in sohar who volunteered for the project and donated blood for the genetic investigations. additionally, the authors thank the cf patients and their parents for their participation in the study. references 1. kerem b, rommens jm, buchanan ja, markiewicz d, cox tk, chakravarti a, et al. identification of the cystic fibrosis gene: genetic analysis. science 1989; 245:1073–80. 2. riordan jr, rommens jm, kerem b, alon n, rozmahel r, grzelczak z, et al. identification of the cystic fibrosis gene: cloning and characterization of complementary cdna. science 1989; 245:1066–73. uwe w. fass, majid al-salmani, said bendahhou, ganji shivalingam, catherine norrish, kallesh hebal, fiona clark, thomas heming and saleh al-khusaiby clinical and basic research | e329 3. rommens jm, iannuzzi mc, kerem b, drumm ml, melmer g, dean m, et al. identification of the cystic fibrosis gene: chromosome walking and jumping. science 1989; 245:1059– 65. 4. sharer n, schwarz m, malone g, howarth a, painter j, super m, et al. mutations of the cystic fibrosis gene in patients with chronic pancreatitis. n engl j med 1998; 339:645–52. doi: 10.1056/nejm199809033391001. 5. daudin m, bieth e, bujan l, massat g, pontonnier f, mieusset r. congenital bilateral absence of the vas deference: clinical characteristics, biological parameters, cystic fibrosis transmembrane conductance regulator gene mutations. and implications for genetic counseling. fertil steril 2000; 74:1164– 74. doi: 10.1016/s0015-0282(00)01625-3. 6. gelfond d, borowitz d. gastrointestinal complications of cystic fibrosis. clin gastroenterol hepatol 2013; 11:333–42. doi: 10.1016/j.cgh.2012.11.006. 7. ciofu o, hansen cr, høiby n. respiratory bacterial infections in cystic fibrosis. curr opin pulm med 2013; 19:251–8. doi: 10.1097/mcp.0b013e32835f1afc. 8. brody as, klein js, molina pl, quan j, bean ja, wilmott rw. high-resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests. j pediatr 2004; 145:32–8. doi: 10.1016/j.jpeds.2004.02.038. 9. bobadilla jl, macek m jr, fine jp, farrell pm. cystic fibrosis: a worldwide analysis of cftr mutations: correlation with incidence data and application to screening. hum mutat 2002; 19:575–606. doi: 10.1002/humu.10041. 10. mathew pm, hamdan ja, nazer h. cystic fibrosis presenting with recurrent vomiting and metabolic alkalosis. eur j pediatr 1991; 150:264–6. doi: 10.1007/bf01955527. 11. frossard pm, lestringant g, girondo e, goossens m, dawson kp. determination of the prevalence of cystic fibrosis in the united arab emirates by genetic carrier screening. clin genet 1999; 55:496–7. doi: 10.1034/j.1399-0004.1999.550618.x. 12. ratbi i, génin e, legendre m, le floch a, costa c, cherkaouideqqaqi s, et al. cystic fibrosis carrier frequency and estimated prevalence of the disease in morocco. j cyst fibros 2008; 7:440–3. doi: 10.1016/j.jcf.2007.12.006. 13. al badi h, al rawahy m, al maskary s, al sarhani s, al maamari l, shivalingam g, et al. epidemiology of cystic fibrosis of the omani population in the north al bathina region in oman. j cyst fibr 2008; 7:s114. 14. wei s, feldman gl, monaghan kg. cystic fibrosis testing among arab-americans. genet med 2006; 8:255–8. doi: 10.109701.gim.0000214453.74456.f3. 15. estivill x, bancells c, ramos c. geographic distribution and regional origin of 272 cystic fibrosis mutations in european populations: the biomed cf mutation analysis consortium. hum mutat 1997; 10:135–54. doi: 10.1002/(sici)10981004(1997)10:2<135::aid-humu6>3.0.co;2-j. 16. kabra sk, kabra m, shastri s, lodha r. diagnosing and managing cystic fibrosis in the developing world. paediatr respir rev 2006; 7:s147–50. doi: 10.1016/j.prrv.2006.04.218. 17. rajab a, patton ma. a study of consanguinity in the sultanate of oman. ann hum biol 2000; 27:321–6. doi: 10.1080/030144600282208. 18. banjar h. geographic distribution of cystic fibrosis transmembrane regulator gene mutations in saudi arabia. east mediterr health j 1999; 5:1230–5. 19. hadj fredj s, fattoum s, chabchoub a, messaoud t. first report of cystic fibrosis mutations in libyan cystic fibrosis patients. ann hum biol 2011; 38:561–3. doi: 10.3109/03014460.2011.557090. 20. de boeck k, wilschanski m, castellani c, taylor c, cuppens h, dodge j, et al; diagnostic working group. cystic fibrosis: terminology and diagnostic algorithms. thorax 2006; 61:627– 35. doi: 10.1136/thx.2005.043539. 21. fanen p, ghanem n, vidand m, besmond c, martin j, costes b, et al. molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (cftr) coding regions and splice site junctions. genomics 1992; 13:770–6. doi: 10.1016/0888-7543(92)90152-i. 22. zielenski j, rozmahel r, bozon d, kerem b, grzelczak z, riordan jr, et al. genomic dna sequence of the cystic fibrosis transmembrane conductance regulator (cftr) gene. genomics 1991; 10:214–28. doi: 10.1016/0888-7543(91)905037. 23. sambrook j, russel dw. molecular cloning: a laboratory manual, 3rd ed. new york, usa: cold spring harbor laboratory press, 2001. pp.13–49. 24. hardy gh. mendelian proportions in a mixed population. science 1908; 28:49–50. 25. weinberg w. on the demonstration of heredity in man, in: boyer sh, ed. papers on human genetics. new jersey, usa: prentice hall, 1963. p.4. 26. wright s. the genetical structure of populations. ann eugen 1951; 15:323–54. doi: 10.1111/j.1469-1809.1949.tb02451.x. 27. cystic fibrosis foundation. clinical and functional translation of cftr (cftr2). from: www.cftr2.org accessed: oct 2013. 28. sosnay pr, siklosi kr, van goor f, kaniecki k, yu h, sharma n, et al. defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. nat genet 2013; 45:1160–7. doi: 10.1038/ng.2745. 29. frossard pm, girodon e, dawson kp, ghanem n, plassa f, lestringant gg, et al. identification of cystic fibrosis mutations in the united arab emirates. hum mutat 1998; 11:412–13. doi: 10.1002/(sici)1098-1004(1998)11:5<412::aidhumu15>3.0.co;2-o. 30. kerem e, kalman y, yahav y, shoshani t, abeliovich d, szeinberg a, et al. highly variable incidence of cystic fibrosis and different mutation distribution among different jewish ethnic groups in israel. hum genet 1995; 96:193–7. doi: 10.1007/bf00207378. 31. quint a, lerer i, sagi m, abeliovich d. mutation spectrum in jewish cystic fibrosis patients in israel: implication to carrier screening. am j med gentet a 2005; 136:246–8. doi: 10.1002/ ajmg.a.30823. 32. cystic fibrosis mutation database. mutation details for c.1175t>g (nl#70). from: www.genet.sickkids.on.ca/mut ationdetailpage.external?sp=816 accessed: oct 2013. 33. abdul wahab a, al thani g, dawod st, kambouris m, al hamed m. heterogeneity of the cystic fibrosis phenotype in large kindred family in qatar with cystic fibrosis mutation (i1234v). j trop pediatr 2001; 47:110–12. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e415–419, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.018. submitted 14 dec 14 revision req. 26 jan 15; revision recd. 16 feb 15 accepted 24 mar 15 although there are approximately 60 published reports on chromosome 7p duplication, the de novo duplication of the short arm of chromosome 7—without involving any rearrangements with other chromosomes in the form of unbalanced translocations—is extremely rare.1–3 the size of the duplicated segment varies from patient to patient.2,3 the phenotype spectrum also varies accordingly, but its association with a clinical manifestation of autism spectrum disorder (asd) is rarely documented. wolpert et al. reported a duplication of the 7p11.2p14 region in a 25-year-old male patient with autism.4 the current report presents an autistic child with unique features and duplication of chromosome 7p21.1p22.2. to the best of the authors’ knowledge, this is the first report of a patient with 7p duplication associated with asd involving region 7p21.1. case report a three-year-old male child presented to the sultan qaboos university hospital in muscat, oman, in january 2012. he was diagnosed with global developmental delay, hypotonia and abnormal repetitive social interactions. he was the first child born to a healthy omani consanguineous couple (first cousins); the mother was 24 years old and the father was 25 years old. the child had a birth weight of 2.11 kg. 1department of genetics, college of medicine & health sciences, sultan qaboos university; departments of 2child health and 3genetics, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: uday.achandira@gmail.com وجود طفرة جينية للتضاعف الصبغي يف 7p21.1p22.2 يف طفل لديه اضطراب طيف التوحد واختالفات خلقية اأت�ساديرا موثابا أوداياكومار، وطفة املعمرية، عبري ال�سائغ، عديلة الكندية abstract: the duplication of the short arm of chromosome 7 as de novo is extremely rare. the phenotype spectrum varies depending on the region of duplication. we report a case of de novo duplication of chromosomal region 7p21.1p22.2 in a three-year-old male child with autism who presented to the sultan qaboos university hospital in muscat, oman, in january 2012. the patient was diagnosed with craniofacial dysmorphism, global developmental delay, hypotonia and bilateral cryptorchidism. the duplication was detected by conventional g-banded karyotype analysis/fluorescence in situ hybridisation and confirmed by array comparative genomic hybridisation. to the best of the authors’ knowledge, this is the first report of chromosomal region 7p21.1 involvement in an autistic patient showing features of a 7p duplication phenotype. identifying genes in the duplicated region using molecular techniques is recommended to promote characterisation of the phenotype and associated condition. it may also reveal the possible role of these genes in autism spectrum disorder. keywords: autism spectrum disorder; array comparative genomic hybridization; craniofacial abnormalities; chromosome 7; duplication 7p; case report; oman. امللخ�ص: يعد الت�ساعف ال�سبغي للذراع الأق�رس لكرومو�سوم 7 حالة نادرة جداً. ويعتمد النمط الظاهري للحالة على املنطقة املت�ساعفة للكرومو�سوم. ونعر�س يف هذا البحث وجود ت�ساعف �سبغي يف الذراع الأق�رس للكرومو�سوم 7 يف املنطقة 7p21.1p22.2 يف طفل قد مت ت�سخي�سه با�سطراب طيف التوحد يف م�ست�سفى جامعة ال�سلطان قابو�س يف يناير 2012م. وي�سمل النمط الظاهري للحالة الآتي: اختالفات خلقية يف الوجه، وتاأخر منائي عام، وارتخاء يف الع�سالت واختالف خلقي يف اخل�سيتني. ومت ت�سخي�س هذا الختالف ال�سبغي عن طريق درا�سة النمط الكرومو�سومي ومت تاأكيده بتقنية امليكرو اأريه. ومبلغ علمنا تعترب هذه احلالة هي الأوىل التي توؤ�رس إىل وجود ارتباط بني الختالفات ال�سبغية يف 7p21.1 وت�سخي�س ا�سطراب طيف التوحد. ن�ستنتج من هذه احلالة وجود جينات يف املنطقة ال�سبغية 7p مرتبطة با�سطراب طيف التوحد و حتث على عمل درا�سة دقيقة للجينات املوجودة يف هذه املنطقة ال�سبغية ودرا�سة مدى اأهميتها لفهم الأ�سباب اجلينية ملر�س ا�سطراب طيف التوحد. مفتاح الكلمات: ا�سطراب طيف التوحد؛ ميكرو اري؛ اختالفات خلقية يف الوجه؛ كرومو�سوم 7؛ الت�ساعف ال�سبغي يف 7p؛ تقرير احلالة؛ عمان. de novo duplication of 7p21.1p22.2 in a child with autism spectrum disorder and craniofacial dysmorphism *achandira m. udayakumar,1 watfa al-mamari,2 abeer al-sayegh,3 adila al-kindy3 online case report de novo duplication of 7p21.1p22.2 in a child with autism spectrum disorder and craniofacial dysmorphism e416 | squ medical journal, august 2015, volume 15, issue 3 upon examination, the patient would not speak spontaneously and rarely vocalised directly to either the examiners or his parents. non-verbal communications (including gestures, smiling, pointing or using other body parts) and the range of distinct facial expressions were very limited. methods of communication were not coordinated with eye contact and the child showed limited enjoyment during interactions. the patient did not request objects and was not interested in showing objects to others. he showed no interest in symbolic/pretend play but demonstrated unusual sensory interest in materials (e.g. licking objects). the patient showed stereotypical motor repetitive behaviour (repetitive hand flicking) and persistent odd hand positioning in the form of bilateral wrist flexion. no disruptive, aggressive or self-injurious behaviours were noted. his communication and reciprocal social interaction scores fell within the range of asd. based on the above clinical and multidisciplinary evaluations, the patient was diagnosed with asd. the patient had delayed developmental milestones, demonstrating head control at the age of 12 months old, sitting with support by 14 months old, standing with support by two years old and walking by the time he was three years old. his hearing test results were normal, although an eye examination showed hypermetropic astigmatism. during a follow-up ophthalmological appointment, a slightly enlarged cup-to-disc ratio was noticed, indicating glaucoma. features of craniofacial dysmorphism were observed, including a high forehead with a prominent metopic ridge; brachycephalic and plagiocephalic closed anterior fontanelle; a low v-shaped posterior hairline; well-arched thin eyebrows; hypoplastic alae naris; narrow anteverted nares; a bulbous nasal tip; ears with prominent crus and overfolded helices; a short philtrum; a prominent lower lip; micrognathia; and bilateral cryptorchidism. the patient had undergone an operation for the cryptorchidism. the coronal sutures were open but appeared narrow. the height and weight of the patient were both at the 50–75th centile, with head circumference at the 25th centile. magnetic resonance imaging of the brain, echocardiography and abdominal ultrasonography findings were unremarkable. the parents refused permission for photographs of the child to be published. peripheral blood chromosomal g-band karyotyping analysis was performed with 400–550 band resolution, which showed a 46, xy, dir dup(7) (p21p22) karyotype [figure 1a]. fluorescence in situ hybridisation using a subtelomeric probe (cytocell ltd., cambridge, uk) showed the presence of telomeres on both short arms of chromosome 7 [figure 1b]. the parental karyotypes were normal, indicating the 7q duplication in the child to be a de novo occurrence. array-based comparative genomic hybridisation (acgh) using 8x60k oligoarray platforms (oxford gene technology, begbroke, oxfordshire, uk) confirmed the presence of a cytogenetically visible duplication within the short arm of one chromosome 7. analysis using cytosure™ interpret software, version 3.4.8 (oxford gene technology), showed that this duplication was ~16.5 million bases (mb) in size. the breakpoints were also refined. the duplication involving the region 7p22.2 to 7p21.1 thus showed arr 7p22.2p21.1(2,811,886-19,358,897)x3, with a minimum size of ~16.5 mb and a maximum size of ~16.7 mb figure 1a & b: a: partial karyotype showing the g-banded pairs of chromosome 7 and the duplicated segment 7p21-22 (arrows) in an autistic child with craniofacial dysmorphism. b: fluorescence in situ hybridisation showing telomeres (arrows) on the 7p region. figure 2: array comparative genomic hybridisation of an autistic child with craniofacial dysmorphism showing a duplication interval of ~16.5 million bases within the breakpoints at chromosome 7p22.2 and 7p21. achandira m. udayakumar, watfa al-mamari, abeer al-sayegh and adila al-kindy online case report | e417 of 7p in a few cases or smaller terminal 7p segments in others.2 arens et al. reported complete 7p trisomy (without the involvement of any other chromosomes) in two patients.6 similar diagnoses have been made in five other patients.4,7 many phenotypic features common to 7p duplication syndrome were present in the patient in the current report [table1];1,4,10,11 these have also been described in earlier case reports.3,6,8 notably, the patient described in the current report did not have any cardiovascular abnormalities and thus had a better prognosis compared to patients in previous reports who died early as a result of these abnormalities.3,6,8 evidence suggests that most 7p duplications occur due to malsegregation of parental balanced translocations or abnormal recombination of parental chromosome inversions and that these duplications rarely result from de novo partial 7p direct [figure 2]. this analysis was done commercially. no other imbalances were detected. the duplication interval contained 67 annotated genes, of which six had morbid entries in the online mendelian inheritance in man® (omim) catalogue. however, the genes in this region were not directly disrupted by the breakpoints. discussion duplication of 7p has been reported previously and the region/size varies among patients.1–13 common features include craniofacial anomalies, a large fontanelle, dysmorphism and psychomotor delay, with hypotonia being the most common complication observed.1–8,10,11,13 in their review of the literature, cai et al. found that 50% of 7p duplications were the result of balanced reciprocal translocation carriers.3 reish et al. suggested that these could be an entire duplication table 1: comparative analysis of cases of de novo 7p duplication in the literature characteristic/clinical finding author and year of case report wolpert et al.4 2001 papadopoulou et al.1 2006 zahed et al.11 2007 chui et al.10 2011 present case region 7p11.2p14.1 7p13p22.1 7p22.1p22.3 7p22.1 7p21.1p22.2 size n/a n/a 5 mb 1.7 mb 16.5 mb confirmatory test wcp fish multicolour fish array cgh array cgh array cgh origin de novo de novo de novo de novo de novo karyotype 46.xy,?dup(7) (p14.1p11.2) 46,xx,dup(7).ish.dup(7) (p-ter>p13::p22.1>qter) 46,xy,add(7) (p22).arr cgh 7p22.3p22.1x3 46,xy.ish. subtle (41x2) .arr7p22.1x3 46,xy,dup(7) (p21p22). arr7p22.2p21.2x3 patient age/gender 25 years/male 9 months/female 1.6 years/male 2.4 years/male 3 years/male nationality or ethnicity caucasian greek lebanese peruvian omani dysmorphism no yes yes yes yes developmental delay no yes n/a yes yes consanguineous parents n/a no yes no yes hypotonia n/a no yes no yes high forehead yes n/a n/a yes yes low nasal bridge yes n/a n/a yes yes low-set ears n/a n/a yes yes no cardiovascular abnormalities yes n/a n/a yes no abnormal palmar creases no n/a n/a yes no skeletal anomalies no n/a n/a no no autism spectrum disorder yes no no no yes cryptorchidism no no bilateral yes bilateral ocular hypertelorism no n/a no yes yes n/a = not available; wcp = whole chromosome painting ; fish = fluorescence in situ hybridisation; cgh = comparative genomic hybridisation. de novo duplication of 7p21.1p22.2 in a child with autism spectrum disorder and craniofacial dysmorphism e418 | squ medical journal, august 2015, volume 15, issue 3 duplication.2,3 the critical region for physical and mental abnormalities is 7p15-pter;2 for craniofacial dysmorphism, it is 7p21.2,3,9 both these patient groups, viz. those with physical and mental abnormalities, have many specific features in common. the range of severity may depend on the size and genes involved. research has suggested that the glioma-associated oncogene family zinc finger 3 (omim entry *165240; 7p13), homeobox a13 (omim entry *142959; 7p15-7p14.2), twist family basic helix-loop-helix transcription factor 1 (twist1; omim entry *601622; 7p21), craniosynostosis type 1 (omim entry 123100; 7p21.3-7p21.2) and mesenchyme homeobox 2 (omim entry *600535; 7p22.1-7p21.3) genes are associated with phenotypic 7p syndromes.1 chui et al. reported a patient with microduplication at 7p22.1 (1.7 mb) who showed all of the common craniofacial features and had cryptorchidism, but did not have global developmental delay or hypotonia.10 although the region 7p22.1 contains 27 genes, 13 of which are omim-annotated, only one gene (β-actin [actb]; omim entry *102630; 7p22.1) was commonly observed in both chui et al.’s patient and the patient in the current report.10 this would mean that actb is likely to be the causative factor for features like hypotonia, global developmental delay and cryptorchidism in the current patient. the segmental size of the duplication in the current patient was larger than those reported elsewhere.10,11 furthermore, there was an association with asd. notably, two reports have associated 7p duplication with this disorder.4,12 wolpert et al. described an inverted duplication of 7p14.1p11.2 in an autistic adult, who lacked many of the characteristic features found in 7p duplication syndrome.4 this may indicate that the critical region was distal. the patient was normocephalic, had normal developmental milestones, meatal stenosis, bilateral esotropia and mild scoliosis.4 cukier et al. reported a pair of autistic first cousins carrying two microduplications, one of whom had a tandem duplication on 7p21 replicating part of the neurexophilin 1 (nxph1; omim entry *604639) and islet cell autoantigen 1 (ica1; omim entry *147625) genes.12 the patient in the current report was a child with direct duplication, clinical features of microcephaly and delayed milestones. none of the other features reported by cukier et al. were present in the current patient.12 however, both patients had common autistic phenotypes and behavioural features.12 the duplication was more proximal in cukier et al.’s case,12 whereas it was distal in the current patient. it has been suggested that the region within the duplication interval (7p21.1 to 7p22.2) observed in the current patient is the critical region for manifestations of the 7p duplication phenotype.13 this region of 7p contains the omim morbid gene twist1, duplications of which are thought to be the cause of the large fontanelles in these patients;13 it is hence likely to be the cause of the current patient’s clinical phenotype. the duplication region of this patient encompassed the whole of the twist1, ica1 and nxph1 genes. these genes, however, were not directly disrupted by the breakpoints of the duplication. the acgh analysis could not determine whether this duplication might have a position effect on the regulation of these genes. parental chromosomal studies confirmed that the duplication in the presently reported patient was de novo and did not occur from a balanced chromosomal rearrangement, which may sometimes occur as insertional translocations.14 these translocations underlie 2.1% of apparently observed de novo interstitial copy number changes detected by acgh.14 further molecular analysis is worth considering for genes of the duplicated region, particularly when they are associated with asd phenotypes, for further delineation of genotype-phenotype correlations. conclusion a de novo duplication of chromosomal region 7p21.1p 22.2 was identified in a three-year-old autistic child with craniofacial dysmorphism, global developmental delay, hypotonia and bilateral cryptorchidism. characterising the genes involved in duplication regions may help in understanding the genotype-phenotype correlation in 7p duplication patients. it may also reveal the possible role of these genes in asd. acgh analysis is an important tool in revealing genetic abnormalities among children with intellectual disabilities and dysmorphic features, as these are usually not detected by conventional cytogenetics. references 1. papadopoulou e, sifakis s, sarri c, gyftodimou j, liehr t, mrasek k, et al. a report of pure 7p duplication syndrome and review of literature. am j med genet a 2006; 140:2802–6. doi: 10.1002/ajmg.a.31538. 2. reish o, berry sa, dewald g, king ra. duplication of 7p. further delineation of the phenotype and restriction of the critical region to the distal part of the short arm. am j med genet 1996; 61:21–5. doi: 10.1002/(sici)10968628(19960102)61:1<21::aid-ajmg4>3.0.co;2-#. 3. cai t, yu p, tagle da, xia j. duplication of 7p21.2-->pter due to maternal 7p;21q translocation: implications for critical segment assignment in the 7p duplication syndrome. am j med genet 1999; 86:305–11. doi: 10.1002/(sici)10968628(19991008)86:4<305::aid-ajmg1>3.0.co;2-b. http://dx.doi.org/10.1002/ajmg.a.31538 http://dx.doi.org/10.1002/%28sici%291096-8628%2819960102%2961:1%3c21::aid-ajmg4%3e3.0.co%3b2-%23 http://dx.doi.org/10.1002/%28sici%291096-8628%2819960102%2961:1%3c21::aid-ajmg4%3e3.0.co%3b2-%23 http://dx.doi.org/10.1002/%28sici%291096-8628%2819991008%2986:4%3c305::aid-ajmg1%3e3.0.co%3b2-b http://dx.doi.org/10.1002/%28sici%291096-8628%2819991008%2986:4%3c305::aid-ajmg1%3e3.0.co%3b2-b achandira m. udayakumar, watfa al-mamari, abeer al-sayegh and adila al-kindy online case report | e419 10. chui jv, weisfeld-adams jd, tepperberg j, mehta l. clinical and molecular characterization of chromosome 7p22.1 microduplication detected by array cgh. am j med genet a 2011; 155a:2508–11. doi: 10.1002/ajmg.a.34180. 11. zahed l, pramparo t, farra c, mikati m, zuffardi o. a patient with duplication (7)(p22.1pter) characterized by arraycgh. am j med genet a 2007; 143a:168–71. doi: 10.1002/ ajmg.a.31511. 12. cukier hn, salyakina d, blankstein sf, robinson jl, sacharow s, ma d, et al. microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21. am j med genet b neuropsychiatr genet 2011; 156:493–501. doi: 10.1002/ ajmg.b.31188. 13. mégarbané a, le lorc’h m, elghezal h, joly g, gosset p, souraty n, et al. pure partial 7p trisomy including the twist, hoxa, and gl13 genes. j med genet 2001; 38:178–82. doi: 10.1136/jmg.38.3.178. 14. nowakowska ba, de leeuw n, ruivenkamp ca, sikkemaraddatz b, crolla ja, thoelen r, et al. parental insertional balanced translocations are an important cause of apparently de novo cnvs in patients with developmental anomalies. eur j hum genet 2012; 20:166–70. doi: 10.1038/ejhg.2011.157. 4. wolpert cm, donnelly sl, cuccaro ml, hedges dj, poole cp, wright hh, et al. de novo partial duplication of chromosome 7p in a male with autistic disorder. am j med genet 2001; 105:222–5. doi: 10.1002/ajmg.1258. 5. pallotta r, dalprà l, fusilli p, zuffardi o. further delineation of 7p trisomy: case report and review of literature. ann genet 1996; 39:152–8. 6. arens yh, toutain a, engelen jj, offermans jp, hamers aj, schrander jj, et al. trisomy 7p: report of 2 patients and literature review. genet couns 2000; 11:347–54. 7. monk d, wakeling el, proud v, hitchins m, abu-amero sn, stanier p, et al. duplication of 7p11.2-p13, including grb10, in silver-russell syndrome. am j hum genet 2000; 66:36–46. doi: 10.1086/302717. 8. kozma c, haddad br, meck jm. trisomy 7p resulting from 7p15;9p24 translocation: report of a new case and review of associated medical complications. am j med genet 2000; 91:286–90. doi: 10.1002/(sici)1096-8628(20000410)91:4<286 ::aid-ajmg9>3.0.co;2-2. 9. franz hb, schliephacke m, niemann g, mielke g, backsch c. de novo direct tandem duplication of a small segment of the short arm of chromosome 7 (p21.22-->22.1). clin genet 1996; 50:426–9. doi: 10.1111/j.1399-0004.1996.tb02401.x. http://dx.doi.org/10.1002/ajmg.a.34180 http://dx.doi.org/10.1002/ajmg.a.31511 http://dx.doi.org/10.1002/ajmg.a.31511 http://dx.doi.org/10.1002/ajmg.b.31188 http://dx.doi.org/10.1002/ajmg.b.31188 http://dx.doi.org/10.1136/jmg.38.3.178 http://dx.doi.org/10.1038/ejhg.2011.157 http://dx.doi.org/10.1002/ajmg.1258 http://dx.doi.org/10.1086/302717 http://dx.doi.org/10.1002/%28sici%291096-8628%2820000410%2991:4%3c286::aid-ajmg9%3e3.0.co%3b2-2 http://dx.doi.org/10.1002/%28sici%291096-8628%2820000410%2991:4%3c286::aid-ajmg9%3e3.0.co%3b2-2 http://dx.doi.org/10.1111/j.1399-0004.1996.tb02401.x sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. e479-481, epub. 25th jun 13 submitted 26th sep 12 revision req. 26th nov 12; revision recd. 9th dec 12 accepted 17th feb 13 1department of surgery, sultan qaboos university hospital, muscat, oman; 2department of plastic surgery, ganga hospital, coimbatore, india *corresponding author e-mail: gvenkat73@gmail.com البليفروسيل احلادث بعد األصابة يف بالغ فينكاتي�س جوفينداراجو و رافيندرا باراثي ر امللخ�ص: البليفرو�شيل هو جتمع ال�شائل النخاعي يف جفن العني. هذه احلالة من النادر حدوثها يف البالغني. هذا تقرير حالة ي�شف مري�س ظهر عندة بعد ا�شابة يف الراأ�س – تورم غري مرتد يف اجلفن العلوي االأي�رس وبالتايل حدوث ارتخاء ميكانيكي للجفن العلوي االأي�رس. عاين املري�س من ك�شور عدة يف عظام اجلمجمة يف منطقة العني �شملت حافة، �شقف، واجلداريني اجلانبيني لعظمة مقلة العني الي�رسى. وجد اي�شا �شمور جيب االأنف االأمامي للمري�س. اثبت الفح�س ال�رسيري وحتاليل الدم واالأ�شعات وجود البليفرو�شيل. مت اأ�شالح قطع االأم اجلافية القاعدي االأي�رس من خالل عظمة اجلمجمة ومت �شفاء املري�س ب�شورة جيدة مفتاح الكلمات: ال�شائل النخاعي؛ جفن العني؛ ك�رس عظام اجلمجمة، قاعدي؛ تقرير حالة؛ الهند. abstract: cerebrospinal fluid (csf) collection in the eyelid is known as blepharocele. it is rarely reported in adults. in this report, we describe one such patient who developed a non-resolving swelling of the left upper eyelid associated with mechanical ptosis following a head injury. he had fractures involving the left orbital rim and roof, and the medial and lateral walls. his left frontal sinus was hypoplastic. the diagnosis of csf blepharocele was made based on clinical, biochemical and radiological findings. he underwent transcranial repair of the left frontobasal dural tear with a good recovery. keywords: cerebrospinal fluid; eyelid; basilar skull fracture; case report; india. post-traumatic blepharocele in an adult *venkatesh govindaraju1 and ravindra bharathi2 online case report cerebrospinal fluid (csf) rhinorrhoea and otorrhoea are well-known complications of head injuries.1 very rarely, csf can enter the orbit and present as an orbitocele following a fracture of the orbital roof.2–5 when the csf collects in the eyelid it is known as blepharocele. only a few cases of blepharocele have been reported so far in english medical literature.6–12 most of the cases were seen in children. in this report, the management of one such rare case of post-traumatic blepharocele in an adult patient is discussed. case report a 43-year-old adult male presented with a swelling of the eye and the inability to open the left upper eyelid following a head injury which he had sustained the previous week. he also had traumatic optic nerve injury with complete loss of vision in the left eye after the injury. an initial computed tomography (ct) scan of the brain showed a mild left frontobasal contusion with fractures of the left frontal bone, the orbital rim and roof, and the medial and lateral walls. he was managed conservatively in a local health centre and later referred to ganga hospital, coimbatore, india, a tertiary referral hospital for further management since the swelling of his left upper eyelid was not subsiding. the patient was fully conscious and oriented. there was no csf rhinorrhoea or excessive tear secretion. he had no perception of light in the left eye. there was mechanical ptosis due to a soft boggy swelling of the left eyelid and eyebrow. a transillumination test was negative. the periorbital skin colour was normal and there was no ecchymosis. the ct scan showed non-enhancing fluid collection in the left eyelid which was isodense with the brain [figure 1]. the left frontal sinus was hypoplastic [figure 2]. the glucose content of the fluid was 87 mg/dl, which was consistent with csf. magnetic resonance imaging (mri) of the brain revealed a frontobasal dural defect with csf collection in the left upper eyelid [figure 3]. post-traumatic blepharocele in an adult 480 | squ medical journal, august 2013, volume 13, issue 3 the patient was referred for surgery. the bicoronal scalp flap was raised and a left frontal craniotomy was done. there was a comminuted fracture of the orbital rim with a depressed segment. a frontobasal dural defect was visualised and was repaired primarily with a pericranial graft. the orbital rim was reconstructed with a titanium plate and screws. postoperatively, the patient recovered well and the swelling of his left eyelid resolved completely. discussion head injuries can result in a csf fistula, which commonly occurs at the frontal sinus, cribriform plate, sphenoid sinus, and petrous bone. cranioorbital fistulas occur very rarely after a head injury and can result in csf leakage through the orbit (orbitorrhoea).4–5 rarely, csf may collect in the upper eyelid (blepharocele) or in the orbit (orbitocele).2,6–13 this results in a periorbital swelling and should be differentiated from a retrobulbar haematoma, orbital abscess, mucocele, or a foreign body cyst.4 when the orbital rim is fractured along with the anterior skull base with an associated dural tear, csf may enter the upper eyelid and present as blepharocele. when there is only csf collection in the eyelid, the swelling may be transilluminant.12 most cases of blepharocele and orbitocele have been reported in children. the patient in this report was an adult, which is rarely reported.8,12 this condition must be thought of in a patient who has a head injury with associated orbital fracture presenting with non-resolving eyelid swelling. galzio et al. described a cranial palpebral fistula that occurred in a patient with a fracture of the orbital roof.9 this patient had frontal sinus agenesis and the researchers formed a hypothesis that the absence of the frontal sinuses allowed the direct passage of csf into the upper eyelid after a head injury. the present case also had a hypoplastic frontal sinus which resulted in csf blepharocele instead of csf rhinorrhoea after the trauma, confirming the hypothesis. figure 1: computed tomography scan showing fluid collection in the left eyelid. figure 2: computed tomography scan with a bone window algorithm showing the hypoplastic left frontal sinus. figure 3: magnetic resonance imaging brain scan (sagittal t2 weighted image) showing cerebral spinal fluid collection in the left upper eyelid. venkatesh govindaraju and ravindra bharathi case report | 481 a high-resolution ct scan of the orbit and anterior skull base is useful in demonstrating the fracture of the orbital walls and rim, and the intraorbital csf collection. ct cisternography is the best investigation for localising the csf fistula in cases of rhinorrhoea and otorrhoea,7 but in the case of blepharocele, an mri is superior to ct cisternography in demonstrating the pathology and establishing the diagnosis. bhatoe described mri as the investigation of choice for diagnosing blepharocele.8 in the present case, mri clearly demonstrated the dural defect, and collection of csf in the eyelid was essential in making the decision for surgery. during surgery, the dural defect was identified and could have been closed either primarily or with a graft. postoperatively, the eyelid swelling resolved with a good cosmetic outcome. conclusion patients with a head injury who sustain fractures of the anterior skull base involving the orbital rim can present with csf blepharocele if the frontal sinus is hypoplastic. orbital ecchymosis is characterised by a discolouration of the eyelids. however, in csf blepharocele there is a swelling of the eyelid without discolouration. this should raise the suspicion of csf blepharocele in the appropriate clinical setting. a brain mri is the investigation of choice in establishing a diagnosis. conservative measures may not be helpful in managing this condition as they would be in cases of csf rhinorrohea or otorrohea. patients usually require surgical repair of the dural defect. references 1. arslantas a, vural m, atasoy ma, ozsandik a, topbas s, tel e. post-traumatic cerebrospinal fluid accumulation within the eyelid: a case report and review of the literature. childs nerv syst 2003; 19:54–6. 2. bagolini b. leakage of spinal fluid into the upper lid following trauma. arch opthal 1957; 57:454–6. 3. bergman ta, rockswold gl. cerebrospinal fluid fistulae. in: youmans jr, ed. neurological surgery. 4th ed. philadelphia: wb saunders, 1996. pp. 1840– 52. 4. bhandari ys. traumatic orbital pseudomeningocele. j neurosurg 1969; 30:612-14. 5. bhatoe hs. blepharocele following head injury. skull base 2002; 12:73–5. 6. colquhoun ir. ct cisternography in the investigation of cerebrospinal fluid rhinorrhea. clin radiol 1993; 47:403–8. 7. galzio rj, lucantoni d, zinobii m, grizzi lc. traumatic craniopalpebral cerebrospinal fistula. j neurosurg sci 1981; 25:105–7. 8. garza-mercado r, argon-lomas j, martinez garza j, hernandez l. cerebrospinal blepharocele. an unusual complication of head injuries. neurosurgery 1982; 11:525–6. 9. bhatoe hs. blepharocele following head injury in a child. indian j neurotrauma 2005; 2:51–3. 10. king ab. traumatic encephaloceles of the orbit. arch opthal 1951; 46:49–56. 11. mathew jm, haren rp, chandy mj. post traumatic blepharocele. neurol india 1997; 45:46–57. 12. salame k, segev y, fliss dm, ouknine ge. diagnosis and management of post traumatic oculorrhea. neurosurg focus 2000; 9:1–4. 13. sibony pa, anand ak, keuskamp pa, zippen ag. post-traumatic cerebrospinal fluid cyst of the orbit. j neurosurg 1985; 62:922–4. 14. till js, marion jr. cerebrospinal fluid masquerading as tears. south med j 1987; 80:639–40 departments of 1internal medicine and 8surgery, armed forces hospital, muscat, oman; departments of 2medicine and 5child health, sultan qaboos university hospital, muscat, oman; department of 3medicine and 4oncology royal hospital, muscat, oman; departments of 6pharmacology & clinical pharmacy, college of medicine & health sciences, sultan qaboos university, muscat, oman; 7department of endemic medicine & hepatology, faculty of medicine, cairo university, egypt *corresponding author’s e-mail: noumani73@gmail.com سرطان الكبد يف ُعمان نتائج حتليل 284 حالة خالد النعماين، زمزم اله�صامية، عمر ال�صيابي، من�صور املنذري، با�صم البحراين، �صهام ال�صنانية، اإبراهيم الزكواين، هبة عمر، �صعيد البو�صايف، هيفاء الزهيبية، عبد اهلل املعمري، بوال راجندرا كاماث، عبد اهلل الكلباين، اإكرام بريين abstract: objectives: hepatocellular carcinoma (hcc) is the most common type of primary liver tumour worldwide and is increasing in incidence. this study aimed to describe the clinical characteristics of hcc among omani patients, along with its major risk factors, outcomes and the role of surveillance. methods: this retrospective case-series study was conducted between january 2008 and december 2015 at the three main tertiary care hospitals in oman. all adult omani patients diagnosed with hcc and visited these hospitals during the study period were included. relevant data were collected from the patients’ electronic medical records. results: a total of 284 hcc patients were included in the analysis. the mean age was 61.02 ± 11.41 years and 67.6% were male. the majority had liver cirrhosis (79.9%), with the most common aetiologies being chronic hepatitis c (46.5%) and b (43.2%). only 13.7% of cases were detected by the hcc surveillance programme. approximately half of the patients (48.5%) had a single liver lesion and 31.9% had a liver tumour of >5 cm in size. approximately half (49.2%) had alpha-fetoprotein levels of ≥200 ng/ml. the majority (72.5%) were diagnosed using multiphase computed tomography alone. less than half of the patients (48.9%) were offered one or more hcc treatment modalities. conclusion: the majority of omani hcc patients were male and had cirrhosis due to viral hepatitis. in addition, few patients were identified by the national surveillance programme and presented with advanced disease precluding therapeutic or even palliative treatment. keywords: hepatocellular carcinoma; liver cirrhosis; human viral hepatitis; public health surveillance; early detection of cancer; alpha-fetoprotein; oman. امللخ�ص: الهدف: تتزايد معدالت حدوث �رسطان الكبد والذي يعد اأحد اأكرث اأورم الكبد االأولية �صيوًعا يف جميع اأنحاء العامل. تهدف الدرا�صة احلالية اإىل و�صف اخل�صائ�ض ال�رسيرية وامل�صببات الرئي�صية للمر�صى العمانيني امل�صابني ب�رسطان الكبد، وعر�ض نتائج املر�ض، وابراز اهمية الكبد �رسطان مر�صى جلميع االلكرتونية ال�صحية امللفات على ا�صرتجاعيه و�صفيه درا�صة اجريت الطريقة: للمر�ض. املبكر الت�صخي�ض العمانيني البالغني والذين مت متابعتهم وعالجهم يف امل�صت�صفيات املرجعية الرئي�صية الثالثة يف �صلطنة عمان خالل الفرتة الزمنية بني يناير 2008 ودي�صمرب 2015. النتائج: �صملت الدرا�صة 284 مري�ض م�صاب ب�رسطان الكبد، حيث بلغ متو�صط اعمار امل�صابني 11.41 ± 61.02 �صنة، وكانت غالبيتهم من الذكور )%67.6(، كما كانت الغالبية )%79.9( من امل�صابني تعاين من تزامن تليف الكبد، وكانت اأكرث االأ�صباب �صيوًعا لالإ�صابة بتليف الكبد هي التهابات الكبد املزمنة من جراء االإ�صابة بفريو�ض( ج ) بن�صبة )%46.5( او بفريو�ض( ب ) بن�صبة )%43.2(. اأظهرت الدرا�صة اأن %13.7 فقط من حاالت �رسطان الكبد مت ت�صخي�صها كنتيجة خل�صوع امل�صابني لفحو�صات الك�صف املبكر عن �رسطان الكبد. كما اأو�صحت الدرا�صة اأن ما يقرب من ن�صف املر�صى )%48.5( كان لديهم بوؤره �رسطانية كبديه واحده، وما يقرب من ثلث عدد املر�صى فيتوبروتني االألفا م�صتويات كانت )49.2%( املر�صى ن�صف من يقرب وما �صم، 5 من اأكرب بحجم الكبد يف بورم م�صاًبا كان )31.9%( لديهم اعلى من 200 نانوغرام/مل. مت ت�صخي�ض غالبية املر�صى )%72.5( با�صتخدام االأ�صعة املقطعية متعددة املراحل فقط. بينت الدرا�صة اأن حوايل ن�صف املر�صى امل�صمولني يف الدرا�صة )%48.9( خ�صع لو�صيله واحدة من الو�صائل املتعارف عليها لعالج �رسطان الكبد او اأكرث. اخلال�صة: كان غالبية املر�صى العمانيني امل�صابني ب�رسطان الكبد من الذكور الذين يعانون من تليف الكبد من جراء االإ�صابة بالتهابات الكبد الفريو�صيه. مت التعرف على ن�صبة قليله من املر�صى من خالل برنامج الك�صف املبكر عن �رسطان الكبد، و مت ت�صخي�صهم يف مراحل متقدمة من املر�ض حالت دون تقدمي عالج �صاف او الرعاية التلطيفية لهم. الكلمات املفتاحية: �رسطان الكبد؛ تليف الكبد؛ التهاب الكبد الفريو�صي؛ مراقبة ال�صحة العامة؛ الك�صف املبكر عن ال�رسطان؛ األفا فيتوبروتني؛ ُعمان. hepatocellular carcinoma in oman an analysis of 284 cases *khalid al-naamani,1 zamzam al-hashami,2 omar al-siyabi,3 mansour al-moundri,2 bassim al-bahrani,4 siham al-sinani,5 ibrahim al-zakwani,6 heba omar,7 said a. al-busafi,2 haifa al-zuhaibi,2 abdullah almamari,8 bola r. kamath,1 abdullah al-kalbani,1 ikram ali burney2 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e316–322, epub. 5 oct 20 submitted 22 oct 19 revisions req. 25 dec 19 & 6 feb 20; revisions recd. 21 jan & 14 feb 20 accepted 19 feb 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.011 clinical & basic research advances in knowledge this study provides clear descriptive data regarding the epidemiology of hepatocellular carcinoma (hcc) and its risk factors in oman, along with the most frequent presentation of hcc cases and commonly used treatment modalities. https://creativecommons.org/licenses/by-nd/4.0/ khalid al-naamani, zamzam al-hashami, omar al-siyabi, mansour al-moundri, bassim al-bahrani, siham al-sinani, et al. clinical and basic research | e317 hepatocellular carcinoma (hcc) is one of the most common cancers around the globe and represents a leading cause of cancer-related mortality.1 however, there is marked variation in the prevalence of hcc in different parts of the world, with more than two-thirds of cases reported from east and south asia as well as subsaharan africa.2 this is mainly due to differences in the prevalence of viral hepatitis, particularly hepatitis b and c, the predominant causes of liver cirrhosis, a known risk factor for hcc.3 the introduction of hepatitis b vaccination in many countries has led to a marked reduction in hcc cases. the improvements in medical facilities with designated screening programmes similarly expected to help increase the detection rate and, therefore, improve the outcome of hcc.4–9 despite recent marked improvements in treatment modalities, the prognosis for hcc patients remains poor, with an average five-year survival rate of approximately ~5–6%.10 unfortunately, this is largely attributable to a lack of access to medical facilities in many underdeveloped countries.11 international guidelines recommend that hcc surveillance be performed on a six-month basis using liver ultrasonography (us), with or without measurement of alpha-fetoprotein (afp) levels, for adults with liver cirrhosis and high-risk patients without cirrhosis such as patients with hepatitis b virus (hbv) infections.12,13 according to a meta-analysis of 47 studies, there is a significant association between hcc surveillance and detection of the tumour at an early stage, thereby increasing the likelihood of success for curative treatments such as surgical resection and liver transplantation and ultimately improving overall survival.14 in oman, the estimated prevalence of the hepatitis c virus (hcv) is approximately 0.4% with genotype 1 being the most common followed by genotypes 3 and 4.15 moreover, prior to the introduction of mass hepatitis b vaccinations in 1990, the estimated prevalence of hbv was 2–7%.16,17 overall, hcc is ranked the fourth most common solid tumour among omani male patients.18 however, there is a lack of national data evaluating the characteristics of hcc cases. as such, the primary objective of this study was to describe the clinical characteristics of hcc cases in oman, with the secondary objectives being to determine the major risk factors, role of surveillance and outcomes of hcc among omani patients. methods this retrospective case-series study was conducted from january 2008 to december 2015 at the sultan qaboos university hospital, armed forces hospital and the royal hospital. all adult omani patients with one or more hepatic lesions who have been diagnosed with hcc were included in the study. nonomani patients and those with benign liver lesions, liver metastasis from a primary distant tumour, cholangiocarcinomas or hepatoblastomas were excluded, as were patients for whom there was no data concerning the number and size of hcc lesion(s). the sample was considered to be nationally representative as these three hospitals are the main tertiary hospitals in the capital city of muscat and are the centres to which all hcc cases are referred to from other regions of oman. relevant data were collected from the electronic medical records at each hospital including information regarding the patients’ sociodemographic characteristics, laboratory findings, tumour aetiology, characteristics and radiological features at the time of presentation as well as the treatment modalities offered. in all cases, the diagnosis of hcc was based on the criteria of the american association for the study of liver disease in terms of typical enhancement patterns upon radiological examination or histopathological analysis.13,19 moreover, the severity of liver cirrhosis cases was classified using the child-pugh scoring system as either class a (scores of 5–6), class b (scores of 7–9) or class c (scores of 10–15).20 detailed information concerning each patient was available from the electronic medical record systems of each of the three participating hospitals along with the findings of any laboratory and radiological investigations conducted both at first presentation and during subsequent visits. patients were either seen initially at one of the three tertiary hospitals or were referred immediately after the initial diagnosis of hcc. laboratory and radiological investigations were repeated for all referred patients at presentation to each of the three tertiary hospitals. in addition, hcc cases were assessed according to the milan criteria regarding their suitability for application to patient care the findings of this study emphasise the importance of appropriate hcc screening for high-risk patients and the implementation of primary prevention strategies and early detection to reduce the rate of hcc and the negative patient outcomes associated with the disease. hepatocellular carcinoma in oman an analysis of 284 cases e318 | squ medical journal, august 2020, volume 20, issue 3 liver transplantation.21 based on overall and diseasefree survival rates, these guidelines state that only patients with one lesion of <5 cm in size or up to three lesions of <3 cm each and with no evidence of extrahepatic disease or vascular invasion are eligible for transplantation.21 performance status was assessed using the eastern clinical oncology group (ecog) scale as follows: grade zero (fully active and able to continue all pre-disease activities without restriction); grade 1 (restricted in physically strenuous activities but ambulatory and able to carry out work of a light or sedentary nature); grade 2 (ambulatory, out of bed for >50% of waking hours and capable of unrestricted self-care, but unable to carry out any work activities); grade 3 (capable of limited self-care and confined to a bed or chair for >50% of waking hours); or grade 4 (completely disabled, unable to perfom any self-care and totally confined to a bed or chair).22 the statistical analyses were conducted using stata® data analysis and statistical software, version 14.2 (statacorp llc, college station, texas, usa). categorical variables were reported using frequencies and percentages, while continuous variables were presented using means and standard deviations. the association between afp levels and status of transplantation eligibility according to the milan criteria was examined using a pearson’s chi-squared test. the a priori two-tailed level of significance was set at p <0.050. this study was approved by the individual institutional research and ethics committees of the sultan qaboos university hospital, armed forces hospital and the royal hospital. results a total of 284 hcc patients were included in the final analysis. the mean age was 61.02 ± 11.41 years (range: 24–84 years) and 67.6% were male. overall, 227 patients (79.9%) had liver cirrhosis, most frequently classified as child-pugh class b (36.8%) followed by class a (34.1%) and class c (29.2%). the underlying aetiology of the liver cirrhosis could be determined in 213 patients (75%); of these cases, the majority were caused by hcv (46.5%) or hbv (43.2%) infections [table 1]. only 39 patients (13.7%) were identified via the surveillance programme using afp and liver us every table 1: sociodemographic and clinical characteristics of omani patients with hepatocellular carcinoma (n = 284) characteristic n (%) mean age in years ± sd 61.02 ± 11.41 gender male 192 (67.6) female 92 (32.4) presence of liver cirrhosis yes 227 (79.9) no 57 (20.1) class of liver cirrhosis* class a 76 (34.1) class b 82 (36.8) class c 65 (29.2) aetiology of liver cirrhosis† hcv 99 (46.5) hbv 92 (43.2) alcoholic liver disease 20 (9.4) cryptogenic 2 (0.9) sd = standard deviation; hcv = hepatitis c virus; hbv = hepatitis b virus. *according to the child-pugh scoring system.19 total dataset for this vari able was 223 as four patients were excluded due to missing data. †total dataset for this variable was 213 as aetiology could not be determined in 10 cases. table 2: tumour characteristics of omani patients with hepatocellular carcinoma (n = 284) characteristic n (%) number of lesions* 1 127 (48.5) 2–3 34 (13) >3 65 (24.8) diffuse lesions 36 (13.7) size of lesions in cm† <2 36 (13.7) 2–5 101 (38.4) >5 84 (31.9) diffuse lesions 42 (16) afp level in ng/ml‡ <200 123 (50.8) 200–400 13 (5.4) >400 106 (43.8) eligibility for transplantation§ eligible 65 (22.9) afp = alpha-fetoprotein. *total dataset for this variable was 262 as 22 patients were excluded due to missing data. †total dataset for this variable was 263 as 21 patients were excluded due to missing data. ‡total data set for this variable was 242 as 42 patients were excluded due to missing data. §according to the milan criteria.20 khalid al-naamani, zamzam al-hashami, omar al-siyabi, mansour al-moundri, bassim al-bahrani, siham al-sinani, et al. clinical and basic research | e319 six months. to confirm the diagnosis, the majority of patients (72.5%) required one modality of imaging (multiphase computed tomography [ct] of the liver), with the remaining patients (27.5%) requiring two modalities (both multiphase ct and contrastenhanced magnetic resonance imaging [mri] of the liver). just under half of the patients (48.5%) had a single focal lesion. in 38.4% of patients, the focal lesions ranged in diameter from 2–5 cm. approximately half of the cohort (50.8%) had afp levels of <200 ng/ml, while only 21.8% were considered suitable for liver transplantation as per the milan criteria [table 2]. there was a significant association between afp levels and transplantation eligibility according to the milan criteria, with 36.6% and 16.7% of patients with afp levels of ≤400 and >400 ng/ml, respectively, considered suitable for liver transplantation (p <0.001) [table 3]. overall, 48.9% were offered one of more modalities of treatment including tumour resection, radiofrequency ablation (rfa), transarterial chemoembolisation, kinase inhibitor drug therapy (in the form of sorafenib) and liver transplantation. however, the remaining 51.1% of patients were beyond curative treatment due to advanced disease stage, the presence of comorbidities and/or poor performance status (i.e. ecog scores of >2) at presentation [table 4]. discussion the oman national cancer registry was first established in 1985 as a hospital-based endeavour, before being incorporated under the umbrella of the department of non-communicable diseases surveillance and control of the ministry of health in 1996. subsequently, the notification and record of all cancer cases in the country was made mandatory in 2001.23 despite governmental efforts, some cancer cases are still not registered in oman for a variety of reasons, including the fact that a considerable number of patients choose to seek diagnosis and medical treatment abroad. to the best of the authors’ knowledge, this study is the first of its kind to analyse the characteristics and risk factors of omani patients with hcc. in the current study, the majority of omani hcc patients were older males. research has shown that hcc is much more common in men, possibly due to behaviours linked to known hcc risk factors such as alcohol consumption and smoking.24 moreover, epidemiological studies from other parts of the world have shown that the incidence of hcc increases with age, although the age of peak incidence varies; for example, hcc incidence increases progressively until 70 years of age in taiwan, whereas it reportedly peaks at 55 years in africa.25,26 high incidence rates in older patients could be attributed to longer durations of viral hepatitis infections leading to advanced fibrosis and cirrhosis. however, the effect of age per se cannot be excluded, since other solid organ tumours also occur at a higher rate in older patients.27 mcmahon et al. reported that an annual hcc incidence of 0.26% in <20-year-old males with hbv, which increased to 1.1% for those aged >50 years.4 the most prevalent risk factor for hcc in the present study was cirrhosis affecting 79.9% of cases. table 3: association between alpha-fetoprotein levels and eligibility for transplantation among omani patients with hepatocellular carcinoma (n = 284)* eligibility for transplantation† afp category,‡ n (%) p value low (n = 131) high (n = 102) eligible 48 (36.6) 17 (16.7) 0.001 ineligible 83 (63.4) 85 (83.3) afp = alpha-fetoprotein. *total dataset was 233 as 51 patients were excluded due to missing data; †according to the milan criteria;20 ‡afp levels were considered high or low at >400 and ≤400 ng/ml, respectively. table 4: treatment modalities offered to omani patients with hepatocellular carcinoma (n = 284) modality n (%) none 145 (51.1) resection alone 14 (4.9) resection plus rfa 2 (0.7) resection plus tace 1 (0.4) resection plus transplantation 2 (0.7) resection plus sorafenib 2 (0.7) rfa alone 16 (5.6) rfa plus tace 5 (1.8) rfa, tace and sorafenib 2 (0.7) rfa plus sorafenib 3 (1.1) tace alone 31 (10.9) tace plus sorafenib 20 (7) tace plus transplantation 1 (0.4) resection, tace and sorafenib 2 (0.7) resection, rfa, tace and sorafenib 1 (0.4) transplantation alone 2 (0.7) sorafenib alone 33 (11.6) transplantation plus sorafenib 2 (0.7) rfa = radiofrequency ablation; tace = transarterial chemoembolisation. hepatocellular carcinoma in oman an analysis of 284 cases e320 | squ medical journal, august 2020, volume 20, issue 3 cirrhosis is a well-known risk factor for hcc; the annual risk of developing hcc is 1–6% for cirrhotic patients with up to 60–80% of hcc patients having underlying cirrhosis.28,29 this wide range in reported incidence reflects differences in the population being studied, for instance in terms of age, gender, aetiology and duration of cirrhosis.29 ethnicity has also been noted to play a role in the incidence of hcc.30,31 the high incidence of hcc in young african patients is most likely secondary to multiple additive factors, such as genetic background, hbv infection and exposure to aflatoxins.24,32 in the current study, hcv was the most common cause of cirrhosis followed by hbv. this is unsurpising, given the dramatic reduction in the seroprevalence of chronic hbv infections in oman following the successful introduction of hbv vaccination in 1990.17 similar findings have also been reported in saudi arabia.33 various decision analysis models have demonstrated the cost-effectiveness of hcc surveillance.34,35 according to these models, twice yearly surveillance is indicated if the incidence of hcc is ≥1.5% per year.34,35 based on international guidelines and recorded tumour doubling time, the hcc surveillance programme in oman involves biannual liver us and serum afp level evaluations.12,13 unfortunately, only 13.7% of patients in the present cohort were detected as a result of this programme. this can be attributed to the asymptomatic nature of most liver diseases or the fact that many individuals choose not to seek routine medical attention until later in life. moreover, many omani patients may lack awareness of the complications of viral hepatitis and the importance of surveillance in the early detection and treatment of hcc. furthermore, patients with hbv infections may have been considered to have chronic inactive hepatitis and thus were not included within the surveillance programme. in a meta-analysis of 19 studies, singal et al. observed that twice yearly surveillance using liver us increased the sensitivity for detecting early-stage hcc to 70%.36 similarly, santi et al. demonstrated a higher detection rate of early-stage hcc cases with biannual rather than annual surveillance, leading to a high cure rate and better prognosis.37 however, decreasing the surveillance interval from six to three months was not found to result in any additional benefit to survival.38 a systematic review of nine studies showed that hcc surveillance rates were significantly higher among patients seen by gastroenterology subspecialists compared to those attended by primary care physicians (51.7% versus 16.9%; p <0.001).39 increasing awareness of liver diseases among medical staff, screening highrisk patients, encouraging early referral of suspected cases and actively counseling patients and their families are recommended measures to enhance the effectiveness of the national hcc surveillance programme in oman. previous research has provided evidence regarding the limited usefulness of afp as a screening modality for hcc.34,35,40 indeed, 50.8% of hcc patients in the present study had afp levels of <200 ng/ml. according to trevisani et al., an afp cutoff value of 20 ng/ml provides the optimal balance between sensitivity and specificity; however, at this level, the sensitivity is low.41 elevated afp levels have been described in non-hcc liver lesions such as intrahepatic cholangiocarcinomas and in cases of liver metastasis from the colon and stomach.42–44 an interesting observation in the present study was the significant association between high afp levels (>400 ng/ml) and ineligibility for liver transplantation as per the milan criteria.21 this confirms findings reported by tangkijvanich et al. in which the researchers described an association between high serum afp levels and large tumour size, bilobar involvement, massive or diffuse-type tumours and portal vein tumour thrombus.45 this is worth investigating further in larger-scale prospective studies. abdominal us was the most frequently employed modality for hcc screening in the current study. however, the diagnosis of hcc was based on multiphase liver ct in the majority of patients (72.5%). generally, us has been reported to have a sensitivity of 65–80% and a specificity of >90% when used as a screening test.46 however, the accuracy of this modality is operator-dependent as a small hcc lesion may be missed against the background of a multinodular liver. in addition, us has lower sensitivity for the detection of early-stage hcc in obese patients and patients with fatty livers.13,47 as such, abdominal us should be followed by multiphase ct of the liver or contrast-enhanced mri in order to identify small or early-stage and small hccs.13,48 however, only a minority of the patients in the present study required more than one modality for the diagnosis of hcc due to atypical radiological patterns. unfortunately, less than half of the patients in the present study were offered treatment. among those who were, various modalities were employed, either alone or in combination, to treat patients with different stages of hcc. few patients received curative treatment in the form of liver resection, rfa or liver transplantation. in many cases, treatment was limited due to high child-pugh scores—with approximately two-thirds of the patients categorised as class b or c— khalid al-naamani, zamzam al-hashami, omar al-siyabi, mansour al-moundri, bassim al-bahrani, siham al-sinani, et al. clinical and basic research | e321 poor performance status (ecog scores of >2) and/ or advanced stages of disease based on the barcelona clinic liver cancer staging system.49 this study was limited by certain factors. due to its retrospective nature, some data were missing for certain variables. moreover, several patients presented in an advanced stage of disease with comorbidities such as renal failure which precluded the use of radiological investigations such as multiphase ct or contrastenhanced mri for definitive diagnosis and staging. another major limitation was the inability to report the true incidence and trend of hcc cases in oman due to the fact that some patients were diagnosed and treated outside of the country. conclusion this study represents the first of its kind to describe the clinical characteristics and risk factors of hcc in oman. the majority of patients were male and had liver cirrhosis caused by viral hepatitis. in addition, approximately two-thirds presented with advanced disease (child-pugh classes b or c). there is an urgent need to enhance the existing hcc surveillance programme in order to encourage early detection of hcc and increase the likelihood of curative treatment. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r c o n t r i b u t i o n s all authors participated in this research. kn contributed to the draft conception, concept design and writing of the manuscript, while zh and ss contributed to the concept design and writing of the manuscript. iz and ho contributed to the data analysis. all other authors contributed equally to the writing of the manuscript including mm, bb, os, sab, am, hz, brk, ak and iab. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin 2011; 61:69–90. https://doi. org/10.3322/caac.20107. 2. choo sp, tan wl, goh bk, tai wm, zhu ax. comparison of hepatocellular carcinoma in eastern versus western popula tions. cancer 2016; 122:3430–46. https://doi.org/10.1002/cncr.3 0237. 3. dhanasekaran r, limaye a, cabrera r. hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. hepat med 2012; 4:19–37. https://doi.org/10.2147/hmer.s16316. 4. mcmahon bj, alberts sr, wainwright rb, bulkow l, lanier ap. hepatitis b-related sequelae: prospective study in 1400 hepatitis b surface antigen-positive alaska native carriers. arch intern med 1990; 150:1051–4. https://doi.org/10.1001/ archinte.150.5.1051. 5. sherman m, peltekian km, lee c. screening for hepatocellular carcinoma in chronic carriers of hepatitis b virus: incidence and prevalence of hepatocellular carcinoma in a north american urban population. hepatology 1995; 22:432–8. https://doi. org/10.1002/hep.1840220210. 6. fattovich g, giustina g, schalm sw, hadziyannis s, sancheztapias j, almasio p, et al. occurrence of hepatocellular carcinoma and decompensation in western european patients with cirrhosis type b: the eurohep study group on hepatitis b virus and cirrhosis. hepatology 1995; 21:77–82. https://doi. org/10.1002/hep.1840210114. 7. fattovich g, giustina g, degos f, tremolada f, diodati g, almasio p, et al. morbidity and mortality in compensated cirrhosis type c: a retrospective follow-up study of 384 patients. gastroenterology 1997; 112:463–72. https://doi. org/10.1053/gast.1997.v112.pm9024300. 8. bruix j, barrera jm, calvet x, ercilla g, costa j, sancheztapias jm, et al. prevalence of antibodies to hepatitis c virus in spanish patients with hepatocellular carcinoma and hepatic cirrhosis. lancet 1989; 2:1004–6. https://doi.org/10.1016/ s0140-6736(89)91015-5. 9. niederau c, lange s, heintges t, erhardt a, buschkamp m, hürter d, et al. prognosis of chronic hepatitis c: results of a large, prospective cohort study. hepatology 1998; 28:1687–95. https://doi.org/10.1002/hep.510280632. 10. buonaguro l, petrizzo a, tagliamonte m, tornesello ml, buonaguro fm. challenges in cancer vaccine development for hepatocellular carcinoma. j hepatol 2013; 59:897–903. https:// doi.org/10.1016/j.jhep.2013.05.031. 11. ladep ng, lesi oa, mark p, lemoine m, onyekwere c, afihene m, et al. problem of hepatocellular carcinoma in west africa. world j hepatol 2014; 6:783–92. https://doi.org/10.4254/wjh. v6.i11.783. 12. omata m, cheng al, kokudo n, kudo m, lee jm, jia j, et al. asia-pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. hepatol int 2017; 11:317–70. https://doi.org/10.1007/s12072-017-9799-9. 13. marrero ja, kulik lm, sirlin cb, zhu ax, finn rs, abecassis mm, et al. diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american assoc iation for the study of liver diseases. hepatology 2018; 68:723–50. https://doi.org/10.1002/hep.29913. 14. singal ag, pillai a, tiro j. early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. plos med 2014; 11:e1001624. https://doi.org/10.1371/journal.pmed.1001624. 15. blach s, zeuzem s, manns m, altraif i, duberg as, muljono dh, et al. global prevalence and genotype distribution of hepatitis c virus infection in 2015: a modelling study. lancet gastroenterol hepatol 2017; 2:161–76. https://doi.org/10.1016/s2468-1253(16) 30181-9. 16. al-naamani k, al-maqbali a, al-sinani s. characteristic of hepatitis b infection in a sample of omani patients. sultan qaboos univ med j 2013; 13:380–5. https://doi. org/10.12816/0003259. 17. al awaidy st, bawikar sp, al busaidy ss, al mahrouqi s, al baqlani s, al obaidani i, et al. progress toward elimination of hepatitis b virus transmission in oman: impact of hepatitis b vaccination. am j trop med hyg 2013; 89:811–15. https://doi. org/10.4269/ajtmh.13-0333. 18. al-lawati ja, santhosh-kumar cr, mohammed aj, jaffer ma. cancer incidence in oman, 1993-1997. east mediterr health j 1999; 5:1035–41. https://doi.org/10.3322/caac.20107 https://doi.org/10.3322/caac.20107 https://doi.org/10.1002/cncr.30237 https://doi.org/10.1002/cncr.30237 https://doi.org/10.2147/hmer.s16316 https://doi.org/10.1001/archinte.150.5.1051 https://doi.org/10.1001/archinte.150.5.1051 https://doi.org/10.1002/hep.1840220210 https://doi.org/10.1002/hep.1840220210 https://doi.org/10.1002/hep.1840210114 https://doi.org/10.1002/hep.1840210114 https://doi.org/10.1053/gast.1997.v112.pm9024300 https://doi.org/10.1053/gast.1997.v112.pm9024300 https://doi.org/10.1016/s0140-6736%2889%2991015-5 https://doi.org/10.1016/s0140-6736%2889%2991015-5 https://doi.org/10.1002/hep.510280632 https://doi.org/10.1016/j.jhep.2013.05.031 https://doi.org/10.1016/j.jhep.2013.05.031 https://doi.org/10.4254/wjh.v6.i11.783 https://doi.org/10.4254/wjh.v6.i11.783 https://doi.org/10.1007/s12072-017-9799-9 https://doi.org/10.1002/hep.29913 https://doi.org/10.1371/journal.pmed.1001624 https://doi.org/10.1016/s2468-1253%2816%2930181-9 https://doi.org/10.1016/s2468-1253%2816%2930181-9 https://doi.org/10.12816/0003259 https://doi.org/10.12816/0003259 https://doi.org/10.4269/ajtmh.13-0333 https://doi.org/10.4269/ajtmh.13-0333 hepatocellular carcinoma in oman an analysis of 284 cases e322 | squ medical journal, august 2020, volume 20, issue 3 19. bruix j, sherman m; american association for the study of liver diseases. management of hepatocellular carcinoma: an update. hepatology 2011; 53:1020–2. https://doi.org/10.1002/ hep.24199. 20. pasqualetti p, di lauro g, festuccia v, giandomenico g, casale r. prognostic value of pugh’s modification of child-turcotte classification in patients with cirrhosis of the liver. panminerva med 1992; 34:65–8. 21. mazzaferro v, regalia e, doci r, andreola s, pulvirenti a, bozzetti f, et al. liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. n engl j med 1996; 334:693–9. https://doi.org/10.1056/ nejm199603143341104. 22. oken mm, creech rh, tormey dc, horton j, davis te, mcfadden et, et al. toxicity and response criteria of the eastern cooperative oncology group. am j clin oncol 1982; 5:649–55. https://doi.org/10.1097/00000421-198212000-00014. 23. nooyi sc, al-lawati ja. cancer incidence in oman, 19982006. asian pac j cancer prev 2011; 12:1735–8. 24. barazani y, hiatt jr, tong mj, busuttil rw. chronic viral hepatitis and hepatocellular carcinoma. world j surg 2007; 31:1243–8. https://doi.org/10.1007/s00268-007-9041-3. 25. beasley rp, hwang ly, lin cc, chien cs. hepatocellular carcinoma and hepatitis b virus: a prospective study of 22 707 men in taiwan. lancet 1981; 2:1129–33. https://doi. org/10.1016/s0140-6736(81)90585-7. 26. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin 2005; 55:74–108. https://doi. org/10.3322/canjclin.55.2.74. 27. william b. ershler, dan l. longo, aging and cancer: issues of basic and clinical science, j natl cancer inst 1997; 89:1489–97. https://doi.org/10.1093/jnci/89.20.1489. 28. mcglynn ka, london wt. epidemiology and natural history of hepatocellular carcinoma. best pract res clin gastroenterol 2005; 19:3–23. https://doi.org/10.1016/j.bpg.2004.10.004. 29. chiesa r, donato f, tagger a, favret m, ribero ml, nardi g, et al. etiology of hepatocellular carcinoma in italian patients with and without cirrhosis. cancer epidemiol biomarkers prev 2000; 9:213–16. 30. nguyen mh, whittemore as, garcia rt, tawfeek sa, ning j, lam s, et al. role of ethnicity in risk for hepatocellular carci noma in patients with chronic hepatitis c and cirrhosis. clin gastroenterol hepatol 2004; 2:820–4. https://doi.org/10.1016/ s1542-3565(04)00353-2. 31. el-serag hb. epidemiology of hepatocellular carcinoma in usa. hepatol res 2007; 37:s88–94. https://doi.org/10.1111/ j.1872-034x.2007.00168.x. 32. liu y, wu f. global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. environ health perspect 2010; 118:818–24. https://doi.org/10.1289/ehp.0901388. 33. alkhayyat s, fallatah hi, akbar ho, al ahwal, ms, al ghamdi ws. causes and stages of hepatocellular carcinoma at patient presentation at a tertiary medical center in western saudi arabia. j cancer ther 2014; 5:1303–10. https://doi.org/10.4236/ jct.2014.514130. 34. sarasin fp, giostra e, hadengue a. cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with child-pugh class a cirrhosis. am j med 1996; 101:422–34. https://doi.org/10.1016/s0002-9343(96)00197-0. 35. arguedas mr, chen vk, eloubeidi ma, fallon mb. screening for hepatocellular carcinoma in patients with hepatitis c cirrhosis: a cost-utility analysis. am j gastroenterol 2003; 98:679–90. https://doi.org/10.1111/j.1572-0241.2003.07327.x. 36. singal a, volk ml, waljee a, salgia r, higgins p, rogers ma, et al. meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. aliment pharmacol ther 2009; 30:37–47. https://doi.org/10.1111/j.13652036.2009.04014.x. 37. santi v, trevisani f, gramenzi a, grignaschi a, mirici-cappa f, del poggio p, et al. semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. j hepatol 2010; 53:291–7. https://doi. org/10.1016/j.jhep.2010.03.010. 38. trinchet jc, chaffaut c, bourcier v, degos f, henrion j, fontaine h, et al. ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3and 6-month perio dicities. hepatology 2011; 54:1987–97. https://doi.org/10.1002/ hep.24545. 39. singal ag, yopp a, skinner cs, packer m, lee wm, tiro ja. utilization of hepatocellular carcinoma surveillance among american patients: a systematic review. j gen intern med 2012; 27:861–7. https://doi.org/10.1007/s11606-011-1952-x. 40. lin os, keeffe eb, sanders gd, owens dk. cost-effectiveness of screening for hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis c. aliment pharmacol ther 2004; 19:1159–72. https://doi.org/10.1111/j.1365-2036.2004.01963.x. 41. trevisani f, d’intino pe, morselli-labate am, mazzella g, accogli e, caraceni p, et al. serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of hbsag and anti-hcv status. j hepatol 2001; 34:570–5. https://doi.org/10.1016/s0168-8278 (00)00053-2. 42. sherman m. alphafetoprotein: an obituary. j hepatol 2001; 34:603–5. https://doi.org/10.1016/s0168-8278(01)00025-3. 43. adachi y, tsuchihashi j, shiraishi n, yasuda k, etoh t, kitano s. afp-producing gastric carcinoma: multivariate analysis of prognostic factors in 270 patients. oncology 2003; 65:95–101. https://doi.org/10.1159/000072332. 44. sato y, sekine t, ohwada s. alpha-fetoprotein-producing rectal cancer: calculated tumor marker doubling time. j surg oncol 1994; 55:265–8. https://doi.org/10.1002/jso.2930550414. 45. tangkijvanich p, anukulkarnkusol n, suwangool p, lertmaharit s, hanvivatvong o, kullavanijaya p, et al. clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. j clin gastroenterol 2000; 31:302–8. https://doi.org/10.1097/00004836-200012000-00007. 46. bolondi l. screening for hepatocellular carcinoma in cirrhosis. j hepatol 2003; 39:1076–84. https://doi.org/10.1016/s01688278(03)00349-0. 47. singal a, volk ml, waljee a, et al. meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. aliment pharmacol ther 2009; 30:37–47. https://doi.org/10.1111/j.1365-2036.2009.04014.x. 48. easl clinical practice guidelines: management of hepato cellular carcinoma. j hepatol 2018; 69:182–236. https://doi. org/10.1016/j.jhep.2018.03.019. 49. llovet jm, fuster j, bruix j; barcelona-clínic liver cancer group. the barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. liver transpl 2004; 10:s115–20. https://doi.org/10.1002/lt.20034. https://doi.org/10.1002/hep.24199 https://doi.org/10.1002/hep.24199 https://doi.org/10.1056/nejm199603143341104 https://doi.org/10.1056/nejm199603143341104 https://doi.org/10.1097/00000421-198212000-00014 https://doi.org/10.1007/s00268-007-9041-3 https://doi.org/10.1016/s0140-6736%2881%2990585-7 https://doi.org/10.1016/s0140-6736%2881%2990585-7 https://doi.org/10.3322/canjclin.55.2.74 https://doi.org/10.3322/canjclin.55.2.74 https://doi.org/10.1093/jnci/89.20.1489 https://doi.org/10.1016/j.bpg.2004.10.004 https://doi.org/10.1016/s1542-3565%2804%2900353-2 https://doi.org/10.1016/s1542-3565%2804%2900353-2 https://doi.org/10.1111/j.1872-034x.2007.00168.x https://doi.org/10.1111/j.1872-034x.2007.00168.x https://doi.org/10.1289/ehp.0901388 https://doi.org/10.4236/jct.2014.514130 https://doi.org/10.4236/jct.2014.514130 https://doi.org/10.1016/s0002-9343%2896%2900197-0 https://doi.org/10.1111/j.1572-0241.2003.07327.x https://doi.org/10.1111/j.1365-2036.2009.04014.x https://doi.org/10.1111/j.1365-2036.2009.04014.x https://doi.org/10.1016/j.jhep.2010.03.010 https://doi.org/10.1016/j.jhep.2010.03.010 https://doi.org/10.1002/hep.24545 https://doi.org/10.1002/hep.24545 https://doi.org/10.1007/s11606-011-1952-x https://doi.org/10.1111/j.1365-2036.2004.01963.x https://doi.org/10.1016/s0168-8278%2800%2900053-2 https://doi.org/10.1016/s0168-8278%2800%2900053-2 https://doi.org/10.1016/s0168-8278%2801%2900025-3 https://doi.org/10.1159/000072332 https://doi.org/10.1002/jso.2930550414 https://doi.org/10.1097/00004836-200012000-00007 https://doi.org/10.1016/s0168-8278%2803%2900349-0 https://doi.org/10.1016/s0168-8278%2803%2900349-0 https://doi.org/10.1111/j.1365-2036.2009.04014.x https://doi.org/10.1016/j.jhep.2018.03.019 https://doi.org/10.1016/j.jhep.2018.03.019 https://doi.org/10.1002/lt.20034 clinical & basic research sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 449-457, epub. 20th nov 12 submitted 17th dec 11 revision req. 10th apr 12, revision recd. 6th may 12 accepted 27th jun 1basrah health directorate, basrah, iraq; 2college of medicine, university of basrah, basrah, iraq *corresponding author e-mail: alasadijasim1951@yahoo.com نوعية احلياة وحمدداهتا عند املصابني بالصرع يف البصرة، العراق حممد �صاكر، جا�صم االأ�صدي امللخ�ص: الهدف: تقييم نوعية احلياة عند املصابني بالصرع وتقييم العوامل املختلفة اليت تؤثر عليها.الطريقة: مشلت هذه الدراسة 116 مريضا من الذين يعانون من الصرع مع جمموعة ضابطة من 116 شخصا من األصحاء، وهي دراسة حاالت وشواهد أجريت يف عيادة طب األعصاب يف العيادة اخلارجية للمستشفى العام بالبصرة يف العراق. مت إجراء املقابالت مع استخدام استبيان خاص يشمل البيانات االجتماعية والدميوغرافية واخلصائص السريرية )ملرضى الصرع فقط(. مت تقييم نوعية احلياة باستخدام الصيغة القصرية للمسح الصحي )sf-36(. النتائج: أظهر مرضى الصرع بشكل عام نوع أدىن من احلياة باملقارنة مع العينة الضابطة. ويف التحليل وحيد املتغري، كانت نوعية احلياة متدنية عند املرضى من كبار السن، واملنحدرين من املناطق الريفية، وذوي التعليم والدخل املنخفضني. وكذلك كان عدد نوبات الصرع وطول فرتة الصرع من العوامل اهلامة لتدين نوعية احلياة. كما أظهر حتليل التحوف متعدد املتغريات أن الُعمر واملستوى التعليمي ومعدل الدخل ووترية نوبات الصرع حمددات كبرية هامة لتحديد نوعية احلياة. اخلال�صة: بعض العوامل االجتماعية والدميغرافية، فضال عن العوامل السريرية كانت حامسة يف حتديد نوعية احلياة عند املصابني مبرض الصرع. وبناء على تلك العوامل ينبغي على املهنيني الصحيني وضع اسرتاتيجيات خمتلفة لتحسني نوعية احلياة عند هؤالء املرضى. مفتاح الكلمات: بالغني، �رصع، نوعية احلياة، وحتليل التخّوف، حالة اجتماعية – اقت�صادية، العراق. abstract: objective: the objective of this study was to assess the quality of life (qol) in people with epilepsy and to evaluate various factors affecting their qol. methods: a total of 116 patients with epilepsy and a control group of 116 apparently healthy persons were included in this case-control study which was conducted at the neurology outpatient clinic of basrah general hospital, iraq. an interview was performed with the use of a special questionnaire, which included data pertaining to socio-demographic characteristics, and clinical characteristics (for patients with epilepsy only). the qol was assessed with the use of a short form (sf-36) health survey. results: epileptic patients showed lower overall qol scores as compared to controls. in the univariate analysis, patients who were older, from rural areas, and with low education and income levels had low er overall qol scores. frequent seizures as well as increased duration of epilepsy were also significant factors associated with reduction in qol scores. in the multivariate regression analysis, age, educational level, income and frequency of seizures were significant determinants of qol. conclusion: certain socio-demographic factors as well as clinical factors were crucial in determining qol in epilepsy patients. recognition of these factors will lead health professionals to develop different strategies to improve the qol of those patients. keywords: adults; epilepsy; quality of life; regression analysis; socioeconomic status; iraq. quality of life and its determinants in people with epilepsy in basrah, iraq mohammed shakir1 and *jasim n. al-asadi2 advances in knowledge although there are numerous studies assessing the quality of life (qol) of people with epilepsy from all over the world, similar studies from developing countries, especially iraq, are sparse. this study most likely marks one of the first studies to assess the qol in patients with epilepsy in basrah, iraq. it is necessary to ascertain the magnitude of the problem as a part of the systematic approach to challenges in epilepsy management. application to patient care information obtained from this study could lead to improvement in quality of care for people with epilepsy. the increased identification of patients' problems with daily functioning and well-being can guide management and lead to improvement in patients' qol. quality of life and its determinants in people with epilepsy in basrah, iraq 450 | squ medical journal, november 2012, volume 12, issue 4 about 45 million people worldwide suffer from epilepsy, with three-quarters of them living in poor countries, and more than 80% living in the tropics.1,2 in 2005, the international league against epilepsy (ilae) and the international bureau for epilepsy (ibe) defined epilepsy as ‘a disorder of the brain characterised by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition’.3 epilepsy is associated with adverse social, physical, and psychological consequences which are reflected on the cognitive functioning and behavioural patterns of affected individuals.4 a person with epilepsy faces uncertainty over the diagnosis of his or her condition, over its nature, and whether and when seizures will occur, how best seizures can be controlled, and whether they will ultimately remit.5 epilepsy is also a known stigmatising condition.6 because of its clinical uncertainty and stigmatisation, the impact of epilepsy on a person's quality of life (qol) can be significant.7 the world health organization (who) defines qol as individuals' perception of their position in life in the context of the culture and value systems in which they live, and in relation to their goals, expectations, standards and concerns. it is a broadranging concept affected in a complex way by the person's physical health, psychological state, level of independence, social relationships, personal beliefs, and their relationship to salient features of their environment.8 people with epilepsy are prone to poorer selfesteem and higher levels of anxiety and depression than people without epilepsy.9 they are more likely to be underor unemployed.10 lower rates of marriage and greater social isolation have been reported in adults with epilepsy as compared with others.11 some, though not all, people with epilepsy feel stigmatised by their condition.12 the relationship between the severity of epilepsy and its impact on qol is complex and may be determined by a number of different factors.13 qol in patients with epilepsy is a function of an interaction of factors which include clinical variables (e.g. seizure frequency, severity, illness duration, treatment side effects, depression and anxiety), social disadvantages (e.g. divorce, unemployment, social stigma, illness intrusion into social life), and family circumstances (e.g. family caregiver characteristics and social support).14–18 qol is sensitive to distress in several domains of living, and a focus on its determinants can help to narrow down the domains in which interventions can be targeted to improve outcome and quality of care.19–21 current instruments that measure qol for people with epilepsy have been developed and tested exclusively in the west; the questionnaires analyse multiple daily functions, which are dependent on culture, ethnicity, and economics. limited data are available to guide qol issues in developing countries’ populations. the level of, and factors affecting, qol in patients with epilepsy in basrah, iraq, have not yet been addressed properly. therefore, this casecontrol study was conducted to determine the qol and its determinants among patients with epilepsy in iraq. methods this case-control study was carried out in basrah, iraq, from june 2010 to march 2011. epilepsy registers were not available, so epileptic patients who fulfilled the inclusion criteria and attended the neurology outpatient clinic of basrah general hospital (one of four major hospitals in basrah governorate) during the period of the study were recruited. participants were included if they satisfied the following criteria: 16 years of age or older; diagnosis of epilepsy for a minimum of one year; not having clinical features of mental retardation (assessed by a clinical judgment); no history of seizure within the last 24 hours, and no chronic illness or disability other than epilepsy. patients were excluded from the study if they had symptomatic epilepsy or a systemic disease that may have affected their health status and qol. a total of 116 epileptic patients were recruited. because no normative short-form 36 (sf36) survey values for the general iraqi population existed, 116 individuals (aged 16 years or older) who were not epileptic, and were free from chronic illnesses or disabilities were chosen by a simple random sampling as a control group. they were either relatives of epileptic patients, or patients who attended the outpatient clinic of basrah general mohammed shakir and jasim n. al-asadi clinical and basic research | 451 hospital for conditions other than epilepsy. both the control group and epileptic patients were matched for age, sex, and educational level. a questionnaire was used to collect data about patients’ socio-demographic status. only the epileptic patients completed the clinical data section of the questionnaire. the socio-demographic data were age; sex; educational level; marital status; per capita monthly family income in iraqi dinars (id), which was classified as low (<100,000 id ≈ <80 $us), medium (100,000–250,000 id ≈ 80–200 $us), and high (>250,000 id ≈ >200 $us); residence, and employment (housewives and students were classified as unemployed). clinical data included seizure frequency, number of antiepileptic drugs, and duration of epilepsy. qol was assessed by the sf-36 health survey, which is widely used as a generic measure of health.22 the sf-36 has also proved a reliable and valid measure of health-related qol, and has been used as an outcome indicator in numerous clinical trials and across various diagnostic groups, including with adults with epilepsy.23,24 the sf-36 assesses 8 qol domains: physical functioning (pf) 10 items; role physical limitations (rp) 4 items; bodily pain(bp) 2 items; general health (gh) 5 items; vitality (vt) 4 items; social functioning (sf) 2 items; role emotional limitations (re) 3 items, and mental health (mh) 5 items. each of the eight health concepts was measured on a scale of 0 to 100.22 a total qol which represents the average of the sum of the eight subscales was calculated. the total qol score was divided into four levels: a poor qol was indicated by a score less than 40; a moderate qol was indicated by a score of 40 to 60; a good qol was indicated by a score of 61 to 80, and an excellent qol was indicated by a score of more than 80.25 seizure frequency was classified according to the number of attacks in the last year: one or more attack per month, fewer than one attack per month, and no attacks in the last year.4,14 after an informed consent was obtained, cases and controls were interviewed by one of the authors. the study was approved by the ethics and research committee of basrah health directorate. data were analysed using statistical package for the social sciences (spss), version 15, (ibm, chicago, illinois, usa) and the results were presented as tables. for categorical variables, frequencies and percentages were reported. differences between groups were analysed using pearson’s chi-squared test, or fisher’s exact tests for small samples (i.e. cells less than 5). for continuous variables, mean and standard deviation were used to present the data while analysis was performed using the student’s t-test or analysis of variance (anova). a multiple regression analysis was used to identify significant predictors of changes in qol. a p value of less than 0.05 was considered statistically significant. table 1: socio-demographic characteristics of the study population characteristic epileptic patients control group p value no. % no. % age (years) 16–25 55 47.4 55 47.4 0.99926–35 41 35.3 41 35.3 ≥36 20 17.3 20 17.3 sex male 70 60.3 70 60.3 0.999 female 46 39.7 46 39.7 educational level illiterate 17 14.7 18 15.5 0.995 primary 42 36.2 39 33.6 intermediate 28 24.1 30 25.9 secondary 18 15.5 18 15.5 university & above 11 9.5 11 9.5 residence urban 54 46.6 58 50 0.694 rural 62 53.4 58 50 income low 33 28.4 14 12.1 0.003medium 50 43.2 50 43.2 high 33 28.4 52 44.7 employment employed 46 39.7 62 53.4 0.024 unemployed 70 60.3 54 46.6 marital status married 51 44 83 71.6 0.001 unmarried 65 56 33 28.4 total 116 100 116 100 quality of life and its determinants in people with epilepsy in basrah, iraq 452 | squ medical journal, november 2012, volume 12, issue 4 results table 1 shows the distribution of socio-demographic characteristics between epileptic patients and the control group. no significant difference was observed between epileptic patients and the control group regarding residence (p >0.05), but there was a significant difference between the two groups regarding income, employment, and marital status (p <0.05). regarding monthly family income, most of the epileptic patients (43.1 %) were medium income earners, while most in the control group (44.8 %) were high income earners. unemployment was the most frequent occupational status (60.3 %) among epileptic patients, and (56 %) were unmarried, while most in the control group were employed (53.4%) and 71.6% were married. as shown in table 2 and figure 1, epileptic patients scored lower in all subscales of qol as compared to control group. the differences were highly significant (p <0.001). the mean total qol scores of epileptic patients was 47.9 ± 18.1 as compared to 71.7 ± 10.2 in the control group with a highly significant difference (p <0.001). figure 2 shows a qualitative grouping of total qol scores of epileptic patients and control group members. as shown in this figure, as compared to members of the table 2: comparison of qol between epileptic patients and controls qol subscale cases controls p value mean ± sd 95% ci mean ± sd 95% ci lower upper lower upper pf 61.8 ± 26.9 57.1 66.7 81.2 ± 13.3 78.9 83.5 <0.001 rp 36.7 ± 34.3 28.3 41.6 71.8 ± 28.6 66.4 76.5 <0.001 re 39.6 ± 39 32.8 46.5 75.6 ± 26.9 70.7 80.2 <0.001 sf 55.4 ± 26.4 50.8 60.7 77.4 ± 30 73.4 80.9 <0.001 bp 47.6 ± 29.7 42.3 53.2 72.6 ± 18 69.5 75.7 <0.001 vit 43.9 ± 20.5 40.2 47.5 62.7 ± 17.8 59.3 65.7 <0.001 mh 51.5 ± 18.5 48.3 55.1 66.7 ± 16.4 63.7 69.7 <0.001 gh 48.6±16.9 45.4 51.8 69 ± 14.8 66.4 71.7 <0.001 total qol scores 47.9 ± 18.1 44.4 51.3 71.7 ± 10.2 69.9 73.5 <0.001 qol = quality of life; sd = standard deviation; ci = confidence interval; pf = physical functioning ; rp = role physical limitations; re = role emotional limitations; sf = social functioning ; bp = bodily pain; vit = vitality; mh = mental health; gh = general health figure 1: comparison of qol subscales (domains) between cases and con trols. qol = quality of life; gh = general health; mh = mental health; vt = vitality; bp = body pain; sf = social functioning ; re = role emotional limitations; rp = role physical limitations; pf = physical functioning. mohammed shakir and jasim n. al-asadi clinical and basic research | 453 control group, most epileptic patients had a poor to moderate qol with a highly significant difference (p <0.001). of the epileptic patients, 43.1 % had had epilepsy for less than 5 years, while 36.2 % had had epilepsy for more than 10 years with a mean duration of 10.6 years. of the epileptic patients, only 21.6 % were seizure free for the last year, and 82.7 % were on one antiepileptic drug. as shown in table 3, older epileptic patients had lower mean qol scores (39 ± 15.3) as compared with younger age groups (55.9 ± 18.3). patients with low educational levels and low income also had lower qol scores, with a significant association. patients who had had epilepsy for less than five years as well as those who had had epilepsy for more than 10 years had lower qol scores (43.9 ± 14.7, 47.9 ± 18.1, respectively) as compared to 60.3 ± 19.7 in those who had had epilepsy for 5–10 years, with a significant association. patients who had been free of epileptic seizures for the last year had a better level of qol as compared to those with more frequent seizures, with a highly significant association. marital status, gender, employment, residency, and number of antiepileptic drugs had no significant influence on qol among epileptic patients. to examine the independent effect of the studied factors on the qol of epileptic patients, a multiple regression analysis was performed [table 4]. income, age, education, and frequency of seizures were found to be the most independent and highly significant factors that predicted qol of epileptic patients. they explained 54.7% of the variability in qol total scores. the excluded variables were sex, residency, marital status, employment, duration of the disease, and number of antiepileptic drugs. discussion the epileptic patients in this study were less likely to be married, more likely to be unemployed, and with a lower income as compared to the control group. this is consistent with other studies which found that people with epilepsy appear at greater risk of problems in relation to marriage, employment, and socio-economic status.26–28 the present study highlights the impact of epilepsy on the qol of epileptic patients in basrah. when compared with the epilepsy-free control group, patients with epilepsy reported a significantly lower qol across all domains. such a result is consistent with many previous studies that have been done in iran, the arabian gulf, the near east, thailand, norway, the uk, russia, and tunisia.14,18,29–32 the epileptic patients’ rather poor qol may be explained by the disease’s chronicity (the mean duration of patients’ illness in this study was 10.6 years), a result which was reported by sillanpää et al., or because most of the epileptic patients in this study (78.4%) had not been seizurefree in the last year. seizure frequency was described as one of the most relevant determinants of poor qol.33,34 similar to other studies, higher qol scores in epileptic patients were associated with youth, and higher levels of education and family income.35-37 it is reasonable to suggest that these factors increase the potential for social support, positive coping methods, and awareness of the disease.14,38 elderly people may have more difficulty in coping with epilepsy than do younger patients who have more physiological reserves and fewer responsibilities.39 education is an important indicator that may directly or indirectly influence qol through its association with employment, higher social class, and economic status, or because well-educated patients are more aware of self-management practices and are better educated about the disease and also know that regular treatment can help patients avoid seizures and hence lead a normal life.40 economic status was recognised as an important predictor of qol in epileptic patients.41 having enough money is important to qol not only to meet 18.10% 7.80% 65.50% 13.80% 16.40% 42.20% 0% 36.20% 0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% excellentgoodmoderatepoor quality of life cases controls p e rc e n ta g e o f p e rso n s figure 2: comparison of quality of life between cases and controls. quality of life and its determinants in people with epilepsy in basrah, iraq 454 | squ medical journal, november 2012, volume 12, issue 4 people’s basic needs, but also to allow participation in society and in holidays and hobbies, and to allow people to enjoy luxuries and be prepared for unexpected expenses and emergencies. in univariate analysis, patients living in rural areas had significantly lower qol scores as compared to those living in urban areas, but this association disappeared in multivariate analysis. the role of residence may have been confounded by the effect of the social and economic levels. it was reported that epilepsy and its sequelae were more prevalent in patients with low social and economic levels.42 current seizure activity was an independent clinical predictor of qol. even patients with infrequent seizures, who would generally be regarded as having good control, had a relatively compromised qol as compared with those who were seizure-free. guekht et al., reported that patients with frequent seizures had low social contact and feelings of stigmatisation.32 considerable emphasis has been placed on the table 3: quality of life (mean ± sd) of epilepsy patients according to socio-demographic and clinical factors risk factor n (%) qol scores (mean ± sd) 95% ci p value age (years) 16–25 26–35 ≥36 55 (47.4) 41 (35.3) 20 (17.3) 55.9 ± 18.3 41.8 ± 14.0 39 ± 15.3 51.3 ± 16.1–61.2 ± 21.2 37.6 ± 11.3–46.7 ± 18.7 32.6 ± 9.6–46.9 ± 18.9 <0.001 sex male female 70 (60.3) 46 (39.7) 47.5 ± 18.6 48.5 ± 17.6 42.3 ± 15.6–51.7 ± 20.9 43.4 ± 13.4–54.1 ± 21.2 0.784 employment employed unemployed 46 (39.7) 70 (60.3) 45.4 ± 14.8 49.6 ± 19.9 41.3 ± 11.4–49.8 ± 17.5 44.9 ± 16.8–54.5 ± 22.7 0.222 residency urban rural 54 (46.6) 62 (53.4) 51.7 ± 20.9 44.6 ± 14.7 46 ± 18.3–57.3 ± 23.4 41.2 ± 11.9–48.4 ± 17.4 <0.05 education illiterate primary intermediate secondary university+ 17 (14.7) 42 (36.2) 28 (24.1) 18 (15.5) 11 (9.5) 42.9 ± 21.8 41.9 ± 13.6 47.2 ± 16 54.9 ± 14.9 68.6 ± 21.1 32.6 ± 14.4–53.9 ± 25.9 37.8 ± 11.5–45.9 ± 15.1 41.3 ± 1.5–53.1 ± 19.2 49.3 ± 7.8–62.1 ± 19.7 69.5 ± 3.1–87.5 ± 16.2 <0.001 income low intermediate high 33 (28.4) 50 (43.2) 33 (28.4) 39.3 ± 10.4 43.7 ± 15.7 62.8 ± 19.2 35.9 ± 8.2–42.9 ± 15.2 39.2 ± 13.4–48.3 ± 18.4 56 ± 15.9–69.4 ± 21.7 <0.001 marital status married unmarried 51 (44) 65 (56) 45.4 ± 16.6 49.9 ± 19.2 40.9 ± 13.1–50.2 ± 19.3 45.1 ± 15.8–54.1 ± 21.9 0.191 duration of epilepsy (years) <5 5–10 >10 50 (43.1) 24 (20.7) 42 (36.2) 43.9 ± 14.7 60.3 ± 19.7 47.9 ± 18.1 39.9 ± 10.9–48.1 ± 18.1 52.9 ± 15.3–68.7 ± 22.7 40.3 ± 15.2–51.2 ± 20.9 <0.01 frequency of seizures ≥1/month <once/month none in the last year 41 (35.3) 50 (43.1) 25 (21.6) 43.9 ± 13.2 43.7 ± 17.8 62.7 ± 18.6 39.9 ± 10.4–48.1 ± 15.4 38.5 ± 14.9–49.6 ± 20.8 56.3 ± 14.1–70.1 ± 21.8 <0.001 no. of anti-epileptic drugs one two or more 96 (82.8) 20 (17.2) 48.4 ± 17.8 45.6 ± 20.2 44.6 ± 15.1–52.1 ± 20 37.3 ± 15.3–54.9 ± 23.9 0.543 qol = quality of life; ci = confidence interval; sd = standard deviation mohammed shakir and jasim n. al-asadi clinical and basic research | 455 desirability of monotherapy. many studies have shown that the prescription of multiple drugs can result in multiple adverse side effects and have a negative effect on qol.14,18,25 in the present study, no significant association was found between the number of drugs and qol. however, epileptic patients who were taking one antiepileptic drug had a slightly higher qol score than those on multiple drugs. in contrast to some earlier reports, patients’ gender, marital status, and duration of the disease did not have a significant association with total qol in this study.43 the association between duration of epilepsy and qol which was identified in univariate analysis was no longer significant after multiple regression analysis. a possible explanation of this discrepancy in significance might be related to age as a potential confounder. a few limitations must be addressed in our study. to generalise our results to all epileptic patients, a random sample of patients with epilepsy would have been suitable. but it has been reported that obtaining a random sample of people with epilepsy is complex and labour-intensive.14 furthermore, with this being a case-control study, certain limitations such as recall bias, the problem of selection and non-response bias may have been encountered. recall bias can exist in obtaining information, as by asking the study population by the mean of the sf-36 instrument whether their work or other regular daily activities, during a previous period, were affected by their physical health. the recall bias in this study was at least reduced by asking respondents to specify the type of effect and limiting the recall period in the questionnaire form to the present time, except in one question about seizure frequency, in which the recall period extended to one year before. another source of possible bias is the nonresponse bias, but in this study the response rate was 100% because all the cases and controls were willing to participate in the study and the data were obtained by means of an interview. age, sex, and educational level as strong confounders were removed by the process of matching. the problem of selection was unlikely to have been eliminated totally. we accept that this study may have had biased sampling as patients with serious physical or mental limitations were excluded from the study. therefore, the results may be biased towards the opinions of people with slightly better general health. in addition, the availability of free antiepileptic drugs should have helped in the inclusion of many patients with a lower socio-economic status, but this assumption may not be true because basrah general hospital is a secondary referral hospital, so it receives people from different socio-economic levels. the control group cannot be claimed to be totally representative of the general population. they were selected in a random manner which is valuable within the framework of a case-control study, but does not allow the generalisability of the sf-36 results to the whole population. a final limitation of this study was that data concerning the type of epilepsy were not collected. despite these limitations, the results are valuable in providing insights into how the qol of people with epilepsy can be improved. conclusion patients with epilepsy in basrah, iraq, had a poor qol. in addition, the results confirm that many issues faced by people with epilepsy are common across cultural boundaries, emphasising the negative effects of epilepsy on patients’ qol. age, educational level, income, and frequency of seizures were significant determinants of qol. our findings call for improved management of patients with epilepsy to become seizure-free through treatment by drugs with minimal side effects and offering them good social support, thus enabling them to accommodate their condition and maximise their qol. a c k n o w l e d g e m e n t s the authors would like to thank the personnel of the neurology outpatient clinic of basrah general hospital in which the study was conducted for their kind help and cooperation. our deep gratitude also goes to our study subjects who took the time to give us relevant information for the study. table 4: multiple regression analysis determinants betacoefficient p value r2 income age education frequency of seizures 0.481 -0.396 0.252 -0.248 0.001 0.001 0.001 0.002 0.547 quality of life and its determinants in people with epilepsy in basrah, iraq 456 | squ medical journal, november 2012, volume 12, issue 4 d e c l a r at i o n o f i n t e r e s t the authors declare that there are no competing interests, and also that there were no sources of funding for this study. references 1. world health organization. epilepsy: social consequences and economic aspects. geneva: world health organization. fact sheet no. 166, 2001. 2. lee sa, yoo hj, lee bi. factors contributing to the stigma of epilepsy. seizure 2005; 14:157–63. 3. fisher rs, van emde bw, blume w, elger c, genton p, lee p, et al. epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ilae) and the international bureau for epilepsy (ibe). epilepsia 2005; 46:470–2. 4. motamedi g, meador k. epilepsy and cognition. epilepsy behav 2003; 4:s25–38. 5. baker ga. assessment of quality of life in people with epilepsy: some practical implications. epilepsia 2001; 42:66–9. 6. suurmeijer t, reuvekamp mf, aldenkamp bp. social functioning, functioning, psychological functioning and quality of life in epilepsy. epilepsia 2001; 42:1160–8. 7. moffat c, dorris l, connor l, espie ca. the impact of childhood epilepsy on quality of life. a qualitative investigation using focus group methods to obtain children’s perspectives on living with epilepsy. epilepsy behav 2009; 14:179–89. 8. world health organization, division of mental health and prevention of substance abuse. measuring quality of life, world health organization quality of life instruments. geneva: world health organization, 1997. 9. collings ja. epilepsy and well-being. soc sci med 1990; 31:165–70. 10. collings j. epilepsy and the experience of employment. a report of a national survey by the british epilepsy association. leeds: british epilepsy association, 1992. 11. wada k, kawata y, murakami t, kamata a, gang zhu g, mizuno k, et al. sociomedical aspects of epileptic patients: their employment and marital status. psychiatry clin neurosci 2001; 55:141–6. 12. thomas sv, nair a. confronting the stigma of epilepsy. ann indian acad neurol 2011; 14:158–63. 13. coolings j. psychosocial well-being and epilepsy: an empirical study. epilepsia 1990; 31:418–26. 14. mrabet h, mrabet a, zouari b, ghachem r. health-related quality of life of people with epilepsy compared with a general reference population: a tunisian study. epilepsia 2004; 45: 838–43. 15. johnson ek, jones je, seidenberg m, hermann bp. the relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. epilepsia 2004; 45:544–50. 16. poochikian-sarkissian s, sidani s, wennberg r, devins gm. seizure freedom reduces illness intrusiveness and improves quality of life in epilepsy. can j neurol sci 2008; 35:280–6. 17. wheless jw. intractable epilepsy: a survey of patients and caregivers. epilepsy behav 2006; 8:756– 64. 18. baker ga, jacoby a, gorry j, stalgis c, monnet d. quality of life of people with epilepsy in iran, the gulf, and near east. epilepsia 2005; 46:132–40. 19. ohaeri ju, awadalla aw, gado om. subjective quality of life in a nationwide sample of kuwaiti subjects using the short version of the who quality of life instrument. soc psychiatry psychiatr epidemiol 2009; 44:693–701. 20. piperidou c, karlovasitou a, triantafyllou n, dimitrakoudi e, terzoudi a, mavraki e, et al. association of demographic, clinical and treatment variables with quality of life of patients with epilepsy in greece. qual life res 2008; 17:987–96. 21. ramaratnam s, baker ga, goldstein lh. psychological treatments for epilepsy. cochrane database syst rev 2008; 16:cd002029. 22. rand corporation. medical outcome study 36item short form survey instrument (sf-36). santa monica, california: rand health, 2009. 23. jacoby a, baker ga, steen n. the sf-36 as a health status measure for epilepsy: a psychometric assessment. qual life res 1999; 8:351–64. 24. freeman ja, hobart jc, langdon dw, thompson aj. clinical appropriateness: a key factor in outcome measure selection: the 36-item short form health survey in multiple sclerosis. j neurol neurosurg psychiatry 2000; 68:150–6. 25. rajabi f, dabiran s, hatmi z, zamani g. quality of life of epileptic patients compared to general population of tehran. acta medica iranica 2009; 47:75–8. 26. ohaeri ju, awadalla aw, farah aa. quality of life in people with epilepsy and their family caregivers: an arab experience using the short version of who quality of life instrument. saudi med j 2009; 30:1328–35. 27. gopinath m, sarma ps, thomas sv. gender-specific psychosocial outcome for women with epilepsy. epilepsy behav 2011; 20:44–7. 28. vibha p, saddichha s, akhtar s. quality of life (qol) and marital adjustment in epilepsy and comparisons with psychiatric illnesses. int j psychosocial rehabil 2010; 14:105–12. 29. phabphal k, geater a, limapichart k, satirapunya p, setthawatcharawanich s. quality of life in epileptic mohammed shakir and jasim n. al-asadi clinical and basic research | 457 patients in southern thailand. j med assoc thai 2009; 92:762–8. 30. stavem k, loge jh, kaasa s. health status of people with epilepsy compared with a general reference population. epilepsia 2000; 41:85–90. 31. baker ga, jacoby a, buck d, stalgis f, monnet y. quality of life of people with epilepsy: a european study. epilepsia 1997; 38:353–62. 32. guekht ab, mitrokhina tv, lebedeva av, dzugaeva fk, milchakova le, lokshina ob, et al. factors influencing on quality of life in people with epilepsy. seizure 2007; 16:128–33. 33. sillanpää m, haataja l, shinnar s. perceived impact of childhood-onset epilepsy on quality of life as an adult. epilepsia 2004; 45:971–7. 34. bautista re, glen et. seizure severity is associated with quality of life independent of seizure frequency. epilepsy behav 2009; 16:325–9. 35. shetty ph, naik rk, saroja ao, punith k. quality of life in patients with epilepsy in india. j neurosci rural pract 2011; 2:33–8. 36. edefonti v, bravi f, turner k, beghi e, canevini mp, ferraroni m, et al. health-related quality of life in adults with epilepsy: the effect of age, age at onset and duration of epilepsy in a multicentre italian study. bmc neurol 2011; 11:33–45. 37. mohammad ms, hemeida sa, rabah am. health status and quality of life in epileptic children and adolescents. egypt j neurol psychiat neurosurg 2010; 47:83–92. 38. buck d, jacoby a, baker ga, ley h, steen n. crosscultural differences in health-related quality of life of people with epilepsy: findings from a european study. qual life res 1999; 8:675–85. 39. pugh m, copeland l, zeber j, cramer j, amuan m, cavazos j, et al. the impact of epilepsy on health status among younger and older adults. epilepsia 2005; 46:1820–7. 40. joseph n, ray a, reshma bk, bhat s, herady m, kumar a. assessment of quality of life, stigma associated and self-management practices among patients suffering from epileptic seizures: a cross sectional study. j neurosci behav health 2011; 3:91– 8. 41. zhao y, wu h, li j, dong y, liang j, zhu j, et al. quality of life and related factors in adult patients with epilepsy in china. epilepsy behav 2011; 22:376– 9. 42. meador kj. research use of the new quality-of-life in epilepsy inventory. epilepsia. 1993; 34:s34–8. 43. djibuti m, shakarishvili r. influence of clinical, demographic, and socioeconomic variables on quality of life in patients with epilepsy: findings from georgian study. j neurol neurosurg psychiatry 2003; 74:570–3. taurine levels in human aqueous humour medical sciences (2000), 2, 33−35 © 2000 sultan qaboos university 1department of obstetrics & gynaecology, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. 33 minimal stimulation protocol: a cheap and effective method of ovulation induction *mathew m, al-busaidi f, krolikowski a طريقة رخيصة : األدنىالتنبيهنظام .وفعّالة إلحداث اإلباضة آروليكوسكي. ، أ البوسعيدي. ماثيو ، ف. م تسجيل معدالت اإلباضة ، الحمل : الطريقة. منضبط للمبايض تنبيهوهو نظام جديد من العالج الهرموني إلحداث " األدنى للمبايض التنبيه"ية وتكلفة نظام تحديد فعال :الهدف: الملخص وآانت نسبة % . 7، ونسبة الحمل بأآثر من جنين % 2 ، نسبة الحمل % 82 نسبة اإلباضة آانت :النتائج. إمرأة تم عالجها بهذا النظام 67، اإلجهاض إلى جانب التكلفة الدوائية في نظام التنشيط األدنى :النتائج. منشط القند أألنسان األدنى للمبايض ثلث تكلفة نظام إستخدام هرمون لتنبيهآما بـلغ معدل تكلفة نظام ا . من إجمالي حاالت الحمل % 36اإلجهاض التلقائي وعليه فإن هذا النظام يستحق الدراسة . وله نفس المفعول ، وهو يتطلب متابعة أقل ولذلك فهو أآثر راحة للمريض ن منشط القند أألنسا ني رموللمبايض أرخص بكثير من نظام العالج به .آعالج للعقم abstract:�������� � – to determine the effectiveness and cost of minimal stimulation protocol (msp), a new combination of human menopausal gonadotrophin (hmg) and clomiphene citrate (cc), for controlled ovarian hyperstimulation. ���� �– the ovulation rates, pregnancy rates, abortion rates and the cost of medication were assessed in respect of 67 women who underwent msp. ������� – ovulation rate in the study group was 82%, pregnancy rate 21% and multiple pregnancies 7%. spontaneous abortion occurred in 36% of the pregnancies. the average cost of msp stimulation was one-third of hmg protocol. ���������� – msp protocol, while substantially cheaper than hmg, gives comparable pregnancy rates with less need for monitoring and better patient comfort. these justify further evaluation of its role in the treatment of infertility. key words: clomiphene citrate, human menopausal gonadotrophin, minimal stimulation protocol varian stimulation has been established to be a reasonably effective treatment for nonovulatory infertility. clomiphene citrate (cc), a cheap and easy-to-administer drug, was the first one used for ovarian stimulation. for women failing to conceive after four to six cycles of cc, gonadotrophins are the accepted alternative.1,2 however, the medication and monitoring expenses are higher than those of cc. cost reduction has been achieved without sacrificing efficacy by using a combination of cc and human menopausal gonadotrophin (hmg).3,4 in 1993, corfman6 described a novel ovarian stimulation protocol termed minimal stimulation (msp). when used in in-vitro fertilization program (ivf), this protocol gave a clinical pregnancy rate comparable to pure hmg stimulation at lower expense.6 although msp has been reported to be effective for ovulation induction, a widespread search of the literature shows only a few studies using it.6,7 our retrospective study describes the experience with msp in a non-ivf population over two years and aims to confirm its effectiveness and to ascertain the costs involved. our results are compared with those for patients treated with a standard hmg ovarian stimulation protocol as described by others.7 method from april 1996 to march 1998, patients presenting to the infertility clinic of sultan qaboos university hospital, muscat, were offered a stimulation protocol combining cc & hmg. this retrospective study involved 221 minimal stimulation cycles in 67 infertile women. o m a t h e w e t a l 34 the mean age of the treatment group was 28.7 years and the average duration of infertility, 6.1 years. the majority (66%) of the women suffered from primary infertility. the causes of infertility included anovulation (in some cases combined with male factor), tubal diseases or endometriosis and unexplained infertility. most of them had failed cc therapy before. intrauterine insemination was performed in women with male factor infertility. the procedure for msp was started with administration of 100 mg of cc daily orally from cycle day 3 to 7. a single injection of hmg 150 iu i.m. was given on the 9th cycle-day. transvaginal ultrasonography was done on the 12th cycle-day to assess follicle size and endometrial thickness. if the leading follicle was seen to be ≥14 mm, its diameter could be expected to increase by 1–2 mm/day, and accordingly, the day of hcg injection was projected. when leading follicle had grown to >18 mm, 10,000 iu hcg was given intramuscularly. if follicle size remained <14 mm, vaginal ultrasound was repeated on the 15th cycle day. if even then there was no follicle ≥ 16 mm, the treatment was considered failed. criteria for ovulation induction failure were ultrasonic finding of a leading follicle <19mm and/or an endometrial thickness <8mm. criterion for treatment failure was inability to become pregnant during 4 courses of treatment. a clinical pregnancy was defined as visualization of the gestational sac by transvaginal ultrasound performed 4 weeks after hcg administration. we follow the criteria published by lu et al.7 results a total of 67 women who completed 221 ovarian stimulation cycles were included in the analysis. ovulation occurred in 82% of treatment cycles and each patient received 10,000 i.u. hcg. the treatment was cancelled in 18% of cycles mainly because of inadequate follicular growth. only ovulatory dysfunction was found in 63% of the patients. the other causes for infertility included male factor, tubal diseases, endometriosis and unexplained infertility (table 1). in the study group, 21% patients (14 out of 67) became pregnant. table 2 summarizes the outcome of these pregnancies. abortion rate was high at 36%, and all except one occurred before 10 weeks gestation. one woman aborted triplets at 20 weeks gestation. there were 9 successful pregnancies, resulting in live babies. table 3 shows the number of pregnancies in each cycle. maximum pregnancy rate was noticed in the first cycle. although the original protocol advocates 4 cycles of treatment, 17% of our patients received more than 4 cycles and 14% of our pregnancies occurred during the 5th and 6th cycles. table 1 characteristics of 67 women treated with msp no. % ovulatory dysfunction 42 63 male factor 12 18 tubal diseases 10 15 endometriosis 9 13 unexplained 8 12 n.b. the total number is > 100% because some of the patients appear more than once due to combined factors of infertility. table 2 outcome of 14 pregnancies achieved with msp no % completed pregnancy 9 64 abortion rate 5 36 total 14 100 singleton pregnancy 13 93 multiple pregnancy 1 7 total 14 100 table 3 number of pregnancies in each treatment cycle cycle pregnancy % 1st 5 36 2nd 4 29 3rd 0 0 4th 3 21 the cost factor squ hospital pharmacy charges were (approximately) rials omani (ro) 2.200 (us $5.70) for 5 days’ treatment with cc at 100 mg per day, ro 3.200 m i n i m a l s t i m u l a t i o n p r o t o c o l 35 ($8.30) for 150 i.u. hmg, and ro 3 ($7.80) for 10,000 i.u. hcg. thus, the average medication expenses for msp is ro 8.400 ($22), one-third of the ro 25.500 ($66) required for hmg stimulation. also to be noted is msp’s lower monitoring requirements: whereas monitoring of hmg cycle usually requires several transvaginal scans and serum estradiol estimations, msp needs only one, or at the most, two transvaginal scans. (due to the variability of the number of serum estradiol estimations in monitoring of hmg-only protocol, and the difficulty in calculating the cost of transvaginal ultrasound examinations, the exact savings on monitoring requirements could not be worked out.) discussion our study shows that msp may be used for achieving late follicular growth. patients who fail to ovulate or do not conceive with cc therapy may benefit from this cc-cum-hmg regime before hmgalone therapy is administered. majority of the patients in this study had previous unsuccessful cc cycles. msp was offered as a ‘next step’ after cc failure. its reduced cost and monitoring were attractive to the patients. single leading follicle of size >18 mm was considered as ovulatory in our study compared to 2 or more follicles of 20mm size in original msp.5-7 it is our practice to cancel the treatment cycle in the presence of a thin endometrium.8,9 endometrial thickness ≥ 8mm occurred in 87% of ovulating cycles. only 30% of non-ovulating cycles had endometrial thickness > 8mm, and none of the patients in this group conceived, thus confirming the results achieved by the other authors.10 ovulation and pregnancy rates were comparable to hmg stimulation reported by lu.7 however, the abortion rate of 36% in our group was significantly higher than in the msp group reported by the above author. the reason for this variation is not clear. the treatment cycle were cancelled in 18% due to poor follicular growth compared to the cancellation rate of 26% in the msp and 14% in the hmg protocol reported by corfman6. although the original protocol suggests a maximum of 4 cycles5-7, 17% of our patients received up to 6 cycles and 14% of pregnancies occurred in this group. combined infertility factors were the reason for extending the therapy. conclusion from the above, msp appears to be an effective protocol for controlled ovarian stimulation in infertile women. it is easy to administer, requires less intense monitoring, fewer medications, and is cheaper. on drug costs alone, msp protocol is 1/3rd cheaper than hmg protocol. in addition to this are the savings on monitoring. these factors make minimal stimulation protocol a reasonable therapeutic option to a pure hmg treatment. references 1. welner s, decherney ah, polan ml. human menopausal gonadotrophins: a justifiable therapy in ovulatory women with long-standing idiopathic infertility. am j obstet gynecol 1988, 158, 111–7. 2. diamond et al. comparison of human menopausal gonadotrophin, clomiphene citrate and combined human menopausal gonadotrophin-clomiphene citrate stimulation protocols for invitro fertilization. fertil steril 1986, 46, 1108–12. 3. march cm, tredway d, mishell d jr. effect of clomiphene citrate upon amount and duration of human menopausal gonadotrophin therapy. am j obstet gynecol 1976, 125, 699–704. 4. jarrell j, mcinnes r, cooke r, arronet g. observations on the combination of clomiphene citrate –human menopausal gonadotrophin– human chorionic gonadotrophin in the management of anovulation. fertil steril 1981, 35, 634–7. 5. rose bi. a conservative low-cost superovulation regimen. int j fertil 1992, 37, 339–42. 6. corfman rs, milad mp, bellavance tl, ory sj. a novel ovarian stimulation protocol for use with the assisted reproductive technologies. fertil steril 1993, 60, 864–70. 7. lu yp, chen al. minimal stimulation achieves pregnancy rates comparable to human menopausal gonodotrophins in the treatment of infertility. fertil steril 1996, 65, 583–7. 8. randal jm, templeton a. transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. fertil steril 1991, 56, 208–12. 9. gonen y, casper rf, jacobson w, blankier j. endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in invitro fertilization. fertil steril 1989, 52, 446–9. 10. shoham z, d carlo c, patel a. is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? the importance of endometrial measurements. fertil steril 1991, 56, 836–41. minimal stimulation protocol: �a cheap and effective method of ovulation induction *mathew m, al-busaidi f, krolikowski a ???? ??????? ??????: ????? ????? ?. ????? ? ?. ????????? ? ?. ?????????? method results table 1 characteristics of 67 women treated with msp n.b. the total number is > 100% because some of the patients appear more than once due to combined factors of infertility. table 2 table 3 number of pregnancies in each treatment cycle the cost factor discussion conclusion references sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. e346-349, epub. 9th may 13 submitted 25th jun 12 revision req. 13th oct 12, revision recd. 18th nov 12 accepted 12th dec 12 dental and periodontal research center, department of endodontics, tabriz dental school, tabriz university of medical sciences, tabriz, iran *corresponding author e-mail: neginghasemi64@gmail.com الرحى األويل للفك العلوي ثنائية قنوات اجلذور �شعيد رحيمي و نيجن قا�شمي امللخ�ص: معرفة الت�رسيح ال�شكلي للرحى الأوىل للفك العلوي تعترب من اأ�شا�شيات جناح عالج لب الأ�شنان. لقد مت عر�ض الت�رسيح ال�شكلي للرحى الأوىل للفك العلوي بكرثة، غري اأن اأحتواء هذه الرحى على قناتني باجلذر نادرا ما يتم ذكره يف الدرا�شات الت�رسيحية لقنوات جذور الأ�شنان. نعر�ض هنا حالة ملري�ض عنده رحى اأويل بالفك العلوي ثنائية قنوات اجلذر مت حتويلها اإىل ق�شم عالج لب الأ�شنان بجامعة تربيز للعلوم الطبية باإيران. مفتاح الكلمات: جوف اللب ال�شني، �شذوذ، عظم الفك العلوي، عالج لب الأ�شنان، تقرير حالة، اإيران. abstract: knowledge regarding the anatomic morphology of maxillary molars is absolutely essential for the success of endodontic treatment. the morphology of the permanent maxillary first molar has been reviewed extensively; however, the presence of two canals in a two-rooted maxillary first molar has rarely been reported in studies describing tooth and root canal anatomies. this case report presents a patient with a maxillary first molar with two roots and two root canals, who was referred to the department of endodontics, tabriz university of medical sciences, iran. keywords: dental pulp cavity, abnormalities; maxillary bone; root canal therapy; case report; iran. maxillary first molar with two root canals saeed rahimi and *negin ghasemi online case report thorough cleaning, shaping and the obturation of the entire root canal system are essential steps for successful endodontic treatment. consequently, a thorough knowledge of root canal morphology and a good anticipation of their possible morphologic variation will help to reduce endodontic failure. unusual root and root canal morphologies associated with molars have been recorded in several studies in the literature.1,2 maxillary first molars have the most complex root and canal morphology in the maxillary dentition; therefore, their anatomy has been studied extensively and there is a wide range of variation in the literature with respect to the number of roots and the number of canals in each root.2–13 it is now generally accepted that the most common form of maxillary first molar has three roots and four canals.4 the wide buccolingual dimension of the mesiobuccal root, and the associated concavities on its mesial and distal surfaces, are consistent with the majority of mesiobuccal roots having two canals, whereas there is usually a single canal in each of the distobuccal and palatal roots.5,6 the incidence of two mesiobuccal canals has been reported to range from 18–96.1%.3,4 other variations include one, four, and five canals, and an unusual morphology of root canal systems within the individual roots.4,6,11 cases with five and six root canals, or with a c-shaped canal configuration,7–8 have also been reported. martínez-berna and ruiz-badanelli reported 3 cases in which the maxillary first molars had six root canals (three in the mesiobuccal, two in the distobuccal, and one in the palatine roots).9 palatal root canal variations were well-established by some case reports.5,10 however, the presence of two canals in a two-rooted maxillary first molar has rarely been reported in studies describing tooth and root canal anatomy.10 such an anatomic variation has been reported in a limited number of previous studies in relation to the second maxillary molar; however, the present report documents the case in relation to the first maxillary molar, which is much less common.10,11 saeed rahimi and negin ghasemi case report | 347 case report a 35-year-old female patient with no history of systemic disease was referred to the department of endodontics of the tabriz university of medical sciences in iran. the patient’s chief complaint was of severe spontaneous pain in the right maxillary first molar. after obtaining informed consent from the patient, pulpal and periapical tests were done. the vitality tests performed showed a severe response to cold and heat, and the electrical pulpal test similarly showed a severe response. the response of the tooth to percussion and pulpation was within normal limits. the initial radiographic evaluation showed the presence of occlusal amalgam fillings and recurrent caries on the mesial surface, as well as a two-rooted maxillary first molar [figure 1]. it should be noted that the left maxillary first molar had the same root canal anatomy [figure 2]. the pre-treatment diagnosis for the pulpal condition was of symptomatic irreversible pulpitis, and for a periapaical condition within normal limits. local anaesthesia was administered with 2% lidocaine and 1:80000 adrenaline, and a rubber dam was placed. after the removal of the caries, the roof of the pulp chamber was removed completely and rinsed with a normal saline solution. one orifice was found in the buccal aspect; it had a large diameter compared to the typical buccal orifices in maxillary first molars. subsequently, the other orifice was found in the palatal aspect [figure 3]. no other orifice was found, even by exploration at x 4.5 magnification using a prismatic loupe (zeiss eyemag pro s®. carl zeiss meditec, arese, italy) and under the dental operating microscope (seiler revelation®, seiler instruments, st louis, missouri, usa). this morphology was confirmed by radiographic examination of the molar with k-files #30 (dentsply maillefer, ballaigues, switzerland) in both canals [figure 4]. the root canals were explored with a k-flexofile iso 20 (dentsply maillefer, ballaigues, switzerland). the lengths of the canals were determined by a root-zx ii apex locator (morita, tokyo, japan) and were confirmed with a periapical radiograph. the canals were then further prepared with race rotary files (fkg dentaire, la-chaux-de-fonds, switzerland) with 0.04 and 0.06 tapers up to 1 mm short of the radiographic apex to #35 with a 0.06 taper using the crown-down technique. during root canal preparation, irrigation was performed using a normal saline solution, 2.5% sodium hypochlorite solution, and 17% ethylenediaminetetraacetic acid (edta). the canals were dried with absorbent figure 1: the initial radiograph showing the two-rooted maxillary first molar. figure 2: the left maxillary first molar with the same root canal anatomy. figure 3: two orifices in the floor of the pulp chamber, in the palatal aspect. maxillary first molar with two root canals 348 | squ medical journal, may 2013, volume 13, issue 2 paper points (dentsply maillefer, ballaigues, switzerland), and obturated using cold lateral compaction of gutta-percha points (dentsply maillefer, ballaigues, switzerland) and ah26® resin sealer (dentsply maillefer, ballaigues, switzerland). postoperative radiography was used to evaluate the obturation quality [figure 5]. the access cavity was then sealed with a temporary restorative material. the patient was referred to the department of operative dentistry for restorative treatment. discussion the root and root canal morphology of teeth varies greatly in the reported literature. prior knowledge of root and canal anatomy facilitates the precise detection of all root canals in a tooth during endodontic treatment. it has been shown that the total number of canals found and endodontically treated does not correspond to the number of canals actually existing in a tooth. the detection of root canals becomes difficult as a result of various factors.4,7,10 it is therefore important that we understand the variables that have a direct influence on the detection and treatment of root canals. many studies have evaluated the root canal morphology of the maxillary first molar, because this tooth presents a complex morphology that often renders treatment difficult.3,4,6 the presence of additional root canals has been reported and discussed by several authors using a variety of study methods, including radiography, magnification, clinical evaluation, dye injection, tooth sectioning, and scanning electron microscopy. cone-beam computed tomography (cbct) scans have attracted a lot of notice in the field of dentistry as a diagnostic and treatment-planning tool. thus far, the chief use of cbct has been in planning the placement of dental implants,13 but many other possibilities exist and are being explored. the different applications of cbct in endodontics include the assessment of non-endodontic or endodontic pathosis, internal and external resorption analysis, pre-surgical planning and canal morphology.14,15 the fusion of two buccal roots is one of the most common aberrations of maxillary molars. a total of 0.4% of first maxillary molars and 2.2% of second maxillary molars have been reported to have this anomaly.4 root canal morphology should be examined further during treatment through the evaluation of radiographs taken from different horizontal angles. the use of a preoperative radiograph and additional radiographic views from a 20º mesial or distal aspect are good techniques to detect root canal morphology and anatomy.3,4 conclusion adequate knowledge of the morphology of the root canal system and its variations is essential for optimal endodontic treatment. the use of highquality radiographs, with careful examination under magnification, is helpful so as to perform successful root canal therapy. figure 4: radiographic examination with files revealed two root canals. figure 5: obturated root canals. saeed rahimi and negin ghasemi case report | 349 references 1. siqueira jf jr, rôças in. clinical implications and microbiology of bacterial persistence after treatment procedures. j endod 2008; 34:1291–301. 2. pasternak júnior b, teixeira cs, silva rg, vansan lp, sousa neto md. treatment of a second maxillary molar with six canals. aust endod j 2007; 33:42–5. 3. malagnino v, gallottini l, passariello p. some unusual clinical cases on root anatomy of permanent maxillary molars. j endod 1997; 23:127–8. 4. gopikrishna v, bhargavi n, kandaswamy d. endodontic management of a maxillary first molar with a single root and a single canal diagnosed with the aid of spiral ct: a case report. j endod 2006; 32:687–91. 5. christie wh, peikoff md, fogel hm. maxillary molars with two palatal roots: a retrospective clinical study. j endod 1991; 17:80–4. 6. barbizam jv, ribeiro rg, tanomaru filho m. unusual anatomy of permanent maxillary molars. j endod 2004; 30:668–71. 7. de almeida-gomes f, maniglia-ferreira c, carvalho de sousa b, alves dos santos r. six root canals in maxillary first molar. oral surg oral med oral pathol oral radiol endod 2009; 108:157–9. 8. dankner e, friedman s, stabholz a. bilateral c shape configuration in maxillary first molars. j endod 1990; 16:601–3. 9. martínez-berna a, ruiz-badanelli p. maxillary first molars with six canals. j endod 1983; 9:375–81. 10. holderrieth s, gernhardt cr. maxillary molars with morphologic variations of the palatal root canals: a report of four cases. j endod 2009; 35:1060–5. 11. torre f, cisneros-cabello r, aranguren e, estévez r, velasco-ortega e. single-rooted maxillary first molar with a single canal: endodontic retreatment. oral surg oral med oral pathol oral radiol endod 2008; 106:66–8. 12. cobankara fk, terlemez a, orucoglu h. maxillary first molar with an unusual morphology: report of a rare case. oral surg oral med oral pathol oral radiol endod. 2008; 106:62–5. 13. blattner tc, george n, lee cc, kumar v, yelton cd. efficacy of cone-beam computed tomography as a modality to accurately identify the presence of second mesiobuccal canals in maxillary first and second molars: a pilot study. j endod 2010; 36:867– 70. 14. loannidis k, lambrianidis t, beltes p, besi e, malliari m. endodontic management and cone-beam computed tomography evaluation of seven maxillary and mandibular molars with single roots and single canals in a patient. j endod 2011; 37:103–9. 15. kim y, lee s, woo j. morphology of maxillary first and second molar analyzed by cone-beam computed tomography in a korean population: variations in the number of roots and canals and the incidence of fusion. j endod 2012; 38:1063–8. hair heterochromia is characterised by the presence of hair of two naturally-occurring different colours in an individual. although scalp and facial hair can often be different colours in fairer-haired individuals, hair on the rest of the body tends to be much darker than the scalp hair.1 eyelashes are usually also more darkly pigmented than scalp hair for most people. moreover, a slight variation in the colour of individual hair shafts can sometimes be seen in a normal scalp.1 this report describes an infant with a circular patch of focal scalp hair heterochromia without any underlying abnormalities. case report a six-month-old omani male infant presented to the department of dermatology, saham hospital, oman, in 2013 with a patch of different coloured hair on his head. the child was active and growing at an age-appropriate rate. a local examination revealed a focal circular area of golden-yellow hair 3 cm in diameter on the right side of the scalp, located at the midline in the occipital area of the head [figure 1a]. the heterochromatic hairs were consistent in colour from the root to the tip of the hair shaft. the rest of the hair on his scalp as well as the eyebrows and eyelashes were light brown. the skin under the lesion was not depigmented. no other family members had previously reported similar pigmentation disorders. routine investigations, including total iron binding capacity, serum ferritin and serum copper levels, did not reveal any nutritional deficiencies. an examination of the heterochromic hair under a light microscope revealed a homogenous distribution of pigment along the hair length. no thinning was noted when compared with the darker scalp hair. a wood’s lamp examination of the skin and hair also did not reveal any abnormalities. the density of the heterochromatic hair was the same as that of the normal scalp hair and there were no loose hairs, as evidenced by a hair pull test. there was no clinical evidence of an underlying naevus or heterochromia of the hair elsewhere on the body. at a one-year follow up, the scalp hair had become dark brown, although the patch of light-coloured heterochromatic hair remained unchanged [figure 1b]. discussion eumelanin and pheomelanin combine to form most of the naturally-occurring hair, eye and skin colours during a process known as mixed melanogenesis.2 although blond hair contains mostly eumelanin, ito et al. concluded that the yellowish tint of blond hair is due to the high dilution of eumelanin, while pheomelanin does not play a significant role.2 while the exact mechanism which makes blond hair appear department of dermatology, saham hospital, saham, oman e-mail: kumarpramod5@rediffmail.com تغاير الشعر البؤري لفروة الرأس يف رضيع برامود كومار abstract: hair heterochromia involves the presence of two different non-artificially induced colours of hair in the same individual which can be due to either iron deficiency anaemia, genetic mutations or mosaicism. we report a six-month old male infant who presented to the department of dermatology, saham hospital, saham, oman, in 2013 with focal scalp hair heterochromia without any detectable underlying abnormalities. the area of heterochromia was still noticeable at a one-year follow-up. keywords: pigmentation disorders; hair color; hair diseases; mosaicism; infant; case report; oman. امللخ�ص: ي�ضمل تغاير ال�ضعر وج�د ل�نني غري م�ضطنعني من ال�ضعر يف نف�ص الفرد والذي عادة ما يك�ن ب�ضبب اإما فقر الدم الناجت عن نق�ص احلديد, اأوالطفرات ال�راثية اأو التزيق. هذا تقرير حالة عن ر�ضيع ذكر عمره �ضتة اأ�ضهر قدم اإىل ق�ضم االأمرا�ص اجللدية يف م�ضت�ضفى �ضحم, �ضحم, عمان, يف عام 2013 مع وج�د تغاير ال�ضعر يف فروة الراأ�ص من دون اأي حاالت مر�ضية اأخرى م�ضببه. وكانت منطقة التغاير ال تزال ملح�ظة بعد �ضنة واحدة من املتابعة. الكلمات املفتاحية: ا�ضطرابات الت�ضبغ؛ ل�ن ال�ضعر؛ اأمرا�ص ال�ضعر؛ التزيق؛ ر�ضيع؛ تقرير حالة؛ عمان. focal scalp hair heterochromia in an infant pramod kumar sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e116–118, epub. 30 mar 17 submitted 8 may 16 revision req. 7 jun 16; revision recd. 30 jun 16 accepted 19 jul 16 case report doi: 10.18295/squmj.2016.17.01.022 pramod kumar case report | e117 yellowish is unknown, the researchers suggested that suppressed melanogenesis in blond hair may lead to smaller eumelanin polymers, resulting in a yellow appearance.2 discrete patches of lighter or darker coloured hair with a blaschkoid distribution may occur in rare cases.3,4 several reports of segmental hair heterochromia have been published in which demarcated variations in colour occur along a single hair shaft.5,6 this variation usually takes the form of an intermittent loss of pigmentation. sato et al. described a 15-yearold girl with segmented heterochromia associated with iron deficiency anaemia; the patient subsequently recovered completely following treatment with an iron supplement.7 tomita et al. reported a case of white scalp hair in an infant with menkes disease who had low levels of eumelanin and pheomelanin; the discolouration resolved after the administration of copper histidinate.8 a solitary case of nummular headache associated with focal hair heterochromia in a child has also been reported.9 three different types of hair heterochromia have been previously described: patchy, segmental and diffuse.10 the patient in the current case had heterochromia of one area of scalp hair and thus was diagnosed with patchy or focal heterochromia. focal hair heterochromia, owing to its presentation in isolated areas, is an indication of mosaicism.11,12 a similar case was reported in japan with systematic naevus depigmentosus and focal blond hair on a portion of the scalp; the eumelanin content in the hair was low although pheomelanin levels were normal.13 however, a systemic examination in the current case did not reveal evidence of the involvement of any other systems. moreover, the patient did not have any nutritional deficiencies and the colouration of the affected hair was uniform along the whole shaft. as such, somatic mosaicism leading to the dilution of hair pigment in a focal area of the scalp was considered the most likely explanation for the heterochromia in the current case. conclusion focal hair heterochromia may be caused by iron deficiency anaemia or menkes disease and can be associated with underlying naevus depigmentosus. this case report described a case of focal scalp hair heterochromia without any underlying abnormalities; moreover, the heterochromia was found to have persisted at a one-year follow-up. as such, somatic mosaicism was concluded to be the most likely explanation for the heterochromia. references 1. messenger ag, de berker da, sinclair rd. disorders of hair. in: burns t, breathnach s, cox n, griffiths c, eds. rook’s textbook of dermatology, 8th ed. oxford, uk: wiley-blackwell, 2010. pp. 66.1–100. doi: 10.1002/9781444317633.ch66. 2. ito s, wakamatsu k. diversity of human hair pigmentation as studied by chemical analysis of eumelanin and pheomelanin. j eur acad dermatol venereol 2011; 25:1369–80. doi: 10.11 11/j.1468-3083.2011.04278.x. 3. iorizzo m, piraccini bm, tosti a. heterochromia of the scalp hair following blaschko lines. pediatr dermatol 2007; 24:69–70. doi: 10.1111/j.1525-1470.2007.00338.x. 4. dumitrascu ci, hoss e, hogeling m. heterochromia of the hair and eyelashes with blaschkoid dyspigmentation. pediatr dermatol 2016; 33:e121–2. doi: 10.1111/pde.12738. 5. yoon kh, kim d, sohn s, lee ws. segmented heterochromia in scalp hair. j am acad dermatol 2003; 49:1148–50. doi: 10.1016/s0190-9622(03)00471-7. figure 1: focal area of heterochromic hair on the scalp of a six-month-old male infant at (a) presentation and (b) a one year follow-up. https://doi.org/10.1002/9781444317633.ch66 https://doi.org/10.1111/j.1468-3083.2011.04278.x https://doi.org/10.1111/j.1468-3083.2011.04278.x https://doi.org/10.1111/j.1525-1470.2007.00338.x https://doi.org/10.1111/pde.12738 https://doi.org/10.1016/s0190-9622%2803%2900471-7 focal scalp hair heterochromia in an infant e118 | squ medical journal, february 2017, volume 17, issue 1 6. cho sb, zheng z, kim jy, oh sh. segmented heterochromia in a single scalp hair. acta derm venereol 2014; 94:609–10. doi: 10.2340/00015555-1790. 7. sato s, jitsukawa k, sato h, yoshino m, seta s, ito s, et al. segmented heterochromia in black scalp hair associated with iron-deficiency anemia: canities segmentata sideropaenica. arch dermatol 1989; 125:531–5. doi: 10.1001/arch derm.1989.01670160079015. 8. tomita y, kondo y, ito s, hara m, yoshimura t, igarashi h, et al. menkes’ disease: report of a case and determination of eumelanin and pheomelanin in hypopigmented hair. dermatology 1992; 185:66–8. doi: 10.1159/000247407. 9. dabscheck g, andrews pi. nummular headache associated with focal hair heterochromia in a child. cephalalgia 2010; 30:1403–5.doi: 10.1177/0333102410368439. 10. park yj, sohn yb, sohn s, kim yc. isolated patchy heterochromia of the scalp hair. eur j dermatol 2015; 25:342–3. doi: 10.1684/ejd.2015.2554. 11. restano l, barbareschi m, cambiaghi s, gelmetti c, ghislanzoni m, caputo r. heterochromia of the scalp hair: a result of pigmentary mosaicism? j am acad dermatol 2001; 45:136–9. doi: 10.1067/mjd.2001.113688. 12. bonamonte d, filoni a, vestita m, angelini g, foti c. scalp hair heterochromia in a 5-year-old child: rare somatic mosaicism? pediatr dermatol 2014; 31:733–4. doi: 10.1111/pde.12393. 13. fukai k, ishii m, kadoya a, hamada t, wakamatsu k, ito s. nevus depigmentosus systematicus with partial yellow scalp hair due to selective suppression of eumelanogenesis. pediatr dermatol 1993; 10:205–8. doi: 10.1111/j.1525-1470. 1993.tb00363.x. https://doi.org/10.2340/00015555-1790 https://doi.org/10.1001/archderm.1989.01670160079015 https://doi.org/10.1001/archderm.1989.01670160079015 https://doi.org/10.1159/000247407 https://doi.org/10.1177/0333102410368439 https://doi.org/10.1684/ejd.2015.2554 https://doi.org/10.1067/mjd.2001.113688 https://doi.org/10.1111/pde.12393 https://doi.org/10.1111/j.1525-1470.1993.tb00363.x https://doi.org/10.1111/j.1525-1470.1993.tb00363.x the classic features of down syndrome (ds) may not initially be apparent in extremely premature newborns. rarely, ds will present in association with a haematologic entity referred to as transient myeloproliferative disorder (tmd), also known as transient leukaemia (tl). tmd can be self-limiting with an estimated incidence of 10% in patients with ds. however, in 20–30% of cases it may transform to true leukaemia.1,2 we report an extremely premature neonate with mosaic down syndrome (mds) who appeared phenotypically normal and presented with multisystem dysfunction, tmd, and subsequently developed acute myeloid leukaemia (aml). case report a male neonate was born at 26 weeks of postmenstrual age to non-consanguineous parents. the mother was a 31-year-old known asthmatic g7p6a1. her intrapartum course was complicated by placenta abruptio; hence, the baby was born by an emergency caesarean section and the mother lost a litre of blood during delivery. in view of the neonate’s poor general condition and marked pallor at birth, immediate resuscitation and ventilatory support were rendered. the right hand was noticeably blanched and had turned cyanotic. the radial and ulnar pulses were not palpable. there were no apparent dysmorphic features. the growth parameters were adequate for gestational age; the baby’s birth weight was 1,020 gr, body length was 34 cm, and head circumference 24 cm. in the first 24 to 48 hours of life, the baby had sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 498-582, epub. 20th nov 12 submitted 12th jan 12 revision req. 29th apr 12, revision recd. 3rd jun 12 accepted 27th jun 12 اضطراب الَتكاثري الِنْقِيّي املؤقت ومتالزمة داون هل مثة رابط؟ زنيدة ري�ض، وفاء ب�صري، اأنيل باثاري امللخ�ص: ُعرَض علينا وليد ذكر خديج للغاية مصاب باضطراب غري عادي يف أجهزة اجلسم املتعددة خالل اليومني األوليني من حياته. وقد بّينت األحداث السريرية والفحوصات اضطراب التكاثري النقيي املؤقت. وقد كان ذلك االضطراب السبب الرئيسي للتنميط النووي هلذا الرضيع اخلديج بدون وجود وصمات ممّيزة ملتالزمة داون. معرفة وجود اضطراب التكاثري النقيي املؤقت لدى وليد تستوجب التنميط النووي حبثا عن التثلث الصبغي 21، والرتّصد الدقيق للحالة وذلك إلمكانية تطوره إىل ابيضاض الدم. مفتاح الكلمات: ا�صطراب التكاثري النقيّي املوؤقت، متالزمة داون الف�صيف�صائية، ابي�صا�ض الدم النقوي احلاد، تقرير حالة، ُعمان. abstract: an extremely premature male neonate presented with an unusual multisystem dysfunction within the first 24 to 48 hours of life. the unfolding of clinical events and investigations revealed a transient myeloproliferative disorder (tmd). tmd was the main indication for karyotyping of this premature infant without clinical symptoms of down syndrome. the awareness of tmd in a newborn warrants karyotype analysis to look for trisomy 21 and a close surveillance because of its potential progression to true leukaemia. keywords: extreme premature; transient myeloproliferative disorder; down syndrome; gata1; acute myelogenous leukemia (aml); case report; oman. transient myeloproliferative disorder and down syndrome is there a link? *zenaida s. reyes,1 wafa bashir,2 anil pathare2 case report departments of 1child health and 2haematology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: zenaida819@gmail.com zenaida s. reyes, wafa bashir and anil pathare case report | 499 severe respiratory distress syndrome (rds) that was treated with a surfactant. the major concern then was the apparent vascular compromise of the right hand, but there was no identifiable reason for the condition. heparin was administered for a few hours and discontinued when the neonate’s activated partial thromboplastin time (appt) rose to 180 seconds. the right hand became pink on the 4th day and his pulses returned to normal by the 12th day. the possibility of feto-maternal haemorrhage as the cause of the neonate’s marked anaemia (haemoglobin 9.3 gr/dl) was unproven. the skin was thick and marked by scattered vesiculopustular lesions in the perianal area. evaluation of and treatment for infection was indicated by the probability of a staphylococcal sepsis. weekly blood cultures in the first 6 weeks of life and a culture of the skin lesions for bacterial and viral infections such as cytomegalovirus (cmv), herpes, parvovirus, mumps, and enteroviruses were negative. the skin appeared normal after 2 to 3 weeks. the initial complete blood count (cbc) from the cord sample showed pancytopenia. the trend of the serial cbc during the first two weeks of life showed leukocytosis of 30–59 x 109/l and an absolute neutrophil count (anc) of 10–37 x 109/l. his platelet count decreased from day 20. blast cells were seen on the peripheral smear on the first day of life [table 1]. the leukaemia immunophenotyping done on the third day of life revealed that the blasts were cd 13, 33, 34, 117 and hla-dr positive, consistent with acute myeloid leukaemia (aml), and were negative for lymphoid markers [figure 1]. these immature blast cells were considered unique to prematurity or possibly secondary to trisomy 21. the diagnosis of tmd was based on the persistence of blast cells on serial peripheral smears beyond one week of life [figure 1]. earlier physical examinations had shown no clinical features consistent with ds. however at about 33 weeks of gestation, a few features, such as epicanthal folds and the low nasal bridge of ds, were noticeable. the cytogenetic analysis revealed mds 47,xy,+21/46, xy. on the second day of life, the baby developed intractable segmental myoclonus characterised as spontaneous and stimulus-sensitive, and involving the palate, and upper and lower limbs. the seizures were controlled completely on the third week with triple anticonvulsants, namely phenobarbital, phenytoin, and levetiracetam. the electroencephalogram (eeg) showed a burstsuppression-like pattern with spike-and-wave discharges. there were no structural abnormalities or thrombosis identified on a magnetic resonance imaging (mri) scan of the brain. the comorbidities that arose during the baby’s adverse clinical course were the following: bronchopulmonary dysplasia (bpd); stage 2 zone ii retinopathy of prematurity (rop) that required laser therapy; cholestasis, and osteopenia of prematurity (oop). table 1: serial complete blood count (cbc)/peripheral smear (ps) day 0 day 1 day 5 day 10 day 14 day 20 rbc 1012/l 1.72 2.32 4.38 4.29 5.35 4.05 haemoglobin gm/dl 6 9.3 13.7 11.6 12.8 10.2 haematocrit l/l 0.17 0.27 0.39 0.34 0.40 0.31 mcv fl 101 116 88 80.3 74.9 75.7 mch pg 35.1 40.5 31.3 27.0 23.9 25.1 mchc g/l 34.9 34.8 35.5 33.7 31.9 33.2 rdw % 27.3 20.2 20.7 24.2 22.5 21.9 nrbc 109/l 0.9 4.6 0 0.4 0.4 0 platelet count 109/l 21 328 309 119 301 67 wbc 109/l 8.6 44.9 56.7 59.6 36.9 11.4 neutrophils 109/l 2.3 5.2 22.8 43.9 27.1 5.2 lymphocytes 109/l 5.4 21.2 21.7 12 8.1 5.2 monocytes 109/l 0.9 17.2 11.9 3.6 1.5 0.9 eosinophils 109/l 0.1 1.2 0.2 0.2 0.1 0 basophils 109/l 0 0.1 0.1 1.1 0 0 retics % 4.2 5.8 2.3 0.8 1.1 0.8 retics absolute 71.6 145 102 46.7 60.7 31.7 peripheral smear: presence of blasts cells (<15%) + + + + + + rbc = red blood cells; mcv = mean corpuscular volume; mch = mean corpuscular haemoglobin; mchc = mean corpuscular haemoglobin concentration; rdw = red blood cell distribution width; nrbc = nucleated red blood cells; wbc = white blood cells. transient myeloproliferative disorder and down syndrome is there a link? 500 | squ medical journal, november 2012, volume 12, issue 4 he was discharged at 85 days of life with growth parameters below the 3rd centile; he weighed 2,160 gr, and was 42 cm in length, with an hc of 29 cm. the baby’s subsequent follow-up would prove to be critically important given his history of tmd. the monitoring protocol used was a cbc every 3 months. the haematological problem resolved at 6 months of age. there were difficulties encountered in obtaining an adequate specimen from serial bone marrow aspirates (bma) at 6 months and 16 months. the findings each time showed no leukaemic markers. however, in the presence of progressive hepatosplenomegaly (hsm) from 16 months of age, a repeat bma at 17 months of age confirmed the finding of aml [figure 2]. his immunophenotype by flowcytometry showed a biphenotypic leukaemia with positive lymphoid and myeloid markers, with a predominance of the latter. he was treated using the 2007 treatment protocol for aml-ds, which consisted of a total of four courses of chemotherapy, with two induction courses followed by two consolidations. the chemotherapy in the induction course included cytarabine, idarubicin, etoposide, and intrathecal cytarabine. in the consolidation phase, the chemotherapy included high dose cytarabine and mitoxanthrone. presently, the baby is 3 years old and has been in remission since 2 years of age. discussion ds is the most common recognised chromosomal abnormality, occurring in 1: 1000 live births. full trisomy 21 presents in 94% of patients, mds in 2.4%, and translocations in 3.3%.3 in mds, there are two populations of cell lines—a normal cell line with 46 chromosomes and a second line with trisomy 21. in patients with mds, clinical features vary from normal to subtle to full expression of ds depending on the level and distribution of the trisomic cells within the tissues.4 our patient was a confirmed case of mds who initially presented without clinical features of ds. all cytogenetic types of ds are predisposed to develop leukaemia. approximately 10% of people with ds present with tmd and, after initial resolution, a significant proportion (20–30%) may subsequently develop any of the following: acute myelogenous leukaemia (aml), acute lymphoblastic leukaemia (all), or acute megakaryocytic leukaemia (amkl). more recent studies have implicated the mutagenesis of haematopoietic transcription of factor gene gata 1 as an initiating agent in ds leukaemogenesis.5 the gata 1 gene, located on the x chromosome, encodes a zinc-finger transcription factor that is essential for normal erythroid and megakaryocytes differentiation. somatic mutations in exon 2 of gata1 have been detected exclusively in trisomy figure 1: peripheral smears in the first 2 weeks of life, with blasts cells indicated by red arrows. zenaida s. reyes, wafa bashir and anil pathare case report | 501 21-associated tl as well as non-ds related amkl. there are three cooperating events in pathogenetic steps in aml-ds: trisomy 21, the gata1 mutation (gata1s), and an undefined genetic alteration. however, it remains unclear which factors in the chromosome 21 cooperate with the oncogenic gata1s and which factors drive this transition from preleukaemia to amlds. the blast cell sensitivity to chemotherapy in aml-ds has been linked to the gene-dosage effect of chromosome 21 localised genes that leads to an increased level in the expression of cystathionine beta-synthase, contributing to cytarabine sensitivity. the generation of gata1s results in interactions and modulation of the expression of different genes, such as the cytidine deaminase gene (cda) localised to chromosome 1. cda is involved in the irreversible hydrolytic deamination of ara-c (cytarabine) to the inactive ara-u (uracil). the expression of anti-apoptotic proteins such as bcl2 (whose gene, bcl2, is localised to chromosome 18), and hsp70 (whose gene, hsp70, is localised to chromosome 5) is lower in ds aml blasts, suggesting that ds megakaryoblasts are more susceptible to chemotherapy-induced apoptosis. overexpression of cbs has been correlated with in vitro generation of ara-ctp, the active intracellular ara-c metabolite, and subsequent increased ara-c sensitivity in ds aml blast cells.6 our patient was diagnosed with tmd on the basis of the 6-month persistence of blast cells, and its resolution was based on serial bma findings negating the presence of leukaemia. however, the presence of hepatosplenomegaly at 16 months indicated that the tmd was not transient and had progressed to aml. the difficult in aspirating specimens in the earlier bmas may have been due to hypercellularity and myelofibrosis, an antecedent myelodysplastic phase. extreme prematurity, significant early leukocytosis, and the reappearance of blast cells after an apparent resolution were considered risk factors for the progression to true leukaemia. the appearance of the neonate’s right hand at birth gave rise to major concerns about an acute vascular compromise or a thromboembolic episode. neonates are particularly susceptible to thromboembolic diseases because of the relative immaturity of the homeostatic system and the potential presence of serious underlying disease.7 investigations to identify its cause ruled out congenital and acquired thrombophilia, and cyanotic heart disease. the right hand may have been entrapped during delivery, leading to an acute arterial vasospasm. the surveillance for the long term effects of this event showed no disparity in growth of the upper limbs. there are many possible causes of vesiculopustular eruptions in babies, but the commonest is infection. its appearance in our patient coincided with leukocytosis, and persistence of blast cells. whether these lesions represented the leukaemic cutis associated with tmd was figure 2: serial bone marrow aspirates (bma) images with blasts cells at 17 (a), 18 (b), 19 (c), and 22 (d) months of age. please note the absence of blast cells at 22 months when the patient was in remission (e & f). transient myeloproliferative disorder and down syndrome is there a link? 502 | squ medical journal, november 2012, volume 12, issue 4 something that was not investigated.7 there are reports in the literature of neonates presenting with tmd and cutaneous lesions without morphologic features of ds that were proven to have mds.8–10 in hindsight, both the unusual slow-healing skin lesions and tmd should have served as clues to the identification of ds in the baby. the early development of intractable seizures was considered hypoxia-induced due to the neonate’s severe anaemia at birth. conclusion neonates, especially extremely premature babies, with an easily recognised syndrome like ds may not present initially with significant physical features; however, ds may present as its rarest associated clinical problem, tmd. references 1. zipursky a. transient leukaemia–a benign form of leukaemia in the newborn infant with trisomy 21. br j haematol 2003; 120:930–38. 2. masey gv, zipursky a, chang mn, doyle jj, nasim s, taub jw, et al. a prospective study of the natural history of transient leukemia (tl) in neonates with down’s syndrome (ds) children’s oncology group (cog) study pog-9481. blood 2006; 107:4606–13. 3. jones, kl. down syndrome. in: jones kl, ed. smith's recognizable patterns of human malformation. 6th ed. philadelphia: elsevier saunders, 2006. p. 7. 4. papavassilliou p, york t, gursoy n, hill g, nicely lv, sundaram u, et al. the phenotype of persons having mosaicism of trisomy 21/down syndrome reflects the percentage of trisomic cells present in different tissues. am j med genet a 2009; 149a:573–83. 5. roy a, roberts i, norton a, vyas p. acute megakaryoblastic leukemia (amkl) and transient myeloproliferative disorder (tmd) in down syndrome: a multi-step model of leukaemogenesis. br j haematol 2009; 147:3–12. 6. xavier ac, taub j. acute leukemia in children with down syndrome. haematologica 2010; 95:1043–5. 7. gault t. vascular compromise in newborn infants. arch dis child 1992; 67:463–7. 8. nijhawan a, baselga e, gonzalez-ersenat a, vicente a, southern jf, camitta bm, et al. vesiculopustular eruptions in down syndrome neonates with myeloproliferative disorders. arch dermatol 2001; 137:760–3. 9. norhold e, li a, rothman il, lakshmenrusimha s, helm tn. vesicular eruption associated with transient myeloproliferative disorder. cutis 2009; 83:234–6. 10. zubizarreta p, muriel fs, fernandez barbieri ma. transient myeloproliferative associated with trisomy 21, a wide range syndrome: report of two cases with trisomy mosaicism. med pediatr oncol 1995; 25:60– 4. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e478−485, epub. 14th oct 14 submitted 30th jan 14 revisions req. 3rd mar & 23rd apr 14; revisions recd. 26th mar & 7th may 14 accepted 11th may 14 departments of 1microbiology & immunology, 3obstetrics & gynaecology and 4medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of community health, al baha university, al baha, saudi arabia; 6these authors contributed equally to this work. *corresponding author e-mail: albuloshi@hotmail.com التقلبات يف مستويات األجسام املضادة للكارديوليبني وبيتا2جليكوبروتني عند النساء احلوامل حممد البلو�سي، �سدقي ح�سن، اإليا�س �سعيد، جمعة البو�سعيدي، منى الديهاين، حممد عثمان، طالل �سالم، حممد اإدري�س، موزة الكلبانية، نيكوال�س وودهاو�س، على اجلابري abstract: objectives: antiphospholipid antibodies fluctuate during a healthy normal pregnancy. this study aimed to investigate the levels of both immunoglobulin m (igm) and immunoglobulin g (igg) antibodies for cardiolipin and β2-glycoprotein (β2gp) among healthy pregnant women. methods: this study was conducted between may 2010 and december 2012. a total of 75 healthy omani pregnant women with no history of autoimmune disease were investigated during their pregnancy and 90 days after delivery at the armed forces hospital in muscat, oman. a control group of 75 healthy omani non-pregnant women were also investigated as a comparison. levels of igm and igg antibodies for both anti-cardiolipin antibodies (acas) and β2gp were measured using a standard enzymelinked immunosorbent assay. results: the aca igm levels were significantly higher in the control group compared to the pregnant women (p <0.001). no significant differences were observed in the aca igm levels between the control group and the pregnant women after delivery. in contrast, aca igg levels were significantly higher during pregnancy and after delivery compared with those of the healthy control group (p = 0.007 and 0.002, respectively). the levels of β2gp igg were significantly higher during pregnancy than after delivery and in the control group (p = 0.001 and <0.001, respectively). conclusion: in this study, aca igg levels increased during healthy pregnancies and after normal deliveries whereas β2gp igg levels increased transiently during the pregnancies. both phenomena were found to be significantly associated with a transient decline in the levels of igm specific for these antigens. therefore, the levels of these antibodies may be regulated during a healthy pregnancy. keywords: anticardiolipin antibodies; beta 2-glycoprotein i; pregnancy; women; oman م�ستويات من للتحقق الدرا�سة هذه هدفت الطبيعي. احلمل فرتة اأثناء يتقلب للفو�سفوليبيد امل�سادة االأج�سام م�ستوى الهدف: امللخ�ص: االأج�سام امل�سادة igm واالأج�سام امل�سادة igg للكارديولبني )aca( و دهون البيتا-2 جليكوبروتني )β2gp( بني الن�ساء العمانيات الدرا�سة و�سملت .2012 االأول/دي�سمرب، وكانون ،2010 اأيار/مايو بني الدرا�سة هذه اأجريت الطريقة: �سليم. �سحي بحمل احلوامل جمموعة أوىل مكونة من 75 إمراأة عمانية حامل بحمل طبيعي �سحي غري م�سابات باأمرا�س املناعة الذاتية ومت حتليل العينات خالل فرتة احلمل و 90 يوما بعد الوالدة. كما �سملت هذه الدرا�سة 75 من الن�ساء غري احلوامل كمجموعة مراقبة على �سبيل املقارنة. مت قيا�س كانت النتائج: .)elisa(االإليزا طريقة 2-جليكوبروتنيبا�ستخدام بيتا و للكارديولبني امل�سادة االأج�سام امل�سادة االأج�سام م�ستويات احلوامل الن�ساء يف igm م�ستويات مع باملقارنة املراقبة جمموعة يف بكثري اأعلى للكارديولبني igm امل�سادة االأج�سام م�ستويات ويف الوالدة. بعد احلوامل الن�ساء وجمموعة املراقبة جمموعة بني igm م�ستويات يف لوحظت مهمة فروق توجد مل .)p >0.001( املقابل كانت م�ستويات igg للكارديولبني اأعلى بكثري اأثناء فرتة احلمل وبعد الوالدة باملقارنة مع جمموعة املقارنة )p = 0.007 و p = 0.002، على التوايل(.اأما االج�سام امل�سادة igg لدهون البيتا-2 جليكوبروتني فكانت امل�ستويات اأعلى بكثري خالل احلمل من بعد الوالدة، ويف جمموعة املقارنة أي�سا )p = 0.001 و0.01<، على التوايل(. الخالصة: يف هذه الدرا�سة، وجدت زيادة يف م�ستويات igg للكارديولبني اأثناء احلمل الطبيعي وبعد الوالدات الطبيعية بينما زادت م�ستويات igg لدهون البيتا-2 جليكوبروتني زيادة عابرة اأثناء فرتة احلمل. ومت العثور على كل هذه الظواهر مرتبطة اإىل حد كبري مع انخفا�س عابر يف م�ستويات حمددة لهذه امل�سادات igm مما قد ينظم م�ستويات هذه االأج�سام امل�سادة اأثناء فرتة احلمل الطبيعي. مفتاح الكلمات: االأج�سام امل�سادة الكارديولبني؛ بيتا 2-جليكوبروتني؛ حمل؛ ن�ساء؛ عمان. fluctuation in the levels of immunoglobulin m and immunoglobulin g antibodies for cardiolipin and β 2 -glycoprotein among healthy pregnant women *mohammed s. al-balushi,1,6 sidgi s. hasson,1,6 elias a. said,1,6 juma z. al-busaidi,1 muna s. al-daihani,1 mohammed s. othman,1 talal a. sallam,2 mohammed a. idris,1 moza al-kalbani,3 nicholas woodhouse,4 ali a. al-jabri1 clinical & basic research mohammed s. al-balushi, sidgi s. hasson, elias a. said, juma z. al-busaidi, muna s. al-daihani, mohammed s. othman, talal a. sallam, mohammed a. idris, moza al-kalbani, nicholas woodhouse and ali a. al-jabri clinical and basic research | e479 antiphospholipid antibodies (aplas) have been detected in up to 5% of healthy omani individuals.1 in a prospective study by lynch et al., these autoantibodies were found to include the antibodies countering cardiolipin and β2-glycoprotein (β2gp), which are directed against phospholipid-binding proteins.2 furthermore, a study by harris et al. indicated that anti-cardiolipin antibodies (acas) were associated with recurrent pregnancy loss.3 these studies have also documented the presence of acas in pregnant women as a valuable indicator for recurrent abortions and fetal wastage, both in patients with autoimmune diseases and in those with no apparent autoimmune diseases.1–3 other studies, however, have not confirmed the significance of the presence of acas during pregnancy.4–7 the changes in apla levels during pregnancy remain obscure.8–16 in an early study based on recurrent miscarriages, it was discovered that approximately 20% of the studied women had persistent aplas before conception.17 in some cases, a rise in the aca titre has been noted during early pregnancy.11–16 pregnancy is known to be associated with a t helper-2 (th2) environment which is thought to enable the maintenance of a normal healthy pregnancy. however, the real mechanisms of and reasons for the shift towards a th2 profile have yet to be elucidated.17,18 this study aimed to detect the levels of both immunoglobulin m (igm) and immunoglobulin g (igg) antibodies specific for both cardiolipin and β2gp during and after a healthy normal pregnancy. methods this study was conducted between may 2010 and december 2012 and included a total of 150 omani women. of this group, 75 were healthy pregnant women who attended the antenatal care outpatient clinic of the department of obstetrics & gynaecology at the armed forces hospital in muscat, oman. healthy non-pregnant women (n = 75) were recruited from the sultan qaboos university hospital blood bank and acted as the control group; they were investigated in parallel with the pregnant women. in both groups, women with the following conditions were excluded from the study: diagnosed connective tissue disease or other autoimmune diseases, or a previous history of thromboembolisms, recurrent abortions or treatments affecting the immune response, such as corticosteroids, immunosuppressive drugs or immunomodulators. the pregnant women were followed up for these conditions throughout their pregnancy and after delivery. blood samples were collected from the control group (never pregnant women) and from the pregnant women, both during their first trimester and 90 days after delivery. the sera were separated after centrifugation at 4,000 rpm in a cooling centrifuge. all sera were tested for aca (using igm and igg) and β2gp levels using a standard enzyme-linked immunosorbent assay (euroimmun corp., lübeck, germany), following the manufacturer’s recommendations. the results were expressed in relative units per millilitre (ru/ml). in order to fulfil the sapporo criteria for antiphospholipid syndrome, autoantibodies were tested twice, with an interval of six weeks between the tests, to distinguish the levels of the antibody response. collected data were then analysed using various statistical tests. a wilcoxon signed-rank test was performed to assess the significance of the changes in antibody levels during pregnancy and after delivery. furthermore, to assess the significance of such changes, the levels of autoantibodies obtained from the pregnant women during pregnancy and after delivery were compared with the control group of nonpregnant women using the mann-whitney u test. the significance of the correlations was calculated using spearman’s rank correlation coefficient. differences in antibody levels were considered significant at p <0.05. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university in muscat, oman (mrec #654). all of the women involved in the study gave signed informed consent before participation. advances in knowledge similarities in the fluctuation patterns of cardiolipin and β2-glycoprotein (β2gp) autoantibodies were noted among a group of healthy pregnant women. levels of both anti-cardiolipin antibodies (acas) and β2gp immunoglobulin g (igg) were found to increase significantly during healthy normal pregnancies. however, the increase of these levels does not pose a danger to either the woman or the fetus during a healthy normal pregnancy unless the levels reach a certain threshold. application to patient care while increased levels of both aca and β2gp igg antibodies may be a normal physiological phenomenon during pregnancy, the factors that lead autoantibodies to become pathogenic are currently obscure. in view of this, the authors of this study support the current autoantibody measurement practices during pregnancy. fluctuation in the levels of immunoglobulin m and immunoglobulin g antibodies for cardiolipin and β 2 -glycoprotein among healthy pregnant women e480 | squ medical journal, november 2014, volume 14, issue 4 results a total of 150 healthy omani women were investigated, with 75 pregnant women and 75 controls. the mean ages of the pregnant women and the control group were 24 and 27 years, respectively. all investigated pregnant women had uncomplicated pregnancies and normal pregnancy outcomes. approximately 80% of the pregnant women had been pregnant before their current pregnancies. increased levels of igg were associated with a transient decrease of aca igm levels during pregnancy. the average igm level after delivery (3.5 ru/ml) was significantly higher than that during pregnancy (2.6 ru/ml; p ≤0.01) [figure 1a]. a similar pattern was found with the serum aca igg, with an average of 3.2 ru/ml after delivery in comparison to an average of 2.4 ru/ml during pregnancy (p ≤0.01) [figure 1b]. the average aca igm level was significantly higher in the control group (3.98 ru/ml) than in the pregnant women during their pregnancies (p <0.001) [figure 2a]. however, no significant differences were seen in the aca igm levels between the control group and the pregnant women after delivery. in contrast, aca igg levels were significantly higher during and after pregnancy when compared to those of the healthy control group, with an average of 1.8 ru/ml (p = 0.007 and 0.002, respectively) [figure 2b]. among the pregnant women, a transient increase in the levels of β2gp igg was associated with a transient decrease of aca igm levels during pregnancy. the average igm level after delivery (8.4 ru/ml) was significantly higher than the average during pregnancy (2.2 ru/ml; p ≤0.01) [figure 3a]. in addition, a decrease was observed in the average level of β2gp igg after delivery (1.4 ru/ml) in contrast to the average level during pregnancy (2.0 ru/ml; p ≤0.01) [figure 3b]. the average level of β2gp igm was significantly figure 1 a & b: increased levels of anti-cardiolipin antibody (a) immunoglobulin m and (b) immunoglobulin g were observed among the pregnant group of women after delivery in comparison to those recorded during their pregnancies (n = 75). aca = anti-cardiolipin antibody; igm = immunoglobulin m; igg = immunoglobulin g; ru/ml = relative units per millilitre. figure 2 a & b: in comparison to the control group (n = 75), there were (a) decreased levels of anti-cardiolipin antibody (aca) immunoglobulin m and (b) increased levels of aca immunoglobulin g among the pregnant women (n = 75), both during pregnancy and after delivery. aca = anti-cardiolipin antibody; igm = immunoglobulin m; igg = immunoglobulin g; ru/ml = relative units per millilitre. mohammed s. al-balushi, sidgi s. hasson, elias a. said, juma z. al-busaidi, muna s. al-daihani, mohammed s. othman, talal a. sallam, mohammed a. idris, moza al-kalbani, nicholas woodhouse and ali a. al-jabri clinical and basic research | e481 lower during pregnancy in comparison to after delivery and in the control group (8.9 ru/ml; p <0.01 and <0.01, respectively) [figure 4a]. however, no significant differences were observed in the aca igm levels during pregnancy in comparison to those recorded after delivery or among the control group. the levels of β2gp igg were found to be significantly higher during pregnancy in contrast to the levels recorded after delivery and in the control group (1.2 ru/ml; p = 0.001 and <0.001, respectively) [figure 4b]. the levels of both aca igg and β2gp igg were significantly higher in the pregnant women than in the healthy non-pregnant control group, by 1.3 and 1.6 times, respectively. moreover, as the pregnant women’s β2gp igg decreased after delivery to levels similar to those found in non-pregnant women, the aca igg levels were still 1.8 times higher after delivery when compared with the control group. interestingly, the increase of igg levels during pregnancy was associated with a transient 40% and 80% decrease in igm levels against both aca and β2gp, respectively [figures 5a & b]. there were similarities in the fluctuation pattern of aca and β2gp autoantibodies in healthy pregnant women. while the results obtained showed that the levels of both aca igg and β2gp igg were significantly correlated during pregnancy (ρ = 0.3; p = 0.008) [figure 6a], no correlation was detected between the level of these autoantibodies after delivery and in the control group. furthermore, the igm levels of both aca and β2gp were significantly correlated during pregnancy (ρ = 0.4; p <0.001) [figure 6b], after delivery (ρ = 0.5; p <0.001) [figure 6c] and in the control group (ρ = 0.4; p <0.001) [figure 6d]. the ratio of igg acas to igm acas was significantly correlated with the igg to igm ratio for β2gp during pregnancy (ρ = 0.5; p <0.001) [figure 6e] and after delivery (ρ = 0.34; p = 0.004) [figure 6f]. figure 3 a & b: when compared to the levels observed during pregnancy, there were (a) increased levels of anti-β2glycoprotein (β2gp) immunoglobulin m and (b) decreased levels of anti-β2gp immunoglobulin g among the women after delivery (n = 75). β2gp = β2-glycoprotein; igm = immunoglobulin m; igg = immunoglobulin g; ru/ml = relative units per millilitre. figure 4 a & b: pregnancy induces (a) a transient decrease of anti-anti-β2-glycoprotein (β2gp) immunoglobulin m levels associated with (b) a transient increase in anti-β2gp immunoglobulin g levels (n = 150; n = 75 for each group). β2gp = β2-glycoprotein; igm = immunoglobulin m; igg = immunoglobulin g; ru/ml = relative units per millilitre. fluctuation in the levels of immunoglobulin m and immunoglobulin g antibodies for cardiolipin and β 2 -glycoprotein among healthy pregnant women e482 | squ medical journal, november 2014, volume 14, issue 4 figure 5 a & b: increased anti-cardiolipin antibody (aca) and β2-glycoprotein (β2gp) immunoglobulin g (igg) levels were observed during pregnancy (n = 75) in comparison to the never pregnant control group (n = 75). this was associated with a transient decrease in immunoglobulin m (igm) levels directed against these self-antigens. a: fold increase of aca igm and igg levels. b: fold increase of anti-β2gp igm and igg levels. the values here are calculated based on the mean values of the previous figures. aca = anti-cardiolipin antibody; β2gp = β2-glycoprotein; igg = immunoglobulin g; igm = immunoglobulin m; ru/ml = relative units per millilitre; np = never pregnant. figure 6 a−f: a correlation was found between anti-cardiolipin antibody (aca) and anti-β2-glycoprotein (anti-β2gp) autoantibodies and (a) immunoglobulin g (igg) levels. additionally, correlations were found between aca and anti-β2gp autoantibodies and immunoglobulin m (igm) levels (b) during pregnancy, (c) after delivery and in (d) non-pregnant women, respectively. correlations were also found between the ratios of igg to igm for aca and anti-β2gp both (e) during pregnancy and (f) after a normal delivery (n = 150; n = 75 for each group). aca = anti-cardiolipin antibody; β2gp = β2-glycoprotein; igg = immunoglobulin g; igm = immunoglobulin m; ru/ml = relative units per millilitre. mohammed s. al-balushi, sidgi s. hasson, elias a. said, juma z. al-busaidi, muna s. al-daihani, mohammed s. othman, talal a. sallam, mohammed a. idris, moza al-kalbani, nicholas woodhouse and ali a. al-jabri clinical and basic research | e483 discussion the results of this study show that levels of aca and β2gp igg were significantly higher during pregnancy when compared with a non-pregnant control group. furthermore, although the β2gp igg levels of the pregnant women decreased after delivery, their aca igg levels remained high. the increase of these igg levels during pregnancy was associated with a transient decrease in igm levels. although these autoantibodies did not reach pathogenic levels, such results suggest that pregnancy promotes the production of these autoantibodies. the presence of autoantibodies at non-pathogenic levels is thought to be important in maintaining homeostasis as they may help the body eliminate the self-structures resulting from cellular or tissue damage.19 levels of these autoantibodies may therefore assist in the avoidance of the accumulation of cellular debris that results from cell death, including the apoptotic process. the potential role of these autoantibodies in tumour surveillance, however, needs to be further investigated.20 the changes in igg and igm levels observed in this study could be due to the th2 cytokine environment that is associated with and thought to enable the maintenance of a normal healthy pregnancy.14 however, the exact mechanisms of and reasons for the shift towards a th2 cytokine profile remain elusive, although hormonal changes have been suggested as a possible cause.21 the inhibition of the t-helper 1 (th1) immune response might be important for the survival of the fetus. in fact, while the th1 response is a pro-inflammatory response, the th2 response has a tolerogenic effect. it is well established that isotype switching from igm to certain subclasses of igg (such as igg1, the predominant igg subclass) is a th2dependent phenomenon.15 therefore, the th2 profile during a normal healthy pregnancy might be related to the increase of self-recognising igm and igg levels. of note, no significant differences were found in the antibody levels of igm and igg specific for acas and β2gps between women who had been pregnant before and those who were pregnant for the first time. interestingly, the results obtained in this study showed that aca and β2gp igg levels were significantly correlated with each other only during pregnancy. this may also be explained by the th2 cytokine environment believed to occur during a normal healthy pregnancy.16 this theory is supported by the present study’s results, which found significant correlations between the ratio of igg to igm levels for both acas and β2gps. moreover, another explanation for such a correlation is that the fifth domain of β2gp contains a phospholipid-binding site (cys281-cys288) and a region recognised by acas.17,18 consequently, when the β2gp antigen is available, it might elicit autoantibodies that recognise both acas and β2gps at the same time. furthermore, and unlike igg levels, aca and β2gp igm levels were significantly correlated in the pregnant group during pregnancy and after delivery, as well as in the control group. the presence of such a correlation (with reference to the levels of igm but not igg in non-pregnant women) can be explained by the induction of this isotype at a basal level, for reasons that remain elusive. the observed correlation of aca and β2gp igm levels during pregnancy and after delivery might be due to the similarities that are found in the patterns of fluctuation for igm levels, which is not the case for igg levels after delivery. the results of this study clearly showed the correlation between aca and β2gp autoantibodies, corroborating previous findings that illustrated similar correlations among pregnant women who experienced spontaneous abortions or preeclampsia.22,23 it is worth noting that the correlation between aca and β2gp igg levels was also found in some autoimmune diseases, such as systemic lupus erythematosus and antiphospholipid syndrome, as well as in some infectious diseases, including human immunodeficiency virus infection, leprosy and malaria.24–27 the increase in aca and β2gp igg levels occurs even during a healthy pregnancy; however, this increase does not present a threat to the maintenance of the pregnancy unless these autoantibodies reach a certain threshold.28 the mechanisms that lead to such a pathogenic effect have yet to be confirmed. in general, autoantibodies have a negative effect on the maintenance of a healthy pregnancy. however, the relationship between aca levels and recurrent pregnancy loss remains controversial.1–5 for example, a decrease in the concentration of aplas has been associated with a successful pregnancy outcome in some studies, whereas others have shown that the relationship between aca levels and pregnancy loss is not significant at all.29–32 consequently, the present study’s results on the fluctuation of aca levels during a normal pregnancy may explain the discrepancies reported by different research groups, as the presence of these autoantibodies did not have a negative influence on the pregnancy, most likely because they were at non-pathogenic levels. finally, it is interesting that the aca igg levels observed in this study increased even after delivery, while β2gp igg levels declined to normal levels. the results of the current study reflect the increase of specific autoantibodies during pregnancy. however, this increase might be general to different autoantibodies, as it is very likely a result of the fluctuation in the levels of immunoglobulin m and immunoglobulin g antibodies for cardiolipin and β 2 -glycoprotein among healthy pregnant women e484 | squ medical journal, november 2014, volume 14, issue 4 particular immunological environment associated with pregnancy. further studies should be performed on a larger sample size and should investigate a greater number of autoantibodies, such as anti-thyroid peroxidase antibodies, anti-nuclear antibodies and anti-double stranded deoxyribonucleic acid. conclusion among these samples of healthy pregnant women, aca and β2gp autoantibodies were found to increase to levels that do not present a threat to the maintenance of a healthy normal pregnancy. this phenomenon could be due to an increase in isotype switching, as seen by the decrease of igm levels. the factors that lead autoantibodies to become pathogenic are currently unknown. acknowledgements this work was partially supported by funds from the department of microbiology & immunology of the college of medicine & health sciences at sultan qaboos university as well as the research council of oman. the authors would like to acknowledge the cooperation of all women who participated in this study. additionally, dr. crystal koh is sincerely thanked for her assistance in revising this manuscript. references 1. al jabri aa, al buloshi ms. anticardiolipin and antinuclear antibodies in the adult healthy omani individuals. saudi med j 2004; 25:313–17. 2. lynch a, marlar r, murphy j, davila g, santos m, rutledge j, et al. antiphospholipid antibodies in predicting adverse pregnancy outcome: a prospective study. ann intern med 1994; 120:470–5. doi: 10.7326/0003-4819-120-6-19940315000004. 3. harris en, spinnato ja. should anticardiolipin tests be performed in otherwise healthy pregnant women? am j obstet gynecol 1991; 165:1272–7. doi: 10.1016/0002-9378(91)90348u. 4. infante-rivard c, david m, gauthier r, rivard ge. lupus anticoagulants, anticardiolipin antibodies, and fetal loss: a case-control study. n engl j med 1991; 325:1063–6. doi: 10.1056/nejm199110103251503. 5. akhlaghi f, keramati mr, tafazoli m. study on antiphospholipid/anticardioliplin antibodies in women with recurrent abortion. iran red crescent med j 2013; 15:718–22. doi: 10.5812/ircmj.4857. 6. velayuthaprabhu s, archunan g. evaluation of anticardiolipin antibodies and antiphosphatidylserine antibodies in women with recurrent abortion. indian j med sci 2005; 59:347–52. doi: 10.4103/0019-5359.16651. 7. schenkein ha, berry cr, burmeister ja, brooks cn, barbour se, best am, et al. anti-cardiolipin antibodies in sera from patients with periodontitis. j dent res 2003; 82:919–22. doi: 10.1177/154405910308201114. 8. levine js, branch dw, rauch j. the antiphospholipid syndrome. n engl j med 2002; 346:752–63. doi: 10.1056/nejmra002974. 9. galli m, barbui t. antiphospholipid antibodies and pregnancy. best pract res clin haematol 2003; 16:211–25. doi: 10.1016/ s1521-6926(02)00094-4. 10. tsapanos v, kanellopoulos n, cardamakis e, fotopoulos a, schinas v, kondakis x, et al. anticardiolipin antibodies levels in healthy pregnant and non-pregnant woman. arch gynecol obstet 2000; 263:111–5. doi: 10.1007/s004040050007. 11. michimata t, sakai m, miyazaki s, ogasawara m, suzumori k, aoki k, et al. decrease of t-helper 2 and t-cytotoxic 2 cells at implantation sites occurs in unexplained recurrent spontaneous abortion with normal chromosomal content. hum reprod 2003; 18:1523–8. doi: 10.1093/humrep/deg280. 12. al-shammri s, rawoot p, azizieh f, abuqoora a, hanna m, saminathan tr, et al. th1/th2 cytokine patterns and clinical profiles during and after pregnancy in women with multiple sclerosis. j neurol sci 2004; 222:21–7. doi: 10.1016/j. jns.2004.03.027. 13. gärdby e, chen xj, lycke ny. impaired cd40-signalling in cd19-deficient mice selectively affects th2-dependent isotype switching. scand j immunol 2001; 53:13–23. doi: 10.1046/j.1365-3083.2001.00824.x. 14. hunt j, krilis s. the fifth domain of beta 2-glycoprotein i contains a phospholipid binding site (cys281-cys288) and a region recognized by anticardiolipin antibodies. j immunol 1994; 152:653–9. 15. matsuura e, igarashi y, yasuda t, triplett a, koike t. anticardiolipin antibodies recognize beta 2-glycoprotein i structure altered by interacting with oxygen modified solid phase surface. j exp med 1994; 179:457–62. doi: 10.1084/ jem.179.2.457. 16. sykes l, macintyre da, yap xj, teoh tg, bennett pr. the th1:th2 dichotomy of pregnancy and preterm labour. mediators inflamm 2012; 2012:967629. doi: 10.1155/2012/967629. 17. quenby sm, farquharson rg. predicting recurring miscarriage: what is important? obstet gynecol 1993; 82:132–8. 18. loncar d. anticardiolipin antibodies in pathogenesis of infertility. vojnosanit pregl 2010; 67:216–9. 19. lutz hu, binder cj, kaveri s. naturally occurring autoantibodies in homeostasis and disease. trends immunol 2009; 30:43–51. doi: 10.1016/j.it.2008.10.002. 20. lutz hu, ed. naturally occurring antibodies (nabs): advances in experimental medicine and biology, volume 750. austin, texas, usa: landes bioscience/springer science + business media, 2012. pp. 27–43. 21. orsi nm. cytokine networks in the establishment and maintenance of pregnancy. hum fertil (camb) 2008; 11:222– 30. doi: 10.1080/14647270802206879. 22. lee rm, brown ma, branch dw, ward k, silver rm. anticardiolipin and anti–β2-glycoprotein-i antibodies in preeclampsia. obstet gynecol 2003; 102:294–300. 23. amengual o, atsumi t, khamashta ma, koike t, hughes gr. specificity of elisa for antibody to beta 2-glycoprotein i in patients with antiphospholipid syndrome. br j rheumatol 1996; 35:1239–43. doi: 10.1093/rheumatology/35.12.1239. 24. inanç m, donohoe s, ravirajan ct, radway-bright el, mackie i, machin s, et al. anti-beta2-glycoprotein i, anti-prothrombin and anticardiolipin antibodies in a longitudinal study of patients with systemic lupus erythematosus and the antiphospholipid syndrome. br j rheumatol 1998; 37:1089–94. doi: 10.1093/ rheumatology/37.10.1089. 25. loizou s, singh s, wypkema e, asherson ra. anticardiolipin, anti-beta(2)-glycoprotein i and antiprothrombin antibodies in black south african patients with infectious disease. ann rheum dis 2003; 62:1106–11. doi: 10.1136/ard.62.11.1106. 26. lynch a, byers t, emlen w, rynes d, shetterly sm, hamman rf. association of antibodies to beta 2-glycoprotein i with pregnancy loss and pregnancy-induced hypertension: a prospective study in low-risk pregnancy. obstet gynecol 1999; 93:193–8. doi: 10.1016/s0029-7844(98)00388-3. mohammed s. al-balushi, sidgi s. hasson, elias a. said, juma z. al-busaidi, muna s. al-daihani, mohammed s. othman, talal a. sallam, mohammed a. idris, moza al-kalbani, nicholas woodhouse and ali a. al-jabri clinical and basic research | e485 27. kwak-kim j, agcaoili ms, aleta l, liao a, ota k, dambaeva s, et al. management of women with recurrent pregnancy losses and antiphospholipid antibody syndrome. am j reprod immunol 2013; 69:596–607. doi: 10.1111/aji.12114. 28. yetman dl, kutteh wh, castorena r, brown c, baskin l. prevalence of elevated anticardiolipin antibodies in pregnant women with unexplained elevations of alpha-fetoprotein. j reprod immunol 1997; 33:71–81. doi: 10.1016/s01650378(97)01014-0. 29. kwak jy, barini r, gilman-sachs a, beaman kd, beer ae. down-regulation of maternal antiphospholipid antibodies during early pregnancy and pregnancy outcome. am j obstet gynecol 1994; 171:239–46. doi: 10.1016/0002-9378(94)904 76-6. 30. petri m. pathogenesis and treatment of the antiphospholipid antibody syndrome. med clin north am 1997; 81:151–77. doi: 10.1016/s0025-7125(05)70509-5. 31. branch dw, silver rm, blackwell jl, reading jc, scott jr. outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the utah experience. obstet gynecol 1992; 80:614–20. 32. mekinian a, loire-berson p, nicaise-roland p, lachassinne e, stirnemann j, boffa mc, et al. outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels. j reprod immunol 2012; 94:222–6. doi: 10.1016/j.jri.2012.02.004. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 399-403, epub. 25th jun 13 submitted 8th jul 12 revisions req. 10th sep & 25th nov 12, 5th mar & 7th may 13; revisions recd. 20th oct 12, 21st jan, 21st apr & 27th may 13 accepted 30th may 13 pediatric department, faculty of medicine, minia university, egypt corresponding author e-mail: basmaelmoez@yahoo.com معدل االصابه بالنوع الثاين من مرض السكري بني أطفال مرضى السكري مبحافظة املنيا يف مصر ب�شمة علي ،�شمري عبد اهلل، اأحالم عبد اهلل، حممود ح�شني جميع يف العامة لل�شحة متزايد قلق م�شدر اأ�شبح واملراهقني االأطفال يف )t2dm( ال�شكري داء من الثاين النوع الهدف: امللخ�ص: اأنحاء العامل. الهدف: تهدف هذه الدرا�شة اإىل تقدير ن�شبة t2dm بني اأطفال مر�شى ال�شكري يف حمافظة املنيا يف م�رس، و الك�شف عن عوامل اخلطر ذات ال�شلة. الطريقة: �شملت الدرا�شه 210 من االأطفال املر�شى بال�شكري يف حمافظة املنيا الذين خ�شعوا للفح�س البدين والفحو�س املخربية. والأخذ تاريخهم الطبي الدقيق. النتائج: وجد t2dm يف 28 مري�شا )%13.3(، و كان حا�رسا ب�شكل ملحوظ يف 18 من االإناث )%64.3( حيث 20 )%17.4( منهم لديهم تاريخ عائلي اإيجابي من dm. وكان موؤ�رس اخلطوط املئوية لكتلة اجل�شم وحميط اخل�رس يف مر�شى t2dm اأعلى بكثري باعتبار العمر واجلن�س من مر�شى t1dm. اأي�شا كانت م�شتويات الهيموجلوبني % ذات �شعيفة اإيجابية ارتباطات هناك كان واأخريا .t1dm مر�شى من t2dm يف بكثري اأعلى و c-الببتيد الكول�شرتول و a1c داللة اإح�شائية بني م�شتوى c-الببتيد و موؤ�رس كتلة اجل�شم وحميط اخل�رس. اخلال�سة: مل يعد مر�س t2dm ي�شيب البالغني فقط ولكن ميكن اأي�شا اأن يحدث يف االأطفال واملراهقني. وت�شري النتائج اىل اأن ال�شمنة، واجلن�س االأنثوي ووجود تاريخ عائلي اإيجابي من dm هي عوامل اخلطر لالإ�شابة ب t2dm. اأي�شا كان املر�شى الذين يعانون من t2dm االأكرث فقدا لل�شيطرة على ارتفاع ن�شبة �شكر الدم و الكول�شرتول من امل�شابني باأنواع مر�س ال�شكري االأخرى. مفتاح الكلمات: مر�س ال�شكري؛ النوع الثاين؛ االأطفال؛ املراهقني؛ c-الببتيد؛ موؤ�رس كتلة اجل�شم؛ الهيموغلوبني a؛ املت�شّكر؛ الكول�شرتول؛ م�رس. abstract: objectives: type 2 diabetes mellitus (t2dm) in children and adolescents is becoming an increasingly important public health concern throughout the world. this study aimed to estimate the frequency of t2dm among diabetic young people in el-minia governorate, egypt, and to detect its risk factors. methods: a total of 210 diabetic patients under 18 years old in minia governorate were included in the study and underwent a thorough history-taking, a physical examination and laboratory investigations. results: t2dm was present in 28 patients (13.3%); it was significantly present in 18 females (64.3%) and 20 (71.4%) of them had a positive family history of dm. t2dm patients had significantly higher bmi and waist circumference centiles for age and sex than those with t1dm. also, haemoglobin a1c %, serum c-peptide and cholesterol levels were significantly higher in t2dm than t1dm patients. finally, there were weak significant positive correlations between c-peptide level and both bmi and waist circumference. conclusion: t2dm is no longer a disease of adults but can also occur in children and adolescents. the results suggested that obesity, female gender and a positive family history of dm are risk factors for t2dm. also, patients with t2dm had poorer glycaemic control and hypercholesterolemia than those with other types of diabetes. keywords: diabetes mellitus, type 2; child; adolescent; c-peptide; body mass index; hemoglobin a, glycosylated; cholesterol; egypt. the frequency of type 2 diabetes mellitus among diabetic children in el minia governorate, egypt basma a. ali, samir t. abdallah, ahlam m. abdallah, mahmoud m. hussein clinical & basic research advances in knowledge in this study, obesity, female gender and a positive family history of diabetes mellitus were risk factors for type 2 diabetes mellitus (t2dm). also, patients with t2dm had poorer glycaemic control and hypercholesterolemia. application to patient care clinicians need alerting to the possibility of non-type 1 diabetes occurring in childhood, and especially to considering the possibility of t2dm. t2dm is often associated with risk factors for cardiovascular disease that may already be present at the time of diagnosis. therefore, prevention and treatment strategies need to be initiated, for example obesity management programmes for obese children, especially those with family history of diabetes. the frequency of type 2 diabetes mellitus among diabetic children in el minia governorate, egypt 400 | squ medical journal, august 2013, volume 13, issue 3 diabetes mellitus (dm) is a group of metabolic diseases characterised by chronic hyperglycaemia resulting from defects in insulin secretion, insulin action, or both.1 there are two major types of diabetes, type 1 dm (t1dm) where there is autoimmune destruction of the pancreas that renders it incapable of making insulin. in type 2 dm (t2dm), patients can still produce insulin, but either not in a sufficient amount to meet their needs, or their body has become resistant to its effects with a compensatory increase in insulin production and release that can also end in beta cell damage.2 non-insulin-dependent dm (t2dm) in children and adolescents is becoming an important public health concern throughout the world.3 although t2dm is widely diagnosed in adults, its frequency has markedly increased in the paediatric age group over the past two decades. depending on the population studies, t2dm now represents 8–45% of all new cases of diabetes reported among children and adolescents.4 therefore, this study aimed to estimate the frequency of t2dm among diabetic children and adolescents in minia governorate, egypt, and to detect its risk factors in this community. methods this study was carried out in the period from january 2010 to december 2010. it included 210 patients on regular follow-up in the diabetes outpatient’s clinic at minia university children hospital, minia governate, egypt. the subjects were 124 (59%) females and 86 (41%) males. their ages ranged from 1 to 18 years, with a mean age of 11.3 ± 4.4 years. the cases were classified into 2 groups according to their fasting serum c-peptide levels. group i (t1dm) included those with a fasting c-peptide level of <0.2 ng/ml, and group ii (t2dm) those with a fasting c-peptide level of 0.2 to ≥3.5 ng/ ml.3–5 written consent was obtained for each subject after approval of the study by the ethical committee of the minia university medical faculty. all patients included in this study underwent a thorough history-taking and a complete physical examination including anthropometric measurements. laboratory investigations included testing fasting c-peptide levels by the enzyme linked immunosorbent assay (elisa) technique (normal paediatric range 0.2–3.5 ng/ml),5 haemoglobin a1(hba1),6 lipid profile (triglycerides [tg] with normal level up to 150 mg/dl7 and serum cholesterol level with normal level up to 220 mg/ dl in paediatric patients).8 both of the latter were assayed by using a fully automated clinical chemistry auto-analyser system konelab 20i (thermo fisher scientific inc., waltham, massachusetts, usa). the data were coded and verified prior to data entry. the statistical package for the social sciences (spss), version 13 for windows (ibm corp., chicago, illinois, usa) was used for data entry and analysis. descriptive statistics were calculated for qualitative data using the chi-square test. for quantitative data, the student’s t-test (for two groups) was used. the z test was used to compare proportions and correlations; p values of less than 0.05 were considered to indicate statistical significance.9 results this study aimed to estimate the frequency of t2dm among diabetic children and adolescents in minia governate. the frequency of t2dm (group ii) was found to be 13.3% (28/210) while t1dm (group i) represented 86.7% (182/210) of the study population. table 1 shows that group ii subjects were significantly older, had a longer disease duration, and a positive family history of dm compared to group i where p <0.05. moreover, there were significantly more females than males with t2dm (64.3% versus 58.2%). on the other hand, there was a non-significant difference between them as regarding the age of onset of the disease. as to the clinical findings, there was a significant difference in body mass index (bmi) percentile between group i and group ii patients because of the relatively recent recognition of t2dm in the paediatric age group, many children with new onset t2dm may be misclassified as having t1dm. conversely, as average weight increases in the population, overweight adolescents with autoimmune diabetes may be misdiagnosed as having t2dm. basma a. ali, samir t. abdallah, ahlam m. abdallah and mahmoud m. hussein clinical and basic research | 401 with most patients in group ii (71.4%) having a bmi of 25‒75% versus 33% in group i where p <0.05. moreover, patients in group ii had a highly significant higher waist circumference than those in group i. the laboratory investigations revealed that hba1c % and cholesterol levels were significantly higher in group ii subjects compared to group i where p <0.05. on the other hand, there was insignificant difference between the two groups as regards tg [table 2]. concerning the different correlations, this study found that there were weak positive significant correlations between c-peptide levels (ng/ml) and bmi on centile (r = 0.24, p value at 0.0001 was significant). discussion the prevalence of t2dm varies among different child and adolescent populations; it was first described in pima indian adolescents of arizona, usa, in 1979.10 among japanese school children, the prevalence of type 2 diabetes has increased in 20 years, from 2 to 76 per 100,000 individuals.11 it was subsequently reported among various minority non-caucasian ethnic groups, for example in the usa, canada, australia, new zealand and among children from japan, hong kong, libya and bangladesh,12 as well as in asian and arab children in the uk.13 as regards the results of the present study, the frequency of t2dm was 13.3% while t1dm was represented in 86.7% of patients. this result was in approximate agreement with the result of another egyptian study which was performed by elsamahy et al., who demonstrated that 88.2% of children and adolescents included in their study had t1dm and only 11.8% had t2dm.14 another study, performed by moussa et al. in kuwait, revealed that t2dm was present in 11.5% of all school children in kuwait.15 contrary to our results, dabelea et al.16 found that the majority of diabetics among the navajo youth had t2dm (80.4%) although autoimmune t1dm was present in 19.6% of the studied cases, especially among younger children. however, the current study found that the group ii t2dm subjects were significantly older than those in group i with t1dm [table 1]. this might be due to pubertal insulin resistance, attributed to increased growth hormone secretion during puberty and not to sex hormone secretion.17 this result was in agreement with the result obtained from the two studies done by elsamahy et al.14 and moussa et al.15 also, our result is in agreement with table 1: comparison of type 1 and type 2 diabetes mellitus (t1dm and t2dm) patients’ demographic and clinical data characteristic group p value group i (t1dm) n = 182 group ii (t2dm) n = 28 age (years) mean ± sd 11.01 ± 4.4 14.14 ± 2.4 0.0001* age of onset of disease (years) mean ± sd 7.6 ± 3.8 10.2 ± 2.4 0.4 duration of disease (months) mean ± sd 39.7 ± 40.7 71.3 ± 42.01 0.0001* gender, n (%) male female 76 (41.8) 106 (58.2) 10 (35.7) 18 (64.3) 0.04* family history of dm, n (%) positive negative 86 (47.3) 96 (52.7) 20 (71.4) 8 (28.6) 0.01 bmi percentile <5 5–25 >25–75 85–95 >95 28 (15.4) 86 (47.3) 60 (33) 6 (3.3) 2 (1.1) 0 (0) 8 (28.6) 20 (71.4) 0 (0) 0 (0) 0.002* mean waist circumference (cm) mean ± sd 64.4 ± 8.78 74.78 ± 5.83 0.0001* sd = standard deviation; dm = diabetes mellitus; * = significant. table 2: comparison of laboratory parameters of groups i and ii laboratory investigation group p value group i mean ± sd group ii mean ± sd mean serum c-peptide (ng/ml) 0.13 ± 0.04 4.2 ± 3.3 0.04* mean hba1c (%) 7.4 ± 1.4 9.1 ± 0.8 0.0001* mean cholesterol (mg/dl) 167.2 ± 36.7 186.8 ± 47.4 0.01* mean triglycerides (mg/dl) 125.1 ± 182.2 144.5 ± 54.1 0.5 * = significant; hba1c = haemoglobin a1c. the frequency of type 2 diabetes mellitus among diabetic children in el minia governorate, egypt 402 | squ medical journal, august 2013, volume 13, issue 3 that of the study performed by fagot-campagna et al.18 who found that the peak age of presentation of t2dm was around 13‒14 years; this corresponds to late puberty, with females reaching this stage one year earlier than males. further, a highly significant difference was found between group i and group ii as regards gender distribution; 64.3% of group ii were females whereas 58.2 % were males (p = 0.04). this result is in agreement with the results obtained by kitagawa et al.11 and kadiki et al.19 who concluded that female children and adolescents were more susceptible to the risk of developing t2dm. in contrast to our result, moussa et al.15 found that the prevalence of t2dm was higher in males than females. further, most of our patients with t2dm (71.4% versus 47.3% of those with t1dm) had a positive family history of dm with a significant difference between them. this result was in agreement with studies by haines et al.,20 elsamahy et al.,14 moussa et al.15 and mayer-davis et al.21 this could be explained by the fact that the patients’ familial predisposition could be related to impaired insulin action as pre-pubertal healthy children; those with a family history of t2dm had a nearly 25% lower in vivo insulin sensitivity compared to cross-matched children without a family history of t2dm.22 concerning anthropometric measurements, it was found that most of the patients in group ii (71.4%) had a bmi of >25‒75% versus 33% of group i with a significant difference between them. this could be explained by the hypothesis which postulated that obesity mediated insulin resistance.23 moreover, the patients in group ii had a significantly higher waist circumference than those in group i. this result was in agreement with the result obtained by dabelea et al.16 and could be explained by the fact that the amount of visceral fat is directly correlated with insulinemia and negatively with insulin sensitivity.18 concerning the laboratory investigations, mean c-peptide levels were significantly higher among group ii compared to group i. moreover, group ii had significantly higher levels of hba1c % and cholesterol than group i. this could be explained by the fact that poor glycaemic control among those with t2dm contributes substantially to a high lipid profile.24,25 this result was in agreement with the results obtained by dabelea et al.16 and mayer-davis et al.21 as regards the different correlations, there was a weak positive significant correlation between c-peptide levels and bmi on centile; this could be explained by the fact that obesity mediated insulin resistance with a subsequently elevated c-peptide level.23 this study has the limitation that autoantibody screening was not performed which might have supported the diagnosis of t2dm. diabetes autoantibody testing should be considered for all paediatric patients with the clinical dignosis of t2dm because of the islet cell autoimmunity in otherwise ‘typical’ t2dm. however, this study may provide a basis for further and wider studies in egypt and elsewhere to detect and evaluate t2dm in children. conclusion t2dm is no longer solely a disease of adults but can also occur in children and adolescents. this study suggested that children and adolescents at risk for t2dm and metabolic syndromes included those of female gender, with obesity and having a positive family history of dm. also, patients with t2dm had poorer glycaemic control and hypercholesterolemia. references 1. craig m, hattersley a, donaghue k. definition, epidemiology and classification of diabetes in children and adolescents. pediatr diabetes 2009; 10:3–12. 2. hother-nielsen o, faber o, sorensen n, becknielsen h. classification of newly diagnosed diabetic patients as insulin requiring or non-insulin-requiring based on clinical and biochemical variables types of diabetes. diabetes care 1988;11:531‒7. 3. palmer jp, fleming ga, greenbaum cj, herold kc, jansa ld, kolb h, et al. c-peptide is the appropriate outcome measure for type 1 diabetes, clinical trials to preserve β-cell function. diabetes 2004; 53:250– 64. 4. pontiroli a. type 2 diabetes mellitus is becoming the most common type of diabetes in school children. acta diabetol 2004; 41:85–90. 5. bonser am, garcia-webb p. c-peptide measurements: methods and clinical utility. crit rev clin lab sci 1984; 19:297–352. 6. nathan d, singer d, hurxthal k, goodson j. the clinical information value of the glycosylated hemoglobin assay. new engl j med 1984; 310:s341‒6. basma a. ali, samir t. abdallah, ahlam m. abdallah and mahmoud m. hussein clinical and basic research | 403 7. mc gowan mw, artiss jd, strandbergh dr. a peroxidase coupled method for the colorimetric determination of serum triglycerides. clin chem 1983; 29:538‒40. 8. dietschy jm, weeks le, delento jj. enzymatic measurement of free and esterfied cholesterol levels using the oxygen electrode in a modified glucose analyzer. clin chem acta 1976; 73:407‒14. 9. daniel ww. biostatistics: a foundation for analysis in the health sciences; 7th ed. hoboken, new york: john wiley & sons, inc., 1999. p. 944. 10. savage p, bennett p, senter r, miller m. high prevalence of diabetes in young pima indians: evidence of phenotypic variation in a genetically isolated population. diabetes 1979; 28:937–42. 11. kitagawa t, owada m, urakami t, tajima n. epidemiology of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in japanese children. diabetes res clin pract 1994; 24:7–13. 12. fagot-campagna a: emergence of type 2 diabetes mellitus in children – epidemiological evidence. j pediatr endocrinal metab 2000; 13:1395–402. 13. ehtisham s, barrett t, shaw n. type 2 diabetes mellitus in uk children – an emerging problem. diabet med 2000; 17:867–71. 14. elsamahy m, ahmed h, kamle r, fam m. assessment of the prevalence of type 2 diabetes mellitus in the diabetes clinic, ain shams university children's hospital, egypt. thesis, 2008. 15. moussa m, alsaeid m, abdella n, refai t, al-sheikh n, gomez j. prevalence of type 2 diabetes mellitus among kuwaiti children and adolescents. med princ pract 2008;17:270–75. 16. dabelea d, joquetta d, carmelita s, martia g, christopher p, charlene a. diabetes in navajo youth: prevalence, incidence, and clinical characteristics. diabetes care 2009; 32:141–47. 17. arslanian s. type 2 diabetes mellitus in children: clinical aspects and risk factors. horm res 2002; 57:19‒28. 18. fagot-campagna a, narayan k, imperatore g. type 2 diabetes in children. bmj 2001; 322:377–8. 19. kadiki o, reddy m, marzouk a. incidence of insulin-dependent diabetes (iddm) and non-insulin dependent diabetes (niddm) in benghazi, libya. diabetes res clin pract 1996; 32:165–73. 20. haines l, wan k, lynn r, barrett t, shield j. rising incidence of type 2 diabetes in children in the u.k. diabetes care 2007; 30:1097‒101. 21. mayer-davis e, beyer j, bell r, dabelea d, d’agostino r, imperatore g, et al. diabetes in african american youth: prevalence, incidence, and clinical characteristics: the search for diabetes in youth study. diabetes care 2009; 32:112–22. 22. danadian k, balasekaran g, lewy v, meza m, robertson r, arslanian s. insulin sensitivity in african-american children with and without family history of type 2 diabetes. diabetes care 1999; 22:1325–29. 23. dabelea d, d’agostino rb jr, mayer-davis e, pettitt d, imperatore g, dolan l, et al. testing the accelerator hypothesis: body size, β-cell function, and age at onset of type 1 (autoimmune) diabetes. diabetes care 2006; 29:290–4. 24. alberti kg, zimmet p, shaw j. metabolic syndrome: a new world-wide definition: a consensus statement from the international diabetes federation. diabet med 2006; 23:469–80. 25. albers j, marcovina s, imperator m, snively bm, stafford j, fujimoto y, et al. prevalence and determinants of elevated apolipoprotein and dense low-density lipoprotein youths with type 1 and type 2 diabetes. j clin endocrinal metab 2008; 93:735–42. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e257-258, epub. 7th apr 14 submitted 6th aug 13 revision req. 26th sep 13; revision recd. 1st oct 13 accepted 23rd oct 13 departments of 1medicine, 2child health, 3radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mails: koul@squ.edu.om and roshankoul@hotmail.com طفلة عمرها ثالثة أعوام مصابة مبتالزمة اسرتيج فيرب من دون ومحة الوجه رو�صان كول، رينيث ماين و رانا �صعيب حامد three-year-old girl with sturge-weber syndrome without facial nevus *roshan koul,1 renjith mani,2 rana s. hamid3 interesting medical image figure 1 a & b: axial images of (a) t2-weighted magnetic resonance imaging (mri) brain scan showing focal left occipitoparietal brain atrophy (black arrows) and (b) t1-weighted post-contrast mri showing cortical enhancement in the gyri (white arrow) consistent with leptomeningeal angiomatosis. sturge-weber syndrome (sws) is a neurocutaneous disorder. classic sws is characterised by the presence of nevus flammeus (port-wine stain) involving the first sensory branch of the trigeminal nerve, ipsilateral leptomeningeal angiomatosis, choroidal angioma and glaucoma.1 the condition is autosomal recessive in inheritance and reported from all over the world. the presence of a cranial component without facial nevus and eye involvement is labelled as type three and is uncommon. we report a girl with sws syndrome and partial epilepsy who had only the cranial component of the syndrome. a three-year-old girl was referred to sultan qaboos university hospital (squh), oman, for evaluation and management of her uncontrolled partial motor seizures. she had been born to consanguineous parents with an uneventful birth. there was nothing relevant in the perinatal period or the family history. the recurrent episodes of seizures had started at the age of three months. the seizures took the form of left-sided gaze deviation with tonic-clonic movements of the left half of the body lasting for five minutes. there were no precipitating factors such as fever or infections. during these episodes, no loss of consciousness or secondary generalisation was noted. the episodes were not followed by postictal weakness. she was diagnosed with epilepsy and prescribed carbamazepine in a peripheral hospital. another anti-epileptic drug was added as the seizures were not controlled. she continued to have one to two episodes per week even with two anticonvulsants. at this time, a third anti-epileptic medication, sodium valproate, was started and the three-year-old girl with sturge-weber syndrome without facial nevus e258 | squ medical journal, may 2014, volume 14, issue 2 previous drugs were discontinued. with the sodium valproate her seizures were better controlled (one episode every 2–3 months) and she was referred to squh for further management. her development was normal for her age. the clinical examination on presentation showed growth parameters (head circumference, height, weight) in the 25th centile with no dysmorphic features and no neurocutaneous markers. she did not have any focal neurological deficit and there was no organomegaly. there was no visual field defect. the seizure history was reviewed and a diagnosis of left simple partial motor seizures was made and the cause investigated. levetiracetam was added to the treatment for better control of her seizures. this drug is specifically designed for partial seizures and has few side-effects. the baseline blood investigations were normal. the electroencephalogram showed intermittent high-amplitude slowing in the left posterior region with no epileptiform discharges. spikes and spike-waves are the diagnostic hallmark for epilepsy, but in a child with a structural lesion these abnormalities may not be present. the magnetic resonance imaging (mri) scan of the brain revealed a focal left occipitoparietal brain atrophy with enhancing gyri [figure 1]. the brain features shown on the mri scan were consistent with leptomeningeal angiomatosis. a computed tomography (ct) scan of the brain revealed calcification in the angiomatosis area [figure 2] thus confirming the diagnosis of sws. the ophthalmic examination was normal. since there were no skin lesions, a diagnosis of sws type 3 was made. comment sws is classified into three types, depending upon the extent of the components involved. type 1 involves the skin, eye and brain. in type 2, there is no brain involvement and in type 3 only the brain is affected. this is due to the variable expressivity seen in inherited diseases. the incidence of classical sws is 1/50,000 live births, but the incidence of sws without facial nevus is not known.2 in one series of 28 patients, three cases were seen with an isolated cranial component, comprising 10.7%.2 the diagnosis of sws type 3 is made by ct and mri scanning and histopathology.2 sws patients need treatment for the associated seizures and glaucoma. surgical therapy should be considered in patients with drug-resistant epilepsy.1,3 references 1. lo w, marchuk da, ball kl, juhász c, jordan lc, ewen jb, et al. updates and future horizons on the understanding, diagnosis, and treatment of sturge-weber syndrome brain involvement. dev med child neurol 2012; 54:214–23. doi: 10.1111/j.14698749.2011.04169.x. 2. jagtap sa, srinivas g, radhakrishnan a, harsha kj. a clinician’s dilemma: sturge weber syndrome ‘without facial nevus’! ann indian acad neurol 2013; 16:118–20. doi: 10.4103/09722327.107725. 3. siri l, giordano l, accorsi p, cossu m, pinelli l, tassi l, et al. clinical features of sturge-weber syndrome without facial nevus: five novel cases. eur j paediatr neurol 2013; 17:91–6. doi: 10.1016/j.ejpn.2012.06.011. figure 2: axial image of the plain computed tomography brain scan showing gyriform hyperdensity in the left occipitoparietal area (arrows) consistent with cortical calicification. clinical & basic research sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 287-295, epub. 9th may 13 submitted 23rd jul 12 revision req. 16th oct 12, revision recd. 19th oct 12 accepted 27th oct 12 departments of 1anesthesia & icu and 2public health & preventive medicine, faculty of medicine, mansoura university, mansoura, egypt *corresponding author e-mail: shamstma@gmail.com اإلجهاد الوظيفي واستنفاذ الطاقة لدى أطباء التخدير ذوي املستقبل األكادميي يف مستشفى مصري جامعى طارق �شم�ض و رجاء امل�رسي امللخ�ص: الهدف: هناك العديد من الأدلة الدامغة على اأن التخدير هو مهنة جمهدة، وعندما تكون هذه املهنة املجهدة مرتبطة بامل�شتقبل الإجهاد انت�شار و التنبوؤ معدلت تقييم اإىل الدرا�شة هذه تهدف اأكرث. الطاقة ونفاذ الداخلي الحرتاق و الإجهاد معدل يكون الأكادميي الوظيفي ونفاذ الطاقة، وكذلك ا�شتك�شاف اخل�شائ�ض الجتماعية واملالمح الوظيفية امل�شاحبة لدى عينة من اأطباء التخدير امل�رسيني ذوي امل�شتقبل اجلامعي. الطريقة: اأجريت درا�شة امل�شح املقطعي العر�شي يف م�شت�شفي جامعة املن�شورة يف م�رس على 98 طبيب تخدير من ذوي امل�شتقبل الأكادميي. مت ا�شتخدم اإ�شدار اللغة الإجنليزية لقائمة جرد ا�شتنفاذ الطاقة ملا�شال�ض ومقيا�ض التعامل مع �شغوط العمل للمعهد الأمريكي لقيا�ض معدل الإجهاد و الحرتاق الوظيفي. مت حتليل البيانات وفقا للدلئل الإر�شادية ملعاجلة البيانات وحتليلها من املقايي�ض امل�شتخدمة. النتائج: بلغت ن�شبة امل�شاركة يف هذه الدرا�شة %73.1 حيث كان %69.4 يعاين من ال�شغط الوظيفي، 62.2% بني اإيجابي ارتباط هناك كان وقد الجناز. على القدرة نق�ض من 58.2% و ال�شخ�شية تبدد من 56.1% العاطفي، ال�شتهالك من الإجهاد الوظيفي و�شالمل القيا�ض الفرعية الثالث لنفاذ الطاقة ملا�شال�ض. كان الأطباء املقيمني واملدر�شني امل�شاعدين هم الأكرث الفئات ت�رسرا. اأثبت التحاليل اأن اأقوى موؤ�رس وحيد للتنبوؤ بجمع اأبعاد ال�شغط الوظيفي ونفاذ الطاقة هو عدم وجود الدعم الوظيفي. اخلال�صة: �شبب الإجهاد الوظيفي ونفاذ الطاقة عند اأطباء التخدير الأكادمييني هو عدم وجود الدعم الوظيفي وهذا اأكرث انت�شارا عند الأطباء املقيمني واملدر�شني امل�شاعدين. اأطباء التخدير الأكادمييني هم يف حاجة اإىل اإ�شرتاتيجية موؤ�ش�شية منظمة تنظيما جيدا للتخفيف من حدة مطالبهم الأكادميية الثقيلة والدعم الوظيفي بهدف التخفيف من ال�شغط والحرتاق الوظيفي. مفتاح الكلمات: الإجهاد الوظيفي؛ الإنهاك والحرتاق الداخلي؛ اأطباء التخدير ذوي امل�شتقبل الأكادميي؛ م�رس. abstract: objectives: there is compelling evidence that anaesthesiology is a stressful occupation and, when this stressful occupation is associated with an academic career, the burnout level is high. this study aimed to assess the predictors and prevalence of stress and burnout, associated sociodemographic characteristics, and job-related features. methods: a cross-sectional survey study was carried out at mansoura university hospital in egypt among 98 anaesthesiologists who had academic careers. the english version of the maslach burnout inventory-human services survey (mbi-hss) scale and the workplace stress scale of the american institute of stress were used to measure job stress and burnout. data were analysed according to the guidelines for data processing and an analysis of the scales used. results: the participation rate of this study was 73.1%, where 69.4% were encountering job stress, while 62.2% experienced emotional exhaustion, 56.1% depersonalisation, and 58.2% reduced personal capacity. there was a significant positive correlation between job stress and mbi-hss subscales. residents and assistant lecturers were the most affected group. the strongest significant single predictor of all burnout dimensions was a lack of job support. conclusion: stress and burnout among academic anaesthesiologists were caused by the lack of job support; this was especially true among residents and assistant lecturers. we can conclude that a well-organised institutional strategy to mitigate the heavy professional demands of academic anaesthesiologists’ will relieve their stress and burnout. keywords: job stress; burnout; university career anesthesiologists; egypt. job stress and burnout among academic career anaesthesiologists at an egyptian university hospital *tarek shams1 and ragaa el-masry2 advances in knowledge there have only been limited studies carried out in the arab world about the effects of the great increase in the demand-supply gap for anaesthesiologists. no study of the effect of their workload has been undertaken, especially if they are involved in research and teaching, and shoulder administrative responsibilities; thus, this study contributes new information. the results of this study have revealed that residents and assistant lecturers were the most affected group of anaesthesiologists, indicating that their heavy academic demands, in comparison to that of others, plays a role in their greater stress and burnout. job stress and burnout among academic career anaesthesiologists at an egyptian university hospital 288 | squ medical journal, may 2013, volume 13, issue 2 burnout may be the result of unrelenting stress but it is not the same as too much stress. stressed people can imagine that if they could only get everything under control, they would feel better.1 in contrast, burnout syndrome is a prolonged response to chronic job-related stressors.2 maslach and jack first described this condition, which is characterised by emotional exhaustion, feelings of low personal accomplishment, and depersonalisation.3 emotional exhaustion is the subjective sense of fatigue related to one's work. a feeling of low personal accomplishment is a feeling of frustration with work-related achievements. depersonalisation is a person's attempt to separate himself or herself from his or her work as a defense mechanism.4 however, handling job stress in general may help to prevent burnout in one’s career.1 anaesthesiology has been identified as a stressful specialty.5 hospital anaesthesiologists’ scope of work has now expanded to include emergency and intensive care, and management of acute and chronic pain. in addition, some anaesthesiologists engage in research and teaching, and shoulder administrative responsibilities. consequently, the gap between the demand for and the supply of aesthesiologists has greatly increased, and those who are working in the field are overworked. it has been reported that, although anaesthesiology may be stressful, anaesthesiologists develop coping mechanisms over time. even inexperienced trainee anaesthesiologists seem to be vulnerable.6 with this in mind, we aimed to assess the prevalence of job stress and burnout among a group of university career anesthesiologists working at mansoura university hospital (muh), egypt. furthermore, we aimed to investigate the associated sociodemographic features, job characteristics, and working conditions with reference to the strongest predictor of the addressed syndromes. methods a cross-sectional survey study was carried out in the anaesthesia department of muh in mansoura, egypt. during the study period (march–june 2011), muh had a total of 134 anesthesiologists. out of those, there were 42 residents, 33 assistant lecturers, 27 lecturers, 15 assistant professors and 17 professors. following approval by the institutional review board of muh, the researchers introduced themselves to anaesthesiologists in different centres affiliated to muh, the informing them about the aims of the study, and guarantees of anonymity and confidentiality. staff gave verbal consent and were allowed to respond voluntarily to the survey in their own time and privacy, with a nearly 73% response rate. an anonymous self-administered questionnaire consisting of 4 parts was constructed to collect data. part 1 gathered sociodemographic data, part 2 data about job characteristics and working conditions, while part 3 was a job stress scale, and part 4 was the maslach burnout inventory-human services survey (mbi-hss). job characteristics and working conditions included in the questionnaire were derived by reviewing the literature and the work situations at egyptian university hospitals, as well as by holding informal discussions with a group of anaesthesiologists to explore their opinions. a total of 8 attributes were listed and the anaesthesiologists’ statements were grouped according to academic status, job demands, how their work time was spent, distribution of duties throughout the week, number of shifts per month, availability of work vacations and job support, and the nature of their work in anaesthesia. our job stress questionnaire was the workplace stress scale™ created by the american institute of stress (ais). the 10 questions evaluate how much job stress is present and how workers handle it. participants were asked to rate stress based on a 10-point scale ranging from ʻstrongly disagreeʼ to applications to patient care this study showed that the strongest significant single predictor of burnout among academic anaesthesiologists was a lack of job support, which indicates that a well-organised institutional strategy to support them may ameliorate their stress and burnout, and consequently improve patient care. anaesthesiologists should be trained to cope with their long term heavy demands in order not to be vulnerable to stress and burnout. this will result in better standards of patient care. tarek shams and ragaa el-masry clinical and basic research | 289 ʻstrongly agreeʼ. each question was scored between 1 and 10. a total score between 10 and 30 indicated good handling of job stress; between 40 and 60 indicated moderately well-handled job stress, and between 70 and 100 indicated that an employee was encountering problems that needed to be addressed and resolved.7 only the data of those who had job stress are presented in this study. the mbi-hss comprises 22 items measuring 3 subscales of burnout: emotional exhaustion, depersonalisation, and personal accomplishment. respondents score items on a scale from zero to 6: 0 = never; 1 = a few times a year; 2 = once a month; 3 = a few times a month; 4 = once a week; 5 = a few times a week, and 6 = every day. the scores were reflected as a high score in the first two scales and a low score in the last subscale of burnout. the questionnaire does not express the total value of burnout; the 3 subscales are calculated independently with the individual dimensions, and therefore the degree of burnout is expressed by the scores of its 3 subscales rather than by a total score.8 only respondents who were above the level of burnout for every subscale are reported here. the mbi-hss is an effective tool of proven reliability and validity in detecting the presence of and assessing the degree of burnout in service workers. a pilot study was done on 8 anaesthesiologists from the anesthesia department at muh who were not included in the full-scale study. during this pilot study, the english version of the mbi-hss was tested for clarity of questions and simplicity of language. the english version of the inventories were used since our participants were egyptian academic anaesthesiologists both educated and working in an english language environment. data were analysed using statistical package for social science (spss), version 11 (ibm, inc. chicago, illinois, usa). descriptive statistics were presented as numbers and percentages. burnout and handling job stress scores and levels were calculated according to the guidelines of the inventories, and the pearson's correlation test was used to determine the relationship between them. a chi-squared test was used for comparison between career groups of anaesthesiologists. the effects of different variables on the level of burnout and job stress were investigated by calculating the odds ratios in univariate analysis. a stepwise multivariate analysis was also conducted by using logistic regression. table 1: job characteristics and working conditions of the studied anaesthesiologists job characteristics n % academic status professor 8 8.2 assistant professor 12 12.2 lecturer 16 16.3 assistant lecturer 32 32.7 resident 30 30.6 job demands both physical and mental effort yes 78 79.6 no 20 20.4 work time directed mainly to patient care only 21 21.4 research only 0 0 both 77 78.6 on duty all week yes 62 63.3 no 36 36.7 shifts per month ≤6 shifts 37 37.8 >6 shifts 61 62.2 availability of vacations yes 59 60.2 no 39 39.8 job support* yes 40 40.8 no 58 59.2 anaesthesia work is boring yes 71 72.4 no 27 27.6 *job support included availability of 1) work equipment; 2) efficient, helpful co-workers, and 3) supportive supervisors. table 2: prevalence of burnout subscales and job stress among the studied anaesthesiologists subscales* n % p value emotional exhaustion 61 62.2 0.651 depersonalisation 55 56.1 reduced personal capacity 57 58.2 encountering job stress 68 69.4 *categories are not mutually exclusive. job stress and burnout among academic career anaesthesiologists at an egyptian university hospital 290 | squ medical journal, may 2013, volume 13, issue 2 a p value of ≤0.05 was considered statistically significant. results most of our sample were males (73.5%) aged ≤35 years (65.3%), living in urban settings (83.7%), where they were married (76.5%) with ≥2 children (59.2%). most of the studied anesthesiologists (73.3%) were table 3: distribution of burnout subscales and encountering job stress according to the sociodemographic characteristics of the studied anesthesiologists sociodemographic characteristics emotional exhaustion n = 61 n (%) depersonalisation n = 55 n (%) reduced personal capacity n = 57 n (%) encountering job stress n = 68 n (%) age ≤35 years 50 (81.9) 45 (81.8) 45 (78.9) 56 (82.4) >35 years 11 (18) 10 (18.2) 12 (21.1) 12 (17.6) p value 0.003* 0.000* 0.000* 0.000* gender male 46 (75.4) 41 (74.5) 42 (73.7) 51 (75) female 15 (24.6) 14 (25.5) 15 (26.3) 17 (25) p value 0.58 0.785 0.955 0.61 residence urban 46 (75.4) 41 (74.5) 44 (77.2) 53 (77.9) rural 15 (24.6) 14 (25.5) 13 (22.8) 15 (22.1) p value 0.004* 0.006* 0.04* 0.021* marital status single 20 (32.8) 16 (29.1) 17 (29.8) 23 (33.8) married 41 (67.2) 39 (70.9) 40 (70.2) 45 (66.2) p value 0.005* 0.138 0.08 0.000* number of children 0 children 21 (34.4) 17 (30.9) 18 (31.6) 24 (35.3) 1 child 14 (22.9) 13 (23.6) 12 (21.1) 15 (22.1) ≥2 children 26 (42.6) 25 (45.5) 27 (47.4) 29 (42.6) p value 0.000* 0.006* 0.02* 0.000* job of spouse** 41 (54.7) 39 (52) 40 (53.3) 45 (60) physician 25 (60.9) 23 (58.9) 25 (62.5) 28 (62.2) others 16 (39) 16 (41) 15 (37.5) 17 (37.8) p value 0.008* 0.003* 0.023* 0.008* income able to save 12 (19.7) 13 (23.6) 13 (22.8) 12 (17.6) satisfactory 37 (60.7) 31 (56.4) 32 (56.1) 42 (61.8) not satisfactory 12 (19.7) 11 (20) 12 (21.1) 14 (20.6) p value 0.01* 0.193 0.09 0.000* *significant at p ≤0.05 level. categories are not mutually exclusive; **the overall rate of burnout was calculated according to the total number of married participants (75). tarek shams and ragaa el-masry clinical and basic research | 291 table 4: distribution of burnout subscales and job stress according to job characteristics and working conditions of the studied anaesthesiologists emotional exhaustion† n = 61 n (%) depersonalisation† n = 55 n (%) reduced personal capacity† n = 57 n (%) encountering job stress† n = 68 n (%) academic status professor (8) 0 1 (1.8) 1 (1.8) 0 asst. professor (12) 5 (8.2) 3 (5.5) 5 (8.8) 5 (7.4) lecturer (16) 3 (4.9) 3 (5.5) 3 (5.3) 4 (5.9) asst. lecturer (32) 27 (44.3) 27 (49.1) 26 (45.6) 29 (42.6) resident (30) 26 (42.6) 21 (38.2) 22 (38.6) 30 (44.1) p value 0.000* 0.000* 0.000* 0.000* job demands both physical and mental effort yes (55) 39 (63.9) 37 (67.3) 37 (64.9) 44 (64.7) no (43) 22 (36.1) 18 (32.7) 20 (35.1) 24 (35.3) p value 0.045* 0.012* 0.039* 0.010* work time is directed mainly to patient care only (21) 17 (27) 34 (61.8) 33 (57.9) 21 (30.9) research only (0) 0 0 0 0 both (77) 44 (72.1) 43 (78.2) 44 (77.2) 47 (69.1) p value 0.046* 0.915 0.695 0.001* on duty all week yes (62) 53 (86.9) 48 (87.3) 48 (84.2) 59 (86.8) no (36) 8 (13.1) 7 (12.7) 9 (15.8) 9 (13.2) p value 0.000* 0.000* 0.000* 0.000* shifts per month ≤6 shifts (37) 9 (14.8) 8 (14.5) 10 (17.5) 9 (13.2) >6 shifts (61) 52 (85.2) 47 (85.5) 47 (82.5) 59 (86.8) p value 0.000* 0.000* 0.000* 0.000* availability of work vacations yes (59) 32 (52.5) 30 (54.5) 33 (57.9) 34 (50) no (39) 29 (47.5) 25 (45.5) 24 (42.1) 34 (50) p value 0.04* 0.196 0.582 0.002* job support* yes (40) 20 (32.8) 17 (30.9) 18 (31.6) 22 (32.4) no (58) 41 (67.2) 38 (69.1) 39 (68.4) 46 (67.6) p value 0.038* 0.024* 0.028* 0.01* anaesthesia work is tedious and boring yes (71) 49 (80.3) 45 (81.8) 47 (82.5) 51 (75) no (27) 12 (19.7) 10 (18.2) 10 (17.5) 17 (25) p value 0.025* 0.02* 0.009* 0.39 † = categories are not mutually exclusive; * = significant at p ≤0.05 level. note: job support included availability of 1) work equipment; 2) efficient helpful co-workers, and 3) supportive supervisors. job stress and burnout among academic career anaesthesiologists at an egyptian university hospital 292 | squ medical journal, may 2013, volume 13, issue 2 married to physicians, and 53.1 % had a satisfactory income. the job characteristics of the studied group are presented in table 1. most respondents were assistant lecturers (32.7%) or residents (30.6%). the overall prevalence of those experiencing burnout and job stress among academic anaesthesiologists is shown in table 2. out of 98 staff, more than half met the criteria for all burnout subscales, while the percentages of those who were suffering emotional exhaustion, depersonalisation, and reduced personal capacity were 62.2%, 56.1%, and 58.2%, respectively. more than two-thirds of the respondents (69.4%) were encountering job stress as defined by ais’s handling job stress scale. our results reveal that job stress positively correlated with all burnout subscales with highly significant differences. table 3 shows the associated sociodemographic characteristics for job stress and each subscale of the mbi-hss. all dimensions of job stress and burnout were much higher among anaesthesiologists who were males ≤35 years of age, urban residents, married (especially to physicians), had ≥2 children, and had a satisfactory income. the prevalence of mbi-hss subscales and job stress by various job characteristics and working conditions of the studied group are shown in table 4. compared to other groups, assistant lecturers showed significantly higher rates of burnout, while residents expressed the most significant higher rate of job stress (p < 0.001). univariate and multivariate regression analysis are presented in table 5 (not all data of the univariate analysis are presented). although the stepwise logistic regression analysis failed to confirm the significance of all identified predictors of encountering job stress, it succeeded in confirming the significance of some predictors related to burnout subscales that were identified by univariate analysis. these were age ≤35 years (odds ratio [or] = 0.15) and lack of job support (or = 13.79) for emotional exhaustion, while only lack of job support was confirmed for depersonalisation (or = 16.24) and reduced personal capacity (or = 19.24). discussion this study assessed the prevalence of job stress and burnout among a group of egyptian university career anesthesiologists. there is a common perception that working in anaesthetics is stressful, especially if it is associated with academic demands. although other studies on anaesthesiology used different metrics, were applied to different subgroups and conducted in different countries, their results provide compelling evidence that it is burnout, more than stress, which constitutes a table 5: univariate and multivariate logistic regression analysis of the predictors of job stress and the maslach burnout inventory-human services survey subclasses among the studied anesthesiologists (not all data are displayed) predictor univariate multivariate p uor 95% ci p aor 95% ci emotional exhaustion age (years) ≤35 >35 0.028* 0.435 1 (r) 0.207–0.91 0.037* 0.152 1 (r) 0.026–0.89 job support no yes 0.000** 3.600 1 (r) 1.787–7.25 0.019* 13.972 1 (r) 1.549– 126.01 depersonalisation job support no yes 0.004** 2.538 1 (r) 1.336–4.82 0.050* 16.238 1 (r) 1.001– 263.38 reduced personal capacity job support no yes 0.001** 3.182 1 (r) 1.616–6.26 0.008** 19.239 1 (r) 2.178– 169.90 p = p value; uor = unadjusted odds ratio; ci = confidence interval; aor = adjusted odds ratio; r = reference group. *significant at p ≤0.05; **highly significant at p ≤0.001. tarek shams and ragaa el-masry clinical and basic research | 293 significant problem for ~40% of anaesthesiologists.9 this common perception was emphasised again in this study, which generally expressed a high prevalence of stress and burnout among muh’s anaesthesiologists. the present study revealed that more than 50% of our respondents suffered from stress. the higher overall prevalence of stress in the current study as compared to other studies could be explained by the fact that whether or not an individual perceives a work demand as stressful depends upon their personal, social, and biological resources; these may buffer the impact of job demands on job strain, including burnout. it was therefore crucial to investigate the social and job characteristics of anaesthesiologists that could be associated with job stress and burnout. this study revealed that more than two-thirds of academic anaesthesiologists encountered job stress and this stress, as expected, correlated significantly with increased rates of all dimensions of burnout. additionally, significant scores on all of these burnout subscales were more evident among assistant lecturers than residents, while nearly all professors were able to deal with job stress more effectively. the latters’ scores were below average in all subscales. these findings could be explained by the fact that postgraduate medical study in all specialties, including anaesthesia, requires a lot of mental and physical effort. this burden increases if the anaesthetist then chooses to follow an academic career. in egypt, in order to advance to a higher grade in any specialty, a person must invest 3 years of teaching, research, publication, and study. additionally, candidates must write theses and pass examinations. these heavy academic demands, in addition to the already stressful nature of working as an anaesthetist, could explain the finding that assistant lecturers and residents were the groups most affected by stress and burnout. abut et al. reported that trainees felt they lacked control in their own field, which may cause feelings of inadequacy and result in low scores on a sense of personal accomplishment.10 this may explain the increase in the perceived stress scale in residents. very few professors in our survey were affected by the problem. this result could be explained by the fact that, in our country, as academic anaesthesiologists grow older and achieve higher positions, they become accustomed to managing stress and coping with stressors. they are also able to adapt their working environment to reduce stress, for example by working fewer hours and less shifts. additionally, most of their working hours are allocated to mentoring junior staff in research and clinical training. burnout is stress-related. some jobs simply cause more stress, taking more of a toll on the workforce and resulting in much higher rates of burnout than others. workers are at higher risk of burnout if 1) the requirements of the job are unclear; 2) the job’s responsibilities exceed the amount of time given to complete it properly; 3) there is an intense workload without downtime for recovery; 4) the overall work experience is stressful as, for example, in the case of a risk of a lawsuit; 5) there is a lack of personal control over one’s work environment and daily decisions; 6) workers are not appreciated or their accomplishments recognised; 7) there is poor communication in the workplace; 8) job demands are unrealistically high, or 9) there is low financial compensation, or 10) there is poor support or leadership.11 the most important finding of our study is the complex relationship between careerrelated demands, job stress, burnout, and the sociodemographic and job characteristics of the subjects. social demands and life stressors represent a burden that could explain our findings of a higher prevalence of job stress and burnout among younger anaesthesiologists, especially in those with a just satisfactory income who are married to physicians and have ≥2 children. in egypt, it is common for academics to marry academics as they can easily understand the work demands of their spouse and relate more easily to one another. this is confirmed by our results which showed that 73.3% of the respondents were married to physicians. this could also explain the significantly higher rates of stress and burnout among them when compared to other groups. contrary to our result, other researchers have reported that marriage and family responsibilities acted as a sort of social support. abut et al. found that anaesthesiologists with ≥2 children had a feeling of significantly higher personal accomplishment with low depersonalisation and emotional exhaustion scores. castelo-branco et al. found that being single was a predisposing factor for the development of burnout.12 it is interesting to note that the male anaesthesiologists in this job stress and burnout among academic career anaesthesiologists at an egyptian university hospital 294 | squ medical journal, may 2013, volume 13, issue 2 study had higher rates of stress and burnout than the females, which could be explained by the fact that most of our sample were male (73.5%) and that traditionally bringing up children is perceived as a personal accomplishment for women in egypt. the maternal experience may prevent the development of depersonalisation. this finding is similar to that of a turkish study that revealed that female anaesthesiologists have a feeling of higher personal accomplishment but lower depersonalisation scores than males.11 although various personal, interpersonal, and organisational factors have been reported to relate to job stress and burnout in the medical environment, several studies have emphasised the importance of extrinsic work-related stressors and organisational factors rather than personal factors.13–16 when the current study examined job-related stressors and working conditions that can be associated with burnout, the finding was that working in anaesthesia while engaging in an academic career was more stressful, because anaesthesiologists who were loaded by physical and mental demands of these two tasks were significantly more stressed and eventually burned out. moreover, this study confirmed that an intense and heavy workload, as well as the lack of job support was generally a strongly significant determinant for job stress. anaesthesiologists who spent most of their work time engaged in both patient care and research activities, were assigned duties on varying shifts throughout the week, took more than 6 different shifts per month, and were lacking job support expressed higher rates of job stress and scored higher on all burnout subscales. the availability of vacation time was not an effective variable in this study. our findings reflected both similarities and differences with other studies. for example, a study conducted on turkish physicians found that those who worked more shifts and took fewer vacations per year seemed to be at higher risk for burnout.2 another study attributed the highest burnout scores among those working in health centres to heavy patient loads and long working hours.17 the difference in the prevalence and determinants of burnout between our study and others could be explained by the differences in culture and medical specialties. these differences in the nature and characteristics of the work-related demands appear to affect the relative prevalence and scores of stress and burnout; thus, it is difficult to reach universal conclusions. furthermore, our finding that 72.4% of those polled responded that anaesthesia is “boring” could explain the higher rate of burnout in this survey as compared to other studies. all dimensions of burnout in our study were much more prevalent than in other studies. according to the stepwise logistic regression analysis of our data, the strongest significant single predictor for all mbi-hss subscales was a lack of job support, which was expressed as deficient work equipment; uncooperative or inefficient co-workers, and unsupportive supervisors. our study did not confirm the findings of researchers who reported that the strongest single predictor of burnout (emotional resilience and personal accomplishment) among different groups of physicians was the control over their work schedule and the number of hours worked.18 de oliveira et al. mentioned low job satisfaction and a lack of family support as significant predictors of a high burnout risk among anaesthesiology chairs.5 another study carried out among turkish physicians concluded that the most significant and common predictors of all burnout dimensions were the low number of vacations at the individual level and the public ownership of healthcare facilities at the group level.2 our study has several limitations. first, although we used validated measures of each construct, our measures of job stress and burnout may not have completely and accurately captured each anaesthesiologist’s feelings. second, the crosssectional design of our study may have created difficulties in ascertaining causality. additionally, the use of self-reported data collection at one point in time necessitates that care should be taken when drawing conclusions about the effects of working conditions on job stress or burnout. third, we chose to study anaesthesiologists with academic careers, so our results may not be generalised to all anaesthesiologists. however, we believe that the results of this study will not only help facilitate a better understanding of egyptian academic anaesthesiologists with their heavy academic demands, job characteristics and key social features, but will also be useful in following up the results of structural changes in egyptian medical colleges, and in launching healthcare reforms. studies should also be undertaken to compare the current findings with tarek shams and ragaa el-masry clinical and basic research | 295 the experience of non-academic anaesthesiologists. studies evaluating system-level interventions designed to optimise workloads, improve efficiency, modify the burden of academic demands on anaesthesiologists, and promote a culture of compassion, engagement, meaning, and support, are urgently needed to reduce the negative consequences for both the burned-out anaesthesiologists and their patients. more studies are needed to address in-depth the other sources of chronic stress in anaesthesiologists. they should not only measure competence factors and production pressures, but also the effects of a noisy environment, poorly-designed work spaces, long working hours, night calls, and fatigue. also valuable would be a measure of the effects of associated problems, like the fear of litigation, low organisational justice, economic uncertainty, and conflicts with co-workers and superiors. conclusion a lack of job support was the main cause of stress and burnout among academic anaesthesiologists, specifically among residents and assistant lecturers who were the the most stressed groups of all of those included in this study. academic anaesthesiologists are in need of a well-organised institutional strategy to mitigate their heavy academic demands and amend the shortcomings of their job support network. such a strategy may serve to lessen their experiences of stress and burnout. references 1. smith m, segal j, segal r. preventing burnout: signs, symptoms, causes and coping strategies. from: http://www.helpguide.org/mental/burnout_signs_ symptoms.htm accessed: jul 2012. 2. ozyurt a, hayran o, sur h. predictors of burnout and job satisfaction among turkish physicians. q j med 2006; 99:161–9. 3. maslach c, jackson se. maslach burnout inventory manual. 2nd ed. palo alto, ca: cpp, inc, 1986. pp. 34, 36–7. 4. de oliveira gs, ahmed s, stock mc, harter rl, almeida md, fitzgerald pc, et al. high incidence of burnout in academic chairpersons of anesthesiology: should we be taking better care of our leaders? anesthesiology 2011; 114:181–93. 5. kain zn, chan km, kaz jd, fleisher l, doler j, rosenfeld le. anesthesiologists and acute perioperative stress: a cohort study. anesth analg 2002; 95:17–83. 6. holmstrom i. being a young and inexperienced trainee anesthetist: a phenomenological study on ought to working conditions. acta anaesthesiol scand 2006; 50:653–8. 7. the american institute of stress (ais). handling job stress questionnaire. from: http://www.stress.org accessed: sep 2011. 8. enzmann d, kleiber d. helfer-leiden: stress und burnout in psychosocialen. heidelberg: assange, 1989; s.204ff. 9. nyssen as, hansez i. stress and burnout in anaesthesia. curr opin anaesthesiol 2008; 21:406– 11. 10. abut yc, kitapcioglu d, erkalp k, toprak n, boztepe a, sivrikaya u, et al. job burnout in 159 anesthesiology trainees. saudi j anaesth 2012; :46– 51. 11. scott e. job burnout: job factors that contribute to employee burnout. what makes some jobs more stressful? from: www.stress.about.com accessed: feb 2010. 12. castelo-branco c, figueras f, eixarch e, quereda f, cancelo mj, gonzález s, et al. symptoms and burnout in obstetric and gynaecology residents. br j gynecol 2007; 45:63–84. 13. visser mrm, smets ema, oort fj, de haes hcjm. stress, satisfaction and burnout among dutch medical specialists. cmaj 2003; 168:271–5. 14. nirel n, shirom a, ismail s. the relationship between job overload, burnout and job satisfaction, and the number of jobs of israeli consultants. harefuah 2004; 143:779–84. 15. maslach c, schaufeli wb, leiter mp. job burnout. ann rev psychol 2001; 52:397–422. 16. goehring c, bouvier gallachi m, kunzi b, bovier p. psychosocial and professional characteristics of burnout in swiss primary care practitioners: a crosssectional survey. swiss med wkly 2005; 135:101–8. 17. olkinuora m, asp s, juntunen j, kauttu k, strid l, aarimaa m. stress symptoms, burnout and suicidal thoughts in finnish physicians. soc psychiatr epidemiol 1990; 25:81–6. 18. keeton k, fenner de, johnson tr, hayward ra. predictors of physician career satisfaction, worklife balance and burnout. obstet gynecol 2007; 109:949–55. squ med j, may 2012, vol. 12, iss. 2, pp. 214-224, epub. 9th apr 2012 submitted 10th oct 11 revision req. 8th jan 12, revision recd. 11th feb 12 accepted 22nd feb 12 1college of medicine, mansoura university, mansoura city, egypt; 2college of medicine, cairo university, cairo, egypt . corresponding author e-mail: mostafapsy@yahoo.com أساليب تقييم مساق الطب النفسي للطالب يف جامعة سعودية م�سطفى عمرو، طارق اأمني يوجد عدد قليل من الدرا�سات حول اأ�ساليب التقييم يف جمال الطب النف�سي يف الدول العربية، وهدف هذه الدرا�سة هو امللخ�ص: الهدف: العربية اململكة في�سل، امللك جامعة يف الطب بكلية اخلام�سة ال�سنة لطالب النف�سي الطب ملقرر املختلفة التقييم اأ�سكال نتائج فح�س ال�سفهي ال�رضيري التقليدي واالختبار املو�سوعي ال�رضيري االختبار يف الطالب من 110 اأداء نتائج فح�س مت الطريقة: ال�سعودية. وحافظة االأن�سطة املنظمة واأ�سئلة االختيار املتعدد التحريري. النتائج: تراوحت درجات الطالب بني 32 – 50 ، 7– 15، 5 10 و التقليدي ال�رضيري ال�سفهي واالختبار ال�رضيري املو�سوعي وحمفظة االأن�سطة املنظمة واأ�سئلة االختيار االختبار من كل يف 45 – 22 املتعدد علي التوايل. ووجد اأن هناك ارتباطا معتّدا بني االختبار ال�رضيري املو�سوعي وباقي اأ�ساليب التقييم با�ستثناء اأ�سئلة االختيار املتعدد يف حتليل االنحدار، حيث �سكل االختبار ال�رضيري املو�سوعي %65.1 من التباين يف الدرجات ال�رضيرية الكلية و%31.5 من ال�رضيرية. الدرجات يف التباين من 74.5% ال�سفهي ال�رضيري التقليدي االختبار مثل حني يف ،)p = 0.001( النهائية الدرجات اخلال�صة: تدل الدرا�سة على وجود تكامل وات�ساق يف اأ�ساليب تقييم الطلبة امل�ستخدمة يف م�ساق الطب النف�سي، وال �سيما العن�رض ال�رضيري. ومن �ساأن تلك املعلومات اأن تكون مفيدة للتطورات امل�ستقبلية يف جمال التدري�س اجلامعي. مفتاح الكلمات: طالب الطب ، تقييم، الطب النف�سي، اململكة العربية ال�سعودية. abstract: objectives: in arab countries there are few studies on assessment methods in the field of psychiatry. the objective of this study was to assess the outcome of different forms of psychiatric course assessment among fifth year medical students at king faisal university, saudi arabia. methods: we examined the performance of 110 fifth-year medical students through objective structured clinical examinations (osce), traditional oral clinical examinations (toce), portfolios, multiple choice questions (mcq), and a written examination. results: the score ranges in toce, osce, portfolio, and mcq were 32–50, 7–15, 5–10 and 22–45, respectively. in regression analysis, there was a significant correlation between osce and all forms of psychiatry examinations, except for the mcq marks. osce accounted for 65.1% of the variance in total clinical marks and 31.5% of the final marks (p = 0.001), while toce alone accounted for 74.5% of the variance in the clinical scores. conclusions: this study demonstrates a consistency among the students’ assessment methods used in the psychiatry course, particularly the clinical component, in an integrated manner. this information would be useful for future developments in undergraduate teaching. keywords: undergraduate medical students; assessment; psychiatry; undergraduate; saudi arabia. assessment methods of an undergraduate psychiatry course at a saudi university *mostafa amr1 and tarek amin2 clinical & basic research advances in knowledge in arab countries there are few studies on assessment methods in the field of psychiatry, so this study contributes new information. the results of this study revealed that there was no significant difference in the students’ scores that correlated with gender differences. the objective structured clinical examination (osce) as a method of student assessment accounted for a sizable part of the variance in total clinical and final marks, which indicated that the implementation of osce is a useful adjunct to other forms of clinical assessment. applications to patient care this study showed that different forms of psychiatric assessment can improve student knowledge and the quality of their practice, and fulfill unmet information needs at the point of patient care. students should be encouraged to become familiar with updated methods of assessment in psychiatry courses. mostafa amr and tarek amin clinical and basic research | 215 in saudi arabia, the college of medicine at king faisal university offers a six-year medical curriculum to selected saudi students who have successfully completed one year of requisite general university studies following secondary school education. the first four years of the curriculum are devoted to pre-clinical (medical sciences and family medicine) learning. students are exposed to behavioural sciences in the third year. in the fourth year, students are introduced to a problem-based learning (pbl) integrated curriculum. they practice communication, history taking, and the physical examination of different body systems, as well as relevant procedural skills. training is conducted in a clinical skills laboratory using different types of simulators. they learn more about the interplay between the physical and psychological components of illnesses. the curriculum in years 5 and 6 is structured around a series of clerkship rotations in the departments of internal medicine, surgery, psychiatry, obstetrics and gynecology, and pediatrics. students graduate after successful completion of 12 semesters (229 hours per semester). the department of psychiatry attachment is a 6-week course based in a dedicated psychiatric hospital. teaching-learning methods employed include lectures, small-group tutorials, and group discussions guided by department faculty. the major objectives of the department for the attachment are that students 1) acquire a basic knowledge of the developmental aspects of psychiatric disorders; 2) identify and make use of all relevant sources of information when assessing each patient; 3) demonstrate competence in mental state examinations and physical assessments; 4) develop skills in appropriate communication with patients and colleagues, and 5) make a clear oral presentation of a case. during the fifth year, students undertake six clinical rotations averaging 180 hours, arranged in two semesters of 3 rotations each. the group size for each rotation varies from 8 to 12 students. since the department was established in 2006, the rotating students have been evaluated through portfolios consisting of peer reviews, group work, case studies, ethics discussions, and critical reviews, and at the end of the course by a traditional oral clinical examination (toce) and an objective structured clinical examination (osce). at the end of the semester, a multiple choice question (mcq) examination is held [figure 1]. furthermore, in 2009, the psychiatry department conducted a survey that assessed the students’ attitudes towards psychiatry that was published as an international education report.1 the survey showed favourable changes in the students’ attitudes following clerkship. however, less positive responses were seen in students’ attitudes towards the quality of the medical school clerkship. to improve the student learning/assessment experience we introduced the osce for the summative assessment of students, in conjunction with a traditional oral examination and portfolio. the potential marks for the written paper, mcq, portfolio, osce and clinical examination are 50, 10, 15 and 25, respectively, for a total of 100 points. although the use of osces in psychiatry has been described as less widespread than in other medical fields, recent years have witnessed an increased interest in its use in psychiatry.2,3 the objective of this study was to assess the outcome of different forms of psychiatric course assessment among fifth-year medical students at king faisal university, saudi arabia. methods this was a cross-sectional survey carried out during the 2010–11 academic year, in two consecutive semesters, in which cohorts of male and female students (54 and 56, respectively) were invited to participate in the study. all students agreed to participate in the study, which was approved by the college authorities. the mcq paper at each examination contained 50 items worth one mark each. the initial item bank of 500 questions was designed to cover the following content areas: causes/risks, signs/ symptoms, course, treatments, and mental health services. two items were included to represent each content area. one item was answered through simple recall, and the other was designed to be answered interpretatively and commonly involved a brief, one to four sentence case presentation. each mcq item consisted of a stem no longer than five sentences in length (though typically only 1–2 sentences), along with four response options. test items were developed following standard, welldescribed mcq writing procedures, and were designed to avoid ambiguity, vagueness, and valueassessment methods of an undergraduate psychiatry course at a saudi university 216 | squ medical journal, may 2012, volume 12, issue 2 laden language.4 reliability (cronbach’s alpha) and concurrent validity (pearson r) coefficients were obtained by correlating the scores of mcq papers with the overall outcome of the examination. they were in the ranges of 0.83–.91 and 0.80–0.93 (p <0.05), respectively. indices of item facility and discrimination were in the ranges of 50–91, and 0.37–.45, respectively. in toce, to explore the student’s understanding of topics deemed relevant to curriculum, students interviewed and examined a real patient for over 45 minutes, and then summarised their findings to two examiners who questioned them by an unstructured oral examination on the patient’s problem. the student’s interaction with the patient was not observed. reliability (alpha) and concurrent validity coefficients (pearson r) were obtained by correlating the scores in the toce with the overall outcome of the examination. they were in the ranges of 0.58– .71 and 0.73–.81, respectively (p <0.05). the osce was based on the curricular constructs that included six thematic topics: mood disorders, anxiety disorders, child psychiatry, psychosis, personality disorders, and substance abuse. a blueprint was developed for each osce to capture the clinical competencies in the covered topics. a map for the stations was devised to guide the examinees and organisers with clear written instructions to the examiners, patients, and examinees. the osce was composed of nine stations which included two manned stations. a manned station (ms) referred to a station that had a real patient and an examiner. students were allowed 15 minutes to perform tasks at each station. the first station included a psychiatric interview, where students were to develop a rapport and conduct the interview within the assigned time frame for a male patient with schizophrenia. at the second station, the students assessed the mental status, with particular attention to the mood and affect, of a female patient with bipolar i mood disorder. in each station, two independent examiners rated the examinees independently according to checklists. the raters were selected from the lecturers who were not involved in the design and/or implementation of the station. checklists contained the desired competencies to be examined (average 28 items). the scores were classified as ‘done’, ‘not done’, or ‘done incorrectly’, with questions on topics such as delusions, hallucinations, and performance. each item was assigned a weight by the station’s authors. at the end of each checklist, there were 4 questions with a 3-point likert scale addressing the interview technique and included factors like empathy, degree of coherence, and verbal and nonverbal expression. following the ms, students moved to an unmanned station (ums) (4 minutes each) which included four dependent data stations (4 minutes each) with questions based on the previously taken history or examination stations, and three independent data stations. in these independent stations, students read a poster giving information regarding a history/examination and/or investigations, and he/ she was required to answer questions related to diagnosis, further investigations, or management. students moved between stations on time keepers’ commands. examiners supervised each station throughout the session and the whole group of students was assessed by a nearly identical process. at the end, the marking and answer sheets were osce and toce exams at the end of 6 weeks final written mcq exam at the end of 18 weeks batch 3 6 weeks 1st semester (18 weeks) psychiatry courses batch one (6 weeks) batch two (6 weeks) portfolio one case/week figure 1: timeline of contents and assessment of psychiatry course, college of medicine, king faisal university. mostafa amr and tarek amin clinical and basic research | 217 table 1: students’ scores along the different types of assessment in the psychiatry course, college of medicine, king faisal university. p value* gender total (n = 110) assessment males (n = 54) females (n = 56) 0.679 35.9 ± 5.1 36.0 28.0-42.0 35.7 ± 3.3 36.0 22.0-45 35.8 ± 4.2 36.0 22.0-45.0 written exam (50 marks) mean ± sd median minimum-maximum 0.143 42.4 ± 3.7 43.5 32.0-50.0 41.6 ± 3.2 41.5 35.0-48.0 42.0 ± 3.5 42.0 32.0-50.0 total clinical exam (50 marks) mean ± sd median minimum-maximum 0.548 11.9 ± 1.4 12.0 9.0-15.0 11.6 ± 1.6 12.0 7.0-14.0 11.7 ± 1.5 12.0 7.0-15.0 osce exam (15 marks) mean ± sd median minimum-maximum 0.059 22.1 ± 1.9 22.5 17.0-25.0 21.4 ± 1.9 22.0 18.0-24.0 21.7 ± 1.9 22.0 17.0-25.0 toce exam (25 marks) mean ± sd median minimum-maximum 0.872 8.5 ± 1.4 9.0 5.0-10.0 8.6 ± 1.0 9.0 6.0-10.0 8.6 ± 1.2 9.0 5.0-10.0 portfolio (10 marks) mean ± sd median minimum-maximum legend: sd = standard deviation; osce = objective structured clinical examination; toce = traditional oral clinical examination * mann whitney test of significance. collected from the examiners and students, respectively. the student answers for the ums were corrected following a pre-designed checklist. a portfolio was instituted to evaluate competency in designated topics specific to the curriculum. students were expected to present one case per week at the ward rounds. cases were discussed at the weekly group tutorial sessions according to the curriculum’s schedule so, for example, students were presented with representative cases for mood disorders in week 1 and anxiety disorders in week 2. two psychiatrists were trained to score each student’s portfolio. for the 6 case areas, the scoring rubric was composed of a 6-point ordinal scale, where 1 = not competent, 3 = competent, and 6 = highly competent. each student’s performance was measured by averaging the two raters’ scores for each case. reliability (alpha) and concurrent validity (pearson r) coefficients (obtained by correlating the scores of the mcq papers with the overall outcome of the examinations) were in the ranges of 0.63–0.71 and 0.66–0.73 (p <0.05), respectively. weighted kappa ranged from 0.84 to 0.95 for interrater reliability. data analysis was carried out using the statistical software for the social sciences (spss) package (version 15, chicago, illinois, usa). median, mean, and standard deviations were calculated for examination marks. statistical comparison was carried out using the mann-whitney test. zero order and partial correlations were performed between test marks, and regression models were fitted to evaluate the predictive value of osce as an independent variable, either alone, or with other examinations, and total clinical score or total final marks as the dependent variables. to assess the reliability and credibility of the osce, statistical analyses of cronbach alpha, kappa, and pearson’s correlation coefficient were used. results table 1 displays the students’ scores along the different assessment methods used to evaluate the outcome. the score range in the toce, osce, portfolio, and mcq were 32–50, 7–15, 5–10 and assessment methods of an undergraduate psychiatry course at a saudi university 218 | squ medical journal, may 2012, volume 12, issue 2 22–45, respectively. there was no significant difference in scores earned by different genders. a significant positive correlation was seen between osce and all forms of psychiatry examinations except for the written/mcq marks [table 2]. strong positive correlations were found between components of the total clinical examination (especially toce and osce), while moderate correlations were found between toce and osce and low correlations with the portfolio (r = 0.86, 0.49 and 0.20, respectively). figure 2 depicts the relationship between the students’ scores on the toce and written/mcq examinations. there was no significant correlation between the two methods of assessment in students’ evaluations. on the contrary, figure 3 shows a moderate and significant correlation between toce and osce (r = .493, p = 0.001). the kappa concordance coefficient and the correlation between the scores of examinees were computed. they ranged from 0.75 for station 1 to 0.64 for station 2. the cronbach’s alpha coefficients for station 1 and 2 were 0.82 and 0.78, respectively. in the generated linear regression model, osce accounted for 65.1% of the variance in total clinical marks and 31.5% of the final marks (p = 0.001). one unit of change was associated with a 1.63 point change in the total clinical score and a 2.05 point change in final marks. in multiple regression analysis, the toce alone accounted for 74.5% of the variance in the clinical scores. conditioned on its presence, the osce explained an extra variance of table 2: correlation matrix between medical student scores in different examinations and total clinical scores (n = 110) examinations pearson correlation total clinical osce toce portfolio written: r coefficient p value 0.162 0.091 0.157 0.102 0.154 0.108 0.020 0.835 total clinical: r coefficient p value -0.807 0.000 0.863 0.000 0.558 0.000 osce: r coefficient p value --0.493 0.000 0.196 0.040 toce: r coefficient p value ---0.379 0.000 legend: osce = objective structured clinical examination; toce = traditional oral clinical examination written exam (50 marks) 50403020 to ta l c lin ic al (5 0 m ar ks ) 50 40 30 gender males females total population rsq = 0.0149 r = 0.162, p = 0.091 figure 2: correlation between written and total clinical assessment in in psychiatry course, colleg of medicine, king faisal university. toce (25 marks) 2523211917 o s c e (1 5 m ar ks ) 15 13 11 9 7 total population r = 0.493, p = 0.001 gender males females figure 3: correlation between toce and osce assessments of included students at psychiatry course, king faisal university. mostafa amr and tarek amin clinical and basic research | 219 19.2%. in regression analysis, the osce accounted for 65.1% of the variance in total clinical marks and 31.5% of the final marks (p = 0.001), while the toce alone accounted for 74.5% of the variance in the clinical scores. discussion findings from this study showed that the results of the mcqs are the most important predictors of final scores, as they accounted for 69.7% of student variability. these results are most likely due to the commonly observed relationship of a good quality mcq test with other performance measures. it has been observed that general ability is the foundation of most performance measures and a well-constructed mcq is the best estimator of this general ability.5,6 also the results might reflect an unbiased evaluation of the medical students.7 the acquisition of clinical skills is paramount to the development of a safe and competent practitioner.8 osce as a performance-based assessment is a well-established assessment tool for many reasons: it is a competency-based, valid, practical, and effective means of assessing clinical skills that are fundamental to the practice of medicine, and to other health care related professions.9 while osce is in use in many medical disciplines in saudi arabia, particularly in general surgery, orthopaedics and internal medicine, psychiatric educators have been slow to adopt this method of evaluation.7,10-12 to the best of the authors’ knowledge, this is the first report that addresses osce in undergraduate psychiatric assessment in saudi arabia. as expected, the implementation of osce in our department has proved to be a useful adjunct to other forms of clinical assessment. the student’ scores on the osce correlated well with the results in clinical examinations and explained a great part of the variance in total clinical marks. similar findings have been reported in different specialties from different countries;13–15 however, these studies did not show a correlation between the results of the osce and the mcqs. this may be attributed to the fact that mcqs assess the students’ cognitive abilities, covering the area of ‘knows’ and ‘knows how’ of miller’s pyramid of assessment, and possibly spanning the levels of bloom’s taxonomy of educational objectives, from the level of comprehension to the level of evaluation.16 additionally, the osce, like other forms of clinical examinations, tests a different domain of clinical skills (covering the area of ‘shows how’ of the miller’s pyramid of assessment) which is a prerequisite for physician performance in real life, such as history taking and physical examinations.3 nonetheless, our results should be interpreted with caution as, according to previous studies in the literature, only two of the stations in our osce examination are considered classic osce stations.3 the results of the study show that the most significant predictor of overall clinical scores is the toce. it alone explained 74.5% of the variance in clinical scores. conditioned on the presence of the toce, the osce explained an extra variance of 19.2%. the examiners awarded high marks to favour a more pleasurable student-teacher encounter which unfortunately created a ‘halo effect’ in the evaluation of the students. the osce significantly correlates with the toce, but still has an important role in predicting total clinical marks. it explained 65.1% of the variance in total clinical marks. a better designed osce and external examiners in the toce would help to increase the accuracy and reliability of clinical assessment. conclusion this study demonstrates that different clinical methods used to assess medical students during their psychiatry course were consistent and integrated. this information would be useful for future developments in undergraduate teaching of this subject. a c k n o w l e d g e m e n t s the authors would like to thank dr. feroze kaliyadan, assistant professor of dermatology at king faisal university, for his assistance in revising the manuscript. c o n f l i c t o f i n t e r e s t no funding was received for this study, and no conflict of interest exists. references 1. el-gilany ah, amr m, iqbal r. students’ attitudes toward psychiatry at al-hassa medical college, saudi assessment methods of an undergraduate psychiatry course at a saudi university 220 | squ medical journal, may 2012, volume 12, issue 2 arabia. acad psych 2010; 34:71–4. 2. vaidya na. psychiatry clerkship: objective structured clinical examination is here to stay. acad psych 2008; 32:177–9. 3. hodges b, hanson m, mcnaughton n, regehr g. university of toronto psychiatric skills assessment project. creating, monitoring, and improving a psychiatry osce: a guide for faculty. acad psych 2002; 26:134–61. 4. haladyna tm, downing sm. a taxonomy of multiple choice item-writing rules. appl meas educ 1989; 37–50. 5. maatsch jl. assessment of clinical competence on the emergency medicine specialty certification examination: the validity of examiner ratings of simulated clinical encounters. ann emerg med 1981; 10:504–7. 6. fabrega h jr, ulrich r, keshavan m. gender differences in how medical students learn to rate psychopathology. j nerv ment dis 1994; 182:471–5. 7. shaheen m, bader a, al-khudairy n. experience of the orthopedic division at king saud university in organizing and conducting the objective structured clinical examination (osce). j kau: med sci 1991; 1:57–64. 8. zyromski nj, staren ed, werrick hw. surgery resident’s perception of the objective structured clinical examination (osce). curr surg 2003; 60:533–7. 9. bakhsh tm, sibiany am, al-mashat fm, meccawy aa, al-thubaity fk. comparison of students’ performance in the traditional oral clinical examination and the objective structured clinical examination. saudi med j 2009; 30:555–7. 10. guraya s, alzobydi a, salman s. objective structured clinical examination: examiners’ bias and recommendations to improve its reliability. j med med sci 2010; 1:269–72. 11. almoallim h. osce in internal medicine for undergraduate students newly encountered with clinical training. from: http://services. aamc .org/30/me de dp or tal/ser vlet/s/seg ment/ mededportal/?subid=429.accessed: may 2011. 12. higazi m, downing sm. objective structured clinical examination as an assessment method in residency training: practical considerations. ann saudi med 2008; 28:192–9. 13. townsend ah, mcllvenny s, miller cj, dunn ev. the use of an objective structured clinical examination (osce) for formative and summative assessment in a general practice clinical attachment and its relationship to final medical school examination performance. med educ 2001; 35:841–6. 14. yu tc, wheeler br, hill ag. clinical supervisor evaluations during general surgery clerkships. med teach 2011; 33:479–84. 15. singhal n, lockyer j, fidler h, keenan w, little g, bucher s. helping babies breathe: global neonatal resuscitation program development and formative educational evaluation. resuscitation 2012; 83:90–6. 16. maatsch jl, huang rr, downing s, barker d, munger b. the predictive validity of test formats and a psychometric theory of clinical competence. proc annu conf res med educ 1984; 23:76–8. ebola is a single-stranded ribonucleic acid (rna) virus that has become one of the most feared and virulent pathogens, affecting both humans and great apes. within a few days, the virus induces acute fever and very often death, and is usually associated with haemorrhagic syndrome in up to 90% of symptomatic individuals.1,2 five species of the genus ebolavirus are known: bundibugyo, sudan, zaïre, reston and taï forest. the reston species does not cause human fatalities, although it kills nonhuman primates such as chimpanzees and monkeys, as well as other animals like duikers.1–3 whilst ebola is endemic in regions of central and west africa and the philippines, outbreaks are usually characterised by widespread fear, exacerbated by worldwide media hype and concern for the international spread of the virus, including via potential bioterrorism by dissident groups around the world.2,4 generally, the disease process is defined by rapid immune suppression and a systemic inflammatory response that leads to vascular, coagulation and immune system impairment. increasingly, this impairment results in multi-organ and multisystem failure and shock, causing death. current treatment is supportive; disease management and containment efforts undertaken in communities and healthcare institutions focus mainly on minimising the further spread of the epidemic while restoring calm.3,5 the haemorrhagic syndrome associated with the viral infection results in a high rate of case fatalities largely because there is no specific and approved postexposure treatment or a vaccine.1,2 however, various studies conducted on animal models have shown promising results using agents that interfere with the viral rna and glycoprotein spikes.2,4,6 1department of fundamentals & administration, college of nursing, sultan qaboos university, muscat, oman; 2department of health studies, college of human sciences, university of south africa, pretoria, south africa; 3christine e. lynn college of nursing, florida atlantic university, boca raton, florida, usa *corresponding author e-mail: gamandu@squ.edu.om فريوس ايبوال ومتالزمة النزف جريالد ماثيو، ديريك فان دروال، روزانوا لوك�سن abstract: the ebola virus is a highly virulent, single-stranded ribonucleic acid virus which affects both humans and apes and has fast become one of the world’s most feared pathogens. the virus induces acute fever and death, with haemorrhagic syndrome occurring in up to 90% of patients. the known species within the genus ebolavirus are bundibugyo, sudan, zaïre, reston and taï forest. although endemic in africa, ebola has caused worldwide anxiety due to media hype and concerns about its international spread, including through bioterrorism. the high fatality rate is attributed to unavailability of a standard treatment regimen or vaccine. the disease is frightening since it is characterised by rapid immune suppression and systemic inflammatory response, causing multi-organ and system failure, shock and often death. currently, disease management is largely supportive, with containment efforts geared towards mitigating the spread of the virus. this review describes the classification, morphology, infective process, natural ecology, transmission, epidemic patterns, diagnosis, clinical features and immunology of ebola, including management and epidemic containment strategies. keywords: hemorrhagic fever, ebola; ebolavirus; hemorrhage; filoviridae; pathogenicity factors; virulence; disease management. امللخ�ص: فريو�ض ايبوال هو فريو�ض �سديد اخلطورة من فئة احلم�ض النووي الريبي اأحادي الطاق والذي ي�سيب الب�رش والقرود واأ�سبح ب�رشعة اأحد اأكرث االأمرا�ض املقلقة عامليًا. الفريو�ض يوؤدي اإىل احلمى احلادة والوفاة مع متالزمة النزف يف حواىل %90 من املر�سى. االأنواع املعروفة من جن�ض فريو�ض ايبوال هي بنديبيجيوا، ال�سودان، زائري، ري�ستون، وتي فور�ست. بالرغم من توطنة يف افريقيا، اأحدث ايبوال قلق عاملي ب�سبب ال�سجيج االإعالمي واخلوف من االأنت�سار الدويل مبا يف ذلك من خالل االإرهاب البيولوجي. اأرتفاع االإماتة يعود اإىل عدم وجود نظام عالجي ر�سمي اأو حت�سني. يعترب املر�ض خميف لتميزة ب�رشعة الكبت املناعي واأ�ستجابة التهاب املجموعة، والذي يوؤدي اإىل ف�سل النظام وجمموعة االأع�ساء، ال�سدمة ويف كثري من االأحيان املوت. حاليًا، عالج املر�ض هو الدعم اإىل حد كبري، مع جهود االإيكولوجية، الطبيعة العدوى، طريقة املورفولوجيا، ايبوال، طراز ت�سف املراجعة هذة الفريو�ض. اأنت�سار تهوين نحو موجهة اأحتواء االنتقال وت�سنيف التوطني، والت�سخي�ض، املظاهر ال�رشيرية وعلم املناعة، مبا يف ذلك العالج واأ�سرتاتيجيات احتواء التوطني. مفتاح الكلمات: حمى نزفية، اإيبوال؛ فريو�ض ايبوال؛ نزف؛ فريو�سات خيطية؛ العوامل االإمرا�سية؛ الفوعة؛ عالج االأمرا�ض. review ebolavirus and haemorrhagic syndrome *gerald a. matua,1 dirk m. van der wal,2 rozzano c. locsin3 sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e171–176, epub. 28 may 15 submitted 15 sep 14 revision req. 28 oct 14; revision recd. 29 oct 14 accepted 20 nov 14 ebolavirus and haemorrhagic syndrome e172 | squ medical journal, may 2015, volume 15, issue 2 in length, with some as long as 14,000 nm. structurally, ebola viruses consist of three layers: a surface glycoprotein layer, a lipid membrane envelope unit and an internal tubular helical nucleocapsid.4,9 the virus surface layer consists of glycoprotein spikes, each about 7–10 nm long, spaced at about 10 nm intervals. these spikes aid the entry of the virus into host cells by specifically acting as mediators for receptor binding and cell membrane fusion. the second layer, the lipid membrane, surrounds the internal helical nucleocapsid. this, in turn, houses the third layer, the negative-stranded viral genome, which controls viral replication in cells.4,8,9 infection of host cells and replication ebola viruses infect different cell types, including macrophages, fibroblasts, hepatocytes and endothelial cells, mediated by the glycoprotein spikes that play an important role in endocytosis, a process vital for the entry of the virus into host cells. when an ebola virus enters the host cells, viral replication starts, resulting in numerous new virus particles.9,10 the process of viral replication is mediated by the synthesis of a positive rna strand that serves as a template for the production of additional viral genomes. as replication continues, the new viruses continually bud off, attaining their outer lipid membrane from the host cell membrane, killing them instantly.1,7 as more and more host cells rupture due to the budding of new viruses, cascades of reactions are triggered, resulting in the lethal ebola haemorrhagic fever (ehf) syndrome.1,4,7 ecology and distribution ehf is considered a classical zoonosis because of its ability to be transmitted naturally from vertebrate animals to humans and other mammalian species.4,11 despite the fact that non-human primates have repeatedly been a source of infection for humans, the natural reservoir of the ebola virus still remains unknown, although bats have been repeatedly implicated as being a natural reservoir of filoviruses.4,5,11,12 this declaration followed the detection of viral rna and antibodies in three specific bat species— hypsignathus monstrosus, epomops franqueti and myonycteris torquata—implying that these bats could be natural reservoirs.11,12 the claim that bats play a central role in ebola transmission followed the discovery that bats infected experimentally did not die.13 this claim received further support when laboratory observations in uganda confirmed that the objective of this integrated review is to describe the classification, morphology, infective process and natural ecology of ebola, as well as the transmission and epidemic patterns of the virus. this review also details the diagnosis, clinical features and immunology of the virus, including current disease management practices and epidemic containment strategies. a literature review was conducted of peer-reviewed, original research and review papers indexed in pubmed, cinahl, medline, scopus, sciencedirect and google scholar databases and published between january 1990 and october 2014. selected medical textbooks and online resources that addressed specific aspects related to the ebola and marburg viruses were also consulted. searches were conducted using the following search terms: ‘viral haemorrhagic fevers’, ‘ebola virus disease’, ‘filoviridae infection’, ‘ecology’, ‘epidemics’, ‘epidemiology’, ‘diagnosis’, ‘signs and symptoms’, ‘immunology’ and ‘disease management’ in various combinations, in order to retrieve articles published in english that addressed various aspects of ebola virus disease (evd). classification and taxonomy the ebola virus is classified as a biosafety risk group 4 agent, which is the highest rating on the biosafety scale, due to the high health risk it poses for laboratory personnel and the public.3 ebola virus is a lipidenveloped, single-stranded, negative-sense rna virus belonging to the genus ebolavirus in the family filoviridae and order mononegavirales.4,7 ebola and marburg viruses are the only filoviruses that cause severe haemorrhagic fever syndrome in humans and non-human primates such as monkeys and chimpanzees.5,8 the marburg virus consists of only one strain while the genus ebolavirus comprises five species, which are named after the country or location in which they were first discovered.1,2,5,7 the four species zaire ebolavirus, sudan ebolavirus, taï forest ebolavirus (formerly cote d'ivoire ebolavirus) and bundibugyo ebolavirus occur in sub-saharan africa, whereas the fifth strain, reston ebolavirus, originated from the philippines, although it was first isolated in reston, virginia, usa. morphology in their innate states, ebola viruses exist as filamentous and pleomorphic structures, often taking on different shapes. they may occur in long filaments or branched, u-shaped, 6-shaped or circular forms.1,4 ebola viruses have a uniform diameter of 80 nm but vary considerably gerald a. matua, dirk m. van der wal and rozzano c. locsin review | e173 african fruit bats (rousettus aegyptiacus) infected naturally with filoviruses looked healthy and did not show any signs of illness, despite testing positive for marburg virus isolates and yielding live viruses from liver and spleen tissue samples.14 this further supports the claim that these bats could harbour filoviruses in between outbreaks.4,15 these findings corroborate reports of studies conducted in gabon and the democratic republic of congo (drc), which concluded that bats of the order chiroptera, among them the african fruit bats of the family pteropodidae and species r. aegyptiacus, naturally host the ebola and marburg viruses.11,12,15 despite these various investigations, to date none of the ebola virus strains have ever been isolated from naturally infected animals. what is certain though, is that the virus is endemic in rain forests of africa and the philippines and, like humans, non-human primates also become infected directly from as yet unknown natural reservoirs.4,5,16 modes of transmission the primary mode of ebola transmission from a natural reservoir to humans or primates remains unknown, although most outbreaks appear to be zoonotic.3–5 however, despite being zoonotic, filoviruses are neither spread continuously from person to person nor do they remain latent in primates.11,15,16 the main secondary mode of transmission from person to person is nosocomial and starts by contact with blood and body fluids from an infected person. infection then occurs through direct inoculation from contaminated instruments and infected droplets via mucous membranes or after humans have handled infected primates.1,3,5 in hospitals, health workers may become infected through close contact with patients, especially when they do not use proper infection prevention precautions or barrier nursing techniques.2,3,16 in community settings, funeral rituals are a key way in which the virus spreads, particularly where there is direct physical contact while performing cultural rituals like shaving and bathing the deceased.3,5,17 infected humans become contagious after developing early signs and symptoms of the disease—particularly a high fever and headache. generally, larger ebola outbreaks tend to occur after infected patients enter healthcare systems where barrier nursing and epidemic control practices are inadequate.2,3,5 clinical manifestations clinically, ehf or evd, which is the human disease caused by any of the five ebola virus strains, present with a sudden onset of signs and symptoms following an incubation period of two to 21 days.1,3,5 the initial signs and symptoms include a severe frontal headache radiating to the occipital region, acute fever exceeding 39 °c, general weakness, incapacitation, cervical and lower back pain and pains of the large joints.3–5 on physical examination, ebola patients typically look very sick and are often lethargic, presenting frequently with a ‘ghost face’, (i.e. an expressionless face with deep-set eyes). these signs and symptoms are followed by rapid and severe weight loss due to the loss of appetite, and dysphagia resulting from very painful throat lesions and severe disease symptoms.16,18,19 after two to three days, patients begin to experience gastrointestinal symptoms, including severe, cramping abdominal pain; haematemesis or vomiting blood; nausea, and bloody diarrhoea.2,3,5 by the fourth day, patients frequently experience a severe sore throat, commonly perceived as a ‘lump’ in the throat, further worsening the dysphagia.4,16,18 by the fifth day, patients present with conjunctivitis, chest pain, coughing, shortness of breath, nasal discharge, dehydration and haemorrhagic symptoms, which may vary from melaena (dark-brown bloody stool) to a slow overt oozing of blood from the gums in severe cases.3–5 after six to eight days, there is involvement of the central nervous system, manifested by somnolence, delirium and coma.3–5 there is also severe metabolic disturbance and diffuse coagulopathy.4,9 this period also marks a bimodal peak of the prognostic disease pattern, characterised by a binary phenomenon where patients either markedly improve or deteriorate further and then die from multiple organ and system failure and shock.18,20 in non-fatal cases, the symptoms are generally less severe, except that the fever persists for several days. these patients begin to show impressive signs of recovery typically at the turn of the first week, a period associated with the appearance of a humoral antibody response.4,9 however, in fatal cases, the clinical picture is more acute with signs and symptoms appearing early in the first week.4,9 as the week progresses, severely sick patients may bleed from the nose, gums, vagina, anus, urethra and injection sites and may even experience the overt vomiting of blood.3–5 other patients develop a pruritic, generalised maculopapular rash, jaundice, tinnitus, haematuria, vertigo, amenorrhoea, oliguria, hiccoughs and lymphadenitis.4,16,19 many severely ebolavirus and haemorrhagic syndrome e174 | squ medical journal, may 2015, volume 15, issue 2 rapid, high-level, immunological response targeting the viral glycoprotein coat is thought to lead to patient survival.4,22 this observation is based on the findings of studies conducted on survivors of the 1996 ebola outbreak in gabon, which concluded that an early immune response appeared to be key to surviving an ebola infection.4,22,23 in the early stages of infection, survivors tend to produce increased levels of igg and igm, which target the viral coat and are associated with a strong inflammatory response, including interleukin β, interleukin 6 and tumour necrosis factor-α. this is followed by clearance of circulating viral antigens and sustained activation of the cytotoxic t cell pathway.4,22–24 studies further show that patients who die of ebola have higher concentrations of interferon-γ and their peripheral blood cells show more extensive apoptosis (programmed cell death) compared to that of survivors.4,24 early and well-regulated inflammatory responses characterised by low levels of interferons and reactive oxygen and nitrogen species indicate higher chances of recovery from ebola.4,25 in contrast, a defective antibody response associated with increased blood concentrations of nitric oxide, resulting from an inappropriate response to the virus particles, is associated with death.4,21 similarly, studies on serial plasma indicate that survival appears to be related to orderly and well-regulated humoural and cellular responses.26 these findings suggest that impaired humoral responses with absent specific igg and barely detectable igm seem to indicate failure to control virus replication, thus leading to death.25,26 these findings imply that the absence of a vigorous immune response and lymphopaenia, or low levels of t cells due to an ineffective immunological response, characterise individuals who do not survive ebola.4,26,27 these studies further suggest that both cellular and humoral responses are essential in protecting patients against ebola infection. in the same way, the levels of immunological response that patients generate determine whether they will survive or succumb to evd. therapeutic interventions and vaccination while several candidate treatment options are being tested, no specific chemotherapeutic or immunisation strategy yet exists for ebola.2,6,27 the danger posed by ebola has been compounded by the discovery of newer virus strains and the existence of ebola virus antibodies in fruit bats in bangladesh, which extends the horizon of future ebola infection far beyond ill patients will also develop hepatosplenomegaly, pancreatitis and facial oedema, and typically die between day six and 16 due to multiple organ and system failure and hypovolemic shock.3,4,9 in patients who survive, recovery is slow, usually lasting several weeks to several months, and is associated with severe incapacitation, weight loss, a persistent headache, poor appetite, body weakness and a reduced libido (among other symptoms). survivors may also experience psychotic disturbances that typically last between three and nine months after the infection, characterised by episodes of mental confusion, anxiety, fatigue, depression, restlessness and aggressiveness.3–5,9 in pregnant women, miscarriages are common and clinical findings suggest an increased risk of death among the children of infected mothers, possibly due to transmission of the ebola virus to their babies, either through breast milk or by direct maternal contact.4,5,9 diagnostic criteria clinical diagnosis of evd is indicated after the occurrence of clusters of cases with prodromal fever, bleeding tendencies and person-to-person transmission, which is frequently associated with prostration, lethargy, wasting, diarrhoea and skin rashes.2–4 laboratory diagnosis of evd may be confirmed using acute-phase serum by measuring the level of the specific immunological response or by detecting viral antigens and genomic rna or isolating viruses.3,5,9 immunoglobulin m (igm) and immunoglobulin g (igg), the antibodies formed against evd, can be measured using an immunofluorescence assay (ifa), immunoblot or enzyme-linked immunosorbent assay (elisa).2,3,5 the viral antigen and genomic rna may also be detected using immunohistochemistry, ifa, elisa and reverse transcription-polymerase chain reaction techniques.2,3,5 direct detection of virus particles may be undertaken using electron microscopy.3–5 however, as a general rule and to ensure safety, it is vitally important that all laboratory diagnoses occur only in biosafety level 4 facilities, ensuring maximum biological containment. this is in order to reduce the risk of infection of laboratory personnel.3–5 immunological response humoral response to ebola viruses can be detected as early as 10–14 days after infection. the specific antibodies formed against the viruses are directed primarily against the viral surface glycoproteins.4,21 a gerald a. matua, dirk m. van der wal and rozzano c. locsin review | e175 africa and the philippines.2,4,12 although no specific therapy exists, convalescent serum has been used in critical situations. this was the case during the 1995 zaire ebolavirus outbreak in kikwit, drc, when eight ebola patients received blood transfusions from ebola survivors, seven of whom recovered.28 in the current outbreak in west africa, an experimental serum has been successfully used to treat five medical workers— two americans and three west africans—following approval by a world health organization panel of experts.29 the sixth recipient, a spanish priest, died despite receiving zmapp™, the experimental drug being co-developed by mapp biopharmaceutical, inc. (san diego, california, usa) and defyrus, inc. (toronto, canada).30 the zmapp™ experimental drug is classified as a humanised monoclonal antibody, harvested from the serum of ebola-infected mice with major components produced in the nicotiana benthamiana strain of tobacco. the drug works by attacking specific proteins on the surface of the ebola virus, thereby reducing its virulence.29,30 another drug currently undergoing human testing is tkm-ebola, which has been developed by tekmira pharmaceuticals corp. (burnaby, british columbia, canada). tkmebola is a systemically delivered, small interfering rna therapeutic that is administered using novel lipid nanoparticle delivery technology. tkm-ebola interrupts the genetic coding of the ebola virus by blocking the expression of the l proteins of the rna polymerase of the ebola virus, thus hampering replication of the virus within the host cells.31 since there is still no specific therapy in response to evd, the most appropriate treatment during outbreaks is supportive therapy. this involves balancing patients’ electrolytes, maintaining optimal oxygenation and blood pressure levels and ensuring their adequate nutrition and comfort.3,5,32 in addition, there should be prompt treatment of any complications such as superinfections and dehydration to prevent cardiovascular collapse and renal insufficiency.32 further, it is recommended that while providing this supportive therapy, caregivers should adhere to strict barrier nursing practices, which are characterised by careful handling of blood and body fluids. finally, it must be ensured that deceased individuals are buried promptly in order to prevent transmission of the virus to others. conclusion ebola virus infection, and the haemorrhagic syndrome that ensues, leads to a high rate of case fatalities largely due to the lack of specific postexposure prophylactic treatments or a vaccine. the disease process is characterised by rapid immune suppression and multisystem involvement, leading to the impairment and eventual collapse of various organs and systems, and resulting in hypovolemic shock and death. current patient management practices mainly involve supportive care, including meeting patients’ needs for hydration, electrolyte balance, nutrition and comfort. this care should be provided in designated health facilities with isolation units so as to limit the further spread of the ebola virus. in summary, in the absence of specific treatments, the most cost-effective outbreak management and containment interventions are preventative in nature and are largely aimed at breaking the human-to-human infection transmission cycle at both institutional and community levels. these measures include early case identification, patient isolation, use of personal protective equipment and safe burial procedures, as well as on-going community education and mobilisation. references 1. leroy em, gonzalez jp, baize s. ebola and marburg haemorrhagic fever viruses: major scientific advances, but a relatively minor public health threat for africa. clin microbiol infect 2011; 17:964–76. doi: 10.1111/j.1469-0691.2011. 2. raabe vn, borchert m. infection control during filoviral hemorrhagic fever outbreaks. j glob infect dis 2012; 4:69–74. doi: 10.4103/0974-777x.93765. 3. centers for disease control and prevention. ebola (ebola virus disease). from: www.cdc.gov/vhf/ebola/pdf/ebola-factsheet. pdf accessed: aug 2014. 4. feldmann h, geisbert tw. ebola haemorrhagic fever. lancet 2011; 377:849–62. doi: 10.1016/s0140-6736(10)60667-8. 5. world health organization. ebola virus disease: fact sheet no. 103, 2014. from: www.who.int/mediacentre/factsheets/fs103/ en/ accessed: aug 2014. 6. geisbert tw, bausch dg, feldmann h. prospects for immunisation against marburg and ebola viruses. rev med virol 2010; 20:344–57. doi: 10.1002/rmv.661. 7. hoenen t, groseth a, feldmann h. current ebola vaccines. expert opin biol ther 2012; 12:859–72. doi: 10.1517/1 4712598.2012.685152. 8. qiu x, fernando l, melito pl, audet j, feldmann h, kobinger g, et al. ebola gp-specific monoclonal antibodies protect mice and guinea pigs from lethal ebola virus infection. plos negl trop dis 2012; 6:e1575. doi: 10.1371/journal.pntd.0001575. 9. sanchez a, geisbert tw, feldmann h. filoviridae: marburg and ebola viruses. in: knipe dm, howley pm, eds. fields virology. philadelphia, usa: lippincott, 2006. pp. 1409–48. 10. richardson js, dekker jd, croyle ma, kobinger gp. recent advances in ebolavirus vaccine development. hum vaccin 2010; 6:439–49. doi: 10.1016/j.vaccine.2010.10.037. 11. pourrut x, délicat a, rollin pe, ksiazek tg, gonzalez jp, leroy em. spatial and temporal patterns of zaire ebolavirus antibody prevalence in the possible reservoir bat species. j infect dis 2007; 15:s176–83. doi: 10.1086/520541. 12. olival kj, islam a, yu m, anthony sj, epstein jh, khan sa, et al. ebola virus antibodies in fruit bats, bangladesh. emerg infect dis 2013; 19:270–3. doi: 10.3201/eid1902.120524. ebolavirus and haemorrhagic syndrome e176 | squ medical journal, may 2015, volume 15, issue 2 13. swanepoel r, leman pa, burt fj, zachariades na, braack le, ksiazek tg, et al. experimental inoculation of plants and animals with ebola virus. emerg infect dis 1996; 2:321–5. doi: 10.3201/eid0204.960407. 14. towner js, amman br, sealy tk, carroll sa, comer ja, kemp a, et al. isolation of genetically diverse marburg viruses from egyptian fruit bats. plos pathog 2009; 5:e1000536. doi: 10.1371/journal.ppat.1000536. 15. towner js, pourrut x, albariño cg, nkogue cn, bird bh, grard g, et al. marburg virus infection detected in a common african bat. plos one 2007; 2:e764. doi: 10.1371/journal. pone.0000764. 16. centre for infectious disease research and policy. viral hemorrhagic fever: current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, treatment, and prophylaxis, 2009. from: www.cidrap.umn.edu/cidrap/content/bt/vhf/biofacts/ vhffactsheet.html accessed: oct 2014. 17. lamunu m, lutwam, jj, kamugish, j, opi a, nambooze j, ndayimirije n, et al. containing haemorrhagic fever epidemic: the ebola experience in uganda (october 2000–january 2001). int j infect dis 2004; 8:27–37. doi: 10.1016/j.ijid.2003.04.001 18. kumar p, clark m, eds. kumar and clark’s clinical medicine, 5th ed. london, uk: saunders ltd, 2002. 19. shoemaker t, macneil a, balinandi s, campbell s, wamala jf, mcmullan lk, et al. reemerging sudan ebola virus disease in uganda, 2011. emerg infect dis 2012; 18:1480–3. doi: 10.3201/ eid1809.111536. 20. matua ag, locsin rc. conquering death from ebola: living the experience of surviving a life-threatening illness. in: lee av, ed. coping with disease. new york, usa: nova science, 2005. pp. 121–73. 21. sanchez a, lukwiya m, bausch d, mahanty s, sanchez aj, wagoner kd, et al. analysis of human peripheral blood samples from fatal and nonfatal cases of ebola (sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels. j virol 2004; 78:10370–7. doi: 10.1128/jvi.78.19.10370-10377.2004. 22. ströher u, west e, bugany h, klenk hd, schnittler hj, feldmann h. infection and activation of monocytes by marburg and ebola viruses. j virol 2001; 75:11025–33. doi: 10.1128/jvi.75.22.11025-11033.2001. 23. volchkov v. processing of the ebola virus glycoprotein. curr top microbiol immunol 1999; 235:35–47. 24. bonn d. surviving ebola infection depends on response. lancet 1999; 353:1161. doi: 10.1016/s0140-6736(05)74383-x. 25. baize s, leroy em, georges aj, georges-courbot mc, capron m, bedjabaga i, et al. inflammatory responses in ebola virusinfected patients. clin exp immunol 2002; 128:163–8. doi: 10.1046/j.1365-2249.2002. 26. baize s, leroy em, georges-courbot mc, capron m, lansoud-soukate j, debré p, et al. defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in ebola virus-infected patients. nat med 1999; 5:423–6. doi: 10.1046/j.1365-2249.2002.01800.x. 27. falzarano d, geisbert tw, feldmann h. progress in filovirus vaccine development: evaluating the potential for clinical use. expert rev vaccines 2011; 10:63–77. doi: 10.1586/erv.10.152. 28. mupapa k, massamba m, kibadi k, kuvula k, bwaka a, kipasa m, et al. treatment of ebola hemorrhagic fever with blood transfusions from convalescent patients. j infect dis 1999; 179:s18–23. doi: 10.1086/514298. 29. sayburn a. who gives go ahead for experimental treatments to be used in ebola outbreak. bmj 2014; 349:g5161. doi: 10.1136/bmj.g5161. 30. zhang y, li d, jin x, huang z. fighting ebola with zmapp: spotlight on plant-made antibody. sci china life sci 2014; 987–8. doi: 10.1007/s11427-014-4746-7. 31. mullard a. experimental ebola drugs enter the limelight. lancet 2014; 384:649. doi: 10.1016/s0140-6736(14)61371-4. 32. kreuels b, wichmann d, emmerich p, schmidt-chanasit j, de heer g, kluge s, et al. a case of severe ebola virus infection complicated by gram-negative septicemia. n engl j med 2014; 1–8. doi: 10.1056/nejmoa1411677. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e27–33, epub. 21 jan 15 submitted 28 feb 14 revisions req. 7 may & 16 jul 14; revisions recd. 16 jun & 31 aug 14 accepted 11 sep 14 according to a 2006 world health organization report, health human resou-rces (hhr), also known as human resources for health or the health workforce, are defined as “all people whose job is to protect and improve the health of their communities”.1 the term ‘workforce’, which aptly reflects the expanded roles and increased numbers of women in health professions, has replaced ‘manpower’ in order to denote the number of professionals available to provide services.2 these include the diverse clinical and non-clinical staff who implement individual and public health interventions. the health workforce is an important component for the functioning and performance of labourintensive healthcare systems.3 workers are not just individuals, but integral parts of functioning healthcare teams in which each member contributes different skills and performs different functions.1 however, some countries facing health worker shortages have been reluctant to develop the detailed hhr policies or strategic plans that are necessary to guide and build the required human infrastructure of their health systems.4 for example, hhr planning has not succeeded in many african countries due to several factors, including insufficient balance between the plan and the planning process; lack of access to and use of planning methods and tools; lack of appropriate and accurate data; low stakeholder involvement in the planning process, and insufficient advocacy to attract resources for implementation.5 such countries usually fail to adopt a planning method, depend essentially on introducing incremental changes in staffing on a year-to-year basis and use fixed standards combined with short-term adjustments to services and staffing in response to emerging health crises.6 in these cases, health systems usually operate without a targeted 1dental department, al nahda hospital, muscat, oman; 2department of planning, research & information, oman medical specialty board, muscat, oman; 3department of community medicine & public health, tanta university, tanta, egypt *corresponding author e-mail: ibtaisam@hotmail.com ختطيط القوى العاملة الصحية نظرة عامة ومنهجية مقرتحة يف عمان عبد العزيز ال�ضواعي و موؤن�س م�ضطفى ال�ض�ضتاوي abstract: in most countries, the lack of explicit health workforce planning has resulted in imbalances that threaten the capacity of healthcare systems to attain their objectives. this has directed attention towards the prospect of developing healthcare systems that are more responsive to the needs and expectations of the population by providing health planners with a systematic method to effectively manage human resources in this sector. this review analyses various approaches to health workforce planning and presents the six-step methodology to integrated workforce planning which highlights essential elements in workforce planning to ensure the quality of services. the purpose, scope and ownership of the approach is defined. furthermore, developing an action plan for managing a health workforce is emphasised and a reviewing and monitoring process to guide corrective actions is suggested. keywords: health workforce, organization and administration; human resources development; health planning; oman. امللخ�ص: يوؤدى عدم وجود تخطيط وا�ضح للقوى العاملة ال�ضحية يف العديد من دول العامل اإىل فقدان التوازن الذي يهدد قدرة اأنظمة الرعاية ال�ضحية على حتقيق اأهدافها. وقد وجهت هذه امل�ضكلة االهتمام نحو اآفاق تطوير اأنظمة الرعاية ال�ضحية لتكون اأكرث ا�ضتجابة الب�رضية للموارد فعالة اإدارة حتقيق من ميكنهم ال�ضحيني للمخططني منهجي اأ�ضلوب توفري خلل من وتطلعاتهم ال�ضكان الحتياجات يف هذا القطاع. يحلل هذا املقال مناهج خمتلفة لكيفية تخطيط القوى العاملة ال�ضحية، ويقدم منهجية ال�ضت مراحل للتخطيط املتكامل للقوى العاملة، والتي ت�ضلط ال�ضوء على العنا�رض االأ�ضا�ضية يف التخطيط الذي يهدف اإىل �ضمان جودة اخلدمات. ويقدم املقال تعريفات لغر�س ونطاق وتبعية املنهجية، كما يوؤكد على وجود خطة عمل حمددة يتم تطويرها الإدارة القوى العاملة ال�ضحية، باالإ�ضافة اإىل عملية املراجعة واملتابعة لتوجيه االإجراءات الت�ضحيحية. مفتاح الكلمات: القوى العاملة ال�ضحية التنظيم واالإداره؛ تنمية املوارد الب�رضية؛ التخطيط ال�ضحي؛ �ضلطنة عمان. review health workforce planning an overview and suggested approach in oman *abdulaziz al-sawai1 and moeness m. al-shishtawy2,3 health workforce planning an overview and suggested approach in oman e28 | squ medical journal, february 2015, volume 15, issue 1 direction and the workforce is often unresponsive to the specific health needs and expectations of the community. it is therefore important that national hhr policies and strategies are formulated using evidence-based planning in order to rationalise decisions regarding a country’s health workforce. such plans can reduce workforce imbalances, strengthen the performance of staff and improve staff retention and adaptation to any major health sector reforms. in addition, they address the human resource development needs of priority health programmes and integrate them into a functional healthcare delivery system.6 a good example is the collaborative pan-canadian standards approach to hhr planning that was launched in 2004 and 2005 to support effective coordination and collaborative hhr planning across the country.7 in this approach, each jurisdiction in canada determines the scope of their delivery system, their present and future needs and the type of service delivery models that would best meet their population’s needs. the jurisdictions are then able to more accurately determine their hhr requirements. however, this will occur within the context of a larger system that shares information and works collaboratively to develop the optimum combination and number of providers to meet all of the jurisdictions’ needs.7 this type of planning provides an opportunity to identify the services needed, innovative ways to deliver those services, the types of professionals required and how to deploy them and make the best use of their skills. this stands in contrast to a planning method based solely on how services are currently delivered and by whom.8 in addition, the health workforce planning model currently utilised in the netherlands since 2002 has been successful in achieving equilibrium in the labour market, taking into account the qualitative fit between supply and demand. in this respect, both policymakers and stakeholders in the netherlands have accepted the health workforce planning system and the model.3 the aim of this review is to highlight the importance of health workforce planning and to describe available models and methods. in addition, this review will examine the extent to which health workforce planning processes have been successful in reaching a balance between supply and demand, both internationally and in oman. a selected collaborative approach for hhr planning and management that can be adapted to local circumstances, the six-step methodology for workforce planning, is also presented. this approach can assist in the delivery of healthcare projects or programmes by considering both the number of workers needed and the characteristics desired in a workforce in order to improve access to and quality of healthcare services.9 imbalances in health workforces in contrast to effective workforce planning, imbalances in the health workforce represent a major challenge for health policymakers and hinder effective planning. imbalances between available inputs and requirements characterise health systems in both developed and developing countries; however, they are often more visible in the latter, perhaps due to a lack of management and insufficient financial resources to attract qualified health professionals from other countries.6 usually, all health workforce assessments begin with an estimation of the current number of physicians in the workforce. indications of a shortage in this category depend on economic and demographic trends that impact the current supply of physicians, as well as estimates from databases of physicians and surgical organisations.10,11 another approach to health workforce assessment involves the estimation of regional or national training needs and the competencies of local public health workers.12 however, many studies have revealed barriers to the success of workforce surveys and training initiatives. these limitations include a lack of organisational support; low response rates;13 the need for intensive follow-up to increase response rates; limited training time and resources,14 and non-representative or role-limited responses. given these obstacles, very few comprehensive surveys of health workforces have been conducted at any level in order to assess the workforce.15 g e o g r a p h i c a l i m b a l a n c e s the unbalanced distribution of the health workforce within countries is a global problem that often results in great disparities in health outcomes between rural and urban populations. this imbalance may be explained economically, as a disequilibrium between labour supply and demand in a given geographic area, and normatively, as differences in staff density resulting from a given standard or social norm.16,17 a needs-based analysis alone does not consider the full labour market for health workers. from a demand perspective, three major sectors that utilise health workers also shape health worker labour markets: public, private and donor sectors. government structures also influence the health worker market by setting rules and establishing the role of public policy in enabling the market to function.18 other determinants abdulaziz al-sawai and moeness m. al-shishtawy review | e29 which workers are recruited, deployed, trained and made redundant. consequently, it has become a major challenge for policy makers to avoid these cyclic variations between shortages and surpluses of healthcare personnel.3 in this way, one of the roles of the hhr planning process is to seek a balance or to address the mismatches between available human resources and the actual requirements for delivering quality health services.21 therefore, a basic workforce planning model consists of analyses in four key areas: supply, demand, gap and solution. supply analysis focuses on identifying organisational competencies, analysing staff demographics and determining employment trends.22 demand analysis measures future activities and workloads, describes the required competencies of the future workforce and quantifies the impact of changes in work arising from technological or other sources.23 gap analysis is an evaluation in which the supply and demand analyses are compared to understand differences between the current and future workforces. this likely results in one of two scenarios—the current number of workers or competencies in the workforce will not meet future needs (e.g. demand exceeds supply) or the current number of workers or competencies exceed future needs (e.g. supply exceeds demand).23 the solution analysis therefore strives to develop strategies to close the identified competency gaps and curtail surpluses.23 in order to estimate hhr supply and requirements, four types of approaches have been traditionally described: needs-based, utilisation or demand-based, health workforce to population ratio and targetsetting.24,25 the difference between these approaches depends on the way that the required health services are identified. these may be based on the health needs of the population, while others are based on the current level of technology being utilised in health facilities. moreover, methods may be based on a population’s demand for certain services and the various health services that are already provided, while others focus on meeting the population’s current health needs or work on projections of future requirements based on expected changes in population structure.24,26 each of the above-described planning approaches have advantages and limitations. problems in securing data are invariably encountered and some compromises have to be made with respect to the degree of precision with which the variables are specified.6 with the exception of the health workforce to population ratios approach, these methods seek to translate the required number and types of health services into time estimates. these estimates are then expressed as fullthat affect geographical distribution are the individual and organisational factors related to healthcare and educational systems, institutional structures and the broader sociocultural environment. r o l e o f t h e g o v e r n m e n t worldwide, governments continue to be the principal employers in the health sector, despite a tendency to give increasingly greater scope to the private sector in the provision of healthcare services.17 many countries, however, lack the human resources needed to deliver essential health interventions for a number of reasons, including limited production capacity, migration of health workers within and across countries, poor combination of skills and demographic imbalances. the formulation of national policies and plans in pursuit of human resources for health development objectives requires sound information and evidence. against the backdrop of an increasing demand for information, building knowledge and databases on the health workforce requires coordination across many sectors.19 health workforce planning effective workforce planning has been defined as “the timely anticipation of potential future imbalances between the supply and demand of skills, enabling action”1 or as “the systematic assessment of future human resource needs and the determinations of the actions required to meet those needs”.20 these definitions reflect the challenge of translating an organisation’s plans and objectives into scheduling requirements; while human resources are considered to be the most valuable component of this process, they are nevertheless also the most volatile and potentially unpredictable. research has shown that it is the role of health planners to ensure that the right number of healthcare workers with the right knowledge, skills, attitudes and qualifications are performing the correct tasks in the right place at the appropriate time in order to achieve predetermined health targets.1,21 however, planning the health workforce is not only a technical process; demographic and epidemiological transitions drive changes in population-based health threats and the workforce must respond to these. also, financing policies, technological advances and consumer expectations can dramatically shift demands of the workforce in health systems. furthermore, workers usually seek opportunities and job security in dynamic health labour markets that are part of the global political economy.1 such factors affect the ways in health workforce planning an overview and suggested approach in oman e30 | squ medical journal, february 2015, volume 15, issue 1 time equivalents of health personnel, using norms and standards on the actual productive time.21 it is also important for health system planners and managers to determine which variables are the dominant ones in any consideration of future requirements.6 context in oman in oman, human resources development in the area of healthcare has been a strategical priority for the past few decades.27 however, it was only in 1976 that the government of oman began using health workforce planning to set staffing levels. until 1990, this planning was erratic, locally based and poorly supported by a cohesive health information system. periodically, the ministry of health (moh) intervened with emergency measures in reaction to health workforce shortages, such as facilitating and accelerating administrative processes to recruit expatriate health workers already present in oman, sponsoring partners of employed workers or attracting health workers from neighbouring countries.28 the moh also implemented training and reorientation for existing healthcare staff to improve their skill levels, motivation and retention as well as increasing remuneration to encourage staff to work for extra hours or carry out additional tasks.29 in 1991, systematic health workforce planning began and the moh adopted a rational staffing policy. this entailed staffing of healthcare institutions based on workload-cum-allocation considerations.28 staffing norms were fixed in 1998 for most health centres and local hospitals in light of nationwide institutional surveys.30 the moh also issued a set of guidelines for staffing primary healthcare institutions.31 periodical reviews and adjustments of the staffing process in these institutions using computer-based hospital workforce planning models were conducted annually. in light of these reviews, planners came up with user-friendly staffing patterns for health centres and local hospitals. in 2006, they designed a simple classification of the health centres and local hospitals and proposed staffing norms for each type of facility.32 planning for the recruitment and deployment of the health workforce in regional and referral hospitals was determined on a top-down basis using workload measurement tools or relying on professional judgments. an alternative approach was to use research findings, where available, to develop the best doctor/ nurse to patient ratios in particular services.28 despite the validity of fixing certain optimum staff to patient ratios, it was often difficult to estimate the required numbers and allocate enough staff to each public hospital.33 in the light of the current situation in oman, the methodology described below is suggested for implementation in the country. the six-step methodology for workforce planning in the past, many countries have experienced limited success in planning and implementing hhr strategies.13–15 the risk of facing a potential hhr crisis has necessitated rethinking methods of health workforce planning. accordingly, new service delivery models were suggested to encourage healthcare providers to work collaboratively and to the full scope of their practice. the six-step methodology to integrated workforce planning was developed by skills for health, a workforce projects team in the uk.34 it is a systematic practical approach that supports the delivery of quality patient care, productivity and efficiency, while ensuring that workforce planning decisions are sustainable and realistic.34 the methodology identifies the elements necessary for any workforce plan, taking into account the current and future demand for healthcare services, the local demographic situation and the impact on other services, while helping planners to cope with budgetary constraints [figure 1]. each of the six steps are described in more detail below. d e f i n i n g t h e p l a n in this step, planners identify why a workforce plan is needed and for whom it is intended by defining its purpose, scope and ownership.35 workforce planners must be clear about the intended use of the plan and why it is required. the scope of the plan must be determined, including whether it will cover a single service area, a particular patient pathway or an entire nation-wide health system. given this, it must also be apparent who will be responsible for ensuring the plan is delivered and who will be involved in the planning process.9 m a p p i n g s e r v i c e c h a n g e this is the first of three interrelated steps. this second step involves the process of service redesign in response to patient choice, changes in modes of delivery, advances in care or financial constraints. planners must be very clear about current costs and outcomes and should identify the intended benefits of any changes to healthcare services. planners should also identify forces that may support or hamper each change. additionally, there must be a clear statement about how the preferred model is more effective in delivering the desired benefits, given anticipated constraints.9 abdulaziz al-sawai and moeness m. al-shishtawy review | e31 recruitment activities that could increase or change the workforce supply.9 d e v e l o p i n g a n a c t i o n p l a n with regard to the previous three steps and after determining the most effective way of ensuring the availability of staff to deliver the redesigned services, planners should develop a plan for delivering the appropriate number of staff with required skills.9 planners should also identify specific policies and practices for acquiring, developing, assessing, rewarding and distributing the workforce as necessary to close any existing gaps in service. these policies and practices should be sufficiently specific to the required workforce and should enable the management of any future changes. at this stage, planners must also estimate the potential effects of the identified policies and practices in reducing identified gaps and any requirements for new or modified resources and authority procedures for their implementation.35,38 planners should also include an assessment of anticipated problems and methods for overcoming these, including clinical engagement.9 i m p l e m e n t i n g, m o n i t o r i n g a n d r e f r e s h i n g t h e p l a n after the plan is launched, periodic review and adjustment are essential. to enable this, the plan should be explicit about how success will be measured. d e f i n i n g t h e r e q u i r e d w o r k f o r c e having established the foundations of the plan and the preferred programme model, planners must assess the workforce and appropriate skills that will be needed for delivery. this will require some consideration of both the key tasks undertaken by hhr and the skills needed to deliver these, along with an analysis of the levels of activity expected through the programme.36 determining the types and number of workers needed is known as establishing the workforce demand. this must be performed as part of wider service and financial planning processes. therefore, in order to estimate workforce demand, planners must consider their existing service model and the challenges of changing it with regards to deployment and required skills.37 u n d e r s ta n d i n g w o r k f o r c e ava i l a b i l i t y this step involves describing the existing workforce in the areas under consideration and the existing skills and deployment, as well as assessing any problem areas arising from age profile or turnover. it may be the case that the ready availability or shortage of staff with particular skills contributes to the service redesign and that steps two and three will need to be revisited. consideration should be given to the practicalities and cost of any retraining, redeployment and/or figure 1: health workforce planning cycle according to the six-step methodology for workforce planning.34 health workforce planning an overview and suggested approach in oman e32 | squ medical journal, february 2015, volume 15, issue 1 in addition, any unintended consequences of changes need to be identified so that corrective actions can be taken.9 planners also need to put in place a reviewing and monitoring process so that they can update the plan according to the changing workforce needs of the project or programme.36 it is worthwhile to mention that, although the six steps presented above are in numerical order, the process of workforce planning is in itself cyclical and not linear.36 accordingly, workforce planners may find themselves revisiting previous steps as they work through the methodology and when new information comes to light after the plan is implemented. conclusion hhr planning occurs within a health system and is driven by the design and models of health service delivery. these are, in turn, based on a population’s health needs. for the success of any healthcare delivery system, workforce planners must continually assess the impact of service design decisions on human resources and make adjustments or corrections as required. workforce planners must be clear about what they expect to achieve through collaborative hhr planning. their objective should allow the development and maintenance of a health workforce with the skills to support the service delivery system and allow patients timely access to high-quality, effective and safe health services. management decisions must be made regarding which hhr model is preferable. in order to ensure a greater capacity for influencing factors affecting hhr roles and work, the six-step methodology to integrated workforce planning is highly recommended for workforce planners in oman and other developing countries. references 1. world health organization. working together for health: the world health report 2006. from: www.who.int/whr/2006/ whr06_en.pdf?ua=1 accessed: may 2014. 2. robiner wn. the mental health professions: workforce supply and demand, issues, and challenges. clin psych rev 2006; 26:600–25. doi: 10.1016/j.cpr.2006.05.002. 3. van greuningen m, batenburg rs, van der velden lf. ten years of health workforce planning in the netherlands: a tentative evaluation of gp planning as an example. hum resour health 2012; 10:21. doi: 10.1186/1478-4491-10-21. 4. adano u. collection and analysis of human resources for health (hrh) strategic plans. from: www.capacityproject. org/images/stories/files/resourcepaper_strategicplans.pdf accessed: may 2014. 5. nyoni j, gbary a, awases m, ndecki p, chatora r; world health organization regional office for africa. policies and plans for human resources for health: guidelines for countries in the who african region. from: www.who.int/workforcealliance/ knowledge/toolkit/15.pdf accessed: may 2014. 6. world health organization. human resources for health observer issue no. 3: models and tools for health workforce planning and projections. from: www.whqlibdoc. who.int/publications/2010/9789241599016_eng.pdf accessed: may 2014. 7. health canada. health care system: health human resource strategy (hhrs). from: www.hc-sc.gc.ca/hcs-sss/hhr-rhs/ strateg/index-eng.php accessed may 2014. 8. federal/provincial/territorial advisory committee on health delivery and human resources (achdhr). a framework for collaborative pan-canadian human health resources planning. from: www.hc-sc.gc.ca/hcs-sss/alt_formats/hpb-dg ps/pdf/pubs/hhr/2007-frame-cadre/2007-frame-cadre-eng.pdf accessed: may 2014. 9. national health service. step-by-step: a guide to planning a portfolio programme and project management team. from: w w w.systems .hscic .gov.uk/p3m/resource/de velopment/ example/planteam.pdf accessed: may 2014. 10. zurn p, dal poz mr, stilwell b, adams o. imbalance in the health workforce. hum resour health 2004; 2:13. doi: 10.1186/1478-4491-2-13. 11. cooper ra, getzen te, mckee hj, laud p. economic and demographic trends signal an impending physician shortage. health aff (millwood) 2002; 21:140–54. doi: 10.1377/hlth aff.21.1.140. 12. alejos a, weingartner a, scharff dp, ablah e, frazier l, hawley sr, et al. ensuring the success of local public health workforce assessments: using a participatory-based research approach with a rural population. public health 2008; 122:1447–55. doi: 10.1016/j.puhe.2008.06.008. 13. acquilla s, o’brien m, kernohan e. ‘not too much, not too little, but just enough?’: observations on continuing professional development in public health in the north of england. public health 1998; 112:211–25. doi: 10.1016/s0033-3506(98)00234-0. 14. freudenstein u, yates b. public health skills in primary care in south west england: a survey of training needs, obstacles and solutions. public health 2001; 115:407–11. doi: 10.1038/ sj.ph.1900805. 15. lawlor da, morgan k, frankel s. caring for the health of the public: cross sectional study of the activities of uk public health departments. public health 2002; 116:102–5. doi: 10.1038/sj.ph.1900820. 16. dussault g, franceschini mc. not enough there, too many here: understanding geographical imbalances in the distribution of the health workforce. hum resour health 2006; 4:12. doi: 10.1186/1478-4491-4-12. 17. dussault g, dubois ca. human resources for health policies: a critical component in health policies. hum resour health 2003; 1:1. doi: 10.1186/1478-4491-1-1. 18. soucat a, scheffler r. the labour market for health workers in africa: a new look at the crisis. from: www.openknowledge. w o rl d b a n k . o rg / b i t s t re a m / h a n d l e / 1 0 9 8 6 / 1 3 8 2 4 / 8 2 5 5 7 . pdf?sequence=5 accessed: may 2014. 19. world health organization. human resources for health: toolkit on monitoring health systems strengthening. from: www.who.int/healthinfo/statistics/toolkit_hss/en_pdf_ toolkit_hss_humanresources_oct08.pdf accessed: may 2014. 20. ripley de. workforce: how to determine future workforce needs. from: www.workforce.com/articles/how-to-determinefuture-work-force-needs accessed: may 2014. abdulaziz al-sawai and moeness m. al-shishtawy review | e33 30. ghosh b. review of hospital bed capacity in oman: an exploratory study. muscat, oman: ministry of health, 1999. pp. 1–56. 31. oman ministry of health. guidelines for staffing primary health care institutions. muscat, oman: ministry of health, 1998. pp. 1–3 32. ghosh b. staffing norms primary health care institutions: a technical appendix to the 7th five-year human resources development plan. muscat, oman: ministry of health, 2006. pp. 1–21. 33. oman ministry of health. the human resources development plan: 7th five-year health development plan (2006-2010). muscat, oman: ministry of health, 2006. pp. 20–4. 34. skills for health. six steps methodology to integrated workforce planning. from: www.clph.net/writedir/5ec5six%20 steps%20refresh.pdf accessed: may 2014. 35. po t. getting it right: a workforce planning approach. from: www.tepou.co.nz/library/tepou/getting-it-right-a-workforceplanning-approach accessed: may 2014. 36. health service journal. six steps to integrated nhs workforce planning: step three. from: www.hsj.co.uk/resource-centre/ s i xs te p s to i nte g r ate d n h s w o rk fo rce p l a n n i n g s te p three/1921079.article#.u4xdzvmsxic accessed: may 2014. 37. brown js, learmonth a. mind the gap: developing the ph workforce in the north east and yorkshire and humber regions: a scoping stakeholder study. public health 2005; 119:32–8. doi: 10.1016/j.puhe.2004.02.008. 38. emmerichs rm, marcum cy, robbert aa. an operational process for working force planning. from: www.rand. org/content/dam/rand/pubs/monograph_reports/2005/ mr1684.1.pdf accessed: may 2014. 21. dreesch n, dolea c, dal poz mr, goubarev a, adams o, aregawi m, et al. an approach to estimating human resource requirements to achieve the millennium development goals. health policy plan 2005; 20:267–76. doi: 10.1093/heapol/ czi036. 22. young m; canadian paediatric society human resource services, center for organizational research. the aging and retiring government workforce. from: www.accenture. com/sitecolle ctiond o cument s/pdf/c p s_ageb ubble_ executivesummary.pdf accessed: may 2014. 23. rayner s. business blogs: workforce planning balancing demand and supply. from: www.businessblogshub. com/2012/10/workforce-planning-balancing-demand-andsupply/ accessed: may 2014. 24. hall tl, mej’ia a; world health organization. health manpower planning: principles, methods, issues. from: apps. who.int/iris/handle/10665/40341 accessed: may 2014. 25. markham b, birch s. back to the future: a framework for estimating health-care human resource requirements. can j nurs adm 1997; 10:7–23. 26. hornby p, ray dk, shipp pj, hall tl. guidelines for health manpower planning: a course book. from: www.whqlibdoc. who.int/public ations/9241541563_%28p1p188%29.p df accessed: may 2014. 27. alshishtawy m. medical specialties in oman: scaling up through national action. oman med j 2009; 24:279–87. doi: 10.5001/omj.2009.57. 28. alshishtawy mm. nursing staffing in oman: an approach for estimating the requirements of the 8th health system. sultan qaboos univ med j 2012; 12:258. 29. ghosh b. health workforce development planning in the sultanate of oman: a case study. hum resour health 2009; 7:47. doi: 10.1186/1478-4491-7-47. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 392-398, epub. 25th jun 13 submitted 5th sep 12 revisions req. 20th oct 12, 9th jan & 28th apr 13; revisions recd. 8th dec 12, 7th apr & 20th may 13 accepted 23rd may 13 قياس املعرفة الذاتية حول مرض السكري بني طلبة املدارس الثانوية يف العامرات وقريات،حمافظة مسقط، عمان بدرية املحروقية، رحمة احل�رسمية، اأمل العامرية، �شيف التميمي، اأ�شماء ال�شيذانية، هادية اللواتية، عايدة االإ�شماعيلية، خولة الهوتية، ثمرة اآلغافرية امللخ�ص: الهدف: يعترب مر�س ال�شكري النوع الثاين اأحد اأكرب امل�شاكل ال�شحية يف العامل، وقد تزايد انت�شاره مبعدل ينذر باخلطر بعد و�شوله اإىل م�شتويات وبائية على م�شتوى العامل. ومع تزايد االإ�شابات بهذا املر�س، اأ�شبحت احلاجة ملحة للرتكيز على تنفيذ الربامج التثقيفية املعززة للوقاية االأولية واالكت�شاف املبكر للمر�س. وقد اأجريت هذه الدرا�شة لتقدير م�شتوى املعرفة مبر�س ال�شكري النوع الثاين بني طلبة املدار�س الثانوية وال�شتك�شاف العوامل املوؤثرة يف هذه املعرفة. الطريقة: اأجريت درا�شة م�شحية �شملت اأربع مدار�س ثانوية يف واليتني من واليات حمافظة م�شقط، �شلطنة عمان، وهما واليتي العامرات وقريات. وقد اأجريت الدرا�شة با�شتخدام ا�شتبانة جمربة �شابقا باللغة االإجنليزية تغطي جميع جوانب مر�س ال�شكري النوع الثاين عن طريق املقابلة ال�شخ�شية. مت ا�شتخدام نظام الت�شجيل لتقييم معرفة الطالب. النتائج: ح�شل %24 فقط من بني 541 طالب م�شجال يف هذه الدرا�شة )%45 ذكور و %55 اإناث(، على معدل اأكرث من 10 من اأ�شل 20 درجة. وكانت اأهم املجاالت الرئي�شية التي بينت افتقار الطلبة فيها من املعرفة هي الت�شورات اخلاطئة عن وجبات الطعام ملر�شى ال�شكري )%73(، واالعتقاد باإمكانية ال�شفاء من مر�س ال�شكري )%63(. اخلال�سة: بينت الدرا�شة تدين امل�شتوى املعريف مبر�س ال�شكري النوع الثاين ب�شكل عام بني طالب املدار�س. اأو�شت الدرا�شة ب�رسورة تكثيف اجلهود القائمة لل�شحة املدر�شية لزيادة الوعي حول مر�س ال�شكري بني هذه الفئة العمرية. مفتاح الكلمات: مر�س ال�شكري، عمان؛ املراهقة؛ تقرير ذاتي؛ املعرفة؛ امل�شاعفات؛ عوامل اخلطر؛ املدار�س. abstract: objectives: type 2 diabetes mellitus (t2dm) is emerging as one of the world’s greatest health problems, and its incidence and prevalence are increasing at an alarming rate and globally reaching epidemic proportions. with this increasing incidence, emphasis is now being placed on implementing primary prevention, early detection, and educational prevention programmes. this study was undertaken to estimate the level of knowledge of t2dm among high school students and to explore the factors influencing the knowledge of t2dm. methods: a cross-sectional study was conducted in four secondary schools in two wilayats (districts) of muscat governate, oman, namely al-amerat and quriyat. the study was conducted using a validated english questionnaire covering all aspects of t2dm in one-to-one interviews. a scoring system was used to assess the students’ knowledge. results: of the 541 students enrolled in the study (45% male and 55% female), only 24% achieved a score of over 10 out of 20. the key areas of poor knowledge were wrong perceptions about diabetic meals (73%), and the possibility of a cure for diabetes (63%). conclusion: overall poor knowledge levels about t2dm were found among school students. national efforts and school-health-based interventions are highly recommended to increase awareness about diabetes among this age group. keywords: diabetes; oman; adolescence; self report; knowledge; complications; risk factors; schools. self-reported knowledge of diabetes among high school students in al-amerat and quriyat, muscat governate, oman *badriya al-mahrooqi,1 rahma al-hadhrami,1 amal al-amri,2 saif al-tamimi,3 asma al-shidhani,4 hadia al-lawati,5 aida al-ismaili,5 khawla al-hooti,6 thamra al-ghafri6 1directorate of health services amerat, ministry of health, muscat; 2quriyat hospital, ministry of health, muscat; 3quriyat polyclinic, ministry of health, muscat; 4amerat health center, ministry of health, muscat; 5hajer health center, ministry of health, muscat; 6quriyat directorate of health services; minsitry of health, muscat, oman *corresponding author e-mail: umsaba@gmail.com advances in knowledge this study has shown that this omani population of high school students had overall low knowledge levels about type 2 diabetes mellitus (t2dm), with less than a quarter of students achieving a 50% knowledge score. the students showed a good knowledge of t2dm symptoms and risk factors. the key areas of poor knowledge were wrong perceptions about diabetic meals and the possibility of a cure for diabetes. application to patient care this study will lead to an action plan and interventions to improve the knowledge of these students about diabetes. clinical & basic research badriya al-mahrooqi, rahma al-hadhrami, amal al-amri, saif al-tamimi, asma al-shidhani, hadia al-lawati, aida al-ismaili, khawla al-hooti and thamra al-ghafri clinical and basic research | 393 type 2 diabetes mellitus (t2dm) is a disease that has taken on epidemic proportions worldwide, with the incidence estimated to reach 5.4% by the year 2025. the number of adults with diabetes in the world will rise from 135 million in 1995 to 300 million in the year 2025.1 in oman, the prevalence of diabetes is high and has increased over the past decade. in 2000, the age-adjusted prevalence of diabetes among omanis aged 30–64 years reached 16.1% compared to 14.7% in 1991.2 primary prevention programmes need to be strengthened urgently in order to counteract major risk factors that promote the development of t2dm. one of the existing prevention programmes in oman is the ministry of health’s national screening program; this screens all people, aged forty and above for chronic non-communicable diseases. an increasing incidence of t2dm is being observed in the young.1 a review of recent literature generally showed suboptimal levels of diabetes awareness. for example, a study conducted between 1998–1999 on 13,293 mexican students (11–24 years) to evaluate knowledge about t2dm risk and prevention revealed that only 1.6% of the students (95% confidence interval [ci] = 1.4–1.8) had high t2dm knowledge levels compared to 85.6% (95% ci = 84.9–86.1) with low levels.3 on the other hand, a study done in 2007 in southeast michigan, usa, demonstrated significant basic knowledge of t2dm risk factors and complications among adolescents. however, despite the high level of knowledge, the study emphasised the importance of novel interventions because of the high prevalence of risk factors among this population, and the need to resolve the discordance between knowledge and behaviour.4 a similar study, conducted in a semi-urban omani population, demonstrated that there is lack of awareness of major risk factors for diabetes mellitus.5 t2dm affects the most productive midlife period and has also started to appear in younger age groups. it largely results from lifestyle and behavioural factors like obesity, physical inactivity and an unhealthy diet. thus any attempt to reduce the incidence of t2dm should include young people as they are at an impressionable age and can be motivated to make appropriate healthy lifestyle modifications.6 they can also, in turn, influence the community at large and determine the health of the next generation. this study therefore aimed to estimate the level of awareness of t2dm and factors influencing this knowledge among a population of omani school students. it is important to know more about awareness levels of t2dm, as knowledge is a critical component of behavioural change. once awareness is created, people are more likely to participate in prevention and control activities.1 this study fitted in well with the omani ministry of health’s (moh) interest in developing a school health programme as part of the overall national primary healthcare programme. methods this cross-sectional study was conducted in 4 secondary schools in two wilayats (districts) of muscat governorate (al-amerat and quriyat), oman. the study was undertaken in one secondary school for girls and one for boys in each of the two wilayats. prior ethical approval was obtained from the moh’s directorate general of health services (dghs), muscat, in january 2011. students from grades 11 and 12, who were willing to participate, were included in the study. the majority of these students (75%) were between 17 and 18 years of age. this age group was selected for two reasons. first, these are the last two grades in school education in oman. therefore, assessing their knowledge about diabetes would evaluate the final results of the health educational programmes provided during their schooling. second, this generation would soon be adults so assessing their awareness of diabetes could be important in order to prevent a further increase in the prevalence of these interventions should improve the quality of care of the students’ diabetic relatives; motivate them to participate in the care of their relatives, such as giving insulin injections and performing blood sugar monitoring, and improve the lifestyle of the students which will help in preventing diabetes. education of these students about diabetes and its complications will help in increasing the compliance of their relatives or even themselves as patients in future. self-reported knowledge of diabetes among high school students in al-amerat and quriyat, muscat governate, oman 394 | squ medical journal, august 2013, volume 13, issue 3 diabetes. out of 4,206 students, 541 were selected by cluster random sampling assuming a prevalence of low knowledge of 10% with an error of 2.5%, power of 80% and design effect of 2.0. the data were collected through one-to-one interviews in the period from 2nd april to 4th may 2011. the questionnaire used in this study was adapted from international questionnaires for similar purposes, used in both awareness and knowledge of diabetes surveys in chennai, india, (the chennai urban rural epidemiology study) and by the australian international diabetes federation in 2010.7,8 the questionnaire was modified by making the questions clearer and adding some questions relating to the source of information as a factor affecting the level of knowledge. this questionnaire was divided into three sections: demographic information, diabetes information history and clinical knowledge of t2dm. the demographic information included age, gender, grade, father’s and mother’s education levels and personal and family history of t2dm. the second section contained questions about the sources and preferred sources of t2dm information (media, school, healthcare staff and the public). the last section was designed to assess the clinical knowledge of t2dm in term of trends of t2dm, definition, symptoms, investigation-risk factors, complications and all aspects of treatment (diet, exercise and drugs). every seventh student in the list was selected for interview to reduce bias. if the seventh student was absent or refused to participate, the eighth student was interviewed instead. written consent was taken from the ministry of education and all heads of the schools participating in the study and from all participating students. the study avoided any physical or moral harm to the students regardless of their level of knowledge, and all data were treated confidentially. one day’s training was conducted by family physicians for the 4 data-collector nurses. the data collectors and family physicians were all arabic speakers. the questionnaire was explained, discussed in arabic and any doubt involving translation was clarified. then role-plays were conducted by the trainees and further doubts were clarified. a scoring system was created by giving one mark for each correct answer. the best answer was given one mark only. questions which contained more than one correct answer were given one mark for each correct answer. the maximum total mark was 20. a pilot study was carried out with a total of 30 secondary school students (grades 11 and 12) in both wilayats by the study team in order to validate the questionnaire. the data were analysed using the statistical package for the social sciences (spss) software, version 16, (ibm corp., chicago, illinois, usa). chi-square tests were used to determine the significance of the results. score results were divided into quartiles and the association between the score quartiles and other demographic factors were determined. logistic regression analysis was performed to determine the association between table 1: demographic data of the students characteristic n (%) gender male 246 (45.5) female 295 (54.5) age in years <17 53 (10) 17–18 407 (75) >18 40 (15) grade 11th grade 314 (58) 12th grade 226 (42) family history of diabetes yes 333 (62) no 208 (38) educational level of father illiterate 123 (23) can read & write 97 (18) primary 72 (13) preparatory 113 (21) secondary 86 (16) advanced 48 (9) educational level of mother illiterate 212 (39) can read & write 111 (21) primary (grades 1–6) 70 (13) preparatory (grades 7–9) 76 (14) secondary (grades 10–12) 52 (10) advanced 20 (4) badriya al-mahrooqi, rahma al-hadhrami, amal al-amri, saif al-tamimi, asma al-shidhani, hadia al-lawati, aida al-ismaili, khawla al-hooti and thamra al-ghafri clinical and basic research | 395 dependent and independent variables. results a total of 541 students participated in the study: 295 (54.5%) from girls’ secondary schools and 246 (45.5%) from boys’ secondary schools. table 1 shows the demographic characteristics of the participants. it can be observed that 75% of the students were between 17 and 18 years. the majority of the students (58%) were from grade 11 and 42% of the students were from grade 12. a positive family history of diabetes was reported by 62% of the students. low levels of family education were noted as 41% of fathers and 60% of mothers were either illiterate or could only read and write. although 82% of the students admitted that they knew little about diabetes, 24% of them achieved a score of more than 10 out of 20. in general, 90% of the students reported that they had received information about diabetes. mass media and the school were the commonest sources of information (48% each), followed by healthcare staff (41%) and then the public (25%). on further questioning the students about their preferred source of information, 61% of the students preferred healthcare staff, followed by the media (56%), school (30%) and the public (12%). awareness about the increase of t2dm cases in oman was observed in 72% of the students. more than half of the students (52%) were able to define diabetes mellitus correctly. in terms of risk factors, 291 of the students (54%) knew at least two or three risk factors leading to diabetes (e.g. obesity, decreased physical activity, a family history of diabetes and mental stress). frequent urination, hunger and thirst were reported by 82% of students as classic symptoms of diabetes. however, only 45% of the students were aware of normal fasting blood sugar levels and only 24% of them knew about normal random blood sugar levels. in terms of diabetic complications, 351 of the students (65%) were aware that diabetes can cause complications. however, 47% of the students could not identify any of those complications. in general, knowledge about managing diabetes was high as 86% of the students knew that diabetics need a special diet, exercise and medications to manage their condition, and 322 (60%) of them reported that exercise can help to control blood sugar levels and that it can lower blood pressure and cholesterol levels. however, only 27% of the students knew that the diabetic meal plan must be individualised to meet the patient's needs. weight reduction was recognised by 64% of the students as part of diabetes management. encouragingly, 375 (70%) of the students agreed that diabetes is a disease which can be prevented. but unfortunately, most of the students (63%) believed that diabetes can be cured. in general, female students and students in grade 11 scored highest with p values of 0.000 and 0.008, respectively. in addition, the percentage of female students with a family history of diabetes was higher than for males (p 0.04). the analysis showed that the subjects’ family history and their parent’s education did not contribute to score levels but did directly affect their knowledge in certain table 2: association between family history and parent’s educational level and knowledge of diabetes by p value demographic factor definition symptoms random blood sugar management of t2dm by exercise possibility of cure prevention t2dm meal family history of dm 0.025 -------------------0.001 ---------------------0.005 father’s education 0.001 ---------0.008 ------------0.017 -------------------mother’s education 0.001 0.015 ---------------------0.023 0.013 -------figure 1: score quartiles distribution among students self-reported knowledge of diabetes among high school students in al-amerat and quriyat, muscat governate, oman 396 | squ medical journal, august 2013, volume 13, issue 3 areas. table 2 shows that students with a family history of diabetes were more knowledgeable about the definition of t2dm, the effect of exercise on diabetes management and the composition of a diabetic meal. on the other hand, having a father with higher education contributed to improving students’ knowledge of normal random blood sugar, the awareness that there is no cure for diabetes, and also to their definition of diabetes. students who had received information about t2dm from the media and their school achieved higher scores compared to other students who received information on diabetes from other sources (p values 0.04 and 0.00, respectively) [table 3]. discussion knowledge about a disease plays a vital role in its future development, early prevention and detection. research has shown that community education about diabetes resulted in a significant increase in knowledge about the disease.1 this study was done to assess the level of diabetes knowledge in a population of omani high school students. a family history of diabetes was reported by 62% of the students, which reflects the real t2dm situation in oman since the last national health survey in 2000 showed that diabetes prevalence had reached 11.6%.5,9 a similar percentage was found by al kawas et al. in the united arab emirates (uae), a neighbouring arabian gulf country.10 the current study revealed relatively low educational levels among parents as almost 75% of fathers and 87% of mothers had below secondary level education. this can be attributed to many factors such as the presence of different races (such as people of east african or pakistani origin), cultural factors and geographical reasons. for example, many people do not send their daughters to school because it is considered shameful for the family for girls to go outside the home. these findings are consistent with another study done in oman in 2006, where educational levels in 63% of the urban and 78% of the rural populations in the study population were below secondary level.11 many previous studies have confirmed the relation between personal education and the increase in knowledge of diabetes mellitus.5,12‒15 since all the subjects in this study had the same level of education, the relationship between paternal educational levels and the knowledge of diabetes was tested as shown in table 2. more students who gave a correct definition of t2dm, had parents with a higher level of education. also, the father’s education level had a direct impact on the knowledge of random blood sugar compared to the mother’s education level which increased the knowledge of symptoms. although parental education levels correlated with increased knowledge about the definition and symptoms of diabetes and random blood sugar, the relationship was not significant in regard to questions about prevention and cure of the disease. in addition to parental education, a family history of diabetes has been found to influence the students’ level of knowledge and perception of diabetes.5,16 this relation was found to influence the level of knowledge in this study about the definition and management of diabetes by exercise and diet. in general, female students in this study had higher scores (p 0.000) compared to males. this may be explained by the high number of females who had received information about diabetes compared to males (p 0.01). furthermore, more female students reported having a family history of diabetes (65%) compared to males (57%). a similar effect of gender was observed in a study done in the uae.10 in this study, 82% of the participants reported that they knew about the condition called diabetes. this is consistent with a study done in both urban and rural areas of chennai, india.7 however, the overall knowledge about diabetes was suboptimal, as only 24% of the students achieved scores of more than 10 out of 20. the study in 2008 by al-shafaee et al. among a semi-urban omani population had similar findings.5 almost half of the students (52%) in the current study were able to define diabetes correctly. this is similar to the findings in the al-shafaee study. a total of 82% of the students table 3: association between score quartiles and other factors factors p value gender <0.001 grade 0.008 reported knowledge about diabetes <0.001 source of information media 0.04 source of information school <0.001 badriya al-mahrooqi, rahma al-hadhrami, amal al-amri, saif al-tamimi, asma al-shidhani, hadia al-lawati, aida al-ismaili, khawla al-hooti and thamra al-ghafri clinical and basic research | 397 in this study recognised the symptoms of diabetes correctly. this can be attributed to a strong family history of the disease among these students.12 in term of risk factors, the results were promising since 99% of students in the current study could identify at least one risk factor of diabetes compared to findings of other studies.1,5,7,17 the complications of diabetes were a major defect in the students’ knowledge as shown in many studies.1,5,7,12 this study's findings supported this since 47% of the students could not identify any of the complications of diabetes—although about 65% of the students were aware that diabetes can cause complications. this discrepancy between the knowledge about risk factors and complications could be due to the type of questions asked since the question about risk factors was multiple choice while the question about complications was open-ended. the majority of the students (70%) in the current study agreed that diabetes was a disease which could be prevented. the high levels of knowledge about risk factors and the possibility of preventing diabetes should help to change the behaviour of these students in future and contribute to preventing diabetes. unfortunately, most of the students (63%) believed that diabetes could be cured. this misconception was also found among a saudi population studied by mohieldein et al.12 the perception of the possibility of a cure for diabetes will lead to poor diabetes control since the patients may decide to stop their medications whenever their diabetes is well-controlled leading to more complications. the media and school were the main source of information on diabetes according to students (48% each) compared to the healthcare staff (41%). however, the preferred source of information was healthcare staff (61%). this corresponds to a study done in the usa where physicians were the preferred source of information for 60% of the study population.18 primary health care (phc) is the first level of professional medical contact in the community and forms the cornerstone of the strategy to attain good levels of health.12 therefore, more efforts should be undertaken by healthcare staff in order to increase the awareness of this young generation about diabetes. intervention could be done through a variety of programmes including theory-based methods like peer education, lectures and educational competitions, and practical methods like workshops, open days and physical education classes. there are several limitations to this study which should be considered if this study were to be repeated elsewhere. although this study population represented part of the omani population, the results cannot be generalised due to the effect of different demographic factors on knowledge levels. the questionnaire was only verbally translated into arabic which may have caused bias due to differences in the way the interviewers translated the questions during the interviews. the study only investigated knowledge of diabetes and did not cover the attitudes and behaviours of the participants that might reflect their awareness of diabetes prevention. conclusion this study found that the knowledge of diabetes among this population of omani high school students was suboptimal. although they showed good knowledge about the symptoms and risk factors, their knowledge about diabetes complications was low. there was also the dangerous misconception among the students that diabetes could be cured. therefore, it is highly recommended to strengthen health education on t2dm through the various school health programmes. healthcare staff should also make more effort to increase the awareness among this young generation about diabetes in order to modify their attitudes and behaviour and thus help prevent diabetes. the interventions should start from the first grades of school in order to be most effective. this can be achieved by collaboration between the ministry of health and the ministry of education. references 1. unadike bc, chineye s. knowledge, awareness, and impact of diabetes among adolescents in uyo, nigeria. african j diabetes med 2009; 12‒14. 2. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954‒7. 3. angeles-llerenas a, carbajal-sánchez n, allen b, zamora-muñoz s, lazcano-ponce e. gender, body mass index and socio-demographic variables associated with knowledge about type 2 diabetes mellitus among 13,293 mexican students. acta self-reported knowledge of diabetes among high school students in al-amerat and quriyat, muscat governate, oman 398 | squ medical journal, august 2013, volume 13, issue 3 diabetol 2005; 42:36‒45. 4. mahajerin a, fras a, vanhecke te, ledesma j. assessment of knowledge, awareness, and selfreported risk factors for type-ii diabetes among adolescents. j adolesc health 2008; 43:188–90. 5. al-shafaee m, al-shukaili s, rizvi s, alfarsi y, khan m, ganguly s, et al. knowledge and perceptions of diabetes in a semi-urban omani population. bmc public health 2008; 8:249. 6. divacaran b, muttapillymiyalil j, sreedharan j, shalini k. lifestyle risk factors of noncommunicable diseases: awareness amon school children. indian j cancer 2010; 47:9‒12. 7. mohan d, raj d, shanthirani cs, datta m, unwin nc, kapur a , mohan v. awareness and knowledge of diabetes in chennai the chennai urban rural epidemiology study. j assoc physicians india 2005; 53:283‒6. 8. colagiuri r. a guide to national diabetes programs. the university of sydney, australia. international diabetes federation, 2010. 9. ministry of health oman. diabetes mellitus management guidelines for primary health care. 2nd ed. muscat: ministry of health, 2003. 10. al-kawas s, abu ghazzi h, suliman n. knowledge and oral health awareness about diabetes among college population in united arab emirates: a pilot study. world j med sci 2011; 6:1‒5. 11. al-mosa s, allin s, jemiai n, al-lawati j, mossialos e. diabetes and urbanization in the omani population: an analysis of national survey data. popul health metr 2006; 4:5. 12. mohieldein a, alzohairy m, hasan m. awareness of diabetes mellitus among saudi non diabetic population in al qassim region, saudi arabia. j diabetes endocrinol 2011; 2:14‒19. 13. caliskan d, ozdemir o, ocaktan e, idil a. evaluation of awareness of diabetes mellitus and associated factors in four health center areas. patient educ couns 2006; 62:142‒7. 14. kamel m, badawy ya, el-zeiny na, merdan ia. socio-demographic determinants of management behavior of diabetic patients part ii. diabetics' knowledge of the disease and their management behavior. eastern mediterr health j 1999; 5:974‒83. 15. powell ck, hill eg, clancy de. the relationship between health literacy and diabetes knowledge and readiness to take health action. diabetes educ 2007; 33:144‒51. 16. walter fm, emery j, braithwaite d, marteau tm. lay understanding of familial risk of common chronic diseases: a systemic review and synthesis of qualitative research. ann fam med 2004; 2:583‒94. 17. cullen k, buzek b. knowledge about type 2 diabetes risk and prevention of african-american and hispanic adults and adolescents with family history of type 2 diabetes. diabetes educa 2009; 35:836‒42. 18. bradford w, david e, gray l, robert t, neeraj k, barbra k, viswanath k. trust and sources of health information, the impact of the internet and its implications for health care providers: findings from the first health information national trends survey. arch intern med 2005; 165:2618‒24. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 156-161, epub. 27th feb 13 submitted 4th mar 12 revision req. 4th jun 12, revision recd. 4th sep 12 accepted 22nd sep 12 reflex epilepsies, which include eating epilepsy (ee), constitute 2–6% of all epilepsy cases, and are unusual in that seizures are triggered predominantly in response to certain forms of sensory stimuli.1 ee is rare and has not been reported in the gulf region. in ee, the ictal semiology mostly consists of simple or complex partial seizures with or without secondary generalisation. while most cases are idiopathic or sporadic, focal structural changes involving the temporal lobe or perisylvian region and, possibly, a genetic predisposition have been reported.2 therapeutic options for medically refractory ee are not well-established. in this case series, we report five ee patients, including a patient with medically refractory ee who was successfully treated by temporal lobectomy. case reports all 5 patients were examined between 2008 and 2011. the ee diagnosis was clinical and based on patient history and witnesses. case 1 a 20-year-old man presented having experienced 10 years of seizures, often beginning during the midday meal, and occurring 2–5 times per month. a few minutes after starting the meal, he would experience palpitation and nausea, followed by a loss of awareness; on some occasions, he had generalised 2–4 minute-long tonic-clonic seizures. his birth, developmental history, and scholastic performance were normal, and no change in mood/ department of medicine, 1college of medicine & health sciences, sultan qaboos university and 2sultan qaboos university hospital, muscat, oman *corresponding author e-mail: jacobcuc@gmail.com النوبات الصرعية الناجتة عن األكل يف عمان سلسله حاالت ومدى فعالية التدخل اجلراحي يف الفص الصدغي اروندايا ر. جوجار، جاكوب ب. �ض. ، نان�صاجوبال رامل �صانديران، عبداهلل العا�صمي. العربي. اخلليج منطقة يف عنها الإبالغ �صابقا يتم ومل ال�رسع من النادرة الأنواع من الأكل ب�صبب املثارة ال�رسعية النوبات امللخ�ص: النوبات ال�رسعية يف هذه النوعية قد تكون جزئية اأوعامة. التغريات يف الت�صوير الدماغي اإذا وجدت تكون مقت�رسه يف كثري من الأحيان يف الف�ض ال�صدغي اأوحولها. اخليارات العالجية اخلا�صة يف هذه احلالت وخا�صة يف املر�صى الذين ل ي�صتجيبون للعالج الدوائي غري متفق عليها ي�صكل عام. نحن نقدم �صل�صلة من احلالت امل�صابة بهذا املر�ض يف عمان الدولة املوجودة يف اجلزء ال�رسقي من منطقة اخلليج التدخل الدوائي. العالج ف�صل بعد ال�صدغي الف�ض با�صتئ�صال اجلراحي التدخل من ا�صتفادوا الذين املر�صى على ال�صوء ون�صلط العربي، اجلراحي يعتربمن اخليارات املهمه لعالج مر�صى ال�رسع وخا�صة الذين ل ي�صتجيبون بالعالج الدوائي. مفتاح الكلمات: نوبات ال�رسع املثارة بالأكل، ال�رسع املنعك�ض، ا�صتئ�صال الف�ض ال�صدغي، تقرير حالة، عمان abstract: eating epilepsy (ee), where seizures are triggered by eating, is rare and has not been reported in the gulf region. in ee, the ictal semiology includes partial or generalised seizures. focal brain changes on imaging, if present, are often confined to the temporal lobe or perisylvian region. therapeutic options, especially in those patients who are refractory to pharmacotherapy, have not been well-established. we report a series of five patients with ee from oman, a country located in the eastern part of the arabian gulf region, and highlight the usefulness of temporal lobectomy in one patient who had medically-intractable ee. surgical intervention could be considered as a potential therapeutic option in carefully selected patients with medically-intractable seizures. keywords: eating induced epilepsy; reflex epilepsy; temporal lobectomy; case report; oman. eating epilepsy in oman a case series and report on the efficacy of temporal lobectomy arunodaya r. gujjar,1 *jacob p. c.,1 nandhagopal ramanchandiran,2 abdullah al-asmi2 case report arunodaya r. gujjar, jacob p. c., nandhagopal ramanchandiran and abdullah al-asmi case report | 157 behaviour was reported. a paternal cousin was diagnosed with epilepsy, but his seizures were not triggered by eating. general physical and neurologic examinations were normal. conventional electroencephalograms (eegs) done on 3 occasions were normal. video-eeg monitoring with the inclusion of meals as an activation procedure failed to demonstrate any ictal abnormalities, though mid-temporal spike discharges were noted inter-ictally [figure 1]. an initial computed tomography (ct) scan of the brain was normal. he tried a series of anticonvulsant medications with dose escalation, including carbamazepine, sodium valproate, clonazepam, topiramate, levetiracetam and lamotrigine. his seizures worsened about 6 years after onset to almost daily attacks, sometimes in clusters of 2–3 in a day. a magnetic resonance imaging (mri) scan of the brain was suspicious of a left medial temporal cortical lesion, possibly glioma or hamartoma. with a diagnosis of refractory complex partial seizures with secondary generalisation triggered by eating, he underwent pre-surgical evaluation at another centre followed by a left temporal lobectomy with amygdalohippocampectomy. except for transient upper facial paresis due to injury to a facial nerve branch, which improved, he had no postoperative complications. clobazam was started post-operatively, and seizures and quality of life improved. over a two-year follow-up period, the seizure frequency decreased to 2–3 attacks of complex partial seizures annually. however, these seizures were not consistently precipitated by eating. case 2 a 27-year-old man was admitted for evaluation of epilepsy. he had experienced seizures almost every day for 10 years, with most episodes occurring during or at the end of a midday meal and consisting of jerky movements of the left arm, with occasional stiffness lasting <5 minutes. on several occasions, he fell unconscious, remained motionless for 1–2 minutes, and then woke with a headache. there was no family history of epilepsy. clinical examination was unremarkable. an eeg revealed inter-ictal figure 1: electroencephalogram (eeg) of case 1 with eating epilepsy (temporolimbic type). long-term video eeg showed isolated interictal epileptiform discharges mainly arising from the left mid-temporal region (arrow). figure 2: (a) case 2 with temporolimbic eating epilepsy. the electroencephalogram shows bursts of right frontotemporal epileptiform discharges. (b) magnetic resonance imaging brain scan showing right temporal horn dilatation (block arrow) and left anterior temporal atrophy (long arrow). eating epilepsy in oman a case series and report on the efficacy of temporal lobectomy 158 | squ medical journal, february 2013, volume 13, issue 1 recurrent right fronto-temporal and generalised spikes and sharp waves [figure 2a]. recording during eating, however, was unremarkable. a mri brain scan revealed left medial temporal atrophy and right temporal horn dilatation [figure 2b]. he was treated with three anticonvulsant agents—levetiracetam, carbamazepine and phenobarbitone—with partial response. case 3 a 21-year-old man presented having had two attacks of generalised tonic-clonic seizures over one year. both attacks began in the middle of lunch and lasted 2–3 minutes. clinical examination was unremarkable. no other precipitating factors were evident. a brain ct scan was normal. an eeg showed normal background activity with one prolonged epoch showing fairly rhythmic sharp wave discharges in the right tempo-parietal region. he began carbamazepine and had no recurrence of seizures over 6 months. case 4 a 27-year-old woman presented having had recurrent generalised tonic-clonic seizures over the previous 6 years. they lasted a few minutes, with falls, frothing, and sometimes injuries. the nature of the attacks had, however, changed; she began to experience brief episodes of sudden loss of awareness while eating, particularly during lunch. these attacks included sudden irrelevant speech and inappropriate mixing of food on the plate and lasted for about a minute, during which time she was unresponsive. after each episode, she had spontaneous recovery with a post-ical headache. clinical examination was unremarkable. a possibility of complex partial seizures triggered by eating, with secondary generalisation was considered; her epilepsy, however, had acquired an eating trigger 6 years after onset. she was started on carbamazepine and her dosage of lamotrigine was increased, resulting in fairly good control of her epilepsy. case 5 a 44-year-old man was referred for recurrent episodes of vacant staring lasting a few minutes at a time, followed by confused behaviour. over a followup period of 3 years, he continued to have similar attacks 1–3 times a month. all his attacks occurred several minutes after he began to eat lunch. though he reported several attacks while eating fish, this relation was inconsistent. conventional eeg was normal. a mri brain scan revealed evidence of leftside mesial temporal sclerosis. he was diagnosed with ee with complex partial seizures. with increased doses of carbamazepine, seizures were controlled with only a single attack occurring over 18 months. discussion reflex epilepsies have a special pathogenetic connotation: they imply that there is an abnormal association between cortical areas subserving specific sensations, motor, or cognitive activities, and an area which is epileptogenic. a variety of activities such as visual stimuli, bathing, sound, movement, reading, listening to music, and doing arithmetic have been known to trigger epilepsy.3–9 while visual stimuli are considered the most common triggers for epilepsy elsewhere, ee and hot-water epilepsy were reported to be the most common reflex epilepsies in sri lanka and parts of south india.2,8,9,11,13 the earliest reports of ee date back to 1962,10 with most reports coming from south asia.2,11-18 ee is found in one to two epilespy patients per thousand; however, two reports from sri lanka noted the prevalence of ee as 5.3% and 14.8% among patients with epilepsy.2,11,14 senanayake et al. reported 150 patients with ee detected over a 9-year period in sri lanka.11 in this series, most patients were men (3:1); onset was in the second decade of life; 28.3% had a positive family history; seizure type was simple or complex partial, and secondarily generalised seizures were also common. eegs were abnormal in 71.6% of cases and showed spikes, sharp/slow waves, and focal background changes in the temporal areas. the response to medication in ee was similar to that of non-reflex epilepsies. clobazam as a monotherapy or adjuvant therapy was found to be useful. case series from india and europe also reported similar seizure semiology, eegs, imaging, and response to treatment.11–18 our ee patients shared most of the features described in arunodaya r. gujjar, jacob p. c., nandhagopal ramanchandiran and abdullah al-asmi case report | 159 the literature with most having onset in the late first or early second decade. three had complex partial seizures with or without generalisation, while one each had partial motor and primary generalised seizures. three of our patients also had additional unprovoked seizures, which were consistent with the findings that unprovoked seizures do occur in ee. eegs were abnormal in three of our patients, though none of the three who underwent an eeg study while eating had seizures. as reported earlier, ee may not occur with every meal; hence, triggering it during an eeg study may not always be successful. three of our patients had structural changes in the brain which were limited to the temporal lobes, including a hamartoma, mesial temporal sclerosis, and temporal lobe atrophy. unlike the reports from sri lanka, where anticonvulsant responses were good, three of our four patients had resistant epilepsy with poor response to multiple anticonvulsants. none of our patients had evidence of neuro-metabolic disorders which could explain the seizures. the exact pathogenesis of ee is unknown. zefkin et al. proposed a pathogenetic mechanism for ee similar to certain other reflex epilepsies.14 in patients with pattern-sensitive epilepsy, generalised seizures occur when excitation involves a critical mass of the visual cortex, with synchronisation and later spread of excitation from the occipital lobe trigger.19 similar phenomena are described in thinking and reading epilepsies. taste sensation is represented within or near the primary somesthetic area of the tongue in the opercular part of the postcentral gyrus. adjacent areas are also responsive to touch and proprioception from the tongue and mouth, as well as anticipation of taste and smell. the nearby secondary sensory area in the parietal lobe located in the upper bank of the sylvian fissure contains bilateral representations of the face, mouth, and throat. zifkin et al. proposed that a build-up of excitation in and around the primary and secondary sensory areas for taste as well as orofacial sensation on reaching a critical extent manifests clinically either as a simple partial or complex partial seizure, depending on whether primary motor/sensory or temporo-frontal cortices are involved. early generalisation may possibly manifest clinically as a primary generalised seizure.14 sri lankan studies also suggested a possible genetic influence by virtue of higher familial incidence and overall restriction to south asian populations.2,12,19 a possible animal model of ee has been developed recently and could assist in elucidating its pathogenesis further.21 remillard et al. described two different ee syndromes.22 those with temporolimbic onset have seizures precipitated by eating from the onset of epilepsy. seizures may occur during any phase of a meal, with few spontaneous seizures co-existing. proposed likely triggers are gustatory, olfactory, autonomic, or emotional-sensory. in contrast, those with extralimbic/suprasylvian onset often have obvious extra-temporal structural lesions with clinical deficits and a long course of epilepsy where seizures later acquire onset in relation to eating. seizures often occur at the beginning of a meal possibly through proprioceptive sensory input from oral, peri-oral, or masticatory structures.14,22 both varieties of ee may involve recruitment of a critical mass of the cortex by their respective combinations of sensory input in seizure generation. in light of this description, 4 of our cases had features consistent with temporolimbic onset. case 4, who had long-standing epilepsy, with a recent acquisition of an eating trigger, appeared to have extralimbic onset; however, the patient had no evidence of structural brain lesions. reflex epilepsy may be refractory to treatment, but options for treatment have not been systematically explored, likely due to the relative infrequency of these cases. though the reports from south asia report good response to anticonvulsant medication, 3 of our 5 patients had resistant epilepsy. modification of stimuli precipitating ee may be beneficial; these may include smaller but more frequent meals, smaller bites, changes in temperature or predominant tastes of foods, or drinking with a straw.22 surgical intervention for ee has been reported very infrequently, with the description by remillard et al. being the most prominent one. several of their 18 ee patients who underwent surgery had good outcomes. the nature of surgery varied from amygdalohippocampectomy to excision of the epileptogenic extra-temporal cortex. intraoperative eeg recordings demonstrated ictal activity in the inferomedial temporal and amygdaloid regions in temporolimbic ee and in frontocentroparietal regions in extralimbic ee. in the recent past, cukiert et al. reported improvement in ee treated with vagal nerve stimulation (vns).23 among 3 patients with intractable ee, seizures eating epilepsy in oman a case series and report on the efficacy of temporal lobectomy 160 | squ medical journal, february 2013, volume 13, issue 1 decreased in frequency by 70–95% and non-reflex seizures by 0–40%; however, no such improvement was observed in hot-water seizures. they suggest vns is useful in patients with ee not amenable to resective surgery. one of our 5 patients who underwent a left amygdalohippocampectomy experienced dramatic improvement in his ee. this report has several implications. an attempt to elicit a triggering factor, including eating, should be made in the evaluation of all patients with epilepsy but such stimuli may not always trigger a seizure; hence, a diagnosis of ee should be considered even in the absence of such evidence. a diligent history is the most important factor in its diagnosis. as in other reflex epilepsies, modification of the triggering factors to reduce seizures should be considered in most patients. while most patients with epilepsy have limitations imposed on certain activities, some patients with ee, where all attacks are limited to the act of eating, may not require such limitations. precautions, however, should be emphasised while eating until seizures are well-controlled (e.g. preventing falls and injuries; avoiding sharp cutlery; mandatory supervision by a relative during eating; avoiding foods that consistently trigger seizures). in patients with seizures in the midor latter part of the meal, multiple short eating sessions may prevent recruiting the cricital mass of the cortex necessary to trigger a seizure. in patients with ee refractory to medications, surgical intervention may be considered after appropriate pre-surgical evaluation. conclusion we report 5 omani patients with ee. similar to reports from south asia, oman’s ee occurs in young adults, with complex partial seizures being common, and temporolimbic onset seen more frequently. however, 3 of our patients had medically-intractable seizures. of interest is the dramatic improvement of refractory seizures following temporal lobectomy in one patient. a search for reflex triggers should be made and surgical intervention could be considered a potential therapeutic option in those with ee in appropriate circumstances. a c k n o w l e d g e m e n t s the authors thank mr. rajesh for assistance with the eeg, and the patients and their families for their cooperation. references 1. engel j jr. international league against epilepsy commission report. a proposed diagnostic scheme for people with epileptic seizures and epilepsy. report of the ilae task force on classification and terminology. epilepsia 2001; 42:796–803. 2. seneviratne u, seetha t, pathirana r, padmamali r. high prevalence of eating epilepsy in sri lanka. seizure 2003; 12:604–5. 3. bickford rg, whelan jl, klass dw, corbin kb. reading epilepsy: clinical and electroencephalographic studies of a new syndrome. trans am neurol assoc 1956; 81:100–2. 4. ingvar dm, nyman ge. epilepsia arithmetices: a new psychologic trigger mechanism in a case of epilepsy. neurology 1962; 12:282–7. 5. wilkins aj, zifkin b, andermann f, mcgovern e. seizures induced by thinking. ann neurol 1982; 11:608–12. 6. senanayake n. epileptic seizures evoked by card games, draughts, and similar games. epilepsia 1987; 28:356–61. 7. senanayake n. epileptic seizures evoked by the rubik’s cube. j neurol neurosurg psychiatry 1987; 50:1553–4. 8. satishchandra p, shivaramakrishna a, kaliaperumal vg, schoenberg bs. hotwater epilepsy: a variant of reflex epilepsy in southern india. epilepsia 1988; 29:52–6. 9. ratnapriya r, satishchandra p, kumar sd, gadre g, reddy r, anand a. a locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3. hum genet 2011;129:545–9. 10. vizioli r. the problem of human reflex epilepsy and the possible role of masked epileptogenic factors. epilepsia 1962; 3:293–302. 11. senanayake n. reflex epilepsies: experience in sri lanka. cylone med j 1994; 39:67–74. 12. senanayake n. ‘eating epilepsy’—a reappraisal. epilepsy research 1990; 5:74–9. 13. devi tkm, iyer gv. pattern of triggering factors among patients with epilepsy from kerala. j assoc physicians india 1985; 33:513–15. 14. zefkin bg, anderman f, remillard gm. epilepsy with seizures induced by eating. in: wolf p, ed. epileptic seizures and syndromes. london: john libbey and co. ltd. 1994. pp. 99–105. 15. nagaraja d, chand rp. eating epilepsy. clinical neurol neurosurg 1984; 86:95–9. 16. koul r, koul s, razdan s. eating epilepsy. acta arunodaya r. gujjar, jacob p. c., nandhagopal ramanchandiran and abdullah al-asmi case report | 161 neurol scand 1989; 80:78–80. 17. ahuja gt, mohandas s, narayanaswamy as. eating epilepsy. epilepsia 1980; 21:85–9. 18. ahuja gk, pauranik a, behari m, prasad k. eating epilepsy. j neurol 1988; 235:444–7. 19. binnie cd, findlay j, wilkins aj. mechanisms of epileptogenesis in photosensitive epilepsy implied by the effects of moving patterns. electroencephalography clin neurophysiol 1985; 61:1–6. 20. senanayake n. familial eating epilepsy. j neurol 1990; 237:388–91. 21. enginar n, nurten a. seizures triggered by food intake in antimuscarinic-treated fasted animals: evaluation of the experimental findings in terms of similarities to eating-triggered epilepsy. epilepsia 2010; 51:80–4. 22. remillard gm, zifkin bg, andermann f. seizures induced by eating. in: zifkin bg, andermann f, beaumanoir a, rowan aj, eds. reflex epilepsies and reflex seizures. advances in neurology, vol. 75. philadelphia: lippincott-raven press. 1998. pp. 227– 40. 23. cukiert a, mariani pp, burattini ja, cukiert cm, forster c, baise c, et al. vagus nerve stimulation might have a unique effect in reflex eating seizures. epilepsia 2010; 51:301–3. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 57-62, epub. 27th feb 13 submitted 4th may 12 revisions req. 9th aug & 10th oct 12, revisions recd. 12th sep & 29th oct 12 accepted 22nd dec 12 department of obstetrics & gynecology, nizwa hospital, nizwa, oman *corresponding author e-mail: drkaukab2010@gmail.com َمَوُه السََّلى كمتنبئ لتعسر نتائج احلمل كوكب تا�صفيني واإلهام مو�صى حمدي املتعلقة باملخاطر املرتبطة العوامل حتليل املفرد، احلمل يف املتكررة َلى ال�صَّ َمَوُه من التحقق اإىل الدرا�صة هذه تهدف الهدف: امللخ�ص: باحلمل وتقييم النتائج المومية والولدية امل�صادة . الطريقة: مت القيام بدرا�صة اإ�صتعادية ملجموعة احلالت املوؤديه اىل تعقيدات داء موه ال�صلى فى كل حالت احلمل املفرد بعد الأ�صبوع 28 من احلمل. مت اإجراء هذه الدرا�صة يف ق�صم الن�صاء والولدة مب�صت�صفى نزوى، عمان من يناير 2002 اإىل دي�صمرب 2007. من عدد 25,979 حالة حمل مت ا�صتعرا�صها، وجد اأن 477 تعاين من داء موه ال�صلى. جمموعة التحكم تكونت من 900 امراأة حامل. حالت داء موه ال�صلى مت ت�صخي�صها على اأنها خفيفة، معتدلة اأو �صديدة م�صتندة على موؤ�رس الكمية الق�صوى من ال�صائل ال�صلوي. متت املقارنة بني احلالت امل�صابة وجمموعة التحكم طبقا للبيانات ال�صكانية، داء ال�صكر، داء عملقة اجلنني، الولدة القي�رسية، تكرار الأجنة ال�صاذة و معدل وفيات الأجنة. النتائج: مت ت�صخي�ض داء موه ال�صلى يف %1.8 من معدل الن�صاء احلوامل . وكانت خفيفة يف 382 حالة)%80(، معتدلة يف 84 حالة )%17.6( و�صديدة يف 12 حالة )%2.4(. 72)%15.3( حالة من اإجمايل حالت وجود مع التحكم، جمموعة يف 10% ب مقارنة امل�صخ�ض( ال�صكري اأو )احلملي ال�صكري بداء بالإ�صابة معقدة كانت ال�صلى موه داء 39)%8.1( وليد م�صاب بت�صوهات خلقية. داء موه ال�صلى كان مرتبط بتقدم عمر الأم ، وكان عمر 58)%12.2( من احلالت اأكرب من 40 �صنة. معدل وفيات املواليد يف احلوامل امل�صابات بداء موه ال�صلى كانت 42 حالة لكل 1000 مولود مقارنة ب 14 حالة لكل 1000 للحمل، العك�صية النتائج خماطر وزيادة ال�صلى موه داء بني ارتباط وجود اإىل ت�صري البيانات هذه التحكم. اخلال�صة: جمموعة يف مولود وكذلك وجود عالقة اإيجابية فيما يتعلق بعمر الأم، الإ�صابة بداء ال�صكري، ت�صوهات اجلنني وداء عملقة اجلنني. مفتاح الكلمات: موؤ�رس ال�صائل ال�صلوي، الولدة القي�رسية، عملقة اجلنني، النتيجة الولدية، عمان. abstract: objectives: this study aimed to ascertain the frequency of polyhydramnios in singleton pregnancies, to determine the associated risk factors, and assess the adverse maternal and perinatal outcomes. methods: a retrospective cohort study of all singleton pregnancies complicated with polyhydramnios after 28 weeks of gestation was carried out in nizwa hospital’s obstetrics & gynecology department, oman, from january 2002 to december 2007. of 25,979 pregnant women reviewed, 477 were found to have polyhydramnios. the control group consisted of 900 pregnant women. cases of polyhydramnios were diagnosed as mild, moderate, or severe based on their highest amniotic fluid index. cases were compared with controls in terms of demographic data; prevalence of diabetes, macrosomia, or caesarean deliveries; frequency of fetal anomalies, and perinatal mortality rate. results: polyhydramnios was diagnosed in 1.8% of pregnancies. it was mild in 382 (80%), moderate in 84 (17.6%), and severe in 12 (2.4%). a total of 72 (15.3 %) cases of polyhydramnios were complicated by diabetes (gestational or established diabetes mellitus) as compared to 10% of the control group and 39 (8.1%) neonates had congenital anomalies. polyhydramnios was associated with advanced maternal age; 58 (12.2%) of subjects were over 40 years old. the perinatal mortality rate with polyhydramnios was 42 per 1,000 births compared to 14 per 1000 births in the control group. conclusion: these data demonstrate that polyhydramnios is associated with an increased risk of adverse perinatal outcomes, and there is a significant positive relation with maternal age, diabetes, fetal anomalies, and fetal macrosomia. keywords: amniotic fluid index; caesarean delivery; macrosomia; perinatal outcome; oman. polyhydramnios as a predictor of adverse pregnancy outcomes *kaukab tashfeen and ilham moosa hamdi clinical & basic research advances in knowledge polyhydramnios occurs in 1–3.5% of pregnancies and is severe in 2.4% of these. the principal factors associated with polyhydramnios includes fetal malformation, maternal diabetes mellitus, and multiple gestations. the majority of cases of polyhydramnios are idiopathic. polyhydramnios as a predictor of adverse pregnancy outcomes 58 | squ medical journal, february 2013, volume 13, issue 1 polyhydramnios refers to an excessive accumulation of amniotic fluid, which is associated with an increased risk of adverse pregnancy outcomes.1 polyhydramnios is diagnosed when a mother’s amniotic fluid index elevates to >24 ± 2 cm standard deviation (sd) in the late second or third trimester.2 it complicates 0.4–1.9% of all pregnancies.3 the aetiology of polyhydramnios is diverse and involves many maternal and fetal conditions including diabetes, congenital anomalies, multiple gestation, and isoimmunisation. if none of these causes can be identified, then a diagnosis of idiopathic polyhydramnios is made. magann reported the incidence of idiopathic polyhydramnios among subjects with polyhydramnios as 50–60%.4 however, it consistently has been documented that perinatal morbidity and mortality rates increased in association with polyhydramnios related to specific causes.5,6 a pregnancy complicated by polyhydramnios can present difficult diagnostic and therapeutic dilemmas for obstetricians. many clinicians have viewed polyhydramnios as a prognostic factor of increased risk of pregnancy complications and have recommended an extensive evaluation of these pregnancies, including multiple comprehensive ultrasound examinations, repeat diabetes screening, and amniocentesis for fetal karyotyping. however, counselling of a couple regarding idiopathic polyhydramnios often creates significant anxiety and fosters the impression of an abnormal pregnancy.7 the rationale of our study was to determine the association between polyhydramnios and adverse obstetric and perinatal outcomes in singleton, third-trimester pregnancies. methods this was a retrospective cohort study of 25,979 women with singleton pregnancies who delivered at nizwa hospital between january 2002 and december 2007. permission was first gained from the research and ethics committee of nizwa hospital, which is a secondary care hospital serving as a regional referral center for the al-dakhliya central region in oman. the study group was composed of 477 women with polyhydramnios, while 900 women with normal amniotic fluid levels formed the control group, which was selected randomly. included in the study were women at 28 or more weeks’ gestation with confirmed polyhydramnios in singleton pregnancies who had been diagnosed by ultrasound examination. pregnancies of less than 28 weeks’ gestation and multiple pregnancies were excluded. polyhydramnios was categorised as mild, moderate, or severe based on an amniotic fluid index of 25–30 cm, 30.1–35 cm, or 35.1 cm or more, respectively.8 pregnancies were evaluated using abdominal ultrasound examinations as a part of routine fetal surveillance in the third trimester of pregnancies by realtime ultrasound equipment with a 3.5 mhz curve linear array transducer (koninklijke philips electronics, eindhoven, netherlands). the frequency of the following were also measured during the study: congenital anomalies, macrosomia (defined as a birthweight of ≥ 4000 grams), preterm deliveries (defined as birth occurring from 24 + 0 weeks to less than 36 + 6 weeks of gestation), caesarean delivery rates, and perinatal mortality (defined as all stillbirths and deaths in the first week after birth).9,10 when polyhydramnios was diagnosed, an ultrasound examination was done to detect possible structural anomalies. a 75 gram 2 hour oral glucose tolerance test was carried out in all women without pre-existing diabetes mellitus. diagnosis of gestational diabetes was confirmed according to oman’s national and who guidelines (a fasting cut off value of >5.8 m mol/l or above, 2 hour value >7.8 m mol/l or above). cases and controls were compared for maternal characteristics application to patient care the obstetrician needs to consider a thorough evaluation of the fetus for congenital anomalies when mothers suffer from polyhydramnios during pregnancy. close attention should be paid during the antepartum, intrapartum and postpartum periods to anticipate complications of polyhydramnios. *kaukab tashfeen and ilham moosa hamdi clinical and basic research | 59 table 1: demographic data of study subjects characteristics polyhydramnios (n = 477) control (n = 900) p value n % n % nulliparous 90 18.9 130 14.5 0.31 multiparous 287 60.2 560 62.2 0.15 grand multiparous 100 20.9 210 23.3 0.26 mean maternal age (years) 30.1 ± 5.1 ns 28.2 ± 4.3 ns ns maternal age >40 years 58 12.2 34 3.7 <0.001 diabetes mellitus 73 15.3 89 9.8 <0.001 ns = non-significant grand multiparity = >6 parity; multiparous = 2–6 parity; nulliparous = 0 parity. table 2: outcome measures for study subjects outcome measure polyhydramnios (n = 477) control (n = 900) p value n % n % preterm delivery(<37 weeks) 20 4.1 60 6.6 0.62 macrosomia (>4000 g) 90 18.8 50 5.5 <0.003 caesarean delivery 115 24.0 96 10.6 <0.001 congenital anomalies 39 8.2 39 4.3 <0.001 perinatal mortality rate 42/1000 14/1000 <0.001 and risk factors known to be associated with polyhydramnios, including diabetes, macrosomia, and congenital anomalies. caesarean delivery rates and perinatal outcomes in the study group were compared with those of the control group. neonatal information was obtained using the computerised obstetric database, which contains pregnancy outcomes for all women who have delivered at our hospital. evaluation for major congenital anomalies was routinely carried out in the immediate neonatal period by attending pediatricians. karyotype analysis was performed at the pediatricians’ discretion. no women had genetic amniocentesis during the antenatal period as we do ot have the facilities for such testing. the control group included singleton pregnancies at ≥28 weeks of gestation who were evaluated during the study period and exhibited normal amniotic fluid levels upon ultrasound. the statistical package for the social sciences (spss), version 10 (ibm, inc., chicago, illinois, usa) was used for statistical analysis. the rate of each specific outcome measure was calculated for patient and control subjects and rates were compared with pearson’s chi-square test. statistical significance was defined as p <0.05. results of the 25,979 singleton pregnancies seen at the hospital during the study period, 477 (1.8%) were diagnosed with polyhydramnios by ultrasound scan. of those diagnosed, the severity was classified as mild, moderate, and severe in 80.1%, 17.6%, and 2.4% of cases, respectively. from our data, we were able to determine three prominent aetiological classifications of polyhydramnios: idiopathic polyhydramnios occurring in 76.8% of cases; diabetes mellitus, occurring in 15.3% of cases; and congenital anomalies, found in 8.2% of cases. the demographic data for the control and study groups are displayed in table i. there was a significant rise in polyhydramnios with advanced maternal age (p <0.001). the analysis of parity distribution did not reveal any significant trend with polyhydramnios. the cohorts of women were evaluated for diabetes, maintaining the view that there is an polyhydramnios as a predictor of adverse pregnancy outcomes 60 | squ medical journal, february 2013, volume 13, issue 1 established association between diabetes and polyhydramnios. the prevalence of diabetes in the control group was 9.8%, while in the polyhydramnios group it was 15.3% (p <0.001) [figure 1]. of those patients, 59 were on a medically supervised diet and 12 were on insulin. only two patients had pre-existing diabetes, as shown in figure 1. the difference is statistically significant. there were 115 caesarean sections in the study group, yielding a 24% rate of caesarean delivery versus a 10.6% rate in the control group (p <0.001), as shown in figure 2. eight (1.6%) of those in the study group had instrumental delivery as compared to 2.4% in the control group. most of those were vacuum deliveries. outcome measures are shown in table 2. as regards neonatal and fetal outcomes, figure 3 details the major congenital anomalies that were detected in the infants of 39 women with polyhydramnios (8.2%), while in the control group 4.3% displayed anomalies (p <0.001). central nervous system (cns) anomalies included hydrocephaly, anencephaly, holoprosencephaly, and myelomeningocele; these were diagnosed in 12 pregnancies. gastrointestinal anomalies included oesophageal and duodenal atresia, diaphragmatic hernia, and trachea esophageal fistula; they were diagnosed in 10 pregnancies. eight pregnancies had cardiovascular malformations including structural cardiac defect, hydrops, and pulmonary oedema. four fetuses had multi-organ system malformations including those of the central nervous system, and the gastrointestinal and genitourinary systems. inherited disorders of renal functioning are a rare cause of polyhydramnios. in our study, we diagnosed one baby with bartter syndrome whose mother had uncontrolled diabetes mellitus. the infant died after 11 days due to associated complex cardiac disease. in regard to macrosomia, the mean birth weight was 3,800 ± 300 grams in the polyhydramnios group, while in the control group it was 3,000 ± 300 grams. the heaviest newborn was 5,000 grams, born to a 7th gravida at 41 weeks of gestation by emergency caesarean section. the incidence of macrosomia in the polyhydramnios group was 18.8%, while in the control group the incidence was 5.5%. a significant positive relationship was observed between polyhydramnios and birth weight (p <0.003) [table 2]. seventy-six (16.0%) neonates were admitted to the special care baby unit (scbu) in the polyhydramnios group, compared to 11 babies (15.5%) from the control group [figure 4]. nineteen babies of the 76 in the study group had perinatal asphyxia and 3 had severe birth asphyxia. the the latter babies had multiple congenital anomalies and died at the age of 3–4 hours. the other 16 were discharged in good condition. seven cases of shoulder dystocia were seen in the study group, while 11 babies in the control group had shoulder dystocia. the average birth weight of the babies who had shoulder dystocia was 3.8–4.0 kg, but none of them had any neurological problem. eleven babies were admitted with hypoglycaemia, but only for observation. the perinatal mortality rate in the polyhydramnios group was 42 per 1,000 births as compared to 14 per 1,000 births in the control. the increased perinatal mortality rate in the case of polyhydramnios was due to the underlying cause of 0 10 20 30 40 50 60 70 80 90 1 2diabetes mellitus 90 80 70 60 50 40 30 20 10 0 control 73 polyhydramnios 89 figure 1: a comparison of diabetes mellitus between polyhydramnios and control groups. 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 24.0% 10.60% polyhydramnios control figure 2: a comparison of caesarean section rates between control and polyhydramnios groups. *kaukab tashfeen and ilham moosa hamdi clinical and basic research | 61 the polyhydramnios (i.e. congenital anomalies and uncontrolled diabetes). discussion recognition of polyhydramnios is of benefit as it allows identification of pregnancies that may be at increased risk of adverse outcomes. once polyhydramnios is identified, patients need a thorough evaluation as it is associated with an increased frequency of both maternal and fetal complications.11 chamberlain cited an increased rate of perinatal morbidity and mortality among patients with hydramnios.6 in reviewing the adverse outcomes in pregnancies complicated by polyhydramnios, we found the overall incidence of polyhydramnios to be 1.8% in our population. of those who were included in our study group, 80% were considered to have mild polyhydramnios, 17.6% of the cases were considered moderate, and 2.4% were considered severe. this is similar to barnhart’s study, which noted polyhydramnios in 1.7% of 2,730 pregnancies.12 a demographic analysis showed that polyhydramnios was more common in older gravida. however, parity had no significant relationship to polyhydramnios. this was consistent with mariam’s study.12 however, biggo et al. found a significant relationship between both rising maternal age and parity in polyhydramnios.13 the association between diabetes and polyhydramnios is well known.14 a commonly supported theory is that increased amniotic fluid volume in diabetic pregnancies could be a result of maternal hyperglycemia which, in turn, produces fetal hyperglycemia and osmotic diuresis. it has consistently been reported that approximately 15% of pregnancies complicated by polyhydramnios occur in diabetic women.15 this figure was consistent with our study. we found that 73 of our polyhydramnios patients (15.3%) were diabetic, including 59 who were being treated for gestational diabetes or were on a medically supervised diet, twelve had gestational insulin-treated diabetes. only two patients had pre-existing diabetes mellitus. the mean gestational age at delivery was 38.2 ± 1.4 weeks. there was no significant increase in preterm delivery as most preterm deliveries were noticed in case of severe polyhydramnios due to uterine overdistension or fetal anomalies. these comprised only 2.5% of the study group. this result was consistent with many, whose study showed no increased rate of preterm delivery with polyhydramnios.16 the mode of delivery was also influenced by polyhydramnios, with a higher proportion of caesarean deliveries as compared with those mothers who had a normal volume of amniotic fluid. we found a significantly elevated caesarean delivery rate in the polyhydramnios group, which had a 24% rate compared to 10.6% in the control group. in our study, polyhydramnios had an impact on perinatal outcomes, the occurrence of fetal macrosomia and fetal congenital anomalies, and scbu admissions of neonates. the prevalence of anomalies was 8.1%, which was fairly comparable 20.00% 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% control polyhydramnios congenital anomalies macrosomia scbu admissions 4.30% 8.20% 5.50% 18.80% 15.50% 16.00% figure 4: a comparison of neonatal outcomes between the polyhydramnios and control groups. scbu = special care baby unit. 12 10 8 6 4 2 0 re na l a no ma lie s mu ltio rg an m alf or ma tio n fa cia l d efe cts cv s de fec ts ga str oin tes tin al de fec ts cn s figure 3: incidence of congenital anomalies in polyhydramnios. cns = central nervous system; cvs = cardiovascular system. polyhydramnios as a predictor of adverse pregnancy outcomes 62 | squ medical journal, february 2013, volume 13, issue 1 with other large series studies. this confirms reports of greater anomaly risks that occur with worsening polyhydramnios.17 dashe reported in his study of polyhydramnios and anomaly detection that 11.0% of the neonates in his study had fetal anomalies.8 in our study, the high incidence of macrosomia associated with polyhydramnios was consistent with several others studies, and showed a correlation between large-for-gestational-age infants and polyhydramnios.18 conclusion the intention of the study was to compare neonatal and maternal outcomes in a control group with women with polyhydramnios. our findings suggest that once a diagnosis of polyhydramnios is confirmed, a woman should be referred to a perinatal centre with expertise in fetal medicine in order for any anomalies to be detected. this study demonstrates that the likelihood of an adverse perinatal outcome increases in association with polyhydramnios. there is a significant positive relationship between maternal age, diabetes, and fetal anomalies and macrosomia. collectively, data from other studies as well as our own suggests that if polyhydramnios is diagnosed a thorough evaluation for fetal or maternal factors is indicated. at minimum, this should include a comprehensive ultrasound examination and screening for diabetes as it is the most common cause of polyhydramnios. careful maternal and fetal surveillance during the antepartum, intrapartum and postpartum periods is warranted to anticipate complications due to polyhydramnios. references 1. golan a, wolman i, sagi j. persistence of polyhydramnios during pregnancy—its significance and correlation with maternal and fetal complications. gynecol obstet invest 1994; 37:18. 2. carlson de, platt ld, medearis ac, horenstein j. quantifiable polyhydramnios: diagnosis and management. obstet gynecol 1990; 75:898–93. 3. phelan jp, martin gi. polyhydramnios: fetal and neonatal implications. clin perinatol 1989; 16:987– 94. 4. magann ef, chauhan sp, doherty da. a review of idiopathic hydramnios and pregnancy outcomes. obstet gynecol surv 2007; 62:795–802. 5. esplin ms, fausett mb, hunter c, shields d, porter tf, varner m. idiopathic polyhydramnios is associated with increased neonatal morbidity [abstract]. am j obstet gynecol 1998; 178:46s. 6. chamberlain pf, manning fa, morrison i, harman cr, lange i. ultrasound evaluation of amniotic fluid volume to perinatal outcome. am j obstet gynecol 1984; 150:250–4. 7. barnhard y, bar-hava i, divon my. is polyhydramnios in an ultrasonographically normal fetus an indication for genetic evaluation? am j obstet gynecol 1995; 173:1523–7. 8. dashe js, mcintiredd, ramus rm, santos-ramos r, twickler dm. hydramnios: anomaly prevalence and sonographic detection. obstet gynecol 2002; 100:134–9. 9. stotland ne, caughey ab, breed em, escobar gj. risk factors and obstetric complications associated with macrosomia. int j gynaecol obstet 2004; 87:220–6. 10. maternal and child health consortium. 6th annual report: confidential enquiries into stillbirths and deaths in infancy (cesdi). london: maternal and child health consortium, 1999. 11. ott wj. current perspectives in antenatal fetal surveillance. ultrasound rev obst gyn 2003; 3:1– 18. 12. shabnam mm, syed s, rizvi g. polyhydramnios: risk factors and outcome. saudi med j 2008; 29:256– 60. 13. biggo jr jr, wenstrom kd, dubard mb, cliver sp. hydramnios prediction of adverse perinatal outcome. obstet gynecol 1999; 94:773–7. 14. vink jy, poggi sh, ghidini a, spong cy. amniotic fluid index and birth weight: is there a relationship in diabetes with poor glycemic control? am j obstet gynecol 2006; 195:848–50. 15. dashe js, nathan l, mclntire d, leveno k. correlation between amniotic fluid glucose concentration and amniotic fluid volume in pregnancy complicated by diabetes. am j obstet gynecol 2000; 182:901–4. 16. many a, lazebnik n, hill lm. the underlying cause of polyhydramnios determines prematurity. prenat diagn 1996; 16:55–7. 17. chen kc, liou jd, hung th, kuo dm, hsu jj, hsieh cc, et al. perinatal outcomes of polyhydramnios without associated congenital fetal anomalies after the gestational age of 20 weeks. chang gung med j 2005; 28:222–8. 18. lazebnik n, hill lm, guzick d, martin jg, many a. severity of polyhydramnios does not affect the prevalence of large-for-gestational-age newborn infants. j ultrasound med 1996; 15:385–8. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 286-294, epub. 15th jul 12 submitted 5th sep 11 revision req. 4th dec 11, revision recd. 13th mar & 10th may 12 accepted 14th may 12 the word dyslexia is derived from two greek words: dys (inadequate or lack of ) and lexicon (word and/or verbal language).1 dyslexia thus means problems learning how to read words and deal with language in print. historically, dyslexia has been used to describe difficulty in reading as a result of brain damage.2 there are two models used in defining dyslexia: the orthodox model and the davis model.2 the orthodox model describes dyslexia as developed rather than innate, with difficulty in reading as a result of cerebral disease rather than brain injury. the davis model describes dyslexia as difficulty in reading or language processing as a result of intermittent disorientation. this disorientation comes from conflicting messages to the brain, for example, when the eyes are telling the brain one thing but senses of balance and movement are saying something different.2 another way of understanding dyslexia is the dual-route model.3,4,5 this model explains two pathways from print to speech.3 one pathway operates via the use of grapheme-phoneme correspondence rules which are termed the nonlexical route for reading aloud. the other pathway operates via access to a semantic system, the lexical route for reading aloud.3 the non-lexical route successfully allows an individual to read non-words, 1department of sports medicine, mcgill university, montreal, quebec, canada; 2department of family & community medicine, university of toronto, ontario, canada; 3department of family medicine & public health, oman medical specialty board, muscat, oman; 4leslie dan faculty of pharmacy, university of toronto, ontario, canada. *corresponding author e-mail: shidhanitutu@gmail.com فهم عسر القراءة لدى األطفال من خالل نظريات التطور البشري ثريا اأحمد ال�سيذاين، فينيتا اأرورا امللخ�ص: ع�رس القراءة هو اإعاقة التعلم املحددة ذات املن�ساأ الع�سبي، وت�سري التقديرات اإىل اإ�سابة %10-5من ال�سكان يف جميع اأنحاء غالبية اأ�سارت فقد الرتميز. فك وقدرات والتهجي والطالقة والإمالء والدقة القراءة يف �سعوبات بوجود القراءة ع�رس يتميز العامل. املن�سورات اإىل اأن فرز احلالت يتم تنفيذها يف فرتة ما قبل املدر�سة. كما ميكن اأي�سا اإجراء الفح�ض عند الولدة اأو خالل ال�سنة الأوىل من احلياة. فهم نظرية التنمية الب�رسية، على �سبيل املثال، نظرية بياجيه للتنمية الب�رسية، قد ت�ساعد يف حتديد املرحلة العمرية املنا�سبة للك�سف عن ع�رس القراءة، وو�سع العالج الالزم لها. الهدف من هذه املراجعة هو تقدمي ملحة موجزة وحديثة عن ع�رس القراءة وعالجها عند الأطفال من خالل ق�سايا التنمية الب�رسية. مفتاح الكلمات: ع�رس القراءة، ا�سطراب القراءة، ا�سطرابات التعلم، �سعوبات التعلم، طفل، ُعمان، تنمية ب�رسية، عائلة. abstract: dyslexia is a specific learning disability that is neurological in origin, with an estimated overall worldwide prevalence of 5–10% of the population. it is characterised by difficulties in reading, accuracy, fluency, spelling and decoding abilities. the majority of publications reviewed indicated that screening is performed at the preschool level. screening can also be conducted at birth or the first year of life. understanding human development theory, for example, piaget’s human development theory, may help determine at which stage of childhood development dyslexia is more detectable, and therefore guide the management of this disability. the objective of this review is to provide a brief and updated overview of dyslexia and its management in children through human development issues. keywords: dyslexia; reading disorder; learning disorders; learning disabilities; child; oman; human development; family. review understanding dyslexia in children through human development theories *thuraya ahmed al-shidhani1,2,3 and vinita arora4 thuraya ahmed al-shidhani and vinita arora review | 287 computations. some children with dyslexia learn how to compensate for their learning difficulties. there are many famous people who had dyslexia including thomas edison, nelson rockefeller, and hans christian andersen.1 around 20 terms are used to describe dyslexia, however the most common include learning disability, specific learning difficulty, minimally brain damaged, neurologically impaired, and perceptually handicapped.1 many specialists do not agree with the use of the general descriptor dyslexia, and think that the specific learning disability should be identified and described in order to effectively inform management.1,8 there may be an association between dyslexia and attention deficit disorders (add) as, out of 100 children with dyslexia, 46 were also reported to have add or attention deficit hyperactivity disorders (adhd), manifesting lack of concentration, behavioural problems and/or allergic reactions to certain foods/drinks.9,10 however, there is also conflicting information that suggests that children with dyslexia are unlikely to show the symptoms of hyperactivity and impulsiveness that are common in some forms of adhd. 9,10 children with dyslexia, unlike some adhd-affected children, will still have a healthy fear of danger and an awareness of the consequences of their actions. they will also have no obvious problems waiting their turn, sitting still or paying attention, especially when activities do not involve reading.10 understanding and summarising human development, specifically piaget’s theory of development and its relation to dyslexia, may contribute to the understanding of challenges encountered by children with dyslexia. that, along with effective communication between health care workers, teachers and parents, and appropriate counselling, may enhance current treatment practices and outcomes.11 the objective of this review is to provide a brief and updated overview of dyslexia and to understand dyslexia through human development issues in children. literature searches were conducted in pubmed and medline (1995–2010), and several text references also reviewed. the key words used were dyslexia, human development, and children, yielding a total of 95 various types of publications. we reviewed those that included children with dyslexia up to 18 years of age, including studies, that is, words not in the english language, but words that can be pronounced by using reading and grammar rules, for example, reading the words gop or tachet; and, regular words, which are real words that conform to typical english grapheme-phoneme conversion rules, for example, tree or market. the lexical route results in successful reading of all words but inability to produce a correct response to nonwords.3 impairment in either one of these routes can present with a specific subtype of dyslexia (see section types of dyslexia below).3,4,5 currently, the definition of dyslexia is not limited to difficulty in reading: dyslexia also includes difficulty in literacy acquisition, cognitive processes and discrepancies in educational outcomes.6 in 2002, the international dyslexia association adopted the following definition of dyslexia: “dyslexia is a specific learning disability that is neurological in origin. it is characterized by difficulties with accurate and/or fluent word recognition and by poor spelling and decoding abilities. these difficulties typically result from a deficit in the phonological component of language that is often unexpected in relation to other cognitive abilities and the provision of effective classroom instruction. secondary consequences may include problems in reading comprehension and reduced reading experience that can impede the growth of vocabulary and background knowledge.”6 according to the american psychiatric association’s diagnostic and statistical manual (dsm-iv), dyslexia is a term used to describe brainbased difficulty in reading, now simply called a reading disorder. it is one of many disorders referred to as learning disorders. a learning disorder exists when a score on an individual achievement test of reading, writing, or mathematics is substantially below expectations for age, schooling, and level of intelligence.7 dyslexia is not a disease but a lifelong condition. the symptoms of this condition are variable from one child to another, but usually, the child has normal or above average intelligence. some children have problems with speech and poor vocabulary, and some have problems in decoding symbols and sounds that are not registered properly in the brain. for example, some children with dyslexia see letters as mixed up, as in reading b for d; read words backwards, as in tac for cat; and, do not see numbers in line, which results in incorrect understanding dyslexia in children through human development theories 288 | squ medical journal, august 2012, volume 12, issue 3 reading and writing in foreign languages as well. environmental, cultural, social and socioeconomic factors can also contribute to dyslexia.1,6,22,23 finally, some studies indicate a relationship between dyslexia and motor system dysfunction.24-26 types of dyslexia dyslexia can be developmental, with no obvious organic damage. acquired dyslexia is a disorder in reading, usually due to confirmed damage to the nervous system, such as a stroke.27,28 acquired dyslexia was studied in the late 19th century by neurologists such as carl wernicke. it can be peripheral where the visual analysis system is damaged, or central where processes beyond the visual analysis system are damaged, resulting in difficulties in comprehension and/or pronunciation of written words.27 peripheral dyslexia can be subdivided into three subtypes: neglect dyslexia, attentional dyslexia, and letter-by-letter reading dyslexia. in neglect dyslexia, there is no attempt to read the first few words of each line. when single words are shown to an affected individual, there are errors affecting the first letter or two, for example, nun misread as run, yellow as pillow, and clove as love. in attentional dyslexia, there is a problem when there are several letters in a row or several words on the page: in the dyslexic's view the letters may migrate from one word to another, and the individual may read glove and/or spade as glade. in letter-by-letter dyslexia reading, the child does not read phonetically, but rather converts letters into their names, such as aitch and vee for h and v, instead of their sounds huh and vuh, respectively.27 central dyslexia, on the other hand, can be subdivided into non-semantic reading, surface dyslexia, phonological dyslexia and deep dyslexia. in non-semantic reading, the comprehension of written words is very poor. affected children have impaired semantic systems but are still able to read words aloud using the connections between the visual input lexicon and the speech output lexicon. in surface dyslexia, there is high reliance on the sublexical procedure in reading aloud. children pronounce once familiar words as if they were unfamiliar, breaking them down into their component letters and letter groups, converting each into phonemes and pronouncing reviews, and case reports. publications on secondary dyslexia due to other causes such as hearing problems, cancer or other disabilities, and studies in adults with dyslexia were excluded. epidemiology the overall prevalence of dyslexia, in a study of thai primary school students, was estimated to be 5–10%.12 between 2% and 16% of all school age children were in need of special education services.8 specifically, the prevalence was estimated to be as follows: england 14%, canada 10–16%, united states 10–15%.8 the ratio of boys to girls was variable from country to country, however, dyslexia had a higher prevalence in boys, approximately 3.4:1.12 aetiology of dyslexia the exact aetiology of dyslexia is unknown but there are many theories about contributing factors. genetic factors can play a major role in the aetiology of dyslexia, and it is estimated that the risk of a father with dyslexia having a son with dyslexia is as high as 40%.13,14 many dyslexia gene studies have identified chromosome 6 as the main chromosome responsible for dyslexia.6 magnetic resonance imaging (mri) and positron emission tomography (pet) studies have indicated that structural and functional brain-related factors were found in dyslexic children, for example, visual and temporal processing, magnocellular visual system, cerebellum and hemispheric asymmetry.1,6,15–20 reid indicated that there are deficiencies in processing information and decoding words. children with dyslexia have difficulties when transferring the information from one hemisphere of the brain to another.6 phonological deficit at 6 years of age was the strongest predictor of reading difficulty, and it has been argued that there is extensive evidence of morphological difficulties in dyslexic readers.1,6,21 glue-ear syndrome (fluid build up behind the tympanic membrane) has also been postulated as a causal factor in dyslexia. children with dyslexia can have problems in memory and speed of processing, and can also have a double deficit which is difficulty in both phonological and naming speed. the learner’s awareness of thinking can be affected in dyslexia, with difficulties in thuraya ahmed al-shidhani and vinita arora review | 289 a better understanding of dyslexia, it is important to learn about developmental theories of cognition, for example, piaget’s theory of cognition, briefly described below. human developmental theory: piaget’s developmental theory of cognition in piaget’s developmental theory of cognition, there are two stages of cognition development: stageindependent conception and stage-dependent conception.11 s ta g e-i n d e p e n d e n t c o n c e p t i o n cognition and intelligence are both parts of biological systems which are stage-independent, that is, independent of a particular stage of development. there are two important processes in cognition: the complementary process and the adaptive system/ process.11 the complementary process is composed of assimilation and accommodation. assimilation happens when reality is distorted by changing the external object to fit the subject, as when a baby knows the breast of its mother by sucking the nipple. accommodation is alteration of already existing cognitive structures in the subject to match new external stimulus objects, as when the same baby will suck differently on a thumb than when nursing.11 the adaptive system is composed of equilibration and functional (reproductive) assimilation. equilibration occurs when there is balance between assimilation and accommodation. after reaching a balance, the child continues with higher assimilation which can cause disequilibrium which needs a return to accommodation: this is called functional (reproductive) assimilation.11 in this stage, the child with dyslexia cannot maintain equilibrium between assimilation and accommodation, with resultant manifestations of disorientation and difficulty with reading/writing.1 s ta g e-d e p e n d e n t c o n c e p t i o n these are divided into four sub-stages. the first is the sensorimotor stage from birth to 2 years. this stage begins with development of primitive reflexes such as sucking, rooting and the babinski reflex. the baby develops a sensory system by way of the the resulting sound sequence. while this may work well for regular words, they are prone to misreading irregular words, and may pronounce them as if they were regular words, for example, island becomes izland, sugar becomes sudger, and broad becomes brode. phonological dyslexia is mirror image of surface dyslexia. affected children are not able to make effective use of the sublexical reading procedure. they are unable to read unfamiliar words or invented non-words. in deep dyslexia, the individual finds words like baby, church or table which have concrete, imaginable referents easier to read than abstract words like belief, truth or justice.27 both phonological and surface dyslexia occur in both developmental and acquired dyslexia. another subtype of dyslexia is direct dyslexia where words are read aloud without comprehension, including irregular words, despite the fact that they cannot be understood.3 stages of childhood development children with dyslexia demonstrate similar stages of development to those without this condition. in early childhood, from 2–5 years, children produce clear imagery, a reason why their nightmares can be so terrifying. their thoughts are bigger, broader, more global, dynamic, less systematic, and less rational than those of older children. as playfulness is a hallmark of this stage, a child with dyslexia may not appear to be affected due to lack of detection of the problem. the second stage is middle childhood, from 5–7 years, where children are starting to acknowledge the significance of things and feel responsibility. imagination is still more important than knowledge at this stage, and the dyslexic child may consider reading, writing or arithmetic as bad or ugly, and may hate going to school. the last stage is late childhood, (the exact age range was not defined in the literature reviewed), when children become part of various social groups. this is a critical stage where maturation of the cortex of adrenal glands occurs, resulting in the initiation of sexual tension between boys and girls. in this stage, learning disabilities will be more obvious as the child may not meet the greater scholastic expectations. in this stage of ingenuity and brainstorming, learning disabilities and dyslexia will be more obvious as the child is scholastically overwhelmed.29 to gain understanding dyslexia in children through human development theories 290 | squ medical journal, august 2012, volume 12, issue 3 indicated screening at 7 years of age, and one showed that screening was conducted between 11 and 16 years of age.45–47 an example is crombie’s screening programme, conducted in the preschool years, outlined in table 1.6 of note, there is often confusion as to whether the problems manifested are normal variations of preschool development, or manifestations of dyslexia.2,6 diagnostic tests diagnostic tests are usually performed by teachers, specialists, doctors, nurses, psychologists, and others who may be involved in care and development of the affected child. a battery of tests should be conducted to rule out other causes: physical examination of the child should be done to make sure that there are no visual, hearing or other physical problems; intelligence tests such as intelligence quotient (iq) tests should be performed to measure mental ability; perception tests should be conducted to see if problems occur when information is flashed back and forth between ears, eyes, hands and brain, and language and reading tests are needed to measure understanding of language and to determine specific reading problems.2 researchers in dyslexia often adopt a set of criteria for diagnosis, for example, a verbal iq of greater than or equal to 90 with a reading age of at least 2 years behind that the child’s actual, chronological age, (assuming, of course, adequate opportunity to learn how to read), and no obvious hearing or visual impairments.27 environment (external stimuli such as sound and touch), and via responses to sensory stimuli that use the motor system like muscle movement.11,24,25 the child with dyslexia has a similar clinical presentation to normal children at this stage. the second is the preoperational stage from 2 to 6 years, a stage of representation or symbolic functioning, for example, language development. as some studies have found that speech perception and production is affected in children with dyslexia at the preschool age, there is some evidence that screening for dyslexia should be conducted during this period.11,15,16,18,30–41 the third stage is the concrete operational stage from 6 to 11/12 years. here, it is difficult to distinguish between learned knowledge and that acquired by personal experience. this may be more pronounced in children with dyslexia.21 the fourth stage is the formal operational stage from 11 or 12 years and continuing for life. in this stage, the individual can distinguish between thoughts about reality and actual reality. there is the ability to explore all possible solutions to solve problems. this may be why some children with dyslexia can adapt to function satisfactorily or better with their learning disabilities, for example, by working harder and/or spending more time on reading/writing.11 screening although dyslexia is more often clinically noted in later childhood, screening methods can be utilised at various stages of childhood development. there are many methods for screening, and it can be done as early as at birth or in the first year of life.38,42–44 the majority of publications indicate that screening is done during preschool years.30–41 two publications table 1: the elements of crombie’s screening program – learning in the preschool years emotional, personal and social development (home background and culture) communication and language (poor phonological skills, lack of awareness of rhyme and rhythm) difficulty in listening to stories difficulty in remembering sequence of events in a story knowledge and understanding of the world (categorisation, naming, ordering and sequencing) expressive and aesthetic development (singing games and simple dance sequence) physical development and movement coordination skills in physical activities, (writing and balancing on one foot) source: reid g. dyslexia: a practitioner’s handbook.6 thuraya ahmed al-shidhani and vinita arora review | 291 at a time. this may facilitate teaching of reading from left to right, often a key problem.2 remedial programmes should be selected so as to be as specific as possible to the learning disability(ies). if the condition is moderate, health care workers and teachers can foster and encourage other interests and strengths of the child, possibly in music, mechanics or arts.1 short term auditory pacing can also be useful as a management tool.48 children with dyslexia who used audio books showed a significant improvement in reading accuracy with a reduction in emotional-behavioural disorders and improvement in school performance and activities.49 rapid automatic naming, spelling instruction, orthographic coding and automatic coordination of phonological and orthographic codes may facilitate transfer of spelling learned to application.50 appropriate counselling is critical for parents and children with dyslexia as it is very important for them to understand the specifics of the condition and how best to manage it. as a general rule, counselling should be conducted with both the parents and child present. a plan of action to improve the child’s learning outcomes should be developed. it is important to provide love and support, and also minimise factors that may worsen dyslexia [table 2].2,6,51,52 it is important to consider the emotional aspects of the child and the parents when applying remedial programmes. parents/caregivers can experience various emotional responses to dyslexia such as denial, guilt, fear, anxiety, depression and frustration. the whole family can be affected when the parents realise that their child has dyslexia. the parents’ relationship may be weakened and, if one or both parents work in health care, the anxiety may worsen, especially in the early stages of diagnosis. sometimes, parents who are also health care workers may be more reluctant to talk about the child’s problems.2,6 reid interviewed a number of parents to identify the challenges and learn about the agenda of the parents who have a child with dyslexia.6 the main challenges noted were to maintain the child’s self-esteem, help the child to learn something new, protect the dignity of the child when dealing with professional therapists, help develop the child’s individual organisational skills, and, minimise peer insensitivity and misconceptions of dyslexia.6 management there are four types of approach in managing a child with dyslexia, summarised by reid:6 1) individualised programmes, which are based on multisensory teaching methods, and are highly structured and phonetically-based; 2) supportive approaches and strategies which have the same principles as individualised programmes, but which are carried out more selectively by teachers, for example, alphabet cards; 3) assisted learning techniques where there is learning from peers, and use of different methods such as word games, paired reading, cued spelling and peer tutoring, and 4) class-wide approaches such as policy framework and whole school screening. according to the davis model, there are simple manifestations to look for and simple measures to implement for every stage and age. for example, in a child of 6–9 years of age, there maybe difficulties in learning to read and write; determining left and right; learning the alphabet and multiplication tables, learning to tie shoes, learning to catch a ball or skip. these problems together with inattention, poor concentration skills, and frustration may all lead to behavioural problems. early awareness and interventions are critical steps, and may help the child compensate for the learning disabilities. examples of specific interventions for reading and spelling are to keep the text covered, exposing one line at a time only, and even one letter of each word table 2: factors that worsen dyslexia and confusion • insufficient rest • poor lighting • varying print styles • certain smells • drugs or medications • excess motion • illness, pain or injury • rearranged furniture • loss • moving house • very small print • fear • very faint print • unscheduled changes • specific sounds • family strife • loud noises • threats of punishment • reminder of unpleasant experience • change in the orderliness of the environment • poor diet or not enough food source: temple r. dyslexia: practical and easy-to-follow advice.2 understanding dyslexia in children through human development theories 292 | squ medical journal, august 2012, volume 12, issue 3 references 1. savage jf. dyslexia: understanding reading problems. new york: j. messner, 1985. 2. temple r. dyslexia: practical and easy-to-follow advice. boston ma: element, 1998. 3. castles a, bates t, coltheart m. john marshall and the developmental dyslexias. aphasiology 2006; 20:871–92. 4. castles a, coltheart m. varieties of developmental dyslexia. cognition 1993; 47:149–80. 5. coltheart m. disorders of reading and their implications for models of normal reading. visible language 1981; 15:245–86. 6. reid g. dyslexia: a practitioner's handbook. 4th ed. malden, ma: john wiley & sons ltd., 2009. p.6. 7. american psychiatric association. diagnostic and statistical manual of mental disorders. 4th ed. washington dc: american psychiatric association, 2000. 8. hynd gw. dyslexia: neuropsychological theory, research, and clinical differentiation. new york: grune & stratton, 1983. 9. dyslexia and diet. from: http://www.dyslexiaparent.com/mag38.html. accessed: feb 2012. 10. add and adhd (attention deficit disorder and attention deficit hyperactivity disorder) adhd and dyslexia. from: http://www.addandadhd.co.uk/ adhd-dyslexia.html. accessed: feb 2012. 11. lerner rm. concepts and theories of human development. 3rd ed. mahwah, nj: l. erlbaum associates, 2002. 12. roongpraiwan r, ruangdaraganon n, visudhiphan p, santikul k. prevalence and clinical characteristics of dyslexia in primary school students. j med assoc thai 2002; 85:s1097–103. 13. meaburn el, harlaar n, craig iw, schalkwyk lc, plomin r. quantitative trait locus association scan of early reading disability and ability using pooled dna and 100k snp microarrays in a sample of 5760 children. mol psychiatry 2008; 13:729–40. 14. gallagher a, frith u, snowling mj. precursors of literacy delay among children at genetic risk of dyslexia. j child psychol psychiatry 2000; 41:203–13. 15. gerrits e, de bree e. early language development of children at familial risk of dyslexia: speech perception and production. j commun disord 2009; 42:180–94. 16. boets b, wouters j, van wieringen a, de smedt b, ghesquiere p. modelling relations between sensory processing, speech perception, orthographic and phonological ability, and literacy achievement. brain lang 2008; 106:29–40. 17. boets b, wouters j, van wieringen a, ghesquiere p. auditory processing, speech perception and phonological ability in pre-school children at highparents can be advocates for their affected child(ren) by supporting them in the early developmental years, teaching them to be their own advocates, offering encouragement to overcome obstacles, and fostering development of their strengths, talents and good working habits.6 good communication with children is paramount through the developmental years, and along with the above, may help minimise the complications of dyslexia such as low selfesteem, refusal to attend school, repetitive failure in school and abnormal/criminal behaviour.51 conclusion understanding dyslexia in children, through the application of human development theories such as piaget’s, can positively inform its detection, management and outcome. in early childhood (2–5 years), the child may not be obviously affected by or manifest dyslexia, and therefore, parents/caregivers may not detect the problem. in middle childhood (5–7 years), when the child starts to become aware of the significance of things and develop feelings of responsibility, the child with dyslexia may not value scholastic achievements, and therefore may dislike school. early detection is very important for early intervention and management of dyslexia, especially before reaching the later childhood stage when socialisation is important and school work demands are greater. appropriate family counselling is also important. we have learned that some children try (successfully) to compensate for their dyslexia by creating equilibrium and balance between their sensory disorientation, reading and writing. this is described in piaget’s developmental theory of cognition (stage-independent conception). while there is a paucity of published information, it is clear that the application of existing human development theories can help explain different types of dyslexia, and why the presentation varies from child to child. for the child with dyslexia, all possible solutions to their problems should be explored in order to foster optimal learning outcomes. a c k n o w l e d g e m e n t s the authors wish to thank fatma ahmed alshidhani for filtering publications for relevance, and iveta lewis for assistance with referencing. thuraya ahmed al-shidhani and vinita arora review | 293 33. puolakanaho a, ahonen t, aro m, eklund k, leppanen ph, poikkeus am, et al. developmental links of very early phonological and language skills to second grade reading outcomes: strong to accuracy but only minor to fluency. j learn disabil 2008; 41:353–70. 34. torkildsen jk, syversen g, simonsen hg, moen i, lindgren m. brain responses to lexical-semantic priming in children at-risk for dyslexia. brain lang 2007; 102:243–61. 35. nergard-nilssen t. longitudinal case-studies of developmental dyslexia in norwegian. dyslexia 2006; 12:231–55. 36. boets b, wouters j, van wieringen a, ghesquiere p. coherent motion detection in preschool children at family risk for dyslexia. vision res 2006; 46:527–35. 37. schuele cm. the impact of developmental speech and language impairments on the acquisition of literacy skills. ment retard dev disabil res rev 2004; 10:176–83. 38. molfese vj, molfese dl, modgline aa. newborn and preschool predictors of second-grade reading scores: an evaluation of categorical and continuous scores. j learn disabil 2001; 34:545–54. 39. snowling m, bishop dv, stothard se. is preschool language impairment a risk factor for dyslexia in adolescence? j child psychol psychiatry 2000; 41:587–600. 40. olofsson a, niedersoe j. early language development and kindergarten phonological awareness as predictors of reading problems: from 3 to 11 years of age. j learn disabil 1999; 32:464–72. 41. mauer dm, kamhi ag. factors that influence phoneme-grapheme correspondence learning. j learn disabil 1996; 29:259–70. 42. deregnier ra. neurophysiologic evaluation of early cognitive development in high-risk infants and toddlers. ment retard dev disabil res rev 2005; 11:317–24. 43. guttorm tk, leppanen ph, poikkeus am, eklund km, lyytinen p, lyytinen h. brain event-related potentials (erps) measured at birth predict later language development in children with and without familial risk for dyslexia. cortex 2005; 41:291–303. 44. lyytinen h, aro m, eklund k, erskine j, guttorm t, laakso ml, et al. the development of children at familial risk for dyslexia: birth to early school age. ann dyslexia 2004; 54:184–220. 45. watson cs, kidd gr, homer dg, connell pj, lowther a, eddins da, et al. sensory, cognitive, and linguistic factors in the early academic performance of elementary school children: the benton-iu project. j learn disabil 2003; 36:165–97. 46. stage sa, abbott rd, jenkins jr, berninger vw. predicting response to early reading intervention from verbal iq, reading-related language abilities, attention ratings, and verbal iq-word reading risk for dyslexia: a longitudinal study of the auditory temporal processing theory. neuropsychologia 2007; 45:1608–20. 18. simos pg, fletcher jm, sarkari s, billingsley rl, francis dj, castillo em, et al. early development of neurophysiological processes involved in normal reading and reading disability: a magnetic source imaging study. neuropsychology 2005; 19:787–98. 19. temple e. brain mechanisms in normal and dyslexic readers. curr opin neurobiol 2002; 12:178–83. 20. jimenez gonzalez je, hernandez valle i. word identification and reading disorders in the spanish language. j learn disabil 2000; 33:44–60. 21. swanson hl, jerman o. the influence of working memory on reading growth in subgroups of children with reading disabilities. j exp child psychol 2007; 96:249–83. 22. harlaar n, dale ps, plomin r. reading exposure: a (largely) environmental risk factor with environmentally-mediated effects on reading performance in the primary school years. j child psychol psychiatry 2007; 48:1192–9. 23. duncan lg, seymour ph. socio-economic differences in foundation-level literacy. br j psychol 2000; 91:145–66. 24. thomson jm, goswami u. rhythmic processing in children with developmental dyslexia: auditory and motor rhythms link to reading and spelling. j physiol paris 2008; 102:120–9. 25. getchell n, pabreja p, neeld k, carrio v. comparing children with and without dyslexia on the movement assessment battery for children and the test of gross motor development. percept mot skills 2007; 105:207–14. 26. mather ds. dyslexia and dysgraphia: more than written language difficulties in common. j learn disabil 2003; 36:307–17. 27. ellis aw. reading, writing and dyslexia: a cognitive analysis. london/hillsdale nj: erlbaum associates, 1984. 28. improvement in reading, spelling, dyslexia, add/ adhd and more ld hope. from: http://www. ldhope.com/dyslexia.htm. accessed: feb 2012. 29. armstrong t. the human odyssey: navigating the twelve stages of life. new york: sterling, 2007. 30. wilson sb, lonigan cj. an evaluation of two emergent literacy screening tools for preschool children. ann dyslexia 2009; 59:115–31. 31. wilson sb, lonigan cj. identifying preschool children at risk of later reading difficulties: evaluation of two emergent literacy screening tools. j learn disabil 2010; 43:62–76. 32. lopez-escribano c, beltran ja. early predictors of reading in three groups of native spanish speakers: spaniards, gypsies, and latin americans. span j psychol 2009; 12:84–95. understanding dyslexia in children through human development theories 294 | squ medical journal, august 2012, volume 12, issue 3 50. amtmann d, abbott rd, berninger vw. identifying and predicting classes of response to explicit phonological spelling instruction during independent composing. j learn disabil 2008; 41:218–34. 51. miles tr. dyslexia : a hundred years on. 2nd ed. buckingham: open university press, 1999. 52. degler t, kason y. love, limits and consequences: a positive, practical approach to kids and discipline. toronto: summerhill press, 1990. discrepancy: failure to validate discrepancy method. j learn disabil 2003; 36:24–33. 47. leonard c, eckert m, given b, virginia b, eden g. individual differences in anatomy predict reading and oral language impairments in children. brain 2006; 129:3329–42. 48. getchell n, mackenzie sj, marmon ar. short term auditory pacing changes dual motor task coordination in children with and without dyslexia. adapt phys act q 2010; 27:32–46. 49. milani a, lorusso ml, molteni m. the effects of audiobooks on the psychosocial adjustment of preadolescents and adolescents with dyslexia. dyslexia 2010; 16:87–97. clinical & basic research sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e176-182, epub. 7th apr 14 submitted 9th sep 13 revisions req. 30th oct 13 & 5th jan 14; revisions recd. 29th nov 13 & 15th jan 14 accepted 6th feb 14 وبائيات سرطان الثدي عند النساء البحرينيات معطيات سجل السرطان البحريين رنده حماده، جناة ابوالفاحت، ماجده فكري، هاله املهزه abstract: objectives: the aim of this study was to describe the epidemiology of breast cancer among the bahraini female population in the years 2000‒2010 and examine its health policy implications. methods: all breast cancer cases in the bahrain cancer registry from 1st january 2000 to 31st december 2010 were included. results: there were 1,005 cases, 12.7% of which were detected by screening. the overall mean age at diagnosis was 50.9 years (95% confidence interval 50.1–51.6). the age-standardised incidence rate declined from 58.2 per 100,000 in 2000 to 44.4 per 100,000 in 2010. the majority of cases were infiltrating ductal carcinoma (76.9%). of the registered cases, 44.1% and 48.1% had an unknown grade and stage, respectively. the five-year survival rate was 63 ± 2%. conclusion: the low percentage of cases detected by screening merits further evaluation of bahrain’s screening programme. more effort should be made to reduce the proportion of unknown stage and grade breast cancers. future research has to be directed towards understanding the reasons for bahrain having the highest incidence rate of breast cancer in the gulf cooperation council countries. keywords: breast cancer; epidemiology; incidence; cancer screening; survival; bahrain; middle east. امللخ�ص: الهدف: وصف وبائيات سرطان الثدي بني السكان البحرينيات اإلناث خالل الفرتة بني 2010-2000م ودراسة السياسات املرتتبة عليها. الطريقة: مت اإدراج جميع حالت �رشطان الثدي امل�صجلة يف �صجل ال�رشطان البحريني من الأول من يناير 2000م اإىل الواحد والثلثني من دي�صمرب 2010م. ci 95%( النتائج: مت ت�صجيل 1,005 حالة، منها %12.7 اكت�صفت بوا�صطة الفح�س الدوري. وكان متو�صط العمر العام عند الت�صخي�س 50.9 عام 51.6، 50.1(. وقد انخف�س معدل الإ�صابة املوحد للعمر من 58.2/100000 يف عام 2000 اإىل/44.4/100,000 يف عام 2010. وقد كانت معظم احلالت من نوع �رشطان الأقنية املت�صلل )%76.9(. مل يتم التعرف على درجة ومرحلة ال�رشطان لدى %44.1 و %48.1 من الن�صاء على التوايل. وكان معدل ن�صبة البقاء ملدة خم�صة اأعوام على قيد احلياة %2 ± 63. اخلال�صة: اإن انخفا�س ن�صبة احلالت املكت�صفة عن طريق الفرز الدوري ت�صتحق املزيد من التقييم لهذا الربنامج. وينبغي بذل املزيد من اجلهود للحد من ن�صب احلالت غري املعروفة الدرجة واملرحلة. يجب على الأبحاث امل�صتقبلية الرتكيز على فهم اأ�صباب ارتفاع ن�صبة الإ�صابة ب�رشطان الثدي يف البحرين مقارنة بدول جمل�س التعاون اخلليجي. مفتاح الكلمات: سرطان الثدي؛ علم الوبائيات؛ نسبة االنتشار؛ الفحص الدوري؛ نسبة البقاء؛ البحرين؛ دول جملس التعاون اخلليجي. epidemiology of breast cancer among bahraini women data from the bahrain cancer registry *randah r. hamadeh,1 najat m. abulfatih,2 majeda a. fekri, 2 hala e. al-mehza2 advances in knowledge there is a lack of concrete data about the epidemiology of breast cancer in arab nations. this study reports on the incidence of breast cancer in bahrain over an 11-year period and describes cancer registration in bahrain. this study also identifies deficiencies in cancer registration and areas for improvement in the registry and breast screening programmes in the country. application to patient care this study has implications for the evaluation and modification of bahrain’s on going breast screening programme and guidelines. worldwide, breast cancer is the commonest cancer among females. it is estimated that more than 1.6 million new cases of breast cancer occurred among women globally in 2010.1 there is great variation between the incidence rates of breast cancer in developed countries in comparison to developing countries. in 2008, incidence rates ranged from 19.3 per 100,000 women in eastern africa to 89.9 per 100,000 women in western europe. the rates were high (>80 per 100,000) in developed countries, except for japan, and low (<40 per 100,000) in most developing regions.2 breast cancer occupies the first rank among 1department of family & community medicine, college of medicine & medical sciences, arabian gulf university, manama, bahrain; 2ministry of health bahrain, manama, bahrain *corresponding author e-mail: randah@agu.edu.bh randah r. hamadeh, najat m. abulfatih, majeda a. fekri and hala e. al-mehza clinical and basic research | e177 all female cancers in all arab countries despite the fact that some rates are relatively low (20‒30 per 100,000).3,4 patients tend to be young with an average age at presentation of 48 ± 2.8 years, which is a decade earlier than in western countries.5,6 in the six gulf cooperation council (gcc) countries, breast cancer is the commonest female cancer. compared to all female cancers, the proportion of breast cancer ranged from 15.7% in oman to 54.4% in bahrain.7 bahrain, kuwait and qatar were classified as high-incidence countries while the united arab emirates, saudi arabia and oman were low-incidence. a comparison of the age-standardised rate (asr) of breast cancer from high-incidence gcc countries with other countries shows that the gcc rates are similar to those of some european countries, meaning that the rates are higher than in japan, but still lower than those of high-incidence countries like the usa [figure 1]. most international and interethnic differences in the incidence of breast cancer have been attributed to the varying environmental factors and lifestyles of the populations.8 however, the disparities observed within the gcc region have been explained partly by the differences in fertility rates and the duration of breastfeeding.8 cancer is the second leading cause of death in bahrain (10%), following cardiovascular diseases.9 however, the proportional mortality rate of cancer has been underestimated due to the high percentage of ill-defined causes of death.10 in a ministerial decree in 1994, cancer notification became mandatory. thus, all physicians in bahrain became obliged to report all cancer cases to the bahrain cancer registry (bcr) at the medical review office of the ministry of health (moh).12 compared to other gcc states, bahrain has a higher incidence of cancers of the breast, lung, bladder, thyroid, uterus and ovary among females. a rising trend in cancer incidence is likely to continue for years or even decades to come. in bahraini females, breast cancer remains the leading type of cancer.13,14 breast cancer screening in bahrain started in december 1992 for women aged 30‒64 years old and included educational activities on clinical breast examination (cbe) and breast self-examination.15 screening by mammography was only performed for suspected and high-risk cases after referral. between 2008‒2010, the primary healthcare centres in bahrain reported a cbe coverage rate of 6.6%, 7.1% and 6.9%, respectively, in women 30 years and above.9 mammography screening of bahraini women 40 years and over was started in september 2005 with a recommendation for it to be performed every two years.16 methods the breast cancer cases included in the study were those in bahraini patients registered in the bcr between 1st january 2000 and 31st december 2010. incidence rates were calculated using canreg4 software (descriptive epidemiology unit, international association of cancer registries, lyon, france), in which the yearly crude incidence rate, age-specific incidence rates (aspirs) and age-standardised incidence rates (asirs) were computed. incidence rates were standardised for age and sex by the direct standardisation method using the world standard population. women were considered premenopausal if they were below 50 years and postmenopausal if they were 50 years old or above. data analysis was performed using the statistical package for the social sciences, version 20.0 (ibm, corp., chicago, illinois, usa). analysis of variance (anova) and least significant difference tests were performed to detect differences in age means. pearson’s chi-squared test was used to detect differences between premenopausal and postmenopausal age groups by type, grade, laterality and detection modality. survival analysis was done using the life table technique. the probability of patient survival in each interval was calculated by taking account of the census observations in that interval. the survival proportion included only the overall survival—not the relapse-free survival. breast cancer patients diagnosed with only a death certificate were excluded from the survival analysis due to the lack of a diagnosis date. the wilcoxon-gehan statistic was utilised to determine the five-year survival differences by age group, grade, figure 1: age-standardised world incidence rates in bahrain and selected countries calculated per 100,000 cases of breast cancer. figure reproduced with blanket permission: international agency for research on cancer and world health organization. globocan: estimated cancer incidence, mortality and prevalence worldwide.11 epidemiology of breast cancer among bahraini women data from the bahrain cancer registry e178 | squ medical journal, may 2014, volume 14, issue 2 stage and detection modality. ethical approval was obtained from the research & ethics committee of the moh in bahrain. results between 2000‒2010, 1,005 breast cancer cases were registered in the bcr, of which 28.7% were still alive by the end of the study period. the annual average number of cases was 91, with 2007 having the highest reported number (120) and 2002 the lowest (66). about three-quarters of the women were married (74.7%) with 12.5% single, 2.3% divorced, 6.1% widowed and the rest unknown (4.4%). the proportion of premenopausal women diagnosed was 51.2% while 48.8% were postmenopausal [table 1]. the median age at diagnosis during the 11-year period was 49 years while the average age was 50.9 years (95% confidence interval [ci] 50.1–51.6). there was a statistically significant difference (p <0.05) in mean age, with an increase in the mean age from the year 2000 to 2010. the lowest mean ages at diagnosis were 48.5 in 2000 and 48.0 in 2001 while the highest mean age at diagnosis was 53.9 in 2006. the majority of the reported cases were from the salmaniya medical complex and the bahrain defence force hospital (91.4%) which are the main governmental general hospitals. the screening programme contributed to the diagnosis in 1.5% of the cases. over half of the patients were diagnosed based on a primary histological diagnosis [table 1]. the average breast cancer asir in bahrain was 52.3 per 100,000. the asirs declined from 58.2 per 100,000 in 2000 to 44.4 per 100,000 in 2010 [figure 2]. the aspirs of the postmenopausal women figure 2: age-standardised incidence rates of breast cancer by year of diagnosis. figure 3: incidence rates in premenopausal and postmenopausal women by year. table 1: characteristics of breast cancer patients (n = 1,005) characteristics n % age at diagnosis in years 20‒24 5 0.5 25‒29 18 1.8 30‒34 42 4.2 35‒39 117 11.6 40‒44 153 15.1 45‒49 180 17.9 50‒54 156 15.5 55‒59 94 9.4 60‒64 84 8.4 65‒69 72 7.2 ≥70 84 8.4 source of notification salmaniya medical complex 833 82.9 bahrain defense force hospital 85 8.5 private hospitals 8 0.8 private clinics 11 1.0 primary healthcare 34 3.4 breast cancer screening programme 15 1.5 unknown 19 1.9 basis of diagnosis death certificate only 12 1.2 clinical only 1 0.1 clinical investigation/ultrasound 6 0.6 cytology/haematology 384 38.2 histology of metastasis 10 1.0 histology of primary cancer 586 58.3 unknown 6 0.6 randah r. hamadeh, najat m. abulfatih, majeda a. fekri and hala e. al-mehza clinical and basic research | e179 were generally higher than those of premenopausal women throughout the period. there was a noticeable variation in the rates of the postmenopausal women with a peak in 2006 while the rates of the premenopausal women had little variation [figure 3]. analysis by five-year age group showed that the age groups 65‒69 and 50‒54 had the highest overall average aspir during the 11-year period (184 per 100,000 and 179.8 per 100,00, respectively) and those of the 20‒24 age group (2.4 per 100,000) and 25‒29 age group (8.7 per 100,000) had the lowest. table 2 shows that the majority of breast cancer cases were infiltrating ductal carcinoma (76.9%) and grade 2 moderately differentiated tumours (28.6%) with regional and distant metastasis (35.1%). both breasts were found to be equally affected. high proportions of cancers of unknown grade (44.1%) and stage (48.1%) were noted. although only 15 cases were notified through the breast cancer screening project, 113 more were detected by the tumour registrar while reviewing medical records, yielding 12.7% of the total cases through screening and 87.3% through routine notification [table 2]. there was a statistically significant difference (p = 0.0043) among premenopausal and postmenopausal women whereby a higher proportion of the latter was detected by screening. further analysis by year showed a statistically significant decline in the proportion of cases detected by screening (p <0.0001) reaching 13.0%, in 2010. it was found that 57 patients (5.7%) did not undergo any treatment while 31 (3.1%) had an unknown modality of treatment. surgery (84.7%) was the commonest modality performed for breast cancer patients, followed by chemotherapy (63.0%), radiotherapy (50.2%) and hormonal therapy (8.7%). there was a progressive decline in the proportion of breast cancer patients’ cumulative survival by year. after one year, 84.0% ± 1.0% survived in contrast to 63.0% ± 2.0% and 49.0% ± 3.0% respectively, for the fiveand ten-year intervals. table 3 shows the cumulative proportion surviving at the end of the five-year interval by age, grade, stage and detection modality. women diagnosed at the age of 35 years or younger had a 73.0% ± 5.0% survival rate compared to 51.0% ± 5.0% in those 65 years old and over. there was an inverse relationship between grade and five-year survival whereby it reached 50.0% ± 35.0% in grade four (undifferentiated anaplastic) compared to 78.0% ± 8.0% in grade one (well-differentiated). patients with unknown grades of cancer had a 58.0% ± 3.0% survival. a similar inverse relationship was noted with respect to stage; however, those with an unknown stage of cancer had a higher five-year survival rate (62%). further, those detected by screening had a 4% higher survival rate (65%) than those detected via routine examination (61%). there were significant differences (p <0.009) in the five-year survival rate with respect to age, stage and detection modality. a lower cumulative survival rate at five years was found among older women, patients with cancers that had advanced to a higher grade or advanced stage, and cancers detected through a routine check-up. discussion the bcr is a reliable national population-based registry covering all residents (bahraini and non-bahraini) in the country; it gathers information on epidemiological, clinical and pathological aspects of the disease. bahrain’s cancer data is entered into the canreg4 software and doctors started reporting this data to the cancer incidence in five continents publication in 2007.13 only five other countries (kuwait, oman, algeria, egypt and tunisia) appeared in that volume; however, jordan, palestine, saudi arabia and qatar also have population-based registries.3 breast cancer is the commonest cancer among females in bahrain.14 the average breast cancer asir in bahrain (52.3 per 100,000) is the highest among all gcc states.7 all other eastern mediterranean countries, except for lebanon (55.4 per 100,000), have rates that are higher than the world average (39.0 per 100,000) and that of less developed regions (27.3 per 100,000), but lower than that of more developed regions (66.4 per 100,000).2 the rates declined from 58.2 per 100,000 in 2000 to 44.4 per 100,000 in 2010. this is in contrast to the trends of other gcc countries but in accord with those of some developed countries.7,17 similar to other studies, breast cancer risk in bahrain increases with age.18 the highest overall average aspir was 184 per 100,000 in patients between 65‒69 years followed by 179.8 per 100,000 in those between 50‒54 years. those aged 65‒69 years had the highest rate, as was also seen in kuwait.7 the mean age at presentation for breast cancer in arab countries is reported to be a decade earlier than western countries.3,6 this difference could be attributed to social, economic and population differences in the age at diagnosis between arab and western populations.6 the median age at diagnosis (49 years) is similar to what has been reported from other arab countries (48.5 years) but lower than the age at diagnosis in industrialised countries (63 years).6 the overall mean age at diagnosis (50.9; 95% ci: 50.1–51.6 years) is slightly lower than that reported for kuwaiti epidemiology of breast cancer among bahraini women data from the bahrain cancer registry e180 | squ medical journal, may 2014, volume 14, issue 2 table 2: type, grade, stage, laterality and detection modality of cases (n = 1,005) premenopausal postmenopausal total p value n % n % n % type infiltrating ductal carcinoma 413 80.2 360 73.5 773 76.9 0.010 nos lobular carcinoma 25 4.9 24 4.9 49 4.9 unclassified neoplasm 18 3.5 31 6.3 49 4.9 nos carcinoma 19 3.7 23 4.7 42 4.2 infiltrating ductal and lobular carcinoma 8 1.6 5 1.0 13 1.3 nos adenocarcinoma 8 1.6 14 2.9 22 2.2 other 24 4.7 33 6.7 57 5.6 grade 1 well-differentiated 15 2.9 35 7.1 50 5.0 0.005 2 moderately differentiated 145 28.2 142 29.0 287 145 3 poorly differentiated 131 25.4 91 18.6 222 22.1 4 undifferentiated and anaplastic 2 0.4 1 0.2 3 0.3 unknown 222 43.1 221 45.1 443 44.1 stage in situ 12 2.3 12 2.4 24 2.4 0.713 localised 71 13.8 74 15.1 145 14.4 regional direct extension 11 2.1 17 3.5 28 2.8 regional lymph nodes 93 18.1 82 16.7 175 17.4 regional direct extension and lymph nodes 8 1.6 8 1.6 16 1.6 distant metastasis 63 12.2 71 14.6 134 13.3 unknown 257 49.9 226 46.1 483 48.1 laterality right 260 50.5 214 43.7 474 47.1 0.193 left 231 44.9 250 51.0 481 47.9 bilateral 9 1.7 9 1.8 18 1.8 paired lateral unknown 15 2.9 17 3.5 32 3.2 detection modality routine 465 90.3 412 84.1 877 87.3 0.004 screening 50 9.7 78 15.9 128 12.7 total 515 100.0 490 100.0 1,005 100.0 nos = non-specific. females (52.3; 95% ci: 51.7–52.9 years).19 however, it is higher than that reported for bahrain between 1998‒2002 (49.0 ± 12.5 years)5 and for iran (46 ± 12.5 years).20 the increase in mean age at diagnosis can be partially explained by the older population targeted by the screening programme. the results of the current study have shown that a higher proportion of postmenopausal (15.9%) cancers were detected by screening than those in premenopausal women (9.7%). the commonest type of breast cancer found in bahrain in this study was infiltrating ductal carcinoma (76.9%), a similar result to that reported for all gcc states combined (76.8%).7 as was found in kuwaiti and saudi arabian studies, in bahrain both breasts were equally affected.19,21 the fact that there was a considerable number of cases with an unknown grade randah r. hamadeh, najat m. abulfatih, majeda a. fekri and hala e. al-mehza clinical and basic research | e181 (44.1%) and stage (48.1%) of cancer is disappointing. having three cases of undifferentiated anaplastic grade could have been an underestimate due to the high percentage of cases with an unknown grade. this reflects the incompleteness of the data and underestimates the true grades and stages. however, the proportion with regional and distant metastasis doubled when the unknown grade cases were excluded and became similar to that of kuwait (68%) but higher than that of saudi arabia (58.9%).19,21 the bcr does not include full details on the types of treatment. surgery was the commonest modality in bahrain, as has also been reported in kuwait.22 the cumulative five-year survival rate among bahraini breast cancer patients (63% ± 2%) was slightly lower than that reported in an earlier study (68.8%) that was based on patients from the salmaniya medical complex prior to the establishment of the bcr. in contrast, the 10-year survival rate found in that study was higher (49% ± 3%) than the current study’s findings (36.4%).23 the five-year survival rate in the current study lies midway between the lowest rate reported among developing countries (45%) and the highest rate among developed countries (89%).8 it is also lower than that previously reported for iran (72%) but is similar to the rate found in saudi arabia (63.1%) for 2000‒2004.20,24 further, the fact that there were high proportions of breast cancer cases with unknown stage and grade might have affected the survival results among premenopausal and postmenopausal women. female breast cancer risk factors in the arab world are similar to those of western countries.3 globally, high breast cancer incidence rates are associated with a high prevalence of reproductive risk factors.17 the decline in total fertility rates, the delay in the age of having one’s first child, the shorter mean duration of breastfeeding and the increased early detection through screening underlie the high rates in bahrain.8,13,14 further, early menarche (mean age 12.7 ± 1.7 years) was reported among breast cancer patients in bahrain.25 lifestyle changes, including sedentary lifestyles, physical inactivity, westernised diets, high-calorie diets and obesity, contribute to the high incidence rates of breast cancer in bahrain.26‒28 in addition, the possibility of certain genetic dispositions may explain the higher bahraini incidence rate compared to other gcc states.4,14 breast cancer is a major public health burden in bahrain that should be addressed by a multidisciplinary collaborative approach and an understanding of the unique risk factors.29 there is an ongoing debate over the benefits and harm of breast screening and new approaches should be considered.30,31 the fact that patients whose cancers had been detected by screening had higher survival rates is reassuring. the marked decrease in case detection with time can be partially explained by the possible inconsistency in the screening awareness programme campaigns and a lack of awareness among physicians and the public. moreover, there is no comprehensive evaluation of the screening programme.29 further, the low percentage (12.7%) of cases detected by screening merits further evaluation of the bahraini cancer prevention programme. table 3: five-year survival by age, grade, stage and detection modality variables cumulative proportion surviving at five years by interval ± sd wilcoxongehan statisic p value age in years <35 0.73 ± 0.05 21.315 <0.0001 35‒49 0.63 ± 0.03 50‒64 0.67 ± 0.03 ≥65 0.51 ± 0.05 grade 1 0.78 ± 0.08 25.903 <0.0001 2 0.68 ± 0.04 3 0.66 ± 0.04 4 0.50 ± 0.35 unknown 0.58 ± 0.03 stage in situ 1.0 ± 0.0 76.294 <0.0001 localised 0.91 ± 0.03 regional direct extension 0.83 ± 0.08 regional lymph nodes 0.77 ± 0.06 regional direct extension and lymph nodes 0.50 ± 0.19 distant metastasis 0.31 ± 0.05 unkown 0.63 ± 0.02 detection modality routine 0.61 ± 0.02 14.537 <0.0001screening 0.65 ± 0.22 overall 0.63 ± 0.02 sd = standard deviation; grade 1 = well-differentiated; grade 2 = moderately differentiated; grade 3 = poorly differentiated; grade 4 = undifferentiated and anaplastic. epidemiology of breast cancer among bahraini women data from the bahrain cancer registry e182 | squ medical journal, may 2014, volume 14, issue 2 conclusion breast cancer is a major public health burden which warrants the attention of health policy-makers. an evaluation of the bahraini breast cancer screening programme, including the ideal age to start screening, and a re-evaluation of the national guidelines is urgently needed. more effort should be made to reduce the proportion of cancers of unknown stage and grade. data on breast cancer risk factors, such as early menarche, hormonal receptors, age at the birth of the first child and oral contraceptive and hormone replacement therapy use are characteristics that should be further considered in breast cancer epidemiology research in bahrain. future research should be directed towards collaborative regional analytical studies to understand the multifaceted role of the interactive risk factors of breast cancer. such research should also clarify the reasons why bahrain has the highest breast cancer incidence rate among the gcc states and one of the highest rates in the eastern mediterranean region. references 1. forouzanfar mh, foreman kj, delossantos am, loranzo r, lopez ad, murray cj, et al. breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. lancet 2011; 378:1461‒84. doi: 10.1016/s0140-6736(11)61351-2. 2. ferlay j, shin hr, bray f, forman d, mathers c, parkin dm. estimates of worldwide burden of cancer in 2008: globocan 2008. int j cancer 2010; 127:2893‒917. doi: 10.1002/ijc.25516. 3. salim ei, moore ma, al-lawati ja, al-sayyad j, bawazir a, bener a, et al. cancer epidemiology and control in the arab world: past, present and future. asian pac j cancer prev 2009; 10:3‒16. 4. chouchane l, boussen h, sastry ks. breast cancer in arab populations: molecular characteristics and disease management implications. lancet oncol 2013; 14:417‒24. doi: 10.1016/s1470-2045(13)70165-7. 5. el saghir ns, khalil mk, eid t, el kinge ar, charafeddine m, geara f, et al. trends in epidemiology and management of breast cancer in developing arab countries: a literature and registry analysis. int j surg 2007; 5:225‒33. doi: 10.1016/j. ijsu.2006.06.015. 6. najjar h, easson a. age at diagnosis of breast cancer in arab nations. int j surg 2010; 8:448‒52. doi: 10.1016/j. ijsu.2010.05.012. 7. gulf center for cancer control and prevention. ten-year cancer incidence among nationals of the gcc states: 19982007. from: www.moh.gov.bh/pdf/publications/gcc%20 cancer%20incidence%202011.pdf accessed: jan 2012. 8. ravichandran k, al-zahrani as. association of reproductive factors with the incidence of breast cancer in gulf cooperation council countries. east mediterr health j 2009; 15:612‒21. 9. kingdom of bahrain ministry of health. ministry of health statistics. from: www.moh.gov.bh/en/aboutmoh/ mohstatistics.aspx accessed: jan 2012. 10. abulfatih nm, hamadeh rr. a study of ill-defined causes of death in bahrain: determinants and health policy issues. saudi med j 2010; 31:545‒9. 11. international agency for research on cancer and world health organization. globocan: estimated cancer incidence, mortality and prevalence worldwide. from: www.globocan. iarc.fr accessed: jan 2008. 12. kingdom of bahrain ministry of health. notification of cancer to the cancer registry office. manama, bahrain: kingdom of bahrain ministry of health. ministerial decree 5/1994. 13. alsayyad j, hamadeh r. cancer incidence among the bahraini population: a five-year (1998-2002) experience. ann saudi med 2007; 27:251‒8. 14. hamadeh rr, alsayyad j. cancer incidence among nationals in bahrain. in: tuncer am (ed). asian pacific organization for cancer prevention cancer report 2010. ankara, turkey: new hope in health foundation, 2010. pp. 295–6. 5. kingdom of bahrain ministry of health. screening services in bahrain in the primary health care. manama, bahrain: kingdom of bahrain ministry of health, 1999. report 29/5/1999. 16. bahrain cancer society. from: www.bahraincancer.com/ accessed: feb 2012. 16. jemal a, center mm, desantis c, ward em. global patterns of cancer incidence and mortality rates and trends. cancer epidemiol biomarkers prev 2010; 19:1893‒907. doi: 10.1158/1055-9965.epi-10-0437. 18. lacey jv jr, devesa ss, brinton la. recent trends in breast cancer incidence and mortality. environ mol mutagen 2002; 39:82‒8. doi: 10.1002/em.10062. 19. elbasmy a, kuwait ministry of health. kuwait cancer registry ten years report: 2000‒2009. kuwait; kuwait ministry of health, 2010. 20. vostakolaei fa, broeders mjm, rostami n, van dijck jaam, feuth t, kiemeney lalm, et al. age at diagnosis and breast cancer survival in iran. int j breast cancer 2012; 2012:517976. doi: 10.1155/2012/517976. 21. saudi arabia ministry of health. cancer incidence report saudi arabia 2008. saudi arabia: saudi cancer registry, 2011. 22. motawy m, el hattab o, fayaz s, oteifa m, ali j, george t, et al. multidisciplinary approach to breast cancer management in kuwait, 1993-1998. j egypt natl canc inst 2004; 16:85‒91. 23. fakhro af, fateha be, al-asheeri n, al-ekri sa. breast cancer: patient characteristics and survival analysis at salmaniya medical complex, bahrain. east meditter health j 1999; 5:430‒9. 24. saudi cancer registry. saudi arabia cancer incidence and survival report 2007. from: www.ghdx. healthmetricsandevaluation.org/record/saudi-arabia-cancerincidence-and-survival-report-2007 accessed: feb 2014. 25. al-saad s, al-shinnawi h, shamsi nm. risk factors of breast cancer in bahrain. bahrain med bull 2009; 31:64‒8. 26. alsayyad j, omran a, amin fa, hamadeh rr. national noncommunicable diseases risk factors survey 2007. manama, bahrain: bahrain ministry of health and undp country programme, 2010. 27. hamadeh rr. risk factors of major noncommunicable diseases in bahrain: the need for a surveillance system. saudi med j 2004; 25:1147‒52. 28. world health organization. noncommunicable diseases country profiles 2011. from: www.who.int/nmh/publications/ ncd_profiles2011/en/ accessed: feb 2014. 29. al hajeri a. prospective view of breast cancer in bahrain. j bahrain med soc 2013; 24:104. 30. al-foheidi m, al-mansour mm, ibrahim em. breast cancer screening: review of benefits and harms, and recommendations for developing and low-income countries. med oncol 2013; 30:471. doi: 10.1007/s12032-013-0471-5. 31. esserman l, shieh y, thompson i. rethinking screening for breast cancer and prostate cancer. jama 2009; 302:1685‒92. doi: 10.1001/jama.2009.1498. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e120–123, epub. 21 jan 15 submitted 25 feb 14 revision req. 22 apr 14; revision recd. 29 jun 14 accepted 23 jul 14 1department of medicine, sultan qaboos university hospital; 3department of medicine, college of medicine & health sciences, sultan qaboos university; 2department of medicine, royal hospital, muscat, oman *corresponding author e-mail: omayma0@hotmail.com مرض كوشنج بسبب زيادة إفراز اهلرمون املوجِّه لقشر الكظر ه لق�رض الكظر من الغدة النخامية أم من خارجها استعمال أوكرتيوتايد ملعرفة مصدر زيادة إفراز الهرمون املوِجّ اأميمة ال�ضفيع، نورالدين ال�ضايف، أحمد ال�ضجواين، نيكوال�س وود هو�س abstract: objectives: adrenocorticotropic hormone (acth) overproduction is usually due to a pituitary tumour which is often not visible on magnetic resonance imaging (mri). however, acth overproduction may be due to an ectopic source. this study aimed to develop a simple non-invasive technique to differentiate these sources. methods: this study took place in king faisal specialist hospital & research centre, riyadh, saudi arabia, and sultan qaboos university hospital, muscat, oman, between 1988 and 2012. serum cortisol levels were measured in nine patients with acth-dependent cushing’s syndrome before and during a 72-hour trial of octreotide. all patients underwent computed tomography (ct) scans. mri scans were performed on six patients. results: ct scans were abnormal in three patients with ectopic acth production. mri scans showed that three patients had pituitary microadenomas. serum cortisol levels returned to normal in those with confirmed ectopic acth production. no response was found in the other six patients. conclusion: a 72-hour trial of octreotide is recommended for patients with acth-dependent cushing’s syndrome and a normal pituitary mri. this trial will be a useful alternative to petrosal sinus sampling. keywords: adrenocorticotrophic hormone; cushing’s syndrome; somatostatin receptors; investigational therapies; octreotide; saudi arabia; oman. ه لق�رض الكظر )acth( امل�ضبب ملر�س كو�ضنج غالبا ما يكون ب�ضبب ورم �ضغري يف الغدة امللخ�ص: الهدف: اإن زيادة اإفراز الهرمون املوِجّ النخامية ويف معظم االأحيان ال ميكن حتديد الورم باأ�ضعة الرنني املغناطي�ضي، كما اأن اإفراز هذا الهرمون قد يكون ب�ضبب ورم خارج الغدة النخامية. الغر�س من هذه الدرا�ضة هو تو�ضيح طريقة ب�ضيطة يتم من خللها معرفة م�ضدر الزيادة يف اإفراز هرمون)acth( ما اإذا كان من الغدة النخامية اأو مكان اآخر يف اجل�ضم. الطريقة: متت هذه الدرا�ضة يف م�ضت�ضفى امللك في�ضل التخ�ض�ضي ومركز االأبحاث، الريا�س، اململكة العربية ال�ضعودية، وم�ضت�ضفى جامعة ال�ضلطان قابو�س، م�ضقط، �ضلطنة عمان، بني عامي 1988 و 2102م. متت الدرا�ضة على ت�ضع مر�ضى يعانون من مر�س كو�ضنج ب�ضبب زيادة اإفراز هرمون اي.�ضي.تي.ايج حيث قمنا مبراقبة م�ضتوى هرمون الكورتيزول يف الدم قبل وخلل 72 �ضاعة من بدء العلج باالوكرتيوتايد. مت اأخذ اأ�ضعة مقطعية جلميع املر�ضى الت�ضعة و اأجري فح�س الرنني املغناطي�ضي على �ضتة مر�ضى. النتائج: كانت نتائج االأ�ضعة املقطعية غري طبيعية يف ثلثة من املر�ضى الذين كانوا م�ضابني باأورام خارج الغدة النخامية. اإىل الكورتزول هرمون م�ضتوى انخف�س النخامية. الغدة يف �ضغري ورم لديهم املر�ضى من ثلثة اأن املغناطي�ضي الرنني نتائج اأظهرت الطبيعي عند املر�ضى الذين كانوا م�ضابني باأورام خارج الغدة النخامية اأما املر�ضى الستة الباقني فإن م�ضتوى الكورتزول بقي مرتفعا. اخلال�صة: نن�ضح با�ضتعمال االوكرتيوتايد ملدة 72 �ضاعة مع كل مر�ضى كو�ضنج ب�ضبب زيادة اإفراز هرمون اي.�ضي.تي.ايج والذين تكون هرمون قيا�س عن كبديل للت�ضخي�س الطريقة هذه ا�ضتعمال ميكن أنه كما لديهم، طبيعية النخامية للغدة املغناطي�ضي الرنني نتيجة )acth( عن طريق �ضحب عينات الدم من داخل اأوردة اجلمجمة. ه لق�رض الكظر؛ مر�س كو�ضنج؛ م�ضتقبلت �ضوماتو�ضتاتني؛ العلجات البحثية؛ األوكرتيوتايد؛ اململكة العربية مفتاح الكلمات: الهرمون املوِجّ ال�ضعودية؛ �ضلطنة عمان. adrenocorticotropic hormone-dependent cushing’s syndrome use of an octreotide trial to distinguish between pituitary or ectopic sources *omayma t. el-shafie,1 nooralddin al-saffi,1 ahmed al-sajwani,2 nicholas woodhouse3 the most common cause of adreno-corticotropic hormone (acth)-dependent cushing’s syndrome is a pituitary adenoma (90%).1 when this cause is identified, the condition is also known as cushing’s disease. other cases of acth-dependent cushing’s syndrome are due to ectopic acth secretion, generally by bronchial or pancreatic neuroendocrine tumours (nets) or, rarely, tumours that secrete corticotropin-releasing hormone (crh).2 however, in 40% of patients with cushing’s disease, magnetic resonance imaging (mri) shows a normal pituitary gland.3 these patients must be distinguished from those with ectopic acth production. the gold-standard practice for differentiating pituitary from ectopic acth overproduction is performing inferior petrosal sinus sampling (ipss) with serial acth measurements after the intravenous administration of crh. this procedure brief communication omayma t. el-shafie, nooralddin al-saffi, ahmed al-sajwani and nicholas woodhouse brief communication | e121 necessitates the cannulation of both jugular veins and is therefore invasive and costly.4 as a result, the sultan qaboos university hospital (squh), a tertiary centre in muscat, oman, relies on indirect testing to confirm or refute the pituitary source. as most nets express somatostatin receptors type 2 and 3, they are therefore amenable to treatment with octreotide which lowers acth and cortisol levels.5–7 patients with cushing’s disease do not respond to octreotide due to the lack of expression or downregulation of somatostatin receptors.8 furthermore, patients with nets secrete chromogranin a (cg-a) as well; it has therefore been theorised that the measurement of cg-a levels may prove to be of additional diagnostic value.9 in light of these factors, and because ipss is not available in all centres, the objective of this study was to test the use of a 72-hour trial of octreotide to distinguish between pituitary and ectopic acth overprodu ction. methods this study took place in king faisal specialist hospital & research centre, riyadh, saudi arabia, and squh between 1988 and 2012. nine patients with acthdependent cushing’s syndrome confirmed by elevated fasting serum cortisol and acth levels were included in the study. four of these patients have previously been reported in the literature.5 computed tomography (ct) scans of the neck, chest and abdomen were carried out on all patients. in addition, six patients underwent mri scans and two had their cg-a levels measured on admission after fasting. each patient undertook a 72-hour therapeutic trial of octreotide, with a dose of 100 mcg administered every eight hours. serial cortisol measurements were taken at the beginning of the trial (8 am) and then subsequently 24, 48 and 72 hours after the trial had begun. some patients had basal samples taken 48 and 24 hours before the trial began. subjects whose serum cortisol levels were unchanged throughout the study period were determined not to have responded to the octreotide trial, while patients whose serum cortisol levels decreased to within a normal range were determined to have responded to the treatment. all patients and their families gave consent for their inclusion in the study. results a total of nine patients with acth-dependent cushing’s syndrome were identified during the study period. serum cortisol levels were unchanged in six patients but fell progressively to normal levels in the remaining three patients [figure 1]. the six subjects who did not respond to the octreotide trial had normal ct results of the neck, chest and abdomen. in comparison, the patients who responded to the treatment had abnormal ct scans of the lung and pancreas. cg-a levels were normal in the two patients who did not respond. of the six patients who did not respond to the octreotide, mri scans revealed pituitary microadenomas in three, while the other three patients had normal mri results. among the three subjects who responded to octreotide, nets were identified as the source of the acth overproduction. before the trial started, one of the three patients was documented to have a benign bronchial carcinoid tumour while the other two were identified as having metastatic pancreatic nets producing acth both radiologically and histologically. the first patient had no need for further treatment following the removal of the benign bronchial carcinoid tumour. the other two patients died within a year of diagnosis. for the six patients who did not respond to octeotride, pituitary adenomas (cushing’s disease) were identified as the source of the acth overproduction. of these, five underwent transsphenoidal surgeries (tss) [table 1]. two patients were cured after their surgeries, while another two relapsed initially but at the time of writing were both in complete remission and receiving cabergoline treatment. one patient relapsed and received external radiotherapy; after this, the patient went abroad and was lost to follow up. at the time of writing, the final patient was in complete remission and was receiving cabergoline therapy without any other interventions. figure 1: serum cortisol levels in nine patients with adrenocorticotropic hormone-dependent cushing’s syndrome before and during a trial of octreotide. only three patients, all of whom were found to have neuroendocrine tumours, responded to treatment. grey bar = normal cortisol levels. adrenocorticotropic hormone-dependent cushing’s syndrome use of an octreotide trial to distinguish between pituitary or ectopic sources e122 | squ medical journal, february 2015, volume 15, issue 1 discussion acth-dependent cushing’s syndrome is rare and usually caused by a pituitary adenoma; however, 10% of cases are ectopic.1,2 if the source of the acth overproduction is not readily apparent, centres with the necessary resources can carry out ipss with acth measurements. this procedure will distinguish pituitary from ectopic sources and help localise the site of the tumour within the pituitary gland. however, as ipss is not yet available in all centres, it is important to develop alternative approaches. one such approach consists of a short trial of octreotide, which has been assessed and reported previously.5 as shown in the current study, only three patients with acth-dependent cushing’s syndrome were found to have decreased cortisol levels and therefore to have responded to the octreotide treatment; these patients were subsequently found to have nets. in comparison, there was no response in the remaining six patients who were diagnosed with cushing’s disease. somatostatin receptors are expressed in normal pituitary acth-producing cells; however, it has been found that the expression of somatostatin receptors 2 and 3 is downregulated by elevated glucocorticoid levels.8 this explains why octreotide is not therapeutically useful in cushing’s disease. a study by de herder et al. using somatostatin receptor imaging further supports the results of the present study, as octreotide scanning was negative in eight patients with acth-secreting pituitary adenomas whereas uptake was positive in all 10 of their patients identified with nets producing ectopic acth.9 most nets co-secrete cg-a with hormones;10 thus, the measurement of circulating cg-a levels was recently added to the octreotide trial procedure reported in the current study. this measurement was included as a further diagnostic tool to distinguish pituitary from ectopic disease. this combination is currently carried out routinely in squh. in another recent study conducted in oman, highdose cabergoline was used successfully to treat four patients with cushing’s disease.11 although one of the patients refused surgery, they were treated with cabergoline monotherapy; the dosage was reduced from 1 mg/day to 1 mg twice weekly and the patient has remained in complete remission for almost three years since the time of writing.11 as a result of these observations, the current practice at squh is to offer a short-term trial of cabergoline to patients with acthdependent cushing’s syndrome who do not respond to octreotide and have normal pituitary mris. if the patient responds, they may be offered long-term cabergoline treatment or a laparoscopic adrenalectomy. should the patient subsequently develop nelson’s syndrome, a tss may then be carried out.12 conclusion the results of this study indicate that a 72-hour trial of octreotide is advisable for all patients with acthdependent cushing’s syndrome and normal mri results. this procedure has been shown to be a safe and simple method that will effectively distinguish between pituitary and ectopic acth overproduction. in addition, it is a useful alternative to ipss in centres where this procedure is not available. table 1: fasting serum cortisol and acth levels and imaging results in nine patients with acth-induced cushing’s syndrome at presentation and subsequently identified source of acth overproduction patient cortisol levels in nmol/l* acth levels in pmol/l** ct/mri tss source 1 675 25 ectopic (lung carcinoid) 2 826 9 ectopic (pancreatic carcinoid) 3 856 27 ectopic (pancreatic carcinoid) 4 612 13 normal performed pituitary 5 812 4 normal performed pituitary 6 752 14 normal not perfomed pituitary 7 923 24 microadenoma perfomed pituitary 8 700 16 microadenoma performed pituitary 9 1,100 6 microadenoma performed pituitary acth = adrenocorticotropic hormone; cg-a = chromogranin a; ct = computed tomography; mri = magnetic resonance imaging; tss = transsphenoidal surgery. *normal range: 184–580 nmol/l; **normal range: 1.6–13.9 pmol/l. omayma t. el-shafie, nooralddin al-saffi, ahmed al-sajwani and nicholas woodhouse brief communication | e123 references 1. howlett ta, drury pl, perry l, doniach i, rees lh, besser gm. diagnosis and management of acth-dependent cushing’s syndrome: comparison of the features of ectopic and pituitary acth production. clin endocrinol (oxf ) 1986; 24: 699–713. doi: 10.1111/j.1365-2265.1986.tb01667.x. 2. jensen rt. endocrine tumors of the gastrointestinal tract and pancreas. in: jameseon jl, ed. harrison’s endocrinology, 2nd ed. new york, usa: mcgraw-hill professional, 2010. pp. 348–66. 3. kaye tb, crapo l. the cushing syndrome: an update on diagnostic tests. ann intern med 1990; 112:434–44. doi: 10.7326/0003-4819-76-3-112-6-434. 4. bonelli fs, huston j 3rd, carpenter pc, erickson d, young wf, jr., meyer fb. adrenocorticotropic hormone-dependent cushing’s syndrome: sensitivity and specificity of inferior petrosal sinus sampling. ajnr am j neuroradiol 2000; 21:690–6. 5. woodhouse nj, dagogo-jack s, ahmed m, judzewitsh r. acute and long-term effects of octreotide in patients with acthdependent cushing’s syndrome. am j med 1993; 95:305–8. doi: 10.1016/0002-9343(93)90283-u. 6. hearn pr, reynolds cl, johansen k, woodhouse nj. lung carcinoid with cushing’s syndrome: control of serum acth and cortisol levels using sms 201-995 (sandostatin). clin endocrinol (oxf ) 1988; 28:181–5. doi: 10.1111/j.13652265.1988.tb03654.x. 7. rodrigues p, castedo jl, damasceno m, carvalho d. ectopic cushing’s syndrome caused by a pulmonary acth-secreting tumor in a patient treated with octreotide. arq bras endocrinol metabol 2012; 56:461–4. doi: 10.1590/s0004-27302012000700009. 8. schonbrunn a. glucocorticoids down-regulate somatostatin receptors on pituitary cells in culture. endocrinology 1982; 110:1147–54. doi: 10.1210/endo-110-4-1147. 9. de herder ww, krenning ep, malchoff cd, hofland lj, reubi jc, kwekkeboom dj, et al. somatostatin receptor scintigraphy: its value in tumour localization in patients with cushing’s syndrome caused by ectopic corticotropin or corticotropinreleasing hormone secretion. am j med 1994; 96:305–12. doi: 10.1016/0002-9343(94)90059-0. 10. syversen u, ramstad h, gamme k, qvigstad g, falkmer s, waldum hl. clinical significance of elevated serum chromogranin a levels. scand j gastroenterol 2004; 39:969–73. doi: 10.1080/00365520410003362. 11. elshafie o, osman a, aamer f, al-mamari a, woodhouse n. cushing’s disease: sustained remission in five cases induced by medical therapy with the dopamine agonist cabergoline. sultan qaboos univ med j 2012; 12:493–7. 12. el-shafie o, abid fb, al-kindy n, sankhla d, woodhouse nj. cushing’s disease: pituitary surgery versus adrenalectomy. sultan qaboos univ med j 2008; 8:211–14. sultan qaboos university med j, august 2014, vol. 14 iss. 3, pp. e414-415, epub. 24th jul 14 submitted 30th jan 14 revision req. 12th mar 14; revision recd. 12th mar 14 accepted 23rd mar 14 ورم اخلاليا القاعدية الظهارية الوعائية يف املرضى املراهقني linear epithelioid haemangioma in an adolescent patient letter to editor sir, a 13-year-old male attended the dermatological outpatient clinic at the jaén hospital complex in jaén, spain. he presented with erythematous violaceous nodules that followed a linear pattern on his left upper limb [figure 1a] and upper back, which had appeared three weeks before. his personal and familiar history was unremarkable. he was not experiencing any itching or pain. the patient denied having had a previous traumatic injury or a herpes zoster infection. on cutaneous examination, no similar lesions were observed in any other locations. routine laboratory tests, including a blood count, a general biochemistry test, a urinalysis and an immunological profile, showed no abnormalities. a magnetic resonance imaging (mri) scan was performed and no arteriovenous (av) shunts were observed. histopathologically, a proliferation of large endothelial cells lining vascular spaces was observed, along with lymphocytic and eosinophilic inflammatory infiltrations in the dermis [figure 1b]. immunochemical staining for cluster of differentiation cells 31 (cd31) and cd34 were both positive. consequently, epithelioid haemangioma (eh) was diagnosed. written informed consent for educational purposes was requested and obtained for publication. eh is a benign, idiopathic vasculoproliferative condition. it was first described by wells and whimster in 1969 as angiolymphoid hyperplasia with eosinophilia (alhe).1 however, the term eh is more suited considering the condition’s histological changes. eh is a very well defined entity and the absence of systemic involvement, lymphadenopathies, blood eosinophilia or a neprothic syndrome provides the key points in the differential diagnosis with kimura’s disease. eosinophilia is described in less than 20% of patients referred to in the scientific literature.2 mainly affecting adult patients of all races, eh is infrequent among the paediatric population. involvement of the trunk and extremities is extremely rare, as most reported cases are located on the head (the preauricular area) and neck. on clinical examination, erythematous violaceous papules or nodules are the most representative cutaneous lesions. they can be superficial or deeper, and have been reported to follow a zosteriform pattern in a few cases.3,4 the lesions are often associated with spontaneous bleeding, pain or pruritus. they may coalesce into confluent plaques. a cutaneous biopsy is mandatory for patients with eh. histologically, the lesions are normally characterised by the presence of endothelial proliferations in which the neoplastic endothelial cells are plump, eosinophilic and polygonal, forming vascular channels. intracytoplasmic vacuoles are also commonly identified. the surrounding stroma contain a mild inflammatory infiltrate with eosinophils and lymphoplasmacytic cells. an immunohistochemical study will usually show that the tumour cells are positive for the endothelial markers cd31 and cd34 and negative for the epithelial marker cytokeratin.5 figure 1 a & b: a: erythematoviolaceus nodules on the right arm and forearm, following a zosteriform pattern. b: haematoxylin and eosin stain showing epithelioid cells in a solid pattern at x40 magnification. ricardo ruiz-villaverde letter to editor | e415 the differential diagnosis for children with eh mainly includes pyogenic granulomas. several drugs, such as rituximab, and minor traumas have been suggested as the possible causes of eruptive pyogenic granuloma. other conditions with varying degrees of malignancy, such as haemangioendothelioma and angiosarcoma, may also be considered. the presence of atypical mitosis, cytological atypia and alterations in the lesions’ architecture may point the histological diagnosis towards the previously mentioned conditions. it has also been suggested that av shunts may be responsible for the development of eh.6 therefore, an mri scan should be performed to rule this out. these av shunts can be observed in some histological stains, however, an experienced dermatopathologist may be required to determine the venule or capillary communication.5 the treatment options for eh include systemic intralesional corticosteroids, conventional surgery, cryotherapy, cautery, sclerotherapy and the use of a pulsed dye laser. recurrences have been observed in almost 10% of cases.7 a spontaneous regression is a known possibility. when treating eh, physicians should consider the patient’s age and elect a conservative therapeutical approach with periodic revisions. ricardo ruiz-villaverde department of dermatology, jaén hospital complex, jaén, spain e-mail: ismenios@hotmail.com references 1. wells gc, whimster iw. subcutaneous angiolymphoid hyperplasia with eosinophilia. br j dermatol 1969; 81:1–14. doi: 10.1111/j.13652133.1969.tb15914.x. 2. jang ka, lee jy, kim ch, choi jh, sung kj, moon kc, et al. angiolymphoid hyperplasia with eosinophilia and kimura’s disease: a clinicopathologic study in korea. korean j dermatol 2001; 39:309–17. 3. kurihara y, inoue h, kiryu h, furue m. epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) in zosteriform distribution. indian j dermatol 2012; 57:401–3. doi: 10.4103/0019-5154.100501. 4. dowlati b, nabai h, mehregan dr, mehregan da, khaleel j. zosteriform angiolymphoid hyperplasia with eosinophilia. j dermatol 2002; 29:178–9. 5. sánchez js, gar ía es, serrano tg. [epithelioid hemangioma in deep and non facial location: report of two cases and review of the literature.] rev esp patol 2008; 41:138–41. doi: 10.1016/s1699-8855(08)70110-7. 6. olsen tg, helwig eb. angiolymphoid hyperplasia with eosinophilia: a clinicopathologic study of 116 patients. j am acad dermatol 1985; 12:781–96. doi: 10.1016/s0190-9622(85)70098-9. 7. weiss sw, goldblum jr. enzinger and weiss’s soft tissue tumors. 4th ed. st louis, usa: mosby, 2001. pp. 345–8. department of 1family medicine & public health, sultan qaboos university hospital; departments of 2behavioural medicine, 3pharmacology & clinical pharmacy and 4family medicine & public health, college of medicine & health sciences, and 5department of mathematics & statistics, college of science, sultan qaboos university, muscat, oman *corresponding author e-mail: ial_zakwani@yahoo.com اسباب األستشاره الطبيه لدى املرضى الزائرين ملراكز الرعايه الصحيه األوليه يف عمان اأحمد املنظري، �شمري العدوي، ابراهيم الزكواين، اأت�شو دورفلو، حممد ال�شافعي امللخ�ص: الهدف: ال�شبيل للرعايه اأو اللجوء للرعايه والتي بالتايل توؤدي لأ�شتخدام الرعايه ال�شحيه قد متت درا�شتها يف العديد من مناطق ملراكز الزائرين خ�شائ�ض معرفة هو الدرا�شه هذه من الهدف كان العربي. اخلليج يف الدرا�شات هذه مثل يف ندره هناك ولكن العامل، الرعايه ال�شحيه الأوليه يف اجلزء ال�شمايل من عمان ومعرفة الأ�شباب املوؤديه للزياره. الطرق: مت اجراء مقابله �شخ�شيه لعدد 676 م�شارك من الزائرين لثني ع�رسة مركز من مراكز الرعايه ال�شحيه الأوليه خالل الفرته من يونيو اىل يوليو من العام 2006. مت اختيار مناطق الدرا�شه لكي تعك�ض الو�شع ال�شكاين يف عمان. مت قراءة ا�شئلة الأ�شتبيان املكونه من 12 �شوؤال لكل خام�ض مري�ض يدخل املركز ال�شحي ح�شب املوعد املحدد له. مت حتليل البيانات باأ�شتخدام التحليل الأحادي. النتائج: كان ما يقارب من ثلث امل�شاركني بالدرا�شه )عدد 200 م�شارك: %29.6( لديهم اأمرا�ض مزمنه. وكان عدد 231 )%34( ي�شتخدمون اأدويه باأنتظام. 211 )%31( كانوا ي�شاركون يف برامج التثقيف ال�شحي وكان 130 )%19( منفتيحني على اأ�شتخدام الطب امل�شاند. غالبية امل�شاركني ذكروا من اأن ن�شيحة الطبيب )عدد 570 دميوغرافيه بعوامل بقوة مرتبطة الطبيب ن�شيحة كانت العك�ض على ال�شحيه. للموؤ�ش�شه اللجوء لقرار �شبب اقوى كانت )84% م�شارك: مت بالتايل هذه ال�شلطنه. �شمال يف ال�شحيه املراكز لزيارة املوؤديه والأ�شباب اخل�شائ�ض بع�ض حددت الدرا�شه هذه الأ�صتنتاج: معينه. مناق�شتها يف اطار الرتابط مع العوامل الأجتماعيه والثقافيه اخلا�شه بال�شلطنه. كذلك مت مناق�شتها من جانب الرتابط مع الوقايه والك�شف عن املر�ض يف عمان. مفتاح الكلمات: �شلوك اللجوء للرعايه ال�شحيه؛ املركز املجتمعي ال�شحي؛ عالقة الطبيب مع املري�ض؛ عمان؛ العامل العربي. abstract: objectives: pathways to care or care-seeking, which translate into healthcare utilisation, have been investigated in many parts of the world, but there is a dearth of studies in the arabian gulf. the aim of this study was to examine the characteristics of attendees at primary healthcare centres in northern oman and their reasons for visiting. methods: face-to-face interviews were conducted with 676 participants attending 12 primary healthcare centres between june and july 2006. the catchment area was selected to represent the population structure in oman. the 12-item questionnaire was read to every fifth eligible patient entering each healthcare centre for a routine appointment. analyses were conducted using univariate statistics. results: about a third (n = 200; 29.6%) of the participants had a history of chronic illness; 231 (34%) were on regular medications; 211 (31%) were taking part in health education programmes; 130 (19%) were open to complementary medicine. the majority of the participants mentioned physician's advice (n = 570; 84%) as the strongest reason for seeking consultation. conversely, physician's advice was strongly related to particular demographic factors. conclusion: this observational study identified some characteristics and reasons for visiting healthcare facilities in northern oman. these are discussed within the context of prevailing sociocultural factors. the implications for the prevention and detection of ill health in oman are also discussed. keywords: patient acceptance of healthcare; attitude to health; community health centers; physician-patient relations; oman. reasons for consultation among patients attending primary healthcare centres in oman ahmed al-mandhari,1 samir al-adawi,2 *ibrahim al-zakwani,3 atsu dorvlo,5 mohammed al-shafaee4 clinical & basic research advances in knowledge the idea of illness as a sociocultural construct has been discussed in this study. it was found that pathways to care are shaped by a number of factors, such as proximity to a healthcare institution, and the reputation of the institutions as well as that of healthcare professionals. a better understanding of healthcare utilisation can be used as a springboard for redressing some of the disparities in healthcare services. the results of this study indicated that literate attendees were twice as likely to seeking a physician's advice compared to their illiterate counterparts. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 248-256, epub. 9th may 13 submitted 3rd jul 12 revision req. 20th oct 12, revision recd. 17th jan 13 accepted 17th mar 13 ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, atsu dorvlo and mohammed al-shafaee clinical and basic research | 249 social and cultural issues have a direct bearing on health, disease, and the practice of medicine.1 this issue is pertinent when considered in the context of care-seeking behaviour, and related mechanisms such as healthcare utilisation or pathways to care. in the current age of a patient-centred approach to healthcare, studies in various parts of the world have documented what type of care services the public prefers.2,3 international studies suggest that pathways to care are shaped by a number of factors, including proximity to the healthcare centre,4 the reputation of the institution and its healthcare professionals,5 advice from significant others,6 and exposure to health education.7 other factors that contribute to care-seeking include the impact of the illness on quality of life, and the perceived threat of being ill.8 the service accessibility, quality and cost of healthcare, as well as the social structures, health beliefs and personal characteristics of the healthcare consumers, have also been demonstrated to play a role in careseeking behaviour.9–11 a better understanding of healthcare utilisation can be used as a springboard for redressing some of the disparities in healthcare services.12,13 this understanding has been used as the basis for devising preventive measures, allocating healthcare resources and dispensing relevant health education.14 while the pattern of care-seeking has been explored in different parts of the world,15,16 there is a dearth of studies examining care-seeking in the arab region of the world, with the notable exception of the united arab emirates.17 most of the available literature on care-seeking has been limited to mental health issues 18,19 or to middleeastern migrants in europe and north america.20 data from the omani ministry of health have shown that, on average, healthcare centres cater to approximately 90% of the population’s needs.21 the majority of oman’s population is located either in the north or in the far south of the sultanate; these two regions are separated by a stretch of desert known as the empty quarter.22 for logistical reasons, the present study was limited to the northern region of oman, which includes a number of large coastal towns, including the capital city muscat, as well as a number of towns in the more mountainous interior region. the population of this region was found to reflect the ethnocultural diversity present in omani society.23 the northern region has a population of approximately two million omani citizens.24 in order to lay the groundwork necessary for developing strategies to improve the awareness and delivery of healthcare in oman, this paper examined the characteristics of attendees at primary healthcare centres and the factors influencing their care-seeking decisions, as well as identifying sociodemographic indices of healthcare resource utilisation that may contribute to careseeking. specifically, this paper examined: 1) the demographic characteristics of attendees seeking consultation at health centres in the northern region of oman, and 2) the reasons behind their visit. to our knowledge, this is the first study on healthcareseeking behaviour in oman. the information derived from this study could be used by public health planners for evidence-based resource allocation in the country. an understanding of care-seeking behaviour would improve overall healthcare planning and health education programmes for the prevention and detection of ill health. methods the protocol for the data collection has already been described elsewhere.25,26 for the present study, the targeted region was the six wilayats (districts) of the northern region, each of which has two to four health centres. two health centres were selected from each wilayat for inclusion in the study. for application to patient care maternal education should be prioritised as it is a strong predictor of care-seeking behavior. physicians should strengthen their rapport with their patients, as physicians’ advice plays a major role in the healthcare-seeking behavior of the community. healthcare institutions should work on developing their reputation as well as the reputation of their staff, as this is found to be the most ranked reason for visiting healthcare centres. broadcast media is considered a primary source of information in the arab world; therefore, healthcare systems should make use of the media to disseminate healthcare information to the community. reasons for consultation among patients attending primary healthcare centres in oman 250 | squ medical journal, may 2013, volume 13, issue 2 those wilayats with more centres, two were selected randomly. every fifth consecutive patient who visited a selected health centre for a routine consultation was invited to participate in the study, and a minimum of 50 participants were recruited from each health centre. the data were collected between june and july 2006. the participants were explicitly informed that any information they provided in the course of the interview would remain completely anonymous, and that their participation would not in any way affect their consultation with medical professionals. a total of 676 subjects participated in this study, and the data were collected through face-to-face interviews. the medical research & ethics committee of sultan qaboos university’s (squ) college of medicine & health sciences approved the study (mrec #299). the questionnaire collected information on the patients’ gender, age, marital status, education level, history of chronic illness and use of regular medication. it also covered the reasons for the current visit, how many times they visited their healthcare facility in one month and if they attended health education sessions. the detailed questions (and results) about the specific reasons for their visit and the impact of these reasons on their decision to visit are shown in table 1. the rationale for particular variables merits some justification, as some variables were included in the questionnaire because of their relevance to the local situation. in a collectivist society like oman, the family plays a central role in directing table 1: demographic, clinical and healthcare resource characteristics of the study cohort (n = 676) characteristic seeking physician’s advice p valuetotal (n = 676) yes (n = 570) no (n = 106) age in years (mean ± sd) 32 ± 13 32 ± 12 32 ± 13 0.785 gender, n (%)* female male 410 (61) 266 (39) 357 (63%) 213 (37%) 53 (50%) 53 (50%) 0.015 marital status, n (%) married single, divorced, widowed 437 (65%) 239 (35%) 374 (66%) 196 (34%) 63 (59%) 43 (41%) 0.222 literacy, n (%) literate (can read or write) illiterate (cannot read or write) 559 (83%) 117 (17%) 476 (84%) 94 (17%) 83 (78%) 23 (22%) 0.193 history of chronic illness, n (%) yes no 200 (30%) 476 (70%) 172 (30%) 398 (70%) 28 (26%) 78 (74%) 0.436 on regular medication, n (%) yes no 231 (34%) 445 (66%) 196 (34%) 374 (66%) 35 (33%) 71 (67%) 0.785 source of healthcare, n (%) government private traditional 473 (70%) 73 (11%) 130 (19%) 402 (71%) 54 (9%) 114 (20%) 71 (67%) 19 (18%) 16 (15%) 0.027 reason to seek healthcare, n (%) treatment of acute condition(s) follow-up visit vaccination(s) or other 271 (40%) 227 (34%) 178 (26%) 228 (40%) 195 (34%) 147 (26%) 43 (41%) 32 (30%) 31 (29%) 0.656 number of visits attended per month mean ± sd median (iqr) 1.29 ± 2.09 1 (0–1) 1.27 ± 1.87 1 (0–1) 1.39 ± 3.02 1 (0–1) 0.939 regularly attended health education programmes, n (%) yes no 211 (31%) 465 (69%) 184 (33%) 386 (68%) 27 (25%) 79 (75%) 0.165 sd = standard deviation; * = percentages are column percentages wherever appropriate; iqr=interquartile range. ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, atsu dorvlo and mohammed al-shafaee clinical and basic research | 251 an individual’s social behaviour, and it was therefore deemed essential to gauge the role of significant others in care-seeking behaviours. further, as healthcare is free for the omani population, which is widely scattered over an area of 309,500 km2,27 it was therefore deemed essential to take into account proximity to a healthcare centre. in oman, physicians are granted an esteemed status in society and are likely to be consulted on all manner of things. therefore, it was important to include variables that indicate whether a physician’s advice impacted the decision to seek care. in this study, physician’s advice was operationalised as any contact with a doctor (inside or outside a health centre) on healthrelated issues that could lead to the respondent seeking formal healthcare. variables eliciting the importance of health education were included because most of the health problems in oman would require a degree of patient empowerment in order to achieve improved health outcomes.28,29 the remaining variables, derived from the available international literature, were selected because they were considered to be important indicators of careseeking behaviour.4 the final questionnaire was piloted on a convenience-based sample among patients attending primary healthcare services in the vicinity of squ, oman, as already described elsewhere.25,26 to accommodate illiterate patients—without introducing methodological inconsistencies—the designated questionnaires were read aloud to all participants, rather than being self-administered. the interviews were conducted in arabic by trained researchers, predominantly second and third year medical students from the college of medicine & health sciences at squ, who had been trained to read the questionnaire and to document participant responses with precision and reliability; substantial inter-coder agreement for the scale items was observed (r = 0.84, p <0.001). descriptive statistics were used to depict the data. for categorical variables, frequencies and percentages were reported. the association between the various possible contributors to healthcare utilisation and care-seeking, and the strength of these effects, were analysed using chi-square or fisher’s exact tests wherever appropriate. for continuous variables, means and standard deviations (sd) or medians were presented as appropriate. analyses were conducted using the students’ t-test and mann-whitney u tests where appropriate. multivariable logistic regression was also used to assess associations between some of the variables against physician's advice as a reason to seek healthcare. statistical analyses were conducted using stata software, version 12.1 (stata corporation, college station, texas, usa). results as depicted in table 1, the overall mean age of the 676 participants was 32 ± 13 years with an age range of 15 to 80 years. a total of 61% (n = 410) of the participants were female. the majority of the participants were married (n = 437; 65%). a total of 17% of the cohort was classified as illiterate, i.e. people who could not read or write although they did have a cursory knowledge of religious teachings. a total of 30% of the cohort documented that they were suffering from chronic illness; this view is further substantiated by the fact that 34% were on regular medication. most of the participants listed government healthcare centres as their main source of healthcare (n = 473; 70%); however, 19% (n = 130) of the participants commonly received their healthcare from traditional healers. only 11% of the participants received their care from private sources (n = 73). about 40% of the sample sought treatment for acute complaints; the second most common reason for seeking treatment was for follow-up visits (34%). vaccinations or other reasons were ranked third and constituted 25% of the cohort. the median number of visits for participants per month was one. in the present sample, out of 676 people, only 211 (31%) individuals endorsed the view that they regularly attended health education programmes. the most prevalent reason for visiting a healthcare facility was physician's advice (84%) [table 2]. the reputations of the institutions (75%) and of the staff (75%) were the second and third most cited reasons respectively for visiting. proximity to a facility was cited by 62% of the participants as a reason for visits, and was the sixth most important reason. the least common reason to visit a healthcare facility was to obtain sick leave (23%), and reading health education articles was the second least cited reason for visiting a healthcare facility. all patients who cited a reason for going to reasons for consultation among patients attending primary healthcare centres in oman 252 | squ medical journal, may 2013, volume 13, issue 2 a healthcare facility also indicated that the effect of that particular reason was strong. for example, for those who selected close proximity as a reason, the strength of this effect was ranked “strong” in 74% of the cases, while those who did not select close proximity as a reason to seek healthcare ranked the strength of this effect as “strong” in 61%, demonstrating a significant difference (p = 0.003) [table 2]. the exception is that even those who did not visit a healthcare facility on the advice of a physician, mostly rated the effect of a physician’s advice as very strong (p = 0.067). the 12 variables were internally consistent (cronbach’s alpha coefficient = 0.635). as depicted in table 3, after adjusting for age, gender, marital status, literacy, and use of regular medications, there was no association between physician's advice and a history of chronic illness (p = 0.383). however, there was a strong negative correlation between gender and physician’s advice. specifically, males were 46% less likely to seek a physician's advice compared to females (95% table 2: reasons affecting healthcare resource utilisation stratified by their strength (n = 676) reason for visit strength of the effect total p value* strong mild don’t know physician advice, n (%) no† yes† 106 (16) 570 (84) 10 (59) 408 (73) 6 (35) 147 (26) 1 (6) 3 (1) 17 (3) 558 (97) 0.067 institution reputation, n (%) no yes 166 (25) 510 (75) 10 (42) 276 (71) 4 (16) 110 (28) 10 (42) 4 (1) 24 (6) 390 (94) <0.001 staff reputation, n (%) no yes 172 (25) 504 (75) 12 (42) 353 (74) 8 (29) 115 (24) 8 (29) 9 (2) 28 (6) 477 (94) <0.001 increased severity of symptoms, n (%) no yes 187 (30) 430 (70) 18 (60) 383 (94) 7 (23) 22 (5) 5 (17) 2 (1) 30 (7) 407 (93) <0.001 advice from a relative, n (%) no yes 212 (31) 464 (69) 8 (4) 262 (56) 32 (15) 184 (40) 4 (2) 3 (1) 44 (9) 449 (91) <0.001 distance of the institution from home, n (%) no yes 257 (38) 419 (62) 28 (61) 284 (74) 16 (35) 98 (26) 2 (4) 0 (0) 46 (11) 382 (89) 0.003 advice from a friend, n (%) no yes 258 (38) 418 (62) 4 (8) 215 (54) 36 (75) 182 (46) 8 (17) 3 (1) 48 (11) 400 (89) <0.001 symptoms, n (%) no yes 280 (41) 396 (59) 13 (39) 301 (82) 12 (36) 63 (17) 8 (24) 2 (1) 33 (8) 366 (92) <0.001 fear of dangerous disease(s), n (%) no yes 293 (43) 383 (57) 32 (56) 301 (84) 12 (21) 54 (15) 13(23) 3 (1) 57 (14) 358 (86) <0.001 watching/listening to health education programmes, n (%) no yes 306 (45) 370 (55) 5 (11) 174 (53) 24 (53) 153 (46) 16 (36) 3 (1) 45 (12) 330 (88) <0.001 reading health education article(s), n (%) no yes 360 (53) 316 (47) 18 (33) 139 (48) 26 (47) 147 (51) 11 (20) 2 (1) 55 (16) 288 (84) <0.001 obtaining sick leave, n (%) no yes 523 (77) 153 (23) 11 (44) 81 (56) 8 (32) 37 (27) 6 (24) 3 (2) 25 (17) 121 (83) <0.001 * = p values are for the association between the reason (yes/no) and the effect of the reason; † = yes means cited reason; † = no means did not cite reason. ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, atsu dorvlo and mohammed al-shafaee clinical and basic research | 253 ci: 0.35 to 0.85; p = 0.007). furthermore, literate respondents were also more than twice as likely to seek a physician's advice compared to their illiterate compatriots (95% ci: 1.01 to 4.29; p = 0.046). additionally, those using private sources of healthcare (49%) were less likely to seek a physician’s advice compared to those using government healthcare as their usual source of healthcare (95% ci: 0.28 to 0.94; p = 0.032). even after the covariate adjustment mentioned above, no relationship was noted between age and physicians' advice as a reason to seek healthcare (p = 0.853). discussion this observational study explored some characteristics of and reasons for visiting healthcare facilities among attendees at primary healthcare centres in northern oman. the data unequivocally suggested that prevailing socio-cultural factors play a strong role in care-seeking behaviour among the population of northern oman. previous studies have reported that females outnumber males in seeking care,30 and this is reflected in the present study. one implicit assumption behind women’s predominance in care-seeking could be that ideas of masculinity equate care-seeking with weakness.31 additionally, a reason for the high proportion of females seeking healthcare may be related to the well-known tendency for females to be diagnosed with more somatic diseases and medically-unexplained physical symptoms.32–34 furthermore, this study suggests that being married with a high level of education is an important predictor for careseeking. feminine identity in oman is deeply tied to a woman’s role as a mother which, in turn, has encouraged high fertility rates.35 in oman, this factor not only leads to many households with large numbers of children, but also to an often overlooked corollary, which is the high healthcare service utilisation for both antenatal care and postnatal care. this supports the view that the presence of children in a household is associated with more care-seeking.36 another characteristic of the attendees at the primary healthcare centres is that literate attendees were twice as likely to seek a physician's advice compared to their illiterate counterparts. this finding is congruent with previous findings that mothers' education is a strong predictor of careseeking behaviour.37 it is possible that those with lower education may be constrained by their social status within the community, for example, in being more dependent on others for their mobility. in addition to identifying the characteristics of the participants, the related aim of this study was to gauge the reasons for their visiting healthcare facilities. the most commonly reported reason for using healthcare resources was physician's advice. this echoes the traditional omani concept of the physician as a hakim, (a sage, wise man or leader).38 it therefore should be expected that the majority of the attendees in oman would naturally respect a physicians’ opinion; this may be the basis for endorsing a physician's advice as a strong catalyst for care-seeking. culturally, one would expect that if a physician's advice is held in the utmost respect, it would be natural to assume that the reputation table 3: predictors of physicians’ advice as a reason for healthcare resource utilisation using multivariable logistic regression* predictor adjusted odds ratio 95% confidence interval p value age 1.00 0.98 – 1.03 0.853 gender (male versus female) 0.54 0.35 – 0.85 0.007 marital status (married versus single/ divorced/widowed) 1.30 0.80 – 2.12 0.288 reading ability (literate versus illiterate) 2.09 1.01 – 4.29 0.046 history of chronic illness 1.41 0.65 – 3.02 0.383 use of regular medications 0.94 0.47 – 1.86 0.849 source of healthcare (private versus government) 0.51 0.28 – 0.94 0.032 source of healthcare (traditional versus government) 1.49 0.80 – 2.75 0.207 chronic follow-up versus acute condition 1.09 0.64 – 1.85 0.745 vaccination versus acute illness 0.98 0.58 – 1.67 0.947 number of hospital visits per month 0.98 0.90 – 1.07 0.600 health education sessions (attending versus nonattending) 1.19 0.73 – 1.95 0.480 * = the final logistic model is statistically significant (lr χ2 (12) = 21; p = 0.047). the hosmer-lemeshow χ2 statistic (a measure of the goodness-of-fit) was 4.65 and the p value was 0.794. reasons for consultation among patients attending primary healthcare centres in oman 254 | squ medical journal, may 2013, volume 13, issue 2 of the health centre and its staff would also be endorsed as reasons for seeking healthcare. in keeping with such a view, the present data suggested that a physician's advice was followed by the reputation of the health centre and its accompanying staff as the most ranked reasons for visiting healthcare centres. a final point worth noting is the fact that reading health education articles was among the least cited reasons for visiting a healthcare facility. it is possible that not enough literature exists, addressing matters of life and health related to the arab world, or that such articles are not exciting or accessible enough. one of the limitations of this study was that as the study was restricted to attendees of healthcare institutions, it is possible that a significant number of people in the community who do not seek medical attention were excluded39,40 and that therefore their views were not available for scrutiny. additionally, there is evidence to suggest that patients in a clinical setting tend to respond to enquiries differently than those elsewhere in the community.41 therefore, this preliminary study, which took advantage of the practicalities of using clinic attendees, should be followed up with a large-scale community survey to test the trends displayed here within the general population. a study comparing those who consulted other healthcare services with those who did not would be essential in order to determine which factors affected this decision. this should then be examined against the background of the recent major changes in oman’s delivery of primary healthcare. furthermore, the data analysed in this study were collected by interview, rather than in a self-administered format. it is therefore possible that this approach may have resulted in the reluctance among participants to reveal sensitive information, due to the presence of the interviewer. another limitation was that some of the questions in the questionnaire were specifically designed with an omani population in mind; this may limit comparisons with studies from other parts of the world. the fact that the study only included participants from the northern region of oman might also hamper the generalisation of the findings to the whole of oman. finally, the study team felt a sample size of at least 50 from each centre was reasonable and practical given cost and time constraints. using this study as a basis, future studies will determine sample sizes that will ensure set error limits and confidence levels. conclusion this study elicited the characteristics of and reasons for patients visiting healthcare facilities in northern oman. the healthcare system could capitalise on the characteristics and reasons for patients visiting healthcare facilities in order to contribute to the improvement of overall healthcare planning and health education programmes for the prevention and detection of ill health. references 1. holtz th, holmes sm, stonington s, eisenberg l. health is still social: contemporary examples in the age of the genome. plos med 2006; 3:e419. 2. more ns, alcock g, das s, bapat u, joshi w, osrin d. spoilt for choice? cross-sectional study of care-seeking for health problems during pregnancy in mumbai slums. glob public health 2010; 27:1–14. 3. ching p. user fees, demands for children's healthcare and access across income groups: the philippine case. soc sci med 1995; 41:37–44. 4. haynes r. geographical access to healthcare. in: gulliford mc, morgan m, eds. access to healthcare. london: routledge, 2003. pp. 13–35. 5. coulter a. what do patients and the public want from primary care? br med j 2005; 331:1199–201. 6. al-krenawi a, graham jr, dean yz, eltaiba n. crossnational study of attitudes towards seeking professional help: jordan, united arab emirates (uae) and arabs in israel. int j soc psychiatry 2004; 50:102–14. 7. leventhal h. illness behaviour and care seeking. in: international encyclopedia of the social & behavioral sciences. london: elsevier science, 2001. 8. chrisman nj, kleinman a. popular healthcare, social network and cultural meanings. in: mechanic d, ed. handbook of health, healthcare and health professions. new york: free press, 1983. pp. 569–90. 9. zola ik. pathways to the doctor. soc sci med 1973; 7:677– 89. 10. schnitzer g, loots g, escudero v, schechter i. negotiating the pathways into care in a globalizing world: help-seeking behavior of ultra-orthodox jewish parents. int j soc psychiatry 2011; 57:153–65. 11. cardol m, groenewegen pp, spreeuwenberg p, van dijk l, van den bosch wj, de bakker dh. why does it run in families? explaining family similarity in help-seeking behaviour by shared circumstances, socialisation and selection. soc sci med 2006; 63:920–32. ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, atsu dorvlo and mohammed al-shafaee clinical and basic research | 255 12. chennaveerappa pk, halesha br, vittal bg, jayashree n. a study on the sociodemographic profile of the attendees at the integrated counselling and testing centre of a medical college in south india. j clin diagn res 2011; 5:430–3. 13. alghanim sa. information needs and seeking behavior among primary care physicians in saudi arabia: implications for policy and practice. sci res & essays 2011; 6:1849–55. 14. bourne pa. socio-demographic determinants of healthcare-seeking behaviour, self-reported illness and self-evaluated health status in jamaica. int j collab res intern med & public health 2009; 1:101–30. 15. tuddenham sa, rahman mh, singh s, barman d, kanjilal b. care seeking for postpartum morbidities in murshidabad, rural india. int j gynaecol obstet 2010; 109:245–6. 16. hildenwall h, nantanda r, tumwine jk, petzold m, pariyo g, tomson g, et al. care-seeking in the development of severe community acquired pneumonia in ugandan children. ann trop paediatr 2009; 29:281–9. 17. rizk dee, shaheen h, thomas l, dunn e, hassan my. the prevalence and determinants of healthcare-seeking behavior for urinary incontinence in united arab emirates women. int urogynecol j pelvic floor dysfunct 1999; 10:160–5. 18. levinson d, ifrah a. the robustness of the gender effect on help seeking for mental health needs in three subcultures in israel. soc psychiatry psychiatr epidemiol 2010; 45:337– 44. 19. aloud n, rathur a. factors affecting attitudes toward seeking and using formal mental health and psychological services among arab muslim populations. j muslim ment health 2009; 4:79–103. 20. barnett vt. bringing it all back home: arab culture, north africa, and intensive care unit family satisfaction. crit care med 2008; 36:2204–5. 21. department of information and statistics, directorate general of planning, ministry of health, oman. ministry of health annual health report 2007. muscat: ministry of health, oman, 2007. 22. burjorjee r, al-adawi s. the sultanate of oman: an experiment in community care. psychiatr bull r coll psychiatr 1992; 16:646–8. 23. al-shafaee m, bhargava k, al-farsi ym, mcllvenny s, almandhari a, al-adawi s, et al. prevalence of pre-diabetes and associated risk factors in an adult omani population. int j diabetes dev ctries 2011; 31:166–73. 24. el shafie k, al farsi y, al zadjali n, al adawi s, al busaidi z, al shafaee m. menopausal symptoms among healthy, middle-aged omani women as assessed with the menopause rating scale. menopause 2011; 18:1113–19. 25. al-mandhari a, al-adawi s, al-zakwani i, al-shafaee m, eloul l. relatives’ advice and healthcare-seeking behaviour in oman. sultan qaboos univ med j 2009; 9:264–71. 26. al-mandhari a, al-adawi s, al-zakwani i, al-shafaee m, eloul l. impact of geographical proximity on healthcare seeking behaviour in northern oman. sultan qaboos univ med j 2008; 8:310–18. 27. central intelligence agency. the world fact-book: oman. from: https://www.cia.gov/library/publications/theworld-factbook/geos/mu.html accessed: august 2011. 28. viernes n, zaidan za, dorvlo as, kayano m, yoshiuchi k, kumano h, et al. tendency toward deliberate food restriction, fear of fatness and somatic attribution in crosscultural samples. eat behav 2007; 8:407–17. 29. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 30. o’brien r, hunt k, hart g. ‘it's caveman stuff, but that is to a certain extent how guys still operate’: men's accounts of masculinity and help seeking. soc sci med 2005; 61:503– 16. 31. mayberry rm, nicewander da, qin h, ballard dj. improving quality and reducing inequities: a challenge in achieving best care. world hosp health serv 2008; 44:16– 31. 32. mabry r, al-riyami a, morsi m. the prevalence of and risk factors for reproductive morbidities among women in oman. stud fam plann 2007; 38:121–8. 33. al lawati j, al lawati n, al siddiqui m, antony sx, alnaamani a, martin rg, et al. psychological morbidity in primary healthcare in oman: a preliminary study. sultan qaboos univ med j 2000; 2:105–10. 34. smits ft, brouwer hj, ter riet g, van weert hc. epidemiology of frequent attenders: a 3-year historic cohort study comparing attendance, morbidity and prescriptions of one-year and persistent frequent attenders. bmc public health 2009; 9:36. 35. dorvlo as, bakheit cs, al-riyami a, morsi m, al-adawi s. a study of fertility patterns of ever married women in oman. sultan qaboos univ med j 2006; 6:33–40. 36. campion p, gabriel j. illness behaviour in mothers with young children. soc sci med 1985; 20:325-30. 37. kutty vr. women's education and its influence on attitudes to aspects of child-care in a village community in kerala. soc sci med 1989; 29:1299–303. 38. adib sm. from the biomedical model to the islamic alternative: a brief overview of medical practices in the contemporary arab world. soc sci med 2004; 58:697–702. 39. molano sm, burdorf a, elders la. factors associated with medical care-seeking due to low-back pain in scaffolders. am j ind med 2001; 40:275–81. 40. elliott am, mcateer a, hannaford pc. revisiting the symptom iceberg in today's primary care: results from a uk population survey. bmc fam pract 2011; 12:16. 41. o'donnell cj, glynn rj, field ts, averback r, satterfield s, friesenger gc 2nd, et al. misclass-ification and underreporting of acute myocardial infarction by elderly persons: implications for community-based observational studies and clinical trials. j clin epidemiol 1999; 52:745–51. department of anatomy, kasturba medical college, manipal, karnataka, india e-mail: billakantibabu@yahoo.co.in القناة إضافية للغدة حتت الفك السفلي بركا�ص باب� باالكانتي accessory duct of the submandibular gland prakash b. billakanti a routine dissection was performed ona 54-year-old adult male cadaver at the department of anatomy, kasturba medical college, manipal, karnataka, india, in 2015. during dissection of the neck, it was noted that the submandibular gland on the right side had an anatomical variation in the form of an extra duct [figure 1]. no other anomalies were observed. the main duct was larger and superior in position and the accessory duct was slightly narrower and inferior. the two ducts were almost parallel to each other, passing between the hyoglossus and mylohyoid muscles. only the upper duct had normal anatomical relations to the lingual nerve. both ducts rose independently from the submandibular gland and opened separately into the floor of the mouth. the main submandibular duct opened at the top of the papilla. the accessory duct adjacent to the main duct produced a slight elevation of mucosa in the floor of the mouth. the submandibular gland on the left side was normal. comment the submandibular gland is one of the three larger pairs of salivary glands.1 it has an excretory duct which emerges from the anterior end of the deeper part of the gland, crosses inwards between the mylohyoid and hyoglossus muscles and opens into the floor of the mouth on the top of the sublingual papilla next to the frenulum of the tongue.1 the submandibular figure 1: photograph of the right submandibular gland of an adult male cadaver showing a main submandibular duct with a lower accessory duct arising independently from the gland. fa = facial artery; ln = lingual nerve; md = main submandibular duct; ad = accessory submandibular duct. interesting medical image sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e119–120, epub. 30 mar 17 submitted 27 jun 16 revisions req. 31 jul & 27 sep 16; revisions recd. 21 sep & 4 oct 16 accepted 6 oct 16 doi: 10.18295/squmj.2016.17.01.023 accessory duct of the submandibular gland e120 | squ medical journal, february 2017, volume 17, issue 1 structure in a 26-year-old woman via sialographic examination.3 using digital sialography and magnetic resonance imaging, gadodia et al. identified a unilateral submandibular duct duplication with a small duct of 2 cm in length passing close to the main submandibular duct and draining a small accessory gland.5 awareness of potential variations of the excretory ducts of the salivary glands can aid in the accurate diagnosis and treatment of patients with salivary conditions as well as help surgeons avoid further complications or duct lacerations during oral surgery. references 1. standring s. grays anatomy: the anatomical basis of clinical practice, 40th ed. philadelphia, pennsylvania, usa: churchill livingstone, 2008. pp. 499−526. 2. pownell ph, brown oe, pransky sm, manning sc. congenital abnormalities of the submandibular duct. int j pediatr otorhinolaryngol 1992; 24:161−9. doi: 10.1016/01655876(92)90142-c. 3. kuroyanagi n, kinoshita h, machida j, suzuki s, yamada y. accessory duct in the submandibular gland. j oral maxillofac surg med pathol 2007; 19:110−12. doi: 10.1016/s0915-6992 (07)80027-6. 4. codjambopoulo p, ender-griepekoven i, broy h. [bilateral duplication of the submandibular gland and the sub mandibular duct]. rofo 1992; 157:185–6. doi: 10.1055/s-20081032994. 5. gadodia a, seith a, neyaz z, sharma r, thakkar a. magnetic resonance identification of an accessory submandibular duct and gland: an unusual variant. j laryngol otol 2007; 121:e18. doi: 10.1017/s0022215107008602. 6. myerson m, crelin es, smith hw. bilateral duplication of the submandibular ducts. arch otolaryngol 1966; 83:488−90. doi: 10.1001/archotol.1966.00760020490017. 7. rose bh. bifurcation of the submaxillary duct. am j surg 1932; 17:257−8. doi: 10.1016/s0002-9610(32)90492-9. 8. gaur u, choudhry r, anand c, choudhry s. submandibular gland with multiple ducts. surg radiol anat 1994; 16:439−40. doi: 10.1007/bf01627668. 9. manzur-villalobos i, pérez-bula l, fang l. anatomical variation of submandibular gland duct. scholars j dent sci 2016; 3:12−4. 10. gates ga, johns me. diagnostic radiology. in: paparella mm, shumrick da, eds. otolaryngology, 2nd ed. philadelphia, pennsylvania, usa: saunders, 1980. pp. 1067−86. 11. rice dh. diagnostic imaging. in: cummings cw, fredrickson jm, harker la, krause cj, schuller de, eds. otolaryngology: head and neck surgery, 1st ed. st louis, missouri, usa: mosby, 1986. pp. 987−98. gland develops during the sixth week of fetal life as an endodermal outgrowth from the floor of the alveologingival groove.2 the edges of the floor of the alveologingival groove gradually fuse together to form the submandibular duct; if the duct branches early or invaginates in two places, it may lead in rare cases to the formation of an accessory submand ibular gland and duct.3–5 accessory submandibular ducts are usually smaller and run parallel to the main duct.5 only eight cases of bilateral anomalies of the sub mandibular duct have previously been reported; of these, two were cases of bilateral submandibular duct duplication.4,6 although the larger duct of the submandibular gland is usually anatomically consistent, rare variations can occur. rose reported a case in which the main duct bifurcated near the gland with one branch opening as usual in the sublingual papilla and the other opening into the oral cavity floor opposite the second molar.7 gaur et al. described a right submandibular gland with three separate ducts which opened independently into the oral cavity.8 manzur-villalobos et al. reported a cadaver in which an externally located right submandibular duct anastomosed with the parotid duct and led to the buccal mucosa adjacent to the second molar.9 in the present case, both the main and accessory ducts opened separately into the floor of the mouth on the right side of the frenulum of the tongue. most duplication anomalies are detected incidentally during sialography and are usually not a cause for concern.3,5 sialography is regarded as the diagnostic procedure of choice for the detection of various conditions of the salivary glands, including mass lesions, inflammatory disorders, calculi and penet rating trauma.10,11 however, the presence of radiolucent stones or disease in accessory ducts may inadvertently be overlooked. therefore, information regarding the possibility of additional ducts opening separately into the floor of the mouth is essential for oral surgeons and radiologists. kuroyanagi et al. observed a duplication of the submandibular duct without any histological abnormalities in duct https://doi.org/10.1016/0165-5876%2892%2990142-c https://doi.org/10.1016/0165-5876%2892%2990142-c https://doi.org/10.1016/s0915-6992%2807%2980027-6 https://doi.org/10.1016/s0915-6992%2807%2980027-6 https://doi.org/10.1055/s-2008-1032994 https://doi.org/10.1055/s-2008-1032994 https://doi.org/10.1017/s0022215107008602 https://doi.org/10.1001/archotol.1966.00760020490017 https://doi.org/10.1016/s0002-9610%2832%2990492-9 https://doi.org/10.1007/bf01627668 hamdan a. al-habsi, mustafa al-hinai, ahmed al-waily, salim al-sudairy and vipula de silva online case report | e575 departments of 1family medicine & public health and 2oral health, sultan qaboos university hospital, muscat, oman; 3department of pathology, faculty of medicine, university of colombo, sri lanka corresponding author e-mail: habsi@squ.edu.om syringocystadenoma papilliferum (scap) is a rare benign skin tumour believed to originate from the pluripotent cells and its histology exhibits either apocrine or eccrine sweat gland differentiation.1 the tumour appears predominantly in childhood; it appears at birth in approximately 50% of those affected and before puberty in a further 15–30%.2–4 however, in some cases it may appear at a later age.5 the tumour is more common in women than men.6 the clinical presentation of scap is not distinctive and may often be misleading—it can present as a solitary patch, papule, plaque, nodule or as several papules often arranged linearly.7–9 the plaque type usually presents as a hairless area on the scalp, while the linear type appears on the face and neck region and the solitary nodular type shows a predilection for the trunk.8,9 the colour of the tumour varies from fleshcoloured to pink, red, brown or grey.6,10 its surface may be smooth, hyperkeratotic, verrucous, papillary or moist and fleshy. the tumour tends to grow slowly and is usually less than 4 cm in size.4 while the clinical features of scap vary widely, its histology is invariably uniform and confirmatory.7 although the lesion is benign, transformation to basal cell carcinoma, metastatic adenocarcinoma or ductal carcinoma may occur.5,8,11 an unusual case of this entity occurring on the upper lip is documented below. to date, only three cases involving the upper lip have been reported in the literature.5 case report a 10-year-old girl presented to the sultan qaboos university hospital in muscat, oman, in february 2012 with a non-tender, non-pruritic, solitary verrucous papule on the left side of the upper lip. the papule had been present since birth and was associated with recurrent ulceration and bleeding. it had been slowly increasing in size over time. she had consulted many different physicians but no definite diagnosis had been made. numerous treatments had been attempted without success, including scraping the lesion on a number of occasions and the application of various topical medications, including traditional medicinal treatments. there was no other significant past medical history. a physical examination revealed a solitary painless raised papule of 4 x 5 mm on the left side of the upper lip, with an area of surrounding blood clots [figure 1]. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e575−577, epub. 14th oct 14 submitted 21st feb 14 revision req. 13th apr 14; revision recd. 11th may 14 accepted 9th jun 14 ورم الغدد العرقية احلليمي يف الشفة العليا حمدان احلب�سي، م�سطفى الهنائي، ِاأحمد الوائلي، �سامل ال�سديري، فيبوال دي �سيلفا abstract: syringocystadenoma papilliferum (scap) is a rare skin tumour believed to arise from the apocrine or eccrine sweat glands. it appears predominantly in childhood, usually at birth. it is exceedingly rare for it to appear on the upper lip. we report a case of scap in a 10-year-old omani girl who presented to the sultan qaboos university hospital in muscat, oman, in february 2012 with a non-tender, non-pruritic, solitary verrucous papule of 4 x 5 mm on the left side of the upper lip. it had been present since birth and had slowly been increasing in size over the years. it was occasionally associated with recurrent ulceration and bleeding and had previously been misdiagnosed and mismanaged. an excisional biopsy was performed and the whole lesion was removed. the surgical site was then sutured and the patient was discharged on the same day. keywords: skin neoplasms; sweat glands; lip; misdiagnoses; basal cell carcinoma; case report; oman. امللخ�ص: ورم الغدد العرقية احلليمي ورم جلدي نادر ي�سيب الغدد العرقية املفرتزة والفارزة يف اجللد. غالبا ما يظهر يف الطفولة عادة عند الوالدة. نادرا جدا ما يظهر هذا الورم على ال�سفاه العليا. يف هذا املقال نقدم تقريرا عن طفلة عمانية تبلغ من العمر 10 �سنوات زارت م�ست�سفى جامعة ال�سلطان قابو�س يف م�سقط، عمان يف فرباير 2012 وعليها ورم ثوؤلويل منفرد )5 × 4 مم( ، غري موؤمل وبغري حكة على اجلانب االأي�رس من ال�سفة العليا كان قد ظهر منذ الوالدة. ازداد حجم الورم ببطء على مدى ال�سنني مع تقرح ونزيف متكرر. مل تكن حماوالت ت�سخي�سه وعالجه ال�سابقة ناجحة. مت اإجراء خزعة ا�ستئ�سالية ومتت اإزالة التقرح كله. مت تخييط املوقع اجلراحي وخرجت املري�سة يف اليوم نف�سه. مفتاح الكلمات: االأورام اجللدية؛ غدد العرق؛ ال�سفة العليا؛ الت�سخي�س اخلاطئ؛ �رسطان اخلاليا القاعدية؛ تقرير حالة؛ عمان. syringocystadenoma papilliferum of the upper lip *hamdan a. al-habsi,1 mustafa al-hinai,1 ahmed al-waily,1 salim al-sudairy,2 vipula de silva3 online case report syringocystadenoma papilliferum of the upper lip e576 | squ medical journal, november 2014, volume 14, issue 4 no other abnormalities were detected around the lesion or on any other parts of the body. an initial diagnosis of a granuloma was made. an excisional biopsy was performed and the whole lesion was removed and sent for a histopathology examination. the defect was then closed with a suture and the patient was discharged on the same day. the pathological findings revealed a gross specimen measuring 15 x 5 x 3 mm, consisting of multiple fragments of soft tissue. the specimen was processed using a haematoxylin and eosin stain. microscopically, a biopsy determined that the specimen was comprised of epidermal, dermal and skeletal muscle cells. the epidermis was hyperplastic, showing cystic invagination into the dermis, with infiltration of the lymphocytes and neutrophils [figure 2]. in the lower part of the epidermis, a lesion was observed. the lesion was composed of a few papillary projections and ducts/gland-like structures lined by luminal and cuboidal cells. the papillary projections were lined by double epithelial cells with an abundance of plasma cell infiltrates in their cores [figures 3 and 4]. no atypia or mitosis was seen. the overall architecture of the lesion revealed an invagination from the epidermis with overlying squamous hyperplasia, papillary projections lined by double epithelial cells and infiltration of the plasma cells. this morphology was consistent with a diagnosis of scap. discussion scap is a rare benign tumour of the skin, usually seen in patients at birth or during infancy or early childhood. most lesions are not distinctive and require a biopsy for the diagnosis; however, the tumour is usually described as ranging from skin-coloured to pink, and taking the form of either a hairless firm plaque, grouped nodules or a solitary nodule.12 figure 1: photograph of a non-tender, non-pruritic solitary verrucous papule on the left side of the upper lip of a 10-year-old girl. this papule had been present since birth. figure 2: histopathology of the skin lesion showing the cystic invagination of the epidermis with papillary projections (black arrows) and duct-like structures (white arrows). the specimen was processed using hematoxylin and eosin stain at x5 magnification. figure 3: duct-like structures (white arrows) and papillary projections (black arrows) lined by double epithelial cells can be observed. plasma cells are visible in the cores (arrow heads). the specimen was processed using hematoxylin and eosin stain at x20 magnification. figure 4: histopathology indicated an abundance of plasma cells (white arrows). the specimen was processed using hematoxylin and eosin stain at x20 magnification. hamdan a. al-habsi, mustafa al-hinai, ahmed al-waily, salim al-sudairy and vipula de silva online case report | e577 the differential diagnosis of scap is broad. it can include nevus sebaceous, hidradenoma papilliferum, molluscum contagiosum, verruca vulgaris, squamous cell carcinoma, keratoacanthoma and basal cell carcinoma.4,13 the clinical presentation of the tumour is non specific and can resemble any of the aforementioned conditions;7,8 however, the histopathological features are specific and diagnostic. the tumour histology shows characteristic epidermal cystic invaginations into the dermis, papillary projections and abundant plasma cell infiltration.2,8,10 the invaginations are lined by a double layer of epithelial cells, whereas the papillary projections are lined by glandular epithelium which often exhibits decapitation secretion.4,8,10 immunohistochemical studies using epithelial membrane antigen and cytokeratin markers show that the epithelium is composed of several cell types at different stages of development, with a tendency to differentiate toward the basal cells in the apocrine lineage or luminal cells in the secretory epithelium.1,11,14 the results of these studies support the theory that scap is a tumour originating from the pluripotent cells. cases of scap are sporadic and most commonly seen in the scalp region. they are only rarely described in other parts of the body.4,10,13 it is hoped that this report will add to the available information on scap involving the upper lip. an extensive search of the literature has shown that only three similar cases have been documented so far. although this lesion is benign, a transformation to basal cell carcinoma, metastatic adenocarcinoma or ductal carcinoma may still occur.15,16 scap has been associated with basal cell carcinoma in about 10% of cases.7,10 squamous cell carcinoma may also develop, but much less frequently. other malignant tumours associated with scap include verrucous and ductal carcinomas.16 rapid growth, pain, ulceration or bleeding in a long-standing lesion may indicate a malignant transformation to syringocystadenocarci noma papilliferum.6,16 conclusion scap is an uncommon tumour and its appearance on the upper lip is very rare. the clinical presentation of this tumour resembles many other skin lesions. it should be considered in the differential diagnosis of any long-standing plaque or nodular lesion, particularly if there is an increase in size or the occurrence of ulceration and/or bleeding. the tumour has characteristic histological features which can be used as the basis for diagnosis. malignant transformation can occur; a complete excision of the lesion is therefore the treatment of choice. references 1. yamamoto o, doi y, hamada t, hisaoka m, sasaguri y. an immunohistochemical and ultrastructural study of syringocystadenoma papilliferum. br j dermatol 2002; 147:936–45. doi: 10.1046/j.1365-2133.2002.05027.x. 2. karg e, korom i, varga e, ban g, turi s. congenital syringocystadenoma papilliferum. pediatr dermatol 2008; 25:132–3. doi: 10.1111/j.1525-1470.2007.00607.x. 3. böni r, xin h, hohl d, panizzon r, burg g. syringocystadenoma papilliferum: a study of potential tumor suppressor genes. am j dermatopathol 2001; 23:87–9. 4. sangma mm, dasiah sd, bhat v r. syringocystadenoma papilliferum of the scalp in an adult male: a case report. j clin diagn res 2013; 7:742–3. doi: 10.7860/jcdr/2013/5452.2900. 5. helwig eb, hackney vc. syringadenoma papilliferum: lesions with and without naevus sebaceous and basal cell carcinoma. ama arch derm 1955; 71:361–72. doi: 10.1001/ archderm.1955.01540270073011. 6. monticciolo nl, schmidt jd, morgan mb. verrucous carcinoma arising within syringocystadenoma papilliferum. ann clin lab sci 2002; 32:434–7. 7. chauhan a, gupta l, gautam rk, bhardwaj m, gopichandani k. linear syringocystadenoma papilliferum: a case report with review of literature. indian j dermatol 2013; 58:409. doi: 10.4103/0019-5154.117353. 8. katoulis a, bozi e, stavrianeas ng. syringocystadenoma papilliferum. from: www.orpha.net/data/patho/gb/uk-syring ocystadenoma-papilliferum.pdf accessed: sep 2014. 9. pinkus h. life history of naevus syringadenomatosus papilliferus. ama arch derm syphilol 1954; 69:305–22. doi: 10.1001/archderm.1954.01540150051004. 10. xu d, bi t, lan h, yu w, wang w, cao f, et al. syringocystadenoma papilliferum in the right lower abdomen: a case report and review of literature. onco targets ther 2013; 6:233–6. doi: 10.2147/ott.s42732. 11. choccalingam c, samuel p, subramaniam d, hammed f, purushothaman v, joshi r. syringocystadenocarcinoma papilliferum: a case report of a rare skin adnexal tumour. our dermatol online 2013; 4:221–3. doi: 10.7241/ourd.20132.54 12. sood a, khaitan bk, khanna n, kumar r, singh mk. syringocystadenoma papilliferum at unusual sites. indian j dermatol venereol leprol 2000; 66:328–9. 13. yap fb, lee br, baba r. syringocystadenoma papilliferum in an unusual location beyond the head and neck region: a case report and review of literature. dermatol online j 2010; 16:4. 14. kurokawa i, mizutani h, nishijima s, kusumoto k, tsubura a. keratinizing squamous epithelium associated with syringocystadenoma papilliferum differentiates towards infrainfundibulum: case report with immunohistochemical study of cytokeratins. j int med res 2005; 33:590–3. doi: 10.1177/147323000503300515. 15. hügel h, requena l. ductal carcinoma arising from a syringocystadenoma papilliferum in a nevus sebaceous of jadassohn. am j dermatopathol 2003; 25:490–3. 16. arai y, kusakabe h, kiyokane k. a case of syringocystadenocarcinoma papilliferum in situ occurring partially in syringocystadenoma papilliferum. j dermatol 2003; 30:146–50. doi: 10.1111/j.1346-8138.2003.tb00363.x. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e420–423, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.019. submitted 29 dec 14 revision req. 9 mar 15; revision recd. 10 mar 15 accepted 30 mar 15 vitamin b12 deficiency is common among individuals in developing countries.1 its prevalence is often underestimated as it is believed to occur only in strict vegetarians and patients with pernicious anaemia.1 however, vitamin b12 deficiency should be suspected in all patients with unexplained anaemia or neurological symptoms.2 various dermatological manifestations associated with b12 deficiency are skin hyperor hypopigmentation, angular stomatitis and hair changes.3 hyperpigmentation as the primary presenting symptom of b12 deficiency is rarely reported in the literature.4 the case reported below describes a 28-year-old omani man who presented with brownish-black hyperpigmentation on both hands, which proved to be due to a b12 deficiency caused by chronic atrophic gastritis. case report a 28-year-old omani male presented to sultan qaboos university hospital (squh) in muscat, oman, in november 2013 with hyperpigmentation of both hands. two months later he developed severe numbness in both hands to the extent that he could no 1department of family medicine & public health, sultan qaboos university hospital; 2department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3department of family medicine, oman medical college, sohar, oman *corresponding author e-mail: nafisa77@squ.edu.om تغيري موضعي لصبغة اجللد إىل اللون الداكن نتيجة لنقص فيتامني ب12 بسبب التهاب مزمن باملعدة كوثر الشافعي، نفي�سه سمري، ريتو لكتاكيا، روبن ديفد�سون، اأحمد الوائلي، منى املعمرية، حممد ال�سافعي abstract: vitamin b12 deficiency is common in developing countries and should be suspected in patients with unexplained anaemia or neurological symptoms. dermatological manifestations associated with this deficiency include skin hyperor hypopigmentation, angular stomatitis and hair changes. we report a case of a 28-year-old man who presented to the sultan qaboos university hospital in muscat, oman, in november 2013 with localised hyperpigmentation of the palmar and dorsal aspects of both hands of two months’ duration. other symptoms included numbness of the hands, anorexia, weight loss, dizziness, fatigability and a sore mouth and tongue. there was no evidence of hypocortisolaemia and a literature search revealed a possible b12 deficiency. the patient had low serum b12 levels and megaloblastic anaemia. an intrinsic factor antibody test was negative. a gastric biopsy revealed chronic gastritis. after b12 supplementation, the patient’s symptoms resolved. family physicians should familiarise themselves with atypical presentations of b12 deficiency. many symptoms of this deficiency are reversible if detected and treated early. keywords: vitamin b12 deficiency; hyperpigmentation; atrophic gastritis; case report; oman. أو ال�سبب جمهول الدم فقر من يعانون الذين املر�سى عند به ال�ستباه وينبغي النامية البلدان يف �سائع ب12 فيتامني نق�س امللخ�ص: أعرا�س ترتبط باجلهاز الع�سبي. املظاهر اجللدية املرتبطة بهذا النق�س ت�سمل زيادة اأو نق�سان �سبغة اجللد، التهاب جوانب الفم وتغيري يف ال�سعر. نعر�س حالة لرجل يبلغ 28 �سنة قدم إىل م�ست�سفى جامعة ال�سلطان قابو�س يف نوفمرب 2013 وهو ي�سكو من زيادة �سبغة اجللد يف راحة وظهر يديه ملدة �سهرين. كما كان ي�سكو من خدر يف اليدين، فقدان ال�سهية و الوزن، الدوخة، إعياء واأمل بالفم والل�سان، وك�سف الفح�س اأنه ل يوجد لدى هذا املري�س نق�س يف الكورتيزون ولكن البحث يف الأدبيات الطبية ك�سف احتمال نق�س فيتامني ب12. واأثبتت نتيجة الفح�س نق�س هذا الفيتامني و فقر الدم �سخم اخلاليا عند املري�س. ومل يكن لديه نق�س يف العامل امل�ساعد على امت�سا�س فيتامني ب12. كما اأثبت فح�س خزعة املعدة التهاب مزمن باملعدة. اختفت كل اأعرا�س املري�س بعد اإعطائه فيتامني ب12. لذلك نن�سح باأن يتعرف اأطباء الأ�رسة على الأعرا�س النادرة لنق�س فيتامني ب12. الكثري من اأعرا�س نق�سان فيتامني ب12 قابلة للرتاجع إذا �سخ�س هذا النق�س وعولج مبكرا. مفتاح الكلمات: نق�س فيتامني ب12؛ زيادة �سبغة اجللد؛ التهاب املعدة ال�سموري؛ تقرير حالة؛ عمان. localised skin hyperpigmentation as a presenting symptom of vitamin b 12 deficiency complicating chronic atrophic gastritis kawther el-shafie,1 *nafisa samir,1 ritu lakhtakia,2 robin davidson,1 ahmed al-waili,1 muna al-mamary,1 mohammed al-shafee3 online case report kawther el-shafie, nafisa samir, ritu lakhtakia, robin davidson, ahmed al-waili, muna al-mamary and mohammed al-shafee online case report | e421 longer carry objects. on further enquiry, he reported symptoms of glossitis and angular stomatitis for the preceding two weeks. he had lost 10 kg within one month (with an initial weight of 86 kg) and was experiencing anorexia, feelings of excessive fatigability and dizziness. his past medical, medication and dietary history was unremarkable. there was no previous history of fever, epigastric pain, diarrhoea, steatorrhea, diabetes mellitus, tuberculosis or use of any over-the-counter medications. a clinical examination revealed a diffuse brownishblack discolouration on both the palmar and dorsal aspects of both hands which was more pronounced at the distal and proximal interphalangeal joints [figure 1a & b]. there was ulceration on both sides of the tongue with angular stomatitis. no abnormal pigmentation was found on any other site of the skin or on the buccal mucosa. on neurological examination, the patient was unable to feel a 10 g monofilament on either hand; however, he could feel vibration on the hands and his proprioception was intact. the patient had brisk reflexes in the upper limbs but diminished reflexes in the lower limbs. the plantar reflexes were equivocal and romberg’s test results were negative. the rest of the physical examination was normal. serum cortisol and adrenocorticotropic hormone levels were normal, ruling out addison’s disease. a complete blood count showed macrocytosis with megaloblastic features, although his haemoglobin level was normal [figure 2]. the patient’s b12 and folate levels were subsequently assessed; his b12 level was found to be significantly low [table 1]. as b12 plays a pivotal role in many metabolic pathways, further metabolic work-up showed high levels of both methylmalonic acid and homocystiene. multiple biopsies from an endoscopy were consistent with a fungal infection at the lower end of the oesophagus and chronic gastritis including focal intestinal metaplasia without any evidence of figure 1a–d: diffuse brownish-black hyperpigmentation on the (a) dorsal and (b) palmar aspects of both hands at presentation. improved (c) dorsal and (d) palmar hyperpigmentation was noted after vitamin b12 supplementation. figure 2a & b: may-grünwald-giemsa stain at x40 magnification showing blood cell morphology (a) before and (b) after treatment with vitamin b12. table 1: summary of haematological, biochemical and other investigation results for the current patient with localised skin hyperpigmentation investigation value normal range haemoglobin 12.2 g/dl 11.5–15.5 g/dl mean corpuscular volume 115 fl ↑↑ 78–96 fl red cell distribution width 17.2% ↑ 11.5–16.5% c-reactive protein 2 mg/l 0–8 mg/l vitamin b12 75 pmol/l ↓↓ 133–675 pmol/l folate 20.4 mmol/l 7.0–45.1 mmol/l cortisol at 10 am 422 nmol/l 185–624 nmol/l adrenocorticotropic hormone at 8 am 98 ug/l 24–336 ug/l homocysteine plasma 36 µmol/l ↑↑ <15 µmol/l methylmalonic acid 3.4 µmol/l ↑↑ <0.5 µmol/l anti-deamidated gliadin antibody 1ga and immunoglobulin g 1 µ/ml 0–25 µ/ml transglutaminase antibody immunoglobulin a 1 µ/ml 0–20 µ/ml human immunodeficiency virus serology negative negative localised skin hyperpigmentation as a presenting symptom of vitamin b 12 deficiency complicating chronic atrophic gastritis e422 | squ medical journal, august 2015, volume 15, issue 3 in addition, malabsorption of b12 has been associated with long-term (>4 years) use of histamine type 2 receptor antagonists and proton-pump inhibitors.5 of these potential causes of b12 deficiency, the only one applicable to this patient was the possibility of inadequate ifa production by the stomach due to histologically-proven chronic atrophic gastritis. amarapurkar et al. reported that there was no statistically significant difference in haematological, biochemical and histological parameters in ifapositive and ifa-negative gastritis.6 these may be part of the spectrum for the same disease, with h. pylori as the agent responsible for initiating the process. it has been reported that patients who are ifa-negative are classified as chronic atrophic gastritis cases.6 in the current patient, the associated candida infection at the lower part of the oesophagus may also be explained by a b12 deficiency, as vitamin b group deficiencies have been reported as one of the causes for a candida albicans infection.7 pigmentation in b12 deficiency can also masquerade as pigmentation due to addison’s disease.4,8‒12 there are few reported cases of vitamin b12 deficiency in which mucocutaneous lesions predate other manifestations.4,8‒12 in these cases, the skin changes were characterised by addisonian brownish-black hyperpigmentation which affected more than one area of the body, including sun-exposed sites, such as the palmar and dorsal aspects of the hands and feet and the knuckles, flexures, tongue, oral mucosa, palmar creases, nails and gluteal region.4,8‒12 the pigmentation observed in the current patient differs from these reported cases in that it was localised only to the hands, which may possibly be due to an early diagnosis of the condition. kannan et al. described a similar case of b12 deficiency where the patient presented over a short period of time (1.5 months) with localised hyperpigmented macular lesions on the dorsum of the middle phalanges of both feet.3 from the current case, it is obvious that skin signs and symptoms, specifically hyperpigmentation, can precede the typical neurological signs and symptoms of b12 deficiency. mori et al. proposed that skin hyperpigmentation can be an important clue in diagnosing b12 deficiency and that dermatologists need to be familiar with the clinical appearance of this disorder.10 the mechanism of hyperpigmentation is not well understood. it has been suggested that the lack of b12 causes depletion in intracellular glutathione levels which normally inhibit tyrosinase activity in melanogenesis; the lack of this inhibitor would lead to an increase in melanogenesis.13 mori et al. reported helicobacter pylori [figure 3]. the duodenal biopsy also revealed mild chronic inflammation and focal villous blunting. an autoimmune work-up was negative, including antiparietal cell, intrinsic factor antibody (ifa), transglutaminase and anti-gliadin antibody tests. a skin biopsy of the hyperpigmented lesions showed dermal vessels with mild lymphocytic cuffing and ectatic capillaries. the patient was prescribed 1,000 µg of intramuscular b12 every day for one week, followed by the same dose once a week for four weeks and then once a month for two months. following the treatment, the patient underwent remarkable symptomatic improvement. his skin pigmentation completely normalised within eight weeks of treatment with b12 [figure 1c & d]. written informed consent was obtained from the patient for publication of this case report and the accompanying images. discussion vitamin b12 deficiency was considered to be the cause of localised hyperpigmentation in the reported patient, due to the fact that the hyperpigmentation disappeared following the normalisation of serum b12 levels with treatment. the most common causes of b12 deficiency are either a strict vegetarian diet or malabsorption of b12 due to inadequate gastric production or defective functioning of ifa.1,2 other causes include a gastrectomy, surgical resection of the terminal ileum, bacterial overgrowth of the small intestine, diverticulitis, coeliac disease, crohn’s disease, chronic alcoholism, human immunodeficiency virus, diphyllobothrium infestation, giardiasis and medications such as metformin and colchicine.1,2 figure 3: haematoxylin and eosin stain of a gastric biopsy sample from the antrum showing crypt disarray and moderate chronic inflammation of the lamina propria with foci of intestinal metaplasia (arrow) at x100 magnification. inset: periodic acid-schiff-alcian blue stain showing foci of intestinal metaplasia with alcianophilic mucinous cells at x400 magnification. kawther el-shafie, nafisa samir, ritu lakhtakia, robin davidson, ahmed al-waili, muna al-mamary and mohammed al-shafee online case report | e423 that the dominant mechanism of hyperpigmentation due to b12 deficiency is not a defect in melanin transport but rather an increase in melanin synthesis.10 conclusion b12 deficiency should be considered as an underlying cause of unexplained hyperpigmentation. in the current case, a patient presented with localised hyperpigmentation of the palmar and dorsal aspects of both hands which resolved rapidly after b12 supplementation. it is essential for family physicians to familiarise themselves with atypical presentations of b12 deficiency, as early detection and adequate treatment of the condition can prevent neurological complications. references 1. allen lh. how common is vitamin b-12 deficiency. am j clin nutr 2009; 89:693s‒6s. doi: 10.3945/ajcn.2008.26947a. 2. hvas am, nexo e. diagnosis and treatment of vitamin b12 deficiency: an update. haematologica 2006; 91:1506–12. 3. kannan r, ng mj. cutaneous lesions and vitamin b12 deficiency: an often-forgotten link. can fam physician 2008; 54:529–32. 4. jithendriya m, kumaran s, p ib. addisonian pigmentation and vitamin b12 deficiency: a case series and review of the literature. cutis 2013; 92:94–9. 5. allen lh. causes of vitamin b12 and folate deficiency. food nutr bull 2008; 29:s20–34. 6. amarapurkar dn, amarapurkar ad. intrinsic factor antibody negative atrophic gastritis: is it different from pernicious anaemia? trop gastroenterol 2010; 31:266–70. 7. akpan a, morgan r. oral candidiasis. postgrad med j 2002; 78:455–9. doi: 10.1136/pmj.78.922.455. 8. agrawala rk, sahoo sk, choudhury ak, mohanty bk, baliarsinha ak. pigmentation in vitamin b12 deficiency masquerading addison’s pigmentation: a rare presentation. indian j endocrinol metab 2013; 17:s254–6. doi: 10.4103/22308210.119591. 9. hoffman cf, palmer dm, papadopoulos d. vitamin b12 deficiency: a case report of ongoing cutaneous hyperpigmentation. cutis 2003; 71:127–30. 10. mori k, ando i, kukita a. generalized hyperpigmentation of the skin due to vitamin b12 deficiency. j dermatol 200l; 28:282–5. doi: 10.1111/j.1346-8138.2001.tb00134.x. 11. cherqaoui r, husain m, madduri s, okolie p, nunlee-bland g, williams j. a reversible cause of skin hyperpigmentation and postural hypotension. case rep hematol 2013; 2013:680459. doi: 10.1155/2013/680459. 12. srivastava n, chand s, bansal m, srivastava k, singh s. reversible hyperpigmentation as the first manifestation of dietary vitamin b12 deficiency. indian j dermatol venereol leprol 2006; 72:389–90. doi: 10.4103/0378-6323.27766. 13. niiyama s, mukai h. reversible cutaneous hyperpigmentation and nails with white hair due to vitamin b12 deficiency. eur j dermatol 2007; 17:551–2. doi: 10.1684/ejd.2007.0285. http://dx.doi.org/10.3945/ajcn.2008.26947a http://dx.doi.org/10.1136/pmj.78.922.455 http://dx.doi.org/10.4103/2230-8210.119591 http://dx.doi.org/10.4103/2230-8210.119591 http://dx.doi.org/10.1111/j.1346-8138.2001.tb00134.x http://dx.doi.org/10.1155/2013/680459 http://dx.doi.org/10.4103/0378-6323.27766 http://dx.doi.org/10.1684/ejd.2007.0285 sultan qaboos university med j, february 2014, vol. 14 iss. 1, pp. e113-119, epub. 27th jan 14 submitted 21st jul 13 revision req. 18th sep 13; revision recd. 23rd oct 13 accepted 21st nov 13 الكتابة هبدف التعلم إجتاهات طلبة التمريض يف جامعة السلطان قابوس �رشيديفي باال�صاندر�ن,ر�مي�س فنكاتي�صابريومال,جوثي كالر�,رغدة �صكري abstract: objectives: the objectives of this study were to assess the attitude of omani nursing students towards writing-to-learn (wtl) and its relationship to demographic variables, self-efficacy and the writing process. methods: a cross-sectional design was used to evaluate attitudes towards wtl by sultan qaboos university nursing students. a convenience sample of 106 students was used and data collected between october 2009 and march 2010. a modified version of the wtl attitude scale developed by dobie and poirrier was used to collect the data. descriptive and inferential statistics were used for analysis. results: senior and junior students had more positive attitudes to wtl than mid-level students who tended to have negative attitudes towards writing. although 52.8% students had negative attitudes towards the writing process, the median was higher for attitudes to the writing process compared to the median for self-efficacy. there was a positive correlation between self-efficacy and writing process scores. conclusion: overall, students had negative attitudes towards wtl. attitudes are learnt or formed through previous experiences. the incorporation of wtl strategies into teaching can transform students’ negative attitudes towards writing into positive ones. keywords: attitude; nursing; students; writing; learning; self efficacy; education; oman. �لدميوغر�فية �ملتغري�ت مع وعالقتها �لتعلم بهدف �لكتابة نحو �لعمانيي �لتمري�س طلبة �جتاهات تقييم هو �لدر��صة هذه هدف الهدف: امللخ�ص: �لتمري�س طلبة خالل من �لتعلم بهدف �لكتابة نحو �الإجتاهات لتقييم �ملقطعية �لدر��صة طريقة ��صتخد�م مت الطريقة: �لكتابة. وعملية �لذ�تية و�لفاعلية يف جامعة �ل�صلطان قابو�س. ��صتخدمت عينة تكونت من 106 طالبًا وطالبة وجمعت �لبيانات يف �لفرتة ما بي �أكتوبر 2009 و مار�س 2010. وجلمع �لبيانات مت ��صتخد�م �ملقيا�س �ملعّدل لالإجتاهات نحو �لكتابة بهدف �لتعلم و�لذي �صممه كل من �لباحثي دوبي و بويرير. مت ��صتخد�م �الإح�صاء�ت �لو�صفية و�ال�صتداللية لعملية �لتحليل. النتائج: �لطلبة �ملنتظمون يف �ملر�حل �ملتقدمة و�الأوىل كانت �جتاهاتهم �أكرث �إيجابية من �جتاهات �لطلبة �ملنتظمي يف �ملرحلة �ملتو�صطة و�لذين كانت لديهم �جتاهات �صلبية نحو �لكتابة. وبالرغم من �أن %52.8 من �لطلبة كانت �جتاهاتهم نحو �لكتابة �صلبية �إال �أن �لعدد �الأو�صط لالجتاهات نحو عملية �لكتابة عند �ملقارنة كان �أعلى من �لعدد �الأو�صط لالجتاهات نحو �لفاعلية �لذ�تية. وقد وجد �أن هناك عالقة �إيجابية بي نتائج �لفاعلية �لذ�تية وعملية �لكتابة. اخلال�سة: �إن �لطلبة لديهم �جتاهات �صلبية نحو �لكتابة بهدف �لتعلم ب�صكل عام, و�إن هذه �الجتاهات يتم تعلمها �أو �لطلبة �جتاهات تغيري �ملمكن من �لتدري�س بعمليات �لقيام �أثناء �لتعلم بهدف �لكتابة �أ�صاليب �إدر�ج خالل من و�أنه �ل�صابقة. �لتجارب خالل من تكونها �ل�صلبية لتغدو �إيجابية. مفتاح الكلمات: �إجتاهات؛ متري�س؛ طلبة؛ كتابة؛ تعلم؛ فاعلية ذ�تية؛ تعليم؛ ُعمان. writing-to-learn attitudes of nursing students at sultan qaboos university *shreedevi balachandran,1 ramesh venkatesaperumal,1 jothi clara,2 raghda k. shukri1 1college of nursing, sultan qaboos university, muscat, oman; 2global hospital, chennai, india *corresponding author e-mail: shreedev@squ.edu.om advances in knowledge writing-to-learn (wtl) is considered to be an important strategy of learning in all disciplines and to improve academic performance across all levels. writing increases self-awareness in students which in turn contributes to their personal growth. a positive attitude towards writing enables students to benefit from this strategy. this study provides new insights into the attitudes of omani nursing students towards writing as a learning strategy. the findings of this study will be incorporated into the selection and design of a wtl educational strategy for nursing students at the college of nursing, sultan qaboos university, oman. application to patient care nurses who have a positive attitude towards writing will be better able to relate theory to practice and be competent in documenting patient care. as accurate documentation is an important part of patient care, nurses with competency in writing can document in a clear, concise and comprehensive manner their patients’ conditions, the care provided and patient response to treatment. this enables all the members of the healthcare team, including those from other disciplines, to follow and continue a care regimen which ensures quality and safety. nurses who are competent in writing will also participate in scientific publishing thus adding to knowledge in their discipline. clinical & basic research writing-to-learn attitudes of nursing students at sultan qaboos university e114 | squ medical journal, february 2014, volume 14, issue 1 writing-to-learn (wtl) is the process of writing about a concept in order to learn about it. learning to write is considered an important step in academic life and one of the essential ways to acquire knowledge; however, in the early 1990’s there was a paradigm shift from ‘learning to write’ to ‘writing to learn’.1 based on the central assumption that writing skills are primarily thinking skills, a higher order conceptual skill can evolve through writing. when students write to learn they essentially sort through ideas, connect thoughts, reflect on the knowledge they have gained and can then ‘see’ what they are learning. a wtl strategy is particularly important in promoting critical thinking skills among nursing students.2 internationally, wtl is an important teaching strategy and researchers have found that higherorder thinking occurs when there is an increased focus on the writing process.3 the writing process is defined as a process of developing a document using techniques which include: pre-writing, drafting, revising, editing and publishing. self-efficacy is a context-specific belief in one’s ability to succeed in a particular task and has farreaching effects on achievement. self-efficacy has a positive influence on attitudes towards the writing process. this includes encouraging students to invest extended time in thinking deeply and writing about issues which are important to them.4 a metaanalysis of six quantitative studies across disciplines at the university level5 as well as a meta-synthesis of 10 qualitative studies cited by webb3 revealed positive evidence that wtl approaches improve academic performance across science topics at all levels. the use of scientific writing heuristics in chemistry laboratory sessions at the universitylevel have also been shown to be highly effective in cognitive development.6 apart from the development of cognitive abilities, the nursing curriculum also demands that students be capable of documentation in clinical practice and the expression of ideas in examinations, assignments and projects. furthermore, nursing curricula incorporate bestevidence clinical practice and prepare students for their future roles in contributing materials to publications and presentations.7 the production of clear, accurate and relevant writing is an essential competency in nursing.8 through writing, students have an opportunity to record their thoughts and ideas, and provide evidence of their mastery of course concepts.9 there are no published data available on the use of the wtl strategy among nursing students in oman. personal observations also suggest that nursing students at sultan qaboos university (squ) appear to be more comfortable when doing assignments that do not require elaborate writing. therefore, a deeper investigation of these students’ attitudes towards writing was undertaken in order to inform attempts to introduce a wtl strategy at the college of nursing (con) at squ. this study used a modified wtl attitude scale (wtlas) to generate data on squ nursing students’ attitudes towards writing. methods a cross-sectional design was used to accomplish the study objectives. the objectives of the study were to identify: (1) the attitudes of nursing students at squ towards writing as a strategy to learn, and (2) the association between this attitude and selected demographic variables. all students enrolled at the squ con in the 2009–2010 academic year were eligible to participate in this study. a convenience sample was obtained. data collection was completed in six months between october 2009 and march 2010. the questionnaire, which included demographic data questions and the wtlas, was initially sent online to each student. as response rates were low (15%) (despite two reminder emails) a hard copy was distributed to the students. the students were then asked to return the completed questionnaire either online or as a hard copy. permission to conduct this study was granted by the research & ethics committee of the con. students were informed of the research and were assured of complete confidentiality and anonymity. participation was voluntary and students were informed that non-participation would not affect their academic grades. all students responded. participants provided verbal and written consent by completing a section on the first page of the questionnaire, where it was also made explicit that the group data were to be used in a research study. the demographic data collected included type of nursing programme, gender, exposure to english shreedevi balachandran, ramesh venkatesaperumal, jothi clara and raghda k. shukri clinical and basic research | e115 courses at secondary school and exposure to online learning. the wtlas was developed by dobie & poirrier.10 the tool is built on a five-point likert scale with response options ranging from ‘strongly agree’ to ‘strongly disagree’ and has 30 statements of which nine are negative statements. it is designed to elicit responses about basic psychosocial apprehensions and positive and negative perceptions about writing. the modified tool used in this study had 35 statements about writing in english of which 11 were negative statements. the statements were grouped into two areas, one on attitudes towards the writing process and the other on the student’s perception of their own self-efficacy in writing. for the purpose of content validity, four expert senior nurse educators at the con reviewed the dobie and poirrier’s wtlas and deleted three items from the questionnaire that were unfamiliar to squ students, i.e. ‘admit slips’, ‘exit slips’ and ‘use of journals’. after consultation with these same educators, these items were then replaced with similar questions using attitudinal concepts more familiar to squ students. five additional questions were included in the questionnaire based on the personal experiences of teaching and interacting with squ nursing students. the modified wtlas was then pilot tested on 10 students. it was found that certain words needed modification for easier understanding. for example ‘impromptu’ was replaced by ‘unprepared’, ‘terrible time’ changed to ‘difficult time’ and words such as ‘brainstorming’ and ‘free writing’ were deleted. the tool was once again validated by the same nurse educators. internal consistency or reliability of the modified wtlas was obtained using cronbach’s alpha, with a value of 0.83. students’ attitudes were measured according to the scores achieved in the questionnaires. the highest score achievable was 175. the results of the attitude scores were skewed to the left and hence the median was taken as the cut-off point. scores above 125 (based on the median) were considered to demonstrate a positive attitude while scores below table 1: demographic and educational characteristics of sultan qaboos university nursing students (n = 106) characteristic description n % gender male 38 35.8 female 68 64.2 programme pathway regular bsn 95 89.6 bridging 11 10.4 level from which english was taught as a subject primary school 85 80.2 secondary school 14 13.2 higher secondary school 1 0.9 university/ college 6 5.7 level from which all courses were taught in english primary school 5 4.7 secondary school 2 1.9 higher secondary school 3 2.8 university/ college 96 90.6 english courses taken at squ none 5 4.7 intensive english learning 69 65.1 challenge test 18 17.0 any other english course 4 3.8 all three of the above 2 1.9 intensive english & challenge test 4 3.8 ielts 4 3.8 online or e-learning courses taken 0 11 10.4 1 11 10.4 2 12 11.3 3 13 12.3 4 34 32.1 ≥5 25 23.6 bsn = bachelor of science in nursing ; bridging = course for diploma in nursing students to gain a bsn. squ = sultan qaboos university; ielts = international english language testing system. table 2: distribution of scores according to components of writing (n = 106) components of writing attitude n % writing process negative 56 52.8 positive 50 47.2 self-efficacy low 55 51.9 high 51 48.1 writing-to-learn attitudes of nursing students at sultan qaboos university e116 | squ medical journal, february 2014, volume 14, issue 1 125 indicated a negative attitude towards writing as a strategy for learning. the statements were grouped into two areas: those reflecting attitudes towards the writing process and those reflecting the student’s perception of their self-efficacy in writing. data entry, management and analysis were performed using the statistical package for the social sciences, version 17 (ibm, corp., chicago, illinois, usa). descriptive and inferential statistics were used. since the survey included both positivelyand negatively-stated items, reverse scoring of the negatively-stated items was performed prior to analysis. a logistic regression analysis was used to estimate the predictive ability of selected independent variables on the dependent variable called ‘writing process’. results this study used a modified wtlas to generate data on squ nursing students’ attitudes towards writing. the demographic and educational variables of the participants are described in detail in table 1. a total of 90% of the respondents were students in the generic baccalaureate nursing program, (i.e. four-year bachelor of science [bsn] degree); the remainder were students with the diploma in nursing who were studying for the bsn. the respondents were primarily female (64%) and 85% had studied english from primary school. however, 5.7% noted that they had only begun to study english for the first time after entering squ. the the vast majority (90.6%) of the students responded that only at squ were all of their subjects taught in english. the first objective of the study was to assess the attitude of students towards writing as a learning strategy. in terms of the wtlas, more than half of the students (55.7%) had a negative attitude towards writing as a learning strategy, while 44.3% had a positive attitude. attitudes towards selfefficacy in writing were also found to be low in 51.9% of students [table 2]. relevant statistical tests were performed; however, the results were not statistically significant. although 52.8% of the students had negative attitudes towards the writing process, the median was higher in the writing process (74%) in comparison to the median for self-efficacy (50%). there was a positive correlation between self-efficacy and scores for writing process. the second objective of the study was to correlate the attitude scores with selected demographic variables. the data were further analysed using inferential statistics. no significant differences (p ≤0.05) were noted between student attitudes to writing and gender; the type of nursing programme; the level at which students started learning english or were first taught subjects in english, and the type of english courses they took prior to starting at squ. there was, however, a statistically significant correlation with the number of online courses taken. students who had taken at least three online courses were three times more likely to have a positive writing attitude compared to students who had fewer experiences with online courses. a logistic regression analysis of six variables revealed that the total number of online courses taken was a statistically significant determinant of the attitude towards the writing process (odds ratio [or] = 3.26; 95% confidence interval [ci]: 1.27–8.36; p <0.01) table 3: logistic regression analysis of the effects of variables on the writing process variable or 95% ci p gender 0.95 0.39–2.31 0.91 first english level subjects 0.57 0.20–1.61 0.29 all english levels 0.68 0.17–2.73 0.58 english course before nursing 1.24 0.49–3.15 0.64 type of study programme 0.56 0.13–2.51 0.45 total online courses 3.26 1.27–8.36 0.01* or = odds ratio; ci = confidence interval; *p = 0.05. coding of independent variables: gender: female = 2; first english level: beyond primary education = 2; level of all english subjects: university or college = 2; english course before nursing : other exposure to english language = 2. programme: bsn = 2; total online courses: 0–2 = 2, ≥3 = 1; coding of dependent variable: writing process: high =2. bsn = bachelor of science in nursing. table 4: mean attitude scores of various levels of students level of students n mean standard deviation f-test p senior 41 128.80 14.27 0.13 0.72 middle 51 118.22 14.49 middle 51 118.22 14.49 0.24 0.62 junior 14 129.14 16.88 senior 41 128.80 14.27 0.08 0.78 junior 14 129.14 16.88 shreedevi balachandran, ramesh venkatesaperumal, jothi clara and raghda k. shukri clinical and basic research | e117 table 5: correlation between the writing process and self-efficacy (n = 106) writing process self-efficacy writing process pearson correlation 1 0.55* significance (2-tailed) 0.00 self-efficacy pearson correlation 0.55* 1 significance (2-tailed) 0.00 *correlation is significant at 0.01 (2-tailed). as shown in table 3. in order to investigate the differences in attitudes towards writing between cohorts of students, they were stratified as senior students (4th year and above), middle level students (3rd and 2nd year students) and junior level students (1st year and foundation level). table 4 shows the distribution of senior, middle, and junior students and their average attitude scores. the senior and junior students had more positive attitudes towards wtl, whereas the middle level students had more negative attitudes towards wtl; however, these results were not statistically significant. although the scale gave the overall attitude score for individual students, it was important to identify the attitudes towards the specific components of writing. hence the statements of attitude were regrouped to separate the writing process per se from the learner’s self-efficacy. table 5 indicates that there is a strong correlation between the respondents’ attitude towards the writing process and their attitude towards self-efficacy. discussion wtl provides nurse educators with a new tool with which they can evaluate and respond to many difficulties encountered in the education of nurses. by focusing on the intellectual development of the nursing students, and with writing skills being viewed as thinking skills, writing can provide important links between courses in the curriculum. writing activities can be planned in several courses to build upon each other while providing students with a wide variety of opportunities to practise this skill. these activities can be developed to enhance the teaching content and thus complement the course objectives.1 however, writing tasks for many students can provoke strong emotions and feelings.11 students are often apprehensive about their abilities to communicate successfully in written form.9 hence, it is worth discussing the affective domains of writing with the aim of helping students to recognise their anxieties and thus improve their writing. the affective domain plays an important role in writing; negative writing experiences affect both the the student’s attitude and the quality of the student’s writing.11,12 nursing students achieved higher aggregate semester scores when they utilised wtl strategies (wtls).13 dobie and poirrier showed that wtls helped nursing students, who had negative attitudes towards writing, to clarify their concepts and experienced a reduction in feelings of nervousness about having to produce written work; thus their attitude towards writing was improved.10 a key finding of this study is that students who had taken more online courses demonstrated a more positive attitude to writing than students who had no or only limited experience of such courses. this likely indicates a higher comfort level with the use of interactive computer programmes and the development of skills that are transferrable to the task of writing. the purpose of this study was to identify the attitudes of nursing students towards writing as a tool for learning. the overall attitude of nursing students towards writing as a learning strategy was negative (55.7%); although a substantial minority (44.3%) had a positive attitude. this is consistent with the findings of dobie and poirrier who also reported that the pre-test evaluation of attitudes towards writing was negative.10 students in the current study also reported low scores in attitudes towards the writing process. this is consistent with the findings of schmidt who evaluated a wtls with undergraduate nursing students.9 attitudes towards self-efficacy in writing were also found to be low in the current study. one possible explanation for these findings could be that once senior students get more exposure to clinical settings they perceive writing as an important competency for professional nurses. on the other hand, junior students have fewer writing assignments but maybe more open to learning. the mid-level students may have been given more writing assignments, but if these assignments were writing-to-learn attitudes of nursing students at sultan qaboos university e118 | squ medical journal, february 2014, volume 14, issue 1 not structured, they may thus not have perceived the benefits of writing in english. this study has several implications for planning the writing component of the nursing curriculum at squ. wtl strategies have helped students to develop critical thinking skills.1 by incorporating wtl into the curriculum, the faculty can help students improve their writing skills and understand course material more fully, as well as encourage critical thinking.7,14 an academic writing workshop embedded in the curriculum and supported by both contentand writing-skill experts may be effective in improving academic writing skills in multidisciplinary groups of students who have low to medium english language proficiency.15 although advanced-level writing assignments in multidisciplinary curricula may seem challenging even to the faculty, with careful planning and followup wtl courses can be successfully implemented in all curricula. this study also draws attention to the need to provide resources to facilitate writing skills among students at the college and university entry level. this study has certain limitations. it was designed to describe the attitudes of nursing students towards writing but did not investigate the reasons for their positive or negative attitudes. nonetheless, it is the first study in oman to examine nursing students’ attitudes towards writing. further studies should be undertaken to investigate the possible causes for positive and negative attitudes to wtl and suggest remedial measures to improve wtls which may serve to make writing an essential component of university learning. an experimental study could also be designed to assess the effectiveness of the wtl strategies among omani students. for example, reflective writing or journaling could be introduced as an intervention to improve attitudes towards writing.10 it is also recommended to investigate the attitudes of nursing students towards wtl in arabic and compare these with the attitude towards wtl in english. conclusion the findings of this study suggest that the students in oman, like students elsewhere, have negative attitudes towards wtl. negative attitudes towards writing provide a strong rationale for including academic writing in the foundation year of the nursing curriculum and then to incorporate writing assignments throughout the nursing curriculum. attitudes are learned or changed through experience; hence, negative attitudes towards writing can be transformed into positive attitudes by the implementation of carefully thought-out structured writing tasks. through writing, students can develop skills of critical thinking and reflection, as well as enhance their communication abilities. efforts can and should be taken to cultivate positive student attitudes towards writing in english. wtl strategies used in other countries, such as reflective writing in personal journals, have improved student attitudes towards writing and learning, increased student-teacher communication and increased student retention of knowledge. perhaps the introduction of a wtls for squ junior level nursing students could yield positive results. a c k n o w l e d g e m e n t s the authors would like to thank the following people most sincerely for their help with this article: dr. paul webb, director of center for educational research, technology & innovation, nelson mandela metropolitan university, south africa, for his encouragement, review and valuable suggestions on this manuscript; prof. erika s. froelicher, visiting consultant, college of nursing, for her critical review of the manuscript and her valuable suggestions; dr. ahmad abu raddaha, college of nursing, for reviewing the statistical analysis, and dr. ann mitchell, for her critical review of the manuscript and valuable suggestions. references 1. allen dg, bowers b, diekelmann n. writing to learn: a reconceptualization of thinking and writing in the nursing curriculum. j nurs educ 1989; 28:6–11. 2. cowles kv, strickland d, rodgers bl. collaboration for teaching innovation: writing across the curriculum in a school of nursing. j nurs educ 2001; 40:363–7. 3. webb p. science education and literacy: imperatives for the developed and developing world. science 2010; 328:448– 50. 4. freedman sw. evaluating writing: linking large-scale testing and classroom assessment. the university of california at berkeley: national center for the study of writing & literacy, 1991. occasional paper, op 27. 5. gunel m, hand b, prain v. secondary analysis of nontraditional writing in science across different grade-levels. int j sci math educ 2007; 4:615–37. shreedevi balachandran, ramesh venkatesaperumal, jothi clara and raghda k. shukri clinical and basic research | e119 6. hand bm. science inquiry, argument and language: a case for the science writing heuristic. rotterdam: sense publishers, 2008. pp. 165–76. 7. luthy ke, peterson ne, lassetter jh, callister lc. successfully incorporating writing across the curriculum with advanced writing in nursing. j nurs educ 2009; 48:54– 9. 8. american association of colleges of nursing. the essentials of baccalaureate education for professional nursing practice. washington dc: american association of colleges of nursing, 2008. p. 12. 9. schmidt la. evaluating the writing-to-learn strategy with undergraduate nursing students. j nurs educ 2004; 43:466– 73. 10. dobie a, poirrier g. when nursing students write: changing attitudes. lang learn across disciplin 1996; 1:23–33. 11. wellington j. more than a matter of cognition: an exploration of affective writing problems of post-graduate students and their possible solutions. teach higher educ 2010; 15:135–50. 12. adams j. understanding writing beliefs of advanced writing students. phd thesis, brigham young university, utah, usa, 2006. p. 256. 13. ashworth te. using writing-to-learn strategy in community college associate degree nursing programs. ph.d. thesis, virginia polytechnic institute and state university, 1992. dissertation abstracts international, a 53/03, 696. 14. jackman m. the write attitude: nursing students write their way to improved patient care write away! the university of louisville’s writing-across-the-curriculum newsletter, 1995; issue 1. 15. salamonson y, koch j, weaver r, everett b, jackson d. embedded academic writing support for nursing students with english as a second language. j adv nurs 2010; 66:413–21. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. e350-352, epub. 9th may 13 submitted 23rd may 12 revision req. 14th oct 12, revision recd. 14th oct 12 accepted 26th nov 12 1department of emergency medicine, mackay memorial hospital, taipei, taiwan; 2department of oral hygiene, college of oral medicine, taipei medical university, taiwan; 3school of dentistry, college of oral medicine, taipei medical university, taiwan. *corresponding author e-mail: yjsu@ms1.mmh.org.tw الكشف باملوجات فوق الصوتية عن أم دم كاذبة يف إصابات األوعية الدموية يف قسم الطوارئ ىل جني �شني، يو جانغ �شو ، وت�شانغ ت�شيه ت�شن ، ويدي ت�شاي امللخ�ص: رجل )31 عاما( من العمر يعاين من جرح ب�شبب طعنة يف طرفه ال�شفلى. كان املري�ض يعاين من عالمة �شعبة لإ�شابة الأوعية الدموية ) تقل�ض النب�ض القا�شي(، فكان لبد من اإخ�شاعه لعملية اإ�شطالحية، لكنه رف�ض. بعد اأ�شبوع واحد، عاد اإىل غرفة الطوارئ لدينا نتيجة لتورم موؤمل يف الفخذ الأمين. مت ا�شتخدام الت�شوير فوق ال�شوتي للك�شف ال�رسيري عن اأم دم كاذبة. الك�شف باملوجات فوق ال�شوتية يف حالت الطوارئ هو اإجراء �رسيع وغري نافذ ل�رسعة اتخاذ القرار يف نهج املمار�شة يف حالت الطوارئ. مفتاح الكلمات: اأم الدم؛ كاذبة؛ ال�رسيان الفخذي؛ اجلرح؛ ال�رسف؛ الت�شوير باملوجات فوق ال�شوتية؛ تقرير حالة؛ تايوان. abstract: a 31-year-old man suffered from a stab wound to the lower extremity. the patient had a hard sign of a vascular injury (a diminished distal pulse) and therefore probably should have undergone operative repair, but refused. one week later, he returned to our emergency department with a painful right thigh swelling. bedside sonography was used to detect a pseudoaneurysm. emergency sonography is a fast, non-invasive, and rapid decision-making approach in emergency practice. keywords: aneurysm, false; femoral artery; wound; drainage; ultrasonography; case report; taiwan. sonographic detection of pseudoaneurysm in vascular injury in emergency department li-jen chien,1 *yu-jang su,1,2 chang-chih chen,1,3 weide tsai1 online case report patients with hard signs of vascular injury (diminished distal pulse) due to various types of wounds should undergo operative repair. bedside sonography can be used to detect pseudoaneurysms (pa). angiograms are often done in the emergency department (ed) when no hard signs of vascular injury are present following penetrating trauma and when pa is a possible diagnosis. case report a 31-year-old man presented to the ed with a knife-inflicted stab wound to his anterior right thigh. the knife had been removed immediately at the scene by the patient. the patient was in a cold sweat with low blood pressure (bp) (78/51 mmhg) and a pulse rate of 115 beats per minute (bpm). a physical examination found a right lower limb wound with continuous bleeding. with the exception of a diminished pulse in the dorsal pedis artery, the capillary refill time (crt), pulse in the posterior tibial artery, and muscle strength were all intact. the patient was experiencing no sensory deficit. we immediately compressed the stab wound and performed a primary wound closure, inserting a drainage tube. the patient also received 1,500 ml of normal saline, 1 unit of whole blood, and 500 ml of 6% polystarch. his vital signs gradually stabilised. computed tomography (ct) angiography revealed a small breakdown of the superficial femoral artery with patent distal flow [figure 1]. despite this finding, and against the physician’s advice, the patient left the hospital without receiving full medical care; this was due to his economic situation. he was, however, advised to return to the ed if he experienced shortness of breath, dizziness, or visible expansion or pulsing of the haematoma. one week later, he returned to the ed with progressive right thigh swelling and pain. the drainage tube was found to be still in place. the patient presented with bp of 112/64 mmhg, a pulse li-jen chien, yu-jang su, chang-chih chen and weide tsai case report | 351 of 136 bpm, and a respiratory rate of 20 breaths per minute. the physical examination revealed a tense right thigh that was painful and grossly tender; however, the rest of the examination was unremarkable. a vascular ultrasound revealed an oval mass, which was suspected to be a pa of the femoral artery [figure 2]. a follow-up ct angiography demonstrated a haematoma on the superficial femoral artery with extravasated contrast medium [figure 3]. the patient again left the ed against the medical advice of physicians. discussion the aetiology of peripheral vascular injuries is primarily divided into blunt and penetrating mechanisms, and the severity of vascular injuries ranges from non-occlusive to occlusive injury, in which all effective perfusion distal to the occlusion is lost. while transections, thrombosis, and reversible spasms typically result in occlusive types of vascular injuries, intimal flaps, dissections, arteriovenous fistulas (avf), and pas result in non-occlusive types of vascular injuries. a true aneurysm contains all three layers of the vessel wall (intima, media, and adventitia). a pa, or false aneurysm, is a haematoma that forms as a result of a leaking hole within an artery. the haematoma is contained by the surrounding fascia, and is gradually encased by a capsule of fibrous tissue. since haematomas lack a normal fibrous aneurysmal wall, they sometimes are described as pulsatile haematomas. the classic hard signs of an active haemorrhage are an expanding or pulsatile haematoma, a bruit or thrill heard when placing a stethoscope over the wound, the absence of a palpable distal pulse, and distal ischaemic manifestations (i.e. pain, pallor, paralysis, paresthesias, poikilothermy, or coolness). when hard signs are present, the incidence of arterial injury is greater than 90%.1 the diagnostic tools used to assess arterial injury include ultrasound, ct, and angiography. further investigation on the applicability of emergency angiography or immediate surgical intervention is warranted, especially in regards to the duration of the warm ischaemia and the overall status of the patient. the combination of a b-mode and doppler ultrasound is typically referred to as a duplex ultrasound. the sensitivity of a duplex ultrasound ranges from 90–100%, and the specificity ranges from 99–100%.2–4 however, a duplex ultrasound is technically limited in examining certain anatomic areas such as the profunda femoris and brachii figure 1: computed tomography angiography showing a small breakdown of the superficial femoral artery (arrow). figure 2: the drainage after primary closure is in situ. the sonographic probe is kept in the axial view (left hand image) and in the coronal view (right hand image) of the right thigh. the vascular ultrasound showed an oval mass, highly suspected to be a pseudoaneurysm (pa) of the right femoral artery. f = femoral bone. sonographic detection of pseudoaneurysm in vascular injury in emergency department 352 | squ medical journal, may 2013, volume 13, issue 2 arteries, and the iliac and subclavian vessels. its accuracy is highly operator-dependent. while angiography is still the gold standard for the evaluation of vascular injury, multidetector ct (mdct) angiography provides non-invasive, high-resolution images with 98.7–100% specificity and 90–95% sensitivity.5,6 additionally, an increasing number of emergency physicians prefer mdct over catheter-based angiography. conclusion our case highlights the importance of using sonographic approaches for vascular injuries in the ed. as detected with sonography, the vascular injury of our patient at the second visit had progressed into a pa. thus, emergency sonography is a fast, non-invasive, and rapid decision-making aid in emergency practice. references 1. gonzalez rp, falimirski me. the utility of physical examination in proximity penetrating extremity trauma. am surg 1999; 65:784–9. 2. knudson mm, lewis fr, atkinson k, neuhaus a. the role of duplex ultrasound arterial imaging in patients with penetrating extremity trauma. arch surg 1993; 128:1033–7. 3. fry wr, smith rs, sayers dv, henderson vj, morabito dj, tsoi ek, et al. the success of duplex ultrasonographic scanning in diagnosis of extremity vascular proximity trauma. arch surg 1993; 128:1368–72. 4. kuzniec s, kauffman p, molnar lj, aun r, puechleão p. diagnosis of limbs and neck arterial trauma using duplex ultrasonography. cardiovasc surg 1998; 6:358–66. 5. rieger m, mallouhi a, tauscher t, lutz m, jaschke wr. traumatic arterial injuries of the extremities: initial evaluation with mdct angiography. ajr am j roentgenol 2006; 186:656–64. 6. inaba k, potzman j, munera p, mckenney m, munoz r, rivas l, et al. multi-slice angiography for arterial evaluation in the injured lower extremity. j trauma 2006; 60:502–6. figure 3: computed tomography angiogram (axial view) of the right thigh. with an extravasated contrast medium, the white arrow indicates haematoma formation on the superficial femoral artery. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e259-260, epub. 7th apr 14 submitted 23rd may 13 revision req. 25th aug 13; revision recd. 26th aug 13 accepted 22nd sep 13 1department of haematology, sultan qaboos university hospital, muscat, oman; 2ministry of health, muscat, oman *corresponding author e-mail: arwa@squ.edu.om تعرض كريات الدم احلمراء للحرارة يؤدي لنتائج خمربية زائفة ومضللة اأروى الريامية، خليل الفار�صي، اإبراهيم ال�صحي، مرت�صى اخلابوري، حممد احلنيني، و هيدي ديفي�س pseudopyropoikilocytosis leading to spurious results *arwa z. al-riyami,1 khalil al-farsi,1 ibrahim al-shehhi,2 murtadha al-khabori,1 mohammed al-huneini,1 heidi davis1 interesting medical image figure 1: blood film showing numerous small basophilic particles in clumps (arrow) and small chains (arrow head). figure 2: blood film showing striking red cell poikilocytosis with numerous microspherocytes (arrow head) and irregular pleomorphic fragments (red arrows). a necrotic neutrophil with distorted nuclei can also be seen in the field (black arrow). pseudopyropoikilocytosis is an unusual phenomenon that is caused by the overheating of blood samples during transportation to the laboratory.1 this results in the red blood cells (rbcs) displaying similar morphological features to blood films of individuals with hereditary pyropoikilocytosis and severe thermal burns. the morphological findings in these two pathological conditions are related to the thermal instability of the rbcs.2 both these morphological changes and the spurious results obtained from overheated samples can result in diagnostic confusion. a 21-year-old female was referred to the department of haematology at the sultan qaboos hospital, muscat, in july 2012 following abnormal laboratory results. her vital signs were stable and the physical examination was unremarkable. a complete blood count (cbc) obtained by the celldyn sapphire haematology analyser (abbott diagnostics, lake forest, illinois, usa) showed marked thrombocytosis with a platelet count of 3,425 x 109/l (normal range: 150–450 x 109/l), leukocytosis with a white blood cell count of 16.8 x 109/l (normal range: 2.4–9.5 x 109/l), microcytosis with a mean corpuscular volume (mcv) of 68.5 fl (normal range: 78–95 fl), a high red cell distribution width (rdw) at 33.9% and an extremely high reticulocyte count of 5,435 x 109/l (normal range: 20–150 x 109/l). the blood film showed numerous small basophilic spherical particles in chains and variable clumps [figures 1 and 2]. in addition, there was severe red cell poikilocytosis with bizarre poikilocytes, including microspherocytes and irregular pleomorphic fragments [figure 2]. the white blood cells appeared necrotic. the potassium (k) level was high at 6.4 mmol/l (normal range: 3.5–5.1 mmol/l). pseudopyropoikilocytosis leading to spurious results e260 | squ medical journal, may 2014, volume 14, issue 2 the patient underwent a repeat cbc, and the new sample revealed normal indices. the repeated blood film and k levels were normal. the initial abnormal results were therefore attributed to the large number of small red cell fragments and the numerous spherical particles, which were thought to be precipitated proteins. the initial collection tube expiry date was verified. gram stains and cultures on the initial sample, as well as on new samples, were negative. since the clinic was located at a distance from the laboratory, it was concluded that the previous abnormal results were due to the possible thermal exposure of the sample during transportation, resulting in in vitro haemolysis, altered morphology and spurious results. however, a manufacturing defect in the original collection tube could not be ruled out. comment spurious results on haematology analysers should be promptly identified to avoid potential misdiagnoses.3 abnormal results require a careful evaluation of the scatter plots obtained by the analyser as well as an examination of a well-stained blood film. this case provides an example of the spurious results that can result after a thermal injury to a blood sample. in addition, it gives a clear illustration of the different morphological abnormalities seen in this setting. these results were obtained by a different instrument than those seen in the previously published literature, illustrating the importance of recognising the different characteristics of various analysers when examining the obtained results. the artificial thrombocytosis is likely to be secondary to the presence of the particles and the red blood cell fragments.4 since the cell-dyn sapphire haematology analyser uses impedance and optical methods (light scattering) of measurement, the presence of these particles caused an overestimation of the counts, as well as the low mcv and high rdw. haematologists and haematology laboratory scientists must be aware of the characteristics of their analysers when evaluating cbc results, and be able to recognise and circumvent anomalous results. the lack of recognition of spurious results can lead to unnecessary investigations, undue anxiety and potentially harmful interventions. any unusual or abnormal findings should prompt a request for a blood film and a repeat sample. references 1. bain bj, liesner r. pseudopyropoikilocytosis: a striking artifact. j clin pathol 1996; 49:772–3. doi:10.1136/jcp.49.9.772. 2. zarkowsky hs, mohandas n, speaker cb, shohet sb. a congenital haemolytic anaemia with thermal sensitivity of the erythrocyte membrane. br j haematol 1975; 29:537–43. doi: 10.1111/j.1365-2141.1975.tb02740.x. 3. bain bj, lewis sm, bates i. basic haematological techniques. in: lewis sm, bain bj, bates i, dacie j (eds). dacie and lewis’s practical haematology, 9th edition. philadelphia: churchill livingston, 2001. pp.19–46. 4. zandecki m, genevieve f, gerard j, godon a. spurious counts and spurious results on haematology analysers: a review. part i: platelets. int j lab hematol 2007; 29:4–20. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e266–274, epub. 28 may 15 submitted 16 jul 14 revision req. 21 sep 14; revision recd. 22 oct 14 accepted 24 nov 14 1department of physiotherapy, school of rehabilitation science, faculty of health sciences and 2department of education & community wellbeing, faculty of education, university kebangsaan malaysia, kuala lumpur, malaysia *corresponding author e-mail: zailani1101@hotmail.com صحة وموثوقية أداة تقييم الكفاءات السريرية الستخدامها يف تقييم طالب العالج الطبيعي دراسة جتريبية زيالين حممد، اي�سه راملي، �سالح اأمات abstract: objectives: the aim of this study was to determine the content validity, internal consistency, testretest reliability and inter-rater reliability of the clinical competency evaluation instrument (ccevi) in assessing the clinical performance of physiotherapy students. methods: this study was carried out between june and september 2013 at university kebangsaan malaysia (ukm), kuala lumpur, malaysia. a panel of 10 experts were identified to establish content validity by evaluating and rating each of the items used in the ccevi with regards to their relevance in measuring students’ clinical competency. a total of 50 ukm undergraduate physiotherapy students were assessed throughout their clinical placement to determine the construct validity of these items. the instrument’s reliability was determined through a cross-sectional study involving a clinical performance assessment of 14 final-year undergraduate physiotherapy students. results: the content validity index of the entire ccevi was 0.91, while the proportion of agreement on the content validity indices ranged from 0.83–1.00. the ccevi construct validity was established with factor loading of ≥0.6, while internal consistency (cronbach’s alpha) overall was 0.97. test-retest reliability of the ccevi was confirmed with a pearson’s correlation range of 0.91–0.97 and an intraclass coefficient correlation range of 0.95–0.98. inter-rater reliability of the ccevi domains ranged from 0.59 to 0.97 on initial and subsequent assessments. conclusion: this pilot study confirmed the content validity of the ccevi. it showed high internal consistency, thereby providing evidence that the ccevi has moderate to excellent inter-rater reliability. however, additional refinement in the wording of the ccevi items, particularly in the domains of safety and documentation, is recommended to further improve the validity and reliability of the instrument. keywords: clinical competence; physiotherapy speciality; validity and reliability; malaysia. امللخ�ص: الهدف: من هذه الدرا�سة هو حتديد �سالحية املحتوى، واالت�ساق الداخلي، وموثوقية االختبار واإعادة االختبار وموثوقية ما بني الت�سنيفات الأداة تقييم الكفاءة ال�رشيرية )ccevi( يف تقييم االأداء ال�رشيري لطالب العالج الطبيعي. الطريقة: اأجريت هذه الدرا�سة يف الفرتة ما بني �سهري يوليو و�سبتمرب 2013 يف جامعة كبانغ�سان ماليزيا. )ukm( مت حتديد ع�رشة خرباء لتحديد �سالحية املحتوى من خالل تقييم وت�سنيف كل من البنودامل�ستخدمة يف ccevi فيما يتعلق باأهميتها يف قيا�ض الكفاءة ال�رشيرية لدى الطالب. مت تقييم 50 موثوقية حتديد مت امل�ستخدمة. البنود �سالحية لتحديد ال�رشيري تن�سيبهم خالل اجلامعية املرحلة يف الطبيعي العالج طالب من طالب موؤ�رش النتائج: النهائية. اجلامعية ال�سنة يف الطبيعي العالج طالب من 14 ل ال�رشيري االأداء تقيم م�ستعر�سة درا�سة خالل من االأداة �سحة املحتوى الأداة ال ccevi كانت 0.91، بينما تراوحت الن�سبة املئوية لالتفاق على حمتوى موؤ�رشات �سحة )1.00–0.83( مت تثبيت موثوقية تاأكيد ومت .0.97 عموما األفا( )كرونباخ الداخلي االت�ساق كان حني يف ،≥0.6 حتميل بعامل ccevi ال البنائية ال�سالحية ccevi مبدى ارتباط بري�سون بني )0.97–0.91( وكان مدى معامل ارتباط الت�سنيف املتداخل ل ccevi االختبار واإعادة االختبار لل يرتاوح بني )0.98–0.95( اأما موثوقية مابني املقيمني ل ccevi فكانت بني )0.97–0.59( يف التقديرات االأولية والالحقة. اخلال�صة: اأكدت هذه الدرا�سة التجريبية �سحة حمتوى ال ccevi وبينت اأن االت�ساق الداخلي لهذه االأداة مرتفع، وبالتايل تتوفر االأدلة على اأن اأداة ال ccevi لديها موثوقية مابني املقيمني متو�سطة اإىل ممتازة. ومع ذلك، فمن امل�ستح�سن ان يتم بع�ض ال�سقل االإ�سايف يف �سياغة البنود الأداة ال ccevi وال �سيما يف جماالت ال�سالمة والوثائق لتح�سني �سحة وموثوقية هذه االأداة. مفتاح الكلمات: الكفاءة ال�رشيرية؛ تخ�س�ض العالج الطبيعي؛ ال�سحة واملوثوقية؛ ماليزيا. validity and reliability of the clinical competency evaluation instrument for use among physiotherapy students pilot study *zailani muhamad,1 ayiesah ramli,1 salleh amat2 clinical & basic research zailani muhamad, ayiesah ramli and salleh amat clinical and basic research | e267 the competency of physiotherapy graduates is becoming a central issue of discussion among physiotherapy clinical educators and academic faculty experts in the healthcare profession.1 the main concern is the instrument used to evaluate the clinical performance of students as a measure of competency.2,3 such instruments should demonstrate psychometric properties that are valid and reliable.4–7 the increasing number of higher educational institutions that offer physiotherapy programmes has led to a vast variation in curriculum design and assessment approaches. in terms of the assessment of clinical competence, many academic programmes have developed their own assessment instrument that fulfils the needs of their curriculum. in most cases, the instruments used for evaluation are not standardised and differ between institutions.8,9 as a consequence, the quality of physiotherapy graduates qualifying for entry level positions in professional practice varies between institutions, potentially compromising the overall standard of physiotherapy care provided to patients. according to wass et al., there is a need to develop an assessment instrument for healthcare students that is accurate and able to measure clinical competence objectively.7 therefore, the validity and reliability of an instrument is crucial in ensuring that it accurately measures the concepts/attributes that need to be measured according to a curriculum’s requirements.10 various assessment instruments have been developed and used by physiotherapy programmes around the world, such as the physiotherapy clinical performance instrument (ptcpi) which is used in the united states and canada,11 and the assessment of physiotherapy practice used by physiotherapy programmes in australia and new zealand.12 these two instruments are used to evaluate students’ clinical competency at the entry level of practice. similarly, tools such as the clinical internship evaluation tool, are used to evaluate students’ clinical competency with regards to patient management skills.13 as a pioneer institution offering the first baccalaureate programme in physiotherapy in malaysia, the academic staff members of the physiotherapy programme in the faculty of health sciences at university kebangsaan malaysia (ukm) in kuala lumpur, malaysia, developed the clinical competency evaluation instrument (ccevi). this instrument was developed to suit the local sociocultural context and the ukm physiotherapy curriculum with the aim of evaluating the clinical competency of ukm’s physiotherapy students. to the best of the author’s knowledge, no investigations of the psychometric properties of this instrument had previously been carried out. therefore, the objective of this study was to determine the content and construct validity, test-retest reliability, internal consistency and the inter-rater reliability of the ccevi among physiotherapy student at ukm. methods this pilot study was carried out between june and september 2013. there were two phases to the methodology. phase one aimed to determine the content validity of the ccevi questionnaire, while phase two involved a test run of the questionnaire in order to determine the construct validity and reliability of the instrument. the ccevi was administered in english. the original version of the ccevi consisted of 42 items in eight domains: (1) subjective; (2) objective; (3) analysis; (4) treatment; (5) plan and education; (6) safety; (7) documentation, and (8) viva. subsequently, the subjective, objective, treatment and plan and education domains were further subdivided into subscales of knowledge, skills and professional traits. in june 2013, content validation in phase one was performed to improve the original version of the ccevi questionnaire that was initially developed by the ukm physiotherapy task force. a panel of 10 experts were identified with each expert possessing more than 10 years of experience in clinical teaching and evaluation of students’ performance; their experience ranged from 10–24 years (mean: 18.9 years). six of these experts were academicians (from ukm, the mara university of technology in shah alam, malaysia, or the training division of the malaysian ministry of health) and the remaining four advances in knowledge the results of this study suggest that the clinical competency evaluation instrument (ccevi) is a valuable preliminary instrument with psychometric properties for assessing the clinical competency of physiotherapy students in physiotherapy education programmes. this study demonstrated that the ccevi has content validity and moderate to excellent inter-rater reliability. application to patient care confirming the validity and reliability of the ccevi ensures that it can effectively assess physiotherapy graduates’ clinical competency, thereby verifying that graduates are providing quality health services in patient care and upholding patient safety standards. validity and reliability of the clinical competency evaluation instrument for use among physiotherapy students pilot study e268 | squ medical journal, may 2015, volume 15, issue 2 were clinical educators from four different teaching hospitals within klang valley in kuala lumpur. a copy of the ccevi questionnaire was attached together with the item evaluation, which was then sent to the expert panel for review.14 a total of three indices (relevance, clarity and representativeness) were used to determine the content validity of each item in the instrument. a likert-type rating scale of 1–4 was used to rate each item of the indices (1 = not relevant, 2 = somewhat relevant, 3 = relevant and 4 = very relevant). the completed rating scores from the experts were then collected to calculate the item content validity index (i-cvi) and the overall content validity of the instrument. the panel of experts were encouraged to give written feedback and recommendations on the overall structure of the ccevi. the i-cvi of the entire instrument was calculated based on the proportion of items in the instrument that achieved a relevant rating by the content experts. it has been shown that an acceptable content validity index (cvi) score from a panel of 3–5 experts is 1.00, while a minimum cvi score of 0.78 is required for a panel of 6–10 experts.14,15 following the analysis of the content validity of the instrument, amendments were made to the initial version of the ccevi. although the original version of the ccevi had 42 items, the revised version had been reduced to 40 items. to score the students’ performance, a grading of a 5-point likert scale ranging from 0–4 (0 = not competent, 1 = poor, 2 = fair, 3 = good and 4 = excellent) was used to reflect clinical competency. the revised version of the ccevi was then sent back to the panel of experts to reevaluate the clarity, appropriate use of language and overall presentation of the instrument. the feedback and comments were revised until no further changes were brought up by the experts. the cvi and interrater agreement of the revised instrument were then calculated again in order to compare it with the initial version of the ccevi. the final revised version of the ccevi was then pilot tested to determine its reliability and validity. over the period of july to september 2013, a crosssectional pilot study was carried out using convenience sampling. a new set of five experts were invited to participate in the study. these experts were clinical physiotherapy educators working at a teaching hospital in kuala lumpur, with clinical experience ranging from 9–20 years (mean: 13.6 years). in addition, ukm undergraduate physiotherapy students in their final year of study, who had completed a minimum of six weeks of clinical placement, were also asked to join the study; a total of 50 students volunteered to participate (mean age: 23.3 years). all of the participants educators and students were briefed on the conduct of study. the clinical educators were requested to assess the clinical competency of the students during their clinical placement using the revised ccevi questionnaire. after assessment, a total of 50 completed ccevi questionnaires were collected from the educators to determine the construct validity of the instrument. in phase two, a test-retest method was used to determine the reliability of the instrument in. two of the five aforementioned experts were randomly selected and were requested to conduct a screening at the physiotherapy outpatient department of sungai buloh hospital in kuala lumpur. the purpose of the screening was to select patients with similar musculoskeletal problems who could be assessed and treated by physiotherapy students in a clinical competency assessment. the selected patients were randomly assigned to 14 final-year ukm undergraduate physiotherapy students. these students were then assessed by the two aforementioned clinical educators as they carried out their assessment and treatment of the selected patients. the educators were requested to independently score the students’ performances using the revised ccevi and were not allowed to discuss the marks they had allocated to the students. the evaluation process was repeated again after a one-week interval. the 14 students were evaluated for a second time by the same clinical educators using the ccevi and while assessing and treating the same patients in the same setting. the outcomes of the two assessments were then statistically analysed to determine stability, internal consistency and inter-rater reliability. data were analysed using the statistical package for the social sciences (spss) version 20.0 (ibm corp., chicago, illinois, usa). to calculate the i-cvi, scores were divided into two groups; relevant (with a score of 3 or 4) versus not relevant (with a score of 1 or 2). the i-cvi for each item on the ccevi was calculated as the number of experts giving a rating of 3 (relevant) or 4 (very relevant) divided by the total number of experts. the cvi for the entire ccevi was recalculated based on the percentage of total items rated by the experts as either 3 or 4. a cvi score of ≥0.80 was considered acceptable.14 the inter-rater agreement was calculated as the percentage of the ccevi questionnaire that was considered relevant or very relevant by all experts. to establish the construct validity of the instrument, each item in each of the ccevi domains was evaluated using the principal components factor analysis with varimax rotation and kaiser normalisation. bartlett’s test of sphericity was performed to determine the significance (p ≤0.005) of correlation among the zailani muhamad, ayiesah ramli and salleh amat clinical and basic research | e269 table 1: content validity index of the revised clinical competency evaluation instrument among physiotherapy students in malaysia domain construct item no. cvi relevance clarity representativeness assessment knowledge a 1 1.00 1.00 1.00 a 2 1.00 1.00 1.00 a 3 1.00 1.00 1.00 a 4 1.00 1.00 1.00 a 5 1.00 1.00 1.00 skills a 6 1.00 1.00 1.00 a 7 1.00 0.60 0.60 a 8 1.00 1.00 1.00 a 9 1.00 1.00 1.00 a 10 1.00 0.70 1.00 a 11 1.00 1.00 1.00 professional traits a 12 1.00 0.70 0.80 a 13 1.00 0.70 1.00 a 14 0.90 0.80 0.80 analysis knowledge b 1 1.00 1.00 0.90 b 2 1.00 1.00 1.00 b 3 1.00 0.80 0.90 b 4 1.00 1.00 1.00 b 5 1.00 1.00 1.00 treatment knowledge c 1 0.80 1.00 1.00 c 2 1.00 0.90 0.90 c 3 1.00 1.00 1.00 skills c 4 1.00 1.00 1.00 c 5 1.00 1.00 1.00 c 6 0.90 0.70 0.90 c 7 0.90 1.00 1.00 c 8 1.00 1.00 1.00 professional traits c 9 0.80 0.80 1.00 c 10 1.00 0.70 1.00 patient and caregiver education knowledge d 1 1.00 1.00 1.00 d 2 1.00 1.00 1.00 skills d 3 1.00 1.00 1.00 d 4 1.00 1.00 0.60 professional traits d 5 1.00 0.70 1.00 safety skills e 1 1.00 1.00 1.00 e 2 1.00 1.00 1.00 e 3 1.00 1.00 1.00 validity and reliability of the clinical competency evaluation instrument for use among physiotherapy students pilot study e270 | squ medical journal, may 2015, volume 15, issue 2 items. the factor analysis needed a bigger sample size; however, the kaiser-meyer-olkin (kmo) measure (cut-off value: 0.60) was used to determine the sampling adequacy. due to the small sample size of this pilot study, factor analysis was run for each domain instead of the entire instrument. the internal consistency of each domain was established using cronbach’s alpha reliability coefficient following the completion of the exploratory factor analysis. for the inter-rater reliability, the two-way random effect model intraclass coefficient correlation (icc 2,1) at a 95% confidence interval was used. data were computed based on the percentage of the total score in each domain for the initial and repeated evaluations. the scores between the raters were compared to ascertain agreement. the following icc values were set: ≤0.40 indicated poor reliability, 0.40–0.75 signified fair to good reliability and ≥0.75 indicated excellent reliability.16 the stability of the instrument was examined through pearson’s correlation coefficient and icc from two evaluations within a one week interval. approval from the ethical committee board of ukm was granted (nn-090-2013) prior to the study and written consent was obtained from all of the clinical educators/experts and physiotherapy students included in the study. results in the original version of the ccevi, the initial 42 items were reviewed by experts for content validity. qualitative and quantitative data were analysed and recommendations from the written feedback were reviewed. quantitative analysis of the items demonstrated that the cvi for relevance, clarity and representativeness was 0.95 (40/42), 0.30 (13/42) and 0.67 (28/42), respectively. to further establish the content validity, the items with a cvi of <0.80 were rephrased. the overall cvi of the entire instrument was found to be 0.64 (81/126). the inter-rater agreement for relevancy, clarity and representativeness was 0.79, 0.19 and 0.24, respectively. as a result, most of the initial items needed rephrasing/rewording to improve their clarity and brevity. for example, the experts suggested merging the subjective and objective domains into one domain, assessment, in order to avoid redundant items in the assessment of the professional traits in both domains. there was also a suggestion that the five items (items 38–42) in the viva domain be relocated to the subscale of knowledge as this could be evaluated in the individual respective domains. the experts also commented on the inadequacy of some items in the documentation domain. this was addressed and one item was added to the subscale of professional traits in the treatment domain: “to comply with professional and ethical standards of practice”. consequently, the revised ccevi contained 40 items for measuring clinical competency in six domains; 14 assessment items; five analysis items; 10 treatment items; five patient and caregiver education items; three safety items, and three documentation items. after the revised version was sent back to the same panel of experts for their evaluation, and was subsequently further revised until no issues were highlighted by the experts, the cvi and inter-rater agreement were recalculated. the final revised version of the ccevi showed improvement in the content validity in all three indices and the entire instrument [table 1]. the items’ cvi for relevance, clarity and representativeness was 1.00 (40/40), 0.83 (33/40) and 0.95 (38/40), respectively. the cvi for the entire instrument improved from 0.64 (81/126) to 0.91 (109/120). the inter-rater agreement for relevancy, clarity and representativeness were 0.88, 0.73 and 0.80 respectively [table 1]. an exploratory factor analysis was employed to confirm the construct validity of each item in the instrument. when the kmo test for sampling adequacy (kmo ≥0.6) and bartlett’s test of sphericity for the significance (p ≤0.005) of correlation among the items were carried out, all items within the revised ccevi met the criteria for both tests. a factor analysis on the items within each domain was run to ascertain the dimension among the items and whether the patterns fit well into each construct. a cut-off value of communalities of 0.5 was set before running the factor documentation skills f 1 1.00 1.00 1.00 f 2 1.00 1.00 1.00 f 3 1.00 1.00 1.00 cvi of content indices 1.00 0.83 0.95 inter-rater agreement 0.88 0.73 0.80 cvi of entire instrument* 109/120 = 0.91 no. = number; cvi = content validity index. *number of items with cvi of >0.80 divided by total number of items. zailani muhamad, ayiesah ramli and salleh amat clinical and basic research | e271 extraction. items with a factor loading of ≥0.60 with an eigenvalue greater than 1.00 were accepted. items a12 and a14 in the assessment domain, item b3 in the analysis and items c4 and c10 in the treatment domain were identified as problematic based on insignificant values in the correlation matrix table, indicating that the value on the communalities was either too low (≤0.40) or too high (≥0.9) [table 2]. as a result, these items were eliminated from the study. the internal consistency using cronbach’s alpha was recalculated for each domain after these items were deleted, resulting in 35 items. the factor loading of each item in their respective domains (assessment, analysis, treatment, patient and caregiver education, safety and documentation) was acceptable (≥0.6). the internal consistency of each domain was good to high, with the highest internal consistency observed in the patient and caregiver education domain (cronbach’s alpha: 0.95) and the lowest internal consistency in the safety domain (cronbach’s alpha: 0.79). the internal consistency overall for the ccevi was 0.97 [table 2]. the test-retest reliability further confirmed the stability of the ccevi indicating a strong consistency between pearson’s correlation (r) (range: 0.91–0.97) and the icc (range: 0.95–0.98) [table 3]. the inter-rater reliability (icc 2,1) was determined by comparing the total score of each domain between the two raters on the initial and subsequent evaluation separately. as observed in table 4, the inter-rater correlation coefficient of the initial evaluation showed that the assessment, analysis, treatment, patient and caregiver education and documentation domains had excellent reliability (icc range: 0.81–0.99). only the safety domain showed moderate inter-rater reliability (icc: 0.59). the inter-rater correlation coefficient on the subsequent evaluation indicated four domains with excellent inter-rater reliability, with iccs of 0.76, 0.83, 0.87 and 0.89 for the safety, assessment, analysis and treatment domains, respectively. the patient and caregiver education and documentation domains showed moderate inter-rater reliability [table 4]. table 2: factor loading and internal consistency of the revised clinical competency evaluation instrument among physiotherapy students in malaysia domain and item no. factor loading internal consistency* a: assessment 0.94 a1 0.68 a2 0.70 a3 0.84 a4 0.85 a5 0.83 a6 0.76 a7 0.75 a9 0.75 a10 0.81 a11 0.87 a13 0.90 b: analysis 0.94 b1 0.88 b2 0.94 b4 0.96 b5 0.91 c: treatment 0.95 c1 0.65 c2 0.79 c3 0.73 c5 0.72 c6 0.71 c7 0.75 c8 0.87 c9 0.68 d: patient and caregiver education 0.95 d1 0.94 d2 0.94 d3 0.93 d4 0.87 d5 0.92 e: safety 0.79 e1 0.79 e2 0.83 e3 0.93 f: documentation 0.88 f1 0.88 f2 0.93 f3 0.91 overall 0.97 no. = number. *using cronbach’s alpha. validity and reliability of the clinical competency evaluation instrument for use among physiotherapy students pilot study e272 | squ medical journal, may 2015, volume 15, issue 2 discussion the results of this pilot study showed that the ccevi was accurate and reproducible when an assessment of competency among physiotherapy students was carried out, suggesting that it is a valid and reliable evaluation instrument. as seen in this study, clinical competency could not be measured directly; therefore, each item in an assessment instrument’s questionnaire should be constructed to represent the domains of competencies intended to be measured. such items should demonstrate a construct’s unidimensionality.17,18 the content validity of an assessment instrument is usually based on the subjective judgment of the researcher, supported by a panel of experts.19 an objective measure to estimate the content validity of an instrument is therefore necessary. by using measures such as the cvi, the experts’ responses can be evaluated and the questionnaire items can be rated according to their relevance.14 in addition, the content validity of an instrument is further established if its items indicate adequacy in representing a range of the attributes intended to be measured.20 as observed in the findings of this study, there was adequate content validity of the overall ccevi construct (cvi: 0.91). through factor analysis, the relationship of the items in the instrument, in terms of which items belonged together, were determined and measured.21 in total, 35 items with factor loading of ≥0.60 were retained in the instrument. predetermined performance categories were clearly identified and each of the ccevi items demonstrated high correlations to clinical competence. the internal consistency of the items was evaluated through cronbach’s alpha coefficient. cronbach’s alpha is a reliability index that determines the inter-correlation of items in the instrument measuring the same construct.22 according to general guidelines, for reliability analysis, items with a cronbach’s alpha of >0.70 are considered to have good internal consistency.23 the findings in the current study demonstrated high internal consistency in all six of the ccevi domains, which is consistent with the findings of fitzgerald et al.13 they reported high internal consistency (cronbach’s alpha: 0.98) for patient management items in the clinical internship evaluation tool.13 a study by roach et al. evaluated the ptcpi and also found that its items showed high internal consistency, as the cronbach’s alpha was 0.99 for the total item scores.11 the reliability of an assessment instrument is related to its consistency in reproducing accurate measurements and its ability to assess an individual’s performance with minimum sources of error.12,24 one factor that may affect an assessment instrument’s reliability is the raters’ judgment of the students’ performance.25,26 in the current study, the focus was on the repeatability and consistency of the scores between assessors when the assessment was conducted by multiple assessors or with the same assessor during repeated assessments. an intraclass correlation of 0.6 to 0.8 was utilised to represent substantial agreement between raters.27 this study demonstrated a high level of agreement between the raters in five domains (icc: 0.78–0.96) and moderate levels of agreement in the safety domain (icc: 0.59) in the initial evaluation. however, with subsequent evaluation, the inter-rater table 3: correlation coefficient for test-retest reliability of the revised clinical competency evaluation instrument among physiotherapy students in malaysia domain correlation, r intraclass correlation coefficient (95% ci) p value assessment 0.96 0.98 (0.96–0.98) <0.01 analysis 0.94 0.97 (0.96–0.97) <0.01 treatment 0.97 0.98 (0.98–0.98) <0.01 patient and caregiver education 0.91 0.95 (0.95–0.96) <0.01 safety 0.93 0.96 (0.96–0.97) <0.01 documentation 0.96 0.97 (0.96–0.97) <0.01 ci = confidence interval. table 4: correlation coefficient for inter-rater reliability of the revised clinical competency evaluation instrument among physiotherapy students in malaysia domain first assessment icc (95% ci) p value second assessment icc (95% ci) p value assessment 0.81 (0.51–0.94) <0.01 0.84 (0.57–0.95) <0.01 analysis 0.91 (0.73–0.97) <0.01 0.88 (0.66–0.96) <0.01 treatment 0.81 (0.50–0.93) <0.01 0.89 (0.70–0.96) <0.01 patient and caregiver education 0.78 (0.33–0.93) <0.01 0.60 (0.10–0.85) 0.01 safety 0.59 (0.14–0.84) <0.01 0.76 (0.40–0.92) 0.01 documentation 0.97 (0.73–0.97) <0.01 0.69 (0.29–0.89) <0.01 icc = intraclass correlation coefficient; ci = confidence interval. zailani muhamad, ayiesah ramli and salleh amat clinical and basic research | e273 reliability coefficient indicated excellent agreement for four of the domains with a moderate level of agreement in the domains of patient and caregiver education and documentation (icc: 0.59 and 0.68, respectively). an earlier study by the american physiotherapy association found that the overall iccs of the clinical performance instruments for inter-rater reliability ranged from 0.50–0.75, which was considered a moderate level of agreement between raters.28 three other studies reported high levels of agreement between raters (clinical educators and academic faculty tutors) on the assessment of clinical performance.12,25,29 of the three studies, coote et al. and meldrum et al. reported a similar icc for the overall score (0.84) of their assessment instruments, while dalton et al. reported an overall icc of 0.92.12,25,29 the findings in these studies demonstrated almost perfect agreement between raters. in contrast, a wide variance of scores between raters might be due to either overly generous or lenient marks given to students, which could lead to a measurement error.2 reubenson et al. suggested that performance scores should be awarded immediately after the observation of a student’s clinical performance in order to avoid measurement errors and improve reliability.26 even so, raters’ understanding of the performance criteria rating scale, the level of training they received regarding the assessment process and their interpretation of each performance item is likely to differ between individual raters.2,24,25 meldrum et al. commented that the assessment of different domains in an assessment instrument may require different assessment skills; thus the competency of raters must be taken into consideration.25 the small sample size in this study may have compromised the reliability of the findings.30 therefore, future studies on the ccevi should be conducted with larger sample sizes in order to confirm the results of this study.31 it would be beneficial for future research to also incorporate extensive training and detailed guidelines for raters with regards to competency performance criteria and to use a single standard scoring scale to improve agreement and consistency between raters.12,25,26,29 conclusion the ccevi demonstrated high content validity and good to excellent internal consistency across all domains. the stability of the instrument was confirmed through the significant consistency of the scores across the two evaluations. the inter-rater reliability indicated a moderate to excellent correlation coefficient. the results of this study suggested that the items in the safety and documentation domains required refinement in order to improve the ccevi’s reliability. further evaluation of the instrument is necessary to strengthen its validity and reliability, as is the replication of this study with a larger sample size. this study suggests that instruments such as the ccevi can provide an effective tool for physiotherapy academic programmes when assessing the clinical competency of students during their clinical education placement. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. panzarella kj, manyon at. using the integrated standardized patient examination to assess clinical competence in physical therapist students. j phys ther educ 2008; 22:24–32. 2. baig la, violato c, crutcher r. a construct validity study of clinical competence: a multitrait multimethod approach. j contin educ health prof 2010; 30:19–25. doi: 10.1002/chp.20052. 3. watson r, stimpson a, topping a, porock d. clinical competence assessment in nursing: a systematic review of the literature. j adv nurs 2002; 39:421–31. doi: 10.1046/j.13652648.2002.02307.x. 4. butler mp, cassidy i, quillinan b, fahy a, bradshaw c, tuohy d, et al. competency assessment methods tools and process: a survey of nurse preceptors in ireland. nurse educ pract 2011; 11:298–303. doi: 10.1016/j.nepr.2011.01.006. 5. chappell k, koithan m. validating clinical competence. j contin educ nurs 2012; 43:293–4. doi: 10.3928/0022012420120621-02. 6. mehrnoosh p, tahereh a, sharareh k, hamid am. a valid and reliable tool to assess nursing students` clinical performance. int j adv nurs studies 2013; 2:36–9. doi: 10.14419/ijans. v2il.346. 7. wass v, van der vleuten c, shatzer j, jones r. assessment of clinical competence. lancet 2001; 357:945–9. doi: 10.1016/ s0140-6736(00)04221-5. 8. adams cl, glavin k, hutchins k. an evaluation of the internal reliability, construct validity, and predictive validity of the physical therapist clinical performance instrument (pt cpi). j phys ther educ 2008; 22:42–50. 9. ayiesah r, leonard j, nor azlin m, asfarina m. reliability and validity of physiotherapy clinical evaluation form. second teaching and learning conference, penang, malaysia, 2010. 10. sangoseni o, hellman m, hill c. development and validation of a questionnaire to assess the effect of online learning on behaviors, attitudes and clinical practices of physical therapists in the united states regarding evidence-based clinical practice. int j allied health sci prac 2013; 11:1–12. 11. roach ke, frost js, francis nj, giles s, nordrum jt, delitto a. validation of the revised physical therapist clinical performance instrument (pt cpi): version 2006. phys ther 2012; 92:416–28. doi: 10.2522/ptj.20110129. 12. dalton m, davidson m, keating jl. the assessment of physiotherapy practice (app) is a reliable measure of professional competence of physiotherapy students: a reliability study. j physiother 2012; 58:49–56. doi: 10.1016/ s1836-9553(12)70072-3. 13. fitzgerald lm, delitto a, irrgang jj. validation of the clinical internship evaluation tool. phys ther 2007; 87:844–60. doi: 10.2522/ptj.20060054. validity and reliability of the clinical competency evaluation instrument for use among physiotherapy students pilot study e274 | squ medical journal, may 2015, volume 15, issue 2 14. lynn mr. determination and quantification of content validity. nurs res 1986; 35:382–5. doi: 10.1097/00006199-198611000-00017. 15. polit df, beck ct. the content validity index: are you sure you know what’s being reported? critique and recommendations. res nurs health 2006; 29:489–97. doi: 10.1002/nur.20147. 16. fleiss jl. statistical methods for rates and proportions. 2nd ed. new york: john wiley & sons ltd., 1981, pp. 38–46. 17. lewis lk, stiller k, hardy f. a clinical assessment tool used for physiotherapy students: is it reliable? physiother theory pract 2008; 24:121–34. doi: 10.1080/09593980701508894. 18. jette du, portney lg. construct validation of a model for professional behavior in physical therapist students. phys ther 2003; 83:432–43. 19. wynd ca, schmidt b, schaefer ma. two quantitative approaches for estimating content validity. west j nurs res 2003; 25:508–18. doi: 10.1177/0193945903252998. 20. devon ha, block me, moyle-wright p, ernst dm, hayden sj, lazzara dj, et al. a psychometric toolbox for testing validity and reliability. j nurs scholarsh 2007; 39:155–64. doi: 10.1111/j.1547-5069.2007.00161.x. 21. munro bh. statistical methods for health care research. 4th ed. philadelphia, usa: lippincott wiliams & wilkins, 2002. 22. devellis rf. scale development: theory and application. 2nd ed. thousand oaks, california, usa: sage publications inc., 2003. 23. field a. discovering statistics using spss (introducing statistical methods series). 3rd ed. thousand oaks, california, usa: sage publications inc., 2009. pp. 675‒679. 24. lagumen ng, butterwick dj, paskevich dm, fung ts, donnon tl. the intra-rater reliability of nine content-validated technical skill assessment instruments (tsai) for athletic taping skills. athlet train educ j 2008; 3:91–101. 25. meldrum d, lydon am, loughnane m, geary f, shanley l, sayers k, et al. assessment of undergraduate physiotherapist clinical performance: investigation of educator inter-rater reliability. physiother 2008; 94:212–19. doi: 10.1016/j.physio.2008.03.003. 26. reubenson a, schnepf t, waller r, edmondson s. interexaminer agreement in clinical evaluation. clin teach 2012; 9:119–22. doi: 10.1111/j.1743-498x.2011.00509.x. 27. shrout pe, fleiss jl. intraclass correlation: uses in assessing rater reliability. psychol bull 1979; 86:420–8. 28. task force for the development of student clinical performance instruments. the development and testing of apta clinical performance instruments: american physical therapy association. phys ther 2002; 82:329–53. 29. coote s, alpine l, cassidy c, loughnane m, mcmahon s, meldrum d, et al. the development and evaluation of a common assessment form for physiotherapy practice education in ireland. physiother ireland 2007; 28:6–10. 30. weir jp. quantifying test-retest reliability using the intraclass correlation coefficient and the sem. j strength and cond res 2005; 19:231–40. doi: 10.1519/15184.1. 31. perkins do, wyatt rj, bartko jj. penny-wise and pound-foolish: the impact of measurement error on sample size requirements in clinical trials. biol psychiatry 2000; 47:762–6. doi: 10.1016/ s0006-3223(00)00837-4. 1department of diagnostic radiology, md anderson cancer center, houston, texas, usa; 2department of diagnostic radiology, university of michigan health system, university of michigan, ann arbor, usa; 3british columbia centre for disease control, vancouver, british columbia, canada; 4school of population & public health, university of british columbia, vancouver, british columbia, canada; 5radiology medical group, santa cruz, california, usa *corresponding author e-mail: tamara.haygood@mdanderson.org نقيلة العضلة اهليكلية من سرطان اخلاليا الكلوية 21 حالة ومراجعة الدراسات املنشورة متارا منري هايجود، حممد �سيوح، جي�سون ووجن، جينفر لني، اآيريليو ماتامورو�س، كارل �ساندلر، جون مادويل abstract: objectives: this study aimed to raise radiologists’ awareness of skeletal muscle metastases (smm) in renal cell carcinoma (rcc) cases and to clarify their imaging appearance. methods: a retrospective analysis was undertaken of 21 patients between 44–75 years old with 72 smm treated from january 1990 to may 2009 at the md anderson cancer center in houston, texas, usa. additionally, 37 patients with 44 smm from a literature review were analysed. results: among the 21 patients, the majority of smm were asymptomatic and detected via computed tomography (ct). mean metastasis size was 18.3 mm and the most common site was the trunk muscles (83.3%). the interval between discovery of the primary tumour and metastasis detection ranged up to 234 months. peripheral enhancement (47.1%) was the most common post-contrast ct pattern and non-contrasted ct lesions were often isodense. magnetic resonance imaging (mri) characteristics were varied. five lesions with available t1-weighted pre-contrast images were hyperintense to the surrounding muscle. other organ metastases were present in 20 patients. of the 44 smm reported in the literature, the majority were symptomatic. average metastasis size was 53.4 mm and only 20.5% of smm were in trunk muscles. the average interval between tumour discovery and metastasis detection was 101 months. other organ metastases were recorded in 17 out of 29 patients. conclusion: smm should always be considered in patients with rcc, even well after primary treatment. smm from rcc may be invisible on ct without intravenous contrast; contrast-enhanced studies are therefore recommended. smm are often hyperintense to the surrounding muscle on t1-weighted mri scans. keywords: renal cell carcinoma; skeletal muscle; metastasis; united states. الكلوية اخلاليا �رسطان حالت يف الهيكلية الع�سلة نقيلة عن الأ�سعة اأخ�سائي وعي زيادة اإىل الدرا�سة هذه تهدف الهدف: امللخ�ص: وتو�سيح مظاهر �سورها الأ�سعاعية. الطريقة: مت اإجراء حتليل اإ�ستعادي على 21 مري�سا اأعمارهم بني 75-44 �سنة لديهم 72 حالة معاجلة لنقيلة الع�سلة الهيكلية من يناير 1990 اإىل مايو 2009 يف مركز اأندر�سون لل�رسطان يف هيو�سنت، تك�سا�س، الوليات املتحدة الأمريكية. بال�سافة اإىل ذلك، مت حتليل 37 مري�سا لديهم 44 حالة نقيلة الع�سلة الهيكلية من الدرا�سات املن�سورة. النتائج: من بني 21 مري�سا، كان معظم �رسطان اخلاليا الكلوية عدمي الأعرا�س ومت ك�سفه عن طريق الأ�سعة املقطعية. متو�سط مقا�س النقيلة كان 18.3 ملم وكان اأكرث موقع �سيوعا هو الع�سالت اجلذعية )%83.3(. الفرتة بني اكت�ساف املر�س الأويل وك�سف النقيلة امتدت اإىل 234 �سهرا. ا�ستعزاز احلافة )%40( كان اأكرث الأمناط �سيوعا يف الأ�سعة املقطعية املتباينة، وكانت الآفات عادة بذات الكثافة يف الأ�سعة املقطعية املتبانية. خ�سائ�س الت�سوير بالرنني املغناطي�سي كانت متعددة. خم�سة اآفات كانت مفرطة الكثافة مقارنة بالع�سالت املحيطة يف ال�سور املوزونة t1 قبل التباين. مع�سمها كان الأدبيات، يف املن�سورة الهيكلية الع�سلة نقيلة حالة 44 بني من مري�سا. 20 يف موجودة كانت الأخرى الأع�ساء نقيلة عر�سية. متو�سط مقا�س النقيلة كان 53.4 ملم و %20.5 من النقيلة كانت يف الع�سالت. اجلذعية متو�سط الفرتة بني اأكت�ساف الورم وك�سف النقيلة كانت 101 �سهرا. نقيلة الأع�ساء الأخرى كانت م�سجلة يف 17 من اأ�سل 29 مري�سا. اخلال�صة: نقيلة الع�سالت الهيكلية يجب اأن توؤخذ يف العتبار يف مر�سى �رسطان اخلاليا الكلوية، حتى بعد مرحلة العالج الأويل. نقيلة الع�سلة الهيكلية من �رسطان اخلاليا الكلوية رمبا تكون غري مرئية يف الأ�سعة املقطعية بدون التباين الوريدي، لذا يو�سى بدرا�سات ا�ستعزاز التباين. نقيلة الع�سلة الهيكلية عادة مفرطة .t1 الكثافة مقارنة بالع�سلة املحيطة يف ت�سوير الرنني املغناطي�سي املوزونة مفتاح الكلمات: �رسطان اخلاليا الكلوية؛ الع�سلة الهيكلية؛ نقيلة؛ الوليات املتحدة الأمريكية. skeletal muscle metastasis from renal cell carcinoma 21 cases and review of the literature *tamara miner haygood,1 mohamed sayyouh,2 jason wong,3,4 jennifer c. lin,5 aurelio matamoros,1 carl sandler,1 john e. madewell1 clinical & basic research advances in knowledge the findings of this study suggest that relatively small and asymptomatic skeletal muscle metastases of the trunk in patients with renal cell carcinoma (rcc) are usually detected by re-staging computed tomography (ct). furthermore, skeletal muscle metastases among the studied rcc patients were often hyperintense to the muscle on pre-contrast t1weighted magnetic resonance images and invisible or barely visible on ct images without contrast. a marked male predominance was observed among the studied rcc patients with skeletal muscle metastases. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e327–337, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.005. submitted 23 dec 14 revision req. 1 feb 15; revision recd. 10 mar 15 accepted 30 mar 15 skeletal muscle metastasis from renal cell carcinoma 21 cases and review of the literature e328 | squ medical journal, august 2015, volume 15, issue 3 renal cell carcinoma (rcc) comprises nearly 90% of all malignant renal neoplasms and the metastatic potential of this cancer is widespread and unpredictable.1 while metastasis to the skeletal muscles is considered unusual, rcc is among the more common primary tumours to metastasise to this type of muscle tissue.2–5 in a review of over 2,000 patients with metastatic solid tumours, surov et al. found that 2.3% of those with rcc had skeletal muscle metastases.6 the location of skeletal muscle metastases can vary widely. furthermore, they may be painless and can sometimes occur long after the primary surgical treatment; therefore, discovering these metastases can be challenging. in order to reduce the chance of overlooking muscle metastases, the possibility of their presence should be considered in patients with a history of rcc, even long after the primary tumour has been resected.7 methods a retrospective analysis was undertaken of 21 patients between 44–75 years old with 72 skeletal muscle metastases treated from january 1990 to may 2009 at the md anderson cancer center in houston, texas, usa. demographic, diagnostic, clinical and radiological data and patient outcome information were collected from teaching files and retrospectively reviewed and analysed. cases were reviewed with regard to age; gender; presenting symptoms; time of diagnosis; histopathological subtype of the primary tumour; time of initial discovery of the skeletal muscle metastases; first time the muscle metastases were visible on retrospective review; evidence of skeletal muscle and other metastases; and patient outcome. skeletal muscle tumours seemingly caused by the direct extension into the skeletal muscles of the cancer from the kidneys or from other metastases were not included. only metastases presumed to have spread haematogeneously were included in the analysis. diagnoses were made from clinical, pathological and radiological data. images from computed tomography (ct) and magnetic resonance imaging (mri) from the time the skeletal muscle metastases were first reported were examined by two radiologists to evaluate the site, size, shape, ct density and mri characteristics (including mri signal intensity, pattern of enhancement and any other special features) of the metastases. in some cases, individual skeletal muscle metastases were never mentioned in the radiological reports. in these cases, the radiologists determined the earliest imaging study on which the metastases were visible. when additional skeletal muscle metastases appeared after the initial discovery, up to eight lesions per patient were also included in the analysis. when more than eight muscle metastases were present, the largest eight lesions were evaluated. mri signal intensity and ct density were compared with those of the adjacent muscles. imaging characteristics were determined by consensus between the two radiologists. additionally, a literature review was also conducted to include 37 patients with 44 skeletal muscle metastases in the analysis. journal articles for the literature review were identified by searching the medline®/pubmed database for articles containing the words “metastasis” and “muscle” in the title. other relevant articles cited in the bibliographies of these articles were also included. the literature review was limited to articles published in english, french or german. the cut-off point for the review was march 2013. this study was performed in accordance with institutional policies and approved by the institutional review board of the university of texas, md anderson cancer center. results the demographic characteristics and ct imaging characteristics of the muscle metastases for the 21 patients studied are shown in table 1. nine of these patients had previously been reported in less detail by haygood et al. in 2012;5 however, the other 12 had not been studied previously. the average age of the patients at the time of discovery of the first skeletal muscle metastasis was 58.1 years (range: 44–75 years). only three of the patients were women and the rest were men. in 17 of the patients (81.0%), the histopathological subtype of the primary rcc was conventional clear cell rcc, with fuhrman nuclear grades ranging from 2–4 (45.5% of the lesions were grade 3). there was one case of chromophobe rcc. in the remaining three patients, the primary tumours had been diagnosed at outside institutions and it was impossible to confirm the subtype of the original tumour. application to patient care as indicated by the results of this study, radiologists interpreting re-staging ct scans of patients with rcc should be alert for signs of possible muscle metastases. tamara miner haygood, mohamed sayyouh, jason wong, jennifer c. lin, aurelio matamoros, carl sandler and john e. madewell clinical and basic research | e329 table 1: demographic characteristics, outcomes and tumour conditions of skeletal muscle metastases as assessed by computed tomography imaging of renal cell carcinoma patients (n = 21) age* in years/ gender interval in months† outcome sites axial size in mm‡ density without contrast§ contrast enhancement¶ 49/m 36 died after nine months paraspinal 5 x 5 isodense homogeneous 50/m presenting sign alive with minimal disease deltoid 40 x 37 hypodense n/a 47/m 2 died after 46 months pectoralis major paraspinal paraspinal gluteal triceps deltoid 14 x 8 11 x 8 2 x 2 10 x 7 113 x 95 13 x 11 hypodense peripheral heterogeneous heterogeneous heterogeneous heterogeneous heterogeneous 62/m 28 died after 46 months paraspinal 8 x 7 n/a homogeneous 44/m 3 died after six months quadriceps soleus 55 x 27 70 x 50 n/a heterogeneous heterogeneous n/a 52/m 44 died after 13 months psoas 47 x 35 hypodense peripheral 54/m 8 lost to follow-up psoas paraspinal gluteal gluteal supraspinatus infraspinatus 14 x 14 14 x 9 16 x 11 6 x 8 16 x 13 25 x 14 n/a peripheral peripheral homogeneous homogeneous peripheral peripheral 61/m 58 died after nine months paraspinal paraspinal 16 x 13 12 x 8 isodense peripheral 73/m 14 died after 52 months paraspinal paraspinal latissimus dorsi gluteal gluteal supraspinitus external oblique iliopsoas 16 x 12 24 x 19 6 x 3 13 x 7 11 x 5 11 x 8 12 x 7 9 x 9 isodense n/a n/a n/a n/a n/a isodense n/a homogeneous isodense homogeneous homogeneous lateral homogeneous peripheral peripheral 66/m 31 died after nine months gluteal gluteal gluteal paraspinal 10 x 8 12 x 7 12 x 10 7 x 6 n/a homogeneous peripheral peripheral homogeneous 63/m 234 died after 13 months paraspinal 11 x 8 isodense homogeneous 71/m 6 died after two months psoas 60 x 56 isodense heterogeneous 66/f 12 died after 37 months intercostal 27 x 24 isodense peripheral 63/m 2 died after four months gluteal 13 x 7 n/a homogeneous 75/f 31 died after approximately 42 months or later gluteal 30 x 17 n/a peripheral 58/m 25 alive with minimal disease after 65 months psoas trapezius latissimus dorsi intercostal paraspinal paraspinal paraspinal teres major 8 x 8 14 x 11 8 x 8 18 x 13 9 x 9 7 x 7 10 x 9 10 x 8 n/a peripheral heterogeneous homogeneous heterogeneous peripheral peripheral peripheral heterogeneous skeletal muscle metastasis from renal cell carcinoma 21 cases and review of the literature e330 | squ medical journal, august 2015, volume 15, issue 3 a total of 72 muscle metastases in this patient group were analysed, with smaller metastases in two patients with more than eight metastases excluded. of these, 60 (83.3%) were in trunk muscles (including the pectoralis major), nine (12.5%) were in muscles of the upper extremities, two (2.8%) were in muscles of the lower extremities and one (1.4%) was in the tongue. most of these metastases were asymptomatic and discovered via ct. two patients complained of a painful swelling at the metastasis site and one reported a painless, palpable swelling. in one patient, the muscle metastasis was the initial presenting complaint. the time interval between the discovery of the primary tumour and the discovery of the skeletal muscle metastases varied. skeletal muscle metastasis was the presenting complaint for one patient and skeletal muscle metastases were omitted in radiological reports for another patient. two patients had had rcc nine and 19 years before subsequently presenting with metastatic disease and a mass in the previously unaffected kidney. in the first of these latter two patients, the new renal mass was relatively large compared with the other masses and it was judged to be a new primary tumour. for the second patient, the new renal mass was distinctly smaller than several of the other masses, so it was judged to be a metastasis from the previous cancer. including these four patients, and with the discovery of the originally unreported metastases considered to have occurred when they were identified on retrospective review, the interval between the discoveries of the primary tumour and the skeletal muscle metastasis ranged from 0–234 months (average interval: 32 months). excluding these four patients, the interval between discoveries ranged from 2–75 months (average interval: 25 months). metastasis to the skeletal muscles was proven by direct biopsy in three patients. among the remaining 18 patients, 13 had pathology-evidenced metastatic rcc in other locations and five had clinical and radiological evidence of metastasis to other organs typical of rcc. the mean size of the muscle metastases at the time they were reported (or when first visible, if not reported) was 18.3 mm in the greatest axial dimension (range: 2–113 mm). the average size of those that were asymptomatic at discovery was 16.3 mm. a total of 39 lesions (54.2%) were oval [figure 1], 16 (22.2%) were round, 15 (20.8%) were irregular and two (2.8%) were lobular. ct images without intravenous contrast were available for 29 lesions, nearly twothirds of which (n = 19; 65.5%) were isodense to the adjacent muscle. of 69 lesions with contrast-enhanced ct images, enhancement on post-contrast ct was homogeneous in 20 (29.0%), heterogeneous in 16 (23.2%) and peripheral in 33 (47.8%) [figure 2]. six patients had mri examinations. all lesions with t2weighted images demonstrated hyperintense signals. five of the seven lesions with available t1-weighted pre-contrast images were hyperintense [figure 3]. although contrast enhancement was variable, all 50/f 37 died after 11 months latissmus dorsi 20 x 15 isodense homogeneous 57/m 7 died same month paraspinal paraspinal gluteal psoas iliacus teres major 16 x 16 7 x 7 15 x 9 14 x 9 13 x 13 13 x 14 isodense isodense n/a isodense n/a n/a peripheral peripheral peripheral peripheral peripheral peripheral 62/m 6 died after five months psoas 11 x 9 isodense peripheral 44/m 75 died after 33 months tongue paraspinal paraspinal paraspinal paraspinal psoas gluteal gluteal 14 x 11 18 x 13 27 x 17 22 x 17 25 x 19 9 x 7 25 x 24 28 x 13 n/a n/a isodense isodense n/a n/a n/a n/a peripheral heterogeneous heterogeneous peripheral heterogeneous heterogeneous heterogeneous heterogeneous 54/m 18// died after four months infraspinatus paraspinal 26 x 22 8 x 6 n/a isodense heterogeneous homogeneous m = male; f = female; n/a = not available. *at the time the skeletal muscle metastases were first discovered or, if not reported, at the time the metastases first became visible on imaging. †interval between the primary tumour and the discovery of the first skeletal muscle metastasis. ‡perpendicular measurements on the axial image in which the lesion appeared largest. measurements were made using electronic callipers. §the surrounding muscle is the reference standard for computed tomography density. for some patients, there were no images available without contrast. ¶one lesion was isodense to the muscle with contrast, so it is unclear whether it was enhanced. heterogeneous enhancement means that the lesion was enhanced in a patchy fashion throughout its substance and not just around the periphery. //interval between the primary tumour and when the muscle metastases were visible in retrospect. tamara miner haygood, mohamed sayyouh, jason wong, jennifer c. lin, aurelio matamoros, carl sandler and john e. madewell clinical and basic research | e331 lesions showed enhancement. small enhancing vessels feeding or draining the skeletal muscle metastases were noticed in five (7.2%) of the lesions for which contrastenhanced ct was available [figure 4]. surrounding muscle oedema was seen in one case. no calcification was found in or around any of the lesions. all but one of the patients with muscle metastases had metastases to other organs at the time the muscles metastases were discovered. these metastases occurred mainly in the lungs (85.7%), liver (28.6%), bones (33.3%) and brain (23.8%). the exception was the patient whose muscular metastasis was the presenting complaint; this patient was noted to have pulmonary nodules on a ct scan eight months after presentation. of the 20 patients for whom follow-up information was available, 18 have died to date. one patient, who presented with very advanced disease and metastases in multiple organs, died within one month of the discovery of the muscle metastases. the other 17 patients survived for between 2–52 months (average: 21 months). at the time of writing, two patients remained alive with minimal disease, one of whom had survived for more than five years after the discovery of the muscle metastases. the literature review revealed 36 case reports detailing 37 cases of rcc metastasis to the skeletal muscles [table 2].2,3,7‒40 there were 19 other patients reported in the literature; however, insufficient information was given regarding individual cases and figure 1a–d: enhanced computed tomography (ct) images of a 58-year-old man with renal cell carcinoma. a: initial detection and reporting of a left trapezius metastasis measuring 14 x 11 mm (arrow). b: the same metastasis was subtler and less well-defined yet still visible 11 months earlier (arrow). this lesion had a heterogeneous pattern of enhancement. c: initial detection and reporting of a left paraspinal metastasis measuring 10 x 9 mm (arrow). d: the same metastasis was much smaller although still visible 11 months earlier (arrow). this lesion had a homogeneous pattern of enhancement when first visible which became peripheral later. both muscle metastases appeared oval when they were first detected in cross-sectional imaging. figure 2: contrast-enhanced computed tomography image of a man with renal cell carcinoma and left gluteus medius muscle metastasis showing peripheral contrast enhancement (arrow). skeletal muscle metastasis from renal cell carcinoma 21 cases and review of the literature e332 | squ medical journal, august 2015, volume 15, issue 3 lower extremities and seven (16.3%) were in muscles of the head and neck.2,7‒40 the majority of the skeletal muscle metastases in the literature were symptomatic. only six patients had skeletal muscle metastases that were discovered incidentally on imaging.7,16,18,23,29,37 in seven reports, the muscle metastasis was the initial presenting complaint.3,8,21,24,27,28,32 skeletal muscle metastasis was found synchronously with the primary tumour in two cases.29,37 there was no information regarding the time interval between the discovery of the primary tumour and discovery of the muscle metastasis in five cases.9,11,26,34 for the remaining 23 cases, the interval ranged from 6–252 months (average: 101 months).2,7,10,12–20,22,23,25,30,31,33,35,36,38–40 the average size of the skeletal muscle metastases at presentation, available for 28 of the lesions reported in the literature these were therefore not included in the analysis.4,8,9 the average age of the patients from the literature review at the time of the first skeletal muscle metastasis discovery was 61.9 years (range: 41–81 years). there were five women and 31 men. the age and gender of one patient was not specified.34 in 18 (81.8%) of the 22 cases for which the histopathological subtype was available, the primary tumour was conventional clear cell rcc.7,10,13,15,16,18,20‒24,27,28,32,35,37,38,40 there was one case each of granular cell and sarcomatoid rcc.31,39 a total of 44 metastases in these 37 literature review cases were analysed, although the information available for each varied. of the 43 lesions for which the location site was available, nine (20.9%) were in trunk muscles, 11 (25.6%) were in muscles of the upper extremities, 16 (37.2%) were in muscles of the figure 3a & b: magnetic resonance imaging (mri) of a 49-year-old man with renal cell carcinoma. a: post-contrast fat-saturated t1-weighted axial mri scan at the l2 level showing a small metastasis in the right paraspinal musculature that is enhanced brightly. b: pre-contrast t1-weighted axial mri scan at the same level shows that this small metastasis is hyperintense to the surrounding muscle (arrow). figure 4a & b: contrasted computed tomography images from a 44-year-old man with renal cell carcinoma showing muscle metastasis with visible feeding or draining vessels in the left quadriceps (arrows). this is also an example of a heterogeneous pattern of enhancement. tamara miner haygood, mohamed sayyouh, jason wong, jennifer c. lin, aurelio matamoros, carl sandler and john e. madewell clinical and basic research | e333 table 2: demographic characteristics, outcomes and tumour conditions of skeletal muscle metastases in selected renal cell carcinoma patients reported in the literature (n = 37) author and year of report cases age in years/gender interval in months† site size in mm chen et al.2 2005 1 50/m 168 vastus medialis 50 x 40 herring et al.3 1998 1 62/m presenting sign n/a n/a sakamoto et al.7 2007 1 65/m 72 gluteal muscles n/a capone et al.8 1990 1 63/m presenting sign extraocular muscles* n/a pretorius et al.9 2000 1 73/f n/a deltoid* n/a nabeyama et al.10 2001 1 81/m 180 triceps brachii brachioradialis 40 x 30 10 x 10 stener et al.11 1984 2 55/m 46/m n/a n/a hamstrings adductor magnus vastus medialis vastus intermedius n/a n/a n/a n/a lee et al.12 2008 1 81/m 60 thigh 50 hur et al.13 2007 1 63/m 228 psoas vastus medialis 28 x 19 n/a pompo et al.14 2008 1 73/m 252 biceps femoris 160 x 75 nakagawa et al.15 1996 1 57/m 48 masseter 10 taira et al.16 2005 1 63/m 168 psoas 15 munk et al.17 1992 1 57/m 8 trapezius 70 x 40 linn et al.18 1996 1 58/m 168 psoas 50 judd et al.19 2000 1 72/f 60 deltoid 100 x 80 manzelli et al.20 2006 1 73/f 96 quadriceps sartorius adductor magnus 90 x 50 35 30 alexiou et al.21 1984 1 74/m presenting sign arm muscles 65 x 60 alimonti et al.22 2003 1 62/m 6 deltoid 30 camnasio et al.23 2010 1 63/m 132 psoas 18 chandler et al.24 1979 1 62/m presenting sign biceps 100 x 80 di tonno et al.25 1993 1 55/m 144 gluteal muscles 47 egund et al.26 1981 1 60/f n/a shoulder muscles large gal et al.27 1997 1 49/m presenting sign masseter 40 x 40 gözen et al.28 2009 1 58/m presenting sign gastrocnemius 40 x 20 hyodo et al.29 2009 1 65/m synchronous infraspinatus n/a kang et al.30 2010 1 71/m 144 temporalis 41 karakousis et al.31 1981 1 63/m 69 thigh muscles n/a kishore et al.32 2006 1‡ 42/m presenting sign shoulder muscles 80 x 70 merimsky et al.33 1990 1 69/m 12 biceps femoris gluteal muscles n/a peyster et al.34 1987 1 n/a n/a extraocular muscles n/a picchio et al.35 2010 1 58/m 60 adductor magnus 50 ruiz et al.36 1991 1 63/f 192 vastus lateralis n/a sano et al.37 2007 1 53/m synchronous paraspinal muscles 150 skeletal muscle metastasis from renal cell carcinoma 21 cases and review of the literature e334 | squ medical journal, august 2015, volume 15, issue 3 normally examined in ct scans of the chest, abdomen and pelvis. the sites of involvement among the study cohort predominantly involved the trunk muscles; this was similar to findings from other research.5,42 surov et al. studied a large group of patients with muscle metastases of all types.43 they found a larger representation of metastases in the extremities and extraocular muscles, likely because the study included both patients from their own institution and those from previous publications.43 in contrast to the study group in the current study, patients in the literature review group were more likely to have metastases in the extremities (61.9%) and to have the lesions discovered due to symptoms. furthermore, metastases were discovered when they were relatively large; metastases in this group were nearly three times larger in diameter on average than those in the study group. it is important to note that the apparent average size of metastases in the patients from the current study group would have been slightly elevated by the exclusion of smaller metastases in the two patients with more than eight metastases in total. it is possible that the pattern of metastasis location and size found among the study cohort was more typical of that expected in patients undergoing routine follow-up of known rcc, while case reports of rcc in the literature tend to describe unusual presentations of the condition. the time interval between the diagnosis of the primary tumour and the detection of the muscle metastases varied greatly, with several very late appearances of metastases. notably, the calculation of intervals in the study group was complicated by four patients (one patient presenting with skeletal muscle metastasis, one whose skeletal muscle metastases were omitted in radiological reports and two who had had rcc many years previously before presenting with metastatic disease). many theories have been proposed to explain late recurrence of metastatic disease, including immunological and hormonal factors.10 it is important that radiologists recognise that delayed skeletal muscle metastasis of rcc can occur so that early diagnosis and intervention are possible, particularly because the surgical excision of isolated metastases may improve disease-free survival.11,44 in addition, recent developments in chemotherapy, review, was 53.4 mm in the greatest dimension (range: 10–160 mm).2,10,12–25,27,28,30,32,35,37–40 of the 14 metastases for which data on ct appearance were available, 10 showed enhancement and one was isodense to the muscle on non-contrasted ct.7,9,12–18,23 of the metastases for which data on mri appearance were available, five had low to intermediate signal intensity and five had high signal intensity on t1-weighted images.2,3,7,10,12,14,17,19,34,35 two had intermediate signal intensity and nine had high signal intensity on t2-weighted images.2,3,7,10,12,14,17,19,30,34,35 one was enhanced with contrast administration.2 metastases in other organs—mainly the lungs and bones—were present at the time of or before the initial diagnosis of muscle metastasis in 17 of the 29 patients for whom this information was specified.2,7,8,10,13,15,19,21,23,24,27,29,32,35,37–39 for 12 patients, the skeletal muscle metastasis was the only known metastasis at the time it was discovered.16–18,20,22,25,28,30,31,33,36,40 discussion the demographic characteristics of patients in both the study and literature review groups were relatively similar, with an average age of approximately 58 and 62 years, respectively. there were over six times more men than women, with a combined total of eight women (14.0%) and 49 men (86.0%). this marked male predominance was greater than would be expected with regards to population studies that have found a male-to-female ratio of less than 2:1 for cases of rcc.1,41 survival rates, which are probably similar to metastasis rates, also do not sufficiently differ between men and women with rcc to account for this male predominance.1 presentation of skeletal metastases differed between the study group and cases from the literature review. the former group was distinctly more likely to have metastases in the trunk muscles (83.3%) and to have metastases discovered by staging studies when the lesions were asymptomatic and relatively small. these facts are probably related as metastases in deep muscles of the trunk (particularly the psoas) are not palpable until very large but do lie in the areas schatteman et al.38 2002 1 69/m 24 trapezius 60 x 30 shibayama et al.39 1993 1 41/m 34 tongue muscles 20 yiotakis et al.40 2001 1 60/m 6 masseter 15 m = male; n/a = not available; f = female. *one large mass involving all of these muscles. †interval between the primary tumour and the discovery of the first skeletal muscle metastasis. ‡seven patients were not included in the analysis due to insufficient details. tamara miner haygood, mohamed sayyouh, jason wong, jennifer c. lin, aurelio matamoros, carl sandler and john e. madewell clinical and basic research | e335 particularly the use of tyrosine kinase inhibitors, have made it possible to treat metastatic rcc, including skeletal muscle metastases, with reasonable chances of prolonging life.45 to date, two of the patients in the study group, both of whom were treated with tyrosine kinase inhibitors, have continued to lead active lives years after the discovery of their skeletal muscle metastases. differentiating skeletal muscle metastases from other soft tissue tumours is important because of their different treatments and prognosis.4,7 in many cases, a biopsy is needed to reach a definitive diagnosis, particularly for isolated lesions. even when a patient has multiple metastases, this procedure can be useful to find muscle metastases. when several masses are present in patients with a known primary tumour, generally only one will need to be biopsied. the authors of the current study believe that masses in skeletal muscle are often fairly superficial and do not move during respiration; for these reasons, they may therefore be a good option for biopsy. slightly more than half of the patients in the literature review group had metastases in other organs before or at the time the skeletal muscle metastasis was discovered, while all but one of the patients in the study group had skeletal muscle metastases concomitant with metastasis in other organs. damron et al. reported that rcc metastases in soft tissues, including skeletal muscle, almost always present as a solitary soft tissue mass after a variable period of time from the initial diagnosis of rcc.46 their view, however, was probably influenced by the fact that this type of metastatic rcc presentation is preferentially described among case reports in the literature as well as by the inclusion of their own cases of biopsy-proven metastases.46 this inclusion criterion would favour isolated metastases because multiple metastases do not individually warrant a biopsy. in general, skeletal muscle metastases are very subtle on non-contrasted ct (isoattenuating to the surrounding musculature) and can easily be missed in most cases.12 after intravenous contrast administration, the most common pattern in the current study group was peripheral enhancement. pretorius et al. found rim enhancement in 83% of skeletal muscle metastases and surov et al. found peripheral enhancement in 32.5% of their cases.6,9 in the current study, some of the patients’ skeletal muscle metastases in the study group had heterogeneous and homogeneous patterns of enhancement with no obvious predominance of one over the other; this was similarly described in several other reports.2,9,12–19 in contrast, surov et al. found that the homogeneous pattern was the most common, with 52.5% of their cases exhibiting homogeneous enhancement.6 in the current study, small feeding vessels to the skeletal muscle metastases were found in a few of the lesions among the study group. this feature has been described in previous reports using various imaging methods and has been theorised to be due to the production of lactic acid by tumours, which signals anoxia.2,16,20 new vessels seek out the source of anoxia and provide vascularisation.20,47 the mri signal intensity of the lesions in the study group was variable. it was not surprising that the signal intensity on t2-weighted images was generally higher than that of the surrounding muscle and that the lesions generally enhanced with contrast administration. skeletal muscle metastases are usually reported to be hypoto isointense to the muscle on t1weighted images, with a small percentage sometimes being hyperintense.12,48 interestingly, however, 71% of the muscle metastases with pre-contrast t1weighted images in the study group and 50% of those in the literature review group were hyperintense to surrounding muscle on t1-weighted images. it is important to note that none of the patients in the study group had a history of melanomas, which may be an explanation for the frequency of hyperintense t1 lesions among this cohort. certain limitations exist with regards to data reported from the current study, including the relative rarity of mri studies for patients in the study group. additionally, variable chemotherapy regimens were received by the patients, which prevented a meaningful study of the effects of specific drugs on the course of the disease and any muscle metastasis. both ct and mri scans were obtained over too long a stretch of time using different scan protocols and on various types of equipment to allow any meaningful analysis of specific imaging parameters. finally, as this was a retrospective study of patients encountered in clinical practice and noted in teaching files, the sample was affected by selection bias. despite this, 17 of the 21 patients presented during a time when information was being collected on all cases of skeletal muscle metastasis encountered. as a result, those patients comprised an essentially consecutive series. another limitation of the current study was that the literature review did not identify or include every published case of rcc metastatic to skeletal muscle available as it was necessary to stop collecting data as of march 2013 and perform the analysis. conclusion the possibility of skeletal muscle metastases should always be considered in patients with rcc, even long after primary treatment, so as to reduce the chance of skeletal muscle metastasis from renal cell carcinoma 21 cases and review of the literature e336 | squ medical journal, august 2015, volume 15, issue 3 15. nakagawa h, mizukami y, kimura h, watanabe y, kuwayama n. metastatic masseter muscle tumour: a report of a case. j laryngol otol 1996; 110:172–4. doi: 10.1017/ s0022215100133080. 16. taira h, ishii t, inoue y, hiratsuka y. solitary psoas muscle metastasis after radical nephrectomy for renal cell carcinoma. int j urol 2005; 12:96–7. doi: 10.1111/j.1442-2042.2004.00976.x. 17. munk pl, gock s, gee r, connell dg, quenville nf. case report 708: metastasis of renal cell carcinoma to skeletal muscle (right trapezius). skeletal radiol 1992; 21:56–9. doi: 10.1007/ bf00243097. 18. linn jf, fichtner j, voges g, schweden f, störkel s, hohenfellner r. solitary contralateral psoas metastasis 14 years after radical nephrectomy for organ confined renal cell carcinoma. j urol 1996; 156:173. doi: 10.1016/s00225347(01)65980-9. 19. judd cd, sundaram m. radiologic case study: metastatic renal cell carcinoma. orthopedics 2000; 23:1123–4. doi: 10.3928/0147-7447-20001001-10. 20. manzelli a, rossi p, de majo a, coscarella g, gacek i, gaspari al. skeletal muscle metastases from renal cell carcinoma: a case report. tumori 2006; 92:549–51. 21. alexiou g, papadopoulou-alexiou m, karakousis cp. renal cell carcinoma presenting as skeletal muscle mass. j surg oncol 1984; 27:23–5. doi: 10.1002/jso.2930270106. 22. alimonti a, di cosimo s, maccallini v, ferretti g, pavese i, satta f, et al. a man with a deltoid swelling and paraneoplastic erythrocytosis: case report. anticancer res 2003; 23:5181–4. 23. camnasio f, scotti c, borri a, fontana f, fraschini g. solitary psoas muscle metastasis from renal cell carcinoma. anz j surg 2010; 80:466–7. doi: 10.1111/j.1445-2197.2009.05195.x. 24. chandler rw, shulman i, moore tm. renal cell carcinoma presenting as a skeletal muscle mass: a case report. clin orthop relat res 1979; 145:227–9. doi: 10.1097/00003086197911000-00036. 25. di tonno f, rigon r, capizzi g, bucca d, di pietro r, zennari r. solitary metastasis in the gluteus maximus from renal cell carcinoma 12 years after nephrectomy: case report. scand j urol nephrol 1993; 27:143–4. doi: 10.3109/00365599309180435. 26. egund n, ekelund l, sako m, persson b. ct of soft-tissue tumors. ajr am j roentgenol 1981; 137:725–9. doi: 10.2214/ ajr.137.4.725. 27. gal tj, ridley mb, arrington ja, muro-cacho c. renal cell carcinoma presenting as a masseteric space mass. am j otolaryngol 1997; 18:280–2. doi: 10.1016/s01960709(97)90011-9. 28. gözen as, canda ae, naser m, stock c, rassweiler j, teber d. painful leg: a very unusual presentation of renal cell carcinoma case report and review of the literature. urol int 2009; 82:472–6. doi: 10.1159/000218540. 29. hyodo t, sugawara y, tsuda t, yanagihara y, aoki k, tanji n, et al. widespread metastases from sarcomatoid renal cell carcinoma detected by (18)f-fdg positron emission tomography/computed tomography. jpn j radiol 2009; 27:111– 14. doi: 10.1007/s11604-008-0305-0. 30. kang s, song bi, lee hj, jeong sy, seo jh, lee sw, et al. isolated facial muscle metastasis from renal cell carcinoma on f-18 fdg pet/ct. clin nucl med 2010; 35:263–4. doi: 10.1097/rlu.0b013e3181d18f37. 31. karakousis cp, rao u, jennings e. renal cell carcinoma metastatic to skeletal muscle mass: a case report. j surg oncol 1981; 17:287–93. doi: 10.1002/jso.2930170312. 32. kishore b, khare p, jain r, bisht s, paik s. unsuspected metastatic renal cell carcinoma with initial presentation as solitary soft tissue lesion: a case report. indian j pathol microbiol 2006; 49:424–5. overlooking skeletal muscle metastases and improve staging. skeletal muscle metastases from rcc may be invisible on ct without intravenous contrast, so contrast-enhanced studies are recommended for these patients. metastases from rcc are often hyperintense to the surrounding muscle on t1-weighted mris. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. lynch cf, west mm, davila ja, platz ce. cancers of the kidney and renal pelvis. in: ries lag, young jl, keel ge, eisner mp, lin yd, horner mj, eds. seer survival monograph: cancer survival among adults u.s. seer program, 1988-2001, patient and tumor characteristics. from: www.seer.cancer.gov/ archive/publications/survival/seer_survival_mono_lowres.pdf accessed: mar 2015. 2. chen ck, chiou hj, chou yh, tiu cm, wu ht, ma s, et al. sonographic findings in skeletal muscle metastasis from renal cell carcinoma. j ultrasound med 2005; 24:1419–23. 3. herring cl jr, harrelson jm, scully sp. metastatic carcinoma to skeletal muscle: a report of 15 patients. clin orthop relat res 1998; 355:272–81. 4. plaza ja, perez-montiel d, mayerson j, morrison c, suster s. metastases to soft tissue: a review of 118 cases over a 30-year period. cancer 2008; 112:193–203. doi: 10.1002/cncr.23151. 5. haygood tm, wong j, lin jc, li s, matamoros a, costelloe cm, et al. skeletal muscle metastases: a three-part study of a not-so-rare entity. skeletal radiol 2012; 41:899–909. doi: 10.1007/s00256-011-1319-8. 6. surov a, hainz m, holzhausen hj, arnold d, katzer m, schmidt j, et al. skeletal muscle metastases: primary tumours, prevalence, and radiological features. eur radiol 2010; 20: 649–58. doi: 10.1007/s00330-009-1577-1. 7. sakamoto a, yoshida t, matsuura s, tanaka k, matsuda s, oda y, et al. metastasis to the gluteus maximus muscle from renal cell carcinoma with special emphasis on mri features. world j surg oncol 2007; 5:88. doi: 10.1186/1477-7819-5-88. 8. capone a jr, slamovits tl. discrete metastasis of solid tumors to extraocular muscles. arch ophthalmol 1990; 108:237–43. doi: 10.1001/archopht.1990.01070040089037. 9. pretorius es, fishman ek. helical ct of skeletal muscle metastases from primary carcinomas. ajr am j roentgenol 2000; 174:401–4. doi: 10.2214/ajr.174.2.1740401. 10. nabeyama r, tanaka k, matsuda s, iwamoto y. multiple intramuscular metastases 15 years after radical nephrectomy in a patient with stage iv renal cell carcinoma. j orthop sci 2001; 6:189–92. doi: 10.1007/s007760100070. 11. stener b, henriksson c, johansson s, gunterberg b, pettersson s. surgical removal of bone and muscle metastases of renal cancer. acta orthop scand 1984; 55:491–500. 12. lee by, choi je, park jm, jee wh, kim jy, lee kh, et al. various image findings of skeletal muscle metastases with clinical correlation. skeletal radiol 2008; 37:923–8. doi: 10.10 07/s00256-008-0510-z. 13. hur j, yoon cs, jung wh. multiple skeletal muscle metastases from renal cell carcinoma 19 years after radical nephrectomy. acta radiol 2007; 48:238–41. doi: 10.1080/02841850601089128. 14. pompo f, king jj, iwenofu oh, ogilvie cm. thigh mass in a 73-year-old man. clin orthop relat res 2008; 466:1764–8. doi: 10.1007/s11999-008-0139-1. http://dx.doi.org/10.1017/s0022215100133080 http://dx.doi.org/10.1017/s0022215100133080 http://dx.doi.org/10.1111/j.1442-2042.2004.00976.x http://dx.doi.org/10.1007/bf00243097 http://dx.doi.org/10.1007/bf00243097 http://dx.doi.org/10.1016/s0022-5347%2801%2965980-9 http://dx.doi.org/10.1016/s0022-5347%2801%2965980-9 http://dx.doi.org/10.3928/0147-7447-20001001-10 http://dx.doi.org/10.3928/0147-7447-20001001-10 http://dx.doi.org/10.1002/jso.2930270106 http://dx.doi.org/10.1111/j.1445-2197.2009.05195.x http://dx.doi.org/10.1097/00003086-197911000-00036 http://dx.doi.org/10.1097/00003086-197911000-00036 http://dx.doi.org/10.3109/00365599309180435 http://dx.doi.org/10.2214/ajr.137.4.725 http://dx.doi.org/10.2214/ajr.137.4.725 http://dx.doi.org/10.1016/s0196-0709%2897%2990011-9 http://dx.doi.org/10.1016/s0196-0709%2897%2990011-9 http://dx.doi.org/10.1159/000218540 http://dx.doi.org/10.1007/s11604-008-0305-0 http://dx.doi.org/10.1097/rlu.0b013e3181d18f37 http://dx.doi.org/10.1002/jso.2930170312 http://dx.doi.org/10.1002/cncr.23151 http://dx.doi.org/10.1007/s00256-011-1319-8 http://dx.doi.org/10.1007/s00330-009-1577-1 http://dx.doi.org/10.1186/1477-7819-5-88 http://dx.doi.org/10.1001/archopht.1990.01070040089037 http://dx.doi.org/10.2214/ajr.174.2.1740401 http://dx.doi.org/10.1007/s007760100070 http://dx.doi.org/10.1007/s00256-008-0510-z http://dx.doi.org/10.1007/s00256-008-0510-z http://dx.doi.org/10.1080/02841850601089128 http://dx.doi.org/10.1007/s11999-008-0139-1 tamara miner haygood, mohamed sayyouh, jason wong, jennifer c. lin, aurelio matamoros, carl sandler and john e. madewell clinical and basic research | e337 33. merimsky o, levine t, chaitchik s. recurrent solitary metastasis of renal cell carcinoma in skeletal muscles. tumori 1990; 76:407–9. 34. peyster rg, shapiro md, haik bg. orbital metastasis: role of magnetic resonance imaging and computed tomography. radiol clin north am 1987; 25:647–62. 35. picchio m, mascetti c, tanga i, spaziani e. metastasis from renal cell carcinoma presenting as skeletal muscle mass: a case report. acta chir belg 2010; 110:399–401. 36. ruiz jl, vera c, server g, osca jm, boronat f, jimenez cruz jf. renal cell carcinoma: late recurrence in 2 cases. eur urol 1991; 20:167–9. 37. sano f, kimura r, fujikawa n, sugiura s, hirai k, ueki t, et al. muscle and small intestinal metastasis of renal cell carcinoma markedly responsive to interferon-alpha therapy: a case report. hinyokika kiyo 2007; 53:635–9. 38. schatteman p, willemsen p, vanderveken m, lockefeer f, vandebroek a. skeletal muscle metastasis from a conventional renal cell carcinoma, two years after nephrectomy: a case report. acta chir belg 2002; 102:351–2. 39. shibayama t, hasegawa s, nakamura s, tachibana m, jitsukawa s, shiotani a, et al. disappearance of metastatic renal cell carcinoma to the base of the tongue after systemic administration of interferon-alpha. eur urol 1993; 24:297–9. 40. yiotakis j, hantzakos a, kostakopoulos a, adamopoulos g. intramasseteric metastasis of renal cell carcinoma. j laryngol otol 2001; 115:65–7. 41. karami s, colt js, schwartz k, davis fg, ruterbusch jj, munuo ss, et al. a case-control study of occupation/industry and renal cell carcinoma risk. bmc cancer 2012; 12:344. doi: 10.1186/1471-2407-12-344. 42. bocchino m, valente t, somma f, de rosa i, bifulco m, rea g. detection of skeletal muscle metastases on initial staging of lung cancer: a retrospective case series. jpn j radiol 2014; 32:164–71. doi: 10.1007/s11604-014-0281-5. 43. surov a, köhler j, wienke a, gufler h, bach ag, schramm d, et al. muscle metastases: comparison of features in different primary tumors. cancer imaging 2014; 14:21. doi: 10.1 186/1470-7330-14-21. 44. assouad j, banu e, brian e, pham dn, dujon a, foucault c, et al. strategies and outcomes in pulmonary and extrapulmonary metastases from renal cell cancer. eur j cardiothorac surg 2008; 33:794–8. doi: 10.1016/j.ejcts.2008.01.045. 45. santoni m, conti a, porta c, procopio g, sternberg cn, basso u, et al. sunitinib, pazopanibor or sorafenib for the treatment of patients with late relapsing metastatic renal cell carcinoma. j urol 2015; 193:41–7. doi: 10.1016/j. juro.2014.07.011. 46. damron ta, heiner j. distant soft tissue metastases: a series of 30 new patients and 91 cases from the literature. ann surg oncol 2000; 7:526–34. doi: 10.1007/s10434-000-0526-7. 47. seely s. possible reasons for the high resistance of muscle to cancer. med hypotheses 1980; 6:133–7. doi: 10.1016/03069877(80)90079-1. 48. surov a, fiedler e, voigt w, wienke a, holzhausen hj, spielmann rp, et al. magnetic resonance imaging of intramuscular metastases. skeletel radiol 2011; 40:439–46. doi: 10.1007/s00256-010-1018-x. http://dx.doi.org/10.1186/1471-2407-12-344 http://dx.doi.org/10.1007/s11604-014-0281-5 http://dx.doi.org/10.1186/1470-7330-14-21 http://dx.doi.org/10.1186/1470-7330-14-21 http://dx.doi.org/10.1016/j.ejcts.2008.01.045 http://dx.doi.org/10.1016/j.juro.2014.07.011 http://dx.doi.org/10.1016/j.juro.2014.07.011 http://dx.doi.org/10.1007/s10434-000-0526-7 http://dx.doi.org/10.1016/0306-9877%2880%2990079-1 http://dx.doi.org/10.1016/0306-9877%2880%2990079-1 http://dx.doi.org/10.1007/s00256-010-1018-x squ med j, may 2012, vol. 12, iss. 2, pp. , epub. 9th apr 2012 submitted 20th sept 11 revision req. 13th dec 11, revision recd. 25th dec 11 accepted 25st jan 12 blunt trauma can cause injuries to a variety of intra-abdominal organs. solid organ injuries are more common than intestinal perforations1 and are usually evident on presentation as these may be associated with varying degrees of shock or clinical signs of peritonitis. while perforation of the gastrointestinal tract is reported in 5–15% of patients,2,3 it may be difficult to diagnose at initial presentation, especially if signs of peritonitis are minimal. studies vary regarding the most common site of intestinal perforation; however, there is a consensus that isolated jejunal blow out (ijbo) is extremely rare.4 clinical presentation is usually delayed if the nature of the trauma is trivial. we report the case of a patient who presented with features of peritonitis 10 days after being injured by a knee kick trauma. an erect abdominal x-ray showed extraluminal air-fluid levels, suggesting a hollow viscous injury which on exploration was found to be ijbo. case report an 18-year-old male with no significant past medical or surgical history was brought to the emergency department 10 days after an incident of blunt trauma to the abdomen. the injury occurred when the patient swung from a great height and sheikh zayed medical complex, rahim yar khan, pakistan e-mail: drkhalidmunirbhatti@yahoo.com مستوى اهلواء السائل خارج األمعاء يف األشعة السينية لبطن مريض مصاب بانفجار معزول للمعي الصائم تقرير حالة رونأا س�يردإا دمحم، قاتس�م رمع، دلاخ ناس�فأا، يلع راقفلا وذ دمحم، يتاهب رينم دلاخ اخلال�صة: املر�سى الذين يعانون من اإ�سابة كليلة ب�سيطة يف البطن قد تظهر على �سكل انفجار معزول للمعي ال�سائم. ينبغي توخي احلذر ال�سديد لال�ستباه بتلك احلالة الأن تاأخر العر�س اأو الت�سخي�س يزيد معدل االإ�سابة باالأمرا�س. وميكن ت�سخي�س عر�س التهاب ال�سفاق الناجت عن ثقب �رضيح بوا�سطة االأ�سعة ال�سينية للبطن. ندرج هنا تقريرا عن حالة مري�س َقِدَم مع مالمح التهاب ال�سفاق بعد 10 اأيام من تعر�سه بركلة ركبة بع�رضة اأيام. اأظهرت االأ�سعة ال�سينية للبطن بو�سع الوقوف م�ستويات هواء �سائل، مما ي�سري اإىل اإ�سابة ع�سو جموف والتي تبني بعد التنقيب اأنها ثقب املعي ال�سائم. مفتاح الكلمات: �سدمة كليلة، تاأخر الت�سخي�س، ثقب االأمعاء، ال�سائم، التهاب ال�سفاق، تقرير حالة، باك�ستان. abstract: patients with trivial blunt abdominal trauma may present with isolated jejunal blow out (ijbo). a high index of suspicion is required as delayed presentation or delayed diagnosis may increase morbidity. presentation with frank perforation peritonitis can be diagnosed by abdominal x-rays. we report the case of a patient who presented with features of peritonitis 10 days after being injured by a knee kick trauma. an erect abdominal x-ray showed extraluminal air-fluid levels, suggesting a hollow viscous injury which on exploration was found to be ijbo. keywords: blunt trauma; delayed diagnosis; intestinal perforation; jejunum; peritonitis; case report; pakistan. extra-luminal air fluid level on abdominal x-ray of a patient with isolated jejunal blow out case report *khalid munir bhatti, mohammed zulfiqar ali, afshan khalid, umar mushtaq, mohammed idrees anwar case report extra-luminal air fluid level on abdominal x-ray of a patient with isolated jejunal blow out case report 222 | squ medical journal, may 2012, volume 12, issue 2 landed on his friend’s knee. this caused trauma to the epigastrium. the patient experienced sudden, severe abdominal pain, which settled after a while. no medical advice was sought for the problem; instead, for one week, the patient took over-the-counter medications for pain, including paracetamol 1 g po (per os = by mouth) every 6 hours, and diclofenac sodium 50 mg po b.i.d. (bis die = twice daily). after a few days, the pain became continuous. over the following week, the patient started vomiting, and developed abdominal distension and absolute constipation. the patient’s condition worsened and he was brought to hospital, after experiencing altered mental states, with an unremitting fever, and decreased urine output. examination in the emergency department revealed a young adult in a state of shock with a pulse of 120 beats per minute, blood pressure of 90/60 mm hg, a respiratory rate of 24 breaths per minute, a temperature of 38.8 0c, and an arterial oxygen saturation (sao2) level of 95% at room air. he was not jaundiced but was extremely pale. a chest examination revealed equal air entry with no added sounds and a gallop rhythm on cardiac auscultation. an abdominal examination revealed distended rigid abdomen with guarding and rebound tenderness. shifting dullness was positive and bowel sounds were absent. a digital rectal examination revealed an empty collapsed rectum. the patient was immediately resuscitated with supplemental oxygen via a face mask, and intravenous fluids and given antibiotics (metronidazole 500 mg at 8-hourly intervals and ceftriaxone 1 g every 12 hours). a nasogastric tube was inserted and urinary catheterisation was done to monitor output. once the patient was stable, baseline investigations were undertaken which revealed a white blood count of 16,000 mm3 with neutrophilia of 75%; hb levels of 6.206 g/l; blood urea levels of 28.6 mmol/l; serum creatinine levels of 132.6 μmol/l; potassium levels of 3.2 mmol/l, and abnormal liver enzymes and function, with a total bilirubin of 29 μmol/l, alanine transaminase (alt) 60 μ/l, and aspartate transaminase (ast) 74 iu/l. his serum amylase level was 82 u/l. radiological investigations yielded a normal chest x-ray, but an erect abdominal x-ray revealed a ground glass appearance, obscured psoas shadows, intraluminal air-fluid levels, free air under the right hemidiaphragm [figure 1]. a computed tomography (ct) scan was not done as clinical pictures and x-ray findings were suggestive of perforation of a hollow organ which needed immediate surgical intervention. the diagnosis of peritonitis due to a hollow viscous injury was made and an exploratory laparotomy was done. findings included 3 litres of fluid containing pus and intestinal contents, and a single 1 x 1 cm perforation in the jejunum, 30 cm away from the dueodeno-jejunal junction. although the general condition of the patient was not good, primary repair of the perforation was done, after refreshing the margins, because of its proximal position. extensive peritoneal lavage was done and the abdomen was closed by retention suturing. recovery from anaesthesia was delayed and patient required observation in the intensive care unit for one night. later he was moved to the ward. his progress in the ward was uneventful. he recovered very well and was discharged on day 10. discussion since razali et al.5 published a report on isolated jejunal injury arising from blunt abdominal trauma in 1974, many other authors have reported such injuries.4,6–11 even so, the total number of reported cases of ijbo in literature is not very high.12 the causes of injury include motor vehicle accidents,4 6,8,10,11 physical assault,9 falls from stairs, and a dhoti (traditional indian male garment) being caught in an engine belt.12 the only reported case of ijbo after knee kick trauma was by coskun et al. in 2007.7 our case is only the second reported incident. the proposed mechanism of a blow-out injury is the sudden transient rise in the intraluminal pressure of the hollow viscous because of compression force.12 in our case, the patient fell from a height of about 10 feet onto the knee of his friend, leading to trauma to the upper abdomen. external compression probably caused a sudden rise in the intraluminal pressure and eventually led to jejunal blow out. the patient initially felt pain, but it faded after some time. the initial pain was because of the trauma, but later the pain worsened because of spillage of the intestinal contents. full blown peritonitis and septic shock developed over the week following the injury. in all reported cases, the time of presentation was just after the trauma although in some cases khalid munir bhatti, mohammed zulfiqar ali, afshan khalid, umar mushtaq and mohammed idrees anwar case report | 223 diagnosis was delayed for some time because of diagnostic uncertainty. a maximum in-hospital delay of 72 hours was reported by kouritas in 2009 in a patient with thoracic trauma having occult jejunal perforation.10 in a community where there is no immediate access to medical services, patients may wait longer before reaching tertiary health care facilities. in our case, the trivial nature of the trauma complicated the picture even more. presentation was 10 days after the trauma; however, there was only a minimal delay of 4 hours between presentation and surgical exploration. a physical examination is generally not sensitive enough to make an accurate diagnosis,13 especially in cases where patients present before the development of peritonitis. in patients who do present with peritonitis, the symptoms may be confused with traumatic pancreatitis. measurement of serum pancreatic enzymes and x-ray findings suggestive of intestinal perforation may be helpful in distinguishing between the two. however, an abdominal ct scan provides more accurate diagnosis. the diagnostic accuracy of abdominal x-rays in identifying free air under the diaphragm is very low, and the chances of missing ijbo are very high.12 however, a delay in presentation allows sufficient time for the free air and fluid to accumulate in the peritoneal cavity. moreover, bacteriological activity on the gastrointestinal contents also produces excessive air, which can lead to the formation of extraluminal air-fluid levels detectible through erect abdominal x-rays. in such cases, an x-ray of the abdomen in erect and supine positions can provide valuable information in the form of the identification of free air under the right hemidiaphragm, a ground glass appearance, and multiple intraluminal airfluid levels. nevertheless, these findings are not specific to ijbo because a similar picture may be seen in any kind of intestinal perforation presenting late, like peptic ulcer perforations, traumatic ileal perforations, or large gut perforations (caecal/ colonic/rectal). moreover, certain cases of extensive caecal dilatation, which may occur because of distal colonic obstruction,14 may have intraluminal airfluid levels, which may be mistaken for extraluminal ones. careful observation and the absence of free air under the diaphragm may help in distinguishing between the two. the role of the ct scan and laparoscopy in the evaluation of patients with blunt trauma is emerging and has replaced diagnostic peritoneal lavage (dpl).15 the ct scan has a sensitivity of 92% and a specificity of 94% in the detection of hollow viscous injuries.16 laparoscopy has an additional benefit of being therapeutic in a certain percentage of cases;17 however, in patients who are haemodynamically unstable or present late with features suggestive of peritonitis, laparotomy will be required and peritoneal lavage will be necessary for the primary closure of the perforation. the morbidity and mortality in small bowel perforation is lower than in colonic perforations. delayed presentation, perforation with shock, and associated organ injuries are the factors which lead to higher morbidity and mortality in such cases. conclusion ijbo is a very rare clinical entity. it may occur even after minimal abdominal trauma. in cases presenting with minimal abdominal signs, diagnosis is very difficult and a high index of suspicion is required where the mode of injury is suggestive of the possibility of ijbo. in such cases, radiological investigations like an abdominal ct scan may be helpful. laparoscopy has an additional benefit, as an isolated perforation can be repaired by minimal figure 1: extraluminal air-fluid level in patient with a post-traumatic isolated jejunal blow out. a: free air under right hemidiaphragm. b: extraluminal airfluid level c: ground glass appearance/loss of psoas shadows. d: airfluid level in stomach (normal) extra-luminal air fluid level on abdominal x-ray of a patient with isolated jejunal blow out case report 224 | squ medical journal, may 2012, volume 12, issue 2 access surgery. if presentation is delayed, signs of perforation peritonitis and systemic signs of toxicity may be evident. in such cases, abdominal x-rays may show free air under the diaphragm or, rarely, extra-luminal air-fluid levels. such patients should undergo exploratory laparotomy and surgical repair of the perforation. early diagnosis with the help of radiological investigations like abdominal ct scans or laparoscopy is helpful in reducing the morbidity and mortality in cases of ijbo. references 1. ong cl, png dj, chan st. abdominal trauma a review. singapore med j 1994; 35:269–70. 2. sule az, kidmas at, awani k, misauno m. gatrointestinal perforation following blunt abdominal trauma. east afr med j 2007; 84:429–33. 3. ameh ea, nmadu pt. gastrointestinal injuries from blunt trauma abdomen in children. east afr med j 2004; 81:194–7. 4. baccolli a, manconi ar, caocci g, pisu s. isolated jejunal perforation after blunt trauma. report of three cases. g chir 2010; 31:167–70. 5. razali h, thomas wm. isolated jejunal injuries arising from blunt abdominal trauma. injury 1974; 6:33–5. 6. chiang wk. isolated jejunal perforation from nonpenetrating abdominal trauma. am j emerg med 1993; 11:473–5. 7. coskun ak, yarici m, ulke e, mentes o, kozak o, tufan t. perforation of isolated jejunum after a blunt trauma: case report and review of literature. am j emerg med 2007; 25:862. 8. lindenmann jm, schmid d, akovbiantz a. jejunal perforation following blunt abdominal trauma. schweiz rundsch med prax 1994; 83:857–60. 9. kostantinidis c, pitsinis v, fragulidis g. isolated jejunal perforation following blunt abdominal trauma. ulus travma acil cerrahi derg 2010; 16:87– 9. 10. kouritas vk, matheos e, baloyiannis i, spyridakis m, desimonas n, hatzitheofilou k. late presentation of jejunal perforation after thoracic trauma. am j emerg med 2009; 27:1177. 11. munshi ia, dirocco jd, khachi g. isolated jejunal perforation after blunt thoracoabdominal trauma. j emerg med 2006; 30:393–5. 12. goudar bv, ambi u, lamani y, telkar s. isolated “blow out” jejunal perforation following blunt abdominal trauma-experience of two cases. j cardiovasc dis res 2011; 5:1120-2. 13. allen gs, moore fa, cox cs jr, wilson jt, cohn jm, duke jh. hollow visceral injury and blunt trauma. j trauma 1998; 45:69–78. 14. shadowfax. movin’ meat: solution to the puzzle. from: http://www.allbleedingstops.blogspot. com/2009/01/solution-to-puzzle.html. accessed: sep 2011. 15. burney re, mueller gl, coon ww, thomas ej, mackenzie jr. diagnosis of isolated small bowel injury following blunt abdominal trauma. ann emerg med 1983; 12:71–4. 16. sherck j, shatney c, sensaki k, selivanov v. the accuracy of computed tomography in the diagnosis of blunt small bowel perforation. am j surg 1994; 168:670–5. 17. townsend ms, pelias me. a technique for the rapid closure of traumatic small intestinal perforation without resection. am j surg 1992; 164:171–2. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 567-573, epub. 8th oct 13 submitted 14th jan 13 revisions req. 16th apr 13; revisions recd. 19th apr 13 accepted 1st may 13 1al-quds university medical school, beit hanina, jerusalem, palestine; 2department of pathology, beit jala hospital, bethlehem, west bank, palestine *corresponding author e-mail: yasin.tayem@gmail.com توجهات وصف العالج باستخدام مضادات االلتهاب غري الستريويدية و املضادات احليوية يف مشفى مركزي يف الضفة الغربية يا�شني تيم, مروان قباجة, ريا�ض �رشمي, عمر طه, عماد الدين ابو ا�شخيدم, مراد اإبراهيم امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل و�شف االجتاهات ال�شائدة للعيادات اخلارجية يف و�شف م�شادات االلتهاب غري ال�شتريويدية و امل�شادات احليوية يف م�شفى مركزي يف ال�شفة الغربية. الطريقة: يف هذه الدرا�شة اال�شتعادية امل�شتعر�شة مت التحقق من 2,208 و�شفة حلم بيت مدينة يف احلكومي جاال بيت مل�شفى التابعة الطوارئ غرفة و اخلارجية العيادات عن كامل عام مدى على �شادرة عالجية بال�شفة الغربية. حيث مت حتليل الو�شفات من حيث كم و نوع م�شادات االلتهاب غري ال�شتريويدية و امل�شادات احليوية املو�شوفة و مدى و�شفة 410 ال�شتريويدية غري االلتهاب م�شادات �شكلت العالجية الو�شفات جمموع من النتائج: الطبي. للت�شخي�ض الو�شفات مالءمة واإندوميثا�شني )15.1%(. )17.8%( ايبوبروفني ,)23.9%( اجلرعة قليل اأ�شربين ديكلوفيناك )40.2%(، ذلك يف مبا ,)18.6%( الإنزمي مثبطا عقارا احتوت فقط واحدة طبية و�شفة .)2.5%( االأدوية هذه من توليفة على احتوت الو�شفات هذه من قليلة ن�شبة �شايلواوك�شيجينيز-2 )0.2%(. وكان مدى مالءمة و�شف هذه االأدوية للت�شخي�ض كما يلي: منا�شب )%58.3(, غري منا�شب )14.4%( امل�شادات العالجية(. الو�شفات جمموع من 669( احليوية 30.3% امل�شادات ا�شتخدام معدل كان التحديد )27.3%(. ممكن غري و احليوية املو�شوفة �شملت اأموك�شي�شيلني )23.3(, اوجيمنتني )%14.3(, كوينولون )%12.7(, اجليل االأول والثاين من ال�شيفالو�شبورين )%9.4 و %12.7, على التوايل(, وماكروليدات )%7.2(. كذلك احتوت ما ن�شبته %9.4 من الو�شفات على اأكرث من م�شاد حيوي واحد كان اأبرزها اجليل الثاين من ال�شيفالو�شبورين مع املرتونيدازول )%4.3(. وكان مدى مالءمة و�شف امل�شادات احليوية وفقا للت�شخي�ض كما يلي: منا�شب %44.8, غري مالئم %20.6 و غري ممكن التحديد %34.6 اخلال�صة: ك�شفت هذه النتائج عددا كبريا ن�شبيا وا�شتخداما غري مالئم للم�شادات احليوية وم�شادات االلتهاب غري ال�شتريويدية. بناء على ذلك ينبغي تبني برنامج يعزز من معرفة االأطباء باأهمية الو�شف املبني على اأ�ش�ض �شحيحة لهذه االأدوية. مفتاح الكلمات: م�شادات االلتهاب غري ال�شتريويدية, امل�شادات احليوية, و�شفة عالج, فل�شطني. abstract: objectives: we aimed to reliably describe the pattern of outpatient prescription of non-steroidal anti-inflammatory drugs (nsaids) and antibiotics (atbs) at a central hospital in the west bank, palestine. methods: this was a retrospective, cross-sectional study investigating a cohort of 2,208 prescriptions ordered by outpatient clinics and the emergency room over one year in beit jala hospital in bethlehem, west bank. the orders were analysed for the rate and types of nsaids and atbs utilised, and the appropriateness of these drugs to the diagnosis. results: of the total prescriptions, 410 contained nsaids (18.6%), including diclofenac (40.2%), low dose aspirin (23.9%), ibuprofen (17.8%) and indomethacin (15.1%). a minority of these prescriptions contained a combination of these agents (2.5%). only one prescription contained cyclooxyeganse-2 inhibitors (0.2%). the appropriateness of nsaid use to the diagnosis was as follows: appropriate (58.3%), inappropriate (14.4%) and difficult to tell (27.3%). the rate of atb use was 30.3% (669 prescriptions). the atbs prescribed were amoxicillin (23.3%), augmentin (14.3%), quinolones (12.7%), first and second generation cephalosporins (9.4% and 12.7%, respectively) and macrolides (7.2%). atb combinations were identified in 9.4%, with the most common being second-generation cephalopsorins and metronidazole (4.3%). regarding the appropriateness of prescribing atbs according to the diagnosis, it was appropriate in 44.8%, inappropriate in 20.6% and difficult to tell in 34.6% of the prescriptions. conclusion: these findings revealed a relatively large number and inappropriate utilisation of atbs and nsaids. an interventional programme needs to be adopted to reinforce physicians’ knowledge of the rational prescription of these agents. keywords: nsaids; antibiotics; prescription; palestine. non-steroidal anti-inflammatory drugs and antibiotics prescription trends at a central west bank hospital *yasin i. tayem,1 marwan m. qubaja,1 riyad k. shraim,2 omar b. taha,1 imadeddin a. abu shkheidem,1 murad a. ibrahim1 clinical & basic research yasin i. tayem, marwan m. qubaja, riyad k. shraim, omar b. taha, imadeddin a. abu shkheidem and murad a. ibrahim clinical and basic research | 568 advances in knowledge non-steroidal anti-inflammatory drugs (nsaids) and antibiotics (atbs) are over-prescribed at the study hospital in the central west bank. a lack of rational utilisation of nsaids and atbs was observed, and this trend may be observed at other institutions as well. application to patient care since nsaids are potentially toxic drugs, physicians must prescribe them only when strictly indicated and take individual patient risk factors into consideration when selecting certain agents. rational prescription of atbs is extremely important to avoid the spread of potentially life-threatening multi-drug-resistant bacteria. therefore, physicians must be very careful when prescribing these drugs. the results may guide interventional programmes focusing on general practitioners and specialists in various clinical settings to improve their prescription habits of these agents. non-steroidal anti-inflammatory drugs (nsaids) are widely used worldwide as anti-inflammatory, antipyretic and analgesic agents.1 low-dose aspirin, however, is prescribed for both primary and secondary prevention of coronary artery and cerebrovascular diseases (cbvd).2,3 despite their established efficacy, these drugs have a wide range of adverse drug reactions, including but not limited to gastric ulceration and bleeding, bleeding tendencies due to the inhibition of platelet aggregation, nephrotoxicity, and sodium/water retention.4–7 therefore, and due to differences in the adverse effect profile among various nsaids, assessing an individual patient’s risk is an important factor when selecting a nsaid.8 agents which selectively inhibit cyclooxygenase-2 enzyme (cox-2 inhibitors), like oxicams and coxibs, are equally effective to non-selective nsaids, such as diclofenac and ibuprofen, and lack many of the serious adverse effects of the latter.9 notably, cox-2 inhibitors offer an excellent alternative for patients at risk for serious gastrointestinal (git) adverse effects, particularly upper git ulceration and bleeding. however, the cardiovascular toxicity associated with cox-2 inhibitors and some other nsaids further complicates the choice of therapy.10 over the last few decades, the prescription rate of nsaids has been on the rise, largely due to an increasingly aged population and the consequent rise in the prevalence of diseases that respond to nsaids, particularly infectious and inflammatory conditions.11 therefore, the utilisation pattern of these drugs and physician awareness of the differences among various nsaids needs to be frequently assessed in various clinical settings.12 the discovery of antibiotics (atbs) constituted a revolution in modern medicine. however, like nsaids, they are a first-line weapon against infectious diseases, and therefore are liable to be overused.13 due to the huge consumption rate of broad-spectrum and combination anti-bacterial drugs, many developing countries have experienced unfavourable trends in atb use and bacterial resistance.14 the emergence of catastrophic multidrug-resistant strains is currently receiving a lot of attention due to increasing morbidity, mortality and health costs.15 the problem is on the rise and the treatment options for combating bacterial resistance are narrowing. ideally, the rational and cost-effective use of atbs should be carefully balanced to maximise the clinical therapeutic effect while minimising drug-related toxicity, and the development of new resistant strains and the spread of existing ones.16 therefore, to prevent bacterial resistance, many countries worldwide have adopted programmes to reduce ambulatory atb consumption as part of an international strategy.17 these include group educational meetings and training, and monitoring and feedback on physician prescribing behaviour and patient education.18 the present investigation was carried out to provide insight into the prescription rate and trend of nsaids and atbs at a central hospital in the west bank. the study aimed to improve the rational and cost-effective use of these drugs and comment upon any lacunae in their consumption pattern. the authors speculate that the results of this study will guide interventional programmes focusing on general practitioners and specialists in various clinical settings to improve their prescription habits of these agents. non-steroidal anti-inflammatory drugs and antibiotics prescription trends at a central west bank hospital 569 | squ medical journal, november 2013, volume 13, issue 4 methods the majority of palestinians residing in the west bank are entitled to governmental healthcare provided by a network of primary healthcare centres and hospitals. patients are initially evaluated by a general practitioner at a primary healthcare centre and are referred, if needed, to a specialist at a hospital outpatient clinic (opc). emergency cases can be treated at the emergency rooms (ers) of these hospitals. most prescriptions originating from primary healthcare centres, opcs or ers are dispensed at pharmacies at governmental hospitals. all prescription orders are collected from patients upon dispensation and are kept at hospital pharmacies. the prescription orders contain elements which should be clearly filled by the prescribing physician. these elements include the source of the prescription, the prescriber’s name, a patient’s details, current diagnosis or diagnoses, and a list of medications with instructions to the pharmacist and patient. physicians in the target hospital were not aware of this study. ethical approval was provided by the al-quds university human research ethics committee. the target hospital was beit jala hospital, which is the central governmental hospital in the bethlehem district. this area has a population of 140,000 people, making up 7.3% of the population of the west bank. opc and er prescriptions from within the hospital, irrespective of the clinic of origin, received and kept by the pharmacy department over a period of one year (20 december 2010–19 december 2011) were analysed retrospectively and systemically. this period was divided into 4 seasons: spring, summer, autumn and winter. in each season, all prescriptions from one randomly selected week (7 days) were analysed. the analysis was carried out from january–march 2012. all prescriptions containing nsaids or atbs were examined to determine the clinic of origin, number and types of nsaids or atbs ordered, and the appropriateness of utilising these drugs with the stated diagnosis on the prescription order. the appropriateness of the drug treatment to the diagnosis was classified as follows: appropriate when drugs prescribed were related to the diagnosis, inappropriate when the drugs were unrelated to the diagnosis, and difficult to tell when the diagnosis was missing or not clearly written. the use of nsaids was considered appropriate if the patient had experienced fever or pain due to an infectious condition (e.g. upper respiratory tract infection or cholecystitis), musculoskeletal condition (e.g. rheumatoid arthritis, gout, osteoarthritis or muscle stiffness), painful condition (e.g. metastatic bone pain, trauma, migraine headache, dysmenorrhoea, postoperative pain or renal colic), or the prophylaxis of ischemic heart disease or cbvd (for low-dose aspirin only). on the other hand, the use of nsaids was considered inappropriate if the physician prescribed a combination of more than one nsaid in the same order, or if the diagnosis stated on the prescription order contained one of the following conditions: peptic ulcer disease, gastroenteritis, non-specific abdominal pain or colic, diarrhoea, pregnancy, renal failure, heart failure, asthma or chronic obstructive pulmonary disease (copd). for atb-containing prescriptions, the treatment was considered appropriate if the diagnosis appearing on the prescription order included any infectious bacterial conditions such as a urinary tract infection, meningitis, cellulitis, pneumonia, etc. however, treatment with atbs was labeled inappropriate if the patient was given a diagnosis which most likely was not a bacterial infection, such as viral infections (gastroenteritis or viral upper respiratory tract infections such as nasopharyngitis, but not otitis media or tonsillitis, which are commonly caused by bacteria). similarly, atb prophylaxis was considered unindicted if atbs were prescribed for normal spontaneous vaginal deliveries, or non-specific abdominal pain or colic. it is worth emphasising that the aim was to examine the appropriateness of using atbs, not to judge the selection of a certain atb for a certain patient. the data were examined using the statistical package for the social sciences (spss), version 17 (ibm corp., chicago, illinois, usa), and simple descriptive statistics were utilised to analyse the results. results the sample was comprised of 2,208 prescription orders. the majority of the prescriptions were issued by the opcs (90.3%) followed by the er (7.8%) while in the rest the source was missing (1.9%). the number of drugs included in the yasin i. tayem, marwan m. qubaja, riyad k. shraim, omar b. taha, imadeddin a. abu shkheidem and murad a. ibrahim clinical and basic research | 570 prescriptions ranged from 1–9, but the majority (90.4%) contained 3 or fewer drugs. the distribution of the prescriptions by season was as follows: winter (30.6%), spring (17.5%), summer (35.6%) and autumn (16.3%). based on the clinic of origin, 30.4% of the prescriptions were sent by the oncology clinic, followed by the departments of internal medicine (21%), orthopaedics (9.5%), surgery (9%), er (7.8%), paediatrics (6.6%) and obstetrics/ gynaecology (6.3%). the nsaid utilisation pattern was examined in this study [table 1]. out of the 2,208 prescriptions analysed, 410 contained nsaids (18.6%). diclofenac was the most commonly prescribed agent (40.2%), followed by low-dose aspirin (27.3%), ibuprofen (17.8%) and indomethacin (15.1%). only one prescription contained cox-2 inhibitor nsaids (0.2%). combination nsaids were identified in a minority of prescriptions (2.8%). the pattern of prescribing nsaids was further analysed for the source of the prescription and the appropriateness of the prescription to the diagnosis. the clinic of origin of nsaids-prescription was as follows: the departments of orthopaedics (33.2%), internal medicine (25.1%), oncology (13.4%), surgery (10%), er (8%), obstetrics/gynaecology (2.2%) and paediatrics (0.5%). the appropriateness of nsaids use to the diagnosis was as follows: appropriate (58.3%), inappropriate (14.4%) and difficult to tell (27.3%). regarding the prescription trend of atbs [table 2], the proportion of outpatient prescriptions which generated atbs was 30.3% (669 prescriptions). amoxicillin was the atb most often prescribed (23.3%), followed by augmentin (14.3%), quinolones (12.7%), firstand second-generation cephalosporins (9.4 and 12.7%, respectively) and macrolides (7.2%). atb combinations were identified in 9.4% of the prescriptions, with the most common table 1: frequency of non-steroidal anti-inflammatory drug prescriptions according to type and clinic of origin in a central hospital in the west bank (n = 410) prescriptions (n) frequency (%) type of nsaid prescribed diclofenac 165 40.2 low-dose aspirin 98 23.8 ibuprofen 73 17.8 indomethacin 62 15.1 cox-2 inhibitors 1 0.2 others 1 0.2 combination nsaids 10 2.7 source of nsaid prescriptions orthopaedics 136 33.2 medicine 103 25.1 oncology 55 13.4 surgery 41 10.0 er 33 8.0 obstetrics/gynaecology 9 2.2 paediatrics 1 0.2 other 32 7.8 nsaid = non-steroidal anti-inflammatory drug; cox = cyclooxygenase; er = emergency room. table 2: frequency of antibiotic prescription according to type and clinic of origin in a central hospital in the west bank (n = 669) prescriptions (n) frequency (%) type of atb prescribed amoxicillin 156 23.3 augmentin 96 14.3 quinolones 85 12.7 second-generation cephalosporins 85 12.7 first-generation cephalosporins 63 9.4 macrolides 48 7.2 metronidazole 25 3.7 other atbs 111 16.7 *combination atbs 58 9.4 source of atb prescriptions orthopaedics 32 4.8 medicine 108 16.1 oncology 70 10.5 surgery 132 19.7 er 89 13.3 obstetrics/ gynaecology 99 14.8 paediatrics 64 9.6 other 75 11.2 *combination atbs do not count as part of the total number of atbs analysed since these prescriptions included more than one atb. atb = antibiotic; er = emergency room. non-steroidal anti-inflammatory drugs and antibiotics prescription trends at a central west bank hospital 571 | squ medical journal, november 2013, volume 13, issue 4 being second-generation cephalopsorins and metronidazole (4.3%). the general surgery clinic was the most frequent source of atbs (19.7%), followed by the departments of internal medicine (16.1%), obstetrics/gynaecology (14.8%), er (13.3%), oncology (10.5%), paediatrics (9.6%) and orthopaedics (4.8%). regarding the appropriateness of prescribing atbs to the diagnosis, it was appropriate in 44.8%, inappropriate in 20.6%, and difficult to tell in 34.6% of the orders. discussion this investigation targeted a cohort of 2,208 outpatient prescriptions issued at a central hospital in the west bank to evaluate the amount and pattern of outpatient prescriptions of nsaids and atbs. the data analysis in the present study revealed a large number and inappropriate prescriptions of nsaids and atbs. results of this study may help address issues related to the prescription pattern of these drugs, especially in the ambulatory setting. almost one-fifth of the prescriptions contained nsaids, emphasising a high tendency towards utilising these drugs, as previously reported.19 the most commonly prescribed nsaid was found to be diclofenac, accounting for more than 40% of the prescriptions, followed by ibuprofen and indomethacin. only one prescription (0.2%) contained cox-2 inhibitors. notably, a tendency towards prescribing diclofenac, with its high git bleeding risk, over other relatively git-tolerable nsaids like ibuprofen, and cox-2 inhibiting agents was highlighted in this study.20 this notion emphasises limited physician attention to the importance of considering individual patients’ gastrointestinal (gi) risk factors when selecting nsaids. there are variations among countries in the selection trend of nsaids. in concert with these findings, a recent study in serbia reported that the most commonly prescribed nsaid was diclofenac followed by ibuprofen.21 however, in sweden the most commonly prescribed nsaid was the cox-2 inhibitor crofecoxib.22 a similar pattern was reported in australia where non-selective nsaidprescribing decreased while cox-2 inhibitor utilisation increased from 1997 to 2006.23 regarding the appropriateness of prescribing nsaids to the diagnosis, this study found that approximately 60% of the prescriptions were appropriate, whereas 14.4% were inappropriate. these findings are far worse than those reported by irshaid et al., who showed that in a teaching hospital in saudi arabia a minority of outpatient nsaid prescriptions (4.2%) were inappropriate.24 adams et al. reported a high prevalence of inappropriate use of nsaids in australia among patients with hypertension (16%), kidney disease (15.9%) and a history of cbvd (20%).25 due to the differences in adverse effects among nsaids, awareness about the rational utilisation and appropriate selection of these drugs for each individual patient needs to be strongly emphasised. moreover, physician awareness of the efficacy and safety of cox-2 inhibitors and paracetamol as alternatives to nsaids needs to be reinforced. this study’s findings regarding the prescription pattern of atbs raise concerns about the high rate and irrational use of these drugs. we report that the average prevalence of atb prescription was very high, with a frequency touching 30.3%. the use of the extended-spectrum penicillins amoxicillin and augmentin accounted for more than one-third while the use of combination atbs was seen in one-tenth of the atb-containing prescriptions in this sample. we also found that atbs were used inappropriately in one-fifth of prescriptions. haphazard use of atbs has caused these essential drugs to lose their effectiveness due to emerging bacterial resistance. in the developing world, the problem is complex, involving inadequate access to more effective atbs along with an inadequate capability to use them appropriately. both circumstances may result in the rapid spread of antimicrobial resistance, which significantly increases the risk of morbidity and mortality. to combat the overuse and misuse of atbs, suitable and sustainable interventions should be introduced to raise physician awareness about the importance of prescribing atbs rationally and cost-effectively. this study has certain limitations which should be taken into consideration when interpreting these findings. in our setting, this investigation was not an accurate measure of the exposure of the west bank population to nsaids and atbs since our sample was taken from only one hospital. a largerscale study involving samples of prescriptions from the several public and private hospitals in the west bank will be needed to measure trends in the use of these drugs as part of a national surveillance system. yasin i. tayem, marwan m. qubaja, riyad k. shraim, omar b. taha, imadeddin a. abu shkheidem and murad a. ibrahim clinical and basic research | 572 moreover, when we evaluated the appropriateness of nsaid and atb utilisation to the diagnosis, we relied on the outpatient prescription order rather than the patient’s files. an examination of the files would have provided more detailed information concerning the patient’s condition(s) and the appropriateness of the prescription. finally, this study focused on the outpatient prescription trends of nsaids and atbs whereas no data were collected about this trend in the inpatient setting. conclusion in summary, a high rate of outpatient prescription and irrational utilisation of nsaids and atbs was reported. these findings emphasise the need for physician educational interventions concerning the rational prescription of nsaids and atbs. national guidelines on the appropriate utilisation of these drugs are urgently warranted to improve the situation. however, the key to success in this endeavor would be strong physician commitment, patient education and governmental support. acknowledgements this research received no specific grant from any funding agency in the public, commercial or nonprofit sectors. the authors also report no financial or other conflicts of interest pertaining to the subjects or products discussed in this article. we express our appreciation to the administration and pharmacy staff at beit jala hospital for their cooperation with the investigators. the valuable support of the ministry of health is also gratefully acknowledged. references 1. middleton c. non-steroidal anti-inflammatory drugs: indications for use. nurs times 2003; 99:30– 2. 2. berger js, roncaglioni mc, avanzini f, pangrazzi i, tognoni g, brown dl. aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. jama 2006; 295:306–13. 3. berger js, brown dl, becker rc. low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. am j med 2008; 121:43–9. 4. garcía rodríguez la, hernández-diaz s. relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal antiinflammatory drugs. epidemiology 2001; 12:570–6. 5. amer m, bead vr, bathon j, blumenthal rs, edwards dn. use of nonsteroidal anti-inflammatory drugs in patients with cardiovascular disease: a cautionary tale. cardiol rev 2010; 18:204–12. 6. musu m, finco g, antonucci r, polati e, sanna d, evangelista m, et al. acute nephrotoxicity of nsaid from the foetus to the adult. eur rev med pharmacol sci 2011; 15:1461–72. 7. stichtenoth do, frolich jc. cox-2 and the kidneys. curr pharm des 2000; 6:1737–53. 8. adebajo a. non-steroidal anti-inflammatory drugs for the treatment of pain and immobility-associated osteoarthritis: consensus guidance for primary care. bmc fam pract 2012; 13:23. 9. kivitz aj, moskowitz rw, woods e, hubbard rc, verburg km, lefkowith jb, et al. comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip. j int med res 2001; 29:467–79. 10. scheiman jm, sidote d. which nsaid for your patient with osteoarthritis? j fam pract 2010; 59:e1– 6. 11. krajcik s, bartosovic i. [non-steroidal antiinflamatory drugs in the elderly]. vnitr lek 2000; 46:360–4. 12. paul ad, chauhan ck. study of usage pattern of nonsteroidal anti-inflammatory drugs (nsaids) among different practice categories in indian clinical setting. eur j clin pharmacol 2005; 60:889–92. 13. mckay rm, vrbova l, fuertes e, chong m, david s, dreher k, et al. evaluation of the do bugs need drugs? program in british columbia: can we curb antibiotic prescribing? can j infect dis med microbiol 2011; 22:19–24. 14. takeshita n. [travellers and multi-drug resistance bacteria]. nihon rinsho 2012; 70:324–8. 15. coker rj, hunter bm, rudge jw, liverani m, hanvoravongchai p. emerging infectious diseases in southeast asia: regional challenges to control. lancet 2011; 377:599–609. 16. ison ca. antimicrobial resistance in sexually transmitted infections in the developed world: implications for rational treatment. curr opin infect dis 2012; 25:73–8. 17. steciwko a, lubieniecka m, muszynska a. [antibiotics in primary care]. pol merkur lekarski 2011; 30:323–6. 18. smeets hm, kuyvenhoven mm, akkerman ae, welschen i, schouten gp, van essen ga, et al. intervention with educational outreach at large scale to reduce antibiotics for respiratory tract infections: a controlled before and after study. fam pract 2009; 26:183–7. 19. hungin ap, kean wf. nonsteroidal antiinflammatory drugs: overused or underused in non-steroidal anti-inflammatory drugs and antibiotics prescription trends at a central west bank hospital 573 | squ medical journal, november 2013, volume 13, issue 4 osteoarthritis? am j med 2001; 110:8s–11s. 20. rainsford kd. ibuprofen: pharmacology, efficacy and safety. inflammopharmacology 2009; 17:275–342. 21. mijatovic v, calasan j, horvat o, sabo a, tomic z, radulovic v. consumption of non-steroidal antiinflammatory drugs in serbia: a comparison with croatia and denmark during 2005–2008. eur j clin pharmacol 2011; 67:203–7. 22. vlahovic-palcevski v, wettermark b, bergman u. quality of non-steroidal anti-inflammatory drug prescribing in croatia (rijeka) and sweden (stockholm). eur j clin pharmacol 2002; 58:209–14. 23. barozzi n, sketris i, cooke c, tett s. comparison of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 (cox-2) inhibitors use in australia and nova scotia (canada). br j clin pharmacol 2009; 68:106–15. 24. irshaid ym, al-homrany ma, hamdi aa. a pharmacoepidemiological study of prescription pattern for upper respiratory infections in a tertiary health care center. saudi med j 2005; 26:1649–51. 25. adams rj, appleton sl, gill tk, taylor aw, wilson dh, hill cl. cause for concern in the use of nonsteroidal anti-inflammatory medications in the community—a population-based study. bmc fam pract 2011; 12:70. taurine levels in human aqueous humour medical sciences (2000), 2, 37−41 © 2000 sultan qaboos university 1department of physiology, sultan qaboos university, p.o.box: 38, postal code: 123, muscat, sultanate of oman; 2department of orthopaedic surgery, khaula hospital, ministry of health, sultanate of oman. *to whom correspondence should be addressed. 37 physical fitness and fatness among omani schoolboys: a pilot study *hassan m o,1 al-kharusy w2 مستوى اللياقة البدنية والبدانة في شريحة دراسة مبدئية: من الطالب العمانيين الخروصي. حسن ، و. م وقد . عينات من الجلد من أماآن محددة من الجسم 5 آم ومجموع سمك 1.6بدنية وهما الزمن للعدو أو المشي لمسافة يعتمد هذا البحث المبدئي على مقياسين للياقة ال : الملخص لد، آما وجد أن هناك عالقة قوية وموجبة بين زمن العدو ومجموع سمك عينات الج . ن بعدة عوامل شخصية وعائلية ذات عالقة باللياقة البدنية والبدانة ين المقياس يتمت مقارنة هذ أما العوامل األخرى مثل نسبة محيط . آان لممارسة الوالدين وخصوصا األب للرياضة عالقة قوية بلياقة األبن، وآانت لبدانة الوالدين وخصوصا األم عالقة عكسية بلياقة األبن ت التي يقضيها الطفل في مشاهدة التلفاز فلم تظهر هذه العوامل تأثيرا واضحا الخصر الى األرداف وعدد األشقاء وعدد األشقاء الذين ينامون في غرفة واحدة وعدد الخدم والساعا على قياسات اللياقة المستخدمة في هذا البحث وقد خلصت هذه الدراسة الى أن مثل هذا البحث الميداني البسيط يمكن أن يأتي بمعلومات قيمة عن اللياقة البدنية ويمكن تطبيقه على .ماننطاق واسع في سلطنة ع abstract: ��������� to study the applicability of simple field measurements of physical fitness in a sample of omani boys and their relationships to selected variables. ���� � two field measures of physical fitness—the time to complete 1.6–km run/walk and the sum of 5 skinfold thicknesses—were correlated with personal and family physical activity–related and other variables in a sample of 109 omani boys aged 9–11 years. ������� obesity in parents, especially in the mother, showed significant correlation with both fitness measures. the waist/buttocks ratio showed no significant correlation with the 1.6–km time. the number of siblings and siblings sharing a room, number of t.v–watching hours and the number of servants in the family showed no correlation with the chosen fitness indices. � ������ � the results of this pilot study indicate that simple field fitness tests can be used in children and they can yield valuable information related to physical fitness. the same protocol used in this study could be applied to a national study in oman. key words: fitness, obesity, anthropometry, questionnaire, exercise, cardiorespiratory endurance, oman hysical fitness, essential for a state of general well being, is an important component of health and health education. precise and reliable measures of physical fitness are of great value to educators and policy makers by providing an essential basis for evolving any programme or policy aimed at improving individual or general levels of fitness.1 one of the criteria of positive health is functional capacity. an important aspect of functional capacity is aerobic capacity (the body’s ability to do heavy, sustained work), which is dependent on the ability of cardiovascular system to deliver blood to working muscles and the capability of the cells to take up and utilize this oxygen in energy production. aerobic capacity is measured by determining the body’s maximal rate of oxygen (o2) consumption. maximal oxygen uptake (vo2max) is the most important indicator of physiological fitness, and is positively correlated with cardiovascular health.2,3 studies in developed countries4,5 tend to show that by improving the levels of physical fitness, the risk of ill health (particularly of cardiovascular disease) could be reduced. however, in developing countries few such studies have been done.6 studies show that obesity is increasing at an alarming rate in arab countries.7,8 although a large number of arab studies have focused on obesity and its associated risk factors,7-10 physical activity and fitness in children and adults have received no attention. the purpose of this pilot project was to study applicability of simple field measurements in a sample of omani boys and their relationships to selected p 37 h a s s a n e t a l 38 variables. the sample was randomly selected from grade 3 and 4 schoolboys attending annual sports summer camp in the muscat area. methods the study used simple field measures of physical fitness and a questionnaire to elicit the required data, which were then statistically analysed. fitness the main fitness measures used in this study were cardiorespiratory endurance, fatness and fat distribution. cardio respiratory endurance this was measured using the time to complete a 1.6 km run/walk. concurrent validity of distance-run tests with directly measured maximal aerobic power (vo2max) has been previously established.11-13 for administration of the 1.6 km run/walk tests, children were organized into 5 groups of two, each with one observer. they ran as far as possible and then walked to complete the 1.6 km distance on a level 400 m circuit. the time to completion was measured to the nearest second. fatness and fat distribution the body mass index (bmi) was measured by dividing the weight in kilograms by the square of the height in meters. skinfolds were measured independently by two matched observers using holden calipers on the right side of the body at five sites: triceps, subscapular, suprailiac, abdominal and thigh. each site was measured twice. if the two values differed by more than 2 mm, a third was taken. the mean of the two closest measures was used as the score. the scores for the five sites were summed to provide a single value for fatness. waist and buttocks were measured to the nearest centimeter over light clothing using a tape measure. the waist was measured half way between the lower coastal margin and the iliac crest, and buttocks circumference was measured over the widest part of the gluteal region.14 the sum of the suprailiac and abdominal skinfolds as well waist /buttock ratios were used as the index of central fatness while the other three skinfolds were used for peripheral fatness. the questionnaire this was a combined simple student and parent questionnaire on obesity, leisure time sports activities as well as some socio-economic markers. parents’ exercise level was measured by number of times per week they spent in any kind of sport: the minimum acceptable was walking for at least 40 minutes twice weekly. parents recorded the extent of their own obesity as perceived by them or as told to them by their doctors. parents also scored the number of hours per day their child spent watching tv and/or playing video or computer games. children recorded their own leisure time activities, number of their siblings, siblings sharing room, and the number of servants in the house. the personal and parental exercise scores were summed as hours per week. statistical analyses all statistical analyses done using the spss package (version 7 for windows). pearson correlation coefficients were computed between the log of the time to complete the 1.6 km run/walk, the log of the sum of 5 skinfolds as the dependent variables and the other independent variables of the study. log transformations were performed since the two fitness variables were found to be positively skewed. the z test was used to compare differences between the means of other studies. results ninety six percent of the questionnaires were completed, demonstrating the simplicity of its layout as well as the interest of the parents in the physical fitness of their children. table 1 shows the personal and parental variables used in the study. the personal variables are: age, the time to complete the 1.6 km run/walk, bmi and fat distribution, leisure time activities and certain socioeconomic factors. the parental ones are the exercise habits of the father and mother as well as presence of obesity in the family. only 68% of the children were able to run the entire distance of 1.6 km; the rest completed part of the distance running and then walking. the mean time of 11.53 minutes achieved by the omani children was approximately 1 minute longer than the mean of 10.56 minutes by american children of the same age group. applying the z test, this difference was found to be significant (p< 0.05), although the bmi and skinfolds thickness were similar in both groups.1 it was seen that 32.5% of the fathers and 8% of the mothers exercised at least twice weekly, mostly by walking (mean time was 0.82 and 0.2 hours per week respectively). parents estimated the mean time spent by children on watching television or playing computer/video games as 3.2 hours per day.15,16 the number of siblings, siblings sharing a room and the number of servants in the each family were included in the expectation that these would give indications of the socio-economic status of the family. parents reported their perception of obesity in the family as 21% in mothers, 11% in fathers and 8% in f i t n e s s a n d f a t n e s s a m o n g o m a n i b o y s siblings. table 2 shows the transformations of the run/walk and the sum relation to the 15 variab negative correlation in r shorter running time a skinfolds) in relation to better fitness such as pe a strong negative corre sum of skinfolds (r = p<0.001 respectively). similarly, the parents’ exercise score, especially that of the father (r = –0.29 p< 0.01, r = –0.26, p< 0.01 respectively) has a strong influence on the child’s performance and leanness. on the other hand, obesity of parents and specially that of the mother shows a positive correlation and a significant increase in time and sum of skinfolds (r = 0.27, p< 0.01, r = 0.39, p< 0.01 respectively). central fat and peripheral fat show strong positive correlation with time (r = 0.38, p< 0.001, r =0.37, p< 0.001) while waist/buttock ratio is not significant but correlates significantly with the sum of skinfolds (r = 0.39, p< 0.01), as expected. central fat and peripheral fat have the same significant positive correlation with time (r = 0.38, p< 0.001, r = 0.37 p< 0.001 respectively). however, the number of siblings and siblings sharing a room, the number of servants and tv watching hours have no influence on the child’s fitness or fatness in this sample. discussion the declining levels of average physical activity and exertion in the daily life of most children mean that sport and physical education are often the only forms of exercise which they have, and obese children tend to become obese adults.17 measuring fitness and providing information and encouragement on how fitness may be improved can promote the use of available sports and recreation facilities provided by most schools, sports clubs and private fitness clubs. this will help to enrich the lives and well being of citizens and reduce their medical bills.18 in most arab countries physical fitness receives little attention from authorities and families alike. when recent affluence with its non-energy requiring daily lifestyle is added the result is an alarming increase in obesity and its associated diseases in children and adults.19 the worst affected is the female gender in whom arab culture still plays a role in promoting and praising a sedentary way of life and obesity.8 although this pilot study descriptive data of person participant variable fitness and fatness age 1.6 km run/walk (min) body mass index (kg/m sum of 5 skin folds (mm sum central (mm) (sub suprailiac + abdomen) sum peripheral (mm) ( triceps) waist/ buttock ratio leisure time activities personal activity score week) father exercise (hours mother exercise (hours television/ video game estimated, hour/day) socio-economic indicato number of siblings siblings sharing room number of servants table 1 al and parental variables of the 109 s ( for details see text ) mean ±s.d 9.68 0.92 11.53 4.3 2 ) 18.9 2.4 ) 62.5 17.0 scapular + 36.9 15.6 thigh + 29.2 14.5 0.91 0.04 (hours per 6.8 3.9 per week) 0.82 1.2 per week) 0.2 0.17 s (parents 3.2 1.5 rs 6.1 2.9 3.2 2.0 1.4 1.0 39 two fitness measures; the log time to complete the 1.6 km of 5 skinfolds and their corles used in the pilot project. a elation to a variable indicates a nd/or less body fat (sum of that variable. this signifies a rsonal activity score, which has lation with both time and the –0.40, p<0.001, r = –0.42, represents a small age band in the male gender, does not represent all oman and may be biased towards children who like sport and whose parents may be supportive of sport, it has provided valuable data for our national study protocol. firstly the study was easy to conduct, required inexpensive equipment and cost very little. as only 68% of the boys were able to complete the 1.6 km running, it may be supposed that few of the girls would be able to complete that distance running. this will necessitate study of a random sample of girls of the same age group using the same protocol. the run/walk distance of the national study will be determined by average time h a s s a n e t a l achieved by the girls. central fat, peripheral fat an bmi have the same correlation with the 1.6 km tim this will allow us to consider bmi, peripheral fat an waist/buttock ratio for the national study becau central fat measurements may be difficult to obtain females. the time spent on watching tv and/or playin computer games was slightly less than their america counterparts.15 although the number of sibling siblings sharing a room, the number of servants an t.v watching hours, did not have significant influen on the child’s fitness or fatness in this sample, the may show some effect on a larger sample especia after applying more advanced statistical methods suc as stepwise multiple regression analysis.14 pearson’s correlation coefficients of log time and the study’s 15 variable variables c co 1 body mass index (bmi) 2 central fat 3 peripheral fat 4 waist/buttock ratio 5 personal activity score 6 father exercise score 7 mother exercise score 8 father & mother exercise score 9 father obese 10 mother obese 11 sibling (s) obese 12 no. of siblings 13 no. of siblings sharing room 14 t.v hours 15 no. of servants n = 109 ns = not significant table 2 to complete 1.6 km run/walk, log sum of 5 skinfolds s among omani boys aged 9–11 years log time log sum of skinfolds orrelation efficient(r) p value correlation coefficient(r) p value 0.69 0.0001 0.88 0.0001 0.38 0.001 0.87 0.0001 0.37 0.001 0.86 0.0001 0.17 ns 0.39 0.01 –0.40 0.001 –0.42 0.001 –0.29 0.01 –0.25 0.01 –0.10 ns –0.09 ns –0.34 0.01 –0.24 0.05 0.24 0.05 0.29 0.05 0.27 0.01 0.39 0.01 0.31 0.05 0.41 0.01 0.11 ns –0.14 ns 0.09 ns 0.10 ns 0.11 ns 0.08 ns 0.12 ns 0.09 ns 40 d e. d se in g n s, d ce se lly h the questionnaire, though not validated in this pilot study, proved to be simple to administer to both children and parents as shown by the high response rates. we would like to point out that the information obtained using a questionnaire in this study should be interpreted with care. a direct interview of parents would have yielded more reliable information but this was technically difficult in the conditions of this pilot study. in conclusion, these preliminary results show that fitness in youth can be studied using simple field tests, and suggest that personal and parental factors are the main contributors to fitness levels in children. f i t n e s s a n d f a t n e s s a m o n g o m a n i b o y s 41 references 1. european tests of physical fitness 2nd edition, 1993, 12–13. 2. pate rr, dowda m, ross jg. associations between physical activity and physical fitness in american children. am j dis child, 1990, 144, 1123–9 3. shephard rj, allen c, benade aj, davies ct, di prampero pe, hedman r, merriman je, myhre k, simmons r. the maximal oxygen intake. an international reference standard of cardiorespiratory fitness. bull world health organ 1968, 38, 757–64. 4. feinleib m. epidemiology of obesity in relation to health hazards. ann intern med 1985, 103, 1019–24. 5. gunnell dj, frankel sj, nanchahal k, peters tj, smith gd. childhood obesity and adult cardiovascular mortality: a 57-y follow-up study based on the boyd orr cohort, am j clin nutr 1998, 67, 1111–8. 6. chu nf, rimm be, wang dj, liou hs, sheih sm. clustering of cardiovascular disease risk factors among obese schoolchildren: the taipei children heart study. am j clin nutr 1998, 67, 1141–6. 7. al-nuaim ar, al-rubeaan k, al mazrou y, alattas o, al-daghari n, khoja t. high prevalence of overweight and obesity in saudi arabia. int j obes relat metab disord 1996, 6, 547–52. 8. al-shammari sa, khoja ta, al-maatoug ma, alnuaim la. high prevalence of clinical obesity among saudi females: a prospective, cross-sectional study in the riyadh region. j trop med hyg 1997, 183–8. 9. moussa ma, shaltout aa, nkansa-dwamena d, mourad m, alsheikh n, agha n, galal do. factors associated with obesity in kuwaiti children. eur j epidemiol 1999, 15(1), 41–9. 10. musaiger ao, al-roomi ka. prevalence of risk factors for cardiovascular disease among men and women in an arab gulf community. nutr health 1997, 11, 149–57. 11. jackson as, coleman ae. validation of distance run tests for elementary school children. res quart 1976, 47, 86–94. 12. safrit j. the validity and reliability of fitness tests of children: a review. pediatr exerc sci 1990, 2, 9–28. 13. sloniger ma, cureton kj, o’bannon pj. one-mile run-walk performance in young men and women: role of anaerobic metabolism. can j appl physiol 1997, 22, 337– 50. 14. gutin b, basch c, shea s, contento i et al. blood pressure, fitness and fatness in 5 and 6 year old children. jama 1990, 264, 1123–27. 15. armstrong ca, sallis jf, alcaraz je, kolody b, mckenzie tl, hovell mf. children’s television viewing, body fat and physical fitness. am j health promot 1998 12, 363–8. 16. katzmarzyk pt, malina rm, song tm, bouchard c. television viewing, physical activity and health-related fitness of youth in the quebec family study. j adolesc health 1998, 23, 318–25. 17. whitaker rc, wright ja, pepe ms, seidel kd, dietz wh. predicting obesity in young adulthood from childhood and parental obesity. n eng j med 1997, 25, 869–73. 18. wolf am, colditz ga. current estimates of the economic cost of obesity in the united states. obes res 1998, 6, 97–106. 19. al nuaim aa, bamgboye ea, al rubeaan ka, al mazrou y. overweight and obesity in saudi arabian adult population, role of socio-demographic variables. j community health 1997, 22, 211–23. physical fitness and fatness among �omani schoolboys: a pilot study intro methods fitness cardio respiratory endurance fatness and fat distribution the questionnaire statistical analyses results discussion references in general, the popularity of the anatomical sciences has lessened over recent years, as testified by the decreased amount of funding allocated to anatomical research.1 this may have negative repercussions in terms of recruiting omani students who aspire to be anatomists. a common fallacy in the scientific academic sphere is that anatomy is outdated and irrelevant. new discoveries in this discipline are thought to be limited as exhaustive investigative and descriptive research has been published over many centuries and a huge body of literature is available on all aspects of anatomy.2 nevertheless, although researchers differ in their investigative works and techniques, anatomical variations—defined as peculiarities, irregularities or abnormalities in structural morphology or a marked deviation from the average or norm—continue to offer new discoveries and opportunities for extended work in various fields.3 by dissecting cadavers and analysing x-rays, angiograms and imaging scans, anatomical research can be inexpensive and requires only sharp observational skills.2,3 there are four clinically significant types of anatomical anomalies: malformations, disruptions, deformations and dysplasias.4 anomalies are increasingly reported in the medical literature, as exemplified by a series of case reports and interesting medical images featured in the august 2016, november 2016 and february 2017 issues of squmj.5–9 this in turn suggests that there are still many discoveries to make in the field of anatomy. while such anomalies are rare, their recognition has important implications for diagnosis and treatment. although case reports are sometimes dismissed as being the least valuable form of research publication, a rare case might represent an interesting phenomenon.10 moreover, it is critical that potential morphological and structural variations be taken into consideration in everyday surgical practice as a lack of awareness could lead to fatal consequences. murugan et al. reported an anomalous sternothyroid muscle characterised by a lateral belly which passed between the internal jugular vein and internal carotid artery and between the glossopharyngeal and hypoglossal nerves to the site of insertion.5 in this case, ossified tissue had also bridged over the right sigmoid sulcus, thus compressing the sigmoid sinus.5 this anomalous belly could potentially lead to the development of collet-sicard syndrome secondary to internal jugular vein thrombosis, unilateral palsy of the involved nerves or idiopathic epileptic seizures due to impaired cerebral venous drainage into the internal jugular vein.11 another report of an anomalous anatomical variation described an additional accessory duct of the right submandibular gland; the anomalous duct drained into the floor of the mouth, while the main duct followed the normal anatomical pathway and drained at the top of the papilla.6 recognising the presence of an anomalous duct is important in diagnosing and treating diseases of the salivary gland and to avoid iatrogenic injuries to these ducts during surgery.12 bhat et al. reported a case whereby the flexor carpi radialis muscle originated from a lateral slip of bicipital aponeurosis and the median cubital vein was located deep to the two slips of the aponeurosis.7 this vein is commonly accessed for medical procedures ranging from simple venepuncture for routine blood collection to the formation of arteriovenous fistulae and the insertion of cardiac catheters; as such, a median cubital vein located deep to the aponeurosis can pose difficulties for practitioners who wish to access this vein.13 raza et al. reported a case in which the musculocutaneous nerve was found to be absent during a routine dissection session.8 the median nerve innervated all of the flexor muscles of the forearm, except for the coracobrachialis muscle, and branched into the lateral cutaneous nerve of the left forearm. the coracobrachialis muscle was innervated department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: habbal@squ.edu.om حبوث علم التشريح املفاهيم اخلاطئة و الفرص املتاحة عمر الحبال comment anatomical research misconceptions and opportunities omar habbal sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e1–2, epub. 30 mar 17 submitted 22 jan 16 revision req. 5 feb 16; revision recd. 23 feb 16 accepted 26 feb 16 doi: 10.18295/squmj.2016.17.01.001 anatomical research misconceptions and opportunities e2 | squ medical journal, february 2017, volume 17, issue 1 by a branch of the lateral root of the median nerve.8 such anatomical variations may present atypically in patients who suffer from paralysis after trauma to the median nerve and pose a challenge when regional anaesthesia is required.14 deshmukh et al. reported another anatomical anomaly in that the obturator artery originated from the superior gluteal artery in a female cadaver.9 according to a study conducted by rajive et al., this anomaly was observed in 2% out of 50 cadavers.15 however, in the same case reported by deshmukh et al., the left obturator vein crossed the pelvic brim and drained into the external iliac vein.9 this variation has important implications during open and laparoscopic surgeries involving the pelvis, such as hernia repairs and gluteal muscle grafts in females undergoing breast augmentation.16,17 in human morphology, we often observe anatomical and functional modifications or variations. indeed, certain structures have lost their original function but are still useful for other purposes, such as with the occipitofrontalis muscle in lower primates, which once served to keep the head lifted up but is now used for facial expressions.18 humans also exhibit various vestigial behaviours and reflexes. the formation of cutis anserina (i.e. goose bumps) under stress is an example of a vestigial reflex in humans; for lower primates, its function was probably to raise the body’s hair to appear larger and scare off predators. another example of a vestigial reflex is that infants will instinctively grasp any object which touches their palm, in some cases strongly enough to support their own weight.18 such observations and findings can be explored and researched in areas of comparative and developmental anatomy. in conclusion, anatomical research is still very much alive and relevant. there are many aspects of anatomy that may provide good topics for research, such as osteology, morphometry, histology, staining techniques and neuroanatomy. in particular, embryology is a field in which further exploration is much needed. successful outcomes in clinical practice are dependent on discoveries in basic medical sciences, such as in the case of anatomical variations. deviations from normal anatomy can, at times, be critical to surgeons when operating on patients. such data are worth researching and publishing to enrich the existing medical literature. references 1. mcdaniel a, fullen dr, cho kr, lucas dr, giordano tj, greenson j, et al. funding anatomic pathology research: a retrospective analysis of an intramural funding mechanism. arch pathol lab med 2013; 137:1270–3. doi: 10.5858/arpa. 2012-0546-oa. 2. bardeen cr. the teaching of anatomy and the inculcation of scientific methods and interest: the value of the roentgenray and the living model in teaching and research in human anatomy. anat rec 1918; 14:337–40. doi: 10.1002/ar.1090140602. 3. sañudo jr, vázquez r, puerta j. meaning and clinical interest of the anatomical variations in the 21st century. eur j anat 2003; 7:1–3. 4. farlex partner medical dictionary. anomaly. from: www. medical-dictionary.thefreedictionary.com/anomaly accessed: feb 2017. 5. murugan ms, sudha r, bhargavan r. clinical significance of an unusual variation: anomalous additional belly of the sternothyroid muscle. sultan qaboos univ med j 2016; 16:e491–4. doi: 10.18295/squmj.2016.16.04.015. 6. billakanti pb. accessory duct of the submandibular gland. sultan qaboos univ med j 2017; 17:e119–20. doi: 10.18295/ squmj.2016.17.01.023. 7. bhat n, bhat km, d’souza as, kotian sr. additional muscle slip of bicipital aponeurosis and its anomalous relationship with the median cubital vein. sultan qaboos univ med j 2017; 17:e103–5. doi: 10.18295/squmj.2016.17.01.018. 8. raza k, singh s, rani n, mishra r, metha k, kaler s. anomalous innervation of the median nerve in the arm in the absence of the musculocutaneous nerve. sultan qaboos univ med j 2017; 17:e106–8. doi: 10.18295/squmj.2016.17.01.019. 9. deshmukh v, singh s, sirohi n, baruhee d. variation in the obturator vasculature during routine anatomy dissection of a cadaver. sultan qaboos univ med j 2016; 16:e356–8. doi: 10.18295/squmj.2016.16.03.016. 10. carey jc. the importance of case reports in advancing scientific knowledge of rare diseases. adv exp med biol 2010; 686:77–86. doi: 10.1007/978-90-481-9485-8_5. 11. neo s, lee ke. collet-sicard syndrome: a rare but important presentation of internal jugular vein thrombosis. pract neurol 2017; 17:63–5. doi: 10.1136/practneurol-2015-001268. 12. pownell ph, brown oe, pransky sm, manning sc. congenital abnormalities of the submandibular duct. int j pediatr otorhinolaryngol 1992; 24:161–9. 13. chevuturu c, somasekhar m, maitra s, agarwala mk. prophylactic ligation of the median cubital vein to improve the patency of a radio cephalic fistula. adv surg sci 2016; 4:1–5. doi: 10.11648/j.ass.20160401.11. 14. neal s, fields kb. peripheral nerve entrapment and injury in the upper extremity. am fam physician 2010; 81:147–55. 15. rajive av, pillay m. a study of variations in the origin of obturator artery and its clinical significance. j clin diagn res 2015; 9:ac12–15. doi: 10.7860/jcdr/2015/14453.6387. 16. tajra jb, lima cf, pires fr, sales l, junqueira d, mauro e. variability of the obturator artery with its surgical implications. j morphol sci 2016; 33:96–8. doi: 10.4322/jms.090015. 17. mu lh, yan yp, luan j, fan f, li sk. [anatomy study of superior and inferior gluteal artery perforator flap]. zhonghua zheng xing wai ke za zhi 2005; 21:278–80. 18. muller gb. vestigial organs and structures. in: pagel m, ed. encyclopedia of evolution, 1st ed. new york, usa: oxford university press, 2002. pp. 1131–3. https://doi.org/10.5858/arpa.2012-0546-oa https://doi.org/10.5858/arpa.2012-0546-oa https://doi.org/10.1002/ar.1090140602 https://doi.org/10.18295/squmj.2016.16.04.015 https://doi.org/10.18295/squmj.2016.17.01.023 https://doi.org/10.18295/squmj.2016.17.01.023 https://doi.org/10.18295/squmj.2016.17.01.018 https://doi.org/10.18295/squmj.2016.17.01.019 https://doi.org/10.18295/squmj.2016.16.03.016 https://doi.org/10.1007/978-90-481-9485-8_5 https://doi.org/10.1136/practneurol-2015-001268 https://doi.org/10.11648/j.ass.20160401.11 https://doi.org/10.7860/jcdr/2015/14453.6387 https://doi.org/10.4322/jms.090015 sultan qaboos university med j, august 2014, vol. 14 iss. 3, p. e416, epub. 24th jul 14 submitted 24th mar 14 accepted 24th apr 14 رد: حالة معقدة اللتهاب جرثومي حتت احلاد للشغاف املبطن للقلب لطفلة لديها فتحة قلبية باحلجاب احلاجز البطيين re: complicated subacute bacterial endocarditis in a patient with ventricular septal defect letter to editor sir, i have two comments on the interesting case report published in the february 2014 issue of the sultan qaboos university medical journal (squmj) by al-senaidi et al.1 first, echocardiography (echo) is included in the diagnostic algorithm of infective endocarditis (ie). in their case report, al-senaidi et al. noted that the echo showed a 4 mm perimembranous ventricular septal defect with a leftto-right shunt and a peak gradient of 85 mmhg. there were also two vegetations attached to the tricuspid valve with moderate regurgitation and no stenosis. the large vegetation measured 8 x 6 mm and the smaller one, 6 x 4 mm. during the patient’s clinical course, the large vegetation was dislodged and caused a pulmonary embolism.1 this embolic event is quite interesting, as anecdotal studies have shown that a mobile vegetation, or vegetations that are >10 mm in length, are significantly associated with embolic phenomena.2,3 i presume that the evolution of the patient’s pulmonary embolism, with a vegetation of less than 10 mm, could be explained by the observation that the different antibiotics used in the treatment of the ie had different effects on the size of the vegetation,4 and hence, the risk of vegetation dislodgement. the studied patient was started on intravenous antibiotics: ampicillin (50 mg/kg, six-hourly), vancomycin (15 mg/kg, eight-hourly) and gentamicin (2.5 mg/kg, eight hourly). in an interesting german study, the effect of different antibiotic regimes on vegetation size was evaluated by transoesophageal echo in 183 patients with ie.4 significant differences in vegetation size were noted with different kinds of antibiotics: treatment with vancomycin showed a 45% reduction; ampicillin a 19% reduction; penicillin a 5% reduction; penicillase-resistant drugs a 15% increase, and cephalosporin a 40% increase.4 penicillin, cephalosporin and penicillase-resistant drugs were associated with an increased embolic risk, while vancomycin was associated with the formation of abscesses and cephalosporin with increased mortality.4 the authors observed that “plotting changes in vegetation size against the incidence of embolism and mortality, linear regression analysis suggested a 40–50% reduction in vegetation size, thereby greatly reducing the risk of embolism and mortality”.4 i presume that both clinicians and echocardiographers should not only consider discernible vegetations as the sole diagnostic parameter for ie, but also the size and mobility of the vegetations. this would be helpful in the prediction of a patient’s pulmonary and systemic embolic risk. in addition, it may encourage the need to adopt a more aggressive antibiotic therapy and to perform an early surgery, if necessary. second, i do agree with al-senaidi et al.’s recommendation that clinicians should have a high index of suspicion for ie as the possible cause of prolonged fever, especially in the presence of congenital heart disease (chd).1 moreover, al-senaidi et al.’s case report could be added to the available literature on ie,1 as ie forming as a late presentation of chd has rarely been reported.5 mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al-senaidi ks, abdelmogheth aa, balkhair aa. complicated subacute bacterial endocarditis in a patient with ventricular septal defect. sultan qaboos univ med j 2014; 14:e130–3. 2. macarie c, iliuta l, savulescu c, moldovan h, gherghiceanu dp, vasile r, et al. echocardiographic predictors of embolic events in infective endocarditis. kardiol pol 2004; 60:535–40. 3. hill ee, herijgers p, claus p, vanderschueren s, peetermans we, herregods mc. clinical and echocardiographic risk factors for embolism and mortality in infective endocarditis. eur j clin microbiol infect dis 2008; 27:1159–64. doi: 10.1007/s10096-008-0572-9. 4. rohmann s, erhel r, darius h, makowski t, meyer j. effect of antibiotic treatment on vegetation size and complication rate in infective endocarditis. clin cardiol 1997; 20:132–40. doi: 10.1002/clc.4960200210. 5. vaz silva p, castro marinho j, martins p, santos i, pires a, sousa g, et al. [infective endocarditis as a form of late presentation of congenital heart disease.] rev port cardiol 2013; 32:145–8. doi: 10.1016/j.repc.2012.05.023. e416 | squ medical journal, august 2014, volume 14, issue 3 endoscopic third ventriculostomy (etv) has been associated with a higher failure rate during infancy.1–3 however, more recent reports have shown encouraging results and it is increasingly being considered an effective alternative to a ventriculoperitoneal shunt or even the procedure of choice.4–6 although it is a safe procedure, etv has several known complications including infection.7,8 fungal granulomas have not been reported so far to the best of our knowledge. case report a 3-month-old child was born at 32 weeks’ gestation, as one of triplets, with a birth weight of 1.75 kg and was treated at another hospital for neonatal sepsis and respiratory distress syndrome. there was no documented evidence of meningitis or intraventricular bleeding during this period. the child was referred to amrita institute of medical sciences, cochin, india, with a history of increasing head size, vomiting, and downward eye gaze over the previous month. at admission, the child was active and alert with a head circumference above the 96th percentile for age, tense fontanelles, sutural diastasis, and a positive “sunset” sign. a computed tomography (ct) scan of the brain which accompanied the child’s referral, showed triventriculomegaly [figure 1]. a magnetic resonance imaging (mri) scan had not been done due to financial constraints. after discussing the various surgical options, it was decided to perform an etv. the procedure was uneventful with the intraoperative findings of clear cerebrospinal fluid (csf) under pressure and a thin floor which was pulsating well after the procedure [figure 2]. the csf studies, including cell count, biochemistry, and cultures were normal. the child did well over the following 6 months with resolution of the symptoms of raised pressure and the head circumference in the normal range. seven months after the procedure, the child presented again with vomiting, irritability, and a downward gaze which had lasted two weeks. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 162-164, epub. 27th feb 13 submitted 20th mar 12 revision req. 13th jun 12, revision recd. 19th jun 12 accepted 8th sep 12 1department of surgery, sultan qaboos university hospital, muscat, oman; 2amrita institute of medical sciences, kochi, kerala, india *corresponding author e-mail: rajeevkariyattil@gmail.com الورم الفطري احلبييب بعد عملية التجويف الثالث باملنظار الستسقاء الرأس يف الرضع راجيف كاريتيل، ديليب بانيكار امللخ�ص: ا�صتخدام املناظري لعالج ا�صت�صقاء الراأ�ض يف �صن الطفولة يف تزايد م�صتمر. امل�صاعفات املعدية نادرا ما حتدث، ولكن العدوى الفطرية اأو الأورام احلبيبية مل يتم ذكرها حتى الآن. املوؤلفون يعر�صون حالة حدوث الورم احلبيبي الفطري بامل�صادفة بعد اإعادة الك�صف باملنظار بعد ف�صل عملية التجويف الثالث الأويل وطرق التعامل معها. مفتاح الكلمات: منظار الأع�صاب، امل�صاعفات، العدوى الفطرية، فطور، الهند. abstract: endoscopic third ventriculostomy (etv) is increasingly being used in the treatment of hydrocephalus in infancy. infective complications rarely occur following etv and fungal infections or granulomas have not been reported so far. the authors report the occurrence and management of a fungal granuloma incidentally detected during a repeat ventriculoscopy for a non-functioning etv. keywords: neuroendoscopy; complication; fungal infection; candida; case report; india. fungal granuloma following endoscopic third ventriculostomy for infantile hydrocephalus *rajeev kariyattil1 and dilip panikar2 case report rajeev kariyattil and dilip panikar case report | 163 a repeat ct brain scan showed significant triventriculomegaly but lesser in size than in the previous scan. as the child had done well with the previous etv, it was decided to do a repeat ventriculoscopy. during surgery, it was found that the third ventricular floor was opaque and the stoma was not visualised. a small white nodule was seen loosely adherent to the floor just posterior to the mamillary bodies [figure 3]. it was presumed to be a foreign body granuloma and was easily removed. a fresh stoma was made in the floor but since the floor pulsations were unsatisfactory, it was decided to go ahead with a ventriculoperitoneal shunt insertion. the child improved immediately. a biopsy of the nodule revealed a fungal granuloma, most probably candida. the csf sent for testing during the procedure was normal and did not grow any organism. although there was no evidence of fungal infection clinically or from the csf laboratory values, it was decided, in view of a shunt hardware being present, and with the concurrence of the paediatricians, to give a course of intravenous amphotericin, which the child tolerated well. the child was doing well at a 24-month followup visit, with normal ventricles on a ct brain scan. discussion this child was born prematurely with related problems including sepsis, but there was no documented evidence of fungal meningitis which has been reported previously in this setting.9 there was no other evidence of hydrocephalus being present antenatally or during the immediate post-natal period. the child had presented with a triventriculomegaly at a corrected age of one month and it was decided to perform an etv based on the ct scan findings. recent reports have shown good outcomes with etv in early infancy.5,6 the child was clinically well over the following 6 months. no imaging was done in the follow-up period due to financial constraints. when there was a recurrence of hydrocephalus, it was decided to have a repeat ventriculoscopy as the procedure had been effective for more than 6 months. failure of etv commonly presents during the first 2 to 4 months.1,3 the conversion to a ventriculoperitoneal shunt during the second surgery was based on the unsatisfactory stoma achieved. the white nodule was presumed to be a foreign body granuloma during the surgery. no infective process was suspected and hence no specimen was taken for culture, and a shunt hardware was inserted. although there was no evidence of active infection figure 1: initial computed tomography scan showing triventriculomegaly. figure 3: endoscopic view at second surgery showing white nodule. figure 2: endoscopic view during the first surgery showing the stenosed aqueduct, the third ventricle floor, and the interpeduncular cistern after endoscopic third ventriculostomy. fungal granuloma following endoscopic third ventriculostomy for infantile hydrocephalus 164 | squ medical journal, february 2013, volume 13, issue 1 clinically or in the csf, it was decided to give antifungal treatment due to the presence of shunt hardware. candidal infections have been reported to be more commonly associated with the presence of a foreign body like a shunt or an external csf drain.10,11 however, conservative management without anti-fungal therapy has also been successful in the absence of clinical features or csf findings, but require close monitoring of the lumbar csf.11 the fungal granuloma in this patient could possibly be attributed to contamination during the earlier etv. irrigation fluid is a possible source, especially when multiple bottles are changed or when air-vents are inserted. aggressive treatment is warranted in such a situation due to the possibility of colonisation of the shunt hardware or even a catastrophic fungal meningitis.11 conclusion fungal granuloma, even an asymptomatic one, is a hitherto unreported complication of an etv procedure. the maintenance of sterile precautions cannot be over-emphasised. the detection of fungus in the ventricular system, even in asymptomatic situations, needs to be aggressively treated, especially in the presence of shunt hardware. a c k n o w l e d g e m e n t s the authors thank dr. seethalekshmi n.v., clinical professor, amrita institute of medical sciences, cochin, india, for the photomicrographs. references 1. baldauf j, oertel j, gaab mr, schroeder hw. endoscopic third ventriculostomy in children younger than 2 years of age. childs nerv syst 2007; 23:623–6. 2. navarro r, gil-parra r, reitman aj, olavarria g, grant ja, tomita t. endoscopic third ventriculostomy in children: early and late complications and their avoidance. childs nerv syst 2006; 22:506–13. 3. koch-wiewrodt d, wagner w. success and failure of endoscopic third ventriculostomy in young infants: are there different age distributions? childs nerv syst 2006; 22:1537– 41. 4. fritsch mj, kienke s, ankermann t, padoin m, mehdorn hm. endoscopic third ventriculostomy in infants. j neurosurg 2005; 103:50–3. 5. sufianov aa, sufianova gz, iakimov ia. endoscopic third ventriculostomy in patients younger than 2 years: outcome analysis of 41 hydrocephalus cases. j neurosurg pediatr 2010; 5:392–401. 6. lipina r, reguli s, dolezilova v, kuncikova m, podesvova h. endoscopic third ventriculostomy for obstructive hydrocephalus in children younger than 6 months of age: is it a first-choice method? childs nerv syst 2008; 24:1021–7. 7. di rocco c, massimi l, tamburrini g. shunts vs endoscopic third ventriculostomy in infants: are there different types and/or rates of complications? a review. childs nerv syst 2006; 22:1573–89. 8. bouras t, sgouros s. complications of endoscopic third ventriculostomy. j neurosurg pediatr 2011; 7:643–9. 9. fernandez m, moylett eh, noyola de, baker cj. candidal meningitis in neonates: a 10-year review. clin infect dis 2000; 31:458–63. 10. o'brien d, stevens nt, lim ch, o'brien df, smyth e, fitzpatrick f, et al. candida infection of the central nervous system following neurosurgery: a 12-year review. acta neurochir (wien) 2011; 153:1347–50. 11. geers ta, gordon sm. clinical significance of candida species isolated from cerebrospinal fluid following neurosurgery. clin infect dis 1999; 28:1139–47. figure 4: photomicrograph (haematoxylin and eosin stain) (a) x 100 and (b) x 400 showing fungal hyphae. departments of 1physiology, 2medicine and 3obstetrics & gynecology, king saud university, riyadh, saudi arabia *corresponding author’s e-mail: hanazamil@yahoo.com التباين بني أطباء النساء والوالدة وأطباء الغدد الصماء يف تشخيص متالزمة تكيس املبايض املتعدد هناء الزامل، خولة العريني، رمي العقيل، اآية غامن، ربى ال�صعران، نورة ال�صومايل، رمي البهالل، لولو النعيم abstract: objectives: this study aimed to compare endocrinologists’ versus gynaecologists’ approaches in using the rotterdam criteria to diagnose polycystic ovarian syndrome (pcos). methods: this cross-sectional study was conducted at physiology department, king saud university, riyadh, saudi arabia, between december 2017 and april 2018. a validated self-administered questionnaire in english was used to obtain information from endocrinologists and gynaecologists regarding their approaches to diagnosing pcos. each group’s diagnostic use of the rotterdam criteria, association between years of experience and clinical decision-making, clinical features leading to diagnosis and considerations in the diagnosis of biochemical parameters that define hyperandrogenism were evaluated. results: a total of 132 physicians were included in this study (response rate: 27%); 77 (58.3%) were endocrinologists and 55 (41.7%) were gynaecologists. most of the respondents (79.5%) had ≤20 years of experience. a statistically significant difference was detected between the endocrinologists and gynaecologists (98.7% versus 81.8%; p = 0.001) in their consideration of hyperandrogenism in the diagnosis. the gynaecologists relied more on ovarian morphology than the endocrinologists did (76.4% versus 45.5%, p <0.0001). physicians with more experience used ovarian ultrasonography more compared to those with less experience (p = 0.006). conclusion: there was disparity in the diagnostic approaches of endocrinologists, who rely more on androgen levels for diagnosis of pcos versus gynaecologists, who more frequently use an ovarian morphology assessment. increased years of experience increased the rate of ultrasonography use for pcos diagnosis in both groups. keywords: polycystic ovary syndrome; gynecology; endocrinology; diagnosis; hyperandrogenism; hirsutism; healthcare disparities; saudi arabia. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل مقارنة اأ�صلوب اأطباء الغدد ال�صماء باأطباء الن�صاء والوالدة يف ا�صتخدامهم معايري روتردام عند ت�صخي�ض متالزمة تكي�ض املباي�ض املتعدد. الطريقة: مت عقد هذه الدرا�صة امل�صتعر�صة يف ق�صم وظائف االأع�صاء يف جامعة امللك �صعود يف الريا�ض-اململكة العربية ال�صعودية ما بني دي�صمرب 2017 وحتى اأبريل 2018. وقد مت عمل ا�صتبيان موزع ذاتيًا باللغة االإجنليزية جلمع روتردام، ملعايري اال�صتخدام مقدار االأ�صئلة قيمت املتعدد. املباي�ض تكي�ض ملتالزمة ت�صخي�صهم طرق عن التخ�ص�صني كال من البيانات ارتفاع عند الظاهرة املختربية والنتائج الت�صخي�ض يف املوجهة ال�رسيرية ال�صفات االإكلينيكية، والقرارات اخلربة �صنني بني العالقة هرمونات الذكورة. النتائج: مت احل�صول على عينة من 132 طبيبًا )مقدار ا�صتجابة: %27(، منهم )%58.3( 77 اأطباء غدد �صماء و )41.7%( 55 اأطباء ن�صاء ووالدة. كان اأغلب امل�صتجيبني )%79.5( ذوي خربة 20≥ �صنة. مت اإيجاد فرق معترب اح�صائيًا بني اأطباء الغدد واأطباء الن�صاء والوالدة )%98.7 مقابل %81.8؛ القيمة االحتمالية p = 0.001( يف اعتمادهم على فرط االأندروجينات عند الت�صخي�ض. اعتمد اأطباء الن�صاء .)p >0.0001 االحتمالية القيمة مقابل 45.5%، ال�صماء )76.4% الغدد باأطباء مقارنة املبي�ض مورفولوجيا على اأكرب ب�صورة والوالدة .)p = 0.006 باالإ�صافة اإىل اأن االأطباء ذوي اخلربة االأطول طلبوا الت�صوير ال�صونوغرايف اأكرث مقارنة بذوي اخلربة االأقل )القيمة االحتمالية باأطباء مقارنة االأندروجينية، الهرمونات على يعتمدون الذين ال�صماء الغدد اأطباء عند الت�صخي�ض اأ�صاليب يف اختالف هناك اخلال�صة: التخ�ص�صني كال يف ال�صوتية االأ�صعة طلب معدل من اخلربة �صنوات عدد زاد املباي�ض. �صكل لتقييم اأكرث مييلون الذين والوالدة الن�صاء لت�صخي�ض متالزمة تكي�ض املباي�ض املتعدد. الكلمات املفتاحية: متالزمة تكي�ض املباي�ض املتعدد؛ طب الن�صاء والوالدة ؛ طب الغدد ال�صماء؛ ت�صخي�ض؛ فرط االأندروجينات؛ زيادة ال�صعر؛ فوارق يف الرعاية ال�صحية؛ العربية ال�صعودية. disparity among endocrinologists and gynaecologists in the diagnosis of polycystic ovarian syndrome *hana alzamil,1 khawlah aloraini,2 reem alageel,2 aya ghanim,2 ruba alsaaran,2 nora alsomali,2 reem albahlal,2 lulu alnuaim3 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e323–329, epub. 5 oct 20 submitted 19 nov 19 revision req. 6 jan 20; revisions recd. 2 feb 20 accepted 27 feb 20 https://doi.org/10.18295/squmj.2020.20.03.012 clinical & basic research advances in knowledge this study sheds light on aspects of diagnosis that might affect polycystic ovarian syndrome (pcos) prevalence estimations and considerations of its impact in the middle east. certain aspects of the use of ultrasonography findings and biochemical features of pcos require further empirical attention. this report is the first from the middle east to demonstrate disparities between gynaecologists and endocrinologists in the use of this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ disparity among endocrinologists and gynaecologists in the diagnosis of polycystic ovarian syndrome 324 | squ medical journal, august 2020, volume 20, issue 3 polycystic ovarian syndrome (pcos), the most common endocrine disorder in women of reproductive age, presents with heterogeneous manifestations and a wide spectrum of severity.1 among all specialty society guidelines, pcos diagnosis is made when two of the following three criteria are met: clinical and/or biochemical signs of hyperandrogenism, chronic oligomenorrhea/ anovulation and morphological changes of the ovaries on ultrasound.2 according to these criteria, pcos can be classified into four phenotypes labelled a–d. patients who experience phenotypes a and b are known to have classic pcos. women with phenotype a meet three criteria (oligomenorrhoea, hyperandrogenism and polycystic ovaries [pco]), while those with phenotype b feature hyperandrogenism and menstrual irregularities. patients with ovulatory pcos (phenotype c) have normal ovulation but elevated androgen levels and pco. non-hyperandrogenic pcos (phenotype d) is the syndrome’s mildest form; women with this phenotype lack hormonal disturbances and the syndrome presents as menstrual irregularity with pcos morphology.3 associations have been made between pcos and dyslipidaemia, obesity, hyperinsulinemia, and hyperglycaemia.4 patients with hyperandrogenism experience irregular menstrual cycles, chronic anovulation, infertility, acne, seborrhoea and male pattern baldness. these distressing symptoms may cause psychological problems and depression and lead to marital and social instability.4 pcos is a significant global public health issue with reproductive, metabolic and psychological features. unfortunately, it is underdiagnosed and poorly managed, and patients often lack the collaborative efforts of a multidisciplinary team to tackle discrepancies in pcos’s diagnosis and management.1 a previous study reported frustration among patients with pcos due to delayed diagnosis, wherein 33.6% of women waited >2 years and had the involvement of three or more health professionals before diagnosis.5 a recent cross-sectional study using an online questionnaire found that women with pcos experienced greater distrust of their primary care physicians’ opinions than women without pcos.6 surprisingly, a recent large-scale survey conducted in north america of pcos patient dissatisfaction with diagnosis and treatment reported that a large proportion of physicians were unaware of the syndrome’s diagnostic criteria. the same survey showed differences in screening practices as well as discrepancies in the management of pcos across specialties.7 a recent systematic review and meta-analysis investigated the prevalence of pcos among different ethnic groups and found variations by ethnicity and across different diagnostic criteria.8 this finding affirms the need for specific guidelines for each ethnic group to avoid underor overdiagnosis. in addition, the study found a 16% prevalence of pcos diagnosed using the rotterdam criteria in turkey and iran.8 the prevalence of pcos in saudi arabia has not yet been determined; however, a study conducted at taibah university, medina, saudi arabia, reported that 53.7% of students with menstrual irregularities, acne and hirsutism had pco.9 more importantly, it is unknown whether physicians of different specialties in saudi arabia consistently use the rotterdam criteria to diagnose pcos or follow different methods, which might lead to significant delays in diagnosis or an underdiagnosis of the disease. therefore, this study aimed to compare the approaches of endocrinologists with those of gynaecologists using the rotterdam criteria to diagnose pcos and explore whether these differences affect the diagnostic process. furthermore, this study aimed to identify the clinical features used to make a diagnosis with the biochemical values used to define hyperandrogenism. methods this cross-sectional study was conducted from december 2017 to april 2018 at physiology depart ment, king saud university, riyadh, saudi arabia, and included endocrinologists and gynaecologists who encounter pcos patients in clinical practice. a standardised english questionnaire from the european society of endocrinology pcos special interest group on the diagnosis and management of pcos was used.10 the authors granted permission to use the questionnaire but only the section pertaining rotterdam criteria to diagnose pcos. application to patient care this study highlights the importance of reinforcing the rotterdam criteria to improve pcos clinical outcomes and patient safety by decreasing diagnostic errors, preventing management delays and utilising resources properly. using the rotterdam criteria consistently and collaborating across specialities may decrease the financial burden on health institutions and patients in regard to pcos in saudi arabia. hana alzamil, khawlah aloraini, reem alageel, aya ghanim, ruba alsaaran, nora alsomali, reem albahlal and lulu alnuaim clinical and basic research | 325 to diagnostics was used. the questionnaire consisted of 16 questions that aimed to understand physicians’ approaches to pcos diagnosis using the rotterdam criteria. the questionnaire was self-administered and distributed via e-mail to endocrinologists, gynaecologists and members of the saudi society of endocrinology and metabolism. the initial response rate was low; hence, paper-based questionnaires were distributed to participants at the 5th international conference of endocrinology and diabetes in riyadh and during clinical meetings of both specialties at king khalid university hospital in riyadh. the questionnaires were collected using convenience sampling due to time limitations. the sample size was estimated to be 64 physicians from each specialty using the two proportions formula. data were analysed using statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). descriptive statistics (i.e. frequencies, percentages, means and standard deviation) were used to describe categorical and quantitative variables. a chi-square test was used to compare answers between specialties. a p value of ≤0.05 was considered statistically significant. this study was approved by the ethical committee of the institutional review board of the college of medicine, king saud university (e-183476). all participants signed a consent form prior to being included in this study and it was explained that participation was voluntary and that they could withdraw from the study at any time. results a total of 132 respondents were included in this study (response rate: 27%), of which 77 (58.3%) were endocrinologists and 55 (41.7%) were gynaecologists. in total, 87 respondents (65.9%) were consultants, 25 (18.9%) were fellows, 16 (12.1%) were residents and four (3%) were registrars. a total of 117 (88.6%) respondents were familiar with the rotterdam criteria. most participants (79.5%) had less than 20 years of clinical experience [table 1]. a statistically significant difference was found between endocrinologists and gynaecologists in the use of hyperandrogenism for diagnosing pcos; almost all endocrinologists (98.7%) used hyperandrogenism always, while significantly fewer gynaecologists (81.8%; p = 0.001) relied on this parameter for their diagnoses [table 2]. no significant difference was found in physicians’ years of experience in relation to their approach to the rotterdam criteria except in their use of ultrasonography to determine polycystic ovarian table 1: characteristics of physicians according to spec ialty at different institutions in riyadh (n = 132) variable specialty, n (%) endocrinology (n = 77) gynaecology (n = 55) gender male 43 (55.8) 18 (32.7) female 34 (44.2) 37 (67.2) job title resident 0 (0) 16 (29.1) registrar 1 (1.3) 3 (5.4) fellow 16 (20.8) 9 (16.4) consultant 60 (77.9) 27 (49) experience in years ≤20 68 (88.3) 37 (67.3) >20 9 (11.7) 18 (32.7) familiar with the rotterdam criteria yes 70 (90.9) 47 (85.5) no 7 (9.1) 8 (14.5) table 2: comparison of approaches to polycystic ovarian syndrome diagnosis between endocrinologists and gynaecol ogists at different institutions in riyadh criteria used frequency* specialty, n(%) p value endocrinology (n = 77) gynaecology (n = 55) hyperandrogenism (clinical/ biochemical) always 76 (98.7) 45 (81.8) 0.001 sometimes or never 1 (1.3) 10 (18.2) oligomenorrhea/amenorrhoea always 66 (85.7) 42 (76.4) 0.17 sometimes or never 11 (14.3) 13 (23.6) polycystic ovarian morphology always 35 (45.5) 42 (76.4) <0.0001 sometimes or never 42 (54.5) 13 (23.6) *the “sometimes” and “never” categories were combined due to small counts. disparity among endocrinologists and gynaecologists in the diagnosis of polycystic ovarian syndrome 326 | squ medical journal, august 2020, volume 20, issue 3 morphology to diagnose pcos (p = 0.006). in this area, physicians with greater experience were more likely to consider ovarian morphology [table 3]. in the two specialities, the percentage of professionals using clinical features for diagnosing pcos was comparable. endocrinologists and gynaecologists reported menstrual disturbances (100% and 96.4%, respectively) and hirsutism (97.4% and 85.5%, respectively) as the main complaints directing physicians toward the clinical diagnosis of pcos. furthermore, most endocrinologists and gynaecologists considered acne (76.6% and 72.7%, respectively) and infertility (71.4% and 72.7%, respectively) as important features, while an elevated body mass index (bmi; 58.4% and 63.6%, respectively) and hair loss (50.6% and 49.1%, respectively) were the least considered features [figure 1]. endocrinologists investigated androgen hormone levels more often than gynaecologists as evidenced by increased orders of dehydroepiandrosterone sulfate (dheas; 75.3% versus 45.5%) and total testosterone (tt; 68.8% versus 47.3%) levels [figure 2]. table 3: comparison of approaches to pcos diagnostic criteria in relation to seniority criteria used frequency* experience in years, n (%) p value ≤20 (n = 105) >20 (n = 27) hyperandrogenism (clinical/ biochemical) always 97 (92.4) 24 (88.9) 0.558 sometimes or never 8 (7.6) 3 (11.1) oligomenorrhea/amenorrhoea always 86 (81.9) 22 (81.5) 0.959 sometimes or never 19 (18.1) 5 (18.5) polycystic ovarian morphology always 55 (52.4) 22 (81.5) 0.006 sometimes or never 50 (47.6) 5 (18.5) *the “sometimes” and “never” categories were combined due to small counts. figure 1: percentage of gynaecologists and endocrinologists using clinical features for polycystic ovarian syndrome diagnosis bmi = body mass index. *p <0.01. figure 2: percentage of gynaecologists and endocrinologists using biochemical parameters as clinical features for polycystic ovarian syndrome diagnosis as = androstendione; fai = free androgen index; dheas = dehydroepiandrosterone sulfate; tt = total testosterone; ft = free testosterone. *p <0.05. †p <0.0001. hana alzamil, khawlah aloraini, reem alageel, aya ghanim, ruba alsaaran, nora alsomali, reem albahlal and lulu alnuaim clinical and basic research | 327 discussion although several international studies have compared approaches taken by different medical professionals to diagnose pcos, to the best of the authors’ knowledge there are no studies examining this in the middle east.1,10–12 one of the main findings of the current study was the disparity in the diagnostic approach to pcos between endocrinologists and gynaecologists in saudi arabia. it was observed that hyperandrogenism coupled with oligomenorrhea/amenorrhoea was the key criteria guiding endocrinologists to a diagnosis. this finding is consistent with the findings of european and australian studies in which endocrinologists considered androgen excess and menstrual disturbances as essential criteria for diagnosing pcos.10,11 conversely, less than half of the endocrinologists (45.5%) who participated in this study considered using ultrasonography to diagnose pcos, which is similar to the practice of australian endocrinologists.11 almost two-thirds of european endocrinologists used ovarian ultrasonography to diagnose pcos in collaboration with gynaecologists.10 this finding may reflect the possibility that specialists typically use practice-specific diagnostic criteria to diagnose pcos as was suggested by a previous european survey.10 in the current study, the majority of gynaecologists gave each criterion—hyperandrogenism, menstrual irregularities and ovarian ultrasonography—equal importance. this finding is in contrast with australian gynaecologists, who reportedly relied heavily on ovarian morphology to make their diagnoses, and german gynaecologists, who also considered pco and androgen excess as the two most important criteria for establishing their diagnoses.11,12 this difference might be explained by the difference in timing between this study and previous studies that were conducted before the spread of awareness of the diagnostic criteria for pcos. another reason for this contrast may be differences in the teaching programmes and practices applied in each country. an online questionnairebased study recently investigated the practices of european, north american and other continents’ physicians, and found that both european physicians and physicians of other continents were more likely to use the rotterdam criteria than american physicians.13 the current study demonstrated that physicians from both specialities with more years of experience were more likely to use ultrasonography to diagnose pcos. this finding may be due to the fact that twothirds of participants who had more than 20 years of experience were gynaecologists. the international evidence-based guidelines recently stated that ovarian ultrasonography is not necessary for a pcos diagnosis in the presence of irregular menstrual cycles and hyperandrogenism.14 variations in the approach to diagnosis could lead to underdiagnosis, misdiagnosis or a delay in the initiation of appropriate management, resulting in serious yet preventable complications.15 currently, consistent care that considers evidencebased guidelines across all features of pcos is lacking, which indicates the need to educate physicians and improve the diagnosis of and holistic care for patients with pcos.5 this study’s participants were asked about the most important clinical and biochemical features of pcos. clinically, both specialties agreed that menstrual disturbances and hirsutism were its two fundamental features, followed by acne, infertility, elevated bmi and hair loss. in line with the researchers’ observations, the european survey reported that the majority of their participants reported hyperandrogenism and menstrual disturbances when diagnosing pcos.10 similar to german gynaecologists, more than 60% of this study’s participating gynaecologists specified a high bmi as an important criterion for a pcos diagnosis.12 the high prevalence of obesity among saudi women might be the reason that our participants believe that menstrual irregularities and hirsutism are more specific to pcos than obesity.16 with regard to alopecia, it is difficult to clinically assess hair loss due to its subjective nature. furthermore, the biochemical parameters most commonly requested by endocrinologists were dheas and tt, while gynaecologists paid more attention to free testosterone (ft) in addition to tt and dheas. this finding might be due to endocrinologists usually managing a variety of adrenal disorders and that they prefer to exclude other causes of hyperandrogenism. as recommended by the international evidence-based guidelines, ft and the free androgen index should be used to confirm a pcos diagnosis. if ft or tt are not elevated, it may be helpful to measure dheas as well as androstenedione, even though both have limited additional value for establishing the diagnosis of pcos.14 this finding raises concerns about the accuracy of routine investigations and how they can hinder the early detection of pcos and delay its management, consequently increasing complications and comorbidities. previous research has indicated that patients with pcos are confused due to healthcare providers’ struggles to make a diagnosis with controversial recommendations.17 one of the most debated disparity among endocrinologists and gynaecologists in the diagnosis of polycystic ovarian syndrome 328 | squ medical journal, august 2020, volume 20, issue 3 criteria is the use of ovarian ultrasonography, which is more closely related to fertility than metabolic outcomes, and its importance is perceived differently among specialties according to patients’ presenting complaints.18 moreover, the diurnal variation in testosterone levels, the effects of sex hormone-binding globulin on tt and the variability of assay methods all play a role in hindering diagnostic accuracy.19 these findings cannot be generalised to saudi arabia’s physician population because of the study’s small sample size, low response rate and limited resources that prompted a convenience sampling method. however, this study is the first in the middle east to address this topic and its findings may provide useful information to serve as a starting point for future pcos studies in the region. in cases of suspected pcos, it is recommended to use the new diagnostic guidelines; however, further studies are necessary to investigate the various dimensions of pcos, such as its prevalence, epigenetics and management modalities. these recommendations should help improve the care of and prevent complications in patients with pcos. conclusion endocrinologists and gynaecologists in saudi arabia use different diagnostic approaches to pcos. the current findings indicate the importance of addressing the health concerns of patients with pcos and establishing a consistent diagnostic and management plan. such plans should be discussed thoroughly with each patient. furthermore, healthcare teams should be educated about recent guidelines for managing pcos and, when appropriate, refer patients to other specialists for diagnosis and management. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the deanship of scientific research of king saud university, riyadh, saudi arabia. references 1. sivayoganathan d, maruthini d, glanville jm, balen ah. full investigation of patients with polycystic ovary syndrome (pcos) presenting to four different clinical specialties reveals significant differences and undiagnosed morbidity. hum fertil (camb) 2011; 14:261–5. https://doi.org/10.3109/14647273.201 1.632058. 2. goodman nf, cobin rh, futterweit w, glueck js, legro rs, carmina e, et al. american association of clinical endo crinologists, american college of endocrinology, and androgen excess and pcos society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome--part 1. endocr pract 2015; 21:1291–300. https://doi.org/10.4158/ep15748.dsc. 3. lizneva d, suturina l, walker w, brakta s, gavrilova-jordan l, azziz r. criteria, prevalence, and phenotypes of polycystic ovary syndrome. fertil steril 2016; 106:6–15. https://doi. org/10.1016/j.fertnstert.2016.05.003. 4. podfigurna-stopa a, luisi s, regini c, katulski k, centini g, meczekalski b, et al. mood disorders and quality of life in polycystic ovary syndrome. gynecol endocrinol 2015; 31:431–4. https://doi.org/10.3109/09513590.2015.1009437. 5. gibson-helm m, teede h, dunaif a, dokras a. delayed diagnosis and a lack of information associated with dissat isfaction in women with polycystic ovary syndrome. j clin endocrinol metab 2017; 102:604–12. https://doi.org/10.1210/ jc.2016-2963. 6. lin aw, bergomi ej, dollahite js, sobal j, hoeger km, lujan me. trust in physicians and medical experience beliefs differ between women with and without polycystic ovary syndrome. j endocr soc 2018; 2:1001–9. https://doi.org/10.1210/js.201800181. 7. dokras a, saini s, gibson-helm m, schulkin j, cooney l, teede h. gaps in knowledge among physicians regarding diagnostic cri teria and management of polycystic ovary syndrome. fertil steril 2017; 107:1380–6. https://doi.org/10.1016/j.fertnstert.20 17.04.011. 8. ding t, hardiman pj, petersen i, wang ff, qu f, baio g. the prevalence of polycystic ovary syndrome in reproductiveaged women of different ethnicity: a systematic review and meta-analysis. oncotarget 2017; 8:96351–8. https://doi. org/10.18632/oncotarget.19180. 9. gurraya ss. prevalence and ultrasound features of polycystic ovaries in young unmarried saudi females. j microsc ultrastruct 2013; 1:30–4. https://doi.org/10.1016/j.jmau.2013.06.002. 10. conway g, dewailly d, diamanti-kandarakis e, escobarmorreale hf, franks s, gambineri a, et al. european survey of diagnosis and management of the polycystic ovary syndrome: results of the ese pcos special interest group’s questionnaire. euro j endocrinol 2014; 171:489–98. https:// doi.org/10.1530/eje-14-0252. 11. cussons aj, stuckey bg, walsh jp, burke v, norman rj. polycystic ovarian syndrome: marked differences between endo crinologist and gynaecologists in diagnosis and management. clin endocrinol (oxf ) 2005; 62:289–95. https://doi.org/10.11 11/j.1365-2265.2004.02208.x. 12. doll i, doll r, buhling kj. diagnosis and therapy of polycystic ovarian syndrome: results of a survey among german gynaecologists with a review on literature. arch gynecol obstet 2012; 285:689–97. https://doi.org/10.1007/s00404-0112014-7. 13. gibson-helm m, dokras a, karro h, piltonen t, teede hj. knowledge and practices regarding polycystic ovary syndrome among physicians in europe, north america, and internationally: an online questionnaire-based study. semin reprod med 2018; 36:19–27. https://doi.org/10.1055/s-0038-1667155. 14. teede hj, misso ml, costello mf, dokras a, laven j, moran l, et al. recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. hum reprod 2018; 33:1602–18. https://doi. org/10.1016/j.fertnstert.2018.05.004. 15. daniilidis a, dinas k. long term health consequences of polycystic ovarian syndrome: a review analysis. hippokratia 2009; 13:90–2. https://doi.org/10.3109/14647273.2011.632058 https://doi.org/10.3109/14647273.2011.632058 https://doi.org/10.4158/ep15748.dsc https://doi.org/10.1016/j.fertnstert.2016.05.003 https://doi.org/10.1016/j.fertnstert.2016.05.003 https://doi.org/10.3109/09513590.2015.1009437 https://doi.org/10.1210/jc.2016-2963 https://doi.org/10.1210/jc.2016-2963 https://doi.org/10.1210/js.2018-00181 https://doi.org/10.1210/js.2018-00181 https://doi.org/10.1016/j.fertnstert.2017.04.011 https://doi.org/10.1016/j.fertnstert.2017.04.011 https://doi.org/10.18632/oncotarget.19180 https://doi.org/10.18632/oncotarget.19180 https://doi.org/10.1016/j.jmau.2013.06.002 https://doi.org/10.1530/eje-14-0252 https://doi.org/10.1530/eje-14-0252 https://doi.org/10.1111/j.1365-2265.2004.02208.x https://doi.org/10.1111/j.1365-2265.2004.02208.x https://doi.org/10.1007/s00404-011-2014-7 https://doi.org/10.1007/s00404-011-2014-7 https://doi.org/10.1055/s-0038-1667155 https://doi.org/10.1016/j.fertnstert.2018.05.004 https://doi.org/10.1016/j.fertnstert.2018.05.004 hana alzamil, khawlah aloraini, reem alageel, aya ghanim, ruba alsaaran, nora alsomali, reem albahlal and lulu alnuaim clinical and basic research | 329 16. memish za, el bcheraoui c, tuffaha m, robinson m, daoud f, jaber s, et al. obesity and associated factors--kingdom of saudi arabia, 2013. prev chronic dis 2014; 11:e174. https://doi. org/10.5888/pcd11.140236. 17. cree-green m. worldwide dissatisfaction with the diagnostic process and initial treatment of pcos. j clin endocrinol metab 2017; 102:375–8. https://doi.org/10.1210/jc.2016-3808. 18. dewailly d, lujan me, carmina e, cedars mi, laven j, norman rj, et al. definition and significance of polycystic ovarian mor phology: a task force report from the androgen excess and polycystic ovary syndrome society. hum reprod update 2014; 20:334–52. https://doi.org/10.1093/humupd/dmt061. 19. handelsman dj, wartofsky l. requirement for mass spectro metry sex steroid assays in the journal of clinical endocrinology and metabolism. j clin endocrinol metab 2013; 98:3971–3. https://doi.org/10.1210/jc.2013-3375. https://doi.org/10.5888/pcd11.140236 https://doi.org/10.5888/pcd11.140236 https://doi.org/10.1210/jc.2016-3808 https://doi.org/10.1093/humupd/dmt061 https://doi.org/10.1210/jc.2013-3375 sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 503-507, epub. 20th nov 12 submitted 4th jan 12 revision req. 30th apr 12, revision recd. 26th may 12 accepted 13th jun 12 departments of 1medicine, 2radiology and molecular imaging, and 4clinical physiology, sultan qaboos university hospital, muscat, oman; 3department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: dr.ammarabd@gmail.com ظهورالصرع عند مريض مصاب بداء ولسن مع شذوذ منائي وريدي يف الدماغ )َوَرٌم ِوعاِئيٌّ َوريِديٌّ ِدماِغّي( عمار العبيدي، في�صل العزري، بي �صي جاكوب، جميلة الكلباين امللخ�ص: يعترب ال�صذوذ النمائي الوريدي )والتي ُتدعى باالأورام الوعائية الوريدية الدماغية( وداء ول�صن من االأمرا�ض النادرة يف االإن�صان ويظهران باأعرا�ض خمتلفة يف اجلهاز الع�صبي وبقية اأجهزة اجل�صم االأخرى. ومن اجلدير ذكره اأن وجود هذين املر�صني يف اآن واحد ُيعترب حمور يكون و�صوف املر�صني، هذين يف معروفا ال�رصع ظهور ُيعترب لذلك اإ�صافة منهما. كل ُندرة احل�صبان يف اأخذنا ما اإذا جدا نادرا النقا�ض يف و�صف حالة مري�ض عمره 21 �صنة، ا�صتطعنا ت�صخي�ض اإ�صابته بكل من مر�ض ول�صن وال�صذوذ النمائي الوريدي عرب الفح�ض ال�رصيري ونتائج كال من الفحو�صات املخربية والت�صوير ال�صعاعي يف م�صت�صفى جامعة ال�صلطان قابو�ض، ُعمان. ظهرت عند املري�ض يف البداية اأعرا�ض ارتعا�ض يف اليد اليمنى مع �صعوبة يف الكتابة، ثم تبع ذلك ظهور نوبات �رصع متكررة. مت عالج املري�ض باالأدوية الطاردة للنحا�ض وم�صادات ال�رصع. كما ا�صتعر�صنا باإيجاز و�صف هذين املر�صني وعالقتهما بظهور ال�رصع مع ذكر اأنواع العالج املمكنة. ُيعد فح�ض التحري الأ�رص املر�صى امل�صابني بداء ويل�صون حموريا ملنع النتائج غري املواتية. مفتاح الكلمات: داء ول�صن، �صذوذ منائي وريدي داخل القحف، �رصع، تقرير حالة، ُعمان. abstract: intracranial developmental venous anomalies (dvas), also called venous angiomas, and wilson's disease are both considered rare disorders with varying degrees of neurologic and systemic manifestations; yet the coexistence of the two disorders is considered extremely rare, bearing in mind the low prevalence of each disorder. epilepsy is a recognised presentation in these disorders and will be the focus of discussion in our report of a 21-year-old male patient who, based on a clinical examination and laboratory and neuroimaging results, was diagnosed with both wilson's disease and dva. he presented initially at sultan qaboos university hospital, oman with tremors and writing difficulties in the right hand followed by the development of epilepsy, and was treated medically by de-coppering and antiepileptic medications. we also present a brief literature review of both disorders, their association with epilepsy, and treatment options. family screening for patients with wilson’s disease is pivotal in preventing unfavourable outcomes. keywords: wilson's disease; intracranial venous angioma; epilepsy; case report; oman. presentation of epilepsy in a patient with wilson's disease and developmental venous anomaly (venous angioma) in the brain *ammar alobaidy,1 faisal alazri,2 p.c. jacob,3 jamila h. al-kalbani4 case report the terms developmental venous anomaly (dva) and venous angioma are used synonymously in medical literature, although the former is currently more widely used as it is generally accepted that dvas are formed in utero.1 dvas are the most frequently recognised malformation among cerebral vascular malformations including capillary telangiectasias, cavernous malformations, and arteriovenous malformations, with an incidence of up to 2.6% in one brain autopsy series. dvas are characterised by a cluster of venous radicles that converge into a collecting vein, resulting in the typical caput medusae appearance of the dva.1 the aetiology of dvas remains uncertain but may relate to arrested development of venous structures.2,3 histologically, they consist of a number of abnormally thickened veins with normal feeding arteries and capillaries.3 the most common locations are frontoparietal region (36–64%) and the cerebellar hemisphere (14–27%); dvas, however, can be seen anywhere, draining both superficially presentation of epilepsy in a patient with wilson's disease and developmental venous anomaly (venous angioma) in the brain 504 | squ medical journal, november 2012, volume 12, issue 4 and deeply.4 the lesions are usually solitary (75%), except in blue rubber bleb naevus syndrome where they are multiple.2 in 8–33% of cases, they are associated with cavernous malformations and are referred to as mixed vascular malformations.2 on the other hand, wilson’s disease, also known as hepatolenticular degeneration, is an autosomal recessive disorder produced by a gene mutation on chromosome 13. the gene encodes a transport protein, the mutation of which causes abnormal deposition of copper in the liver, brain (especially the basal ganglia), and corneas. wilson’s disease typically begins in childhood but in some cases has its onset as late as the fifth or sixth decade. about one-third of patients present with psychiatric symptoms, one-third present with neurological features, and one-third present with hepatic disease. neurological manifestations are largely extrapyramidal, including chorea, tremor, and dystonia. other symptoms include dysphagia, dysarthria, ataxia, gait disturbance, and a fixed (sardonic) smile. seizures may also occur in a minority of cases.5 in this particular patient, we are describing a unique coexistence of both wilson's disease and dva with a rare presentation of epilepsy. case report a 21-year-old college student presented at sultan qaboos university hospital, oman, with an insidious onset tremor in the right hand and complained of difficulty in writing over a period of one year. he was a right-handed person with unremarkable past medical or surgical histories. his elder brother had died six years earlier at the age of 45 years because of acute fulminant hepatic failure while he was being prepared for liver transplantation; the underlying cause was found to be wilson's disease. however, no screening tests were performed on other family members. this patient’s neurological examination was significant for rigidity, and exaggerated deep tendon reflexes in the right upper limb with the presence of action tremor. there were no other significant neurologic or systemic findings. a blood workup revealed low serum caeruloplasmin (0.04 g/l, reference range: 0.22– 0.58 g/l) and thrombocytopenia of 86 x 109/l. other investigations, including a liver function test, coagulation profile, thyroid function test, and a serum polymerase chain reaction (pcr) viral screening for epstein–barr virus (ebv) and cytomegalovirus, (cmv) were unremarkable. a 24hour urinary copper was 2.4 umol/24 hour (reference figure 1a & b: (a) brain magnetic resonance imaging (mri) scan of the patient, axial view, fluid-attenuated inversion recovery (flair) sequence, showing hyper-intense lesions involving the right basal ganglia, left basal ganglia, left internal capsule and left thalamus. (b) coronal view, gadolinium enhanced brain mri scan of the patient showing abnormal vessels enhancement in the left basal ganglia. ammar alobaidy, faisal alazri, p.c. jacob, jamila h. al-kalbani case report | 505 range: 0.38 to 0.77 umol/24 hours). ultrasonography of the abdomen showed splenomegaly with altered liver echoes suggestive of early fibrosis. a slit-lamp examination confirmed the presence of kayser– fleischer rings in both eyes, and the diagnosis of wilson's disease was established. he was started on de-coppering therapy, namely penicillamine and zinc sulfate. contrast-enhanced brain magnetic resonance imaging (mri) revealed hyperintense lesions seen on t2-weighted and fluid-attenuated inversion recovery (flair) sequences involving the right basal ganglia, left basal ganglia, left internal capsule, and left thalamus [figure 1a] with abnormal vessel enhancement in the left basal ganglia [figure 1b]. a computed tomography (ct) angiography of the brain showed small veins at the left basal ganglia draining into a large vein and thence into the vein of galen with no evidence of a feeding artery or aneurysms [figure 2a & b]. these radiological features were consistent with a diagnosis of dva. two months later, the patient presented at the emergency department with an attack of generalised tonic-clonic convulsions and prolonged postictal state. clinically, he was confused for two hours after which he recovered slowly with no new neurological deficit and his systemic examination was normal. a basic workup was remarkable for thrombocytopenia of 80 x 109/l, but other tests including electrolytes, bone profile, serum magnesium, renal function test, and liver function test were normal. an urgent brain ct scan did not show any new pathology. he was admitted to the high dependency unit for observation and after 6 hours he had a second witnessed generalised tonic-clonic convulsion for five minutes that was aborted by intravenous diazepam. antiepileptic treatment (levetiracetam) was started and his electroencephalogram (eeg), done one day later, showed a normal background with occasional generalised slowing, but no definite epileptiform discharges were recorded. no further generalised tonic-clonic convulsions occurred after starting levetiracetam, but he had two episodes of staring and loss of awareness, suggestive of complex partial seizures. the levetiracetam dose was upgraded and after two days he was discharged home with follow-up appointments at the neurology and haematology outpatient clinics. appointments also were arranged to screen for wilson's disease in his siblings. discussion dvas are often asymptomatic, follow a benign clinical course, and do not require follow-up imaging studies or specific medical management.1,6 however, dvas may manifest clinically as figure 2a & b: sequential sagittal views of brain computed tomography (ct) angiography of the patient showing a developmental venous anomaly (dva) consisting of small veins like caput medusae, seen at the left basal ganglia (a), draining into a large vein and thence into the vein of galen (b). there is no evidence of a feeding artery or aneurysms. presentation of epilepsy in a patient with wilson's disease and developmental venous anomaly (venous angioma) in the brain 506 | squ medical journal, november 2012, volume 12, issue 4 headache, seizure, focal neurological deficits, and altered levels of consciousness due to thrombosis, haemorrhage, or mass effect of the dva.6,7 acute thrombosis of the draining vein of malformation was documented in 19 cases of symptomatic thrombosed dvas leading to haemorrhagic or venous ischaemic infarctions.1,6 a symptomatic haemorrhage rate of 0.34% per year was observed, usually with minor manifestations, although fatal intracranial hemorrhages have been described.8 dvas are associated with cavernous malformations in 13–40% of cases, and might be responsible for the majority of symptomatic cases previously attributed to dvas. mechanical compression of intracranial structures by a component of the dva was also reported, and the most common associated symptoms were hydrocephalus, tinnitus, brainstem deficits, hemifacial spasms, and trigeminal neuralgia.7 cerebral angiography is considered the gold standard for the diagnosis of dvas, but they are usually identified with contrast-enhanced cross-sectional imaging modalities such as mri, magnetic resonance angiography (mra), and ct angiography.4,9 in our case, the diagnosis of dva was based on enhancement of the abnormal vessels in the mri [figure 1b], as well as the classic caput medusa sign showed by ct angiography [figure 2]. there was no other associated vascular malformation; neither bleeding nor thrombosis was observed in either study. dvas should be treated conservatively in the vast majority of cases, with associated symptoms such as headaches and seizures managed medically.10 surgery may be required in patients with haemorrhages associated with a dva or with uncontrolled seizures.8 thrombotic complications of dvas require the same treatment and laboratory workup as cortical venous or sinus thrombosis (i.e. anticoagulation treatment with investigation of procoagulating factors or prothrombotic conditions).7 while focusing on epilepsy as a presentation in our patient, the prevalence of seizures in wilson's disease was reported to be 6.2–7.5%; these figures are 10 times higher than the prevalence in the general population.11–12 the diagnosis of epilepsy in our patient was established mainly on clinical bases, as his eeg showed occasional slowing with no epileptiform discharges. this can be explained by the fact that eeg has a relatively low sensitivity in the diagnosis of epilepsy, ranging from 25–56% accuracy. its specificity is better, but again variable at 78–98%.13 the reported incidence of abnormal eegs in wilson's disease varies considerably from 41–80%, and this was attributed to the methodological differences in each study group. in one large cohort of 282 patients with wilson's disease, the following eeg abnormalities were observed: a reduction in alpha frequency in six patients; an increase in beta frequency in five patients; an increase in theta activity in seven patients; an increase in delta activity in one patient; focal epileptiform discharges in four patients, and low voltage indeterminate activity in two patients. in our case, the mri changes in the right basal ganglia, left basal ganglia, left internal capsule, and left thalamus [figure 1a] are well-recognised radiological findings in wilson’s disease with central nervous system involvement and are related to copper deposition in these sites.11 the exact pathophysiology of seizures in wilson's disease is not well understood; the following mechanisms were postulated: 1) direct toxicity of copper, probably by inhibition of membrane atpase; 2) pyridoxine deficiency due to penicillamine, and 3) metabolic encephalopathy.11 treatment of seizures in wilson's disease relies mainly on antiepileptic therapy, a low copper diet, and proper de-coppering medications including pyridoxine supplement if penicillamine is used. pyridoxine is not required if the other copper chelating agents, trientine or tetrathiomolybdate, are used as an alternative to penicillamine due to intolerance or development of serious side effects.11,12 we used levetiracetam as an antiepileptic drug because of its pharmacokinetic advantages including rapid and almost complete absorption, absence of enzyme induction, absence of interactions with other drugs, and effectiveness in treatment of partial seizures with or without secondary generalisation.14,15 conclusion dvas and wilson's disease are recognised as causes of broad spectrum central nervous system manifestations ranging from asymptomatic to life threatening. epilepsy is a well-known complication of each disorder but it is unclear whether its ammar alobaidy, faisal alazri, p.c. jacob, jamila h. al-kalbani case report | 507 incidence will increase if the disorders coexist; however, the management of coexisting cases may not differ from the management of each disorder individually. dvas are treated conservatively in most cases, while wilson’s disease is treated with de-coppering and epilepsy with appropriate antiepileptic therapy. further management, including surgical intervention, will depend upon clinical progress and the appearance of further complications. screening of asymptomatic family members of a wilson’s disease patient would prevent unfavourable outcomes. references 1. ruíz ds, yilmaz h, gailloud p. cerebral developmental venous anomalies: current concepts. ann neurol 2009; 66:271–83. 2. boukobza m, enjolras o, guichard jp, gelbert f, herbreteau d, reizine d, et al. cerebral developmental venous anomalies associated with head and neck venous malformations. ajnr am j neuroradiol 1996; 17:987–94. 3. saba pr. the caput medusae sign. radiology 1998; 207:599–600. 4. lee c, pennington ma, kenney cm. mr evaluation of developmental venous anomalies: medullary venous anatomy of venous angiomas. ajnr am j neuroradiol 1996; 17:61–70. 5. bradley wg, daroff rb, fenichel gm, jankovic j. neurology in clinical practice, vol. 1. 5th ed. london: elsevier 2007. p. 119. 6. parker bj, sabb bj. developmental venous anomaly complicated by cerebral venous infarction. j radiol case rep 2007; 2:48. 7. pereira vm, geibprasert s, krings t, aurboonyawat t, ozanne a, toulgoat f, et al. pathomechanisms of symptomatic developmental venous anomalies. stroke 2008; 39:3201–15. 8. malik gm, morgan jk, boulos rs, ausman ji. venous angiomas: an underestimated cause of intracranial hemorrhage. surg neurol 1988; 30:350– 8. 9. peebles tr, vieco pt. intracranial developmental venous anomalies: diagnosis using ct angiography. j comput assist tomogr 1997; 21:582–6. 10. garner tb, del curling o jr, kelly dl jr, laster dw. the natural history of intracranial venous angiomas. j neurosurg 1991; 75:715–22. 11. taly ab, meenakshi-sundaram s, sinha s, swamy hs, arunodaya gr. wilson disease: description of 282 patients evaluated over 3 decades. medicine (baltimore). 2007; 86:112–21. 12. dening tr, berrios ge, walshe jm. wilson’s disease and epilepsy. brain 1988; 111:1139–55. 13. s. smith. eeg in the diagnosis, classification, and management of patients with epilepsy. j neurol neurosurg psychiatry 2005; 76:ii2–7. 14. abou-khalil b. levetiracetam in the treatment of epilepsy. neuropsychiatr dis treat 2008; 4:507–23. 15. lyseng-williamson ka. levetiracetam: a review of its use in epilepsy. drugs. 2011; 71:489–514. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 458-464, epub. 20th nov 12 submitted 17th dec 11 revision req. 10th apr 12, revision recd. 1st jun 12 accepted 27th jun 12 department of ophthalmology, university of aden, khormakser, aden, yemen e-mail: raga_56@yahoo.co.uk مضاعفات العني عند املصابني باجلذام يف اليمن رجا عبده اأحمد �صامل امللخ�ض: الهدف: حتديد امل�صاعفات الرئي�صية التي تهدد العني والب�رص والناجمة عن مر�ض اجلذام يف اليمن. الطريقة: اأجريت هذه الدرا�صة املقطعية خالل الفرتة من فرباير 2010 حتى يوليو 2010 و�صملت املر�صى الذين ترددوا على م�صت�صفى االأمرا�ض اجللدية والتنا�صلية يف مدينة النور مبدينة تعز )اليمن( من قبل اأخ�صائي عيون وذلك بعد اأخد موافقتهم. مت اأخذ التفا�صيل الدميوغرافية والطبية لكل مري�ض مع فح�ض دقيق للعني �صامال فح�ض حّدة الب�رص، وفح�ض امل�صباح ال�صقي، وفح�ض قاع العني على كل مري�ض من قبل طبيب عيون موؤهل. النتائج: �صملت الدرا�صة 192 مري�صا )180 رجال و 12 امراأة ( بن�صبة تقدر1:15 للرجال اإىل الن�صاء . كان عمر معظم املر�صى )157 %81.8 ( فوق االأربعني عاما، واأكرث من ُثُلثي املر�صى )129 %67.2( كانوا يعانون من مر�ض اجُلذام الأكرث من 20 عاما. وجدنا م�صاعفات العيون يف )%97( من احلاالت، ويف ٍ)150 %39.1( من العيون اإ�صابة مبر�ض واحد على االأقل. كانت اإ�صابة اجلفون مبر�ض اجلذام االأكرث �صيوعا )102 %26.5(. وكانت قوة االإب�صار اأقل من 60/6 يف )192 %50(، كما كانت عتامة القرنية من اأكرث االأ�صباب املوؤدية للعمى )69 %35.9(. اخلال�صة: م�صاعفات العيون الناجتة عن مر�ض اجلذام منت�رصة يف اليمن، وهي تهدد بفقدان الب�رص. من ال�رصوري منع حدوث هذه امل�صاعفات بوا�صطة الت�صخي�ض املبكر والعالج املنا�صب. مفتاح الكلمات: جذام، عمى، عتامة القرنية، جفون العني، اليمن. abstract: objectives: this study was conducted to identify the main ocularand vision-threatening complications of leprosy in yemen. methods: this is a cross-sectional observational study which took place from february to july 2010. leprosy patients attending the skin and venereal diseases hospital in the city of light in taiz, yemen, who consented to participate in the study, were enrolled. detailed demographic and medical histories were taken and clinical examination findings were recorded. a detailed eye examination, including visual acuity (va), slit-lamp, and fundus examinations, was conducted on each patient by a qualified ophthalmologist. results: a total of 192 patients (180 male, 12 female, with a male to female ratio of 15:1) were included in the study. the majority of the patients (157; 81.8%) were over 40 years. over two-thirds of the patients (129; 67.2%) had had leprosy for more than 20 years. ocular complications were found in 97% of cases; 150 (39.1%) of the patients’ eyes had at least one pathology. eyelid involvement was the most common problem observed in 102 (26.5%) patients. half of the eyes (192; 50%) had a va of <6/60. the main cause of blindness among these patients was corneal opacity detected in 69 out of 192 patients (35.9%). conclusion: ocular complications are frequent among leprosy patients in yemen. they are true vision-threatening lesions. it is important to prevent these lesions through early diagnosis and adequate treatment. keywords: leprosy; blindness; corneal opacity; eyelid; yemen. ocular complications of leprosy in yemen raga a. a. salem clinical & basic research advances in knowledge this is the first study of its kind in yemen that reports ocular complications among leprosy patients. ocular complications of leprosy are a social and economic burden but these debilitating diseases are largely preventable in those with leprosy. application to patient care this study highlights the importance of regular ophthalmic exams and of providing appropriate and early treatment for leprosy patients in order to prevent avoidable blindness. medical and paramedical personnel should be aware of leprosy and its ocular complications. the study emphasises the importance of promoting and improving ophthalmic services to leprosy patients. raga a. a. salem clinical and basic research | 459 leprosy is a chronic infectious disease caused by mycobacterium leprae, or hansen's bacillus. this disease, which is as old as humanity, is always terrifying because it mutilates, disfigures, and causes blindness.1 it may affect the eye through infection of the skin of the lids, tear ducts, or the lacrimal glands; it may also involve the facial and ophthalmic division of the trigeminal nerve, or direct invasion of the anterior segment, or sensitisation of the tissue to m. leprae.2–6 known as gutham in arabic, the history of leprosy in yemen dates back to ad 747 when the then ruler, the abbasid wali, m.z. aboual-madan, collected huge quantities of wood to burn the leprosy patients in sana'a as a way of eradicating this problem; however, he died before he could carry out this act.7 these well-documented events in yemen’s history clearly demonstrate the social stigma attached to leprosy. over-crowding, unhygienic living conditions, and malnutrition are considered principal causes of the endemicity of leprosy. before 1964, leprosy patients in most parts of yemen were subjected to obligatory isolation in unsanitary houses.8 clinics in aden, sana'a, taiz, and mukalla were the only places providing very basic medical care for lepers. from 1974, leprosy work in yemen was carried out by the missionaries of charity. in 1982, dr. al-qubati took up the duties at the skin and venereal disease hospital in the city of light, taiz, which was the only referral hospital in the country for the treatment of leprosy and its complications at that time.9 in 1991, the missionaries of charity left the service of the leper colonies and the national leprosy control program (nlcp) and under the jurisdiction of the ministry of public health took over that responsibility. the nlcp currently provides services to 80% of the country.9 in yemen, leprosy patients are isolated, excluded, and even abandoned by families and society. yemen’s leprosy caseload has declined from a peak of 2,314 patients registered for multidrug therapy (mdt) in 1989 to 765 patients registered in 1996. moreover, the registered prevalence of leprosy sufferers had declined from 1.9 per 10,000 in 1989 to 0.5 per 10,000 in 1996.10 although leprosy control has been a public health success over the past decades, leprosy patients still suffer from avoidable blindness. worldwide, an estimated 200,000–300,000 leprosy patients are blind.11 many of them could have been spared this dreaded outcome by early detection and treatment of eye involvement through patient and physician education and awareness. blindness for leprosy patients is disastrous as they depend on their vision to protect their limbs from the injuries and burns that are due to the numbness and loss of sensation caused by the disease. this visual disability is to a large extent preventable, provided that the ocular involvement is diagnosed at an early stage and appropriate measures are undertaken in time. globally, many studies have been carried out on the ocular complications of leprosy;12,13 however, in yemen these complications have never been documented or reported. therefore, this study was conducted to determine the main ocular findings, the presence of vision-threatening eye conditions, and the causes of visual impairments and blindness among leprosy patients in yemen. this information will allow the establishment of a plan for eye care services through leprosy control and blindness prevention programmes. methods this was a cross-sectional observational study, which was conducted from february to july 2010. approval of the research and ethics committee of the university of aden, faculty of medicine & health sciences, was granted retrospectively in january 2011. a total of 192 leprosy patients (irrespective of the type of leprosy), who attended the skin and venereal diseases hospital located at the city of light in taiz, were examined. after explaining the purpose of the study, verbal consent was obtained. some of the patients were still on mdt while others had already been released from treatment. individuals’ data on age, sex, and duration of the disease were recorded, and a short history taken regarding eye complications. patients were first observed for any obvious facial or ocular deformities and visual acuity (va) was assessed using a snellen or tumbling e chart at 6 metres. an eye was considered to be severely disabled or blind when va was <6/60. a torch light examination was done to determine eyelid position, and pupil size, shape, and reaction. the patients were then ocular complications of leprosy in yemen 460 | squ medical journal, november 2012, volume 12, issue 4 subjected to slit lamp biomicroscopy. thereafter, the pupils were dilated using tropicamide 1% eye drops, and a fundus examination was done by a qualified ophthalmologist using a direct ophthalmoscope. intraocular pressure was recorded using a schiotz tonometer and corneal sensation was checked with a tuft of cotton. a visual field test was not done. data were analysed using statistical package for the social sciences (spss), version 17, (ibm, chicago, illinois, usa). descriptive statistics was done with a frequency distribution and a 95% confidence interval (ci). the chi-square and fischer exact probability tests were used to test the association between ocular findings and the affected eye with a p value of <0.05 considered the cut-off point for statistical significance. results a total of 192 leprosy patients were enrolled in this study, 180 (93.8%) males and 12 (6.2%) female patients, with a male to female ratio of 15:1. the age range was 22–77 years (mean + standard deviation (sd) = 55.4 ± 12.5 years). the majority of patients (157; 81.8%) were over 40 years old. the mean duration of the disease varied from 1–50 years (sd = 22.1 ± 10.3 years). more than two-thirds (129; 67.2%) had had the disease for more than 20 years, the duration being derived from patients’ statements. out of 384 eyes examined, 150 (39.1%) had at least one pathology, with many eyes (57.6%) exhibiting more than one lesion. table 1 shows the major ocular lesions detected in these 192 patients as follows: eyelid involvement (trichiasis, entropion, madarosis) (26.5%); lagophthalmos (23%); corneal opacity (21.9%); uveitis (20%), and cataracts (14%). a total of 50% (192 eyes) were determined to have a va of <6/60. four lesions were encountered, with a higher frequency in the left eye as compared to the right. however, a statistically significant difference was detected for uveitis (p = 0.02); retinal lesions (fisher exact probability [fep]) = 0.0002), and phthisis bulbi (fep = 0.03). the right eye was affected with lid lesions and lagophthalmos more commonly than the left. the difference was statistically significant for lagophthalmos (p = 0.0005). age, duration of disease, and ocular findings in leprotic patients are shown in table 2. a higher percentage of ocular findings were found in patients of >40 years (69.5%), and in those having had leprosy for >20 years (55.5%). patients with a va of <6/60 underwent a detailed examination to evaluate the cause of blindness. table 3 shows the prevalence of blindness in different leprotic lesions. sixty-nine eyes (35.9%) were blind due to corneal opacity, whereas 60 eyes (31.3%) had cataracts, and 45 (23.4%) were blind table 1: ocular findings in leprosy patients findings no. of eyes total (n = 384) no (%) χ2 p value right (n = 192) left (n = 192) lid involvement 54 48 102 (26.5) 0.48 0.488 lagophthalmos 60 30 90 (23.0) 13.06 0.001 corneal opacity 42 42 84 (21.9) 0.00 1.00 uveitis 30 48 78 (20.0) 5.21 0.02 cataract 24 30 54 (14.0) 0.78 0.378 retinal lesions 0 12 12 (3.0) 0.001 phthisis bulbi 0 6 6 (1.6) 0.03 va <6/60 90 102 102 (50%) 1.50 0.2206 fep = fisher exact probability; * = statistically significant; va = visual acuity raga a. a. salem clinical and basic research | 461 because of uveitis. thirty-seven (19%) patients had binocular blindness. table 4 gives a summary of the ocular pathologies and main causes of blindness in different studies of leprosy. discussion this study, the first of its kind in yemen, identified the main ocularand vision-threatening complications of leprosy. ocular complications were found in 97% of cases studied. over one-third of the patients’ eyes had at least one pathology. eyelid involvement was the most common problem observed. half of the eyes had a va of <6/60. the main cause of blindness among these patients was corneal opacity detected in more than a third of patients. most of the world's leprosy sufferers live in developing countries where the prevalence of many other diseases is high and medical care is very limited. generally, patients suffer from stigmatisation, which is an experience common to leprosy patients in all societies, and this limits their use of the scarce medical services that are available. unfortunately, the resulting delays in treatment worsen long-term outcomes. many studies that have dealt with leprosy either in yemen or in its neighbouring gulf cooperation council (gcc) countries have been epidemiological and therefore, have not reported the ocular complications and sequelae of the disease which are challenging for patients.14–17 in this study, out of 384 eyes, 97% of the patients had ocular complications, which is comparable to results in iran (98.53%)18 and india (87%),19 but a much higher than that reported in nepal (57%),20,21 brazil (31.5%),22 or south korea (34%).23 this could be explained by the fact that a higher proportion of yemeni patients usually present late for treatment and have more limited access to medical care. in the present study, the majority of patients were males (93.8%), a similar percentage to that noted in other studies.20,24,25 however, the male to female ratio in this study was 15:1, which is considerably higher than that of a study in nepal21 that reported a ratio of 3:1 and a study by holmes that reported a ratio of 2:1.26 in addition to the stigma presented by the disease itself, this ratio can be explained by the cultural habits and socioeconomics of yemeni people as yemeni women make use of health services less frequently than men. the mean age of the patients in this study was 55.4 years which was significantly higher than the 35.2 years reported in a study done by wade et al.27 in the present study, a higher proportion of the patients (81.8%) were over 40 years of age, which is similar to the earlier observations from nepal,21 south korea,24 and south vietnam.25 gupta et al. reported that ocular lesions were seen more frequently with increasing patient age and disease duration.28 similar results were documented table 2: distribution of ocular findings in leprosy patients according to age and duration of disease findings n = 384 eyes, (192 patients) age in years duration in years 20-40 n (%) >40 n (%) <10 n (%) 10-20 n (%) >20 n (%) lid involvement 30 (7.8) 72 (18.7) 15 (3.9) 36 (9.3) 51 (13.3) lagophthalmos 39 (10) 51 (13.2) 12 (3) 33 (8.5) 45 (11.7) corneal opacity 30 (7.8) 54 (14.1) 12 (30 33 (8.5) 45 (11.7) uveitis 45 (11.7) 33 (8.6) 15 (3.9) 33 (8.6) 30 (7.8) cataract 12 (3) 42 (11) 9 (2.3) 15 (3.9) 30. (7.8) retinal lesions 3 (.8) 9 (2.3) 0 6 (1.6) 6 (1.6) phthisis bulbi 0 6 (1.6) 0 3 (.8) 3 (.8) total 159 (41.1) 267 (69.5) 57 (14.8) 156 (40.6) 213 (55.5) without lesions 12 (3) 0 9 (2.3) 3 (.8) 0 va <6/60 6 (1.6) 186 (48.4) 30 (7.8) 24 (6.3) 138 (36) va = visual acuity. ocular complications of leprosy in yemen 462 | squ medical journal, november 2012, volume 12, issue 4 in this study where ocular involvement increased with disease duration and patient age. only 14.8% of patients who had had leprosy for <10 years had ocular involvement as opposed to 55.5% who had had the disease for >20 years. similar findings were reported in nepal20 and nigeria.29 eyelid involvement was the most frequent ocular complication observed in this study (26.5%). however, the possibility of trachoma as a contributing factor cannot be excluded, although leprosy itself can cause lid affection. lagophthalmos and corneal opacity were other common ocular complications, representing 23 and 21.9% of cases, respectively. this finding was similar to a study done in nepal where 45% of patients experienced either lagophthalmos or corneal opacity.21 this finding is not surprising as leprosy is a granulomatous disease primarily affecting the peripheral nerves. uveitis (20%) and cataracts (14%) were the next two most common ocular complications observed in this study. cataract was seen with higher frequency among patients >40 years (11%) as compared to 3% in patients of <40 years. this could simply be age-related; however, some cataracts may have been due to long-term steroid use in severe or recurrent leprosy immune reactions, or due to chronic uveitis. at the level of the posterior segment we noticed only 12 cases (3%). most of them were not related to the disease but showed age-related macular degeneration, comparable to the observation by chams et al., who reported macular degeneration in 5.2% of patients.18 lid lesions and lagophthalmos were observed with a higher frequency in the right as opposed to the left eye, which was statistically significant. moreover, there was a significantly higher percentage of uveitis observed in the left eye compared to the right one. however, retinal lesions and phthisis bulbi were only documented in patients’ left eyes. the significant difference in the rate of occurrence of ocular complications between right and left eyes remains a mystery. among yemeni patients with ocular complications, 50% of eyes were blind which is comparable to results in nepal (48%), and in cameroon (38.3%); however, these rates are much higher than those reported by vedy et al.1 (2– 5%), sansarricq (5.4%)31 and nepal et al.21 these differences could be due to lack of uniformity in the definition of blindness, with blindness being defined as va ranging from <0.1, to <6/60, or <6/120 with table 3: prevalence of blindness in different ocular leprotic lesions (n = 192 eyes) causes n (%) 95% confidence interval corneal opacity 69. (35.9) 29.3–43.2 cataract 60 (61.3) 24.9–38.4 uveitis 45 (23.4) 17.8–30.2 retinal lesions 12 (6.3) 3.0–10.9 phthisis bulbi 6 (3.1) 1.2–7.0 table 4: prevalence of ocular pathologies (oc) and main cause of blindness in different studies of leprosy author/year country sample size prevalence of oc in % prevalence and main cause of blindness in % ocular complications lamba, 198415 india 650 87.3 co = 33.6 lago = 45 lago, co, cat, uveits lewallen, 200019 korea 270 34 cat = 46 co = 87 cat, co, uveitis, lago mvogo, 200126 cameroon 218 77.5 cat = 38.3 lago = 33.2 co, lago, lid lesions, iritis nepal, 200417 nepal 58 57 cs = 48 co = % unreported cs, co, lago, uveitis, cat. mpyet, 200525 nigeria 480 47 cat = 31.9 lago = 46 cat, lago, co, uveitis present study yemen 192 97 co = 50 lago = 35.9 lid lesion, lago, co, uveitis, cat co = corneal opacity; lago = lagophthalmos; cat = cataract; cs = corneal sensitivity raga a. a. salem clinical and basic research | 463 best correction in the better eye.12–30 out of these blind eyes, 37 patients (19%) were completely disabled due to binocular blindness. corneal opacity was the commonest cause of blindness in this study (69 out of 192 patients; 35.9%) which is logical as lagophthalmos and lid involvement were the most frequent complications; they may lead to exposure keratitis, corneal ulceration or corneal anaesthesia. corneal opacity was the second commonest cause of blindness among leprosy patients in a study done in nigeria (28%), which also confirms that in leprosy the cornea is a target organ either indirectly or directly through the spread of bacilli by an exogenous, haematogenous, or neurogenous route.1,29 cataracts ranked as the second most common cause of blindness (31.3%) in this study, while it was the most common cause in nigeria (46%) and south korea (87%).23–32 in nepal, uveitis with secondary glaucoma was a primary cause of blindness in the past but with increased knowledge of the disease and its complications, and the introduction of new treatments, these causes have declined dramatically.20 in contrast, in the current study, uveitis was found to be the third most common blinding condition (23.4%). this could be explained by the fact that most of the patients with chronic cases of uveitis had extremely constricted pupils, and treatment to dilate them was unsatisfactory due to the atrophy of the iris dilator muscles and synechia. conclusion ocular complications from leprosy are frequent in yemen regardless of the form of leprosy, with lid involvement being the most frequent complication. of the 384 eyes examined, 50% were blind due to leprosy. corneal opacity, cataracts, and uveitis were the most common causes of this blindness. since ocular involvement occurs late in the course of the disease, blinding lesions could be prevented by early diagnosis, and prompt and adequate treatment. therefore, all health and paramedical personnel in charge of leprosy patients must be trained in the basics of the disease and its ocular complications. additionally, a policy should be enacted whereby health care providers ensure patient follow-up during and after mdt, with periodic ophthalmic examinations in leprosaria. further research should be done to relate the ocular complications to the type and reactions of leprosy, and to ascertain whether released patients are still undergoing mdt. there is an urgent need for better collaboration between leprosy control and blindness prevention programmes, and their integration into general health services to enable patient access to high quality eye care services and to allay unjustified fears of leprosy. a c k n o w l e d g e m e n t s i appreciate the support and cooperation of the administration and staff of the university of aden hospital who helped with facilitating this study, and the technicians rafeq a. mohamed, abdula s. mahmood, and sulaiman abdul-raqueeb, who assisted me with the patient survey. references 1. vedy j. precis d'ophtalmologie tropicale. 2nd ed. marseille: diffusion de librairie, 1988. p. 251. 2. choyce dp. ocular leprosy with references to certain cases shown. proc r soc med 1955; 48:108–12. 3. cochrane rg. leprosy in india: a survey. london: world dominion press 1927. p. 22. 4. duke-elder s. diseases of the eyelids. in: duke es, jay bs, eds. system of ophthalmology, vol. xiii, part i. london: henry kimpton 1974. p. 501. 5. dharmendra ns. notes on leprosy. 2nd ed. new delhi: indian ministry of health 1967. p. 408. 6. job ck. pathology of leprous osteomylitis. int j lepr 1963; 31:26–33. 7. al-jnadi aaa. bibliography of rulers of yemen (arabic) part i. republic of yemen: ministry of education 1983. p. 207. 8. fawdry al. notes on leprosy in aden. lepr rev 1959; 30:114–7. 9. al-qubati y. leprosy in yemen. world health 1996; 49:18–19. 10. al-qubati y, al-kubati as. dermatologists combat leprosy in yemen. intl j dermatol 1997; 36:920–2. 11. hogeweg m, kenyon je. prevention of blindness in leprosy and the role of the vision 2020 programme. eye (lond) 2005; 19:1099–105. 12. courtright p, daniel e, sundarrao, ravanes j, mengistu f, balachew m, et al. eye diseases in multibacillary leprosy patients at the time of their leprosy diagnosis: findings from the longitudinal study of ocular leprosy (losol) in india, the philippines, and ethiopia. lepr rev 2002; 73:225–38. 13. thompson kj, allardice gm, babu gr, roberts h, kerketta w, kerketta a. patterns of ocular morbidity ocular complications of leprosy in yemen 464 | squ medical journal, november 2012, volume 12, issue 4 and blindness in leprosy—a three centre study in eastern india. lepr rev 2006; 77:130–40. 14. al-kandari s, al-anezi a, pugh rn, al-qasaf f, al-abyad s. leprosy in kuwait: an epidemiological study of new cases. ann trop med parasitol 1990; 84:513–22. 15. bahr gm, chugh td, behbehani k, shaaban ma, abdul-aty m, et al. unexpected findings amongst the skin test responses to mycobacteria of bcg vaccinated kuwaiti school children. tubercle 1987; 68:105–12. 16. ibrahim ma, kordy mn, aiderous ah, bahnassy a. leprosy in saudi arabia, 1986-89. lepr rev 1990; 61:379–85. 17. al-mutairi n, al-doukhi a, ahmad ms, elkhelwany m, al-haddad a. changing demography of leprosy: kuwait needs to be vigilant. int j infect dis 2010; 14:e876–80. 18. chams h, sadeghi-tari a, farokh d, stanford jl, dolatti y, feval f. la lèpre en iran. ophtalmologie 1993; 7:80–2. 19. lamba pa, kumar ds. ocular involvement from leprosy. indian j ophthalmol 1984; 32:61–3. 20. malla ok, brandt f, anten jg. ocular findings in leprosy patients in an institution in nepal (khokana). br j ophthalmol 1981; 65:226–30. 21. nepal bp, shrestha ud. ocular findings in leprosy patients in nepal in the era of multidrug therapy. am j ophthalmol 2004; 137:888–92. 22. monteiro lg, campos wr, orefice f, grossi ma. study of ocular changes in leprosy patients. indian j lepr 1998; 70:197–202. 23. lewallen s, tungpakorn nc, kim sh, courtright p. progression of eye disease in ‘cured’ leprosy patients: implications for understanding the pathophysiology of ocular disease and for addressing eye care needs. br j ophthalmol 2000; 84:817–21. 24. ffytche tj. cataract surgery in the management of the late complications of lepromatous leprosy in south korea. br j ophthalmol 1981; 65:243–8. 25. hornblass a. ocular leprosy in south vietnam. am j ophthalmol 1973; 75:478–80. 26. holmes wj. the eyes in leprosy. trans ophthalmol soc u k 1961; 81:397–420. 27. wade a, nadiaye mr, balo kp, ceccon jf. oeil et lèpre. med afr noire 1985; 32–7. 28. gupta hr, shakya s, shah m, pradhan hm. leprosy blindness in nepal. nepal med coll j 2006; 8:140–2. 29. mpyet c, solomon aw. prevalence and causes of blindness and low vision in leprosy villages of north eastern nigeria. br j ophthamol 2005; 89:417–9. 30. mvogo ce, bella-hiag al, ellong a, achu jh, nkeng pf. ocular complications of leprosy in cameroon. acta ophthalmol scand 2001; 79:31–3. 31. sansaricq h. la lèpre, vol. 1. paris: editions ellipsesaupelf/uref, 1995. 32. courtright p, lewallen s, narong, tungpakorn n, cho b, lim y, et al. cataract surgical coverage, barriers to acceptance of surgery and outcome of surgery in a population based survey in korea. br j ophthalmol 2001; 85:643–47. clinical & basic research sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e330-336, epub. 24th jul 14 submitted 27th oct 13 revision req. 5th jan 14; revision recd. 2nd feb 14 accepted 18th feb 14 السمنة وحماوالت إنقاص الوزن عند من لديهم تاريخ شخصي لإلصابة بالسرطان اأمربيا موتن،كاين جيفريز، دانيال لربي، روك�سانا ا�سمث-وايت، تليتا تايلور، لوري ويل�سن، بابا فيني بادونقا، وين فيدريك، وادينكا ليوميو abstract: objectives: obesity is a risk factor for many cancers and obese cancer patients have a poorer prognosis. this study aimed to evaluate the prevalence of obesity and attempts to lose weight among cancer survivors. the effects of cancer treatment and time since cancer treatment were also evaluated. methods: the 2007 health information national trends survey data were analysed between 2011 and 2013; respondents with (n = 966) and without (n = 6,093) a personal history of cancer were identified. each respondent’s body mass index (bmi) was calculated using self-reported height and weight measurements and categorised as normal (<25 kg/m2), overweight (25‒29.9 kg/m2) or obese (≥30 kg/m2). results: cancer survivors were older (mean age = 63.4 versus 44.7 years for those with no history of cancer). overall, there were similar percentages of overweight (37.6% versus 34.1%; relative risk ratio [rrr] = 0.99; 95% confidence interval [ci]: 0.75‒1.31) and obese (31.4% versus 27.5%; rrr = 1.04; 95% ci: 0.79‒1.39) respondents among both cancer survivors and those without a history of cancer. among overweight and obese participants, cancer survivors did not demonstrate increased weight loss attempts compared to those without a history of cancer (61.6% versus 66.3%; odds ratio = 0.94; 95% ci: 0.73‒1.20). conclusion: a high prevalence of overweight and obese cancer survivors were identified without any association with cancer treatment. however, cancer survivors did not demonstrate increased attempts to lose weight in comparison to those without a history of cancer despite awareness of their degree of body fatness. increased efforts to promote the maintenance of a healthy weight among cancer survivors are needed. keywords: cancer; body mass index; overweight; obesity; weight loss. امللخ�ص: الهدف: تعد ال�سمنة واحدة من عوامل اخلطورة لالإ�سابة مبختلف اأنواع ال�رسطان، ولدى امل�ساب بال�رسطان وال�سمنة معا تنبوؤا اأ�سواأ من امل�سابني بال�رسطان اأو ال�سمنة فقط. وتهدف هذه الدرا�سة لتقييم معدل انت�سار ال�سمنة وحماولت اإنقا�س الوزن عند من تعافوا من ال�رسطان. ومت كذلك تقييم تاأثري العالج من ال�رسطان ومدة الإ�سابة به. الطريقة: مت حتليل اجتاهات امل�سح الوطني للمعلومات ال�سحية لعام 2007 م بني عامي 2011 و2013م عند 966 من من لهم تاريخ مر�سي بال�رسطان و6,093 من غري امل�سابني به. ومت ح�ساب موؤ�رس كتلة اجل�سم من قيا�سات الأطوال والأوزان التي قام بها امل�ساركون يف البحث باأنف�سهم، والتي �سنفت امل�ساركني على اأنهم اإما ذوي وزن طبيعي )اأقل من 25 كجم لكل مرت2( اأو وزن زائد )25 اإىل 29.9 كجم لكل مرت2( اأو بدناء )30 اأو اأكرث كجم لكل مرت2(. النتائج:وجد عاما مقارنة بـ 44.7 عاما(، وكانت ن�سبة ذوي الأوزان اأن الذين تعافوا من ال�رسطان كانوا اأكرب �سنا من غريهم )يف املتو�سط 63.4 الزائدة عند من تعافوا من ال�رسطان ومن لي�س لديهم تاريخ مر�سي به متقاربة )%37.6 و %31.4؛ ون�سبة املخاطرة الن�سبية 0.99 وفا�سل الثقة %99 هو )1.31–0.75(. اأما عند البدناء فقد كانت هذه الن�سب هي %31.4 و%27.5؛ ون�سبة املخاطرة الن�سبية 1.40 وفا�سل الثقة %99 هو )1.39–0.79(. ووجد كذلك اأن عدد حماولت خف�س الوزن عند ذوي الأوزان الزائدة اأو البدناء من املتعافني من ال�رسطان مل تكن خمتلفة عنها عند غري امل�سابني بال�رسطان )%61.6 مقابل %66.3؛ مع ن�سبة اأرجحية 0.94، وفا�سل الثقة %95 هو )1.20–0.73(. اخلال�صة: مت التعرف على عدد كبري ن�سبيا من ذوي الأوزان الزائدة والبدناء يف اأو�ساط املتعافني من ال�رسطان دون اأن يكون لذلك ارتباط بعالج ال�رسطان. ومل تكن حماولت تقليل الأوزان خمتلفة عند هوؤلء عنها عند غري امل�سابني بال�رسطان رغم معرفتهم بالزيادة يف اأوزانهم. هنالك حاجة ل�ستمرار اجلهود للدعوة للحفاظ على اأوزان مثالية عند املتعافني من ال�رسطان. مفتاح الكلمات: ال�رسطان؛ موؤ�رس كتلة اجل�سم؛ وزن زائد؛ �سمنة؛ اإنقا�س الوزن. obesity and weight loss attempts among subjects with a personal history of cancer ambria moten,1 kayin jeffers,1 daniel larbi,1 roxanne smith-white,1 teletia taylor,2 lori wilson,3 babafemi adenuga,4 wayne frederick,2,3 *adeyinka laiyemo1 advances in knowledge it is unknown whether cancer treatment affects the body mass index of cancer survivors. the present study evaluated data on a large sample of american adults and found that the type of cancer treatment and the elapsed time since treatment did not affect the prevalence of obesity among cancer survivors. despite their poorer prognosis and awareness of their degree of body fatness, obese and overweight cancer survivors did not demonstrate increased efforts to lose weight in comparison to those without cancer. departments of 1medicine and 3surgery, howard university, washington d.c., usa; 2howard university cancer center, washington d.c., usa; 4howard university hospital, washington d.c., usa *corresponding author e-mail: adeyinka.laiyemo@howard.edu ambria moten, kayin jeffers, daniel larbi, roxanne smith-white, teletia taylor, lori wilson, babafemi adenuga, wayne frederick and adeyinka laiyemo clinical and basic research | e331 cancer is the second leading cause of death in the usa. in 2012, there were approximately 1.6 million new cases of cancer and 577,000 deaths from cancer; however, more people are surviving after being diagnosed with cancer.1 the five-year relative survival rate for cancers diagnosed between 1975 and 1977 was only 49%; this rose to 67% for cancers diagnosed between 2001 and 2007.1 in 2006, there were 11.4 million cancer survivors in the usa.1 the prevalence of obesity has increased in many parts of the world. for example, an estimated 72.5 million american adults are obese, representing approximately 36% of the population.2 in oman, it has been estimated that 30% of the population is overweight and 20% is obese.3 while there have been major advances in the management of cancer, leading to an improvement in the survival rate, obesity has nevertheless been shown to have a negative impact on the prognosis of those with cancer.4 therefore, the rising incidence of obesity could undermine the improvement in cancer survival achieved in the last two decades. obesity increases the risk of many cancers including cancers of the colon and pancreas.1 obese cancer survivors also have an increased risk of cancer recurrence, second primary cancer occurrence and the development of comorbidities such as osteoporosis, diabetes and cardiovascular disease.1,5‒7 furthermore, being overweight and/or obese are contributory factors in 14‒20% of all cancer mortalities.1 the reported prevalence of obesity among cancer survivors varies, ranging from 15‒28%.8,9 although obesity is associated with an increased risk of cancer, it is uncertain whether the experience or diagnosis of cancer encourages cancer survivors to modify their lifestyle choices, thereby leading to a decrease in the prevalence of obesity after the cancer diagnosis. previous studies have suggested that there is no difference between the body mass indexes (bmi) of cancer survivors and those without a history of cancer; however, these studies were limited in that they focused on either one gender, a particular type of cancer or on participants from one geographical area.9‒13 no previous study has evaluated the effect of cancer treatment on the prevalence of obesity among cancer survivors. this study examines the prevalence of overweight and obesity among a nationally representative sample of adult cancer survivors in the usa. it also evaluates the time interval since the cancer treatment as well as the cancer survivors’ perception of their own body weight and examines weight loss attempts among overweight and obese cancer survivors. methods this cross-sectional study was conducted between 2011 and 2013 at howard university hospital, washington, d.c., usa, using data from the 2007 health information national trends survey (hints).14 hints collects biennial data on cancerrelated information in the usa. the hints 2007 data were collected between january and may 2008 using two different modalities, telephone and postal questionnaire. one sample was obtained via random digit dial in which participants completed a 30-min telephone survey; there were 4,092 respondents with an overall response rate of 24.2%. the other sample was obtained via a random selection of addresses from a list provided by the usa postal service, where participants were mailed a printed survey and given a postage-paid envelope in which to return the survey. this yielded 3,582 respondents with an overall response rate of 31%. these two modalities had a combined sample of 7,674 participants, representative of the national population.14 the analytic sample used in this study included 7,059 participants who provided information regarding their height, weight and cancer history. the respondents answered questions which ascertained whether they had ever been diagnosed with cancer, the site of that cancer, the treatment received and the time since completion of the treatment. overall, there were 966 respondents with and 6,093 respondents without a personal history of cancer. the outcomes of interest were the bmi of overweight or obese respondents and their perceptions of body weight and attempts to lose weight in the previous 12 months. the bmi of the respondents was calculated as the body weight in kg divided by the height in metres squared and categorised application to patient care the findings of this study underscore the need to implement changes in the routine patient care of cancer survivors. patient-provider discussions regarding maintaining a healthy weight should be emphasised among cancer survivors to improve patient outcomes. these discussions should focus on the importance of a healthy diet and engaging in physical exercise. in addition, the organisation of support groups with a focus on weight maintenance may provide additional social support for cancer survivors. obesity and weight loss attempts among subjects with a personal history of cancer e332 | squ medical journal, august 2014, volume 14, issue 3 as normal (<25 kg/m2), overweight (25–29.9 kg/m2) or obese (≥ 30 kg/m2). of note, only seven (0.7%) cancer survivors had a bmi <18, four of whom had bmis of 17.2–17.9 kg/m2. in the current study, data from these seven respondents were included in the normal category. based on the recommendation of hints investigators, the effect of the survey modes (mail and telephone) was evaluated to determine whether a combined analysis was appropriate. there was no difference in modes regarding history of cancer and bmi (p >0.1 for all analyses). therefore, the combined data of the two modes were used for these analyses. the demographic characteristics of subjects without a history of cancer were compared with those of cancer survivors. the mean age by cancer survival status was evaluated. categorical variables were also compared between cancer survivors and subjects without a history of cancer. multinomial regression models were used to evaluate the association of bmi categories with a personal history of cancer (yes versus no), cancer treatment (yes versus no) and time since cancer treatment (currently undergoing cancer treatment versus completed treatment less than one year previously versus completed treatment more than one year previously). relative risk ratios (rrr) and 95% confidence intervals (ci) were also calculated. logistic regression models were used to evaluate the association of cancer survival status with weight loss attempts within the previous 12 months among overweight and obese participants and to determine the odds ratios (or) and 95% cis. due to the concern that the risk of poor outcomes with nonmelanoma skin cancers might be lower than other cancers, subjects with non-melanoma skin cancers (n = 234) were excluded and the analysis was repeated. the results were unchanged (data not shown). missing variables (22 education levels, 80 smoking statuses, 142 races, 937 income levels, 25 marital statuses and 98 insurance statuses) were set to missing without the use of dummy variables. hints data contained sample weights to obtain population-level estimates and a set of 50 replicated sampling weights to obtain the correct standard errors.14 in this study, survey weights were used in all analyses and variance estimations were performed using the taylor series (linearisation) method to account for the complex survey design. all reported p values corresponded to two-sided tests and only weighted percentages were reported in this analysis. stata® statistical software, version 11.2 (statacorp lp, college station, texas, usa) was used for all analyses. results the mean age of the respondents was 46.1 years and 50.8% were women. approximately 70.2% of respondents identified themselves as white/caucasian, 11.4% as black and 12.1% as hispanic. a total of 966 (7.3%) respondents had a previous cancer diagnosis while 6,093 (92.7%) had no history of cancer. the most common cancer types were non-melanoma skin cancer (22.7%), breast cancer (16.2%), prostate cancer (10.5%), melanoma skin cancer (9.6%), cervical cancer (10.4%), colon cancer (5.9%) and endometrial cancer (2.9%). cancer survivors were older and more likely to be female [table 1]. furthermore, former smokers, non-hispanic caucasians and respondents with a lower socioeconomic status were more likely to have table 1: characteristics of respondents by cancer status (n = 7,059)* characteristics† no history of cancer n (weighted %) cancer survivors n (weighted %) p value mean age in years 44.7 (95% ci: 44.4‒45.0) 63.4 (95% ci: 62.4‒64.4) gender male female 2,388 (93.5) 3,705 (91.9) 403 (6.5) 563 (8.1) 0.001 education less than high school high school college/ vocational school college graduate 533 (91.4) 1,491 (92.5) 1,856 (94.0) 2,194 (91.7) 96 (8.6) 237 (7.5) 259 (6.0) 371 (8.3) 0.013 smoking status never former current 3,228 (94.1) 1,730 (88.1) 1,067 (94.8) 413 (5.9) 411 (11.9) 130 (5.2) <0.001 race non-hispanic white caucasian non-hispanic black hispanic other 4,464 (91.2) 599 (94.6) 532 (96.9) 375 (97.2) 821 (8.8) 54 (5.4) 39 (3.1) 33 (2.8) <0.001 income <$20,000 $20,000‒34,999 $35,000‒49,999 $50,000‒74,999 ≥$75,000 921 (92.3) 864 (92.0) 716 (91.0) 1,029 (93.9) 1,772 (94.0) 153 (7.7) 157 (8.0) 134 (9.0) 142 (6.1) 234 (6.0) 0.025 marital status single married 2,459 (93.8) 3,612 (91.8) 389 (6.2) 574 (8.2) 0.002 health insurance no yes 695 (97.1) 5,317 (91.9) 60 (2.9) 889 (8.1) <0.001 ci = confidence interval. *survey weights were used for all analyses. the weighted total population estimate was n = 205,672,703. †some data were missing for respondents: 22 education levels, 80 smoking statuses, 142 races, 937 income levels, 25 marital statuses and 98 insurance statuses. ambria moten, kayin jeffers, daniel larbi, roxanne smith-white, teletia taylor, lori wilson, babafemi adenuga, wayne frederick and adeyinka laiyemo clinical and basic research | e333 a history of cancer [table 1]. a total of 2,607 (37.8%) respondents were in the normal bmi category, while 2,476 (34.4%) respondents were classified as overweight and 1,976 (27.8%) respondents were obese. approximately 38% of cancer survivors were overweight and 31.4% were obese in comparison to 34.1% overweight and 27.5% obese respondents without a history of cancer [table 2]. after adjusting for age, sex, education, smoking, race, income, marital status and health insurance status, cancer survivors were as likely to be overweight (rrr = 0.99; 95% ci: 0.75–1.31) or obese (rrr = 1.04; 95% ci: 0.79–1.39) as those without cancer [table 2]. a total of 114 of the 953 cancer survivors (12.7%) reported that they did not undergo any cancer treatment even though 95.7% of these respondents had health insurance. cancer survivors who did not receive treatment had a non-statistically significant increased risk of being overweight (rrr = 1.42: 95% ci: 0.66‒3.06) or obese (rrr = 1.46; 95% ci: 0.64‒3.35) as compared to those without a history of cancer. however, cancer survivors who had received treatment had a similar risk of being overweight (rrr = 0.95; 95% ci: 0.70‒1.27) or obese (rrr = 1.00; 95% ci: 0.74‒1.35). the amount of time that had passed since undergoing cancer treatment had no significant effect on the risk of being overweight or obese [table 2]. participants’ opinions regarding their body weight are shown in table 3. the self-assessed perceptions of cancer survivors regarding their body weight were similar to those without a history of cancer. among respondents categorised as obese, 71.3% of cancer survivors and 65.4% of those without a history of cancer acknowledged that they were overweight. the majority of respondents believed that obesity was largely due to overeating and lack of exercise, regardless of cancer status. although there were no statistically significant differences between cancer survivors and those without a history of cancer, a general pattern was observed that cancer survivors displayed less frequent attempts to lose weight in the previous 12 months [table 3] and among all those with a bmi ≥25 kg/m2 [table 4]. discussion the prevalence of overweight (25–29 kg/m2) and obese (≥30 kg/m2) bmi categories among cancer survivors was evaluated. in addition, the effect of cancer treatment on bmi and weight loss attempts was assessed using nationally representative data. this study showed a high prevalence of excessive body size among cancer survivors; this prevalence was comparable to those without a history of cancer. table 2: adjusted* relative risk ratios for cancer status, cancer treatment and time since treatment by respondents’ body mass index (n = 7,059)† characteristics n bmi <25 n = 2,607 (37.8%) bmi 25–29 n = 2,476 (34.4%) bmi ≥30 n = 1,976 (27.8%) n (weighted %) n (weighted %) rrr (95% ci) n (weighted %) rrr (95% ci) cancer status no history of cancer 6,093 2,285 (38.3) 2,110 (34.1) reference 1,698 (27.5) reference cancer survivors 966 322 (31.1) 366 (37.6) 0.99 (0.75‒1.31) 278 (31.4) 1.04 (0.79‒1.39) cancer treatment no history of cancer 6,093 2,285 (38.3) 2,110 (34.1) reference 1,698 (27.5) reference no treatment 114 32 (23.8) 42 (38.9) 1.42 (0.66‒3.06) 40 (37.3) 1.46 (0.64‒3.35) treatment 839 286 (32.1) 322 (37.6) 0.95 (0.70‒1.27) 231 (30.3) 1.00 (0.74‒1.35) time since cancer treatment no history of cancer 6,093 2,285 (38.3) 2,110 (34.1) reference 1,698 (27.5) reference still undergoing treatment 90 29 (32.3) 41 (43.8) 0.94 (0.41–2.14) 20 (23.9) 0.71 (0.32‒1.55) completed treatment <1 year ago 144 47 (32.3) 67 (43.8) 0.87 (0.46‒1.64) 30 (23.9) 0.66 (0.26‒1.66) completed treatment ≥1 year ago 534 185 (32.2) 187 (34.3) 0.88 (0.63‒1.23) 162 (33.5) 1.11 (0.75‒1.64) bmi = body mass index in kg/m2; rrr = relative risk ratio; ci = confidence interval. *adjusted for age, sex, education, smoking, race, income, marital status and health insurance status. †survey weights were used for all analyses. the weighted total population estimate was n = 205,672,703. obesity and weight loss attempts among subjects with a personal history of cancer e334 | squ medical journal, august 2014, volume 14, issue 3 cancer survivors did not demonstrate greater efforts to lose weight despite their increased risk of poor health outcomes. this underscores the need for care providers to place more emphasis on the maintenance of healthy body weight in routine care for cancer survivors. analysis of the characteristics of the study population revealed that cancer survivors were significantly more likely to be female, white/caucasian, married and have health insurance. this is consistent with the published literature. for example, courneya et al. reported that a greater proportion of canadian cancer survivors were female (59.6% versus 49.4%) and white/caucasian (91.6% versus 81.5%) when compared to those without cancer.15 similarly, fairley et al. reported that cancer survivors from massachusetts were more likely to be female (62.1% versus 52.4%) and white/caucasian (94.3% versus 84.0%) compared to those without a history of cancer; however, there was no difference in marital status between the two groups.12 the similarity in the prevalence of overweight and obese bmi categories among respondents with and without a personal history of cancer in this study was comparable to prior studies. for instance, rogers et al. compared lifestyle behaviours, obesity and perceived health among 2,524 men with prostate cancer and 61,138 men without it.11 the investigators found no significant difference in the prevalence of obesity between the two groups. similarly, fairley et al. analysed data from the 2006 massachusetts behavioral risk factor surveillance system survey and found no significant difference between 716 cancer survivors and 7,375 participants without cancer with respect to smoking, obesity and physical activity.12 eakin et al. investigated the health behaviours of cancer survivors in australia and reported that cancer survivors were slightly more likely to be obese than those without a history of cancer.16 in an analysis of physical activity and obesity among canadian cancer survivors, courneya et al. reported in a subgroup analysis that prostate cancer survivors were less likely to be obese table 3: respondents’ responses regarding their body weights and weight loss attempts by cancer status and body mass index* responses no history of cancer cancer survivors bmi <25 bmi 25–29 bmi ≥30 bmi <25 bmi 25–29 bmi ≥30 your opinion regarding your body weight overweight 2.2 21.1 65.4 6.0 24.8 71.3 slightly overweight 25.1 54.2 29.5 25.8 54.3 24.4 underweight 3.9 0.3 0 4.9 0 0 slightly underweight 10.9 0.9 0.4 9.3 0.2 0 just about right 57.9 23.5 4.6 54.0 20.8 4.3 extent you believe that obesity is caused by overeating and lack of exercise a lot 73.5 75.7 72.9 73.0 81.7 65.5 some 22.2 20.0 21.0 23.5 13.9 29.1 a little 3.2 3.2 5.5 3.5 2.6 3.5 not at all 0.7 0.8 0.6 0 1.8 1.6 attempts to lose weight in the past 12 months yes 33.3 60.1 74.1 27.5 53.0 71.9 no 66.7 39.9 25.9 72.5 47.0 28.1 bmi = body mass index in kg/m2.*data shown in weighted percentages. table 4: odds ratios of weight loss attempts among overweight and obese* respondents by cancer status cancer status tried to lose weight in the past 12 months n (weighted %) attempted versus not attempted to lose weight or (95% ci) no yes unadjusted adjusted† no history of cancer 1,237 (33.7) 2,563 (66.3) reference reference cancer survivors 247 (38.4) 397 (61.6) 0.81 (0.64‒1.03) 0.94 (0.73‒1.20) or = odds ratio; ci = confidence interval. *body mass index of ≥25 kg/ m2. †adjusted for age, sex, education, smoking, race, income, marital status and insurance status. ambria moten, kayin jeffers, daniel larbi, roxanne smith-white, teletia taylor, lori wilson, babafemi adenuga, wayne frederick and adeyinka laiyemo clinical and basic research | e335 (or = 0.71; 95% ci: 0.56–0.90) compared to men without the disease.15 moreover, it was noted that prostate cancer survivors were 27% more likely to be physically active (or = 1.27; 95% ci: 1.01–1.59). this increase in physical activity may account for the lower incidence of obesity in men with prostate cancer. there were no other significant differences in the prevalence of obesity between those with and without other types of cancer.15 it is conceivable that the dietary patterns of cancer survivors could be affected by cancer treatment— partly due to the side-effects of the treatment and the amount of time that has elapsed since treatment— and that this may affect the relationship between body weight and cancer survival status. however, the authors are not aware of any previous study that has evaluated the association of cancer treatment on the prevalence of overweight and obesity among cancer survivors. in the current study, no correlation was noted between the effect of receiving cancer treatment and the time since completing cancer treatment on the body weight of cancer survivors. prior studies have reported inconsistent or conflicting results with respect to physical activity levels between cancer survivors and those without a history of cancer. for instance, cancer survivors were more likely to be active,17 less likely to participate in strenuous physical activity,9,12 and there was no difference in the level of physical activity among cancer survivors and those without a history of cancer.16 although physical activity levels have been assessed in other studies, a search of the literature did not reveal any studies evaluating overall perceived weight loss attempts among those with and without a history of cancer. the findings of this study revealed that cancer survivors were not more likely to attempt to lose weight than those without a history of cancer. this is an area of research worthy of further investigation in order to discover the factors that motivate important behavioural changes among cancer survivors. given the poorer health outcomes that are associated with being overweight or obese, particularly among cancer survivors, the high prevalence of overweight and obesity among cancer survivors observed in this study should be viewed as a call for action. this may be applicable to other countries as well. these findings underscore the importance of addressing this issue with comprehensive interdisciplinary efforts in order to motivate cancer survivors to maintain a healthy weight and to equip healthcare providers with the resources to facilitate cost-effective targeted interventions for their patients. there is a need to improve communication between oncologists, primary care providers and patients as well as enhance public awareness through a process of education and information dissemination on cancer, an emphasis on discussing the prevention and effective treatment of cancer upon diagnosis.18 apart from encouraging the adoption of a healthy diet and increasing physical activity, obese cancer survivors should be evaluated for bariatric surgical intervention. recent research has suggested that the procedure can be safely performed among cancer survivors.19 in addition, reports that obese patients had a reduced risk of cancer after undergoing bariatric surgeries also raises the possibility that maintaining a healthy weight through this modality may reduce the recurrence of cancer or second primary cancer incidence among cancer survivors.20–22 it is recommended that healthcare providers remain aware of the importance of maintaining a healthy weight and emphasise this to their patients, especially those who have a prior history of cancer. there is a need to increase public awareness of the health problems associated with obesity, particularly for cancer survivors. a multidisciplinary approach should be used to manage obesity among cancer survivors by involving nutritionists, social workers and personal trainers as local resources allow. physicians should also discuss and advocate weight loss surgery for qualified cancer survivors. there are some notable strengths of the current study, particularly that the study utilised a large, nationally representative sample of adults. in addition, the effects of cancer treatment and time since cancer treatment on obesity were also evaluated. however, there are some limitations to the study. the data used were based on self-reports by the patients. furthermore, it was impossible to analyse the exact types of cancer treatment received, such as radiation therapy and locoregional versus systemic therapy, as the information was not available. conclusion in conclusion, a high prevalence of overweight and obesity among cancer survivors was found, without any association with cancer treatment or elapsed time since treatment. the current study also revealed that cancer survivors, even though they had insight into their degree of body fatness, did not display greater efforts to lose weight in comparison to those without cancer. it is imperative that healthcare providers increase their efforts to encourage cancer survivors to maintain a healthy weight. obesity and weight loss attempts among subjects with a personal history of cancer e336 | squ medical journal, august 2014, volume 14, issue 3 references 1. american cancer society. cancer facts & figures 2012. from: www.cancer.org/research/cancerfactsfigures/ acspc-031941 accessed: aug 2013. 2. centers for disease control and prevention (cdc). vital signs: state-specific obesity prevalence among adults: united states, 2009. mmwr morb mortal wkly rep 2010; 59:951‒5. 3. lakhtakia r. conspicuous consumption and sedentary living: is this our legacy to our children? sultan qaboos univ med j 2013; 13:336‒40. 4. burney ia, al-moundhri ms. major advances in the treatment of cancer: what does a non-oncologist need to know? sultan qaboos univ med j 2008; 8:137‒48. 5. majed b, moreau t, senouci k, salmon rj, fourquet a, asselain b. is obesity an independent prognosis factor in woman breast cancer? breast cancer res treat 2008; 111:329‒42. doi: 10.1186/bcr3572. 6. chlebowski rt, aiello e, mctiernan a. weight loss in breast cancer patient management. j clin oncol 2002; 20:1128‒43. doi: 10.1200/jco.20.4.1128. 7. demark-wahnefried w, aziz nm, rowland jh, pinto bm. riding the crest of the teachable moment: promoting longterm health after the diagnosis of cancer. j clin oncol 2005; 23:5814‒30. doi: 10.1200/jco.2005.01.230. 8. rabin c, politi m. need for health behavior interventions for young adult cancer survivors. am j health behav 2010; 34:70‒6. doi: 10.5993/ajhb.34.1.9. 9. rausch sm, millay s, scott c, pruthi s, clark mm, patten c, et al. health behaviors among cancer survivors receiving screening mammography. am j clin oncol 2012; 35:22‒31. doi: 10.1097/coc.0b013e318200598e. 10. mayer dk, terrin nc, menon u, kreps gl, mccance k, parsons sk, et al. health behaviors in cancer survivors. oncol nurs forum 2007; 34:643‒51. doi: 10.1188/07.onf.643-651. 11. rogers lq, courneya ks, paragi-gururaja r, markwell sj, imeokparia r. lifestyle behaviors, obesity, and perceived health among men with and without a diagnosis of prostate cancer: a population-based, cross-sectional study. bmc public health 2008; 8:23. doi: 10.1186/1471-2458-8-23. 12. fairley tl, hawk h, pierre s. health behaviors and quality of life of cancer survivors in massachusetts, 2006: data use for comprehensive cancer control. prev chronic dis 2010; 7:a09. 13. coups ej, ostroff js. a population-based estimate of the prevalence of behavioral risk factors among adult cancer survivors and noncancer controls. prev med 2005; 40:702–11. doi: 10.1016/j.ypmed.2004.09.011. 14. cantor d, coa k, crystal-mansour s, davis t, dipko s, sigman r. health information national trends survey (hints) 2007: final report. from: www.hints.cancer.gov/docs/ hints2007finalreport.pdf accessed: may 2012. 15. courneya ks, katzmarzyk pt, bacon e. physical activity and obesity in canadian cancer survivors: population-based estimates from the 2005 canadian community health survey. cancer 2008; 112:2475‒82. doi: 10.1002/cncr.23455. 16. eakin eg, youlden dr, baade pd, lawler sp, reeves mm, heyworth js, et al. health behaviors of cancer survivors: data from an australian population-based survey. cancer causes control 2007; 18:881‒94. doi: 10.1007/s10552-007-9033-5. 17. bellizzi km, rowland jh, jeffery dd, mcneel t. health behaviors of cancer survivors: examining opportunities for cancer control intervention. j clin oncol 2005; 23:8884‒93. doi: 10.1200/jco.2005.02.2343. 18. burney ia. the trend to seek a second opinion abroad amongst cancer patients in oman: challenges and opportunities. sultan qaboos univ med j 2009; 9:260‒3. 19. gagné dj, papasavas pk, maalouf m, urbandt je, caushaj pf. obesity surgery and malignancy: our experience after 1500 cases. surg obes relat dis 2009; 5:160‒4. doi: 10.1016/j. soard.2008.07.013. 20. tee mc, cao y, warnock gl, hu fb, chavarro je. effect of bariatric surgery on oncologic outcomes: a systematic review and meta-analysis. surg endosc 2013; 27:4449‒56. doi: 10.1007/ s00464-013-3127-9. 21. christou nv, lieberman m, sampalis f, sampalis js. bariatric surgery reduces cancer risk in morbidly obese patients. surg obes relat dis 2008; 4:691‒5. doi: 10.1016/j.soard.2008.08.025. 22. ashrafian h, ahmed k, rowland sp, patel vm, gooderham nj, holmes e, et al. metabolic surgery and cancer: protective effects of bariatric procedures. cancer 2011; 117:1788‒99. doi: 10.1002/cncr.25738. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century sultan qaboos university med j, may 2013, vol. 13, iss.2, pp. 296-300, epub. 9th may 13 submitted 16th jul 12 revision req. 10th sep 12, revision recd. 5th jan 13 accepted 8th jan 13 department of psychiatry, ministry of health, manama, bahrain e-mail: aansari@health.gov.bh قياس درجة االعتالل عند االطفال ناقصي االنتباه وفارطي احلركة كجزء من عملية تقييم خمرجات العالج اأحمد مال اهلل الن�شاري العيادة يف )adhd( احلركة وفارطي النتباه ناق�شي لالأطفال العالج وخمرجات العتالل تقيم الدرا�شة هذه الهدف: امللخ�ص: اخلارجية لوحدة الطفال النف�شية با�شتعمال عدة م�شادر منها مقيا�ض التقييم ال�شامل لالأطفال )c-gas(. الطرق: مت اإختيارع�رسين طفاًل من �شن (4-16) �شنة بنظام ت�شل�شلي يف عام 2010 يف عيادة وحدة الطب النف�شي لالأطفال م�شت�شفى الطب النف�شي ، املنامة ، البحرين. مت ت�شخي�ض جميع الأطفال با�شطراب نق�ض النتباه وفرط احلركة ح�شب الدليل الت�شخي�شي والإح�شائي لال�شطرابات النف�شية حمايد باحث بوا�شطة الطفال هوؤلء على )c-gas( لالأطفال ال�شامل التقييم مقيا�ض طبق الرابع. املرجعي )dsm-iv-tr( لدى حت�شن حدوث الأطفال اأمور اأولياء لحظ النتائج: عليه. �شنة مرور بعد اأخرى ومرة العالج بداية مرهفي الأطفال يعرف ل جميع الطفال.اأظهرت نتائج قيا�ض درجة العتالل بعد مرور �شنة على العالج با�شتخدام )c-gas(حدوث حت�شن ذو دللة اإح�شائية .)p = 0.07( بينما مل يكن التح�شن بنف�ض الدرجة عند الأطفال ذوي ال�شطرابات امل�شاحبة الأخرى )p = 0.001( جلميع احلالت ال�صتنتاج: يعترب قيا�ض التح�شن با�شتخدام مقي ا�ض التقييم ال�شامل لالأطفال )c-gas( طريقة منا�شبة للح�شول على املعلومات وعليه فاإن البهحث ين�شح با�شتخدامة يف الأطفال امل�شابني با�شطراب نق�ض النتباه وفرط احلركة كجزء من العمل ال�رسيري العادي �شواء يف مرحلة الت�شخي�ض اأو قيا�ض م�شار احلالة وخمرجات العالج. مفتاح الكلمات: ا�شطراب نق�ض النتباه وفرط احلركة؛ تقييم املخرجات )الرعاية ال�شحية(؛ البحري. abstract: this study assesses the impairment and treatment outcome of children with attention deficit hyperactivity disorder (adhd) in an outpatient child psychiatry clinic, using multiple sources, including the children global assessment scale (c-gas). methods: a total of 20 children, aged 4 to 16 years, were recruited serially in 2010 from the child psychiatric unit of the psychiatric hospital, manama, bahrain. the children received a diagnosis of adhd using the diagnostic and statistical manual of mental disorders text revision (dsm-iv-tr). the children were assessed with the c-gas by a blinded investigator, initially at the beginning of the treatment and then one year later. results: the parents of the patients reported improvement in all cases; the improvement in impairment after one year, assessed using the c-gas, was significant for all of the cases (p = 0.001) and low for those with comorbidity (p = 0.07). conclusion: measurement of improvement using the c-gas was a suitable method of collecting data, and hence should be included in routine clinical practice for both adhd diagnosis and outcome measurement. keywords: attention deficit disorder with hyperactivity; outcome assessment (health care); bahrain. brief communication measurement of impairment among children with attention deficit hyperactivity disorder as part of evaluating treatment outcome ahmed m. al-ansari attention deficit hyperactivity disorder (adhd) has proved to be the most common disorder during childhood among the disruptive behaviour disorders.1–2 the diagnostic criteria for adhd in the diagnostic and statistical manual of mental disorders, 4th edition, text revision (dsm-iv-tr), is based on the identification of symptoms and level of impairment. the factors significantly associated with impairment, as measured by clinicians, were the severity of adhd symptoms, peer relationship problems and comorbidity with conduct disorders.3 symptomatology and impairment are moderately related but not identical; they are likely to have distinct correlations and importance in the diagnosis and assessment of adhd.4–6 in addition, impairment may be more of a universal notion, as opposed to the potentially culturally biased ahmed m. al-ansari brief communication | 297 measurement of symptomatology.7 the measurement of functional impairment, in addition to symptomatology, is the focus of recent child psychiatric epidemiological studies. the findings of these studies add emphasis to impairment, measured using a multidimensional approach, in the daily activities essential to success in school and interpersonal relationships.8 such interest has contributed to the identification of a true prevalence rate by reducing the number of false positive cases and determining community needs. impairment can be measured either by a diagnostic interview linked to individual symptoms, case vignettes, or by global ratings.2 global ratings have many advantages over other methods, as it is timeefficient, links impairment to clinical judgment, and forecasts service utilisation and community needs. the disadvantages of a global ratings system lie in its lack of specificity in linking impairment with individual symptoms.4,8 global rating scales, such as the child and adolescent psychiatric assessment (capa), children’s global assessment scale (c-gas), global assessment of function (gaf) and children’s problems checklist (cpc), were used in several studies to assess the severity of functional impairment in preschool and schoolaged children.9–12 both gaf and c-gas rate the severity of impairment on a scale of 1–100, where lower scores indicate greater impairment. the prevalence rate of adhd, using the c-gas score of <61, varied in different studies. in the usa, figures were low (1.85%), medium (6%) or high (10%).2,13,14 in europe, the rate of adhd using the same global rating scale was 7.9%; in the netherlands, it was 5.6% and in the uk, 11.1%.15 data on the rate of adhd in bahrain are not available; however, it is estimated that in 2011, 66 out of 348 new referrals received a diagnosis of adhd at the child and adolescent psychiatric unit (capu) of the bahrain psychiatric hospital. the capu is the main facility for children with psychological and behavioural problems in bahrain. it has a busy outpatient clinic as well as an inpatient/day-care programme for 12 children. the unit programme utilises structured behavioural modification principles with a reward system within a token economy system. it provides a living and learning environment in which staff present the opportunity for modelling behaviour and counselling the family. global rating scales are not used routinely in clinical practice; the clinician comes to a clinical judgment by assessing the degree of impairment. this study aimed to examine the use of c-gas in measuring initial functionality and treatment outcomes. methods the design of the study was to carry out a prospective analysis of events, by measuring both preand posttreatment variants one year apart. the sample consisted of 20 children aged between 4 and 16 years who attended the capu outpatient clinic at the psychiatric hospital, bahrain in 2010, who received a dsm-iv-tr diagnosis of adhd, and who were supported by conner’s parent/teacher scale ratings. children who were diagnosed with intellectual disabilities or seizure disorders in addition to adhd were excluded from the study. children who met the criteria for admission into the study were recruited serially up to a total of 20 cases. the process of confirming the diagnosis took up to 6 weeks. c-gas was used to assess the baseline of general functioning at the beginning of the treatment (score 1) and was then repeated after one calendar year (score 2). in addition, the investigator filled out a form specifically designed for the study, which evaluated the biodemographic data and treatment received. a psychiatrist who did not know the patients, but was familiar with the structure and functions of the capu, was used as a blind investigator for data collection. the investigator completed the initial and followup c-gas assessments. before deciding on the degree of impairment, the investigator collected information from multiple sources, such as: 1) clinical notes, and 2) parent, school teacher and therapist reports. the social class variable in the study was defined following a modified hollingshead and redlich five-point likert-type scale, where 1 is the highest and 5 is the lowest social class.16 the parents consented to their children’s participation in the study, and the study was approved by the ministry of health’s research ethical committee. psychiatric hospital, bahrain. the c-gas was published in 1983 by shaffer et al, based on the global assessment scale (gas) with the anchor points adapted for children.17 the measurement of impairment among children with attention deficit hyperactivity disorder as part of evaluating treatment outcome 298 | squ medical journal, may 2013, volume 13, issue 2 c-gas allows the scorer to assimilate and synthesise their knowledge about many different aspects of the patient’s social and psychiatric functioning, and subsequently condense this information into a single, clinically-meaningful index of the severity of the disturbance. the c-gas is brief and easy to use, has clear instructions, substantial inter-rater reliability, and is a better measure of change and predictor of outcomes.12 the c-gas was used in this study to assess general function regarding the treatment or programme for the most impaired function, for one month in children between 4–16 years.17 the cut-off point of 60 on a scale of 100 was considered to be a significant clinical disturbance.18 the statistical package for the social sciences (spss), version 17 (ibm, chicago, illinois, usa) was used to analyse the data. a paired t-test was used to assess the differences between score 1 and score 2. results the sample biodemographic data is shown in table 1. the male to female ratio was 4:1, the age range was 4–16 years and the mean age 7.9 years. more mothers had a college education compared to the fathers, 8 (40%) and 5 (25%) respectively. one father (5%) was unemployed while 12 (60%) of the mothers were homemakers. the majority of the cases were middle class (point 3, 13 [65%]); none of the cases were high class (point 1) or low class (point 5). the majority of the cases (95%) were from intact families. one fifth of cases (20%) were below grade-level in academic assessments. comorbidity was present among 6 of the cases (30%). out of the patients, 4 (20%) had specific learning difficulties and 2 (10%) exhibited conduct disorders. five of the cases (25%) received medication only, while 6 (30%) underwent behaviour therapy and 9 (45%) received combined therapy. table 2 shows the preand post-intervention c-gas scores. all children showed improvement in the degree of impairment after one year (p = 0.001). significant improvement was recorded among all three types of interventions; however, the difference between preand post-intervention scores for comorbid cases was not significant (p = 0.07) in comparison to non-comorbid cases (p = 0.001). discussion the cases studied here had similar characteristics to the reported data in terms of gender distribution, presence of learning problems and co-morbidity.19 however, the social class representation of the cases seemed to be different, as middle class parents were more prevalent in comparison to the usual clinical population. nearly half of the mothers had completed college education compared to 25% of fathers. nine cases, (45%) received medication combined with behaviour therapy, while 6 (30%) table 1: sample biodemographic data items n % sex male female 16 4 80 20 father’s education grades 7–12 college and above 15 5 75 25 mother’s education grades 7–12 college and above 12 8 60 40 father’s occupation middle management clerical job skilled/non skilled retired/unemployed 7 4 8 1 35 20 40 5 mother’s occupation middle management clerical job skilled/non-skilled homemaker 2 5 1 12 10 25 5 60 social class* point 2 point 3 point 4 3 13 4 15 65 20 family structure intact non-intact 19 1 95 5 patient academic level at or above grade standard below grade standard 6 14 30 70 comorbidity present absent 6 14 30 70 treatment received medication behavioural therapy combined 5 6 9 25 30 45 total 20 100 * = calculated using a modified hollingshead and redlich five-point likert-type scale. ahmed m. al-ansari brief communication | 299 received only behavioural therapy and 5 (20%) medication alone. all cases attended their followup appointments a year later. the high level of compliance with treatment might be due to the high level of education and low level of divorce or separation among the parents. the clinical improvement, as indicated by the application of c-gas preand post-intervention scores, was in accordance with the improvement reported by parents and therapists. the improvement in impairment was not related to the type of intervention. the presence of complicating factors, such as comorbidity, had a negative effect on the effectiveness of the intervention; the presence of comorbidity complicates the list of problems and therefore expands the treatment objectives. the use of c-gas in the clinical practice proved to be an easy and appropriate measure of impaired function, as well as an indicator of outcomes, in addition to clinical assessment and the reports of parents and teachers. there were limitations to this study, particularly 1) the small sample size did not allow for further analysis and evaluation of each type of intervention, and 2) the cases were not randomly assigned from the beginning of the study according to the severity or treatment received. conclusion the use of a global rating scale such as c-gas is an appropriate method of collecting data with regards to measuring functional impairment on a longitudinal basis. c-gas is easy to administer and can be included in general clinical practice for the diagnosis and evaluation of outcomes in children with adhd. using c-gas in addition to the usual clinical skills will add to the strength of data collection. furthermore, a larger study with a strict protocol for the random assignment of cases according to their severity or the treatment received is recommended in future. references 1. mcardle p, prosser j, kolvin i. prevalence of psychiatric disorder, with or without psychosocial impairment. eur child adolesc psychiatry 2004; 13:347–53. 2. shaffer d, fisher p, dulcan m, davis m, placentini j, schwab-stone m, et al. the nimh diagnostic interview schedule for children version 2.3. description, acceptability, prevalence rates, and performance in the meca study. j am acad child adoles psychiatry 1996; 35:865–77. 3. coghill d, spiel g, balursson g, dopner m, lorenzo m, ralston s, et al. which factors impact on clinician-rated impairment in children with adhd? euro child adolesc psychiatry 2006; 15:130–7. 4. gathje ra, lewandowski lj, gordon m. the role of impairment in the diagnosis of adhd. j atten disord 2008; 11:529–37. 5. gordon m, antshel k, faraone s. barkly r, lewandowski l, hudziak j, et al. symptoms versus impairment, the case for respecting dsm iv’s criteria d. j atten disord 2006; 9:465–75. 6. park jh, lee si, schachar rj. reliability and validity of the child and adolescent functioning impairment scale in children with attention deficit hyperactivity disorder. psychiatry investig 2011; 8:113–22. 7. haack lm, gerdes ac. functional impairment in latino children with adhd: implications for culturally appropriate conceptualization and measurement. clin child fam psychol rev 2011; 14:318–28. 8. harrison jr, vannest kj, reynolds cd. behaviors that discriminate adhd in children and adolescents: primary symptoms, symptoms of comorbid conditions, or indicators of functional impairment? j atten disord 2011; 15:147–60. 9. heally dm, miller cj, castelli kl, marks dj, halperin jm. the impact of impairment criteria on rates of adhd diagnoses in preschoolers. j abnorm child psychol 2008; 36:771–8. 10. prosser j, mcardle p. the changing mental health of children and adolescents: evidence for a deterioration? psychol med 1996; 26:715–25. 11. costello e, angold a, burns b, erkanli a, stangl d, tweed d. the great smoky mountains study of table 2: preand post-intervention (scores 1 and 2) children’s global assessment scale scores items n c-gas c-gas p value score 1† score 2† all interventions 20 45.7 60.8 0.001 medication only 5 43.2 63.8 0.02 behavioural therapy 6 53.17 69.16 0.05 medication & behavioural therapy 9 42.11 53.55 0.01 comorbid 6 41.67 55 0.07 non-comorbid 14 47.43 63.28 0.001 non-comorbid 14 47.43 63.28 0.001 c-gas = children’s global assessment scale. † = mean scores used. measurement of impairment among children with attention deficit hyperactivity disorder as part of evaluating treatment outcome 300 | squ medical journal, may 2013, volume 13, issue 2 youth: functional impairment and serious emotional disturbance. arch gen psychiatry 1996; 53:1137–43. 12. schorre be, vandvik ih. global assessment of psychosocial functioning in child and adolescent psychiatry: a review of three unidimensional scales (cgas, gaf, gapd). eur child adolesc psychiatry 2004; 13:273–86. 13. costello e, angold a, burns b, stangl d, tweed d, erkanli a, et al. the great smoky mountains study of youth: goals, design, methods and the prevalence of dsm-iii-r disorders. arch gen psychiatry 1996; 53:1129–36. 14. bird h, canino g, rubio-stipec m, gould m, ribera j, sesman m, et al. estimates of the prevalence of childhood maladjustment in a community survey in puerto rico: the use of combined measures. arch gen psychiatry 1988; 45:1120–6. 15. verhulst f, van der ende j, ferdinand r, kasius m. the prevalence of dsm-111-r diagnoses in a national sample of dutch adolescents. arch gen psychiatry 1997; 54:329–36. 16. hollingshead ab, redlich fc. social class and mental illness. new york: wiley, 1958. 17. shaffer d, gould m, brasic j, ambrosini p, fisher p, bird h, et al. a children’s global assessment scale (cgas). arch gen psychiatry 1983; 40:1228–31. 18. taylor e, döpfner m, sergeant j, asherson p, banaschewski j, buitelaar j, et al. european clinical guidelines for hyperkinetic disorder – first upgrade. eur child adolesc psychiatry 2004; 13:17–30. 19. bauermeister jj, shrout pe, chávez l, rubio-stipec m, ramírez r, padilla l, et al. adhd and gender: are risks and sequela of adhd the same for boys and girls? j child psychol psychiatry 2007; 48:831– 9. department of medicine, medical college kolkata, kolkata, india *corresponding author e-mail: docr89@gmail.com طفح دوائي ثابت منتشر بسبب دواء ديكلوفيناك ريدراجيت ب�ل, ق�اتام ليهريي, تامني ج�تي �ضاو, ك�نال هالدار, راجي�ص باندي, عا�ضم �ضاها extensive fixed drug eruption due to diclofenac *rudrajit paul, gautam lahiri, tanmay j. sau, kunal haldar, rajesh pandey, asim saha a 46-year-old male construction workerwas admitted to a clinic in kolkata, india, in 2016 with a sudden-onset black rash appearing in patches all over his body. he had sprained his left foot two days previously for which he was prescribed oral diclofenac tablets at a dose of 50 mg three times a day. he had taken three doses of the drug before noticing the skin lesions; however, he continued taking the drug due to the pain and presented to the clinic on the third day when the lesions became extensive. he was not currently taking any other drugs and had no history of similar skin lesions. on examination, the patient was noted to have darkly pigmented patches on his trunk and both the upper and lower limbs [figure 1]. the patches covered more than 50% of his body surface and were nonpruritic and non-tender, with sharply demarcated margins and surrounding erythema. no evidence of mucosal lesions or hair or nail changes was seen. the patient was treated with local emollients and a steroid cream. a skin biopsy revealed interface dermatitis with vacuolar changes. the patient was diagnosed with a fixed drug eruption (fde) caused by the diclofenac. after 10 days, the patches became scaly and started to desquamate [figure 2]. figure 1: extensive hyperpigmented patches on the (a) trunk, (b) arms and (c) legs of a 46-year-old man after taking 50 mg of diclofenac three times a day for three days. sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e121–122, epub. 30 mar 17 submitted 18 sep 16 revision req. 26 oct 16; revision recd. 28 oct 16 accepted 10 nov 16 doi: 10.18295/squmj.2016.17.01.024 interesting medical image extensive fixed drug eruption due to diclofenac e122 | squ medical journal, february 2017, volume 17, issue 1 of similar lesions at the same site. sometimes, fdes may not occur on initial use of the drug and manifest only after a certain dose is attained.1 nonetheless, drug rechallenge is not always ethically possible; a skin biopsy is therefore sufficient to diagnose the condition at first onset.2 with diclofenac, various cutaneous reactions can occur after oral or parenteral administration, including anaphylactic reactions, urticaria, exanthema and fdes.6 while there is no definitive histology pattern for fdes, severe vacuolar interface dermatitis is suggestive of the condition, along with other phenotypic features, such as confluent epidermal necrosis and extension of the infiltrate into the lower half of the dermis.2,5 the use of the naranjo algorithm, particularly the sections regarding previous exposure and readministration, is not always applicable in these cases on ethical grounds.7 however, a thorough history-taking, specifically with regards to recent exposure to certain drugs, can help to confirm the diagnosis. in addition, the new world health organization-uppsala monitoring centre scale may help to determine aetiology in such cases.8 clinicians should be aware of rare cutaneous reactions to common drugs often used in clinical practice, such as that observed in the current case with diclofenac. references 1. augustine m, sharma p, stephen j, jayaseelan e. fixed drug eruption and generalised erythema following etoricoxib. indian j dermatol venereol leprol 2006; 72:307−9. doi: 10.4103/03786323.26732. 2. jain sp, jain pa. bullous fixed drug eruption to ciprofloxacin: a case report. j clin diagn res 2013; 7:744–5. doi: 10.7860/ jcdr/2013/4757.2901. 3. lin tk, hsu mm, lee jy. clinical resemblance of widespread bullous fixed drug eruption to stevens-johnson syndrome or toxic epidermal necrolysis: report of two cases. j formos med assoc 2002; 101:572–6. 4. hsiao cj, lee jy, wong tw, sheu hm. extensive fixed drug eruption due to lamotrigine. br j dermatol 2001; 144:1289–91. doi: 10.1046/j.1365-2133.2001.04266.x. 5. fathallah n, ben salem c, slim r, boussofara l, ghariani n, bouraoui k. acetaminophen-induced cellulitis-like fixed drug eruption. indian j dermatol 2011; 56:206–8. doi: 10.4103/00195154.80419. 6. deepalatha c, prasad rv, chandra s, mohan pm, lakshmi v. diclofenac-induced urticaria in paediatric patient. asian j pharm clin res 2013; 6:1–2. 7. naranjo ca, busto u, sellers em, sandor p, ruiz i, roberts ea, et al. a method for estimating the probability of adverse drug reactions. clin pharmacol ther 1981; 30:239–45. doi: 10.1038/ clpt.1981.154. 8. gupta lk, beniwal r, khare ak, mittal a, mehta s, balai m. non-pigmenting fixed drug eruption due to fluoroquinolones. indian j dermatol venereol leprol 2017; 83:108–12. doi: 10.4103/0378-6323.190890. comment fdes are drug-induced lesions which may appear as patches, vesicles or bullae.1 hyperpigmentation is usually noted at the site of the lesions and recurs at the same sites with subsequent exposure to the drug.1 usually, the lesions are limited to a small area of the skin or mucosa.2 however, extensive fdes have been reported with nonsteroidal anti-inflammatory drugs (nsaids), lamotrigine and antibiotics such as vancomycin.3,4 lin et al. reported two patients with nsaid-induced extensive bullous eruptions mimicking steven-johnson syndrome.3 in another case, an extensive paracetamol-induced eruption was initially suspected to be cellulitis; the patient was treated with antibiotics before new lesions appeared and a skin biopsy led to a fde diagnosis.5 extensive hyperpigmented dermal patches can sometimes be confused with photoallergic/toxic reactions, café-aulait macules or addison’s disease.4 the mainstay of treatment for fdes is with drawal of the drug.1,5 although local steroids and/or emollients may be used, systemic therapy is usually not needed.5 in general, fdes are easy to diagnose if the presenting features are typical. however, atypical lesions—such as non-pigmenting fdes or psoriasiform lesions—may also occur.2 as fdes recur at the same site on subsequent contact with the drug, a diagnosis can be made if there is a previous history figure 2: scaling and desquamation of hyperpigmented patches caused by a diclofenac-induced fixed drug eruption on the (a) arms and (b) legs of a 46-year-old man after 10 days of treatment with local emollients and a steroid cream. https://doi.org/10.4103/0378-6323.26732 https://doi.org/10.4103/0378-6323.26732 https://doi.org/10.7860/jcdr/2013/4757.2901 https://doi.org/10.7860/jcdr/2013/4757.2901 https://doi.org/10.1046/j.1365-2133.2001.04266.x https://doi.org/10.4103/0019-5154.80419 https://doi.org/10.4103/0019-5154.80419 https://doi.org/10.1038/clpt.1981.154 https://doi.org/10.1038/clpt.1981.154 https://doi.org/10.4103/0378-6323.190890 sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e13-25, epub. 27th jan 14 submitted 26th may 13 revisions req. 18th jun & 1st aug 13; revisions recd. 28th jun & 2nd sep 13 accepted 19th sep 13 multiple sclerosis (ms) is the most common prototypic inflammatory disorder, characterised by inflammation, oligodendrocyte depletion, reactive astrogliosis and demyelination in the brain, optic nerve and spinal cord.1 ms plaque is the major pathological hallmark of ms. it is a unique feature of central nervous system (cns) demyelination, which is characterised by oligodendrocyte destruction along with the loss of myelin, axonal damage and loss, and glial scar formation.2 ms usually occurs in young adults and is more common in women than men, with about 300,000 patients suffering from ms in north america alone. literature reviews robustly imply an increased prevalence of ms in recent times.3 ms patients show a variety of clinical symptoms, including visual difficulties, muscle weakness, sensory damage and difficulties with speech and coordination. briefly, there are four types of ms, with each having a mild, moderate or severe course.4 most patients (~85%) initially experience relapsing1department of immunology, school of public health, tehran university of medical sciences, tehran, iran; 2antimicrobial resistance research center, faculty of medicine, iran university of medical science, tehran, iran; 3cellular & molecular research center, yasuj university of medical sciences, yasuj, iran; 4imam hassan mojtaba hospital, alborz university of medical sciences, karaj, iran *corresponding author e-mail: azizi_g@razi.tums.ac.ir أمهية األنزميات املعدنية احملللة للربوتني يف تطور مرض التصلب العصيب املتعدد وعالجه عبا�س مر�صافعي, باباك �أ�صغري, قا�صم غاالمفار�صا, فرهاد جديدي نري�غ, غالمر�صا عزيزي abstract: multiple sclerosis (ms) is an autoimmune disease of the central nervous system (cns). the major pathological outcomes of the disease are the loss of blood-brain barrier (bbb) integrity and the development of reactive astrogliosis and ms plaque. for the disease to occur, the non-resident cells must enter into the immune-privileged cns through a breach in the relatively impermeable bbb. it has been demonstrated that matrix metalloproteinases (mmps) play an important role in the immunopathogenesis of ms, in part through the disruption of the bbb and the recruitment of inflammatory cells into the cns. moreover, mmps can also enhance the cleavage of myelin basic protein (mbp) and the demyelination process. regarding the growing data on the roles of mmps and their tissue inhibitors (timps) in the pathogenesis of ms, this review discusses the role of different types of mmps, including mmp-2, -3, -7, -9, -12 and -25, in the immunopathogenesis and treatment of ms. keywords: multiple sclerosis; blood-brain barrier; matrix metalloproteinases; inflammation; central nervous system. امللخ�ص: يعد مر�س �لت�صلب �لع�صبي �ملتعدد )ms( �أحد �أمر��س �ملناعة �لذ�تية يف �جلهاز �لع�صبي �ملركزي )cns(. ونتيجه لالإ�صابه به يحدث خلل يف �صالمة حاجز �لدم يف �لدماغ )bbb( �إىل جانب تطور يف رد فعل �لدباق �لنجمي و لويحات �لت�صلب �لع�صبي �ملتعدد. يحدث هذ� �ملر�س عندما تدخل �خلاليا غري �ملقيمه �ىل �جلهاز �لع�صبي �ملركزي �ملحمي مناعيا من خالل ثغرة يف حاجز �لدم يف �لدماغ. وقد تبّي �أن �الأنزميات �ملعدنية �ملحللة للربوتي )mpps( تلعب دور� مهما يف تطور مر�س �لت�صلب �لع�صبي �ملتعدد, من خالل تعطيل حاجز �لدم وتوجيه �خلاليا �اللتهابية �ىل �جلهاز �لع�صبي باملعلومات يتعلق فيما �أما غطائه. ونزع للمايلي �ال�صا�س بروتي يف �النق�صام بتعزيز تقوم �أن ميكن �الأنزميات هذه �أن ذلك �ىل ي�صاف . �ملركزي هنا فاننانناق�س �ملتعدد, �لع�صبي �لت�صلب مر�س يف �لت�صبب يف �الن�صجة يف مثبطاتها و للربوتي �ملحللة �ملعدنية �الأنزميات دور حول �ملتنامية دور�الأنو�ع �ملختلفة من �الأنزميات �ملعدنية �ملحللة للربوتي , مبا يف ذلك mmp-2، -3، -7، -9، -25, يف تطور مر�س �لت�صلب �لع�صبي �ملتعدد وعالجه. مفتاح الكلمات: مر�س �لت�صلب �لع�صبي �ملتعدد؛ حاجز �لدم يف �لدماغ؛ �الأنزميات �ملعدنية �ملحللة للربوتي؛ �لتهاب؛ �جلهاز �لع�صبي �ملركزي. review the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis abbas mirshafiey,1 babak asghari,2 ghasem ghalamfarsa,3 farhad jadidi-niaragh,1 *gholamreza azizi4 the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis e14 | squ medical journal, february 2014, volume 14, issue 1 remitting ms (rrms); the majority is predisposed to the establishment of secondary-progressive ms (spms) which is characterised by an initial rrms disease course followed by a progression with or without occasional relapses, minor remissions, and plateaus. nearly 10% of patients display primaryprogressive ms (ppms), which indicates the disease progression from onset with occasional plateaus and temporary minor improvements. finally, the least common form of the disease is progressiverelapsing ms (prms), which occurs in ~5% of ms patients and is characterised by the progressive disease from onset, with clear acute relapses, with or without full recovery.5,6 although the precise cause of ms is unknown, the aetiology of ms seems to be linked to a variety of genetic and environmental factors. current opinion suggests that the activation of autoreactive, adaptive and innate immune responses which target neural antigens leads to ms.2 the self-reactive t cells are the main factors in the immunopathogenesis of ms. there is consistent evidence showing the central role of t helper 17 cell (th17)-producing interleukin 17 and interferon γ (ifn-γ)-secreting type 1 t helper (th1) cells in the disease’s development, in part through the secretion of inflammatory mediators and the activation of microglial cells.7 although the microglia is involved in the phagocytosis of myelin debris and apoptotic cells during demyelination, the activation of the microglia and the release of inflammatory mediators has been suggested as a possible mechanism by which innate immunity enhances the demyelination process in ms.2,8 therefore, microglial cells, which constitute about 10% of the cns, are one of the first cells that cause neuronal damage and play an important role in neuroinflammatory processes.8 in ms, neural factors generated by acute stress, including myelin basic protein (mbp), substance p and corticotropin-releasing hormones, can activate brain mast cells to release inflammatory mediators and stimulate the autoreactive t cells.9 astrocytes are involved in nearly all immunopathological processes in the brain. it has been reported that astrocytes could release factors which regulate the oligodendrocyte progenitor differentiation and myelin formation.1,10 oligodendrocytes enhance the inflammatory cytokine production in t cells as well as chemokines that may recruit additional peripheral inflammatory leukocytes.10 the localisation of astrocytes in ms is similar to mast cells in the perivascular area.11 two types of phagocytes (including the microglia and inflammatory macrophages) in ms and its animal model, experimental autoimmune encephalomyelitis (eae), are derived from proliferating resident precursors and the recruitment of blood-borne progenitors, respectively.12 these phagocytes and astrocytes can recognise pathogen-associated molecular patterns (pamps) via toll-like receptors (tlrs) and generate pro-inflammatory signals that trigger adaptive immune responses. moreover, these cells enhance the autoimmune responses through the secretion of effector molecules such as nitric oxide (no), matrix metalloproteinases (mmps) and calpain-1 that may also play a role in the initiation of myelin and axon damage.13,14 the recruited inflammatory cells are mainly composed of cluster of differentiation 4 (cd4+) t cells, b cells, monocyte/macrophages, neutrophils and dendritic cells.15 however, these non-resident cells have to penetrate the blood-brain barrier (bbb) to reach the immunologically-privileged cns.16 the bbb is a dynamic interface that separates the brain from the circulatory system and protects the cns from potentially harmful chemicals. therefore, the bbb restricts the exchange of humoral factors and cells between the blood and brain, thus playing a crucial role in maintaining cerebral homeostasis. disruption of the bbb is considered an initial key step of the disease process in ms.17 the breakdown of the bbb usually lasts for about a month and then resolves, leaving a site of damage that can be investigated by conventional magnetic resonance imaging (mri).18 in ms, the bbb may be impaired by mmps attacking the basal lamina macromolecules before the formation of demyelinating foci or t-cell infiltration around the small vessels; however, once the bbb is disrupted, the massive infiltration of t cells, the augmented expression of adhesion molecules on the endothelial cell surface and the leakage of the inflammatory cytokines and antibodies aggravate the ms lesions.17 in the brains of ms patients, mast cells are placed on the perivascular area and secrete numerous vasoactive molecules and proinflammatory mediators that can contribute to the bbb disruption.9 abbas mirshafiey, babak asghari, ghasem ghalamfarsa, farhad jadidi-niaragh and gholamreza azizi review | e15 different physiological and pathological processes, such as placental development, morphogenesis, reproduction, wound repair, inflammation, angiogenesis, neurological disorders, and cancer cell invasion and metastasis.24 mmps affect a variety of extracellular proteins in the cns, including cytokines, chemokines, antimicrobial peptides and immune regulatory proteins. using quantitative reverse transcriptase polymerase chain reaction (rt-pcr), bar-or et al. systematically evaluated the expression of 23 mmp members in subsets of leukocytes isolated from the blood of normal populations. they found a specific pattern of mmp expression in different cellular populations: mmp-11, -26 and -27 were the mmps or matrixins represent a large family of zinc-dependent proteolytic enzymes that are known for their capacity to degrade extracellular matrix (ecm) components.19 mmps are a family of proteases, classified into subfamilies based on their substrate preferences. currently, there are 23 known mmps, including: gelatinases (mmp-2 and ‒9); collagenases (mmp-1, -8, -13 and -18); stromelysins (mmp-3, -10 and -11); matrilysins (mmp-7 and -26); membrane type (mt) mmps (including mmp-14, -15, -16, -17, -24 and -25), and a group of unnamed members (mmp-11, -12, -19, -20, -21, -23a, -23b, -27 and -28). all mmps are secreted as proenzymes and require extracellular activation.20–23 recent findings indicate that mmps are involved in figure 1: in multiple sclerosis, matrix metalloproteinases (mmps) are expressed in the central nervous system (cns) by various cell types, including vascular endothelial cells, neuron, reactive astrocytes and the microglia, and accumulated inflammatory cells. in the cns, the high numbers of mmps lead to the perpetuation of neuroinflammation, which contributes to myelin degradation and axonal damage. bbb = blood-brain barrier; mbp = myelin basic protein; mag = myelin-associated glycoprotein. the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis e16 | squ medical journal, february 2014, volume 14, issue 1 plentiful in b cells, while mmp-15, -16, -24 and -28 showed up more often in t cells. the majority of mmp members are reported in monocytes: mmp1, -3, -9, -10, -14, -19 and -25. in addition, mmp2 and -17 were mainly represented in monocytes, although b lymphocytes had significant amounts of these mmps.25,26 growing evidence implies that the normal, mature cns contains low or non-detectable levels of most mmps; the principal cells that express these mmps are perivascular and parenchymal microglia. on the other hand, studies on the serum, cerebrospinal fluid (csf) and brain tissue of ms patients have shown an increase of mmp-1, -2, -3, -7, -9, -12 and -14 activity.27–29 some data suggest that microglial-derived mmps may mediate the turnover of the cns’s ecm under normal conditions in microglial nodules, but in many neuroinflammatory conditions, such as encephalitis, meningitis, brain tumours, cerebral ischaemia, guillain-barré syndrome and ms, these enzymes are significantly upregulated.30–32 in neuroinflammatory conditions, mmps are expressed in the cns by a variety of cell types, including vascular endothelial cells, meninges, resident cells such as neuronal cells, astrocytes, microglial cells and accumulated inflammatory cells [figure 1]. it has been shown that astrocytes can release mmp-1, -2, -3 and -9, whereas the microglia secretes mmp-7, -9, -12 and -19.33,34 most table 1: some important matrix metalloproteinases in the central nervous system and their relationship with the pathogenesis of multiple sclerosis mmp mw in kda cell source functions timps pro-enzyme active form mmp‒1 57 and 52 42 astrocytes, monocytes, macrophages and microglia •unknown •activator for mmp‒2 and ‒9 •breaks down the interstitial collagens (types i, ii and iii) timp‒1 mmp‒2 72 63 astrocytes, microglia, monocytes, macrophages and endothelial cells •bbb disruption, which facilitates immune cell transmigration into the cns •fragmentation of the mbp •demyelination •axonal injury •activator for mmp‒1 and ‒9 timp‒2 and timp‒4 mmp‒3 57 54 astrocytes, monocytes, macrophages, endothelial cells and microglia •bbb disruption •activates microglia or ‘white matter’ brain cells •activator for mmp‒1, ‒7 and ‒9 •normal functioning as neuronal migration •neurite outgrowth and cns development •stem cell migration •neuroprotection •remyelination in the injured cns timp‒1 and timp‒3 mmp‒7 29 20 microglia, monocytes and macrophages •cleaves nr1 (an obligate sub-unit of the nmda receptor) •activator for mmp‒1, ‒2 and ‒9 timp‒1 mmp‒9 92 67 astrocytes, microglia, monocytes, macrophages, endothelial cells, neurons, neutrophils and ccr2+ ccr5+ t cells •increases the permeability of the bbb •facilitates the infiltration of leukocytes into the cns •myelin sheath degradation •neuronal damage timp-1 mmp‒12 ~54 48 macrophages, microglia and astrocytes •unknown •potentially partakes in myelinogenesis timp‒1 mmp‒14 66 ~54 monocytes •activator for mmp‒2 •receptor for timp‒2 and/or the prommp‒2/timp‒2 complex timp‒2 and timp‒4 mmp = matrix metalloproteinase; mw = molecular weight; kda = kilodaltons; timp = tissue inhibitors of metalloproteinases; bbb = blood-brain barrier; cns = central nervous system; mbp = myelin basic protein; nmda = n-methyl-d-aspartate. abbas mirshafiey, babak asghari, ghasem ghalamfarsa, farhad jadidi-niaragh and gholamreza azizi review | e17 findings on mmp secretion by blood monocytes can be useful in improving our understanding of the immunopathogenesis of ms.41 to summarise, it seems that monocytes are key contributors to the neuroinflammatory process in ms through a mechanism that involves the high expression of different mmps, such as mmp-1, -2, -3, -7, -9, -14 and decreased expression of timp-1 and timp-2.25,42 matrix metalloproteinase ‒2 matrix metallopeptidase-2 (also known as gelatinase a and a 72 kilodalton [kda] type ii collagenase) plays an important role in inflammation and immunity in addition to its physiological function in degrading and remodelling the ecm. the expression of mmp-2 is upregulated in many human diseases as well as in animal models of inflammatory and immune diseases. bar-or et al., following analyses of all mmps in leukocytes, implicated monocytes as major inflammatory cells in ms. they found higher levels of monocyte-expressed mmp-2 and -14 in ms patients compared to normal subjects.25 moreover, another report suggested that mmp-2 can be expressed not only in monocytes but also in the astrocytes, microglia and macrophages.43 although the correlation between the frequency of macrophages and reactive glial cells with axon injuries in the acute plaques is well-established, little is known about the precise role of mmp-2 in the immunopathogenesis of ms.44,45 anthony et al.46 and maeda et al.32 showed that mmp-2 was upregulated not only in plaques but also in the seemingly normal white matter adjacent to the acute plaques. in these acute plaques, the myelin was degraded and engulfed by the reactive glial cells and macrophages, leading to demyelination.35 in addition, newman et al. showed that a microinjection of mmp-2 into rat subcortical white matter led to axonal injury.47 it seems that mmp-2 plays a key role in the bbb disruption, which facilitates immune cell transmigration into the cns and the development of ms.38,43,48 therefore, the downregulation of mmp2 may inhibit the bbb disruption and migration of the inflammatory cells to the cns. although little is known about the involvement of mmp-2 and its tissue inhibitor timp-2 in ms, it has been shown that timp-2 is elevated in the monocytes of ms microvessel endothelial cells in the cns express mmp-3 and -9 but not -1 or -2. also, the majority of macrophages in active ms and necrotic lesions are positive for mmp-l, -2, -3, -7, -9 and -19, whereas chronic ms lesions have fewer mmp-positive macrophages.32,35 neurons may also release mmps. it is reported that in normal adult rat brains, mmp9 (but not -2) is highly expressed by neurons and localised in neuronal cell bodies and dendrites.36 in the damaged sites of the cns, there are complex and dynamic regulations of mmp expression by different cell types.32 the imbalance between mmp activity and the inhibitory action of tissue inhibitors of metalloproteinases (timps) are implicated in ms development [table 1], as one of the mmp roles may be to facilitate the transmigration of circulating leukocytes into the cns.25 therefore, it is possible that the mmps attack the basal lamina macromolecules that line the blood vessels, disrupting the bbb’s integrity.31 moreover, mmps can be involved in the fragmentation of mbp and myelin-associated glycoprotein (mag), and injury to the myelin. in the cns, the mbp gene is expressed in the oligodendrocytes and is named classic-mbp; in the immune cells it is named golli-mbp.37 therefore, mmp-mediated proteolysis of the mbp isoforms is a source of immunogenic peptides in autoimmune ms.38 consequently, through the remodelling of the blood vessels, mmps cause hyalinosis and gliosis, and they attack the myelin, disrupting the myelin sheath and axons. excessive proteolytic activity is detected in the csf and blood of patients with acute ms. moreover, mmps are induced in immunological and non-immunological forms of demyelination.31 regarding the high expression of many mmps by monocytes which facilitate the transmigration of the leukocytes, bar-or et al. showed that monocytes migrate more rapidly through the bbb than t or b lymphocytes, in vitro.25 although data about the role of mmps in monocyte trafficking are limited, lucchinetti et al.18 suggested that the frequency of macrophages/microglia in ms is approximately 10 times higher compared to lymphocytes. also, in active ms lesions, macrophages were found to be positive for mmp-2, -7, -9, -12 and -19.39,40 since monocytes constitute a major cell population in acute ms lesions, it may be possible that mmp secretion facilitates their entrance into the cns. the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis e18 | squ medical journal, february 2014, volume 14, issue 1 patients. however, it should be noted that there are no data regarding the functionality of timp-2 in ms patients. timp-2 is an inhibitor of activated mmps; it inhibits the cell surface activation of pro-mmp-2 by mmp-14.25,49 mmp-14 acts as a receptor for timp-2 (but not timp-1) and the pro-mmp-2/ timp-2 complex, thereby facilitating the activation of pro-mmp-2. in addition, the serum mmp2:timp-2 ratio may represent a useful indicator for monitoring the ms patient during a recovery phase.45 benesová et al. observed in 2009 that there was a significant elevation in mmp-2 serum levels and the mmp-2:timp-2 ratio in the ppms and spms groups compared to the rrms group. this increase was also associated with the level of disability in the patient and the severity of the disease.43 thus, it seems that mmp-2, -14 and timp-2 can be considered interesting targets for potential therapeutic interventions to inhibit the entry of monocytes into the cns, and to alleviate injuries of the cns in ms patients.25 matrix metalloproteinase-3 also known as stromelysin‒1, mmp-3 is an enzyme involved in ecm remodelling. mmp-3 is an activator of other mmps, including mmp-1, -7 and -9.50 it has been demonstrated that mmp3 contributes to different pathological conditions, such as rheumatoid arthritis (ra), asthma, cancer and neurological disorders, including ms, parkinson’s disease (pd) and alzheimer’s disease (ad).51 in ms, the increased circulatory level of mmp-3 correlates with disease activity in rrms. this may contribute to the breakdown of the bbb at the time of relapse.52 moreover, the release of mmp-3 into the ecm activates microglial or brain cells in the white matter.53 some evidence strongly suggests that the distinctive signal of neuronal apoptosis is the release of the active form of mmp3 that activates the microglia and subsequently exacerbates neuronal degeneration.54 it has been shown consistently that the inhibition of mmp-3 leads to the suppression of inducible nitric oxide synthase, (inos), proinflammatory cytokines and the inflammatory transcription factors nuclear factor kappa b (nf-κb), activator protein 1 (ap1) and mitogen-activated protein kinases (mapks) in the microglia.53 interestingly, it has been reported that mmp3 can be involved in normal cns-remodelling and in the remyelination process, as shown by the strict spatiotemporal mmp-3 upregulation in the injured cns, which may contribute to stem cell migration, neuroprotection and remyelination in the injured sites.51 an involvement of mmp-3 in remyelination during the regenerative period after a cns injury was demonstrated for the first time in the murine cuprizone-induced demyelination model. it was reported that not only during the early demyelination stage, but also during the stage of remyelination, mmp-3 was highly expressed in astrocytes of the corpus callosum. although the exact mechanism is unknown, mmp-3 might be involved in remyelination through enhancing insulin growth factor (igf) secretion, which is essential for the proliferation and differentiation of myelin-forming cells.55–57 in addition, mmp-3 might stimulate remyelination by removing and cleaving the myelin debris, which inhibits the oligodendrocyte precursor cell differentiation.51,58 matrix metalloproteinase-7 also known as matrilysin, mmp-7 is increased in the serum, csf and brain tissues of ms patients.27 it has been shown that the messenger ribonucleic acid (mrna) levels of mmp-7 and -9 are elevated in all stages of lesion formation in ms patients.59 moreover, mmp-7 expression was found to be upregulated in microglia/macrophages within acute ms lesions. in chronic ms lesions, the expression of mmp-7 was confined to the macrophages within the perivascular cuffs, whereas only a low level of mmp-7 expression was detected in normal brain tissue.46 in a study by cossins et al., mmp-7 immunoreactivity was weakly detected in microglial-like cells in normal brain tissue sections, and was very strongly detected in the parenchymal macrophages in active demyelinating ms lesions. mmp-7 immunoreactivity was not detected in macrophages in the spleen or tonsils, indicating that it is specifically induced in infiltrating macrophages in active demyelinating ms lesions.35 elevated levels of mmp-7 and -9 have also been detected in cases of eae. in one study of adoptive transfer eae, mrna for mmp-7 was increased, with maximum abbas mirshafiey, babak asghari, ghasem ghalamfarsa, farhad jadidi-niaragh and gholamreza azizi review | e19 granulocyte chemotactic protein-2 was decreased.66 it was found that young mmp-9 knockout mice are partially resistant to the development of eae.61,67 however, when both gelatinases (mmp-2 and -9) were genetically knocked out, a complete resistance against myelin oligodendrocyte glycoprotein peptide-induced eae was observed.68 the latter study is important as it shows that many proteinases act in these cascades or networks.69 indeed, investigations of mmp-2 indicate that it is able to activate mmp-9 in vitro.70 both enzymes thus reinforce each other and they also share a number of substrates, including denatured collagen or gelatin.71 in addition, decreased serum mmp8 and -9 levels were correlated with a decreased number of contrast-enhanced t2-weighted mri lesions in ms patients.72 in the same study, ms patients treated with interferon β 1b (ifn-β1b) showed a reduction in serum mmp-8 and -9 in parallel with the disease stabilisation. the authors concluded that the serial measurement of mmps and other inflammatory mediators may serve as sensitive markers for measuring therapeutic response to ifn-β1b during the first year of treatment. as mentioned earlier, it is suggested that mmp9 has a role in ms by mediating t-cell migration through the bbb. during a relapse course, the ccr2+ccr5+ t cells are abundant in the csf of ms patients. these t cells have the potent ability to produce osteopontin and mmp-9, both of which have an important role in the ms pathology.73 also, in ms patients in the relapse phase, these subtypes of t cells are reactive to mbp, as this ability can be evaluated by ifn-γ production. other findings suggested that the ccr6subtype (but not the ccr6+ subtype within ccr2+ccr5+ t cells) is very abundant in the csf during a ms relapse and can produce higher levels of mmp-9 and ifn-γ.73,74 as timp-1 is a tissue inhibitor of mmp-9, a considerable elevation in the mmp-9:timp-1 ratio and in mmp-9 serum levels was observed in ms patients in the rrms and spms groups.43 fainardi et al. have suggested that a shift in the mmp-9:timp-1 ratio towards mmp-9 proteolytic activity can be the consequence of ms immune downregulation.75 moreover, using immunohistochemistry, timp-1 was found to be upregulated in chronic plaques.62 the concentrations of these metalloproteinases inhibitors in the csf and plasma were low in patients levels at the peak of the disease.60 matrix metalloproteinase-9 also known as gelatinase b and type iv collagenase, mmp-9 is secreted from neutrophils, macrophages and a number of transformed cells in zymogen form.50 upon activation, mmp-9 acts on many inflammatory processes and is involved in the progression of cardiovascular disease, ra, chronic obstructive pulmonary disease and ms.24 mmp9 is also important in cytokine and protease modulation; it degrades the serine protease inhibitor α1-antitrypsin, which may lead to the destruction of the lungs.24 different studies have indicated the increased expression of mmp-9 in ms.61 in one study, zymography methods showed that mmp-9 levels were high in the csf of ms patients and in patients with infections of the cns and other inflammatory diseases.28 in patients with ms, high mmp-9 levels were associated with the immunoglobulin g (igg) index. hence, mmp-9 is an unspecific laboratory marker of inflammation. for instance, the expression of mmp-9 as well as other mmps (for instance, mmp-2, -7 and -12) is increased in ms brain sections as measured by immunohistochemical analysis.32,35,46,62 in addition, high mmp-9 levels in serum or leucocytes were detected by immunochemical methods.63 longterm follow-up studies have enabled patterns to be recorded with mri; additionally, enhanced mmp-9 steady-state mrna levels were measured in ms.59 in the cns, mmp-9 can be expressed in the vascular endothelial cells, meninges, microglia, astrocytes and accumulated inflammatory cells, as well as in inflamed ms plaques and in the seemingly normal white matter or cerebral-infarction tissue.64 it has been also observed that mmp-9 was strongly expressed by the neutrophils in patients up to one week after an infarction—at that point a large number of macrophages were expressing mmp-9.46 in wistar rat eae models, an elevated expression of mmp-9 may play a role in some pathological changes, similar to mmp-2.65 for example, it increases the permeability of the bbb, facilitates the infiltration of leukocytes into the cns and causes myelin sheath degradation and neuronal damage.24 also, in mmp-9-deficient mice, the chemotaxis of neutrophils to intradermally-injected the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis e20 | squ medical journal, february 2014, volume 14, issue 1 with ms, whereas during treatment with interferon β (ifn-β), their concentrations increased.48,76,77 moreover, the levels of active mmp-9 in the serum and csf of ms patients may represent indicators for the monitoring of disease activity. in particular, the serum active mmp-9:timp-1 ratio seems to be a very suitable and easily measurable biomarker of the continuous inflammation in ms.75 furthermore, in a ms clinical trial, erythropoietin induced the expression of timp-1 in the endothelial cells, which helped to maintain the bbb integrity. the protective effects of erythropoietin were associated with an increase in the number of astrocytes expressing timp-1 in the brain and spinal cord in cases of eae.78 it has also been demonstrated that there is a significant association between the gene polymorphism of mmp-9 and ms susceptibility and severity.74,79,80 matrix metalloproteinase-12 mmp‒12 is a macrophage-specific mmp with a broad substrate specificity and is expressed in ms lesions at various stages.39 moreover, the transient expression of mmp-12 has also been reported in the microglial cells and astrocytes of ms patients.39 it has also been demonstrated that in active demyelinating lesions, phagocytic macrophages express mmp-12. moreover, in inactive lesions and chronic active demyelinating lesions, lower ratios of phagocytic cells were mmp-12-positive.39 out of all of the mmps that could be measured in the spinal cord tissue at the peak of the disease, mmp-12 is significantly upregulated.81 in contrast to previous data, weaver et al. demonstrated that an elevation in mmp-12 expression was related to protection against eae. in this study, mmp-12-null mice had significantly severe eae when compared to the control mice. in addition, in vitro findings showed that the lymph node and spleen cells of the mmp-12-null mice had a significantly higher th1 to type 2 t helper cell (th2) cytokine proportion compared with similar cells in the control mice. evaluations of the main transcription factors of t cell polarisation also showed that mmp-12-null cells had reduced gata-3 and increased the t-bet expression, a situation that is in favor of th1 bias.82 matrix metalloproteinase-25 mmp-25 is a member of the mt mmps, which is expressed almost exclusively in peripheral blood leukocytes and in anaplastic astrocytomas and glioblastomas, but not in meningiomas.83 it was previously shown that the gene expression of the majority of mmps was upregulated in the spinal cords of swiss/jackson laboratory (sjl) mice with severe eae. here, four of the six mt mmps (mmp-15, -16, -17 and -24) were downregulated and the two remaining mt mmps (mmp-14 and -25) were upregulated in whole tissue.84 mmp-25 proteolysis can inactivate a ms regulator known as αb-crystallin. therefore, mmp-25 functions and their restricted cell/tissue expression patterns play an important role in demyelinating diseases such as ms.37,85 mmp-25 cleaves golli-mbp isoforms in the immune cells, therefore stimulating specific clones of the autoreactive t cells.37 it is possible that the transmission of these autoreactive t cells, through the disrupted bbb, and the appearance of mbp in the neuronal cells can lead to inflammation and self-reactive responses. the activation of different elevated mmps and the dysregulation of timps enhances inflammation, autoreactive responses, mbp cleavage and demyelination and, consequently, the development of ms.37,85 matrix metalloproteinasebased therapeutic approaches to multiple sclerosis in view of the above, it seems that the direct inhibition of proteolysis or the induction of a balance between the endogenous proteinases and their natural inhibitors could be possible approaches to ms treatment. however, further proof is needed to demonstrate the pathogenic role of extracellular proteolysis.86 generally, the role of mmp involvement in pathology is that of matrix degradation, so mmp inhibition may be of therapeutic benefit. the first disease targeted with mmps was ra but the range of potential applications has broadened to include the treatment of cancer.87 however, the multiple roles of mmps in the cns make them a therapeutic target for the treatment of neurological abbas mirshafiey, babak asghari, ghasem ghalamfarsa, farhad jadidi-niaragh and gholamreza azizi review | e21 to a greater alleviation of the eae severity score and histological outcomes, compared to either medication alone.106 however, because several mmps are elaborated, it seems that a non-selective mmp inhibitor might be more efficient than those that target only specific mmps or subclasses of the mmp family. it is suggested that current mmp inhibitors should only be used in short treatment courses, so that they do not inhibit the mmpmediated repair processes that subsequently ensue after an injury. thus, careful selection of the time frames and doses of mmp inhibitors is recommended and patients can benefit from their utilisation in neurological conditions.88 another strategy to treat ms is targeting the upstream molecules which regulate the expression of mmps and timps. for instance, the ecm metalloproteinase inducer emmprin (also known as cd147) induces mmps and this constitutes a new therapeutic target.107 it is reported that emmprin is upregulated on the peripheral leukocytes before the onset of eae. in brain sections of eae cases, emmprin expression was localised with mmp-9 protein and activity. the increased emmprin levels were also characteristic of brain samples from ms subjects, particularly in plaque-containing areas. as emmprin regulates leukocyte trafficking by increasing mmp activity, it may be a novel therapeutic target in the treatment of ms.107 additionally, in keeping with this concept to interfere with the proteinase/inhibitor balances in ms, statins have also been studied as they have been shown to reduce the expression level of mmp9.108,109 the effect of intravenous igg in ms is disputed; however, it has been reported in animal models that intravenous igg might be effective as a prophylaxis, preventing disease development, and exerting its function by suppressing the activation of mmps-2 and -9 by blocking mmp activities at the interface between the blood stream and cns.110 another interesting strategy is the control of mmp regulator cytokines and chemokines; by using neutralising antibodies or pharmacological antagonists against cytokines, chemokines and/or their receptors may bring considerable change in the therapeutic landscape for ms.86,111 disorders. further complications are that the various mmp members induce or compensate for one another, and most mmp inhibitors are nonselective for particular mmp members. there is also the likelihood that, while mmp inhibitors may protect against certain of the detrimental effects of some mmps, they will also block the useful actions of these mmps, thus slowing disease recovery.88 the first synthetic mmp inhibitor was developed in the early 1980s as a pseudopeptide derivative based on the structure of the collagen molecule at the site of the initial cleavage by interstitial collagenase.89 a number of synthetic inhibitors of mmp activity have been developed and have been shown to decrease the incidence and severity of eae. these inhibitors include gm6001,90,91 ro-31-9790,92 bb1101,93 uk221 and d-penicillamine.94 a semi-synthetic tetracycline derivative, minocycline, also has a mmp inhibitory function.95 in eae mice models, it has been shown that minocycline decreases the expression and function of mmp-9 in t cells and attenuates the disease severity and neuropathology.96 in the clinical trial of minocycline in rrms, it significantly decreased gadolinium-enhanced mri activity within the first two months of treatment; this effect was associated with the role of mmps in reducing disruption of the bbb.97 however, the decreased function of mmp-9 during treatment would also support this mechanism.98 the beneficial effect of ifn-β, which is the current drug in ms therapy, is also associated with the reduced production of mmp-9 by t cells, the decreased ability of t cells to transmigrate a basement membrane barrier and the reduced gadolinium-enhanced mri activity.99–101 these results imply that ifn-β exerts alleviating effects in part through the suppression of the mmps’ functions. clinical studies support the possibility that ifn-β regulates mmp and timp-1 levels in patients with ms.48,102,103 however, there is no justified data regarding the anti-mmp effects of glatiramer acetate, another current drug in ms therapy.101 interestingly, it has been shown that mmp-9 could disrupt ifn-β and that this was inhibited by minocycline through antagonism of the mmp-9 functioning.104 thus, it seems that the combination of ifn-β and minocycline leads to promising results in ms therapy.105 it has been shown consistently that the combination of ifn-β and minocycline in the treatment of eae leads the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis e22 | squ medical journal, february 2014, volume 14, issue 1 conclusion in ms disease, increased mmp activity and reduced timp levels contribute to a loss of the bbb integrity and infiltration of inflammatory immune cells to the cns. therefore, mmps and their timps play a key role in the immunopathogenesis of ms, and are suggested as potential targets to treatments. hence, more research in mmps/timps domain and their roles in immunopathogenesis of disease might be recommended as a therapeutic toll for controlling ms. references 1. john gr. investigation of astrocyte oligodendrocyte interactions in human cultures. methods mol biol 2012; 814:401–14. 2. sriram s. role of glial cells in innate immunity and their role in cns demyelination. j neuroimmunol 2011; 239:13– 20. 3. koch-henriksen n, sørensen ps. the changing demographic pattern of multiple sclerosis epidemiology. lancet neurol 2010; 9:520–32. 4. frohman em, racke mk, raine cs. multiple sclerosis: the plaque and its pathogenesis. n engl j med 2006; 354:942– 55. 5. noseworthy jh, lucchinetti c, rodriguez m, weinshenker bg. multiple sclerosis. n engl j med 2000; 343:938–52. 6. jadidi-niaragh f, mirshafiey a. th17 cell, the new player of neuroinflammatory process in multiple sclerosis. scand j immunol 2011; 74:1–13. 7. murphy ac, lalor sj, lynch ma, mills kh. infiltration of th1 and th17 cells and activation of microglia in the cns during the course of experimental autoimmune encephalomyelitis. brain behav immun 2010; 24:641–51. 8. olah m, amor s, brouwer n, vinet j, eggen b, biber k, et al. identification of a microglia phenotype supportive of remyelination. glia 2012; 60:306–21. 9. theoharides tc, kempuraj d, kourelis t, manola a. human mast cells stimulate activated t cells: implications for multiple sclerosis. ann n y acad sci 2008; 1144:74–82. 10. rodgers jm, zhou l, miller sd. act 1, scene brain: astrocytes play a lead role. immunity 2010; 32:302–4. 11. kim dy, hong gu, ro jy. signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through cd40-cd40l. j neuroinflammation 2011; 8:25. 12. ajami b, bennett jl, krieger c, mcnagny km, rossi fm. infiltrating monocytes trigger eae progression, but do not contribute to the resident microglia pool. nat neurosci 2011; 14:1142–9. 13. guo x, harada c, namekata k, matsuzawa a, camps m, ji h, et al. regulation of the severity of neuroinflammation and demyelination by tlr-ask1-p38 pathway. embo mol med 2010; 2:504–15. 14. batoulis h, addicks k, kuerten s. emerging concepts in autoimmune encephalomyelitis beyond the cd4/t(h)1 paradigm. ann anat 2010; 192:179–93. 15. li h, nourbakhsh b, safavi f, li k, xu h, cullimore m, et al. kit (w-sh) mice develop earlier and more severe experimental autoimmune encephalomyelitis due to absence of immune suppression. j immunol 2011; 187:274– 82. 16. sayed ba, christy al, walker me, brown ma. meningeal mast cells affect early t cell central nervous system infiltration and blood-brain barrier integrity through tnf: a role for neutrophil recruitment? j immunol 2010; 184:6891–900. 17. shimizu f, kanda t. [disruption of the blood-brain barrier in inflammatory neurological diseases]. brain nerve 2013; 65:165–76. 18. morales y, parisi je, lucchinetti cf. the pathology of multiple sclerosis: evidence for heterogeneity. adv neurol 2006; 98:27–45. 19. van horssen j, vos cm, admiraal l, van haastert es, montagne l, van der valk p, et al. matrix metalloproteinase-19 is highly expressed in active multiple sclerosis lesions. neuropathol appl neurobiol 2006; 32:585–93. 20. woessner jf jr. matrix metalloproteinases and their inhibitors in connective tissue remodeling. faseb j 1991; 5:2145–54. 21. birkedal-hansen h. matrix metalloproteinases. adv dent res 1995; 9:16. 22. visse r, nagase h. matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. circ res 2003; 92:827–39. 23. nagase h, visse r, murphy g. structure and function of matrix metalloproteinases and timps. cardiovasc res 2006; 69:562–73. 24. muroski me, roycik md, newcomer rg, van den steen pe, opdenakker g, monroe hr, et al. matrix metalloproteinase-9/gelatinase b is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis. curr pharm biotechnol 2008; 9:34–46. 25. bar-or a, nuttall rk, duddy m, alter a, kim hj, ifergan i, et al. analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. brain 2003; 126:2738–49. 26. nguyen hx, o’barr tj, anderson aj. polymorphonuclear leukocytes promote neurotoxicity through release of matrix metalloproteinases, reactive oxygen species, and tnf-alpha. j neurochem 2007; 102:900–12. 27. kurzepa j, bartosik-psujek h, suchozebrska-jesionek d, rejdak k, stryjecka-zimmer m, stelmasiak z. [role of matrix metalloproteinases in the pathogenesis of multiple sclerosis]. neurol neurochir pol 2005; 39:63–7. 28. gijbels k, masure s, carton h, opdenakker g. gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. j neuroimmunol 1992; 41:29–34. 29. gijbels k, proost p, masure s, carton h, billiau a, opdenakker g. gelatinase b is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. j neurosci res 1993; 36:432–40. 30. yong vw, power c, forsyth p, edwards dr. metalloproteinases in biology and pathology of the nervous system. nat rev neurosci 2001; 2:502–11. abbas mirshafiey, babak asghari, ghasem ghalamfarsa, farhad jadidi-niaragh and gholamreza azizi review | e23 46. anthony dc, ferguson b, matyzak mk, miller km, esiri mm, perry vh. differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. neuropathol appl neurobiol 1997; 23:406–15. 47. newman ta, woolley st, hughes pm, sibson nr, anthony dc, perry vh. t-celland macrophage-mediated axon damage in the absence of a cns-specific immune response: involvement of metalloproteinases. brain 2001; 124:2203–14. 48. galboiz y, shapiro s, lahat n, rawashdeh h, miller a. matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclerosis patients. ann neurol 2001; 50:443–51. 49. emmert-buck mr, emonard hp, corcoran ml, krutzsch hc, foidart jm, stetler-stevenson wg. cell surface binding of timp-2 and pro-mmp-2/timp-2 complex. febs lett 1995; 364:28–32. 50. ogata y, enghild jj, nagase h. matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. j biol chem 1992; 267:3581–4. 51. van hove i, lemmens k, van de velde s, verslegers m, moons l. matrix metalloproteinase-3 in the central nervous system: a look on the bright side. j neurochem 2012; 123:203–16. 52. kanesaka t, mori m, hattori t, oki t, kuwabara s. serum matrix metalloproteinase-3 levels correlate with disease activity in relapsing-remitting multiple sclerosis. j neurol neurosurg psychiatry 2006; 77:185–8. 53. woo ms, park js, choi iy, kim wk, kim hs. inhibition of mmp-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and inos in microglia. j neurochem 2008; 106:770–80. 54. kim ys, kim ss, cho jj, choi dh, hwang o, shin dh, et al. matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. j neurosci 2005; 25:3701–11. 55. dubois-dalcq m, murray k. why are growth factors important in oligodendrocyte physiology? pathol biol (paris) 2000; 48:80–6. 56. fowlkes jl, serra dm, bunn rc, thrailkill km, enghild jj, nagase h. regulation of insulin-like growth factor (igf)-i action by matrix metalloproteinase-3 involves selective disruption of igf-i/igf-binding protein-3 complexes. endocrinology 2004; 145:620–6. 57. mccawley lj, matrisian lm. matrix metalloproteinases: they’re not just for matrix anymore! curr opin cell biol 2001,13:534–40. 58. skuljec j, gudi v, ulrich r, frichert k, yildiz o, pul r, et al. matrix metalloproteinases and their tissue inhibitors in cuprizone-induced demyelination and remyelination of brain white and gray matter. j neuropathol exp neurol 2011; 70:758–69. 59. lindberg rl, de groot cj, montagne l, freitag p, van der valk p, kappos l, et al. the expression profile of matrix metalloproteinases (mmps) and their inhibitors (timps) in lesions and normal appearing white matter of multiple sclerosis. brain 2001; 124:1743–53. 60. kieseier bc, kiefer r, clements jm, miller k, wells gm, schweitzer t, et al. matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis. brain 1998; 121:159–66. 31. rosenberg ga. matrix metalloproteinases and neuroinflammation in multiple sclerosis. neuroscientist 2002; 8:586–95. 32. maeda a, sobel ra. matrix metalloproteinases in the normal human central nervous system, microglial nodules, and multiple sclerosis lesions. j neuropathol exp neurol 1996; 55:300–9. 33. conant k, mcarthur jc, griffin de, sjulson l, wahl lm, irani dn. cerebrospinal fluid levels of mmp-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia. ann neurol 1999; 46:391–8. 34. vos cm, sjulson l, nath a, mcarthur jc, pardo ca, rothstein j, et al. cytotoxicity by matrix metalloprotease-1 in organotypic spinal cord and dissociated neuronal cultures. exp neurol 2000; 163:324–30. 35. cossins ja, clements jm, ford j, miller km, pigott r, vos w, et al. enhanced expression of mmp-7 and mmp-9 in demyelinating multiple sclerosis lesions. acta neuropathol 1997; 94:590–8. 36. szklarczyk a, lapinska j, rylski m, mckay rd, kaczmarek l. matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. j neurosci 2002; 22:920–30. 37. shiryaev sa, remacle ag, savinov ay, chernov av, cieplak p, radichev ia, et al. inflammatory proprotein convertasematrix metalloproteinase proteolytic pathway in antigenpresenting cells as a step to autoimmune multiple sclerosis. j biol chem 2009; 284:30615–26. 38. shiryaev sa, savinov ay, cieplak p, ratnikov bi, motamedchaboki k, smith jw, et al. matrix metalloproteinase proteolysis of the myelin basic protein isoforms is a source of immunogenic peptides in autoimmune multiple sclerosis. plos one 2009; 4:e4952. 39. vos cm, van haastert es, de groot cj, van der valk p, de vries he. matrix metalloproteinase-12 is expressed in phagocytotic macrophages in active multiple sclerosis lesions. j neuroimmunol 2003; 138:106–14. 40. strongin ay, collier i, bannikov g, marmer bl, grant ga, goldberg gi. mechanism of cell surface activation of 72-kda type iv collagenase. isolation of the activated form of the membrane metalloprotease. j biol chem 1995; 270:5331–8. 41. kouwenhoven m, ozenci v, gomes a, yarilin d, giedraitis v, press r, et al. multiple sclerosis: elevated expression of matrix metalloproteinases in blood monocytes. j autoimmun 2001; 16:463–70. 42. altimiras j, borras jm, mendez e, pastor e, bassons t. knowledge of medication in hospitalized chronic respiratory patients. pharm weekbl sci 1992; 14:174–9. 43. benesová y, vasku a, novotná h, litzman j, stourac p, beránek m, et al. matrix metalloproteinase-9 and matrix metalloproteinase-2 as biomarkers of various courses in multiple sclerosis. mult scler 2009; 15:316–22. 44. diaz-sanchez m, williams k, deluca gc, esiri mm. protein co-expression with axonal injury in multiple sclerosis plaques. acta neuropathol 2006; 111:289–99. 45. fainardi e, castellazzi m, tamborino c, trentini a, manfrinato mc, baldi e, et al. potential relevance of cerebrospinal fluid and serum levels and intrathecal synthesis of active matrix metalloproteinase-2 (mmp-2) as markers of disease remission in patients with multiple sclerosis. mult scler 2009; 15:547–54. the significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis e24 | squ medical journal, february 2014, volume 14, issue 1 61. opdenakker g, nelissen i, van damme j. functional roles and therapeutic targeting of gelatinase b and chemokines in multiple sclerosis. lancet neurol 2003; 2:747–56. 62. cuzner ml, gveric d, strand c, loughlin aj, paemen l, opdenakker g, et al. the expression of tissue-type plasminogen activator, matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution. j neuropathol exp neurol 1996; 55:1194–204. 63. sellebjerg f, madsen ho, jensen cv, jensen j, garred p. ccr5 delta32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. j neuroimmunol 2000; 102:98–106. 64. kawasaki y, xu zz, wang x, park jy, zhuang zy, tan ph, et al. distinct roles of matrix metalloproteases in the early and late-phase development of neuropathic pain. nat med 2008; 14:331–6. 65. dong m, liu r, guo l, li c, tan g. pathological findings in rats with experimental allergic encephalomyelitis. apmis 2008; 116:972–84. 66. d’haese a, wuyts a, dillen c, dubois b, billiau a, heremans h, et al. in vivo neutrophil recruitment by granulocyte chemotactic protein-2 is assisted by gelatinase b/mmp-9 in the mouse. j interferon cytokine res 2000; 20:667–74. 67. dubois b, masure s, hurtenbach u, paemen l, heremans h, van den oord j, et al. resistance of young gelatinase b-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. j clin invest 1999; 104:1507–15. 68. agrawal s, anderson p, durbeej m, van rooijen n, ivars f, opdenakker g, et al. dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. j exp med 2006; 203:1007–19. 69. cuzner ml, opdenakker g. plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. j neuroimmunol 1999; 94:1–14. 70. fridman r, toth m, peña d, mobashery s. activation of progelatinase b (mmp-9) by gelatinase a (mmp-2). cancer res 1995; 55:2548–55. 71. van den steen pe, proost p, grillet b, brand dd, kang ah, van damme j, et al. cleavage of denatured natural collagen type ii by neutrophil gelatinase b reveals enzyme specificity, post-translational modifications in the substrate, and the formation of remnant epitopes in rheumatoid arthritis. faseb j 2002; 16:379–89. 72. alexander js, harris mk, wells sr, mills g, chalamidas k, ganta vc, et al. alterations in serum mmp-8, mmp-9, il12p40 and il-23 in multiple sclerosis patients treated with interferon-beta1b. mult scler 2010; 16:801–9. 73. sato w, tomita a, ichikawa d, lin y, kishida h, miyake s, et al. ccr2(+)ccr5(+) t cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis. j immunol 2012; 189:5057–65. 74. zivković m, djurić t, dincić e, raicević r, alavantić d, stanković a. matrix metalloproteinase-9 -1562 c/t gene polymorphism in serbian patients with multiple sclerosis. j neuroimmunol 2007; 189:147–50. 75. fainardi e, castellazzi m, bellini t, manfrinato mc, baldi e, casetta i, et al. cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (mmp-9) as markers of disease activity in patients with multiple sclerosis. mult scler 2006; 12:294–301. 76. lee ma, palace j, stabler g, ford j, gearing a, miller k. serum gelatinase b, timp-1 and timp-2 levels in multiple sclerosis. a longitudinal clinical and mri study. brain 1999; 122:191–7. 77. ozenci v, rinaldi l, teleshova n, matusevicius d, kivisäkk p, kouwenhoven m, et al. metalloproteinases and their tissue inhibitors in multiple sclerosis. j autoimmun 1999; 12:297–303. 78. thorne m, moore cs, robertson gs. lack of timp1 increases severity of experimental autoimmune encephalomyelitis: effects of darbepoetin alfa on timp-1 null and wild-type mice. j neuroimmunol 2009; 211:92– 100. 79. benesová y, vasků a, stourac p, hladiková m, beránek m, kadanka z, et al. matrix metalloproteinase-9 and matrix metalloproteinase-2 gene polymorphisms in multiple sclerosis. j neuroimmunol 2008; 205:105–9. 80. fernandes ks, brum dg, sandrim vc, guerreiro ct, barreira aa, tanus-santos je. matrix metalloproteinase-9 genotypes and haplotypes are associated with multiple sclerosis and with the degree of disability of the disease. j neuroimmunol 2009; 214:128–31. 81. ulrich r, gerhauser i, seeliger f, baumgärtner w, alldinger s. matrix metalloproteinases and their inhibitors in the developing mouse brain and spinal cord: a reverse transcription quantitative polymerase chain reaction study. dev neurosci 2005; 27:408–18. 82. weaver a, goncalves da silva a, nuttall rk, edwards dr, shapiro sd, rivest s, et al. an elevated matrix metalloproteinase (mmp) in an animal model of multiple sclerosis is protective by affecting th1/th2 polarization. faseb j 2005; 19:1668–70. 83. pei d. leukolysin/mmp25/mt6-mmp: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage. cell res 1999; 9:291–303. 84. toft-hansen h, babcock aa, millward jm, owens t. downregulation of membrane type-matrix metalloproteinases in the inflamed or injured central nervous system. j neuroinflammation 2007; 4:24. 85. devy l, dransfield dt. new strategies for the next generation of matrix-metalloproteinase inhibitors: selectively targeting membrane-anchored mmps with therapeutic antibodies. biochem res int 2011; 2011:191670. 86. opdenakker g, van damme j. probing cytokines, chemokines and matrix metalloproteinases towards better immunotherapies of multiple sclerosis. cytokine growth factor rev 2011,22:359-365. 87. brown pd. matrix metalloproteinase inhibitors. breast cancer res treat 1998; 52:125–36. 88. agrawal sm, lau l, yong vw. mmps in the central nervous system: where the good guys go bad. semin cell dev biol 2008; 19:42–51. 89. brown pd, giavazzi r. matrix metalloproteinase inhibition: a review of anti-tumour activity. ann oncol 1995; 6:967– 74. abbas mirshafiey, babak asghari, ghasem ghalamfarsa, farhad jadidi-niaragh and gholamreza azizi review | e25 101. yong vw. differential mechanisms of action of interferonbeta and glatiramer aetate in ms. neurology 2002; 59:802– 8. 102. fawcett ha, wansbrough-jones mh, clark ae, leigh im. prophylactic topical acyclovir for frequent recurrent herpes simplex infection with and without erythema multiforme. br med j (clin res ed) 1983; 287:798–9. 103. trojano m, avolio c, liuzzi gm, ruggieri m, defazio g, liguori m, et al. changes of serum sicam-1 and mmp-9 induced by rifnbeta-1b treatment in relapsing-remitting ms. neurology 1999; 53:1402–8. 104. nelissen i, martens e, van den steen pe, proost p, ronsse i, opdenakker g. gelatinase b/matrix metalloproteinase-9 cleaves interferon-beta and is a target for immunotherapy. brain 2003,126:1371–81. 105. yong vw, zabad rk, agrawal s, goncalves dasilva a, metz lm. elevation of matrix metalloproteinases (mmps) in multiple sclerosis and impact of immunomodulators. j neurol sci 2007; 259:79–84. 106. giuliani f, fu sa, metz lm, yong vw. effective combination of minocycline and interferon-beta in a model of multiple sclerosis. j neuroimmunol 2005; 165:83–91. 107. agrawal sm, silva c, tourtellotte ww, yong vw. emmprin: a novel regulator of leukocyte transmigration into the cns in multiple sclerosis and experimental autoimmune encephalomyelitis. j neurosci 2011; 31:669– 77. 108. stüve o, prod’homme t, slavin a, youssef s, dunn s, steinman l, et al. statins and their potential targets in multiple sclerosis therapy. expert opin ther targets 2003; 7:613–22. 109. antel jp, miron ve. central nervous system effects of current and emerging multiple sclerosis-directed immunotherapies. clin neurol neurosurg 2008; 110:951–7. 110. niimi n, kohyama k, kamei s, matsumoto y. intravenous immunoglobulin therapy prevents development of autoimmune encephalomyelitis and suppresses activation of matrix metalloproteinases. neuropathology 2011; 31:392–400. 111. opdenakker g, van damme j. cytokine-regulated proteases in autoimmune diseases. immunol today 1994; 15:103–7. 90. gijbels k, galardy re, steinman l. reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. j clin invest 1994; 94:2177–82. 91. graesser d, mahooti s, madri ja. distinct roles for matrix metalloproteinase-2 and alpha4 integrin in autoimmune t cell extravasation and residency in brain parenchyma during experimental autoimmune encephalomyelitis. j neuroimmunol 2000; 109:121–31. 92. hewson ak, smith t, leonard jp, cuzner ml. suppression of experimental allergic encephalomyelitis in the lewis rat by the matrix metalloproteinase inhibitor ro31-9790. inflamm res 1995; 44:345–9. 93. chandler s, miller km, clements jm, lury j, corkill d, anthony dc, et al. matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. j neuroimmunol 1997; 72:155–61. 94. norga k, paemen l, masure s, dillen c, heremans h, billiau a, et al. prevention of acute autoimmune encephalomyelitis and abrogation of relapses in murine models of multiple sclerosis by the protease inhibitor d-penicillamine. inflamm res 1995; 44:529–34. 95. yong vw, wells j, giuliani f, casha s, power c, metz lm. the promise of minocycline in neurology. lancet neurol 2004; 3:744–51. 96. brundula v, rewcastle nb, metz lm, bernard cc, yong vw. targeting leukocyte mmps and transmigration: minocycline as a potential therapy for multiple sclerosis. brain 2002; 125:1297–308. 97. metz lm, zhang y, yeung m, patry dg, bell rb, stoian ca, et al. minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. ann neurol 2004; 55:756. 98. zabad rk, metz lm, todoruk tr, zhang y, mitchell jr, yeung m, et al. the clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study. mult scler 2007; 13:517–26. 99. stüve o, dooley np, uhm jh, antel jp, francis gs, williams g, et al. interferon beta-1b decreases the migration of t lymphocytes in vitro: effects on matrix metalloproteinase-9. ann neurol 1996; 40:853–63. 100. leppert d, waubant e, bürk mr, oksenberg jr, hauser sl. interferon beta-1b inhibits gelatinase secretion and in vitro migration of human t cells: a possible mechanism for treatment efficacy in multiple sclerosis. ann neurol 1996; 40:846–52. the importance of genetics in oman said al-yahyaee deputy vice-chancellor academic affairs & community service, sultan qaboos university, muscat, oman. e-mail: syahyaee@squ.edu.om the sultanate of oman is located in the south east of the arabian peninsula with a coast line stretching from yemen in the south to the arabian gulf in the north. this location served as a crossroads for the prehistoric worldwide spread of humans out of africa. for centuries, the coast of oman had been a sea gate to asia and africa through which omanis traded and intermixed with other populations. over the last forty-two prosperous years, the omani population has grown approximately four-fold due to an increased birth rate and substantial decline in the death rate. the current population is mainly tribal arab, but the numbers of asian and african ethnic descendants are significant. the increased population growth as well as traditionally preferred consanguineous marriages has led to the emergence of a wide spectrum of genetic diseases. recent public database searches reveal that only a fraction of those diseases have been studied at the molecular level. interestingly, over 70% of the reported mutations and loci were novel. commendable efforts by the ministry of health and sultan qaboos university hospital to offer a comprehensive genetic service are progressing. the service’s main challenges are to educate the public on the importance of genetic disease prevention as well as to identify disease-causing mutations or markers through transitional research. this surely calls for well-structured national and international collaboration. the return of the human genome project to clinical genetics david valle johns hopkins university, usa. e-mail: dvalle@jhmi.edu traditionally, medical geneticists have relied on linkage, association, or candidate gene approaches to identify the genes responsible for mendelian disorders. in aggregate, these methods have found about 2,700 disease genes or about 12% of our total complement of genes. recent advances in genomics, plus the development of new sequencing technologies, provide the tools necessary to speed up dramatically the progress in disease gene identification. an essential requirement in this effort is the identification and careful characterisation of patients and families with mendelian phenotypes that have not yet been explained at the molecular level. for example, online mendelian inheritance in man (omim) currently lists ~2500 mendelian disorders for which the responsible gene is yet unidentified and in any active genetics clinic there are many patients and families with undiagnosed disorders that segregate as mendelian traits. a high frequency of consanguineous unions increases the incidence of rare recessive disorders of this type. by combining these resources, we can expect that over the next few years there will be a substantial increase in the number of identified disease genes and, correspondingly, in the number of human phenotypes that we can connect to genes and biological networks. my presentation will focus on the lessons we can expect to learn by “solving” a large number of currently unexplained disorders. these lessons will include immediate benefits in diagnosis, counselling, and treatment, as well as long-term insights into the mechanisms of disease and its prevention. genetics and society myles axton chief editor, nature genetics. e-mail: m.axton@us.nature.com for much of human history, our common ancestors worldwide have practiced consanguinity, or “close cousin marriage”. this has great مؤمتر ُعمان الدويل األول للتمريض االبتكارات يف جمال تعليم التمريض واملمارسة اليت تؤدي اىل الرعاية اجليدة جامعة ال�سلطان قابو�ض، �سلطنة ُعمان; 29-28 نوفمرب 2011 international conference on consanguinity towards the discovery of genes predisposing to and protecting from disease sultan qaboos university, 17-19 march 2011 abstracts sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 382-390, epub. 15th jul 12 abstracts | 383 sultan qaboos university, 17-19 march 2011 social benefits in keeping economic resources in the family and ensuring alliances with well-known and like-minded people; however, it also produces an extra risk of congenital birth defects. the gulf region, with relatively high rates of consanguinity, natural fertility, and large families, presents an ideal training ground for internationally significant research and highly relevant clinical delivery that can make a big difference to local people’s welfare. the information gained is important not only for the development of this region but also for information needed throughout the world. people living with genetic differences hold the key pieces to the jigsaw of the human genome. without them we cannot make sense of the code we all share, and we cannot extract the messages of health and disease contained in the genetic framework. highly motivated families play a hub role in research. they outline the family differences, find the experts, get their set of traits onto the funding agenda, and even help to write the scientific reports. the work involved in establishing genetic differences is rarely straightforward because a set of unusual features caused by a gene variant may play out in different degrees. contrasting with these are traits that members of any family can share. however, when the gene variant is found, the different problems collapse onto the single underlying cause and this understanding makes it easier to coordinate services. rare familial traits create a bond linking affected families when they can find one another. organisations like the genetic alliance allow us to pool our efforts. with genetic testing comes the possibility of understanding genetic disorders and applying appropriate prevention measures such as family and premarital counselling. positive examples of families and their supporters are very important in this effort, and journalists can help once they are given examples like the portraits of rick guidotti, founder of positive exposure, a non-profit organisation, that challenges stigma associated with difference by pioneering a new vision of the beauty and richness of genetic diversity. consanguineous marriage: facts versus fiction alan bittles centre for comparative genomics, edith cowan university, perth, australia. e-mail: a.bittles@ecu.edu.au the most common misunderstanding with respect to consanguineous marriage is that somehow they causes genetic disease. while there is no doubt that the expression of rare recessive disorders is more probable in the progeny of a close kin marriage, the assumption of a causal relationship between consanguinity and inherited disease is erroneous and ignores factors such as founder effect, effective population size, drift and population stratification. in conjunction with failure to control for adverse demographic, social, and economic issues, exaggerated estimates of the harmful health outcomes of marriages between close family members have resulted. globally, more than 1 billion people live in countries where 20–50+ % of marriages are contracted between couples related as second cousins or closer (f = 0.0625), and in these different societies intra-familial marriage has been preferential for many generations. recent multi-national meta-analyses have indicated a mean excess of 0.5/1000 stillbirths, 12.5/1000 infant deaths, and 37/1000 pre-reproductive deaths in the offspring of first cousins. from a public health perspective, it is important to assess these statistics within a local context, and the lack of control for non-genetic variables in a majority of the studies strongly suggests that the mortality estimates are maximal. significant variability was observed in complementary studies on morbidity, with reported excess birth defects at the first cousin level ranging from 0.3% to 10.0%, once again suggesting inadequate control for non-genetic variables, including maternal nutrition and medication, and trans-placental infection. comprehensive multidisciplinary studies on consanguinity are urgently needed, with a thorough assessment of the perceived social and cultural benefits considered alongside epidemiological data, the patterns and extent of genomic homozygosity, and population genetic structure. to date, the primary focus on consanguinity has been on reproductive behaviour and health outcomes in the early years of life. given the rapid ageing of most human societies, equivalent emphasis on the influence of consanguinity on adult health is overdue. community needs for genetics services in oman anna rajab clinical genetics, department of child health, royal hospital, muscat, oman. e-mail: drarajab@omantel.net.om over the past 30 years, oman has witnessed remarkable social and economic growth, which is best reflected in its well-organised and efficient health care system. as a consequence, there has been an epidemiological shift in disease patterns, with a significant decrease in the incidence of communicable diseases, and in the mortality and morbidity rates of infants and children under 5 years. with the application of high quality standard medical care, natural selection forces are no longer in place, and children disadvantaged by birth defects and genetic conditions who would have died in past decades are now surviving. a recent population-based study confirmed genetic and congenital disorders are major contributors to childhood disabilities and handicaps. the figures of morbidity and mortality in newborns, infants, and children reflect the situation in a traditional muslim community where communicable diseases were successfully controlled and primary prevention is in the preparation phase. future planning of genetic services and effective prevention programmes will be discussed. genetic/genomic studies of consanguinity in inbred populations giovanni romeo european genetics foundation, bologna, italy. e-mail: egf.giovanni.romeo@gmail.com classical studies of consanguinity have taken advantage of the relationship between the gene frequency for a rare autosomal recessive disorder (q) and the proportion of offspring of consanguineous couples who are affected with the same disorder. we developed a new approach for estimating q using mutation analysis of affected offspring of consanguineous couples based on the possibility that the child born of consanguineous parents carries a double copy of the same mutation (true homozygosity), or alternatively carries 384 | squ medical journal, august 2012, volume 12, issue 3 international conference on consanguinity towards the discovery of genes predisposing to and protecting from disease two different mutations in the same gene (compound heterozygosity) inherited through two different ancestors. the proportion of compound heterozygotes among children affected with a given autosomal recessive disorder, born of consanguineous parents, can be taken therefore as an indirect indicator of the frequency of the same disorder in the general population. data from the offspring of consanguineous marriages affected with different autosomal recessive disorders collected by different molecular diagnostic laboratories in mediterranean countries, and in particular in arab countries where the frequency of consanguineous marriages is high, show the validity of this approach. finally, recent experimental data show that the causative mutation for a rare autosomal recessive disorder can be identified by whole exom sequencing of only two affected children of first cousin parents. in conclusion, consanguinity becomes a powerful tool for the identification of disease genes and of the corresponding causative mutations in any inbred population when an effective collaboration is established between molecular geneticists, clinical geneticists and other clinical specialists. the present conference gives the opportunity to launch a common genome project based on the patient and population resources of each country of the gulf region which are characterised by a typical social structure based on consanguinity. the aim would be to identify regions of homozygosity of the human genome harboring genes predisposing to or protecting from disease. the return of the human genome project to genetic studies of populations thomas meitinger institute of human genetics, technical university munich, germany. e-mail: meitinger@helmholtz-muenchen.de population-based studies constitute an essential tool for harvesting the wealth of genomic information made available by the human genome project. the initial aim of these studies was to provide a clinical dataset from a random sample of a population in addition to environmental information in order to evaluate epidemiological risk factors. the kooperative gesundheitsforschung in der region augsburg (kora = cooperative health research project in augsburg region) project is an example of such a population-based study. it led by the epidemiology departments of the helmholtz center in munich. it started in 1984 with a succession of four surveys plus corresponding follow-up studies, and collected information and biomaterials from more than 16,000 individuals. its continuing output is based to a great extent on genome-wide analyses of quantitative traits of medical relevance, and in contributing genotyped control samples to the study of dichotomous traits such as diabetes or myocardial infarction. currently, this generation of transcriptomic and metabolomic data adds to the information content already available on the genomic and the phenotypic level. cohorts such as kora can only fulfill their potential in combination with studies in other populations, which provide increased power and the possibility of replication. advancements in sequencing technology will allow the extension of genetic investigations to rare variants on a genome wide level. in this context, the study of genetically isolated populations with their specific spectra of allele frequencies becomes critical. while donors in population-based studies have clearly made personal contributions to the advancement of scientific projects, it remains to be demonstrated how these participants can directly profit from such studies. it can be argued that the latter is not essential for the field, as new insights into molecular mechanisms will foster pharmacological innovation in general. nonetheless, the addition of rare genetic variation, the inclusion of transcriptomic and metabolomic datasets and, finally, the analysis of longitudinal datasets clearly have the potential to become relevant for individual study participants. genetic basis of common diseases riad bayoumi department of biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: bayoumi@squ.edu.om the recent advances in genomics and microarray technology at manageable cost, have enabled research groups, worldwide, to conduct successful genome wide association (gwa) studies. these studies have unravelled some aspects of the genetics of complex traits and common diseases, such as type 2 diabetes, obesity, myocardial infarction, stroke, asthma, schizophrenia, bipolar disorders, alzheimer’s disease, crohn’s disease, autoimmune diseases, and some cancers. the newly discovered genetic architecture of these diseases is helping in the understanding of pathophysiology and the development of novel approaches to prevention and therapeutic applications. however, most of the gwa studies have been designed to detect potential susceptibility in loci and genes attributable to common single nucleotide polymorphisms (snps), which are limited by the very design of microarrays. in almost all diseases tested to date, the variants discovered could only explain 10–15% of the inherited predisposition (heritability). the next major step will be to identify the probable source of this unknown heritability. an examination of copy number variants and rare variants that occur with low frequency await the design of novel microarrays and low-cost through sequencing. newborn screening program for oman: the need of the hour surendranath joshi department of child health, sultan qaboos university hospital, muscat, oman. e-mail: joshisnj@yahoo.com compared to western countries, metabolic diseases are at least 3 to 5 times more common in middle eastern countries, and oman is no exception. delay in diagnosis is the major cause of the region’s high morbidity and mortality. a large proportion of metabolic diseases are now amenable to simple and low cost, effective drug treatments, or simple modification of diet. early intervention in the presymptomatic stage of disease is the only hope for a good outcome. without a doubt, this is only possible by implementing an effective national newborn screening programme. since the invention of the first screening test for phenylketonuria by dr. robert guthrie in 1959, most western countries have adopted the screening programme. screening tests have now become even more efficient and, through tandem mass spectrometry, can detect multiple diseases from a single drop of blood. in the middle east, saudi arabia, qatar abstracts | 385 sultan qaboos university, 17-19 march 2011 and the united arab emirates (uae) have already adopted a viable screening programme. why should oman lag behind? without a shade of doubt, the investment in a screening programne today will certainly be rewarded many times over in terms of quality of life and the reduction of the burden of genetic diseases in the future. the role of consanguinity in reproductive health and disease gene identification in arab populations ghazi tadmouri centre for arab genomic studies, dubai, uae. e-mail : tadmouri@hotmail.com consanguineous marriages have been practised since the times of the earliest humans. until recent times, consanguinity was widely practised in several global communities at variable rates depending on religion, culture, and geography. arab populations have a long tradition of consanguinity due to socio-cultural factors. many arab countries display some of the highest rates of consanguineous marriages in the world, and first cousin marriages specifically may constitute 25–30% of all marriages. while the frequency of consanguineous marriages in some arab states (e.g. bahrain, jordan, lebanon, palestine) is decreasing, in other countries consanguinity rates are increasing in the current generation (e.g. qatar, the uae, and yemen). research among arabs and worldwide has indicated that consanguinity could have an effect on some reproductive health parameters such as postnatal mortality and rates of congenital malformations. the main impact of consanguinity, however, is an increase in the rate of homozygotes for autosomal recessive genetic disorders. the catalogue of transmission genetics in arabs (ctga) database indicates a relative abundance of recessive disorders (63%) compared to a smaller proportion of dominantly inherited traits (27%). among 451 genetic disorders reported in the uae, bahrain, and oman, 36.6% document the presence of patients resulting from consanguineous marriages, mostly among first cousins. on the other hand, the study of highly consanguineous populations in the region offers a unique advantage that could lead to the identification and characterisation of many genes responsible for human disease, and provide a new genotype-phenotype map of the human genome. the success of this approach can be seen in the large number of disease genes that have been identified by studying arab families. yet, of the 615 recessive diseases that have been reported in arab families, the responsible loci are not known for 171 of them. many other recessive diseases, especially those confined to single families, are not even reported. sickle cell disease (scd): genetic variations salam al-kindy department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: sskindi@yahoo.com sickle cell disease is a highly prevalent disease in oman, with 5.7% of omani people carrying the gene, and 0.2% of the population affected. although scd has been traditionally regarded as a disease of the red blood cells, it is in fact a complex disease which demonstrates a model for red cell interactions with white cells and endothelial cell lining. recent work from our laboratory on acute chest syndrome, which is one of the major causes of death associated with scd, and vaso-occlusive crisis (voc), the most frequent presentation of scd, has just demonstrated this complex interaction. an alteration in the level of nitric oxide as well as a shift in lymphocytes and monocytes activations plays a role in both conditions. similarly, the altered red cells (sickled cells) leading to perturbed platelets and haemostatic functions plays an important role in stroke development, added to the hereditary component of thrombophilia in this scd. these changes are promising an important opening for studies in the various therapeutic interventions that are available for scd, such as hydroxyurea, and, more recently, low molecular weight heparin, nicosan, and other agents that are undergoing testing. more recently the work on interactions of scd with other genetic markers has led to studies on its relationships with thalassaemia, particularly alpha thalassaemia and also co-inheritance with hereditary persistence of fetal haemoglobin (hpfh). all of these are definitely contributing to modulation of the disease’s behaviour and allowing variations even among siblings within the same family. i am sure that other markers are also playing a role and, in particular, environmental factors need to be explored. studying autosomal recessive disorders: model for genechip technology in the sultanate of oman aisha al-khayat, department of biology, college of science, sultan qaboos university, muscat, oman. email: alkhayat@squ.edu.om the use of genechip technology has revolutionised science advancements, and has directly impacted the medical field. its application has become an integral part of the biological sciences across the board. in the sultanate of oman, this technology was purchased through his majesty’s trust fund, which supported a research project tilted “family genetic understanding of autosomal recessive disorders (famguard)”. this investigation utilised single nucleotide polymorphism (snp) chips and was aimed at setting a model of identifying disease loci. recently, a generous fund from the omani research council (trc) has been granted to continue the previous work. about 40 families with autosomal recessive disorders have been processed using affymetrix 10k snp genechip technology. the genotypes were analysed and regions of consecutive homozygous snp calls were identified. the results showed new loci for some diseases and novel mutations for some known disorders. population mutations that were previously reported in the literature for other populations were reported for the first time in oman. the use of microarray technology has assisted greatly in defining regions and excluding others in an efficient way. the model has proved successful. however, the use of this technology does not remove the need for microsatellite utilisation; the methods in fact complement each other. 386 | squ medical journal, august 2012, volume 12, issue 3 international conference on consanguinity towards the discovery of genes predisposing to and protecting from disease pushing the envelope with mendelian genetics fowzan s. alkuraya king faisal specialist hospital & research center, riyadh, saudi arabia. e-mail: falkuraya@kfshrc.edu.sa everybody was excited at the turn of the 21st century by the belief that mendelian genetics in the post-human genome era would witness its golden era. however, the focus has now shifted to solving the genetics of common diseases. with few exceptions, the unprecedented investment that was made in the study of genetics of common diseases, mostly through the genome-wide association study (gwas) approach, failed to deliver medically actionable results such as those routinely seen in mendelian genetics. this juncture of time is best described as one of reflection upon where to go next with the study of the genetics of common diseases. i will argue in this presentation that there is much to be learned from mendelian genetics in informing research into common diseases. in the gulf region, we are in a unique position to take advantage of our population structure in order to make significant contribution to the field of common diseases by utilising mendelian genetics to its full potential. the presentation will include both the utilisation of mendelian genetics in common diseases (using such approaches as mendelian phenocopies and the carrier phenome project) as well as discussing how our unique population structure can inform research into the human genome, again using mendelian genetics approaches. population genomics of hearing loss in palestine moien kannan department of molecular genetics, bethlehem university, palestine. e-mail: moienkanaan@gmail.com recessively inherited phenotypes are frequent in the palestinian population as a result of a long historical tradition of marriages within extended families. traditionally, gene localisation in these families has been achieved with microsatellite linkage mapping. we demonstrate that genome-wide screening with high-density single nucleotide polymorphism (snp) arrays is an effective method for pinpointing causative genes and novel loci in consanguineous palestinian families. we generated deafness-associated homozygosity profiles from the snp data in each family. sequencing the relevant gene from each peak region identified 12 deleterious alleles, 10 of which were novel. using advanced targeted dna capture and massively parallel sequencing technologies in conjunction with homozygosity mapping, we identified five genomic regions likely to harbour novel genes for human hearing loss on chromosomes 1p13.3 (dfnb82), 9p23-p21.2/p13.3-q21.13 (dfnb83), 14q23.1-q31.1, and 17p12-q11.2 (dfnb85). next generation sequencing of the captured exons in dfnb82 revealed a chr1:109,440,214 c>t resulting in a r128x mutation in the g protein stimulator regulator (gpsm2) protein. functional biology is underway to reveal gpsm2’s role in hearing loss. we just constructed a custom 1.6 mb design of complimentary ribonucleic acid (crna) oligonucleotides containing 250 genes, responsible for both human and mouse deafness. we prepared paired-end libraries, followed by cluster amplification on v4 illumina flow cells with our bar-coded multiplexed samples. a 2x72bp paired end recipe was used, resulting in a median base coverage of 572x and, overall, 94.7% of our targeted bases were covered by more than 10 reads, which was our cut-off for variant detection. we generated snp and indel calls for our samples and filtered the variants against those of dbsnp131 and the 1000 genomes project to identify private and rare variants. novel mutations were identified. discovery of additional deafness genes and mutations will allow for early clinical diagnosis, enabling prediction of phenotypes and enhanced rehabilitation. characterisation of the proteins encoded by these genes will enable a comprehensive understanding of the biological mechanisms involved in the pathophysiology of hearing loss. in vitro fertilisation/pre-implantation genetic diagnosis in the gulf region maha al-khadouri department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: mahak@squ.edu.om in high-prevalence consanguineous societies, there is a need for well-established prenatal diagnostic services. these include preconception genetic screening, pre-implantation genetic diagnosis (pgd), and prenatal genetic and genomic testing. these tests may have implications related to the choice of a spouse, having children whether by spontaneous or assisted conception, and the continuity of a pregnancy depending on the cultural and religious values of the society. the advancement in technology, specifically assisted reproductive technology and pgd, will prove to be essential in couples with a known history of genetic diseases, especially if the termination of pregnancy is not an option. with pgd, disease-free embryos can be identified and transferred into the uterus reducing the risk of transmitting inherited disorders. unfortunately, the availability of these services is limited in developing countries. the limitations may be due to a shortage of resources or training, or limited availability of experts in this field. additionally, health care systems may not rank these services as a priority even though they can prove to be cost effective in term of health care resources in the long run. cultural backgrounds and legislations on pre-implantation diagnosis (pgd) in europe luca gianaroli ex-president, european society of human reproduction & embryology, belgium. e-mail: luca.gianaroli@sismer.it although pre-implantation genetic diagnosis (pgd) is regularly practised in most european countries, this technique and its application are still debated, and national legislations differ significantly. in medicine and clinical genetics, pgd is considered a form of prenatal diagnosis, however, as pgd involves the manipulation and discarding of embryos, it raises a variety of legal and ethical issues connected abstracts | 387 sultan qaboos university, 17-19 march 2011 to the legal status of embryos and on the possible misuses of this technique for eugenic purposes. the ethical and legal aspects of pgd have been approached differently in different european countries due to cultural, religious, legal, and political factors. although the restrictions applied to pgd vary significantly from country to country, in general national legislations prohibit pgd for non-medical purposes, in particular as far as sex selection is concerned. of course, differing legislations affect access to treatment, forcing people residing in countries where this technique is not allowed to engage in “cross-border reproductive care”. european institutions have expressed views on this issue, but in general the european union has not yet adopted a clear, unified opinion on the practice of pgd. the situation is made even more difficult by the fact that pgd is still a very recent technique, whose areas of application and efficacy are constantly expanding, but also creating ambiguities in the use of this technology. this will certainly lead to further debates as far as regulation of these new developments is concerned. the european society for human reproduction and embryology (eshre) pgd consortium was set up in 1997 aiming to: survey the availability of pgd; collect data on the accuracy, reliability, and effectiveness of pgd; initiate follow-up studies; produce guidelines and recommended pgd protocols; formulate a consensus on the use of pgd, and to educate in the science of genetics and reproduction. since 1999, the consortium has published 10 data collections, analysing data related to 21,743 cycles. according to the consortium’s data, between 1999 and 2008, about 5,135 babies were born worldwide following preimplantation genetic diagnosis and screening (pgd/pgs) with no reports of increased fetal abnormalities. however, possible long-term consequences on the fetus are still unknown and will require further monitoring and follow-up studies. gene database banking in a developing country: social, cultural, legal and ethical issues related to gene databases in oman zakiya al-lamki department of child health, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: zakiya@squ.edu.om the main objectives of this study were to investigate omani public awareness of ethical, cultural, religious and legal aspects of gene studies (with consideration to regional variation) and to assess the public acceptance of initiating gene banking in oman. the study will also help address society’s concerns, thus building trust and cooperation with the people in carrying out meaningful work in the genomic sciences. the results will contribute to the country’s policy-making in establishing gene databases for future research in the various genetic disorders in the country and the region. the study was undertaken through questions (on a self-designed arabic questionnaire) chosen to explore the basic knowledge of the studied population sample in the field of genetics and the gene database. it was composed of a 5-point rating scale with close-and open-ended questions to give the sample the opportunity to report their own views on the subject. for illiterate subjects, structured interviews were conducted. a total of 1,644 (96.8%) questionnaires were successfully answered. the key findings showed that only 17% of those polled knew of or had heard about gene banking. in general, there was a statistically significant difference at a 99% confidence level in the level of education and regional variation in regard to the acceptance of gene banking, participation in research, and the requirement of protective laws and regulations framework. further, public opinion on gene banking acceptance and participation in genetic research achieved good scores of 87% and 67% respectively in both those who were aware and non-aware. after explanation, 92% indicated that islam encourages evolution and scientific research but that genomic sciences should adhere to ethical standards (80%). organisations that supported the project included the world health organization (who) and the committee on scientific and technological cooperation (comstech). the who office in oman coordinated the study while the omani ministry of health acted as the directorate of research and studies. dr.muna al-sadoon, department of child health, sultan qaboos university, was the co-principal investigator. archeology and structure of ancient omani society: prehistoric peopling of arabia jeffrey rose institute of archaeology and antiquity, university of birmingham, uk. e-mail: jeffrey.i.rose@gmail.com recent investigations in southern arabian prehistory have yielded a number of startling discoveries which have significantly augmented our understanding of modern human emergence and the peopling of arabia. new findings in palaeolithic archaeology, palaeoenvironmental studies, and mitochondrial deoxyribonucleic acid (mtdna) phylogenetic history indicate that the arabian peninsula was home to some of the first modern humans on earth, with the population expanding from africa between 130,000 and 100,000 years ago. at that time, the arabian peninsula enjoyed much greater annual precipitation, providing ample grasslands for grazing animals and plentiful sources of freshwater across the landscape. although a subsequent climatic downturn between 75,000 and 60,000 years ago may have culled many of these early populations in arabia, traces of very ancient mtdna lineages bearing haplogroup n1 and n2 were identified earlier this year among living peoples spread throughout the peninsula. scholars now regard arabia as the “staging post” for the rapid modern human colonisation of the earth that began some 50,000 years ago. little is known of the period between 50,000 and 10,000 years ago; the previously widespread occupation of arabia appears to have contracted into discrete environmental refugia in response to growing aridity, and early people’s fate in this area is not yet known. the modern peopling of the peninsula only began some 10,000 years ago. until recently, it was thought that these first immigrants were cattle pastoralists expanding southward from the levant. new discoveries in dhofar, however, have revealed a phase of late palaeolithic occupation reaching as far back as 13,000 years ago, complementing mtdna studies of hapologroups r0a and r2 that also reveal deeply rooted populations in southern arabia. the origins of these lineages remain a mystery. 388 | squ medical journal, august 2012, volume 12, issue 3 international conference on consanguinity towards the discovery of genes predisposing to and protecting from disease neural tube defects (spina bifida) in prehistoric fish-eaters from the necropolis of rh5 (qurum, muscat sultanate of oman, 3.700-3.400 b.c.): a case of consanguinity in an isolated population. alfredo coppa department of human and animal biology, university of rome ‘la sapienza’, italy. e-mail: coppa49@hotmail.com the extremely high frequency of neural tube defects (spina bifida) observed in the population of ras al-hamra 5 (rh5) seems to indicate that consanguinity rates were elevated in the past. this population of fish-eaters has been dated back to 3700–3400 bc. in the sample comprised of 79 individuals, the frequency of those affected by neural tube defects regarding all 5 sacral vertebrae is approximately 50% (48.1) but it increases to 65.4% when taking into account only the 26 individuals who died before reaching adulthood (with estimated ages at death below 20). when considering neural tube defects involving at least 3 of the 5 sacral vertebrae, these frequencies increase significantly, reaching 65.3% and 90.5%, respectively. the average age at death for the individuals with such defects was 25 years of age while it is 32 years in those not affected. even though nutritional factors cannot be excluded, the most plausible cause remains that of consanguinity, a hypothesis that seems to be further supported by high frequencies in other morphological skeletal markers. dental morphology seems, moreover, to indicate a great distance between this population and the other, both coeval and more recent, populations of the arabian peninsula and, more in general, of the middle east. this distance, currently being confirmed through a dna study, would support the hypothesis that the rh5 population was isolated from the surrounding populations. this would help explain the presence of these high consanguinity rates. consanguinity link in autism research in oman and gcc countries yahya al-farsi department of family medicine & public health, sultan qaboos university, muscat, oman. e-mail: ymfarsi@squ.edu.om autistic spectrum disorder (asd) is considered one of today’s most urgent public health challenges. based on world health organization estimates, asdis a larger burden to society than type 1 diabetes, childhood leukemia, and cystic fibrosis. since the 1970s, there has been a dramatic rise in the number of reports documenting increasing rates of asd cases, especially in western countries; however, there has not been a similar increase in research on autism or other child psychiatry topics in the middle east. in fact, published research in child psychiatry is scarce in our region and asd is not a frequent subject of research. the presentation will provide an overview of the current status of asd-related research in oman and other gcc countries. the strategic direction of research and services needed for autistic children will be highlighted. as consanguinity is the theme of the conference, results of preliminary observations and findings will be presented which might be useful in guiding towards developing more cost-effective strategies in the search for genetic markers. the presentation will also call for systematic, multi-disciplinary, and integrative research activities in the region. genetics of autism joachim hallmayer department of psychiatry and behavioral sciences, stanford university, usa. e-mail: joachimh@stanford.edu the presentation will provide an overview over the latest findings on the genetics of autism. autism is a complex neurodevelopmental disorder that interferes with the normal course of social, communicative, and cognitive development. autism is considered the most strongly genetically influenced of all multifactorial child psychiatric disorders. several genome-wide association and linkage studies have been completed. the evidence that common alleles affect the risk for autism is limited; however, researchers have identified multiple rare mutations and it is now assumed that a substantial proportion of genetic risk for autism resides in rare variants. recent twin and sib studies also suggest that the heritability of autism may have been overestimated. management of autism marwan al-sharbati department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: marwan@squ.edu.om autistic spectrum disorders (asds) are lifelong, developmental neurobiological disabilities which usually present in children before the age of three years. asds are characterised by impairments in both social and communication skills, in addition to the presence of stereotyped/repetitive behaviors and interests. asds consist of five disorders, but the clinical distinctions among them are not reliable even in the most experienced centres where standardised instruments are used. asds affect boys 3 to 4 times more than girls; however, when girls are affected they suffer from more cognitive impairments. the aetiology of asds is not yet known exactly, but it is attributed to the interaction between genetic factors in susceptible individuals and environmental factors. comorbidity is high in asds, including mainly mental retardation, attention deficit hyperactivity disorder, epilepsy, and emotional disorders. as there are no biological markers for asds, detection is made by trained clinicians who evaluate the children’s developmental progress to identify the presence of developmental disorders, and although symptoms appear early in life, the diagnosis is often delayed until after the age of 6 years. the prevalence of asd increased dramatically during the last few years, to approach 1% in the usa. in oman, a study showed that the prevalence of asds is 1.4 per 10,000, which is much less than the prevalence in other countries. until now there has been no specific treatment for autism; however, early diagnosis and intervention will considerably improve the outcome of children with asds. medical treatment is required in some cases of asd, which can improve associated disorders (e.g. sleep problems, violent and selfabstracts | 389 sultan qaboos university, 17-19 march 2011 injurious behaviour, hyperactivity), or reduce the severity of the autistic behaviour (e.g. repetitive and stereotypical movements), thus improving the health and the quality of life of the patients and their families. the presentation will discuss the management of asds. cancer genetics: the mean side muhammad furrukh department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: furrukh_1@yahoo.com the aetiology of cancer is multi-factorial, with genetic, environmental, medical, and lifestyle factors interacting to produce a known cancer. with the advent of molecular biology, our knowledge of cancer genetics is rapidly evolving and improving understanding, helping to identify at-risk individuals and families; furthering the ability to characterise various malignancies and evolution to molecular classification of cancers; establishing treatment tailored to the molecular blueprint of the disease, leading to the development of new therapeutic modalities, and studying and overcoming drug resistance in cancer therapy. this expanding knowledge base has consequent implications for all aspects of cancer management, including prevention, screening, and treatment. cancer genetics is providing a platform for customised, individualised management of cancer patients; the theory of ‘one size fits all’ is no longer applicable to many cancers. the presentation will cover the application of genetics in the management of some common cancers seen in oncology clinics. functional genomics of breast cancer allal ouhtit department of genetics, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: aoutit@squ.edu.om the majority of common human diseases represent the culmination of lifelong interactions between the genome and the environment. predicting the contribution of genes to complex disorders is a challenge, and determining the interactions between genes and the environment during any disease process is a daunting task. identification of disease-associated genes requires functional studies to validate their biological relevance. many human genetics diseases, including cancer, are caused by interactions of different genes, and between genes and the environment. our work has long been focused on the identification of these genes, their interactions into signalling pathways, and the validation of their functional relevance in cancer. specifically, we have been investigating the function, the downstream transcriptional gene targets, and interactions of two cell adhesion receptors, cd44 and cd146, in breast cancer. we have developed a novel validated enhanced green fluorescent protein gfp—an inducible system to study the function and understand the molecular mechanisms of the action of cd44 and cd146 using a microarray gene expression analysis as well as in vitro and in vivo experimental models. the results as well as future plans will be discussed during the presentation. breast cancer in oman adil al-ajmi department of surgery, sultan qaboos university hospital, muscat, oman. e-mail: aljarrah_adil@hotmail.com breast cancer represents the most common cancer in terms of incidence in females in oman. females with breast cancer in oman tend to be younger than their western counterparts and the majority of patients present with the disease already in advanced stages. their tumours generally display aggressive features. the presentation will include a description of the clinico-pathological features of the disease in oman, with analysis of prognostic factors and survival. a small proportion of patients have breast conserving surgery, and a relatively small number of patients received preoperative chemotherapy despite the advanced nature of the disease. the survival and disease-free survival rates as compared to other asian and arab countries are quite low. the presentation will explain in part the inferior survival figures as compared to caucasian american and european females. the following are strongly recommended to improve morbidity and mortality: 1) increase breast cancer awareness; 2) introduce breast screening programs; 3) establish a multidisciplinary approach to breast cancer management, and 4) support molecular biology and genetic research to further explore breast cancer in oman. genetic heterogeneity in ovarian cancer ikram burney department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: ikramburney@hotmail.com epithelial ovarian cancer (eoc) is the second most frequently diagnosed cancer of the female genital tract, yet remains the leading cause of mortality amongst gynecological cancers. a vast majority of cases are diagnosed at a late stage, and despite the current standardof-care, debulking surgery, and combination chemotherapy, only 10–15% patients have long-term, disease-free survival. although the first line chemotherapy yields response rates approach 80%, the majority of patients relapse within 2 years, and the median survival of patients diagnosed at stages iii and iv is 36 and 24 months, respectively. unlike many other cancers where targeted therapies have offered new and realistic hope, there have been no significant breakthroughs in the management of eoc. lots of questions remain unanswered or are only beginning to be answered. is it possible to classify eoc into molecular sub-types, some of which may be candidates for targeted therapy? is it possible to identify aggressive tumors from those of low malignant potential, and hence tailor the treatment, so as to include intra-peritoneal chemotherapy, and the use of anti-angiogenic compounds, which are known to enhance the response rates, but are also known to be fairly toxic, and hence not used in routine practice? is it possible to identify patients who are 390 | squ medical journal, august 2012, volume 12, issue 3 international conference on consanguinity towards the discovery of genes predisposing to and protecting from disease likely to develop eoc, and hence could be candidates for screening and early detection programs? is it possible to identify prognostic groups? and finally, but most importantly, are there predictors of response to treatment, especially, when the disease relapses after first line paclitaxel-carboplatin combination chemotherapy? genome-wide expression profiling has begun to provide data, which enhances our understanding of the genes which influence the development of eoc, histological sub-types, prognostic factors and response and prediction to chemotherapy. these data will be presented. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 404-410, epub. 25th jun 13 submitted 28th oct 12 revisions req. 2nd jan & 11th mar 13; revisions recd. 13th feb & 15th mar 13 accepted 30th mar 13 department of medical microbiology & immunology, faculty of medicine, sana'a university, sana'a, yemen e-mail: shmahe@yemen.net.ye معدل انتشار داء الكلب يف أنواع احليوانات املختلفة يف اليمن وعوامل االختطار املسامهة يف انتشاره ح�شن عبد الوهاب ال�شماحي، اأمرية اأحمد �شنهوب، خالد عبد الكرمي املوؤيد املخترب اإىل املقدمة والربية الداجنة احليوانات خمتلف بني الكلب داء فريو�س انت�شار معرفة اإىل الدرا�شة هذه هدفت الهدف: امللخ�ص: البيطري املركزي من مناطق خمتلفة يف اليمن، كذلك هدفت هذه الدرا�شة اإىل معرفة العامل امل�شاحب خلطر االإ�شابة املوؤدية اإىل االنت�شار بني احليوانات والعوامل امل�شاهمة النتقاله للب�رس. الطريقة: مت احل�شول على عينة من الدماغ لكل من ال180 حيوان املقدمة اإىل املخترب البيطري املركزي الختبار فريو�س داء الكلب بوا�شطة اختبار االأج�شام امل�شادة التاألقي املبا�رس. النتائج: من بني العدد االإجمايل للحيوانات التي هجمت على الب�رس، كانت %63.3 منها اإيجابي لداء الكلب. كانت الكالب هي احليوانات الرئي�شية التي �شاركت يف الهجمات بن�شبة %92، منها %62.7 كانت اإيجابية لداء الكلب. وكانت ن�شبة الذكور %70.6 منها %60.6 اإيجابية لداء الكلب ، ون�شبة االإناث 29.4% منها %68.9 كانت ايجابية لداء الكلب. �شكل الذكور ن�شبة %69.8 من جمموع الب�رس الذين تعر�شوا للهجوم، منهم %62.9 تعر�شوا للهجوم من قبل حيوانات م�شابة بداء الكلب. ب�شكل عام كانت عوامل اخلطر التي �شاهمت يف انت�شار داء الكلب هي وجود جثث الدواجن والنفايات االأخرى يف املنطقة املجاورة للهجمات )العامل امل�شاحب خلطر االإ�شابة = 9.5( مع ن�شبة %84.8، يليها الوقت من ال�شنة، وخ�شو�شا العطل املدر�شية )العامل امل�شاحب خلطر االإ�شابة= 3.8( مع ن�شبة %78. اخلال�سة: ميكن اأن نخل�س من هذه الدرا�شة اإىل اأن داء الكلب متوطن يف اليمن مع ارتفاع كبري يف ن�شبة احليوانات امل�شابة بداء الكلب التي �شاركت يف الهجمات على الب�رس، وخ�شو�شا بني ذكور الكالب ال�شالة. يعترب االأطفال الذكور هم االأكرث عر�شة للهجوم بوا�شطة احليوانات امل�شابة بفريو�س داء الكلب. كذلك متت معرفة ان وجود النفايات )ذبائح الدواجن ب�شكل خا�س( وفرتات العطل املدر�شية لها ارتباط ملحوظ بزيادة خطر تعر�س االإن�شان لداء الكلب. مفتاح الكلمات: داء الكلب؛ الب�رس؛ احليوانات؛ عوامل االختطار؛ اليمن. abstract: objectives: this study aimed to describe for the first time the prevalence of the passively-reported rabies virus among different domestic and wild animals submitted to the central veterinary laboratory from various areas in yemen, and to study prevalence proportion ratios (ppr) that contributed to the spread of rabies among animals, and its transmission to humans. methods: a brain sample was obtained from each of the 180 animals and tested for rabies virus by a direct fluorescent antibody test. results: out of the total number of animals involved in attacks on humans, 63.3 % were positive for rabies. of these, dogs were the main animal involved in attacks with a percentage of 92%, of which 62.7% were positive for rabies. of animals involved in attacks, 70.6% were males of which 60.6% were positive, and 29.4% were females of which 69.8% were positive. males comprised 68.9% of the total human individuals attacked, of whom 62.9% were attacked by rabies-positive animals. the significant risk factors that contributed to the spread of rabies in general included the presence of poultry carcasses and other waste in the vicinity of the attacks (ppr = 9.5) with a percentage of 84.8%, followed by the time of year, in particular school vacations (ppr = 3.8) with a percentage of 78%. conclusion: rabies is endemic in yemen with a very high rabies-positive rate for animals involved in attacks, particularly for stray male dogs. male children were most often involved in attacks by rabies-positive animals. the presence of food waste (particularly poultry carcasses) and school vacation periods were found to correlate significantly with increased risk for human exposure to rabies. keywords: rabies; humans; animals; risk factors; yemen. prevalence of rabies in various species in yemen and risk factors contributing to the spread of the disease *hassan a. al-shamahy, ameera sunhope, khaled a. al-moyed clinical & basic research advances in knowledge previously, few studies have focused on rabies in arab countries. this study provides new information about rabies in yemen, including the prevalence of passively-reported rabies virus among different domestic and wild animals from different areas in yemen, and the risk factors that contribute to the spread of rabies among animals and its transmission to humans. such information is important in recommending policy for the prevention and control of rabies in yemen. moreover, rabies is likely to be a growing problem in yemen, in spite of its decrease or disappearance world-wide and particularly in neighbouring countries in the arabian peninsula. hassan a. al-shamahy, ameera sunhope and khaled a. al-moyed clinical and basic research | 405 rabies is a zoonotic viral infection of the central nervous system that causes encephalitis, with a fatality rate of nearly 100%. the annual number of human deaths worldwide caused by this disease is estimated to be 55,000, and more than 99% of all human deaths occur in developing countries, mainly in asia.1 rabies is considered one of the most important public health problems in the world health organization’s (who) eastern mediterranean region (emr). the majority of human deaths due to rabies during the 1990s occurred in afghanistan, egypt, iran, iraq, morocco, syria, tunisia and yemen.1,2 yemen is a country in which canine rabies is endemic; the number of people bitten by rabid dogs has increased noticeably since 1990, mostly due to the increase in the population of dogs throughout yemen’s cities and villages, which seriously affects the lives of the inhabitants. there are more than a million dogs in yemen, of which about 10–20% are owned while the rest are strays, living on food from garbage and spreading diseases among people and other animals.3 additionally, until now no official measures have been in place for the control and prevention of rabies in yemen, and a vaccine has not been available for domestic or wild animals. people bitten by positive animals receive one dose of human rabies immunoglobulin (hrig) and 4 doses of rabies vaccine over a 14-day period. the first dose of rabies vaccine is given as soon as possible after exposure, with additional doses on days 3, 7, and 14. the vaccine is administered in rabies control units under the supervision of the national rabies control program (nrcp).3 annually, up to 7,000 people are exposed to animal bites in yemen since records began.3 in some years, more than 30 persons have died of rabies. however, the official death rates in humans are known to be highly inaccurate and do not represent the actual size of the problem, since only a limited number of people bitten by animals in yemen go to rabies control units and many are not documented by the nrcp.3 the aims of this study were, first, to estimate the prevalence of the rabies virus among different animal species in yemen; second, to analyse the animal case histories with a view to rabies risk and prevention and, finally, to study the risk factors that contribute to the spread of rabies among animals and humans. methods a cross-sectional analytical study was used to estimate the prevalence of the rabies virus among different animal species, then to analyse the animal case histories with a view to assessing the rabies risk and the means of prevention and, finally, to study the risk factors that contribute to the spread of rabies among animals and humans. the central veterinary laboratory (cvl) in sana’a, the capital city of yemen, is the reference laboratory which receives samples from villages, poultry farms, quarantine stations and veterinary clinics from all the governorates in yemen. the study was carried out over a period of 7 months, from june to december 2011. the study proposal was approved by the department of medical microbiology & clinical immunology at the faculty of medicine & health sciences at sana’a university. a full history was taken for each of the 180 individuals who were attacked and brought in specimens, and the findings were recorded in a predesigned questionnaire. the data collected included personal information on the individuals attacked, the characteristics of the animal which inflicted the bite, the type of contact, predisposing factors, and so on. a consent form was completed by each participant. specimens from the animal inflicting the bite were obtained from the person attacked (or from parents or others), and usually consisted of brain application to patient care the findings of this research could contribute to the formulation of treatment and control policies for human and animal rabies and, ultimately, to the prevention of its spread. the findings highlight the deficiency or absence of control programmes in yemen. the very high rabies-positive rate for animals involved in attacks, particularly for stray dogs, suggests that these animals should be vaccinated or eradicated. the risk factors identified as being highly correlated with a positive rabies diagnosis are helpful in identifying measures that could help in disease control (e.g. a safer system for the disposal of chicken carcasses). prevalence of rabies in various species in yemen and risk factors contributing to the spread of the disease 406 | squ medical journal, august 2013, volume 13, issue 3 tissue or a spinal cord swab. such specimens may be stored at 2–8° c when they are to be tested within 24 hours. if specimens are to be kept for longer periods, they should be stored at -70° c in flame-sealed or taped vials until tested. in each case, the head was removed from the body of the animal at the base of skull, exposing the spinal cord adjacent to the medulla oblongata. a sterile cotton wool swab was introduced into the occipital foramen towards the direction of the eye, rotated several times, removed, and used to prepare the slides. samples were collected from the base of the cerebellum, hippocampus and medulla oblongata. the slides were air dried and fixed in acetone.4,5 the rabies virus was detected by a commercially available direct fluorescent antibody test (fat) (fujirebio diagnostics, inc., malvern, pennsylvania, usa). for direct rabies diagnosis, smears prepared from the brain were fixed in cold acetone and then stained with monoclonal anti-rabies conjugated with fluorescein isothiocyanate (fitc). in the presences of the rabies virus, an antigen-antibody complex will form. if the tissue being examined contains no viral antigen, specific complexes will not be formed. rabies virus anti-rabies antibody complexes are visualised using a fluorescence microscope. positive reactions demonstrate bright apple-green fluorescence of particles ranging in size and morphology from dust particles to prominent negri body cytoplasmic inclusions. analysis was carried out using a prevalence proportion ratio (ppr) for the association of positive rabies with personal information on individuals attacked, characteristics of the animal inflicting the bite, type of contact and risk factors. the taylor series 95% confidence intervals (ci) were calculated by analysis of a single table. furthermore, the chi-square value for statistical significance was calculated using the yates continuity corrected statistics, but fisher’s exact test was table 1: rabies positivity results for the 180 animals suspected of having rabies brought to the central veterinary laboratory in yemen, june to december 2011, stratified by demographic characteristics total attacking animals animals positive for rabies n % n % species of animal dog 166 92 104 62.7 fox 3 1.7 3 100 donkey 3 1.7 3 100 cat 3 1.7 1 33.3 goat 2 1.1 2 100 hyena 1 0.6 1 100 cow 1 0.6 0 0 rat 1 0.6 0 0 gender of animal male 127 70.6 77 60.6 female 53 29.4 37 69.8 ownership status owned 106 58.9 59 55.7 stray 74 41.1 55 74.3 table 2: the relationship of rabies-positivity results with animal attack rate and provocation status in 180 rabiessuspicious animals brought to the central veterinary laboratory, yemen, june to december 2011 attack rate total animals involved in attacks rabies-positive animals rabies-negative animals ppr ci p value n % n % n % 1 individual 130 72.2 71 54.6 59 45.4 02 0.07– 0.49 0.0001 2–3 individuals 44 24.5 37 84.0 7 16.0 4.1 1.59– 10.7 0.001 5–9 individuals 6 3.3 6 100.0 0 0.0 undefined 0.14 provocation provoked 40 22.2 25 62.5 15 37.5 0.96 0.44–2.1 0.9 unprovoked 140 77.8 89 63.6 51 36.4 1.05 0.48–2.3 0.9 ppr = prevalence proportion ratio; ci = 95% confidence interval; ppr >1 = at risk; significant result = p <0.05. hassan a. al-shamahy, ameera sunhope and khaled a. al-moyed clinical and basic research | 407 used for small cell sizes with a two-tailed p value using epi info, version 6 (centers for disease control, atlanta, georgia, usa). results out of the 180 samples tested by fat, 63.3% were positive for rabies. dogs were the main species involved in attacks (166/180; 92%) of which 104 (62.7%) were diagnosed as positive for rabies. foxes, donkeys, cats, goats, and hyenas were also found to be positive for rabies in this study [table 1]. of the animals involved in attacks, 70.6% were males, of which 60.6% tested positive for rabies, and 29.4% were females, of which 69.8% were positive. of the animals involved in attacks, 58.9% were owned, of which 55.7% were positive for rabies, and 41.1% were strays, of which 74.3% tested positive [table 1]. table 2 shows the attack rate and provocation status of animals involved in attacks. there was a significant correlation (p <0.05) between high attack rates and the rabies positivity of the animals involved. males comprised 68.9% of the total individuals attacked, of whom 62.9% were attacked by rabiespositive animals, and females comprised 31.1%, of whom 64.3% were attacked by rabies-positive animals. of those attacked, 76.5% were bitten by the rabies-positive animals in the head or neck, 67.1% were bitten in the arms or trunk, and 52.2% were bitten in the lower extremities [tables 3 and 4]. there was a significant association between a category iii severity of attack and positivity for rabies, in which the ppr = 4.9, ci = 1.33–19.6, and p = 0.001 [table 4]. most attacks occurred in rural areas (86.7%), and the positive rate of rabies was slightly higher in rural than in urban areas (64.1% versus 58.3%, respectively) [table 5]. regarding the risk factors that contributed to the spread of rabies among susceptible animals table 3: distribution of attacked individuals according to their gender and age in relation to rabies-positive animals characteristics of individuals attacked total attacked individuals rabies-positive animals ppr ci p value n % n % male 124 68.9 78 62.9 0.94 0.46–1.9 0.85 female 56 31.1 36 64.3 1.06 0.5–2.6 0.99 ≤10 years old 101 56.1 74 73.3 2.67 1.4–5.24 0.003 11–20 years old 47 26.1 26 55.3 0.63 0.3–1.3 0.25 >20 years old 32 17.8 14 43.8 0.37 0.16–0.87 0.019 ppr = prevalence proportion ratio; ci = 95% confidence interval; ppr >1 = at risk; significant result = p <0.05. table 4: distribution of attacked individuals according to exposed body site and severity characteristics total attacked individuals positive animals ppr ci p value area of bite n % n % head or neck 34 18.9 26 76.5 2.14 0.85–5.6 0.11 arms or trunk 79 43.9 53 67.1 1.34 0.6–2.6 0.44 lower extremities 67 37.2 35 52.2 0.47 0.24–9.2 0.026 severity of attack **category i 2 1.1 1 50.0 0.58 0.02–21.4 >0.05* **category ii 12 6.7 3 25.0 0.17 0.09–0.73 0.009 **category iii 166 92.2 110 66.3 4.9 1.33–19.6 0.011 ppr = prevalence proportion ratio; ci = 95% confidence interval; ppr >1 = at risk; significant result = p <0.05; * = fisher exact p value. **2004 world health organization terminology for severity: category i = touching or licking by the animal on intact skin; category ii = minor scratches or abrasions without bleeding or being licked by the animal on broken skin; category iii = transdermal bites or scratches, or contamination of mucous membranes with saliva.20 prevalence of rabies in various species in yemen and risk factors contributing to the spread of the disease 408 | squ medical journal, august 2013, volume 13, issue 3 and transmission from dogs to humans, the major factor was the presence of poultry carcasses and waste food with a prevalence of 84.8%, ppr = 9.5, ci = 4.4–20.7, p >0.001. next in importance was the time of year, since during school vacations the exposure of children to animal bites increased (ppr = 3.8, ci = 1.9–7.71, p >0.001). another factor was the cultivation of qat (a tropical plant whose leaves are commonly used in yemen as a stimulant), with a percentage of 67%, but this was not statistically significant [table 6]. discussion this study revealed a high percentage of positivity in animals brought to the laboratory for rabies analyses (63.3%). this result agreed with the cvl results, in which two-thirds of the animals examined were positive for rabies. similar findings have been reported in iran (66.8%) and tanzania (68%).6,7 dogs were found to be the main source of infection in yemen (92%). this agreed with two previous studies in yemen, and in those done in several other developing countries.8–13 these similarities were due to the fact that most of these countries have common characteristics and practices, such as poor solid waste disposal and a high dog population co-occurring with the absence of measures to control numbers. consequently, standard policies should be applied to ensure the proper disposal of poultry carcasses and other waste, as well as to control the dog population. these policies should be implemented in parallel with programs of vaccination against rabies for domestic and wild animals under the supervision of the nrcp, and improved surveillance of rabies among wild and domestic animals in yemen. concerning animal ownership, 74.3% of stray dogs were positive for rabies as opposed to 55.7% of owned dogs [table 1]; the higher rate in strays might be attributed to their contact with other stray dogs that have been infected, or with infected endemic table 5: distribution of attacked individuals according to residence in relation to the rabies-positive animals residence total attacked individuals rabies-positive animals ppr ci p value n % n % rural 156 86.7 100 64.1 1.3 0.49–3.3 0.75 urban 24 13.3 14 58.3 0.78 0.3–2.05 0.58 ppr = prevalence proportion ratio; ci = 95% confidence limits; ppr >1 = at risk; significant result = p <0.05. table 6: risk factors attributed to the spread of rabies in yemen risk factors total individuals attacked rabies-positive animals ppr ci p value n % n % presence of wild animals 139 77.2 87 62.6 0.87 0.39–1.9 0.84 school vacations 91 50.6 71 78.0 3.8 1.9–7.7 <0.001 uncontrolled dog population increase 152 84.4 96 63.2 0.95 0.38–2.37 0.92 poultry carcasses and waste 99 55.0 84 84.8 9.5 4.4–20.7 <0.001 solid waste 59 32.8 35 59.3 0.78 0.39–1.5 0.58 slaughter and markets waste 141 78.3 92 65.2 1 0.48–2.1 0.86 qat cultivation 146 81.1 98 67.0 0.84 0.31–2.26 0.89 cultivation of crops other than qat 120 66.7 77 64.2 1.1 0.56–2.2 0.86 dairy farms 10 5.6 6 60.0 0.86 0.2–3.8 0.9 livestock grazing 164 91.1 105 64.0 1.4 0.44–4.3 0.73 ppr = prevalence proportion ratio; ci = 95% confidence interval; qat = tropical plant whose leaves are commonly used in yemen as a stimulant; ppr >1 = at risk; significant result = p <0.05. hassan a. al-shamahy, ameera sunhope and khaled a. al-moyed clinical and basic research | 409 wild animals. this latter explanation is supported by the fact that in this study, and previous studies in yemen, all the foxes and hyenas tested were positive for rabies.8,9 this was similar to the findings of a who report in oman in 1997.2 of the animals involved in attacks, 77.8% were unprovoked by the individual attacked, and 63.6% of these animals were positive for rabies. this also agreed with a previous study in chad, in which 81% of the animals involved in attacks were unprovoked and 61.8% of these animals were also positive for rabies.13 this could be explained by the fact that a normal dog does not attack unless it or its offspring are themselves attacked. conversely, a rabid dog attacks without any prior provocation. moreover, a single rabid animal may attack more than one individual, as observed in this study, where 37 of the rabid animals had attacked 2–3 individuals with statistical significance (p <0.001) and another 6 rabid animals had attacked 5–9 individuals separately. this finding agree with studies conducted in uganda and alaska.10–14 in this study, it was found that males were attacked more than females, with a ratio of 2.2:1; this ratio was similar to that found in a number of reports from turkey (2:1), asian countries (1.6:1) and the usa (1.7:1).15–18 the main reason behind these findings is that males spend more time outside the home than females, and so are more exposed to the possibility of animal bites. about 56.1% of all bites observed in this study were inflicted on children ≤10 years of age, of whom 73.3% were attacked by rabid animals, giving a significant ppr of nearly twice that of other age groups [table 3]. this result is similar to those reported from tanzania and uganda.7,10 the finding is also consistent with the rabies mortality annual report of the nrcp in yemen, in which more than two-thirds of the rabies deaths in 2008 were among children.3 this could be explained by the fact that children spend more time outdoors, face animals alone, provoke animals and are less able to protect themselves. a further possible factor is that their height is parallel to the heads of animals, which makes children's heads more exposed to severe bites. concerning the parts of the body exposed to attack, the arms or trunk were the most frequently bitten, being the objects of attack in 43.9% of the total individuals attacked, of whom 67.1% were attacked by rabies-positive animals [table 4]. similarly, an iranian study documented that the upper extremities of the attacked individuals were the most frequently bitten, with a percentage of 53.8%.19 according to the who terminology for the severity of such injuries,20 92.2% of the individuals attacked in this study had category iii injuries, while only 6.7% had category ii, and 1.1% had category i injuries [table 4].21 these findings are comparable with the findings of studies in chad, the usa and thailand.12–14 the burden of rabies falls mostly on poor rural communities, since 86.7% of attacked individuals in this study resided in rural areas. this percentage is higher than the findings of other studies conducted in iran (79.4%), spain (75%) and turkey (56%).15,17,22 school vacations were a significant risk factor contributing to the contraction of rabies [table 6]. this finding is consistent with that observed in thailand and could be explained by the fact that children spend a lot of time playing outdoors during vacations.12 it also highlights the pressing need for dedicated safe areas for children to play such as parks and clubs. concerning the presence of poultry carcasses and other waste food in the vicinity of attacks, animals involved in attacks were using the waste as a source of food. the high statistical significance of this factor (p = 0.0001) is nearly 9 times greater than that recorded for other factors involved in the spread of rabies. this risk should be reviewed with particular concern, since the poultry sector is considered to be one of the most important recipients of investment in yemen and has been increasing over the last decade. however, little attention has been paid to these farms in terms of bio-security and the hygienic handling of poultry carcasses and waste. conclusion two-thirds of the total number of animals brought to the laboratory were positive for rabies. dogs were the main animals involved in attacks, and constituted the main reservoir for rabies. the burden of rabies falls mostly on poor rural communities, and particularly on children. the presence of poultry carcasses and other waste was the main predisposing factor contributing to the spread of rabies, followed by the time of year, namely during school vacations. prevalence of rabies in various species in yemen and risk factors contributing to the spread of the disease 410 | squ medical journal, august 2013, volume 13, issue 3 references 1. knobel dl, cleaveland s, meltzer mi, miranda me. re-evaluating the burden of rabies in africa and asia. bull world health organ 2005; 83:360–8. 2. seimenis a. the rabies situation in the middle east. dev biol 2008; 131:43–53. 3. ministry of public health & population. national rabies control program. the ministry of public health and population, sana’a, yemen, 2008. 4. stanley mj. modified method for taking suspected rabies material. trop anim health prod 1987; 19:177–8. 5. office international des epizooties standards commission. oie manual of standards for diagnostic tests and vaccines, 4th ed. paris: oie, 2000. pp. 2.2.5. 6. zeynali m, fayaz a, nadim a. animal bites and rabies: situation in iran. arch iran med 1999; 2:120– 4. 7. cleaveland s, fèvre em, kaare m, coleman pg. estimating human rabies mortality in the united republic of tanzania from dog bite injuries. bull world health organ 2002; 80:304–10. 8. stanley mj. short communication: rabies in yemen arab republic, 1982 to 1986. trop anim health prod 1990; 22:273–4. 9. alarashi am. the control potential of new development in rabies with special reference to yemen. m.sc. thesis, centre for tropical veterinary medicine, university of edinburgh, 1994. 10. fèvre em, kaboyo rw, persson v, edelsten m, coleman pg, cleaveland s. the epidemiology of animal bite injuries in uganda and projections of the burden of rabies. trop med int health 2005; 10:790– 8. 11. kitala pm, mcdermott jj, kyule mn, gathuma jm. community-based active surveillance for rabies in machakos district, kenya. prev vet med 2000; 44:73–85. 12. sriaroon c, sriaroon p, daviratanasilpa s, khawplod p, wilde h. retrospective: animal attacks and rabies exposures in thai children. trav med infect dis 2006; 4:270–4. 13. kayali u, mindekem r, yémadji n. incidence of canine rabies in n’djaména, chad. prev vet med 2003; 61:227–33. 14. mclaughlin j, gessner bd. rabies vaccine: alaska post-exposure prophylaxis summary and preexposure restrictions. post-exposure summary 2002–2007. from: http://www.epi.alaska.gov/ bulletins/docs/b2008_15.pdf accessed: aug 2012. 15. kilic b, unal b, semin s, konakci sk. an important public health problem: rabies suspected bites and post-exposure prophylaxis in a health district in turkey. int j infect dis 2006; 10:248–54. 16. dodet b, goswami a, gunasekera a. rabies awareness in eight asian countries. vaccine 2008; 26:6344–8. 17. alavi sm, alavi l. epidemiology of animal bites and stings in khuzestan, iran, 1997–2006. j infect public health 2008; 1:51–5. 18. harrigan ra, kauffman fh. post-exposure rabies prophylaxis in an urban emergency department. j emerg med 1996; 14:287–92. 19. eslamifar a, ramezani a, razzaghi-abyaneh m. animal bites in tehran, iran. arch iran med 2008; 11:200–2. 20. parviz s, luby s, wilde h. post-exposure treatment of rabies in pakistan. clin infect dis 1998; 27:751–6. 21. world health organization. who expert consultation on rabies. who technical report series 931. first report, 2004. from: http://www. who.int/rabies/expertconsultationonrabies.pdf accessed: aug 2012. 22. rosado b, garcía-belenguer s, león m, palacio j. spanish dangerous animals act: effect on the epidemiology of dog bites. j veterinary behavior 2007; 2:166–74. clinical & basic research sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 63-68, epub. 27th feb 13 submitted 13th may 12 revision req. 13th jun 12, revision recd. 13th jul 12 accepted 5th aug 12 department of medicine, 1sultan qaboos university hospital, and 2college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: drjayakrish@hotmail.com هل يكفي احلكم السريري لتقدير مدى السيطرة على مرض الربو؟ مسح استباقي يف عيادة األمراض التنفسية مبستشفى مرجعي ثالثي �صو�صن بدر، جايا كري�صنان، عمر الروا�ض، جوجي جورج، خلفان الزيدي امللخ�ص: الهدف: توجد �صعوبة يف قيا�ض مدى ال�صيطرة على مر�ض الربو. تهدف هذه الدرا�صة لعمل مقارنة بني احلكم ال�رسيري و بني يف التنف�صي اجلهاز عيادة اأطباء قام الطريقة: الربو. مر�ض على ال�صيطرة م�صتوى تقدير يف )gina(الربو ملر�ض العاملية املبادرة ذلك بعد ثم متتايل. مري�ض 157 ل ال�رسيري احلكم با�صتخدام الربو مر�ض على ال�صيطرة مدى بتقدير مبدئيا ثالثي مرجعي م�صت�صفى با�صتخدام التقدير املبني على املبادره العامليه للربو)gina( لكل مري�ض على حده. النتائج: بلغت ن�صبة التوافق بني احلكم ال�رسيري معدل كان ،)32.5% ;51( التناق�ض حالت بقية يف .)67.5%( حالة 106 يف لالأطباء )gina(للربو العاملية املبادرة وتقدير ال�صيطرة على املر�ض با�صتخدام احلكم ال�رسيرى اعلى مب�صتوى درجه واحدة مقارنه مع املبادرة العاملية. ن�صبة التوافق كانت اأعلى لدى اأخ�صائيي الأمرا�ض ال�صدرية )%72( مقارنة بغري الأخ�صائيني )p = 0.009 ;47%(. تقديرالأطباء ملدى ال�صيطرة على املر�ض كان مثايل ل76 )%48.4( باإ�صتخدام احلكم ال�رسيري مقارنه مع 48 )%30.6( با�صتخدام معايري gina )p >0.001(. يف اجلانب الخر قدر الأطباء اأن ن�صبة عدم ال�صيطرة على املر�ض بلغ 34 )%21.7( مري�ض با�صتخدام احلكم ال�رسيري مقارنة مع 57 )36.3%( مري�ض با�صتخدام معيار p >0.001( .gina( يف 28 مري�ض الذين �صنفوا على اأن مدى ال�صيطرة على املر�ض لديهم كان كامال الزفريي التدفق ذروة مقيا�ض فى النق�ض اإىل راجع الختالف هذا ،gina مبادرة با�صتخدام كامل وغري ال�رسيري احلكم با�صتخدام )pefr( )%46.7( و النق�ض يف الن�صاط اليومي )%21.4( واللذان يعتربان اأكرث العوامل املوؤديه اىل انخفا�ض م�صتوى التباين يف تقدير مدى ال�صيطرة على املر�ض. اخلال�صة: الإعتماد علي احلكم ال�رسيري قد يوؤدي اإىل عدم الدقه يف تقدير مدى ال�صيطرة على املر�ض. مبا اأن قرارات العالج تعتمد على ت�صور ن�صبة ال�صيطرة على املر�ض، هذا التباين ميكن ان يوؤدى اإىل ق�صور يف تقدمي العالج و بالتايل اإىل عدم ال�صيطرة الكاملة على املر�ض. مفتاح الكلمات: ال�صيطره على مر�ض الربو، عالج الربو، الأطباء، العالج، عمان abstract: objectives: asthma control is often difficult to measure. the aim of this study was to compare physicians’ personal clinical assessments of asthma control with the global initiative for asthma (gina) scoring. methods: physicians in the adult pulmonary clinics of a tertiary hospital in oman first documented their subjective judgment of asthma control on 157 consecutive patients. immediately after that and in the same proforma, they selected the individual components from the gina asthma control table as applicable to each patient. results: the same classification of asthma control was achieved by physicians’ clinical judgment and gina classification in 106 cases (67.5%). in the other 32.5% (n = 51), the degree of control by clinical judgment was one level higher than the gina classification. the agreement was higher for the pulmonologists (72%) as compared to non-pulmonologists (47%; p = 0.009). physicians classified 76 patients (48.4%) as well-controlled by clinical judgment compared to 48 (30.6%) using gina criteria (p <0.001). conversely, they classified 34 patients (21.7%) as uncontrolled as compared to 57 (36.3%) by gina criteria (p <0.001). in the 28 patients who were clinically judged as well-controlled but, by gina criteria, were only partially controlled, low peak expiratory flow rate (pefr) (46.7%) and limitation of activity (21.4%) were the most frequent parameters for downgrading the level of control. conclusion: using clinical judgment, physicians overestimated the level of asthma control and underestimated the uncontrolled disease. since management decisions are based on the perceived level of control, this could potentially lead to under-treatment and therefore sub-optimal asthma control. keywords: asthma control; asthma management; physicians; treatment; oman. is clinical judgment of asthma control adequate? a prospective survey in a tertiary hospital pulmonary clinic sawsan baddar,1 *jayakrishnan b.,1 omar al-rawas,2 jojy george,1 khalfan al-zeedy1 is clinical judgment of asthma control adequate? a prospective survey in a tertiary hospital pulmonary clinic 64 | squ medical journal, february 2013, volume 13, issue 1 asthma management is based on regular follow-up for assessment and treatment to achieve maximal control. although complete asthma control is possible in the majority of patients using the available therapies, worldwide studies have repeatedly shown that complete control is only achieved in a small number of patients.1–5 this has been attributed to many factors related to both health care providers and patients.4,6–8 factors linked to health care providers include poor follow-up and instructions, incomplete and often subjective assessment, poor knowledge of inhaler technique, and underestimation of disease severity leading to inadequate treatment. for their part, patients do not often comply well with the treatment, have an inadequate inhaler technique, or perceive the level of their asthma control inaccurately. the lack of standardised definitions for asthma control, and the discrepancy in assessments between the patients and their physicians are also important contributory factors to the reported poor asthma control.9 management guidelines recommend a composite score including the presence of symptoms, need for rescue medications, limitation of activity, objective measurements, and the patient’s history of exacerbations.10 however, many physicians are not aware of the practice guidelines.11,12 by and large, they use subjective measures to assess asthma control which are often individualised and may not truly reflect the clinical severity of the disease.13,14 specialists tend to supplement their assessment with objective measures like forced expiratory volume in one second (fev1) or peak expiratory flow rate (pefr) compared to general practitioners who use pefr measurements infrequently.15 in this study, we compared physicians’ subjective judgment of asthma control with the categorisation of control recommended in the global initiative for asthma (gina) guidelines. methods all consecutive patients with asthma followed up in the adult pulmonary clinics of sultan qaboos university hospital (squh), muscat, oman, during a three-month period (october–december 2010) were prospectively evaluated using a structured assessment protocol. the project was approved by the ethics committee of sultan qaboos university. the diagnosis of asthma was made by the physician on the basis of a typical history of wheezing breathlessness, recurrent exacerbations, spirometric results, pefr variability, and previous response to asthma medications. a positive family history, serum total immunoglobulin e (ige), and skin tests were also considered. being a tertiary teaching hospital, the patients at squh were seen by physicians with experience ranging from consultant pulmonologists to the newly recruited postgraduate internal medicine residents. as a part of the routine assessment, physicians rated the individual patients’ levels of asthma control to decide on that day’s prescription. this is often entered in the clinical notes with the justification for the treatment plan, either continuing the current treatment or making appropriate adjustments in the prescription. for the purpose of this study, we requested doctors in the pulmonary clinic to complete a specifically prepared data sheet consisting of three sections: 1) the patient’s demographics and the consulting physician’s status (consultant, specialist or resident); 2) the consulting physician’s judgment of the level of asthma control based on the overall clinical assessment; and 3) the asthma control classification table as reproduced from the gina guidelines.10 the doctors were not guided in the way they assessed control and were allowed to use their usual tools of assessment. after documenting their clinical judgment of the level of asthma control (by selecting one of three options advances in knowledge subjective clinical judgment alone is likely to overestimate the degree of asthma control when compared to a guideline-based classification. overestimation of control often leads to under-treatment and the patients remain symptomatic. this study highlights the need to adhere to the standard asthma management guidelines. application to patient care control of asthma symptoms has to be properly assessed to prescribe appropriate medications. objective assessment tools have to be used in all situations to assess control properly. sawsan baddar, jayakrishnan b., omar al-rawas, jojy george and khalfan al-zeedy clinical and basic research | 65 in the form: well controlled, partially controlled, or uncontrolled), doctors were requested to select the individual components from the gina asthma control table as applicable to each patient without making any changes in their earlier clinical assessment. they were asked not to make any new judgments on the level of control from this selection. the selections by the physicians on the gina table were analysed and used to classify the level of asthma control based on gina criteria and were then compared with those based on the clinical judgments of the physicians. the data were analysed using statistical package for the social sciences, version 19 (ibm, inc. chicago, illinois, usa). summaries and cross tables were generated. chi-square tests were used to test for equality of proportions and corresponding p values reported. results a total of 157 patients (65.6% females) were evaluated. the evaluations were done by both consultant and specialist pulmonologists in 127 patients (80.9%) and the rest were evaluated by internal medicine residents. the mean age of the patients was 41.78 ± 15.18 years, the median age being 40 years. the baseline characteristics are given in table 1. all of the patients were on inhaled corticosteroids (beclomethasone, budesonide, or fluticasone) and 139 (88.5%) were also receiving long-acting beta agonists either as a separate inhaler or in a combination device. the majority of the patients (106; 67.5%) had associated allergic rhinitis and 102 of these (96.2%) were receiving antihistamines and/or topical nasal corticosteroids. table 2 compares the physicians’ classifications of asthma control by clinical judgment with gina scoring. physicians classified 76 (48.4%) patients as well-controlled, 47 (29.9%) as partially controlled, and 34 (21.7%) as uncontrolled by clinical judgment, as compared to 48 (30.6%), 52 (33.1%), and 57 (36.3%) patients, respectively, by gina classification (p <0.001). the same classification of asthma control was achieved by clinical judgment and gina criteria in 106 (67.5%) [table 3]. in all the cases of discrepancy (51; 32.5%), the degree of control by clinical judgment was one level higher than the gina classification. of the 76 patients classified as well-controlled by clinical judgment, agreement with gina was seen in only 48 (63.2%). the remaining 28 (36.8%) patients only met “partially controlled” gina criteria. even greater discrepancy was noted in the classification of patients under partial control. there was agreement with gina for only 24 (51.1%) patients. in contrast, all the 34 patients classified as uncontrolled by clinical judgment were similarly classified using the gina criteria. low pefr (46.7%) and limitation of activity (21.4%) were the most frequent parameters for downgrading the level of control by the gina criteria in these patients [table 4]. table 1: demographic characteristics of the patients characteristics n % gender male female 54 103 34.4 65.6 diagnosis asthma asthma + allergic rhinitis 51 106 32.5 67.5 age <20 21–40 41–60 >61 13 66 59 19 8.3 42.0 37.6 12.1 treatment ics with laba ics without laba theophylline montelukast antihistaminics nasal steroids 139 18 23 22 87 69 88.5 11.5 14.6 14 55.4 43.9 ics = inhaled corticosteroid; laba = long-acting beta agonist. table 2: comparison of the classification of asthma control according to guideline recommendations with the physician’s clinical assessment controlled partially controlled uncontrolled p value n % n % n % classification gina physicians 48 76 30.6 48.4 52 47 33.1 29.9 57 34 36.3 21.7 <0.001 specialty specialists nonspecialists 62 14 48.8 46.7 39 8 30.7 26.7 26 8 20.5 26.7 0.746 gina = global initiative for asthma. is clinical judgment of asthma control adequate? a prospective survey in a tertiary hospital pulmonary clinic 66 | squ medical journal, february 2013, volume 13, issue 1 the agreement between clinical judgment and gina classifications occurred in 72% of patients evaluated by pulmonologists as compared to 47% of patients evaluated by the non-pulmonologists (p = 0.009). out of the 51 diagnosed with asthma alone, there was disagreement in 31% as compared to 33% in the 106 patients with asthma and allergic rhinitis (p = 0.858). although the degree of disagreement between clinical judgment and gina classification was higher in the older age group (41–60 years), this was not statistically significant (p = 0.378). discussion this study showed that “usual” clinical judgment alone overestimates the degree of asthma control when compared to guideline-based classifications. in all cases of discrepancy (32.5%) in the classification of asthma control, the degree of control by clinical judgment was one level higher than the gina classification. this may lead to under-treatment and thus keep patients at sub-optimal levels of asthma control. low pefr and limitation of activity were the most frequent gina parameters for downgrading the level of control, suggesting that physicians are not adequately addressing these two important elements of control in their clinical judgment. asthma control has become an increasingly important focus in the management of asthma. several instruments, like the asthma control test,16 the asthma quality of life questionnaire,17 the asthma therapy assessment questionnaire18 and the asthma control scoring system, have been developed, tested, and validated.16–19 in addition, most of the guidelines have similar criteria to assess asthma control. however, these tools are not always used in day-to-day practice. as a result, physicians as well as patients tend to overestimate the level of control achieved.13,20 molimard et al. report that not only the patients but also their partners and even their respiratory physicians overestimated asthma control when compared with the current guidelines.21 similarly, we found that when using individual clinical judgment, physicians overestimated good control and underestimated both partial and uncontrolled asthma. in a large study on 10,428 patients, physicians’ assessments of asthma control were not concordant with guideline assessments in 31% of uncontrolled patients, 13% of well-controlled patients, and 2% of totally controlled patients.2 our physicians identified only 60% of the uncontrolled patients. since management decisions are based on judgment of the level of control, the misclassified patient may table 3: distribution of physicians’ clinical assessments and global initiative for asthma scoring assessments p hy si ci an g lo ba l a ss es sm en t gina classification controlled partially controlled uncontrolled total (n or %) controlled (n) (%) 48 63.2 28 36.8 0 0 76 100 partial (n) (%) 0 0 24 51.1 23 48.9 47 100 uncontrolled (n) (%) 0 0 0 0 34 100 34 100 total (n) (%) 48 30.6 52 33.1 57 36.3 157 100 gina = global initiative for asthma. table 4: percentage of each factors in those 28 patients who were judged to be in control by physicians but found to be not so by global initiative for asthma scoring control factors gina (n = 28)* n % daytime symptoms 3 10.7 activity limitation 6 21.4 night symptoms 0 0 salbutamol use 3 10.7 pefr 13 46.4 exacerbations 5 17.9 gina = global initiative for asthma; pefr = peak expiratory flow rate. sawsan baddar, jayakrishnan b., omar al-rawas, jojy george and khalfan al-zeedy clinical and basic research | 67 not receive adequate treatment and therefore will remain uncontrolled. our physicians accepted a rating of “well-controlled” in 37% of patients who were only partially controlled on the basis of gina guidelines, indicating that they might have made no changes in the treatment, or even stepped it down instead of stepping it up to achieve complete control. as expected, the degree of agreement with gina criteria for asthma control was significantly higher for pulmonologists as compared to nonpulmonologists. boulet et al. showed that the selection of control criteria among a group of physicians was not uniform, with paediatricians more frequently making judgments based on cough, whereas pulmonologists often supplemented their judgment with objective measures such as spirometry and pefr.13 one might argue that even with standardised assessment tools such as gina criteria and the asthma control test, it remains unclear which combination of questions or measurements actually determines control as these tools may emphasise different aspects of the disease. for example, using gina criteria we are measuring the control at that particular point of time whereas physicians may consider summative assessment over a longer period of time. in addition, physicians tend to use information about acute care, symptoms, and the direction that an illness is taking in order to assign treatment.14 our physicians might have used the severity of symptoms, clinical findings, (e.g. the extent of wheezes heard on chest auscultation), the need for frequent rescue medications, and the frequency of unscheduled emergency visits to judge the level of control. in addition, they might have used their views and experience to judge the maximum amount of control that could be achieved in an individual patient based on assessments made in previous visits. moreover, patients’ answers as to how they are faring could also have influenced their assessment of control. it is known that the physicians often consider patient-centred concerns in making treatment decisions.14 however, studies have shown that clinicians’ assessments of asthma control which are made without a specific objective tool perform poorly.22 at the same time, documentation of clinical assessment has been found to be low among physicians.23 one limitation in our study could be a bias in assessing control by clinical judgment during the latter part of the study period, as repeated exposure to the gina table of the control parameters might have improved the physicians’ independent clinical judgments. our findings indicate that subjective clinical judgment alone tends to overestimate the level of asthma control, which could lead to undertreatment and leaving the patients with poor asthma control. these findings highlight the need to encourage adherence to standard management guidelines which emphasise the use of objective assessment in asthma management. a c k n o w l e d g e m e n t s we thank professor atsu dorvlo, department of mathematics and statistics, college of science, sultan qaboos university, for the help with the statistical analysis. references 1. carlton bg, lucas do, ellis ef, conboy-ellis k, shoheiber o, stempel da. the status of asthma control and asthma prescribing practices in the united states: results of a large prospective asthma control survey of primary care practices. j asthma 2005; 42:529–35. 2. chapman kr, boulet lp, rea rm, franssen e. suboptimal asthma control: prevalence, detection and consequences in general practice. eur respir j 2008; 31:320–5. 3. greenblatt m, galpin js, hill c, feldman c, green rj. comparison of doctor and patient assessments of asthma control. respir med 2010; 104:356–61. 4. leuppi jd, steurer-stey c, peter m, chhajed pn, wildhaber jh, spertini f. asthma control in switzerland: a general practitioner based survey. curr med res opin 2006; 22:2159–66. 5. rabe kf, adachi m, lai ck, soriano jb, vermeire pa, weiss kb, et al. worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. j allergy clin immunol 2004; 114:40–7. 6. braido f, baiardini i, stagi e, piroddi mg, balestracci s, canonica gw. unsatisfactory asthma control: astonishing evidence from general practitioners and respiratory medicine specialists. j investig allergol clin immunol 2010; 20:9–12. 7. jones kp, bain dj, middleton m, mullee ma. correlates of asthma morbidity in primary care. bmj 1992; 304:361–4. 8. kendrick ah, higgs cm, whitfield mj, laszlo g. accuracy of perception of severity of asthma: patients treated in general practice. bmj 1993; is clinical judgment of asthma control adequate? a prospective survey in a tertiary hospital pulmonary clinic 68 | squ medical journal, february 2013, volume 13, issue 1 307:422–4. 9. reddel hk, taylor dr, bateman ed, boulet lp, boushey ha. busse ww. an official american thoracic society/european respiratory society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. am j respir crit care med 2009; 180:59–99. 10. bateman ed, hurd ss, barnes pj, bousquet j, drazen jm, fitzgerald m. global strategy for asthma management and prevention: gina executive summary. eur respir j 2008; 31:143–78. 11. grimshaw jm, russell it. effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. lancet 1993 27; 342:1317–22. 12. levy ml. guideline-defined asthma control: a challenge for primary care. eur respir j 2008; 31:229–31. 13. boulet lp, phillips r, o'byrne p, becker a. evaluation of asthma control by physicians and patients: comparison with current guidelines. can respir j 2002; 9:417–23. 14. diette gb, patino cm, merriman b, paulin l, riekert k, okelo s. patient factors that physicians use to assign asthma treatment. arch intern med 2007; 167:1360–6. 15. grant en, moy jn, turner-roan k, daugherty sr, weiss kb. asthma care practices, perceptions, and beliefs of chicago-area primary-care physicians. chicago asthma surveillance initiative project team. chest 1999; 116:145–54s. 16. nathan ra, sorkness ca, kosinski m, schatz m, li jt, marcus p. development of the asthma control test: a survey for assessing asthma control. j allergy clin immunol 2004; 113:59–65. 17. juniper ef, o'byrne pm, guyatt gh, ferrie pj, king dr. development and validation of a questionnaire to measure asthma control. eur respir j 1999; 14:902–7. 18. vollmer wm. assessment of asthma control and severity. ann allergy asthma. immunol 2004; 93:409–13. 19. juniper ef. assessing asthma control. curr allergy asthma rep 2007; 7:390–4. 20. pedersen s. from asthma severity to control: a shift in clinical practice. prim care respir j 2010; 19:3–9. 21. molimard m, vervloet d, le gros v, bourdeix i, ponthieux a. insights into severe asthma control as assessed by guidelines, pulmonologist, patient, and partner. j asthma 2010; 47:853–9. 22. szefler sj. challenges in assessing outcomes for pediatric asthma. j allergy clin immunol 2001; 107:s456–64. 23. baddar s, worthing ea, al-rawas oa, osman y, al-riyami bm. compliance of physicians with documentation of an asthma management protocol. respir care 2006; 51:1432–40. a case of an undifferentiated embryonal sarcoma of the liver mimicking a liver abscess e578 | squ medical journal, november 2014, volume 14, issue 4 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e578−581, epub. 14th oct 14 submitted 4th oct 13 revisions req. 21st nov 13 & 29th apr 14; revisions recd. 2nd apr & 8th may 14 accepted 15th may 14 1medical imaging unit, universiti teknologi mara, selangor, malaysia; departments of 2pathology, 3surgery and 4radiology, universiti kebangsaan malaysia medical center, kuala lumpur, malaysia *corresponding author e-mail: minyaacob@yahoo.com حالة ساركومة مضغية المتميزة يف الكبد حتاكي اخلراج الكبدي حممد حنيفة، ازياين يحى، زامري زهدي، زامني يعقوب abstract: an undifferentiated embryonal sarcoma of the liver is a rare malignant tumour. we highlight the diagnostic dilemma and differential diagnosis of a case involving a large cystic liver lesion in a young adult. a 20-year-old man presented with a large liver lesion to the universiti kebangsaan malaysia medical center, kuala lumpur, malaysia, in february 2012. the initial clinico-radiological presentations were suggestive of a liver abscess. a total tumour resection was performed and the final histopathological results of the resected specimen indicated an undifferentiated embryonal sarcoma of the liver. the ultrasound and computed tomographic images of the tumour were reviewed and found to be contradictory in appearance, as the tumour seemed predominantly solid in the ultrasound image and predominantly cystic in the computed tomographic image. familiarisation with the imaging appearance of this tumour and a high index of suspicion is therefore crucial in making a successful diagnosis. keywords: sarcoma; liver abscess; ultrasound imaging; x-ray computed tomography; case report; malaysia. امللخ�ص: تعد ال�صاركومة امل�صغية الالمتميزة يف الكبد من الأورام اخلبيثة النادرة. وهنا ن�صلط ال�صوء على حالة مثلت مع�صلة ت�صخي�صية مبركز اجلامعي للمستشفى عاما ع�رشين عمره �صاب ح�رش بالغ. �صاب كبد يف كبرية كي�صية اآفة بوجود تتعلق تفريقية وت�صخي�صية وال�صعاعي ال�رشيري الفح�ص دلئل وكانت 2012م. عام من فرباير يف وذلك مت�صخمة كبدية باآفة ماليزيا يف اجلامعي كيباقا�صان الأويل تدل على وجود خراج كبدي. واأجريت عمليات قطع كامل للورم، وعمل فح�ص هي�صتوباثوجلي له اأثبت وجود �صاركومة م�صغية لمتميزة. ومت عمل فح�ص فائق ال�صوت و ت�صوير مقطعي للورم كانت نتائجهما متناق�صة، اإذ بدا الورم �صلبا يف الغالب يف �صور اجلهاز الفائق ال�صوت، بينما كان كي�صي املظهر يف �صور الت�صوير ال�صعاعي املقطعي. لذا نرى �رشورة التزام جانب ال�صك واحلر�ص والتدقيق عند ت�صخي�ص مثل هذه احلالت والتدريب على ت�صخي�صها التفريقي حتى ميكن الو�صول لت�صخي�ص ناجح. مفتاح الكلمات: �صاركوما؛ خراج كبدي؛ اأ�صعة مقطعية؛ ت�صوير فائق ال�صوت؛ حالة مر�صية؛ ماليزيا. a case of an undifferentiated embryonal sarcoma of the liver mimicking a liver abscess mohammad hanafiah,1 azyani yahya,2 zamri zuhdi,3 *yazmin yaacob4 undifferentiated embryonal sar-coma (ues) of the liver is a rare malignant tumour with a primitive mesenchymal phenotype. it usually occurs in older children, with the peak age of presentation occurring in individuals between 6 and 10 years old.1,2 despite its rarity, ues is an important but often overlooked differential diagnosis for a large cystic liver lesion in young adults. the diagnosis relies on a postoperative pathological analysis and immunohistochemical results. familiar isation with the imaging findings is useful for a preoperative diagnosis and to avoid delay in commencing appropriate management. this paper presents a case of a ues of the liver mimicking a liver abscess in its initial clinico-radiological presentation. case report a 20-year-old immunocompetent man was admitted to the universiti kebangsaan malaysia medical center in kuala lumpur, malaysia, in february 2012. he presented with a two-week history of pain in the right hypochondriac region, intermittent high-grade fever, nausea and vomiting. he had no history of hepatitis b or c viral infections and denied any recent history of travelling. a physical examination revealed gross hepatomegaly. a routine liver function test was unremarkable, with the white blood cell count in the upper limits of normal (9.4 x 109/l). the erythrocyte sedimentation rate, c-reactive protein and carbohydrate-associated antigen (ca)-19.9 were elevated, at 118 mm/hour, 6.4 mg/dl and 808 u/ml, respectively. the rest of the tumour markers, including the carcinoembryonic antigen and alpha-fetoprotein (afp) markers, were within normal limits. all of the blood cultures were negative. virology screening tests for the hepatitis viruses and a serology test for echinococcosis were also negative. ultrasonography (us) of the hepatobiliary online case report mohammad hanafiah, azyani yahya, zamri zuhdi and yazmin yaacob online case report | e579 system revealed a large, well-defined heterogeneous lesion in the right lobe of the liver [figure 1]. a few anechoic locules were also noted within the lesion. there was no evidence of cirrhosis of the underlying liver parenchyma. a subsequent contrast-enhanced abdominal computed tomography (ct) scan performed on the same day showed a predominantly cystic lesion, with thick and irregular wall and internal septations. the cystic component had a hounsfield unit (hu) of 18–30 hu, which was in keeping with complex fluid [figures 2a & b]. in view of the patient’s age, fever, raised inflammatory markers and the cystic liver lesion observed via ct imaging, a preliminary diagnosis of a liver abscess was made. the solid components seen on the us images were thought to be unliquefied parts of the abscess. a us-guided pigtail drainage procedure was planned; however, aspiration from the initial puncture revealed minimal blood with no pus. following this, a percutaneous liver biopsy of the lesion was performed instead. the histopathological results of the specimen were compatible with a non-specific malignant tumour. subsequently, the patient underwent an extended right hepatectomy. intraoperatively, a huge right lobe liver mass was revealed [figure 3]. cut sections of the resected tumour demonstrated extensive central necrosis and haemorrhage. microscopically, the tumour was separated from the surrounding liver parenchyma by a dense sclerotic band. the tumour was composed of pleomorphic cells with spindle and satellite shapes, which were distributed in myxoid stroma [figure 4a]. some cells contained intracytoplasmic eosinophilic globules [figure 4b], which were periodic acid-schiff-positive and diastase labile. the tumour cells stained positively for desmin [figure 4c], myogenic differentiation 1 protein [figure 4d] and cluster of differentiation 10. the surgical margin was clear. postoperatively, the patient developed intraabdominal sepsis and ascending colon bowel necrosis, requiring relaparotomy and a right hemicolectomy. the bowel necrosis was due to blood pressure-related ischaemia due to the prolonged retraction during the initial surgery. the patient was discharged 15 days figure 2 a & b: abdominal contrast-enhanced computed tomography images in both (a) axial and (b) coronal views, showing a large lesion (arrows) of predominantly cystic appearance with irregular wall and internal septations in the right lobe of the liver. figure 1: ultrasound image of the liver showing a heterogenous hypovascular solid mass (thick arrows) with a small anechoic locule (thin arrows). figure 3: photo of the resected right liver lobe containing the liver mass. a case of an undifferentiated embryonal sarcoma of the liver mimicking a liver abscess e580 | squ medical journal, november 2014, volume 14, issue 4 after the operation. a follow-up ct scan performed six months later showed a large tumour recurrence in the residual left liver lobe. his prognosis was not favourable and no surgery was attempted due to the small residual liver volume. as a result, palliative chemotherapy using doxorubicin was the only option for treatment. ideally, a liver transplantation should be considered in cases such as this; however, a living donor liver transplant programme is not yet in place for the adult population in malaysia. discussion a ues of the liver was first described in 1978.3 although it is commonly seen in children, many cases have been reported among adult patients. there is a preponderance of the tumour to involve the right lobe of the liver.4 the tumour is usually large at presentation, often exceeding 10 cm, and can be as large as 30 cm. the macroscopic examination usually shows a well-demarcated soft mass that frequently has gelatinous, cystic, haemorrhagic and necrotic foci. microscopically, the tumour is typically composed of spindle, oval or stellate cells, with ill-defined borders that are embedded in an abundant myxoid stroma.5 while there are no specific clinical features at presentation, tumour-related symptoms include abdominal mass, pain and weight loss. fever is not unusual and has been reported in previous cases without any superimposed infections.1,6,7 the fever is likely related to the haemorrhage and necrosis found in the majority of these tumours, as exemplified in the present case, which may lead to an erroneous preliminary diagnosis of an underlying infective process. usually, laboratory studies are non-specific and the tumour markers are not increased.8 this is contrary to the present case, where the ca-19.9 was noted to be significantly high. abdominal radiographs of patients with ues are typically normal. however, the sarcoma is large enough to be detected by us, ct or magnetic resonance imaging (mri). these imaging techniques are useful to assess the extension of the tumour, including information regarding any associated vascular invasion, biliary obstruction or hilar adenopathies. while us is useful in demonstrating the solid nature of the tumour, ct and mri findings can resemble those of cystic lesions. the predominant cystic appearance is related to the high water content of the abundant myxoid stroma within the tumour.9 hence, findings of a large hepatic lesion with a seemingly cystic appearance on ct or mri images and a paradoxically solid appearance on us images are highly suggestive of this tumour.9,10 similar findings were observed in the present case but were only noted to be of significance in retrospect. the features depicted on the ct and the us images were later perceived to be non-specific. while a positron emission tomography scan is possible in cases of ues, its findings would also prove to be nonspecific as the uptake of fluorodeoxyglucose would occur mostly in the periphery of the tumour.2,11 cases of ues may be mistaken for a benign inflammatory pathology such as a hydatid cyst or pyogenic abscess.12 most cases of embryonal sarcomas mimic hydatid cysts. the clinical symptoms and radiological images often overlap between these two diagnoses. various reports have discussed this diagnostic dilemma,7,9,10 however the prevalence of hydatid disease in malaysia is uncommon, especially in urban areas.13 furthermore, malaysia is considered a non-endemic area for echinococcus.13 in the current patient, there were no visible daughter lesions or peripheral calcifications, which are the hallmarks of a hydatid cyst.5 in addition, no splenic lesions were detected.5 other differential diagnoses for a large, solitary, predominantly cystic liver lesion observed on a ct included a necrotic hepatocellular carcinoma, pyogenic abscess, chronic haematoma and a cavernous haemangioma. a pyogenic abscess or hydatid cyst were initially suspected in view of the pyrexia and raised inflammatory markers;2,3,7,10 however, cultures and serology tests were negative for echinococcus. hepatocellular carcinoma was less likely considering the patient’s age, normal afp level and the lack of underlying liver cirrhosis or viral hepatitis infection. there was also no history of trauma to support a diagnosis of chronic haematoma. a ues is a rare mesenchymal tumour and usually figure 4 a–d: images of the histological specimen. haematoxylin and eosin stains showed (a) a sheet of round to spindle-shaped malignant cells with an entrapped bile duct (white arrow) at x20 magnification and (b) the typical presence of cytoplasmic eosinophilic hyaline globules (black arrow) at x40 magnification. immunohistochemistry showed positivity for (c) desmin and (d) myogenic differentiation antigen 1 at x40 magnification. mohammad hanafiah, azyani yahya, zamri zuhdi and yazmin yaacob online case report | e581 a diagnosis of exclusion and histopathology are the determining factors in its diagnosis. diagnoses such as a ruptured hydatid cyst, primary liver cancer or abscesses are more common than ues. in the current case, as the patient was of a young age and presented with both fever and pain, a pyogenic abscess was considered to be the most likely working diagnosis. while the prognosis for a ues of the liver is poor, cases of long-term survival have been reported after complete surgical resection with adjuvant chemotherapy.14,15 early and prompt diagnosis and therapy are therefore crucial. the prognosis is not related to the size and degree of differentiation of the ues, but to the degree of invasion and metastasis.2 conclusion a ues of the liver can be difficult to diagnose and both the clinical presentation and imaging appearance of this sarcoma may be misleading. any discordance between ct and us images regarding the appearance of a large liver lesion, i.e. if the liver appears solid via us but predominantly cystic with ct imaging, should raise the possibility of ues as the diagnosis with a high index of suspicion. references 1. noguchi k, yokoo h, nakanishi k, kakisaka t, tsuruga y, kamachi h, et al. a long-term survival case of adult undifferentiated embryonal sarcoma of liver. world j surg oncol 2012; 10:65. doi: 10.1186/1477-7819-10-65. 2. gao j, fei l, li s, cui k, zhang j, yu f, et al. undifferentiated embryonal sarcoma of the liver in a child: a case report and review of the literature. oncol lett 2013; 5:739–42. doi: 10.3892/ol.2012.1087. 3. stocker jt, ishak kg. undifferentiated (embryonal) sarcoma of the liver: report of 31 cases. cancer 1978; 42:336–48. doi: 10.1002/1097-0142(197807)42:1<336::aidcncr2820420151>3.0.co;2-v. 4. chen jh, lee ch, wei ck, chang sm, yin wy. undifferentiated embryonal sarcoma of the liver with focal osteoid picture: a case report. asian j surg 2013; 36:174–8. doi:10.1016/j. asjsur.2012.06.012. 5. buetow pc, buck jl, pantongrag-brown l, marshall wh, ros pr, levine ms, et al. undifferentiated (embryonal) sarcoma of the liver: pathologic basis of imaging findings in 28 cases. radiology 1997; 203:779–83. doi: 10.1148/ radiology.203.3.9169704. 6. kim m, tireno b, slanetz pj. undifferentiated embryonal sarcoma of the liver. ajr am j roentgenol 2008; 190:w261–2. doi: 10.2214/ajr.07.3058. 7. kalra n, vyas s, jyoti das p, kochhar r, srinivasan r, khandelwal n. undifferentiated embryonal sarcoma of liver in an adult masquerading as complicated hydatid cyst. ann hepatol 2011; 10:81–3. 8. tokunaga y, ryo j, hoppou t, kitaoka a, tokuka a, osumi k et al. hepatic undifferentiated (embryonal) sarcoma in an adult: a case report and review of the literature. eur j gastroenterol hepatol 2000; 12:1247–51. 9. crider mh, hoggard e, manivel jc. undifferentiated (embryonal) sarcoma of the liver. radiographics 2009; 29:1665– 8. doi: 10.1148/rg.296085237. 10. mortelé kj, ros pr. cystic focal liver lesions in the adult: differential ct and mr imaging features. radiographics 2001; 21:895–910. doi: 10.1148/radiographics.21.4.g01jl16895. 11. lee mk, kwon cg, hwang kh, choe w, kim je, tchah h, et al. f-18 fdg pet/ct findings in a case of undifferentiated embryonal sarcoma of the liver with lung and adrenal gland metastasis in a child. clin nucl med 2009; 34:107–8. doi: 10.1097/rlu.0b013e318192c36b. 12. kwon on, kim sh, shin jy, shin hw. undifferentiated embryonal sarcoma of the liver in an adult: the verification of the high growth rate in the tumor. j korean soc radiol 2013; 69:457–60. doi: 10.3348/jksr.2013.69.6.457. 13. kutty mk, krishnan m, nambiar b. a case of pulmonary hydatid disease. med j malaya 1970; 24:302–5. 14. kim dy, kim kh, jung se, lee sc, park kw, kim wk. undifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy. j pediatr surg 2002; 37:1419–23. doi: 10.1053/jpsu.2002.35404. 15. baron pw, majlessipour f, bedros aa, zuppan cw, benyoussef r, yanni g, et al. undifferentiated embryonal sarcoma of the liver successfully treated with chemotherapy and liver resection. j gastrointest surg 2007; 11:73–5. doi: 10.1007/ s11605-006-0044-4. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e124–128, epub. 21 jan 15 submitted 17 feb 14 revisions req. 7 apr & 1 jul 14; revisions recd. 8 jun & 17 jul 14 accepted 19 aug 14 heerfordt’s syndrome is described as part of the spectrum of sarcoidosis, occurring in approximately 0.3% of sarcoidosis cases.1 it is defined as a combination of uveitis, parotid gland enlargement, fever and facial nerve palsy.2 a typical case of heerfordt’s syndrome is rare and patients usually have atypical presentations. unilateral facial nerve palsy without a specific cause is most commonly diagnosed as bell’s palsy. although it is a diagnosis of exclusion, a comprehensive analysis is usually performed only for patients who do not respond to treatment. heerfordt’s syndrome as a cause of unilateral facial palsy is rare, thus invariably delaying diagnoses and increasing morbidity for patients with this condition.3 the case presented below establishes the need for a comprehensive analysis in specific cases of idiopathic facial palsy that do not respond to treatment or are recurrent in nature. a review of published literature from 2003 to 2013 in the medline database was also carried out, based on a search for heerfordt’s syndrome and its clinicopathological presentations. case report a 52-year-old indian female was referred for an evaluation of her bilateral facial palsy to the all india institute of medical sciences in bhubaneswar, india. she had a history of right-sided facial palsy dating from january 2013, which was diagnosed as bell’s palsy and treated with short-term oral steroids. however, recovery was only partial. in may 2013, she subsequently developed left-sided facial palsy and was referred for further evaluation. a history of swelling in department of otorhinolaryngology & head & neck surgery, all india institute of medical sciences, bhubaneswar, india *corresponding author e-mail: rajeev9843@yahoo.co.in متالزمة هريفوردز املصاحبة لتكرار شلل العصب الوجهي تقرير حالة ومراجعة أدبيات عشرة أعوام بريتم �ضابيتي، راجيف كومار، اأجنان كومار �ضاحو abstract: heerfordt’s syndrome is defined as a combination of facial palsy, parotid swelling, uveitis and fever in sarcoidosis cases. heerfordt’s syndrome as a cause of facial palsy is very rare. we report a case of alternating facial nerve palsy in a 52-year-old female initially treated for bell’s palsy. the patient was referred to the all india institute of medical sciences, bhubaneswar, india, in january 2013 for clinical evaluation. she was found to have a parotid swelling and anterior intermediate uveitis. a pathoradiological evaluation suggested sarcoidosis and a final diagnosis of heerfordt’s syndrome was made. steroid treatment was initiated which led to an improvement in the facial palsy and uveitis as well as the disappearance of the parotid swelling with a corresponding decrease in angiotensin-converting enzyme levels. an english literature review was carried out to analyse the varied presentation of this syndrome. the analysis focused on presenting symptoms, biochemical markers and radiological findings of heerfordt’s syndrome cases. keywords: heerfordt syndrome; sarcoidosis; facial palsy; case report; india. امللخ�ص: تعرف متلزمة هريفوردز باأنها مزيج من االأعرا�س التي تتمثل يف �ضلل يف الوجه، تورم الغدة النكافية، التهاب القزحية واحلمى يف حاالت ال�ضاركويد. متلزمة هريفورد امل�ضببة لل�ضلل الوجهي حالة نادرة جدا. نقدم هنا حالة �ضلل الع�ضب الوجهي المراأة تبلغ من العمر 52 عاما عوجلت مبدئيا ل�ضلل بيل. اأحيلت املري�ضة اإىل معهد عموم الهند للعلوم الطبية، بوبان�ضوار، الهند، يف يناير 2013 للتقييم ال�رضيري. وجد عندها تورم يف الغدة النكافية والتهاب العنبية االأمامية املتو�ضطة. اأ�ضار التقييم اإل�ضعاعي ملر�س ال�ضاركويد ومت الت�ضخي�س النهائي مع النكفية تورم اختفاء وكذلك القزحية والتهاب الوجه �ضلل يف حت�ضن اإىل اأدت والتي بال�ضتريويد العلج بداأ وقد هريفوردز. ملتلزمة وركز املتلزمة. لهذه املتنوع العر�س لتحليل االإجنليزية االأدبيات ا�ضتعرا�س مت للأجنيوتن�ضني. املحول اأنزمي م�ضتويات يف انخفا�س التحليل على االأعرا�س، العلمات البيوكيميائية والنتائج االإ�ضعاعية من حاالت متلزمة هريفوردز. مفتاح الكلمات: متلزمة هريفوردز؛ مر�س ال�ضاركويد؛ �ضلل الع�ضب الوجهي؛ تقرير حالة؛ الهند. heerfordt’s syndrome presenting with recurrent facial nerve palsy case report and 10-year literature review preetam chappity, *rajeev kumar, anjan k. sahoo online case report preetam chappity, rajeev kumar, and anjan k. sahoo case report | e125125 | squ medical journal, february 2015, volume 15, issue 1 the parotid region on the left side and undocumented low-grade fever was elicited. on physical examination, the patient had housebrackmann grade iv bilateral lower motor neuron facial nerve palsy. a diffuse ill-defined swelling was noted in the left parotid region with no palpable lymphadenopathy, while the right parotid gland was normal. an examination of her chest, lungs and cardiovascular system was unremarkable. other cranial nerves, motor and sensory physical examinations were normal. cytology from the left parotid gland was suggestive of non-suppurative chronic granulomatous disease. her serum angiotensin-converting enzyme (ace) levels were significantly elevated (129 u/l; normal range: 8–65 u/l). serum, urinary calcium levels and erythrocyte sedimentation rate were all within normal limits. a computed tomography scan of the thorax revealed mediastinal and hilar lymphadenopathy. except for occasional irritation of the eyes, the patient had no other significant ophthalmological history. on a slit-lamp examination, features of anterior intermediate uveitis were detected. a diagnosis of heerfordt’s syndrome was made and the patient was initiated on long-term steroid therapy. after two months of treatment with oral steroids, the left facial palsy had completely improved although there was still residual palsy on the right side (grade iii). her ace levels were 45 u/l. discussion heerfordt’s syndrome was first described in 1909 by the danish ophthalmologist, christian frederick heerfordt.4 a case of unilateral facial palsy with no evident cause is usually diagnosed as bell’s palsy and treated empirically.5 the lack of typical symptomatology in cases of heerfordt’s syndrome is a diagnostic hurdle for the treating physician. the incidence of cranial nerve palsy in sarcoidosis is about 5%,6 with the facial nerve followed by the optic nerve being the most common nerves involved.7 facial nerve palsy forms an important defining component of heerfordt’s syndrome. the approximate incidence of facial nerve palsy in this syndrome is 25–50%.8 sharma et al. analysed the rare manifestation of sarcoidosis in an indian population and, according to their results, heerfordt’s syndrome was present in 1.2% of cases.9 the aetiology of this syndrome is still ambiguous and, as a result, so is the pathogenesis. the pathology of neurosarcoidosis is due to a non-caseating epithelioid granuloma. there is an accumulation of cluster of differentiation 4 cells at the sites of inflammation. generally, these granulomas resolve spontaneously or with treatment. persistence of the inflammatory process induces fibrotic changes, resulting in irreversible tissue damage.10 nerve root and cranial nerve involvement is either caused by the compressive effect of an adjacent granuloma or because of perivascular and intraneural lymphocytic infiltration.11,12 the sarcoid granuloma involves the peripheral nerves and is responsible for the varied clinical presentation of the syndrome. neurosarcoidosis has no definite modality of treatment. spontaneous remission has been observed, but in progressive or non-resolving cases, such as the one observed in the current report, steroid treatment is required. head and neck manifestations of heerfordt’s syndrome are non-specific and a high index of suspicion is required to diagnose the condition early. common otological manifestations include sensorineural hearing loss, facial nerve paralysis, labyrinthine involvement with vestibular dysfunction and temporal bone involvement.13 nasal symptoms include obstruction, epistaxis, pain and anosmia. the characteristic finding of a yellowcoloured sub-mucosal nodule is not always found. however, involvement of the airway and salivary gland is frequently noted.14 non-caseating epithelioid cell granulomas do not always indicate sarcoidosis; diseases such as tuberculosis, fungal and parasitic infections, wegener’s granulomatosis or leptomeningeal lymphoma may also have such granulomas and should be excluded by the appropriate clinical and pathoradiological investigations.15 the symptoms of the current case correspond with the typical diagnosis for heerfordt’s syndrome— bilateral facial palsy, parotid gland enlargement, anterior intermediate uveitis and a low-grade nonspecific fever. although elevated calcium levels were not seen, elevated levels of ace, mediastianal and hilar lymphadenopathy and evidence of non-caseating granulomas on the cytology of the left parotid gland substantiated the diagnosis. the decline in ace levels after steroid treatment further confirmed the diagnosis. unfortunately, the right facial nerve palsy still persisted at follow-up, with only partial improvement. to analyse the varied presentation of heerfordt’s syndrome, a search of the medline database of literature published between 2003 and 2013 to yielded 31 articles. after excluding articles lacking online abstracts and those not specifically dealing with heerfordt’s syndrome, a total of 14 articles were reviewed.2,3,16–27 the findings of these articles have been tabulated [table 1]. the seventh cranial nerve was most commonly involved,16 followed by the trigeminal nerve.6 polyradiculopathy was observed heerfordt’s syndrome presenting with recurrent facial nerve palsy case report and 10-year literature review e126 | squ medical journal, february 2015, volume 15, issue 1 table 1: literature review of heerfordt’s syndrome cases and their varied findings author findings facial palsy ophthalmological parotid swelling fever cytology biochemistry radiology other denny et al.3 ul anterior uveitis bl present pre-auricular lymph node ncg increased ace levels cxr showing prominent hilar marking coughing, night sweats and weight loss fieß et al.24 ul panuveitis bl present turbinectomy specimen ncg refractory sinusitis, fever and poor general condition otani et al.20 bl bl granulomatous uveitis bl parotid ncg cxr showing bl hilar lymphadenopathy paralysis of the left second branch of the fifth cranial nerve kato et al.18 bl anterior uveitis bl present parotid ncg gbs shimizu et al.25 ul anterior uveitis bl present parotid ncg pericardial infusion and a family history of sarcoidosis fukuhara et al.17 bl anterior uveitis bl present parotid ncg radiculopathy in the trunk and trigeminal area fieß et al.21 right anterior and posterior uveitis bl present parotid ncg poor general condition yagi et al.23 bl anterior uveitis present progressive multifocal leukoencephalopathy petropoulos et al.2 left anterior and posterior uveitis bl present transbronchial lymph node biopsy night sweats, weight loss, headaches and left otalgia tamme et al.27 right bl swelling of eyelids bl present parotid ncg bihilar lymphadenopathy ishiwata et al.16 right myodesopsia present parotid ncg involvement of the fifth canial nerve ishimatsu et al.19 right anterior uveitis right present lung biopsy ncg increased ace and lysozyme levels cxr showing bihilar lymphadenopathy increased serum tnfalpha levels braido et al.26 bl anterior uveitis bl present parotid ncg present bl sarcoid involvement of the gasser’s ganglion cisternae walter et al.22 bl anterior uveitis bl parotid ncg current case bl anterior uveitis left present parotid ncg increased ace levels chest ct showing hilar lymphadenopathy ul = unilateral; bl = bilateral; ncg = non-caseating epithelioid granuloma; ace = angiotensin-converting enzyme; cxr = chest x-ray; gbs = guillain-barré syndrome; tnf = tumour necrosis factor; ct = computed tomography. preetam chappity, rajeev kumar, and anjan k. sahoo case report | e127 in one instance.17 furthermore, the literature review demonstrated that bilateral facial nerve palsy can be confused with other differential diagnoses, such as lyme disease, guillain-barré syndrome or syphilis.18,28 kato et al. depicted this potential ambiguity in their report of a case of heerfordt’s syndrome which was initially misdiagnosed and treated as guillain-barré syndrome.18 in sarcoidosis, involvement of the eye reportedly occurs in 11–83% of patients.29 the most common manifestation described is anterior uveitis, with symptoms of increased lacrimation, photophobia, myodesopsia (seeing ‘floaters’) and blurred vision.29 parotid gland involvement reportedly has a documented incidence of 6%.30 it is usually bilateral in up to 73% of cases, but unilateral involvement has been reported.19,31 the majority of patients with heerfordt’s syndrome experience some degree of fever; only four patients in the literature review had no documented evidence of fever.16,20,22,23 histological examinations of tissue exhibiting non-caseating granulomas are highly suggestive of heerfordt’s syndrome. in the majority of cases in the review, fine needle aspiration cytology of the parotid gland exhibited pathognomic findings. in one patient with refractory sinusitis, fieß et al. found non-caseating granulomas in a turbinectomy specimen.24 granulomas were also observed in lymph node and pulmonary tissue.2,3,19 ace levels and hilar lymphadenopathy, though not important on their own, become highly suggestive of heerfordt’s syndrome when found in association with multiple symptoms since these features are found in sarcoidosis. although facial nerve involvement is commonly described, few reports suggest the involvement of other cranial nerves. two case reports indicated involvement of both the fifth and seventh cranial nerve while one patient in the literature review had involvement of only the fifth cranial nerve.17,29,31 other noteworthy presentations of heerefordt’s syndrome included pericardial effusion,25 progressive multifocal leukoencephalopathy,23 ear pain,2 involvement of the bilateral gasser’s ganglion,26 pre-auricular lymphadenopathy,3 poor general condition,21 bilateral swelling of the eyelids27 and elevated serum tumour necrosis factor-alpha levels.30 conclusion the presentation of heerfordt’s syndrome is rare and varied. in the current case, symptoms of bilateral facial palsy, parotid gland enlargement, anterior intermediate uveitis and a low-grade non-specific fever corresponded with the typical diagnosis for heerfordt’s syndrome. a literature review suggested that eye involvement is the most consistent finding in patients presenting with heerfordt’s syndrome, along with unilateral or bilateral facial nerve palsy or parotid gland swelling. it is recommended that cases of unilateral facial palsy which do not respond to treatment or are recurrent in nature be evaluated for any systemic involvement. in suspected cases, further analyses such as blood investigations, radiology and a parotid gland assessment should be performed to rule out heerfordt’s syndrome. references 1. sugawara y, sakayama k, sada e, kajihara m, semba t, higashino h, et al. heerfordt syndrome initially presenting with subcutaneous mass lesions: usefulness of gallium-67 scans before and after treatment. clin nucl med 2005; 30:732– 3. doi: 10.1097/01.rlu.0000182264.76461.74. 2. petropoulos ik, zuber jp, guex-crosier y. heerfordt syndrome with unilateral facial nerve palsy: a rare presentation of sarcoidosis. klin monbl augenheilkd 2008; 225:453–6. doi: 10.1055/s-2008-1027356. 3. denny mc, fotino ad. the heerfordt-waldenström syndrome as an initial presentation of sarcoidosis. proc (bayl univ med cent) 2013; 26:390–2. 4. heerfordt cf. über eine “febris uveo-parotidea subchronica” an der glandula parotis und der uvea des auges lokalisiert und häufug mit paresen cerebrospinaler nerven kompliziert. albrecht von grafes archiv für ophthalmologie 1909; 70:254–73. 5. murthy jm, saxena ab. bell’s palsy: treatment guidelines. ann indian acad neurol 2011; 14:s70–2. doi: 10.4103/09722327.83092. 6. burns tm. neurosarcoidosis. arch neurol 2003; 60:1166–8. doi: 10.1001/archneur.60.8.1166. 7. christoforidis ga, spickler em, recio mv, mehta bm. mr of cns sarcoidosis: correlation of imaging features to clinical symptoms and response to treatment. ajnr am j neuroradiol 1999; 20:655–69. 8. joseph fg, scolding nj. neurosarcoidosis: a study of 30 new cases. j neurol neurosurg psychiatry 2009; 80:297–304. doi: 10.1136/jnnp.2008.151977. 9. sharma sk, soneja m, sharma a, sharma mc, hari s. rare manifestations of sarcoidosis in modern era of new diagnostic tools. indian j med res 2012; 135:621–9. 10. thomas pd, hunninghake gw. current concepts of the pathogenesis of sarcoidosis. am rev respir dis 1987; 135:747–60. 11. stern bj, krumholz a, johns c, scott p, nissim j. sarcoidosis and its neurological manifestations. arch neurol 1985; 42:909– 17. doi: 10.1001/archneur.1985.04060080095022. 12. babin rw, liu c, aschenbrener c. histopathology of neurosensory deafness in sarcoidosis. ann otol rhinol laryngol 1984; 93:389–93. doi: 10.1177/000348948409300421. 13. hybels rl, rice dh. neuro-otologic manifestations of sarcoidosis. laryngoscope 1976; 86:1873–8. 14. schwartzbauer hr, tami ta. ear, nose, and throat manifestations of sarcoidosis. otolaryngol clin north am 2003; 36:673–84. 15. bottaro l, calderan l, dibilio d, mosconi e, maffessanti m. pulmonary sarcoidosis: atypical hrtc features and differential diagnostic problems. radiol med 2004; 107:273–85. 16. ishiwata t, koyama r, homma n, fujii m, iwakami n, nakao y, et al. [case of heerfordt’s syndrome with prolonged peripheral nerve involvement]. nihon kokyuki gakkai zasshi heerfordt’s syndrome presenting with recurrent facial nerve palsy case report and 10-year literature review e128 | squ medical journal, february 2015, volume 15, issue 1 2006; 44:749–53. 17. fukuhara k, fukuhara a, tsugawa j, oma s, tsuboi y. [radiculopathy in patients with heerfordt’s syndrome: two case presentations and review of the literature]. brain nerve 2013; 65:989–92. doi: 10.11477/mf.1416101577. 18. kato k, kato y, tanaka y, miyazaki m, nakaseko y, uji y. [case of heerfordt's syndrome presenting polyneuropathy]. nihon ganka gakkai zasshi 2011; 115:460–4. 19. ishimatsu y, takatani h, doutsu y, mukae h, kohno s. [a case of heerfordt’s syndrome with an elevated serum tnf alpha]. nihon kokyuki gakkai zasshi 2006; 44:636–40. 20. otani k, noda k, ukichi t, kingetsu i, kurosaka d. [a case of abortive type of heerfordt syndrome associated with paralysis of trigeminal nerve]. nihon rinsho meneki gakkai kaishi 2013; 36:115–21. 21. fieß a, frisch i, wicht s, hofstetter p, knuf m, gosepath j, et al. [a rare manifestation of sarcoidosis]. ophthalmologe 2012; 109:794–7. doi: 10.1007/s00347-012-2594-z. 22. walter c, schwarting a, hansen t, weibrich g. [heerfordt’s syndrome: a rare initial manifestation of sarcoidosis]. mund kiefer gesichtschir 2005; 9:43–7. doi: 10.1007/s10006-0040582-4. 23. yagi t, hattori h, ohira m, nakamichi k, takayama-ito m, saijo m, et al. progressive multifocal leukoencephalopathy developed in incomplete heerfordt syndrome, a rare manifestation of sarcoidosis, without steroid therapy responding to cidofovir. clin neurol neurosurg 2010; 112:153–6. doi: 10.1016/j. clineuro.2009.10.005. 24. fieß a, frisch i, halstenberg s, steinhorst u. [three cases, one diagnosis: ocular manifestations of sarcoidosis]. klin monbl augenheilkd 2013; 230:530–5. doi: 10.1055/s-0032-1328160. 25. shimizu k, takeda h, tai h, kuwano k. [a case of familial sarcoidosis accompanied by heerfordt syndrome with pericardial effusion]. nihon kokyuki gakkai zasshi 2010; 48:113–17. 26. braido f, zolezzi a, stea f, canonica gw, perotti l, cavallero gb, et al. bilateral gasser’s ganglion sarcoidosis: diagnosis, treatment and unsolved questions. sarcoidosis vasc diffuse lung dis 2005; 22:75–7. 27. tamme t, leibur e, kulla a. sarcoidosis (heerfordt syndrome): a case report. stomatologija 2007; 9:61–4. 28. jain v, deshmukh a, gollomp s. bilateral facial paralysis: case presentation and discussion of differential diagnosis. j gen intern med 2006; 21:c7–10. doi: 10.1111/j.15251497.2006.00466.x. 29. holmes j, lazarus a. sarcoidosis: extrathoracic manifestations. dis mon 2009; 55:675–92. doi: 10.1016/j.disamonth.2009.05.002. 30. longo n, ghaderi m. primary parotid gland sarcoidosis: case report and discussion of diagnosis and treatment. ear nose throat j 2010; 89:e6–10. 31. darlington p, tallstedt l, padyukov l, kockum l, cederlund k, eklund a, et al. hla-drb1* alleles and symptoms associated with heerfordt’s syndrome in sarcoidosis. eur respir j 2011; 38:1151–7. doi: 10.1183/09031936.00025011. sultan qaboos university med j, may 2014, vol. 14 iss. 2, pp. e261-262, epub. 7th apr 14 submitted 12th nov 13 revision req. 31st dec 13; revision recd. 8th jan 14 accepted 19th jan 14 الورم الليفي املرن الثنائي الظهري جراحة متزامنة أو متتابعة؟ bilateral elastofibroma dorsi synchronic or sequential surgery? letter to editor sir, elastofibroma dorsi (ed) is a relatively rare soft-tissue pseudotumour localised in the periscapular area (under the rhomboid and serratus anterior muscles). it has a clinical appearance of a malignant tumor since the lesion is firmly attached to the rib cage. i would like to highlight the case of a 55-year-old woman with hypertension, coronary disease and platelet inhibitor treatment, who presented with a one-year history of a bilateral subscapular mass causing mild discomfort. she denied recent trauma or weight loss. the physical examination revealed a bilateral subscapular mass [figure 1]. the right mass was more voluminous (15 x 12 x 15 cm) but the left side was more painful and became prominent on abduction of the arm. sequential surgery was selected in order to allow free activity of the non-operated shoulder. the left mass was removed through an elective subscapular incision. in surgery, the lesion was evident underneath the latissimus dorsi muscle, adhering tenaciously to the deeper planes, but detachable from the overlying muscle plane. macroscopically, it was not capsulated, rubbery and exhibited gray-white fibrous tissue with interposing small areas of adipose tissue. the lesion was totally excised and the postoperative course was uneventful. three months later, the patient underwent the contralateral surgery. the postoperative course was marked by a postoperative subscapular seroma and acute lung oedema secondary to a myocardial infarction on the fifth day. invasive ventilation (six days) and puncture of the seroma led to a successful outcome. six weeks following surgery, the patient had fully recovered. although the prevalence of bilateral ed reaches 10% in certain series,1,2 ed is most frequently unilateral. a bilateral occurrence is rare and few cases of bilateral ed were found in a search of the english and french medical literature. ed is usually asymptomatic, but symptoms can include pain, snapping, clicking, or scapular clunking on movement. on computed tomography (ct) scans, ed is a poorly circumscribed mass, isodense with the surrounding musculature and with characteristic hypodense striations suggestive of dense fat. magnetic resonance imaging (mri) which is considered the imaging technique of choice for the diagnosis of ed usually shows clearly a heterogeneous ill-defined lesion with an alternating pattern of fibrous and fatty tissue. on a t1-weighted mri scan, ed is isointense with the muscle tissue which explains why these tumours are often overlooked. t1and t2-weighted images both show alternating linear and curvilinear hyperintense areas representing fat. lastly, on positron-emission tomography/ct images, ed is seen as a non-encapsulated mass with low-grade, diffuse 18f fluorodeoxyglucose uptake. in the authors’ opinion, radiological investigations (ultrasound, ct and mri) can succeed in clarifying the nature of the lesion since the differential diagnosis is other soft tissue neoplasms, such as fibroma, desmoid tumor, neurofibroma, liposarcoma, haemangioma, or subacute haematoma. the histological study (haematoxylin and eosin stain) in this case revealed the presence of islets of fatty tissue and a scantly cellular component (fibroblasts and myofibroblasts) associated with intensely eosinophilic figure 1: clinical feature of the bilateral subscapular elastofibroma dorsi. bilateral elastofibroma dorsi synchronic or sequential surgery? e262 | squ medical journal, may 2014, volume 14, issue 2 bands composed of collagen and elastic fibres that define this type of lesion. weigert’s elastic stain showed the large branched or unbranched fibres to have a dense core and irregular serrated margins. although the elastinlike material is removed by prior treatment of the sections with pancreatic elastase, it is more resistant to the digestion than that of unaffected skin. the treatment of bilateral ed is controversial. excision may be offered to symptomatic patients. conservative treatment is recommended in elderly, asymptomatic patients since malignant transformation has not been reported.3 a preoperative biopsy is not the standard practice in our institute in typical cases. in this case, surgery was indicated sequentially in order to avoid greater patient morbidity; however, the patient had postoperative problems. in the literature, synchronous as well as sequential or unilateral approaches have been used,4,5 each with a favourable outcome and without relapses. the surgery could have been better synchronised in the current case as in the case reported by ahmed ma, et al.5 the use of postoperative tube drainage and compression bandages reduces the incidence of complications such haematoma and seroma. ed is a rare benign condition. the clinical and radiological diagnosis is based on the typical location and very obvious radiological characteristics. surgery, if indicated, affords good results. bilateral synchronic or sequential surgery should be undertaken according to the characteristics and needs of the individual patient. massine el hammoumi, siham hentour, el hassane kabiri mohammed v. military teaching hospital, faculty of medicine, mohammed v. university souissi, rabat, morocco corresponding author e-mail: hamoumimassine@hotmail.fr references 1. muramatsu k, ihara k, hashimoto t, seto s, taguchi t. elastofibroma dorsi: diagnosis and treatment. j shoulder elbow surg 2007; 16:591–5. 2. turna a, yilmaz ma, ürer n, bedirhan ma, gürses a. bilateral elastofibroma dorsi. ann thorac surg 2002; 73:630–2. 3. daigeler a, vogt pm, busch k, pennekamp w, weyhe d, lehnhardt m, et al. elastofibroma dorsi--differential diagnosis in chest wall tumours. world j surg oncol 2007; 5:15. doi: 10.1186/1477-7819-5-15. 4. martínez hernández nj, almanzar sf, obrer aa. elastofibroma dorsi bilateral: una muy rara presentación para una rara patología. arch bronconeumol 2011; 47:536–7. doi: 10.1016/j.arbres.2011.05.010 5. ahmed ma, subramanian sk, al-hashmi i, koliyadan sv. bilateral elastofibroma dorsi. sultan qaboos univ med j 2011; 11:415–6. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e177–183, epub. 28 may 15 submitted 30 may 14 revisions req. 5 aug & 30 sep 14; revisions recd. 18 aug & 15 oct 14 accepted 28 oct 14 low birth weight (lbw) is defined by the world health organization (who) as a birth weight of less than 2.5 kg.1 it is considered an important indicator of neonatal (under one month of age) and infant (under one year of age) morbidity and mortality, as well as a predictor of a child’s physical, emotional, psychological and educational development.1‒4 extensive research confirms that lbw children are at greater risk of cognitive and school performance problems than their normal birth weight peers.5,6 epidemiological studies have shown that lbw babies are 20 times more likely to die than normal weight babies.2,3,7 lbw has been linked to many adverse health outcomes in early and later life, including delays in cognitive and behavioural development,8 growth retardation and neurological problems in childhood,2 and chronic diseases such as hypertension, stroke, coronary heart disease (and related disorders) and diabetes in adulthood.9,10 as lbw is considered an important indicator of public health and a predictor of the future population’s health, many world organisations, including the who and the united nations international children's emergency fund (unicef), have adopted different strategies to reduce the incidence of lbw. reducing lbw rates by at least one-third is one of the major goals for the current decade in the ‘world fit for children’, section of the declaration and plan of action adopted at the united nations general assembly special session on children in 2002.11 the reduction of lbw rates is also related to the united nation’s millennium development goal (mdg) for reducing child mortality.12 lbw is therefore an important indicator for monitoring progress towards these internationally agreed-upon goals and thus given high priority by national governments and the international community. lbw is either the result of prematurity (birth at under 37 weeks of gestation) or intrauterine growth restriction. the duration of gestation and fetal growth department of mathematics & statistics, college of science, sultan qaboos university, muscat, oman e-mail: mislam@squ.edu.om ازدياد معدل املواليد املنخفضي الوزن يف عمان مزهارول اإ�سالم abstract: this review article provides an overview of the levels, trends and some possible explanations for the increasing rate of low birth weight (lbw) infants in oman. lbw data from national health surveys in oman, and published reports from oman’s ministry of health and the world health organization were collected and assessed between january and august 2014. oman’s lbw rate has been increasing since the 1980s. it was approximately 4% in 1980 and had nearly doubled (8.1%) by 2000. since then, it has shown a slow but steady rise, reaching 10% in recent times. high rates of consanguinity, premature births, number of increased pregnancies at an older maternal age and changing lifestyles are some important factors related to the increasing rate of lbw in oman. the underlying causes of this increase need to be understood and addressed in obstetric policies and practices in order to reduce the rate of lbw in oman. keywords: low birth weight; premature birth; infant mortality; consanguinity; oman. يف املواليد وزن انخفا�ض لتزايد املحتملة التف�سريات وبع�ض واالجتاهات امل�ستويات عن عامة مراجعة املقال هذا يعر�ض امللخ�ص: �سلطنة عمان. مت جمع وحتليل بيانات نق�ض وزن املواليد من امل�سح ال�سحي الوطني ، والتقارير التي ن�رشت لوزارة ال�سحة يف عمان ومنظمة ال�سحة العاملية يف الفرتة من يناير اىلاأغ�سط�ض 2014 لقد ازداد تناق�ض وزن املواليد يف �سلطنة عمان منذ 1980. فقد كان ما يقرب من %4 يف عام 1980 وت�ساعف تقريبا )%8.1( بحلول عام 2000. ومنذ ذلك احلني تبني ارتفاع بطيء ولكن ثابت وبلغ %10 يف االآونة االأخرية. ان ارتفاع معدالت زواج االأقارب، الوالدة املبكرة، وتزايد معدالت الوالدة يف االأعمار املتقدمة واأ�سلوب احلياة املتغري هي بع�ض العوامل املهمة املتعلقة بتزايد معدل نق�ض الوزن عند املواليد يف �سلطنة عمان. البد من فهم هذه الظاهرة لتوجيه �سيا�سات و ممار�سات التوليد خلف�ض معدل نق�سان وزن املواليد يف �سلطنة عمان. مفتاح الكلمات: انخفا�ض وزن املواليد؛ الوالدة املبكرة؛ معدل وفيات الر�سع؛ زواج االأقارب؛ عمان. review increasing incidence of infants with low birth weight in oman m. mazharul islam increasing incidence of infants with low birth weight in oman e178 | squ medical journal, may 2015, volume 15, issue 2 are affected by many factors related to the infant, the mother, the physical environment and genetics, and play an important role in determining an infant’s birth weight and future health.7 risk factors for lbw include, among others, maternal age; risky health behaviours; insufficient antenatal care; psychosocial stress; a low maternal body mass index; disease; poor nutrition, diet and/or lifestyle choices during pregnancy; the socioeconomic characteristics and parity of the mother; the gender of the baby; genetic factors, and environmental pollution.7 certain genetic conditions and congenital anomalies are also related to a higher incidence of lbw.13 according to the report of a joint study from unicef and the who, which investigated global, regional and country-specific lbw rates in 2000, more than 20 million infants around the world (16% of total births) were born with lbw and approximately 95% of these infants were born in developing countries.7 however, these numbers are mainly based on births that occurred in healthcare facilities and have been recorded officially.7 as more than half the number of babies born in the developing world are not weighed, since they are born outside health facilities, the actual number could be double this official statistic.7 the aforementioned study showed that the rate of lbw in developing countries (17%) was more than double the rate in developed regions (7%).7 half of these lbw neonates were born in south central asia, where more than 27% of all infants were considered to have a lbw. sub-saharan africa had the second highest rate of lbw babies (15%). central and south america and oceania had lower lbw rates (10%), while the caribbean had a similar rate (14%) to that of subsaharan africa.7 oman is passing through a crucial phase of health transition and facing the burden of morbidities, which could be considered a specific characteristic of newly developing countries. oman has made impressive gains in the achievement of key mdgs, and several diseases have been eliminated from the country.14 almost all health indicators have improved over the past four decades and this achievement has been widely recognised and acclaimed by various international organisations, including the who.15 despite improved health statistics, recent concern has focused on childhood health indicators. in particular, lbw and infant and under-five mortality rates (u5mrs) have been examined given their static or increasing trends; these have been indicated by recent health statistics released by oman’s ministry of health (moh) in 2012.16 these statistics show that lbw was the second leading cause of early neonatal mortality, the third leading cause of mortality among infants with congenital anomalies and the leading cause of early childhood mortality.16 thus, lbw and childhood mortality have emerged as new challenges for the improvement of child health in oman. the current review article provides an overview of the levels and trends of lbw in oman and speculates on the possible reasons for recent trends in lbw. the findings presented here may have important policy implications for the improvement of adverse pregnancy outcomes in oman. sources of oman’s low birth weight information since its first five-year health plan was instituted in 1976, oman has developed a well-organised health information system under the moh that can be used to monitor changes in major health indicators. thus, the data for the current study were obtained from reports of the oman national health information statistics (nhis), which cover the period of 1970 to 2012; these data were included in the moh’s 2012 annual health report.16 data were also extracted from other national-level health surveys such as the 2000 oman national health survey (onhs) and the 2008 oman world health survey (owhs).17,18 the only limitation in using the rich array of health service statistics of the nhis is uncertainty about the coverage of these services. additionally, certain population characteristics are not well represented by these data.19 an additional limitation of the use of secondary information is that it lacks analysis of risk factors across the full spectrum of socioeconomic levels and behavioural factors. low birth weight and childhood mortality in oman table 1 and figure 1 present the levels and trends of lbw in oman since 1980. data from the nhis reveal that 5,897 (9.5%) out of the 62,065 live births that occurred in 2012 were lbw infants.16 among those with lbw, 745 (1.2%) had a very low birth weight (vlbw) which is a birth weight of <1,500 g. thus, vlbw rates infants constituted 13% of the total cases of lbw in oman. there is an increasing trend in both lbw and vlbw in oman.16 according to the nhis’s routine data, the prevalence of lbw was approximately 4.2% in 1980, doubling to 8.1% in 2000. since then the prevalence has shown a slow but steady increase, reaching 9.5% in 2012 [figure 1].16 table 1 also presents a comparative analysis of the two estimates of the incidence of lbw and vlbw m. mazharul islam review | e179 obtained from the 2000 onhs data and the 2000 nhis routine data. the two estimates appeared to be consistent and very close in agreement. however, the 2000 onhs indicated a slightly higher estimate of lbw (9.1%) than the estimate obtained from the official data of the 2000 nhis (8.1%) for the same period.16,17 however, the difference was not statistically significant (t = 1.08; p >0.250). the results thus validate the estimates of health indicators obtained from the nhis in oman.16 the rate of infant mortality (i.e. death during the first year of life) dropped from 118 per 1,000 live births in 1970 to 9.5 per 1,000 live births in 2012, a decline of 92% within four decades [figure 1]. mortality in children under five years dropped by 94% (from 181 to 11.5 per 1,000 live births) in the same period.16 the data indicate that more than 80% of under-five mortalities have been due to infant mortality in recent decades; in fact, since 2000, the infant and u5mrs in oman have remained almost unchanged, despite continued efforts at reducing childhood mortality.16 this might have some relation with the increased incidence of lbw. figure 1: levels and trends in lbw, infant mortality, child mortality and under-five mortality rates in oman from 1970–2012.16 imr = infant mortality rate; u5mr = under-five mortality rate; cmr = child mortality rate; lbw = low birth weight. low birth weight in other countries the incidence of lbw (~9%) in oman was found to be higher than that in many countries with similar socioeconomic and cultural backgrounds. according to the joint unicef and who study of global, regional and country estimates of lbw in 2000, oman had a higher incidence of lbw than lebanon (6%), syria (6%), algeria (7%), kuwait (7%), libya (7%), tunisia (7%) and bahrain (8%).7 however, the incidence was lower than jordan (10%), qatar (10%), morocco (11%), saudi arabia (11%), egypt (12%), nigeria (14%), sudan (31%) and yemen (32%) [figure 2].7 regional variation in low birth weight rates in oman there are significant regional variations in lbw in oman [table 2]. according to the 2012 nhis data, the al-dakhiliyah region had the highest incidence of lbw (11.12%) followed by muscat (9.95%), north ash table 1: birth weights in oman from 1980–2012 by category, survey and year category* live births per survey and year, % p values† 1980 nhis 2000 onhs 2000 nhis 2012 nhis 2000 onhs versus 2000 nhis 2000 nhis versus 2012 nhis nbw 95.8 90.9 91.9 90.5 t = 1.08; p >0.250 t = 7.79; p <0.001 lbw 4.2 9.1 8.1 9.5 t = 1.08; p >0.250 t = 7.79; p <0.001 mlbw n/a 8.4 7.3 8.3 t = 1.23; p >0.200 t = 5.87; p <0.001 vlbw n/a 0.7 0.8 1.2 t = 0.37; p >0.500 t = 7.30; p <0.001 live births, n n/a 977 40,382 62,065 nhis = national health information statistics survey;16 onhs = oman national health survey;17,18 nbw = normal birth weight; lbw = low birth weight; mlbw = moderately low birth weight; vlbw = very low birth weight; n/a = not available. *infants of ≥2,500 g were considered of nbw, <2,500 g of lbw, 1,500–2,499 g of mlbw and <1,500 g of vlbw. †p values are based on student’s t-test, comparing two proportions. increasing incidence of infants with low birth weight in oman e180 | squ medical journal, may 2015, volume 15, issue 2 figure 2: prevalence of lbw in selected countries.7 lbw = low birth weight. sharqiyah (9.90%) and al-batinah (9.57%). the alwusta region had the lowest incidence (2.34%).16 this regional comparison, however, may be misleading, particularly for the muscat region, because many of the women who deliver in hospitals and clinics in muscat live elsewhere. as muscat is oman’s capital city and has specialised hospitals and clinics, women from all over the country, and especially those with complicated pregnancies, come to muscat to use the delivery facilities. as a result, the declared rate of lbw is likely to be higher in muscat, despite the improved health and socioeconomic conditions of the population. in this regard, national-level household survey or census data may provide a more accurate comparative picture of regional variations. thus, in this study, data from the 2000 onhs were used to analyse regional variations in lbw in oman. according to the 2000 onhs data, the highest lbw rate was observed in al-batinah (~12%) followed by ad-dhahirah and north ash sharqiyah (11% each). the lowest level of lbw was observed in muscat (5.5%).17 epidemiological transition as a newly developed country, oman is facing a double burden of morbidity. it carries the burden of the present epidemiological changes as well as the health problems that result from unhealthy lifestyles typical in developed countries. recent economic development and modernisation have led to changing nutritional habits and a decrease in habitual physical exercise. as a result, the country is passing through an epidemiological transition from communicable to non-communicable diseases.18 the main diseases or complications resulting from these changes include obesity, cardiac and coronary diseases, hypertension, diabetes, infectious diseases, cancers, chronic kidney diseases, stroke and geriatric diseases.16 many of these health problems manifest in women and lead to preterm births and lbw babies. underlying causes of increased low birth weight in oman globally, more than one in 10 infants are born preterm and 70% of them are born with a lbw; both of these rates are increasing.20 while oman is not exempt from the increase in lbw babies, there is no precise national estimate of preterm births due to a lack of routine data collection through the nhis or any other health survey on prematurity. a recent hospital-based study reported that about 10% of births in oman are table 2: regional variations in low birth weight rates in oman* region rate per year 2012 2000 muscat 9.95 5.5 dhofar 7.79 6.0 al-dakhiliyah 11.12 10.4 ash sharqiyah (north) 9.90 10.8 ash sharqiyah (south) 7.86 8.8 al-batinah (north) 9.57 11.6 al-batinah (south) 8.88 12.2 ad-dhahirah 9.48 11.0 al-wusta 2.34 6.7 total 9.45 9.1 *data from the national health information statistics and oman national health survey.16,17 m. mazharul islam review | e181 their desired family size.30,31 for example, the singulate mean age at marriage for females in oman has increased from 19.2 years in 1988 to 26.8 years in 2008, and the corresponding total fertility rate has declined dramatically from 8.6 births per woman in 1988 to 3.3 births per woman in 2008.17,18,28 concurrently, the proportion of births occurring to women aged 35–49 years has increased from 23.9% in 1988 to 29.8% in 2008; an increase of 25% over a 20-year period [figure 3].18,32 consequently, fertility has declined in younger women, shifting instead towards older women. the age distribution of fertility shows a broad, flat top, indicating a continuation of fertility at a higher rate until the age of 35–39 years.18 as mothers older than 35 are at greater risk for certain complications during pregnancy that may require a cs, such births are likely to continue to increase, simultaneously contributing to an increase in lbw. various reasons have been ascribed to explain the increased risk of cs deliveries among older women.33–36 it has also been observed that advanced maternal age alone may be a factor influencing both mothers’ and physicians’ decisions to have a cs.35,36 in many cases, physicians’ concerns might prompt a cs delivery to avoid the risk of adverse pregnancy outcomes. this rising trend in cs delivery and its possible association with the rising lbw in oman needs special attention in healthcare planning. with recent advances in modern obstetric and neonatal care and technological developments in oman, high-risk neonates have a greater chance of survival in the newly formed intensive care units. because of this, an increasing number of more and more small and lbw babies appear to be reported as live births. this may also cause an increase in the rate of lbw infants and, subsequently, an increased rate of long-term neurological problems as these infants are at high risk of health and developmental problems.16 preterm births.21 this rate is quite high and might play an important role in increasing the lbw rate in oman, as most preterm infants have a lbw. like other arab countries, consanguineous marriages, or marriages between close kin or blood relations, are a deeply-rooted cultural trend in oman, with more than half of all marriages considered consanguineous (52%).22 the long tradition of consanguineous marriages in omani society may have important ramifications on the prevalence of genetic diseases, congenital abnormalities, high preterm birth rates and adverse pregnancy outcomes, including lbw. the effects of consanguinity on human reproduction and the health of the resulting offspring are well-documented.23,24 recent hospitaland clinicbased studies in oman have demonstrated a higher risk of congenital disorders and ill health among the offspring of consanguineous couples, but these studies did not examine the link between consanguinity and lbw.25,26 more in-depth research is needed to identify the causal link between consanguinity and lbw. many preterm births happen spontaneously, while others result from early induction of labour or caesarean section (cs), whether for medical or nonmedical reasons. although the cs was introduced in clinical practice as a lifesaving procedure both for the mother and baby, its use follows the healthcare inequity pattern of the world: underuse in low-income settings and adequate or even unnecessary use in middle and high-income settings.27,28 the who stated that cs rates higher than 10–15% are an unnecessary economic burden.29 according to nhis data, the rate of cs deliveries has increased from 6.6% in 1995 to 11.6% in 2000, and has further increased to 17.5% in 2012.16 in oman, with couples marrying later in life and the preference for a large family size, the childbearing age is increasing, and more women are choosing to have children at the age of 35 years and above to achieve figure 3: proportion of total births and age-specific birth rate per woman in 1988 and 2008 in oman.17,18,32 ochs = oman child health survey; onrhs = oman national reproductive health survey; asfr = age-specific fertility rate. increasing incidence of infants with low birth weight in oman e182 | squ medical journal, may 2015, volume 15, issue 2 as a result, a number of them do not survive through early childhood. thus, the rates of infant mortality and u5mrs are not declining to the same extent that they have in the past. to some extent, the levelling off of decreasing infant and childhood mortality rates in oman could be attributed to the increasing rate of lbw babies. policy implications oman has a moderately high incidence of lbw infants compared to other middle-income and highincome countries and the rate is increasing. as lbw is one of the most important biomarkers of the health, survival and future development of newborn babies, it is important to identify the risk factors of lbw in oman and its ramifications for the educational development of children so that appropriate measures can be taken for the improvement of health, survival and development of infants. since many of these children are now attending school, it is important to investigate how they are coping academically. the poor outcomes of lbw children have economic and social consequences that go beyond immediate healthcare and special education costs as they may have much longer-term effects. neonatal and infant mortality rates can be greatly reduced by improving both maternal care of mothers during pregnancy and childbirth, as well as both neonates and infant care of lbw infants. experience from developed countries has clearly shown that appropriate care of lbw infants, including their feeding, temperature maintenance, and early detection and treatment of infections and complications, including respiratory distress syndrome, can substantially reduce mortality.20,37 since preterm birth, whether it is spontaneous or provider-initiated, is one of the important causes of lbw, its prevention or reduction could be one of the best ways to prevent babies being born with lbw. considering the moderately high incidence of preterm births in oman, appropriate policies and programmes need to be undertaken to reduce this phenomenon. for spontaneous preterm births, the underlying causes need to be understood and addressed, while in the case of provider-initiated preterm births, both the underlying conditions, such as pre-eclampsia, and obstetric policies and practices need to be assessed and addressed. prenatal care is a key factor in preventing preterm births and lbw babies. at prenatal visits, the health of both the mother and the fetus can be checked. because maternal nutrition and weight gain are linked with fetal weight gain and birth weight, eating a healthy diet and gaining the proper amount of weight in pregnancy are essential. mothers need to be advised to maintain a healthy lifestyle and avoid habits that can contribute to poor fetal growth and other obstetric complications. conclusion this paper provides an overview of the levels, trends, possible explanations and the policy implications of oman’s increasing lbw rate. oman is passing through an epidemiological transition. despite a dramatic improvement in the health and survival of individuals, childhood mortality and lbw have emerged as major national public health issues. the nhis of the moh indicate that the national infant mortality rate has remained at an almost unchanged level of 10 per 1,000 live births since 2000 while the lbw rate has shown an increasing trend since the 1980s. the incidence of lbw in oman is higher than observed in many other arab countries. high rates of consanguinity, premature births, the increased number of pregnancies at an older age, improved medical technologies and changing lifestyles are some important factors related to the increasing rate of lbw in this country. the underlying causes of their lbw increase in need to be understood and addressed in obstetric policies and practices in order to reduce this rate in oman. a c k n o w l e d g e m e n t s the author would like to thank the moh of oman, especially the directorate of research & studies, for providing the annual health reports and the national health survey reports, on the basis of which this review article was prepared. the author is a statistician and adept in the application of statistical techniques in analysing data on public health issues. no medical expert was consulted in the preparation of this article, and therefore, the views expressed herein are solely those of the author and do not necessarily reflect the views of any other individual or institution. references 1. world health organization and united nations children's fund. low birthweight: a tabulation of available information. geneva: who maternal health and safe motherhood programme, 1992. who/mch/92.2. 2. mccormick mc. the contribution of low birth weight to infant mortality and childhood morbidity. n engl j med 1985; 312:82– 90. doi: 10.1056/nejm198501103120204. 3. kramer ms. determinants of low birth weight: methodological assessment and meta-analysis. bull world health organ 1987; 65:663–737. 4. villar j, belizán jm. the relative contribution of prematurity and fetal growth retardation to low birth weight in developing countries and developed societies. am j obstet gynecol 1982; 143:793–8. m. mazharul islam review | e183 21. islam mm, al-thihli k, abdellatif m. maternal and neonatal factors influencing preterm birth and low birth weight in oman: a hospital based study. inter j child health nutr 2013; 2:281–95. doi: 10.6000/1929-4247.2013.02.04.2. 22. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571– 94. doi: 10.1017/s0021932012000016. 23. bittles ah. the role and significance of consanguinity as a demographic variable. pop devel rev 1994; 20:561–84. doi: 10.2307/2137601. 24. bittles ah, black ml. the impact of consanguinity on neonatal and infant health. early hum dev 2010; 86:737–41. doi: 10.1016/j.earlhumdev.2010.08.003. 25. rajab a, vaishnav a, freeman nv, patton ma. neural tube defects and congenital hydrocephalus in the sultanate of oman. j trop pediatr 1998; 44:300–3. doi: 10.1093/tropej/44.5.300. 26. sawardekar kp. profile of major congenital malformations at nizwa hospital, oman: 10-year review. j paediatr child health 2005; 41:323–30. doi: 10.1111/j.1440-1754.2005.00625.x. 27. world health organization. package of interventions: family planning, safe abortion care, maternal, newborn and child health, 2010. from: www.who.int/maternal_child_adolescent/ documents/fch_10_06/en/ accessed: oct 2014. 28. althabe f, belizán jm. cesarean section: the paradox. lancet 2006; 368:1472–3. doi: 10.1016/s0140-6736(06)69616-5. 29. world health organization. appropriate technology for birth. lancet 1985; 2:436–7. doi: 10.1016/s0140-6736(85)92750-3. 30. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32–42. 31. ecker jl, chen kt, cohen ap, riley le, lieberman es. increased risk of caesarean delivery with advancing maternal age: indications and associated factors in nulliparous women. am j obstet gynecol 2001; 185:883–7. doi: 10.1067/ mob.2001.117364. 32. sulaiman, m, al-ghassany a, farid s. oman child health survey 1988/1989, 1992. muscat, oman: ministry of health. 33. cleary-goldman j, malone fd, vidaver j, ball rh, nyberg da, comstock ch, et al. impact of maternal age on obstetric outcome. obstet gynecol 2005; 105:983–90. 34. lin hc, sheen tc, tang ch, kao s. association between maternal age and the likelihood of a caesarean section: a population-based multivariate logistic regression analysis. acta obstet gynecil scand 2004; 83:1178–83. doi: 10.1111/j.00016349.2004.00506.x. 35. bianco a, stone j, lynch l, lapinski r, berkowitz g, berkowitz rl. pregnancy outcome at age 40 and older. obstet gynecol 1996; 87:917–22. 36. peipert jf, bracken mb. maternal age: an independent risk factor for caesarean delivery. obstet gynecol 1993; 81:200–5. 37. darmstadt gl, bhutta za, cousens s, adam t, walker n, de bernis l; lancet neonatal survival steering team. evidencebased, cost-effective interventions: how many newborn babies can we save? lancet 2005; 365:977–88. doi: 10.1016/s01406736(05)71088-6. 5. mccormick mc, brooks-gunn j, workman-daniels k, turner j, peckham gj. the health and developmental status of very low-birth-weight children at school age. jama 1992; 267:2204–8. doi: 10.1001/jama.1992.03480160062035. 6. hack m, weissman b, breslau n, klein n, borawski-clark e, fanaroff aa. health of very low birth weight children during their first eight years. j pediatr 1993; 122:887–92. doi: 10.1016/ s0022-3476(09)90012-9. 7. united nations children’s fund and world health organization. low birthweight: country, regional and global estimates 2004. from: www.unicef.org/publications/index_24840.html accessed: oct 2014. 8. strauss rs. adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 british birth cohort. jama 2000; 283:625–32. doi: 10.1001/ jama.283.5.625. 9. barker djp. the fetal origins of adult disease. fetal matern med rev 1994; 6:71–80. doi: 10.1017/s0965539500001005. 10. huxley rr, shiell aw, law cm. the role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. j hypertens 2000; 18:815–31. doi: 10.1097/00004872-200018070-00002. 11. united nations. resolution adopted by the general assembly: s-27/2. a world fit for children, 2002. from: www.unicef. org/specialsession/docs_new/documents/a-res-s27-2e.pdf accessed: oct 2014. 12. united nations. road map towards the implementation of the united nations millennium declaration, report of the secretary-general a/56/326, 2001. from: http:// preventionweb.net/go/13543. accessed: oct 2014 13. kramer ms. the epidemiology of adverse pregnancy outcomes: an overview. j nutr 2003; 133:1592s–6s. 14. al-lamki l. un millennium development goals and oman: kudos to oman on its 40th national day. sultan qaboos univ med j 2010; 10:301–5. 15. world health organization. the world health report 2000: health systems—improving performance. from: www.who.int/ whr/2000/en/ accessed: oct 2014. 16. oman ministry of health. annual health report, 2012. muscat, oman: ministry of health, 2013. 17. al-riyami a, afifi m, al-kharusi h, morsi, m. national health survey 2000, volume 2: reproductive health survey, 2000. muscat, oman: ministry of health. 18. al-riyami a, abd-el-aty ma, jaju s, morsi m, al-kharusi h, al-shekaili w. national reproductive health survey, 2008. muscat, oman: ministry of health, 2008. 19. hill ag, muyeed az, al-lawati ja, eds. the mortality and health transitions in oman: patterns and processes. from: w w w.unicef.org/e valdatabase/files/2000_oman_health_ transition_rec_347399.pdf accessed: oct 2014. 20. march of dimes, partnership for maternal, newborn & child health, save the children, world health organization. born too soon: the global action report on preterm birth. from: www.who.int/maternal_child_adolescent/documents/born_ too_soon/en/ accessed: oct 2014. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 295-299, epub. 15th jul 12 submitted 21st sep 11 revision req. 23rd nov 11, revision recd. 25th apr 12 accepted 12th feb 1departments of genetics and 2child health, sultan qaboos university hospital, muscat, oman; 3college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: alfutaisiamna@hotmail.com طيف اضطرابات االختزان يف اجُلَسْيَماِت احلَالَّة عند األطفال يف ُعمان املنذر املعويل، �سوريندرا جو�سي، رو�سان كول، علي عبداهلل املعويل، هالل �سالح ال�سديري، بدر حممد العمري، اآمنة حممد الفطي�سي امللخ�ص: الهدف: درا�سة طيف ا�سطرابات الختزان يف اجُل�َسْيَماِت احَلالَّة عند الأطفال يف ُعمان. طيف ا�سطرابات الختزان يف اجُل�َسْيَماِت احَلالَّة هي جمموعة غري متجان�سة من الأمرا�ض الأي�سية املوروثة. هناك درا�سات قليلة حول انت�سار هذه املجموعة عند الولدة وبعدها ت�سع خالل ت�سخي�سهم مت احَلالَّة اجُل�َسْيَماِت يف الختزان با�سطرابات م�سابا طفال بدرا�سة 86 قمنا العربية. الطريقة: اجلزيرة �سبه يف �سنوات، من يونيو 1998 اإىل مايو 2007. وقد مت جمع البيانات ال�رسيرية املف�سلة، مبا يف ذلك ال�سن عند بداية املر�ض واجلن�ض وطريقة يف احلالة اجل�سيمات يف الختزان ا�سطرابات طيف انت�سار اأن اإىل املتوفرة البيانات ت�سري النتائج: القرابة. �سلة ووجود املر�ض بدء �سلطنة ُعمان 1 لكل 4700 ولدة حية. وكانت ال�سحامات ال�سفينغولية املجموعة الأكرث �سيوعا بن�سبة )47.7%(، تليها الليبوفو�سينية ال�سريويدية الع�سبية )23.2%( من ثم عديد ال�سكاريد املخاطي )23.2%(. كانت ن�سبة زواج الأقارب عالية اإذ بلغت 87.5%. اخلال�صة: متثل املعطيات مدى انت�سار ا�سطرابات طيف ا�سطرابات الختزان يف اجل�سيمات احلالة يف �سلطنة ُعمان، والتي ُتعد من اأحد اأكرث جمتمعات ال�رسق الأو�سط يف انت�سار زيجات الأقارب. مفتاح الكلمات: ا�سطرابات تخزين اجُل�َسْيَماِت احَلالَّة، ُعمان؛ انت�سار؛ العرب. abstract: objectives: the aim of this study was to look at the spectrum of paediatric lysosomal disorders in oman. lysosomal storage disorders (lsds) are a heterogeneous group of inherited metabolic diseases. few studies on the birth prevalence and prevalence of lsds have been reported from the arabian peninsula. methods: we studied 86 children with lsds diagnosed over a period of nine years, from june 1998 to may 2007. detailed clinical data, including age of onset, sex, age and mode of first presentation, and presence of consanguinity were collected. results: our data showed the combined birth prevalence for all lsds in oman to be around 1 in 4,700 live births. sphingolipidoses was the most common group of disorder encountered (47.7%), followed by neuronal ceroid lipofuscinoses (ncl) (23.2%) and mucopolysaccharidoses (mps) (23.2%). the proportion of consanguineous marriages in our series was found to be 87.5%. conclusion: our data represent the birth prevalence and clinical spectrum of such disorders in oman, one of the highly consanguineous societies in the middle east. keywords: lysosomal storage disorders; oman; prevalence; arabs. spectrum of paediatric lysosomal storage disorders in oman almundher a al-maawali,1 surendra n joshi,2 roshan l koul,2 ali a al-maawali,3 hilal s al-sedari,3 bader m al-amri,3 *amna m al-futaisi2 clinical & basic research advances in knowledge this is the first report of lysosomal storage disorders (lsds) from oman. the study highlights the birth prevalence, spectrum, and clinical characteristics of various disorders, and their relevance in a population with a very high consanguinity rate. the study’s findings add to the knowledge of hereditary disorder screening in the people of the arabian peninsula. application to patient care knowledge of lsds will direct appropriate and necessary testing programmes for patients in oman. the importance of high-risk testing lies in the prevention of lsds by premarital and prenatal screening, as well as in early initiation of treatment, when available. lysosomal storage disorders (lsds) are relatively rare inborn errors of metabolism, with a combined global birth prevalence of 1 in 1,500 to 7,000 live births. 1 they represent a group of more than 40 distinct genetic disorders.2,3 deficiency of lysosomal proteins or, spectrum of paediatric lysosomal storage disorders in oman 296 | squ medical journal, august 2012, volume 12, issue 3 less frequently, non-lysosomal proteins involved in lysosomal biogenesis, result in the accumulation of non-metabolised macromolecules.4 most of these disorders are inherited in an autosomal recessive manner, except fabry’s disease and mucopolysaccharidoses type ii (mps ii) which are inherited in an x-linked recessive manner.4 major groups of lsd disorders include mps, lipidoses, glycogenoses, and oligosaccharidoses.4 most disorders present clinically with multi-system involvement. common clinical features involve bony dysplasia, hepatosplenomegaly, central nervous system dysfunction, haematological abnormalities, and coarse hair and facial features. there are many phenotypical similarities within the categories. potential treatments for some of these disorders are available in the form of enzyme replacement therapy (ert) and bone marrow transplantation (bmt). most of the reports on lsd’s birth prevalence and general prevalence are from western countries.4–9 data on the frequency of lsds in the arab population are quite sparse; however, a recent report described prevalence of inborn error of metabolism (iem) in oman.10 the aim of this study was to investigate the relative frequency of various lsds in oman. estimating the baseline birth prevalence is of increasing importance given the interest in newborn screening for lsds, and the availability of expensive ert and substrate reduction therapy. methods sultan qaboos university hospital (squh) in muscat, oman, is the main referral centre for metabolic genetic diseases in the country. we studied 86 paediatric cases referred over a period of nine years from june 1998 to may 2007. the institution’s ethical committee approved the study. detailed clinical data, including sex, age of onset of disease, age at diagnosis, mode of presentation, family history, consanguinity rates, and high-risk screening results were collected. detailed results of laboratory investigations and medical imaging were obtained. the willink biochemical genetics unit in manchester, uk, (which has uk clinical pathology accreditation [cpa]) assessed the lysosomal enzyme levels from blood samples of all patients. all patients in this study had a confirmatory enzymatic diagnosis. genetic mutation analysis was only performed in cases of patients who received enzyme replacement therapy (ert) or a bone marrow transplant (bmt). we determined the annual number of live births in oman from the national health statistics for the years in which our study subjects were born. the total number of live births and the total number of lsd patients then were averaged to a total number of cases per year. the birth prevalence rate of lsds was calculated by dividing the average number of postnatal diagnoses per year by the average number of live births per year between 1998 and 2007. results between june 1998 and may 2007, a total of 86 patients (male to female ratio = 1:0.7) were diagnosed with lsd. the average number of live births during the study period was 45,000 per year. the combined birth prevalence for all lsds was therefore 1 in 4,700 live births per year. sphingolipidoses as a group was the most frequent lsd (47.7%), followed by neuronal ceroid lipofucinoses (ncl) (23.2%) and mps (23.2%). detailed frequencies of lsds are presented in table 1. the proportion of consanguineous marriages in the referred families was 87.5%, and 35% of patients had a sibling with a similar illness at the time of diagnosis. the patients ranged in age from 3 days old (neonates) to 18 years of age. a total of 47.5% patients became symptomatic between 1 and 6 months of age, 27.5% between 6 months and 1 year old, and 25% presented with symptoms after one year old. among sphingolipidosis, sandhoff disease was one of the most commonly encountered diseases (15.1%), followed by gaucher disease (8.1%). late infantile neuronal ceroid lipofuscinosis (ncl) was the single most common disease diagnosed in our series (23%). the majority of these patients presented between 1 to 4 years of age with regression in their development and intractable seizures. it was noted that all the children with disease had myoclonic seizures, microcephaly and maculopathy. in general, global developmental delay/regression (40%), coarse facial features and hepato-splenomegaly (30%) were the most common presenting features at diagnosis. other presenting features were nystagmus, abdominal distension, deafness, recurrent infections, and failure to thrive. almundher a al-maawali, surendra n joshi, roshan l koul, ali a al-maawali, hilal s al-sedari, bader m al-amri, amna m al-futaisi clinical and basic research | 297 a couple of patients were diagnosed by testing done to siblings previously diagnosed with the same disease. discussion the lsds are rare disorders resulting from the accumulation of substrates within the lysosomes. these disorders are under-diagnosed and their birth prevalence is underestimated.1 the exact birth prevalence of lsds in the arab population remains unknown. this is the first report of lsds in oman which highlights the birth prevalence, spectrum, and clinical characteristics of the various disorders identified during a nine-year period. it is also one of the few studies to report the birth prevalence and prevalence of lsds in one of the highly consanguineous societies of the middle east. in our study, we estimated the combined birth prevalence rate of lsds at 1 per 4,700 live births. in australia, the birth prevalence rate was estimated to be 1 per 9,000, excluding prenatal diagnosis.4 poorthuis et al. reported the combined birth prevalence for all lsds in the netherlands as 14 per 100,000 live births.5 in oman, the birth prevalence rate of all inborn errors of metabolism as a group was reported as 1 per 1,555 out of which 25% were lsds.10 this is a much higher birth prevalence than that reported in caucasians. in saudi arabia, 125 cases of lsds of different types were reported in births occurring over a three-year period.9 sphingolipidoses was the most frequent lsd encountered in our study. these cases constituted 47.7% of cases. this finding was consistent with and comparable to different reports. many of these disorders present in infantile form. in our group, 45.7% of the patients developed symptoms between the ages of 1 and 6 months. sandhoff disease was one of the most commonly encountered diseases (15.1%). it is a relatively rare metabolic disease, but seen more commonly in certain populations, including the argentinean creoles, the metis indians, and the lebanese.11 the birth prevalence rate of sandhoff disease is 1 per 309,000 births in non-jewish populations.12 fourteen of the 125 lsd patients in saudi arabia (11.2%) presented with sandhoff disease.9 gaucher disease was confirmed in 8.1 % (7/86) in the study group. worldwide, gaucher disease has a birth prevalence of approximately 1.5 per 100,000 births; however, ashkenazi jews have a higher frequency of this disorder. in saudi arabia, ozand et al. reported that 3 patients out of the 125 total patients seen with lsd had gaucher disease. a retrospective study for lsds from the united arab emirates (uae) reported only four cases of gaucher disease.13 at squh, two siblings with type iii gaucher disease with a homozygous l444p/ l444p mutation have been undergoing ert for table 1: number of patients and relative frequency of different categories of lysosomal storage disorders (lsds) diagnosis sub-types no. % sphingolipidoses 41 47.7 gaucher disease type 1 2 2.3 type 2 1 1.2 type 3 4 4.7 niemann-pick disease a and b 3 3.5 metachromatic leukodystrophy 8 9.3 krabbe disease 1 1.2 gm1 gangliosidosis 4 4.7 tay-sachs disease 5 5.9 sandhoff disease 13 15.1 mucopolysaccharidoses 20 23.2 type i 3 3.5 type ii 2 2.3 type iii 7 8.1 type iv 4 4.7 type vi 3 3.5 type vii 1 1.2 mucolipidosis 1 1.2 i cell disease 1 oligosaccharidoses 2 2.3 siladosis 2 lipid storage diseases 20 23.2 late infantile neuronal ceroid lipofuscinoses 20 lysosomal glycogen storage disease— pompe’s disease 2 2.3 total 86 spectrum of paediatric lysosomal storage disorders in oman 298 | squ medical journal, august 2012, volume 12, issue 3 eight and seven years, respectively. although one of the children suffered from a severe progressive course of the disorder, he has shown remarkable improvement in terms of organomegaly and haematological parameters as a result of the treatment. his younger sibling was diagnosed and began ert much earlier, at four months of age, and to date his mental development is improving. we observed that early treatment offers much better outcomes, except in the case of ophthalmoplegia, the course of which could not be altered. late infantile ncl was the single most common disease diagnosed in our cohort. a series of eleven cases had previously been reported, with most of the patients being from five families.14 late-infantile ncl, or jansky-bielschowsky disease (cln2 type), was the most common type of ncl seen.14 over time, the number of cases had increased from nine to twenty families. in general, cln2 remains the most frequently encountered type of ncl in oman. however, other types of ncl are now diagnosed in omani patients due to better availability of diagnostic tests. ncl is not an uncommon disease in arab populations. recently, goldberg-stern et al. reported two siblings of israeli-arab origin with cln2 having a novel mutation.15 taschner et al. reported a patient with cln3 from morocco.16 sarpong et al. reported a large consanguineous lebanese family with five affected siblings with a protracted course.17 they had juvenile cln associated with a novel cln3 mutation (p.y199*). al-muhaizea et al. reported on three families from saudi arabia with a variant of late infantile ncl, one of them having a novel mutation in the cln6 gene.18 zelnik et al. described a different variant of cln (cln8) in a 10-year-old israeli-arab boy.19 mps as a group constituted 23.2% of the total lsd cases. most of the subtypes in our group were evenly distributed. however, mps iii was the most frequently noted subtype. ozand et al. reported 19 patients with mps iv out of 30 total patients with mps. in tunisia, the birth prevalence of mps iva was higher than in other communities (2.8:100,000). we treated one child with severe mps i by ert for 9 months in preparation for a bmt. this child no longer needs ert after a successful bone marrow engraftment. the proportion of consanguineous marriages in the omani population in general is 56%.20,21 about 24.1% of marriages were reported between first cousins, 11.8% between second cousins, and 20.4% of marriages were within specific tribal groups.20 the proportion of consanguineous marriages in our patients’ families was 87.5%, with most of those being firstand second-cousin marriages. interestingly, 35% (30/86) of patients had a sibling with a similar illness at diagnosis. only two patients in our series were diagnosed through high-risk screening. the importance of high-risk testing lies in prevention by premarital and prenatal screening, as well as in early initiation of treatment when available. it also helps in identifying those families who may benefit from appropriate genetic counselling, and it is strongly recommended to initiate such testing programmes for high-risk families.22,23 high-risk testing programmes have now been established in oman. conclusion in this study, we report a combined birth prevalence of 1 in 4,700 live births for lsd in oman. the limitation in our study is that it is retrospective and hospital-based. additionally, we may have missed some cases which were not referred to squh. therefore, this study likely underestimates the birth prevalence; diagnosis through a paediatric hospital setting such as ours will exclude the milder forms of the disease that may present in adulthood. there is also a bias due to missed diagnosis or death before diagnosis. such factors cause an underestimation of the real prevalence. oman’s birth prevalence is less than that reported in other gulf countries, such as saudi arabia. a testing programme for high-risk families in oman has been successfully established at squh. a prospective study, along with a national screening programmes would help identify the exact birth prevalence of lsds in oman. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest. references 1. staretz-chacham o, lang tc, lamarca me, krasnewich d, sidransky e. lysosomal storage disorders in the newborn. pediatrics 2009; 123:1191– 207. 2. wraith je. lysosomal disorders. semin neonatol 2002; 7:75–83. almundher a al-maawali, surendra n joshi, roshan l koul, ali a al-maawali, hilal s al-sedari, bader m al-amri, amna m al-futaisi clinical and basic research | 299 3. vellodi a. lysosomal storage disorders. br j haematol 2005; 128:413–31. 4. meikle pj, hopwood jj, clague ae, carey wf. prevalence of lysosomal storage disorders. jama 1999; 281:249–54. 5. poorthuis bj, wevers ra, kleijer wj, groener je, de jong jg, van weely s, et al. the frequency of lysosomal storage diseases in the netherlands. hum genet 1999; 105:151–6. 6. pinto r, caseiro c, lemos m, lopes l, fontes a, ribeiro h, et al. prevalence of lysosomal storage diseases in portugal. eur j hum genet 2004; 12:87– 92. 7. tylki-szymanska a, czartoryska b, lugowska a, górska d. the prevalence and diagnosis of lysosomal storage diseases in poland. eur j pediatr 2001; 160:261–2. 8. michelakakis h, dimitriou e, tsagaraki s, giouroukos s, schulpis k, bartsocas cs. lysosomal storage diseases in greece. genet couns 1995; 6:43– 7. 9. ozand p, gascon l, al aqeel a, roberts g, dhalla m, subramanyalvl s. prevalence of different types of lysosomal storage diseases in saudi arabia. j inhert metab dis 1990; 13:849–61. 10. joshi s, hashim j, venugopalan p. pattern of inborn errors of metabolism in an omani population of the arabian peninsula. ann trop paediatr 2002; 22:93– 6. 11. der kaloustian vm, khoury mj, hallal r, deeb me, wakid nw, et al. sandhoff disease: a prevalent form of infantile gm2 gangliosidosis in lebanon. am j hum genet 1981; 33:85–9. 12. sandhoff k, conzelmann e. the biochemical basis of gangliosidoses. neuropediatrics 1984; 86:85–92s. 13. tadmouri g, al ali m. genetic disorders in the arab world. dubai, uae: centre for arab genomic studies, 2004. 14. koul r, al-futaisi a, ganesh a, rangnath bs. lateinfantile neuronal ceroid lipofuscinosis (cln2/ jansky-bielschowsky type) in oman. j child neurol 2007; 22:555–9. 15. goldberg-stern h, halevi a, marom d, straussberg r, mimouni-bloch a. late infantile neuronal ceroid lipofuscinosis: a new mutation in arabs. pediatr neurol 2009; 41:297–300. 16. taschner pe, de vos n, thompson ad, callen df, doggett n, mole se, et al. chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (batten disease). am j hum genet 1995; 56:663–8. 17. sarpong a, schottmann g, rüther k, stoltenburg g, kohlschütter a, hübner c, et al. protracted course of juvenile ceroid lipofuscinosis associated with a novel cln3 mutation (p.y199x). clin genet 2009; 76:38–45. 18. al-muhaizea ma, al-hassnan zn, chedrawi a. variant late infantile neuronal ceroid lipofuscinosis (cln6 gene) in saudi arabia. pediatr neurol 2009; 41:74–6. 19. zelnik n, mahajna m, iancu tc, sharony r, zeigler m. a novel mutation of the cln8 gene: is there a mediterranean phenotype? pediatr neurol 2007; 36:411–3. 20. rajab a, patton ma. analysis of the population structure in oman. j community genet 1999; 2:23– 5 21. rajab a, patton ma. a study of consanguinity in the sultanate of oman. ann hum biol 2000; 27:321–6. 22. fletcher jm. screening for lysosomal storage disorders—a clinical perspective. j inherit metab dis 2006; 29:405–8. 23. pollitt rj. international perspectives on newborn screening. j inherit metab dis 2006; 29:390–6. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 256-262, epub. 9th may 13 submitted 28th may 12 revision req. 19th dec 12, revision recd. 20th dec 12 accepted 8th jan 13 departments of 1psychiatry and 2anesthesia & icu, mansoura university hospital, mansoura city, egypt; 3department of surgery, king faisal university, al ahsaa, saudi arabia *corresponding author e-mail: mostafapsy@yahoo.com هل الوقاية باهلالوبرييدول حتد من اهلذيان احلادث بعد التخدير بالكيتامني يف األطفال؟ م�شطفى عمرو، طارق �شم�ض، حامد الودعانى امللخ�ص: الهدف: الكيتامني هو عقار خمدر ل ينتمى اىل جمموعة الباربيتيوريت ويتميز ببداية مفعول �رسيعة تدفع اىل التخدير العميق. الهالوبرييدول عقار فعالية تقييم اىل الدرا�شة هذه تهدف الهذيان. ظهور من اخلوف ب�شبب ا�شتخدامه عن الطوارئ اأطباء بع�ض يحجم والبكاء، ، للهياج ظهور باأي املتعلقة الالحقة البيانات ت�شجيل مت الدرا�صة: اجلراحية. العمليات بعد الكيتامني هذيان من الوقاية يف املرتددين املر�شي كل يف الأعرا�ض هذه على لل�شيطرة الكيتامني عقار اإعطاء بعد والهذيان الدراك تغري و والأحالم، الهالو�ض، و مري�شا. 537 حلواىل النتائج �شجلت النتائج: 2011 مايو اىل 2010 يونيو من الفرتة فى م�رس اجلامعى املن�شورة م�شت�شفى على تلقى، 267 )%49.7( الهالوبرييدول الوقائي قبل ا�شتخدام الكيتامني )جمموعة 1( بينما كان هناك 270 )%50.3( مل يتلقوا عقار جمموعة اظهرت التخدير. بعد ما املر�شى �شلوك فى املجموعتني بني اح�شائية دللة ذو كبري فرق ظهر جمموعة 2(. ( الهالوبرييدول الهالوبرييدولالكتامني مزيد من النعا �ض والهدوء )p ≤0.01( بينما قل التوتر )p ≤0.01( وال�شياح )p ≤0.01( واختالل التوجه ) التوهان( )p ≤0.01(. اخلال�صة: اأظهرت الدرا�شة اأن اإعطاء الهالوبرييدول قبل العمليات اجلراحية الب�شيطة من �شاأنه اأن يقلل اإىل حد كبري من حدوث الهذيان بعدها يف عينة من الأطفال امل�رسيني وهذا يتوافق مع العمل ال�شابق الذي اأجري يف البالغني. يحمل هذا العمل الكثري من المل يف احلد و الوقاية من الهذيان لكل اأنواع املر�شى من الأطفال اخلا�شعني للتخدير بعقار الكيتامني. مفتاح الكلمات: الكيتامني؛ التخدير؛ الطفال؛ الهذيان؛ الهالوبريدول. abstract: objectives: ketamine is a non-barbiturate agent with rapid action onset that induces profound sedation; however, some emergency physicians tend not to use ketamine because of the risk of emergence delirium (ed). this study aimed to evaluate the effectiveness of haloperidol prophylaxis in postoperative ketamine delirium in children. methods: prospective data relating to any emergence dreams, delirium, hallucinations, agitation, crying, altered perceptions, and necessary interventions were recorded in consecutive cases of ketamine delirium in patients attending mansoura university hospital, egypt, from june 2010 to may 2011. results: a total of 537 records were available for analysis. of those, 267 received prophylactic haloperidol (49.7%). there were significant differences between the two groups regarding post-anaesthetic care unit behaviour. the ketamine-haloperidol groups included more patients who were sleepy, calm (p ≤0.01) and less irritable (p ≤0.01), with a lower incidence of crying (p ≤0.01) and disorientation (p ≤0.01). conclusion: we found that preoperative administration of haloperidol decreases the incidence of postoperative delirium in a sample of egyptian children undergoing minor surgery. this is congruent with earlier work conducted in adults. this work carries great hope to decrease and even prevent ed in hospitalised, non-surgical patients. keywords: ketamine; anesthesia; children; delirium; haloperidol; egypt. does haloperidol prophylaxis reduce ketamine-induced emergence delirium in children? *mostafa a. m. amr,1 tarek shams,2 hamid al-wadani3 clinical & basic research advances in knowledge this study is unique in investigating the use of prophylactic haloperidol in children to reduce postoperative ketamine delirium in our region. the results of this study revealed that the preoperative administration of haloperidol will reduce the incidence of postoperative delirium in children undergoing minor surgery. applications to patient care this study throws light on the possibility of haloperidol use in hospitalised patients to decrease or even prevent delirium. mostafa a. m. amr, tarek shams and hamid al-wadani brief communication | 257 ketamine is a non-barbiturate agent with a rapid onset of action that induces profound analgaesia, sedation, and amnesia, with a short duration of action (15–30 minutes) and hence is associated with rapid recovery.1,2 ketamine appears to have both central nervous system action and local anaesthetic properties. the main effects of this drug are mediated by the noncompetitive antagonism of the n-methyl-d-aspartate (nmda) receptor in addition to binding to the muscarinic and opioid receptors.3 the main advantage of ketamine over other categories of sedatives lies in maintaining airway reflexes with minimal cardiovascular and respiratory side effects.4 ketamine-induced emergence delirium (ed) is characterised by restlessness, agitation, and combativeness, and a non-cognisant state in relation to the patient’s surroundings. transient physical restraint may be the only way to deal with the patients’ disorientation.5,6 anaesthesiologists attempt to prevent patients from having such adverse effects by the co-administration of short acting benzodiazepine (midazolam). early anaesthetic literature supports this practice.7,8 the rate of emergence agitation with midazolam displayed no change when comparing ketamine alone to a combination of ketamine and midazolam.9,10 haloperidol is another psychotropic medication that has been commonly used for the treatment of elderly and adult delirium.11 haloperidol prophylaxis has been a matter of debate in the last two decades. schrader et al. used haloperidol with a dose of 0.5 mg three times daily in the elderly, resulting in a reduction of delirium duration (from a mean of 11.8 to 5.4 days) and length of hospital stay in affected participants (from a mean of 22.6 to 17.1 days).12 however, atlas and milles used haloperidol for the treatment of adult ketamine-induced ed in a single dose of 5 mg, administered intravenously (iv) to control delirium following maxillofacial surgery.13 delirium among children and adolescents was managed well by haloperidol.14 in children with psychomotor agitation that was acutely threatening to their health status, iv haloperidol (at a loading dosage of 0.15–0.25 mg) was used over a period of 30–45 minutes, followed by a maintenance dose of 0.05–0.5 mg/kg/24 hour.15–17 critically ill children reportedly tolerate doses up to 1–1.5 mg/kg/day (maximum 230 mg).18–20 the pharmacological half-life of haloperidol is significantly longer than that of ketamine. specifically, haloperidol has a half-life of 14 to 26 hours, whereas ketamine has a half-life of 15 minutes for its alpha phase and 2.5 hours for its beta phase.21,13 therefore, multiple doses or infusions of haloperidol would ordinarily not be necessary for the treatment of ketamine-induced ed. normally, a single dose should suffice.22 haloperidol is associated with cardiac dysrythmias and extrapyramidal side effects such as dystonia, tardative dyskinesia, akathisia, and neuroleptic malignant syndrome.23,24 however, these side effects occur infrequently, this is particularly notable given the relatively low dose of haloperidol which appears necessary for the treatment of ketamine-induced ed.22,25 to the best of the authors’ knowledge, no similar studies have been conducted in children who received haloperidol for the sake of preventing consequent postoperative ed. furthermore, most of the studies were carried out in developed countries. this work aimed to evaluate the effectiveness of haloperidol prophylaxis on postoperative ketamine -induced delirium in children. the authors hypothesised that preoperative administration of haloperidol would greatly decrease the incidence of postoperative ed. methods the subjects for this clinical prospective randomised study were 537 consecutive children undergoing minor surgery at the mansoura university hospital in mansoura city, egypt, between june 2010 and may 2011. eligibility criteria included children aged 6–16 years undergoing removal of stitches, laceration repair, removal of foreign bodies, abscess incision and drainage, and any examination for which general anaesthesia was required. inclusion criteria included those classified under the american society of anaesthesiologists’ (asa) designations of class i or ii. exclusion criteria included children allergic to ketamine, those with porphyria or active respiratory tract infections, and those undergoing surgery of the oropharynx. patients with hepatic or renal impairment or a previous history of psychiatric illness, or those taking antidepressants, benzodiazepines, or antipsychotics were also excluded. does haloperidol prophylaxis reduce ketamine-induced emergence delirium in children? 258 | squ medical journal, may 2013, volume 13, issue 2 written informed consent was signed by a parent of each patient. for all patients, tests of preoperative liver or renal function, evaluations of the patient’s complete blood count and coagulation profile, and tests for levels of blood sugar and serum electrolytes were done. a systematic sample was taken (a sample design in which a list of the population is used as a sampling frame and cases are selected by skipping through the list at regular intervals) and the patients were classified into two groups. one hour before the start of anaesthesia, patients in group i (haloperidol group, n = 267) were given a haloperidol 0.025 mg/kg in 5 ml of distilled water iv while patients in group ii (placebo group, n = 270) were given a 5 ml distilled water iv. all equipment for intubation and ventilation was kept on standby. anaesthesia was induced by ketamine 0.5–1 mg/kg iv and increments as needed to facilitate surgery. the asa standard of monitoring was carried out in the form of peripheral oxygen saturation, indirect blood pressure, and an electrocardiogram (ecg) and pulse rate were taken at intervals of 5 minutes during the procedure and 10 minutes during recovery. at the end of the surgery, the patients were moved to the postanaesthesia care unit (pacu) which was under the supervision of an anaesthesiologist. for all patients, pain was assessed and treated so as to obtain a pain level <4 on the 0–10 visual analogue scale (vas).26 paracetamol (perfalgan®) was given at a dose of 15 mg/kg every 4–6 hours as a slow iv infusion over 15 minutes, for pain registering at a vas score of above 3. at the pacu, which was also staffed by a wellqualified nurses, the parents were guided to give their children psychological support, and there was no need to dim the lights or eliminate auditory and visual stimuli. as recommended by cole et al., a prospective observation of the children’s behaviour was made in the recovery room 30 minutes after the patient’s arrival in the pacu.27 the children were eventually discharged under the supervision of the family and the treating physician. a followup telephone call was carried out by the research assistant and or the authors at the end of the first postoperative month. data were analysed using the statistical package for social sciences (spss), version 11 (ibm, inc., chicago, illinois, usa). quantitative variables were tested for normality distribution by the kolmogorov-smirnov test. quantitative variables were displayed as mean ± standard deviation (sd). qualitative variables were presented as numbers and percentages. the differences between the means of the two groups were assessed using an independent t-test. the chi-square test was used for comparison of count and percentage of the two groups. a value of p ≤0.05 was considered statistically significant. results a total of 537 children (386 males, 151 females) at mansoura university hospital were anaesthetised in 2010–2011 for minor surgery. the mean ages for the first group and second group were 10.69 ± 2.3 years and 10.98 ± 2.8 years, respectively. the mean anaesthesia time for the first and second groups was 23.8 ± 5.6 minutes and 24.4 ± 4.7 minutes, respectively. the mean surgery times for the first and second groups were 17.9 ± 3.9 minutes and 18.4 ± 3.5 minutes, respectively. the patients’ demographic features are shown in table 1. insignificant haemodynamic changes were observed preoperatively, every five minutes intraoperatively and postoperatively between the two groups for both indirect blood pressure and heart rate [figures 1 and 2]. there were significant pacu behavioural differences between the two groups. the ketaminehaloperidol group yielded more sleepy, calm patients. in contrast, the ketamine group showed more irritability, inconsolable crying, and disorientation [table 2]. there was a significant difference in vas. the mean was 3.8 for the ketamine group and 2.1 for the ketamine-haloperidol group (p <0.001). the mean pacu stay duration for the ketamine group was 143.6 ± 12.9 minutes. for the table 1: pertinent characteristics of the study subjects ketamine (n = 270) ketamine and haloperidol (n = 267) p value age 10.69 ± 2.3 10.98 ± 2.8 0.19 weight 34.9 ± 11.3 36.2 ± 9.4 0.148 anaesthesia time 23.8 ± 5.6 24.4 ± 4.7 0.1795 surgical time (minutes) 17.9 ± 3.9 18.4 ± 3.5 0.1186 sex (m/f) 202/68 184/83 0.128 mostafa a. m. amr, tarek shams and hamid al-wadani brief communication | 259 ketamine-halperidol group it was 56.4 ± 8.7 minutes (p = 0.000). a telephone follow-up was attempted in all cases, and was successful in 434 patients (80.8%). in the haloperidol group, three patients (1.1%) experienced extrapyramidal side effects in the form of a dystonic reaction. in the ketamine group,11 4.07% of patients reported nightmares. two could not see properly and one complained of the room spinning in the postoperative weeks. in the ketamine-haloperidol group, only two (0.75%) patients reported difficulties—one of them reported crying and another reported having nightmares (p 0.0126). discussion kalisvaart et al. reported that haloperidol prophylaxis significantly reduced the severity and duration of delirium and facilitated a rapid discharge from hospital.28 in a retrospective cohort study, milbrandt et al.29 reported that haloperidol use was associated with a decreased mortality rate in mechanically ventilated patients.30 as a result, the burden of postoperative delirium on the patients and caregivers was less, as was the number of days patients stayed in the intensive care unit (icu). in this study, we found that preoperative administration of haloperidol decreased the incidence of postoperative delirium from 6.3% to 1.9% in a sample of children undergoing minor surgery in mansoura, egypt, which is congruent with earlier work conducted in elderly adults.11 moreover, haloperidol prophylaxis was found to be better than other medications used in previous paediatric practice. midazolam is often combined with small doses of ketamine for sedation during local anaesthesia because it attenuates the cardiostimulatory response of ketamine and prevents unpleasant emergence reactions.31 unfortunately, when small doses of ketamine are administered in combination with midazolam, patients may still become confused, disoriented, and experience vivid dreaming or blurred vision during the operation.32,33 table 2: observations of child behaviour in the recovery room. feature ketamine (n = 270) n (%) ketamine and haloperidol (n = 267) n (%) p sleeping 175 (64.8) 234 (87.6) 0.004** awake, calm 41 (15.2) 17 (6.4) 0.002** irritable, crying 21 (7.8) 6 (2.2) 0.004** inconsolable crying 16 (5.9) 5 (1.9) 0.016* (severe restlessness) disorientation 17 (6.3) 5 (1.9) 0.01** p = p value; * = significant (p ≤0.05); ** = highly significant (p ≤0.01). figure 1: mean blood pressure in the studied groups. does haloperidol prophylaxis reduce ketamine-induced emergence delirium in children? 260 | squ medical journal, may 2013, volume 13, issue 2 extrapyramidal symptoms, hypotension, altered cardiac conduction, and sedation are side effects associated with haloperidol and are dose-dependent; hence, it is advised that low doses of haloperidol are given for short periods of time, especially for elderly patients. in our study, it was administered iv by a bolus injection (0.5 mg), followed by a continuous infusion (at a rate of 0.1 mg/hour) for 12 hours. the aim of the bolus injection was to facilitate the patient reaching a therapeutic blood level rapidly once the drug was started. the bolus dose was chosen according to the suggested starting dose for the treatment of delirium in elderly patients.34 in critical children, haloperidol has to be given by iv, but continuous iv is associated with a more stable plasma level.35,36 in contrast to other studies, we used prophylactic haloperidol for a much shorter period of time in order to limit the icu stay (143.6 ± 12.9 minutes; for the ketamine-haloperidol group the stay was 56.4 ± 8.7 minutes) and it decreased the incidence, course, and complications of early postoperative delirium.28,35 in our study, the use of haloperidol had a positive effect in reducing the duration of the pacu stay (143.6 ± 12.9 minutes for the ketamine group and 56.4 ± 8.7 minutes for the ketaminehaloperidol group). honkaniemi et al. reported that the use of 5 mg of haloperidol in patients with migraines decreased vas values. the current study also showed that the vas was less in the ketamine-haloperidol group as compared to the ketamine group, as evidenced by more patients being able to remain sleepy and calm.37 generally, low doses of haloperidol have been adequate in eliminating, or significantly reducing, the ed associated with ketamine. it is our recommendation that practitioners using ketamine have haloperidol readily available. there are three limitations to the study. first, our study was conducted only in one faculty hospital; thus, we are not able to generalise our findings to all of egypt. secondly, only children undergoing minor surgery were recruited. thirdly, risk factors that could possible modify our results, such as the temperaments of the children, were not assessed. conclusion the administration of haloperidol greatly decreased the incidence of postoperative ed in a sample of children undergoing minor surgery. this work provides great hope of decreasing and even preventing delirium in hospitalised, nonsurgical patients. limited resources and lack of well qualified nursing staff magnify the benefit of pharmacological approaches to delirium prevention in developing countries. it is our recommendation that haloperidol should be available for those children who are delirious from the use of ketamine. figure 2: heart rate in the studied groups. mostafa a. m. amr, tarek shams and hamid al-wadani brief communication | 261 references 1. gilger ma, spearman rs, dietrich cl, spearman g, wilsey mj, zayat mn. safety and effectiveness of ketamine as a sedative agent for pediatric gi endoscopy. gastrointest endosc 2004; 59:659–63. 2. kirberg a, sagredo r, montalva g, flores e. ketamine for pediatric endoscopic procedures and as a sedation complement for adult patients. gastrointest endosc 2005; 61:501–2. 3. durieux me. inhibition by ketamine of muscarinic acetylcholine receptor function. anaesth analg 1995; 81:57–62. 4. bishop ra, litch ja, stanton jm. ketamine anesthesia at high altitude. high alt med biol 2000; 1:111–14. 5. wells l, rasch d. emergence ‘delirium’ after sevoflurane anesthesia: a paranoid delusion? anesth analg 1999; 88:1308–10. 6. uezono s, goto t, terui k, ichinose f, ishguro y, nakata y, et al. emergence agitation after sevoflurane versus propofol in pediatric patients. anesth analg 2000; 91:563–6. 7. white pf, way wl, trevor aj. ketamine – its pharmacology and therapeutic uses. anesthesiology 1982; 56:119–36. 8. cartwright pd, pingel sm. midazolam and diazepam in ketamine anaesthesia. anaesthesia 1984; 39:439– 42. 9. wathen je, roback mg, mackenzie t, bothner jp. does midazolam alter the clinical effects of intravenous ketamine sedation in children? a double-blind, randomized, controlled, emergency department trial. ann emerg med 2000; 36:579–88. 10. sherwin ts, green sm, khan a, chapman ds, dannenberg b. does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? a randomized, double blind, placebo-controlled trial. ann emerg med 2000; 35:229–38. 11. campbell n, boustani ma, ayub a, fox gc, munger sl, ott c, et al. pharmacological management of delirium in hospitalized adults—a systematic evidence review. j gen intern med 2009; 24:848–53. 12. schrader sl, wellik ke, demaerschalk bm, caselli rj, woodruff bk, wingerchuk dm. adjunctive haloperidol prophylaxis reduces postoperative delirium severity and duration in at-risk elderly patients. neurologist 2008; 14:134–7. 13. atlas gm, milles m. haloperidol for the treatment of ketamine-induced emergence delirium. j anaesthiol clin pharmacol 2007; 23:65–7. 14. hatherill s, flisher aj, nassen r. delirium among children and adolescents in an urban sub-saharan african setting. j psychosom res 2010; 69:187–92. 15. schieveld jnm, leentjens afg. delirium in severely ill young children in the pediatric intensive care unit. j am acad child adolesc psychiatry 2005; 44:392–4. 16. brown rl, henke a, greenhalgh dg, warden gd. the use of haloperidol in the agitated, critically ill pediatric patient with burns. j burn care rehabil 1996; 17:34–8. 17. harrison am, lugo ra, lee we, appachi e, bourdakos d, davis sj, et al. the use of haloperidol in agitated, critically ill children. clin pediatr 2002; 41:51–4. 18. tesar ge, murray gb, cassem nh. use of high-dose intravenous haloperidol in the treatment of agitated cardiac patients. j clin psychopharmacol 1985; 5:344–7. 19. adams f. emergency intravenous sedation of the delirious, medically ill patient. j clin psychiatry 1988; 49:22–6. 20. schieveld jn, leroy pl, van os j, nicolai j, vos gd, leentjens af. pediatric delirium in critical illness: phenomenology, clinical correlates and treatment response in 40 cases in the pediatric intensive care unit. intensive care med 2007; 33:1033–40. 21. hassaballa ha, balk ra. torsade de pointes associated with the administration of intravenous haloperidol. amer j therap 2003; 10:58–60. 22. burke c, fulda gj, castellano j. neuroloeptic malignant syndrome in a trauma patient. j trauma 1995; 39:796–8. 23. kudo s, ishizaki t. pharmacokinetics of haloperidol. clin pharmacokinet 1999; 37:425–38. 24. clements ja, nimmo ws, grant is. bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. j pharm sci 1982; 71:539–42. 25. tollefson gd, beasley cm, ramura rn, tran pv, potvin jh. blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. am j psy 1997; 154:1248–54. 26. wewers me, lowe nk. a critical review of visual analogue scales in the measurement of clinical phenomena. res nurs health 1990; 13:227–36. 27. cole jw, murray dj, mcallister d, hirshberg ge. emergence behavior in children: defining the incidence of excitement and agitation following anaesthesia. pediatr anesth 2002; 12:442–7. 28. kalisvaart kj, de jonghe jf, bogaards mj, vreeswijk r, egberts tc, burger bj, et al. haloperidol prophylaxis for elderly hip surgery patients at risk for delirium: a randomized placebo-controlled study. j am geriatr soc 2005; 53:1658–66. 29. milbrandt eb, kersten a, kong l, weissfeld la, clermont g, fink mp, et al. haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. crit care med 2005; 33:226–9. 30. motamed f, aminpour y, hashemian h, soltani does haloperidol prophylaxis reduce ketamine-induced emergence delirium in children? 262 | squ medical journal, may 2013, volume 13, issue 2 ae, najafi m, farahmand f. midazolam-ketamine combination for moderate sedation in upper gi endoscopy. j pediatr gastroenterol nutr 2012; 54:422–6. 31. white pf. comparative evaluation of intravenous agents for rapid sequence induction: thiopental, ketamine, and midazolam. anesthesiology 1982; 57:279–84. 32. white pf, vasconez lo, mathes sa, way wl, wender la. comparison of midazolam and diazepam for sedation during plastic surgery. j plast reconstr surg 1988; 81:703–12. 33. monk tg, rater mj, white pf. comparison of alfentanil and ketamine infusions in combination with midazolam for outpatient lithotripsy. anesthesiology 1991; 74:1023–8. 34. riker rr, fraser gl, cox pm. continuous infusion of haloperidol controls agitation in critically ill patients. crit care med 1994; 22:89–97. 35. seneff mg, mathews ra. use of haloperidol infusions to control delirium in critically ill adults. ann pharmacother 1995; 29:690–3. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century squ med j, may 2012, vol. 12, iss. 2, pp. , epub. 9th apr 2012 submitted 26th nov 11 revision req. 31st jan 12, revision recd. 8th feb 12 accepted 12th feb vitamin d is not really a vitamin. 1 vitamin d (which includes both d2 and d3) behaves like a hormone and carries out essential biological functions through endocrine, paracrine, and intracrine mechanisms.2 vitamin d2 (ergocalciferol) is a synthetic product produced by irradiation of plant sterols, while vitamin d3 (cholecalciferol) is a prohormone made in the skin in response to the action of ultraviolet (uv) b irradiation on a cholesterol precursor, 7-dehydrocholesterol.1,3 when the skin absorbs uvb radiation, the precursor is converted to previtamin d3, which undergoes a thermally induced transformation to vitamin d3 [figure 1].3 a small part of vitamin d3 comes from dietary intake, especially fatty fish (e.g. herring, mackerel, sardines, tuna, salmon), eggs, and fortified foods. 4,5 thus, the major source of vitamin d is sunlight exposure. however, variables such as time of day, season, latitude, clothing, skin pigmentation, and age affect the amount of vitamin d converted in the skin.3 department of community medicine & public health, tanta university, egypt, and department of health planning, ministry of health, muscat, oman. e-mail: drmoness@gmail.com نقص فيتامني )د( هذا املرض املتوّطن الّسّري مل يُعد خفّيا موؤن�س م�سطفى ال�س�ستاوي امللخ�ص: وّفر العلماء حديثًا جمموعة قوية من الرباهني التي قّدمت معلومات جديدة عن التاأثري الوقائي لفيتامني »د« على جمموعة وا�سعة من احلاالت املر�سية. وت�سري هذه االأدلة اإىل اأّن فيتامني »د« هو اأكرث بكثري من جمرد مادة غذائية الزمة ل�سّحة العظام بل هو هرمون اأ�سا�سي �رضوري لتنظيم عدد كبري من الوظائف الف�سيولوجية. اإن وجود تركيز كايف من 25 -هيدروك�سي فيتامني »د« يف م�سل الدم هو اأمر �رضوري لتح�سني �سّحة االإن�سان. ن�ستعر�س يف هذا املقال احلالة الراهنة للمعارف العلمية حول و�سع فيتامني »د« يف جميع اأنحاء العامل، ون�سري اإىل مقاالت ُن�رضت حديثا والتي تناق�س بع�سا من اجلوانب املهمة العامة لفيتامني »د«، مبا يف ذلك امل�سادر، الفوائد، واحلاجة اليومية لفيتامني »د« الغذائية ونق�س تناوله خ�سو�سا يف فرتة احلمل. وتوفر الدرا�سة اأدلة على اأن نق�س فيتامني »د« ميكن اأن يكون عبئا كبريا على ال�سحة العامة يف اأجزاء كثرية من العامل، ومعظمها ب�سبب احلرمان من التعر�س الأ�سعة ال�سم�س. كما نناق�س اأي�سا اجلدل الدائر حول الرتكيز االأمثل ملادة 25 -هيدروك�سي فيتامني »د« يف م�سل الدم، وا�ستطالع وجهات النظر املختلفة ب�ساأن الكمية املطلوبة من مكمالت فيتامني »د« لتحقيق هذا الرتكيز واحلفاظ عليه. مفتاح الكلمات: نق�س فيتامني »د«، 52-هيدروك�سي فيتامني »د«، فيتامني »د2« )اإرجوكال�سيفرول(، فيتامني »د3« )كولكال�سيفرول(،اأ�سعة ال�سم�س، ُعمان. abstract: recently, scientists have generated a strong body of evidence providing new information about the preventive effect of vitamin d on a broad range of disorders. this evidence suggests that vitamin d is much more than a nutrient needed for bone health; it is an essential hormone required for regulation of a large number of physiological functions. sufficient concentration of serum 25-hydroxyvitamin d is essential for optimising human health. this article reviews the present state-of-the-art knowledge about vitamin d’s status worldwide and refers to recent articles discussing some of the general background of vitamin d, including sources, benefits, deficiencies, and dietary requirements, especially in pregnancy. they offer evidence that vitamin d deficiency could be a major public health burden in many parts of the world, mostly because of sun deprivation. the article also discusses the debate about optimal concentration of circulating serum 25-hydroxyvitamin d, and explores different views on the amount of vitamin d supplementation required to achieve and maintain this concentration. keywords: vitamin d deficiency; 25-hydroxyvitamin d; vitamin d2 (ergocalciferol); vitamin d3 (cholecalciferol); sunlight; oman. review vitamin d deficiency this clandestine endemic disease is veiled no more moeness moustafa alshishtawy moeness moustafa alshishtawy review | 141 kidney to 1,25-dihydroxyvitamin d (1,25(oh)2d), which circulates in the blood as a hormone to regulate mineral and skeletal homeostasis [figure 1].3 in addition to the kidney’s endocrine production of circulating 1,25(oh)2d, vitamin d vitamin d, whether absorbed through the skin or consumed, is metabolised in the liver by 25-hydroxylase to 25-hydroxyvitamin d (25(oh) d), a prehormone form.1,3 in its endocrine action, 25(oh)d is converted by hydroxylation in the figure 1: production, metabolism and functions of vitamin d vitamin d deficiency this clandestine endemic disease is veiled no more 142 | squ medical journal, may 2012, volume 12, issue 2 an adequate intake of dairy products.19 in oman, according to the 2004 ministry of health survey, out of 298 non-pregnant women of child bearing age, 21.4% were found to be vitamin d deficient (<27.0 nmol/l).20 almost half of the women included in the survey (47%) had serum 25(oh)d concentrations below 37.5 nmol/l, while only 10% of them had concentrations above 75 nmol/l.21 a more recent study tested serum 25(oh) d concentrations in 41 apparently healthy omani women of childbearing age. the study indicated that all women had serum 25(oh)d concentrations of <50 nmol/l.22 another study examined serum 25(oh)d concentrations in 103 healthy omani pregnant women on their first antenatal visit to the hospital. the study revealed that 33% of cases had ‘at risk’ concentrations (25(oh)d) <25 nmol/l), and that 65% had serum concentrations of 25(oh) d between 25 and 50 nmol/l, and not one case was found in the optimal range (25(oh)d >75 nmol/l).23 similarly, vitamin d deficiency was found to be highly prevalent in the united arab emirates (uae). studying the efficacy of daily and monthly supplementation with vitamin d2 in lactating and nulliparous emirati women, the results revealed that most women had vitamin d deficiency (25(oh)d ≤ 50 nmol/l at study entry).24 also, dawodu et al. investigated the effect of sun exposure at recommended levels on the vitamin d status of eight healthy arab women of childbearing age working in the al ain district of the uae. serum 25-hydroxyvitamin d concentrations were measured preand post-intervention. although vitamin d concentrations remained suboptimal, median serum 25(oh)d concentrations were significantly higher post-intervention (23.0 nmol/l) than pre-intervention (17.6 nmol/l).25 a very recent study done by anouti et al. in 2011 investigated a random sample of 208 young emirati university students in abu dhabi, 138 females and 70 males. the mean serum 25(oh)d concentration for female students tested in april was 31.3 ± 12.3 nmol/l, while in october, it was 20.9 ± 14.9 nmol/l. 26 this difference was statistically significant, suggesting that seasonal variation plays an important role in vitamin d status. female students scored significantly higher than males on the sun avoidance inventory (sai), indicating that females tend to avoid sun exposure to a greater extent than also acts through a paracrine-intracrine pathway. in this system, 25(oh)d is converted to 1,25(oh)2d intracellularly by 25(oh)d 1-a-hydroxylases in a variety of end-organ tissues such as the prostate gland, breasts, colon, lungs, and keratinocytes [figure 1].6 the conversion of 25(oh)d to 1,25(oh)2d in these tissues appears not to be controlled by calcium, but rather to be directly linked to the substrate availability of 25(oh)d. that is a complex endocrine reaction which begins in the largest organ of the body, the skin.2 in contrast to 1,25(oh)2d, which has a short half-life of ~4–15 hours, the serum concentration of 25(oh)d has a fairly long circulating half-life of ~15 days,7 and is considered the best indicator of vitamin d status that can be measured.8 serum 25(oh)d reflects vitamin d produced cutaneously and also that obtained from food and supplements.7–9 vitamin d status around the world vitamin d status has been studied on all continents and in most countries throughout the world. in total, approximately 5,060 epidemiological studies have been done according to a pubmed search conducted in february 2012. these studies revealed that vitamin d deficiency was prevalent across all age-groups, geographic regions, and seasons.10–12 despite ample sunshine, vitamin d deficiency is very common in the middle east (15°–36°n) and african (35°s–37°n) countries.13,14 the first study to reveal low vitamin d concentrations in people of the middle east region was conducted by woodhouse and norton in 1982 among ethnic saudi arabians.15 their results were confirmed in 1983, when sedrani et al. recorded a mean 25(oh)d concentration ranging between 10–30 nmol/l (2.496 nmol/l being equivalent to 1 ng/ ml) among saudi university students and the elderly.16,17 a more recent study that was conducted in the eastern province of saudi arabia revealed vitamin d deficiency (25(oh)d of ≤50 nmol/l) among 28–37% of 200 randomly selected healthy men.18 another study, also conducted in the eastern regions of saudi arabia, showed low serum 25(oh) d concentrations among both males and females (25.25 nmol/l and 24.75 nmol/l, respectively) despite the fact that >65% of participants had adequate exposure to sunlight and >90% reported moeness moustafa alshishtawy review | 143 elsewhere, vitamin d deficiency was found to be common among pregnant women.35 most clinicians believe that vitamin d deficiency has been essentially eliminated in the usa, but recent data indicate that the diagnosis exists in epidemic proportions.36 data from the national health and nutrition examination survey (nhanes) showed that the number of persons with 25(oh)d concentrations below 75 nmol/l nearly doubled between the 1994 and 2004 surveys, each of which extended for several years each.37 data from the nhanes iii 2004 survey showed that 65–75% of the population had 25(oh) d concentrations of <50 nmol/l.12 less than 3% of african-american mothers were vitamin d sufficient, and the mean cord blood concentrations of 25(oh)d in their infants was very low (25 ± 15 nmol/l).37,38 more recent research from the usa also studied vitamin d concentrations in different ethnic groups, and included 154 african-american, 194 hispanic, and 146 caucasian women at <14 weeks of gestation. in logistic regression models, race was the most important risk factor for vitamin d deficiency or insufficiency. african-american women and hispanic women were more likely to have vitamin d insufficiency and deficiency than caucasian women.39 also, bodnar et al. conducted a study to assess, by race and season, the vitamin d status of pregnant women and their neonates residing in pittsburgh. the serum 25(oh)d of 200 white and 200 black pregnant women was measured throughout gestation (4–21 weeks), previous to delivery, and in the cord blood of their neonates. the results suggested that black and white pregnant women and their neonates residing in the northern usa were at high risk of vitamin d insufficiency.40 thus, it seems that the world is facing today what is, in fact, a new endemic disease that was, until recently, totally veiled. the actual percentage of vitamin-d-deficient people seems to be far greater than reported, so identifying the reasons for the dramatic increase in vitamin d insufficiency is not an easy task. vitamin d deficiency causes and questions declines in 25(oh)d concentrations are usually the result of dietary inadequacy, impaired absorption and use, increased requirements, or increased males, a possible explanation of the lower vitamin d status.26 in qatar, the mean overall vitamin d concentration among health care professionals working at hamad medical corporation in doha, was found to be 29.3 nmol/l. vitamin d concentration was lower in females (25.8 nmol/l) than in males (34.3 nmol/l). a total of 97% of all participants had a mean concentration <75 nmol/l, while 87% had a mean concentration of <50 nmol/l.27 in another study, vitamin d deficiency was prevalent (68.8%) among young qatari children below 16 years of age, mostly in the age group 11– 16 years (61.6%). girls were affected more than boys (51.4% versus 48.6%).28 even in north african countries there is a high prevalence of low vitamin d status; 25(oh)d is in the rachitic range. veiled women, or women wearing purdahs (cloth that covers the whole of the body), have a lower vitamin d status than their peers within the same country.29 studies in turkey and jordan showed also a strong relationship with clothing.30,31 serum 25(oh)d levels were highest in women who wore western clothing, decreasing in traditional women wearing a hijab (veil that covers the whole head except the face), and the lowest levels were measured in completely veiled women who wore a niqab (additional veil covering the whole face, or all of it except the eyes). men in these countries have higher concentrations than women. in iran, a population study that included 1,210 men and women between 20 and 69 years old, showed that the mean serum 25(oh)d was 20.6 nmol/l.32 in india, among 20 pregnant women in delivery at sant parmanand hospital in delhi, more than 75% were deficient in 25(oh)d (<50 nmol/l).33 serum 25(oh)d concentrations are not only suboptimal in eastern or southern countries or specific risk groups, but also in adults in many western countries.4 for instance, in the netherlands, a study that assessed the prevalence of vitamin d deficiency in 358 pregnant women of several ethnic backgrounds living in the hague, recorded that mean serum 25(oh)d concentrations in turkish women were 15.2 ± 12.1 nmol/l; in moroccan women 20.1 ± 13.5 nmol/l, and in other non-western women 26.3 ± 25.9 nmol/l. these concentrations were significantly (p ≤0.001) lower than those in the western women living in that country (52.7 ± 21.6 nmol/l).34 in the uk and vitamin d deficiency this clandestine endemic disease is veiled no more 144 | squ medical journal, may 2012, volume 12, issue 2 to maintain blood calcium concentrations.1 moreover, sufficient concentrations of vitamin d may be important in reducing the occurrence of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes, and some cancers.46–48,10 adequate vitamin d may also allow for a normal innate immune response to pathogens, improve cardiovascular function and mortality and increase insulin responsiveness1,49,50 a recent work by grant aimed to estimate the reduction in mortality rates for six geopolitical regions of the world. it was based on an interpretation of the journal literature relating to the effects of solar uvb and vitamin d in reducing the risk of vitamin d-sensitive diseases. six major diseases that account for more than half of global mortality rates (i.e. cardiovascular disease (cvd), cancer, respiratory infections, respiratory diseases, tuberculosis and diabetes mellitus) were studied in addition to vitamin d-sensitive diseases and conditions that account for 2–3% of global mortality rates such as alzheimer’s disease, falls, meningitis, parkinson’s disease, maternal sepsis, maternal hypertension (pre-eclampsia) and multiple sclerosis. the study showed that increasing serum 25(oh) d concentrations from 54 to 110 nmol/l would reduce the vitamin d-sensitive disease mortality rates by an estimated 20%. the reduction in allcause mortality rates ranged from 7.6% for african females to 17.3% for european females. reductions for males were on average 0.6% lower than for females. the estimated increase in life expectancy was 2 years for all six regions.51 why should we be concerned about vitamin d deficiency during pregnancy? generally, there are many important health benefits from vitamin d for both mother and fetus. however, new clinical research results over the past decade indicate that appropriate intakes of vitamin d may provide greater health benefits than previously thought, benefits that include not only improved bone health, but other effects as well.2,52,53 recent data suggest that 1,25(oh)2d aids implantation and maintains normal pregnancy. it also supports fetal growth through delivery of calcium, controls secretion of multiple placental hormones, and limits excretion.9 no doubt, the major cause of vitamin d deficiency is inadequate exposure to sunlight.41–44 the upward trend in body mass index is also accused of causing vitamin d deficiency, and obesity is now added as a major contributory factor to the increasing prevalence of vitamin d insufficiency.3 genetic predisposition may also have an effect on vitamin d blood concentrations and it has to be accounted for in the design of preventive measures against vitamin d deficiency.1,45 a century since the discovery of its dual origin, many questions have been raised and remain unanswered about vitamin d’s concentrations in human beings. for example, why is vitamin d so important? why should we be concerned about vitamin d deficiency during pregnancy? what concentrations of the vitamin are optimal in adults and children? do these optimal concentrations vary for the prevention of various disorders or in differing human populations? what amount of supplementation or sunlight exposure is needed to achieve and maintain these concentrations? and how much vitamin d can we really take safely? luckily, in the last few years, numerous clinical studies, including crucial randomised controlled trials (rcts) of vitamin d supplementation were conducted in the search for answers to the above mentioned questions and more. successful completion of experimental trials was essential to obtain valuable information on the effect of vitamin d in preventing a wide range of disorders, and also for establishing the efficacy and safety of vitamin d supplementation. why is vitamin d so important? vitamin d is much more than a nutrient needed for bone health; it is an essential hormone required for the regulation of a large number of physiological functions. its receptors were found to be present in nearly every tissue and cell in the body. that is why sufficient concentrations of serum 25(oh)d are essential for optimal functioning of these tissues and cells.3 the major function of vitamin d compounds is to enhance the active absorption of ingested calcium (and phosphate). this assists in building bone at younger ages and ensures that, despite obligatory urinary losses, bone does not need to be desorbed moeness moustafa alshishtawy review | 145 literature. the panel reached substantial agreement about the need for vitamin d supplementation in adult patients with, or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer. a target range of at least 75 to 100 nmol/l was recommended.53 however, one study of a convenience sample of 93 healthy young adults recruited from the university of hawaii and a honolulu skateboard shop questioned the frequently suggested serum 25(oh)d sufficiency cutoff of 75 nmol/l. the investigators recruited these prototypic “surfer dudes” (mean age: 24 years; mean body mass index [bmi], in kg/m2: 23.6). on the basis of a self-reported minimum outdoor sun exposure of 15 hours (mean: 29 hours) per week during the preceding 3 months; 40% reported never using sunscreen, and the group overall reported an average of 22.4 hours per week of unprotected sun exposure. all were clinically tanned. nevertheless, the group’s mean 25(oh) d concentration was 79 nmol/l, and 51% had a concentration below the suggested 75 nmol/l cutoff for sufficiency. the study group was multiracial, but even among the 37 white subjects, the mean value was only 92.8 nmol/l and the highest value was 155 nmol/l.63 on the other hand, luxwolda et al. measured the sum of serum 25-hydroxyvitamin d2 and d3 (25(oh)d) concentrations of thirty-five pastoral maasai (mean age: 34 ± 10 years, 43% male) and twenty-five hadzabe hunter-gatherers (mean age: 35 ± 12 years, 84% male) living in tanzania. they had skin type vi, wore a moderate degree of clothing, spent the majority of the day outdoors, but avoided direct exposure to sunlight when possible. the mean serum 25(oh)d concentrations of maasai and hadzabe were 119 (range 58–167) and 109 (range 71–171) nmol/l, respectively. these concentrations were not related to age, sex, or bmi.64 these recent data suggest that a public health goal of ≥75 nmol/l, or even ≥100 nmol/l, for the entire population can be achieved by sun exposure. how much vitamin d is required to optimise bone and global health? in 2011, the iom released revised recommendations for the daily intake of vitamin d based on the body’s need for skeletal health.9 the recommended dietary the production of proinflammatory cytokines.35,54 maternal nutritional vitamin d status has a good effect on childhood bone mineral accrual and is important also for fetal “imprinting” that may affect neurodevelopment, immune function, and chronic disease susceptibility later in life, as well as soon after birth.55,56 also, maternal vitamin d insufficiency during pregnancy is significantly associated with offspring language impairment. maternal vitamin d supplementation during pregnancy may reduce the risk of developmental language difficulties among children.57 meanwhile, substandard vitamin d intake during pregnancy may lead to decreased birth weight.58 moreover, maternal vitamin d deficiency in early pregnancy may be an independent risk factor for preeclampsia59 and may be associated with increased odds of primary caesarean section.60 merewood et al. found that 28% of women with serum 25(oh)d concentrations less than or equal to 37.5 nmol/l had a caesarean section, compared with only 14% of women with higher 25(oh)d concentrations (≥37.5 nmol/l).60 what is the “normal” circulating 25(oh)d concentration in human beings? vitamin d deficiency has been historically defined and recently recommended by the institute of medicine (iom), usa, as a 25(oh)d concentration of less than 50 nmol/l. vitamin d insufficiency has been defined as a 25(oh)d concentration of 50– 75 nmol/l.61 vitamin d deficiency can be further classified as mild (25–50 nmol/l), moderate (12.5– 25.0 nmol/l), and severe (<12.5 nmol/l).5 however, the preponderance of evidence points to optimal serum 25(oh)d concentrations of at least 80 nmol/l to maximise vitamin d’s effect on calcium, bone, and muscle metabolism.3,50,62 based on a quick review of the literature for vitamin d during pregnancy, as well as a more detailed review for other diseases, grant found that serum 25(oh)d concentrations above 75–100 nmol/l are required for good pregnancy outcomes, fetal health, and optimal health in general.35 similarly, an international expert panel formulated recommendations on vitamin d for clinical practice, taking into consideration the best recent evidence available based on published vitamin d deficiency this clandestine endemic disease is veiled no more 146 | squ medical journal, may 2012, volume 12, issue 2 received 400, 2,000 or 4,000 iu vitamin d3 per day until delivery. the relative risk (rr) for achieving ≥80 nmol/l within one month of delivery was significantly different between 2,000 and 400 iu. circulating 25(oh)d had a direct influence on circulating 1,25(oh)2 d concentrations throughout pregnancy with maximal production of 1,25(oh)2 d in all strata in the 4,000 iu group. there were no differences between groups on any safety measure. not a single adverse event was attributed to vitamin d supplementation or circulating 25(oh) d concentrations.69 another study by hollis was conducted in columbia, south carolina, usa. the study included diverse groups of women who were randomised to 2,000 or 4,000 iu vitamin d3/ day irrespective of baseline 25(oh)d at <16 weeks’ gestation. the aim was to confirm the nih/nichd study findings and to prove that no adverse events are associated with vitamin d supplementation.70 both of these studies proved that vitamin d supplementation with 4,000 iu vitamin d/day for pregnant women was safe and effective in achieving vitamin d sufficiency in a racially diverse group. in both studies, higher maternal circulating 25(oh)d was associated with a lower risk of co-morbidities of pregnancy. what are the possible effects on health of high concentrations of vitamin d? according to heaney, an intake of 1,000 iu vitamin d/day results in an increase of approximately 25 nmol/l in 25(oh)d, although individual responses vary.71 accordingly, most international authorities consider a vitamin d intake of 2,000 iu/ day as absolutely safe, although literature review revealed that even doses of up to 10,000 iu/day supplemented over several months did not lead to any adverse events.52 in 2011, the iom re-evaluated the potential for high intakes of vitamin d to produce adverse effects and set a safe tolerable upper intake level (ul) for vitamin d of 4,000 iu/day for ages 9 and older and lower for infants (0–6 months: 1,000 iu/day; 6–12 months: 1500 iu/day) and younger children (1–3 years: 2,500 iu/day; 4–8 years: 3,000 iu/day).9 according to ross et al., the starting point for the announced ul for vitamin d was 10,000 iu/day. allowances (rdas) for vitamin d are 600 iu/d for ages 1–70 years and 800 iu/d for ages 71 years and older, corresponding to a serum 25-hydroxyvitamin d concentration of at least 50 nmol/l. rdas for vitamin d were based on conditions of minimal sun exposure due to wide variability in vitamin d synthesis from uv light and the risks of skin cancer.65 the recommendations of the american academy of pediatrics (aap) are 400 iu/day of vitamin d for exclusively and partially breastfed infants shortly after birth, to be continued until they are weaned and consume ≥1,000 ml/day of vitamin d-fortified formula or whole milk. similarly, all non-breastfed infants ingesting <1,000 ml/day of vitamin d-fortified formula or milk should receive a vitamin d supplement of 400 iu/day. the aap also recommends that older children and adolescents who do not obtain 400 iu/day through vitamin d-fortified milk and foods should take a 400 iu vitamin d supplement daily.66 however, this latter recommendation, issued in november 2008, is less than the food and nutrition board’s vitamin d rda of 600 iu/day for children and adolescents that was issued in november 2010.67 all these recommendations have stimulated considerable debate. many scientists thought that to increase nutritional vitamin d to meaningful concentrations, dietary intakes of ≥2,000 iu/day may be required. in order to calculate the needs of a human body, one should know that sunlight exposure sufficient to result in a mild sunburn for a caucasian adult in a bathing suit raises the serum 25(oh)d to a concentration comparable to that of a person taking 10,000 to 20,000 iu of vitamin d2 orally; which could be the daily requirement for human beings. 68 thus, raising the blood concentration of 25(oh)d consistently above 75 nmol/l may require at least 1,000–2,000 iu/day of supplemental vitamin d.53 higher concentrations of 2,000 iu/day for children 0–1 years, 4,000 iu/ day for children 1–18 years, and 10,000 iu/day for children and adults 19 years and older may be needed to correct vitamin d deficiency.50 to end the debate, bruce hollis et al. have recently conducted a randomised controlled trial, the national institutes of health/national institute of child health & human development (nih/nichd) study, in which women with a singleton pregnancy at 12–16 weeks’ gestation moeness moustafa alshishtawy review | 147 of calculating uv exposure times and clearly indicates that it is impractical to generate a simple nationally uniform message that prescribes minutes of sun exposure to the general population, given the number of variables that need to be taken into consideration.79 in response to potential confusion over mixed messages about the risks and benefits of sun exposure, a collaboration of the cancer council australia, the australian and new zealand bone and mineral society, osteoporosis australia and the australasian college of dermatologists gathered australian experts in melbourne in december 2006, to review the latest evidence on vitamin d and develop a position statement.80 those experts suggested that people should continue to protect themselves from overexposure, especially during peak ultraviolet radiation periods (10 am to 3 pm). for most people, sun protection to prevent skin cancer is required when the uv index is moderate or above (i.e. uv index is 3 or higher). at such times, sensible sun protection behaviour is warranted and is unlikely to put people at risk of vitamin d deficiency. most people probably achieve adequate vitamin d concentrations through the uvb exposure they receive during typical day-to-day outdoor activities. for example, fair skinned people can achieve adequate vitamin d concentrations (>50 nmol/l) in summer by exposing the face, arms and hands or the equivalent area of skin to a few minutes of sunlight on either side of the peak uv periods on most days of the week. in winter, when uv radiation concentrations are less intense, maintenance of vitamin d concentrations may require 2–3 hours of sunlight exposure to the face, arms and hands or equivalent area of skin over a week.80 second, some groups in the community are at increased risk of vitamin d deficiency. they include naturally dark-skinned people, those who cover their skin for religious or cultural reasons, the elderly, infants of vitamin d deficient mothers, and people who are housebound or are in institutional care.80 naturally dark-skinned people (fitzpatrick skin type 5 and 6) are relatively protected from skin cancer by the pigment in their skin; they could therefore safely increase their sun exposure. others on this list should discuss their vitamin d status with their medical practitioner as some might benefit from dietary supplementation with vitamin d.80 given that toxicity is not the appropriate basis for a ul that is intended to reflect long-term chronic intake and to be used for public health purposes, this value was corrected for uncertainty based on chronic disease outcomes and all-cause mortality to 4,000 iu/day.65 however, garland and colleagues pointed out that the supplemental dose, ensuring that 97.5% of the population study achieved a serum 25(oh)d of at least 100 nmol/l, was 9,600 iu/day.72 it should be mentioned here that sunbathing can produce vitamin d doses equivalent to an oral vitamin d intake of up to 20,000 iu/day and in healthy subjects who spent prolonged periods in a sunny environment, measured 25(oh) d concentrations rarely exceed 250 nmol/l, suggesting that this level may be considered a safe upper limit for serum 25(oh)d levels.73–75 furthermore, a benefit-risk assessment of vitamin d supplementation conducted by bischoff-ferrari et al. reported that hypercalcaemia caused by excess vitamin d in generally healthy adults was observed only if daily intake was >100,000 iu or if the 25(oh) d level exceeded 250 nmol/l.76 accordingly, they pointed out that 250 nmol/l should be considered a safe limit, but not as an upper limit to target in clinical practice.53 similarly, hathcock et al., noting the absence of toxicity in clinical trials conducted in healthy adults that used vitamin d doses of ≥10,000 iu, supported the confident selection of this value as the ul.52 conclusion over the past two decades, scientists, clinicians and researchers have generated a strong body of evidence to address the problem of vitamin d deficiency and provide advice for correcting its status among all ages, genders and racial/ethnic groups. many studies, some randomised and some not, have suggested that a population with a higher vitamin d intake would be healthier overall. accordingly, the following can be recommended first, vitamin d can be obtained from production by the skin after brief uv exposure. exposure to bright midday sunlight, rich in uvb wavelengths, is a very efficient way to make vitamin d. unfortunately, the action spectrum for vitamin d photosynthesis is essentially identical to the spectrum that damages dna and causes skin cancer.77,78 the study done by samanek et al. in 2006 illustrates the complexities vitamin d deficiency this clandestine endemic disease is veiled no more 148 | squ medical journal, may 2012, volume 12, issue 2 both the usa and canada mandate the fortification of infant formula with vitamin d: 40–100 iu/100 kcal in the usa, and 40–80 iu/100 kcal in canada.9 sixth, in supplements and fortified foods, vitamin d is available in two forms, d2 (ergocalciferol) and d3 (cholecalciferol), which differ chemically only in their side-chain structure. however, vitamin d3 is approximately 87% more potent in raising and maintaining serum 25(oh)d concentrations and produces 2to 3-fold greater storage of vitamin d than does vitamin d2. 81 accordingly, vitamin d3 should be the preferred treatment option when correcting vitamin d deficiency through supplementation using an intermittent regimen.82,83 however, when given as daily doses, vitamin d2 and d3 seem to have similar effects on 25(oh)d levels. 84 seventh, the use of uvb irradiance may be useful in certain cases. solar uvb radiation with a wavelength of 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin d3, which in turn becomes vitamin d3. 9 however, the most commonly used lamps do a poor job of simulating the uvb light intensity of natural sunlight. the only lamps that come close to the intensity of natural sunlight are “sunlamps”, which are sometimes used to treat psoriasis.85 the moderate use of commercial tanning beds that emit 2–6% uvb radiation is also effective.86,87 eighth, in practice, testing for 25(oh) d is recommended after at least 3 months of supplementation (usually 6–12 months).50 currently, 25(oh)d measurement is reasonable in groups of people at high risk for vitamin d deficiency and in whom a prompt response to optimisation of vitamin d status is expected.61 however, serum 25(oh) d assays are expensive, and the need for universal screening has not yet been proven.3 a c k n o w l e d g m e n t i should particularly like to acknowledge the insights and expert guidance given to me by william b. grant, director of sunlight, nutrition, and health research center (sunarc), san francisco, california, usa. dr. grant was consistently encouraging and supportive and i appreciate very much his efforts in critically reviewing my article and making numerous helpful suggestions. third, some people are at high risk of skin cancer. they include people who have had skin cancer, have received an organ transplant, or are highly sun sensitive. these people need to have more sun protection, and therefore should discuss their vitamin d requirements with their medical practitioner to determine whether dietary supplementation with vitamin d would be preferable to sun exposure.80 fourth, public education should be provided about the safety of vitamin d supplementation. individuals with limited sun exposure need to include reliable sources of vitamin d in their diet or take a supplement to achieve recommended concentrations of intake. needless to say, there is considerable variation in how individuals respond to vitamin d supplementation. the response to treatment varies with season, population, local experience and with the starting concentrations of 25(oh)d. supplementation without baseline 25(oh)d measurement is recommended for darkskinned or veiled subjects not exposed much to the sun; individuals with musculoskeletal health problems; cardiovascular disease; autoimmune diseases and cancer; those over 65 years of age, and institutionalised subjects. in these individuals, a dose of 800 iu/day (the standard dose of most rcts) or its equivalent with an intermittent dosing regimen (i.e. 100,000 iu orally every 3 to 4 months) is recommended.53,72 all adults who are vitamin d deficient should be treated with 50,000 iu of vitamin d once a week for 8 weeks, or its equivalent of 6,000 iu/day of vitamin d, to achieve a blood concentration of 25(oh)d ≥ 75nmol/l, followed by maintenance therapy of 1,500–2,000 iu /day.61 similarly, pietras et al. effectively treated vitamin d deficiency in most patients with 50,000 iu of ergocalciferol weekly for 8 weeks, then continued treatment with 50,000 iu of ergocalciferol every other week for up to 6 years to prevent recurrent vitamin d deficiency.17 fifth, compulsory fortification of some foods (such as milk, infant formula, margarine, and other food products) with vitamin d should be seriously considered. fortified foods can provide sufficient amounts of vitamin d in the diet. they provide most of the vitamin d in the american diet, and almost all of the usa milk supply is voluntarily fortified with 100 iu/cup. in canada, milk is fortified by law with 35–40 iu/100 ml, as is margarine at ≥530 iu/100 g. moeness moustafa alshishtawy review | 149 17. pietras sm, obayan bk, cai mh, holick mf. vitamin d2 treatment for vitamin d deficiency and insufficiency for up to 6 years. arch intern med 2009; 169:1806–8. 18. sadat-ali m, alelq a, al-turki h, al-mulhim f, alali a. vitamin d levels in healthy men in eastern saudi arabia. ann saudi med 2009; 29:378–82. 19. elsammak my, al-wossaibi aa, al-howeish a, alsaeed j. high prevalence of vitamin d deficiency in the sunny eastern region of saudi arabia: a hospitalbased study. east mediterr health j 2011; 17:317–22. 20. ministry of health, oman. micronutrients testing, community health & disease surveillance newsletter (2008). muscat: ministry of health, 2008. pp. 12–13. 21. alasfoor d, kaur m, al kiyumi s, al busaidy s, suleiman aj, ruth l, et al. vitamin d deficiency: a public health problem in oman. from: www. m i c ro nu t r i e nt fo r u m . o rg / m e e t i n g 2 0 0 9 / p d fs / poster%20presentations/3_thursday/dkb/th66_ kaur.pdf accessed: apr 2010. 22. al-kindi mk. vitamin d status in healthy omani women of childbearing age: study of female staff at the royal hospital, muscat, oman. squ med j 2011; 11:56–61. 23. al kalbani m, elshafie o, rawahi m, al mamari a, al zakwani a, woodhouse n. vitamin d status in pregnant omanis: a disturbingly high proportion of patients with low vitamin d stores. squ med j 2011; 11:52–5. 24. saadi hf, dawodu a, afandi bo, zayed r, benedict s, nagelkerke n. efficacy of daily and monthly high dose calciferol in vitamin d deficient nulliparous and lactating women. am j clin nutr 2007; 85:1565–71. 25. dawodu a, kochiyil j, altaye m. pilot study of sunlight exposure and vitamin d status in arab women of childbearing age. east mediterr health j 2011; 17:570–74. 26. anouti fai, thomas j, abdel-wareth l, rajah j, grant wb, haq a. vitamin d deficiency and sun avoidance among university students at abu dhabi, united arab emirates. dermatoendocrinol 2011; 3:1–5. 27. mahdy s, al-emadi sa, khanjar ia, hammoudeh mm, sarakbi ha, siam am, et al. vitamin d status in health care professionals in qatar. saudi med j 2010; 31:74–7. 28. bener a, al-alim, hoffmann gf. high prevalence of vitamin d deficiency in young children in a highly sunny humid country: a global health problem. minerva pediatr 2009; 61:15–22. 29. prentice a, schoenmakers i, jones ks, jarjou lma, goldberg gr. vitamin d deficiency and its health consequences in africa. clinic rev bone miner metab 2009; 7:94–106. 30. alagöl f, shihadeh y, boztepe h, tankol r, yarman s, azizlerli h. sunlight exposure and vitamin d references 1. mason rs, sequeira vb, gordon-thomson c. vitamin d: the light side of sunshine. eur j clin nutr 2011 sep; 65:986–93. 2. hollis bw, wagner cl. nutritional vitamin d status during pregnancy: reasons for concern. cmaj 2006; 174: 1287–90. 3. lappe jm. the role of vitamin d in human health: a paradigm shift. j evid based complementary altern med 2011; 16:58–72. 4. van schoor nm, lips p. worldwide vitamin d status. best pract res clin endocrinol metab 2011; 25:671– 80. 5. stroud ml, stilgoe s, stott ve, alhabian o, salman k. vitamin d: a review. aust fam physician 2008; 37:1002–5. 6. norman aw. from vitamin d to hormone d: fundamentals of the vitamin d endocrine system essential for good health. am j clin nutr 2008; 88:491–9s. 7. jones g. pharmacokinetics of vitamin d toxicity. am j clin nutr 2008; 88:582–6s. 8. lips p. vitamin d deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. nat rev endocrinol 2001; 22:477–501. 9. iom (institute of medicine). dietary reference intakes for calcium and vitamin d. washington, dc: the national academies press, 2011. from: http:// www.iom.edu/reports/2010/dietary-referenceintakes-for-calcium-and-vitamin-d.aspx accessed: oct 2011. 10. garland cf, gorham ed, mohr sb, garland fc. vitamin d for cancer prevention: global perspective. ann epi 2009; 19:468–83. 11. holick mf. high prevalence of vitamin d inadequacy and implications for health. mayo clin proc 2006; 81:353–73. 12. yetley ea. assessing the vitamin d status of the us population. am j clin nutr 2008; 88:558–64s. 13. el-rassi r, baliki g, fulheihan geh. vitamin d status in middle east and africa. from: www.iofbonehealth. org/download/osteofound/filemanager/health_ professionals/pdf/vitamin-d-reports/vitamin_dmeast_africa.pdf accessed: jan 2012. 14. alshishtawy mm. to be or not to be exposed to direct sunlight: vitamin d deficiency in oman. squ med j 2011; 11:196–200. 15. woodhouse nyj, norton wl. low vitamin d level in saudi arabians. king faisal spec hosp med j 1982; 2:127–31. 16. sedrani sh, elidrissy awth, el arabi km. sunlight and vitamin d status in normal saudi subjects. am j clin nutr 1983; 38:129–32. vitamin d deficiency this clandestine endemic disease is veiled no more 150 | squ medical journal, may 2012, volume 12, issue 2 to 2000–2004. am j clin nutr 2008; 88:1519–27. 45. baroncelli gi, bereket a, el kholy m, audi l, cesur y, ozkan b, et al. rickets in the middle east: role of environment and genetic predisposition. j clin endocrinol metab 2008; 93:1743–50. 46. willer cj, dyment da, sadovnick ad, rothwell pm, nurray t, ebers gc. timing of birth and risk of multiple sclerosis: population based study. bmj 2005; 330:120. 47. merlino la, curtis j, mikuls tr, cerhan jr, criswell la, saag kg. vitamin d intake is inversely associated with rheumatoid arthritis: results from the iowa women’s health study. arthritis rheum 2004; 50:72–7. 48. hypponen e, laara e, reunanen a, jarvelin mr, virtanen sm. intake of vitamin d and risk of type 1 diabetes: a birth-cohort study. lancet 2001; 358:1500–3. 49. liu pt, stenger s, li h, wenzel l, tan bh, krutzik sr, et al. toll-like receptor triggering of a vitamin d-mediated human antimicrobial response. science 2006; 311:1770–3. 50. holick mf, binkley nc, bischoff-ferrari ha, gordon cm, hanley da, heaney rp, et al. evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. j clin endocrinol metab 2011; 96:1911–30. 51. grant wb. an estimate of the global reduction in mortality rates through doubling vitamin d levels. eur j clin nutr 2011; 65:1016–26. 52. hathcock jn, shao a, vieth r, heaney r. risk assessment for vitamin d. am j clin nutr 2007; 85:6–18. 53. souberbielle jc, body jj, lappe jm, plebani m, shoenfeld y, wang tj, et al. vitamin d and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: recommendations for clinical practice. autoimmun rev 2010; 9:709–15. 54. shin js, choi my, longtine ms, nelson dm. vitamin d effects on pregnancy and the placenta. placenta 2010; 31:1027–34. 55. javaid mk, crozier sr, harvey nc, gale cr, dennison em, boucher bj, et al. maternal vitamin d status during pregnancy and childhood bone mass at 9 years: a longitudinal study. lancet 2006; 367:36– 43. 56. mcgrath j. does “imprinting” with low prenatal vitamin d contribute to the risk of various adult disorders? med hypotheses 2001; 56:367–71. 57. whitehouse ajo, holt bj, serralha m, holt pg, kusel mmh, hart ph. maternal serum vitamin d levels during pregnancy and offspring neurocognitive development. pediatrics 2012; 129:485–93. 58. mannion ca, gray-donald k, koski kg. association of low intake of milk and vitamin d during pregnancy with decreased birth weight. cmaj 2006; 174:1273– deficiency in turkish women. j endocrinol invest 2000; 23:173–7. 31. mishal aa. effects of different dress styles on vitamin d levels in healthy young jordanian women. arch osteoporos 2001; 12:931–5. 32. hashemipour s, larijani b, adibi h, javadi e, sedaghat m, pajouhi m, et al. vitamin d deficiency and causative factors in the population of tehran. bmc public health 2004; 4:38. 33. agarwal n, arya sc. vitamin d(3) levels in pregnant women and newborns at a private tertiary care hospital in delhi, india. int j gynaecol obstet 2011; 113:240–1. 34. van der meer im, karamali ns, boeke ajp, lips p, middelkoop bjc, verhoeven i, et al. high prevalence of vitamin d deficiency in pregnant non-western women in the hague, netherlands. am j clin nutr 2006; 84:350–3. 35. grant wb. importance of vitamin d for pregnant women and developing fetuses. f r o m : w w w . v i t a m i n d a s s o c i a t i o n . o r g / e ventpdfs/20110517/20110517%20vitamin%20 d % 2 0 & % 2 0 o b s t e t r i c s % 2 0 % 2 0 d a t a % 2 0 overview%20-%20grant.pdf accessed: oct 2011. 36. caplan rh. vitamin d deficiency in the united states: a reassessment. gundersen lutheran med j 2006; 4:16–21. 37. ginde aa, liu mc, camargo ca, jr. demographic differences and trends of vitamin d insufficiency in the us population, 1988-2004. arch intern med 2009; 169:626–32. 38. greer fr. 25-hydroxyvitamin d: functional outcomes in infants and young children. am j clin nutr 2008; 88:529–33s. 39. johnson dd, wagner cl, hulsey tc, mcneil rb, ebeling m, hollis bw. vitamin d deficiency and insufficiency is common during pregnancy. am j perinatol 2011; 28:7–12. 40. bodnar lm, simhan hn, powers rw, frank mp, cooperstein e, roberts jm. high prevalence of vitamin d insufficiency in black and white pregnant women residing in the northern united states and their neonates. j nutr 2007; 137:447–52. 41. holick mf, chen tc. vitamin d deficiency: a worldwide problem with health consequences. am j clin nutr 2008; 87:1080–6s. 42. holick mf, chen tc, sauter er. vitamin d and skin physiology: a d-lightful story. j bone miner res 2007; 22:v28–33. 43. moan j, porojnicu ac, dahlback a, setlow rb. addressing the health benefits and risks, involving vitamin d or skin cancer, of increased sun exposure. proc natl acad sci usa 2008; 105:668–73. 44. looker ac, pfeiffer cm, lacher da, schleicher rl, picciano mf, yetley ea. serum 25-hydroxyvitamin d status of the us population: 1988–1994 compared moeness moustafa alshishtawy review | 151 71. heaney rp. vitamin d in health and disease. clin j am soc nephrol 2008; 3:1535–41. 72. garland cf, french cb, baggerly ll, heaney rp. vitamin d supplement doses and serum 25-hydroxyvitamin d in the range associated with cancer prevention. anticancer res 2011; 31:617–22. 73. barger-lux mj, heaney rp. effects of above average summer sun exposure on serum 25-hydroxyvitamin d and calcium absorption. j clin endocrinol metab 2002; 87:4952–6. 74. haddad jg, chyu kj. competitive protein-binding radioassay for 25-hydroxycholecalciferol. j clin endocrinol metab 1971; 33:992–5. 75. haddock l, corcino j, vazques md. 25(oh)d serum levels in the normal puerto rican population and in subjects with tropical sprue and parathyroid disease. p r health sci 1982; 1:85–91. 76. bischoff-ferrari ha, shao a, dawson-hughes b, hathcock j, giovannucci e, willett wc. benefitrisk assessment of vitamin d supplementation. osteoporos int 2010; 21:1121–32. 77. wolpowitz d, gilchrest ba. the vitamin d questions: how much do you need and how should you get it? j am acad dermatol 2006; 54:301–17. 78. el ghissassi f, baan r, straif k, grosse y, secretan b, bouvard v, et al. a review of human carcinogens – part d: radiation. lancet oncol 2009; 10:751–2. 79. samanek aj, croager ej, gies p, milne e, prince r, mcmichael aj, et al. estimates of beneficial and harmful sun exposure times during the year for major australian population centres. mja 2006; 184:338–41. 80. the australian and new zealand bone and mineral society, osteoporosis australia, the australian college of dermatologists and the cancer council australia. risks and benefits of sun exposure: position statement. from: w w w. c a n c e r. o r g . a u / fi l e / po l i c y p u b l i c a t i o n s / p s r i s k s b e n e fi t s s u n e x p o s u r e 0 3 m a y 0 7 . p d f accessed: feb 2012. 81. heaney rp, recker rr, grote j, horst rl, armas la. vitamin d(3) is more potent than vitamin d(2) in humans. j clin endocrinol metab 2011; 96:e447–52. 82. armas lag, hollis bw, heaney rp. vitamin d2 is much less effective than vitamin d3 in humans. j clin endocrinol metab 2004; 89:5387–91. 83. romagnoli e, mascia ml, cipriani c, fassino v, mazzei f, d’erasmo e, et al. short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin d2) or cholecalciferol (vitamin d3) in the elderly. j clin endocrinol metab 2008; 93:3015–20. 84. holick mf, biancuzzo rm, chen tc, klein ek, young a, bibuld d, et al. vitamin d2 is as effective as vitamin d3 in maintaining circulating concentrations of 25-hydroxyvitamin d. j clin endocrinol metab 2008; 93:677–81. 7. 59. bodnar lm, catov jm, simhan hn, holick mf, powers rw, roberts jm. maternal vitamin d deficiency increases the risk of preeclampsia. j clin endocrinol metab 2007; 92:3517–22. 60. merewood a, mehta sd, chen tc, bauchner h, holick mf. association between vitamin d deficiency and primary caesarean section. j clin endocrinol metab 2009; 94:940–5. 61. the endocrine society. the endocrine society’s clinical guidelines: evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. j clin endocrinol metab 2011; 96:1911–30. 62. vieth r. why the minimum desirable serum 25-hydroxyvitamin d level should be 75 nmol/l (30 ng/ml). best pract res clin endocrinol metab 2011; 25:681–91. 63. binkley n, novotny r, krueger d, kawahara t, daida yg, lensmeyer g, et al. low vitamin d status despite abundant sun exposure. j clin endocrinol metab 2007; 92:2130 –5. 64. luxwolda mf, kuipers rs, kema ip, janneke dijckbrouwer da, muskiet fa. traditionally living populations in east africa have a mean serum 25-hydroxyvitamin d concentration of 115 nmol/l. br j nutr 2012; 23:1–5. [epub ahead of print]. 65. ross ac, manson je, abrams sa, aloia jf, brannon pm, clinton sk, et al. the 2011 report on dietary reference intakes for calcium and vitamin d from the institute of medicine: what clinicians need to know. j clin endocrinol metab 2011; 96:53–8. 66. wagner cl, greer fr. american academy of pediatrics section on breastfeeding; american academy of pediatrics committee on nutrition. prevention of rickets and vitamin d deficiency in infants, children, and adolescents. pediatrics 2008; 122:1142–52. 67. office of dietary supplements (ods). dietary supplement fact sheet: vitamin d. from: /ods. od.nih.gov/factsheets/vitamind accessed: nov 2011. 68. holick mf. vitamin d: the underappreciated d-lightful hormone that is important for skeletal and cellular health. curr opin endocrinol diabetes 2002; 9:87–98. 69. hollis bw, johnson d, hulsey tc, ebeling m, wagner cl. vitamin d supplementation during pregnancy: double blind, randomized clinical trial of safety and effectiveness. j bone miner res 2011; 26:2341–57. 70. hollis bw, wagner cl. the vitamin d requirement during pregnancy and lactation. f r o m : h t t p : / / v i t a m i n d a s s o c i a t i o n . o r g / e ventpdfs/20110517/20110517%20vitamin%20 d%20&%20obstetrics%20-%20effectiveness%20 &%20safety%20-%20hollis.pdf accessed: jul 2011. vitamin d deficiency this clandestine endemic disease is veiled no more 152 | squ medical journal, may 2012, volume 12, issue 2 nov 2011. 86. seppa n. the power of d: sunshine vitamin’s potential health benefits stir up, split scientists. home 2011; 180:22. 87. holick mf. vitamin d deficiency. n engl j med 2007; 357:266–81. 85. ball jc. a comparison of the uv-b irradiance of lowintensity, full-spectrum lamps with natural sunlight. from: www.anapsid.org/jamesball.html accessed: sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 491-501, epub. 8th oct 13 submitted 21st feb 13 revision req. 22nd apr 13; revision recd. 19th jul 13 accepted 1st sep 13 1department of nuclear medicine, royal hospital, muscat, oman; 2department of nuclear medicine, royal north shore hospital, new south wales, australia; 3regional cneter of nuclear medicine, department of translational medicine & advanced technologies in medicine & surgery, university of pisa, italy *corresponding author e-mail: nkd004@hotmail.com احلالة الطبية للتصوير املقطعي باالنبعاث البوزيرتوين املدمج بالتصوير املقطعي )pet/ct( يف سلطنة عمان نعيمة خمي�س البلو�شي، ديل بايلي، جوليانو مارياين الت�شخي�س، دقة حيث من )pet/ct( املقطعي بالت�شوير املدمج البوزيرتوين باالنبعاث املقطعي الت�شوير قيمة اإن امللخ�ص: والفعالية من حيث التكلفة والتاأثري على اتخاذ القرارات ال�رسيرية موثق توثيقًا جيدا يف املن�شورات الطبية. ودورها ملر�شى ال�رسطان pet/ctال تطبيق امتد حاليا، للعالج. لال�شتجابة املبكر التقييم اإىل الت�شخي�س واإعادة املبكر الت�شخي�س من تدريجيا يتحول ال ا�شتخدام هو احلديثة التطبيقات اأحد واأن كما الروماتيزم. واأمرا�س القلب واأمرا�س الع�شبية كاالأمرا�س االأورام؛ غري للتخ�ش�شات pet/ct لت�شوير مر�شى العدوى/اأو االلتهاب. تو�شح هذه املقالة بع�س تطبيقات pet/ct ملر�شى االأورام وغري االأورام على حد �شواء. ونظراً لعدم وجود هذه االأ�شعة يف عمان، تهدف هذه املادة اإىل زيادة الوعي باأهمية هذه النوع من الت�شوير واأثره الكبري على الت�شخي�س واملتابعة يف تخ�ش�شات االأورام وغري االأورام ، للمر�شى من جميع الفئات العمرية، ف�شال عن �شانعي القرار. مفتاح الكلمات: الت�شوير املقطعي باالنبعاث البوزيرتوين؛ الت�شوير املقطعي؛ علم االأورام الطبية؛ عمان. abstract: the value of a positron emission tomography and x-ray computed tomography (pet/ct) combined service in terms of diagnostic accuracy, cost-effectiveness and impact on clinical decision-making is welldocumented in the literature. its role in the management of patients presenting with cancer is shifting from early staging and restaging to the early assessment of the treatment response. currently, the application of pet/ct has extended to non-oncological specialties—mainly neurology, cardiology and rheumatology. a further emerging application for pet/ct is the imaging of infection/inflammation. this article illustrates some of the pet/ct applications in both oncological and non-oncological disorders. in view of the absence of this modality in oman, this article aims to increase the awareness of the importance of these imaging modalities and their significant impact on diagnosis and management in both oncological and non-oncological specialties for patients of all age groups as well as the decision-makers. keywords: positron emission tomography; x-ray computed tomography; medical oncology; oman. sounding board the medical case for a positron emission tomography and x-ray computed tomography combined service in oman *naima k. al-bulushi,1 dale bailey,2 giuliano mariani3 the minstry of health in oman was established in august 1970 by a royal decree that stated that all omani citizens shall get free of charge health services. today, four decades later the omani health sector has developed immensely. this is evidenced by the increases in the number of hospitals; the number of hospital beds; the purchasing of new equipment; the number, type and complexity of therapies; the technical proficiency of the staff, including those who are national, and the variety of procedures performed. above all, the quality of the health service in the country has vastly improved. four decades ago, there was only a very basic health service which provided, for instance, life-saving treatments only to those fortunate few who could reach a health centre or hospital. nowadays highly complicated and skilled procedures and surgery are available to everyone. currently, both those living in urban areas and those living in very remote areas can access the health services they need.1 the inauguration of the national oncology centre (noc) at the royal hospital (rh), muscat, oman, in december 2004 was one of the naima k. al-bulushi, dale bailey and giuliano mariani sounding board | 492 biggest recent additions to health services in the country. it included a well-equipped radiotherapy department with two linear accelerators, the first in the country. this meant that oncology patients no longer needed to travel to nearby countries for radiotherapy treatments. the noc also includes departments of medical and paediatric oncology, haemato-oncology and nuclear medicine. however, an important contemporary key modality is missing in this centre and in the country as a whole: that of a pet/ct service. this article highlights the importance of pet/ct in managing cancer. by illustrating some of the applications of pet/ct, we hope to raise awareness of its importance and costeffectiveness. positron emission tomography (pet) was introduced in the 1970s as a research device in neurosciences and cardiology. two decades later, x-ray computed tomography (ct) technology was added to the pet scanner, producing so-called fusion, or hybrid, imaging. a pet/ct combined scanner was first introduced in 1998. since then, patients can be scanned both with pet and ct at the same time without having to move. the aim of this hybrid imaging was to combine the functional molecular imaging of pet with the high-contrast anatomical images provided by ct. the value of combining pet and ct (pet/ct) in terms of diagnostic accuracy, cost-effectiveness and the impact on clinical decision-making and health outcomes are well-documented in the literature.2 pet/ct imaging with the main radiopharmaceutical used, 18f-fluorodeoxyglucose (18f-fdg), is considered today, in most of the developed world, to be essential in the management of a range of malignancies. table 1 lists the major malignancies or cancers where pet/ct provides a unique clinical value. in addition, the role of pet/ ct in the management of patients presenting with cancer is shifting from early staging and restaging after recurrence to the early assessment of treatment response.3,4 currently, the use of 18f-fdg pet/ct has extended to non-oncological applications as well. the main non-oncological use of 18f-fdg pet is in neurology (mostly for diagnosing patients with dementia, or for localising the ictal focus in patients with drug-refractory epilepsy) and in cardiology (for assessing the myocardial viability). a further emerging indication for 18f-fdg pet/ct includes imaging of infection and inflammation. regarding the applications in cardiology, scintigraphy with technetium (99mtc)-sestamibi evaluates the semi-quantitative myocardial blood flow, and therefore underestimates the myocardial viability.5 different pet imaging agents can be used to assess myocardial perfusion (such as 13n-ammonia, 15o-water and, more recently, rubidium-82 [82rb]-chloride), while 18f-fdg uptake reflects the metabolic activity. a positive 18f-fdg uptake in the region with reduced perfusion indicates myocardial viability, thus predicting that the patient will benefit from revascularisation procedures. on the other hand, a reduced 18f-fdg uptake in the region, with reduced perfusion as well (i.e., matched perfusion/metabolic defects), indicates an irreversibly-damaged myocardium.6 of special interest to cardiology is a new agent for myocardial perfusion labelled with 18f, the 18f-bms-747158-02, which is in an advanced stage of clinical validation. as mentioned above, important non-oncological applications include neurological disorders, mainly to differentiate the various types of dementia. in addition, 18f-fdg pet may have a role in the presurgical assessment of patients with partial complex seizures, where magnetic resonance imaging (mri) is either normal or equivocal.7 the use of 18f-fdg in rheumatology has been documented, with applications including the assessment of disease activity in arthritis, based on evaluating the metabolic activity in synovitis; this parameter helps to measure disease activity in patients with rheumatoid arthritis.8 additionally, 18f-fdg-pet is employed to evaluate the disease extent/activity in arteritis.9 recently, 18f-fdg has also been used to evaluate the response to therapy, especially when using expensive biological drugs such as antitumour-necrosis factor (anti-tnf) drugs, as an early prediction of the clinical outcome reduces the overall cost of treatment.10 an emerging use of pet/ct is to assess infection and inflammation. pet has both high sensitivity and specificity in imaging osteomyelitis. in addition, it has been used to evaluate sarcoidosis and inflammatory bowel disease.11 furthermore, 18f-fdg pet/ct has an important role in evaluating patients with a fever of unknown origin (fuo), as it helps in the precise localisation and early identification of the underlying cause of this the medical case for a positron emission tomography and x-ray computed tomography combined service in oman 493 | squ medical journal, november 2013, volume 13, issue 4 future uses of 18f-labelled radiotracers among the 4 short-lived cyclotron-produced pet isotopes, 18f has the longest half-life (110 mins), making it the most suitable isotope to label pet radiotracers. it can be commercially produced, hence reducing the necessity of in-house cyclotron production in each pet/ct institute. this has resulted in a wide range of research projects worldwide to develop new 18f-labelled pet radiotracers. one example of a newly developed pet radiotracer is 3’-deoxy-3’-18f-fluorothymidine (18f-flt). it is a thymidine analogue and its clinical condition. in most patients with fuo, the main cause will turn out to be due to an infection, autoimmune disease or malignancy; using pet/ct as a single modality can diagnose and assess those diseases with a high level of sensitivity.12 in spite of the wide range of applications mentioned above, however, the vast majority of clinical pet scans performed today worldwide are in the setting of cancer staging and restaging, in which pet/ct often ‘upstages’ many patients [figure 1]. table 1: optimal indications of positron emission tomography/x-ray computed tomography in various malignancies malignancy tracer(s) role lung cancers/mesotheliomas 18f-fdg diagnosis; staging; recurrent disease; ebrt planning; therapy response. colorectal cancers 18f-fdg staging of distant metastases; recurrent disease. breast cancers 18f-fdg; 18f-flt staging of distant metastases; recurrent disease; re-staging; therapy response. lymphomas 18f-fdg; 11c-met staging; therapy response. multiple myelomas 18f-fdg staging; diagnosis; therapy response. gynaecological cancers 18f-fdg staging; recurrent disease; therapy response; re-staging. melanomas 18f-fdg staging of distant metastases; therapy response; recurrent disease. sarcomas 18f-fdg staging; re-staging; therapy response. primary brain tumours 18f-fdg; 11c-met; 18f-flt grading/prognosis; guide for biopsy; recurrence versus scar post-therapy. head and neck cancers 18f-fdg; 18f-miso staging; therapy response; cancer of unknown primary; ebrt planning; recurrent disease. oesophageal/gastric cancers 18f-fdg; 18f-flt staging of distant metastases; therapy response. biliary tract cancers 18f-fdg staging of distant metastases. pancreatic cancers 18f-fdg staging of distant metastases; recurrent disease; therapy response. prostate cancers 11c-choline; 18f-choline staging of distant metastases; recurrent disease. follicular thyroid cancers 18f-fdg re-staging of radioiodide-negative, thyroglobulin-positive cancer. medullary thyroid cancers 18f-fdg; 18f-dopa staging. neuroendocrine tumours 68ga-dota-toc re-staging; selection for prrt. 18f-fdg = 18f-fluorodeoxyglucose; ebrt = external beam radiation therapy; 18f-flt = 18f-fluorothymidine; 11c-met =11c-methionine; 18f-miso = 18f-fluoromisonodazol; 18f-dopa = 18f-dihydroxyphenylalanine; 68ga-dota-toc = gallium-68-dota-toc; prrt = peptide radio-receptor therapy (with somatostatin analogues). adapted from: strauss hw, mariani g, volterrani d, larson sm. nuclear oncology: pathophysiology and clinical applications. new york: springer verlag, 2013. with pet evaluation, the term “staging” refers to parameters n and m, since parameter t is best staged with morphological imaging such as computed tomography and/or magnetic resonance imaging. furthermore, a common feature of positron emission tomography imaging with 18f-fdg is the prognostic information it provides, based on the intensity of uptake, as an indirect parameter of tumour aggressiveness. naima k. al-bulushi, dale bailey and giuliano mariani sounding board | 494 uptake detects cellular proliferation.13 it shows a good uptake in a number of tumours: lung cancer, lymphoma, breast cancer and glioma. the sensitivity and specificity of flt compared to that of fdg in those tumours is, however, beyond the scope of this article. another 18f-labelled pet radiotracer is 2-18f-fluoro-l-tyrosine (8f-tyr), a marker of amino acid transport. it has shown good uptake in meningiomas even after irradiation. it can clearly aid in the visualisation and follow-up of such tumours.14 imaging of alzheimer’s disease (ad) has developed over the last decade. by using pet, it has been possible to detect the deposition of amyloid b in the human brain. recently, 18f-labelled amyloid pet radiotracers have been approved for clinical trials aiming to assess the effect of drugs for ad therapy. the latest so far is 18f-florbetapir; this agent was approved by the united states food & drug administration (fda) in april 2012. it also received marketing authorisation in october 2012 from the european medicines agency’s committee for medicinal products for human use.15 another recently addition to the 18f pet radiotracer family is 18f-fluorocholine. this agent is used for imaging prostate cancer, where its main applications are to evaluate local recurrence or metastatic disease. it is being increasingly used in europe and japan [figure 2].16 last but not least, is the radiotracer 18f-sodium fluoride (naf). it has been known for decades that 18f-fluoride has a high affinity for bone, yet it was not widely used. this was mainly due to its high energy (511 kilo-electron volts [kev]) which limited its use with the existing gamma cameras due to the scintillation employed—sodium iodide activated with thallium [nai(tl)]—being too low in density and of insufficient thickness, and hence having a low stopping power. furthermore, 99mtc-methylene diphosphonate (mdp) was readily available and suitable for use with the gamma camera. since the introduction of modern pet and pet/ct scanners, 18f-fluoride has been more frequently used for evaluating bone abnormalities that are due to both benign and malignant diseases. there are a number of studies that have compared 99mtcmdp bone scanning to 18f-fluoride pet and found that the latter has a higher diagnostic accuracy in detecting skeletal diseases.17 pet imaging agents other than 18f-fluorodeoxyglucose the use of 18f-fdg suffers from important limitations in certain oncological conditions, due either to the physiological biodistribution (for instance, very high uptake in the brain cortex or at the excretion sites) that hampers identification of the tumour lesions, or to the low expression of the glucose transporter system in certain cancers (such as in prostate cancers, mucinous cancers, hepatocellular carcinomas and bronchioloalveolar lung cancers, among others). alternative pet tracers can be employed in these conditions, for instance radiolabelled amino acids (such as tyrosine figure 1 a & b. 18f-fluorodeoxyglucose positron emission tomography (pet) / x-ray computed tomography (ct) for a patient diagnosed with nasopharyngeal carcinoma in which the pet/ct imaging upstaged the disease by revealing a bone lesion that was not detected by ct. a: the fused pet/ct image revealed a focal uptake in the neck of the left femur (arrow). b: the ct image, bone window, did not show any bone abnormalities. the technetium (99mtc)-methylene diphosphonate (mdp) bone scan of this patient was also negative (images not included). the medical case for a positron emission tomography and x-ray computed tomography combined service in oman 495 | squ medical journal, november 2013, volume 13, issue 4 somatostatin analogues mentioned above are especially useful for pet imaging in patients with neuroendocrine tumours, another oncological condition where 18f-fdg imaging is suboptimal. additionally, the 68ga pet label on these compounds can be substituted with a therapeutic radionuclide, such as yttrium-90 (90y) or lutetium-177 (177lu), to deliver treatment to 68gadota-tate-positive tumours. international atomic energy agency expert missions to oman: evaluating the status of nuclear medicine and recommendations regarding a pet/x-ray ct and cyclotron facility since oman became a member of the international atomic energy agency (iaea) in february 2009, a number of expert missions have taken place. the ones that concern us in this article are those undertaken to evaluate the status of nuclear medicine in the country and their feedback reports and recommendations. the first of these was in december 2009. it concluded that “oman has currently a capacity to fully utilize two pet/ct cameras to be located in muscat region. a single or choline analogues) or radiolabelled precursors of deoxyribonucleic acid (dna) synthesis (such as thymidine analogues). perhaps the best established occurrence of this type is the use of 11c-choline or 18f-fluorocholine in patients with prostate cancer, with tumours that are generally characterised by the low expression of the glucose transporter proteins. 11c-acetate is instead most frequently employed in patients with a hepatocellular carcinoma, another tumour characterised by the low expression of the glucose transporter proteins. proximity with the very high uptake in the brain cortex can hamper the detection of primary brain tumours; in these patients, discrimination of tumour recurrence from post-radiotherapy scar/necrosis (which is not an easy task with conventional ct/mri) is better achieved by using alternative pet tracers such as 11c-methionine or 11c-thymidine/18f-fluoroethyll-tyrosine (fet). still another imaging alternative is to use somatostatin analogues labelled with gallium-68 [68ga] (i.e., 68ga-dota-toc/noc/ tate). this radionuclide is especially attractive for pet centres since, despite its short physical half-life of only 68 mins, it is available even without an inhouse cyclotron as the product of a germanium-68 [68ge]/68ga generator. in fact, the physical half-life of the parent radionuclide 68ge (approximately 9 months) enables a single generator to meet clinical needs over at least 6 months. the 68ga-labelled figure 2 a & b. 18f-fluorocholine positron emission tomography (pet)/x-ray computed tomography (ct) scan in a patient with prostatic adenocarcinoma. this imaging was done to assess the efficacy of therapy in this patient with a single bone metastasis, appearing one year after primary treatment (serum prostate-specific antigen was 2.4 ng/ml). the images are of the fused pet/ct transaxial section at the level of the femoral heads. a: the baseline images showed focal accumulation of the tracer in the left acetabulum, the only site of metastatic disease. b: the favorable response after external beam radiation therapy (ebrt) is shown in this image. naima k. al-bulushi, dale bailey and giuliano mariani sounding board | 496 pet/ct should be introduced as soon as possible with a second one to follow.”18 this was followed shortly with another expert mission in march 2010 which recommended: “a national pet/ct scanner centre including a cyclotron should be planned and built. the logical location for this would be the royal hospital as it has a large oncology program.”19 this was shortly followed by another expert mission that took place in october 2010. in the feedback report the expert wrote: “the level of nm practice in oman is of a remarkably high quality. the country looks very well prepared for pet. the medical doctors would only require a limited period of very focused training for pet practice. however, it would still require many of the other professionals needed to run a complex facility such as a cyclotron/ pet centre, namely radiopharmacists/chemists and medical physicists. their preparation would be longer and training should start as soon as a positive decision is taken about the implementation of a cyclotron in the country.”20 two years later in 2012, the iaea undertook an external audit of the practice of nuclear medicine in oman. one of the recommendations of this expert mission was “consider introduction of pet/ct in the country. this will have positive return in the management of cancer patients and saving in the use of high cost chemotherapeutic drugs”.21 in the same year, another expert mission took place in september. it concluded: “there is a need for pet/ ct in royal hospital and sultan qaboos university hospital (squh). cyclotron facility in muscat region is needed to supply radiopharmaceuticals for both centers. such a project will take time and in view of the urgent need for pet/ct, exporting the radioactivity as a temporary solution should be considered. this is not cost-effective for long-term practice. the best option to establish such centre is to do it as a turnkey project.”22 the last expert mission that took place at the time of writing this paper was in march 2013 and concluded: “there is an urgent need to (establish) two pet/ct scanners in royal hospital and squh, which is fully justified. there is also a need to establish a national cyclotron facility that can produce and supply the pet tracers to the local centers”.23 how many scanners are needed to provide appropriate access to pet/ct? a detailed derivation of the population need is difficult to ascertain from the literature, but the most quoted current figures suggest that the appropriate number of pet scanners to provide adequate care for the population’s clinical needs is approximately 1 per 1–1.5 million people, although the geographical spread of a nation’s population may skew this.24,25 as the clinical utility and benefits to patient management of pet have been increasingly demonstrated in the most recent literature, even greater access to pet is likely in the future with a 20% annual growth rate of pet procedures expected after the year 2014.26 in a recent review of pet access in europe, it was recommended that one pet camera is needed per 1.2 million people to meet the population’s needs,24 and the report of the department of health in the uk recommended one camera per 1–1.5 million people.25 the population number per pet scanner is much lower when it comes to the usa and other european countries, where there is one pet camera per 300,000–900,000 people [table 2];27 a similar distribution of pet cameras exists in some of the gulf cooperation council (gcc) countries.28 in the australian pet report, the state health departments of queensland and victoria recommended 4 scanners in each state, hence assuming a ratio of one camera per 900,000 people and one camera per 1.2 million people, respectively.29 however, australia is not a densely populated country and by the end of 2012 there were 36 pet/ct cameras serving the population of 22.5 million. a more useful metric may be that for every one radiation therapy linear accelerator, a pet/ct camera is required. current utilisation of pet/ ct services in oman in oman the importance of pet/ct imaging has been acknowledged for nearly a decade, especially for cancer patients. due to the lack of pet/ct facilities in the country, patients are being sent abroad at the expense of the ministry of health. the medical case for a positron emission tomography and x-ray computed tomography combined service in oman 497 | squ medical journal, november 2013, volume 13, issue 4 would pet/ct be a costeffective modality in oman? reviewing the latest available cancer incidence statistics in oman shows that there were 950 new cases diagnosed in 2010.30 additionally, the top 10 most common cancers in oman are similar to the rest of the world. breast cancer and cervical cancer represent the top two cancers in women, while prostate cancer is the top ranking cancer in men, followed by non-hodgkin’s lymphoma.30 bearing in mind the ideal utilisation of pet/ct imaging, there will be about 800–900 patients per year needing to be scanned for primary staging; about one-third of those patients will have early evaluations of the response to chemotherapy/radiotherapy by a second early scan, and later on a third scan will be needed to evaluate the response at completion of treatment. the above considerations will add to the current practice in oman for cancer patients, who will benefit from restaging using pet/ct imaging; alternatively, as is currently the case, pet/ct can be used as a problem-solving tool when other investigations are inconclusive. using the above figure, it is calculated that more than 2,000 patients in departments of adult and paediatric oncology will benefit from pet/ct if it is available in the country. also, it should be noted that these numbers were published two years ago and that there is an expected increase in the number of new cancer cases worldwide over the coming two decades, more so in developing countries. there will be an expected increase in the incidence of cancer cases from 12.7 million new cases in 2008 to 22.2 million cases in 2030.31 this is further exacerbated in oman by the rapidly increasing mean age of the population; more cancers are to be expected as the population lives longer. furthermore, there are several instances in which patients with benign conditions will benefit from in-house pet/ct imaging, such as patients with coronary artery disease being evaluated for myocardial viability as well as patients with infectious diseases, and rheumatological and neurological conditions. in the long term, it would be neither affordable nor cost-effective to send such a large number of patients abroad for pet/ct scans. furthermore, the time factor in some of these cases is even more critical than the cost, especially for those patients the cases sent abroad are specially selected, and pet/ct is used in such cases as a problem-solving tool in cases where both the existing imaging modalities and the histopathology reports are inconclusive. those patients are mainly from the medical oncology, haemato-oncology, paediatric oncology and endocrinology departments. other medical specialties began sending patients with benign conditions for pet/ct imaging, primarily to evaluate viability in patients with coronary artery disease, or rheumatology patients (mainly those with vasculitis in whom the available imaging modalities, namely ct and mri, were inconclusive). so far, pet/ct imaging has not been fully utilised, particularly for oncology patients. although experts in medical oncology and nuclear medicine realise the importance of using pet/ct in staging, mid-therapy evaluation, end-of-therapy evaluation, and restaging, they are not able to use pet/ct in this way. the fact that such a modality is not available in oman places several important logistical limitations on the treatment options, as it is not cost-effective to send all of those patients abroad. table 2: number of positron emission tomography/ computed tomography units per population in some developed countries and the gulf cooperation council countries19,20 country pet/ct units units per population usa 1,000 1 per 297,000 austria 17 1 per 477,000 belgium 21 1 per 490,000 germany 85 1 per 970,000 switzerland 7 1 per 1,000,000 japan 100 1 per 1,270,000 sweden 7 1 per 1,290,000 denmark 4 1 per 1,350,000 netherlands 10 1 per 1,600,000 france 36 1 per 1,650,000 spain 19 1 per 2,100,000 ksa 12 1 per 2,400,000 uae 3 1 per 1,800,000 kuwait 3 1 per 857,000 bahrain 2 1 per 500,000 qatar 1 1 per 1,853,563 pet = positron emission tomography; ct = computed tomography; ksa = saudi arabia; uae = united arab emirates. naima k. al-bulushi, dale bailey and giuliano mariani sounding board | 498 who require re-evaluation half-way through treatment. in this regard, mid-treatment pet/ct scans to evaluate the response to chemotherapy have proven to be very useful for clinical decision-making regarding early changes in the treatment regimens [figure 3]. this approach helps in the efficient use of certain expensive chemotherapy drugs. for example, pet/ct imaging after 3 chemotherapy cycles in patients with non-hodgkin lymphomas has helped save eur 1,879 per patient in belgium.32 in this manner, pet/ct has the potential to enable personalised patient management.5 this is the real future challenge for physicians in general, and not solely oncologists. how many pet/ct scanners and cyclotrons are needed in oman? the ratio of pet/ct scanners per population varies worldwide: the numbers vary from one scanner per population of 300,000 to one scanner per one million. at the time of writing, the population in oman is approaching 3 million; hence, two pet/ ct scanners would be fully utilised, provided they were acquired soon. if, on the other hand, the approval/planning phase takes longer and 2–3 additional years are needed to begin building the facility (with an anticipated clinical introduction of 5 years), then 3 pet/ct scanners will be needed. this is due to both the increase in population and the number of newly diagnosed cancer cases, as well as the additional numbers of older cancer patients. further delay in starting this project will only increase expenditure in the health sector, both by increasing the number of patients sent abroad for pet/ct and by the inappropriate usage of expensive, and potentially futile, chemotherapy. the cyclotron, on the other hand, is a different issue. there is a need to install a national medium energy cyclotron. the two feasible options at present would be for the facility to be based either at the rh or squh. this cyclotron should be capable of producing all pet tracers for use within the same institutition and, additionally, 18f-fdg or other 18f-labelled radiotracers that can be transported to other pet/ct scanners located elsewhere. one of these facilities needs to be properly planned and then implemented immediately. once it is fully functional, a second cyclotron could be planned for the other institute; in the long term, both the rh and squh need to have their own cyclotrons. this is because those two centres should be able to utilise pet/ct technology fully by using all radiotracers. whereas 18f-fdg (with a half-life of 110 mins) can be transported between the two centres, the other short-lived radiotracers, 15o, 11c and 13n, have a very short half-life ranging between 2–20 mins. they can only be used in the institute where the cyclotron is installed. it is envisaged that a minimum of 3 years is required to install a fully operational cyclotron, with this sometimes taking up to 5 years. one might ask if oman should wait for the cyclotron before figure 3 a & b. 18f-fluorodeoxyglucose (18f-fdg) positron emission tomography (pet)/x-ray computed tomography (ct) performed as a mid-therapy scan for the early assessment of treatment response. the pet/ct images are of a patient with a gastrointestinal stromal tumour. a: the image revealed intense 18f-fdg uptake in the primary tumour (arrow). a follow-up scan at the mid-therapy stage to assess treatment response revealed a mild reduction in the tumour size in the ct image (not included). b: the pet/ct image revealed a significant reduction in the 18f-fdg uptake, indicating a good response to treatment (arrow). the medical case for a positron emission tomography and x-ray computed tomography combined service in oman 499 | squ medical journal, november 2013, volume 13, issue 4 radiochemists) and technologists for the operation of the equipment is absolutely mandatory. some of this should be undertaken abroad in facilities with pet experience and working practices similar to those in oman. • the education of referrers as to the appropriate use of pet imaging in the management of their patients is essential. • clear evidence-based guidelines should be developed as to the appropriate use of 18f-fdgpet scanning. • a funding model should be developed, allowing for flexibility in addressing cancer issues of key importance in oman. these may be slightly different to those in developed countries. conclusion this article illustrates some of the applications of pet/ct in oncological and non-oncological patients. in view of the increase in the number of newly diagnosed cancer patients, in addition to the long-term follow-up needed for oncological patients in general, the demand for pet/ct will definitely increase in the future. it is important to consider that the number of new cancer patients mentioned is based on a ministry of health publication of new cancer cases registered in 2008. first, it should be noted that these figures do not include those patients who went abroad for diagnosis and/or treatment, either at private or government expense. second, these numbers also do not include benign, non-oncological patients who received pet/ct scans abroad, either at government expense or privately sought second opinions. therefore, if 2,000 oncological patients could have benefited from a pet/ct service 5 years ago and a further two years are required before pet/ct service will be available—assuming planning for such a service begins immediately—it is likely that, 7 years later, this number will definitively have doubled, if not tripled. in conclusion, thousands of patients would benefit from an in-house pet/ct and cyclotron facility and thousands of omani riyals would be saved in the long term. however, it important to remember that hypothetical calculations of the number of patients or money spent are easy, but the same is not true of calculations regarding the quality starting the pet/ct facility. the answer would be no; the best way to proceed would be to start planning for a comprehensive, integrated pet/ct and cyclotron facility. installing a pet/ct scanner requires less time and it can be started in one to two years; until the cyclotron is functional, the scans can be perfomed using imported radiotracers, although in this case only 18f-labelled tracers such as 18f-fdg could be used. this will be a useful temporary solution until the cyclotron starts functioning. it would also provide a good back-up if the cyclotron has technical problems or needs maintenance. it is worth mentioning that importing 18f-fdg should only be considered as a temporary solution. it will not be cost-effective in the long term and, additionally, will not allow the full utilisation of pet/ct. building the national capacity is desirable and should be established in parallel with the planning of the pet/ct and cyclotron facility. a team of highly trained and qualified staff is needed to run such a facility efficiently and safely. this team should include qualified medical physicists, radiochemists, radiopharmacists and nuclear medicine technologists. planning for the future in oman any omani pet/ct initiative should address these key issues prior to introducing a local service: • a long-term plan is needed to consider the number of pet/ct scanners required, the location of the facilities and a possible timeline for their introduction. • a consideration of the need for a cyclotron within oman versus a supply of radiotracers from other gcc states should be undertaken. even with an internal source of positron-emitting tracers, consideration should be given to external backup facilities to allow for continued service during scheduled maintenance and unexpected outages. • taking into consideration the complexity of such facilities and international requirements, particularly the good manufacturing practice (gmp) guidelines, a turnkey project would be the best option for building such facilities. • the education and training of physicians/ radiologists, scientists (physicists and naima k. al-bulushi, dale bailey and giuliano mariani sounding board | 500 of the service. in a country like oman, where there have been tremendous improvements in the health services over the last four decades, and where there is good will towards further improvement, it is the authors’ opinions that pet/ct is no longer an option, but a necessity. declaration the second and third authors were iaea experts who visited oman in 2009 as part of the technical cooperation programme with the iaea. also part of the data in this paper was presented as a white paper to moh in 2010 written by the first author and dr zahid al-mandhari, national oncology centre, royal hospital, muscat. references 1. alshishtawy mm. four decades of progress: evolution of the health system in oman squ med j 2010; 10:12–22. 2. krause bj, schwarzenböck s, souvatzoglou m. fdg pet and pet/ct. recent results cancer res 2013; 187:351–69. 3. vranjesevic d, filmont je, meta j, silverman dh, phelps me, roa j, et al. whole-body 18f-fdg pet and conventional imaging for predicting outcome in previously treated breast cancer patients. j nucl med 2002; 43:325–9. 4. ben-haim s, ell p. 18f-fdg pet and pet/ct in the evaluation of cancer treatment response. j nucl med 2009; 50:88–99. 5. altehoefer c, vom dahl j, biedermann m, uebis r, beilin i, sheehan f, et al. significance of defect severity in technetium-99m-mibi spect at rest to assess myocardial viability: comparison with fluorine-18-fdg pet. j nucl med 1994; 35:569–74. 6. hess b, tägil k, cuocolo a, anagnostopoulos c, bardiés m, bax j, et al. eanm/esc procedural guidelines for myocardial perfusion imaging in nuclear cardiology. eur j nucl med mol imaging 2005; 32:855–97. 7. barrington s, scarsbrook a. evidence-based indications for the use of pet/ct in the united kingdom 2012. london: the royal college of physicians and royal college of radiologists, 2012. 8. beckers c, ribbens c, andré b, marcelis s, kaye o, mathy l, et al. assessment of disease activity in rheumatoid arthritis with (18)f-fdg pet. j nucl med 2004; 45:956–64. 9. kobayashi y, ishii k, oda k, nariai t, tanaka y, ishiwata k, et al. aortic wall inflammation due to takayasu arteritis imaged with 18f-fdg pet coregistered with enhanced ct. j nucl med 2005; 46:917–22. 10. elzinga eh, van der laken cj, comans ef, boellaard r, hoekstra os, dijikmans ba, et al. 18f-fdg pet as a tool to predict the clinical outcome of infliximab treatment of rheumatoid arthritis: an explorative study. j nucl med 2011; 52:77–80. 11. gotthardt m, bleeker-rovers cp, boerman oc, oyen wj. imaging of inflammation by pet, conventional scintigraphy, and other imaging techniques. j nucl med 2010; 51:1937–49. 12. keidar z, gurman-balbir a, gaitini d, israel o. fever of unknown origin: the role of 18f-fdg pet/ ct. j nucl med 2008; 49:1980–5. 13. van waarde a, cobben dc, suurmeijer aj, maas b, vaalburg w, de vries ef, et al. selectivity of 18f-flt and 18f-fdg for differentiating tumor from inflammation in a rodent model. j nucl med 2004; 45:695–700. 14. rutten i, cabay j-e, withofs n, lemaire c, aerts j, baart v, hustinx r. pet/ct of skull base meningiomas using 2-18f-fluoro-l-tyrosine: initial report. j nucl med 2007; 48:720–5. 15. johnson ka, minoshima s, bohnen ni, donohoe kj, foster nl, herscovitch p, et al. appropriate use criteria for amyloid pet: a report of the amyloid imaging task force, the society of nuclear medicine and molecular imaging, and the alzheimer’s association. j alzheimers dement 2013; 9:e1–16. 16. jadvar h. prostate cancer: pet with 18f-fdg, 18for 11c-acetate, and 18for 11c-choline. j nucl med 2011; 52:81–9. 17. grant fd, fahey fh, packard ab, davis rt, alavi a, treves st. skeletal pet with 18f-fluoride: applying new technology to an old tracer. j nucl med 2008; 49:68–78. 18. bailey d, mariani g. fact finding mission on current status of clinical practice of nuclear medicine and diagnostic imaging (oma /6/302), 5–9 dec 2009. department of technical cooperation (tc). endof-mission report. vienna: international atomic energy agency, 2010. 19. parker w, seuntjens j. review and make recommendations on medical physics in oman; urgent needs for diagnostic imaging and therapeutic oncology services in oman (oma 6003-0), 6–10 mar 2010. department of technical cooperation (tc). end of mission report. vienna: international atomic energy agency, 2010. 20. dondi m. project review mission; fact finding mission on national needs in nm; upstream work for the next tc cycle (oma/6002), 24–28 oct 2010. department of technical cooperation (tc). end of mission report. vienna: international atomic energy agency, 2011. 21. marengo m, hilson aj, descristoforo c. assessment of quality assurance practices in nuclear medicine in oman; strengthening national capacity in radiation medicine and dosimetry. (oma 6002/04/01), 4–8 feb 2012. department of technical cooperation the medical case for a positron emission tomography and x-ray computed tomography combined service in oman 501 | squ medical journal, november 2013, volume 13, issue 4 28. the cooperation council for arab states of the gulf. member states. available at: http://www.gcc-sg.org/ eng/indexc64c.html?action=gcc accessed: jan 2013. 29. medicare services advisory committee (msac). positron emission tomography. canberra: commonwealth of australia, 2001. publications approval number: 2822. 30. ministry of health sultunate of oman. cancer incidence in oman report of 2010. available at: http://www.moh.gov.om/en/reports/cancer%20 incidence%20in%20oman%202010.pdf accessed: jan 2013. 31. bray f, jemal a, grey n, ferlay j, forman d. global cancer transitions according to the human development index (2008–2030): a populationbased study. lancet oncol 2012; 13:790–801. 32. moulin-ramsee g, spaepen k, stroobants s, mortelmans. non-hodgkin lymphoma: retrospective study on the cost-effectiveness of early treatment response assessment by fdg-pet. eur j nucl med mol imaging 2008; 35:1074–80. (tc). end of mission report. vienna: international atomic energy agency, 2012. 22. vora m, schlyer d. technical, physical and human resource requirements for cyclotron/pet radiopharmaceutical facility (oma/6/401),1–5 sep 2012. department of technical cooperation (tc). end of mission report. vienna: international atomic energyagency, 2013. 23. soloviev d, saeid hm. design of cyclotron and associated facility (oma/6/004), 9–13 mar 2013. department of technical cooperation (tc). end of mission report. vienna: international atomic energy agency, 2013. 24. bedford m, maisey mn. requirements for clinical pet: comparisons within europe. eur j nucl med mol imaging 2004; 31:208–21. 25. uk department of health. a framework for the development of positron emission tomography services in england. london: uk department of health, 2005. 26. burns m. pet and spect markets to top $6 billion by 2021. from: www.biotechsystems.com/ breakingmarketnews/pet-and-spect-markets-totop-6-billion-by-2021.asp accessed: jan 2013. 27. bailey d. survey conducted jan‒feb 2003. nuclear medicine list serve (nucmed@imaging.robarts.ca). update 2005 includes data presented at the society of nuclear medicine annual meeting, toronto, canada, jun 2005 and at the anzsnm annual meeting, melbourne, may 2005. from: http://irus. rri.on.ca/mailman/listinfo/nucmed. accessed: jan 2013. squ med j, may 2012, vol. 12, iss. 2, pp. 225-227, epub. 9th apr 2012 submitted 29th sep 11 revision req. 8th jan 12, revision recd. 14th feb 12 accepted 15th feb 12 departments of 1surgery, and 3obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman; 2college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: surgeonkamran@yahoo.com فتق املبيض حالة نادرة كمران مالك، رقية ال�سحي، هاين القا�سي، موزه الكلباين، عبداهلل احلارثي امللخ�ص: ُيعّد فتق املبي�س من احلاالت النادرة جدا، اإذ ت�سكل %9.2 من حاالت الفتق االآربي القابلة للتدخل اجلراحي. نقدم هنا و�سفا حلالة غري اعتيادية من هذا النوع من الفتق عند امراأة بالغة قدمت اإلينا باأعرا�س ت�سابه الفتق املنحب�س باجلهة الي�رضى. احتوى كي�س الفتق على املبي�س االأي�رض على كي�س دموي مع بوق فالوب االأي�رض والرباط العري�س. خ�سعت احلالة جلراحه ا�ستئ�سال التكي�س الدموي املوجود باملبي�س واإ�سالح الفتق االأربي ب�سبكة طبية. مفتاح الكلمات: الفتق االآربي، املبي�س، تقرير حالة، ُعمان. abstract: ovarian hernias are extremely rare. the prevalence of ovaries and fallopian tubes in operable inguinal hernias is only about 2.9%. we report here an unusual case of an ovary in a hernia sac in an adult female. she presented with symptoms and signs of an incarcerated left inguinal hernia. the left ovary contained a haemorrhagic cyst and, along with the left fallopian tube and broad ligament, these were found in the sac. she underwent a left ovarian cystectomy and the inguinal hernia was repaired with mesh. keywords: inguinal hernia; ovary; case report; oman. ovarian hernia a rarity *kamran a malik,1 ruqaiya m al shehhi,2 hani al qadhi,1 moza al kalbani,3 abdullah al harthy1 case report a hernia is defined as a protrusion of the small intestines or omentum through a defect in the abdominal wall. hernias present as bulges in the groin area that can become more prominent when coughing, straining, or standing up. although inguinal hernias are more common in males, they still can occur in females, most commonly in tandem with herniation of the omentum or small bowel. it is rare to find unusual contents in the hernia sac. a retrograde analysis of 1,950 cases of operable inguinal herniae showed that the vermiform appendix was present in 0.51% of the cases, ovaries and fallopian tubes in 2.9%, and urinary bladder in 0.36%.1 we report here on unusual contents within a hernia sac in an adult female who presented with symptoms and signs of an incarcerated left inguinal hernia. the left ovary, containing a haemorrhagic cyst along with the left fallopian tube and broad ligament, were found in the sac. after adequate resuscitation, the patient underwent an ovarian cystectomy and her hernia was repaired with mesh. case report a married 31-year-old woman with two children who was known to have sickle cell disease, presented to the accident and emergency department of sultan qaboos university hospital, oman, with a 5-day history of left-sided inguinal swelling associated with colicky abdominal pain and loss of appetite. she denied any history of constipation, nausea or vomiting. she was also known to have bronchial asthma, which was controlled with inhalers. clinically, she was in distress with haemodynamically normal vital signs. local examination revealed a 7 x 5 cm non-pulsatile, smooth-surfaced, warm, tender, irreducible swelling with a positive cough impulse. the rest of the systemic examination was within normal limits. her routine blood workups were normal except for a leucocytosis of 13 x 109/l. a diagnosis of strangulated inguinal hernia was made and she was taken for emergency surgery after adequate resuscitation with intravenous fluids and ovarian hernia a rarity 226 | squ medical journal, may 2012, volume 12, issue 2 antibiotics. on exploration of the left inguinal canal, a thin sac containing a partially torted left ovarian cyst with a viable ovary and fallopian tube was found [figures 1 and 2]. she underwent a left ovarian cystectomy and the inguinal hernia was repaired with ethicon ultrapro mesh, (size 15 x 15 cm, johnson & johnson medical ltd., ascot, uk). a histopathology study confirmed the finding of a haemorrhagic corpus luteum cyst. the patient had an uneventful recovery and was discharged home in a stable condition, with no recurrence seen on her recent follow-up appointment in the surgical clinic 6 months after surgery discussion the inguinal canal in the female is not welldemarcated as compared to the inguinal canal in males. normally, different structures pass through it including the round ligament of the uterus, a vein, an artery from the uterus that forms a cruciate anastomosis with the labial arteries, and extra peritoneal fat.2 it is reported in literature that ovarian hernias are extremely rare in premenopausal women. on the contrary, most cases of gonadal hernias were reported in the paediatric age group in association with other genital tract anomalies.3 t. okada et al. suggested a few hypotheses as to the mechanism by which this may occur.4 one of these hypotheses speculates that weakness of the broad ligaments or ovarian suspensory ligaments can contribute to ovarian herniation into the inguinal ring. this can be augmented by high intra-abdominal pressure as a result of carrying heavy things, or due to a chronic cough secondary to respiratory disease, as could be the case with our patient. although considered extremely rare, there have been case reports of different unusual contents found in inguinal hernia sacs, including parts of the genitourinary tract. mcmillan reported a case of a rudimentary uterus in a 30-year-old female which had presented as a right groin lump for eight years.5 despite the efforts made to diagnose the contents of inguinal hernias prior to surgery, most of them are made intraoperatively, as in our patient. yao et al. suggested that in premenopausal women the morphological characteristics of the ovary in the hernia sac can be assessed through sonographic examinations, which provide information on ovarian function that cannot be obtained in younger females. these characteristics include eliciting a mass with multiple small sonolucent cysts indicating the ovary. a hyperechoic portion of the mass surrounded by an arterial flow can be observed on colour doppler ultrasonography consistent with the presence of a corpus luteum. furthermore, transabdominal sonographic scans of the pelvis may reveal the absence of one ovary in the lower pelvis on the same side as the inguinal hernia.6 although ovarian cysts are not commonly encountered by surgeons, a high index of suspicion is required in order to avoid any delay in diagnosis and treatment. it was reported that about 4–37% of female inguinal hernias, which have been found intraoperatively, present with non-reducible figure 1: left indirect hernia . figure 2: hc: left ovarian hemorrhagic cyst; hs: hernia sac; ft: left fallopian tube. kamran a malik, ruqaiya m al shehhi, hani al qadhi, moza al kalbani and abdullah al harthy case report | 227 ovaries. ovarian torsion and infarction have been encountered in 2–33% of these patients, which necessitates treating all cases, even when asymptomatic.7 ovarian cysts can be dealt with effectively with the help of laparoscopy, particularly if the cyst is benign, with concomitant repair of inguinal hernia if the diagnosis is made preoperatively.8 this was not applicable in our patient as our preoperative diagnosis was a strangulated inguinal hernia. conclusion in most cases, the contents of the hernia sac can be detected intraoperatively. although considered to be a very rare entity, the possibility of ovarian hernia should be kept in mind in a female patient presenting with an irreducible swelling in the inguinal or femoral region in order to avoid serious complications. whenever suspected, it must be treated as a surgical emergency. references 1. oozkan ov, semerci e, aslan e, ozkan s, dolapcioglu k, besirov e. a right sliding indirect inguinal hernia containing paraovarian cyst, fallopian tube, and ovary: a case report. arch gynecol obstet 2009; 279:897–9. 2. gurer a, ozdogan m, ozlem n, yildirim a, kulacoglu h, aydin r. uncommon content in groin hernia sac. hernia 2006; 10:152–5. 3. golash v, cummins rs. ovulating ovary in an inguinal hernia. surgeon 2005; 3:48. 4. okad t, sasaki s, honda s, miyagi h, minato m, todo s. irreducible indirect inguinal hernia containing uterus, ovaries, and fallopian tubes. hernia 2011; 1:1–3. 5. mcmillan wm. unusual viscera in indirect inguinal hernia. ann surg 1942; 116:266–70. 6. yao l, mouy, wang hx. sonographic diagnosis of an ovary-containing inguinal hernia with the formation of a corpus luteum in an adult female. ultrasound obstet gynecol 2009; 34:359–60. 7. al omari w, hashimi h, al bassam mh. inguinal uterus, fallopian tube, and ovary associated with adult mayer-rokitansky-kuster-hauser syndrome. fertil steril 2011; 95:1119–23. 8. machado no, machado lsm, al ghafri w. laparoscopic excision of a large ovarian cyst herniating into the inguinal canal: a rare presentation. surg laparosc endosc percutan tech 2011; 21:215– 8. clinical & basic research sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e486−494, epub. 14th oct 14 submitted 11th feb 14 revisions req. 12th mar & 5th may 14; revisions recd. 10th apr & 19th may 14 accepted 4th jun 14 departments of 1medical physiology and 2human anatomy & embryology, faculty of medicine, assiut university, assiut, egypt *corresponding author e-mail: ghadaszam@gmail.com املعاجلة املشرتكة هبرمون النمو و هرمون الكورتيكوستريون يزيد من بروتني )nr2b( و نسبة )nr2b:nr2a( ويؤدى اىل زيادة سرعة انتقال اإلشارات العصبية عرب نقاط االشتباك العصىب يف احلصني غاده حممود و�أمين عامر abstract: objectives: this in vitro study aimed to investigate the possible mechanism underlying the protective effect of growth hormone (gh) on hippocampal function during periods of heightened glucocorticoid exposure. methods: this study was conducted between january and june 2005 at the joan c. edwards school of medicine, marshall university, in huntington, west virginia, usa. the effects of the co-application of gh and corticosterone (cort) were tested at different concentrations on the field excitatory postsynaptic potentials (fepsps) of the hippocampal slices of rats in two different age groups. changes in the protein expression of n-methyl-d-aspartate receptor (nmdar) subunits nr1, nr2b and nr2a were measured in hippocampal brain slices treated with either artificial cerebrospinal fluid (acsf), low doses of cort alone or both cort and gh for three hours. results: the co-application of cort and gh was found to have an additive effect on hippocampal synaptic transmission compared to either drug alone. furthermore, the combined use of low concentrations of gh and cort was found to have significantly higher effects on the enhancement of fepsps in older rats compared to young ones. both gh and cort enhanced the protein expression of the nr2a subunit. simultaneous exposure to low concentrations of gh and cort significantly enhanced nr2b expression and increased the nr2b:nr2a ratio. in contrast, perfusion with cort alone caused significant suppression in the nr1 and nr2b protein expression and a decrease in the nr2b:nr2a ratio. conclusion: these results suggest that nmdars provide a potential target for mediating the gh potential protective effect against stress and age-related memory and cognitive impairment. keywords: growth hormone; corticosterone; biological stress; postsynaptic potentials; n-methyl-d-aspartate receptors; hippocampus; neuronal plasticity; western blotting. �لتعر�ض فرت�ت الحصنيخالل وظيفة على )gh( �لنمو لهرمون �لو�قي �لتاأثري �آلية من للتحقق تهدف �لدر��سة هذه الهدف: امللخ�ص: �مل�سرتكة �ملعاجلة �ختبار مت .2005 يونيو و يناير بني ما �لفرتة يف �لدر��سة هذه �أجريت الطريقة: �جللوكورتيكويد. لهرمون �ملتز�يد �ال�ستباك نقاط عرب �لع�سبية �الإ�سار�ت �نتقال �رسعة على خمتلفه بجرعات )cort( �لكوتيكو�ستريون هرمون و �لنمو بهرمون ،nr2b ،nr1( nmdar لع�سبي فى �حل�سني على فئتني عمريتني لفئر�ن �لتجارب. در�سنا �لتعبري�لربوتيني عن م�ستقبالت� و nr2a( يف �رس�ئح �حل�سني �لتى يتم معاجلتها ملدة ثالث �ساعات بهرمون �لكوتيكو�سترين �أو هرمون �لكوتيكو�ستريون مع هرمون �لنمو يف �آن و�حد �أو �ل�سائل �ل�سحائى �ال�سطناعي. النتائج: وجدنا �أن �إ�سافة هرمون �لنمو لهرمون �لكوتيكو�سترين له تاأثري �أقوى على زيادة �رسعة �نتقال اإل�سار�ت �لع�سبية عرب نقاط �ال�ستباك العصبي فىالحصني فى جميع �جلرعات �لتى ��ستخدمت مقارنة با�ستخد�م كل هرمون على حد�. وعالوة على ذلك ، وجدنا �أن �جلمع بني ��ستخد�م جرعة منخف�سة من هرمون �لنمو و هرمون �لكوتيكو�سترين لها �آثار �أعلى بكثري على تعزيز �نتقال اإل�سار�ت �لع�سبية يف �لفئر�ن �لكبرية فى �ل�سن مقارنة مع �سغار�ل�سن. �أظهرنا �أن كال من هرمون �لنمو و هرمون �لكوتيكو�سترين يزيد من �لربوتني nr2a. كما �أثبتنا �أن �لعالج �مل�سرتك جلرعات منخف�سة من هرمون �لنمو و �لكوتيكو�ستريون يزيد من بروتني nr2b ويوؤدى إىل زيادة ن�سبة nr2a/nr2b مقارنة بهرمون �لكوتيكو�سترين لوحدة . وكذلك وجدنا �أن �لعالج .nr2a/nr2b ن�سبة يف و�نخفا�ض nr2b و nr1 بروتينات يف كبري نق�ض ي�سبب لوحدة �لكورتيكو�ستريون بهرمون النتيجة: تدل نتائج هذ� �لبحث على �أن هرمون �لنمو له تاأثريوقائي من خالل تاأثريه على م�ستقبالت nmdar �سد �سعف �لذ�كرة و �الإدر�ك �ملتعلقة بتقدم �لعمر و �لتوتر �لنف�سي و�لع�سب. ميثيل ن م�ستقبالت �لع�سبي؛ �ال�ستباك نقاط عرب �ملنتقلة �لع�سبية �الإ�سار�ت �لع�سبي؛ و �لتوتر�لنف�سي كوتيكو�سترين؛ �لنمو؛ هرمون الكلمات: مفتاح �أ�سبارتيت؛ �حل�سني؛ تقوية �لو�سالت �لع�سبية؛ لطخة و�سرتن. co-application of corticosterone and growth hormone upregulates nr2b protein and increases the nr2b:nr2a ratio and synaptic transmission in the hippocampus *ghada s. mahmoud1 and ayman s. amer2 ghada s. mahmoud and ayman s. amer clinical and basic research | e487 stress causes large amounts of glucocorticoids (gcs) to be released; these affect the brain and, in particular, the hippocampus.1 corticosteroids released during stress induce memory retrieval impairment; however, moisan et al. found that this could be abolished by lowering the blood gc pool in corticosteroid-binding globulin knockout mice and restored by an infusion of corticosterone (cort) in the hippocampus.2 the early exposure of the immature hippocampus to a traumatic experience is known to be associated with post-traumatic stress disorder in humans, although there is no recall of the trauma in most cases.3 previous studies have indicated that growth hormone (gh) therapy has a protective effect on cognitive brain function.4,5 an earlier study demonstrated that gh had a beneficial effect on synaptic transmission in the cornu ammonis 1 (ca 1) area of rat hippocampi.4 ageing and repeated stress have been demonstrated to damage the hippocampus, a vulnerable structure of the central nervous system.6 research has shown that the overexpression of gh can reverse a stress-induced decrease in both the acquisition and long-term storage of fear memories, thus enhancing the ability of the hippocampus to combat stress.5 this study therefore aimed to investigate the possible beneficial effects of the co-application of gh and cort at low concentrations on hippocampal synaptic transmission, compared to cort alone. the effects of this co-exposure were tested at different concentrations on the field excitatory postsynaptic potentials (fepsps) in hippocampal slices from rats of two different age groups. a previous study proved that n-methyl-d-aspartate receptor (nmdar) antagonist 3-((r)-2-carboxypiperazin-4-yl)-propyl1-phosphonic acid impaired both long-term potentiation (ltp) and long-term depression (ltd) in the hippocampal dentate gyrus of rats.7 it was therefore the hypothesis of the current study that cort would modulate hippocampal synaptic function through the nmdars. to this end, the change in protein expression of the nmdar subunits nr1, nr2b and nr2a were tested in hippocampal brain slices treated with either artificial cerebrospinal fluid (acsf), low concentrations of cort alone or both cort and gh. methods this study was conducted between january and june 2005 at the joan c. edwards school of medicine, marshall university, in huntington, west virginia, usa. male adult sprague-dawley rats were obtained from hilltop lab animals inc. (scottdale, pennsylvania, usa) and divided into two groups. the first group consisted of rats aged 2.5–3 months while the second group was made up of rats aged 15–18 months. rats were sedated using a mixture of 95% carbon dioxide (co2) and 5% oxygen (o2) administered by inhalation in a closed container. the skull was opened and the brain was removed and submerged in chilled oxygenated (95% o2 and 5% co2) low calcium and high magnesium acsf composed of 124.0 of mm sodium chloride (nacl), 26.0 mm of sodium bicarbonate, 3.0 mm of potassium chloride, 0.5 mm of calcium chloride, 5.0 mm of magnesium sulfate and 10.0 mm of glucose. the preparation of the hippocampal slices, synaptic stimulation and recording of field potentials were performed using a previously described method.4 in order to study the interactions of gh and cort on synaptic transmission, hippocampal slices from the younger rats were divided into four groups: group 1 was perfused with gh only (at a concentration of 0.1, 0.5 or 2.0 nm) for two hours; group 2 was perfused with cort only (at 0.5, 5.0 or 30.0 nm) for two hours; group 3 was perfused with both cort and gh (either cort at 0.5 nm plus gh at 0.1 nm, cort at 5.0 nm plus gh at 0.5 nm or cort at 30.0 nm plus gh at 2.0 nm) starting with cort alone in the first hour and both hormones in the second hour, and group 4 was advances in knowledge the perfusion of hippocampal brain slices in vitro with corticosterone (cort) for a short period of time was found to enhance the synaptic transmission of the hippocampus. this result did not change significantly when the duration of treatment was extended. an additive effect on hippocampal synaptic function was observed when using low doses of growth hormone (gh) and cort, resulting in the enhanced protein expression of the nr2a subunit of the n-methyl-d-aspartate receptors. additionally, exposure to low doses of gh and cort was demonstrated to reverse the cort-induced downregulation of the nr2b subunit protein expression as well as the decrease in the nr2b:nr2a ratio. application to patient care the results of this study could explain the mechanism underlying the previously reported benefits of long-term gh treatment on memory and cognitive brain function among the elderly. a possible mechanism is also suggested regarding the beneficial effect of gh in combating memory deficits associated with anxiety disorders. co-application of corticosterone and growth hormone upregulates nr2b protein and increases the nr2b:nr2a ratio and synaptic transmission in the hippocampus e488 | squ medical journal, november 2014, volume 14, issue 4 perfused with both cort and gh (cort at 5.0 nm plus gh at 0.5 nm) starting with gh alone in the first hour and both hormones in the second hour. there were approximately five or six rats in each group. to test if any additive effect could be gained by applying cort to slices pretreated with gh, hippocampal slices from older rats were divided into two groups: group 1 was perfused with gh alone (0.5 nm) for two hours and group 2 with gh (0.5 nm) for one hour followed by gh (0.5 nm) plus cort (5.0 nm) for another hour. there were eight rats in each group. rat cort and recombinant rat gh were obtained from cell sciences inc. (canton, massachusetts, usa). low impedance (3–4 mω) glass micropipettes filled with standard acsf were placed into the stratum radiatum of area ca1 of the hippocampi to record the extracellular potentials. the signals were amplified (at a gain of 1,000) and filtered (0.1–3,000 hz) using a dam50 bio-amplifier (world precision instruments, inc., sarasota, florida, usa). the signals were then digitised at 10 khz using a ni 5102 digitiser (national instruments corp., austin, texas, usa) and stored on a personal computer. postsynaptic potentials were evoked by delivering constant voltage stimuli through a bipolar stimulating electrode placed into the stratum radiatum of the rat hippocampal slices. stimuli were delivered at 15-second intervals. a 15-minute baseline recording of the postsynaptic potentials using standard acsf was taken before the application of any drug. the postsynaptic potentials evoked while using standard acsf were quantified by measuring the slope of the linear portion of the initial response. any changes in synaptic response caused by the drug treatment were expressed as a percentage of the change from the average baseline response prior to treatment. the effects of cort application alone and the possible interaction of cort and gh on the protein expression of nmdar subunits were examined by western blotting. hippocampal tissue was removed from the animals, sliced and incubated for one hour in acsf. hippocampal slices obtained from the same animal were separated into three interface chambers. the first chamber contained acsf alone and served as a control, the second chamber contained acsf and cort (5.0 nm) and the third chamber contained acsf, cort (5.0 nm) and gh (1.0 nm). each group was incubated for three hours. immediately after the incubation period, the three groups were placed in dry ice, frozen and stored at −80 °c. to isolate hippocampal protein, slices were homogenised in a protein lysis buffer composed of 1% octylphenoxypolyethoxyethanol, 1% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 0.15 m of nacl, 0.01 m of sodium phosphate (ph 7.2), 2 mm of ethylenediaminetetra-acetic acid (edta) and a 1% protease inhibitor cocktail. the hippocampal tissue proteins were then sonicated for <10 second bursts. following this, they were centrifuged at a speed of 14,000 × g for 20 minutes at 4 °c. the supernatant solution was obtained and the total protein was estimated using the bradford method.8 equal amounts of total protein (200 μg) from the hippocampal slices treated with cort, gh or both and the control hippocampal slices were separated on 8% polyacrylamide gels. the separated proteins were transferred to nitrocellulose membranes (micron separations inc., westborough, massachusetts, usa).9 the membranes were incubated for one hour at room temperature in 5% non-fat dry milk in a tris tween saline (t-t-s) solution (0.5% polysorbate 20, 10.0 mm of tris hydrochloride buffer solution [ph 8.0], 150.0 mm of nacl and 0.2 mm of edta) to block non-specific binding sites.10 the membranes were then incubated with a primary antibody overnight at 4 °c. to correct for possible loading differences, blots were probed with a primary antibody against neuronspecific enolase (nse). next, membranes were washed and incubated with horseradish peroxidase-conjugated secondary antibodies (1:10,000) for one hour at room temperature. both primary and secondary antibodies were diluted in 5% non-fat dry milk in t-t-s solution. the blots were washed again and proteins were detected using amersham-pharmacia ecl prime western blotting detection reagents (general electric healthcare, little chalfont, buckinghamshire, uk). x-ray autoradiograms were scanned and their images were saved. the following primary antibodies were used: antinse (ab951, merck millipore, darmstadt, germany) at a dilution of 1:6,000; anti-nmdar1 (60021a, bd biosciences pharmingen, san diego, california, usa) at a dilution of 1:1,000; anti-nmdar2a (ab1555p, merck millipore) at a dilution of 1:500, and antinmdar2b (n38120, bd biosciences transduction laboratories, franklin lakes, new jersey, usa) at a dilution of 1:2,000. data were collected and analysed using the windows whole cell program (winwcp), version 5.01 (university of strathclyde, glasgow, scotland, uk). the western blotting bands representing different nmdar protein expressions were quantified for their relative densities using the gel analysis densitometry tool from imagej, version 1.31c (national institutes of health [nih], bethesda, maryland, usa).11–13 additional analysis was completed using graphpad prism, version 5 (graphpad software inc., la jolla, california, usa) and origin® graphing and analysis software, version 5.0 (originlab corp., northampton, ghada s. mahmoud and ayman s. amer clinical and basic research | e489 massachusetts, usa). statistical significance was assessed using paired and unpaired t-tests, as appropriate, and a p value of <0.05 was considered significant. data were compared among the groups using a two-way analysis of variance (anova) with the bonferroni post hoc test. all experimental procedures in this study were done in accordance with the nih’s guide for the use and care of laboratory animals.14 this study was approved by the institutional animal care & use committee of the joan c. edwards school of medicine at marshall university. results the effect of the co-application of cort (0.5 nm) and gh (0.1 nm) in hippocampal slices pretreated with cort are shown in figures 1a and b. the application of cort caused a significant enhancement of the fepsps compared to the baseline recordings or the control slices perfused with standard acsf for 1–2 hours. the continuous treatment of cort for the second hour did not demonstrate any significant changes to the enhanced fepsps compared to the first hour. no significant differences were found between exposure to gh for two hours or cort plus gh for two hours. perfusion with gh plus cort in the second hour caused a significant additional enhancement of the fepsps caused by cort alone for 1–2 hours. a significant interaction was found by the two-way anova. the interaction accounted for 15.71% of the total variance (f = 3.76; df [3, 16]; p = 0.032). the treatment groups accounted for 27.78% of the total variance after adjusting for matching (f = 6.82; df [3, 16]; p = 0.004). time accounted for 12.49% of the total variance after adjusting for matching (f = 8.97; df [1, 16]; p = 0.009). the effect of the application of cort (5.0 nm) figure 2 a & b: the effect of the co-application of corticosterone (cort) at 5.0 nm and growth hormone (gh) at 0.5 nm in hippocampal slices pretreated with cort or gh alone. a: results of a one-hour treatment with artificial cerebrospinal fluid (acsf), cort, gh or cort plus gh after pretreatment with gh or cort. b: average field excitatory postsynaptic potentials recorded over 10 minutes at the end of the first or second hour of treatment compared to acsf (n = 5). cort = corticosterone; gh = growth hormone; acsf = artificial cerebrospinal fluid; epsp = excitatory postsynaptic potentials. ++p <0.01 for the second hour compared to the first hour in cases of gh or both gh and cort in slices pretreated with cort. figure 1 a & b: the effect of the co-application of corticosterone (cort) at 0.5 nm and growth hormone (gh) at 0.1 nm in hippocampal slices pretreated with cort (0.1 nm). a: results of a one-hour treatment with either artificial cerebrospinal fluid (acsf), cort, gh or cort plus gh. b: average field excitatory postsynaptic potentials recorded over 10 minutes at the end of the first or second hour of treatment compared to acsf (n = 5). cort = corticosterone; gh = growth hormone; acsf = artificial cerebrospinal fluid; epsp = excitatory postsynaptic potentials. **p <0.01 for gh plus cort compared to cort; +p <0.05 for the second hour of treatment compared to the first hour. co-application of corticosterone and growth hormone upregulates nr2b protein and increases the nr2b:nr2a ratio and synaptic transmission in the hippocampus e490 | squ medical journal, november 2014, volume 14, issue 4 and gh (0.5 nm) on hippocampal slices primed with either drug alone was as follows. treatment with either cort, gh or cort plus gh after pretreatment with gh or cort alone caused a significant enhancement of the fepsps compared to the baseline recordings or the control slices (p <0.01). the continuous perfusion of the hippocampal slices with cort for the second hour did not cause any significant changes in the enhanced fepsps compared to the first hour. the continuous perfusion of hippocampal slices with gh for the second hour had a moderately significant effect on enhancing fepsps compared to the first hour (p <0.01). co-exposure to gh and cort in the second hour caused a significant additional enhancement of the fepsps caused by cort alone in the first hour (p <0.01). conversely, co-exposure to gh and cort in the second hour did not cause a significant additional enhancement of the fepsps caused by gh alone for 1–2 hours [figures 2a & b]. in this regard, a non-significant interaction was found by the twoway anova. the interaction accounted for 5.38% of the total variance (f = 1.51; df [4, 20]; p = 0.238). the treatment groups accounted for 28.35% of the total variance after adjusting for matching (f = 3.87; df [4, 20]; p = 0.017). time accounted for 11.75% of the total variance after adjusting for matching (f = 13.14; df [1, 20]; p <0.005). the effect of cort (30.0 nm) and gh (2.0 nm) in hippocampal slices pretreated by cort was also observed. cort caused a significant enhancement of the fepsps compared to the baseline recordings or the control slices (p <0.05). the continuous perfusion of hippocampal slices with cort for the second hour did not cause any significant changes in the enhanced fepsps compared to the first hour. no significant differences were found between the perfusion of gh for two hours and cort plus gh. perfusion with gh plus cort in the second hour caused a significant additional enhancement of the fepsps caused by cort alone for 1–2 hours (p <0.05) [figures 3a & b]. in this case, a significant interaction was found by the two-way anova. the interaction accounted for 5.59% of the total variance (f = 9.17; df [3, 20]; p <0.001). the treatment groups accounted for 33.79% of the total variance after adjusting for matching (f = 4.27; df [3, 20]; p = 0.018). time accounted for 3.81% of the total variance after adjusting for matching (f = 18.74; df [1, 20]; p <0.001). the study also attempted to determine if the additive effect of cort and gh in young adult rats would be seen in older rats as well. in the older rats figure 3 a & b: the effect of the co-application of corticosterone (cort) at 30.0 nm and growth hormone (gh) at 2.0 nm in hippocampal slices pretreated with cort. a: results of a one-hour perfusion with artificial cerebrospinal fluid (acsf), cort, gh or cort plus gh (0.5 nm). b: average field excitatory postsynaptic potentials recorded over 10 minutes at the end of the first or second hour of treatment as compared to acsf (n = 6). cort = corticosterone; gh = growth hormone; acsf = artificial cerebrospinal fluid; epsp = excitatory postsynaptic potentials. *p <0.05 for cort plus gh compared to cort alone; +++p <0.01 for the second hour of treatment compared to the first hour. figure 4: the effect of the co-application of corticosterone (cort) and growth hormone (gh) on the field excitatory postsynaptic potentials (fepsps) of young and older rats. the average fepsps recorded over 10 minutes at the end of the first or second hour of treatment were compared to artificial cerebrospinal fluid (p <0.01), baseline recordings, the first hour in old rats only and old rats compared to young rats (n = 8). cort = corticosterone; gh = growth hormone; acsf = artificial cerebrospinal fluid; epsp = excitatory postsynaptic potentials. +++p <0.005 for the old rats compared to baseline recordings; ****p <0.001 for the old rats compared to young rats. ghada s. mahmoud and ayman s. amer clinical and basic research | e491 only, the effect of co-exposure to a low dose of cort (5.0 nm) and gh (0.5 nm) in the second hour on the enhanced fepsps by gh alone in the first hour was significantly higher than baseline recordings and when compared to the first hour. the same was true in old rats compared to young rats in both the first and second hour [figure 4]. a significant interaction was found by the two-way anova. the interaction accounted for 6.33% of the total variance (f = 3.67; df [2, 21]; p = 0.043). the treatment groups accounted for 47.10% of the total variance after adjusting for matching (f = 26.05; df [2, 21]; p <0.001). the rats’ age accounted for 9.46% of the total variance after adjusting for matching (f = 10.97; df [1, 21]; p <0.005). the effect of cort and gh on the protein expression of nmdar subunits in hippocampal slices was also investigated. to test for the role of nmdars in mediating the additive effect of gh and cort on enhancing hippocampal synaptic transmission, hippocampal slices were perfused with acsf alone, with cort (5.0 nm) alone or with cort plus gh (1.0 nm) in standard acsf for three hours. the protein expressions of nmdar subunits nr1, nr2a, nr2b and the nr2b:nr2a ratio were then sought. three hours of treatment with cort significantly decreased the expression of the nr1 and nr2b subunits and increased the nr2a subunit when compared to the control slices [figures 5a & c]. three hours of treatment with cort plus gh significantly increased the expression of nr2a and nr2b and did not change the nr1 protein expression compared to the control slices [figures 5b & c]. the exposure of hippocampal slices to cort alone caused significant suppression in the nr2b:nr2a ratio compared to the control slices [figure 5d]. co-exposure of hippocampal slices to cort plus gh for three hours significantly increased the nr2b:nr2a ratio when compared to the control slices as well as cort exposure alone [figure 5d]. discussion a normal ageing-induced decrease in gh is associated with a decrease in the learning and memory functions of the hippocampus and its glutamatergic function in both rats and humans.15 a previous study found that gh has a beneficial effect on hippocampal synaptic function.4 in addition, another study found that adrenal figure 5 a−d: the effect of the co-exposure of corticosterone (cort) and growth hormone (gh) on protein expression of n-methyl-d-aspartate receptor subunits in hippocampal brain slices. a: effect of cort (5.0 nm) perfusion for three hours (n = 9). b: effect of cort (5.0 nm) plus gh (1.0 nm) perfusion for three hours (n = 7). c: sample western blot of the nr1, nr2a, nr2b subunits and neuron specific enolase. d: nr2b:nr2a ratio of protein expression in hippocampal slices which had been perfused with either artificial cerobrospinal fluid, cort or cort plus gh for three hours. nmdar = n-methyl-d-aspartate receptor; od = optical density; ns = not significant; acsf = artificial cerebrospinal fluid; cort = corticosterone; gh = growth hormone; nse = neuron specific enolase. *p <0.05; **p <0.01; ***p <0.005 compared to the control; +++p <0.005 compared to cort-treated slices. co-application of corticosterone and growth hormone upregulates nr2b protein and increases the nr2b:nr2a ratio and synaptic transmission in the hippocampus e492 | squ medical journal, november 2014, volume 14, issue 4 steroids given at low to moderate doses over several hours enhanced synaptic and memory functions, while higher doses had the opposite effect.16 the current study aimed to determine whether co-exposure to gh and cort had any additive or subadditive effect on hippocampal synaptic transmission and if this effect differs with age. the results demonstrated that there is an additive effect on hippocampal fepsps in cases of co-exposure to gh and cort when compared to cort alone; this response was both concentrationand age-dependent. the additive effect was significantly higher in the older rats than in the younger rats, suggesting a protective effect of gh against stress, especially in old age. the beneficial effect of gh in both young and old rats is supported by a previous study which found that acute gh treatment improved spatial learning among both young and old rats in a radial maze.17 in agreement with the current study’s findings, molina et al. reported that both gh and insulin-like growth factor-1 enhanced the fepsps of in vitro ca1 hippocampal slices to a similar extent in both young and older rats, mediated via a postsynaptic mechanism.15 while both gh and cort have been evidenced to enhance synaptic transmission upon short-term exposure, the question remains as to how this additive effect affects the long-term storage of information. this is related to how much calcium enters the postsynaptic cells and for how long. a high calcium signal that only lasts seconds causes the activation of protein kinases and the insertion of more glutamate receptors by exocytosis, favouring ltp; in comparison, a low calcium signal for minutes causes the activation of phosphatases and an internalisation of the synaptic glutamate receptors by endocytosis and ltd.18–20 nmdars are the major route of calcium entry into the postsynaptic neurons. corticostrerone enhances glutamate release and the overactivation of nmdars, causing excitotoxicity.21 molina et al. observed that gh had a direct effect on restoring age-induced nmdar-mediated changes in the basal synaptic functions of the hippocampus in older rats.15 the effects of co-exposure to gh and cort on the protein expression of nmdars compared to cort alone were investigated in the current study. this revealed that perfusing hippocampal slices with cort alone significantly increased the expression of nr2a, decreased nr2b and nr1 protein expression and decreased the nr2b:nr2a ratio. these results are supported by those of a previous study which found that implanting mice with a 21-day release cort formulation (20 mg/kg/day) caused a decreased protein expression of postsynaptic density protein 95, nr1 and synaptopodin in the postsynaptic membranes.22 chronic restraint stress has been reported to induce a loss of dendritic spines and nmdar subunits in cultured hippocampal ca1 neurons.23 in addition, both acute and chronic stressors have been shown to inhibit neuronal synthesis and reduce cell survival through a mechanism that involves nmdars in the dentate gyrus.24 however, the results of the present study found that the co-exposure of hippocampal slices to a low concentration of both cort and gh for three hours significantly increased the nr2a and nr2b subunit expression compared to control slices. it also increased the nr2b:nr2a ratio, which was significantly suppressed by exposure to cort alone, while no change in the nr1 protein expression was obtained. although the nr1 subunit is obligatory for channel function, the nr2 composition plays an important functional modulatory role, affecting channel kinetics and pharmacology.25 the beneficial effects of the upregulation of nr2b on memory and synaptic transmission have been proven by several previous studies. one of these reported a reduction in synaptic plasticity due to a lower nr2b:nr2a ratio through a calcium/ calmodulin-dependent protein kinase ii-dependent mechanism.26 another study showed an enhancement of nr2b expression by the administration of d-cycloserine; this enhanced retention and the recall of fear extinction memories in the dentate gyrus as well as the ca1 and ca3 areas of the hippocampus.27 müller et al. found that nr2b upregulation enhances ltp in the ca1 synapses of the hippocampus, while nr2b inhibition in tissue from epileptic animals significantly increased epileptic activity and susceptibility to hyperexcitability.28 additionally, chronic restraint stress, acute cort treatment or gc receptor agonists have been demonstrated to seriously deteriorate the contextual fear memory function of the hippocampus through an effect that involves protein transcription.29,30 an acute and chronic stress-induced rise of gcs in the prefrontal cortex and hippocampus has been shown to cause changes in glutamate transmission and the cognitive functions that underlie stress-induced mental illnesses.31 in view of these findings and those of the literature, the ability of gh to reverse the effect of cort through maintaining nr1, upregulating nr2b and increasing the nr2b:nr2a ratio may be greatly important in the management of age-related disorders in memory function. furthermore, the use of gh may also have implications in the management of stressrelated disorders, particularly depression and anxiety disorders. further in vitro as well as in vivo studies are needed to demonstrate other mechanisms that ghada s. mahmoud and ayman s. amer clinical and basic research | e493 may explain the beneficial effects of gh in combating stress. conclusion the results of this study demonstrated an additive effect of the co-exposure of low concentrations of gh and cort on hippocampal synaptic transmission. this beneficial effect was significantly greater in older rats in comparison to younger rats, suggesting a possible protective effect of gh against age-related stress and memory impairment. although short-term treatments of low concentrations of cort for two hours enhanced the fepsps in the ca1 area of the in vitro rat hippocampi, it decreased nr2b expression, which is known to increase synaptic excitability and susceptibility to epilepsy, especially in old age. the co-exposure to both gh and cort reversed these effects by the upregulation of nr2b and by increasing the nr2b:nr2a ratio, which is suppressed by cort alone. the present study also demonstrated the direct role of gh in reversing cort-related changes in the nmdar subunits component of the hippocampus. acknowledgements the authors would like to thank dr. larry grover and dr. todd green of the department of pharmacology, physiology & toxicology of the joan c. edwards school of medicine, marshall university, usa, for their great help and support. references 1. xiao l, feng c, chen y. glucocorticoid rapidly enhances nmda-evoked neurotoxicity by attenuating the nr2acontaining nmda receptor-mediated erk1/2 activation. mol endocrinol 2010; 24:497–510. doi: 10.1210/me.2009-0422. 2. moisan mp, minni am, dominguez g, helbling jc, foury a, henkous n, et al. role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain. steroids 2014; 81:109–15. doi: 10.1016/j.steroids.2013.10.013. 3. poulos am, reger m, mehta n, zhuravka i, sterlace ss, gannam c, et al. amnesia for early life stress does not preclude the adult development of posttraumatic stress disorder symptoms in rats. biol psychiatry 2014; 76:306–14. doi: 10.1016/j.biopsych.2013.10.007. 4. mahmoud gs, grover lm. growth hormone enhances excitatory synaptic transmission in area ca1 of rat hippocampus. j neurophysiol 2006; 95:2962–74. doi: 10.1152/ jn.00947.2005. 5. vander weele cm, saenz c, yao j, correia ss, goosens ka. restoration of hippocampal growth hormone reverses stressinduced hippocampal impairment. front behav neurosci 2013; 7:66. doi: 10.3389/fnbeh.2013.00066. 6. afadlal s, polaboon n, surakul p, govitrapong p, jutapakdeegul n. prenatal stress alters presynaptic marker proteins in the hippocampus of rat pups. neurosci lett 2010; 470:24–7. doi: 10.1016/j.neulet.2009.12.046. 7. medvedev ni, popov vi, rodriguez arellano jj, dallérac g, davies ha, gabbott pl, et al. the n-methyl-d-aspartate receptor antagonist cpp alters synapse and spine structure and impairs long-term potentiation and long-term depression induced morphological plasticity in dentate gyrus of the awake rat. neuroscience 2010; 165:1170–81. doi: 10.1016/j. neuroscience.2009.11.047. 8. bradford mm. a rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. anal biochem 1976; 72:248– 54. doi: 10.1016/0003-2697(76)90527-3. 9. towbin h, staehelin t, gordon j. electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. proc natl acad sci u s a 1979; 76:4350–4. 10. spinola sm, cannon jg. different blocking agents cause variation in the immunologic detection of proteins transferred to nitrocellulose membranes. j immunol methods 1985; 81:161–5. doi: 10.1016/0022-1759(85)90132-2. 11. humphries bj, newton ru, abernethy pj, blake kd. reliability of an electrophoretic and image processing analysis of human skeletal muscle taken from m.vastus lateralis. eur j appl physiol occup physiol 1997; 75:532–6. doi: 10.1007/s004210050200. 12. melrose j, shen b, ghosh p. affinity and western blotting reveal homologies between ovine intervertebral disc serine proteinase inhibitory proteins and bovine pancreatic trypsin inhibitor. proteomics 2001; 1:1529–33. doi: 10.1002/1615-9861(200111)1:12<1529:: aid-prot1529 >3.0.co;2-j. 13. sage d, unser m. easy java programming for teaching image processing. from: www.bigwww.epfl.ch/publications/sage0101. html accessed jan 2014. 14. national institutes of health. guide for the care and use of laboratory animals: eighth edition. from: www.grants.nih. gov/grants/olaw/guide-for-the-care-and-use-of-laboratoryanimals.pdf accessed: aug 2014. 15. molina dp, ariwodola oj, weiner jl, brunso-bechtold jk, adams mm. growth hormone and insulin-like growth factor-i alter hippocampal excitatory synaptic transmission in young and old rats. age (dordr) 2013; 35:1575–87. doi: 10.1007/ s11357-012-9460-4. 16. joëls m. corticosteroid effects in the brain: u-shape it. trends pharmacol sci 2006; 27:244–50. doi: 10.1016/j.tips.2006.03.007. 17. ramis m, sarubbo f, sola j, aparicio s, garau c, miralles a, et al. cognitive improvement by acute growth hormone is mediated by nmda and ampa receptors and mek pathway. prog neuropsychopharmacol biol psychiatry 2013; 45:11–20. doi: 10.1016/j.pnpbp.2013.04.005. 18. bear mf. mechanism for a sliding synaptic modification threshold. neuron 1995; 15:1–4. doi: 10.1016/0896-6273(95) 90056-x. 19. lisman je, mcintyre cc. synaptic plasticity: a molecular memory switch. curr biol 2001; 11:r788–91. doi: 10.1016/ s0960-9822(01)00472-9. 20. manabe t. [molecular mechanisms for memory formation]. brain nerve 2008; 60:707–15. 21. armanini mp, hutchins c, stein ba, sapolsky rm. glucocorticoid endangerment of hippocampal neurons is nmda-receptor dependent. brain res 1990; 532:7–12. doi: 10.1016/0006-8993(90)91734-x. 22. cohen jw, louneva n, han ly, hodes ge, wilson rs, bennett da, et al. chronic corticosterone exposure alters postsynaptic protein levels of psd-95, nr1, and synaptopodin in the mouse brain. synapse 2011; 65:763–70. doi: 10.1002/syn.20900. co-application of corticosterone and growth hormone upregulates nr2b protein and increases the nr2b:nr2a ratio and synaptic transmission in the hippocampus e494 | squ medical journal, november 2014, volume 14, issue 4 23. pawlak r, rao bs, melchor jp, chattarji s, mcewen b, strickland s. tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. proc natl acad sci u s a 2005; 102:18201–6. doi: 10.1073/pnas.0509232102. 24. nacher j, mcewen bs. the role of n-methyl-d-asparate receptors in neurogenesis. hippocampus 2006; 16:267–70. doi: 10.1002/hipo.20160. 25. yoshimura y, ohmura t, komatsu y. two forms of synaptic plasticity with distinct dependence on age, experience, and nmda receptor subtype in rat visual cortex. j neurosci 2003; 23:6557–66. 26. barria a, malinow r. nmda receptor subunit composition controls synaptic plasticity by regulating binding to camkii. neuron 2005; 48:289–301. doi: 10.1016/j.neuron.2005.08.034. 27. ren j, li x, zhang x, li m, wang y, ma y. the effects of intra-hippocampal microinfusion of d-cycloserine on fear extinction, and the expression of nmda receptor subunit nr2b and neurogenesis in the hippocampus in rats. prog neuropsychopharmacol biol psychiatry 2013; 44:257–64. doi: 10.1016/j.pnpbp.2013.02.017. 28. müller l, tokay t, porath k, köhling r, kirschstein t. enhanced nmda receptor-dependent ltp in the epileptic ca1 area via upregulation of nr2b. neurobiol dis 2013; 54:183–93. doi: 10.1016/j.nbd.2012.12.011. 29. yun j, koike h, ibi d, toth e, mizoguchi h, nitta a, et al. chronic restraint stress impairs neurogenesis and hippocampusdependent fear memory in mice: possible involvement of a brain-specific transcription factor npas4. j neurochem 2010; 114:1840–51. doi: 10.1111/j.1471-4159.2010.06893.x. 30. furukawa-hibi y, yun j, nagai t, yamada k. transcriptional suppression of the neuronal pas domain 4 (npas4) gene by stress via the binding of agonist-bound glucocorticoid receptor to its promoter. j neurochem 2012; 123:866–75. doi: 10.1111/ jnc.12034. 31. popoli m, yan z, mcewen bs, sanacora g. the stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. nat rev neurosci 2011; 13:22–37. doi: 10.1038/ nrn3138. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 336-340, epub. 25th jun 13 submitted 27th may 13 peer reviewed accepted 4th jun 13 this issue of the journal highlights issues which significantly impact the physical, mental and environmental health of a generation of children and adolescents. whether it is mute exposure to passive smoking,1 the mental stress faced by professional scholars2 or the frightening emergence of a new generation of young ‘maturity’ onset diabetics,3 it is a clarion call for parents, society and the medical fraternity to stand up and take responsibility. childhood obesity: the silent epidemic the alarming emergence of the silent epidemic of childhood obesity as a prelude to lifelong morbidity (with diabetes, hypertension, dyslipidaemia, insulin resistance, obstructive sleep apnoea being possible consequences)4,5 deserves to be tackled on a war footing. sleep apnoea as a manifestation of corpulence earned literary reknown through the popularity of early dickensian writings, long before authoritative scientific publications linked the two physical phenomena6,7 [figure 1]. charles dickens’ classic description of the frequent somnolence of ‘joe, the fat boy’ is an acknowledged example of the power of observation of a clinical phenomenon by a non-physician.6 the interplay of genetic, physiological and familial factors, physical activity, sedentary behaviour, dietary intake and social cognitive, family and peer, school and community factors are at the heart of this malady.8 the complex problem of an ‘obesogenic’ childhood and adolescence is well summarised in an excellent treatise on the subject.9 the authors provide a comprehensive overview of obesity statistics, the complexity of contributing factors and policies, both existing and required, to address this socio-cultural-environmental health hazard. while a debate still rages as to whether obesity should be considered a disease at all, therapeutic professionals have opened their doors to department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ritu@squ.edu.om ظاهرة االستهالك وحياة اخلمول هل هذه وصيتنا ألطفالنا؟ ريتو الكتكيا editorial conspicuous consumption and sedentary living is this our legacy to our children? ritu lakhtakia the earth is not a gift from our parents, it is a loan from our children kenyan proverb figure 1: “…and on the box sat a fat and red-faced boy, in a state of somnolency”. the posthumous papers of the pickwick club, charles dickens, 1837.6 ritu lakhtakia editorial | 337 a bewildering array of medical and surgical options that have serious implications when advocated for children.10 do we need to be concerned in oman? rapid social and economic transition in the span of just four decades has catapulted the omani population into an affluent lifestyle with its attendant burden of lifestyle diseases. the world health organization (who) predicted an increase of 190% in the number of subjects living with diabetes in oman over the next 20 years, rising from 75,000 in 2000 to 217,000 in 2025.11 the scenario is even more horrifying when you consider that 12% of the population already has diabetes, 30% is overweight, 20% is obese, 41% has high cholesterol, and 21% has the metabolic syndrome.12 if even a small proportion of this astronomical figure are obesity-driven youth diabetics, in a nation where 53% of the population is below 20 years,12 the enormity of the situation cannot be overemphasised. ali et al.’s figures on childhood diabetes in egypt, bring home the stark reality that the disease of ‘maturity’ has changed gears to a much younger and ‘immature’ age group.3 in a study of university students in oman, al-kilani et al. found that almost 28% of students were overweight or obese and, more pertinently, that almost 50% had a high or very high body fat score.13 in studies across the region in oman, lebanon and kuwait, obesity is significantly higher in males compared to females.13–15 obesity, particularly in females, is related to high leptin levels. impact on health type 2 diabetes mellitus (t2dm), coronary heart disease, stroke, osteoporosis, some forms of cancer, and gall bladder disease are the long term outcomes of obesity.4,5 if obesity begins in childhood, the lifetime probability of early onset of one or more of these diseases and the consequent morbidity will obviously increase. early onset cardiovascular disease in arab countries has its origins in improper diet and physical inactivity.16 the hormonal and metabolic consequences of obesity in young people parallel those in obese adults.17 psychological effects such as victimisation, poor self-esteem, negative stereotypes and stigmatisation are just some of the outcomes of obesity. anorexia nervosa is an extreme of this example that may have its origins in childhood obesity.4,5 prejudice and discrimination against the obese often go unnoticed and unreported with significant effects on personality development. who is responsible? the aetiology of obesity encompasses a complex and multifactorial interplay of parents, caregivers, medical practitioners, society, food manufacturers and their advertisers and policy makers; the continuum begins with deranged food habits at home and extends to societal influences and peer pressure. of these, the burden of responsibility lies heavily on parents who are often in denial until adolescence forces the underlying issues to the surface.18 a lack of quality parenting is increasingly being spotlighted as an overwhelming contributor to a range of biological and psychosocial outcomes in later life.19 several genetic and subcellular evolutionary changes serve as theories for abnormal fat accumulation.20 unusual causes include childhood obesity in communities exposed to violence for a sustained period as a manifestation of post-traumatic stress.21 conspicuous consumption there appears to be enough scientific support for traditional breast feeding practices. obesity is one of several unwelcome proven outcomes of the early replacement of breast milk by formula milk and other supplements.22 a high proportion of carbohydrate-rich refined foods in the lists of imports to oman, with minor increases in fruits, is evidence of availability and hence consumption.23 a comparison of food habits in muscat and the southern region of oman showed changed dietary patterns compared to the previous two decades. a decline in breast feeding and the early institution of infant formula and weaning foods, and food composition weighing heavily in favour of fat, cholesterol, refined sugar and salt, is the cost of urbanisation and globalisation and produces heavier and unhealthier children.24 improper diet and physical inactivity in arab countries are leading contributors to obesity and consequently to early onset cardiovascular disease.16 nutritional knowledge has been found to be low in students irrespective of low or high body fat scores in oman.13 the effects of environmental, social and nutritional factors are evidenced by the fact that diabetes affects 17.7% of urban adults versus 10.5% of rural adults (2006 data).25 conspicuous consumption and sedentary living is this our legacy to our children? 338 | squ medical journal, august 2013, volume 13, issue 3 sedentary lifestyles an interesting study done on omani schoolboys of grades 3 and 4 (average age 9 years) and their parents displayed the possible effects of adult behaviour on childhood obesity, revealing that only 32.5% of fathers and 8% of mothers exercised twice weekly. the perception of obesity in the family was 21% in mothers, 11% in fathers and 8% in siblings.26 active lifestyles are most effective when initiated from childhood. there are certainly those who begin later in life but this initiative demands a high sense of self-discipline and motivation to sustain exercise as a part of ones lifestyle. ironically, it appears, the very miracles of scientific gadgetry that fascinate growing children (e.g., mobiles, remote controls, playstations) and supposedly stimulate mental activity in fact restrict bodily activity to rapid finger movements. a rate of car ownership of 69% in oman may be a hallmark of affluence but it also unfortunately means the exertion of minimal physical exertion to get from place to place.27 demographics, family environment and cultural influences urbanisation in oman, rising from 11 to 79% between 1970 and 2005, and expected to reach a mindboggling level of 86% by 2030, has already brought with it a tide of changed dietary and behavioural patterns that directly impact obesity, among other concerns.27 communities, schools and urban planners are considered at the heart and not on the sidelines of addressing the problem of t2dm. addressing obesity, as it is a prelude to t2dm, similarly needs to be family-centric in its approach because long before a child leaves the home, their food habits, tastes and olfactory senses have developed deep-rooted connections in the brain. aggressive food marketing and advertising tactics assault the last efforts at resistance; the golden arches framing ‘m’ against the skyline beckon and stimulate gastric juices from miles away. freebies of cuddly toys or miniatures of the latest cartoon characters blatantly packaged with ‘combo’ meals capture even a toddler’s imagination. there is little counterbalance in attractive, eye-catching and inspiring suggestions for equally tasty, satisfying, balanced foods. a particularly insightful analysis of the influence of cultural practices, beliefs and a distancing of communication between globallyeducated omani health providers and locallyrooted family members, illustrates the yawning gap between health education delivery and receptivity.28 these extend to culturally-acceptable nuances of ‘health’ or even ‘beauty’ when appraising a cherubic child or a well-endowed female form, respectively. notably, a study reports the lack of fat-phobia in omani adolescents in direct contrast to their peers in other countries.29 awareness the bright light at the end of the tunnel is another article in this very issue that illustrates the ongoing efforts for studying and stimulating population awareness.30 it details some of the measures already in place through governmental five-year plans to inculcate healthy lifestyles in children— with obvious lifelong benefits. al-shafaee et al. found 29.5% and 20.8% of adults in a semi-urban population knowledgeable about the contribution to diabetes of obesity and physical inactivity, respectively.31 prevention: family, state and society charity, they say, begins at home. this is certainly true of childhood obesity. parents’ knowledge of balanced nutrition, the establishment of ground rules of food procurement for the family, good old joint family eating practices setting an example through minimising tv snacking by adults, the provision of home-made school snacks and even family cooking sessions—the list is endless, restricted only by the imagination. it is pertinent to note that the traditional omani diet that is regulated in its frequency and content provides a simple ‘back to basics’ formula for stemming the tide of imbalanced dietary practices. fish as a choice of high-protein low-fat food is one such vital ingredient that families relish. salad (khudra) as a regular accompaniment provides vitamins, roughage and, in adequate quantities, satiety. a greater emphasis on home-made versus ready-made will provide the subtle shift from a higher to lower carbohydrate, refined sugar and salt content. regulating quantity of portions is easy when families 'share' organised meals but difficult in fridge-to-couch snacks. it takes a persistent but rewarding lifestyle effort by modern and working mothers to slip fruits and cereals into the routine of planned meals. ritu lakhtakia editorial | 339 adopting ‘the family that plays together…’ adage is really the initiation of a child in preparation for his/her own forays into the world of sports later in life. that this has additional benefits in family bonding and mental health is another achievement. these practices yield the greatest benefit when an early start is made. sending conflicting signals by trying to impose these practices later on tweens and older adolescents is guaranteed to invite rebellious reactions and be entirely counterproductive. within the ministry of health, a separate directorate for non-communicable diseases surveillance and control addresses communitybased initiatives, especially preventive measures like health education.12 deep penetration of awareness measures into secondary and primary health care, however, needs simultaneous educational measures. school health and awareness of the killer diseases related to childhood obesity deserve a media blitz through communication channels patronised by the ever younger tech-savvy youth (twitter, facebook, etc.). a unique attempt to analyse objectively the impact of this epidemic is the arab teens lifestyle study (atls). this is a multicenter collaborative project for assessing the lifestyle habits of adolescents from 11 arab cities across the region, including muscat, and is ultimately aimed at guiding public health policy.32 in 2005, gadget manufacturers tried to extend corporate social responsibility to preventive health by creating aibo, the robotic dog, a pet that reflects the owner’s anti-obesity struggles.33 therapy pharmacotherapy and/or bariatric surgery for childhood/adolescent obesity brings with it moral debates on ethics and child rights.9,34‒36 for extreme situations, anti-obesity medication may be an obligatory inclusion in the pharmacopoeia.12 advances in hygiene, science, automation and the consequent longevity will all come to naught if the weighty shall inherit the earth. through the simple remedial interventions of good parenting, legislation of food products and appropriate advertising, the snowballing epidemic of obesity can not only be halted but reversed. it would be a pity if human evolution leads to a shorter life expectancy punctuated by obesity-associated illnesses—for lack of the simple wisdom of balanced eating and exercise. references 1. furrukh m. tobacco smoking and lung cancer: perception-changing facts. sultan qaboos university med j 2013; 13:345–58. 2. waghachavare vb, dhumale gb, kadam yr, gore ad. a study of stress among students of professional colleges from an urban area in india. sultan qaboos university med j 2013; 13:429–36. 3. ali ba, abdallah st, abdallah ah, hussein mm. the frequency of type 2 diabetes mellitus among diabetic children in el-minia governate, egypt. sultan qaboos university med j 2013; 13:399–403. 4. ludwig ds. childhood obesity–the shape of things to come. n engl j med 2007; 357:2325–7. 5. daniels sr. complications of obesity in children and adolescents. int j obes (lond) 2009; 33:s60–5. 6. kryger m. charles dickens: impact on medicine and society. j clin sleep med 2012; 8:333–8. 7. kryger mh. fat, sleep, and charles dickens: literary and medical contributions to the understanding of sleep apnea. clin chest med 1985; 6:555‒62. 8. patel rr, o’neill jr, liese ad, janz kf, granberg em, colabianchi n, et al. factors associated with development of excessive fatness in children and adolescents: a review of prospective studies. obes rev 2013 apr 22; doi: 10.1111/obr.12035 [epub ahead of print]. 9. lobstein t, baur la, jackson-leach r. the childhood obesity epidemic. in: waters e, swinburn b, seidell j, uauy r. eds. preventing childhood obesity: evidence policy and practice. oxford: wiley-blackwell, bmj books, 2010. pp. 3‒14. 10. hofmann b. bariatric surgery for obese children and adolescents: a review of the moral challenges. bmc medical ethics 2013; 14:18. 11. al-shookri a, khor gl, chan ym, loke sc, almaskari m. type 2 diabetes in the sultanate of oman. malays j nutr 2011; 17:129‒41. 12. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:1‒7. 13. al-kilani h, waly m, yousef r. trends of obesity and overweight among college students in oman: a cross sectional study. sultan qaboos university med j 2012; 12:69‒76. 14. yahia n, achkar a, abdallah a, rizk s. eating habits and obesity among lebanese university students. nutr j 2008; 7:32. 15. al-isa an, campbell j, desapriya e, wijesinghe n. social and health factors associated with physical activity among kuwaiti college students. j obes 2011; 2011:512363. 16. al-hazzaa hm, musaiger ao, arab teens lifestyle study research group. physical activity patterns and eating habits of adolescents living in major arab conspicuous consumption and sedentary living is this our legacy to our children? 340 | squ medical journal, august 2013, volume 13, issue 3 cities: the arab teens lifestyle study. saudi med j 2010; 31:210-11. 17. artz e, haqq a, freemark m. hormonal and metabolic consequences of childhood obesity. endocrinol metab clin north am 2005; 34:643–58. 18. white a, o'brien b, houlihan t, darker c, shea bo. childhood obesity; parents fail to recognise. general practitioners fail to act. ir med j 2012; 105:10‒13. 19. scott s. parenting quality and children's mental health: biological mechanisms and psychological interventions. curr opin psychiatry 2012; 25:301‒6. 20. bhopal rs, rafnsson sb. could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular diseases in south asian populations? int j epidemiol 2009; 38:1072‒81. 21. llabre mm, hadi f. war-related exposure and psychological distress as predictors of health and sleep: a longitudinal study of kuwaiti children. psychosom med 2009; 71:776‒83. 22. hornell a, lagstrom h, lande b, thorsdottir i. breastfeeding, introduction of other foods and effects on health: a systematic literature review for the 5th nordic nutrition recommendations. food nutr res 2013; 57:20823. 23. key statistics of food and agriculture external trade. rome (it): food and agricultural organization of the united nations; 2007. from: http://www.fao.org/ es/ess/top-trade/trade.asp?lang=en&country=221 accessed: may 2013. 24. musaiger ao. food habits of mothers and children in two regions of oman. nutr health 1996; 11:29‒48. 25. al-moosa s, allin s, jemiai n, al-lawati j, mossialos e. diabetes and urbanization in the omani population: an analysis of national survey data. popul health metr 2006; 4:5. 26. hassan mo, al-kharusy w. physical fitness and fatness among omani schoolboys: a pilot study. sultan qaboos university j sci res: med sci 2000; 2:37−41. 27. globalis. oman: urban population. arendal (no): norwegian ministry of foreign affairs, norwegian agency for development cooperation; 2007. from: http://globalis.gvu.unu.edu/indicator_detail. cfm?country=om&indicatorid=30 accessed: may 2013. 28. al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos univ med j 2006; 6:3–9. 29. viernes n, zaidan za, dorvlo as, kayano m, yoishiuchi k, kumano h, et al. tendency toward deliberate food restriction, fear of fatness and somatic attribution in cross-cultural samples. eat behav 2007; 8:407‒17. 30. al mahrouqui b, alhadrami r, al-amri a, altamimi s, al-shidhani a, al-lawati h, et al. self-reported knowledge of diabetes among high school students in al-amerat and quriyat, muscat governate, oman. sultan qaboos university med j 2013; 13:392‒8. 31. al shafaee ma, al-shukaili s, rizvi sg, al farsi y, khan ma, ganguly ss, et al. knowledge and perceptions of diabetes in a semi-urban omani population. bmc public health 2008; 8:249. 32. al-hazzaa hm, musaiger ao, atls research group. arab teens lifestyle study (atls): objectives, design, methodology and implications. diabetes metab syndr obes 2011; 4:417‒26. 33. haslam d. obesity: a medical history. obes rev 2007; 8:s31–6. 34. sundar s, meena s. childhood obesity to type ii diabetes mellitus pathogenesis, importance of behavioral modifications and limitations of pharmacotherapy. int j recent adv pharm res 2011; 4:27‒31. 35. garrett jr, mcnolty la. bariatric surgery and the social character of the obesity epidemic. am j bioeth 2010; 10:20–22. 36. waters e, de silva-sanigorski a, hall bj, brown t, campbell kj, gao y, et al. interventions for preventing obesity in children. cochrane database syst rev 2011; 12:cd001871. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 165-168, epub. 27th feb 13 submitted 3rd mar 12 revision req. 4th jun 12, revision recd. 29th sep 12 accepted 27th oct 12 departments of 1radiology and 3cardiothoracic surgery, faculty of medicine, sütcü imam university, kahramanmaras, turkey; 2department of radiology, educational & research hospital, ahi evran university, kırşehir, turkey *corresponding author e-mail: dryakup23@hotmail.com عملية تسديد تكيس عداري كبدي متمزق إىل الشريان الرئوي يف مريض مسن نتائج التصوير املقطعي احملوسب فوؤاد اأوزكان، يعقوب ي�صلكايا، حمموت توكور، نوري اوزكان، مهمت فاحت ان�صي الن�صداد الرئوي ب�صبب مر�ض العدارية هو عر�ض غري عادي ناجت عن متزق تكي�ض عداري يف القلب اأو فتح عداري الكبد اإىل الدورة الدموية الوريدية. دخل املري�ض البالغ من العمر 78 عاما اإىل ق�صم الطوارئ لدينا وهو ي�صكو من �صيق التنف�ض وال�صعال واآلم �صديدة يف ال�صدر. ك�صف فح�ض الت�صوير املقطعي املحو�صب )mdct( لل�صدر وجود عقيدات متعددة يف كلتا الرئتني، مع غلبة يف الي�صار. اأي�صا وجد خلل اأظهرت mdctفان صور ذلك اإىل وبالإ�صافة ال�صماكة. منخف�صة كتعبئه يظهر وفروعه الرئي�صي الأي�رس الرئوي ال�رسيان يف متكرر كتلتني من التكي�صات منخف�صة ال�صماكة على الف�ض الأي�رس من الكبد مع �صمة كي�صية يف الأذين الأمين. يجب اأن نبقي يف العتبار لدينا احتمال الن�صداد الرئوي يف املر�صى الذين لديهم العداري الكبدية اإذا فاجاأهم اأمل يف ال�صدر و�صيق التنف�ض ، وخا�صة يف املناطق التي يكرث فيها مر�ض العداري. مفتاح الكلمات: الن�صداد الرئوي، متزق، مر�ض الأكيا�ض املائية الكبدي، الت�صوير املقطعي املحو�صب، كبار ال�صن، تقرير حال. abstract: pulmonary embolism due to hydatid disease is an unusual condition resulting from the rupture of a hydatic heart cyst or the opening of liver hydatidosis into the venous circulation. a 78-year old male patient complaining of dyspnea, cough and severe chest pain was admitted to our emergency department. a multidetector computed tomography of the chest revealed the presence of multiple nodules in both lungs especially in left and multiple hypodense filling defect in left main pulmonary artery and its branches. in addition, coronal reformatted multidetector computed tomography images also showed two hypodense cystic parenchymal masses on the left lobe of the liver with a cystic embolus in the right atrium. pulmonary embolism should be kept in mind in patients who have hepatic hydatidosis if suddenly chest pain and dyspnoea occurs, especially in regions where hydatidosis is endemic. keywords: pulmonary embolism; rupture; echinococcosis; hepatic; multidetector computed tomography; aged people; case report; turkey. embolization of ruptured hepatic hydatid cyst to pulmonary artery in an elderly patient multidetector computed tomography findings fuat ozkan,1 *yakup yesilkaya,2 mahmut tokur,3 nuri ozcan,1 mehmet fatih inci1 case report hydatid disease is still an important worldwide health problem. although more dominant in definite sheep-raising countries, worldwide travel has made hydatid liver disease much more prevalent in previously unaffected regions such as northern europe or north america. hydatidosis is a parasitic infection produced by the larvae of echinococcus granulosus. humans may contact the infection either by direct contact with a dog, which is the definitive host, or by ingestion of foods or fluids contaminated by the e. granulosus eggs, which can be present in dog faeces.1–3 after ingestion, the embryos in the eggs release and migrate, most commonly to the liver and lungs; however, other organs can also become involved.2,3 the hydatid cyst of e. granulosus tends to develop in liver (50–70%), lungs (20–30%), or, less frequently, in other parts of the body, such as the brain, heart, and bones.1,4 hydatid pulmonary embolism is an uncommon condition. it is usually seen in cardiac hydatidosis but it can be also due to inferior vena cava (ivc) or hepatic vein invasion in liver hydatidosis.5 we present multidedector computed embolization of ruptured hepatic hydatid cyst to pulmonary artery in an elderly patient multidetector computed tomography findings 166 | squ medical journal, february 2013, volume 13, issue 1 tomography(mdct) findings of a case of with liver hydatidosis causing massive pulmonary emboli. case report a 78-year-old male patient was admitted to the emergency department of kahramanmaras sutcu imam university hospital, kahramanmaras, turkey, complaining of dyspnoea, cough and severe chest pain. the patient had undergone coronary artery bypass grafting 10 years before. on admission, the patient was dyspneic and mildly cyanotic. on examination, the respiration rate was 36 breaths/minute and chest auscultation revealed crackles in his lower left pulmonary fields. his blood pressure (bp) was 130/80 mmhg. the pulse rate was 96 beats/minute. the electrocardiogram was normal, there was no leg oedema, and a laboratory evaluation was within normal limits. the patient had no symptoms suggestive of an anaphylactic reaction. an mdct pulmonary angiography was performed on suspicion of a pulmonary embolism. the mdct of the chest with intravenous contrast administration showed multiple cysts in both lungs, with a predominance in the lower left lung [figure 1], and a hypodense mass located in the left main pulmonary artery which was consistent with an intra-arterial hydatid cyst [figure 2]. in addition, coronal reformatted mdct images also showed two hypodense cystic parenchymal masses on the left lobe of the liver and a cystic embolus in the right atrium [figure 3]. the patient’s clinical history and imaging findings, and the prevalence of hydatid cysts in turkey led to the diagnosis of a pulmonary embolism complicating a liver hydatid cyst. the patient refused surgical intervention and so was treated with a 30-day course of albendazole (andazol®) 10 mg/kg/day in two divided oral doses, and cetirizine hydrochloride (zyrtec®), oral 10 mg tablet, once a day. after several days, the patient’s dyspnea and chest pain resolved with medical treatment and was discharged with his consent. discussion the growth of hydatid cysts is usually slow and asymptomatic, and clinical manifestations are caused by compression of the involved organs. additionally, if hydatid cysts are not detected in time, the cyst may become life-threatening and rupture.6 intrabiliary rupture is the most common and life-threatening complication but intracaval rupture of hydatid disease of the liver is a rare complication. pulmonary artery embolism due to hydatid cyst is an extremely rare entity. there have been a few reports of embolisation following cyst rupture into the ivc or hepatic veins, but these reports have been made based mainly on postmortem examinations.7–10 to the best of our knowledge, this is the first case in the literature where a ruptured liver echinococcal cyst resulted in pulmonary embolus in an elderly patient. in other studies, all patients were figure 1: multidedector computed tomography scan showing irregular, defined patchy lesions (black arrow in right, white arrows in left) in bilateral lung paranchima, especially in the left on lung window. figure 2: multidedector computed tomography angiography shows hypodense masses located in the left main pulmonary artery (white arrow) and in the left distal pulmonary artery to the segmentary branches of the upper lobe. fuat ozkan, yakup yesilkaya, mahmut tokur, nuri ozcan and mehmet fatih inci case report | 167 dissemination of the disease, anaphylactic shock, embolism, and pseudoaneurysm formation.3 the degree of the degenerative changes in the arterial wall, proximal or distal localisations of the pulmonary artery occlusion and irreversible parenchymal changes are factors influencing the selection of the operative procedure.3,4 some patients who refuse surgery should be treated with albendazole due to the disseminated nature of the hydatidosis.4,13 conclusion a ruptured liver echinococcal cyst resulting in pulmonary embolus in an elderly patient is extremely rare. pulmonary hydatid cyst emboli should always be one of the differential diagnoses of the hypodense and/or cystic intr-arterial pulmonary mass in a patient with hepatic hydatid cyst adjacent to the ivc or hepatic veins. references 1. yesilkaya y, ozer c, kilic ya, akpinar e, türkbey b. case report: local allergic reaction of bowel wall secondary to ruptured hydatid cyst. turkiye parazitol derg 2009; 33:286‒8. 2. amr ss, amr zs, jitawi s, annab h. hydatidosis in jordan: an epidemiological study of 306 cases. ann trop med parasitol 1994; 88:623‒7. 3. akgun v, battal b, karaman b, ors f, deniz o, daku a. pulmonary artery embolism due to a ruptured hepatic hydatid cyst: clinical and radiologic imaging findings. emerg radiol 2011; 18:437‒9. 4. koksal c, baysungur v, okur e, sarikaya s, halezeroglu s. a two-stage approach to a patient with hydatid cysts inside the right pulmonary artery and multiple right lung involvement. ann thorac cardiovasc surg 2006; 12:349‒51. 5. pasaoglu i, dogan r, hazan e, oram a, bozer ay. right ventricular hydatid cyst causing recurrent pulmonary emboli. eur j cardiothorac surg 1992; 6:161‒3. 6. torbicki a, perrier a, konstantinides s, agnelli g, galiè n, pruszczyk p, et al. guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the european society of cardiology (esc). eur heart j. 2008; 29:2276‒315. 7. kurt n, oncel m, gulmez s, ozkan z, uzun h. spontaneous and traumatic intra-peritoneal perforations of hepatic hydatid cysts: a case series. j gastrointest surg 2003; 7:635‒41. younger than our patient. being an elderly patient the possibility of a malignant disorder had to be excluded.11 serology, laboratory studies, and skin tests are useful in the diagnosis of hydatid diseases but they lack prognostic value in the determination of intravenous rupture of the hydatid cyst.12 the diagnosis of a hydatid pulmonary embolism is more effectively made through clinical and radiological findings.1 on enhanced ct, the intra-arterial cyst shows the typical hypodense appearance.1 coronal reformatted imaging can be a helpful diagnostic method in identifying the origin of the pulmonary hydatid emboli by showing the involvement in the ivc. specifically, mdct, which is non-invasive and easily available, is a very useful imaging modality for hydatidosis in the liver or other organs. clinically, our case was not considered to be thromboembolic disease. intra-arterial hypodense masses did not show contrast enhancement and that finding was interpreted as not in favour of an intra-arterial tumour. surgical intervention is the primary treatment for pulmonary artery hydatid embolus. embolectomy and/or enucleation are often the preferred surgical options.13 however, rupture of the artery and/or the cyst during surgical intervention may cause figure 3: coronal reformatted multidetector computed tomography images show cystic embolus in the right atrium (white arrow), and hepatic hypodense cystic masses (*). embolization of ruptured hepatic hydatid cyst to pulmonary artery in an elderly patient multidetector computed tomography findings 168 | squ medical journal, february 2013, volume 13, issue 1 8. smith gj, irons s, schelleman a. hydatid pulmonary emboli. australas radiol 2001; 45:508‒11. 9. franquet t, plaza v, llauger j, gimenez a, bordes r. hydatid pulmonary embolism from a ruptured mediastinal cyst: high-resolution computed tomography, angiographic, and pathologic findings. j thorac imaging 1999; 14:138‒41. 10. herek d, karabulut n. ct demonstration of pulmonary embolism due to the rupture of a giant hepatic hydatid disease. clin imaging 2012; 36:612‒4. 11. leila a, laroussi l, abdennadher m, msaad s, frikha i, kammoun s. a cardiac hydatid cyst underlying pulmonary embolism: a case report. pan afr med j. 2011; 8:12. 12. karantanas ah. hydatid bronchial impaction: ct findings. eur radiol 2000; 10:873. 13. eyal i, zveibil f, stamler b. anaphylactic shock due to rupture of a hepatic hydatid cyst into a pericystic blood vessel following blunt abdominal trauma. j pediatr surg 1991; 26:217‒8. 14. bayezid o, ocal a, isik o, okay t, yakut c. a case of cardiac hydatid cyst localized on the interventricular septum and causing pulmonary emboli. j cardiovasc surg (torino) 1991; 32:324‒6. فهرسة اجمللة الطبية جلامعة السلطان قابوس يف ®ميد الين قفزة عالية لألمام يف جمال البحوث احليوية–الطبية والنشر يف منطقة اخلليج العريب medline® indexing of the sultan qaboos university medical journal a great leap forward for biomedical research and publishing in the gulf region sir, i would like to extend my congratulations to the editorial team members, authors and reviewers of the squmj for succeeding in securing indexing of the journal in medline® (national library of medicine, bethesda, maryland, usa), the largest and most prestigious biomedical bibliographic database worldwide.1,2 published quarterly, squmj is an internationally peer-reviewed journal which is also indexed in scopus (elsevier, amsterdam, netherlands), the directory of open access journals, the al-manhal database of arab journals (dubai, united arab emirates) and the world health organization (who) index medicus for the eastern mediterranean region (imemr).3 squmj is a respected journal which attracts original high-quality submissions from oman and other countries in the gulf cooperation council (gcc) region, as well as europe, australasia and north and south america.4 the achievement of acquiring indexing in medline® is indicative of the substantial improvements squmj has made over the past decade. furthermore, this accomplishment will help to increase the accessibility and visibility of research published in squmj to a wider international scientific audience and is expected to result in a rise in the number of citations and submissions of original high-quality research.5 hopefully, this will in turn put oman and the gcc region on the world map of biomedical research and publishing. the ultimate goal of emerging biomedical journals is to achieve international acceptance and visibility through inclusion in major bibliographic databases, such as medline® or the imemr database. around 636 imemr-indexed journals are published in the who eastern mediterranean region, originating from 22 countries and territories.6 there has been a gradual rise in the number of biomedical journals from this region and, as of december 2016, there were 52 peer-reviewed imemr-indexed biomedical journals published in the gulf region.6 however, middle eastern and gcc-based journals are still confronted with several challenges, such as a lack of infrastructure and funding, limited access to new high-quality research due to low visibility and perceived poor peer-review standards.4,7,8 the national library of medicine grants medline® indexing following an application to the literature selection technical review committee.9 this committee convenes three times per year and examines approximately 180 journals at each meeting; subsequently, after rigorous evaluation against pre-defined criteria, only 12–15% of considered journals are recommended for indexing.9 unfortunately, few gcc-based journals meet the minimum requirements to be indexed in mainstream biomedical databases; including squmj, only six of 5,634 medline®-indexed journals are from gcc countries.10 it has been argued that journals from this region tend to publish poor-quality papers due to substandard peer-review processes.7 furthermore, due to a dominant culture of ‘publish or perish’ and its resulting implications, local researchers often submit their high-quality original research to international journals with higher impact factors.7,8 as such, journals from this region may find themselves competing with other recognised international journals for high-quality and original submissions. in order to achieve international recognition and visibility, gcc-based biomedical journals should strive to secure indexing in medline® and other major biomedical databases. editors of different journals should work together to improve the quality and accessibility of their journals by sharing their experiences, exchanging ideas and learning from one another. this could be achieved through close collaboration with the eastern mediterranean association of medical editors and its committees.11 moreover, the contributions of both authors and reviewers letter to the editor sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e123–124, epub. 30 mar 17 submitted 31 dec 16 peer-reviewed accepted 12 jan 17 doi: 10.18295/squmj.2016.17.01.025 medline® indexing of the sultan qaboos university medical journal a great leap forward for biomedical research and publishing in the gulf region e124 | squ medical journal, february 2017, volume 17, issue 1 are crucial to achieving this goal, by submitting original high-quality research and providing rigorous peer reviews, respectively. for squmj, now that it has been indexed in medline® and is visible to an international biomedical audience via the pubmed database (national library of medicine), the journal should continue to maintain its high quality and standards. ibrahim s. al-busaidi edgar diabetes & obesity research centre, dunedin school of medicine, university of otago, dunedin, new zealand e-mail: ibra.3sk@gmail.com references 1. u. s. national library of medicine. fact sheet: medline®. from: www.nlm.nih.gov/pubs/factsheets/medline.html accessed: dec 2016. 2. u. s. national library of medicine. nlm catalog: sultan qaboos university medical journal. from: www.ncbi.nlm.nih.gov/nlmcatalog/ 101519915 accessed: dec 2016. 3. sultan qaboos university medical journal. home page. from: http://web.squ.edu.om/squmj/index.asp accessed: dec 2016. 4. al-maawali a, al busadi a, al-adawi s. biomedical publications profile and trends in gulf cooperation council countries. sultan qaboos univ med j 2012; 12:41−7. 5. lippi g, favalor ej, simundic am. biomedical research platforms and their influence on article submissions and journal rankings: an update. biochem med (zagreb) 2012; 22:7−14. doi: 10.11613/bm.2012.002. 6. world health organization. index medicus for the eastern mediterranean region (imemr). from: www.emro.who.int/informationresources/imemr/imemr.html accessed: dec 2016. 7. habibzadeh f. scientific research in the middle east. lancet 2014; 383:e1−2. 8. habibzadeh f. medical journals in the middle east. lancet 2012; 379:e1. 9. u. s. national library of medicine. faq: journal selection for medline® indexing at nlm. from: www.nlm.nih.gov/pubs/factsheets/j_ sel_faq.html accessed: dec 2016. 10. u. s. national library of medicine. nlm catalog. from: www.ncbi.nlm.nih.gov/nlmcatalog/?term=currentlyindexed accessed: dec 2016. 11. world health organization regional office for the easter mediterranean region. eastern mediterranean association of medical editors. from: www.emro.who.int/entity/emame/ accessed: dec 2016. https://doi.org/10.11613/bm.2012.002 sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e39–45, epub. 21 jan 15 submitted 25 apr 14 revision req. 9 jun 14; revision recd. 22 jun 14 accepted 10 jul 14 departments of 1non-communicable disease control, 2research & studies and 4information & statistics, ministry of health; 3office of the world health organization, muscat, oman; 5weill cornell medical college, doha, qatar *corresponding author e-mail: jallawati@gmail.com االجتاهات يف خطورة ظهور أمراض القلب واألوعية الدموية عند البالغني املصابني بداء السكري يف سلطنة عمان جواد اأحمد اللواتي، جمدي مر�ضي، اآ�ضيا الريامية، روث مابري، مدحت كمال ال�ضيد، حممود عبد العاطي، حوراْء اللوايت abstract: objectives: this study aimed to investigate trends in the estimated 10-year risk for developing cardiovascular disease (cvd) among adults with diagnosed diabetes in oman. in addition, the effect of hypothetical risk reductions in this population was examined. methods: data from 1,077 omani adults aged ≥40 years with diagnosed diabetes were collected and analysed from three national surveys conducted in 1991, 2000 and 2008 across all regions of oman. the estimated 10-year cvd risk and hypothetical risk reductions were calculated using risk prediction algorithms from the systematic coronary risk evaluation (score), diabetes epidemiology collaborative analysis of diagnostic criteria in europe (decode) and world health organization/international society of hypertension (who/ish) risk tools. results: between 1991 and 2008, the estimated 10-year risk of cvd increased significantly in the total sample and among both genders, regardless of the risk prediction algorithm that was used. hypothetical risk reduction models for three scenarios (eliminating smoking, controlling systolic blood pressure and reducing total cholesterol) identified that reducing systolic blood pressure to ≤130 mmhg would lead to the largest reduction in the 10-year risk of cvd in subjects with diabetes. conclusion: the estimated 10-year risk for cvd among adults with diabetes increased significantly between 1991 and 2008 in oman. focused public health initiatives, involving recognised interventions to address behavioural and biological risks, should be a national priority. improvements in the quality of care for diabetic patients, both at the individual and the healthcare system level, are required. keywords: risk assessment; risk reduction behavior; trends; diabetes mellitus; cardiovascular disease; oman. امللخ�ص: الهدف: تهدف هذه الدرا�ضة اإىل درا�ضة اجتاه االأمناط يف تقدير خطورة ظهور مر�س القلب واالأوعية الدموية خلل فرتة 10 �ضنوات وقيا�س تقليل خطورتها االفرتا�ضية بني البالغني الذين يعانون من مر�س ال�ضكري يف �ضلطنة عمان. الطريقة: ا�ضتخدمت بيانات من 1,077 من العمانيني البالغني من العمر 40 عاما فما فوق ممن مت ت�ضخي�س مر�س ال�ضكري لديهم �ضمن ثلثة م�ضوحات وطنية اأجريت يف عام 1991م و2000م و 2008م. ومت ح�ضاب خطورة ظهور مر�س القلب واالأوعية الدموية خلل فرتة 10 �ضنوات، وتخفي�س خطره االفرتا�ضي با�ضتخدام خوارزميات التنبوؤ باملخاطر من درا�ضة ا�ضكور، وديكود وجداول ظهور مر�س القلب واالأوعية الدموية ملنظمة ال�ضحة العاملية واجلمعية الدولية الرتفاع �ضغط الدم. النتائج: خلل الفرتة 1991-2008م، ازدادت خطورة ظهور االأمرا�س القلبية واالأوعية الدموية بني لقيا�س امل�ضتخدمة املعادلة عن النظر بغ�س اجلن�ضني كلي وبني العينة اإجمايل يف كبرية زيادة �ضنوات 10 مدى على ال�ضكري مر�ضى اخلطورة. ومن درا�ضة النماذج االفرتا�ضية للحد من املخاطر لثلثة �ضيناريوهات )وهي الق�ضاء على التدخني اأو ال�ضيطرة على �ضغط الدم االنقبا�ضي اأو احلد من الكولي�ضرتول( تبني اأن خف�س �ضغط الدم االنقبا�ضي اإىل 130 ملم زئبق اأو اأقل �ضيوؤدي اإىل اأكرب خف�س يف م�ضتوى خطورة االأمرا�س القلبية الوعائية خلل ع�رض �ضنوات بني امل�ضابني بداء ال�ضكري. اخلال�صة: لقد ازدادت خطورة ظهور االأمرا�س القلبية الوعائية على مدى ع�رض �ضنوات بني البالغني الذين يعانون من داء ال�ضكري ب�ضكل ملحوظ يف الفرتة من1991 2008م يف �ضلطنة عمان. ويو�ضى برتكيز العمل على تدخلت ال�ضحة العامة ملعاجلة املخاطر ال�ضلوكية والبيولوجية واعتباره من االأولويات، واملطلوب هو حت�ضني نوعية الرعاية على امل�ضتوى الفردي والنظام ال�ضحي. مفتاح الكلمات: تقييم املخاطر؛ �ضلوكيات خفظ املخاطر؛ اأمناط؛ مر�س ال�ضكري اأمرا�س القلب واالأوعية الدموية؛ ُعمان. trends in the risk for cardiovascular disease among adults with diabetes in oman *jawad al-lawati,1 magdi morsi,2 asya al-riyami,2 ruth mabry,3 medhat el-sayed,4 mahmoud abd el-aty,2 hawra al-lawati5 advances in knowledge utilising data from three large cross-sectional surveys conducted in oman, this study shows that the nationwide population-based 10year risk of cardiovascular disease (cvd) has increased over the last two decades among omani diabetic patients who were reportedly free of cvd at the time they were surveyed. application to patient care this study demonstrates that controlling systolic hypertension among diabetic patients will lead to the greatest 10-year risk reduction of cvd among this group, in comparison to the elimination of smoking or the reduction of cholesterol. the results of this study may help to improve the evaluation and management of patients with diabetes within the omani healthcare system. clinical & basic research trends in the risk for cardiovascular disease among adults with diabetes in oman e40 | squ medical journal, february 2015, volume 15, issue 1 cardiovascular disease (cvd) is amajor cause of morbidity and mortality in people with diabetes mellitus, accounting for at least 50% of all diabetes-related disabilities and fatalities in most populations.1,2 strokes, all manifestations of acute coronary syndrome and sudden death are at least twofold more common in people with type 2 diabetes than in non-diabetic individuals.3 furthermore, over 80% of diabetesrelated deaths occur in lowand middle-income countries, thus posing a major threat to public health in most developing countries.4,5 in addition, the arabian peninsula has a higher percentage of excess deaths attributable to diabetes (9%) in comparison to north american (8.5%) or african countries (2.4%).6 the diabetes epidemic is sweeping across the middle east; five of the top 10 globally ranked countries for diabetes prevalence in 2010 were countries in the arabian peninsula.7 thus, a surge in mortality attributed to cvd is expected in such high-risk populations. despite the gravity of this situation, only limited evidence is available regarding the trends in cvd risk factors among arab populations in this region, including one review on nutrition-related noncommunicable diseases.8 the aim of the current study was to investigate temporal trends in the estimated 10-year risk of developing cvd among adults with diagnosed diabetes in oman over the past two decades. in addition, this study examined the effect of hypothetical risk reductions in this population. methods this study used data from three population-based national surveys conducted in oman in 1991, 2000 and 2008.9–11 each survey was designed to include a nationally representative sample from all 11 administrative regions of oman based on census enumeration strategies. additionally, the surveys used multi-stage stratified cluster sampling techniques. in 1991, participants were interviewed at home and then asked to visit the nearest hospital or health centre within the following 72 hours after fasting overnight for at least eight hours. at the hospital/health centre, the participants then underwent various examinations and provided fasting venous blood samples. for the 2001 and 2008 surveys, a trained team collected early morning blood samples from survey participants following an interview at home. investigations were conducted as follows. for the 1991 and 2000 surveys, blood pressure (bp) was measured 10 minutes after the subject was seated using a mercury sphygmomanometer on the upper arm, while the 2008 survey used a digital sphygmomanometer applied to the wrist. in all three surveys, three readings were taken and the average recorded as the final reading. blood samples for measuring glucose levels and cholesterol were collected in sodium fluoride oxalate anticoagulant and lithium heparin anticoagulant containers, respectively. in the 1991 survey, serum glucose and cholesterol were measured using a synchron cx7 biochemistry analyser (beckman coulter, inc., brea, california, usa), while the 2000 and 2008 surveys used the hitachi 911, 912 or 902 automated chemistry analysers (boehringer ingelheim gmbh, ingelheim am rhein, germany). all machines were used as per their instructions and proprietary reagents were supplied by the manufacturers. in the 1991 survey, all samples were collected and transferred for analysis in a central tertiary hospital. in the 2000 and 2008 surveys, samples from each region were analysed in the local regional referral hospital. no attempt was made to assess the effect of methodology changes in the measured biochemical parameters between the three survey periods or between hospitals within the same survey. however, for the 2000 and 2008 surveys, all laboratories used the same methods and machines and applied the same internal and external quality control measures. a diagnosis of diabetes among the participants was based on an oral glucose tolerance test (ogtt) in the 1991 survey and fasting plasma glucose (fpg) values in the 2000 and 2008 surveys using the 1999 diagnostic criteria recommended by the world health organization (who).12 subjects were also classified as having diabetes if they reported a previous diagnosis of diabetes by a physician, regardless of their ogtt results or fpg values. current smokers included participants smoking any type of tobacco at the time of the survey. total/absolute 10-year cvd risk estimates were calculated for diabetic subjects who reported that they had never been diagnosed with a heart condition or heart disease by a physician. these estimates were calculated using three gender-specific tools: the systematic coronary risk evaluation (score), the diabetes epidemiology collaborative analysis of diagnostic criteria in europe (decode) and the joint who/international society of hypertension (ish) risk prediction chart.13–15 these tools were selected because the risk calculation formulae used were readily available and because the variables required had been measured and collected during the three national surveys. since two of the three tools (score and who/ish charts) were directed towards subjects jawad al-lawati, magdi morsi, asya al-riyami, ruth mabry, medhat el-sayed, mahmoud abd el-aty and hawra al-lawati clinical and basic research | e41 aged ≥40 years, the risk estimates for this study were also calculated using a cohort of the same age. all three tools incorporated age, gender, current smoking and diabetic status, systolic bp (sbp) and total cholesterol (tc) to estimate 10-year cvd risk (except score which did not include diabetic status). score and decode published equations; thus calculated estimates using these tools were presented as mean cvd risk over a 10-year period. conversely, who/ish risk prediction charts were published according to incremental risk categories and estimates were therefore presented as proportions of subjects with ≥30% risk over 10 years. since who/ish charts were developed to be region-, countryand incomespecific, the eastern mediterranean region charts in category b were utilised as oman falls within this regional and income category.15 tests for linear trends in cvd risk were conducted using logistic regression analyses, in which the survey period was used as a continuous independent variable and 10-year cvd risk as the dependent variable. hypothetical estimates of 10-year risk reduction for adults with diabetes were calculated using all three risk tools and under the following scenarios: eliminating all current smoking; reducing systolic bp to <130 mmhg for subjects with a systolic bp of ≥130 mmhg, and reducing tc to <5.2 mmol/l for those with a tc concentration of ≥5.2 mmol/l. statistical analyses were performed using stata software, version 11.1 (stata corp., college station, texas, usa). results the overall response rate for the three surveys was 93%, 83% and 79% for the 1991, 2000 and 2008 surveys, respectively.9–11 a total of 1,900 subjects aged ≥40 years were diagnosed with diabetes in the three surveys. a total of 53% were female. pregnant women (n = 24) and individuals missing data required to estimate 10-year cvd risk (n = 799) in the three surveys were excluded, giving a total sample of 1,077. over two decades, the mean age of diabetic subjects significantly increased from 51.5 to 57.7 years (p <0.001). in contrast, the mean tc trend in the entire cohort showed a significant decline from 6.0 mmol/l in 1991 to 5.4 mmol/l in 2008 (p <0.001). this trend was observed in both men and women. in addition, the proportion of male current smokers doubled from 9.7% in 1991 to 19.6% in 2008 (p = 0.03). mean sbp in men increased by more than 10 mmhg during the same time period (139.3 mmhg in 1991 to 149.9 mmhg in 2008; p = 0.002). no significant linear trends were noted with respect to the percentage of women (p = 0.379), current smokers (p = 0.163) or sbp (p = 0.135) in the entire sample [table 1]. a consistent and significant increase in the 10-year risk of cvd in the entire diabetic cohort and between both genders was observed, regardless of the risk tool used [figure 1]. the mean estimated 10-year risk for developing cvd using the score tool increased significantly in the total sample (regression coefficient = 10.4%; standard error [se] = 2.3; p <0.001) as well as among males (regression coefficient = 10.8%; se = 2.5; p <0.001) and females (regression coefficient = 13.9%; se = 5.7; p = 0.013). although lower in magnitude, the table 1: characteristics of variables used to calculate the estimated 10-year risk of cardiovascular disease among omani diabetic adults aged ≥40 years between 1991–2008* (n = 1,077) variables survey year† p value 1991 2000 2008 total n 379 470 228 women in % 54.6 (2.6) 50.0 (2.3) 56.3 (4.6) 0.379 mean age in years 51.5 (0.5) 56.7 (0.5) 57.7 (0.8) <0.001 current smoker in % 5.6 (1.2) 6.8 (1.1) 8.5 (2.1) 0.163 mean sbp in mmhg 142.1 (1.1) 138.6 (0.9) 146.4 (1.6) 0.135 mean tc in mmol/l 6.0 (0.1) 5.8 (0.1) 5.4 (0.1) <0.001 men n 172 235 100 mean age in years 51.8 (0.7) 56.8 (0.8) 58.4 (1.3) <0.001 current smoker in % 9.7 (2.3) 12.0 (2.1) 19.6 (4.7) 0.030 mean sbp in mmhg 139.3 (1.6) 137.2 (1.2) 149.9 (2.7) 0.002 mean tc in mmol/l 5.9 (0.1) 5.7 (0.1) 5.4 (0.1) 0.002 women n 207 235 128 mean age in years 51 (0.6) 57 (0.6) 57.2 (0.9) <0.001 current smoker in % 2.1 (1.1) 1.7 (1.2) 0 (-) 0.157 mean sbp in mmhg 144.3 (1.6) 140.0 (1.3) 143.6 (1.9) 0.463 mean tc in mmol/l 6.0 (0.9) 5.9 (0.1) 5.3 (0.1) <0.001 sbp = systolic blood pressure; tc = total cholesterol. *data from three population-based national surveys.9–11 †numbers in brackets signify standard error. trends in the risk for cardiovascular disease among adults with diabetes in oman e42 | squ medical journal, february 2015, volume 15, issue 1 decode risk tool also showed a similar pattern. over the period of 1991–2008, men had the highest relative increase (120%) in the mean 10-year cvd risk using the score tool (5% in 1991 to 11% in 2008). although the relative increase in score risk was less marked among women (60%), an increase was also noted (2% in 1991 to 3.2% in 2008). the proportion of subjects with a 10-year cvd risk of ≥30% increased from 26.1% in 1991 to over 47% in 2008 (p <0.001) using the who/ish charts. calculations of four hypothetical risk reduction scenarios (eliminating all current smoking, controlling sbp, attaining a favourable tc profile or all three combined) suggested that the largest reduction in the 10-year risk of developing cvd would be gained by improving sbp control compared to the other two interventions. this finding was consistently seen across risk tools and for all three periods studied. simultaneous modifications of all three risk reduction techniques produced an additional yet modest reduction in the 10-year risk of cvd among people with diabetes [table 2]. discussion morbidity and mortality resulting from all forms of cvd are 2–8-fold higher among individuals with diabetes than in those without.16 diabetes management should therefore include recommendations to prevent and control cvd risk. using the score, decode and who/ish risk tools, this study found an increasing trend in the 10-year cvd risk among both men and women with diabetes in oman between 1991–2008. in contrast, studies from industrialised nations have reported a declining trend in death rates and 10-year cvd risk among diabetic patients over the past two decades.17,18 this decline is largely attributed to improved management of cvd risk factors and hyperglycaemia through medication and behavioural changes.18,19 in oman, a small number of community-based interventions focusing on both individual and community-wide behavioural change have been initiated at the provincial level. the largest of these was implemented in the nizwa region in 2001.20 however, the 2010 nizwa healthy lifestyle project evaluation report indicated that the prevalence of diabetes in nizwa had increased from 9.2% in 2001 to 9.7% in 2010 (p = 0.61).21 similar increases were seen in the prevalence of cvd risk factors during the same time period, including pre-hypertension (8% to 13%; p = 0.0001), clinical hypertension (12% to 24%; p <0.001), being overweight (28% to 33%; p = 0.001) and obesity (13% to 17%; p = 0.001), although it is possible that these trends are not as dramatic as those observed nationally.21 for community-based interventions aiming to reduce cvd risk impact, policies and legislation related to tobacco control, salt reduction in foods and food taxes or subsidies to support healthy eating need to be developed in coordination with other sectors and implemented within communities in order for them to have the desired effect.4 in the present study, men were shown to have an absolute 10-year cvd risk that was 2–6 times higher than women. this may be a function of the observed increase among men of all the studied cvd risk factors; in comparison, only the risk factors of age and tc levels were found to increase among figure 1a–c: estimated trends of the 10-year risk for developing cardiovascular disease among adults with diabetes mellitus in oman by gender and year using data from three population-based national surveys.9–11 risk prediction was calculated using the (a) systematic coronary risk evaluation (score), (b) diabetes epidemiology collaborative analysis of diagnostic criteria in europe (decode) and (c) world health organization (who)/international society of hypertension (ish) tools.13–15 for score and decode, each point on the graph represents the mean for 10-year risk and the bars represent the upper and lower limits of the 95% confidence intervals. *significance of linear trend test. jawad al-lawati, magdi morsi, asya al-riyami, ruth mabry, medhat el-sayed, mahmoud abd el-aty and hawra al-lawati clinical and basic research | e43 women. in a study of 2,551 people with diabetes, al-lawati et al. reported that men, on average, were older and had worse glycaemic and lipid profiles (glycated haemoglobin a1c ≥7% and tc ≥5.2 mmol/l) compared to women.22 thus, the gender difference may be due at least partly to increased biological cvd risk levels in men,23 as well as a higher prevalence of behavioural risk factors among males (e.g. the prevalence of daily smoking in men is 14.8% compared to <0.5% in women).12 furthermore, the mean age of the subjects increased by seven years over the span of two decades and this may also partially explain the increase in cvd risk in the total cohort. a small intervention study found that treatment plans were adhered to more closely among women than men; this may also partially explain the gender difference.24 it is also possible that the observed gender difference is a function of the equations used by the three risk tools to estimate 10-year cvd risk. further research on ways to improve the implementation of diabetes management guidelines in oman may prove useful in reducing gender disparities in cvd risk. in the current study, the possible impact of hypothetical scenarios on 10-year cvd risk reduction was assessed. among the risk factors studied (smoking, high cholesterol and hypertension), the analysis revealed that reducing sbp to ≤130 mmhg would result in the greatest reduction in 10-year cvd risk for the omani population. in contrast, a similar analysis in the usa using the uk prospective diabetes study (ukpds) risk engine determined that reducing tc to <5.2 mmol/l and raising high-density lipoprotein levels to 1.05 mmol/l in men and 1.3 mmol/l in women were the factors that would most significantly reduce the 10-year coronary risk in their population.18 this difference is possibly due to decreasing tc levels and a simultaneous increase in hypertension among the general population of oman.12,25 more intense population-based efforts to address risk factors for hypertension in oman are warranted, particularly regarding behavioural risks such as high salt intake, unhealthy diets and physical inactivity. the who has identified the most cost-effective interventions to address cvd risk factors fueling the global epidemic of non-communicable diseases;4 these could be used to guide public health action in oman. suboptimal management of glycaemia and cardiovascular risk factors among individuals with diabetes has been reported widely.26 similar concerns have been raised regarding the quality of care provided for diabetic patients in oman.22,27–29 based on local evidence, strengthening patient education and selfmanagement, training health workers in the primary care setting on behavioural change and redesigning delivery of care systems at the local level have been identified as key factors to improving quality of care.24,30 in addition, promoting more aggressive diabetes management may decrease the incidence of cvd.31–35 table 2: estimated 10-year risk for cardiovascular disease among omani diabetic adults aged ≥40 years according to different risk reduction scenarios and risk tools13–15 between 1991–2008* (n = 1,077) survey year† 1991 (n = 379) 2000 (n = 470) 2008 (n = 228) current risk mean score risk 3.5 (0.3) 5.7 (0.4) 6.6 (0.7) mean decode risk 2.5 (0.2) 3.3 (0.2) 3.5 (0.2) who/ish risk in % with risk ≥30% 26.1 (2.3) 37.3 (2.2) 47.1 (4.6) smoking elimination scenario mean score risk 3.4 (0.3) 5.3 (0.4) 6.3 (0.7) mean decode risk 2.4 (0.2) 3.1 (0.2) 3.2 (0.2) who/ish risk in % with risk ≥30% 25.3 (2.3) 36.2 (2.2) 45.5 (4.6) sbp <130 mmhg scenario mean score risk 2.2 (0.2) 3.9 (0.3) 3.9 (0.3) mean decode risk 1.7 (0.1) 2.4 (0.1) 2.4 (0.2) who/ish charts in % with risk ≥30% 15.3 (1.9) 25.6 (2.1) 32.5 (4.5) tc level <5.2 mmol/l scenario mean score risk 2.9 (0.3) 4.7 (0.4) 5.8 (0.6) mean decode risk 2.2 (0.1) 3.0 (0.1) 3.2 (0.2) who/ish risk in % with risk ≥30% 26.1 (2.3) 36.9 (2.2) 47.1 (4.6) overall combined scenario mean score risk 1.7 (0.1) 3.0 (0.2) 3.2 (0.3) mean decode risk 1.4 (0.1) 2.0 (0.1) 2.1 (0.1) who/ish risk in % with risk ≥30% 14.7 (1.9) 27.7 (2.1) 31.8 (4.5) score = systematic coronary risk evaluation; decode = diabetes epidemiology collaborative analysis of diagnostic criteria in europe; who/ish = world health organization/international society of hypertension; sbp = systolic blood pressure; tc = total cholesterol. *data from three population-based national surveys.9–11 †numbers in brackets signify standard error. trends in the risk for cardiovascular disease among adults with diabetes in oman e44 | squ medical journal, february 2015, volume 15, issue 1 the strength of the current study lies in the utilisation of three population-based national surveys with similar methodologies to estimate the 10-year cvd risk among omanis with diabetes. however, some uncertainty exists regarding the reported age of participants. all studied cohorts were born before or around 1968 when the entire country had only one hospital. at this time, birth registration was not a statutory requirement; even during the 1970s and 1980s, there was no emphasis on registering events such as deaths or births.36 it is possible, therefore, that the selected sample of adults does not include all those who were eligible for inclusion in this study due to inaccurate reporting among older adults. this may therefore have diluted the real mean estimates of the 10-year cvd risk. a second source of bias may have been introduced with missing variables, particularly with data obtained from the 2008 survey, as approximately 700 blood samples were not obtained. this missing data may indicate that certain subjects were excluded (for example, diabetic subjects who did not attend a scheduled blood test), thereby further diluting the measured effect on cvd trends. in addition, cvd-free status was self-reported by participants and not objectively verified. given that illness-denial is not uncommon among survey subjects,37 this may have resulted in an overestimation of the 10-year cvd risk. a further limitation of this study was that two of the tools used to estimate 10-year cvd risk (score and decode) were developed for european patients who are likely to differ from an arab population in the middle east. a study by coleman et al. determined that these tools were not reliable across all patient populations.38 this factor may have biased risk estimates. finally, the score risk tool did not include any variable on glucose status as diabetes is often regarded as a coronary heart disease risk equivalent.39 nonetheless, this tool was used in the current study to evaluate cvd risk in people with diabetes. conclusion the increasing incidence of diabetes and associated risk factors for cvd is a serious public health concern in oman. using risk prediction tools, this study found an increasing trend in the 10-year cvd risk among both men and women with diabetes in oman between 1991–2008. focused community-based public health action based on recognised interventions to address behavioural risks for cvd should be a priority. improving the quality of care, both at the individual and health system level, requires extra clinical emphasis in addition to personnel and financial resources. further research on populationand individual-based interventions should be undertaken to guide specific public health actions to minimise the cvd risk among diabetic patients in oman. a c k n o w l e d g e m e n t s the authors thank the department of research & studies, ministry of health, oman, for sharing the dataset of the 2008 oman world health survey. additionally, the authors would also like to thank the nizwa healthy lifestyle project team for sharing selected results from their 2010 survey. the views expressed in this paper are those of the authors and do not necessarily reflect those of the who. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. international diabetes federation. complications of diabetes. from: www.idf.org/complications-diabetes accessed: oct 2013. 2. barrett-connor e, pyörälä k. long-term complications: diabetes and coronary heart disease. in: j-m ekoé, p zimmet, williams r, eds. the epidemiology of diabetes mellitus: an international perspective. west sussex, uk: john wiley & sons ltd., 2001. pp. 301–18. 3. laakso m, lehto s. epidemiology of macrovascular disease in diabetes. diabetes rev 1997; 5:294–315. 4. world health organization. global status report on noncommunicable diseases 2010: description of the global burden of ncds, their risk factors and determinants. from: www.who.int/nmh/publications/ncd_report2010/en/ accessed: mar 2014. 5. pradeepa r, prabhakaran d, mohan v. emerging economies and diabetes and cardiovascular disease. diabetes technol ther 2012; 14:s59–67. doi: 10.1089/dia.2012.0065. 6. roglic g, unwin n, bennett ph, mathers c, tuomilehto j, nag s, et al. the burden of mortality attributable to diabetes: realistic estimates for the year 2000. diabetes care 2005; 28:2130–5. doi: 10.2337/diacare.28.9.2130. 7. shaw je, sicree ra, zimmet pz. global estimates of the prevalence of diabetes for 2010 and 2030. diabetes res clin pract 2010; 87:4–14. doi: 10.1016/j.diabres.2009.10.007. 8. ng sw, zaghloul s, ali hi, harrison g, popkin bm. the prevalence and trends of overweight, obesity and nutritionrelated non-communicable diseases in the arabian gulf states. obes rev 2011; 12:1–13. doi: 10.1111/j.1467-789x.20 10.00750.x. 9. asfour mg, lambourne a, soliman a, al-behlani s, al-asfoor d, bold a, et al. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabet med 1995; 12:1122–5. doi: 10.1111/j.1464-5491.1995.tb00431.x. 10. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. doi: 10.1046/j.1464-5491.2002.00818.x. 11. al-riyami a, abdelaty ma, jaju s, morsi m, al-kharusi h, al-shekaili w. world health survey 2008. muscat, oman: ministry of health, 2012. jawad al-lawati, magdi morsi, asya al-riyami, ruth mabry, medhat el-sayed, mahmoud abd el-aty and hawra al-lawati clinical and basic research | e45 12. alberti kg, zimmet pz. definition, diagnosis and classification of diabetes mellitus and its complications. part 1: diagnosis and classification of diabetes mellitus, provisional report of a who consultation. diabet med 1998; 15:539–53. doi: 10.1002/ (sici)1096-9136(199807)15:7<539::aid-dia668>3.0.co;2-s. 13. conroy rm, pyörälä k, fitzgerald ap, sans s, menotti a, de backer g, et al; score project group. estimation of ten-year risk of fatal cardiovascular disease in europe: the score project. eur heart j 2003; 24:987–1003. doi: 10.1016/s0195668x(03)00114-3. 14. balkau b, hu g, qiao q, tuomilehto j, borch-johnsen k, pyörälä k; decode study group; european diabetes epidemiology group. prediction of the risk of cardiovascular mortality using a score that includes glucose as a risk factor: the decode study. diabetologia 2004; 47:2118–28. doi: 10.1007/s00125-004-1574-5. 15. world health organization. who/ish risk prediction charts for 14 who epidemiological sub-regions. from: www.ishworld.com/downloads/activities/colour_charts_24_aug_07. pdf accessed: jan 2012. 16. grundy sm, howard b, smith s jr., eckel r, redberg r, bonow ro. prevention conference vi: diabetes and cardiovascular disease: executive summary: conference proceeding for healthcare professionals from a special writing group of the american heart association. circulation 2002; 105:2231–9. doi: 0.1161/01.cir.0000013952.86046.dd. 17. gregg ew, cheng yj, saydah s, cowie c, garfield s, geiss l, et al. trends in death rates among u.s. adults with and without diabetes between 1997 and 2006: findings from the national health interview survey. diabetes care 2012; 35:1252–7. doi: 10.2337/dc11-1162. 18. ford es. trends in the risk for coronary heart disease among adults with diagnosed diabetes in the u.s.: findings from the national health and nutrition examination survey, 1999– 2008. diabetes care 2011; 34:1337–43. doi: 10.2337/dc10-2251. 19. ford es, ajani ua, croft jb, critchley ja, labarthe dr, kottke te, et al. explaining the decrease in u.s. deaths from coronary disease, 1980-2000. n engl j med 2007; 356:2388–98. doi: 10.1056/nejmsa053935. 20. al-lawati ja, mohammed aj, al-hinai hq, jousilahti p. prevalence of the metabolic syndrome among omani adults. diabetes care 2003; 26:1781–5. doi: 10.2337/diacare.26.6.1781. 21. ministry of health. nizwa healthy lifestyle project evaluation report 2010. muscat, oman: ministry of health, 2014. 22. al-lawati ja, n barakat m, al-zakwani i, elsayed mk, almaskari m, m al-lawati n, et al. control of risk factors for cardiovascular disease among adults with previously diagnosed type 2 diabetes mellitus: a descriptive study from a middle eastern arab population. open cardiovasc med j 2012; 6:133– 40. doi: 10.2174/1874192401206010133. 23. lloyd-jones dm, larson mg, beiser a, levy d. lifetime risk of developing coronary heart disease. lancet 1999; 353:89–92. doi: 10.1016/s0140-6736(98)10279-9. 24. al-sinani m, min y, ghebremeskel k, qazaq hs. effectiveness of and adherence to dietary and lifestyle counselling: effect on metabolic control in type 2 diabetic omani patients. sultan qaboos univ med j 2010; 10:341–9. 25. al-riyami a, afifi m, al-kharusi h, morsi m. national health survey, study of lifestyle risk factors 2000. muscat, oman: ministry of health, 2003. 26. gakidou e, mallinger l, abbott-klafter j, guerrero r, villalpando s, ridaura rl, et al. management of diabetes and associated cardiovascular risk factors in seven countries: a comparison of data from national health examination surveys. bull world health organ 2011; 89:172–83. doi: 10.2471/ blt.10.080820. 27. abdulhadi n, al shafaee m, freudenthal s, ostenson cg, wahlström r. patient-provider interaction from the perspectives of type 2 diabetes patients in muscat, oman: a qualitative study. bmc health serv res 2007; 7:162. doi: 10.1186/1472-6963-7-162. 28. elliott ja, abdulhadi nn, al-maniri aa, al-shafaee ma, wahlström r. diabetes self-management and education of people living with diabetes: a survey in primary health care in muscat oman. plos one 2013; 8:e57400. doi: 10.1371/journal. pone.0057400. 29. al-mandhari a, al-zakwani i, el-shafie o, al-shafaee m, woodhouse n. quality of diabetes care: a cross-sectional observational study in oman. sultan qaboos univ med j 2009; 9:32–6. 30. al-shookri a, khor gl, chan ym, loke sc, al-maskari m. effectiveness of medical nutrition treatment delivered by dietitians on glycaemic outcomes and lipid profiles of arab, omani patients with type 2 diabetes. diabet med 2012; 29:236– 44. doi: 10.1111/j.1464-5491.2011.03405.x. 31. kesteloot h, sans s, kromhout d. dynamics of cardiovascular and all-cause mortality in western and eastern europe between 1970 and 2000. eur heart j 2006; 27:107–13. doi: 10.1093/ eurheartj/ehi511. 32. ferrannini e, cushman wc. diabetes and hypertension: the bad companions. lancet 2012; 380:601–10. doi: 10.1016/ s0140-6736(12)60987-8. 33. mannucci e, monami m, lamanna c, gori f, marchionni n. prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials. nutr metab cardiovasc dis 2009; 19:604–12. doi: 10.1016/j. numecd.2009.03.021. 34. kelly tn, bazzano la, fonseca va, thethi tk, reynolds k, he j. systematic review: glucose control and cardiovascular disease in type 2 diabetes. ann intern med 2009; 151:394–403. doi: 10.7326/0003-4819-151-6-200909150-00137. 35. gaede p, vedel p, larsen n, jensen gv, parving hh, pedersen o. multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. n engl j med 2003; 348:383–93. doi: 10.1056/nejmoa021778. 36. elsayed mk. civil registration in the sultanate of oman: its development and potential implications on vital statistics. global forum on gender statistics. from: www. en.istat.it/istat/eventi/2007/globalforum/martedimattina/ civilregistrationoman.pdf accessed: jan 2014. 37. covino jm, stern tw, stern ta. denial of cardiac illness: consequences and management. prim care companion cns disord 2011; 13. doi: 10.4088/pcc.11f01166. 38. coleman rl, stevens rj, retnakaran r, holman rr. framingham, score, and decode risk equations do not provide reliable cardiovascular risk estimates in type 2 diabetes. diabetes care 2007; 30:1292–3. doi: 10.2337/dc06-1358. 39. whiteley l, padmanabhan s, hole d, isles c. should diabetes be considered a coronary heart disease risk equivalent? results from 25 years of follow-up in the renfrew and paisley survey. diabetes care 2005; 28:1588–93. doi: 10.2337/diacare.28.7.1588. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e424–428, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.020. submitted 17 nov 14 revision req. 8 feb 15; revision recd. 18 mar 15 accepted 9 apr 15 departments of 1child health and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mails: mnaggari@squ.edu.om, mnaggari@yahoo.com and mnaggari@hotmail.com متالزمة اعتالل مؤخرة الدماغ العكسي يف اثنني من األطفال العمانيني الذين يعانون من أمراض الكلى الكامنة حممد عاطف النجاري، دانا النبهاين، ابت�سام النور، عالء املنزلوي، اأن�س الوجود عبد املغيث abstract: posterior reversible encephalopathy syndrome (pres) is a neurological condition with a combination of clinical and radiological features. clinical symptoms include headaches, confusion, seizures, disturbed vision or an altered level of consciousness. classic magnetic resonance imaging (mri) findings indicate subcortical and cortical oedema, affecting mainly the posterior cerebral region. we report two paediatric cases of pres with underlying renal diseases presenting at the sultan qaboos university hospital in muscat, oman, in april 2010 and august 2011. the first case was an 11-year-old girl diagnosed with systemic lupus erythematosus and the second was a six-and-a-half-year-old boy on peritoneal dialysis due to multi-drug-resistant nephrotic syndrome. both patients were hypertensive and treated with blood pressure control medications. no residual neurological dysfunction was noted in the patients at a one-year follow-up and at discharge, respectively. the role of hypertension in paediatric pres cases, among other important risk factors, is emphasised. additionally, mri is an important diagnostic and prognostic tool. prompt diagnosis and aggressive management is fundamental to preventing permanent neurological damage. keywords: posterior reversible encephalopathy syndrome; pediatrics; peritoneal dialysis; systemic lupus erythematosus; magnetic resonance imaging; case report; oman. امللخ�ص: متالزمة اعتالل موؤخرة الدماغ العك�سي )pres( هي حالة ع�سبية مع مزيج من العالمات ال�رسيرية و عالمات �سور الأشعة السينية. ت�سمل الأعرا�س ال�رسيرية ال�سداع، الرتباك، الت�سنجات، ا�سطراب الروؤية اأو تغري م�ستوى الوعي. ت�سري النتائج النموذجية للت�سوير بالرنني املغناطي�سي )mri( اإىل ا�ست�سقاء حتت الق�رسية املخية و يف الق�رسية، والتي توؤثر ب�سكل رئي�سي على منطقة الدماغ اخللفية. هذا تقرير عن حالتني ملتالزمة اعتالل موؤخرة الدماغ العك�سي يف الأطفال الذين يعانون من اأمرا�س الكلى الكامنة يف م�ست�سفى جامعة ال�سلطان قابو�س يف م�سقط، عمان، يف اأكتوبر 2010 و اأغ�سط�س 2011. احلالة الأوىل لفتاة تبلغ من العمر اأحد ع�رس عاما �سخ�ست مبر�س الذئبة احلمراء والثانية ل�سبي يبلغ من العمر �ستة اأعوام ون�سف على غ�سيل الكلى الربيتوين نتيجة متالزمة كلوية متعددة املقاومة لالأدوية. عانت كال احلالتني من ارتفاع �سغط الدم ومت عالجهم باأدوية لل�سيطرة على �سغط الدم. مل يالحظ وجود اأي خلل وظيفي يف اجلهاز الع�سبي لدى املري�سني عند خروجهم من امل�ست�سفى و ملدة عام من املتابعة. ي�سري هذا التقرير إىل دور ارتفاع �سغط الدم بني عوامل اخلطورة الهامة الأخرى يف حدوث حالت متالزمة اعتالل موؤخرة الدماغ العك�سي يف الأطفال. بالإ�سافة اإىل ذلك، فإنه يجب التاأكيد علي اأهمية الت�سوير بالرنني املغناطي�سي كاأداة ت�سخي�سية واإنذارية هامة. الت�سخي�س ال�رسيع والعالج الفاعل هما اأمران اأ�سا�سيان لوقاية من الأ�رسار الع�سبية الدائم يف هذه املتالزمة. مفتاح الكلمات: متالزمة اعتالل موؤخرة الدماغ العك�سي؛ الأطفال؛ غ�سيل الكلى الربيتوين؛ الذئبة احلمراء؛ الت�سوير بالرنني املغناطي�سي؛ تقريرحالة؛ عمان. posterior reversible encephalopathy syndrome in two omani children with underlying renal diseases *mohamed a. el-naggari,1 dana al-nabhani,1 ibtisam el-nour,1 alaa el-manzalawy,2 anas-alwogud a. abdelmogheth1 online case report the following two cases are, to the best of the authors’ knowledge, the first reported cases of paediatric pres with underlying renal diseases in the omani population. the aim of this report was to increase awareness among physicians and emphasise early recognition of this condition in order to improve management and outcomes. common renal risk factors that may cause pres are also elucidated, as well as the important role of mri as a diagnostic and prognostic tool. posterior reversible encephalopathy syndrome (pres) is a neurological condition that combines a number of clinical and radiological features. clinical symptoms include headaches, confusion, seizures, disturbed vision and an altered level of consciousness.1 the classic magnetic resonance imaging (mri) findings are subcortical and cortical oedema, mainly affecting the posterior cerebral region.2 mohamed a. el-naggari, dana al-nabhani, ibtisam el-nour, alaa el-manzalawy, and anas-alwogud a. abdelmogheth online case report | e425 case 1 an 11-year-old girl with systemic lupus erythematosus (sle) presented to the sultan qaboos university hospital (squh) in muscat, oman, in october 2009. the immunological diagnosis of sle was confirmed by positive tests for antinuclear, anti-double-stranded dna, anti-histone and anti-smith antibodies. pathology assessment of a renal biopsy indicated class iv diffuse lupus nephritis with a focal crescent formation. the course of the first six months of the illness was severe. initially, she responded to mycophenolate mofetil, oral prednisolone and hydroxychloroquine. however, the patient had severe hypertension which was difficult to control. this was eventually regulated with four antihypertensive medications (lisionpril, frusemide, hydralazine and amlodipine). the hypertension was monitored at the patient’s local health centre and peripheral hospital. at a follow-up visit in april 2010, the patient’s blood pressure (bp) was high at 180/100 mmhg (normal ageand gender-matched range: 95th percentile, 119/78 mmhg; 99th percentile, 126/86 mmhg). during the follow-up visit, the patient suddenly developed severe headaches while showing signs of agitation and abnormal behaviour. in addition, she began having generalised tonic-clonic seizures. a central nervous system examination revealed an impaired attention span, good coordination and normal cranial nerve activity. no meningeal or cerebellar signs and no focal neurological deficit were observed. however, there was a marked weakness in the proximal muscle group, which was associated with normal tone and increased reflexes in the lower limbs. an eye examination showed equal pupils reactive to light, while a fundus examination showed small retinal and conjunctival haemorrhages with no signs of papilloedema. other clinical systemic examinations were normal. the child was admitted to the squh paediatric intensive care unit (picu) for respiratory support, due to recurrent seizures that led to altered sensorium. in addition, she had very high bp readings (200/130 mmhg) [table 1]. the differential diagnosis for the patient included hypertensive encephalopathy, intracranial bleeding, a cerebrovascular stroke and cerebral vasculitis. on admission to the picu, urgent brain scans were performed in order to correlate the patient’s clinical deterioration and neurological manifestations. initial mri brain examinations revealed hyperintense areas in the bilateral cortical and subcortical white matter, observed at the frontal-parietal and parietal-occipital junctions. mild cortical involvement was also noted [figure 1]. diffusion images and apparent diffusion coefficient mapping displayed no evidence of diffusion restriction. the radiological findings indicated a diagnosis of pres. electroencephalography showed bilateral slow wave activity and no epileptic discharges. the laboratory investigations indicated anaemia with a haemoglobin level of 10 g/dl, a normal coagulation profile and the following other blood levels: sodium of 138 mmol/l (normal range: 135–145 mmol/l); potassium of 3.5 mmol/l (normal range: 2.5–5.1 mmol/l); creatinine of 45 μmol/l (normal range: 15–31 μmol/l); urea of 6.5 mmol/l (normal range: 2.1–7.1 mmol/l); calcium of 2.45 mmol/l (normal range: 2.15–2.55 mmol/l); and serum magnesium of 0.9 mmol/l (normal range 0.7–0.95 mmol/l). methylprednisolone and low-dose cyclophosphamide were prescribed for the control of sle figure 1a & b: axial fluid-attenuated inversion recovery magnetic resonance images of an 11-year-old girl diagnosed with systemic lupus erythematosus showing bilateral cortical and subcortical white matter. hyperintense areas can be seen in the frontal, posterior temporal, parietal and occipital regions (arrows). based on clinical and radiological findings, a diagnosis of posterior reversible encephalopathy syndrome was made. table 1: summary of the clinical characteristics and risk factors for the two presented patients with posterior reverse encephalopathy syndrome characteristic case one case two age in years/ gender 11/female 6.5/male diagnosis sle with multisystem involvement esrd on renal replacement therapy and capd clinical findings headaches, partial seizures, agitated behaviour and altered sensorium headaches and partial seizures sbp in mmhg 200 180 dbp in mmhg 130 120 risk factors hypertension, cyclophosphamide and steroid use hypertension and renal failure sle = systemic lupus erythematous; ersd = end-stage renal disease; capd = continuous ambulatory peritoneal dialysis; sbp = systolic blood pressure; dbp = diastolic blood pressure. posterior reversible encephalopathy syndrome in two omani children with underlying renal diseases e426 | squ medical journal, august 2015, volume 15, issue 3 in august 2011, the child was transferred with assisted mechanical ventilation to the department of child health at squh. on initial clinical assessment, the patient showed signs of dehydration with fair peripheral perfusion and warm extremities. his apex beat was forceful with normal heart sounds, a grade two ejection systolic murmur at the base of the heart and no gallop rhythm. there were no signs suggestive of cardiac failure and no evidence of pericardial effusion. the chest was clear with no crepitation. the central nervous system exam showed no neurological deficits and normal bilateral deep tendon reflexes. a fundus examination showed grade one hyper tensive retinopathy. laboratory investigations revealed anaemia with a haemoglobin level of 7 g/dl, a normal coagulation profile, normal inflammatory markers and the following other blood levels: sodium of 123 mmol/l (normal range: 135–145 mmol/l); potassium of 3.2 mmol/l (normal range: 2.5–5.1 mmol/l); creatinine of 586 μmol/l (normal range: 15–31 μmol/l); urea of 15.8 mmol/l (normal range: 2.1–7.1 mmol/l); calcium of 2.3 mmol/l (normal range: 2.15–2.55 mmol/l); and serum magnesium of 0.8 mmol/l (normal range: 0.7–0.95 mmol/l). echocardiography showed left ventricular hypertrophy with trivial aortic regurgitation and no pericardial effusion. an initial computed tomography scan showed bilateral hypodense areas at the occipital regions with a vasogenic oedema pattern distribution [figure 2]. mri brain images showed typical subcortical white matter areas of oedema at the frontal-parietal-temporal-occipital regions [figure 3]. based on the clinical and radiological findings, pres was suspected. management of the patient’s high bp required a labetalol infusion. after controlling the hypertension, activity and labetalol and hydralazine infusions were administered for bp control. the patient was weaned from the ventilator after the hypertension had been controlled and she was shifted gradually to oral antihypertensive medications. a follow-up mri showed a significant improvement, with residual abnormally hyperintense areas at the superior frontal and left parietal regions. clinical and radiological assessments after one year showed no residual neurological dysfunction. case 2 a six-and-a-half-year-old boy presented to squh in muscat, oman, in august 2011 with end-stage renal disease secondary to multi-drug-resistant nephrotic syndrome. the diagnosis of nephrotic syndrome had been established at the age of 14 months when the patient presented to a regional hospital in oman with proteinuria, haematuria and hyper tension. he showed no response to pulse methylprednisolone, cyclophosphamide or mycophenolate mofetil. the patient started continuous ambulatory peritoneal dialysis at the age of six years due to a progressive deterioration of renal function, fluid overload and hypertension. he continued on dialysis for six months with other renal replacement medications, including vitamin d and darbepoetin alfa. the child presented to squh with hypertension, generalised oedema, depressed sensorium and generalised tonic-clonic convulsions. bp readings were very high, reaching 180/120 mmhg. while in a state of disturbed consciousness, he was intubated and ventilated in order to secure his respiratory airway. the differential diagnosis was hypertensive or uremic encephalopathy, intracranial bleeding and a cerebrovascular stroke. figure 2a & b: axial non-enhanced computed tomography images of a six-and-a-half-year-old boy on peritoneal dialysis due to multi-drug-resistant nephrotic syndrome and with suspected posterior reversible encephalopathy syndrome. bilateral subcortical hypodense areas were observed in the occipital and posterior parietal regions (arrows). similar areas can be seen to a lesser extent in the frontal regions (arrowheads). figure 3a & b: axial magnetic resonance fluid attenuation inversion recovery images of a six-and-ahalf-year-old boy on peritoneal dialysis due to multidrug-resistant nephrotic syndrome showing bilateral subcortical hyperintense areas, mainly at the frontaloccipital-parietal regions (arrows). similar areas are also seen at the right posterior temporal region (arrowhead). based on clinical and radiological findings, a diagnosis of posterior reversible encephalopathy syndrome was made. mohamed a. el-naggari, dana al-nabhani, ibtisam el-nour, alaa el-manzalawy, and anas-alwogud a. abdelmogheth online case report | e427 the patient was successfully weaned off the ventilator and was started on oral antihypertensive medications. a neurological examination at the time of discharge was normal. both of the patients’ guardians gave consent to use the patients’ medical information and images for scientific purposes. discussion pres is a neurological syndrome with a combination of clinical and radiological features. clinical presentations include seizures, headaches, visual disturbance and focal neurological signs.1 headaches are the main clinical presentation followed by confusion and drowsiness. focal neurological deficit is an uncommon association with pres.2 the typical radiological findings are subcortical and cortical oedema in the posterior cerebral regions. hypertension is the main triggering factor for pres while other risk factors that predispose to hypertension can also be present.2 pres is a reversible condition if it is managed early and appropriately, but can otherwise be fatal.1,2 the underlying mechanism that triggers this disease is not well understood and two conflicting theories exist regarding its pathogenesis. both postulated mechanisms are based on the central role of hypertension. the first theory suggests that hypertension could cause a breakdown of the autoregulatory system in cerebral circulation, leading to brain oedema. according to the second theory, hypertension causes activation of the autoregulatory system, which results in vasoconstriction of the brain vessels with hypoperfusion, ischaemia and subsequent fluid leakage.3,4 however, a large number of patients with pres do not have hypertension.3,4 consequently, marra et al. recently described the endothelial hypothesis; this theory differs from those earlier as it asserts that hypertension does not necessarily have to be present for pres to develop.4 the hypothesis suggests that an immune-related cascade can cause pres through the weakening of brain vessels, leading to fluid leakage and oedema.4 pres has been extensively described in both adults and children. the most common risk factor is a hypertensive crisis.5 therefore, any condition that predisposes to hypertension can lead to the development of pres. this includes many renal conditions affecting the glomerulus, such as lupus nephritis;6,7 the renal vessels, such as renal artery stenosis;8 and those conditions with renal anatomical defects such as grade four vesicoureteral reflux.9 in addition, many medications like steroids and cyclosporine can raise bp and therefore increase the risk of pres.10,11 patients on dialysis can also develop pres if they become hypertensive.12,13 seizures are a common and frequently encountered symptom of pres, among a wide range of other neuro logical symptoms.5 in the first case presented in the current report, the patient had multiple risk factors that contributed to the onset of pres. these included lupus nephritis confirmed by renal biopsy, the use of methylprednisone for disease control and extremely high bp. the patient also presented with headaches, drowsiness and seizures, which are the most common clinical signs of pres.1 the second case emphasised the role of hypertension in patients on peritoneal dialysis. however, darbepoetin alfa may also be a contributing factor to the development of pres, as it may have contributed to the raised bp. both of the cases were managed promptly and appropriately, which led to favourable outcomes for both patients. mri can be used as a diagnostic and prognostic tool for pres. the classic mri feature in pres cases is subcortical oedema in the parietal-occipital region.14 however, in recent years, more atypical findings of pres have been described. kastrup et al. reported that the frontal region was the area most commonly affected in a study of pres cases.15 the mri brain scans of the two patients in the current report confirm this, as the frontal region was involved in both cases. reversibility of mri findings is suggestive of a good prognosis.16 thus, leukoencephalopathy with severe hypertension is reversible both clinically and radiologically in the majority of children after the control of hypertension.17 however, the literature has shown that a few patients may have residual damage and need to be followed-up.17 the present report highlights the role of risk factors such as hypertension in the development of pres in two paediatric renal cases. strict monitoring is mandatory for such critical patients, including the use of bp measurement devices with appropriate paediatric cuffs for the child’s age. it is important to recognise such cases early to allow for prompt treatment and potential reversal of the syndrome. the two cases presented here demonstrated that regions other than the posterior brain can be affected in pres and that mri is a useful diagnostic tool. more mri devices are needed in hospitals throughout oman, as well as more training for physicians in diagnosing typical and atypical forms of pres. finally, prompt diagnosis and aggressive management is the cornerstone for the prevention of permanent neurological damage in pres patients. posterior reversible encephalopathy syndrome in two omani children with underlying renal diseases e428 | squ medical journal, august 2015, volume 15, issue 3 7. chan dy, ong ys. posterior reversible encephalopathy syndrome: an acute manifestation of systemic lupus erythematous. singapore med j 2013; 54:193–5. doi: 10.11622/ smedj.2013182. 8. benoist g, dossier c, elmaleh m, dauger s. posterior reversible encephalopathy syndrome revealing renal artery stenosis in a child. bmj case rep 2013; 23:2013. doi: 10.1136/bcr-2013010110. 9. sharma s, gupta r, sehgal r, aggarwal kc. atypical presentation of posterior reversible encephalopathy: in a child with bilateral grade iv vesicoureteric reflux. j trop pediatr 2014; 60:331–3. doi: 10.1093/tropej/fmu019. 10. i̇ncecik f, hergüner mö, yıldızdaş d, yılmaz m, mert g, horoz öo, et al. posterior reversible encephalopathy syndrome due to pulse methylprednisolone therapy in a child. turk j pediatr 2013; 55:455–7. 11. jennane s, mahtat el m, konopacki j, malfuson jv, doghmi k, mikdame m, et al. cyclosporine-related posterior reversible encephalopathy syndrome after cord blood stem cell transplantation. hematol oncol stem cell ther 2013; 6:71. doi: 10.1016/j.hemonc.2013.05.002. 12. girişgen i, tosun a, sönmez f, ozsunar y. recurrent and atypical posterior reversible encephalopathy syndrome in a child with peritoneal dialysis. turk j pediatr 2010; 52:416–19. 13. ermeidi e, balafa o, spanos g, zikou a, argyropoulou m, siamopoulos kc. posterior reversible encephalopathy syndrome: a noteworthy syndrome in end-stage renal disease patients. nephron clin pract 2013; 123:180–4. doi: 10.1159/000353731. 14. stevens cj, heran mk. the many faces of posterior reversible encephalopathy syndrome. br j radiol 2012; 85:1566–75. doi: 10.1259/bjr/25273221. 15. kastrup o, schlamann m, moenninghoff c, forsting m, goericke s. posterior reversible encephalopathy syndrome: the spectrum of mr imaging patterns. clin neuroradiol 2015; 25:161–71. doi: 10.1007/s00062-014-0293-7. 16. moon sn, jeon sj, choi ss, song cj, chung gh, yu ik, et al. can clinical and mri findings predict the prognosis of variant and classical type of posterior reversible encephalopathy syndrome (pres)? acta radiol 2013; 54:1182–90. doi: 10.117 7/0284185113491252. 17. prasad n, gulati s, gupta rk, kumar r, sharma k, sharma rk. is reversible posterior leukoencephalopathy with severe hypertension completely reversible in all patients? pediatr nephrol 2003; 18:1161–6. doi: 10.1007/s00467-003-1243-9. conclusion hypertension is known to be one of the most important risk factors leading to pres but is uncommon among patients with renal diseases. to the best of the authors’ knowledge, these two paediatric pres cases with underlying renal diseases are the first reported among the omani population. the findings from these two cases suggest that an increased awareness of effective bp monitoring in peripheral hospitals in oman is necessary. mri scanning is also recommended as a valuable diagnostic and prognostic tool. pres is under-recognised and requires multidisciplinary care because of its potentially severe consequences. prompt diagnosis and treatment of risk factors are critical in helping to prevent permanent neurological damage among these patients. references 1. mccoy b, king m, gill d, twomey e. childhood posterior reversible encephalopathy syndrome. eur j paediatr neurol 2011; 15:91–4. doi: 10.1016/j.ejpn.2010.10.002. 2. prasad n, gulati s, gupta rk, sharma k, gulati k, sharma rk, et al. spectrum of radiological changes in hypertensive children with reversible posterior leucoencephalopathy. br j radiol 2007; 80:422–9. doi: 10.1259/bjr/81758556. 3. ishikura k, hamasaki y, sakai t, hataya h, mak rh, honda m. posterior reversible encephalopathy syndrome in children with kidney diseases. pediatr nephrol 2012; 27:375–84. doi: 10.1007/s00467-011-1873-2. 4. marra a, vargas m, striano p, del guercio l, buonanno p, servillo g. posterior reversible encephalopathy syndrome: the endothelial hypotheses. med hypotheses 2014; 82:619–22. doi: 10.1016/j.mehy.2014.02.022. 5. chen th, lin wc, tseng yh, tseng cm, chang tt, lin tj. posterior reversible encephalopathy syndrome in children: case series and systematic review. j child neurol 2013; 28:1378–86. doi: 10.1177/0883073813500714. 6. gatla n, annapureddy n, sequeira w, jolly m. posterior reversible encephalopathy syndrome in systemic lupus erythematosus. j clin rheumatol 2013; 19:334–40. doi: 10.1097 /rhu.0b013e3182a21ffd. http://dx.doi.org/10.11622/smedj.2013182 http://dx.doi.org/10.11622/smedj.2013182 http://dx.doi.org/10.1136/bcr-2013-010110 http://dx.doi.org/10.1136/bcr-2013-010110 http://dx.doi.org/10.1093/tropej/fmu019 http://dx.doi.org/10.1016/j.hemonc.2013.05.002 http://dx.doi.org/10.1159/000353731 http://dx.doi.org/10.1259/bjr/25273221 http://dx.doi.org/10.1007/s00062-014-0293-7 http://dx.doi.org/10.1177/0284185113491252 http://dx.doi.org/10.1177/0284185113491252 http://dx.doi.org/10.1007/s00467-003-1243-9 http://dx.doi.org/10.1016/j.ejpn.2010.10.002 http://dx.doi.org/10.1259/bjr/81758556 http://dx.doi.org/10.1007/s00467-011-1873-2 http://dx.doi.org/10.1016/j.mehy.2014.02.022 http://dx.doi.org/10.1177/0883073813500714 http://dx.doi.org/10.1097/rhu.0b013e3182a21ffd http://dx.doi.org/10.1097/rhu.0b013e3182a21ffd departments of 1biochemistry, 2family medicine & public health, 4medicine, 5physiology, 6genetics, college of medicine & health sciences, sultan qaboos university; departments of 3medicine, 7clinical physiology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: sawsan.alsinani@gmail.com معدل إنتشار مرحلة ما قبل السكري يف العمانيني الذين ليس لديهم تاريخ عائلي للنوع الثاين من داء السكري �صو�صن ال�صنانية، حممد ال�صافعي، علي املعمري، نيكول�س وودهاو�س، اأميمة ال�صافعي، حممد عثمان ح�صن، �صعيد اليحيائي، �صليمه الربوانية، ديبايل جاجو، خمي�س الها�صمي، حممد العربي، �صيد رزيف، ريا�س بيومي abstract: objectives: the aim of this study was to estimate the prevalence of impaired fasting glucose (ifg) among omani adults with no family history (fh) of diabetes and to investigate the factors behind the risk of developing type 2 diabetes (t2d), while excluding a fh of diabetes. methods: a total of 1,182 omani adults, aged ≥40 years, visited the family medicine & community health clinic at sultan qaboos university hospital, oman, on days other than the diabetes clinic days, from july 2010 to july 2011. the subjects were interviewed and asked if they had t2d or a fh of t2d. results: only 191 (16%) reported no personal history of t2d or fh of the disease. of these, anthropometric and biochemical data was complete in 159 subjects. of these a total of 42 (26%) had ifg according to the american diabetes association criteria. body mass index, fasting insulin, haemoglobin a1c and blood pressure (bp), were significantly higher among individuals with ifg (p <0.01, p <0.05, p <0.01 and p <0.01, respectively). in addition, fasting insulin, bp and serum lipid profile were correlated with obesity indices (p <0.05). obesity indices were strongly associated with the risk of ifg among omanis, with waist circumference being the strongest predictor. conclusion: despite claiming no fh of diabetes, a large number of omani adults in this study had a high risk of developing diabetes. this is possibly due to environmental factors and endogamy. the high prevalence of obesity combined with genetically susceptible individuals is a warning that diabetes could be a future epidemic in oman. keywords: prediabetic state; diabetes mellitus, type 2; obesity; prevalence; oman. لي�س الذين العمانيني الأ�صخا�س من جمموعة يف ال�صكري قبل ما مرحلة اإنت�صار تقديرمعدل اإىل الدرا�صة هذه تهدف الهدف: امللخ�ص: لديهم تاريخ عائلي للنوع الثاين من داء ال�صكري، وكذلك التحقيق يف عوامل الختطار وراء الإ�صابة بالنوع الثاين من ال�صكري مع اإ�صتبعاد وجود تاريخ عائلي لل�صكري. الطريقة: متت درا�صة عدد 1,182 �صخ�صًا عمانيًا، اأعمارهم 40≤ �صنة، من املراجعني لعيادة طب الأ�رشة و املجتمع يف م�صت�صفى جامعة ال�صلطان قابو�س،عمان،يف غري اأيام عيادة ال�صكري خلل الفرتة من يوليو 2010 اإىل يوليو 2011. متت مقابلة الأ�صخا�س وال�صتف�صار عن اإ�صابتهم بال�صكري اأو وجود تاريخ عائلي للنوع الثاين من مر�س ال�صكري. النتائج: اإدعى عدد 191 )%16( �صخ�صًا فقط اأنهم غري م�صابني مبر�س ال�صكري اأو عدم وجود تاريخ عائلي لديهم ملر�س ال�صكري. اأكمل 159 �صخ�صا فقط من هذه املجموعة القيا�صات اجل�صمية والبيوكيميائية. مت ت�صنيف جمموع 42 )%26( �صخ�صا كم�صابني باعتلل ما قبل ال�صكري ح�صب معايري الدم و�صغط ،a1c هيموغلوبني ال�صوم، وقت الإن�صولني م�صتوى اجل�صم، كتلة من�صب قيا�صات كانت ال�صكري. ملر�س الأمريكية اجلمعية مرتفعة بني الأ�صخا�س الذين هم يف مرحلة ما قبل ظهور ال�صكري. و قد لوحظ اأرتباط ن�صبة الن�صولني وقت ال�صيام، و�صغط الدم ون�صبة الدهون يف الدم مع موؤ�رشات ال�صمنة. معدلت ال�صمنة كانت مرتبطة ب�صدة بعامل الإ�صابة مبرحلة ما قبل ال�صكري عند العمانيني، مع اعتبار كفاف اخل�رش منبئ قوي للإ�صابة. اخلال�صة: على رغم الإدعاء من عدم وجود تاريخ تاريخ عائلي لل�صابة بال�صكري مت الإ�صتنتاج اأن عدد كبري من الأ�صخا�س العمانيني يف هذه الدرا�صة كان لديهم عوامل اختطار عالية للإ�صابة مبر�س ال�صكري. وهذا يعترب نتيجة لعوامل بيئية وزواج الأقارب. اأرتفاع معدل ال�صمنة بالإ�صرتاك مع ال�صتعداد الوراثي لل�صخ�س يعترب حتذير من اأن مر�س ال�صكري ميكن اأن يتوطن يف امل�صتقبل يف عمان. مفتاح الكلمات: مرحلة ما قبل ال�صكري، مر�س ال�صكري، النوع الثاين، ال�صمنة، معدل، عمان. impaired fasting glucose in omani adults with no family history of type 2 diabetes *sawsan al-sinani,1 mohammed al-shafaee,2 ali al-mamari,3 nicolas woodhouse,4 omayma el-shafie,3 mohammed o. hassan,5 said al-yahyaee,6 sulayma albarwani,5 deepali jaju,7 khamis al-hashmi,4 mohammed al-abri,7 syed rizvi,2 riad bayoumi1 clinical & basic research advances in knowledge in spite of having no family history of diabetes, a sizable sector of omani adults are at a high risk of developing diabetes due to environmental factors and endogamy. application to patient care all adult omanis should be screened routinely for impaired fasting glucose at all health facilities. obesity management clinics should be set up in all healthcare centres in oman. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e183-189, epub. 7th apr 14 submitted 18th sep 13 revision req. 9th dec 13; revision recd. 5th jan 14 accepted 30th jan 14 impaired fasting glucose in omani adults with no family history of type 2 diabetes e184 | squ medical journal, may 2014, volume 14, issue 2 type 2 diabetes (t2d) has a strong genetic component and its heritability has been estimated at approximately 25%.1 to date, more than 70 common t2d susceptibility gene variants and loci have been identified; however, all these common gene variants only explain ~10–15% of the heritability of t2d, suggesting that other rare variants have yet to be discovered.2,3 t2d is also known to cluster amongst relatives whose households share similar environmental, dietary and cultural lifestyles.4 recent studies have further demonstrated the impact of obesity and environmental factors on the risk of developing t2d.5,6 the interact project study showed that the interaction between obesity and a family history (fh) of diabetes increases the risk of t2d by more than 20-fold compared with lean subjects without a fh of t2d.6 as body mass index (bmi) is influenced by both environmental and genetic factors, this interaction could be attributed to gene-environment and genegene interactions.5 the expert committee on the diagnosis and classification of diabetes mellitus, working under the sponsorship of the american diabetes association (ada), defined prediabetics in 1997 and 2003 as an intermediate group of individuals whose glucose levels are elevated above normal values but are not high enough to be classified as having t2d.7‒9 these individuals were defined as having impaired fasting glucose (ifg), i.e. fasting plasma glucose levels of 5.6–6.9 mmol/l, or impaired glucose tolerance (igt) with values of 7.8–11.0 mmol/l in the two-hour oral glucose tolerance test. the world health organization (who), on the other hand, defines the cut-off for ifg at 6.1 mmol/l rather than the 5.6 mmol/l value defined by the ada.10 therefore, the exact number of individuals with ifg differs according to the definition used. over a 10-year period, ifg carries a 50% risk of progression to t2d. in a recent study, the progession to t2d was reported to occur in under three years.11 the prediabetic state is also associated with abdominal obesity, insulin resistance, dyslipidaemia and hypertension. one in nine adults in the middle east and north africa have diabetes and more than half of them are unaware of their condition.12 in addition, 6.7% of the population in this region have igt; this number is expected to double by 2030.12 following the oil boom of the past four decades, major socioeconomic changes have taken place in oman and other arabian gulf countries. these include rapid urbanisation and westernisation, with increased levels of inactivity and changes in food habits. four countries in this region (kuwait, saudi arabia, qatar and bahrain) are among the 10 countries in the world with the highest t2d prevalence for adults aged 20‒79 years.12 in addition to the lifestyle, activity and dietary changes brought about by rapid economic development, these populations have a high genetic susceptibility due to the frequency of consanguineous marriages and endogamy.13,14 in oman, according to the national health surveys of 1991 and 2000, the prevalence of diabetes mellitus rose from 8.3% in 1991 to 11.6% in 2000 among adults aged 20 years or older.15 the survey also showed that 7.1% of men and 5.1% of women had ifg.16 other studies, using the ada criteria, have shown that abnormal glucose metabolism is common in omanis, with 35% of adults having prediabetes.17,18 the ministry of health (moh) in oman has accordingly established a nationwide screening programme to detect prediabetes among those aged ≥40 years.19 this study aimed to determine the prevalence of ifg among a group of omani adults claiming not to have a fh of diabetes. the risk factors of developing t2d among these omani adults were also investigated. methods this hospital-based cross-sectional study recruited subjects from a primary healthcare clinic, the family medicine & community health clinic (famco) at sultan qaboos university hospital (squh) in muscat, oman. famco offers a range of services, including: general appointments; dermatology consultations; walk-in appointments; diabetes clinic days; antenatal, postnatal and baby care; birth spacing advice; immunisations, and general counselling. a total of 1,182 omani adults aged ≥40 years visited famco with general appointments on days other than the diabetes clinic days from july 2010 to july 2011. all of the subjects were interviewed and asked whether they had t2d and/or a fh of t2d in their first-degree relatives. pregnant women were not included in the study. inclusion and exclusion criteria are explained in figure 1. out of the 1,182 subjects, 191 (16%) reported not having t2d or a fh of the disease. these subjects were then asked to fast overnight and report the following morning for glucose measurements. according to their fasting glucose results, they were classified into three categories using the ada criteria: normoglycaemic (<5.6 mmol/l), ifg (5.6‒6.9 mmol/l) or diabetic (≥7.0 mmol/l). participants were also classified as having ifg according to the 2006 who diagnostic criteria (6.1‒6.9 mmol/l). of the 191 test subjects, 32 were excluded either because they were found to sawsan al-sinani, mohammed al-shafaee, ali al-mamari, nicolas woodhouse, omayma el-shafie, mohammed o. hassan, said al-yahyaee, sulayma albarwani, deepali jaju, khamis al-hashmi, mohammed al-abri, syed rizvi and riad bayoumi clinical and basic research | e185 have frank diabetes (5) or because they did not report back for fasting glucose measurement (27). after these exclusions, complete data were obtained from the remaining 159 subjects. demographic (age and sex), anthropometric (height, weight, waist and hip circumference) and biochemical information was collected from all of these subjects. their obesity status was also determined using the international classification of bmi (weight in kg/height in m2).20 the subjects were classified as being normal if they had a bmi of 18.50‒24.99 kg/ m2, overweight with a bmi of 25.00‒29.99 kg/m2 and obese with a bmi of ≥30.00 kg/m2. height and weight were measured using standard methods with the subjects wearing indoor clothes without shoes. waist circumference (wc) was measured in cm at a midway level between the lower rib margin and iliac crest using a non-stretchable measuring tape. hip circumference was measured in cm around the widest portion of the buttocks using a non-stretchable measuring tape with the tape parallel to the floor. a wc of ≥94 cm for males and ≥80 cm for females was considered to be a risk factor for insulin resistance.21 the waist-to-hip ratio (whr) was also calculated for each subject. the whr was considered a health risk for males according to the following ranges: low risk was considered for a whr of 0.95 or below, moderate risk at 0.96 to 1.0 and high risk for a whr of over 1.0. female whr was considered a health risk according to the following ranges: low risk for a whr of 0.80 or below, moderate risk at 0.81 to 0.85 and high risk for those with a whr of over 0.85.22 blood pressure (bp) was also measured in mmhg for all of the subjects by nurses using standard methods. the biochemical investigations included measurements of fasting glucose levels, fasting insulin, glycated haemoglobin (hba1c), serum creatinine, serum lipid profile (total cholesterol, low density lipoprotein [ldl] cholesterol, high density lipoprotein [hdl] cholesterol and triglycerides) and apolipoprotein b. the statistical package for the social sciences (spss) software, version 20.0 (ibm, corp., chicago, illinois, usa), was used for the statistical analysis of the data. the anthropometric and biochemical parameters were tested for normal distribution using the one-sample kolmogorov-smirnov test. the student’s t-test was used to test the significance of the difference in the mean values for the parameters with a normal distribution, while the mann-whitney u test was used for the variables with a skewed distribution. in addition, bivariate correlation and simple linear regression analyses were carried out to evaluate the influence of obesity indices (bmi, wc and whr) on diabetes-related parameters. all of the subjects were informed about the project and provided written consent. this study was approved by the ethics & research committee of the college of medicine & health sciences at sultan qaboos university, oman. results according to the ada criteria,7 42 (26%) of the 159 participants had ifg (males = 19, females = 23). however, according to the 2006 who diagnostic figure 1: the setting, design and population of the current hospital-based cross-sectional study. famco = family medicine & community health clinic; squh = sultan qaboos university hospital; t2d = type 2 diabetes; fh = family history; who = world health organization; ifg = impaired fasting glucose; ada = american diabetes association. impaired fasting glucose in omani adults with no family history of type 2 diabetes e186 | squ medical journal, may 2014, volume 14, issue 2 criteria, only 15 (9.4 %) had ifg. table 1 shows the demographic, anthropometric and biochemical characteristics of the ifg and normoglycaemic groups. age, weight, bmi, bp, fasting glucose, fasting insulin and hba1c levels were significantly different between the ifg and normoglycaemic subjects. there was approximately a five-year age difference between the two groups (p <0.01). the mean bmi among ifg subjects was in the obese range, while the mean for normoglycaemics was in the overweight range (p <0.01). the prevalence of overweight and obese subjects among the ifg and normoglycaemic subjects were 88% and 74%, respectively. with regards to wc, 37% and 91% of ifg males and females, respectively, had an elevated wc, while 41% and 88% of normoglycaemic males and females, respectively, had an elevated wc.20 in addition, the mean value of the participants’ whrs indicated moderate risk among males with ifg (0.96 ± 0.05 cm) but low risk among normoglycaemic males (0.95 ± 0.04 cm). however, it indicated high risk in both ifg (0.94 ± 0.1 cm) and normoglycaemic (0.92 ± 0.1 cm) females. there was no significant difference in the serum lipids concentrations among ifg and normoglycaemic subjects. however, total cholesterol and ldl cholesterol mean values were borderline high, while hdl cholesterol was moderately low among both groups [table 1]. tables 2 and 3 show the results of the pearson correlation and simple linear regression analyses, respectively. increased fasting insulin, systolic and diastolic bp and serum lipids were found to correlate significantly with an increase in obesity indices. approximately 48% (r2 = 0.48) and 33% (r2 = 0.33) of the variance of the fasting insulin and 11% (r2 = 0.11) and 4% (r2 = 0.04) of the variance of the diastolic bp among ifg and normoglycaemic subjects, respectively, could be accounted for by an increase in wc. in addition, 15% (r2 = 0.15) and 8% (r2 = 0.08) of the variance of the systolic bp among ifg and normoglycaemic subjects, respectively, could be accounted for by an increase in whr. for the lipids profile, approximately 18% (r2 = 0.18) of the variance of the total cholesterol and 14% (r2= 0.14) of the variance of the triglycerides among ifg subjects could be accounted for by an increase in whr. both the pearson correlation and simple linear regression analyses revealed that the increase in wc had a stronger influence on the parameters related to diabetes than the increase in bmi. discussion this study was conducted on a random hospital cohort of 159 omani adults who reported no personal or fh of t2d and who were not excluded due to incomplete data or other exclusion criteria. using the ada criteria, 26% of those who were unaware of a personal or fh of diabetes had ifg. however, using the who criteria, ifg was found in 9.4%. this is considered a high percentage among this unique sample of subjects table 1: demographic, anthropometric and biochemical characteristics of the impaired fasting glucose and normoglycaemic groups of omani participants with no family history of type 2 diabetes (n = 159) characteristic ifg group (n = 42) normoglycaemic group (n = 117) p value mean ± sd mean ± sd age in years (range) 52 ± 10 46 (35‒79)* <0.01 weight in kg 77 ± 15 72 ± 13 <0.05 height in cm 156 ± 11 157 ± 8 0.478 bmi in kg/m2 32 ± 8 29 ± 5 <0.01 wc in cm 96 ± 11 92 ± 14 0.099 hip circumference in cm (range) 99 ± 9 97 (76‒191)* 0.223 whr 0.97 ± 0.1 0.94 ± 0.1 0.076 systolic bp in mmhg 138 ± 20 127 ± 20 <0.01 diastolic bp in mmhg 81 ± 10 77 ± 9 <0.01 fasting glucose in mmol/l (range) 5.8 (5.6‒6.7)* 4.9 ± 0.4 <0.001 fasting insulin in miu/l 9.9 ± 5.4 7.4 ± 3.9 <0.05 hba1c in % 5.9 ± 0.5 5.7 ± 0.4 <0.01 serum creatinine in μmol/l 69 ± 20 63 ± 16 0.071 total cholesterol in mmol/l 5.5 ± 1.0 5.4 ± 0.9 0.575 ldl cholesterol in mmol/l 3.5 ± 1.1 3.5 ± 0.9 0.803 hdl cholesterol in mmol/l 1.2 ± 0.3 1.3 ± 0.3 0.339 triglycerides in mmol/l (range) 1.6 ± 0.8 1.2 (0.3‒4.0)* 0.167 apolipoprotein b in g/l 1.0 ± 0.2 1.0 ± 0.3 0.621 ifg = impaired fasting glucose; sd = standard deviation; bmi = body mass index; wc = waist circumference; whr = wasit-to-hip ratio; bp = blood pressure; hba1c = glycated haemoglobin; ldl = low-density lipoprotein; hdl = high-density lipoprotein. *the median (range of minimum–maximum) is displayed if the variable does not follow a normal distribution pattern. sawsan al-sinani, mohammed al-shafaee, ali al-mamari, nicolas woodhouse, omayma el-shafie, mohammed o. hassan, said al-yahyaee, sulayma albarwani, deepali jaju, khamis al-hashmi, mohammed al-abri, syed rizvi and riad bayoumi clinical and basic research | e187 with no fh of diabetes. the risk factors for diabetes, such as age and bmi, were found to be significantly higher among subjects with ifg compared to the normoglycaemic group. furthermore, diabetesassociated conditions, such as an increase in fasting insulin, hba1c and bp, were significantly higher among subjects with ifg compared to normoglycaemics. obesity indices had some influence on the measured parameters among both ifg and normoglycaemic subjects. an increase in obesity indices seems to correlate with an increase in fasting insulin, bp and serum lipids. the findings of this study are in agreement with previous omani studies, where the isolated ifg prevalence among omani adults was reported at 30% using the ada criteria.18 however, it was reported at 6.1% (in subjects ≥20 years) and 8.3% (in subjects ≥30 years) using the who criteria.15,23 the oman world health survey (owhs), also using the who criteria, estimated the prevalence of prediabetes among omani adults at 4.4% in those aged ≥18 years, 8.4% in those aged 45‒54 years and 11.2% in those aged 55‒64 years.22 using the who criteria, ifg among emiratis (8.8%) was very similar to the omani figures.25 however, using the ada criteria, it was reported at 1.3% among qataris and 3.1% among saudis.26,27 these values are considered low in comparison with the prevalence of diabetes among their populations. furthermore, using the ada criteria, ifg was found to be 13.8% among kuwaitis.28 in spain, ifg was reported at 2.8% and 3.4% (using the who criteria), while in the usa it was reported at 26% (using the ada criteria).29‒31 table 2: pearson correlation (r) of measured biochemical paramenters with body mass index, waist circumference and waist-to-hip ratio among the impaired fasting glucose and normoglycaemic groups of omani patients (n = 159) biochemical parameters pearson correlation (r) bmi wc whr ifg ngg ifg ngg ifg ngg fasting insulin in miu/l 0.223 0.501** 0.691** 0.576** 0.440** 0.227* systolic bp in mmhg 0.113 0.193* 0.189 0.249** 0.387* 0.282** diastolic bp in mmhg 0.177 0.143 0.331* 0.210* 0.195 0.288** total cholesterol in mmol/l 0.048 0.104 0.254 0.188* 0.421** 0.118 hdl cholesterol in mmol/l 0.251 -0.119 0.008 -0.227* -0.161 -0.186 triglyceride in mmol/l 0.054 0.133 0.228 0.187 0.370* 0.235* apolipoprotein b in g/l -0.132 0.127 0.070 0.277** 0.242 0.299** bmi = body mass index; wc = waist circumference; whr = waist-to-hip ratio; ifg = impaired fasting glucose group; ngg = normoglycaemic group; bp = blood pressure; hdl = high-density lipoprotein. *significant at the p <0.05 level (two-tailed); **significant at the p <0.01 level (two-tailed). table 3: regression coefficient (b) of measured biochemical parameters with body mass index, waist circumference and waist-to-hip ratio among the impaired fasting glucose and normoglycaemic groups of omani patients (n = 159) biochemical parameters regression coefficient bmi wc whr ifg ngg ifg ngg ifg ngg fasting insulin in miu/l 0.137 0.373** 0.316** 0.216** 29** 10.2* systolic bp in mmhg 0.274 0.753* 0.333 0.496** 97* 71** diastolic bp in mmhg 0.218 0.247 0.296* 0.182* 24.8 31.8** total cholesterol in mmol/l 0.006 0.018 0.021 0.012* 5.0** 1.3 hdl cholesterol in mmol/l 0.008 -0.007 0.0 -0.005* -0.540 -0.698 triglyceride in mmol/l 0.006 0.019 0.017 0.010 3.9* 2.1* apolipoprotein b in g/l -0.005 0.006 0.001 0.005** 0.662 0.861** bmi = body mass index; wc = waist circumference; whr = waist-to-hip ratio; ifg = impaired fasting glucose group; ngg = normoglycaemic group; bp = blood pressure; hdl = high-density lipoprotein. *significant at the p <0.05 level (two-tailed); **significant at the p <0.01 level (two-tailed). impaired fasting glucose in omani adults with no family history of type 2 diabetes e188 | squ medical journal, may 2014, volume 14, issue 2 in omani subjects, 88% of the ifg subjects were either overweight or obese compared to 74% of the normoglycaemic group. a recent study found that 51% of omani adults and 75% of isolated ifg individuals were either overweight or obese.18 among the qatari population, 86% of diabetics and 75% of normoglycaemics were overweight or obese.26 these findings are similar to the figures found in the subjects of the current study. family and twin studies have shown that bmi and abdominal obesity, measured by wc or whr, is 40–60% heritable.32,33 in this study, it was found that an increase in wc had a stronger influence on diabetes-associated conditions than an increase in bmi. approximately 48% and 33% of the variance of the fasting insulin among ifg and normoglycaemic subjects, respectively, could be accounted for by an increase in wc. these results are similar to an earlier study, which found that all three indices of obesity were strongly and independently associated with the risk of t2d among omanis, with wc being the strongest predictor.34 in this study, omani females were found to have a higher prevalence of elevated wc than omani males. furthermore, females with ifg were found to have a higher prevalence of elevated wc than normoglycaemic females. the mean value of whr indicated a moderate risk among males with ifg, but a low risk among normoglycaemic males. however, it indicated high risk in both ifg and normoglycaemic females. in a previous study, the prevalence of elevated wc among omanis was found to be 23% and 65% among males and females, respectively.35 in a complex disease like diabetes, with a multitude of potential interacting genes and environmental factors, and with no control for socioeconomic status or endogamy, the outcome of the current study is not surprising.14 this study found a high prevalence of ifg in an omani cohort of subjects with no fh of diabetes; therefore, the high prevalence is believed to be due primarily to changes in diet and lifestyle. however, it may not be possible to claim this as the precise cause, since oman has an endogamous society where approximately half of all marriages are consanguineous.36 therefore, the omani subjects in this study may still have had diabetic ancestors of whom they were unaware.14,37,38 also, obesity, which is a major predisposing factor for diabetes, has both genetic and environmental elements. the main limitation of this study was the small sample size. however, this study aimed to separate the influence of genetics from the environmental factors of developing t2d among the omani population. previous studies among the omani population concentrated on finding the prevalence of ifg among the whole population. this study discovered that obesity among the omani population has a strong effect on developing t2d, even without the presence of a fh of diabetes. the difficulty in recruiting omani adults with no fh of diabetes was the main reason for the small sample of subjects in this study as almost everybody has a relative with diabetes mellitus. conclusion in this study, 26% of the omani population sample reported no fh of diabetes, but had ifg. obesity indices are strongly associated with the risk of ifg and t2d among omanis, with wc being the strongest predictor. the high prevalence of central obesity among this omani population acting on genetically susceptible individuals warns of a future diabetes epidemic in oman. health education programmes could make a substantial difference in promoting lifestyle modifications, which are important tools to prevent diabetes and its complications. a c k n o w l e d g e m e n t s this project was funded by the research council, oman (rc/med/bioc/10/01). references 1. poulsen p, kyvik ko, vaag a, beck-nielsen h. heritability of type ii (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance: a population-based twin study. diabetologia 1999; 42:139‒45. doi: 10.1007/ s001250051131. 2. kato n. insights into the genetic basis of type 2 diabetes. j diabetes investig 2013; 4:233‒44. doi: 10.1111/jdi.12067. 3. wheeler e, barroso i. genome-wide association studies and type 2 diabetes. brief funct genomics 2011; 10:52‒60. doi: 10.1093/bfgp/elr008. 4. valdez r. detecting undiagnosed type 2 diabetes: family history as a risk factor and screening tool. j diabetes sci technol 2009; 3:722‒6. 5. wikner c, gigante b, hellénius ml, de faire u, leander k. the risk of type 2 diabetes in men is synergistically affected by parental history of diabetes and overweight. plos one 2013; 8:e61763. doi: 10.1371/journal.pone.0061763. 6. scott ra, langenberg c, sharp sj, franks pw, rolandsson o, drogan d, et al.; interact consortium. the link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the epic-interact study. diabetologia 2013; 56:60‒9. doi: 10.1007/s00125-012-2715-x. 7. american diabetes association. standards of medical care in diabetes: 2012. diabetes care 2012; 35:s11‒63. doi: 10.2337/dc12-s011. 8. expert committee on the diagnosis and classification of diabetes mellitus. report of the expert committee on the diagnosis and classification of diabetes mellitus. diabetes care 1997; 20:1183‒97. doi: 10.2337/diacare.20.7.1183. sawsan al-sinani, mohammed al-shafaee, ali al-mamari, nicolas woodhouse, omayma el-shafie, mohammed o. hassan, said al-yahyaee, sulayma albarwani, deepali jaju, khamis al-hashmi, mohammed al-abri, syed rizvi and riad bayoumi clinical and basic research | e189 9. genuth s, alberti kg, bennett p, buse j, defronzo r, kahn r, et al. follow-up report on the diagnosis of diabetes mellitus. diabetes care 2003; 26:3160‒7. doi: 10.2337/ diacare.26.11.3160. 10. world health organization and international diabetes federation. definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a who/idf consultation. from: www.who.int/diabetes/publications/ definition%20and%20diagnosis%20of%20diabetes_new. pdf accessed: feb 2014. 11. nichols ga, hillier ta, brown jb. progression from newly acquired impaired fasting glucose to type 2 diabetes. diabetes care 2007; 30:228‒33. doi: 10.2337/dc06-1392. 12. international diabetes federation. idf diabetes atlas: 5th edition, 2012 update. from: www.idf.org/sites/default/ files/5e_idfatlasposter_2012_en.pdf accessed: aug 2013. 13. saadi h, nagelkerke n, al-kaabi j, afandi b, al-maskari f, kazam e. screening strategy for type 2 diabetes in the united arab emirates. asia pac j public health 2010; 22:54‒9s. doi: 10.1177/1010539510373036. 14. bittles ah, hamamy ha. endogamy and consanguineous marriage in arab populations. in: teebi as, ed. genetic disorders among arab populations. 2nd edition. berlin, germany: springer, 2010. pp. 85‒108. 15. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954‒7. doi: 10.1046/j.14645491.2002.00818.x. 16. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 17. al-shafaee ma, ganguly ss, bhargava k, duttagupta kk. prevalence of metabolic syndrome among prediabetic omani adults: a preliminary study. metab syndr relat disord 2008; 6:275‒9. doi: 10.1089/met.2008.0019. 18. al-shafaee ma, bhargava k, al-farsi ym, mcilvenny s, al-mandhari a, al-adawi s, et al. prevalence of prediabetes and associated risk factors in an adult omani population. int j diabetes dev ctries 2011; 31:166‒73. doi: 10.1007/s13410-011-0038-y. 19. al shereiqi s. non-communicable diseases screening: starts in oman. from: www.moh.gov.om/en/reports/ publications/newsletter17-3.pdf accessed: feb 2014. 20. world health organization. bmi classification. from: www.apps.who.int/bmi/index.jsp?intropage=intro_3.html accessed: aug 2013. 21. international diabetes federation. the idf consensus worldwide definition of the metabolic syndrome. from: w w w.idf.org/webdata/docs/idf_meta_def_final.pdf accessed: feb 2014. 22. bmi calculator. waist-to-hip ratio chart. from: www.bmicalculator.net/waist-to-hip-ratio-calculator/waist-to-hipratio-chart.php accessed: aug 2013. 23. al-riyami aa, afifi m. distribution and correlates of total impaired fasting glucose in oman. east mediterr health j 2003; 9:377‒89. 24. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1: methodology, sociodemographic profile and epidemiology of non-communicable diseases in oman. oman med j 2012; 27:425‒43. 25. malik m, bakir a, saab ba, king h. glucose intolerance and associated factors in the multi-ethnic population of the united arab emirates: results of a national survey. diabetes res clin pract 2005; 69:188‒95. doi: 10.1016/j. diabres.2004.12.005. 26. bener a, zirie m, janahi im, al-hamaq ao, musallam m, wareham nj. prevalence of diagnosed and undiagnosed diabetes mellitus and its risk factors in a population-based study of qatar. diabetes res clin pract 2009; 84:99‒106. doi: 10.1016/j.diabres.2009.02.003. 27. al-baghli na, al-ghamdi aj, al-turki ka, al elq ah, el-zubaier ag, bahnassy a. prevalence of diabetes mellitus and impaired fasting glucose levels in the eastern province of saudi arabia: results of a screening campaign. singapore med j 2010; 51:923‒30. 28. alattar a, al-majed h, almuaili t, almutairi o, shaghouli a, altorah w. prevalence of impaired glucose regulation in asymptomatic kuwaiti young adults. med princ pract 2011; 21:51‒5. doi: 10.1159/000330024. 29. boronat m, varillas vf, saavedra p, suárez v, bosch e, carrillo a, et al. diabetes mellitus and impaired glucose regulation in the canary islands (spain): prevalence and associated factors in the adult population of telde, gran canaria. diabet med 2006; 23:148‒55. doi: 10.1111/j.14645491.2005.01739.x. 30. soriguer f, goday a, bosch-comas a, bordiú e, callepascual a, carmena r, et al. prevalence of diabetes mellitus and impaired glucose regulation in spain: the di@bet.es study. diabetologia 2012; 55:88‒93. doi: 10.1007/s00125011-2336-9. 31. palangio ma. american diabetes association consensus statement on ifg and igt. clin med insights endocrinol diabetes 2007; 10:2‒3. 32. maes hh, neale mc, eaves lj. genetic and environmental factors in relative body weight and human adiposity. behav genet 1997; 27:325‒51. doi: 10.1023/a:1025635913927. 33. rose km, newman b, mayer-davis ej, selby jv. genetic and behavioral determinants of waist-hip ratio and waist circumference in women twins. obes res 1998; 6:383‒92. doi: 10.1002/j.1550-8528.1998.tb00369.x. 34. al-asfoor dh, al-lawati ja, mohammed aj. body fat distribution and the risk of non-insulin-dependent diabetes mellitus in the omani population. east mediterr health j 1999; 5:14‒20. 35. al-lawati ja, tuomilehto j. diabetes risk score in oman: a tool to identify prevalent type 2 diabetes among arabs of the middle east. diabetes res clin pract 2007; 77:438‒44. doi: 10.1016/j.diabres.2007.01.013. 36. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32‒42. 37. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571‒94. doi: 10.1017/s0021932012000016. 38. rajab a, patton ma. a study of consanguinity in the sultanate of oman. ann hum biol 2000; 27:321‒6. doi: 10.1080/030144600282208. malignant melanoma is predomi-nantly a skin disease but in rare instances it may occur at other sites, including the mucous membrane of vulva, vagina, lips, throat, oesophagus, or perianal region, as well as the eye (uvea or retina). malignant melanoma of the vagina is a rare entity, first reported by poronas in 1887.1 it accounts for 2.6–2.8% of all primary malignant tumors of the vagina and 0.4–0.8 % of all malignant melanomas in females.2 being of black race is considered as an adverse prognostic factor for melanoma; however, the relative risk in white and black women was found to be equal.3 vaginal melanoma is a highly malignant disease due to extensive lymphatic invasion. additionally, its propensity for haematogenous spread due to early metastases is very common;2 hence, it is associated with a worse prognosis. regardless of the therapy chosen, results of treatment have been poor, with reported five-year survival rates ranging from 10–20%.4,5 we report the case of a malignant melanoma having an uncommon morphology arising at the vaginal introitus. the morphological details and salient features of the case are discussed. case report a 66-year-old postmenopausal female presented to the outpatient department with complaints of a sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 508-511, epub. 20th nov 12 submitted 8th dec 11 revision req. 2nd apr 12, revision recd. 15th jun 12 accepted 27th jun 12 سرطان اخللية املهبلية املدّورة امليالنيين اخلبيث حالة نادرة نينا ت�صوهان، د�صينت جور، ويد باثاك امللخ�ض: ي�صاب اجللد غالبا بال�رصطان امليالنيني اخلبيث، ولكن يف حاالت نادرة قد ي�صيب هذا ال�رصطان اأن�صجة اأخرى. وُيعد �رصطان يَمُة امليالنني يف املهبل حالة نادرة، كما اأّن نوع اخلاليا املدّورة غري ماألوف. على الرغم من ت�صخي�ض هذه احلالة �رصيريا بو�صفها حُلَ املدّورة املهبلية اخللية �رصطان اأنها على املناعي ال�صبغ وفح�ض املناعية ّية امَلَر�صِ االأن�صجة فح�ض بوا�صطة �ُصخ�صت لكنها اإِْحليِليَّة، امل�صبوغة امليالنيني اخلبيث. رف�صت املري�صة اإجراء عملية جراحية جذرية واأعطيت دورة كاملة من العالج االإ�صعاعي لكنها توفيت بعد ذلك بعام. يكون ماآل �رصطان امليالنني املهبلي اخلبيث �صيئا للغاية حتى عندما تكون االآفة مو�صعية حني اكت�صافها، ويرتاوح معدل البقاء على قيد احلياة ملدة خم�ض �صنوات بني %20-10 ، ويتاأثر املاآل ح�صب حجم الورم، حيث يكون اأكرث �صوءا عندما يكون حجم الورم ≥3سم. وال يتاأثر معدل البقاء بالعمر وعدد اخلاليا ومرحلة ومكان االآفة. مفتاح الكلمات: ميالنوما، مهبل، خباثة، �صبغة ما�صون فونتانا، �صبغة مناعية ن�صيجية كيميائية، اأورام خلية مدورة، تقرير حالة، الهند. abstract: malignant melanoma is predominantly a skin disease but in rare instances it may occur at other sites. a vaginal melanoma is a rare clinical entity and the round cell type is an uncommon variant. although the present case was clinically diagnosed as a urethral caruncle, on histopathological examination and immunostaining it was diagnosed as a round cell pigmented malignant melanoma. the patient refused radical surgery and was given a full course radiotherapy treatment but died a year later. malignant vaginal melanoma carries a very poor prognosis even when lesion is localised at the time of presentation. the five-year survival rate ranges from 10–20% with the prognosis being influenced by tumour size. a tumour size ≥3cm has a poor prognosis. age, mitotic count, stage, and location of the lesion do not influence survival rates. keywords: melanoma; vagina; malignancy; fontana-masson stain; immunohistochemical staining; round cell tumors; case report; india. round cell vaginal malignant melanoma a rare entity *neena chauhan, dushyant s. gaur, ved p. pathak case report department of pathology, himalayan institute of medical sciences, jolly grant, dehradun, uttarakhand, india *corresponding author e-mail: neenachauhan2012@gmail.com neena chauhan, dushyant s. gaur, ved p. pathak case report | 509 growth near the vaginal introitus and blood-stained discharge per vaginum for the previous 2 months. there were no urinary symptoms. a vaginal hysterectomy had been performed 6 years before for a third degree uterovaginal prolapse. on general examination, the vital signs were within normal limits and a systemic examination did not reveal any significant abnormal findings. on local examination, a dark brown nodular swelling measuring 30 x 25 mm was noted in between the urethra and the vaginal introitus. the surface of the tumour was ulcerated and bled on touch. on cystoscopic examination, the bladder was normal but the posterior wall of the urethra was stretched; however, no ulceration was seen. on per speculum examination, the anterior vaginal wall showed hyperpigmentation. on the basis of a clinical examination, the provisional diagnosis was an urethral caruncle. an excision biopsy showed a firm, greyish-brown soft tissue piece measuring 30 x 25 x 15 mm. the cut surface showed dark brown areas towards the periphery. the depth of tumour invasion was >20 mm. microscopic examination revealed an infiltrative cellular malignant tumour showing a diffuse pattern. the tumour cells were small and round with a small amount of pinkish cytoplasm, and rounded rather than uniform nuclei. many nuclei showed prominent and large nucleoli. mitotic figures were frequent. occasionally, the cells and nuclei were oval and spindle shaped. a few multinucleate cells were also seen. in many places, the cells contained dark brown melanin pigment in the cytoplasm, which was confirmed histochemically by a fontana-masson ammoniatedsilver nitrate stain. the tumour cells were positive for s100 and hmb-45 immunostaining. the overlying mucosa was ulcerated and infiltrated by tumour cells. lymphovascular invasion was also seen. a diagnosis of malignant melanoma was made. the patient refused radical surgical treatment; hence, radiotherapy was advised. the patient was referred to a radiotherapy centre where she received a full course of treatment. she lived for about one year but then died suddenly at home with complaints of sudden abdominal pain, possibly a complication of widespread metastatic disease. discussion the present case is the first vaginal melanoma detected at our institution in 10 years. during this period, 6,080 malignancies were reported out of which 15 (0.24%) were malignant melanomas. in a comparative review constituting 84,836 cases of malignant melanomas occurring between 1985 and 1994 from the national cancer data base at memorial sloan kettering cancer hospital centre in new york, 91.2% were cutaneous, 5.2% were ocular, and 1.3% were mucosal malignancies, while 2.2% had unknown primaries. it also revealed that in women, only 1.6% of melanomas were genital and only 21% of these, involved the vagina. the common presenting symptoms in 35 women treated for vaginal melanomas were vaginal bleeding in figure 1: a photomicrograph showing ulcerated hyperplastic squamous epithelium (a). the deeper tissue shows a very infiltrative cellular tumour (b) with a diffuse pattern and a few clusters in some places (haematoxylin & eosin stain × 100). figure 2: a photomicrograph showing tumour cells which are mostly tiny with a small amount of cytoplasm and rounded nuclei with a prominent nucleolus. the inset shows tumour cells containing dark brown pigment in the cytoplasm (a) (haematoxylin & eosin stain × 400; inset × 200). round cell vaginal malignant melanoma a rare entity 510 | squ medical journal, november 2012, volume 12, issue 4 23 patients (66%), and pain in 1 patient (3%); the remaining 11 patients (31%) had no symptoms, with the disease being discovered during routine screening examinations.4 our patient complained of a mass at the vaginal introitus and blood-stained discharge. the tumour was dark brown and ulcerated at the surface. as mentioned above, it was clinically misdiagnosed as an urethral caruncle.6 also, because of the epithelial ulceration, it may have been mistaken for a squamous cell carcinoma.1 although it was predominantly a small round cell tumour having a diffuse arrangement, the diagnosis was not a problem because of the presence of melanin pigment in the cytoplasm of the tumour cells. however, scambia g. et al. reported that 6% of vaginal melanomas were amelanotic.7 if this small round cell melanoma had been amelanotic, the differential diagnosis could have included lymphoma, peripheral neuroectodermal tumour (pnet), merkel cell tumour, and rhabdomyosarcoma.7 amelanotic melanomas would require the help of immunohistochemical stains such as s100, hmb45, vimentin, cytokeratin, leucocyte common antigen (lca) and neuron-specific enolase (nse) for diagnosis and to exclude other tumours. if the amelanotic melanoma had been a spindle-cell type then it would have had to be differentiated from malignant fibrohistiocytoma (mfh), a malignant peripheral nerve sheath tumour, and hemangiosarcoma.8 other differential diagnoses which could have been considered were metastatic deposits of poorly differentiated malignancy, vaginal hemangioma, or endometriosis. malignant vaginal melanoma carries a very poor prognosis even when the lesion is localised at the time of presentation. the five-year survival rate ranges from 10–20%, with prognosis influenced by tumour size. a tumour measuring ≥3 cm has a poor prognosis. patient age, mitotic count, tumour stage, and lesion location do not influence survival.9 the disease is associated with a high risk of local recurrence, distant metastasis, and poor clinical outcome. a retrospective review of 37 cases of vaginal melanoma showed a survival rate of 19.1 months for stage i disease. other studies revealed that tumour size and nodal status were significant prognostic factors, whereas, tumour thickness was a weak predictor of survival. several figure 3: a photomicrograph showing melanin pigment in tumour cells (a). (fontana-masson silver stain × 200). figure 4: (a) photomicrograph showing tumour cells’ positivity for s-100 protein (polyclonal anti-s-100 immunostain using 3-amino-9-ethyl-l-carbazole [aec] chromogen, counterstain with harris haematoxylin x 400). (b) photomicrograph showing tumor cells positive for hmb-45. (hmb-45 antibody using 3,3'-diaminobenzidine [dab] chromogen, counter stain with harris haematoxylin stain x 400). neena chauhan, dushyant s. gaur, ved p. pathak case report | 511 types of treatment can be administered but none of them is considered a standard approach. there is no difference in survival between patients who have radical surgical procedures and those who have more conservative surgical procedures. immunotherapy with interferon-alpha (ifn-alpha) has been demonstrated to reduce recurrence rates and offers a better chance of survival.10 treatment modalities include surgical removal/ extirpation, irradiation, and chemotherapy either singly or in combination with other treatments. in the present case, excision was done. wide local excision with pelvic node dissection was advised but the patient refused this surgery; hence, radiotherapy was advised. follow-up treatment was not available at our institution. conclusion vaginal melanoma is a rare clinical entity and the round cell type is an uncommon variant. although the present case was clinically diagnosed as an urethral caruncle, histologically it was diagnosed as a round cell pigmented malignant melanoma. immunostaining assisted in confirming the diagnosis. references 1. manlucu ed, dickson h, mahood l, nath me. final diagnosis: primary malignant melanoma of the vagina. from: path.upmc.edu/cases/case167/ dx.html. accessed: may 2012. 2. park bj, yoon jh, lee hy, lee sh, han kt, ryu ks, et al. a case of primary malignant melanoma of the vagina. korean j obstet gynecol 2003; 46:667–71. 3. weinstock ma. malignant melanoma of the vulva and vagina in the united states: patterns of incidence and population-based estimates of survival. am j obstet gynecol 2004; 171:1225–30. 4. miner tj, delgado r, zeisler j, busam k, alektiar k, barakat r, et al. primary vaginal melanoma: a critical analysis of therapy. ann surg oncol 2004; 11:34–9. 5. ragnarsson-olding b, johansson h, rutqvist le, ringborg u. malignant melanoma of the vulva and vagina. trends in incidence, age distribution, and long-term survival among 245 consecutive cases in sweden, 1960–1984. cancer 1993; 71:1893–7. 6. ali s, siddiqui e, ojha h, koneru s, hock l. malignant melanoma of the female urethra. from: www.ispub. com/ostia/index.php?xmlfilepath=journals/iju/ vol2n1/melanoma.xml. accessed: may 2012. 7. scambia g, benedetti panici p, baiocchi g, coli a, ferrone s, natali pg, et al. a primary amelanotic melanoma of the vagina diagnosed by immunocytochemistry. int j gynaecol obstet 1989; 29:159–64. 8. şahande e, dilek sa, handan a, abdullah t, gulhan a. amelanotic malignant melanoma of the vagina. turk j canc 2000; 30:126–30. 9. chung a, casey m, flannery j, woodruff jm, lewis jl jr., et al. malignant melanoma of the vagina-report of 19 cases. obstet gynecol 1980; 55:720. 10. lin lt, liu cb, chen sn, chiang aj, liou ws, yu kj. primary malignant melanoma of the vagina with repeated local recurrences and brain metastasis. j chin med assoc 2011; 74:376–9. sultan qaboos university med j, may 2014, vol. 14 iss. 2, p. e263, epub. 7th apr 14 submitted 20th dec 13 accepted 9th mar 13 رد: معّدل وفيات ما حول الوالدة كمؤشر على جودة الرعاية الصحية يف حمافظة الداخلية يف سلطنة عمان re: perinatal mortality rate as a quality indicator of healthcare in al-dakhiliyah region, oman letter to editor sir, with reference to the interesting study published in the squmj november 2013 issue by santosh et al.,1 i presume that consanguinity is closely linked to the preponderance of congenital anomalies (53.50%) and prematurity with its complications (23.56%) which are the leading causes of early neonatal deaths in their studied cohort. my assumption is based on the following evidence. first, the practice of consanguineous marriage has been the culturally-preferred form of marriage in oman as more than half (52%) of the total marriages in oman are consanguineous.2 first cousin unions are the most common type of consanguineous unions, constituting 39% of all marriages and 75% of all consanguineous marriages.2 second, it is well-known that consanguineous couples have a higher risk of having children with congenital malformations than non-related couples. the consanguinity rate of 76% was reported among omani births with major malformations.3 third, infants of consanguineous parents has been shown to have a statistically significant 1.6-fold net increased risk of being born at less than 33 weeks’ gestation compared with infants of unrelated parents.4 fourth, consanguinity has been noticed to significantly increase pregnancy loss and birth weight of <2,500 g.5 accordingly, i presume that the continuing popularity of consanguineous marriage might have an important negative impact on the many effective measures suggested by santosh et al. to reduce the perinatal mortality rate in oman.1 mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. santosh a, zunjarwad g, hamdi i, al-nabhani ja, sherkawy be, al-busaidi ih. perinatal mortality rate as a quality indicator of healthcare in al-dakhiliyah region, oman. sultan qaboos univ med j 2013; 13:545–50. 2. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32–42. 3. sawardekar kp. profile of major congenital malformations at nizwa hospital, oman: 10-year review. j paediatr child health 2005; 41:323– 30. doi: 10.1111/j.1440-1754.2005.00625.x. 4. mumtaz g, nassar ah, mahfoud z, el-khamra a, al-choueiri n, adra a, et al. consanguinity: a risk factor for preterm birth at less than 33 weeks' gestation. am j epidemiol 2010; 172:1424–30. doi: 10.1093/aje/kwq316. 5. bellad mb, goudar ss, edlavitch sa, mahantshetti ns, naik v, hemingway-foday jj, et al. consanguinity, prematurity, birth weight and pregnancy loss: a prospective cohort study at four primary health center areas of karnataka, india. j perinatol 2012; 32:431–37. doi: 10.1038/jp.2011.115. letter to editor | 263 sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e120-125, epub. 27th jan 14 submitted 11th may 13 revision req. 20th jun 13; revision recd. 3rd jul 13 accepted 25th aug 13 histomorphology & stereology research center, shiraz university of medical sciences, shiraz, iran *corresponding author e-mail: karbalas@sums.ac.ir هل هنج طريقة التعلم القائم على الفريق لعلم التشريح أفضل من إلقاء احملاضرات التعليمية؟ نغمة قرباين, �صعيد كرباليي دو�صت, علي نور�ف�صان abstract: objectives: team-based learning (tbl) is used in the medical field to implement interactive learning in small groups. the learning of anatomy and its subsequent application requires the students to recall a great deal of factual content. the aims of this study were to evaluate the students’ satisfaction, engagement and knowledge gain in anatomy through the medium of tbl in comparison to the traditional lecture method. methods: this study, carried out from february to june 2012, included 30 physical therapy students of the shiraz university of medical science, school of rehabilitation sciences. classic tbl techniques were modified to cover lower limb anatomy topics in the first year of the physical therapy curriculum. anatomy lectures were replaced with tbl, which required the preparation of assigned content, specific discussion topics, an individual self-assessment test (irat) and the analysis of discussion topics. the teams then subsequently retook the assessment test as a group (grat). the first eight weeks of the curriculum were taught using traditional didactic lecturing, while during the second eight weeks the modified tbl method was used. the students evaluated these sessions through a questionnaire. the impact of tbl on student engagement and educational achievement was determined using numerical data, including the irat, grat and final examination scores. results: students had a higher satisfaction rate with the tbl teaching according to the likert scale. additionally, higher scores were obtained in the tbl-based final examination in comparison to the lecture-based midterm exam. conclusion: the students’ responses showed that the tbl technique could be used alone or in conjunction with traditional didactic lecturing in order to teach anatomy more effectively. keywords: learning; anatomy; physical therapy specialty; education; curriculum. �لت�رشيح تعلم يحتاج �ل�صغرية. �ملجموعات يف �لتفاعلي �لتعليم لتطبيق �لطبي �ملجال يف �لفريق على �لقائم �لتعلم طريقة ت�صتخدم الهدف: امللخ�ص: وتطبيقاته �إيل حفظ وتذكر قدر هائل من �حلقائق �لعلمية.هدفت �لدر��صة �إيل تقييم مدى حت�صيل �لطالب �ملعريف لعلم �لت�رشيح بطريقة �لتعلم �لقائم على �لفريق باملقارنة مع طريقة �لقاء �ملحا�رش�ت �لعلمية �لتقليدية. الطريقة: �أجريت �لدر��صة خالل �لفرتة من فرب�ير �إيل يونيو 2012 يف جامعة �صري�ز )�إير�ن(. مت تعديل طريقة �لتعلم �لقائم على �لفريق �لتقليدية لت�صتخدم يف تدري�س ت�رشيح �لطرف �ل�صفلي لثالثي من طالب �ل�صنة �الأوىل يف كلية �لعالج �لطبيعي. مت ��صتبد�ل حما�رش�ت �لت�رشيح �لتقليدية بطريقة �لتعلم �لقائم على �لفريق و�لتي تتطلب �لتح�صري �مل�صبق للمحتوي �لتدري�صي و�لعناوين مو�صع �لنقا�س �لتقليدية �ملحا�رش�ت بطريقة �الأويل �أ�صابيع �لثمانية تدري�س مت للجاهزية. �لفريق �ختبار من ذلك بعد �لنقا�س. مو��صيع وحتليل �لفردي �لتقييم و�ختبار بينما ��صتخدمت طريقة �لتعلم �لقائم على �لفريق يف فرتة �لثمانية �الأ�صابيع �لتالية. مت حتديد تاأثري طريقة �لتعلم �لقائم على �لفريق علي م�صاركة �لطالب وحت�صيلهم �ملعريف با�صتخد�م �لنتائج �لرقمية الختباري �لتقييم �لفردي وتقييم �لفريق باالإ�صافة �إيل نتائج �الإختبار �لنهائي. قام �لطالب بتقييم جل�صات �لدر��صة بطريقة �لتعلم �لقائم على �لفريق عن طريق ��صتبيان. النتائج: �أظهر مقيا�س ليكرت نتائج �أعلى ملعدل ر�صا �لطالب عن طريقة �لتعلم �لقائم على �لفريق. وبالالإ�صافة �إيل ذلك كانت نتائج �لطالب يف �الإمتحان �لنهائي �ملبني علي طريقة �لتعلم �لقائم على �لفريق �أف�صل من تلك �لتي ح�صل عليها �لطالب يف �متحان منت�صف �لف�صل �لدر��صي. اخلال�صة: �أظهرت ��صتجابات �لطالب �أنه من �ملمكن تطبيق طريقة �لتعلم �لقائم على �لفريق �إما وحدها �و باالإ�صافة �إيل �ملحا�رش�ت �لتقليدية لتدري�س علم �لت�رشيح بطريقة �أكرث فاعلية. مفتاح الكلمات: �لتعلم؛ علم �لت�رشيح؛ تخ�ص�س �لعالج �لطبيعي؛ �لتعليم؛ �ملناهج. is a team-based learning approach to anatomy teaching superior to didactic lecturing? naghme ghorbani, *saied karbalay-doust, ali noorafshan clinical & basic research advances in knowledge team-based learning (tbl) can be applied successfully with students in physical therapy education. tbl can trigger active participation of students in learning anatomy. application to patient care advances in medical education will indirectly improve patient care. the social skills required for working effectively in teams and collaborating are essential for good patient treatment and care. this can be experienced by students at a very early stage in their careers, thus making them ready for future teamwork. naghmeh ghorbani, saied karbalay-doust and ali noorafshan clinical and basic research | e121 team-based learning (tbl) was a term first popularised by michaelsen to describe an educational strategy that he developed for use in academic teaching. tbl is a teacherdirected method that promotes the application of knowledge using small groups in a class. the method increases learner engagement, promotes active learning and is reported as enjoyable by learners.1–3 tbl is increasingly being used in medical education.2,3 the objective of tbl is to go beyond the simple coverage of content and to focus on ensuring that the students practise using course concepts to solve problems. in other words, tbl can be defined as an instructional strategy that is based on techniques for developing high-performance learning teams and that can enhance the quality of student/trainee learning in almost any course. tbl promotes active learning within a group of students for three reasons. first, group work is central to exposing students to and improving their ability to apply course content. second, the greater part of class time is used for this group work. third, tbl involves multiple group tasks that are designed to improve learning and promote the development of self-managed learning groups. students involved in tbl learn content in three phases. in phase one, the students complete assignments, such as textbook reference readings, outside of the classroom. the students are responsible for the completion of these assignments. in phase two, student groups meet, as well as taking readiness assurance tests (rats), first individually (irat) and then in assigned small groups (grat). in the third phase, the students in the assigned teams consult to solve complex problems, triggering active participation and learning.4,5 the benefits of tbl include maximising student engagement, improving teamwork, developing communication skills, enhancing problem-solving skills and promoting knowledge outcomes.5–9 there are limited studies comparing tbl to other educational methods. these studies are also varied in their methodology as well as their choice of subjects. despite this, the studies have demonstrated higher engagement and enjoyment among tbl participants. nevertheless, there are controversial data on whether tbl improves knowledge outcomes compared to other educational techniques.6,10–12 human anatomy is a basic science course in any physical therapy curriculum. anatomy teaching has recently seen the introduction of several controversial changes. these include a reduction in course hours, the integration of preclinical and clinical courses, the abolition of cadaver dissection, the introduction of new educational methods, a change in students’ learning objectives and a decreased supply and demand for gross anatomy dissectors and instructors.13 the teaching of anatomy using tbl has received much attention in recent years.14–16 as an understanding of anatomy is fundamental to the understanding of other subjects in the physical therapy curriculum, especially the anatomy of the limbs and the vertebral column, it has to be learned effectively. in limb anatomy, the anatomy of related bones, muscles, and nerves are taught together. this gives a holistic understanding of the upper and lower limbs of the body and the mutual relationship of the limb structures.17 the hypothesis of this study was that tbl would be effective for teaching limb anatomy; this would be tested on undergraduate physical therapy students by comparing tbl to a traditional lecture course, measuring knowledge and the students’ satisfaction with the outcomes. methods this study was conducted at the school of rehabilitation sciences, shiraz university of medical science, iran, from february to june 2012. the participants were first-year physical therapy students who voluntarily took part in the study. all the procedures were performed under the supervision of the ethics committee of shiraz university of medical sciences, shiraz, iran. the lower limb anatomy instruction programme began in the second semester of the first academic year. lower limb anatomy serves as the basic anatomy course of the curriculum. in february 2012, 30 students were enrolled in the course. the class met once a week for two hours and the students participated in all class sessions for 16 weeks. the course was divided into six parts: bones, joints, gluteal region, thigh, leg and foot. the same students were taught using traditional lectures and tbl in the first and second eight-week periods of the semester, respectively. information regarding the dates of the midterm and final examinations, study guides, and textbook references were offered is a team-based learning approach to anatomy teaching superior to didactic lecturing? e122 | squ medical journal, february 2014, volume 14, issue 1 to the students at the beginning of the term. it should be noted that approximately half of the course time was spent in the laboratory. the final examination covered only the last eight weeks of content. in the first eight weeks of the semester, the traditional lecture-based method for teaching lower limb anatomy was used; this included eight hours of teaching and eight hours of laboratory dissection. the students (both male and female) were assigned to two laboratory groups receiving the usual traditional lectures by the faculty members. the most widely used method for theoretical classes are traditional lectures, which are a direct technique to encourage the students’ motivation and intellectual stimulation. all of the important material related to the lectures on lower limb anatomy, including pure anatomy and clinical problems, were explained to the students. the students were asked to answer five short-answer questions related to the lecture before the beginning of the lecture and at the end of the class (preand post-tests). later, in the midterm examination, they had to answer 30 multiple choice questions (mcqs) on lower limb anatomy. in the second eight-week period, students were again instructed through eight hours of teaching and eight hours of laboratory dissection. one week prior to the first modified tbl session, 30 undergraduate physical therapy students (both male and female) were randomly assigned to five groups (n = 6) for both the theoretical lectures and laboratory practice. one week before the class, all of the students were given a student guide explaining the learning objectives and textbook readings. before the beginning of the class, the preparatory material was individually studied and the modified tbl procedure was explained to the students.2,17 the students were required to complete five short-answer questions related to the lecture on lower limb anatomy in five mins before the beginning of the class (pre-test). the questions on the individual readiness assurance test (irat) assessed whether the students understood and could apply the important concepts of basic limb anatomy to the practice of physiotherapy. the answers were recorded on paper and considered for later grading. immediately after the irat, the pre-assigned teams of five students re-evaluated the same irat quiz within 15 mins, coming to a group consensus regarding the answers (post-test). this was the group readiness assurance test (grat). the team questions were reviewed by having the teams show their answers simultaneously. if the team answers did not agree, the problem was addressed by asking the teams to defend their answers (rat question/ discussion); this discussion phase was scheduled for 15 mins. the whole procedure filled the first hour of the class.2,17 the student groups were asked to study readings, copies of their textbooks, the standard atlas of anatomy and powerpoint presentations (microsoft powerpoint 2010, microsoft corporation, redmond, washington, usa) in order to encourage an active learning process and higher-order learning, which included discussions, problemsolving and clinical anatomy studies. the instructor was responsible for planning the sessions, preparing the material and evaluating the sessions. the instructor also presented a powerpoint presentation about each topic to clear any doubts that emerged during the discussion. once the instructor felt that the students had mastered the main concepts of the rat, the class would proceed to an application exercise. in this exercise, student teams worked on two questions that provided opportunities to apply their theoretical knowledge to complex real-world problems. the questions in the exercises were designed to be more challenging than the rat questions, requiring problem-solving skills beyond the simple recall of theoretical knowledge, such as these found in actual limb anatomy cases.2,17 one of the objectives of the study was to determine if student satisfaction was greater using the tbl method or traditional lecturing. after the students had completed the tbl and lecture sessions, they were asked to fill out a likert-scale six-item questionnaire, which included five options of strongly agree, agree, neutral, disagree and strongly disagree, in order to evaluate their levels of satisfaction with each session. this questionnaire was designed specifically to compare the tbl sessions to the traditional lecture-based classes on important key aspects of learning. the number of students responding to each item was noted and the mean value for each item was calculated. students’ suggestions were also elicited. the secondary objective of the study was to evaluate knowledge gain, which was assessed by an improvement in the students’ scores at pretest and post-test (using the individual and group rats). the third objective was determining the naghmeh ghorbani, saied karbalay-doust and ali noorafshan clinical and basic research | e123 impact of tbl sessions or lectures on student engagement. the educational achievements were evaluated based on the results of the midterm and final examinations. in the preand post-tests (irat and grat, respectively), as well as the midterm and final examinations, the students were scored for correct answers; however, they got full marks for the best answer in the application exercise. the pre-test scores were compared to the post-test scores, and the midterm examination results after the lecture sessions were compared to the final examination scores after tbl sessions, in order to evaluate the effectiveness of tbl in comparison to lecturing.2,17 the data were shown as mean ± standard deviation (sd) and analysed by the application of a paired sample t-test and an independent sample t-test. significance was defined as p <0.05. the difficulty of the examinations was tested using statistical approaches. results the results of the paired sample t-test revealed a statistically significant increase in knowledge gain between the students’ pre-test and post-test scores in both the traditional lectures and the tbl groups [table 1]. the maximum score was 5 and the mean pre-test scores were low in both groups. a statistically significant difference was observed between the scores of the lecture-based midterm examination and those of the tblbased final examination (p <0.01) [table 1]. the maximum score was 8 and the scores of the tblbased examination were higher than those of the lecture-based examination [table 1]. statistical analysis showed that the midterm and final examinations were of equal difficulty. the post-test results of the tbl group also showed a significant difference in comparison with the post-test results of the lecture-based learning group. the difference in mean satisfaction rating was statistically significant in the tbl group [table 2]. the students in the tbl group reported higher scores on the five-point likert scale. discussion this study was the first one to evaluate the effectiveness of tbl for teaching lower limb anatomy education to first-year physical therapy students. a unique application of the tbl curriculum was used, which is also utilised in other physical therapy specialties. one of the findings of this study was that there was increased student satisfaction with tbl compared to the traditional lecture-based method of teaching. regardless of when the students had participated in the study, they all displayed low pre-test and lecture examination scores. these low pre-test and lecture examination scores may reflect the students’ lack of acquaintance with the anatomy curriculum. in this study, knowledge gain was assessed using the posttest and tbl examination scores, and a significant difference was found between the lecture-based and tbl groups regarding score improvement. table 1: pre-test, post-test, midterm and final examination scores for the lecture and team-based learning groups group mean scores (sd) examinations pre-test post-test lecture 1.5 (1.0) 2.2 (1.20)* 6.0 (1.3) tbl 1.5 (1.0) 2.6 (1.20)* 6.5 (1.0)** sd = standard deviation; tbl = team-based learning. *p <0.01, (post-test versus pre-test scores), (post-test of tbl versus post-test of the lecture). **p <0.01, final (tbl) versus midterm (lecture) examination scores. table 2: student satisfaction of the lecture and teambased learning groups using a five-point likert scale questions satisfaction mean (sd) lecture tbl 1. i found that this learning style helped me understand anatomical concepts. 2.9 (0.7) 3.4 (0.6)* 2. i found that this style of learning encouraged clinical anatomy problem-solving. 3.0 (0.7) 3.5 (0.5)* 3. i found that this type of learning encouraged questions, discussions and interactions. 2.9 (0.9) 3.4 (0.7)* 4. i found that this type of learning forced me to study more consistently. 3.0 (0.8) 3.4 (0.7)* 5. i found that this learning style improved my problem-solving skills. 2.8 (1.0) 3.4 (0.7)* sd = standard deviation; tbl = team-based learning. *p <0.05, lecture-based versus tbl. is a team-based learning approach to anatomy teaching superior to didactic lecturing? e124 | squ medical journal, february 2014, volume 14, issue 1 this finding agrees with previous studies which reported on the effectiveness of the tbl method in medical sciences education.18,19 educational experiences using the tbl format were also compared with other methods.20,21 for example, mody et al. compared tbl with the lecture-based method and showed that tbl can be used as a novel approach for medical students’ education in family planning.2 this is in agreement with our work. moreover, tan et al. compared tbl with passive learning and reported that tbl is an effective technique for improving knowledge in undergraduate clinical neurology education.20 in this study, the post-test scores were significantly higher than the pre-test scores. by working together in highly prepared and structured settings, the students performed better as a group. this result is consistent with those of chung et al. and nieder et al.17,19 a similar study by vasan et al. compared tbl and traditional lectures with anatomy curricula.12 the results of that study also revealed a significantly greater improvement in knowledge gain in the tbl group compared to the lecture group. vasan et al. reported that the subjects’ scores in the tblbased anatomy courses were higher than those of lecture-based anatomy courses. moreover, our results agree with those of another study demonstrating that knowledge is retained better after tbl.17 nevertheless, a study by haidet et al. did not find any significant difference between tbl and lecturing regarding knowledge gain outcomes, possibly due to a lack of follow-up or because of learner heterogeneity.6 this study had some limitations. it is possible that the students may have performed better on the final examination because of their having been in the course for a longer period of time. however, the students were nevertheless more satisfied with the tbl method [table 2]. one of the greatest advantages of tbl is also one of its limitations; as tbl shifts the focus of instruction from learning about concepts and ideas to learning how to apply them in a meaningful way, this necessarily means that the method relies more upon the instructor. the instructor must be ready and willing to reward students for individual and pre-emptive study and provide them with the opportunity to learn how to use basic content in a meaningful and applicative way. encouraging the students to undertake study before the class was the main problem in the present study. another limitation of the present tbl study was the limited tendency of some students to participate in group work. thus, if the instructor’s primary focus was on simply covering the curriculum content and consequently failing to utilise the necessary application-focused assignments, students would therefore be less likely to invest their time and energy in carrying out additional pre-class study. another limitation of the present study was the evaluation of the methods over such a short period of time. one semester may be inadequate to evaluate all aspects of the tbl method in comparison to traditional lecturing. an additional limitation was the uncontrolled interventions regarding the reading guidance during the lecturebased tests. unlike tbl, where students were given a reading guide, no reading guidance was given with the lecture group. therefore, this aspect should be controlled in future studies. furthermore, another aspect of evaluating tbl is considering the peer evaluation of the students; the current study did not take into account peer evaluation in the modified tbl group. conclusion the present study demonstrates that tbl can be applied to cover lower limb anatomy topics in a physical therapy curriculum. according to the current study’s results, this method results in an improved knowledge gain and higher satisfaction ratings for the students. the students obtained improved results in their final examination, undertaken after tbl, in comparison to their midterm examination, undertaken after lecturebased learning. by utilising tbl, anatomy students can learn to collaborate and work effectively in teams at a very early stage in their careers. references 1. vasan ns, defouw do, holland bk. modified use of team-based learning for effective delivery of medical gross anatomy and embryology. anat sci educ 2008; 1:3–9. 2. mody sk, kiley j, gawron l, garcia p, hammond c. team-based learning: a novel approach to medical student education in family planning. contraception 2013; 88:239– 42. naghmeh ghorbani, saied karbalay-doust and ali noorafshan clinical and basic research | e125 3. michaelsen l, richards b. drawing conclusions from the team-learning literature in health-sciences education: a commentary. teach learn med 2005; 17:85–8. 4. thompson bm, schneider vf, haidet p, perkowski lc, richards bf. factors influencing implementation of teambased learning in health sciences education. acad med 2007; 82:s53–6. 5. searle ns, haidet p, kelly pa, schneider vf, seidel cl, richards bf. team learning in medical education: initial experiences at ten institutions. acad med 2003; 78:s55–8. 6. haidet p, morgan ro, o’malley k, moran bj, richards bf. a controlled trial of active versus passive learning strategies in a large group setting. adv health sci educ theory pract 2004; 9:15–27. 7. thompson bm, schneider vf, haidet p, levine re, mcmahon kk, perkowski lc, et al. team-based learning at ten medical schools: two years later. med educ 2007; 41:250–7. 8. hunt dp, haidet p, coverdale jh, richards b. the effect of using team learning in an evidence-based medicine course for medical students. teach learn med 2003; 15:131–9. 9. kelly pa, haidet p, schneider v, searle n, seidel cl, richards bf. a comparison of in-class learner engagement across lecture, problem-based learning, and team learning using the strobe classroom observation tool. teach learn med 2005; 17:112–8. 10. levine re, o’boyle m, haidet p, lynn dj, stone mm, wolf dv, et al. transforming a clinical clerkship with team learning. teach learn med 2004; 16:270–5. 11. tai bc, koh wp. does team learning motivate students’ engagement in an evidence-based medicine course? ann acad med singapore 2008; 37:1019–23. 12. vasan ns, defouw do, compton s. a survey of student perceptions of team-based learning in anatomy curriculum: favorable views unrelated to grades. anat sci educ 2009; 2:150–5. 13. carlson bm. the changing face of anatomy in the united states. kaibogaku zasshi 1999; 74:497–502. 14. inuwa im. perceptions and attitudes of first-year medical students on a modified team-based learning (tbl) strategy in anatomy. sultan qaboos univ med j 2012; 12:336–43. 15. inuwa im, taranikanti v, al-rawahy m, habbal o. perceptions and attitudes of medical students towards two methods of assessing practical anatomy knowledge. sultan qaboos univ med j 2011; 11:383–90. 16. habbal o. the state of human anatomy teaching in the medical schools of gulf cooperation council countries: present and future perspectives. sultan qaboos univ med j 2009; 9:24–31. 17. chung ek, rhee ja, baik yh, a os. the effect of teambased learning in medical ethics education. med teach 2009; 31:1013–7. 18. dunaway ga. adaption of team learning to an introductory graduate pharmacology course. teach learn med 2005; 17:56–62. 19. nieder gl, parmelee dx, stolfi a, hudes pd. team-based learning in a medical gross anatomy and embryology course. clin anat 2005; 18:56–63. 20. tan nck, kandiah n, chan yh, umapathi t, lee sh, tan k. a controlled study of team-based learning for undergraduate clinical neurology education. bmc med educ 2011; 11:91. 21. masters k. student response to team-based learning and mixed gender teams in an undergraduate medical informatics course. sultan qaboos univ med j 2012; 12:344–51. taurine levels in human aqueous humour medical sciences (2000), 2, 43−47 © 2000 sultan qaboos university 1department of behavioural medicine, college of medicine, sultan qaboos university, p.o.box: 35, postal code: 123, muscat, sultanate of oman. 2ministry of health, al-ain, uae. 3ministry of health, irbid, jordan *to whom correspondence should be addressed. 43 psychiatric morbidity in northern jordan: a ten-year review * zaidan z1, alwash r2, al-hussaini a1, al-jarrah m3. :الحاالت المرضية النفسية في شمال األردن جاعيةعشر سنوات دراسة إستر ، مز الجارحالحسيني. علوش ، ع. زيدان ، د. ز مريضًا 2335 تم دراسة سجالت :الطريقة . الحاالت النفسية في شمال األردن لمعرفة نسبة هذه الحاالت لغرض التخطيط للخدمات النفسية المطلوبة هو دراسة : الهدف: الملخص آان التشخيص حسب الجدول . كمبيوتردراسة تفصيلية وقد حللت النتائج بال ) 1984�1993(نوات ـنفسيًا والذين راجعوا العيادة النفسية الوحيدة في شـمال األردن لمـدة عشر س إناثًا ، وآانت نسبة المراجعة أآثر للفئة % 45منهم ذآورًا و % 55 مريضًا خالل فترة الدراسة وآان 2335 راجع العيادة :النتائج والخالصة . العالمي التاسع لتصنيف األمراض وآان أآثر المرضى زيارة للعيادة هم مرضى الفصام يليهم . ذآور والذهان العاطفي أآبر نسبة عند اإلناثشكل مرض الفصام العقلي أآبر نسبة تشخيص عند ال. سنة44-22العمرية شكل مرض القلق النفسي أآبر نسبة تشخيص يليه مرض الفصام ثم مرض الذهان ) 1993سنة (في السنة األخيرة من البحث . مرضى الذهان العاطفي ثم مرضى القلق النفسي .العاطفي abstract: ��������� – to study the psychiatric morbidity in the northern part of jordan and to determine the frequency distribution of various psychiatric disorders, for planning services. ���� – all records of 2,335 psychiatric patients attending the only psychiatric clinic in northern part of jordan during a ten-year period from 1984 to 1993 were extensively reviewed and subjected to computerized analysis. diagnosis was made as per icd-9. ������� – out of the 2335 patients who attended the clinic, 55% were males and 45% were females. those in the age group 25–44 recorded the maximum attendance. among the male attendees of the clinic, schizophrenia was the commonest diagnosis(19.9%), while among females, affective disorders were the commonest(15.9%). ���������� – schizophrenia was found to be the commonest diagnosis in general among attendance of the clinic for the ten-year research period, while anxiety disorders were the commonest diagnosis among attendance of the clinic for the year 1993. key words: attendance rate, schizophrenia, anxiety, affective psychosis. sychiatric disorders are the problem of the century. it has been estimated that as many as 500 million people in the world may be suffering some kind of mental disorder1, a prevalence which is expected to rise with the growth of population.2 world health organisation has declared mental well being to be an integral part of health. who and psychiatric epidemiologists are in a position now to confidently answer questions about changes of psychiatric morbidity over time.3 estimation of the prevalence of psychiatric disorders in the community and the variations of the rates of their prevalence4 are essential in planning health programs and in evaluating the results of community treatment programs.5 epidemiological research in psychiatry could also help in providing clues to aetiology and therefore, to prevention strategies.6 in developed countries, such statistics are readily available. in u.s.a., 15% of the population is estimated to be in need of mental health care at any given time.7 such essential information is scarce for the developing countries due to lack of research.8 further, among the medical profession of these countries,9 knowledge and recognition of the extent of psychiatric morbidity is poor in spite of an increase in interest lately. the patients themselves are much more likely to seek traditional help than avail of psychiatric services.10 jordan is a typical case of such informationscarcity. this study attempts to help fill this gap to the extent possible, by giving an indication of psychiatric morbidity in the population of northern jordan, attendance rate, socio-demographic characteristics, and diagnostic categories of patients who attended the mental health clinic in irbid during the period 1984– 1993. p z a i d a n e t a l method the study was carried out at the mental hea clinic of princess basma hospital, irbid, jordan. it in uded all psychiatric attendances recorded during period of ten years from january 1984 to decem 1993. the clinic was (and still is) the only governm mental health facility in irbid city, and opera through open door policy. it was also the referral cl for psychiatric patients coming from primary hea centres in irbid and its peripheries, the health centre jordan university of science & technology, priv practitioners and other health care facilities in the r ion such as united nations refugees welfare age (unrwa). the clinic was run daily by a rotation te of four psychiatrists. each psychiatric patient w required to have a file containing information his/her case history, clinical examination, diagno management and notes of follow up. the clinic ser as the only referral clinic for irbid governorate, wh had a population of 1.02 million in 1993, represent about 24.2% of the whole jordanian populati during 1984-1993, a total of 1,285 males & 1,0 females attended the clinic at different times, a constituted the population of this study. data w collected from their record files, which w extensively reviewed and analysed. the follow variables were included: age, sex, residen occupation, employment status, education, mar status, frequency of attendance and final diagnosis. attendance rate of psychiatric patien male diagnosis no attendance rate/100,000 anxiety disorders 169 9.2 schizophrenia 363 19.9 affective psychosis 218 11.9 other non-organic psychosis 44 2.4 dementia 21 1.1 epilepsy 209 11.4 mental retardation 99 5.4 personality disorders 70 3.8 alcohol & drug dependence 26 1.4 others 66 3.6 total 1285 70.3 * denominator population is 1988 population (mid-term). table 1 ts for both sexes for the period from 1984-1993 female both no attendance rate/100,000 no attendance rate/100,000 216 13.0 385 11.0 194 11.7 557 15.9 264 15.9 482 13.8 52 3.1 96 2.7 18 1.1 39 1.1 149 9.0 358 10.3 62 3.7 161 4.6 27 1.6 97 2.8 2 0.1 28 0.8 66 4.0 132 3.8 1050 63.1 2335 66.9 44 lth cl a ber ent ted inic lth of ate egncy am as on sis, ved ich ing on. 50 nd ere ere ing ce, ital prior to the beginning of data collection, a pilot study was conducted to ascertain the availability of the required information, with the aim to determine the variables to be finally included in the study. it revealed that all the variables were well recorded in the patients’ files. the final diagnosis of each case was made by the attending senior psychiatrist and was classified into major diagnostic categories based on international classification of diseases – 9th revision (icd-9)11: (a) age of patients by years at the attendant time, which were grouped into five categories. (1) child: 0–14, (2) adolescent: 15–24, (3) young adult: 25– 44. (4) middle-aged: 45–64, and (5) elderly: 65+. (b) sex. (c) residence: whether the patient lived in irbid city or was from the peripheries (d) marital status: whether single, married, divorced or widowed. (e) occupation. (f) education:(1)child, (2) illiterate & primary, (3) intermediate & secondary, (4) college and university. (g) frequency of attendance at the clinic. the study consisted of two parts (part i and part ii). in part i, the variables of age, sex, years, residence and final diagnosis of all the 2335 patients who attended the clinic from 1984 to 1993 were studied. part ii, which studied only 500 patients who attended the clinic during the year 1993, considered the following additional variables: level of education, occupation, employment status, marital status and frequency of attendance in the clinic. part ii also coded all diagp s y c h i a t r i c m o r b i d i t y i n n o r t h e r n j o r d a n 45 nostic categories according to icd-9. data from both part i and ii were analysed by a computer using spss programme to produce frequency distribution and cross tabulation of the various variables. table 2 characteristics of psychiatric patients who attended the mental health clinic in 1993 variables characteristics no % anxiety disorders 118 23.6 schizophrenia 103 20.6 affective psychosis 92 18.4 other non organic psychosis 23 4.6 dementia 12 2.4 epilepsy 45 9.0 mental retardation 33 6.6 personality disorders 20 4.0 alcohol/drug dependence 10 2.0 others 44 8.8 diagnosis total 500 100.0 professional 52 11.7 skilled / skilled worker student 51 11.5 others* 49 11 housewife 127 28.5 occupation unemployed . 162 37.3 employed 116 44.4 employment status unemployed 162 55.6 child (0–14 year) 37 10 illiterate & primary 111 29.9 intermediate & secondary 151 40.7 education college & university 72 19.4 single (including 40 children) 207 46 married 222 49.3 widowed/divorced 21 4.7 marital status once 202 40.4 twice 91 18.2 three times 54 10.8 frequency of attendance four times and more 153 30.6 irbid city 244 50.7 place of residence irbid peripheries 237 49.3 * ‘others’ include students, retired and military. results: in both part i and ii, the majority (55% and 58% respectively) were male; higher rates were found among the 25–44 age group in both males and females. the attendance rates were relatively higher in males 164(i)-113(ii) per 100,000 population) compared with 147(i)–87(ii)/100,000 for females (the latter mostly aged 45 and above). for part i, schizophrenia was the overall major diagnosis (15.9/100,000), and this was also the major diagnosis for the males (19.9/100,000), with the maximum attendance rates, while dementia figured the lowest (1.1/100,000). for females, the highest was affective psychosis (15.9/100,000) and the lowest, alcohol and drug dependence (0.1/100,000). anxiety disorders, which were common in females than in males, occupied the third place in general frequency (11/100000). the fourth place went to epilepsy (10.3/100000), which was more common in males (table 1). attendance rates were slightly higher from irbid city than from the peripheries, and in both, there was a gradual increase in the attendance rates from 26.2/100,000 in 1984 to 106.4/100,000 in 1993. in part ii (1993), anxiety disorders, at 23.6%, accounted for the highest attendance followed by schizophrenia (20.6%) and affective disorders (18.4%). 55.6% of the subjects were unemployed. while 29.9% of the subjects were illiterate or had primary education, 40.7% had intermediate or secondary school education, and 19.4% had college or university education. about half the patients (49.3%) were married, 46% were single (including 40 children), while 4.7% were divorced or widowed. as regards attendance rates in the clinic, 40.4% of the patients attended only once, while 30.6% did four times or more (table 2). discussion for part i (1989–1993), in contrast with the universal excess of females among psychiatric patients as reported in most western studies,4,12-14 this study found overall attendance rates to be higher in males (70.3/100,000) than in females (63.1/100,000). similar findings have been reported from other arab countries, mainly saudi arabia.10,15-18 the reason for this could be that females in this region tend to seek help from the local support system for longer period than males do before availing of specialized services. women are more encouraged to seek traditional healers than men and, culturally speaking, they are great believers in these. it could also be that families tend to have greater tolerance for mental illnesses in females. the stigma attached to mental illnesses might z a i d a n e t a l 46 affect the girls’ chances of getting married, due to which, they might try to hide their problems. significantly, we found more married female patients than married males. the 25–44 age group had the highest attendance rates throughout. this agrees with findings from other studies in developed & developing countries.19-22 the reasons for this are, the largest number of population falls in this age group; they are more educated and hence seek psychiatric help more than others; they are also more prone to stress from marital and family conflicts and work pressures. attendance rates were higher in females above 45 years of age possibly due to the increase frequency of affective disorders at that age group. attendance rates increased through the years from 1984 to1993 in respect of both the sexes (24.6/100000 in 1984 to 100.7/100000 in 1993). this is in line with other studies in u.k. and usa,23,24 and is so possibly because of increased popular awareness and improvement of services. the study also showed higher attendance rates in male schizophrenics while in females it was among those with affective psychosis. overall, schizophrenic patients had the highest attendance rate (15.9/100,000). these results agree with other studies in the arab world and in the west.10,15,20,25 the data also showed that proportionately more patients from irbid city attended the clinic (71.5/100,000) compared to those from the peripheries (64.4/100,000). this again, is in line with many studies in developed and developing countries15,20,26,27 which showed that psychiatric morbidity is more common in urban than in rural areas. the easy access for city patients to the clinic, could be another factor. parts i and ii of the study agreed with each other regarding attendance rates (higher in males compared with females). in part ii (1993), most attendees had anxiety disorder (23.6%), a finding that is in agreement with other studies28,29 including one in usa.7 most of the attendees to the clinic were unemployed. this seems to be in agreement with findings in kuwait,17 in saudi arabia30 and egypt.19 the majority of patients who attended the clinic in 1993 had intermediate or secondary education. this finding does not agree with several studies13,14,31 which showed that the higher the education level, the lower the psychiatric morbidity. most of the patients attended the clinic in 1993 were married and this is in agreement with other studies in arab countries.3,5,25,26,30 studies in the western world show that psychiatric morbidity is more common in those who are widowed, divorced or single.22,32 conclusion most of the attendees were males, majority of whom were of 25–44 years of age. most of the patients were unemployed, married, and there was an increase in attendance over the years. schizophrenia had the highest attendance rates followed by affective psychosis & anxiety disorders. the lowest rates were for alcohol & drug abuse. the commonest diagnoses among attendees to the clinic in 1993 were anxiety disorders, schizophrenia and affective psychosis, in that order. further epidemiological studies on psychiatric morbidity are recommended. acknowledgement we would like to thank dr. mohammed shaban and all the staff of the psychiatric outpatient clinic, basma hospital for help in collecting data. we are grateful to mr. k. ravindran for secretarial assistance. references 1. world health organization. intercountry meeting on national programes of mental health, demascus, syrian arab republic, who geneva 1986, 2–6. 2. henderson as. epidemiology of mental disorders and psychosocial problems: dementia, who, geneva 1994, 1–5. 3. sartorius n, nielsen ja, stromgren e. changes in frequency of mental disorder over time (results of repeated surveys of mental disorders in the general population). acta psychiatr scand 1989, 79 (suppl.348), 5–10. 4. myers jk, weissman mm, tischler gl, holzer ce, leaf pj, orvaschel h, anthony jc, boyd jh, burke jd, kramer m, stoltzman r. six month prevalence of psychiatric disorders in three communities. arch gen psychiatry 1984, 41, 959–67. 5. stanley b, gibson at. the prevalence of chronic psychiatric morbidity: a community sample. br j psychiatry 1985, 146. 372–6. 6. boyd j h, weissman mm. epidemiology of affective disorders. arch gen psychiatry 1981. 33, 1039–47. 7. bourdon kh, rae ds, lock ebz, narrow we, regier da. estimating the prevalence of mental disorders in u.s. adults from the epidemiological catchment area survey. public health rep 1992, 107, 663–667. 8. stromgren e, nielsen ja, sartorius n. changes in frequency of mental disorders over time. acta psychiatr scand, 1989, 79 (suppl:348), 167–8. 9. jacobsson l. psychiatric morbidity and psychosocial background in an outpatient population of general hospital in western ethiopia. acta psychiat scand 1985, 71, 417–26. 10. osman aa, alkateeb so, ali as. the pattern of admission to jeddah psychiatric hospital, saudi medical journal 1993, 14, 334–9. 11. institute for health studies. the international classification of diseases, 9th rev, clinical modification, annotated edition, 1988, edwards brothers, inc., ann arbor, michigan, vol 1. p s y c h i a t r i c m o r b i d i t y i n n o r t h e r n j o r d a n 47 12. ihezue uh, okpara e. psychiatric disorders of old age in enugue, nigeria – sociodemographic and clinical characteristics. acta psychiatr scand 1989, 79, 332–7. 13. craig tj, huffine c. correlates of patient attendance in an inner-city mental health clinic. am jpsychiatry 1976, 133, 61–5. 14. madianos m, vlachonikolis i, madianou d, stefanis c. prevalence of psychological disorders in the athens area. acta psychiat scand 1985, 71, 479–87. 15. daradkeh tk, al-zayer m. psychiatric morbidity in the arabian american oil company (aramco) – calls for the setting up of gp psychiatric clinics. jordan medical journal 1990, 24, 35–48. 16. el-assra a, amin h. hospital admissions in a psychiatric division in saudi arabia. saudi medical journal 1988 9, 25–33. 17. suleiman ma, malasi th , mirza ia, el-islam mf some characteristics of the psychiatric population attending a primary care centre in kuwait. acta psychiatr scand 1989, 79, 199–204. 18. el-gaaly aa, rahim fe, al-wohaibi aa. psychiatric emergencies at king khalid university hospital. saudi medical journal, 1987, 8, 382–386. 19. el-akabawi as, nusseir e, kamel f. psychiatric morbidity in an egyptian village: a community survey. egypt j psychiat, 1983, 6, 126–40. 20. regier da, boyd jh, burke jd, rae ds, myers jk, kramer m, robins ln, george lk, karno m, locke bz. one-month prevalence of mental disorders in the united states. arch gen psychiatry 1988, 45, 977–87. 21. abu-hijleh ns. psychiatric consultations in jordan university hospital: a comparative report on 861 referrals. jordan medical journal 1987, 2, 149–58. 22. sytema s, balestrier m, giel r, horn gh, tansella m. use of mental health services in south verona and groningen. acta psychiatr scand 1989, 79, 153–62. 23. redlich f, kellert sr. trends in american mental health. am j psychiatry 1978, 135, 22–8. 24. woof k, freeman hl, fryers t. psychiatric service use in salford: a comparison of point prevalence ratios 1968 and 1978. br j psychiatry 1983, 142, 88–97. 25. el-rufaie oef, abu mediny ms. psychiatric inpatients in a general teaching hospital: an expert from saudi arabia. arab journal of psychiatry 1991, 2, 138–45. 26. al-fares eam, al-shammari sa, al-ahmad amy. prevalence of psychiatric disorders in an academic primary care department in riyadh. saudi medical journal 1992, 13, 49–53. 27. freeman h. schizophrenia and city residence. br j psychiatry 1994, 23 (suppl) 39–50. 28. nielsen j, nielsen ja. eighteen years of community psychiatric service in the island of samso. br j psychiatry 1977, 131, 41–8. 29. hooilim m. a psychiatric emergency clinic: a study of attendances over six months. brit j psychiatry 1983, 143, 460–6. 30. qureshi na, al-quraishi ny, hegazy is. some characteristics of mental patients admitted to a psychiatric hospital. arab journal of psychiatry 1991, 2,146–58. 31. filho nda. social epidemiology of mental disorders: a review of latin-american studies. acta psychiatr scand 1987, 75, 1–10. 32. surtees pg. dean c, ingham jg, kreitman nb, miller pm, sashidharan sp. psychiatric disorders in women from an edinburgh community: associations with demographic factors. brj psychiatry 1983, 142, 238–4. psychiatric morbidity in northern jordan:�a ten-year review intro method table 2 characteristics of psychiatric patients who attended the mental health clinic in 1993 diagnosis occupation results: discussion conclusion acknowledgement references sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e338–343, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.006. submitted 7 dec 14 revision req. 9 mar 15; revision recd. 26 mar 15 accepted 19 apr 15 department of nuclear medicine, royal hospital, muscat, oman *corresponding author e-mail: b_saqri@hotmail.com تصوير اجلسم باستخدام مسح الغاليوم-67 يف عصر التصوير املقطعي باإلصدار البوزيرتوين والتصوير املقطعي جتربة مركز رعاية ثالثية بدرية ال�سقرية و نعيمة البلو�سية abstract: objectives: although 18f-fluorodeoxyglucose positron emission tomography (pet)/computed tomography (ct) has largely replaced the use of gallium-67 (67ga) scintigraphy in the evaluation and follow-up of lymphoma patients, 67ga scans are still of value, particularly in countries where no pet/ct service is available. the current study presents the experience of a tertiary care centre using 67ga scintigraphy for the evaluation of lymphomas and infections. methods: a retrospective review was conducted of all 67ga scans performed between 2007 and 2011 at the royal hospital in muscat, oman. images and reports of 67ga scans were compared to clinical and radiological follow-up data including ct and pet/ct scans and biopsies when available. results: a total of 74 patients were referred for 67ga scintigraphy during this period with 12 patients excluded due to lack of follow-up data, resulting in 62 patients. among these patients, 90 67ga scans were performed, including 59 for lymphoma, 29 for infection and two for sarcoidosis assessment. of the infection assessment scans, 22 were performed to assess pyrexia of unknown origin and seven for follow-up after known infections. sensitivity and specificity were found to be 80% and 88%, respectively, for the lymphoma assessment scans. for the infection assessment scans, sensitivity and specificity were reported to be 80% and 100%, respectively. conclusion: results from this study were consistent with other reported rates of 67ga scan sensitivity and specificity in the evaluation of lymphomas and infections. this indicates that 67ga scintigraphy is a useful tool for these types of evaluations when pet/ct services are not available. keywords: gallium-67-citrate; gallium radioisotopes; fluorodeoxyglucose f18; scintigraphy; lymphoma; infection; fever of unknown origin; oman. اإىل حل قد 18f-fluorodeoxyglucose املقطعي البوزيرتوين/الت�سوير بالإ�سدار املقطعي الت�سوير اأن من الرغم على الهدف: امللخ�ص: حد كبري حمل م�سح اجل�سم باإ�ستخدام الغاليومـ-67ga( 67( يف تقييم ومتابعة مر�سى �رسطان الغدد الليمفاوية، اإل اأن م�سح 67ga ل يزال ذي قيمة، ول �سيما يف البلدان التي تكون فيها خدمة pet/ct غري متاحة. تقدم الدرا�سة احلالية جتربة مركز رعاية ثالثية يف ا�ستخدام 67ga م�سح لها اأجري التي احلالت جلميع رجعي باأثر ا�ستعرا�س اأجرى واللتهابات. الطريقة: اللمفاوية الأورام لتقييم 67ga م�سوحات املتابعة لبيانات 67ga م�سح وتقارير �سور مقارنة ومتت عمان. �سلطنة م�سقط، يف ال�سلطاين امل�ست�سفى يف 2011 و 2007 عامي بني مت متاحة. النتائج: تكون عندما اخلزعات ونتائج البوزيرتوين باإل�سدار املقطعي الت�سوير وتقارير املقطعية الشعة وتقارير ال�رسيرية حتويل ما جمموعه 74 مري�سا مل�سح اجل�سم با�ستخدام 67ga خالل هذه الفرتة. مت ا�ستبعاد 12 مري�سا نظرا لعدم وجود بيانات املتابعة، فكان املجموع املتبقي 62 مري�سا اأجري لهم ما جمموعه 90 م�سحا با�ستخدام 67ga، مبا يف ذلك 59 م�سحا ل�رسطان الغدد الليمفاوية، 29 م�سحا للعدوى واثنان لتقييم مر�س ال�ساركويد. اأو�سحت النتائج اأن احل�سا�سية واخل�سو�سية مل�سح 67ga لتقييم �رسطان الغدد الليمفاوية كان %88 و %80 على التوايل، و %100 و %80 مل�سح تقييم العدوى على التوايل. اخلال�صة: كانت نتائج هذه الدرا�سة تتفق مع الدرا�سات الخرى التي اأجريت لنف�س الغر�س. وهذا يدل على اأن م�سح اجل�سم با�ستخدام 67ga هو اأداة مفيدة لهذه الأنواع من التقييمات يف املناطق التي ل تتوافر فيها خدمات. مفتاح الكلمات: الغاليوم -67�سيرتيت؛ النظائر امل�سعة للغاليوم؛ فلورايد-18 فلوروديوك�سيجلوكوز؛ م�سح اجل�سم؛ �رسطان الغدد الليمفاوية؛ عدوى؛ حمى غري معروفة املن�ساأ؛ �سلطنة عمان. gallium-67 scintigraphy in the era of positron emission tomography and computed tomography tertiary centre experience *badriya al-suqri and naima al-bulushi advances in knowledge results of the current study confirmed that the sensitivity and specificity of gallium-67 (67ga) scintigraphy in this tertiary centre were consistent with those reported in the international literature. application to patient care 67ga scintigraphy can help in localising the foci of infection. scans can also show positive findings in patients with neoplastic disease clinical & basic research badriya al-suqri and naima al-bulushi clinical and basic research | e339 the clinical impact and cost-effect-iveness of combined 18f-fludeoxyglucose (18f-fdg) positron emission tomography (pet) and computed tomography (ct) is well documented in the literature and this technology has a wide range of applications in both benign diseases and oncology.1 additionally, the role of pet/ct in the diagnosis and management of lymphomas has been well established for more than a decade.2 nonpet radiotracers that were previously used for the evaluation of lymphomas and infections are now seldom utilised in current practice. however, despite the advances this technology has brought to patient management, some centres still lack pet/ct facilities. in other institutions where pet/ct is available, not all pet radiotracers are accessible or approved for clinical practice. hence, the old radiotracers used in nuclear medicine still exist and play a role in today’s modern practice. one of the most commonly used radioisotopes in tumour imaging, as well as in the imaging of infection and inflammation, is gallium-67 citrate (67ga).3 this group iiia metal has been used for decades for the imaging of various solid neoplasms, particularly lymphomas, and in the investigation of acute inflammatory conditions. it is also used to assess infections and to identify the site of disease in patients with pyrexia of unknown origin (puo).4 67ga is produced by cyclotron and has a half-life of 78.26 hours and energy abundances of 93 kilo electron volts ([kev] 40%), 184 kev (20%), 300 kev (17%) or 393 kev (5%). for medical radiology purposes, 67ga is provided in the form of a sterile solution of gallium citrate.3,5,6 the human body reacts to 67ga similarly to the way that it handles ferric iron. gallium iii ions bind to transferrin glycoproteins, leukocyte lactoferrin, bacterial siderophores, inflammatory proteins and cell membranes in neutrophils and become concentrated in areas of inflammation and rapid cell division.3,7 this retrospective study aimed to evaluate the use of 67ga in a tertiary care hospital over a period of five years and compare outcomes with available clinical and radiological follow-up data, including ct and pet/ct scans and biopsies. methods this retrospective review included all 67ga scintigraphy scans performed in the department of nuclear medicine at the royal hospital, muscat, oman, from 2007–2011. only patients who were referred to this department and with follow-up appointments at the royal hospital were included in the study. at the royal hospital, 67ga scans were performed by nuclear medicine technologists with a siemens e-cam dual-head variable angle gamma camera (siemens medical solutions usa inc., malvern, pennsylvania, usa). adult patients undergoing 67ga scintigraphy received a dose of 180 megabecquerels (mbq) while the dose for child patients was calculated by multiplying their weight in kg by 180 mbq and dividing the total by 70 kg.8 all patients with excessive bowel activity were given laxatives and scanned one or two days afterward. whole body imaging for lymphoma patients was performed 48 hours after the 67ga injection using both detectors with a matrix size of 256 x 1,024 pixels. however, patients with puo or infections were imaged 24 hours after the injection. additional imaging was performed after 48 hours or later, if deemed necessary. spot views of the chest and abdomen were acquired with both detectors with a matrix size of 256 x 256 pixels. imaging was halted either after five minutes had elapsed or if 500 kilo counts had been obtained. the whole process usually took 30–45 minutes, although sometimes longer if single photon emission ct images were also required. the 67ga images and reports were compared to subsequent clinical and radiological follow-up data, including ct and pet/ct scans and biopsies, if available. these data were collected from hospital records retrospectively. this study was approved by the research & ethical committee at the royal hospital (#mesrc 17/2014). results a total of 74 patients were referred to the department of nuclear medicine at the royal hospital for 67ga scintigraphy between 2007 and 2011; however, 12 presenting with pyrexia of unknown origin. follow-up 67ga scans can be performed to assess the response to treatment or resolution of the infective process. despite current hybrid and molecular imaging services provided by combined 18f-fluorodeoxyglucose positron emission tomography and computed tomography, this study demonstrated that 67ga scintigraphy remains a useful tool for the evaluation and follow-up of patients with lymphoma. gallium-67 scintigraphy in the era of positron emission tomography and computed tomography tertiary centre experience e340 | squ medical journal, august 2015, volume 15, issue 3 figure 1: gallium-67 scintigraphy images revealing pericardial uptake (arrows) in a patient with pyrexia of unknown origin. echocardiography and aspiration revealed tuberculosis (tb) pericarditis. the patient was subsequently treated with anti-tb medication. rt = right; lt = left. for sarcoidosis. of the 67ga scans carried out for lymphoma patients, 32 were for hodgkin’s lymphomas (hl), 23 were for non-hodgkin’s lymphomas (nhl), three were for mucosa-associated lymphoid tissue lymphomas and one was for t cell lymphoma. lymphoma scans were divided into six baseline scans, 10 mid-therapy response assessment scans and 43 post-therapy scans for the assessment of relapse [table 1]. of the six baseline studies, five scans yielded true-positive results and one showed a false-negative result. of the 10 mid-therapy studies performed to assess response to therapy, six were true-negative, three were true-positive and one yielded a falsenegative result. the majority of the 67ga lymphoma scans were performed to assess relapse: 24 scans yielded true-negative results (i.e. no evidence of gallium-avid lesions); 11 scans produced true-positive patients were excluded due to a lack of follow-up data. as a result, 62 patients were included in the final sample. the mean age of these patients was 43 years old. a total of 28 patients were male (45%). the majority of referrals were from medical oncologists referring lymphoma patients (n = 24; 39%) and infectious diseases specialists referring patients (n = 9; 15%), primarily for the localisation of infection sites. seven patients (11%) were paediatric haematology cases; the remaining patients were chest medicine, paediatric, rheumatology, nephrology, neurology or acute medicine cases. a total of 90 67ga scans were performed during the study period. assessment of lymphomas constituted the bulk of the referrals, with a total of 59 scans (66%). of the remaining scans, 29 (32%) were performed for infection assessment and two (2%) were performed table 1: comparison of the findings of gallium-67 scintigraphy lymphoma assessment scans to subsequent clinical and radiological follow-up data (n = 59) scan type result total truepositive falsepositive truenegative falsenegative baseline 5 0 0 1 6 midtherapy 3 0 6 1 10 posttherapy 11 5 24 3 43 total 19 5 30 5 59 table 2: comparison of the findings of gallium-67 scintigraphy infection assessment scans to subsequent clinical and radiological follow-up data (n = 29) scan type result total truepositive truenegative falsepositive falsenegative puo 12 7 0 3 22 follow-up of known infection 5 2 0 0 7 total 17 9 0 3 29 puo = pyrexia of unknown origin. badriya al-suqri and naima al-bulushi clinical and basic research | e341 results (either recurrence in the same sites or relapses in new sites); and five scans gave false-positive results (infection sites which were mistaken for lymphoma lesions). the remaining three scans yielded falsenegative results as the lesions were not avid on 67ga scans but were positive on a subsequent 18f-fdgpet/ct scan or via biopsy. these results indicated a sensitivity and specificity of 80% and 88%, respectively, for assessing lymphomas using 67ga scintigraphy. infection assessments were carried out either for patients with puo in order to localise the source of infection (n = 22) or for follow-up of a known infection (n = 7) [table 2]. for known infection followup scans, five yielded true-positive results while two yielded true-negative results. of the 22 patients who were scanned for puo, nine indicated positive uptake at different sites and these areas were subsequently targeted during treatment. one of these patients had a positive 24-hour whole body 67ga scan with pericardial uptake indicating active pericarditis, which turned out to be secondary to tuberculosis [figure 1]. a further three patients were found to have 67ga-avid lesions. of the three, one patient showed suprarenal uptake, with a biopsy revealing neuroblastoma [figure 2]. the second patient had supraclavicular lymph node uptake revealing hl [figure 3], while the third patient showed lung uptake which was found to be wegener’s granulomatosis. there were no 67ga-avid lesions found in the remaining 10 puo assessment scans. in three patients, no source of infection was found and the patients were treated empirically with antibiotics. in another three patients, the negative scans were attributed to prolonged antibiotic therapy (n = 2) and fungal infection (n = 1). in the final four negative 67ga scans, no source of infection was found and the fevers were attributed to different disease processes, including systemic lupus erythematosus, adult-onset still’s disease, a connective tissue disease and myelodysplastic syndrome. these results showed sensitivity and specificity rates of 80% and 100%, respectively, in the assessment of infection using 67ga scintigraphy. two patients were known to have sarcoidosis and were referred for an assessment of disease activity. one was negative with no 67ga-avid uptake related to figure 2: gallium-67 scintigraphy images showing left suprarenal uptake (arrows) in a child with pyrexia of unknown origin. computed tomography and a subsequent biopsy revealed a neuroblastoma. rt = right; lt = left. figure 3: gallium-67 scintigraphy images showing mediastinal (red arrow) and thymic uptake (blue arrow) in a patient referred for lymphoma assessment. a biopsy revealed hodgkin’s lymphoma. rt = right; lt = left. gallium-67 scintigraphy in the era of positron emission tomography and computed tomography tertiary centre experience e342 | squ medical journal, august 2015, volume 15, issue 3 used for more than a decade to image soft tissue infections and osteomyelitis.15 at the royal hospital, 99mtc sulesomab has been used since 2013 to evaluate patients with total knee replacements for septic loosening. it is also valuable in detecting osteomyelitis in patients with sickle cell disease, particularly when a three-phase bone scan might yield a false-positive result in sites with regenerating bone marrow following vaso-occlusive crises.15 18f-fdg-pet/ct imaging is not yet available in oman.16 almost all oncology patients from the royal hospital are sent abroad for 18f-fdg-pet/ct imaging for initial staging and the evaluation of residual disease and treatment response. currently, 67ga citrate is used for the imaging of patients with puo and the evaluation of patients with malignant otitis externa. in addition to a three-phase bone scan, 67ga is also used to evaluate patients with total knee replacements for septic loosening. conclusion although the utilisation of 67ga citrate has become less common with the introduction of new imaging modalities such as pet/ct and new radiotracers such as 99mtc, the findings of this study confirm that there is a continuing role for this radiotracer in infection and tumour imaging, particularly when pet/ ct facilities are not available. furthermore, the results from this study were consistent with other reported rates of 67ga scan sensitivity and specificity in the evaluation of lymphomas and infections. references 1. krause bj, schwarzenböck s, souvatzoglou m. fdg pet and pet/ct. recent results cancer res 2013; 187:351–69. doi: 10.1007/978-3-642-10853-2_12. 2. morton ka, jarboe j, burke em. gallium-67 imaging in lymphoma: tricks of the trade. j nucl med technol 2000; 28:221–32. 3. khan mu, usmani ms. radionuclide infection imaging: conventional to hybrid. in: gholamrezanezhad a, ed. 12 chapter on nuclear medicine. rijeka, croatia: intech, 2011. pp. 73–96. 4. bartold sp, donohoe kj, haynie tp, henkin re, silberstein eb, lang o. society of nuclear medicine procedure guideline for gallium scintigraphy in the evaluation of malignant disease. from: snmmi.files.cms-plus.com/docs/pg_ch23_0403.pdf accessed: mar 2015. 5. bombardieri e, aktolun c, baum rp, bishof-delaloye a, buscombe j, chatal jf, et al. 67ga scintigraphy: procedure guidelines for tumour imaging. eur j nucl med mol imaging 2003; 30:bp125–31. doi: 10.1007/s00259-003-1356-1. 6. seabold je, palestra cj, brown ml, datz fl, forstrom la, greenspan bs, et al. procedure guideline for gallium scintigraphy in inflammation: society of nuclear medicine. j nucl med 1997; 38:994–7. sarcoidosis, while the other showed bilateral breast uptake which, upon clinical examination, was found to be caused by bilateral mastitis. discussion pet/ct has almost replaced 67ga scintigraphy in the assessment of both oncology and infection; this imaging modality plays a well-documented and clinically proven role not only in tumour staging, but also in evaluating treatment response and predicting treatment outcomes.1,8,9 in addition, the use of pet/ct in the imaging of inflammation and in the evaluation of patients with puo is well-known.10,11 in spite of the efficacy of this modality, some nuclear medicine departments may nevertheless lack pet/ct facilities or resources. hence, 67ga scintigraphy is still used for tumour and infection imaging. 67ga uptake is highest in diffuse large cell and highand intermediate-grade lymphomas due to their high cell division rates.4,5 67ga citrate was used extensively in the past for several pathological conditions, particularly when the presence of tumours, infection or inflammation was in question.3 in past decades, the role of 67ga scintigraphy in nuclear oncology mainly focused on assessing the response of lymphoma to therapy. however, it was also used as a baseline for staging and to assess gallium avidity, patient response to treatment and residual disease activity post-therapy.5 in a study evaluating 50 lymphoma patients, 67ga was used in routine staging and was found to provide information that was missed or equivocal by other diagnostic modalities in 20–25% of patients.12 another study compared the positive and negative predictive values and disease-free survival rates in 43 patients with hl and 56 patients with nhl.13 a significant difference in disease-free survival was found between patients with positive and negative 67ga scans. it was concluded that 67ga was a reliable predictor of clinical outcomes in these cases.13 regarding the use of 67ga scintigraphy in evaluating infection and inflammation, high sensitivity has been demonstrated for both infectious as well as non-infectious inflammation processes.14 the most common clinical scenarios where 67ga is still utilised include puo, sarcoidosis and in cases of malignant otitis externa. in addition, 67ga has been successfully utilised in the evaluation of spinal discitis and vertebral osteomyelitis, mainly to assess disease activity.3 technetium-99m (99mtc) sulesomab is another modality for evaluating infection and can be used instead of 67ga in most indications.15 this antigranulocyte antigen-binding fragment has been http://dx.doi.org/10.1007/978-3-642-10853-2_12 http://dx.doi.org/10.1007/s00259-003-1356-1 badriya al-suqri and naima al-bulushi clinical and basic research | e343 7. love c, palestro cj. radionuclide imaging of infection. j nucl med technol 2004; 32:47–57. 8. gelfand mj, parisi mt, treves st; pediatric nuclear medicine dose reduction workgroup. pediatric radiopharmaceutical administered doses: 2010 north american consensus guidelines. j nucl med 2011; 52:318–22. doi: 10.2967/ jnumed.110.084327. 9. vranjesevic d, filmont je, meta j, silverman dh, phelps me, roa j, et al. whole-body (18)f-fdg pet and conventional imaging for predicting outcome in previously treated breast cancer patients. j nucl med 2002; 43:325–9. 10. ben-haim s, ell p. 18f-fdg pet and pet/ct in the evaluation of cancer treatment response. j nucl med 2009; 50:88–99. doi: 10.2967/jnumed.108.054205. 11. gotthardt m, bleeker-rovers cp, boerman oc, oyen wj. imaging of inflammation by pet, conventional scintigraphy, and other imaging techniques. j nucl med 2010; 51:1937–49. doi: 10.2967/jnumed.110.076232. 12. seabold je, votaw ml, keyes jw jr, foley wd, balachandran s, gill sp. gallium citrate ga 67 scanning: clinical usefulness in lymphoma patients. arch intern med 1976; 136:1370–4. doi: 10.1001/archinte.1976.03630120022010. 13. front d, ben-haim s, israel o, epelbaum r, haim n, evensapir e, et al. lymphoma: predictive value of ga-67 scintigraphy after treatment. radiology 1992; 182:359–63. doi: 10.1148/ radiology.182.2.1732950. 14. keidar z, gurman-balbir a, gaitini d, israel o. fever of unknown origin: the role of 18f-fdg pet/ct. j nucl med 2008; 49:1980–5. doi: 10.2967/jnumed.108.054692. 15. skehan sj, white jf, evans jw, parry-jones dr, solanki ck, ballinger jr, et al. mechanism of accumulation of 99mtcsulesomab in inflammation. j nucl med 2003; 44:11–18. 16. al-bulushi nk, bailey d, mariani g. the medical case for a positron emission tomography and x-ray computed tomography combined service in oman. sultan qaboos univ med j 2013; 13:491–501. http://dx.doi.org/10.2967/jnumed.110.084327 http://dx.doi.org/10.2967/jnumed.110.084327 http://dx.doi.org/10.2967/jnumed.108.054205 http://dx.doi.org/10.2967/jnumed.110.076232 http://dx.doi.org/10.1001/archinte.1976.03630120022010 http://dx.doi.org/10.1148/radiology.182.2.1732950 http://dx.doi.org/10.1148/radiology.182.2.1732950 http://dx.doi.org/10.2967/jnumed.108.054692 sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 301-305, epub. 9th may 13 submitted 2nd sep 12 revision req. 24th nov 12, revision recd. 24th nov 12 accepted 24th nov 12 stuve-weidemann syndrome (stws) [mim #601599], also known as neonatal schwartz-jampel syndrome type 2 (sjs-2), is a severe neuromuscular disorder of prenatal onset characterised by congenital joint contractures, distinctive campomelic metaphyseal skeletal dysplasia, respiratory and feeding difficulties, dysautonomia with a tendency towards hyperthermia, and frequent death in infancy.1 the condition is classified as a genetic skeletal disorder in the congenital bent bone dysplasia group, as the bowing of the long bones in these disorders is a major manifestation. infants with stws usually present with joint stiffness, and difficulty in feeding or opening their eyes. these infants are usually affected with mask-like facies, hypotonia, bowing of the long bones (particularly the tibia and the femur), camptodactyly, and autonomic disturbances. hypotonia is a common presentation in childhood, and stws should be considered in the differential diagnosis.2 we report three omani siblings born with stws to consanguineous parents, having neonatal hypotonia as the presenting feature, with intermittent pyrexia, mild incurvature and shortening of their long bones, and myotonia in one case. the constellation of these signs, family history, and radiographic features pointed to the departments of 1child health and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: roshankoul@hotmail.com واحدة يف ثالثة : أمراض احنناء العظام اخللقية وحرارة مفرطة متقطّعة يف ثالثة أشقاء مع متالزمة ستوف-ويدمان رو�شن كول ،عديلة الكندي، رجنيث ماين ، ديليب �شنكهال ، اأمنة الفطي�شي امللخ�ص: متالزمة �ضتوف-ويدماّن ا�ضطراب نادر يتمّيز باإنحناء خلقي للعظام الطويلة, تقفعات املفا�ضل, �ضيق يف التنف�ص منذ الوالدة, �ضعوبات يف امل�ص و البلع, ا�ضطراب ع�ضبي ذاتي يكون على �ضكل حمى مفرطة عر�ضّية, وعادة موت مبّكر. ثالثة ا�ضقاء ولدوا من زواج اقارب و ظهرت عليهم �ضمات �رسيرّية مماثلة على مدى 16 عاما. مت ت�ضحي�ص املتالزمة لدى العائلة عند والدة اخر طفلة يف بداية 2012. كان جميع االأطفال يف البداية يعانون منذ الوالدة من حمى مفرطة ونق�ص التوتر العام. ك�ضف الفح�ص ال�رسيري جلميع الر�ضع عن انعطاف االإ�ضبع امل�ضتدمي, �ضغر الفك, انحناء العظام الطويلة مع كرادي�ص وا�ضعة, ونق�ص التوتر. فقط كان الطفل الثاين مت�رسرا من التوتر الع�ضلي من خالل ر�ضم كهرباء الع�ضل. احلمى املفرطة �ضمة غري عادية يف هذه املتالزمه وميكن ان ت�ضاعد على التعرف املبكر لهذه املتالزمة بحيث ميكن جتنب عمل فحو�ضات مو�ضعة ومف�ضلة. هذه املتالزمة نتيجة طفرة يف جني م�ضتقبالت العامل املثبط ل�رسطان الدم. مفتاح الكلمات: متالزمة �شتوف-ويدمان؛ متالزمة �شوارتز جامبل؛ التوتر الع�شلي؛ حمى؛ تقرير حاله؛ عمان. abstract: stuve-wiedemann syndrome (stws) is a rare disorder characterised by congenital bowing of the long bones, contractures of the joints, neonatal onset of respiratory distress, sucking and swallowing difficulties, dysautonomia presenting as episodic hyperthermia, and usually an early death. three siblings from a consanguineous marriage presented with similar clinical features over 16 years. stws was established with their last child at the beginning of 2012. all the children exhibited the onset of stws in the neonatal period with fever and generalised hypotonia. examinations of all the infants revealed camptodactyly, micrognathia, bent long bones with wide metaphyses, and hypotonia. only the second affected child had myotonia, demonstrated by electromyography. unusual pyrexia as a presenting feature in this syndrome needs early recognition so that extensive and elaborate investigations can be avoided. the disorder is usually caused by a mutation in the leukaemia inhibitory factor receptor gene. keywords: stuve-weidemann syndrome; schwartz-jampel syndrome; myotonia; pyrexia; case report; oman. one in three: congenital bent bone disease and intermittent hyperthermia in three siblings with stuve-wiedemann syndrome *roshan koul,1 adila al-kindy,1 renjith mani,1 dilip sankhla,2 amna al-futaisi1 case report one in three: congenital bent bone disease and intermittent hyperthermia in three siblings with stuve-wiedemann syndrome 302 | squ medical journal, may 2013, volume 13, issue 2 diagnosis of stws, especially when associated with myotonia as this is an uncommon presentation during childhood. pyrexia as a presenting feature due to autonomic instability and should not always be considered as a sign of infection. although the condition is rare worldwide, it is relatively common in the middle east.3 case one the couple’s third child, a female, was first seen 16 years ago at sultan qaboos university hospital (squh), oman. she was referred at 26 days of age with poor feeding, hypotonia, severe failure to thrive, intermittent fever, and recurrent infections. on examination, she had micrognathia, lowset ears, narrow and short palpebral fissures, long eyelashes, and short curved limbs. she was hypotonic with flexion deformities of both the upper and lower limbs. the basic blood work-up was normal including a septic work-up and a serum creatine kinase (s-ck) test. the nerve conduction study (ncs) and electromyography (emg) were both normal. no definitive diagnosis was made and the child died at 3 months of age from a respiratory infection. case two the second affected infant was the couple’s seventh child. he was referred to squh at the age of 4 months with poor feeding habits and failure to thrive. he was born full-term after a vacuum extraction for shoulder dystocia. his apgar scores were 6 and 8 at 1 and 5 minutes, respectively. he had a history of abnormal movements (shaking of the lower limbs) noted transiently in the first week of life, and presented with recurrent episodes of a highgrade fever. on examination, he was microcephalic and emaciated, with hypotonia, bilateral elbow contractures and facial myotonia presenting with blepharospasms and pursing of the lips on stimulation. in addition, he was micrognathic and dysmorphic, with long eyelashes, low-set ears, an inverted v-shaped mouth, and pectus carinatum. a baseline blood work-up, septic work-up, and s-ck were normal, as was the ncs. an emg showed myotonia at rest and at action with no denervation pattern. in view of the infant’s clinical features and the emg findings, a diagnosis of sjs-2 was made. the child died at 11 months of age. case three the third affected child was the couple’s ninth child. the mother had had two spontaneous mid-trimester abortions before this baby’s birth, but her four other offspring were healthy [figure 1]. antenatally, she had had oligohydramnios late in the pregnancy and reported normal fetal movements. this child was first seen at 14 days of age with hypotonia, a weak cry, and poor sucking. he was born post-term at 41 weeks’ gestation by an emergency lower segment caesarean section due to non-progress of the labour. the infant’s apgar scores were 8 and 9 at 1 and 5 minutes, respectively. his birth parameters were appropriate for gestation. he developed respiratory distress and figure 1: the family tree showing affected siblings and consanguineous parents. roshan koul, adila al-kindy, renjith mani, dilip sankhla and amna al-futaisi case report | 303 desaturation one hour after birth and required facial oxygen. clinically, he had a poor sucking reflex, a weak cry, hypotonia, and generalised weakness of grade 4/5 with normal reflexes. he also had recurrent episodes of pyrexia with a normal septic work-up. he was still tube-fed at 8 months of age and exhibited a failure to thrive, with his weight well below the 3rd centile, a head circumference on the 3rd centile, and length on the 50th centile. he was noted to have dysmorphic features including a narrow and short palpebral fissure, a broad nasal bridge, a short nose with a wide base, low-set ears, and micrognathia. he had limited extension of the elbow and knees and camptodactyly [figure 2]. he had fixed contracture of the right thumb and single palmar creases. his lower extremities were short and mildly curved with bilateral prominent heels. he had no myotonia clinically or on emg. the blood tests at squh, including complete blood count, liver function, electrolytes, blood gases, lactate, and ammonia, were all normal. tandem mass spectrometry and s-ck levels were also normal. a complete skeletal survey revealed bent long bones and an increase in cortical thickness of the tibia bone at the point of angulation (dysplastic femora epiphysis) [figures 3–5]. there was a widening of the metaphyses with trabeculation [figure 3]. echocardiography showed a small atrial septal defect. an ultrasound and computed tomography (ct) scan of the head and an ophthalmology examination were normal. the parents refused molecular studies despite detailed genetic counselling. at the time of writing this child was still alive. discussion all three siblings had similar clinical features with a neonatal onset of hypotonia, feeding difficulties, and hyperthermia. clinically, they all exhibited short, bowed long bones and camptodactyly. only case two had clinical and emg evidence of myotonia. the classical facies of stws with blepharospasm and pursing of the lips were also noted in this case. the clinical and radiological features of these 3 cases were characteristic of stws. although this is a rare condition affecting all ethnic groups, it is over-represented in middle eastern populations due to the high coefficient of inbreeding. it should be figure 2: x-ray of the left hand showing camptodactyly (bent fingers and thumb). figure 3: x-ray of lower limbs showing the thickened cortex and bent long bones with enlarged diaphysis. one in three: congenital bent bone disease and intermittent hyperthermia in three siblings with stuve-wiedemann syndrome 304 | squ medical journal, may 2013, volume 13, issue 2 considered in the differential diagnosis of a neonate presenting with recurrent fevers, hypotonia, and respiratory and feeding difficulties who is not responding to broad-spectrum antibiotics and who presents with a normal metabolic work-up. these infants usually have bent long bones and camptodactyly with evidence of facial myotonia on clinical examination.1 the condition was first described by stuve and wiedemann in 1971 in a patient with bowing of the long bones, camptodactyly, respiratory distress, hyperthermic episodes, and death in the first year of life.2 long term survival has rarely been reported.1 this syndrome has features similar to sjs-2, which was once described as a separate entity but is now regarded as stws.3–5 there have been a number of reports from the arabian gulf in genaral, and oman in particular, of children with sjs-2.3,6 stws should be suspected in the prenatal period when encountering ultrasonographic findings of oligohydramnios; sometimes in cases of intrauterine growth restriction; in cases of mild to moderate shortening and bowing of the long bones; when noting reduced fetal movements, or in a family with a previous history of a similarly affected child. abnormal skeletal features can be recognised on examination, and a skeletal survey can confirm the campomelic dysplasia affecting the tibia more than the femur, with internal cortical thickening of the medial part of the long bones, relative sparing of fibula and upper limb involvement, and normal thoracic dimensions. enlarged metaphyses with an abnormal trabecular pattern are invariably present. stws is one of the differential diagnoses of campomelic dysplasia. the myotonia, if present, can be clinically recognised by pursed lips and blepharospasms. recurrent respiratory infections and hyperthermia are typical features in the first year of life usually resulting in early death. other typical features, apart from the bowing and shortening of the lower limbs which can be recognised in utero, are the enlarged joints and contractures at the elbows, knees, and fingers. differential diagnoses include other congenital bent long bone dysplasias such as campomelic dysplasia [mim #11429]. this is an autosomal dominant condition that usually presents with sex reversal and severe respiratory distress due to severe tracheobronchial and pulmonary hypoplasia, and distinctive skeletal radiographic abnormalities. another differential diagnosis is kyphomelic dyslasia [mim #211350], a probable figure 4: x-ray of right upper limb showing the thick and bent long bones. figure 5: x-ray of left upper limb showing the thick and bent long bones. roshan koul, adila al-kindy, renjith mani, dilip sankhla and amna al-futaisi case report | 305 x-linked, autosomal recessive disorder with major incurvature of the femur and short stature, sometimes associated with immunodeficiency.7 management of stws is symptomatic, requiring intensive care initially, including attention to feeding and nutrition, physiotherapy, and orthopedic intervention for the progressive skeletal abnormalities and osteopaenia in the few long term survivors.8 the main cause of death in infancy is aspiration pneumonia due to defective swallowing, which improves with age in some patients. management of the consequences of dysautonomia include protection of the tongue and eyes against repeated trauma because of the reduced pain sensation. excessive sweating and intermittent hyperthermia should be managed by hydration and environmental modification without antipyretics. the microcephaly seen in our second and third cases could be a result of overall malnutrition. microcephaly is not a feature of stws and development is usually normal in these children. the diagnosis of stws can usually be confirmed molecularly by a finding of null mutations in the leukaemia inhibitory factor receptor (lifr) gene which usually leads to the absence of lifr protein. this is a transmembrane protein important in intracellular signalling of the janus kinase-signal transducer and activator of transcription (jak/ stat)-3 signalling pathway.9 the jak-stat signalling pathway plays an important role in transmitting information from extracellular polypeptide signals to target gene promoters in the nucleus. jak-stat signalling regulates many cellular processes, including development, cell proliferation, differentiation, and apoptosis. however, the causative mutations in the lifr gene are not found in some patients with stws, suggesting genetic heterogeneity. null mutations in the lifr gene have also been found to cause both sjs-2 and stws, leading to the conclusion that these disorders should be considered a single, homogeneous disease.7 conclusion neonatal presentation of campomelic dysplasia with normal thoracic dimensions, unexplained fevers, and consanguinity in the middle eastern population should alert paediatricians to a differential diagnosis of stws, a potentially lethal condition. myotonia is a classic symptom of this condition. molecular testing can not only confirm the clinical diagnosis but also provide reproductive choices for the family and their relatives. extensive genetic counselling, coupled with carrier screening and premarital testing, should be undertaken as a preventative strategy in families with a history of this mutation. references 1. gasper im, saldanha t, cabral p, manuel vilhena m, tuna m, costa c, et al. long term follow up in stuve-wiedemann syndrome. am j med genet 2008; 146a:1748–53. 2. stuve a, wiedemann mr. congenital bowing of the long bones in two sisters. lancet 1971; 2:495. 3. al gazali l, varghese m, varady e, altalabani j, scorer j, bakalinova d. neonatal schwartzjampel syndrome: a common autosomal recessive syndrome in the united arab emirates. j med genet 1996; 33:203–11. 4. dirocco m, stella g, bruno c, doria lamba l, bado m, superti furga a. long term survival in stuve-wiedemann syndrome: a neuro-myo-skeletal disorder with manifestaions of dysautonomia. am j med genet 2003; 118:362–8. 5. cormier-daire v, superti-furga a, munnich a, lyonnet s, rustin p, delezoide al, et al. clinical homogeneity of the stuve-wiedemann syndrome and overlap with schwartz-jampel syndrome type 2. am j med genet 1998; 78:146–9. 6. koul rl, bashri wa, otto f. schwartz-jampel syndrome in two siblings. saudi med j 1997; 18:525– 6. 7. akawi na, ali br, al-gazali l. review of stuvewiedemann syndrome and related bent bone dysplasias. clin genet 2012; 82:12–21. 8. jung c, dagoneau n, baujat g, lemerrer m, david a, dirocco m, et al. stuve-wiedemann syndrome: long term follow up and genetic heterogeneity. clin genet 2010; 77:266–72. 9. dagoneau n, scheffer d, huber c, al-gazali li, dirocco m, godard a, et al. null leukemia inhibitory factor receptor (lifr) mutations in stuvewiedemann/schwartz-jampel type 2 syndrome. am j med genet 2004; 74:298–305. a possible case of systemic lupus erythematosus presenting with generalised oedema e582 | squ medical journal, november 2014, volume 14, issue 4 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e582−584, epub. 14th oct 14 submitted 3rd dec 13 revisions req. 6th feb & 7th may 14; revisions recd. 14th apr & 19th may 14 accepted 5th jun 14 systemic lupus erythematosus (sle) is an autoimmune disease of unknown aetiology affecting various systems within the body. it has various clinical and laboratory manifestations and a variable course and prognosis. polyserositis and subcutaneous oedema are common manifestations of sle. they are usually associated with nephrotic syndrome, constrictive pericarditis, congestive heart failure, portal hypertension, malignancy and pleural infection.1 however, generalised subcutaneous oedema as the first manifestation of sle and without a specific cause is rare.1 a case of a young female with generalised subcutaneous oedema as the initial and only presenting feature of sle is reported. case report a 21-year-old unmarried female university student with no previous medical problems presented to the sultan qaboos university hospital in muscat, oman, in april 2013 with symptoms of generalised swelling of the body which had been present for two years. the swelling was located mainly in the face, abdomen and lower limbs and was gradually increasing over time. the swelling was at its worst in the morning, to the extent that sometimes she was unable to open her eyes fully for 30 minutes after waking. over the twoyear period, the patient noted that her weight had increased by 17 kg; she had begun regular exercise, but had not succeeded in losing any weight. the patient denied experiencing any of the following symptoms: joint pain, chest pain, shortness of breath, palpitations, dizziness, skin rashes, oral ulcers, hair loss, changes in appetite or menstrual problems. there was no history of allergies or any significant family history. the patient was not currently taking any medication. a physical examination revealed puffiness of the face and pitting pedal oedema extending up to the departments of 1family medicine & public health and 2medicine, sultan qaboos university hospital; 3family medicine training programme, oman medical specialty board, muscat, oman *corresponding author e-mail: kawther@squ.edu.om حالة حمتملة ملرض الذئبة احلمامية اجلهازية ظهر يف شكل تورم عام يف اجلسم كوثر ال�سفيع، علي ال�سرياوي، بثينة امل�سكري، نفي�سة سمري abstract: systemic lupus erythematosus (sle) is an autoimmune disease of unknown aetiology affecting various systems within the body. we report the case of a patient with generalised subcutaneous oedema as the only presenting feature, which led to the possible diagnosis of sle without a specific cause. the patient presented to the sultan qaboos university hospital in muscat, oman, in april 2013. the oedema had been present for two years before admission. other potential causes of oedema in patients with sle were excluded, including sle of renal origin and sle due to protein-losing enteropathy or drugs. this was confirmed by the patient’s normal serum albumin level and negative proteinuria. laboratory investigations showed high levels of positive antinuclear antibodies (>1:640), positive anti-double-stranded deoxyribonucleic acid results, high levels of antiβ2-glycoprotein 1 and immunoglobulin m and low levels of both complement components 3 and 4. the oedema improved immediately in response to steroids and immunosuppressive medications. physicians should be aware that generalised subcutaneous oedema can be the only manifestation of sle. keywords: edema; systemic lupus erythematosus; case report; oman. امللخ�ص: الذئبة احلمامية اجلهازية هو اأحد اأمرا�ض املناعة الذاتية و�سببه غري معروف، وهو يوؤثر على اأجهزة خمتلفة داخل اجل�سم. وهنا نن�رش حالة مري�ض كان ي�سكو فقط من تورم عام حتت اجللد، وهو ما قادنا اإىل اإمكانية ت�سخي�ض احلالة كحالة الذئبة احلمامية اجلهازية دون �سبب حمدد. زار املريض مستشفى جامعة السلطان قابوس يف مسقط، عامن خالل شهر أبريل 2013. كان التورم موجوداً ملدة �سنتني. ومت ا�ستبعاد الأ�سباب املحتملة الأخرى للتورم يف املر�سى امل�سابني مبر�ض الذئبة احلمراء، مبا يف ذلك فقد بروتينات بوا�سطة الكلى اأو الأمعاء. ومت التاأكد من ذلك لأن تركيزالألبومني يف م�سل الدم كان طبيعيا ، ومل يوجد بروتني يف البول. اأظهرت الفحو�سات املخربية م�ستويات عالية من اإيجابية الأج�سام امل�سادة للنواة )1:640<(، ونتائج اإيجابية احلم�ض اخللوي ال�سبغي امل�سادة، ووجود م�ستويات منخف�سة من كل من مكونات تكملة 3 و 4. وحت�سن التورم فورا عقب إعطاء ال�ستريودات والأدوية املثبطة للمناعة. نقرتح اأن يدرك الأطباء اأن التورم حتت اجللد املعمم ميكن اأن يكون مظهرا من مظاهر الذئبة احلمامية اجلهازية. مفتاح الكلمات: ورم؛ الذئبة احلمامية اجلهازية؛ تقرير حالة؛ عمان. a possible case of systemic lupus erythematosus presenting with generalised oedema *kawther t. el-shafie,1 ali al-shirawi,2 buthaina al-maskari,3 nafisa samir1 online case report kawther t. el-shafie, ali al-shirawi, buthaina al-maskari and nafisa samir online case report | e583 knees. there were no indicators of pallor, jaundice or lymphadenopathy and all of her vital signs were within the normal range. her weight was 60 kg and a systematic examination was normal, apart from oedema of the abdominal wall without ascites. the investigation results favoured a diagnosis of sle [table 1]. the patient’s antinuclear antibody (ana) level was positive (>1:640) and her anti native double-stranded nuclear deoxyribonucleic acid (n-dna) count was 150 iu/ml (normal range: 0–45 iu/ml). these results were highly suggestive of sle. accordingly, she was started on a regimen of hydroxychloroquine, mycophenolate and prednisolone. over the following six months, the patient began to show marked improvement and her oedema subsided. discussion the most likely diagnosis for the findings observed in the current patient was sle, due to the high levels of positive ana and anti n-dna antibodies recorded. however, her clinical condition fulfilled neither the diagnostic criteria of sle (according to the revised guidelines of the american college of rheumatology)2 nor those of mixed connective tissue disease or undifferentiated connective tissue disease.3,4 the diagnosis was predominantly based on immunological findings. since her autoimmune profile was strongly indicative of sle, it was thought likely that this was a possible case of sle, potentially progressing to definite sle in the future. the response of the oedema to immunosuppressive therapy also supported this diagnosis. more common causes of subcutaneous oedema (such as heart failure, liver disease, malnutrition, renal disease or drugs) were excluded in this patient by a careful history-taking as well as clinical and other relevant investigations. oedema, especially the localised form, has been reported in the literature as a rare presenting symptom of sle.5–9 there are reports of periorbital oedema,5 lower limb pitting oedema,6 facial oedema,7 remitting asymmetrical pitting oedema8 and angioedema,9 all as initial presentations of sle. there are several cases of sle presenting with generalised oedema due to either protein-losing enteropathy (ple),10–12 an association with idiopathic nephrotic syndrome,13 or polyserositis in the form of massive bilateral pleural and pericardial effusions.1 nephrotic syndrome as a cause of oedema in this patient was excluded by the absence of urinary protein. moreover, ple was unlikely to be the cause of the generalised subcutaneous oedema in this patient, as patients with table 1: investigation results indicative of a diagnosis of systemic lupus erythematosus in the reported patient investigation result normal range esr in mm/hour 2 35–52 c-reactive protein in mg/l <1 0–5 albumin-adjusted calcium in mmol/l 2.31 2.15–2.55 phosphate in mmol/l 1.2 0.81–1.45 serum creatinine in µmol/l 43 45–84 urea in mmol/l 2.7 2.8–8.1 potassium in mmol/l 3.6 3.5–5.1 sodium in mmol/l 139 135–145 urine negative for blood and protein urine excretion over 24 hours in g 0.09 0.05–0.14 urine albumin in mg/l <3 3.0–400 total creatine kinase in u/l 48 26–192 serum cortisol in nmol/l 359 185–624 complement component 3 in g/l 0.50 0.79–1.52 complement component 4 in g/l 0.07 0.16–0.38 total protein in g/l 69 66–87 antinuclear antibody levels >1:640 anti n-dna antibody levels in iu/ml 150* 0–45 rheumatoid factor negative extractable nuclear antigens strong positive antisjögren’s syndrome antigen a anti-ribonuclear proteins positive anti-ro52 antibodies positive anti-histones antibodies moderately positive anti-smith antigen weakly positive other nuclear antigens negative anti-β-2 glycoprotein 1 (immunoglobulin g) in u/ml 1 0–20 anti-β-2 glycoprotein 1 (immunoglobulin m) in u/ml 105† 0–20 anti-cardiolipin antibody (immunoglobulin g) in u/ml 9 0–12 anti-cardiolipin antibody (immunoglobulin m) in u/ml 51 0–12 complete blood count normal liver function tests normal thyroid function tests normal thyroid antibodies negative uric acid normal lipids normal electrocardiogram normal chest x-ray normal esr = erythrocyte sedimentation rate; n-dna = native double-stranded nuclear deoxyribonucleic acid. *highly suggestive of systemic lupus erythematosus. †strongly positive. a possible case of systemic lupus erythematosus presenting with generalised oedema e584 | squ medical journal, november 2014, volume 14, issue 4 ple usually have low serum protein and albumin measurements.10–12 as a result, tests to detect ple, such as technetium-99m albumin scintigraphy or a 24hour stool alpha-1-antitrypsin clearance test, were not justified in this case.7,8 the underlying cause of generalised oedema in sle patients without systemic manifestations, such as renal disease, is not yet clear. günaydin et al. postulated that the localised oedema observed in his reported case was most likely due to vasculitis, which had led to an obstruction of the lymphatic vessels.6 the aetiology of localised periorbital oedema in patients with sle flares is also not apparent. a case series reported by gómez-puerta et al. found that while some cases were related to nephrosis, there was no evidence in others.14 pittau et al. believed that oedema may be due to a transient impairment in lymphatic drainage or pre-existing increased capillary permeability, as demonstrated in patients with connective tissue disorders.8 marks et al. proposed that there was an increase in vascular permeability in patients with connective tissue diseases.15 in yet another patient with periorbital oedema, increased dermal mucin deposits were observed during a biopsy.16 angioedema due to c1-inhibitor deficiency has also been described in the literature.17 the findings of this case report are limited by certain factors. photographs of the patient were not taken before the initiation of treatment and a skin biopsy was not sent to a pathologist to determine the exact pathophysiological mechanisms of the patient’s symptoms. conclusion the first possible case of sle presenting with generalised subcutaneous oedema without a definite cause is described. the cause of oedema in this patient could not be explained by other reported causes of generalised oedema associated with sle, such as ple, nephrotic syndrome or polyserositis. the presence of generalised oedema is a rare cutaneous manifestation of sle and can be the initial and sole manifestation of this disease. references 1. lu l, zhao z, cai h. generalized subcutaneous edema and polyserositis as unusual presentation in systemic lupus erythematosus. int j rheum dis 2012; 15:e50–2. doi: 10.1111/j.1756-185x.2011.01695.x. 2. petri m, orbai am, alarcón gs, gordon c, merrill jt, fortin pr, et al. derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. arthritis rheum 2012; 64:2677– 86. doi: 10.1002/art.34473. 3. cappelli s, bellando randone s, martinović d, tamas mm, pasalić k, allanore y, et al. “to be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. semin arthritis rheum 2012; 41:589–98. doi: 10.1016/j. semarthrit.2011.07.010. 4. conti v, esposito a, cagliuso m, fantauzzi a, pastori d, mezzaroma i, et al. undifferentiated connective tissue disease an unsolved problem: revision of literature and case studies. int j immunopathol pharmacol 2010; 23:271–8. 5. erras s, benjilali l, essaadouni l. periorbital edema as initial manifestation of chronic cutaneous lupus erythematosus. pan afr med j 2012; 12:57. 6. günaydin i, daikeler t, mohren m, kanz l, kötter i. lower limb pitting edema in systemic lupus erythematosus. rheumatol int 1999; 18:159–60. doi: 10.1007/s002960050077. 7. anzai m, maezawai r, ohara t, kodama k, fukuda t, kurasawa k. systemic lupus erythematosus associated with facial edema, overproduction of interleukin-5, and eosinophilia. j clin rheumatol 2008; 14:361–2. doi: 10.1097/ rhu.0b013e31818f3b15. 8. pittau e, passiu g, mathieu a. remitting asymmetrical pitting oedema in systemic lupus erythematosus: two cases studied with magnetic resonance imaging. joint bone spine 2000; 67:544–9. doi: 10.1016/s1297-319x(00)00217-7. 9. lahiri m, lim ay. angioedema and systemic lupus erythematosus: a complementary association? ann acad med singapore 2007; 36:142–5. 10. wu cc, lin sh, chu p, lai jh, chang dm, lin yf. an unrecognized cause of oedema in a patient with lupus nephritis: protein losing enteropathy. nephrol dial transplant 2004; 19:2149–50. doi: 10.1093/ndt/gfh226. 11. ratnayake ec, riyaaz aa, wijesiriwardena bc. systemic lupus erythematosus presenting with protein losing enteropathy in a resource limited centre: a case report. int arch med 2012; 5:1. doi: 10.1186/1755-7682-5-1. 12. ranawaka n, atukorala i, fernandopulle n, nawarathna m. an unusual cause of generalized oedema in systemic lupus erythematosus. rheumatology (oxford) 2012; 51:2298–300. doi: 10.1093/rheumatology/kes157. 13. hertig a, droz d, lesavre p, grünfeld jp, rieu p. sle and idiopathic nephrotic syndrome: coincidence or not? am j kidney dis 2002; 40:1179–84. doi: 10.1053/ajkd.2002.36875. 14. gómez-puerta ja, levy s, khamashta ma, hughes gr. periorbital oedema in systemic lupus erythematosus. lupus 2003; 12:866–9. doi: 10.1191/0961203303lu455xx. 15. marks j, birkett da, shuster s. “capillary permeability” in patients with collagen vascular diseases. br med j 1972; 1:782– 4. doi: 10.1136/bmj.1.5803.782 . 16. maeguchi m, nogita t, ishiguro n, nihei h, kawashima m. periorbital oedema and erythema in systemic lupus erythematosus. br j dermatol 1996; 134:601–2. doi: 10.1046/ j.1365-2133.1996.t01-5-53778.x. 17. thong by, thumboo j, howe hs, feng ph. life-threatening angioedema in systemic lupus erythematosus. lupus 2001; 10:304–8. doi: 10.1191/096120301680417011. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 574-580, epub. 8th oct 13 submitted 31st oct 12 revisions req. 5th jan & 20th mar 13; revisions recd. 5th feb & 20th apr 13 accepted 14th may 13 1department of oral medicine, oral & dental diseases research center, kerman university of medical sciences, kerman, iran; 2kerman medical school, kerman physiology research center, kerman university of medical sciences, kerman, iran; 3department of endodontics, esfahan dental school, esfahan university of medical sciences, esfahan, iran *corresponding author e-mail: m_s_hashemipour@yahoo.com and m_hashemipoor@kmu.ac.ir عوامل االختطار املرتبطة باعتالل الفم الناتج عن البدلة السنية يف األشخاص األصحاء املراجعني ملستشفى طب األسنان جبنوب شرق إيران نادر نفابي، اأحمد غالم ح�شينيان، بدري بقايي، مرمي ال�شادات ها�شمي بور امللخ�ص: الهدف: هناك نق�ض يف املعلومات املتعلقة بالعوامل املتعددة امل�شببة ملر�ض اعتالل الفم الناجت عن البدلة ال�شنية يف العامل، بالرغم من كرثة التواتر، هذا بالإ�شافة اإىل عدم الفهم الكامل للعوامل امل�شاحبة. هدفت هذه الدرا�شة اإىل بحث عوامل اخلطر التي ميكن اأن تكون م�شاحبة لهذه الآفة. الطريقة: مت تق�شيم جمموع 70 مري�شًا عدمي الأ�شنان ممن لديهم بدلت �شنية متحركة اإىل جمموعتني. جمموعة طبيا مثبتني �شخ�شا 27 من مكونة التحكم وجمموعة ال�شنية البدلة عن الناجت الفم باعتالل م�شابًا مري�شًا 43 من مكونة الفح�ض ب�شحة الغ�شاء املخاطي احلنكي. مت القيام باأخذ التاريخ املر�شي ال�شامل بالإ�شافة اإىل الفح�ض ال�رسيري للمر�شى، مت اأي�شا الإجابة على ال�شتبيان من قبل امل�شاركني. مت قيا�ض م�شتوى م�شل فيتامني اأ لكل م�شارك من عينة الدم املاأخوذة بعد عملية الفح�ض. النتائج: اأظهرت هذه الدرا�شة وجود عالقة معتدة بني حدوث اعتالل الفم الناجت عن البدلة ال�شنية والعوامل الرئي�شية الثالثة: عمر البدلة ال�شنية )بال�شنوات(، واملمار�ض امل�شنع للبدلة ال�شنية )طبيب اأ�شنان عام مقابل معالج �شحة �شنية(، لب�ض البدلة ال�شنية ليال. كذلك كان معدل م�شتوى م�شل فيتامني اأ منخف�ض يف %94.29 من امل�شاركني )جمموعة الفح�ض والتحكم(. اخلال�صة: بالرغم من وجود عدة عوامل عار�شة لهذه احلالة، كان اأكرثها �شيوعا هو ال�شتخدام املتوا�شل للبدلة ال�شنية. مفتاح الكلمات: فيتامني اأ؛ اعتالل الفم؛ بدلة �شنية؛ ال�شببيات؛ العادات؛ عوامل الختطار؛ اإيران. abstract: objectives: there is scant information regarding the multifactorial aetiology of denture stomatitis (ds) in the world and, despite its frequency, associated factors are not completely understood. the aim of this study was to investigate the risk factors that may be associated with this lesion. methods: a total of 70 edentulous patients, all wearing removable dentures, were divided into two groups. the test group comprised 43 patients with ds and the control group comprised 27 subjects with clinically healthy palatal mucosa. a thorough history-taking and physical examination were carried out; the subjects also answered a questionnaire. the serum level of vitamin a for each subject was assayed from a blood sample taken after the examination. results: this study showed a significant relationship between the incidence of ds and three major factors: denture age (in terms of years), the practitioner manufacturing the dentures (general dental practitioner versus dental hygienist), and the nightlong wearing of dentures. also, the vitamin a serum level was low in 94.29% of all subjects (cases and controls). conclusion: although many predisposing conditions were related to this situation, the most important risk factor was the continuous use of the dentures. keywords: vitamin a; stomatitis; denture; etiology; habits; risk factors; iran. risk factors associated with denture stomatitis in healthy subjects attending a dental school in southeast iran nader navabi,1 ahmad gholamhoseinian,2 badri baghaei,3 *maryam a. hashemipour1 clinical & basic research advances in knowledge according to the literature review, the aetiology of denture stomatitis (ds) is not fully understood, despite its high prevalence rate, and is somewhat controversial. application to patient care the results of this study will help in increasing awareness of ds for dentists. dentists can help prevent this condition by instructing patients to take their dentures out for 6–8 hrs each day. mechanical plaque control and appropriate denture-wearing habits are the most important measures in preventing and treating the disease. risk factors associated with denture stomatitis in healthy subjects attending a dental school in southeast iran 575 | squ medical journal, november 2013, volume 13, issue 4 denture stomatitis (ds) is a common inflammatory response which usually manifests as a shiny erythematous area with varying intensities in the palatal mucous membrane under the acrylic base of removable prosthetic appliances.1–4 epidemiological studies have indicated a prevalence rate of 15–70% of denture-wearers.1,2 this wide range of prevalence rates has been attributed to the diversity of populations studied; however, a high prevalence rate has been reported for ds in women and individuals older than 60 years of age.2,5 the affected area is not tender to touch and in almost all of the patients, the entity remains unknown due to the asymptomatic nature of the lesion.5 according to a classification proposed by newton in 1962, ds is divided into three types based on the clinical features.6,7 despite its high prevalence rate, the aetiology of ds is not fully understood8 and is also somewhat controversial; however, researchers believe that the entity has a complex and multifactorial pathogenesis.9 infection by candida albicans has been surmised to be the main aetiological agent and it has been correlated with the incidence of ds in various studies.10–12 other factors have also been reported in the aetiology of ds. in 1981, abelson reported that ds is related to the triad of loose-fitting dentures, trauma from denture-wear and poor denture hygiene.13 some studies have reported the continuous and round-the-clock wearing of dentures as an aetiological local factor involved in the pathogenesis of ds.14,15 poorlyfabricated dentures have a lot of porosities in their acrylic base, which encourages the adhesion of c. albicans, making it difficult to maintain denture hygiene.1,7 the frequency of dental visits by denturewearing patients each year and the number of years since denture manufacture (denture age) have also been reported as local factors contributing to ds.1 various studies on the aetiology of ds have indicated that diabetes mellitus and smoking might have a role in inducing the lesion.5,7,16 a review of 15 studies, published in the years 1989–2011 in various parts of the world, on the factors involved in the pathogenesis of ds, showed that the most significant factors are continuous and overnight denture-wearing;3–5,8–11 poor denture hygiene;2,4,12,17–19 smoking;14–16,20,21 denture age and poor denture manufacturing techniques;22,23 low serum levels of vitamin a; young age, and the number of visits to the dental surgery.7 nimri showed that nocturnal denture-wearing habits, deficient oral and denture hygiene, and cigarette smoking were all important predisposing factors to ds; however, none of these factors was the sole cause of mucosal inflammation.3 also, shulman et al., showed that ds prevalence was associated with the amount of tissue covered by the dentures, low vitamin a levels, cigarette smoking, and constant denture-wear.7 in their study on an asian edentulous population, jeganathan et al. observed a relationship between denture hygiene habits, denture-wearing behaviours, denture cleanliness and the presence of ds.14 the treatment of patients with ds does not yield high success rates because of its complex aetiology; there is also no uniform treatment protocol for all patients.1,12 on the other hand, with an increase in the proportion of elderly persons in various communities, the identification of the specific aetiological factors of the condition is of utmost importance.21 there are great discrepancies in the results of studies on the role of various aetiological agents in the pathogenesis of ds.21–23 the research work carried out by shulman in 2005 is the only study that deals with the role of vitamin a in the pathogenesis of ds.7 based on the evidence available, vitamin a deficiency makes individuals susceptible to infections. the previous studies showed that a higher percentage of neutrophils from vitamin a-deficient rats are hypersegmented and contain lower levels of cathepsin g than the neutrophils from control rats.24 the aim of the present work was to study the risk factors associated with ds in healthy subjects attending a dental school clinic in southeast iran. methods in this case-control study, the subjects with and without ds were divided into case and control groups, respectively. the subjects were selected from the patients referred to the dental clinic of the kerman faculty of dentistry using a convenience sampling method. patients unwilling to participate in the study, those who were using solid oils, taking oral contraceptives, who had a history of diabetes mellitus, or who might have had nutritional problems interfering with vitamin a level measurement, were excluded from the study.7,24 the inclusion criteria nader navabi, ahmad gholamhoseinian, badri baghaei and maryam a. hashemipour clinical and basic research | 576 were the continuous wearing of complete or partial dentures in one arch or both arches for at least the previous 6 months.19 all of the 76 subjects included in the study signed a written consent form (6 of the patients examined did not present themselves at the laboratory; therefore n = 70). in the case of any pathological lesions present in the oral cavity, the patients were accordingly referred to the department of oral medicine at kerman faculty of dentistry for treatment. the study was approved by the ethics committee of kerman university of medical sciences under the protocol no. k.88.218. a questionnaire was used to collect information from the subjects. the questions related to dentures were read by the researcher to the patient and the questionnaire was completed for each patient. clinical examinations were carried out by a dental practitioner. in the first part of the examination, the diagnosis of ds was based on criteria proposed by newton.7 in the second part, the denture was evaluated using the following criteria: denture extension, stability, occlusion, polishing and tissue side surface characteristics.17,19 after the clinical examination, all the subjects were sent to the laboratory for a vitamin a test. the subjects’ blood samples were used for the test in the laboratory (haemoglobin a1c [hba1c] test). a columnar chromatography technique was used to measure vitamin a (retinol) serum levels using centrifugation to separate the blood sera. high performance liquid chromatography (hplc) (sigma-aldrich co., yongin, korea) was used to measure vitamin a levels. vitamin a serum levels of less than 30 μgr/ml were considered to indicate vitamin a deficiency.7 median statistical parameters were used to express the position of each quantitative risk factor. odds ratios, 95% confidence intervals and chances of encounter with each risk factor were calculated in both groups. the effects of various independent variables (age, gender and education) on the presence or absence of ds (as a dependent variable) were evaluated using a logistic regression model by considering the role of confounding factors and the reciprocal effects of predictors. all statistical analyses were carried out using stata software, version 10 (statacorp lp, college station, texas, usa) at a significance level of 0.05 and a strength of 80%, as a default for the test carried out. results in this study, the 70 subjects who participated were examined for ds. they were 33–89 years of age with a mean age of 58.24 ± 12.3 years. a total of 36 subjects (51.43%) were female; in relation to the educational status, the majority of the subjects (51.43%) had had high school education but had not graduated from high school. the mean denturewearing period was 5 years, and the longest period was 37 years (mean ± standard deviation [sd] = 15.26 ± 7.11). the dentures had been manufactured by a general dental practitioner for 77.4% of the subjects and the rest had been manufactured by a dental hygienist. a total of 92.86% of the subjects cleaned their dentures on a daily basis, with the highest frequency being three times daily (43.08%). a total of 57.14% of the subjects wore their dentures table 1: frequency of risk factors for denture stomatitis characteristics of the denture-wearers n % gender male 34 48.57 female 36 51.43 level of education illiterate 18 25.71 pre-diploma 36 51.43 diploma 11 15.71 academic 5 7.14 denture manufacturer general dentist 54 77.14 dental hygienist 16 22.86 denture hygiene cleaning 65 92.86 no cleaning 5 7.14 frequency of cleaning per day once 14 20 twice 18 25.7 three times 28 40 more 10 14.3 overnight denture-wear yes 40 57.14 no 30 42.86 overnight denture solutions water 18 25.7 saline 12 17.2 none 40 57.1 dental check-ups per year yes 6 8.57 no 64 91.43 smoking yes 18 25.71 no 52 74.29 risk factors associated with denture stomatitis in healthy subjects attending a dental school in southeast iran 577 | squ medical journal, november 2013, volume 13, issue 4 during the night. of the subjects who removed their dentures at night, 18 patients kept them in water and 12 patients kept them in a saline solution [table 1]. only 8.57% of the subjects paid an annual visit to a dental practitioner. a total of 25.71% of the subjects smoked, with an average of 1.8 cigarettes per day. according to the classification proposed by newton in 1962, ds is divided into three types based on clinical features. type i is characterised by pin-point hyperaemic lesions (a localised simple inflammation), type ii shows as diffuse erythema confined to the mucosa in contact with the denture (a generalised simple inflammation) and type iii has a granular surface (an inflammatory papillary hyperplasia).25 a total of 61.5% of the subjects examined had ds, with 62.79% of these having type i ds (the most severe) and 4.65% having type iii ds (the least severe). a total of 88.37% of patients with ds wore complete dentures and the rest wore partial dentures. dentures were ill-fitting in 37.88% of ds cases. the study showed a significant relationship between three factors: denture age (in terms of years), the practitioner manufacturing the denture (general dental practitioner versus dental hygienist), and the overnight denture-wear and the incidence of ds (p = 0.03, p = 0.02 and p = 0.001, respectively). in other words, patients with a significantly high incidence rate of ds had had their dentures manufactured by a dental hygienist a long time previously and wore their dentures during the night [table 2]. an important and interesting finding of the present study was the fact that only 4 out of the 70 subjects (5.71%) had a normal vitamin a blood level. however, a low vitamin a blood level did not exhibit a significant relationship with the ds incidence rate (p = 0.09), compared to factors such as age, gender, education, denture hygiene, the number of annual visits to a dental surgery, smoking and denture quality, which exhibited a significant relationship with ds. the logistic regression model of odds ratio (95% confidence interval [ci]) showed an increase in the chance of ds affliction related to three factors: the denture-manufacturer, overnight denture-wear and denture age; this was after eliminating the effect of other factors involved. the highest odds ratio (or) (6.92, 0.75–51.1) was related to the effect of the denture-manufacturer, followed by overnight denture-wear (or = 3.98, 1.3–12.1). table 2: the relationship between multiple risk factors and denture stomatitis factors control group (n = 27) study group (n = 43) p age ± sd 59.8 ± 12.3 57.2 ± 12.4 0.08 gender n (%) male 13 (48.15) 21 (48.84) 0.124 female 14 (51.85) 22 (51.16) level of education n (%) illiterate 3 (11.11) 15 (34.88) 0.08 prediploma 17 (62.96) 19 (44.19) diploma 4 (14.81) 7 (16.28) academic 2 (11.11) 3 (4.65) years of dentureuse ± sd 13.30 ± 2.98 18.42 ± 6.69 0.03 denture manufacturer n (%) general dentist 26 (96.3) 28 (65.12) 0.02 dental hygienist 1 (3.7) 15 (34.88) denture hygiene n (%) no cleaning 27 (100) 38 (88.37) 0.6 cleaning 0 (0) 5 (11.63) frequency of cleaning n (%) once 5 (18.52) 9 (23.68) 0.07 twice 6 (22.22) 12 (31.58) three times 12 (44.44) 16 (42.11) more 4 (14.81) 1 (2.63) overnight denturewear n (%) yes 9 (33.33) 31 (72.09) 0.001 no 18 (66.67) 12 (27.91) denture solution at night n (%) water 10 (55.56) 8 (66.67) 0.08 saline 8 (44.44) 4 (33.33) dental check-ups per year n (%) yes 2 (7.41) 4 (9.30) 0.1 smoking n (%) no 25 (92.59) 39 (90.7) 0.14 yes 22 (81.48) 30 (69.77) denture quality n (%) non-ideal 20 (74.07) 38 (88.37) 0.09 ideal 7 (25.93) 5 (11.63) sl of vitamin a ± sd 0.66 ± 0.14 0.59 ± 0.13 0.09 sd = standard deviation; sl = serum level. nader navabi, ahmad gholamhoseinian, badri baghaei and maryam a. hashemipour clinical and basic research | 578 discussion in the present study, the highest frequency of ds was related to grade i of the lesion, which is consistent with the results of studies carried out by diaz et al. and kossioni et al.18,21 this supports the previous findings that this grade of lesion is more likely to be encountered in clinical situations compared to the two other grades. the results of the present study showed a significant relationship between ds and denture age, the denture-manufacturer, and overnight denturewear as local factors for this condition. denture age has been correlated to ds in three recent studies carried out by figuerial et al.,15 bilhan et al.4 and kossioni et al.21 which are consistent with the results of the present study. an important finding of the present study is the relationship between the higher incidence of ds in patients whose dentures had been manufactured by a dental hygienist, a factor which has not been evaluated in any similar studies. this finding might be attributed to the fact that general dental practitioners observe scientific principles in protecting the tissues covered by the denture base. continuous and overnight denture-wear is the factor most associated with ds in previous studies, which is consistent with the results obtained in the present study. furthermore, the logistics model showed an increase in the odds of ds incidence in patients with low serum levels of vitamin a. it is noteworthy that the logistic model (by maintaining the effect of other confounding variables) has only been used in two other studies, those carried out by shulman et al. and kossioni et al.7,21 an increase in the odds of ds incidence (or) due to overnight denture-wear was higher in a study carried out by shulman et al. compared to the present study. however, the results of the present study showed a higher or with vitamin a deficiency in relation to ds compared to shulman’s study.7 the highest or in the logistic model in the present study was related to the denturemanufacturer, whereas kossioni reported overnight denture-wear as the most important risk factor for ds.21 another important finding of the present study was the fact that low serum levels of vitamin a were observed in 92.29% of the subjects (including healthy and patients with ds). it was, therefore, concluded that most subjects in the present study suffered from malnutrition. the results of the national health survey conducted in 2002 have shown that 2.5% of the population over two years old in iran have night blindness. the criteria proposed by the world health organization state that in a society where 1% of children more than two years old have experiences of night blindness, there is vitamin a deficiency.25 in kerman, the last survey of clinical vitamin a deficiency was performed in 2001. this survey showed that the serum levels of vitamin a in the population of kerman were low (vitamin a serum levels between 13–24 μgr/ml).26 the majority of studies carried out in this regard have been designed to examine a large number of cases in a cross-sectional manner to determine ds prevalence definitively; however, the design of the present study (information collected on: denturemanufacture date; denture-manufacturer; the way in which the patient washed his/her hands; the overnight wearing of dentures by the patient; the number of annual dental check-ups and tobacco use) was similar to that of studies carried out by jeganathan et al.14 and kulak et al.27 both of these studies highlighted poor denture hygiene as a significant risk factor for ds, which is not consistent with the results of the present study. however, overnight denture-wear was found to be a major risk factor in jeganathan’s study,14 and this is consistent with the present findings. it is possible that the similarity in the identified ds risk factors is somehow related to the study design. it appears therefore that longitudinal studies are necessary to clarify the effect of various risk factors involved in ds, so that recovery from ds might be evaluated over time by controlling for various factors (such as improvements in denture hygiene). figueiral et al. showed significant associations between ds and yeasts, gender, age and alcohol consumption.15 a study carried out by pires et al. was very important in this regard because differences in the incidence of ds in various populations under study were evaluated at two intervals (6 months apart), before and after the delivery of new higher quality dentures. this resulted in a decrease in the incidence of ds from 50.6% to 18.2% in the same population.12 of the factors in the present study not exhibiting a significant relationship with ds, poor denture hygiene and smoking can be mentioned. the evaluation of denture hygiene in various studies risk factors associated with denture stomatitis in healthy subjects attending a dental school in southeast iran 579 | squ medical journal, november 2013, volume 13, issue 4 has been carried out by asking questions about the daily washing of dentures (similar to the present study) and a direct assessment of plaque formation on the denture surface. regarding smoking, based on the results of the present study, it appears the selection of subjects in the present study did not favour smokers, with a mean of 1.8 cigarettes per day. however, in a study carried out by al-dwairi, 70% of subjects (210 cases, aged 50–78 years-old) with grade 3 ds were heavy smokers (more than 15 cigarettes/day).28 the number and diversity of discussions in relation to the aetiology of ds necessitate devising a standard protocol to finalise clinical decisionmaking processes. at present, there is a need to determine to what extent the control of each aetiological factor for ds can control the lesion.29 research is now focusing on new treatment modalities for ds;30 therefore, there is a need for clinical trials to evaluate their effectiveness. also, this study showed that the connection between vitamin a and ds is weak; this is very likely due to the multifactorial causes of ds. conclusion the prevalence of ds was high in denture-wearers. although many predisposing conditions were recorded, the most important risk factor was the continuous use of dentures. also, ds may be associated with low vitamin a levels but more studies are required to confirm this impression. acknowledgement this study was supported by the kerman university of medical sciences. the authors would like to thank the dean of research & technology for their financial support (research project #88/203). references: 1. salerno c, pascale m, contaldo m, esposito v, busciolano m, milillo l, et al. candida-associated denture stomatitis. med oral patol oral cir bucal 2011; 16:139–43. 2. gendreau l, loewy zg. epidemiology and etiology of denture stomatitis. j prosthodont 2011; 20:251– 60. 3. nimri gm. the effect of denture stability, occlusion, oral hygiene and smoking on denture-induced stomatitis. saudi dent j 2008; 20:156–62. 4. bilhan h, sulun t, erkose g, kurt h, erturan z, kutay o, et al. the role of candida albicans hyphae and lactobacillus in denture-related stomatitis. clin oral investig 2009; 13:363–8. 5. dorocka-bobkowska b, zozulinska-ziolkiewicz d, wierusz-wysocka b, hedzelek w, szumala-kakol a, budtz-jörgensen e. candida-associated denture stomatitis in type 2 diabetes mellitus. diabetes res clin pract 2010; 90:81–6. 6. arendorf tm, walker dm. denture stomatitis: a review. j oral rehabil 1987; 14:217–27. 7. shulman jd, hidalgo fr, beach mm. risk factors associated with denture stomatitis in the united states. j oral pathol med 2005; 34:340–6. 8. casaroto ar, lara vs. phytomedicines for candidaassociated denture stomatitis. fitoterapia 2010; 81:323–8. 9. emami e, de grandmont p, rompré ph, barbeau j, pan s, feine js. favoring trauma as an etiological factor in denture stomatitis. j dent res 2008; 87:440– 4. 10. jose a, coco bj, milligan s, young b, lappin df, bagg j, et al. reducing the incidence of denture stomatitis: are denture cleansers sufficient? j prosthodont 2010; 19:252–7. 11. barbeau j, séguin j, goulet jp, de koninck l, avon sl, lalonde b, rompré p, deslauriers n. reassessing the presence of candida albicans in denture-related stomatitis. oral surg oral med oral pathol oral radiol endod 2003; 95:51–9. 12. pires fr, santos eb, bonan pr. denture stomatitis and salivary candida in brazilian edentulous patients. j oral rehabil 2003; 29:1115–9. 13. abelson dc. denture plaque and denture cleansers. j prosthet dent 1981; 45:376–9. 14. jeganathan s, payne ja, thean hp. denture stomatitis in an elderly edentulous asian population. j oral rehabil 1997; 24:468–72. 15. figueiral mh, azul a, pinto e, fonseca pa, branco fm. denture-related stomatitis: identification of aetiological and predisposing factors – a large cohort. j oral rehabil 2007; 34:448–55. 16. evren ba, uludamar a, iseri u, ozkan yk. the association between socioeconomic status, oral hygiene practice, denture stomatitis and oral status in elderly people living different residential homes. arch gerontol geriatr 2011; 53:252–7. 17. sadig w. the denture hygiene, denture stomatitis and role of dental hygienist. int j dent hyg 2010; 8:227–31. 18. diaz em, balaez ab, velez ju, lesa jm. denture stomatitis: epidemiological study of 6302 patients with removable dental prostheses. rev cubana estomatol 1989; 26:71–80. 19. compagnoni ma, souza rf, marra j, pero ac, barbosa db. relationship between candida and nader navabi, ahmad gholamhoseinian, badri baghaei and maryam a. hashemipour clinical and basic research | 580 nocturnal denture wear: quantities study j oral rehabilit 2007; 34:600–5. 20. dos santos cm, hilgert jb, padilha dm, hugo fn. denture stomatitis and its risk indicators in south brazilian older adults. gerodontol 2010; 27:134–40. 21. kossioni ae. the prevalence of denture stomatitis and its predisposing conditions in an older greek population. gerodontol 2010; 28:85–90. 22. emami e, séguin j, rompré ph, de koninck l, de grandmont p, barbeau j. the relationship of myceliated colonies of candida albicans with denture stomatitis: an in vivo/in vitro study. inter j prosthod 2007; 20:514–20. 23. mikkonen m, nyyssonen n, paunio i, rajala m. oral hygiene, dental visits and age of denture for prevalence of denture stomatitis. community dent oral epidemiol 1984; 12:402–5. 24. twining ss, schulte dp, wilson pm, zhou x, fish bl, moulder je. neutrophil cathepsin g is specifically decreased under vitamin a deficiency. biochim biophys acta 1996; 1317:112–18. 25. newton av. denture sore mouth. br dent j 1962; 112:357–9. 26. tulane university. vitamin a deficiency iran. from: www.tulane.edu/~internut/countries/iran/ iranvitamina.html accessed: sep 2012. 27. kulak y, arikan a. aetiology of denture stomatitis. j marmara univ dent fac 1993; 1:307–14. 28. al-dwairi zn. prevalence and risk factors associated with denture-related stomatitis in healthy subjects attending a dental teaching hospital in north jordan. j ir dent assoc 2008; 54:80–3. 29. pereira-cenci t, del bel cury aa, crielaard w, ten cate jm. development of candida-associated denture stomatitis: new insights. j appl oral sci 2008; 16:86–94. 30. uludamar a, özkan yk, kadir t, ceyhan i. in vivo efficacy of alkaline peroxide tablets and mouthwashes on candida albicans in patients with denture stomatitis. j appl oral sci 2010; 18:291–96. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e129–132, epub. 21 jan 15 submitted 3 jun 14 revision req. 9 aug 14; revision recd. 27 aug 14 accepted 10 sep 14 trichilemmal (pilar) cysts mainly occur in areas of dense hair follicle concentration, with 90% arising in the scalp and the other 10% occurring on the face, neck, torso and extremities.1,2 these benign encapsulated lesions are seen in adults and are solitary in only 30% of patients.1,2 a familial predisposition to these cysts has been recognised with an autosomal dominant pattern of inheritance.3 familial trichilemmal cysts occur in patients younger than 45 years old and are usually large (>5 cm), either solitary or multiple and have histological features of proliferation and ossification.3 proliferating trichilemmal cysts are progressive slow-growing nodules commonly seen in women with a mean age of 65 years.4 trichilemmal cysts have been known to occur in atypical locations with no hair follicles, such as on the pulp of the fingertips.5–7 the first case of a penile trichilemmal cyst is reported here and the differential diagnosis elucidated. case report a healthy five-year-old caucasian boy presented to the cooper health clinic, dubai, united arab emirates, in march 2012. he presented with an asymptomatic progressive slow-growing mass over the ventral aspect of the frenulum of the penis. he had undergone a modified tubularised incised urethral plate urethroplasty for subcoronal hypospadias at the age of 18 months [figure 1].8 the distal hypospadias repair involved performing a longitudinal incision on an adequate urethral plate. the incisions in the lateral glans were made longitudinally, wide enough to allow two strips of epithelium for a size 10-fr catheter in the neo-urethra. the neo-urethra was tubularised in the midline in two layers and was subsequently reinforced with a dartos flap. a waterproof layer harvested from the hooded prepuce and juxtaposed ventrally completed the repair. the glans wings were closed in the midline and a meatoplasty ensured a ventral slit in the glanular neomeatus. the hooded foreskin was excised and the skin closure was completed. 1department of paediatric surgery, cooper health clinic, dubai, united arab emirates; 2east midlands deanery, royal derby hospital, derby, uk *corresponding author e-mail: madan.samuel@yahoo.co.uk كيسة يف غمد جذر الشعرة يف قضيب طفل صاموئيل مادان و را�ضي جو�ضي abstract: paediatric penile cysts are uncommon. we report a five-year-old child with an asymptomatic progressively growing cyst on the ventral aspect of the penis after a hypospadias repair. the patient presented to the cooper health clinic, dubai, united arab emirates, in march 2012. a complete excision of the cyst was performed. histology results delineated a capsulated benign trichilemmal cyst. no recurrence or complications were reported in the 26 months following the excision. we recommend an early and complete excision of all penile cysts to prevent the risk of urethral obstruction, infection, inflammation and rare malignant changes. this is the first reported case of a penile trichilemmal cyst in a child. keywords: trichilemmal cyst; penis; hypospadias; child; case report; united arab emirates. امللخ�ص: يعد وجود كي�ضات يف الق�ضيب اأمرا غري �ضائع عند االأطفال. وهنا ن�ضجل حالة طفل عمره خم�س �ضنوات كان ي�ضكو من كي�ضة كانت هيلث كزبر مل�ضت�ضفى املري�س واأح�رض حتتاين. مبال تعديل عملية بعد للق�ضيب البطني اجلانب على اأعرا�س دون مرتقية ب�ضورة تنمو بدبي يف مار�س 2012م. ومت ا�ضتئ�ضال كامل للكي�ضة. واأثبتت نتائج الفح�س الهي�ضتلوجي كي�ضة حميدة ذات حمفظة يف غمد جذر ال�ضعرة. وبعد مرور 26 �ضهرا بعد اال�ضتئ�ضال مل حتدث انتكا�ضة اأو م�ضاعفات للطفل. اإننا نن�ضح باإجراء ا�ضتئ�ضال مبكر وكامل لكل كي�ضة تظهر يف الق�ضيب ملنع اختطار ان�ضداد االإحليل، والعدوى وااللتهاب، واأي�ضا التغريات اخلبيثة يف حاالت نادرة. هذه هي احلالة االأوىل امل�ضجلة لطفل م�ضاب بكي�ضة يف غمد جذر ال�ضعرة يف الق�ضيب. مفتاح الكلمات: كي�ضة يف غمد جذر ال�ضعرة؛ ق�ضيب؛ مبال حتتاين؛ طفل؛ تقرير حالة؛ اإلمارات العربية املتحدة. trichilemmal cyst of the penis in a paediatric patient *samuel madan1 and rashi joshi2 online case report trichilemmal cyst of the penis in a paediatric patient e130 | squ medical journal, february 2015, volume 15, issue 1 following the repair, the child had a ventral slit in the glanular meatus and a circumcised penis. at three-, sixand 10-month postoperative follow-ups, the child was observed to have a functional circumcised penis without complications [figure 2]. at 30 months of age, the patient had a visible mass which had slowly but progressively increased in size. the mass was soft, cystic, smooth-surfaced, elastic, non-tender and relatively mobile, measuring 1.5 x 1.6 x 1.5 cm. it was not inflamed and no punctum was visible. following a provisional diagnosis of an epidermoid cyst, the mass was excised under general anaesthesia. excision involved the removal of the intact cyst which extended below the glans penis. proximally, the ventral aspect of the glans was incised longitudinally and the two glanular wings were mobilised laterally away from the capsule of the cyst. a hemi-circumferential transverse incision was made distally at the level of the mucosal cuff and the penile shaft skin. the skin was mobilised away from the capsule of the cyst. following the excision of the intact cyst, an iatrogenic hole was noticed in the urethra at the coronal level. proximally, 2 mm of the meatus was excised with the cyst. the dorsal nodular skin was also excised and the hole in the urethra was closed in two layers. neoglanular meatus was created and the glanular wings were approximated in the midline. skin closure was completed by suturing the skin to the mucosal cuff. histology revealed that the cyst was surrounded by a fibrous capsule that was lined by a palisade of small cuboidal basal epithelial cells with no intercellular bridging. no granular cell layers were seen. there were foci of calcification, mitoses and keratinisation. there was no cell atypia, cellular necrosis or cyst wall penetration. the keratin was stained with antikeratin antibodies derived from human hair. the histological diagnosis indicated a trichilemmal cyst [figures 3a & b]. figure 1: illustration of a modified incised tubularised urethral plate repair. a vascularised waterproof layer is harvested from the dorsal aspect and buttonholed and transposed ventrally to cover the neo-urethra. glanuloplasty, meatoplasty and hemi-circumcision are then performed to complete the repair. figure 2: photograph of the functional circumcised penis post-hypospadias repair. the child also underwent a bilateral inguinal herniotomy. inguinal hernias can occur in association with hypospadias in 7–13% of children.8 figure 3a & b: histology of the encapsulated benign trichilemmal cyst showing the eosinophilic centre lined by walls of stratified squamous epithelium. a: haematoxylin and eosin (h&e) stained specimen at x100 magnification showing calcification and keratinisation (arrowheads), as seen by the lobulation of the cyst wall with bulwarks of squamous epithelium. the arrows show the palisades of squamous epithelium without a granular layer. b: h&e stain x1,000 magnification with oil immersion highlighting the palisades of squamous epithelium (arrows) and keratinisation with mitotic figures (arrowheads). these features are characteristic of a trichilemmal cyst. samuel madan and rashi joshi case report | e131 at a 26-month post-excision follow-up, there was no evidence of recurrence or other complications. figure 4 shows the patient’s normal circumcised penis with a ventral slit in the glanular meatus after the excision of the trichilemmal cyst. a retrospective in-depth family history revealed the absence of trichilemmal cysts occurring in any other members of the family (either paternal or maternal). discussion this is the first report of a penile trichilemmal cyst occurring in a paediatric patient after a hypospadias repair. trichilemmal cysts are lined by stratified squamous epithelium. the squamous epithelium is analogous to that seen in the isthmus of the hair follicle. the isthmus bridges the erector pili muscle and the sebaceous gland duct.1–4 an inner root sheath is absent and the squamous epithelium undergoes rapid keratin formation without a granular cell layer. these are the characteristic findings of a benign, non-inflamed, non-infected and non-malignant trichilemmal cyst.1–4 the contents of the cyst may extrude to form a soft cutaneous horn.9,10 although they occur mainly in hairy areas such as the scalp, cysts can arise on the face, neck, extremities and in atypical areas that are devoid of hair follicles, such as the fingertips.2,5–7 in the current patient, squamous epithelial metaplasia with associated keratinisation at the isthmus, likely due to the hypospadias repair, resulted in the formation of a trichilemmal cyst. a complete excision of the cyst, as in this case, prevents recurrence. moreover, early excision of these cysts is recommended in order to prevent infection, inflammation and, in rare cases, malignant changes.11 penile cysts are usually solitary and occur in various sizes.1–4 the differential diagnoses of cystic lesions of the male genitalia are varied and wideranging. critically, lesions that can occur after a hypospadias repair include urethral diverticula, ureth-rocutaneous fistulae and, less commonly, epidermoid cysts.8 epidermoid cysts can be congenital or acquired; acquired epidermoid cysts occur following mechanical implantation of epidermal fragments.1–4,9 the latter was a possibility in the current patient due to his previous history of a distal hypospadias repair. therefore, the initial working clinical diagnosis was of an epidermoid inclusion cyst following the repair. histopathology provided the definitive and conclusive diagnosis of a trichilemmal cyst. it was hypothesised that the distal hypospadias repair had triggered squamous metaplasia with keratinisation, leading to the development of a trichilemmal cyst in a non-hairbearing area of the body. early and complete excision of penile cysts are indicated to prevent the risk of urethral obstruction, infection, inflammation, proliferative growth, impediments to coitus in the future and malignant changes as well as for aesthetic purposes. conclusion this case report adds a rare diagnosis of penile cysts to the literature, as this is the first reported incidence of a penile trichilemmal cyst occurring in a paediatric patient after a hypospadias repair. early and complete excision is recommended to prevent complications and recurrence. references 1. james wd, berger tg, elston dm. andrews’ diseases of the skin: clinical dermatology. 11th ed. philadelphia, pennsylvania, usa: elsevier inc., 2011. pp. 668–9. 2. kirkham n. tumors and cysts of the epidermis. in: elder de, elenitsas r, johnson bl jr, murphy gf, xu x, eds. lever’s histopathology of the skin. 10th ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2009. pp. 801–3. 3. seidenari s, pellacani g, nasti s, tomasi a, pastorino l, ghiorzo p, et al. hereditary trichilemmal cysts: a proposal for the assessment of diagnostic clinical criteria. clin genet 2013; 84:65–9. doi: 10.1111/cge.12040. 4. satyaprakash ak, sheehan dj, sanqüeza op. proliferating trichilemmal tumors: a review of the literature. dermatol surg 2007; 33:1102–8. doi: 10.1111/j.1524-4725.2007.33225.x. 5. melikoglu c, eren f, keklik b, aslan c, sutcu m, zeynep tarini e. trichilemmal cyst of the third fingertip: a case report. hand surg 2004; 19:131–3. doi: 10.1142/s0218810414720113. 6. el hassani y, beaulieu jy, tschanz e, marcheix ps. [proliferating trichilemmal tumor of the pulp of a finger: case report and review of the literature]. chir main 2013; 32:117–19. doi: 10.1016/j.main.2013.02.002. 7. ikegami t, kameyama m, orikasa h, yamazaki k. trichilemmal cyst in the pulp of the index finger: a case report. hand surg 2003; 8:253–5. doi: 10.1142/s0218810403001765. figure 4: photograph of the patient’s normal circumcised penis with a ventral slit in the glanular meatus after the excision of the trichilemmal cyst. trichilemmal cyst of the penis in a paediatric patient e132 | squ medical journal, february 2015, volume 15, issue 1 8. samuel m, wilcox dt. tubularized incised-plate urethroplasty for distal and proximal hypospadias. bju int 2003; 92:783–5. doi: 10.1046/j.1464-410x.2003.04478.x. 9. ramaswamy as, manjunatha hk, sunilkumar b, arunkumar sp. morphological spectrum of pilar cysts. n am j med sci 2013; 5:124–8. doi: 10.4103/1947-2714.107532. 10. haro r, gonzález-guerra e, fariña mc, martín-moreno l, requena l. [trichilemmal horn: a new case and review of the literature]. actas dermosifiliogr 2009; 100:65–8. 11. goyal s, jain bb, jana s, bhattacharya sk. malignant proliferating trichilemmal tumor. indian j dermatol 2012; 57:50–2. doi: 10.4103/0019-5154.92679. 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: sf.daar@gmail.com نتائج احلمل يف النساء املصابات بأنيميا البحر املتوسط بيتا الثالسيميا خربة مركز واحد يف ُعمان نهال الريامية، مها اخل�سورية، �ساهينا داعر abstract: objectives: pregnancy in women with homozygous beta thalassaemia (hbt) carries a high risk to both the mother and fetus. the aim of this study was to investigate pregnancy outcomes among this group at a single tertiary centre. methods: this retrospective descriptive study was conducted between january 2006 and december 2012 on all women with hbt who received prenatal care and subsequently delivered at sultan qaboos university hospital, muscat, oman. women who delivered elsewhere and women with the beta thalassaemia trait were excluded. results: ten women with hbt were studied with a total of 15 pregnancies and 14 live births. the mean maternal age ± standard deviation (sd) was 27.9 ± 3.7 years, with a range of 24‒35 years. there were 14 spontaneous pregnancies and one pregnancy following hormone treatment. eight women had been on chelation therapy before pregnancy, one of whom needed chelation during late pregnancy. of the pregnancies, 93% had a successful outcome with a mean ± sd gestational age at delivery of 38.6 ± 0.9 weeks, with a range of 37‒40 weeks. eight babies (57%) were delivered by caesarean section. the mean ± sd birth weight was 2.6 ± 0.2 kg, with a range of 1.9‒3.0 kg. three babies (21%) were born with low birth weights. conclusion: pregnancy is safe and usually has a favourable outcome in patients with hbt, provided that a multidisciplinary team is available. this is the first study of omani patients with hbt whose pregnancies have resulted in a successful outcome. keywords: thalassemia, beta; pregnancy; fetus; mother; assessment, patient outcomes; chelation therapy; oman. هدفت واجلنني. الأم من كل على عالية خماطر على الثال�سيميا بيتا مبر�س امل�سابات الن�ساء يف احلمل ينطوي الهدف: امللخ�ص: بني الو�سفية الإ�ستعادية الدرا�سة هذه اأجريت الطريقة: واحد. مركز يف املري�سات من املجموعة هذه يف احلمل نتائج ر�سد اإىل الدرا�سة م�ست�سفى يف و�سعن و الولدة قبل الرعاية تلقوا الذين ثال�سيميا بالبيتا امل�سابات الن�ساء جميع على 2012 دي�سمرب و 2006 يناير ثال�سيميا البيتا �سفة حامالت والن�ساء اأخرى اأماكن يف و�سعن الالئي الن�ساء ا�ستبعاد مت عمان. �سلطنة م�سقط، قابو�س، ال�سلطان جامعة النتائج: در�ست ع�رس ن�ساء م�سابات بالبيتا الثال�سيميا حيث حدث 15 حمال اأ�سفرت عن 14 ولدة حية. بلغ متو�سط عمر الأمهات يف عينة الدرا�سة 3.7 ± 27.9 وتراوحت اعمارهن بني 35-24 عاما. كان هناك 14 حالة حمل عفوي وحالة واحدة بعد العالج الهرموين. تعاطت ثمانية ن�ساء عقاقري اإزالة معدن احلديد من اجل�سم قبل احلمل بينما تعاطت حالة واحدة فقط هذه العقاقري يف اأواخر احلمل. اأ�سفرت %93 من الولدات عن نتيجة ناجحة وبلغت فرتة حمل اجلنني من 0.9 ± 38.6 اأ�سابيع يف املتو�سط، وتراوحت فرتة احلمل بني 40-37 اأ�سبوعا. ولد ثمانية اأطفال )%57( بعمليات قي�رسية.بلغ متو�سط وزن الطفل عند الولدة 0.2 ± 2.6 كلغ وتراوحت اأوزانهم بني 3.0-1.9 كلغ. كان وزن الولدة منخف�سا يف ثالثة اأطفال فقط )%21(. اخلال�صة: اأظهرت هذه الدرا�سة نتائج اإيجابية للحمل و اأمان يف امل�سابات بالبيتا ثال�سيميا، �رسيطة اأن يكونوا حتت رعاية فريق متعدد من املتخ�س�سني. هذه هي الدرا�سة الأوىل يف املر�سى العمانيني. مفتاح الكلمات: الثال�سيميا، بيتا؛ احلمل؛ اجلنني؛ الأم؛ تقييم، النتائج ؛ عقاقري اإزالة معدن احلديد من اجل�سم؛ عمان. pregnancy outcomes in women with homozygous beta thalassaemia a single-centre experience from oman nihal al-riyami,1 maha al-khaduri,1 *shahina daar2 clinical & basic research advances in knowledge thalassaemia is not well-studied during pregnancy, especially in oman. however, thalassaemia is an important blood disorder in oman and carries major risks during pregnancy to both the mother and fetus. the results of this study will increase knowledge of this disorder in the region. specifically, the findings of this study will increase the awareness of the safe outcomes of pregnancies in women with homozygous beta thalassaemia in oman, especially for healthcare professionals. application to patient care this study highlights certain issues in pregnant women with homozygous thalassaemia, which will help obstetricians in their management of this patient group. recent advances in the treatment and management of thalassaemic patients are discussed in this study. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e337-341, epub. 24th jul 14 submitted 29th oct 13 revisions req. 30th dec 13 & 9th feb 14; revisions recd. 22nd jan & 19th feb 14 accepted 4th mar 14 pregnancy outcomes in women with homozygous beta thalassaemia e338 | squ medical journal, august 2014, volume 14, issue 3 beta thalassaemia is one of the most common genetic blood disorders in oman, the mediterranean region, arabian peninsula and far east. the prevalence of the beta thalassaemia gene in oman is reported to be 2.2‒2.6%.1,2 patients with homozygous beta thalassaemia (hbt) have high morbidity and mortality rates due to the consequences of blood transfusions and iron overload. two forms of thalassaemia are distinguished, with different clinical phenotypes: thalassaemia major (tm), which is transfusion-dependent, and thalassaemia intermedia (ti), which varies in clinical severity and has variable transfusion requirements. in recent years, tm survival rates have improved with patients suffering fewer complications due to the advances in transfusion treatment and the use of chelation therapy.3‒6 as a consequence, pregnancy is feasible in these patients. the main cause of infertility in tm is due to pituitary gland haemosiderosis leading to hypogonadotropic hypogonadism.7,8 ti has a wide clinical spectrum ranging from patients presenting late, after the age of three years, and then requiring regular blood transfusions, to those who are completely transfusion-independent. the latter group requires occasional transfusions during periods of stress such as pregnancy and infection, as well as preoperatively. patients with hbt require close follow-up throughout the duration of their pregnancy due to the physiological changes and high demands of pregnancy.9 chelation therapy should be halted during pregnancy due to the teratogenicity of this treatment and haemoglobin (hb) levels should be checked regularly to assess the need for transfusions. an increased frequency of blood transfusions is usually noted in these patients. complications for both the mother and the fetus include gestational hypertension, gestational diabetes, thromboembolism, anaemia, cardiac failure, premature delivery, intrauterine growth restriction and fetal death.10 the aim of this study was to review the maternal and fetal outcomes of pregnant women with hbt at sultan qaboos university hospital (squh), muscat, oman. methods this retrospective descriptive study was conducted between january 2006 and december 2012 on all pregnant women with hbt who received both prenatal and postnatal care and delivered at squh. data were obtained from the squh database including the patients’ medical and delivery ward records. women who delivered elsewhere and women with the beta thalassaemia trait were excluded from the study. a total of 10 women (seven with ti and three with tm) were included giving a total of 15 pregnancies. the patients were followed closely in the squh high-risk pregnancy clinic by both an obstetrician and a haematologist. they were screened for infectious diseases upon presentation, including hepatitis b, syphilis and human immunodeficiency virus (hiv). an obstetric ultrasound was performed to confirm gestational age. maternal weight gain, blood pressure and fetal well-being were assessed at each visit. a fetal anatomy scan was performed at 18‒20 gestational weeks and fetal growth scans were performed monthly. patients received blood transfusions approximately every two to three weeks to maintain hb levels above 9.0 g/dl. the maternal medical records were reviewed for age, parity, use of fertility-inducing agents, any history of splenectomy, baseline hb levels at first visit as well as at delivery, frequency of blood transfusions, serum ferritin levels and the use of chelation therapy during pregnancy. pregnancy outcomes were defined as follows: an abortion was defined as a pregnancy loss before 20 weeks’ gestation;11 intrauterine fetal death was defined as the death of the fetus in utero after 20 weeks’ gestation;11 preterm delivery was defined as a delivery before 37 weeks’ gestation;11 fetal growth restriction was recorded if the estimated fetal weight was less than the 10th percentile;12 low birth weight (lbw) was defined as a birth weight of less than 2,500 g,12 and the mode of delivery was recorded as either vaginal delivery or a caesarean section. maternal complications were also recorded, including gestational hypertension, gestational diabetes, infections and antepartum and postpartum haemorrhaging. descriptive data are presented as means, standard deviations (sd) and percentages. the study was approved by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university. results this study evaluated 15 pregnancies in 10 women with hbt. one patient with tm became pregnant twice but miscarried during her first pregnancy. three patients with ti had subsequent pregnancies during the study period, with one of these patients becoming pregnant three times. the mean maternal age ± sd was 27.9 ± 3.7 years, with a range of 24‒35 years. nine women were nulliparous at the start of the study. all of the women nihal al-riyami, maha al-khaduri and shahina daar clinical and basic research | e339 conceived spontaneously, apart from one of the three women with tm, who conceived using hormone treatments. in total, four women (40%)—one with tm and three with ti—were splenectomised. all women required blood transfusions every two to three weeks during their pregnancies, including the seven patients with ti who had not received regular blood transfusions before pregnancy. eight women (80%)—three with tm and five with ti—had been on chelation therapy before their pregnancies [table 1]. the pregnancy outcomes of all patients with ti and tm are presented in table 2. in patients with ti, there were 11 live births. the mean ± sd gestational age at delivery was 38.6 ± 1.0 weeks with a range of 37‒40 weeks. three babies were delivered by elective caesarean section due to a fetal breech presentation in two patients and a previous caesarean section in one patient. two further patients underwent emergency caesarean sections due to fetal distress. the mean ± sd birth weight was 2.5 ± 0.3 kg, with a range of 1.9‒3.0 kg. three babies were born with lbws of 1.9, 2.2 and 2.3 kg. the first baby was born to a 28-year-old gravida one para zero (g1p0) woman who had no antepartum complications. she had been on regular blood transfusions every two weeks during her pregnancy. her lowest hb level was 6.4 g/dl in the first trimester and her highest serum ferritin level was 1,469 ng/ml at the end of the pregnancy. her baby was born by vacuum-assisted delivery at 38 weeks’ gestation due to a non-reassuring fetal heart rate in the second stage of labour. the baby was female with a birth weight of 1.9 kg; she demonstrated good apgar scores and therefore did not require admission to the neonatal intensive care unit (nicu). the second baby was born to a 30-year-old primigravida woman who had no antepartum complications. her lowest hb level during pregnancy was 8.7 g/dl in the second trimester and her highest serum ferritin level was 336 ng/ml at the end of the pregnancy. she delivered by emergency caesarean section at 40 weeks’ gestation due to a nonreassuring fetal heart rate during labour. the baby was male, with good apgar scores and normal ph levels as determined by the cord blood gas, indicating normal hydrogen ions in the blood. the third baby was born to a 30-year-old g1p0 woman whose lowest hb level in pregnancy was 7.5 g/dl in the middle of the first trimester and whose highest ferritin level was 1,334 ng/ml at the end of the pregnancy. she delivered at 37 weeks’ gestation by elective caesarean section due to a breech presentation; the boy had a birth weight of 2.3 kg and good apgar scores. in patients with beta tm, the mean ± sd gestational age was 38.3 ± 0.6 weeks, with a range of 38‒39 weeks. the mean ± sd birth weight was 2.8 ± 0.2 kg, with a range of 2.7‒3.0 kg. two patients had elective caesarean sections, one because of a fetal breech presentation and one at the patient’s request. the third patient had an emergency caesarean section due to fetal distress. one patient elected to restart chelation therapy during her pregnancy. the patient was a 26-year-old primigravida woman who conceived spontaneously and was progressing well during pregnancy. her baseline serum ferritin level was 522 ng/ml, however this increased throughout her pregnancy and reached 2,767 ng/ml at 28 weeks’ gestation. after extensive counselling, the patient opted for iron chelation with table 1: maternal characteristics of pregnant women with homozygous beta thalassaemia (n = 10) characteristics mean range age in years 27.9 24‒35 gravidity 2.7 1‒9 parity 1.1 0‒6 hb levels during pregnancy in gm/dl 8 6.4‒9.8 sf levels before pregnancy in ng/ml (normal range 20‒300 ng/ml) 585.6 236‒1,258 sf levels at the end of pregnancy in ng/ml 1,357.5 336‒3,054 hb = haemoglobin; sf = serum ferritin. table 2: pregnancy outcomes of women with homozygous beta thalassaemia* (n = 15 pregnancies) outcomes ti patients (n = 7) tm patients (n = 3) miscarriage 0 1 iugr 3 0 uti 1 0 gdm 1 0 mean ga at delivery in weeks 38.6 38.3 mean birth weight in kg 2.5 2.8 c/s 5 3 vacuum-assisted delivery 2 0 svd 4 0 postpartum fever 3 1 ti = thalassaemia intermedia; tm = thalassaemia major; iugr = intrauterine growth restriction; uti = urinary tract infection; gdm = gestational diabetes mellitus; ga = gestational age; c/s = caesarean section; svd = spontaneous vaginal delivery. *only one patient with tm underwent chelation therapy during her pregnancy. pregnancy outcomes in women with homozygous beta thalassaemia e340 | squ medical journal, august 2014, volume 14, issue 3 deferoxamine in the middle of her third trimester. repeat testing of her serum ferritin levels showed marked improvement, with a level of 1.536 ng/ml by the end of her pregnancy. she had an elective caesarean section at 38 weeks’ gestation and delivered a live male baby with a birth weight of 2.7 kg and apgar scores of nine and ten at one and five min, respectively. all tm women underwent t2* magnetic resonance imaging (mri) before and soon after pregnancy to investigate their iron status. all three patients, and in particular the first two patients, had increased liver iron loads during their pregnancies. the third patient had undergone chelation therapy in her third trimester, as mentioned above. the cardiac iron status of all the three patients remained normal [table 3]. all women were on prophylactic low-molecularweight heparin in the postpartum period and were encouraged to breastfeed their infants for the first 12 weeks before restarting chelation therapy. discussion this study found a 93% rate of successful pregnancy outcomes among 10 women with homozygous beta thalassaemia. only one patient with tm suffered a first trimester abortion. such excellent results are heartening, particularly considering the difficulties that are usually expected in these high-risk pregnancies. the major contributing factors to this excellent rate were the multidisciplinary approach used in the care of these patients as well as the close patient follow-up. all of the women with tm in this study underwent counselling before pregnancy and had achieved low serum ferritin levels (236–522 ng/ml) with extensive chelation therapy before conception. patients with ti demonstrated slightly higher serum ferritin levels of 194‒1,597 ng/ml (median 625 ng/ml). all of the women’s partners had been screened and tested for haemoglobinopathies prior to their marriage. there were no preterm births noted in the current study and only three babies (21%) were born with lbws. however, none required admission to the nicu or suffered any neonatal complications. the results of this study are comparable to two large studies reported in the literature.13,14 an italian multicentre study by origa et al. of 57 pregnant women reported a 91% rate of successful pregnancy outcomes.13 they also noted favourable maternal and neonatal outcomes; however, women with ti who were not transfused or were on minimal blood transfusions before their pregnancies required more transfusions due to anaemia during their pregnancies.13 this finding was also observed in the current study. as reported in other studies, the increase in blood transfusions, due to the physiological changes and increased demands of pregnancy as well as the cessation of chelation therapy, resulted in an increased iron overload and aggravates haemosiderosis; this caused further iron deposits in major organs such as the heart, leading to cardiac dysfunction and complications.15,16 due to intensive patient counselling and chelation therapy prior to pregnancy, none of the patients with tm in the current study developed iron overload in their hearts and all had minimal liver iron loads before pregnancy. however, an increase in liver iron load was apparent in all patients after pregnancy; this was expected as the liver is the primary target of iron loading secondary to blood transfusion. cardiac iron status measured by t2* mri showed no significant change before or after pregnancy. studies have shown that iron loading of the heart usually lags behind that of the liver, which is the initial site of the transfusional iron uptake.17 as the present study’s patients were well-chelated prior to their pregnancies, with low liver iron loads, this may have ensured that a buffer was present, possibly protecting them from accumulating cardiac iron while they ceased chelation therapy during pregnancy. the use of iron chelation therapy during pregnancy has not been wellstudied; the main concern is that of fetal teratogenicity, especially if the therapy is used in the first trimester.18 however, there have been a few reports of successful outcomes with chelation therapy.19,20 one case reported the use of chelation therapy during the first trimester with a normal outcome for the child.21 the pregnancy had not been identified until 22 weeks gestation as the patient was on hormone replacement therapy. fortunately, the fetus was healthy. another case reported the use of chelation therapy from 18 weeks gestation until delivery, with a successful outcome and a normal assessment of the child at 10 months of age.20 however, these are aberrant cases, and chelation therapy should be avoided during the first trimester. in later pregnancy, a multidisciplinary assessment before starting chelation is critical and the potential maternal table 3: liver and cardiac iron status in three patients with transfusion-dependent thalassaemia major based on t2* mri values before pregnancy/after delivery patient 1 patient 2 patient 3 liver iron in mg/g dry weight 2.9/10.8 2.6/9.6 2.1/3.6 cardiac t2* mri in ms 19.7/20.3 34.8/37.4 46.4/46.8 mri = magnetic resonance imaging ; ms = milliseconds. nihal al-riyami, maha al-khaduri and shahina daar clinical and basic research | e341 benefits should outweigh the risk to the fetus. after a detailed multidisciplinary assessment and intensive counselling, one of the women with tm in the current study was started on chelation therapy during her third trimester, resulting in a positive outcome. however, more studies are required to determine the safety of chelation therapy during pregnancy.15 the mean gestational age of delivery in the present study was 38.6 weeks, with caesarean section as the mode of delivery in 8 out of the 14 term pregnancies (57%). the preferable mode of delivery was usually vaginal, however one of the patients insisted on a caesarean section despite counselling. results from origa et al.’s study on 58 pregnancies in 46 women with hbt showed a very high rate of caesarean sections (90%) and a joint study from lebanon and milan also showed a high rate (72.7%).12,22 compared to other published studies, the rate of caesarian section in the current study was relatively low; however, this may be because the total number of pregnancies studied was smaller. conclusion pregnancy is safe and usually has a favourable outcome in patients with hbt, provided that a multidisciplinary team is available for intensive patient evaluation and follow-up. advances in fertility treatment and chelation therapy have made it possible for women with tm to become pregnant. pre-pregnancy counselling and assessment, proper care and close follow-up during the antepartum, intrapartum and postpartum periods are essential for a good outcome. this is the first study of omani patients with hbt showing a high rate of successful pregnancy outcomes. a c k n o w l e d g e m e n t s the authors wish to thank all hospital staff at squh for their help and support. references 1. al-riyami aa, suleiman aj, afifi m, al-lamki zm, daar s. a community-based study of common hereditary blood disorders in oman. east mediterr health j 2001; 7:1004‒11. 2. alkindi s, al zadjali s, al madhani a, daar s, al-haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135‒44. doi: 10.3109/03630261003677213. 3. cunningham mj. update on thalassemia: clinical care and complications. pediatr clin north am 2008; 55:447‒60. doi: 10.1016/j.pcl.2008.02.002. 4. modell b, khan m, darlison m, westwood ma, ingram d, pennell dj. improved survival of thalassemia major in the uk and relation to t2* cardiovascular magnetic resonance. j cardiovasc magn reson 2008; 10:42. doi:10.1186/1532429x-10-42. 5. telfer p, coen pg, christou s, hadjigavriel m, kolnakou a, pangalou e, et al. survival of medically treated thalassaemia patients in cyprus. trends and risk factors over the period 1980-2004. hematologica 2006; 91:1187‒92. 6. borgna-pignatti c, rugolotto s, de stefano p, zhao h, cappellini md, del vecchio gc et al. survival and complications in patients with thalassaemia major treated with transfusion and deferoxamine. hematologica 2004; 89:1187‒93. 7. skordis n, christou s, koliou m, pavlides n, angastiniotis m. fertility in female patients with thalassaemia. j pediatr endocrinol metab 1998; 11:935–43. 8. bajoria r, chatterjee r. current perspectives of fertility and pregnancy in thalassemia. hemoglobin 2009; 33:s131‒5. doi: 10.3109/03630260903365023. 9. malhotra m, sharma jb, batra s, sharma s, murthy ns, arora r. maternal and perinatal outcome in varying degrees of anemia. int j gynaecol obstet 2002; 79:93–100. doi: 10.1016/s0020-7292(02)00225-4. 10. leung ty, lao tt. thalassaemia in pregnancy. best pract res clin obstet gynaecol 2012; 26:37‒51. doi: 10.1016/j. bpobgyn.2011.10.009. 11. cunningham f, bloom s, hauth j, rouse d, spong c. williams obstetrics. 23rd ed. new york: mcgraw-hill professional, 2010. 12. mandruzzato g, antsaklis a, botet f, chervenak fa, figueras f, grunebaum a, et al.; world association of perinatal medicine (wapm). intrauterine restriction (iugr). j perinatal med 2008; 36:277‒81. doi: 10.1515/ jpm.2008.050. 13. origa r, piga a, quarta g, forni gl, longo f, melpignano a, et al. pregnancy and beta-thalassemia: an italian multicenter experience. hematologica 2010; 95:376‒81. doi: 10.3324/haematol.2009.012393. 14. karagiorga-lagana m. fertility in thalassemia: the greek experience. j pediatr endocrinol metab 1998; 11:945–51. 15. tsironi m, karagiorga m, aessopos a. iron overload, cardiac and other factors affecting pregnancy in thalassemia major. hemoglobin 2010; 34:240‒50. doi: 10.3109/03630269.2010.485004. 16. farmaki f, gotsis e, tzoumari i, berdoukas v. rapid iron loading in a pregnant woman with transfusion-dependent thalassemia after brief cessation of iron chelation therapy. eur j haematol 2008; 81:157‒9. doi: 10.1111/j.16000609.2008.01092.x. 17. noetzli lj, carson sm, nord as, coates td, wood jc. longitudinal analysis of heart and liver iron in thalassemia major. blood 2008; 112:2973‒8. doi: 10.1182/ blood-2008-04-148767. 18. tuck sm, jensen ce, wonke b, yardumian a. pregnancy management and outcomes in women with thalassemia major. j pediatr endocrinol metab 1998; 11:923–8. 19. tsironi m, ladis v, margellis z, deftereos s, kattamis c, aessopos a. impairment of cardiac function in a successful full-term pregnancy in a homozygous beta-thalassemia major: does chelation have a positive role? eur j obstet gynecol reprod biol 2005; 120:117–18. doi: 10.1016/j. ejogrb.2004.08.005. 20. singer st, vichinsky ep. deferoxamine treatment during pregnancy: is it harmful? am j hematol 1999; 60:24–6. doi: 10.1002/(sici)1096-8652(199901)60:1<24::aid-ajh 5>3.0.co;2-c. 21. vini d, servos p, drosou m. normal pregnancy in a patient with β-thalassaemia major receiving iron chelation therapy with deferasirox (exjade®). eur j haematol 2011; 86:274–5. doi: 10.1111/j.1600-0609.2010.01569.x. 22. nassar ah, naja m, cesaretti c, eprassi b, cappellini md, taher a. pregnancy outcome in patients with betathalassemia intermedia at two tertiary care centers, in beirut and milan. haematologica 2008; 93:1586‒7. doi: 10.3324/haematol.13152. 1toxicology unit, clinical pharmacy, faculty of pharmacy, university of port-harcourt, port-harcourt, nigeria; 2department of pharmacology, faculty of pharmacy, university of uyo, uyo, nigeria; 3department of medical laboratory science, faculty of science, rivers state university of science & technology, port-harcourt, nigeria *corresponding author e-mail: orishebere@gmail.com املعادن الثقيلة يف املأكوالت البحرية و النتوجات الزراعية أويو، نيجرييا املستويات و اآلثار الصحية اوري�ض اوري�ساكوي، هاربرت جماو، جودين اجازي، اوميي اديت، باتريك اوانا abstract: objectives: this study aimed to obtain representative data on the levels of heavy metals in seafood and farm produce consumed by the general population in uyo, akwa ibom state, nigeria, a region known for the exploration and exploitation of crude oil. methods: in may 2012, 25 food items, including common types of seafood, cereals, root crops and vegetables, were purchased in uyo or collected from farmland in the region. dried samples were ground, digested and centrifuged. levels of heavy metals (lead, cadmium, nickel, cobalt and chromium) were analysed using an atomic absorption spectrophotometer. average daily intake and target hazard quotients (thq) were estimated. results: eight food items (millet, maize, periwinkle, crayfish, stock fish, sabina fish, bonga fish and pumpkin leaf ) had thq values over 1.0 for cadmium, indicating a potential health risk in their consumption. all other heavy metals had thq values below 1.0, indicating insignificant health risks. the total thq for the heavy metals ranged from 0.389 to 2.986. there were 14 items with total thq values greater than 1.0, indicating potential health risks in their consumption. conclusion: the regular consumption of certain types of farm produce and seafood available in uyo, akwa ibom state, nigeria, is likely adding to the body burden of heavy metals among those living in this region. keywords: heavy metals; food; recommended daily intake; risk assessment; food safety analysis; nigeria. امللخ�ص: الهدف: هدفت هذه الدرا�سة للح�سول على معلومات عن تركيزات املعادن الثقيلة يف االأطعمة البحرية واملنتجات الزراعية التي ي�ستهلكها عامة ال�سكان يف يو مبحافظة اأكوا ابيوم يف نيجرييا، وهي منطقة تتم فيها ا�ستك�ساف وا�ستغالل النفط اخلام. الطريقة: مت يف واملحا�سيل البحرية االأطعمة من ال�سائعة االأنواع �سملت يو منطقة يف املزارع من جمعها اأو االأطعمة من نوعا 25 �رشاء 2012م مايو والكادميم )الر�سا�ض الثقيلة املعادن تركيزات قيا�ض ثم وطردها، وه�سمها اجلافة االأطعمة عينات �سحن ومت واخل�رشوات. اجلذرية وحوا�سل يوميا امل�ستهلكة الكمية متو�سط تقدير ومت الذري. ال�سوئي الطيف معامل جهاز بوا�سطة فيها والكروميم( والكوبلت والنيكل و�سمك )القديد( اململح وال�سمك ال�سمك وجراد ال�سامية والذرة )الدخن االأطعمة من اأنواع ثمانية اأن وجد النتائج: .)thq( الهدف خطر �سابينا و�سمك بوجنا ونبات اليقطني( لها thq اأعلى من 1.0 بالن�سبة للكادميم، مما ي�سري اإىل احتماال حدوث اآثار خطرة على ال�سحة عند تناول هذه االأطعمة. وكان الـ thq بالن�سبة لبقية االأطعمة االأخرى اأقل من 1.0. وكان الـ thq الكلي بالن�سبة للمعادن الثقيلة يرتاوح بني 0.389 و 2.986. وكانت الأربعة ع�رش من تلك االأطعمة قيم thq اأكرث من 1.0 مما ي�سري اإىل خطر حمتمل على ال�سحة من تناول تلك االأطعمة. اخلال�صة: اإن التناول املنتظم الأنواع معينة من االأطعمة البحرية واملنتجات الزراعية يف منطقة يو بنيجرييا قد يزيد من عبء املعادن الثقيلة عند الذين يعي�سون يف تلك املنطقة. مفتاح الكلمات: املعادن الثقيلة؛ االأغذية؛الكمية املو�سى بها يوميا؛ تقييم املخاطر؛ حتليل �سالمة االأغذي؛ نيجرييا. heavy metals in seafood and farm produce from uyo, nigeria levels and health implications *orish e. orisakwe,1 herbert o. c. mbagwu,2 godwin c. ajaezi,3 ukeme w. edet,2 patrick u. uwana2 clinical & basic research advances in knowledge heavy metals, particularly lead and cadmium, have been implicated in metabolic syndrome and other chronic diseases which have been increasing in sub-saharan africa. although food, water, air and the soil are known sources of these heavy metals, the exact individual contribution of these is unknown. the present study therefore sought to determine the levels of heavy metals in seafood and farm produce in uyo, nigeria. application to patient care determining the health risks of consuming seafood and farm produce from uyo, nigeria, is of the utmost importance to public health since the results of this study indicate that these foods likely add to the body burden of heavy metals among individuals residing in this region. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e275–282, epub. 28 may 15 submitted 24 aug 14 revisions req. 22 oct & 4 dec 14; revisions recd. 31 oct & 11 dec 14 accepted 15 jan 14 heavy metals in seafood and farm produce from uyo, nigeria levels and health implications e276 | squ medical journal, may 2015, volume 15, issue 2 the southeastern coastal region of akwa ibom state is currently the highest oil and gas producing state in nigeria. it is characterised by rich marine biodiversity as well as agricultural and crude oil exploration activities. heavy metals are ubiquitous in the environment, arising from both natural and anthropogenic activities.1 humans are exposed to these metals through various pathways.1 seafood is widely consumed as part of the local diet in nigeria, due in part to its high protein content, low saturated fats and omega fatty acids which are known to contribute to good health.2 fish can be very nutritious as they are rich in many vitamins, with a good selection of minerals and all of the essential amino acids in the right proportions.3 however, fish absorb heavy metals from the surrounding environment depending on a variety of factors, such as the characteristics of a species, the exposure period and concentration of the element, as well as abiotic factors such as temperature, salinity, ph and seasonal changes.4 hence, harmful substances like heavy metals released by anthropogenic activities may accumulate in marine organisms; as a result, the consumption of fish contaminated by toxic chemicals may present a risk to human health. vegetables constitute an essential dietary component by contributing protein, vitamins, iron, calcium and other nutrients which are usually in short supply;5,6 furthermore, this component also acts as a buffer for acidic substances produced during digestion. vegetables, fruit and cereals can accumulate heavy metals, potentially posing a direct threat to human health.6–8 plants can absorb heavy metals from contaminated soil or via exposure to polluted air.9 it has been reported that nearly half of the mean ingestion of lead (pb), cadmium (cd) and mercury through food is due to the consumption of plant products.9 moreover, some population groups may be more exposed to these heavy metals, e.g. vegetarians, since they consume higher quantities of these types of food within their daily diets.9 risk assessments of the bioaccumulation of heavy metals in various foods are important. this study attempted to obtain representative data on the levels of heavy metals in seafood and farm produce consumed by the general population in uyo, akwa ibom state, nigeria. nevertheless, while sometimes the levels of contaminants in food items exceed the legal limits set by various regulatory bodies, they may not always represent a significant risk to human health. for that reason, target hazard quotients (thqs) were estimated in order to evaluate potential hazards to human health. this study also aimed to estimate the dietary intake and thq of heavy metals via the consumption of selected seafood and farm produce items from uyo. methods samples of 25 commonly consumed food crops, vegetables and seafood were either purchased from the metropolis in uyo or collected from farmlands in the region in may 2012. only edible parts of the selected food items were used for the analysis. where purchased, the sources of the food items were authenticated by suppliers in order to ensure they were locally caught or grown in uyo. all samples were first washed with deionised water and then oven-dried at 70–80 °c for 24 hours. dried samples were ground using a pestle and mortar and sieved through a muslin cloth. for each sample, 0.5 g was placed in crucibles. samples were then placed for ashing in a furnace for four hours at 550 °c. the ash was digested in a solution of perchloric acid and nitric acid (at a volume ratio of 1:4). following this, samples were left to cool. a final volume of 25 ml was made by adding deionised water. the hydrolysed samples were then well shaken and transferred to a centrifuge tube for centrifugation at a rate of 3,000 x g to remove solid particles. the resulting samples were thoroughly mixed before sub-samples were taken to ensure homogeneity. the presence of pb, cd, nickel (ni), cobalt (co) and chromium (cr) were analysed using an atomic absorption spectrophotometer (model 929 unicam, spectronic unicam, cambridge, uk) at wavelengths of 217.0, 228.8, 232.0, 242.5 and 357.9 nm, respectively. the limit of detection for the heavy metals were 0.005 µg/g, with blank values reading as 0.00 µg/g for the metals in deionised water with an electrical conductivity value of <5 μs cm-1. appropriate quality procedures and precautions were carried out to reduce the risk of contamination and assure the reliability of the results. double-distilled deionised water was used throughout the study. glassware was properly cleaned and all reagents were of analytical grade. blank determinations of reagents were used to correct instrument readings. for validation of the analytical procedure, several samples that had already been analysed were spiked and homogenised with various amounts of standard solutions of the metals. daily intake rate (dir) in g person-1 day-1 was calculated based on the following formula:10 where cmetal is the metal concentration in food in μg dir = cmetal x dfood intake / baverage weight orish e. orisakwe, herbert o. c. mbagwu, godwin c. ajaezi, ukeme w. edet and patrick u. uwana clinical and basic research | e277 g-1, dfood intake is the daily intake of food in kg person -1 and baverage weight is average body weight in kg person -1. using an adapted method, an average daily consumption of 345 g of rice was assumed.11 this method was originally calculated by wang et al. in a chinese population where rice is eaten in different forms, as it is in the nigerian population.11 since the local population of uyo is predominantly comprised of subsistence farmers who do not have the luxury of variety in their menu, daily consumption of other farm produce and seafood was assumed to be 345 g/person/ day and 34.5 g/person/day, respectively.11,12 average adult body weight was considered to be 60 kg.11,12 noncarcinogenic risk estimation of heavy metal consumption was determined using thq values. thq is a ratio of the determined dose of a pollutant to a reference level considered harmful. thq values were determined based on the following formula:10 where efr is exposure frequency in 365 days year-1, ed is exposure duration in 70 years (equivalent to an average lifetime),13 fir is average daily consumption in g person-1 day-1, c is concentration of metal in food sample in μg g-1, rfdo is reference dose in μg g -1 day-1 and atn is average exposure time for noncarcinogens in days. the following reference doses were used: cr = 1.5 μg g-1 day-1, ni = 2.0 x 10-2 μg g-1 day-1, pb = 4.0 x 10-3 μg g-1 day-1 and cd = 1.0 x 10-3 μg g-1 day-1.12 atn was based on the following formula: where edtotal is the total number of exposure years, which was assumed to be 70 years.13 a thq value of >1.0 was considered to indicate that the level of exposure was smaller than the reference dose, implying that daily exposure at this level was unlikely to cause any harmful effects in a human subject during their lifetime. thus, the exposed population was considered unlikely to experience obvious adverse effects at this level.11,14 thqs were calculated according to the methodology described by the environmental protection agency (epa) in the usa.15 doses were calculated using the standard assumption for an integrated risk analysis and an average adult body weight of 60 kg.11,15 in addition, based on epa guidelines, it was assumed that ingested doses were equal to absorbed contaminant doses.16,17 the total thq of heavy metals for individual food samples was calculated as the sum of the individual thq of the toxic metals.12 a reference value for tolerable weekly intakes of heavy metals has been established.18,19 therefore, the daily intake of these heavy metals was compared with the provisional tolerable weekly intake (ptwi) and the proposed maximum permissible level.18,19 table 1: levels of selected heavy metals in farm produce and seafood from uyo, nigeria food item heavy metal levels in μg g-1 pb cd ni co cr cereals rice <0.05 0.13 0.84 <0.05 0.41 wheat <0.05 0.16 0.41 <0.05 0.42 soya bean <0.05 0.07 0.24 <0.05 0.58 millet <0.05 0.21 0.39 <0.05 0.43 maize <0.05 0.22 0.81 <0.05 0.47 fruit cucumber <0.05 <0.05 0.11 <0.05 0.09 orange <0.05 <0.05 0.10 <0.05 0.09 guava <0.05 <0.05 0.15 <0.05 0.11 watermelon <0.05 <0.05 0.14 <0.05 0.12 pawpaw <0.05 <0.05 0.13 <0.05 0.09 root crops potato <0.05 0.11 0.56 <0.05 0.64 yam <0.05 0.14 0.74 <0.05 0.83 cocoyam <0.05 0.14 0.83 <0.05 0.84 sweet potato <0.05 0.15 0.91 <0.05 0.86 water yam <0.05 0.16 0.74 <0.05 0.81 vegetables pumpkin leaf 0.07 0.35 1.45 0.12 1.08 water leaf <0.05 <0.05 0.74 <0.05 0.53 scent leaf <0.05 <0.05 0.68 <0.05 0.41 bitter leaf <0.05 <0.05 0.75 <0.05 0.38 editan leaf <0.05 <0.05 0.69 <0.05 0.39 seafood periwinkle 0.09 0.34 0.05 0.13 1.07 crayfish 0.09 0.21 0.11 0.15 1.08 stockfish 0.09 0.43 1.32 0.07 1.06 sabina fish 0.08 0.33 1.41 0.11 1.05 bonga fish 0.08 0.33 1.43 0.14 1.07 pb = lead; cd = cadmium; ni = nickel; co = cobalt; cr = chromium. thq = efr x ed x fir x c / rfdo x baverage weight x atn x 10 -3 atn = efr x edtotal heavy metals in seafood and farm produce from uyo, nigeria levels and health implications e278 | squ medical journal, may 2015, volume 15, issue 2 results the concentrations of heavy metals (pb, cd, ni, co and cr) in selected farm produce and seafood from uyo are shown in table 1. periwinkle, crayfish and stockfish had the highest pb content (0.09 μg g-1), followed by sabina and bonga fish (0.08 μg g-1 each) and pumpkin leaf (0.07 μg g-1). all other food items had pb levels <0.05 μg g-1. pb ranged from 0.08–0.09 μg g-1 in seafood samples and <0.05–0.07 μg g-1 in vegetable samples. concentrations of cd ranged from <0.05–0.35 μg g-1 in vegetable samples, with the highest levels in pumpkin leaf (0.35 μg g-1). in seafood samples, concentrations ranged from 0.21–0.43 μg g-1. higher concentrations of cd were noted in the fish samples, with the highest amount found in stockfish (0.43 μg g-1). cd concentrations in cereals, fruit and root crops ranged from <0.05–0.22 μg g-1. ni levels were highest in pumpkin leaf, with a concentration of 1.45 μg g-1. concentrations ranged from 0.68–1.45 μg g-1 in vegetable samples and 0.05–1.43 μg g-1 in seafood samples. concentrations of ni in cereals, fruit and root crops ranged from 0.10–0.91 μg g-1. the highest concentration of co was recorded in crayfish (0.15 μg g-1). concentrations ranged from <0.05–0.12 μg g-1 in vegetable samples and 0.07–0.15 μg g-1 in seafood samples. in root crop, fruit and cereal samples, concentrations of co were <0.05 μg g-1. for cr, crayfish and pumpkin leaf had the highest concentrations (1.08 μg g-1 each). cr content ranged from 0.38–1.08 μg g-1 in vegetable samples and 1.05–1.08 μg g-1 in seafood samples. among root crop, fruit and cereal samples, sweet potato had the highest level of cr (0.86 μg g-1) while cucumber, oranges and pawpaw had the lowest concentration (0.09 μg g-1) each. as can be seen in table 2, the daily intake of heavy metals from the consumption of analysed food items showed large variations. cr levels were found to be above permissible levels in all of the food items. while still at permissible values, crayfish and pumpkin leaf contained the highest levels of cr (0.00062 and 0.00621 g person-1 day-1, respectively). table 3 shows the permissible intake levels of selected heavy table 2: estimated daily intake rates of selected heavy metals through the consumption of farm produce and seafood from uyo, nigeria food item daily intake rate of heavy metals in g person-1 day-1 pb cd ni co cr cereals rice 0.00029 0.00075 0.00483 0.00029 0.00236 wheat 0.00029 0.00092 0.00236 0.00029 0.00241 soya bean 0.00029 0.00004 0.00138 0.00029 0.00334 millet 0.00029 0.00121 0.00225 0.00029 0.00247 maize 0.00029 0.00127 0.00466 0.00029 0.00270 fruit cucumber 0.00029 0.00029 0.00063 0.00029 0.00052 orange 0.00029 0.00029 0.00029 0.00029 0.00052 guava 0.00029 0.00029 0.00087 0.00029 0.00063 watermelon 0.00029 0.00029 0.00080 0.00029 0.00069 pawpaw 0.00029 0.00029 0.00075 0.00029 0.00052 root crops potato 0.00029 0.00063 0.00322 0.00029 0.00368 yam 0.00029 0.00080 0.00426 0.00029 0.00477 cocoyam 0.00029 0.00080 0.00477 0.00029 0.00483 sweet potato 0.00029 0.00087 0.00524 0.00029 0.00495 water yam 0.00040 0.00092 0.00426 0.00029 0.00466 vegetables pumpkin leaf 0.00040 0.00201 0.00895 0.00069 0.00621 water leaf 0.00029 0.00029 0.00425 0.00029 0.00305 scent leaf 0.00029 0.00029 0.00391 0.00029 0.00236 bitter leaf 0.00029 0.00029 0.00431 0.00029 0.00219 editan leaf 0.00029 0.00029 0.00397 0.00029 0.00225 seafood periwinkle 0.00005 0.00020 0.00003 0.00007 0.00061 crayfish 0.00005 0.00012 0.00006 0.00009 0.00062 stockfish 0.00005 0.00025 0.00008 0.00004 0.00061 sabina fish 0.00005 0.00019 0.09398 0.00006 0.00060 bonga fish 0.00005 0.00019 0.00082 0.00008 0.00061 pb = lead; cd = cadmium; ni = nickel; co = cobalt; cr = chromium. table 3: permissible intake levels of heavy metals as per food and agriculture organization and world health organization recommendations13,18 heavy metal ptwi in μg kg-1 week-1 daily intake in μg kg-1 day-1 intake for a 60 kg individual in μg day-1 pb 25.0 5.0 300.0 ni 1.0 0.2 12.0 cd 7.0 0.4–2.0 60.0 cr 0.5 0.1 6.0 ptwi = provisional tolerable weekly intake; pb = lead; cd = cadmium; ni = nickel; cr = chromium. orish e. orisakwe, herbert o. c. mbagwu, godwin c. ajaezi, ukeme w. edet and patrick u. uwana clinical and basic research | e279 metals as per recommendations from the food and agriculture organization (fao) and the world health organization (who).13,18 figure 1 shows the estimated total thqs caused by consumption of the food items. estimated thq values for the selected heavy metals ranged from 0.000–2.473. total thq values for the metals ranged from 0.389–2.986. a total of 14 of the food items had total thq values greater than 1.0, indicating some health risks. for cd, eight food items, comprising of cereals (millet and maize), vegetables (pumpkin leaf ) and seafood (periwinkle, crayfish, stockfish, sabina and bonga fish), had thq values greater than 1.0, indicating potential health risks. all other metals had total thq values below 1.0, indicating an insignificant health risk. discussion in order to assess the health risk of any pollutant, it is essential to estimate the level of exposure by quantifying the exposure routes of the pollutant to the target organisms. while there are various possible exposure pathways of pollutants to humans, the food chain is one of the most important. as for many dietary components, the intake of metals can be both beneficial and harmful. for example, many nigerian families exhibit low levels of dietary calcium due to poverty, which has potentially harmful effects.20 however, preventative measures should be in place to avoid the surplus ingestion of potentially toxic metals. many developed countries spend significant resources to avoid excessive metal intake by the general population, from monitoring endogenous metal levels figure 1: target hazard quotient values of selected heavy metals via consumption of farm produce and seafood from uyo, nigeria. thq = target hazard quotient; pb = lead; cd = cadmium; ni = nickel; cr = chromium. in foods to detecting contamination during food preparation processes.21,22 cases of excessive intake of trace metals have been implicated in pathological events and inflammation.23 in the current study, pb levels were observed to be lower than those noted in a similar study by orisakwe et al., which reported a pb range of 0.00–61.17 μg g-1 in different foodstuffs from southeastern nigeria.24 however, like the current study, pb concentrations were found to be highest in seafood. according to the fao and who, the safe limit for pb in fruit, root crops and cereals is 0.1 μg g-1, 0.1 μg g-1 and 1.00 μg g-1, respectively.25 therefore, the food items analysed could be considered to have safe levels of pb. a ptwi of 25 μg kg-1, equalling 1,500 μg pb/week for a 60 kg person, has been established.18 in taiwan, huang et al. demonstrated that low-level prenatal exposure to pb among fetuses can lead to decreased intelligence and delayed cognitive function.26 furthermore, a recent nigeria-based study found that prenatal pb exposure was significantly associated with crown rump length at birth.27 among individuals of reproductive age, exposure to pb is a public health issue of great concern, since evidence indicates that even low levels of exposure to this metal can affect fetal growth and development.28 conditions associated with pb poisoning (impaired mental and physical development, poor school performance, anaemia, under-nutrition, cardiovascular diseases, metabolic syndrome, infertility, etc.) represent a significant social, financial and health burden on affected individuals and their families and communities.29 in nigeria, there are multiple sources of exposure to pb, including automobiles which burn leaded petrol.30,31 despite heavy metals in seafood and farm produce from uyo, nigeria levels and health implications e280 | squ medical journal, may 2015, volume 15, issue 2 exposure to cr can occur through air, water, food or skin contact. in human beings and animals, it is considered an essential metal for carbohydrate and lipid metabolism within a certain concentration (up to 200 μg day-1).39 however, exceeding this concentration leads to an accumulation and toxicity that can result in hepatitis, gastritis, ulcers and lung cancer.39 in the current study, cucumber, oranges and pawpaw had the lowest concentration of cr and were within acceptable limits of 250 μg day-1 for adults equivalent to 1,500 μg g-1 for an average weight of 60 kg.40 however the cr concentration was above the permissible level in all the other tested food items. the recommended value of cr is 0.5 μg kg-1 body weight week-1 and 0.1 μg kg-1 body weight day-1 for adults.18 levels of pb, cd, and ni have been previously investigated in three popular types of seafood in ondo state, nigeria (fish, crab and periwinkle), in order to evaluate the ecosystem of this oil-polluted coastal region.30,41 increasing levels of pb, cd, and ni could pose a potential threat to the ecology of the area and the health of the local population.30,41 using reference doses, estimates of thqs for heavy metals in eight food items analysed in the current study found cd values of over 1.0, indicating a potential health risk.14,15 multiple exposure to heavy metals or pesticides may lead to additive and/or interactive effects according to the risk addition hypothesis.12,42 there are several limitations of the current study that should be considered. these include the unavailability of national food diaries and nutrition data in nigeria and the absence of national standard nutritional limits and guidelines. in humans, the degree of toxicity of heavy metals is dependent on the daily intake.32 in view of the paucity of food consumption data and the absence of food diaries in nigeria, the current study assumed a daily consumption of 345 g of rice based on an adaptation of wang et al.’s study of a chinese population.11 rice is a staple food throughout west africa. like china, rice is one of the most important cereals in nigeria and is a staple food for both urban and rural dwellers. in nigeria, urban consumers have developed a preference for imported rice, mainly due to a perception of superior quality. most of the rice consumed in nigeria is imported from china.12 uyo is a riverine community with a local population of subsistence farmers; it was therefore assumed that intake of rice would be complemented by farm produce and seafood. daily ingestion rates of farm produce and seafood were therefore estimated to be 345 g/person/ day and 34.5 g/person/day, respectively.11,12 these assumptions require a cautionary interpretation of the results as they may not give an accurate view of health the introduction of a planned clean air initiative to reduce levels of pb in nigerian petrol from 0.74 g/l to 0.15 g/l by 2002, there is as yet no evidence to suggest that the programme has been implemented.30 concentrations of cd observed in the current study agreed with a similar study in southeastern nigeria which reported a range of 0.00–0.24 μg g-1 of cd in various items of food.32 safe limits of cd in cereals, fruit and root crops are 0.2 μg g-1, 0.05 μg g-1 and 0.1 μg g-1, respectively, according to the european commisson.25 in the current study, cd was below the permissible level in all the food items. the recommended value of cd is within the range of 7.0 μg kg-1 body weight week-1 for adults.19 considering the accumulative properties and long biological half-life of cd, a level of 0.4–2.0 μg kg-1 body weight day-1 has been set as permissible.33 this equals 60 μg day-1 for an individual of 60 kg. absorption following the oral exposure of cd likely depends on physiological status, such as age and levels of iron, calcium and zinc stored in the body. there is epidemiological evidence that in utero exposure to cd may have adverse effects on a newborn’s health.34 mostly present in the pancreas, ni plays an important role in the production of insulin and is required in small quantities by the body; a deficiency of ni can result in liver disorders.35 however, increased concentrations of ni can have many adverse effects, namely kidney damage, cancers of the lung and nasal sinus, pneumonitis, chronic bronchitis, allergic reactions and mild skin rashes.35 concentrations of ni in cereals, fruit and root crops in the current study were in line with another study which reported a range of 0.00–3.13 μg g-1 among various food items.24 the recommended daily intake of ni is approximately 0.2 μg kg-1 body weight day-1.18 unfortunately, in the current study, ni levels in the cereals, root crops, vegetables, stockfish, sabina fish and bonga fish were found to be higher than recommended for all food items. while the body requires trace amounts of co, this metal is toxic in elevated concentrations. for diabetic patients, a total of 2.0 μg day-1 is required in the form of vitamin b12. high intake of co can lead to gastrointestinal, vision and heart problems, as well as thyroid damage.25,36 the co concentrations of the studied samples conformed with those reported by dabeka et al. among canadians (<0.003– 0.0759 μg g-1).37 according to another nigerian study, normal daily intake of co is between 2.5–3.0 mg day-1, which is equivalent to 180 mg kg-1 body weight day-1 for an adult of 60 kg.38 poisoning therefore occurs when daily co intake is greater than this range. orish e. orisakwe, herbert o. c. mbagwu, godwin c. ajaezi, ukeme w. edet and patrick u. uwana clinical and basic research | e281 concerns associated with heavy metal consumption in nigeria. further studies are recommended to investigate consumption patterns in this region. conclusion consumption of certain types of seafood and farm produce is likely to add to the body burden of heavy metals among individuals living in uyo, nigeria. heavy metal analysis of millet, maize, periwinkle, crayfish, stockfish, sabina fish, bonga fish and pumpkin leaf indicated a potential health risk with regards to cd content. as the excessive ingestion of heavy metals can have severe public health implications, the monitoring of these metals in seafood and farm produce in nigeria is of the utmost importance. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. wilson b, pyatt fb. heavy metal dispersion, persistence, and bioaccumulation around an ancient copper mine situated in anglesey, uk. ecotoxicol environ saf 2007; 66:224–31. doi: 10.1016/j.ecoenv.2006.02.015. 2. kennedy a, martinez k, chuang cc, lapoint k, mcintosh m. saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: mechanisms of action and implications. j nutr 2009; 139:1–4. doi: 10.3945/jn.108.098269. 3. savikko n, pitkälä kh, laurila jv, suominen mh, tilvis rs, kautiainen h, et al. secular trends in the use of vitamins, minerals and fish-oil products in two cohorts of community dwelling older people in helsinki: population-based surveys in 1999 and 2009. j nutr health aging 2014; 18:150–4. doi: 10.1007/s12603-013-0381-4. 4. ginsberg gl, toal bf. quantitative approach for incorporating methylmercury risks and omega-3 fatty acid benefits in developing species-specific fish consumption advice. environ health perspect 2009; 117:267–75. doi: 10.1289/ehp.11368. 5. islam ms, ahmed mk, habibullah-al-mamun m. determination of heavy metals in fish and vegetables in bangladesh and health implications. hum ecol risk assess 2015; 21:986–1006. doi: 10.1080/10807039.2014.950172. 6. umoru pe. heavy metal content in vegetables from an irrigated farmland in kaduna metropolis, nigeria. int j adv res technol 2013; 2:1–1. 7. türkdoğan mk, kilicel f, kara k, tuncer i, uygan i. heavy metals in soil, vegetables and fruits in the endemic upper gastrointestinal cancer region of turkey. environ toxicol pharmacol 2003; 13:175–9. doi: 10.1016/s13826689(02)00156-4. 8. damek-poprawa m, sawicka-kapusta k. damage to the liver, kidney, and testis with reference to burden of heavy metals in yellow-necked mice from areas around steelworks and zinc smelters in poland. toxicology 2003; 186:1–10. doi: 10.1016/ s0300-483x(02)00595-4. 9. dorne jl, fink-gremmels j. human and animal health risk assessments of chemicals in the food chain: comparative aspects and future perspectives. toxicol appl pharmacol 2013; 270:187–95. doi: 10.1016/j.taap.2012.03.013. 10. singh a, sharma rk, agrawal m, marshall fm. risk assessment of heavy metal toxicity through contaminated vegetables from waste water irrigated area of varanasi, india. trop ecol 2010; 51:375–87. 11. wang x, sato t, xing b, tao s. health risks of heavy metals to the general public in tianjin, china via consumption of vegetables and fish. sci total environ 2005; 350:28–37. doi: 10.1016/j.scitotenv.2004.09.044. 12. ge ky. the status of nutrient and meal of chinese in the 1990s. beijing, china: people’s hygiene press, 1992. pp. 415–34. 13. bennett dh, kastenberg we, mckone te. a multimedia, multiple pathway risk assessment of atrazine: the impact of age differentiated exposure including joint uncertainty and variability. reliab eng syst saf 1999; 63:185–98. doi: 10.1016/ s0951-8320(98)00046-5. 14. chien cl, hung tc, choang ky, yeh cy, meng pj, shieh mj, et al. daily intake of tbt, cu, zn, cd and as for fishermen in taiwan. sci total environ 2002; 285:177–85. doi: 10.1016/ s0048-9697(01)00916-0. 15. united states environmental protection agency. mid-atlantic risk assessment: human health risk assessment. from: www. epa.gov/reg3hwmd/risk/human/index.htm accessed: oct 2014. 16. united states environmental protection agency. assessing human health risks from chemically contaminated fish and shellfish: a guidance manual. from: nepis.epa.gov/exe/ zypurl.cgi?dockey=2000dglf.txt accessed: oct 2014. 17. cooper cb, doyle me, kipp k. risks of consumption of contaminated seafood: the quincy bay case study. environ health perspect 1991; 90:133–40. 18. food and agriculture organization/world health organization. evaluation of certain food additives and contaminants: fortyfirst report of the joint fao/who expert committee on food additives. from: whqlibdoc.who.int/trs/who_trs_837.pdf accessed: oct 2014. 19. food and agriculture organization/world health organization. joint fao/who expert committee on food additives: fifty-third meeting: summary and conclusions. from: ftp://ftp.fao.org/codex/ meetings/ccfac/ccfac32/jecfa_53.pdf accessed: oct 2014. 20. hu h. bone lead as a new biologic marker of lead dose: recent findings and implications for public health. environ health perspect 1998; 106:961–7. 21. european commission. rasff food and feed safety alerts. from: ec.europa.eu/food/food/rapidalert/index_en.htm accesssed: oct 2014. 22. marvin c, charlton m, milne j, thiessen l, schachtschneider j, sardella g,et al. metals associated with suspended sediments in lakes erie and ontario, 2000-2002. environ monit assess 2007; 130:149–61. doi: 10.1007/s10661-006-9385-4. 23. naughton dp, petróczi a. the metal ion theory of ageing: dietary target hazard quotients beyond radicals. immun ageing 2008; 5:3. doi: 10.1186/1742-4933-5-3. 24. orisakwe oe, kanayochukwu nj, nwadiuto ac, dike d, onyinyechi o. evaluation of potential dietary toxicity of heavy metals of vegetables. j environ analytic toxicol 2012; 2:136. doi: 10.4172/2161-0525.1000136. 25. european commission. commission regulation (ec) no 1881/2006: setting maximum levels for certain contaminants in food stuff. from: eur-lex.europa.eu/legal-content/en/ all/?uri=celex:32006r1881 accessed: oct 2014. 26. huang pc, su ph, chen hy, huang hb, tsai jl, huang hi, et al. childhood blood lead levels and intellectual development after ban of leaded gasoline in taiwan: a 9-year prospective study. environ int 2012; 40:88–96. doi: 10.1016/j.envint.2011.10.011. 27. obi e, orisakwe oe, okafor c, igwebe a, ebenebe j, afonne oj, et al. towards prenatal biomonitoring in eastern nigeria: assessing lead levels and anthropometric parameters of newborns. j uoeh 2014; 36:159–70. doi: 10.7888/juoeh.36.159. heavy metals in seafood and farm produce from uyo, nigeria levels and health implications e282 | squ medical journal, may 2015, volume 15, issue 2 37. dabeka rw, mckenzie ad. survey of lead, cadmium, fluoride, nickel, and cobalt in food composites and estimation of dietary intakes of these elements by canadians in 1986-1988. j aoac int 1995; 78:897–909. 38. agency for toxic substances and disease registry (atsdr), public health service, us department of health and human services. toxicological profile for cobalt. from: www.atsdr.cdc. gov/toxprofiles/tp.asp?id=373&tid=64 accessed:oct 2014. 39. parveen z, khuhro mi, rafiq n. market basket survey for lead, cadmium, copper, chromium, nickel, and zinc in fruits and vegetables. bull environ contam toxicol 2003; 71:1260–4. doi: 10.1007/s00128-003-8640-4. 40. european food safety authority. scientific opinion on the safety of trivalent chromium as a nutrient added for nutritional purposes to foodstuffs for particular nutritional uses and foods intended for the general population (including food supplements). from: www.efsa.europa.eu/en/search/ doc/1882.pdf accessed:oct 2014. 41. ololade ia, lajide l, olumekun vo, ololade oo, ejelonu bc. influence of diffuse and chronic metal pollution in water and sediments on edible seafoods within ondo oil-polluted coastal region, nigeria. j environ sci health a tox hazard subst environ eng 2011; 46:898–908. doi: 10.1080/10934529.2011.580208. 42. amirah mn, afiza as, faizal wiw, nurliyana mh, laili s. human health risk assessment of metal contamination through consumption of fish. j environ pollut human health 2013; 1:1– 5. doi: 10.12691/jephh-1-1-1. 28. xie x, ding g, cui c, chen l, gao y, zhou y, et al. the effects of low-level prenatal lead exposure on birth outcomes. environ pollut 2013; 175:30–4. doi: 10.1016/j.envpol.2012.12.013. 29. united nations. millennium development goals: 2005 progress chart. from: www.un.org/millenniumgoals/pdf/ mdg2005progresschart.pdf accessed: oct 2014. 30. orisakwe oe, blum jl, sujak s, zelikoff jt. metal pollution in nigeria: a biomonitoring update. j health pollut 2014; 4:40–52. 31. nriagu j, afeiche m, linder a, arowolo t, ana g, sridhar mk, et al. lead poisoning associated with malaria in children of urban areas of nigeria. int j hyg environ health 2008; 211:591– 605. doi: 10.1016/j.ijheh.2008.05.001. 32. orisakwe oe, nduka jk, amadi cn, dike do, bede o. heavy metals health risk assessment for population via consumption of food crops and fruits in owerri, south eastern, nigeria. chem cent j 2012; 6:77. doi: 10.1186/1752-153x-6-77. 33. bellinger d, bolger m, goyer r, barraj l, baines j. who food additives series 46: cadmium. from: www.inchem.org/ documents/jecfa/jecmono/v46je11.htm accessed:oct 2014. 34. lin cm, doyle p, wang d, hwang yh, chen pc. does prenatal cadmium exposure affect fetal and child growth? occup environ med 2011; 68:641–6. doi: 10.1136/oem.2010.059758. 35. khan sa, khan l, hussain i, shah h akhtar n. comparative assessment of heavy metals in euphorbia helioscopia l. pak j weed sci res 2008; 14:91–100. 36. kumar u, singh dn. electronic waste: concerns and hazardous threats. int j curr eng technol 2014; 4:801–11. revalidation: what does it offer a national health service? anita donley plymouth hospitals national health service trust, uk. e-mail: thomasanita@me.com the purpose of revalidation is to provide greater assurance that licensed doctors are up-to-date and fit to practise. the introduction of medical revalidation throughout the uk means doctors who wish to retain their licences to practice in the uk will need to demonstrate they fit these criteria. revalidation is a new way of regulating the medical profession, providing a focus for doctors’ efforts to maintain and improve their practice; facilitate medical organisations in supporting doctors in keeping their practice up to date, and encourage patients and the public to provide feedback about the medical care they receive from doctors. in these ways, revalidation will contribute to the ongoing improvement in the quality of medical care delivered to patients throughout the uk. the successful introduction of revalidation is a shared responsibility involving the general medical council, the health departments in england, northern ireland, scotland and wales, the medical royal colleges, the medical profession and the revalidation support team (rst) working with the national health service and other employers in the uk. this group of interested parties should work together to develop, test, and implement a system of revalidation throughout the uk that is feasible, flexible, proportionate, cost effective, and provides the necessary level of assurance to the public. revalidation will be based on a local evaluation of doctors’ performance through appraisal, which will be conducted annually in the workplace. the responsible officer, informed by the appraisal and appraiser, will make a recommendation to the gmc concerning the doctor’s fitness to practise. this presentations by the medical director for the department of health england revalidation support, will give an overview of the design and implementation of this programme, with particular reference to the implications for and improvements offered to integrated clinical governance. thyrotoxicosis neil gittoes queen elizabeth hospital, birmingham, uk. e-mail: neil.gittoes@uhb.nhs.uk thyrotoxicosis affects ~3% of the population and thus represents a significant workload to endocrinologists, general physicians, and primary care clinicians alike. clinical presentation is often stereotyped, but in the elderly there may be an atypical presentation as apathetic thyrotoxicosis. autoimmune and nodular hyperthyroidism represent the vast majority of causes of thyrotoxicosis; however, it is important to have a clear understanding of rarer causes, such as post-infectious/post-partum thyroiditis or amiodarone-induced thyrotoxicosis as the clinical management differs in such cases. approaches to definitive treatment differ across the world. anti-thyroid drugs are used to render patients euthyroid prior to radioiodine treatment or thyroid surgery and, in some instances, longer term antithyroid drugs are used in an attempt to induce a long-term remission in patients with graves’ disease. there are clinical markers to help predict which patients are likely to do well/poorly with such approaches. this presentation will highlight the optimum management of patients with different forms of thyrotoxicosis, with particular emphasis on markers for success, adverse effects of treatment and longterm outcomes following treatment of thyrotoxicosis. املؤمتر الطيب العام املتقدم بالتعاون بني كلية األطباء امللكية )لندن( ووزارة الصحة يف ُعمان وجامعة السلطان قابوس فرباير 2012 22-23 advanced general medical conference the royal college of physicians (london), the ministry of health, oman, and sultan qaboos university 22-23 february 2012 abstracts sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 391-396, epub. 15th jul 12 392 | squ medical journal, august 2012, volume 12, issue 3 advanced general medical conference the royal college of physicians (london), the ministry of health, oman, and sultan qaboos university 4-5th may 2011 epigenetics of cancer mansour s. al moundhri oncology unit, department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: mansours@squ.edu.om epigenetics is a fascinating and rapidly expanding field in medical research. it has wide applications in early diagnosis, prognosis, and therapeutic interventions, particularly in cancer. in this presentation, the basic mechanisms of post translational epigenetic alterations will be discussed with particular emphasis on the role of deoxyribonucleic acid (dna) methylation, histone modifications and chromatin remodelling, and micro-ribonucleic acid (mirna) transcription regulation in carcinogenesis. the second part will be devoted to translational epigenomics with presentation of some available data on the significance of epigenetics in determining cancer risk predispositions and its value as early diagnostic, predictive and prognostic tool. furthermore, the therapeutic interventions utilising dna methylation, in particular, will be presented. obesity in pregnancy nick finer university of central london hospital centre for weight loss, uk. e-mail: n.finer@ucl.ac.uk obesity is increasingly recognised as harmful to the mother, affecting fertility and causing higher incidence of gestational diabetes, pre-eclampsia, caesarian section and postoperative infection. it is also potentially harmful to the foetus through higher incidence of macrosomia, congenital anomalies, premature or stillbirth, and epigenetic effects leading to obesity and metabolic syndrome. guidelines from the institute of medicine suggest that overweight women should gain only 7–12 kg, and obese women 5–9 kg during pregnancy. while few women receive adequate counselling or weight management, and over half exceed these recommended weight gains, a recent systematic review concluded that even ‘intense’ interventions did not prevent weight gain during pregnancy. can better interventions be devised, in the context that so far no pharmacological aids have been shown to be safe or effective? the acceptability of bariatric surgery has resulted in increasing numbers of obese women of child bearing age receiving surgery, sometimes as a prelude to infertility treatment. increasing numbers of women who have had bariatric surgery present later with pregnancies from which arise specific concerns and weight management problems. although evidence syntheses of pregnancy outcomes find poor quality evidence, surgery seems to improve maternal health, markedly decreases the incidence of gestational diabetes mellitus, and probably also decreases incidences of hypertension and eclampsia. fetal outcomes are improved in respect of decreased macrosomia, without adverse effects on prematurity, low birth weight or perinatal mortality. cutaneous sarcoidosis: diagnosis and management nilesh morar chelsea and westminster hospital and imperial college, london, uk. e-mail: n.morar@imperial.ac.uk sarcoidosis is a multi-organ immune-mediated disease of unknown aetiology with varying clinical presentations. the skin can be involved in close to one-third of patients. the cutaneous manifestations are protean and often masquerade as several other skin diseases; hence, the diagnosis is often missed or delayed. dermatologists are often the first to diagnosis sarcoidosis. the treatment is challenging and there are no randomised clinical trials on any treatment modality. options include topical or systemic steroids, anti-malarials, immunosuppressive drugs, novel therapies and, more recently, the anti-tumour necrosis factor biologic therapies. the latter has been a significant advancement in therapy. this talk will discuss the clinical spectrum and differential diagnosis of cutaneous sarcoidosis. traditional and recent advances in the management of this challenging disease drawing on experience from a tertiary referral centre will be discussed. the management of severe hypoxaemic respiratory failure in critical care simon baudouin newcastle university and royal victoria infirmary, newcastle upon tyne, uk. e-mail: s.v.baudouin@ncl.ac.uk the recent h1n1 pandemic has once again brought focus on the management of severe acute hypoxaemic respiratory failure. a significant number of young and previously fit individuals suffered severe respiratory failure. these patients received both conventional and experimental forms of respiratory support. conventional ventilatory support is based on the findings of the multi-centre ardsnet trial (2000). this found that ventilation with lower tidal volumes reduced mortality in patients with severe acute lung injury (ali). this was despite the fact that, at early stages, the lower tidal volume patients were on average more hypoxaemic and hypercapnic as a result of the lower volumes/pressures used in that group. positive end expiratory pressure (peep) is also part of a standard approach to ali and can improve oxygenation. however, a number of studies have not found a significant improvement in mortality when peep levels have been compared. although this conventional approach was effective in many patients, a number developed intractable hypoxaemia following h1n1 infection. this group received a number of interventions including steroids, prone positioning, tight fluid control, airway recruitment manoeuvres, high frequency oscillation, and extra corporeal membrane oxygenation (ecmo). all these approaches have been subjected to various studies with often promising results in small initial studies, but lack of confirmation of efficacy in larger, randomised trials. for example a recent rct of ecmo reported improved outcomes in the intervention group. however, the study design was complex and the interpretation of the results remains controversial. further studies of other treatments are on-going. case series from a number of large centres during the h1n1 outbreak indicate a good outcome in many patients despite the lack of a strong evidence base for rescue treatment. one explanation may be the efficacy of these techniques in the most severely ill group of patients. abstracts | 393 22-23 february 2012 relatively few of these are included in individual rcts but a meta-analysis of the effect of prone positioning suggested better outcomes in the most hypoxaemic patients. the role of pet/ct in cancer diagnosis naima k. al bulushi royal hospital, muscat, oman. e-mail: nkd004@hotmail.com positron emission tomography/computed tomography (pet /ct) imaging uses radiolabelled molecules to take images of molecular interactions of biological processes in vivo. it enables inspection of glucose metabolism in all organ systems in a single examination. this hybrid imaging system utilises short-lived radiotracers that are cyclotron products with a short half-life ranging between 2 and 110 minutes. cancer cells have higher metabolic activity and use more glucose. the hexokinase activity levels increase and the phosphorelated glucose moves to the glycolysis pathway. fludeoxyglucose (fdg) is a glucose analogue; hence, there is an increased uptake in cancer cells due to an increase in glucose transporter activity and hexokinase levels, leading to elevated levels of phosphorelated fdg. on the other hand, g-6-phosphatase levels are low in the cancer cells; therefore, the phosphorelated glucose cannot diffuse out of the cells. unlike glucose, fdg is not metabolised further and remains trapped in the cancer cells. it is well-documented in the literature that there is a dramatic improvement in the diagnostic accuracy of pet/ct for lung, colorectal, breast, head and neck, and thyroid cancers, and lymphoma. pet/ct is important in improving the detection and staging of cancer, selecting therapies, assessing therapeutic response, and in restating in cases of disease recurrence. in addition, it is more accurate in evaluating residual lesions and in differentiating fibrosis versus active disease. pet/ct is cost effective when used for evaluating therapy response. it can be used following 1–3 chemotherapy cycles to assess therapy response. effective treatment sharply reduces metabolic tumour activity and helps guide physicians in effective use of expensive chemotherapy medications. pet/ct is a cost effective, essential imaging tool for evaluating various tumours. it is essential for staging, therapy response, and residual tumour evaluation, and to gauge effective use of chemotherapy. acute non-invasive ventilation mark elliott st. james’s university hospital, leeds, uk. email: mwelliott@doctors.org.uk non-invasive ventilation (niv) now has a major role in the management of patients presenting with respiratory failure on the acute medical take. it has a number of potential advantages compared with invasive mechanical ventilation (imv). the obvious attraction is the avoidance of intubation and its attendant complications. its use opens up new opportunities in the management of patients with ventilatory failure, particularly with regard to location and the timing of intervention. with niv, paralysis and sedation are not needed and ventilation outside the intensive care unit (icu) is an option; given the considerable pressure on icu beds in some countries, the high costs, and the potentially distressing experience of icu, this is an attractive option. ventilatory support can be introduced at an earlier stage in the evolution of ventilatory failure. additionally, it is possible with niv to give very short periods of ventilatory support, which in some cases may be sufficient to reverse the downward spiral into life-threatening ventilatory failure. patients can cooperate with physiotherapy and eat normally. intermittent support is possible, and patients can start mobilising at an early stage. they remain able to communicate with medical and nursing staff, and with their families; this is likely to reduce feelings of powerlessness and anxiety associated with ventilatory support. a reduction in complications, particularly infections, is a consistent and important finding. however, niv does have limitations; concerns have been voiced that it may delay endotracheal intubation (eti) and mechanical ventilation, resulting in a worse outcome. niv may be time consuming for medical and nursing staff, though in part this may represent a learning effect. the use of niv for patients with acute exacerbations of chronic obstructive pulmonary disease (copd), cardiogenic pulmonary oedema, and acute on chronic hypercapnic respiratory failure due to other causes will be discussed. targeted treatment in haematological cancers gareth morgan institute of cancer research and the royal marsden nhs foundation trust, london, uk. e-mail: gareth.morgan@icr.ac.uk developing targeted treatment for haematological cancers is a key aim of current research. these stratified cancer medicine strategies are being developed in colon cancer and sarcoma, and offer improvements in patient outcomes and the value of novel therapies. the key concept underlying this approach is to identify a specific molecular lesion found within the tumour cells which can be switched off using a targeted treatment. the access to tumour tissue in haematological cancers has allowed the generation of many years of clinical data which. these data provide insights into how these approaches can work in the clinic. the disease that has exemplified the role of targeted treatment best is chronic myeloid leukaemia. this disease is characterised by a chromosomal translocation bcr/abl, which leads to the over-expression of a tyrosine kinase. this tyrosine kinase can be targeted using imatinib, a specific inhibitor. this use of this drug in the clinic results in patients achieving complete remissions. this tolerable treatment strategy has lead to a rapid decline in allogeneic transplantation, which was previously the key clinical treatment for this disease. a surprising result of the treatment has been the emergence of treatment resistance mediated via tumour specific mutations, affecting the ability of the targeted treatment to inhibit its target. this emerging treatment resistance has led to the development of a range of different kinase inhibitors which have different characteristics and abilities to overcome resistance. targeted treatment is also relevant to other haematological diseases, including b-cell lymphomas and acute leukaemias. overall, we have made big strides in the application of targeted treatments strategies in haematological cancers and it is expected this will form the basis of improved outcomes in other haematological conditions over the next years. 394 | squ medical journal, august 2012, volume 12, issue 3 advanced general medical conference the royal college of physicians (london), the ministry of health, oman, and sultan qaboos university emergency oxygen therapy mark elliott st. james’s university hospital, leeds, uk. e-mail: mwelliott@doctors.org.uk oxygen is one of the most common treatments in emergencies, with many patients given supplementary oxygen. however, oxygen supplementation is not without risk, and there are occasional deaths due to under or over-use of oxygen. audits of oxygen use have consistently shown poor performance, but there are few randomised controlled trials to guide practice, which is largely guided by precedent. tissue hypoxia and cell death can occur, especially in the brain, after just a few minutes of profound hypoxaemia, such as occurs during cardiac arrest. sudden exposure to oxygen saturations below about 80% can cause altered consciousness, even in healthy subjects. however, the degree of hypoxia that will cause cellular damage is not well-established. dogma is that a high fio2 is protective and gives a margin of safety; therefore, practitioners should err on the side of generous oxygen supplementation. however, some patients may be placed at risk by the use of high dose oxygen therapy. oxygen is a drug and should be prescribed with the same rigour and monitoring of effect as pharmaceutical preparations. in most situations, a target of 94 to 98% is appropriate, but there are a few situations in which a lower target range should be used. most commonly, this will be for patients whose level of oxygenation when “well” is known, and in whom adverse effects of oxygen have been previously been documented or can reasonably be expected. additionally, bleomycin-induced pulmonary fibrosis, paraquat ingestion, and probably acid aspiration should be treated with a lower target saturation. supraphysiological oxygen is seldom warranted, except in cases of carbon monoxide poisoning and occasionally pneumothorax. all clinicians should be trained to recognise and treat hypoxia; this must include understanding of the role and limitations of pulse oximetry and interpretation of blood gas samples. the cutaneous manifestations of hiv nilesh morar chelsea and westminster hospital and imperial college, london, uk. e-mail: n.morar@imperial.ac.uk hiv continues to be a medical problem worldwide, and almost all hiv patients develop skin disease. skin disease is often the presenting sign and certain skin conditions are markers for diagnosing hiv. conditions have either a typical appearance, or exaggerated and unusual manifestations occur. the therapy for hiv with highly active antiretroviral therapy (haart) has resulted in unusual manifestations as a result of immune reconstitution. having previously worked in south africa, which is the epicentre for hiv, and now working at the largest hiv dermatology unit in europe, tremendous experience on hiv and skin has been acquired. this talk will describe the diverse cutaneous manifestations, complications from medication, and clinical clues to diagnosis, and provide an update on the management of hiv-associated skin disease. targeted therapy in cancer management bassim al-bahrani division of oncology, royal hospital, muscat, oman. e-mail: bassim@hotmail.com agents that target a multitude of both haematopoietic and solid malignant tumours are state-of-the-art available therapy. they have become an integral part of cancer management when used alone or in combination with cytotoxic agents. the target therapy, since its inception in the modern era with trastuzumab and crizotinib, is an ever expending area and a success story. newer targets are identified on a regular basis and should be exploited therapeutically by the identification of newer molecules. primary hyperparathyroidism – surgery or conservative management? neil gittoes queen elizabeth hospital, birmingham, uk. e-mail: neil.gittoes@uhb.nhs.uk primary hyperparathyroidism (phpt) is a common, usually coincidentally discovered diagnosis made on ‘routine’ blood testing. most patients with phpt are, therefore, asymptomatic at presentation. therein lies the dilemma of whether to treat surgically or manage by conservative follow up although the risks of overt phpt are well-established in terms of end organ damage (e.g. fractures and nephrolithiasis). there is far less evidence that mild, asymptomatic disease has such effects and that parathyroidectomy (ptx) can reverse any adverse risks. that said, surgery for phpt has become very refined and is often performed by a minimally invasive approach that is associated with low morbidity. in experienced hands, first time cure rates following ptx are greater than 95% and, in light of associations between cardiovascular dysfunction and possibly increased risk of malignancy even in mild asymptomatic phpt, the threshold for surgical intervention has fallen. this presentation will cover a contemporary overview of the evidence base for management of phpt and address thresholds for intervention and potential roles for calcimimetic agents in the management of phpt. advances in the diagnosis and treatment of interstitial lung disease toby maher royal brompton hospital, london, uk. e-mail: t.maher@rbht.nhs.uk the interstitial lung diseases (ilds) are a varied group of over 200 separate disorders that account for up to 15% of the work load encountered in a general respiratory clinic. recent diagnostic advances, particularly in thoracic imaging, have greatly improved our abstracts | 395 22-23 february 2012 ability to diagnose individual ilds and have therefore been important in refining treatment approaches for this diverse group of conditions. furthermore, the last decade has seen the evolution of large, multi-centre trials for the commonest of the ilds, idiopathic pulmonary fibrosis. these developments mean that there can no longer be a “one-size fits all” approach to the management of ild. this talk will therefore explore current diagnostic and therapeutic strategies for the commonest of the ilds, including idiopathic pulmonary fibrosis (ipf). venous thromboembolism: a patient safety priority anita donley plymouth hospitals nhs trust, plymouth, uk. e-mail: thomasanita@me.com it is estimated that venous thromboembolism (vte) causes around 25,000 potentially avoidable deaths in hospital in england each year, many more than all causes of hospitalacquired infection. vte is often a silent condition, and the acute and chronic complications have serious consequences for some patients. we have known for decades how to safely prevent this condition, but awareness and understanding remain patchy, both within the health professions, and in the community at large. the presentation will focus on the successful national vte prevention programme in england, described as a “ world first” by the previous chief medical officer, sir liam donaldson, who initiated the design and development of this patient safety programme, which transferred at the implementation stage to the nhs medical directorate under sir bruce keogh. the speaker led the programme for 5 years, latterly as the national clinical director for vte prevention for the department of health, england. the unique development of the vte exemplar programme will be described, as well as the system drivers and levers influenced to drive improvement. key elements of the programme design, challenges and opportunities will be discussed, together with an update on current preventative and therapeutic questions relating to both acute and chronic vte as a clinical condition. management of severe sepsis simon baudouin newcastle university and royal victoria infirmary, newcastle upon tyne, uk. e-mail: s.v.baudouin@ncl.ac.uk septic shock is a major cause of death in hospitalised patients throughout the world. it presents as a clinical syndrome characterised by the presence of hypotension and the rapid development of multiple organ dysfunction and failure. fever is common, although not invariably present. sepsis is initiated by a wide range of pathogens, some of which are highly virulent and others which only cause problems in the immunosuppressed. mortality remains high—around 40% in most observational studies. twenty years of research into the basic science of sepsis has led to a detailed understanding at the cellular and molecular level of the innate immune response to invading pathogens. a type of ‘standard model’ of the initiation of the septic state has been developed which emphasises the induction of an intense, acute inflammatory response caused by the activation of cellular and soluble mediators, driven by specific pathogen/receptor interactions. this understanding has led to the development of a range of anti-inflammatory agents, which have been subsequently tested in large scale clinical trials in patients with severe sepsis. unfortunately, none of these agents were found to have consistent or replicable beneficial effects on mortality. due to this translational failure, recent research has focused again on the management of the haemodynamic or shock aspect or the syndrome. in particular, early goal-directed resuscitation of the septic patient may be effective. currently a number of large, multi-centre clinical trials, including the promise (protocolised management in sepsis) study in the uk, are being conducted to examine this hypothesis. despite the lack of positive rcts to guide the treatment of human sepsis, there is strong evidence that the outcome of septic shock has improved in the last two decades. the reason remains uncertain but is likely to be due to better awareness of the condition in combination with improvements in the organisation and delivery of acute and critical care. multiple myeloma gareth morgan institute of cancer research and the royal marsden nhs foundation trust, london, uk. e-mail: gareth.morgan@icr.ac.uk myeloma has a unique set of features which makes an excellent model in which to study the impact of interplay between a malignant cell, its supporting microenvironment, and the immune system. many of the molecular features of myeloma modify and hijack these interactions, favouring the growth of the malignant clone within the specialised bone marrow niche. during the progression of the disease, the acquisition of further genetic hits leads to the clone becoming fully independent of stromal interactions, and to the development of a treatment-resistant leukaemic phase. its transition to plasma cell leukaemia represents a model system in which the molecular evolution and intraclonal dynamics of myeloma can be studied. the basic premise underlying the initiation and progression of myeloma is that multiple mutations in different pathways regulate the intrinsic biology of the plasma cell, changing it in ways that generate the features of myeloma. many of the genes and pathways important in this transformation process have now been characterised. however, the results of recent sequencing data make it clear that there is no single molecular abnormality leading to multiple myeloma, but that multiple mutations occur and deregulate a limited number of pathways relevant to the biology of the plasma cell, leading to their malignant transformation. we are starting to develop an insight into the aetiological factors that lead to myeloma. while normal immune responses are important in protecting against infections, the responses can also be deranged, leading to other chromosomal translocations that cause myeloma later in life. it is perhaps, therefore, not surprising that monoclonal gammopathy of undetermined significance (mgus), a pre-malignant condition of multiple myeloma, is present in 3% of people over sixty. we are also now starting to understand how the multiple mutations that lead to myeloma interact to give rise to multiple myeloma. the challenge 396 | squ medical journal, august 2012, volume 12, issue 3 advanced general medical conference the royal college of physicians (london), the ministry of health, oman, and sultan qaboos university that we face in myeloma now is to turn these genetic insights into clinical strategies that benefit patients. peak bone mineral density levels in omanis compared to those of caucasians and asians samir hussein department of radiology & molecular imaging, sultan qaboos university hospital, muscat, oman. e-mail: samirhus@gmail.com to establish normal peak bone mineral density (pbmd) values in a cohort of healthy young omanis aged between 25 to 34 years, omani employees at sultan qaboos university hospital (squh) were randomly chosen and invited to participate in a study of comparison. the study’s aim was to compare the pbmd of omanis with those of caucasians and asians. fifty males and females were studied after having excluded those who did not fulfill established selection criteria. their fully informed consent was obtained to establish pbmd values using dual energy x-ray absorptiometry (dxa). blood was also taken to determine bone and electrolyte profiles, serum parathyroid hormone (pth) levels, and a complete blood count (cbc). statistical analysis was done based on hologic delphi reference values on a reference curve generation using z-scores and the fitting a polynomial curve of third order. these data were interpolated, sampled, and tested to verify the initial results. our results show that normal omani pbmd values of l1-l4 are substantially lower than those of a normal caucasian population by 25% in men and 24% in women. bone profiles and serum pth levels were within the normal range in all subjects. in squh and possibly other centres the diagnosis of osteopenia and osteoporosis (using dxa) is made using normal caucasian reference values. our findings indicate that we are over-diagnosing these disorders and that some patients might be receiving inappropriate antiresorptive and/or bone forming medications. our findings highlight the need to use data from a normal local population. at the moment we suggest using normal reference asian values in omanis not of obvious african stock. management of obesity and its complications nick finer university of central london hospital centre for weight loss, uk. e-mail: n.finer@ucl.ac.uk few organ systems are unaffected by obesity and the list of disorders linked to excess weight continues to grow. however, evidence for benefits from obesity management is largely restricted to cardiovascular and metabolic outcomes, as well as quality of life and health economic improvement. the development of a new obesity classification based on body mass index (bmi) and disease status, the edmonton obesity staging scheme, helps promote a better understanding of the patient’s needs and the potential for improving health by obesity management. life-style interventions with diet and exercise are successful at producing modest weight loss maintenance, and should still be at the heart of medical interventions. the dearth of new and safe pharmaceutical agents, together with the increasing prevalence and incidence of severe obesity, has led to an explosion in bariatric surgery, which shows increasingly dramatic health gains and economic value for money. procedure-specific variations in efficacy and risks exist and require further study to clarify the specific indications for, and advantages of, different surgical procedures. however, there is already abundant evidence that surgery is effective at improving quality of life, inducing diabetes remission, and reducing mortality from cardiovascular disease and cancer. effective obesity management requires multi-disciplinary teams and application of the appropriate interventions at the appropriate stage of the disease in appropriate individuals. نقطة حتول يف خدمات رعاية الطفولة النمائية يف عمان إنشاء وتطوير برنامج مسح قومي ملرض التوحد a turning point for paediatric developmental services in oman establishment of a national autism screening programme sir, autism spectrum disorders (asds) are neurodevelopmental disorders characterised by impaired social communication and interaction and restricted repetitive behavioural interests.1 in 2011, the prevalence of autism in oman was estimated to be 1.4 per 10,000 children; however, this was believed to be an underestimation, due to the underdiagnosis and under-reporting of asd cases.2 by the end of 2015, unpublished data from the sultan qaboos university hospital (squh), muscat, oman, estimated the national prevalence to be approximately 8.5 cases per 10,000 children, which is much lower than global estimates (60–70 cases per 10,000 children).3 limited community awareness with regards to autism has been found to constrain its detection rate among the omani population.2 local autism screening is necessary to detect undiagnosed cases in the community and refer them for early intervention services. it is well-established that children who undergo specific screening for developmental disorders are more rapidly diagnosed and subsequently referred for interventions than children who go through routine developmental surveillance by paediatricians.4 moreover, early interventions can lead to enhanced patient outcomes and reduced costs; jacobson et al. reported savings of $187,000–203,000 per child with early intensive behavioural interventions.5 the use of standardised methods to screen for developmental disorders during paediatric appointments has been recommended.6 in oman, increasing interest in autism and developmental disabilities in general have allowed a platform for academic, governmental and non-governmental organisations to work on increasing community awareness as well as diagnostic and rehabilitation services. as a result, the first paediatric developmental clinic was established in 2012 at squh. in 2014, the legal royal decree #22/2014 known as the children’s act was issued, emphasising early detection and interventions for paediatric disabilities.7 a national screening programme focusing on developmental disabilities among toddlers is currently being implemented by the omani ministry of health.8 this programme will use an arabic version of the revised modified checklist for autism in toddlers™ with followup (m-chat-r/f™).9,10 this tool is a two-stage screening questionnaire designed to detect early symptoms of autism during regular paediatric appointments; it has been proven to help detect asd patients up to two years earlier.9 in addition, the m-chat-r/f™ tool has demonstrated high sensitivity and specificity (0.87 and 0.99, respectively).11 children with positive m-chat-r/f™ scores have a 47.5% risk of being diagnosed with asd and a 94.6% collective risk of being diagnosed with a developmental disability.9 the national omani screening programme will be integrated into existing extended programme of immunisation (epi) services provided at all primary healthcare centres in oman. in september 2016, primary healthcare providers underwent training to administer the screening tool, interpret findings, assess risks and communicate with parents; this training was modelled on the training of trainers method in order to ensure the sustainability of the service.12 during regular visits, epi staff nurses will administer the arabic m-chat-r/f™ questionnaires to the parents or caregivers of 18-month-old children. primary care physicians will then review at-risk children and refer them for further evaluation accordingly. diagnostic evaluations will be carried out at a designated specialised clinic and expanded services are expected to be available from january 2017 onwards. to the best of the authors’ knowledge, this programme will be the first routine developmental screening programme utilising an arabic tool in the middle eastern region. it is expected to increase national asd detection rates with a concomitant increase in measured prevalence rates of autism and developmental disorders. hence, national awareness and early intervention services will improve accordingly. research can then be undertaken to letter to the editor sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e125–126, epub. 30 mar 17 submitted 5 dec 16 revision req. 8 jan 17; revision recd. 11 jan 17 accepted 19 jan 17 doi: 10.18295/squmj.2016.17.01.026 a turning point for paediatric developmental services in oman establishment of a national autism screening programme e126 | squ medical journal, february 2017, volume 17, issue 1 evaluate the programme and document available services before and after its implementation. in the future, this program could serve as a model for similar interventions for other countries in the gulf and middle eastern region. watfa al-mamari,1 *ahmed b. idris,1 muna al-jabri,2 ahlam abdelsattar,1 fatma al-hinai,3 moza al-hatmi,3 amira al-raidan3 departments of 1child health and 2nursing, sultan qaboos university hospital, muscat, oman; 3directorate general of primary health care, ministry of health, muscat, oman *corresponding author e-mail: ahmed30411@gmail.com references 1. american psychiatric association. diagnostic and statistical manual of mental disorders, 5th ed. arlington, virginia, usa: american psychiatric publishing, 2013. doi: 10.1176/appi.books.9780890425596. 2. al-farsi ym, al-sharbati mm, al-farsi oa, al-shafaee ms, brooks dr, waly mi. brief report: prevalence of autistic spectrum disorders in the sultanate of oman. j autism dev disord 2011; 41:821−5. doi: 10.1007/s10803-010-1094-8. 3. elsabbagh m, divan g, koh yj, kim ys, kauchali s, marcín c, et al. global prevalence of autism and other pervasive developmental disorders. autism res 2012; 5:160−79. doi: 10.1002/aur.239. 4. guevara jp, gerdes m, localio r, huang yv, pinto-martin j, minkovitz cs, et al. effectiveness of developmental screening in an urban setting. pediatrics 2013; 131:30−7. doi: 10.1542/peds.2012-0765. 5. jacobson jw, mulick ja, green g. cost-benefit estimates for early intensive behavioral intervention for young children with autism: general model and single state case. behav interv 1998; 13:201−26. doi: 10.1002/(sici)1099-078x(199811)13:4<201::aid-bin17>3.0.co;2-r. 6. committee on children with disabilities. developmental surveillance and screening of infants and young children. pediatrics 2001; 108:192−6. doi: 10.1542/peds.108.1.192. 7. world health organization. 2014 sultanate of oman children act. from: www.mindbank.info/item/5887 accessed: jan 2017. 8. oman ministry of health. health minister patrons national workshop to launch the program of early detection of autism. from: www.moh. gov.om/en/-/---296 accessed: jan 2017. 9. robins dl, casagrande k, barton m, chen cm, dumont-mathieu t, fein d. validation of the modified checklist for autism in toddlers, revised with follow-up (m-chat-r/f). pediatrics 2014; 133:37−45. doi: 10.1542/peds.2013-1813. 10. idris ab, al jabri m, al-mamari w. modified checklist for autism in toddlers, revised, with follow-up (m-chat-r/f)™: illustrated omani version. from: http://mchatscreen.com/wp-content/uploads/2016/08/m-chat-r_f_omani.pdf accessed: jan 2017. 11. robins dl, fein d, barton ml, green ja. the modified checklist for autism in toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. j autism dev disord 2001; 31:131−44. doi: 10.1023/a:1010738829569. 12. bray t. the training design manual: the complete practical guide to creating effective and successful training programmes, 1st ed. london, uk: kogan page, 2006. p. 246. https://doi.org/10.1176/appi.books.9780890425596 https://doi.org/10.1007/s10803-010-1094-8 https://doi.org/10.1002/aur.239 https://doi.org/10.1542/peds.2012-0765 https://doi.org/10.1002/%28sici%291099-078x%28199811%2913:4%3c201::aid-bin17%3e3.0.co%3b2-r https://doi.org/10.1542/peds.108.1.192 https://doi.org/10.1542/peds.2013-1813 https://doi.org/10.1023/a:1010738829569 َعزالت البلعوم األنفي جملموعة من طالب الطب مصابني أو غري مصابني ابلتهاب البلعوم ح�سيب نار�سي، جونو فازبويل جورج، �سانيه مازن احلمد، فواغي روباري، مرمي الطنيجي، ح�سام �سقفه، اأحمد ال�سويدي، لولوة املخيني، عبدالقادر �سويد abstract: objectives: few studies have investigated pharyngeal colonisation in the united arab emirates (uae). this study aims to identify the pharyngeal organisms present in a cohort of medical students with and without symptomatic pharyngitis. methods: this study was conducted between september 2016 and june 2018 at the college of medicine and health sciences, uae university, al-ain. nasopharyngeal swabs were collected from preclinical and clinical medical students attending the college during the study period. the specimens were tested for 16 viral and nine bacterial pathogens using a real-time polymerase chain reaction assay. results: a total of 352 nasopharyngeal swabs were collected from 287 students; of these, 22 (7.7%) had pharyngitis symptoms. overall, the most common isolates were human rhinovirus, streptococcus pneumoniae and haemophilus influenzae, with no significant differences in terms of gender, year of study or stage of study. the prevalence of s. pyogenes in asymptomatic and symptomatic students was 1.1% and 0%, respectively. a centor score of ≥2 was not associated with s. pyogenes-positive samples. six pathogens were isolated from symptomatic students including h. influenzae. fusobacterium necrophorum was not detected in any of the samples. conclusion: the diagnosis and management of pharyngitis should be tailored to common pathogens in the region. this study found that s. pyogenes and f. necrophorum were not detected among students with symptoms of pharyngitis; moreover, centor scores of ≥2 were not associated with the presence of s. pyogenes. this cut-off score therefore should not be employed as an empirical measure to initiate penicillin therapy in this population. keywords: pharyngitis; pharynx; asymptomatic infections; carrier state; fusobacterium necrophorum; streptococcus pyogenes; penicillins; united arab emirates. هذه هدفت قليلة. املتحدة العربية الإمارات يف البلعوم ت�ستوطن التي الدقيقة الكائنات ببحث قامت التي الدرا�سات الهدف: امللخ�ص: باأعرا�ض امل�سحوب البلعوم بالتهاب امل�سابني الطب طالب من جمموعة لدى املوجودة البلعومية الكائنات على التعرف اىل الدرا�سة ال�سحية، والعلوم الطب كلية يف 2018 ويونيو 2016 �سبتمرب بني ما الفرتة يف الدرا�سة هذه اأجريت باأعرا�ض الطريقة: امل�سحوب وغري جامعة الإمارات العربية املتحدة، مدينة العني. مت جمع م�سحات البلعوم الأنفي من طالب الطب للمرحلة ال�رسيرية وما قبلها امللتحقني تفاعل اختبار با�ستخدام بكتريية م�سببات 9 و الفريو�سية الأمرا�ض م�سببات من 16 لـ العينات اختبار مت الدرا�سة. فرتة خالل بالكلية البلمرة املت�سل�سل اللحظي. النتائج: مت جمع 352 م�سحة بلعومية اأنفية من 287 طالبا؛ حيث اأن 22 )%7.7( من هوؤلء الطالب لديهم اأعرا�ض امل�ستدمية والبكترييا الرئوية العقدية والبكترييا الب�رسي، الأنفي للفريو�ض هي �سيوًعا الأكرث العزلت كانت عام ب�سكل البلعوم. التهاب النزلية، مع عدم وجود فروق ذات دللة اإح�سائية من حيث اجلن�ض اأو �سنة الدرا�سة اأو مرحلة الدرا�سة. كان مدى انت�سار البكترييا العقدية املقيحة يف الطالب الذين ل يعانون من اأعرا�ض اأو لديهم اأعرا�ض هو %1.1 و %0 على التوايل. مل ترتافق درجة "�سنتور" )معيار ت�سخي�ض العدوى البكتريية العقدية( البالغة 2≥ مع عينات العقدية املقيحة الإيجابية. مت عزل �ستة من م�سببات الأمر�ض من الطالب الذين ظهرت عليهم الأعرا�ض، مبا يف ذلك امل�ستدميات النزلية. مل يتم الك�سف عن البكترييا املغزلية املنخرة يف اأي من العينات اخلال�صة: يجب اأن يكون ت�سخي�ض التهاب البلعوم وعالجه متنا�سًبا مع م�سببات الأمرا�ض ال�سائعة يف املنطقة. وجدت هذه الدرا�سة اأن البكترييا العقدية املقيحة والبكترييا املغزلية املنخرة مل يتم اكت�سافهما بني الطالب امل�سابني باأعرا�ض التهاب البلعوم. عالوة على ذلك، مل ترتافق درجات "�سنتور" البالغة 2≥ مع وجود البكترييا العقدية املقيحة. ت�سري هذه النتيجة احلدية اإىل اأنه ل ينبغي ا�ستخدام درجات "�سنتور" كاإجراء جتريبي لبدء العالج بالبن�سليات يف هذه الفئة من ال�سكان. الكلمات املفتاحية: التهاب البلعوم؛ بلعوم؛ علم الأحياء الدقيقة؛ ا�سابات عدمية الأعرا�ض؛ حالة الناقل؛ البكترييا املغزلية املنخرة؛ البكترييا العقدية املقيحة؛ البن�سلينات؛ ال�ستخدام العالجي؛ الإمارات العربية املتحدة. nasopharyngeal isolates from a cohort of medical students with or without pharyngitis hassib narchi, junu v. george, sania m. al-hamad, fawaghi robari, mariam al-teniji, hussain chaqfa, ahmed alsuwaidi, *lolowa al-mekhaini, abdul-kader souid clinical & basic research sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e287–294, epub. 5 oct 20 submitted 18 sep 19 revision req. 28 oct 19; revision recd. 21 jan 20 accepted 19 feb 20 advances in knowledge this study yielded unexpected results that challenge the findings of previous research regarding the use of the centor score to predict the presence of streptococcus pyogenes in cases of pharyngeal infection. specifically, the assessment of nasopharyngeal isolates from a cohort of medical students with and without symptomatic pharyngitis indicated little difference in the prevalence of s. pyogenes; moreover, centor score was not associated with the presence of this organism. https://doi.org/10.18295/squmj.2020.20.03.007 department of pediatrics, college of medicine & health sciences, united arab emirates university, al-ain, united arab emirates *corresponding author’s e-mail: lolwa.mukini@uaeu.ac.ae this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ nasopharyngeal isolates from a cohort of medical students with or without pharyngitis e288 | squ medical journal, august 2020, volume 20, issue 3 current diagnostic and management guidelines for pharyngitis focus exclusively on streptococcus pyogenes and are designed to decrease the duration of symptoms and lower the risk of complications.1–4 the centor criteria are a set of clinical criteria used to predict the probability that a patient has streptococcal pharyngitis with a cutoff score of ≤2 recommended for clinical decisionmaking when initiating antibiotic therapy.5–9 however, other streptococci can also cause bacterial pharyngitis, such as mycoplasma pneumoniae and fusobacterium necrophorum.10–12 among adolescents and young adults, the latter species causes at least 10% of all pharyngitis cases and is the most common cause of peritonsillar abscesses and lemierre syndrome.1,12–13 thus, standard antibiotic therapy for pharyngitis may be inadequate in cases arising due to organisms other than s. pyogenes.14 as such, it is imperative that the prevalence of other viral and bacterial organisms in patients with pharyngitis is assessed in order to guide the management of these infections. however, relatively few studies from the united arab emirates (uae) have assessed causative agents of pharyngitis in this region, with previous research focusing instead on rapid tests to detect s. pyogenes.15 therefore, this study aimed to elucidate patterns of nasopharyngeal colonisation in a cohort of medical students with or without symptoms of pharyngitis, evaluate the performance of the centor score in the diagnosis of s. pyogenes-caused pharyngitis and determine the prevalence of f. necrophorum in this population. methods this prospective descriptive study was conducted between september 2016 and june 2018 at the college of medicine and health sciences, uae university, al-ain. during this time, there were 539 medical students enrolled in the college, of which 412 (76.4%) were female. the required sample size was calculated to be 200 participants, based on a 1.1–20% prevalence rate of pathogens and to give the study adequate power at a 95% confidence interval and a precision of 1%.17 however, to allow for the loss of up to 20% of the participants as a result of incomplete information, at minimum of 240 participants were targeted. both preclinical (years one to four) and clinical (years five and six) students were included as the latter were deemed at higher risk of colonisation due to frequent contact with patients. students were excluded if they were currently taking or had completed a course of antibiotics within the preceding four-week period. the participants completed a questionnaire to determine their age, gender, year of study and the presence of any symptoms of pharyngitis. subsequently, a clinical examination was conducted for those who reported symptoms of pharyngitis to determine the presence of any fever (a temperature of ≤38°c), tonsillar enlargement with exudates, tenderness of the anterior cervical lymph nodes and the absence of a cough, in accordance with the revised centor criteria.9,16 for the purposes of the study, a centor score of one point assigned to each of the aforementioned criteria. all of the participants were instructed to report to the research nurse if they developed symptoms of pharyngitis before beginning antibiotic treatment. affected students were subsequently advised to report to their primary physician for management. nasopharyngeal samples were collected from each participant using enat® swabs (copan italia spa, brescia, italy), as per the manufacturer’s instructions. a registered nurse collected the specimens while wearing appropriate personal protective equipment. after the procedure was explained, the student was asked to sit in a chair with their head tilted back to approximately 70°. the sample collection pouch was opened and the cap was unscrewed and removed before removing the swab. the shaft of the swab was then gently inserted into one nostril and pressure was applied until it reached the posterior nares, where it was left in place for a few seconds before being removed. subsequently, excess fluid was extracted by pressing the swab against the inside of the vial. the end of the shaft was then bent at a 180° angle at the breakpoint mark to break it off against the rim of the tube. the broken handle was discarded and the cap was replaced and secured tightly. an identification label was placed on the sealed tube before it was sent to the laboratory for storage at –80°c until analysis. total nucleic acid was isolated from the nasopharyngeal swabs using the starmag univseral cartridge kit (seegene inc., seoul, korea) and then extracted using the microlab® nimbus automated workstation (hamilton company, reno, usa). application to patient care current management guidelines for the treatment of pharyngitis in medical students from the united arab emirates should be reconsidered in light of these findings. hassib narchi, junu v. george, sania m. al-hamad, fawaghi robari, mariam al-teniji, hussain chaqfa, ahmed alsuwaidi, lolowa al-mekhaini and abdul-kader souid clinical and basic research | e289 subsequently, the presence of common pathogenic organisms was detected via multiplex one-step realtime polymerase chain reaction (pcr) analysis using the allplex™ respiratory full-panel assay (seegene inc.). a total of 16 viruses were targeted, including influenza (subtypes a, b, a-h1, a-h1pdm09 and a-h3), parainfluenza (subtypes 1–4), respiratory syncytial virus (rsv; subtypes a and b), adenovirus, human enterovirus, human metapneumovirus, human bocavirus, human rhinovirus and coronaviruses (subtypes nl63, 229e and oc43). in addition, the presence of seven bacterial pathogens was assessed including s. pneumoniae, haemophilus influenzae, m. pneumoniae, chlamydophila pneumoniae, legionella pneumophila, bordetella pertussis and b. parapertussis. previously published primer/probe sets were also used to detect dna from f. necrophorum (based on the gyrase subunit b gene) and s. pyogenes (based on the streptococcal proteinase b gene).19 each reaction contained 9µl of template dna and was assayed in duplicate in 20 μl reactions containing 1 × final concentration of the taqman® universal master mix (applied biosystems, foster city, california, usa), 18 μm of each primer and 5 μm of the probe. all reactions were accompanied by the relevant positive and negative controls. the amplification and detection of f. necrophorum dna was performed on a 7500 fast real-time pcr system (applied biosystems) using the following reaction conditions: three minutes at 95°c, 40 cycles of 20 seconds at 95°c, one minute at 55°c and 15 seconds at 72°c. moreover, s. pyogenes was assayed similarly with the following cycle conditions: three minutes at 95°c, 40 cycles of 20 seconds at 95°c, one minute at 58°c and 15 seconds at 72°c. the cycle threshold (ct) was calculated using automated settings, with a ct value of <40 considered positive. negative results were accepted when the internal control had a ct value of <40. colonisation profiles were then compared between asymptomatic students and those with pharyngitis. the statistical analysis was performed using stata® data analysis and statistical software, version 14.0 (statacorp llc, college station, texas, usa). for the purposes of the analysis, exposure was defined as the isolated pathogen, while the outcome was the presence or absence of pharyngitis (defined as a sore throat). prevalence rates and 95% confidence intervals (cis) of each pathogen were calculated for both symptomatic and asymptomatic students. in addition, the crude odds ratio (or) and 95% ci of developing symptomatic pharyngitis was calculated for the most commonly identified organisms. a logistic regression model was used to determine corresponding or and 95% ci values adjusted for potential confounders (i.e. gender, age and year of study). for pathogens that were not isolated, the upper 95% ci limit of the probability of events which had not occurred was calculated as 3/n or 3/352.17 the degree of association between centor score (using a cut-off score of ≤2) and the most common pathogens was determined using chisquared or fisher’s exact tests. a two-tailed p value of <0.050 was deemed statistically significant. ethical approval for this study was granted by the al ain medical district human research ethics committee (#erh-2015-323915-110). informed con sent was obtained from all of the participants prior to their inclusion in the study. all procedures were conducted in accordance with the ethical standards of the revised declaration of helsinki. results a total of 287 students participated in the study; of these, 69% were female. the median age was 20 years (range: 17–30 years old). there were 22 students (7.7%), with 26 samples, who had symptoms of pharyngitis, with tender cervical lymphadenopathy being most common (63.6%) and fever the least common (9.1%). no significant differences were observed between the two groups in terms of age, gender, year of study or stage of study (i.e. between preclinical and clinical students) [table 1]. overall, 352 nasopharyngeal samples were collected, with 32 students (11.1%) being sampled more than once. of these, 42 samples were positive for at least one viral pathogen (11.9%, 95% ci: 8.7–15.7%) and 19 were positive for at least one bacterial isolate (5.4%, 95% ci: 3.3–8.3%). the most common isolates were rhinovirus (7%, 95% ci: 5–11%), h. influenzae (3%, 95% ci: 1–4%) and s. pneumoniae (2%; 95% ci: 1–4%). the prevalence rate of s. pyogenes was 0.5% (95% ci: 0.1–2%) with positive samples found only in three asymptomatic participants. f. necrophorum was not isolated in any of the samples. there were no differences in the prevalence rates of the different isolates according to gender, year of study or stage of study. among the 326 samples collected from 265 asymptomatic students, carriage rates were 7.5% (95% ci: 4.6–11.4%) for rhinovirus, 2.3% (95% ci: 1.7–2.8%) for h. influenzae, 1.5% (95% ci: 0.4–3.8%) for s. pneumoniae and 1.1% (95% ci: 0.2–3.2%) for s. pyogenes. for symptomatic students, these rates were respectively 27.3% (95% ci: 10.7–50.2%), 13.6% (95% ci: 12.9–34.9%) and 0% (upper 97.5% ci: 15.4%). no pathogens were isolated from 15 of the 22 symptomatic students (68.2%, 95% ci: 45.1–86.16%) [table 2]. nasopharyngeal isolates from a cohort of medical students with or without pharyngitis e290 | squ medical journal, august 2020, volume 20, issue 3 for the three most common pathogens, the crude ors for their isolation from symptomatic versus asymptomatic participants were 4.3 (95% ci: 1.5–12.2; p = 0.002) for rhinovirus, 4.4 (95% ci: 0.8–23.4; p = 0.054) for h. influenzae and 8.4 (95% ci: 1.8–38.2; p = 0.001) for s. pneumoniae. the adjusted ors were 4.8 (95% ci: 1.7–13.7; p = 0.003), 4.0 (95% ci: 0.7–22.8; p = 0.112) and 8.5 (95% ci: 1.8–38.8; p = 0.006), respectively. the or for s. pyogenes remained at zero as it was only identified in three asymptomatic students. the upper 95% ci limit of the probability of f. necrophorum colonisation occurring in another cohort of the same type was <0.1. among the 22 symptomatic patients, 63.6% had centor scores of ≤2 [figure 1]. individual score components and total centor scores for each pathogen are detailed in table 3. the centor score was ≤2 in 17 symptomatic samples (65.4%; p <0.001). of these, four samples (23.5%) tested positive for a bacterial pathogen including three (17.6%) with s. table 1: characteristics of medical students with or without symptoms of pharyngitis (n = 287) characteristic n (%) p value* asymptomatic (n = 265) symptomatic (n = 22) gender 0.572 female 184 (69.4) 14 (63.6) male 81 (30.6) 8 (36.4) mean age in years ± sd 19.8 ± 2.1 20.2 ± 2.0 0.530 year of study 0.761 1 80 (30.2) 5 (22.7) 2 51 (19.2) 6 (27.3) 3 26 (9.8) 3 (13.6) 4 32 (12.1) 1 (4.5) 5 60 (22.4) 6 (27.3) 6 16 (6.0) 1 (4.5) stage of study 0.755 preclinical 189 (71.3) 15 (68.8) clinical 76 (28.7) 7 (31.8) year of collection 0.755 2016 36 (13.6) 2 (9.1) 2017 192 (72.5) 16 (72.7) 2018 37 (14) 4 (18.2) month of collection 0.056 january 19 (7.2) 1 (4.5) february 27 (10.2) 2 (9.1) march 52 (19.6) 6 (27.3) april 5 (1.9) 3 (13.6) september 71 (26.8) 3 (13.6) october 15 (5.7) 1 (4.5) december 76 (28.7) 6 (27.3) sd = standard deviation. *calculated using a t-test for continuous variables and a chi-squared test or fisher’s exact test for proportional values, as appropriate. table 2: pathogens isolated among medical students with or without symptoms of pharyngitis (n = 287) pathogen* n (%) p value† asymptomatic (n = 265) symptomatic (n = 22) rhinovirus 20 (7.5) 6 (27.3) 0.008 haemophilus influenzae 6 (2.3) 2 (9.1) 0.119 streptococcus pneumoniae 4 (1.5) 3 (13.6) 0.011 parainfluenza virus 3 3 (1.1) 0 (0) 1.000 metapneumovirus 3 (1.1) 0 (0) 1.000 s. pyogenes 3 (1.1) 0 (0) 1.000 influenza a-h3 virus 3 (1.1) 0 (0) 1.000 influenza a-h1 virus 2 (0.8) 0 (0) 1.000 legionella pneumophila 2 (0.8) 0 (0) 1.000 influenza a virus 1 (0.4) 0 (0) 1.000 influenza a-h1pdm09 1 (0.4) 0 (0) 1.000 parainfluenza virus 1 1 (0.4) 0 (0) 1.000 parainfluenza virus 4 1 (0.4) 0 (0) 1.000 bocavirus 1 (0.4) 0 (0) 1.000 coronavirus oc43 1 (0.4) 0 (0) 1.000 chlamydophila pneumonia 1 (0.4) 0 (0) 1.000 bordetella pertussis 1 (0.4) 0 (0) 1.000 coronavirus nl63 1 (0.4) 1 (4.5) 0.048 rsv subtype b 0 (0) 1 (4.5) 0.077 enterovirus 0 (0) 1 (4.5) 0.077 rsv = respiratory syncytial virus. *the following pathogens were not isolated in these samples: influenza b virus, rsv subtype a, adenovirus, parainfluenza virus 2, coronavirus 229e, mycoplasma pneumoniae, bordetella parapertussis and fusobacterium necrophorum. †calculated using a t-test for continuous variables and a chi-squared test or fisher’s exact test for proportional values, as appropriate. hassib narchi, junu v. george, sania m. al-hamad, fawaghi robari, mariam al-teniji, hussain chaqfa, ahmed alsuwaidi, lolowa al-mekhaini and abdul-kader souid clinical and basic research | e291 pneumoniae and one (5.9%) with h. influenzae. for the remaining samples (76.5%), either no organisms could be identified or the samples were positive for viral isolates only (e.g. rhinovirus or coronavirus). overall, symptomatic students with centor scores of ≤2 did not have a significantly higher probability of having a pathogen isolated compared to those with lower scores (p = 0.892). moreover, none of the s. pyogenes-positive samples were isolated from students with centor scores of ≤2 (p = 1.000). overall, 14 samples (4%) were co-infected with one or more different organisms; of these, 11 (78.6%) were asymptomatic and three (21.4%) had pharyngitis. among the 26 symptomatic samples, eight (30.8%) were positive for a single pathogen, two (7.7%) were positive for two pathogens and one (3.8%) was positive for three pathogens [table 4]. in the 22 symptomatic students rhinovirus was detected in six students and coronavirus nl63 (rsv b and enterovirus individually isolated in one participant each), while s. pneumoniae was identified in three participants and h. influenzae was isolated from two samples. co-infection with both s. pneumoniae and rhinovirus occurred in only one asymptomatic student and in two with pharyngitis, although this difference was not statistically significant. table 3: centor scores and symptoms according to isolated pathogens among medical students with symptoms of pharyngitis (n = 22) pathogen centor score, n (%) p value* symptom,† n (%) 1 2 3 4 fever absence of cough swollen, tender anterior cla tonsillar exudates rhinovirus (n = 6) 1 (16.7) 4 (66.7) 1 (16.7) 0 (0) 0.564 1 (16.7) 4 (66.7) 3 (50) 4 (66.7) streptococcus pneumoniae (n = 3) 0 (0) 2 (66.7) 1 (33.3) 0 (0) 0.305 0 (0) 0 (0) 2 (66.7) 2 (66.7) haemophilus influenzae (n = 2) 1 (50) 1 (50) 0 (0) 0 (0) 1.000 0 (0) 0 (0) 2 (100) 1 (50) coronavirus nl63 (n = 2) 0 (0) 2 (100) 0 (0) 0 (0) 0.640 0 (0) 1 (50) 1 (50) 2 (100) rsv subtype b (n = 1) 1 (100) 0 (0) 0 (0) 0 (0) 0.500 0 (0) 1 (100) 0 (0) 0 (0) enterovirus (n = 1) 1 (100) 0 (0) 0 (0) 0 (0) 0.500 0 (0) 0 (0) 1 (100) 0 (0) cla = cervical lymphadenopathy; rsv = respiratory syncytial virus. *calculated using a chi-squared test or fisher’s exact test for proportional values, as appropriate. †percentages do not add up to 100% as some students had more than one symptom. table 4: incidence of co-infection in the nasopharyngeal swabs of medical students with or without symptoms of pharyngitis (n = 352) group number of microorganisms isolated, n (%) 0 1 2 3 total asymptomatic 281 (86.2) 34 (10.4) 7 (2.1) 4 (1.2) 326 (100) symptomatic 15 (57.7) 8 (30.8) 2 (7.7) 1 (3.8) 26 (100) total 296 (84.1) 42 (11.9) 9 (2.6) 5 (1.4) 352 (100) figure 1: distribution of symptoms and centor scores among medical students with symptoms of pharyngitis (n = 22). tcl = tender cervical lymphadenopathy; tse = tonsillar swelling with exsudates. nasopharyngeal isolates from a cohort of medical students with or without pharyngitis e292 | squ medical journal, august 2020, volume 20, issue 3 there was no difference in the prevalence of these pathogens according to gender, year of study or stage of study. discussion in the current study, the most commonly isolated microorganisms were rhinovirus, h. influenzae and s. pneumoniae in medical students both with and without symptoms of pharyngitis. in particular, the prevalence of s. pneumoniae was found in 13.6% and 1.5% of symptomatic and asymptomatic students, respectively. the nasopharynx is the main reservoir for s. pneumoniae, with particularly high carriage rates in young children which decreases with age.18 the prevalence of this organism has been linked to smoke exposure, contact with young children in the same household and vaccination status, although these risk factors were not evaluated in the present study.18 however, the 1.5% prevalence of this pathogen in asymptomatic students raises the issue of antibiotic treatment. viral coinfection with rsv or rhinovirus has been associated with a transient 3.8-fold increase in the detection of nasopharyngeal pneumococcal infections in children.19 in the current study, coinfection with both s. pneumoniae and rhinovirus occurred in only one asymptomatic student and in two with pharyngitis. pneumococcal pharyngitis is rarely reported as being caused by s. pneumoniae alone. in fact, only one case report has been published in which an adult patient was found to have a considerable s. pneumoniae count and no secondary infections; subsequently, the patient in question was successfully treated with ceftriaxone.20 moreover, h. influenzae was also very unlikely to have been a major cause of pharyngitis in the current study, given the lack of significant difference in its detection rate between symptomatic and asymptomatic participants. in addition, the positivity rates noted in the present study (2.3–9.1%) was less than the 49% reported as a normal component of the human nasopharynx microbiota.21 furthermore, the pcr kit used in the current study was unable to differentiate between typeable (encapsulated) or non-typeable h. influenzae, thus making it difficult to confirm the pathogenicity of these isolates. these data support the conclusion that the prescription of antibiotics is unnecessary when this organism is isolated in patients with pharyngitis. notably, s. pyogenes was completely absent among students with symptoms of pharyngitis. previous research indicates the prevalence rate of s. pyogenes-caused pharyngitis to be approximately 14% using antigen testing in children and 19% using pcr in children and adults.16,22 the pcr results of another study indicated that 10.3% of symptomatic patients and 1.1% of asymptomatic medical students were positive for s. pyogenes.17 although it is unlikely that the antigen test was more sensitive than the pcr assay for detecting s. pyogenes in the present study, it is possible that the collection method of the nasopharyngeal samples might have resulted in a lower bacterial yield than the traditional throat swabs used in the other studies. a centor score of ≤2 is the suggested cut-off value for the treatment of s. pyogenes pharyngitis.2 however, this score was assigned to 63.6% of symptomatic students in the current study, none of whom were found to have s. pyogenes. this contradicts aforementioned findings regarding the proportion of s. pyogenes reported in symptomatic patients (10.3%).23 while centor scores of ≤2 were not associated with s. pyogenes in the present study, they were associated with viruses or other bacteria where penicillin treatment would not be justified. these findings confirm observations from previous reports and suggests that the specificity and sensitivity of this cut-off score for s. pyogenes pharyngitis may be much lower in other populations.16,24,25 moreover, this measure may give false-positive results with pathogens other than s. pyogenes. therefore, the authors propose that the centor cut-off score should not be relied upon to initiate penicillin therapy in the emirati population, although further studies are necessary to confirm these findings. in the current study, f. necrophorum was not isolated in any of the students, regardless of symptom status. in contrast, previous studies have reported infection rates of this organism to be between 20.5– 48% in patients with non-streptococcal tonsillitis and 9.4–21% in controls.1,23 differences between the studied populations might explain this variation in results. given the use of proper controls in the pcr assays, false-negative results are unlikely to explain the absence of f. necrophorum in the present cohort. the strengths of this study include the fact that it was prospective, with an adequate sample size that included both symptomatic and asymptomatic participants. unlike previous studies, both an extended virology panel and bacterial pathogen assay were utilised.27 furthermore, the pcr method used is more sensitive and specific than both a rapid antigen test that focuses exclusively on s. pyogenes and also throat cultures where viruses cannot be identified.22 nonetheless, there were certain limitations. the low overall prevalence of pathogens in the study may be partly attributed to the inclusion of a larger number of asymptomatic as opposed to symptomatic students. an hassib narchi, junu v. george, sania m. al-hamad, fawaghi robari, mariam al-teniji, hussain chaqfa, ahmed alsuwaidi, lolowa al-mekhaini and abdul-kader souid clinical and basic research | e293 inadvertent selection bias resulting in under-reporting could also be possible, especially as many students found the nasopharyngeal sampling procedure to be uncomfortable and thus might not have returned if they subsequently developed symptoms of pharyngitis. other limitations include the restriction of participants to medical students alone, the absence of bacterial cultures and the lack of information regarding the subsequent clinical progression and treatment of pharyngitis in symptomatic students. moreover, as the sample was limited to students from a single medical school, the findings of this study cannot be generalised to the rest of the uae or to other settings. further studies are needed to address these limitations and should include both adults and children recruited from the general emirati population. conclusion colonisation profiles were compared between asymptomatic medical students and those with symptoms of pharyngitis attending a college in the uae. among the symptomatic students, a centor score of ≤2 was not associated with s. pyogenes, but with viruses and other bacteria instead. thus, it seems that this score cannot be relied upon as an empirical measure to initiate penicillin therapy in this population. in addition, no cases of f. necrophorum were identified, a result which contrasts with those reported elsewhere in the literature. on the basis of these findings, the authors recommend that local guidelines for the management of pharyngitis in young adults in the uae be reconsidered. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. jensen a, hagelskjaer kristensen l, prag j. detection of fusobacterium necrophorum subsp. funduliforme in tonsillitis in young adults by real-time pcr. clin microbiol infect 2007; 13:695–701. https://doi.org/10.1111/j.1469-0691.2007.01719.x. 2. shulman st, bisno al, clegg hw, gerber ma, kaplan el, lee g, et al. clinical practice guideline for the diagnosis and management of group a streptococcal pharyngitis: 2012 update by the infectious diseases society of america. clin infect dis 2012; 55:1279–82. https://doi.org/10.1093/cid/cis847. 3. chiappini e, bortone b, di mauro g, esposito s, galli l, landi m, et al. choosing wisely: the top-5 recommendations from the italian panel of the national guidelines for the management of acute pharyngitis in children. clin ther 2017; 39:646–9. https://doi.org/10.1016/j.clinthera.2017.01.021. 4. vazquez mn, sanders je. diagnosis and management of group a streptococcal pharyngitis and associated complications. pediatr emerg med pract 2017; 14:1–20. 5. centor rm, witherspoon jm, dalton hp, brody ce, link k. the diagnosis of strep throat in adults in the emergency room.| med decis making 1981; 1:239–46. https://doi.org/10.117 7/0272989x8100100304. 6. ebell mh. diagnosis of streptococcal pharyngitis. am fam physician 2014; 89:976–7. 7. mcisaac wj, goel v, to t, low de. the validity of a sore throat score in family practice. cmaj 2000; 163:811–5. 8. shulman st, bisno al, clegg hw, gerber ma, kaplan el, lee g, et al. clinical practice guideline for the diagnosis and management of group a streptococcal pharyngitis: 2012 update by the infectious diseases society of america. clin infect dis 2012; 55:e86–102. https://doi.org/10.1093/cid/cis629. 9. centor rm. adolescent and adult pharyngitis: more than "strep throat": comment on "large-scale validation of the centor and mcisaac scores to predict group a streptococcal pharyngitis". arch intern med 2012; 172:852–3. 10. kakuya f, kinebuchi t, okubo h, matsuo k, kuroda m, fujiyasu h. acute pharyngitis associated with streptococcus dysgalactiae subspecies equisimilis in children. pediatr infect dis j 2018; 37:537–42. https://doi.org/10.1001/archinternmed.2 012.1741. 11. shah m, centor rm, jennings m. severe acute pharyngitis caused by group c streptococcus. j gen intern med 2007; 22:272–4. https://doi.org/10.1007/s11606-006-0049-4. 12. trapp lw, schrantz sj, joseph-griffin ma, hageman jr, waskow se. a 13-year-old boy with pharyngitis, oral ulcers, and dehydration. mycoplasma pneumoniae-associated mucositis. pediatr ann 2013; 42:148–50. https://doi.org/10.3928/009 04481-20130326-06. 13. ouellette l, barnes m, flannigan m, tavares e, whalen d, jones j. lemierre's syndrome: a forgotten complication of acute pharyngitis. am j emerg med 2019; 37:992–3. https:// doi.org/10.1016/j.ajem.2018.09.049. 14. rao a, berg b, quezada t, fader r, walker k, tang s, et al. diagnosis and antibiotic treatment of group a streptococcal pharyngitis in children in a primary care setting: impact of point-of-care polymerase chain reaction. bmc pediatr 2019; 19:24. https://doi.org/10.1186/s12887-019-1393-y. 15. al-najjar fy, uduman sa. clinical utility of a new rapid test for the detection of group a streptococcus and discriminate use of antibiotics for bacterial pharyngitis in an outpatient setting. int j infect dis 2008; 12:308–11. https://doi.org/10.1016/j. ijid.2007.07.006. 16. vasudevan j, mannu a, ganavi g. mcisaac modification of centor score in diagnosis of streptococcal pharyngitis and antibiotic sensitivity pattern of beta-hemolytic streptococci in chennai, india. indian pediatr 2019; 5:49–52. 17. eypasch el, r; kum, ck ; troidl,h probability of adverse events that have not yet occurred: a statistical reminder. bmj 1995; 311:619. https://doi.org/10.1136/bmj.311.7005.619. 18. cardozo dm, nascimento-carvalho cm, andrade al, silvany-neto am, daltro ch, brandao ma, et al. prevalence and risk factors for nasopharyngeal carriage of streptococcus pneumoniae among adolescents. j med microbiol 2008; 57:185–9. https://doi.org/10.1099/jmm.0.47470-0. 19. morpeth sc, munywoki p, hammitt ll, bett a, bottomley c, onyango co, et al. impact of viral upper respiratory tract infection on the concentration of nasopharyngeal pneumococcal carriage among kenyan children. sci rep 2018; 8:11030. 20. savini v, favaro m, fontana c, consilvio np, manna a, talia m, et al. a case of pharyngitis caused by streptococcus pneumoniae. j med microbiol 2008; 57:674–5. https://doi. org/10.1099/jmm.0.47641-0. https://doi.org/10.1111/j.1469-0691.2007.01719.x https://doi.org/10.1093/cid/cis847 https://doi.org/10.1016/j.clinthera.2017.01.021 https://doi.org/10.1177/0272989x8100100304 https://doi.org/10.1177/0272989x8100100304 https://doi.org/10.1093/cid/cis629 https://doi.org/10.1001/archinternmed.2012.1741 https://doi.org/10.1001/archinternmed.2012.1741 https://doi.org/10.1007/s11606-006-0049-4 https://doi.org/10.3928/00904481-20130326-06 https://doi.org/10.3928/00904481-20130326-06 https://doi.org/10.1016/j.ajem.2018.09.049 https://doi.org/10.1016/j.ajem.2018.09.049 https://doi.org/10.1186/s12887-019-1393-y https://doi.org/10.1016/j.ijid.2007.07.006 https://doi.org/10.1016/j.ijid.2007.07.006 https://doi.org/10.1136/bmj.311.7005.619 https://doi.org/10.1099/jmm.0.47470-0 https://doi.org/10.1099/jmm.0.47641-0 https://doi.org/10.1099/jmm.0.47641-0 nasopharyngeal isolates from a cohort of medical students with or without pharyngitis e294 | squ medical journal, august 2020, volume 20, issue 3 21. moxon er. the carrier state: haemophilus influenzae. j antimicrob chemother 1986; 18 suppl a:17–24. https://doi. org/10.1093/jac/18.supplement_a.17. 22. dunne em, marshall jl, baker ca, manning j, gonis g, danchin mh, et al. detection of group a streptococcal pharyngitis by quantitative pcr. bmc infect dis 2013; 13:312. https://doi.org/10.1186/1471-2334-13-312. 23. centor rm, atkinson tp, ratliff ae, xiao l, crabb dm, estrada ca, et al. the clinical presentation of fusobacteriumpositive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. ann intern med 2015; 162:241–7. https://doi.org/10.7326/m14-1305. 24. kumar p, goyal jp. is modified centor score sensitive for diagnosis of streptococcal pharyngitis in indian children? indian pediatr 2019; 56:508. 25. nibhanipudi kv. a study to determine if addition of palatal petechiae to centor criteria adds more significance to clinical diagnosis of acute strep pharyngitis in children. glob pediatr health 2016; 3:2333794x16657943. https://doi. org/10.1177/2333794x16657943. https://doi.org/10.1093/jac/18.supplement_a.17 https://doi.org/10.1093/jac/18.supplement_a.17 https://doi.org/10.1186/1471-2334-13-312 https://doi.org/10.7326/m14-1305 https://doi.org/10.1177/2333794x16657943 https://doi.org/10.1177/2333794x16657943 sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e126-127, epub. 27th jan 14 submitted 7th apr 13 revision req. 8th may 13; revision recd. 31st may 13 accepted 25th aug 13 1department of surgery, sultan qaboos university hospital, muscat, oman; 2department of surgery, armed forces hospital, muscat oman *corresponding author e-mail: humaid44@gmail.com انغالف قولوقولوين بسبب ورم شحمي حميد حمود �لفرعي, �صلمى �ل�رشيف, �إبر�هيم �لعلوي colocolic intussusception with lipoma as lead point *humaid h. al-farai,1 salma al-sharif,2 ibrahim al-alawi2 interesting medical image figure 1 a & b: coronal view of contrast abdominal ct scan (a) with presence of lipoma (arrow). b: axial view showing the presence of an intra-mural lipoma in the descending colon with colocolic intussusception (arrow). a 25-year-old man, with no significant medical or surgical history, presented with a three-week history of leftsided, colicky abdominal pain which was aggravated by eating. it was associated with a four kg weight loss and per rectum bleeding three days prior to presentation. clinically, the patient looked well; his vital signs and haemodynamic parameters were stable. his abdomen revealed a mildly tender and mobile mass over the left lumbar area of c. 4 x 5 cm; the rest of the abdomen was soft. the abdominal computed tomography (ct) scan showed a c. 40 x 30 mm intra-mural lipoma in the descending colon with colocolic intussusception [figure 1a and 1b]. the patient underwent a laparotomy and segmental colonic resection with primary anastomosis. the operative findings of the left colon indentified the presence of a lipoma in the left colon [figure 2]. the histopathological examination of the mass confirmed the presence of a submucosal ulcerated lipoma. comment approximately, 95% of all reported cases of intestinal intussusception present in childhood.1 the commonest ‘lead points’ for intussusception in adults, in up to 60% of cases, are colonic malignant tumours.2 lipomas are the second most frequently occurring benign tumours of the large bowel, the commonest being adenomas.3 adult intussusception does not have any specific clinical manifestations, but most have at least a humaid h. al-farai, salma al-sharif and ibrahim al-alawi interesting medical image | e127 one-month history of episodes of intermittent abdominal pain associated with vomiting.4 the diagnosis for colonic lipoma can be obtained by a combination of ultrasound examination, barium studies, a colonoscopy and ct scanning, the latter being the most sensitive test.5 the treatment of a symptomatic colonic lipoma is surgical resection; since most colonic lipomas are submucosal, endoscopic resection is seldom feasible.5 in general, colonoscopies may play a role as diagnostic and therapeutic tool, especially for an asymptomatic lipoma of less than two cm in size.7,8 laparoscopic surgery has not yet been fully investigated as an alternative to open surgery because most patients with intussusception usually present in an emergency setting.6 however, conservative management (reduction with barium or air and close observation) is still an optional treatment of colocolic intussusception for younger age groups and patients for whom radiological investigations do not reveal a demonstrable anatomical ‘lead point’.7 references 1. wulff c, jespersen n. colo-colonic intussusception caused by a lipoma. acta radiol 1995; 36:478–80. 2. azar t, berger dl. adult intussusception. ann surg 1997; 226:134–8. 3. geraci g, pisello f, arnone e, sciuto a, modica g, sciumè c. endoscopic resection of a large colonic lipoma: case report and review of literature. case rep gastroenterol 2010; 4:6–11. 4. farrokh d, saadaoui h, hainaux b. [contribution of imaging in intestinal intussusception in the adults. apropos of a case of ileocolic intessusception secondary to cecal lipoma.] ann radiol (paris) 1996; 39:213–6. 5. dolan k, khan s, goldring jr. colo-colic intussusception due to lipoma. j royal soc med 1998; 91:94. 6. ma k-w, li w-h, cheung m-t. adult intussusceptions: a 15-year retrospective review. surg pract 2012; 16:6–11. 7. ongom pa, wabinga h, lukande rl. a ‘giant’ intraluminal lipoma presenting with intussusception in an adult: a case report. j med case reps 2012; 6:370. 8. aftab s, waqar ahmed, nilofar m, abhishek g, adnan m, satyajeet g. colocolic intussusception in an adult due to pedunculated lipoma. bombay hosp j 2009; 51:540. figure 2: operative specimen showing the presence of an oval-shaped lipoma with yellow-reddish discoloration (arrow). مؤمتر عمان ألمراض الصدر 2013 املؤمتر املشرتك للرابطة العمانية للجهاز التنفسي وجامعة السلطان قابوس جامعة ال�سلطان قابو�س، 29-31 اكتوبر 2013 oman thoracic conference 2013 the oman respiratory society and sultan qaboos university sultan qaboos university, 29–31 october 2013 online abstracts respiratory disorders in oman prof. omar al-rawas department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: orawas@squ.edu.om respiratory diseases are very common, accounting for significant morbidity and mortality worldwide. they comprise a wide range of conditions affecting both the upper and lower respiratory tracts in both adults and children. these diseases can be categorised as acute or chronic, although they often overlap between categories. significant advances have been made in the control of many respiratory disorders and essential facilities are now accessible country-wide within oman. however, the available respiratory services are often perceived to be inadequate and lacking sufficient coordination. in addition, there is limited data on the burden of common respiratory diseases in oman. as an example, our studies showed that the prevalence rate of self-reported asthma diagnoses was 10.5% in children and 20.7% in adolescents, with a relatively high prevalence of severe asthma symptoms. there are no data on the rates of chronic pulmonary disease or asthma in adults. studies on asthma management among adults suggest that this condition is underdiagnosed and sub-optimally managed, despite the availability of the national asthma management guidelines. this presentation highlights the paucity of information on respiratory disorders in oman. data from the limited number of national studies on the management and control of respiratory disease have identified important deficiencies and areas for improvement, as well as the need for further coordinated research on respiratory disorders in oman. management of chronic obstructive pulmonary disease dr. issa al-jahdami department of medicine, armed forces hospital, muscat, oman. e-mail: essajah111@yahoo.co.uk chronic obstructive pulmonary disease (copd) is a common respiratory illness that affects a large population of patients, the majority of whom are smokers. this condition remains underdiagnosed and undertreated within oman. traditionally, identifying the stage of the disease’s severity was mainly achieved by using the post-bronchodilator forced expiratory volume in one second (fev1) percentage as the marker of disease severity. recently this has been challenged and a new staging algorithm was designed by the global initiative for chronic obstructive lung disease (gold). this includes the patient’s symptoms, risk of exacerbation, as well as the degree of airflow obstruction measured by fev1. cessation of smoking remains a key issue in the management of all copd patients who are current smokers. medical therapy mainly aims to reduce symptoms and the frequency and severity of the exacerbations, as well as improving the patient’s exercise tolerance. so far, no intervention has been proven to prevent lung function decline or reduce mortality. treatment is initiated according to the overall assessment of disease severity, with bronchodilators being the first line of therapy. long-acting anticholinergics (e.g. tiotropium) are the preferred starting agents. long-acting beta 2 agonists (labas) can then be added if the patient remains symptomatic. combined therapy with labas and inhaled corticosteroids is recommended for patients with a severe or very severe form of the disease. the phosphodiesterase-4 inhibitor, roflumilast, may also be used for such patients. the treatment of existing medical comorbidities is of paramount importance. long-term oxygen therapy remains the only intervention that prolongs survival in patients with severe copd and resting hypoxaemia. bronchoscopic lung volume reduction is a relatively new technique which has been tried in patients with severe emphysema. these patients were found to show some improvement in their lung function and exercise tolerance. management of severe allergic asthma: an update dr. mona s. al-ahmad al-rashed allergy centre, ministry of health, kuwait. e-mail: monaalahmad@yahoo.com asthma is a chronic lung inflammatory disease affecting 5 to 10% of the population. although patients do have symptom-free periods, inflammation is always present in their airways. asthma manifests with paroxysmal bronchospasms, wheezing, dyspnoea and respiratory distress. allergic asthma is the most common form of asthma, affecting over 50% of asthma sufferers. symptoms are triggered by allergens, such as dust mites, skin flakes or materials shed by pets, pollens, moulds, etc. studies have shown an increase in the serum levels of circulating immunoglobulin e (ige). most patients have mild or moderate asthma, which can be well controlled with β-agonists and inhaled corticosteroids. a subgroup of patients have a more troublesome form of the disease, reflected by high medication requirements, persistent symptoms, asthma exacerbations and persistent airflow obstructions. omalizumab, an anti-ige monoclonal antibody that binds the cε3 domain of ige, is currently a favoured add-on therapy to improve asthma control in adult and adolescent patients who are suffering from severe persistent allergic asthma. omalizumab induces a conformational change of the immunoglobulin and a concealment of the fcεri and fcεrii receptors’ binding sites, preventing the binding of ige. as a result, the e418 | squ medical journal, august 2014, volume 14, issue 3 oman thoracic conference 2013 the oman respiratory society and sultan qaboos university release of inflammatory mediators is prevented. omalizumab has been used in the control of moderate to severe allergic asthma that does not respond to a combination of high-dose inhaled corticosteroids and long-acting beta agonists, with or without leukotriene inhibitors. researchers are currently investigating the efficacy and safety of omalizumab in this subgroup of asthmatics. asthma clinic programme at primary health care level dr. sawsan baddar department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: sawsanbaddar@hotmail.com an asthma clinic programme was formulated under the auspices of the omani ministry of health and the oman respiratory society. their aims were to: evaluate the current management of asthma in oman; standardise management across all primary health care centres; improve outcomes, and to minimise management costs. the programme, to be completed in an 18–20 month period, was designed in four phases: (i) health centres located in focal points of the region establish an asthma team consisting of doctors, nurses and pharmacists; (ii) each health centre collects baseline data on the current management of asthma, including information on exacerbations and the availability of asthma-related resources in their centre; (iii) asthma teams attend workshops covering strategies for establishing the clinic, the management of asthma in adults and children (including non-pharmacological aspects of management), the use of spirometry and conducting clinical audits, and (iv) clinical audits are performed to assess the centres' compliance with the programme requirements, their patient outcomes and management cost minimisation. based on the feedback from these audits, the main challenges facing these clinics are identified and corrective measures applied. all the asthma clinics follow standardised protocols and guidelines and have common procedures, charts and forms. between 2011 and 2013, 42 asthma clinics were established across oman and more than 600 health care providers attended the workshops from different governorates. although there were initially a limited number of asthma teams, the programme will later be implemented in oman’s remaining health centres and polyclinics. management of bronchiectasis dr. jojy george department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: drjojy@hotmail.com bronchiectasis refers to the abnormal permanent dilatation and destruction of the bronchi. this leads to the stasis of mucus in the respiratory tract, which results in recurrent chest infections. it can be congenital, as in ciliary dyskinaesia, cartilage deficiency and immunological problems, or it may be an acquired condition, such as in post-infectious states like tuberculosis, local airway obstructions or secondary to connective tissue diseases. currently, the diagnosis of bronchiectasis is made using high-resolution computed tomography (hrct). characteristic features on a hrct scan include airway dilatation, lack of airway tapering, bronchial thickening and cystic changes. the treatment goal is to prevent progression of the disease, maintain or improve lung function, reduce exacerbations, improve quality of life and, in children, to achieve normal growth. the management of this condition includes the identification and treatment of its underlying cause, education of the patient and their family, airway clearance strategies, airway drug therapy, antibiotics, surgical interventions and the management of complications. in children it is very important to identify the cause of the condition, as specific goal-directed therapy can improve the outcome in these patients. these include an immunoglobulin deficiency, foreign body aspiration, typical and atypical cystic fibrosis and ciliary dyskinaesia. patients should be educated about the disease process, management principles and the early identification of exacerbations. airway clearance using physiotherapy, exercise, mucolytic and hyperosmolar therapies are vital in the management of this condition. drug therapies targeting the airways, such as inhaled bronchodilators and inhaled corticosteroids, are useful for patients with obstructive airways. exacerbations are identified by the worsening of respiratory symptoms like coughing, wheezing, breathlessness, sputum purulence, increased sputum volume and a change in viscosity, with or without systemic upset. the judicious use of antibiotics, including the selection and duration of therapy, is vital in the management of exacerbations. cystic fibrosis in oman dr. hussein al-kindy department of child health, sultan qaboos university hospital, muscat, oman. e-mail: husseink30@yahoo.com cystic fibrosis (cf) is an autosomal recessive disease. it is the most common lethal genetic disease in the caucasian population, occurring in one per 3,500 newborns. cf is caused by a mutation in the cf transmembrane conductance regulator (cftr) gene, which is located on the long arm of human chromosome seven, at the q31.2 locus with 27 exons. the clinical features of cf present in the organs affected by the cftr gene dysfunction. an involvement of the gastrointestinal system manifests as meconium ileus in about 10–15% of newborns, obstruction of the small bile ducts and pancreatic insufficiency which results in a failure to thrive (ftt) from early infancy. in the respiratory system, thick mucus secretions lead to chronic airway obstruction and infections, which can cause bronchiectasis and respiratory failure. in 95% of male cf patients, there is a congenital absence of the vas deferens, resulting in infertility. the sweat glands have a very high concentration of sodium chloride, which can lead to hyponatraemic dehydration in the summer months and patients may present with a blood chemistry suggestive of pseudo-bartter syndrome (hypokalaemia, hyponatraemia and metabolic alkalosis). in most children, a diagnosis of cf depends on the clinical manifestations, a positive sweat test and/or two disease-causing cftr mutations. among 74 omani cf patients, who were followed-up in sultan qaboos university hospital and royal hospital, we found that the median age of onset was two months, although the median age of diagnosis was five months. of these cases, 80% were diagnosed by the age of three years and 60% had a positive family history of cf. furthermore, 35% of the subjects presented with only recurrent chest infections, 20% presented with chest infections and ftt, 7% with diarrhoea and ftt, 5% with only ftt and 19% with meconium ileus. the treatment of cf is complex and relies on a multidisciplinary team including a cf specialist, a nurse, a dietician and a physiotherapist. abstracts | e419 sultan qaboos university, 29–31 october 2013 overview of interstitial lung diseases dr. ali al-talag riyadh military hospital, riyadh, saudi arabia. e-mail: drtalag@yahoo.com interstitial lung diseases (ilds) are a diverse group of diseases affecting the pulmonary interstitium or parenchyma, hence the name ‘diffuse parenchymal lung diseases’. in fact, the only factor linking these diseases is the location affected—the interstitial part of the lung structure. otherwise, they are diverse in aetiology, epidemiology, age of onset, clinical presentation, method of diagnosis, management and prognosis. they are commonly classified as idiopathic interstitial lung diseases or interstitial lung diseases with a known aetiology. an important step in the management of these conditions is early detection, as little can be done once the disease is advanced. however, many of these conditions are clinically and radiologically silent in their early phases. pulmonary function tests measuring diffusion, such as the diffusing capacity of the lung for carbon monoxide (dlco), can be of help in the early disease stages, however, these are generally underutilised. in some ilds, a high-resolution computed tomography (ct) scan of the chest is sufficient to make a confident diagnosis, while in others an open lung biopsy is necessary. management varies from disease to disease and from one variant of the same disease to another. some require only observation and follow-up, whereas others may need extensive therapy with immunosuppressive medications or even a lung transplant. in this session, an overview of interstitial lung diseases will be presented together with an elaboration on some of the common ilds in the region, particularly idiopathic pulmonary fibrosis and sarcoidosis. beyond community-acquired pneumonia dr. abdullah balkhair department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: balkhair2020@gmail.com community-acquired pneumonia (cap) is a global public health concern. it is the seventh most-common cause of death worldwide and the leading cause of infectious disease-related deaths. up to 75% of cap patients are hospitalised; among these, 10% require admission to an intensive care unit (icu). patients with severe cap have a mortality rate of up to 50%, despite appropriate antibiotic coverage and supportive measures. cap puts an enormous strain on healthcare resources and the management of these patients remains a considerable challenge. since the introduction of penicillin, cap mortality rates have not changed substantially. therefore, efforts should be focused on optimising the processes of care and developing new treatment modalities. over the past few decades, several clinical advances have emerged in a number of areas that may aid in the care of cap patients. in support of these new concepts, this presentation will focus on some of the most controversial questions related to processes of care for cap patients. the presentation will outline the different faces of cap management beyond antibiotic therapy and provide an update on the diagnosis, site-of-care decisionmaking, classifications and the management of severe sepsis in cap patients. management of pleural effusion dr. dimitrije ponomarev department of medicine, royal hospital, muscat, oman. e-mail: dponomarevster@gmail.com in a case of pleural effusion it is important to determine whether it is exudative or transudative. transudate implies that there is an extrapleural condition to be diagnosed and treated while exudate reflects a disorder of the pleura and requires adequate treatment of the underlying disease. the intention of this presentation is to shed light on non-invasive diagnoses of pleural diseases and disorders, based on the biochemical properties of the fluid and the presence of certain biomarkers. light’s criteria remain the cornerstone in differentiating between exudative and transudative pleural effusions. if in bias, n-terminal pro-brain natriuretic peptide (ntprobnp) is a specific marker of cardiogenic transudative effusions. adenosine deaminase (ada) is an important biomarker of pleural tuberculosis. distinguishing benign from malignant pleural effusion remains a challenge. there is a potential role for tumour markers in avoiding more invasive procedures, but these are not sensitive or specific enough for any histological type of malignancy. potentially, ‘fingerprinting’ specific disease markers, by means of proteomics and gene profiling, may prove to be of significant diagnostic value in pleural diseases in the future. metastatic non-small-cell lung cancer: expanding the molecular horizon dr. suad al-kharusi department of oncology, royal hospital, muscat, oman. e-mail: suadalkharusi99@gmail.com non-small-cell lung cancer (nsclc) is one of the few solid tumours to undergo a recent expansion in treatment options. the last few years have brought new hope to the treatment of metastatic nsclc. there is a very poor prognosis for those with stage iv nsclc as the five-year survival rate does not exceed 1%. considering all of the stages, the five-year survival is approximately 15%. the histopathological subtyping of nsclc is mandatory in order to explore potential options for targeted therapy. due to two genetic alterations that are key oncogenic events in nsclc, selective pathway-directed systemic therapy is now a possible treatment. the presence of epidermal growth factor receptor (egfr)-activating and -sensitising mutations is predictive of a response to egfr inhibitors, such as erlotinib and gefitinib. anaplastic lymphoma kinase (alka) gene rearrangement is present in about 5% of nsclc cases; however, this is effectively suppressed by alka inhibitors like crizotinib. tuberculosis: where we are dr. mohamed r. al-lawati department of internal & respiratory medicine, al nahdha hospital, muscat; department of communicable diseases surveillance & control, directorate general of health affairs, ministry of health, oman. e-mail: ntbcp@cdscoman.org in 2012, there were 8.7 million cases of tuberculosis (tb) and 1.4 million tb-related deaths worldwide. the vast majority of deaths were in cases of human immunodeficiency virus (hiv) co-infection and multidrug-resistant (mdr) tb. in oman, the incidence of tb is low, with 375 new cases in 2012 and 13 deaths. the incidence of tb/hiv co-infections and mdr tb is also low, with 13 cases and four cases, respectively, reported in 2012. however, there is a rising number of tb cases among non-omanis, especially house-maids. the main risk factors for nationals are a family history of tb and a history of smoking and diabetes mellitus. the low incidence of tb in oman causes diagnostic challenges, including delays in diagnosis and low detection rates in primary health centres. however, the national sputum e420 | squ medical journal, august 2014, volume 14, issue 3 oman thoracic conference 2013 the oman respiratory society and sultan qaboos university conversion and treatment success rates are excellent. there is also a satisfactory level of contact screening and treatment of latent tb cases where indicated. the national tb control programme is acquiring new tools to meet some of the current challenges. this includes the acquisition of rapid molecular diagnostic tools along with the introduction of the public-private mix (ppm) and practical approach to lung health (pal) strategies. there is a continuous tb training programme at the central and regional levels. in addition, the social welfare of families affected by tb is being given special attention. acute respiratory distress syndrome: current concepts dr. abdulhakim al-hashim department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: ah.alhashim@gmail.com acute respiratory distress syndrome (ards) is a life-threatening condition affecting patients in all age groups. the syndrome was first described by ashbaugh in 1967. since then, there have been two main challenges associated with ards—diagnostic criteria and effective management. until recently the definition used was based on criteria set by the american-european consensus conference in 1994. however, the reliability and validity of this definition and criteria have been questioned. a panel of experts convened in 2011 (an initiative of the european society of intensive care medicine, the american thoracic society and the society of critical care medicine) and developed the ‘berlin’ definition, which focuses on feasibility, reliability, validity and an objective evaluation of performance. this panel came up with new and practical criteria to define ards. it has always been a great challenge to manage patients with severe ards. very few management strategies have shown to improve the survival rates of these patients. the treatment strategies that have demonstrated some efficacy include protective lung ventilation, prone position and extracorporeal life support. non-invasive ventilation in the management of acute respiratory failure dr. nabil al-lawati department of medicine, royal hospital, muscat, oman. e mail: nabil.allawati@gmail.com non-invasive ventilation (niv) refers to the delivery of positive airway pressure via a non-invasive interface, as opposed to invasive ventilation through an endotracheal or tracheostomy tube. over the past 15 years, niv has become a standard of care in managing commonly encountered cardio-respiratory emergencies, namely acute hypercapnic respiratory failure in patients presenting with acute exacerbation of chronic obstructive pulmonary disease (aecopd) and cardiogenic pulmonary oedema. as there is a wealth of data demonstrating the efficacy of niv, the national institute of clinical excellence in the uk recommends that niv should be available in all hospitals admitting patients with copd. the only absolute contraindication for niv is when there is a need for emergency intubation. however, it could also be argued that cardio-respiratory arrest is another contraindication, as niv, in essence, is applied on conscious patients and those breathing spontaneously. niv should be started within the first hour of the patient’s arrival at the hospital, in a well-monitored area, such as a high-dependency or intensive care unit. prior to this, it is important to counsel the patient and obtain verbal consent as some may be initially reluctant. every two niv patients should be monitored by at least one nurse. a patient's response to niv is assessed by evaluating a combination of clinical and physiological parameters, including their effort in breathing, heart rate, chest expansion, oxygen saturation, serial arterial carbon dioxide levels and level of consciousness. on average, patients may require continuous niv for 48 hours, after which they can be weaned off if their clinical condition permits. however, the treating clinician must assess the niv’s efficacy in the first four hours, as delaying invasive ventilation for those who need it can worsen their prognosis and even increase mortality. obstructive sleep apnoea dr. mohammed a. al-abri department of clinical physiology, sultan qaboos university hospital, muscat, oman. e-mail: malabri@squ.edu.om sleep is a physiological phenomenon divided into two main stages—non-rapid eye movement (nrem) and rapid eye movement (rem). obstructive sleep apnoea (osa) is the main sleep-related breathing disorder, affecting 4% of men and 2% of women. osa is characterised by repetitive nocturnal airway obstructions associated with hypoxaemia. excessive daytime sleepiness is a major complication of osa. the main risk factors for this condition are obesity, tonsillar and adenoid enlargements, gender (male) and facial deformities. the standard treatment is continuous positive airway pressure using different interfaces. untreated osa may result in serious complications such as hypertension, diabetes and ischaemic heart diseases. in addition, daytime sleepiness carries a high risk of causing or being involved in road traffic accidents. obesity hypoventilation syndrome dr. nasser a. al-shekaili ibri regional hospital, ibri, oman. e-mail: nasser_shekeili2000@yahoo.com obesity hypoventilation syndrome (ohs) is a disease entity that is distinct from simple obesity and obstructive sleep apnoea. ohs was described well before obstructive sleep apnoea—in 1956 burwell popularised the term 'pickwickian syndrome' by noting the similarities between his patient and a character in the charles dickens’s novel, the posthumous papers of the pickwick club. ohs is characterised by the triad of obesity (body mass index ≥30 kg/m2), chronic awake alveolar hypoventilation (partial pressure of carbon dioxide [paco2] >45 mmhg and partial pressure of oxygen [pao2] <70 mmhg at sea level) and a sleep-related breathing disorder, in the absence of other causes of hypoventilation. as ohs is a diagnosis of exclusion, pulmonary parenchymal or obstructive diseases, neurological disorders, musculoskeletal diseases, hypothyroidism and medication-induced hypoventilation must be ruled out. its prevalence is estimated to be 10–20% in obese patients with obstructive sleep apnoea and 0.15–0.3% in the general adult population. the presentation is usually indolent with symptoms arising due to hypercapnia and sustained hypoventilation (hypersomnolence, altered cognitive functioning, headaches, peripheral oedema, hypertension and congestive cardiac failure). the pathophysiology of ohs is complex, as obesity is not the only risk factor; this may explain why some obese individuals develop ohs while others maintain a normal gas exchange. generally, it is thought that obese subjects who have developed daytime hypoventilation will have a reduced sensitivity to the rising level of paco2 as well as leptin resistance. the interaction between these factors, amongst others, leads to the development of ohs. the management of patients with ohs requires a multidisciplinary approach combining different medical and surgical subspecialties. affected patients abstracts | e421 sultan qaboos university, 29–31 october 2013 will require the input of: an internist and endocrinologist regarding diabetes mellitus, hypertension, hyperlipedaemia, heart failure and hypothyroidism; a dietician for advice on weight reduction; a respirologist for the management of respiratory failure (positive airway pressure ventilation), and a surgeon regarding potential bariatric surgery. tobacco dependence treatment dr. feras hawari department of pulmonary & critical care, king hussein cancer center, amman, jordan. email: fhawari@khcc.jo providing tobacco dependence treatment (tdt) is a growing novel specialty in the middle east. the world economic forum statistics on tobacco use among youth, as well as the cost of resulting non-communicable diseases (ncds), are staggering. over the next 15 years the cost of various ncds, such as cardiovascular diseases, cancer-related respiratory illnesses and diabetes, is expected to exceed usd 15 trillion. this includes the lost income due to mortality and morbidity, as well as the amount required to be invested in healthcare developments in order to manage this epidemic. these numbers are fuelled by the alarming increase in the prevalence of youth smoking and the expected shift in the population age pyramid over the next 15 years. studies have shown that the treatment of tobacco dependence must move in parallel with education and awareness to reduce the burden of tobacco-related ncds. tdt and oxygen therapy are the only treatments shown to improve survival in patients with chronic obstructive pulmonary disease (copd). smoking cessation in copd cases minimises symptoms, improves quality of life, reduces hospitalisation and improves survival rates. combining motivational interviews with pharmacological therapy increases the rate of smoking abstinence. it is recommended that healthcare providers (hcps) receive special training on approaching patients for tdt. global collaboration in providing such training is gaining popularity and momentum—an example of such an alliance, global bridges, has trained close to 2,000 hcps worldwide with a total of 600 or more trained in the eastern mediterranean region. the impact of this mass training is yet to be measured. however, due to the immense impact of tobacco-related ncds, as well as the accelerated increase in the prevalence of tobacco use, healthcare providers must apply all necessary interventions in order to prevent an imminent disaster. the pulmonary vasculitides dr. ali al-shirawi department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: shirawi04@yahoo.com the vasculitides are a heterogeneous group of disorders characterised by the histopathological findings of inflammation and necrosis of the blood vessel wall. pulmonary vasculitis may present in a variety of ways, including an alveolar haemorrhage, pulmonary nodules, cavitating lesions or an airway disease. the american college of rheumatology and the chapel hill consensus conference on vasculitis attempted to classify the main pulmonary vasculitides. these classifications do not cover other potential diseases that affect the lungs with similar presentations. these include behçet’s disease, systemic lupus erythematosus, antiphospholipid syndrome and other connective tissue diseases. fortunately the diagnostic advancements and similarities in therapeutic approaches for the different vasculitides enable clinicians to initiate lifesaving interventions before such diagnoses become clearly marked. moreover, vasculitides rarely affect a single organ and a detailed clinical history may uncover clues to guide clinicians to the correct diagnosis. similarly, geographical and ethnic variations show a distinct incidence and prevalence of different vasculitides in different countries. the aim of this presentation is to explore these issues. pulmonary embolism dr. yaqoub al-mahrouqi department of medicine, royal hospital, muscat, oman. e-mail: yaqpal@yahoo.com the severity of an acute pulmonary embolism (pe) ranges from asymptomatic, incidentally detected subsegmental thrombi to a massive, pressor-dependent pe complicated by cardiogenic shock and multisystem organ failure. risk factors include venous stasis, hypercoagulable states, immobilisation, surgery trauma, pregnancy, the use of oral contraceptives and oestrogen replacement therapy, malignancy, hereditary factors or an acute medical illness. the classical symptoms are dyspnoea (73%), pleuritic chest pain (66%), coughing (37%) and haemoptysis (13%). the most commonly used method to predict a patient's clinical probability of developing pe is the wells’ score. a positive d-dimer is not synonymous with pe, but a negative d-dimer almost always excludes pe. the positive predictive value of ischaemia-modified albumin (ima) is more effective than d-dimer, although it cannot confirm a diagnosis of pe without additional investigations. elevated troponin levels are associated with a higher risk for in-hospital mortality and a complicated clinical course. brain natriuretic peptide (bnp) and n-terminal prohormone of brain natriuretic peptide (nt-probnp) are associated with the diagnosis of a right ventricular dysfunction and are significant predictors of in-hospital mortality. although the gold standard for pe diagnosis is pulmonary angiography, this is seldom used due to the availability of non-invasive techniques. in most cases, computed tomography (ct) pulmonary angiography is the recommended first-line diagnostic imaging test. a ventilation/perfusion scan is also accurate but is not usually freely available. rapid risk stratification is also important to assess a patient’s risk of early death. the pulmonary embolism severity index (pesi) is currently the most extensively validated prognostic clinical score. anticoagulant therapy continues to be the mainstay of treatment along with supportive treatments, such as oxygen or analgesia. unfractionated heparin, low-molecular-weight heparin or fondaparinux is usually administered initially, followed by oral agents like warfarin or rivaroxaban. a massive pe-causing haemodynamic instability is an indication for thrombolysis. the use of thrombolysis in non-massive pes is not yet clear. a catheter or a surgical embolectomy can be considered in select cases, especially where thrombolysis is contraindicated. pulmonary arterial hypertension dr. nasser al-busaidi department of medicine, royal hospital, muscat, oman. e-mail: enhsa@hotmail.com pulmonary hypertension (ph) has been defined as an increase in mean pulmonary arterial pressure (pap) to 25 mmhg at rest, as assessed by right heart catheterisation. the normal mean pap at rest is 14 ± 3 mmhg, with an upper limit of 20 mmhg. between 1967 and 1973, a 10-fold increase in unexplained ph was reported in central europe. the rise was subsequently traced to aminorex fumarate, an amphetamine-like drug introduced in europe in 1965 to control appetite. the pathogenesis of ph is attributed to a small, e422 | squ medical journal, august 2014, volume 14, issue 3 oman thoracic conference 2013 the oman respiratory society and sultan qaboos university distal pulmonary artery obstruction due to vasoconstriction and thrombosis as well as smooth muscle and endothelial cell proliferation. this leads to severe concentric laminar intimal fibrosis, medial hypertrophy and in situ thrombosis of the small residual lumen. ph is classified as (1) pulmonary arterial hypertension; (2) pulmonary venous hypertension; (3) ph associated with hypoxaemia; (4) ph due to chronic thrombotic disease and/or embolic disease, and (5) miscellaneous ph. the symptoms are generally non-specific and patients usually present with progressive dyspnoea on exertion, fatigue, dizziness, palpitations, chest pain, syncope or oedema. management requires close observation, periodic echocardiographic assessment, oxygen and the judicious use of specific drugs. pulmonary arterial hypertension is usually treated with prostanoids (epoprostenol and ilioprost), endothelin receptor antagonists (bosentan) and phosphodiesterase inhibitors (sildenafil). pulmonary venous hypertension is usually treated with diuretics, calcium channel blockers, nitrates, beta-blockers and angiotensin-converting enzymes. generally, ph associated with lung disease does not require specific therapy other than long-term oxygen and optimal treatment for the primary chronic lung disease. surgical interventions, such as a pulmonary thromboendarterectomy, can be considered in select cases of ph due to a chronic thromboembolism. occupational lung diseases dr. fatma m. al-hakmani directorate general of health services, ministry of health, oman. e mail: hakma76@hotmail.com occupational lung diseases (old) are a group of illnesses caused by the inhalation of toxic substances present in a working environment. they are either caused by a prolonged and repeated exposure to irritant or toxic substances, leading to a chronic illness, or a single severe exposure, potentially leading to an acute medical emergency. globally, old are the most common type of work-related injuries. potentially harmful materials that can affect the lungs when inhaled can be classified according to their nature; organic dust (cotton dust, grain dust, agriculture dust and toxic chemicals and gases) or inorganic dust (silica, coal dust, asbestos and beryllium). the defence mechanisms in the lungs will fail to expel these particles either during a highly toxic exposure, after repeated exposures or if the particles have an irregular structure. the size and structure of the particles will also determine where it will be deposited in the respiratory tract. old include obstructive lung diseases, restrictive lung diseases, respiratory cancer and mesothelioma. occupational asthma is the most commonly reported form of old. taking the patient’s occupational history, as well as information on their living environment, is an important element in the early recognition and diagnosis of old. the prevention of old is a significant challenge worldwide. environmental and medical hazard surveillance in the workplace aids in the modification and improvement of the working environment. furthermore, the application of health and safety hazard control measures (risk assessment and management) and health promotion are the gold-standard strategies for controlling occupational health hazards. in conclusion, old are the most common work-related injuries and physicians should be made aware of this group of illnesses. video-assisted thoracoscopy dr. adil al-kindi department of surgery, sultan qaboos university hospital, muscat, oman. e-mail: alkindi2001@gmail.com ever since the introduction of scopes in surgical procedures, their use in thoracic surgery has grown exponentially to include both diagnostic and therapeutic procedures. with the increasing use of computed tomography (ct) scans in diagnoses, the number of thoracic pathologies detected has also increased. using direct visualisation and biopsies, video-assisted thoracoscopic surgery (vats) can be used to diagnose mediastinal, pleural and lung diseases. studies have demonstrated that, despite the increased resolution of ct scans, concordance of the final diagnosis with the radiological diagnosis was as low as 15%, with only 34% of the cases including the final diagnosis in the differential. on the other hand, vats had almost 98% sensitivity and 90% specificity for reaching diagnoses in pathologies such as interstitial lung disease. with increased experience in the use of vats, therapeutic applications now include the resection of mediastinal masses, pleural resection and fusion, and the resection of lung masses, including cancers. in the early stages of lung cancer, studies have demonstrated that vats has the same oncological outcome as a thoracotomy. however, vats has a lower morbidity rate including bleeding and transfusions, pneumonia, arrhythmias, air leaks and renal failure. as a result, the overall medical cost is lower due to shorter hospital stays and the lower rate of morbidities. interpretation of pulmonary function tests dr. jayakrishnan b. department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: drjayakrish@hotmail.com pulmonary function tests (pft) are an essential tool that can be used to detect, follow and manage patients with lung disorders. pfts can be divided into approximately six basic components: spirometry; flow-volume loop; lung volume; diffusing capacity; bronchial challenge, and cardiopulmonary exercise testing. a spirometry is easily performed with simple instruments, wheras the other tests require more sophisticated apparatus. values vary with age, stature, gender and ethnic group. therefore, measurement results must be compared with a reference value based on healthy subjects. the true lower limit of normal (lln) is better expressed as -1.645 x standard deviation rather than a fixed predicted percentage. changes in the contour of the flow-volume loop, as well as plotting inspiratory and expiratory flow against volume during the performance of maximally forced inspiratory and expiratory manoeuvres, can provide information on the validity of the test, the site of obstruction and the presence of a restrictive defect. the most important parameter for identifying an obstructive impairment is a low forced expiratory volume in one second (fev1) to forced vital capacity (fvc) ratio. an airway obstruction is considered reversible if the fev1 increases 12% after bronchodilator administration. the forced expiratory flow, fef25–75%, is often checked to identify an obstructive pattern. lung volume (total lung capacity and residual volume) will generally be high, more so in emphysema. diffusion will be low in emphysema, but this is not usually the case for asthma or chronic bronchitis. if the fev1:fvc ratio is normal, the test could be either normal (normal fvc) or indicating a restrictive defect (low fvc). a restrictive defect is further confirmed by the measurement of lung volume. lung volume is low in patients with involvement of the chest wall (eg. khyphoscolisis) or parenchyma (eg. interstitial lung disease). however, the diffusing capacity for carbon monoxide (dlco) will be low only in cases of parenchymal involvement. in the simplest sense, the diffusing capacity is the ability of gas to move from the air across the interstitium and into the blood. although pfts usually generate a lot of measurements and the results may seem complex, only a few of these values are needed for routine interpretation. abstracts | e423 sultan qaboos university, 29–31 october 2013 clinical cases dr. khalfan al-zeedy department of medicine, sultan qaboos university hospital, muscat, oman. e-mail: khalfanalzidi@hotmail.com three interesting cases were presented with clinical pictures, radiology images and videos of bronchoscopies. a young university student presented with a fever, cough, shortness of breath and a history of two previous hospital admissions for pneumonia mostly occurring during long vacations. a computed tomography (ct) scan of the chest showed bilateral patchy ground glass opacities. basic investigations, including cultures and autoimmune and immunodeficiency work-ups, were all negative. an environmental history revealed that the patient kept a lot of birds, including pigeons, at home. hypersensitivity pneumonitis (bird fancier’s lung) is caused by a sensitisation to the repeated inhalation of dust containing organic antigens. this condition is characterised by the diffuse inflammation of the lung parenchyma and airways. clinical presentations are categorised as acute, sub-acute and chronic-progressive. a 53-year-old man was referred for an evaluation of a right hilar mass. he had been experiencing a cough and mild haemoptysis for the previous four months. a ct scan of the chest showed multiple pulmonary artery aneurysms with intraluminal thrombi. the patient developed massive haemoptysis after admission. the autoimmune work-up was negative and the patient did not have features of beçhet’s disease. hughesstovin syndrome is a very rare clinical entity, characterised by pulmonary artery aneurysms and deep vein thrombosis. he was managed successfully with high-dose steroids in combination with cyclophosphamide. a young male presented with a persistent right lower zone opacity seen in the chest radiograph and ct scan. the patient had undergone a bone marrow transplant (bmt) for thalassaemia major 10 years previously. a deep swelling was noted in his right thigh. a bronchoscopy showed a well-defined endobronchial lesion. biopsies from the endobronchial and thigh lesions were consistent with anaplastic large cell lymphoma involving the t-cells. although secondary malignancies can occur after a bmt, their incidence in patients undergoing bmts for non-malignant diseases is very similar to that of the normal population. moreover, the incidence of malignancy in beta thalassemia patients is approximately the same in those who have undergone a bmt and those who have not. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 411-416, epub. 25th jun 13 submitted 11th sep 12 revisions reqd. 25th nov 12 & 5th feb 13; revisions recd. 2nd jan & 10th feb 13 accepted 17th mar 13 1department of paediatrics, college of medicine & health sciences, united arab emirates university, al ain, united arab emirates; 2tawam hospital, al ain, united arab emirates; 3faculty of medicine & health sciences, united arab emirates university, al ain, united arab emirates *corresponding author e-mail: aljasmif@uaeu.ac.ae استهالك األوكسجني ىف املايتوكوندريا من قبل القلفة و اخلاليا الليفية فاطمة اجل�شمي، ثكالت برامازان ، عدنان �شويد، بهجت �شحاري، هاريف بنيفي�شكي، عبد القادر �شويد امللخ�ص: الهدف: درا�شة اإمكانية ا�شتخدام طريقة ا�شتهالك االأوك�شجني يف امليتوكوندريا لقيا�س التنف�س اخللوي يف عينات القلفة و اخلاليا الليفية با�شتخدام جهاز حتليل االأوك�شجني احل�شا�س للفو�شفور. الطريقة: مت جمع عينات من القلفة لر�شع طبيعيني على الفور بعد اخلتان وقيا�س )ii( د ب بورفريين بنزو ترتا ميزو مادة با�شتخدام االأوك�شجني ا�شتهالك �رسعة حتديد مت اخللوي. التنف�س لقيا�س وا�شتخدمت حمكمة زجاجات يف الزمن مع خطية بطريقة االأوك�شجني تركيز تناق�س النتائج: امليتوكوندريا. يف للفو�شفور احل�شا�س حتللها �رسعة االإغالق حتتوي على القلفة وجلوكوز مما يثبت ا�شتهالك االأوك�شجني بوا�شطة ال�شيتوكروم اوك�شيداز اخللوي. مادة ال�شيانيد اأوقفت ا�شتهالك القلفة تنف�س �رسعة متو�شط كان االأوك�شجني. ا�شتخدام عن امل�شئولة هي امليتوكندريا اأن توؤكد النتائج هذه القلفة. قبل من االأوك�شجني 0.02 + 0.074 دقيقة 2اأ مرت -1 جمم -1 )العدد=23( و�رسعة تنف�س اخلاليا اللليفية دقيقة 2اأ مرت 2.43 + 9.84 -1 جمم -1 )العدد=15(. كان تنف�س اخلاليا الليفية اأقل يف املر�شى امل�شابني بنق�س الثنائي هيدروليباميد )dld( .هذا النق�س حت�شن باإ�شافة الثيامني اأو الكارنيتني. اخلال�سه: ميكن ا�شتخدام القلفة واخلاليا الليفية لتقييم التنف�س اخللوي. الفائدة ال�رسيرية من عينات القلفة للك�شف عن ا�شطرابات الطاقة احليوية يتطلب مزيداً من البحث. مفتاح الكلمات: االأوك�شجني؛ امليتوكوندريا؛ القلفة؛ التنف�س؛ اخلاليا الليفية؛ نق�س الثنائي هيدروليباميد؛ الثيامني؛ الكارنيتني. abstract: objectives: this study investigated the feasibility of using a phosphorescence oxygen analyser to measure cellular respiration (mitochondrial o2 consumption) in foreskin samples and their fibroblast-rich cultures. methods: foreskin specimens from normal infants were collected immediately after circumcision and processed for measuring cellular respiration and for culture. cellular mitochondrial o2 consumption was determined as a function of time from the phosphorescence decay of the pd (ii) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. results: in sealed vials containing a foreskin specimen and glucose, o2 concentration decreased linearly with time, confirming the zero-order kinetics of o2 consumption by cytochrome oxidase. cyanide inhibited o2 consumption, confirming that the oxidation occurred mainly in the mitochondrial respiratory chain. the rate of foreskin respiration (mean ± sd) was 0.074 ± 0.02 μm o2 min -1 mg-1 (n = 23). the corresponding rate for fibroblast-rich cultures was 9.84 ± 2.43 μm o2 min -1 per 107 cells (n = 15). fibroblast respiration was significantly lower in a male infant with dihydrolipoamide dehydrogenase gene mutations, but normalised with the addition of thiamine or carnitine. conclusion: the foreskin and its fibroblast-rich culture are suitable for assessment of cellular respiration. however, the clinical utility of foreskin specimens to detect disorders of impaired cellular bioenergetics requires further investigation. keywords: oxygen; mitochondria; foreskin; respiration; fibroblasts; dihydrolipoamide dehydrogenase; thiamine; carnitine. mitochondrial oxygen consumption by the foreskin and its fibroblast-rich culture *fatma al-jasmi,1 thachillath pramathan,1 adnan swid,2 bahjat sahari,2 harvey s. penefsky,3 abdul-kader souid1 clinical & basic research advances in knowledge this study demonstrates the feasibility of using foreskin samples to measure cellular respiration (cellular mitochondrial oxygen consumption). application to patient care foreskin specimens and their fibroblast-rich cultures can be used to screen for disorders of impaired cellular bioenergetics. this study shows the potential use of fibroblast respiration to predict responses to therapeutic interventions. mitochondrial oxygen consumption by the foreskin and its fibroblast-rich culture 412 | squ medical journal, august 2013, volume 13, issue 3 clinicians frequently use skin and muscle biopsies for investigating mitochondrial disorders.1–4 the skin is also used for generating fibroblasts, which are easily obtained and used for repetitive biochemical analyses and research purposes. circulating lymphocytes are also available and suitable for these measurements.4–7 more novel approaches for monitoring cellular bioenergetics have been reported recently.8–10 al-jasmi et al. described the use of a phosphorescence oxygen analyser to measure lymphocyte respiration in patients.10 their method was based on previously published principles.11 the lymphocytes from patients were shown to be suitable for the screening of certain mitochondrial disorders. the same analytical tool is applied here to measure respiration in foreskin samples and their fibroblast-rich cultures. the results demonstrate that the foreskin tissue permits accurate determination of cellular mitochondrial o2 consumption. the primary aim of this study was to investigate the use of the phosphorescence oxygen analyser to measure cellular respiration (mitochondrial o2 consumption) in foreskin specimens and their fibroblast-rich cultures. the secondary aim was to utilise the foreskin to screen for metabolic disorders that impair cellular respiration (mitochondrial o2 consumption and accompanying adenosine triphosphate [atp] synthesis). the hypothesis was that the foreskin and its fibroblast-rich culture can be utilised for assessment of cellular metabolic fuels and their energy conversion processes. methods the following reagents and solutions were used. a pd (ii) complex of meso-tetra-(4-sulfonatophenyl)tetrabenzoporphyrin was obtained from porphyrin products (logan, utah, usa). minimum essential medium (mem alpha modification), phosphatebuffered saline (pbs), fetal bovine serum, trypsin, penicillin, streptomycin and lyophilised collagenase (clostridiopeptidase prepared from clostridium histolyticum, cat. no. 17018-029) were obtained from invitrogen corporation (carlsbad, california, usa). the thiamin hcl injection (100 mg/ml, 300 mm, m.w. 337.3) was obtained from app pharmaceuticals (division of fresenius kabi, schaumburg, illinois, usa). the levocarnitine injection (1.0 g/5 ml, 1.24 m, m.w. 161.2), glucose oxidase (powder from aspergillus niger), d(+) glucose anhydrous and remaining reagents were purchased from sigma-tau pharmaceuticals, inc. (gaithersburg, maryland, usa). two mg of the pd phosphor were dissolved in 1.0 ml of distilled water (dh2o) and stored at -20o c. a glucose oxidase solution was prepared in dh2o (10 mg/ml) and stored at -20 o c. one m of sodium cyanide (nacn) was prepared in dh2o; the ph was adjusted to ~7.0 with 12n hcl and stored at -20o c. pbs (137 mm nacl, 2.7 mm kcl, 4.3 mm na2hpo4, and 1.4 mm kh2po4, ph 7.4) containing 10 mm glucose was stored at 4o c. foreskin specimens (22–34 mg) were collected from normal infants (<6 months of age) immediately after circumcision and stored at 4o c in 50 ml mem supplemented with penicillin and streptomycin for <24 hours until o2 analysis or culture. for o2 measurement, the foreskin samples were placed in 1-ml o2 vials and processed as described below. for culture, the foreskin specimens were incubated at 37o c in a sterile vial containing pbs with 2.0 mg/ml collagenase. after tissue disintegration (typically in 2–3 hours), the samples were transferred to 25-cm3 tissue culture flasks containing 10 ml mem with fetal-bovine serum, penicillin, and streptomycin. for passage, the cells were washed with 5 ml pbs and then treated at 37o c with 2 ml of 0.25% trypsin (w/v in pbs) for 5 minutes. the flasks were inspected for cell detachment; 1.0 ml of fetal-bovine serum and 5.0 ml of mem with fetal-bovine serum, penicillin and streptomycin were then added. the suspension was split between 2–4 flasks, depending on the cell concentration. fibroblast-rich cultures were harvested at confluence. cells were washed with pbs and treated at 37o c with 0.25% trypsin for 5 minutes. the cells were then collected in mem with fetal-bovine serum, penicillin and streptomycin and centrifuged at 1,000 g (25o c for 5 minutes). the pellet was suspended in 1.3 ml of pd solution (pbs, 3 µm pd phosphor, 0.5% fat-free albumin, and 5 mm glucose) and processed for o2 measurement. thiamin or carnitine was added to confluent fibroblast-rich cultures and the cells were harvested after 24 hours. cell count and viability were determined by light microscopy using a haemocytometer under standard trypan blue staining condition. only trypan blue-negative cells (>95%) were counted. it fatma al-jasmi, thachillath pramathan, adnan swid, bahjat sahari, harvey s. penefsky and abdul-kader souid clinical and basic research | 413 is worth emphasising that foreskin samples should be immediately placed in a large volume (e.g., 50 ml) of ice-cold medium and stored at 4o c until processing. this procedure produces better sample viability. sample collection from all participants was approved by the institutional review board for protection of human subjects. informed consent was obtained for each patient. ethical permission was granted by the al ain medical district human research ethics committee (16th april 2012, protocol no. 11/59). the rate of cellular respiration was determined using a phosphorescence analyser to measure the concentration of dissolved oxygen as a function of time.10 this method is based on the principle that o2 quenches the phosphorescence of a palladium phosphor.11 the pd (ii) derivative of meso-tetra(4-sulfonatophenyl)-tetrabenzoporphyrin had a maximum absorption at 625 nm and a maximum phosphorescence emission at 800 nm. samples were exposed to light flashes (10 per second) from a pulsed light-emitting diode array with a peak output of 625 nm. emitted phosphorescent light was detected by a hamamatsu photomultiplier tube (hamamatsu, japan) after first passing it through a wide-band interference filter centered at 800 nm. amplified phosphorescence was digitised at 1–2 mhz using an analogue/digital converter (pci-das 4020/12 i/o board) with 1 to 20 mhz outputs. pulses were captured at 1.0 mhz. the phosphorescence decay rate (1/τ) was characterised by a single exponential i = aet/τ, where i = pd phosphor phosphorescence intensity. the values of 1/τ were linear with dissolved o2: 1/ τ = 1/τº + kq[o2], where 1/τ = the phosphorescence decay rate in the presence of o2, 1/τº = the phosphorescence decay rate in the absence of o2 and kq = the second-order o2 quenching rate constant in sec-1 µm-1.11 cellular respiration was measured at 37o c in 1-ml sealed vials containing pbs, 3 µm pd phosphor, table 1: respiration of foreskin samples and their fibroblast-rich cultures from normal infants rates of respiration tissue foreskin* (µm o2 min -1 mg-1) fibroblast† (µm o2 min -1 per 107 cells) lymphocyte‡ (µm o2 min -1 per 107 cells) mean ± sd (n) 0.074 ± 0.02 (23) 9.84 ± 2.43 (15) 2.0 ± 0.9 (20) median (range) 0.074 (0.04–0.13) 10.50 (6.6 –14.3) 2.0 (0.9–3.7) sd = standard deviation; n = number of subjects. * the samples were stored at 4o c in mem for <24 hours before o2 measurement and culture. † the fibroblasts were prepared from foreskin samples; 107 fibroblasts had a net weight of 70.4 ± 12.5 mg (n = 13). ‡ the data are from reference 10. table 2: respiration of foreskin samples, fibroblasts and lymphocytes from patients gender age clinical presentation rates of respiration foreskin fibroblast value ± sd lymphocyte m 1 yr dld homozygous gene mutation (c.1436a>t) reduced pdhc activity in fibroblasts not done 5.7 ± 1.4 (n = 6)* p <0.0001 0.79‡ p = 0.091 m 2 m congenital lactic acidosis 0.076 5.6 ± 0.3 (n = 3)† p = 0.002 1.0 f 15 m global developmental delay not done 10.1 ± 0.4 (n = 2)‡ 0.62 dld = dihydrolipoamide dehydrogenase; pdhc = pyruvate dehydrogenase complex; sd = standard deviation; n = number of repeats using independence samples; p = p value. the lymphocyte and fibroblast respiration is expressed in μm o2 min -1 per 107 cells. the foreskin respiration is expressed in μm o2 min -1 per mg. the results in table 2 are in comparison to table 1. *the fibroblasts were from a skin biopsy. the p value is for fibroblast respiration in normal infants versus fibroblast respiration in the patient. †the fibroblasts were from a foreskin sample. ‡the patient is receiving thiamin. this rate was 1.5 μm o2 per min per 10 7 cells at 1 week of age (from reference 10). the p-value is for lymphocyte respiration in age-matched normal individuals versus lymphocyte respiration in the patient.4 mitochondrial oxygen consumption by the foreskin and its fibroblast-rich culture 414 | squ medical journal, august 2013, volume 13, issue 3 0.5% fat-free albumin, and 5 mm glucose. the respiratory substrates were endogenous metabolic fuels supplemented by glucose. o2 concentration (calculated using the equation 1/ τ = 1/τº + kq[o2]) decreased linearly with time, indicating the kinetics of mitochondrial o2 consumption was zero-order. the rate of respiration (k, in µm o2/min) was, thus, the negative of the slope d[o2]/dt. nacn inhibited respiration by at least 96%, confirming oxygen was mainly consumed by the mitochondrial respiratory chain. a programme was developed using microsoft visual basic 6 and access database 2007 (microsoft corp., redmond, washington, usa), and universal library (measurement computing corporation, norton, massachusetts, usa) components.12,13 calibration with β-d-glucose plus glucose oxidase was performed as follows. glucose oxidase catalyses the oxidation reaction of β-d-glucose + o2 to d-glucono-1,5-lactone + h2o2. the reactions contained pbs + 3 µm pd phosphor, 0.5% fat-free albumin, 50 µg/ml glucose oxidase, and 0-500 µm β-glucose. the value of kq, the negatives of the slope of 1/τ versus [β -glucose], was 101.1 sec-1 µm-1. data were analysed using statistical package for the social sciences (spss), version 19 (ibm corp., chigaco, illinois, usa). the mann-whitney nonparametric test (2 independent variables) was used to compare treated and untreated samples. results the rates of foreskin and fibroblast respiration are shown in table 1, and representative runs are shown in figure 1a. a summary of all studied samples is shown in figure 1b and table 1. for comparison, the reference values for lymphocyte respiration are also shown in table 1.10 the rate of respiration (kc, µm o2 min -1 mg-1) in foreskin samples that was determined within one hour of circumcision was 0.076 ± 0.01 (coefficient of variation [cv] = 14%; n = 8). for samples that were stored at 4o c in mem for 16 to 23 hours, the respiration rate was 0.074 ± 0.025 (cv = 33%, n = 16, p = 0.697), and for samples that were stored at 4o c in mem for >24 hours the rate was 0.033 ± 0.023 (cv = 70%, n = 3, p = 0.012). thus, the samples were stable for up to 23 hours. an infant with congenital lactic acidaemia (plasma lactate 18 mm; normal range <1.5) was investigated. his plasma lactate decreased to 6–8 mm within one week of thiamin treatment (500 mg/ kg). the pyruvate dehydrogenase complex (pdhc) activity in fibroblasts was low (2.7 mu/ucs; controls = 9.7 to 36 mu/ucs; this test was done on a clinical sample analysed by stichting klinisch-genetisch centrum, nijmegen, netherlands. sequencing the dihydrolipoamide dehydrogenase (dld) gene showed homozygous c.1436a> t (p. asp 479 val) (refseq accession number nm_000108). the respiration rate of the infant’s lymphocytes and fibroblasts was consistently low [table 2]. his fibroblasts were then treated with various concentrations of thiamin (cofactor of pdhc) and carnitine over 24 hours, as patients with impaired pyruvate dehydrogenase complex are typically treated with these agents. the value of kc (µm o2 min-1 mg-1) with 100 µm thiamin was 4.3, with 200 µm thiamin 7.1, and with 400 µm thiamin 8.6. the value of kc with 50 µm carnitine was 5.1, with 100 µm carnitine 8.6, and with 200 µm carnitine 8.8. another patient with congenital lactic acidosis, a 2-month-old infant, was also investigated. his plasma lactate was 17.9 mm and cerebrospinal fluid lactate 8.27 mm (normal = 0.86–2.19). his foreskin respiration (0.076 µm o2 min -1 per mg) and lymphocyte respiration (1.0 µm o2 min -1 per 107 cells) was normal, while his fibroblast (from a foreskin sample) respiration was low (5.6 ± 0.3 µm o2 min -1 per 107 cells, n = 3, p = 0.002). a 15-month-old female presented with global developmental delay and failure to thrive. the urine organic acid analysis showed elevated 2-ketoglutaric acid and lactate levels. plasma alanine was mildly elevated. the lymphocyte respiration was low (0.62 µm o2 min -1 per 107 cells) while the fibroblast respiration was normal (10.1 ± 0.4 µm o2 min -1 per 107 cells, n = 2). discussion the main finding in this study is the consistency of the rate of cellular respiration in foreskin samples (cv = 27%) and their fibroblast-rich cultures (cv = 25%) [table 1]. these variations are significantly lower than that of the lymphocytes (cv = 45%) [table 1], which are typically more fragile than the ectodermal tissue. therefore, the foreskin appears to be a reliable source of cells for measuring cellular respiration. the other important observation is the relative stability of foreskin samples over several hours. these features make the foreskin suitable for fatma al-jasmi, thachillath pramathan, adnan swid, bahjat sahari, harvey s. penefsky and abdul-kader souid clinical and basic research | 415 metabolic disorder screening. the term cellular bioenergetics covers all of the biochemical processes involved in the energy conversion. cellular respiration (mitochondrial oxygen consumption), on the other hand, implies the generation of metabolic fuels, delivery of metabolites and o2 to the mitochondria, oxidation of reduced metabolic fuels with passage of electrons to o2, and synthesis of atp. thus, impaired cellular bioenergetics entails an interference with any of these critical processes. to our knowledge, this report is the first to show the feasibility of measuring cellular respiration in the foreskin. the procedure is relatively simple, and the tissue is stable at 4o c for several hours after circumcision. the clinical applications of using foreskin samples include the immediate reading of cellular respiration, as well as processing the tissue for fibroblast-rich cultures, with a success rate of >90%. the rates of oxygen consumption by fibroblasts and lymphocytes differ markedly (p <0.001); the lymphocyte rate is about 5 times lower than that of the fibroblast [table 1]. due to their in vitro stability, fibroblasts appear to be more reliable for measuring respiration than circulating lymphocytes. the infant with the homozygous dld gene mutations (c.1436a>t), and reduced pdhc activity, had low rates of fibroblast and lymphocyte respiration. these results confirm the suitability of using these types of tissues in the screening for this disorder. thiamine and carnitine supplements are recommended for patients with impaired pyruvate dehydrogenase complexes. therefore, these agents were tested on the pdh-deficient patient. fibroblast respiration normalised with the addition of thiamin or carnitine (see results section). thus, the potential response to these therapeutic interventions could be predicted in vitro. in one patient with congenital lactic acidosis, the foreskin and lymphocyte respiration rates were normal, while the fibroblast respiration was low.the 15-month-old female with global developmental delay of undetermined aetiology had low lymphocyte respiration, but normal fibroblast respiration [table 2]. the source of these discrepancies is unclear, but could reflect heteroplasmy;3 thus, respiration should always be determined in multiple tissue sources. in one study, 50% of patients with confirmed respiratory chain defects had abnormal measurements in muscle and lymphocyte samples, 45% in muscle samples only and 5% in lymphocyte samples only.4 pearson’s syndrome, on the other hand, consistently expresses abnormalities in the figure 1 panels a & b: rates of cellular respiration of foreskins and foreskin cultures from healthy infants. panel a: representative runs of a foreskin sample (33 mg) and its fibroblast-rich culture (1.2 x 107 cells) from the same infant. the o2 measurements were performed at 37º c in 1-ml sealed vials of pbs supplemented with 5 mm glucose, 3 µm pd phosphor and 0.5% fat-free bovine serum albumin. the rates of respiration (k, in µm o2 min -1) were set as the negative of the slopes of [o2] versus time. the slopes were calculated from the best-fit curve (r 2 >0.920). the values of kc in µm o2 min-1 per mg (foreskin) and µm o2 min -1 per 107 cells (fibroblast-rich culture) are also shown. the additions of 5 mm nacn and 50 μg/ml glucose oxidase are shown. glucose oxidase (catalyses the reaction of d-glucose + o2 to d-gluconoδ-lactone + h2o2) depleted the remaining o2 in the solution. the depletion of o2 after the addition of glucose oxidase confirmed that the halt of respiration following the cyanide injection occurred despite available o2 in the solution. panel b: the values of kc for all studied foreskins (white circles) and foreskin cultures (black circles) are shown. the short horizontal lines on the y-axis reflect the mean values. mitochondrial oxygen consumption by the foreskin and its fibroblast-rich culture 416 | squ medical journal, august 2013, volume 13, issue 3 lymphocytes.5 these results again highlight the need for investigating several tissues. cellular respiration is a reliable indicator of mitochondrial function [figure 1]. this important biomarker is underutilised, mostly due to the traditional limitations of the polarographic method.14 polarography (clark-type o2 electrode) and spectroscopy have been used as analytical methodologies for measuring o2 consumption by fresh lymphocytes.14 reported rates of lymphocyte respiration (all in nmol o2 min -1 per 107 cells) include 3.5 ± 0.5, 2.0 ± 0.07 (varied by the cell density), and 1.0 ± 0.2 (in equine lymphocytes).5–7 more recently, the fluorescence and phosphorescence o2 sensors have permitted relatively simple and accurate monitoring of respiration in clinical samples of small quantities.8–11 measurements of mitochondrial respiration in digitonin-permeabilised fibroblasts and in isolated mitochondria from muscle specimens using phosphorescent microplates have been reported.8 other analytic instruments for assessing cellular bioenergetics are also described.9 of note, the phosphorescence oxygen analyser used here was calibrated using the clark electrode, and validated for measurements of respiration in various cells and tissues.10,11,15 conclusion this study demonstrates the feasibility of using the foreskin and its fibroblast-rich culture to measure cellular mitochondrial o2 consumption. this tissue is dispensable and relatively stable for several hours; it is therefore ideal for screening. muscle and skin biopsies, on the other hand, are relatively invasive and available in minute quantities. these more precious samples are thus more suitable for confirmatory biochemical or molecular testing. the clinical utility of foreskin samples in detecting disorders of impaired cellular bioenergetics, however, requires further investigation. references 1. chretien d, rustin p. mitochondrial oxidative phosphorylation: pitfalls and tips in measuring and interpreting enzyme activities. j inherit metab dis 2003; 26:189–98. 2. chretien d, rustin p, bourgeron t, rotig a, saudubray jm, munnich a. reference charts for respiratory chain activities in human tissues. clin chim acta 1994; 228:53–70. 3. rustin p, chretien d, bourgeron t, gerard b, rotig a, saudubray jm, et al. biochemical and molecular investigations in respiratory chain deficiencies. clin chim acta 1994; 228:35–51. 4. robinson bh. use of fibroblast and lymphoblast cultures for detection of respiratory chain defects. methods enzymol 1996; 264:454–64. 5. rotig a, cormier v, blanche s, bonnefont jp, ledeist f, romero n, et al. pearson's marrow-pancreas syndrome. a multisystem mitochondrial disorder in infancy. j clin invest 1990; 86:1601–8. 6. hedeskov cj, esmann v. respiration and glycolysis of normal human lymphocytes. blood 1966; 28:163– 74. 7. pachman lm. the carbohydrate metabolism and respiration of isolated small lymphocytes. in vitro studies of normal and phytohemagglutinin stimulated cells. blood 1967; 30:691–706. 8. jonckheere ai, huigsloot m, janssen aj, kappen aj, smeitink ja, rodenburg rj. high-throughput assay to measure oxygen consumption in digitoninpermeabilized cells of patients with mitochondrial disorders. clin chem 2010; 56:424–31. 9. ferrick da, neilson a, beeson c. advances in measuring cellular bioenergetics using extracellular flux. drug discov today 2008; 13:268–74. 10. al-jasmi f, penefsky hs, souid ak. the phosphorescence oxygen analyzer as a screening tool for disorders with impaired lymphocyte bioenergetics. mol genet metab 2003; 104:529–36. 11. lo lw, koch cj, wilson df. calibration of oxygendependent quenching of the phosphorescence of pdmeso-tetra (4-carboxyphenyl) porphine: a phosphor with general application for measuring oxygen concentration in biological systems. anal biochem 1996; 236:153–60. 12. anderson nr, lee es, brockenbrough js, minie me, fuller s, brinkley j, et al. issues in biomedical research data management and analysis: needs and barriers. j am med inform assoc 2007; 14:478–88. 13. shaban s, marzouqi f, al mansouri a, penefsky hs, souid ak. oxygen measurements via phosphorescence. comput methods programs biomed 2010; 100:265–8. 14. clark lc. electrochemical device for chemical analysis. us patent no. 291338, 1959. 15. al-jasmi f, al-suwaidi ar, al-shamsi m, marzouqi f, al mansouri, shaban s, et al. phosphorescence oxygen analyzer as a measuring tool for cellular bioenergetics. from: http://cdn.intechopen.com/ pdfs/30413/intech-phosphorescence_oxygen_ a n a l y z e r _ a s _ a _ m e a s u r i n g _ to o l _ fo r _ cel l u l a r _ bioenergetics.pdf accessed: aug 2012. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 341-344, epub. 25th jun 13 submitted 23rd may13 peer reviewed accepted 4th jun 13 one of the very interesting articles in this issue is tobacco smoking and lung cancer: perception-changing facts.1 the author has raised a salient issue by stressing that strict regulations to control tobacco smoking can reduce mortality due to lung cancer and other diseases. the problem is that tobacco use has become a mass global phenomenon—currently an estimated 794 million adults use tobacco, smoking 5,884 billion cigarettes a year. a further 350 million are exposed to second-hand smoke (shs) at work.2 the problem is centuries old. tobacco was brought to europe by christopher columbus, who discovered it in cuba in 1492.3 by the beginning of the 16th century, the tobacco trade was already established between the caribbean and india, soon extending to china, japan and the malay peninsula. about the same time, the portuguese and spanish brought tobacco down the east coast of africa, then to central africa. by the 17th century, tobacco was being produced in russia, persia, india and japan.3 in the early 20th century, tobacco use rose to epidemic proportions, mostly due to aggressive marketing by the tobacco industry after the invention of the cigarette machine.4 tobacco consumption rose again after world war i, and after world war ii it became very common.5 in the 20th century, tobacco killed approximately 100 million people.2 if present patterns of use persist, tobacco use could cause as many as 1 billion premature deaths during the 21st century.6 presently, the burden of tobacco use is greatest in high-income countries (18% of deaths attributable to tobacco use), intermediate in middle-income countries (11%), and lowest in low-income countries (4%).7 however, because rates of smoking are increasing in many low-income and middleincome countries and decreasing in most highincome countries, the proportion of deaths from tobacco use could increase in lowand middleincome countries as the number of tobacco-related deaths increases.6,7 although most of the tobacco that is consumed throughout the world is in the form of manufactured cigarettes, it is also smoked in other products, such as cigars, cigarillos, pipes, water pipes, kreteks (clove cigarettes), bidis (tobacco rolled in a tendu or temburni dried indian ebony leaf that is tied with a cotton thread), and papirosy (russian cardboardtube-tipped cigarettes). water pipes (sheesha) are common in middle eastern and some asian countries.8 tobacco use is now the world’s single leading preventable cause of death. more deaths are caused each year by tobacco use than by all deaths from human immunodeficiency virus (hiv), tuberculosis, and malaria combined.2 scientific knowledge about the effects of tobacco smoking accumulated during the last century after evidence linking smoking and cancer appeared in the 1920s. between 1920 and 1940, a chemist, angel honorio roffo, published articles showing that cancers could be experimentally induced by exposure to tar from burned tobacco. roffo et al. further showed that cancer could be induced by nicotine-free tobacco, meaning that the tar itself was carcinogenic.9 department of community medicine & public health, tanta university, egypt, and department of health planning, ministry of health, muscat, oman e-mail: drmoness@gmail.com تدخني التبغ احلقائق والسلوكيات موؤن�س م�شطفى ال�ش�شتاوي editorial tobacco smoking facts and actions moeness m. alshishtawy tobacco smoking facts and actions 342 | squ medical journal, august 2013, volume 13, issue 3 evidence that smoking causes cancer mounted in 1951 when hill et al. in great britain, and wynder et al. in the usa demonstrated a statistically significant correlation between smoking and lung cancer.5 in 1957, the first official usa government statement on smoking and health was televised; the surgeon general, leroy burney, announced that scientific evidence supported cigarette smoking as a causative factor in the aetiology of lung cancer. by 1960, joseph garland, editor of the new england journal of medicine confirmed that the evidence has become sufficiently strong to suggest a causative role.9 smoking causes an estimated 90% of all lung cancer deaths in men and 80% of all lung cancer deaths in women.7 the major diseases caused by tobacco include other cancers, coronary heart disease, cardiovascular diseases, chronic respiratory diseases, pregnancy complications, and respiratory diseases in children.10 despite this large volume of evidence, cigarette manufacturers have told smokers their products are not injurious to health. in fact, cigarette companies frequently promised consumers that their brands were better for them than their competitor’s brands because the smoke was less irritating, smoother, and milder.11 however, internal industry documents revealed that by the late 1950s the tobacco companies knew and accepted the evidence that cigarette smoking was a cause of cancer. these documents revealed also that the tobacco companies deliberately conspired to confuse the public debate about smoking and health and co-opted scientists by research funding offers channeled through third party organisations.9 it is shameful that the cigarette companies which signed the 1954 frank statement to cigarette smokers, which denied the link between smoking and cancer, did not fulfill their promises to support unbiased research into tobacco and health.11 tobacco manufacturers only recently admitted that smoking causes lung cancer and other diseases, and in varying degrees. despite this, they have rebutted charges made in personal injury lawsuits that their products caused cancer.12 their defence experts testified that most people start smoking because of peer pressure or because family members smoke, not because they were influenced by advertising. defence witnesses stated that the tobacco companies do not advertise their products to under 21-year-olds. expert witnesses testified that nicotine is not addictive; that motivated people can quit smoking; that cigarettes, unlike hard drugs, are not intoxicating and withdrawal symptoms are mild; that nicotine does not impair human judgment or decision-making, and that people smoke for relaxation, taste, and enjoyment, not because they are addicted.12 the global response to the pandemic of tobaccoinduced death and disease has been the world health organization’s (who) framework convention on tobacco control (fctc), the first ever global health treaty.4 the who fctc exhorted countries to develop action plans for public policies, such as bans on direct and indirect tobacco advertising, tobacco tax and price increases, the promotion of smoke-free public places and workplaces, and the printing of health warnings on tobacco packaging. it also called for countries to establish programmes for national, regional, and global tobacco-use surveillance.13 by august 2012, the who fctc had been ratified by 176 countries, accounting for 88% of the world’s population.14 the global monitoring framework for noncommunicable diseases urged countries to implement the who fctc to achieve a relative reduction in tobacco smoking of 30% by 2025.15 indeed, many countries have recently implemented stricter measures, in line with the who fctc. guidelines adopted by the first session of the fctc conference of the parties16 has led to achievements such as smoking bans at beaches in some australian states and parks in canada. brazil has banned the use of additives in cigarettes and tobacco products. some countries have increased the size of their pictorial health warnings—uruguay (to 80%) and mauritius (to 65%)—while australia now requires plain packaging of tobacco products with other countries likely to follow suit. nine countries have banned the display of tobacco products, and five have banned tobacco advertising at points of sale. nepal now forbids the sale of tobacco products not only to minors but also to pregnant women, while bhutan has legislated for a comprehensive tobacco sale ban. finally, finland and new zealand are endeavouring to become tobacco-free countries.16 oman is one of the countries where a large number of people smoke. the 2008 oman world health survey revealed 14.7% of males were current smokers (12.3% averaged 16 cigarettes a day, 2.4% moeness m. alshishtawy editorial | 343 were occasional smokers). this shows an increasing trend compared to the 2000 survey where only 10.7% of males smoked. in both surveys, only <0.5% of females smoked.17 according to a third study undertaken in oman in 2004, as many as 7.0% (males 13.4%, females 0.5%) were current smokers, and 2.3% were former smokers. the group with the highest prevalence was omanis aged 40–49 years where the rate was 11.1% (18.7% of males, 0.9% of females). the mean age for starting smoking was 18.7 years for males and 24.3 years for females. in oman and neighbouring countries, females start smoking later than men and smoke fewer cigarettes, mainly as a result of sociocultural, religious or economic factors.18 fortunately, in 2010, a study measuring indoor shs was conducted in oman. a special monitoring instrument measured particulate matter (pm2.5) which is solid or liquid particles emitted to the air. of 30 venues monitored, active smoking was only observed in recreation venues (although they had signs prohibiting smoking). all schools, hospitals, government offices, and public transportation monitored in this study appeared to be compliant with the smoke-free policies. a level of pm2.5 (256 μg/m3) was found in one recreation venue (a sheesha coffee shop) which was 25 times higher than smoking-free venues and outdoors.19 visitors to such a venue would be subjected to a short-term exposure of pm2.5 10 times higher than what is acceptable for a whole day (25 μg/m3), as defined by the who. however, long-term exposure to pm2.5 concentrations, associated with adverse effects on chronic cardiovascular and respiratory disease, is identified at 10 μg/m3 as an annual average.20 in the light of such studies, oman has already banned tv, radio and outdoor cigarette advertising. citizens have since been pressing for smoking bans in shopping malls, cinemas and restaurants. from april 2010, the muscat municipality banned smoking in all public places. anyone flouting the ban is fined up to omr 100 and omr 300 from the third offence. private establishments, lax in enforcing the new curbs, also face fines and even risk having their establishments closed down for 3 to 7 days. the licences of persistently offending establishments can be permanently cancelled. establishments covered by the new measure must display english and arabic ‘no smoking zone' signs and smoking in these establishments is permitted only in designated ‘smoking zones'. since november 2012, cigarette packs in oman must be printed with a message alerting smokers to the dangers of smoking and a compelling image aiming to persuade them to kick the habit. all cigarette manufacturers and distributors should also keep such messages as part of anti-smoking campaigns. the activities of the oman tobacco control programme includes the following interventions: higher taxes on tobacco products; comprehensive bans on tobacco advertising; information in the media on the health consequences of smoking, and school-based anti-smoking programmes in combination with community-based activities. all these efforts assure us that there are now unprecedented opportunities to prevent and eradicate tobacco dependence by proven interventions aimed at both the population and individuals. the effectiveness of tobacco control policies will depend on coordination and cooperation between the various government and non-government organisations. in oman, we need to increase awareness among adolescents in order to reduce rates of smoking initiation, increase quit attempts through improved access to cessation therapies, and protect non-smokers by reexamining smoke-free policies in recreation venues. references 1. furrukh m. tobacco smoking and lung cancer: perception-changing facts. sultan qaboos university med j 2013; 13:345–58. 2. cohen j. global tobacco epidemic and public health response. u.s. department of health and human services, centers for disease control and prevention. from: http://www.cdc.gov/about/grandrounds/archives/2012/p dfs/gr-tobacco-allfinal-jul24.pdf accessed: may 2013. 3. mackay j, croftont j. tobacco and the developing world. br med bull 1996; 52:206–21. 4. hosseinpoor ar, parker la, d’espaignet et, chatterji s. social determinants of smoking in low and middle-income countries: results from the world health survey. plos one 2011; 6:e20331. 5. grzybowski a. the history of anti-tobacco actions in the last 500 years. part 1. non-medical actions. przegl lek 2006; 63:1126–30. 6. world health organization. who report on the global tobacco epidemic, 2011: warning about the dangers of tobacco. geneva: world health tobacco smoking facts and actions 344 | squ medical journal, august 2013, volume 13, issue 3 organization, 2011. 7. world health organization. global health risks: mortality and burden of disease attributable to selected major risks. geneva: world health organization, 2009. 8. giovino ga, mirza sa, samet jm, gupta pc, jarvis mj, bhala n, et al. tobacco use in 3 billion individuals from 16 countries: an analysis of nationally representative cross-sectional household surveys. lancet 2012; 380:668–79. 9. cummings km, brown a, o’connor r. the cigarette controversy. cancer epidemiol biomarkers prev 2007; 16:1070–6. 10. giovino ga. the tobacco epidemic in the united states. am j prev med 2007; 33:s318–26. 11. cummings km, morley cp, hyland a. failed promises of the cigarette industry and its effect on consumer misperceptions about the health risks of smoking. tobacco control 2002; 11:i110–17. 12. milberger s, davis ronald m, douglas ce, beasley jk, burns d, houston t, et al. tobacco manufacturers’ defence against plaintiffs’ claims of cancer causation: throwing mud at the wall and hoping some of it will stick. tobacco control 2006; 15:iv17–26. 13. sirichotiratana n, techatraisakdi c, rahman k, warren cw, jones nr, asma s, et al. prevalence of smoking and other smoking-related behaviors reported by the global youth tobacco survey (gyts) in thailand. bmc public health 2008, 8:s3. 14. the framework convention alliance for tobacco control. status of the who framework convention on tobacco control (who fctc). updated 14 august 2012. from: http://www.fctc.org/ accessed: may 2013. 15. world health organization. a comprehensive global monitoring framework including indicators and a set of voluntary global targets for the prevention and control of noncommunicable diseases. second who discussion paper, 22 march 2012. from: http://www. searo.who.int/linkfiles/mhnd_gmf.pdf accessed: may 2013. 16. world health organization framework convention on tobacco control (who fctc). 2012 global progress report on implementation of the who framework convention on tobacco control. geneva: world health organization, 2012. 17. al-riyami a, abd el aty ma, jaju s, morsi m, alkharusi h, al-shekaili w. world health survey 2008. muscat: ministry of health, 2008. 18. al riyami aa, afifi m. smoking in oman: prevalence and characteristics of smokers. east mediterr health j 2004; 10:600–9. 19. al -lawati ja, al-thuhli ys, al-hajri kh. a study on measuring secondhand smoke. muscat: ministry of health, oman, and oman national tobacco control committee, 2012. 20. krzyzanowski m, cohen a. update of who air quality guidelines. air qual atmos health 2008; 1:7–13. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 300-305, epub. 15th jul 12 submitted 11th nov 11 revision req. 10th mar 12, revision recd. 22nd mar & 21st apr 12 accepted 25th apr 12 1department of biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: clifab@gmail.com أكسيد النيرتيك واإلنزميات املضادة لألكسدة يف الدم الوريدي ودم احلبل السري لألمهات الُعمانيات للولدان ْبَتَسرين املتأخرين والولدان الناضجني ُ امل كليفورد اأبياكا، لوفينا ما�سادو امللخ�ص: الهدف: تقييم دور �سغط الأك�سدة يف الولدة عند الأمهات العمانيات بعد ورود تقارير متزايدة على اأن الولدان حديثي الولدة جمع مت الطريقة: بالِولَدة. امُلحيَطِة الَفرْتَِة َوَفَياُت حيث من النا�سجني الولدة حديثي من اأكرب خطر يف متاأخر وقت يف الأوان قبل والولدان املتاأخرين امُلْبَت�رَسين الولدان لأمهات الولدة بعد ال�رسي احلبل دم من اأخرى وعينات الولدة اأثناء الوريدي الدم من عينات النا�سجني يف م�ست�سفى جامعة ال�سلطان قابو�ض، ُعمان. مت قيا�ض تركيز اأك�سيد النيرتيك يف البالزما ون�ساط كاتالز كريات الدم احلمراء امُلْبَت�رَسين الولدان اأمهات عند النيرتيك اأك�سيد تركيز كان احلمراءالنتائج: الدم لكريات اجللوتاثيون بريوك�سيديز ن�ساط قيا�ض مت كما ،)p <0.0001( 5.5 ± 11.0 باملقارنة مع اأمهات الولدان النا�سجني )املتاأخرين اأعلى ب�سكل ملحوظ 17.1 ± 3.3 )مايكرومول/ لرت 110.4 مقابل الهيموغلوبني( من جرام لكل )وحدة 12.9 ± 94.1 احلمراء الدم لكريات اجللوتاثيون بريوك�سيديز لن�ساط اأدنى وقيم )p = 0.027( وكانت اأمهات الولدان امُلْبَت�رَسين املتاأخرين اأ�سغر �سنا بكثري من اأمهات الولدان النا�سجني .)p <0.0001( 12.3 ± اجللوتاثيون بريوك�سيديز ن�ساط وكان ،)p <0.0001( النا�سجني الولدان من بكثري وزنا اأقل املتاأخرين امُلْبَت�رَسين الولدان وكان . ومل النا�سجني. الولدان مع باملقارنة املتاأخرين امُلْبَت�رَسين الولدان يف )p = 0.001( ملحوظ ب�سكل منخف�سا احلمراء الدم لكريات يظهر اأي فرق يف ن�ساط كاتالز كريات الدم احلمراء بني املجموعتني. اخلال�صة: كانت قيم اأك�سيد النيرتيك يف البالزما اأعلى عند اأمهات الولدان امُلْبَت�رَسين املتاأخرين من نظريتها لأمهات الولدان النا�سجني، كما كان ن�ساط بريوك�سيديز اجللوتاثيون لكريات الدم احلمراء عند املجموعة الأوىل منخف�سا مقارنة باملجموعة الثانية. ولوحظ كذلك انخفا�ض يف ن�ساط بريوك�سيديز اجللوتاثيون لكريات الدم احلمراء عند الولدان امُلْبَت�رَسين املتاأخرين بالن�سبة للولدان النا�سجني والذي يدل على خل للموازنة املوالية لالأك�سدة وامل�سادة لها نظرا لزيادة عبء الأك�سدة يف الولدة قبل الأوان. الإجهاد الولدة؛ حديثي النا�سجني، الأطفال اأمهات متاأخر، ُمْبَت�رَس ولد اجللوتاثيون، بريوكيديز كتالز، النرتيك، اأك�سيد الكلمات: مفتاح التاأك�سدي، ُعمان. abstract: objectives: this study assessed the role of oxidative stress in parturition in omani mothers following growing reports that late preterm neonates were at greater risk than term neonates of perinatal death. methods: venous blood samples were collected during labour, and cord (neonatal) blood samples were taken after childbirth in late preterm and term from women at sultan qaboos university hospital, oman. plasma nitric oxide (no) concentrations, erythrocyte catalase (cat). erythrocyte glutathione peroxidase (gpx) activities were measured using spectrophotometric methods. results: when compared with term mothers, late preterm mothers had markedly higher no concentrations (µmol/l) 17.1 ± 3.3 versus 11.0 ± 5.5 (p <0.0001), and lower gpx values (u/g hb) 94.1 ± 12.9 versus 110.4 ± 12.3 (p <0.0001). late preterm mothers were significantly younger (p = 0.027) than term mothers and had neonates that weighed significantly less (p <0.0001) than term neonates. gpx activity was significantly reduced (p = 0.001) in late preterm neonates as compared to term neonates. cat showed no change in activity in any comparison. conclusion: distinctly higher values of no and lower gpx activity were found in late preterm mothers relative to term mothers; also, lower gpx in late preterm neonates relative to term neonates suggested a pro-oxidant-antioxidant imbalance due to the greater oxidative burden in late preterm parturition. keywords: nitric oxide; catalase; glutathione peroxidase; late preterm birth; term birth; neonates; oxidative stress; oman. nitric oxide and antioxidant enzymes in venous and cord blood of late preterm and term omani mothers *clifford abiaka1 and lovina machado2 clinical & basic research clifford abiaka and lovina machado clinical and basic research | 301 advances in knowledge oxidative stress is more a feature of parturition at late preterm than at term. late preterm mothers are at greater risk of oxidative stress than term mothers. late preterm neonates are more susceptible to oxidative stress than term neonates. application to patient care identifying modifiable factors in the obstetric setting may be an inexpensive and noninvasive therapy for preventing preterm parturition. antioxidants (including the carotenoids, and vitamins c and e) and antioxidant cofactors (such as copper, selenium, and zinc) are capable of disposing, scavenging, or suppressing the generation of reactive oxygen species implicated in oxidative stress. physicians should identify antioxidant-laden diets and educate pregnant omani women about their benefits, and also advise them to take daily multivitamins and microminerals throughout pregnancy and beyond. regular assays of plasma nitric oxide (no) and erythrocyte glutathione peroxidase (gpx) should be considered in suspected late preterm pregnancy. the gestational age window termed “late preterm birth” occurs between 34 weeks 1 day and 36 weeks 6 days.1–3 the greatest number of obstetric interventions and adverse neonatal outcomes occur at late preterm births.4 compared with term neonates, late preterm neonates are at higher risk for hospital readmissions, post-neonatal mortality, sudden infant death syndrome, white matter injury, and neuro-developmental problems well into the school age years.5–8 nitric oxide (no) is the product of a fiveelectron oxidation of l-arginine mediated by one of three no synthases: endothelial, neuronal, and inducible no synthases (enos, nnos and inos).9 neuronal nos and enos are responsible for the continuous basal release of no. endothelial nos is expressed in theca cells, granulosa cells, and the surface of oocyte during follicular development.10,11 inducible nos expressed in monocytes and macrophages in response to pro-inflammatory cytokines, catalyses the synthesis of a large amount of no in pathological conditions.12,13 no itself comprises a nitrogen atom bound to an oxygen atom, forming a reactive nitrogen species depicted as .no, a short-lived, readily diffusible molecule that reacts with superoxide (o2 .-) to form the highly reactive and cytotoxic pro-oxidant, peroxinitrite anion (onoo-).13–15 both glutathione peroxidase (gpx) and catalase (cat) function as enzymatic antioxidants by neutralising pro-oxidants and thus prevent damage to the cellular structure. the selenoprotein, gpx, is cytosolically located in most tissues. it catalyses the breakdown of hydrogen peroxide (h2o2) and organic peroxide (roo) supported by reduced glutathione (gsh) to form glutathione disulphide (gssg), water, and organic alcohol (roh). in erythrocytes from adult humans, all gpx activity appears to be selenium-dependent.16 catalase, a haemoprotein, specifically converts h2o2 to yield o2, and h2o, and does not decompose roo. in this context, information about oxidative stress in parturition at late preterm and term is lacking. the objective of this study was to assess the strength of oxidative stress at parturition by measuring and comparing concentrations of plasma no, and activities of erythrocyte gpx and cat in venous and cord blood of omani mothers who delivered at late preterm and at term. methods ethical approval was granted for the study by the research review board at the authors’ institution. enrollment was voluntary, and all participants signed a consent form previously approved by the institution’s ethics committee for the protection of human subjects in research. a total of 37 mothers who delivered at late preterm were registered, as well as 37 mothers who delivered at term. they were non-smokers, normotensive, and had singleton gestations ranging from 34 to 42 weeks. gestational age at entry was determined by an obstetric estimate of the last menstrual period, uterine size, and ultrasound examination.17 late preterm mothers delivered between 34 weeks and <37 weeks and their ages ranged from 14–44 years (mean 28 years). term mothers delivered between 37 and 42 weeks and were aged 22–45 years (mean 33 years). no medical complications were encountered during pregnancy and all deliveries occurred vaginally and were free of artificial support. the cord blood was deemed neonatal. late preterm neonates (20 nitric oxide and antioxidant enzymes in venous and cord blood of late preterm and term omani mothers 302 | squ medical journal, august 2012, volume 12, issue 3 males, 17 females) born to late preterm mothers, had a mean ± sd birth weight of 2,463 ± 415 g. term neonates (17 males, 20 females) born to term mothers, had a mean ± sd birth weight of 3,292 ± 491 g. maternal venous blood samples were taken during labour from the median cubital vein into evacuated lithium heparinised tubes. samples of umbilical cord blood were collected immediately after delivery by aseptic puncture of the umbilical veins connected to the maternal placenta into evacuated lithium heparinised tubes. the specimens were centrifuged at 4o c; cord and venous plasma were separated for assay of no. haemolysates were prepared from the packed cells for the assays of gpx and cat. measurement of no concentration was performed in a 96-well microtitre plate using reagents from cayman (cayman chemical company, michigan, usa) and was a two-step process based on the method of green et al.18 the first step is the conversion of nitrate to nitrite utilising nitrate reductase; the second is the addition of the greiss reagents which, on reaction with nitrite, develop a deep purple azo chromophore. absorbance is read after 10 minutes at 540 nm using a plate reader, the thermo labsystem multiskan spectrum (thermo electron corporation, zantaa, finland). standards, controls and samples were measured in triplicate and expressed in µm haemolysates were prepared from the remaining packed cells as previously described for the gpx assay, using ransel kits.19 ransel controls (randox laboratories, crumlin, uk) were used to monitor the gpx activity. catalase activity in the haemolysates and controls was assayed in a 96-well microtitre plate, using catalase assay kits (cayman chemical company, michigan, usa), which utilise the peroxidative function of cat for determination of enzyme activity. the method is based on the reaction of cat with methanol in the presence of an optimal concentration of h2o2 to form formaldehyde, measured with purpald (4-amino3-hadrazino-5mercapto-1,2,4-triazole) as the chromogen.20,21 purpald specifically forms a bicyclic heterocycle with aldehydes, which upon oxidation changes from colourless to a purple colour.19,20 the absorbance was read at 540 nm using a plate reader, the thermo labsystem multiskan spectrum (thermo fisher scientific, massachusetts, usa). the imprecision study was done using the internal quality control sera supplied in the commercial kits. analyses of twelve aliquots of the controls revealed an intra-assay coefficient of variations (%) of 2.9, 3.6 and 4.1 for no, gpx and cat, respectively; the inter-assay cv values (%) performed over six days were 3.6, 5.0 and 5.4 for no, gpx and cat, respectively. each data set was confirmed to have gaussian distribution by the one-sample kolmogorovsmirnoff test and, additionally, by histogram plots. then all data were presented as mean ± sd. the mean differences between more than two groups were determined by one-way analysis of variance (anova) using scheffe’s post-hoc test for a multiple comparison. probability (p) values were two-tailed and p <0.05 was considered to be significant. results the data comparisons (mean ± sd) of the parameters of late preterm versus term neonates are presented in table 1. late preterm neonates weighed significantly (p = <0.0001) less and had lower gpx activity (p = 0.001) as compared to term neonates. no concentrations and cat activity were similar in both groups of neonates. table 2 represents maternal data (mean ± sd) of age, no, gpx and cat. late preterm mothers were significantly younger (p = 0.027), had strikingly higher no concentrations (p <0.0001), and a markedly lower level of gpx activity (p = <0.0001) relative to term mothers. catalase activities of both mothers were similar. table 1: comparisons of parameters (mean ± sd) of birth weights, nitric oxide, glutathione peroxidase, and catalase of term neonates versus late preterm neonates parameter late preterm neonates term neonates p value (n = 37) (n = 37) birth weight (g) 2,463 ± 415 3,292 ± 491 <0.0001 no (µmol/l) 5.32 ± 3.67 5.07 ± 2.96 0.910 gpx (u/g hb) 48.8 ± 22.7 77.6 ± 26.9 0.001 cat (nmol/ min/ml) 96.5 ± 44.3 91.3 ± 45.8 0.993 note: statistical significance was considered at p <0.05. legend: no = nitric oxide; gpx = glutathione peroxidase; cat= catalase. clifford abiaka and lovina machado clinical and basic research | 303 data on the effect of gender on neonatal parameters are omitted because the differences did not attain statistical significance. discussion earlier studies carried out on animal and human tissues generally reported decreasing no synthesis concomitant with declining nos activity as gestation approached term.22–28higher no values found in late preterm mothers compared with term mothers table 2 complement those reports.22–28 some earlier studies reported a greater expression of the isoforms of nos (enos, inos) in the myometrium of the preterm ‘not in labour’ group compared with all other groups: non-pregnant women, pregnant women in the early third trimester, and pregnant women at term (both before and after labour).27,28 since inos promotes inflammation, and inflammation in turn promotes pro-oxidant formation, this may explain why late preterm mothers and not term mothers had more elevated plasma no concentrations and reduced erythrocyte antioxidant (gpx) activity table 2.12 high prooxidant levels, coupled with reduced antioxidants, signify a disturbance of the pro-oxidant-antioxidant balance otherwise known as oxidative stress.29,30 the placenta synthesises, on a weight-for-weight basis, more no than the foetal membrane or the myometrium.26 from early pregnancy, the mitochondria replete placenta influences maternal homeostasis and consumes about 1% of the basal metabolic rate of the pregnant woman.31 the placenta in addition, is highly vascular and, on exposure to high maternal oxygen tension, generates superoxide (1o2 .-); about 5% of all electrons in the mitochondrial respiratory chain seep out of the mitochondria.31 superoxide dismutase is the vanguard cytoprotective enzyme in that it disproportionates 1o2 .to o2 and h2o2 the latter being a substrate for gpx and cat. glutathione peroxidase and cat are both predominantly intracellular cytoprotective enzymes, but in addition to scavenging h2o2, gpx and not cat, also scavenges lipid (organic) hydroperoxides (rooh). hence, it follows that gpx, because of its greater antioxidant burden as compared to cat was the cytoprotective enzyme most utilised and consistently depleted in this study [tables 1 and 2]. according to a literature search, there are no previous studies related to the effect of gpx and cat on late preterm and term labour or parturition to which it is possible to make comparisons. conclusion the findings of the present study suggest that oxidative stress was more a feature of childbirth at late preterm than at term. it is anticipated that this information would be of use to the medical community in general, and particularly, to obstetricians, midwives, and neonatologists who deal with neonatal morbidity, high neonatal hospital readmissions, and post-neonatal mortality, including sudden infant death syndrome among others. a c k n o w l e d g e m e n t the authors would like to thank ms. barbara swales (head midwife) and the midwives of the delivery ward at squh for their cooperation and assistance in sample collection for this study. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest. table 2: comparisons of parameters (mean ± standard deviation) of age, nitric oxide, glutathione peroxidase, and catalase of term mothers versus late preterm mothers parameter late preterm mothers (n = 37) term mothers (n = 37) p value age (years) 27.5 ± 6.5 32.5 ± 6.0 0.027 no (µmol/l) 17.1 ± 3.3 11.0 ± 5.5 <0.0001 gpx (u/g hb) 94.1 ± 12.9 110.4 ± 12.3 <0.0001 cat (nmol/min/ml) 93.9 ± 32.6 96.3 ± 32.3 0.998 note: statistical significance was considered at p <0.05. legend: no = nitric oxide; gpx = glutathione peroxidase; cat= catalase. nitric oxide and antioxidant enzymes in venous and cord blood of late preterm and term omani mothers 304 | squ medical journal, august 2012, volume 12, issue 3 15. dweik ra. nitric oxide, hypoxia, and superoxide: the good, the bad, and the ugly! thorax 2005; 60:265–67. 16. paglia de, valentine wn. studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. j lab clin med 1967; 70:158–69. 17. villar j, abdel-aleem h, merialdi m, mathai m, ali mm, zavaleta n, et al. world health organization calcium supplementation for the prevention of preeclampsia trial group. am j obstet gynecol 2006 194:639–49. 18. green lc, wagner da, glogowski j, skipper pl, wishnokj s, tennenbaum sr. analysis of nitrate, nitrite, and [15n] nitrate in biological fluids. anal biochem 1982; 126:131–8. 19. abiaka c, al-awadi f, olusi o. effect of prolonged storage on the activities of superoxide dismutase, glutathione reductase and glutathione peroxidase. clin chem 2000; 46:566–7. 20. johansson lh, borg la. a spectrophotometric method for determination of catalase activity in small tissue samples. anal biochem 1988; 174:331–6. 21. wheeler cr, salzman ja, elsayed nm, omaye st, korte dw. automated assays for superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. anal biochem 1990; 184:193–9. 22. yallampalli c, izumi h, byam-smith m, garfield re. an arginine-nitric oxide-cyclic guanosine monophosphate system exists in the uterus and inhibits contractility during pregnancy. am j obstet gynecol 1994; 170:175–85. 23. sladek sm, regenstein ac, lykins d, roberts jm. nitric oxide synthase activity in pregnant rabbit uterus decreases on the last day of pregnancy. am j obstet gynecol 1993; 169:1285–91. 24. weiner cp, lizasoain i, baylis sa, knowles rg, charles ig, moncada s. induction of calciumdependent nitric oxide synthase by sex hormones. proc natl acad sci u s a 1994; 91:5212–16. 25. kakui k, itoh h, sagawa n, yura s, korita d, takemura m, et al. augmented endothelial nitric oxide synthase (enos) protein expression in human pregnant myometrium: possible involvement of enos promoter activation by estrogen via both estrogen receptor (er)a and erb. mol hum reprod 2004; 10:115–22. 26. angelidou e, hillhouse new, grammatopoulos dk. up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin ii or urocortin iii in cultured human pregnant myometrial cells. proc nat acad sci 2002; 99:3300– 5. 27. bansal rk, goldsmith pc, he y, zaloudek cj, ecker jl, riemer rk. a decline in myometrial nitric oxide references 1. spong cy, mercer bm, d’alton m, kilpatrick s, blackwell s, saade g. timing of indicated latepreterm and early-term birth. obstet gynecol 2011; 118:323–33. 2. martin ja, hamilton be, ventural sj. births: final data for 2009. natl vital stat rep 2011; 60:1. 3. raju tn, higgins rd, stark ar, leveno kj. optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the national institute of child health and human development. pediatrics 2006; 118:1207–12. 4. bastek ja, sammel md, pere e, srinivas sk, posencheg ma, elovitz ma. adverse neonatal outcomes: examining the risk between preterm, late preterm, and term infants. am j obstet gynecol 2008; 199:367e1–8. 5. escobar gj, gonzales vm, armstrong ma, flock bf, xiong b, newman tb. re-hospitalization for neonatal dehydration: a nested case-control study. arch pediatr adolesc med 2002; 156:155–61. 6. kinney hc. the near-term (late preterm) human brain and risk for periventricular leukomalacia: a review. semin perinatol 2006; 30:81–8. 7. billiards ss, pierson cr, haynes r, folkerth rd, kinney hc. is the late preterm infant more vulnerable to gray matter injury than the term infant? clin perinatol 2006; 33:915–33. 8. mclaurin kk, hall cb, jackson ea, owens ov, mahadevia pj. persistence of morbidity and cost differences between late-preterm and term infants during the first year of life. pediatrics 2009; 123:653– 9 9. moncada s, higgs a. the l-arginine-nitric oxide pathway. new engl j med 1993; 329:202–12. 10. bao s, rai j, shreiber j. expression of nitric oxide synthase isoforms in human pregnant myometrium at term. j soc gynecol investig 2002; 9:351–6. 11. tessaro i, luciano am, franciosi f, lodde v, corbani d, modina sc. the endothelial nitric oxide synthase/ nitric oxide system is involved in the defective quality of bovine oocytes from low mid-antral follicle count ovaries. j anim sci 2011; 89:2389–96. 12. ma ch, yan ly, qiao ch, qiao j, sha w, li l, et al. effects of tumor necrosis factor-alpha on porcine oocyte meiosis progression, spindle organization, and chromosome alignment. fertil steril 2010; 93:920–6. 13. liu b, gao hm, wang jy, jeohn gh, cooper c, hong js. nitric oxide: novel actions, deleterious effects, and clinical potential. ann n y acad sci 2002; 962:318–31. 14. pierce jd, cackler ab, arnett mg. why should you care about free radicals? rn 2004; 67:38–42. clifford abiaka and lovina machado clinical and basic research | 305 synthase expression is associated with labour and delivery. j clin invest 1997; 99:2502–8. 28. tiboni gm, giampietro f, lamonaca d. the soluble guanylate cyclase inhibitor, methylene blue evokes preterm delivery and foetal growth restriction in mouse model. in vivo 2001; 15:333–8. 29. halliwell b. oxidative stress and cancer: have we moved forward? biochem j 2007; 401:1–11. 30. valko m, leibfritz d, moncol j, cronin med, mazur m, telser j. free radicals and antioxidants in normal physiological functions and human diseases. int j biochem cell biol 2007; 39:44–84. 31. wang y. vascular biology of the placenta. in: granger dn, granger dp, eds. colloquium series on integrated systems physiology: from molecule to function. san rafael (ca): morgan & claypool publishers, 2009–2011. pp. 1–98. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 465-472, epub. 20th nov 12 submitted 6th feb 12 revision req. 30th apr 12, revision recd. 3rd jun 12 accepted 1st aug 12 1department of cardiology, sanjay gandhi postgraduate institute of medical sciences, lucknow, uttar pradesh, india; departments of 2cardiology and 3community medicine & public health, king george’s medical university, lucknow, uttar pradesh, india *corresponding author e-mail: golf_pgi@yahoo.co.in ترابط الربوتني الدهين )أ( ومقياس syntax مع شدة تصلب الشريان التاجي يف مشال اهلند فوزية اأ�صفق، بي كي غويل، ناجراجا مورثي، ري�صي �صيثي، حممد اإدري�ض خان، حممد ظفر اإدري�ض امللخ�ض: الهدف: هدف هذه الدرا�صة املقطعية درا�صة الرتابط بني م�صتويات الربوتني الدهني )اأ( كموؤ�رص لت�صلب ال�رصايني وعالقتها ب�صدة الطبية العلوم مبعهد العليا للدرا�صات غاندي �صاجناي معهد يف التوايل على مري�صا ت�صجيل 360 مت الطريقة: التاجي، ال�رصيان ت�صلب وم�صت�صفى جامعة امللك جورج الطبية، لكناو، �صمال الهند، من الذين كانوا يعانون من اآالم يف ال�صدر واأعرا�ض ت�صلب ال�رصيان التاجي وبنف�ض الوقت كانوا يتناولون عالج تخفي�ض دهون، بني يونيو 2009 واأكتوبر 2011. مت �صحب الدم �صباحا قبل الفطور قبل ت�صوير ال�رصيان التاجي لقيا�ض م�صتويات الدهون والربوتني الدهني )اأ(. مت ح�صاب التاآزر بني التدخل التاجي عن طريق اجللد بتاك�صو�ض ومقيا�ض جراحة القلب )syntax( وفقا لنتائج ت�صوير ال�رصيان التاجي. مت تق�صيم املر�صى اإىل 3 جمموعات بناء على �صدة اإ�صابة ال�رصيان م�صتويات وكانت مري�صا، يف 270 التاجي ال�رصيان اإ�صابة الدموية االأوعية ت�صوير ك�صف النتائج: .)syntax( ومقيا�ض التاجي الربوتني الدهني )اأ( اأعلى عند امل�صابني مبر�ض ال�رصيان التاجي مقارنة بغريهم )48.73 ± 23.85 ملجم / دل مقابل 18.95 11.15 بامل�صابني مقارنة واحد �رصيان بت�صّيق امل�صابني عند اأقل )اأ( الدهني الربوتني م�صتويات كانت كما p >0.0001 دل / ملجم ± بت�صّيق �رصيانني اأو ثالثة )39.28 ± 18.41 ملجم / دل مقابل 58،01 22.98 ± ملجم / دل، و69.22 24.13 ± ملجم / دل )syntax( اأعلى بكثري عند امل�صابني مبر�ض ال�رصيان التاجي ال�صديد مع نقاط )(. كانت م�صتويات الربوتني الدهني )اأ]p>0.05[ syntax( )r = 0.70,( ب�صكل كبري مع موؤ�رص )اأكرث من 30 )88.16 ± 24.35 ملجم/ دل(. ارتبطت م�صتويات الربوتني الدهني )اأ p>0.0001(. اخلال�صة: ثبت يف هذه الدرا�صة الرتابط االإيجابي بني م�صتويات الربوتني الدهني )اأ( وموؤ�رص )syntax( يف االأوعية تخفي�ض التاجية. القلب الأمرا�ض م�صتقل م�صبب اختطار عامل املرتفع )اأ( الدهني الربوتني م�صتوى كان ذلك، على وعالوة امل�صابة. م�صتويات الربوتني الدهني )اأ( �صوف تقلل االإ�صابة باأمرا�ض القلب التاجية يف الوقاية االأولية والثانوية. هناك حاجة ملحة لتحديد اأي من املر�صى ينبغي اأن ُيعالج، واأي منهم الذي يجب اأن ُي�صتهدف للتدخل املبكر. مفتاح الكلمات: الربوتني الدهني )اأ(؛ ال�صحوم الثالثية؛ االأوعية التاجية؛ موؤ�رص كتلة اجل�صم؛ ت�صلب ال�رصايني. abstract: objectives: this cross-sectional study investigated the association of lipoprotein(a) [lp(a)] levels as an atherosclerosis predictor and their relationship to the severity of coronary artery disease (cad). methods: 360 consecutive patients at sanjay gandhi postgraduate institute of medical sciences and king george’s medical university hospitals, lucknow, north india, with chest pains, cad symptoms and on lipid-lowering therapy were enrolled between june 2009 and october 2011. before coronary artery angiography (cag), a fasting blood sample was assessed for lipid and lp(a) levels. the synergy between percutaneous coronary intervention with taxus and cardiac surgery (syntax) score was calculated according to the cag results. patients were divided into 3 groups based on cad severity and syntax scores. results: angiography revealed cad in 270 patients. lp(a) levels were higher in cad compared to non-cad patients (48.7 ± 23.8 mg/dl versus 18.9 ± 11.1 mg/dl [p <0.0001]). the levels of lp(a) were lower in single than in double and triple vessels (39.3 ± 18.4 mg/dl versus 58.0 ± 23.0 mg/dl, and 69.2 ± 24.1 mg/dl, [p <0.05]). lp(a) levels were significantly higher in severe cad with syntax score >30 (88.0±24.0 mg/dl). lp(a) levels correlated significantly with syntax scores (r = 0.70, p <0.0001). conclusion: in this study, lp(a) levels were positively associated with a patient’s syntax score in diseased vessels. furthermore, an elevated lp(a) level was a causal, independent risk factor of cad. lowering lp(a) levels would reduce cad in primary and secondary prevention settings. there is an urgent need to define more precisely which patients to treat and which to target for earlier interventions. keywords: lipoprotein (a); triglycerides; coronary vessels; body mass index; atherosclerosis. lipoprotein(a) and syntax score association with severity of coronary artery atherosclerosis in north india fauzia ashfaq,1 *p.k. goel,1 nagraja moorthy,1 rishi sethi,2 mohammed idrees khan,3 mohammed zafar idris3 clinical & basic research lipoprotein(a) and syntax score association with severity of coronary artery atherosclerosis in north india 466 | squ medical journal, november 2012, volume 12, issue 4 advances in knowledge this study establishes the level of lipoprotein (a) [lp(a)] which could be a predictive factor for angiographic-proven coronary artery disease (cad) in northern indians. high levels of triglycerides (tg) are a contributing factor in atherosclerosis. an increase in atherogenic particles, especially small dense low-density lipoprotein (ldl) cholesterol, may be a causative factor for the initiation and precipitation of coronary atherosclerosis. every region and race must have standardised cut-off levels for the early detection and prevention of cad. application to patient care the study indicates that the presence of lp(a) is strongly associated with the level of severity of coronary atherosclerosis even in the case of normal total cholesterol, moderately increased tg, and low high-density lipoprotein (hdl) cholesterol levels in patients. intervention with lp(a)-lowering agents are required to prevent progressive coronary disease. it may be helpful to estimate serum tg levels to identify the presence of cad even in patients who are receiving treatments such as hypolipidemic drugs like statins. atherosclerosis is a disease of large and mediumsized arteries such as the carotid and coronary arteries, and arteries of the lower extremities. it is characterised by focal lesions of one of the following types: fatty streak, fibrous plaque, or complicated lesions. a great number of hypotheses have been published about the pathogenesis of atherosclerosis, such as the lipid hypothesis, thrombogenic hypothesis, and the endothelial cell injury hypothesis. many epidemiological studies have revealed that chronically elevated lipid and cholesterol levels are associated with an increased incidence of atherosclerosis.1 approximately 20% of the general population has high circulating levels of lipoprotein(a) [lp(a)].2 the presence of lp(a) has emerged as a powerful genetic risk factor for coronary artery disease (cad).3–5 it is a complex molecule of low-density lipoprotein (ldl) to which a large, hydrophilic glycoprotein, apolipoprotein (a) [apo(a)], is covalently linked via disulfide bonds. based on its structure, lp(a) has both atherogenic and prothrombotic properties.6 in advanced atherosclerosis, lp(a) is an independent risk factor not dependent on ldl. lp(a) represents a coagulant risk of plaque thrombosis.7 apo(a) contains domains that are very similar to plasminogen, whose main function is to dissolve fibrin blood clots. lp(a) accumulates in the vessel wall and inhibits the binding of plasminogen to the cell surface. this inhibition of lp(a) also promotes the proliferation of smooth muscle cells. this unique feature suggests it causes the generation of clots and atherosclerosis. triglyceride-(tg) rich lipoproteins, which originate both in the intestines and liver, are considered an atherogenic factor.8,9 the aim of this study was to evaluate, in judging the severity of cad, the association between the level of lp(a) as a biomarker, and lipid status. methods a cross-sectional study was conducted on 360 consecutive patients (300 male and 60 female) who underwent coronary angiography between june 2009 and october 2011 at the sanjay gandhi postgraduate institute of medical sciences and the king george’s medical university (kgmu) tertiary care hospitals in lucknow, uttar pradesh, north india. the study was approved by kmgu's ethics committee. subjects were informed of the objectives and procedure of the study and informed consent was taken with the consent form in both english and hindi. the patients’ demographic profiles, socioeconomic status, personal habits, and disease risk factor histories were recorded. blood pressure (bp) was measured before the patients were sent to the catheterisation laboratory. patients with a history of chest pain, angina, acute myocardial infarction (ami), non st-segment elevation myocardial infarction (nstemi), unstable angina, and stable angina were included. all patients received long-term treatment with angiotensin-converting-enzyme (ace) inhibitors, calcium (ca) antagonists, or αand β-adrenergic blocking agents. almost all cases received statin treatment—most frequently atorvastatin. patients with nephrotic syndrome, acute or chronic renal failure, thyroid disorders, acute infections, stroke, or diabetic ketoacidosis were excluded. coronary angiography was performed using the judkins technique, or a radial approach.10 coronary angiography results were evaluated by fauzia ashfaq, p.k. goel, nagraja moorthy, rishi sethi, mohammed idrees khan and mohammed zafar idris clinical and basic research | 467 interventional cardiologists, who were blinded to the serum lp(a) analysis. in coronary angiography, the complexity of cad was determined by an angiographic grading tool—the synergy between percutaneous coronary intervention with taxus and cardiac surgery (syntax) score.11-12 in principle, the syntax score is the sum of the points assigned to each individual lesion identified in the coronary tree with >50% narrowing in the diameter of the vessels that measure greater than 1.5 mm. the percentage of stenosis was not a consideration. only the presence of a stenosis from 50–99% in diameter, a narrowing of less than 50% in diameter, or a total occlusion were considered. the entire patient group was divided into two subgroups: subjects with cad who had a syntax score >0 and subjects without significant coronary artery stenosis with a syntax score of 0. fasting blood samples were collected after a 10 to 12 hour fast and before cardiac catheterisation. samples were taken in sterile tubes, centrifuged at 3000 rpm for 10 minutes at 4°c, and then stored at -80°c until assayed. fasting blood glucose (fbg), serum total cholesterol, high-density lipoprotein cholesterol (hdl-c), serum tg, and ldl-cholesterol (ldl-c) levels were estimated by standard methods. lp(a) was measured by agglutination due to an antigen-antibody reaction between lp(a) in a sample and anti-lp(a) antibodies absorbed to latex particles. the assay range is approximately 3–90 mg/dl. higher values of lp(a) were rechecked by diluting the sample with normal saline. results were then standardised. the results are presented in mean ± standard deviation (sd) and percentage. the unpaired t-test was used to compare the two continous variables and one way analysis of variance (anova) was used to compare more than two continous variables. the 95% confidence interval (ci) of means was also calculated. the pearson correlation coefficient was calculated to find out the correlation between two variables. the p value <0.05 was considered significant. all the analysis was carried out by using the statistical package for the social sciences (spss), version 15.0 (ibm, chicago, il, usa). results the mean age of the patients was 54.0 ± 8.0 years, ranging from 30–65 years. a total of 270 patients (75%) of the 360 patients had angiographicallytable 1: comparison of clinical and biochemical parameters between coronary artery disease (cad) and non-cad patients as defined by angiography parameters cad (syntax score > 0) (n = 270) non-cad (syntax score = 0) (n = 90) p value sbp (mmhg) 142 ± 18 138 ± 16 <0.001 dbp (mmhg) 86 ± 10 82 ± 11 <0.001 bmi (kg/m2) 26 ± 2.1 24.9 ± 2.7 <0.001 tc (mmol/l) 3.9 ± 0.8 (150.8 ± 30.2) 3.6 ± 0.8 (139.9 ± 30.3) 0.03 tg (mmol/l) 2.1 ± 0.5 (182.8 ± 43.9) 1.4 ± 0.5 (124 ± 44) 0.001 hdl-c (mmol/l) 0.8 ± 0.2 (30.9 ± 7.5) 1.3 ± 0.2 (40 ± 9) <0.001 ldl-c (mmol/l) 2.2 ± 0.7 (83 ± 28.9) 1.9 ± 0.7 (75 ± 27) 0.02 vldl-c (mmol/l) 0.9 ± 0.2 (36 ± 9.2) 0.6 ± 0.2 (24.7 ± 8.9) <0.001 atherogenic marker lipoprotein(a) (mg/dl) 48.7 ± 23.8 18.9 ± 11 <0.001 all results expressed in mean and standard deviation (sd). all values are reported in mmol/l and mg/dl, respectively. cad = coronary artery disease; syntax = synergy between percutaneous coronary intervention with taxus; sbp= systolic blood pressure; dbp = diastolic blood pressure; bmi = body mass index; tc = total cholesterol; tg = triglycerides; hdl-c = high density lipoproteins cholesterol; ldl-c = low density lipoproteins cholesterol; vldl-c = very low density lipoproteins cholesterol; lp(a) = lipoprotein(a). table 2: lipoprotein(a) levels in normal coronary and diseased vessels vessels grade no. of patients lp(a) level (mg/dl) mean ± sd (min– max) 95% ci of mean normal coronary* 90 18.9 ± 11 (3.00–40.0) 16.61–21.28 single vessel disease† 163 39.3 ± 18 (21.4–104) 36.43–42.12 double vessel disease‡ 58 58 ± 23 (22.8–108) 51.97–64.05 triple vessel disease 49 69 ± 24 (22.8–110) 62.29–76.76 f and p values 95.72; <0.001 lp(a) = lipoprotein(a); sd = standard deviation; ci = confidence interval; *significantly different from single, double and triple vessel disease (p <0.0001); †significantly different from double and triple vessel disease (p <0.0001); ‡significantly different from triple vessel disease (p = 0.01) (holm-bonferroni multiple comparison test.). lipoprotein(a) and syntax score association with severity of coronary artery atherosclerosis in north india 468 | squ medical journal, november 2012, volume 12, issue 4 proven cad and 90 (25%) had normal coronary arteries (non-cad group). the systolic and diastolic blood pressure was significantly higher in cad patients (p <0.001) as compared to the noncad patients. the body mass index (bmi) was significantly higher in cad patients (p <0.0001) as compared to non-cad patients. there was a highly significant difference (p <0.0001) in the level of tg between cad (2.0 ± 0.5 mmol/l) and non-cad (1.4 ± 0.5 mmol/l) patients. a highly significant difference was observed in the level of very low density lipoproteins (vldl) between cad (0.9 ± 0.2 mmol/l) and non-cad (0.6 ± 0.2 mmol/l) patients. however, the hdl was significantly lower (p <0.0001) in cad patients (0.8 ± 0.2 mmol/l) as compared to non-cad (1.0 ± 0.2 mmol/l) patients. lp(a) levels were significantly higher in cad (49 ± 24 mg/dl) than non-cad patients (19 ± 11 mg/dl) [table 1]. parameters were compared by vessel gradeslp(a) levels were significantly different among normal and different grades (p <0.0001). the holmbonferroni pairwise comparison test showed that lipoprotein levels were significantly higher in all diseased vessels than those categorised as normal (p <0.0001) [table 2]. cad subjects with diseased vessels had higher tg and vldl levels, and lower hdl cholesterol concentrations in diseased vessels as compared to people with normal coronary status [table 3]. a subgroup analysis indicated that lp(a) levels were significantly higher (p <0.0001) in patients with tg levels ≥150 mg/dl (47.6 ± 25.1 mg/dl) as compared to those with tg levels of <150 mg/ dl (25.2 ± 15.6 mg/dl). however, lp(a) was higher (p <0.0001) in those with hdl-c levels of ≤40 mg/ dl (43.6 ± 24.9 mg/dl) than those with levels >40 (26.7 ± 20.0 mg/dl). furthermore, lp(a) levels were significantly lower (p <0.0001) among those whose tg levels were <150 mg/dl and hdl was >40 mg/ dl (15.6 ± 8.9 mg/dl) as compared to others (43.3 ± 24.6 mg/dl) [table 4]. cad patients were classified according to their syntax scores: <20, 20–30, and >30; lp(a) levels in these subgroups were analysed and found significantly different [table 5]. according to the correlation coefficient, there was a positive association between lp(a) levels and syntax scores for the diseased vessel patient group (r = 0.70, p <0.0001) [figure 1]. discussion in this study, lp(a) level >20 mg/dl was not only associated with the presence of coronary disease but also with the severity of the coronary atherosclerosis. this finding is consistent with previous reports.13 a study carried out in southern india reported the cut-off level of lp(a) as being 25 mg/dl for determination of a patient’s risk of coronary heart disease (chd).14 higher mean levels of lp(a) were observed in our cases as compared to the control group in studies reported in other parts of india, where levels ranged from 12 to 41 mg/dl in cad patients, and 8 to 24 mg/dl in healthy controls.15–18 mean lp(a) levels in patients in our study were also within the range of values reported in earlier indian studies.19 upper limits of normal lp(a) have not been defined in the indian population.15 in caucasians, an lp(a) of 30 mg/dl is considered the upper limit of normal. erbagci et al. showed that the optimal cut-off values for lp(a) levels were 22.6 and 9.8 mg/dl for men and women, respectively, in cases of chd, with or without angiographically table 3: lipid parameters in normal coronary and diseased vessels of patients parameters units: mmol/l (mg/dl) vessel grades nc svd dvd tvd p value tc 3.6 ± 0.8 (140 ± 30) 3.0 ± 0.7 (151 ± 28) 3.9 ± 0.9 (152 ± 35) 3.8 ± 0.8 (148 ± 31) 0.78 tg 1.4 ± 0.5 (124 ± 44) 1.9 ± 0.4 (177 ± 39) 2.1 ± 0.5 (187 ± 42) 2.2 ± 0.6 (197 ± 57) <0.001 hdl-c 1.0 ± 0.2 (40 ± 9) 0.8 ± 0.2 (31 ± 7) 0.8 ± 0.2 (31 ± 8) 0.8 ± 0.2 (30 ± 6) <0.001 ldl-c 1.4 ± 0.7 (75 ± 27) 2.2 ± 0.7 (84 ± 27) 2.2 ± 0.8 (83 ± 32) 2.0 ± 0.7 (79 ± 29) 0.08 vldl-c 0.6 ± 0.2 (25 ± 9) 0.9 ± 0.2 (35 ± 8) 0.9 ± 0.2 (37 ± 8) 1.0 ± 0.3 (39 ± 12) <0.001 nc = normal coronary; svd = single vessel disease; dvd = double vessel disease; tvd = triple vessel disease; tc = total cholesterol; tg = triglycerides; hdl-c = high density lipoproteins cholesterol; ldl-c = low density lipoproteins cholesterol; vldl-c = very low density lipoproteins cholesterol. fauzia ashfaq, p.k. goel, nagraja moorthy, rishi sethi, mohammed idrees khan and mohammed zafar idris clinical and basic research | 469 coronary status. high tg levels in our patients appeared to contribute to cad risk. tg levels >130 mg/dl are strongly associated with the extent of a patient’s coronary atherosclerosis; therefore, the present coronary angiography proven study is in agreement with the documented epidemiologic observations reported by austin, which was that hypertriglyceridemia commonly occurrs in cad patients [table 3].21-23 a delayed clearance of vldl and chylomicron, and/or increased hepatic production of large vldl results in the increased production of precursors of small dense ldl particles, a phenotype of which was reported to be associated with increased production of potentially atherogenic remnant-like particles.24 enrichment of the tg of this product through the action of cholesteryl ester transfer protein, together with hydrolysis of tg by hepatic lipase leads to an increased production of small dense ldl. increased demonstrable lesions.20 our results showed lp(a) as 21.4 mg/dl in minimal angiographically-proven single vessel disease even when cardiovascular risk factors and specific treatments (statins and/or aspirin) were taken into account; therefore, a level >20 mg/dl should be considered the cut-off value in the northern indian population [table 2]. contrary to the notion that these risk factors are highly prevalent in northern indians, we found increased tg and very low hdl levels in diseased vessel patients as compared to those with normal table 4: lipoprotein(a) levels as a subgroup of triglycerides and high-density lipoprotein cholesterol (hdl-c) parameters parameters no. lp(a) mg/dl p value tg <150 mg/dl 102 25.2 ± 15.6 <0.001 >150 mg/dl 258 47.6 ± 25.1 hdl-c <40 mg/dl 311 43.6 ± 24.9 <0.001 >40 mg/dl 49 26.7 ± 20.0 tg <150 and hdl-c >40 mg/dl 26 15.6 ± 8.9 <0.001tg >150 and hdl-c <40 mg/dl 334 43.3 ± 24.6 tg = triglycerides; hdl-c = high density lipoprotein cholesterol; lp(a) = lipoprotein (a). table 5: lipoprotein(a) level by synergy between percutaneous coronary intervention with taxus and cardiac surgery (syntax) score syntax score no. of patients lipoprotein(a) mg/dl <20 226 42 ± 18 20–30 21 75 ± 16 >30 23 88 ± 24 figure 1: scatter diagram showing the correlation between lipoprotein (a) [lp(a)] levels and synergy between percutaneous coronary intervention with taxus and cardiac surgery (syntax) scores. pearson correlation coefficient (r = 0.70, p <0.0001) lipoprotein(a) and syntax score association with severity of coronary artery atherosclerosis in north india 470 | squ medical journal, november 2012, volume 12, issue 4 levels of small dense ldl have been identified as a risk factor for an increased incidence of cad in several epidemiological studies.25 furthermore, a subgroup analysis of tg and hdl-c cut-offs showed significant lp(a) variation in our study. significantly higher lp(a) levels increased tg >150 mg/dl and it was also observed that lp(a) levels markedly increased in subjects with low levels of hdl-c (p <.0001). lp(a) levels depend on lipid profiles and suggest that treatment of dyslipidemia may also affect lp(a) concentrations. future studies are needed to clarify common mechanisms, enzymes, and receptors involved in lp(a) and hdl/tg metabolism with a focus on how these mechanisms are modified in the setting of hypertriglyceridemia. a marked raise in lp(a) levels was found in patients with a syntax score >30 (88 ± 24mg/ dl). subjects with an intermediate to high syntax score (20–30) observed higher lp(a) levels (75 ± 16 mg/dl, p = 0.0001] as compared to subjects with low syntax scores <20 (42 ± 18 mg/dl). these values shows that lp(a) is directly related to syntax score grading of atherosclerotic lesions. our findings show that lp(a) levels correlate with cad severity [table 5] and with syntax scores. assuming that the syntax score has the ability to describe anatomical and functional features of cad, we suggest that lp(a) levels can predict the extent of coronary artery impairment. the syntax score predicts mortality and morbidity in patients irrespective of disease severity, at both shortand long-term follow-ups. the relationship between lp(a) and the extent of cad assessed by syntax score had not been investigated in previous studies. the mechanism implicated in the atherogenicity of lp(a) includes proatherogenic lp(a), via its apo(a) moiety, which is a proinflammatory molecule that directly interacts with the leukocyte β2-integrin mac-1, thereby facilitating the recruitment of inflammatory cells. tgf-β1 activation is another mechanism via which lp(a) contributes to the development of atherosclerotic vasculopathies. tgf-β1 is subject to proteolytic activation by plasmin and its active form leads to an inhibition of the proliferation and migration of smooth muscle cells, which play a central role in the formation and progression of atherosclerotic vascular diseases. if tgf-β1 fails to be activated, for example due to lp(a) accumulation in the vascular wall, it is associated with an increased proliferation and migration of the smooth vascular muscle cells and the formation of atherosclerotic lesions.26 in assessing appropriate cardiovascular preventive measures, clinical investigations using niacin alone or in combination with other lipidlowering agents such as statins have provided evidence for its dose-dependent cardiovascular benefit of up to 40%, and its amelioration of the global cardiovascular risk profile of patients.27,28 bruckert et al. published a meta-analysis of 11 randomised controlled trials, involving 2,682 patients in the active group and 3,934 in the control group, which examined the effects of niacin alone or in combination with other lipidlowering drugs on cardiovascular events and atherosclerosis.29 recently, a report suggested that a 2-month treatment with a ginkgo biloba extract reduced lp(a), with results attributed due to the anti-inflammatory effect of this natural extract.30 finally, there is reliable evidence to show that antiplatelet therapy with aspirin decreases platelet function, and may decrease plasma lp(a) as well. the physiological basis of this pleiotropic effect of aspirin is still uncertain, although it may decrease the hepatic synthesis of apo(a) by inhibiting the transcriptional activity of the gene and suppressing messenger ribonucleic acid (rna) expression.31 other studies investigated the effect of other compounds like carnitine and coenzyme q10.32–37 a large number of apheresis techniques have been described based on plasma separation (lipid filtration, ldl-precipitation, and direct adsorption of lipoproteins). all methods have been primarily developed for treatment of high plasma ldl concentrations. however, because of the numerous structural similarities between ldl and lp(a), the effect of these methods on both lipoproteins is very similar. essentially, depending on the treated plasma or blood volume concentrations of lp(a) and ldl, levels are lowered by 50–74 %, and >60 % at each therapy. even other haemorheological parameters such as fibrinogen and viscosity are positively influenced.38 this study confirms lp(a) levels >20 mg/dl as a cut-off value to predict the severity of coronary atherosclerosis, suggesting that lp(a) levels should be determined in patients with cad, especially in normolipidemic individuals. lp(a), considered an emerging risk factor by the national cholesterol fauzia ashfaq, p.k. goel, nagraja moorthy, rishi sethi, mohammed idrees khan and mohammed zafar idris clinical and basic research | 471 vascular disease, and mortality in the elderly. new engl j med 2003; 349:2108–15 3. danesh j, collins r, peto r. lipoprotein(a) and coronary heart disease: a meta-analysis of prospective studies. circulation 2000; 102:1082–5. 4. von eckardstein a, schulte h, cullen p, assmann g. lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. j am coll cardiol 2001; 37:343–9. 5. luc g, bard jm, arveiler d, ferrieres j, evans a, amouyel p, et al. lipoprotein(a) as a predictor of coronary heart disease: the prime study. atherosclerosis 2002; 163:377–84. 6. utermann g. the mysteries of lipoprotein(a). science 1989; 246:904–10. 7. caplice nm, panetta c, peterson te, kleppe ls, mueske cs, kostner gm, et al. lipoprotein(a) binds and inactivates tissue factor pathway inhibitor; a novel link between lipoproteins and thrombosis. blood 2001; 98:2980–7. 8. philips nr, waters d, havel rj. plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. circulation 1993; 88:2762–70. 9. zilversmit db. atherogenic nature of triglycerides, postprandial lipemia, and triglyceride-rich remnant lipoproteins. clin chem 1995; 41:153–8. 10. judkins mp. a percutaneous transfemoral technique. radiology 1967; 89:815–21. 11. serruys pw, morice mc, kappetein ap, colombo a, holmes dr, mack mj, et al. for the syntax investigators. percutaneous coronary intervention versus coronary artery bypass grafting for severe coronary artery disease. n engl j med 2009; 360:961–72. 12. sianos g, morel ma, kappetein ap, morice m-c, colombo a, dawkins k, et al. the syntax score: an angiographic tool grading the complexity of cad. eurointervention 2005; 1:219–27. 13. velmurugan k, deepa r, ravikumar r, enas ea, lawrence jb, anshoo h, et al. relationship of lipoprotein(a) with initmal medial thickness of the carotid artery in type 2 diabetic patients in south india. diabet med 2003; 20:455–61. 14. rajasekhar d, saibaba kss, srinivasa rao pvln, latheef saa, subramanyam g. lipoprotein(a): better assessor of coronary heart disease risk in south indian population. indian j clin biochem 2004; 19:53–9. 15. gambhir jk, harsimrut k, gambhir ds, prabhu km. lipoprotein(a) as an independent risk factor for coronary artery disease in patients below 40 years of age. indian heart j 2000; 52:411–5. 16. muthuswamy v, amuthan v, kumaravel v. lipoprotein(a) and premature coronary artery disease. indian heart j 2000; 52:765. education program’s (ncep) adult treatment panel (atp) iii, has been implicated in the development of the premature atherosclerotic disease seen in south asians.39 among patients with excessive lp(a), cad risk increases 3-fold in the absence of other risk factors. the risk increases 8-fold with low hdl-c, 12-fold with high ldl-c, 16-fold with diabetes, and 25-fold with a tc/ hdl-c ratio. the higher the lp(a) level the lower the age of first heart attack, and the most affected individuals develop myocardial infarction (mi) by the third to fifth decade of life. high levels of lp(a) correlate with the prematurity, severity, extent, and progression of coronary atherosclerosis as well as the occurrence and recurrence of mi among asian indians.40 although all patients with hypertension and cad require aggressive risk modification, the subgroup with high lp(a) and tg levels may have multiple-vessel involvement and probably will need close clinical surveillance. there are limitations to our study. the enrolled subjects might not be representative of the entire cad population, as subjects recruited were referred to tertiary care for a coronary angioplasty restenosis trial (cart) and percutaneous transluminal coronary angioplasty (ptca) and syntax score grading considers over 50% coronary artery luminal reduction. the generally used estimation of luminal reduction is not exact and can be incorrect in spite of an investigator’s experience. conclusion in conclusion, this cross-sectional analysis suggests that lp(a) levels differ significantly among indians. the association between lp(a) and cardiovascular outcomes may differ by race/ethnicity as well. further studies should strive to disaggregate racial/ethnic groups and stratify by gender when examining lp(a) among asians. if replicated, our study suggests that the determination of lp(a) levels may be particularly important in asian indians for the prevention of cardiovascular disease. references 1. abdelhalim ma, sato m, ohshima n. effects of cholesterol feeding periods on aortic mechanical properties of rabbits. jsme int j 1994; 37:79–86. 2. ariyo aa, thach c, tracy r. lp(a) lipoprotein, lipoprotein(a) and syntax score association with severity of coronary artery atherosclerosis in north india 472 | squ medical journal, november 2012, volume 12, issue 4 17. vasisht s, gulati r, srivastava r, narang lm, agarwal n, manchanda sc. apolipoprotein(a) polymorphism and its association with plasma lipoprotein(a) levels: a north indian study. indian heart j 2000; 52:407–10. 18. gupta r, kastia s, rastogi s, kaul v, nagar r, enas, ea. lipoprotein(a) in coronary heart disease: a case-control study. indian heart j 2002; 52:407–10. 19. singh y, srivastava s, ahmad s, mishra sk, shirazi n, raja m, et al. is lipid tetrad index the strongest predictor of premature coronary artery disease in north india? j indian acad clin med 2010; 11:175– 9. 20. erbagci ab, tarakcioglu m, aksoy m, kocabaş r, nacak m, aynacioğlu as, et al. diagnostic value of crp and lp(a) in coronary heart disease. acta cardiol 2002; 57:197–204. 21. austin ma. epidemiology of hypertriglyceridemia and cardiovascular disease. am j cardiol 1999; 83:13. 22. mclaughlin t, abbasi f, cheal k, chu j, lamendola c, reaven g. use of metabolic markers to identify overweight individuals who are insulin resistant. ann intern med 2003; 139:802–9. 23. reaven gm. insulin resistant compensatory hyperinsulinemia, essential hypertension, and cardiovascular disease. j clin endocrinol metab 2003; 88:2399. 24. koba s, hirano t, murayama s, kotani t, tsunoda f, iso y. small dense ldl phenotype is associated with postprandial increases of large vldl and remnantlike particles in patients with acute myocardial infarction. atherosclerosis 2003; 170:131–40. 25. krauss rm. lipids and lipoproteins in patients with type 2 diabetes. diabetes care 2004; 276:1496–504. 26. sotiriou sn, orlova vv, al-fakhri n, ihanus e, economopoulou m, isermann b. lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with mac-1 integrin. faseb j 2006; 20:559–61. 27. nordestgaard bg, chapman mj, ray k, et al. european atherosclerosis society consensus panel. lipoprotein(a) as a cardiovascular risk factor: current status. eur heart j 2010; 31:2844–53. 28. scanu am, bamba r. niacin and lipoprotein(a): facts, uncertainties, and clinical considerations. am j cardiol 2008; 101:44b–47b. 29. bruckert e, labreuche j, amarenco p. meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. atherosclerosis 2010; 210:353–61. 30. lippi g, targher g, guidi gc. ginkgo biloba, inflammation and lipoprotein(a). atherosclerosis 2007; 195:417–8 31. lippi g, franchini m, targher g. platelets and lipoprotein(a) in retinal vein occlusion: mutual targets for aspirin therapy. j thromb haemost 2007; 97:1059–60. 32. solfrizzi v, capurso c, colacicco am, capurso a, panza f. efficacy and tolerability of combined treatment with l-carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus. atherosclerosis 2006; 188:455–61. 33. derosa g, cicero af, gaddi a, mugellini a, ciccarelli l, fogari r. the effect of l-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. clin ther 2003; 25:1429–39. 34. rahbar ar, shakerhosseini r, saadat n, taleban f, pordal a, gollestan b. effect of l-carnitine on plasma glycemic and lipidemic profile in patients with type ii diabetes mellitus. eur j clin nutr 2005; 59:592–6. 35. sirtori cr, calabresi l, ferrara s, pazzucconi f, bondioli a, baldassarre d, et al. l-carnitine reduces lipoprotein(a) levels in patients with hyper lp(a). nutr metab cardiovasc dis 2000; 10:247–51. 36. cicero af, derosa g, miconi a, laghi l, nascetti s, gaddi a. treatment of massive hypertriglyceridemia resistant to pufa and fibrates: a possible role for the coenzyme q10? biofactors 2005; 23:7–14. 37. cicero af, derosa g, miconi a, laghi l, nascetti s, gaddi a. possible role of ubiquinone in the treatment of massive hypertriglyceridemia resistant to pufa and fibrates. biomed pharmacother 2005; 59:312–7. 38. bambauer r. is lipoprotein(a)–apheresis useful? ther apher dial 2005; 9:142–7. 39. eapen d, kalra gl, merchant n, arora a, khan bv. metabolic syndrome and cardiovascular disease in south asians. vasc health risk manag 2009; 5:731– 43. 40. enas ea, chacko v, pazhoor sg, chennikkara h, devarapalli hp. dyslipidemia in south asian patients. curr atheroscler rep 2007; 5:367–74. squ med j, may 2012, vol. 12, iss. 2, pp. 228-231, epub. 9th apr 2012 submitted 09th aug 11 revision req. 2nd nov 11, revision recd. 16th nov 11 accepted 28th dec 11 departments of 1social and pediatric dentistry, 2pathology and clinical propaedeutics, and 4prosthodontics, araçatuba school of dentistry, unesp, araçatuba, brazil; 3department of pediatric dentistry, university of cuiabá, unic, cuiabá, brazil. *corresponding author e-mail: goiato@foa.unesp.br عرض غري عادي لسرطان اخلاليا احلرشفية يف الفم عند امرأة شابّة دايوريان فرانكا، لريا مونتي، اإلفيمار دي كا�سرتو، اآنا �سبحية، لوي�س فولباتو، �ساندرا اأغيار، مار�سيلو جي جوياتو امللخ�ص: �رضطان اخلاليا احلر�سفية يف الفم من اأكرث االأورام اخلبيثة، وي�سيب ب�سكل رئي�سي االأ�سخا�س فوق �سن 50 �سنة الذين يعتادون على تعاطي التبغ والكحول. يندر حدوث هذا النوع من ال�رضطان عند من هم اأقل من 40 �سنة، وعندما يحدث ال يكون هناك عالقة بعوامل اخلطر، ويكون انت�ساره اأكرث �سدة. نظرا لندرة التقارير يف هذه الفئة من ال�سكان، فاإنه من ال�سعب اأن يثبت االجتاه املتزايد للمر�س. نو�سح قي هذا التقرير حالة �رضطان اخلاليا احلر�سفية يف الفم عند امراأة عمرها 39 عاما، ولي�س لها تاريخ من تعاطي التبغ اأو الكحول. ونناق�س اال�ستنتاجات ال�رضيرية والت�رضيحية املر�سية، امل�سببات املر�سية والعالج. االجتاه املتزايد حلدوث �رضطان اخلاليا احلر�سفية يف الفم عند ال�سابات دون وجود عوامل اخلطر املعروفة ي�سلط ال�سوء على اأهمية ا�ستعداد االأطباء لت�سخي�س هذه االآفة ب�رضعة وبدقة، وتوفري اأف�سل النتائج، الإبقاء املري�س على قيد احلياة، وحت�سني نوعية حياة املري�س. مفتاح الكلمات: �رضطان، اخلاليا احلر�سفية، اأورام الفم؛ عوامل اخلطر، تقرير حالة، الربازيل. abstract: oral squamous cell carcinoma (oscc) is the most common oral malignant neoplasm, mainly affecting individuals over 50 years old with a history of tobacco and alcohol use. the occurrence of this oral cancer in individuals under 40 years old is unusual and, when it does occur, shows a weaker relation to those risk factors and a more aggressive clinical course. due to the paucity of reports in this population, it is difficult to prove its increasing trend. a case of oral squamous cell carcinoma in a 39-year-old woman with no history of tobacco or alcohol use is reported. clinical and histopathological findings, aetiology, and treatment are discussed. the increasing trend of oral squamous cell carcinoma in young women without known risk factors highlights the need for clinicians to be prepared to diagnose this lesion quickly and precisely, providing a better prognosis, chance of survival, and quality of life for the patient. keywords: carcinoma, squamous cell; mouth neoplasms; risk factors; case report; brazil. unusual presentation of oral squamous cell carcinoma in a young woman diurianne cc frança,1 lira m monti,2 alvimar l de castro,2 ana mp soubhia,2 luiz er volpato,3 sandra mhc á de aguiar,1 *marcelo c goiato4 case report throughout the last century, the number of cancer cases increased worldwide, now representing one of the most important public health problems in the world. the incidence of oral cancer has also increased.1 oral squamous cell carcinoma (oscc) represents between 90% and 95% of all malignant neoplasms of the oral cavity. lesions are located mainly on the tongue, especially on the lateral posterior border.2 historically, scientific literature has demonstrated a preferential incidence of oral cancers in men aged 50 to 70 years.2–7 however, recent epidemiological studies have shown an increase in the development of oscc in patients under 45 years old.8,9 in those cases, tumour behaviour is different and patients have a poor prognosis in comparison to cancer in older adults.10 the modification of social and cultural habits, specifically those concerning male and female behaviours, could be related to the increase in the occurrence in women.1,11,12 however, the absence of traditional risk factors such as alcoholism and excessive tobacco use2,7 in young patients has suggested that in these cases cancer may be diurianne cc frança, lira m monti, alvimar l de castro, ana mp soubhia, luiz er volpato, sandra mhc á de aguiar and marcelo c goiato case report | 229 a different disease from that occurring in older patients, and may have a different aetiology and clinical progress.13–15 in this article, we report the case of oscc in a woman with no history of tobacco or alcohol use, and discuss the clinical and histopathological findings, aetiology and treatment. case report a 39-year-old female patient with no history of alcoholism, excessive tobacco use, or any other harmful habit, sought treatment for the complaint of an ulcerated lesion with one month’s evolution in the buccal mucosa. the lesion was defined by the patient as a common aphthous ulcer. the patient revealed a family history of cancer, as her grandmother had died of stomach cancer. clinically, facial asymmetry with tumefaction at the right side was observed [figure 1]. intra-orally, there was an ulcerated lesion 5 cm in diameter, with irregular borders, and a necrotic bed located at the right buccal mucosa [figure 2]. whitish areas could be observed in the periphery of the ulceration. the radiographic examination did not reveal any signs of bone destruction, and the proposed clinical diagnosis was a traumatic ulcer. an incisional biopsy was performed. areas of great inflammatory infiltrate were identified as well as hornish pearls, intact stratified pavemented epithelium, islets of neoplastic epithelium, polymorphism, and hyperchromatism, thus establishing the diagnosis as oscc [figure 3]. the tumour-node-metastasis (tnm) staging system revealed was stage iii disease (t3n0m0) based on the mouth cancer tnm classification criteria of the american joint committee for cancer staging (uicc/ajc). the patient was referred to an oncological centre for treatment, which included surgery for resection of the oral mucosa involving the upper alveolar ridge, labial commissure, and mandibular retromolar area, and radiotherapy (5040 cgy). currently, the patient is in complete remisssion, and follow-up treatment includes speech therapy and nutritional counselling. discussion oscc occurs less frequently in young individuals (<40 years). those cases represent 3 to 6% of all osccs.3,4,7 in up to 72% of these younger patients, one or more behavioural risk factors are present. also, men are affected twice as often as women.16 of the many different factors associated with an increased risk for oscc, tobacco and alcohol seem to be the most studied. individuals who smoke more than 20 cigarettes a day and consume more than 100 g of alcohol a day are at increased risk of oral epithelial dysplasia, but ex-smokers of 10 or more years seem to have no greater risk than nonsmokers.16 few reports have shown distinct molecular differences between younger and older patients with oscc, as well as between non-smoking and smoking patients, supporting the hypothesis that different subgroups of oscc exist, especially with respect to exposure to tobacco carcinogens.7 figure 1: front and lateral profile of patient showing facial asymmetry with swelling at the right side of cheek. unusual presentation of oral squamous cell carcinoma in a young woman 230 | squ medical journal, may 2012, volume 12, issue 2 many people are exposed to such risk factors and only a small percentage develops the disease, which determines the necessity of searching for other risk factors such as immunological or nutritional deficiencies, genetic factors, and microbiological agents in etiogenesis. among these factors, human papillomavirus and epstein-barr virus have already been suggested as aetiological factors.1,12 in summary, the factors that should be investigated in order to explain the aetiology of oscc in young patients, include genetic predisposition, previous viral infections, nutritional patterns, immunodeficiency, occupational exposure to carcinogens, socioeconomic conditions, and oral hygiene.2 there is some agreement regarding the poor prognosis and short survival rates in younger patients who develop oscc in the absence of the usual risk factors,3 although some studies were based on small numbers of patients.4,15 conclusion we described the case of a 39-year-old lady who was diagnosed to have oscc of the buccal mucosa.2,7,16 there were no known risk factors. oscc in this age is rare, but should always be considered in the differential diagnosis of non-healing buccal ulcers. the association a young female patient without exposure to the most common risk factors, and more aggressive tumoural behavior in an unusual area, suggest that oscc, when occurring in non-smokers, represents a different clinical it is hypothesised that a subgroup of individuals, characterised by the development of the disease at early ages and by shorter exposure time to behavioural risk factors, develops a histologically similar, but genetically different oscc, as compared to their older counterparts. this may be due to an increased susceptibility to the development of oral cancer as a result of a lower expression of single nucleotide polymorphisms of the gstp1 gene. this encodes an enzyme that functions in xenobiotic metabolism of polycyclic aromatic hydrocarbons, which is involved in the metabolism of carcinogens and/or dna repair, as seen in other tumour types.7 clinical manifestations of oscc in younger patients have no features to distinguish them from that of older patients; nevertheless, many clinicians tend not to include oscc as a differential diagnosis in young patients, simply because such disease does not often present in that age range.2 the reported case presents different characteristics from the oscc usually reported in epidemiological studies; the patient was young and without a history of alcoholism or excessive tobacco use. in this case, in consideration of the family’s health history, the genetic hypothesis must be reinforced in the lesion aetiology. this is consistent with the observation of other workers who report oscc without a history of alcoholism or excessive tobacco use.3,14,17 alcoholism or excessive tobacco use have been reported in only a small number of young patients, and even in cases where a correlation is found, the exposure to carcinogens was not sufficient for the development of a malignant lesion.14,18 moreover, figure 2: intra-oral view of the right buccal mucosa showing the presence of an exophytic ulcerated lesion with irregular margins and necrotic bed. figure 3: photomicrograph of the right buccal mucosa showing areas of inflammatory infiltration, presence of hornish pearls (arrows), stratified pavement epithelium, and islets of neoplastic epithelium (haematoxylin-eosin stain, x 10 magnification) diurianne cc frança, lira m monti, alvimar l de castro, ana mp soubhia, luiz er volpato, sandra mhc á de aguiar and marcelo c goiato case report | 231 and molecular disease. further studies would be necessary to identify other risk factors involved in tumoural development in order to improve prevention programmes and early detection. references 1. liu l, kumar sk, sedghizadeh pp, jayakar an, shuler cf. oral squamous cell carcinoma incidence by subsite among diverse racial and ethnic populations in california. oral surg oral med oral pathol oral radiol endod 2008; 105:470−80. 2. hirota sk, migliari da, sugaya nn. oral squamous cell carcinoma in a young patient – case report and literature review. ann bras dermatol 2006; 81:251−4. 3. alsharif mj, jiang wa, he s, zhao y, shan z, chen x. gingival squamous cell carcinoma in young patients: report of a case and review of the literature. oral surg oral med oral pathol oral radiol endod 2009; 107:696−700. 4. llewellyn cd, linklater k, bell j, johnson nw, warnakulasuriya kaas. risk factors for squamous cell carcinoma of the oral cavity in young people a comprehensive literature review. oral oncology 2001; 37:401−18. 5. cheung ej, wagner h jr, botti jj, fedok f, goldenberg d. advanced oral tongue cancer in a 22-year-old pregnant woman. ann otol rhinol laryngol 2009; 118:21−6. 6. mosleh-shirazi ms, mohammadianpanah m, mosleh-shirazi ma. squamous cell carcinoma of the oral tongue: a 25-year, single institution experience. j laryngol otol 2009; 123:114−20. 7. tremblay s, dos reis pp, bradley g, galloni nn, perez-ordonez b, freeman j et al. young patients with oral squamous cell carcinoma. arch otolaryngol head neck surg 2006; 132:958−66. 8. binahmed a, charles m, campisi p, forte v, carmichael rp, sándor gk. primary squamous cell carcinoma of the maxillary alveolus in a 10-year-old girl. j can dent assoc 2007; 73:715−8. 9. cudney n, ochs mw, johnson j, roccia w, collins bm, costello bj. a unique presentation of a squamous cell carcinoma in a pregnant patient. quintessence int 2010; 41:581−3. 10. martin-granizo r, rodriguez-campo f, naval l, diaz gonzalez fj. squamous cell carcinoma of the oral cavity in patients younger than 40 years. otolaryngol head neck surg. 1997;117:268−75. 11. hashibe m, brennan p, benhamou s, castellsague x, chen c, curado mp, et al. alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the international head and neck cancer epidemiology consortium. j natl cancer inst 2007; 99:777−89. 12. curado mp, hashibe m. recent changes in the epidemiology of head and neck cancer. curr opin oncol 2009; 21:194−200. 13. hirota sk, braga fpf, penha ss, sugaya nn, migliari da. risk factors for oral squamous cell carcinoma in young and older brazilian patients: a comparative analysis. med oral patol oral cir bucal 2008; 13:227−31. 14. oliver rj, dearing j, hindle i. oral cancer in young adults: report of three cases and review of the literature. br dent j 2000; 188:362−5. 15. popovtzer a, shpitzer t, bahar g, marshak g, ulanovski d, feinmesser r. squamous cell carcinoma of the oral tongue in young patients. laryngoscope 2004; 114:915−7. 16. jaber ma. oral epithelial dysplasia in non-users of tobacco and alcohol: an analysis of clinicopathologic characteristics and treatment outcome. j oral sci 2010; 52:13−21. 17. kruse al, bredell m, grätz kw. oral squamous cell carcinoma in non-smoking and non-drinking patients. head neck oncol 2010; 2:3−24. 18. nicolai g, lorè b, prucher g, de marinis l, calabrese l. treatment of n in the upper maxillary tumors. j craniofac surg 2010; 21:1798−800. خزعة العقدة الليمفاوية اخلافرة هنج جديد يف معاجلة سرطان الرأس والعنق ديبيت شارما, جورج كوشي, سونال جروفر, بوشان شارما abstract: cervical lymph node metastasis affects the prognosis and overall survival rate of and therapeutic planning for patients with head and neck squamous cell carcinomas (hnsccs). however, advanced diagnostic modalities still lack accuracy in detecting occult neck metastasis. a sentinel lymph node biopsy is a minimally invasive auxiliary method for assessing the presence of occult metastatic disease in a patient with a clinically negative neck. this technique increases the specificity of neck dissection and thus reduces morbidity among oral cancer patients. the removal of sentinel nodes and dissection of the levels between the primary tumour and the sentinel node or the irradiation of target nodal basins is favoured as a selective treatment approach; this technique has the potential to become the new standard of care for patients with hnsccs. this article presents an update on clinical applications and novel developments in this field. keywords: head and neck cancer; squamous cell carcinomas; neck dissection; sentinel lymph node biopsy; lymphoscintigraphy. امللخ�ص: ي�ؤثر انت�ضار �رسطان العقدة الليمفاوية يف الرقبة على الت�ضخي�ص ومعدل البقاء على قيد احلياة والتخطيط العالجي للمر�ضى الذين يعان�ن من �رسطان اخلاليا احلر�ضفية يف الراأ�ص والعنق. مع ذلك ال تزال طرق الت�ضخي�ص املتط�ر تفتقر اإىل الدقة يف الك�ضف عن هذا االنت�ضار ال�رسطاين اخلفي. اأخذ خزعة من العقدة الليمفاوية احلار�ضة و�ضيلة م�ضاعدة لتقييم وج�د املر�ص املنت�رس الغري ظاهر �رسيريا. هذا االأ�ضل�ب ي�ضهل حتديد مكان عملية ت�رسيح الرقبة, وبالتايل يقلل من ن�ضبة انت�ضاراملر�ص عند مر�ضى �رسطان الفم. يف�ضل اإزالة العقده احلار�ضة والطبقات بني ال�رم الرئي�ضي والعقدة احلار�ضة اأو العالج االإ�ضعاعي لتجمعات عقدية م�ضتهدفة كنهج للعالج االنتقائي. ميكن لهذه التقنية اأن ت�ضبح معيارا جديدا لتقييم ورعاية املر�ضى الذين يعان�ن من �رسطان اخلاليا احلر�ضفية يف الراأ�ص والرقبة. تقدم هذه املقالة حتديثا على التطبيقات ال�رسيرية والتط�رات اجلديدة يف هذا املجال. ت�ض�يرالعقد اخلافرة؛ الليمفاوية العقدة خزعة العنق؛ ت�رسيح احلر�ضفية؛ اخلاليا �رسطان والعنق؛ الراأ�ص �رسطان املفتاحية: الكلمات اللمفاوية احلار�ضة. sentinel lymph node biopsy a new approach in the management of head and neck cancers *deepti sharma, george koshy, sonal grover, bhushan sharma review sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e3–10, epub. 30 mar 17 submitted 13 jul 16 revision req. 6 sep 16; revision recd. 21 sep 16 accepted 6 oct 16 doi: 10.18295/squmj.2016.17.01.002 as opposed to primary tumours, metastasis is responsible for the high mortality rate of most cancer patients; moreover, cancer cells primarily invade the regional lymph nodes before spreading to other parts of the body.1 genetic instability results in tumour cell heterogeneity, lead ing to the emergence of metastatic clones and dissemination of the cancer from the primary tumour site.2 malignant cells metastasise due to an interaction between the host factors and tumour cells. genes related to the extracellular matrix, adhesion, motility and protease inhibition constitute a significant part of the metastatic process.3 nodal metastasis n o d a l m e ta s tat i c c a s c a d e the migration and invasion of cancer cells into the lymphatic system is governed by a variety of intricate genotypic, phenotypic and microenvironmental processes. after entering the lymphatic drain ing channels, the tumour cells metastasise to the regional lymph nodes in the neck and form the metastatic foci.4 macrometastases refer to lymph nodes that appear suspicious on clinical or radiographical examinations; in contrast, nodal metastases—which are not detectable by imaging methods or physical examination—indicate occult or subclinical metastasis. hermanek microscopically differentiated occult metastases into macrometastases (metastatic deposits of >2 mm), micrometastases (metastatic deposits of <2 mm) and isolated or small clusters of tumour cells (metastatic deposits of <0.2 mm).5 isolated tumour cells (itcs) can also be defined as a cluster of ≤200 tumour cells visible on one histology slide; these cells can further be categorised into those detectable by light microscopy, immunohistochemistry or mole cular methods.6 chemoradiation or elective neck dissection (end) should be considered in patients department of oral & maxillofacial pathology, christian dental college & hospital, ludhiana, punjab, india *corresponding author e-mail: deepti_dentist@yahoo.co.in sentinel lymph node biopsy a new approach in the management of head and neck cancers e4 | squ medical journal, february 2017, volume 17, issue 1 with itcs or those with a high risk of occult micrometastasis.7 the microenvironment of the lymph node is initially hostile to cancer cells due to a predominance of immune effector cells and cytokines; immunoresistant clones in the hostile lymph node milieu subsequently proliferate, spread and invade the rest of the lymphatic system to establish metastasis.8 malignant cells follow an orderly sequence, spreading from one nodal basin to the next as the disease progresses down the neck. in some situations, lymph node groups can be bypassed, which can result in a process known as skip metastasis.9 however, controversial reports exist as to whether lymphatic tumours spread through new lymphatic vessels (i.e. lymphangiogenesis) or pre-existing peritumoural lymphatic vessels.10 different molecular components are also involved in the metastatic cascade, including prospero homeobox 1, lymphatic vessel endothelial hyaluronan receptor 1, podoplanin, vascular endothelial growth factor receptor-3, epithelial cadherin, catenins, syndecans, focal adhesion kinase, matrix metalloproteinases-2 and -9, metallothioneins and laminins.11 these markers have recently been explored as a result of increased research interest in tumour lymphatics.12 a s i g n i f i c a n t p r o g n o s t i c fa c t o r lymph nodes in the head and neck constitute approximately 30% of the 800 lymph nodes in the human body.13 neck node metastasis is a major determinant in the prognosis of oral, oropharyngeal and other head and neck cancers; the disease-free survival rate decreases to approximately 50% with the presence of a single cancer-positive lymph node.14 the extent of lymph node involvement should be considered as an indirect index of the systemic tumour load and is an important aspect of tumour staging; thus, the size, level and presence of a metastatic neck node determines overall survival and treatment planning.15 in patients with oral cancer, the lymph node levels i to iii are most commonly involved.16 the frequency of skip metastasis to levels iv or v, bypassing the upper nodal levels, is approximately 4–5% in oral cancer, although this can increase to 16% in the tongue.17 a clinically negative neck indicates a primary tumour of either ≤2 cm or 2–4 cm with no regional lymph node metastasis (n0).18 the incidence of occult neck metastasis in stage i/ii disease for patients with clinically negative necks is 30–34%.12,19 the traditional approach to treatment has been to proceed with wide-margin radical neck surgery. however, prophylactic end for all patients with carcinomas of the oral cavity and a clinically negative neck results in an overtreatment rate of 65–70%; nevertheless, overall survival may be jeopardised if the carcinoma is not treated.20 predictive factors associated with occult metastasis of the cervical nodes include primary tumour site, size, degree of differentiation, perineural and vascular invasion, inflammatory response and tumour ploidy status.21 advanced diagnostic approaches with greater accuracy are required, since these factors alone or along with conventional methods are insufficient to assess neck metastasis.13 advanced imaging modalities such as computed tomography, magnetic resonance imaging, ultrasonography, positron emission tomography (pet), lymphoscintigraphy and ultrasoundguided fine-needle aspiration cytology are often used for neck evaluation and screening in patients with oral cancer. nonetheless, these approaches can fail to detect occult neck metastasis and subcentimetric or microscopic metastatic foci.22 for patients presenting clinically without regional disease, treatment approaches for oral squamous cell carcinoma (oscc), and head and neck cancers in general, have been debated.23 in cases of more advanced oral cancer, clinically evident and diagnostically proven locoregional metastasis give a clearcut indication for treatment of the neck, based on the treatment approach for the primary tumour.24 however, the management of patients with stage i/ii disease and a n0 neck remains unclear; patients can be treated either with prophylactic end, irradiation or observation with regular follow-ups.14 a surveillance approach can result in poor survival and increased risk of occult metastasis.25 however, performing ends on all patients with n0 necks would lead to undue surgeries with large incisions, skin flaps and scars, the sacrifice of the spinal accessory nerve and the involvement or sacrifice of the sternocleidomastoid muscle and internal jugular vein, particularly if the surgery is bilateral.26 neck dissection could also lead to other sequelae, including shoulder and neck dysfunction, pain, contour changes, haemorrhage, nerve injury, lower lip paresis, lymphoedema, an increased need for postoperative radiotherapy, poor cosmetic outcomes and greater expenses.27 sentinel lymph node biopsy a n o v e l a p p r o a c h recently, the concept of a sentinel lymph node (sln) was introduced in head and neck squamous cell carcinomas (hnsccs) in order to more precisely deepti sharma, george koshy, sonal grover and bhushan sharma review | e5 detect and evaluate neck metastasis and unpredictable lymphatic drainage patterns, following its successful application in melanomas and breast cancer.22,28 several validation studies involving ends have resulted in sln cancer detection rates of >95%.12 following the orderly and sequential drainage in the lymphatic stream from the tumour site, the first node reached is the sln, which could help predict the nodal stage of metastasis [figure 1]. in theory, if the sln is free from cancer cells, then distal node involvement is assumed to be rare.29 thus, the lymphatic basin status can be ascertained along with a reduction in poor prognosis and morbidity rates.28,30 a sln biopsy is an ancillary diagnostic method for assessing the presence of occult metastatic disease in a n0 neck. this minimally invasive technique eliminates the need for a neck dissection, which until recently was thought to be the only means of neck staging.31 a sln biopsy is a selective procedure based on the identification and evaluation of echelon nodes (i.e. first station or levels i and ii) for metastatic spread; hence, the first drainage node or group of nodes, known as the sln, are chosen for dissection as the location at which a primary tumour first metastasises.14 in 1996, the first successful sln biopsy was performed by alex et al. on a patient with a laryngeal supraglottic carcinoma; koch et al. subsequently proved the feasibility of this procedure in 1998 for selected patients with head and neck mucosal lesions.27 morton et al. found that selective lymphatic dissection performed after a sln biopsy was therapeutically equivalent to a comprehensive elective lymphatic dissection among patients with skin melanomas.32 t r e at m e n t p r o t o c o l s in recent decades, improved understanding of lymphatic drainage patterns in the head and neck region have simplified the assessment of higher risk nodal levels.27 there has been a gradual shift towards a more conservative/selective surgical approach for patients with clinically negative necks, progressing from radical neck dissection to modified radical neck dissection and subsequently selective neck dissection.33 the techniques and methodology for sln identification in head and neck cancers have been widely debated and are still under investigation [tables 1 and 2].5,14,15,22,24,27–31,34–46 shoaib et al. suggested a protocol involving preoperative lymphoscintigraphy, intraoperative blue dye and gamma probe localisation [figure 2].30 this technique is based on observing the route of lymphatic flow via imaging after the injection of a radioactive contrast agent near the primary tumour.42 the flow and direction of the lymph, comparable to the possibly metastatic flow from the tumour, can be visualised preoperatively by means of lymphoscintigraphy or single-photon emission computed tomography (spect). lymphoscintigraphy reveals slns associated with the primary tumour, unexpected lymphatic drainage patterns and lymphatic vessels associated with different lymphatic drainage basins.14 to enhance the detection rate, blue dye is often used in combination with radioisotopes.47 during the surgery, a handheld gamma probe is used for radionuclide detection to trace the sln perioperatively and a gamma camera is used for dynamic monitoring of lymphatic drainage. the site of the radioactive lymph nodes, which are important anatomical landmarks, are marked using a gamma camera and the ex vivo radioactivity of the nodes and surgical bed is checked after removing the nodes.31 histopathological evaluation, immunohistochemistry and molecular markers have been suggested for a small number of harvested slns to help detect occult metastasis in serial lymph node sections, including molecular techniques such as polymerase chain reaction and immunohistochemistry using cytokeratin markers.43 these could potentially lead to more accurate nodal staging and the detection of nodal micrometastatic deposits and itcs.48 it has been suggested that step serial sectioning at 150 μm intervals with pan-cytokeratin enhances nodal detection by approximately 20% in comparison to the initial routinely stained section.15 murer et al. reported lower postoperative morbidity rates and better shoulder function following a sln biopsy in comparison to an end.49 hernando et al. observed figure 1: flowchart depicting the process of primary tumour spread to a sentinel lymph node. sentinel lymph node biopsy a new approach in the management of head and neck cancers e6 | squ medical journal, february 2017, volume 17, issue 1 table 1: literature review of studies regarding lymph node identification and the utility of a sentinel lymph node biopsy in the management of head and neck cancers22,24,28,29,31,34–41 author and year of study n lymphatic mapping method sen/spec association conclusion werner et al.35 (2002) 90 99mtc nanocolloidal injection during lymph node dissection sen: 89% •serial sectioning may serve to increase the diagnostic reliability of a limited nd •there is a need to remove all radioactive slns chikamatsu et al.22 (2004) 11 lsg (99mtc-labelled colloidal rhenium sulphide), gamma probe and gamma camera for radiolocalisation and monitoring spec: 100%* npv: 100% •a nd is not necessary for patients with a n0 neck as determined by a sln biopsy, even if a physical examination or imaging is positive for lymph node metastasis alvarez amézaga et al.29 (2007) 25 lsg (colloidal human serum albumin), vital dye and gamma probe sen: 93.4% spec: 100% or: 183.71 •due to its high sen, a sln biopsy can be performed even in the initial stages of oscc stefanicka et al.31 (2010) 12 lsg (99mtc-labelled radiocolloidal human serum albumin), gamma probe and gamma camera for radiolocalisation and monitoring sen: 100% npv: 100% •identification of slns in patients with osccs is technically feasible and accurate and can predict occult metastasis civantos et al.28 (2010) 140 lsg (99mtc colloidal sulphur) and gamma probe for radiolocalisation npv: 96% •a sln biopsy with step sectioning and immunohistochemistry correctly predicts a pathologically-confirmed n0 neck broglie et al.36 (2011) 79 lsg, spect and intraoperative use of a handheld gamma probe •a sln biopsy can help to select patients with stage i/ii oscc and occult lymph node disease for an elective nd •the occult metastasis recurrence rate in slnnegative patients is superior to that of sln-positive patients melkane et al.24 (2012) 53 lsg (99mtc-labelled colloidal rhenium sulphur) and gamma probe for radiolocalisation npv: 95.2% •a sln biopsy may be an excellent staging method in early oral cancers •routinely undiagnosed micrometastasis may also be clinically significant borbón-arce et al.37 (2014) 25 lsg (hybrid tracer with icg dye and a 99mtc nanocolloid) followed by spect two hours later, a portable gamma camera with a nir fluorescence camera and a handheld gamma ray probe for detection •a multimodal approach resulted in the identification of 26% additional slns compared to a traditional method rigual et al.38 (2013) 38 preoperative lsg with intraoperative gamma probe localisation sen: 71% npv: 94% •most patients with positive sln biopsy results also had additional positive nodes on nd •there was a low rate of isolated neck recurrence among patients with negative sln biopsy results •patients with negative sln biopsy results had better overall/disease-specific survival rates milenović et al.34 (2014) 30 lsg and ultrasound-guided puncture of the lymph nodes, gamma probe and gamma camera for radiolocalisation sen: 93% •a sln biopsy should be performed in selected cases, as it is sometimes easier to perform a nd in certain localisations flach et al.39 (2014) 62 preoperative lsg, blue dye and intraoperative gamma probe for detection sen: 80% npv: 88% •a sln biopsy reduces occult lymph node metastasis risk in t1/t2 oral cancer (40% versus 8%) •patients with negative slns and no elective nd achieve an excellent rate of occult metastasis recurrence with a sln biopsy which compares favourably with primary elective nd outcomes den toom et al.40 (2015) 90 preoperative lsg and intraoperative blue dye and gamma probe for detection sen: 93% npv: 97% •a sln biopsy is a reliable diagnostic staging technique for early-stage n0 oral cancer salazar-fernandez et al.41 (2015) 96 cervical lsg and spect sen: 88% npv: 94% •a sln biopsy is an excellent oscc staging method •there is a small risk of additional lymph node metastasis with sln micrometastasis sen = sensitivity; spec = specificity; 99mtc = technicium-99m; nd = neck dissection; sln = sentinel lymph node; lsg = lymphoscintigraphy; npv = negative predictive value; n0 = without regional lymph node metastasis; or = odds ratio; oscc = oral squamous cell cancer; spect = single-photon emission computed tomography; icg = indocyanine green; nir = near-infrared; t1 = primary tumour of ≤2 cm; t2 = primary tumour of 2–4 cm. *for all n0 patients. deepti sharma, george koshy, sonal grover and bhushan sharma review | e7 statistically significant increased shoulder function and reduced average scar length among patients receiving a sln biopsy in comparison to those undergoing end; neck haematomas and orocervical communication were reported only in the end group and sln biopsies were associated with lower rates of postoperative morbidity.44 alkureishi et al. reported that the pathological review of a sln or neck dissection specimen can affect the staging of a lymph node if it reveals occult or additional positive lymph nodes which might have been missed on a routine physical examination or radiographical evaluation.43 this alteration in lymph node staging could increase the risk for distant metastasis and change the patient’s prognosis and treatment plan.50,51 in hnscc cases, a sln biopsy has been suggested as a valid method to improve the accuracy of pathological staging of lymph nodes and subsequently allow treatments to be tailored.32 in a meta-analysis, thompson et al. found that a positive sln biopsy confirmed occult metastasis in 31% of patients; this correlates with a previously reported occult metastatic rate of 33%.45,52 evaluation of a positive lymph node status is critical as it is a major indicator for adjuvant radiation and chemotherapy. the use of a sln biopsy allows adjuvant or elective chemoradiation to be avoided, as well as the associated morbidities of these treatment options.53 for example, hnscc patients receiving chemoradiation are more likely to develop acute mucositis, oral pain, dysphagia and xerostomia; in addition, they are more frequently hospitalised.45,54 patients with a negative sln biopsy can therefore table 2: indications, contraindications, advantages and disadvantages of a sentinel lymph node biopsy5,14,15,27–30,42–46 indications contraindications advantages disadvantages •for patients with t1/t2/n0 head and neck tumours •to assess bilateral t1/t2/n0 primary head and neck tumours close to or crossing the midline •to clarify the need for contralateral dissection in tumours with one clinically positive side close to the midline •to ensure accurate radiocolloid application in well accessible primary tumours •for clinically positive neck nodes, as metastatic involvement interferes with the normal lymph node architecture, leading to anomalous draining patterns •for patients with a history of prior surgeries or treatments that may have altered normal lymphatic drainage patterns •for pregnant or lactating patients, as the extent of the sln biopsy may need to be modified to minimise the risk of radiation exposure and blue dye injections •for large primary tumours which can directly compress the draining lymphatic vessels •allows the accurate detection and staging of sln metastasis with minimal morbidity as the technique is minimally invasive •guides decision-making during the management of head and neck tumours •limits the necessity of performing prophylactic end for all patients •prevents the unnecessary removal of functional nodes •allows selective excision of the sln •allows adequate assessment of the nodal status of the remaining neck tissue with a subsequent histopathological examination •helps to identify skip metastasis, micrometastasis and unpredictable lymphatic drainage patterns •improves the histological evaluation of surgical specimens •reduces the number of lymph nodes required for a detailed history and physical examination in comparison to an end •saves time and expense •shortens the recovery period •for medically fit patients •may be difficult as the approach is technique-sensitive •the use of blue dye may elicit an allergic response •false-negatives can occur due to uneven radionuclide injection, the obscuring of the sln by the radioactive signal of the primary tumour and the obstruction of the lymphatic vessels by the gross tumour, resulting in a redirection of lymphatic flow •the accuracy of this technique in identifying true slns is inadequate in patients with tumours of the floor of the mouth •in cases of multiple slns and slns at different levels, the number of slns to be removed is still unknown, which may lead to an extensive procedure similar to that of an end •the ‘shine through’ phenomenon and scatter radiation due to the primary tumour can obscure identification •variability in head and neck lymphatic drainage may result in collateral channels leading to skip metastasis t1 = primary tumour of ≤2 cm; t2 = primary tumour of 2–4 cm; n0 = without regional lymph node metastasis; sln = sentinel lymph node; end = elective neck dissection. figure 2: proposed treatment protocol for a sentinel lymph node biopsy.30 *a clinically negative neck indicates a primary tumour of either ≤2 cm or 2–4 cm with no regional lymph node metastasis.18 lsg = lymphoscintigraphy sn = sentinel node; t/t = treatment. sentinel lymph node biopsy a new approach in the management of head and neck cancers e8 | squ medical journal, february 2017, volume 17, issue 1 avoid adjuvant therapy, which would lessen patient morbidity; this option can be reserved for a later time in the event of a second primary diagnosis or tumour recurrence.46 while a sln biopsy is not yet considered the standard of care for cancers of the oral cavity, many singleand multi-centre studies have successfully demonstrated its feasibility in oral cancers with high detection rates (approximately 95%) and negative predictive values (88–100%), thus substantiating its significance and use in the staging and treatment of early-stage head and neck cancers.43,55,56 advances and future developments a variety of soluble tracers and radiocolloids have been used in lymphoscintigraphy, including technetium99m (99mtc)-labelled colloidal human serum albumin, colloidal sulphur, 99mtc colloidal rhenium sulphide and a dextran-based product modified to allow 99tc-labelling.13,21,44,57 tsuchimochi et al. proposed performing a sln biopsy using multimodality imaging and polyamidoamine-coated silica nanoparticles loaded with 99mtc and indocyanine green dye.47 deeply situated slns can be detected more accurately with the use of near-infrared dyes; recently, hybrid tracers combined with radiotracers and fluorescence dyes have resulted in high sensitivity for preoperative sln mapping.57 bluemel et al. evaluated the feasibility and potential advantages of freehand spect in oral cancer in comparison with conventional intraoperative localisation techniques for a sln biopsy; they found that one of the most important limitations of a sln biopsy—the ‘shine-through’ phenomenon—was overcome by freehand spect.58 according to denoth et al., metastatic deposits are not randomly distributed within slns but are predominantly found in the central planes, closer to the lymphatic inlet; analysis of the distribution pattern of metastatic spread within slns with a virtual microscope resulted in a detection rate of 90% and 80% for micrometastasis and itcs, respectively.59 van den berg et al. introduced the concept of hybrid tracers containing both radioactive and fluorescent labels which allowed for the direct integration of pre and intraoperative guidance technologies when used in combination with new surgical imaging modalities and navigation tools in sln detection.57 using ultrasound-guided spectroscopic photoacoustic imaging of molecularly-activated plasmonic nanosensors in an oscc murine model, luke et al. demonstrated that lymph node metastases as small as 50 μm could be detected in vivo at a depth of 1 cm with high sensitivity and specificity; this new approach could potentially be a sensitive alternative to a sln biopsy.1 in various animal studies, attempts to combine several techniques have been reported, including the addition of 99mtc, iodine-125 or iodine-111 to phthalocyanine tetrasulfonate, dextran and evans blue, methylene blue or blue ficoll dyes.47,60 tsopelas et al. found 99mtc-evans blue to be useful in differentiating the initial draining lymph node from higher-tier nodes in linked chains.61 the clinical applications of a sln biopsy could be enhanced through on-going developments and innovations. these might include the preoperative use of pet, the biological staging of primary site biopsies, the discovery of more radionuclide-avid lymph nodes or ultrasound-detectable injectable contrast agents as potential second tracers, the application of intraoperative reverse transcriptase polymerase chain reaction analysis of the sentinel node and the use of endoscopic sln biopsies.14,26,27,62,63 conclusion a sln biopsy can prevent the unnecessary removal of functional lymph nodes and limit the extent of neck dissection surgery. however, surgical precision and experience as well as specific technical devices are required for its successful application and implementation in the head and neck region. although a review of the current literature demonstrated the reliability and worldwide acceptance of this approach, the role of sln biopsies in hnsccs is still under investigation. using the sentinel node concept helps to define the surgical approach to a clinically negative neck and identify skip metastasis and unpredictable lymphatic drainage patterns, resulting in a more favourable prognosis for patients with head and neck cancers. references 1. luke gp, myers jn, emelianov sy, sokolov kv. sentinel lymph node biopsy revisited: ultrasound-guided photoacoustic detection of micrometastases using molecularly targeted plasmonic nanosensors. cancer res 2014; 74:5397–408. doi: 10.1158/0008-5472.can-14-0796. 2. klein ca. parallel progression of primary tumours and metastases. nat rev cancer 2009; 3:302–12. doi: 10.1038/nrc 2627. 3. fidler ij. critical factors in the biology of human cancer metastasis: twenty-eighth g.h.a. clowes memorial award lecture. cancer res 1990; 50:6130–8. 4. chen z, smith cw, kiel d, van waes c. metastatic variants derived following in vivo tumor progression of an in vitro transformed squamous cell carcinoma line acquire a differential growth advantage requiring tumor-host interaction. clin exp metastasis 1997; 15:527–37. doi: 10.1023/a:1018474910432. https://doi.org/10.1158/0008-5472.can-14-0796 https://doi.org/10.1038/nrc2627 https://doi.org/10.1038/nrc2627 https://doi.org/10.1023/a:1018474910432 deepti sharma, george koshy, sonal grover and bhushan sharma review | e9 5. hermanek p, hutter rv, sobin lh, wittekind c. international union against cancer: classification of isolated tumor cells and micrometastasis. cancer 1999; 86:2668–73. doi: 10.1002/(sici)1097-0142(19991215)86:12<2668::aid-cn cr11>3.0.co;2-r. 6. čelakovský p, kalfeřt d, smatanová k, chrobok v, laco j. detection of cervical lymph node micrometastases in patients with squamous cell carcinoma of the oral cavity, pharynx and larynx. acta medica (hradec kralove) 2015; 58:62–5. doi: 10.14712/18059694.2015.95. 7. leong sp, tseng ww. micrometastatic cancer cells in lymph nodes, bone marrow, and blood: clinical significance and biologic implications. ca cancer j clin 2014; 64:195–206. doi: 10.3322/caac.21217. 8. pereira er, jones d, jung k, padera tp. the lymph node microenvironment and its role in the progression of metastatic cancer. semin cell dev biol 2015; 38:98–105. doi: 10.1016/j. semcdb.2015.01.008. 9. gurney ba, schilling c, putcha v, alkureishi lw, alvarez aj, bakholdt v, et al. implications of a positive sentinel node in oral squamous cell carcinoma. head neck 2012; 34:1580–5. doi: 10.1002/hed.21973. 10. baradaranfar mh, zahir st, atighechi s, dadgarnia mh, bayati f, mohajerani mr. lymphatic metastasis in head and neck squamous cell carcinoma. pak j med sci 2011; 27:303–6. 11. longatto filho a, oliveira tg, pinheiro c, de carvalho mb, curioni oa, mercante am, et al. how useful is the assessment of lymphatic vascular density in oral carcinoma prognosis? world j surg oncol 2007; 5:140. doi: 10.1186/1477-7819-5-140. 12. noguti j, de moura cf, de jesus gp, da silva vh, hossaka ta, oshima ct, et al. metastasis from oral cancer: an overview. cancer genomics proteomics 2012; 9:329–35. 13. essig h, warraich r, zulfiqar g, rana r, eckardt am, gellrich nc, et al. assessment of cervical lymph node metastasis for therapeutic decision-making in squamous cell carcinoma of buccal mucosa: a prospective clinical analysis. world j surg oncol 2012; 10:253. doi: 10.1186/1477-7819-10-253. 14. rakheja m, radhakrishnan r, solomon mc. sentinel lymph node biopsy in oral squamous cell carcinoma: ensuing from elective to selective. j res med dent sci 2014; 2:5–10. doi: 10.5455/jrmds.2014222. 15. sloan p. head and neck sentinel lymph node biopsy: current state of the art. head neck pathol 2009; 3:231–7. doi: 10.1007/ s12105-009-0132-3. 16. narendra h, tankshali ra. prevalence and pattern of nodal metastasis in pt4 gingivobuccal cancers and its implications for treatment. indian j cancer 2010; 47:328–31. doi: 10.4103/0019509x.64720. 17. byers rm, weber rs, andrews t, mcgill d, kare r, wolf p. frequency and therapeutic implications of “skip metastases” in neck from squamous cell carcinoma of oral tongue. head neck 1997; 19:14–19. doi: 10.1002/(sici)1097-0347(199701) 19:1<14::aid-hed3>3.0.co;2-y. 18. stevenson mm. head and neck cancer staging: tnm classification for head and neck cancer. from: http://emedicine. medscape.com/article/2007181-overview accessed: sep 2016. 19. russolo m, giacomarra v, papanikolla l, tirelli g. prognostic indicators of occult metastases in oral cancer. laryngoscope 2002; 112:1320–3. doi: 10.1097/00005537-200207000-00035. 20. ho cm, lam kh, wei wi, lau sk, lam lk. occult lymph node metastasis in small oral tongue cancers. head neck 1992; 14:359–63. doi: 10.1002/hed.2880140504. 21. pimenta amaral tm, da silva freire ar, carvalho al, pinto ca, kowalski lp. predictive factors of occult metastasis and prognosis of clinical stages i and ii squamous cell carcinoma of the tongue and floor of the mouth. oral oncol 2004; 40:780–6. doi: 10.1016/j.oraloncology.2003.10.009. 22. chikamatsu k, kamada h, ninomiya h, takahashi k, sakurai t, oriuchi n, et al. a preliminary study on sentinel lymph node biopsy: feasibility and predictive ability in oral cavity cancer. ann nucl med 2004; 18:257–62. doi: 10.1007/ bf02985008. 23. ross gl, soutar ds, macdonald dg, shoaib t, camilleri ig, robertson ag. improved staging of cervical metastases in clinically node-negative patients with head and neck squamous cell carcinoma. ann surg oncol 2004; 11:213–18. doi: 10.1245/ aso.2004.03.057. 24. melkane ae, mamelle g, wycisk g, temam s, janot f, casiraghi o, et al. sentinel node biopsy in early oral squamous cell carcinomas: a 10-year experience. laryngoscope 2012; 122:1782–8. doi: 10.1002/lary.23383. 25. moreno-garcía c. elective neck dissection in early oral squamous cell carcinoma: necessary? plast aesthet res 2016; 3:167–74. doi: 10.20517/2347-9264.2016.12. 26. kurokawa h, yamashita y, takeda s, zhang m, fukuyama h takahashi t. risk factors for late cervical lymph node metastases in patients with stage i or ii carcinoma of the tongue. head neck 2002; 24:731–6. doi: 10.1002/hed.10130. 27. calabrese l, bruschini r, ansarin m, giugliano g, de cicco c, ionna f, et al. role of sentinel lymph node biopsy in oral cancer. acta otorhinolaryngol ital 2006; 26:345–9. 28. civantos fj, zitsch rp, schuller de, agrawal a, smith rb, nason r, et al. sentinel lymph node biopsy accurately stages the regional lymph nodes for t1-t2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. j clin oncol 2010; 28:1395–400. doi: 10.1200/jco.2008.20.8777. 29. alvarez amézaga j, barbier herrero l, pijoan del barrio ji, martín rodríguez jc, romo simón l, genolla subirats j, et al. diagnostic efficacy of sentinel node biopsy in oral squamous cell carcinoma: cohort study and meta-analysis. med oral patol oral cir bucal 2007; 12:e235–43. 30. shoaib t, soutar ds, macdonald dg, camilleri ig, dunaway dj, gray hw, et al. the accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically n0 neck. cancer 2001; 91:2077–83. doi: 10.1002/1097-0142 (20010601)91:11<2077::aid-cncr1235>3.0.co;2-e. 31. stefanicka p, profant m, duchaj b, valach m, gal v, dolezal p, et al. sentinel lymph node radiolocalization and biopsy in oral cavity and oropharynx mucosal squamous cell carcinoma. bratisl lek listy 2010; 111:590–4. 32. morton dl, wen dr, wong jh, economou js, cagle la, storm fk, et al. technical details of intraoperative lymphatic mapping for early stage melanoma. arch surg 1992; 127: 392–9. doi: 10.1001/archsurg.1992.01420040034005. 33. antonio jk, santini s, politi d, sulfaro s, spaziante r, alberti a, et al. sentinel lymph node biopsy in squamous cell carcinoma of the head and neck: 10 years of experience. acta otorhinolaryngol ital 2012; 32:18–25. 34. milenović a, virag m, kneević p, boras vv, ostović kt, pandurić dg, et al. evaluation of sentinel node biopsy in oral carcinomas. coll antropol 2014; 38:279–82. 35. werner ja, dünne aa, ramaswamy a, folz bj, lippert bm, moll r, et al. sentinel node detection in n0 cancer of the pharynx and larynx. br j cancer 2002; 87:711–15. doi: 10.1038/ sj.bjc.6600445. 36. broglie ma, haile sr, stoeckli sj. long-term experience in sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma. ann surg oncol 2011; 18:2732–8. doi: 10.1245/ s10434-011-1780-6. 37. borbón-arce m, brouwer or, van den berg ns, mathéron h, klop wm, balm aj, et al. an innovative multimodality approach for sentinel node mapping and biopsy in head and neck malignancies. rev esp med nucl imagen mol 2014; 33:274–9. doi: 10.1016/j.remn.2013.11.005. https://doi.org/10.1002/%28sici%291097-0142%2819991215%2986:12%3c2668::aid-cncr11%3e3.0.co%3b2-r https://doi.org/10.1002/%28sici%291097-0142%2819991215%2986:12%3c2668::aid-cncr11%3e3.0.co%3b2-r https://doi.org/10.14712/18059694.2015.95 https://doi.org/10.3322/caac.21217 https://doi.org/10.1016/j.semcdb.2015.01.008 https://doi.org/10.1016/j.semcdb.2015.01.008 https://doi.org/10.1002/hed.21973 https://doi.org/10.1186/1477-7819-5-140 https://doi.org/10.1186/1477-7819-10-253 https://doi.org/10.5455/jrmds.2014222 https://doi.org/10.1007/s12105-009-0132-3 https://doi.org/10.1007/s12105-009-0132-3 https://doi.org/10.4103/0019-509x.64720 https://doi.org/10.4103/0019-509x.64720 https://doi.org/10.1002/%28sici%291097-0347%28199701%2919:1%3c14::aid-hed3%3e3.0.co%3b2-y https://doi.org/10.1002/%28sici%291097-0347%28199701%2919:1%3c14::aid-hed3%3e3.0.co%3b2-y https://doi.org/10.1097/00005537-200207000-00035 https://doi.org/10.1002/hed.2880140504 https://doi.org/10.1016/j.oraloncology.2003.10.009 https://doi.org/10.1007/bf02985008 https://doi.org/10.1007/bf02985008 https://doi.org/10.1245/aso.2004.03.057 https://doi.org/10.1245/aso.2004.03.057 https://doi.org/10.1002/lary.23383 https://doi.org/10.20517/2347-9264.2016.12 https://doi.org/10.1002/hed.10130 https://doi.org/10.1200/jco.2008.20.8777 https://doi.org/10.1002/1097-0142%2820010601%2991:11%3c2077::aid-cncr1235%3e3.0.co%3b2-e https://doi.org/10.1002/1097-0142%2820010601%2991:11%3c2077::aid-cncr1235%3e3.0.co%3b2-e https://doi.org/10.1001/archsurg.1992.01420040034005 https://doi.org/10.1038/sj.bjc.6600445 https://doi.org/10.1038/sj.bjc.6600445 https://doi.org/10.1245/s10434-011-1780-6 https://doi.org/10.1245/s10434-011-1780-6 https://doi.org/10.1016/j.remn.2013.11.005 sentinel lymph node biopsy a new approach in the management of head and neck cancers e10 | squ medical journal, february 2017, volume 17, issue 1 38. rigual n, loree t, frustino j, jayaprakash v, cohan d, sullivan m, et al. sentinel node biopsy in lieu of neck dissection for staging oral cancer. jama otolaryngol head neck surg 2013; 139:779–82. doi: 10.1001/jamaoto.2013.3863. 39. flach gb, bloemena e, klop wm, van es rj, schepman kp, hoekstra os, et al. sentinel lymph node biopsy in clinically n0 t1-t2 staged oral cancer: the dutch multicenter trial. oral oncol 2014; 50:1020–4. doi: 10.1016/j.oraloncology.2014.07.020. 40. den toom ij, heuveling da, flach gb, van weert s, karagozoglu kh, van schie a, et al. sentinel node biopsy for early-stage oral cavity cancer: the vu university medical center experience. head neck 2015; 37:573–8. doi: 10.1002/ hed.23632. 41. salazar-fernandez ci, gallana-alvarez s, pereira s, cambill t, infante-cossio p, herce-lopez j. sentinel lymph node biopsy in oral and oropharyngeal squamous cell carcinoma: statistical validation and impact of micrometastasis involvement on the neck dissection decision. j oral maxillofac surg 2015, 73:1403–9. doi: 10.1016/j.joms.2015.01.033. 42. coughlin a, resto va. oral cavity squamous cell carcinoma and the clinically n0 neck: the past, present, and future of sentinel lymph node biopsy. curr oncol rep 2010; 12:129–35. doi: 10.1007/s11912-010-0090-7. 43. alkureishi lw, ross gl, shoaib t, soutar ds, robertson ag, thompson r, et al. sentinel node biopsy in head and neck squamous cell cancer: 5-year follow-up of a european multicenter trial. ann surg oncol 2010; 17:2459–64. doi: 10.1245/s10434-010-1111-3. 44. hernando j, villarreal p, alvarez-marcos f, gallego l, garcíaconsuegra l, junquera l. comparison of related complications: sentinel node biopsy versus elective neck dissection. int j oral maxillofac surg 2014; 43:1307–12. doi: 10.1016/j.ijom. 2014.07.016. 45. thompson cf, st john ma, lawson g, grogan t, elashoff d, mendelsohn ah. diagnostic value of sentinel lymph node biopsy in head and neck cancer: a meta-analysis. eur arch otorhinolaryngol 2013; 270:2115–22. doi: 10.1007/s00405012-2320-0. 46. hassan o, taha ms, el mehairy h. sentinel lymph node biopsy versus elective neck dissection in evaluation of cn0 neck in patients with oral and oropharyngeal squamous cell carcinoma: systematic review and meta-analysis study. egypt j ear nose throat allied sci 2015; 16:25–34. doi: 10.1016/j. ejenta.2014.10.001. 47. tsuchimochi m, hayama k, toyama m, sasagawa i, tsubokawa n. dual-modality imaging with 99mtc and fluorescent indocyanine green using surface-modified silica nanoparticles for biopsy of the sentinel lymph node: an animal study. ejnmmi res 2013; 3:33. doi: 10.1186/2191-219x-3-33. 48. stoeckli sj, pfaltz m, ross gl, steinert hc, macdonald dg, wittekind c, et al. the second international conference on sentinel node biopsy in mucosal head and neck cancer. ann surg oncol 2005; 12:919–24. doi: 10.1245/aso.2005.11.024. 49. murer k, huber gf, haile sr, stoeckli sj. comparison of morbidity between sentinel node biopsy and elective neck dissection for treatment of the n0 neck in patients with oral squamous cell carcinoma. head neck 2011; 33:1260–4. doi: 10.1002/hed.21622. 50. kapoor c, vaidya s, wadhwan v, malik s. lymph node metastasis: a bearing on prognosis in squamous cell carcinoma. indian j cancer 2015; 52:417–24. doi: 10.4103/0019-509x. 176750. 51. greenberg js, el naggar ak, mo v, roberts d, myers jn. disparity in pathologic and clinical lymph node staging in oral tongue carcinoma: implication for therapeutic decision making. cancer 2003; 98:508–15. doi: 10.1002/cncr.11526. 52. shah jp. patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. am j surg 1990; 160:405–9. doi: 10.1016/s0002-9610(05)80554-9. 53. höft s, maune s, muhle c, brenner w, czech n, kampen wu, et al. sentinel lymph-node biopsy in head and neck cancer. br j cancer 2004; 91:124–8. doi: 10.1038/sj.bjc.6601877. 54. trotti a, bellm la, epstein jb, frame d, fuchs hj, gwede ck, et al. mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. radiother oncol 1997; 66:253–62. doi: 10.1016/s0167-8140(02) 00404-8. 55. ramamurthy r, kottayasamy seenivasagam r, shanmugam s, palanivelu k. a prospective study on sentinel lymph node biopsy in early oral cancers using methylene blue dye alone. indian j surg oncol 2014; 5:178–83. doi: 10.1007/s13193-0140337-0. 56. hart rd, nasser jg, trites jr, taylor sm, bullock m, barnes d. sentinel lymph node biopsy in n0 squamous cell carcinoma of the oral cavity and oropharynx. arch otolaryngol head neck surg 2005; 131:34–8. doi: 10.1001/archotol.131.1.34. 57. van den berg ns, buckle t, kleinjan gi, klop wm, horenblas s, van der poel hg, et al. hybrid tracers for sentinel node biopsy. q j nucl med mol imaging 2014; 58:193–206. 58. bluemel c, herrmann k, kübler a, buck ak, geissinger e, wild v, et al. intraoperative 3-d imaging improves sentinel lymph node biopsy in oral cancer. eur j nucl med mol imaging 2014; 41:2257–64. doi: 10.1007/s00259-014-2870-z. 59. denoth s, broglie ma, haerle sk, huber gf, haile sr, soltermann a, et al. histopathological mapping of metastatic tumor cells in sentinel lymph nodes of oral and oropharyngeal squamous cell carcinomas. head neck 2015; 37:1477–82. doi: 10.1002/hed.23782. 60. kogashiwa y, sakurai h, akimoto y, sato d, ikeda t, matsumoto y, et al. sentinel node biopsy for the head and neck using contrast-enhanced ultrasonography combined with indocyanine green fluorescence in animal models: a feasibility study. plos one 2015; 10:e0132511. doi: 10.1371/journal. pone.0132511. 61. tsopelas c, bellon m, bevington e, kollias j, shibli s, chatterton be. lymphatic mapping with 99mtc-evans blue dye in sheep. ann nucl med 2008; 22:777–85. doi: 10.1007/s12149008-0171-y. 62. yamazaki y, saitoh m, notani k, tei k, totsuka y, takinami s, et al. assessment of cervical lymph node metastases using fdg-pet in patients with head and neck cancer. ann nucl med 2008; 22:177–84. doi: 10.1007/s12149-007-0097-9. 63. alkureishi lw, burak z, alvarez ja, ballinger j, bilde a, britten aj, et al. joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/ oropharyngeal squamous cell carcinoma. eur j nucl med mol imaging 2009; 36:1915–36. doi: 10.1007/s00259-009-1248-0. https://doi.org/10.1001/jamaoto.2013.3863 https://doi.org/10.1016/j.oraloncology.2014.07.020 https://doi.org/10.1002/hed.23632 https://doi.org/10.1002/hed.23632 https://doi.org/10.1016/j.joms.2015.01.033 https://doi.org/10.1007/s11912-010-0090-7 https://doi.org/10.1245/s10434-010-1111-3 https://doi.org/10.1016/j.ijom.2014.07.016 https://doi.org/10.1016/j.ijom.2014.07.016 https://doi.org/10.1007/s00405-012-2320-0 https://doi.org/10.1007/s00405-012-2320-0 https://doi.org/10.1016/j.ejenta.2014.10.001 https://doi.org/10.1016/j.ejenta.2014.10.001 https://doi.org/10.1186/2191-219x-3-33 https://doi.org/10.1245/aso.2005.11.024 https://doi.org/10.1002/hed.21622 https://doi.org/10.4103/0019-509x.176750 https://doi.org/10.4103/0019-509x.176750 https://doi.org/10.1002/cncr.11526 https://doi.org/10.1016/s0002-9610%2805%2980554-9 https://doi.org/10.1038/sj.bjc.6601877 https://doi.org/10.1016/s0167-8140%2802%2900404-8 https://doi.org/10.1016/s0167-8140%2802%2900404-8 https://doi.org/10.1007/s13193-014-0337-0 https://doi.org/10.1007/s13193-014-0337-0 https://doi.org/10.1001/archotol.131.1.34 https://doi.org/10.1007/s00259-014-2870-z https://doi.org/10.1002/hed.23782 https://doi.org/10.1371/journal.pone.0132511 https://doi.org/10.1371/journal.pone.0132511 https://doi.org/10.1007/s12149-008-0171-y https://doi.org/10.1007/s12149-008-0171-y https://doi.org/10.1007/s12149-007-0097-9 https://doi.org/10.1007/s00259-009-1248-0 sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e429–432, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.021. submitted 30 nov 14 revisions req. 21 jan & 4 mar 15; revisions recd. 17 feb & 31 mar 15 accepted 2 apr 15 pregnancy in a rudimentary horn is extremely rare and is reported to occur only in one in 76,000 pregnancies.1 rupture of a rudimentary horn pregnancy is a surgical emergency which is usually diagnosed intraoperatively, with high maternal and fetal morbidity and mortality.1 fetal salvage is rare as these pregnancies seldom reach the third trimester with a live fetus,2 emphasising the importance of the current case. the sensitivity of ultrasonography in the diagnosis of uterine anomalies is low, especially in advanced gestation, and can often be missed.3 a unique case of rudimentary horn pregnancy is presented, which was diagnosed preoperatively via magnetic resonance imaging (mri) as the ultrasonography was inconclusive. prompt surgical intervention resulted in a good maternal and fetal outcome. case report a 31-year-old gravida 5 para 2 woman of >32 gestational weeks presented to the department of emergency medicine at the sultan qaboos university hospital in muscat, oman, in january 2013. she complained of generalised abdominal pain of one week’s duration, which had worsened overnight prior to presentation. there was no nausea, vomiting or vaginal bleeding or leaking. she had previously delivered two babies departments of 1obstetrics & gynaecology, 2radiology & molecular imaging and 3pathology, sultan qaboos university hospital; 4department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: siljarenjit@gmail.com تشخيص متزق احلمل يف قرن الرحم البدائي قبل اجلراحة عن طريق الرنني املغناطيسي نتج عنه والدة طفل حي �سيلجا اروموجام بيالي، مرمي ماثيو، نورين ا�رسات، انوبام كاكاريا، عا�سم قري�سي، جاوري فيديانيثان abstract: pregnancy in a rudimentary horn is very rare. the rupture of the horn during pregnancy is an obstetric emergency which can be life-threatening for both the mother and fetus. preoperative diagnosis of such pregnancies can be challenging and they are usually diagnosed intraoperatively. we report a unique case of a 31-year-old multiparous woman who presented to the sultan qaboos university hospital in muscat, oman, in january 2013 at 32 gestational weeks with abdominal pain. ultrasonography was inconclusive. a rudimentary horn pregnancy was subsequently diagnosed via magnetic resonance imaging (mri). an emergency laparotomy revealed haemoperitoneum and a ruptured rudimentary horn pregnancy. a live baby with an apgar score of 2 at one minute and 7 at five minutes was delivered. the rudimentary horn with the placenta in situ was excised and a left salpingooophorectomy was performed. the postoperative period was uneventful. the authors recommend mri as an excellent diagnostic modality to confirm rudimentary horn pregnancies and to expedite appropriate management. keywords: uterus, abnormalities; pregnancy; magnetic resonance imaging; live birth; case report; oman. امللخ�ص: يعترب احلمل يف القرن البدائي من احلالت النادرة، ويعد متزق هذا القرن الرحمي أثناء احلمل هو اأحد احلالت الطارئة واملهددة حلياة األم واجلنني معا. ويعترب ت�سخي�س مثل هذه احلالت قبل إجراء اجلراحة حتديا كبريا يف اأغلب احلالت التي يتم ت�سخي�سها اأثناء اجلراحة فقط. نعر�س هنا هذه احلالة املميزة والتي ت�سم مري�سة يف الواحدة والثالثني من عمرها والتي ح�رست إىل م�ست�سفى جامعة ال�سلطان قابو�س مب�سقط-عمان يف الثاين من يناير 2013 م، وهي يف الأ�سبوع الثاين والثالثني من احلمل وتعاين من اأوجاع يف البطن. ومل يكن فح�س املوجات ال�سوتية حا�سما يف الت�سخي�س. ومت ت�سخي�س حالة احلمل يف القرن البدائي يف وقت لحق عن طريق فح�س حي. طفل وولدة البدائي، القرن ومتزق ال�سفاق، يف مرتاكم �سائل فيها وجد البطن لفتح طارئة عملية إجراء ومت املغناطي�سي. الرنني وكان معامل ابجار نقطتني بعد دقيقة واحدة، وسبعة بعد خم�س دقائق من الولدة. ومت ا�ستئ�سال القرن الرحمي البدائي مت�سمنا امل�سيمة. الطبية املراجع تو�سي معوقات. دون اجلراحة بعد ما فرتة املري�سة وتخطت الأي�رس. اجلانب من واملبي�س فالوب قناة ا�ستاأ�سلت كما اتخاذ إمكانية من ولت�رسع البدائي القرن يف احلمل حالت ت�سخي�س لتاأكيد الأف�سل الو�سيلة باعتباره املغناطي�سي الرنني با�ستعمال التدابري العالجية ال�سحيحة. مفتاح الكلمات: رحم، غري الطبيعية؛ رنني مغناطي�سي؛ مولود حي؛ حترير حالة؛ عمان. ruptured rudimentary horn pregnancy diagnosed by preoperative magnetic resonance imaging resulting in fetal salvage *silja a. pillai,1 mariam mathew,1 noreen ishrat,1 anupam kakaria,2 asim qureshi,3 gowri vaidyanathan4 online case report ruptured rudimentary horn pregnancy diagnosed by preoperative magnetic resonance imaging resulting in fetal salvage e430 | squ medical journal, august 2015, volume 15, issue 3 a cervical fibroid measuring 4.7 x 6 cm. she gave a vague history of abdominal cramps continuing without relief throughout her pregnancy. on admission, the patient was haemodynamically stable but displayed diffuse abdominal tenderness. the uterine contour appeared globular and the height of the uterus corresponded to the gestation. a cardiotocogram revealed a reactive fetal heart with no uterine contractions. vaginal examination showed a long closed uterine cervix. an abdominal ultrasound revealed an appropriately grown fetus, the presence of minimal free fluid and a possible cervical fibroid. an urgent mri was arranged within 24 hours; this gave differentials of an abdominal or rudimentary horn pregnancy [figure 1]. the cervical cavity was continuous with an empty uterus lying on the right side of the pelvis. the endometrium was thickened and prominent and there was evidence of a gestational sac in the left lumbar region. the sac was surrounded by a thin hypointense rim, without signal intensity features characteristic of the myometrium. it seemed to be connected to the left side of the uterus by a narrow pedicle. there did not seem to be any cervical canal connected to the gestational sac. there was a moderate amount of free fluid in the lower abdomen and pelvis. both kidneys and the collecting system were normal. an abdominal pregnancy was ruled out due to the vaginally (both cephalic presentations), followed by two first trimester miscarriages. during her current pregnancy, an ultrasound scan performed at a local health centre at 24 gestational weeks had reported an appropriately grown fetus with no anomalies and figure 1a–d: t2-weighted fat-saturated (a & b) sagittal and (c & d) coronal magnetic resonance imaging (mri) of the abdomen and pelvis of a pregnant patient. there was evidence of a pregnancy apparently remote from the cervix, with a very thin hypointense wall in the left hypochondrium (long arrows). on the sagittal mri images, an (a) empty normallooking uterine body (short arrow) could be observed, which was (b) connected to the cervix (short arrow). the (c & d) bowel loops seemed to be interpositioned between the gestational sac and the cervix (white arrowheads). there was (d) free fluid in the abdomen (red arrowhead). figure 2: photograph of the fibrous band connecting the uterus and the rudimentary horn. silja a. pillai, mariam mathew, noreen ishrat, anupam kakaria, asim qureshi and gowri vaidyanathan online case report | e431 presence of a rim of uterine muscle surrounding the gestational sac. haemoglobin showed a progressive drop from 9 to 7.8 g/dl. an emergency laparotomy was performed, which revealed haemoperitoneum (800 ml) with clots. the pregnancy was located in the left horn with active bleeding from a 1 cm rent in the posterior surface where the placenta was implanted. the unicornuate uterus with the right tube and ovary was normal and was connected to the rudimentary horn by a fibrous band [figure 2]. a vertical incision was made in the horn and a baby girl weighing 1,510 g with apgar scores of 2 at one minute and 7 at five minutes was delivered. the left tube was attached superolaterally to the rudimentary horn and the ovary was closely attached to the posterior aspect of the bleeding rudimentary horn. the placenta did not separate and appeared to be adherent to the uterine wall. the rudimentary horn with the placenta was excised [figure 3] and a left salpingo-oophorectomy was performed. the fibrous band had a lumen confirmed by histopathology to be a communicating horn. the fibrous band appeared stretched due to the advanced pregnancy; however, it connected the unicornuate uterus to the rudimentary horn. a pelvic drain was inserted and the abdomen was closed. the estimated blood loss was 2,300 ml, including the haemoperitoneum. the patient received four units each of packed red blood cells, fresh frozen plasma and cryoprecipitate. the postoperative period was uneventful and the patient was discharged on the sixth postoperative day. the histopathology report of the placenta was consistent with placenta increta. the baby was in good health, despite some postural deformities due to the limited space in the horn, and was discharged on the 16th postnatal day. informed consent was obtained from the patient for the publication of this case report. discussion congenital anomalies of the female genital tract are relatively common; however, as they are often asymptomatic, they may go unrecognised. while the exact incidence of genital tract anomalies is difficult to determine, it is estimated to occur in 2–4% of fertile women with normal reproductive outcomes.4 in patients with adverse pregnancy outcomes, the prevalence could be much higher. the modified american fertility society classification by rock et al. correlates anatomical anomalies with arrested embryologic development.5 thus, utero vaginal anomalies are categorised as dysgenesis disorders or vertical or lateral fusion defects. these are further subdivided into obstructive or non-obstructive forms. unicornuate uteri account for 5% of all müllerian anomalies and are an example of a class 3b disorder of lateral fusion.5 these result from a complete or partial failure of development of one müllerian duct and an incomplete fusion with the contralateral side. one cavity is normal while the defective side may exhibit varying degrees of disruptive development. müllerian anomalies are de novo congenital abnormalities, although familial aggregates of such conditions have rarely been reported.6 the connection of the rudimentary horn with the uterus may be fibrous or fibromuscular. in 72% of cases, there is no communication between the two cavities and pregnancies in the horn occur following the transperitoneal migration of the sperm or of the fertilised ovum.1 the overall rupture rate in rudimentary horn pregnancies is 50% and the majority of these occur in the second trimester; nahum et al. reported that only 30% of such pregnancies reach term.1 however, fetal salvage is rare, which emphasises the importance of the current case. rupture is thought to be a result of an underdeveloped myometrium and a dysfunctional endometrium.2 the gestational age at which such pregnancies rupture varies according to the thickness of the myometrial wall. patients with a non-communicating horn with a functional endometrium may have a positive history of dysmenorrhoea and endometriosis.6 due to the close embryologic association, evaluation of the renal system is warranted in such patients. studies show there is approximately a 31–40.5% likelihood of renal anomalies in patients with unicornuate uteri.6 early diagnosis of rudimentary horn pregnancies can be quite challenging. any ruptures will necessitate immediate surgical intervention leading to higher morbidity and mortality. the maternal mortality rate associated with rudimentary horn pregnancies has improved from 18% in the 19th century to 0.5% in the figure 3: photograph of the normal empty uterus showing the rudimentary horn (black arrow) with the attached placenta (white arrow). ruptured rudimentary horn pregnancy diagnosed by preoperative magnetic resonance imaging resulting in fetal salvage e432 | squ medical journal, august 2015, volume 15, issue 3 rudimentary horn in an early pregnancy.10 surgical intervention and excision of the rudimentary horn should be considered if the diagnosis is confirmed, as the rupture of the horn results in serious maternal morbidity or even mortality.1 conclusion the advent of new diagnostic techniques like mri has enabled the preoperative diagnosis of rare conditions— such as rudimentary ruptured horn pregnancies— which were previously diagnosed during laparotomies. in the current case, the use of mri as the diagnostic modality resulted in fetal salvage; this is rare as this type of pregnancy seldom reaches the third trimester with a live fetus. excision of a rudimentary horn is recommended, as the rupture of the horn during pregnancy can be life-threatening for both the mother and fetus. a definite preoperative diagnosis helps in counselling the patient and preparing them for an emergency surgical intervention. references 1. nahum gg. rudimentary uterine horn pregnancy: the 20thcentury worldwide experience of 588 cases. j reprod med 2002; 47:151–63. 2. jain r, gami n, puri m, trivedi s. a rare case of intact rudimentary horn pregnancy presenting as hemoperitoneum. j hum reprod sci 2010; 3:113–15. doi: 10.4103/0974-120 8.69335. 3. kanagal dv, hanumanalu lc. ruptured rudimentary horn pregnancy at 25 weeks with previous vaginal delivery: a case report. case rep obstet gynaecol 2012; 2012:985076. doi: 10.1155/2012/985076. 4. iverson re jr, decherney ah, laufer md. clinical manifestations and diagnosis of congenital anomalies of the uterus. from: www.uptodate.com/contents/clinicalmanifestations-and-diagnosis-of-congenital-anomalies-of-theuterus accessed: apr 2015. 5. rock ja, adam ra. surgery to repair disorders of development. in: nichols dh, clarke-pearson dl, eds. gynecologic, obstetric and related surgery. 2nd ed. st louis, missouri, usa: mosby, 2000. pp. 780–813. 6. reichman d, laufer mr, robinson bk. pregnancy outcomes in unicornuate uteri: a review. fertil steril 2009; 91:1886–94. doi: 10.1016/j.fertnstert.2008.02.163. 7. siwatch s, mehra r, pandher dk, huria a. rudimentary horn pregnancy: a 10-year experience and review of literature. arch gynecol obstet 2013; 287:687–95. doi: 10.1007/s00404-0122625-7. 8. tsafrir a, rojansky n, sela hy, gomori jm, nadjari m. rudimentary horn pregnancy: first-trimester prerupture sonographic diagnosis and confirmation by magnetic resonance imaging. j ultrasound med 2005; 24:219–23. 9. oral b, güney m, ozsoy m, sönal s. placenta accreta associated with a ruptured pregnant rudimentary uterine horn: case report and review of literature. arch gynecol obstet 2001; 265:100–2. doi: 10.1007/s004040000140. 10. kadan y, romano s. rudimentary horn pregnancy diagnosed by ultrasound and treated by laparoscopy: a case report and review of literature. j minim invasive gynecol 2008; 15:527–30. doi: 10.1016/j.jmig.2008.05.010. present decade, owing to improvements in healthcare and diagnostic facilities.7 however, jain et al. reported that the fetal salvage rate is still only 2%.2 common diagnostic modalities include hysterosalpingography, combined laparoscopy and hysteroscopy, ultrasonography (preferably three-dimensional) and mri. an ultrasound scan is used as an initial imaging tool to diagnose such uterine anomalies; however, the sensitivity of this modality is only 26% and this decreases in advanced pregnancies,3 as was found in the current case. suggested sonographic criteria by tsafrir et al. include pseudo-patterns of an asymmetrical bicornuate uterus, a lack of visual continuity between the cervical canal and the lumen of the pregnant horn and evidence of myometrial tissue around the gestational sac.8 typical hypervascularisation of placenta accreta may support the diagnosis. common misdiagnoses with ultrasonography include an ectopic, cornual, intrauterine or abdominal pregnancy. in the case of the current patient, the normal uterus was mistaken for a cervical fibroid in an early pregnancy scan, whereas the scan was inconclusive once the pregnancy was advanced. mri has been described as a valuable tool to diagnose uterine anomalies, especially in advanced gestation. a recent systematic literature review evaluated a total of 77 cases of rudimentary horn pregnancy over a 10-year period in order to determine radiological criteria to diagnose rudimentary horn pregnancies antenatally before uterine rupture.5 out of the 35 cases which were imaged, mri scans were performed in only 11 cases, whereas ultrasounds were performed in all cases. in five of the 11 cases with mri findings, the diagnosis had been missed on the initial ultrasound;5 this emphasises the significance of mri in the diagnosis of such anomalies. almost all of the women in the review were either in their first or second trimester. there was only one case at 28 gestational weeks.5 the current case reported here involved a rare presentation at 32 weeks of gestation. the low sensitivity of ultrasound scans for such an advanced pregnancy indicated the use of mri, which helped to expedite the necessary surgical intervention. abnormal placentation and adherence is reported frequently in rudimentary horn pregnancies due to the poorly developed musculature, insufficient decidualisation and small size of the horn.1 oral et al. estimated the prevalence of placenta accreta in rudimentary horn pregnancies to be over 10%.9 the thinning of the myometrium and the invasive nature of the placenta predisposes the rupture and severe bleeding. in the current case, the placenta was found to invade into the myometrial layer and was reported as increta on histopathological examination. kadan et al. reported successful laparoscopic excision of a http://dx.doi.org/10.4103/0974-1208.69335 http://dx.doi.org/10.1155/2012/985076 http://dx.doi.org/10.1016/j.fertnstert.2008.02.163 http://dx.doi.org/10.1007/s00404-012-2625-7 http://dx.doi.org/10.1007/s00404-012-2625-7 http://dx.doi.org/10.1007/s004040000140 http://dx.doi.org/10.1016/j.jmig.2008.05.010 sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 512-516, epub. 20th nov 12 submitted 19th feb 12 revision req. 23rd apr 12, revision recd. 28th may 12 accepted 9th jul 12 king fahad central hospital, jizan, saudi arabia e-mail: drmohamedalbarrag@hotmail.com الرتقويَخْلٌع َرْضِحّي ثُنائي اجلانب ال متناظر للمفصل الَقصِّيٌّ حممد الرباق امللخ�ص: اخلَْلٌع الَرْضِحّي للمفصل الَقصِّيٌّ الرتقوي من جانب واحد أو جانبني من اإلصابات النادرة. صعوبة تقييم هذه احلالة غالبا ما تؤدي إىل تأخري يف التشخيص والعالج. نُدرج هنا حالة نادرة من َخْلٌع َرْضِحّي ثُنائي اجلانب ال متناظر للمفصل الَقصِّيٌّ الرتقوي يف رُجل يبُلغ من الُعُمر 45 عاما. مت عالج اخللع األمامي األمين يف غرفة الطوارئ وأسفرت عن وجود عدم استقرار متبقي، بينما كان اخللع اخللفي األيسر بدون أعراض ومل جيلب االنتباه ملدة ستة أشهر. من املهم إمكانية تشخيص وعالج مثل هذه احلاالت من قبل األطباء العاملني يف صالة الطوارئ وجرّاحي العظام لتكون قادرة حتديد وعالج هذه احلالة. وينبغي تقييم مجيع املرضى املشتبه بإصابتهم خبَْلٌع املفصل الَقصِّيٌّ الرتقوي يف اجلهتني بواسطة التصوير املقطعي احملوسب للتأكد من التشخيص ولتقييم حالة املفصلني. اخللع اخللفي للمفصل القصي الرتقوي قد يكون إصابة قاتلة، وينبغي أال يُغفل بسبب وجود إصابات أخرى. التدخل اجلراحي غالبا ما يكون ضروريا يف احلاالت احلادة والقدمية. يٌّ ترقوّي، خلع، طوارئ، تقرير حالة؛ اململكة العربية ال�صعودية. مفتاح الكلمات: كتف، مف�صل َق�صِّ abstract: unilateral and bilateral sternoclavicular joint (scj) dislocations are rare injuries. the difficulty in assessing this condition often leads to delay in diagnosis and treatment. we report a rare case of bilateral asymmetrical traumatic scj dislocations in a 45-year-old male. the right anterior scj dislocation was reduced in the emergency room (er) and resulted in residual instability. the left posterior scj dislocation was asymptomatic and unnoticed for six months. it is important for er physicians and orthopaedic surgeons to be able identify and treat this condition. all suspected scj dislocations should be evaluated by computed tomography (ct) scan for confirmation of the diagnosis and evaluation of both scjs. posterior scj dislocation is a potentially fatal injury and should not be overlooked due to the presence of other injuries. surgical intervention is often necessary in acute and old cases. keywords: shoulder; sternoclavicular joint; dislocations; emergency; case report; saudi arabia. bilateral asymmetrical traumatic sternoclavicular joint dislocations mohammed k. albarrag case report traumatic bilateral sternoclavi-cular joint (scj) dislocation is a very rare injury, as 95% are unilateral. anterior scj dislocation represents 3% of all injuries of the shoulder girdle and comprises 1% of all joint dislocations;1 a ratio of approximately 20 anterior dislocations to each posterior was given in a large series.2 in another study, the frequency of posterior scj dislocations represents 0.019% of all shoulder injuries.3 the diagnosis of this injury requires good evaluation of the patient in the emergency room (er). a chest x-ray is not always helpful but, in suspected cases, a computed tomography (ct) scan of the chest with a 3-d reconstruction has the advantage of showing an obscure injury of the scj.4 treatment of an anterior scj dislocation is close reduction under general anaesthesia or intravenous sedation by direct pressure over the medial portion of the clavicle of a supine patient with a solid pad placed between the shoulders. this injury is often unstable after close reduction with the risk of recurrent instability, but this rarely results in a functional deficit.5 a posterior scj dislocation is potentially lifethreatening, with the possibility of concomitant injuries to thoracic structures such as the trachea, oesophagus, or great vessels. acute surgical mohammed k. albarrag case report | 513 intervention is often necessary by close reduction, excision and reconstruction under general anaesthesia. case report a 45-year-old healthy male soldier was involved in a motor vehicle accident in august 2006. he was the driver, was not wearing a seat belt and, when he fell asleep, hit a big truck in front of him. the patient sustained blunt chest trauma with transient loss of consciousness, and multiple abrasions to the face and body, mainly on the left shoulder and forearm. when this patient was seen in the er, he was stable but drowsy. the chest x-ray was normal. the patient, however, complained of chest pain without dyspnoea, haemoptysis, or dysphagia. the deformity of anterior scj dislocation was obvious on the right side for which a successful trial of close reduction was done in the er under intravenous sedation, and the limb was held in a shoulder immobiliser. a ct scan of the chest was not done for the initial evaluation. three weeks later the patient noticed recurrence of the deformity and instability in the right scj, which was treated conservatively by immobilisation, non-steroidal anti-inflammatory drugs, and physiotherapy. the patient had split skin grafting for the large abrasions. at a 6-month follow-up, the patient was complaining of a prominent medial end of the right clavicle, instability and discomfort. on examination, the patient was a moderatelybuilt healthy male with good air entry of the chest, no abnormal sounds, no hoarseness of voice, and no tenderness over the scjs. the right scj was prominent, mobile and unstable [figure1]. both shoulders had full range of movement with normal sensation and power in the upper limbs. radiological evaluations included a chest x-ray, which was interpreted as normal and did not illustrate the magnitude of the injury [figure 2]. a ct scan of the chest with 3-d reconstruction showed anterior dislocation of the scj on the right side as well as an unexpected and potentially lifethreatening left scj dislocation in the superior and posterior direction without compression of the mediastinum [figure 3]. the left posterior scj dislocation was overlooked at the beginning and the patient was surprisingly asymptomatic. surgical intervention was discussed and advocated but the patient preferred to continue with conservative management, including physiotherapy and analgesics. he was followed up for three years and was without neurovascular symptoms or disability at the final follow-up. figure 1: clinical image of the patient shows the deformity of the anterior dislocation of the right sternoclavicular joint (scj) and the absence of the normal shape of the left scj. bilateral asymmetrical traumatic sternoclavicular joint dislocations 514 | squ medical journal, november 2012, volume 12, issue 4 discussion unilateral and bilateral traumatic anterior scj dislocations have rarely been reported.2,4 unilateral and bilateral traumatic posterior scj dislocations are even less common;3,6 however, similar cases with asymmetrical presternal and retrosternal scj dislocations, (for example, the reports by hotchkiss in 1896, and stapelmohr in 1932) have been mentioned in a historical review.7 the scj is stabilised by a joint capsule, by the anterior and posterior sternoclavicular and interclavicular ligaments, and particularly by the costoclavicular ligament. the posterior structures are stronger than the anterior and this is why posterior scj dislocations are rarer than anterior dislocations. good knowledge of the anatomy of the scj and its variations is important to identify the pathology, as more than 10% of asymptomatic patients show substantial asymmetry in scjs.8 this injury commonly results from high-energy trauma, such as motor vehicle crashes, sport injuries, or falls from a height.2 asymmetrical scj dislocation is an extremely unusual injury which could be explained by the indirect mechanism of injury to produce anterior and posterior dislocations with forces applied to the shoulder girdle from the anterolateral and posterolateral directions, respectively. a posterior scj dislocation may also occur from a direct force applied to the medial end of the clavicle. the key to diagnosis is a detailed patient history and physical examination. nevertheless, before ct scan evaluation became possible, such injuries were often discovered post-mortem.9 the delay in the diagnosis of the posterior scj dislocation on the left side occurred because of the slight deformity, and the presence of other injuries in the left forearm with the right anterior scj dislocation, which drew the attention of the treating team. the absence of mediastinal compression symptoms which include shortness of breath, hoarseness, and dysphagia was another reason the potentially fatal posterior scj dislocation on the left side was overlooked. the literature supports conservative treatment for most patients with chronic anterior sternoclavicular instability. those patients with ongoing disability may be candidates for joint reconstruction. patients with posterior dislocations are typically stable after reduction, but require surgery if they redislocate or if there is ongoing symptomatic instability.10 however, a neglected or incompletely reduced retrosternal dislocation constitutes a constant danger to the patient.7 an optimal, standardised operative procedure has not been established because of the small number of cases. many surgical procedures have been advocated to treat scj dislocations such as kirschner wires or steinmann pin fixation; however, these are now contraindicated by the figure 2: chest x-ray showing both clavicles on the same level with no obvious sternoclavicular joint injury. mohammed k. albarrag case report | 515 potential for migration into vital structures.11 the use of more stable implants, such as wire sutures, or using polydioxane (pds) cords or custommade plates is possible, although these implants have a substantial risk of intrathoracic migration if breakage or loosening occurs.12 arthrodesis of the scj is also contraindicated because of the marked restriction in shoulder movement which it produces.13 resection of approximately 1 to 2 cm of the medial clavicle is an alternative procedure when there is no residual soft tissue attached to the medial clavicle, but the outcome of resectioning is poor, with painful restricted movement of the shoulder, and limited abduction.14 the best outcomes were shown with the use of the semitendinosus tendon graft in a figure-of-eight fashion through drill holes in the sternum and manubrium.10,15 conclusion scj dislocations are rare injuries. bilateral scj dislocation is extremely rare and can appear symmetrically or asymmetrically. a careful patient history and examination is invaluable. additionally, a 3-d ct scan should be done to confirm the diagnosis, to evaluate the extent of the injury, and to figure 3: (a) a 3-d chest computed tomography scan which clearly shows the right anterior and left posterior sternoclavicular joint dislocations. (b) a 3-d chest computed tomography scan with a superior view of the dislocated right anterior and left posterior sternoclavicular joints. bilateral asymmetrical traumatic sternoclavicular joint dislocations 516 | squ medical journal, november 2012, volume 12, issue 4 look for bilateral involvement. avoiding improper patient selection and surgical complications are two cornerstones of the management of this problem. conservative treatment for chronic anterior scj dislocation will produce satisfactory results. potentially life-threatening complications can occur due to acute posterior scj dislocation if not diagnosed and treated early. old and neglected posterior scjs should be operated upon because of the constant risk of late complications. references 1. renfree kj, wright tw. anatomy and biomechanics of the acromioclavicular and sternoclavicular joints. clin sports med 2003; 22:219–37. 2. nettles jl, linscheid r. sternoclavicular dislocations. j trauma 1968; 8:158–64. 3. camara es, bousso a, tall m, sy mh. posterior sternoclavicular dislocations. eur j orthop surg traumatol 2009; 19:7–9. 4. chien lc, hsu il, tsai mc, lo cj. bilateral anterior sternoclavicular dislocation. j trauma 2009; 66:1504. 5. yeh gl, williams gr, jr. conservative management of sternoclavicular injuries. orthop clin north am 2000; 31:189–203. 6. baumann m, vogel t, weise k, muratore t, trobisch p. bilateral posterior sternoclavicular dislocation. orthopedics 2010; 33:510. 7. tyer hdd, sturrock wds, mccallow f. retrosternal dislocation of the clavicle. j bone joint surg br 1963; 45-b:132–7. 8. tuscano d, banerjee s, terk mr. variations in normal sternoclavicular joints; a retrospective study to quantify scj asymmetry. skeletal radiol 2009; 38:997–1001. 9. rajaratnam s, kerins m, apthorp l. posterior dislocation of the sternoclavicular joint: a case report and review of the clinical anatomy of the region. clin anat 2002; 15:108–11. 10. thut d, hergan d, dukas a, day m, sherman oh. sternoclavicular joint reconstruction--a systematic review. bull nyu hosp jt dis 2011; 69:128–35. 11. liu hp, chang ch, lin pj, chu jj, hsieh hc, chang jp, et al. pulmonary artery perforation after kirschner wire migration: case report and review of the literature. j trauma 1993; 34:154–6. 12. franck wm, jannasch o, siassi m, hennig ff. balser plate stabilization: an alternate therapy for traumatic sternoclavicular instability. j shoulder elbow surg 2003; 12:276–81. 13. robinson cm. jenkins pj. markham pe. beggs i. disorders of the sternoclavicular joint. j bone joint surg br 2008; 90-b:685–96. 14. eskola a, vainionpaa s, vastamaki m, slätis p, rokkanen p. operation for old sternoclavicular dislocation: results in 12 cases. j bone joint surg br 1989; 71b:63–5. 15. bae ds, kocher ms. chronic recurrent anterior sternoclavicular joint instability: results of surgical management. j pediatr orthop 2006; 26:71–4. clinical and basic research | 263 clinical & basic research sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 263-268 epub. 9th may 13 submitted 18th jun 12 revision req. 15th dec 12, revision recd. 29th dec 12 accepted 21st jan 13 1paediatric and 2biochemistry departments, minia university, minia, egypt *corresponding author e-mail: basmaelmoez@yahoo.com دراسة األديبونكتني يف األطفال الذين يعانون من مرض السكري ب�شمة عبد املعز علي، دعاء حممد حمرو�ض، اأحالم حممد عبد اهلل و مينا جرج�ض فكري ق�شم طب الأطفال، الكيمياء احليوية و وال�شكري بالبدانة عالقة له و الدهنيه اخلاليا من فقط ويفرز الدهني الن�شيج بوا�شطة يفرز هرمون الأديبونكتني الهدف: امللخ�ص: بالإ�شابة ترابطه ومدي والثاين الأول بنوعيه ال�شكري بداء امل�شابني الأطفال يف الأديبونكتني م�شتوي تقييم الهدف: م�شاعفاتهما. مب�شاعفات الأي�ض يف مر�شي ال�شكري. الطريقه: اأجريت هذه الدرا�شة بعيادة الغدد ال�شماء مب�شت�شفى الأطفال اجلامعي جامعة املنيا خالل الفرتة من اأبريل 2011 حتى يوليو 2011 و�شملت 314 طفل ترتاوح اأعمارهم من 2 اإىل 18 �شنة.ومت تق�شيم احلالت اإىل جمموعتني :املجموعة الأوىل: ت�شتمل على 164 مري�ض مت ت�شخي�شهم م�شبقا كمر�شى بداء ال�شكري ثم ق�شمت هذه املجموعة اإىل جمموعتني فرعيتني: املجموعة الأوىل اأ: ت�شتمل على 142 مري�ض بداء ال�شكري من النوع الأول.املجموعة الأوىل ب: ت�شتمل على 22 مري�ض بداء ال�شكري من النوع الثاين واملجموعة الثانية: ت�شتمل على 150 طفل اأ�شحاء ظاهريا ومتماثلني يف ال�شن واجلن�ض .وقد خ�شعت كلتا املجموعتني اإيل: اخذ التاريخ املر�شى املف�شل، الفح�ض الإكلينيكي والختبارات املعملية وت�شمل ن�شبة الهيموجلوبني ال�شكري، وقيا�ض م�شتوي الكول�شرتول والدهون الثالثية واأي�شا ن�شبة الأديبونكتني وال�شي-ببتيد( يف الدم. النتائج: وجد اأن ن�شبة الأديبونكتني بالدم مل تختلف كثريا يف الأطفال املجموعة عن ال�شكري مر�شى يف اأعلى لكنها و الثاين. النوع ال�شكري بداء امل�شابني الأطفال عن الأول النوع ال�شكري بداء امل�شابني ال�شابطة ومن حيث عالقة الأديبونكتني بالعوامل الأخرى وجد انه توجد عالقة تنا�شب طردية ذات دللة اإح�شائية مل�شتوى الأديبونكتني بالدم مع حميط الو�شط وفرتة الإ�شابة باملر�ض يف الأطفال امل�شابني بداء ال�شكري من النوع الأول وكذلك عالقة تنا�شب طردية ذات دللة اإح�شائية مل�شتوى الأديبونكتني بالدم مع جرعة الأن�شولني اليومية يف الأطفال امل�شابني بداء ال�شكري من النوع الثاين ومن ناحية اأخرى مت اإيجاد عالقة تنا�شب عك�شية ذات دللة اإح�شائية مل�شتوى الأديبونكتني بالدم مع كل من ن�شبة الكول�شرتول وال�شي-ببتيد بالدم و �شغط الدم النب�شاطي يف الأطفال امل�شابني بداء ال�شكري من النوع الثاين اخلال�شة : نتوقع من نتائج هذا البحث ان الأديبونكتني له اأهمية يف احلمايه من م�شاعفات الأي�ض يف مر�شي ال�شكري. مفتاح الكلمات: ال�شكري؛ الأديبونيكتني؛ مقاومة الأن�شولينز؛ م�رس. abstract: objectives: adiponectin is a hormone produced by adipose tissue. it is secreted exclusively by adipocytes and appears to play a role in the pathophysiology of obesity, diabetes mellitus (dm), and its comorbidities. the aim of this study was to assess adiponectin levels in diabetic children with type 1 dm (t1dm) and type 2 dm (t2dm), and to detect its prognostic role in them. methods: this study was undertaken from april to july 2011 at minia university children’s hospital, egypt, and included 314 children aged 2–18 years divided into two patient groups. group i consisted of 164 pre-diagnosed diabetic patients, further subdivided into group ia which included 142 patients with t1dm and group ib, 22 patients with t2dm; group 2 included 150 apparently healthy children as a controls; they were ageand sex-matched to the diseased group. patients were subjected to a thorough history taking, clinical examination, and laboratory investigations including assessment of hba1c percentages, fasting c-peptide levels, lipid profiles and fasting serum adiponectin levels. results: adiponectin levels did not differ significantly between patients with t1dm and t2dm, but it was significantly higher in diabetic patients than in the controls. in t1dm, adiponectin had positive significant correlations with the duration of the disease and waist circumference, while in t2dm, it had a positive significant correlation with the dose of insulin given and negative significant associations with diastolic blood pressure, cholesterol, and c-peptide levels. conclusion: the results of the study suggest that adiponectin can play a protective role against the metabolic complications of dm. keywords: diabetes mellitus; adiponectin; insulin resistance; egypt. a study of adiponectin in children with diabetes mellitus *basma a. ali,1 doaa m. mahrous,1 ahlam m. abdallah,2 mina fikri1 advances in knowledge adiponectin, a hormone produced and secreted by adipocytes, is present in the blood in high circulating concentrations suggesting an important physiological role. an indirect regulator of glucose metabolism, adiponectin increases insulin sensitivity, improves glucose tolerance, and inhibits inflammation. adiponectin is emerging as a risk factor for health problems such as diabetes, hypertension, and heart disease, yet there is very limited information on the distribution of this hormone in some populations, especially in children. a study of adiponectin in children with diabetes mellitus 264 | squ medical journal, may 2013, volume 13, issue 2 egypt has one of the world’s ten highest rates of diabetes mellitus (dm) and impaired glucose tolerance.1 the ageing population together with socioeconomic and lifestyle changes has resulted in a dramatic increase in the prevalence of dm.1 in dm, the improper regulation of glucose and lipid metabolism due to the lack of insulin leads to an increased lipolysis rate and decreased stored fat tissue, which is reversible after insulin administration. adiponectin is a hormone produced by the adipose tissue.2 it is secreted exclusively by adipocytes, circulates at relatively high levels in the blood stream, and appears to play a role in the pathophysiology of obesity, dm, and its comorbidities.2 this is because of its involvement in the regulation of carbohydrate and fat metabolism, as demonstrated in several animal and in vitro studies.3 by acting through two distinct membrane receptors, adiponectin receptors 1 and 2 (which utilise 5-adinosine monophosphateactivated protein kinase phosphorylation, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha as key cellsignalling elements), increase hepatic and skeletal muscle sensitivity to insulin, enhance fatty acid oxidation, suppress monocyte-endothelial interaction, support endothelial cell growth, lower blood pressure, and moderate adipose tissue growth. the secretion of adiponectin can be suppressed by adipose factors, which are turned on once fat cell mass increases, such as cytokines, the adipose renin-angiotensin system, and increased oxidative stress. inhibition of adiponectin secretion results in the loss of an array of mechanisms which, under normal conditions of fat cell homeostasis, provide protection from insulin resistance, dm, and atherosclerosis.4 the aim of this study was to assess adiponectin levels in diabetic children with type 1 dm (t1dm) and type 2 dm (t2dm), and to detect their role as a prognostic factor. methods this study included 164 patients with dm, 70 males (42.7%) and 94 females (57.3%); information on them was collected from april to july 2011 and they were classified as group i. they had regular follow-up in the paediatric endocrinology outpatient clinic of minia university children’s hospital, minia, egypt. informed consent was obtained from every subject after the study received the approval of the ethical committee of the faculty of medicine of minia university. participants were further subdivided into two groups. group ia (t1dm) consisted of 142 patients (86.6 %) with a mean of age of 10.9 ± 4.2 years. in this group, there were 64 males (45.1%) and 78 females (54.9%) with a mean duration of illness of 40.2 ± 12 months. group ib (t2dm) consisted of 22 patients (13.4 %) with a mean of age 14.5 ± 2.7 years. in this group, there were 6 males (27.3%) and 12 females (72.7%), with a mean duration of illness of 82.1 ± 39.6 months. another 150 children (group ii) acted as a control group which was ageand sex-matched to the study group. both groups underwent a thorough history taking. a clinical examination included anthropometric measurements, including weight, height, body mass index (bmi), and waist circumference (wc). each measurement was taken as the mean of three consecutive readings. laboratory investigations included a measure of glycosylated haemoglobin (hba1c%), cholesterol, and triglycerides (tg).5,6 three ml venous blood samples were taken in the morning after 12 hours overnight using a complete aseptic technique. they were then centrifuged at 1000 rpm for 5 minutes. the sera were separated and stored at -20° c until an assay of c-peptide levels by enzyme-linked immunosorbent assay (elisa) technique was performed. this was carried out using c-peptide elisa kits (intermedical, villarica, italy). adiponectin levels were also determined by immunoassay technique using quantikine (human total adiponectin/acrp30 immunoassay) drp300 kits (r&d systems, minneapolis, minnesota, usa).7,8 application to patient care the use of intensive insulin therapy in the management of type 2 diabetes mellitus might be protective as it improves insulin sensitivity by increasing adiponectin levels and normalising c-peptide, while adiponectin could also provide protection by affecting metabolic complications in the form of dyslipidaemia and hypertension. basma a. ali, doaa m. mahrous, ahlam m. abdallah and mina fikri clinical and basic research | 265 the data were coded and verified prior to data entry. all statistical analyses were carried out using the statistical package for social sciences (spss), version 19.0 (ibm, inc., chicago, illinois, usa). for descriptive statistics, continuous variables were presented as mean followed by standard deviation (sd), and categorical variables were presented as frequency and percentage. in regards to analytical statistics, for qualitative data pearson’s chi-square test (χ2) was used; for quantitative data, an independent samples t-test (for two groups) and a one-way analysis of variance (anova) test and post hoc multiple comparisons with the least significant difference (lsd) equal variance assumed (for three groups), were used. two-tailed partial correlation coefficients (r), adjusted for age, sex, and bmi were used to assess the relationships between adiponectin and other variables. a p value <0.05 was considered significant.9 results the study group (group i) had significantly higher fasting serum levels of adiponectin than the controls (group ii) where p = 0.003 and 0.002, respectively. on the other hand, there was a non-significant difference between groups ia and b, where p = 0.4, although patients of group ib had the highest mean levels of adiponectin of all the studied groups [table 1]. in the different laboratory investigations, the current study found that there were non-significant differences between groups ia and b in regards to the hba1c percentage and triglycerides levels, while group ib had significantly higher levels of c-peptide and cholesterol than group ia (p = 0.0001 and 0.01, respectively) [table 2]. finally, concerning different correlations, we found that in group ia, there were significant fair positive correlations between mean adiponectin levels and both the duration of dm and wc, where r = 0.28 and p = 0.001 and r = 0.19 and p = 0.02, respectively. on the other hand, in group ib, there was a moderate positive significant correlation between mean adiponectin table 1: comparison between the studied groups as regarding the fasting serum level of adiponectin (µg/ml) fasting serum adiponectin (µg/ml) group ia (t1dm) (n =142) group ib (t2dm) (n = 22) group ii (control) (n = 150) p value p† p‡ p§ p¶ mean ± sd 9.5 ± 4.9 10.4 ± 5.7 4.9 ± 2.3 0.4 0.003* 0.002* 0.006* median 8.9 10.3 5.5 range 1.3–18.5 1.1–18.5 1.5–7.9 t1dm = type 1 diabetes mellitus; t2dm = type 2 diabetes mellitus; sd = standard deviation; * = significant; † = difference between groups ia and b; ‡ = difference between groups ia and ii; § = difference between groups ib and ii; ¶ = comparison between the studied groups. table 2: laboratory investigations of groups ia and b laboratory investigations group ia group ib p value mean sd mean sd hba1c (%) 7.5 1.4 8.1 0.62 0.06 c-peptide (ng/ ml) 0.26 0.07 0.77 0.8 <0.001* cholesterol (mg/dl) 168.6 38.9 191.1 52.2 0.01* triglyceride (mg/dl) 131.2 205.3 140 54.2 0.8 sd = standard deviation; hba1c = glycosylated haemoglobin; * = significant. table 3: partial correlation coefficients adjusted for age, sex and body mass index between collected data and mean adiponectin in diabetic patients group ia group ib r p r p insulin dose (iu/kg/day) -0.08 ns 0.66 0.002* duration of dm (months) 0.28 0.001* 0.37 ns waist circumference (cm) 0.19 0.02* 0.2 ns dbp (mmhg) -0.002 ns -0.73 <0.001* hba1c (%) 0.03 ns -0.32 ns cholesterol (mg/dl) 0.14 ns -0.54 0.01* triglycerides (mg/dl) 0.1 ns 0.35 ns c-peptide (ng/ml) 0.05 ns -0.49 0.03* ns = not significant; * = significant; dm = diabetes mellitus; dbp = diastolic blood pressure; hba1c = glycosylated haemoglobin. grades of r: 0.00 to 0.24 (weak or no association); 0.25 to 0.49 (fair association); 0.50 to 0.74 (moderate association); ≥0.75 (strong association). a study of adiponectin in children with diabetes mellitus 266 | squ medical journal, may 2013, volume 13, issue 2 levels and the doses of insulin, and a moderate negative highly-significant correlation with diastolic blood pressure (dbp) (r = 0.66 and p = 0.002; r = -0.73 and p = 0.0001, respectively). furthermore, there were negative significant correlations between the mean adiponectin level and both cholesterol and c-peptide, which displayed a moderate relationship with the former and a fair relationship with the latter (r = -0.45 and p = 0.01; r = -0.49 and p = 0.03, respectively) [table 3]. discussion several experimental studies have shown the antiinflammatory and anti-atherosclerotic effects of adiponectin.10 furthermore, there is substantial evidence that adiponectin has protective effects against the development of atherosclerosis.11 therefore, the aim of our study was to assess the difference of adiponectin levels in children with t1dm and t2dm, and to detect its prognostic role. in regards to the results of the current study, mean adiponectin levels in t1dm patients did not differ significantly from those in patients with t2dm (p = 0.4). this may have been due to the fact that our paediatric t2dm patients were on insulin therapy. insulin downregulates adiponectin receptor expression, and insulin replacement could induce adiponectin resistance, making increased levels necessary to achieve physiological effects.12 also, several authors have observed that intensive insulin treatment increases circulating adiponectin levels, improving insulin sensitivity.13,14 moreover, the positive highly-significant correlation between the mean fasting serum adiponectin level and the dose of insulin in patients with t2dm in our study supports this result (r = 0.66 and p = 0.002). on the other hand, the mean adiponectin levels were significantly higher in diabetic patients than the controls. this result correlated with the results obtained by furuta et al. who found that adiponectin levels increased in conjunction with β-cells dysfunction.15 also, barnes et al. and ljubic et al. found that adiponectin levels were significantly higher in diabetics than in controls.16,17 concerning laboratory investigations, the current study found that there was an insignificant difference between patients in groups ia and ib in regards to hba1c percentage. on the other hand, group ib had significantly higher mean c-peptide levels than group ia. furthermore, they had significantly higher cholesterol levels than group ia. it is possible that poor glycaemic control among those with t2dm contributed substantially to the high lipid profile.18 this result correlated with the results obtained by dabelea et al. and mayerdavis et al., who found that t2dm patients had higher c-peptide levels and cholesterol than t1dm patients.19,20 contrary to our results, wadwa et al. found that there was a non-significant difference between t1dm and t2dm in regards to cholesterol levels.21 concerning different correlations, in group ia mean serum adiponectin had a significant fair positive correlation with duration of dm. this result was in agreement with the result obtained by lindström et al.22 also, there was a significant weak positive correlation between mean adiponectin levels and wc. this was possibly due to the fact that 93% of group ia were lean patients. on the other hand, in group ib there was a moderate positive significant correlation between mean adiponectin level and dose of insulin. this might be due to the fact that insulin therapy increased circulating adiponectin levels and decreased insulin resistance by increasing the metabolic insulin signal in human skeletal muscles.13 furthermore, there was a moderate negative highly significant correlation between adiponectin and dbp. this result correlated with the results obtained by degawa-yamauchi et al. in their study of african boys, weiss et al. in their study of french adolescents, and hassan et al. in their study of obese children.23–25 this could possibly be due to the beneficial role of adiponectin in the management of endothelial dysfunction as adiponectin acts directly on vascular endothelial cells and exerts salutary effects on endothelial function through endolethial nitric oxide synthase (enos)-dependent and cyclooxygenase-2 (cox2) dependent regulatory mechanisms.26 also, there was a moderate negative significant correlation between mean adiponectin and total cholesterol among group ib. this may have been due to the anti-inflammatory and anti-atherosclerotic effects of adiponectin.27 finally, there was a fair negative significant correlation between serum adiponectin levels and c-peptide. this could be explained by the adiponectin level increase in conjugation with β-cell dysfunction, which was estimated by fasting serum c-peptide. basma a. ali, doaa m. mahrous, ahlam m. abdallah and mina fikri clinical and basic research | 267 conclusion based on the results of this study, we concluded that there was a non-significant difference in the adiponectin levels between t1dm and t2dm, but that diabetic patients had significantly higher levels than the control group. the increase in circulating adiponectin concentrations in patients with t1dm appeared to be associated with a longer duration of illness and a greater wc. on the other hand, pancreatic β-cell function is a significant regulator for serum adiponectin concentrations in t2dm patients where serum adiponectin concentrations were associated with c-peptide. also, in t2dm, adiponectin had a significant negative association with dbp and hypercholesterolaemia, suggesting its protective role against the metabolic complications of dm. references 1. international diabetes federation. idf diabetes atlas: regional overviews. from: http://www.idf. org/diabetesatlas/5e/regional-overviews accessed: jul 2011. 2. lau d, dhillon b, yan h, szmitko p, verma s. adipokines. molecular links between obesity and atheroslcerosis. am j physiol heart circ physiol 2005; 288:h2031–41. 3. kadowaki t, yamauchi t. adiponectin and adiponectin receptors. endocr rev 2005; 26:439–51. 4. stern n, osher e, greenman y. hypoadiponectinemia as a marker of adipocyte dysfunction -part i: the biology of adiponectin. j cardiometab syndr 2007; 2:174–82. 5. rewers m, pihoker c, donaghue k, hanas r, swift p, klingensmith g. assessment and monitoring of glycemic control in children and adolescents with diabetes. pediatr diabetes 2009; 10:71–81. 6. nicholson jf, pesce ma. reference ranges for laboratory tests and procedures in: kliegman rm, stanton bmd, st. geme j, schor nf, behrman re, eds. 19th ed. nelson textbook of pediatrics. philadelphia: wb saunders co., 2010. pp. 2396–427. 7. rendell m, drew hm, nickoloff e. c-peptide as a clinical assay. ligand q 1979; 2:20–3. 8. quantikine elisa. human total adiponectin/ acrp30 immunoassay drp300 kit (user manual). from: http://www.rndsystems.com/pdf/drp300.pdf accessed: jun 2011. 9. daniel ww. biostatistics: a foundation for analysis in the health sciences. 7th ed. new york: john wiley and sons, inc.,1999. p. 944. 10. goldstein b, scalia r, ma x. protective vascular and myocardial effects of adiponectin. nat clin pract cardiovasc med 2009; 6:27–35. 11. koerner a, kratzsch j, kiess w. adipocytokines: leptin-the classical, resistin the controversial, adiponectin the promising, and more to come. best pract res clin endocrinol metab 2005; 19:525–46. 12. tsuchida a, yamauchi t, kadowaki t. nuclear receptors as targets for drug development: molecular mechanisms for regulation of obesity and insulin resistance by peroxisome proliferator-activated receptor and gamma. creb-binding protein, and adiponectin. j pharmacol sci 2005; 97:164–70. 13. langouche l, vander perre s, wouters p, d'hoore a, hansen t, van den berghe g. effect of intensive insulin therapy on insulin sensitivity in the critically ill. j clin endocrinol metab 2007; 92:3890–7. 14. pereira ri, snell-bergon jk, erickson c, schauer ie, bergman bc, rewers bc, maaha dm. adiponectin dysregulation and insulin resistance in type 1 diabetes. j clin endocrinol metab 2012; 97:e6427. 15. furuta m, tamai m, hanabusa t, yamamoto y, nanjo k, sanke t. serum adiponectin is associated with fasting serum c-peptide in non-obese diabetic patients. diabetes res clin pr 2006; 72:302–7. 16. barnes m, curran-everett d, hamman r, maahs d, mayer-davis e, d'agostino r, et al. determinants of adiponectin levels in young people with type 1 diabetes. diabet med 2008; 25:365–9. 17. ljubic s, boras j, jazbec a, lovrencic m, vidjak v, erzen d, et al. adiponectin has different mechanisms in type 1 and type 2 diabetes with c-peptide link. clin invest med 2009; 32:e271–9. 18. alberti k, zimmet p, shaw j. metabolic syndrome—a new world-wide definition. a consensus statement from the international diabetes federation. diabet med 2006; 23:469–80. 19. dabelea d, d'agostino r, mayer-davis e, pettitt d, imperatore g, dolan l, et al. testing the accelerator hypothesis: body size, beta-cell function, and age at onset of type 1 (autoimmune) diabetes. diabetes care 2006; 29:290–4. 20. mayer-davis e, beyer j, bell r, dabelea d, d'agostino r, imperatore g, et al. diabetes in african american youth: prevalence, incidence, and clinical characteristics: the search for diabetes in youth study. diabetes care 2009; 32:s112–22. 21. wadwa r, urbina e, anderson a, hamman r, dolan l, rodriguez b, et al. measures of arterial stiffness in youth with type 1 and type 2 diabetes: the search for diabetes in youth study. diabetes care 2010; 33:881–6. 22. lindström t, frystyk j, hedman c, flyvbjerg a, arnqvist h. elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration. clin endocrinol 2006; 65:776–82. 23. degawa-yamauchi m, dilts j, bovenkerk j, saha c, a study of adiponectin in children with diabetes mellitus 268 | squ medical journal, may 2013, volume 13, issue 2 pratt j, considine r. lower serum adiponectin levels in african-american boys. obes res 2003; 11:1384– 90. 24. weiss r, dziura j, burgert t, tamborlane w, taksali s, yeckel c, et al. obesity and the metabolic syndrome in children and adolescents. n engl j med 2004; 350:2362–74. 25. hassan n, el-ashry h, awad a, el-masry s, youssef m, sallam m, et al. adiponectin in obese children and its association with blood pressure and anthropometric markers. med res j 2011; 10:1–4. 26. ohashi k, ouchi n, matsuzawa y. adiponectin and hypertension. am j hyperten 2005; 24:263–9. 27. el-mesallamy ho, hamdy nm, ibrahim sm. adiponectin and pro-inflammatory cytokines in obese diabetic boys. indian pediatr 2011; 48:815–6. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e495−499, epub. 14th oct 14 submitted 24th nov 13 revisions req. 6th feb & 2nd apr 14; revisions recd. 5th mar & 16th apr 14 accepted 1st may 14 1department of pharmacology & clinical pharmacy, 2college of medicine & health sciences, sultan qaboos university; 3department of pharmacy, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mme51@squ.edu.om اجتاهات وصف املضادات احليوية يف عينة من األطفال العمانيني خالد البلو�صي، فاطمة الغافري، فاطمة ال�صوايف، اإبراهيم الزكواين abstract: objectives: this study aimed to evaluate antibiotic prescribing patterns for paediatric patients at sultan qaboos university hospital (squh), a tertiary care hospital in muscat, oman. methods: this retrospective cross-sectional study included all 1,186 prescriptions issued for 499 patients at the paediatric outpatient clinic and paediatric inpatient ward at squh between march and may 2012. results: of the 499 patients, 138 (27.6%) were prescribed a total of 28 different antibiotics. a total of 185 (15.6%) antibiotic prescriptions were issued among the total drug prescriptions. preschool children aged 0–6 years were prescribed antibiotics most frequently (n = 110). co-amoxiclav was the most commonly prescribed antibiotic in both inpatients and outpatients (27.0% and 33.9%, respectively), followed by cefuroxime in inpatients (13.5%) and azithromycin in outpatients (18.6%). co-amoxiclav was the most commonly prescribed antibiotic in both 0–6 (31.3%) and 7–11 (23.3%) year-olds, while cefuroxime was most commonly prescribed in children ≥12 years old (25.0%). conclusion: antibiotic prescription patterns in this population were similar to those in north america, europe and asia. to confirm the findings of this study, further research on antibiotic prescription trends across the wider paediatric population of oman should be initiated. keywords: antibiotics; pediatrics; drug prescription, trends; oman. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل تقييم اأمناط و�صف امل�صادات احليوية للأطفال املر�صى يف م�صت�صفى جامعة ال�صلطان قابو�س )م�صت�صفى مرجعي يف م�صقط، �صلطنة عمان(. الطريقة: �صملت هذه الدرا�صة اال�صتعادية امل�صتعر�صة جميع الو�صفات )1,186( ال�صادرة ل 499 مري�صا يف العيادة اخلارجية للأطفال واالأطفال املنومني يف امل�صت�صفى بني مار�س ومايو 2012 النتائج: مت و�صف ما جمموعه 28 م�صادا حيويا ل 138 )%27.6( مري�صا و�صدر ما جمموعه 185 )%15.6( و�صفات امل�صادات احليوية بني اإجمايل الو�صفات الطبية .)110 = �صنوات )ن 0-6 بني اأعمارهم ترتاوح الذين املدر�صة �صن قبل االأطفال يف اأكرب ب�صكل احليوية امل�صادات و�صف مت للأدوية. 33.9% و )27.0%( اخلارجية العيادات ومر�صى املنومني املر�صى من كل يف �صيوعا االأكرث هو االأموك�صيكلف عقار و�صف كان على التوايل، يليه عقار ال�صفيورك�صيم يف املر�صى املنومني بامل�صت�صفى )%13.5( و عقاراالأزيرثومي�صني يف مر�صى العيادات اخلارجية )%18.6(. كان و�صف عقار االأموك�صيكلف هو االأكرث �صيوعا يف االأطفال الذين ترتاوح اأعمارهم بني 6-0 �صنوات )%31.3( و7-11 �صنوات )%23.3(، يف حني كان ال�صفيورك�صيم االأكرث �صيوعا يف االأطفال 12≤ �صنة )%25.0(. اخلال�صة: كانت اأمناط و�صف امل�صادات لهذه الفئة العمرية مماثلة لتلك املر�صودة يف اأمريكا ال�صمالية واأوروبا وا�صيا. و لتاأكيد نتائج هذه الدرا�صة، ينبغي ال�رشوع يف اإجراء املزيد من البحوث ب�صاأن اجتاهات و�صف امل�صادات احليوية يف عينة ت�صمل عددا اأكرب من االأطفال يف �صلطنة عمان. مفتاح الكلمات: امل�صادات احليوية؛ االأطفال؛ و�صف االأدوية، االجتاهات؛ عمان. antibiotic prescribing trends in an omani paediatric population *khalid al-balushi,1 fatma al-ghafri,2 fatma al-sawafi,2 ibrahim al-zakwani1,3 clinical & basic research advances in knowledge this study investigates antibiotic prescription trends in a paediatric population in oman. the results of this study found that children aged 0–6 years old were prescribed antibiotics most frequently. application to patient care the results of this study highlight the need for hospitals to follow more guideline-based antibiotic prescription practices. furthermore, hospitals should implement uniform antibiotic prescription policies based on national antibiotic sensitivity patterns. they are primarily administered for acute respiratory illnesses, with 70% of all prescriptions issued for upper respiratory tract infections in paediatric patients.3,4 a study performed in norway found that preschool children were the group most commonly exposed to antibiotics.5 antibiotics are often prescribed for children, antibiotics are one of the most commonly prescribed type of drugs in the world. studies indicate that approximately one-third of all hospitalised patients receive antimicrobial therapy.1 a study from 1999 to 2005 in the netherlands found that antibiotics were the most commonly prescribed medications among children.2 antibiotic prescribing trends in an omani paediatric population e496 | squ medical journal, november 2014, volume 14, issue 4 especially in primary care settings, without there being any likely therapeutic effects; this practice was noted among a group of children in british columbia, canada.6 the increase in antibiotic prescriptions, accompanied by their inappropriate use, augments the rates of antibiotic resistance and the burden on healthcare budgets worldwide.7,8 antibiotic resistance can lead to prolonged hospitalisation, failed treatments, increased healthcare costs and mortality.9 to ensure the appropriate use of antibiotics, several factors need to be addressed concerning the individual microorganism, patient, disease and drug.9 the centers for disease control and prevention in the usa define appropriate antibiotic prescription practices as “prescribing antibiotics only when they are likely to be beneficial to the patient, selecting agents that will target the likely pathogens and using these agents at the correct dose and for the proper duration”.10 moreover, the world health organization (who) defines appropriate use as “the cost-effective use of antimicrobials which maximises clinical therapeutic effect while minimising both drug-related toxicity and the development of antimicrobial resistance”.11 there are many reasons behind the misuse of antibiotics. these include misdiagnoses due to human error, technical reasons and factors related to pharmaceutical industry promotion.12 many hospitals have attempted to deal with the issue of antibiotic misuse by creating guidelines and restricting the use of certain antibiotics in order to reduce the emergence of drug-resistant bacterial strains and increase the life span of these medications. it is therefore essential to apply a rationalisation and evaluation policy to the prescription of anti-infectious drugs in healthcare facilities.13 research to date has focused on adult populations with a limited emphasis on the antibiotic prescribing trends for paediatric patients.14 to the best of the authors’ knowledge, there are few local data from oman on drug prescription trends in the paediatric population.15 in consequence, this study aimed to understand antibiotic prescribing patterns for paediatric patients at sultan qaboos university hospital (squh), a tertiary hospital in muscat, oman. methods in this retrospective cross-sectional study, patients’ electronic record data from the period of march to may 2012 were analysed. all paediatric patients who visited squh during the catchment period were included in the study. records were included from both the outpatient paediatric clinics and inpatient paediatric wards at the hospital. a total of 1,186 prescriptions for 499 patients were analysed. descriptive statistics were used to describe the data. for categorical variables, frequencies and percentages were reported. for continuous variables, the mean and standard deviation (or median and interquartile range, wherever appropriate) were used to summarise the data. the statistical package for the social sciences (spss), version 19.0 (ibm corp., chicago, illinois, usa) was used to analyse the data. this study was approved by the medical research & ethics committee of the sultan qaboos university college of medicine & health sciences (mrec#567). results a total of 1,186 prescriptions for 499 patients were analysed. the mean age was 5.0 ± 4.4 years. the most frequently encountered age group was children aged 0−6 years (n = 329), with males representing 56.9% of all patients. most of the children were outpatients (64.3%) visiting the paediatric outpatient clinic at squh. the median treatment duration was seven days [table 1]. among the children who were prescribed antibiotics, the most common diseases were respiratory diseases (n = 62; 44.9%) followed by haematological conditions (n = 18; 13.0%) and gastrointestinal diseases (n = 8; 5.8%). of the 499 patients, 138 (27.6%) were prescribed a total of 28 different antibiotics. the number of antibiotic prescriptions was similar between genders (70 and 68 for males and females, respectively). there was a trend towards more antibiotic prescriptions table 1: patient demographic characteristics (n = 499) characteristic n (%) age in years 0−6 329 (65.9) 7−11 117 (23.4) ≥12 53 (10.6) mean ± sd 5.0 ± 4.4 gender male 285 (56.9) female 214 (42.9) weight in kg, mean ± sd 18.5 ± 15.1 patient status inpatient 178 (35.7) outpatient 321 (64.3) treatment duration in days, median (iqr) 7.0 (0.0–30.0) sd = standard deviation; iqr = interquartile range. khalid al-balushi, fatma al-ghafri, fatma al-sawafi and ibrahim al-zakwani clinical and basic research | e497 among inpatients compared to outpatients (80 versus 58 patients). preschool children between 0−6 years old received antibiotics most frequently (n = 110; 79.7%) followed by 7−11 and ≥12-year-olds (n = 22; 15.9% and n = 6; 4.3%, respectively). among the total drug prescriptions, antibiotics were prescribed in 185 cases (15.6%). co-amoxiclav was the most commonly prescribed antibiotic in both inpatients and outpatients (27.0% and 33.9%, respectively), followed by cefuroxime in inpatients (13.5%) and azithromycin in outpatients (18.6%) [table 2]. co-amoxiclav was the most commonly prescribed antibiotic in both 0−6 (31.3%) and 7−11-year-olds (23.3%), while cephalosporins were the most commonly prescribed antibiotic in the ≥12-year-old age group (50%) [table 2]. in the 0‒6-year-old age group, co-amoxiclav was the leading antibiotic prescribed for both inpatients and outpatients (29.7% and 36.1%, respectively). this was followed by cefuroxime among the inpatients (12.6%) and phenoxymethylpenicillin among the outpatients (25.0%). in the 7−11-year-old age group, co-amoxiclav was the most commonly prescribed antibiotic among outpatients (30.0%) while azithromycin was the predominant antibiotic prescribed among inpatients (30.0%). discussion the aim of this study was to describe the antibiotic prescribing patterns among paediatric patient prescriptions at squh. in this study, 27.6% of the patients were prescribed a total of 28 different antibiotics. this is similar to the results of a large cohort study in three european countries which showed an antibiotic prescription rate of 30%.16 a review of antibiotic prescribing trends in paediatric outpatients noted a prescription rate ranging from 14.2% in the uk to 52.4% in canada.17 in addition, a study of who core drug-prescribing indicators in an indian neonatology unit showed that 30.2% of the patients were prescribed antibiotics.18 in a study performed in nepal, antibiotics were shown to be the most commonly prescribed drug (23%; n = 1,614 drugs in 356 patients) while ampicillin was the most commonly prescribed drug in paediatric wards.19 a pakistani study of 2,433 prescriptions in children under five years of age showed that antibacterials table 2: the most commonly prescribed antibiotics in inpatients and outpatients by age group (n = 185 antibiotics)* antibiotics prescribed n (%) age group total 0−6 years 7−11 years ≥12 years all ip op all ip op all ip op all ip op amc: 46 (31.3) amc: 33 (29.7) amc: 13 (36.1) amc: 7 (23.3) azt: 3 (30.0) amc: 6 (30.0) cfm: 2 (25.0) cfm: 1 (33.3) azt: 1 (20.0) amc: 54 (29.2) amc: 34 (27.0) amc: 20 (33.9) azt: 16 (10.9) cfm: 14 (12.6) pmp: 9 (25.0) azt: 7 (23.3) cfm: 2 (20.0) azt: 4 (20.0) cef: 2 (25.0) cef: 1 (33.3) amc: 1 (20.0) azt: 23 (12.4) cfm: 17 (13.5) azt: 11 (18.6) cfm: 15 (10.2) azt: 10 (9.0) azt: 6 (16.7) cef: 5 (16.7) cef: 2 (20.0) cef: 3 (15.0) azt: 1 (12.5) tet: 1 (33.3) cef: 1 (20.0) cfm: 20 (10.8) cef: 16 (12.7) pmp: 10 (16.9) pmp: 11 (7.5) ctx: 10 (9.0) cef: 2 (5.6) cfm: 3 (10.0) amc: 1 (10.0) van: 2 (10.0) amc: 1 (12.5) ctx: 1 (20.0) cef: 16 (8.6) azt: 12 (9.5) amo: 4 (6.8) ctx: 10 (6.5) cef: 7 (6.3) amo: 1 (2.8) van: 2 (6.7) tob: 1 (10.0) pmp: 1 (5.0) mup: 1 (20.0) pmp: 12 (6.5) ctx: 10 (7.9) cfm: 3 (5.1) cipx: 1 (5.0) total 147 111 36 30 10 20 8 3 5 185 126 59 ip = inpatients; op = outpatients; amc = co-amoxiclav; azt = azithromycin; cfm = cefuroxime; cef = ceftriaxone; pmp = phenoxymethylpenicillin; tet = tetracycline; amo = amoxicillin; ctx = cefotaxime; van = vancomycin; tob = tobramycin; mup = mupirocin; cipx = ciprofloxacin. antibiotic prescribing trends in an omani paediatric population e498 | squ medical journal, november 2014, volume 14, issue 4 were prescribed in 49% of encounters and ampicillin and cotrimoxazole were the two most commonly prescribed antibacterials.20 it is difficult to draw firm conclusions by comparing the results of the current study to those cited above, as each study had a different design and populations with differing morbidity profiles and socioeconomic statuses. the current study had some limitations. first, it should be noted that antibiotic prescribing patterns vary between winter and summer.21 the current study’s data were recorded during the period of march to may, which is a transitional period between summer and winter. it is possible that the pattern of antibiotic prescriptions may differ during other seasons of the year. furthermore, specific prescribing details such as indications and dosage frequency were not recorded in this study. in addition, as the study was performed in a single institution, the results may not be generalisable to the whole population of oman. the choice of agents prescribed in the study was similar to those observed in other european and asian countries.19,20,22 however, the percentage of children prescribed each antibiotic as a first choice varies between countries. co-amoxiclav was the most commonly prescribed antibiotic (29.2%) in the study for both inpatients and outpatients (27.0% and 33.9%, respectively). the comparison between these data and data from other countries may reflect true clinical differences, along with other factors such as prescribing attitudes among physicians, economic determinants, pharmaceutical industry promotion and sociocultural factors. however, this comparison should take into account heterogeneity between studies. antibiotic misuse among paediatric patients is a major public health concern as infections are the most frequent cause of childhood diseases and systemic antibiotics account for one-third of all prescriptions in preschool children.23 young patients and children admitted to intensive care units are particularly at risk of receiving multiple courses of antibiotics.24 as antibiotic resistance develops in this setting, strategies to control antibiotic use should focus on these patient populations.24 several professional societies have issued guidelines designed to optimise the use of antibiotics worldwide by means of various control strategies.1,10−12,24 conclusion this study highlights the trends of antibiotic use among an important patient population in oman. antibiotic prescribing patterns in oman are similar to those in north america, europe and asia; however, the findings of this study should be interpreted in light of its limitations. with the emergence of antibiotic resistance and rising healthcare costs, hospitals should encourage more guideline-based antibiotic prescription practices and implement a uniform antibiotic prescribing policy based on local sensitivity patterns. references 1. gould im. a review of the role of antibiotic policies in the control of antibiotic resistance. j antimicrob chemother 1999; 43:459‒65. doi: 10.1093/jac/43.4.459. 2. de jong j, van den berg pb, de vries tw, de jong-van den berg lt. antibiotic drug use of children in the netherlands from 1999 till 2005. eur j clin pharmacol 2008; 64:913‒9. doi: 10.1007/s00228-008-0479-5. 3. moro ml, marchi m, gagliotti c, di mario s, resi d; progetto bambini a antibiotici [proba] regional group. why do paediatricians prescribe antibiotics? results of an italian regional project. bmc pediatr 2009; 9:69‒102. doi: 10.1186/1471-2431-9-69. 4. finkelstein ja, metlay jp, davis rl, rifas-shiman sl, dowell sf, platt r. antimicrobial use in defined populations of infants and young children. arch pediatr adolesc med 2000; 154:395‒400. doi: 10.1001/archpedi.154.4.395. 5. blix hs, engeland a, litleskare i, rønning m. ageand genderspecific antibacterial prescribing in norway. j antimicrob chemother 2007; 59:971‒6. doi: 10.1093/jac/dkm032. 6. marra f, patrick dm, chong m, bowie wr. antibiotic use among children in british columbia, canada. j antimicrob chemother 2006; 58:830‒9. doi: 10.1093/jac/dkl275. 7. hariharan s, pillai g, mcintoch d, bhanji z, culmer l, harper-mcintosh k. prescribing patterns and utilization of antimicrobial drugs in tertiary care teaching hospital of a caribbean developing country. fundam clin pharmacol 2009; 23:609‒15. doi: 10.1111/j.1472-8206.2009.00713.x. 8. butler cc, hood k, verheij t, little p, melbye h, nuttall j, et al. variation in antibiotic prescribing and its impact on recovery in patients with acute cough in primary care: prospective study in 13 countries. bmj 2009; 338:b2242. doi: 10.1136/bmj.b2242. 9. gyssens ic. antibiotic policy. int j antimicrob agents 2011; 38:11‒20. doi: 10.1016/j.ijantimicag.2011.09.002. 10. besser re. antimicrobial prescribing in the united states: good news, bad news. ann intern med 2003; 138:605–6. doi: 10.7326/0003-4819-138-7-200304010-00020. 11. world health organization. who global strategy for containment of antimicrobial resistance. from: www.who. int/csr/resources/publications/drugresist/en/eglobal_strat. pdf accessed: nov 2013. 12. radyowijati a, haak h. improving antibiotic use in low-income countries: an overview of evidence on determinants. soc sci med 2003; 57:733‒44. doi: 10.1016/s0277-9536(02)00422-7. 13. levent t, delfosse f, lambiotte f, dezorzi s, gosteau l, vasseur m. does high antibiotic consumption still reflect bad practices? med mal infect 2012; 42:309‒14. doi: 10.1016/j. medmal.2012.05.003. 14. spyridis n, sharland m. the european union antibiotic awareness day: the paediatric perspective. arch dis child 2008; 93:909‒10. doi: 10.1136/adc.2008.149625. 15. al balushi ka, al-sawafi f, al-ghafri f, al-zakwani i. drug utilization pattern in an omani pediatric population. j basic clin pharm 2013; 4:68–72. doi: 10.4103/0976-0105.118808. khalid al-balushi, fatma al-ghafri, fatma al-sawafi and ibrahim al-zakwani clinical and basic research | e499 16. sturkenboom mc, verhamme km, nicolosi a, murray ml, neubert a, caudri d, et al. drug use in children: cohort study in three european countries. bmj 2008; 337:a2245. doi: 10.1136/bmj.a2245. 17. clavenna a, bonati m. differences in antibiotic prescribing in paediatric outpatients. arch dis child 2011; 96:590‒5. doi: 10.1136/adc.2010.183541. 18. chatterjee s, mandal a, lyle n, mukherjee s, singh ak. drug utilization study in a neonatology unit of a tertiary care hospital in eastern india. pharmacoepidemiol drug saf 2007; 16:1141‒5. doi: 10.1002/pds.1469. 19. shankar pr, upadhyay dk, subish p, dubey ak, mishra p. prescribing patterns among paediatric inpatients in a teaching hospital in western nepal. singapore med j 2006; 47:261‒5. 20. nizami sq, khan ia, bhutta za. paediatric prescribing in karachi. j pak med assoc 1997; 47:29‒32. 21. elseviers mm, ferech m, vander stichele rh, goossens h; esac project group. antibiotic use in ambulatory care in europe (esac data 1997‒2002): trends, regional differences and seasonal fluctuations. pharmacoepidemiol drug saf 2007; 16:115‒23. doi: 10.1002/pds.1244. 22. keogh c, motterlini n, reulbach u, bennett k, fahey t. antibiotic prescribing trends in a paediatric sub-population in ireland. pharmacoepidemiol drug saf 2012; 21:945‒52. doi: 10.1002/pds.2346. 23. lusini g, lapi f, sara b, vannacci a, mugelli a, kragstrup j, et al. antibiotic prescribing in paediatric populations: a comparison between viareggio, italy and funen, denmark. eur j public health 2009; 19:434‒8. doi: 10.1093/eurpub/ckp040. 24. van houten ma, luinge k, laseur m, kimpen jl. antibiotic utilisation for hospitalised paediatric patients. int j antimicrob agents 1998; 10:161–4. doi: 10.1016/s0924-8579(98)00022-3. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 169-174, epub. 27th feb 13 submitted 21st mar 12 revisions req. 12th jun & 7th oct 12, revisions recd. 24th jun & 10th oct 12 accepted 18th oct 12 departments of 1surgery and 2anaesthesia & intensive care, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drashoksharma1@gmail.com عالج جراحى ناجح لسبعيىن ىف العمر معه منشأ غري طبيعى للشريان التاجى األمين من الشريان الرئوي مع أحد عشر عاما من املتابعة تقرير حالة ومراجعة األدبيات باري�ض كومار كوبا، جازفيندر �صارما، اأ�صوك �صارما امللخ�ص: يعد من�صاأ ال�رسيان التاجي الأمين من ال�رسيان الرئوي حالة نادرة احلدوث ويوجد 98 حالة فقط م�صجلة فى الإح�صائيات حتى الآن.ن�صجل فى هذا التقرير ، اأكرب مري�ض عمرا و�صمن اأربعة حالت فقط فى ال�صبعينيات من العمر مت ت�صخي�صه وعالجه مع متابعة حلالته على مدى اأحد ع�رس عاما. مت اأي�صا مراجعة اأدبيات هذه احلالة النادرة ومناق�صتها وذلك لتو�صيح التطبيقات الأكلينكية. مفتاح الكلمات: عيوب الأوعية التاجية،ال�رسيان الرئوي، ت�صوير الأوعية التاجية، الدورة الدموية لالأوعية التاجية، نيوزلندا. abstract: an anomalous origin of the right coronary artery from the pulmonary artery (arcapa) is a very rare coronary artery anomaly with only 98 cases reported in literature till date. we report the oldest surgically treated patient and the fourth ever septuagenarian with this anomaly diagnosed ante-mortem with an eleven year followup. the literature on this anomaly was reviewed and discussed to highlight the clinical implications. keywords: coronary vessel anomalies; pulmonary artery; coronary angiography; coronary circulation; case report; new zealand. successful surgical treatment of a septuagenarian with anomalous right coronary artery from the pulmonary artery with an eleven year follow-up case report and review of literature paresh kumar kuba,1 jasvinder sharma,2 *ashok sharma1 case report anomalous right coronary artery from the pulmonary artery (arcapa) is a very rare coronary artery anomaly, with only 98 cases reported in the literature to date.1,2 as most patients are asymptomatic until late adulthood, sudden cardiac death is often misreported as cause of death; hence, surgical management, even in asymptomatic patients, is highly recommended.1 case report a 71-year-old hypertensive male who was a diabetic ex-smoker with a positive family history of coronary artery disease (cad) was referred by a general practitioner for evaluation of recent onset of episodes of upper abdominal pain on exertion. his past history included treatment for duodenal ulcer, nephrolithiasis, bilateral inguinal hernia, and prostatism, and had undergone a right acromioplasty. in addition to other relevant investigations, he underwent a stress test which was strongly positive for inducible ischaemia. a coronary angiogram (cag) showed critical disease involving the left anterior descending artery (lad) and arcapa. the right coronary artery (rca) was dilated and filling in a retrograde manner by collaterals from the lad and draining into the pulmonary artery [figures 1]. the aortic root injection did not show the rca. the treatment plan was to re-implant the rca into the ascending aorta and graft the lad with the left internal mammary artery (lima). the patient was reluctant to undergo surgery and instead underwent stenting of the lad using a bare-metal stent. he was successful surgical treatment of a septuagenarian with anomalous right coronary artery from the pulmonary artery with an eleven year follow-up case report and review of literature 170 | squ medical journal, february 2013, volume 13, issue 1 discharged 7 days after the procedure having been prescribed anti-platelet medications, including aspirin and ticlopidine as per the hospital protocol. he presented the next day with sudden severe chest pain with echocardiogram (ecg) evidence of acute myocardial infarction (mi). a repeat cag showed a thrombus proximal to the previous stent and a small area of dissection downstream from the previous stent. two additional stents were inserted in the artery to open up the thrombosed as well as the dissected areas. however, he sustained a large anterior infarct and developed congestive heart failure. an ecg done two days later showed concentric left ventricular hypertrophy (lvh), an akinetic septum, and a hypokinetic inferior wall with an ejection fraction (ef) of 45%. since he was still symptomatic, he underwent a myocardial perfusion scan and cag after stabilisation of the congestive heart failure (chf). this was in order to complete an assessment of his condition and assess the reversibility of the ischaemia. a myocardial perfusion scan showed a satisfactory perfusion of the lateral wall. the apical infarcted area was not perfused. the inferior wall and posterior septum supplied by the rca arising from main pulmonary artery (mpa) was underperfused at all times, and more so with effort. cardiac catheterisation showed moderate pulmonary hypertension (pulmonary artery [pa] pressure = 58/24 mmhg, mean = 36 mmhg). left ventricular end-diastolic pressure was 28 mmhg. a left ventriculogram showed akinesis of the lower third of the anterolateral wall and apex. the left main coronary artery was normal. the stented segment of the lad was patent, but segments of irregularity were noted within it, approaching 40%, and there was some downstream irregularity beyond the stented segment of about 50%. the left circumflex coronary artery (lcx) was normal. only the distal rca was found to be filling by collaterals from left, and runoff into mpa was not seen, as noted in the previous cag, probably because of pulmonary hypertension. being symptomatic, he was advised to undergo surgery, to which he agreed. he was operated for coronary artery bypass grafting (cabg) to the lad, and a re-implantation of the rca into the aorta. significant findings during surgery included cardiomegaly and a dilated right ventricle. the rca was a 3 mm vessel arising from right side of the mpa and running in the groove between the aorta and the pulmonary artery. the lad was a 1.5 mm atherosclerotic vessel. on cardio-pulmonary bypass (cpb) on the beating heart, the mpa was separated from the aorta, the rca was isolated and dissected free of the aorta, the mpa, and the right ventricle. it was taken off the mpa as a small button and was re-implanted anteriorly into the ascending aorta using a side-biting aortic clamp. the hole in the pulmonary artery was closed using a pericardial patch. the lima was then anastomosed to the lad on the cross-clamped arrested heart using cardioplegia. the post-operative period was uneventful. an ecg done 3 weeks after the surgery showed a moderately dilated left atrium (5.44 cm), a dilated left ventricle with moderately reduced contractility with the left ventricular, and an ef of 32%. the patient has been on a regular follow-up schedule since then with his general practitioner, cardiologist, and surgeon. eleven years later, during a follow-up, he was asymptomatic with no history of angina or any features suggestive of congestive cardiac failure. he had good exercise tolerance. an ecg showed improved left ventricular function with an ejection fraction of 43% and minimal regional wall motion abnormalities. a ct angiogram showed good flow through the reimplanted rca [figures 2 and 3] and a functioning lima to lad graft [figure 4]. figure 1: pre-operative angiogram showing a normally arising left anterior descending artery (lad) with the right coronary artery filled in a retrograde fashion by collaterals from the lad and draining into the pulmonary artery. ashok sharma, paresh kumar kuba and jasvinder sharma case report | 171 discussion arcapa is a very rare anomaly with only 98 cases having been reported in the literature to date, the first one described in 1885 by brooks.2 it has been estimated to occur in 0.002% of the population.3 however, since most patients remain asymptomatic or are diagnosed post-mortem, the actual incidence may be higher. abnormalities in the embryologic development lead to positional anomalies of the coronary arteries. the coronary artery buds appear at about the 12th day of life after the division of the truncus arteriosus that leads to the separation of the aorta and the pulmonary artery.4 coronary artery anomalies can arise secondary to either malrotation of the spiral septum dividing the truncus or malpositioning of the coronary buds themselves. the four possible anomalous coronary artery connections were described by soloff in 1942 and included the following: 1) anomalous left coronary artery from pulmonary artery (alcapa), (this variant is the most common and presents early in life with myocardial ischaemic features); 2) arcapa is the next most common variant and generally presents later in life; 3) origin of both coronaries from the pulmonary artery, (this is a rare variant and is not compatible with life), and 4) origin of the accessory coronary artery from pulmonary artery, (this is an extremely rare variant).5 in our experience, direct implantation using a button led to a successful repair. to avoid kinking of the right coronary artery, the following precautions need to be taken: 1) a long length of the rca is mobilised from its origin in the mpa and anastomosed to the anterior ascending aorta such that it lies in a loop in front of the aorta; 2) insertion of the mobilised rca into the ascending aorta is done as high as possible in the ascending aorta, and 3) proximal ligation and re-implantation without a button is potentially technically more challenging with a higher risk of stenosis and kinking at the implantation site. the pathophysiologic effects of alcapa and arcapa are related to the direction of blood flow in the coronary artery and to the impact on oxygen delivery to the myocardium. the direction of blood flow in the anomalous coronary artery appears to vary with age.6 in the fetus and neonate, blood flows from the pulmonary artery into the anomalous coronary artery because of the high pulmonary vascular resistance. although the oxygen content of the blood entering the anomalous coronary artery via the pulmonary artery is lower than that entering the coronary artery from the aorta, it is sufficient to meet the demands of the myocardium, and the neonate remains asymptomatic. over the first few days of life, the pulmonary vascular resistance falls and three possible scenarios ensue: 1) insufficient collateralisation between the right and left coronary arteries results in ischaemia and death; 2) adequate collateralisation produces a steal phenomenon due figure 2: a reconstructed image of a postoperative follow-up computed tomography angiogram showing the proximal anastomosis of the right coronary artery to the ascending aorta with no evidence of kinking or angulation and the full course of the right coronary artery. figure 3: proximal anastomosis of the re-implanted right coronary artery to the ascending aorta. successful surgical treatment of a septuagenarian with anomalous right coronary artery from the pulmonary artery with an eleven year follow-up case report and review of literature 172 | squ medical journal, february 2013, volume 13, issue 1 to relative differences in the diastolic pressures between the pulmonary and systemic arterial beds, or 3) massive collateralisation may maintain adequate myocardial perfusion even in the presence of the steal phenomenon. in the adult, the retrograde flow is suggested by several observations: 1)the anomalous vessel is usually thin walled;3,4,7 2) angiograms have shown blood flow from the left system into the right coronary artery and then into the pulmonary artery,8 and 3) ligation of the anomalous vessel at its origin in one case caused distention of the distal vessel without electrocardiographic evidence of ischaemia.6 in 70% of reported cases, it is an isolated anomaly.2 however, there are isolated reports of arcapa being associated with other cardiac defects like ventricular septal defect, tetralogy of fallot, aortopulmonary window, atrial septal defect, and a double outlet right ventricle. most patients are asymptomatic. however, the patients may present with angina pectoris, congestive heart failure, dyspnoea, cyanosis, palpitations, acute myocardial infarction, myocarditis, and bradycardia.9–12 the modality of diagnosis of arcapa has changed over time.13 before 1965, most of the diagnoses were made during autopsy or surgery. since 1965, angiography has been the most commonly used modality for diagnosis of arcapa. in 1985, the first case of arcapa was diagnosed by echocardiography.7 since then, it has been the main diagnostic tool. cag has been used as a confirmatory method. in two cases, diagnosis was made by multi-slice ct angiography.14,15 cardiovascular magnetic resonance was used for the first time in 2007 for the diagnosis of arcapa.16 multislice ct and cardiovascular mri (cmr) are non-invasive three-dimensional (3d) imaging modalities with high diagnostic accuracy for coronary artery anatomic anomalies. if echocardiography and conventional angiography have been non-conclusive, multislice computed tomography (ct) and cmr can be especially important diagnostic tools.16 coronary artery imaging with echocardiography may be difficult in some patients due to poor acoustic windows. cardiac ct is an effective noninvasive test but uses ionising radiation and requires intravenous administration of iodinated contrast agent. conventional x-ray cineangiography is an invasive test and may also be difficult because of the lack of 3d information that relates the coronary artery to its surrounding structures. however, despite the fact that ct uses contrast and radiation, it has emerged as the cross-sectional imaging of choice for optimal evaluation of the anomalies of the origin of the coronary arteries. as compared to invasive angiography or coronary ct angiography, the spatial resolution of magnetic resonance (mr) angiography is significantly lower.17 the electrocardiographical features are nonspecific for arcapa. however, the reported features include left or right or biventricular enlargement or hypertrophy, ischaemic changes, bundle branch blocks and atrial fibrillation, or bradycardia. the anomalous rca has been described in surgical and pathological reports to be thin-walled, dilated, and/or vein-like in character. the origin of the anomalous coronary artery may be from the anterior sinus of valsalva of the pulmonary artery, the right posterior sinus, or the anterior aspect of the pulmonary trunk.1,18-20 corrective surgery has been recommended for arcapa, even in asymptomatic patients and mainly for two reasons. first, with the reimplantation of the aberrant vessel into the aorta, a double ostium coronary system is established with a potentially lower risk for sudden cardiac death. figure 4: reconstructed image of a post-operative computed tomography angiogram showing good flow in the left anterior descending artery through the left internal mammary artery. ashok sharma, paresh kumar kuba and jasvinder sharma case report | 173 second, the operation provides relief from coronary steal phenomenon, which may be responsible for myocardial ischaemia. three different surgical procedures have been advocated as follows: 1) ligation of rca at the origin from the pulmonary trunk to eliminate coronary steal, (it is well-tolerated but the longterm results are unpredictable); 2) ligation of the rca at its origin and the cabg to restore blood flow; however, the long term patency of the vein graft is questionable, or 3) direct re-implantation of the rca from the pulmonary artery into the anterior wall of ascending aorta to re-establish a double coronary artery system. the latter is the most physiological procedure and has been shown to have good long-term results.21 in a few cases, a post-operative impairment of flow has been observed in the restored right coronary artery and it has been hypothesised to be due to long-term hypokinetic circulation associated with arcapa, probably due to persistent small vessel disease.22 conclusion the patient reported here was, at the time of surgery, a 71-year-old gentleman who presented with ischaemic symptoms and was diagnosed by coronary angiogram as having arcapa. in addition, there was a significant stenotic lesion of the lad. although surgery was advised, he opted instead for stenting of the lad. unfortunately, he re-presented with recurrent angina and had further stenting of the lad but sustained acute mi. he remained symptomatic and further investigation revealed ischaemic rca territory with moderate disease in the lad. he then agreed to surgery and underwent re-implantation of the rca and a lima graft to the lad. eleven years after surgery, during a follow-up, the patient remained asymptomatic with improved ef on echocardiogram. a ct angiogram showed patent lima to the lad and a well-functioning re-implanted rca. the patient had returned to his normal routine of swimming, playing golf, and enjoying other regular exercise. references 1. radke pw, messmer bj, haager pk, klues hg. anomalous origin of right coronary artery: preoperative and post-operative hemodynamics. ann thorac surg 1998; 66:1444–9. 2. brooks hsj. two cases of an abnormal coronary artery of the heart arising from the pulmonary artery with some remarks upon the effect of this anomaly in producing cirsoid dilatation of the vessels. j anat physiol 1885; 20:26–9. 3. jordan ra, dry tj, edwards je. anomalous origin of the right coronary artery from pulmonary trunk. mayo clin proc 1950; 25:673–8. 4. danias pg, stuber m, mcconnell mv, manning wj. the diagnosis of congenital coronary anomalies with magnetic resonance imaging. coron artery dis 2001; 12:621–6. 5. soloff la. anomalous coronary arteries arising from the pulmonary artery. am heart j 1942; 24:118–27. 6. eugster gs, oliva pb. anomalous origin of the right coronary artery from the pulmonary artery. chest 1973; 63:294–6. 7. suzuki k, yokochi k, yoshioka f, kato h. anomalous origin of the right coronary artery from the pulmonary artery: report of a case. j cardiogr 1985; 15:241–8. 8. ogden ja. congenital anomalies of the coronary arteries. am j cardiol 1970; 25:474–9. (additional information also received through personal communication from ogden ja). 9. di luozzo, berni a, nigri a. origine anomala della coronaria destra dalla arteria polmonare: descrizione di un caso clinico. g ital cardiol 1998; 28:57–60. 10. yamanaka o, hobbs re. coronary artery anomalies in 126,595 patients undergoing coronary arteriography. cathet cardiovasc diagn 1990; 21:28–40. 11. ross tg, lantham rd, craig we. anomalous origin of the right coronary artery from the main pulmonary artery. south med j 1987; 80:783–6. 12. nakano m, emoto h, koyanagi k, okuyama h, saitoh f, kurosawa h. report of a case of the anomalous origin of the right coronary artery from the pulmonary artery with atrial fibrillation and bradycardia. j jpn assoc thor surg 1993; 41:479–85. 13. modi h, ariyachaipanich a, dia m. anomalous origin of right coronary artery from pulmonary artery and severe mitral regurgitation. j invasive cardiol 2010; 22:49–55. 14. waite s, ng t, afari a, gohari a, lowery r. ct diagnosis of isoloated anomalous origin of the rca arising from the main pulmonary artery. j thorac imag 2008; 23:145–7. 15. tedeschi c, briguori c, de rosa r, ratti g, cademartiri f, sacco m, et al. right coronary artery arising from pulmonary trunk: assessment with conventional coronary angiography and multislice computed tomography coronary angiography. j cardiovasc med (hagerstown) 2009; 10:178–82. 16. gilmour j, hafka h, ropchan g and johri a m. successful surgical treatment of a septuagenarian with anomalous right coronary artery from the pulmonary artery with an eleven year follow-up case report and review of literature 174 | squ medical journal, february 2013, volume 13, issue 1 case report, anomalous right coronary artery : a multimodality hunt for the origin. cardiol 2011; article id 286598. doi:10.1155/2011/286598 17. bleumke da, achenbach s, budoff m, gerber tc, gersh b, hillis ld, hundley wg, et al. noninvasive coronary artery imaging: magnetic resonance angiography and multidetector computed tomography angiography: a scientific statement from the american heart association committee on cardiovascular imaging and intervention of the council on cardiovascular radiology and intervention, and the councils on clinical cardiology and cardiovascular disease in the young. circulation 2008; 118:586–606. 18. huang ty, hsueh y, tsung sh. endocardial fibroelastosis and myocardial calcification secondary to an anomalous right coronary artery arising from the pulmonary trunk. hum pathol 1985; 16:959–60. 19. achtel ra, zaret bl, iben ab, hurley ej surgical correction of left coronary artery-main pulmonary artery fistula in association with anomalous right coronary artery. j thorac cardiovasc surg 1975; 70:46–51. 20. mintz gs, iskandrian as, bemis ce, mundth ed, owens js. myocardial ischemia in anomalous origin of the right coronary artery from the pulmonary trunk. proof of a coronary steal. am j cardiol 1983; 51:610–12. 21. donaldson rm, raphael m, radley-smith r, yacoub m angiographic diagnosis of anomalous origin of the right coronary artery from the pulmonary artery. br j radiol 1983; 56:17–19. 22. schley j. abnormer ursprung der rechten kranzarterie and der pulmonalis bei einem 61 jahrigen mann. frankfurt z path 1925; 32:1–7. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e184–190, epub. 28 may 15 submitted 21 jul 14 revision req. 21 sep 14; revision recd. 7 oct 14 accepted 23 oct 14 the pathophysiology of asthma involves an interaction between several cells, such as neutrophils, mast cells, eosinophils and lymphocytes, and their mediators. this interaction gives rise to chronic inflammation of the already hyper-responsive airways resulting in severe yet reversible airflow limitation. this is responsible for the coughing, wheezing, chest tightness and shortness of breath commonly seen in asthmatic patients.1 despite an adequate understanding of the underlying mechanism of this disease and the relative ease and availability of treatment, asthma continues to be a major health concern around the world. according to estimates from the world health organization, about 300 million of the world’s population suffer from asthma.2 it is a major contributor of morbidity in both children and adults, and an important cause of mortality as well, causing an estimated 250,000 premature deaths annually.3 it is no surprise then that asthma represents a significant economic burden on healthcare systems. a study in the usa estimated the annual direct medical expenditure for asthma treatment in 2007 to be $37.2 billion.4 individuals who have a poor level of control over their asthma may face difficulties not only physiologically, but also psychologically and socioeconomically. therefore, the goal of treatment in these patients is to improve health status, and, in turn, quality of life. prevalence of asthma in oman although no studies have yet been conducted in oman to determine the prevalence of asthma, oman was one of the few gulf cooperative council (gcc) countries to participate in the international study of asthma and allergies in childhood (isaac).5 the isaac epidemiological research program was established in 1991 due to the rise in the prevalence and severity of asthma and allergic disorders, which highlighted the 1department of medicine, respiratory unit and 2internal medicine unit, royal hospital, muscat, oman *corresponding author e-mail: enhsa@hotmail.com and enhsa1966@gmail.com عبء الربو يف سلطنة عمان نا�رش البو�سعيدي، ذو الفقار حبيب اهلل، مالفيكا باهتانقار، نبيل اللواتي، يعقوب املحروقي abstract: asthma is a common lung disease worldwide, although its prevalence varies from country to country. oman is ranked in the intermediate range based on results from the international study of asthma and allergies in childhood. a 2009 study revealed that the majority of asthmatic patients in oman reported both daytime and nocturnal symptoms, while 30% of adults and 52% of children reported absences from work or school due to their symptoms. despite these findings, there is little data available on the economic burden of asthma in oman. the only accessible information is from a 2013 study which concluded that oman’s highest asthma-related costs were attributable to inpatient (55%) and emergency room (25%) visits, while asthma medications contributed to less than 1% of the financial toll. these results indicate a low level of asthma control in oman, placing a large economic burden on healthcare providers. therefore, educating asthmatic patients and their families should be prioritised in order to improve the management and related costs of this disease within oman. keywords: economic burden of disease; asthma; lung diseases; burden of illness; oman. امللخ�ص: الربو هو مر�ض رئوي �سائع يف كل اأنحاء العامل، غري اأن معدل انت�ساره يختلف من قطر الآخر. وبح�سب نتائج درا�سة عاملية عن معدالت انت�سار الربو وفرط التح�س�ض )االأرجية( عند االأطفال، يعد معدل انت�سار هذه االأمرا�ض يف اأطفال عمان متو�سط امل�ستوى. واأو�سحت درا�سة ن�رشت يف عام 2009م اأن اأغلب مر�سي الربو يف عمان ي�سكون من اأعرا�ض هذا املر�ض يف النهار والليل معا، واأن نحو %30 من البالغني و%52 من االأطفال يغيبون عن العمل اأو الدرا�سة ب�سبب اأعرا�ض الربو. ورغم هذه النتائج، اإال اأنه ال تتوفر اأي معلومات عن العبء االقت�سادي للربو يف عمان. ولي�ض هنالك غري مرجع واحد عن هذا املو�سوع، والذي اأو�سح اأن عبء الربو يف عمان يتمثل يف ال�رشف على املر�سى املنومني )%55( ويف غرفة الطوارئ )%25(، وال ت�سكل اأدوية الربو �سوى اأقل من %1 من العبء املايل. وت�سري هذه الدرا�سة اإىل امل�ستوى املنخف�ض ملكافحة الربو يف عمان، مما ي�سع عبئا اقت�ساديا كبريا على اأكتاف مقدمي اخلدمات ال�سحية. لذا يجب اأن تكون عمليات تعليم واإر�ساد مر�سى الربو من االأولويات، حتى يتح�سن التدبري العالجي للمر�ض وتقل تكاليفه يف عمان. مفتاح الكلمات: العبء االقت�سادي؛ الربو؛ اأمرا�ض الرئة؛ عبء املر�ض؛ عمان. the burden of asthma in oman *nasser al-busaidi,1 zulfikar habibulla,1 malvika bhatnagar,2 nabil al-lawati,1 yaqoub al-mahrouqi1 review nasser al-busaidi, zulfikar habibulla, malvika bhatnagar, nabil al-lawati and yaqoub al-mahrouqi review | e185 year. exercise-induced wheezing was more prevalent among older children (19.2% versus 6.9%; p <0.001).18 among the eastern mediterranean countries participating in the isaac program, oman showed the highest prevalence of asthma in children, although it was in the intermediate range of the isaac global ranking. over the three phases, omani children were found to have a relatively high prevalence of severe asthma symptoms, including sleep disturbances and speech-limiting wheezing.19 different results were noted in the prevalence of asthma, its diagnosis and symptoms (depending on the participants’ geographical regions in oman). in the east, the ash sharqiyah region scored the highest prevalence of self-reported asthma diagnoses and the presence of all asthma symptoms in both age groups over the six-year period between the first and third isaac phases.20 the participants in the younger group displayed a significant increase in the prevalence of wheezing (8.7– 13.8%; p = 0.002) and asthma diagnoses (13.8–17.8%; p = 0.046) over a period of 12 months during isaac phase three, while those in the older group showed an increase in nighttime coughing (21.6–27.8%; p = 0.039) in the same time frame. none of the other regions were found to have a change in prevalence from that indicated by the initial study in 1995, with some regions even showing a declining trend in a few self-reported asthma symptoms.21 a cause for concern is the finding in both isaac phase one and two surveys that over 60% of current wheezers reported severe asthma symptoms, even though only 60% reported an asthma diagnosis.7‒9 this highlights the fact that asthma was not only underdiagnosed in the data collected, but that the symptoms of the condition were poorly recognised with no indication of improvement over time. oman was not able to formally participate in the full isaac phase two protocol due to cost and logistics. however, a similar study using the same questionnaire was conducted, with the addition of a few questions addressing the use of arabian incense.22 arabian incense, which is also called frankincense or aluban, is an aromatic resin obtained from trees of the genus boswellia. it is burnt using wood charcoal, which is a common practice in omani households. a study of aluban’s effect on asthma symptoms was conducted to investigate the potential risk factors for asthma and allergies in two representative regions of oman.19,22 a total of 2,441 school-going 10-year-olds were used as the target sample, having been selected randomly from public schools in the muscat (n = 1,241) and south ash sharqiyah (n = 1,200) regions using the stratified multi-stage sampling method. the intention behind selecting these two regions was to magnitude of asthma worldwide and sought to discern the factors contributing to its prevalence.5 the first phase of the isaac program involved 700,000 children and adolescents from 156 centres in 56 countries, demonstrating the widespread concern associated with asthma and allergic disorders. the data collection methodology involved the use of simple questionnaires, thus allowing an easy comparison of data from different countries.6 the results of the study showed that the symptoms of asthma vary largely even in populations that share genetic similarities, thereby suggesting that environmental factors play an important role in the disease pathophysiology.7–10 several aspects of the environment were incorporated into the ecological data analysis from phase one of isaac. of these, economic development, dietary factors, climate, infections and pollen were implicated as factors contributing to this phenotypical variation.11–16 the second phase involved the use of detailed questionnaires with measurements of physiological variables and indoor exposure.17 the third phase took the form of a cross-sectional survey across several countries, primarily targeting two groups of children aged 6–7 years and 13–14 years, respectively. this was conducted five years after phase one of the isaac program, which served as a baseline.17 there was a six-year gap between the implementation of these three phases of the isaac program in oman. during the first two phases, groups of 6–7-year-olds and 13–14-year-olds were involved. the proportion allocations method was used to get national samples, which were arbitrarily chosen from 10 regional areas of oman. in phase one of isaac, which took place in april 1995, arabic questionnaires were distributed (n = 7,625) of which 4,079 were given to 6–7-year-olds and 3,546 were given to 13–14-year-olds. in phase three, which was conducted in april 2001, questionnaires were again distributed (n = 8,080), of which 4,235 were given to 6–7-year-olds and 3,853 were given to the 13–14-year-olds. an isaac arabic asthma video questionnaire was also completed by the 13–14-year-olds.7 in 1995, oman’s prevalence rate of reported asthma diagnoses, as seen in phase one of the isaac results, was higher in older children (20.7%) than in younger children (10.5%).18 among older children, 283 were current wheezers, of which 30% were suffering from sleep-disturbing wheezing at least once a week and 37.5% had had speech-limiting wheezing during the previous year. in younger children, 277 were current wheezers, of which 40.8% had sleepdisturbing wheezing at least once a week while 45.1% had had speech-limiting wheezing during the previous the burden of asthma in oman e186 | squ medical journal, may 2015, volume 15, issue 2 draw a comparison between the potential offending environmental factors that were responsible for the different prevalence rates as seen in phase one. the statistics from the muscat region can be considered representative of the national average as, being the capital city, it houses individuals from all over the country. the south ash sharqiyah region, however, had the highest prevalence rate of all asthma symptoms. the results of this survey showed that the south ash sharqiyah region continued to report the highest prevalence of asthma symptoms in oman. it also identified exposure to arabian incense as a common trigger for asthma symptoms in omani children.22 the cost of asthma in oman study addressed the prevalence and cost of asthma management in oman.23 a revised delphi method was used to collect the agreement of data estimations from an asthma management expert panel which consisted of 10 expert physicians in asthma management from oman.23–26 one important advantage of this method over a face-to-face group panel method was to obtain information from each involved member without the influence of others on the panel. this study found that the prevalence of asthma in oman was estimated to be 7.3% of adults (n = 96,470) and 12.7% of children (n = 58,344). of this group, 95% used governmental healthcare services.23 control of asthma in oman despite an international agreement on the goals of asthma management, available epidemiological statistics from europe, the usa and other countries indicate that the treatment of patients with asthma is very poor.27 the asthma insights and reality in the gulf and the near east (airgne) study was conducted in five countries including oman, the united arab emirates (uae), kuwait, jordan and lebanon. the study aimed to examine and evaluate asthma characteristics and the quality of asthma management and control in these countries.28 in addition, the study was intended to define asthma management and evaluate how closely the global initiative for asthma (gina) guidelines were being followed.29 the airgne study also assessed other aspects of asthma, such as patient knowledge and perceptions of asthma symptoms.28 in oman, the airgne study was performed in the most populated cities including muscat (and the areas) seeb and mutrah, sohar and nizwa. the sampling was designed by gender and age within each city.28 asthmatic patients reported that they had experienced significant daytime asthma symptoms (68%) and nocturnal symptoms (51%) in the previous four weeks. the participants also reported frequent use of health facilities in the previous year with frequent emergency room (er) visits (52%) and hospitalisations (23%) leading to work and school absences. lung function testing was generally underemployed, with 66% never having undergone a lung function test. peak expiratory flow was used only by a small proportion of the patients and only 17% owned their own peak flow meters.28 the overall airgne results showed that the level of asthma control in the studied countries lagged far behind the gina guidelines for asthma management.28,29 however, there were differences in the level of control in each country. in oman, there were wide-ranging discrepancies in asthma perceptions. while 57% of asthmatics perceived their asthma symptoms as “well or completely controlled”, 54% had “poorly or not well-controlled” asthma. advice issued for asthma control by gina was mostly disregarded, especially in children, evidenced by the fact that 44% cited nocturnal awakenings due to asthma symptoms in the previous four weeks and 47% recalled exerciseinduced asthma symptoms in the previous year. these incidents led to a large number of patients reporting asthma-related school/work absences in the preceding year (32.6% of children and 34.8% of adults).28 one finding of concern was that only 5% of omani asthmatics were found to be using preventive medications in the form of inhaled corticosteroids (ics). this figure was one of the lowest in the studied countries, evidenced by an improper ratio of ics to short-acting beta-agonists (ics/saba) of 0.054 among omani asthmatic patients.30 although the results of the airgne study were eye-opening, they were comparable to those of a study conducted in oman in 2009.31 in this study, the authors evaluated the level of asthma control among patients visiting the chest clinic in the royal hospital in muscat, oman, using the asthma control test™ (qualitymetric inc., lincoln, rhode island, usa). the results of the study revealed that 61% of asthma patients scored between 20 and 25, classifying their asthma as well controlled. however, 17.7% scored between 15 and 19, indicating that their asthma was not well controlled. the remainder of patients (21.3%) scored between 5 and 14, signifying that their asthma was poorly controlled. half of the patients stated that their asthma had a large impact on their work, school or home lives.31 a large number of patients (66%) reported nighttime symptoms and 70% had used rescue medications such as albuterol in the previous four weeks. the results showed that patients also had an inaccurate perception of their asthma severity; the majority of patients (65%) stated that their asthma was well controlled but in reality their symptoms nasser al-busaidi, zulfikar habibulla, malvika bhatnagar, nabil al-lawati and yaqoub al-mahrouqi review | e187 puts oman at the intermediate prevalence level on the isaac’s international scale for the same age group.8 however, among 13–14-year-olds, oman had the highest prevalence of asthma (20.7%) of the seven eastern mediterranean countries in the isaac study. in comparison, the following countries had a lower prevalence: iran (2.7%), kuwait (17.5%), lebanon (11.7%), malta (11.1%(, morocco (11.7%( and pakistan (7.3%).32 in 13–14-year-olds, the prevalence of asthma diagnoses and the self-reporting of asthma symptoms was higher compared to the younger age group.8 the most likely reason for this is a cumulative effect— asthma which starts early in childhood persists into adolescence and, in addition, new cases are diagnosed during adolescence.18 a regional view of oman’s asthma control levels the airgne study was the first and most comprehensive survey of the current state of asthma management in the region. the results of this study revealed that the current level of asthma control in the region was not up to standard and that oman’s levels were far below the goals outlined by the gina guidelines for long-term asthma management.30 there are several aspects of asthma management and control in oman that are as poor or poorer than other parts of the world.27 the airgne study showed that asthma morbidity in oman was elevated, with an unacceptably high dependence on the use of rescue medications.30 several causes have been attributed to this, including the poor detection of uncontrolled asthma by doctors; inaccurate perceptions by patients of the severity of their asthma symptoms; underutilisation of preventive asthma medications, namely ics; poor asthma education provided to patients and their families, and the very small percentage of asthmatic patients undergoing a lung function test for a diagnosis or the monitoring of their asthma control levels.30 asthma is poorly managed in oman as compared to other regions analysed in the different asthma insights and reality studies.28,30 based on the results of the airgne survey, 54% of asthmatic patients in oman have uncontrolled or not well controlled asthmas according to the definition outlined in the gina guidelines.29,30 the asthma insight and reality in europe (aire) and airgne studies both showed that approximately 50% of adult patients had daytime symptoms. generally, the average rate of inadequate asthma control in the airgne countries (68%) was found to be unacceptably high and this rate was even higher in oman (71%).28,30 these findings were limited their daily activities and caused frequent nocturnal awakenings.31 moreover, a recent study on the cost of asthma in oman showed that inpatient and er visits accounted for the majority of overall asthma costs (55% and 25%, respectively), thereby indicating poor control of asthma in oman.23 cost of asthma care in oman there are currently no accurate governmental data or studies that directly address the issue of the cost of asthma care in oman. however in 2013, al-busaidi et al. reported the general cost of asthma in oman following a study that was conducted using a modified version of the delphi method.23 the results of the study were as follows: hospital stays and er visits contributed to the majority of asthma-related costs in oman (55% and 25%, respectively), whereas outpatient visits and asthma medications accounted for 20%. in fact, it was found that medication accounted for less than 0.2% of the total direct cost of asthma. the annual amount spent on asthma management in oman, excluding medication, was found to be omani riyals 34,273,696 for adults and omr 27,014,735 for children.23 it can be assumed that when inpatient and er visits account for a large portion of the total cost of asthma management, there is a strong correlation with poor asthma control, which in turn leads to a potential burden on oman’s ministry of health (moh). factors leading to the varying asthma prevalence in oman the isaac studies found that asthma symptoms were common in oman and significant differences were seen in the prevalence of asthma and its symptoms in different regions, with the ash sharqiyah region reporting the highest prevalence.18,20,21 the reason for these findings remains unknown. however, many aspects of the environment were evaluated in the environmental and biological assessment in phase one. certain factors might influence the variation seen in the prevalence of the disease and its symptoms. these factors include economic development, dietary factors, climate, infections and pollen levels.11–16 it would be beneficial to conduct a study in the ash sharqiyah region to elucidate the risk factors contributing to these regional variations. the investigation of these factors would also help in developing a national plan of health and environmental strategies to control asthma.18 the national estimation of the prevalence of asthma in 6–7-year-olds is 10.5%. this, therefore, the burden of asthma in oman e188 | squ medical journal, may 2015, volume 15, issue 2 similar to those of al rawas et al., which showed that nearly 60% of all current wheezers among omani schoolchildren noted the presence of at least one asthma symptom, indicating severe or uncontrolled asthma.21 the airgne survey revealed that nocturnal disturbances were also found to be common in oman (44%).30 this finding parallels that of al-riyami et al., where the frequency of sleep disturbance in oman was nearly four times that in iran (3.5% versus 0.9%), twice that of malta (3.5% versus 1.5%) and greater than that of australia (3.5% versus 2.8%).20 based on the results of airgne, the frequency of hospitalisations and er visits in oman reported in the year before the study was conducted was unacceptably high (30% and 58%, respectively), while the existing use of preventive medications for asthma, namely ics, was unacceptably low.28,30 the use of ics in asthma patients in oman was only 5%, which was significantly and statistically lower than the average reported in the other countries included in the airgne study (14.6%; p <0.05). the daily use of rescue medications in oman was extraordinarily high compared to that of other airgne countries (92% versus 55.5%, respectively).30 a large number of asthmatic patients in oman overrated their level of asthma control and underrated the severity of their disease, as indicated by the discrepancy in their subjective perceptions compared to objective asthma severity.28 of the patients with asthma, 57% perceived their symptoms as well or completely controlled. however, 54% had poorly or not well controlled asthma as assessed by the asthma control test™ (qualitymetric inc.) (p <0.05). the lung function test is considered an important test for asthma diagnosis and level monitoring. omani asthmatics’ performances were very low as only 35% of patients stated that they had done a lung function test and only 25% had their own peak flow meter.30 generally, in comparison to other airgne countries, oman had on average the worst asthma management as reflected by the very high use of rescue medications, the very low number of prescriptions for ics and an unacceptably high frequency of asthmarelated visits to the er.30 a global view of oman’s total asthma costs al-busaidi et al. found that the cost of asthma management resulted in a significant economic load on the healthcare system in oman.23 their study found the total cost of asthma to be omr 61,500,293 per year. hospital stays and er visits were the factors that mainly drove this expenditure, equating to almost 80% of direct costs. in contrast, the cost of asthma medications was negligible, representing less than 1% of the total direct cost of asthma.23 the airgne study determined that 21% of omani asthmatic adults and children had visited the er in the year before the study.30 in comparison, in the aire study, only 10% of asthmatic patients reported visiting the er in the year before the study.32 the airgne study also reported that, in the year prior to the study, 30% required overnight hospital stays, in comparison to 7% in the aire study.30,32 inpatient stays and er visits are both linked directly to poorer levels of asthma control, which leads to a larger cost liability on the moh.23 the annual direct cost of asthma in europe was found to be €7.9 billion distributed between outpatient treatment (48%), drug costs (46%) and inpatient care (6%).33 similarly, in the usa, drug prescriptions and outpatient visits accounted for the majority of costs, comprising nearly 38% of the total cost for asthma in children and 49% of the cost in adults.34 the larger share of expenses for inpatient care and er visits for asthmatics in oman appears to reveal a lower level of asthma control in contrast to that of asthmatics in europe and the usa. recommendations for reducing the burden of asthma in oman asthma morbidity is largely preventable. it appears that this fact is not widely known in oman, suggesting the need to improve levels of understanding and communication between asthmatic patients and their doctors. among physicians, there should be an emphasis on following the gina guidelines to achieve and monitor asthma control among all patients.29 the authors suggest that the most effective way to reach this objective is to promote thorough education for all asthmatic patients and their families, including information on the regular use of preventative steroid inhalers. conclusion the who estimates that more than 300 million people have asthma worldwide, although there are noteworthy discrepancies in its prevalence between countries. in oman, the asthma prevalence is relatively high compared to other countries in the region. in addition, oman features regional discrepancies in asthma prevalence, with ash sharqiyah playing host to the highest rate of asthma in the country. the reason for this discrepancy is not clear and there is a need for further research in order to help with future nasser al-busaidi, zulfikar habibulla, malvika bhatnagar, nabil al-lawati and yaqoub al-mahrouqi review | e189 13. ellwood p, asher mi, björkstén b, burr m, pearce n, robertson cf; international study for asthma and allergy in childhood phase one study group. diet and asthma, allergic rhinoconjunctivitis and atopic eczema symptom prevalence: an ecological analysis of the international study of asthma and allergies in childhood (isaac) data. eur respir j 2001; 17:436–43. 14. weiland s, husing a, strachan d, rzehak p, pearce n. climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. occup environ med 2004; 61:609– 15. doi: 10.1136/oem.2002.006809. 15. von mutius e, pearce n, beasley r, cheng s, von ehrenstein o, bjorksten b, et al. international patterns of tuberculosis and the prevalence of symptoms of asthma, rhinitis and eczema. thorax 2000; 55:449–53. doi: 10.1136/thorax.55.6.449. 16. burr ml, emberlin jc, treu r, cheng s, pearce ne; international study for asthma and allergy in childhood phase one study group. pollen counts in relation to the prevalence of allergic rhinoconjunctivitis, asthma and atopic eczema in the international study of asthma and allergies in childhood (isaac). clin exp allergy 2003; 33:1675–80. doi: 10.1111/j.1365-2222.2003.01816.x. 17. ellwood p, asher mi, beasley r, clayton to, stewart aw; international study for asthma and allergy in childhood steering committee. the international study of asthma and allergies in childhood (isaac): phase three rationale and methods. int j tuberc lung dis 2005; 9:10–6. 18. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. a relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirology 2003; 8:69–76. doi: 10.1046/j.1440-1843.2003.00426.x. 19. the international study of asthma and allergies in childhood: the isaac story. sultanate of oman, eastern mediterranean. from:isaac.auckland.ac.nz/story/centres/countries.php?cen =66 accessed: oct 2014. 20. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. prevalence of asthma symptoms in omani schoolchildren. j sci res med sci 2001; 3:21–7. 21. al-rawas oa, al-riyami bm, al-kindy h, al-maniri aa, al-riyami aa. regional variation in the prevalence of asthma symptoms among omani school children. sultan qaboos univ med j 2008; 8:157–64. 22. al-rawas oa, al-maniri aa, al-riyami bm. home exposure to arabian incense (bakhour) and asthma symptoms in children: a community survey in in oman. bmc pulmonary medicine 2009; 9:23. doi: 10.1186/1471-2466-9-23. 23. al-busaidi nh, habibullah z, soriano jb. the asthma cost in oman. sultan qaboos univ med j 2013; 13:218–23. 24. rosengart mr, nathens ab, schiff ma. the identification of criteria to evaluate prehospital trauma care using the delphi technique. j trauma 2007; 62:708–13. doi: 10.1097/01. ta.0000197150.07714.c2 25. bramwell l, hykawy e. the delphi technique: a possible tool for predicting future events in nursing education. nurs pap 1974; 6:23–32. 26. kumaran km, lemieux m, satchell g. problem solving with the delphi technique. dimens health serv 1976; 53:34–5. 27. rabe kf, adachi m, lai ck, soriano jb, vermeire pa, weiss kb, et al. worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. j allergy clin immunol 2004; 114:40–7. doi: 10.1016/j.jaci.2004.04.042. 28. khadadah m, mahboub b, al-busaidi nh, sliman n, soriano jb, bahous j. asthma insights and reality in the gulf and the near east. int j tuberc lung dis 2009; 13:1015–22. health strategic plans. the high number of asthmarelated er visits and admissions to hospital reflect the poor control of the condition in oman. therefore, closely following the gina guidelines and educating asthmatic patients and their families should be prioritised in order to improve the management and related costs of this disease within oman. references 1. global initiative for asthma. pocket guide for asthma management and prevention. from: www.ginasthma.org/ documents/1/pocket-guide-for-asthma-management-andprevention accessed: oct 2014. 2. bousquet j, kiley j, bateman ed, viegi g, cruz aa, khaltaev n, et al. prioritised research agenda for prevention and control of chronic respiratory diseases. eur respir j 2010; 36:995–1001. doi: 10.1183/09031936.00012610. 3. bousquet j, khaltaev n; global alliance against chronic, respiratory diseases. global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. from: www.who.int/gard/publications/gard_ manual/en/ accessed: oct 2014 4. kamble s, bharmal m. incremental direct expenditure of treating asthma in the united states. j asthma 2009; 46:73–80. doi: 10.1080/02770900802503107. 5. asher mi, keil u, anderson hr, beasley r, crane j, martinez f, et al. international study of asthma and allergies in childhood (isaac): rationale and methods. eur respir j 1995; 8:483–91. doi: 10.1183/09031936.95.08030483. 6. enarson da. fostering a spirit of critical thinking: the isaac story. int j tuberc lung dis 2005; 9:1. 7. the international study of asthma and allergies in childhood (isaac) steering committee. worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: isaac. lancet 1998; 351:1225–32. doi: 10.1016/s0140-6736(97)07302-9. 8. worldwide variations in the prevalence of asthma symptoms: the international study of asthma and allergies in childhood (isaac). eur respir j 1998; 12:315–35. doi: 10.1183/09031936.98.12020315. 9. strachan d, sibbald b, weiland s, aït-khaled n, anabwani g, anderson hr, et al. worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the international study of asthma and allergies in childhood (isaac). pediatr allergy immunol 1997; 8:161–76. doi: 10.1111/j.1399-3038.1997.tb00156.x. 10. williams h, robertson c, stewart a, aït-khaled n, anabwani g, anderson hr, et al. worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood. j allergy clin immunol 1999; 103:125–38. doi: 10.1016/s0091-6749(99)70536-1. 11. stewart aw, mitchell ea, pearce n, strachan dp, weiland sk; international study for asthma and allergy in childhood steering committee. the relationship of per capita gross national product to the prevalence of symptoms of asthma and other atopic diseases in children (isaac). int j epidemiol 2001; 30:173–9. doi: 10.1093/ije/30.1.173. 12. weiland sk, von mutius e, hüsing a, asher mi; international study for asthma and allergy in childhood steering committee. intake of trans fatty acids and prevalence of childhood asthma and allergies in europe. lancet 1999; 353:2040–1. doi: 10.1016/ s0140-6736(99)01609-8. the burden of asthma in oman e190 | squ medical journal, may 2015, volume 15, issue 2 29. bateman ed, hurd ss, barnes pj, bousquet j, drazen jm, fitzgerald m, et al. global strategy for asthma management and prevention: gina executive summary. eur respir j 2008; 31:143–78. doi: 10.1183/09031936.00138707. 30. al-busaidi n, soriano jb. national results within the asthma insights and reality in the gulf and the near east (airgne) study. sultan qaboos univ med j 2011; 11:45–51. 31. al busaidi n, al mukhaini s. level control of asthma patients in chest specialist clinics. oman med j 2009; 24: 195–8. doi: 10.5001/omj.2009.38. 32. rabe kf, vermeire pa, soriano jb, maier wc. clinical management of asthma in 1999: the asthma insights and reality in europe (aire) study. eur respir j 2000; 16:802–7. 33. european respiratory society. european lung white book. sheffield, uk: european respiratory society, 2003. 34. barnett sb, nurmagambetov ta. costs of asthma in the united states: 2002–2007. j allergy clin immunol 2011; 127:145–52. doi: 10.1016/j.jaci.2010.10.020. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 502-509, epub. 8th oct 13 submitted 18th nov 12 revisions req. 29th jan & 1st may 13; revisions recd. 1st apr & 8th jul 13 accepted 1st aug 13 1department of biology, college of science; departments of 2pathology and 3genetics, sultan qaboos university hospital; 4department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: alansari@squ.edu.om حتديد الطفرات املسببة ملرض بوميب يف عينات أنسجة حمفوظة وتطوير الفحص اجلزيئي علياء الأن�سارية، �سمرية الرواحية، طاهر باعمر، مرمي النبهانية، اأناند داتي مر�ض بومبي )مر�ض تخزين الغليكوجني من النوع الثاين( هو مر�ض �سبغى ج�سدي متنحي لالختزان يف اجل�سيمات امللخ�ص: الهدف: بهذا امل�سابني الطفال يفيد ان ميكن الأنزميية بال�ستعا�سة للعالج املبكر ال�ستخدام غلوكوزيداز. األفا حم�ض نق�ض عن ينتج احلالة الأن�سجة من النووي احلم�ض ا�ستخراج مت الدرا�سة، هذه يف ال�رسيرية. املظاهر وتغايرية املر�ض ندرة الت�سخي�ض يعوق ولكن املر�ض الأر�سيفية )ffpet( لتحديد الطفرات امل�سببة ملر�ض بومبي يف عمان و عمل اختبار جزيئي. الطريقة: مت ت�سميم امل�رسعات الإنرتونية مل�ساعفة مقاطع ق�سرية )454-193 قاعدة مزدوجة( من املحورات 20-2( للبحث عن الطفرات با�ستخدام الت�سل�سل املبا�رس. النتائج: مت التعرف على طفرتني من الطفرات املت�سببة للمر�ض الوخيم يف عينتني. الأوىل برمز طفرة p.arg854x( c.2560c<t(، والثانية مت التي الطفرات عن للك�سف )pcr-rflp( اجلزيئي الختبار ت�سميم مت .c.1327-2a<g امل�سفر املتقبل موقع عند وجدت حتديدها. اخلال�صة: ميكن لهذه الختبارات ت�سهيل الت�سخي�ض قبل الولدة وامل�ساعدة يف حتديد الأفراد الذين يحملون الطفرات يف الأ�رس التي مت حتديد الطفرات فيها. مفتاح كلمات: مرض بوميب؛ غلوكان 4،1 ألفا غلوكوزيداز؛ نسيج؛ الطفرات؛ طرق التنميط اجليين؛ عمان. abstract: objectives: pompe disease (glycogen storage disease type ii) is a rare autosomal recessive lysosomal storage disease that is caused by acid alpha-glucosidase deficiency. early enzyme replacement therapy can benefit infants with the disease but the diagnosis is complicated by the rarity of the disease and the heterogeneity of the clinical manifestations. in this study, dna extracted from archival postmortem formalin-fixed paraffin-embedded tissues was used to identify pompe disease mutations in oman and develop a rapid molecular-based test. methods: intronic primers were designed to amplify short fragments (193–454 base pairs [bp]) from coding exons (2–20) and screen for mutations using direct sequencing (ds). results: two mutations known to cause severe disease were identified in two samples. one was a coding mutation, c.2560c>t (p.arg854x), and the second was found at a splice acceptor site, c.1327-2a>g. polymerase chain reactionand restriction fragment length polymorphism-based tests were designed for the rapid genotyping of the identified mutations. conclusion: these tests can facilitate prenatal diagnosis and help in identifying carriers in families with the identified mutations. keywords: pompe disease; glucan 1,4-alpha-glucosidase; tissue; mutations; genotyping techniques; oman. the identification of pompe disease mutations in archival tissues and development of a rapid molecular-based test *aliya alansari,1 samira al-rawahi,2 taher ba-omar,1 mariam al-nabhani,3 anand date4 clinical & basic research advances in knowledge this study identified two genetic mutations causing pompe disease in two omani patients. application to patient care the molecular test designed in this study can facilitate prenatal diagnosis and the screening of at-risk infants. pompe disease is a rare autosomal recessive disease, classified as a lysosomal storage disorder. it is caused by an acid alpha-glucosidase (gaa ec. 3.2.1.20) deficiency, which results in the accumulation of glycogen within the lysosomes and the cytoplasm of the cardiac, skeletal and smooth muscle cells. the clinical spectrum of the disease varies in terms of the age of onset, the disease progression rate and the extent of organ involvement.1,2 because of the continuous clinical spectrum of pompe disease, gungor and reuser proposed three identification of pompe disease mutations in archival tissues and development of a rapid molecular-based test 503 | squ medical journal, november 2013, volume 13, issue 4 subtypes: classic infantile, childhood and adult.3 the first is characterised by an onset of symptoms within the first year of life, which is always associated with hypertrophic cardiomyopathy and a total lack of acid α-glucosidase activity; the second subtype covers patients with an onset of symptoms between birth and adolescence, but without persistent and/or progressive cardiac hypertrophy, and the third subtype covers patients with an onset of symptoms between adolescence and late adulthood.3,4 early diagnosis and enzyme-replacement therapy can benefit infants with pompe disease.5 to establish a diagnosis of pompe disease, both clinical evaluation and diagnostic tests are required.1 rapid blood-based activity tests were developed for pre-symptomatic diagnoses at birth and for at-risk individuals, to allow optimal conditions for enzyme replacement therapy;6 however, a second confirmatory test is recommended to support the diagnoses. dna-based testing is an approach that can rapidly confirm the diagnosis and identify the nature of the mutations (genotypes) that alter the level of residual enzyme activity and are responsible for the clinical phenotype heterogeneity.7,8 the gaa gene is about 28 kilo-base pairs (kb) long, contains 20 exons and maps to human chromosome 17q25.2–q25.3. the first exon is non-coding and the complementary dna (cdna) encodes a protein of 952 amino acids.2 nearly 250 mutations have been identified as causing pompe disease, and they are rated by severity and divided into different classes.9 some of these mutations are common in certain populations.2 the identification of mutations in a population overcomes the problem of a lengthy, timeconsuming and expensive search for a mutation approach—due to the size of the gene—by providing a limited number of mutations to be tested. this in turn facilitates diagnoses and aids in the counselling of patients and families with the disease. in this study, we utilised archived formalin-fixed paraffin embedded (ffpe) tissues in pathology laboratories to identify retrospectively gaa mutations causing pompe disease (glycogen storage disease type ii) in oman, which enabled the design of a rapid molecular test for families with the identified mutations. methods archived muscle tissues were collected in 2000 and 2002 from two infants of arab origin (a 3-monthold male and a 4-month-old female, respectively) with clinical presentations consistent with infantile onset pompe disease. both infants had presented with bronchitis, hypotonia and hypertrophic cardiomyopathy. their creatine kinase (ck) levels were high at 571 u/l and 410 u/l, respectively (range 0–6 u/l), and lactate dehydrogenase (ldh) levels were high at 2,415 u/l and 626 u/l, respectively (range 91–180 u/l). the electromyograms (emg) showed mixed myopathic and neuropathic pictures. for the dna extraction, 10 sections of 7 micrometres (μm) were collected from archived muscle biopsies for each infant and kept in 2 ml microcentrifuge tubes. normal archived muscle tissue sections were used as a control. dna extraction was performed using a modified phenolchloroform extraction method.10 the sections were deparaffinised twice in 1 ml of pre-heated xylene (for 5 mins each) and then re-hydrated with 1 ml of 99% ethanol and 95% ethanol (twice, for 3 mins). for digestion, the tissues were incubated overnight at 60 ºc with 300 µl of lysis buffer solution containing 100 µl of 5 mg/ml proteinase k (the proteinase k was inactivated at 95 ºc for 15 mins). to purify the dna, the samples were extracted twice with 300 µl of phenol and once with 350 µl of chloroformisoamyl alcohol (at a ratio of 24:1). finally, the dna was precipitated with one ml of 100% ethanol and one u/l of glycogen (20 mg/ml). the mix was incubated at -20 ºc for one hr and then centrifuged at 4 ºc for 15 mins at 13,000 rpm. after washing the pellet with 1 ml of 70% ethanol, the extracted dna was left to air-dry and was then resuspended in 50 µl of double-distilled water (ddh2o). the integrity of the dna was checked using 1% agarose gel electrophoresis and the quality of the dna was analysed by polymerase chain reaction (pcr) for different primer sets that amplify different fragment sizes (250–500 bp). for the pcr and sequencing process, 17 sets of intronic primers flanking exons were designed to amplify the coding regions [table 1]. exon 2 is a large exon and was therefore amplified with two overlapping fragments. the primers were designed to amplify short fragments (193–454 bp) suitable for degraded dna.11 pcr was performed using a 25 µl aliya alansari, samira al-rawahi, taher ba-omar, mariam al-nabhani and anand date clinical and basic research | 504 reaction volume containing the pcr buffer, 5 µl of genomic dna, 1.5 millimolars (mm) of magnesium chloride (mgcl2), 0.5 unified atomic mass units (u) of taq dna polymerase (promega corporation, madison, wisconsin, usa), 200 micromolars (µm) of deoxyribonucleotide triphosphates (dntp) and 0.5 µm of each primer. the pcr was performed under the following conditions: 95 °c for 5 mins followed by 35 cycles of denaturation at 95 °c for 30 secs, annealing at 58– 63 °c for 30 secs and then extension at 72 °c for 30 secs. a final extension step was carried out at 72 °c for 5 mins. the dna isolated from the peripheral blood was used as positive controls and ddh2o was used as a negative control. the product was checked for specificity and yield using 2% agarose gel stained with ethidium bromide. the direct sequencing (ds) of the pcr products was performed by a commercial company (macrogen, inc., seoul, korea). chromatograms were edited and analysed using the software bioedit, version 6.0.7 (ibis biosciences, carlsbad, california, usa). regarding the restriction fragment polymorphism (rflp), the mutation at codon 854 in exon 18, c.2560c>t, correlated with a bsu36i restriction site in the t allele. for the restriction fragment length polymorphism (rflp) reaction, 7 µl of the exon 18 pcr product was digested for 4 hrs with 10 u of the bsu36i gene (new england biolabs, (uk) ltd., hitchin, herts, uk ) at 37 °c. after the inactivation of the enzyme at 80 °c for 30 mins, the restriction fragments were separated by electrophoresis using a 2.5% agarose gel. the 250 bp pcr product was cleaved into two fragments of 151 and 99 bp in the t allele and uncleaved in the c allele. the intron 8 splicing site mutation, c.13272a>g, correlated with a smai restriction site in the g allele. for the rflp reaction, 7 µl of exon 7 and 8 of the pcr product was digested for 4 hrs with 10 u of the smai (new england biolabs) at 37 °c. after the inactivation of the enzyme at 80 °c for 30 mins, the restriction fragments were separated by electrophoresis using a 2.5% agarose gel. the 252 bp pcr product was cleaved into two fragments of 162 and 90 bp in the g allele and uncleaved in the a allele. the project was approved by the ethics research committee of the college of medicine & health sciences at sultan qaboos university in muscat, oman. results the examination of the muscle biopsies by light microscopy and electron microscopy for both patients showed vacuolar myopathy with storage of glycogen consistent with pompe disease [figures 1 and 2]. table 1: primer sequences, fragment sizes and annealing temperatures exon primers sequence (5' to 3') fragment size (bp) annealing temp. ˚c 2 a f ctgagcccgctttcttctc 365 61 2 a r cactgttcctgggtgatgg 365 61 2 b f ccatcacccaggaacagtg 330 61 2 b r gtgaggtgcgtgggtgtc 330 61 3 f ggtggctgtggggaacat 210 59 3 r ctggcacagagcccagaa 210 59 4 + 5 f ggtgctctcaggctcgtgt 454 59 4 + 5 r aggcagcacggaggagac 454 59 6 f tgaagaatctgtcccccaac 342 61 6 r ggtcatgttctccaccacct 342 61 7 + 8 f ctcatgaagtcggcgttgg 400 61.5 7 + 8 r ccttcccaaagacccacagt 400 61.5 9 f cccagcctcatcctctcact 252 63 9r gctggaggcctctgctttct 252 63 10 + 11 f cactgcagcctctcgttgtc 396 58 10 + 11 r gctaagtctcccaggccaga 396 58 12 f gaggaagctccctggaaacc 202 59 12 r acaggctgtgagggcagag 202 59 13 f ctctgcctcatcccagaaag 287 63 13 r cccggctctactctgctg 287 63 14 f cctgaggaccagcctgact 248 59 14 r attcccaggggagagtcttg 248 59 15 f agcacccaagtgcttcctt 209 61.5 15 r gcccctgcctaggtcact 209 61.5 16 f gtatgcctgtgtgcccatc 193 59 16 r ggcttagggtccccagact 193 59 17 f cccagaatcctcaaagcaac 232 61.5 17 r ctctgcagtgtgctgtccac 232 61.5 18 f cacgtgtccttccctttcc 250 61.5 18 r ccctcaccccttctcaacc 250 61.5 19 f ctgtctgctgacacctccac 239 61.5 19 r cgatccctgtgccactct 239 61.5 20 f tgctccatttgtgctctctc 200 61.5 20 r ctccaggtgacacatgcaac 200 61.5 bp = base pairs; temp. = temperature. identification of pompe disease mutations in archival tissues and development of a rapid molecular-based test 505 | squ medical journal, november 2013, volume 13, issue 4 dna was successfully extracted from the two archived tissues from the patients with pompe disease using a modified phenol-chloroform extraction method. the checking of the integrity and quality of the dna by agarose gel electrophoresis and pcr, respectively, indicated a good dna quality for pcr and post-pcr methods. two mutations were identified in the pompe disease samples. infant 1 (female) was homozygous for mutation c.2560c>t (p.arg854x) [figure 3] and infant 2 (male) was homozygous for mutation c.1327-2a>g [figure 4]. neither of the two identified mutations were found in the dna control sample, nor was the sequence retrieved from the genbank sequence database (nw_926918),12 but both were found in the pompe center database.13 the pcr and rflp tests for both mutations were designed to be used as fast confirmatory tests figure 1 a to f. micrographs of infant 1. a & b: light micrographs showing vacuolated fibres (arrows) stained with haematoxylin and eosin and masson’s trichrome. c: light micrograph showing the rich glycogen accumulation (arrows) with periodic acid-schiff (pas) stain. d: light micrograph showing the digested glycogen with a diastase (arrow) stained with pas diastase. e: light micrograph showing type i (arrows) and type ii (arrows) fibres stained with adenosine triphosphatase (ph = 9.5). f: electron micrograph showing lysosomal vacuoles containing small aggregates of glycogen (arrows). scale is 200 µm for a–e and 500 nm for f. aliya alansari, samira al-rawahi, taher ba-omar, mariam al-nabhani and anand date clinical and basic research | 506 for diagnosis and screening. typical genotyping results are shown in figures 5 and 6. discussion muscle biopsies have always been considered the standard method for diagnosing pompe disease.4 however, biopsies are invasive methods requiring anaesthesia, which is not recommended for infants with pompe disease. in 2006, enzyme replacement therapy became available and, to ensure the patient’s optimal benefit, new rapid and less invasive diagnostic tests were developed.4 testing gaa in dried blood is one of the methods developed and it is considered to be reliable and suitable for newborn screening, as it only requires a drop of blood to be collected, either from the heel or using the finger stick method.6 however, the pompe disease figure 2 a to f. micrographs of infant 2. a & b: light micrographs showing the funicular architecture of the tissue; there are many vacuoles of variable sizes within the fibres (arrows) stained with haematoxylin and eosin and masson’s trichrome. c: light micrograph showing the glycogen accumulation (arrows) with periodic acid-schiff (pas) stain. d: light micrograph showing the digested glycogen with a diastase (arrows) stained with pas diastase. e: light micrograph showing type i and ii fibres (arrows) stained with nicotinamide adenine dinucleotide-tetrazolium reductase. f: electron micrograph showing lysosomal vacuoles containing aggregated granules of glycogen (arrows). scale is 200 µm for a–e and 500 nm for f. identification of pompe disease mutations in archival tissues and development of a rapid molecular-based test 507 | squ medical journal, november 2013, volume 13, issue 4 diagnostic working group emphasised the need for a second confirmatory test to support the clinical and/or biochemical diagnosis due to the absence of developed quality assurance measures.4 the detection of pompe disease-causing mutation(s) is considered a definitive and rapid confirmatory test. it can be utilised in screening at-risk infants and for the identification of carriers, as well as in prenatal diagnosis and the genetic counselling of families with a history of pompe disease. in this retrospective study, the pathology archival formalin-fixed paraffin-embedded (ffpe) tissues provided a source of good quality dna to investigate the molecular bases of pompe disease in two omani infants. optimisation of the dna extraction method was very important and the primers for pcr were designed to amplify short fragments (less than 450 bp). the analysis of exons 2–20 of the gaa gene using direct sequencing identified two mutations. in infant 1, a c.2560c>t (p.arg854x) mutation in a cpg dinucleotide, which is susceptible to recurrent mutations, was identified. it is a transition, nonsense mutation at the c-terminal end that is known to be associated with infantile onset pompe disease.8 although found among pakistani, mexicanamerican and french ethnicities, the mutation has been observed in up to 60% of patients of african descent with a common haplotype.2 in infant 2, a c.1327-2a>g mutation modifying the splice acceptor site of exon 9 was identified. this mutation is associated with very severe effects, and has been reported in pompe disease cases from uk, iran and in patients of arab origin.14 the presence of both mutations as a homozygous genotype is an indicator of parental consanguinity, which has been reported in more omani patients with inborn errors of metabolism (81%) compared to the general population (33%).15 furthermore, consanguineous marriage in oman (52%) has been found to be dominated by first-cousin marriages (75%).16 conclusion this study provided valuable information regarding pompe disease-causing mutations in the gaa gene and has enabled the development of specific molecular tests for omani families. an rflp test was developed to identify each mutation. the timescale for carrying out the pcr and rflp test on a routine basis is about 3–8 hrs and is therefore fast compared to other available methods. to the best of our knowledge, this is the first retrospective study to utilise ffpe tissues in oman to identify the mutations causing pompe disease. we were successful in identifying two pompe disease-causing mutations and developing a rapid specific genetic test that can be used for prenatal figure 3 panels a & b. the c.2560c>t (p.arg854x) mutation in exon 18. a: the alignment of the wild type and mutant sequences. b: direct sequencing chromatograms for the homozygous wild type (cont.) and mutation (infant 1) sequences. figure 4 panels a & b. the c.1327-2a>g mutation in intron 8. a: the alignment of the wild type and mutant sequences. b: direct sequencing chromatograms for the homozygous wild type (cont.) and mutation (infant 2) sequences. aliya alansari, samira al-rawahi, taher ba-omar, mariam al-nabhani and anand date clinical and basic research | 508 diagnosis and carrier screening in omani families with the identified mutations. references 1. acmg work group on management of pompe disease: kishnani ps, steiner rd, bali d, berger k, byrne bj, et al. pompe disease diagnosis and management guideline. genet med 2006; 8:267–88. 2. raben n, plotz p, byrne bj. acid alpha-glucosidase deficiency (glycogenosis type ii, pompe disease). curr mol med 2002; 2:145–66. 3. güngör d, reuser aj. how to describe the clinical spectrum in pompe disease? am j med genet 2013; 161a:399–400. 4. beckemeyer aa, mendelsohn nj, kishnani ps. response to the letter “how to describe the clinical spectrum in pompe disease?”. am j med genet a 2013; 161a:401–2. 5. chien yh, lee nc, thurberg bl, chiang sc, zhang xk, keutzer j, et al. pompe disease in infants: improving the prognosis by newborn screening and early treatment. pediatrics 2009; 124:e1116–25. 6. gasparotto n, tomanin r, frigo ac, niizawa g, pasquini mb, blanco m, et al. rapid diagnostic testing procedures for lysosomal storage disorders: alpha-glucosidase and beta-galactosidase assays on dried blood spots. clin chim acta 2009; 402:38–41. 7. kroos ma, van der kraan m, van diggelen op, kleijer wj, reuser aj, van den boogaard mj, et al. glycogen storage disease type ii: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients. j med genet 1995; 32:836–7. 8. hermans mm, van leenen d, kroos ma, beesley ce, van der ploeg at, sakuraba h, et al. twenty-two novel mutations in the lysosomal alpha-glucosidase gene (gaa) underscore the genotype-phenotype correlation in glycogen storage disease type ii. hum mutat 2004; 23:47–56. 9. kroos m, hoogeveen-westerveld m, michelakakis h, pomponio r, van der ploeg a, halley d, et al. update of the pompe disease mutation database with 60 novel gaa sequence variants and additional studies on the functional effect of 34 previously reported variants. hum mutat 2012; 33:1161–5. 10. cao w, hashibe m, rao jy, morgenstern h, zhang zf. comparison of methods for dna extraction from paraffin-embedded tissues and buccal cells. cancer detec prev 2003; 27:397–404. 11. libório tn, etges a, da costa neves a, mesquita ra, nunes fd. evaluation of the genomic dna extracted from formalin-fixed, paraffin-embedded oral samples archived for the past 40-years. j bras patol med lab 2005; 41:405-10. 12. national center for biotechnology information. genbank overview. available at: http://www.ncbi. nlm.nih.gov/genbank/ accessed: aug 2013. 13. erasmus university. pompe center. available at: http://w w w.erasmusmc .nl/klinische_genetica/ research/lijnen/pompe_center/?lang=en accessed: aug 2013. figure 5 panels a & b. the assay design (a) and results (b) of the polymerase chain reaction restriction fragment length polymorphism analysis for the c.2560c>t (p.arg854x) mutation in exon 18. a: first, a 250 bp fragment of the gaa gene covering the mutation was amplified by polymerase chain reaction (pcr); next, the pcr product was digested with the bsu36i restriction enzyme, which recognizes only the t allele, and generated two fragments, 151 bp and 99 bp. b: the electrophoretic separation of the bsu36i enzymatic restriction products using 2.5% (weight/volume percentage) agarose gel. lanes: 1 = dna ladder; 2 = tt homozygote (mutant type) digested product; 3 = cc homozygote (wild type) undigested fragment (250 bp), and 4 = cc homozygote (wild type) undigested fragment (250 bp). figure 6 panels a & b. the assay design (a) and results (b) of the polymerase chain reaction restriction fragment length polymorphism analysis for the c.1327-2a>g mutation in intron 8. a: first, a 252 bp fragment of the gaa gene covering the mutation was amplified by polymerase chain reaction (pcr); next, the pcr product was digested with the smai restriction enzyme which recognizes only the g allele, and generated two fragments, 162 bp and 90 bp. b: the electrophoretic separation of the smai enzymatic restriction products using 2.5% (weight/volume percentage) agarose gel. lanes: 1 = dna ladder; 2 = gg homozygote (mutant type) digested product; 3 = gg homozygote (mutant type) digested product, and 4 = aa homozygote (wild type) undigested fragment (252 bp). identification of pompe disease mutations in archival tissues and development of a rapid molecular-based test 509 | squ medical journal, november 2013, volume 13, issue 4 14. kroos m, pomponio rj, van vliet l, palmer re, phipps m, van der helm r, et al. update of the pompe disease mutation database with 107 sequence variants and a format for severity rating. hum mutat 2008; 29:e13–26. 15. joshi sn, venugopalan p. clinical characteristics of neonates with inborn errors of metabolism detected by tandem ms analysis in oman. brain dev 2007; 29:543–6. 16. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32–42. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e26-36, epub. 27th jan 14 submitted 18th jun 13 revisions req. 18th aug & 19thsep 13; revisions recd. 24th aug & 24th sep 13 accepted 23rd oct 13 recurrent pregnancy loss (rpl), either early or late in the gestational period, is a serious problem and has both psychological and social impacts on the women who suffer from it. in some cases, it may lead to divorce or other social problems. miscarriage is common, with most studies showing that the incidence of this complication occurring before 20 weeks’ gestation varies between 8–20%, with 80% of these occurring in the first 12 weeks of pregnancy.1 the real rate of miscarriage may be much higher than reported, since many women miscarry before realising that they are pregnant. in one study, human chorionic gonadotrophin was checked daily from the expected time of ovulation until the next menstrual period in order to detect a pregnancy as early as possible; this yielded a miscarriage rate of 31%.2 habitual or recurrent miscarriage (rm) is defined as the loss of three or more consecutive and clinically-recognised pregnancies before 20 weeks’ gestation; this affects 1–2% of women.3 this incidence increases to 5% when it is defined as a loss of two or more clinically-recognised pregnancies before 20 weeks’ gestation.4 rpl may be classified as early (losses at or before 20 weeks’ gestation) or late (losses after 20 weeks’ gestation). patients may be classified as suffering from primary rpl when they have never had a live birth or from secondary rpl when they have had recurrent losses following department of obstetrics & gynecology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: abuheija2008@hotmail.com أهبة التخثر وفقدان احلمل املتكرر هل اهليبارين اليزال العالج املفضل؟ عادل �أبو �لهيجاء abstract: the association between thrombophilia and recurrent pregnancy loss (rpl) has become an undisputed fact. thorombophilia creates a hypercoaguable state which leads to arterial and/or venous thrombosis at the site of implantation or in the placental blood vessels. anticoagulants are an effective treatment against rpl in women with acquired thrombophilia due to antiphospholipid syndrome. the results of the use of anticoagulants for treating rpl in women with inherited thrombophilia (it) are encouraging, but recently four major multicentre studies have shown that fetal outcomes (determined by live birth rates) may not be as favourable as previously suggested. although the reported side-effects for anticoagulants are rare and usually reversible, the current recommendation is not to use anticoagulants in women with rpl and it, or for those with unexplained losses. this review examines the strength of the association between thrombophilia and rpl and whether the use of anticoagulants can improve fetal outcomes. keywords: thrombophilia; recurrent abortions; spontaneous abortions; heparin, low-molecular-weight; aspirin. يف خثار �إىل بالتايل و �لدم يف �لتخرث زيادة �إىل �لتخرث �أهبة توؤدي و�قعة. حقيقة هي �ملتكرر �حلمل وفقد�ن �لتخرث �أهبة بي �لعالقة �إن امللخ�ص: �ل�رش�يي �أو �الأوردة يف موقع �لعلوق �أو يف �الأوعية �لدموية للم�صيمة. تعمل �الأدوية �مل�صادة للتخرث بفعالية يف عالج فقد�ن �حلمل �ملتكرر عند �ل�صيد�ت �للو�تي يعاني من �أهبة �لتخرث �ملكت�صبة �لناجتة عن ظاهرة �الأج�صام �مل�صادة �ل�صحمية �لفو�صفورية .�إن نتائج �لدر��صات �لتي مت فيها ��صتعمال �الأدوية �مل�صادة للتخرث ملعاجلة فقد�ن �حلمل �ملتكرر كانت م�صجعة للغاية حتى �صدور �أربعة در��صات كربى متعددة �ملر�كز بينت �أن ن�صبة �ملو�ليد �الأحياء رمبا ال تكون م�صجعة كما كان يعتقد �صابقا. على �لرغم من �أن �مل�صاعفات و�الأعر��س �جلانبية لتلك �الأدوية نادرة �حلدوث ولي�صت خطرية فان تلك �لدر��صات ال تو�صي با�صتعمال �الأدوية �مل�صادة للتخرث لعالج �الأمهات �للو�تي يعاني من فقد�ن �حلمل �ملتكرر �أهبة �لتخرث �لور�ثية لعالج فقد�ن �حلمل �ملتكرر �لذي ال يعرف له �صبب. مفتاح الكلمات: �أهبة �لتخرث؛ �حلمل �ملتكرر؛ �لهيبارين ذو �لوزن �جلزيئي �ملنخف�س؛ �الأ�صربين �ملعتاد. review thrombophilia and recurrent pregnancy loss is heparin still the drug of choice? adel abu-heija adel abu-heija review | e27 a successful pregnancy. rpl has now been deemed a major cause of female infertility.5 thrombophilia is a common cause of rpl and may be seen in 40–50% of cases.6,7 pregnancy is a hypercoaguable state and if the pregnancy is affected by thrombophilia, the hypercoaguable state becomes worse and may impair blood flow through the maternal veins, leading to deep vein thrombosis, and clots in the placental blood vessels, leading to fetal growth restriction and/or fetal demise.8,9 due to this fact, anticoagulants have become very popular for treating rpl. the aim of this review is to find the strength of the association between thrombophilia and rpl and whether the use of anticoagulants can improve fetal outcomes. thrombophilia thrombophilia is a term which describes the increased tendency of excessive blood clotting. it is a normal phenomenon during pregnancy, where there is an increase in most clotting factors, such as factor viii, von willebrand factor, platelets, fibrinogen and factor vii. during pregnancy, there is also an increase in prothrombin fragment 1 + 2 and d-dimer.10,11 when investigating patients with rpl, it is very important to exclude other possible causes of the losses, such as uterine malformation; diabetes mellitus; connective tissue diseases such as systemic lupus erythematosus (sle); chromosomal abnormalities, and thyroid dysfunction.12–15 currently, many clinicians treat rpl—either associated with all types of thrombophilia or unexplained—with low-molecular-weight heparin (lmwh) combined with low-dose aspirin (lda). this treatment became popular in the late 1990s, after sanson et al. reported that thrombophilia is associated with the high risk of fetal loss in early and late pregnancy.16 thrombophilia is either inherited, acquired or a combination of both. i n h e r i t e d o r g e n e t i c t h r o m b o p h i l i a in inherited or genetic thrombophilia, there is usually a family history of excessive clotting. more commonly, the diagnosis is based on the demonstration of a gene mutation such as a factor v leiden (fvl) mutation (c677t), a hyperhomocysteinaemia mutation (a506g), a prothrombin mutation (g20210a) or prothrombin ii (ptii) mutation, or a protein s and/or c deficiency. clinical studies suggest that hypercoagulation is the main underlying pathophysiological mechanism which leads to uteroplacental insufficiency and, subsequently, pregnancy loss. it is believed that inherited thrombophilia (it) impairs the placental function by causing arterial and/or venous thrombosis at the maternal-fetal interface. it is also believed that activated protein s and protein c inhibit the action of certain clotting factors, such as factors v and viii. this shows that proteins s and c act as anticoagulants. if the actions of these proteins are reduced, the inhibition of the clotting mechanism is removed and, subsequently, placental arterial and venous thrombosis may occur; this mechanism might be the basis of rpl associated with thrombophilia. when there is a mutation of the fvl gene (arginine amino acid is substituted by glutamine amino acid at position number 506 of factor v), this may result in the formation of a protein which is resistant to the action of activated protein c, called anti-protein c (apc). the apc removes the inhibitory effect of protein c on the clotting mechanism and enhances the conversion of prothrombin to thrombin, subsequently enhancing the formation of clots.17–19 this absent or reduced activity of antithrombin leads to increased levels of thrombin and clot formation. a mutation of the prothrombin gene (g20210a) will facilitate the formation of thrombin and clot formation in heterozygous individuals, who have a two-fold higher risk of clotting in comparison to non-carriers. women with hyperhomocysteinaemia show a folic acid deficiency, also resulting in a two-fold increase in clotting within homozygous women.20–23 the exact mechanism by which it causes implantation failure and subsequent rpl is unclear. it has been suggested that thrombophilia may lead to a syncytiotrophoblast invasion of the maternal blood vessels, which in turn leads to the formation of microthrombosis at the site of implantation, resulting in implantation failure and rpl.24 in a study of the effect of ethnicity on rm and it, baumann et al. found that in a uniform ethnic group the prevalence of various congenital thrombophilic thrombophilia and recurrent pregnancy loss is heparin still the drug of choice? e28 | squ medical journal, february 2014, volume 14, issue 1 combination of acquired and it, or a combination of more than one inherited thrombophilic gene defect) has been identified by several researchers as a cause of both early and late rpl; however, the frequency of combined thrombophilia is not clear.36,37 low-molecular-weight heparin heparin exerts an effect on women with thrombophilia through various mechanisms; it potentiates the antithrombin effects of the condition, thus preventing clot formation.38 heparin also binds to the apl, rendering them inactive; this is important as these antibodies adhere to the cell surface and impede the differentiation and invasiveness of the cytotrophoblasts. it has been reported that low-molecular-weight heparin (lmwh) reduces the binding of the apl to the trophoblast cells, subsequently restoring the cytotrophoblasts’ invasiveness and differentiation.39 unfractionated and lmwh reduce e-cadherin protein expression in rat pregnancies. this may enhance the trophoblast invasion in patients with pregnancy loss.40 the treatment of women with aps and rpl with heparin is beneficial because complement activation is essential for the apl to induce fetal damage; heparin, whether fractionated or lmwh, inhibits the complement activation in vivo and in vitro in pregnant mice, thus preventing fetal damage.41 in the absence of apl, lmwh induces a potentially detrimental proinflammatory and anti-angiogenic profile in the trophoblast. in the presence of apl, single-agent lmwh may be the optimal therapy to counter the trophoblast inflammation, however it also induces an antiangiogenic response.42 treatment of women with antiphospholipid syndrome and recurrent pregnancy loss the evidence in the literature favours treating aplpositive women with aps who are suffering from rpl. the cochrane review by empson et al. was conducted to assess the efficacy of all treatment markers did not differ. thus, when investigating a multi-ethnic cohort of women, the prevalence of hereditary thrombophilia may differ due to the fact that the basic prevalence in different ethnic groups varies.25 the prevalence of thrombophilia in the general population varies from 1.1% in lebanon to 2.5% in india.26,27 in acquired thrombophilia, antiphospholipid syndrome (aps) can be due to either lupus anticoagulant antibodies or anticardiolipin antibodies, as seen in women with sle. in aps, the body’s immune system recognises the phospholipids, which are a part of the cell membrane, as a foreign substance and thus produces antibodies against them. however, other studies have shown that antiphospholipid antibodies (apl) often act against a protein cofactor called β2glycoprotein 1. this protein cofactor helps the apl to adhere to the phospholipids in the cell membrane.28 the apl consist of 20 antibodies, but only the lupus anticoagulant and anticardiolipin antibodies (immunoglobulin g and immunoglobulin m, but not immunoglobulin a [iga]) have been shown to be of clinical significance.29,30 in one study, 55% of women with rpl tested positive for apl.31 in women with sle, adverse live-birth outcomes were significantly associated with posititive anticardiolipin iga and anti-beta 2 glycoproteins.32 the mechanism by which aps causes implantation failure and subsequent rpl is unclear. it has been suggested that, as in thrombophilia, aps may lead to a syncytiotrophoblast invasion of the maternal blood vessels, leading to the formation of microthrombosis at the site of implantation, resulting in implantation failure and rpl.24 histopathological examinations of the placentas in women with aps showed thrombosis, acute atherosis, a decreased number of syncytiovascular membranes, an increased number of syncytial knots and obliterative arteriopathy. these placental changes, although common, are not specific to aps.33 it has been suggested that in women with aps and rpl, the presence of apl during pregnancy is a major risk factor for adverse fetal outcomes.34 in a recent study, the incidence of apl was 27.8% in couples with rpl.35 c o m b i n e d t h r o m b o p h i l i a combined thrombophilia (which is either a adel abu-heija review | e29 options in order to improve pregnancy outcomes in apl-positive women suffering from rpl.43 the studies reviewed were either randomised or quasirandomised studies of pregnant women with a history of rpl and apl. the selection criteria (women with rpl and aps with positive apl) (n = 849) were fulfilled in 13 studies. they found that combining unfractionated heparin with lda (two trials; n = 140) resulted in a significant reduction in pregnancy loss when compared to a trial in which patients used lda alone (relative risk [rr] = 0.46; 95% confidence interval [ci]: 0.29–0.71). one trial (n = 98) compared pregnancy loss outcomes when lmwh was combined with lda in one group and lda was given alone in another group. this did not show a significant reduction in pregnancy loss rate (rr = 0.78: 95% ci: 0.39–.57). one trial (n = 50) failed to show any advantage in giving high-dose or low-dose unfractionated heparin. the use of lda alone was reported in three trials (n = 135) and these showed no significant reduction in pregnancy loss (rr = 1.05; 95% ci: 0.66–1.68). treatment with prednisone and lda was reported in three trials (n = 286). the results showed a significant increase in prematurity with lda alone in comparison to a combination of heparin with lda, and both of these treatment options were compared to a placebo. in fact, there was an increase in gestational diabetes. intravenous immunoglobulin and/ or unfractionated heparin and lda were used in two trials (n = 58). this was associated with a higher frequency of pregnancy loss and premature deliveries when compared to unfractionated heparin or lmwh combined with lda (rr = 2.51; 95% ci: 1.27–4.95). when compared to lda alone and prednisone alone, intravenous immunoglobulin (one trial; n = 82) showed no significant difference in outcome. the authors concluded that the combination of unfractionated heparin and lda may reduce pregnancy loss by 54% in women with aps and who are apl-positive. mak et al. conducted a meta-analysis of studies involving women with rpl who were aplpositive.44 the study (n = 334) was conducted in order to ascertain whether the combination of heparin and lda worked better than lda alone to achieve live births. the authors found that the overall frequency of live births was 74.27% in women who used the combination compared to 55.83% in the group using lda alone. women who received a combination of heparin and lda had a significantly higher live birth rate (rr = 1.301; 95% ci: 1.040, 1.629) than women who used lda alone. the authors concluded that the combination of heparin and lda resulted in more live births in apl-positive women than using lda alone. in cohn et al.’s study (n = 693), only 176 women (25%) were apl-positive, while the rest had unexplained rpl.45 of the apl-positive women, 69% (n = 122) had a subsequent live birth compared with 63% (n = 324) of the women with unexplained rpl (odds ratio [or] = 1.3; 95% ci: 0.9–1.9). when the authors analysed the results, they found that 79% of apl-positive women receiving a combination of heparin and lda had a live birth compared with 62% of those receiving lda alone (adjusted or = 2.7; 95% ci: 1.3–5.8). in the unexplained rpl group, there was no difference in outcome for women receiving a combination of heparin and lda or lda only. the authors concluded that a combined table 1: live birth rates in women with antiphospholipid syndrome and recurrent pregnancy loss treated with lowmolecular-weight heparin plus low-dose aspirin compared with those treated with low-dose aspirin alone study number of patients medication commencement in gestational weeks treatment for each group live birth rate % p value empson et al. (2005)43 119 7 1. lmwh + lda 2. lda 73 34 <0.05 mak et al. (2010)44 334 6 1. lmwh + lda 2. lda 74.27 55.83 <0.05 cohn et al. (2010)45 176 6 1. lmwh + lda 2. lda 79 62 <0.05 al abri et al. (2000)46 88 7 1. lmwh + lda 2. lda 75 54 <0.05 lmwh = low-molecular-weight heparin; lda = low-dose aspirin. thrombophilia and recurrent pregnancy loss is heparin still the drug of choice? e30 | squ medical journal, february 2014, volume 14, issue 1 is inherited thrombophilia associated with recurrent pregnancy loss? the following studies, all of them prospective casecontrol studies, did not find an association between it and adverse pregnancy outcomes. in said et al.’s prospective cohort study, 2,034 nulliparous women were recruited before 22 weeks’ gestation.48 genotyping for fvl mutations, mutations of the prothrombin gene, methylenetetrahydrofolate reductase enzymes (mthfr) c677t, mthfr a1298c and thrombomodulin polymorphisms were performed. the thrombophilia investigation results were disclosed neither to the women nor to their physicians. the thrombophilia tests results and pregnancy outcomes were available in 1,707 women. pregnancy complications such as placental abruption, severe pre-eclampsia, intrauterine growth restriction, stillbirths and early neonatal deaths occurred in 136 women (8%). the authors concluded that the majority of asymptomatic women with it will have a successful pregnancy outcome. silver et al.’s study tried to ascertain whether women carrying mutations of the prothrombin gene g20210a were at higher risk of rpl, placental abruption, severe pre-eclampsia or intrauterine growth restriction.49 they recruited 5,188 women, and 4,167 blood samples were taken in the first trimester and analysed for the gene mutation g20210a. in this study, only 3.8% of the women tested had a mutation of prothrombin g20210a and their pregnancy loss rates were similar to those of women without the mutation. the authors thus concluded that the prothrombin gene mutation g20210a was not associated with pregnancy loss or the other obstetric complications studied. dizon-townson et al. studied pregnancy rates among women who were heterozygous carriers of the fvl mutation.50 only women with singleton pregnancies before 14 weeks’ gestation were enrolled. in this study, the researchers failed to show any increase in pregnancy loss or other obstetric complications. such as pre-eclampsia, placental abruption or intrauterine growth restriction, when compared with non-carriers. they concluded that women who are heterozygous carriers of the fvl gene mutation do not require either screening or treatment of lda and heparin is superior to lda alone in apl-positive women, but not for women with unexplained rpl. in their study, al abri et al. analysed the outcomes of pregnancies in a cohort of 21 arab women and four women from other parts of asia, who had had one or more episodes of fetal loss associated with raised levels of anticardiolipin antibodies.46 they found that the rate of pregnancy loss was significantly higher in the first trimester than in the second or third. in the group that had received both lda and prednisolone, 75% of pregnancies were successful compared to 54% in the group receiving aspirin alone, while 17% were successful in those who received no therapy. they concluded that lda, either alone or with prednisolone, appears to improve significantly the chances for successful pregnancies in patients with anticardiolipin antibodies. the results of these studies are summarised in table 1. which heparin should be used to treat antiphospholipid syndrome and antiphospholipid antibodies? one question to consider is which heparin should be used in women with aps and who are positive for apl. in fouda et al.’s study, 60 women with a history of three or more consecutive pregnancy losses and positive for apl were divided equally into two groups.47 one group received unfractionated heparin (5,000 units, twice daily) plus lda. the second group received lmwh (enoxaparin 40 mg, once daily) plus lda immediately after their pregnancy was confirmed. the authors found that 25 of the women who received lmwh (80%) and 20 of the women who received unfractionated heparin (66.67%) had successful pregnancies and deliveries (p = 0.243). the authors concluded that lmwh plus lda was a better alternative to unfractionated heparin plus lda. another advantage of lmwh is that it can be given once daily subcutaneously and can be self-administered. adel abu-heija review | e31 treatment during pregnancy if there is no history of thromboembolisms. roqué et al. studied the association between inherited and acquired maternal thrombophilias and adverse pregnancy events.51 a cohort of 491 patients with a history of adverse pregnancy outcomes was evaluated for activated protein c resistance, fvl and prothrombin g20210a mutations, hyperhomocysteinaemia, antithrombin deficiencies, proteins c and s, and both anticardiolipin antibodies and lupus anticoagulants. they found that the presence of maternal thrombophilia was not associated with an increased risk of fetal loss before 14 weeks’ gestation. prospective case-control studies that showed an association between it and adverse pregnancy outcomes were also found, and are summarised below. in preston et al.’s study, 1,384 women were enrolled in the european prospective cohort on thrombophilia.52 they found an increased risk of fetal loss in women with it (168/571 versus 93/395; or = 1.35; 95% ci: 1.01–1.82). the or was greater for stillbirths than for miscarriages (3.6 [1.4–9.4] versus 1.27 [0.94–1.71]). the highest or for stillbirth was in women with combined defects at 14.3 (2.4–86.0), which can be compared with 5.2 (1.5–18.1) in those with antithrombin deficiencies; 2.3 (0.6–8.3) in those with protein c deficiencies; 3.3 (1.0–11.3) in those with protein s deficiencies, and 2.0 (0.5–7.7) in those with fvl mutations. the or for miscarriage in these subgroups was 0.8 (0.2–3.6) in women with combined defects; 1.7 (1.0–2.8) in those with antithrombin deficiencies; 1.4 (0.9–2.2) in those with protein c deficiencies; 1.2 (0.7–1.9) in those with protein-s deficiencies, and 0.9 (0.5–1.5) in women with fvl mutations. the authors concluded that women with familial thrombophilia, especially those with combined defects or antithrombin deficiencies, have an increased risk of fetal loss. kocher et al. studied 5,000 pregnant women and found a significant association between fvl mutations and stillbirths (or = 19.9; 95% ci: 2.07–56.94), but not early fetal loss (or = 1.76; 95% ci: 0.85–3.65).53 sottilotta et al.’s study included 102 consecutive women with pregnancy loss who were tested for thrombophilia. of these, 55 women with rpl (47 of whom had had a stillbirth) were tested for thrombophilia.54 they found that the prevalence of prothrombin ii, fvl and prothrombin g20210a mutations was higher in women with unexplained stillbirths. this finding was statistically significant. the prevalence of it thrombophilia was higher in women with rpl, but the difference was not statistically insignificant. treating recurrent pregnancy loss in cases of inherited thrombophilia there are a few studies that show that treating women who suffer from it and rpl with anticoagulants is beneficial; however, these studies have many limitations. the live-enox study compared two doses of lmwh (enoxaparin, 40 versus 80 mg) for women with and without thrombophilia.55 treatment with lmwh commenced between 5–10 weeks’ gestation. the prevalence of thrombophilia was similar in both treatment groups and the live birth rate was 84.3% in women who received 40 mg of enoxaparin and 78.3% in women who received 80 mg of enoxaparin. live birth rates were 70.0%, 84.4%, 76.9% and 81.3% for women with fvl mutations, hyperhomocysteinaemia, aps and other types of thrombophilia, respectively. the differences in these live birth rates were not significant (p = 0.484). the major limitation of this study was that the researchers did not compare lmwh with either lda or a placebo. in deligiannidis et al.’s study, all of the subjects had rm and it. the women in the experimental group (n = 29) received a combination of lmwh and lda, while the control group (n = 23) received no treatment.56 there was a significantly lower miscarriage rate among the women who received lmwh plus lda when compared with those who received no treatment. however, the study was not randomised. in carp et al.’s cohort study, 58 women who had rm and it were investigated.57 within this cohort, 37 received 40 mg of enoxaparin and 48 received no treatment. they found that 26 out of 37 (70.2%) of the women who received lmwh had live births compared with 21 out of 48 (43.8%) untreated women. (p <0.02; or = 3.03; 95% ci: 1.12–8.36). the limitation of this study was that it was neither controlled nor randomised. thrombophilia and recurrent pregnancy loss is heparin still the drug of choice? e32 | squ medical journal, february 2014, volume 14, issue 1 scan. live birth rates were 85% in the combined therapy group and 81% in the lmwh alone group compared to 48% in women who received the placebo (p <0.05). the results of these studies are summarised in table 2 and all show a favourable outcome in women with rpl, either with or without thrombophila. prescribing anticoagulants to women with recurrent pregnancy loss: is the current practice justified? because of the results of the previously summarised investigations, the majority of clinicians worldwide have started prescribing heparin and/or aspirin for pregnant women with rpl, either with or without thrombophilia. however, because of the limitations of these studies, many researchers have conducted controlled, randomised, double-blind, multicentre studies to find out whether the current practice of prescribing anticoagulants to women with rpl with or without thrombophilia is justified. those studies and their results are summarised below [table 3]. the scottish pregnancy intervention (spin) study was a multicentre, randomised, controlled trial of lmwh and lda in women with rm.60 this study included 294 women at less than seven weeks’ gestation. all of the women had had two or more consecutive pregnancy losses before 24 weeks’ gestation. other causes of rpl were excluded, such as rpl due to endocrinological, chromosomal, immunological or anatomical abnormalities. treating unexplained recurrent pregnancy loss with heparin the use of lmwh in the treatment of patients with rpl without identified thrombophilia is based on two retrospective studies that reported a higher rate of successful pregnancy outcomes. both studies had methodological limitations. in badawy et al.’s prospective randomised study, 340 women with first-trimester rm with no identifiable cause were investigated.58 the women were randomised into two groups, with one group receiving lmwh and folic acid while the other group received only folic acid. in the lmwh group, treatment commenced once the fetal heartbeat was visible by ultrasound scan and continued until 34 weeks’ gestation. folic acid was discontinued at 13 weeks’ gestation in both groups. the researchers found that the early miscarriage rate was 4.1% in the combined lmwh and folic acid group as compared with 8.8% in the folic acid alone group, while late pregnancy loss was 1.1% in the combined group compared with 2.3% in the folic acid alone group. this study showed modest improvements in the rates of pregnancy loss in women with rpl in the first trimester without thrombophilia (live birth risk ratio = 1.07; 95% ci: 1.00–1.14). in fawzy et al.’s prospective randomised, singleblinded, placebo-controlled study, 160 women diagnosed with idiopathic rm (more than three miscarriages) were recruited.59 they received either lmwh (enoxaparin) alone; prednisone, lda and progesterone, or a placebo in treatment, once the pregnancy had been confirmed by an ultrasound table 2: pregnacy outcomes in women with idiopathic recurrent pregnancy loss treated with low-molecular-weight heparin, prednisone, aspirin and a placebo study number of patients medication commencement in gestational weeks treatment outcomes p value early miscarriage at <13 weeks late miscarriage at >13 weeks badawy et al. (2008)58 340 7 1. lmwh 2. folic acid alone 4.1 8.1 1.2 2.3 <0.05 live birth rate % fawzy et al. (2008)59 160 7 1. lmwh 2. prednisone + lda + progesterone 3. placebo 81 85 48 <0.05 lmwh = low-molecular-weight heparin; lda = low-dose aspirin. adel abu-heija review | e33 women were randomised into two groups. group one received lmwh and lda (40 mg of enoxaparin and 75 mg of aspirin daily) until 36 weeks’ gestation with intensive surveillance, while group 2 had only intensive surveillance during the pregnancy. after randomisation, blood was sent from all of the women for thrombophilia testing. the results were not disclosed, either to the patient or to the clinician, until six weeks after the delivery. in this study, 10 women had it, eight were heterozygous carriers of fvl mutations and five were identified in the pharmacological intervention group. two cases had the prothrombin g20210a mutation, with one identified in each arm of the trial. the authors found that the pregnancy loss rate was 22% in women receiving both lmwh and lda, while the pregnancy loss rate was 20% in the group who were only intensively monitored. they concluded that their results do not support the use of lmwh and/or lda in women with rpl not due to aps. in kaandorp et al.’s randomised anticoagulants for living fetuses (alife) trial, the participants (n = 364) all had a history of unexplained rpl.61 they were randomised equally into three groups. group 1 received a daily dose of 80 mg of aspirin plus lmwh (2,850 iu) daily, group 2 received a daily dose of 80 mg of aspirin only and group 3 received a placebo. in this study, 299 women became pregnant. the live birth rates were similar in the three groups, with 69.1% (67/97) in group 1, 6% (61/99) in group 2 and 67.% (69/103) in group 3. this study showed that neither a combination of lmwh and lda nor lda alone improved the live birth rate when compared with the use of a placebo in women with rpl. in visser et al.’s low molecular weight heparin and/or aspirin in prevention of habitual abortion (habenox) study, a randomised, double-blind, multicentre study, 207 women were recruited.7 all had had three or more consecutive miscarriages in the first trimester (less than 13 weeks’ gestation), or two or more second trimester consecutive miscarriages. all women were tested for thrombophilia and were randomised before seven weeks’ gestation to receive either lmwh (40 mg of enoxaparin) plus a placebo (n = 68), lmwh (40 mg of enoxaparin) plus 100 mg of aspirin (n = 63) or 100 mg of aspirin alone (n = 76). the live birth rate was 71% in women who received lmwh plus a placebo, 65% for those who received lmwh plus lda and 61.5% in those who received lda alone. the differences in the live birth rates were not statistically significant among the three groups, regardless of their thrombophilic statuses. the heparin and aspirin (hepasa) trial studied 88 pregnant women with rpl who were either aplpositive, or who had it or antinuclear antibodies.62 women were randomised into two groups, with group one (n = 45) receiving lmwh plus lda while group two (n = 43) received lda alone. in each group, 47.7% of women were apl-positive. the live birth rate was 77.8% (35/45) in group 1 and 79.1% (34/43) in group 2. the authors concluded that lmwh plus lda showed no benefit over lda alone in women with rpl. table 3: a review of controlled, randomised, double-blind, multicentre studies to determine whether prescribing anticoagulants to women with recurrent pregnancy loss, with or without thrombophilia, is justified trial number of patients miscarriages n (%) medication commencement in gestational weeks treatment for each group live birth rate % p value alife (2010)61 299 2 (40.1) ≥3 (59.9) <6 1. lmwh + lda 2. lda 3. placebo 69 62 67 0.63 habenox (2011)7 207 2 (1.0) ≥3 (99.0) <7 1. lmwh + lda 2. lda 3. lmwh 65 61 71 0.45 spin (2010)60 294 2 (57.1) ≥3 (42.9) <7 1. lmwh + lda 2. placebo 78 80 0.85 hepasa (2009)62 88 2 (100) <6 1. lmwh + lda 2. lda 77.8 79.2 0.75 alife = anticoagulants for living fetuses; lmwh = low-molecular-weight heparin; lda = low-dose aspirin; habenox = low molecular weight heparin and/or aspirin in prevention of habitual abortion; spin = scottish pregnancy intervention; hepasa = heparin and aspirin. thrombophilia and recurrent pregnancy loss is heparin still the drug of choice? e34 | squ medical journal, february 2014, volume 14, issue 1 15. akbaş h, isi h, oral d, türkyılmaz a, kalkanlı-taş s, simşek s, et al. chromosome heteromorphisms are more frequent in couples with recurrent abortions. genet mol res 2012; 11:3847–51. 16. sanson bj, friederich pw, simioni p, zanardi s, hilsman mv, girolami a, et al. the risk of abortion and stillbirth in antithrombin-, protein c-, and protein s-deficient women. thromb haemost 1996; 75:387–8. 17. finan rr, tamim h, ameen g, sharida he, rashid m, almawi wy. prevalence of factor v g1691a (factor v-leiden) and prothrombin g20210a gene mutations in a recurrent miscarriage population. am j hematol 2002; 71:300–5. 18. lockwood cj. inherited thrombophilias in pregnant patients: detection and treatment paradigm. obstet gynecol 2002; 99:333–41. 19. sehirali s, inal mm, yildirim y, balim z, kosova b, karamizrak t, et al. prothrombin g20210a mutation in cases with recurrent miscarriage: a study of the mediterranean population. arch gynecol obstet 2005; 273:170–3. 20. cosmi b, legnani c, pengo v, ghirarduzzi a, testa s, poli d, et al. the influence of factor v leiden and g20210a prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs. thromb haemost 2013; 109:510–6. 21. yildiz g, yavuzcan a, yildiz p, süer n, tandoğan n. inherited thrombophilia with recurrent pregnancy loss in turkish women--a real phenomenon. ginekol pol 2012; 83:598–603. 22. nair rr, khanna a, singh k. mthfr c677t polymorphism and recurrent early pregnancy loss risk in north indian population. reprod sci 2012; 19:210–5. 23. govindaiah v, naushad sm, prabhakara k, krishna pc, radha rama devi a. association of parental hyperhomocysteinemia and c677t methylene tetrahydrofolate reductase (mthfr) polymorphism with recurrent pregnancy loss. clin biochem 2009; 42:380–6. 24. azem f, many a, ben ami i, yovel i, amit a, lessing jb, et al. increased rates of thrombophilia in women with repeated ivf failures. hum reprod 2004; 19:368–70. 25. baumann k, beuter-winkler p, hackethal a, strowitzki t, toth b, bohlmann mk. maternal factor v leiden and prothrombin mutations do not seem to contribute to the occurrence of two or more than two consecutive miscarriages in caucasian patients. am j reprod immunol 2013; 70:518–21. 26. hoteit r, taher a, nassar r, otrock z, halawi r, mahfouz ra. frequency of triple mutations involving factor v, prothrombin, and methylenetetrahydrofolate reductase genes among patients referred for molecular thrombophilia workup in a tertiary care center in lebanon. genet test mol biomarkers 2012; 16:223–5. 27. mukhopadhyay r, saraswathy kn, ghosh pk. mthfr c677t and factor v leiden in recurrent pregnancy loss: a study among an endogamous group in north india. genet test mol biomarkers 2009; 13:861–5. 28. mcneil hp, simpson rj, chesterman cn, krilis sa. anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein i (apolipoprotein h). proc natl acad sci u s a 1990; 87:4120–4. conclusion in women with rpl associated with it, lmwh therapy has been shown to improve live birth rates when compared to lda or a placebo. however, lmwh for women with rpl which is not associated with aps it is not recommended. in women with rpl and aps, lmwh can be used as early as six weeks’ gestation until 34–36 weeks’ gestation. references 1. regan l, rai r . epidemiology and the medical causes of miscarriage. baillieres best pract res clin obstet gynaecol 2000; 14:839–54. 2. wilcox aj, weinberg cr, o’connor jf, baird dd, schlatterer jp, canfield re, et al. incidence of early loss of pregnancy. n engl j med 1988; 319:189–94. 3. saravelos sh, li tc. unexplained recurrent miscarriage: how can we explain it? hum reprod 2012; 27:1882–6. 4. hogge wa, byrnes al, lanasa mc, surti u. the clinical use of karyotyping spontaneous abortions. am j obstet gynecol 2003; 189:397–400. 5. sarig g, younis js, hoffman r, lamir n, blumenfeld z, brenner b. thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. fertil steril 2002; 77:342–7. 6. brenner b, sarig g, weiner z, younis j, blumenfeld z, lanir n. thrombophilic polymorphisms are common in women with fetal loss without apparent cause. thromb haemost 1999; 82:6–9. 7. visser j, ulander vm, helmerhorst fm, lampinen k, morin-papunen l, bloemenkamp kwm, et al. thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia habenox*: a randomized multicentre trial. thromb haemost 2011; 105:295–301. 8. colman-brochu s. deep vein thrombosis in pregnancy. mcn am j matern child nurs 2004; 29:186–92. 9. abbate r, lenti m, fatini c, gazzini a, lapini i, fedi s. l’ipercoagulabilità gravidica e puerperale. haematologica 2003; 88:1–2. 10. hathaway we, goodnight sh jr. thrombosis in pregnancy. in: hathaway we, goodnight sh jr, eds. disorders of hemostasis and thrombosis: a clinical guide, new york: mcgraw-hill professional, 1993. pp. 430–6. 11. de boer k, ten cate jw, sturk a, borm jj, treffers pe. enhanced thrombin generation in normal and hypertensive pregnancy. am j obstet gynecol 1989; 160:95–100. 12. smyth a, garovic vd. systemic lupus erythematosus and pregnancy. minerva urol nefrol 2009; 61:457–74. 13. kaprara a, krassas ge. thyroid autoimmunity and miscarriage. hormones (athens) 2008; 7:294–302. 14. castori m. diabetic embryopathy: a developmental perspective from fertilization to adulthood. mol syndromol 2013; 4:74–86. adel abu-heija review | e35 29. ruiz-irastorza g, khamashta ma. [systematic lupus erythematosus and antiphospholipid syndrome during pregnancy]. z rheumatol 2006; 65:192–4, 196–9. 30. hauser ac, hauser l, pabinger-fasching i, quehenberger p, derfler k, hörl wh. the course of anticardiolipin antibody levels under immunoadsorption therapy. am j kidney dis 2005; 46:446–54. 31. hossain n, shamsi t, soomro n. frequency of thrombophilia in patients with adverse pregnancy outcome. j pak med assoc 2005; 55:245–7. 32. molad y, borkowski t, monselise a, ben-haroush a, sulkes j, hod m, et al. maternal and fetal outcome of lupus pregnancy: a prospective study of 29 pregnancies. lupus 2005; 14:145–51. 33. levy ra, avvad e, oliveira j, porto lc. placental pathology in antiphospholipid syndrome. lupus 1998; 7:s81–5. 34. martínez-zamora má, cervera r, balasch j. recurrent miscarriage, antiphospholipid antibodies and the risk of thromboembolic disease. clin rev allergy immunol 2012; 43:265–74. 35. ganapathy r, whitley gs, cartwright je, dash pr, thilaganathan b. effect of heparin and fractionated heparin on trophoblast invasion. hum reprod 2007; 22:2523–7. 36. ozdemir o, yenicesu gi, silan f, köksal b, atik s, ozen f, et al. recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. genet test mol biomarkers 2012; 16:279–86. 37. ivanov p, komsa-penkova r, konova e, gecheva s, ivanov i, kovacheva k, et al. [combined thrombophilic factors among women with late recurrent spontaneous abortions]. akush ginekol (sofiia) 2011; 50:8–12. 38. hirsh j, anand ss, halperin jl, fuster v. mechanism of action and pharmacology of unfractionated heparin. arterioscler thromb vasc biol 2001; 21:1094–6. 39. di simone n, caliandro d, castellani r, ferrazzani s, de carolis s, caruso a. low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin g fractions obtained from patients with antiphospholipid syndrome. hum reprod 1999; 14:489–95. 40. erden o, imir a, guvenal t, muslehiddinoglu a, arici s, cetin m, et al. investigation of the effects of heparin and low molecular weight heparin on e-cadherin and laminin expression in rat pregnancy by immunohistochemistry. hum reprod 2006; 21:3014–8. 41. girardi g, redecha p, salmon je. heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. nat med 2004; 10:1222–6. 42. han cs, mulla mj, brosens jj, chamley lw, paidas mj, lockwood cj, et al. aspirin and heparin effect on basal and antiphospholipid antibody modulation of trophoblast function. obstet gynecol 2011; 118:1021–8. 43. empson m, lassere m, craig j, scott j. prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. cochrane database syst rev 2005; 2:cd002859. 44. mak a, cheung mw, cheak aa, ho rc. combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. rheumatol (oxford) 2010; 49:281–8. 45. cohn dm, goddijn m, middeldorp s, korevaar jc, dawood f, farquharson rg. recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. j thromb haemost 2010; 8:2208–13. 46. al abri s, vaclavinkova v, richens er. outcome of pregnancy in patients possessing anticardiolipin antibodies. j sci res med sci 2000; 2:91–5. 47. fouda um, sayed am, abdou am, ramadan di, fouda im, zaki mm. enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. int j gynaecol obstet 2011; 112:211–5. 48. said jm, higgins jr, moses ek, walker sp, borg aj, monagle pt, et al. inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. obstet gynecol 2010; 115:5–13. 49. silver rm, zhao y, spong cy, sibai b, wendel g jr, wenstrom k, et al. prothrombin gene g20210a mutation and obstetric complications. obstet gynecol 2010; 115:14– 20. 50. dizon-townson d, miller c, sibai b, spong cy, thom e, wendel g jr, et al. the relationship of the factor v leiden mutation and pregnancy outcomes for mother and fetus. obstet gynecol 2005; 106:517–24. 51. roqué h, paidas mj, funai ef, kuczynski e, lockwood cj. maternal thrombophilias are not associated with early pregnancy loss. thromb haemost 2004; 91:290–5. 52. preston fe, rosendaal fr, walker id, briët e, berntorp e, conard j, et al. increased fetal loss in women with heritable thrombophilia. lancet 1996; 348:913–6. 53. kocher o, cirovic c, malynn e, rowland cm, bare la, young ba, et al. obstetric complications in patients with hereditary thrombophilia identified using the lcx microparticle enzyme immunoassay: a controlled study of 5,000 patients. am j clin pathol 2007; 127:68–75. 54. sottilotta g, oriana v, latella c, luise f, piromalli a, ramirez f, et al. genetic prothrombotic risk factors in women with unexplained pregnancy loss. thromb res 2006; 117:681–4. 55. brenner b, hoffman r, carp h, dulitsky m, younis j, liveenox investigators. efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the live-enox study. j thromb haemost 2005; 3:227–9. 56. deligiannidis a, parapanissiou e, mavridis p, tabakoudis g, mavroudi a, papastavrou t, et al. thrombophilia and antithrombotic therapy in women with recurrent spontaneous abortions. j reprod med 2007; 52:499–502. 57. carp h, dolitzky m, inbal a. thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. j thromb haemost 2003; 1:433–8. 58. badawy am, khiary m, sherif ls, hassan m, ragab a, abdelall i. low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. j obstet gynaecol 2008; 28:280–4. 59. fawzy m, shokeir t, el-tatongy m, warda o, el-refaiey aa, mosbah a. treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. arch gynecol obstet 2008; 278:33–8. thrombophilia and recurrent pregnancy loss is heparin still the drug of choice? e36 | squ medical journal, february 2014, volume 14, issue 1 62. laskin ca, spitzer ka, clark ca, crowther mr, ginsberg js, hawker ga, et al. low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled hepasa trial. j rheumatol 2009; 36:279–87. 60. clark p, walker id, langhorne p, crichton l, thomson a, greaves m, et al. spin (scottish pregnancy intervention) study: a multicenter, randomized controlled trial of lowmolecular-weight heparin and low dose aspirin in women with recurrent miscarriage. blood 2010; 115:4162–7. 61. kaandorp sp, goddijn m, van der post ja, hutten ba, verhoeve hr, hamulyák k, et al. aspirin plus heparin or aspirin alone in women with recurrent miscarriage. n engl j med 2010; 362:1586–96. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e585−586, epub. 14th oct 14 submitted 3rd jan 14 revisions req. 9th feb & 2nd mar 14; revisions recd. 16th feb & 26th mar 14 accepted 2nd apr 14 departments of 1child health and 2clinical physiology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: koul@squ.edu.om ارختاء املعصمني يف طفل لديه ضمور العضالت الشوكي من النوع األول رو�سان كول، رنا عبد الرحيم، �سوزان النبهاين، اآمنة الفطي�سي bilateral wrist drop at presentation in a child with spinal muscular atrophy type i *roshan koul,1 rana abdelrahim,1 susan al-nabhani,2 amna al-futaisi1 interesting medical image spinal muscular atrophy (sma) is a hereditary degenerative disease affecting the anterior horn cells of the spinal cord and cranial motor nerve nuclei, particularly the hypoglossal nerve, leading to progressive paralysis.1 based on clinical features, the disease is classified into three types: type i, type ii and type iii.2 data suggest that 98% of children with sma have survival of motor neuron (smn) gene deletion.3 the diagnosis of sma is based on clinical features, electromyography, muscle histopathology and genetic studies. with the advent of genetic tests, muscle biopsies are now rarely performed. sma type i is not an uncommon disorder, with six to eight cases diagnosed every year at the sultan qaboos university hospital in muscat, oman.4 children with sma type i do not usually survive beyond two years of age.5 cases of wrist drop (hand drop) are uncommon among paediatric patients. a case of sma type i in an infant, with bilateral wrist drop at presentation, is described below. a five-week-old male infant presented to sultan qaboos university hospital in april 2013 with decreased movements of the upper and lower limbs. the child had been born with no complications to consanguineous parents. throughout her pregnancy, the mother had felt normal fetal movements. when the infant was just over one month old, the mother noted that his right hand was weak, with wrist drop. after a week, wrist drop was noted in his left hand and wrist as well. over the following two weeks the infant’s lower limbs also became weak. the infant’s two older siblings were normal and the mother denied any history of trauma or pressure on the infant’s arms. on examination, the child was alert with normal cranial nerves, other than tongue fasciculations. he had weak respiratory muscles, generalised hypotonia figure 1: photograph of a five-week-old male infant with spinal muscular atrophy type i, presenting with bilateral wrist drop (left wrist). bilateral wrist drop at presentation in a child with spinal muscular atrophy type i 586 | squ medical journal, november 2014, volume 14, issue 4 and areflexia. the lower limbs were weaker (grade 1 of 5) than the upper limbs (grades 2–3 of 5), with the proximal limbs weaker than the distal. the patient showed obvious bilateral wrist drop [figure 1]. electromyography (emg) revealed pure axonal motor neuropathy in the upper and lower limbs, with neurogenic emg confirming the clinical suspicion of sma. a radial nerve conduction test revealed bilateral motor axonopathy with preserved sensory action potentials and velocity, which is a feature suggestive of a lesion in the anterior horn cells and excludes radial neuropathy. the sensory nerve action potential and the conductions in the other nerves were normal. although the diagnosis was clear from electrophysiology and the patient’s clinical features, blood test results confirmed that the smn1 exons 7 and 8 were deleted on both alleles of the gene. comment wrist drop or hand drop is uncommon in childhood. the first case of unilateral wrist drop was reported in an eight-year-old boy in 1926.1,6,7 lesions of the anterior horn cells in the spinal cord, motor nerve roots, brachial plexus or the radial nerve can produce a unilateral wrist drop.2,8 in rare cases, nevo syndrome and cortical lesions can also result in wrist drop.9 bilateral wrist drop has been reported in cases of paediatric lead poisoning and infantile chronic immunemediated demyelinating polyneuropathy.10,11 guillainbarré syndrome and human immunodeficiency virus can also produce neuropathy and wrist drop.8 bilateral transient wrist drop was reported in a one-month-old baby after adhesive bandages were applied to both forearms in order to stabilise intravenous cannulas.12 sma and poliomyelitis are other conditions which can result in wrist drop.11 the presentation of wrist drop in children with sma type i is very rare. however, in view of the current case, sma type i should be considered as a potential cause of wrist drop in infancy. references 1. dubowitz v, ed. muscle disorders in childhood. 2nd ed. london, uk: bailliere tindall, 1995. 2. munsat tl, davies ke. international sma consortium meeting (26‒28 june 1992, bonn, germany). neuromuscular disord 1992; 2:423–8. doi: 10.1016/s0960-8966(06)80015-5. 3. lefebvre s, bürglen l, reboullet s, clermont o, burlet p, viollet l, et al. identification and characterization of a spinal muscular atrophy-determining gene. cell 1995; 80:155–65. doi: 10.1016/0092-8674(95)90460-3. 4. koul r, al futaisi a, chacko a, rao v, simsek m, muralitharan s, et al. clinical and genetic study of spinal muscular atrophies in oman. j child neurol 2007; 22:1227–30. doi: 10.1177/0883073807306268. 5. cobben jm, lemmink hh, snoeck i, barth pa, van der lee jh, de visser m. survival in sma type i: a prospective analysis of 34 consecutive cases. neuromuscular disord 2008; 7:541–4. doi: 10.1016/j.nmd.2008.05.008. 6. rao r, balachandran c. multiple grade ii deformities in a child: tragic effect of leprosy. j trop pediatr 2010; 56:363–5. doi: 10.1093/tropej/fmp138. 7. sutherland ga. case of wrist drop in a child. proc r soc med 1926; 19:48–9. 8. duman o, uysal h, skjei kl, kizilay f, karauzum s, haspolat s. sensorimotor polyneuropathy in patients with sma type-1: electroneuromyographic findings. muscle nerve 2013; 48:117– 21. doi:10.1002/mus/23722. 9 al-gazali li, bakalinova d, varady e, scorer j, nork m. further delineation of nevo syndrome. j med genet 1997; 34:366–70. doi: 10.1136/jmg.34.5.366. 10. imbus ce, warner j, smith e, pegelow ch, allen jp, powars dr. peripheral neuropathy in lead-intoxicated sickle cell patients. muscle nerve 1978; 1:168–71. doi: 10.1002/mus.880010211. 11. majumdar a, hartley l, manzur ay, king rh, orrell rw, muntoni f. a case of severe congenital chronic inflammatory demyelinating polyneuropathy with complete spontaneous remission. neuromuscular disord 2004; 14:818–21. doi: 10.1016/j.nmd.2004.09.003. 12. shime n, kato y, tanaka y, kim wc. bilateral transient radial nerve palsies in an infant after cardiac surgery. can j anaesth 2001; 48:200–3. doi: 10.1007/bf03019736 taurine levels in human aqueous humour medical sciences (2000), 2, 49−53 © 2000 sultan qaboos university department of surgery, college of medicine, sultan qaboos university, p.o.box: 35, postal code: 123, muscat, sultanate of oman *to whom correspondence should be addressed. 49 laparoscopic surgery at sultan qaboos university hospital * grant c s, al-kindy n, machado n, daar a s جراحة المناظير بمستشفى جامعة السلطان قابوس داعر. مشادو ، ع. الكندي ، ن. جرانت ، ن. ك وذلك بعد االطالع . م1992م قد أصبحت حقيقة واقعة بمستشفى جامعة السلطان قابوس في عام 1980 أواخر عام إن الشهرة التي اآتسبتها عملية الجراحة بالمنظار في :الملخص تتضمن ورقة العمل هذه . عدوا تلك الدراسات أعلى الدراسات والبحوث العلمية التي أعدت في شأن العمليات الجراحية باستخدام المنـظار وآذلك االطالع على خبرات الذين المختلفة في مجال الجراحة بالمنظار والمستخدمة حاليا بالمستشفى الجامعي ومن بينها استئصال المرارة، إستئصال الزائدة الدودية، تشخيص بعض األمراض، وآذلك اتالتقني بالمستشفى الجامعي المتمثل في توفير المختبر الالزم الورقة بيان الدور الذي يقوم به مرآز تدريب جراحة المناظير تظهر باإلضافة إلى آل ما تقدم . عالج دوالي الخصيتين في الخالصة تتضمن الورقة أن العمليات الجراحية باستخدام المنظار بالمستشفى الجامعي سوف تستمر في التطور والتقدم وذلك . للمتدربين في مجال الجراحة والممارسين لها . المتقدمةالتقنياتمن خالل إجراء العمليات الجراحية الجديدة واستخدام abstract: laparoscopic surgery, which gained prominence in the late 1980s, became an established surgical practice in sultan qaboos university hospital (squh) in 1992. drawing on available literature and the authors’ own experiences, this paper gives an overview of various laparoscopic surgical techniques currently available at squh, including laparoscopic cholecystectomy, laparoscopic appendicectomy, diagnostic laparoscopy and laparoscopic varicocoelectomy. it also highlights the role of surgical endoscopic training centre at squh, which provides a laboratory setting for surgical trainees and practising physicians. laparoscopic surgery at squh would continue to evolve spurred on by surgical innovations and advances in technology. key words: laparoscopic surgery, oman he era of laparoscopic general surgery arguably began in 1987 when the first laparoscopic cholecystectomy was performed in lyon.1 this landmark surgery remained largely unnoticed until the technique was popularised a couple of years later in north america and in europe.1-4 the perceived advantages of the technique caused it to be rapidly adopted into surgical practice worldwide without being evaluated by formal randomised studies, unlike any other innovation in modern surgical history.4 by early 1990s it had become the operation of choice for symptomatic gallstones.5 the phenomenal technical success of laparoscopic cholecystectomy, made possible by the rapid advances in videotechnology and operative instrumentation, spurred surgeons to develop and expand the application of laparoscopy to other intra abdominal operations, thus establishing laparoscopic surgery as a dynamic and expanding specialty with a new name: minimally invasive surgery. at sultan qaboos university hospital (squh), we embraced the promises of laparoscopic surgery in 1991 and carefully planned its introduction into surgical practice. our first laparoscopic cholecystectomy, successfully performed on april 25, 1992, marked the beginning of laparoscopic general surgery at squh and indeed, in oman. we have since then gone through the learning curve like most other institutions in the world. now laparoscopic surgery is firmly established at squh, with a fair number of operations other than cholecystectomy being done using laparoscopic techniques. this paper aims to give an overview of laparoscopic general surgical operations done at squh and indicate the technique’s benefits, problems and future trends. laparoscopic cholecystectomy laparoscopic cholecystectomy is now the single most common general surgical operation being performed at squh. it is offered as an elective procedure mainly for patients with symptomatic gallstones proven usually by ultrasonography. a few patients with gallstones are not eligible for the procedure. for example, unfitness for general anaesthesia, uncorrectable coagulopathy and concurrent diseases requiring t g r a n t e t a l at squh since 1992, with minimal morbidity and no mortality. the diagnosis and management of common bile duct (cbd) stones is controversial.5 we generally attempt to diagnose and treat cbd stones before surgery. all patients with gallstones with any one of the following—a history of jaundice or pancreatitis, abnormal liver function tests or raised amylase level, dilatation of the biliary tree on ultrasonography—first undergo endoscopic retrograde cholangio pancreatography (ercp) and if indicated, papillotomy followed by laparoscopic cholecystectomy two or three days later. we use operative cholangiography selectively, based largely on the pre-surgery investigations and operative findings. the advantages of laparoscopic cholecystectomy over open cholecystectomy have been well documented: tiny incisions, less post-operative pain, rapid recovery and early return to normal activity.5,6 the overall savings on healthcare costs have also been well-reported.7 most of our patients, barring social problems, are discharged by 48 hours after surgery and resume normal activity by 2 weeks. however, compared to open surgery, there is a slightly increased risk of damage to the cbd. injury to the cbd has been reported in 0–2% of laparoscopic cholecystectomies compared with 0–0.6% for open cases.6-8 the rate of cbd injury for our series of 900 cases was 0.6%, most of which occurred during our early learning phase, reflecting the generally reported trend. with increasing experience and improvements in techniques, these dis figure 1. laparoscopic cholecystectomy being performed at squh figure 2. gall bladder being removed through a tiny epigastric incision 50 laparotomy are considered absolute contraindications. acute cholecystitis and dense adhesions from a previous surgery increase the chances of conversion from laparoscopic to open procedure. the technique of laparoscopic cholecystectomy involves first creating a pneumoperitoneum with carbon dioxide and passing a set of long, thin instruments (the first one being an endoscope) through four tiny separate incisions in the abdominal wall, each of 1 cm or less in length. the gallbladder is then dissected out under endoscopic video-monitored vision, and then removed through one of the incisions. over 900 laparoscopic cholecystectomies have been performed advantages can be reduced to the barest minimum,5,6 and we have achieved this. thus, our safety level with laparoscopic cholecystectomy is comparable to some of the best units in the world, and is still improving. laparoscopic appendicectomy although laparoscopic appendicectomy was described as early as 1983,8 general surgeons were not enthusiastic, partly because of the cumbersome and inadequate instrumentation and optics of the time and partly because there was no perceived advantage over open appendicectomy. however, the recent advances in video-laparoscopy and enthusiasm generated by l a p a r o s c o p i c s u r g e r y i n s q u h 51 laparoscopic cholecystectomy have resulted in resurgence in laparoscopic appendicectomy. we introduced laparoscopic appendicectomy into surgical practice at squh at about the same time as laparoscopic cholecystectomy. unlike the latter, most of the laparoscopic appendicectomies at squh were emergencies. furthermore, due to shortage of supporting staff at night, the procedure has largely been restricted to cases of acute appendicitis presenting during working hours or during daytime at weekends. in spite of this, over 200 laparoscopic appendicectomies have been performed at squh since 1992, with minimal morbidity. two recent reports of prospective randomised trials comparing laparoscopic appendicectomy with open appendicectomy suggest that the laparoscopic approach results in less pain, a shorter post-operative hospital stay and fewer wound complications.9,10 preliminary analysis of our series, however, suggests that these perceived advantages of laparoscopic over open appendicectomy might be less than the advantages of laparoscopic cholecystectomy. at least in our hands, there is usually minimal post-operative pain and disability after open appendicectomy for uncomplicated appendicitis. laparoscopic appendicectomy is also viewed as not being cost-effective, mainly because of the cost of the disposable instruments used. we have minimised the cost by using re-usable instruments for this procedure. nonetheless, we believe the laparoscopic approach offers a great advantage over open appendicectomy in obese patients, as the latter method often requires extensive incisions to achieve a safe appendicectomy. the technique is also particularly useful in female patients in whom the diagnosis of acute appendicitis is more often unclear. even if the appendix is found normal, the laparoscopic method affords the surgeon a better view of the rest of the viscera. it is also likely that the laparoscopic approach causes fewer adhesions than the open procedure.11 diagnostic laparoscopy this well-established investigative procedure pioneered by gynaecologists is also being widely adopted by general surgeons. the indications for diagnostic laparoscopy in surgical practice are expanding; the main ones currently are evaluation of abdominal pain, staging of abdominal malignancies and evaluation of abdominal trauma. we frequently use the procedure to evaluate patients with undiagnosed acute and chronic abdominal pain, when clinical examination and standard tests have not yielded a diagnosis. the diagnostic accuracy of laparoscopy in the evaluation of acute abdominal pain has been reported to be 80– 90%,12 and this is approximately what we have also observed. our experience with laparoscopic staging of abdominal malignant tumours is limited by the numbers and the pattern of referrals. laparoscopy has proved useful in the diagnosis and staging of abdominal tumours through direct visual assessment and accurate biopsies of lesions. unlike imaging techniques such as ultrasound, computed tomography or magnetic resonance imaging, laparoscopy can detect peritoneal metastases and lesions smaller than 1 cm in diameter on the surface of the liver.13 we have very little experience with diagnostic laparoscopy for abdominal trauma. the results of a recently reported prospective series suggest that the procedure is superior to peritoneal lavage since it can potentially reduce the number of unnecessary open laparotomies and therefore would be increasingly used in the evaluation of abdominal trauma.14 laparoscopic varicocoelectomy by 1995, laparoscopic treatment of varicocoeles was included in the laparoscopic procedures offered at squh. the advantages claimed for this approach, as compared with the open technique, include the certainty of vein ligation and the benefits of minimal access. the laparoscopic procedure also appears to offer a particular advantage in patients with bilateral disease or recurrence following open varicocoelectomy. so far about 54 patients with symptomatic varicocoeles have been treated laparoscopically at squh with very encouraging results. laparoscopic inguinal herniorrhaphy open repair of inguinal hernia is one of the most commonly performed operations worldwide. it is often associated with significant post-operative pain and a delayed return to normal activities. the open repair has a recurrence rate of 5 to 10% in nonspecialized centres.15 it was initially believed that laparoscopic repair of inguinal hernia had the potential to duplicate the superior results achieved by laparoscopic cholecystectomy. several techniques of laparoscopic hernia repair have been developed, but some were quickly recognised to be associated with high rates of recurrence and were abandoned.16 in 1993, when we first performed laparoscopic inguinal herniorrhaphy, we used the trans-abdominal pre-peritoneal approach and a stapled patch of prosthetic (polypropylene) mesh over the inguinal floor. though the early trial results in 17 cases were encouraging, 3 patients developed significant post-operative g r a n t e t a l 52 thigh pain, which led us to suspend the laparoscopic technique. this complication, very likely due to nerve entrapment by the staples used to hold the mesh, is well recognised now and as a result many centres have abandoned the procedure.17 we still regard the laparoscopic technique to be experimental and risky compared to the conventional open technique and, so far, as not being cost-effective. nevertheless, newer techniques are evolving to overcome some of these acknowledged disadvantages. we are keenly awaiting the results of randomised prospective multicentre trials in the us and europe comparing open hernia repair with laparoscopic minimal access hernia repair. miscellaneous procedures we have performed various other laparoscopic procedures but rather infrequently, either electively or as emergencies. these include highly selective vagotomy for chronic duodenal ulcer, closure of perforated duodenal ulcers, lysis of intestinal adhesions, deroofing of solitary hepatic cyst, and fashioning of colostomy. laparoscopic fundoplication (nissen’s procedure) was performed on 3 patients with severe reflux oesophagitis. it is noteworthy that while surgery for gastro-oesophageal reflux disease (gord) is fairly common in north america and europe, it is rare in oman and in the gulf. one explanation for this is that physicians in the gulf may have a very high threshold for referring patients with gord for surgery. it is also possible that significant gord is less prevalent in the gulf, but this has to be verified by a survey. video-assisted thoracoscopic surgery is also rapidly evolving worldwide in the wake of the success of laparoscopic surgery as it is also perceived to have similar advantages, namely, minimal access, less postoperative pain, rapid recovery and early return to normal activity. our thoracoscopic surgical practice is at present quite limited but procedures accomplished at squh include fashioning a pericardial window, resection of apical bullae in recurrent spontaneous pneumothorax and lung biopsies. training and development training is vital for endoscopic surgery. we have trained four senior registrars, four registrars and several senior house officers since our programme started. currently, all registrars in the department competently perform laparoscopic cholecystectomy, appendicectomy and diagnostic procedures. general surgical residency programmes now require all trainees to be proficient in the basic laparoscopic techniques. to meet these demands, a surgical endoscopic training centre (setc) was set-up at squ in december 1996. when the centre is fully fledged, surgical residents would be able to sharpen their laparoscopic skills by practising on models and animals in laboratory setting. regular courses are envisaged in basic and advanced laparoscopic techniques, with the assistance of invited experts, for the benefit of practising surgeons in the region. two courses have been run so far. the setc, which we set up together with colleagues from the ministry of health, would also provide a setting for innovative endoscopic surgeons to test new techniques or do experimental work. in conclusion, laparoscopic surgery is now well established at squh and will continue to evolve, fuelled by surgical innovation and improvements in instrumentation and video-technology. however, the issue of cost will continue to be a limiting factor. references 1. dubois f, icard p, berthelot g, levard h. celioscopic cholecystectomy: preliminary report of 36 cases. ann surg 1990, 211, 60–2. 2. reddick ej, olsen do. laparoscopic laser cholecystectomy. surg endosc. 1989, 3, 131. 3. perissat j, collect d, belliard r. gallstones: laparoscopic treatment; cholecystectomy; cholecystoscopy and lithotripsy. surg endosc 1990, 4, 1–5. 4. cuschieri a, dubois f, mouiel j, mouret p, becker h, buess g, trede m, troidl h. the european experience with laparoscopic cholecystectomy. am j surg 1991, 161, 385–7. 5. nih consensus conference. gallstones and laparoscopic cholecysectomy. jama 1993, 269, 1018–24. 6. wilson rg, macintyre imc. impact of laparoscopic cholecystectomy in the uk: a survey of consultants. br j surg 1993, 80, 346. 7. bass eb, pitt ha, lillemoe kd. cost-effectiveness of laparoscopic cholecystectomy versus open cholecystectomy. am j surg 1993, 165, 466–71. 8. semm k. endoscopic appendectomy. endoscopy 1983, 15, 59–64. 9. mcanena oj, austin o, o’connel pr et al. laparoscopic versus open appendicectomy: a prospective evaluation. br j surg 1992, 79, 818–20. 10. attwood sea, hill adk, murphy pg, thornton j, stephens rb. a prospective randomised trial of laparoscopic versus open appendicectomy. surgery 1992, 112, 497–501. 11. de wilde ri. goodbye to late bowel obstruction after appendicectomy. lancet 1991, 338, 1012. 12. reiertsen o, rosseland ar, hoivik b, solheim k. laparoscopy in patients admitted for acute abdominal pain. acta chir scand 1985, 151, 521–4. 13. spinelli p, di felice g. laparoscopy and abdominal malignancies. probl gen surg 1991, 8, 329–47. 14. cuschieri a, hennessy tpj, stephens rb, berci g. diagnosis of significant abdominal trauma after road traffic accidents: preliminary results of a multicentre l a p a r o s c o p i c s u r g e r y i n s q u h 53 clinical trial comparing mini-laparoscopy with peritoneal lavage. ann r coll engl 1988, 70, 153–5. 15. condon re, nyhus lm. complications of groin hernia. in: nyhus lm, condon re: eds. hernia (jb lippincott, philadelphia) 1989, 253–69. 16. macfayden bv jr, arregui me, corbitt jd et al. complications of laparoscopic herniorrhaphy. surg endosc 1993, 7, 155–8. 17. warshaw al. reflections on laparoscopic surgery. surgery 1993, 114, 629–30. laparoscopic surgery at �sultan qaboos university hospital ????? ???????? ??????? ????? ??????? ????? ?. ????? ? ?. ?????? ? ?. ????? ? ?. ???? laparoscopic cholecystectomy laparoscopic appendicectomy diagnostic laparoscopy laparoscopic varicocoelectomy laparoscopic inguinal herniorrhaphy miscellaneous procedures training and development references clinical and basic research | 69 clinical & basic research sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 69‒79, epub. 27th feb 13 submitted 16th may 12 revision req. 7th aug 12, revision recd. 6th sep 12 accepted 6th oct 12 1diagnostic genetics, labplus, auckland city hospital, auckland, new zealand; 2roche diagnostics new zealand ltd., auckland, new zealand; 3school of biological sciences, university of auckland, auckland, new zealand *corresponding author e-mail: donaldl@adhb.govt.nz استعراف مبين على منظومة تغيريات ارقام النسخ لضبط التشخيص حتليل كامل للجينوم باستخدام طريقيت الرتكيز اجليين والتميز املنخفض يف آن واحد رينات مرق�ض نيكل�صون، ايلني دوروتي، جنيفر م لوف، �صون �صينج لن، الي�ض م جورج، دونالد ر لوف، انتوين ثرا�ض بطريقتي اجلينوم كامل بتحليل ت�صمح مقارن جيني تهجني منظومة �صحة من والتحقق تطوير اإىل الدرا�صة هدفت الهدف: امللخ�ص: 12x135 الأ�صتهداف لعدد من جينات املر�ض والتميز املنخف�ض يف اآن واحد. طرق الدرا�صة: مت ت�صميم منظومة بي�صبوك رو�ض نيمبلجني ك للتهجني اجليني املقارن )�رسكة رو�ض نيمبلجني، مادي�صون، وينكون�صينو الوليات املتحدة الأمريكية( لتمحي�ض املناطق ال�صفرية يف 66 جني مع ا�صتخدام م�صبارات اإ�صافية مت�صعة القاعدة من اأجل التغطية الكلية لكامل اجلينوم. مت حتليل احلام�ض النووي ثنائي الريبوز )د ن ا( من ع�رسين مري�صًا ذوي تغريات اأرقام ن�صخ �صابقة التعريف و ثمانية مر�صى مل يتم حتديد اجلرعة اجلينية لهم من قبل. النتائج: بنجاح اي�صا مت كما الع�رسين. املر�صى كل يف الن�صخ ارقام تغريات حتدد اأن مقارن جيني تهجني نيمبلجني رو�ض منظومة ا�صتطاعت الت�صخي�ض اجلزيئي لأحد املر�صى الأربعة الذين مل يتم تاأكيد ت�صخي�صهم ال�رسيري بوا�صطة حتليل املتوالية من قبل. مت اأي�صا بنجاح حتديد حمل �صفة تغريات اأرقام الن�صخ للمر�صى الأربعة الباقني. اخلال�صة: منظومة رو�ض نيمبلجني تهجني جيني مقارن املو�صوفة يف هذا البحث هي طريقة دقيقة، �صامدة، وعالية املردود و مثالية لال�صتخدام يف املختربات الت�صخي�صية ال�صغرية. من املمكن ا�صتخدام هذة الطريقة كبديل للطرق الأخرى ال�صائعة ال�صتخدام مثل طريقة الربط املتعدد املعتمد علي ت�صخيم امل�صبار. مفتاح الكلمات: منظومة تهجني جيني مقارن، جرعة جينية، متغريات اأرقام الن�صخ، ميكروارراي ال د ن ا، الت�صخي�ض اجلزيئي. abstract: objectives: the aim of this study was to develop and validate a comparative genomic hybridisation (cgh) array that would allow simultaneous targeted analysis of a panel of disease genes and low resolution whole genome analysis. methods: a bespoke roche nimblegen 12x135k cgh array (roche nimblegen inc., madison, wisconsin, usa) was designed to interrogate the coding regions of 66 genes of interest, with additional widelyspaced backbone probes providing coverage across the whole genome. we analysed genomic deoxyribonucleic acid (dna) from 20 patients with a range of previously characterised copy number changes and from 8 patients who had not previously undergone any form of dosage analysis. results: the custom-designed roche nimblegen cgh array was able to detect known copy number changes in all 20 patients. a molecular diagnosis was also made for one of the additional 4 patients with a clinical diagnosis that had not been confirmed by sequence analysis, and carrier testing for familial copy number variants was successfully completed for the remaining four patients. conclusion: the custom-designed cgh array described here is ideally suited for use in a small diagnostic laboratory. the method is robust, accurate, and cost-effective, and offers an ideal alternative to more conventional targeted assays such as multiplex ligation-dependent probe amplification. keywords: array comparative genomic hybridization (acgh); gene dosage; copy number variants (cnvs); dna microarray; molecular diagnosis. array-based identification of copy number changes in a diagnostic setting simultaneous gene-focused and low resolution whole human genome analysis renate marquis-nicholson,1 elaine doherty,1 jennifer m. love,1 chuan-ching lan,1 alice m. george,1 anthony thrush2, *donald r. love,1,3 advances in knowledge customised comparative genomic hybridisation (cgh) arrays, such as the one described here, allow robust high density gene-targeted as well as low density whole genome analysis to be undertaken simultaneously in the diagnostic setting. our data has shown that complicated gene rearrangements may underlie disease and that these rearrangements may be missed by more conventional diagnostic techniques. array-based identification of copy number changes in a diagnostic setting simultaneous gene-focused and low resolution whole human genome analysis 70 | squ medical journal, february 2013, volume 13, issue 1 the importance of gene deletion and duplication in the pathogenesis of disease has become increasingly evident over the last decade. these deletions/duplications range from intragenic changes that are too large to be detected by sequence analysis, to larger genomic rearrangements responsible for the microdeletion and microduplication syndromes, and finally to whole chromosome loss or gain as seen in the aneuploidies. in the discipline of cytogenetics, molecular karyotyping using high-density oligonucleotide arrays has recently become the recommended firstline diagnostic test for patients with developmental delay/intellectual disability, autistic spectrum disorder, or multiple congenital anomalies, replacing more conventional techniques such as g-banded karyotyping.1,2 large deletions and duplications have long been recognised as playing an important part in the pathogenesis of several disorders traditionally diagnosed using molecular techniques, such as duchenne muscular dystrophy and charcotmarie-tooth disease type 1a.3,4 in addition to these classical deletion/duplication disorders, the role of partial or whole gene deletions in the aetiology of a wide variety of single-gene disorders is becoming more apparent. a 2008 review of the entries in the online human gene mutation database showed that large deletions and duplications comprise 10% of the listed mutations, compared to 6% in 2003.5,6 this number is likely to increase further as more individuals are subjected to dosage analysis as part of routine molecular diagnostics. a variety of dosage analysis methods are available to the diagnostic laboratory, including multiplex ligation-dependent probe amplification (mlpa), quantitative real-time polymerase chain reaction (qpcr), and customised fluorescence in situ hybridisation (fish).7–9 each of these methods, however, is relatively expensive, principally as a result of the price of the probes, and in the case of mlpa and qpcr, is usually confined to a limited number of exons across a limited number of genes.10,11 finally, in the case of a small diagnostic laboratory, low sample throughput decreases costeffectiveness, together with the attendant issue of maintaining staff proficiency in a range of dosage techniques. in order to address the above difficulties, we designed a bespoke nimblegen 12x135k comparative genomic hybridisation (cgh) array (roche nimblegen inc., madison, wisconsin, usa). this array targets a panel of genes chosen to complement the sequencing assays offered in-house, as well as a number of other genes for which deletions and duplications are known to be implicated in a disease phenotype. in addition to this gene-focused coverage, the design of the array also involved low-density coverage of the entire human genome. here, we report the use of this custom-designed array to analyse a series of 28 clinical samples in order to investigate the suitability of this approach for dosage analysis in the diagnostic environment. methods a group of 20 individuals with a range of previously characterised copy number changes were selected for array comparative genomic hybridisation (acgh) analysis. the patients, or parents in the case of neonates, provided informed consent for diagnostic testing; the new zealand multiregion ethics committee has ruled that cases of patient management do not require formal ethics committee approval. the copy number changes included both cytogenetic and molecular abnormalities, and spanned a spectrum from aneuploidy to intragenic deletion with three cases of aneuploidy, two of unbalanced translocations, three microdeletions, two microduplications, seven intragenic deletions, and three intragenic duplications. these changes had been identified using a range of techniques, including conventional and molecular karyotyping, fish and mlpa [table 1]. acgh was also completed for an additional 8 individuals without known copy number changes for whom dosage analysis was desirable either for applications to patient care the targeted cgh array with backbone format allows for diagnostic flexibility in a clinical laboratory setting. the added advantage of the approach described here is that it removes the need to batch the mutation screening of patients based on their clinical phenotype. renate marquis-nicholson, elaine doherty, jennifer m. love, chuan-ching lan, alice m. george, donald r. love, anthony thrush clinical and basic research | 71 diagnostic purposes or for completion of family studies. peripheral blood ethylenediaminetetraacetic acid (edta) samples from each of these 28 individuals were submitted to the diagnostic genetics department at labplus, auckland city hospital, new zealand, for either molecular or cytogenetic analysis, as clinically indicated. genomic diribonucleic acid (gdna) was extracted from peripheral blood leucocytes using the gentra puregene dna extraction kit (qiagen, germantown, maryland, usa). in those samples referred for conventional karyotype or fish analysis, classical phenol/chloroform extraction with ethanol precipitation was used to isolate dna from cultured leucocytes, in order to provide a source of gdna for molecular testing. a primer design protocol was used to design primers flanking the region spanning exons 11–14 of the kcnh2 gene.12,13 in brief, the messenger rna (mrna) sequence of interest was identified using the university of california santa cruz (ucsc) genome browser.14 all primers were checked for single nucleotide polymorphisms using the software tool available from the national genetic reference laboratory, manchester, uk.15 the primers were tailed with m13 sequences and were synthesised by invitrogen ltd., renfrewshire, uk (primer sequences are available on request). table 1: copy number changes used to validate the roche nimblegen custom-designed comparative genomic hybridisation array patient disorder/copy number variants description previous testing method 1 klinefelter syndrome xxy karyotype 2 down’s syndrome trisomy 21 karyotype 3 edward's syndrome trisomy 18 karyotype 4 unbalanced translocation t (7;22) 46,xx,der(7)t(7;22)(q36.3;q13.1) mat.ish der(7)t(7;22)(q36.3;q13.1) (arsa+) karyotype, fish 5 unbalanced translocation t (3;4) 46,xx,der(4)t(3;4)(q23;q35.1)pat karyotype 6 microdeletion chr2 del chr2:102176600-119933523 illumina humancytosnp 300k microarray 7 autistic spectrum disorder del chr2: 44305631-44425668; dup chr15: 36188779-36655207; del chr16: 29522477-30107306 affymetrix snp 6.0 microarray 8 prader-willi syndrome deletion of snrpn gene southern blot, fish 9 williams-beuren duplication syndrome dup chr7: 71914639-73718403 affymetrix snp 6.0 microarray 10 rett syndrome duplication mecp2 gene mlpa 11 lqts del exons 6, 7,10,11,15 kcnh2 gene mlpa 12 lqts dup exons 10,11, 15 kcnh2 gene mlpa 13 familial adenomatous polyposis del exons 11-12 apc gene mlpa 14 dmd del exon 45-52 dmd gene mlpa and multiplex pcr 15 dmd, carrier dup exon 63 (heterozygous) dmd gene mlpa 16 familial breast cancer del exon 1, 2 brca1 gene mlpa 17 dmd del ex3-44 dmd gene mlpa 18 hnpcc del exon 6 mlh1 gene mlpa 19 familial breast cancer dup exon13 brca1 gene mlpa 20 familial breast cancer del exons 1,2 brca2 gene mlpa fish = fluorescence in situ hybridization; del chr = deleted chromosome; dup chr = duplicated chromosome; snp = single nucleotide polymorphisms; lqts = long qt syndrome; mlpa = multiplex ligation-dependent probe amplification; dmd = duchenne muscular dystrophy; pcr = polymerase chain reaction; hnpcc = hereditary non-polyposis colorectal cancer. array-based identification of copy number changes in a diagnostic setting simultaneous gene-focused and low resolution whole human genome analysis 72 | squ medical journal, february 2013, volume 13, issue 1 table 2: human disease genes selected for inclusion on the roche nimblegen custom-designed comparative genomic hybridisation array disorder gene accession number (transcript) accession number (protein) uniprot number omim lqt kcnq1 nm_000218.2 np_000209 p51787 607542 kcnh2 nm_000238.2 np_000229 q12809 152427 scn5a nm_198056.2 np_932173 q14524 600163 gpd1l nm_015141.2 np_055956 q8n335 611778 scn1b nm_001037.4 np_001028 q07699 611778 nm_199037.3 np_950238 q6tn97 600235 scn3b nm_018400.3 np_060870 q9ny72 608214 cacnb2 nm_201596.2 np_963890 q08289 600003 kcne3 nm_005472.4 np_005463 q9y6h6 604433 ank2 nm_001148.3 np_001139 q01484 106410 kcne1 nm_000219.3 np_000210 p15382 176261 kcne2 nm_172201.1 np_751951 q9y6j6 603796 kcnj2 nm_000891.2 np_000882 p63252 600681 cacna1c nm_001129827.1 np_001123299 q13936 114205 cav3 nm_033337.1 np_203123 p56539 601253 scn4b nm_174934.3 np_777594 q8iwt1 608256 akap9 nm_005751.4 np_005742 q8iwt1 604001 hcm myh7 nm_000257.2 np_000248 p12883 160760 mybpc3 nm_000256.3 np_000247 q14896 600958 tnnt2 nm_000364.2 np_000355 p45379 191045 tnni3 nm_000363.4 np_000354 p19429 191044 tpm1 nm_001018020.1 np_001018020 o15513 191010 actc1 nm_005159.4 np_005150 p68032 102540 myl2 nm_000432.3 np_000423 p10916 160781 myl3 nm_000258.2 np_000249 p08590 160790 lamp2 nm_001122606.1 np_001116078 q6q3g8 309060 prkag2 nm_016203.3 np_057287 q9ugj0 602743 gla nm_000169.2 np_000160 p06280 301500 cpvt ryr2 nm_001035.2 np_001026 q92736 180902 casq2 nm_001232.2 np_001223 o14958 114251 arvc dsp nm_004415.2 np_004406 p15924 125647 pkp2 nm_001005242.2 np_001005242 a0av37 602861 dsg2 nm_001943.3 np_001934 q14126 125671 dsc2 nm_024422.3 np_077740 q02487 125645 jup nm_002230.2 np_002221 p14923 173325 tgfb3 nm_003239.2 np_003230 p10600 190230 tmem43 nm_024334.2 np_077310 q9btv4 612048 renate marquis-nicholson, elaine doherty, jennifer m. love, chuan-ching lan, alice m. george, donald r. love, anthony thrush clinical and basic research | 73 polymerase chain reaction (pcr) amplification was performed in a total volume of 25 µl, containing 50 ng of genomic deoxyribonucleic acid (dna), 0.20 µm of each primer, 1 mm of each dntp, and 1.75 u of expand long template enzyme mix in buffer 2 (f. hoffmann-la roche ltd., basel, switzerland). after an initial denaturation for 2 minutes at 94º c, the pcr amplification included 10 cycles of 94º c for 10 seconds, 60º c for 30 seconds, and 68º c for 2 minutes, followed by 20 cycles of 94º c for 15 seconds, 60º c for 30 seconds, 68º c for 4 minutes, and a final extension at 68º c for 10 minutes. pcr products were separated by a 2% agarose gel and the lower band, corresponding to the allele carrying the dmd dmd nm_004006.2 np_003997 p11532 300377 ald abcd1 nm_000033.2 np_000024.2 p33897 300371 fap apc nm_000038.3 np_000029.2 p25054 611731 type 1 citrullinaemia ass1 nm_000050.4 np_000041.2 p00966 603470 type ii citrullinaemia slc25a13 nm_014251.2 np_001153682.1 q9ujs0 603859 thyroid carcinoma/melanoma braf1 nm_004333.4 np_004324.2 p15056 164757 familial breast and ovarian cancer brca1 nm_007294.2 np_009225.1 p38398 113705 brca2 nm_000059.3 np_000050.2 p51587 600185 x-linked congential stationary night blindness type 2 cacna1f nm_005183.2 np_005174.2 o60840 300110 e-cadherin related stomach cancer cdh1 nm_004360.2 np_004351.1 p12830 192090 larsen syndrome flnb nm_001457.2 np_001157789.1 o75369 603381 nkh gldc nm_000170.2 np_000161.2 p23378 238300 holocarboxylase synthetase deficiency hlcs nm_000411.4 np_000402.3 p50747 609018 mody gck nm_000162.3 np_000153.1 p35557 138079 hnf1a nm_000545.4 np_000536.5 p20823 142410 hnf1b nm_000458.2 np_000449.1 p35680 189907 hnf4a nm_000457.3 np_000448.3 p41235 600281 familial hypercholesterolemia ldlr nm_000527.3 np_000518.1 p01130 606945 rett syndrome mecp2 nm_004992.3 np_001104262.1 p51608 300005 hnpcc mlh1 nm_000249.2 np_000240.1 p40692 120436 msh2 nm_000251.1 np_000242.1 p43246 609309 pms1 nm_000534.4 np_000525.1 p54277 600258 pms2 nm_000535.5 np_000526.1 p54278 600259 men2a ret nm_020630.4 np_065681.1 p07949 64761 familial phaeochromocytoma/ paraganglioma sdhaf2 nm_017841.1 np_060311.1 q9nx18 613019 sdhb nm_003000.2 np_002991.2 p21912 185470 sdhc nm_003001.3 np_001030588.1 q99643 602413 sdhd nm_003002.1 np_002993.1 o14521 602690 dyt11 sgce nm_003919.2 np_001092870.1 o43556 604149 vhl vhl nm_000551.2 np_000542.1 p40337 608537 lqt = long qt syndrome; hcm = hypertrophic cardiomyopathy; cpvt = catecholaminergic polymorphic ventricular tachycardia; arvc = arrhythmogenic right ventricular cardiomyopathy; dmd = duchenne muscular dystrophy; ald = adrenoleukodystrophy; fap = familial adenomatous polyposis; nkh = nonketotic hyperglycinemia; mody = maturity onset diabetes of the young : hnpcc = hereditary non-polyposis colorectal cancer; men2a = multiple endocrine neoplasia type 2a; dyt11 = myoclonus dystonia; vhl = von-hippel lindau syndrome. array-based identification of copy number changes in a diagnostic setting simultaneous gene-focused and low resolution whole human genome analysis 74 | squ medical journal, february 2013, volume 13, issue 1 deletion, was excised and purified using the roche high pure pcr cleanup micro kit (roche applied sciences, roche diagnostics, penzberg, germany). bidirectional dna sequencing was performed using m13 forward and reverse primers and bigdye terminator, version 3.0 (applied biosystems ltd., carlsbad, california, usa). using an automated clean-seq procedure (agencourt bioscience corp., beverly, massachusetts, usa), 20 µl of sequenced product was purified with the aid of an epmotion 5075 liquid handling robot (eppendorf, hamburg, germany). using the applied biosystems model 3130xl genetic analyser (applied biosystems, inc., foster city, california usa), 15 µl of purified product was then subjected to capillary electrophoresis. genes of interest, including those already sequenced in-house and those pertaining to common disorders known to frequently involve deletions/duplications (such as duchenne muscular dystophy), were selected and the appropriate nm accession numbers identified using the ucsc genome browser. the final gene list comprising 66 genes was forwarded to nimblegen and formed the basis of their design for a 12-plex 135k oligonucleotide array (see table 2 for gene list). each probe was 60–85 bp in length and possessed similar isothermal characteristics. exonic probes were designed to overlap by 25 bp in order to provide high resolution detection of deletions or duplications within the coding regions of the genes of interest. intronic probes were spaced on average every 175 bp. to minimise the occurrence of false positive results due to a one-off failure of hybridisation to a particular probe, each gene-focused probe was spotted in duplicate. in addition to the targeted probes tiled over the genes of interest, approximately 75,000 ‘backbone’ probes were also included. these probes were spaced across the entire genome (with a mean probe interval of 46 kbp) to provide lowdensity whole genome interrogation, as well as increase the accuracy of data normalisation during the analysis procedure. following completion of the design process, the array was manufactured by nimblegen, inc. a total of 250 nanograms of genomic deoxyribonucleic acid (gdna) were processed according to the nimblegen array user’s guide: cgh and cnv arrays, version 6.0. in brief, extracted gdna from samples and promega controls was denatured in the presence of a cy3 for the test group or cy5for the control group, labelled random primers and incubated with the klenow fragment of dna polymerase, together with deoxyribonucleotide triphosphates (dntps) (5 mm of each dntp), at 37º c for 2 hours. the reaction was terminated by the addition of 0.5 m edta (21.5 µl), prior to isopropanol precipitation and ethanol washing. following quantification, the test and sex-matched control samples were combined in equimolar amounts and applied to one of the twelve arrays on the microarray slide. hybridisation was carried out in a nimblegen hybridisation chamber for a period of 48 hours. slides were washed and scanned using a nimblegen ms 200 microarray scanner. array image files (.tif ) produced by the ms 200 data collection software were imported into nimblescan version 2.6 for analysis. each genomic region exhibiting a copy number change within one of the genes of interest was examined using the ucsc genome browser to determine the location and significance of the change. data was filtered using the default log2 ratio thresholds recommended in the nimblegen array user’s guide of less than -0.2 for a deletion and greater than 0.2 for duplication. for mlpa, the salsa mlpa p114 lqt kit (lot 0805) was purchased from mrc-holland (amsterdam, netherlands). this mix contains probes for 17 exons of the kcnq1 gene, 9 probes for the kcnh2 gene, 4 probes for the scn5a gene, as well as 4 and 3 probes for kcne1 and kcne2, respectively. this kit also contains four control probes mapping to other autosomes. mlpa analysis was carried out according to the mrc holland protocol. briefly, 125 ng of genomic dna from each sample was diluted in 5 µl te buffer and denatured at 98º c for 5 minutes. mlpa buffer and probe mix (1.5 µl of each) were then added to allow the probes to anneal to their target sequences by heating at 95º c for one minute and incubating for 16 hours at 60º c. a buffer/ligase mixture (32 µl) was added to each sample and incubated at 54º c for 15 minutes followed by heating to 98º c for 5 minutes. ten microlitres of the ligation reaction were used for multiplex pcr amplification using a single universal primer pair suitable for all the probes in the kit. the salsa polymerase was added at 60º c, followed by 36 cycles of 95º c for 30 seconds, 60º c for 30 seconds, 72º c for one minute, and a final extension renate marquis-nicholson, elaine doherty, jennifer m. love, chuan-ching lan, alice m. george, donald r. love, anthony thrush clinical and basic research | 75 table 3: customdesigned cgh array results for all samples patient previous result custom array raw result significance of result 1 xxy arr xp22.33q28(6,329-154,894,377)x3 xxy 2 trisomy 21 arr 21q11.2q22.3(9,931,865-46,914,745)x3 trisomy 21 3 trisomy 18 arr 18p11.32q23(102,328-76,093,443)x3 trisomy 18 4 46,xx,der(7)t(7;22)(q36.3;q13.1)mat.ish der(7)t(7;22)(q36.3;q13.1)(arsa+) arr 7q36.3(156,973,768-158,816,034)x1,22 q13.1q13.33(37,139,349-49,522,598)x3 t(7;22), coordinates consistent with previous result 5 46,xx,der(4)t(3;4)(q23;q35.1)pat arr 4q34.3q35.2(182,454,628-191,220,565) x1,3q23q29(144,114,087-199,377,478)x3 t(3;4), coordinates consistent with previous result 6 del chr2:102176600-119933523 arr 2q12.1q14.2(102,195,252-119,812,387) x1 del chr2, coordinates consistent with previous result 7 del chr2: 44305631-44425668; dup chr15: 36188779-36655207; del chr16: 2952247730107306 arr 2p21(44,325,958-44,373,442) x1,15q14(36,244,896-36,615,176)x3 16p11.2(29,653,824-30,100,122)x1 multiple cnvs, coordinates consistent with previous result 8 deletion of snrpn gene arr 15q11.2q13.1(21,450,428-26,192,737) x1 del entire snrpn gene 9 dup chr7: 71914639-73718403 arr 7q11.23(71,964,201-73,874,826)x3 dup chr7, coordinates consistent with previous result 10 dup mecp2 gene arr xq28(152,900,329-153,202,330)x3 dup entire mecp2 gene 11 del exons 6, 7,10,11,15 kcnh2 gene arr 7q36.1(150,250,593-150,283,627)x1 del exons 6-15 (inclusive) 12 dup exons 10,11, 15 kcnh2 gene arr 7q36.1(150,250,593150,275,172x3,150,275,345150,276,020x1,150,276,456-150,279,665x3) dup exons 7,8,9,10,11; del exons 12,13; dup exons 14,15 13 del exons 11-12 apc gene arr 5q22.2(112,190,700-112,191,901)x1 del exons 11,12 14 del exon 45-52 dmd gene arr xp21.1(31,625,116-31,904,144)x0 del exons 45-52 (inclusive) 15 dup exon 63 (heterozygous) dmd gene arr xp21.2(31,155,081-31,194,353)x3 dup exon 63 (heterozygous) 16 del exon 1, 2 brca1 gene arr 17q21.31(38,525,107-38,531,019)x1 del exons 1,2 17 del ex3-44 dmd gene arr xp21.2p21.1(31,048,707-32,916,496)x0 del exons 3-44 (inclusive) 18 del exon 6 mlh1 gene arr 3p22.2(37,025,008-37,027,636)x1 del exon 6 19 dup exon13 brca1 gene arr 17q21.31(38,484,216-38,488,483)x3 dup exon 13 20 del exons 1,2 brca2 gene arr 13q13.1(31,787,734-31,788,803)x1 del exons 1,2 individuals with no known copy number change referral reason custom array raw result significance of result 21 mother of patient 9 no cnv detected de novo dup chr7 in patient 9 22 father of patient 9 no cnv detected de novo dup chr7 in patient 9 23 mother of patient 7 arr 15q14(36,188,779-36,655,207)x3 carrier of chr15 dup; de novo deletion chr16 in patient 7 24 father of patient 7 arr 2p21(44,325,958-44,373,442)x1 carrier of chr2 del; de novo deletion chr16 in patient 7 25 lqts no cnv detected pathogenic mutation not detected 26 lqts no cnv detected pathogenic mutation not detected 27 mody no cnv detected pathogenic mutation not detected 28 hnpcc arr 2p21(47,486,274-47,559,311)x1 del exons 2-14 msh2 gene del chr = deleted chromosome; dup chr = duplicated chromosome; lqts = long qt syndrome; mody = maturity onset diabetes of the young ; hnpcc = hereditary non-polyposis colorectal cancer. array-based identification of copy number changes in a diagnostic setting simultaneous gene-focused and low resolution whole human genome analysis 76 | squ medical journal, february 2013, volume 13, issue 1 step of 72º c for 20 minutes. one microlitre of each pcr product was mixed with 0.5 µl genescan 600 liz size standard (applied biosystems, ltd.) and 8.5 µl of deionized formamide and 1µl was injected into a 36 cm capillary (applied biosystems model 3130xl)) at 60º c. the electropherogram was analysed using genemapper software (applied biosystems ltd.). for each sample, the relative peak area (rpa) was calculated and compared to 5 healthy controls using custom-designed software. the software calculates rpas for each probe within the same test and compares each rpa to those obtained from the 5 controls. results we developed a custom-designed nimblegen 12x135k acgh that combines targeted highdensity coverage of 66 genes of interest with genome-wide coverage to produce a low-resolution molecular karyotype. for the validation of this array we analysed 20 patients with known copy number abnormalities. the custom designed nimblegen cgh array was able to accurately identify these copy number changes in all 20 patients [table 3]. the array results for patient 12 revealed an additional alteration that had not been recognised previously. patient 12 is a member of a large pedigree with multiple members suffering from long qt syndrome (lqts). analysis using the mrc-holland salsa p114 lqt mlpa kit, which interrogates a limited number of exons of the kcnh2 gene (exons 1-4,6,7,10,11,15), had identified a duplication of exons 10, 11, and 15 in all affected individuals [figure 1, panel a].16 this duplication had therefore been the focus of predictive testing using mlpa for additional at-risk members of the family. the acgh results clarified the extent of the duplication, not only showing that it involved a breakpoint within exon 7 and encompassed the whole of exons 8, 9, 10, 11, 14 and 15, but also that the genotype was more complex than previously thought. a critical micro-deletion encompassing exons 12 and 13 was figure 1: graphic representation of copy number changes in the kcnh2 gene in patient 12. (a) dosage changes were detected using a multiplex ligation-dependent probe amplification (mlpa) approach. the graphic representation shows the increased dosage detected by probes that lie in exons 10, 11, and 15 of the kcnh2 gene. (b) dosage changes were detected in the kcnh2 gene with a copy number gain (x3 copy number) defined by the chromosome 7 coordinates (ncbi36/hg18 assembly) 150,276,456-150,279,665bp (within exon 7 to within exon 11, log2 ratio 0.45) and 150,250,593-150,275,172 (encompassing exons 14 and 15, log2ratio 0.5), and an apparent 676bp deletion (x1 copy number, log2ratio -0.53) located at 150,275,345-150,276,020bp (encompassing exons 12 and 13). (c) transcripts expressed from the kcnh2 gene are shown, together with the distal exons of transcript 1 of the kcnh2 gene (refseq accession number nm_000238.3). renate marquis-nicholson, elaine doherty, jennifer m. love, chuan-ching lan, alice m. george, donald r. love, anthony thrush clinical and basic research | 77 detected [figure 1, panels b and c]. pcr and dna sequencing determined the exact breakpoints of the 1041 bp deletion, the length of which compares favourably to the 676 bp copy number change detected by the array [figure 2]. of the 8 patients who had not yet undergone any form of copy number analysis, 4 had a clinical diagnosis that had not been confirmed by sequence analysis of the implicated genes: two had a diagnosis of long qt syndrome, one of hereditary nonpolyposis colorectal cancer (hnpcc), and one of maturity onset diabetes of the young (mody). no copy number changes were identified in the panel of long qt syndrome genes in either of the long qt patients, nor within the mody genes in the mody patient. however, a large deletion involving exons 2–14 inclusive of the msh2 gene was detected in the individual with a clinical diagnosis of hereditary non-polyposis colorectal cancer (hnpcc). mutations in the mismatch repair gene msh2 are known to be responsible for 40% of cases of hnpcc; 20% of these mutations involve exonic or full gene deletions.17 the referral reason for acgh analysis for the remaining 4 individuals without a known copy number change was to provide additional information for genetic counselling and family planning. individuals 21 and 22 are the parents of patient 9, an eight-year-old girl with mild dysmorphic features and speech delay, who had been found to have a duplication involving the williams-beuren syndrome (wbs) critical region at 7q1123 using an affymetrix single nucleotide polymorphisms (snp) 6.0 array (affymetrix, santa clara, california, usa). while a microdeletion of the wbs critical region results in a well-characterised pattern of facial dysmorphism, supravalvular aortic stenosis, connective tissue abnormalities, hypercalcaemia, and a recognisable behavioural phenotype, duplication of the same region results in a much less distinctive set of characteristics.18 foremost among these, as was seen in our patient, are mildly dysmorphic facial features and prominent speech delay. parental transmission of the 7q11.23 duplication is relatively frequent in the wbs duplication syndrome, but reduced penetrance and variable expression mean that determination of carrier status based on phenotype alone is not simple. an approximately 1.5 mb duplication of the wbs critical region was readily indentified in the affected girl by our customdesigned nimblegen cgh array, which agreed with the earlier affymetrix snp 6.0 array data, but was not detected in either of her parents. figure 2: location and extent of the kcnh2 gene deletion in patient 12. a partial sequence of the kcnh2 gene is shown that encompasses exons 11 to 13, inclusive (in blue). the sequence-confirmed location and extent of the 1041bp deletion detected in the genome of patient 12 is highlighted in yellow (chromosome 7: 150,276,375-150,275,335bp; ncbi36/hg18 assembly). array-based identification of copy number changes in a diagnostic setting simultaneous gene-focused and low resolution whole human genome analysis 78 | squ medical journal, february 2013, volume 13, issue 1 the conclusion is that the genomic copy number change detected in patient 9 is a de novo event and that future pregnancies are not at high risk of this mutation event. individuals 23 and 24 are the parents of patient 7, a six-year-old boy who was referred for investigation of developmental delay and features consistent with autistic spectrum disorder. highdensity affymetrix snp 6.0 microarray analysis had revealed several copy number changes in the child, including a deletion at chromosome 2p21, a duplication at chromosome 15q14, and a deletion at chromosome 16p11.2 (see table 3 for full coordinates). each of these changes was also identified by our nimblegen custom cgh array, with only minor differences in breakpoint location, despite the difference in probe density [table 3]. the 16p11.2 deletion is consistent with the phenotypic features in this case, as dosage changes at 16p11.2 have been described in association with autistic spectrum disorder.19 the acgh results confirmed that the chromosome 16p11.2 deletion is de novo and that each of the other two copy number changes are most likely to be benign, as each is inherited from one of his parents. discussion the purpose of the work described above was to design and validate a cgh array that could be used as an alternative to mlpa, quantitative pcr, and customised fish in the diagnostic genetics laboratory. although there have been several reports in the recent literature of custom-designed cgh arrays being used to screen for either exonic dosage changes in a large set of disease-specific genes, or for one of a panel of known genomic disorders, this is the first report, to our knowledge, of a custom-designed cgh array that provides both high-resolution coverage of a comprehensive set of genes and low-resolution whole genome coverage.20-25 the array design we report here is ideally suited to a small diagnostic laboratory. it enables the simultaneous interrogation of a large number of genes using a process that eliminates the risk of false negatives inherent in pcr-based techniques due to the possibility of polymorphisms lying under primer binding sites. twelve patient samples are able to be tested at once, reducing the overall cost of the assay. the overlapping probes tile the exons at a high density and allow changes involving the coding regions of the gene(s) of interest, including single exon changes, to be readily and reliably detected. this design feature is in contrast to some previously reported designs which could not reliably detect single exon changes due to insufficient probe coverage over affected regions.23 the intron probes enable clarification of breakpoints, which is not possible with mlpa or qpcr, and the backbone probes facilitate the identification of larger genomic rearrangements, either as confirmation following high-density molecular karyotyping, or for carrier testing and family studies. conclusion we have shown that our custom-designed nimblegen cgh array can be used to accurately identify exonic deletions and duplications in a gene set of interest as well as offer a low resolution whole genome screen for larger genomic rearrangements. the technique is robust and cost-effective and allows for comprehensive analysis. this approach overcomes the problems associated with the use of expensive kits in the context of low sample throughput, and allows for consolidation of dosage analysis assays to a single validated technique. references 1. miller dt, adam mp, aradhya s, biesecker lg, brothman ar, carter np, et al. consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. am j hum genet 2010; 86:749–64. 2. manning m, hudgins l. array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. genet med 2010; 12:742–5. 3. kunkel lm, hejtmancik jf, caskey ct, speer a, monaco ap, middlesworth w, et al. analysis of deletions in dna from patients with becker and duchenne muscular dystrophy. nature 1986; 322:73–7. 4. roa bb, garcia ca, lupski jr. charcot-marie-tooth disease type 1a: molecular mechanisms of gene dosage and point mutation underlying a common inherited peripheral neuropathy. int j neurol 19911992; 25–26:97–107. 5. stenson pd, mort m, ball ev, howells k, phillips ad, thomas ns, et al. the human gene mutation renate marquis-nicholson, elaine doherty, jennifer m. love, chuan-ching lan, alice m. george, donald r. love, anthony thrush clinical and basic research | 79 database: 2008 update. genome med 2009; 1:13. 6. stenson pd, ball ev, mort m, phillips ad, shiel ja, thomas ns, et al. human gene mutation database (hgmd): 2003 update. hum mutat 2003; 21:577– 81. 7. eijk-van os pg, schouten jp. multiplex ligationdependent probe amplification (mlpa) for the detection of copy number variation in genomic sequences. methods mol biol 2011; 688:97–126. 8. sieber om, lamlum h, crabtree md, rowan aj, barclay e, lipton l, et al. whole gene apc deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas. proc natl acad sci usa 2002; 99:2954–8. 9. bendavid c, kleta r, long r. fish diagnosis of the common 57-kb deletion in ctns causing cystinosis. hum genet 2004; 115:510–14. 10. gouas l, goumy c, veronese l, tchirkov a, vago p. gene dosage methods as diagnostic tools for the identification of chromosome abnormalities. pathol biol (paris) 2008; 56:345–53. 11. armour jal, barton de, cockbuen dj, taylor gr. the detection of large deletions or duplications in genomic dna. hum mutat 2002; 20:325–37. 12. doherty e, marquis-nicholson r, brookes c, love jm, prosser d, love dr. from primer design to sequence analysis: a pipeline tool for use in a diagnostic genetics laboratory. in: ivanov o. applications and experiences of quality control. pittsburgh, pa: intech publishers, 2011. pp. 257–72. 13. lai d, love dr. automation of a primer design and evaluation pipeline for subsequent sequencing of the coding regions of all human refseq genes. bioinformation 2012; 8:365–8. 14. genome browser. university of california santa cruz (ucsc) from: http://genome.ucsc.edu accessed: apr 2012. 15. national genetic reference laboratory, manchester, uk, software tool. from: http://ngrl.man.ac.uk/ snpcheck.html accessed: apr 2012. 16. eddy c-a, maccormick j, crawford jr, chung s-k, crawford jr, love dr, et al. identification of large gene deletions and duplications in kcnq1 and kcnh2 in patients with long qt syndrome. heart rhythm 2008; 5:1275–81. 17. kohlmann w, gruber sb. lynch syndrome. in: pagon ra, bird td, dolan cr, stephens k. genereviews [internet]. seattle: university of washington; 1993– 2004. 18. merla g, brunetti-pierri lm, fusco c. copy number variants at williams–beuren syndrome 7q11.23 region. hum genet 2010; 128:3–26. 19. weiss la, shen y, korn jm, arking de, miller dt, fossdal r, et al. association between microdeletion and microduplication at 16p11.2 and autism. n engl j med 2008; 358:667–75. 20. landsverk ml, wang j, schmitt es, pursley an, wong lj. utilization of targeted array comparative genomic hybridization, mitomet®, in prenatal diagnosis of metabolic disorders. mol genet metab 2011; 103:148–52. 21. wong lj, dimmock d, geraghty mt, quan r, lichter-konecki u, wang j, et al. utility of oligonucleotide array-based comparative genomic hybridization for detection of target gene deletions. clin chem 2008; 54:1141–8. 22. saillour y, cossée m, leturcq f, vasson a, beugnet c, poirier k, et al. detection of exonic copy-number changes using a highly efficient oligonucleotidebased comparative genomic hybridization-array method. hum mutat 2008; 29:1083–90. 23. del gaudio d, yang y, boggs ba, schmitt es, lee ja, sahoo t, et al. molecular diagnosis of duchenne/ becker muscular dystrophy: enhanced detection of dystrophin gene rearrangements by oligonucleotide array-comparative genomic hybridization. hum mutat 2008; 29:1100–7. 24. piluso g, dionisi m, del vecchio blanco f, torella a, aurino s, savarese m, et al. motor chip: a comparative genomic hybridization microarray for copy-number mutations in 245 neuromuscular disorders. clin chem 2011; 57:1584–96. 25. cheung sw, shaw ca, yu w, li j, ou z, patel a, et al. development and validation of a cgh microarray for clinical cytogenetic diagnosis. genet med 2005; 7:422–32. squ med j, may 2012, vol. 12, iss. 2, pp. 153-160, epub. 9th apr 2012 submitted 23rd sep 11 revision req. 31st dec 11, revision recd. 30th jan 12 accepted 29th feb there has been an increase in the number of near-term and term infants reported with acute bilirubin encephalopathy, which has resulted in an increase in the number of readmissions of infants to hospitals. this can partially be attributed to shorter postpartum hospital stays, and limited post-natal followup. to prevent kernicterus, clinicians need to understand the physiology of bilirubin production and excretion, and develop a systematic approach to the causes and management of neonatal icterus. this issue is highlighted here with specific relation to near-term and term newborns. epidemiology nearly all newborn infants have a total serum bilirubin (tsb) value greater than 1 mg/dl (17.1 µmol/l), which is at the upper limit of normal for an adult. most newborns appear clinically jaundiced. department of paediatrics and child health, aga khan university hospital, karachi, pakistan *corresponding author e-mail: shakeel.ahmed@aku.edu الريقان الوليدي يف الرضَّع الناضجني والقريبني من النضوج نظرة عامة ريحان علي، �ساكيل اأحمد، مقبول قادر، خليل اأحمد ْلَبة العني عند االأطفال حديثي الوالدة ب�سبب تر�سب مادة البيلريوبني يف امللخ�ص: الريقان الوليدي هو اللون االأ�سفر يف اجللد و/اأو �سُ االأن�سجة. الريقان الف�سيولوجي يكون خفيفا عادة ب�سبب الِبيلريوبني الاَل ُمْقرَتِن وي�سيب جميع املواليد اجلدد تقريبا. ترتفع م�ستويات الريقان الف�سيولوجي ما بني 5 و 6 ملغ / دي�سيلرت )103-86 مايكرو مول / لرت( عند 72 اإىل 96 �ساعة من العمر، وال تتجاوز 17 حتى 18 ملغ / دي�سيلرت )308-291 مايكرو مول / لرت(. لكن م�ستويات البلريوبني قد ال ت�سل اإىل ذروتها حتى اليوم ال�سابع من العمر عند ع الذين يولدون قبل االأوان )يف االأ�سبوع 37-35 من احلمل(. وتعترب م�ستويات الِبيلريوبني الاَل ُمْقرَتِن ع االآ�سيويني اأو عند الر�سّ الر�سّ التي تكون اأعلى مما ُذكر حالة مر�سية وحتدث يف جمموعة متنوعة من الظروف. مت يف هذه الورقة مراجعة املظاهر ال�رضيرية وعالج الريقان الف�سيولوجي عند الر�سع االأ�سحاء، النا�سجني والقريبني من الن�سوج، وكذلك �سمية البيلريوبني والوقاية من الرَيَقان الَنَوِوّي، ومناق�سة االآلية املر�سية وامل�سببات املر�سية لهذا اال�سطراب على انفراد. مفتاح الكلمات: الوليد، يرقان، ارتفاع البيلريوبني. abstract: neonatal jaundice is the yellowish discoloration of the skin and/or sclerae of newborn infants caused by tissue deposition of bilirubin. physiological jaundice is mild, unconjugated (indirect-reacting) bilirubinaemia, and affects nearly all newborns. physiological jaundice levels typically peak at 5 to 6 mg/dl (86 to 103 µmol/l) at 72 to 96 hours of age, and do not exceed 17 to 18 mg/dl (291–308 µmol/l). levels may not peak until seven days of age in asian infants, or in infants born at 35 to 37 weeks’ gestation. higher levels of unconjugated hyperbilirubinaemia are considered pathological and occur in a variety of conditions. the clinical features and management of unconjugated hyperbilirubinaemia in healthy near-term and term infants, as well as bilirubin toxicity and the prevention of kernicterus, are reviewed here. the pathogenesis and aetiology of this disorder are discussed separately. keywords: newborn; icterus; hyperbilirubinaemia; jaundice. review icterus neonatorum in near-term and term infants an overview rehan ali, *shakeel ahmed, maqbool qadir, khalil ahmad icterus neonatorum in near-term and term infants an overview 154 | squ medical journal, may 2012, volume 12, issue 2 pathologic hyperbilirubinaemia occurs when the tsb exceeds the hour-specific 95th percentile using the published nomogram in figure 1.1 the nomogram was developed for a racially diverse population in philadelphia in which nearly 60% were breastfed. infants were excluded if they had haemolytic conditions or required phototherapy before 60 hours to control rapidly rising tsb levels. however, rates of hyperbilirubinaemia vary substantially between centres because of racial differences, haemolytic conditions, and breastfeeding practices. in a multinational study, the proportion of infants with tsb levels at or above the 95th percentile at 30 hours ranged from approximately 5% in hong kong and china, to 40% in kobe, japan.2 clinical features risk factors for the development of jaundice in nearterm infants were obtained from clinical histories. they included gestational age of 35 to 37 weeks; polycythaemia; assisted deliveries through such methods as vacuum or forceps instrumentation; trauma during labour or delivery; maternal diabetes; asian race; blood group incompatibility; poor breastfeeding practices, or a previous sibling with jaundice.3 visual inspection of skin colour can be used to detect jaundice, but it is not a reliable method to assess the level of bilirubin or identify infants at risk for rapidly rising bilirubin levels, especially in those with dark skin.4 the examination should be performed with adequate ambient light. pressing on the skin with a finger reduces local skin perfusion and may facilitate detection of jaundice. jaundice progresses in a cephalocaudal direction. the face and sclera typically appear icteric when bilirubin levels reach 6 to 8 mg/dl (103 to 137 µmol/l), whereas the entire body, including palms and soles, appears jaundiced at values of 12 to 13 mg/dl (205 to 222 µmol/l).5 tsb or transcutaneous bilirubin (tcb) levels should be measured in an infant with jaundice detected below the umbilicus. physical examination may identify signs that suggest risk for pathological jaundice. they include pallor, enclosed haemorrhage such as cephalhaematoma, and bruising. 25 428 342 257 171 85 0 20 15 10 5 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 hig h in term edia te r isk zon e high risk zone low risk zone 95th percentile 75th percentile 40t h percent ile low inte rme diat e ri sk z one m ic ro m ol /l to ta l s er um b ili ru bi n (m g/ dl ) age (h) 1mg/dl = 17.1 micromol/l figure 1: hour specific nomogram (adapted from bhutani et al.1) rehan ali, shakeel ahmed, maqbool qadir and khalil ahmad review | 155 the tsb concentration is compared to an hourspecific percentile-based nomogram. tsb levels in a term newborn typically peak at 5 to 6 mg/dl (86 to 103 µmol/l) at 72 to 96 hours of age, and do not exceed 17 to 18 mg/dl (291-308 µmol/l).1 the peak may not be reached until seven days of age in asian infants, or in infants born at 35 to 37 weeks’ gestation. infants with hour-specific values that are greater than or equal to the 95th percentile are at increased risk for the development of clinically significant hyperbilirubinaemia, requiring intervention. in a racially diverse population with a 60% rate of breastfeeding, 95th percentile values for tsb were approximately 8, 10, 12, and 16 mg/dl (137, 171, 205, and 274 µmol/l) at 24, 36, 48, and 72 hours, respectively.1 infants who have tsb values greater than or equal to the 95th percentile, or who are suspected of having haemolytic disease, require subsequent measurement of tsb levels and further evaluation to determine the aetiology of their jaundice. initial tests that should be obtained are blood type and direct anti-globulin tests, a complete blood count and smear, and a reticulocyte count. the mother’s blood type and antibody status usually are known from the prenatal history. if an infant is of asian origin and the tsb concentration is ≥18 mg/dl (222 µmol/l), glucose-6-phosphate dehydrogenase (g6pd) should be measured.11 however, g6pd measurements are not universally available, and the results usually are not timely enough to affect clinical decisions. e n d-t i d a l c a r b o n m o n o x i d e end-tidal measurement of carbon monoxide (co) corrected for ambient co (etcoc) provides a noninvasive assessment of bilirubin production because catabolism of heme results in equimolar quantities of bilirubin and co.11–12 elevated etcoc values (>2.0 parts per million) can identify infants with increased bilirubin production (most often caused by haemolysis) who require additional evaluation or close monitoring. in one study, the etcoc value at 30 hours of age exceeded the mean value (1.48 ppm) in 76% of hyperbilirubinaemic infants.12 kernicterus bilirubin is a potential neurotoxin.6–7 unconjugated bilirubin that is not bound to albumin (free bilirubin) can enter the brain and cause focal necrosis of the neurons and glia, resulting in bilirubin encephalopathy, which is also known as kernicterus. the regions most often affected include the basal ganglia and the brain stem nuclei for oculomotor and auditory function, accounting for the clinical features of this condition.8 near-term and term infants are at risk for kernicterus when tsb concentrations exceed 25 to 30 mg/dl (428 to 513 µmol/). however, the relationship between tsb and kernicterus is variable and influenced by other factors such as bilirubin affinity for albumin, which is reduced in premature and sick infants.9 most unconjugated bilirubin is normally bound to albumin, resulting in low levels of free bilirubin. high tsb concentrations may exceed the capacity of albumin to bind bilirubin and lead to higher levels of free bilirubin, which may be neurotoxic. although measurement of free bilirubin concentration would be useful to guide therapy, clinical testing is not universally available. drugs such as sulfisoxazole, moxalactam, and ceftriaxone can displace bilirubin from albumin and increase the risk of kernicterus. acidosis increases movement of bilirubin into tissues and, thus, can contribute to the development of kernicterus.10 kernicterus can occur in healthy term infants. however, infants at increased risk are those who are near term (35 to 37 weeks), breastfed, have haemolytic disease, and are discharged home before 48 hours. to minimise the risk of bilirubin encephalopathy, these infants require close surveillance because the peak tsb levels will be reached after discharge.7 laboratory evaluation tsb and the direct-reacting serum bilirubin concentration are measured in infants with jaundice. if the direct-reacting bilirubin is greater than 1.5 to 2.0 mg/dl (26 to 34 µmol/l), causes of cholestatic jaundice should be investigated. the following discussion applies to healthy term and near-term infants with hyperbilirubinaemia. infants who appear ill or are premature require more extensive evaluation. icterus neonatorum in near-term and term infants an overview 156 | squ medical journal, may 2012, volume 12, issue 2 t r a n s c u ta n e o u s b i l i r u b i n m e a s u r e m e n t transcutaneous devices that use multi-wavelength spectral reflectance can be used to estimate tsb in order to avoid blood sampling. in contrast to older devices, this method is not affected by skin pigmentation.13 in one report of a racially and ethnically diverse group of 490 newborns, a close correlation was found between transcutaneous and tsb measurements. prevention of severe hyperbilirubinaemia infants with severe hyperbilirubinaemia are at risk for developing kernicterus, although only a small number will do so (see section on kernicterus above). timely identification and treatment of infants with severe hyperbilirubinaemia will prevent most cases of kernicterus. infants at risk require close surveillance and follow-up.14 term and near-term infants should be evaluated for jaundice between 72 and 96 hours of age, the time at which tsb levels typically peak.1 however, many infants are discharged from the hospital prior to 48 hours of age; these infants should be examined for jaundice by a clinician within one to two days of discharge. tsb levels are often higher in breastfed than in formula-fed infants. in addition, milk intake may be inadequate until lactation is well established, resulting in volume depletion and weight loss. increased surveillance is needed for infants born at 35 to 37 weeks’ gestation because they are at increased risk for early difficulty with breastfeeding. counselling regarding jaundice and breastfeeding should be provided before discharge where the importance of frequent feedings should be emphasised. lactation consultants and home visits by a nurse may be helpful. until lactation is well-established in significantly jaundiced infants, it may be helpful to interrupt breast feeding briefly and supplement with formula for a short period (supplementation with water is not recommended).15 a root cause analysis of factors contributing to cases of kernicterus identified potentially correctable causes.15 these include: 1) discharge within 48 hours of birth with no follow-up within 48 hours of discharge; 2) failure to measure the bilirubin concentrations in an infant with jaundice within 24 hours of birth; 3) failure to recognise risk factors for hyperbilirubinaemia; 4) lack of concern regarding the presence of jaundice; 5) delayed measurement of tsb in infants with severe jaundice; 6) delayed initiation of phototherapy in infants with elevated tsb levels, and 7) lack of response to parental concerns regarding jaundice, lethargy, or poor feeding. p r e d i c t i o n o f s e v e r e h y p e r b i l i r u b i n a e m i a a percentile-based nomogram, such as that in figure 1, can be used to predict the subsequent risk for severe hyperbilirubinaemia.1 in another report, the combined use of an hour-specific tsb measurement and etcoc did not improve the predictive ability of an hour-specific tsb alone.16 however, these clinical devices are not currently available. in this study, in contrast to the report on which the nomogram was based that used tsb alone, 4 of 620 infants with tsb levels in the low risk zone (<40th percentile) at 30 ± 6 hours subsequently developed tsb levels greater or equal to those in the 95th percentile. this finding supports the need for early follow-up of all infants regardless of their risk zone at discharge. u n i v e r s a l s c r e e n i n g universal screening of infants for tsb levels prior to discharge has been proposed to facilitate identification of infants at high risk for the development of severe hyperbilirubinaemia.2 limitations of this approach are the need for blood sampling and the cost of tsb measurement. use of transcutaneous methods for screening may decrease the need for phlebotomy, and reduce costs.13,16 an alternative approach is clinical assessment of jaundice before and within one to two days of discharge, and subsequent tsb measurement in jaundiced infants. treatments phototherapy is the standard treatment for pathologic unconjugated hyperbilirubinaemia.17 rare cases of extremely high tsb levels (>25 mg/dl) require an exchange transfusion. rehan ali, shakeel ahmed, maqbool qadir and khalil ahmad review | 157 can cause thermal injury. they should be placed at the manufacturer recommended distance from the patient. fibre optic blankets generate little heat and can be placed close to the infant and provide higher irradiance than do fluorescent lights.19 however, blankets are small and rarely cover sufficient surface area to be effective when used alone in near-term and term infants. they can be used as an adjunct to overhead fluorescent or halogen lights. high intensity gallium nitride light emitting diodes (leds), such as neoblue, are as effective as conventional fluorescent light phototherapy.20 for intensive phototherapy (30 µw/cm2/nm) of infants with tsb levels greater than 25 mg/dl (428 µmol/l), a bank of special blue lights should be placed 10 to 12 cm from the infant’s body to expose the maximum surface area to light. premature and hypothermic babies should be placed in an open crib or on a warmer. the area covered by the diaper should be minimised and the infant’s eyes should be shielded with a blindfold with care taken so that the blindfold does not cover the nose. temperature, time of exposure, irradiance (if possible), and the infant’s hydration status should all be monitored. infants should continue oral feedings by breast or bottle. intravenous hydration is needed only in cases of significant volume depletion. phototherapy should be continuous, with interruptions only for feeding. if the tsb is at a near toxic level, fibre optic blanket exposure can continue during the feedings. the following discussion applies to healthy term and near-term infants. infants who appear ill or are premature require more aggressive intervention. for healthy term and near-term infants, we initiate phototherapy according to the 2004 practice and parameter recommendations of the american academy of pediatrics (aap) on the management of hyperbilirubinaemia. phototherapy is started if tsb levels are 15, 18, or 20 mg/dl (257, 308, and 342 µmol/l) at 25 to 48, 49 to 72, or >72 hours after birth, respectively.2 these values exceed the 95th percentile for hour-specific tsb concentrations, predicting increased risk for developing severe hyperbilirubinaemia after discharge. for this reason, clinicians often initiate treatment for tsb levels that are 2 to 3 mg/dl (34–51 µmol/l) lower than the above values, especially for near term infants (35–37 weeks), or infants with other risk factors.2 p h o t o t h e r a p y phototherapy consists of exposing the infant’s skin to blue-to-green light in wavelengths ranging from 400–520 nm. it is a safe and efficient method to reduce the toxicity of bilirubin and increase its elimination. phototherapy detoxifies bilirubin by three mechanisms: structural isomerisation to lumirubin, photoisomerisation to a less toxic isomer, and photooxidation to polar small molecules. these processes are thought to occur in the blood vessels or interstitial spaces of the skin. phototherapy with blue light phototherapy converts bilirubin into lumirubin in a process of structural isomerisation that is not reversible.18 lumirubin, a more soluble substance than bilirubin, is excreted without conjugation into bile and urine. it is the principal mechanism by which phototherapy reduces the tsb concentration. phototherapy with blue light phototherapy also converts the stable 4z, 15z bilirubin isomer to the 4z, 15e isomer, which is more polar and less toxic than the common form. like lumirubin, it is excreted into bile without conjugation. unlike structural isomerisation to lumirubin, photoisomerisation is reversible, and some of the 4z, 15e isomer in the bile is converted back into the stable 4z, 15z isomer. photoisomerisation is the second important mechanism to increase bilirubin excretion. tsb photo oxidation reactions convert bilirubin to colourless, polar compounds that are excreted primarily in the urine. this mechanism accounts for a small proportion of bilirubin elimination.10 the dose of phototherapy, known as irradiance, times duration determines its efficacy. irradiance depends upon the intensity of the blue light, its distance from the infant, and the surface area exposed. it usually is expressed for a certain wavelength band (spectral irradiance). fluorescent blue light typically is used at a dose of approximately 30 µw/cm2/nm of area exposed. blue lights are more effective at reducing bilirubin but may interfere with the detection of cyanosis.17,18 the use of white daylight fluorescent lights/lamps is better than no phototherapy. fluorescent lights are placed 15 to 20 cm above the infant. we use light banks with eight alternating white and blue fluorescent bulbs. this combination increases the irradiance but lessens the eye strain for clinicians. halogen white light lamps are hot and icterus neonatorum in near-term and term infants an overview 158 | squ medical journal, may 2012, volume 12, issue 2 infants with clinical jaundice within the first 24 hours of birth frequently have haemolysis. they require immediate evaluation and close surveillance to assess the need for phototherapy. in infants with other causes of increased bilirubin production, such as cephalohaematoma or extensive bruising, or in infants suspected of having conjugation disorders, we start phototherapy when the hour-specific tsb concentration is in a high intermediate risk zone (>75th percentile). when tsb values are ≥20 mg/dl (342 µmol/l), the measurement should be repeated four to six hours after phototherapy is initiated to assess the response. for lower initial values, tsb should be measured after 24 hours and then once daily while phototherapy continues. however, measurement of serum bilirubin will also depend on the aetiology of the jaundice, rate of rise, etc., and may be indicated more often even when levels are not yet at 20 mg/ dl. a decrease in tsb level can be measured as soon as two hours after initiation of treatment. intensive phototherapy should result in a decline of tsb of at least 1 to 2 mg/dl (1734 µmol/l) within four to six hours.2 our centre discontinues phototherapy when the hour-specific tsb level falls to a value less than the 95th percentile, or has decreased 4 to 5 mg/dl (68–86 µmol/l) when measured 18 to 24 hours later. although the value following discontinuation is known as the rebound bilirubin, typically it is lower than the previous tsb during treatment. in one study of 161 infants with birth weights of more than 1800 grams, the rebound tsb was significantly lower 17 hours after termination of phototherapy (11.5 versus 12.2 mg/dl, 197 versus 209 µmol/l).21 phototherapy is considered safe. side effects include transient erythematous rashes, loose stools and hyperthermia. increased insensible water loss caused by enhanced peripheral blood flow may lead to dehydration. as an alternative to readmission to the hospital, phototherapy can be administered at home. home phototherapy is less disruptive to the family and can be considered for healthy infants without haemolysis who are feeding well and can be closely followed. e x c h a n g e t r a n s f u s i o n exchange transfusion is used to remove bilirubin from the circulation when intensive phototherapy fails. it is especially useful for infants with increased bilirubin production from immune-mediated haemolysis because the circulating antibodies and the sensitised red blood cells also are removed. an exchange transfusion is performed when severe hyperbilirubinaemia does not respond to intensive phototherapy. according to the aap practice parameters, an exchange transfusion is indicated in healthy near-term and term infants when tsb levels are greater than or equal to 20 mg/ dl (342 µmol/l) at 24 to 48 hours of age, or are at or greater than 25 mg/dl (428 µmol/l) thereafter. failure of intensive phototherapy occurs if tsb levels do not decrease by 1 to 2 mg/dl (17–34 µmol/l) within four to six hours of initiation of phototherapy. an exchange transfusion also should be performed in infants with high tsb levels as per the nomogram, and in any infant with any signs of bilirubin neurotoxicity. exchange transfusion is indicated in cases of haemolysis, especially immune-mediated, if the anaemia is severe and resulting in hydrops, or the tsb is rising rapidly and is expected to reach 25 mg/dl (428 µmol/l) within 48 hours. exchange transfusions will correct the anaemia without causing circulatory overload and remove maternal antibodies and sensitised erythrocytes. less severely affected patients can be managed with intensive phototherapy to reduce tsb levels, and transfusions of packed red blood cells to correct the anaemia. a double-volume exchange transfusion removes approximately twice the infant’s circulating blood volume (blood volume is approximately 80 to 90 ml/kg), replacing it with appropriately crossmatched fresh or reconstituted (from packed red blood cells and fresh frozen plasma) whole blood. the procedure involves placement of a central catheter and the subsequent removal and replacement of the maximum amount of blood that should be withdrawn at any one time (approximately 5 ml per kg body weight). most of the bilirubin is extravascular; as a result, an exchange transfusion removes approximately 25% of the total body bilirubin.22 an infusion of albumin (1 g/kg) one to two hours before the procedure moves more extravascular bilirubin into the infant’s circulation, allowing removal of more bilirubin.23 after the procedure, tsb levels typically fall to approximately half of the pre-exchange value, and rehan ali, shakeel ahmed, maqbool qadir and khalil ahmad review | 159 m e ta l l o p o r p h y r i n s synthetic metalloporphyrins, such as tin mesoporphyrin (snmp), reduce bilirubin production by competitive inhibition of heme oxygenase.25 in one report, for example, term and near-term infants with g6pd deficiency given snmp at approximately 27 hours of age had lower and earlier peak tsb values than did control infants with and without g6pd deficiency.11 no treated infant required phototherapy, compared to 31% and 15% in the controls with and without g6pd deficiency, respectively. however, metalloporphyrins are not available for clinical use. conclusion the following recommendations only apply to healthy term and near-term infants. infants who appear ill, are premature, or have evidence of haemolysis require more intensive evaluation and management. infants should be assessed for jaundice at 24 to 48 hours of age and prior to hospital discharge. measurement of serum or transcutaneous bilirubin concentration is preferred. alternatively, the infant can be assessed by visual inspection and a measurement of tsb levels should be obtained in those who appear jaundiced. tsb values should be compared to an hour-specific nomogram to predict the risk of subsequent development of clinically significant hyperbilirubinaemia. infants at high risk require increased surveillance. infants discharged within 48 hours of birth require a follow-up evaluation within 24 to 48 hours of discharge. infants at high risk for the development of significant hyperbilirubinaemia should be evaluated within 24 hours of discharge. in addition, parents should also be told to return immediately if the infant becomes visibly more jaundiced or develops any sort of neurological symptom. lactation counselling should be provided for breastfeeding mothers. near-term (35 to 37 weeks) infants are at greater risk of receiving inadequate fluid and nutrition, and require increased surveillance. then increases to approximately two-thirds of that level as the extravascular and vascular bilirubin reequilibrate. a double volume exchange transfusion replaces approximately 85% of the infant’s red blood cells. the risks of exchange transfusions result from the use of blood products and from the procedure itself. possible complications include blood-borne infection, thrombocytopenia, coagulopathy, graftversus-host disease, necrotising enterocolitis, portal vein thrombosis, electrolyte abnormalities, cardiac arrhythmias, and sudden death.24 most complications occur in sick infants and are rare in healthy infants. in a retrospective review of 15 years of experience at two academic medical centres, one of 81 healthy infants developed necrotising enterocolitis after exchange an transfusion, and none died.22 pharmacological agents pharmacological agents, including intravenous immunoglobulin (ivig), phenobarbital, and metalloporphyrins can be used to inhibit haemolysis, increase conjugation and excretion of bilirubin, or inhibit the formation of bilirubin. however, ivig is currently used only to treat unconjugated hyperbilirubinaemia. i n t r av e n o u s i m m u n o g l o b u l i n intravenous immunoglobulin ivig (500 mg/kg per dose iv over two hours) may reduce the need for exchange transfusions in infants with haemolytic disease caused by rh or abo incompatibility.23 the mechanism is uncertain, but ivig is thought to inhibit haemolysis by blocking antibody receptors on red blood cells. p h e n o b a r b i ta l phenobarbital increases the conjugation and excretion of bilirubin and decreases postnatal tsb levels when given to pregnant women or infants; however, prenatal administration of phenobarbital may adversely affect cognitive development and reproduction.24 as a result, phenobarbital is not used to treat indirect hyperbilirubinaemia. there are exceptional circumstances, like prolonged jaundice in gilbert’s syndrome, where it might be useful. icterus neonatorum in near-term and term infants an overview 160 | squ medical journal, may 2012, volume 12, issue 2 references 1. bhutani vk, johnson l, sivieri em. predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. pediatrics 1999; 103:6–14. 2. stevenson dk, fanaroff aa, maisels mj, young bw, wong rj, vreman hj, et al. prediction of hyperbilirubinemia in near-term and term infants. pediatrics 2001; 108:31–9. 3. adekunle-ojo ao, smitherman hf, parker r, ma l, caviness ac. managing well-appearing neonates with hyperbilirubinemia in the emergency department observation unit. pediatr emerg care 2010; 26:343–8. 4. national collaborating centre for women’s and children’s health. neonatal jaundice. london: national institute for health and clinical excellence (nice), 2010. p. 53. 5. hatzenbuehler l, zaidi ak, sundar s, sultana s, abbasi f, rizvi a, et al. validity of neonatal jaundice evaluation by primary health-care workers and physicians in karachi, pakistan. j perinatol 2011; 30:616–21. 6. ebbesen f. kernicterus. acta obstet gynecol scand 2012; 89:726. 7. kaplan m, merlob p, regev r. israel guidelines for the management of neonatal hyperbilirubinemia and prevention of kernicterus. j perinatol 2008; 28:389– 97. 8. mezzacappa ma, facchini fp, pinto ac, cassone ae, souza ds, bezerra ma, et al. clinical and genetic risk factors for moderate hyperbilirubinemia in brazilian newborn infants. j perinatol 2011; 30:819–26. 9. management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. pediatrics 2004; 114:297–316. 10. (no authors listed). clinical chemistry and physiology of bilirubin. semin liver dis 1994; 14:346–51. 11. kaplan m, hammerman c. glucose-6-phosphate dehydrogenase deficiency and severe neonatal hyperbilirubinemia: a complexity of interactions between genes and environment. semin fetal neonatal med 2009; 15:148–56. 12. okuyama h, yonetani m, uetani y, nakamura h. end-tidal carbon monoxide is predictive for neonatal non-hemolytic hyperbilirubinemia. pediatr int 2001; 43:329–33. 13. fouzas s, mantagou l, skylogianni e, mantagos s, varvarigou a. transcutaneous bilirubin levels for the first 120 postnatal hours in healthy neonates. pediatrics 2011; 125:e52–7. 14. gamaleldin r, iskander i, seoud i, aboraya h, aravkin a, sampson pd, et al. risk factors for neurotoxicity in newborns with severe neonatal hyperbilirubinemia. pediatrics 2011; 128:e925–31. 15. neonatal jaundice and kernicterus. supplemental feeding in the first days of life -effects on the recipient infant. pediatrics 2001; 108:763–5. 16. varvarigou a, fouzas s, skylogianni e, mantagou l, bougioukou d, mantagos s. transcutaneous bilirubin nomogram for prediction of significant neonatal hyperbilirubinemia. pediatrics 2009; 124:1052–9. 17. naderi s, safdarian f, mazloomi d, bushehri e, hamidian r. efficacy of double and triple phototherapy in term newborns with hyperbilirubinemia: the first clinical trial. pediatr neonatol 2009; 50:266–9. 18. ferreira al, nascimento rm, verissimo rc. irradiance of phototherapy equipment in maternity wards in maceio. rev lat am enfermagem 2009; 17:695–700. 19. mills jf, tudehope d. fibreoptic phototherapy for neonatal jaundice. cochrane database syst rev 2001; 1:cd002060. 20. seidman ds, moise j, ergaz z, laor a, vreman hj, stevenson dk, et al. a new blue light-emitting phototherapy device: a prospective randomized controlled study. j pediatr 2000; 136:771–4. 21. al-saedi sa. rebound hyperbilirubinemia in term infants after phototherapy. saudi med j 2002; 23:1394–7. 22. jackson jc. adverse events associated with exchange transfusion in healthy and ill newborns. pediatrics 1997; 99:e7. 23. huizing k, roislien j, hansen t. intravenous immune globulin reduces the need for exchange transfusions in rhesus and ab0 incompatibility. acta paediatr 2008; 97:1362–5. 24. o’riordan jm, fitzgerald j, smith op, bonnar j, gorman wa. transfusion of blood components to infants under four months: review and guidelines. ir med j 2007; 100:s1–24, following 496. 24. kumar r, narang a, kumar p, garewal g. phenobarbitone prophylaxis for neonatal jaundice in babies with birth weight 1000-1499 grams. indian pediatr 2002; 39:945–51. 25. beri r, chandra r. chemistry and biology of heme. effect of metal salts, organometals, and metalloporphyrins on heme synthesis and catabolism, with special reference to clinical implications and interactions with cytochrome p-450. drug metab rev 1993; 25:49–152. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e133–135, epub. 21 jan 15 submitted 10 apr 14 revision req. 11 jun 14; revision recd. 3 jul 14 accepted 9 aug 14 cerebellar mutism (cm) was first described by rekate et al. in 1985 following posterior fossa surgery in children;1 since then, it has increasingly been reported, mainly occurring as a postoperative complication. it has also been reported in both children and adults following several other cerebellar insults, including vascular events, infections and trauma.2 however, post-traumatic cm has only rarely been reported.3–6 its unique clinical features, heterogeneous anatomical localisation and unclear pathophysiology make it a curious clinical entity. case report a seven-year-old right-handed boy was brought to the casualty department of sultan qaboos university hospital in muscat, oman, in may 2013. he had fallen off a cupboard which he had been climbing and the cupboard had subsequently fallen on top of him. on admission, the emergency room physicians recorded his glasgow coma scale (gcs) as 8/15; however, the analysis of different components of the score was not documented. an examination showed bilaterally equal and symmetrical reactive pupils, without evidence of any unilateral motor deficit. the patient subsequently vomited and had one seizure episode. he was quickly intubated and ventilated. a plain computed tomography (ct) scan of the brain showed a comminuted fracture of the right occiput with a small underlying cerebellar contusion and minimal blood in the fourth ventricle [figures 1a & b]. a repeat ct scan the next day showed no increase in the cerebellar haematoma or any new lesions. he was extubated after 48 hours of elective ventilation. a neurological examination soon after extubation revealed a gcs of 10/15, no vocalisation and the presence of mild right lower motor neuron facial nerve palsy and mild weakness in the upper extremities. magnetic resonance imaging (mri) of the brain revealed right cerebellar oedema and a resolving small right cerebellar contusion without supratentorial lesions [figures 2a & b]. by the sixth day, he was obeying commands fully and his facial weakness and upper limb weakness had resolved. he started crying by the 10th day but still could not speak. he could walk with minimal ataxia at 13 days after admission. he was discharged two weeks after admission once he had spoken a few words. no emotional lability was noted at any time. the patient did not return to the hospital for his department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: rajeevkariyattil@gmail.com اخلرس الدماغي عقب إصابة الرأس املغلقة عند طفل راجيف كراياتيل، حممد. رحيم، يوين كري�ضان موثوكوتيابراميل abstract: cerebellar mutism is a rare occurrence following paediatric trauma. although it is quite common after posterior fossa surgery in children, this phenomenon has rarely been reported following other insults, such as trauma, and its pathophysiology remains poorly understood. we report a seven-year-old child who presented to the casualty department of sultan qaboos university hospital in muscat, oman, in may 2013 with a traumatic right cerebellar contusion. the child presented with clinical features of cerebellar mutism but underwent a rapid and spontaneous recovery. the possible mechanism of this occurrence is discussed. keywords: head injury; mutism; paediatrics; complications; case report; oman. امللخ�ص: يعد اخلر�س الدماغي نادر احلدوث عقب الر�ضح عند االأطفال. وعلى الرغم من اأنه �ضائع بعد عمليات اجلراحة يف احلفرة اخللفية عند االأطفال، اإال اأنه مل ي�ضجل اإال نادرا عقب خمتلف اأنواع االأذية مثل الر�ضح. وما زالت فيزيولوجيته املر�ضية غري مفهومة متاما. وهنا 2013م مايو يف بعمان م�ضقط يف قابو�س ال�ضلطان جامعة م�ضت�ضفى يف احلوادث لق�ضم اأح�رض عمره من ال�ضابعة يف طفل حالة ن�ضجل م�ضابا بر�ضة ر�ضحية يف ميني الدماغ. واأظهر الطفل علمات �رضيرية للخر�س الدماغي، اإال اأنه �رضعان ما �ضفا ب�رضعة وبتلقائية. ونناق�س هنا اآلية حدوث هذه احلالة. مفتاح الكلمات: اإ�ضابات الراأ�س؛ اخلر�س؛ االأطفال؛ م�ضاعفات؛ �ضجل حالة؛ عمان. cerebellar mutism following closed head injury in a child *rajeev kariyattil, mohamed i. a. rahim, unnikrishnan muthukuttiparambil online case report cerebellar mutism following closed head injury in a child e134 | squ medical journal, february 2015, volume 15, issue 1 one-month follow-up. however, when contacted by telephone, his family reported that he had regained normal speech. at his first review eight months after discharge, the child was back at school and taking part in normal activities. he had no speech, cranial nerve, motor or cerebellar deficits. a detailed neuropsychological assessment was suggested but not performed. discussion mutism is defined as the inability to speak in an otherwise cognitively alert patient.4 this can occur due to lesions in several locations of the brain, including broca’s area and the supplementary motor cortex, thalamus and mesencephalic reticular formation regions, as well as due to bilateral hemispheric lesions.4 mutism is more commonly seen following posterior fossa surgery, predominantly in children, with a reported incidence varying from 2–40%.7 it has also been reported uncommonly in other cerebellar pathologies including trauma, vascular events and infection.3–6,8,9 in a recent review, several terms were found in the literature to describe associated features of mutism: cm, transient cerebellar mutism, mutism and subsequent dysarthria, cm syndrome and posterior fossa syndrome.2 these encompass a spectrum of neurological deficits from mutism alone to ataxia, hypotonia, cranial nerve palsies, haemiparesis and emotional lability.2 in its typical form, cm has a delayed onset (1–6 days) and limited duration (between one day and four months) followed by a variable period of recovery.2 in this particular patient, it was not possible to identify the precise time of onset due to the low gcs score at presentation and the subsequent 48-hour ventilation period. nevertheless, other features of the case—the failure to speak for 10 days, the subsequent gradual return of verbalisation and the rapid recovery within one month—were typical of the usual course of cm. the anatomical substrate of cm is reportedly variable. to date, damage to the midline cerebellar structures have been described in more than 90% of paediatric and 70% of adult cm cases.8 the most commonly implicated regions are the vermis, dentate nuclei and the cerebellar peduncles—particularly the superior and middle cerebellar peduncles.2 these findings are mainly based on postoperative imaging of patients with midline posterior fossa tumours. in the current case, the vermis and the peduncles appeared intact on the mri scan. the right cerebellar hemisphere was predominantly involved, as indicated by the diffuse oedema of the entire right hemisphere and the small contusion close to the cerebellopontine angle. neurocognitive studies have suggested that the right cerebellar hemisphere has a dominant role in language tasks.10,11 however, even left cerebellar contusion has been known to produce cm.5,6 it has therefore been suggested that any bilateral disruption of the dentato-thalamo-cortical pathway, regardless of the specific location, can result in cm.2 in addition, the pathophysiological mechanisms responsible for cm are also unclear, with vasospasm, oedema and the resultant cerebello-cerebral diaschisis being variously attributed.2 oedema of the right cerebellar hemisphere was the prominent feature in the mri scan of the presented patient. the delayed figure 1a & b: computed tomography scans of the brain showing (a) the right occipital fracture and (b) the right cerebellar contusion with intra-ventricular haemorrhage. rajeev kariyattil, mohamed i. a. rahim and unnikrishnan muthukuttiparambil case report | e135 onset of symptoms correlates approximately with the onset of oedema; however, the duration of symptoms outlasts the oedema, especially in severe cases.2 with less severe injuries, as in this case, the oedema and the consequent mass effect and midline shift could cause a transient disturbance of the bilateral dentato-thalamocortical pathway. most reports of cases with postoperative cm mention long-term residual deficits including dysarthria, ataxia and behavioural changes.7 in this case, the child most probably had a full recovery due to less severe cerebellar involvement. however, minor residual abnormalities, including language, memory and learning disabilities, may not have been discovered in the absence of a detailed neuropsychological evaluation. only five cases of post-traumatic mutism have been reported in the literature, although this entity is probably under-reported.2 of these cases, two were due to right cerebellar contusions, two to left cerebellar contusions and one was due to a right posterior fossa acute subdural haematoma.3–6 this further highlights the heterogeneous anatomical localisation of cm. prognosis for these patients, as in the current case, was excellent; however, residual dysarthria was mentioned in one patient after six months.3 conclusion although cm is fairly common following posterior fossa surgery in children, its mechanism remains poorly understood. its occurrence in other pathologies, especially trauma, may help in understanding its pathophysiology. references 1. rekate hl, grubb rl, aram dm, hahn jf, ratcheson ra. muteness of cerebellar origin. arch neurol 1985; 42:697–8. doi: 10.1001/archneur.1985.04060070091023. 2. gudrunardottir t, sehested a, juhler m, schmiegelow k. cerebellar mutism: review of the literature. childs nerv syst 2011; 27:355–63. doi: 10.1007/s00381-010-1328-2. 3. erşahin y, mutluer s, saydam s, barçin e. cerebellar mutism: report of two unusual cases and review of the literature. clin neurol neurosurg 1997; 99:130–4. doi: 10.1016/s03038467(97)80010-8. 4. fujisawa h, yonaha h, okumoto k, uehara h, le t, nagata y, et al. mutism after evacuation of acute subdural hematoma of the posterior fossa. childs nerv syst 2005; 21:234–6. doi: 10.1007/ s00381-004-0999-y. 5. koh s, turkel sb, baram tz. cerebellar mutism in children: report of six cases and potential mechanisms. pediatr neurol 1997; 16:218–19. doi: 10.1016/s0887-8994(97)00018-0. 6. yokota h, nakazawa s, kobayashi s, taniguchi y, yukihide t. [clinical study of two cases of traumatic cerebellar injury]. no shinkei geka 1990; 18:67–70. 7. wells em, khademian zp, walsh ks, vezina g, sposto r, keating rf, et al. postoperative cerebellar mutism syndrome following treatment of medulloblastoma: neuroradiographic features and origin. j neurosurg pediatr 2010; 5:329–34. doi: 10.3171/2009.11.peds09131. 8. frassanito p, massimi l, caldarelli m, di rocco c. cerebellar mutism after spontaneous intratumoral bleeding involving the upper cerebellar vermis: a contribution to the physiopathogenic interpretation. childs nerv syst 2009; 25:7–11. doi: 10.1007/ s00381-008-0711-8. 9. mewasingh ld, kadhim h, christophe c, christiaens fj, dan b. nonsurgical cerebellar mutism (anarthria) in two children. pediatr neurol 2003; 28:59–63. doi: 10.1016/s08878994(02)00503-9. 10. mariën p, de smet hj, wijgerde e, verhoeven j, crols r, de deyn pp. posterior fossa syndrome in adults: a new case and comprehensive survey of the literature. cortex 2013; 49:284– 300. doi: 10.1016/j.cortex.2011.06.018. 11. marien p, engelborghs s, fabbro f, de deyn pp. the lateralized linguistic cerebellum: a review and a new hypothesis. brain lang 2001; 79:580–600. doi: 10.1006/brln.2001.2569. figure 2a & b: magnetic resonance imaging scans of the brain showing (a) the right hemispheric oedema with minimal mass effect and (b) the resolving right cerebellar contusion. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e128-129, epub. 27th jan 14 submitted 23rd apr 13 revision req. 26th jun 13; revision recd. 2nd jul 13 accepted 1st aug 13 department of radiology, atatürk training and research hospital, ankara, turkey *corresponding author e-mail: droktayalgin@gmail.com العمى عرض استثنائي لتكيسات غروانية �أيفريم �أوزمن و �أوكتاي �أجلن blindness an uncommon presentation of colloid cysts evrim ozmen and *oktay algin interesting medical image figure 1 a–k: preoperative computed tomography (ct) and postoperative magnetic resonance (mr) images of the patient. a, b & c: preoperative sequential axial ct images showing hydrocephalus and periventricular oedema. d, e, f & g: postoperative axial t2-weighted, fluid-attenuated inversion recovery (flair), diffusion-weighted and apparent diffusion coefficient (adc) images showing the shunt catheter (black arrow), bilateral occipital infarction (white arrows) and the decreased diameters of the lateral ventricles. h: axial time-of-flight mr angiography (tof-mra) source image showing the hyperintense colloid cyst at the foramen of monro (arrow). i: the calibrations of the posterior circulation arteries were normal on the axial maximum intensity projection (mip) tof-mra image. j & k: sagittal (j) and coronal (k) reformatted images obtained from the tof-mra sequence showing the hyperintense colloid cyst at the foramen of monro level (arrows). evrim ozmen and oktay algin interesting medical image | e129 colloid cysts may obstruct the foramina of monro and lead to acute hydrocephalus.1,2 in patients with colloid cysts, intraventricular pressure can increase suddenly due to acute obstructive hydrocephalus.3,4 a sudden and dramatic rise in ventricular pressure may lead to cerebral herniation, infarction and may result in death.4 these images show a patient who was admitted to atatürk training and research hospital, ankara, turkey, with complaints of visual loss. acute bilateral blindness is an emergent condition that may signal a life-threatening disease. a 46-year-old man with no previous neurological complaints was admitted to our hospital with symptoms of headache, loss of consciousness and the progressive loss of vision. a physical examination revealed less than 20/20 central visual acuity. moderate hydrocephalus and bilateral periventricular oedema were detected by a computed tomography (ct) scan performed in the emergency department [figure 1]. magnetic resonance (mr) imaging and diffusion-weighted imaging (dwi) were recommended for the patient, as the aetiology of hydrocephalus could not be determined exactly by the initial ct scan. on mr imaging, a colloid cyst and acute hydrocephalus were detected. in addition, diffusion-weighted imaging (dwi) revealed areas with restricted diffusion on the bilateral occipital lobes. as a result of these findings, ventriculoperitoneal shunting was performed five hours after the patient was admitted. mr images were obtained after the procedure, which detected regression in the sizes of the lateral ventricles and in the periventricular cerebrospinal fluid reabsorption [figure 1]. in addition, there were infarctions in the bilateral occipital lobes and no recovery of vision. the posterior circulation was normal and there were early subacute infarctions in the occipital lobes on the mr images taken one week after the shunt therapy. there was no improvement in the loss of vision of the patient at the second week follow-up. comment colloid cysts may lead to hydrocephalus by obstructing the foramina of monro. the enlargement of the ventricular system and increase in the ventricular pressure may lead to brain herniation and neurologic symptoms.2,3 occasionally, the ‘sudden downward brain herniation’ can occlude the posterior communicating arteries that run in the tentorial incisura as well.3,4 this condition may cause cortical blindness. an infarction can develop in the other parts of the brain and in the spinal cord with a similar mechanism.4 in such cases, other causes of the infarct, such as thromboembolism in the posterior circulation, should be excluded.5 severe traumatic injury, shunt malfunction, optic neuritis, intoxication, hyperosmolar-iodinated contrast agents and visual pathway tumours may also cause bilateral visual loss.5 time-of-flight magnetic resonance angiography (tof-mra) with dwi can be useful in patients with a suspicion of arterial occlusion. the assessment of the morphology and relation of the colloid cysts with the foramina can be far more easily done on the reformatted images, since tof-mra is a three-dimensional technique. colloid cysts are hyperintense on t1-weighted images as well as tof-mra images. in conclusion, symptomatic colloid cysts should be evaluated and treated quickly. herniation, blindness or sudden death may occur in patients for whom treatment is delayed. rapid assessment with mr imaging and ct-mra, in patients in whom arterial occlusion is suspected, could decrease the morbidity and mortality rates. references 1. osborn ag, preece mt. intracranial cysts: radiologicpathologic correlation and imaging approach. radiology 2006; 239:650–64. 2. algin o, ozmen e, arslan h. radiologic manifestations of colloid cysts: a pictorial essay. can assoc radiol j 2013; 64:56–60. 3. el khoury c, brugières p, decq p, cosson-stanescu r, combes c, ricolfi f, et al. colloid cysts of the third ventricle: are mr imaging patterns predictive of difficulty with percutaneous treatment? ajnr am j neuroradiol 2000; 21:489–92. 4. siu tl, bannan p, stokes ba. spinal cord infarction complicating acute hydrocephalus secondary to a colloid cyst of the third ventricle: case report. j neurosurg spine 2005; 3:64–7. 5. van tassel p, mafee mf, atlas sw, galetta sl. eye, orbit, and visual system. in: atlas sw, ed. magnetic resonance imaging of the brain and spine. 4th ed. philadelphia: lippincott williams & wilkins, 2009. pp. 1357–8. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e46–51, epub. 21 jan 15 submitted 16 apr 14 revision req. 9 jun 14; revision recd. 6 jul 14 accepted 16 aug 14 1department of medicine, armed forces hospital; departments of 2pharmacology & clinical pharmacy and 5haematology, college of medicine & health sciences, sultan qaboos university; departments of 3child health and 4haematology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: sf.daar@gmail.com مدى انتشار االلتهاب الكبدي الوبائي سي يف مرضى الثالسيميا متعددي نقل الدم يف سلطنة عمان خربة مركز واحد خالد النعماين، ابراهيم الزكواين، �ضهام ال�ضنانية، فوزية و�ضيم، �ضاهينة داعر abstract: objectives: regular blood transfusions are essential for patients with thalassaemia major. however, infections with hepatotropic viruses remain a major concern. the objective of this study was to evaluate the prevalence and characteristics of hepatitis c viral (hcv) infection among patients with homozygous beta thalassaemia in a single centre in oman. methods: a retrospective chart review of 200 patients treated at the thalassemia unit of sultan qaboos university hospital (squh) in muscat, oman, between august 1991 and december 2011 was performed. relevant demographic and clinical characteristics were collected, including age, gender, hcv status and the presence of endocrinopathies. results: a total of 81 patients (41%) were found to be anti-hcv-antibody (anti-hcv)-positive. hcv ribonucleic acid tests were performed on 65 anti-hcv-positive patients and were positive among 33 (51%); the remaining 16 patients died before these tests were available. anti-hcv-positive patients were significantly older than anti-hcv-negative patients (p <0.001) and were more likely to be diabetic than anti-hcv-negative patients (27% versus 8%; p <0.001). a total of 100 patients had been transfused before they were transferred to squh in 1991; of these, 70 (70%) were anti-hcv-positive. only 11 (11.5%) of the 96 patients who were seronegative in 1991, or who were transfused later, became seropositive. conclusion: it is likely that the high prevalence of hcv among multi-transfused thalassaemic patients in oman is due to blood transfusions dating from before the implementation of hcv screening in 1991 as the risk of hcvassociated transfusions has significantly reduced since then. additionally, results showed that anti-hcv-positive patients were more likely to be diabetic than anti-hcv-negative patients. keywords: hepatitis c; anti-hcv antibodies; beta thalassemia; seroprevalence; blood transfusions; blood safety; oman. امللخ�ص: الهدف: نقل الدم املنتظم �رضوري ملر�ضى الثل�ضيميا الكربى.لكن تظل التهابات الكبد الفريو�ضية م�ضدر قلق كبري. الهدف من هذه الدرا�ضة هو تقييم مدى انت�ضار االلتهاب الكبدي الوبائي �ضي والتعرف على خ�ضائ�ضه بني املر�ضى الذين يعانون من مر�س الثل�ضيميا م�ضت�ضفى يف الثل�ضيميا وحدة يف متابعتهم متت ممن مري�س 200 ملفات مراجعة متت عمان. الطريقة: �ضلطنة يف واحد مركز يف بيتا الدميوغرافية اخل�ضائ�س جمعت .2011 دي�ضمرب و 1991 اأغ�ضط�س بني ما الفرتة يف عمان، �ضلطنة م�ضقط، يف قابو�س ال�ضلطان جامعة )hcv( وجود اختلل هرموين.النتائج: م�ضادات االأج�ضام �ضد )hcv( وال�رضيرية ذات ال�ضلة، مبا يف ذلك العمر واجلن�س وحالة الفريو�س )hcv( يف 65 مري�ضا ممن كانت لديهم م�ضادات االأج�ضام �ضد )rna( مت فح�س احلم�س النووي .)ضد وجدت يف 81 مري�س )%41� وكان الفح�س اإيجابيا يف 33 مري�ضا )%51(. تويف 16 مري�ضا قبل اأن تكون هذه االختبارات متوفرة. املر�ضى الذين كانت نتائج م�ضادات االأج�ضام لديهم اإيجابية كانوا اأكرب �ضنا بكثري من املر�ضى الذين كانت نتائج م�ضادات االأج�ضام عندهم �ضلبية )p >0.001( وكانوا اأكرث عر�ضة لداء ال�ضكري )%27 مقابلp >0.001،8%(. 100 مري�س مت نقل الدم لهم قبل حتويلهم مل�ضت�ضفى جامعة ال�ضلطان قابو�س يف عام 1991، من هوؤالء 70 )%70( كانت نتائج م�ضادات االأج�ضام �ضد )hcv( اإيجابية. اأحد ع�رض مري�ضا فقط )%11.5( من اأ�ضل 96 مري�ضا والذين كانت نتائج م�ضادات االأج�ضام عندهم �ضلبية اأو مت نقل الدم لهم بعد عام 1991 حتولت نتائجهم اإىل اإيجابية. اخلال�صة: من املرجح اأن ارتفاع معدل انت�ضار فريو�س التهاب الكبدي الوبائي �ضي بني مر�ضى الثل�ضيميا متعددي نقل الدم يف عمان �ضببه عمليات نقل الدم التي يعود تاريخها قبل بدء تنفيذ فح�س )hcv( يف عام 1991 حيث اإنه انخف�س معدل خطر االإ�ضابة بالفريو�س منذ ذلك احلني. باالإ�ضافة اإىل اأن النتائج ت�ضري اإىل اأن املر�ضى احلاملني مل�ضادات االأج�ضام �ضد الفريو�س اأكرث عر�ضة للإ�ضابة بداء ال�ضكري مقارنة باملر�ضى الذين ال يحملونها. مفتاح الكلمات: الكبدي االلتهاب الكبدي الوبائي �ضي؛ االأج�ضام امل�ضادة للفريو�س؛ ثل�ضيميا بيتا؛ االنت�ضار امل�ضلي؛ نقل الدم؛ �ضلمة الدم؛ عمان. prevalence of hepatitis c among multi-transfused thalassaemic patients in oman single centre experience khalid al-naamani,1 ibrahim al-zakwani,2 siham al-sinani,3 fauzia wasim,4 *shahina daar5 clinical & basic research khalid al-naamani, ibrahim al-zakwani, siham al-sinani, fauzia wasim and shahina daar clinical and basic research | e47 homozygous beta thalassaemia (βthalassaemia) is an inherited anaemia characterised by deficient synthesis of the beta globin subunits of the haemoglobin. oman has a high prevalence of thalassaemia in both the beta and alpha forms.1 the incidence of homozygous β-thalassaemia in oman is approximately eight in 10,000, while the global prevalence is reported to be around 0.07%.2,3 regular blood transfusions administered from early childhood onwards are the mainstay of treatment in β-thalassaemia major patients, while thalassaemia intermedia patients only require occasional transfusions. most thalassaemia major patients require 2–4 blood transfusions per week while those with thalassaemia intermedia can usually maintain reasonable haemoglobin levels without regular transfusions. however, the latter group may occasionally need blood transfusions during pregnancy, prior to surgery or if they develop an infection. chronic hepatitis c viral (hcv) infections are a comorbidity associated with regular blood transfusions; up to 80% of multi-transfused thalassaemic patients around the globe are infected with transfusion-related viral hepatitis.4–6 transfusionrelated hepatitis infections are therefore a major concern for those with β-thalassaemia. in addition to the risk of viral hepatitis transmission, multiple blood transfusions may lead to iron overload. the rate of liver fibrosis reportedly accelerates in patients with iron overload and hcv when compared to patients with either one alone.7 zurlo et al. found that advanced liver fibrosis is one of the most common causes of death in transfusion-dependent thalassaemia patients over 15 years old.8 in comparison to the previous two decades, recent advances in the treatment of thalassaemia, iron overload and hcv have led to improved outcomes and survival rates. the early identification and treatment of infections among thalassaemic patients, before the development of advanced fibrosis, can yield better patient responses and outcomes. the prevalence of hcv among multi-transfused patients varies from one area to another and depends on the endemicity of viral hepatitis in different regions. the highest reported prevalence was in egypt, where 75% of patients with homozygous β-thalassaemia are infected with hcv, while the prevalence ranges from 33–67.3% in the neighbouring countries of kuwait and iraq.9–11 as reported in a study from iran, the introduction of screening blood products for hcv in 1990 led to a marked reduction in the incidence of new transfusionrelated chronic hcv cases,12 while the majority of currently infected cases are due to infected blood products transfused before the implementation of screening. testing for hcv was introduced at sultan qaboos university hospital (squh) in muscat, oman, in 1991. this initially began with the firstgeneration enzyme-linked immunosorbent assay (elisa); in subsequent years, new generations of both the elisa and recombinant immunoblot assay (riba) were used as they became commercially available. the use of real time-polymerase chain reaction (rt-pcr) technology was introduced in 2000.13 the objective of the current study was to evaluate the prevalence and characteristics of hcv among multi-transfused β-thalassaemia patients in oman. methods this retrospective chart review was conducted between august 1991 and december 2011. a total of 200 homozygous β-thalassaemia patients treated and followed up at the squh thalassemia unit during the study period were evaluated. the squh thalassemia unit is the largest single centre in oman for thalassaemia management. all patients with either thalassaemia major (transfusion-dependent; n = 180) or thalassaemia intermedia (transfusion-independent; advances in knowledge the results of this study indicate that the prevalence of hepatitis c viral (hcv) infections in multi-transfused homozygous beta thalassaemic patients in oman is high, especially among older patients. this is likely due to blood transfusions occurring before the implementation of hcv screening in 1991. this study found that anti-hcv-antibody (anti-hcv)-positive patients were more likely to be diabetic than anti-hcv negative patients. application to patient care the results of this study support public health efforts to reduce hcv in oman. national health authorities in oman can contribute to the further reduction of hcv by supporting and recommending advanced blood screening procedures, such as nucleic acid testing. furthermore, promoting endogenous blood donations as well as screening blood products will lead to the further reduction of transfusionrelated hcv among thalassaemic patients in oman. as diabetes is becoming increasingly prevalent in the omani population, long-term health plans will need to take into account the significant correlation between hcv and diabetes found in this study. prevalence of hepatitis c among multi-transfused thalassaemia patients in oman single centre experience e48 | squ medical journal, february 2015, volume 15, issue 1 n = 20) who had been managed in the thalassemia unit at squh from 1991 onwards were included in the study. patients with missing or irretrievable data were excluded. relevant demographic and clinical characteristics were collected. the following equipment was used to test for hcv. in 1991, the first-generation elisa (orthoclinical diagnostics, inc., raritan, new jersey, usa) was used to measure anti-hcv antibody. between 1992 and 1996, second-generation enzyme immunoassays (abbott laboratories, abbott park, illinois, usa) were then used. a second-generation riba (hcv 2.0, chiron corp., emeryville, california, usa) was introduced in the squh laboratory in mid-1994. it was then replaced by third-generation ribas, the hcv 3.0 (chiron corp.) and hcv blot (genelab diagnostics pte. ltd., singapore) at the end of 1996. between 1997 and 2001, sera screening was performed by a third-generation microparticle enzyme immunoassay (axsym, abbott laboratories). sera that were initially reactive by elisa were retested and the results were interpreted according to the manufacturers’ specifications. all sera which were repeatedly reactive by elisa were subjected to additional testing by riba. hcv ribonucleic acid (rna) was tested on samples using the rt-pcr kit cobas® amplicor hcv test, version 2.0 (roche molecular systems inc., pleasanton, california, usa). in 2009, squh started testing samples for hcv rna using quantitative cobas® taqman® analysers (roche molecular systems inc.) with a linear quantification range between 43 and 6.9 x 107 iu/ml and a lower limit of detection of 12.6 iu/ml. descriptive statistics were used to present the data. for categorical variables, frequencies and percentages were reported. analyses were performed using pearson’s chi-squared test. for continuous variables, means and standard deviations were used to summarise the variables while analysis was conducted using student’s t-test. a priori was set at 0.05. analyses were performed using stata, version 13.1 (stata corp., college station, texas, usa). ethical approval for this study was obtained from the medical research & ethics committee at the college of medicine & health sciences, sultan qaboos university (mrec#402). results of the 200 homozygous β-thalassaemia patients included in the study, 52.5% were male and the mean age was 23 ± 7 years (range: 7–50 years). the majority of the patients had thalassaemia major and the rest had thalassaemia intermedia [table 1]. a total of 81 patients (41%) were found to be anti-hcv-antibody (antihcv)-positive; including 77 with thalassaemia major and four with thalassaemia intermedia. there were 100 patients (50%) who had been transfused before 1991; of these, 70 tested positive for anti-hcv. additionally, 11 of 96 patients with thalassaemia major (11.5%) who were anti-hcv-negative in 1991, or who started transfusions after that date, became seropositive. four patients with thalassaemia intermedia had never been transfused. repeat anti-hcv testing using a third-generation elisa confirmed the positive results of the first and second-generation elisas. anti-hcv-positive patients were significantly older than their anti-hcvnegative counterparts (28 versus 20 years; p <0.001) and were significantly more likely to be diabetic than the anti-hcv-negative patients (27% versus 8%; p <0.001). no hepatitis b co-infections were noted among the patients. four patients were co-infected with hcv and human immunodeficiency virus (hiv). there were 41 deaths (20.5%) during the study period; all but 10 of these patients were infected with hcv. the most common causes of death were cardiac complications (41%) followed by sepsis (24%). before hcv rna testing was available, 16 of the 81 patients who tested table 1: demographic characteristics of homozygous beta thalassaemia patients in oman between 1991 and 2011 (n = 200) characteristics n (%) mean age in years 23 ± 7 male gender 104 (52.5) thalassaemia major 180 (90) thalassaemia intermedia 20 (10) hcv infections before 1991 70 (70) deaths 41 (20.5) hcv = hepatitis c virus. figure 1: distribution of hepatitis c genotypes among homozygous beta thalassaemia patients in oman between 1991 and 2011 (n = 200). khalid al-naamani, ibrahim al-zakwani, siham al-sinani, fauzia wasim and shahina daar clinical and basic research | e49 positive for anti-hcv died; four from hiv-related causes, eight from cardiac iron load-related causes and four due to bacterial sepsis. therefore, rt-pcr to detect hcv rna was performed for 65 anti-hcv-positive patients. hcv rna was detected in 33 patients (51%); 18 (55%) had genotype 1, three (9%) had genotype 2, three (9%) had genotype 3 and nine (27%) had genotype 4 [figure 1]. half of these patients had advanced stage fibrosis (stages three and four) according to ludwig et al.’s staging system.14 of the 33 patients with hcv rna, 16 (48.5%) underwent a liver biopsy. the mean serum ferritin level in patients who tested positive for anti-hcv was 3,381 ± 3,290 ng/ml (normal range: 20–300 ng/ml). of the 200 patients, high liver enzymes were found in 76 (38%). mean alanine aminotransferase levels were significantly higher in thalassaemic patients who were positive for anti-hcv than in those who were negative (82 ± 111 versus 46 ± 39 u/l; p = 0.011) and significantly higher in those who were hcv rna-positive than those who were hcv rna-negative (106 ± 150 versus 45 ± 35 u/l; p = 0.042). discussion unlike hepatitis b, there is as yet no vaccination for hcv and multi-transfused thalassaemic patients who are at high risk of acquiring viral hepatitis.4 there has been a marked reduction in transfusion-related viral hepatitis worldwide since the implementation of screening tests for hcv in the early 1990s.15 as observed in a study by velati et al., transfusion-related viral hepatitis cases have also decreased due to the introduction of advanced screening methods such as nucleic acid testing.16 the current study revealed that 41% of investigated β-thalassaemia patients had been infected with hcv. this is comparable to the prevalence of anti-hcv observed in a similar cohort of patients in jordan (40.5%) but higher than those reported in india (30%), pakistan (35%) and kuwait (33%).10,17–19 however, active hcv infections were found in 33 of the 65 antihcv-positive patients (51%) in the current study who could be tested using rt-pcr to detect hcv rna. important factors to keep in mind when evaluating the prevalence of hcv in different countries include its prevalence in specific populations, the source of blood utilised during transfusions, the blood product screening methods employed and the age of the cohort being studied. there is currently no true populationbased prevalence of hcv in oman. one study reported the seroprevalence of hepatitis c antibodies using a second-generation enzyme immunoassay which detected antibodies to three hcv antigens in 26.5% of patients undergoing haemodialysis, 13.4% of kidney transplant patients and 1% of non-dialysed nontransplanted patients with various renal diseases.20 in another study, al dhahry et al. investigated the prevalence of hcv among omani blood donors between 1991 and 2001 using three generations of elisas and ribas to confirm positive elisa tests.13 out of 30,012 samples, 272 (0.91%) were positive for anti-hcv and 46.5% of these were confirmed positive by riba, giving a true prevalence of 0.42%. the proportion of sera that were confirmed to be antihcv-positive varied from 95% among intravenous drug users to 81% in patients with hepatitis and 70% in those with haemoglobinopathies.13 the proportion of positive anti-hcv findings among the multi-transfused thalassaemic patients in the current study is much higher than the 0.42% prevalence reported by al dhahry et al.13 it is likely that this discrepancy is due to the fact that healthy blood donors were used rather than patients with thalassaemia. furthermore, oman relied on imported blood from the usa from the mid-1970s to the early 1990s; during this time, the national health and nutrition examination survey iii (1988–1994) showed hcv to be the most common chronic bloodborne infection in the usa.21,22 there was also a lack of hcv testing for blood products during the specified period.22 in addition, the authors of the current study observed that many patients travelled to the indian subcontinent for splenectomies in the 1970s and had transfusions performed there. in 1984, the screening of imported blood for hbv and hiv using hbv surface antigen and hiv antigen tests was initiated with the help of the world health organization.22 in the early 1990s, the omani ministry of health decided to rely on local blood donations to meet the required demand and by july 1991 no more imported blood was being used in oman.22 the majority of the thalassaemic patients assessed in the current study were infected with hcv before the implementation of screening in 1991. this is also reflected in the finding that anti-hcv-positive patients were significantly older than their counterparts. this is in agreement with data from a neighbouring country— alavian et al. showed that the pooled odds ratio of the hcv infection rate for patients transfused before the era of screening in iran was 7.6 (95% confidence interval [ci]: 4.7–12.3).23 the current study shows that promoting endogenous blood donation and instituting a policy of screening blood products has led to a reduction of transfusion-related hcv infection in oman. false-positive anti-hcv results have been reported with the use of firstand second-generation elisas.24 however, the patients found to be positive in prevalence of hepatitis c among multi-transfused thalassaemia patients in oman single centre experience e50 | squ medical journal, february 2015, volume 15, issue 1 the present study were tested with a third-generation elisa which confirmed their anti-hcv status. of the anti-hcv-positive patients, 41% had positive hcv rna tests, implying active viral replication. more than half were infected with genotype 1. this is fitting considering the source of imported blood in oman before 1991, as genotype 1a was common in the usa in the early 1990s.25 genotype 4 was the second most common genotype in the current study; this genotype is reportedly common in africa.25 its high prevalence among the studied omani patients is therefore no surprise considering the historical and cultural relationship between oman and east africa and the migratory patterns of many families between these two regions. in comparison to other genotypes, genotypes 1 and 4 have been associated with a reduced response to the combination treatment of pegylated interferon and ribavirin.26 one interesting finding of the current study was the significant correlation between those who were anti-hcv-positive and the presence of diabetes mellitus (dm) when compared to anti-hcvnegative thalassaemic patients. dm is a well-known complication of iron overload in multi-transfused thalassaemic patients. the worldwide incidence of impaired glucose tolerance among thalassaemic patients is approximately 4–24% while the incidence of dm ranges between 0–26%.27,28 factors such as insulin resistance and insulin deficiency secondary to iron deposition in islet cells have been suggested to explain the high incidence of dm among thalassaemic patients.29 the association between hcv and dm has been well-established in the literature.30,31 the national health and nutrition examination survey iii, which included more than 9,000 subjects aged ≥20 years, demonstrated that the odds ratio of dm developing in anti-hcv-positive subjects ≥40 years old is 3.77 (95% ci: 1.80–7.87). this association was independent of gender, race and body mass index.32 the main mechanism that may explain the onset of dm in patients with hcv is the development of insulin resistance secondary to alterations in the intracellular signalling of insulin in such patients.33 the synergic effect of hcv and thalassaemia in the development of dm has been described in a study by labropouloukaratza et al.34 their findings demonstrated that thalassaemic patients with hcv were more likely to be diabetic compared to thalassaemic patients without hcv infections (45.3% versus 11.3%; p <0.001). the current study also confirms this association. anti-hcv-positive patients were significantly older than their counterparts. however, it is important to note that these older patients were poorly chelated and thus had significantly higher iron loads. in fact, it is likely that the advanced stage fibrosis present in a group of relatively young patients (mean age: 28 years) is secondary to the synergistic effect of hcv and iron overload. in the current study, four patients were co-infected with hcv and hiv. they were born in the early 1980s and thus were infected before the implementation of blood screening. all of these co-infected patients died of hiv-related complications. the main causes of death in the study (cardiac complications and sepsis) were similar to those reported by ladis et al. while investigating survival rates and causes of death in thalassaemic patients from greece.35 they found that heart failure was the most common cause of death (71.3%) followed by sepsis (7.8%). similar results were also reported from italy and iran.8,36 in the current study, 75.6% of the patients who died were infected with hcv. this finding affirms the results of previous studies describing the morbidity and mortality associated with hcv infection in multi-transfused thalassaemic patients.37 conclusion a total of 200 homozygous β-thalassaemia patients were included in the study and 41% were anti-hcvpositive. anti-hcv-positive patients were significantly more likely to be diabetic than anti-hcv-negative patients. in addition, anti-hcv-positive patients were significantly older compared to their counterparts. this indicates that the high prevalence of hcv among multi-transfused thalassaemic patients in oman is likely due to transfusions of hcv-infected blood before the implementation of hcv screening in 1991, suggesting that blood screening implemented after this time has significantly reduced the risk of hcv associated with blood transfusions. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. white jm, christie bs, nam d, daar s, higgs dr. frequency and clinical significance of erythrocyte genetic abnormalities in omanis. j med genet 1993; 30:396–400. doi: 10.1136/ jmg.30.5.396. 2. al-riyami aa, suleiman aj, afifi m, al-lamki zm, daar s. a community-based study of common hereditary blood disorders in oman. east mediterr health j 2001; 7:1004–11. 3. alkindi s, al zadjali s, al madhani a, daar s, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. doi: 10.3109/03630261003677213. 4. angelucci e. antibodies to hepatitis c virus in thalassemia. haematologica 1994; 79:353–5. khalid al-naamani, ibrahim al-zakwani, siham al-sinani, fauzia wasim and shahina daar clinical and basic research | e51 5. alavian sm, adibi p, zali mr. hepatitis c virus in iran: epidemiology of an emerging infection. arch iran med 2005; 8:84–90. 6. wonke b, hoffbrand av, brown d, dusheiko g. antibody to hepatitis c virus in multiply transfused patients with thalassaemia major. j clin pathol 1990; 43:638–40. doi: 10.1136/ jcp.43.8.638. 7. ardalan fa, osquei mr, toosi mn, irvanloo g. synergic effect of chronic hepatitis c infection and beta thalassemia major with marked hepatic iron overload on liver fibrosis: a retrospective cross-sectional study. bmc gastroenterol 2004; 4:17. doi: 10.1186/1471-230x-4-17. 8. zurlo mg, de stefano p, borgna-pignatti c, di palma a, piga a, melevendi c, et al. survival and causes of death in thalassaemia major. lancet 1989; 2:27–30. doi: 10.1016/s01406736(89)90264-x. 9. el gohary a, hassan a, nooman z, lavanchy d, mayerat c, el ayat a, et al. high prevalence of hepatitis c virus among urban and rural population groups in egypt. acta trop 1995; 59:155–61. doi: 10.1016/0001-706x(95)00075-p. 10. al-fuzae l, aboolbacker kc, al-saleh q. beta-thalassaemia major in kuwait. j trop pediatr 1998; 44:311–12. doi: 10.1093/ tropej/44.5.311. 11. al-kubaisy wa, al-naib kt, habib m. seroprevalence of hepatitis c virus specific antibodies among iraqi children with thalassaemia. east mediterr health j 2006; 12:204–10. 12. alavian sm, kafaee j, yektaparast b, hajarizadeh b, doroudi t. the efficacy of blood donor screening in reducing the incidence of hepatitis c virus infection among thalassemic patients in iran. transfusion today 2002; 53:3–4. 13. al dhahry sh, nograles jc, rajapakse sm, al toqi fs, kaminski gz. laboratory diagnosis of viral hepatitis c: the sultan qaboos university hospital experience. j sci res med sci 2003; 5:15–20. 14. ludwig j, batts kp, moyer tp, poterucha jj. advances in liver biopsy diagnosis. mayo clin proc 1994; 69:677–8. doi: 10.1016/ s0025-6196(12)61347-0. 15. donahue jg, muñoz a, ness pm, brown de jr, yawn dh, mcallister ha jr, et al. the declining risk of post-transfusion hepatitis c virus infection. n engl j med 1992; 327:369–73. doi: 10.1056/nejm199208063270601. 16. velati c, romanò l, fomiatti l, baruffi l, zanetti ar; simti research group. impact of nucleic acid testing for hepatitis b virus, hepatitis c virus, and human immunodeficiency virus on the safety of blood supply in italy: a 6-year survey. transfusion 2008; 48:2205–13. doi: 10.1111/j.1537-2995.2008.01813.x. 17. al-sheyyab m, batieha a, el-khateeb m. the prevalence of hepatitis b, hepatitis c and human immune deficiency virus markers in multi-transfused patients. j trop pediatr 2001; 47:239–42. doi: 10.1093/tropej/47.4.239. 18. irshad m, peter s. spectrum of viral hepatitis in thalassemic children receiving multiple blood transfusions. indian j gastroenterol 2002; 21:183–4. 19. rahman m, lodhi y. prospects and future of conservative management of beta thalassemia major in a developing country. pak j med sci 2004; 20:105–112. 20. al-dhahry sh, aghanashinikar pn, al-hasani mk, buhl mr, daar as. prevalence of antibodies to hepatitis c virus among omani patients with renal disease. infection 1993; 21:164–7. doi: 10.1007/bf01710538. 21. alter mj, kruszon-moran d, nainan ov, mcquillan gm, gao f, moyer la, et al. the prevalence of hepatitis c virus infection in the united states, 1988 through 1994. n engl j med 1999; 341:556–62. doi: 10.1056/nejm199908193410802. 22. joshi sr, shah al-bulushi sn, ashraf t. development of blood transfusion service in sultanate of oman. asian j transfus sci 2010; 4:34–40. doi: 10.4103/0973-6247.59390. 23. alavian sm, tabatabaei sv, lankarani kb. epidemiology of hcv infection among thalassemia patients in eastern mediterranean countries: a quantitative review of literature. iran red crescent med j 2010; 12:365–76. 24. barrera jm, francis b, ercilla g, nelles m, achord d, darner j, et al. improved detection of anti-hcv in post-transfusion hepatitis by a third-generation elisa. vox sang 1995; 68:15– 18. doi: 10.1111/j.1423-0410.1995.tb02538.x. 25. dusheiko g, schmilovitz-weiss h, brown d, mcomish f, yap pl, sherlock s, et al. hepatitis c virus genotypes: an investigation of type-specific differences in geographic origin and disease. hepatology 1994; 19:13–18. doi: 10.1002/hep.1840190104. 26. hadziyannis sj, sette h jr, morgan tr, balan v, diago m, marcellin p, et al. peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis c: a randomized study of treatment duration and ribavirin dose. ann intern med 2004; 140:346–55. doi: 10.7326/0003-4819-140-5-20040302000010. 27. italian working group on endocrine complications in non-endocrine diseases. multicentre study on prevalence of endocrine complications in thalassaemia major: italian working group on endocrine complications in nonendocrine diseases. clin endocrinol (oxf ) 1995; 42:581–6. doi: 10.1111/j.1365-2265.1995.tb02683.x. 28. chern jp, lin kh, lu my, lin dt, lin ks, chen jd, et al. abnormal glucose tolerance in transfusion-dependent betathalassemic patients. diabetes care 2001; 24:850–4. doi: 10.2337/diacare.24.5.850. 29. merkel pa, simonson dc, amiel sa, plewe g, sherwin rs, pearson ha, et al. insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion. n engl j med 1988; 318:809–14. doi: 10.1056/nejm19880 3313181303. 30. fraser gm, harman i, meller n, niv y, porath a. diabetes mellitus is associated with chronic hepatitis c but not chronic hepatitis b infection. isr j med sci 1996; 32:526–30. 31. mason al, lau jy, hoang n, qian k, alexander gj, xu l, et al. association of diabetes mellitus and chronic hepatitis c virus infection. hepatology 1999; 29:328–33. doi: 10.1002/ hep.510290235. 32. mehta sh, brancati fl, sulkowski ms, strathdee sa, szklo m, thomas dl. prevalence of type 2 diabetes mellitus among persons with hepatitis c virus infection in the united states. ann intern med 2000; 133:592–9. doi: 10.7326/0003-4819-1338-200010170-00009. 33. yazicioglu g, isitan f, altunbas h, suleymanlar i, ozdogan m, balci mk, et al. insulin resistance in chronic hepatitis c. int j clin pract 2004; 58:1020–2. doi: 10.1111/j.17421241.2004.00170.x. 34. labropoulou-karatza c, goritsas c, fragopanagou h, repandi m, matsouka p, alexandrides t. high prevalence of diabetes mellitus among adult beta-thalassaemic patients with chronic hepatitis c. eur j gastroenterol hepatol 1999; 11:1033–6. 35. ladis v, chouliaras g, berdousi h, kanavakis e, kattamis c. longitudinal study of survival and causes of death in patients with thalassemia major in greece. ann n y acad sci 2005; 1054:445–50. doi: 10.1196/annals.1345.067. 36. bazrgar m, peiravian f, abedpour f, karimi m. causes for hospitalization and death in iranian patients with β-thalassemia major. pediatr hematol oncol 2011; 28:134–9. doi: 10.3109/08880018.2010.503336. 37. angelucci e, muretto p, nicolucci a, baronciani d, erer b, gaziev j, et al. effects of iron overload and hepatitis c virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. blood 2002; 100:17–21. doi: 10.1182/blood.v100.1.17. رد: حدوث اضطراب طيف التوحد واضطراب التصلب الدرين يف وقت واحد يف ثالثة أطفال تقارير حالة ومراجعة األدبيات re: coexistence of autism spectrum disorders among three children with tuberous sclerosis complex case reports and review of literature sir, i read with interest the case report by al-futaisi et al. published in the november 2016 issue of squmj which described three children with both autism spectrum disorders (asds) and tuberous sclerosis complex (tsc).1 in case one, computed tomography (ct) of the brain appeared normal. in case two, a magnetic resonance imaging (mri) scan of the brain revealed nodular heterotopias and tubers in the brain, adjacent to the right lateral ventricle; these mri findings, along with clinical features, confirmed a diagnosis of tsc.1 in the third case, an mri scan demonstrated multiple cortical and subcortical tubers and subependymal nodules in the brain, which subsequently led to the tsc diagnosis. although the tsc diagnoses were confirmed by mri or ct scans in all three cases, the authors stated that it was difficult to correlate mri findings with the severity of autistic features in each patient.1 however, i believe for the following two reasons that an in-depth evaluation of the mri findings could help to establish that correlation. first, the appearance of cortical tubers on an mri represents an important feature in the diagnosis of tsc. gallagher et al. identified three different types of cortical tubers: (1) type a tubers which were isointense on volumetric t1-weighted images and subtly hyperintense on t2-weighted and fluid-attenuated inversion recovery (flair) images; (2) type b tubers which were hypointense on volumetric t1-weighted images and homogeneously hyperintense on t2-weighted and flair images; and (3) type c tubers which were hypointense on volumetric t1-weighted images, hyperintense on t2-weighted images and heterogeneous on flair images with a hypointense central region surrounded by a hyperintense rim.2 accordingly, the clinical significance of the dominant tuber type was identified, with patients with type a tubers demonstrating a milder tsc phenotype.2 moreover, those with tubers predominantly of type c had an increased number of mri abnormalities—such as subependymal giant cell tumours—and were more likely to have an asd compared to patients with type a or b tubers.2 second, cortical tubers vary widely in size, location and appearance.2 cortical tubers in the temporal lobe and insular area have been found to be associated with asds.3 moreover, the presence of cystic-like tubers on mri scans might also offer a structural marker for asds in tsc.3 on the other hand, large tubers are reportedly more likely to be associated with asds, even in comparison to cases with numerous smaller tubers.4 mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al-futaisi a, idris a, al-sayegh a, al-mamari ws. coexistence of autism spectrum disorders among three children with tuberous sclerosis complex: case reports and review of literature. sultan qaboos univ med j 2016; 16:e520−4. doi: 10.18295/squmj.2016.16.04.022. 2. gallagher a, grant ep, madan n, jarrett dy, lyczkowski da, thiele ea. mri findings reveal three different types of tubers in patients with tuberous sclerosis complex. j neurol 2010; 257:1373−81. doi: 10.1007/s00415-010-5535-2. 3. huang ch, peng ss, weng wc, su yn, lee wt; national taiwan university hospital tuberous sclerosis complex (ntuh tsc) study group. the relationship of neuroimaging findings and neuropsychiatric comorbidities in children with tuberous sclerosis complex. j formos med assoc 2015; 114:849−54. doi: 10.1016/j.jfma.2014.02.008. 4. pascual-castroviejo i, hernández-moneo jl, pascual-pascual si, viaño j, gutiérrez-molina m, velazquez-fragua r, et al. significance of tuber size for complications of tuberous sclerosis complex. neurologia 2013; 28:550−7. doi: 10.1016/j.nrl.2012.11.002. letter to the editor sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e127–128, epub. 30 mar 17 submitted 24 dec 16 accepted 19 jan 17 doi: 10.18295/squmj.2016.17.01.027 re: coexistence of autism spectrum disorders among three children with tuberous sclerosis complex case reports and review of literature e128 | squ medical journal, february 2017, volume 17, issue 1 response from the authors sir, thank you for your interest in our article. recently, several studies have suggested an association between tuberous sclerosis complex (tsc) severity and parameters such as the genotype of the mutation, morphological and radiological features of tubers on magnetic resonance imaging (mri) and the pathological characteristics of brain biopsies.1–4 however, the clinical phenotype of tsc is highly variable, thus making prediction of the phenotype based on just one parameter challenging.2 in addition, to the best of our knowledge, there are currently no published studies focusing on the accumulative effects of all known tsc parameters on its clinical phenotype. furthermore, the exclusive correlation of neuromorphological features to clinical phenotype may underestimate the fact that tsc is a global disorder of brain development. conventional mri features of brain hamartomas may represent only a small portion of brain tsc lesions, as extensive disease has been found in white matter which appears structurally normal but has abnormal microstructures as demonstrated by histopathological analysis.5 in addition, increased axial diffusivity has been noted in major white matter tracts on diffusion tensor imaging.6 therefore, mri findings alone are not a good tool for predicting the phenotype severity of tsc cases. in conclusion, according to the current available literature, predicting the clinical phenotype of tsc is not possible. more clinical and genetic data are needed from large numbers of patients to help define more valid and clinicallyoriented genotype or phenotype correlations. amna al-futaisi,1 ahmed idris,1 abeer al-sayegh,2 *watfa s. al-mamari1 departments of 1child health and 2genetics, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: watfa.almamari@gmail.com references 1. overwater ie, swenker r, van der ende el, hanemaayer kb, hoogeveen-westerveld m, van eeghen am, et al. genotype and brain pathology phenotype in children with tuberous sclerosis complex. eur j hum genet 2016; 24:1688−95. doi: 10.1038/ejhg.2016.85. 2. curatolo p, moavero r, roberto d, graziola f. genotype/phenotype correlations in tuberous sclerosis complex. semin pediatr neurol 2015; 22:259−73. doi: 10.1016/j.spen.2015.10.002. 3. hu s, hu d, zhu wz, wang l, wang z. tuberous sclerosis complex: imaging characteristics in 11 cases and review of the literature. j huazhong univ sci technolog med sci 2016; 36:601−6. doi: 10.1007/s11596-016-1632-5. 4. ridler k, suckling j, higgins n, bolton p, bullmore e. standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. j child neurol 2004; 19:658−65. doi: 10.1177/08830738040190090501. 5. meikle l, talos dm, onda h, pollizzi k, rotenberg a, sahin m, et al. a mouse model of tuberous sclerosis: neuronal loss of tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. j neurosci 2007, 27:5546−58. doi: 10.1523/ jneurosci.5540-06.2007. 6. zikou ak, xydis vg, astrakas lg, nakou i, tzarouchi lc, tzoufi m, et al. diffusion tensor imaging in children with tuberous sclerosis complex: tract-based spatial statistics assessment of brain microstructural changes. pediatr radiol 2016; 46:1158−64. doi: 10.1007/s00247016-3582-2. https://doi.org/10.1038/ejhg.2016.85 https://doi.org/10.1016/j.spen.2015.10.002 https://doi.org/10.1007/s11596-016-1632-5 https://doi.org/10.1177/08830738040190090501 https://doi.org/10.1523/jneurosci.5540-06.2007 https://doi.org/10.1523/jneurosci.5540-06.2007 https://doi.org/10.1007/s00247-016-3582-2 https://doi.org/10.1007/s00247-016-3582-2 sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 1-2, epub. 27th feb 13 submitted 1st oct 12 revision reqd. 8th jan 13, revision recd. 10th jan 13 accepted 12th jan 13 the article in this issue by khitamy, divergent views on abortion and the period of ensoulment is not only interesting but also thought provoking.1 the word abortion (abortion is the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability2) is generally used interchangeably for spontaneous miscarriage and induced abortion. the royal college of obstetricians and gynecologists in the uk recommends the term miscarriage for spontaneous abortion.3 the term abortion most commonly refers to the induced abortion of a human pregnancy.3 badawy has clearly started with arguments from a philosophical point of view. it is worth noting that from a religious standpoint most religions discourage medical termination for any reason other than maternal welfare. according to the hindu scholar chandrasekhar, the hindu scriptures from the vedic age down to the smritis (100 bc to 100 ad) called it "bhrunahatya" ("fetus murder") or farbhahatya ("pregnancy destruction"), and condemned it as a serious sin.4 according to vishnu smriti (c. 100 bc to 100 ad), “the destruction of an embryo is tantamount to the killing of a holy or learned person” as quoted by chandrasekhar in his book. the catholic church opposes abortion because it believes that life is sacred and inviolable.5 the church of england combines strong opposition to abortion with the recognition that there can be strictly limited conditions under which it may be morally preferable to any available alternative.6 the teachings of buddhists, jains and even atheists and agnostics do not authorise abortion. the views of islam are well known and described in badawy’s article. most of the religions support the view that ‘abortion’ to save the life of the mother is acceptable. it would appear therefore that most religions do not support termination of pregnancy. but then how did medical and surgical terminations come into vogue? the abortion act of 1967, which became a law on 28th april 1968 in the uk, defined the acceptable reasons for medical termination of pregnancy.7 during the twelve years before the act, abortion was the leading cause of maternal mortality in england and wales. the first confidential enquiry into maternal deaths in 1952–54 reported 153 deaths from abortion, which was “procured by the woman herself in 58 instances.” the terminal event in 50% of illegal cases was sepsis but in 25% it was air embolus from “the injection under pressure of some fluid, nearly always soapy water, into the cervix or into the vagina.” this report commented that most of the women were “mothers of families”. after 1968, maternal deaths from illegal abortion fell slowly in the uk but did not disappear until 1982.8 in india, the shantilal shah committee (1964) recommended liberalisation of abortion law in 1966 to reduce maternal morbidity and mortality associated with illegal abortion. on this basis, in 1969, the medical termination of pregnancy bill was introduced in rajya sabha and lok sabha and passed by the indian parliament in august 1971.9 this editorial is incomplete without mentioning the famous cases of roe v. wade and doe v. bolton. in 1973, the supreme court in the usa handed down its landmark roe v. wade and doe v. bolton decisions legalising abortion in all 50 us states during all nine months of pregnancy, for any reason, medical, social, or otherwise.10 while roe declares department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: gowri@squ.edu.om اإلجهاض ونفخ الروح فيديناثان غوري editorial abortion and ensoulment vaidyanathan gowri abortion and ensoulment 2 | squ medical journal, february 2013, volume 13, issue 1 that the state may proscribe late term abortions in the interest of protecting fetal life after viability, it adds the caveat "except when it is necessary to preserve the life or health of the mother," which doe explains is to include not only physical health but mental health, to be understood to include factors such as age, familial status, emotional state, etc. from the above arguments, it is very obvious that termination of pregnancy is legally available in many countries and it came into effect to save the lives of mothers.11,12 the time of ensoulment is defined differently in various religions, varying from conception to the seventh month. the islamic view of 134 days (19 weeks + 1 day of conception) is well described by badawy;1 but the greeks believed it occurred during birth.12 however the theories of ensoulment and the legalisation of abortion laws do not always concur. most of the abortion acts support a maximum limit of 24 weeks and thus they address viability, which is physiologically demonstrable, whereas ensoulment is not. the case of abortion of a fetus with spina bifida, described by badawy, is one that is allowed legally in many countries where abortion laws exist, but not here in oman.1 although many anomalies can be diagnosed in the prenatal period, it is not always easy to quantify the amount of disability and the burden on a family/society that such anomalies will impose. the decision to terminate a pregnancy will have to be individualised by the clinician within the confines of the law of the country (if such a law exists) and it will always be up to the individual despite religious views. references 1. badawy abk. divergent views on abortion and the period of ensoulment. sultan qaboos university med j 2013; 13:26–31. 2. wikipedia. abortion. from: http://en.wikipedia.org/ wiki/abortion accessed oct 2012. 3. royal college of obstetricians and gynecologists. early pregnancy loss management tutorial. from: http://www.rcog.org.uk/stratog/page/appropriateterminology-1 accessed oct 2012. 4. chandrasekhar s. ed. abortion in a crowded world: the problem of abortion with special reference to india (the john danz lectures). washington, dc: university of washington press, 1974; p. 44. 5. society for the protection of unborn children. religious views on abortion. from: http://www. spuc .org .uk/youth/student_info_on_ab ortion/ religion accessed oct 2012. 6. the church of england. abortion. from: http:// w w w.churchofengland.org/our-vie ws/medicalethics-health-social-carepolic y/abortion.aspx accessed oct 2012. 7. uk legislation. medical termination of pregnancy. from: http://www.legislation.gov.uk/ukpga/1967/87/ section/1 accessed oct 2012. 8. royal college of obstetricians and gynecologists. human fertilisation and embryology bill. from: http://www.rcog.org.uk/what-we-do/campaigninga n d o p i n i o n s / b r i e fi n g s a n d q a s / h u m a n fertilisation-and-embryology-bill/-abor. accessed oct 2012. 9. legal service india. medical termination of pregnancy act, 1971. from: http://www. l e g a l s e r v i c e s i n d i a . c o m / a r t i c l e s / p r e g a c t . h t m accessed oct 2012. 10. us supreme court center. roe v. wade, 410 u.s.; 113, 163-164 (1973) and doe v. bolton, 410 u.s. 179, 191-192 (1973). from: http://supreme.justia.com/ cases/federal/us/410/179/case.html accessed oct 2012. 11. yari k, kazemi e,yarai r, tajehmiri a. islamic bioethics for fetus abortion in iran. am j sci res 2011; 18:118–121. 12. asman o. abortion in islamic countries: legal and religious aspects. med law 2004; 23:73–89. 13. philosophical, theological and scientific arguments. in: tyler a, zackin e, gilbert sf, eds. bioethics & the new embryology: springboards for debate. from http://www.sinauer.com/pdf/bioethicsch02.pdf accessed oct 2012. molecular karyotype analysis is becoming the standard tool for interrogating the genome of individuals with referrals of global developmental delay and related conditions.1,2 in this rapidly expanding field, the interpretation of detectable copy number losses and gains is becoming more challenging. we report here the first case of the paternal inheritance of a 6.3 mb interstitial deletion in 7q21 that appears to be associated with global developmental delay. the data suggest that haploinsufficiency of one or more genes that lie in this region may be playing a role in the proband’s phenotype. case report the proband, weighing 3 kg at birth, was the second child of a non-consanguineous couple. his motor milestones were slightly delayed; he walked at 18 months, at which time he was also able to feed himself with a spoon. he said his first words soon after his first birthday and was combining words before two years of age. challenging behaviours and symptoms of hyperactivity began to appear in the third and fourth years of life. the conners’ teacher rating scale, administered at 4 years of age, showed t-scores of 60 for conduct, 85 for hyperactivity, 66 for inattention/passivity, and 62 for hyperactivity. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 306-310, epub. 9th may 13 submitted 17th may 12 revision req. 4th jul 12, revision recd. 6th jul 12 accepted 25th sep 12 1diagnostic genetics,labplus, 2northern regional genetic service, auckland city hospital, auckland, new zealand; 3school of medical sciences, university of auckland, auckland, new zealand *corresponding author e-mail: donaldl@adhb.govt.nz األثار املرتتبة على فقدان اخلنب الصبغي اجلزيئي ودور جني pclo يف صعوبات التعلم روبرتو ل. مازت�ض، ا�شتون فريون ،�شامل اأفيتمو�ض، األي�ض م. جورج، دونالد ر. لوف. امللخ�ص: هذا تقرير حالة ل�شبي عمره 4 �شنوات م�شاب بتاأخر التطور العام وقد مت حتويله اإىل امل�شت�شفى من اأجل عمل التنميط النووي وفح�ض ال�شبغ الوراثي. اأثبت الفح�ض وجود خنب �شبغي خاليل على ال�شبغ الوراثي رقم 7 يف الربطة 7q21 يف كل اخلاليا و اأظهر حتليل التنميط النووي اجلزيئي نتائج تف�شيلية يف 6.3 م ب خنب ال�شبغ الأحادي املحتوي على منطقة ال�شبغ الوراثي 7q21.11م ويف هذه املنطقة فقرية اجلينات فاإنه من املمكن اأن فقدان اأرقام ال�شنخ يف جني pclo هو امل�شوؤول عن النمط الظاهري ال�رسيري و با�شتخدام حتليل ال�شبغات الوراثية بطريقة الرابطة ج لالآباء ثبت اأن هذا اجلني ال�شبغي قد ورث من الأب. وبتحليل التنميط النووي اجلزيئي لكامل اجلينوم لالأب ثبت اأنها متماثلة مع املوجودة يف الأبن بالرغم من اختالف النمط الظاهري لالأب والأبن. هذا اخلنب ال�شبغي الظاهر هو مثال اأخر لإعادة تنظيم الأ�شباغ الوراثية بالرغم من اختالف النمط الظاهري لأفراد العائلة الواحدة. مفتاح الكلمات: بروتني pclo؛ الب�رسي؛ النق�شان الن�شفي؛ ال�شبغ الوراثي 7؛ التثلث ال�شبغي 7q؛ نيوزيالندا؛ تقرير حالة. abstract: we report here a 4-year-old boy with global developmental delay who was referred for karyotyping and fragile x studies. a small interstitial deletion on chromosome 7 at band 7q21 was detected in all cells examined. subsequent molecular karyotype analysis gave the more detailed result of a 6.3 mb heterozygous deletion involving the interstitial chromosome region 7q21.11. in this relatively gene-poor region, the presynaptic cytomatrix protein, piccolo (pclo) gene appears to be the most likely candidate for copy number loss leading to a clinical phenotype. g-banded chromosome analysis of the parents showed this deletion was inherited from the father. molecular karyotype analysis of the father’s genome confirmed that it was the same deletion as that seen in the son; however, the father did not share the severity of his son’s phenotype. this cytogenetically-visible deletion may represent another example of a chromosomal rearrangement conferring a variable phenotype on different family members. keywords: pclo protein, human; haploinsufficiency; chromosome7, trisomy 7q; case report; new zealand. implications of a chr7q21.11 microdeletion and the role of the pclo gene in developmental delay roberto l. mazzaschi,1 fern ashton,1 salim aftimos,2 alice m. george,1 *donald r. love1,3 case report roberto l. mazzaschi, fern ashton, salim aftimos, alice m. george and donald r. love case report | 307 he was a non-dysmorphic child with a completely normal physical examination, growing along the 75th centile for height. the proband’s 7-year-old sister had no behavioural or developmental problems and was performing at an above-average level at school. the proband’s father had had learning difficulties throughout his childhood which were referred to as dyslexia. he had particular difficulties in mathematics and english and required extra help and tuition. he was able to complete his high school studies and went on to obtain a training certificate and a diploma from a technical college. peripheral blood was taken for both routine g-banding and molecular karyotype analysis. in respect to the latter, genomic deoxyribonucleic acid (dna) was isolated from the peripheral blood using the gentra puregene® blood kit (qiagen genomics, bothell, washington, usa) according to the manufacturer’s instructions. using the affymetrix® cytogenetics reagent kit (affymetrix, santa clara, california, usa) 0.1 micrograms of genomic dna were labelled. the labelled dna was applied to an affymetrix® cytogenetics array (2.7 million probes) according to the manufacturer’s instructions, and the array was scanned. the data were analysed using the affymetrix® chromosome analysis suite (chas), version 1.0.1 and interpreted with the aid of the university of california santa cruz genome browser (hg18 assembly).3 routine g-banded chromosome analysis was undertaken in duplicate for the proband and his parents, which identified a subtle interstitial deletion in the long arm of one chromosome 7, both in the proband and his father [figure 1] 46,xy,del(7) (q21.1q21.1). molecular karyotype analysis of the proband confirmed a 6.3 mb interstitial heterozygous deletion in the chromosome region 7q21.11 (hg18 coordinates chr7: 79,573,97585,833,865) [figure 2], as well as a 458 kb terminal duplication in the chromosome region xp22.33 (hg18 coordinates chrx:858,113-1,316,852). this terminal x chromosome region carries the crfl2 gene (cytokine receptor-like factor 2), which is a receptor for thymic stromal lymphopoietin and so would not appear to play any role in the phenotype of the proband. molecular karyotyping of the father figure 1 panels a–c: partial karyotype and ideograms of chromosomes 7 of proband and father. panel a: the homologous chromosomes 7 from two metaphase spreads (m1 and m2) of the proband. panel b: the homologous chromosomes 7 from two metaphase spreads (m1 and m2) of the proband’s father. panel c: an ideogram of the location of the deletion on chromosome 7 (left), and a normal chromosome 7 (right). figure 2 panels a&b: schematic of the chromosome 7 region that is deleted in the proband. panel a: ideogram of chromosome 7, together with the location and extent of the deletion detected in the proband (7q21.11; hg18 coordinates chr7: 79,573,975-85,833,865; boxed in red). panel b: shows the refseq genes that are localised to the deleted region, those genes that are curated in the online mendelian inheritance in man (omim) database4 and cases reported in the decipher database.13 the images were taken from the ucsc genome browser.3 implications of a chr7q21.11 microdeletion and the role of the pclo gene in developmental delay 308 | squ medical journal, may 2013, volume 13, issue 2 showed the same 6.3 mb heterozygous deletion in 7q21.11 (hg18 coordinates chr7:79,573,96785,835,041); the small x chromosome duplication event detected in the proband was not found in the father. the 6.3 mb deletion was not detected in the paternal grandparents of the proband; hence, the deletion arose de novo in the father. table 1 summarises the genes that are localised to the chromosome 7 region which were deleted in the proband. discussion the deleted region of chromosome 7 encompasses 10 genes [table 1]. of these, the online mendelian inheritance in man (omim)4 database shows that 3 are disease-causing: omim 173510 (platelet glycoprotein iv deficiency), omim 142409 (hepatic growth factor), and omim 608166 (semaphorin 3e/ coloboma, heart defect, atresia choanae, retarded growth and development, genital abnormality, and ear abnormality [charge] syndrome). in terms of the latter, disruption of, or mutations in, the sema3e gene are rare in patients with charge syndrome, which is associated with mental retardation but usually occurs in combination with eye defects (coloboma) and heart anomalies that were not detected in the case reported here.5 only one charge patient has been described with a mutation in the sema3e gene, and this was a missense mutation resulting in a serine to leucine substitution at amino acid position 243.5 of the table 1: genes that lie in the chromosome 7 region: 79,573,975-85,833,865 (hg18 coordinates) gene protein omim description gnai1 guanine nucleotide binding protein g(i) subunit alpha-1 139310 the encoded protein is part of a complex that responds to beta-adrenergic signals by inhibiting adenylate cyclase. cd36 cd36 molecule (thrombospondin receptor) 173510 this protein may have important functions as a cell adhesion molecule. mutations in this gene cause platelet glycoprotein deficiency. sema3c semaphorin 3c 602645 this protein is a non-multidrug resistance gene of human cancers hgf hepatocyte growth factor (hepapoietin a; scatter factor) 142409 hepatocyte growth factor regulates cell growth, cell motility, and morphogenesis by activating a tyrosine kinase signaling cascade after binding to the proto-oncogenic c-met receptor. cacna2d1 voltage-dependent calcium channel subunit alpha-2/delta-1 114204 this gene encodes a member of the alpha-2/ delta subunit family, which is a protein in the voltage-dependent calcium channel complex. pclo piccolo (presynaptic cytomatrix protein) 604918 the protein encoded by this gene is part of the presynaptic cytoskeletal matrix, which is involved in establishing active synaptic zones and in synaptic vesicle trafficking. variations in this gene have been associated with bipolar disorder and major depressive disorder. sema3e semaphorin 3e 608166 semaphorins serve as axon guidance ligands via multimeric receptor complexes. screening of patients with charge syndrome for mutations in the sema3e gene revealed a de novo missense mutation in an unrelated patient. sema3a semaphorin 3a 603961 this secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. in both cases, the protein is vital for normal neuronal pattern development. increased expression of this protein is associated with schizophrenia. sema3d semaphorin 3d 609907 knockdown of the zebrafish orthologue of semaphorin 3d (sema3d) reduces the number of peripheral axons, and expression in the chick suggests that this protein may play an important role in heart development. omim = online mendelian inheritance in man; charge = coloboma, heart defect, atresia choanae, retarded growth and development, genital abnormality, and ear abnormality. roberto l. mazzaschi, fern ashton, salim aftimos, alice m. george and donald r. love case report | 309 remaining genes located in the deleted region, the presynaptic cytomatrix protein, piccolo (pclo), gene appears to be a likely candidate to be associated with developmental delay. the pclo gene expresses piccolo (presynaptic cytomatrix protein) which is a component of the presynaptic cytoskeletal matrix that is involved in maintaining the neurotransmitter release site in register with the postsynaptic reception apparatus.6–9 piccolo appears be involved in the cycling of synaptic vesicles at presynaptic nerve terminals of glutamatergic and gamma aminobutyric acid-ergic (gabaergic) central nervous system synapses. overexpression of the pclo gene has been implicated in bipolar/mood disorders in humans.10 interestingly, knockdown studies in mice show that piccolo controls the extracellular levels of glutamate in the hippocampus when stimulated, and appears to play a pivotal role in synaptic plasticity in area ca1 and in hippocampus-dependent learning.11 it is tempting to speculate that the semaphorin genes that are localised to the deleted chromosome 7 region may also play a role, together with the pclo gene, in the proband’s phenotype. the semaphorins have roles in axonal guidance and haploinsufficiency for these proteins may affect normal brain development; however, animal modelling data are limited in terms of heterozygous knockdown studies of these genes. at least for semaphorin 3c, targeted disruption of the mouse orthologue leads to cardiovascular defects although only in the homozygous state; heterozygous mice are indistinguishable from their wild-type littermates.12 significantly, the database of chromosomal imbalance and phenotype in humans using ensembl resources (decipher) database13 contains two patients’ entries, cases 854 and 855 carrying deletions of 35.4 mb and 17 mb, respectively, that largely overlap the region identified in the case reported here; these patients exhibited a developmental delay/mental retardation phenotype. in addition, courtens et al. reported a patient with moderate developmental delay and mild dysmorphic features with maternal monosomy in chromosome 7q21 (between 75.82 mb and 92.59 mb).14 also of relevance is the almost complete absence of large genomic variation among unaffected individuals within this region of chromosome 7 suggesting that copy-number variations (cnvs) in this region are not benign. if piccolo contributed to the phenotype observed in our case study, then a number of mechanisms might explain why the same deletion that was present in the proband’s father resulted in a less severe clinical phenotype. clinical variability may be due to a two hit model, or allelespecific expression.15,16 in respect of the former, an additional cnv, or a mutation below our detection threshold, may underlie differing clinical severity. in respect of the latter, it is unclear if there are parent-of-origin expression differences of the pclo gene. interestingly, imprinting of chromosome 7 is well-documented, but appears to be limited to those genes that lie distally in 7q23.1.17–19 this case represents another example of a chromosomal rearrangement conferring a variable phenotype on different family members.20 conclusion this rare case is the first to report a small but detectable interstitial deletion in 7q11.23 that is paternally-inherited and appears to be implicated in developmental delay. haploinsufficiency of the pclo gene seems to be the most likely explanation for the clinical phenotype. further cases of deletions that lie in this region of chromosome 7 should help confirm the role of piccolo in developmental delay, and the mechanism underpinning clinical variability. references 1. george a, marquis-nicholson r, zhang lt, love jm, ashton f, aftimos s, et al. chromosome microarray analysis in a clinical environment: new perspective and new challenge. br j biomed sci 2011; 68:100–8. 2. marquis-nicholson r, aftimos s, hayes i, george a, love dr. array comparative genomic hybridisation: a new tool in the diagnostic genetic armoury. nz med j 2010; 123:50–61. 3. genome browser. university of california santa cruz (ucsc). from: http://genome.ucsc.edu accessed: apr 2012. 4. online mendelian inheritance in man (omim) database. from: http://www.ncbi.nlm.nih.gov/omim accessed: apr 2012. 5. lalani sr, safiullah am, molinari lm, fernbach sd, martin dm, belmont jw. sema3e mutation in a patient with charge syndrome. j med genet 2004; 41:e94. 6. fenster sd, chung wj, zhai r, cases-langhoff c, implications of a chr7q21.11 microdeletion and the role of the pclo gene in developmental delay 310 | squ medical journal, may 2013, volume 13, issue 2 voss b, garner am, et al. piccolo, a presynaptic zinc finger protein structurally related to bassoon. neuron 2000; 25:203–14. 7. fenster sd, garner cc. gene structure and genetic localization of the pclo gene encoding the presynaptic active zone protein piccolo. int j dev neurosci 2002; 20:161–71. 8. fenster sd, kessels mm, qualmann b, chung wj, nash j, gundelfinger ed, et al. interactions between piccolo and the actin/dynamin-binding protein abp1 link vesicle endocytosis to presynaptic active zones. j biol chem 2003; 278:20268–77. 9. mukherjee k, yang x, gerber sh, kwon hb, ho a, castillo pe, et al. piccolo and bassoon maintain synaptic vesicle clustering without directly participating in vesicle exocytosis. proc natl acad sci usa 2010; 107:6504–9. 10. choi kh, higgs bw, wendland jr, song j, mcmahon fj, webster mj. gene expression and genetic variation data implicate pclo in bipolar disorder. biol psychiatry 2011; 69:353–9. 11. ibi d, nitta a, ishige k, cen x, ohtakara t, nabeshima t, et al. piccolo knockdown-induced impairments of spatial learning and long-term potentiation in the hippocampal ca1 region. neurochem int 2010; 56:77–83. 12. feiner l, webber al, brown cb, lu mm, jia l, feinstein p, et al. targeted disruption of semaphorin 3c leads to persistent truncus arteriosus and aortic arch interruption. development 2001; 128:3061–70. 13. database of chromosomal imbalance and phenotype in humans using ensembl resources (decipher) database. from: http://decipher.sanger.ac.uk/ accessed: apr 2012. 14. courtens w, vermeulen s, wuyts w, messiaen l, wauters j, nuytinck l, et al. an interstitial deletion of chromosome 7 at band q21: a case report and review. am j med genet a 2005; 134a:12–23. 15. girirajan s, rosenfeld ja, cooper gm, antonacci f, siswara p, itsara a, et al. a recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. nat genet 2010; 42:203–9. 16. nord as, roeb w, dickel de, walsh t, kusenda m, o'connor kl, et al. reduced transcript expression of genes affected by inherited and de novo cnvs in autism. eur j hum genet 2011; 19:727–31. 17. okita c, meguro m, hoshiya h, haruta m, sakamoto yk, oshimura m. a new imprinted cluster on the human chromosome 7q21-q31, identified by humanmouse monochromosomal hybrids. genomics 2003; 81:556–9. 18. monk d, wagschal a, arnaud p, müller ps, parkerkatiraee l, bourc'his d, et al. comparative analysis of human chromosome 7q21 and mouse proximal chromosome 6 reveals a placental-specific imprinted gene, tfpi2/tfpi2, which requires ehmt2 and eed for allelic-silencing. genome res 2008; 18:1270–81. 19. dória s, sousa m, fernandes s, ramalho c, brandão o, matias a, et al. gene expression pattern of igf2, phlda2, peg10 and cdkn1c imprinted genes in spontaneous miscarriages or fetal deaths. epigenetics 2010; 5:444–50. 20. al-murrani a, ashton f, aftimos s, george am, love dr. amino-terminal microdeletion within the cntnap2 gene associated with variable expressivity of speech delay. case rep genet 2012; 2012:172408. عالقة مسك البطانة الداخلية والوسطى وقطر اللمعية للشريان السبايت مع مؤشر كتلة اجلسم وعوامل اخلطورة القلبية الوعائية األخرى عند البالغني �سميعة عبدالرحمن ر�سيد و �رسب�ست حممود abstract: objectives: this study aimed to examine the correlation between carotid artery intima-media thickness (imt) and luminal diameter (ld) with body mass index (bmi) and other cardiovascular risk factors. methods: this observational cross-sectional study took place between june 2013 and march 2014 in the radiology department of rizgary teaching hospital in erbil, iraq. non-randomly selected subjects ≥20 years old (n = 140) were divided into bmi groups and evaluated for the following cardiovascular risk factors: gender, age, hypertension (htn), diabetes (dm), smoking, alcohol consumption, blood pressure, serum total cholesterol and triglyceride (tg) levels. imt and ld of the extracranial carotid arteries were measured by b-mode ultrasonography. results: the mean imt was 0.8 ± 0.3 mm, ranging from a total mean of 0.7 mm in the normal bmi group to 1.0 mm in the extremely obese group. a significant correlation was found between imt and bmi (p = 0.04), but not between bmi and ld (p = 0.3). no significant difference in mean imt or ld was seen between genders. significant correlations were found between imt and age, htn, dm, high serum cholesterol and tg levels (p <0.001). an increase of one bmi unit caused a 0.009 mm increase in imt and an increase of one year in age caused a 0.011 mm increase in imt. conclusion: age, obesity, htn, dm, high serum cholesterol and tg levels were found to have an impact on carotid imt, which is a strong marker for the early development of atherosclerosis. keywords: carotid intima-media thickness; ultrasonography; atherosclerosis; body mass index; risk factors; iraq. امللخ�ص: الهدف: تهدف هذه الدرا�سة اإىل فح�س العالقة بني �سمك البطانة الداخلية والو�سطى )imt( وقطر اللمعية )ld( لل�رسيان ال�سباتي مع موؤ�رس كتلة اجل�سم وغريها من عوامل اخلطورة القلبية الوعائية. الطريقة: اأجريت هذه الدرا�سة م�ستعر�سة الر�سد يف الفرتة ما بني يونيو 2013 و مار�س 2014 يف ق�سم الأ�سعة يف م�ست�سفى رزكاري التعليمي يف اأربيل، بالعراق. ومت تق�سيم احلالت املختارة بطريقة غري ع�سوائية ،)htn( و قيمت عوامل اخلطر القلبية الوعائية كالتايل: نوع اجلن�س،ال�سن،ارتفاع �سغط الدم )bmi( اإىل جمموعات )20≤ �سنة )140 حالة ld و imt يف الدم. ومت قيا�س )tg( التدخني وا�ستهالك الكحول، و م�ستويات الكول�سرتول الكلي والدهون الثالثية ،)dm( مر�س ال�سكري لل�رسايني ال�سباتية خارج القحف عن طريق املوجات فوق ال�سوتية نوع b. النتائج: اإن متو�سط imt كانت 0.3 ± 0.8 مم، بدءا من املعدل الكلي لـ 0.7 مم يف جمموعة bmi العادية ل 1.0 مم يف املجموعة ذات ال�سمنة املفرطة للغاية. مت العثور على ارتباط وثيق بني imt و p = 0.04( bmi( ولكن لي�س بني موؤ�رسي كتلة اجل�سم و ld )p = 0.3(. ومل يوجد فرق كبري يف متو�سط imt و ld بني اجلن�سني. مت العثور على ارتباط كبري بني imt والعمر، dm ،htn، ارتفاع ن�سبة الكولي�سرتول وtg يف الدم ) p >0.001( .وقد لوحظ اأن زيادة وحدة واحدة لـ bmi ت�سبب يف زيادة 0.009 مم يف imt و زيادة �سنة واحدة يف العمر توؤدي اىل زيادة 0.011 مم يف imt. اخلال�سة: خل�ست الدرا�سة اإىل اأن العمر وال�سمنة وhtn، وارتفاع ن�سبة الكولي�سرتول و dm وم�ستويات tg يف الدم لها تاأثري معنوي على imt لل�رسيان ال�سباتي، والذي يعترب موؤ�رسا قويا للن�سوء املبكر لت�سلب ال�رسايني. مفتاح الكلمات: �سمك البطانة الداخلية والو�سطى لل�رسيان ال�سباتي؛ املوجات فوق ال�سوتية؛ ت�سلب ال�رسايني؛ موؤ�رس كتلة اجل�سم؛ عوامل اخلطورة؛ العراق. correlation between carotid artery intima-media thickness and luminal diameter with body mass index and other cardiovascular risk factors in adults *sameeah a. rashid1 and sarbast a. mahmud2 sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e344–350, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.007. submitted 28 sep 14 revisions req. 22 jan & 16 mar 15; revisions recd. 18 feb & 25 mar 15 accepted 29 mar 15 departments of 1surgery and 2radiology, college of medicine, hawler medical university, hawler, iraq *corresponding author e-mail: samiaaabdulrahman77@yahoo.com advances in knowledge obesity, age, hypertension, diabetes, high serum cholesterol and triglyceride levels had a large impact on carotid intima-media thickness (imt) among the studied sample in iraq. this is important as an increased carotid imt can be an indicator of early-stage atherosclerosis. the results of this study found that a one unit increase in body mass index caused a 0.009 mm increase in imt and a one year increase in age caused a 0.011 mm increase in imt. application to patient care carotid imt measurement using b-mode ultrasonography can be used as a surrogate marker for monitoring the development of atherosclerosis. clinical & basic research sameeah a. rashid and sarbast a. mahmud clinical and basic research | e345 atherosclerosis can develop as a result of the thickening of the intimal layer of the arterial wall; however, it is currently impossible to measure intima thickness alone in vivo.1 ultrasonography is therefore often used to indirectly assess intima thickness by measuring the intimamedia thickness (imt). in atherosclerotic-prone vasculature, it is known that an increase in imt is an indicator of intimal thickening.1 before non-invasive procedures were developed, ethical considerations prevented any investigation of the carotid arteries in healthy subjects. without direct observation and quantification, atherosclerotic changes and their complications were believed to be a manifestation of ageing and hence unavoidable.1 assessments of arterial wall atherosclerosis were restricted to pathology and angiography studies.2 however, the introduction of ultrasound technology permitted the study of healthy subjects as well as those who are symptomatic. whereas angiography and pulse-wave doppler sonography measure arterial stenosis, b-mode ultrasonography measures arterial wall thickness and is therefore capable of detecting early atheromatous lesions before they induce disturbed flow patterns.3 early phases of atherosclerotic plaque formation may result in thickened arterial walls with simultaneous dilatation, thereby preserving the lumen.1 thus, there is growing interest in using b-mode ultrasonography as a non-invasive, sensitive, readily available and reproducible technique to measure imt and luminal diameter (ld) in order to study the natural history of early atherosclerosis changes, long before a decrease in ld would occur naturally.1 early detection of arteriosclerosis is crucial to ensure that appropriate prophylactic measures can be undertaken before cardiovascular events occur. unfortunately, the drawbacks of studies investigating the incidence of acute vascular disease endpoints include high costs and the need for long timelines and large sample populations. hence, the use of a surrogate marker is important since it allows researchers to gather reliable data in a reduced timeframe using smaller samples.4 carotid imt (c-imt) measurements are an accepted surrogate marker of atherosclerosis and impart prognostic information independent of traditional cardiovascular risk factors.5 coll et al. emphasised the importance of c-imt measurements, stating that the significance of these measurements are commensurate to traditional cardiovascular risk factors.4 obesity and other atherosclerotic risk factors for myocardial infarction and stroke are very common in iraq.6,7 to the best of the authors’ knowledge, there are no previous studies from iraq reporting the effects of being overweight on atherosclerosis of the extracranial carotid arteries. this study therefore aimed to investigate the effects of body mass index (bmi) on carotid atherosclerosis using measurements of ld and c-imt in an iraqi population. in addition, this study aimed to detect possible relationships between cardiovascular risk factors and early stage arteriosclerosis. methods this observational cross-sectional study was carried out in the radiology department of rizgary teaching hospital in erbil, iraq, between june 2013 and march 2014. a total of 150 non-randomly selected adults underwent b-mode ultrasonography of the extracranial carotid arteries. subjects of both genders, diverse ages and with differing bmi measurements were included. cases were selected non-randomly in collaboration with outpatient clinics to preserve a bmi, age and sex equilibrium and avoid discrepancy in their numbers. bodybuilders, pregnant women and patients with a history of ischaemic heart disease (ihd) and stroke were excluded from the study as the former two conditions could result in false-high bmis while the latter two could interfere with the interpretation of the results. subjects under 18 years of age were also excluded as c-imt is only affected by age or gender after this cut-off point.8 six female and four male subjects were also excluded from the study due to technical difficulties in determining acceptable imt and ld measurements from the internal carotid artery (ica; n = 8) and carotid bifurcation (cbif; n = 2), resulting in a total sample of 140 subjects. subjects were classified according to bmi into the following subgroups: underweight (<18.5 kg/m2), normal (18.5–24.99 kg/m2), overweight (25–29.99 kg/m2), obese (30–39.9 kg/m2) and extremely obese (bmi ≥40 kg/m2). the subjects were also divided into age groups (20–29 years old, 30–39 years old, 40–49 years old, 50–59 years old and ≥60 years old). ultrasound scans were performed by a radiologist with five years’ experience in the field. each case was examined once but measurements for each segment of interest were taken and revised several times. mean increased imt measurements in a patient should alert healthcare providers that primary prevention measures may be needed to avoid cardiovascular events. correlation between carotid artery intima-media thickness and luminal diameter with body mass index and other cardiovascular risk factors in adults e346 | squ medical journal, august 2015, volume 15, issue 3 maximum measurements were recorded to reduce the chance of errors. the ultrasound machine (hd11 xe ultrasound system, version 2010, philips healthcare, bothell, washington, usa) was equipped with a 7–10 megahertz linear array transducer. subjects were examined in supine positions with their heads slightly elevated and turned to the contralateral side. the site of the carotid segments to be studied was determined according to the distance from the flow divider as follows: common carotid artery (cca) 1 cm segment proximal to the dilation of the carotid bulb; 1 cm segment proximal to the flow divider (cbif); and 1 cm segment in the internal branch distal to the flow divider (ica).2 c-imt measurements were taken from the leading edges of the far wall echoes while ld measurements were taken from the leading edge of the near wall intima-lumen echo to the leading edge of the echo from the far wall lumen-intima interface (the same location as the imt measurements).9 both sides of the carotid arteries were examined with longitudinal scans. when an optimal longitudinal image was obtained, the image was magnified and frozen and the imt and ld were measured. a transverse scan was occasionally performed when needed. plaque identified within the segment of interest was also included in the measurement. to obtain proper measurements in an atherosclerotic region, the same ultrasound acoustic settings (such as dynamic range, gain, mechanical index and probe frequency) used for the normal region (baseline settings) were also applied for the thickened region, with special attention to focal zone adjustment. variables for the study included maximum c-imt values and the means of these maximums. maximum values for the common c-imt (cc-imt), cbif, ica and the whole carotid tree were taken for both the right and left side. subsequently, the means of both sides were taken and stated as the total maximum c-imt. the same parameters were used for ld. correlations between the total maximum c-imt and total maximum carotid ld (c-ld) variables were made with bmi, age and cardiovascular risk factors table 1: demographic characteristics of a sample of iraqi adults according to body mass index and age group (n = 140) bmi category* total n (%)uw n ow o eo a ge g ro up in y ea rs 20–29 1 15 12 3 1 32 (22.9) 30–39 0 9 15 10 1 35 (25) 40–49 1 6 8 11 0 26 (18.6) 50–59 1 4 5 10 6 26 (18.6) ≥60 1 7 5 7 1 21 (15) total, n (%) 4 (2.9) 41 (29.3) 45 (32.1) 41 (29.3) 9 (6.4) 140 (100) bmi = body mass index; uw = underweight; n = normal; ow = overweight; o = obese; eo = extremely obese. *categories were defined as follows: underweight (bmi <18.5 kg/m2), normal (bmi = 18.5–24.99 kg/m2), overweight (bmi = 25–29.99 kg/m2), obese (bmi = 30–39.9 kg/m2) and extremely obese (bmi ≥40 kg/m2). table 2: correlations between body mass index and the intima-media thickness and luminal diameter of carotid arteries among a sample of iraqi adults (n = 140) mean maximum imt in mm mean maximum ld in mm mean maximum tc in mmcca cbif ica whole carotid cca cbif ica whole carotid rt lt rt lt rt lt rt lt rt lt rt lt rt lt rt lt imt ld b m i c at eg or y* uw 0.9 0.8 1.4 0.9 0.7 0.8 0.98 0.8 5.9 5.5 6.8 6.7 4.9 4.5 5.9 5.6 0.9 5.8 n 0.6 0.7 0.8 0.8 0.7 0.7 0.7 0.7 5.7 5.7 6.8 6.7 4.7 4.6 5.7 5.7 0.7 5.7 ow 0.7 0.7 0.7 0.8 0.7 0.7 0.7 0.7 6.0 5.9 7.4 7.1 4.8 4.5 6.1 5.8 0.7 6.0 o 0.8 0.8 0.9 0.9 0.8 0.8 0.8 0.8 6.1 5.9 7.2 7.2 4.6 4.8 6.0 6.0 0.8 6.0 eo 0.9 0.8 1.1 0.9 0.9 0.9 1.0 0.9 5.8 5.8 7.3 7.3 4.8 4.7 6.0 5.9 1.0 6.0 total 0.7 0.7 0.8 0.8 0.7 0.7 0.8 0.8 6.0 5.8 7.1 7.0 4.7 4.6 5.9 5.8 0.8 5.9 sd 0.2 0.2 0.4 0.4 0.3 0.3 0.3 0.3 0.7 0.7 1.1 1.0 0.8 0.8 0.8 0.7 0.3 0.67 p value <0.001 0.06 0.003 0.8 0.6 0.1 0.001 0.21 0.3 0.4 0.1 0.2 0.8 0.4 0.3 0.3 0.04 0.3 imt = intima-media thickness; ld = luminal diameter; tc = total carotid; cca = common carotid artery; cbif = carotid bifurcation; ica = internal carotid artery; rt = right; lt = left; bmi = body mass index; uw = underweight; n = normal; ow = overweight; o = obese; eo = extremely obese; sd = standard deviation. *categories were defined as follows: underweight (bmi <18.5 kg/m2), normal (bmi = 18.5–24.99 kg/m2), overweight (bmi = 25–29.99 kg/m2), obese (bmi = 30–39.9 kg/m2) and extremely obese (bmi ≥40 kg/m2). sameeah a. rashid and sarbast a. mahmud clinical and basic research | e347 for atherosclerosis. cardiovascular risk factors for atherosclerosis were determined using a standardised questionnaire administered to every participant. risk factors included a personal history of diabetes mellitus (dm), hypertension (htn), smoking and alcohol consumption. family histories of stroke and ihd were also evaluated. height and weight were assessed on a single scale. blood pressure was measured using mercury sphygmomanometers (alpk2, danyang sai fukang medical instrument co. ltd., tokyo, japan) with participants in a sitting position. serum total cholesterol and triglycerides (tg) measurements were taken for each subject; however, lowand highdensity lipoprotein testing was not performed due to technical issues. statistical analysis was performed using the statistical package for the social sciences (spss), version 16.0 (ibm corp., chicago, illinois, usa). descriptive quantitative data were presented as frequencies or means ± standard deviation (sd). sideto-side differences between right and left sides and differences between bmi groups were tested with independent sample tand analysis of variance tests. a p value of <0.05 was considered statistically significant. this study was approved by the research ethics committee of hawler medical university in erbil, iraq. informed consent was obtained from all participants before inclusion. results a total of 140 subjects between 20–88 years old were included in the study (mean age: 43.11 ± 15.47 years old). there were 84 males (60%; mean age: 41.95 ± 15.79 years old) and 56 females (40%; mean age: 44.84 ± 14.95 years old). the demographic characteristics of the subjects by bmi category and age group are shown in table 1. statistical analysis revealed a significant correlation between bmi and mean maximum total c-imt (p = 0.04) while the correlation between bmi and mean maximum total c-ld was not significant (p = 0.3) [table 2]. there was no significant difference for sideto-side ld or imt in the paired cca, cbif and ica values. additionally, no significant differences were noted between mean maximum imt or ld values in males and females [table 3]. pearson correlation plots demonstrated close relationships between c-imt and table 3: mean maximum luminal diameter and intimamedia thickness values among a sample of iraqi adults according to body mass index and gender (n = 140) mean maximum imt in mm mean maximum ld in mm male female male female b m i c at eg or y* underweight 0.86 1.03 5.56 6.16 normal 0.74 0.67 5.80 5.46 overweight 0.72 0.64 6.10 5.40 obese 0.79 0.79 6.23 5.70 extremely obese 0.91 5.96 total 0.75 0.75 6.02 5.63 p value 0.6 0.02 0.11 0.1 imt = intima-medial thickness; ld = luminal diameter; bmi = body mass index. *categories were defined as follows: underweight (bmi <18.5 kg/m2), normal (bmi = 18.5–24.99 kg/m2), overweight (bmi = 25–29.99 kg/m2), obese (bmi = 30–39.9 kg/m2) and extremely obese (bmi ≥40 kg/m2). figure 1a & b: pearson correlation plots showing (a) a fair correlation between bmi and carotid imt (p = 0.005; pearson correlation coefficient = 0.236) and (b) a strong correlation between age and carotid imt (p <0.001; pearson correlation coefficient = 0.731) among a sample of iraqi adults (n = 140). imt = intima-media thickness; bmi = body mass index. correlation between carotid artery intima-media thickness and luminal diameter with body mass index and other cardiovascular risk factors in adults e348 | squ medical journal, august 2015, volume 15, issue 3 bmi [figure 1a] and age [figure 1b]. a regression coefficient analysis between imt and bmi and between imt and age was used to find the rate of wall thickness progression [table 4]. a one-unit increase in bmi caused a 0.009 mm increase in imt. a one year increase in age caused a 0.011 mm increase in imt. a one unit increase in bmi was equivalent to a 0.81 year (9.81 month) increase in age. a significant correlation between htn and both mean maximum imt and mean maximum ld was observed (p <0.001 for both). additionally, dm and high serum cholesterol and tg levels showed significant correlations with imt (p = 0.016, 0.028 and 0.045, respectively) but not with mean maximum ld. no correlation was detected between either imt or ld with regards to other risk factors, including a family history of stroke or ihd, alcohol intake and smoking [table 5]. discussion in the current study, a significant positive correlation was observed between c-imt and bmi. the change was greater in higher bmi groups (obese and extremely obese individuals) than in lower groups (normal and overweight individuals), suggesting a more rapid change in imt for bmi values >30 kg/m2 (obese and extremely obese groups). several crosssectional studies have reported similar positive associations between body weight or bmi with carotid artery imt.10–12 in the current study, an unexpectedly high mean imt value was detected in the underweight group. however, only four subjects belonged to this group; these subjects were 22, 47, 57 and 70 years old with mean imt values of 0.50 mm, 0.67 mm, 1.43 mm and 1.03 mm, respectively. these results suggest that age was a more predominant influencing factor than weight in this subgroup. apart from those who were underweight, the imt measurements of the younger subjects were normal. in three of the six carotid artery segments, imt values were very slightly higher in the normal bmi group than the overweight group. this was also reflected in the total mean imt measurements. two explanations for this are possible; first, in the classification of normal imt and ld values in a previous study, the normal group was defined as those with a bmi of <30 kg/m2.5 this classification was made because of a lack of agreement between the imt values of two groups (normal and overweight individuals) in a previously published study.13 the second explanation is the effect of age, since vascular ageing is associated with different principal structural and functional changes (intima-media thickening, table 4: expected differences in mean wall thickness between participants differing in age by one year and body mass index by one unit among a sample of iraqi adults (n = 140) carotid segment in mm total bmi age total male female tc 0.009 0.011 0.011 0.012 rt c 0.009 0.012 0.011 0.013 rt cca 0.010 0.010 rt bif 0.007 0.015 rt ica 0.009 0.011 lt c 0.008 0.011 0.009 0.010 lt cca 0.007 0.009 lt bif 0.008 0.015 lt ica 0.010 0.009 bmi = body mass index; tc = total carotid artery; rt = right; c = carotid; cca = common carotid artery; bif = bifurcation; ica = internal carotid artery; lt = left. table 5: prevalence of cardiovascular risk factors and correlation with carotid intima-media thickness and luminal diameter among a sample of iraqi adults (n = 140) risk factor n (%) presence of risk factor mean max. imt in mm p value mean max. ld in mm p value htn 25 (17.9) no 0.7 <0.001 5.76 <0.001 yes 0.96 6.33 dm 9 (6.4) no 0.74 0.016 5.85 0.26 yes 0.94 6.11 high sc 20 (14.3) no 0.7 0.028 5.85 0.12 yes 0.82 6.13 high stg 37 (26.4) no 0.69 0.045 5.83 0.14 yes 0.78 6.04 ac 4 (2.85) no 0.75 0.7 5.86 0.58 yes 0.7 6.08 smoking 30 (21.4) no 0.74 0.7 5.8 0.09 yes 0.78 5.99 fh of stroke 25 (17.9) no 0.74 0.41 5.84 0.32 yes 0.79 5.99 fh of ihd 21 (15) no 0.75 0.81 5.89 0.25 yes 0.76 5.71 max. = maximum; imt = intima-media thickness; ld = luminal diameter; htn = hypertension; dm = diabetes mellitus; sc = serum cholesterol; stg = serum triglycerides; ac = alcohol consumption; fh = family history; ihd = ischaemic heart disease. sameeah a. rashid and sarbast a. mahmud clinical and basic research | e349 arterial dilatation and the deterioration of elastic wall properties with vascular stiffening).13 the mean ages of the normal and overweight groups in the current study were very similar, although the sd was higher in the normal group. this was also the cause of failure in a previous study to investigate the impact of bmi on c-imt.13 ozdemir et al. did not find a correlation between bmi and carotid artery imt when comparing participants with normal bmis to overweight subjects only (bmi = 25–29.9 kg/m2).13 however, their results might have differed had they also included obese subjects with bmis over 30 kg/m2 in the study. it is important to note, however, that performing tortuous ica and high-seated bifurcation procedures on obese subjects in the current study was difficult. in the current study, no significant correlation was found between c-ld and bmi. crouse et al. concluded that imt is often related to little or no narrowing of the arterial lumen.14 the researchers went on to explain that studies previously indicating straightforward relationships between risk factors and lumen reduction may have been influenced by the utilisation of symptomatic population samples and incorrect methodologies.14 an example of the latter is the use of doppler ultrasonography, as this technique is unable to determine minor decreases in ld.14 in contrast, the sample in the current study included both normal and diseased individuals. in the current study, imt and ld were found to increase significantly with advancing age in all carotid segments. this finding corresponded with those of najjar et al.15 additionally, it was discovered that the mean imt increased by approximately 0.095 mm/year, 0.015 mm/year and 0.010 mm/year at the cca, cbif and ica, respectively. these findings were very similar to those of a previous study which showed a mean imt increase of 0.010 mm/year, 0.016 mm/year and 0.011 mm/year at the cca, cbif and ica, respectively.2 the greatest increase in mean imt in the current study occurred in the cbif rather than in the cca and ica; this was in accordance with autopsy studies reporting that the extent of atherosclerotic involvement was greatest near the cbif and in the proximal portion of the ica.16,17 thus, the stronger association between imt and age at the cbif and ica suggest more rapid atherosclerotic progression at these segments. limbu et al. demonstrated no relevant sideto-side differences in any of the parameters in the extracranial carotid arteries, with similar cc-imt readings for both left and right sides.18 the results of the current study were similar. however, limbu et al. noted a difference between separate left and right ld measurements among men and women for all carotid artery segments.18 no significant differences were found between women and men with respect to imt measurements in the extracerebral carotid vessels;18 this was also reflected in the present research. however, another study reported significantly smaller ld measurements in the left cca than the right, which was attributed to the right cca being dominant.13 the current study showed that both left and right cca, cbif and ica measurements tended to be larger in men than women. three previous studies reported similar gender-related differences in ld measurements of the ccas.2,16,19 davis et al. reported cross-sectional associations between c-imt and cardiovascular risk factors and prevalent cardiovascular disease.20 a previous study found a positive association between c-imt and the incidence of all types of stroke.21 in the current study, the correlation between carotid atherosclerosis and htn was highly significant. significant correlations also existed between other cardiovascular risk factors (dm and high serum cholesterol and tg levels) and c-imt, although the same was not true of ld. early measurement of imt via ultrasonography is closely associated with plasma lipids (total cholesterol, tg and lowand high-density lipoproteins) and htn, while smoking and age are the two factors that have been most consistently associated with stroke and carotid atherosclerosis.2 the present study suggests that increased blood pressure is a strong predictor of early carotid atherosclerosis. a significant positive association between the severity of carotid atherosclerotic lesions (plaques and stenosis) and cigarette smoking (p <0.0001) has been previously reported.8 there is also evidence that smoking is positively associated with carotid atherosclerosis in patients with symptomatic ihd, based on both angiographic and ultrasonographic studies.3 the lack of a relationship between these variables in the present study could be explained by the fact that patients with ihd were excluded and the small sample may not have been representative of the entire population. no correlation between carotid atherosclerosis and a family history of stroke and ihd was found in the current study, although a positive correlation between these factors has been reported previously.22 this may be because the present study was dependent on a small sample and because familial ihd was determined by history-taking. additionally, imt was viewed as a marker for subclinical atherosclerosis. there are several additional limitations to the current study which should be acknowledged. the effect of imt on ld may have been misrepresented as ld increases and decreases during the systolic and diastolic periods of the cardiac cycle, respectively. correlation between carotid artery intima-media thickness and luminal diameter with body mass index and other cardiovascular risk factors in adults e350 | squ medical journal, august 2015, volume 15, issue 3 additionally, scans for this sample population were performed by a single radiologist who was aware of the other variables in the study, potentially introducing bias. the use of manual b-mode ultrasound technology can also cause technical difficulties and induce inherent variability. there was also a lack of detection of intra-individual variability in the methodology and a lack of multivariate adjustment of the data into different bmi categories for standard risk factors. finally, the study could have been improved by comparing the ultrasonographic findings to another standard modality, such as computed tomography angiography. conclusion a strong positive association was found between c-imt and bmi in this iraqi sample. additionally, a positive correlation was also noted with age, htn, dm, high serum cholesterol and tg levels. imt and ld were found to increase significantly with advancing age in all carotid segments. in overweight patients, an increase in imt can indicate the early stages of atherosclerosis. references 1. wikstrand j. methodological considerations of ultrasound measurement of carotid artery intima-media thickness and lumen diameter. clin physiol funct imaging 2007; 27:341–5. doi: 10.1111/j.1475-097x.2007.00757.x. 2. howard g, sharrett ar, heiss g, evans gw, chambless le, riley wa, et al. carotid artery intimal-medial thickness distribution in general populations as evaluated by b-mode ultrasound: aric investigators. stroke 1993; 24:1297–304. doi: 10.1161/01.str.24.9.1297. 3. bonithon-kopp c, scarabin py, taquet a, touboul pj, malmejac a, guize l. risk factors for early carotid atherosclerosis in middle-aged french women. arterioscler thromb 1991; 11:966–72. doi: 10.1161/01.atv.11.4.966. 4. coll b, nambi v, feinstein sb. new advances in noninvasive imaging of the carotid artery: cimt, contrast-enhanced ultrasound, and vasa vasorum. curr cardiol rep 2010; 12:497– 502. doi: 10.1007/s11886-010-0139-0. 5. al-asadi jn, habib os, al-naama lm. cardiovascular risk factors among college students. bahrain med bull 2006; 28:1–8. 6. qadir ms, rampal l, sidik sm, said sm, ramzi zs. prevalence of obesity and associated factors among secondary school students in slemani city kurdistan region, iraq. malays j med health sci 2014; 10:27–38. 7. lim tk, lim e, dwivedi g, kooner j, senior r. normal value of carotid intima-media thickness: a surrogate marker of atherosclersosis quantitative assessment by b-mode carotid ultrasound. j am soc echocardiogr 2008; 21:112–16. doi: 10.1016/j.echo.2007.05.002. 8. sass c, herbeth b, chapet o, siest g, visvikis s, zannad f. intima-media thickness and diameter of carotid and femoral arteries in children, adolescents and adults from the stanislas cohort: effect of age, sex, anthropometry and blood pressure. j hypertens 1998; 11:1593–602. 9. coll b, feinstein sb. carotid intima-media thickness measurement: techniques and clinical relevance. curr atheroscler rep 2008; 10:444–50. doi: 10.1007/s11883-0080068-1. 10. chambless le, folsom ar, davis v, sharrett r, heiss g, sorlie p, et al. risk factors for progression of common carotid atherosclerosis: the atherosclerosis risk in communities study, 1987-1998. am j epidemiol 2002; 155:38–47. doi: 10.11 61/01.str.0000088643.07108.19. 11. li s, chen w, srinivasan sr, bond mg, tang r, urbina em, et al. childhood cardiovascular risk factors and carotid vascular changes in adulthood: the bogalusa heart study. jama 2003; 290:2271–6. doi: 10.1001/jama.290.17.2271. 12. bonithon-kopp c, touboul pj, berr c, magne c, ducimetière p. factors of carotid arterial enlargement in a population aged 59 to 71 years: the eva study. stroke 1996; 27:654–60. doi: 10.1161/01.str.27.4.654. 13. ozdemir h, artas h, serhatlioğlu s, oğur e. effect of overweight on luminal diameter, flow velocity and intimamedia thickness of carotid arteries. diagn interv radiol 2006; 12:142–6. 14. crouse jr, goldbourt u, evans g, pinsky j, sharrett ar, sorlie p, et al. risk factors and segment-specific carotid arterial enlargement in the atherosclerotic risk in communities (aric) cohort. stroke 1996; 27:69–75. doi: 10.1161/01. str.27.1.69. 15. najjar ss, scuteri a, lakatta eg. arterial aging: is it an immutable cardiovascular risk factor? hypertension 2005; 46:454–62. doi: 10.1161/01.hyp.0000177474.06749.98. 16. martin mj, whisnant jp, sayre gp. occlusive vascular disease in the extracranial cerebral circulation. arch neurol 1960; 5:64–72. doi: 10.1001/archneur.1960.00450050050006. 17. solberg la, eggen da. localization and sequence of development of atherosclerotic lesions in the carotid and vertebral arteries. circulation 1971; 43:711–24. doi: 10.1161/01. cir.43.5.711. 18. limbu yr, gurung g, malla r, rajbhandari r, regmi sr. assessment of carotid artery dimensions by ultrasound in nonsmoker healthy adults of both sexes. nepal med coll j 2006; 8:200–3. 19. weskott hp, holsing k. us-based evaluation of hemodynamic parameters in the common carotid artery: a nomogram trial. radiology 1997; 205:353–9. doi: 10.1148/ radiology.205.2.9356614. 20. davis ph, dawson jd, riley wa, lauer rm. carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the muscatine study. circulation 2001; 104:2815–19. doi: 10.1161/ hc4601.099486. 21. bots ml, hoes aw, koudstaal pj, hofman a, grobbee de. common carotid intima-media thickness and risk of stroke and myocardial infarction: the rotterdam study. circulation 1997; 96:1432–7. doi: 10.1161/01.cir.96.5.1432. 22. kishimoto c, hirata m, hama k, tanaka m, nishimura k, kubo s, et al. carotid intima-media thickness is increased in subjects with ischemic heart disease having a familial incidence. exp clin cardiol 2006; 11:8–10. http://dx.doi.org/10.1111/j.1475-097x.2007.00757.x http://dx.doi.org/10.1161/01.str.24.9.1297 http://dx.doi.org/10.1161/01.atv.11.4.966 http://dx.doi.org/10.1007/s11886-010-0139-0 http://dx.doi.org/10.1016/j.echo.2007.05.002 http://dx.doi.org/10.1007/s11883-008-0068-1 http://dx.doi.org/10.1007/s11883-008-0068-1 http://dx.doi.org/10.1161/01.str.0000088643.07108.19 http://dx.doi.org/10.1161/01.str.0000088643.07108.19 http://dx.doi.org/10.1001/jama.290.17.2271 http://dx.doi.org/10.1161/01.str.27.4.654 http://dx.doi.org/10.1161/01.str.27.1.69 http://dx.doi.org/10.1161/01.str.27.1.69 http://dx.doi.org/10.1161/01.hyp.0000177474.06749.98 http://dx.doi.org/10.1001/archneur.1960.00450050050006 http://dx.doi.org/10.1161/01.cir.43.5.711 http://dx.doi.org/10.1161/01.cir.43.5.711 http://dx.doi.org/10.1148/radiology.205.2.9356614 http://dx.doi.org/10.1148/radiology.205.2.9356614 http://dx.doi.org/10.1161/hc4601.099486 http://dx.doi.org/10.1161/hc4601.099486 http://dx.doi.org/10.1161/01.cir.96.5.1432 sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e190-196, epub. 7th apr 14 submitted 22nd sep 13 revision reqd. 18th nov 13; revision recd. 11th dec 13 accepted 9th jan 14 1rheumatology unit, department of medicine and 2department of haematology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: jkalkaabi@hotmail.com متثابتات املرقئات لدى مرضى مصابني مبرض هبجت جمعة الكعبي، ديفد جرافل، حمود الهدابي، اأنيل بثاري abstract: objectives: this study aimed to evaluate the cause of thrombosis in behçet’s disease (bd) patients, since abnormalities in coagulation and fibrinolytic parameters have shown contradictory results. methods: haemostatic parameters were retrospectively evaluated in bd patients treated between january 2007 and january 2011 at sultan qaboos university hospital, oman. the blood samples of 35 omani bd patients and 30 healthy controls were analysed for factor viii:c levels, activated protein c resistance (apcr), von willebrand factor (vwf) antigens (ag), collagen binding and ristocetin co-factor activity (ricof), antithrombin (at), protein c (chromogenic and clotting), protein s, homocysteine, tissue plasminogen activator, plasminogen activator inhibitor, plasminogen, alpha 2-antiplasmin, lupus anticoagulant and anticardiolipin and beta2-glycoprotein-1 antibodies. results: the mean values of factor viii:c, vwf ag, at and protein s were significantly higher in the patient group (p = 0.01, 0.006, 0.04 and 0.01, respectively). there was no deficiency in protein c. screening for apcr, anticardiolipin antibodies, anti-beta2-glycoprotein-1 antibodies and lupus anticoagulant was negative and there were no differences in homocysteine levels, nor were there differences between patients with and without thrombosis. six patients had elevated factor viii:c levels (>150 iu/dl, p <0.02) which normalised on repeat measurements after three months. conclusion: the elevation of factors viii:c, vwf ag and at most likely represent an acute phase phenomenon. in this study, thrombophilic factors did not seem to explain thrombotic tendency. therefore, further mechanistic studies in a larger group of patients are needed to elucidate the basis for thrombosis in bd. we hypothesise that active bd causes vasculitic endothelial perturbation with dysfunction, leading to the observed increased propensity for thrombosis. keywords: behcet syndrome; vasculitis; blood vessels; thrombosis; hemostasis; oman. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل معرفة �صبب خثار الدم عند مر�صى بهجت، حيث اإن درا�صات �صابقة كانت قد اأظهرت نتائج مت�صاربة يف موؤ�رشات اأخذت .2011 يناير و يناير 2007 بني بهجت مبر�س م�صابني عمانيني ملر�صى ا�صتعاديا امُلْرِقئات موؤ�رشات حللت الِفرْبين. الطرق: واْنِحَلُل التخرث )apcr( املن�صط c ومقاومة بروتني viii :c عينات من دم 35 مري�صا وقورنت بعينات دم من 30 اأ�صخا�صا اأ�صحاء ومت قيا�س املوؤ�رشات الآتية: عامل وم�صت�صد عامل فون فيلي برانرد )vwf( واحتاد الكولجني ون�صاط متيم عامل ري�صتو�صتني )ricof( وم�صادات الرثمبني )at( وبروتني c وبروتني s وهومو�صي�صتني و من�صطات ومثبطات بلزمنوجني الأن�صجة والبلزموجنني و الفا 2 م�صاد البلزمني وم�صادات تخرث الذئبة وم�صادات كارديوليبني واأ�صداد بيتا 2 غليكو بروتينات 1. النتائج: وجد اأن هنالك ارتفاعا يف متو�صط املوؤ�رشات الآتية:، s protein ،at ،vwfag ،viii:c يف املر�صى مقارنة بالأ�صحاء )and 0.04 ،0.006 ،0.01 = p 0.01، بالتتابع( مل يوجد اختلف يف بقية املتثبتات. مل يوجد اأي�صا اختلف يف م�صتوى متثبتات p ،iu/dl 150<( fviii متثابتة م�صتوى قيا�س عندهم املر�صى بني من 6 كان امل�صابني. وغري بالتجلطات امل�صابني املر�صى بني التخرث ،at ،vwfag ،viii:c ،اإىل امل�صتوى الطبيعي بعد 3 اأ�صهر بعد اإعادة قيا�صه. اخلال�صة: اإن ارتفاع موؤ�رشات التخرث fviii 0.02(. رجعت متثابتة> s protein رمبا كانت نتيجة لزيادة ن�صاط املر�س. مل تثبت هذه الدرا�صة اأن عوامل التخرث تف�رش ب�صكل مبا�رش قابلية التخرث يف هذا املر�س. يجب عمل مزيد من الدرا�صات لت�صمل عدد اأكرب من املر�صى ملعرفة �صبب قابلية التخرث يف هذا املر�س. نعتقد باأن التهاب جدار الأوعية الدموية نتيجة مر�س بهجت رمبا يكون هو ال�صبب الذي يوؤدي اىل قابلية التخرث. ْرِقئات؛ عمان. ُ مفتاح الكلمات: مرض هبجت؛ التهاب األوعية الدموية؛ األوعية الدموية؛ التخثر؛ امل haemostatic parameters in patients with behçet’s disease *juma k. alkaabi,1 david gravell,2 hamood al-haddabi,2 anil pathare2 clinical & basic research advances in knowledge the study showed that thrombophilia is unlikely to play a role in the thrombosis associated with behçet’s disease. application to patient care anti-inflammatory and immunosuppressive therapies, rather than prolonged anticoagulation treatment, seem to be an appropriate therapeutic approach to behçet’s disease. juma k. alkaabi, david gravell, hamood al-haddabi and anil pathare clinical and basic research | e191 behçet’s disease (bd) is a multisystem vasculitic, chronic relapsing disorder of unknown aetiology associated with considerable morbidity and mainly occurring with eye involvement.1 it is also associated with an increase in mortality. yazici et al. reported an overall mortality of 4% among a group of 152 turkish patients after 10 years of follow-up.2 however, a long-term outcome survey of turkish patients showed an even higher mortality rate. kural-seyahi et al. surveyed the 20year outcome in a cohort of bd patients and found an overall mortality rate of 9.8%.3 the standardised mortality rate (smr) was higher among males and, in particular, younger males (14–24 years), with a smr reaching 10 times that observed in the general population. a significant proportion of this mortality (40%) was related to vascular thrombosis.3 in another study by hamuryudan et al., a 50% mortality rate among 24 young male patients with pulmonary artery aneurysms was observed two years after the onset of the aneurysms.4 the vascular involvement in bd varies depending on the ethnic group.5 a turkish study reported a 27% rate of vascular events,6 while a british study showed a prevalence of 32% with vascular thrombosis.7 a study from saudi arabia showed a prevalence of 43%.8 the pathogenesis of thrombotic events in bd is unknown. although vasculitis is the predominant histopathological feature of the disease, it only partially explains the thrombotic phenomenon because endothelial-leukocyte interaction and plasma hypercoaguability both play an important role.9–19 in fact, in other groups of vasculitic disorders, the frequency of major venous thrombosis is not as common as in bd. the extent of the thrombosis and its predilection for unusual sites suggests the presence of an underlying hypercoaguable state. it is believed that anticoagulant proteins and co-factors in plasma as well as the endothelium regulate the blood coagulation system. under normal conditions, procoagulant and anticoagulant mechanisms are balanced and any disturbances result in thrombosis or bleeding. abnormalities in coagulation and fibrinolytic systems have been reported in bd, but previous studies have shown contradictory results and as yet no single abnormality has been identified as the sole leading cause [table 1]. in this study the coagulation and fibrinolytic factors were investigated in a group of omani patients with bd and compared with the findings of other studies. methods the subjects for this retrospective cross-sectional study fulfilled the criteria of the international study group for diagnosis of behçet’s disease and were recruited from patients of the rheumatology outpatient department at sultan qaboos university hospital, muscat, oman, treated between january 2007 and january 2011. informed consent was obtained from the patients and approval was granted from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrs/06/04). pregnant patients, those with malignancies or those receiving medications known to interfere with haemostasis were excluded, as were those patients unwilling to give informed consent. a total of 35 consecutive patients were thus enrolled along with a control group of 30 subjects matched for age, race and sex. various clinical data were recorded, including age at onset, disease duration, current disease activity and manifestations of the disease (current and past). these data included vascular involvement, the presence of associated cardiovascular disorders and treatment regimens. patients were considered to have an active form of the disease if they had shown any of the following criteria within the previous month: oral, gastrointestinal or genital ulcers; eye or vascular lesions; arthritis, or central nervous system (cns) involvement. venous blood samples were collected from all subjects between 9 and 10 am to minimise diurnal variation in the levels of biological, haemostatic and rheological factors. blood was collected from the antecubital vein and anticoagulated with k2 ethylene-diamine-tetra-acetic acid (edta) and trisodium citrate (0.11 m: 9:1 v:v). citrated plasma was double-centrifuged the same day within two hours of collection and stored at -70 °c for further studies. plasma activities of coagulation inhibitors (antithrombins [at]; proteins c and s; von willebrand factor (vwf) antigens (ag); factor viii:c; tissue plasminogen activators (t-pa) antigens and activity; plasminogen activator inhibitors (pai1); plasminogen; alpha 2-antiplasmin, and activated protein c resistance [apcr]) were determined using standard techniques as per the manufacturers’ advice. the reagents were obtained from diagnostica stago, inc. (asnières-sur-seine, france) and instrumentation laboratory (barcelona, spain). the reference ranges used were as follows: functional protein s 77–143 iu/ dl for males and 55–123 iu/dl for females; functional chromogenic protein c 65–110 iu/dl; functional protein c (clotting assay) 66–131 iu/dl; functional haemostatic parameters in patients with behçet’s disease e192 | squ medical journal, may 2014, volume 14, issue 2 at 67–109 iu/dl; factor viii:c levels 50–150 iu/dl; vwf ag 50–158 iu/dl; vwf:ristocetin cofactor activity (ricof) 40–150 iu/dl; vwf:collagen binding activity (cba) 50–400 iu/dl; plasminogen 73–127 iu/dl; alpha 2-antiplasmin 89–112 iu/dl; t-plasminogen activator 1–12 ng/ml; plasminogen activator inhibitors (pai-1) 4–43 ng/ml plasma, and homocysteine 5–15 µmol/l. for apcr, if the sample showed an apc ratio of <2.1, then factor v leiden was considered positive. statistical analysis was performed using the statistical package for the social sciences, version 10.0 (ibm, corp. chicago, illinois, usa). data were expressed as mean ± standard deviation (sd). for all table 1: results of selected previous studies author and year of study n/n* parameters studied main findings conclusion hampton et al.9 18/7 fibrinogen, vwf, tpa, pai-1, protein c, protein s, at, factor viii, fibrinogen peptides a, plasminogen and alpha 2-antiplasmin. -increased fibrinogen, vwf, tpa, pai-1 and plasminogen activator. -decreased protein c. -no difference between t+ and t-. no abnormality of coagulation or fibrinolytic activity. guermazi et al.10 30/16 protein c, protein s and at. decreased free protein s and protein s activity. protein s deficiency may be involved in thrombosis in bd. mader et al.11 25/8 aca, la, protein c, protein s, at and apcr. elevated aca and igg but no relation to thrombosis. no association with thrombophilia. sengül et al.12 96/22 protein c, protein s, at and fibrinogen. -increased at. -no difference between t+ and t-. procoagulant activity. demirer et al.13 127/34 protein c, protein s, at, fibrinogen, vwf, tm, prothrombin fragment f 1+2 and tpa. -increased vwf and tpa in t+. -decreased thrombomodulin. endothelial damage and no activation of coagulation. akarsu et al.14 30/5 tfpi, aca, fibrinogen, pai-1, tpa, vwf, protein c, protein s, plasminogen and lipids. -increased tfpi and fibrinogen. -increased pai-1 and aplpositive in one subject. tfpi may contribute to thrombotic tendency. ozatli et al.15 39/7 factor vii, gfc, protein c, protein s, at, fibrinogen, lipids, apcr, aptt, pt, tt and aca. -increased factor vii, decreased protein s in one patient, decreased protein c in one subject and apcr in one subject. -no differences between t+ and t-. coagulation is activated and there is relative hypofibrinolysis. probst et al.16 24/7 fibrinogen, vwf, factor viii, factor xi, protein c, protein s, at, la and apcr. increased factor viii, ix, at, vwf and fibrinogen. evidence of hypercoagubility and endothelial dysfunction. navarro et al.17 39/12 protein c, protein s, at, apcr, factor viii, vwf, tm, alpha 1-antitrypsin and fibrinogen. -increased protein s, at, alpha 1-antitrypsin, factor viii and vwf. -decreased apcr and tm (also decreased in t+). reduced apcr levels. lee et al.18 32/4 24/12 fibrinogen, at, protein c, protein s, vwf, aca, la, apcr and homocysteine. -increased fibrinogen, vwf and homocysteine. -decreased at. -apl positive in one subject and la positive in four subjects. -no evidence of activation of coagulation -hypercysteinaemia may be a risk factor. leiba et al.19 107/33 factor v, factor viii, prothrombin g 20210a, mthfr c 677t, plasma glucosylceramide, homocysteine and lipids. -increased factor viii in t+. -increased lipids. -no role for thrombophilia. -dyslipidaemia may be a risk factor. n* = number of patients with thrombosis; vwf = von willebrand factor; tpa = tissue plasminogen activator; pai-1 = plasminogen activator inhibitor; at = antithrombin; t+/t= patients with/without thrombosis; bd = behçet's disease; aca = anticardiolipin antibodies; la = lupus anticogulant; apcr = activated protein c resistance; igg = immunoglobulin g; tm = thrombomodulin; tfpi = tissue factor pathway inhibitor; apl = antiphospholipid antibodies; gfc = global fibrinolytic capacity; aptt = activated partial thromboplastin time; pt = prothrombin time; tt = thrombin time; g 20210 a = prothrombin mutation g20210a; mthfr = methylenetetrahydrofolate reductase. juma k. alkaabi, david gravell, hamood al-haddabi and anil pathare clinical and basic research | e193 tests, values of p <0.05 (two-tailed) were considered statistically significant. fisher’s exact test, the mannwhitney (mw) test and spearman’s correlation test were used. results the male to female ratio was approximately 2:1. the mean age ± sd of the patients and controls were 32 ± 8 and 32 ± 7 years, respectively. the mean ± sd disease duration was 10 ± 6.5 years. the demographic details of all subject and the clinical manifestations of the patients are summarised in tables 2 and 3. eight patients with bd had thrombotic events. of those patients, four had current vascular events: one had deep vein thrombosis (dvt); two had pulmonary artery aneurysms; one had a concomitant stroke, and one a stroke. the other four bd patients had a previous history of thrombosis (stroke = 1; dvt = 2; pulmonary artery aneurysms =1). the mean age of patients with thrombosis was 24 years (range 15–37 years). the mean time-lag between blood tests and vascular events in patients with a past history of thrombosis was seven years (range 2–15 years). the blood samples showed significantly elevated factor viii:c, vwf ag, at and protein s function in bd patients compared with the controls [figure 1]. six patients with a raised factor viii of >150 iu/dl had an active form of the disease. one of these patients had a vascular event at the time of measurement. there were no deficiencies in protein c or apcr. furthermore, no differences in anticardiolipin antibodies, antibeta2-glycoprotein-1 antibodies, lupus anticoagulant, tpa, pai-1, plasminogen, alpha 2-antiplasmin, homocysteine, total cholesterol, triglycerides or blood glucose levels were found in bd patients compared to the controls. there were no differences in the thrombophilic or fibrinolytic factors studied between patients with and without thrombosis. elevated factor viii levels normalised on repeating the measurements after three months and once the disease became inactive. figure 1 and table 4 summarise the haemostatic results. there was no difference between erythrocyte sedimentation rates or c-reactive protein levels between patients and controls. however, the 20 patients with clinically active forms of the disease had raised levels of factor viii:c (p = 0.01); vwf ag (p = 0.02); vwf:ricof (p = 0.04), and vwf:cba (p = 0.01), as compared to the 15 patients with the inactive form of the disease. positive correlations were found between factor viii:c and vwf ag levels (r = 0.63, p = 0.001); factor viii:c and vwf:ricof levels (r = 0.64, p = 0.001); factor viii:c, and vwf:cba levels (r = 0.7, p = 0.001) after performing the different blood tests in the patient group. discussion the vascular complications of bd represent a challenging aspect of the disease in terms of determining the aetiopathogenesis and, more importantly, considering management options. moreover, there is still no clear or adequate explanation for the thrombotic tendency. table 2: demographic details and clinical manifestations of study patients and controls with behçet’s disease variable patients (n = 35) controls (n = 30) p value patients t+ (n = 8) patients t (n = 27) p value age in years, mean ± sd 32 ± 8 32 ± 7 0.65 31 ± 8 32 ± 7 0.70 gender by male:female ratio 23:12 18:12 disease duration in years, mean ± sd 10 ± 6.5 10 ± 7 9 ± 6 0.40 clinically active disease 20 5 15 0.90 t+ = patients with thrombosis; t= patients without thrombosis; sd = standard deviation. table 3: clinical manifestations of study patients with behçet’s disease clinical manifestations % oral ulcers 100 genital ulcers 91 skin 91 eye 91 articular 40 gi* 23 cns** 21 epididymo-orchitis 23 gi = gastrointestinal: cns = central nervous sustem. *abdominal pain, constipation or ulcer; **headache, numbness, paresis and without imaging evidence of thrombosis. haemostatic parameters in patients with behçet’s disease e194 | squ medical journal, may 2014, volume 14, issue 2 high levels of factor viii were associated with an increased risk of vascular thrombosis in the leiden thrombophilia study.20 individuals with factor viii activity levels ≥150 iu/dl are associated with a fiveto six-fold increased risk of venous thrombosis compared to levels <100 iu/dl. significantly higher levels of factor viii were found in bd patients compared to controls as has also been reported by other investigators as well as in some case series associated with thrombosis;16,17,19,21,22 however, other studies have shown normal results.9 nonetheless, in contrast to other studies, follow-up studies found that the level of factor viii normalised on repeated measurements which suggests that this elevation was merely due to an acute phase reaction.23 this might explain the lack of association of thrombosis and raised factor viii levels in the patients of the current study, as well as other studies. this is because the level of factor viii concentration varies with disease activity; an acute phase reactant may not necessarily predict a thrombotic risk unless follow-up studies show persistently elevated levels. in support of this, the current study clearly shows that all patients with raised factor viii levels had an active form of the disease and that once their disease status/activity was under control, the factor viii levels returned to within normal laboratory reference ranges. furthermore, studies which investigated factor viii level as a risk factor for venous thrombosis in the general population with idiopathic dvt found that high levels of factor viii usually persisted over time—up to five years in some cases—and were independent of acute phase proteins.23 thus, the reported differences in factor viii levels could be partially explained by the inherently different disease activity statuses in different series in the reported literature. as an endothelial cell product, which mediates platelet aggregation and adhesion to the injured endothelium, vwf helps in platelet plug formation. the other important function of vwf is that it enhances the coagulation system by stabilising as well as protecting factor viii from its proteolytic inactivation.23,24 in bd, elevated levels of vwf have been recorded, as is the case in several other atherosclerotic diseases. in fact, table 4: haemostatic parameters in behçet’s disease patients with and without thrombosis (n = 35) variable t+ (n = 8) t(n = 27) p value factor viii:c in iu/dl 120 ± 30 102 ± 52 0.10 protein c [ch] in iu/dl 199 ± 21 127 ± 41 0.90 protein c [clot] in iu/dl 124 ± 28 143 ± 46 0.48 protein s [func] in iu/dl 103 ± 19 100 ± 30 0.60 antithrombin in iu/dl 111 ± 12 107 ± 12 0.45 plasminogen in iu/dl 118 ± 14 113 ± 16 0.40 alpha 2-antiplasmin in iu/dl 118 ± 12 119 ± 16 0.90 apcr ratio* >2.1 >2.1 tpa in ng/ml 8 ± 5 7 ± 3 0.98 pai-1 in ng/ml 26 ± 14 33 ± 22 0.70 vwf ag in iu/dl 99 ± 14 102 ± 38 0.76 vwf:ricof in iu/dl 106 ± 19 99 ± 50 0.22 vwf:cba in iu/dl 105 ± 27 99 ± 50 0.36 t+ = patients with thrombosis; t= patients without thrombosis; [ch] = chromogenic; [func] = functional; apcr = activated protein c resistance; tpa = tissue plasminogen activator; pai-1 = plasminogen activator inhibitor; vwf ag = von willebrand factor antigen; ricof = ristocetin co-factor activity; cba = collagen binding activity. *if activated protein c ratio was <2.1 then factor v leiden was considered positive. figure 1: haemostatic parameters in behçet’s disease patients and controls. bd = behçet’s disease; [ch] = chromogenic; [func] = functional; apc = activated protein c; tpa = tissue plasminogen activator; pai-1 = plasminogen activator inhibitor; vwf-ag = von willebrand factor antigen; ricof = ristocetin co-factor activity; cba = collagen binding activity. juma k. alkaabi, david gravell, hamood al-haddabi and anil pathare clinical and basic research | e195 some studies have suggested that high plasma levels of vwf in subjects with cerebrovascular disease (cvd) can predict the subsequent occurrence of major clinical events such as death and myocardial infarction.24 furthermore, levels of vwf are elevated in other comorbid conditions which predispose individuals to atherosclerosis, such as hypertension and diabetes. the precise mechanism for the increase in vwf in cvd remains uncertain and there is debate as to whether the high levels of vwf seen in cvd disorders are the cause or consequence of the disease process.24 high levels may merely reflect the extent of vascular damage or may reflect platelet activation which is a consistent companion of endothelial damage. in most studies in the literature, as was found in the patients of the current study, raised vwf levels in cases of bd was an almost constant finding. this could be the consequence of a chronic perturbation and stimulation of the vascular endothelium. the current study is in agreement with many other studies in that the results showed no deficiencies in the natural anticoagulants levels of at, protein s or protein c. on the contrary, the levels of both at and protein s were elevated. sengül et al.12 and probst et al.16 found elevated levels similar to those in the current study. these authors explained this elevation as a result of a compensatory mechanism against the increased procoagulant activity. however, these differences could be multifactorial and may result from the different disease activity statuses in different series and/or may reflect a response to the endothelial damage. thus, a combination of vasculitis, endothelialleucocyte interaction with altered function, alterations in procoagulant and anticoagulant levels and altered cytokines will result in the variability of the disease activity and severity. no significant differences in the plasma homocystine levels between bd patients and controls were found in this study, although two patients had significantly elevated plasma levels. however, there is increasing evidence to suggest that the vascular effects of elevated plasma homocysteine are mediated through an action on the endothelium by lipid peroxidation, altered vascular tone and a hypercoaguable prorombotic state leading to atherothrombogenesis.25 conclusion although this study is limited by the small number of patients and its retrospective design, the findings show that underlying thrombophilia is unlikely to play a significant role in the pathogenesis of thrombosis in bd patients. like many other studies, no distinct abnormalities were found either in the coagulants, anticoagulants or in the fibrinolytic system. endothelial dysfunction as a consequence of the vasculitic process seems to be the most probable initial event. this has implications for the management of vascular bd as anti-inflammatory and immunosuppressive therapy, rather than prolonged anticoagulation treatment, seems to be the most appropriate therapeutic approach to treatment. in fact, the latest european league against rheumatism guidelines for the management of bd state that “there are no controlled data on, or evidence of benefit from, uncontrolled experience with anticoagulants, anti-platelet or fibrinolytic agents in the management of deep vein thrombosis, or for the use of anticoagulation for the arterial lesions of bd”.26 the recommendation is to use immunosuppressive agents to manage the vascular aspect of bd. a prospective study in a sufficiently large number of patients would be able to test this management strategy by randomising patient treatment with anti-inflammatory/immunosuppressive versus anticoagulation therapy. this would require a multicentre, multinational approach. it is the authors’ endeavour to initiate a multicentre registry so that the above strategy can be implemented. references 1. benezra d, cohen e. treatment and visual prognosis in behçet’s disease. br j ophthalmol 1986; 70:589–92. doi: 10.1136/ bjo.70.8.589. 2. yazici h, başaran g, hamuryudan v, hizli n, yurdakul s, mat c, et al. the ten-year mortality in behçet’s syndrome. br j rheumatol 1996; 35;139–41. doi: 10.1093/ rheumatology/35.2.139. 3. kural-seyahi e, fresko i, seyahi n, ozyazgan y, mat c, hamuryudan v, et al. the long-term mortality and morbidity of behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated centre. medicine (baltimore) 2003; 82:60–76. 4. hamuryudan v, yurdakul s, moral f, numan f, tüzün h, tüzüner n, et al. pulmonary arterial aneurysms in behçet’s syndrome: a report of 24 cases. br j rheumatol 1994; 33:48–51. doi: 10.1093/rheumatology/33.1.52. 5. alkaabi jk, pathare a. pattern and outcome of vascular involvement of omani patients with behcet’s disease. rheumatol int 2011; 31:731–5. doi: 10.1007/s00296-0101363-z. 6. koç y, güllü i, akpek g, akpolat t, kansu e, kiraz s, et al. vascular involvement in behçet’s disease. j rheumatol 1992; 19:402–10. 7. ames pr, steuer a, pap a, denman am. thrombosis in behçet’s disease: a retrospective survey from a single uk centre. rheumatology (oxford) 2001; 40:652–5. doi: 10.1093/ rheumatology/40.6.652. 8. al-dalaan an, al balaa sr, el ramahi k, al-kawi z, bohlega s, bahabri s, et al. behçet’s disease in saudi arabia. j rheumatol 1994; 21:658–61. 9. hampton kk, chamberlain ma, menon dk, davies ja. coagulation and fibrinolytic activity in behçet’s disease. thromb haemost 1991; 66:292–4. haemostatic parameters in patients with behçet’s disease e196 | squ medical journal, may 2014, volume 14, issue 2 10. guermazi s, hamza m, dellagi k. protein s deficiency and antibodies to protein s in patients with behçet’s disease. thromb res 1997; 86:197–204. doi: 10.1016/s0049-3848(97)00063-7. 11. mader r, ziv m, adawi m, mader r, lavi i. thrombophilic factors and their relation to thromboembolic and other clinical manifestations in behçet’s disease. j rheumatol 1999; 26:2404– 8. 12. sengül n, demirer s, yerdel ma, terzioğlu g, akin b, gürler a, et al. comparison of coagulation parameters for healthy subjects and behçet disease patients with and without vascular involvement. world j surg 2000; 24:1584–8. doi: 10.1007/ s002680010282. 13. demirer s, sengül n, yerdel ma, tüzüner a, ulus at, gürler a, et al. haemostasis in patients with behçet’s disease. eur j vasc endovasc surg 2000; 19:570–4. doi: 10.1053/ejvs.2000.1091. 14. akarsu m, dermirkan f, ozsan gh, onen f, yüksel f, ozkan s, et al. increased levels of tissue factor pathway inhibitor may reflect disease activity and play a role in thrombotic tendency in behçet’s disease. am j hematol 2001; 68:225–30. doi: 10.1002/ ajh.1186. 15. ozatli d, sayinalp n, büyükaşik y, karakuş s, haznedaroglu ic, kirazli s, et al. unchanged global fibrinolytic capacity despite increased factor viia activity in behçet’s disease: evidence of a prethrombotic state. rheumatol int 2002; 21:137–40. doi: 10.1007/s00296-001-0143-1. 16. probst k, fijnheer r, rothova a. endothelial cell activation and hypercoagulability in ocular behçet’s disease. am j ophthalmol 2004; 137:850–7. doi: 10.1016/j.ajo.2003.12.010. 17. navarro s, ricart jm, medina p, vayá a, villa p, todolí j, et al. activated protein c levels in behçet’s disease and risk of venous thrombosis. br j haematol 2004; 126;550–6. doi: 10.1111/j.1365-2141.2004.05072.x. 18. lee yj, kang sw, yang ji, choi ym, sheen d, lee eb, et al. coagulation parameters and plasma total homocysteine levels in behçet’s disease. thromb res 2002; 106:19–24. doi: 10.1016/ s0049-3848(02)00085-3. 19. leiba m, seligsohn u, sidi y, harats d, sela ba, griffin jh, et al. thrombophilic factors are not the leading cause of thrombosis in behçet’s disease. ann rheum dis 2004; 63:1445–9. doi: 10.1136/ard.2003.014241. 20. koster t, blann ad, briët e, vandenbroucke jp, rosendaal fr. role of clotting factor viii in effect of von willebrand factor on occurrence of deep-vein thrombosis. lancet 1995; 345:152–5. doi: 10.1016/s0140-6736(95)90166-3. 21. conard j, horellou mh, weschler b, fassin d, bletry o, godeau p, et al. [is behçet’s disease associated with characteristic abnormalities of coagulation and fibrinolysis? apropos of 70 case reports]. j mal vasc 1988; 13:257–61. 22. atalay f, ernam d, okten f, akar n. elevated fviii and fix level in a behçet’s disease patient with intracardiac thrombosis and pulmonary arterial aneurysms. thromb res 2005; 115:159– 61. doi: 10.1016/j.thromres.2004.08.010. 23. o’donnell j, mumford ad, manning ra, laffan m. elevation of fviii: c in venous thromboembolism is persistent and independent of the acute phase response. thromb haemost 2000; 83:10–13. 24. jansson jh, nilsson tk, johnson o. von willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. br heart j 1991; 66:351–5. doi: 10.1136/hrt.66.5.351. 25. sarican t, ayabakan h, turkmen s, kalaslioglu v, baran f, yenice n. homocysteine: an activity marker in behçet’s disease? j dermatol sci 2007; 45:121–6. doi: 10.1016/j. jdermsci.2006.11.008. 26. hatemi g, silman a, bang d, bodaghi b, chamberlain am, gul a, et al. eular recommendations for the management of behçet disease. ann rheum dis 2008; 67; 1656–62. doi: 10.1136/ard.2007.080432. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 402-405, epub. 20th nov 12 submitted 21st sep 12 peer reviewed accepted 26th sep 12 over the past few years, the survival rate for all cancers has improved considerably.1 the improvement has been ascribed to a combination of early detection and better treatment strategies and modalities. with the advent of systemic treatment, more and more cancers are being cured, whether they were seemingly localised, or even metastatic at presentation. the improvement in survival has been for most of the part in small incremental gains; however, there have also been some quantum leaps. a glance at the last half century reveals that by 1961, with the advent of combination chemotherapy including nitrogen mustard compounds, more than 60% patients with hodgkin’s lymphoma (hl) could be cured.2 this outcome was improved further by using non-nitrogen mustard combination chemotherapy, which not only improved the chances of survival by almost 10%, but also significantly reduced the long-term toxic effects, such as infertility and secondary cancers.3 today, 80–90% of the patients diagnosed to have hl are cured of their illness. the next major advance was the advent of cisplatin which transformed the management of certain cancers, such as the germ cell cancers; they became curable in more than 80% of patients, even when the cancer was metastatic at the time of presentation.4 to date, cisplatin-based chemotherapy remains the standard of care for these cancers. the third major advance was the realisation that the addition of chemotherapy to surgery improved the outcomes of patients with breast cancer. two groups working independently in the united states and italy published landmark studies showing that the addition of chemotherapy after mastectomy improved the survival of patients with localised and locally advanced breast cancer.5,6 the fourth major advance was the use of allogeneic transplants which were to change the outlook for patients with relapsed acute leukaemia.7,8 however, allogeneic transplant is associated with significant toxicity, including mortality, preventing its use for the majority of patients with diseases in which it has been shown to be effective. the fifth major advance was the use of autologous stem cell transplant in patients with relapsed high grade non-hodgkin’s lymphoma (nhl). it became the standard of care for relapsed nhl.9 although all these advances are considered quantum leaps, few treatment modalities have fundamentally changed the paradigm of cancer treatment. except for the advent of cisplatin, and the use of adjuvant chemotherapy, none of these treatments or modalities changed the outlook for the majority of cancer patients, as the effects were limited either to the tumour type, or were limited by excess toxicity. adjuvant and neo-adjuvant chemotherapies are now an integral part of the management plan for a vast majority of cancers. department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: ikramburney@hotmail.com من زرع النخاع اىل احلبوب نقلة نوعية يف علم األورام اإكرام بورين ومن�صور املندري editorial from transplant to tablets a paradigm shift in oncology *ikram a. burney and mansour s. al-moundhri ikram a. burney and mansour s. al moundhri editorial | 403 in the late 1990s, two significant advances revolutionised the way cancer is treated today. the advent of anti-cd20 antibody and the antibody to the her-2/neu protein expressed by breast cancers have significantly changed the way that b-cell lymphoma, and about 25% of breast cancers, are treated.10,11 the second major advance was the advent of a tyrosine kinase inhibitor (tki), imatinib mesylate, which transformed the management and outcomes of chronic myeloid leukaemia (cml).12,13 both these two types of targeted treatment, the monoclonal antibodies and the tkis, have resulted in a paradigm shift in the management of not only the cancers for which they were initially tested, but for an ever-expanding variety of cancer types. tyrosine kinase (tk) is an enzyme which either activates or deactivates other proteins by transferring a phosphate molecule to tyrosine. the process is called phosphorylation, and may become uncontrolled in cancers.12 about 90 different tks have been identified, two thirds of which are attached to trans-membrane receptors, and the rest are cytoplasmic.13 the tks transduce signals through the cytoplasm, and are specific to cancers. for example, epidermal growth factor receptor (egfr), a trans-membrane receptor, is closely related to c-erb b-2 oncogene, and is over-expressed in several cancers, including, breast cancer.14 tks attached to egfr are autophosphorylated in these cancers. similarly, bcr-abl fusion protein, formed as a result of reciprocal translocation between long arms of chromosomes 9 and 22 in cml, is a cytoplasmic tk.15 both types of tks are either mutated or activated in several cancers, and have emerged as targets for tkis, drugs specifically designed to block these tks. a compound, previously called sti571, and now called imatinib mesylate, was first shown to inhibit the bcr-abl tk through competitive inhibition at the atp-binding site of the enzyme, leading to inhibition of tyrosine phosphorylation, arresting the growth of the leukaemic cells, and inducing apoptosis.15 in this issue of squmj, shaun mccann has reviewed the history of the diagnosis and management of cml, and has asked the question, whether cml is a strange disease or a paradigm for malignancy.16 it is intriguing to note that a disease characterised by abnormal white blood cells in the peripheral blood was first described even when the microscope had not been invented; the specific chromosomal translocation was defined as early as 1960, and the resultant fusion protein bcr-abl was described in 1990. the bcr-abl fusion protein is sufficient to cause cml, and the mutational studies established that phosphorylation of tk was required for oncogenic activity. lack of technology was the limiting factor in exploitation of those discoveries and, for a long time, the treatment aimed at reducing the white blood cells in the peripheral blood, without affecting the natural history of the disease. only interferon alpha (ifn-α) was shown to prolong survival marginally, but was associated with considerable toxicity.17 once allogeneic transplantation became available, selected patients could be cured, but at the expense of significant mortality. furthermore, transplantation was available to people who were otherwise fit, and had a suitable donor. it was only after developing the capacity to block the phosphorylation of the tk domain that a new form of treatment emerged. the drug received an unprecedented rapid approval by the food and drug administration (fda) authority of the usa following the publication of a phase i trial.18 this was several years before the publication of the first phase iii trial,19 something considered by many as a pre-requisite for the approval of a new medicine by the fda. so what brought about one of the greatest practice-changing concepts in the history of malignant haematology and medical oncology? in a proof-of-principle study, escalating doses of sti571 were administered to 83 patients in the chronic phase of cml.18 all patients had failed to respond to treatment with the standard-of-care at that stage, ifn-α. complete haematological responses were observed in 53 of 54 patients treated with a daily oral dose of more than 300 mg; cytogenetic responses occurred in 17 patients, and 7 patients had complete cytogenetic remission. adverse events were minimal, merely nausea, myalgia, oedema, and diarrhoea. since then, the outcome of patients with cml has changed forever. at 7 years, 86% of the patients are alive compared with a median survival of 2–3 years, just a decade ago.20 so massive were the implications of tkis that soon after the description of the activity of imatinib in cml, tk targets specific to other cancers were explored. imatinib was also found to inhibit the tk associated with the c-kit and platelet-derived growth factor (pdgfr), expressed from transplant to tablets a paradigm shift in oncology 404 | squ medical journal, november 2012, volume 12, issue 4 on gastrointestinal stromal tumours (gist).21 metastatic gist, so far known to be refractory to treatment, was treated with imatinib, and more than 80% of the patients receive clinical benefit. not only did imatinib become the gold-standard of care for the treatment of metastatic gist22 but it also became a model for the quest of targets in solid tumours. tkis have now become the standard of care for the management of several cancers and are used either in combination with cytotoxic chemotherapy in breast cancer, or as a single agent in several difficult-to-treat cancers, such as the clear cell carcinoma of the kidney,23 hepatocellular carcinoma,24 adenocarcinoma of the lung,25,26 and melanoma.27 despite the advances, there are several hurdles still to be overcome. the issue of primary and acquired resistance, side effects and everincreasing cost of medicines are real challenges, and need to be dealt with if tkis are to have an impact on the vast majority of common cancers. for almost half a century, the treatment of cancer sat on a three-legged stool of surgery, radiotherapy and chemotherapy. with the addition of the targeted therapy in the last decade, it now seems to be sittting on a stable chair with four legs. over the last 10 years, a total of 33 targeted agents have been approved by the fda for treatment of various cancers. this is in comparison with 14 cytotoxic agents, approved during the same period.28 the advent of imatinib and its application in cml paved the way for the change. registries have reported a reduction in the number of transplants for cml,29 and in this ‘imatinib era’ patients are treated with tablets.30 tkis and other targeted therapies are now being used either to cure cancers, or to convert cancer to chronic disease. cml has led the way this time. truly, the disease has brought about a paradigm shift. references 1. byers te. trends in cancer mortality. in: devita vt jr, lawrenece ts, rosenberg sa, depinto a, weinberg ra, eds. devita, hellman and rosenberg’s cancer: principles and practice of oncology. 9th ed. philadelphia: wolters kluwer health/lippincott williams and wilkins, 2011. pp. 261–8. 2. devita vt jr, serpick aa, carbone pp. combination chemotherapy in the treatment of advanced hodgkin's disease. ann intern med 1970; 73:881–95. 3. bonadonna g, zucali r, monfardini s, de lena m, uslenghi c. combination chemotherapy of hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus mopp. cancer 1975; 36:252–9. 4. einhorn lh, donohue j. cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. ann intern med 1977; 87:293–8. 5. fisher b, carbone p, economou sg, frelick r, glass a, lerner h, et al. l-phenylalanine mustard (l-pam) in the management of primary breast cancer. n eng j med 1975; 292:110–22. 6. bonadonna g, brusamolino e, valagussa p, rossi a, brugnatelli l, brambilla c, et al. combination chemotherapy as an adjuvant treatment in operable breast cancer. n eng j med 1976; 2894:405–10. 7. thomas ed, storb r, clift ra, fefer a, johnson l, neiman pe, et al. bone-marrow transplantation (second of two parts). n engl j med 1975; 292:895– 902 8. jonson fl, hartmann jr, thomas ed, chard rl, hersman ja, buckner cd, et al. marrow transplantation in treatment of children with aplastic anaemia or acute leukaemia. arch dis child 1976; 51:403–10. 9. philip t, guglielmi c, hagenbeek a, somers r, van der lelie h, bron d, et al. autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-hodgkin's lymphoma. n engl j med 1995; 333:1540–5. 10. mclaughlin p, grillo-lópez aj, link bk, levy r, czuczman ms, williams me, et al. rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. j clin oncol 1998; 16:2825–33 11. pegram md, lipton a, hayes df, weber bl, baselga jm, tripathy d, et al. phase ii study of receptorenhanced chemosensitivity using recombinant humanized anti-p185her2/neu monoclonal antibody plus cisplatin in patients with her2/neuoverexpressing metastatic breast cancer refractory to chemotherapy treatment. j clin oncol 1998; 16:2659–71. 12. levitzki a, gazit a. tyrosine kinase inhibition: an approach to drug development. science 1995; 267:1782–8. 13. blume-jensen p, hunter t. oncogenic kinase signalling. nature 2001; 411:355–65. 14. mccann a, johnston pa, dervan pa, gullick wj, carney dn. c-erb-2 oncoprotein expression in malignant and nonmalignant breast tissue. ir j med sci 1989; 158:137–40. 15. horita m, andreu ej, benito a, arbona c, sanz c, benet i, et al. blockade of the bcr-abl kinase activity ikram a. burney and mansour s. al moundhri editorial | 405 induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of bcl-xl. j exp med 2000; 191:977–84. 16. mccann rs. chronic myeloid leukaemia: a paradigm for malignancy or just a strange disease! sultan qaboos university med j 2012; 12:422–28. 17. talpaz m, kantarjian hm, mccredie k, trujillo jm, keating mj, gutterman ju. hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha a in chronic myelogenous leukemia. n engl j med 1986; 314:1065–9. 18. druker bj, talpaz m, resta dj, peng b, buchdunger e, ford jm, et al. efficacy and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukemia. n engl j med 2001; 344:1031–7. 19. o'brien sg, guilhot h, larson ra. imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic–phase chronic myeloid leukemia. n engl j med 2003; 348:994–1004. 20. pavlovsky c, kantarjian h, cortes je. first-line therapy for chronic myeloid leukemia: past, present, and future. am j hematol 2009; 84:287–93 21. demetri gd. targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. review. semin oncol 2001; s17:19–26. 22. blanke cd, rankin c, demetri gd, ryan cw, von mehren m, benjamin rs, et al. phase iii randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: s0033. j clin oncol 2008; 26:626–32. 23. patard jj, porta c, wagstaff j, gschwend je. optimizing treatment for metastatic renal cell carcinoma. review. expert rev anticancer ther 2011; 11:1901–11. 24. llovet jm, ricci s, mazzaferro v, hilgard p, gane e, blanc jf, et al. sharp investigators study group. sorafenib in advanced hepatocellular carcinoma. n engl j med 2008; 359:378–90. 25. mok ts, wu y-l, thongprasert s, yang c-h, chu d-t, saijo n, et al. gefitinib or carboplatin/paclitaxel in pulmonary adenocarcinoma. n engl j med 2009; 361:947–57. 26. rosell r, carcereny e, gervais r, vergnenegre a, massuti b, felip e, et al. spanish lung cancer group in collaboration with groupe français de pneumocancérologie and associazione italiana oncologia toracica. erlotinib versus standard chemotherapy as first-line treatment for european patients with advanced egfr mutation-positive non-small-cell lung cancer (eurtac): a multicentre, open-label, randomised phase 3 trial. lancet oncol 2012; 13:239–46. 27. chapman pb, hauschild a, robert c, haanen jb, ascierto p, larkin j, et al. improved survival with vemurafenib in melanoma with braf v600e mutation. n engl j med 2011; 364:2507–16. 28. cancer drugs and oncology drugs. from: http:// w w w. m e d i l ex i co n . co m / d r u g s l i s t / c a n ce r. p hp accessed: sep 2012. 29. gratwohl a, brand r, apperley j, crawley c, ruutu t, corradini p, et al.; chronic leukemia working party of the european group for blood and marrow transplantation. allogeneic hematopoietic stem cell transplantation chronic myeloid leukemia in europe 2006. transplant activity and longterm data and current results. an analysis by the leukemia working party of the european group for blood and bone marrow transplantation (ebmt). haematologica 2006; 91:513–21. 30. radich j. stem cell transplant for cml in the imatinib era. semin hematol 2010; 47:354–61. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e283–287, epub. submitted 3 jul 14 revision req. 21 sep 14; revision recd. 30 sep 14 accepted 23 oct 14 1academic partnership unit, coventry university, coventry, uk; 2department of behavioural medicine, oman medical college, sohar, oman e-mail: mark.norrish@coventry.ac.uk الكشف عن األخطاء الطبية يف عمان تفضيالت العامة وتصورات املمارسة احلالية مارك نوري�ض abstract: objectives: this study aimed to provide insight into the preferences for and perceptions of medical error disclosure (med) by members of the public in oman. methods: between january and june 2012, an online survey was used to collect responses from 205 members of the public across five governorates of oman. results: a disclosure gap was revealed between the respondents’ preferences for med and perceived current med practices in oman. this disclosure gap extended to both the type of error and the person most likely to disclose the error. errors resulting in patient harm were found to have a strong influence on individuals’ perceived quality of care. in addition, full disclosure was found to be highly valued by respondents and able to mitigate for a perceived lack of care in cases where medical errors led to damages. conclusion: the perceived disclosure gap between respondents’ med preferences and perceptions of current med practices in oman needs to be addressed in order to increase public confidence in the national health care system. keywords: medical error; disclosure; ethics, medical; oman. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل عر�ض ت�سور العامة يف �سلطنة عمان عما اإن كان الك�سف عن اخلطاأ الطبي مف�سال ونظرتهم اىل ذلك. الطريقة: مت ا�ستخدام ا�ستطالع على االنرتنت بني يناير ويونيو 2012 جلمع ردود من 205 فرد من عامة النا�ض عرب خم�ض حمافظات يف �سلطنة عمان. النتائج: اأظهرت نتائج هذه الدرا�سة وجود فجوة بني تف�سيل امل�ساركني الك�سف عن االأخطاء الطبية و املمار�سات املتبعة حاليا يف �سلطنة عمان. هذه الفجوة تراوحت بني نوع اخلطاأ وال�سخ�ض الذي يحتمل اأن يك�سف عن اخلطاأ. وجد اأن االأخطاء التي ينتج عنها �رشر للمري�ض لها تاأثري قوي على نظرة االأفراد اىل جودة الرعاية. باالإ�سافة اإىل ذلك، فاإن الك�سف التام عن اخلطاأ له قيمة عالية من قبل الفجوة اإن اخلال�صة: االأ�رشار. اإىل الطبية االأخطاء اأدت التي احلاالت يف الرعاية افتقار اىل النظرة تخفيف على القدرة وله امل�ساركني الظاهرة بني تف�سيل امل�ساركني الك�سف عن اخلطاأ الطبي و املمار�سات احلالية يف �سلطنة عمان حتتاج اإىل معاجلة من اأجل زيادة ثقة النا�ض يف نظام الرعاية ال�سحية الوطني. مفتاح الكلمات: االأخطاء الطبية؛ الك�سف؛ االأخالق، الطبية؛ عمان. disclosure of medical errors in oman public preferences and perceptions of current practice mark i. k. norrish1,2 a medical error is defined as an act or omission that would have been judged as erroneous by knowledgeable peers at the time of occurrence.1 this definition includes both acts and omissions that result in harm to the patient (adverse events) and those that do not cause any harm (near misses). it is generally accepted that the best course of action to take following an identified medical error is full and appropriate disclosure. while there seems to be an international consensus in favour of full disclosure when there has been an adverse event, in situations which were not harmful, so-called ‘near misses’, there is no consensus on disclosure.2 some medical ethicists insist on full disclosure, citing reasons such as respect for autonomy and the imperative principle of truth-telling.3 however, others prefer to allow physicians and hospitals some discretion on this issue. the oman ministry of health’s (moh) code of professional conduct for doctors in oman is an accurate reflection of this debate. it states that doctors should “act immediately to put matters right, if a patient under [their] care has suffered serious harm, through misadventure or any other reason”.4 it goes on to state that doctors should give a full explanation to the patient and explain the possible shortand longterm effects of the error. doctors are also urged to offer an apology to the patient, when appropriate.4 however, on the topic of near misses, the moh code, like many other national codes, is conspicuously silent. studies show that patients prefer that medical errors be disclosed and generally feel that disclosure practices could be improved.5–7 hobgood et al. found that this disclosure preference is associated with measures of patient satisfaction: “teaching physicians about error disclosure techniques may help to avoid online brief communication disclosure of medical errors in oman public preferences and perceptions of current practice e284 | squ medical journal, may 2015, volume 15, issue 2 and government-funded national healthcare system. it therefore seems that there is a gap between public perception and the reality of error disclosure and quality of care from health providers in oman. as such, this study aimed to provide insight into the preferences for and perceptions of medical error disclosure by members of the public in oman. methods between january and june 2012, an online survey was used to collect responses from members of the public across five governorates of oman. a convenience snowball sampling technique was used to source respondents which involved students at the sohar campus of oman medical college passing on the web address of the survey to their friends and relatives. there were three main sections to the survey, which was administered in english. the first two sections were based on similar survey items used in a study conducted in saudi arabia.17 questions in these sections covered the types of medical errors to be disclosed and responsibility for disclosing such errors. respondents were asked to provide three different responses for each question (their personal preference, what they believed was generally appropriate and what they believed was the current practice in oman). the dependent variable for each of these survey items was an ordinal set of response options. the final section of the survey involved a case scenario of a medical error. respondents were asked to rate the quality of care provided by the doctor in the case scenario. the dependent variable was the rating of quality of care on a 10-point scale. this section involved two between-group independent variables. medical errors and increase patient satisfaction”.8 a study by witman et al. found that virtually all patients (98%) desired some acknowledgment of even minor errors.9 while full disclosure is the recommendation, the corollary to this is that non-disclosure is in violation of ethical principles and is also likely to increase chances of litigation.10 it is also clear from the literature that patients want full disclosure of both harmful and potentially harmful events.5–10 furthermore, such disclosure has been shown to positively influence the response of patients and their relatives to medical errors.5–10 unfortunately, full disclosure is not always a regular component of physician behaviour, with one study reporting that 76% of doctors admitted to not disclosing a serious error to a patient.11 concern about the occurrence of a medical error seems to be a global phenomenon, with several studies in different countries identifying high rates of patient anxiety (39% and 48% in the usa and iran, respectively).12,13 a study by ghalandarpoorattar et al. identified a perceived gap in medical error disclosure, where members of the public believed that medical errors were not fully disclosed.14 nevertheless, not all patients want the same level of disclosure and the nature of disclosure is likely to depend on culture. cultural differences relating to error disclosure are beginning to emerge from the literature.15 in oman, the topic of medical errors is openly discussed at the governmental level as well as within the moh.16 a community survey carried out in oman assessed understanding of the term ‘medical error’. the survey revealed that 49% believed they knew what a medical error was and 49% felt that the primary cause of a medical error was due to uncaring healthcare professionals.16 omanis are known to travel overseas for costly medical care despite an improving figure 1: cumulative distribution curve showing the personal (dashed line) and general (dotted line) preferences regarding the types of medical errors to be disclosed and perceptions of current error disclosure practices in oman (solid line) among members of the omani public (n = 205). figure 2: cumulative distribution curve showing the personal (dashed line) and general (dotted line) preferences regarding the responsibility of disclosing a medical error and perceptions of current error disclosure practices in oman (solid line) among members of the omani public (n = 205). mark i. k. norrish online brief communication | e285 the stem description of the case scenario and the nature of the error was identical in all four cases. the stem read: mr ahmed is admitted to the hospital to receive an intravenous treatment. he receives the treatment in his room. unfortunately, mr ahmed does not tolerate the treatment well; he starts sweating and feels nauseous. when the doctor realizes that mr ahmed has received an overdose of the drug by mistake, the intravenous line is stopped immediately and he is transferred to the intensive care unit to be watched closely and to receive treatment to remove the drug. this stem description of the case scenario was then followed by one condition of each of the two independent variables: whether there was full disclosure following the error and whether an adverse event resulted from the error. there were therefore four different versions of the case scenario, covering harm to patient/no harm to patient and full disclosure/ no disclosure [table 1]. each respondent received one of the four versions. a repeated measures friedman analysis of variance (anova) test was used to assess the distribution of the variables. ethical approval for this study was granted by the institutional research review board at the oman medical college. consent was obtained from all of the participants in the study. results a total of 205 adult members of the public completed the survey, of which 77% were omani. the male to female ratio was 11:8. more than 60% of the participants had studied at a higher education level and less than 8% of the respondents had not completed secondary school. there were no significant differences between the personal preferences of the respondents and what they felt was generally appropriate with regards to medical error disclosure. only 5% of the respondents reported that they would not like to be informed of a medical error. a total of 60% of the respondents reported a desire to be informed of an error even if it caused no or minor harm (29% and 31%, respectively). the repeated measures friedman anova by rank indicated statistically significant differences in the distributions regarding what type of medical errors should be disclosed (f [2,158] = 265.4; p <0.001). in the question about perceived medical error disclosure practices in oman, 42% of respondents felt that they would only be informed if the error caused serious harm and a further 27% felt that they would not be informed of any error. this difference between preferences and perceived practices is demonstrated by the leftward shift towards less disclosure in the cumulative distribution curve shown in figure 1. using the repeated measures friedman anova by rank, significant differences were also found in the distributions regarding who should disclose a medical error (f [2,158] = 53.2; p <0.001]. there were no significant differences between the personal preferences of respondents and what they thought was generally acceptable. the majority of the respondents (69%) believed that the doctor who was responsible for the error should be the one to disclose it (95% confidence interval: 62.1–77.7). however, there was a significantly different distribution with perceived current practices of medical error disclosure in oman, with fewer respondents thinking that the responsible doctor would be the one to disclose the error and more respondents believing that another physician would take responsibility for the disclosure. similarly to error type, this difference was also observable as a leftwards shift in the cumulative distribution curve [figure 2]. although the core content relating to the medical error in the stem description of the case scenario was identical, very different responses were noted depending on the two between-group variables table 1: case scenario endings for the two independent variables with four different combinations independent variable disclosure harm full disclosure the doctor takes the time to explain the situation to mr ahmed. he admits that an error was made and apologises to the patient. he also tells him that the hospital will take all necessary measures to ensure that such an incident does not occur again. harm mr ahmed’s kidneys were seriously damaged in spite of the treatment given in the icu. therefore he cannot receive the original treatment. he will have to be treated with a less effective drug. no disclosure the doctor does not mention the error to mr ahmed, who assumes that it was just an unforeseeable complication. no harm mr ahmed stays in the icu for two days and then he leaves the hospital without further health problems. icu = intensive care unit. table 2: median scores* rating the quality of physician care in four combinations of a medical error case scenario (n = 205) independent variable quality of care median score (mode) harm no harm full disclosure 5 (3) 9 (9) no disclosure 2 (1) 3 (1) *scores ranged from 1 (extremely poor care) to 10 (extremely good care). disclosure of medical errors in oman public preferences and perceptions of current practice e286 | squ medical journal, may 2015, volume 15, issue 2 in the current study, the amount of harm caused by the medical error and the extent of disclosure both strongly influenced the respondents’ ratings of the quality of patient care. the fact that an adverse event had an influence on this rating is not surprising as this has been repeatedly demonstrated in the literature.5,8,9,21 it is presumably the harm factor that is alluded to in the moh code of professional conduct when it asserts that there should be full disclosure with an apology, “if appropriate”.4 although this information is useful, it is not of particular clinical use, as there are limited possibilities to affect change on the patient’s condition retrospectively. a more useful finding is the significant influence of full disclosure on the respondents’ ratings of physician-provided patient care; in fact, disclosure, rather than harm, appeared to have a greater influence on these ratings. in the current study, when case scenarios involving adverse events were compared, there was a dramatic increase in the patient care ratings for scenarios which resulted in full disclosure, with an increase in the median value from two to five. in the scenarios with full disclosure, the doctor was rated more highly, even if other situational and health factors were identical. this study found that the omani public’s willingness to accept medical errors made by health professionals was particularly high, with quality of care ratings being very high when a near-miss error was fully disclosed. the literature suggests that patients are less likely to make a formal complaint or initiate legal proceedings following a medical error if there has been full disclosure.10,11 in at least one other islamic country, the disclosure gap regarding medical errors has been attributed to a paternalistic culture in medical practice, in which the physician decides whether telling the patient about the error would be of benefit.16 a similar paternalistic culture has been noted in oman.22 however, as is clear from the findings of the current study, there is a strong preference by members of the public for full disclosure following an error, even in the case of a near miss. automated geolocation tagging of respondents taking part in the online survey showed that the survey was completed across a wide geographical area, including five governorates in oman. this is likely to ameliorate the potential limitations of representation of the general population arising from data collected using a convenience snowball sampling method. it must also be emphasised that this study did not collect any data on rates of error disclosure in oman. the disclosure gaps that were identified, therefore, were gaps between the preferences of the members of the public and what they believed to be common practice in oman. thus it is not possible to comment on the (the nature of the disclosure and the outcome of the error) [table 2]. in the case scenario where the physician provided full disclosure following a near miss, the quality of the care was rated as extremely good [median: 9; mode: 9]. a two-way anova revealed significant between-group differences for both factors of harm and disclosure. the score given for quality of care was significantly lower for the case scenarios which resulted in an adverse event (f [1,160] = 35.7; p <0.001). the score given for quality of care was significantly higher for the case scenario which resulted in full disclosure (f [1,160] = 95.6; p <0.001). discussion the results of this survey suggest that members of the omani public preferred that medical errors be disclosed, whether they resulted in harm or not. as in similar studies, there was a broad agreement between the personal preferences of the respondents and what they thought would generally be considered acceptable by other members of society.17 this high level of agreement likely arises from the belief conformity common in traditionally collectivist societies, such as oman, in which an individual’s beliefs are encouraged to match those of wider society. however, both personal and general preferences regarding medical errors were clearly divergent from what the respondents considered to be normal practice in oman; comparatively few individuals believed that doctors in oman would disclose medical errors that caused moderate, minor or no harm. in addition, some respondents believed that even major errors would not be disclosed to patients. thus, there was a disclosure gap between preferences for full disclosure and what the respondents believed would typically be disclosed in an omani hospital. similar perceived disclosure gaps have been reported in other countries, including the usa, iran, canada, egypt and saudi arabia.16,18‒20 respondents showed a strong preference that the disclosure of a medical error should be undertaken by the physician who committed the error. this preference has been well-documented in the literature.3,5,6,8‒10,16‒18,20,21 again, there was a perceived gap between the preferences indicated and what members of the public considered to be normal practice in oman, with more respondents indicating that the person to disclose the medical error would be someone other than the physician responsible. a study performed in saudi arabia found that 60% of respondents preferred the doctor responsible for the error to be the person to disclose it, which is slightly lower than the findings of the current study.17 mark i. k. norrish online brief communication | e287 veracity of these beliefs, only that they are widely held by members of the public. increasing patient satisfaction in relation to medical error disclosure in oman is an important but ancillary goal to the primary objective of improving patient safety. these findings regarding the omani public’s preferences for error disclosure should be set within the patient safety context, where the overarching goal is to reduce the occurrence of medical errors in oman. the relationship between patient satisfaction and patient safety in oman should be explored in future research. conclusion there is a gap between personal and general preferences for medical error disclosure and the perception of current error disclosure practices in oman among members of the omani public. there is a need to address this apparent lack of confidence in error disclosure. furthermore, there is a need to ensure that doctors in oman take a more active and demonstrable role in proximate error disclosure with their patients. the results of this study suggest that the omani population is very generous in their willingness to accept errors as long as there is full and complete disclosure, as shown by the high ratings of care given to doctors who fully disclosed their medical errors. this mitigating effect may enable omani patients who have been the recipient of a medical error to be more understanding and accepting of even harmful events if medical professionals in oman develop an appropriate culture of open disclosure. a c k n o w l e d g e m e n t s the author would like to acknowledge dr saleh alkhusaiby, dean of the oman medical college, for his invaluable guidance regarding contextual aspects of medical ethics as well as medical error reporting in oman. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. references 1. kohn lt, corrigan jm, donaldson ms. to err is human: building a safer health system. from: www.iom.edu/~/media/ files/report%20files/1999/to-err-is-human/to%20err%20is%20 human%201999%20%20report%20brief.pdf accessed: sep 2014. 2. elder nc, pallerla h, regan s. what do family physicians consider an error? a comparison of definitions and physician perception. bmc fam pract 2006; 7:73. doi: 10.1186/14712296-7-73. 3. birks y. duty of candour and the disclosure of adverse events to patients and families. clinical risk 2014; 20:1–2,19–23. doi: 10.1177/1356262213516937. 4. oman ministry of health. code of professional conduct for doctors. muscat, oman: ministry of health, 2007. 5. gallagher th, waterman ad, ebers ag, fraser vj, levinson w. patients’ and physicians’ attitudes regarding the disclosure of medical errors. jama 2003; 289:1001–7. doi: 10.1001/ jama.289.8.1001. 6. manser t, staender s. aftermath of an adverse event: supporting health care professionals to meet patient expectations through open disclosure. acta anaesthesiol scand 2005; 49:728–34. doi: 10.1111/j.1399-6576.2005.00746.x. 7. o'connor e, coates hm, yardley ie, wu aw. disclosure of patient safety incidents: a comprehensive review. int j qual health care 2010; 22:371–9. doi: 10.1093/intqhc/mzq042. 8. hobgood c, peck cr, gilbert b, chappell k, zou b. medical errors–what and when: what do patients want to know? acad emerg med 2002; 9:1156–61. doi: 10.1197/aemj.9.11.1156. 9. witman ab, park dm, hardin sb. how do patients want physicians to handle mistakes? a survey of internal medicine patients in an academic setting. arch intern med 1996; 156:2565–9. doi: 10.1001/archinte.1996.00440210083008. 10. mazor km, simon sr, yood ra, martinson bc, gunter mj, reed gw, gurwitz jh. health plan members’ views on forgiving medical errors. am j manag care 2005; 11:49–52. 11. wu aw, cavanaugh ta, mcphee sj, lo b, micco gp. to tell the truth: ethical and practical issues in disclosing medical mistakes to patients. j gen intern med 1997; 12:770–5. doi: 10.1046/j.1525-1497.1997.07163.x. 12. burroughs te, waterman ad, gallagher th, waterman b, jeffe db, dunagan wc, et al. patients' concerns about medical errors during hospitalization. jt comm j qual patient saf 2007; 33:5–14. 13. kianmehr n, mofidi m, saidi h, hajibeigi m, rezai m. what are patients’ concerns about medical errors in an emergency department? sultan qaboos univ med j 2012; 12:86–92. 14. ghalandarpoorattar sm, kaviani a, asghari f. medical error disclosure: the gap between attitude and practice. postgrad med j 2012; 88:130–3. doi: 10.1136/postgradmedj-2011-130118. 15. berlinger n, wu aw. subtracting insult from injury: addressing cultural expectations in the disclosure of medical error. j med ethics 2005; 31:106–8. doi: 10.1136/jme.2003.005538. 16. al-mandhari as, al-shafaee ma, al-azri mh, al-zakwani is, khan m, al-waily am, et al. a survey of community members' perceptions of medical errors in oman. bmc med ethics 2008; 9:13. doi: 10.1186/1472-6939-9-13. 17. hammami mm, attalah s, al qadire m. which medical error to disclose to patients and by whom? public preference and perceptions of norm and current practice. bmc med ethics 2010; 11:17. doi: 10.1186/1472-6939-11-17. 18. beer z, guttman n, brezis m. discordant public and professional perceptions on transparency in healthcare. qjm 2005; 98:462–3. doi: 10.1093/qjmed/hci076. 19. levinson w, gallagher th. disclosing medical errors to patients: a status report in 2007. cmaj journal 2007; 177:265–7. doi: 10.1503/cmaj.061413. 20. dorgham sr, mohamed lk. personal preference and perceived barriers toward disclosure and report of incident errors among healthcare personnel. life sci j 2012; 9;4869–80. doi: 10.1.1.381.3895. 21. schwappach dl, koeck cm. what makes an error unacceptable? a factorial survey on the disclosure of medical errors. int j qual health care 2004; 16:317–26. doi: 10.1093/ intqhc/mzh058. 22. al-adawi s, dorvlo as, burke dt, al-bahlani s, martin rg, al-ismaily s. presence and severity of anorexia and bulimia among male and female omani and non-omani adolescents. j am acad child adolesc psychiatry 2002; 41:1124–30. doi: 10.1097/00004583-200209000-00013. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e428−431, epub. 14th oct 14 submitted 10th aug 14 revision req. 19th aug 14; revision recd. 27th aug 14 accepted 28th aug 14 in this issue of squmj, yadav et al. present a very interesting article about opportunistic infections and complications in children infected with human immunodeficiency virus (hiv)-1.1 it is well known that both hiv1 and hiv-2 progressively destroy lymphocytes, rendering the patient susceptible to a variety of other infectious agents; these infections are known as opportunistic infections.2 at least 90% of hivinfected children acquire the infection from their mothers through mother-to-child transmission (mtct).2 approximately half of these cases occur late in pregnancy, possibly in the days before the delivery, as the placenta begins to separate from the uterine wall.3 only a small proportion of cases (<4%) seem to occur in the first trimester, less than 20% by 36 weeks of gestation and approximately one-third during delivery.3 many factors may increase the transplacental transmission of the virus to the fetus in utero, such as an increased plasma viral load; this also exposes the baby to increased concentrations of the virus in the female genital tract during childbirth. maternal sexually transmitted diseases, epstein-barr virus infection, viral shedding, vaginal candidiasis and cervical inflammation are known risk factors for the mtct of hiv.4 the risk of hiv transmission is also higher in cases of prolonged rupture of the amniotic membranes before delivery,3 which is usually associated with acute and chronic inflammation of the placental membranes.5 in spite of its importance in terms of other health benefits, breastfeeding unfortunately puts the infant at risk of acquiring hiv throughout the entire breastfeeding period, even if the infant is initially uninfected. in the absence of preventive interventions, about 5−20% of infants with hiv-positive mothers become infected through the process of breastfeeding.6 there is assuredly a potential benefit to testing infants for hiv infection soon after birth, i.e. before the infant is 48 hours old, so as to quickly identify infants infected in utero and prevent early mortality.7 however, certain rapid diagnostic tests, such as the current available hiv serological assays, cannot be used for diagnosis in infants below 18 months of age. this is due to the presence of maternal hiv antibodies,8 although these usually clear by 9−12 months.6 while these tests can undoubtedly be used to screen for hiv exposure among children >18 months old, a definitive diagnosis of hiv infection can only be confirmed with virological testing.9 in this regard, the panel on antiretroviral therapy and medical management of hiv-infected children recommended two assays for virological detection: the hiv ribonucleic acid (rna) and hiv branched deoxyribonucleic acid (bdna) polymerase chain reaction (pcr) assays.10 between the two, the latter is usually less expensive.11 further virological testing in infants with known perinatal hiv exposure is recommended when the infant is 14 days, one month and four months old.11 testing when the infant is 14 days old allows for the earlier detection of hiv in infants who have had negative test results within the first 48 hours of life. at the age of one month old, testing confirms the previous results, as pcr testing has a 96% sensitivity and 99% specificity for identifying hiv at this age.11 once hiv infection has been diagnosed, the course of the infection must be frequently monitored by determining the number of cluster of differentiation 4 positive (cd4+) lymphocytes (otherwise known as the cd4+ count, which decreases as the infection worsens) and the number of virus particles in the blood (also termed the viral load, which increases as the infection worsens).2 children born with hiv infections rarely display symptoms in the first few months of life. even without department of planning & research, oman medical specialty board, muscat, oman; department of community medicine & public health, tanta university, tanta, egypt e-mail: drmoness@gmail.com األطفال والعدوى بفريوس نقص املناعة البشري الفرص والتحديات م�ؤن�س م�شطفى ال�ش�شتاوي editorial children and human immunodeficiency virus infection opportunities and challenges moeness m. al-shishtawy moeness m. al-shishtawy editorial | e429 treatment, approximately 80% of infected children do not develop problems during their first or second year.2 for the remaining children, problems may not appear until the age of three years or later.2 the rate of progression to a stage of clinically apparent immunosuppression depends on maternal, infant and viral factors.12 once this occurs, hiv/acquired immunodeficiency syndrome (aids) will negatively affect the children’s health, education and well-being. early signs of infection include delayed growth and recurring bacterial infections.2 in a significant number of hiv-infected children, progressive brain damage prevents or delays developmental milestones, such as walking and talking. these children may also have impaired intelligence and a small head in relation to their body size.2 up to 20% of infected children who are left untreated progressively lose social and language skills as well as muscle control.2 the initiation of antiretroviral therapy (art) in infants and children should be based on age, cd4+ count and clinical stage. an infected infant aged one year or older suffering from aids or showing significant symptoms of the disease should be immediately treated, regardless of the results of cd4+ percentage and count or virological assays.11 for children, the drugs used during treatment are more or less the same as those used for adults—typically a combination of two nucleoside or nucleotide reverse transcriptase inhibitors (nrtis) plus one nonnucleoside reverse transcriptase inhibitor (nnrti) or one protease inhibitor (pi).11 the effectiveness of the treatment should be monitored by regularly measuring the viral load in the blood and the cd4+ count.2 yadav et al. observed that the severity and frequency of opportunistic complications in paediatric patients infected with hiv-1 increased with a fall in the cd4+ count.1 the authors hypothesised that treating the opportunistic infections, along with art, might lead to both clinical and immunological recovery and a decreased incidence of future opportunistic infections.1 while opportunistic infections in adults are secondary to the reactivation of opportunistic pathogens acquired when the host’s immune system was still intact, opportunistic infections in children usually reflect a primary infection.4 among children with perinatal hiv infection, the primary opportunistic infection occurs after hiv infection is established and the child’s immune system has already been compromised. this can lead to different disease manifestations than those witnessed among adult patients.4 in general, hiv treatment should continue indefinitely, or at least until the child is five years old, though it may sometimes be stopped following the successful completion of art.13 it is important to mention here that treating infected children is not an easy task. some of the drugs used to treat adult patients, which are not in liquid form, are not suitable for infants and young children. complicated drug regimens can also limit the effectiveness of chosen therapies as they may be difficult to follow for both parents and children in the long term.2 additionally, the side-effects of certain drugs, though better tolerated by children in comparison to adults, may also limit the treatment of hiv-infected children.2 current advances in hiv treatment are changing the pattern of hiv/aids in clinical settings. prior to effective antiviral suppressive therapies, the majority of hiv-infected infants developed marked immunosuppression and aids-defining conditions at an early age. today, art makes it possible for children to experience prolonged viral suppression and live well into their adolescence and early adulthood.14 the prognosis is worse for those in whom the virus is detected within the first week of life or for those who develop symptoms in the first year of life.2 the latest report by the united nations children’s fund explores the strides that have been made in the fight against hiv.15 in this report, more than 850,000 children in lowand middle-income countries, whose mothers were living with hiv, were estimated to have been born without contracting the infection between 2005 and 2012.15 however, despite the progress achieved, there is still a long way to go—in 2012, around 260,000 children in lowand middle-income countries were newly infected with hiv and during that year almost 600 children died from aids-related causes every day.16 as stated by yadav et al., hiv infection is rapidly increasing among the paediatric hiv population in india and, with the current rate of increase, india will soon have the highest aids prevalence worldwide.1 in the middle eastern and north african (mena) region, the hiv epidemic has been rising since 2001. this region is currently among the top two regions (along with sub-saharan africa) in the world with the fastest growing hiv epidemics.17 the number of children younger than 15 years living with hiv and those newly infected with hiv in the region is increasing.17 also, art coverage in the region remains one of the lowest in the world. in 2010, the percentage of pregnant women receiving the most effective antiretroviral regimen for the prevention of mtct was less than 5% and the percentage of infants exposed to hiv who received antiretroviral prophylaxis was only 2%.17 hiv-related stigma and discrimination are no doubt still rife in the mena region and these are major barriers to the utilisation of hiv-preventive children and human immunodeficiency virus infection opportunities and challenges e430 | squ medical journal, november 2014, volume 14, issue 4 services. accordingly, the use of counselling and testing services is generally low; it may be even lower for women, given the prevailing cultures and traditions of this region.17 moreover, women with an increased risk of contracting hiv suffer from a lack of services that are adapted to their needs. there is an inadequate understanding of the vulnerability of women who do not themselves engage in high-risk behaviours but are nevertheless exposed to hiv infections.17 one encouraging sign in the mena region is in the case of oman, a nation which has demonstrated an acceptance of hiv-specific screening interventions despite the inherent cultural sensitivities of this topic. in 2009, oman offered hiv testing to all women attending antenatal care clinics, with 99% of them opting for the test.17 furthermore, the percentage of art coverage recorded in oman was the highest in the region (78%), followed by morocco (26%).17 in recent years, the global efforts expended to combat hiv/aids have increased, with an accelerated global commitment to the prevention of mtct. for instance, the joint united nations programme on hiv/aids (unaids) and the world health organization (who) introduced a new initiative in june 2010 aiming to achieve and sustain universal access to art and maximise the benefits of different hiv-preventive interventions through focused work in five priority areas.18 one important priority area is to provide hiv testing nearer to the point-of-care (poc).18 this is particularly important because new innovations such as simplified virological testing make it possible to provide an earlier diagnosis for infants closer to the poc and facilitate the introduction of rapid and integrated treatment. in 2011, the united nations hosted a high-level meeting on aids in new york, in which the general assembly adopted the political declaration on hiv/ aids.19 one of the targets of this declaration was to eliminate the mtct of hiv by 2015.20 in this instance, elimination is defined as a 90% reduction in the number of new paediatric hiv infections, or a mtct rate of below 5%.20 all nations will have to show great dedication to achieving this target as the deadline approaches. the who validation requirements for this elimination are based on documented evidence on the achievement of the elimination targets for at least three consecutive years, the existence of an adequate surveillance system and evidence of each programme’s capacity to sustain the elimination targets and objectives in the future.17 crucially, sustained national commitment, sufficient human and financial resources and the delivery of critical interventions are key points for the success of any programme aiming to eliminate the mtct of hiv. interventions should focus on simplifying and enhancing accessibility to treatment and other services for pregnant women living with hiv and on relieving the suffering of those most afflicted by the epidemic. with all these factors in hand, an hiv/ aids-free generation may well be within reach and will be a strong foundation for a better future. references 1. yadav j, nanda s, sharma d. opportunistic infections and complications in human immunodeficiency virus 1-infected children: correlation with immune status. sultan qaboos univ med j 2014; 14:484–92. 2. merck manuals. human immunodeficiency virus (hiv) infection in children. from: www.merckmanuals.com/home/ childrens_health_issues/viral_infections_in_infants_and_ children/human_immunodeficiency_virus_hiv_infection_in_ children.html accessed: jul 2014. 3. kourtis ap, bulterys m. mother-to-child transmission of hiv: pathogenesis, mechanisms and pathways. clin perinatol 2010; 37:721–37. doi: 10.1016/j.clp.2010.08.004. 4. mofenson lm, oleske j, serchuck l, van dyke r, wilfert c. treating opportunistic infections among hiv-exposed and infected children: recommendations from cdc, the national institutes of health, and the infectious diseases society of america. clin infect dis 2005; 40:s1–84. doi: 10.1086/427295. 5. lawn sd, butera st, folks tm. contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection. clin microbiol rev 2001; 14:753–77. doi: 10.1128/cmr.14.4.753-777.2001. 6. world health organization. early detection of hiv infection in infants and children: guidance note on the selection of technology for the early diagnosis of hiv in infants and children. from: www.who.int/hiv/paediatric/ earlydiagnostictestingforhivver_final_may07.pdf accessed: jul 2014. 7. lilian rr, kalk e, bhowan k, berrie l, carmona s, technau k, et al. early diagnosis of in utero and intrapartum hiv infection in infants prior to 6 weeks of age. j clin microbiol 2012; 50:2373–7. doi: 10.1128/jcm.00431-12. 8. phillips an, gazzard bg, clumeck n, losso mh, lundgren jd. when should antiretroviral therapy for hiv be started? bmj 2007; 334:76–8. doi: 10.1136/bmj.39064.406389.94. 9. world health organization. diagnosis of hiv infection in infants and children: who recommendations. from: www.who.int/hiv/pub/paediatric/diagnosis/en/index.html accessed: jul 2014. 10. panel on antiretroviral therapy and medical management of hiv-infected children. guidelines for the use of antiretroviral agents in pediatric hiv infection. from: www.aidsinfo.nih. gov/contentfiles/pediatricguidelines.pdf accessed: jul 2014. 11. rivera dm, frye re, steele re. pediatric hiv infection. from: ww w.emedicine.medscape.com/article/965086-over view accessed: jul 2014. 12. moss wj, clements cj, halsey na. immunization of children at risk of infection with human immunodeficiency virus. bull world health organ 2003; 81:61–70. 13. avert charity. hiv opportunistic infections: what are opportunistic infections? from: www.avert.org/hivopportunistic-infections.htm accessed: jul 2014. 14. chiu ss, lau yl. update on perinatally acquired human immunodeficiency virus infection in children followed at one centre in hong kong. hong kong j paediatr 2006; 11:215–22. moeness m. al-shishtawy editorial | e431 15. united nations children’s fund. towards an aids-free generation: children and aids sixth stocktaking report, 2013. from: www.childrenandaids.org/files/str6_full_report_ interactive_29-11-2013.pdf accessed: jul 2014. 16. bull d. world may soon be free of aids. times of oman, december 1, 2013. from: www.timesofoman.com/ columns/1518/article-world-may-soon-be-free-of-aids accessed: jul 2014. 17. world health organization regional office for the eastern mediterranean. towards the elimination of mother-to-child transmission of hiv: conceptual framework for the middle east and north africa region. from: www.emro.who.int/ images/stories/asd/documents/emtct_framework_-_en_-_ final_web_-_26_sep_2012.pdf accessed: jul 2014. 18. world health organization and joint united nations programme on hiv/aids. hiv/aids programme: the treatment 2.0 framework for action catalysing the next phase of treatment, care and support. from: www. unaids .org/en/me dia/unaids/contentassets/documents/ u n a i d s p u b l i c a t i o n / 2 0 1 1 / 2 0 1 1 0 8 2 4 _ j c 2 2 0 8 _ o u t l o o k _ treatment2.0_en.pdf accessed: jul 2014. 19. united nations general assembly. a/res/65/277: political declaration on hiv and aids intensifying our efforts to eliminate hiv and aids. from: www.un.org/en/ga/search/ view_doc.asp?symbol=a/res/65/277 accessed: jul 2014. 20. world health organization. towards the elimination of mother-to-child transmission of hiv: report of a who technical consultation, 9–11 november 2010, geneva, switzerland. from: www.whqlibdoc.who.int/ publications/2011/9789241501910_eng.pdf accessed: jul 2014. squ med j, may 2012, vol. 12, iss. 2, pp. 232-236, epub. 9th apr 2012 submitted 10th oct 11 revision req. 31st dec 11, revision recd. 20th jan 12 accepted 15th feb 12 the contents of inguinal hernia sacs differ from case to case. various structures contained therein have been described, but the presence of the appendix in an inguinal hernia sac is rare. this anomaly was first described by claudius amyand in an 11-year-old boy who underwent a successful appendectomy in 1735.1 the incidence of appendicitis within an inguinal hernia is estimated at 0.07–0.13 %. 2 the eponym amyand’s hernia was first coined by creese in 1953, then by hiatt and hiatt in 1988, followed by hutchinson in 1993.3–6 we report four cases of amyand's hernia operated upon in the department of surgery at sultan qaboos university hospital, oman, in the period 2007 to 2011. patient follow-up ranged from one month to three years with no surgical site infection seen in the immediate post-operative period, or recurrence of the hernia. the purpose of this report is to create general awareness among surgeons who might be dealing with this hernia surgery, as they may encounter unexpected intraoperative findings such as amyand’s hernia. it is important to be aware of all clinical possibilities and appropriate management techniques. case one a 64-year-old male, who had had a left-sided reducible inguinal hernia for the previous 5 years, presented with a 2-day-history of fever, pain, vomiting, and irreducibility of the hernia. he had noticed a recent increase in the swelling size. on examination, he was found to be dehydrated with a temperature of 38° c and a heart rate of 104 beats per minute (bpm). he had bilateral pedal oedema and bibasilar crepitations in his chest. his abdomen was distended with exaggerated bowel sounds. there was a 30 x 15 cm pear-shaped left inguino-scrotal department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ali _2051@hotmail.com, and alismc2051@gmail.com فتق امياند تقرير عن أربع حاالت مع مراجعة املنشورات �سّيد علي، كمران مالك، هاين القا�سي امللخ�ص: فتق امياند هو عبارة عن احتواء الزائدة الدودية بكي�س الفتق االآربي. يعترب فتق امياند من احلاالت النادرة التي ال تكت�سف غالبا اإال اأثناء التدخل اجلراحي للفتق االآربي. قد تكون الزائدة الدودية بكي�س الفتق بحالتها الطبيعية اأو تكون بحالة ملتهبة مع امل�ساعفات للجراحة احلاالت هذه خ�سعت قابو�س، ال�سلطان جامعه مب�ست�سفى امياند فتق من حاالت الأربع و�سفا التقرير هذا يف ندرج املحتملة. با�ستئ�سال الزائدة الدودية مع اإ�سالح الفتق ب�سبكة طبية يف ثالث حاالت، اأما احلالة الرابعة فقد قمنا باإ�سالح الفتق بغرزة برولني. مفتاح الكلمات: الفتق االآربي، زائدة دودية داخل فتق،التهاب الزائدة الدودية احلاد، تقرير حالة، ُعمان. abstract: the presence of the appendix in an inguinal hernial sac is described as amyand’s hernia. it is a rare entity which presents mostly at the exploration of the inguinal canal. the appendix may be apparently normal or have all the features of acute appendicitis with its possible complications. we report four cases of amyand’s hernia which were treated at sultan qaboos university hospital, oman. all patients underwent appendectomy. in three cases, the inguinal hernia were repaired with vipro mesh while, in the remaining case, a darning repair was done with prolene sutures. keywords: inguinal hernia; appendix in hernia; acute appendicitis; case report; oman. amyand’s hernia study of four cases and literature review *syed m. ali, kamran a. malik, hani al-qadhi case report syed m ali, kamran a malik and hani al-qadhi case report | 233 swelling extending up to the base of the scrotum. the lump was tense, tender, and irreducible. both testes were palpable in the scrotum. after adequate resuscitation he was taken to surgery under general anaesthesia. the left inguinal canal was explored, and a strangulated irreducible indirect inguinal hernia was found, with constriction at the external ring. about 1.2 litres of an amber-coloured fluid was aspirated upon opening the sac, and the gangrenous caecum and appendix were removed. the small bowel loops were dusky initially, but became pink upon release of the constriction the contents of the sac were pushed inside and a lower midline laparotomy was performed. a gangrenous floppy mobile caecum was seen, along with a gangrenous appendix which had herniated through the deep ring on the left side. there was no situs inversus or malrotation of the gut. the rest of the viscera were normal. a limited right hemicolectomy was done with ileocolic anastomosis. before closing the abdomen, the hernia was repaired by darning with size 0 prolene (ethicon, inc., manlo park, california, usa). the patient was treated with broad spectrum antibiotics and had an uneventful recovery. the histopathology was consistent with a gangrenous caecum and appendix. after one year, the patient was well with no recurrence of the hernia. case two a 19-year-old male was admitted for right inguinal hernia repair. he had had the hernia for six months. it was increasing in size, especially during walking, but was reducible upon lying down. examination showed swelling in the right inguinal region, which was non-tender, partially reducible, and had a positive cough impulse. the patient underwent inguinal hernia repair under general anaesthesia. per-operatively, he was found to have an indirect sac containing a congested appendix with palpable fecolith. an appendectomy was performed and repair of the hernia was accomplished with vipro mesh (ethicon, inc., manlo park, california, usa). the patient had an unremarkable recovery and was discharged three days after the surgery. he was seen for follow-up after one month; the incision site was uninfected. the histopathology result showed a figure 1: amyand’s hernia in patient 2: (a) right inguinal hernia sac, (b) appendix. amyand’s hernia study of four cases and literature review 234 | squ medical journal, may 2012, volume 12, issue 2 congested appendix with lymphoid hyperplasia. case three a 75-year-old male presented with a 2-month history of swelling in the right inguinal region, which had increased recently causing discomfort but no significant pain. it was reducible with incomplete swelling, but the patient had a positive cough impulse. on exploration of the inguinal canal, the appendix was discovered to be adherent to an indirect hernia sac. the appendix was normal looking, but was removed after dealing with the adhesions. the histopathology revealed an inflamed appendix. the posterior wall was repaired with vipro mesh (ethicon, inc., manlo park, california, usa) and the patient was discharged two days after surgery. he was seen for follow-up one month after surgery and there was no infection at the surgical site. on his last visit to the surgical clinic, two years after surgery, no recurrence was found. case four a 26-year-old male was admitted for an elective repair of a right-sided inguinal hernia. he had had reducible swelling for the previous two years. the hernia had recently become partially irreducible, but the patient was without pain or any other symptoms other than a positive cough impulse. per-operatively, it was noted that he had an indirect inguinal hernia, and a caecum and appendix which were not inflamed on gross appearance. an appendectomy was performed along with repair of the hernia with vipro mesh (ethicon, inc., manlo park, california, usa). he recovered without any complications. histopathology of the appendix was consistent with lymphoid hyperplasia without any inflammation. he was doing well three years after surgery. discussion a hernia is the protrusion of the viscus or a part of the viscus through the wall of its containing cavity. by far the most commonly encountered hernia is in the inguinal region which also normally contains bowels, or omentum. among the unusual contents are the bladder, meckle’s diverticulum (known as littre’s hernia), or a portion of the circumference of the intestine (called richter’s hernia), but amyand’s hernia is relatively unknown despite being first reported in 1735 by claudius amyand.1 the term amyand’s hernia is used to refer to a hernial sac containing an inflamed or non-inflamed appendix in an irreducible inguinal hernia.7 losanoff and basson suggested a distinct classification to improve the management of amyand’s hernias.8 the incidence of a normal appendix being found inside an inguinal hernia sac is about 1%; however, only 0.1% of these cases have appendicitis.9 solecki et al. observed that acute appendicitis was found in 0.62% of all groin hernia sacs.10,11 in most of the patients who present with a right-sided amyand’s hernia, its location can be explained by the normal anatomical position of the appendix; also, rightsided inguinal hernias are more common. in this study, three patients had right-sided hernias. however, left-sided amyand’s hernias have also been described in the literature and may be associated with situs inversus, malrotation of the gut, or mobile caecum, as was found in one of our cases.6,12 the pathophysiology of amyand’s hernia is unknown. weber et al. proposed that due to herniation the appendix can become more table: classification of amyand’s hernias8 classification description surgical management type i normal appendix in inguinal hernia hernia reduction, mesh repair; appendectomy in young patients type ii acute appendicitis within an inguinal hernia and no abdominal sepsis appendectomy through hernia; primary repair of hernia; no mesh type iii acute appendicitis within an inguinal hernia or the abdominal wall, or peritoneal sepsis laparotomy; appendectomy; primary repair of hernia; no mesh type iv acute appendicitis within an inguinal hernia with related or unrelated abdominal pathology manage as hernias type i–iii; investigate or treat second pathology as appropriate syed m ali, kamran a malik and hani al-qadhi case report | 235 vulnerable to micro-trauma, causing adherence to the hernia sac due to fibrosis.13 this hypothesis that inflammatory swelling may lead to incarceration, subsequent impaired blood supply, and bacterial overgrowth was supported by abu dalu, barut, and house.14–16muscle contractions and changes in abdominal pressure can cause compression of the appendix, resulting in reduced blood supply and secondary inflammation.11 diagnosing amyand’s hernia pre-operatively is not straight forward. in the majority of cases, it is diagnosed when the hernia sac is opened, as most patients undergo emergency surgery. although a preoperative computed tomography (ct) scan of the abdomen can be helpful in diagnosing the condition, it is not routinely employed in such cases. if the diagnosis is established by ct, it is possible to treat amyand’s hernia laparoscopically.17 the recommended treatment is appendectomy with primary hernia repair. use of synthetic mesh is avoided in the repair of contaminated abdominal defects because prosthetic material can increase the inflammatory response and result in wound infection and a rare but possible complication of appendiceal stump fistula.18–20 preigo et al. carried out appendectomies in six patients, using mesh in three. one patient developed a wound infection after being treated with mesh.21 bailey reported a wound infection rate of 3% in hospital that went up to 9% in community surveillance.22 however, saggar et al. reported endoscopic total extraperitoneal repair with mesh in a right-sided incarcerated inguinal hernia without any complications.23 we performed appendectomies in all of our cases and repaired the hernia with mesh in three of our patients. in case 1, we decided not to use mesh due to the presence of a gangrenous appendicitis. this guarded the hernia from a possible future extension of inflammation into the mesh. however, we did repair the hernia with mesh in cases 2 to 4 as the appendices were mildly inflamed with no purulent fluid in the hernial sac. the follow-up period in our patients ranged from one month to three years with no surgical site infection seen during the immediate post-operative period. no recurrence of the hernias was found. conclusion amyand’s hernia is a rare clinical entity that is difficult to diagnose pre-operatively. the presence of an inflamed or gangrenous appendix increases the rate of complication, particularly increasing the rate of wound infection. diagnosis is usually made at the time of surgery, which is usually indicated in all incarcerated hernias. consequently, our recommendation is that the decision to perform an appendectomy and/or to use mesh to repair hernias should always be individualised. references 1. hutchinson r. amyand’s hernia. j r soc med 1993; 86:104–5. 2. sharma h, gupta a, shekhawat ns, memon b, memon ma. amyand’s hernia: a report of 18 consecutive patients over a 15 year period. hernia 2007; 11:31–5. 3. constantine s. review of literature: computed tomographic appearances of amyand’s hernia. j comput assist tomogr 2007; 33:359–62. 4. d’alia, lo schiavo mg, tonante a, taranto f, gagliano e, bonanno et al. amyand’s hernia: case report and review of the literature. hernia 2007; 7:89–91. 5. carey lc. acute appendicitis occurring in herniae: a report of 10 cases. surgery 1967; 61:236–8. 6. gupta s, sharma r, kaushik r. left-sided amyand’s hernia. singapore med j 2005; 46:424–5. 7. bakhshi gd, bhandarwar ah, govila aa. acute appendicitis in left scrotum. (comment on: indian j gastroenterol 2004; 23:150) indian j gastroenterol 2004; 23:195. 8. losanoff je, basson md. amyand hernia, a classification to improve management. hernia 2008; 12:325–6. 9. logan mt, nottingham jm. amyand’s hernia: a case report of an incarcerated and perforated appendix within an inguinal hernia and review of the literature. am surg 2001; 67:628–9. 10. yazicioglu m, yavas y, polat c. amyand›s hernia: a case report. case rep clin prac rev 2007; 8:321–3. 11. solecki r, matyja a, milanowski w. amyand’s hernia: a report of two cases. hernia 2003; 7:50–1. 12. anagnastopoulou s, dimitroulis d, troupis tg, allamani m, paraschos a, mazarakis a, et al. amyand’s hernia: a case report. world j gastroenterol 2006; 12:4761–3. 13. weber rv, hunt zc, kral jg, amyand’s hernia: etiologic and therapeutic implications of two complications. surg rounds 1999; 22:552–6. 14. abu dalu j, ucra i. incarcerated inguinal hernia with a perforated appendix and periappendicular abscess. amyand’s hernia study of four cases and literature review 236 | squ medical journal, may 2012, volume 12, issue 2 dis colon rectum 1972; 15:464–5. 15. barat i, tarhan dr. a rare variation of amyand’s hernia: gangrenous appendicitis in an incarcerated inguinal hernia sac. eur j gen med 2008; 5:112–4. 16. house mg, goldin sb, chen h. perforated amyand’s hernia. south med j 2001; 94:496–8. 17. vermillion jm, abernathy sw, snyder sk. laparoscopic reduction of amyand’s hernia. hernia 1999; 3:159–60. 18. logan mt, nottinggham jm. amyand’s hernia: a case report of an incarcerated and perforated appendix with an inguinal hernia and review of the literature. am surg 2001; 67:628–9. 19. javaid m, rahman n, manzar s. amyand’s hernia: appendix within an inguinal hernia. pak j surg 2006; 22:181–2. 20. carey lc. acute appendicitis occurring in herniae: a report of 10 cases. surgery 1967; 61:236–8. 21. priego p, lobo e, moreno i, sanchez-picot s, olarte mag, alonso n, et al. acute appendicitis in an incarcerated crural hernia: analysis of our experience. rev esp enferm dig 2005; 97:707–15. 22. bailey is, karran se, toyn k, brough p, ranaboldo c, karran sj. community surveillance of complication after hernia surgery. bmj 1992; 304:469–71. 23. saggar vr, suigh k, sarngi r. endoscopic total extra peritoneal management of amyand’s hernia. hernia 2004; 8:164–5. مؤمتر الطب العام املتقدم الكلية الطبية امللكية )لندن(، وزارة الصحة العمانية وجامعة السلطان قابوس جامعة ال�صلطان قابو�س، 29-30 يناير2014 advanced general medicine conference the royal college of physicians (london), the ministry of health (oman) and sultan qaboos university sultan qaboos university, 29–30 january 2014 abstracts cytokines and medicine 1: from fever to phenome prof. sir gordon duff chair, uk medicines & healthcare products regulatory agency (mhra); chair, academic health sciences centres, imperial college, london, uk, and trinity college, dublin, ireland; fellow of: st peter’s college, oxford; academy of medical sciences; royal colleges of physicians (london and edinburgh) and royal society edinburgh, uk. e-mail: g.w.duff@sheffield.ac.uk fever is one of the oldest and most frequently recorded physical signs in clinical medicine, but its pathophysiological significance remains unclear. however, over the last 40 years, attempts to understand the mechanism of fever contributed key insights that led to the discovery of several families of intercellular protein messengers and growth factors, now called cytokines. understanding the cytokines that are produced by blood monocytes and tissue macrophages (monokines) has been especially important in inflammatory and immune diseases. there have already been notable therapeutic successes in chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. we can expect further significant therapeutic and diagnostic developments in the future. cytokines and medicine 2: from phenome to genome and back again prof. sir gordon duff chair, uk medicines & healthcare products regulatory agency (mhra); chair, academic health sciences centres, imperial college, london, uk, and trinity college, dublin, ireland; fellow of: st peter’s college, oxford; academy of medical sciences; royal colleges of physicians (london and edinburgh) and royal society edinburgh, uk. e-mail: g.w.duff@sheffield.ac.uk modern molecular technologies have allowed an ever-increasing understanding of the role of cytokines and growth factors in a wide range of human diseases. we already have many new cytokine-related medicines that have been highly successful in the clinic. knowledge of cytokine genes and their epigenetic modifications is contributing to an understanding of inherent susceptibility to infectious and inflammatory diseases and their clinical outcomes, or phenotypes. looking to the future, these advances promise genomic and phenomic tools for the stratification of patient populations in new medicines development (‘stratified’ or ‘precision’ medicine) and for effectively targeted public health strategies in preventive medicine. venomous and poisonous animals of the arabian peninsula prof. david a. warrell centre for tropical medicine, nuffield department of clinical medicine, university of oxford, uk; international director, royal college of physicians, london, uk. e-mail: david.warrell@ndm. ox.ac.uk snakes: the arabian peninsula is inhabited by 12 species of medically-important terrestrial venomous snakes, all but three of which occur in oman, although four (atractaspis microlepidota andersonii, naja arabica, bitis arietans and echis pyramidum) are virtually confined to the dhofar region in the south of the country. the most frequently encountered snakes are horned vipers (cerastes) and saw-scaled vipers (echis). viper venoms contain cytotoxic hydrolases responsible for local swelling, bleeding, bruising, lymphangitis, blistering and necrosis; metalloprotease haemorrhagins causing spontaneous systemic bleeding; procoagulant enzymes causing consumption coagulopathy, platelet inhibitors and other anti-haemostatic toxins, and hypotensive oligopeptides causing shock. microangiopathic haemolysis and shock are two of the possible mechanisms for acute kidney injury (aki). ten species of sea-snakes are found in the seas surrounding arabia but are absent from the red sea. sea-snake venoms contain paralysing neurotoxins and myotoxic phospholipases a2 that cause generalised rhabdomyolysis complicated by hyperkalaemia and aki. the venoms of burrowing asps (atractaspis) contain oligopeptide sarafotoxins that are potent endothelin homologues causing coronary vasoconstriction. the venom of the arabian cobra (naja arabica) has post-synaptic neurotoxic activity causing descending paralysis. first-aid involves reassurance, compression of local veins and lymphatics with a pressure-pad, immobilisation with a splint or sling and rapid transport to medical care. specific antivenom is indicated if there are evident haemostatic abnormalities, shock, neurotoxicity, myotoxicity, haemolysis or severe rapidly progressive local envenoming. appropriate specific antivenoms are manufactured by the national antivenom and vaccine production center (navpc) in riyadh, saudi arabia (www.antivenom-center.com) but a variety of antivenoms of uncertain effectiveness are imported from india and elsewhere. the risk of snake-bite is reduced by wearing protective clothing, especially footwear; using lights when walking after dark, and either sleeping off the ground or underneath a well-tucked-in mosquito net. scorpions: throughout arabia, scorpionstings are more frequent than snake-bites but fatalities are rare except in children. the most dangerous genera are androctonus and leiurus (buthidae) and nebo (scorpionidae). intense local pain in the stung digit is best treated by digital block with local anaesthetic. for severe systemic envenoming, antivenom is manufactured by the navpc. spiders: there are a few reports in this region of severe muscle spasms, suggesting the possibility of bites by imported latrodectus (black widow) spiders. hymenoptera (wasps, hornets, bees): abstracts | e265 sultan qaboos university, 29–30 january 2014 sensitised people may be protected from sting anaphylaxis by self-injectable adrenaline or desensitisation. marine stingers: many species of venomous fish (stingrays, catfish, stonefish, lionfish, scorpionfish), jellyfish (cnidaria), sea urchins, bristleworms (polychaetes) and coneshells inhabit the tropical waters of the gulf and arabian sea. enormous swarms of jellyfish occasionally invade the coastline of oman (e.g. crambionella orsini in 2002). although no fatal jellyfish stings have been reported here, many painful stings and a few near-fatal systemic envenomings have occurred. cubozoans (box jellyfish) were implicated in the worst cases, at least one of which had features of irukandji syndrome (delayed headache, musculoskeletal, chest and abdominal pains, nausea, vomiting, diaphoresis, hypertension, tachycardia and pulmonary oedema) that has been associated with fatalities in australia. dangerous genera found in arabian waters include tamoya and alatina (carybdea) but chiropsalmus and chironex have never been recorded. portuguese men o’ war (physalia) are also present. apart from direct envenoming, sensitised people may suffer anaphylaxis if they are stung on a second occasion. seafood poisoning: algal blooms of dinoflagellates (alexandrium sp.) create red tides, creating the risk of shellfish poisoning and threating the fishing industry, wildlife and desalination plants in oman. high levels of histamine have been found in imported dried anchovies (arabic, qasha), carrying the risk of scombroid fish poisoning. there are many species of potentially tetrodotoxic pufferfish in these waters, but no cases of poisoning have yet been reported. malaria and other imported tropical diseases prof. david a. warrell centre for tropical medicine, nuffield department of clinical medicine, university of oxford, uk; international director, royal college of physicians, london, uk. e-mail: david.warrell@ndm. ox.ac.uk oman has succeeded or made substantial progress in eliminating many of its endemic tropical infectious diseases such as malaria, lymphatic filariasis and schistosomiasis but others persist at varying levels of incidence or prevalence, such as tuberculosis, typhoid, leishmaniasis, hookworm, brucellosis, trachoma, rabies and crimean-congo haemorrhagic fever. since oman employs an increasingly large foreign labour force from developing countries, contributing 30% of its population, the country has a growing susceptibility to imported tropical infections such as malaria, a risk compounded by rising international tourism and pilgrimage, together with influxes of immigrants from neighbouring countries, such as from somalia in 1998. one result of disease globalisation is that medical staff anywhere in the world may be confronted by a patient suffering from an imported disease acquired in an exotic location. an expanded range of differential diagnoses should be considered including the following pathogens, some of which are opportunistic infections in hiv-immuno-suppressed patients. viruses: hepatitis, haemorrhagic fevers, encephalomyelitis (arboviruses, lyssaviruses, henipaviruses, etc.); bacteria: enteric fevers, melioidosis, tularaemia, leptospirosis, rickettsioses, relapsing fevers, antibiotic-resistant strains (totally drug-resistant mycobacterium tuberculosis (tb), acinetobacter barmannii, carbapenem-resistant enterobacteriaceae, etc.); fungi: penicillium marneffei, paracoccidioides brasiliensis, cryptococcus gattii, etc.; protozoa: malaria, babesiosis, visceral leishmaniasis (kala-azar), trypanosomiasis, amoebiasis, etc.; helminths: strongyloides, trichinella, etc. typical “blind” broad-spectrum antibiotic treatment regimens for patients with assumed community-acquired sepsis such as a broad-spectrum antipseudomonal penicillin or broad-spectrum cephalosporin with an aminoglycoside would fail in all the virus infections, some of the bacteria (carbapenemresistant enterobacteriaceae, miliary tb, rickettsiae, listeria monocytogenes), and all the fungi, protozoa and helminths. in all cases of suspected imported infection, a detailed travel history is essential, including the precise itinerary, type of accommodation, style of travel, activities, sexual contacts, accidents, unusual events and exposures, infestations with ticks, fleas and other arthropods and bites. the traveller’s special vulnerabilities should be explored, such as lack of pre-travel vaccinations (e.g. yellow fever, poliomyelitis, diphtheria, rabies, viral hepatitis a and b) and appropriate chemoprophylaxis (e.g. malaria, rickettsiae, leptospirosis); splenectomy (past surgical or sickle cell anaemia autosplenectomy, e.g. malaria, babesiosis, encapsulated bacteria); pregnancy (e.g. malaria, amoebiasis, listeriosis, hepatitis e virus); drugs (e.g. corticosteroids for tb, amoebiasis, melioidosis, invasive strongyloidiasis, gastric acid secretion inhibitors for gastrointestinal infections), and chronic illnesses (human immunodeficiency virus, human t-lymphotropic virus 1, diabetes mellitus, alcoholic cirrhosis, chronic renal failure, renal stones, sickle cell anaemia). awareness of current epidemics in the countries where the illness may have been acquired can be provided by websites such as www.promedmail.org/. severe falciparum malaria is one of the commoner imported tropical diseases. exceptionally, it may prove fatal less than 24 hours after the first symptoms. malaria must be excluded in every case of acute fever with possible exposure in an endemic area, especially during the previous few months. none of the typical symptoms are specific (fever, chills, pains in head, muscles, back or joints), fatigue, anorexia, prostration, malaise, gastrointestinal and respiratory symptoms, postural fainting). malaria may be misdiagnosed as influenza, travellers’ diarrhoea, hepatitis, viral encephalitis or viral haemorrhagic fever. patients may not volunteer their history of travel to a malarious country and competent parasitological diagnosis may not be generally available. patients with suspected severe malaria should be admitted to hospital immediately. their malaria chemoprophylaxis should be stopped to improve chances of microscopic diagnosis. preferably, thick and thin blood films should be examined daily for at least 72 hours (or rapid antigen detection) or until an alternative diagnosis can confidently be made. if features of severe malaria develop (e.g. declining level of consciousness), a therapeutic trial of intravenous artesunate should be initiated without delay. other travel companions should also be checked for malaria as they are likely to have shared the same exposure risk as the index case.in the future. advances in the treatment of bone diseases prof. graham russell the botnar research centre & oxford institute of musculoskeletal sciences, nuffield orthopaedic centre, oxford university, uk; the mellanby centre for bone research, sheffield university, uk. e-mails: graham.russell@ndorms.ox.ac.uk and graham.russell@sheffield.ac.uk there have been impressive advances in recent years in understanding the genetic basis of bone disorders, and the regulatory systems that control bone formation and resorption. these advances have not only led to a better understanding of the pathophysiological basis of osteoporosis and other bone diseases, but also to new approaches to therapy. currently the bisphosphonates (bps), e.g. alendronate, risedronate and zoledronate, dominate the market as extremely effective agents for the treatment of bone diseases characterised by increased bone resorption, such as paget’s disease, osteolytic bone metastases, myeloma and osteoporosis. the molecular actions of bps are now well understood and this is leading to a better appreciation of the important but subtle differences among the members of the bp class of drugs. many bps are now becoming generic and current issues include how long they should be used and concerns about rare side-effects, such as atypical fractures. overall the benefits of using these drugs far outweigh any disadvantages, and there is evidence that bps may have important non-skeletal effects, including anti-cancer effects and extension of the life span. in terms of the e266 | squ medical journal, may 2014, volume 14, issue 2 advanced general medicine conference the royal college of physicians (london), the ministry of health (oman) and sultan qaboos university development of drugs to inhibit bone resorption, the discovery of the receptor activator of nuclear kappa beta ligand (rankl) system has had a profound impact, and the introduction of denosumab, an anti-rankl fully human antibody, is proving very effective for treating osteoporosis and others disorders of bone resorption. inhibition of the bone-specific protease cathepsin k is another approach and one such drug, odanacatib, is still in clinical development. among other approaches, the interest in selective estrogen receptor modulators has declined. there is still intense interest in the development of drugs that stimulate bone formation, but the search for pharmacological stimulants of bone formation to build bone and prevent fractures has proved to be difficult, with only one such agent, parathyroid hormone (pth), given as pulsatile therapy, having been licensed for this purpose. developing alternate forms of pth has not yet been successful, while the attractive concept of using calcilytic drugs, working via the ca-sensing receptor to stimulate endogenous pth secretion, has also not yet been successfully accomplished. much interest is currently focussed on the opportunities that have arisen from the discovery of the genetic basis of the high bone mass syndromes, including sclerosteosis. the targets lie in the bone morphogenetic proteins (bmps) and the wnt/lrp5/6 pathway. blockade of sclerostin (encoded by the sost gene), an osteocytederived protein that blocks bmps and wnt signalling, by using neutralising antibodies, has already been demonstrated to augment bone mass in animals and man. bone as an endocrine organ prof. graham russell the botnar research centre & oxford institute of musculoskeletal sciences, nuffield orthopaedic centre, oxford university, uk; the mellanby centre for bone research, sheffield university, uk. e-mails: graham.russell@ndorms.ox.ac.uk and graham.russell@sheffield.ac.uk there have been remarkable recent advances in knowledge about skeletal biology and the changes that take place in disease. these are largely the result of discoveries in genetics and cell biology. skeletal development is programmed by the sequential activation of specific genetic pathways, that culminate in the production of the adult skeleton which is light but strong. systemic hormones—including the parathyroid hormone (pth), vitamin d metabolites, and calcitonin—regulate blood calcium levels and contribute to the overall calcium economy of the body. many other hormones have effects on skeletal behaviour and its modelling and remodelling activity. in addition to understanding how osteoblasts form bone and osteoclasts resorb bone, the osteocytes are now recognised to have an important role as mechanosensors and endocrine cells. it is becoming clear that bone may itself function as an endocrine organ, not only locally but also sytemically. at a local level, the integration of cellular differentiation and function within the microenvironment of bone is under the influence of a large number of cytokines and growth factors. there are several important recently discovered pathways that are involved in osteoblast regulation and osteoblast/osteoclast interactions; some of these are suitable for pharmacological interventions, including the wnt/lrp5 pathway, the ephrin system, pth-rp and particularly the receptor activator of nuclear kappa beta (rank) and ligand/ rank/osteoprotegerin system. at a systemic level, there is evidence that products of bone cells may have distant endocrine effects. indeed osteocytes have their own repetoire of regulatory molecules, including fgf23, which is involved in phosphate metabolism, and sclerostin, which is a powerful negative regulator of bone formation. furthermore there is evidence that osteocalcin, secreted by osteoblasts, may act as a systemic metabolic regulator by controlling insulin secretion and sensitivity. there are also potential regulatory links between the hypothalamus, gut and adipose tissue involving leptins, serotonin and adipokines. these phenomena link in to the crosstalk between muscle and bone, and into understanding various aspects of ageing. all this new knowledge is offering exciting opportunities for therapeutic interventions. acute medical problems in pregnancy prof. catherine nelson-piercy professor of obstetric medicine, king’s college, london, uk; guy’s & st thomas’ and queen charlotte & chelsea hospitals, london, uk; president of the international society of obstetric medicine. e-mail: catherine.nelson-piercy@gstt.nhs.uk medical diseases, either pre-existing or new onset in pregnancy, are now the commonest cause of maternal death in the uk. successive reports of the confidential enquiries into maternal deaths have demonstrated no significant fall in the number of these maternal deaths due to ‘indirect’ causes over the last 20 years. furthermore, the majority of these deaths are associated with substandard care and in one-third of cases, this is classified as major substandard care, where different care might have prevented death of the mother. this substandard care includes failure to diagnose appropriately, investigate and treat women with new onset chest pain, headaches or other medical symptoms. this often arises when well-meaning clinicians prioritise the health of the fetus over that of the mother, withholding essential investigations or drugs, resulting in the demise of both mother and fetus. cardiac disease (aortic dissection, ischaemic heart disease, cardiomyopathy) is the commonest cause of maternal death in the uk, followed by neurological causes such as epilepsy and subarachnoid haemorrhage. physicians should be familiar with the interaction between pregnancy and medical disease, with the safety of radiological investigations in pregnancy and with the risk/benefit ratio for the use of different drugs in pregnancy. physicians looking after pregnant women in their clinics, or in the acute medicine setting, need to have the skills to assess the ‘common’ symptoms of pregnancy, including breathlessness, headaches, palpitations and epigastric pain. mostly, these symptoms are benign and a careful history is reassuring but physicians need to be aware of red flag symptoms and signs. the normal ranges of many blood tests are altered by pregnancy and the results must be interpreted with knowledge of normal ranges in pregnancy. chest x-rays, computed tomography (ct) scans of the head, ct pulmonary angiograms, magnetic resonance imaging and ventilation/perfusion scans are all safe in pregnancy and should never be withheld if clinically indicated. algorithms for the diagnosis and management of acute medical problems such as acute severe asthma, acute coronary syndrome and headaches are little changed compared to the non-pregnant patient. however, there are important adaptations in the investigation and management of acute venous thromboembolic disease and cardiac arrest in pregnancy. renal disease in pregnancy prof. catherine nelson-piercy professor of obstetric medicine, king’s college, london, uk; guy’s & st thomas’ and queen charlotte & chelsea hospitals, london, uk; president of the international society of obstetric medicine. e-mail: catherine.nelson-piercy@gstt.nhs.uk kidney disease is relatively common in pregnancy and can be broadly divided into chronic kidney disease (ckd) and acute kidney injury (aki). the risks for women with ckd include an increased chance of developing pre-eclampsia, a growth-restricted fetus and preterm delivery. the outcome for women with ckd is dependent on the degree of renal impairment, the presence and severity of coabstracts | e267 sultan qaboos university, 29–30 january 2014 existing hypertension and proteinuria and, to a lesser extent, the underlying cause of the ckd. drugs suitable to control hypertension in pregnancy included labetalol, nifedipine and amlodipine, methyldopa and doxasocin. angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated in pregnancy. if used to control proteinuria and for renal protection, they may be stopped as soon as pregnancy is confirmed; when used for hypertension they should be changed to a safer alternative prior to pregnancy. statins should also be stopped prior to pregnancy. immunosuppressant drugs used for transplantation and in glomerulonephritis that are safe to continue in pregnancy include corticosteroids, azathioprine, tacrolimus and ciclosporin. these drugs are also safe in breastfeeding. teratogenic drugs that should be stopped prior to pregnancy included cyclophosphamide and mycophenolate mofetil. intravenous iron and synthetic erythropoietin may be safely administered during pregnancy. the pregnancy outcome for women with renal transplants is usually good but again depends on the pre-pregnancy allograft function. data from a recent prospective uk study of 105 pregnancies in 101 patients with a median pre-pregnancy creatinine 118 μmol/l showed that pre-eclampsia developed in a quarter, median gestation at delivery was 36 weeks and over 50% of babies were born preterm (<37/40) and a quarter were born small for gestational age (<10th centile). predictive factors for poor pregnancy outcome were first trimester creatinine >125 μmol/l (p = 0.001), and diastolic bp >90 mmhg in the second or third trimester. although previously associated with very poor fetal outcomes, women with ckd on dialysis are now usually able to have successful pregnancies, although most deliver preterm babies. aki in pregnancy is most commonly associated with postpartum haemorrhage and other hypovolaemic states, pre-eclampsia syndromes and sepsis. aki is also seen in association with use of non-steroidal anti-inflammatory drugs which is common after caesarean section. the management of women with ckd in pregnancy should involve a multidisciplinary team and should begin with pre-pregnancy counselling to ensure women are informed of the risks and understand any changes necessary in their medication. the timing of delivery involves balancing the risks of early delivery for the baby versus the risks of continuing the pregnancy (potentially resulting in irreversible decline in renal function) for the mother. hormone replacement therapy in 2014 prof. john a. h. wass academic vice president of the royal college of physicians, london, uk; professor of endocrinology, university of oxford, uk; consultant physician, department of endocrinology, oxford centre for diabetes, endocrinology & metabolism, churchill hospital, oxford, uk. e-mail: john.wass@noc.anglox.nhs.uk there have been many advances and improvements in hormone replacement therapy for all sorts of endocrine deficiencies. in the field of thyroid hormone deficiency, a proportion of patients do not respond to simple thyroxine therapy. thyroxine needs to be converted to liothyronine and some people have a genetically determined decrease in the enzyme that achieves this. therefore they may need triiodothyronine replacement therapy if the symptoms of hypothyroidism persist despite thyroxine therapy. a meta-analysis of the use of liothyronine in hypothyroidism does not reveal that this is a problem because of the prevalence of this genetic deficiency. in addition, the treatment of a persistently elevated thyroid-stimulating hormone level in the presence of hypothyroidism and thryoxine therapy has multifarious causes. this therefore needs careful consideration of such aspects as the type of thyroxine preparation being utilised, the presence of coeliac disease and interference with either the absorption or metabolism of thyroxine. there are new ways of treating hypoparathyroidism and parathyroid hormone is becoming available. this is a rare problem most frequently occurring after total thyroidectomy. in the field of adrenal gland problems, long-acting daily-dose steroid preparations are becoming available. monitoring is done by measuring cortisol levels and urinary steroids. mineralocorticoid deficiency is treated by fludrocortisone and the adequacy is monitored by measuring renin. in the field of male testosterone deficiency, longer acting preparations of testosterone are now available which may only necessitate therapy every three months. it is important to monitor the haemoglobin for polycythaemia and the prostate-specific antigen for prostate cancer. the latter is not caused but may possibly be exacerbated by testosterone replacement therapy. growth hormone deficiency is commonly seen in patients with pituitary disease. double-blind studies suggest that treating such patients with growth hormone, even if they are adult, improves muscle strength, mental function and decreases cardiovascular risk. concepts in obesity prof. john a. h. wass academic vice president of the royal college of physicians, london, uk; professor of endocrinology, university of oxford, uk; consultant physician, department of endocrinology, oxford centre for diabetes, endocrinology & metabolism, churchill hospital, oxford, uk. e-mail: john.wass@noc.anglox.nhs.uk obesity is increasingly prevalent and this is particularly the case in the usa, the uk, australia and sri lanka. a national survey carried out in 2012 in sri lanka shows the rates of overweight and obesity are rising to epidemic proportions, especially among women. it is clear that obesity causes an increase in a number of different problems, including diabetes mellitus, hypertension, sleep apnoea and increased rates of cancer. there are also clear problems with obese children who will tend to grow up to be obese adults. bariatric surgery remains an effective means of combating severe obesity but other treatments also work. currently, no developed nation has developed an effective strategy to reduce levels of obesity. this would involve the coordination of different government departments, including health, education, agriculture, sport and the treasury. a coordinated approach is necessary but no country on the planet can yet serve as a model for how to tackle the problem. acute rheumatological emergencies dr. charles mackworth-young rheumatology consultant, chelsea & westminster hospital, london, uk. e-mail: charles.mackworth-young@chelwest.nhs.uk rheumatological emergencies are not uncommon and appropriate management can radically affect the eventual outcome. the presentation focusses on conditions most commonly seen, including those that often cause the greatest diagnostic difficulty such as septic arthritis, crystal arthritis, giant cell arteritis and cerebral lupus. diagnostic pitfalls and immediate management will be discussed. e268 | squ medical journal, may 2014, volume 14, issue 2 advanced general medicine conference the royal college of physicians (london), the ministry of health (oman) and sultan qaboos university antiphospholipid syndrome dr. charles mackworth-young rheumatology consultant, chelsea & westminster hospital, london, uk. e-mail: charles.mackworth-young@chelwest.nhs.uk it is 30 years since the substantive clinical description of the antiphospholipid syndrome was made. since then the importance of the condition in many areas of medical practice has been recognised. while it was initially described in the context of connective tissue diseases such as systemic lupus erythematosus, it soon became apparent that the syndrome can exist as an independent, primary disorder. it is a frequent cause of venous and arterial thrombosis, and the most common acquired cause of recurrent foetal loss. it explains many cases of early stroke and myocardial infarction, and can account for certain atypical neurological syndromes. the presentation includes a brief history of the condition, a summary of the clinical features and an overview of current management. evidence-led improvement of patient outcome and patient experience dr. ian bullock chief operating officer, national clinical guideline centre, royal college of physicians, london, uk. e-mail: ian.bullock@rcplondon.ac.uk the royal college of physicians (london) has a highly respected track record of a whole healthcare systems approach and delivering first class evidence-based healthcare products. we offer an international consultancy service providing a range of evidence-based healthcare and quality initiatives tailored to a country’s individual requirements. whether it is setting up international evidence-based guideline development groups or quality initiatives, tailored programmes are shaped in partnership with local healthcare experts to improve both patient outcome and the quality and experience of care. a key aspect of this work is our experience and understanding of the relationships that exist between the evidence, the geographical context and culture where evidence is implemented into practice, as well as understanding the way in which change is facilitated. we are sensitive to cultural needs and aim to bring about evidence translation and utilisation which lead to sustainable healthcare improvements through application of the promoting action on research implementation in health services (parihs) framework. the presentation illustrates how, through consultancy support, evidence translation and utilisation should remain high priorities for developing healthcare systems. redesigning service delivery in stroke care to continuously improve the quality of patient care dr. ian bullock chief operating officer, national clinical guideline centre, royal college of physicians, london, uk. e-mail: ian.bullock@rcplondon.ac.uk the oman evidence translation and utilisation (oetu) project commenced in 2011. in partnership with the royal college of physicians (london), the burden of disease areas of national importance to the omani population were identified with the top five of these prioritised for evidence work. expert clinicians (stroke, cardiac disease, diabetes, respiratory disease and obesity) from a range of health disciplines, including medicine, nursing and allied health professions, met for a two-day conference focussed on developing knowledge and expertise in evidence-based healthcare, leadership and quality improvement. of these high-priority areas, experts in stroke care were formed into a quality development group and worked to produce the first omani national clinical guideline—in the management of stroke—launched in december 2013. the oetu project has provided a framework for evidence use, healthcare system improvement, continuous quality improvement and hospital redesign. the diagnosis and management of cardiac failure dr. adam darowski geratology unit, department of medicine, john radcliffe hospital, oxford, uk; oxfordshire falls prevention service, uk. e-mails: adam.darowski@msd.ox.ac.uk and darowski@doctors.org. uk the principles of treatment of heart failure are well-established. diuretics relieve symptoms, angiotensin-converting enzyme inhibitors, beta-blockers and anti-aldosterone diuretics improve survival. non-pharmacological approaches such as exercise, cardiac resynchronisation and implantable cardioverter-defibrillators also improve survival. heart failure is a syndrome caused by a wide spectrum of different conditions. there are two broad groups of patients: those whose left ventricular systolic function is impaired (systolic failure), and those in whom it is preserved. cardiac failure with preserved left ventricular function is the more common form of heart failure, but the variety of methods used to diagnose it lead to confusion in the literature. it has been little studied compared to systolic failure. the presentation will discuss what is known about making the diagnosis of these two conditions and the evidence for their management. making sense of transient loss of consciousness dr. adam darowski geratology unit, department of medicine, john radcliffe hospital, oxford, uk; oxfordshire falls prevention service, uk. e-mails: adam.darowski@msd.ox.ac.uk and darowski@doctors.org. uk brief episodes of loss of consciousness are rarely witnessed, and only a limited and frequently misleading history is available from the patient. had sherlock holmes been a doctor, this would have been his chosen field. the doctor has to establish whether there really was any loss of consciousness and try to recreate the ‘crime scene’. he has to gather evidence of what factors might have led to the event and which of them—there are often several ‘suspects’—actually caused it. frequently, we are left with several possibilities and no ‘smoking gun’. the key is to exclude serious causes and work on a balance of probabilities for the others. the likely underlying diagnosis depends to a large extent on the patient’s age. half of our medical students admit to an episode of loss of consciousness. usually the cause is vasovagal syndrome—a reflex common to all vertebrates—but occasionally sudden death occurs in young people. in older age groups, the focus is on the diagnosis and management of rhythm disorders. drug-induced paroxysmal hypotension (mostly orthostatic hypotension and vasovagal syndrome) is the most common cause. abstracts | e269 sultan qaboos university, 29–30 january 2014 metabolic surgery in diabetes: cutting to the solution dr. ebaa al-ozairi department of medicine, faculty of medicine, kuwait university. e-mail: alozairi@hsc.edu.kw obesity, which is arguably the single most important public health challenge nowadays, is directly linked to several diseases such as type 2 diabetes mellitus (t2dm), hypertension, ischaemic heart disease, obstructive sleep apnoea, osteoarthritis and various cancers. public health and legislative approaches are essential to tackling the global epidemic of obesity, together with diet, exercise and medications. however, bariatric surgery remains the most clinically effective and cost-effective intervention for morbid obesity and its global uptake has increased exponentially in the past decade. in kuwait, more than 6,000 metabolic surgeries are performed each year. patients with t2dm undergoing bariatric surgical procedures demonstrate substantial and sustained weight loss, reductions in diabetes medications and remission of hyperglycaemia. surgical intervention in patients with a more recent onset of t2dm appears to result in higher rates of resolution than in patients with a longer duration of the disease. these findings suggest bariatric surgery may represent a potential first-line therapeutic management strategy for t2dm, particularly in those with lesser degrees of obesity or a shorter duration of the disease. although this has generated substantial interest in the scientific community, minimal level one data is available to guide such an approach. there was what can only be described as a cultural disconnect when bariatric surgery was being promoted for the treatment of t2dm. diabetologists were interested in the percentage reduction in body weight, hba1c, lipid profiles and blood pressure, whereas surgeons reported on the reduction in excess body weight and ‘cure’ rates for t2dm, dyslipidaemia and hypertension. the presentation highlights the current evidence for the success of various types of metabolic surgery and focuses mainly on t2dm from various metabolic and nutritional points of view. acute kidney injury dr. dawood al-riyami nephrology unit, department of medicine, college of medicine & health sciences, sultan qaboos university, oman. e-mail: alriyamidawood@yahoo.com acute kidney injury (aki) remains a common complication of many non-renal medical problems. it requires hospital admission and a variety of therapies. with improved renal replacement therapy, it is rare for a patient to die directly as a result of renal failure; however, the mortality of patients requiring acute dialysis therapy remains high. recent evidence has shown that relatively small changes in renal function are associated with substantial increases in mortality. moreover, acute renal failure is an independent risk factor for death. this presentation highlights issues related to the diagnosis, new pathophysiological aspects and the non-dialytic management of critically ill aki patients as well as renal replacement therapy. volume responsiveness dr. abdul hakeem al-hashim department of medicine, college of medicine & health sciences, sultan qaboos university, oman. e-mail: hakeemyaqoob@yahoo.com volume responsiveness remains an important question in critically ill hypotensive patients. timely and appropriate use of intravenous fluids can rapidly stabilise a patient’s condition and avoid the use of vasoactive drugs. however, excessive fluid resuscitation has been associated with increased complications, increased length of intensive care unit stay and hospital stay and increased mortality. traditionally, physicians use clinical examination (e.g. jugular venous pressure), central venous pressure (cvp) and pulmonary capillary wedge pressure (pcwp) to assess volume responsiveness in an unstable patient. multiple studies have demonstrated that these parameters are unreliable and they have poor sensitivity and specificity. in the past decade, new volume responsiveness methods have been described and studied. examples of these dynamic methods are pulse pressure variation (ppv), stroke volume variation (svv) and passive leg raising (plr). in contrast to static measures (cvp, pcwp), dynamic parameters (ppv, svv, plr) rely on the changing physiology of heart-lung interactions to determine whether a patient will benefit from intravenous fluid or an increase in preload. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e587−588, epub. 14th oct 14 submitted 14th feb 14 revision req. 1st apr 14; revision recd. 1st apr 14 accepted 17th apr 14 departments of 1dermatology and 2pathology, complejo hospitalario de jaen, jaen, spain *corresponding author e-mail: ismenios@hotmail.com سرطان الغدد الليمفاوية ذو اخلاليا b الكبرية املنتشر تشخيص ال جيب نسيانه يف كبار السن ريكاردو رويزفيالفريدي وفران�سي�سكو رامو�س-بلجيوزيولو�س diffuse large b-cell lymphoma, leg type a diagnosis not to forget in the elderly *ricardo ruiz-villaverde1 and francisco ramos-pleguezuelos2 interesting medical image figure 1: infiltrated erythematous nodules on the anterior aspect of the left leg with severe hyperkeratosis and secondary impetiginisation. an 83-year-old woman, with a past medical history of hypertension, diabetes mellitus and ischemic cardiomyopathy, was referred to the dermatology clinic of complejo hospitalario de jaen in jaen, spain, in october 2013. the patient presented with erythematous indurated tumoural lesions with severe hyperkeratosis and impetiginisation on the anterior aspect of her left leg, which had appeared eight months prior [figure 1]. fever, night sweats, weight loss, itching or other constitutional symptoms were absent. neither hepatosplenomegaly nor axillary or generalised lymphadenopathy were detected. a systemic examination of the patient did not reveal any further abnormalities. all laboratory tests were negative, including a full blood count; biochemistry, protein electrophoresis, routine urine, lactate dehydrogenase, β2microglobulin and immunoglobulin tests; a peripheral blood smear, and serology tests for viruses (human immunodeficiency virus and hepatitis b and c viruses) and borrelia burgdorferi. no evidence of malignancy was observed during a whole-body computed tomography scan or a bone marrow biopsy. a cutaneous biopsy was also performed. a histological examination of the skin specimen revealed a b-lymphocyte proliferation with mild epidermotropism and antigen cd20/45 positivity. the following profile was obtained from an immunohistochemical assay: positive multiple myeloma oncogene 1 (mum-1), positive b-cell lymphoma 6 (bcl-6), negative chromosome 10 (c10), positive b-cell lymphoma 2 (bcl-2) and antigen ki67 >90%. these findings were consistent with a diagnosis figure 2: b-lymphocyte inflitration with a predominance of medium size and split non-cleaved cells with blastic differentiation. diffuse large b-cell lymphoma, leg type a diagnosis not to forget in the elderly 588 | squ medical journal, november 2014, volume 14, issue 4 of diffuse large b-cell lymphoma, leg type [figure 2]. in addition, testing for the epstein-barr virus by in situ hybridisation was negative. comment diffuse large b-cell lymphoma, leg type is a subset of primary cutaneous lymphoma, characterised by the presence of nodules or tumours on the legs of elderly people, mainly females.1 it represents 1–4% of all cutaneous lymphomas and has a five-year survival rate of less than 50%.2 this form of lymphoma was identified as an independent entity in the classification of cutaneous lymphomas developed by the european organisation for research and treatment of cancer.3 although these lymphomas are mostly limited to the skin at presentation, in 10% of reported cases the tumoural lesions begin in locations other than the legs.4 when the malignancy spreads, it frequently advances to the lymph nodes, bone marrow and the central nervous system.4 as the majority of the patients with this condition are elderly, the therapeutical management may be complicated due to comorbidities and the potentially frequent number of relapses. spontaneous remission only occurs in rare cases.5 rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (r-chop) chemotherapy and chemotherapeutic compounds applied for relapsing systemic b-cell non-hodgkin’s lymphoma have previously proven to be effective therapies.6 however, the current first line of treatment for this variety of lymphoma involves anti-cd20 antibodies, such as rituximab. these therapies can be used even during the early stages of the condition in order to improve rates of survival.7 references 1. hernández-machín b, fernández-misa r, alfonso jl, maeso mc, marrero c, borrego l. [primary cutaneous diffuse large b-cell lymphoma of the leg according to the new whoeortc classification: two cases]. actas dermosifiliogr 2005; 96:607–11. 2. suárez al, pulitzer m, horwitz s, moskowitz a, querfeld c, myskowski pl. primary cutaneous b-cell lymphomas: part i clinical features, diagnosis, and classification. j am acad dermatol 2013; 69:329. doi: 10.1016/j.jaad.2013.06.012. 3. willemze r, jaffe es, burg g, cerroni l, berti e, swerdlow sh, et al. who-eortc classification for cutaneous lymphomas. blood 2005; 105:3768–85. doi: 10.1182/blood-2004-09-3502. 4. grange f, bekkenk mw, wechsler j, meijer cj, cerroni l, bernengo m, et al. prognostic factors in primary cutaneous large b-cell lymphomas: a european multicenter study. j clin oncol 2001; 19:3602–10. 5. alcántara-gonzález j, gonzález-garcía c, fernández-guarino m, jaén-olasolo p. spontaneous regression of primary diffuse large b-cell lymphoma, leg type. actas dermosifiliogr 2014; 105:78–83. doi: 10.1016/j.ad.2012.07.009. 6. ekmekci tr, koslu a, sakiz d, barutcuoglu b. primary cutaneous large b-cell lymphoma, leg type, presented with a migratory lesion. j eur acad dermatol venereol 2007; 21:1000– 1. doi: 10.1111/j.1468-3083.2006.02073.x. 7. gopal mm, malik a. primary cutaneous diffuse large b-cell lymphoma of the upper limb: a fascinating entity. indian j dermatol 2013; 58:366–8. doi: 10.4103/0019-5154.117303. taurine levels in human aqueous humour medical sciences (2000), 2, 55−57 © 2000 sultan qaboos university 1department of obstetrics & gynaecology, 2department of radiology college of medicine, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. 55 unilateral uterine artery embolization and systemic methotrexate therapy in cervical pregnancy *sejekan p 1, vaclavinkova v 1, leven h2, krolikowski a1 عالج حمل عنق الرحم بإحداث جلطة في أحد .شرايين الرحم مع إستخدام حقن الميثوتريكسيت آروليكوسكي. ليفن ، أ. فاآالفينوفا ، هـ .سيجيكان ، ف. ب إن إحداث جلطة في . س]جل المؤلف]ون حال]ة حم]ل ف]ي عنق الرحم تم عالجها بنجاح عن طريق إحداث جلطة في أحد شرايين الرحم باإلضافة إلى إستخدام حقن الميثوتريكسيت :الم$لخص . على الوظيفة اإلنجابية للرحمأحد شرايين الرحم في مثل هذه الحالة قد يلعب دورًا في الحفاظ abstract: the authors report a case of cervical pregnancy successfully treated with combined methods of uterine artery embolization and systemic methotrexate therapy. unilateral selective embolization may play a role in preserving reproductive functions. key words: cervical pregnancy, omani, methotrexate, uterine artery embolization ervical pregnancy, though representing less than 0.1% of all ectopic gestations, tends to be a therapeutic challenge with its risk of profuse hemorrhage, often requiring hysterectomy to control the bleeding.1-3 we describe a case of cervical pregnancy (suspected clinically and confirmed by abdominal and vaginal ultrasound), successfully managed with unilateral uterine artery embolization and systemic methotrexate therapy. the case a 35 year old woman presented at our accident and emergency department at 10 weeks gestation. she complained of painless vaginal bleeding since one week. her obstetric history revealed one first trimester abortion, which had necessitated dilatation and curettage. for the second and third pregnancies, she had cesarean section at term. this was her first visit to hospital during the current pregnancy. on pelvic examination, scanty vaginal bleeding was noted. the uterus was bulky and the cervix, soft and wide. trans-abdominal and trans-vaginal ultrasound examinations showed an empty uterus and a well-defined gestational sac within the cervical canal, with the placenta embedded in the left lateral wall of the cervix (figure 1). there was no fetal pole. a diagnosis of cervical pregnancy was made and the patient transferred to the angiography suite. a simmons nb.2 sidewinder catheter (outer diameter 1.83 mm) was introduced into the left internal iliac artery and inserted selectively into the left uterine artery, revealing a distinct area of placental vasculature in the cervical region (figure 2). the left uterine artery was then embolized with gelgoam sludge mixed with contrast medium; thereafter, the right internal iliac artery was catheterized. since there was no evidence of placental vasculature on the right side, no embolization was attempted there. the following day, the methotrexate therapy was started at a dose of 50 mg/m2 every 24 hours alternately with citrorum factor. the patient was given 3 doses of methotrexate. laboratory data before the therapy was started had shown normal liver and renal functions tests, as well as normal coagulation profile. the β-hcg value was 5824 miu/ml. the patient was observed for 7 days. on day 3 after the procedure, she expelled some tissue, which was confirmed histologically as products of conception. there were no episodes of bleeding during this period and she was discharged. ultrasound examination, repeated on the day of discharge, showed an empty uterus and cervix. the β-hcg level regressed to <5 miu/ml on day 23 after the procedure. her menstruation returned on day 32, lasted for 4 days, without excessive bleeding. no side effects of methotrexate were noticed. c 55 s e j e k a n p. e t a l curettage to remove the fetus and often hysterectomy to stop the ensuing bleeding.4 ultrasound has dramatically improved the early detection of cervical pregnancy, leading to the development of conservative methods of treatment such as chemotherapy, cerclage and arterial embolization.5 arterial embolization has proved excellent for controlling pelvic hemorrhage caused by trauma, cervical cancer and genital tract lacerations. complications from this procedure, such as sciatic nerve injury and necrosis of the bladder or rectum, are uncommon, but have been documented.6 recently there were also reports on the use of arterial embolization before or after dilatation and curettage for successful treatment of cervical pregnancy, although the authors suggest arterial embolization only if significant bleeding occurs.6,7 our case illustrates that conservative management of cervical pregnancy using methotrexate and arterial embolization may obviate surgical procedure like hysterectomy, dilatation and curettage.5 conclusion our patient made a full recovery. post procedure ultrasound examinations were normal and final β-hcg result was negative. to the best of our knowledge, unilateral uterine artery embolization has not been described before in this context. this particular approach should, at least theoretically improve the odds for future reproductive capability and further minimize the risk of complications. references 1. parente jt, chau-su, levy g, legatt e. cervical pregnancy analysis: a review and report of five cases. obstet gynecol 1983, 62, 79–82. 2. palazzetti pl, cipriano l, spera g, aboulkilair mn, pochi a. hysterectomy in women with cervical pregnancy complicated by life-threatening bleeding: a case report. figure 2. selective angiography of the left uterine artery. the straight arrow points to the placental vasculature in the cervix. curved arrow indicates a gelfoam at the beginning of embolization. e l figure 1. sagittal ultrasound image of the uterus. the arrow points to the intumescense in the cervix where the ectopic pregnancy is located. 56 discussion cervical pregnancy represents less than 0.1% of all ctopic gestations, but is frequently a therapeutic chalenge. traditional treatment involved dilatation and clin exp obstet gyncol 1997, 24, 74–5. 3. poon kf, chan lk, tan hk, wong sy. cervical ectopic pregnancy – a case report. singapore med j 1997, 38, 27–8. c e r v i c a l p r e g n a n c y 57 4. van de meerssche m, verdonk p, jaequemyn y, serryn r, gerris j. cervical pregnancy: three case reports and a review of the literature. hum reprod 1995, 10, 1850–5. 5. frates mc, benson cb, doubilet pm, di salvo dn, brown dc, laing fc. cervical ectopic pregnancy: results of conservative treatment. radiology 1994, 191, 773–5. 6. cosin ja, bean m, grow d, wiczyk h. the use of methotrexate and arterial embolization to avoid surgery in a case of cervical pregnancy. fertil steril 1997, 67, 1169–71. 7. meyerovitz mf, lobel sm, harrington dp, bengtson jm. preoperative uterine artery embolization in cervical pregnancy. j vasc interv radiol 1991, 2, 95–7. s e j e k a n p. e t a l 58 *sejekan p 1, vaclavinkova v 1, leven h2, krolikowski a1 ???? ??? ??? ????? ?????? ???? ?? ???�?????? ????? ?? ??????? ??? ?????????????. ?. ??????? ? ?. ??????????? ? ?? . ???? ? ?. ?????????? the case discussion conclusion references clinical and basic research | 417 clinical & basic research sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 424-428, epub. 25th jun 13 submitted 29th aug 12 revisions req. 25th nov 12 & 2nd feb 13; revisions recd. 24th dec 12 & 23rd mar 13 accepted 17th apr 13 1department of paediatrics & child health, aga khan university hospital, karachi, pakistan; 2department of paediatrics, bahria university medical & dental college, karachi, pakistan *corresponding author e-mail: shakeel.ahmed@aku.edu أمناط املرض والنتائج حلديثي الوالدة املرقدين يف مستشفى مرجعي ثانوي يف باكستان �شيد ريحان علي، �شكيل اأحمد، هريماين لوهانا باك�شتان يف ثانوي مرجعي م�شت�شفى يف املرقدين الوالدة حلديثي والنتائج املر�س اأمناط حتديد اإىل الدرا�شة هدفت الهدف: امللخ�ص: خالل الفرتة من يناير اإىل دي�شمرب2009. االطريقة: مت حتليل بيانات املر�س يف ال�شجالت الطبية لكل حديثي الوالدة املرقدين باأثر رجعي خالل فرتة الدرا�شة )العمر، الوزن، اجلن�س، �شبب الرتقيد، مدة الرتقيد، الت�شخي�س، النتيجة النهائية للعالج(. مت فح�س االجتاهات ملعرفة موؤ�رسات الوفاة يف حديثي الوالدة املرقدين يف امل�شت�شفى. النتائج: مت ح�رس 1,554 حالة منهم 979 من الذكور )%63( و575 حالة من االإناث )%37(. متت والدة 891 حالة يف امل�شت�شفى )%57.3( بينما ولدت 663 حالة خارجها )%42.7(. مت ترقيد معظم احلاالت خالل االأربع والع�رسين �شاعة االأوىل بعد الوالدة )%51.3(. اأظهرت النتائج اأن وزن الوالدة يف 13 حالة )%0.8( كان اأقل من 1 كجم، يف 27.9% االبت�شار هو للرتقيد الرئي�شي ال�شبب كان .)37.7%( يف 587 كجم 1.5–2.5 من و )5.4%( يف 85 كجم 1–1.49 والعدوى يف %20.33 من احلاالت تالهما االختناق اثناء الوالدة )%13( والريقان الوليدي )%11.3(. مت ال�شماح لعدد 1,287 حالة اإىل )3.79% ( حالة 59 حتويل ومت الطبية، امل�شورة �شد امل�شت�شفي )2.6%( حالة 41 تركت بينما امل�شت�شفى، مبغادرة )82.8%( م�شت�شفيات الرعاية الثالثية. بلغ العدد االإجمايل للوفيات 106 حالة )%6.8(. اخلال�سة: يف هذه الدرا�شة كانت االأ�شباب الرئي�شية لرتقيد العناية طريق عن الن�شب هذه خف�س املمكن من الوليدي. والريقان الوليدي واالختناق الوليد وزن ونق�س االبت�شار هي الوالدة حديثي املالئمة والتدخل املبكر والتحويل يف الوقت املنا�شب اإىل م�شت�شفيات الرعاية الثالثية. وكان ال�شبب الرئي�شي للوفاة هو االبت�شار. مفتاح الكلمات: ر�شيع؛ مبت�رس؛ نق�س الوزن عند الوالدة؛ الريقان؛ الوليدي؛ االختناق؛ باك�شتان. abstract: objectives: this study aimed to determine the disease patterns and outcome of patients admitted to the neonatal unit of a secondary care hospital in pakistan from january to december 2009. methods: retrospective data from the medical records of all neonates admitted during the study period were reviewed and analysed for age, weight, sex, reason for admission, duration of hospital stay, diagnosis and final outcome. trends were examined to identify the indicators of inpatient neonatal deaths. results: the total number of neonates admitted during the study period was 1,554; 979 were male (63%), and 575 were female (37%). a total of 891 patients (57.3%) were born in the hospital while 663 (42.7%) were born elsewhere. the majority were admitted during the first 24 hours of life (51.3%). a total of 13 patients (0.8%) weighed <1 kg; 85 (5.4%) weighed 1–1.49 kg, and 587 (37.7%) between 1.5–2.5 kg. prematurity and infection were the main reasons for admission (27.9% and 20.33%, respectively), followed by birth asphyxia (13%) and neonatal jaundice (11.3%). a total of 1,287 patients (82.8%) were discharged, 41 left against medical advice (2.6%), 59 were referred to tertiary care hospitals (3.79%) and 106 (6.8%) died. conclusion: prematurity, low birth weight, birth asphyxia and neonatal jaundice were the major causes of neonatal admissions. this could be reduced by appropriate antenatal care, timely intervention, and in-time referral to tertiary care centres for the deliveries of all high-risk pregnancies. the major cause of neonatal mortality was prematurity. keywords: neonatal prematurity; infant, low birth weight; neonatal jaundice; asphyxia neonatorum; pakistan. disease patterns and outcomes of neonatal admissions at a secondary care hospital in pakistan syed r. ali,1 *shakeel ahmed,2 heeramani lohana1 advances in knowledge this study supports using research to identify the most prevalent causes of neonatal morbidity and mortality since mortality rates for under-5-year-olds in developing countries have declined significantly in the last 30 years, while maternal and newborn mortality rates have not changed noticeably it may also facilitate a dialogue with policy makers regarding the importance of investing in measures to ensure neonatal health. disease patterns and outcomes of neonatal admissions at a secondary care hospital in pakistan 418 | squ medical journal, august 2013, volume 13, issue 3 neonatal morbidity and mortality rates reflect a nation’s socioeconomic status, as well as the efficiency and effectiveness of their healthcare services.1 these important indicators are useful in planning for improved healthcare delivery.1 basic neonatal care (level i) is not available at the majority of centres in pakistan where neonates are delivered or admitted;2 therefore, these babies are referred to secondary level hospitals. annually, approximately 3,000 births take place at the aga khan maternal and child care center (akmcc) in hyderabad. the akmcc neonatal service has an experienced, full-time paediatrician and staff who are trained in newborn care. akmcc is also a primary referral centre for the primary care centres in the inner sindh province. almost half of the infant deaths in pakistan occur within the first 28 days of life, which is the most precarious period of time in terms of healthcare.3 the prognosis for these neonates depends upon their underlying condition, its severity and the subsequent management. in view of this situation, a neonatal audit is periodically carried out in the akmcc in order to raise awareness of neonatal problems and their management. this study aimed to help identify the major causes of neonatal morbidity and mortality in pakistan, which may facilitate dialogue with policy makers about investing in this often neglected area of healthcare. methods the study was conducted from january to december 2009 at the neonatal unit of the akmcc in hyderabad, the second largest city in the sindh province, pakistan. the study was approved by the ethical review committee of the aga khan university hospital (approval #2213-ped-erc-12). the neonatal unit admits all neonatal patients except those with tetanus, as no separate facilities are available. neonates requiring surgical intervention and mechanical ventilation are referred to tertiary care hospitals after being stabilised. the following data were extracted for analysis and documented: age, sex, place of birth, weight on admission, duration of hospital stay, and diagnosis both upon admission and discharge. furthermore, the presence of fever, cough, convulsion, diarrhoea, vomiting, jaundice, hypoxaemia, respiratory distress, impaired consciousness, agitation or bulging fontanelle and impaired perfusion were also recorded. additionally, the study also noted culture results, full blood count and the patient’s survival outcome upon discharge. the diagnosis of prematurity and low birth weight (lbw) was mainly based on the world health organization definitions. prematurity is described as live born neonates delivered before 37 weeks. lbw is described as the patient having a birth weight of <2.5 kg; very low birth weight (vlbw) is a birth weight of <1.5 kg and extremely low birth weight (elbw) is a birth weight of <1 kg.4 the diagnosis of sepsis and meningitis was made after isolating the pathogenic organism from the blood or cerebral spinal fluid whenever possible. congenital heart disease was diagnosed on the basis of a clinical examination, supported by chest x-rays; babies were then referred to a tertiary care hospital for a confirmation of this diagnosis by echocardiography and further management. birth asphyxia was mainly diagnosed with a history of delayed crying or poor respiratory effort after birth. neonatal jaundice (nnj) was determined by an estimation of the serum bilirubin level. diagnosis of pneumonia, meconium aspiration syndrome and transient tachypnoea of the newborn were made on the basis of clinical, haematological and radiological findings. results the total number of neonates admitted during the study period was 1,554. there were 979 males (63%) while 575 (37%) were females. of the 1,554 admitted, 891 (57.3%) were born in the hospital while a significant 663 (42.7%) were born elsewhere and referred to the akmcc neonatal unit for further management—as this unit is the only applications to patient care this study may help to improve neonatal care in developing countries by understanding the causes of admission, complications, length of stay and outcome for neonatal patients. syed r. ali, shakeel ahmed and heeramani lohana clinical and basic research | 419 secondary care centre catering to three districts in the sindh province. the majority of the newborns (51.3%) were admitted during the first 24 hours of life. regarding the birth weight of these babies, 13 patients were categorised as having elbw (0.8%), 85 as vlbw (5.4%) and 587 as lbw (37.8%). prematurity and infections were the main causes of admission to the neonatal unit, at 27.9% and 20.33%, respectively. birth asphyxia was the third most common cause of admission (13%) followed by nnj (11.3%). the major causes of infections were sepsis (70.8%), pneumonia (12.6%) and acute gastroenteritis (8.22%). there were 115 neonates admitted for observation due to other causes (7.4%). among them, 23.4% had feeding issues, 19.1% had a history of meconium-stained liquor and 16.5% of babies had a history of maternal complications related to pregnancy and admitted for observation in the neonatal unit [table 1]. among the 106 neonates who did not survive, the leading causes of death were prematurity and lbw (56, 52.8%), followed by birth asphyxia (22, 20.8%) and neonatal infections (10, 9.4%). the case fatalities for the main neonatal diagnoses were prematurity (12.8%), neonatal encephalopathy (10.8%), neonatal infections (3.2%) and other causes (3%). the major causes of neonatal mortality are compiled in table 2, and the outcomes of neonatal admissions are shown in table 3. table 1: disease pattern of the neonatal admissions diagnosis n (n = 1,554) % 1. prematurity 435 27.9 without sepsis 182 41.8 with sepsis 87 20 with respiratory distress syndrome 68 15.6 with asphyxia 35 8 with jaundice 34 7.8 other 29 6.67 2. neonatal infections 316 20.33 sepsis 224 70.8 pneumonia 40 12.6 acute gastroenteritis 26 8.22 meningitis 12 3.79 aspiration pneumonia 12 3.79 urinary tract infection 02 0.63 3. birth asphyxia 203 13 4. nnj 176 11.3 5. respiratory distress 121 7.78 transient tachypnoea of the newborn 53 43.8 meconium aspiration syndrome 37 30.5 pneumothorax 2 2.47 6. observation 115 7.4 feeding issues 27 23.4 meconium-stained liquor 22 19.1 poor obstetric history 19 16.5 excessive crying 03 0 birth injury 02 0 other 20 17.3 reason not given 22 19.1 7. iugr 70 4.5 8. idm 40 2.57 9. neonatal seizures 26 1.67 10. surgical problems 13 0.83 11. congenital heart disease 12 0.77 nnj = neonatal jaundice; iugr = intrauterine growth restriction; idm = infant of a diabetic mother. table 2: major causes of neonatal deaths (n = 106) cause deaths n (%) case fatality rate (%) prematurity, lbw (n = 435) 56 (52.8) 12.8 neonatal infections (n = 316) 10 (9.4) 3.2 birth asphyxia (n = 203) 22 (20.8) 0.8 others (n = 600) 18 (17.0 ) 3 lbw = low birth weight. table 3: outcomes of the neonatal admissions outcome (n = 1,554) n % discharge 1,348 86.7 death 106 6.8 referral 59 3.8 leaving against medical advice 41 2.7 disease patterns and outcomes of neonatal admissions at a secondary care hospital in pakistan 420 | squ medical journal, august 2013, volume 13, issue 3 discussion this study showed that 51.3% of newborns were admitted during the first 24 hours of life. this figure is higher than studies conducted elsewhere in pakistan; for instance the figure was 35% in a study in peshawar,5 33.6% in a karachi study,6 44.47% in a larkana one,7 and is lower than a study conducted in lahore, which reported 75% of neonates admitted during the first 24 hours of life.8 there is also a male predominance noted in this study, which is consistent with the above studies conducted in pakistan. this is most likely due to cultural and social factors, whereby male children are more likely to receive medical care compared to females. for more than 25 years, lbw has been observed to be one of the major risk factors for neonatal admissions in multiple studies conducted in many developing countries.9 in this study, lbw was found in 37.7% of patients; this can be compared to 39% in lahore,8 36% in larkana,7 55.4% in karachi6 and 41.2% in peshawar.5 the incidence of lbw is higher in pakistan compared to other developing countries; for instance, lbw was 20% in a study done in india,10,11 13.25% in a bangladesh study12 and 11.02% in an ethiopian one.13 the higher rate of lbw observed in pakistan may be due to multiple factors, including the poor nutritional status of mothers, inadequate facilities for antenatal care and the high illiteracy rate. preterm birth rates have been reported to range from 5% to 7% of live births in some developed countries, but are estimated to be substantially higher in developing countries.14 in this study, prematurity was the reason for admission in 27.9% of neonates. this rate was higher than in a study done in karachi6 which reported that 6.8% of neonates were admitted for prematurity. the figure from the current study is higher as the akmcc neonatal unit is the primary referral center for newborns from rural areas, and the majority of preterm babies (41.8%) are admitted for care. in this study, infection as the reason for admission accounted for 20.33% of cases, as compared to 28.72% reported in peshawar5 and 45.2% in karachi.6 the majority of neonatal infections are due to unhygienic conditions and unsterilised delivery practices.9 neonatal sepsis continues to be a major cause of morbidity and mortality in pakistan. it is also one of the major causes of neonatal mortality in developing countries in general—contributing to 15% of all neonatal deaths.15 neonatal sepsis in this study was the most prevalent infection, accounting for 70.8% of all infections. additionally, acute gastroenteritis was also seen in 8.22% of the cases. in this study, birth asphyxia was 13% as compared to 16.52% of neonates in the study conducted in peshawar,5 18.85% in the karachi study6 and 40.66% in lahore.8 the important risk factors for birth asphyxia reported from a study conducted in hyderabad, india, include the lack of antenatal care, poor nutritional status, antepartum haemorrhaging, maternal toxaemia and having a home delivery.2 antenatal monitoring of high-risk pregnancies, timely referrals, resuscitation at the time of birth and improving maternal health levels are mandatory to reduce the high number of case fatalities and morbidities related to birth asphyxia. neonatal hyperbilirubinaemia resulting in clinical jaundice is a common problem among infants.16 information about the incidence of nnj in developing countries is lacking, as the vast majority of births occur at home. the majority of the data is from tertiary care or intensive care nurseries with no population denominator.17 nnj was responsible for 11.3% of neonatal admissions to the akmcc neonatal unit, in comparison to 20% in the study done in peshawar,5 15% in karachi6 and 8.3% in lahore.8 higher incidences of jaundice in neonates have been reported from other developing countries, such as bangladesh and nigeria (30.71% and 17.25%, respectively).18,19 the neonatal mortality rate reported in this study was 6.8%. this is significantly lower than the rates reported from other locations, for instance in the peshawar study the rate was 14.87%,5 in the karachi one 25.85%,6 in lahore 34%8 and in larkana 38%.7 the major causes of neonatal mortality in the current study were prematurity (52.8%), birth asphyxia (20.8%) and neonatal infections (9.4%) [table 2]. this study showed that 7.4% of the neonates required admission during the initial 24 hours after birth only for observation; there is no comparative data available from other studies. the major reason for neonates needing admission for observation were feeding issues, meconium-stained liquor or a previous poor obstetric history. this rate of admission for observation is due to the nonsyed r. ali, shakeel ahmed and heeramani lohana clinical and basic research | 421 availability of ‘rooming-in’ nurseries (where the baby stays in the same room as the mother) and the inadequate care of newborns at maternal wards in primary care centres across the sindh province. in this study, 86.7% were satisfactorily discharged after receiving the necessary treatment. this percentage could be due to an increased awareness among health workers about neonatal care, and the provision of the best possible care in spite of limited resources. the second factor is the large number of infants (7.4%) admitted with minor problems requiring observation. additionally, the rate of patients leaving against medical advice in this study was lower than that reported in the peshawar study (7.08%),5 and is potentially due to the increased awareness among parents regarding the better management of their children in hospitals. a limitation of this study was that blood cultures and other markers suggestive of neonatal infections, including c-reactive protein, were not performed in all cases of suspected neonatal sepsis. conclusion prematurity, lbw, birth asphyxia and nnj were the major causes of neonatal admissions in this study. the number of admissions due to these causes could be reduced by encouraging proper antenatal care for pregnant women, timely interventions, and the proper and in-time referral of all high-risk pregnancies to tertiary care centre. references 1. bhutta za, qadir m. addressing maternal nutrition and risks of birth asphyxia in developing countries. arch pediatr adolesc med 2009; 163:671–2. 2. azra haider b, bhutta za. birth asphyxia in developing countries: current status and public health implications. curr probl pediatr adolesc health care 2006; 36:178–88. 3. lawn je, cousens s, zupan j. 4 million neonatal deaths: when? where? why? lancet 2005; 365:891– 900. 4. world health organization. promoting optimal fetal development: report of a technical consultation. geneva: world health organization, 2006. p. 3. 5. fazlur r, amin j, jan m, hamid i. pattern and outcome of admissions to neonatal unit of khyber teaching hospital peshawar. pak j med sci 2007; 23:249–53. 6. alam ay. health equity, quality of care and community based approaches are key to maternal and child survival in pakistan. j pak med assoc 2011; 61:1–2. 7. abbasi ka. neonatal disease profile in larkana before and after establishment of neonatal ward. j pak med assoc 1995; 45:235–6. 8. hagekull br, nazir r, jalil f, karlberg j. early child health in lahore, pakistan: iii. maternal and family situation. acta paediatr suppl 1993; 82s, 390:27–37. 9. lawn je, cousens sn, darmstadt gl, bhutta za, martines j, paul v, et al. 1 year after the lancet neonatal survival series: was the call for action heard? lancet 2006; 367:1541–7. 10. bhutta za. the ignominy of low birth weight in south asia. indian pediatr 2012; 49:15–6. 11. goldenberg rl, culhane jf, iams jd, romero r. epidemiology and causes of preterm birth. lancet 2008; 371:75–84. 12. darmstadt gl, baqui ah, choi y, bari s, rahman sm, mannan i, et al. validation of community health workers’ assessment of neonatal illness in rural bangladesh. bull world health organ 2009; 87:12–9. 13. gebremariam a. factors predisposing to low birth weight in jimma hospital south western ethiopia. east afr med j 2005; 82:554–8. 14. nicolau s, teodoru g, popa i, nicolescu s, feldioreanu e. the role of maternal care in reducing perinatal and neonatal mortality in developing countries. rev pediatr obstet ginecol pediatr 1989; 38:185–92. 15. shadoul af, akhtar f, bile km. maternal, neonatal and child health in pakistan: towards the mdgs by moving from desire to reality. east mediterr health j 2010; 16:s39–46. 16. sarici su. incidence and etiology of neonatal hyperbilirubinemia. j trop pediatr 2010; 56:128–9. 17. tikmani ss, warraich hj, abassi f, rizvi a, darmstadt gl, zaidi ak. incidence of neonatal hyperbilirubinemia: a population-based prospective study in pakistan. trop med int health 2010; 15:502–7. 18. choi y, el arifeen s, mannan i, rahman sm, bari s, darmstadt gl, et al. can mothers recognize neonatal illness correctly? comparison of maternal report and assessment by community health workers in rural bangladesh. trop med int health 2010; 15:743–53. 19. ahlfors ce. pre exchange transfusion administration of albumin: an overlooked adjunct in the treatment of severe neonatal jaundice? indian pediatr 2010; 47:231–2. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 175-178, epub. 27th feb 13 submitted 24th mar 12 revision req. 31st jul & 29th sep 12, revisions recd. 8th oct & 4th nov 12 accepted 24th nov 12 fetal ascites commonly occurs linked to fetal hydrops. after the recognition of ascites in antenatal ultrasound, it is essential to establish whether this is an isolated fetal ascites or associated with hydrops.1 isolated fetal ascites is defined as “ascites not associated with fetal hydrops”.2 it is an uncommon condition and mainly occurs as an early manifestation of hydrops fetalis. isolated ascites is commonly caused by intra-abdominal disorders due to urinary tract obstruction. around 20% of cases occur as a result of gastrointestinal tract disorders.1,3–5 intestinal obstruction resulting in meconium peritonitis is considered to be one of the commonest gastrointestinal disorders associated with isolated ascites.3,6 case report a 37-year-old omani (gravida 3, para 0) woman presented with isolated fetal ascites diagnosed at 20 weeks’ gestation. fetal parameters and amniotic fluid volume were normal according to ultrasound examination. there was no evidence of hydrops fetalis or any other abnormality, particularly in the urinary and gastrointestinal systems. ultasonographic examination revealed no cardiomegaly or placental enlargement to indicate fetal anaemia. the findings upon medical examination included the discovery that the mother was blood group o and rh positive with a normal complete blood picture, a negative veneral disease research laboratory (vdrl) test, and a negative finding for parvovirus antibodies, cytomegalovirus, and toxoplasmosis. amniocentesis showed a normal female fetal karyotype. departments of 1child health, 2surgery, 3obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: molatif66@yahoo.com الشفاء التلقائي من االستسقاء يف األجنة و املواليد بعد الوالدة حممد عبداللطيف، �صهام ال�صناين، زينب البلو�صي، متيمة الدغي�صي، مازن اأبوعنزة، نهال الريامي امللخ�ص: اإن ا�صت�صقاء اجلنني هو مر�ض غري ماألوف ينتج عن عدة اأ�صباب منها غري املناعية. حيث اأن عدد وفيات الأجنة واملواليد مرتفعة، ل�صيما عندما يتطور ال�صت�صقاء قبل الأ�صبوع 24 من احلمل. اإن التناق�ض من �صدة ا�صت�صقاء اجلنني دون تدخل عالجي عند املواليد اأمر غري معروف. نعر�ض هنا حالة ا�صت�صقاء اجلنني املعزولة والتي اك�صفت يف الأ�صبوع العشرين للحمل. كانت جميع الفحو�صات التي اأجريت طبيعية ولكن اأظهرت الفحو�صات املتتالية باملوجات ال�صوتية عن وجود ا�صت�صقاء اجلنني عند الأ�صبوع 20 من احلمل. كما اأن متابعة الفحو�صات باملوجات فوق ال�صوتية للطفل عند عمر 6 اأ�صهر بعد الولدة اأظهر �صفاء كامل من ال�صت�صقاء. اإن ال�صفاء التلقائي من ا�صت�صقاء اجلنني ذي التنبوؤ اجليد ميكن اأن يحدث يف احلالت جمهولة ال�صبب. مفتاح الكلمات: ا�صت�صقاء اجلنني، ال�صفاء التلقائي، تنبوؤ، تقرير حالة، عمان. abstract: fetal ascites is an uncommon abnormality usually reported in relation to nonimmunological causes. the prospect for fetal and neonatal mortality is high, particularly when the ascites develops before 24 weeks of gestation. the diminution of severe fetal ascites without intrauterine management, especially with an uncomplicated neonatal outcome, is unusual. we report a case of isolated fetal ascites detected at 20 weeks' gestation. all investigations carried out were normal. consecutive ultrasound examination showed ascites at 20 weeks’ gestation. a follow-up ultrasound examination at 6 months of age revealed complete recovery from the ascites. spontaneous resolution of fetal ascites, with a good prognosis, can occur in cases with an idiopathic aetiology. keywords: fetal ascites; spontaneous resolution; prognosis; case report; oman. spontaneous resolution of fetal and neonatal ascites after birth *mohamed abdellatif,1 siham alsinani,1 zenab al-balushi,2 tamima al-dughaishi,3 mazen abuanza,1 nihal al-riyami3 case report spontaneous resolution of fetal and neonatal ascites after birth 176 | squ medical journal, february 2013, volume 13, issue 1 spontaneous vaginal delivery occurred at 38 weeks’ gestation. a female infant weighing 3,390 grams was delivered with apgar scores of 9 and 9 at 1 and 5 minutes, respectively. there was no abdominal dystocia during delivery. systemic examination was normal with no evidence of dysmorphic features. the infant did not require respiratory support and oxygen saturation was 100% at room air. ultrasonography after birth revealed moderate ascites [figure 1]. other radiological investigations included an anterioposterior plain x-ray view of the abdomen and a barium enema. the follow-through of the gastrointestinal tract was normal. following abdominal paracentesis, 150 ml of clear, yellow, sterile fluid was obtained. ascitic fluid showed white blood cells (50 x 106/l), red blood cells (10 x l06/l), albumin (27 g/l), and glucose (6 mmol/l). the initial serum albumin was 33 g/l. serum-ascites albumin gradient (saag) is frequently used to find out the cause of ascites and to discriminate between transudate and exudate. in this case it was 6 g/l, indicating portal hypertension versus non-portal hypertension aetiology for the ascites in this patient. blood count, serum electrolytes, liver function tests, and serum triglycerides and lactate dehydrogenase were within normal limits. the ascites progressively resolved over a two-week period. oral feeding with normal infant formula was instituted and tolerated. the patient was discharged home in good condition. a follow-up after 6 months revealed normal growth and development. no recurrent ascites could be detected by abdominal sonography [figure 2]. discussion the aetiology of isolated fetal ascites can be idiopathic or may occur as a result of many conditions, including fetomaternal haemorrhage, glucose-6-phosphate dehydrogenase deficiency, and thalassaemia affecting the mother. in the fetus, chromosomal abnormalities tend to occur mostly due to congenital heart disease, congenital infections, hepatic and metabolic storage disorders, and lymphatic disorders of the peritoneum.1,2,9 it is essential to differentiate hydrops from fetal ascites, as fetal hydrops is more commonly caused by systemic diseases, whereas the latter occurs more frequently due to local intra-abdominal causes. despite the fact that hydrops is usually considered a serious condition, fetal ascites is not necessarily considered thus.7–9 isolated fetal ascites presents antenatally with fluid around the “spleen, liver, bowel, bladder, extrahepatic portion of the umbilical vein, falciform ligament, and/or greater omentum”, usually discovered by ultrasonography.1 other features of hydrops, including skin oedema, and pleural and pericardial effusion, are not present. after the diagnosis of fetal ascites, a follow-up ultrasound after one week is required to establish if there has been progression to fetal hydrops. the development of hydrops is not likely to occur if the ascites remains localised to the abdominal cavity.1,7 possible fatal complications of isolated fetal ascites include the development of lung hypoplasia and hydrops.9,10 pulmonary hypoplasia leading to respiratory distress following birth can develop as a result of the ascites moving the diaphragm upwards, thereby compressing the lungs.11 seeds et al. were figure 1: moderate ascites. figure 2: complete resolution of ascites after 6 months. mohamed abdellatif, siham alsinani, zenab al-balushi, tamima al-dughaishi, mazen abuanza and nihal al-riyami case report | 177 the first ones to report in utero abdomino-amniotic shunting as useful in managing fetal ascites. nevertheless, the procedure is not a prerequisite in cases of simple isolated ascites, as such an intervention might predispose a fetus to preterm delivery.12 abdominal paracentesis performed prenatally has been recommended as helpful in improving the outcome of pulmonary function and preventing abdominal dystocia if done prior to a vaginal delivery.13,14 on the other hand, the ascitic fluid generally reaccumulates quickly following the procedure. seeds and fung et al. recommended abdominoperitoneal shunting to avoid recurrent paracentesis.15,16 occasionally, polyhydramnios and fetal ascites can occur together. the mechanism of the development of polyhydramnios in such cases is still not clear. in our case, there was no evidence of polyhdramnios in the mother, and the baby did not require any respiratory support after birth. the outcome and prognosis of isolated fetal ascites is determined by the primary cause, given that a good prognosis has been documented in affected newborns with idiopathic fetal ascites.4,5 earlier reports have analysed the wide range of diseases that can present as isolated fetal ascites.8,13 as reported by el bishry, in a series of 12 patients with isolated fetal ascites, 10 survived after delivery out of whom 9 had no other anomalies detected on antenatal or postnatal ultrasound. only one of the 10 cases had ileal atresia detected postnatally which was surgically corrected. two cases diagnosed before 20 weeks’ gestation died. one of them was found to have laryngeal atresia, which was lifethreatening.8 in another report by favre et al., a 100% survival rate was reported in 8 patients with idiopathic isolated ascites and no abnormalities were detected.13 furthermore, a patient’s prognosis depends on an antenatal diagnosis of dystocia. fetal demise has been documented in cases that were not predicted during antenatal follow up.11–13 satoko et al. reported that gestational age is inversely correlated with the severity of the ascites at diagnosis and carries a major risk factor for prognosis.17 nevertheless, the outcome of fetal ascites in this case report was favourable in spite of an early antenatal diagnosis. the work-up to determine the aetiology of the fetal ascites in this patient was negative; however, the serum ascites albumin gradient (saag) was less than 11 g/l, indicating a non-portal hypertension aetiology. there was no evidence of infectious, malignant, or inflammatory peritoneal disease. although we were not able to identify a cause for the ascites, in a large proportion of cases the cause was never determined, even with wide-ranging investigations.8 conclusion this patient was diagnosed with isolated fetal and neonatal ascites without other related abnormalities, which is an entity separate from hydrops fetalis. the patient had a favourable perinatal outcome. references 1. ulreich s, gruslin a, nodell cg, pretorius hd. fetal hydrops and ascites. in: nyberg da, mcgahan jp, pretorius dh, pilu g, eds. diagnostic imaging of fetal anomalies. new york: lippincott williams & wilkins, 2003. pp. 713–45. 2. winn hn, stiller r, grannum pa, crane jc, coster b, romero r. isolated fetal ascites: prenatal diagnosis and management. am j perinatol 1990; 7:370–3. 3. agrawala g, predanic m, perni sc, chasen st. isolated fetal ascites caused by bowel perforation due to colonic atresia. j matern fetal neonatal med 2005; 17:291–4. 4. ohno y, koyama n, tsuda m, arii y. antenatal ultrasound appearance of cloacal anomaly. obstet gynecol 2000; 95:1013–15. 5. persutte wh, lenke rl, kropp ka. atypical perentation of fetal obstructive uropathy. j diagn med sonogr 1989; 1:12–15. 6. chen fy, chen m, shih jc, tsao pn, lee cn, hsieh fj. meconium peritonitis presenting as a massive fetal ascites. prenat diagn 2004; 24:930–1. 7. arikan ilker, barut a, harma m, harma m, dogan s. isoalted fetal ascites. a case report. j med case rep 2012; 3:110–12. 8. el bishry g. the outcome of isolated fetal ascites. eur j obstet gynecol reprod biol 2008; 137:43–6. 9. stocker jt. congenital cytomegalovirus infection presenting as massive ascites with secondary pulmonary hypoplasia. hum pathol 1985; 16:1173– 5. 10. bernaschek g, deutinger j, hansmann m, bald r, holzgreve w, bollmann r. feto-amniotic shunting— report of the experience of four european centres. prenatal diag 1994; 14:821–33. 11. ng ht, chang sp, ho sc. dystocia due to fetal ascites. mod med asia 1976; 12:10. spontaneous resolution of fetal and neonatal ascites after birth 178 | squ medical journal, february 2013, volume 13, issue 1 12. cederqvist ll, williams lr, symchych rs, sarry zi. prenatal diagnosis of fetal ascites by ultrasound. am j obstet gynecol 1977; 15:229–30. 13. favre r, dreux s, dommergues m, dumez y, luton d, oury jf, et al. nonimmune fetal ascites: a series of 79 cases. am j obstet gynecol 2004; 190:407–12. 14. de crespigny lc, robinson hp, mcbain jc. fetal abdominal paracentesis in the management of gross fetal ascites. aust nz j obstet gynaecol 1980; 20:228–30. 15. seeds jw, herbert wn, bowes wa jr, cefalo rc. recurrent idiopathic fetal hydrops: results of prenatal therapy. obstet gynecol 1984; 64:s30–33. 16. fung hy, lau tk, chang am. abdominoamniotic shunting in isolated fetal ascites with polyhydramnios. acta obstet gynecol scand 1997; 76:706–7. 17. nose s, usui n, soh h, kamiyama m, tani g, kanagawa t, et al. the prognostic factors and the outcome of primary isolated fetal ascites. pediatr surg int 2011; 27:799–804. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e433–437, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.022. submitted 7 dec 14 revision req. 8 feb 15; revision recd. 8 mar 15 accepted 29 mar 15 rhabdomyosarcoma (rms) affects the female reproductive tract and is one of the most common soft tissue sarcomas in childhood.1 sarcoma botryoides or botyroid rmss are a polypoid variant of embryonal rms, arising from embryonal rhabdomyoblasts and constituting approximately 3% of all rmss.1 the primary site of these tumours is closely related to the age of the patient; it is found in the vagina during infancy and early childhood, in the cervix during the active reproductive stage and in the corpus uteri for postmenopausal patients.2 although vaginal tumours are five times more common than the cervical type, the latter appears to have a better prognosis than the former.3 botryoid rms has a marked tendency for local recurrence after excision, often invading the adjacent organs.4 the management of this tumour is challenging as it presents at a younger age; at this age, the preservation of hormonal, sexual and reproductive function is essential. there are many methods of surgical approach and variations in adjuvant therapy in the management of these tumours. over the past few decades, there has been a dramatic change in management strategy, from radical and often mutilating exenterative surgeries to a more conservative approach with adjuvant chemotherapy.1 this report describes the management of a young girl with botryoid rms of the cervix. case report in august 2007, a 14-year-old female was referred to kasturba hospital, a university hospital in manipal, india, for treatment and management of botryoid rms of the cervix. she presented with a mass protruding 1department of obstetrics & gynaecology, kasturba medical college, manipal, india; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: manjunathattibele@gmail.com سرطان العضالت احملززة العنقودي يف عنق الرحم تقرير حالة ومراجعة األدبيات باجباي نيها، اأتيبيلي بالك�سا، ماجنونا�س، �سيفارودرايا جرييجا، كومار براتاب abstract: botryoid rhabdomyosarcoma is an aggressive malignancy that arises from embryonal rhabdomyoblasts. it is commonly seen in the genital tract of female infants and young children. due to the young age of affected patients, this malignancy poses a management challenge as the preservation of hormonal, sexual and reproductive function is essential. there is currently no consensus regarding management. however, treatment strategies for these tumours have evolved from radical exenterative surgeries to more conservative management options. we report a case of botryoid rhabdomyosarcoma in an adolescent girl presenting to kasturba hospital, in manipal, india, in august 2007 with botryoid rhabdomyosarcoma of the cervix. she was treated with surgery and adjuvant chemotherapy. the patient remained healthy until eight months after the surgery. after acquiring a varicella zoster virus infection, she died due to septic shock and multiple organ failure. awareness of such an uncommon lesion and its clinical implications is important to avoid misdiagnosis. keywords: cervix; rhabdomyosarcoma; surgery; chemoradiotherapy; case report; india. مايتم غالبا الجنينية. الع�سلية الأرومة من تن�ساأ والتي ال�رس�سة ال�رسطانات من العنقودي املحززة الع�سالت �رسطان يعترب امللخ�ص: ت�سخي�س هذا الورم يف الر�سع والفتيات �سغار ال�سن. ميثل عالج هذا الورم حتديا كبريا وذلك للحفاظ على الوظائف التنا�سلية واجلن�سية تطورت فقد ذلك من وبالرغم املر�س. لهذا الأمثل العالج على اإجماع الآن حتى يوجد ول ال�سن. �سغار املر�سى هوؤلء يف والهرمونية ا�سرتاتيجيات العالج من اجتثاث الأح�ساء اجلذري اإىل اختيارات اأخرى اأكرث حتفظا. هذا تقرير حالة ل�رسطان الع�سالت املحززة العنقودي يف فتاة مراهقة ح�رست مل�ست�سفى كا�ستوربا مبانيبال، الهند يف اأغ�سط�س 2007 م�سابه ب�رسطان الع�سالت املحززة العنقودي يف عنق الرحم. مت عالج هذه الفتاة باجلراحة والعالج الكيميائي امل�ساعد. وقد ظلت الفتاة يف حالة �سحية جيدة ملدة 8 اأ�سهر عندما اأ�سيبت بعدوى فريو�س احلماق النطاقي ثم توفيت ب�سبب �سدمة اإنتانية مع ف�سل العديد من اأجهزة اجل�سم. من املهم زيادة الوعي بهذه الأورام غري الشائعة واآثارها ال�رسيرية لتجنب الت�سخي�س اخلاطئ. مفتاح الكلمات: عنق الرحم؛ �رسطان الع�سالت؛ اجلراحه؛ العالج الكيميائي الإ�سعاعي؛ تقرير حالة؛ الهند. botryoid rhabdomyosarcoma of the cervix case report with review of the literature bajpai neha,1 *attibele p. manjunath,2 shivarudraiah girija,2 kumar pratap1 online case report botryoid rhabdomyosarcoma of the cervix case report with review of the literature e434 | squ medical journal, august 2015, volume 15, issue 3 adequate margins along with the grape-like polypoidal yellowish-red cervix growth of 4–5 cm [figure 1]. postoperative histopathology revealed botryoid rms of the cervix with no residual disease. all margins were free of tumours. microscopy revealed a columnar and squamous epithelium overlying a malignant neoplasm [figure 2]. the rhabdomyoblasts (strap cells) were visible [figure 3]. no malignant cells were seen via peritoneal cytology. the patient was classified as category 1a according to the staging classification criteria of the intergroup rhabdomyosarcoma study group (irsg).5 she received six cycles of postoperative adjuvant chemotherapy consisting of vincristine, actinomycin and cyclophosphamide (vac) with the following regimen: 1.8 mg of vincristine weekly (at 1.5 mg/m2) and 0.5 mg of dactinomycin (at 0.015 mg/kg/day), 1,200 mg of cyclophosphamide (at 1 mg/m2) and 200 mg of mesna at zero, four and eight hours, respectively, every 21 days. the patient had episodes of neutropaenia which delayed the above treatment regimen on several occasions during the chemotherapy course. from the introitus which had been present for the previous six months and was particularly noticeable during menstruation. the patient also complained of a white discharge that was occasionally blood-stained. she did not have any significant medical or surgical history. general and systemic examinations were unremarkable. upon local examination of the vulva, the mass was not apparent. however, on straining in a squatting position, a fleshy grape-like mass could be seen protruding from the vagina. it appeared reddish, friable and bled to the touch. an examination under anaesthesia revealed a reddish, smooth, glistening, polypoidal mass connected to the cervix by a thin pedicle. the fornices and both parametria were free of tumours. a histopathological slide review performed at kasturba hospital confirmed the diagnosis of botryoid rms. a metastatic work-up, including magnetic resonance imaging of the pelvis, computed tomography of the thorax and a bone scan, revealed that the disease was confined to the lower cervix. all routine preoperative laboratory parameters were normal. unfortunately, detailed descriptions pertaining to surgical interventions and histopathological prognostic factors of rms cases were not available for many previously published case reports. due to the limited data available in the literature regarding the outcome of patients managed conservatively, clinicians counselled the patient’s parents about the condition and presented various management options. the parents opted for their daughter to undergo a hysterectomy. in august 2007, the patient underwent a type b1 radical hysterectomy under general anaesthesia. intraoperatively, no lymph nodes were palpable and the upper abdomen was tumour-free with the botryoid rms confined to the cervix. the uterus and cervix were removed with figure 1: hysterectomy specimen taken from an adolescent girl with botryoid rhabdomyosarcoma showing the grape-like polypoidal yellowish-red lesion connected to the cervix by a thin pedicle. the lesion was 4–5 cm in size. figure 2: haematoxylin and eosin histopathology stain demonstrating a prominent cambium layer overlying a malignant botryoid rhabdomyosarcoma at x10 magnification. figure 3: haematoxylin and eosin histopathology stain showing the periglandular infiltration of the botryoid rhabdomyosarcoma tumour cells (rhabdomyoblasts or strap cells) at x10 magnification. bajpai neha, attibele p. manjunath, shivarudraiah girija and kumar pratap online case report | e435 the patient was followed-up regularly. she appeared to be healthy until approximately eight months after surgery, when she acquired a varicella zoster virus infection while undergoing chemotherapy. this later progressed to pneumonia and septicaemia. she was transferred to an intensive care unit where she died due to septic shock and multiple organ failure. discussion botryoid rms is a rapidly growing rare malignancy seen in infants and young children.1 although more than 100 nomenclatures exist for this tumour, the term ‘sarcoma botryoides’ was first used by pfannenstiel in 1892.6 the appearance of the botryoid rms results when the tumour arises under the mucosal surface of the organs, which forces the growth to assume a typical grape-like structure. a distinct cambium layer beneath the epithelium is characteristic of botryoid rms.7 the patient reported here satisfied all three criteria essential for the botryoid variety of rms (i.e. a polypoid appearance, an origin below a mucous membrane-covered surface and the presence of a cambium layer).8 in order to avoid misdiagnosis and mismanagement, it is essential for clinicians to know of this uncommon disease, particularly common sites and the aggressive nature and clinical implications of the tumour. the currently reported patient presented with a mass in the vagina, which is among the most common presenting complaints for those with rms.3 however, young children may present with vaginal bleeding or urinary or bowel symptoms.3 since the occurrence of benign polyps in the vagina or cervix is extremely rare in childhood, the authors recommend that any polypoidal mass found in a child be regarded as botryoid rms unless proven otherwise. only a few case series and reports regarding the management of botryoid rms of the female genital tract are currently available in the literature. due to the rare occurrence of these tumours, there is limited literature on the evaluation of optimal therapy and a lack of level 1 evidence. hence, there is no uniform consensus in the management approach to these tumours. over the decades, there has been a paradigm shift in management strategies for botryoid rmss. although ultra-radical surgery like pelvic exenteration was considered the treatment of choice in the late 1960s, outcomes were often unsatisfactory. in the 1970s, limited surgery with adjuvant chemotherapy and/or irradiation showed improved survival. surgical aggressiveness gradually reduced from mutilating exenterative procedures to simple local excisions.9 the spectrum of surgical therapy now includes radical hysterectomies with or without lymphadenectomies,2,3,7,10–14 hysterectomies,3,15,16 vaginectomies,16 cervicectomies,3 polypectomies,9,17–19 local excisions,10,11,20 and diathermy loop excisions.9 botryoid rmss are mostly either treated with surgery alone or with adjuvant chemotherapy and/or radiotherapy.21 even with adjuvant chemotherapy regimens, there is no uniform agreement in the management of these tumours. most investigators have used a combination of two or three chemotherapeutic agents.22,23 the most widely used chemotherapy regimen is vac,11 which was also used in the current case. vac is the current gold-standard chemotherapy treatment. phase ii trials from europe and the usa have shown that ifosfamide, as a single agent, is an active drug against rms. in combination with other drugs, the response rate is even better. irinotecan (a topoisomerase i inhibitor) also appears to have promising activity against rms, with minimal haematopoietic toxicity.21 there are variations in the type, dose and number of chemotherapy agents used. the number of cycles and the sequence of chemotherapy also differ.10,18 there are even reports of neoadjuvant chemotherapy being used to shrink large tumours before operations.11,16 although in earlier reports radiotherapy was used as a treatment modality, it has since been abandoned as it is now generally agreed that these tumours are not radiosensitive and this therapy would interfere with ovarian function and cause pelvic contractions. it is hence generally reserved only for residual tumours.23 copeland et al. conducted one of the largest case series on botryoid rms of the female genital tract (n = 14) which showcased the evolution of treatment over a 30-year period.24 the second largest series was carried out by daya et al. who were the first to demonstrate a conservative approach in the management of these tumours with a favourable outcome.3 another series showed a successful outcome in 12 out of 14 cases treated via local excision followed by multidrug chemotherapy.11 however, two patients in this series required radical hysterectomies to control the disease.11 other reports have also shown favourable outcomes for cervical botryoid rms patients who were treated via local resection and chemotherapy, with preservation of fertility.9,17,18,20 the progression to less extensive therapy over recent years is partly due to the response of this neoplasm to the vac chemotherapy regimen.24 it should be emphasised that successful therapy with limited surgery is applicable only for patients who fall into irsg categories 1 or 2.24 it is unknown whether localised well-differentiated lesions can be safely botryoid rhabdomyosarcoma of the cervix case report with review of the literature e436 | squ medical journal, august 2015, volume 15, issue 3 of the infection. the infection may be presumed to be due to the transient altered immunological status of the patient while undergoing chemotherapy and exposure to varicella infection in a prevalent area; karnataka in south india is a high prevalence area for varicella infections, especially in adolescents.27 eight deaths have been similarly documented as a result of infection during management of genitourinary rms in patients who received chemotherapy.5 therefore, due to the limited literature on this issue, an evaluation of infective morbidity and mortality rates during chemotherapy treatment would be of great value for future reports. however, due to the rarity of these tumours, it may not be feasible to conduct randomised controlled trials to demonstrate the most appropriate treatment approach. conclusion rms of the female genital tract is a rapidly growing rare malignancy seen in infants and young children. the most effective treatment for this tumour has still not been well established and is a subject of on-going investigation. due to the lack of data pertaining to surgical interventions and histopathological prog nostic factors of rms cases, in addition to the diversity in management approaches, it is difficult to draw absolute conclusions regarding overall treatment outcomes. however, there has been an increasing tendency towards conservative therapy in recent years. from the available literature, it appears that limited surgery with adjuvant multi-agent chemotherapy is feasible in the treatment of early cervical rms in young patients. references 1. bell j, averette h, davis j, toledano s. genital rhabdomyosarcoma: current management and review of the literature. obstet gynecol surv 1986; 41:257–63. doi: 10.1097/00006254198605000-00001. 2. atlante m, dionisi b, cioni m, di ruzza d, sedati p, mariani l. sarcoma botryoides of the uterine cervix in a young woman: a case report. eur j gynaecol oncol 2000; 21:504–6. 3. daya da, scully re. sarcoma botryoides of the uterine cervix in young women: a clinicopathological study of 13 cases. gynecol oncol 1988; 29:290–304. doi: 10.1016/0090-8258(88)90228-4. 4. cywes s, louw jh. sarcoma botryoides of the vagina: a report of two cases. s afr med j 1961; 35:911–17. 5. ind t, shepherd j. pelvic tumours in adolescence. best pract res clin obstet gynaecol 2003; 17:149–68. doi: 10.1053/ ybeog.2002.0345. 6. pfannenstiel j. das traubige sarkom der cervix uteri. virchows arch path anat 1892; 127:305–37. 7. mousavi a, akhavan s. sarcoma botryoides (embryonal rhabdomyosarcoma) of the uterine cervix in sisters. j gynecol oncol 2010; 21:273–5. doi: 10.3802/jgo.2010.21.4.273. treated with conservative surgery alone without the use of adjuvant therapy. daya et al. reported favourable outcomes in four young patients with cervical botryoid rmss who were treated only by polypectomy or cervicectomy without chemotherapy.3 however, fatal recurrence with poor outcomes have been reported with the use of conservative surgery alone.24 therefore, postoperative chemotherapy should be administered even for irsg category 1 patients with cervical botryoid rms, regardless of the type of surgical intervention performed. unfortunately, the optimal number of adjuvant chemotherapy cycles needed is unknown. the role of histopathology in the prognosis of rms cannot be underestimated. although three varieties of rms have been described (embryonal, alveolar and undifferentiated), the embryonal type is the most common and has a favourable prognosis, whereas the alveolar type is rare with a poorer prognosis.8 embryonal rms of the cervix must be distinguished pathologically from adenosarcomas with heterologous elements, malignant mixed müllerian tumours and low-grade stromal sarcomas as the optimal management strategies and clinical outcomes differ for each.11 the tumour site, deep myometrial invasion,3 and lymphatic invasion are important prognostic factors. cervical rmss have a better prognosis than similar tumours arising from other sites of the female genital tract.9 the survival rates for vaginal and cervical lesions are 60% and 96% respectively.20 overall survival has been reported as 79% in patients treated with surgery and adjuvant chemotherapy.25,26 although some patients may be cured by simple surgical procedures, the risk of recurrence and metastatic spread remains a concern.1 the pelvis is the most common site of primary recurrence and the recurrence of this disease is rarely cured after definitive initial therapy.24 there are reports of extensive metastasis to the lung with high mortality, despite surgery and chemotherapy.1 cervical botryoid rmss invade and recur despite adjuvant chemotherapy,9,11 and patients have died due to the recurrent disease.3 in the current case, the patient died due to sepsis during the follow-up period. her death was not due to persistence or recurrence of the botyroid rms. there was no evidence of residual disease and no deep infiltration to the myometrium. therefore, there was a good chance of prolonged survival had the patient not contracted the varicella infection. moreover, in retrospect, she would have been an ideal candidate for a conservative surgical approach. the patient acquired the varicella infection while undergoing chemotherapy; however, it is difficult to determine whether the chemotherapy was the causative agent http://dx.doi.org//10.1097/00006254-198605000-00001 http://dx.doi.org//10.1097/00006254-198605000-00001 http://dx.doi.org//10.1016/0090-8258%2888%2990228-4 http://dx.doi.org/10.1053/ybeog.2002.0345 http://dx.doi.org/10.1053/ybeog.2002.0345 http://dx.doi.org/10.3802/jgo.2010.21.4.273 bajpai neha, attibele p. manjunath, shivarudraiah girija and kumar pratap online case report | e437 8. wenig bm. undifferentiated malignant neoplasms of the sinonasal tract. arch pathol lab med 2009; 133: 699–712. doi: 10.1043/1543-2165-133.5.699. 9. zanetta g, rota sm, lissoni a, chiari s, bratina g, mangioni c. conservative treatment followed by chemotherapy with doxorubicin and ifosfamide for cervical sarcoma botryoides in young females. br j cancer 1999; 80:403–6. doi: 10.1038/ sj.bjc.6690370. 10. behtash n, mousavi a, tehranian a, khanafshar n, hanjani p. embryonal rhabdomyosarcoma of the uterine cervix: case report and review of the literature. gynecol oncol 2003; 91:452–5. doi: 10.1016/s0090-8258(03)00539-0. 11. dehner lp, jarzembowski ja, hill da. embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. mod pathol 2012; 25:602–14. doi: 10.1038/modpathol.2011.185. 12. golbang p, khan a, scurry j, macisaac i, planner r. cervical sarcoma botryoides and ovarian sertoli-leydig cell tumor. gynecol oncol 1997; 67:102–6. doi: 10.1006/gyno.1997.4807. 13. qiang jx, takahashi o, hatazawa j, karube a, ohyama n, sato h, et al. sarcoma botryoides of the uterine cervix: a case report. j obstet gynaecol res 1998; 24:197–201. doi: 10.1111/ j.1447-0756.1998.tb00075.x. 14. scaravilli g, simeone s, dell’aversana orabona g, capuano s, serao m, rossi r, et al. case report of a sarcoma botryoides of the uterine cervix in fertile age and literature review. arch gynecol obstet 2009; 280:863–6. doi: 10.1007/s00404-009-1022-3. 15. miyamoto t, shiozawa t, nakamura t, konishi i. sarcoma botryoides of the uterine cervix in a 46-year-old woman: case report and literature review. int j gynecol pathol 2004; 23:78–82. doi: 10.1097/01.pgp.0000101147.41312.54. 16. deligeoroglou e, tsimaris p, creatsa m, athanasopoulos n, creatsas g. application of creatsas vaginoplasty after radical surgical treatment of sarcoma botryoides. j pediatr adolesc gynecol 2014; 27:93–5. doi: 10.1016/j.jpag.2013.12.004. 17. gordon an, montag tw. sarcoma botryoides of the cervix: excision followed by adjuvant chemotherapy for preservation of reproductive function. gynecol oncol 1990; 36:119–24. doi: 10.1016/0090-8258(90)90121-z. 18. bernal kl, fahmy l, remmenga s, bridge j, baker j. embryonal rhabdomyosarcoma (sarcoma botryoides) of the cervix presenting as a cervical polyp treated with fertility-sparing surgery and adjuvant chemotherapy. gynecol oncol 2004; 95:243–6. doi: 10.1016/j.ygyno.2004.06.049. 19. rosenberg p, carinelli s, peiretti m, zanagnolo v, maggioni a. cervical sarcoma botryoides and ovarian sertoli-leydig cell tumor: a case report and review of literature. arch gynecol obstet 2012; 285:845–8. doi: 10.1007/s00404-011-2017-4. 20. gruessner se, omwandho co, dreyer t, blütters-sawatzki r, reiter a, tinneberg hr, et al. management of stage i cervical sarcoma botryoides in childhood and adolescence. eur j pediatr 2004; 163:452–6. doi: 10.1007/s00431-004-1469-y. 21. agarwala s. pediatric rhabdomyosarcomas and nonrhabdomyosarcoma soft tissue sarcoma. j indian assoc pediatr surg 2006; 11:15–23. doi: 10.4103/0971-9261.24632. 22. arndt ca, donaldson ss, anderson jr, andrassy rj, laurie f, link mp, et al. what constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? cancer 2001; 12:2454–68. doi: 10.1002/1097-0142(20010615)91 :12<2454::aid-cncr1281>3.0.co;2-c. 23. dayyabu al, adogu io, makama bs. sarcoma botryoides, a management dilemma: a review of two cases. int j case rep imag 2014; 5:15–20. doi: 10.5348/ijcri-201458-cs-10044. 24. copeland lj, gershenson dm, saul pb, sneige n, stringer ca, edwards cl. sarcoma botryoides of the female genital tract. obstet gynecol 1985; 66:262–6. 25. montag tw, d’ablaing g, schlaerth, jb, gaddis o jr, morrow cp. embryonal rhabdomyosarcoma of the uterine corpus and cervix. gynecol oncol 1986; 25:171–94. doi: 10.1016/0090-8258(86)90098-3. 26. brand e, berek js, nieberg rk, hacker nf. rhabdomyosarcoma of the uterine cervix: sarcoma botryoides. cancer 1987; 60:1552– 60. doi: 10.1002/1097-0142(19871001)60:7<1552::aid-cncr2 820600724>3.0.co;2-w. 27. girish pn, shetty nj, shetty vh, vaz gf. study of the clinical patterns in varicella in a tertiary hospital at coastal karnataka. online j health allied sci 2011; 10:6. http://dx.doi.org/10.1043/1543-2165-133.5.699 http://dx.doi.org/10.1038/sj.bjc.6690370 http://dx.doi.org/10.1038/sj.bjc.6690370 http://dx.doi.org/10.1016/s0090-8258%2803%2900539-0 http://dx.doi.org/10.1038/modpathol.2011.185 http://dx.doi.org/10.1006/gyno.1997.4807 http://dx.doi.org/10.1111/j.1447-0756.1998.tb00075.x http://dx.doi.org/10.1111/j.1447-0756.1998.tb00075.x http://dx.doi.org/10.1007/s00404-009-1022-3 http://dx.doi.org/10.1097/01.pgp.0000101147.41312.54 http://dx.doi.org/10.1016/j.jpag.2013.12.004 http://dx.doi.org/10.1016/0090-8258%2890%2990121-z http://dx.doi.org/10.1016/j.ygyno.2004.06.049 http://dx.doi.org/10.1007/s00404-011-2017-4 http://dx.doi.org/10.1007/s00431-004-1469-y http://dx.doi.org/10.4103/0971-9261.24632 http://dx.doi.org/10.1002/1097-0142%2820010615%2991:12%3c2454::aid-cncr1281%3e3.0.co%3b2-c http://dx.doi.org/10.1002/1097-0142%2820010615%2991:12%3c2454::aid-cncr1281%3e3.0.co%3b2-c http://dx.doi.org/10.5348/ijcri-201458-cs-10044 http://dx.doi.org/10.1016/0090-8258%2886%2990098-3 http://dx.doi.org/10.1002/1097-0142%2819871001%2960:7%3c1552::aid-cncr2820600724%3e3.0.co%3b2-w http://dx.doi.org/10.1002/1097-0142%2819871001%2960:7%3c1552::aid-cncr2820600724%3e3.0.co%3b2-w gingival hyperplasia is an unusual condition which interferes with speech, mastication, occlusion, lip continence, and facial appearance of the affected individual, causing aesthetic, functional, psychological, and masticatory disturbances. drug-induced gingival enlargements are the commonest form. the inherited condition in which the gingival tissue spontaneously and progressively enlarges is identified as hereditary gingival fibromatosis (hgf).1 it is a rare condition, affecting only one in 750,000 people, with males and females being equally affected.2 hgf is characterised by a slowly progressive, non-haemmorhagic fibrous enlargement of gingival tissue, occurring peripheral to the alveolar bone, which does not involve the periodontal ligament. the hyperplastic gingival tissue usually presents with a normal colour and has a firm consistency with abundant stippling.3,4 furthermore, hgf usually develops as an isolated disorder but can be one feature of a syndrome or a chromosomal abnormality. accordingly, it has been divided into two forms: non-syndromic and syndromic.5 the gingival enlargement usually begins with the eruption of the permanent or deciduous dentition.1 the growth may worsen throughout adolescence, suggesting an influence of growth hormones.6 the clinical presentation of hgf is highly variable, both in the number of teeth involved and degree of sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 517-521, epub. 20th nov 12 submitted 10th jan 12 revision req. 16th apr 12, revision recd. 14th may 12 accepted 16th jun 12 1departments of 1oral medicine and radiology, 2periodontics, hazaribag college of dental sciences & hospital, hazaribag, india; 3department of oral medicine & radiology, maitri dental college, durg, india; 4department of oral medicine & radiology, government dental college & hospital, nagpur, india *corresponding author e-mail: drpushpanshu@yahoo.co.in ضخامة اللثة الشاملة عند األشقاء تقرير حالة كومار بو�صبان�صو، رات�صنا كو�صيك، اآ را�ض �صاذاوين، رايف اأثاويل امللخ�ص: يتميز ُوراٌم اللثة الليفي بدرجات متفاوتة من فرط منو اللثة التلّيفي الذي ميكن اأن ي�صببه عوامل متنوعة. النوع الوراثي من ورام اللثة الليفي هو ا�صطراب نادر، يتميز بكونه حميدا، وينمو ببطء يف اخلاليا املتقرنة لّلثة. ميكن اأن تنتج احلالة من ا�صطرابات �صبغية ج�صدية �صائدة اأو متنحية، والنوع االأول اأكرث انت�صارا. وعادة ما يكون ا�صطرابا معزوال، غري اأنه ميكن اأن يكون �صمن متالزمة ت�صمل اأع�صاء عديدة يف اجل�صم. وتبعا لذلك ميكن تق�صيم ُورام اللثة الليفي الوراثي اإىل نوعني: وجوده مع املتالزمة اأو مبفرده بدون متالزمة. كما ميكن اأن تكون �صخامة اللثة مو�صعية اأو عامة، ولكنها عادة ما ت�صيب كال القو�صني. هذا و�صف حلالة من ُوراِم اللثة الليفي الوراثي ال�صديد املنفرد، �صامال قو�صي الفك العلوي وال�صفلي يف اأخوين. يرّكز هذا التقرير على ت�صخي�ض وعالج املر�ض وال�صيطرة عليه. كما مت التاأكيد على النمط الوراثي واخل�صائ�ض الن�صيجية امَلَر�صية. مفتاح الكلمات: ج�صدية �صائدة، ُوراُم اللثة الليفي، وراثي، االأ�صقاء، تقرير حالة، الهند. abstract: gingival fibromatosis is characterised by varying degrees of fibrotic gingival overgrowth that can be caused by a variety of aetiological factors. hereditary gingival fibromatosis (hgf) is a rare genetic disorder, characterised by a slowly progressive, benign enlargement of keratinised gingiva. the condition may be found in an autosomal dominant or autosomal recessive mode of inheritance, the former being more common. it usually develops as an isolated disorder but can be one feature of a multisystem syndrome. accordingly, hgf has been divided into two forms: non-syndromic and syndromic. the gingival enlargement can be localised or generalised, but usually involves both arches. the authors describe a case of non-syndromic generalised severe hgf, involving the maxillary and mandibular arches in two brothers. this report focuses on the diagnosis, treatment, and control of the disease. the pattern of inheritance and histopathologic characteristics are also emphasised. keywords: autosomal dominant; gingival fibromatosis; hereditary; siblings; case report; india. extensive gingival enlargement in siblings a case report *kumar pushpanshu,1 rachna kaushik,2 r. s. sathawane,3 ravi p. athawale4 case report extensive gingival enlargement in siblings a case report 518 | squ medical journal, november 2012, volume 12, issue 4 severity. gingival enlargement may be generalised to all gingival areas, or quite focal and limited in its distribution. the severity may range from slight enlargement to total coverage of the dentition. buccal and lingual tissues of both maxilla and mandible may be involved, and the degree of hyperplasia may vary between individuals within the same family.2,7 we report a rare clinical presentation of an extensive hereditary gingival fibromatosis in two siblings. the report focuses on the clinically relevant aspects of hgf, highlighting an unusually severe non-syndromic gingival fibromatosis. diagnosis was based on family history, and clinical and radiographic assessments. family history suggested an autosomal dominant inheritance. case report a 19-year-old unmarried male reported enlarged gums from the time that he was six years old. according to the patient, the swelling appeared at the time of eruption of permanent teeth without any associated pain; however, it caused functional and masticatory difficulty and the patient was unhappy with the appearance of his gingiva. his medical history was unremarkable. he denied taking any medications and did not appear to have any mental impairment. his family history was of significance, since his brother had a similar condition. genetic history revealed that the patient’s deceased mother had a similar gingival condition; however, her medical and dental records were not available to confirm this. neither the patient’s maternal aunt nor the patient’s sister had the disease. extraoral examination showed facial disfigurement with incompetent protruding lips. excessive gingival growth was observed protruding out of the oral cavity, which interfered with lip closure [figure 1]. intraoral examination revealed severe gingival overgrowth, reddish pink in colour, involving both the maxillary and mandibular arches on both buccal and the lingual/palatal sides. gingival tissue was firm, dense and fibrotic in consistency, and was non-haemorrhagic and non-tender. the enlargement in the maxillary arch obliterated the vestibular as well as palatal vault spaces and caused obliteration of the maxillary teeth and palatal displacement of the right maxillary second molar tooth [figure 2]. examination of the patient’s 24-year-old brother revealed generalised gingival enlargement, though of a lesser severity. based on the above findings and in combination with the patient's family history and absence of any relevant medication history, a provisional diagnosis of hgf was made. radiographic examination revealed generalised moderate bone loss [figure 3]. an incisional biopsy was performed and the tissue was examined by an oral pathologist. the histopathological examination revealed a parakeratinised stratified squamous acanthotic epithelium with thin long rete ridges figure 1: severe gingival enlargement protruding out of the oral cavity, preventing lip closure. figure 2: gingival enlargement seen obliterating the palatal vaults space and completely embedding maxillary teeth . kumar pushpanshu, rachna kaushik, r. s. sathawane and ravi p athawale case report | 519 extending into the connective tissue [figure 4]. the underlying connective tissue showed dense wavy bundles of collagen fibres, containing numerous fibrocytes and fibroblasts. deep connective tissue was characterised by dense, mature parallel collagen bundles. a mild chronic inflammatory cell infiltrate was also noted. these microscopic findings supported the diagnosis of hgf. a multidisciplinary approach to treatment was considered. treatment included full-mouth gingivectomy, extraction of mobile teeth, and prosthetic rehabilitation with upper and lower partial dentures. quadrant by quadrant external bevel gingivectomy was planned in association with gingivoplasty followed by 0.2% chlorhexidine oral rinses twice a day for two weeks after each surgery. however, the patient did not report back to the hospital for the treatment and was lost to follow-up. discussion generalised gingival fibromatosis can be caused by a number of factors, including inflammation, leukaemic infiltration, and medication use such as phenytoin, cyclosporine, or nifedipine.2 it can also be inherited (hgf). gingival enlargement results in both aesthetic and functional problems in affected individuals. the most common effects are diastemas, malpositioning of teeth, prolonged retention of primary dentition, delayed eruption, cross and open bites, prominent lips, and open lip posture.1 severe overgrowth can result in crowding of the tongue, speech impediments, and difficulty with mastication.8 although the gingival enlargement does not directly affect the alveolar bone, the gingival swelling may increase the bacterial plaque accumulation, causing periodontitis, bone resorption, and halitosis.1 in the present report, both patients had functional discomfort, and they were unhappy with the appearance of their gingiva. hgf is mainly inherited in an autosomal-dominant manner, although autosomal-recessive inheritance has also been reported.5 hgf as an isolated feature is believed to be expressed as an autosomal dominant trait.9 according to the genetic history of the present case, autosomal-dominant inheritance is a feasible diagnosis because family members of both sexes were affected, and the condition was present in two successive generations (mother and two sons); however, there was no history of consanguinity in the family. hgf can develop as an isolated disorder affecting only gingiva, or more rarely as part of a syndrome such as murray-puretic-drescher syndrome (multiple hyaline fibromas), rutherford syndrome (corneal dystrophy), laband syndrome (ear, nose, bone and nail defects with hepatosplenomegaly), jones syndrome (progressive deafness), and cross syndrome (microphthalmia, mental retardation, athetosis and hypopigmentation).2 syndromic gingival fibromatosis has been associated with ancillary features such as hypertrichosis, mental retardation, epilepsy, progressive sensorineural hearing loss, and abnormalities of the extremities, particularly of the fingers and toes.10–11 clinically, hgf is characterised by a firm, painless gingival growth, which is not especially liable to trauma.1 the hyperplastic gingiva usually figure 3: panoramic radiograph of 19-year-old patient showing moderate generalised bone loss. figure 4: well-structured epithelium displaying elongated rete pegs and dense connective tissue (original magnification x10). extensive gingival enlargement in siblings a case report 520 | squ medical journal, november 2012, volume 12, issue 4 presents a normal colour with abundant stippling.3 the clinical manifestations of both the cases reported here were consistent with most descriptions in the literature. hgf can vary from focal sites of gingival enlargement to generalised involvement, with the degree of overgrowth varying from slight to severe.12 unlike drug-induced gingival overgrowth, hgf is not influenced by plaque, and the incidence and severity of the disease appears to depend on the penetrance of the mutated gene.8 the patients reported here exhibited a generalised and severe gingival overgrowth. furthermore, the condition seemed to become evident with the emergence of the permanent dentition. it is evident from the previous reported cases that the condition usually begins at the time of eruption of the permanent dentition, but it can develop with the eruption of the deciduous dentition and is even more rarely seen at birth.12 in a study involving 17 family members with gingival fibromatosis, fletcher reported that the most extensive enlargement appeared to occur either during loss of the deciduous teeth or in early stages of eruption of the permanent dentition.4 he noted that the enlargement seemed to progress rapidly during "active" eruption and decrease with the end of this stage. he also reported that the presence of teeth appears to be necessary for hgf to occur because the condition is not seen before the eruption of teeth and disappears or recedes with the loss of teeth.9 the histologic features of the gingiva were also consistent with previously reported cases. the gingival tissues were composed of fibrous connective tissue, with elongated and thin papillae.5,12 histologically, hgf is benign, the main feature being accumulation of mature collagenous connective tissue.7 the results of the histopathologic evaluation of the biopsied tissues of our patient were consistent with those for fibrous gingival hyperplasia.11 however, the histologic features of gingival fibromatosis are usually nonspecific and a definitive diagnosis should be established based on family history and clinical findings. hgf cannot be cured, but can be controlled with varying degrees of success. when the enlargement is minimal, good scaling of teeth and home care may be all that is required to maintain good oral health. as the excess tissue increases, appearance and function indicate a need for surgical intervention.2 many techniques have been used for the excision of the enlarged gingival tissues, including external or internal bevel gingivectomy in association with gingivoplasty, an apically positioned flap, electrocautery, and carbon dioxide laser.1 in consideration of the severity of the involvement in this case, external bevel gingivectomy in association with gingivoplasty was planned. several authors have reported the recurrence of hyperplastic tissue following gingivectomy, necessitating a repeat of the procedure.13,14 this often causes a further increase in the psychological and emotional stress of parents and patients; hence, psychological counselling is a must for both parties.15 although recurrence is unpredictable, it is most often seen in children and teenagers rather than adults.1 the correct physiologic contour of marginal gingiva and good plaque control are important to prevent recurrence. normally, recurrence is minimal or delayed if good oral hygiene is achieved by a combination of monthly examinations with professional cleaning and oral hygiene instructions.15 although there is a large consensus on the modality of treatment to be performed in hgf patients, there are controversies with regard to the exact period in which it should be accomplished.15 according to several authors, the best time is when all of the permanent dentition has erupted, because the risk of recurrence is higher before then.3 however, in some cases, a delay in surgical treatment may result in significant consequences for the patient, such as primary dentition retention with a delay in the eruption of permanent teeth, difficulties in mastication and phonation, malpositioning of teeth, aesthetic effects, and psychological problems for the patients and relatives.5,15 thus, if the patient is unhappy with his/her gingival condition or if the enlarged tissue interferes with normal functioning, the treatment should be performed once the patient is cooperative and shows good oral hygiene.1 cosmetic concerns aside, a compromised oral cavity may cause several functional and periodontal problems. in addition, social consequences can be dramatic, forcing patients to lead an isolated, reclusive life. the local and psychological benefits, even temporary, must not be underestimated and may outweigh the probability of recurrence.1 kumar pushpanshu, rachna kaushik, r. s. sathawane and ravi p athawale case report | 521 conclusion we have reported two siblings affected with hgf, with an autosomal dominant mode of inheritance. the diagnosis was confirmed by the typical presentation, family history and histopathological features. although the clinical and histopathological aspects of hgf are well understood, the pathogenic mechanism still remains unclear. surgical intervention is the usual treatment of hgf, but the patients still have to deal with the risk of recurrence. once the correlations between gene mutations, molecular changes, histology, and clinical situation are clear, they can be applied clinically, providing novel methods for disease prognosis and diagnosis and targets for disease prevention and treatment. references 1. coletta rd, graner e. hereditary gingival fibromatosis: a systematic review. j periodontol 2006; 77:753–64. 2. ramer m, marrone j, stahl b, burakoff r. hereditary gingival fibromatosis: identification, treatment, control. j am dent assoc 1996; 127:493–5. 3. ramakrishnan t, kaur m. multispeciality approach in the management of patient with hereditary gingival fibromatosis: 1-year followup: a case report. int j dent 2010; 2010:575979. 4. sharma s, goyal d, shah g, ray a. familial gingival fibromatosis: a rare case report. contemp clin dent 2012; 3:s63–6. 5. shi j, lin w, li x, zhang f, hong x. hereditary gingival fibromatosis: a threegeneration case and pathogenic mechanism research on progress of the disease. j periodontol 2011; 82:1089–95. 6. bansal a, narang s, sowmya k, sehgal n. treatment and two-year follow-up of a patient with hereditary gingival fibromatosis. j indian soc periodontol 2011; 15:406–9. 7. hart tc, pallos d, bozzo l, almeida op, marazita ml, o'connell jr, et al. evidence of genetic heterogeneity for hereditary gingival fibromatosis. j dent res 2000; 79:1758–64. 8. häkkinen l, csiszar a. hereditary gingival fibromatosis: characteristics and novel putative pathogenic mechanisms. j dent res 2007; 86:25–34. 9. martelli-junior h, lemos dp, silva co, graner e, coletta rd. hereditary gingival fibromatosis: report of a five-generation family using cellular proliferation analysis. j periodontol 2005; 76:2299–305. 10. kulkarni p, agrawal n, tyagi s, kambalimath h. a rare case of gingival fibromatosis associated with hypertrichosis and a dysmorphic face. j clin pediatr dent 2011; 35:305–8. 11. chaturvedi r. idiopathic gingival fibromatosis associated with generalized aggressive periodontitis: a case report. j can dent assoc 2009; 75:291–5. 12. martelli-júnior h, bonan pr, dos santos la, santos sm, cavalcanti mg, coletta rd. case reports of a new syndrome associating gingival fibromatosis and dental abnormalities in a consanguineous family. j periodontol 2008; 79:1287–96. 13. fletcher j. gingival abnormalities of genetic origin: a preliminary communication with special reference to hereditary generalized gingival fibromatosis. j dent res 1966; 45:597–612. 14. bhavsar jp, damle sg, bhatt ap. idiopathic gingival fibromatosis associated with mild hypertrichosis. j indian soc pedod prev dent 1991; 9:31–3. 15. ramnarayan bk, sowmya k, rema j. management of idiopathic gingival fibromatosis: report of a case and literature review. pediatr dent 2011; 33:431–6. department of family & community medicine, college of medicine, basrah university, basrah, iraq *corresponding author’s e-mail: jnk5511@yahoo.com لقاح عصية كامليت-غريان هل هو خيار أمثل لعالج الثآليل الفريوسية؟ اأ�سعد قدوري اليا�سني، �سكرية كامل املالكي، جا�سم نعيم الأ�سدي abstract: objectives: this study aimed to compare the effectiveness of the bacillus calmette-guérin (bcg) vaccine with topical salicylic acid (sa) in the treatment of viral warts. methods: this non-randomised controlled trial was conducted at the al-sader teaching hospital, basrah, iraq, from january 2016 to april 2017. a total of 201 patients with viral warts were injected with an intradermal purified protein derivative. subsequently, those with negative tuberculin test results received an intradermal bcg vaccination, while those with positive results underwent conventional treatment with topical sa. patients were assessed for any signs of improvement at one, two and three months. results: overall, 190 patients completed the trial; of these, 133 (70%) received the bcg vaccine and 57 (30%) were treated with topical sa. complete response to treatment was observed in 9.8% and 5.3% of patients in the bcg and sa groups, respectively (p <0.001). cure rates were significantly higher for patients with genital (22.2% versus 7.7%; p = 0.002) and common warts (8.5% versus 0%; p = 0.001) treated with the bcg vaccine; however, the reverse was true for flat warts (12.9% versus 25%; p = 0.041). a binary logistic regression analysis indicated that bcg therapy was the only significant independent predictor of positive treatment response (odds ratio: 7.56, 95% confidence interval: 3.72–15.36; p <0.001). conclusion: the bcg vaccine was more effective than topical sa for treating viral warts, with the best response noted in the treatment of genital warts, followed by flat warts. however, plantar warts demonstrated least response to this treatment. keywords: human papilloma viruses; warts; immunotherapy; bcg vaccine; salicylic acid; clinical trial; treatment effectiveness. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل مقارنة فعالية لقاح ع�سية كاملني-غريان )bcg( مع حم�ض ال�سالي�سيليك املو�سعي )sa( يف عالج الثاآليل الفريو�سية. الطريقة: اأجريت هذه التجربة غري الع�سوائية ذات ال�سوابط يف م�ست�سفى ال�سدر التعليمي بالب�رصة يف العراق، من يناير 2016 اإىل اأبريل 2017. مت حقن ما جمموعه 201 مري�سا م�سابا بالثاآليل الفريو�سية مب�ستق الربوتني املنقى داخل اجللد، بعد ذلك، تلقى اأولئك الذين ظهرت نتائجهم �سلبية لقاح bcg داخل اجللد، يف حني خ�سع اأولئك الذين كانت نتائجهم اإيجابية للعالج املعتاد با�ستخدام sa املو�سعي. مت تقييم املر�سى لأي عالمات حت�سن بعد فرتات �سهرو �سهرين وثالثة اأ�سهر. النتائج: اأكمل 190 مري�سًا التجربة منهم 133 مري�سًا )%70( تلقوا لقاح bcg وعولج 57 )%30( منهم با�ستخدام sa املو�سعي. وقد لوحظت اأن هناك ا�ستجابة كاملة للعالج يف %9.8 و %5.3 من املر�سى يف جمموعتي bcg و sa على التوايل وبفارق معتد به اح�سائيًا )p >0.001(. وكانت معدلت ال�سفاء اأعلى بكثري للمر�سى الذين كانوا يعانون من ثاآليل الأع�ساء التنا�سلية )%22.2 مقابل %7.7؛ p = 0.002( والثاآليل ال�سائعة )%8.5 مقابل %0؛ p = 0.001( للذين عوجلوا بلقاح bcg؛ يف املقابل، كان العك�ض �سحيًحا بالن�سبة للثاآليل امل�سطحة )%12.9 مقابل %25؛ p = 0.041( كما اأ�سار حتليل النحدار اللوج�ستي الثنائي اإىل اأن عالج bcg كان املتنبئ امل�ستقل الوحيد املهم لال�ستجابة العالجية الإيجابية )ن�سبة الأرجحية: 7.56، فا�سل الثقة %95: 15.36-3.72؛ p >0.001(. اخلال�صة: كان لقاح bcg اأكرث فعالية من sa املو�سعي يف عالج الثاآليل الفريو�سية، مع مالحظة اأن الإ�ستجابة كانت اأف�سل يف عالج الثاآليل التنا�سلية، تليها الثاآليل امل�سطحة بينما اأظهرت الثاآليل الأخم�سية اأقل ا�ستجابة لهذا العالج. الكلمات املفتاحية: فريو�سات الورم احلليمي الب�رصي؛ البثور؛ العالج املناعي؛ لقاح ع�سوية كامليت غورين؛ حم�ض ال�سالي�سيليك؛ جتربة �رصيرية؛ فعالية العالج. the bacillus calmette-guérin (bcg) vaccine is it a better choice for the treatment of viral warts? asaad q. al-yassen, shukrya k. al-maliki, *jasim n. al-asadi sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e330–336, epub. 5 oct 20 submitted 23 oct 19 revision req. 24 dec 19; revision recd. 22 jan 20 accepted 19 feb 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.013 clinical & basic research advances in knowledge the treatment of viral warts is challenging, with some warts resistant to conventional therapy; however, immunotherapy is a relatively new yet promising modality, particularly the bacillus calmette-guérin (bcg) vaccine. results from this non-randomised controlled trial indicate that immunotherapy with the bcg vaccine was more effective than conventional treatment using topical salicylic acid. application to patient care the results of this trial highlight the effectiveness of the bcg vaccine as an alternative treatment for viral warts. this modality can be simply and cheaply implemented into clinical practice. https://creativecommons.org/licenses/by-nd/4.0/ asaad q. al-yassen, shukrya k. al-maliki and jasim n. al-asadi clinical and basic research | e331 viral warts are common benign skin growths caused by human papilloma virus (hpv) infections.1 diverse hpv strains are responsible for specific types of warts, such as common, flat, intermediate, plantar, mosaic, anogenital and oral warts.2 in general, warts predominantly affect children compared to infants and adults and more frequently affect the face and upper and lower limbs.1,3,4 viral warts can proliferate and increase in both dimension and quantity; on the other hand, spontaneous remission within a two-year period has also been reported.4,5 in addition, viral warts often recur and are unresponsive to conventional management.4,6 as such, the prognosis of individual cases is usually uncertain. various modalities exist in the treatment of viral warts, including surgical excision, electrocauterisation, cryotherapy and laser ablation; however, these options are often time-consuming, painful and potentially disfiguring.4 topical salicylic acid (sa), although usually readily available and a convenient method of treating warts at the focus location, can be irritating and is inefficient in cases with numerous warts or warts in several sites; moreover, patients must adhere to a strict daily application schedule for the treatment to be effective.7,8 optimally, the goal of treatment is to eliminate the warts with no subsequent recurrence (i.e. lifelong immunity) and without disfiguring the patient; however, no single therapy is currently guaranteed to cure viral warts and prevent their recurrence.5 this has made treatment somewhat of a challenge for both dermatologists and patients. immunotherapy represents a promising new modality for the management of recurring and resistant viral warts.9–11 this method can resolve warts without physically altering or damaging the surrounding tissue; moreover, it enhances the host response against the causal agent, leading to widespread resolution and diminishing the likelihood of recurrence.6,7 although the exact mechanism of its action in treating viral warts is not yet completely understood, immunotherapy is believed to stimulate a systemic t cell-mediated response resulting in resolution both at the site of contact and distally.12,13 the objective of this study was to compare the effectiveness and safety of the bacillus calmette-guérin (bcg) vaccine as a form of immunotherapy in comparison to conventional topical sa application for the treatment of viral warts. methods this non-randomised controlled trial was carried out from january 2016 to april 2017 at the dermatology outpatient clinic of the al-sader teaching hospital in basrah, iraq. all consecutive patients attending the clinic during this period with more than five clinically-diagnosed viral warts were included in the trial. however, immunosuppressed patients and those with chronic diseases such as diabetes mellitus, vitiligo and lupus or local or systemic inflammation were excluded, as were pregnant or lactating women. none of the participants had received any recorded treatment for warts within the three-month period preceding the start of the trial. interviews were conducted to collect information regarding the patients' age, gender and duration of warts; in addition, a clinical examination was conducted to determine the type, site and number of warts. subsequently, each patient underwent a mantoux tuberculin skin test in which 0.1 ml of purified protein derivative was injected intradermally into the left forearm at the volar aspect. approximately 48–72 hours later, a trained researcher inspected and palpated the skin to determine the presence or absence of an induration. in order to standardise the results of the test, the diameter of the induration was measured to determine the presence (i.e. induration of ≥15 mm) or absence (i.e. induration of <15 mm) of cell-mediated immunity to tuberculin.14 based on this, patients were assigned to either the bcg group if they had negative results or the sa group if they had positive results. the former received one intradermal dose of the bcg vaccine while the latter underwent conventional treatment involving the daily application of 15–20% sa in a suitable base. subsequently, patients in both groups were followed-up for three months. clinical evaluation and photographic measurement of the lesions were performed at baseline before treatment and at one, two and three months after treatment. based on these indicators, response to treatment was calculated as either a complete response to treatment (defined as the total resolution of all warts), partial response (defined as a decrease in the number and/or apparent size of the warts), mild response (defined as a <25% resolution in the number and/or apparent size of the warts) or no response (defined as no decrease in the number and/or apparent size of the warts). data analysis was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp, armonk, new york, usa). the results were reported using descriptive statistics. quantitative results were presented as means and standard deviations while nominal results were presented as percentages and frequencies. differences were assessed using chi-squared or fisher’s exact tests, wherever applicable. non-parametric mann-whitney-u, t test and analysis of variance tests were performed to compare the means of independent variables. a the bacillus calmette-guérin (bcg) vaccine is it a better choice for the treatment of viral warts? e332 | squ medical journal, august 2020, volume 20, issue 3 binary logistic regression analysis was conducted to determine independent factors predicting response to treatment. for the purposes of the regression analysis, response to treatment was dichotomised into either a positive response (i.e. complete or partial response to treatment) or no response. a p value of <0.050 was considered to be statistically significant. this study was approved by the ethical committee of the college of medicine, university of basrah [code 030407042-2016]. informed written consent was obtained from all participants. results a total of 201 patients were originally enrolled in the trial; however, five received only the tuberculin injection and another six were lost to follow-up, resulting in a final sample of 190 patients (94.5%). of these, 129 (67.9%) were male and 61(32.1%) were female (ratio: 2.1:1). the mean age was 27.8±8.7 years and mean number and duration of viral warts was 20.9 ± 7.3 warts and 9.0±3.7 months, respectively. the face was the most common site affected (30.5%), followed by the hands (23.7%), upper & lower limbs (20.6%), genitalia (14.7%), and neck (2.6%). multiple sites were involved in 7.9% of cases. in terms of wart type, 43.2% presented with common warts, while 20.5% had flat warts, 16.3% had genital warts, 11.6% had filiform warts and only 8.4% had plantar warts. based on the results of the mantoux test, 133 patients (70%) received the bcg vaccine, while the remaining 57 patients (30%) received conventional figure 1: flowchart showing the group allocation and intervention processes applied to the clinical trial. tst = tuberculin skin test; sa = salicylic acid; bcg = bacillus calmette-guérin. table1: comparison of treatment response to the bacillus calmette-guérin vaccine or conventional treatment with salicylic acid among patients with viral warts (n = 190) type of wart response, n (%) p value bcg group* (n =133) sa group†(n =57) complete partial none complete partial none common 5 (8.5) 45 (76.3) 9 (15.3) 0 (0) 4 (17.4) 19 (82.6) 0.001 flat 4 (12.9) 26 (83.9) 1 (3.2) 2 (25) 4 (50.0) 2 (25) 0.041 genital 4 (22.2) 13 (72.2) 1 (5.6) 1 (7.7) 4 (30.8) 8 (61.5) 0.002 filiform 0 (0) 12 (80) 3 (20) 0 (0) 4 (57.1) 3 (42.9) 0.334 plantar 0 (0) 4 (40) 6 (60) 0 (0) 4 (66.7) 2 (33.3) 0.608 total 13 (9.8) 100 (75.2) 20 (15) 3 (5.3) 20 (35.1) 34 (59.6) <0.001 bcg= bacillus calmette-guérin; sa = salicylic acid. *χ2 = 25.387; p = 0.002. †χ2= 17.944; p = 0.019. asaad q. al-yassen, shukrya k. al-maliki and jasim n. al-asadi clinical and basic research | e333 treatment with topical sa [figure 1]. the overall cure rate was significantly higher among those who received the bcg vaccine compared to those receiving conventional treatment (9.8% versus 5.3%; p<0.001). moreover, in the bcg group, rates of partial response and non-response to treatment were 75.2% and 15%, respectively, compared to 35.1% and 59.6% in the sa group. in terms of wart type, complete clearance was figure 2: photographs of the foot sole and toes of a patient showing (a) multiple plantar warts before treatment and (b) complete clearance two months after receiving the bacillus calmette-guérin vaccine. figure 3: photographs of the fingers of a patient showing (a) common warts before treatment and (b) complete clearance two months after receiving the bacillus calmette-guérin vaccine. figure 4: comparison of treatment response to the bacillus calmette-guérin vaccine or conventional treatment with salicylic acid according to number of warts among patients with viral warts (n = 190). the difference between groups was statistically significant (p = 0.043). bcg= bacillus calmette-guérin; sa= salicylic acid. table 2: literature review of previous studies assessing use of the bacillus calmette-guérin vaccine for the treatment of viral warts12,16,22–24 author and year of study mode of administration duration of follow-up number of sessions interval between sessions cc rate side-effects sharquie et al.12 (2008) intradermal 3 months after the last dose 3 4 weeks 39.7% •none kenawi et al.22 (2012) intralesional until cc or up to four treatment sessions 4 3 weeks 40% •pain, ulcers and constitutional symptoms (i.e. fever, necrosis and lymphadenitis) podder et al.16 (2017) intradermal 4 weeks after treatment 3 4 weeks 48.5% •pain during the injection and abscess formation and scarring at the injection site rajashekar et al.23 (2018) intralesional 6 months 4 2 weeks 30.8% • pain, fever, myalgia and flu-like symptoms jaisinghani et al.24 (2019) intralesional 3 months 3 3 weeks 73.53% • pain, flu-like symptoms, erythema, oedema and bcgitis present study (2020) intradermal 3 months 1 9.8% • minimal scarring at the injection site cc = complete clearance; bcg = bacillus calmette-guérin the bacillus calmette-guérin (bcg) vaccine is it a better choice for the treatment of viral warts? e334 | squ medical journal, august 2020, volume 20, issue 3 more frequently observed with bcg therapy among those with common warts (8.5% versus 0%; p = 0.001) and genital warts (22.2% versus 7.7%; p = 0.002), while the reverse was true for flat warts (12.9% versus 25%; p = 0.041) [table 1]. in both groups, patients most frequently started responding to treatment by the second month [figures 2 and 3], with a significantly greater response observed in the bcg group compared to the sa group (10.5% versus 1.8%; p = 0.042). by the third month, 84.9% of the bcg group were partially or completely cured in comparison to 40.4% of the sa group (p <0.001). moreover, while the rate of response to treatment increased alongside the number of warts in both groups, the response was significantly greater in the bcg group (p =0.043) [figure 4]. although the cure rate was higher among those with longer disease durations (≥10 months) compared to those with shorter durations (<10 months), this difference was not statistically significant (11.9% versus 8.8%; p = 0.451). the binary logistic regression analysis showed that bcg therapy was the only significant independent determinant of response to treatment (odds ratio: 7.56, 95% confidence interval: 3.72–15.36; p <0.001). all other variables were non-significant, including age, gender and the number, site, type and duration of the warts. in terms of possible complications from treatment, no side-effects were documented in any of the patients regardless of group, except for mild scarring due to the intradermal injection of the vaccine in the bcg group. discussion immunotherapies can be administered via topical, intralesional or systemic routes, with systemic immunotherapy found to be a safe, affordable and effective option for multiple intractable viral warts.4,9,15 originally, the bcg vaccine was formulated as a prophylactic against tuberculosis; however, this immunotherapy has since been incorporated in the management of other diseases with varying success rates, including malignant melanomas, alopecia areata and transitional cell carcinomas.16–19 the bcg vaccine affects the immune system and offers protection against infections—including those viral in origin— via the stimulation of innate immune memory and activation of the heterologous lymphocytes, resulting in enhanced cytokine production.20 the current clinical trial aimed to compare two methods of treating viral warts—the bcg vaccine as a form of immunotherapy and conventional treatment with topical sa—in terms of both effectiveness (i.e. response to treatment) and safety (i.e. the occurrence of any medical complications). the bcg vaccine was found to result in a significantly higher rate of complete response to treatment compared to topical sa (9.8% versus 5.3%). this is potentially because immunotherapy is more effective at destroying the infected cells by activating a systemic inflammatory response; in addition, it removes any potential issue of non-adherence to treatment as the vaccine is injected by clinicians, while topical treatment is carried out by the patients themselves.21 in iraq, the bcg vaccine is provided to all citizens free of charge at primary health centres; as such, it is an excellent option for low-income patients. nevertheless, other studies have reported much higher rates of complete clearance with bcg therapy (39.7–40%).12,22 variations in specific treatment details might play a role in the rate of complete clearance [table 2].12,16,22–24 the low rate in the present study could be due to the shorter duration of follow-up (three months) or the fact that patients received only one bcg injection via an intradermal route; it is possible that some of the partial responses would have cleared completely with more time, alternative routes or additional bcg injections. rajashekar et al. observed a clearance rate of 30.8% with multiple intralesional bcg injections and a longer duration of follow-up (six months).23 another study noted a clearance rate of 73.53% using three doses of intralesional bcg vaccine.24 both the intralesional administration and the increased number of doses might explain such high clearance rates, considering that drug effect is a function of both dose and time.25 indeed, repeated bcg injections seem to result in a booster effect or dose-response relationship.23,24 in the current study, treatment response was found to be linked to greater numbers of warts with both types of therapy, although better responses were noted in the group receiving the bcg vaccine. this is in agreement with results reported by kenawi et al.22 these findings could be explained by the fact that patients with larger numbers of warts in the sa group might be less likely to comply with a treatment regimen which involved the daily topical application of sa on each individual wart over a 12-week period; in contrast, bcg therapy is much more convenient for the patient as it simply involves a single injection performed by a clinician and results in the clearance of warts from multiple sites. regardless of type of treatment, the best responses in the present study were noted for genital and flat warts, with plantar warts demonstrating the least response. similar results have been reported by other researchers.12,26,27 genital warts are typically asaad q. al-yassen, shukrya k. al-maliki and jasim n. al-asadi clinical and basic research | e335 caused by hpv types 6 and 11 which have a low risk of inducing intraepithelial dysplasia; this could potentially explain better responses to bcg treatment for these types of warts.28 in contrast, youn et al. reported that plantar warts exhibited superior cure rates with liquid nitrogen cryotherapy compared to other types of warts; the authors attributed this to the effectiveness of routine paring (i.e. the elimination of excessive keratin) before each cryotherapy session.29 generally, patients in both groups in the current study began exhibiting responses to treatment after two months. podder et al. similarly reported that clinical results first became apparent four weeks after bcg therapy was initiated.16 moreover, while the difference was not statistically significant, cases with longer disease duration in the present study appeared to exhibit better responses to bcg therapy, but not sa treatment. this result is consistent with those obtained by kenawi et al.22 patients with persistent viral warts may demonstrate better enhancement and stimulation of immune response with bcg therapy, in which case maintaining a healthy immune status could prevent recurrence.29 in contrast, bruggink et al. and choi et al. concluded that longer-lasting warts were more difficult to treat with either conventional treatments alone (i.e. liquid nitrogen and topical sa) or combined with an immunomodulator (dinitrochlorobenzene), which they also assumed to be due to an immunityrelated issue.8,21 in the current study, patients with negative mantoux test results were given the bcg vaccine to prove its ability to reactivate immunity and, consequently, its potential role in the treatment of viral warts. prior to their assignment to the bcg or sa groups, all patients in the current trial underwent tuberculin skin tests on the assumption that a positive mantoux test would measure the degree of hypersensitivity to tuberculin.14 however, the absence of an induration (or one under 15 mm in diameter) may be due to the lack of previous sensitisation; moreover, positive results may indicate intact or persistent cellmediated immunity, while negative results could indicate a weakened immune system due to a myriad of reasons, such as a concurrent viral infection.14,30 the study was subject to certain limitations. first, the lack of randomisation in the allocation of treatment groups could have resulted in potential confounding bias, restricting complete confirmation of the causal effect of each treatment. however, such confounding was adjusted for by applying multiple regression analyses.31 another limitation was that the precise cytokine levels of the patients in the bcg group were not measured due to financial reasons. finally, although the diameter of the induration in each patient was measured after the tuberculin skin test, false-negative results could not be excluded.14,30 conclusion topical sa is widely used as treatment modality in the management of cutaneous viral warts. however, the results of this clinical trial provide evidence to support the efficacy of intradermal bcg therapy over this conventional treatment, particularly for common and genital warts. however, further randomised controlled studies are necessary to support these findings and more clearly ascertain the effectiveness of bcg therapy in the treatment of viral warts. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bruggink sc, de koning mn, gussekloo j, egberts pf, ter schegget j, feltkamp mc, et al. cutaneous wart-associated hpv types: prevalence and relation with patient characteristics. j clin virol 2012; 55:250–5. https://doi.org/10.1016/j.jcv.20 12.07.014. 2. de villiers em, fauquet c, broker tr, bernard hu, zurhausen h. classification of papillomaviruses. virology 2004; 3217–27. https://doi.org/10.1016/j.virol.2004.03.033. 3. sanfilippo am, barrio v, kulp-shorten c, callen jp. common pediatric and adolescent skin conditions. j pediatr adolesc gynecol 2003; 16:269–83. https://doi.org/10.1016/s1083-3188 (03)00147-5. 4. lynch md, cliffe j, morris-jones r. management of cutaneous viral warts. bmj 2014: 348:g3339. https://doi.org/10.1136/bmj. g3339. 5. sterling jc, handfield-jones s, hudson pm; british association of dermatologists. guidelines for the management of cutaneous warts. br j dermatol 2001; 144:4–11. https://doi. org/10.1046/j.1365-2133.2001.04066.x. 6. nimbalkar a, pande s, sharma r, borkar m. tuberculin purified protein derivative immunotherapy in the treatment of viral warts. indian j drugs dermatol 2016; 2:19–23. https://doi. org/10.4103/2455-3972.184103. 7. sefcik rs, burkhart cg. wart immunotherapies: a short review. open dermatol j 2017; 11:30–34. https://doi.org/10.2 174/1874372201711010030. 8. bruggink sc, gussekloo j, berger my, zaaijer k, assendelft wj, de waal mw, et al. cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. cmaj 2010; 182:1624–30. https://doi.org/10.1503/cmaj.092194. 9. el-khalawany m, shaaban d, aboeldahab s. immunotherapy of viral warts: myth and reality. egypt j dermatol venereol 2015; 35:1–13. https://doi.org/10.4103/1110-6530.162451. 10. thappa dm, chiramel mj. evolving role of immunotherapy in the treatment of refractory warts. indian dermatol online j 2016; 7:364–70. https://doi.org/10.4103/2229-5178.190487. https://doi.org/10.1016/j.jcv.2012.07.014 https://doi.org/10.1016/j.jcv.2012.07.014 https://doi.org/10.1016/j.virol.2004.03.033 https://doi.org/10.1016/s1083-3188%2803%2900147-5 https://doi.org/10.1016/s1083-3188%2803%2900147-5 https://doi.org/10.1136/bmj.g3339 https://doi.org/10.1136/bmj.g3339 https://doi.org/10.1046/j.1365-2133.2001.04066.x https://doi.org/10.1046/j.1365-2133.2001.04066.x https://doi.org/10.4103/2455-3972.184103 https://doi.org/10.4103/2455-3972.184103 https://doi.org/10.2174/1874372201711010030 https://doi.org/10.2174/1874372201711010030 https://doi.org/10.1503/cmaj.092194 https://doi.org/10.4103/1110-6530.162451 https://doi.org/10.4103/2229-5178.190487 the bacillus calmette-guérin (bcg) vaccine is it a better choice for the treatment of viral warts? e336 | squ medical journal, august 2020, volume 20, issue 3 11. bacelieri r, johnson sm. cutaneous warts: an evidence-based approach to therapy. am fam physician 2005; 72:647–52. 12. sharquie ke, al-rawi jr, al-nuaimy aa, radhy sh. bacille calmette-guerin immunotherapy of viral warts. saudi med j 2008; 29:589–93. 13. clifton mm, johnson sm, roberson pk, kincannon j, horn td. immunotherapy for recalcitrant warts in children using intra lesional mumps or candida antigens. pediatr dermatol 2003; 20:268–71. https://doi.org/10.1046/j.1525-1470.2003.20318.x. 14. nayak s, acharjya b. mantoux test and its interpretation. indian dermatol online j 2012; 3:2–6. https://doi.org/10.4103/22295178.93479. 15. singh s, chouhan k, gupta s. intralesional immunotherapy with killed mycobacterium indicus pranii vaccine for the treatment of extensive cutaneous warts. indian j dermatol venereol leprol 2014; 80:509–14. https://doi.org/10.4103/03786323.144145. 16. podder i, bhattacharya s, mishra v, sarkar tk, chandra s, sil a, et al. immunotherapy in viral warts with intradermal bacillus calmette-guerin vaccine versus intradermal tuberculin puri fied protein derivative: a double-blind randomized controlled trial comparing effectiveness and safety in a tertiary care center in eastern india. indian j dermatol venereol leprol 2017; 83:411. https://doi.org/10.4103/0378-6323.193623. 17. lardone rd, chan aa, lee af, foshag lj, faries mb, sieling pa, et al. mycobacterium bovis bacillus calmette-guérin alters melanoma microenvironment favoring antitumor t cell responses and improving m2 macrophage function. front immunol 2017; 8:965. https://doi.org/10.3389/fimmu.2017.00965. 18. sharquie ke, lafta rk, al samarrai a, bcg-immunotherapy in patients with alopecia areata, yemeni j. med. sci. 2003;3: 15–9. 19. kamel ai, el baz ag, abdel salam wt, el din ryad me, mahena aa. low dose bcg regimen in t1 transitional cell carcinoma of the bladder: long term results. j egypt natl canc inst 2009; 21:151–5. 20. moorlag sjcfm, arts rjw, van crevel r, netea mg. nonspecific effects of bcg vaccine on viral infections. clin microbiol infect 2019; 25:1473–8. https://doi.org/10.1016/j. cmi.2019.04.020. 21. choi jw, cho s, lee jh. does immunotherapy of viral warts provide beneficial effects when it is combined with conventional therapy? ann dermatol 2011; 23:282–7. https:// doi.org/10.5021/ad.2011.23.3.282. 22. kenawi mz, el-rahman sh, abdel salam oh. efficacy of intralesional 5-fluorouracil versus bcg vaccine in the treatment of warts. egypt j dermatol androl 2012; 32:3–14. 23. rajashekar ts, amulya r, sathish s, kumar s. comparative study of intralesional bcg and ppd in the treatment of multiple cutaneous warts. indian j clin exp dermatol 2018; 4:1–6. https://doi.org/10.18231/.2018.0001. 24. jaisinghani ak, dey vk, suresh ms, saxena a. bacillus calmette-guerin immunotherapy for recurrent multiple warts: an open-label uncontrolled study. indian j dermatol 2019; 64:164. https://doi.org/10.4103/ijd.ijd_558_16. 25. curriegm. pharmacology, part 1: introduction to pharmacology and pharmacodynamics. j nucl med technol 2018; 46:81–6. https://doi.org/10.2967/jnmt.117.199588. 26. soni p, khandelwal k, aara n, ghiya bc, mehta rd, bumb ra. efficacy of intralesional bleomycin in palmo-plantar and periungual warts. j cutan aesthet surg 2011; 4:188–91. https:// doi.org/10.5021/ad.2011.23.1.53. 27. salem a, nofal a, hosny d. treatment of common and plane warts in children with topical viable bacillus calmette-guerin. pediatr dermatol 2013; 30:60–3. https://doi.org/10.1111/ j.1525-1470.2012.01848.x. 28. wiley dj, douglas j, beutner k, cox t, fife k, moscicki ab, et al. external genital warts: diagnosis, treatment, and prev ention. clin infect dis 2002; 35:s210–24. https://doi.org/10.1 086/342109. 29. youn sh, kwon ih, park ej, kim kh, kim kj. a two-week interval is better than a three-week interval for reducing the recurrence rate of hand-foot viral warts after cryotherapy: a retrospective review of 560 hand-foot viral warts patients. ann dermatol 2011; 23:53–60. https://doi.org/10.5021/ad.20 11.23.1.53. 30. pande s, sontakke a, tayade bo. purified protein derivative immunotherapy for viral warts and interpretation of tuberculin skin tests and interferon gamma release assay for diagnosis of tuberculosis in india. indian j drugs dermatol 2016; 2:73–4. https://doi.org/10.4103/2455-3972.196165. 31. schmoor c, gall c, stampf s, graf e. correction of confounding bias in non-randomized studies by appropriate weighting. biom j 2011; 53:369–87. https://doi.org/10.1002/bimj.201000154. https://doi.org/10.1046/j.1525-1470.2003.20318.x https://doi.org/10.4103/2229-5178.93479 https://doi.org/10.4103/2229-5178.93479 https://doi.org/10.4103/0378-6323.144145 https://doi.org/10.4103/0378-6323.144145 https://doi.org/10.4103/0378-6323.193623 https://doi.org/10.3389/fimmu.2017.00965 https://doi.org/10.1016/j.cmi.2019.04.020 https://doi.org/10.1016/j.cmi.2019.04.020 https://doi.org/10.5021/ad.2011.23.3.282 https://doi.org/10.5021/ad.2011.23.3.282 https://doi.org/10.18231/.2018.0001 https://doi.org/10.4103/ijd.ijd_558_16 https://doi.org/10.2967/jnmt.117.199588 https://doi.org/10.5021/ad.2011.23.1.53 https://doi.org/10.5021/ad.2011.23.1.53 https://doi.org/10.1111/j.1525-1470.2012.01848.x https://doi.org/10.1111/j.1525-1470.2012.01848.x https://doi.org/10.1086/342109 https://doi.org/10.1086/342109 https://doi.org/10.5021/ad.2011.23.1.53 https://doi.org/10.5021/ad.2011.23.1.53 https://doi.org/10.4103/2455-3972.196165 https://doi.org/10.1002/bimj.201000154 التعرض السابق لألكسدة باألوزون حيمي ضد التسمم القليب الذي حيدثه دواء دوكسوروبسني يف جرذان سرباق داويل ليفان. رو�سي، يانت هرينانديزماتو�س، اميليو . مدينا، داليا . مورجون، ماتي جونزال�س، جريجوريوا مارتينينز�سان�سيز abstract: objectives: induced dilated cardiomyopathy is the main limitation of the anti-cancer drug doxorubicin, which causes oxidative stress and cardiomyocyte death. as ozone therapy can activate the antioxidant systems, this study aimed to investigate the therapeutic efficacy of ozone-oxidative preconditioning against doxorubicin-induced cardiotoxicity. methods: the study was carried out from september 2013 to january 2014. sprague-dawley rats were randomly distributed in the following treatment groups: group 1 were treated with 2 mg/kg intraperitoneal (i.p.) of doxorubicin twice a week for 50 days; group 2 were treated with 0.3 mg of ozone/oxygen mixture at 50 μg/ ml of ozone per 6 ml of oxygen by rectal insufflation and then treated with doxorubicin; group 3 were treated as group 2 but only with the oxygen, and group 4 were treated with oxygen first, and then with sodium chloride i.p. as the control group. results: the results showed that ozone therapy preserved left ventricle morphology which was accompanied by a reduction of serum pro-brain natriuretic peptide levels. the cardioprotective effects of ozoneoxidative preconditioning were associated with a significant increase (p <0.05) of antioxidant enzymes activities and a reduction of lipid and protein oxidation (p <0.05). conclusion: ozone-oxidative preconditioning prevents doxorubicin-induced dilated cardiomyopathy through an increase of antioxidant enzymes and a reduction of oxidised macromolecules. this establishes the background for future studies to determine if ozone therapy can be used as a complementary treatment for attenuating doxorubicin-induced cardiotoxicity in cancer patients. keywords: ozone; doxorubicin; dilated cardiomyopathy; cardiotoxins; oxidative stress. اإجهادا الدواء هذا ي�سبب اإذ دوك�سوروب�سني، ال�رسطان لدواء ال�سمية الآثار اأحد هو التو�سعي القلب ع�سلة اعتالل يعد الهدف: امللخ�ص: لتقومي الدرا�سة هذه عملت لالأك�سدة، امل�سادة اجل�سم اأنظمة ين�سط اأن ميكن بالأوزون العالج اأن ومبا القلبية. للخاليا وموتا تاأك�سديا الفعالية العالجية للتعر�س ال�سابق لالأك�سدة بالأوزون �سد الت�سمم القلبي الذي يحدثه دوك�سوروب�سني. الطريقة: اأجريت الدرا�سة بني �سبتمرب 2013 اإىل يناير 2014م. وق�سمت جرذان �سرباق دايل اإىل املجموعات التالية: عوجلت املجموعة الأوىل بحقن دوك�سوروب�سني يف ال�سفاق بجرعة 2 جمم لكل كجم مرتني يف الأ�سبوع ملدة 50 يوما متوا�سلة. واأعطيت املجموعة الثانية عن طريق امل�ستقيم خليطا من الأك�سجني والوزون قدره 0.3 جمم )50 ميكروجرام لكل مل من الأوزون لكل 6 مل من الأك�سجني( ثم عوجلت بالأوزون. وعوجلت املجموعة الثالثة مبثل ما عوجلت به املجموعة الثانية، ولكنها اأعطيت اأك�سجني فقط. واأعطيت املجموعة الرابعة الأك�سجني اأول ثم اأعطيت كلوريد ال�سودمي باحلقن ال�سفاقي، وعدت كمجموعة �سابطة. النتائج: وجد اأن العالج بالأوزون قد حافظ على مورفوجليا البطني الأي�رس للقلب، و�ساحب )0.05> p( ذلك نق�س يف تركيز البيبتيد املدر لل�سوديوم. وارتبطت احلماية التي وفرها التعر�س امل�سبق لالأوزون للقلب بزيادة معنوية بالأوزون لالأك�سدة امل�سبق التعر�س مينع اخلال�صة: .)0.05> p( والربوتني الدهن اأك�سدة يف ونق�س امل�سادة، الأنزميات ن�ساط يف اجلزئيات وتقليل لالأك�سدة امل�سادة النزميات ن�ساط زيادة طريق عن وذلك دوك�سوروب�سني، ي�سببه الذي التو�سعي القلب ع�سلة اعتالل الكبرية املوؤك�سدة. تقدم هذه الدرا�سة خلفية لدرا�سات م�ستقبلية تقرر عما اإذا كان بالإمكان ا�ستخدام العالج بالأزون كعالج مكمل يقلل من اآثار �سمية دواء دوك�سوروب�سني عند مر�سى ال�رسطان. مفتاح الكلمات: الأوزون؛ دوك�سوروب�سني؛ اعتالل ع�سلة القلب التو�سعي؛ ال�سموم القلبية؛ الإجهاد التاأك�سدي. ozone-oxidative preconditioning prevents doxorubicin-induced cardiotoxicity in sprague-dawley rats livan delgado-roche,1 yanet hernández-matos,1 emilio a. medina,1 dalia á. morejón, maité r. gonzález,2 *gregorio martίnez-sánchez3 clinical & basic research sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e342-348, epub. 24th jul 14 submitted 28th sep 13 revision req. 12th nov 13; revision recd. 8th mar 14 accepted 20th mar 14 1center of studies for research & biological evaluations, pharmacy & food science college, university of havana, cuba; 2labiofam pharmaceutical laboratories, havana, cuba; 3medical center beauty benefit, osimo, ancona, italy *corresponding author e-mail: gregorcuba@yahoo.it advances in knowledge ozone therapy can activate antioxidant systems. this study was the first to investigate the therapeutic efficacy of ozone-oxidative preconditioning against doxorubicin-induced cardiotoxicity. application to patient care the results of this study suggest that ozone therapy could be used to attenuate doxorubicin-induced cardiotoxicity as a complementary treatment for cancer patients. these results require further pharmacological and toxicological investigations. livan delgado-roche, yanet hernández-matos, emilio a. medina, dalia á. morejón, maité r. gonzález and gregorio martínez-sánchez clinical and basic research | e343 doxorubicin (dox) is an anthracycline antibiotic which is used to treat a wide range of cancers.1,2 like most of the anticancer drugs, dox causes various toxic effects, the commonest of which is dose-dependent cardiotoxicity.3 studies have reported dox-induced cardiac abnormalities in a significant number of patients.4 in both animal and human models, dox induces dilated cardiomyopathy (dcm), cardiac muscle wasting and congestive heart failure.5,6 cellular injury induced by dox is mediated by the intermediary iron-anthracycline complex that generates free radicals, which in turn causes serious damage due to oxidative stress (os).2 dox localises to the mitochondria and is highly susceptible to enzymatic reduction, generating superoxide radicals (o2 •–) and reactive oxygen species (ros) which alter mitochondrial function.7 dox increases the susceptibility of the cardiomyocytes to os by reducing superoxide dismutase (sod) activity, therefore reducing the ability of the cardiac cells to deactivate the ros.8 dox-induced cardiotoxicity is also mediated by impaired calcium ion (ca2+) fluxes, the suppression of cardiac-specific genes expression and myofibrillar and mitochondrial degeneration in the cardiomyocytes.3,9 in patients with dcm, the left ventricle dysfunction causes an augmentation of the circulating levels of amino-terminal pro-brain natriuretic peptide (pro-bnp). this peptide is a sensitive biomarker of myocarditis and congestive heart failure.10 in this context, it is possible to evaluate the efficacy of cardioprotective drugs by measuring probnp levels. therapeutic strategies that focus on increasing cellular endogenous defence systems have been identified as a valid approach against os-associated diseases such as dcm.2 there is proven evidence that antioxidant enzymes, nitric oxide pathways and other subcellular activities could be modulated by low doses of ozone and could support the effects of ozone therapy in many pathological conditions such as hepatic and renal ischaemia-reperfusion injuries,11 diabetes mellitus,12 parkinson’s disease13 and coronary artery disease.14,15 in light of more recent pharmacological findings, ozone can be considered a prodrug which, at non-toxic doses, can induce a rearrangement of the biochemical pathways with the activation of second messengers in a cascade with multiple system actions.13,16,17 the present study was designed to evaluate the effects of ozone-oxidative preconditioning (ozoneop) on dox-induced cardiotoxicity in spraguedawley rats. in particular, the animals were examined for antioxidant enzyme activity, biomolecular damage, systemic levels of pro-bnp and the histopathological characteristics of the cardiac tissue. methods the study was carried out from september 2013 to january 2014. all reagents were purchased from sigmaaldrich corp. (st. louis, missouri, usa), except for the dox, which was provided by the manufacturer (center of drug research and development, havana, cuba). adult male sprague-dawley rats (n = 40) weighing 250–300 g were obtained from the national center for production of laboratory animals (cenpalab, mayabeque, cuba) and adapted to laboratory conditions (60% humidity and 25 ± 1 °c) for at least one week before the experiments. the rats were housed in groups of five and exposed to a 12hour light/darkness cycle with free access to food and water. ozone was obtained by an ozomed® device (ozone research center, havana, cuba). ozone was generated from medical-grade oxygen and was used immediately upon generation. the ozone represented only about 3% of the oxygen plus ozone gas mixture. the ozone concentration was measured by using a built-in ultraviolet (uv) spectrophotometre set at 254 nm.15 four groups of 10 rats were assigned to different treatments [table 1]. prior to ozone/oxygen insufflation, the rectum was stimulated to eliminate excrement. dox was administered twice a week for 50 days to both the ozonised and the oxygen group after 20 sessions of ozone or oxygen, respectively. on the final day of dox administration, the animals were processed as previously described in order to conduct the biochemical and histological analysis.18 the animals were anaesthetised with 5 mg/kg of ketamine hydrochloride intramuscularly and euthanised with an overdose of 90 mg/kg of sodium pentobarbital table 1: experimental design and effects of ozone therapy on the pro-bnp levels of the experimental groups of sprague-dawley rats experimental groups mean ± sd of pro-bnp levels in pg/ml* controla,b 2.01 ± 0.23 doxc 48.95 ± 1.78† oxygen plus doxa,c 50.01 ± 0.99† ozone-op plus doxc,d 8.62 ± 0.84†‡ pro-bnp = pro-brain natriuretic peptide; sd = standard deviation; dox = doxorubicin; ozone-op = ozone-oxidative preconditioning. arectal insufflation of oxygen (6 ml) once on alternating days for 20 sessions; ban intraperitoneal injection of 0.9% sodium chloride (2 ml/kg ) twice a week for 50 days; can intraperitoneal injection of dox (2 mg/kg ) twice a week for 50 days; drectal insufflaction of ozone/oxygen mixture (0.3 mg ) with 50 μg/ml of ozone per 6 ml once on alternating days for 20 sessions.*values higher than 5 pg/ml are considered pathological. †statistical differences (p <0.05) compared to control group. ‡statistical differences (p <0.05) compared to the dox and oxygen plus dox groups. ozone-oxidative preconditioning prevents doxorubicin-induced cardiotoxicity in sprague-dawley rats e344 | squ medical journal, august 2014, volume 14, issue 3 intravenously (abbott laboratories s.a. de c.v., mexico city, mexico). the cardiovascular system was subsequently perfused with a solution of ice-cold 0.9% sodium chloride (nacl). the hearts were harvested and used to determine biomarkers of os (n = 5) and for histopathological analysis (n = 5). to determine the pro-bnp levels, ethylenediamine-tetra-acetic acid (edta)-anticoagulated blood samples (1 ml) were obtained by penetrating the retro-orbital plexus with a capillary tube after a 12-hour overnight fast and 24 hours after the final administration of dox. the samples were immediately centrifuged at 3,000 g at 4 °c for 10 min. finally, the serum was collected and aliquots were stored at -80 °c until analysis. the hearts were treated as previously described.19 they were placed in 0.1 mol/l of ice-cold tris(hydroxymethyl)aminomethane-hydrochloric acid (tris-hcl) buffer solution (ph 7.6) with 1.0 mmol/l of edta and 0.2 mmol/l of butylated hydroxytoluene. they were macerated before homogenisation at 3,000 rpm-1 for 10 min in a tissue homogeniser (edmund bühler gmbh, tübingen, germany). the homogenised tissue was then centrifuged at 4,500 g for 20 min at 4 °c and the supernatants were collected and stored at -80 °c until the os biomarker determination. the hearts were cut transversally in order to enhance observation of the four chambers. the samples were then rinsed in an ice-cold phosphatebuffered saline (pbs) solution (ph 7.4) and fixed in a solution of 10% formaldehyde for 24 hours. samples were subsequently embedded in paraffin as previously described.19 tissue sections of 5 µm were cut, air-dried on glass slides with different grades of alcohol/xylene, deparaffinised and then rehydrated. finally, the tissue sections were stained with haematoxylin and eosin via the standard procedures.18 the sections were analysed using a bx51 optic microscope (olympus® europa holding gmbh, hamburg, germany). the serum levels of pro-bnp were quantified using an electrochemoluminescence immunoassay kit (elecsys® nt-probnp, roche diagnosticsgmbh, basel, switzerland). all biochemical variables were analysed using spectrophotometric methods with a 1000 spectrophotometer (pharmacia lkb, uppsala, sweden) and a microplate reader (suma, center of immunoassay, havana, cuba). total protein concentrations were assayed with bovineserum albumin (#a7906, sigma-aldrich corp., st. louis, missouri, usa) as the standard, using the method described by bradford.20 the sod activity was determined using a ransod kit (randox laboratories, crumlin, uk) and measured by the inhibition degree of the reaction.19 catalase (cat) activity was determined spectrophotometrically by following hydrogen peroxide (h2o2) decomposition at 240 nm at 10-second intervals for one min.21 the advanced oxidation protein products (aopps) were measured as described previously.18,22 samples in a pbs solution (ph 7.4) at 10 mm were treated with 50 μl of potassium iodide at 1.16 m followed by the addition of 100 μl of acetic acid. the absorbance was immediately read at 340 nm. the concentration of aopps was expressed in μm of chloramine-t. the concentration of malondialdehyde (mda) was determined using the lpo-586 assay kit obtained from calbiochem (la jolla, california, usa). the production of a stable chromophore after 40 min of incubation at 45 °c was measured at 586 nm. for standards, freshly prepared solutions of mda bis (dimethyl acetal) were employed and assayed under identical conditions.18,23 statistical analysis was performed using the statistical package for the social sciences (spss), version 11.5 (ibm corp., chicago, illinois, usa). levene’s test was used to analyse the homogeneity of variance. the differences between the four groups were determined by analysis of variance (anova) followed by the bonferroni post-hoc test. data were expressed as means ± standard deviation (sd). a p value of <0.05 was considered statistically significant. growth curves were analysed using the comparison of the slope of a regression line fitted to each individual. this animal study was performed in line with international ethical guidelines and with the approval of the institutional animal ethics committee of the college of pharmacy & food sciences at havana university (approval protocol #2012as671211). results the survival rates of the animals are shown in figure figure 1: the corresponding survival rates for each experimental group of sprague-dawley rats. the survival rate in the dox group was 60% in comparison to 90% for the ozonised rats. dox = doxorubicin. livan delgado-roche, yanet hernández-matos, emilio a. medina, dalia á. morejón, maité r. gonzález and gregorio martínez-sánchez clinical and basic research | e345 1. the ozone-treated group displayed a 90% survival rate while survival was lower for the groups who were only treated with dox or with oxygen plus dox (70% and 60%, respectively). in addition, ozone treatment was able to reduce the loss of body weight which is normally associated with the administration of dox [figure 2]. although the body weight of the ozonised rats was lower than that of the controls (p <0.05), it was significantly higher in comparison to those only treated with dox or those treated with oxygen plus dox (p <0.05). body weight did not vary significantly in any of the experimental groups before the administration of dox. macroscopic and microscopic examinations of the organs did not show any relevant disease or abnormalities during ozone-op. the effect of ozone-op on left ventricle dysfunction was determined by evaluating pro-bnp levels. significantly high levels of serum pro-bnp were observed in the rats who were only treated with dox and those treated with oxygen and dox when compared to the control and ozonised rats (p <0.05). it is important to highlight that the rats undergoing ozone treatment demonstrated a significant reduction in pro-bnp levels in comparison to the animals treated with dox and oxygen pus dox (p <0.05) [table 1]. table 2 shows the effect of ozone-op on the oxidised macromolecules and antioxidant enzymes in the cardiac tissue homogenates. mda and aopps concentrations were measured as surrogate markers of lipid and protein damage, revealing a significant increase of these variables in the group treated with dox only and the one treated with oxygen plus dox (p <0.05). however, in ozonised rats there was a significant reduction of biomolecule damage in comparison to non-ozonised animals (p <0.05). furthermore, ozone treatment was shown to preserve the activity of sod and cat, regulating the cat/sod ratio. the activity of these enzymes in the ozone-op group did not differ from control animals; moreover, a significant increase was observed in respect to the animals only treated with dox or the ones treated with oxygen plus dox (p <0.05). a microscopic analysis of the left ventricle sections from the control rats showed a normal morphology [figure 3a]. significant tissue injuries with the subendocardial loss of longitudinal muscular fibres, mild oedema and necrosis were seen in the dox group [figure 3b]. conversely, only minor damage was observed in the ozone-treated animals with a preservation of the morphology of the cardiac muscular fibres [figure 3c]. discussion the results of this study showed that ozone-op improved dox-induced dcm in rats. ozone therapy preserved left ventricle morphology, which table 2: effect of ozone therapy on oxidative stress biomarkers among the experimental groups of sprague-dawley rats* heart redox biomarkers experimental groups control dox oxygen plus dox ozone-op plus dox mda in µm/mg pr 6.49 ± 0.81 17.34 ± 1.95† 18.21 ± 0.99† 7.02 ± 0.68 aopp in µm of chloramines/mg pr 10.32 ± 0.99 22.70 ± 3.21† 20.69 ± 2.11† 14.52 ± 1.26†‡ cat in u/l/min/mg pr 1,025.87 ± 19.67 790.76 ± 54.56† 779.45 ± 34.92† 1,049.80 ± 27.43 sod in u/ml/min/mg pr 54.36 ± 4.99 32.21 ± 6.12† 34.54 ± 4.21† 60.21 ± 5.33 cat/sod in u/ml/min/mg pr 0.018 ± 0.003 0.024 ± 0.001 0.022 ± 0.008 0.017 ± 0.005 dox = doxorubicin; ozone-op = ozone-oxidative preconditioning ; mda = malondialdehyde; mg pr = protein concentration; aopp = advanced oxidation protein products; cat = catalase; sod = superoxide dismutase. *values are expressed as mean ± standard deviation with respect to the protein concentration (mgpr). †statistical differences (p <0.05) compared to control group. ‡statistical differences (p <0.05) compared to the dox and oxygen plus dox groups. figure 2: changes in body weight among the experimental groups of sprague-dawley rats. the reduction of body mass in the dox and oxygen plus dox groups was significantly higher in comparison to the controls and ozonised rats (p <0.05). dox = doxorubicin. ozone-oxidative preconditioning prevents doxorubicin-induced cardiotoxicity in sprague-dawley rats e346 | squ medical journal, august 2014, volume 14, issue 3 was accompanied by a reduction of the serum probnp levels. the mechanism was associated with a significant increase of antioxidant enzyme activities and a reduction of lipid and protein oxidation (p <0.05). the histopathological evaluation of the heart sections revealed the deleterious effects of dox on myocardial morphology. conversely, ozoneop prevented the loss of muscular fibres, with a preservation of their longitudinal disposition. also, ozone treatment prevented the development of dox-induced oedema and necrosis. in accordance with these findings, the serum pro-bnp levels were significantly reduced in the rats treated with ozone compared to those only treated with dox or with oxygen plus dox. furthermore, a higher survival rate (90%) and lower body weight loss was observed in the ozonised group compared to the dox group. as a whole, these results demonstrate the protective effect of ozone-op against dox-induced cardiotoxicity. in order to examine further the mechanisms responsible for the cardioprotective action of ozoneop, the effects of ozone-op on heart os biomarkers were evaluated. dox-induced lipid and protein peroxidation has been well documented in the literature.2,24 in the current study, significant increases of mda and aopps (surrogate markers of lipid and protein oxidation) were observed (p <0.05). both mda and aopps were decreased by ozone insufflation in comparison to those animals only treated with dox or with oxygen plus dox. the reduction of mda levels in the ozonised animals is indicative of the antioxidant effect of ozone therapy; this is of major importance due to the central role of lipid oxidation in dox-induced dcm.24 aopps are closely connected with the degree of monocyte activation and the increase of inflammatory cytokines.25 the generation of aopps is based on the chlorinated oxidation of proteins. in addition, there is evidence that aopps act as inflammatory mediators since they are able to trigger an oxidative burst and the synthesis of cytokines.26 the action of ozonemodulating aopps may explain, at least in part, the control of the dox-induced inflammatory process. dox increases cardiomyocyte susceptibility to os by reducing antioxidants and, therefore, reducing the ability of cardiac cells to inactivate ros.27 in this respect, sod and cat are two enzymes which act to detoxify ros and ameliorate dox toxicity.28 an increase in sod enzymatic activity is usually interpreted as beneficial in the context of the antioxidant system. notwithstanding, it has been documented that a rise in sod activity, without a concomitant rise in the activity of cat and/or glutathione peroxidase (gpx), might be detrimental.29 this is because of the production of h2o2 by sod, which is cytotoxic and has to be scavenged by gpx or cat. hence, a contemporary increment in gpx and/ or cat enzymatic activity is crucial for the globally beneficial effect of increased sod activity. in the present study, the attenuation of dox-induced os and tissue injuries might be attributed to the increase in both myocardial sod and cat activities, as shown by the rate of cat/sod. dox-induced cardiomyopathy has long been a serious side-effect in the treatment of human cancers using this drug as it limits the clinical dosage.30 os is generally held to be the mediating mechanism in the multiple biological processes leading to dox cardiotoxicity.31 consequently, developing a palliative treatment that can attenuate dox cardiotoxicity is of major importance. in this context, ozone therapy, administered prior to dox, may represent a promising approach for correcting os levels and diminishing the toxic side-effects of this anthracycline antibiotic. therapeutic strategies using antioxidants and figure 3 a–c: effects of ozone therapy on doxorubicin (dox)-induced cardiotoxicity at x20 magnification and a scale bar of 50 μm. control rats showed a normal morphology (a), whereas the dox group showed significant tissue injuries (b), with evidence of damaged muscular fibres where the necrosis was present (arrows). conversely, only slight damage was observed in ozone-treated animals with a normal morphology of cardiac fibres (c). livan delgado-roche, yanet hernández-matos, emilio a. medina, dalia á. morejón, maité r. gonzález and gregorio martínez-sánchez clinical and basic research | e347 iron-chelators to protect the heart against dox damage have been used. traditional antioxidants, like n-acetylcysteine or tocopherols, have not been very successful in the prevention of dox-induced cardiotoxicity.32,33 dexrazoxane, an iron chelator that possesses potent antioxidant properties, is currently approved by the food and drug administration (fda) for the prevention of dox cardiotoxicity; however, due to the high incidence of side-effects such as myelosuppression, its use has also been limited to the advanced stages of some malignant disorders.2,34 currently, a body of evidence links the modulation of different biomarkers (e.g. antioxidant enzymes, nitric oxide pathways or 2,3-diphosphoglycerate) when low ozone doses are applied. these facts support many of the current clinical applications of ozone therapy.15,35,36 the biological effect of rectal insufflation of ozone has been demonstrated extensively both experimentally and clinically in many diseases.15 preclinical studies have demonstrated its low toxicity.37 due to the oxidative preconditioning effect of ozone therapy, a cycle of 20 treatments will be enough to sustain the effect for approximately three months, depending on the os status of the patients.15 once the rectal mucosa comes into contact with ozone, there are several reactive intermediaries that act as signaling molecules, including h2o2, aldehydes and other inorganic and organic peroxides.38 these reactive intermediaries have different diffusion rates according to their liposolubility and molecular dimensions. h2o2 is the ros that most easily crosses the cell membranes. this ability makes h2o2 the most probable candidate of the observed effect of ozone treatment. another group of ozone intermediaries that could be related to this are the long-chain aldehydes, such as hexanal, heptanal and nonenal aldehydes.38 the subsequent pathway involving the ozone preconditioning may be likened to the nuclear factor erythroid-2 (nrf2)/ electrophile-responsive element (epre) activation pathway.39 nrf2 is a redox-sensitive transcription factor regulating the expression of a number of cytoprotective genes.40 the effect of ozonised serum in an ex vivo experiment demonstrated a dose effect activation of nrf2 and the subsequent induction of haeme oxygenase 1 and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase in endothelial cell cultures.39 nrf2 is a key protein located within the cells and is activated by an nrf2 activator. once released, it migrates into the cell nucleus and binds to the deoxyribonucleic acid at the location of the epre, which is the master regulator of the entire antioxidant system located in all human cells. however, nrf2 has emerged as an important contributor to chemoresistance in cancer therapy.41 future studies should examine the interaction between the pharmacological effects of dox (the inhibition of tumour growth, reduction of cell proliferation and inductor of apoptosis) and its toxicological effects (cardiotoxicity) in the presence of ozone. conclusion in summary, the results of this study suggest that ozoneop prevents dox-induced dcm through an increase of antioxidant enzymes and a reduction of oxidised macromolecules, avoiding the dox-induced probnp increase. the results of this study require further pharmacological and toxicological investigations. the present work establishes the background for future studies in order to determine the pre-clinical/ clinical efficacy or interaction of ozone in oncological interventions using dox among humans. c o n f l i c t o f i n t e r e s t the authors report no conflicts of interest. a c k n o w l e d g e m e n t s the authors wish to acknowledge the technical assistance of the staff at the clinical laboratory of the centro de investigaciones médico quirúrgicas (cimeq) hospital, havana, cuba. references 1. blum rh, carter sk. adriamycin: a new anti-cancer drug with significant clinical activity. ann intern med 1974; 80:249–59. doi: 10.7326/0003-4819-80-2-249. 2. mukherjee s, banerjee sk, maulik m, dinda ak, talwar kk, maulik sk. protection against acute adriamycin-induced cardiotoxicity by garlic: role of endogenous antioxidants and inhibition of tnf-alpha expression. bmc pharmacol 2003; 3:16. doi: 10.1186/1471-2210-3-16. 3. konorev ea, vanamala s, kalyanaraman b. differences in doxorubicin-induced apoptotic signaling in adult and immature cardiomyocytes. free radic biol med 2008; 45:1723–8. doi: 10.1016/j.freeradbiomed.2008.09.006. 4. lipshultz se, colan sd, gelber rd, perez-atayde ar, sallan se, sanders sp. late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. n engl j med 1991; 324:808–15. doi: 10.1056/nejm199103213241205. 5. schwarz er, pollick c, dow j, patterson m, birnbaum y, kloner ra. a small animal model of non-ischemic cardiomyopathy and its evaluation by transthoracic echocardiography. cardiovasc res 1998; 39:216–23. doi: 10.1016/s0008-6363(98)00009-1. 6. leiper ad. non-endocrine late complications of bone marrow transplantation in childhood: part i. br j haematol 2002; 118:3– 22. doi: 10.1046/j.1365-2141.2002.03470.x. 7. kim ds, woo er, chae sw, ha kc, lee gh, hong st, et al. plantainoside d protects adriamycin-induced apoptosis in h9c2 cardiac muscle cells via the inhibition of ros generation and nf-kappab activation. life sci 2007; 80:314–23. doi: 10.1016/j.lfs.2006.09.019. ozone-oxidative preconditioning prevents doxorubicin-induced cardiotoxicity in sprague-dawley rats e348 | squ medical journal, august 2014, volume 14, issue 3 8. yen hc, oberley td, vichitbandha s, ho ys, st clair dk. the protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. j clin invest 1996; 98:1253–60. doi: 10.1172/jci118909. 9. lebrecht d, setzer b, ketelsen up, haberstroh j, walker ua. time-dependent and tissue-specific accumulation of mtdna and respiratory chain defects in chronic doxorubicin cardiomyopathy. circulation 2003; 108:2423–9. doi: 10.1161/01. cir.0000093196.59829.df. 10. hunt pj, richards am, nicholls mg, yandle tg, doughty rn, espiner ea. immunoreactive amino-terminal pro-brain natriuretic peptide (nt-probnp): a new marker of cardiac impairment. clin endocrinol (oxf ) 1997; 47:287–96. doi: 10.1046/j.1365-2265.1997.2361058.x. 11. ajamieh h, merino n, candelario-jalil e, menéndez s, martinez-sanchez g, re l, et al. similar protective effect of ischaemic and ozone oxidative preconditionings in liver ischaemia/reperfusion injury. pharmacol res 2002; 45:333–9. doi: 10.1006/phrs.2002.0952. 12. martínez-sánchez g, al-dalain sm, menéndez s, re l, giuliani a, candelario-jalil e, et al. therapeutic efficacy of ozone in patients with diabetic foot. eur j pharmacol 2005; 523:151–61. doi: 10.1016/j.ejphar.2005.08.020. 13. re l, martínez-sánchez g, malcangi g, mercanti a, labate v. ozone therapy: a clinical study on the pain management. int j ozone therap 2008; 7:37–44. 14. delgado-roche l, martínez-sánchez g, díaz-batista a, re l. effects of ozone therapy on oxidative stress biomarkers in coronary artery disease patients. int j ozone therap 2011; 10:99–104. 15. martínez-sánchez g, delgado-roche l, díaz-batista a, pérezdavison g, re l. effects of ozone therapy on haemostatic and oxidative stress index in coronary artery disease. eur j pharmacol 2012; 691:156–62. doi: 10.1016/j.ejphar.2012.07.010. 16. bocci va. scientific and medical aspects of ozone therapy: state of the art. arch med res 2006; 37:425–35. doi: 10.1016/j. arcmed.2005.08.006. 17. bocci va, zanardi i, travagli v. ozone acting on human blood yields a hormetic dose-response relationship. j transl med 2011; 9:66. doi:10.1186/1479-5876-9-66. 18. delgado-roche l, martínez-sánchez g, re l. ozone oxidative preconditioning prevents atherosclerosis development in new zealand white rabbits. j cardiovasc pharmacol 2013; 61:160–5. doi: 10.1097/fjc.0b013e31827a820d. 19. delgado roche l, acosta medina e, fraga pérez a, bécquer viart ma, soto lópez y, falcón cama v, et al. lipofundininduced hyperlipidemia promotes oxidative stress and atherosclerotic lesions in new zealand white rabbits. int j vasc med 2012; 2012:898769. doi: 10.1155/2012/898769. 20. bradford mm. a rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. anal biochem 1976; 72:248– 54. doi: 10.1016/0003-2697(76)90527-3. 21. haining jl, legan js. improved assay for catalase based upon steady-state substrate concentration. anal biochem 1972; 45:469–79. doi: 10.1016/0003-2697(72)90209-6. 22. witko-sarsat v, friedlander m, nguyen khoa t, capeillèreblandin c, nguyen at, canteloup s, et al. advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. j immunol 1998; 161:2524–32. 23. esterbauer h, cheeseman kh. determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. methods enzymol 1990; 186:407–21. doi: 10.1016/00766879(90)86134-h. 24. ibrahim ss, barakat ma, helmy hm. role of selenium in attenuating cardiac and hepatic damages induced by the antitumor agent, doxorubicin. life sci j 2011; 8:1–12. 25. witko-sarsat v, nguyen khoa t, jungers p, drüeke t, descamps-latscha b. advanced oxidation protein products: oxidative stress markers and mediators of inflammation in uremia. adv nephrol necker hosp 1998; 28:321–41. 26. martínez-sánchez g, giuliani a, pérez-davison g, leónfernandez os. oxidized proteins and their contribution to redox homeostasis. redox rep 2005; 10:175–85. doi: 10.1179/135100005x57382. 27. nitobe j, yamaguchi s, okuyama m, nozaki n, sata m, miyamoto t, et al. reactive oxygen species regulate flice inhibitory protein (flip) and susceptibility to fas-mediated apoptosis in cardiac myocytes. cardiovasc res 2003; 57:119– 28. doi: 10.1016/s0008-6363(02)00646-6. 28. doroshow jh, locker gy, myers ce. enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. j clin invest 1980; 65:128–35. doi: 10.1172/jci109642. 29. harman d. the aging process: major risk factor for disease and death. proc natl acad sci u s a 1991; 88:5360–3. doi: 10.1073/ pnas.88.12.5360. 30. horan pg, mcmullin mf, mckeown pp. anthracycline cardiotoxicity. eur heart j 2006; 27:1137–8. doi: 10.1093/ eurheartj/ehi702. 31. kotamraju s, chitambar cr, kalivendi sv, joseph j, kalyanaraman b. transferrin receptor-dependent iron uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells: role of oxidant-induced iron signaling in apoptosis. j biol chem 2002; 277:17179–87. doi: 10.1074/jbc.m111604200. 32. myers c, bonow r, palmeri s, jenkins j, corden b, locker g, et al. a randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by n-acetylcysteine. semin oncol 1983; 10:53–5. 33. nagata y, takata j, karube y, matsushima y. effects of a watersoluble prodrug of vitamin e on doxorubicin-induced toxicity in mice. biol pharm bull 1999; 22:698–702. doi: 10.1248/ bpb.22.698. 34. seifert cf, nesser me, thompson df. dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. ann pharmacother 1994; 28:1063–72. doi: 10.1177/10600280 9402800912. 35. re l, mawsouf mn, menéndez s, león os, sánchez gm, hernández f. ozone therapy: clinical and basic evidence of its therapeutic potential. arch med res 2008; 39:17–26. doi: 10.1016/j.arcmed.2007.07.005. 36. steppan j, meaders t, muto m, murphy kj. a metaanalysis of the effectiveness and safety of ozone treatments for herniated lumbar discs. j vasc interv radiol 2010; 21:534–48. doi: 10.1016/j.jvir.2009.12.393. 37. díaz-llera s, gonzález-hernández y, gonzález mesa je, martínez-sánchez g, re l. induction of dna primary damage in peripheral blood leukocytes and exfoliated colorectal epithelial cells in rats treated with ozone. int j ozone therap 2009; 8:217–21. 38. martínez-sánchez g, re l. rectal administration and its application in ozonetherapy. int j ozone therap 2012; 11:41–9. 39. pecorelli a, bocci v, acquaviva a, belmonte g, gardi c, virgili f, et al. nrf2 activation is involved in ozonated human serum upregulation of ho-1 in endothelial cells. toxicol appl pharmacol 2013; 267:30–40. doi: 10.1016/j.taap.2012.12.001. 40. nguyen t, sherratt pj, pickett cb. regulatory mechanisms controlling gene expression mediated by the antioxidant response element. annu rev pharmacol toxicol 2003; 43:233– 60. doi: 10.1196/annals.1323.001. 41. gao am, ke zp, wang jn, yang jy, chen sy, chen h. apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma bel-7402/adm cells to doxorubicin via inhibiting pi3k/akt/ nrf2 pathway. carcinogenesis 2013; 34:1806–14. doi: 10.1093/ carcin/bgt108. clinical & basic research sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 269-274, epub. 9th may 13 submitted 24th aug 12 revision req. 13th oct 12, revision recd. 11th nov 12 accepted 19th dec 12 departments of 1midwifery, 2nursing, 3obstetrics & gynaecology, and 4community medicine, hawler medical university, erbil, kurdistan, iraq *corresponding author e-mail: hamdia76@gmail.com معدل انتشار سلس البول وعوامل اخلطورة احملتملة بني جمموعة من النساء الكرديات حمدية مريخان اأحمد، فيان عفان عثمان، �شهلة كرمي العالف، منري غامن الطويل العمر على اعتمادا البالغات من 15–50% ي�شيب والذي احلو�ض، قاعدة اعتالل مظاهر اأهم من البول �شل�ض يعترب الهدف: امللخ�ص: وعوامل اخلطورة للعينة املدرو�شة. الهدف: ح�شاب معدل انت�شار �شل�ض البول وعوامل اخلطورة املحتملة، درا�شة خوا�ض الن�شاء امل�شابات، من للفرتة العراق كرد�شتان اأربيل، يف المومة م�شت�شفى يف مقطعية درا�شة اإجريت امل�شابات. الطريقة: لدى البول �شل�ض اأنواع وو�شف �شباط اىل اب 2011. �شملت الدرا�شة 1,107 اإمراأة من مرافقات املري�شات الراقدات يف امل�شت�شفى. مت ت�شميم اإ�شتمارة جلمع املعلومات من قبل الباحثني. مت ا�شتخدام فح�ض كاي الح�شائي لدرا�شة العالقة بني �شل�ض البول وعوامل اخلطورة. اإ�شتخدم كذلك فح�ض النحدار اللوج�شتي الثنائي. النتائج: معدل اإنت�شار �شا�ض البول كان %51.7. كان معدل اإنت�شار �شل�ض البول الجهادى، والع�شبى، والنوع املختلط %5.4، %13.3، و %33 على التوايل. كانت هناك عالقة معتدة اإح�شائيا بني �شل�ض البول واإنقطاع الطمث، زيادة عدد الأطفال، داء ال�شكر، ال�شعال املزمن، الإم�شاك، وتاريخ اإجراء عمليات ن�شائية. بينما كانت هناك عالقة عك�شية )�شالبة( بني �شل�ض البول وتاريخ الولدة ب�شكل طبيعي اأو بالعملية القي�رسية. اخلال�صه: كان معدل اإنت�شار �شل�ض البول مرتفعا يف العينة املدرو�شة، وكانت عوامل اخلطورة املحتملة هي تعدد الولدات، اإنقطاع الطمث، الإم�شاك، ال�شعال املزمن، وداء ال�شكري. مفتاح الكلمات: معدل النت�شار؛ الن�شاء؛ عوامل اخلطورة؛ اإنقطاع الطمث؛ نوعية احلياة؛ �شل�ض البول؛ العراق. abstract: objectives: the most common manifestation of pelvic floor dysfunction is urinary incontinence (ui) which affects 15–50% of adult women depending on the age and risk factors of the population studied. the aim of this study was to determine the probable risk factors associated with ui; the characteristics of women with ui; describe the types of ui, and determine its prevalence. methods: a cross-sectional study was conducted between february and august 2011, in the maternity teaching hospital of the erbil governorate, kurdistan region, northern iraq. it included 1,107 women who were accompanying patients admitted to the hospital. a questionnaire designed by the researchers was used for data collection. a chi-square test was used to test the significance of the association between ui and different risk factors. binary logistic regression was used, considering ui as the dependent variable. results: the overall prevalence of ui was 51.7%. the prevalence of stress, urgency, and mixed ui was 5.4%, 13.3% and 33%, respectively. there was a significant positive association between ui and menopause, multiparity, diabetes mellitus (dm), chronic cough, constipation, and a history of gynaecological surgery, while a significant negative association was detected between ui and a history of delivery by both vaginal delivery and caesarean section. conclusion: a high prevalence of ui was detected in the studied sample, and the most probable risk factors were multiparity, menopausal status, constipation, chronic cough, and dm. keywords: prevalence; women; risk factors; menopause; quality of life; urinary incontinence; iraq. prevalence of urinary incontinence and probable risk factors in a sample of kurdish women *hamdia m. ahmed,1 vian a. osman,2 shahla k. al-alaf,3 namir g. al-tawil4 advances in knowledge this study provides information for the first time on the prevalence of all types of urinary incontinence (ui) in a sample of the kurdish population of northern iraq. knowing probable risk factors of ui may help in counselling people regarding changing their lifestyles and improving conditions so that ui can be avoided. applications to patient care this study provides information to healthcare providers on the risk factors for ui in order to help screen high-risk populations. physicians and nurses should screen for ui during gynaecological examinations by directly questioning patients about symptoms of involuntary urine loss. prevalence of urinary incontinence and probable risk factors in a sample of kurdish women 270 | squ medical journal, may 2013, volume 13, issue 2 the most common manifestation of pelvic floor dysfunction is urinary incontinence (ui). incontinence can have a significant impact on women’s health, leading to physical problems such as skin breakdown, infection, and rashes. psychosocial consequences include embarrassment, isolation and withdrawal, and feelings of worthlessness, helplessness, and depression.1–3 through epidemiological studies, the international continence society (ics) has developed a new definition of ui and its types. ui is defined as a complaint of involuntary loss of urine. stress urinary incontinence (sui) is defined as a complaint of involuntary loss of urine on effort or physical exertion. urgency urinary incontinence (uui) is defined as a complaint of involuntary loss of urine associated with urgency. mixed urinary incontinence (mui) is defined as a complaint of involuntary loss of urine associated with both urgency and physical exertion.4 urinary incontinence is a medical condition affecting 15–50% of adult women depending on the age and risk factors of the population studied. it is considered one of the top 10 sources of expenditure for treatment of illness.5 approximately 50% of persons residing in nursing homes are incontinent and it is the tenth leading cause of hospitalisation.6 although half of all elderly people experience episodes of incontinence, it is also a problem that affects younger women.7 even though information concerning its prevalence and incidence in the population as a whole remains uncertain, clinical attention is increasingly focused on ui and its treatment.8 the lack of adequate epidemiological data on the prevalence of female ui in the kurdish population of erbil led us to conduct a cross-sectional study on a sample of women attending the maternity teaching hospital in erbil, iraq. the aim of the present study was to determine the prevalence and characteristics of women with ui, to describe types of ui, and to find probable risk factors associated with ui. methods a cross-sectional study was conducted between 10th february and 10th august 2011 in the erbil maternity teaching hospital in the kurdistan region of northern iraq. the erbil maternity teaching hospital is the only governmental maternity hospital in erbil and so receives obstetrical and gynaecological cases from all over the erbil governorate. erbil is the capital of the iraqi kurdistan region with a population approaching two million. the study was approved by the erbil directorate of health and the scientific and ethical committees of the nursing college. included in the study were women accompanying patients admitted to the hospital. the purpose of the study was explained to each woman during personal interviews, and informed verbal consent was obtained from all participants. participants were excluded if they were pregnant or had urinary system problems. data were collected via an english-language questionnaire which was designed by the researchers after reviewing published literature and consultating with experts. the questionnaire was translated into the kurdish language and then reverse translated by an independent party to ensure accuracy. a pilot study was prepared by testing the final questionnaire, on 20 women attending the erbil maternity teaching hospital, to ensure a correct translation and easy understandability for ordinary women and to explore any unclear points. the questionnaire was completed during personal interviews with the women. data collection was performed by three kurdish-speaking nurses who were working in inpatient wards. the nurses were trained regarding how to administer the questionnaire by one of the investigators. the questionnaire was designed to investigate the following: women's demographic characteristics; medical and obstetric history; maternal age; marital status; place of residence; parity and mode of previous deliveries (i.e. vaginal or caesarean delivery); previous deliveries of macrosomic babies; previous abdominal surgery; presence of chronic diseases, including diabetes mellitus (dm); chronic cough or constipation; smoking, and menopausal state. the types of ui were diagnosed by asking about the frequency of micturition during the day, the presence of nocturia or a sudden desire to urinate which could not be deferred, and the leakage of urine on coughing or sneezing. the sample size was estimated using the epi info 6 statistical software, version 6.04 (centers hamdia m. ahmed, vian a. osman, shahla k. al-alaf and namir g. al-tawil clinical and basic research | 271 for disease control, atlanta, georgia, usa, and the world health organization, geneva, switzerland). the following data were entered into the programme: the estimated number of admitted women during the 6-month study period was 21,708. the estimated prevalence of ui was 30% based on the average prevalence of some studies.2,5 the absolute precision was set at 2.5% (above and below the 30%) with a 95% confidence level. accordingly, the estimated sample size was 1,218 women. a total of 1,107 women who were accompanying patients admitted to different departments of the same hospital were willing to participate in the study, so the non-response rate was 9.1%. data were analysed using the statistical package for social sciences (spss), version 18 (ibm, inc., chicago, illinois, usa). a chi-squared test of association was used to test the significance of the association between ui and different factors. binary logistic regression was used considering the ui as the dependent variable. a p value of ≤0.05 was considered statistically significant. results the mean age (± standard deviation [sd]) of participating women was 50.59 ± 6.77 years, ranging from 28 to 85 years. all of the women were married. the overall prevalence of ui was 51.7%. the prevalence of sui, uui, and mui was 10.5%, 25.7% and 63.8%, respectively. the prevalence among those living outside the city (66.2%) was significantly higher than the prevalence among those living in the city (48%) (p <0.001). also, the prevalence was higher among smokers (69.4%) as compared with the prevalence among non-smokers (48.7%) (p <0.001). table 1 shows a highly significant association between certain age groups and ui prevalence. a high prevalence of ui (95.3%) was found among those aged less than 45 years. the prevalence rates of ui among age groups 50–54 (68.9%), 55–59 (76.4%), and ≥60 (65.9%) were high. however, no consistent pattern of ui prevalence could be detected in different age groups. table 2 shows a highly significant association between age groups and types of ui. the highest proportion of usi (29.3%) was in those aged 45 years or less. the overall proportion of uui was 25.7%, while it was present in 33.3% in 45–49 year olds. the same table shows that 70.4% of those aged ≥ 60 years complained of mui. results of the study showed a highly significant association between ui and menopause; parity (≥5); vaginal delivery; a history of giving birth to neonates weighing ≥4 kg; or a history of dm, chronic cough, constipation, or pelvic surgery [table 3]. table 4 shows that there was significant positive association between ui and many factors like menopause (odds ratio [or] = 1.9); parity (or = 2.5); dm (or = 4.2); chronic cough (or = 4.02); constipation (or = 2.1), and a history of gynaecological surgery (or = 2.9), while a significant negative association was detected between ui and a history of either vaginal or caesarean delivery (or = 0.11). discussion the prevalence of ui ranges from 3–55% depending on the definition of incontinence and the age of the population studied.2 the results of the present study showed that 51.7% of the sample had ui, which is table 1: association between urinary incontinence and age age group (years) n ui n (%) p value <45 43 41 (95.3) <0.001 45–49 573 183 (31.9) <0.001 50–54 190 131 (68.9) <0.001 55–59 178 136 (76.4) <0.001 ≥60 123 81 (65.9) <0.001 total 1,107 572 (51.7) ui = urinary incontinence. table 2: association between types of urinary incontinence and age age group (in years) n types of urinary incontinence p value sui n (%) uui n (%) mui n (%) <45 41 12 (29.3) 1 (2.4) 28 (68.3) <0.001 45–49 183 19 (10.4) 61 (33.3) 103 (56.3) <0.001 50–54 131 13 (9.9) 34 (26.0) 84 (64.1) <0.001 55–59 136 13 (9.9) 30 (22.1) 93 (68.4) <0.001 ≥60 81 3 (3.7) 21 (25.9) 57 (70.4) <0.001 total 572 60 (10.5) 147 (25.7) 365 (63.8) sui = stress urinary incontinence; uui = urgency urinary incontinence; mui = mixed urinary incontinence. prevalence of urinary incontinence and probable risk factors in a sample of kurdish women 272 | squ medical journal, may 2013, volume 13, issue 2 much higher than the neighbouring countries of turkey and iran. in a study done by kocak et al. in turkey on 242 women, the overall prevalence of ui was 23.9%.9 in another study conducted in iran on 411 married women, the overall prevalence of ui was 18.9%.10 the high prevalence of ui in the present study could be due to the high number of vaginal deliveries in the kurdistan region which is responsible for pelvic floor dysfunction. also, ui health education is limited in our locality. regarding nutrition, which is responsible for the development of dm and overweight, both are strong risk factors for ui and could have been the cause of the high prevalence of ui in our sample. in a study conducted by al-bader et al. on 379 saudi women with a mean age of 35 years, the overall prevalence of ui was 41.4%.11 in another study done in egypt on 1,652 women, the overall prevalence of ui was 54.8%, which is consistent with the present study.12 in a study conducted by katz et al. on 851 women aged 18 years and older who were selected randomly in australia, 267 women (31.3%) stated that they had noted some degree of incontinence during the preceding 12 months, and 142 (16.6%) suffered two or more regular episodes of leakage per month. daily incontinence was reported by 5%, and 2.3% were incontinent often or continuously.13 kim et al. conducted a study on 276 women in south korea and found that the prevalence of ui by type was 12.8% (uui), 38.5% (sui), and 48.7% (mui). these rates were higher than those in the present study.14 the prevalence of the types of ui in a study conducted in the turkey was 25.6% (uui), 33.1% (sui), and 41.3% (mui), which was more or less consistent with the results of the present study.9 the prevalence of different types of ui in a study conducted in iran was 4.1% (uui), 18.7% (sui) and 4.1% (mui); the prevalence of sui was higher than that in the results of the present study, where we found a 10.5% incidence of sui, while the incidence of uui, and mui was much lower.10 studies in western countries have revealed that uui is the most common type of ui in the elderly, occurring in 40–70% of those who present to physicians with table 3: prevalence of urinary incontinence by obstetrical history variables n ui n (%) p value menopausal status yes no 455 652 315 (69.2) 257 (39.4) <0.001 parity ≤4 ≥5 331 776 96 (29) 476 (61.3) <0.001 mode of delivery vaginal caesarean section both 949 127 30 516 (54.4) 50 (39.4) 5 (16.7) <0.001 delivery of baby ≥4 kg yes no 319 788 225 (70.5) 347 (44) <0.001 diabetes yes no 125 981 104 (83.2) 467 (47.6) <0.001 chronic cough yes no 131 973 108 (82.4) 462 (47.5) <0.001 constipation yes no 250 855 181 (72.4) 390 (45.6) <0.001 previous pelvic surgery yes no 218 844 166 (76.1) 406 (45.7) <0.001 ui = urinary incontinence. table 4: output of binary logistic regression showing the association between urinary incontinence as a dependent variable, and some other independent variables factor b p or 95% ci of or lower upper residence 0.352 0.065 1.422 0.979 2.066 smoking -0.042 0.857 0.959 0.609 1.510 menopause 0.753 <0.001 2.124 1.421 3.174 grand multiparity 0.882 <0.001 2.415 1.667 3.498 mode of delivery cesarean section (reference) vaginal delivery history of both types 0.442 -2.201 0.100 <0.001 1.556 0.111 0.919 0.033 2.632 0.374 delivery of baby ≥4 kg 1.514 <0.001 4.543 3.109 6.638 diabetes 1.347 <0.001 3.845 2.198 6.727 chronic cough 1.457 <0.001 4.293 2.479 7.434 constipation 0.740 <0.001 2.095 1.458 3.010 history of pelvic operation 1.154 <0.001 3.172 2.129 4.726 age (years) -0.016 0.264 0.984 0.956 1.012 constant -1.462 0.047 0.232 b = regression coefficient; p = p value; or = odds ratio; ci = confidence interval. hamdia m. ahmed, vian a. osman, shahla k. al-alaf and namir g. al-tawil clinical and basic research | 273 complaints of incontinence.15 brown et al.’s study of the prevalence of ui among 2,763 postmenopausal women found the prevalence of ui as follows: 14.4% (uui), 12.8% (sui), and 12.3% (mui); the mean age in their study was 66.7 years.16 in the present study, the percentage of ui among those in the <45 years age group was high. this research is the first conducted in our locality related to ui in those of kurdish ethnicity. this is significant as race/ethnicity differences exist in selfreported incontinence.17,18 however, it is unknown how ethnic differences affect ui prevalence in young women. further research should be conducted in a larger sample size of young kurdish females to correlate the risk factors, as the sample size in this study (n = 43) was too small for this purpose. bunyavejchevin found a significant association between ui and chronic cough and constipation in the study on 360 postmenopausal thai women, which is consistent with the result of the present study.19 tseng et al., in their study on 4,470 taiwanese women, found a significant association between ui and multiparity, and no association with age, which was also consistent with the result of the present study.20 in the current study, there was a significant association between ui and dm, chronic cough, and constipation which is consistent with the results of other studies.11 sui is triggered by physical exertion, including coughing, sneezing, straining, or exercise. in women, a weakness in the pelvic floor muscles, due to vaginal childbirth, may cause a defect in the support of the internal sphincter, ultimately leading to sui. multiparous women are prone to cystocele and urethrocele, which are also linked to sui. a patient with dm has a 30–70% increased risk of developing uui or mui. advanced age can also contribute to uui.8,11,12 different studies have found a significant relationship between a history of pelvic surgery and ui, which is consistent with the result of the current study.9–11 the limitations of the present study were as follows: there was no validated instrument to detect prevalence rates of ui in kurdish women, the prevalence of ui was not studied in one specific age group, and ui was not studied in relation to obesity. further studies should be conducted to test these important correlations. conclusion a high prevalence of ui was detected in a selected sample of kurdish women in the maternity teaching hospital in erbil, iraq. associated risk factors were found to be the delivery of a baby ≥4 kg, chronic cough, dm, a history of a pelvic operation, multiparity, menopausal status, and constipation. a history of both types of delivery had no protective effect against ui. references 1. lemone p, burke k. medical-surgical nursing, 3rd ed. new jersey: pearson education 2004. pp. 733–5. 2. holroyd-ledue jm, straus se. management of urinary incontinence in women. jama 2004; 297: 986–95. 3. abreu ns, baracho es, tirado mga, dias rc. quality of life from the perspective of elderly women with urinary incontinence. rev bras fisioter, são carlos, 2007; 11:429–36. 4. haylen bt, de ridder d, freeman rm, swift se, berghmans b, lee j, et al. an international urogynecological association (iuga)/international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. int urogynecol j pelvic floor dysfunct 2010; 21:5–26. 5. scott jr, gibbs rs, karlan by, haney af. danforth's obstetrics and gynecology, 9th ed. philadelphia: lippincott williams & wilkins, 2003. pp. 845–50. 6. krauss na, altman bm. us department of health and human services. characteristics of nursing home residents. from: http://meps.ahrq.gov/ mepsweb/data_files/publications/rf5/rf5.shtml accessed: jul 2012. 7. littleton l, engebretson j. maternal, neonatal and women's health nursing. albany ny: delmar, thomson learning, inc., 2002. p. 245. 8. smith da. urinary incontinence: epidemiology, demographics and costs. director 2003; 11:115–9. 9. kocak i, okyay p, dundar m, erol h, beser e. female urinary incontinence in the west of turkey: prevalence, risk factors, and impact on quality of life. eur urol 2005; 48:634–41. 10. nojomi m, amin eb, rad rb. urinary incontinence: hospital-based prevalence and risk factors. jrms 2008; 13:22–8. 11. al-badr a, brasha h, al-raddadi r, noorwali f, ross s. prevalence of urinary incontinence among saudi women. int j gyecol obstet 2012; 117:160–3. 12. ei-azab as, mohamed em, sabra hi. the prevalence and risk factors of urinary incontinence and its influence on the quality of life among egyptian women. neurourol urodyn 2007; 26:783–8. prevalence of urinary incontinence and probable risk factors in a sample of kurdish women 274 | squ medical journal, may 2013, volume 13, issue 2 13. katz vl, lobo ra, lentz gm, gershenson dm. comprehensive gynecology, 5th ed. philadelphia: mosby, 2007. 14. kim js, lee eh, park hc. urinary incontinence: prevalence and knowledge among communitydwelling korean women aged 55 and over. j korean acad nurs 2004; 34:609–16. 15. merkelj i. urinary incontinence in the elderly. south med j 2001; 94:952–7. 16. brown js, grady d, ouslander jg, herzog ar, varner re, posner sf. prevalence of urinary incontinence and associated risk factors in postmenopausal women. obstet gynecol 1996; 87:715–21. 17. thom dh, eeden sk, ragins ai, wassel-fyr c, vittinghof e, subak ll, et al. differences in prevalence of urinary incontinence by race/ethnicity. j urol 2006; 175:259–64. 18. dooley y, kenton k, cao g, luke a, durazo-arvizu r, kramer h, et al. urinary incontinence prevalence: results from the national health and nutrition examination survey. j urol 2008; 179:656–61. 19. bunyavejchevin s. risk factors of female urinary incontinence and overactive bladder in thai postmenopausal women. j med assoc thai 2005; 88:s119–23. 20. tseng lh, liang cc, lo hp, lo ts, lee sj, wang ac. the prevalence of urinary incontinence and associated risk factors in taiwanese women with lower urinary tract symptoms. chang gung med j 2006; 29:596–601. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 306-314, epub. 15th jul 12 submitted 14th nov 11 revision req. 29th feb 12, revision recd. 10th apr 12 accepted 25th apr 12 departments of 1biochemistry and 2pharmacology, and 3research division, gulf medical university, ajman, united arab emirates. *corresponding author e-mail: nelofer99@hotmail.com معرفة طالب جامعة عجمان يف دولة اإلمارات العربية املتحدة مبرض السكري نيلوفر خان ، كاظيام غوماثي ، �سيد اليا�ض �سهناز ، جياكوماري متابياليميالل امللخ�ص: تهدف هذه الدرا�سة اإىل تقييم مدى معرفة وممار�سات طالب جامعة عجمان )يف الإمارت العربية املتحدة( يف الكليات التي ل تقع �سمن جمال العلوم الطبية حول داء ال�سكري.الطريقة: مت توزيع ا�ستبيان جُمّرب �سابقا حول مدى املعرفة بداء ال�سكري بني الطالب املذكورين اأعاله، ومت حتليل املعطيات بوا�سطة برنامج )pasw( )�سيكاغو، اللينوي، الوليات املتحدة الأمريكية، اإ�سدار 18(. النتائج: %27 ومار�ض بدانة، اأو وزن زيادة امل�ساركني من %25 لدى وكان طالبة(، 121 و طالبا 47( جامعيا طالبا 168 الدرا�سة �سملت بارتفاع يتميز ال�سكري داء باأن علم على امل�ساركني من %70 كان ال�سكري، بداء مبعرفتهم يتعلق وفيما بانتظام. الريا�سة منهم بقليل امل�ساركني ن�سف من اأكرث باأن للده�سة املثري العائلة. يف املر�ض تاريخ هو الرئي�سي الخت�سار عامل واأن بالدم، ال�سكر م�ستوى ي�ستطيعون ربط ال�سمنة املفرطة وقلة الن�ساط البدين كعوامل اإختطار توؤدي اإىل داء ال�سكري، اأو اأن يدركوا اأن ال�سعور املفرط بالعط�ض وكرثة التبول وفقدان الوزن هي من اأعرا�ض املر�ض. مدى معرفتهم مب�ساعفات داء ال�سكري كالغرغرينا وفقدان الإح�سا�ض بالأطراف وم�ساعفات الفم والأ�سنان واللتهابات املتكررة واحتمالية الإ�سابة باأمرا�ض القلب كانت متو�سطة. وكانت معرفة الطالبات باملر�ض اأعلى مقارنة بالطالب. مل يالحظ وجود اختالفات كبرية يف ال�سلوك ال�سحي للم�ساركني مع اأو بدون تاريخ عائلي بداء ال�سكري. اخلال�صة: ك�سفت درا�ستنا اأنه بالرغم من التعر�ض مل�سادر املعلومات املختلفة، اإل اأن م�ستوى معرفة امل�ساركني بداء ال�سكري مل تكن كافية . لذلك نو�سي باإ�رساك املهنيني يف املجال ال�سحي يف جمال التعليم من اأجل تعزيز املعلومات املتعلقة بال�سحة وجعلها جزء من منط احلياة ال�سحية للطالب . مفتاح الكلمات: مر�ض ال�سكري، املعرفة، اأ�سلوب احلياة، ال�سباب البالغني، الإمارات العربية املتحدة. abstract: objectives: the aim of this study was to assess diabetes mellitus (dm)-related knowledge and practices among university students enrolled in non-health care related professional courses in the united arab emirates. methods: a pre-tested questionnaire assessing the knowledge of dm was administered to the above-mentioned students. data collected were transferred to pasw statistics (chicago, il, usa, version 18) and analysed. results: data on 168 university students (47 males and 121 females) were included in the analysis. of the participants, 25% were overweight or obese and only 27% exercised regularly. regarding their knowledge of dm, 70% knew that it is characterised by high blood sugar levels and identified family history as a major risk factor. surprisingly, only just over half could link obesity and physical inactivity as risk factors for developing dm, or could identify an excessive feeling of thirst, frequent urination, and weight loss as symptoms. knowledge of the complications of diabetes, including gangrene, loss of sensation in limbs, oral and dental complications, recurrent infections, and risk for cardiovascular disease got a moderate response. knowledge of diabetes was found to be higher in females compared to males. no significant differences were observed in the health behaviour of participants with or without a family history of dm. conclusion: our study revealed that in spite of exposure to various sources of information, the participants’ level of dm-related knowledge was not adequate. we recommend the engagement of health professionals in educational settings in order to enhance health-related knowledge and inculcate healthy lifestyle practices in students. keywords: diabetes mellitus; knowledge; lifestyle; young adult; united arab emirates. diabetes mellitus-related knowledge among university students in ajman, united arab emirates *nelofer khan,1 kadayam g gomathi,1 syed ilyas shehnaz,2 jayakumary muttappallymyalil3 clinical & basic research advances in knowledge the results of our study, though preliminary, reveal the following : knowledge related to diabetes mellitus (dm) in the educated young adult population residing in the united arab emirates is limited. gaps identified in young peoples’ knowledge of dm provide directions for future research as well as for the planning of appropriate interventional measures. nelofer khan, kadayam g gomathi, syed ilyas shehnaz and jayakumary muttappallymyalil clinical and basic research | 307 research indicates that diabetes mellitus (dm) has become an epidemic in many parts of the world.1 it is an increasing public health concern and among the leading causes of death and disability.2 type 2 dm (t2d) is now increasingly diagnosed among adolescents and younger adults, but it is a potentially preventable disease if its risk factors are identified early and avoided.3,4 hence, it is crucial that young people be well-informed about the risk factors for the development of dm, as well as preventive measures. the known major risk factors for the development of t2d include obesity, a family history of the disease, and a sedentary lifestyle.5 family history is a major non-modifiable risk factor that is closely linked to the expression of dm. not only does it represent an inherited genetic susceptibility, but also represents shared environmental factors that include cultural values and practices, such as food choices and exercise habits.6 overweight and obese adults are at an increased risk for a wide range of chronic diseases including dm, cardiovascular diseases (cvds), hypertension, dyslipidaemia, gall bladder disease, and cancer.7 long-term treatment and prevention of obesity in adults includes healthy diet and exercise. behavioural interventions designed to facilitate maintenance of these lifestyle changes throughout a person’s life play a very important role in the control of obesity.8,9 among the adult population, leisure time physical activity is a critical factor in the prevention and control of dm, and has been associated with lower rates of t2d.10,11 knowledge forms a basis for the adoption of good health-related practices. schools and colleges are some of the best places to implement programmes which will increase knowledge and awareness about lifestyle-related diseases, healthy nutrition, and the importance of physical activity. several studies have been conducted among medical students to assess their clinical knowledge of dm.12 studies have also been conducted among the general population to assess their knowledge of dm.13 however, to the best of our knowledge, no study has specifically targeted the young adult population. the objectives of this study were, first, to evaluate knowledge and practice among university students regarding dm, and, second, to assess differences in knowledge and practice regarding dm with respect to gender and family history of dm. the results of this study, by identifying areas of knowledge deficiency, will assist in developing health education programmes for young adults. methods a cross-sectional survey using a pre-tested, self-administered, structured questionnaire was conducted in march 2011. the questionnaire was administered to students enrolled in non-health care related professional courses in a university in ajman, uae. students who were willing to complete the questionnaire were selected by the “convenience sampling” method. explanations were given about the objectives of the study and how to complete the questionnaire. ethical approval was obtained from the ethics and research committee of the authors’ institution. written permission was also obtained from the officials of the university to conduct this study on their students. participation was anonymous and voluntary, and verbal consent was acquired from each participant. all the study participants were assured full confidentiality of the data collected. a structured questionnaire with closedended questions was developed after an extensive literature search and based on the studies of aljoudi et al., mohieldein et al., and wee et al.13–15 the validity of the questionnaire’s content was tested through a review process with professors in the subject, and a socio-psychologist. the statements in the questionnaire were assessed by the panel to ensure that they covered the study’s objectives. the questionnaire was pre-tested on a group of 10 university students to identify any problems application to patient care early adulthood is a time when lifestyle behaviours and practices are adopted. assessment of dm-related knowledge and lifestyle practices can help to identify gaps in knowledge and therefore areas for future interventions. the adoption of healthy lifestyle practices by young adults can help to reduce the burden of non-communicable diseases, including dm, on society. diabetes mellitus-related knowledge among university students in ajman, uae 308 | squ medical journal, august 2012, volume 12, issue 3 related to question design, flow, or interpretation. following the pilot study, identified inconsistencies and inaccuracies were corrected. the data obtained during the pilot study were excluded from the analysis. the participants were required to answer the questionnaire using ‘yes’, ‘no’, or ‘unsure’. the questionnaire was divided into the following seven sections: 1) socio-demographic characteristics— including age, sex, height, weight, and education; 2) students’ medical history—including a personal and family history of dm, hypertension, hypercholesterolaemia, and heart attack; 3) knowledge of dm—including risk factors, symptoms, and complications; 4) health behaviours and practices of participants; 5) perceived beneficial behavioural changes—participants were asked to select those which they thought would prevent dm; 6) perceptions of non-diabetic participants about diabetes with statements like “if i am going to get diabetes, there is not much i can do about it.”; “people who make a good effort to control the risks of developing diabetes were much less likely to develop diabetes.”; “if i don’t change my life style behaviors, such as diet or exercise, i am at risk of developing diabetes over the next 10 years.”, and 7) participants were asked to select all sources from which they obtained their information. data were analysed using the statistical package for the social sciences (spss, chicago, illinois, usa, version 19). participants with dm were excluded from the analysis. categorical variables were described by frequency analysis. the chisquare test of significance was used to assess the association between gender and knowledge and practices. also, descriptive statistics were compared between those with and without a family history of dm. comparisons were considered to be statistically significant at p ≤0.05. as we anticipated a study sample involving a narrow range of ages, we did not sub-analyse our data with respect to age. from participants’ self-reported height and weight, body mass index (bmi) was calculated. a respondent with a bmi of 25 to 29.9 was regarded as overweight and one with a bmi ≥30 was considered obese.16 gh: have very good health hcu: had a health checkup in last 12 months bs: had blood sugar tested o/o: overweight or obese ht: hypertensive hc: high cholesterol level ha: heart attack 0 10 20 30 40 50 60 37% gh hcu bs o/o ht hc dm ht ha 33% 39% 25% 12% 9% 51% 41% 37% personal history f amily h is tory figure 1: medical history of participants. nelofer khan, kadayam g gomathi, syed ilyas shehnaz and jayakumary muttappallymyalil clinical and basic research | 309 results a total of 182 students returned completed questionnaires. pre-existing dm was found in 7.7% of the participants. to make this study more meaningful, they were excluded from the study and analysis was done on the remaining 168 participants. among the study sample, 121 were females and 47 were males of various ethnic groups. the majority of the participants was between 18 and 24 years of age and had been living in the uae for more than 10 years, indicating that they had received their secondary schooling in the uae. the data regarding the medical history of participants are shown in figure 1. surprisingly, major health-related issues like overweight and obesity (25%), hypertension (12%), and hypercholesterolaemia (9%) were self-reported by these young adults. a very high prevalence of family histories of dm (51%), hypertension (41%), and heart attack (33%) was also reported. table 1 shows participants’ general knowledge of dm, including its risk factors, symptoms and complications. of the total, 65% felt that dm was curable. although 74% thought that the development of dm can be prevented or delayed, only 44% knew that the risk increases as people age. an excessive feeling of thirst, frequent urination, and weight loss were identified as symptoms by almost half of the participants. knowledge of diabetic complications, including loss of sensation in limbs, oral and dental complications, recurrent infections, and an increased risk of cvd also got a moderate positive response. when compared to males, females had better general knowledge of dm and its complications; however, there was no significant difference table 1: general knowledge of diabetes mellitus (dm), risk factors, symptoms and complications, in which participants were asked to select either “yes”, “no”, or “unsure” as a response. general knowledge of dm percentage of correct responses diabetes is a condition of high blood sugar 70 diabetes is a condition of inadequate insulin action * 54 diabetes is non-contagious * 67 diabetes is curable 65 insulin is required for some diabetic patients 79 diabetes is a disease affecting the pancreas * 46 there are several types of diabetes * # 57 can diabetes be prevented/delayed? * 74 diabetes is a long-term disease 72 diabetes is related to lifestyle 67 knowledge of risk factors for dm family history # 71 obesity 55 decreased physical activity # 53 age above 40 years old # 44 pregnancy (delivering a baby of more than 4 kg) 23 race/ethnicity 19 excessive consumption of sugar 57 knowledge of symptoms of diabetes excess feeling of thirst 56 excess urination 58 unexplained weight loss # 49 excessive eating 36 blurred vision 39 slow healing of cuts and wounds 59 tiredness and weakness 69 burning feet 39 joint stiffness/pain 52 knowledge of complications of diabetes eye problems 54 kidney problems * 57 pain in joints 55 loss of sensation in arms and legs * 48 gangrene in limbs requiring surgical removal * 29 cardiovascular disease 40 oral and dental complications 37 recurrent infection * 29 psychological problems 28 high blood cholesterol/lipids 56 erectile dysfunction/loss of libido* 28 *significant difference seen between genders (p = ≤0.05) #significant difference between participants with and without a family history of diabetes (p = ≤0.05) diabetes mellitus-related knowledge among university students in ajman, uae 310 | squ medical journal, august 2012, volume 12, issue 3 between the sexes in terms of the knowledge of risk factors or symptoms. not surprisingly, participants with a family history of dm had significantly higher knowledge of the risk factors for dm. the health behaviour and practices of participants are illustrated in figure 2. though the dietary habits were good, very low levels of physical activity were reported among these young adults. in spite of a campaign to discourage smoking in the uae, approximately 11% of the subjects were smokers. there was no significant association between health behaviours and practices with regards to gender or a family history of dm. males reported exercising more regularly than females. compared to males, a significantly higher number of the female participants had correct perceptions of behavioural changes likely to prevent dm such as increased physical exercise, increased consumption of vegetables and fruits, and avoiding too many sweet foods in the diet [figure 3]. there was no significant association between students having a family history of diabetes and their perception of beneficial behavioural changes. the non-diabetic participants were divided in their viewpoints about preventive care, with half of them feeling that if they were going to develop dm, then there was not much they could do about it, and the other half perceiving that people who make a good effort to control the risks of developing dm were much less likely to develop the disease. half of these non-diabetic participants agreed with the statement “if i don’t change my life style behaviours, such as diet or exercise, i am at a risk of developing diabetes over the next 10 years”, and so were planning to make changes in their life style behaviours in the near future. these changes, they believed, would lower their chances of developing dm. students were using, to varying extents, many different sources of information to gain knowledge regarding dm. the majority of the participants got their information from friends and relatives (75%), television and the internet (70%), newspapers, books and magazines (64%). health professionals and their talks and seminars (50%) were the least identified sources of information. the majority of participants (75%) thought that more information was needed and considered media to be the best mode to convey the information to the public. discussion the prevalence of t2d is increasing, even in younger age groups, including teenagers and children.3,17 27% 60% 74% 69% 11% 0% 10% 20% 30% 40% 50% 60% 70% 80% *exercise regularly (150 min/week) trying to reduce/ maintain weight diet includes vegetables diet includes fruits use tobacco note: * more men exercised regularly (p 0 05) no significant difference was seen when compared between participants with or without family history of diabetes figure 2: health behaviour of participants. nelofer khan, kadayam g gomathi, syed ilyas shehnaz and jayakumary muttappallymyalil clinical and basic research | 311 by changing diet, increasing physical activity, and improving lifestyle, 80% of t2d cases can be prevented.17 however, without effective prevention and control programmes, the incidence of t2d will continue to escalate globally. the world health organization (who) estimates that, globally, deaths caused by dm and other non-communicable diseases will increase by 17% over the next decade.18 measures need to be taken to prevent dm from developing in communities; this will be possible only by increasing the general public’s awareness of dm. the present study was therefore conducted to estimate dm-related knowledge among university students. this will help in identifying the gaps in their knowledge and practices, which can then be addressed in prevention programmes which target schools, colleges, and universities. in spite of the high prevalence of a family history (51%) among the study’s participants, their level of knowledge regarding dm cannot be considered sufficient, especially since the study involved an educated population. also disturbing is the fact that 30% of the participants did not know that dm is a disease of high blood sugar levels or that family history is a risk factor. almost half of the participants did not know that obesity and decreased physical activity were the major modifiable risk factors for the development of the disease. this level of knowledge is much lower than that reported in the saudi non-diabetic, mixed educational level population, where 62.3% had this knowledge.14 in another study from singapore, 67.7% had positively identified obesity and physical inactivity as risk factors.15 studies conducted in the usa also reported low levels of general knowledge of dm among african-americans and hispanic adults, with only a quarter of them identifying obesity and physical inactivity as risk factors.19,20 more than half of the participants felt that dm is curable, with the same misconception reported in other studies as well.14,15 however, we think that this may not be a misconception but rather a confusion between the terms “treatable” and “curable”. sedentary lifestyle and obesity are the most 79 % 63 % 65 % 69 % 75% 72 % 80 % 55 % 63 % 48 % 0% 10% 20 % 30 % 40 % 50% 60 % 70 % 80 % 90 % *increase physical exercise *reduce weight *quit tobacco *quit alcohol *increase vegetable intake *increase fruit intake *avoid too much sweet food reduce carbohydrate rich diet eat low fat food *reduce total calorie intake )*identified by higher number of women than men (p 0 .05 no significant difference was seen when compared between participants with or without family history of diabetes note: figure 3: perceived beneficial behavioural changes. diabetes mellitus-related knowledge among university students in ajman, uae 312 | squ medical journal, august 2012, volume 12, issue 3 important modifiable contributors to the prevalence of dm, hypertension, and coronary artery disease.21,22 lack of exercise is a serious concern, as only 27% of our study population mentioned that they exercised for 150 minutes per week. similar low levels of physical activity have been reported among several other college student populations including one in kuwait.23,24 a study conducted among college students in the usa reported that only 38% of them exercised regularly.25 lack of time, lack of exercise facilities (especially for women), and an extremely hot climate are the main reasons reported for low levels of physical activity among kuwaiti college students. the same may also be applicable to our study population. the low level of physical activity has resulted in unhealthy bmis, with 25% of the participants being overweight or obese. increased levels of obesity among the university students also have been reported in other studies.26,27 several studies have reported that individuals who have even one family member with dm are more likely to have healthier diets—consuming more fruits and vegetables and less fat or simple sugars; engage in regular physical activity; and get screened for t2d—compared to those with no family history.6,28,29 the health belief model also explains the relationship between a family history of t2d and the individual’s preventive behaviour.30 however, contrary to these studies, our sample showed that a high prevalence of dm in families was not statistically associated with perceptions of beneficial behavioural changes or healthy behaviours of these young adults. nonetheless, almost 75% of the participants thought that discontinuing the use of alcohol and tobacco would be beneficial for their health. although many perceived increased physical activity as a beneficial change for protection against dm, the majority had not translated the belief into practice. the most interesting finding of the study is that females are more knowledgeable about dm compared to males, as a higher number of females correctly identified the behavioural changes beneficial for the prevention of dm. the media is actively participating in increasing people’s awareness regarding dm. a large amount of medical information is available on the world wide web, and present day students can access it easily as use of the internet has increased dramatically. the results of this study present a general picture of university students’ knowledge of dm. should it be considered adequate or is further intervention needed? in our opinion, university students’ knowledge is unsatisfactory and more efforts should be made to increase it, as students do not actively seek out this information themselves. the limitations of our study stem from the use of a questionnaire to assess the perceptions of university students, because there is the possibility that we have omitted some components of a specific context. as ours was a convenience sample, the participants may have been more healthconscious than students unwilling to complete the questionnaire. another limitation is the use of selfreported data and the assumption that participants responded honestly and accurately. we are aware that our sample size is small and may not be representative of the university student population throughout the uae. conclusion a large number of university-level students are at a higher risk of developing dm in their lifetime due to low levels of physical activity, high bmi, lack of knowledge regarding the disease, and its high prevalence in their families. students are also uninformed about the fact that dm can be prevented or delayed. we recommend that health professionals become involved in educational settings to enhance health-related knowledge and inculcate healthy lifestyle practices among students. institutes of higher education can also help to promote physical activity and healthy eating behaviours. a c k n o w l e d g e m e n t s we acknowledge the help rendered by dr. jayadevan and members of the research division of the gulf medical university for data entry and analysis. we thank the students for their participation. d e c l a r at i o n this research was conducted by the department of biochemistry at gulf medical university between march and june 2011. funding was not required. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest. nelofer khan, kadayam g gomathi, syed ilyas shehnaz and jayakumary muttappallymyalil clinical and basic research | 313 references 1. engelgau mm, geiss ls, saaddine jb, boyle jp, benjamin sm, gregg ew, et al. the evolving diabetes burden in the united states. ann intern med 2004; 140:945–50. 2. gu k, cowie cc, harris mi. mortality in adults with and without diabetes in a national cohort of the us population, 1971–1993. diabetes care 1998; 21:1138–45. 3. duncan ge. prevalence of diabetes and impaired fasting glucose levels among us adolescents: national health and nutrition. examination survey, 1999-2002. arch pediatr adolesc med 2006; 160:523–8. 4. yamaoka k, tango t. efficacy of lifestyle education to prevent type 2 diabetes. diabetes care 2005; 28:2780–6. 5. mainous ag, diaz va, everett cj. assessing risk for development of diabetes in young adults. ann fam med 2007; 5:425–9. 6. baptiste-roberts k, gary t, beckles g, gregg ew, owens w, porterfield d, et al. family history of diabetes, awareness of risk factors, and health behaviors among african americans. am j public health 2007; 97:907–12. 7. pi-sunyer fx. medical hazards of obesity. ann intern med 1993; 119:655–60. 8. us dept. of health and human services, public health service, national institutes of health, national heart, lung, and blood institute. clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. from: www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf. accessed: jun 2011. 9. american medical association, council on scientific affairs. treatment of obesity in adults. jama 1988; 260:2547–51. 10. hu g, qiao q, silventoinen k, eriksson jg, jousilahti p, lindström j, et al. occupational, commuting, and leisure-time physical activity in relation to risk for type 2 diabetes in middle-aged finnish men and women. diabetologia 2003; 46:322–9. 11. speer em, reddy s, lommel ts, fischer jg, heather s, park s et al. diabetes self-management behaviors and a1c improved following a community-based intervention in older adults in georgia senior centers. j nutr elder 2008; 27:179–200. 12. mumtaz s, ashfaq t, siddiqui h. knowledge of medical students regarding diabetes mellitus at ziauddin university, karachi. j pak med assoc 2009; 59:163–6. 13. aljoudi as, taha aza. knowledge of diabetes risk factors and preventive measures among attendees of a primary care center in eastern saudi arabia. ann saudi med 2009; 29:15–19. 14. mohieldein ah, al zohairy ma, hasan m. awareness of diabetes mellitus among saudi nondiabetic population in al-qassim region, saudi arabia. j diabetes endocrinol 2011; 2:14–19. 15. wee hl, ho hk, li sc. public awareness of diabetes mellitus in singapore. singapore med j 2002; 43:128– 34. 16. world health organization. obesity: preventing and managing the global epidemic. report of a who consultation. who technical report, series 894. geneva: world health organization, 2000. 17. world diabetes foundation. diabetes fact sheet. from: www.worlddiabetesfoundation.org. accessed: jun 2011. 18. international diabetes foundation. position statement – diabetes and cvd. from: www.idf.org/ position-statement-diabetes-and-cvd. accessed: jun 2011. 19. cullen kw, buzek bb. knowledge about type 2 diabetes risk and prevention of african-american and hispanic adults and adolescents with family history of type 2 diabetes. diabetes educ 2009; 35:836–42. 20. linda c, debra cw. health-promoting lifestyle and diabetes knowledge in hispanic american adults. home health care manage pract 2006; 18: 378–85. 21. american diabetic association. screening for type ii diabetes. diabetes care 2000; 23:20–3. 22. mohan d, raj d, shanthirani cs, datta m, unwin nc, kapur a, et al. awareness and knowledge of diabetes in chennai: the chennai urban rural epidemiology study. j assoc physician india 2005; 53:283–7. 23. al-isa an, campbell j, desapriya e, wijesinghe n. social and health factors associated with physical activity among kuwaiti college students. j obes 2011; 512363. 24. brevard pb, ricketts cd. residence of college students affects dietary intake, physical activity, and serum lipid levels. j am diet assoc 1996; 96:35–8. 25. lowry r, galuska da, fulton je, wechsler h, kann l, collins jl. physical activity, food choice, and weight management goals and practices among us college students. am j prev med 2000; 18:18–27. 26. al-rethaiaa as, fahmy aa, al-shwaiyat nm. obesity and eating habits among college students in saudi arabia: a cross sectional study. nutr j 2010; 9:39. 27. yahia n, achkar a, abdallah a, rizk s. eating habits and obesity among lebanese university students. nutr j 2008; 7:32. 28. forsyt lh, goetsch v. perceived threat of illness and health protective behaviors in offspring of adults with non-insulin-dependent diabetes mellitus. behav med 1997; 23:112–21. diabetes mellitus-related knowledge among university students in ajman, uae 314 | squ medical journal, august 2012, volume 12, issue 3 29. harrison ta, hindorff la, kim h, wines rc, bowen dj, mcgrath bb, et al. family history of diabetes as a potential public health tool. am j prev med 2003; 24:152–9. 30. glanz k, rimer d, lewis f. the health belief model. theory, research, and practice in health behavior and health education. san francisco: jossey bass, 2002. pp. 45–66. malaria cases are generally divided into imported or local cases, with local cases further subdivided into introduced (i.e. imported infections which are then transmitted locally due to vectors such as mosquitoes), induced (i.e. other sources of transmission such as infected blood transfusions) and indigenous (i.e. de novo cases).1 globally, there were approximately 212 million cases of malaria in 2015, with an estimated 429,000 malariarelated deaths.2 on the occasion of world malaria day, which was recently celebrated on 25 april 2017, we saw yet another challenge incorporated into the existing malaria burden this year—the potential addition of the plasmodium simium parasite to the plasmodium species already known to infect humans.3 malaria used to be endemic in oman; early reports from 1916 indicate that there were 100–400 cases of fever each month per 1,000 troops based in muscat, the capital city, with most fevers due to plasmodium falciparum infections.4 moreover, in the 1950s and 1960s, almost one-third of the omani population had malaria.5 parasitological surveys conducted in the 1970s revealed that much of the northern areas of the country were mesoendemic for malaria, with the highest rates reported in the al batinah region where parasite rates of 13% were detected among omani schoolchildren.5 in 1975, a malaria control programme was initiated in oman with financial assistance from the united nations development programme; by 1979, 17 malaria units and a malaria training centre had been established.5 this first malaria control programme had several key objectives, although it was aimed principally at source reduction via the biological control of the indigenous larvivorous fish aphanius dispar. unfortunately, this strategy showed only partial success and was replaced by widespread use of larvicides containing temephos between 1977– 1979.5 in addition, the detailed mapping of highrisk areas with aerial photography to keep track of larval control was a key feature of the vector control programme. in collaboration with the ministry of education, schoolchildren in certain highly endemic areas were given weekly chloroquine prophylaxis treatments between 1973 and 1979.5 however, this was discontinued in 1980, due in part to fears of emerging drug resistance, with chloroquine thereafter reserved for use among pregnant women and young children. in 1976, dichlorodiphenyltrichloroethane (ddt) residual spraying was implemented, but was replaced with phosphorothioate insecticides in 1993 following the emergence of ddt-resistant vectors in 1980. nonetheless, by 2003, anopheles culicifacies insects were resistant to both of these insecticides.5 in 1991, the omani ministry of health (moh) launched a new malaria eradication programme, with the ambition of completely interrupting malaria transmission and eliminating the existing reservoir of infected cases.6 once again, the programme was almost entirely focused on source reduction using temephos; however, 231 peripheral government health facilities and 500 private healthcare institutions were also passively screened in an attempt to identify and control existing malaria cases.5 in addition, all travellers arriving from east african nations at the international airport were evaluated for malaria before being allowed into the country. by 1999, the annual incidence of locally-acquired malaria had dropped from 21.5 to 0.1 per 10,000 individuals, with approximately 77% of the population targeted by malaria elimination strategies.5 between 2004 and 2006, there were no malaria cases reported in oman; however, in 2007, 12 cases were detected.5 in 2016, 803 cases were reported, three of which were local and were introduced due to the storage of drinking water tanks at construction sites, which served as a good breeding site for mosquitoes.7 isolated outbreaks of malaria continue to be reported in oman to date.5 department of medicine, sultan qaboos university hospital, muscat, oman e-mail: kowhassan@gmail.com اليوم العاملي للمالريا قصتنا مع املالريا يف عمان كوثر �سلمان ح�سن editorial world malaria day our story with malaria in oman kowthar s. hassan sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e133–134, epub. 20 jun 17 submitted 1 may 17 revision req. 11 may 17; revision recd. 23 may 17 accepted 25 may 17 doi: 10.18295/squmj.2016.17.02.001 world malaria day our story with malaria in oman e134 | squ medical journal, may 2017, volume 17, issue 2 complete malaria eradication mandates complete elimination of the mosquito vector, which appears to be impossible. moreover, the declaration of malaria eradication in some countries has lead to a laxity in surveillance programmes, resulting in the reemergence of malaria cases.8 in oman, plans were therefore redirected towards the control of malaria rather than its eradication. currently, a strong surveillance system is in place for the early detection and treatment of all reported cases as well as prompt epidemiological investigation of known patients.5 the diagnosis of malaria at major health institutions in oman is mainly based on blood films and rapid diagnostic tests, with molecular testing not widely used by most health institutes. moreover, malaria prophylaxis is provided to all omani nationals travelling to africa or other malariaendemic countries by local health centres, although it is not compulsory and not all individuals may utilise such services; this may be because the public is not adequately aware of the need for preventative treatment or because some individuals think they are protected due to their frequent visits to endemic areas.9,10 in addition to successfully controlling this once-endemic disease, the department of malaria eradication at the omani moh is officially recognised by the world health organization as a centre of excellence for malaria microscopy in the eastern mediterranean region and training programmes in malaria microscopy were held for neighbouring countries in the region until 2014.11 in conclusion, although we have not achieved complete eradication, the story of malaria control in oman is one of success. references 1. world health organization. malaria policy advisory committee meeting: annex 1 defining the term “malaria case”. from: www.who.int/malaria/mpac/mpac-sept2015-terminologyannex1.pdf accessed: may 2017. 2. world health organization. 10 facts on malaria. from: www. who.int/features/factfiles/malaria/en/ accessed: may 2017. 3. brasil p, zalis mg, de pina-costa a, siqueira am, bianco jr c, silva s, et al. plasmodium simium causing human malaria: a zoonosis with outbreak potential in the rio de janeiro brazilian atlantic forest. biorxivorg 2017; 122127. [epub before print]. doi: 10.1101/122127. 4. buxton pa. rough notes: anopheles mosquitoes and malaria in arabia. trans r soc trop med hyg 1944; 38:205–14. doi: 10.1016/s0035-9203(44)80004-9. 5. snow rw, amratia p, zamani g, mundia cw, noor am, memish za, et al. the malaria transition on the arabian peninsula: progress towards a malaria-free region between 1960-2010. adv parasitol 2013; 82:205–51. doi: 10.1016/b9780-12-407706-5.00003-4. 6. oman ministry of health. annual health report 2003: chapter 1 introduction. from: www.moh.gov.om/en_us/web/statistics/-/2003 accessed: may 2017. 7. oman ministry of health representative. personal communication, 2017. 8. oloo aj, vulule jm, koech dk. some emerging issues on the malaria problem in kenya. east afr med j 1996; 73:50–3. 9. pavli a, maltezou hc. malaria and travellers visiting friends and relatives. travel med infect dis 2010; 8:161–8. doi: 10.1016/j.tmaid.2010.01.003. 10. fulford m, keystone js. health risks associated with visiting friends and relatives in developing countries. curr infect dis rep 2005; 7:48–53. doi: 10.1007/s11908-005-0023-z. 11. world health organization regional office for the eastern mediterranean. oman: fifth international course on advanced malaria microscopy and quality assurance, 6 december–2 january 2013. from: www.emro.who.int/omn/oman-news/5thinternational-course-on-advanced-malaria-microscopyand-quality-assurance-6-december-to-2-january-2013.html accessed: may 2017. https://doi.org/10.1101/122127 https://doi.org/10.1016/s0035-9203%2844%2980004-9 https://doi.org/10.1016/b978-0-12-407706-5.00003-4 https://doi.org/10.1016/b978-0-12-407706-5.00003-4 https://doi.org/10.1016/j.tmaid.2010.01.003 https://doi.org/10.1007/s11908-005-0023-z sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e136–139, epub. 21 jan 15 submitted 22 mar 14 revision req. 11 jun 14; revision recd. 25 jul 14 accepted 19 oct 14 wheezing is a common medicalproblem during early childhood.1,2 most of the conditions that cause wheezing in children are benign and self-limiting. however, when wheezing presents itself before the age of one year, it requires careful evaluation. similarly, as noted by payne et al., a thorough reassessment of an asthmatic patient who is not responding to classic treatment is essential so as to establish the aetiology of the condition.3 poorly controlled childhood asthma may be due to the improper use of inhalation devices, poor compliance to treatment or recurrent triggering factors.4 in a young child with a persistent wheeze who is not responding to treatment, other rare causes need to be identified. aortic arch malformations occur in 3% of the general population.4 usually, incomplete vascular anomalies of the aortic arch do not cause respiratory symptoms and, therefore, can remain undetected in childhood.5 however, significant respiratory and gastrointestinal symptoms are common with complete vascular anomalies due to the resulting compression of the trachea and oesophagus.6 a chest x-ray may show unremarkable findings or a right-sided aortic arch, with the absence of a left-sided aortic knuckle. a high index of suspicion alongside investigations such as departments of 1child health and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mnaggari@squ.edu.om and mnaggari@yahoo.com عيوب األوعية الدموية لدى األطفال ذوى التشخيص اخلطأ كحاالت الربو سلسلة من احلاالت ها�ضم جافاد، خلفان ال�ضنيدي، ان�س الوجود عبد املغيث، ديليب �ضانكل، حمود الذهلي، �ضنان عزاوي، حممد النجاري abstract: in most asthmatic children, inhaled steroids can relieve and control the symptoms of asthma. persistent wheezing and respiratory symptoms in young children despite appropriate treatment may indicate other diagnostic considerations. delays in this diagnosis can result in unnecessary investigations, inappropriate treatment and further complications. we report three patients who presented to sultan qaboos university hospital, muscat, oman, in the period between september 2010 and may 2012 with persistent wheezing due to compression of the trachea caused by vascular anomalies. all patients had double aortic arches putting pressure on the trachea, leading to respiratory manifestations and feeding problems. following surgery, all cases showed improvement and no longer required medication. without clinical suspicion and appropriate imaging, congenital vascular anomalies may remain undetected for years. infants and children with chronic wheezing should be evaluated for vascular anomalies as soon as possible. general practitioners should refer all such patients to a tertiary-level hospital for further investigations and management. keywords: vascular malformations; aortic arch syndromes; asthma; x-ray computed tomography; wheezing; stridor; case report; oman. امللخ�ص: يف معظم االأطفال امل�ضابني بالربو ميكن لل�ضتريويدات امل�ضتن�ضقة اأن تخفف وتتحكم يف اأعرا�س الربو. قد ي�ضري ا�ضتمرار ال�ضفري و اأعرا�س اجلهاز التنف�ضي عند االأطفال ال�ضغار رغم العلج املنا�ضب اإىل اعتبارات ت�ضخي�ضية اأخرى. ميكن اأن يوؤدي التاأخري يف الت�ضخي�س اإىل قدموا مر�ضى ثلثة التقرير هذا يف هنا نعر�س التعقيدات. من مزيد و منا�ضب غري علج وتلقي لها، داعي ال فحو�ضات اإجراء اإىل م�ضت�ضفى جامعة ال�ضلطان قابو�س، م�ضقط، �ضلطنة عمان، يف الفرتة ما بني سبتمرب 2010 حتى مايو 2012 وهم يعانون من �ضفري م�ضتمر ب�ضبب الضغط عىلالق�ضبة الهوائية الناجم عن عيوب يف االأوعية الدموية. �ضكل ازدواج القو�س االأبهري �ضغطا على الق�ضبة الهوائية يف جميع املر�ضى ، مما اأدى اإىل ظهور اأعرا�س اجلهاز التنف�ضي و م�ضاكل يف التغذية. اأظهرت جميع احلاالت حت�ضنا بعد اإجراء اجلراحة، وعدم احلاجة اإىل االأدوية. بدون االشتباه ال�رضيري و الت�ضوير الطبي املنا�ضب قد يتاأخر اكت�ضاف عيوب االأوعية الدموية اإىل �ضنوات. ينبغي تقييم الر�ضع و االأطفال الذين يعانون من ال�ضفري املزمن ال�ضتبعاد عيوب االأوعية الدموية يف اأقرب وقت ممكن. يجب على االأطباء املمار�ضني حتويل جميع هوؤالء املر�ضى اإىل م�ضت�ضفى مركزي الإجراء مزيد من الفحو�ضات والعلج. مفتاح الكلمات: ت�ضوهات االأوعية الدموية؛ متلزمة القو�س االأبهري؛ الربو؛ الت�ضويراملقطعي الأ�ضعة اإك�س؛ ال�ضفري؛ �رضير؛ تقرير حالة؛ عمان. vascular anomalies in children misdiagnosed with asthma case series hashim javad,1 khalfan al-sineidi,1 anas a. abdelmogheth,1 dilip sankhla,2 humoud al-dhuhli,2 sinan i. azzawi,2 *mohamed a. el-naggari1 online case report hashim javad, khalfan al-sineidi, anas a. abdelmogheth, dilip sankhla, humoud al-dhuhli, sinan i. azzawi and mohamed a. el-naggari case report | e137 upper gastrointestinal contrast studies, echocardiograms and computed tomography (ct) angiograms of the chest are critical in the diagnosis.7 the timely identification and treatment of a vascular anomaly is essential in order to prevent complications. case one an eight-month-old male infant was referred to sultan qaboos university hospital (squh) in muscat, oman, in october 2011 with persistent wheezing that had continued since birth. he was born by emergency caesarian section due to fetal bradycardia; however, after birth, he demonstrated an acceptable apgar score. from two weeks of age the infant had attended various health facilities as he had noisy breathing and mild difficulty with feeding. he showed no response to treatment with bronchodilators and steroids. on examination, it was found that the infant’s growth parameters were below the third percentile. biphasic wheezing was heard all over his chest by auscultation. findings from other systemic examinations, as well as his vital signs and oxygen saturation levels, were normal. a flexible endoscopy of the upper airway and chest x-rays showed no abnormal signs. however, the infant’s symptoms worsened with time. an echocardiogram revealed a double aortic arch (daa). a chest ct angiography confirmed this finding and showed that the daa was pressing gently on the trachea and oesophagus [figure 1]. the infant was operated on at 10 months of age. during surgery, pressure on the trachea and oesophagus from the daa was observed and the posterior aortic arch was divided to release the obstruction. the infant’s symptoms and growth parameters improved after surgery and he was not on any medication at the time of follow-up. case two a three-year-old male child was referred to squh in september 2010 with a history of wheezing, dysphagia and cyanosis while feeding. from the age of six months, he had been undergoing regular follow-up with an ear, nose and throat (ent) surgeon at squh for suspected laryngomalacia. his growth parameters were between the 25th and 50th percentile. his vital signs and oxygen saturation levels were normal. on auscultation, wheezing was heard bilaterally. a clinical examination of his cardiovascular system was unremarkable. routine blood investigations and a chest x-ray showed no abnormal findings. a barium swallow test with fluoroscopy revealed an indentation of the oesophagus at the t4–t5 vertebral level. an echocardiogram revealed a left-sided hypoplastic aortic arch with two branches; the left carotid and left subclavian. the right aortic arch was dominant with both the right carotid and the subclavian arising from it. these findings were consistent with a diagnosis of daa. a coronal ct angiogram showed both aortic arches compressing the distal trachea as well as the junction of both posterior arches [figure 2]. at the age of three-and-a-half years, the patient underwent an operation whereby the posterior aortic arch was divided to release the obstruction. on follow-up, he was not taking any medication and was asymptomatic and thriving. case three a three-month-old female infant was referred to squh in may 2012 with noisy breathing, wheezing and difficulty with feeding since birth. she was born normally with a good apgar score and a birth weight of 2.7 kg. soon after the infant’s birth, her parents figure 1: axial computed tomography angiography image of the first case, demonstrating both aortic arches with a mildly compressed trachea and oesophagus. figure 2: coronal computed tomography angiography image of the second case, showing both aortic arches compressing the distal trachea. vascular anomalies in children misdiagnosed with asthma case series e138 | squ medical journal, february 2015, volume 15, issue 1 noticed the aforementioned symptoms. it was also observed that she was not gaining any weight. she received nebulised bronchodilators and antibiotics which had no effect. laryngomalacia was suspected by the squh ent surgeon. the infant’s growth parameters were below the third percentile and she had biphasic wheezing. the findings of a chest x-ray were normal. a barium swallow test revealed a posterior indentation on the upper oesophagus which was suggestive of an extrinsic vascular compression. a ct chest angiogram was performed and showed a daa compressing the trachea. a three-dimensional volume-rendered ct angiography of the chest also showed the daa [figure 3]. the infant was operated on at the age of 10 months. during the surgery, it was observed that the daa was putting pressure on the trachea and oesophagus. the posterior aortic arch was therefore divided to release the obstruction. the infant’s symptoms persisted for some time after surgery due to the indentation caused by the daa on the trachea and oesophagus. however, on follow-up, a gradual improvement in her symptoms and growth parameters was seen and she was not on any medication. a summary of the details and clinical findings for all three cases in this series is presented in table 1. discussion a daa is a prevalent vascular ring malformation whereby the two arches surround the trachea and oesophagus.7 the paired aortic arch arteries fail to remodel properly, resulting in two aortic arches connecting both the ascending and descending aortas. the ascending aorta bifurcates anteriorly to the trachea and oesophagus, with one arch coursing to the left of the trachea and oesophagus and the other to the right.7 the arches rejoin into a single descending aorta behind the trachea and oesophagus, thereby completely encircling the two structures.7 in children with a daa, stridor is considered a common clinical presentation, followed by recurrent respiratory infections, respiratory distress, wheezing and coughing.8 gastrointestinal symptoms are usually elicited during the patient history and include dysphagia, feeding difficulty and vomiting.8 all three patients in this case series presented with breathing difficulties, wheezing and dysphagia. a dominant right-sided aortic arch raises clinical suspicion for a vascular ring. at present, ct and magnetic resonance imaging angiograms are used as an effective diagnostic and assessment tool for aortic arch anomalies, including daa.9 a daa compressing the trachea table 1: summary of the details and clinical findings for the three presented patients with vascular anomalies detail/finding case 1 2 3 age at presentation eight months three years three months gender male male female age at onset of symptoms since birth six months since birth presenting features persistent wheezing wheezing and dysphagia noisy breathing growth ftt* normal+ ftt* development afa afa afa auscultation biphasic wheezing bilateral wheezing bilateral wheezing cvs ur ur ur chest x-ray ur ur ur upper gi contrast study not performed indentation of upper oesophagus indentation of upper oesophagus echocardiogram daa daa daa chest ct angiogram daa daa daa diagnosis daa daa daa treatment received surgical division of paa surgical division of paa surgical division of paa outcome cured cured slowly improving ftt = failure to thrive; afa = appropriate for age; cvs = chorionic villus sampling ; ur = unremarkable; gi = gastrointestinal; daa = double aortic arch; ct = computed tomography; paa = posterior aortic arch. *below the third percentile. +between the 25th and 50th percentile. figure 3: three-dimensional volume-rendered computed tomography chest angiography image of the third case, showing a double aortic arch (marked 1 and 2). hashim javad, khalfan al-sineidi, anas a. abdelmogheth, dilip sankhla, humoud al-dhuhli, sinan i. azzawi and mohamed a. el-naggari case report | e139 and oesophagus in the first two cases of this series were confirmed by a ct angiogram. in these patients, compression of the trachea and oesophagus from the daa was observed during surgery and the posterior aortic arch was divided to release the obstruction. following surgery, both of the patients became asymptomatic. a study by stewart et al. revealed cleavage of the vascular ring in three out of 15 patients with a vascular ring.10 in the management of children with vascular rings, phelan et al. indicated that a high index of clinical suspicion is required in order to ensure a rapid and timely diagnosis.11 mild vascular rings can be missed in very young patients and manifest only at an older age. however, noisy breathing sounds are usually the classical presentation soon after delivery.11 these symptoms often worsen during a respiratory infection. wheezing in a very young infant is another typical clinical presentation. sometimes, the vascular ring can be misdiagnosed as cardiac disease, unless the history points to airway problems, as clinical examinations can appear normal.10 multi-view chest imaging scans are very helpful in distinguishing many subtle pulmonary and cardiac abnormalities. identification of the rightsided aortic arch on a chest radiograph is crucial as it may be associated with a ring anomaly. missed or late identification of vascular anomalies can result in unnecessary investigations and treatment, while a prolonged and inappropriate use of inhaled corticosteroids may cause hazardous effects on growth, bones and adrenal glands.12 if the airway is compressed by a vascular ring for an extended period of time, it may cause a permanent indentation of the airway. establishing the correct diagnosis and ensuring appropriate surgery will assist in the improvement of symptoms and the avoidance of unnecessary treatment. when treating a patient with poorly controlled persistent respiratory complaints, physicians should consider alternative diagnoses by carefully reviewing the patient history and chest images. furthermore, all children with persistent wheezing should be referred to tertiary level hospitals for further investigations and management. conclusion a diagnosis of bronchial asthma in young children should be made cautiously, after excluding other conditions that can cause persistent wheezing. chronic or recurrent wheezing in young children who do not respond to classic treatment requires thorough reassessment to establish the aetiology and to avoid complications and unnecessary medication. in the absence of clinical suspicion and appropriate imaging, congenital vascular anomalies can remain undetected until adulthood. general practitioners should refer all children with persistent wheezing for further investigations at a tertiary level hospital. references 1. taussig lm, wright al, holberg cj, halonen m, morgan wj, martinez fd. tucson children’s respiratory study: 1980 to present. j allergy clin immunol 2003; 111:661–75. doi: 10.1067/mai.2003.162. 2. bloomberg gr. recurrent wheezing illness in preschoolaged children: assessment and management in primary care practice. postgrad med 2009; 121:48–55. doi: 10.3810/ pgm.2009.09.2052. 3. payne dn, lincoln c, bush a. lesson of the week: right sided aortic arch in children with persistent respiratory symptoms. bmj 2000; 321:687–8. doi: 10.1136/bmj.321.7262.687. 4. balfour-lynn i. difficult asthma: beyond the guidelines. arch dis child 1999; 80:201–6. doi: 10.1136/adc.80.2.201. 5. humphrey c, duncan k, fletcher s. decade of experience with vascular rings at a single institution. pediatrics 2006; 117:e903– 8. doi: 10.1542/peds.2005-1674. 6. woods rk, sharp rj, holcomb gw 3rd, snyder cl, lofland gk, ashcraft kw, et al. vascular anomalies and tracheoesophageal compression: a single institution’s 25-year experience. ann thorac surg 2001; 72:434–8. doi: 10.1016/ s0003-4975(01)02806-5. 7. juraszek al, fulton dr. vascular rings. from: www.uptodate. com/contents/vascular-rings accessed: jan 2014. 8. backer cl, mavroudis c, rigsby ck, holinger ld. trends in vascular ring surgery. j thorac cardiovasc surg 2005; 129:1339–47. doi: 10.1016/j.jtcvs.2004.10.044. 9. felson b, palayew mj. the two types of right aortic arch. radiology 1963; 81:745–59. doi: 10.1148/81.5.745. 10. stewart jr, kincaid ow, titus jl. right aortic arch: plain film diagnosis and significance. am j roentgenol radium ther nucl med 1966; 97:377–89. doi: 10.2214/ajr.97.2.377. 11. phelan e, ryan s, rowley h. vascular rings and slings: interesting vascular anomalies. j laryngol otol 2011; 125:1158– 63. doi: 10.1017/s0022215111001605. 12. pedersen s, o’byrne p. a comparison of the efficacy and safety of inhaled corticosteroids in asthma. allergy 1997; 52:1–34. doi: 10.1111/j.1398-9995.1997.tb05047.x. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e130-133, epub. 27th jan 14 submitted 3rd jul 13 revision req. 19th aug 13; revision recd. 10th sep 13 accepted 3rd oct 13 departments of 1child health and 2medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: alsineidiksk@hotmail.com حالة معقدة اللتهاب جرثومي حتت احلاد للشغاف املبطن للقلب لطفلة لديها فتحة قلبية باحلجاب احلاجز البطيين خلفان �سامل ال�سنيدي ,اأن�س-الوجود اأحمد عبد املغيث,عبداهلل باخلري حياة املري�س. وعلى الرغم لكنها خطرية وذات م�ساعفات متعددة قد تهدد ماألوفة, للقلب ظاهره غري املبطن ال�سغاف بالتهاب اال�سابة تعد امللخ�ص: من التقدم يف العالج, اإال ان هناك ارتفاع م�ستمر يف معدالت االعتالل والوفيات. يف هذه الدرا�سة نقدم حالة فتاة تبلغ من العمر مثانية �سنوات كانت تعاين اأن لديها اإذ ثبت قد مت ت�سخي�سها بوجود عيب خلقي يف القلب يف مرحلة الطفولة االأوىل, من اأعرا�س ارتفاع درجة حرارة اجل�سم ملدة �سهرين ون�سف و فتحة �سغرية يف احلجاب البطيني. وقد مت ت�سخي�س احلاله باعتبارها التهاب بالغ�ساء املبطن للقلب �سببه جرثومة �سرتبتوكوكا�س ميوتان�س. وقد حدث لديها انتقال للتعفن ت�سبب يف ان�سداد رئوي. ومع ذلك فقد مت �سفاوؤ ها با�ستخدام م�سادات امليكروبات املنا�سبة. وعليه, ينبغي على االأطباء التح�سب بدرجة عالية لعدوى التهاب ال�سغاف باعتباره �سببا حمتمال للحمى التي متكث لفرتات طويلة وبخا�سة مع وجود اأمرا�س القلب اخللقية. ومع التغيريات اجلديدة يف تعليمات اإعطاء االأدوية, مل تعد اأمرا�س القلب غري االإزرقاقية, التي مل تتم معاجلتها بعمليات جراحية من �سمن احلاالت التي تو�سف لها هذه االأدوية الوقائية وهذا بالطبع يدفع باجتاه مزيد من الدرا�سات امل�ستفي�سة ملعرفة ن�سبة حدوث مثل هذه احلاالت قبل اال�ستنتاج للمدى الطويل. مفتاح الكلمات: التهاب ال�سغاف اجلرثومي حتت احلاد؛ �سرتبتوكوكا�س ميوتان�س؛ ان�سداد رئوي متعفن؛ حمامي عقدية؛ تقرير حاله؛ عمان. abstract: infective endocarditis (ie) is an uncommon but life-threatening infection. despite advances in management, it still causes high morbidity and mortality. we report the case of an 8-year-old girl who presented with a prolonged fever of 2.5 months duration and a history of a small perimembranous ventricular septal defect. she was diagnosed with subacute bacterial endocarditis secondary to streptococcus mutans. the patient developed a septic pulmonary embolism; however, with the use of appropriate antimicrobial therapy, she made an uneventful recovery. clinicians should have a high index of suspicion for ie as the possible cause of a prolonged fever, especially in the presence of congenital heart disease (chd). currently, ie prophylaxis is not indicated for unrepaired acyanotic chd. nevertheless, with the new changes in the guidelines, more prospective studies are needed to investigate the incidence of ie in such lesions, before long-term conclusions can be drawn. keywords: endocarditis, subacute bacterial; streptococcus mutans; pulmonary embolism, septic; erythema nodosum; case report; oman. complicated subacute bacterial endocarditis in a patient with ventricular septal defect *khalfan s. al-senaidi,1 anas-alwogud a. abdelmogheth,1 abdullah a. balkhair2 online case report i infective endocarditis (ie) is a relatively a rare condition in children but it causes significant morbidity and mortality. repaired and unrepaired congenital heart diseases (chd) are associated with a high lifetime risk of ie; patients with ventricular septal defect (vsd) have the highest risk.1 a vsd can present in an acute or subacute phase due to many organisms like the streptococcus viridans group (s. mutans, s. mitis), and the enterococcus and staphylococcus species.2 ie results from complex interactions between the microbial pathogen in the bloodstream, the matrix molecules and platelets at the sites of the endocardial cell damage. for many years antibiotic prophylaxis has been advocated but the guidelines have recently changed. early diagnosis and prompt therapy can prevent the drastic complications which can ensue from ie. case report an 8-year-old girl presented to the emergency department of sultan qaboos university hospital, oman, with a 2.5 month history of an intermittent low-grade fever associated with a decrease in appetite and weight loss. there was a history of an itchy erythematous skin rash on the lower limbs which had initially lasted for a few days. there was khalfan salim al-senaidi, anas-alwogud ahmed abdelmogheth and abdullah a. balkhair case report | e131 no history of cough, chest pain, urinary or bowel symptoms; neither was there a history of a recent dental extraction or of joint pain or swelling. she had visited the local hospital and health centres a few times and had been prescribed some oral antibiotics and topical cream which had only resulted in minimal improvement. during the neonatal period, she had been diagnosed with a small perimembranous vsd (pmvsd) and was under follow-up for this condition. three days prior to presentation, she had developed a high-grade fever of 40 °c; this was associated with a mild cough but with no shortness of breath or chest pain. clinical examination revealed a girl of slight build, afebrile, and with a heart rate of 146/min, respiratory rate 20/min, blood pressure 93/66, weight 16.3 kg (below 3rd percentile), height 163 cm (below 3rd percentile) with normal oxygen saturation. there was no significant lymphadenopathy. an oral assessment revealed multiple dental caries. the cardiac examination revealed a hyperdynamic precordium with thrill and a grade 4/6 pansystolic murmur heard best in the left lower sternal border. an abdominal examination showed non-tender hepatomegaly (the liver span was 12 cm) and splenomegaly (8 cm) below the costal margin. the laboratory investigations revealed a picture of hypochromic microcytic anaemia with haemoglobin of 7.2 g/dl, a high red blood cell distribution width of 27, a white cell count of 6.5 × 109/l and platelets of 302 × 109/l. the c-reactive protein level was 32 mg/l and the erythrocyte sedimentation rate 20 mm/hr. the liver and kidney function tests were normal. an echocardiography showed a 4 mm pmvsd with a left-to-right shunt with a peak gradient of 85 figure 1: echocardiographic modified right ventricular inflow view showing the vegetations (arrow) attached to the tricuspid valve. ra = right atrium; rv = right ventricle. figure 2: purplish macular skin rash at the dorsum of the left foot indicating erythema nodosum. figure 3: posterior-anterior chest x-ray showing a large dense consolidation (arrow) in the left lower zone consistent with a pulmonary embolism. figure 4: computed tomography scan of the chest (axial view) showing the large wedge-shaped pulmonary embolism involving the basal segment of the left lower lobe (arrow). complicated subacute bacterial endocarditis in a patient with ventricular septal defect e132 | squ medical journal, february 2014, volume 14, issue 1 mmhg. there were two vegetations attached to the tricuspid valve with moderate regurgitation and no stenosis. the large one measured 8 x 6 mm and the smaller one 6 x 4 mm [figure 1]. the patient’s left atrium and left ventricle were not dilated and there was no pericardial effusion. the ventricular systolic function was normal. a diagnosis of subacute bacterial endocarditis (sbe) was made based on the clinical picture and the echocardiographic findings. after taking three blood cultures, the patient was started on intravenous antiobiotics: ampicillin 50 mg/kg six hourly, vancomycin 15 mg/kg eight hourly and gentamicin 2.5 mg/kg eight hourly. all blood cultures grew s. mutans. on the eighth day of admission, the patient developed a painful small macular lesion on the dorsum of her left foot measuring about 2 x 1 cm; this was consistent with erythema nodosum [figure 2]. the patient remained clinically stable until day 13 of admission when she developed a sudden lower left chest pain associated with a shortness of breath and vomiting and a fever of 38.6 °c. her vital signs were normal. both the chest x-ray [figure 3] and the computed tomography (ct) scan [figure 4] showed a wedge-shaped consolidation with an air bronchogram on the basal segment of the left lower lobe consistent with a pulmonary embolism. a repeat echocardiography showed the disappearance of the larger tricuspid valve vegetation with the small one still attached. the patient’s cardiac function remained normal with no evidence of pulmonary hypertension. there was no evidence of other embolic phenomena or complications. both the neurological status and urine analysis were normal. the patient was observed initially in the intensive care unit and remained haemodynamically stable. the patient was continued on ampicillin and gentamicin and repeat blood cultures were negative. intravenous antiobiotics were continued for total of six weeks after which she was discharged in a good condition. on follow-up, the patient remained afebrile with an improvement in her appetite, the regression of her hepatosplenomegaly and the normalisation of the inflammatory markers. a follow-up echocardiography done after the discharge showed a mild tricuspid valve regurgitation with resolution of the vegetation. she was referred for dental review and vsd repair. discussion we here reported a young girl known to have a small pmvsd who developed serious sbe secondary to s. mutans; this is a commensal of the oral cavity and considered a primary cause of dental caries. the organism can survive in the bloodstream and has been reported as a cause of ie with significant morbidity and mortality.3–5 ie has serious complications in both paediatric and adult patients with chd with an increasing incidence relative to the decrease in rheumatic fever. despite improvements in early diagnosis, management and therapy, it can still lead to high rates of morbidity and mortality; these vary from 7–25%.6–7 hence, ie is an ongoing, life-threatening complication that may affect the long-term outcome of chd. the classic presentation of ie includes fever, anaemia, positive blood cultures and heart murmur, all of which were present in our patient; however, there was a delay in the diagnosis despite the presence of the clinical and laboratory findings which were suggestive of sbe. this case highlights the importance of keeping a high index of suspicion for ie as it could present in a subacute phase. the diagnosis of ie is based on the modified duke criteria and, once diagnosed, the therapy includes appropriate antimicrobial therapy for 2–6 weeks.8 our patient had two major criteria and several minor criteria for the diagnosis of ie. the presence of ie in chd can lead to major complications in and outside the heart. congestive heart failure occurs in up to 40% of cases and is the leading cause of haemodynamic compromise; this could be due to many factors including the destruction of valves, myocarditis or arrhythmias.9 extracardiac complications are also frequent—in up to 43% of cases—and are caused either by embolic events or immune phenomena.9,10 in this patient, the reappearance of fever and the sudden respiratory symptoms were due to a septic pulmonary embolism. the diagnosis of septic pulmonary embolism was based on the clinical presentation, the chest x-ray and the ct findings, in addition to the echocardiographic findings of the dislodgement of the vegetation. one differential diagnosis is splenic rupture; however, this patient was haemodynamically stable. other differential diagnoses include embolic episodes to the spleen, bowel or other related vascular structures. this khalfan salim al-senaidi, anas-alwogud ahmed abdelmogheth and abdullah a. balkhair case report | e133 patient’s abdominal doppler ultrasound only showed hepatospleenomegaly with no evidence of embolic episodes. the hepatomegaly was most likely due to the immunological response secondary to the ie as she was not in heart failure. because she was haemodynamically stable and the blood cultures were negative within a few days of starting the antibiotics, with normal cardiac function, no surgical intervention was warranted. given the prognosis, morbidity and the high cost of ie management, antibiotic prophylaxis has long been recommended in order to minimise the incidence of ie and, in fact, the rate has decreased dramatically. based on expert opinions, case control studies and daily practice, the american heart association (aha) guidelines, last revised in 2007, have led to a significant reduction and limitation of cardiac diseases and procedures in which ie prophylaxis is indicated.11 currently, ie prophylaxis is not indicated for unrepaired acyanotic chds such as vsd, bicuspid aortic valve and patent ductus arteriosus. nevertheless, given the new changes in the aha guidelines, more prospective studies are needed, especially in developing countries, to monitor carefully the incidence of ie in such lesions before long-term conclusions can be reached. conclusion we have reported a case of sbe secondary to s. mutans in an 8-year-old girl who had a small pmvsd complicated by a septic pulmonary embolism. she made an uneventful recovery with the appropriate therapy. ie still carries high morbidity and mortality despite advances in management. physicians should have a high index of suspicion for ie as early detection and prompt therapy are mandatory to optimise patient outcomes, especially in the presence of chd. long-term data should be collected concerning the efficacy of antibiotic prophylaxis against ie, especially in acyanotic chd, before long-term conclusions on patient management can be reached. a c k n o w l e d g e m e n t s we express our appreciation to our colleagues and trainees who helped in the management of this patient. references 1. li w, somerville j. infective endocarditis in the grown-up congenital heart (guch) population. eur heart j 1998; 19:166–73. 2. rosenthal lb, feja kn, levasseur sm, alba lr, gersony w, saiman l. the changing epidemiology of pediatric endocarditis at a children's hospital over seven decades. pediatr cardiol 2010; 31:813–20. 3. jung cj, zheng qh, shieh yh, lin cs, chia js. streptococcus mutans autolysin atla is a fibronectinbinding protein and contributes to bacterial survival in the bloodstream and virulence for infective endocarditis. mol microbiol 2009; 74:888–902. 4. biswas s, bowler ic, bunch c, prendergast b, webster dp. streptococcus mutans infective endocarditis complicated by vertebral discitis following dental treatment without antibiotic prophylaxis. j med microbiol 2010; 59:1257–9. 5. ullman rf, miller sj, strampfer mj, cunha ba. streptococcus mutans endocarditis: report of three cases and review of the literature. heart lung 1988; 17:209–12. 6. baumgartner h, bonhoeffer p, de groot nm, de haan f, deanfield je, galie n, et al. esc guidelines for the management of grown-up congenital heart disease (new version 2010). eur heart j 2010; 31:2915–57. 7. di filippo s, delahaye f, semiond b, celard m, henaine r, ninet j, et al. current patterns of infective endocarditis in congenital heart disease. heart 2006; 2:1490–5. 8. li js, sexton dj, mick n, nettles r, fowler vg, jr., ryan t, et al. proposed modifications to the duke criteria for the diagnosis of infective endocarditis. clin infect dis 2000; 30:633–8. 9. bitar ff, jawdi ra, dbaibo gs, yunis ka, gharzeddine w, obeid m. paediatric infective endocarditis: 19-year experience at a tertiary care hospital in a developing country. acta paediatr 2000; 89:427–30. 10. knirsch w, nadal d. infective endocarditis in congenital heart disease. eur j pediatr 2011; 170:1111–27. 11. wilson w, taubert ka, gewitz m, lockhart pb, baddour lm, levison m, et al. prevention of infective endocarditis: guidelines from the american heart association: a guideline from the american heart association rheumatic fever, endocarditis, and kawasaki disease committee, council on cardiovascular disease in the young, and the council on clinical cardiology, council on cardiovascular surgery and anesthesia, and the quality of care and outcomes research interdisciplinary working group. circulation 2007; 116:1736–54. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century sultan qaboos university med j, november 2013, vol. 13, iss.4, pp. 581-584, epub. 8th oct 13 submitted 9th may 13 revision req. 30th jun 13; revision recd. 2nd jul 13 accepted 11th jul 13 1department of cardiothoracic surgery, centre hospitalier universitaire de poitiers, poitiers, france; 2department of cardiology, centre hospitalier universitaire de caen, caen, france *corresponding author e-mail: ziad_dahdouh@hotmail.com أثر نوع بدلة الصمام على النتائج القلبية الوعائية ملرضى الغسيل املزمن جميل حاج �ساهني، زياد �سعيد دحدوح، طوين عبدامل�سيح الكلوي. بالغ�سيل يعاجلون الذين الكلوي الف�سل مر�سى يف البديل ال�سمام اإختيار اإىل املر�سدة البيانات يف تعار�ض يوجد امللخ�ض: قررنا البحث، بعد مراجعة الدرا�سات املتعلقة املن�سورة، عن اأف�سل بديل لل�سمام يف مر�سى الغ�سيل الكلوي املزمن. جمموعة 9 درا�سات اإ�ستعادية قارنت نتائج نوعني من ال�سمامات، اأظهرت نتائج مت�سابهة واأبرزت اآمان اإ�ستخدام ال�سمامات البيولوجية يف مر�سى الغ�سيل الكلوي املزمن. لقد تغريت معايري اإختيار ال�سمامات البديلة عرب الزمن، لفرتة طويلة كان يعتقد اأن �سمامات الأن�سجة تخ�سع للتكل�ض املبكر ب�سبب خلل اإ�ستقالب الكال�سيوم يف مر�سى الف�سل الكلوي يف املراحل املتاأخرة. النزف كان اأكرث امل�ساعفات املتعلقة بال�سمامات وميثل اأكرب ق�سور لإ�ستخدام ال�سمامات امليكانيكية. اأو�سحت درا�ستان اأن زرع ال�سمامات امليكانيكية كان له ميزة البقاء لعمر اأطول للمر�سى. ميكن الإ�ستنتاج باأن جراحني القلب يجب األ يرتددوا يف زرع ال�سمامات البيولوجية لأن تلف هذه ال�سمامات يعترب حالت فردية وغري منت�رش يف هذه املجموعة من املر�سى. اإختيار ال�سمام البديل يجب اأن يكون مبنى على نف�ض املعايري املطبقة على املر�سى الذين ل يعانون من الف�سل الكلوي. مفتاح الكلمات: غ�سيل كلوي، بدلت ال�سمام القلبي، بدلت بيولوجية، بدلت وغر�سات، حتليل. abstract: there is conflicting evidence guiding valve prosthesis selection in patients with end-stage renal disease on dialysis. we sought to determine, after reviewing the relevant literature, the best valve substitute in patients on chronic dialysis. a total of 9 retrospective studies compared the outcomes of two valves, showing similar results and highlighting the safety of implanting bioprostheses in patients on chronic dialysis. standards of valve selection have changed over time; it has long been believed that tissue valves undergo premature degeneration due to calcium metabolism derangements in patients with end-stage renal disease. bleeding was the most common valve-related complication and represented a major drawback of mechanical valves. two studies demonstrated a survival advantage in favour of mechanical prostheses. it can be concluded that surgeons should not hesitate to implant bioprostheses because singular valve decomposition would be uncommon in this patient population. prosthesis selection should be based on the same criteria as those used for non-dialysis patients. keywords: renal dialysis; heart valve prostheses; bioprostheses; prostheses and implants, analysis. technical note impact of valvular prosthesis type on cardiovascular outcomes in patients on chronic dialysis jamil hajj-chahine,1 *ziad s. dahdouh,2 tony abdel-massih the best valve substitute in patients on chronic dialysis undergoing valve replacement surgery is still a matter of ongoing debate. when choosing a mechanical valve, the preservation and durability of the biological components of a bioprosthesis should be weighed against the risk of life-threatening bleeding or major thrombo-embolism generally linked to the use of life-long anticoagulants. methods the standards of valve selection have changed over time. it has long been believed that tissue valves undergo premature degeneration due to the derangements in calcium metabolism in patients with end-stage renal disease. this is based on a report by lamberti who described two patients with accelerated degeneration of their bioprosthetic valves.1 in 1998, american college of cardiology/ american heart association (acc/aha) guidelines recommended the use of mechanical valves in patients on dialysis. however, 7 retrospective studies from north america and two from japan specifically compared the outcomes of the two valves and showed similar results, highlighting the safety of implanting a bioprosthesis in patients on chronic dialysis.2–10 recently, accumulating data supporting the very low incidence of rapid tissue valve degeneration in dialysis patients has been taken into consideration, and the 2006 acc/aha practice guidelines do not specify the best choice for valve replacement in dialysis patient. to provide the best evidence to address this issue, a literature review of the most relevant studies was performed using pubmed. the most relevant papers treating this problem are listed and summarised in table 1. results lucke et al. reviewed 19 consecutive patients with end-stage renal disease from a single institution who had undergone aortic, mitral or aortomitral valve replacement.2 the mechanical valve patients (n = 10) had a significantly higher rate of postoperative cerebrovascular events or bleeding complications than the bioprosthetic patients (n = 9). no subsequent reoperations were required for biological valve failure. the overall estimated kaplan-meier survival was 42 ± 14% at 60 months. kaplon et al., from the cleveland clinic foundation, found comparable results for both types of valves when reviewing 42 patients on preoperative dialysis undergoing valve replacements;3 17 received mechanical valves and 25 received a bioprosthesis. of the 25 fitted with bioprosthetic valves, 4 required reoperation with one admitted for mitral bioprosthesis degeneration. prosthetic valve-related complications and survival were similar for both mechanical and bioprosthetic valves. herzog et al. reviewed the us renal data system database. dialysis patients (n = 5,858) hospitalised for heart valve replacement surgery were the subjects of the study.4 tissue valves were used in 881 patients (15%). aortic valve replacement was performed in 58%, mitral valve replacement in 32%, and combined aortic and mitral valve replacement in 10%. there was no significant difference in survival related to type of valve. the two-year survival rate was 39.7 ± 3.5% with tissue valves versus 39.7 ± 1.4% for non-tissue valves. brinkman et al. found that the choice of valve substitute used in dialysis patients did not influence early and late survival; however, with a mechanical valve there were a six-fold higher incidence of late bleeding or stroke in patients on dialysis.5 chan et al. investigated the results of 69 valve replacements in patients with end-stage renal disease.6 one case of structural valve deterioration (svd) occurred in the bioprosthesis group, requiring reoperation at 95 months after surgery. a survival advantage was observed in favour of mechanical prostheses at 5 years. nevertheless, composites of complications were similar between the two groups. toole et al. reviewed 50 dialysis patients undergoing left-sided valve replacement.7 the tissue valve group had significantly higher kaplanmeier freedom from valve-related morbidity and mortality at three years. freedom from reoperation was not significantly different. filsoufi et al. analysed data from 155 patients with renal failure who underwent left-sided valve surgery, of whom 108 patients were on chronic dialysis.8 regarding the type of prosthesis, hospital mortality and freedom from reoperation were similar in patients with mechanical and biological valves. umezu et al. analysed data from 63 consecutive dialysis patients who underwent valvular surgery.9 the mechanical group had a higher rate of bleeding events but there was no svd up to the 5-year followup. however, both mechanical and bioprosthetic valve patients had similar survival and event-free rates. tanaka et al. performed a retrospective review on 73 aortic valve replacements for dialysis patients.10 no svd of the bioprosthesis was seen in this series. valve-related complications were documented in 12 of 44 patients in the mechanical valve group and in 2 of 21 patients in the bioprosthesis group. the all-cause survival rate of patients with bioprosthesis was significantly worse than that of patients with mechanical valves. discussion a major concern of cardiovascular surgical teams when implanting a bioprosthesis in a patient on dialysis is svd, and many papers have been written on the subject. however, none of the studies have been randomised controlled trials. only 4 cases of svd requiring reoperation (at 10-96 months after impact of valvular prosthesis type on cardiovascular outcomes in patients on chronic dialysis 582 | squ medical journal, november 2013, volume 13, issue 4 impact of valvular prosthesis type on cardiovascular outcomes in patients on chronic dialysis 583 | squ medical journal, november 2013, volume 13, issue 4 c om m en ts a n d co n cl us io n s li tt le in si gh t i nt o th e ac tu al c au se o f ad ve rs e su rv iv al o f d ia ly si s pa tie nt s af te r v r . d ec is io n on v r ty pe b as ed o n cl ai m s da ta . c ur re nt pr ac tic e gu id el in es o f u se o f b h ea rt v al ve s in ha em od ia ly si s pa tie nt s sh ou ld b e re sc in de d. r el at iv el y sh or t f ol lo w -u p pe ri od . f ol lo w -u p co m pl et ed in 7 8% . p re fe re nc e sh ou ld b e gi ve n to b va lv e in st ea d of m v al ve p ro st he se s. lo ng -t er m fo llo w -u p av ai la bl e in o nl y 46 p at ie nt s. b va lv es a re th e va lv e su bs tit ut e of c ho ic e. th e st ud y en co m pa ss es d at a fr om 4 h os pi ta ls o ve r 27 y ea rs . v ar ia bi lit y su ch a s su rg ic al te ch ni qu e ca n in flu en ce o ut co m es . fo llo w -u p w as 1 00 % . s ur ge on s sh ou ld n ot he si ta te to im pl an t b v al ve s. fo llo w -u p w as a cc om pl is he d in 9 5. 2% . p ro st he si s se le ct io n sh ou ld b e ba se d on p at ie nt ’s pr ofi le a s w el l a s cr ite ri a fo r no ndi al ys is p at ie nt s. n o st an da rd is ed p ro to co ls u se d fo r pr os th es is ch oi ce ; d at a su bj ec t t o in di vi du al s ur ge on b ia se s. a ls o, n um be r of m v al ve r ec ip ie nt s w as s m al l. u na cc ep ta bl y hi gh r at es o f c om pl . a nd d ea th w ith m v al ve s. c on co m ita nt p ro ce du re s pe rf or m ed in 4 9% o f ca se s. th e ad va nt ag e in th e al lca us e su rv iv al in fa vo ur o f t he m v al ve g ro up is d iffi cu lt to in te rp re t, be ca us e th e pa tie nt s w ho r ec ei ve d b w er e si gn ifi ca nt ly o ld er . r eg ar di ng a or tic v r , di al ys is p at ie nt s ca n be tr ea te d ju st li ke n on di al ys is p at ie nt s. c lin ic al o ut co m es li m ite d to m aj or p os top er at iv e m bd a nd m rt . n o in fo rm at io n on la te c om pl ., q ol o r ca us e of d ea th d ur in g fo llo w -u p. b s sh ou ld b e m or e w id el y us ed in p at ie nt s. o ve ra ll s ur vi va l a t 2ye ar s b : 3 9. 7 ± 3. 5% / m : 9 .7 ± 1 .4 % p = 0. 7 a t 12 m on th s: 6 0% ± 1 2% a t 60 m on th s: 4 2% ± 1 4% a t 3 m on th s: 7 2. 8% a t 1 ye ar : 6 0. 5% a t 6 ye ar s: 1 5. 9% a t 5 ye ar s b : 2 1. 9 ± 7. 1% / m : 5 2 ± 12 .9 % p = 0. 02 99 a t 3 ye ar s b : 3 6% / m : 5 0% a t 5 ye ar s b : 2 7% / m : 3 3% p = 0. 3 su rv iv al r at e at m id te rm b = m p = 0. 87 ev en tfr ee r at e at m id te rm b = m p = 0. 27 3ye ar f f ro m v /r m b d a n d m r t b : 6 9. 9 ± 9% / m : 3 7 ± 14 % p = 0. 03 7 5ye ar a ll -c au se s ur vi va l r at e m b et te r th an b p = 0. 00 1 5ye ar v /r s ur vi va l r at e b = m p = 0. 20 2 a t 5 ye ar s b : 4 2. 4 ± 11 % / m : 5 5 ± 8% p = 0. 44 b le ed in g a n d th ro m bo em bo li c ev en ts n /r b : n on e m : a ll st ro ke b : 4 / m : 8 b le ed in g b : 1 / m : 1 3 5ye ar f f ro m v /r c om pl . b : 8 2. 8 ± 8. 1% / m : 7 6. 4 ± 12 % p = 0. 58 st ro ke b : 1 / m : 2 5ye ar f f ro m h ae m or rh ag e b : 8 1% / m : 7 6% p = 0. 5 b le ed in g b : 5 / m : 1 3 3ye ar f f ro m v /r m b d b : 7 4 ± 9% / m : 4 2 ± 16 % p = 0. 04 3 b le ed in g b : 1 / m : 6 st ro ke b : 1 / m : 4 5ye ar f f ro m r eo pe ra ti on b : 5 1 ± 10 % / m : 5 5 ± 8% p = 0. 75 b f ai lu re n /r 1 ao rt ic a ft er 15 6 m on th s (n ot r eq ui ri ng re op er at io n) 1 m itr al fa ilu re a ft er 54 m on th s; 1 ao rt ic fa ilu re af te r 15 m on th s 1 m itr al fa ilu re a ft er 9 5 m on th s 1 m itr al fa ilu re a ft er 1 0 m on th s 3 fo r al lo gr af t en do ca rd iti s n on e 1 fa ilu re a ft er 11 m on th s hy pe rpt h n on e n on e m ea n fo ll ow -u p 18 .8 ± 2 2. 5 m on th s 32 ± 5 3 m on th s n /r b : 6 8. 4 pa tie nt -y m : 6 0. 4 pa tie nt -y b : 2 .3 ± 1 .2 ye ar s m : 3 .4 ± 2 .5 ye ar s 49 m on th s b : 2 1. 4 ± 18 m on th s m : 1 9. 4 ± 21 m on th s 42 ± 3 1 m on th s 3. 9 ± 2. 5 ye ar s n um be r or % ; m ea n a ge in ye ar s b : 8 81 ; n /r m : 4 ,9 77 ; n /r b : 9 ; 56 .5 m : 1 0 ; 5 6. 6 b : 2 9 ; 6 2. 2 ± 13 m : 4 3 ; 3 .4 ± 1 3 b : 4 7 ; 6 4. 7 ± 14 m : 2 2 ; 5 5. 5 ± 12 b : 2 5 ; 5 9 ± 15 m : 1 7 ; 5 4 ± 18 b : 2 2 ; 6 1. 5 ± 7. 7 m : 3 7 ; 5 6. 5 ± 9. 4 b : 3 3 ; 5 3 m : 1 7 ; 5 1 b : 2 2 ; 7 3. 4 ± 4. 2 m : 5 1 ; 6 1. 5 ± 7. 9 b : 4 1% ; 67 ± 1 2 m : 3 2% ; 55 ± 1 4 a or ti c/ m it ra l/ a or to m it ra l 3, 39 8/ 1, 87 5/ 58 5 12 /5 /2 55 /3 7/ 0 3 tr ic us pi d 40 /2 2/ 0 7 m ul tip le 27 /1 1/ 4 44 /1 3/ 7 31 /2 9 73 /0 /0 n /r a ut ho r an d st ud y pe ri od o ve ra ll p at ie nt s h er zo g, e t a l.4 1 97 8– 19 98 5, 85 8 lu ck e, e t a l.2 1 97 9– 19 94 19 b ri nk m an , e t a l.5 1 98 5– 20 00 72 (7 4 v r ) c ha n, e t a l.6 1 98 5– 20 00 69 k ap lo n, e t a l.3 1 98 6– 19 98 42 u m ez u, e t a l.9 1 99 0– 20 07 63 (6 4 v r ) to ol e, e t a l.7 1 99 1– 20 04 50 (6 0 v r ) ta na ka , e t a l.1 0 1 99 5– 20 07 73 fi ls ou fi, e t a l.8 1 99 8– 20 06 g 1 : 4 7 n d d r f g 2 : 1 08 d ia ly si s b = bi op ro st he sis ; m = m ec ha ni ca l; v r = va lv e r ep la ce m en t; n /r = n ot re co rd ed ; p at ie nt -y = p at ie nt -y ea r; f = fr ee do m ;v /r = v al ve -r el at ed ; c om pl . = co m pl ic at io ns ; h yp er -p t h = h yp er pa ra th yr oi di sm ; m bd = m or bi di ty ; m rt = m or ta lit y; g = g ro up ; n d d rf = n on -d ia ly sis -d ep en de nt re na l f ai lu re ; q ol = q ua lit y of li fe . ta bl e 1: l it er at ur e re vi ew c om pa ri ng th e ou tc om es o f b io pr os th es is v er su s m ec ha ni ca l v al ve re pl ac em en t i n pa ti en ts w it h en dst ag e re na l d is ea se o n ch ro ni c di al ys is jamil hajj-chahine, ziad s. dahdouh and tony abdel-massih technical note | 584 c om m en ts a n d co n cl us io n s li tt le in si gh t i nt o th e ac tu al c au se o f ad ve rs e su rv iv al o f d ia ly si s pa tie nt s af te r v r . d ec is io n on v r ty pe b as ed o n cl ai m s da ta . c ur re nt pr ac tic e gu id el in es o f u se o f b h ea rt v al ve s in ha em od ia ly si s pa tie nt s sh ou ld b e re sc in de d. r el at iv el y sh or t f ol lo w -u p pe ri od . f ol lo w -u p co m pl et ed in 7 8% . p re fe re nc e sh ou ld b e gi ve n to b va lv e in st ea d of m v al ve p ro st he se s. lo ng -t er m fo llo w -u p av ai la bl e in o nl y 46 p at ie nt s. b va lv es a re th e va lv e su bs tit ut e of c ho ic e. th e st ud y en co m pa ss es d at a fr om 4 h os pi ta ls o ve r 27 y ea rs . v ar ia bi lit y su ch a s su rg ic al te ch ni qu e ca n in flu en ce o ut co m es . fo llo w -u p w as 1 00 % . s ur ge on s sh ou ld n ot he si ta te to im pl an t b v al ve s. fo llo w -u p w as a cc om pl is he d in 9 5. 2% . p ro st he si s se le ct io n sh ou ld b e ba se d on p at ie nt ’s pr ofi le a s w el l a s cr ite ri a fo r no ndi al ys is p at ie nt s. n o st an da rd is ed p ro to co ls u se d fo r pr os th es is ch oi ce ; d at a su bj ec t t o in di vi du al s ur ge on b ia se s. a ls o, n um be r of m v al ve r ec ip ie nt s w as s m al l. u na cc ep ta bl y hi gh r at es o f c om pl . a nd d ea th w ith m v al ve s. c on co m ita nt p ro ce du re s pe rf or m ed in 4 9% o f ca se s. th e ad va nt ag e in th e al lca us e su rv iv al in fa vo ur o f t he m v al ve g ro up is d iffi cu lt to in te rp re t, be ca us e th e pa tie nt s w ho r ec ei ve d b w er e si gn ifi ca nt ly o ld er . r eg ar di ng a or tic v r , di al ys is p at ie nt s ca n be tr ea te d ju st li ke n on di al ys is p at ie nt s. c lin ic al o ut co m es li m ite d to m aj or p os top er at iv e m bd a nd m rt . n o in fo rm at io n on la te c om pl ., q ol o r ca us e of d ea th d ur in g fo llo w -u p. b s sh ou ld b e m or e w id el y us ed in p at ie nt s. o ve ra ll s ur vi va l a t 2ye ar s b : 3 9. 7 ± 3. 5% / m : 9 .7 ± 1 .4 % p = 0. 7 a t 12 m on th s: 6 0% ± 1 2% a t 60 m on th s: 4 2% ± 1 4% a t 3 m on th s: 7 2. 8% a t 1 ye ar : 6 0. 5% a t 6 ye ar s: 1 5. 9% a t 5 ye ar s b : 2 1. 9 ± 7. 1% / m : 5 2 ± 12 .9 % p = 0. 02 99 a t 3 ye ar s b : 3 6% / m : 5 0% a t 5 ye ar s b : 2 7% / m : 3 3% p = 0. 3 su rv iv al r at e at m id te rm b = m p = 0. 87 ev en tfr ee r at e at m id te rm b = m p = 0. 27 3ye ar f f ro m v /r m b d a n d m r t b : 6 9. 9 ± 9% / m : 3 7 ± 14 % p = 0. 03 7 5ye ar a ll -c au se s ur vi va l r at e m b et te r th an b p = 0. 00 1 5ye ar v /r s ur vi va l r at e b = m p = 0. 20 2 a t 5 ye ar s b : 4 2. 4 ± 11 % / m : 5 5 ± 8% p = 0. 44 b le ed in g a n d th ro m bo em bo li c ev en ts n /r b : n on e m : a ll st ro ke b : 4 / m : 8 b le ed in g b : 1 / m : 1 3 5ye ar f f ro m v /r c om pl . b : 8 2. 8 ± 8. 1% / m : 7 6. 4 ± 12 % p = 0. 58 st ro ke b : 1 / m : 2 5ye ar f f ro m h ae m or rh ag e b : 8 1% / m : 7 6% p = 0. 5 b le ed in g b : 5 / m : 1 3 3ye ar f f ro m v /r m b d b : 7 4 ± 9% / m : 4 2 ± 16 % p = 0. 04 3 b le ed in g b : 1 / m : 6 st ro ke b : 1 / m : 4 5ye ar f f ro m r eo pe ra ti on b : 5 1 ± 10 % / m : 5 5 ± 8% p = 0. 75 b f ai lu re n /r 1 ao rt ic a ft er 15 6 m on th s (n ot r eq ui ri ng re op er at io n) 1 m itr al fa ilu re a ft er 54 m on th s; 1 ao rt ic fa ilu re af te r 15 m on th s 1 m itr al fa ilu re a ft er 9 5 m on th s 1 m itr al fa ilu re a ft er 1 0 m on th s 3 fo r al lo gr af t en do ca rd iti s n on e 1 fa ilu re a ft er 11 m on th s hy pe rpt h n on e n on e m ea n fo ll ow -u p 18 .8 ± 2 2. 5 m on th s 32 ± 5 3 m on th s n /r b : 6 8. 4 pa tie nt -y m : 6 0. 4 pa tie nt -y b : 2 .3 ± 1 .2 ye ar s m : 3 .4 ± 2 .5 ye ar s 49 m on th s b : 2 1. 4 ± 18 m on th s m : 1 9. 4 ± 21 m on th s 42 ± 3 1 m on th s 3. 9 ± 2. 5 ye ar s n um be r or % ; m ea n a ge in ye ar s b : 8 81 ; n /r m : 4 ,9 77 ; n /r b : 9 ; 56 .5 m : 1 0 ; 5 6. 6 b : 2 9 ; 6 2. 2 ± 13 m : 4 3 ; 3 .4 ± 1 3 b : 4 7 ; 6 4. 7 ± 14 m : 2 2 ; 5 5. 5 ± 12 b : 2 5 ; 5 9 ± 15 m : 1 7 ; 5 4 ± 18 b : 2 2 ; 6 1. 5 ± 7. 7 m : 3 7 ; 5 6. 5 ± 9. 4 b : 3 3 ; 5 3 m : 1 7 ; 5 1 b : 2 2 ; 7 3. 4 ± 4. 2 m : 5 1 ; 6 1. 5 ± 7. 9 b : 4 1% ; 67 ± 1 2 m : 3 2% ; 55 ± 1 4 a or ti c/ m it ra l/ a or to m it ra l 3, 39 8/ 1, 87 5/ 58 5 12 /5 /2 55 /3 7/ 0 3 tr ic us pi d 40 /2 2/ 0 7 m ul tip le 27 /1 1/ 4 44 /1 3/ 7 31 /2 9 73 /0 /0 n /r a ut ho r an d st ud y pe ri od o ve ra ll p at ie nt s h er zo g, e t a l.4 1 97 8– 19 98 5, 85 8 lu ck e, e t a l.2 1 97 9– 19 94 19 b ri nk m an , e t a l.5 1 98 5– 20 00 72 (7 4 v r ) c ha n, e t a l.6 1 98 5– 20 00 69 k ap lo n, e t a l.3 1 98 6– 19 98 42 u m ez u, e t a l.9 1 99 0– 20 07 63 (6 4 v r ) to ol e, e t a l.7 1 99 1– 20 04 50 (6 0 v r ) ta na ka , e t a l.1 0 1 99 5– 20 07 73 fi ls ou fi, e t a l.8 1 99 8– 20 06 g 1 : 4 7 n d d r f g 2 : 1 08 d ia ly si s the initial valve replacement surgery) were identified from the 9 retrospective studies.2–10 of note, the mean follow-up of each study was relatively short; therefore, definite conclusions about the longterm performance of tissue valves in this patient population cannot be drawn. bleeding was the most common valve-related complication, representing a major drawback of mechanical valves. thromboembolic events were reported in 35 patients, of whom 31 received mechanical prostheses. a total of 7 of the 9 studies did not demonstrate a survival difference according to prosthesis type. the remaining two studies demonstrated a survival advantage in favour of mechanical prostheses.6,10 however, patients who received bioprosthetic valves were older and more likely to have had a previous myocardial infarction or to have received concomitant coronary artery bypass grafting. recently, chan et al. performed a systematic review and meta-analysis of valve replacement in patients on dialysis.11 in 9 studies published from 1997 to 2010, no difference in survival was observed between the valve types (bioprosthesis versus mechanical prosthesis; hazard ratio 1.3, 95% ci 1.0– 1.9, p = 0.09). however, bioprosthetic valves were associated with fewer valve-related complications compared with mechanical prostheses (odds ratio 0.4, 95% ci 0.2–0.7, p = 0.002). they concluded that there was no survival difference following valve replacement with either bioprosthesis or mechanical prosthesis in patients on dialysis. more recently, pai et al. published their review on the same subject. they found 8 relevant retrospective studies and concluded that there was no significant difference in the results and survival between patients receiving a mechanical and those receiving a bioprosthetic valve.12 however, bleeding complications were more common with mechanical valves. conclusion it can be concluded that dialysis patients after cardiac valve replacement suffer poor midterm and long-term survival rates. therefore, due to the limited life expectancy of these patients, physicians should not hesitate to implant bioprosthetic valves because svd will be uncommon in this patient population. prosthesis selection should be based on the same criteria used for non-dialysis patients. references 1. lamberti jj, wainer bh, fisher ka, karunaratne hb, al-sadir j. calcific stenosis of the porcine heterograft. ann thorac surg 1979; 28:28–32. 2. lucke jc, samy rn, atkins bz, silvestry sc, douglas jm jr, schwab sj, et al. results of valve replacement with mechanical and biological prostheses in chronic renal dialysis patients. ann thorac surg 1997; 64:129–32. 3. kaplon rj, cosgrove dm 3rd, gillinov am, lytle bw, blackstone eh, smedira ng. cardiac valve replacement in patients on dialysis: influence of prosthesis on survival. ann thorac surg 2000; 70:438–41. 4. herzog ca, ma jz, collins aj. long-term survival of dialysis patients in the united states with prosthetic heart valves: should acc/aha practice guidelines on valve selection be modified? circulation 2002; 105:1336–41. 5. brinkman wt, williams wh, guyton ra, jones el, craver jm. valve replacement in patients on chronic renal dialysis: implications for valve prosthesis selection. ann thorac surg 2002; 74:37–42. 6. chan v, jamieson wr, fleisher ag, denmark d, chan f, germann e. valve replacement surgery in end-stage renal failure: mechanical prostheses versus bioprostheses. ann thorac surg 2006; 81:857–62. 7. toole jm, stroud mr, kratz jm, crumbley aj 3rd, crawford fa jr, ikonomidis js. valve surgery in renal dialysis patients. j heart valve dis 2006; 15:453–8. 8. filsoufi f, chikwe j, castillo jg, rahmanian pb, vassalotti j, adams dh. prosthesis type has minimal impact on survival after valve surgery in patients with moderate to end-stage renal failure. nephrol dial transplant 2008; 23:3613–21. 9. umezu k, saito s, yamazaki k, kawai a, kurosawa h. cardiac valvular surgery in dialysis patients: comparison of surgical outcome for mechanical versus bioprosthetic valves. gen thorac cardiovasc surg 2009; 57:197–202. 10. tanaka k, tajima k, takami y, okada n, terazawa s, usui a. early and late outcomes of aortic valve replacement in dialysis patients. ann thorac surg 2010; 89:65–70. 11. chan v, chen l, mesana l, mesana tg, ruel m. heart valve prosthesis selection in patients with endstage renal disease requiring dialysis: a systematic review and meta-analysis. heart 2011; 97:2033–7. 12. pai vb, tai ck, bhakri k, kolvekar s. should we use mechanical valves in patients with end-stage renal disease? interact cardiovasc thorac surg 2012; 15:240–3. 1department of ear, nose & throat, al zahra hospital, dubai, united arab emirates; 2department of anaesthesia & critical care, muscat private hospital, muscat, oman; 3department of oto-rhino-laryngology & bronchology, heim pál children's hospital, budapest, hungary *corresponding author e-mail: levente.deak@azhd.ae مقارنة مدى شدة األمل الذي يعقب عملية استئصال اللوزة عند األطفال باستخدام طريقيت بضع اللوزة داخل احملفظة و الطريقة التقليدية اإلنضار الدقيق و الرتددات الشعاعية مقابل الطريقة التقليدية ليفنيت ديك، ديفيد ساكستون، كيث جونسون، باملا بينديك، جابور كاتونا abstract: objectives: the aim of this study was to compare the duration and severity of postoperative pain for two different tonsillotomy techniques (radiofrequency [rf] and microdebrider [md]) with the standard tonsillectomy. methods: this non-randomised retrospective study, carried out from february 2011 to september 2012, investigated 128 children in two independent centres: heim pál children’s hospital in budapest, hungary, and muscat private hospital in muscat, oman. those undergoing conventional tonsillectomies acted as the control group. one centre tested the md technique (n = 28) while the other centre tested the rf technique (n = 31). results: the pain-free period after the tonsillotomies was similar between the two techniques and ranged up to three days. other indicators of pain resolution, like the use of a single analgesic, reduced night-time waking and the time taken to resume a normal diet, were also similar for the two groups. however, patients benefited significantly from having a tonsillotomy rather than a tonsillectomy. conclusion: the partial resectioning of tonsillar tissue using the md and rf techniques showed promising outcomes for a better postoperative quality of life when compared to a traditional tonsillectomy. in this study, the results of both the md and rf tonsillotomy methods were almost identical in terms of the duration of postoperative pain and recovery time. keywords: quality of life; postoperative pain; obstructive sleep apnoea; tonsillotomy; tonsillectomy. الإن�ضار بطريقتي الأطفال عند املحفظة داخل اللوزة ب�ضع عملية يعقب الذي الأمل و�ضدة مدة ملقارنة الدرا�ضة هذه تهدف امللخ�ص: الهدف: 2011م فرباير بني ع�ضوائيا املختارة وغري ال�ضتعادية الدرا�ضة هذه اأجريت الطريقة: التقليدية. الطريقة مقابل ال�ضعاعية والرتددات الدقيق و�ضبتمرب 2012م على 128 طفل مبركزين م�ضتقلني هما م�ضت�ضفى هامي بال للأطفال مبدينة بوداب�ضت باملجر، وم�ضت�ضفى خا�ص يف م�ضقط بعمان. وا�ضتخدمت جمموعة من الأطفال الذين اأجريت عليهم عمليات تقليدية ل�ضتئ�ضال اللوزتني كمجموعة �ضابطة. واأجريت العمليات بطريقة تكن مل الآخر.النتائج: املركز يف طفل 31 على ال�ضعاعية الرتددات بطريقة اأجريت بينما طفل، 28 على املركزين اأحد يف الدقيق الإن�ضار هنالك فروقات معنوية بني الطريقتني يف الفرتة الزمنية التي مل يكن فيها اأمل عقب العملية، والتي ا�ضتمرت اإىل نحو ثلثة اأيام، ول يف موؤ�رشات الربء من الأمل مثل ا�ضتخدام م�ضكن واحد �ضد الأمل، وتقليل فرتة ال�ضتيقاظ ليل، والوقت اللزم الستئناف تناول الطعام العادي. غري اأن ا�ضتفادة الأطفال من عمليات ب�ضع اللوزة كانت اأكرب منها عقب عمليات ا�ضتئ�ضال اللوزتني. اخلال�صة: كانت نتائج القطع اجلزئي لأن�ضجة اللوزة عن طريق الإن�ضار الدقيق اأو الرتددات ال�ضعاعية م�ضجعة يف ما يتعلق بنوعية احلياة بعد العملية، واأف�ضل من نتائجها عند اإجراء عمليات تقليدية ل�ضتئ�ضال اللوزتني. واأثبتت هذه الدرا�ضة عدم وجود فروقات معنوية بني نتائج طريقتي الإن�ضار الدقيق والرتددات ال�ضعاعية يف مدة الأمل الذي يعقب العملية، ومدة الإفاقة. مفتاح الكلمات: نوعية احلياة؛ اأمل ما بعد العمليةة؛ انقطاع النف�ص النومي الن�ضدادي؛ ب�ضع اللوزة؛ ا�ضتئ�ضال اللوزتني. comparison of postoperative pain in children with two intracapsular tonsillotomy techniques and a standard tonsillectomy microdebrider and radiofrequency tonsillotomies versus standard tonsillectomies *levente deak,1 david saxton,1 keith johnston,2 palma benedek,3 gábor katona3 clinical & basic research advances in knowledge the purpose of this study was to promote the intracapsular tonsillotomy technique among surgeons in the middle east. previous studies have found that this technique is as effective as the tonsillectomy technique in the management of childhood sleep disorders caused by tonsillar tissue hypertrophy. intracapsular tonsillotomies, performed using either the radiofrequency (rf) or microdebrider (md) method, could provide a better quality of life for patients after surgery, compared to a standard tonsillectomy. although this study did not look at the long-term results of these methods, it still portrays clear evidence of patient benefit, specifically in the areas of postoperative pain and recovery time. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e500−505, epub. 14th oct 14 submitted 12th feb 14 revision req. 26th mar 14; revision recd. 7th may 14 accepted 28th may 14 levente deak, david saxton, keith johnston, palma benedek and gábor katona clinical and basic research | e501 the frequency of upper respiratory infections during childhood commonly leads to an enlargement of the adenotonsillar tissue. this, combined with the relatively narrow airway of a child, can ultimately lead to airway obstruction.1 a partial or complete upper airway obstruction disrupts normal sleeping patterns and is known as obstructive sleep apnoea. this can manifest as daytime sleepiness, poor concentration, morning headaches or developmental problems.2 the management of sleep disorders caused by tonsillar tissue hypertrophy involves surgery. this surgery can either be partial, where the tonsillar capsule remains intact, or total, which involves the removal of the enlarged lymphoid tissue. both methods have similar long-term beneficial effects on sleeping patterns.3,4 in the past, tonsillar surgery involved bulk tissue reduction by guillotine. later, with the advent of instruments of greater precision, surgeries were extended to include the removal of the tonsillar capsule. the rationale behind this surgical extension was so as to leave no residual infected tissue behind. as surgical methods have changed, so has the indication for the surgery—from eliminating chronic infection to enlarging the airway by reducing the adenotonsillar tissue size.5,6 recently, several new tonsillar reduction techniques have been introduced, including microdebrider (md), radiofrequency (rf), laser and coblation techniques.7,8 all of these approaches manipulate the tonsils with the aim of improving a patient’s quality of life (qol) while reducing the operating time and patient blood loss. a recent systematic review of intracapsular versus total tonsillectomies indicated that procedures to reduce tonsillar size were as safe as a conventional tonsillectomy,9 while wireklint et al. found that a tonsillotomy could provide similar long-term results to that of a tonsillectomy.4 as observed in a study by sorin et al., a patient’s qol during the postoperative period following a tonsillar procedure may be influenced by the technique used to manipulate the tonsils.10 it follows, therefore, that a partial resection of the tonsillar tissue can potentially reduce the postoperative complication rate. by keeping the capsules intact, the remaining tonsillar tissue acts as an additional protective layer for the underlying neurovascular tissues. for practical purposes, a partial tonsillectomy is effectively a refinement of the historical tonsillar guillotine method.11 most of the published literature on the effects of tonsillotomy and tonsillectomy techniques lack standardisation for factors such as steroid or analgesic use, postoperative antibiotic treatment or the surgical method employed, all of which may influence overall patient outcomes.12,13 the purpose of this study, therefore, was to study a standardised normative population in order to achieve two research objectives: (1) to define the role of the tonsillar capsule in limiting patients’ postoperative qol, and (2) to investigate whether a md modified cold steel technique or a temperature-controlled rf method would demonstrate more favourable outcomes when compared with a total tonsillectomy. methods in this prospective non-randomised study, a total of 128 children (78 boys and 50 girls, with an age range of 3–11 years) were recruited among patients of heim pál children`s hospital (hpch) in budapest, hungary, and muscat private hospital (mph) in muscat, oman. all of the patients had been referred for tonsillar surgery by their primary physician due to an obstructed airway, with a diagnosis of adenotonsillar hypertrophy. the protocol for this study was designed by two experienced ear, nose and throat surgeons and the study population was standardised for surgical methodology and postoperative pain management. a full clinical history was taken from the patients’ caregivers during the initial consultation. on clinical examination, tonsillar size was assessed and patients were included in the study if their tonsils occupied at least 50% of the pharyngeal space. patients with a diagnosis of chronic tonsillitis, suspected severe obstructive sleep apnoea or any congenital deformities were automatically excluded from the study as these application to patient care since the tonsillar capsule is left intact during a tonsillotomy, the underlying vulnerable arteries and nerves are not exposed; therefore, the risk of patients developing postoperative bleeding or experiencing uncontrolled pain is reduced with this procedure. postoperative pain after a tonsillotomy can be managed with the use of oral paracetamol alone. in contrast, a patient receiving a tonsillectomy requires a combination of postoperative therapies. as the potential for postoperative complications is reduced, a rf or md tonsillotomy can be performed easily on an outpatient basis as a day case procedure. comparison of postoperative pain in children with two intracapsular tonsillotomy techniques and a standard tonsillectomy microdebrider and radiofrequency tonsillotomies versus standard tonsillectomies e502 | squ medical journal, november 2014, volume 14, issue 4 patients require a longer hospitalisation period with specialised care which could have directly influenced the results of the study.14 all patients who were referred for a tonsillectomy due to adenotonsillar hypertrophy between february and october 2011 at either hospital underwent a standard cold steel tonsillectomy. those who were referred between november 2011 and september 2012 to either hospital underwent a tonsillotomy. the tonsillectomy groups from each centre acted as control groups in order to measure four specific morbidity points: the severity and duration of postoperative pain and the time taken to return to a normal diet and lifestyle. the control group from hpch was labelled ttc1 while the control group from mph was labelled ttc2. the morbidity outcomes for the two control groups were then compared. since there were no significant differences in the measured outcomes between the two centres, data from each site were used to represent a single control group. thereafter, mph elected to perform tonsillotomies using the md method while hpch chose to use the rf technique. the studied patients were all routinely assessed preoperatively by the same anaesthetist who would administer the anaesthesia during their surgical procedure. since the patients had all been diagnosed as having mild obstructive symptoms, no further sleep studies or cardiac investigations were deemed necessary. in all cases, a full health history and systematic examination was done. as per hospital protocol, a blood test, including a complete blood count and a coagulation measurement, was requested for all patients. premedication with midazolam and chloral hydrate was avoided due to the potential risk of preoperative airway obstruction. the induction of anaesthesia was either done intravaenously or inhalationally, depending on the child. patients were paralysed using a non-depolarising muscle relaxant and then intubated with a south-facing ring-adairelwyn tube. the anaesthesia was maintained with sevoflurane. dexamethasone (5 mg/kg up to a maximum of 25 mg) was also given during the surgery as the use of steroids has been shown to improve postoperative oral intake and reduce vomiting and pain among patients.14 all surgeries were performed under general anaesthesia. patients were put in the rose position with a mouth gag to retract the mandible. tonsillectomies were performed by standard extra-capsular dissection and bipolar forceps were used for coagulation. adenoidectomies, if needed, were performed using a standard curettage technique. all procedures were performed by experienced consultants and care was taken to preserve the mucosa around the tonsillar tissue, uvula and anterior and posterior pillars. the md tonsillotomies were carried out using a unidrive® s iii eco (karl storx gmbh & co. kg., tuttlingen, germany) high-speed drill with both straight and curved blades. a hurd tonsil dissector and pillar retractor was used to mobilise the palatoglossus muscle for better visualisation of the tonsillar tissue during the operation. initially, a lower rotation rate was selected, permitting the removal of a larger portion of tonsillar tissue. the frequency was increased up to 4,500 rpm upon reaching the core of the tonsil. if minor bleeding was observed at the end of the procedure, the tonsillar bed and residual tissue was covered for a short time with tonsil packs soaked in adrenaline (1:100,000). in most cases, the bleeding was self-limiting, abating during the time taken to complete the procedure on the opposite tonsil. in seven cases, minor bipolar cauterisation (20 w) was applied to the tonsillar surface, taking care to avoid deep thermal damage. with the temperature-controlled rf tonsillotomies, tonsillar reduction was achieved using the surgitron® dual frequency rf/120 iec with empire® microincision™ needles and loop electrodes (ellman international, inc., hicksville, new york, usa). with the unit set to the cutting/coagulation mode (power = 45 w, frequency = 4 mhz), an incision was started 2 mm from the tonsillar pillar. after marking the height of the resection, the loop electrode was used to reduce the size of the tonsillar tissue from the bed, leaving behind a small amount of tonsillar tissue and the capsule. following the procedure, both of the tonsillar beds were covered with adrenaline-soaked tonsil packs. in three cases, further coagulation in the device’s haemostasis mode was used to complete the haemostasis. pain management after tonsillar surgery remains challenging. it is now recommended that physicians avoid prescribing opioid analgesics; once common, this form of pain management is now discouraged due to the possibility of respiratory depression, which could be fatal in patients already prone to sleep disturbances.15,16 instead, non-steroidal antiinflammatory drugs, which are not associated with an increased risk of postoperative bleeding, are now widely used for postoperative pain management in combination with paracetamol.17,18 studies often employ standardised pain assessment rating scales such as the visual analog scale or the wong-baker faces pain rating scale. however, in this study, an inhouse questionnaire was designed to assess specific surrogate factors of pain: the use of either a single analgesic (paracetamaol) or combined analgesics (paracetamol and ibuprofen); the number of days levente deak, david saxton, keith johnston, palma benedek and gábor katona clinical and basic research | e503 where painkillers were necessary; the number of nights during which the child woke up due to pain; the number of days before the resumption of a normal diet (abated discomfort from swallowing), and the number of days before the child was able to return to school. during the patients’ postoperative care, caregivers were instructed to provide analgesics as needed. as a first-line therapy, oral paracetamol (15 mg/kg–1) was given and repeated as necessary up to four times daily. for cases where oral analgesia was not tolerated, or the maximum permissible dose of paracetamol had been reached, ibuprofen (5 mg/kg–1) was provided either orally or as a suppository. caregivers were asked to keep a record of analgesic use and frequency as well as of the other factors outlined in the pain assessment questionnaire. a research assistant at each centre was assigned to coordinate the patients’ follow-up using the in-house pain assessment questionnaire. this was done with each patient’s caregiver either personally or over the phone after seven postoperative days. for those still recovering, a second interview was scheduled after a further seven days. postoperative days were counted from the first day after surgery (24 hours after the procedure). data were excluded in cases where the pain assessment questionnaire was either incomplete or not attempted at all. for the statistical analysis, the non-parametric mann-whitney u test was used and data were presented as mean ± standard deviation. statistical significance was established at p <0.05. this study was approved by the institutional ethical committees of hpch in budapest, hungary, and mph in muscat, oman (approval nos. 01/2011 and ec/mph/11/2010, respectively). informed consent was received from the caregivers of all patients included in the study. results during the study period, 69 tonsillectomies were performed in the ttc1 (n = 39) and ttc2 (n = 30) groups, while 28 patients underwent an md tonsillotomy and 31 patients underwent an rf tonsillotomy. in two cases, the patients’ caregivers declined the tonsillotomy and requested a tonsillectomy. all of the patients were discharged one day after their surgery, with no patients requiring prolonged hospitalisation. in terms of the postoperative pain evaluation, those undergoing a tonsillectomy were pain-free after 7 ± 3.4 and 9 ± 2.1 days in the ttc1 and ttc2 groups, respectively. the difference was not statistically significant. a total of 25 patients (64%) from the ttc1 group and 16 (53%) from the ttc2 group reported the need for combined analgesics (paracetamol and ibuprofen). pain severity was also measured by the supplementary use of analgesics during the night. among the control groups, 19 patients (48%) in the ttc1 group and 17 patients (56%) in the ttc2 group requested a supplementary night-time dose of analgesics. the extent of analgesic use among the tonsillotomy groups (md and rf) was also assessed. those who had had a partial tonsillectomy using the md reported a mean painful period of 3 ± 1.7 days. when compared with one of the control groups (ttc1), this difference was statistically significant (p <0.01) [figure 1]. a combination of paracetamol and an nsaid was necessary in only one of the 28 patients, and none of the children from this group awoke during the night due to pain. patients treated by the rf procedure reported a mean painful period of 3 ± 2.4 days. this was again statistically significant (p <0.01) when compared with the control group (ttc2). three rf patients required the use of combined analgesics, and seven patients (23%) needed a supplementary dose of an analgesic during the night. when assessing the time taken for the patient to resume a normal diet of solids after their initial fluid diet, the mean time for the md subjects was 3 ± 1.3 days. this was significantly reduced in comparison to the ttc1 group which took 6.2 ± 4 days (p <0.05). for those in the rf group, the transition took longer, with a mean duration of 5 ± 2.8 days. however, this was still significantly reduced in comparison to the control group (ttc2) which took 9.5 ± 5 days (p <0.05). a figure 1: comparison of the number of days with postoperative pain among the two tonsillectomy control groups, the microdebridation tonsillotomy group and the radiofrequency tonsillotomy group. md = microdebridation; ttc1 = control group affiliated with heim pál children's hospital; rf = radiofrequency; ttc2 = control group affiliated with muscat private hospital. comparison of postoperative pain in children with two intracapsular tonsillotomy techniques and a standard tonsillectomy microdebrider and radiofrequency tonsillotomies versus standard tonsillectomies e504 | squ medical journal, november 2014, volume 14, issue 4 comparison between the time taken in both the rf and md groups was not statistically significant. one of the specific postoperative outcomes assessed was whether the children were able to return to school within 1–2 weeks following the operation. in this study, all patients were currently attending either a nursery or primary school. if the sixth and seventh postoperative days coincided with a weekend, these were considered to be two extra recovery days. a total of 26 children (91%) in the md group and 25 children (80%) in the rf group returned to school within seven postoperative days. in the control groups, none of the 69 children were able to resume their school activities within the first postoperative week. in terms of postoperative complications, all three methods were found to be safe, with none of the cases requiring surgical intervention due to postoperative bleeding. of the patients from the tonsillectomy control groups, three out of 69 had to be readmitted for observation due to reports of blood in the sputum. discussion the concept of a partial tonsillectomy, otherwise known as a tonsillotomy, was conceived by hultcrantz,19 koltai7 and friedman,8 who used different methods to achieve the same result: a reduction in the bulk of tonsillar tissue. the main advantage of an intracapsular tonsillotomy is the protection of the arteries and nerves behind the tonsillar capsule, which can be damaged during the operation or exposed to local infections during the postoperative period. it has been shown that retaining a small amount of tonsillar tissue between the anterior and posterior pillar can significantly reduce the postoperative recovery time.9,11 however, it should be noted that there are some possible disadvantages of leaving residual tissue in tonsillotomy surgeries, as a later progression to lymphoid hyperplasia may be possible. theoretically, the remaining tissue could also be a focus point for chronic inflammation, which may later require a tonsillectomy. however, this possibility is low (1–3%) and is offset by the increased morbidity associated with tonsillectomies.10 although three out of 69 children undergoing tonsillectomies in the current study had to be readmitted for observation due to reports of blood in the sputum, no conclusions could be made regarding the relative risk of postoperative haemorrhage among the different methods due to the relatively small sample size. all three methods were found to be safe, with none of the cases requiring surgical intervention due to postoperative bleeding. the results of this current study clearly demonstrate the benefits of tonsillotomies over tonsillectomies, since patients from both the rf and md groups required postoperative pain relief for approximately four days only. this is significantly shorter than the mean seven days required by the tonsillectomy control groups. additionally, the postoperative pain among the children undergoing tonsillotomies was easier to manage since most of the patients required paracetamol alone (96% and 90% in the md and rf groups, respectively); within the tonsillectomy groups, between 53−64% of the children required a combination of analgesics (paracetamol with ibuprofen), suggesting more severe pain in these groups. other surrogate factors, like the earlier resumption of a normal diet and return to school, indicate that the less traumatic approach of a tonsillotomy has a significant positive impact on postoperative qol among children. these recorded values and findings closely correlate with those of other researchers investigating the outcomes of tonsillotomies.9,19 a previous study by leinbach et al. has shown that thermal injury, occurring as a result of the cauterisation of the tonsillar fossa, correlates directly with the extent of postoperative pain, due to injury to the underlying branches of the glossopharyngeal and vagal nerves.11 the rf tonsillotomy technique generates heat at around 40–70 oc, which could potentially cause such a thermal injury, although this temperature range is lower than that produced during electrocautery.8 this temperature range during rf surgery might explain why more rf patients required a combination of analgesics (10% versus 4% in the md group) and why 23% needed supplementary doses of analgesics due to night-time waking in comparison to 0% among the md group. however, the average recovery time between the md and rf groups was the same. the results of this study should be interpreted with caution as the sample size used was too small to infer any statistical significance. further studies with larger cohorts would be useful in determining any differences between the two tonsillotomy methods. conclusion in all previously published studies, tonsillotomy methods have been compared to the standard tonsillectomy surgery without using standardised controls. using standardised methodology, meaningful comparisons can be made when considering surgery for tonsillar hypertrophy. the results of this standardised study demonstrated that the recovery period after a tonsillotomy is superior to that levente deak, david saxton, keith johnston, palma benedek and gábor katona clinical and basic research | e505 required after a tonsillectomy. a comparison of the two tonsillotomy methods showed no difference in the duration of postoperative pain or time taken to recover. therefore, a tonsillotomy by either md or rf methods should be considered as the first choice of surgery for tonsillar tissue reduction. these techniques are recommended for surgeons in the middle east and around the world. references 1. bhattacharyya n, lin hw. changes and consistencies in the epidemiology of pediatric adenotonsillar surgery, 19962006. otolaryngol head neck surg 2010; 143:680–4. doi: 10.1016/j.otohns.2010.06.918. 2. baldwin cm, quan sf. sleep disordered breathing. nurs clin north am 2002; 37:633–54. doi: 10.1016/s00296465(02)00030-0. 3. stewart mg, liotta dr. is partial tonsillectomy equivalent to total tonsillectomy for obstructive symptoms? laryngoscope 2011; 12:6–7. doi: 10.1002/lary.21340. 4. wireklint s, ericsson e. health-related quality of life after tonsillotomy versus tonsillectomy in young adults: 6 years postsurgery follow-up. eur arch otorhinolaryngol 2012; 269:1951–8. doi: 10.1007/s00405-012-1990-y. 5. curtin jm. the history of tonsil and adenoid surgery. otolaryngol clin north am 1987; 20:415–19. 6. koempel ja, solares ca, koltai pj. the evolution of tonsil surgery and rethinking the surgical approach to obstructive sleep-disordered breathing in children. j laryngol otol 2006; 120:993–1000. doi: 10.1017/s0022215106002544. 7. koltai pj, solares ca, mascha ej, xu m. intracapsular partial tonsillectomy for tonsillar hypertrophy in children. laryngoscope 2002; 112:17–19. doi: 10.1002/ lary.5541121407. 8. friedman m, losavio p, ibrahim h, ramakrishnan v. radiofrequency tonsil reduction: safety, morbidity, and efficacy. laryngoscope 2003; 113:882–7. doi: 10.1097/00005537-200305000-00020. 9. walton j, ebner y, stewart mg, april mm. systematic review of randomized controlled trials comparing intracapsular tonsillectomy with total tonsillectomy in a pediatric population. arch otolaryngol head neck surg 2012; 138:243–9. doi: 10.1001/archoto.2012.16. 10. sorin a, bent jp, april mm, ward rf. complications of microdebrider-assisted powered intracapsular tonsillectomy and adenoidectomy. laryngoscope 2004; 114:297–300. doi: 10.1097/00005537-200402000-00022. 11. leinbach rf, markwell sj, colliver ja, lin sy. hot versus cold tonsillectomy: a systematic review of the literature. otolaryngol head neck surg 2003; 129:360–4. doi: 10.1016/s0194-5998(03)00729-0. 12. steward dl, grisel j, meinzen-derr j. steroids for improving recovery following tonsillectomy in children. cochrane database syst rev 2011; 8:cd003997. doi: 10.1002/14651858.cd003997.pub2. 13. dhiwakar m, clement wa, supriya m, mckerrow w. antibiotics to reduce post-tonsillectomy morbidity. cochrane database syst rev 2010; 7:cd005607. doi: 10.1002/14651858.cd005607.pub3. 14. schwengel da, sterni lm, tunkel de, heitmiller es. perioperative management of children with obstructive sleep apnea. anesth analg 2009; 109:60–75. doi:10.1213/ ane.0b013e3181a19e21. 15. duedahl th, hansen eh. a qualitative systematic review of morphine treatment in children with postoperative pain. paediatr anaesth 2007; 17:756–74. doi: 10.1111/j.14609592.2007.02213.x. 16. warwick jp, mason dg. obstructive sleep apnoea syndrome in children. anaesthesia 1998; 53:571–9. doi: 10.1046/j.1365-2044.1998.00370.x. 17. pickering ae, bridge hs, nolan j, stoddart pa. doubleblind, placebo-controlled analgesic study of ibuprofen or rofecoxib in combination with paracetamol for tonsillectomy in children. br j anaesth 2002; 88:72–7. doi: 10.1093/bja/88.1.72. 18. riggin l, ramakrishna j, sommer dd, koren g. a 2013 updated systematic review & meta-analysis of 36 randomized controlled trials: no apparent effects of non steroidal anti-inflammatory agents on the risk of bleeding after tonsillectomy. clin otolaryngol 2013; 38:115–29. doi: 10.1111/coa.12106. 19. hultcrantz e, linder a, markström a. tonsillectomy or tonsillotomy? a randomized study comparing postoperative pain and long-term effects. int j pediatr otorhinolaryngol 1999; 51:171–6. doi: 10.1016/s0165-5876(99)00274-8. دور دوافع السفر واملخاطر املتصورة وقيود السفر على الصورة املستهدفة ونوايا الزيارة للسياحة الطبية منوذج نظري حممد جمال خان, �ضانكر �ضيلليه, حممد �ضربي هارون, �ضهري�ص اأحمد abstract: travel motivations, perceived risks and travel constraints, along with the attributes and characteristics of medical tourism destinations, are important issues in medical tourism. although the importance of these factors is already known, a comprehensive theoretical model of the decision-making process of medical tourists has yet to be established, analysing the intricate relationships between the different variables involved. this article examines a large body of literature on both medical and conventional tourism in order to propose a comprehensive theoretical framework of medical tourism decision-making. many facets of this complex phenomenon require further empirical investigation. keywords: medical tourism; travel; trends; motivation; risks; intentions; theoretical model. امللخ�ص: تعترب دوافع ال�ضفر واملخاطر املت�ض�رة وقي�د ال�ضفر مع �ضمات وخ�ضائ�ص ال�ضياحة الطبية من الع�امل الهامة امل�ؤثرة يف هذه ال�ضياحة. وعلى الرغم من اأهمية هذه الع�امل معروفة بالفعل, فانه مل يتم حتى االأن عمل من�ذج نظري �ضامل لعملية �ضنع القرار لل�ضياح الطبيني وذلك لتحليل العالقات املعقدة بني املتغريات املختلفة امل�ؤثرة يف القرار. يتناول هذا املقال جمم�عة كبرية من امل�ؤلفات يف من العديد هناك الطبية. ال�ضياحة القراريف ل�ضنع �ضامل نظري اإطار اقرتاح اأجل من �ض�اء حد على والتقليدية الطبية ال�ضياحة جمال ج�انب هذه الظاهرة املعقدة والتي تتطلب املزيد من االأبحاث التجريبية. الكلمات املفتاحية: ال�ضياحة الطبية؛ ال�ضفر؛ اجتاهات؛ التحفيز؛ املخاطر؛ الن�ايا؛ من�ذج نظري. role of travel motivations, perceived risks and travel constraints on destination image and visit intention in medical tourism theoretical model *mohammad j. khan,1 shankar chelliah,1 mahmod s. haron,2 sahrish ahmed3 review sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e11–17, epub. 30 mar 17 submitted 18 sep 16 revision req. 19 oct 16; revision recd. 17 nov 16 accepted 8 dec 16 doi: 10.18295/squmj.2016.17.01.003 medical tourism commonly refers to the act of travelling to a foreign country in order to seek healthcare services.1 until recently, the concept of medical tourism was relatively unknown as it was difficult to envisage a connection between the two very different areas of international travel and medical care; however, the rate of medical tourism has sharply accelerated in the last two decades.2 modern medical tourism is characterised by an influx of middle-class patients from industrialised countries and affluent patients from less economically developed countries making use of the medical services available at foreign destinations. although medical tourism is an economically successful business venture for many countries, exact data regarding its market size and revenue remain largely unavailable.3 according to the medical tourism guidebook patients beyond borders, approximately 14 million medical travellers travelled abroad for treatment in 2015; as such, it was estimated that the medical tourism market was worth usd $45.5−72 billion.4 another source reported that over 19 million trips for the purposes of medical tourism were made in 2005 for a total value of usd $20 billion, amounting to 2.5% of the total annual tourism volume; this was estimated to increase to 40 million trips per annum and comprise 4% of the total annual tourism volume by 2010.5 economically, medical travel has benefited several southern countries, including india, cuba, costa rica, mexico, malaysia, thailand, and south africa, where the cost of medical procedures is extremely low compared to those of more northern countries.6 it is estimated that the annual number of americans travelling abroad for healthcare services will increase to 23 million by 2017.7 however, the number of medical tourists moving between southern countries is also extremely high; approximately 500,000 medical tourists travelled to south africa from other african 1international business section and departments of 2marketing and 3organizational behaviour, school of management, universiti sains malaysia, penang, malaysia *corresponding author e-mail: jamal.phd.usm@gmail.com role of travel motivations, perceived risks and travel constraints on destination image and visit intention in medical tourism theoretical model e12 | squ medical journal, february 2017, volume 17, issue 1 countries in 2009 and over half of the medical tourists in malaysia (670,000) and singapore (850,000) in 2012 were from indonesia.8,9 thailand also receives a large number of medical travellers from neighbouring countries (2.5 million in 2012).10 moreover, approximately 100,000 people from east africa are estimated to travel to india every year for medical purposes.11 among all global medical tourists, 40% travel due to a lack of advanced technology in their own country, 32% travel to seek better quality services and 12% travel for lower-cost treatments.12 although a number of studies exploring different aspects of medical tourism have recently been published, empirical insight into medical tourism is still lacking.6,9 much of the available literature is exploratory, anecdotal in nature and highly speculative or comprised of review articles exploring different aspects of medical tourism.13–16 some studies have attempted to establish relationships between various factors, such as motivation, service quality, service satisfaction and revisit intention.10,17,18 recently, models to explain destination selection by medical tourists have been proposed; however, these models are limited to a specific source or destination and are not comprehensive.19,20 fetscherin et al. developed a scale to validate the causative factors in destination decision-making, but failed to explain these factors from the traveller’s perspective.6 other models to explain the decision-making processes of medical travellers do not consider geographical location, country of origin or socioeconomic status.6,8,14,16,18 these models are mainly based on travel motivations, perceived risks and destination image and characteristics, factors which are then linked to destination selection and visit intention.21,22 other researchers have also proposed travel constraints among the factors influencing individual decision-making.23 based on a thorough review of the literature, the current article introduces a comprehensive theoretical framework on medical tourism decision-making, combining causative factors related to the characteristics of both the destination and the tourist [figure 1]. this proposed framework may help in enhancing understanding of the behaviour of medical tourists and assist destination marketing specialists in formulating specific strategies to attract medical tourists. travel motivations motivation can be defined as an internal psychological force arising from an unsatisfied need, which subsequently pushes individuals to engage in a specific need-fulfilling behaviour or activity.24 in tourism research, motivation is considered a major force in compelling tourist behaviours.25 psychosocial motivations in tourist behaviour can be divided into ‘push’ and ‘pull’ factors leading individuals to travel.22,26 motivations in medical tourism differ from those in leisure tourism, based on the specific needs of these types of travellers. medical tourists from northern countries often travel for a variety of reasons, including cost-saving purposes or because of the prohibitive expense of healthcare services in their own country; access to procedures banned in their home country; cultural or family reasons; in order to combine a minor medical procedure with leisure travel; and the long waiting lists for procedures in countries with publicly-funded healthcare systems, such as the uk and canada.2,16 crooks et al. categorised the travel motivations of tourists from northern countries as either procedurerelated, travel-related or cost-related.27 in contrast, the travel motivations of medical tourists from southern countries differ. medical figure 1: theoretical model of medical tourism decision-making. note the unidirectional arrows which indicate the complexity of the relationships between the factors in the model. mohammad j. khan, shankar chelliah, mahmod s. haron and sahrish ahmed review | e13 tourists from southeast asia often travel abroad because of their mistrust in the quality of local medical services or the level of staff professionalism.28 on the other hand, medical tourists from the middle east reportedly travel abroad due to family pressure and the misconception that services at home are inadequate.29 in most gulf cooperation council countries, health services are entirely government-funded and free to nationals; for this reason, patients may not value the services available.30 rokni et al. found that irani patients were highly motivated to travel to a particular destination because of their emotional attachment to the doctors, hospitals or the destination.31 a decision to undergo treatment abroad can reflect broader social values and experiences; for instance, it is a common view in the yemeni community that individuals have a responsibility to ensure the health of their family members, even if doing so is very expensive.32 travellers from africa often visit other countries for medical purposes because of the unavailability of modern procedures and diagnostic services, a mistrust of local service providers and the poor state of public healthcare systems.8 individuals from various east african countries travel to india because they cannot afford the high medical fees at home.11 overall, most tourists from southern countries travel principally to obtain medical care, with a very minor leisure component to their trip.3 perceived risks the perceived probability that an action may expose an individual to danger can influence travel decisions if the perceived danger is deemed to be beyond an acceptable level.33 in tourist decision-making, perceived risks hold the greatest influence in terms of destination selection.34 medical services are considered to be credence goods as their quality cannot be accurately ascertained, even after usage; as such, the associated risk of utilising medical services is high.35 furthermore, patients may be vulnerable to other risks when using medical services outside of their own country, including health, service quality, destination, travel and preand postoperative risks.36 while staying at their travel destination, medical travellers may contract an infection before or after the medical procedure, develop thrombosis during long-haul flights which might slow down wound healing or be affected by the unavailability of blood transfusion components during the recuperation process.37 specifically, taking long-haul flights while in poor health can result in both physical and psychological pain; for many patients, existing conditions may worsen if they undertake journeys with multiple stopovers.32 the likelihood of compensation in the case of complications has also been researched.38 most healthcare service providers willing to provide services to medical tourists are private and, as such, there are no enforced guidelines or control mechanisms in place to monitor treatment practices.38 this can lead to a situation whereby unnecessary treatments are prescribed for reasons of monetary gain rather than medical necessity. undergoing a procedure that is illegal in their home country can also expose medical travellers to unknown risks.2 more importantly, making medical tourism decisions primarily as a result of cost-related motivations can be risky and may lead to negative outcomes. some patients have been known to suffer from psychological and emotional distress while recovering from a procedure in a foreign destination.39 medical tourists from southern countries are usually considered more vulnerable to certain risks, given their often insufficient knowledge, limited resources and the potential prejudices they may face, as well as their vulnerability to various crimes, such as robbery or physical and sexual assault.40 another risk of medical tourism is an increase in patient-physician mistrust. after treatment, medical tourists often return to their home country with new and potentially hazardous prescriptions without effective guidelines or monitoring of use. alternatively, they may return just as their disease becomes more advanced and/or incurable, at which point fewer treatment options are available.39,40 as such, patients subsequently compare the late-stage treatment received in their home country to the early-stage treatment received at the foreign destination and form negative perceptions of their local healthcare services.41,42 travel constraints travel constraints are defined as factors which inhibit either initial or further travel, constrain an individual’s ability to maintain or increase the frequency of travel and/or negatively affect their quality of travel.43 hung et al. argued that the existence of travel constraints does not necessarily result in a lack of travelling; their findings indicated that most individuals adopted negotiation measures to counter travel constraints.43 indirect evidence shows that medical tourists face different types of constraints; however, there is a lack of empirical research exploring the travel constraints of medical tourists. role of travel motivations, perceived risks and travel constraints on destination image and visit intention in medical tourism theoretical model e14 | squ medical journal, february 2017, volume 17, issue 1 the travel constraints of individuals with chronic illnesses or disabilities have been categorised as intrinsic (e.g. lack of knowledge, health-related problems, social ineffectiveness and physical or psychological dependency), environmental (e.g. attitudinal, architectural, ecological or transportationrelated problems) and interactive (e.g. skill/challenge incongruities and communication/language barriers).44 short-term illnesses can also restrict the movement of individuals and alter their mental and psychological abilities.45 medical tourists travelling to other countries with the sole aim of acquiring medical services may also face constraints similar to those of individuals with disabilities; a few anecdotal examples in the medical tourism literature support this claim.44 one study of yemeni medical travellers found that many individuals did not possess appropriate knowledge and simply followed advice from their relatives and friends who had travelled earlier.32 existing ailments may also restrict certain patients from travelling, for instance in cases of cardiac, respiratory or orthopaedic conditions. additionally, current literature on this topic indicates that travellers from southern countries face further constraints in the form of air connectivity, visa processing, local transportation and language barriers.42,46 some medical tourists may also be concerned about the opinions of their friends and family if they choose to use medical services in less economically developed countries.2,47 perceived destination image destination image reflects the sum total of an individual’s ideas, beliefs, and impressions of a travel destination.48 according to echtner et al., destination image consists of two components: attribute-based and holistic.49 destination image covers attributes common to all destinations, as well as the unique attributes of a specific destination. in a tourism consumer behaviour model, three components of destination image formation are incorporated: awareness formed after acquiring information about a destination, attitudes formed as a result of beliefs and feelings regarding a destination and expectations formed based on the benefits associated with a destination.50 gallarza et al. mentioned that destin ation image is a mental representation of the attributes and benefits on the part of the traveller.51 two major factors, attributes and benefits, then combine to form the overall destination image. at t r i b u t e s the attributes of a destination are of the utmost importance in influencing the destination image.52 the evaluation of a destination is multidimensional and both general as well as specific attributes are important in its promotion.53 tasci et al. argued that the image of a destination can be conceptualised in terms of cognitive components based on the attributes of that destination.54 measurements of a cognitive image vary according to the destination; however, descriptiveness, direct observability and measurability of a cognitive image have been established as the best tools to assess the uniqueness of a destination.55 medical tourism destination images are formed from the various tangible characteristics—both medical and non-medical—of a destination. tangible attributes can include the price, quality of medical services, type of services offered, accreditation of the institutions or hospitals, credentials of the doctors or healthcare providers, supportive services, quality of the infrastructure, the socioeconomic environment and determinants of personal safety and security.2,56,57 as such, some destinations are recognised for their cheap and high-quality services (e.g. india) whereas others are known for combining medical procedures with leisure, such as thailand and the caribbean; some destinations, such as singapore, offer expensive but highly sophisticated services.58,59 destination image formation can also be affected by word-of-mouth. most travellers, especially from southern countries, select medical tourism destin ations and doctors based on personal recommendations from their friends and relatives.60 yu et al. have reported that medical tourists emphasise costsaving, sociocultural factors, medical facilities and professional and leisure tourism opportunities when selecting a destination.61 musa et al. found that excellent medical and support services were important pull factors in destination selection.28 other studies have indicated that religious beliefs and emotional attachments can also influence the destination choices of medical tourists, especially among those from southern countries.28,29 b e n e f i t s destination image formation is not necessarily solely influenced by tangible destination attributes; researchers have noted that the benefits associated with a destination can sometimes drive tourists to destinations with negative attributes.62 in one study, individuals reported liking one country and disliking another even though the two countries were very similar.63 moutinho argued that the physical attributes of a destination work only as stimuli consistent with certain pre-existing associations, thereby leading to a destination image which is subjective rather than objective.50 mohammad j. khan, shankar chelliah, mahmod s. haron and sahrish ahmed review | e15 according to lefkoff-hagius et al., products have symbolic aspects which determine the degree to which ownership or consumption of the product enhances the image of the consumer.64 the theory of consumption value focuses on the consumption values of product and services and explains why consumers either choose or do not choose to buy/consume a particular product or service. this theory has previously been tested in areas such as the dining industry, eco-friendly products and visit intentions and choices of tourism destinations.65 tapachai et al. found that the consumption value theory was fit to measure the beneficial image of a destination.66 the conditional value dimension of the consumption value theory denotes a specific situation which leads individuals to buy a product or service. in medical tourism, patients travel outside of their home country due to their medical condition. a heart bypass surgery that costs around usd $100,000 in the usa can be performed to the same level of quality for around usd $10,000–20,000 at five-star hospitals in various destinations worldwide;2 this demonstrates the functional consumption value (i.e. the perceived value for money) of destinations. kangas also noted epistemic value (i.e. curiosity, novelty and knowledge-seeking behaviours) in the medical tourism decision-making process, as medical tourism can also provide opportunities for patients to explore new regions.32 relationships between model factors the theory of planned behaviour (tpb) is a theoretical model designed to elucidate the relationships between consumers’ beliefs, attitudes, intentions and behaviours. various studies exploring visit and revisit intentions and the consumption behaviours of tourists based on travel motivations, risks, constraints and destination image have used the tpb hypothesis to support their models.67,68 motivation has been found to have a direct and positive relationship with behavioural intention, indicating that the motivations of medical tourists positively influence their visit intentions.69−72 researchers have also found a strong negative relationship between the perceived risks of travelling and visit/revisit intentions.73−75 disinterest has also been reported to have a significant negative impact on revisit intentions.76 hung et al. argued that higher travel constraints reduces the likelihood of a person travelling.43 lee et al. found that travel constraints and learned helplessness significantly negatively influenced the travel intentions of people with disabilities.77 as the sociopsychological motivations of tourists strongly influence the cognitive and affective evaluation of a destination, medical tourists’ motivations are assumed to have a positive influence on destination image.25,78 chew et al. identified a significant relationship between perceived risks and destination image.55 bearing in mind that perceived risks directly influence visit intention, this construct can also be argued to negatively influence destination image; however, further studies are needed to fully explore this relationship. while the role of travel constraints on destination image requires further research, an initial study by chen et al. found a significant negative relationship between travel constraints and destination image in early decision-making.23 destination image has also been noted to have a strong direct relationship with tourist behaviour.79−82 conclusion different factors play important roles in medical tourism. motivations encouraging patients to travel to a foreign country for treatment vary based on different needs, while perceived risks can influence medical tourists to avoid certain destinations or decide not to travel altogether. travel constraints may also influence the decision-making of medical tourists and are dependent on factors such as nationality, expense, destination and the presence of existing health conditions. moreover, the attributes and image of a particular destination can also influence the visit and revisit intentions of medical tourists. this article provides a comprehensive theoretical model of medical tourism decision-making in an attempt to provide a frame of reference for future studies in this field. however, the relationships in this model are relatively complex and many aspects of this complex phenomenon require further empirical research. references 1. debata br, patnaik b, mahapatra ss, sreekumar k. efficiency measurement amongst medical tourism service providers in india. int j responsible tour 2013; 1:24−31. 2. connell j. contemporary medical tourism: conceptualisation, culture and commodification. tour manag 2013; 34:1−13. doi: 10.1016/j.tourman.2012.05.009. 3. wongkit m, mckercher b. desired attributes of medical treatment and medical service providers: a case study of medical tourism in thailand. j travel tour mark 2016; 33:14−27. doi: 10.1080/10548408.2015.1024911. 4. patients beyond borders. medical tourism statistics and facts. from: www.patientsbeyondborders.com/medical-tourism-stat istics-facts accessed: nov 2016. 5. association for tourism and leisure education and research. medical tourism: a global analysis. from: www.atlas-webshop. org/medical-tourism-a-global-analysis accessed: nov 2016. https://doi.org/10.1016/j.tourman.2012.05.009 https://doi.org/10.1080/10548408.2015.1024911 role of travel motivations, perceived risks and travel constraints on destination image and visit intention in medical tourism theoretical model e16 | squ medical journal, february 2017, volume 17, issue 1 6. fetscherin m, stephano rm. the medical tourism index: scale development and validation. tour manag 2016; 52:539−56. doi: 10.1016/j.tourman.2015.08.010. 7. flanigan be. medical tourism: consumers in search of value. from: http://medicaltourisminturkey.org/panel/panel1/3delo itte.pdf accessed: nov 2016. 8. crush j, chikanda a. south-south medical tourism and the quest for health in southern africa. soc sci med 2015; 124:313−20. doi: 10.1016/j.socscimed.2014.06.025. 9. ormond m, sulianti d. more than medical tourism: lessons from indonesia and malaysia on south-south intraregional medical travel. curr issues tour 2017; 20:94−110. doi: 10.1080/13683500.2014.937324. 10. noree t, hanefeld j, smith r. medical tourism in thailand: a cross-sectional study. bull world health organ 2016; 94:30−6. doi: 10.2471/blt.14.152165. 11. mwijuke g. rising medical bills sending east african patients abroad. from: www.theeastafrican.co.ke/news/rising-medicalbills-sending-east-african-patients-abroad/-/2558/2723450//139ke5gz/-/index.html accessed: nov 2016. 12. gross dl. medical tourism: india, thailand, and singapore. from: www.calhospital.org/sites/main/files/file-attachments/walt er-sullivan-award-dan-gross-7-12.pdf accessed: nov 2016. 13. oh km, jun j, zhou q, kreps g. korean american women’s perceptions about physical examinations and cancer screening services offered in korea: the influences of medical tourism on korean americans. j community health 2014; 39:221−9 doi: 10.1007/s10900-013-9800-z. 14. viladrich a, baron-faust r. medical tourism in tango paradise: the internet branding of cosmetic surgery in argentina. ann tour res 2014; 45:116−31. doi: 10.1016/j.annals.2013.12.007. 15. connell j. reducing the scale? from global images to border crossings in medical tourism. glob netw 2016: 16:531−50. doi: 10.1111/glob.12136. 16. lunt n, horsfall d, hanefeld j. medical tourism: a snapshot of evidence on treatment abroad. maturitas 2016; 88:37−44. doi: 10.1016/j.maturitas.2016.03.001. 17. guiry m, scott jj, vequist dg 4th. experienced and potential medical tourists’ service quality expectations. int j health care qual assur 2013; 26:433−46. doi: 10.1108/ ijhcqa-05-2011-0034. 18. wang hy. value as a medical tourism driver. j serv theory pract 2012; 22:465−91. doi: 10.1108/09604521211281387. 19. zailani s, ali sm, iranmanesh m, moghavvemi s, musa g. predicting muslim medical tourists’ satisfaction with malaysian islamic friendly hospitals. tour manag 2016; 57:159−67. doi: 10.1016/j.tourman.2016.05.009. 20. na sa, onn cy, meng cl. travel intentions among foreign tourists for medical treatment in malaysia: an empirical study. procedia soc behav sci 2016; 224:546−53. doi: 10.1016/j. sbspro.2016.05.434. 21. lepp a, gibson h, lane c. image and perceived risk: a study of uganda and its official tourism website. tour manag 2011; 32:675−84. doi: 10.1016/j.tourman.2010.05.024. 22. klenosky db. the “pull” of tourism destinations: a meansend investigation. j travel res 2002; 40:396−403. doi: 10.1177/ 004728750204000405. 23. chen hj, chen pj, okumus f. the relationship between travel constraints and destination image: a case study of brunei. tour manag 2013; 35:198−208. doi: 10.1016/j.tourman.2012.07.004. 24. schiffman lg, kanuk ll. consumer behaviour, 8th ed. upper saddle river, new jersey, usa: prentice-hall, 2004. p. 45. 25. san martín h, rodríguez del bosque ia. exploring the cognitive-affective nature of destination image and the role of psychological factors in its formation. tour manag 2008; 29:263−77. doi: 10.1016/j.tourman.2007.03.012. 26. baloglu s, uysal m. market segments of push and pull motivations: a canonical correlation approach. int j contemp hosp manag 1996; 8:32−8. doi: 10.1108/09596119610115989. 27. crooks va, kingsbury p, snyder j, johnston r. what is known about the patient’s experience of medical tourism? a scoping review. bmc health serv res 2010; 10:266. doi: 10.1186/14726963-10-266. 28. musa g, thirumoorthi t, doshi d. travel behaviour among inbound medical tourists in kuala lumpur. curr issues tour 2012; 15:525−43. doi: 10.1080/13683500.2011.626847. 29. moghimehfar f, nasr-esfahani mh. decisive factors in medical tourism destination choice: a case study of isfahan, iran and fertility treatments. tour manag 2011; 32:1431−4. doi: 10.1016/j.tourman.2011.01.005. 30. deloitte. 2015 health care outlook: middle east. from: www2. deloitte.com/content/dam/deloitte/global/documents/lifesciences-health-care/gx-lshc-2015-health-care-outlookmiddle-east.pdf accessed: nov 2016. 31. rokni l, pourahmad a, moteiey langroudi mh, rezaeiy mahmoudi m, heidarzadeh n. appraisal the potential of central iran, in the context of health tourism. iran j public health 2013; 42:272−9. 32. kangas b. hope from abroad in the international medical travel of yemeni patients. anthropol med 2007; 14:293−305. doi: 10.1080/13648470701612646. 33. mansfeld y, pizam a. tourism, security and safety: from theory to practice, 1st ed. oxford, uk: routledge, 2005. pp. 27−90. 34. sönmez sf, graefe ar. influence of terrorism risk on foreign tourism decisions. ann tour res 1998; 25:112−44. doi: 10.1016/ s0160-7383(97)00072-8. 35. yeoh e, othman k, ahmad h. patient-centeredness communication strategy for the medical tourism industry. j tour res hosp 2013; 2:2. doi: 10.4172/2324-8807.1000113. 36. penney k, snyder j, crooks va, johnston r. risk communication and informed consent in the medical tourism industry: a thematic content analysis of canadian broker websites. bmc med ethics 2011; 12:17. doi: 10.1186/1472-6939-12-17. 37. rodríguez jy, rodríguez gj, morales-lópez se, cantillo ce, le pape p, álvarez-moreno ca. saksenaea erythrospora infection after medical tourism for esthetic breast augmentation surgery. int j infect dis 2016; 49:107−10. doi: 10.1016/j. ijid.2016.05.032. 38. cohen ig. protecting patients with passports: medical tourism and the patient protective-argument. iowa law rev 2010; 95:1467−567. 39. li z. attractive forces and risks of international medical tourism: a study based on india. j chem pharm res 2014; 6:125−9. 40. goldbach ar, west dj. medical tourism: a new venue of healthcare. j glob bus issues 2010; 2:43. 41. crooks va, turner l, cohen ig, bristeir j, snyder j, casey v, et al. ethical and legal implications of the risks of medical tourism for patients: a qualitative study of canadian health and safety representatives’ perspectives. bmj open 2013; 3:e002302. doi: 10.1136/bmjopen-2012-002302. 42. kangas b. traveling for medical care in a global world. med anthropol 2010; 29:344−62. doi: 10.1080/01459740.2010.50 1315. 43. hung k, petrick jf. developing a measurement scale for constraints to cruising. ann tour res 2010; 37:206−28. doi: 10.1016/j.annals.2009.09.002. 44. smith rw. leisure of disable tourists: barriers to participation. ann tour res 1987; 14:376−89. doi: 10.1016/0160-7383(87) 90109-5. https://doi.org/10.1016/j.tourman.2015.08.010 https://doi.org/10.1016/j.socscimed.2014.06.025 https://doi.org/10.1080/13683500.2014.937324 https://doi.org/10.2471/blt.14.152165 https://doi.org/10.1007/s10900-013-9800-z https://doi.org/10.1016/j.annals.2013.12.007 https://doi.org/10.1111/glob.12136 https://doi.org/10.1016/j.maturitas.2016.03.001 https://doi.org/10.1108/ijhcqa-05-2011-0034 https://doi.org/10.1108/ijhcqa-05-2011-0034 https://doi.org/10.1108/09604521211281387 https://doi.org/10.1016/j.tourman.2016.05.009 https://doi.org/10.1016/j.sbspro.2016.05.434 https://doi.org/10.1016/j.sbspro.2016.05.434 https://doi.org/10.1016/j.tourman.2010.05.024 https://doi.org/10.1177/004728750204000405 https://doi.org/10.1177/004728750204000405 https://doi.org/10.1016/j.tourman.2012.07.004 https://doi.org/10.1016/j.tourman.2007.03.012 https://doi.org/10.1108/09596119610115989 https://doi.org/10.1186/1472-6963-10-266 https://doi.org/10.1186/1472-6963-10-266 https://doi.org/10.1080/13683500.2011.626847 https://doi.org/10.1016/j.tourman.2011.01.005 https://doi.org/10.1080/13648470701612646 https://doi.org/10.1016/s0160-7383%2897%2900072-8 https://doi.org/10.1016/s0160-7383%2897%2900072-8 https://doi.org/10.4172/2324-8807.1000113 https://doi.org/10.1186/1472-6939-12-17 https://doi.org/10.1016/j.ijid.2016.05.032 https://doi.org/10.1016/j.ijid.2016.05.032 https://doi.org/10.1136/bmjopen-2012-002302 https://doi.org/10.1080/01459740.2010.501315 https://doi.org/10.1080/01459740.2010.501315 https://doi.org/10.1016/j.annals.2009.09.002 https://doi.org/10.1016/0160-7383%2887%2990109-5 https://doi.org/10.1016/0160-7383%2887%2990109-5 mohammad j. khan, shankar chelliah, mahmod s. haron and sahrish ahmed review | e17 45. boyd km. disease, illness, sickness, health, healing and wholeness: exploring some elusive concepts. med humanit 2000; 26:9–17. doi: 10.1136/mh.26.1.9. 46. indian institute of tourism and travel management. a study of problems and challenges faced by medical tourists visiting india. from: http://incredibleindia.org/lang/images/docs/trade pdf/surveys-and-studies/study-reports/a%20study%20on%20 problems%20and%20challenges%20faced%20by%20medical%20 tourists%20visiting%20india.pdf accessed: nov 2016. 47. connell j. medical tourism: sea, sun, sand and… surgery. tour manag 2006; 27:1093−100. doi: 10.1016/j.tourman.2005.11.005. 48. gartner wc. image formation process. j travel tour mark 1994; 2:191−216. doi: 10.1300/j073v02n02_12. 49. echtner cm, brent ritchie jr. the measurement of destination image: an empirical assessment. j travel res 1993; 31:3−13. doi: 10.1177/004728759303100402. 50. moutinho l. consumer behaviour in tourism. eur j mark 1987; 21:5−44. doi: 10.1108/eum0000000004718. 51. gallarza mg, saura ig, garcía hc. destination image: towards a conceptual framework. ann tour res 2002; 29:56−78. doi: 10.1016/s0160-7383(01)00031-7. 52. sparks b, pan gw. chinese outbound tourists: understanding their attitudes, constraints and use of information sources. tour manag 2009; 30:483−94. doi: 10.1016/j.tourman.2008.10.014. 53. stepchenkova s, morrison am. russia’s destination image among american pleasure travelers: revisiting echtner and ritchie. tour manag 2008; 29:548−60. doi: 10.1016/j. tourman.2007.06.003. 54. tasci ad, gartner wc, cavusgil st. conceptualization and operationalization of destination image. j hosp tour res 2007; 31:194−223. doi: 10.1177/1096348006297290. 55. chew ey, jahari sa. destination image as a mediator between perceived risks and revisit intention: a case of postdisaster japan. tour manag 2014; 40:382−93. doi: 10.1016/j. tourman.2013.07.008. 56. crooks va, turner l, snyder j, johnston r, kingsbury p. promoting medical tourism to india: messages, images, and the marketing of international patient travel. soc sci med 2011; 72:726−32. doi: 10.1016/j.socscimed.2010.12.022. 57. khan mj, chelliah s, haron ms. medical tourism destination image formation process: a conceptual model. int j healthc manag 2016; 9:134−43. doi: 10.1080/20479700.2016.1142046. 58. deloitte. evolving medical tourism in canada: exploring a new frontier. from: www2.deloitte.com/content/dam/deloitte/ca/ documents/life-sciences-health-care/ca-en-health-care-lifesciences-evolving-medical-tourism-exploring-a-new-frontier. pdf accessed: nov 2016. 59. rerkrujipimol j, assenov i. marketing strategies for promoting medical tourism in thailand. j tour hosp culinary arts 2011; 3:95−105. 60. al-hinai ss, al-busaidi as, al-busaidi ih. medical tourism abroad: a new challenge to oman’s health system al dakhilya region experience. sultan qaboos univ med j 2011; 11:477−84. 61. yu jy, ko tg. a cross-cultural study of perceptions of medical tourism among chinese, japanese and korean tourists in korea. tour manag 2012; 33:80−8. doi: 10.1016/j.tourman.2011.02. 002. 62. nadeau j, heslop l, o’reilly n, luk p. destination in a country image context. ann tour res 2008; 35:84−106. doi: 10.1016/j. annals.2007.06.012. 63. wish m. individual differences in perceptions and preferences among nations. in: king cw, tigert d, eds. attitude research reaches new heights. chicago, illinois, usa: american marketing association, 1971. pp. 312–28. 64. lefkoff-hagius r, mason ch. characteristic, beneficial, and image attributes in consumer judgments of similarity and preference. j consum res 1993; 20:100−10. doi: 10.1086/209336. 65. sheth jn, newman bi, gross bl. why we buy what we buy: a theory of consumption values. j bus res 1991; 22:159−70. doi: 10.1016/0148-2963(91)90050-8. 66. tapachai n, waryszak r. an examination of the role of beneficial image in tourist destination selection. j travel res 2000; 39:37−44. doi: 10.1177/004728750003900105. 67. park sh, hsieh cm, lee ck. examining chinese college students’ intention to travel to japan using the extended theory of planned behavior: testing destination image and the mediating role of travel constraints. j travel tour mark 2017; 34:113−31. doi: 10.1080/10548408.2016.1141154. 68. wu k, raab c, chang w, krishen a. understanding chinese tourists’ food consumption in the united states. j bus res 2016; 69:4706−13. doi: 10.1016/j.jbusres.2016.04.018. 69. baloglu s. the relationship between destination images and sociodemographic and trip characteristics of international travellers. j vacation mark 1997; 3:221−33. doi: 10.1177/13 5676679700300304. 70. yoon y, uysal m. an examination of the effects of motivation and satisfaction on destination loyalty: a structural model. tour manag 2005; 26:45−56. doi: 10.1016/j.tourman.2003. 08.016. 71. park db, yoon ys. segmentation by motivation in rural tourism: a korean case study. tour manag 2009; 30:99−108. doi: 10.1016/j.tourman.2008.03.011. 72. lo as, lee cy. motivations and perceived value of volunteer tourists from hong kong. tour manag 2011; 32:326−34. doi: 10.1016/j.tourman.2010.03.002. 73. floyd mf, gibson h, pennington-gray l, thapa b. the effect of risk perceptions on intentions to travel in the aftermath of september 11, 2001. j travel tour mark 2004; 15:19−38. doi: 10.1300/j073v15n02_02. 74. wong jy, yeh c. tourist hesitation in destination decision making. ann tourism res 2009; 36:6−23. doi: 10.1016/j. annals.2008.09.005. 75. simpson p, cruz-milán o, gressel j. perceived crime and violence: effects on winter migrants. j travel res 2013; 53:597−609. doi: 10.1177/0047287513513162. 76. huang s, hsu ch. effects of travel motivation, past experience, perceived constraint, and attitude on revisit intention. j travel res 2009; 48:29−44. doi: 10.1177/0047287508328793. 77. lee m, han h, lockyer t. medical tourism: attracting japanese tourists for medical tourism experience. j travel tour mark 2012; 29:69−86. doi: 10.1080/10548408.2012.638564. 78. li m, cai la, lehto xy, huang j. a missing link in understanding revisit intention: the role of motivation and image. j travel tour mark 2010; 27:335−48. doi: 10.1080/10548408.2010.481559. 79. hudson s. consumer behavior related to tourism. in: pizam a, mansfeld y, eds. consumer behavior in travel and tourism, 1st ed. oxford, uk: routledge, 1999. pp. 7−32. 80. chen cf, tsai dc. how destination image and evaluative factors affect behavioral intentions? tour manag 2007; 28:1115−22. doi: 10.1016/j.tourman.2006.07.007. 81. chi cg, qu h. examining the structural relationships of destination image, tourist satisfaction and destination loyalty: an integrated approach. tour manag 2008; 29:624−36. doi: 10.1016/j.tourman.2007.06.007. 82. assaker g, vinzi ve, o’connor p. examining the effect of novelty seeking, satisfaction, and destination image on tourists’ return pattern: a two factor, non-linear latent growth model. tour manag 2011; 32:890−901. doi: 10.1016/j. tourman.2010.08.004. https://doi.org/10.1136/mh.26.1.9 https://doi.org/10.1016/j.tourman.2005.11.005 https://doi.org/10.1300/j073v02n02_12 https://doi.org/10.1177/004728759303100402 https://doi.org/10.1108/eum0000000004718 https://doi.org/10.1016/s0160-7383%2801%2900031-7 https://doi.org/10.1016/j.tourman.2008.10.014 https://doi.org/10.1016/j.tourman.2007.06.003 https://doi.org/10.1016/j.tourman.2007.06.003 https://doi.org/10.1177/1096348006297290 https://doi.org/10.1016/j.tourman.2013.07.008 https://doi.org/10.1016/j.tourman.2013.07.008 https://doi.org/10.1016/j.socscimed.2010.12.022 https://doi.org/10.1080/20479700.2016.1142046 https://doi.org/10.1016/j.tourman.2011.02.002 https://doi.org/10.1016/j.tourman.2011.02.002 https://doi.org/10.1016/j.annals.2007.06.012 https://doi.org/10.1016/j.annals.2007.06.012 https://doi.org/10.1086/209336 https://doi.org/10.1016/0148-2963%2891%2990050-8 https://doi.org/10.1177/004728750003900105 https://doi.org/10.1080/10548408.2016.1141154 https://doi.org/10.1016/j.jbusres.2016.04.018 https://doi.org/10.1177/135676679700300304 https://doi.org/10.1177/135676679700300304 https://doi.org/10.1016/j.tourman.2003.08.016 https://doi.org/10.1016/j.tourman.2003.08.016 https://doi.org/10.1016/j.tourman.2008.03.011 https://doi.org/10.1016/j.tourman.2010.03.002 https://doi.org/10.1300/j073v15n02_02 https://doi.org/10.1016/j.annals.2008.09.005 https://doi.org/10.1016/j.annals.2008.09.005 https://doi.org/10.1177/0047287513513162 https://doi.org/10.1177/0047287508328793 https://doi.org/10.1080/10548408.2012.638564 https://doi.org/10.1080/10548408.2010.481559 https://doi.org/10.1016/j.tourman.2006.07.007 https://doi.org/10.1016/j.tourman.2007.06.007 https://doi.org/10.1016/j.tourman.2010.08.004 https://doi.org/10.1016/j.tourman.2010.08.004 sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 80-87, epub. 27th feb 13 submitted 15th may 12 revision req. 5th aug, revision recd. 2nd sep 12 accepted 6th oct 12 1diagnostic genetics, labplus, auckland city hospital, auckland, new zealand; 2genetic health services new zealand – northern hub, auckland city hospital, auckland, new zealand; 3school of biological sciences, university of auckland, auckland, new zealand *corresponding author e-mail: donaldl@adhb.govt.nz التحليل اجلزيئي حلالة خلل التنسج املميت يكشف عن طفرتني مغلوطتني جديدتني جلني fgfr3 تقعان على السيس رينات مرق�ض نيكل�صون، �صامل افتيمو�ض، دونالد ر لوف امللخ�ص: الهدف: ان خلل التن�صج املميت هو اأكرث اأنواع خلل التن�صج الهيكلي القاتل �صيوعا وينتج عن �صقة ج�صمية �صائدة ويتميز بوجود كرب يف حجم الراأ�ض، �صيق يف حجم ال�صدر، اأ�صلع ق�صرية، اأ�صابع ق�صرية و ارتخاء يف الع�صالت. وبالإ�صافة اإىل هذه املالمح الظاهرية وا�صتقامة الأطراف ب�صغر الثاين النوع يتميز بينما الفخذ عظام وانحناء الأطراف ب�صغر املر�ض هذا من الأول النوع فيتميز اجلوهرية عظام الفخذ ووجود ت�صوه بر�صيمي يف �صكل اجلمجمة. من املعروف اأن كل حالت هذا املر�ض تنتج عن طفرات يف جني ال ف ج ف ر3. هدفت الدرا�صة ايل التعرف على طيف الطفرات امل�صوؤوله عن حدوث هذا املر�ض. طرق الدرا�صة: مت ا�صتخدام تفاعل البلمرة ال�صل�صلي التقليدي والأليلي والتحليل الت�صل�صلي لتحديد طفرات جني ال ف ج ف ر3 يف جنني م�صاب بخالل التن�صج املميت والذي مت اكت�صافة اثناء احلمل با�صتخدام املوجات فوق ال�صوتية. النتائج: يف هذا البحث ن�صتعر�ض كيفية حتديد طفرتني مغلوطتني جديدتني جلني ال ف ج ف ر3 تقعان على ال�صي�ض يف جنني لديه العالمات الظاهرية ملر�ض خلل التن�صج املميت. اخلال�صة: هذه هي املرة الثانية التي يتم فيها و�صف حالة خلل التن�صج املميت نتيجة لوجود طفرتني مغلوطتني جديدتني جلني ال ف ج ف ر3 تقعان على ال�صي�ض مما يدل على اأن طيف الطفرات امل�صببة لهذا املر�ض قد يكون اكرث �صيوعا مما هو معتقد. مفتاح الكلمات: خلل التن�صج املميت، جني ف ج ف ر3، خلل التن�صج الهيكلي، تفاعل البلمرة ال�صل�صلي الأليلي. abstract: objectives: thanatophoric dysplasia (td) is the most common form of lethal skeletal dysplasia. it is primarily an autosomal dominant disorder and is characterised by macrocephaly, a narrow thorax, short ribs, brachydactyly, and hypotonia. in addition to these core phenotypic features, td type i involves micromelia with bowed femurs, while td type ii is characterised by micromelia with straight femurs and a moderate to severe clover-leaf deformity of the skull. mutations in the fgfr3 gene are responsible for all cases of td reported to date. the objective of the study here was to delineate further the mutational spectrum responsible for td. methods: conventional polymerase chain reaction (pcr), allele-specific pcr, and sequence analysis were used to identify fgfr3 gene mutations in a fetus with a lethal skeletal dysplasia consistent with td, which was detected during a routine antenatal ultrasound examination. results: in this report we describe the identification of two de novo missense mutations in cis in the fgfr3 gene (p.asn540lys and p.val555met) in a fetus displaying phenotypic features consistent with td. conclusion: this is the second description of a case of td occurring as a result of double missense fgfr3 gene mutations, suggesting that the spectrum of mutations involved in the pathogenesis of td may be broader than previously recognised. keywords: thanatophoric dysplasia; fgfr3; skeletal dysplasia; allele-specific pcr. molecular analysis of a case of thanatophoric dysplasia reveals two de novo fgfr3 missense mutations located in cis renate marquis-nicholson,1 salim aftimos,2 *donald r. love1,3 clinical & basic research advances in knowledge this study is only the second report in which the mutations in the fgfr3 gene differ from those classically implicated in the development of thanatophoric dysplasia (td). applications to patient care the findings suggest that confirmation of a clinical diagnosis of thanatophoric dysplasia should include a comprehensive screen for mutations in all coding exons of the fgfr3 gene, particularly in the absence of one of the classic td mutations. renate marquis-nicholson, salim aftimos and donald r. love brief communication | 81 thanatophoric dysplasia (td) is the most common form of lethal short-limb skeletal dysplasia with a prevalence of approximately 2/100,000 births.1 it was first described as thanatophoric dwarfism by maroteaux and lamy in 1967, undergoing a name change in 1977 as a result of a decision reached at the 2nd international conference on the nomenclature of skeletal dysplasias.2 it is characterised by a range of phenotypic features, foremost among which are macrocephaly, a narrow thorax, short ribs, brachydactyly, and micromelia.3 there are two forms of td, designated td type i and td type ii, which can be differentiated principally by the presence of bowed, rather than straight, femurs in td type i and of a moderate to severe clover-leaf deformity of the skull in td type ii.3 a clover-leaf skull deformity may also occur in td type i but is infrequent and less severe than in td type ii.3 both subtypes of td are considered lethal with most affected infants dying as a result of respiratory insufficiency within the first few hours of life; however, there are reports of a small number of affected individuals who have survived into childhood by virtue of aggressive ventilatory support.4 as with the other severe skeletal dysplasias, td is frequently diagnosed following a routine antenatal ultrasound screening in the first or second trimester. the earliest radiological signs are increased nuchal thickness and short limbs, but these signs are nonspecific.5,6 a molecular diagnosis may be made prenatally if genetic testing for td is requested on deoxyribonucleic acid (dna) extracted from a chorionic villus or amniocentesis sample, but is more commonly made following a post-mortem examination carried out to clarify the nature of the lethal skeletal dysplasia in question.5,6 td is primarily an autosomal dominant disorder, resulting from heterozygous mutations in the fgfr3 gene that lead to ligand-independent activation of the receptor and disruption of cartilage function during linear bone growth.7 mutations in the fgfr3 gene cause a spectrum of skeletal dysplasias ranging from the relatively mild hypochrondroplasia through to achondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (saddan), and thanatophoric dysplasia.7 as expected from the severity of the disorder, the majority of td-related mutations in the fgfr3 gene are de novo and the recurrence risk for parents with a previously affected pregnancy is very low, particularly if both parents are phenotypically normal.3 a single case of somatic and germline mosaicism for the td type 1 mutation arg248cys has been described.8 the mosaic individual in this instance was affected by a disproportionate asymmetric rhizomelic shortening of the limbs. her only pregnancy was complicated by severe pre-eclampsia and resulted in the stillbirth of an infant with a phenotype consistent with td.8 we present here a case in which td was diagnosed prenatally by ultrasound scanning and describe the results of subsequent molecular analysis, which revealed a double de novo mutational event. methods informed consent was provided by the parents of the proband reported here; the proband was studied at the genetic level to confirm a clinical diagnosis of td. the new zealand multi-region ethics committee has ruled that cases of patient management do not require formal ethics committee approval. a skin biopsy from the affected fetus was taken at autopsy and the tissue was cultured according to conventional cytogenetic techniques. genomic dna (gdna) was isolated from the cultured cells by phenol/chloroform extraction and ethanol precipitation. in the case of peripheral blood in ethylenediaminetetraacetic acid (edta), gdna was isolated using the gentra puregene dna extraction kit (qiagen pty ltd, doncaster, australia). the messenger ribonucleic acid (mrna) sequence of transcript 1 of the fgfr3 gene was identified using the university of california santa cruz (ucsc) genome browser.9 this website provides a direct link to exonprimer for the design of primers flanking coding exons. the first coding exon of transcript 1 of the fgfr3 gene is exon 2, so primers were not designed against exon 1. exonprimer is a perl script that uses a combination of primer3 and blat to design intronic primers against a complementary dna (cdna) of interest. default parameters were used. the coverage (entire coding exon and at least 20 bp of flanking intronic sequence to allow interrogation of splice sites) and specificity of the primers were confirmed using the in-silico polymerase chain reaction (pcr) tool also molecular analysis of a case of thanatophoric dysplasia reveals two de novo fgfr3 missense mutations located in cis 82 | squ medical journal, february 2013, volume 13, issue 1 available on the ucsc genome browser. all primers were checked for single nucleotide polymorphisms using the software tool available from the national genetic reference laboratory, manchester, uk.10 the primers were tailed with m13 sequences for ease of subsequent sequence analysis, and were synthesised by invitrogen ltd., (renfrewshire, uk) [table 1]. we used the freely accessible online tetraprimer amplification refractory mutation system (arms)-pcr primer design programme11 to design allele-specific pcr primers to target the dna variants of interest.12 specificity is ensured by not only using allele-specific primers with differing 3' terminal bases but also including an additional mismatched base at position -2 from the 3' end. two pairs of primers were designed. each pair contained one allele-specific primer that would result in amplification of only the wild-type allele of each of the two variants in question. the other primer in each pair was positioned such that the second variant was also included within the amplicon, thereby allowing the phase of the variants to be determined. these two additional primer pairs were likewise tailed with m13 sequences and were synthesised by invitrogen ltd. (renfrewshire, uk). conventional and allele-specific pcr were performed using 1u faststart taq dna polymerase (invitrogen ltd, renfrewshire, uk), 50 ng genomic dna, 2mm mgcl2, and 0.8 μm forward and reverse primers with the following cycle conditions: 95° c for 4 minutes, 35 cycles of 94° c for 45 seconds, 60° c for 30 seconds, 72° c for 30 seconds, and a final extension at 72° c for 10 minutes. all amplicons amplified efficiently under these conditions. an amount of 5 µl of each pcr was cleaned with table 1: primers for the amplification of all coding exons of the fgrf3 gene (refseq accession number nm_000142.4) exon forward primer reverse primer amplicon size (bp) 2 tgtaaaacgacggccagtgagctgccttc ctcctcc caggaaacagctatgacccggggcgtca ctcacac 380 3 tgtaaaacgacggccagtgctgtgtctgt aaacggtgc caggaaacagctatgaccgacccacgca gggactc 441 4 tgtaaaacgacggccagttctctctggtc attggtgga caggaaacagctatgaccagcccctcctg tatcctgag 394 5 tgtaaaacgacggccagttcctacacagg acgggaaac caggaaacagctatgaccggatgctgcca aacttgttc 507 6 tgtaaaacgacggccagtccatctcctgg ctgaagaac caggaaacagctatgacctgcgtcactgt acaccttgc 500 7 tgtaaaacgacggccagttggacgtgct gggtgag caggaaacagctatgacccaacccctaga cccaaatcc 433 8 tgtaaaacgacggccagttgtggactctg tgcggtg caggaaacagctatgaccctttggcgtg tcccgag 316 9 tgtaaaacgacggccagtctcccagtgg tgcctgc caggaaacagctatgaccagagagggctc acacagcc 422 10 tgtaaaacgacggccagtcttcattcaat gctggtgga caggaaacagctatgaccacagaacccca gccacac 436 11 tgtaaaacgacggccagtgagcatggag ggcttcct caggaaacagctatgacctttcccgatca tcttcatca 436 12 tgtaaaacgacggccagtgccaagcctgt caccgtag caggaaacagctatgaccacaccaggtcc ttgaaggtg 487 13-14 tgtaaaacgacggccagtggtaggtgcg gtagcgg caggaaacagctatgaccccaggcgtcc tactggc 594 15-16 tgtaaaacgacggccagtggggtcatgc cagtagg caggaaacagctatgacctattcgggaac agcctgaag 619 17-18 tgtaaaacgacggccagtcaggctgttcc cgaataagg caggaaacagctatgacccaccagcagc agggtgg 589 blue and red coloured bases represent m13 sequences that tail the forward and reverse primers. renate marquis-nicholson, salim aftimos and donald r. love brief communication | 83 exosap-it (affymetrix, santa clara, california, usa) prior to bidirectional dna sequencing using m13 forward and reverse primers and big-dye terminator, version 3.0 (applied biosystems ltd., carlsbad, california, usa). an amount of 20 µl of sequenced product was purified using an automated agencourt cleanseq (agencourt bioscience corp., beverly, massachusetts, usa) procedure with the aid of an epmotion 5075 liquid handling robot (eppendorf, hamburg, germany). an amount 15 µl of purified product was then subjected to capillary electrophoresis using an applied biosystems model 3130xl genetic analyser. the analysis of sequence traces was performed using variant reporter, version 1.0 (applied biosystems). genebank nm_000142.4 was used as the reference sequence, with cdna number +1 corresponding to the a of the translation initiation codon. amino acid numbering began at the first amino acid in refseq accession number np_000133.1. exons were numbered sequentially, with exon 2 being the first exon analysed (exon 1 is non-coding). variant reporter uses advanced algorithms and quality metrics to automate the detection of variants and to streamline the analysis process. traces produced from the sequencing of allele-specific pcr amplicons were analysed manually. results the fetus was the third child to non-consanguineous parents. the first antenatal ultrasound scan at 13 weeks gestation demonstrated a nuchal thickness of 2.0 mm. the second ultrasound at 19 weeks was technically very difficult because of fetal lie and maternal habitus. however, it demonstrated the presence of a grossly enlarged skull with an abnormal shape (biparietal diameter [bpd] 59 mm, head circumference [hc] 207 mm). the fetal chest was subjectively small and the limbs were short with both femoral length (fl) and humeral length (hl) well below the 5th centile (fl 22 mm; hl 19 mm). these findings were indicative of a lethal skeletal dysplasia. the parents were counselled accordingly and decided to proceed with a termination which was performed at 19 weeks and 5 days’ gestation. skeletal radiographs [figure 1] showed a narrow thorax in both anteroposterior and lateral views. the skull was large in relation to the facial bones and abnormally shaped but without a clover-leaf appearance. the vertebral bodies were flat with an h-shaped appearance but no notching of the central portions of the upper and lower plates. there was narrowing of the lumbar interpediculate distances from l1–l3. the long bones were short and relatively broad with mild bowing of the femora. the metaphyseal regions were cupped and flared. the pelvic bones were short and broad with horizontal inferior margins of the iliac bones. figure 1: fetal phenotype: skeletal radiographs of anteroposterior (i), lateral (ii) and pelvic (iii) views. molecular analysis of a case of thanatophoric dysplasia reveals two de novo fgfr3 missense mutations located in cis 84 | squ medical journal, february 2013, volume 13, issue 1 overall, the radiologic findings were consistent with td with an overlap between td type i and td type ii. the vertebral abnormalities were more consistent with td type ii, while the mild femoral angulation was not characteristic of td type ii, but was not as severe as would be expected in td type i. conventional pcr and bidirectional sequence analysis of all coding exons of the fgfr3 gene in the affected fetus detected compound heterozygosity for the mutations c.1620c>a (p.asn540lys) and c.1663g>a (p.val555met) in exons 12 and 13, respectively, of the fgfr3 gene [figure 2]. in order to determine the phase of these mutations, subsequent allele-specific pcr was performed [figure 3]. sequencing of the amplicons produced by allele-specific pcr demonstrated that the variants were present in cis [figure 4]. dna extracted from the peripheral blood of both parents was analysed for the presence of each of these variants. both variants proved to be absent in each parent, indicating that they were most probably de novo in the fetus (gonadal mosaicism in one of the parents has not been excluded). discussion the case we present here exhibits the classic phenotypic features of td with overlapping features of type i and type ii. molecular genetic testing for td type i involves either full sequence analysis of all coding exons of the fgfr3 gene (as was the approach taken in this case), or more targeted initial analysis of exons 7, 10, 15, and 19, which are the exons containing the mutations responsible for 99% of cases of td type i reported to date. this is followed by full analysis if no mutation is identified.3 the mutations themselves can be placed into two classes. the first includes the two most common td type i mutations, arg248cys and tyr373cys, and involves the creation of new unpaired cysteine residues.3 the second class of pathogenic td type i mutations result in obliteration of the native stop codon and addition of a hydrophobic alpha helixcontaining domain to the carboxyl terminus of the protein.3 the single mutation known to cause td type ii, p.lys650gly, destabilises the activation loop of the second portion of the split tyrosine kinase domain resulting in ligand-independent activation.11 figure 2: (panel a) fetal genotype: sequence electropherograms show the c.1620c>a (p.asn540lys); (panel b) c.1663g>a (p.val555met) variants in exons 12 and 13, respectively, of the fgfr3 gene in the affected fetus. renate marquis-nicholson, salim aftimos and donald r. love brief communication | 85 neither of the mutations detected in the fetus described above fall into these categories. the first variant, c.1620c>a (p.asn540lys), is present in the heterozygote state in approximately 72% of individuals with classic hypochondroplasia.14 the second variant, c.1663g>a (p.val555met), is not listed in the online human gene mutation database (hgmd) and does not appear to be reported in the literature. bioinformatic analysis using the online prediction tools polyphen-215 and sift16 suggests that it is highly likely to be of pathogenic significance. in addition, valine at position 555 is conserved across species. compound heterozygosity in trans for the asn540lys mutation and the gly380arg mutation that is responsible for 98% of cases of achondroplasia17 has been reported.18–21 individuals who are compound heterozygotes for these two variants typically display a more severe skeletal phenotype than seen in classical achondroplasia, but the condition is still compatible with survival, unlike the lethal form of achondroplasia that results from homozygosity for the gly380arg mutation. it has been shown that the level of ligandindependent tyrosine kinase activity is directly related to the skeletal phenotype, so it is to be expected that the combination of the less-activating mutation asn540lys and gly380arg will result in a less severe phenotype than that caused by homozygosity for gly380arg alone.13 in contrast, a case of apparent td type i in association with compound heterozygosity for asn540lys and a second previously unreported mutation, gln485arg, has also been described.22 in this instance, as in our case, the two fgfr3 mutations identified were de novo in the affected fetus and in cis. analysis of the deduced x-ray crystallographic structure of fgfr3 led the authors to postulate that the presence of two mutations in cis alters the receptor structure to such an extent that it is held in a fully activated state, with each mutation attenuating the effect of the other, leading to the lethal form of skeletal dysplasia characteristic of td.22 each of the mutations identified in our fetus is located within the first portion of the split intra-cellular tyrosine kinase domain.23 it has been recognised that the activation of fgfr3 caused by substitutions within the tyrosine kinase domain is due to a mechanism that mirrors the conformational changes that are normally a result of ligand-mediated fgfr3 dimerisation and figure 3: sequences and primers for allele-specific pcr: allele-specific primer sequences are shown to determine the phase of the fgfr3 gene mutations detected in the affected fetus. molecular analysis of a case of thanatophoric dysplasia reveals two de novo fgfr3 missense mutations located in cis 86 | squ medical journal, february 2013, volume 13, issue 1 autophosphorylation.23,24 double mutation alleles have been reported in association with a range of disorders, often complicating genotype-phenotype correlations.25,26 it is probable that the basis of the severe phenotype seen in our case, in contrast to the phenotype that results from the asn540lys mutation alone or in combination with gly380arg, is related to the ‘double-hit’ effect of two mutations both acting in this critical region of the protein. it is the combination of the location of the mutations and the attenuating effect they have upon each other that is significant. a recent review of the current understanding of fgfr3 signalling in the skeletal dysplasias concludes that, although progress is being made, there are still a large number of questions to be answered regarding almost every aspect of the action of fgfr3, particularly when it comes to cartilage.23 the rate of de novo double mutations occurring in the same gene in cis is predicted to be very low at approximately,12–13 therefore it is unlikely to be a common mechanism in the pathogenesis of td.27 conclusion the case we describe is the second report in which the mutations differ from those classically implicated in the development of td. findings such as this may be usefully incorporated into the design of functional studies in the future, and suggest that the range of genotypes potentially responsible for the characteristic td phenotype is likely to be broader than previously recognised. references 1. martınez-frıas ml, de frutos ca, bermejo e, ecemc working group, nieto ma. review of the recently defined molecular mechanisms underlying thanatophoric dysplasia and their potential therapeutic implications for achondroplasia. am j med genet part a 2010; 152a:245–55. 2. schild rl, hunt gh, moore j, davies h, horwell dh. antenatal sonographic diagnosis of thanatophoric dysplasia: a report of three cases and a review of the literature with special emphasis on the differential diagnosis. ultrasound obstet gynecol 1996; 8:62–7. 3. karczeski b, cutting gr. thanatophoric dysplasia. in: pagon ra, bird td, dolan cr, et al., eds. figure 4: sequence electropherograms of allele-specific pcr. (panel a)amplicon produced by primers specific for wildtype allele at c.1663. the red arrow indicates position c.1620—note the apparent homozygosity for wild-type c.1620c. (panel b) amplicon produced by primers specific for wild-type allele at c.1620. the red arrow indicates position c.1663— note the apparent homozygosity for wild-type c.1663g. renate marquis-nicholson, salim aftimos and donald r. love brief communication | 87 genereviews™. seattle: university of washington, 1993. 4. macdonald im, hunter ag, macleod pm, macmurray sb. growth and development in thanatophoric dysplasia. am j med genet 1989; 33:508–12. 5. giancotti a, castori m, spagnuolo a, binni f, d'ambrosio v, pasquali g, et al. early ultrasound suspect of thanatophoric dysplasia followed by first trimester molecular diagnosis. am j med genet part a 2011; 155:1756–8. 6. delahaye s, rosenblatt j, costa jm, bazin a, bénifla jl, jouannic jm. first-trimester molecular prenatal diagnosis of a thanatophoric dysplasia. prenat diagn 2010; 30:1222–3. 7. hatzaki a, sifakis s, apostolopoulou d, bouzarelou d, konstantinidou a, kappou d, et al. fgfr3 related skeletal dysplasias diagnosed prenatally by ultrasonography and molecular analysis: presentation of 17 cases. am j med genet part a 2011; 155:2426–35. 8. hyland vj, robertson sp, flanagan s, savarirayan r, roscioli t, masel j, et al. somatic and germline mosaicism for a r248c missense mutation in fgfr3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia. am j med genet part a 2003; 120:157–68. 9. genome browser. university of california santa cruz (ucsc) from: http://genome.ucsc.edu accessed: apr 2012. 10. national genetic reference laboratory, manchester, uk, software tool. from: http://ngrl.man.ac.uk/ snpcheck.html accessed: apr 2012. 11. primer1: primer design for tetra-primer armspcr. from: http://primer1.soton.ac.uk/primer1. html accessed: apr 2012. 12. ye s, dhillon s, ke x, collins ar, day in. an efficient procedure for genotyping single nucleotide polymorphisms. nucl acids res 2001; 29:e88. 13. bellus ga, spector eb, speiser pw, weaver ca, garber at, bryke cr, et al. distinct missense mutations of the fgfr3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. am j hum genet 2000; 67:14–21. 14. francomano ca. hypochondroplasia. in: pagon ra, bird td, dolan cr, et al., eds.genereviews™. seattle, washington: university of washington, 1993. 15. polyphen-2 prediction tool. from: http://genetics. bwh.harvard.edu/pph2/index.shtml accessed: apr 2012. 16. sift prediction tool. from: http://sift.jcvi.org/www/ sift_enst_submit.html accessed: apr 2012. 17. pauli rm. achondroplasia. in: pagon ra, bird td, dolan cr, et al., eds. genereviews™. seattle: university of washington, 1993. 18. mckusick va, kelly te, dorst jp. observations suggesting allelism of the achondroplasia and hypochondroplasia genes. j med genet 1973; 10:11– 16. 19. sommer a, young-wee t, frye t. achondroplasiahypochondroplasia complex. am j med genet 1987; 26:949–57. 20. huggins mj, smith jr, chun k, ray pn, shah jk, whelan dt. achondroplasia-hypochondroplasia complex in a newborn infant. am j med genet 1999; 84:396–400. 21. chitayat d, fernandez b, gardner a, moore l, glance p, dunn m, et al. compound heterozygosity for the achondroplasia-hypochondroplasia fgfr3 mutations: prenatal diagnosis and postnatal outcome. am j med genet 1999; 84:401–5. 22. pannier s, martinovic j, heuertz s, delezoide al, munnich a, schibler l, et al. thanatophoric dysplasia caused by double missense fgfr3 mutations. am j med genet part a 2009; 149a:1296–1301. 23. foldynova-trantirkova s, wilcox wr, krejci p. sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (fgfr3) signaling in skeletal dysplasias. hum mutat 2012; 33:29–41. 24. webster mk, d’avis py, robertson sc, donoghue dj. profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type i. mol cell biol 1996; 16:4081–7. 25. savov a, angelicheva d, balassopoulou a, jordanova a, noussia-arvanitakis s, kalaydjieva l. double mutant alleles: are they rare? hum mol genet 1995; 4:1169–71. 26. blair e, price sj, baty cj, östman-smith i, watkins h. mutations in cis can confound genotype-phenotype correlations in hypertrophic cardiomyopathy. j med genet 2001; 38:385–423. 27. kondrashov as. direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases. hum mutat 2002; 21:12–27. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e589−590, epub. 14th oct 14 submitted 1st may 14 peer-reviewed accepted 19th aug 14 قراصنة االنتحال دورات عمل مقرتحة للتعامل مع السرقة األدبية pirates of plagiarism proposed courses of action to deal with plagiarism letter to the editor sir, creativity in scientific writing has been adversely affected by plagiarism. the phrase stating that ‘originality is the art of hiding the source’ no longer holds true in the current internet era. protecting the rights of creative thinkers in science and literature is a major concern due to the knowledge explosion of the new millennium. the fight against plagiarism is designed to give due credit to the innovator, thus respecting the novelty of the creation. whether a minor modification to existing knowledge makes it ‘new’ is a vital question. the world association of medical editors (wame) has explicitly defined plagiarism as the “use of others’ published and unpublished ideas or words (or other intellectual property) without attribution or permission, and presenting them as new and original rather than derived from an existing source”.1 it can take various forms, including the plagiarism of ideas; plagiarism of text; mosaic plagiarism; duplicate publication or salami slicing; self-plagiarism, and cyber-plagiarism. journals are beset with articles giving practical advice to researchers on how to avoid plagiarism. with the advent of software programs to detect plagiarism, e.g. turnitin or ithenticate (iparadigms, llc, oakland, california, usa), many plagiarised articles have been identified and retracted from eminent journals. the responsibility for a published article is shared by three players: the author, editor and reader. the office of research integrity (ori) in the usa and the committee on publication ethics (cope) in the uk have issued guidelines for editors and institutes on how to deal with publication misconduct.2,3 documents which include instructions to the authors focus on the requirements of the publishing journal. however, readers are often left in the lurch when they encounter plagiarism or when their own paper has been plagiarised. they should be made aware of the approach to be adopted in order to expose scientific misconduct. the reported case of asim kurjak provides an inconclusive ending to the eternal problem of plagiarism.4 an eminent academic and obstetrician, kurjak was declared guilty of “violations of the [committee’s] ethics code... and of common norms in biomedical publishing” by the croatian committee for ethics in science & higher education.4 his institution, the university of zagreb school of medicine in croatia, kept the matter quiet so as to protect the integrity of their reputation for research. despite the matter being pursued for over 15 years, very little could be achieved.4 similarly, the authors of this letter also encountered an article which had been plagiarised from two other articles.5–7 in spite of our communications to the editor with relevant evidence, the article in question unfortunately continues to enjoy a place on the journal’s website.5 possible courses of action are suggested below to be undertaken by either the reader on encountering plagiarism or by the author whose article has been plagiarised. in the case of a non-response from the offending parties, approaches for rectification are also expressed. there is a need to come up with ways to sternly deal with situations of this kind. we believe the approaches listed below will stimulate readers to ponder over several issues that need to be addressed on a larger scale. first, one may ask: what can or should be done by the reader on encountering plagiarism? the reader has a moral responsibility to inform the editor publishing the plagiarised article. concrete evidence of this misdemeanor must be provided for verification. the whistleblower (reader) should be kept in the loop regarding the progress of the investigation. moreover, the reader should pursue the issue to its culmination. failing a response from the editor of the plagiarised article, the reader should approach the journal owning the copyright of the original article and the plagiarised author for necessary rectification. the second question is: what can be done by the plagiarised author? in cases of plagiarism, the plagiarist and the editor of the plagiarised article are accountable. the plagiarised author should request a detailed investigation and disciplinary action by the editor. if the plagiarism has been proved beyond doubt, the offending article should be retracted along with an apology rendered by the plagiarist. in case of an unsatisfactory response, the plagiarist’s pirates of plagiarism proposed courses of action to deal with plagiarism 590 | squ medical journal, november 2014, volume 14, issue 4 institute and/or funding agencies can be notified about the misconduct. in addition, the author can request for the intervention of relevant scientific associations, such as cope, wame, ori and the general medical council.8 both readers and authors may be interested to learn if legal action can be initiated against a plagiarist. since the author assumes full responsibility for the paper and legally transfers the copyright to the publisher, any violations can result in criminal/civil charges and are liable for compensation. if the plagiarist escapes legal repercussions, they may be exposed publicly through the media and censured by the entire research community. a variety of sanctions may also be imposed on the plagiarist, such as a ban on any future publications for a stipulated period of time, the withdrawal of research funds or the suspension of their practice license, etc.8 plagiarism is tempting and the ease of misappropriating the work of others has damaged the creative thinking abilities of many authors. however, it cannot serve as a shortcut to success. any scientific misconduct, if unreported, may result in the duplication of data, theft of intellectual property, deception and a breach of collegial trust. moreover, investigations of a plagiarist’s research profile often exposures them as repeat offenders.5 a multipronged approach is essential to deal with this menace. editors, reviewers and readers should be aware of all forms of plagiarism and the means by which they can be detected. simultaneously, budding researchers must be trained and educated in ethical scientific writing from the beginning of their careers.8 clear policies on plagiarism should be outlined by journals and shared with authors. stringent action by editors to publicly expose the plagiarist and the fear of losing a professional reputation or employment may also serve as a deterrent to many potential offenders. this may also help to maintain the reputation of the editor, the reviewers, the journal and the publishing organisation. claims by potential whistleblowers should be taken seriously when they are substantiated by concrete evidence. all academic institutions should have explicit anti-plagiarism guidelines and mandated policies in cases of proven misconduct. it is imperative that a culture of conscientious publishing be inculcated within the academic community to protect the interests of all scientists. anoop k. agarwal and *syed i. shehnaz department of pharmacology, gulf medical university, ajman, united arab emirates *corresponding author e-mail: shehnazilyas@yahoo.com references 1. world association of medical editors. recommendations on publication ethics policies for medical journals. from: www.wame.org/ about/recommendations-on-publication-ethics-policie#plagiarism accessed: aug 2014. 2. the office of research integrity. sample policy and procedures for responding to allegations of research misconduct. available from: www.ori.hhs.gov/sites/default/files/samplepolicyandprocedures-5-07.pdf accessed: aug 2014. 3. committee on publication ethics. code of conduct and best practice guidelines for journal editors. from: www.publicationethics.org/ files/code_of_conduct_for_journal_editors_mar11.pdf accessed: aug 2014. 4. chalmers i. role of systematic reviews in detecting plagiarism: case of asim kurjak. bmj 2006; 333:594–6. doi: 10.1136/bmj.38968.61 1296.f7. 5. patel pm, prajapati ak, ganguly b, gajjar b. study on impact of pharmacology teaching on knowledge, attitude and practice on selfmedication among medical students. int j med sci public health 2013; 2:181–6. doi: 10.5455/ijmsph.2013.2.173-178. 6. zafar sn, syed r, waqar s, zubairi aj, vaqar t, shaikh m, et al. self-medication amongst university students of karachi: prevalence, knowledge and attitudes. j pak med assoc 2008; 58:214–17. 7. james h, handu ss, al khaja ka, otoom s, sequeira rp. evaluation of the knowledge, attitude and practice of self-medication among firstyear medical students. med princ pract 2006; 15:270–5. doi: 10.1159/000092989. 8. al-lamki l. plagiarism and other types of publication misconduct: a case for teaching publication ethics in medical schools. sultan qaboos univ med j 2009; 9:1–4. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e42-49, epub. 27th jan 14 submitted 16th jun 13 revisions reqd. 28th jul & 19th sep 13; revisions recd. 7th aug & 6th oct 13 accepted 10th oct 13 1tawam hospital, al ain, united arab emirates; 2department of paediatrics, college of medicine & health sciences, united arab emirates university, al ain, united arab emirates *corresponding author e-mail: aljasmif@uaeu.ac.ae الطفرات الوراثية و نسبة شيوع األمراض االستقالبية عند اإلماراتيني دراسة من مركز األمراض االستقالبية مبستشفى توام – اإلمارات العربية املتحدة عائ�صة �ل�صام�صي, جوزيف هريتكنت, �صنية �حلماد, عبد �لقادر �صوعيد, فاطمة �جل�صمي abstract: objectives: this study aimed to determine the mutation spectrum and prevalence of inborn errors of metabolism (iem) among emiratis. methods: the reported mutation spectrum included all patients who were diagnosed with iem (excluding those with lysosomal storage diseases [lsd]) at tawam hospital metabolic center in abu dhabi, united arab emirates, between january 1995 and may 2013. disease prevalence (per 100,000 live births) was estimated from data available for 1995–2011. results: in 189 patients, 57 distinct iem were diagnosed, of which 20 (35%) entities were previously reported lsd (65 patients with 39 mutations), with a birth prevalence of 26.87/100,000. this study investigated the remaining 37 (65%) patients with other iem (124 patients with 62 mutations). mutation analysis was performed on 108 (87%) of the 124 patients. five patients with biotinidase deficiency had compound heterozygous mutations, and two siblings with lysinuric protein intolerance had two homozygous mutations. the remaining 103 (95%) patients had homozygous mutations. as of this study, 29 (47%) of the mutations have been reported only in emiratis. two mutations were found in three tribes (biotinidase deficiency [btd, c.1330g>c] and phenylketonuria [pah, c.168+5g>c]). two mutations were found in two tribes (isovaleric aciduria [ivd, c.1184g>a] and propionic aciduria [pccb, c.990dupt]). the remaining 58 (94%) mutations were each found in individual tribes. the prevalence was 48.37/100,000. the most prevalent diseases (2.2–4.9/100,000) were biotinidase deficiency; tyrosinemia type 1; phenylketonuria; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type ia, and mitochondrial deoxyribonucleic acid depletion. conclusion: the iem birth prevalence (lsd and non-lsd) was 75.24/100,000. these results justify implementing prevention programmes that incorporate genetic counselling and screening. keywords: metabolism, inborn errors; mutations; prevalence; founder effect; united arab emirates. امللخ�ص: الهدف: هدفت �لدر��صة �إىل حتديد مدى �نت�صار �الأمر��س �ال�صتقالبية ومعرفة طفر�تها �لور�ثية الطريقة: ت�صمنت ت�صجيل كل �لطفر�ت �لو�رثية يف جميع �ملر�صى �لذين مت ت�صخي�صهم باالأمر��س �ال�صتقالبية )بعد ��صتبعاد �أمر��س �الختز�ن يف �جل�صيمات �حلالة ) �أمر��س �لتخزين �للي�صو�صومية( يف مركز �الأمر��س �ال�صتقالبية مب�صت�صفى تو�م بابوظبي – �الإمار�ت �لعربية �ملتحدة خالل �لفرتة من يناير 1995 �إىل مايو 2013 ومن ثم مت تقديرمعدل �نت�صار �الأمر��س �ال�صتقالبية )لكل 100,000 مو�ليد �أحياء( النتائج: مت ت�صخي�س 57 مر�صا من خمتلف �الأمر��س �ال�صتقالبية يف 189 مري�س منهم 20 )35%( من فئة �أمر��س �الختز�ن يف �جل�صيمات �حلالة )65 مري�س لديهم 39 طفرة ور�ثية( بن�صبة 26.87 لكل 100,000 .و �ل�صبعه و�لثالثون مري�صا �لباقون طفر�ت وجدت )87%( مري�صا �أ�صل 124 من يف 108 للطفر�ت حتليل مت ور�ثية(. طفرة لديهم 62 مري�صا 124( �حلالية در��صتنا مو�صع هم )65%( �لتحمل عدم مر�س لديهم �صقيقي يف �الأالئل متماثلة زيجوت طفرتي حتديد مت �لبيوتنيديز �نزمي عوز لديهم مر�صى خم�س يف �ملركبة �الأالئل متخالفة لربوتي �لليزين �أما باقي �ملر�صى 103 )%95( فوجدت لديهم طفر�ت زيجوت متماثلة �الأالئل. ومن �جلدير بالذكر �أن 29 )%47( طفرة ور�ثية مت ح�رشها يف �الإمار�تيي فقط �ىل �الآن. وجدت طفرتي يف 3 قبائل فقط )عوز �نزمي �لبيوتنيديز و بيلة �لفينل كيتونبينما وجدت طفرتي يف قبيلتي )�حم�صا�س �لدم �اليزوفالرييكي و �حم�صا�س �لدم �لربوبيونيكي( ووجد 58 )%94( طفرة يف عدد من �لقبائل �لفردية مبعدل �نت�صار 48.37 لكل 100,000. وكانت �أكرث �الأمر��س �صيوعا )4.9 –100,000/2.2( كاالآتي: عوز �نزمي �لبيوتنيديز وفرط تريوزين �لدم و بيلة �لفينل كيتون و �حم�صا�س �لدم �لربوبيونيكي و بيلة حم�س �لغلوتاريك �لنوع �الأول ود�ء �ختز�ن �لغليكوجي �لنوع �الأول �أ ونفاذ �حلم�س �لنووي �مليتوكوندري اخلال�صة: معدل �نت�صار�الأمر��س �ال�صتقالبية يف �ملو�ليد �الإمار�تيي )�أمر��س �الختز�ن يف �جل�صيمات �حلالة �أو غريها( يقدر بحو�يل ,100,000/75.24. هذه �لنتائج تربر تنفيذ �لرب�مج �لوقائية �لتي تت�صمن �ال�صت�صارة �لور�ثية و�مل�صح �جليني عند �لوالدة. مفتاح الكلمات: �أمر��س �ال�صتقالب يف �ملو�ليد؛ �لطفر�ت �جلينية؛ معدل �نت�صار؛ تاأثري موؤ�ص�س؛ �الإمار�ت �لعربية �ملتحدة. mutation spectrum and birth prevalence of inborn errors of metabolism among emiratis a study from tawam hospital metabolic center, united arab emirates aisha al-shamsi,1 jozef l. hertecant,1 sania al-hamad,2 abdul-kader souid,2 *fatma al-jasmi2 clinical & basic research aisha al-shamsi, jozef l. hertecant, sania al-hamad, abdul-kader souid and fatma al-jasmi clinical and basic research | e43 studies of the mutation spectrum and prevalence of iem in the middle east and north africa (mena) are still insufficient.1 these disorders, which are usually autosomal recessive, are more frequent in the mena region due to “founder mutations” and consanguinity.2 the primary objective of this study was to provide data from the united arab emirates (uae) that justify initiating prevention programmes, such as premarital screening and counselling. these data are also required to assess the impact of managing these patients within the uae health systems. the population of emiratis is ethnically diverse, claiming ancestry from the arabian peninsula, persia, baluchistan and east africa. emirati society consists of at least 70 distinct tribes. despite the ethnic diversity, inter-tribal marriages are much less common than intra-tribal ones.3 in 2010, the uae’s population was estimated at 8,264,070; 87% of this population was expatriate.4 in 2011, the total live birth in uae was 83,950, of whom only 40% were emiratis.5 the center for arab genomic studies reports 334 genetic diseases in the uae, including iem, congenital anomalies and mental retardation.6 moreover, the prevalence and mutation spectrum of lsd in the uae was recently reported and compared with published data from western countries.7,9–11 this study was designed to report on other iem entities among emiratis. methods this project was approved by the al-ain medical human research ethics committee (protocol #12/59). the study’s population did not include patients who had received treatment exclusively abroad as they represent an unknown number of patients, nor did the study include the 22 patients managed at the latifa hospital in dubai. for calculating the disease birth prevalence, all citizens of the uae with iem (excluding those with lsd) who were evaluated between january 1995 to december 2011 at tawam hospital, the only metabolic referral center in abu dhabi, were included. the mutation spectrum for non-lsd iem included all patients evaluated from january 1995 to may 2013. the diagnosis of iem was based on the clinical findings and screening tests, and was confirmed by biochemical and/or genetic studies. in many patients, the diagnosis was also supported by family studies. direct genomic sequencing and multiplex ligation-dependent probe amplification (mlpa) studies for deletion/duplication mutations of iem genes were performed by accredited genetic diagnostic laboratories. novel variants were verified by extended family genetic testing as well as damage-prediction assessment using three different prediction tools: sift (sorting intolerant from tolerant),12 polyphen-2 (polymorphism phenotyping version 2)13 and mutationtaster.14 the estimated birth prevalence of each disease was calculated as the number of patients with a specific disease divided by the total number of emirati live births in the uae during the birth period (the time interval between the year of birth of the oldest patient and the year of birth of the youngest patient).10 the birth prevalence of a single patient was calculated as one divided by the number of total emirati live births in the uae between 1995 and 2011.11 the affected deceased siblings and fetuses that had not been evaluated at the metabolic center were not included in this study. the number advances in knowledge the birth prevalence of inborn errors of metabolism (iem) among emiratis is 75.24 per 100,000 (1 per 1,329 live births). of the 62 mutations identified in this study, 29 (47%) have so far been reported only in emiratis. the most prevalent iem in the united arab emirates (uae) are biotinidase deficiency; tyrosinaemia type 1; phenylketonuria; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type ia, and mitochondrial deoxyribonucleic acid depletion. application to patient care the high prevalence of iem in the uae justifies implementing intensive prevention programmes that incorporate genetic counselling and screening. the prevention of iem requires premarital and prenatal testing, as well as counselling. early detection through newborn screening will improve patient outcomes, although prevention of these iem is the ultimate goal. prevention programmes will decrease the burden of iem on the uae’s health system. mutation spectrum and birth prevalence of inborn errors of metabolism among emiratis a study from tawam hospital metabolic center, united arab emirates e44 | squ medical journal, february 2014, volume 14, issue 1 of live births per year was obtained from the uae national bureau of statistics but data were available only up to 2011.4 however, the mutation spectrum of patients who were diagnosed after 2011 was also included. results excluding those with lsd, 37 distinct iem were diagnosed in the 124 patients between january 1995 and may 2013. mutation analysis was performed on 108 (87%) patients. in 43 tribes, 62 mutations were found, with most of the reported mutations being homozygous. five patients with biotinidase deficiency had compound heterozygous mutations, and two siblings with lysinuric protein intolerance had two homozygous mutations. the remaining 103 (95%) patients had homozygous mutations. as of the date of this study, 29 (47%) of the mutations had been reported only in emiratis [table 1]. biotinidase deficiency (btd, c.1330g>c) and phenylketonuria (pku) (pah, c.168+5g>c) occurred in three separate tribes. isovaleric aciduria (ivd, c.1184g>a) and propionic aciduria (pccb, c.990dupt) occurred in two separate tribes. the two tribes with propionic aciduria were originally from oman. the remaining 58 (94%) mutations occurred in individual tribes [table 1]. the 29 mutations unique to the uae point to a “founder effect”. diseases with a prevalence of 2.2–4.9 per 100,000 live births were biotinidase deficiency; tyrosinaemia type 1; pku; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type ia; mitochondrial deoxyribonucleic acid (dna) depletion; melanocortin 4 receptor deficiency, and chloride diarrhoea [table 1]. diseases with a prevalence of 1.1–1.9 per 100,000 live births were isovaleric aciduria; fructose 1,6-bisphosphatase deficiency; glutaric aciduria type ii; lipoamide dehydrogenase deficiency; alphamethylacyl-coa racemase, and neonatal diabetes [table 1]. diseases with a prevalence of ≤0.98 per 100,000 live births were alkaptonuria; sulfite oxidase deficiency; nonketotic hyperglycinaemia; maple syrup urine disease; 3-methylcrotonylglycinuria; carbamoyl phosphate synthetase deficiency; citrullinaemia type 1; argininosuccinate lyase deficiency; lysinuric protein intolerance; cobalamin b deficiency; cobalamin c deficiency; pyridoxinedependent seizures; medium-chain acyl-coa dehydrogenase deficiency; carnitine deficiency; 3-ketothiolase deficiency; lipoamide dehyrogenase deficiency; adrenoleukodystrophy; zellweger syndrome; bile acid disorder; progressive familial intrahepatic cholestasis; crigler-najjar syndrome; osteopetrosis, and butyrylcholinesterase deficiency [table 1]. discussion the uae has a very high net migration rate, making it challenging to estimate the birth prevalence of a disease as a ratio of the entire population, so this study only estimated the birth prevalence of iem among emiratis.5 intra-tribal marriages are dominant in the uae, occurring in over 50% of unions. first-cousin marriages account for about 30% of those cases.3 the mutation spectrum and birth prevalence of lsd among emiratis has recently been reported, focusing on other iems in the same population [table 1].6,7 the main purpose of this study was to provide data that justify implementing prevention programmes, such as prenatal and premarital screening and counselling. the results show a birth prevalence for non-lsd iem of 48.37 per 100,000 (1:2,067 live births) [table 1], giving an overall iem birth prevalence (lsd and non-lsd) of 75.24 per 100,000 (1:1,329 live births).7 this level of occurrence justifies the need for intensive prevention programmes. the data also point to the need for prenatal and premarital genetic testing and counselling. the overall disease prevalence of iem in british columbia, canada, (1969–1996) is about 40 patients per 100,000 live births (1:2,500 live births); the prevalence in italy (1985–1997) is 1:3,707 live births.15,16 the prevalence of classical iem of amino acids, organic acids and fatty acid oxidation in hong kong is 1:4,122 live births.17 in our study, 62 distinct mutations were identified [table 1]. most mutations (95%) were homozygous, and 19 mutations were novel, not having been reported previously. as mentioned earlier, 29 (47%) have so far only been reported in emiratis [table 1]. the centre for arab genomic studies (cags) aisha al-shamsi, jozef l. hertecant, sania al-hamad, abdul-kader souid and fatma al-jasmi clinical and basic research | e45 table 1: disorder, estimated prevalence, gene and mutation spectrum of non-lysomal storage disorders inborn errors of metabolism in the united arab emirates iem omim# genes/ refseq mutations pku† 261600 pah nm_000277.1 n = 17 c.168+5g>c (splicing mutation)††; c.782g>a (p.r261g); c.970-2a>g**; c.1066-11g>a; c.755g>a** (p.r252q)** alkaptonuria§ 203500 hgd nm_000187.2 n = 1 c.174dela (p.r58fs) tyrosinaemia type i† 276700 fah nm_000137.2 n = 2 c.1156g>c (p.d386h); c.1a>g (p.m1v) sulfite oxidase deficiency§ 606887 suox nm_000456.2 n = 1 c.650g>a (p.217r>q) nonketotic hyperglycinaemia§ 238300 gldc nm_000170.2 n = 1 c.919g>t (p.e307*) maple syrup urine disease§ 248600 dbt nm_001918.2 n = 1 c.1281+1 g>t propionic aciduria† 606054 pcca nm_000282.3 n = 2 c.1598_1601delttgt (p.f533wfs*5) pccb nm_000532.3 n = 3 c.1142g>a (p.c381y); c.990dupt (p.e331*)‡‡ 3-methylcrotonyl glycinuria§ 210200 mccc1 nm_020166.2 n = 3 c.89+2_89+34del; c.1106c>g (p.p369r); c.694c>t (p.r232w) mccc2 nm_022132.3 n = 1 c.735dupc (p.v247gfs*2) isovaleric aciduria‡ 243500 ivd nm_002225.3 n = 9 c.1193g>a (p.r398q); c.295+5g>a; c.1175g>a (p.r392h); c.1184g>a**‡‡ (p.r395q)**; c.1136_1138+4delttggtga (p.f382fs)** glutaric aciduria type i† 231670 gcdh nm_000159.2 n = 5 c.242c>t (p.p81l); c.427g>a (p.v143i); c.1204c>t (p.r402w) carbamoyl phosphate synthetase deficiency§ 237300 cps1 nm_001875.2 n = 1 c.1590dup (p.v531cfsx91)** citrullinaemia type 1§ 603470 ass1 nm_000050.4 n = 2 c.535t>c (p.w179r) argininosuccinate lyase deficiency§ 207900 asl nm_001024943.1 n = 1 c.332g>a (p.r111q) lysinuric protein intolerance§ 222700 slc7a7 nm_001126105.2 n = 4 c.499+1g>c**; c.999g>c¶ (p.r333s); c.1005c>a¶ (p.f335l) mutation spectrum and birth prevalence of inborn errors of metabolism among emiratis a study from tawam hospital metabolic center, united arab emirates e46 | squ medical journal, february 2014, volume 14, issue 1 biotinidase deficiency† 253260 btd nm_000060.3 n = 7 c.1330g>c (p.d444h)††; c.1207t>g (p.f403v); c.968a>g (p.h323r); c.1489c>t (p.p497s); c.557g>a (p.c186y) cobalamin b deficiency§ 251110 mmab nm_052845.4 n = 1 c.197-1 g>t (intronic) cobalamin c deficiency§ 277400 mmachc nm_015506.2 n = 1 c.271insa (p.r91kfsx14) pyridoxine-dependent seizures§ 266100 aldh7a1 nm_001182.4 n = 1 deletion of exon 7 fructose-1, 6-bisphosphatase deficiency‡ 611570 fbp1 nm_000507.2 n = 2 c.616_619delaaag (p.k206fs*70)** glycogen storage disease type ia† 232200 g6pc nm_000151.2 n = 2 c.59a>g (p.q20r) glutaric aciduria type ii‡ 231680 etfdh nm_004453.2 n = 4 c.807a>c (p.q269h) medium-chain acylcoa dehydrogenase deficiency§ 607008 acadm nm_000016.2 n = 1 c.985a>g (p.k329e) carnitine deficiency§ 212140 slc22a5 nm_003060.2 n = 1 c.248g>t (p.r83l) 3-ketothiolase deficiency§ 607809 acat1 nm_000019.3 n = 3 c.86_87duptg (p.e30wfs*11); c.854c>t (p.t285i) lipoamide dehyrogenase deficiency‡ 238331 dld nm_000108.3 n = 2 c.685g>t (p.g229c) mitochondrial dna depletion† 203700 polg nm_002693.2 n = 7 c.3286c>t (p.r1096c) 251880 dguok nm_080916.1 n = 1 c.427 t>c (p.s143p) 609560 tk2 nm_004614.4 n = 2 c.173a>g (p.n58s) adrenoleukodystrophy§ 300100 abcd1 nm_000033.3 n = 1 c.309c>g (p.s103r) zellweger syndrome§ 614862 pex6 nm_000287.3 n = 1 c.611c>g (p.s204*)** alpha-methylacyl-co a racemase‡ 614307 amacr nm_001167595.1 n = 3 c.877t>c (p.c293r) bile acid synthesis disorder§ 235555 akr1d1 nm_005989.3 (n = 1) c.781c>t (p.r261c)** aisha al-shamsi, jozef l. hertecant, sania al-hamad, abdul-kader souid and fatma al-jasmi clinical and basic research | e47 has reported 29 published iem in uae (16 lsd and 13 other iem). only nine of the 13 non-lsd iem entities are listed in table 1. the remaining four disorders (argininaemia, mevalonic aciduria, homocystinuria and menkes disease) occurred in the uae, but data are lacking on whether these disorders exist in emiratis or people of other nationalities. the 28 additional non-lsd iem [table 1] entities need to be included in the catalogue of transmission genetics in arabs database.8 several iem mutations in middle eastern populations have been reported.6,18–21 in the case of isovaleric aciduria, three mutations (p.r392h, p.r395q and p.f382fs) were reported in four unrelated emirati families and one mutation (p.e408k) in an egyptian family.20 alkaptonuria, due to the single nucleotide deletion of c.342dela (c.174dela), was reported in a family from al ain, uae; the allelic prevalence was estimated at about 1%.21 in the uae, screening began for pku in 1995, for congenital hypothyroidism in 1998, sickle cell disease in 2002, congenital adrenal hyperplasia in 2005 and biotinidase deficiency in 2010.22–24 the expanded national neonatal screening programme, implemented in 2011, covers over 90% of all neonates. it includes amino acid disorders (pku, maple syrup disease, citrullinaemia type i and argininosuccinic aciduria); organic acid disorders (isovaleric aciduria; hmg-coa lyase deficiency; beta-ketothiolase deficiency; glutaric aciduria type i; propionic aciduria, and methylmalonic aciduria) and fatty acid oxidation disorders (medium-chain acyl-coa dehydrogenase deficiency). the registry for congenital anomalies and hereditary disorders, along with premarital genetic testing and counselling, were started in 1999.23 biochemical studies can identify most iem. the limitations to this approach, however, include the invasive sample collection (skin, liver or muscle biopsy), the limited availability of clinically accredited biochemical diagnostic laboratories and the need for relatively laborious analyses. thus, the current clinical practice relies on combining biochemical and genetic studies. identifying a mutation confirms the diagnosis, allows screening for asymptomatic family members, supports pre-implantation genetic programmes and may influence patient management. for example, progressive familial intrahepatic cholestasis§ 601847 abcb11 nm_003742.2 n = 1 c.1897a>c (p.t633p) crigler-najjar syndrome§ 606785 ugt-1 nm_000463.2 n = 1 c.1073a>g (p.n358s)** melanocortin 4 receptor deficiency† 601665 mc4r nm_005912.2 (n = 2) c.485c>t (p.t162i) chloride diarrhoea† 214700 slc26a3 nm_000111.2 n = 3 c.559g>t (p.g187*) osteopetrosis§ 259730 ca2 nm_000067.2 n = 2 c.232+1g>a butyrylcholinesterase deficiency§ 177400 bche nm_000111.2 n = 1 c.293a>g (p.d98g) neonatal diabetes mellitus‡ 176730 ins nm_001185098.1 n = 3 c.-331c>g iem = inborn errors of metabolism; omim = online mendelian inheritance in man; refseq = national center for biotechnology information reference sequence database; pku = phenylketonuria; dna = deoxyribonucleic acid. † estimated birth prevalence of 2.2–4.9 per 100,000; ‡ estimated birth prevalence of 1.1–1.9 per 100,000; § estimated birth prevalence of <0.98 per 100,000; ¶ both mutations found in the same patient in a homozygous state; ** mutations reported so far only in emiratis; †† the two mutations found in three separate tribes and ‡‡ the two mutations found in two separate tribes (the remaining mutations occurred in individual tribes); bold = novel mutations that have not previously been reported. mutation spectrum and birth prevalence of inborn errors of metabolism among emiratis a study from tawam hospital metabolic center, united arab emirates e48 | squ medical journal, february 2014, volume 14, issue 1 pku patients with c.168+5g>c, c.782g>a or c.970-2a>g typically respond to sapropterin, while patients with c.1066-11g>a or c.755g>a are unresponsive.25 in our practice, only ~50% of patients with c.168+5g>c responded to sapropterin and none of the patients with c.782g>a or c.9702a>g responded to this treatment. as shown in table 1, the most prevalent diseases in the uae are biotinidase deficiency; tyrosinaemia (type 1); pku; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type ia; mitochondrial dna depletion; melanocortin 4 receptor deficiency and chloride diarrhoea. of the seven patients with biotinidase deficiency, most had a partial deficiency. when mutation analysis was performed on six patients, only one had a homozygous mutation with partial enzyme deficiency, while the other five carried compound heterozygous mutations (all born to parents of different tribes). six of the seven patients were diagnosed by newborn screening after 2012, reflecting a high carrier frequency. two siblings with lysinuric protein intolerance had two different homozygous mutations [table 1]. the remaining patients had homozygous mutations. ten novel missense mutations were reported in this study [table 1], all in patients with clinical and/ or biochemical findings consistent with the disease. future studies are needed to explain the functional effects associated with each of these mutations. two mutations (involving biotinidase deficiency and pku) each occurred in three separate tribes. two mutations (involving isovaleric aciduria and propionic aciduria) each occurred in two separate tribes. the remaining 58 mutations (94%) each occurred in individual tribes [table 1]. the need for effective premarital testing and counselling and prenatal/pre-implantation genetic diagnoses was highlighted by the 19 families with more than one affected child. this study reports 62 mutations. the 19 novel mutations that had not been previously reported are identified in table 1 in bold. the 10 mutations that have been previously reported only in emiratis are denoted by double asterisks in table 1.17–20 the remaining 33 mutations are known mutations, which are available at the human gene mutation database.26 identifying mutations allows the screening of asymptomatic family members and also supports pre-implantation genetic programmes. in the future, incorporating mutation analysis into newborn screenings as a second-tier test will decrease the number of false-positive cases and facilitate early treatment. nevertheless, disease prevention remains the ultimate goal. this study has some limitations. first, the birth prevalence of iem was estimated based only on patients who presented clinically or were referred by the national newborn screening programme. tawam hospital is the uae’s only referral center for metabolic diseases, and the 22 emirati patients referred to latifa hospital were not included in this study. thus it is possible that some patients who may have iems were not included in this study. second, the uae’s expanded national newborn screening programme only started in 2011 so the population that has been screened for newborn iem is limited. third, patients who were born in 2012 and 2013 were not included in the calculation of disease prevalences since the total live births for those years were not yet available at the time of writing. therefore, the reported iem birth prevalences in table 1 should be considered as rough estimations. fourth, the iem disorders in table 1 were diagnosed primarily by biochemical studies, which is the gold-standard approach. the mutation analyses were done by an accredited laboratory and the novel missense variants were not investigated by functional assays, such as expression analyses. preferably, chromosomes originating from emirati tribes should be studied to verify whether the sequence variants represented polymorphisms versus disorders. thus, the responsibility of some mutations for causing a disease may require future studies. conclusion the estimated birth prevalence of iem among emiratis is 75.24 per 100,000 (1 per 1,329 live births). distinct iem (n = 57) and 101 mutations have been identified thus far. these data strongly point to the need for genetic counselling and screening. identifying mutations unique to the uae will allow for more effective pre-implantation genetic testing and premarital testing in order to prevent further cases from occurring within families. early detection through newborn screening and treatment may prevent irreversible organ damage. aisha al-shamsi, jozef l. hertecant, sania al-hamad, abdul-kader souid and fatma al-jasmi clinical and basic research | e49 however, in spite of the possibility of treatment, the prevention of genetic diseases should remain the ultimate goal. references 1. tadmouri go, al ali mt, al-haj ali s, al khaja n. ctga: the database for genetic disorders in arab populations. nucleic acids res 2006; 34:d602–6. 2. teebi as (ed). genetic disorders among arab populations (2nd ed). new york: springer, 2010. p.612. 3. al-gazali l, ali br. mutations of a country: a mutation review of single gene disorders in the united arab emirates (uae). hum mutat 2010; 31:505–20. 4. united arab emirates national bureau of statistics. methodology of estimating the population in uae. from: w w w.uaestatistics .gov.ae/reportpdf/population%20 estimates%202006%20-%202010.pdf accessed: august 2013. 5. united arab emirates national bureau of statistics. health 2011. from: www.uaestatistics.gov.ae/ englishhome/reportdetailsenglish/tabid/121/default. aspx?itemid=2180&ptid=104&menuid=1 accessed: aug 2013. 6. tadmouri go. genetic disorders in arab populations. from: www.cags.org.ae/cbc02ga.pdf accessed: may 2013. 7. al-jasmi fa, tawfig n, berniah a, ali br, taleb m, hertecant jl, et al. prevalence and novel mutations of lysosomal storage disorders in united arab emirates: lsd in uae. jimd rep 2013; 10:1–9. 8. centre for arab genomic studies. the catalogue of transmission genetics in arabs. from: http://www.cags. org.ae/ctga_search.html accessed: may 2013. 9. poupětová h, ledvinová j, berná l, dvořáková l, kožich v, elleder m. the birth prevalence of lysosomal storage disorders in the czech republic: comparison with data in different populations. j inherit metab dis 2010; 33:387–96. 10. poorthuis bj, wevers ra, kleijer wj, groener je, de jong jg, van weely s, et al. the frequency of lysosomal storage diseases in the netherlands. hum genet 1999; 105:151–6. 11. pinto r, caseiro c, lemos m, lopes l, fontes a, ribeiro h, et al. prevalence of lysosomal storage diseases in portugal. eur j hum genet 2004; 12:87–92. 12. ng pc, henikoff s. predicting deleterious amino acid substitutions. genome res. 2001; 11:863–74. 13. adzhubei ia, schmidt s, peshkin l, ramensky ve, gerasimova a, bork p, et al. a method and server for predicting damaging missense mutations. nat methods 2010; 7:248–9. 14. schwarz jm, rödelsperger c, schuelke m, seelow d. mutationtaster evaluates disease-causing potential of sequence alterations. nat methods 2010; 7:575–6. 15. applegarth da, toone jr, lowry rb. incidence of inborn errors of metabolism in british columbia, 1969-1996. pediatrics 2000; 105:e10. 16. dionisi-vici c, rizzo c, burlina ab, caruso u, sabetta g, uziel g, et al. inborn errors of metabolism in the italian pediatric population: a national retrospective survey. j pediatr 2002; 140:321–7. 17. lee hc, mak cm, lam cw, yuen yp, chan ao, shek cc, et al. analysis of inborn errors of metabolism: disease spectrum for expanded newborn screening in hong kong. chin med j (engl) 2011; 124:983–9. 18. ben-rebeh i, hertecant jl, al-jasmi fa, aburawi he, alyahyaee sa, al-gazali l, et al. identification of mutations underlying 20 inborn errors of metabolism in the united arab emirates population. genet test mol biomarkers 2012; 16:366–71. 19. ali br, hertecant jl, al-jasmi fa, hamdan ma, khuri sf, akawi na, et al. new and known mutations associated with inborn errors of metabolism in a heterogeneous middle eastern population. saudi med j 2011; 32:353–9. 20. hertecant jl, ben-rebeh i, marah ma, abbas t, ayadi l, ben salem s, et al. clinical and molecular analysis of isovaleric acidemia patients in the united arab emirates reveals remarkable phenotypes and four novel mutations in the ivd gene. eur j med genet 2012; 55:671–6. 21. abdulrazzaq ym, ibrahim a, al-khayat ai, nagelkerke n, ali br. r58fs mutation in the hgd gene in a family with alkaptonuria in the uae. ann hum genet 2009; 73:125– 30. 22. al-hosani h, salah m, saade d, osman h, al-zahid j. united arab emirates national newborn screening programme: an evaluation 1998-2000. east mediterr health j 2003; 9:324–32. 23. al hosani h, salah m, abu-zeid h, farag hm, saade d. the national congenital anomalies register in the united arab emirates. east mediterr health j 2005; 11:690–9. 24. al hosani h, salah m, osman hm, farag hm, anvery sm. incidence of haemoglobinopathies detected through neonatal screening in the united arab emirates. east mediterr health j 2005; 11:300–7. 25. blau n, yue w, perez b. databases of pku and pnd variations. from: www.biopku.org/home/home.asp accessed: aug 2013. 26. institute of medical genetics in cardiff. the human gene mutation database. from: www.hgmd.org/ accessed: aug 2013. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 311-317, epub. 9th may 13 submitted 18th may 12 revision req. 14th oct 12, revision recd. 15th oct 12 accepted 24th nov 12 1diagnostic genetics, labplus, and 2genetic health service nz – northern hub, auckland city hospital, auckland, new zealand; 3school of medical sciences, university of auckland, auckland, new zealand *corresponding author e-mail: donaldl@adhb.govt.nz النتائج السريرية ومشاكل املشورة ملتالزمة التثلث الصبغي اجلزئي لطرف صبغ xp يف طفل مصاب بتأخر التطور. كارين ل. �شيث، روبرتو ل مازا�شى، �شامل اأفتيمو�ض، نريين جريجر�شن، األي�ض م جورج، دونالد ر. لوف امللخ�ص: متثل الن�شاء حاملى الأزفاء ال�شبغي املتوازن املحتوى على �شبغ x و�شبغ ج�شدي حتديا كبريا يف امل�شورة الوراثية نظرا للعديد من الحتمالت النت�شافية واأي�شا نتيجة لتاأثري اجلينات املتمركزة على ال�شبغ x التي قد ل تخ�شع لعملية التعطيل. هذا تقرير حالة تقدم قد اجلزيئي النووي التنميط با�شتخدام اجل�شدي ال�شبغ م�شتق على x ال�شبغ على املتمركزة اجلينات تاأثر مدى اإظهار اأن يو�شح معلومات قاطعة يف �شياق امل�شورة الوراثية. للجا�شرتين؛ املفرز الببتيد امل�شتقبالت؛ اأك�ض؛ ال�شبغ تعطيل xp22؛ ال�شبغي الإحاد x؛ �شبغ ال�شبغي؛ التثلث الكلمات: مفتاح بروتني ك اأ ل – 1؛ تقرير حالة؛ نيوزيالند. abstract: female carriers of balanced translocations involving an x chromosome and an autosome offer genetic counselling challenges. this is in view of the number of possible meiotic outcomes, but also due to the impact of x chromosome-localised genes that are no longer subject to gene silencing through the x chromosome inactivation centre. we present a case where delineation of the extent of x chromosome-localised genes on the derivative autosome using molecular karyotyping offers critical information in the context of genetic counselling. keywords: trisomy; x chromosome, monosomy xp22 pter; x chromosome inactivation; receptors, gastrinreleasing peptide; kal-1 protein; case report; new zealand. clinical outcomes and counselling issues regarding partial trisomy of terminal xp in a child with developmental delay karen l. sheath,1 roberto l. mazzaschi,1 salim aftimos,2 nerine e. gregersen,2 alice m. george,1 *donald r. love1,3 case report female carriers of balanced translocations between an x chromosome and an autosome can exhibit a range of phenotypes from apparently normal to those with a range of abnormalities.1 this outcome is due almost entirely to a skewed x inactivation pattern. in phenotypically normal females, the translocated x is preferentially activated and the intact x is inactivated. from a counselling perspective, this presents problems. there are many possible genotypic outcomes for the offspring of a balanced carrier and, unlike an autosome-autosome translocation, there is the added complication of estimating risk when there is the possibility of functional disomy. functional disomy occurs when the translocated portion of the x chromosome is separated from the x chromosome inactivation centre located at xq13.,2 and is therefore unable to undergo x chromosome-based inactivation. about 30% of genes on the short arm of the x chromosome escape x chromosome inactivation and continue to be expressed from the inactive x chromosomes.2 this is true even in females with trisomy x; the increased dosage is unlikely to have any deleterious effect, as most trisomy x females are phenotypically normal.2 from this we can assume that an abnormal phenotype is the result of the expression of duplicated genes, normally silenced during x chromosome inactivation. previously reported cases of functional disomy for chromosome xp vary substantially both from the extent of the p-arm that is involved and the severity of the phenotype. not surprisingly, those patients clinical outcomes and counselling issues regarding partial trisomy of terminal xp in a child with developmental delay 312 | squ medical journal, may 2013, volume 13, issue 2 who have all (or almost all) of the xp arm exhibit more severe phenotypic features.3–5 those with smaller regions of functional xp disomy generally exhibit a less severe phenotype.6–9 a comparison of the phenotypic features of these cases is shown in table 1. here we describe a case of a maternally inherited 17 mb duplication of xp22.33p22.13 detected by molecular karyotype in a 17-month-old female infant. g-banding analysis of the mother and the molecular karyotype data of the proband led to a deduced karyotype of the proband. the molecular karyotype data also allowed for a more informed discussion of the implications of future pregnancies for the mother. case report the 3 kg proband was born at term to nonconsanguineous parents. at delivery, her mother and father were 29 and 34 years old, respectively. there was no history of recurrent miscarriages, stillbirths, neonatal deaths, or individuals with intellectual disability and/or unusual physical features. poor growth was observed during the last 4 weeks of pregnancy and the mother noted reduced fetal movements compared to her first pregnancy. during the first year of life, the proband’s length followed the 50th centile and her weight the 10th centile. she sat at 5 months of age but did not crawl until 15 months. repeated significant respiratory infections and minimal weight gain prompted a hospital admission at 17 months of age. at that time, she was pulling to stand but not walking. she was babbling and waving “bye-bye” appropriately. she could point to objects, was developing a pincer grip in both hands, and had a vocabulary of 7 words. a genetic assessment at that time noted a head circumference at the 10th centile, mild brachycephaly, and a flat bridge of the nose in the absence of telecanthus or hypertelorism. in view of the history of unexplained growth and developmental retardation, a molecular karyotype was requested. radiology revealed the presence of right upper and lower lobe pneumonia for which she received appropriate antibiotic treatment and fully recovered. no underlying anatomic or immune abnormalities were identified to explain her repeated respiratory infections and she had no further infections over the ensuing months. a molecular karyotype analysis was performed on extracted deoxyribonucleic acid (dna) using the affymetrix® cytogenetics whole-genome 2.7m array (affymetrix, santa clara, california, usa). regions of copy number change were calculated using the affymetrix® chromosome analysis suite software (chas) v.1.0.1 which was interpreted with the aid of the university of california santa cruz genome browser (hg18 assembly).10 the proband’s molecular karyotype identified an extra copy of the 17.2 mb terminal region of the x chromosome; arr xp22.33p22.13(125,959-17,372,584)x3. conventional g-banded chromosome analysis was performed on peripheral blood samples taken from the proband’s mother, which showed an abnormal female karyotype with an apparently balanced translocation between the short arm of one x chromosome and the short arm of chromosome 13; 46,x,t(x;13)(p22.13;p11.2). conventional g-banded chromosome analysis on blood samples from the mother’s parents showed normal karyotypes, confirming that the balanced translocation in the mother was a de novo event. discussion due to the uncertain nature of x chromosome inactivation (and prenatal inactivation studies may not be predictive of phenotype), a balanced female chromosome complement identified at prenatal diagnosis is not necessarily associated with a normal phenotype, and some abnormal outcomes may not give rise to a significant abnormality. male x-autosome translocation carriers have been recorded previously with normal and abnormal phenotypes. consequently, a detailed fetal ultrasound examination is recommended. the estimated overall risk for liveborn offspring with structural and/or functional imbalance is difficult to estimate but would be in the region of 20–40%.11 the risk of fetal loss is also likely to increase compared to the general population’s risk of 15%.11 critically, prenatal diagnosis should be available, and unbalanced products of the translocation would be detectable on cultured chorionic villus cells or amniocytes. karen l. sheath, roberto l. mazzaschi, salim aftimos, nerine e. gregersen, alice m. george and donald r. love case report | 313 the duplicated maternal x chromosome region of 17 mb reported in the proband contains numerous genes. the genes within the pseudoautosomal region (par1), which encompasses approximately 2.7 mb of the terminal short arm of the x chromosome and comprising 24 genes, obviously escape x inactivation.12 escape genes are often clustered with as many as 13 genes in large domains ranging in size between 100 kb and 7 mb. interestingly, recent data suggest that those x-linked genes that apparently escape inactivation as determined by somatic cell hybrid data may exhibit monoallelic expression, or expression at levels that may be as low as 25% of the same gene on an active x chromosome.13,14 table 1: summary of cases of functional disomy of chromosome xp reference gustashaw et al., 19946 matsuo et al., 19993 kokalj vokac et al., 20027 kolomietz et al., 20054 monnot et al., 20088 hunter et al., 20099 myszka et al., 20105 index case region of functional disomy xp21.1→pter xp11.21p21.3 xp11.2p22.23 xp11.2→pter xp11.23-p11.4 xp11.1p11.22 xp11.2→pter xp22.33p22.13 iugr/gr + + facial dysmorphism + + + + + + + + hypertelorism + + + ear abnormalities + + + + myopia + developmental delay/cognitive impairment + + + + + + + + hypotonia + + + + myoclonal seizures + + + + small hands and feet + + clinodactyly + + + digital clubbing + hypermelanosis of ito + + foramen ovale apertum + + hydronephrosis + + nystagmus + + tachypnea supernummery nipple sacral mongolian spot broad forehead, posterior scalp line + + respiratory distress + ++ iugr = intrauterine growth restriction; gr = growth restriction. clinical outcomes and counselling issues regarding partial trisomy of terminal xp in a child with developmental delay 314 | squ medical journal, may 2013, volume 13, issue 2 figure 1 panels a–r: meiotic outcomes of the proband’s mother’s balanced translocation. panels a, b, k, and l are the most likely products (normal and balanced) from the proband’s mother’s reciprocal translocation. the panel l outcome may result in infertility; panel b may be associated with an abnormal clinical phenotype if the normal x chromosome is not preferentially inactivated; panel c is known to be viable; panel m would be expected to have the same degree of viability; panel d is expected to have a less severe phenotype if the derivative x is preferentially inactivated. the outcomes shown in panels e, g, i, j, o, and q are known to be viable, and would be expected to show features of triple x, turner syndrome or klinefelter’s syndrome; however, panels e, g, o, and q may have a more severe phenotype if the normal x homologues are not inactivated. the outcome shown in panel n is considered to be less viable and associated with a more severe phenotype. the outcomes shown in panels f, h, p, and r would result in trisomy 13. other modes of segregation would have larger imbalances that are considered more unlikely to be viable. karen l. sheath, roberto l. mazzaschi, salim aftimos, nerine e. gregersen, alice m. george and donald r. love case report | 315 of those genes that lie outside the par1 region of the maternal 17.2 mb duplication in the proband, it is largely unclear which ones could have played a role in the proband’s clinical phenotype. mutations in the kal1 gene have been detected in patients diagnosed with kallman syndrome,15–17 but overexpression of this protein in caenorhabditis elegans induces axon branching and axon misrouting.18,19 in the case of the grpr gene, bolton et al. and ishikawa-brush et al. reported a female patient with a balanced translocation 46,x,t(x;8) (p22.13;q22.1).20,21 the woman presented with multiple exostoses around the ankles, knees, wrists, and left clavicle. she was short, with small hands, mild brachycephaly, mental retardation, epilepsy, and autism. the translocation breakpoint on the x chromosome occurred in the first intron of the grpr gene, which suggested that haploinsufficiency of the grpr gene may have contributed to this patient’s phenotype. interestingly, and in the context of the proband reported here, recent studies have shown that overexpression of grpr in the chick brain leads to laminar disorganisation in the telencephalon, tectum, and particularly in the cerebellum, which exhibits severe atrophy.22 it is therefore tempting to suggest that overexpression of kal1 and grpr may underlie some aspects of the proband’s phenotype. this case also highlights genetic counselling issues. genetic counselling provided an opportunity to explain the proband’s karyotype abnormality to the parents, how it may have accounted for her phenotype, and to discuss recurrence risks. establishing that the mother carried a de novo balanced translocation removed the need to counsel extended family members, but confirmed the need to explain to the couple the variety of possible outcomes in a future pregnancy. at first glance, and given the overwhelming number of possible segregations [figure 1; not all possible segregations are shown], a discussion about possible pregnancy outcomes would appear to be daunting. practically, one way to approach such counselling may be to consider the outcomes by gender. in female fetuses with a turner, turner variant, or trisomy 13 chromosome complement (segregation patterns i, j, f, and h, respectively), a high rate of spontaneous miscarriage is to be expected. the turner variant of pattern d possibly carries a lower risk of abortion. females with these genotypes who survive to delivery could be expected to have an abnormal phenotype: trisomy 13 would carry the greater degree of morbidity and mortality. females with greater or lesser degrees of trisomy x (segregation patterns c, e, and g) would be expected to survive to term and have a milder phenotype. these phenotypes, and those resulting from segregation pattern d, may be modified by unpredictable x chromosome inactivation, and may range from normal to the phenotype observed in the proband, or have more severe problems. the carrier mother could also have normal females (patterns a and b) though a female with pattern b may be affected, depending on x chromosome inactivation. in male fetuses, one would expect those with segregation patterns n, p, and r to have a high risk of spontaneous abortion. patterns p and r result in trisomy 13 and, for pattern n, some of the genes in the deleted xp region cause x-linked dominant conditions which are lethal in males in the hemizygous state. certainly, some males with trisomy 13 may survive to birth. males with segregation patterns o and q would be expected to have a klinefelter’s syndrome phenotype, although those with pattern q could manifest additional rare x-linked dominant conditions not usually seen in males. infertility may be part of some phenotypes, but would possibly only be clinically relevant in males with pattern l. it is difficult to predict the clinical outcome of pattern m (partial duplication of xp22.3p22.13). given the number of omim genes in the region, a range of possibilities (from normal to affected) could be considered. of relevance in terms of the latter outcome is a report of a male with a mild learning disability and the karyotype 46,xdup(x)(p22.13-p22.31),y.23 tzschach et al. provide a summary of male mental retardation patients with a duplication or disomy of xp22.24 critically, the challenge in counselling is the characterisation of patients with smaller duplications than those reported to date that could provide a better insight into those genes that play a significant role in mental retardation. genetic counselling was greatly aided in this case by the identification of the exact breakpoints and genes involved in the chromosome rearrangement in the mother of the proband. for almost all the segregation patterns, fairly clear information can be conveyed to the parents about clinical outcomes and counselling issues regarding partial trisomy of terminal xp in a child with developmental delay 316 | squ medical journal, may 2013, volume 13, issue 2 the expected outcome or phenotype. this would aid in reproductive decision-making, either before or during a future pregnancy. the case illustrates how patient care benefits from close collaboration between clinicians and the laboratory. conclusion carriers of balanced translocations involving the x chromosome offer challenges in terms of genetic counselling; however, delineation of the breakpoints of the rearranged chromosomes can aid the clinician in their conversations with carriers in the context of reproductive decision-making. references 1. powell cm, taggart rt, drumheller tc, wangsa d, qian c, nelson lm, et al. molecular and cytogenetic studies of an x autosome translocation in a patient with premature ovarian failure and review of the literature. am j med genet 1994; 52:19–26. 2. carrel l, cottle aa, goglin kc, willard hf. a first-generation x-inactivation profile of the human x chromosome. proc natl acad sci usa 1999; 96:14440–4. 3. matsuo m, muroya k, kosaki k, ishii t, fukushima y, anzo m, et al. random x-inactivation in a girl with duplication xp11.21-p21.3: report of a patient and review of the literature. am j med genet 1999; 86:44–50. 4. kolomietz e, godbole k, winsor ej, stockley t, seaward g, chitayat d. functional disomy of xp: prenatal findings and postnatal outcome. am j med genet 2005; 134:393–8. 5. myszka a, karpinski p, makowska i, lassota m, przelozna b, slezak r, et al. dna methylation analysis of a de novo balanced x;13 translocation in a girl with abnormal phenotype: evidence for functional duplication of the whole short arm of the x chromosome. j appl genet 2010; 51:331–5. 6. gustashaw km, zurcher v, dickerman lh, stallard r, willard hf. partial x chromosome trisomy with functional disomy of xp due to failure of x inactivation. am j med genet 1994; 53:39–45. 7. kokalj vokac n, seme ciglenecki p, erjavec a, zagradisnik b, zagorac a. partial xp duplication in a girl with dysmorphic features: the change in replication pattern of late-replicating dupx chromosome. clin genet 2002; 61:54–61. 8. monnot s, giuliano f, massol c, fossoud c, cossée m, lambert jc, et al. partial xp11.23-p11.4 duplication with random x inactivation: clinical report and molecular cytogenetic characterization. am j med genet a 2008; 146a:1325–9. 9. hunter m, bruno d, amor dj. functional disomy of proximal xp causes a distinct phenotype comprising early hypotonia, hypertelorism, small hands and feet, ear abnormalities, myopia and cognitive impairment. am j med genet a 2009; 149a: 1763–7. 10. genome browser. university of california santa cruz (ucsc). from: http://genome.ucsc.edu accessed: apr 2012. 11. gardner rjm, sutherland gr. chromosome abnormalities and genetic counseling, 3rd ed. new york: oxford university press, 2004. 12. mangs ah, morris bj. the human pseudoautosomal region (par): origin, function and future. curr genomics 2007; 8:129–36. 13. talebizadeh z, simon sd, butler mg. x chromosome gene expression in human tissues: male and female comparisons. genomics 2006; 88:675–81. 14. carrel l, willard hf. x-inactivation profile reveals extensive variability in x-linked gene expression in females. nature 2005; 434:400–4. 15. franco b, guioli s, pragliola a, incerti b, bardoni b, tonlorenzi r, et al. a gene deleted in kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. nature 1991; 353:529–36. 16. hardelin jp, levilliers j, del castillo i, cohen-salmon m, legouis r, blanchard s, et al. x chromosomelinked kallmann syndrome: stop mutations validate the candidate gene. proc natl acad sci usa 1992; 89:8190–4. 17. hardelin jp, levilliers j, blanchard s, carel jc, leutenegger m, pinard-bertelletto jp, et al. heterogeneity in the mutations responsible for x chromosome-linked kallmann syndrome. hum mol genet 1993; 2:373–7. 18. bülow he, berry kl, topper lh, peles e, hobert o. heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the kallmann syndrome gene kal-1. proc natl acad sci usa 2002; 99:6346–51. 19. rugarli ei, di schiavi e, hilliard ma, arbucci s, ghezzi c, facciolli a, et al. the kallmann syndrome gene homolog in c. elegans is involved in epidermal morphogenesis and neurite branching. development 2002; 129:1283–94. 20. bolton p, powell j, rutter m, buckle v, yates jrw, ishikawa-brush y, et al. autism, mental retardation, multiple exostoses and short stature in a female with 46,x,t(x;8)(p22.13;q22.1). psychiat genet 1995; 5:51–5. 21. ishikawa-brush y, powell jf, bolton p, miller ap, francis f, willard hf, et al. autism and multiple exostoses associated with an x;8 translocation occurring within the grpr gene and 3-prime to the sdc2 gene. hum molec genet 1997; 6:1241–50. 22. iwabuchi m, maekawa f, tanaka k, ohki-hamazaki h. overexpression of gastrin-releasing peptide karen l. sheath, roberto l. mazzaschi, salim aftimos, nerine e. gregersen, alice m. george and donald r. love case report | 317 receptor induced layer disorganization in brain. neuroscience 2006; 138:109–22. 23. robertshaw ba, macpherson j. scope for more genetic testing in learning disability: case report of an inherited duplication on the x-chromosome. br j psych 2006; 189: 99–101. 24. tzschach a, chen w, erdogan f, hoeller a, ropers hh, castellan c, et al. characterization of interstitial xp duplications in two families by tiling path array cgh. am j med genet a 2008; 146a:197–203. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 406-410, epub. 20th nov 12 submitted 17th sep 12 peer reviewed accepted 22nd sep 12 health ensures vitality and productivity, and health care is a basic human right encompassed in various un declarations and who commitments.1,2 provision of health to its people demands structural organisation and systems planning by a government. this in turn requires emphasis on health professions education and material resources, after analyses of demographic inputs and unique local health issues. the flexner report of 1910 was a watershed in providing a roadmap for marrying technological advances in medicine with systemic reforms in health education—translating into better health care.3 an in-depth review of the 100 years that have elapsed since the flexner report by a global commission of experts (published in the lancet in 2010), has provided a reality check for health planners of the 21st century.4 the commission estimated a global count of 2,420 medical schools, 467 schools or departments of public health, and an indeterminate number of postsecondary nursing educational institutions, training about 1 million new doctors, nurses, midwives, and public health professionals every year. this seemingly positive picture is, unfortunately, counter-balanced by the realisation that four countries (china, india, brazil, and usa) each have more than 150 medical schools, whereas 36 countries have no medical schools at all.4 besides these astounding figures, the report points out glaring gaps in health professions education due to outdated curricula, poor manpower planning (qualitative and quantitative) and a dismal financial outlay on health education (only 2% of the annual budget in some of the most advanced countries).5 against this backdrop, a very contemporary article by gillian white, transforming education to strengthen health systems in the sultanate of oman, is published in this issue of squmj.6 its comprehensive framework reviews the links between education and health systems in oman. through interaction with the labour market, the provision of educational services supplies an educated workforce to meet the demand for professionals to work in the health system. the author refers extensively to the findings outlined in the lancet commission’s report 2010,4 and its recommendations for new instructional and institutional strategies for the design of health care professions education subsystems. it is noteworthy that, like other gulf cooperation council (gcc) countries, oman was a net importer of its health workforce only four decades ago. visionary self-reliance initiatives, prompted by an increasing competition for health workforce in the global market place and the urgency to create more employment opportunities for citizens, improved the public health sector manpower. from just 13 physicians and a few nurses in 1970 (serving a total population of approximately 732,000), by 2007 the physician-population ratio had risen from 0.18 per 10,000 to 17.9 per 10,000 and a nurse-population ratio to 37.9 per 10,000. the total number of physicians employed by the تعليم املهن الصحية يف سلطنة ُعمان منظور معاصر ريتو الختاكيا editorial health professions education in oman a contemporary perspective ritu lakhtakia department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ritu@squ.edu.om ritu lakhtakia editorial | 407 ministry of health (moh) grew 5.4-fold during the period 1985–2007 (from 638 to 3,459). during the same period, the number of nurses grew 4.5-fold (from 1947 to 8,143). the representation of omanis in the moh workforce grew from about 52% in 1990 to 68% in 2007, including leading categories such as physicians, nurses and laboratory technicians.7 contributing to this remarkable achievement were moh-established nursing and allied health science institutes, the college of medicine & health sciences at sultan qaboos university (squ) established in 1986, the oman medical college (a private medical school) and the oman medical specialty board pioneering postgraduate residency programmes in the country. in all, 1,053 students earned their mds from squ during 1993–2007.8 these figures classically illustrate the sequential progression from assessing health needs to planning health education, with a resultant trained workforce to meet the health delivery challenges of the country. the lancet commission report, and in turn the article by gillian white,6 refer to three sequential generations of educational reforms through the last century: the first taught a science-based curriculum; the second introduced problem-based instructional innovations; the third now proposes to refine educational systems by adapting core professional competencies to specific local contexts, while drawing on global knowledge.4,6 the process of achieving this is through transformative learning and interdependence in education. transformative learning involves three fundamental shifts: from fact memorisation to searching, analysis, and synthesis of information for decision making; from seeking professional credentials to achieving core competencies for effective teamwork in health systems, and from non-critical adoption of educational models to creative adaptation of global resources to address local priorities. ‘instructional’ reforms enable this form of learning.4 interdependence in education also involves three fundamental shifts: from isolated to harmonised education and health systems; from stand-alone institutions to networks, alliances, and consortia; and from inward-looking institutional preoccupations to harnessing global flows of educational content, teaching resources, and innovations. ‘institutional’ reforms are the key to achieving these transformations.4 gillian white effectively summarises the emerging generations of health profession educational reforms over the last century and the complexities of the health challenges of the new millennium detailed in the 2010 lancet commission report. she then provides a historical overview of health planning, delivery and education over the last 40 years in the sultanate of oman and discusses the implications and applicability of the report for health profession education in the country. the article lays specific emphasis on the organisation and education of nursing and allied health sciences, the achievements thus far and an incisive critique of unaccomplished goals.6 it is pertinent to draw the reader’s attention to a number of existing transformations already in place in the college of medicine & health sciences at squ, the premier public university of oman, and in the oman medical specialty board which governs postgraduate medical residency training in oman. the succeeding paragraphs highlight how these measures fulfil in part or whole the six recommendations of the lancet report4 for instructional, and four recommendations for institutional reforms in health professions education to achieve the outcomes of transformative learning and interdependence in education. instructional reforms competency-based curricula with a local context in keeping with 21st century global health management systems have already been initiated and remain under close and periodic evaluation to maintain relevance and dynamism. newer learning styles like team-based learning9 and contemporary evaluation processes form a vital part of this evolution. accreditation processes are well under way to offer credibility and provide checks and balances. reducing inter-professional barriers has formed the basis of combined educational modules in the first two years of the medical & laboratory sciences degree curriculum providing an insight and dialogue between interlinked professions. the new curricula foster an environment of analytical skills and actively promote leadership, management and communication skills. health professions education in oman a contemporary perspective 408 | squ medical journal, november 2012, volume 12, issue 4 information technology (it) has been actively harnessed for teaching, student-teacher communication, research and analysis, and selflearning. educational software, evaluation on-line, and statistical tools are some examples of the many ways it has already integrated effectively with medical and allied health science education. incorporation of local and cultural aspects to learning has led to the introduction of a foundation year to strengthen basic knowledge of language and science. active institutional support promotes electives and international research exchange programmes for students. squ benefits from short and long term transnational faculty that enriches curricular content and educational delivery. educational resource centres are replete with a variety of books, journals and software tools. faculty development in teaching technologies and active participation in conferences sustains and improves faculty performance and career progression. professionalism is addressed by specific measures including didactic teaching, rolemodelling, measures of accountability of performance and resource management, and use of evidence-based medicine. institutional reforms joint planning mechanisms between the education and health ministries, professional associations and academic community are in place and evolving as exhaustively covered in dr. white’s article.6 workforce planning, health outreach and incentives for professionals to be drawn from, and to deliver back to marginalised geographical areas and communities, has formed the driving force behind health planning and is a work in progress. transforming academic centres to academic systems which form the backbone of a vertical continuum between secondary and graduate and postgraduate programmes and horizontally between disciplines and professions still needs a yeoman’s effort and change in mindsets. overcoming shortages through alliances and consortia are part of future global health planning. already in place in selected institutions in the gcc region in general and in oman, these alliances provide a means to enhance quality standards, growth and wider exposure to global health perspectives. nurturing critical enquiry encompasses inculcating this habit at all levels of academia, and within students and stakeholders from society. excellent examples of ongoing processes include the research council of oman’s funding of national level projects looking into genetic and haematological disorders, and autism. the foregoing sections constitute benchmarks for the introduction of global standards with local emphasis and interdisciplinary synergy, and can provide a template for emulation by other institutions in the country. this illustrative but not exhaustive ‘report card’ emphasises the steady steps which apex institutions have already put in place towards achieving global standards. today, oman is well on its way to rub shoulders with global benchmark health care delivery systems. this work-in-progress needs pace and direction to achieve its goals, for which the lancet commission report exhorts a four-pronged approach: 1) mobilise leadership: academic leadership backed by a political strategy; 2) enhance investments: public, private and philanthropic; 3) align accreditation to meet global standards, and 4) strengthen global learning through shared academic and research knowledge. pitfalls and hurdles gillian white’s article lists a number of local issues that need to be taken into account for the fructification of quality health education.6 a few other aspects that need to be addressed critically and managed through institutional systems are detailed below. the necessity to enhance standards in english, and the measures already in place, have been highlighted by the article. it cannot, however, be overemphasised that the preparatory levels in preuniversity education need a comprehensive review of the curriculum of basic sciences, mathematics and information technology. an in-depth joint effort by educators in secondary and higher education is the need of the hour. the benefits accrued from elevating standards (especially of schools outside urban areas) may show surprising results: increased representation in the stream of higher education and, in turn, the return of trained health professionals to their regions to serve the community. ritu lakhtakia editorial | 409 attitudinal changes are vital to health care delivery systems: the profession demands an approach of service and empathy in the highest specialised academic as well as the lowest rung health care worker. initiating, inspiring and sustaining these are the arduous tasks of health educators. personal examples set by pioneering generations of omani physicians will stimulate this beyond the homilies that a didactic module on ethics and professionalism can instill. straitjacketing of academic achievement, in ‘degrees’ earned, stifles the development of the persona of a health professional whose role and success in health care will depend as much (if not more) on a lifelong ‘professional’ behaviour pattern. inculcation of these paradigms merits attention by educators and internalisation by students. despite excellent and comprehensive governmental incentives through long years of professional education in the country and abroad, attrition erodes the trained workforce base. the reasons for this range from personal to careerrelated decisions. compounding this outflow are premature lateral or vertical ‘shifts’ from professional to administrative roles. on the other hand, excellent individual instances of professionalism and performance, that have provided leadership by example, should be rewarded by incentives that should be a part of institutional reform. of concern, is an almost predictable trend among physicians returning after training to shun academic appointments in favour of positions in clinical service. a variety of personal and professional reasons have dictated this drift, one being the stringent demand of teaching hours and research. the latter aspect, in particular, weighs heavily in determining career advancement. if oman is to build a strong academic workforce for its universities and other professional teaching institutions, these issues need to addressed. the world over, burnout and a greater value placed on contributions in clinical, non-clinical and research areas over teaching, deter young physicians from opting for an academic career.10 greater care to judicious planning of levels of higher education for health professionals demands an in-depth analysis of the job grades on offer. over qualification, while helping individuals actualise their academic aspirations, may result in disgruntlement and frustration when stagnation occurs in the available positions without foreseeable promotion to a more senior level. equitable distribution of trained quality health personnel to non-urban or semi-urban populations will remain an ongoing challenge.11 higher education, being state-sponsored, must include its students’ commitment for short and long term service in regional areas after graduation. more concrete incentives to make such jobs attractive could combine allowances with regular opportunities for professional updating and retraining. every health educator, professional and stakeholder in oman’s health care system must consider the review article and the lancet commission report as a clarion call to deliberate seriously over the issues raised. this would enable their effective participation in improvement of the health education system and health care delivery in oman. references 1. international covenant on economic, social and cultural rights. article 12. from: http://www2. ohchr.org/english/law/cescr.htm accessed: sep 2012. 2. the right to health. from: http://www.who.int/ m e d i a ce nt re / f a c t s h e e t s / f s 3 2 3 / e n / i n d ex . ht m l accessed: sep 2012. 3. flexner a. medical education in the united states and canada: a report to the carnegie foundation for the advancement of teaching. new york: the carnegie foundation for the advancement of teaching, 1910. 4. frenk j, chen l, bhutta za, cohen j, crisp n, evans t et al. health professionals for a new century: transforming education to strengthen health systems in an interdependent world (the lancet commission). e-pub 29 nov 2010. doi10:1016/50140-6736(10)61854-5. 5. keehan s, sisko a, truffer c, smith s, cowan c, poisal j, et al. health spending projections through 2017: the baby-boom generation is coming to medicare. health aff (millwood) 2008; 27:w145–55. 6. white g. transforming education to strengthen health systems in the sultanate of oman. sultan qaboos university med j 2012; 12:429–34. 7. ghosh b. health workforce development planning in the sultanate of oman: a case study. human resour health 2009; 7:47. 8. ghosh b. omanization of health manpower. the 7th five-year plan prospects: a technical appendix to the 7th five-year human resources development health professions education in oman a contemporary perspective 410 | squ medical journal, november 2012, volume 12, issue 4 plan (document no. a.12/2001-10). muscat: ministry of health, 2006. 9. inuwa im. perceptions and attitudes of first-year medical students on a modified team-based learning (tbl) strategy in anatomy. sultan qaboos university med j 2012; 12:336–43. 10. blades ds, ferguson g, richardson hc, redfern n. a study of junior doctors to investigate the factors that influence career decisions. br j gen pract 2000; 50:483–5. 11. al-mandhari a, al-adawi s, al-zakwani i, alshafaee m, eloul l. impact of geographical proximity on health care seeking behavior in northern oman. sultan qaboos university med j 2008; 8:310–18. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 179-182, epub. 27th feb 13 submitted 21st apr 12 revision req. 7th aug 12, revision recd. 1st sep 12 accepted 6th oct 12 1sultan qaboos university hospital, muscat, oman; 2amrita institute of medical sciences, kochi, kerala, india *corresponding author e-mail: rajeevkariyattil@gmail.com انزالق مشابك سبائك الكوبالت أثناء جراحة متدد األوعية الدموية الدماغية تقرير حالة ومراجعة املنشورات راجيف كاريتيل،ديليب بانيكار هذه معظم نتجت وقد نادرا. يزال ما الدموية الأوعية متدد م�صابك التواء اأو وتداخل احلدوث، نادرة ظاهرة امل�صابك انزلق امللخ�ض: احلالت من م�صابك التيتانيوم. وا�صفو التقرير اأبلغوا عن حدوثه اأثناء ا�صتخدام م�صابك �صبيكة الكوبالت املنخلة يف جراحة متدد الأوعية الدموية يف ال�رسيان ال�صباتي الداخلي التي مت حتديدها خالل العملية با�صتخدام الأ�صعة امل�صبغة لالأوعية وت�صحيحه من خالل اإعادة و�صع م�صبك �صبيكة الكوبالت الغري املنخل. الآلية املحتملة لهذه امل�صاعفات، والتدابري التي قد حتول دون حدوثه، مبا يف ذلك الت�رسيح احلذر، اإزالة اأو تخفيف ال�صغط عندما يكون ذلك ممكنا، اختيار امل�صبك املنا�صب، والأ�صعة امل�صبغة اأثناء العملية. مفتاح الكلمات: متدد الأوعية الدموية الدماغية، ف�صل امل�صبك؛ الأ�صعة امل�صبغة ؛ تقرير حالة؛ الهند. abstract: clip slippage is a rare occurrence, and the scissoring or torsional failure of aneurysm clips is rarer still. titanium clips have been implicated in a few such reported cases. the authors report its occurrence while using a fenestrated cobalt alloy clip for an internal carotid artery aneurysm which was identified by intraoperative angiography and rectified by re-applying a non-fenestrated cobalt alloy clip. the possible mechanism of this complication, and measures that may prevent its occurrence, including meticulous dissection, decompression when possible, proper clip selection, and intraoperative angiogram are described. keywords: cerebral aneurysm; clip failure; intra-operative angiogram; case report; india. scissoring of a cobalt alloy aneurysm clip causing slippage during cerebral aneurysm surgery case report and review of literature *rajeev kariyattil1 and dilip panikar2 case report secure clip placement is the key to successful aneurysm surgery. clip failure after application, caused by twisting of the blades or scissoring rarely has been described in the literature.1–3 the failures that have been reported have followed the use of titanium clips. in these cases, the tensile property of the metal itself was suspected to be the main cause. however, other factors related to the aneurysm itself and clip application techniques may play an equally important role. case report a 53-year-old hypertensive male presented with a good grade sub-arachnoid haemorrhage (sah) of 3 days’ duration. a computed tomography (ct) scan of the brain showed a fischer grade 4 sah with ventriculomegaly. a digital subtraction angiogram (dsa) showed a 1.47 cm trilobed internal carotid artery (ica) aneurysm of the communicating segment with a 2.7 mm wide neck. there was irregular narrowing of the ica, suggestive of atherosclerosis [figure1]. the patient was admitted to amrita institute of medical sciences, cochin, india, for clipping of the aneurysm through a right pterional approach. exposure of the region showed the ica to have scissoring of a cobalt alloy aneurysm clip causing slippage during cerebral aneurysm surgery case report and review of literature 180 | squ medical journal, february 2013, volume 13, issue 1 atheromatous changes extending into the aneurysm neck and sac. after the neck was sufficiently exposed, a parallel clipping was achieved with a 10 mm bayonet-shaped fenestrated cobalt alloy yasargil aneurysm clip (b. braun melsungen ag, meslungen, germany) with the fenestra enclosing the middle cerebral artery (mca). there was evidence of parent vessel compromise which was corrected by readjusting the clip distally along the neck. the dome was aspirated to confirm satisfactory clipping. an intraoperative angiogram was then performed. the initial fluoroscopy images showed scisssoring of the blades and the angiogram showed refilling of the aneurysm [figure 2]. on returning back to the operative field, it was found that the aneurysm had refilled with blood, which was leaking through the puncture site. additionally, the clip was found to have rotated clockwise with the inner surface of one of the blades exposed [figure 3]. temporary clipping was not considered due to the extensive atheromatous changes in the ica. instead the clip was gently de-rotated and removed. there was considerable distortion of the aneurysm neck, ica, and mca during this manoeuvre. clipping was then achieved after a more complete dissection around the aneurysm neck, with a perpendicularly placed 9 mm curved cobalt alloy yasargil aneurysm clip. the check angiogram was found to be satisfactory [figure 4 ]. the postoperative course was complicated by a delayed left sided hemiparesis due to multiple mca territory infarcts secondary to vasospasm, which figure 1: preoperative angiogram showing internal carotid artery (ica) aneurysm. figure 2: intraoperative angiogram showing scissoring of clip and filling of aneurysm. figure 3: intraoperative view showing rotated clip. figure 4: final intraoperative angiogram showing complete clipping and vasospasm rajeev kariyattil and dilip panikar case report | 181 improved with medical measures. discussion the phenomenon of a “slipped” aneurysm following routine postoperative angiograms, although first described by charles drake, has been documented infrequently in the literature, and failure due to twisting of the blades or scissoring is rarer still.1–5 the stability of an aneurysm clip during surgery depends on various factors operating simultaneously, most of which cannot be predicted based on the mechanical properties of the clip alone. additionally, the current data are from in vitro testing and hardly mimic the real life situation.6-12 of these, only one study shows the effect of torque on the twisting of clip blades.11 of the several factors that are responsible for the stability of the clip, the one most commonly reported is that of the clip’s mechanical properties. pure titanium and titanium alloy clips have been implicated in all the reported cases of scissoring malfunction so far.1–3 although there are several studies which show reliable closing forces and the stability of these clips, one of these showed inferior stability of titanium clips to torque forces compared to cobalt alloy clips.9–13 there are also concerns in using titanium clips for larger aneurysms due to the decreased opening of the clip blades.14 for cobalt alloy clips, the make, length, and geometry of the clips have all been shown to influence the closing forces.7,8,10 in particular, bayonet and fenestrated clips have been shown to have weaker closing forces when compared to standard straight clips.8 the clip used in our patient was a fenestrated bayonet-shaped cobalt alloy clip. this is an alpha-type clip with a single box lock mechanism for stability. other similar clips like the sugita (mizuho medical co., tokyo, japan) have stabilisation bars to prevent scissoring. the next most important factor is aneurysmrelated. large complex aneurysms, especially those with a neck wider than 2 mm, require greater closing forces, which is often not achievable with a single clip. the presence of atherosclerosis further adds to the complexity by increasing wall thickness and stiffness.2,3,14 both these factors were present in this case. but the nature of failure, (i.e. the rotation and scissoring occurring in a slightly delayed manner), cannot be explained by size and wall thickness alone. however, if the atheroma is non-uniformly distributed around the neck, one of the clip blades may gradually slide over a rigid part of the plaque, resulting in their scissoring over a short period of time after the clip placement, as occurred in this patient. the third—and probably most important factor—is procedure-related. a good neck exposure freeing all adhesions, decreasing intra-luminal pressure, and choosing the right clip and final placement, all contribute to clip stability.14 torsional forces created while readjusting a clip in a large atheromatous neck can also result in scissoring, especially if the plaque is hard and eccentric, thereby preventing proper apposition of the blades. temporary clip occlusion of the ica and aspiration of the aneurysm provide the best conditions for a satisfactory clipping in such circumstances; however, these were not considered due to the presence of gross atheromatous changes in the parent vessel as seen in the angiogram as well as during surgery. parallel clipping was initially performed to avoid kinking of the ica. an additional clip, parallel and distal to the first after collapsing the sac, might have prevented the slipping. in the end, a simpler clipping solution with a standard clip in a perpendicular direction was found to be effective. the role of the intraoperative angiogram in achieving satisfactory clipping has been highlighted previously and cannot be over-emphasised.15,16 conclusion clip failure is a rare but distinct possibility and occurs when the clip is made to function in situations beyond its design parameters, irrespective of its make and mechanical properties. a good technique adhering to the basic principles of aneurysm surgery and choosing the right clip(s) for the right aneurysm are the keys to a successful outcome. the intraoperative angiogram is a valuable tool in identifying various unexpected and correctable problems, especially in complex aneurysms. scissoring of a cobalt alloy aneurysm clip causing slippage during cerebral aneurysm surgery case report and review of literature 182 | squ medical journal, february 2013, volume 13, issue 1 references 1. hirashima y, kurimoto m, kubo m, endo s. blade crossing of a pure titanium clip applied to a cerebral aneurysm: case report. neurol med chir (tokyo) 2002; 42:123–4. 2. horiuchi t, li y, seguchi t, sato a, aoyama t, hanaoka y, hongo k. clip blade scissoring with titanium bayonet clip in aneurysm surgery. neurol med chir (tokyo) 2012;52:84–6. 3. carvi y nievas mn, hollerhage hg. risk of intraoperative aneurysm clip slippage: a new experience with titanium clips. j neurosurg 2000; 92:478–80. 4. drake cg, allcock jm. postoperative angiography and the "slipped" clip. j neurosurg 1973; 39:683–9. 5. asgari s, wanke i, schoch b, stolke d. recurrent hemorrhage after initially complete occlusion of intracranial aneurysms. neurosurg rev 2003; 26:269–74. 6. takayasu m, nagatani t, noda a, shibuya m, yoshida j. clinical safety and performance of sugita titanium aneurysm clips. acta neurochir (wien) 2000; 142:159–63. 7. atkinson jl, anderson re, piepgras dg. a comparative study in opening and closing pressures of cerebral aneurysm clips. neurosurgery 1990; 26:80–5. 8. ooka k, shibuya m, suzuki y. a comparative study of intracranial aneurysm clips: closing and opening forces and physical endurance. neurosurgery 1997; 40:318–23. 9. papadopoulos mc, apok v, mitchell ft, turner dp, gooding a, norris j. endurance of aneurysm clips: mechanical endurance of yasargil and spetzler titanium aneurysm clips. neurosurgery 2004; 54:966–72. 10. dujovny m, kossovsky n, kossowsky r, perlin a, segal r, diaz fg, et al. intracranial clips: an examination of the devices used for aneurysm surgery. neurosurgery 1984; 14:257–67. 11. horiuchi t, hongo k, shibuya m. scissoring of cerebral aneurysm clips: mechanical endurance of clip twisting. neurosurg rev 2012; 35:219–25. 12. lawton mt, ho jc, bichard wd, coons sw, zabramski jm, spetzler rf. titanium aneurysm clips: part i--mechanical, radiological, and biocompatibility testing. neurosurgery 1996; 38:1158–64. 13. lawton mt, heiserman je, prendergast vc, zabramski jm, spetzler rf. titanium aneurysm clips: part iii--clinical application in 16 patients with subarachnoid hemorrhage. neurosurgery 1996; 38:1170–5. 14. schmid-elsaesser r, steiger hj. aneurysm clip slippage. j neurosurg 2000; 93:371–3. 15. tang g, cawley cm, dion je, barrow dl. intraoperative angiography during aneurysm surgery: a prospective evaluation of efficacy. j neurosurg 2002; 96:993–9. 16. chiang vl, gailloud p, murphy kj, rigamonti d, tamargo rj. routine intraoperative angiography during aneurysm surgery. j neurosurg 2002; 96:988– 92. methemoglobinaemia is an infrequent haematological disorder that can result from congenital and acquired conditions. the congenital form is rare and not always compatible with life, but acquired methemoglobinaemia is more common and can result from a wide variety of environmental agents, including prescribed and recreational drugs. oxygen therapy and intravenous methleyne blue is usually the first line treatment for this disorder. a high level of suspicion is necessary for the accurate and timely diagnosis of this condition, as any delay can be catastrophic. case one a 39-year-old male with no significant past medical history presented to the emergency department after collapsing following recreational ingestion of alkyl nitrates (‘poppers’). he denied using any other recreational, prescribed, or over-the-counter drugs. upon presentation, the patient was fully awake and oriented, with a glasgow coma score (gcs) of 15/15, and no significant abnormal findings on initial clinical examination. the electrocardiogram (ecg), chest radiograph, and initial blood investigations were within the normal stated local limits. pulse oximetry revealed oxygen saturations of 85–88% whilst breathing room air. arterial blood gas (abg) analyses and oxygen saturations as measured on pulse oximetry are shown in table 1. a diagnosis of acquired methemoglobinaemia was made and, as such, definitive treatment with high flow oxygen (15 litres delivered via a non-rebreathing mask) and intravenous methylene blue (1.5 mg/kg infused over 10 minutes) was initiated. the measured abg (including methaemoglobin [methb] levels) returned to within normal limits within 24 hours of his admission, as shown in table 1. squ med j, may 2012, vol. 12, iss. 2, pp. 237-241, epub. 9th apr 2012 submitted 18th jul 11 revision req. 2nd nov 11, revision recd. 20th dec 11 accepted 11th jan 12 1the royal london hospital, london, uk; 2the royal free hospital, london, uk *corresponding author e-mail: dr.fadhlani@hotmail.com بِيَلُة امليتهيموغلوبني املكتسبة عادل اللواتي، نك مريج امللخ�ص: بيَلُة امليتهيموغلوبني املكت�سبة حالة نادرة ن�سبيا، ولهذا كانت قليلة الورود يف املمار�سة الطبية احلادة. قد ينجم اال�ستباه يف اأَْك�ُسج النب�سي. ُندرج يف هذا احلالة عندما يكون قيا�س �سغط االأك�سجني ال يتنا�سب مع ت�سبع االأك�سجني التي يتم اكت�سافها حني ِقيا�ُس التَّ التقرير و�سفا حلالتني منف�سلتني من بيَلُة امليتهيموغلوبني الناجتة عن ا�ستعمال األكيل نرتيت الأغرا�س الرتفيه. راجع املري�سان يف فرتات خمتلفة اثنني من امل�ست�سفيات التعليمية املختلفة يف لندن، اململكة املتحدة. وقد اأدى الت�سابه بني هاتني احلالتني اإىل �رضورة رفع م�ستوى الوعي اجتاه هذه احلالة القاتلة، وارتباطها باالأدوية املتاحة على نطاق وا�سع لالأغرا�س الرتفيهية، الأنه اأمر �رضوري ل�سمان الت�سخي�س ال�سحيح ويف الوقت املنا�سب. مفتاح الكلمات: بيلة امليتهيموجلوبني، ميثيلني اأزرق، تقرير حالة، اململكة املتحدة. abstract: acquired methemoglobinaemia is a relatively rare condition and, therefore infrequently encountered in acute medical practice. suspicion of the condition may be triggered when the measured pao2 is ‘out of keeping’ with the oxygen saturations that are discovered with pulse oximetry. we describe two separate cases of acquired methemoglobinaemia secondary to the recreational use of alkyl nitrites (’poppers’). the patients presented at separate times to two different teaching hospitals in london, uk. the similarity of these cases has led the authors to conclude that a raised awareness of this potentially fatal condition, and its association with a widely-available recreational drug, is necessary to ensure a correct and timely diagnosis. keywords: methaemoglobinaemia; methylene blue; case report; uk. acquired methemoglobinaemia *adil al-lawati1 and nick murch2 case report acquired methemoglobinaemia 238 | squ medical journal, may 2012, volume 12, issue 2 the patient was discharged after an uneventful 48-hour inpatient stay, having received counselling regarding the potential dangers associated with the misuse of poppers. case two a 40-year-old male with a significant smoking history was found collapsed after ingesting two beers and a bottle of poppers within a period of 30 minutes. the patient voluntarily provided a full glass bottle similar to the one ingested [figure 1]. on arrival in the emergency department the patient was fully orientated, with a gcs of 15/15. on clinical examination he was unkempt with tarstained fingers. the patient was also noted to be centrally cyanosed with a mild bilateral expiratory wheeze. the rest of the initial clinical examination was largely unremarkable. an ecg revealed a sinus tachycardia with left axis deviation. abg analyses and oxygen saturations as measured on pulse oximetry are shown in table 2. acquired methemoglobinaemia with possible previously unidentified chronic obstructive pulmonary disease was diagnosed; therefore, the patient was started on monitored high flow oxygen therapy with serial clinical assessments and abgs, as well as intravenous methylene blue. the patient was discharged after education about the potential effects of abusing poppers, smoking cessation advice, and inhaled bronchodilator therapy for his probable chronic obstructive pulmonary disease. he was also given follow-up appointments with the chest clinic for further evaluation of his chest condition, but he did not attend. discussion methemoglobinaemia is a disorder in which the haemoglobin (hb) molecule is altered to prevent efficient carriage of oxygen, essentially shifting the oxygen dissociation curve to the left, leading to a functional anaemia. a variety of aetiologies including genetic, dietary, idiopathic, and toxicological have been implicated.1 acquired methemoglobinaemia is much more common than the hereditary form, occurring when an exogenous substance oxidises hb to m e t h a e m o g l o b i n (methb) at rates of 100 to 1000 times greater than it can be reduced back to its original form [figure 2].2 congenital methemoglobinaemia can occur from a cytochrome b5 reductase deficiency or from a structural hb defect, collectively called hbm. there table 1: case 1 arterial blood gas (abg) results and measured oxygen saturation (sao2) (on pulse oximetry) normal range admission 24 hours after admission i n s p i r e d o x y g e n ( fi o 2) room air (0.21) room air (0.21) room air (0.21) s a o 2 >96% 85–88% 98% p a o 2 10–13 kpa 8.5 kpa 12.4 p a c o 2 5.4–6.8 kpa 5.7 kpa 5.8 kpa methb % <1% (non-smokers) 23.5% 0.7% legend: fio2 = fraction of inspired oxygen; sao2 = oxygen saturation; pao2 = partial pressure of oxygen in blood; paco2 = partial pressure of carbon dioxide in blood; methb = methaemoglobin; kpa = kilopascal. figure 1: bottle of alkyl nitrite provided by patient 2 adil al-lawati and nick murch case report | 239 are two types of congenital methaemogloninaemia. in type 1, the enzyme deficiency is confined to the red blood cells, whereas in type 2 a range of cells, including brain cells, is affected. type 2 usually results in mental retardation, neurological abnormalities, or death in childhood. lifelong use of agents having the same effect as the deficient reducing enzyme, such as ascorbic acid (vitamin c) and/or riboflavin (vitamin b2) can be used to try to alleviate some of the clinical features of the condition, especially in type 1. hbm results from a single amino acid substitution in either alpha or beta polypeptide chains at the region where the iron-containing heme portion is attached. this results in a failure to convert methb to hb.3 normally, there is a continuous conversion of hb to methb, and vice versa. the reduction of methb to hb happens through two different pathways. the nicotinamide dinucleotide (nadh)dependent cytochrome b5-methaemoglobin reductase pathways account for 99% of methb reduction to hb. the other mechanism depends on utilising nicotinamide-adenine dinucleotide phosphate hydrogenase (nadph) generated by glucose-6-phosphate dehydrogenase (g6pd) in the hexose monophosphate pathway. this mechanism is physiologically inactive and needs extrinsic agents, like methylene blue, to activate it. whereas the former mechanism is the main physiologically active reducing mechanism, the later pathways are highly important when the physiologically active mechanism is overwhelmed and the therapeutic correction of methb is attempted via methylene blue.3 poppers are potent oxidisers of oxyhaemoglobin (converting fe2+ to fe3+) resulting in the formation of methb, and are volatile liquids that are sometimes abused by both sexes for euphorigenic rushes and altered states of consciousness. the name ‘poppers’ may have been derived from the sound caused by breaking open the glass vials which were originally used to store the volatile contents.4 methemoglobinaemia has been reported to develop after the ingestion of as little as 10 ml of alkyl nitrite.5 factors that may predispose to pharmacologically-induced methemoglobinaemia include the use of large quantities of the offending agent, any discontinuation of the body’s normal mucosal barriers, and the concomitant use of other drugs known to cause methaemoglobinaemia, such as acetaminophen (paracetamol), primaquine, or cocaine.6 in addition, dapsone has been implicated in almost 50% of cases of acquired methaemoglobinaemia, which is clinically important as, due to its relatively long half-life, cimetidine may be required to try to block its table 2: case 2 arterial blood gas (abg) results and measured oxygen saturation (sao2) (on pulse oximetry) normal range admission 24 hours after admission inspired oxygen (fio2) room air (0.21) non-rebreathe reservoir mask at 15l/min o2 (~ 0.90)? room air (0.21) sao2 >96% 90% 96% pao2 10–13 kpa 8.3 kpa 8.3 kpa paco2 5.4–6.8kpa 6.2 kpa 6.1 kpa methb % <1% (non-smokers) 46.0% 0.5% legend: fio2 = fraction of inspired oxygen; sao2 = oxygen saturation; pao2 = partial pressure of oxygen in blood; paco2 = partial pressure of carbon dioxide in blood; methb = methaemoglobin; kpa = kilopascal. g6p r5p nadp leukomethylene blue methylene blue nadph methb hb g-6-pd nadph methb reductase figure 2: the role of methylene blue in the treatment of methaemoglobinemia legend: g6p = glucose 6 phosphate; g-6-pd = glucose6-phosphate dehydrogenase; r5p = ribose-5-phosphate; nadp = nicotine adenine dinucleotide phosphate; nadph = nicotine adenine dinucleotide phosphate hydrogenase; methb = methaemaglobin; hb = haemoglobin acquired methemoglobinaemia 240 | squ medical journal, may 2012, volume 12, issue 2 metabolism via hepatic microsomal cytochrome p450 (cyp450).7 topical local anaesthetic agents (e.g. lidoncaine or benozocaine) for procedures such as bronchoscopy, laryngoscopy, or upper gastroduodenoscopy can also result in acquired methaemoglobinaemia.2 another risk factor for developing pharmacologicallyinduced methemoglobinaemia is the presence of concomitant illnesses, including cardiac and respiratory diseases.8 this condition should be suspected if cyanosis develops after suspected exposure to potent oxidizing agents, or if chocolate brown arterial blood does not turn red on exposure to air.1 some of the more common non-specific clinical features are listed in table 3.6 however, clinical presentation may vary greatly and definitive treatment with methylene blue might not always be needed depending on the clinical condition. pulse oximetry is a useful tool to diagnose suspected methaemoglobinaemia. it basically works by emitting lights at two different wavelengths (660 nm in the red spectrum wavelength and 940 nm in the infrared spectrum wavelength). these wavelengths are absorbed differently by deoxyhaemoglobin and oxyhaemoglobin (i.e. deoxyhaemoglobin absorbs more light at 660 nm wavelengths and oxyhaemoglobin absorbs more light at 940 nm wavelengths). by calculating the differences, the microprocessor in the pulse oximeter can measure the sao2 (sometimes referred as spo2 when measured by a pulse oximeter). whereas methb absorbs more light than either oxyhaemoglobin and deoxyhaemoglobin at 940 nm wavelength, its absorption is similar to that of deoxyhaemoglobin at 660 nm wavelengths resulting in falsely low sao2 due to an incorrectly high deoxyhaemoglobin perception by the pulse oximeter. however, newer pulse oximeters are able to omit light at 8 different wavelengths making it possible to measure methb and carboxyhaemoglobin as well.9 the diagnosis of methemoglobinaemia can be confirmed with an abg sample that demonstrates a discrepancy between arterial oxyhaemoglobin saturation (sao2) and measured arterial oxygen partial pressure (pao2). 6 a high saturation gap should also lead to the suspicion of methaemoglobinaemia. the gap is defined as the difference between oxygen saturation measured by the pulse oximeter and that calculated by abg. this gap is usually >5 in cases of methaemoglobinaemia. 10 methylene blue can be an effective treatment for acquired methemoglobinaemia [figure 2] and should be administered at a dose of 1–2 mg/ kg intravenously over 3–10 minutes. an obvious clinical improvement should be evident within one hour, but if cyanosis persists, a second dose may be considered.8 higher doses of methylene blue (>7 mg/kg) may cause haemolysis and persistent cyanosis, as the agent can paradoxically oxidise haemoglobin to methb, as opposed to acting as a reducing agent at lower doses.5 relapsing methemoglobinaemia has also been described in the literature with a delayed, biphasic rise in the level of methb. this may be due to a secondary paradoxical cyclical formation of methb by the offending agent (e.g. dapsone or methylene blue). cyp450 inhibitors (e.g. cimetidine) and exchange transfusion might be needed to treat these patients.8 also, individuals with g6pd deficiency may not produce sufficient nadph to reduce methylene blue to leukomethylene blue, potentially rendering the therapy ineffective.6 furthermore, methylene blue might induce haemolysis in g6pd-deficient patients. alternative treatments with cimetidine, ascorbic acid, and possibly exchange transfusions ,should be considered in patients with a g6pd, deficiency. n-acetylcysteine is also under study as a possible treatment for this category of patients.8 conclusion we report a fatal medical condition which may result from the abuse of a widely-available recreational drug. physicians in acute medical specialities should have a raised clinical suspicion table 3: common clinical features associated with approximate methb concentration methb concentration % possible clinical features may include <10 often asymptomatic 10–20 cyanosis, skin discolouration 20–30 anxiety, light-headedness, headaches, tachycardia 30–50 fatigue, confusion, dizziness, tachypnoea 50–70 coma, seizures, acidosis, arrhythmias >70 death adil al-lawati and nick murch case report | 241 for this condition when there is a possible history of drug misuse and a significant discrepancy between the clinical picture and measured sao2 and pao2 levels. this raised level of awareness can ensure acquired methaemoglobinaemia’s accurate diagnosis and timely treatment. both of our patients were discharged safely after timely diagnosis and management of a potentially life-threatening condition. a c k n o w l e d g m e n t s the authors reported no conflict of interest and no funding was received on this work. references 1. brunato f, garziera mg, briguglio e. a severe methaemoglobinemai induced by nitrate. eur j emerg med 2003; 10:326–30. 2. chiedozie u, bittikofer j, sum-ping st. severe methaemoglobinemia on exposure to benzocaine. j clin anesth 2001; 13:128–30. 3. higgins c. causes and clinical significance of increased methaemoglobin. amer j phys 1942; 137:56–8. 4. macher am. abuse of club drugs: volatile nitrites. american jails 2010. from: http://readperiodicals. com/201009/2165269311.html accessed: jun 2011. 5. aagaard nk. amyl nitrite poisoning. ugeskr laeg. 1998; 160:3740–1. 6. kwok s, fischer jl, rogers jd. benzocaine and lidocaine induced methaemoglobinemia after bronchoscopy. j med case reports 2008; 2:16–19. 7. pallaris jc, mackool bt, pitman mb. a 52-yearold man with upper respiratory symptoms and low oxygen saturation levels. n engl j med 2011; 364:957–66. 8. wright ro, lewander wj, woolf ad. methaemoglobinemia: etiology, pharmacology and clinical management. ann emerg med 1999; 34:646–56. 9. ortega r, hansen cj, elterman k, woo a. pulse oximetry. n engl j med 2011; 364:33–6. 10. hamirani ys, franklin w, grifka rg. methemoglobinemia in a young man. tex heart inst j 2008; 35: 76–7. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century squ med j, may 2012, vol. 12, iss. 2, pp. 161-168, epub. 9th apr 2012 submitted 15th aug & 10th sep 11 revision req. 18th jan 12, revision recd. 14th feb 12 accepted 7th mar 12 the american academy of sleep medicine (aasm) defines snoring as a sound originating from the upper airway (ua) that does not occur with apnoea or hypoventilation, and that is caused by vibrations of different tissues in the pharynx.1 a person who snores for more than 10–20% of a monitored night, or more than 3 or 4 nights a week is classified as a habitual snorer.2 an association between snoring and obstructive sleep apnoea syndrome (osas) was first observed in 1975.3 osas is considered a progressive disorder that starts, often early in life, with habitual snoring.4 based on different epidemiological studies performed between 1980 and 2007, the mean prevalence of snoring in the general population is approximately 32% in men and 21% in women;5 however, the prevalence of obstructive sleep apnoea (osa) is 4% in men and 2% in women.6,7 osas involves the intermittent cessation of breathing due to ua obstruction. in a person with osas, the ua muscles relax excessively during sleep. this allows tissues (e.g. tonsils and adenoids) supported by the department of clinical physiology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: rajeshthrissur@yahoo.com يف جمرى اهلواء العلوي آفات العصب الناتج عن الّشخري راجي�س بوثريكوفيل بو�سباكام، حممد عبداهلل العربي امللخ�ص: ينت�رض ال�سخري املعتاد ب�سكل وا�سع النطاق بني النا�س، وت�سري التقارير اإىل اأّنه ي�سيب ما يقرب من %40 من الرجال و 20% اإ�سابات حتديدا اأكرث وب�سكل التنف�س، جمرى ع�سالت يف اإ�سابة ال�سخري اأثناء املنخف�س الرتدد ذات االهتزازات ت�سبب قد الن�ساء. من االأع�ساب املحيطية، متاما كما يح�سل عند العمال الذين ي�ستخدمون اأدوات تهتز ب�سدة على مدار �سنوات عديدة توؤدي بالنتيجة اإىل تلف االأع�ساب يف االأيدي. اأظهرت التحليالت الن�سيجية املر�سية يف الع�سالت التنف�سية العليا وجود اأدلة قوية على وجود خطورة متفاوتة من االآفات الع�سبية يف جمموعات من مر�سى يعانون من ال�سخري. اأظهر تقييم الوظائف الع�سبية دليال على اإزالة التع�سيب الن�سط واملزمن، واإعادة التع�سيب يف الع�سالت احلنكية البلعومية عند مر�سى انقطاع النف�س النومي. االآفات الع�سبية للع�سالت التنف�سية العليا الناجتة التنف�س جمرى انهيار احتمال زيادة اإىل يوؤدي مما الع�سالت لتلك االنعكا�سي التمدد قدرات �سعف اإىل توؤدي االهتزازات �سدمة عن لالأ�سخا�س مبكر تقييم �رضورة تربر النومي االن�سدادي النف�س انقطاع تقدم عن جزئيا م�سئولة تعترب التي الع�سبية العوامل العلوي. اللذين يعانون من ال�سخري العادي. مفتاح الكلمات: ع�سبي املن�ساأ، متالزمة انقطاع النف�س االن�سدادي النومي، الع�سلة احلنكية البلعومية، ال�سخري، جمرى الهواء العلوي، �سدمة. abstract: the prevalence of habitual snoring is extremely high in the general population, and is reported to be roughly 40% in men and 20% in women. the low-frequency vibrations of snoring may cause physical trauma and, more specifically, peripheral nerve injuries, just as jobs which require workers to use vibrating tools over the course of many years result in local nerve lesions in the hands. histopathological analysis of upper airway (ua) muscles have shown strong evidence of a varying severity of neurological lesions in groups of snoring patients. neurophysiological assessment shows evidence of active and chronic denervation and re-innervation in the palatopharyngeal muscles of obstructive sleep apnoea (osa) patients. neurogenic lesions of ua muscles induced by vibration trauma impair the reflex dilation abilities of the ua, leading to an increase in the possibility of ua collapse. the neurological factors which are partly responsible for the progressive nature of osas warrant the necessity of early assessment in habitual snorers. keywords: neurogenic; obstructive sleep apnoea syndrome (osas); palatopharyngeal muscle; snoring; upper airway; trauma. review snoring-induced nerve lesions in the upper airway *rajesh p poothrikovil and mohammed a al abri snoring-induced nerve lesions in the upper airway 162 | squ medical journal, may 2012, volume 12, issue 2 patients than in non-obese controls. sleep disordered breathing (sdb) results from an imbalance between negative pharyngeal pressure and the opposing force of the ua muscles. abnormal function of the ua, such as sleep-related suppression of ua muscle activity and a decrease in ua dilator muscle force are thought to be the main source of obstructions and symptoms in the osas.15,16 phasic activation of the muscles of the nose, pharynx and larynx has been shown to occur before diaphragm and intercostal muscle activity, suggesting a pre-activation of the ua muscles in preparation for the development of negative pressure.17,18 the ua is rich in neural receptors which is a key factor of tonic genioglossus electromyogram (emg) activity. during inspiration, the ua dilatory muscles, the genioglossus and geniohyoid contract, or shorten, their muscle fibres through an increase in emg activity. these inspiration-related muscle activations result in the enlargement of the ua.19 loss of genioglossus emg tone may lead to an increase in pharyngeal resistance.20 in order to compensate for abnormal anatomy and/or a more collapsible pharyngeal airway, osas patients display augmented genioglossus muscle activity during wakefulness as compared with healthy subjects.21 this reflex compensatory neuromuscular mechanism is lost at sleep onset (loss of awake compensation) in both the control and in osas patients, but is associated with pharyngeal collapse under conditions of chronic airway loading.22 when the tongue moves posteriorly due to a decrease in genioglossus muscle activity, the base of the ua muscles to be drawn into the airway with each inspiration, and thereby obstruct the airflow. the sufferer makes increasingly stronger respiratory efforts to overcome the blockage, but ultimately arouses briefly to take several fast, deep breaths. during the arousal, the sufferer may gasp or snore loudly. this whole cycle recurs on resumption of sleep. if left untreated, osas leads to excessive daytime sleepiness, cognitive dysfunction, and impaired work performance, and is detrimental to the sufferer’s health and quality of life. clinical research shows that osas is strongly linked to a range of serious and even life-threatening chronic diseases such as stroke, heart failure, hypertension, diabetes, obesity and coronary heart diseases.8 the aetiology of osas is only partly known. anatomy and physiology of the upper airway during sleep the ua is a complicated structure, usually divided into four anatomical subsegments: the nasopharynx, between the nares and hard palate; the velopharynx, between the hard palate and soft palate; the oropharynx, from the soft palate to the epiglottis, and the hypopharynx, from the base of the tongue to the larynx [figure 1]. this total structure forms a passageway for movement of air from the nose to the lungs, and also participates in many competing physiological functions such as phonation and deglutition.9 the ua is surrounded by 20 or more muscles, known collectively as ua muscles, which actively constrict and dilate the ua lumen.10 these muscles can be broadly classified into four groups: muscles regulating the position of the soft palate, tongue, hyoid apparatus, and the posterolateral pharyngeal walls. these muscle groups interact in a complex fashion to determine the patency of the airway. the mandible and hyoid bones are the main craniofacial bony structures that determine the airway’s size.11 as there is no rigid structural support, the shape and size of the ua is dependent upon the position of soft tissue structures, like the soft palate, tongue, and the walls of the oropharynx. radiographic images show that the narrowest region in both patients with osas and non-obese controls, while awake, is the region posterior to the soft palate.12,13 the cross sectional area of this retropalatal region is smaller in osas figure 1: anatomy of the upper airway showing the main segments: nasopharynx, velopharynx, oropharynx, and hypopharynx.14 rajesh p poothrikovil and mohammed a al abri review | 163 takes multiple physiological measurements and is an excellent tool for evaluating sleep disorders.27 snoring can be detected and evaluated by means of small sensors in the form of piezo crystals or dynamic microphones taped laterally to the thyroid cartilage, or by utilising a nasal pressure transducer which continuously samples nasal air turbulence through a cannula. psg provides an opportunity to assess the consequences of sdb, such as nocturnal desaturation, frequent arousals, and excessive day time sleepiness, and also plays an important role in the titration of continuous positive airway pressure (cpap) treatment. the palatopharyngeal muscle is of anatomical importance in the pharynx as it forms the internal longitudinal muscular layer around the wall of the pharynx. the muscle is located at the major site of obstruction in patients with osas and is therefore exposed to the vibration and stretch induced by heavy snoring and obstructive breathing.28,29 it has been reported that long term employment which involves the use of vibrating tools such as jack hammers can cause local nerve lesions in the hands.30,31 researchers observed pathological changes in the vibration-exposed fingers, including a marked loss of nerve fibres suggestive of demyelinating neuropathy in the peripheral tongue may push against the anterior wall of the soft palate causing narrowing of the velopharynx. reduction in the traction between the tongue and the soft palate may increase the collapsibility of the velopharynx.23 apnoeas were shown to resolve with a burst of genioglossus emg activation. it has been demonstrated that the velopharynx is the primary site of narrowing in 80% of patients, whereas two or more sites of narrowing are commonly observed in 82% of these.24 an evaluation of the static properties of the pharyngeal wall and its surrounding muscles revealed a fundamental difference between the airway of the control subjects and those with osas in that the airway was closed at atmospheric pressure in subjects with osas, while active negative pressure was required to close the controls’ airways, even in the absence of ua muscle activity.25 one of the commonest consequences of the changes in the properties of the ua that occur during sleep is the occurrence of snoring. the snoring sound is the result of vibrations of the soft tissues of the pharynx, soft palate and uvula having specific acoustic characteristics with frequencies ranging from 5 to 136 hz.26 sdb, such as snoring and other obstructive events, could be easily detected with a polysomnography (psg) recording [figure 2]. polysomnography figure 2: a 30-second epoch of a full night polysomnographic recording of non-rapid eye movement (nrem) sleep stage ii (n2). note the periodic snoring signals in the snore channel. snoring-induced nerve lesions in the upper airway 164 | squ medical journal, may 2012, volume 12, issue 2 and osas patients, and compared with agematched controls.34 they also assessed two control points (lower lip and hand) for each subject. this study showed that the sensory detection threshold using both methods was significantly increased in snorers and osas patients as compared to controls. importantly, there was no significant difference between snorers and patients with osas. in contrast, the sensory threshold at control sites was similar in patients and controls. vibrometry is usually employed to assess the functional integrity of the largest afferent sensory fibres to diagnose polyneuropathy. these findings reinforce the presence of a selective impairment of ua mucosal sensory function in patients with osas and in those who are heavy snorers. they suggest that this impairment may be an early change in the progression of ua obstruction during sleep, possibly developing as a consequence of vibration-related oedema or neural damage during snoring. interestingly, after 6 months of continuous cpap usage, osas patients showed a significant improvement in vibration sensory thresholds34 thus providing strong evidence of the effectiveness of cpap treatment. these results increase the importance of cpap usage in the field of sleep medicine as an effective and non-comparable treatment. however, cpap treatment fails to improve two-point discrimination, indicating a degree of permanent injury. beginning cpap treatment before symptoms worsen could be useful in limiting the severity of this permanent neural injury to the pharyngeal muscles. h i s t o pat h o l o g i c f e at u r e s woodson et al. analysed the histopathologic features of pharyngeal tissue.35 transverse sections of the distal soft palate and uvula were qualitatively compared between apnoeics, severe snorers, and non-snorers using light and electron microscopy. light microscopy of both apnoeics and nonapnoeic snorers revealed similar abnormalities such as mucous gland hypertrophy, focal atrophy of muscle fibres, and extensive oedema of the lamina propia with vascular dilation. no distinctive histopathologic findings were associated with the development of apnoea. electron microscopy was used to reveal frequent focal degeneration of myelinated nerve fibres and axons in severe apnoeics. similar histopathologic changes were nerves. similarly, snoring produces a low-frequency vibration which may also cause peripheral nerve injury and physical trauma. snoring-induced upper airway nerve damage t h e r m a l s e n s i t i v i t y larsson et al. reported an impairment of thermal sensitivity in the oropharynx of patients with osas as compared with non-snoring age-matched control subjects.32 some patients with osas were completely unable to differentiate between heat and cold while tested on the tonsillar pillars, whereas no differences was noted at the tip of the tongue in patient and control groups, which indicates a local sensory dysfunction. they postulated that snoring-related vibrations and the deformation of ua structures in the case of apnoeas could lead to a very local pharyngeal sensory neuropathy, which could contribute to ua dysfunction during sleep. as there were only osas and non-snoring control groups in this study, a comparison between apnoeic snorers and non-apnoeic snorers was not possible. va s o d i l at i o n in another study, laser doppler perfusion monitoring combined with electrical stimulation (a method used to test vascular reactivity) was performed in the mucosa of the soft palate in patients with various degrees of ua obstruction and control subjects. habitual snorers and patients with mild osa showed exaggerated vasodilation as compared to controls. this could be the result of minor lesions with consequent re-innervation which increased the sensitivity to mechanical stimuli.33 in contrast, patients with severe osas showed significantly reduced vasodilation as compared to controls, which could be due to the almost complete loss of afferent c-fibres, representing a permanent injury. these disturbances in the micro-circulation indicate the presence of a local afferent nerve lesion with a progressive nature in heavy snorers, both those with and without osas. s e n s o r y f u n c t i o n s kimoff et al. assessed sensory functions of the ua (oropharynx) using two-point discrimination and vibration sensory threshold methods in snorers rajesh p poothrikovil and mohammed a al abri review | 165 motor neuropathy (chronic denervation and reinnervation). two patients showed spontaneous denervation activity (fibrillations and positive waves) suggestive of an active neuropathic process. such findings were present in only 3 out of 15 habitual snorers. this study was of great importance in that it gives strong electrophysiological evidence of motor neuropathy in the ua muscles of osa patients. these findings reinforce the causative role of peripheral neurogenic lesions, in the progression from habitual snoring to clinical osas. upper airway neuropathy in progressive snorers’ disease it is obvious that the local ua afferent (sensory) and efferent (motor) nerve lesions are present due to snoring-induced vibration trauma in some patients with snoring and in most patients with osas. it has been reported that the higher sound intensity in apnoeic snorers versus non-apnoeic snorers is a result of greater negative pressures on the resumption of breathing, resulting in high flow rates, turbulent flow, and greater forces on the vibrating structures.41 several studies indicate that airway patency depends on a reflexogenic mechanism of afferent and efferent nerve pathways in the mucosa and upper airway muscles.42,43 this reflex mechanism, as a reaction to the negative intrapharyngeal pressure, is responsible for the activation of dilatory muscles. numerous studies have described protective ua dilator reflex responses to pulses of negative airway pressure, which act to maintain airway patency during sleep.44,45 this reflex is assumed to be mediated by intraor submucosal mechanosensory receptors. the neural drive to the ua dilator muscles is integrated at the level of brainstem motor nuclei where multiple neural inputs combine to produce a unitary output to the muscles.46 neurogenic lesions affecting upper airway muscles impair the ability of its reflexogenic dilation, leading to increased possibility of ua collapse. a reduced pharyngeal lumen and other risk factors (i.e. obesity and anatomic abnormalities) lead to an increased degree of periodic obstructed breathing. this causes more morphological abnormalities and neurogenic lesions, which supports the hypothesis of the progressive nature of snorers’ disease. noted in apnoeics and non-apnoeic snorers. this is an indication of a common aetiology related to snoring-induced vibration trauma to pharyngeal tissue rather than directly related to apnoea or desaturation. d e n e r vat i o n friberg et al. described a proliferation (increased density of sensory nerve terminals with abnormal localisation and appearance) of nerve endings in a pattern suggestive of nerve injury in biopsy specimens from the oropharyngeal mucosa of some snorers. however, the study focused mostly on osas subjects.36 no such abnormalities were detected in non-snoring control subjects. other muscle biopsy studies illustrated similar denervation type changes in palatopharyngeal muscles.37 the relationship between vibration and stretch-induced trauma was reinforced in a study which showed a significant increase of morphological abnormalities characteristic of neurogenic lesions (type grouping, fascicular atrophy, and grouped atrophy) in the palatopharyngeal muscle of the entire group of snoring patients as compared to non-snoring controls.38 they observed that the degree of muscle pathology increased in parallel with the proportion of obstructive breathing during sleep. this indicates that the proportion of the total sleep time spent in periodic obstructive breathing may be a surrogate quantitative measure of the magnitude of the snoring trauma to the pharyngeal tissues. another finding in this study is that the vibration trauma of habitual snoring itself could initiate a local neurogenic lesion in vulnerable patients, before the additional trauma of stretch caused by periodic obstructive breathing. palatopharyngeal muscle hypertrophy noted in some snorers could be neurogenic and could be due to the chronic stretching of innervated and denervated muscle fibres and/or overuse of partially denervated muscles.39 n e u r o p h y s i o l o g i c a l a s s e s s m e n t s finally, in a recent study, svanborg conducted neurophysiological assessments of ua muscles by recording concentric needle emg activity of palatopharyngeal muscles in 12 osas patients.40 ten out of 12 cases showed reduced emg activity (recruitment pattern) at maximal voluntary effort with long and polyphasic (increased duration) motor unit potentials. these features typify snoring-induced nerve lesions in the upper airway 166 | squ medical journal, may 2012, volume 12, issue 2 be partly explained neurologically. osas begins with snoring-induced vibration trauma of nerves associated with the ua muscles. histopathological, neurological, and neurophysiological signs of nerve lesions are detected in simple snorers without obstructive episodes. periodic obstructive breathing phases expressed as a fraction of total sleep time could be a quantitative measure of the magnitude of snoring trauma to the pharyngeal tissues. subjects with habitual snoring at risk of development of osas should be identified early. beginning cpap therapy before symptoms worsen should be considered as a preventive measure against permanent ua neuronal injury. other options such as weight loss in obese individuals, surgical intervention for nasal obstructions, and mandibular advancement devices for craniofacial anomalies and narrow airway can also be considered in suitable patients, especially those who cannot tolerate cpap. studies of novel techniques may help in developing protocols to assess and manage habitual snorers. a c k n o w l e d g e m e n t s the authors would like to thank dr. abdullah alasmi md, frcp(c), neurology unit, department of medicine, squh, and mrs. susan al-nabhani, department of clinical physiology, squh, for their advice on this article. also they would like to thank mrs. maryam al hooti, department of clinical physiology, squh, for her help with the arabic translation of the abstract. references 1. thorpy mj. the international classification of sleep disorders: diagnostic and coding manual. lawrence ks, ed. kansas usa: allen press, inc., 1990. pp. 195– 7. 2. bearpark h, elliott l, grunstein r, cullen s, schneider h, althans w et al. snoring and sleep apnea. a population study in australian men. am j respir crit care med 1995; 151:1459–65. 3. lugaresi e, cirignotta f, montagna p. clinical approach to heavy snorers’ disease and other sleeprelated respiratory disorders. in: peter jh, podszus t, wichert p, eds. sleep related disorders and internal diseases. berlin: springer-verlag, 1975. pp. 201–10. 4. lugaresi e, cirignotta f, gerardi r, montagna p. snoring and sleep apnea: natural history of heavy snorers disease. in: guilleminault c, partinen m, eds. obstructive sleep apnea syndrome: clinical research and treatment. new york: raven press. causes and treatment options for snoring other causes of habitual snoring, such as nasal septal deviation, nasal valve obstruction, chronic nocturnal nasal congestion, and craniomandibular abnormalities should be well identified.47–49 patients with chronic nasal obstruction often struggle to tolerate nasal cpap. humidification of inhaled air, correction of potential leakage of the nasal mask, and a trial of an oro-nasal mask are initial steps that can be considered to acclimatise patients to the cpap treatment. patients who still cannot tolerate cpap, or have obvious nasal polyps or a distinctive abnormality of the nasal anatomy, should consider surgical treatment.48 correction of nasal obstructions has been reported to be an effective treatment of osas in patients who have nasal obstructions, but in those with craniomandibular abnormalities, correction has proved ineffective.50 improving nasal patency by external nasal dilators has some beneficial effects on subjective snoring, but not in patients with apnoeas.51 current evidence suggests that the nose may not play a significant role in the pathogenesis of osa, but it seems to be of some relevance in the origin of snoring.51 obesity is an independent risk factor for the development of snoring.52 simple snoring can be treated with general measures, including weight control and loss, avoidance of detrimental habits and toxic substances that interfere with sleep, modification of sleeping position and physical exercise.5 advancement of the mandible using a dental appliance has been shown to reduce the severity of osa.53 it is an effective alternate to cpap in the treatment of snoring and milder form of osas.54 variable mandibular advancement devices have also been successful in the treatment of patients with severe osas.55 because the tongue attaches to the mandible directly, the tongue is expected to move anteriorly with the forward displacement of the mandible, thus improving oropharyngeal airway patency. however, no studies have been published to prove the efficacy of mandibular advancement devices in the improvement of upper airway neural injury in snoring patients. conclusion in summary, the progressive nature of osas can rajesh p poothrikovil and mohammed a al abri review | 167 80:1595–604. 20. white dp, lombard rm, cadieux rj, zwillich cw. pharyngeal resistance in normal humans: influence of gender, age, and obesity. j appl physiol 1985; 58:365–71. 21. mezzanotte ws, tangel dj, white dp. waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). j clin invest 1992; 89:1571–9. 22. mezzanotte ws, tangel dj, white dp. influence of sleep onset on upper-airway muscle activity in apnea patients versus normal controls. am j respir crit care med 1996; 153:1880–7. 23. isono s, tanaka a, sho y, konno a, nishino t. advancement of the mandible improves velopharyngeal patency. j appl physiol 1995; 79:2132–8. 24. morrison dl, launois sh, isono s, feroah tr, whitelaw wa, remmers je. pharyngeal narrowing and closing pressures in patients with obstructive sleep apnea. am rev respir dis 1993; 148:606–11. 25. isono s, morrison dl, launois sh, feroah tr, whitelaw wa, remmers je. static mechanics of the velopharynx of patients with obstructive sleep apnea. j appl physiol 1993; 75:148–54. 26. beck r, odeh m, oliven a, gavriely n. the acoustic properties of snores. eur respir j 1995; 8:2120–8. 27. douglas nj, thomas s, jan ma. clinical value of polysomnography. lancet 1992; 339:347–50. 28. suratt pm, dee p, atkinson rl, armstrong p, wilhoit sc. fluoroscopic and computed tomographic features of the pharyngeal airway in obstructive sleep apnea. am rev respir dis 1983; 127:487–92. 29. shepard jw jr, thawley se. localization of upper airway collapse during sleep in patients with obstructive sleep apnea. am rev respir dis 1985; 132:211–15. 30. takeushi t, futatsuka m, imanishi h, yamada s. pathological changes observed in the finger biopsy of patients with vibration-induced white finger. scand j work environ health 1986; 12:280–3. 31. lundborg g, dahlin l, hansson ha, kanje m, necking le. vibration exposure and peripheral nerve fiber damage. j hand surg am 1990; 15:346– 51. 32. larsson h, carlsson-nordlander b, lindblad le, norbäck o, svanborg e. temperature thresholds in the oropharynx in patients with obstructive sleep apnea syndrome. am rev respir dis 1992; 146:1246–9. 33. friberg d, gazelius b, lindblad le, nordlander b. habitual snorers and sleep apnoics have abnormal vascular reactions of the soft palate mucosa on afferent nerve stimulation. laryngoscope 1998; 108:431–6. 1990. pp. 25–36. 5. fiz ja, prat jm, jané r. treatment of patients with simple snoring. arch bronconeumol 2009; 45:508– 15. 6. young t, palta m, dempsey j, skatrud j, weber s, badr s. the occurrence of sleep-disordered breathing among middle-aged adults. n engl j med 1993; 328:1230–5. 7. stardling jr. obstructive sleep apnoea: definitions, epidemiology, and natural history. thorax 1995; 50:683–9. 8. shahar e, whitney cw, reline s, lee et, newman ab, javier nf, et al. sleep disordered breathing and cardiovascular disease: cross-sectional results of the sleep heart health study. am j respir crit care med 2001; 163:19–25. 9. smith j, wolkove n, colacone a, kreisman h. coordination of eating, drinking and breathing in adults. chest 1989; 96:578–82. 10. fouke jm, teeter jp, strohl kp. pressure-volume behavior of the upper airway. j appl physiol 1986; 61:912–8. 11. lyberg t, krogstad o, djupesland g. cephalometric analysis in patients with obstructive sleep apnoea syndrome i. skeletal morphology. j laryngol otol 1989; 103:287–92. 12. ryan cf, lowe aa, li d, fleetham ja. threedimensional upper airway computed tomography in obstructive sleep apnea. a prospective study in patients treated by uvulopalatopharyngoplasty. am rev respir dis 1991; 144:428–32. 13. horner rl, shea sa, mcivor j, guz a. pharyngeal size and shape during wakefulness and sleep in patients with obstructive sleep apnoea. q j med 1989; 168:719–35. 14. fogel rb, malhotra a, white dp. sleep.2: pathophysiology of obstructive sleep apnoea/ hypopnoea syndrome. thorax 2004; 59:159–63. 15. remmers je, degroot wj, sauerland ek, anch am. pathogenesis of upper airway occlusion during sleep. j appl physiol 1978; 44:931–8. 16. brouillette rt, thach bt. a neuromuscular mechanism maintaining extrathoracic airway patency. j appl physiol 1979; 46:772–9. 17. strohl kp, hensley mj, hallett m, saunders na, ingram rhj. activation of upper airway muscles before onset of inspiration in normal humans. j appl physiol 1980; 49:638–42. 18. van lunteren e, van de graaff wb, parker dm, mitra j, haxhiu ma, strohl kp, et al. nasal and laryngeal reflex responses to negative upper airway pressure. j appl physiol 1984; 56:746–52. 19. kobayashi i, perry a, rhymer j, wuyam b, hughes p, murphy k, et al. inspiratory coactivation of the genioglossus enlarges retroglossal space in laryngectomized humans. j appl physiol 1996; snoring-induced nerve lesions in the upper airway 168 | squ medical journal, may 2012, volume 12, issue 2 45. mortimore il, douglas nj. palatal muscle emg response to negative pressure in awake sleep apneic and control subjects. am j respir crit care med 1997; 156:867–73. 46. bianchi a, denavit-saubie m, champagnat j. central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. physiol rev 1995; 75:1–31. 47. young t, finn l, palta m. chronic nasal congestion at night is a risk factor for snoring in a population-based cohort study. arch intern med 2001; 161:1514–19. 48. lofaso f, coste a, d’ortho mp, zerah-lancner f, delclaux c, goldenberg f, et al. nasal obstruction as a risk factor for sleep apnoea syndrome. eur respir j 2000; 16:639–43. 49. battagel jm, l’estrange pr. the cephalometric morphology of patients with obstructive sleep apnoea (osa). eur j orthod 1996; 18:557–69. 50. dayal vs, phillipson ea. nasal surgery in the management of sleep apnea. ann otol rhinol laryngol 1985; 94:550–4. 51. kohler m, bloch ke, stradling jr. the role of the nose in the pathogenesis of obstructive sleep apnoea and snoring. eur respir j 2007; 30:1208–15. 52. kauffman f, annesi j, neukirch f, oryszcezym mp, alpezovitch a. the relation between snoring and smoking, body mass index, age, alcohol consumption and respiratory symptoms. eur respir j 1989; 2:599– 603. 53. eveloff se, rosenberg cl, carlisle cc, millman rp. efficacy of a herbst mandibular advancement device in obstructive sleep apnea. am j respir crit care med 1994; 149:905–9. 54. o’sullivan ra, hillman dr, mateljan r, pantin c, finucane ke. mandibular advancement splint: an appliance to treat snoring and obstructive sleep apnea. am j respir crit care med 1995; 151:194–8. 55. lowe aa, sjöholm tt, fleetham ja, fregusson ka, remmers je. treatment, airway and compliance effects of a titrable oral appliance. sleep 2000; 23:s172–8. 34. kimoff rj, sforza e, champagne v, ofiara l, gendron d. upper airway sensation in snoring and obstructive sleep apnea. am j respir crit care med 2001; 164:250–5. 35. woodson bt, garancis jc, toohill rj. histopathologic changes in snoring and obstructive sleep apnea syndrome. laryngoscope 1991; 101:1318–22. 36. friberg d, gazelius b, tomas hökfelt, nordlander b. abnormal afferent nerve endings in the soft palatal mucosa of sleep apnoics and habitual snorers. regul pept 1997; 71:29–36. 37. edstrom l, larsson h, larsson l. neurogenic effects on the palatopharyngeal muscle in patients with obstructive sleep apnoea: a muscle biopsy study. j neurol neurosurg psychiatry 1992; 55:916–20. 38. friberg d, ansved t, borg k, carlsson-nordlander b, larsson h, svanborg e. histological indications of a progressive snorer’s disease in an upper airway muscle. am j respir crit care med 1998; 157:586– 93. 39. gutmann, l. neurogenic muscle hypertrophy. muscle nerve 1996; 19:811–18. 40. svanborg e. impact of obstructive apnea syndrome on upper airway respiratory muscles. respir physiol neurobiol 2005; 147:263–72. 41. wilson k, stoohs ra, mulrooney tf, johnson lj, guilleminault c, huang z. the snoring spectrum: acoustic assessment of snoring sound intensity in 1,139 individuals undergoing polysomnography. chest 1999; 115:762–70. 42. horner rl, innes ja, murphy k, guz a. evidence for reflex upper airway dilator muscle activation by sudden negative airway pressure in man. j physiol 1991; 436:15–29. 43. wheatley jr, tangel dj, mezzanotte ws, white dp. influence of sleep on response to negative airway pressure of tensor palatini muscle and retropalatal airway. j appl physiol 1993; 75:2117–24. 44. horner rl, innes ja, morrell mj, shea sa, guz a. the effect of sleep on reflex genioglossus muscle activiation by stimuli of negative airway pressure in humans. j physiol 1993; 476:141–51. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e52–57, epub. 21 jan 15 submitted 16 feb 14 revision req. 24 mar 14; revision recd. 28 jun 14 accepted 10 jul 14 colorectal unit, western general hospital, edinburgh, uk *corresponding author e-mail: sjafferbhoy@doctors.org.uk االستعمال االنتقائي للتصوير املقطعي ذو االنبعاث البيزوتروين املستخدم ملادة فلورو ديوكسي جلكوز والتصوير املقطعي يف معاجلة املرض املنتشر من سرطان القولون واملستقيم نتائج مركز إقليمي �ضدف جعفربهوئي، اآدم �ضامبريز، جيم�س ماندر، هيو باتري�ضون abstract: objectives: computed tomography (ct) scans are routinely used for primary staging and disease surveillance in patients with colorectal cancer. however, these scans have limited sensitivity in some organs and can only detect lesions with morphological changes, whereas 18f-fluorodeoxyglucose-positron emission tomography (18f-fdg-pet) scans are able to detect areas of metabolic change before morphological changes appear. the aim of this study was to evaluate the impact of 18f-fdg-pet/ct scans over conventional imaging during preoperative work-ups or follow-ups in a selected group of patients. methods: this retrospective cohort study, which took place between july 2009 and may 2011, assessed 1,043 patient records from the south east scotland cancer network colorectal cancer database. a total of 102 patients who underwent 18f-fdg-pet/ct scans in addition to conventional imaging were included in the study. these patients had potentially resectable metastases, equivocal findings on ct scans and elevated carcinoembryonic antigen levels with negative conventional imaging. results: of the 102 patients included in the study, 22 underwent a preoperative 18f-fdg-pet/ct scan and 80 underwent a follow-up 18f-fdg-pet/ct scan. in the preoperative scan group, the 18f-fdg-pet/ct scan had a major impact on 16 patients (72.75%) and no impact on six patients (27.25%). in the follow-up scan group, the 18f-fdg-pet/ct scan had a major impact on 51 (63.75%), a minor impact on four (5%), no impact on 22 (27.5%) and a negative impact on three (3.75%) patients. conclusion: the results of this study demonstrated that 18f-fdgpet/ct scans have a considerable effect on disease management when undertaken among indicated colorectal cancer patients. keywords: 18f fluorodeoxyglucose; positron emission tomography; colorectal cancer; metastases; cancer staging; recurrence; carcinoembryonic antigen; united kingdom. امللخ�ص: الهدف: ت�ضتخدم فحو�ضات الت�ضوير املقطعي )ct( روتينيا يف التحديد االأويل ملر�س �رضطان القولون وامل�ضتقيم، ويف مراقبة يف اإال واالأذى االإ�ضابات عن الك�ضف ميكنها وال االأع�ضاء، بع�س يف احل�ضا�ضية حمدودة الفحو�ضات هذه اأن غري ومتابعتهم املر�ضى االأع�ضاء التي حدثت فيها بالفعل تغريات مورفولوجية. وعلى العك�س من ذلك، فاإن فحو�ضات الت�ضوير املقطعي ذو االنبعاث البيزوتروين قبل اأي�ضية تغريات فيها حدثت التي اجل�ضم مناطق عن الك�ضف ميكنها )18f-fdg-pet/ct( جلكوز ديوك�ضي فلورو ملادة امل�ضتخدم ظهور تغريات مورفولوجية فيها. وغر�س هذه الدرا�ضة هو تقييم تاأثري ومزايا فحو�ضات 18f-fdg-pet/ct على الفحو�ضات التقليدية يف مرحلة الت�ضخي�س قبل العملية، اأو متابعة ذلك التاأثري عند جمموعة خمتارة من املر�ضى. الطريقة: متت هذه الدرا�ضة اال�ضتعادية بني يوليو 2009 ومايو 2011م ملفات مبراجعة ملفات جمموعة بها 1,043 مري�ضا يف قاعدة بيانات مر�س �رضطان القولون وامل�ضتقيم يف �ضبكة ال�رضطان يف جنوب �رضق ا�ضكتلندا. و�ضملت الدرا�ضة اأي�ضا متابعة حالة 102 مري�ضا من هوؤالء الذين خ�ضعوا لفح�س بالت�ضوير بـ وكانت اجلراحية، للإزالة قابل ال�رضطان يف انت�ضار لديهم املر�ضى اأولئك وكان التقليدية. للفحو�س باالإ�ضافة 18f-fdg-pet/ct نتائج فح�ضهم بـ ct ملتب�ضة، ولديهم اأي�ضا تركيزات مرتفعة من م�ضت�ضدات �رضطانية م�ضغية عند فح�ضهم بالطرق التقليدية. النتائج: قبل العملية، مت عمل فحو�ضات بوا�ضطة 18f-fdg-pet/ct يف 22 من املر�ضى يف هذه الدرا�ضة )وعددهم 102(، ومتت متابعة حاالت 80 منهم بعد فح�ضهم بوا�ضطة 18f-fdg-pet/ct. ووجد اأنه كان هنالك تاأثري لذلك الفح�س عند 16 مري�ضا )اأي ما ن�ضبته 72.75%(، /ct بينما مل يكن للفح�س اأي تاأثري عند �ضتة مر�ضى )اأي بن�ضبة %27.25(. ويف املجموعة التي متت متابعتها بعد العملية كان لفح�س selective use of 18f-fluorodeoxyglucose-positron emission tomography and computed tomography in the management of metastatic disease from colorectal cancer results from a regional centre *sadaf jafferbhoy, adam chambers, james mander, hugh paterson clinical & basic research sadaf jafferbhoy, adam chambers, james mander and hugh paterson clinical and basic research | e53 colorectal cancer is one of the most common malignancies in the uk and is a major health problem worldwide.1 accurate disease staging is fundamental to making appropriate management decisions. approximately 20% of cancer patients present with distant metastases; if untreated, these patients face a five-year survival rate of 7%.1 furthermore, local and distant recurrences develop in 30–50% of patients during follow-up after primary surgery.2 the early detection of recurrence is vital because surgery, radiotherapy and chemotherapy (either separately or as part of a multidisciplinary approach) may improve patient survival and quality of life. although only 20–30% of patients with recurrent metastatic disease are suitable candidates for curative resection, the five-year survival rate in this group is 30–40%.3 metastatic disease in colorectal cancer is most commonly detected in the liver or lungs but can affect any part of the body. conventional imaging has limitations of sensitivity and specificity depending on the disease and the organ affected. for example, computed tomography (ct) is usually performed for primary staging and surveillance but has a high false-positive rate for pulmonary and extrahepatic intra-abdominal lesions.4,5 these shortcomings have led to the increased use of 18f-fluorodeoxyglucose (18f-fdg)-positron emission tomography (pet)/ct as an additional imaging modality, both in preoperative settings and during follow-up. however, a recent review showed this modality to be cost-effective only in determining the staging of recurrent colorectal and metastatic cancers.6 in the colorectal unit of the western general hospital in edinburgh, scotland, 18f-fdg-pet/ct scans are performed selectively in patients who appear to have potentially curable metastatic disease on initial imaging or in those suspected of having occult recurrence. the aim of this study was to evaluate the clinical impact on patient management of performing 18f-fdg-pet/ct during preoperative work-up or follow-up in a select group of patients. methods this retrospective cohort study took place between july 2009 and may 2011. patient data were retrieved from the electronic south east scotland cancer network (scan) colorectal cancer database during the study period. records from the scan colorectal cancer database were included in the study if the patients had undergone 18f-fdg-pet/ ct in addition to conventional imaging. indications for the use of 18f-fdg-pet/ct were as follows: potentially resectable metastases identified by a ct scan at primary staging or during post-resection surveillance; equivocal ct findings at primary tumour staging or during post-resection surveillance, and rising carcinogenicembryonic antigen (cea) levels identified by negative conventional imaging during follow-up surveillance. the following data were recorded from the electronic patient record database: primary operative procedure; pathological findings; neoadjuvant treatment; indications of the use of 18f-fdg-pet/ct; intervals between surgeries and 18f-fdg-pet/ct 18f-fdg-pet تاأثري مهم يف 51 مري�ضا )اأي ما ن�ضبته %63.75(، وتاأثري قليل عند اأربعة مر�ضى )اأي ما ن�ضبته %5(، وعند 22 مري�ضا )اأي ما ن�ضبته %27.5( مل يكن هنالك اأي تاأثري. ووجد اأن لذلك الفح�س تاأثريا �ضار يف ثلثة مر�ضى )%3.75(. اخلال�صة: اأو�ضحت الدرا�ضة اأن فحو�ضات 18f-fdg-pet/ct لها اأثر كبري يف معاجلة مر�س �رضطان القولون وامل�ضتقيم عندما جترى يف اأعداد كبرية من املر�ضى املحددين. القولون �رضطان جلكوز؛ ديوك�ضي فلورو ملادة امل�ضتخدم البيزوتروين االنبعاث ذو املقطعي الت�ضوير املقطعي؛ الت�ضوير الكلمات: مفتاح وامل�ضتقيم؛ انت�ضار ال�رضطان؛ حتديد درجة ال�رضطان؛ عودة ال�رضطان؛ م�ضت�ضدات �رضطانية م�ضغية؛ اململكة املتحدة. advances in knowledge this study demonstrates that 18f-fluorodeoxyglucose (18f-fdg)-positron emission tomography (pet)/computed tomography (ct) is a useful diagnostic tool and can have a valuable impact on the disease management of indicated colorectal cancer patients. only a select group of patients with colorectal cancer, i.e. those with potentially curable disease and resectable metastases, benefit from fdg-pet/ct in addition to ct during preoperative work-ups and disease follow-ups. 18f-fdg-pet/ct is beneficial during follow-up treatment for cancer patients, particularly in the identification of occult recurrence among those with elevated carcinogenicembryonic antigen levels. application to patient care 18f-fdg-pet/ct is useful in identifying metastatic or recurrent disease at an early stage in patients with colorectal cancer. early identification may improve patient survival. results from 18f-fdg-pet/ct scans can inform disease management in patients with potentially resectable disease or in those with equivocal findings from conventional imaging. selective use of 18f-fluorodeoxyglucose-positron emission tomography and computed tomography in the management of metastatic disease from colorectal cancer results from a regional centre e54 | squ medical journal, february 2015, volume 15, issue 1 scans (where applicable); results of conventional imaging and 18f-fdg-pet/ct scans; clinical actions taken after 18f-fdg-pet/ct and/or ct scan results, and follow-up information. following data collection, the additional value of 18f-fdg-pet/ct over conventional imaging was assessed with regards to patient management. the clinical impact of 18f-fdg-pet/ct was divided into the following four categories. 18f-fdg-pet/ct imaging was determined to have had a major impact if there was evidence of inoperable disease that was either indeterminate or occult on prior conventional imaging or if there were additional 18f-fdg-pet/ ct findings which had altered disease management. additionally, 18f-fdg-pet/ct was considered to have had a minor impact if ct findings were indeterminate and 18f-fdg-pet/ct did not identify any disease. imaging was classified as having had no impact when 18f-fdg-pet/ct showed no additional findings and no alterations were made to planned treatments as a result. finally, 18f-fdg-pet/ct scans were deemed to have had a potential negative impact in cases of falsepositive findings which had potentially led to further investigations or inappropriate disease management. ethical approval for this study was granted by the audit department of western general hospital, in edinburgh, scotland. results a total of 1,043 patients were identified in the scan colorectal cancer database during the study period. of these, 102 patients had undergone 18f-fdg-pet/ ct as well as conventional imaging either as part of primary staging or for disease surveillance. there were 40 female and 62 male patients. the median age of the patients was 63 years (range: 29–88 years). a total of 22 patients received 18f-fdg-pet/ct for preoperative staging while 80 patients received 18f-fdg-pet/ct during follow-up. overall, 18f-fdgpet/ct findings were concordant with conventional imaging results in only 28 patients (27.4%). in the preoperative group, potentially resectable metastases were detected in 11 patients by 18f-fdgpet/ct whereas the other 11 patients had equivocal ct findings. among those with detected resectable diseases, ct findings denoting resectable diseases were confirmed by 18f-fdg-pet/ct in six cases (54.5%). however, three patients whose ct results had detected potentially resectable metastases were instead deemed inoperable by 18f-fdg-pet/ct. furthermore, two patients were downstaged after their 18f-fdg-pet/ct findings were negative. of the 11 patients with equivocal ct findings, 18f-fdg-pet/ ct identified six patients with resectable metastases and five patients with unresectable metastases. a comparison of ct and 18f-fdg-pet/ct findings is provided in table 1. in the follow-up group, indications for 18f-fdgpet/ct included rising cea levels identified by negative ct results (n = 10), resectable metastases or local recurrence on conventional imaging (n = 31) and equivocal ct findings (n = 39). the operative and pathological details of the patients in the followup group can be seen in table 2. the mean interval between surgery and 18f-fdg-pet/ct scanning was 587 days (range: 15–2,555 days). of the 10 patients table 1: comparison of conventional imaging and 18f-fdg-pet/ct findings among preoperative colorectal cancer patients (n = 22) ct finding 18f-fdg-pet/ct finding total resectable unresectable negative resectable 6 3 2 11 equivocal 6 5 0 11 ct = computed tomography; 18f-fdg-pet/ct = 18f-fluorodeoxyglucosepositron emission tomography/computed tomography. table 2: summary of the treatment and pathological findings of colorectal cancer patients during follow-up (n = 80) treatment n operative procedure 80 right hemicolectomy 25 anterior resection 17 anterior resection with tme 33 abdominoperineal resection of rectum 3 total colectomy 2 neoadjuvant treatment 27 short course radiotherapy 23 preoperative chemoradiotherapy 4 tnm stage t stage 80 t1 6 t2 8 t3 43 t4 23 n stage 80 n0 37 n1 29 n2 14 tme = total mesorectal resetion; tnm = tumours/nodes/metastases staging system. sadaf jafferbhoy, adam chambers, james mander and hugh paterson clinical and basic research | e55 with rising cea levels, two patients had negative 18f-fdg-pet/ct scan results, five patients were found to have resectable disease and three patients had unresectable distant metastases. of the 31 patients with resectable disease findings on ct scans, 18f-fdg-pet/ct confirmed these findings in 20 patients, demonstrated unresectable metastases in eight patients and excluded local or distant recurrence in three patients. among the 39 patients with equivocal ct findings, 18f-fdg-pet/ct scans demonstrated negative results in four patients, resectable local recurrence or distant metastases in 22 patients and unresectable disease in 13 patients [figure 1]. combined 18f-fdg-pet/ct imaging had a major clinical impact for 16 patients (72.7%) in the preoperative group, including eight patients whose treatment was altered from curative to palliative due to the presence of inoperable disease, six with resectable metastases identified after an indeterminate ct scan and two who avoided unnecessary surgery due to negative 18f-fdg-pet/ct findings. furthermore, 18f-fdg-pet/ct findings had a major impact and altered disease management for 51 patients (63.7%) in the follow-up group. of these, 24 patients were offered palliative treatment due to findings which indicated inoperable recurrent disease that had not been diagnosed from ct scans; this included 13 patients with indeterminate ct findings, eight whose ct findings had indicated resectable metastases and three with negative ct results. resectable recurrent disease was found in 24 patients (five and 19 patients with negative and indeterminate ct findings, respectively). all of the patients who underwent curative resection were later confirmed to have recurrent colorectal cancer on histological examination. surgery was avoided in three patients whose ct results had detected resectable disease but subsequent 18f-fdgpet/ct imaging had revealed a negative result. these patients remained under close follow-up with no clinical or radiological evidence of disease recurrence. a minor impact on the clinical disease management of four patients (5%) in the follow-up group was noted due to 18f-fdg-pet/ct imaging. these patients had had equivocal ct scan results but were downstaged as a result of their 18f-fdg-pet/ct results. three of these patients had lesions detected in their lungs and one patient had a liver lesion which was 18f-fdgpet/ct-negative and which remained unchanged on serial imaging. disease management remained unaltered for six patients (27.2%) in the preoperative group and 22 patients (27.5%) in the follow-up group. in these cases, 18f-fdg-pet/ct imaging had no impact as the combined imaging confirmed the original ct findings. in the follow-up group, a total of 20 patients were found to have recurrent disease while two patients with elevated cea levels had a negative result from both ct and 18f-fdg-pet/ct scans. two patients with liver metastases confirmed by ct and 18f-fdg-pet/ ct findings refused surgery and one patient underwent a hepatic segmentectomy for a malignant lesion which had a complete response to chemotherapy. the clinical impact of 18f-fdg-pet/ct imaging was negative in three patients (3.7%) who had equivocal ct findings and positive 18f-fdg-pet/ ct results revealing uptake at the anastomotic site. all three patients underwent direct visualisation of the anastomosis; two via colonoscopies with biopsy and one via an examination under anaesthesia with biopsy. no histological or clinical evidence of disease recurrence was found for any of the patients. in addition, one patient underwent excision of an umbilical lesion identified on both ct and 18f-fdgpet/ct scans. this lesion was later revealed to be histologically benign. figure 1: comparison of computed tomography and 18f-fluorodeoxyglucose-positron emission tomography/computed tomography findings among colorectal cancer patients during follow-up (n = 80). selective use of 18f-fluorodeoxyglucose-positron emission tomography and computed tomography in the management of metastatic disease from colorectal cancer results from a regional centre e56 | squ medical journal, february 2015, volume 15, issue 1 in terms of patient outcomes, 56 patients (54.9%) were offered curative surgery and 50 underwent metastasectomies as a result of their 18f-fdgpet/ct findings. metastatic lesion resection was performed in 46 patients, including the liver only (n = 32), the lungs (n = 7), the abdominal wall (n = 3) and the peritoneum (n = 3). additionally, one patient underwent a synchronous renal tumour and liver resection. four patients did not undergo surgery; this was either due to the progression of the lesion to an unresectable form (n = 1), the complete resolution of a lung lesion following chemotherapy (n = 1), comorbidities (n = 1) or the patient’s choice (n = 1). palliative treatment was offered to 32 patients (31.3%). nine patients (8.8%) were downstaged, three (2.9%) were over-investigated (pet/ct showed suspected local recurrence but there was no evidence of this on endoscopic examination) and two (1.9%) did not require further investigations or treatment. discussion the present study investigated the role of 18f-fdgpet/ct imaging in the clinical management of 102 patients with metastatic or recurrent colorectal cancer being considered for curative resection. the data in the current study showed that 18f-fdg-pet/ ct scans are a useful diagnostic tool in managing patients with colorectal cancer since treatment based on conventional ct imaging was modified in almost two-thirds of the cohort. in this study, 18f-fdg-pet/ct findings were consistent with conventional imaging findings in only 27.4% of the patients, which is much lower than other studies reported in the literature.7,8 a possible explanation is that 18f-fdg-pet/ct scans were carried out selectively among the studied cohort, in patients whose management could have been altered by the additional imaging. combined 18f-fdg-pet/ ct imaging proved particularly useful in differentiating lesions which were considered indeterminate on ct scans, allowing more accurate characterisation in almost half of the patients in this cohort. the liver is the most common site for colorectal metastases and the reported sensitivity of 18f-fdgpet/ct scans in detecting hepatic metastases varies. selzner et al. found that while 18f-fdg-pet/ct was comparable to conventional ct in detecting liver lesions, it was superior in detecting extrahepatic lesions.9 in their study, 18f-fdg-pet/ct imaging was performed on all patients being considered for liver metastasis resection and had a major impact on 21%. a study by ruers et al. showed that the rate of futile laparotomies among their cohort was reduced from 45% to 28% through the utilisation of 18f-fdgpet/ct scans.10 weiring et al. also demonstrated the utility of 18f-fdg-pet/ct scans, as this modality was found to reduce futile laparotomies by 38%.11 there have been no large series or comparative studies so far between 18f-fdg-pet/ct scans and conventional ct scans concerning the detection of pulmonary metastases. the accurate determination of pulmonary metastases which are indeterminate via ct imaging is particularly important if curative resection is being considered elsewhere in the body. in the present study, six patients with liver metastases were also found to have lung metastases on 18f-fdg-pet/ct scans. serum cea levels are commonly monitored during follow-up in colorectal cancer patients, in addition to physical examinations and conventional imaging. while some researchers consider cea levels to be the most effective indicator in detecting recurrent disease,12 others have found marginal benefits and concluded that the majority of potentially curable recurrent tumours are detected by surveillance imaging techniques when cea levels are normal.13,14 patients with elevated tumour markers and negative results on conventional imaging pose a clinical challenge. several studies have demonstrated the value of 18f-fdg-pet/ct imaging in patients with rising serum cea levels and no identifiable lesions on conventional imaging.15–17 in the present study, eight out of 10 patients with elevated cea levels were found to have metastatic disease even when conventional imaging did not show disease recurrence. the other two patients with normal 18f-fdg-pet/ct results showed no clinical or radiological signs of subsequent disease recurrence. other studies have also reported that a negative 18f-fdg-pet/ct scan result is accurate in excluding recurrence.18,19 in the case of local recurrence at the site of primary colorectal cancer, ct findings are often difficult to interpret due to benign post-surgical or radiotherapeutical changes. selzner et al. reported a 93% accuracy rate in detecting local recurrence with the use of 18f-fdg-pet/ ct imaging.9 however, three out of eight patients with equivocal ct results in the current study had false-positive 18f-fdg-pet/ct readings, suggesting anastomotic recurrence. these cases required direct visual examination to exclude disease recurrence. although the current study’s results showed that the use of 18f-fdg-pet/ct imaging had a primarily positive impact on disease management, several disadvantages of this modality have been reported. research has indicated that 18f-fdg-pet/ct imaging has reduced sensitivity in detecting subcentimetre lesions, which means that small metastatic deposits can therefore be missed on the scans.20 in addition, 18f-fdg-pet/ct imaging can reportedly yield false-positive readings among patients with benign sadaf jafferbhoy, adam chambers, james mander and hugh paterson clinical and basic research | e57 inflammatory conditions and false-negative readings for patients with high blood glucose levels or those who have had recent chemotherapy treatments.9,21 a major limitation of this study was the lack of histopathological confirmation of 18f-fdg-pet/ctpositive lesions in 36 out of 88 patients (41%). this lack of histopathological confirmation occurred primarily because the distant metastases in question were inoperable. the results of this study should therefore be interpreted in light of this. conclusion this study demonstrates that, when undertaken in selected colorectal cancer patients for clear indications, 18f-fdg-pet/ct imaging provides valuable information and has a considerable impact on disease management in a significant proportion of patients. this impact was primarily seen via improvements in staging accuracy and the avoidance of unnecessary surgeries. additionally, 18f-fdg-pet/ct imaging enabled the identification of recurrent disease at an early stage at which point curative surgery can be offered to the patient. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. cancer research uk. cancer incidence statistics. from: www. cancerresearchuk.org/cancer-info/cancerstats/incidence/ukcancer-incidence-statistics accessed: dec 2012. 2. chen lb, tong jl, song hz, zhu h, wang yc. (18)f-dg pet/ ct in detection of recurrence and metastasis of colorectal cancer. world j gastroenterol 2007; 13:5025–9. doi: 10.3748/ wjg.v13.i37.5025. 3. elias d, sideris l, pocard m, ouellet jf, boige v, lasser p, et al. results of r0 resection for colorectal liver metastases associated with extrahepatic disease. ann surg oncol 2004; 11:274–80. doi: 10.1245/aso.2004.03.085. 4. pfannschmidt j, bischoff m, muley t, kunz j, zamecnik p, schnabel pa, et al. diagnosis of pulmonary metastases with helical ct: the effect of imaging techniques. thorac cardiovasc surg 2008; 56:471–5. doi: 10.1055/s-2008-1038887. 5. wiering b, ruers tj, krabbe pf, dekker hm, oyen wj. comparison of multiphase ct, fdg-pet and intra-operative ultrasound in patients with colorectal liver metastases selected for surgery. ann surg oncol 2007; 14:818–26. doi: 10.1245/ s10434-006-9259-6. 6. brush j, boyd k, chappell f, crawford f, dozier m, fenwick e, et al. the value of fdg positron emission tomography/ computerised tomography (pet/ct) in pre-operative staging of colorectal cancer: a systematic review and economic evaluation. health technol assess 2011; 15:1–192. doi: 10.3310 /hta15350. 7. heriot ag, hicks rj, drummond eg, keck j, mackay j, chen f, et al. does positron emission tomography change management in primary rectal cancer? a prospective assessment. dis colon rectum 2004; 47:451–8. doi: 10.1007/s10350-003-0089-3. 8. ruers tj, langenhoff bs, neeleman n, jager gj, strijk s, wobbes t, et al. value of positron emission tomography with [f-18]fluorodeoxyglucose in patients with colorectal liver metastases: a prospective study. j clin oncol 2002; 20:388–95. doi: 10.1200/jco.20.2.388. 9. selzner m, hany tf, wildbrett p, mccormack l, kadry z, calvien pa. does the novel pet/ct imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? ann surg 2004; 240:1027–34. doi: 10.1097/01. sla.0000146145.69835.c5. 10. ruers tj, wiering b, van der sijp jr, roumen rm, de jong kp, comans ef, et al. improved selection of patients for hepatic surgery of colorectal liver metastases with (18)f-fdg pet: a randomized study. j nucl med 2009; 50:1036–41. doi: 10.2967/ jnumed.109.063040. 11. wiering b, adang em, van der sijp jr, roumen rm, de jong kp, comans ef, et al. added value of positron emission tomography imaging in the surgical treatment of colorectal liver metastases. nucl med commun 2010; 31:938–44. doi: 10.1097/mnm.0b013e32833fa9ba. 12. graham ra, wang s, catalano pj, haller dg. postsurgical surveillance of colon cancer: preliminary cost analysis of physician examination, carcinoembryonic antigen testing, chest x-ray, and colonoscopy. ann surg 1998; 228:59–63. 13. tan e, gouvas n, nicholls rj, ziprin p, xynos e, tekkis pp. diagnostic precision of carcinoembryonic antigen in the detection of recurrence of colorectal cancer. surg oncol 2009; 18:15–24. doi: 10.1016/j.suronc.2008.05.008. 14. bleeker wa, mulder nh, hermans j, otter r, plukker jt. value and cost of follow-up after adjuvant treatment of patients with dukes’ c colonic cancer. br j surg 2001; 88:101–6. doi: 10.1046/j.1365-2168.2001.01638.x. 15. flamen p, hoekstra os, homans f, van cutsem e, maes a, stroobants s, et al. unexplained rising carcinoembryonic antigen (cea) in the postoperative surveillance of colorectal cancer: the utility of positron emission tomography (pet). eur j cancer 2001; 37:862–9. doi: 10.1016/s0959-8049(01)00049-1. 16. libutti sk, alexander hr jr, choyke p, bartlett dl, bacharach sl, whatley m, et al. a prospective study of 2-[18f] fluoro2-deoxy-d-glucose/positron emission tomography scan, 99m tc-labeled arcitumomab (cea-scan), and blind second-look laparotomy for detecting colon cancer recurrence in patients with increasing carcinoembryonic antigen levels. ann surg oncol 2001; 8:779–86. doi: 10.1007/s10434-001-0779-9. 17. zervos ee, badgwell bd, burak we jr, arnold mw, martin ew. fluorodeoxyglucose positron emission tomography as an adjunct to carcinoembryonic antigen in the management of patients with presumed recurrent colorectal cancer and nondiagnostic radiologic workup. surgery 2001; 130:636–43. doi: 10.1067/msy.2001.116919. 18. kyoto y, momose m, kondo c, itabashi m, kameoka s, kusakabe k. ability of 18f-fdg pet/ct to diagnose recurrent colorectal cancer in patients with elevated cea concentrations. ann nucl med 2010; 24:395–401. doi: 10.1007/s12149-0100372-z. 19. ozkan e, soydal c, araz m, kir km, ibis e. the role of 18f-fdg pet/ct in detecting colorectal cancer recurrence in patients with elevated cea levels. nucl med commun 2012; 33:395–402. doi: 10.1097/mnm.0b013e32834f7dbe. 20. zealley ia, skehan sj, rawlinson j, coates g, nahmias c, somers s. selection of patients for resection of hepatic metastases: improved detection of extrahepatic disease with fdg pet. radiographics 2001; 21:s55–69. doi: 10.1148/ radiographics.21.suppl_1.g01oc05s55. 21. staib l, schirrmeister h, reske sn, beger hg. is (18) f-fluorodeoxyglucose positron emission tomography in recurrent colorectal cancer a contribution to surgical decision making? am j surg 2000; 180:1–5. doi: 10.1016/s00029610(00)00406-2. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 522-525, epub. 20th nov 12 submitted 10th jan 12 revision req. 23rd apr 12, revision recd. 28th apr & 17th jul 12 accepted 1st aug 12 department of neurological surgery, ohio state university, columbus, ohio, usa *corresponding author e-mail: tariq.lamki@osumc.edu ورم ليفي عصيب شوكي يتنكر على شكل انزالق غضرويف تقرير حالة طارق ملكي و ماريو امرياتي ت خطاأ على امللخ�ض: نقدم هنا تقرير احلالة الوحيدة يف االأدبيات الطبية االجنليزية لورم ليفي ع�صبي �صوكي يف العمود الفقري �ُصخ�صّ اأنها انزالق غ�رصويف با�صتخدام الت�صوير بالرنني املغناطي�صي.كانت اأعرا�ض هذه احلالة والنتائج االإ�صعاعية منوذجية لت�صخي�ض انزالق غ�رصويف. واأثناء العملية اجلراحية لوحظ خلل يف كم جذر الع�صب العجزي االأول، وظهر بعد اال�صتك�صاف وجود ورم ليفي ع�صبي �صوكي، مت ا�صتئ�صاله بالكامل، مما اأدى اإىل حت�صن يف اأعرا�ض املري�ض. حاليا، هناك اعتماد كبري على الت�صوير بالرنني املغناطي�صي كاأداة ح�صا�صة للغاية وحمددة ت�صتخدم يف ت�صخي�ض فتق الغ�صاريف القطنية. واإن كانت هناك تقارير متفرقة من عدم دقة الت�صخي�ض با�صتخدام الت�صوير بالرنني املغناطي�صي، لكن ال توجد تقارير عن ت�صخي�ض خاطئ لالأورام الليفية الع�صبية يف العمود الفقري على اأنها انزالق غ�رصويف. على الرغم من التطور الكبري يف الت�صوير االإ�صعاعي الت�صخي�صي ال تزال املفاجاآت اجلراحية حتدث. يف نهاية املطاف، ال يزال من ال�رصوري اتخاذ القرارات اأثناء العملية اجلراحية. املتحدة الواليات حالة، تقرير ع�صبي، ليفي ورم املغناطي�صي، بالرنني ال�صوئي امل�صح ت�صخي�ض، اإ�صاءة غ�رصويف، انزالق الكلمات: مفتاح االأمريكية. abstract: we present the only case in english medical literature of a spinal neurofibroma misdiagnosed as a herniated disc using magnetic resonance imaging (mri). this case presented with typical symptoms and radiological findings of a herniated disc. intraoperatively, an abnormality was noted at the s1 nerve root sleeve. further exploration revealed a spinal neurofibroma which was completely resected, resulting in an improvement in the patient’s symptoms. currently, there is heavy reliance on mri as a highly sensitive and specific tool used in the diagnosis of herniated lumbar discs. although there have been occasional reports of misdiagnoses using mri, there are no reported cases of a spinal neurofibroma being misdiagnosed as a herniated lumbar disc. despite great advances in radiological diagnostic imaging, surgical surprises do still occur. ultimately, instinct is still essential in intraoperative surgical decisions. keywords: herniated disc; misdiagnosis; mri scan; neurofibroma; case report; usa. spinal neurofibroma masquerading as a herniated disc a case report *tariq lamki and mario ammirati case report magnetic resonance imaging (mri) is widely considered to be both very sensitive and specific in diagnosing herniated discs.1 however, there have been occasional reports of false positive mris vis-àvis herniated discs. we report a case where a lumbar spinal neurofibroma was misdiagnosed as a herniated lumbar disc with a review of the pertinent literature. we present the only case in the english literature of such a misdiagnosis using mri. as such, we highlight the fact that even in such a mundane neurosurgical procedure as a lumbar microdiscectomy, intradural exploration may be necessary when the intraoperative findings do not match the neuroradiological ones. case report a 44-year-old man presented with a 1-month history of acute onset back pain associated with s1 tariq lamki and mario ammirati case report | 523 radiculopathy on the right that was progressively worsening and not responding to conservative treatment. he had had several episodes of sciatica during the past 10–15 years. he reported that the pain had increased acutely in severity. the pain involved the posterior right buttock, the posterolateral thigh, posterior calf, and the outer aspect and ball of the right foot. a neurological examination was positive for a 4/5 weakness in the right s1 innervated muscles (gastrocnemius and soleus, flexors of toes). he also had an absent ankle reflex on the right. his straight leg raising test was positive at 45° on the right side. an mri of the lumbosacral spine was obtained and reported as showing an obvious extruded disc at l5/s1 [figure 1]. he had neither a family history of neurofibromatosis nor a significant history of tumours. he had no café au lait spots, freckling, or cutaneous neurofibromas anywhere on the body. the conclusion was that he had an s1 radiculopathy caused by an extruded disc at l5/s1. considering that he was not responding to conservative treatment, a microdiscectomy at l5/s1 was performed. a routine l5/s1 lumbar microdiscectomy approach was executed. using the operating microscope, the thecal sac and the s1 nerve root were identified. both of them were observed to be under substantial pressure, as expected. there was an obvious defect in the posterior longitudinal ligament and a very small disc fragment was identified and removed. the intervertebral disc space was further opened and the remaining portion of the disc was removed. with this removal, it was felt that the amount of disc did not seem commensurate with the appearance suggested by the mri. we proceeded to do a complete foraminotomy over the s1 nerve root where an obvious abnormality on the lateral aspect of the s1 nerve root was found [figures 2 & 3]. we cautiously used intraoperative direct nerve root stimulation up to 4 milliamps and could not obtain any stimulation on the lateral aspect of the nerve. in contrast, there was clear cut stimulation along the medial aspect where the deformity lay. we then proceeded to open the dura in order to ascertain the nature of the pathology. we came across a mass that was intermingled with the rootlets. under high magnification and frequent electrical stimulation, it was possible to remove this mass completely. a frozen section was consistent with schwannoma. after the tumour had been completely removed, the exposed rootlets were covered with a small fat graft pre-soaked in methylprednisolone sodium succinate solution. the wound was then closed in the routine fashion. postoperatively, the patient experienced immediate relief of the right leg pain. he also exhibited increased right leg strength and reappearance of the ankle reflex. at a 3-month follow-up, the right leg strength was found to be 5/5 and he had already resumed duties at work although figure 1: the pre-operative magnetic resonance imaging scan is a t2 weighted sagittal image showing what appears to be an extruded disc at l5s1. figure 2: pictured is the intra-operative image after foraminotomy. it shows a bulge at the s1 nerve root. this bulge, combined with the finding of a disc herniation disproportionate to the clinical findings, raised suspicion and prompted further investigation. spinal neurofibroma masquerading as a herniated disc a case report 524 | squ medical journal, november 2012, volume 12, issue 4 there was some residual intermittent paresthesia in the 4th and 5th toes. a postoperative mri of the whole neuraxis showed complete removal of the l5/s1 abnormality and an absence of other lesions. at the one-year post-operative visit, the patient explained that his symptoms had significantly improved. however, he did complain of mild to moderate pain on exertion, felt in the lower back region, and continued intermittent paresthesias in the 4th and 5th toes. the 16-month post-operative mri showed no recurrence of the tumour. the final pathology report was consistent with neurofibroma. [figure 4]. this conclusion was based on the visualisation of small fragments of myelinated nerve that were focally expanded with the proliferation of spindle elements. discussion lumbar mri is widely considered sensitive and specific in diagnosing a herniated nucleus pulposus (hnp).1-8 in a recent retrospective study of about 2,000 patients, three unexpected histopathological findings were reported during a routine operation on what was believed to be a herniated lumbar disc.3 one patient had a metastatic carcinoma involving a prolapsed disc while another patient had an l5/s1 herniated disc associated with lymphoma in the same location. the third case described a cavernous haemangioma within the disc material. the decision to operate on the lymphoma patient was based on an mri, while the other two patients underwent surgery based on the findings of the computed tomography (ct) scan.3 this finding of about 1:1,000 unexpected important pathologies occurred during routine discectomy procedures.3 our finding is more intriguing because of the natural history of events. our case began as a routine discectomy but then evolved to a tumour excision. this gross, intraoperative revelation of a mribased misdiagnosis is rare indeed with a herniated nucleus pulposus. while there have been isolated reports of other tumours being misdiagnosed as hnp, there has been no report in the mri era of a spinal neurofibroma being misdiagnosed as a herniated disc.3,4,6 to our knowledge, this is the first case that was misdiagnosed despite the use of mri. isolated lumbar spinal neurofibromas are extremely rare and very few cases have been reported to date. the key to avoid missing an associated lesion is to match the neuroradiological findings to what is seen during surgery. whenever there is a significant mismatch, consideration must be given to other lesions mimicking hnp, and necessary intraoperative adjustments must be made. at this juncture, the surgeon has several options. in our case, a clear abnormality appeared intraoperatively within the neural sleeve. this prompted further surgical investigation. had this not been so obvious, the other option would have been to conclude the surgery and follow up with an immediate mri scan, utilising contrast and thinner slices to achieve a more detailed study. conclusion in conclusion, despite great advances in radiological figure 3: once the nerve root sleeve was opened, a neurofibroma was exposed. pictured are the s1 nerve fibres (triangular arrow) and the neurofibroma (lined arrow). methodical dissection was needed to separate the tumour from the fibres. figure 4: this shows the tissue under 200x magnification after undergoing s-100 protein stain showing characteristic neurofibroma properties. tariq lamki and mario ammirati case report | 525 diagnostic imaging, surgical surprises do still occur. this should be considered when approaching even the most routine cases. for us, a sporadic neurofibroma of the s1 dorsal root sleeve masqueraded as a herniated intervertebral disc. this is a very rare occurrence and this case is, to our knowledge, the first such case reported in the mri era in english medical literature. this reinforces the idea that a surgeon should ‘follow his (or her) gut’ and investigate for more complex pathology when intraoperative findings do not seem to match the neuroradiological ones. this is yet a new twist on the old adage “treat the patient not the images.” references 1. boos n, rieder r, schade v, spratt k, semmer n, aebi m. the diagnostic accuracy of magnetic resonance imaging, work perception, and psychological factors in identifying symptomatic disc herniations. spine 1995; 20:2613–25. 2. ferner r, o’doherty m. neurofibroma and schwannoma. curr opin in neurol 2002; 15:679–84. 3. hasselblatt m, maintz d, goll t, wildforster u, schul c, paulus w. frequency of unexpected and important histopathological findings in routine intervertebral disc surgery. j neurosurg spine 2006; 4:20–3. 4. hirsh l, finneson b. intradural sacral nerve root metastasis mimicking herniated disc. j neurosurg 1978; 49:764–8. 5. jensen m, brantz-zawadzki m, obuchowski n, modic m, malkasian d, ross j. magnetic resonance imaging of the lumbar spine in people without back pain. n engl j med 1994; 331:69–73. 6. menku a, koc r, tucer b, kulaksizoglu o, akdemir h. ependymoma of filum terminale mimicking lumbar disc herniation. turk neurosurg 2004; 14:105–8. 7. seppala m, haltia m, sankila r, jaaskelainen j, heiskanen o. long-term outcome after removal of spinal neurofibroma. j neurosurg 1995; 82:572–7. 8. wassenaar m, van rijn rm, van tulder mw, verhagen ap, van der windt, koes bw, et al. magenetic resonance imaging for diagnosing lumbar spinal pathology in adult patients with low back pain or sciatica: a diagnostic systematic review. eur spine j 2012; 21:220–7. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e288–291, epub. submitted 3 aug 14 revision req. 22 sep 14; revision recd. 21 oct 14 accepted 6 nov 14 2tobacco control section, 1department of non-communicable disease control, directorate general of health affairs, ministry of health, muscat, oman; 3tobacco free initiative, eastern mediterranean office of the world health organization, cairo, egypt *corresponding author e-mail: jallawati@gmail.com قياس التعرض للتدخني السليب يف مسقط، سلطنة عمان جواد اأحمد اللواتي، يو�سف الذهلي، فاروق قري�سي abstract: objectives: this study aimed to measure exposure to secondhand smoke (shs) and assess venue compliance with the municipal law against smoking indoors in public places in muscat, oman. methods: following the selection of 30 public indoor venues within the muscat governorate, the concentration of suspended shs particulate matter (pm2.5) in the venues’ indoor air was measured throughout july and august 2010. results: almost all of the venues were found to be compliant with the smoke-free municipal, with the exception of a café that served waterpipes for smoking indoors. the concentration of pm2.5 in this venue showed an average level of 256 µg/m3 which was 64 times the level of that found in the non-smoking venues. conclusion: aside from one café, the majority of the assessed indoor public venues abided by the smoke-free municipal law. however, the enforcement of policies banning smoking in indoor public recreational venues should be re-examined in order to protect member of the public in oman from exposure to shs. keywords: tobacco products; secondhand smoke; particulate matter; oman. امللخ�ص: الهدف: هدفت الدرا�سة اإىل قيا�ض التعر�ض للتدخني ال�سلبي وتقييم امتثال االأماكن التي مت اختيارها لقرار البلدية بحظر التدخني يف االأماكن العامة املغلقة يف م�سقط، بعمان. الطريقة: حدد الباحثون 30 موقعًا من االأماكن العامة املغلقة يف حمافظة م�سقط، مت قيا�ض تركيز مادة اجل�سيمات املعلقة )pm2.5( الناجتة من التدخني ال�سلبي فيها خالل �سهري يوليو واأغ�سط�ض 2010م. النتائج: تبني اأن معظم االأماكن ممتثلة لقانون حظر التدخني يف االأماكن العامة املغلقة با�ستثناء مقهى واحد يوفر االأرجيلة يف القاعات املغلقة. و�سجل متو�سط م�ستوى تركيز pm2.5 فيها 256 ميكروغرام/م3. وكان هذا 64 مرة �سعف م�ستوى تلك التي وجدت يف اأماكن يحظر التدخني فيها. اخلال�صة: يف التدخني بحظر البلدي بالقانون التزمت تقييمها مت التي املغلقة االأماكن من العظمى الغالبية فاإن املقهى، هذا عن النظر وب�رشف االأماكن العامة. ورغم ذلك فاإنه يجب اإعادة النظر يف تنفيذ �سيا�سات حظر التدخني يف االأماكن الرتفيهية املغلقة مثل املقاهي والتي التزال ت�سمح بالتدخني فيها من اأجل حماية اجلمهور يف �سلطنة عمان من التعر�ض للتدخني ال�سلبي. مفتاح الكلمات: منتجات التبغ؛ دخان التبغ ال�سلبي؛ مادة اجل�سيمات؛ عمان. measuring secondhand smoke in muscat, oman *jawad a. al-lawati,1 yusuf al-thuhli,2 farrukh qureshi3 global tobacco use is the second leading cause of preventable mortality and the sixth leading cause of disability-adjusted life years lost.1 the world health organization (who) estimates that almost six million people die from tobacco use each year, both from direct tobacco use and secondhand smoke (shs).2 it has been projected that by 2020, this number will increase to 7.5 million, accounting for 10% of all deaths worldwide.2 tobacco use is also a major cause of morbidity. in total, 11% of deaths from ischaemic heart disease (leading cause of mortality worldwide) and more than 70% of deaths from lung, trachea and bronchus cancers are attributable to tobacco use.3 exposure to shs is estimated to kill 600,000 people (10% of all tobacco-related deaths) each year.4 in addition, it is a well-documented risk factor for coronary artery diseases and multiple malignancies in adults, as well as asthma, middle-ear infections and sudden infant death syndrome.5 in 2005, oman acceded to the who framework convention on tobacco control (fctc), a global treaty to reduce the world’s tobacco burden.6 article 8 of this international framework requires parties to adopt and implement measures to protect individuals from exposure to tobacco smoke in indoor workplaces, indoor public places, public transport and other public places as appropriate.7 in october 2009, for the first time, the muscat municipal council issued a ban on all forms of indoor smoking in public places in the capital city, effective from april 2010.8 this study, conducted in july 2010, aimed to test the extent of compliance with this ban and to monitor shs levels in a variety of public indoor venues within the muscat governorate, oman. the smoking behaviour of people within these venues was also observed in order to identify sources of shs exposure and subsequently provide evidence to support more progressive smoke-free policies. online brief communication jawad a. al-lawati, yusuf al-thuhli and farrukh qureshi online brief communication | e289 methods the areas targeted for this study were government offices with public access, healthcare and educational facilities, recreational venues (cafés/restaurants/ bars) and public transportation. the selected sample of indoor venues included the following: six tertiary hospital areas (including hospital visitor cafeterias), six public and private educational colleges (including student canteens and teacher lounges), nine government buildings (including working offices, lobbies and staff cafeterias), six recreational venues (two bars, two restaurants [one of which was a waterpipe café] and two fast food outlets) and three public transportation buses. visits to the government, educational and health buildings, as well as the public buses, were made between 7 july and 12 august 2010 at times of typical occupancy (9:00 am to 2:00 pm), while visits to the recreational sites were made between 10:00 pm and 1:00 am. the study was conducted by two trained personnel using a belt-mounted laser photo meter sidepak® personal aerosol monitor am510 (tsi inc., shoreview, minnesota, usa) that measured the concentration of suspended shs particulate matter (pm2.5) in indoor air. 9 indoor air monitoring was conducted for 30 minutes at each of the selected venues. a 10-minute measurement of pm2.5 was also recorded outside each venue before and after entering so as to control for outdoor ambient contributions. a special form was developed to record the entry time, recording start time, recording end time and the exit time at each venue, in order to determine the duration of indoor and outdoor measurements. approximate dimensions (height, length and width) of the room under observation were noted. the number of active smokers, the number of cigarette butts on the floor and the presence, or lack of, a tobacco smell in the venue were also documented. daily recorded data on the sidepak® personal aerosol monitor am510 were downloaded and saved using the manufacturersupplied trakpro software, version 3.40 (tsi inc., shoreview, minnesota, usa). prior to each visit, a formal letter was sent to the administration of the selected government, health or educational facilities explaining the objectives of the study and requesting their assistance to facilitate the required work. no formal letter was given to the recreational venues or public buses as these venues are open and accessible to the public as long as the services provided are paid for. prior to the commencement of the study, ethical approval was obtained from the ethical & research committee of the oman ministry of health (#2/d/39/1288). the study was conducted in collaboration with the johns hopkins bloomberg school of public health and the eastern mediterranean regional office of the who. results a total of 30 venues were monitored for an overall duration of 2,400 minutes. it was found that 83% of the recreational venues included in the study had visible ‘no smoking’ signs displayed in the venue, while active smokers were noticed in 17% of the recreational venues and a tobacco smell detected in 33%. in public buses, 67% exhibited ‘no smoking’ signs with no noticeable cigarette butts or tobacco smell [table 1]. of all the studied public venues, evidence of smoking was found in only one building: a café serving waterpipes for smoking. this venue had an average pm2.5 level of 256 µg/m 3, which was 64 times higher than the indoor venues where no smoking was observed [table 2]. the waterpipe café was the venue where the highest concentration of pm2.5 was detected (20 times higher than the concentration in the outdoor control area), followed by public buses (on average 1.8 times higher than outdoor control areas). the concentration of pm2.5 was lowest in educational, table 1: observational findings of tobacco use in public indoor venues by venue type in muscat, oman, 2010 venue type n frequency in % smoking cigarette butts tobacco smell signs prohibiting smoking educational colleges 6 0 0 0 100 government hospitals 6 0 0 0 100 government public offices 9 0 0 0 100 transportation 3 0 0 0 67 recreation 6 17 0 33 83 measuring secondhand smoke in muscat, oman e290 | squ medical journal, may 2015, volume 15, issue 2 places (schools, hospitals, government offices and public buses).11 shs is a pollutant that causes serious illnesses in adults and children.12 there is no risk-free level of shs exposure; even brief exposure can be detrimental to human health.13 in the current study, the average pm2.5 level detected in the recreational venue where smoking was observed (the waterpipe café), was 256 µg/m3 over a period of 30 minutes. as such, visitors to this venue would be exposed to levels 10 times higher than the acceptable limits for a whole day (25 µg/m3), as defined by the who.12 similar findings of high average pm2.5 levels were reported from recreational sites in bahrain (200 µg/m3), pakistan (200 µg/m3), djibouti (250 µg/m3) and sudan (2,000 µg/m3).11 on the other hand, lower average pm2.5 levels were reported from recreational venues in yemen (30 µg/ m3), iran (50 µg/m3) and iraq (70 µg/m3) than the average levels reported in the current study.11 of all of the recreational venues included in the current study, the waterpipe café was the only place where smoking was observed and where high levels of pm2.5 were recorded. thus, in muscat, such cafés appear to be the main source of exposure to shs in indoor public places and are in clear violation of the 2010 local municipal law against smoking in indoor public venues. public buses displayed the lowest proportion (67%) of signs prohibiting smoking compared to schools, health facilities and other public places. throughout 2009 and 2013, the oman national tobacco control committee (ntcc) printed and freely distributed ‘no smoking’ sign stickers to selected government and private sector businesses to display in indoor public areas. thus, public transport facilities might have a higher display rate of such signs if the ntcc worked closely with the national transport authorities. to further facilitate and maintain good compliance with legislation designating smoke-free public places, there is a need for national health authorities to consistently raise awareness and inform the public about the dangers of shs exposure. policymakers should also consider extending the current ban on indoor smoking to include other public places, such as those accessible to children or mass-gatherings, such as open-door sport events. fully enforcing existing smoke-free laws and policies with effective and deterrent penalties for violators may enhance the implementation of these laws in the muscat governorate and beyond. regular monitoring and evaluations of compliance to 100% smoke-free policies is paramount to the success of any national tobacco control programme. health and government venues (on average three to four times lower than the outdoor control areas). discussion this is the first study to provide a brief examination of shs levels in 30 venues within the governorate of muscat in oman. no evidence of smoking was found inside the selected colleges, hospitals, government offices or public buses. despite the lack of comprehensive national legislation for tobacco control in oman, several of the examined facilities (with the exception of a waterpipe café) appeared to be fully compliant with the guidelines for article 8 of the fctc.10 this may be attributed to the recent law passed by the muscat municipality council which banned smoking in all indoor public places, as well as several ministerial decisions to ban smoking in educational, health and public transportation facilities.8 similar educational establishments in bahrain and iran were also found to have no evidence of shs when measured using identical methods.11 however, in other eastern mediterranean countries, such as djibouti, iraq, pakistan, sudan and yemen, smoking was observed with high levels of pm2.5 detected in similar public table 2: concentrations of particulate matter in selected indoor public venues in muscat, oman, 2010 smoking observed per venue type n pm2.5 concentration in µg/m 3 mean min median max educational colleges no 6 4 0 3 11 yes 0 government hospitals no 6 5 2 4 9 yes 0 government public offices no 9 6 3 4 11 yes 0 transportation no 3 20 4 22 34 yes 0 recreation no 5 13 6 10 22 yes 1 256 256 256 256 outdoor/ control 30 13 3 12 37 pm 2.5 = particulate matter; min = minimum; max = maximum. jawad a. al-lawati, yusuf al-thuhli and farrukh qureshi online brief communication | e291 the 2007 global youth tobacco survey reported that 29.8% of males and 25.2% of females aged between 13 and 15 years old in oman were exposed to shs outside of their homes.14 as such, a further survey with a wider scope than the current study is warranted to gauge current levels of exposure to shs and to further evaluate the recent municipal law banning smoking in indoor public areas in muscat. the current study had several limitations. first, the venue selection was arbitrary and did not follow a random sample selection from a sampling frame. this may have led to an underestimation of shs levels. second, the administrations of the government, health and educational venues were informed of the date of the monitoring visit. this may have biased results and also led to an underestimation of shs levels at these venues. however, this study also measured public smoking behaviours and these individuals visited the selected facilities at random. thus, the authors believe that this bias would have been minimal, if it occurred at all. third, the pm2.5 measurements in this study were not specific to tobacco smoke but also included pollutants from other sources, such as cooking, vehicles and other ambient/background sources. however, this bias was minimised by avoiding measurements where such pollutants co-existed and by measuring ambient outdoor pm2.5 levels. conclusion all indoor public places assessed in this study appeared to adhere to the municipal smoking ban in muscat, with the exception of a café serving waterpipes for smoking in indoor areas. the enforcement of smokefree policies in recreational venues in oman needs to be urgently re-examined in order to protect the health of the visitors and workers in such venues. efforts are needed to ensure that waterpipe cafés comply with the municiapal smoke-free indoor law of 2010. enforcing this law will fulfil one of oman’s main obligations towards article 8 of the fctc. a c k n o w l e d g m e n t s the authors would like to acknowledge that a brief summary of the results of this study were published in a ministry of health publication designed for the general public. this report can be found at the national tobacco control committee office, alkhuwair, muscat, oman. the authors would like to thank the who office in oman for their support during the study as well as dr ruth mabry for the critical comments on this manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. world health organization. global health risks: mortality and burden of disease attributable to selected major risks. from: www.who.int/healthinfo/global_burden_disease/globalhea lthrisks_report_full.pdf accessed: jul 2014. 2. world health organization. global status report on noncommunicable diseases 2010. from: www.who.int/nmh/ publications/ncd_report_full_en.pdf accessed: jul 2014. 3. world health organization. why tobacco is a public health priority. from: www.who.int/tobacco/health_priority/en/ accessed: jul 2014. 4. world health organization. mpower brochure: protect people from tobacco smoke. from: www.who.int/tobacco/ mpower/publications/en_tfi_mpower_brochure_p.pdf?ua=1 accessed: jul 2014. 5. united states department of health and human services. the health consequences of involuntary exposure to tobacco smoke: a report of the surgeon general. from: www.surgeongeneral.gov/library/reports/secondhandsmoke/ fullreport.pdf accessed: jul 2014. 6. oman ministry of legal affairs. the royal decree (20/2005) for oman's accession to the world health organization framework convention on tobacco control. official gazette 2005; 786:52. 7. world health organization. who framework convention on tobacco control. from: www.who.int/fctc/text_download/en/ accessed: jul 2014. 8. muscat municipality council. administrative decision 10/2010 for the designation of enclosed places under the local law 2/2009 regulating smoking in enclosed public places. muscat, oman: muscat municipality council. 9. tsi. sidepak personal aerosol monitor am510. from: www.tsi. com/productview.aspx?id=23270 accessed: jul 2014. 10. world health organization guidelines for implementation of the framework convention on tobacco control. from: http:// www.who.int/fctc/treaty_instruments/adopted/guidel_2011/ en/ accessed: jul 2014. 11. world health organization regional office for the eastern mediterranean. clearing the air: measuring secondhand smoke. from: www.emro.who.int/images/stories/tfi/ documents/fact_sheets/fs_shs_emr/fs_shs_emr_ mar_2012.pdf accessed: jul 2014. 12. world health organization. who air quality guidelines for particulate matter, ozone, nitrogen dioxide, and sulphur dioxide. global update 2005. from: whqlibdoc.who.int/ h q / 2 0 0 6 / w h o _ s d e _ p h e _ o e h _ 0 6 . 0 2 _ e n g . p d f ? u a = 1 accessed: jul 2014. 13. centers for disease control and prevention. health effects of secondhand smoke. from: www.cdc.gov/tobacco/data_ statistics/fact_sheets/secondhand_smoke/health_effects/ index.htm#overview accessed: aug 2014. 14. al-muzahmi sn, el-aziz sa, al-lawati ja, al-thuhli ys, foad dh. results of the global youth tobacco survey in oman: report of the sultanate of oman. muscat, oman: ministry of health. clinical & basic research sultan qaboos university med j, november 2013, vol. 13, iss.4, pp. 510-519, epub. 8th oct 13 submitted 16th mar 13 revision req. 30th apr & 24th jun 13; revision recd. 2nd jun & 27th jun 13 accepted 7th jul 13 1department of physical education, college of education, sultan qaboos university, muscat, oman; 2exercise physiology laboratory, department of physical education & movement sciences, college of education, king saud university, riyadh, saudi arabia; 3food science & nutrition department, college of agricultural & marine sciences, sultan qaboos university, oman; 4arab center for nutrition, manama, bahrain, and nutrition & health studies unit, deanship of scientific research, university of bahrain *corresponding author e-mail: hakilani@squ.edu.om عادات منط احلياة الغذاء و النشاط البدين ومدة النوم بني املراهقني العمانيني ها�صم الكيالين، وهزاع الهزاع، وم�صطفى وايل، وعبد الرحمن م�صيقر )sd( ومدة النوم ، )eh( وعادات الغذاء )pa( امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل التحقيق يف عادات منط احلياة والن�صاط البدين ب�صكل العمانيني املراهقني من 802 ا�صتقطاب مت الطريقة: املتغريات. هذه يف اجلن�صني بني الفروق ودرا�صة العمانيني، املراهقني بني ع�صوائي )442 اإناث و 360 ذكور(،ترتاوح اأعمارهم ما بني 15-18 �صنة. وجرى تقييم موؤ�رشات قيا�س اجل�صم الب�رشي، وم�صتوى الن�صاط البدين، وعادات الغذاء eh ومدة النوم sd بوا�صطة اال�صتبيان املعد لنمط احلياة يف �صن املراهقة العربية)atls(، كما طبقت اأي�صًا لديهم احلياة منط كان للدرا�صة اخلا�صعني اأن من الرغم على اأنه النتائج اأظهرت الغذاء. النتائج: لتقييم الكمية �صبه التكرارات ا�صتبانة خاماًل )عدم وجود الن�صاط البدين، ومتو�صط �صاعات النوم 6.7، وا�صتهالك االأطعمة العالية ال�صعرات احلرارية(، اإال اأن موؤ�رش كتلتهم اجل�صمية كان طبيعيًا )اأقل من kg/m2 25(. ولقد تبني اأن الذكور اأكرث من ال�صعف ن�صاطًا من االإناث. فيما يتعلق بعادات الغذاء، كانت هناك بع�س االختالفات بني اجلن�صني، اإال يف تناول منتجات االألبان واللحوم حيث تناول %62.5 و %55.5 من الذكور اأكرث من 3 ح�ص�س على التوايل مقارنة ب %18.78 و %35.2 من االإناث على التوايل. باالإ�صافة اإىل ذلك، كانت م�رشوبات الطاقة، وا�صتهالك البطاط�س، وتناول داللة ذات م�صتقلة متنبئات الن�صاط حتدد التي واالأ�صباب والطول، اخل�رش/الطول، ون�صبة واالإفطار القوية البدنية واالأن�صطة احللويات، اإح�صائية ملوؤ�رش كتلة اجل�صم )p >0.05( بالن�صبة للذكور واالإناث. اخلال�صة: ك�صفت هذه الدرا�صة عن ارتفاع معدل انت�صار ال�صلوكيات اخلاملة وانخفا�س م�صتوى الن�صاط البدين بني عينة البحث، وخا�صة بني االإناث. كما مت العثور على نطاق وا�صع من العادات الغذائية غري ال�صحية بني كال اجلن�صني. هناك حاجة ما�صة ملزيد من البحوث وكذلك �صيا�صة وطنية لتعزيز منط احلياة ال�صحي والن�صاط البدين و العادات الغذائية وتثبيط ال�صلوكيات اخلاملة بني املراهقني العمانيني. مفتاح الكلمات: املراهقون؛ عمان؛ منط احلياة؛ الن�صاط البدين؛ العادات الغذائية؛ موؤ�رش كتلة اجل�صم؛ مدة النوم. abstract: objectives: this study aimed to investigate the lifestyle habits—physical activity (pa), eating habits (eh), and sleep duration (sd)—of omani adolescents, and to examine gender differences in such variables. methods: 802 omani adolescents (442 females and 360 males), aged 15‒18 years were randomly recruited. anthropometric indices, pa level, and eh and sd were evaluated by the arab teenage lifestyle questionnaire. a semi-quantitative food frequency questionnaire for dietary assessment was also administered. results: the results showed that although the study subjects had a sedentary lifestyle (lack of pa, average of 6.7 hours sleep, and consumption of high calorie foods), they maintained a normal body mass (less than 25 kg/m2). males were more than twice as active as females. with respect to eh, there were few gender differences, except in dairy and meat consumption where 62.5% and 55.5% of males consumed more than 3 servings, respectively, compared to 18.78 % and 35.2% of females, respectively. in addition, waist/height ratio, height, reasons for being active, energy drinks, potato consumption, eating sweets, vigorous pa and breakfast ehs were statistically significant independent predictors for bmi, p <0.05 for both males and females. conclusion: this study revealed a high prevalence of sedentary behaviors and a low level of physical activity, especially among females. unhealthy dietary habits were also widely found among both genders. there is an urgent need for more research as well as a national policy promoting active living and healthy eating and discouraging sedentary behaviour among omani adolescents. keywords: adolescent; oman; lifestyle; physical activity; dietary habits; index, body mass; sleep; habits. lifestyle habits diet, physical activity and sleep duration among omani adolescents *hashem kilani,1 hazzaa al-hazzaa,2 mostafa i. waly,3 abdulrahman musaiger4 advances in knowledge the results of this research supply comprehensive and recent data on physical activity (pa)/inactivity patterns, eating habits and sleep duration in omani adolescents, and their relationships to risk factors measures. these data represent baseline lifestyle characteristics to be used for potential intervention programmes in oman. information on the lack of pa, low amounts of sleep, the consumption of high calorie foods and a normal body mass index could be used for further research, including on the heritability of the omani phenotype. lifestyle habits diet, physical activity and sleep duration among omani adolescents 511 | squ medical journal, november 2013, volume 13, issue 4 worldwide, a lifestyle that incorporates a healthy diet and physical activity (pa) is well-documented as being preventative of non-communicable diseases (ncds) including type 2 diabetes (t2dm) and heart diseases. lifestyle and well-being patterns are rooted in the habits of late adolescence and early adulthood and affect health in the long term. in 2005, the world health organization (who) estimated that 61% of deaths (35 million) and 49% of the global burden of diseases were attributable to ncds, with 80% of such deaths occurring in low and middle-income developing countries where health resources are limited.1 oman, located in the southeastern corner of the arabian peninsula, is one of the developing countries in the arabian gulf. oman’s population numbers 3,090,150 of which 51% are under 24 years old.2 in terms of its health profile, oman has moved in less than half a century from a country dominated by infectious diseases to a country burdened by ncds, including cardiovascular diseases, t2dm, obesity, hyperlipidaemia, and metabolic syndrome disorders.3 overweight and obesity are linked to the aetiology of ncds, including t2dm, and are two conditions for which omanis are considered a high-risk group.3,4 the westernisation of lifestyle is associated with a high incidence of obesity and ncds in the gulf countries, including oman.5 the risk of ncds among the arab population is reported to start at adolescence and is indicated by a high body mass index (bmi).6,7 physical inactivity and lack of knowledge about healthy and energydense foods might be considered risk factors for overweight and obesity among omani adolescents, yet there are little data on the lifestyle habits of omani adolescents.8,9 it is important to monitor the lifestyle habits of young adolescents, as recent research has indicated an association between young people’s lack of exercise, unhealthy dietary behaviour, self-imposed sleep reduction and an increased risk of developing ncds.1,10 in addition, recent research on adolescents in saudi arabia has observed a high prevalence of sleep deprivation which was significantly associated with an increased risk of overweight and obesity.11,12 epidemiological studies suggest that self-reported sleep complaints are associated with an increased relative risk of cardiovascular morbidity and mortality.13 according to the national commission on sleep disorders research and reports from the national highway safety administration, highprofile accidents can partly be attributed to people suffering from a severe lack of sleep.14 this is a matter of alarm as those subjecting themselves to self-imposed sleep curtailment are at an increased risk for such accidents as well as likely to develop a sedentary lifestyle and obesity. it is helpful to understand the omani risk factors and relate those to our results. indeed, omani lifestyle changes during the last 5 decades have influenced the culture, and it has become apparent that certain phenotypical factors seem to have influenced the omani population’s anthropometry. few studies have tackled the problem of sedentary behaviours, limited pa, sleep duration (sd) or the eating habits (eh) of arab adolescents. therefore, the aim of this study was to investigate the lifestyle habits, including pa, eh and sd of omani adolescents, and to examine the gender differences in such variables. we also sought to address the following specific questions: (1) what are the current lifestyle habits related to diet, pa/inactivity, and sleep deprivation among omani adolescents? (2) are there associations between lifestyle habits and bmi or overweight? (3) are there differences between male and female lifestyles? methods the participants were drawn from students attending secondary schools in the city of muscat, the capital of oman. the data were collected during application to patient care the information in this study will stimulate society and healthcare providers to encourage increased pa, reduced electronic screen exposure, healthy dietary choices and sufficient amounts of sleep. awareness of sleep deprivation may reduce automobile accidents, a significant percentage of which occur due to lack of sleep. this study provides information on characteristic lifestyle patterns for the consideration of oman’s ministry of education, physical education curriculum supervisors, public health authorities, policy makers and healthcare providers. hashem kilani, hazzaa al-hazzaa, mostafa waly and abdulrahman musaiger clinical and basic research | 512 october and november 2010. two questionnaires were simultaneously used for the study’s cohort: the arab teens lifestyle study (atls) for the assessment of pa, anthropometrics and sleeping hours, and a semi-quantitative food frequency questionnaire (ffq) for dietary intake assessment.6 anthropometric measurements (body weight, height and waist circumference [wc]) were also taken. this research is part of the atls, an epidemiological, cross-sectional and multicentre project designed to study the lifestyle of adolescents living in major arab cities.6 the minimum sample size needed (± 0.05 of the population proportion with a 95% confidence level) was calculated as 770 adolescents, assuming the population proportion to be 0.50. the sample size was estimated using epi info 2008 (centers for disease control and prevention, atlanta, georgia, usa) and was based on a population of 40,000 students. a multistage stratified-cluster random sampling technique was used to select the required sample. at the first stage, stratification was determined based on gender and geographical locations. therefore, 6 schools were randomly selected from the three major geographical areas in muscat, the northern, central and southern areas. to select the schools, a systematic random sampling procedure was used. later on, classes were selected at each grade (level) using a simple random sampling design. thus, we selected 18 classes (9 classes each at boys’ and girls’ schools). the study subjects were recruited on a voluntary basis. the inclusion criteria required participants to be healthy, and free of endocrine disorders and chronic diseases. this inclusion criterion was important since we wanted to examine the lifestyle habits of healthy people. the exclusion criteria included physical deformities and chronic diseases. this information was obtained from the school students’ medical records. the total sample size consisted of 802 adolescents (males = 360; females = 442). the study protocol and procedures were approved by the office of the advisor for academic affairs at sultan qaboos university (squ) as well as by the ministry of education’s directorate general of school education in the muscat governorate. we also obtained school and parent consent for conducting the survey as well as the agreement of students to participate. anthropometric variables included body weight, height and wc. measurements were taken in the morning by trained researchers using standardised procedures. all research assistants were volunteers from the physical education department at the college of education at squ. body weight was measured to the nearest 100 g with minimal clothing and without shoes, using a calibrated portable scale. height was measured to the nearest cm with the subject in the full standing position without shoes and using a calibrated portable measuring rod. bmi is defined as the individual's body mass divided by the square of their height (kg/m2). the international obesity task force’s (iotf) ageand sexspecific bmi reference values were used to define overweight and obesity in adolescents aged 14–17 years. for adolescents 18 years and older, we used the cut-off points for adults (normal, overweight and obese, based on 18–24.9, 25–29.9, and ≥30 kg/ m2, respectively). wc was measured horizontally at navel level and at the end of gentle expiration to the nearest 0.1 cm using a non-stretchable measuring tape.6 the atls research instrument was used to record lifestyle information.3,7 the questionnaires included items for the assessment of pa, sedentary behaviours, ehs and sd. to ensure accurate and consistent measurements throughout this study, the research assistants were trained and provided with a standardised written protocol. different pas were assigned metabolicequivalent (met) values based on a compendium of pas and the compendium of pas for youth.6 moderate-intensity pas include normal paced walking, brisk walking, recreational swimming, household activities, and recreational sports such as volleyball, badminton and table tennis. moderateintensity recreational sports were assigned an average met value equivalent to 4 mets. household activities were given an average met value of 3. slow walking, normal paced walking and brisk walking were assigned values of 2.8, 3.5 and 4.5 mets respectively, based on the modified met values in the compendium of pa for youth.15 vigorous-intensity pas and sports include stair climbing, jogging, running, cycling, self-defense, weight training, soccer, basketball, handball, and singles tennis. vigorous-intensity sports were assigned an average met value of 8. to measure the lifestyle habits diet, physical activity and sleep duration among omani adolescents 513 | squ medical journal, november 2013, volume 13, issue 4 participants’ levels of pa, the total mets-mins per week and the mets-mins per week spent in each of the moderateand vigorous-intensity pas were used. for pa cut-off values, three categories (low, medium and high activity) based on tertiles of total mets-mins per week, mets-mins per week from vigorous-intensity pa, and mets-mins per week from moderate-intensity pa were used. inactivity was defined as 1,680 mets (60 mins per day × 7 days per week × 4 mets). the atls instrument also included questions on sedentary behaviours, assessing the typical amount of time spent per day on screen-related activities, including television viewing, electronic games, and computer and internet use. participants were asked to state their typical time (hrs) per week spent on these activities without differentiating between weekdays and the weekend. for total screen-viewing time cut-off values, we used the american academy of paediatrics (aap) guidelines of a maximum of 2 hours per day.6,7 the retrospective dietary intake of the study participants was estimated using a semiquantitative ffq where all subjects were asked to report the frequency and portion size for each food item consumed over the past 6 months.16 this period was chosen to take into account the seasonal variation in food consumption. also, all study subjects were asked if they had changed their diets from their usual routines in the last 12 months. the ffq was adapted according to portion sizes based on commonly used household serving units/ utensils in oman, and was tested for its validity, reliability and reproducibility before conducting the study.17 the different food groups included in the questionnaire were as follows: breads/cereals, vegetables, fruits, meat/meat substitutes, milk/dairy products, desserts, beverages, sandwiches, and traditional omani dishes. the collected dietary data were categorised into two groups: (1) food group analysis, or the number of daily servings of food groups based on the frequency of consumption. all participants were subsequently grouped according to the food guide pyramid from usa departments of agriculture and health and human services.18 (2) nutrient density, or the percentage of energy contribution from the daily macronutrients intake to the total energy intake. the food processor software, version 10.2 (esha research, salem, oregon, usa) was used to calculate the means of daily nutrient intake of macronutrients and total energy intake as estimated from the portion sizes and nutrient content for all foods reported by each participant. all participants were asked about the number of typical sleeping hours per day (night and day) using a self-reported questionnaire included in the atls. no differentiaton between weekdays and weekends in sleeping hours was ascertained. in this study, insufficient sleep was defined as sleeping less than 7 hours per night according to the definition of the national sleep foundation for the adolescent population.14 data were presented as means ± standard deviation (sd). statistical analysis was conducted using the statistical package for social sciences (spss), version 19 (ibm, corp., chicago, il, usa). the chi-square test was used to analyse categorical variables. the one-way analysis of variance (anova) followed by freeman-tukey’s test or the unpaired student’s t-test were used for analysing continuous variables. multinomial logistic regression analysis was used where the dependent variable was bmi. a p value of <0.05 was considered statistically significant. results the descriptive characteristics of the participants are shown in table 1. all the omani adolescents who participated in this study were similar in age (17.1 ± 1.2 years for males and 16.7 ± 1.3 years for females). the percentage of females in the sample slightly exceeded that of males (55.1% versus 44.9%). although males and females had similar values for bmi and wc, the prevalence of overweight table 1: general characteristics of the study subjects variable male (n = 360) female (n = 442) age in years 17.1 ± 1.2 16.7 ± 1.3 weight in kg 59.6 ± 13.1* 53.2 ± 11.1 height in cm 168.9 ± 7.6* 158.3 ± 6.5 bmi in kg/m2 20.9 ± 4.2 21.3 ± 4.4 wc in cm 69.8 ± .5 72.9 ± .5 total screen time in hrs/day 2.86 ± 2.3 3.70 ± 2.9* data are means ± standard deviation; *p <0.05. bmi = body mass index; wc = waist circumference. hashem kilani, hazzaa al-hazzaa, mostafa waly and abdulrahman musaiger clinical and basic research | 514 or obesity was higher in females than males, but only by a very small proportion. however, the total screen time was also higher in females than males (3.7 versus 2.8 hours/day, respectively). table 2 shows that the intake of energy drinks, sweets, french fries and potato chips based on ≥3 times/week consumption was higher in males than in females and significantly different (p <0.05). there was also a higher percentage (64.9%) of females who skipped breakfast regularly (based on a response of doing so >4 times/week), while a high percentage of both genders consumed fast food. the assessment of pa levels was based on metabolic equivalent levels and the routine exercise practices of males versus females. the activity levels based on <1,680 mets (inactive) was higher in females than males and significantly different (76.9% versus 33.3%). although the amount of weekly exercise time was limited for both genders, males engaged in pa and routine exercise more frequently than females (p <0.05) [table 2]. despite the fact that subjects were classified as normal, as indicated by bmi, the frequency of overweight and obese subjects was 11.5% for males and 18.1% for females. no significant percentages of underweight were found in the male or female respondents (0% and 2%, respectively). in addition, the mean sd was 6.72 hrs per day with no significant difference between males and females. about 57.6% of the participants had less than 7 hours of sleep per day with no significant difference relative to gender, while approximately 77.1% got ≤8 hours of daily sleep. a total of 42.5% of subjects (in both males and females) slept less than the mean while only 23% slept longer than the mean. females spent more time than males (55.2% versus 44.8%, respectively) on total screen time. females also had a higher percentage of screen time and sitting in comparison to males (24.8% versus 17.9%, respectively) [figure 1]. nevertheless, the males spent more time on the computer than watching tv as compared to females. highly significant differences were observed table 2: frequency of selected variables among the enrolled study subjects variable male (n = 360) % female (n = 442) % energy drinks 65* 47 sweets ≥ 3 times/week 65* 47.3 potato fries/chips ≥ 3 times/ week 65* 47.3 fast food consumption, based on < or > 4 times/week 50.2* 63.3 skipping breakfast, based on < or > 4 times/week 36.9* 64.9 activity levels, based on < 1, 680 mets (inactive) 33.3* 76.9 bmi (normal) 87.2 87.5 bmi (overweight) 6.3 12 bmi (obese) 5 9.2 sleep < 7 hrs/day (mean 6.76) 41.5 43 *p <0.05. met = metabolic-equivalent; bmi = body mass index. table 3: frequency of consumption of different categories of food by study subjects food group and number of servings/ day males n = 360 females n = 442 test n % n % bread, cereal, rice and pasta <6 40 11.11 50 11.31 χ2 = 0.001 p = 0.99 6‒11 285 79.17 348 78.74 ≥11 35 9.72 44 9.95 vegetables <3 35 9.72 43 9.73 3‒5 281 78.06 347 78.51 χ2 = 0.038 p = 0.98 ≥5 44 12.22 52 11.76 fruit <2 60 16.67 71 16.07 2‒4 250 69.44 308 69.68 χ2 = 0.067 p = 0.96 >4 50 13.89 63 14.25 dairy (milk, yogurt and cheese products) <2 12 3.33 10 2.26 2‒3 123 34.17 416 94.12 χ2 = 79.29 p = 0.001* ≥3 225 62.5 16 3.62 meat (red meat, poultry, fish, dry beans, eggs and nuts) <2 33 9.17 40 9.05 χ2 = 31.55 p = 0.001* 2‒3 127 35.28 319 72.17 ≥3 200 55.55 83 18.78 *p<0.05. lifestyle habits diet, physical activity and sleep duration among omani adolescents 515 | squ medical journal, november 2013, volume 13, issue 4 between males and females in the area of consumption of dairy and meat groups (p <0.05). of the male subjects, 62.5% consumed more than 3 servings of dairy products per day as compared to 3.62% of female subjects [table 3]. the same pattern was observed for meat consumption, where it was found that 55.55% of male subjects consumed more than 3 servings of meat products and substitutes/ day as compared to 18.78% for female subjects. on the other hand, no significant differences were observed in the daily intake of servings from the cereal and milk groups (p >0.05). figure 2 illustrates the nutrient density as presented by the percentage of energy derived from each macronutrient to the daily total energy intake. it was found that for male subjects, the nutrient density for carbohydrates, fat and protein was 55.46 ± 7.93, 30.43 ± 6.66, and 22.54 ± 4.48, respectively. the same pattern was observed for female subjects: 51.12 ± 8.42 for carbohydrates, 22.61 ± 5.93 for fat and 18.67.54 ± 3.34 for protein. the difference was significantly higher among male subjects versus female subjects based on one-way anova analysis followed by the freeman-tukey’s test (f = 38.33, r square = 0.9623, p = 0.007). the association between bmi and other independent predictors for weight gain was determined using the multinomial logistic regression analysis stepwise method as presented in table 4. the model presented in this table for males shows that participants’ waist/height ratios and height; reasons for being active; consumption of breakfast, energy drinks, potato products, and sweets; frequency of vigorous pa and breakfast eh were the highest independent predictors for bmi levels (p <0.05). the same pattern was observed for females. meanwhile, other study variables were not associated with bmi (p >0.05). discussion our results showed that although the study subjects had a sedentary lifestyle (lack of pa, low number of sleeping hours and consumption of high caloric foods), they maintained a normal bmi of <25 kg/ m2. if this lifestyle pattern were to prevail in the long term, the genetic predisposition might synergise with environmentally-driven factors like pa and diet in the aetiology of obesity and overweight among omani adolescents; thus, this may be considered a multifactorial health problem in oman. in addition, the results of this study revealed that raised bmi levels are found less frequently than in other similar studies in the middle east; furthermore, trudeau et al. found that adolescents appear to experience a marked decline in pa as they get older.19 changes occurring during adolescence, including the adoption of positive and negative health habits, are acquired before adulthood.19 in subsequent studies, numerous researchers have shown that the rate of children and adolescents table 4: the association of body mass index with different variables among males and females b (standard error) standardised coefficients p value independent predictors males waist/height 167.47 (9.11) 0.670 <0.001* height in m 90.933 (5.887) 0.554 <0.001* reasons for being active 0.945 (0.270) 0.125 <0.001* energy drinks 1.375 (0.334) 0.158 <0.001* potato snacks 1.127 (0.294) 0.165 <0.001* sweets 0.694 (0.286) 0.101 0.016* vigorous exercise mins/ week 0.007 (0.003) 0.084 0.023* breakfast intake 1.051 (0.509) 0.075 0.040* independent predictors females waist/height 4.609 (0.371) 0.543 0.000* height in m 0.879 (0.346) 0.110 0.012* reasons for being active 0.52 (0.018) 0.127 0.004* energy drinks -1.287 (0.471) 0.105 0.007* potato snacks 0.469 (0.187) 0.097 0.013 sweets 0.028 (0.010) 0.120 0.007* vigorous exercise mins/ week 0.0 (0.0) 0.169 0.006* breakfast intake 0.077 (0.027) 0.127 0.004* *p <0.05. hashem kilani, hazzaa al-hazzaa, mostafa waly and abdulrahman musaiger clinical and basic research | 516 engaging in pa has decreased over recent years due to the increasing influence of sedentary activities such as television viewing, internet surfing and video games.20 in support of this trend, gordonlarsen et al. found that adolescents spend less time in physical education sessions than younger children.21 although some health benefits can occur through an average of 30 minutes of pa per day, pa guidelines for children and adolescents recommend that they should participate in at least 60 mins of moderate to vigorous pa on a daily basis.22 in the present study, the cut-off score of 1,680 mets-mins per week was used to correspond to one hr of daily moderate-intensity pa, and 2,520 mets-mins per week was used as a cut-off score corresponding to one hr of daily moderateto vigorous-intensity pa.11 based on these cut-off scores, we found a considerably higher prevalence of physical inactivity, especially among omani females. about 40% of the males and less than 30% of the females met the current recommendations of one hr daily of moderate-intensity pa. such high rates of low pa levels represent an area of great concern because of the association of inactivity with increased cardiovascular and metabolic risk factors in children and adolescents.23 major factors that contribute to youth inactivity in oman include a reliance on cars rather than walking for short-distance travel, including trips to and from school, and the limited quality of physical education programmes in schools, especially for girls. the rate of private car ownership is as high as 69% among omanis.24 females in the present study were found to be not only significantly more sedentary than males, but they were also much less physically active, especially in terms of vigorous pa. insufficient vigorous pa was shown to be a risk factor for higher bmi for adolescent boys and girls. thus, our findings suggest that omani figure 1: low, moderate and high screen time for male and female subjects. *significantly different = p <0.05. figure 2: nutrient density, the percentage of energy contribution from different macronutrients consumed by study subjects in comparison to their total energy intake. cho = carbohydrates. lifestyle habits diet, physical activity and sleep duration among omani adolescents 517 | squ medical journal, november 2013, volume 13, issue 4 females may be a good target for pa interventions. it is noteworthy that the pa levels of arab females, irrespective of the region, have generally been reported to be much lower than those of males.25 families may not encourage females to take part in pa for cultural reasons.26 another study showed that males were found more likely than females to participate in sports and pa.8 the prevalence of sedentary behaviours found in the present study among omani adolescents was remarkably high. the aap has expressed concern about the amount of time that children and adolescents spend viewing tv and has issued guidelines recommending that screen time should not exceed 2 hours per day.27 it seems that males spend more time sitting at computers than females, but the opposite is true of tv-viewing habits. females spend more time sitting and watching tv than males [figure 1]. both the males and females in our study exceeded the aap recommendations for daily screen time. the implication of this finding is that there is a need to reduce the time spent by adolescents on tv viewing and computer use. excessive tv viewing in adolescence appears to be related to an unfavourable cardiovascular risk factor profile.28 in addition, it is now recognised that sedentary behaviours are associated with other harmful health outcomes than those that are attributable to the lack of pa.8 the females in the present study spent on average more of their leisure hours on screen time than the males indicating that females are less active than males and prone to a sedentary lifestyle. similarly in the united arab emirates (uae) watching tv was found to be the predominant leisure time pursuit among 14 to 16-year-old adolescents in the united arab emirates, with an average of 2.5 hrs viewed per day.29 the male subjects in this study indicated they had a diet with a high frequency consumption of red meat and saturated fat, and a moderate consumption of fruits and vegetables as compared to the female subjects. the who global strategy for diet and physical activity recommendations call for achieving an energy balance, limiting the energy intake from fats, reducing the intake of free sugars and increasing fruit and vegetable consumption.30 in the present study, the prevalence of daily fruit and vegetable consumption by both genders was noticeably good [table 3] and was higher than that previously reported for adolescents in jeddah, saudi arabia, which amounted to 27.6% and 26.4% for fruits and vegetables, respectively.31 in the uae fruit and vegetable consumption was reported to range from 49–69% for both males and females.32 skipping breakfast is another unhealthy eh that was found to be very common in the present study. skipping breakfast was reported at 32% among omani adolescents from muscat. skipping breakfast was also shown to be prevalent in the usa and europe, ranging from 10–30% depending on the age-group, population and definition.33 the consumption of fast food more than three times per week was 50.2% and 63.3% for male and female adolescents in oman, respectively; therefore, interestingly, female students were more likely to consume fast food than males. these percentages are higher than the rate of fast food intake reported recently for other arab countries.34 the main findings of this study indicate that 42.5–57.6% of omani adolescents do not obtain enough sleep. the average sd (6.721 hrs/day) found among omani adolescents in the current study appears lower than that reported by saudi arabian or australian adolescents (ranging from 6.4–7.2 and 8.40–9.10 hrs/day for 14–19 and 15.5– 17.5 year olds, respectively).35 the findings of the present study showed that about half of the omani adolescents did not sleep 7 hrs nightly, while about 70% of the participants slept less than 8 hrs a night. in comparison with our findings, mcknight-eily et al. have reported that 68.9% of usa high school students get insufficient sleep (<8 hrs/day) on an average school day.36 in japan, the proportions of adolescent boys and girls who reported less than 6 hrs of daily sleep were 28.7% and 32.6%, respectively.37 among taiwanese adolescents, 54% reported that they slept less than the suggested 6–8 hrs per day.38 the reduced sd observed among omani adolescents in the current study may be attributed to several factors. adolescence is a critical period in which a growing sense of autonomy and increased socialisation may dominate life. our modern lifestyle, with round-the-clock satellite television programming and high-speed internet availability, along with the increased demands for more studying and homework, may distract adolescents from going to bed early. in our study we could not assess the relationship hashem kilani, hazzaa al-hazzaa, mostafa waly and abdulrahman musaiger clinical and basic research | 518 between short sleep and obesity and/or overweight due to the normal scores in our participants’ bmis and the low incidence of overweight. conclusion the present study reported on the prevalence of the several lifestyle factors among adolescents aged 15–18 years from public schools in muscat, oman. the findings of this study provide evidence of the high prevalence of sedentary behaviours and low levels of pa, especially among females. unhealthy eh were also widely found among both genders. furthermore, correlation analyses revealed that unhealthy behaviours, such as increased electronic screen time and unhealthy ehs, appear to aggregate in this group of omani adolescents. future investigations in other regions of oman, to test the effects of urban versus rural lifestyles, are needed before any national intervention plan could be drawn up. nonetheless, the promotion of a healthy lifestyle should be a national public health priority. in addition, there is an urgent need for national policy promoting active living and healthy eating while reducing sedentary behaviours among omani children and adolescents. future research needs to address the determinants of sedentary behaviours, pa and inactivity, and unhealthy ehs. future interventions should investigate whether the adoption of a healthy lifestyle by omani adolescents with sleep deprivation would improve the sleeping habits of 15–18-year-olds residing in rural areas versus the habits of those living in urban areas using muscat as an urban model. references 1. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 2. index mundi. oman demographics profile 2013. from: http://www.indexmundi.com/oman/demogra phics_profile.html accessed: jun 2013. 3. waly mi, ali a, essa mm, al-shuaibi y, al-farsi ym. the global burden of type 2 diabetes: a review. internat j biol med res 2010; 1:326–9. 4. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1—methodology, sociodemographic profile and epidemiology of non-communicable diseases in oman. oman med j 2012; 27:425–43. 5. musaiger ao, al-hazzaa hm. prevalence and risk factors associated with nutrition-related noncommunicable diseases in the eastern mediterranean region. int j gen med 2012; 5:199– 217. 6. al-hazzaa a, musaiger m, abahussain n, tayyem r, al sobayel h, alsulaiman n, et al. arab teens lifestyle study (atls): objectives, design, methodology and implications. diabetes metab syndr obes 2011; 4:417‒26. 7. al-hazzaa hm, musaiger a, atls group: physical activity patterns and eating habits of adolescents living in major arab cities. the arab teens lifestyle study. saudi med j 2010; 31:210‒11. 8. kilani h, waly m, yousef r. trends of obesity and overweight among college students in oman: a cross sectional study. sultan qaboos university med j 2012; 12:620–7. 9. kilani h, abu eisheh a. optimum anthropometric criterion for ideal body composition. squ med j 2010; 10:74–9 10. al-barwani s, al-abri m, al-hashmi k, al-shukeiry m, tahlilkar k, al-zuheibi t, et al. assessment of aerobic fitness and its correlates in omani adolescents using the 20-meter shuttle run test: a pilot study. sultan qaboos univ j sci res: med sci 2001; 3:77–80. 11. al-hazzaa hm, musaiger ao, abahussain na, alsobayel hi, qahwaji dm. prevalence of short sleep duration and its association with obesity among adolescents 15to 19-year olds: a cross-sectional study from three major cities in saudi arabia. ann thorac med 2012; 7:133–9. 12. al-hazzaa hm, abahussain na, al-sobaye hi, qahwaji dm, musaiger ao. physical activity, sedentary behaviors and dietary habits among saudi adolescents relative to age, gender and region. int j behav nutr phys act 2011; 8:140. 13. national sleep foundation. how much sleep do we really need? from: http://www.sleepfoundation.org/ article/how-sleep-works/howmuch-sleep-do-wereally-need accessed: oct 21, 2011. 14. national highway safety administration. commission on sleep disorders research epidemiological studies, meta-analysis, and review. washington, dc: us government printing office, 1998. 15. epstein lh, myers md, raynor ha, saelens be. treatment of pediatric obesity. pediatrics 1998; 101:554–70. 16. block g, hartman am, naughton d. a reduced dietary questionnaire: development and validation. epidemiology 1990; 1:58–64. 17. pietinen p, hartman am, haapa e, rasanen l, haapakoski j, palmgren j, et al. a self-administered food use questionnaire with a portion size picture booklet. am j epidemiol 1988; 128:655–66. lifestyle habits diet, physical activity and sleep duration among omani adolescents 519 | squ medical journal, november 2013, volume 13, issue 4 18. united states department of health & human services and united states department of agriculture (hhs/usda). dietary guidelines for americans. 6th ed. washington, dc: us government printing office, 2005. 19. trudeau f, laurencelle l, tremblay j, rajic m, shephard rj. daily primary school physical education: effects on physical activity during adult life. med sci sports exerc 1999; 1:111–7. 20. hassan o, al-kharusy w. physical fitness and fatness among omani schoolboys: a pilot study. sultan qaboos univ j sci res: med sci 2000; 2:37–41. 21. gordon-larsen p, mcmurray rg, popkin bm. determinants of adolescent physical activity and inactivity patterns. pediatrics 2000; 6:83–105. 22. physical activity guidelines advisory committee. physical activity guidelines advisory committee report washington, dc: u.s. public health service, 2008. 23. telama r, yang x. decline of physical activity from youth to young adulthood in finland. med sci sports exerc 2000; 9:1617–22. 24. ministry of the national economy. results of the family income and expenditure survey. muscat, oman: ministry of national economy, 2001. [report in arabic]. 25. kilani h, kingesly b. sports and jordanian women. 11th international conference for women in sport. alexandria, egypt, 13‒15 oct 2010. 26. mehana m, kilani h. enhancing physical education in omani basic education curriculum: rationale and implications, int j cross-discip sub educ (ijcdse) 2010; 1:2. 27. american academy of pediatrics: committee on public education. american academy of pediatrics: children, adolescents, and television. pediatrics 2001; 107:423–6. 28. isaac a, saginur m, hartling l, robinson jl. quality of reporting and evidence in american academy of pediatrics guidelines. pediatrics 2013; 131:732–8. 29. henry cj, lightowler hj, al-hourani hm. physical activity and levels of inactivity in adolescent females ages 11-16 years in the united arab emirates. am j hum biol 2004; 16:346–53. 30. world health organization. global strategy on diet, physical activity and health. geneva, switzerland: world health organization. wha57.17. 31. washi sa, ageib mb. poor diet quality and food habits are related to impaired nutritional status in 13to 18-year-old adolescents in jeddah. nutr res 2010; 30: 527–34. 32. bin zaal aa, musaiger ao, d’souza r. dietary habits associated with obesity among adolescents in dubai, united arab emirates. nutr hosp 2009; 24:437–44. 33. rampersaud gc, pereira ma, girard bl, adams j, metzl jd. breakfast habits, nutritional status, body weight, and academic performance in children and adolescents. j am diet assoc 2005; 105:743–60. 34. musaiger ao, miladi s. food consumption patterns and dietary habits in the arab countries of gulf. cairo: food & agriculture organization, regional office for the near east, 1995. 35. olds t, maher c, blunden s, matricciani l. normative data on the sleep habits of australian children and adolescents. sleep 2010; 33:1381–8. 36. mcknight-eily lr, eaton dk, lowry r, croft jb, presley-cantrell l, perry gs. relationships between hours of sleep and health-risk behaviors in us adolescent students. prev med 2011; 53:271–3. 37. ohida t, osaki y, doi y, tanihata t, minowa m, suzuki k, et al. an epidemiologic study of self-reported sleep problems among japanese adolescents. sleep 2004; 27:978–85. 38. huang ys, wang ch, guilleminault c. an epidemiologic study of sleep problems among adolescents in north taiwan. sleep med 2010; 11:1035–42. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e351–356, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.008. submitted 29 jun 14 revisions req. 13 oct 14 & 17 mar 15; revisions recd. 19 feb & 1 apr 15 accepted 9 apr 15 department of child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: asad99khan@yahoo.com تغري معدل البقاء للرضع املواليد قبل األسبوع 26 من احلمل دراسة مركز واحد اأ�سد رحمن، حممد عبدالطيف، �رسيف وعد اهلل �رسيف، حممد ف�سل اهلل، خلفان ال�سنيدي، اأ�سفاق اأحمد خان، �سعود اأحمد، ماثيو كريبايل، مازن اأبو عنزة، ما فلورديلزا بتكالن abstract: objectives: this study aimed to evaluate the changing survival rate and morbidities among infants born before 26 gestational weeks at the sultan qaboos university hospital (squh) in muscat, oman. methods: this retrospective study assessed the mortality and morbidities of all premature infants born alive at 23–26 gestational weeks at squh between june 2006 and may 2013. infants referred to squh within 72 hours of birth during this period were also included. electronic records were reviewed for gestational age, gender, birth weight, maternal age, mode and place of delivery, antenatal steroid administration, morbidity and outcome. the survival rate was calculated and findings were then compared with those of a previous study conducted in the same hospital from 1991 to 1998. rates of major morbidities were also calculated. results: a total of 81 infants between 23–26 gestational weeks were admitted to the neonatal unit during the study period. of these, 58.0% were male and 42.0% were female. median gestational age was 25 weeks and mean birth weight was 770 ± 150 g. of the 81 infants, 49 survived. the overall survival rate was 60.5% compared to 41% reported in the previous study. respiratory distress syndrome (100.0%), retinopathy of prematurity (51.9%), bronchopulmonary dysplasia (34.6%), intraventricular haemorrhage (30.9%) and patent ductus arteriosus (28.4%) were the most common morbidities. conclusion: the overall survival rate of infants between 23–26 gestational weeks during the study period had significantly improved in comparison to that found at the same hospital from 1991 to 1998. there is a need for the long-term neurodevelopmental follow-up of premature infants. keywords: extremely premature infants; neonates; survival rate; morbidity; oman. جامعة م�ست�سفى يف احلمل من الأ�سبوع 26 قبل املواليد الر�سع يف املرا�سة و البقاء معدل يف التغري تقييم اإىل الدرا�سة هذة تهدف الهدف: امللخ�ص: ال�سلطان قابو�س مب�سقط، �سلطنة عمان. الطريقة: قيمت هذة الدرا�سة اال�ستعادية معدل الوفيات و املرا�سة جلميع املواليد اخلدج الأحياء يف الأ�سابيع 23-26 للحمل من يونيو 2006 اإىل مايو 2013. املواليد املحولون مل�ست�سفى جامعة ال�سلطان قابو�س خالل 72 �ساعة من الولدة يف نف�س الفرتة مت اأي�سا اإدراجهم يف الدرا�سة. امللفات الإلكرتونية متت مراجعتها و�سملت عمر احلمل، اجلن�س، الوزن عند الولدة، عمر الأمومة، طريقة ومكان الولدة، اإعطاء ال�ستريويد اأثناء معدلت ح�ساب اأي�سا مت .1998 اإىل 1991 من بامل�ست�سفى �سابقة درا�سة نتائج مع النتائج ومقارنة البقاء معدل ح�ساب مت والنتائج. املرا�سة احلمل، الوفيات الرئي�سية. النتائج: جمموع 81 ر�سيعا من 26-23 اأ�سبوع حمل مت إدخالهم اإىل وحدة املواليد خالل فرتة الدرا�سة. منهم %58.0 ذكورا و 42.0% اإناثا. متو�سط عمر احلمل كان 25 أ�سبوعا و متو�سط الوزن عند الولدة كان150 ± 770 جم. من اأ�سل 81 ر�سيعا، 49 بقوا على قيد احلياة. معدل البقاء الكلي كان %60.5 مقارنة بـ %41 يف درا�سة �سابقة. كان اأكرث الأمرا�س �سيوعا متالزمة ال�سائقة التنف�سية )%100(، اعتالل ال�سبكية للخدج )51.9%(، خلل التن�سج الق�سبي الرئوي )%34.6(، نزف داخل البطني )%30.9(، القناة ال�رسيانية ال�سالكة )%28.4(. اخلال�صة: اإجمايل معدل البقاء ملواليد 23-26 اأ�سبوع حمل خالل فرتة الدرا�سة حت�سنت ب�سكل ملحوظ مقارنة مع النتائج املتوفرة من نف�س امل�ست�سفى من 1991 اإىل 1998. هناك حاجة ملتابعة طويلة املدى للنمو الع�سبي يف املواليد اخلدج. مفتاح الكلمات: الر�سع �سديدى اخلدج؛ املواليد؛ معدل البقاء؛ املرا�سة؛ عمان. changing survival rate of infants born before 26 gestational weeks single-centre study *asad rahman, mohamed abdellatif, sharef w. sharef, muhammad fazalullah, khalfan al-senaidi, ashfaq a. khan, masood ahmad, mathew kripail, mazen abuanza, flordeliza bataclan advances in knowledge the survival rate of extremely premature infants in a tertiary care centre in oman was calculated over a seven-year period. improvement in the overall survival rate of premature infants, potentially due to advances in neonatal care, was noted in comparison to a similar study at the same hospital conducted a decade previously. common short-term complications arising among infants admitted to a neonatal intensive care unit are illustrated. application to patient care knowledge of survival rates can advise patient care decision-making and determine whether active resuscitation and management of infants with extremely low birth weight is justified. the results of this study may aid in the establishment of guidelines for the care of infants born at the limits of viability. clinical & basic research changing survival rate of infants born before 26 gestational weeks single-centre study e352 | squ medical journal, august 2015, volume 15, issue 3 the survival of extremely premature infants has improved significantly over the last several decades.1–5 the reasons for this improvement are multifactorial—technological advances, use of antenatal steroids, surfactant therapy, improvement in neonatal resuscitation and standard antenatal and postnatal care are major contributing factors. the survival rate of extremely premature infants is much higher in developed countries than in developing countries.6–8 however, there is limited information about the survival and long-term outcome of extremely preterm infants in oman.9–11 survival and shortand long-term morbidity rates are needed to determine if active perinatal management is rational for preterm infants born at or before 26 gestational weeks.3 the limits of viability and the gestational age at which a neonate can be resuscitated and supported are still a challenge in the eastern mediterranean region. given the limited resources and infrastructure for supporting disabled children, it is very important to know the outcomes of extremely preterm infants in oman. sultan qaboos university hospital (squh) in muscat, oman, is a tertiary care centre with an obstetrics unit which accepts high-risk delivery cases from other health institutes in the country. the newborn service operates as a referral neonatal intensive care unit (nicu). a previous study from squh indicated much lower survival rates of extremely preterm infants born between 1991 to 1998 compared with other reports from developed countries.9 the aim of this study was to determine and evaluate the survival rate and morbidities of preterm infants at 23–26 gestational weeks at squh. these were then compared with the results of the study conducted in the same unit approximately a decade previously to ascertain the change in survival rate.9 additionally, survival rates and common morbidities among the infants from the current study were compared with international data.12,13 methods all premature infants born between 23–26 gestational weeks and admitted to the nicu at squh between june 2006 and may 2013 were included in the study. infants referred to squh 72 hours or later after birth were excluded. data were collected retrospectively from hospital electronic records, including maternal data, mode and place of delivery, antenatal complications, course of treatment during nicu stay and patient outcome (discharge or death). standard definitions from the literature were used to define chorioamnoitis, morbidities and complications.14–17 gestational age was determined from early ultrasound scans or calculated from the date of the last maternal menstrual period. data were analysed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). descriptive statistics and the incidence of neonatal mortality during the study period and among each gestational age group were calculated. for categorical variables, frequencies and percentages were reported. for numerical variables, the mean ± standard deviation or median and ranges were reported according to a normal distribution. a comparison of categorical data was performed using chi-squared or fisher’s exact tests as appropriate. numerical variables were compared using the student’s t-test for continuous data and the mann-whitney u test for non-continuous data. an a priori two-tailed value (p value) of ≤0.05 was considered significant. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec#898). table 1: maternal demographic characteristics, complications and mode of delivery of infants born before 26 gestational weeks (n = 81) characteristic n (%) demographic variables age in years, mean ± sd 27 ± 5 gravidity, median (iqr) 2 (1–3) parity, median (iqr) 0 (0–2) admission 36 (44.4) steroid administration 43 (53.1) complication hypertension 1 (1.2) diabetes mellitus 5 (6.2) cervical cerclage 7 (8.6) antepartum haemorrhage 18 (22.2) abruptio placenta 10 (12.3) ruptured membrane >18 hours 21 (25.9) chorioamnionitis 8 (9.9) mode of delivery vaginal 55 (67.9) caesarean section 26 (32.1) sd = standard deviation; iqr = interquartile range. asad rahman, mohamed abdellatif, sharef w. sharef, muhammad fazalullah, khalfan al-senaidi, ashfaq a. khan, masood ahmad, mathew kripail, mazen abuanza and flordeliza bataclan clinical and basic research | e353 results between june 2006 and may 2013, a total of 81 extremely preterm infants were admitted to the nicu at squh. only 44% of mothers were admitted to squh and received antenatal follow-up. a total of 14 mothers (17.3%) received one dose of antenatal steroids, 29 (35.8%) received two doses of antenatal steroids, 21 (25.9%) had prolonged rupture of the membranes (>18 hours) and eight (9.9%) had chorioamnionitis [table 1]. table 2 shows the demographic characteristics of preterm infants admitted to the nicu during the study period. out of the 81 neonates, 47 were male (58.0%) and 34 were female (42.0%). the median gestational age was 25 weeks and the mean birth weight was 770 g. the infants were assessed for common morbidities [table 3]. all of the infants were diagnosed with respiratory distress syndrome on the basis of clinical and radiological findings. a total of 37 infants (45.7%) received one dose of surfactant and 39 (48.1%) received two doses or more; five (6.2%) did not receive surfactant treatment. a total of 62 infants (76.5%) were screened for intraventricular haemorrhage (ivh) using cranial ultrasonography. of these, 25 developed various degrees of ivh (seven neonates with grade i, five with grade ii, four with grade iii and nine with grade iv). a total of 10 infants (12.3%) developed necrotising enterocolitis while 17 (21.0%) and 11 (13.6%) infants developed moderate and severe table 2: demographic characteristics of infants born before 26 gestational weeks (n = 81) characteristic birth weight in g, mean ± sd 770 ± 150 gestational age in weeks, median (range) 25 (23–26) male, n (%) 47 (58.0) female, n (%) 34 (42.0) apgar score at 1 minute, mean ± sd 4 ± 2 apgar score at 5 minutes, mean ± sd 7 ± 2 sd = standard deviation. table 3: morbidities of infants born before 26 gestational weeks (n = 81) morbidity or treatment n (%) respiratory distress syndrome 81 (100.0) surfactant therapy one dose 37 (45.7) two or more doses 39 (48.1) patent ductus arteriosus 23 (28.4) intraventricular haemorrhage grade i 7 (8.6) grade ii 5 (6.2) grade iii 4 (4.9) grade iv 9 (11.1) pneumothorax 3 (3.7) pulmonary haemorrhage 7 (8.6) bronchopulmonary dysplasia moderate 17 (21.0) severe 11 (13.6) retinopathy of prematurity any stage 42 (51.9) stage 3 4 (4.9) necrotising enterocolitis 10 (12.3) table 4: comparison of demographic and clinical characteristics of infants born before 26 gestational weeks by patient outcome (n = 81) characteristic outcome, n (%) p value died (n = 32) survived (n = 49) admission 11 (34.4) 25 (51.0) 0.119 received antenatal steroids 10 (31.3) 33 (67.3) 0.001 born outside the delivery room 5 (15.6) 1 (2.0) 0.016 antepartum haemorrhage 5 (15.6) 13 (26.5) 0.229 ruptured membrane >18 hours 20 (62.5) 11 (22.4) 0.331 chorioamnionitis 5 (15.6) 3 (6.4) 0.256 caesarean section 6 (18.8) 20 (40.8) 0.071 birth weight in g, mean ± sd 710 ± 160 810 ± 85 0.002 gestation age in weeks, mean (range) 24 (23–26) 25 (23–26) <0.001 male 18 (56.3) 29 (59.2) 0.794 female 14 (43.8) 20 (40.8) apgar score at 1 minute, mean ± sd 3 ± 2 4.5 ± 2 0.014 apgar at 5 minutes, mean ± sd 6 ± 2.5 7 ± 2 0.029 received two or more doses of surfactant therapy 15 (46.9) 26 (53.1) 0.586 sd = standard deviation. changing survival rate of infants born before 26 gestational weeks single-centre study e354 | squ medical journal, august 2015, volume 15, issue 3 bronchopulmonary dysplasia, respectively. a total of 49 infants survived (survival rate: 60.5%). the demographic and clinical characteristics of preterm infants who survived were compared with those who died during the nicu stay [table 4]. among the fatality group, fewer infants received antenatal steroids (31.3% versus 67.3%; p = 0.001) and the mean birth weight was significantly lower (710 versus 810 g; p = 0.002) compared with the survivors. gestational age was also lower in comparison with those who survived (24 versus 25 weeks; p <0.001). apgar scores were significantly higher in the group that survived, both at one and five minutes (p = 0.014 and 0.029, respectively). although pneumothorax and ivh occurred more frequently in the group of preterm infants who died, these differences were not significant. out of eight infants born at 23 gestational weeks, only one survived. survival rates among the cohort at 24, 25 and 26 gestational weeks were 33.3%, 72.4% and 75.9%, respectively. these rates were compared with those from a multi-centre study performed by the eunice kennedy shriver national institute of child health & human development neonatal research network (nichd) in the usa as well as those reported in a previous study from squh [table 5].5,9 there were more hospital admissions of infants born <26 gestational weeks between 2006–2013 (n = 81) in comparison to 1991–1998 (n = 32).9 the overall survival rate for the present cohort had increased to 60.5% from 41%, the rate observed a decade previously at the same institution.9 there was an improving survival trend for infants of 24 and 26 gestational weeks. in the current study, survival rates for infants at 25 and 26 gestational weeks (72.4% and 75.9%, respectively) were comparable to those observed in the usa study (72.0% and 83.7%, respectively); however, decreased survival was noticed at 24 gestational weeks for the omani infants at squh (33.3% versus 54.6%).5 overall, survival rates increased with gestational age in both the comparative studies and present research.5,9 common short-term morbidities among the table 5: comparison of survival rates of preterm infants in oman and the usa author and year of study location study period gestational age 23 weeks 24 weeks 25 weeks 26 weeks n survived, n (%) n survived, n (%) n survived, n (%) n survived, n (%) stoll et al.5 2010 nichd centres, usa 2003– 2007 871 226 (25.9) 1,370 748 (54.6) 1,498 1,078 (72.0) 1,576 1,319 (83.7) manzar9 2000 squh, muscat, oman 1991– 1998 2 0 (0.0) 4 1 (25.0) 1 1 (100.0) 25 11 (44.0) current study squh, muscat, oman 2006– 2013 8 1 (12.5) 15 5 (33.3) 29 21 (72.4) 29 22 (75.9) nichd = eunice kennedy shriver national institute of child health & human development neonatal research network; squh = sultan qaboos university hospital. table 6: comparison of morbidities of preterm infants in oman with very low birth weight infants in the usa and saudi arabia author and year of study location study period morbidity or treatment, % mean birth weight in g antenatal steroids bronchopulmonary dysplasia severe ivh necrotising enterocolitis pda al hazzani et al.12 2011 kfsh, riyadh, saudi arabia 2006– 2008 1,062 74.2 17.7 8.1 7.5 31.2 fanaroff et al.13 2007 nichd centres, usa 1990– 2002 1,033 79.0 22.0 10.0 7.0 29.0 current study squh, muscat, oman 2006– 2013 770 53.0 34.6 14.0 12.0 28.0 ivh = intraventricular haemorrhage; pda = patent ductus arteriosus; kfsh = king faisal specialist hospital; nichd = eunice kennedy shriver national institute of child health & human development neonatal research network; squh = sultan qaboos university hospital. asad rahman, mohamed abdellatif, sharef w. sharef, muhammad fazalullah, khalfan al-senaidi, ashfaq a. khan, masood ahmad, mathew kripail, mazen abuanza and flordeliza bataclan clinical and basic research | e355 current preterm cohort were compared with data from american and saudi arabian cohorts of very low birthweight infants between 21 and 36 gestational weeks [table 6].12,13 incidences of bronchopulmonary dysplasia, severe ivh, necrotising enterocolitis and patent ductus arteriosus were comparable between the present study and the two international cohorts. discussion the survival of extremely preterm infants has significantly improved over last the two decades due to improvements in perinatal and neonatal care.1–5 very limited local data are available on the perinatal and neonatal mortality and morbidity rates of extremely preterm infants in oman.9–11 additionally, there is a lack of data from the middle east regarding common short-term complications and morbidities of infants born <28 gestational weeks.10–12,18–21 the findings of this study indicated a significant increase in the number of admissions of infants born at <26 gestational weeks in comparison to a previous study conducted at the same institution.9 furthermore, the survival rate of preterm infants observed in the current study was comparable with those of extremely preterm infants from multi-centre studies in the usa and switzerland and very low birth weight infants from another multi-centre study in the usa.5–7 significant improvement was observed in the survival rate of preterm infants in oman compared to hospital data from the 1990s.9 this may be due to specific institutional improvements in antenatal and postnatal care, staff training and subspecialty support as well as the modernisation of equipment and the implementation of standard international guidelines for the management of extremely premature infants. one of the limitations of this study was that infants born between 22–24 gestational weeks who were not admitted to the nicu were not included in the sample. this is because it was difficult to retrieve these records retrospectively. however, all infants born at 25 and 26 gestational weeks were admitted to the nicu during the study period according to admission protocol. the exclusion of non-admitted infants between 22– 24 gestational weeks may have resulted in a falsely low mortality rate in this cohort. furthermore, this was a retrospective single-centre study with a small sample size; thus, the results cannot be generalised to all extremely preterm infants in oman. the results of the current study provided information regarding mortality and the most severe short-term morbidities only. long-term outcomes—including formal neurodevelopment follow-up data—for the survivors were lacking. although major developmental delays are assessed in neonatal follow-up clinics, more resources are needed to ensure thorough follow-up of extremely preterm infants and thus assess the overall survival rate of this patient group. conclusion the overall survival rate of extremely premature infants admitted to the nicu at squh improved significantly from a previous study at the same institution, suggesting an improvement in care. this study emphasises the need for long-term neurodevelopmental follow-up of this patient group in order to reveal the true clinical situation concerning preterm survival. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. muliga lj, katz m. the enigma of spontaneous preterm birth. n engl j med 2010; 362:529–35. doi: 10.1056/nejmra0904308. 2. iamas jd, romero r, culhane jf, goldenberg rl. primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. lancet 2008; 37:164–75. doi: 10.1016/s0140-6736(08)60108-7. 3. nwaesei cg, young dc, byrne jm, vincer mj, sampson d, evans jr, et al. preterm birth at 23-26 weeks’ gestation: is active obstetric management justified? am j obstet gynecol 1987; 157:890–7. doi: 10.1016/s0002-9378(87)80080-7. 4. allen mc, donohue pk, dusman ae. the limit of viability: neonatal outcome of infants born at 22 to 25 weeks’ gestation. n eng j med 1993; 329:1597–601. doi: 10.1056/ nejm199311253292201. 5. stoll bj, hansen ni, bell ef, shankaran s, laptook ar, walsh mc, et al. neonatal outcomes of extremely preterm infants from the nichd neonatal research network. pediatrics 2010; 126:433–56. doi: 10.1542/peds.2009-2959. 6. fischer n, steurer ma, adams m, berger tm; swiss neonatal network. survival rates of extremely preterm infants (gestational age <26 weeks) in switzerland: impact of the swiss guidelines for the care of infants born at the limit of viability. arch dis child fetal neonatal ed 2009; 94:f407–13. doi: 10.1136/adc.2008.154567. 7. fanaroff aa, wright ll, stevenson dk, shankaran s, donovan ef, ehrenkranz ra, et al. very-low-birth-weight outcomes of the national institute of child health and human development neonatal research network, may 1991 through december 1992. am j obstet gynecol 1995; 173:1423–31. doi: 10.1016/0002-9378(95)90628-2. 8. express group, fellman v, hellström-westas l, norman m, westgren m, källén k, et al. one-year survival of extremely preterm infants after active perinatal care in sweden. jama 2009; 301:2225–33. doi: 10.1001/jama.2009.771. 9. manzar s. survival pattern among extreme preterm infants. saudi med j 2000; 21:168–70. 10. manzar s, nair ak, pai mg, al-khusaiby sm. changing survival statistics among extreme premature infants in oman. saudi med j 2004; 25:1120–1. http://dx.doi.org/10.1056/nejmra0904308 http://dx.doi.org/10.1016/s0140-6736%2808%2960108-7 http://dx.doi.org/10.1016/s0002-9378%2887%2980080-7 http://dx.doi.org/10.1056/nejm199311253292201 http://dx.doi.org/10.1056/nejm199311253292201 http://dx.doi.org/10.1542/peds.2009-2959 http://dx.doi.org/10.1136/adc.2008.154567 http://dx.doi.org/10.1016/0002-9378%2895%2990628-2 http://dx.doi.org/10.1001/jama.2009.771 changing survival rate of infants born before 26 gestational weeks single-centre study e356 | squ medical journal, august 2015, volume 15, issue 3 11. abdellatif m, ahmed m, bataclan mf, khan aa, al battashi a, al maniri a. the pattern and causes of neonatal mortality at a tertiary hospital in oman. oman med j 2013; 28:422–6. doi: 10.5001/omj.2013.119. 12. al hazzani f, al-alaiyan s, hassanein j, khadawardi e. shortterm outcome of very low-birth-weight infants in a tertiary care hospital in saudi arabia. ann saudi med 2011; 31:581–5. doi: 10.4103/0256-4947.87093. 13. fanaroff aa, stoll bj, wright ll, carlo wa, ehrenkranz ra, stark ar, et al. trends in neonatal morbidity and mortality for very low birthweight infants. am j obstet gynecol 2007; 196:147.e1–8. doi: 10.1016/j.ajog.2006.09.014. 14. papile la, burstein j, burstein r, koffler h. incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. j pediatr 1978; 92:529–34. doi: 10.1016/s0022-3476(78)80282-0. 15. salama h, da silva o. images in clinical medicine: neonatal necrotizing enterocolitis. n engl j med 2001; 344:108. doi: 10.1056/nejm200101113440205. 16. flynn jt. an international classification of retinopathy of prematurity: clinical experience. ophthalmology 1985; 92:987–94. 17. bancalari e, calure n, sosenko ir. bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition. semin neonatol 2003; 8:63–71. doi: 10.1016/s1084-2756(02)00192-6. 18. majeed-saidan ma, kashlan ft, al-zahrani aa, ezzedeen fy, ammari an. pattern of neonatal and postneonatal deaths over a decade (1995-2004) at a military hospital in saudi arabia. saudi med j 2008; 29:879–83. 19. arafa ma, alshehri ma. predictors of neonatal mortality in the intensive care unit in abha, saudi arabia. saudi med j 2003; 24:1374–6. 20. nabi g, karim ma. predictors of neonatal mortality in the intensive care unit in abha, kingdom of saudi arabia. saudi med j 2004; 25:1306. 21. abdelmoneim i. a study of determinants of low birth weight in abha, saudi arabia. afr j med med sci 2004; 33:145–8. http://dx.doi.org/10.5001/omj.2013.119 http://dx.doi.org/10.4103/0256-4947.87093 http://dx.doi.org/10.1016/j.ajog.2006.09.014 http://dx.doi.org/10.1016/s0022-3476%2878%2980282-0 http://dx.doi.org/10.1056/nejm200101113440205 http://dx.doi.org/10.1016/s1084-2756%2802%2900192-6 sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 585-586, epub. 8th oct 13 submitted 31st dec 12 revisions req. 9th mar & 13th apr 13; revisions recd. 18th mar & 17th apr 13 accepted 27th apr 13 departments of 1child health, 2genetics and 3radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: roshankoul@hotmail.com اعتالل وتضخم بيضاء الدماغ مع تكيسات حتت قشرة املخ رو�سان كول، خالد ال، في�سل العزري، اآمنة الفطي�سية megalencephalic leukoencephalopathy with subcortical cysts *roshan koul,1 khalid al-thihli,2 faisal al-azri,3 amna al-futaisi1 interesting medical image megalencephalic leucoencepha-lopathy with subcortical cysts (mlc) is a genetic degenerative disease of the white matter of the brain. the white matter degenerates and swells, resulting in patients with large head sizes. cysts are also seen in white matter.1 children with mlc usually present in the first year of life, though some discrepancy has been reported in their clinical course.1 mlc is a rare neurodegenerative disorder and is reported here for the first time in two siblings in oman. two children of consanguineous parents presented in 2004, a girl (a), currently 19 years of age, and a boy (t), currently 11 years. their main complaint was mild developmental delay and the large head size, the latter noted by the parents during the first year of life, compared to their siblings. the patients gained initial milestones normally but after the first year had difficulty walking. over time there was an increase in spasticity and weakness of the limbs. at the time of writing, neither child could walk or sit unsupported. the elder sibling (a) had eating difficulties and was fed through a nasogastric tube. she could understand simple commands but had difficulty in speaking. the younger sibling (t) was still able to eat with assistance and had preserved speech. however, he had recently developed gastrooesophageal reflux. neither sibling had a history of seizures. the other 6 children in the family (3 sons and 3 daughters) were normal; there was no family history of similar or other neurologic conditions in the past two to three generations. in 2004, upon examination at presentation, there was macrocephaly in both patients. the head circumference of patient t was 58 cm at 4 years of age and 59 cm in patient a at 11 years; both measurements are well above the 97th percentile for their ages. the cranial nerves and language were figure 1 a to c. a: axial magnetic resonance images (t2-weighted) of patient t, showing diffuse white matter swelling and hyperintensity (arrows). b: axial fluid liquid attenuation inversion recovery (flair) image showing subcortical cysts in the frontal region (arrows). c: axial flair image with subcortical cysts in the anterior temporal region (arrows). roshan koul, khalid al-thihli, faisal al-azri and amna al-futaisi interesting medical image | 586 normal. bipyramdial signs were noted in the upper and lower limbs. there was spasticity in lower limbs with upgoing plantar responses. although the upper limb muscles were wasted, the power was normal (medical research council grade 5), with brisk deep tendon reflexes. routine blood and metabolic investigations were normal. electroencephalography and visual evoked potentials were not performed, as there were no seizures or visual abnormalities. a magnetic resonance imaging (mri) brain scan revealed bilateral white matter diffuse changes with subcortical cysts [figure 1]. a diagnosis of mlc was made after consultation with an expert.1,2 although the diagnosis was clinically certain, there was no genetic confirmation. recently, mlc1 gene sequencing revealed a homozygous c.432+1g>a mutation. the mutation is predicted to cause aberrant splicing, and it was not found in more than 400 control chromosomes; features which suggest the likely pathogenicity of this mutation.1 both patients were severely handicapped and on symptomatic treatment only, not yet having developed seizures. patient a was bedridden and on nasogastric feeding. conclusion mlc is a rare entity, inherited in an autosomal recessive manner. the classic phenotype presents in the first year of life with macrocephaly, often present at birth. the early development is normal or mildly delayed. slow deterioration starts in early childhood, and spasticity, extrapyramidal signs and cerebellar signs develop with time. seizures are often seen,1 and mental decline usually occurs later in life. by their teens, patients are generally wheelchair-bound. clinically, there could be other conditions with macrocephaly and bipyramidal signs in differential diagnoses, e.g. alexander disease, metachromatic leukodystrophy, gangliosidosis or canavan disease. however, the mri images are helpful in the differential diagnosis; findings of diffuse white matter abnormalities with swelling and subcortical cysts in the frontal, anterior temporal and parietal regions are diagnostic of mlc. all these abnormalities were noted in the mri scans of patients a and t, with both having cysts in the frontal and anterior temporal regions. mutations in the mlc1 gene have been identified as one of the causes for mlc.3 typically, mlc is due to the biallelic mutation of the mlc1 gene (75% of all cases). atypically, mlc occurs due to the biallelic mutation of the hepacam gene (c. 20% of cases). the management of mlc is currently symptomatic care and physiotherapy, with no definite curative treatment being available. the condition has been reported worldwide; however, this is the first case of siblings from oman with genetic confirmation of mlc. references 1. van der knaap ms, barth pg, stroink h, nieuwenhuizen o, arts wf, hoogenraad f, et al. leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. ann neurol 1995; 37:324–34. 2. ilja boor pk, de groot k, mejaski-bosnjak v, brenner c, van der knaap ms, scheper gc, et al. megalencephalic leucoencephalopathy with subcortical cysts: an update and extended mutation analysis of mlc1. hum mutat 2006; 27:505–12. 3 leegwater paj, boor pk, yuan bq, van der steen j, visser a, könst aa, et al. identification of novel mutations in mlc1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. hum genet 2002; 110:279–83. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e140–142, epub. 21 jan 15 submitted 15 apr 14 revision req. 11 jun 14; revision recd. 6th jul 14 accepted 5 aug 14 1department of haematology, college of medicine & health sciences, sultan qaboos university; departments of 2haematology and 3radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: sf.daar@gmail.com الفائدة من التصوير بالرنني املغناطيسي *t2 يف تشخيص ومراقبة ترسب احلديد القلب والكبد احلاد �ضاهينة داعر، معز ح�ضن، فينوده بنجواين، اأنيل بثري، حمود الذهلي، اأروى الريامية utility of magnetic resonance imaging t2* in diagnosing and monitoring severe cardiac and hepatic siderosis *shahina daar,1 moez hassan,2 vinodh panjwani,2 anil pathare,2 humoud al-dhuhli,3 arwa z. al-riyami2 figure 1 a–f: magnetic resonance t2* images showing the degree of iron overload in the patient over a six-year period (2008–2014). the interventricular septum (arrow) is the region of interest when assessing cardiac siderosis. a & b: images taken in 2008 showing the severe cardiac siderosis (t2*: 4.5 ms) and marked hepatic iron overload (t2*: 1.3 ms; liver iron concentration [lic]: 25.6 mg per g of dry weight [mg/gdw]). c & d: images taken in 2010 showing minimal improvement in the cardiac iron content (t2*: 5.6 ms) despite the early effect of iron chelation on the liver (t2*: 5 ms; lic: 5.3 mg/gdw). e & f: images taken in 2014 showing appreciable lightening of both organs with improvement in cardiac iron content (t2*: 11.4 ms) and normalisation of hepatic iron (t2*: 14.1ms; lic: 2 mg/gdw). lv = left ventricle; rv = right ventricle; l = liver. interesting medical image shahina daar, moez hassan, vinodh panjwani, anil pathare, humoud al-dhuhli and arwa z. al-riyami interesting medical image | e141 patients with beta thalassaemia major (tm) require regular blood transfusions in order to survive; however, these transfusions are associated with a risk of iron overload. toxic levels of iron accumulate mainly in the liver, heart and endocrine organs, causing multiple complications, and can only be removed by the regular use of iron chelating agents. different modalities exist for monitoring body iron levels. serum ferritin (sf) has been commonly used as it is widely available and has a low cost. however, sf is an acute-phase reactant and can be spuriously elevated in the presence of inflammation or infection. in addition, although serial measurements of sf are useful in monitoring patients with iron overload, they do not reflect organ-specific iron levels. historically, a liver biopsy for the assessment of hepatic iron (in mg per g of dry weight [mg/gdw]) has been the gold standard.1 a liver iron concentration (lic) of >15 mg/gdw indicates severe iron overload and is associated with increased morbidity and mortality.2 however, it is invasive and does not accurately reflect hepatic iron content in the presence of heterogeneous iron distribution. the current stateof-the-art methods for measuring organ iron overload are magnetic resonance imaging (mri) techniques. although r2 mri is a robust technique for measuring hepatic iron content, mri t2* is more widely available and can assess both hepatic and cardiac iron.3,4 the latter is particularly important as in many cases neither sf nor lic correlates well with cardiac iron content.4 for instance, a patient can have a relatively low sf level and lic but still have dangerously high levels of myocardial iron. anderson et al. showed that a cardiac mri t2* of <20 ms is indicative of cardiac iron overload, while measurements of <10 ms are associated with severe cardiac siderosis.4 recent data confirm that patients with cardiac mri t2* of <10 ms are at a much higher risk of heart failure and other cardiac events than those with measurements of >10 ms.5 using mri techniques, it is possible to evaluate iron overload in different organs in a noninvasive manner as well as safely monitor the effects of chelation therapy. mri t2* imaging has been used at the sultan qaboos university hospital (squh) in muscat, oman, as part of the regular management of tm patients since 2006. mris are performed using the 1.5t siemens sonata scanner (siemens healthcare corp., malvern, pennsylvania, usa) according to protocols described by anderson et al. and westwood et al.4,6 t2* values were calculated using software from cmrtools (cardiovascular imaging solutions ltd., london, uk). hepatic iron (lic) was calculated from liver mri t2* scans as described by wood et al.7 comment figures 1 and 2 show mri t2* images of a patient with tm over a six-year period. the patient was referred to squh in 1991 at the age of seven years and had never previously been chelated. he subsequently underwent different chelation protocols including monotherapy with deferoxamine (dfo) from 1991– 2001 and combined dfo and deferiprone (dfp) from 2001–2005. poor family compliance with the chelation therapy resulted in the patient having persistently high sf levels, ranging between 6,000 and 7,500 ng/ ml (normal range: 20–300 ng/ml). in 2005, he was enrolled in a multicentre trial on the efficacy of deferasirox. although his sf levels had fallen from 7,400 ng/ml to 6,042 ng/ml by the end of the trial in 2008, mri t2* images revealed significant cardiac and hepatic siderosis (4.5 ms and 25.6 mg/gdw, respectively) [figures 1a & b]. intensive chelation with continuous intravenous dfo and oral dfp was recommended; however, the patient was reluctant to commit to the prolonged hospitalisation necessary for this protocol. after further counselling, the patient opted to use continuous subcutaneous dfo (4 gm/ day) and dfp (100 mg/kg/day) and subsequently demonstrated excellent compliance to this treatment. reviewing the mri t2* images during follow-up helped to support this compliance, as the patient was able to see for himself that the images progressively became lighter in colour with the decrease in iron overload over time [figures 1a–f]. figure 1 highlights the advantage of mri t2* in assessing and monitoring organ-specific iron levels. a review of the patient’s serial mri t2* results revealed that his hepatic iron content decreased well before any change in the cardiac iron levels. this is consistent with the findings demonstrated by noetzli et al. in a longitudinal study; there appears to be a ‘lag’ period for iron overload and the effect of chelation therapy on the liver and heart, whereby the former is the first organ to ‘load’ with iron if chelation is inadequate.8 the liver is also the organ that shows an earlier effect of chelation compared to the heart [figures 1c & d].8 recent imaging studies [figures 1e & f] of this patient showed that the cardiac mri t2* had improved to 11.4 ms and his hepatic iron content had fallen to normal levels (2 mg/gdw). his latest sf level was 403 ng/ml. it is probable that removal of cardiac iron could have been achieved much faster if intravenous dfo had been used. this case highlights a number of points. firstly, it underlines that the use of mri t2* can be an invaluable tool in the assessment and follow-up of organ iron load. secondly, severe iron overload may take a long time to respond to chelation therapy. it is utility of magnetic resonance imaging t2* in diagnosing and monitoring severe cardiac and hepatic siderosis e142 | squ medical journal, february 2015, volume 15, issue 1 important that neither the physician nor the patient expect rapid results, particularly regarding cardiac iron. persistent counselling and support are essential. thirdly, as illustrated in this case and as confirmed in other studies, sf is a poor indicator of cardiac siderosis. finally, this case demonstrates that it is rarely too late to reverse severe iron overload. continuous efforts should therefore be made in counselling noncompliant patients. references 1. angelucci e, baronciani d, lucarelli g, baldassarri m, galimberti m, giardini c, et al. needle liver biopsy in thalassaemia: analyses of diagnostic accuracy and safety in 1184 consecutive biopsies. br j haematol 1995; 89:757–61. doi: 10.1111/j.1365-2141.1995.tb08412.x. 2. brittenham gm, griffith pm, nienhuis aw, mclaren ce, young ns, tucker ee, et al. efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. n engl j med 1994; 331:567–73. doi: 10.1056/nejm199409013310902. 3. st pierre tg, el-beshlawy a, elalfy m, al jefri a, al zir k, daar s, et al. multicenter validation of spin-density projectionassisted r2-mri for the noninvasive measurement of liver iron concentration. magn reson med 2014; 71:2215–23. doi: 10.1002/mrm.24854. 4. anderson lj, holden s, davis b, prescott e, charrier cc, bunce nh, et al. cardiovascular t2-star (t2*) magnetic resonance for the early diagnosis of myocardial iron overload. eur heart j 2001; 22:2171–79. doi: 10.1053/euhj.2001.2822. 5. kirk p, roughton m, porter jb, walker jm, tanner ma, patel j, et al. cardiac t2* magnetic resonance for prediction of cardiac complications in thalassemia major. circulation 2009; 120:1961–8. doi: 10.1161/circulationaha.109.874487. 6. westwood ma, anderson lj, firmin dn, gatehouse pd, lorenz ch, wonke b, et al. interscanner reproducibility of cardiovascular magnetic resonance t2* measurements of tissue iron in thalassemia. j magn reson imaging 2003; 18:616–20. doi: 10.1002/jmri.10396. 7. wood jc, enriquez c, ghugre n, tyzka jm, carson s, nelson md, et al. mri r2 and r2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. blood 2005; 106:1460–5. doi: 10.1182/blood-2004-10-3982. 8. noetzli lj, carson sm, nord as, coates td, wood jc. longitudinal analysis of heart and liver iron in thalassemia major. blood 2008; 112:2973–8. doi: 10.1182/blood-2008-04-148767. figure 2a & b: analysis of the liver t2* magnetic resonance image (mri) using cmrtools (cardiovascular imaging solutions ltd., london, uk). the greater the tissue iron load, the lower the t2* value. a: liver mri analysis in 2008, with a t2* of 1.3 ms (25.6 mg per g of dry weight [mg/gdw]). b: by 2014, a marked improvement can be observed (t2*: 14.1 ms; iron content: 2 mg/gdw). taurine levels in human aqueous humour medical sciences (2000), 2, 59−64 © 2000 sultan qaboos university department of child health, sultan qaboos university hospital, p.o.box: 38, postal code: 123, muscat, sultanate of oman *to whom correspondence should be addressed. 59 supraventricular tachycardia in children: a report of three cases, diagnosis and current management *venugopalan p, shakeel a, al amry a, jaya s : القلب الفوق بطيني في األطفالتسرع التشخيص وأساليب العالج في تقرير لثالث حاالت جايا. العامري ، س. شكيل ، ع.فينوجوباالن ، أ. ب الفحص السريري . الفوق بطيني متطرقين إلى التشخيص وأساليب العالج بتسرع القلب في هذا التقرير نستعرض ثالث حاالت ألطفال عمانيين مصابين : الملخص ولكن العالج على " األدينوسين " يعالج المصاب بعقار في الحاالت الطارئة .وتخطيط القلب يساعدان في تشخيص هذا النوع الشائع من اضطراب نبضات القلب .المدى الطويل مازال موضوعًا خاضعًا للنقاش abstract: the article presents three omani children with supraventricular tachycardia and discusses the diagnosis and management. clinical features along with ecg help diagnosis of this common paediatric arrhythmia. acute management has been facilitated with the introduction of adenosine. however, longterm management continues to be a topic for debate. key words: tachycardia, supraventricular, pathophysiology, case report, diagnosis, drug therapy, oman, child upraventricular tachycardia (svt) is the most common cardiac arrhythmia in children requiring therapy. this arrhythmia is usually the manifestation of an accessory conduction pathway that allows the atrioventricular impulses to re-enter the normal pathway, thus completing a circuit and stimulating atrium and ventricle at a fast rate. infants and young children generally present with poor feeding and tachypnea, while palpitation and chest discomfort are prominent symptoms in older children. electrocardiogram (ecg) shows a narrow complex tachycardia at a rate >220 per minute, and together with the clinical picture, helps in making a firm diagnosis in the majority of patients. recognition is made difficult by the non-specific symptoms and the often self-limiting nature of the disorder and long-term management continues to be a topic for debate.1 however, in recent years, there have been new insights into the natural history of and the mechanisms responsible for supraventricular tachycardia in infants and children. with advances in antiarrhythmic therapy, there are now many therapeutic options. in this article we present three recently encountered cases of svt from oman and discuss the diagnosis, as well as a framework that may help to choose the appropriate treatment for the infant or child with svt. case 1 a 5-year-old omani girl was admitted with fever and cough of 2 days. she was stable, pulse rate was >200/minute; the rest of cardiovascular system was normal. chest examination showed evidence of pneumonia in the right lower lobe. ecg revealed narrow complex tachycardia at 230/min thus confirming svt (figure 1a), and there were abnormal p waves following the qrs complexes. since carotid sinus massage, valsalva maneuver and application of ice packs to the face failed to change the heart rate, intravenous bolus of adenosine 0.1 mg/kg was given followed by a push of 10-ml normal saline. rhythm reverted to sinus in a few seconds and a simultaneously running ecg documented the change. a 12 lead ecg at that time failed to show any pre-excitation pathway. the child was started on digoxin, and antibiotics were commenced for pneumonia. thyroid function tests yielded normal results. the child was discharged on maintenance digoxin and advised follow up. she discontinued digoxin and did not come for s v e n u g o p a l a n e t a l 60 follow up. two months later she was readmitted with recurrence of svt. this time also the rhythm reverted to sinus with adenosine and the parents were counselled on compliance to medication. case 2 a 9-year-old omani girl operated for congenital heart disease (atrial and ventricular septal defects) at the age of 7 years was admitted with chest pain and palpitation of 2 days’ duration. the significant abnormality on examination was the pulse rate which was >200/min. she was not in heart failure. ecg confirmed svt (figure 1b). abnormal p waves following qrs complexes were present. vagal maneuvers failed and adenosine was given. rhythm reverted to sinus. the 12-lead ecg was normal except for the incomplete right bundle branch block that was secondary to her cardiac surgery. the 24-hour ecg holter record showed multiple episodes of self limiting svt and the child was commenced on digoxin. three months later she was readmitted with svt and this time she required 3 doses of adenosine to arrest svt. she was commenced on oral amiodarone and discharged home. she did not have any recurrence of symptoms or svt episode on repeat holter record 2 months later. case 3 a 4½ year-old omani girl was admitted with epigastric pain of one day duration. her father, a hospital employee, had noted the fast heartbeat and brought the child for evaluation. the only abnormality on examination was the pulse rate which was >200/ min. ecg confirmed svt (figure 1c) and she responded to adenosine. there was no evidence of preexcitation on 12 lead ecg. she was discharged home after counselling her parents on vagal maneuvers and was advised to report to hospital if symptoms recurred and could not be controlled. discussion svt is a rapid, paroxysmal regular tachyarrhythmia that commonly involves the atrioventricular (av) conduction system and an accessory av pathway. this figure 1. ecg (lead ii) of cases 1 (figure 1 a), 2 (figure 1 b) and 3 (figure 1 c) respectively, showing svt s u p r a v e n t r i c u l a r t a c h y c a r d i a i n c h i l d r e n is the most frequent sustained dysrhythmia in children. infants and young children are more commonly affected; however a child may experience the first episode at a higher age also.2 all our patients were older than 4 years at presentation. mechanism of origin ko3 has demonstrated that in 90% of infants and about 50% of older children, an av re-entrant pathway initiates svt. this accessory pathway normally conducts impulses from atrium to ventricle, giving rise to the delta wave on the surface ecg, as in wolffparkinson-white syndrome (wpw syndrome). when the accessory pathway is non-conducting and does not appear on surface ecg, it is referred to as concealed. svt is triggered when for some reason the accessory pathway is refractory to the impulse it receives from the atrium, but later conducts the impulse in the reverse direction from ventricle to atrium, in turn initiating a second quick forward impulse that reenters the ventricle via atrioventricular node and normal conduction pathway (figure 2). this sets up a circular movement of electrical impulses from atrium to ventricle through the normal pathway and then in the reverse direction through the accessory pathway. the ventricular response is quick and heart rates of 300/ min are not uncommon. the initiating event may be an episode of premature supraventricular or ventricular beat, sinus pause or sinus tachycardia.4 the second common mechanism of svt in children involves an accessory pathway in or around the atrioventricular node (av nodal reentry). ectopic atrial tachycardia, atrial flutter and junctional tachycardia are the other varieties of svt. atrial flutter forms a significant proportion of foetal and 5–10% of neonatal tachycardias. diagnosis regardless of mechanism of origin, svt has a common mode of presentation. symptoms are nonspecific in infants and young children and include poor feeding, tachypnea, irritability and excessive crying. table 1 distinguishing between supraventricular and sinus tachycardias criterion supraventricular tachycardia sinus tachycardia heart rate >220/minute <180/minute heart rate variability no marked variation marked variation present surface ecg p wave absent or abnormal if detected p wave normal if detected identifiable cause not obvious obvious (eg. sepsis, fever) palpitation and chest discomfort are more often complained of in older children,5 as in our case 2. epigastric pain was the presenting complaint in one of our patients (case 3). patients usually manifest acutely without any identifiable precipitating factor; however, one of our patients (case 1) had pneumonia at the time of admission. diagnosis of svt is based on history, physical examination and ecg. tachycardia is obvious on examination, but is at times difficult to differentiate from sinus tachycardia secondary 61 to septicaemia or pneumonia (table 1). the elevated heart rate and the narrow qrs complexes are most helpful in this respect. it is to be remembered that 10% of svt cases have a wide qrs secondary to aberrant conduction. p waves are generally not visible on the surface ecg in svt and if present are abnormal. these abnormal p waves can be better appreciated if a rhythm strip is recorded at 50 mm/second rather than the usual 25 mm/ second. management treatment of acute episode sustained svt in children requires intervention, because of the risk of haemodynamic deterioration. in infants it is often a medical figure 2� initiation of atrioventricular (av) re-entrant tachycardia v e n u g o p a l a n e t a l 62 emergency, as they go rapidly into a state of shock. vagal stimulation by carotid sinus massage, valsalva maneuver, application of ice cubes to the face (diving reflex), or a combination of these is attempted initially in the stable child and these have a role even in the unstable patient while awaiting more definitive therapy.6 eyeball pressure should never be used because of the risk of injury to the eye. adenosine is the universal drug of choice in all patients with svt.7 adenosine is an adenine nucleoside that acts by inducing transient block of atrioventricular node, thereby interrupting the re-entrant pathway. it has an extremely short half-life (10–15 seconds) and is effective in aborting an attack in most of the patients. the most important point to be remembered is the mode of administration. adenosine should be administered as a bolus into a good venous access in the upper limb, using a three-way connection. the initial dose is 0.1 mg/kg and repeat doses 0.2 mg/kg with a maximum of 0.3 mg/kg. adenosine loaded syringe and a second syringe with 3–5 ml normal saline are both connected to the three-way. the physician administers the adenosine as a bolus push and just as he completes it, an assistant pushes in the saline, after changing the direction of the threeway. a running ecg rhythm strip monitors the effect of adenosine reaching the heart. there is a period of cardiac asystole lasting 5–15 seconds followed by return of sinus rhythm (figure 3). however episodes of junctional and ventricular complexes may be seen during the period of asystole, as was evident in all three of our patients. there is also risk of immediate recurrence of svt. usual side effects are confined to autonomic disturbances like a feeling of impending doom, excessive salivation, abdominal pain, vomiting, flushing and headache (10–25%). occasionally adenosine can precipitate bronchospasm in a predisposed individual.8 more recently, major side effects of the drug have also been reported, such as apnea, prolonged asystole, accelerated ventricular rhythm, atrial fibrillation and wide complex tachycardia.9 therefore resuscitation equipment should be kept ready before administering adenosine. adenosine is less effective in patients receiving aminophylline. in critically ill patients intravenous access is not easily obtained and direct current electrical cardioversion has to be resorted to. the recommended dose of energy is 0.5 j/kg to 2 j/kg. paediatric paddles are used for infants; children >10kg require adult-size paddles.10 if condition permits, the child should be sedated and paralysed necessitating insertion of an intravenous line. this line could as well be used for adenosine injection. thus it is clear that the option of using adenosine exists for all patients except for the extremely sick who are treated by immediate electrical cardioversion without sedation and paralysis. immediate steps after conversion to sinus rhythm the child requires continued monitoring to identify and treat recurrences. a 12 lead ecg is taken to look for evidence of pre-excitation (wpw syndrome) and good intravenous access maintained. recurrences are treated in the same manner with adenosine using increasing doses and taking care to optimise the mode of administration. even if vagal manoeuvres failed initially, at times they may be effective during recurrence. frequent recurrences may necessitate therapy with digoxin (in the absence of wpw syndrome) or propranolol (in the presence of wpw syndrome). though intravenous verapamil is another option, it is not recommended in infants due to the risk of hypotension and shock.11 all these drugs act by producing av block. they have longer lasting effects than adenosine and repeat doses can be administered orally. however side effects are more common and patients on these medications require more intensive monitoring. resistant or frequently recurring svt is one of the few indications for use of parenteral digoxin. the loading dose is 30 mcg/kg and is given in three divided doses as infusion over 20 minutes each at an interval of 8 hours. the initial dose is usually half the total dose (15 mcg/kg) and the subsequent doses one fourth (7.5 mcg/kg). ecg and serum potassium should be monitored during therapy. the maintenance dose is figure 3. ecg showing the typical response to intravenous bolus of adenosine in patients with supraventricular tachycardia s u p r a v e n t r i c u l a r t a c h y c a r d i a i n c h i l d r e n 63 10 mcg/kg daily in one or two divided doses administered orally. in selected patients when all other measures fail, there is a role for transesophageal atrial pacing to terminate the tachyarrhythmia. long term management long-term therapy with antiarrhythmic medication is so widely used in children with svt that it is difficult to get data on the pure natural history. generally infants are more likely to ‘outgrow’ their svt. lundburg12 showed that up to 70% of infants with svt do not relapse when treatment was discontinued at the age of one year, while perry and garson13 reported a recurrence rate of 78% in children aged >5 years at the time of first episode. the presence or absence of structural heart disease did not influence the outcome.5 however the presence of wpw syndrome on the surface ecg did indicate a chance for recurrent episodes and even sudden death in symptomatic patients.13 the three available long-term treatment options are discussed below. 1. no-treatment option franklin14 and weidling15 have shown good results with this option. the success rate with digoxin or propranolol or a combination was similar, indicating that they might have acted only as placebo. controlled multicentre studies are needed to provide meaningful data on this issue. however the ‘no-treatment option’ is not recommended in infants and young children who have difficulty in communicating the problem to their carers and hence stand the risk of heart failure and shock. it may be suitable for older children who can recognize the problem early and attempt vagal manoeuvres to terminate the episode. simple reassurance may be all that is required in some instances. 2. long-term antiarrhythmic drug therapy digoxin is the traditional drug used to prevent svt in children. rarely deaths have been reported in patients on digoxin. in the case of patients with wpw syndrome propranolol is recommended. flecainide is used for resistant cases. patients with myocardial dysfunction need amiodarone. therapy with any of the second line drugs (table 2) is to be planned in consultation with a paediatric cardiologist. 3. radiofrequency (rf) catheter ablation the major advantage of this mode of therapy is the prospect of a cure. data on rf catheter ablation of accessory pathway in svt has shown an initial success rate of 94%16 and a freedom from recurrence of 85%, 77% and 66% at 1,2 and 3 years respectively after the procedure.17 however it can be performed only in specialized centres and there is a major complication rate of 2.9% even in the best of centres.18 table 2 drugs useful for long-term management of svt summary we have presented three children with svt and discussed the diagnosis and management options. intravenous bolus of adenosine is the treatment of choice to terminate an acute episode that does not respond to vagal stimulation (valsalva manoeuvre, application of ice packs to face and/or carotid sinus massage). infants and young children need long-term drug therapy, while older children with single episode of svt and absence of wpw syndrome may be followed up without medication (‘no treatment’ option). in resistant cases rf catheter ablation of the accessory pathway has to be considered. references 1. kertesz nj, friedman ra, fenrich al, garson a jr. current management of infant and child with supraventricular tachycardia. cardiol rev 1998, 6, 221–30. 2. fish f, benson w. disorders of cardiac rhythm and conduction. in emmanouilides gc, allen hd, riemenschneider ta, gutgesell hp, eds, moss and adams heart disease in infants, children, and adolescents including the fetus and young adult. baltimore: williams & wilkins, 1995, 1555– 603. 3. ko jk, deal bj, strasburger jf, benson dw. supraventricular tachycardia mechanisms and their age distribution in pediatric patients. am j cardiol 1992, 69, drug oral maintenance dose major side effects digoxin 5 micrigram/kg q12hr nausea, vomiting, heart block, tachyarrhythmias (atrial and ventricular) propranolol 1–3 mg/kg q6–8hr heart failure, hypotension, bronchospasm, nightmares verapamil 1–3 mg/kg q8hr hypotension, skin rash, heart block, tachyarrhythmias (atrial and ventricular) flecainide 1.5–3 mg/kg q12hr* heart block, tachyarrhythmias (atrial and ventricular) amiodarone 5 mg/kg q24hr** heart block, tachyarrhythmias (atrial and ventricular), hypo/hyperthyroidism, corneal microdeposits, pulmonary fibrosis * 1–2 mg/kg q6–8 hour in infants, due to shorter half-life in infancy ** loading dose 5 mg/kg q8 hr for first week, q12 hr for 2nd week v e n u g o p a l a n e t a l 64 1028–32. 4. dunnigan a, bendirt dg, benson dw jr. modes of onset (“initiating events”) for paroxysmal atrial tachycardia in infants and children. am j cardiol 1986, 57, 1280–7. 5. garson a jr, gillette pc, mcnamara dg. supraventricular tachycardia in children: clinical features, response to treatment, and long-term follow-up in 217 patients. j pediatr 1981, 98, 875–82. 6. muller g, deal bj, benson dw jr. “vagal maneuvers” and adenosine for termination of atrioventricular reentrant tachycardia. am j cardiol 1994, 74, 500–3. 7. ralston ma, knilans tk, hannon dw, daniels sr. use of adenosine for diagnosis and treatment of tachyarrhythmias in pediatric patients. j pediatr 1994, 124, 139–43. 8. till j, shinebourne ea, rigby ml, clarke b, ward de, rowland e. efficacy and safety of adenosine in the treatment of supraventricular tachcardia in infants and children. br heart j 1989, 62, 204–11. 9. rankin ac, rae ap, houston a. acceleration of ventricular response to atrial fltter after intravenous adenosine. br heart j 1993, 69, 263–5. 10. atkins dl, kerber re. pediatric defibrillation: current flow is improved by using “adult” electrode paddles. pediatrics 1994, 94, 90–3. 11. epstein ml, kiel ea, victoria be. cardiac decompensation following verapamil therapy in infants with supraventricular tachycardia. pediatrics 1985, 75, 737–40. 12. lundberg a. paroxysmal atrial tachycardia in infancy: long-term follow-up study of 49 subjects. pediatrics 1982, 70, 638–42. 13. perry jc, garson a jr. supraventricular tachycardia due to wolff-parkinson-white syndrome in children: early disappearance and late recurrence. j am coll cardiol 1990, 16, 1215–20. 14. franklin wh, deal bj, strasburger jf. do infants have medically refractory supraventricular tachycardia [abstract]? j am coll cardiol 1994, 23, 250a. 15. weindling sn, saul jp, walsh ep. efficacy and risks of medical therapy for supraventricular tachycardia in neonates and infants. am heart j 1996, 131, 66–72. 16. kugler jd, danford da, deal bj, gillette pc, perry jc, silka mj, van hare gf, walsh ep, for the pediatric electrophysiology society. radiofrequency catheter ablation in children and adolescents. n engl j med 1994, 330, 1481–7. 17. kugler jd, danford da, felix g, houston k, other members of pediatric electrophysiology society rfca registry. follow-up of pediatric radiofrequency catheter ablation registry patients. circulation 1995, 92, 765a. 18. kugler jd, houston k, other participating members of pediatric ep society. pediatric radiofrequency catheter ablation (rfca) registry: update of immediate results. pace 1995, 18, 814a. svt (heading) intro case 1 case 2 case 3 discussion mechanism of origin diagnosis table 1 distinguishing between supraventricular and sinus tachycardias management treatment of acute episode immediate steps after conversion to sinus rhythm long term management 1. no-treatment option 2. long-term antiarrhythmic drug therapy 3. radiofrequency (rf) catheter ablation table 2 drugs useful for long-term management of svt summary references sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e191–201, epub. 28 may 15 submitted 1 aug 14 revision req. 22 sep 14; revision recd. 26 nov 14 accepted 18 dec 14 1centre for accident research & road safety–queensland, queensland university of technology, brisbane, australia; 2department of occupational & environmental health, directorate general of disease control, ministry of health, muscat, oman; 3department of epidemiology, college of medicine & health sciences, sultan qaboos university; 4department of civil engineering, college of engineering, sultan qaboos university, muscat, oman *corresponding author e-mail: jason.edwards@qut.edu.au خصائص حوادث املركبات الثقيلة يف عمان 2009-2011 اإ�سالم البلو�سي، جي�سن اأدواردز، جريمي ديفي، كريي اأرم�سرتوجن، حمد الريي�سي، خالد ال�سام�سي abstract: in recent years, oman has seen a shift in the burden of diseases towards road accidents. the main objective of this paper, therefore, is to describe key characteristics of heavy vehicle crashes in oman and identify the key driving behaviours that influence fatality risks. crash data from january 2009 to december 2011 were examined and it was found that, of the 22,543 traffic accidents that occurred within this timeframe, 3,114 involved heavy vehicles. while the majority of these crashes were attributed to driver behaviours, a small proportion was attributed to other factors. the results of the study indicate that there is a need for a more thorough crash investigation process in oman. future research should explore the reporting processes used by the royal oman police, cultural influences on heavy vehicle operations in oman and improvements to the current licensing system. keywords: traffic accidents; accident prevention; automobile driving; safety; oman. امللخ�ص: يف ال�سنوات االأخرية، �سهدت عمان تغري يف اأعباء االأمرا�ض نحو حوادث الطرق. الهدف من هذة الورقة هو و�سف اخل�سائ�ض الرئي�سية حلوادث املركبات الثقيلة يف عمان وحتديد �سلوكيات القيادة التى توؤثر على خماطر الوفاة. ثم فح�ض بيانات احلوادث من يناير 2009 اإىل دي�سمرب 2011 والتى اأظهرت وقوع 22,543 حادثًا على الطرق يف هذة الفرتة الزمنية �سمل منها 3,114 مركبات ثقيلة. على الرغم من اأن معظم هذة احلوادث كانت ب�سبب �سلوكيات القيادة، كانت هناك ن�سبة �سغرية ب�سبب عوامل اأخرى. اأظهرت نتائج هذة الدرا�سة اإىل اأنه هناك حاجة اإىل حتقيق �سامل للحوادث يف عمان. البحوث امل�ستقبلية يجب اأن تفح�ض عمليات اإعداد تقارير احلوادث امل�ستخدمة من قبل �رشطة عمان ال�سلطانية، والثاأثريات الثقافية لعمل املركبات الثقيلة يف عمان وحت�سني نظام تراخي�ض املركبات احلايل. مفتاح الكلمات: حوادث الطرق؛ الوقاية من احلوادث؛ قيادة املركبات؛ ال�سالمة؛ عمان. special contribution heavy vehicle crash characteristics in oman 2009–2011 islam al-bulushi,1,2 *jason edwards,1 jeremy davey,1 kerry armstrong,1 hamed al-reesi,3 khalid al-shamsi4 oman, along with other gulf cooperation council (gcc) countries— the united arab emirates (uae), saudi arabia (ksa), kuwait, bahrain and qatar—has experienced substantial social and economic development as a result of the discovery of oil. with targeted effort from governing bodies, this development has contributed to a reduction in the burden of many life-threatening infectious diseases. as a result, the burden of disease has now shifted towards non-communicable diseases.1 in particular, the prevalence of road traffic injuries in oman is very high; in 2007, road traffic injuries accounted for 73.3% of total hospital deaths due to external causes.2 moreover, a significant number of those who sustain injuries as a result of traffic accidents live with pervasive and debilitating physical, emotional and behavioural impairments.3 within the arab world, oman has one of the highest rates of road traffic fatalities.4 between 1985 and 2009, 13,722 men, women and children lost their lives in car crashes in oman and 165,757 were injured.5,6 in 2011, more than 7,700 road traffic crashes were recorded in oman, averaging close to one crash every hour and one fatality every 10 hours.4 definitions of fatalities resulting from traffic crashes vary from country to country. internationally, the world health organization (who) defines a road traffic fatality as a death occurring within 30 days of involvement in a traffic crash.7 however, in oman, this definition is not applied as the royal oman police (rop) define road traffic fatalities as those in which death related to a crash occurs between the time of the crash and the closure of the case file in january of the next year;6 thus, it is difficult to determine the accuracy of a direct comparison with other countries using the who definition. heavy vehicle crash characteristics in oman 2009-2011 e192 | squ medical journal, may 2015, volume 15, issue 2 recently, there has been a growing effort within oman to reduce the impact of traffic incidents. a number of policy changes have been made, such as the introduction of seatbelt and mobile phone laws as well as fixed and mobile speed detection devices. however, significant effort is still required across a number of organisations, government departments and the wider population to stem the increasing number of road traffic accidents in oman. one area which may require specific attention is that of heavy vehicle safety. as countries, including oman, witness economic development, the use of heavy vehicles becomes crucial for the transportation of goods and with increased use comes an increase in the number of heavily vehicle crashes. in 2010, heavy vehicles represented 12.5% of registered vehicles in oman.7 however, research from other countries suggests that mortality and morbidity as a result of heavy vehicle crashes are proportionally higher than their percentage of registrations.8 in finland, between 1990 and 1997, heavy vehicles represented approximately 6% of registered vehicles yet accounted for 16% of crashes.8 research to date has yet to explore heavy vehicle crashes within oman. the purpose of the current research, therefore, was to analyse road traffic crash data pertaining to heavy vehicles in oman in order to identify the key characteristics of these crashes and the factors that influence the likelihood of fatalities. this analysis will aid in identifying road traffic accident trends in order to enable future efforts to be directed towards improving heavy vehicle safety in oman. methods crash data were obtained from the rop directorate general of traffic and included details on all ropattended heavy vehicle crashes occurring from january 2009 until december 2011, including all serious crashes but omitting minor crashes. in the rop data, serious crashes were defined as those where there is either an injury, public property damage or an inability for the involved drivers to determine, among themselves, who was at fault. this definition is a result of the 2006 rop policy which states that minor crashes (where the three aforementioned criteria do not apply) are to be resolved between drivers’ insurance companies without police involvement.6,9 as the original rop crash database is in arabic, translation into english was performed according to the published bilingual statistical report of the rop (for the purpose of this research). in some cases, translation was based on terms or definitions used by three omani academics familiar with road safety literature. the data collected were predominantly concerned with the at-fault vehicle and driver and in labelling crash causes; thus, the data were divided into three sub-datasets—crash, person and vehicle. for the purpose of this analysis, a new combined dataset was developed in order to enable characterisation of at-fault crashes, and to differentiate between fatal and nonfatal crashes in relation to characteristics of drivers, vehicles and crashes. driver-related data included age, gender, nationality, seatbelt usage and licence status of the driver. vehicle-related data included the type of vehicle. crash-related data included the time, place, reason and severity of the crash, including whether a fatality occurred before file closure. internationally, there are several definitions related to heavy vehicles. however, within this dataset, the rop’s traffic safety institute’s definition was used. according to this definition, a heavy vehicle is a motor vehicle with a weight of >4,000 kg (4 tonnes) when unladen, as recorded by the rop at the time of registration.10 the combined dataset was explored and analysed using the statistical package for the social sciences (spss), version 16 (ibm, corp., chicago, illinois, usa). the severity of the heavy vehicle crashes (fatal versus non-fatal) was explored and then linked to characteristics related to the driver, vehicle and crash. due to the policy that minor crashes are to be handled by insurance companies, property damageonly crashes in the dataset represented only serious accidents. in light of this, it was decided to group injury and property damage crashes and compare them with fatal crashes to determine the factors most associated with loss of life. due to the small number of crashes in some categories, fisher’s exact tests were conducted (using r) to identify whether the occurrence of a fatality was independent of certain factors. further, the adjusted standardised residuals for each variable and the effect size (cramér’s v)were calculated.11 the factors that were significantly related to the likelihood of fatality were then included in a multiple logistic regression model to further indicate important predictors for fatalities within at-fault heavy vehicle crashes. results over the three-year sample period, there were 2,543 police-reported road traffic crashes in oman. as a result of these crashes, 2,829 people were killed and a further 31,313 were injured. close to 50% of the crashes were reported to involve more than one vehicle. of the total number of crashes in oman during this timeframe, 3,114 incidents involved heavy islam al-bulushi, jason edwards, jeremy davey, kerry armstrong, hamed al-reesi and khalid al-shamsi special contribution | e193 vehicles (13.8%). of these heavy vehicle crashes, 11.7% involved a fatality, 62.6% involved an injury and 25.7% resulted in no physical harm to those affected. the crashes resulted in 268 deaths and 2,134 individuals being injured. there were limited data available on heavy vehicle crashes in which the heavy vehicle driver was not at fault. of the 3,114 heavy vehicle crashes, 59.7% (n = 1,859) were deemed the fault of the driver. the at-fault crashes were the focus of the remaining analysis. as shown in table 1, within at-fault heavy vehicle crashes, almost half of the drivers were aged 21–30 years (46.2%), the vast majority were male (99.3%) and over 40% were expatriates. the majority of drivers were reported to be wearing a seatbelt (97.7%) and approximately two-thirds of the drivers were unlicensed (65.2%). of the unlicensed drivers, 94.4% held either an omani light vehicle licence or one from another gcc country and 2.2% held no driving licence at all. in terms of crash characteristics, 70% of these crashes occurred during the daytime and around half involved other vehicles. with regards to the principal reason identified for the crash, the majority were the result of common unsafe driving behaviours such as speeding, incorrect vehicle manoeuvres, inattention and not keeping a safe distance from the preceding car. only a small number of heavy vehicle crashes were deemed to be the result of fatigue (0.5%) or alcohol (1.8%). furthermore, the rop attributed a small number of the crashes (8.8%) to factors other than driver behaviour, such as vehicle or road conditions or the climate [table 1]. the majority of the heavy vehicles involved in these crashes were standard ‘trucks’, meaning they were rigid and articulated trucks not including tankers and heavy equipment vehicles. fata l a n d n o n-fata l c r a s h e s univariate analysis a number of factors were significantly associated with fatalities [table 1]. these included the age and nationality of the driver, whether the driver was wearing a seatbelt, their licence status, the type of crash that occurred and the reasons for the crash. there was a small effect (v = 0.10) of age on the likelihood of a fatality, with crashes involving drivers aged 21–30 years less likely, and crashes with drivers aged 41–50 years more likely to result in a fatality. nationality also had a small effect (v = 0.06) on the likelihood of a fatality with crashes involving non-omani drivers more likely to lead to a fatality. increased reported use of seatbelts also had a small effect (v = 0.18) in lessening the likelihood of fatality. surprisingly, licenced drivers were slightly more likely to be involved in a fatal crash (v = 0.09). with regards to the type of crash, there was again a small effect (v = 0.21), with fatalities less likely in overturns and collisions with fixed objects and more likely when a person or animal was run over. in addition, when the reasons for the crash were attributed to driver fatigue (increased risk), overtaking (increased risk) and incorrect vehicle manoeuvres (decreased risk), there was a small effect (v = 0.20) on the likelihood of a fatality occurring. multivariate analysis the results were further examined through a multivariate logistic regression model including only the significant univariate predictors (age, nationality, seatbelt, licence status, crash type and reason) [table 2]. the hosmer-lemeshow test (5.741; p = 0.676) indicated a good level of fit and the model explained 20.8% of the variance in occurrence of fatal crashes (nagelkerke’s r2 = 0.208).11 for each predictor, the most numerous category was selected as the referent group to calculate the odds ratios (or). the results of the logistic regression are shown in table 2. age group was a significant predictor for fatal crashes, with drivers aged 41–50 years being 2.09 times as likely to have a fatal crash than those aged 21– 30 years (p <0.01). no other age groups significantly differed from the referent category. not wearing a seatbelt increased the likelihood of fatality by 6.58 (p <0.01). licence status was also found to be associated significantly with the likelihood of a fatality, with licenced drivers 1.64 times more likely to be involved in fatal crashes compared to drivers who were not licenced (p = 0.01). both crash type and the reason for the crashes were significantly associated with the likelihood of a fatality occurring. compared to vehicle collisions, crashes involving a person or animal being run-over were 2.38 times more likely to lead to a fatality (p <0.01), while overturned vehicles (p <0.01) and fixedobject collisions (p <0.01) were 0.26 and 0.30 times as likely, respectively. when compared to crashes caused by speeding, fatigue (or = 10.65; p <0.01), overtaking (or = 2.77; p <0.01) and vehicle defect-related crashes (or = 3.06; p <0.01) were at an increased likelihood of fatality, while failure to keep a safe distance (or = 0.27; p = 0.01) and incorrect vehicle manoeuvres (or = 0.42; p <0.01) decreased the likelihood of fatality. discussion the purpose of the current study was to analyse crash data pertaining to heavy vehicle accidents in oman in order to identify trends and enable future efforts to heavy vehicle crash characteristics in oman 2009-2011 e194 | squ medical journal, may 2015, volume 15, issue 2 improve heavy vehicle safety. prior to discussing the findings of this analysis, it is important to recognise the limitations inherent to the nature of the data source. while the data should only include serious crashes, due to the potential for confusion as to the nature of minor or serious crashes, there is still a possibility that minor crashes have been recorded incorrectly as serious crashes by the police. furthermore, crashes are investigated by police officers at the scene, who then complete a crash report and send it later to the table 1: heavy vehicle crashes by fatality in 2009–2011 variable total n (%) fatal n (%) non-fatal n (%) % fatal age group in years* ≤20 118 (6.3) 13 (6.0) 105 (6.4) 11.0 21–30 859 (46.2) 78 (35.8) 781 (47.6) 9.1 31–40 523 (28.1) 64 (29.4) 459 (28.0) 12.2 41–50 231 (12.4) 45 (20.6) 186 (11.3) 19.5 ≥51 128 (6.9) 18 (8.3) 110 (6.7) 14.1 gender male 1,846 (99.3) 218 (100.0) 1,628 (99.2) 11.8 female 13 (0.7) 0 (0.0) 13 (0.8) 0.0 nationality* omani 1,071 (57.6) 106 (48.6) 965 (58.8) 9.9) non-omani 788 (42.4) 112 (51.4) 676 (41.2) 14.2 seat belt use* yes 1,817 (97.7) 197 (90.4) 1,620 (98.7) 10.8 no 42 (2.3) 21 (9.6) 21 (1.3) 50.0 licence status* licensed 647 (34.8) 101 (46.3) 546 (33.3) 15.6 unlicensed 1,212 (65.2) 117 (53.7) 1,095 (66.7) 9.7 crash time† early morning 175 (9.4) 22 (10.1) 153 (9.3) 12.6 morning 733 (39.4) 82 (37.6) 651 (39.7) 11.2 evening 543 (29.2) 59 (27.1) 484 (29.5) 10.9 night 408 (21.9) 55 (25.2) 353 (21.5) 13.5 crash type* vehicle collision 874 (47.0) 106 (48.6) 768 (46.8) 12.1 person or animal run over 176 (9.5) 54 (24.8) 122 (7.4) 30.7 overturned vehicle 402 (21.6) 28 (12.8) 374 (22.8) 7.0 fixed-object collision 393 (21.1) 26 (11.9) 367 (22.4) 6.6 motorcycle/ bicycle 14 (0.8) 4 (1.8) 10 (0.6) 28.6 reasons for crash*‡ speed 835 (44.9) 90 (41.3) 745 (45.4) 10.8 inattention 182 (9.8) 28 (12.8) 154 (9.4) 15.4 fatigue 9 (0.5) 4 (1.8) 5 (0.3) 44.4 alcohol 33 (1.8) 2 (0.9) 31 (1.9) 6.1 overtaking 83 (4.5) 27 (12.4) 56 (3.4) 32.5 climatic conditions 20 (1.1) 4 (1.8) 16 (1.0) 20.0 sudden stopping 19 (1.0) 0 (0.0) 19 (1.2) 0.0 lack of safe distance 100 (5.4) 4 (1.8) 96 (5.9) 4.0 incorrect manoeuvre 434 (23.4) 31 (14.2) 403 (24.6) 7.1 vehicle failure 108 (5.8) 21 (9.6) 87 (5.3) 19.4 road conditions 35 (1.9) 7 (3.2) 28 (1.7) 20.0 heavy vehicle type truck 1,618 (87.0) 183 (83.9) 1,435 (87.4) 11.3 heavy equipment 63 (3.4) 10 (1.5) 53 (4.4) 15.9 water tanker 164 (8.8) 22 (3.4) 142 (11.7) 13.4 sewage tanker 12 (0.6) 3 (0.5) 9 (0.7) 25.0 oil tanker 2 (0.1) 0 (0.0) 2 (0.2) 0.0 *significant (p <0.01) difference between licensed and unlicensed crashes. bold = figures with adjusted standardised residuals greater than +2.58 (p <0.01). †crash times were classified as early morning (1:00 am to 5:59 am), morning (6:00 am to 12:59 pm), evening (1:00 pm to 5:59 pm) or night (6:00 pm to12:59 am). ‡total dataset for crash reasons was 1,858 due to one missing data point. islam al-bulushi, jason edwards, jeremy davey, kerry armstrong, hamed al-reesi and khalid al-shamsi special contribution | e195 directorate general of traffic to be entered into the database.6,9 thus, all crash data is manually handled, leading to the potential for errors while transcribing crash reports to the database or to investigator bias. with these limitations in mind, this paper focused on the characteristics of at-fault serious heavy vehicle crashes; these findings therefore may not reflect prevalence within oman’s general heavy vehicle driving population. as there was a lack of previous research on the prevalence of various risk factors, for example table 2: logistic model estimation and odds ratios for significant independent variables for heavy vehicle fatal crashes in 2009–2011 variable b se significance odds ratio 95% ci age group in years ≤20 0.120 0.350 0.732 1.127 0.568 2.237 21–30 1.000 31–40 0.131 0.204 0.520 1.140 0.764 1.702 41–50 0.739 0.234 0.002 2.094 1.324 3.314 ≥51 0.322 0.308 0.295 1.380 0.755 2.523 nationality omani 1.000 non-omani 0.145 0.202 0.474 1.156 0.777 1.718 seat belt use yes 1.000 no 1.884 0.378 0.000 6.579 3.135 13.803 licence status licensed 0.495 0.194 0.011 1.641 1.123 2.399 unlicensed 1.000 crash type vehicle collision 1.000 person or animal run over 0.868 0.240 0.000 2.382 1.488 3.814 overturned vehicle -1.358 0.269 0.000 0.257 0.152 0.436 fixed-object collision -1.217 0.266 0.000 0.296 0.176 0.499 motorcycle/bicycle 0.690 0.682 0.312 1.993 0.524 7.588 reasons speeding 1.000 inattention -0.202 0.263 0.441 0.817 0.488 1.367 fatigue 2.366 0.735 0.001 10.652 2.524 44.955 drink driving -1.252 0.814 0.124 0.286 0.058 1.410 overtaking 1.019 0.300 0.001 2.771 1.538 4.992 climatic conditions 0.722 0.614 0.240 2.058 0.618 6.855 sudden stopping -19.370 8,962.844 0.998 0.000 0.000 0.000 lack of safe distance -1.329 0.542 0.014 0.265 0.091 0.766 incorrect manoeuvre -0.857 0.256 0.001 0.424 0.257 0.701 vehicle failure 1.119 0.298 0.000 3.063 1.707 5.496 road conditions 0.791 0.507 0.119 2.205 0.816 5.958 se = standard error; ci = confidence interval. heavy vehicle crash characteristics in oman 2009-2011 e196 | squ medical journal, may 2015, volume 15, issue 2 regarding speeding, the analysis also could not indicate the relative risk of crashes for the identified factors. the factors analysed do, however, represent important areas of focus for future interventions. importantly, these factors also pose a high risk for road crashes. at a general level, heavy vehicle crashes accounted for 13.8% of all crashes that occurred in the three-year study period. this appeared to be representative of the 12.5% of registered vehicles in oman that are heavy vehicles. given that the present data explored crashes serious enough to be reported by police, it is surprising that heavy vehicles were not over-represented. specifically, the mass of a heavy vehicle should increase the average crash severity, leading to a higher level of reporting. it is also worth noting, however, that this comparison may not take into account heavy vehicles not registered in oman that are engaged in cross-border transport. furthermore, heavy vehicles typically conduct a greater amount of travel than other vehicles and the number of km travelled is often used to estimate levels of exposure to traffic hazards. unfortunately, there is no record of km travelled in oman for specific vehicle types. thus, it is not possible to draw conclusions regarding the overall representative level of heavy vehicle involvement in crashes, nor draw accurate comparisons to other countries. of all heavy vehicle crashes, 59.7% were the fault of the driver. this is reasonably low when compared with findings from australia. recent reports for the main insurer of heavy vehicles in australia, the national transport insurance company, have indicated that truck drivers were at fault in multivehicle crashes in 46.3% and 70% of cases during 2007 and 2011, respectively.12,13 given that multivehicle crashes accounted for 24.1–24.6% of crashes, truck drivers therefore were at fault in 86.8–92.8% of all crashes. however, it should be noted that differences in reporting practices between countries and the different sources of data (insurance company versus police data) may partially account for this difference in fault rates, particularly considering multivehicle crashes accounted for close to half of the crashes in the current report. just over half of the drivers involved in heavy vehicle crashes in oman were under the age of 30 years. this aligns with similar trends in road safety research internationally, yet contradicts a recent report of serious australian heavy vehicle crashes which revealed a greater trend towards older drivers.13 it is, however, important to note that the australian heavy vehicle industry is often considered an ageing industry which is struggling to renew its workforce and most companies refuse to hire drivers below 25 years of age due to increased insurance costs. furthermore, census data from oman has shown that a significant proportion of the population of oman are young, with 44.7% of the population under the age of 20 years.14 the high proportion of drivers under the age of 30 years in the current sample suggests the need for targeted safety initiatives for younger heavy vehicle drivers, such as those included in graduated licensing systems. the high number of expatriate heavy vehicle drivers is not surprising given that 29.4% of oman’s population in 2010 were expatriate.15 heavy vehicle drivers in oman also may be transporting goods to or from the uae, ksa or yemen, which conduct trade with oman. anecdotally, it is also commonly suggested that the majority of heavy vehicle drivers are expatriate. while it is difficult to tell how representative the proportion of omanis and expatriates is in the current sample, it does highlight the need for a safety initiative that would account for cultural differences. in the context of traffic safety, the influence of culture has recently gained increased attention, even forming the topic of a recent special edition of a traffic-related journal.16 when such a high proportion of truck drivers are from other nations, it would be an error to assume that standardised approaches known to be effective for one culture would necessarily have a sufficient impact on the industry as a whole. thus, it is important for future research to examine the influence of culture on safety in the heavy vehicle industry of oman and identify safety initiatives which either operate effectively across cultural barriers or provide education targeted to specific subcultural groups in the industry. with regards to the types of crashes, 52.4% did not involve any other vehicle, which is substantially higher than reports on serious major highway crashes in the usa, where approximately 34% of accidents involve just a single vehicle.17 however, this finding is higher than serious crash insurance statistics from australia, where approximately 75% involved a single vehicle.12,13 it is important, however, to recognise that the current statistics do not include non-fault crashes due to the data collection focus of the rop. if it is assumed that the remainder of crashes in which the heavy vehicle driver was not at fault all involved another vehicle, single vehicle crashes would represent 31.6% of crashes, which would be comparable to rates in the usa. similar to other reports published in the literature, the majority of heavy crashes in the current study were caused by common driver behaviours such as speeding, incorrect manoeuvres and inattention.18–21 worth noting, however, is the fact that fatigue was a factor in very few of the serious heavy vehicle crashes in the dataset (n = 9). this is quite different to statistics from australia where fatigue accounted for 11.9% of serious islam al-bulushi, jason edwards, jeremy davey, kerry armstrong, hamed al-reesi and khalid al-shamsi special contribution | e197 crashes; however, similar statistics from the usa with fatigue accounting for approximately 0.7% of serious crashes.13,17 it should be recognised that oman is a geographically smaller nation than australia and the usa, and that therefore there may be less longdistance driving resulting in reduced likelihood of road fatigue. however, there may be alternative explanations for this finding. research has shown fatigue to be a major contributor to heavy vehicle crashes, while driving long hours has been associated with falling asleep at the wheel and increased injury severity in the case of a crash.8,17,22–25 however, fatigue is commonly under-represented in crash statistics.26,27 whenever a driver is fatally injured, it is impossible to enquire directly regarding fatigue; thus, it can be difficult to determine fatigue as the crash cause within police investigations. in the literature, a number of factors have been used to determine the involvement of fatigue in crashes, including single-vehicle crashes during high risk fatigue times (e.g. 12:00–6:00 am and 2:00–4:00 pm), head-on collisions while overtaking, the absence of evidence of evasive actions and the location of the crash being clearly visible for several seconds prior to the crash.6,28 the rop do not have a formal inspection process by which fatigue is determined. in oman, a crash is classified as being caused by fatigue according to the findings and view of the rop investigator or by a direct confession from the driver. additionally, the crash database does not indicate all factors contributing to crashes, but only the single predominant cause. thus, fatigue-related crashes could be primarily identified as being caused by incorrect manoeuvres or other behaviours. by introducing a more thorough approach to determining fatigue as well as enabling the use of multiple causal factors, it may be possible to increase the accuracy of investigation reports and gain better insight into the impact of fatigue on the drivers of heavy vehicles in oman. an important category of crash causes, is the influence of external factors, including those related to the vehicle, road and climate. as previously stated, this analysis reviewed at-fault serious crashes. the fact that 8.8% of heavy vehicle driver at-fault crashes were attributed to factors not directly under the driver’s control again brings into question the classification of crash causes on rop reports. in such cases, it is anticipated that some driver behaviours were unsuitable for the conditions at the time of the crash and this further highlights the need for changes to the rop crash investigation processes. fa c t o r s a s s o c i at e d w i t h fata l c r a s h e s with regards specifically to fatal crashes, it is important to note the differences between statistical significance and real-world applicability. factors which were found to be associated with the likelihood of a fatality did not always represent those which account for the greatest number of fatalities. in both the univariate and multivariate analyses, drivers aged 41–50 years were at higher risk of fatalities. the fact that this statistic remained significant in the multivariate model suggests that other factors do not account for this variance. while it could be argued that older drivers are more susceptible to a greater severity of injuries in crashes, drivers over the age of 50 years were not at a higher risk. the sample size of these older drivers may have been insufficient to reveal trends; however, there is a need for further research to examine the risks associated with drivers over the age of 41 years. nonetheless, drivers aged 21–30 years (35.8%) and 31–40 years (29.4%) showed a higher proportion of crashes in comparison to drivers aged 41–50 years (20.9%). thus, while older drivers may need specific attention in order to address the reasons for their increased likelihood of fatal crashes, younger drivers represent the highest proportion of drivers in oman and should be targeted to reduce the total number of fatalities. nationality was significant in the univariate analysis, with expatriates at a higher risk of fatalities due to the over-representation of omanis in non-fatal crashes. however, this significance did not hold in the multivariate analysis. this suggests that the difference in fatality rates may be accounted for by other predictors, such as the cause of crashes. additionally, it should be noted that the overall differences in the proportions of fatal and non-fatal crashes may highlight differences in the reporting of crashes. given that expatriate drivers may be on visas which could be lost if they are found to have broken any laws, less severe crashes may therefore not be reported. furthermore, differing employment conditions have been shown, internationally, to have an impact on heavy vehicle safety. for example, subcontractors, owner-operators and informal employees have higher rates of crash involvement and associated injuries.29–31 regardless of the reasons for these differences, the loss of significance when accounting for other variables suggests differences of behaviour or other crash factors which should be explored to better understand how nationality and/or culture influences heavy vehicle crashes. in both the univariate and multivariate analyses, the lack of seatbelt use increased the likelihood of fatalities. given the nature of seatbelts, the difference in the likelihood of fatalities may directly relate to the potential loss of life for truck drivers; however, further heavy vehicle crash characteristics in oman 2009-2011 e198 | squ medical journal, may 2015, volume 15, issue 2 research is needed to confirm whether this is the case or whether individuals who do not wear seatbelts are also more likely to engage in other high-risk behaviours. it should be noted that the frequency of seatbelt use in the reported dataset was very high. in the current dataset, almost all of drivers were reported to be wearing a seatbelt at the time of the crash. although seatbelt use is mandatory for truck drivers in both australia and oman, one study found that seatbelt use was very low among australian heavy vehicle drivers, with many seeing seatbelt use as unrelated to safety.32 given the reliance on police investigation data in the current dataset, it is thought that seatbelt use can only be confidently ascertained from crashes in which the truck driver died in other crashes there may be a high level of over-reported seatbelt use by drivers who do not want to admit to breaking the law in front of a police officer. an investigation into the prevalence of seatbelt use in the heavy vehicle industry of oman is needed to better understand usage rates and associated behaviours. furthermore, to see the direct benefits of seatbelt use, a more detailed analysis of crashes in which the heavy vehicle driver was injured or killed is required. licence status was found to be associated significantly with the severity of the crashes in both the univariate and multivariate analyses. interestingly, drivers holding valid heavy vehicle licences contributed more to the occurrence of fatal crashes compared to those not licensed to drive heavy vehicle. research on driving in the general population has shown that unlicensed drivers are over-represented in serious crashes and are more likely to engage in higher-risk behaviours.33 it is unclear why unlicensed drivers would not be more frequently involved in fatal crashes given their representation in the total sample. it is important to recognise that, in this analysis, the classification of “unlicensed” included drivers with the wrong class of licence as well as those with no licence. it is important to note, however, that there is no current licence demerit point system in oman, meaning that unlicensed drivers in the current sample represent those who have never received the appropriate type of licence for heavy vehicle driving. the finding that holding a licence increases the likelihood of a fatality could be explained predominantly by the much higher prevalence of unlicensed drivers in non-fatal crashes, perhaps indicating a higher proportion of minor error-related crashes from lack of driving skills and experience. nonetheless, it is clear that the proportion of drivers without a licence in the current sample demonstrates a need to increase appropriate licensing in oman. moreover, the unexpected trend of crash severity related to licence status may highlight a need to improve the current licensing standards. crash type was also significantly predictive of the likelihood of fatalities. it is to be expected that when a heavy vehicle crash is classified as involving an animal or person being run over, those involving humans would have a much higher fatality rate. unfortunately, it was not possible to distinguish in the database which crashes involved an animal and which involved a human being run over; thus, gaining a further understanding of the exact likelihood of these types of crashes influencing fatality rates was not possible. for example, it may be the case that 100% of crashes which involved a human being run over were fatal. single-vehicle crashes (overturned and fixed vehicles-object collisions) were less likely to result in a fatality. given the mass of heavy vehicles, and the relative protection given to truck drivers inside the vehicle, it is not surprising that crashes involving other vehicles would result in a higher risk of fatalities than single-vehicle crashes. nonetheless, it should be noted that recent reports from australia have shown that fatalities resulting from multivehicle crashes are typically the fault of the other vehicle’s driver.13 when a single-vehicle crash occurs, it is more likely to lead to a truck driver’s death. thus, it is an unusual finding that, within at-fault heavy vehicle crashes in oman, single-vehicle crashes were at lower risk of resulting in fatalities. without further examination to separate truck driver fatalities from other road user fatalities, and to better understand factors related to the non-fault vehicles, it is difficult to understand the implication of this finding. the final category of factors which contributed to the likelihood of fatalities was the reason for a crash. while there were only three crash reasons that were significant in the univariate analysis, the use of speeding as a reference category revealed five significant predictors within this category. specifically, crashes caused by fatigue, overtaking and vehicle defects were all more likely to result in fatalities than crashes predominantly attributed to speeding. while the issues associated with detecting fatigue in crashes were discussed above, it is worth noting that despite the significant finding in the current analysis, the very small number of fatigue-related crashes, most likely due to under-reporting, prevents any meaningful interpretation of the associated likelihood of fatalities. overtaking may be viewed internationally as an unusual predictor of crashes; however, it should be noted that, within oman, heavy vehicles are not permitted to overtake. for this reason, there may be other dangerous behaviours that occur while overtaking, as drivers may be in a rush to complete the manoeuvre. further investigation is required to understand the association between overtaking and islam al-bulushi, jason edwards, jeremy davey, kerry armstrong, hamed al-reesi and khalid al-shamsi special contribution | e199 fatalities in heavy vehicle crashes. vehicle defects have been commonly associated with the likelihood of crashes; however, tyre defects have specifically been associated with increased crash severity.17 while it is not possible to determine what type of vehicle defects were associated with crash severity in the current dataset, anecdotally, a high number of trucks have bald tyres in oman. additionally, the fines that exist for bald tyres in oman are insufficient when compared to the cost of replacing tyres. in fact, when considering only the financial implications, it is cheaper to receive a high number of fines than to replace a single tyre. while further research is needed to explain the variation in fatalities associated with vehicle defects, tyre defects may play a significant role in these crashes. the final two crash causes that were significantly less likely to produce fatalities than speeding were failure to keep a safe distance behind the preceding vehicle and incorrect manoeuvres. failing to keep a safe distance typically results in rear-end crashes which could be expected to produce lower fatality rates. unfortunately, an incorrect manoeuvre is a somewhat vague category that is not easily interpretable. f u t u r e d i r e c t i o n s during the analysis of the findings, a number of key directions for future research emerged. due to the nature of the data analysed and their inherent limitations, this analysis primarily highlighted specific areas requiring research in the omani context. there is a need for an estimation of km travelled per vehicle in order to understand the relative risk presented by heavy vehicles. in the current data, heavy vehicles appeared representative of their registration numbers, which may actually indicate that these drivers are under-represented in the statistics, given that trucks usually travel further and more often than other vehicles. there is also a need for research to examine why drivers aged 41–50 years were at a higher risk of fatalities; to understand the impact of cultural differences between expatriate and omani drivers so as to enable targeted initiatives; to differentiate between fatality risks for truck drivers and members of the general public in heavy vehicle crashes, and to better understand the role of overtaking in heavy vehicle crashes in oman. due to the high representation of younger drivers in the current dataset, it is clear that specific initiatives should be aimed at these drivers, perhaps by implementing a graduated driver licensing system, as well as investigating potential issues with the current licensing system of heavy vehicle drivers in oman. finally, there is a need for a more thorough crash investigation process. the current investigation process may be sufficient for identifying culpability and resolving legal issues related to crashes, but the data do not seem sufficient for understanding road safety in oman. without more comprehensive data, it is difficult to determine the relative contributions of different factors and to determine paths forward for future initiatives. the main issues in the current investigation process and dataset include unclear methods to determine the impact of fatigue; a lack of information about the involved vehicles and drivers who were not deemed culpable; a lack of data regarding multiple crash causes and behaviour; unclear information about vehicle defects and incorrect manoeuvres, and the combination of crashes involving a pedestrian or animals being run over into a single category. if police data are to provide sufficient information about crashes to help direct future government and policing efforts, there is a need to address each of these issues and conduct an evaluation of the current investigation process to identify weaknesses. despite limitations in the data, a broad range of factors were found to be significantly related to fatal crashes, including factors associated with people, society and culture, behaviour, vehicles, roads and government policies and practices, including licensing. this highlights the need for a broad approach to address the issue of heavy vehicle safety in oman. as can be seen by these data, road safety is a complex topic, requiring strategies which target the many groups that share responsibility for improving outcomes. this lends itself to a ‘safe system’ approach, in which all aspects of the road network are addressed and all associated parties are involved to produce a safer road network for all users. this approach is used in other countries, including australia, to great effect.34 additionally, it is important to recognise that, unlike private road users, heavy vehicle drivers are performing a transportation service and typically do so under the employment of an organisation. there is a need for all parties associated with the transportation of goods and customers via roads to play a role in ensuring everyone’s safety. some countries, such as australia, have implemented laws which require that all parties who have a role in heavy vehicle transport be accountable for safety. within oman, the inclusion of heavy vehicles as workplaces under health and safety legislation could increase employer involvement in ensuring safety. furthermore, the introduction of supply chain laws which hold both customers and organisations accountable should further ensure that safety is sufficiently prioritise within the industry. heavy vehicle crash characteristics in oman 2009-2011 e200 | squ medical journal, may 2015, volume 15, issue 2 conclusion increased development within oman has also increased the need for heavy vehicles, thereby increasing the risk of traffic accidents involving these vehicles. data analysis of police records revealed that there were 3,114 crashes in oman involving heavy vehicles (between january 2009 and december 2011). while the majority of these crashes were attributed to driver behaviours, a small proportion were attributed to factors relating to the vehicle, road and climate. fatalities were more likely for drivers aged 41–50 years, those not wearing seatbelts and those who had the correct licence. when compared to the most common crash cause (speeding), fatigue, overtaking and vehicle defect-related crashes were more likely to result in a fatality. this analysis highlighted the need for further research on crash investigation processes as well as an improvements to the current licensing system in oman and methods to incorporate age and culture-targeted road safety initiatives for heavy vehicle operators. a c k n o w l e d g e m e n t s the research team wishes to acknowledge the support of the rop in providing and sharing the data required for the analysis and interpretation of the results. the research team also acknowledges the assistance of the research council-oman in supporting communication with several governmental agencies and private organisations to enable this work. this report reflects research findings only and not the legislation or policy positions of the rop or any other governmental associated bodies. references 1. ganguly ss, al-shafaee ma, al-lawati ja, dutta pk, duttagupta kk. epidemiological transition of some diseases in oman: a situational analysis. eastern med health j 2009; 15:209–18. 2. ministry of health. annual health reports (1985–2009). muscat, oman: ministry of health. 3. al-adawi s, dorvlo as, al-naamani a, glenn mb, karamouz n, chae h, zaidan za, et al. the ineffectiveness of the hospital anxiety and depression scale for diagnosis in an omani traumatic brain injured population. brain inj 2007; 21:385–93. doi: 10.1080/02699050701311059. 4. directorate general of traffic. traffic statistics report, 2011. muscat, oman: royal oman police. 5. al-reesi h. the epidemiology of road traffic injuries in the sultanate of oman: evaluating the contribution of risky driver behavior. master's thesis, 2011. muscat, oman: sultan qaboos university, 2011. 6. al-reesi h, ganguly ss, al-adawi s, laflamme l, hasselberg m, al-maniri a. economic growth, motorization, and road traffic injuries in the sultanate of oman, 1985-2009. traffic inj prev 2013; 14:322–8. doi: 10.1080/15389588.2012.694088. 7. world health organization. global status report on road safety 2013: supporting a decade of action. from: www.who. int/violence_injury_prevention/road_safety_status/2013/en/ accessed: jul 2014. 8. häkkänen h, summala h. fatal traffic accidents among trailer truck drivers and accident causes as viewed by other truck drivers. accident anal prev 2001; 33:187–96. doi: 10.1016/ s0001-4575(00)00030-0. 9. al-maniri aa, al-reesi h, al-zakwani i, nasrullah m. road traffic fatalities in oman from 1995 to 2009: evidence from police reports. int j prev med 2013; 4:656–63. 10. directorate general of traffic, traffic safety institute. heavy vehicle driver's handbook. muscat, oman: royal oman police. 11. field a. discovering statistics using ibm spss. 2nd ed. thousand oaks, california, usa: sage publications inc., 2005. 12. driscoll op; national centre for truck accident research. major accident investigation report, 2009. from: www.nti. com.au/files/files/n tarc/major_accident_investigation_ report_20091.pdf accessed: jul 2014. 13. driscoll op; national centre for truck accident research. major accident investigation report, 2013. from: www. dieselnews.com.au/wp-content/uploads/2013/05/2013_nti_ major_accident_investigation_report_-_web.pdf accessed: jul 2014. 14. national center for statistics and information, 2012. the statistical year book, 2012. muscat, oman: national center for statistics and information. 15. national center for statistics and information, 2010. final results of census 2010. muscat, oman: national center for statistics and information. 16. ward nj, özkan t. in consideration of traffic safety culture. transp res part f traffic psychol behav 2014; 26:291–2. doi: 10.1016/j.trf.2014.09.004. 17. chen f, chen s. injury severities of truck drivers in singleand multi-vehicle accidents on rural highways. accid anal prev 2011; 43:1677–88. doi: 10.1016/j.aap.2011.03.026. 18. golob tf, recker ww. an analysis of truck-involved freeway accidents using log-linear modeling. j safety res 1987; 18:121– 36. doi: 10.1016/0022-4375(87)90003-x. 19. hanowski rj, perez ma, dingus ta. driver distraction in longhaul truck drivers. transp res part f traffic psychol behav 2005; 8:441–58. doi: 10.1016/j.trf.2005.08.001. 20. mcknight aj, bahouth gt. analysis of large truck rollover crashes. traffic inj prev 2009; 10:421–6. doi: 10.1080/153 89580903135291. 21. sullman mj, meadows ml, pajo kb. aberrant driving behaviours amongst new zealand truck drivers. transp res part f traffic psychol behav 2002; 5:217–32. doi: 10.1016/ s1369-8478(02)00019-0. 22. carter n, ulfberg j, nyström b, edling c. sleep debt, sleepiness and accidents among males in the general population and male professional drivers. accid anal prev 2003; 35:613–7. doi: 10.1016/s0001-4575(02)00033-7. 23. hanowski rj, hickman js, wierwille ww, keisler a. a descriptive analysis of light vehicle-heavy vehicle interactions using in situ driving data. accid anal prev 2007; 39:169–79. doi: 10.1016/j.aap.2006.06.016. 24. mccartt at, rohrbaugh jw, hammer mc, fuller sz. factors associated with falling asleep at the wheel among long-distance truck drivers. accid anal prev 2000; 32:493–504. doi: 10.1016/ s0001-4575(99)00067-6. 25. brodie l, bugeja l, ibrahim je. heavy vehicle driver fatalities: learnings from fatal road crash investigations in victoria. accid anal prev 2009; 41:557–64. doi: 10.1016/j.aap.2009.02.005. islam al-bulushi, jason edwards, jeremy davey, kerry armstrong, hamed al-reesi and khalid al-shamsi special contribution | e201 26. gander ph, marshall ns, jamesb i, le quesne l. investigating driver fatigue in truck crashes: trial of a systematic methodology. transp res part f traffic psychol behav 2006; 9:65–76. doi: 10.1016/j.trf.2005.09.001. 27. maclean aw, davies dr, thiele k. the hazards and prevention of driving while sleepy. sleep med rev 2003; 7:507–21. doi: 10.1016/s1087-0792(03)90004-9. 28. curnow g. australian transport safety bureau heavy truck crash databases: what do the statistics tell us? from: www.researchgate.net/publication/267201257_australian_ transport_safety_bureau_heavy_truck_crash_databases_ what_do_the_statistics_tell_us accessed: jul 2014. 29. birdsey j, alterman t, li j, petersen mr, sestito j. mortality among members of a truck driver trade association. aaohn j 2010; 58:473–80. doi: 10.3928/08910162-20101018-01. 30. lemos lc, marqueze ec, sachi f, lorenzi-filho g, moreno cr. obstructive sleep apnea syndrome in truck drivers. j bras pneumol 2009; 35:500–6. 31. mayhew c, quinlan m. economic pressure, multi-tiered subcontracting and occupational health and safety in australian long-haul trucking. employee relat 2006; 28:212–29. doi: 10.1108/01425450610661216. 32. edwards j. safety culture and the australian heavy vehicle industry: a concept in chaos: an industry in need. from: e pr int s .qut .e du.au/72870/1/ja s on_edw ards_the sis .p df accessed: jul 2014. 33. watson bc. the crash involvement of unlicensed drivers in queensland. from: eprints.qut.edu.au/1555/1/1555.pdf accessed: jul 2014. 34. transport and infrastructure council. national road safety action plan 2015‒2017. from: www.transportinfrastructur ecouncil.gov.au/publications/files/national_road_safety_ action_plan_2015-2017.pdf accessed: jul 2014. sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e591−592, epub. 14th oct 14 submitted 26th jun 14 accepted 7th aug 14 رد: نتائج احلمل ثالثي التوائم يف األمهات واألجنة يف مستشفى رعاية ثالثي يف سلطنة عمان re: maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman letter to the editor sir, i read with interest the study by al-shukri et al. published in the squmj may 2014 issue.1 of the 18 sets of triplets, the authors stated that 16 (89%) were conceived through assisted reproductive technology (art) and the remaining two (11%) were conceived spontaneously.1 among the 54 studied neonates, neonatal complications included hyaline membrane disease in 25 (46%), hyperbilirubinaemia in 23 (43%), sepsis in 18 (33%), anaemia in 8 (15%), patent ductus arteriosus/atrial septal defect in 5 (9%) and necrotising enterocolitis in two neonates (4%). surprisingly, there were no cases of birth defects reported. this seems interesting considering the following two points. first, it is well-known that art is significantly associated with various genetic and chromosomal anomalies.2,3 it is unclear if such an association is related to underlying infertility, the use of art or maternal and paternal risk factors. recently, there is increasing evidence that infertility or subfertility is an independent risk factor for obstetrical complications and adverse perinatal outcomes, even without the use of art.4 second, birth defects are common in oman with a substantial birth prevalence of major malformations (25.2 per 1,000 births), where genetic factors were found to be generally implicated for 63.4% of congenital malformations.5 i presume that the reasons behind the lack of cases of birth defects in al-shukri et al.’s study might be related to the short three-year study period (between january 2009 and december 2011) as well as to the other three limitations already mentioned by the authors, namely the small study population (n = 18), the retrospective nature of the study and the fact that it was a single centre experience.1 conducting large-scale multicentre studies over extended periods of time could better address the exact perinatal outcomes of art-associated triplet pregnancies in oman. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al-shukri m, khan d, al-hadrami a, al-riyami n, gowri v, haddabi r, et al. maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman. sultan qaboos univ med j 2014; 14:e204–10. 2. farhi a, reichman b, boyko v, mashiach s, hourvitz a, margalioth ej, et al. congenital malformations in infants conceived following assisted reproductive technology in comparison with spontaneously conceived infants. j matern fetal neonatal med 2013; 26:1171–9. doi: 10.3109/14767058.2013.776535. 3. hansen m, kurinczuk jj, milne e, de klerk n, bower c. assisted reproductive technology and birth defects: a systematic review and metaanalysis. hum reprod update 2013; 19:330–53. doi: 10.1093/humupd/dmt006. 4. society of obstetricians and gynaecologists of canada; okun n, sierra s. pregnancy outcomes after assisted human reproduction. j obstet gynaecol can 2014; 36:64–83. 5. sawardekar kp. profile of major congenital malformations at nizwa hospital, oman: 10-year review. j paediatr child health 2005; 41:323– 30. doi: 10.1111/j.1440-1754.2005.00625.x. re: maternal and fetal outcomes of triple gestation in a tertiary hospital in oman 592 | squ medical journal, november 2014, volume 14, issue 4 response from the authors sir, we thank you for your interest in our work and for your valuable comments. although it was not highlighted in our article, birth defects or congenital abnormalities were included in the collected data. among the 54 neonates, no birth defects were found (either major or minor) up to the point of their discharge from the hospital.1 the study which reported the prevalence of birth defects in oman (25.2 per 1,000) studied 524 neonates among 20,828 omani singleton births over a 10-year period.2 the data were also from a single hospital that covered one unique area of oman (the al-dakhiliyah region in nizwa). a total of 70 out of the 524 neonates (12.9%) were reported to have chromosomal abnormalities.2 a study from another region of oman does not match this high prevalence.3 the small population of patients in our study were heterogeneous in terms of their regional background.1 cytogenetics testing for chromosomal abnormalities were not performed for any of the neonates as there was no clinical suspicion of birth defects or dysmorphic features. in the united arab emirates, 401 out of 24,233 infants had a major defect, with an incidence of 16.6 per 1,000.4 if it is assumed that the reported incidence of birth defects (25 per 1,000) is representative of the whole omani population,2 one congenital abnormality would have been missed in our studied population.1 although 16 out of 18 of the studied pregnancies were treated for infertility,1 this number is not powered to support either infertility or art as risk factors for birth defects. as highlighted in your comments, our study had limitations in terms of reporting a significant rate of birth defects.1 we strongly agree that large-scale multicentre studies over an extended period of time are imperative to determine the outcomes of art-associated triplet pregnancies in oman. maryam al-shukri,1 durdana khan,1 atka al-hadrami,2 nihal al-riyami,1 *vaidyanathan gowri,3 rahma haddabi,1 mohammed abdellatif,4 tamima al-dughaishi1 departments of 1obstetrics & gynaecology and 4child health, sultan qaboos university hospital; 2oman medical specialty board; 3department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: gowri@squ.edu.om references 1. al-shukri m, khan d, al-hadrami a, al-riyami n, gowri v, haddabi r, et al. maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman. sultan qaboos univ med j 2014; 14:e204–10. 2. sawardekar kp. profile of major congenital malformations at nizwa hospital, oman: 10-year review. j paediatr child health 2005; 41:323– 30. doi: 10.1111/j.1440-1754.2005.00625.x. 3. patel pk. profile of major congenital anomalies in the dhahira region, oman. ann saudi med 2007; 27:106–11. 4. al talabani j, shubbar ai, mustafa ke. major congenital malformations in united arab emirates (uae): need for genetic counselling. ann hum genet 1998; 62;411–18. doi: 10.1046/j.1469-1809.1998.6250411.x. املؤمتر العاملي األول للتطورات يف طب التوليد وأمراض النساء جامعة السلطان قابوس، 6–4 دي�صمرب 2013م 1st international conference on advances in obstetrics & gynaecology oral presentations selected abstracts sultan qaboos university, 4–6 december 2013 abstracts male infertility for a generalist: what can you offer? dr. sandro esteves director, androfert referral center for male reproduction in brazil, campinas, brazil. e-mail: s.esteves@androfert.com.br in the era of assisted reproductive techniques (art), the current challenge is to accommodate established and new treatment modalities that are both cost-effective and evidence-based. the presentation reviews the evolving concepts in male infertility for gynaecologists involved in the care of men and women experiencing difficulty in conceiving. novel diagnostic testing allows the identification of a significant proportion of patients previously misdiagnosed as having idiopathic or unexplained male infertility. sperm deoxyribonucleic acid fragmentation and oxidative stress are two of the tests already available in the modern clinical andrology laboratory; their results aid the clinician to define the best management strategy. when treating the male partner by medical and surgical therapy, our focus is not only to improve the couple’s chance of having an unassisted pregnancy but also to ameliorate their chances of success with art. the use of oral antioxidant supplementation is now commonplace, especially given the evidence that antioxidants improve the outcomes of pregnancy and live birth in subfertile couples undergoing art. hormonal therapy, including aromatase inhibitors and recombinant human chorionic gonadotropin, are easy-to-use medications intended to treat hypogonadal infertile males. in the surgical field, we have incorporated microsurgery to treat common male diseases such as varicocele; this not only increases the chances of spontaneous conception, but also increases the likelihood of pregnancy with art. for azoospermic men with obstructive problems, microsurgery offers the best method to reconstruct the reproductive tract. the method also improves the likelihood of retrieving sperm for use with intracytoplasmic sperm injections for azoospermic men with non-treatable conditions, such as those with non-obstructive azoospermia. obesity and male infertility: a problem of pandemic proportions dr. sandro esteves director, androfert referral center for male reproduction in brazil, campinas, brazil. e-mail: s.esteves@androfert.com.br obesity has achieved pandemic proportions around the world and is considered a major risk factor for male infertility. this presentation examines the top questions involved in obesity-related male infertility. first, it covers why and how obesity causes male infertility; the effects of elevated aromatase activity and secretion of adipose-derived hormones are also discussed, exploring how hormone imbalance can result in secondary hypogonadism and infertility. second, the presentation describes how to identify patients who are candidates for medical treatment; for example, the testosterone/estradiol (t/e2) ratio is a practical tool to assess aromatase hyperactivity in men. finally, modern strategies to treat obese men with difficulties in conceiving are presented, including the use of oral third-generation aromatase inhibitors and assisted-conception modalities. tailoring ovarian stimulation using biomarkers dr. sandro esteves director, androfert referral center for male reproduction in brazil, campinas, brazil. e-mail: s.esteves@androfert.com.br biomarkers are useful tools in the context of controlled ovarian stimulation (cos) not only to predict the ovarian response to stimulation but also to define an individualised treatment strategy. although several biomarkers are available (hormonal, functional and genetic), two of them, anti-müllerian hormone (amh) and antral follicle count (afc), have dominated the clinical scenario in recent years. amh and afc are valid biomarkers because they can identify with similar accuracy (~80%) patients with diminished ovarian reserve (dor) and those at risk of excessive response. amh is a dimeric glycoprotein exclusively produced by granulosa cells of preantral (primary and secondary) and small antral follicles. unlike follicle stimulating hormone (fsh) and inhibin b, amh correlates to the number of follicles at a gonadotropin independent stage, and therefore reflects the pool of remaining follicles in the ovary. in contrast, afc assesses the cohort of follicles measuring 2–10 mm in the early follicular phase. these follicles are in an early antral phase and easily detected by transvaginal ultrasound, as they contain a small amount of antral fluid. the number of small follicles at the beginning of the cycle represents the actual functional quantitative ovarian reserve as they can be stimulated by exogenous gonadotropins. a gradual decrease in amh serum levels and number of sonographically-detectable antral follicles occurs with advancing age. amh has low intraand inter-cycle variability, making it possible to assess its levels at any day and in a single measurement. assays to measure amh are basically enzyme-linked immunosorbent assays (elisa); recently there has been an evolution from in-house assays to commercial amh kits such as dsl and immunotech. however, because of different monoclonal antibodies and different standards, reported the abstracts for the poster presentations of this conference can be found online at: www.web.squ.edu.om/squmj/index.asp sultan qaboos university, 4–6 december 2013 abstracts | e271 values can differ substantially. dsl and immunotech are now one company and produce a single kit to measure amh, named the beckman-couter generation ii assay, a hybrid of the previous ones. yet, in-house assays are still used and an international standard does not exist. importantly, amh results can be affected by other factors (improper sample handling, storage and transportation). before applying the amh cut-off points, we need to ensure that the assay is the same one used in the reference population and to determine whether the reference population matches our own patient’s profile. afc has moderate to low inter-cycle fluctuation and is associated with high intraand inter-observer reliability in the hands of experienced observers. nevertheless, difficulties with interpretation and standardisation have been reported due to the different methods of scanning the ovaries and counting the follicles. we should exercise caution in applying afc cut-off points because afc reflects a given potential oocyte yield that can be altered by the stimulation strategy. the main clinical utility of amh and afc is to help clinicians correctly identify patients at risk of elevated response and duration of response, and therefore individualise cos accordingly. one example is the use of lower starting doses of recombinant human (rec-h) fsh in association with gonadotropin-releasing hormone (gnrh) antagonists in women at risk of excessive response. this approach is shown to sustain pregnancy rates while minimising the ovarian hyperstimulation syndrome (ohss) risk. in addition, it allows the use of a gnrh-agonist trigger that can virtually eliminate ohss. another example is luteinising hormone (lh) supplementation in women screened as having dor which can increase pregnancy rates by c. 30% by adding rec-hlh to fsh. an increase in androgen production, for its later aromatisation to estrogens by a dose-dependent lh activity at the follicular level, may improve the follicular milieu and oocyte quality, which reflect on embryo quality and implantation. our strategy has been to individualise cos in accordance with amh levels. cut-off points of 2.1 and 0.82 ng/ml have been shown to predict excessive and poor response to cos, respectively. in the former, lower starting doses of rec-h fsh (112.5–150 iu) and gnrh antagonists are used. in the latter, 75–150 iu of rec-h lh is added to the rec-h fsh regimen in both gnrh analogue protocols. approximately 70% of patients with a predicted high or poor response by amh then achieve a normal response. moreover, moderate/severe ohss has been practically eliminated while cancellation rates have been kept around 10% in patients with dor. in summary, there is now sound evidence to support the clinical use of amh and afc before cos. however, given the limitations of the biomarkers, clinicians should interpret cut-off points cautiously when using amh and afc as sole predictors of ovarian response. for pregnancy, none of the biomarkers are accurate predictors. ovarian response to cos reflects the quantitative ovarian reserve; occurrence of pregnancy after in vitro fertilisation is related to several factors including qualitative ovarian reserve, gametes/embryo quality and endometrial receptivity. fetal renal anomalies dr. greg ryan division of feto-maternal medicine, mount sinai hospital, university of toronto, canada. e-mail: toronto-gryan@mtsinai.on.ca the ultrasound examination of the normal and abnormal fetal urinary tract are presented. specific renal abnormalities will be reviewed, including hydronephrosis/pyelectasis, renal agenesis, megacystis and lower urinary tract obstruction (luto), megaureter and megalouretha, renal dysplasia, echogenic kidneys, ectopic kidneys and polycystic and multicystic kidney disease. we present the options for evaluation and treatment of luto, including the results of the recent percutaneous shunting in lower urinary tract obstruction (pluto) trial. intrauterine transfusion dr. greg ryan division of feto-maternal medicine, mount sinai hospital, university of toronto, canada. e-mail: toronto-gryan@mtsinai.on.ca the aetiology, evaluation and treatment of fetal anaemia, including rhesus alloimmunisation, parvovirus infection and transplacental haemorrhage are discussed. we present the role of amniocentesis and discuss both non-invasive and invasive testing. the emerging role of cell-free fetal deoxyribonucleic acid (cff-dna) is presented and the optimal timing of delivery and neonatal management reviewed. complications of monochorionic (mc) twins dr. greg ryan division of feto-maternal medicine, mount sinai hospital, university of toronto, canada. e-mail: toronto-gryan@mtsinai.on.ca the crucial importance of early correct identification of chorionicity is discussed. national guidelines and standards for monitoring mc twins are reviewed. the aetiology of twin-twin transfusion syndrome (ttts) are reviewed, and the differentiation between ttts and selective mc intrauterine growth restriction presented. the therapy for ttts, including selective laser ablation of placental anastomoses, serial amnioreduction and cord occlusion and the shortand long-term development of fetuses undergoing laser for ttts are discussed. essential ingredients in developing a faculty of medical educators mr. hani w. fawzi south tyneside nhs foundation trust, uk. e-mail: hani.fawzi@sthct.nhs.uk this presentation discusses the development of medical education as an emerging interest. it will outline the 12 roles of a medical teacher within a tool that would support development of a faculty of medical educators. it will attempt to define professional development and then highlight how to develop professionally as an individual in the first instance and then how the institute should develop. the conscious competence model and styles of learning, as well as the experiential learning cycle, are discussed in the context of assessing oneself and one’s abilities. the presentation will highlight the need for personal development as an individual and have the ripple effect of opportunities to identify gaps in the institute. morbid obesity and pregnancy dr. lovina machado department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: lovina1857@gmail.com the prevalence of obesity has reached pandemic proportions worldwide. in 2005, who estimated that worldwide 1.6 billion adults were overweight and 400 million adults obese. current predictions are that by 2015 a total of 2.3 billion adults will be overweight and 700 million obese. the incidence of obesity among pregnant women is presently estimated at between 18.5% and 38.3%. adiposity has 1st international conference on advances in obstetrics & gynaecology oral presentations selected abstracts e272 | squ medical journal, may 2014, volume 14, issue 2 a damaging effect on every aspect of female reproductive life. morbid obesity in pregnancy is linked to a myriad of adverse pregnancy outcomes. during the antepartum period, there is an increased risk of miscarriages, hypertensive disorders, gestational diabetes mellitus, venous thromboembolism, iatrogenic preterm delivery and respiratory complications. intrapartum risks include an increased incidence of induction of labour, slow progression of labour, higher caesarean section rates, postpartum haemorrhage and infection. from the fetal perspective, congenital malformations, large-for-gestational-age infants, stillbirths and shoulder dystocia occur with increased frequency. such newborns are at increased risk of developing metabolic syndrome later in life. operative delivery in morbidly obese parturients is technically and logistically challenging for the anaesthetist and obstetricians. it is no surprise, then, that maternal and neonatal morbidity and mortality are increasing. the presentation focuses on the adverse impact of morbid obesity on the continuum of pregnancy with special reference to oman and suggests methods to optimise obstetric outcomes in these women. a concerted effort must be made to promote lifestyle changes and adequate exercise across society, especially among children and young women. the role of laparoscopy in gynaecological oncology dr. stephen dobbs belfast city hospital, uk. e-mail: stephendobbs@yahoo.com laparoscopy was developed in the late 1960s. since then, the applications for laparoscopy have increased dramatically with the development of modern laparoscopic systems. today in gynaecological oncology, laparoscopic surgery (ls) plays a key role in providing a comprehensive surgical service. ls provides the benefits of shorter inpatient stays, reduced blood loss, reduced postoperative morbidity and equable surgical results compared to open surgery. on the other hand, ls requires a long and steep learning curve for the surgeon and longer operating times compared to open procedures. a recent survey estimated that only 20% of gynaecological oncology operations in the uk were performed laparoscopically. this may in part be due to a lack of mentoring and a deficiency of advanced laparoscopic courses. in gynaecological oncology, ls can be used for diagnostic assessment, the staging of local and advanced disease and assessment for debulking surgery. ls can be utilised in most treatments for endometrial cancer including hysterectomy, pelvic and para-aortic nodal dissection. in cervical cancer, ls is used for radical hysterectomy, radical trachelectomy and para-aortic nodal dissection in locally advanced cancer. there is also a role for ls in the assessment/treatment of isolated recurrent cancers. recent developments include robotic surgery and 3-d ls. the future of gynaecological oncology will be centred around the provision of ls. cervical screening and the role of the human papilloma virus (hpv) vaccine dr. stephen dobbs belfast city hospital, uk. e-mail: stephendobbs@yahoo.com cervical cancer remains the commonest cause of death from gynaecological cancer worldwide. it is accepted that hpv infection is the major risk factor for cervical cancer. there are over 120 different subtypes of hpv and around 20 high-risk types are responsible for over 99% of all cervical cancers. of the high-risk group, types 16 and 18 are the most prevalent, causing over 70% of cervical cancers. up to 80% of sexually active women will be infected with hpv at some time during their lives. exposure is reduced with barrier contraception. currently, in the uk all 12to 13-year-old girls are offered hpv vaccinations through a national immunisation programme introduced in 2008. vaccination offers protection against hpv types 16 and 18. the vaccines are over 98% effective in preventing cervical abnormalities associated with these types. hpv testing is currently utilised in the cervical screening programme in two ways. in women with low grade changes (borderline or mild dyskaryosis) the presence of high-risk hpv indicates a higher risk of occult high-grade cervical intraepithelial neoplasia (cin) and these patients are referred for colposcopy. conversely, those patients with mild abnormalities and who are hpv-negative have a negligible risk of cancer and can return to normal screening frequency. the hpv testing is used as a ‘test of cure’ in women who have undergone treatment for cin at the six-month post-treatment smear. those patients who are cytology negative and hpv-negative can return to the normal three-yearly screening, whereas those patients who are hpv-positive are at a higher risk of residual/recurrent cin and need referral to colposcopy. despite the advances in hpv immunisation and testing, women still need to attend regular cervical cytology to detect other hpv causes of cervical cancer and pre-cancer. worldwide, strategies are needed to implement cheap and effective methods of screening for cervical cancer, utilising our knowledge and understanding of the disease process. hysterectomy for enlarged uteri: total laparoscopic or minimally invasive vaginal hysterectomy? dr. mohamed mabrouk senior consultant, gynecologic oncology & minimally invasive pelvic surgery unit, sacred heart hospital, negrar, verona, italy; lecturer in obstetrics and gynecology, faculty of medicine, alexandria university, egypt. e-mail: mohamed.mabrouk@sacrocuore.it hysterectomy remains the second most common gynaecological operation, after caesarean section. the three main approaches for hysterectomy are the abdominal, vaginal and laparoscopic routes. for the large-sized uterus with benign pathologies, the abdominal approach is the most commonly used, while uterine dimensions are considered a limitation for the laparoscopic and vaginal routes. laparoscopic hysterectomy (lh) for large uteri has been the subject of controversy. the vaginal approach for hysterectomy (vh) is becoming widely utilised for non-prolapsed uteri with benign uterine diseases. some studies support the choice of vaginal hysterectomy as a valid alternative to the abdominal hysterectomy for enlarged uteri. recently, there has been a quest for efficient and fast haemostatic techniques that can safely replace conventional suture ligature in this approach. bipolar vessel sealing systems (bvss) are haemostatic control devices that can seal blood vessels up to 7 mm in diameter by denaturing collagen and elastin within the vessel wall and in the surrounding connective tissue. the use of variable bvss has been evaluated in gynaecological surgery and there is a general consensus about the effectiveness and safety of their use in vaginal hysterectomy, with varying degrees of difficulty. endometriosis: get to know your enemy better dr. mohamed mabrouk senior consultant, gynecologic oncology & minimally invasive pelvic surgery unit, sacred heart hospital, negrar, verona, italy; lecturer in obstetrics and gynecology, faculty of medicine, alexandria university, egypt. e-mail: mohamed.mabrouk@sacrocuore.it endometriosis prevalence rates in the general population are unknown, because a definitive diagnosis is established only at laparoscopy and diagnostic accuracy depends on the surgeon’s skills and experience in the disease. however, based on community prevalence sultan qaboos university, 4–6 december 2013 abstracts | e273 estimates of symptoms, endometriosis probably affects 10% of all and 30%–50% of symptomatic premenopausal women. this represents 176 million women worldwide. endometriosis may develop anywhere within the pelvis and on other extra-pelvic sites. macroscopically, three forms of endometriosis are described: (1) superficial (peritoneal); (2) ovarian endometriosis (endometriotic cyst of the ovary or ovarian endometrioma); (3) and deep infiltrating endometriosis (die). in die, endometriotic nodules extend >5 mm under the peritoneal surface and may involve the utero-sacral ligaments, vagina, bowel, bladder or ureters. the depth of infiltration is related to the type and severity of symptoms. where present, endometriotic tissues can be associated with extensive fibrosis and adhesion formation, causing marked distortion of pelvic anatomy. the disease severity can be assessed by simply describing the findings at surgery or quantitatively, using a classification system such as the one developed by the american society for reproductive medicine in 1997. however, there is no correlation between such classification systems and the type or severity of pain symptoms. pregnancy-associated breast cancer dr. ikram burney department of medical oncology, sultan qaboos university hospital, muscat, oman. e-mail: ikramburney@hotmail.com pregnancy-associated cancer (pac) is defined as a cancer diagnosed during pregnancy or within one year post-partum. pac constitutes 0.07–0.1% of all cancers. breast cancer is the most common pac, followed by carcinoma of the cervix, lymphoma, leukaemia, melanoma and ovarian cancer. the incidence of breast cancer during pregnancy is reported to be 1:3,000–1:10,000 pregnancies. between 0.2–3.8% of all breast cancers occur coincidentally with pregnancy. the prevalence of pregnancy-associated breast cancer (pabc) has been shown to increase with maternal age, especially in the developed countries. the treatment of breast cancer is multi-modal and often involves surgery, sometimes with radiotherapy, systemic chemotherapy and hormone therapy. pabc is unusual; many surgeons, obstetricians and oncologists have only a limited, if any, experience in the management of cancer during pregnancy. the average obstetrician would see 2–3 cases in a 40-year career. for several years, treatment of breast cancer and the continuation of pregnancy were considered mutually exclusive. however, with recent experience in the use of cytotoxic chemotherapy in the second and the third trimester, it is possible to continue the pregnancy and the systemic treatment. however, monoclonal antibodies are contraindicated and exposure to radiation should be minimised and kept to less than 10cgy. stage for stage, the prognosis of pabc has been shown to be the same as for cancer not associated with pregnancy. the fetal outcome is dependent mainly on the term pregnancy, rather than exposure to surgery and chemotherapy while in utero. the risk of recurrence does not increase with subsequent pregnancies. while there is a plethora of data on the incidence, management and outcomes of pabc from the developed world, there are very little data from developing countries, especially in the middle east, where the demographic features of breast cancer are different. for example, the mean age at the time of diagnosis of breast cancer in oman is 47 years and almost one-third of patients are in the child-bearing (less than 40 years) age. on the other hand, the fertility rate is high, and the mean number of pregnancies in the country is more than seven. it is plausible to think therefore that pabc may be even more common in developing countries. the incidence, pattern of presentations, the outcomes of breast cancer and of pregnancy of women treated for pabc from oman are presented. use of ultrasound to improve care of diabetes in pregnancy prof. badreldeen i. ahmed feto-maternal medicine centre, doha, qatar, and professor of obstetrics, weill cornell medical college, doha, qatar. e-mail: profbadreldeen@hotmail.com diabetes mellitus (dm) is one of the most serious non-communicable diseases (ncd). it has been described as a ‘slow-motion disaster’ and it is associated with morbidity, mortality and long-term disability. two out of three deaths globally are attributable to ncd. this presentation explores the means by which ultrasound can be helpful to the clinician managing a diabetic pregnancy. the following issues are addressed: (1) screening for vasculopathy in the first trimester; (2) deviation in fetal weight; (3) diagnosis of congenital malformation, and (4) how to monitor diabetic pregnant patients. regarding fetal weight, the importance and limitations of the transabdominal diameter formula to estimate fetal weight will be discussed. we discuss the role of 3-d technology in improving weight estimation in diabetic pregnancy. fractional limb volume which is based on 3-d technology and its role in diagnosis of small-forgestational age infants is also addressed. congenital anomalies are more common among diabetic pregnant patients. the cardiovascular system is the system most likely to be affected; however, diagnosis of fetal cardiac defect is very challenging. we discuss the role of new techniques of spatial-temporal image correlation (stic). stic is an automated device incorporated into the ultrasound probe and has the capacity to perform a slow sweep to acquire a single 3-d volume. this acquired volume is composed of a great number of 2-d frames and can be analysed and reanalysed as required to demonstrate all the required cardiac views. it also provides the examiner with the ability to review all images in a looped cine sequence. it is very critical in this new technology to acquire adequate volume. the monitoring of fetus growth and well-being in a diabetic pregnant patient can be difficult. the standard doppler test of the umblical and middle cerebral arteries is not very reliable and can give false reassurance. fetal acidaemia correlates significantly with changes in the ductus venous and hepatic artery blood flow. this relationship is explored in this presentation. regulating fertility treatment dr. maha al-khaduri senior consultant, department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: m.khaduri@gmail.com treatment for infertile couples has become widely available in many countries. there are several regulatory bodies around the world for fertility treatments. in the middle east there are fewer countries with fertility treatment regulations. in the arabian gulf, the two countries that have implemented fertility treatment regulations are saudi arabia and the united arab emirates. as infertility treatment advances in oman, there is a greater need to have a mechanism to regulate it. the principal tasks of this regulatory body are to license and monitor clinics that carry out in vitro fertilisation, insemination, pre-implantation genetic diagnosis, human embryo research and the storage of gametes (eggs and sperm) and embryos, in order to ensure that human embryos are used responsibly and that infertile patients are not exploited at a vulnerable time. is there evidence for cerclage in twins and higher-order pregnancies? dr. nihal al-riyami departments of obstetrics & gynaecology and maternal fetal medicine, sultan qaboos university hospital, muscat, oman. e-mail: drriyami@hotmail.com multiple gestation is increasing due to the expanded use of fertility treatments and older maternal age. it is associated with higher 1st international conference on advances in obstetrics & gynaecology oral presentations selected abstracts e274 | squ medical journal, may 2014, volume 14, issue 2 rates of almost every potential complication of pregnancy, with the exceptions of post-term pregnancy and macrosomia. the most serious risk is spontaneous preterm delivery, which plays a major role in the increased perinatal mortality and short-term and longterm morbidity observed in these infants. preterm delivery is caused by several risk factors including multiple gestation. in theory, the identification of risk factors for preterm delivery before conception or in early pregnancy provides an opportunity for intervention to prevent this complication. however, many preterm births occur among women with no risk factors and few interventions have been proven to prolong pregnancy in women at risk. these interventions include progesterone treatment modalities and cervical cerclage. the use of cervical cerclage to prevent preterm delivery in multiple gestation is controversial. the presentation includes the evidence of using cerclage in twins and higher-order pregnancies. progesterone therapy for prevention of preterm labour dr. tamima al-dughaishi department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: aldughaishit@hotmail.com preterm birth remains a major clinical problem. the prevalence in the usa increased from 6.3% of live births in 1981–1983 to 6.6% in 1991 and 7.6% in 2000, although a large portion of this increase is related to multiple pregnancies. there are very few interventions that improve the prognosis of preterm labour. the use of antenatal corticosteroids has been consistently shown to have such an effect, but most studies on tocolysis, with the exception of one recent report on nitroglycerin, have very limited clinical applications. almost 50 years ago, csapo et al. promoted the progesterone see-saw theory, which is that high progesterone levels prevent uterine contractions and low levels facilitate such contractions. this is one reason for the use of progesterone therapy in early pregnancy and the use of ru486, a progesterone antagonist, to induce abortions. it seems that the hormonal control of contractions and labour in humans is more complex than in other animals and that progesterone may have a more limited role than in animal models. recently several studies on the use of progesterone to prevent preterm labour have been published. the purpose of this presentation is to review these studies and outline the current role for the use of progesterone for this indication. breast cancer status in oman dr. adil alajmi consultant breast reconstructive surgeon, department of surgery, sultan qaboos university hospital, muscat, oman. e-mail: adilalajmi@hotmail.com breast cancer is the cancer with the highest incidence among females in oman. females with breast cancer in oman tend to be younger than theirwestern counterparts. the majority of patients present with advanced stage cancer and the tumours display aggressive features. this presentations describes the clinico-pathological features of the disease in oman with an analysis of prognostic factors and survival rates. a small propor¬tion of patients have breast conserving surgery; a relatively small number receive preoperative chemotherapy despite the locally advanced nature of disease. the overall survival and disease-free survival rates are favourable compared to other asian and arab countries. the presentation explains in part the inferior survival figures compared to white-american and european females. the following measures are strongly recommended to improve morbidity and mortality: increasing the awareness of breast cancer; the introduction of breast screening programmes; a multi-disciplinary approach to breast cancer management, and research on the molecular biology and genetic aspects of breast cancer to explore further the characteristics of breast cancer in oman. breast lumps, bumps and pain dr. sukhpal sawhney department of radiology & molecular imaging, sultan qaboos university hospital, muscat, oman. e-mail: sukh@squ.edu.om breast disease in women encompasses a wide variety of benign and malignant disorders. the most common breast problems are lumps, bumps, pain and nipple discharge. the majority of these women have benign breast disease. irrespective of the type of breast problem, the goal of imaging is to rule out cancer and address the patient’s symptoms. during the last decade, there have been tremendous advances in breast imaging. with the introduction of newer technologies, today’s breast care specialists are faced with challenges; not only because they have to understand the relative merits and weaknesses of each imaging approach, but also because they have to choose the right imaging modality for each particular patient. currently, mammography is the gold standard for the detection of breast cancer. despite recent technical advances and the introduction of digital imaging, mammography may miss as many as 10–25% of cancers, especially in dense breasts. newer modalities, such as digital tomosynthesis, ultrasound scans and magnetic resonance imaging help to increase cancer detection and to characterise benign and malignant disease, thus decreasing the need to perform invasive procedures and allaying patient anxiety. the presentation will familiarise clinicians with the different aspects of breast disease and their appearances in commonly-used imaging modalities. further, the breast imaging-reporting and data system (birads) classification will be introduced to enable a more comprehensive understanding of breast radiology reports. the pitfalls and benefits of advanced imaging modalities will be described. thromboprophylaxis in high-risk pregnancy as applied to the middle east dr. salam alkindi department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: sskindi@yahoo.com physiologically, pregnancy is a hypercoagulable state. thromboembolic disease has remained one of the leading major causes of morbidity and mortality in pregnancy and the early post-partum period. obvious risk factors include a family history of thromboembolic disease, immobilisation, increased maternal age, obesity, sickle cell disease, smoking, assisted-reproduction techniques, twins, intrauterine growth restriction and the presence of a heritable or acquired predisposition to thrombosis. there are different scoring systems adapted to assess the risk of thrombosis, including age, weight, previous thrombosis and the presence of thrombophilia. thromboembolic prophylaxis is a necessity for at-risk patients; however, the guidelines need to be evidence-based and take into consideration the above mentioned risk factors. also there needs to be a balance between the risk-benefit evaluation and the resources available to monitor these patients. national as well as regional data are emerging and may help omani obstetricians to tailor their therapy to the needs of pregnant women in this country. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 345-358, epub. 25th jun 13 submitted 4th nov 12 revision req. 29th jan 13; revision recd. 5th feb 13 accepted 30th mar 13 it is estimated that one third of the world’s adult population, and around 1.1 billion individuals, smokes tobacco, which makes every sixth human being a smoker.1 smoking-related illness is estimated to cause ~ 5 million deaths per annum around the globe, but is considered a leading preventable cause of death.2 in developed countries, the rates of smoking have either leveled off or declined, but smoking-related deaths are on the rise in developing countries and are most common among the least-educated people. initially, cigarette smoking prevalence was higher in males, but since the 1980s the gender gap has narrowed and plateaued.3 in 2003, in a school-based cross-sectional survey on water pipe-based tobacco smoking (sheesha) in oman, 1,962 students were interviewed (26.6% were ever-smokers and 9.6% were current smokers). among the current smokers, 15.5% were males and only 2.6% were females.4 in the usa in 2009, approximately 20.6% of adults and nearly 20% of high school students were cigarette smokers. an estimated 9% of them were smokeless tobacco consumers. smokeless tobacco products include products such as moist snuff, chewing tobacco, snus (moist powdered tobacco) and dissolvable nicotine products such as strips and sticks. current evidence, however, does not support the opinion that the use of these products is safer than smoking. additionally, there is substantial evidence that these products can be implicated in oral and pancreatic cancers, precancerous oral lesions, gingival recession, gingival bone loss around the teeth, tooth-staining, and nicotine addiction.5,6 in the usa, tobacco use is responsible for nearly 1 in 5 deaths.7 in 2012, the estimated percentage of new lung cancers in males (116,470 cases) and females (109,690 cases) was 14% each. among these department of medicine, sultan qaboos university hospital, muscat, oman e-mail: furrukh_1@yahoo.com تدخني التبغ وسرطان الرئة إدراك تغري احلقائق حممد فروخ امللخ�ص: على مدى ال�شنوات كان تدخني التبغ ال�شبب االأكرث ر�شوخا لعمليات الت�رسطن الرئوي وغريها من االأمرا�س ال�شدرية. وعلى مدى اخلم�شني عاما املا�شية ، حدث تطور يف عملية �شقل التبغ وتر�شيحه مما ت�شبب بتغري يف نوع ال�رسطان الرئوي ، حيث اأ�شبح ال�رسطان الغدي هو النوع االأكرث انت�شارا. وقد برز التدخني باعتباره نذير متنبئ قوي خل�شائ�س املر�س جنبا اإىل جنب مع غريها من املتغريات. ويف هذا املقال ن�شتعر�س باإيجاز احلقائق العلمية حول التبغ وكيفية حدوث �رسطان الرئة يف املدخنني وغري املدخنني ، كما �شن�شتعر�س اأي�شا نتائج عالج �رسطان الرئة يف التجارب ال�رسيرية املختلفة. مفتاح الكلمات: تدخني التبغ؛ ال�شجائر؛ اأورام الرئة؛ النيكوتني؛ الربوتني االلتحامي؛ اإن�شاين؛ اجلني؛ امل�شتقبل؛ عامل منو الب�رسة؛ امل�رسطنات. abstract: tobacco smoking remains the most established cause of lung carcinogenesis and other disease processes. over the last 50 years, tobacco refinement and the introduction of filters have brought a change in histology, and now adenocarcinoma has become the most prevalent subtype. over the last decade, smoking also has emerged as a strong prognostic and predictive patient characteristic along with other variables. this article briefly reviews scientific facts about tobacco, and the process and molecular pathways involved in lung carcinogenesis in smokers and never-smokers. the evidence from randomised trials about tobacco smoking’s impact on lung cancer outcomes is also reviewed. keywords: tobacco smoking; lung neoplasms; nicotine; eml4 alk fusion protein, human; k-ras gene; receptor, epidermal growth factor; carcinogens. review tobacco smoking and lung cancer perception-changing facts muhammad furrukh tobacco smoking and lung cancer perception-changing facts 346 | squ medical journal, august 2013, volume 13, issue 3 lists in reviews and original papers were scanned for further sources of information. only english language articles were searched. tobacco tobacco is processed from the leaves of plants in the genus nicotiana.12 besides its use as a drug, the tobacco plant is also used in bioengineering and as an ornamental plant. for many developed as well as developing countries, it remains a valuable cash crop. nicotiana tabacum and rustica are considered the main commercial species, with alkaloid nicotine as the addictive constituent of tobacco responsible for its tolerance and dependence; however, it is not a carcinogen.13,14 after harvest, tobacco is cured over many days, allowing slow oxidation and degradation of the constituent carotenoids. this allows for the ‘smoothness’ of the smoke, giving cured tobacco its aromatic flavours. after curing, tobacco is moved to a storage area for processing. for the intact plants, the leaves are removed from the tobacco stalks in a process called stripping, which makes the smoke milder and more inhalable. tobacco is subsequently packed into various forms for consumption (i.e. smoking, chewing, snuffing, etc.) it is the cured tobacco which is easily inhalable and causes lung cancer and other disease processes.15 patient characteristics, environmental factors, and lung cancer certain patient characteristics have consistently shown an impact on lung cancer outcomes. for example, lung cancer is a disease of the elderly, although advancing age was not a prognostic factor for survival but high scores on the charlson comorbidity index (cci) were a factor. taken together, toxicity, age and high cci scores were significant predictors.16 the incidence of lung cancer is higher among men (34%) as compared to women (13.5%). the age-standardised ratio for cancer incidence is 33.81%, and for mortality is 29.2% in men alone.17 in the past, the incidence was lower in females, but worldwide it is now the fourth most frequent lung cancers, 29% of male and 26% of female cases were estimated to be fatal.3 smoking accounts for at least 30% of all cancer deaths and 87% of lung cancer deaths.8 cases of small-cell lung carcinoma (sclc) cancer in never-smokers are exceptionally rare. active smoking also increases the risk of numerous other cancers, including those of the nasal passages, sinuses, oral cavity, upper aerodigestive tract, pancreas, gynaecological system, kidney, bladder, stomach, colorectum and acute myeloid leukaemia.9 the world health organization (who) has published guidelines to measure smoking, and classifies individuals as smokers, non-smokers, or ever-smokers, and then establishes further subcategories.10 passive smoking, or environmental tobacco smoke, is also classified as a known human carcinogen and is considered the cause of ~50,000 deaths annually. passive smoking is a mixture of two forms of smoke from burning tobacco: sidestream smoke, which comes from the end of a lighted source (cigarette, pipe, or cigar), that contains smaller particles which easily make their way into the cells and is rich in carcinogens, and the mainstream smoke which is exhaled by a smoker.11 methods to find relevant information and articles, searches were made on pubmed, google, clinical-trials. gov, the cochrane library, abstracts of the world conference for lung cancer, and the annual meetings of the american society of clinical oncology (asco) and the european society for medical oncology (esmo). online abstracts and full articles were also accessed from the national library of medicine (nlm) catalogue, including journals referenced in the national center for biotechnology information (ncbi) database: journal of clinical oncology, lancet, cancer, lung cancer, clinical lung cancer, new england journal of medicine, clinics, cancer research, journal of thoracic oncology, journal of the national cancer institute, expert review of molecular diagnostics, cancer epidemiology, biomarkers & prevention, clinician reviews, and ca: a cancer journal for clinicians. the medical subjects heading (mesh) terms were searched to confirm keywords. in addition to computer-based searches, the reference muhammad furrukh review | 347 cancer in women (516,000 cases; 8.5% of all cancers) and the second most common cause of cancer deaths (427,000 deaths; 12.8% of the total).18 the highest incidence rate in women is observed in north america, where lung cancer is now the second most frequent cancer in women. this is attributed to smoking. it is the lowest in central africa, where it is the 15th most frequent cancer in women. as one in 5 women who develop lung cancer is a never-smoker, it remains a mystery as to what exactly causes their cancer. lung cancer in never-smokers is proposed to be due to multiple risk factors, including genetic predisposition—although this is exceedingly rare (1% with >3 affected relatives). genetics mutations remain an underlying cause as we do encounter lung cancer at a relatively earlier age when it runs in families. among the first studies revealing a genetic link was one conducted over 40 years ago by tokuhata et al.19 the study revealed that neversmokers with lung cancer were 40% more likely than never-smoking controls to report a first degree relative with lung cancer. women were more likely to report such a family history and 10–15% had at least one first-degree relative with the disease. in a landmark hormonal therapy study of 16,608 post-menopausal females, the risk of developing non-small-cell lung cancer (nsclc) was not significant (p 0.21) in the experimental arm (treatment with oestrogen/medroxyprogesterone acetate) compared to the placebo group; however, after a follow-up of 5 years a divergence emerged, with more lung cancer diagnoses in the treatment arm. in addition, these females had poorlydifferentiated tumours and a higher incidence of metastatic disease. there was a 30% increase in cardiovascular events, a 26% increase in breast cancer, and a 40% increase in cerebral vascular accidents (cvas) compared to the placebo group. the hormonal treatment of postmenopausal women did not increase incidence of lung cancer, yet, it increased the lung cancer specific mortality, in particular deaths from nsclc.20 passive, or second-hand smoke from a spouse, friends, roommates, or childhood exposure from parents; vehicle or factory exhausts; cooking fumes in poorly ventilated kitchens; residence in mountainous areas (radon a, b, and c exposure), and occupational exposure or environmental toxins (asbestos and arsenic), have all been implicated in lung carcinogenesis. certain occupations are also associated with a higher risk of developing lung cancer (e.g. miners, asbestos workers, glass manufacturers, painters, printers and masonry workers). many occupational substances carry a substantial risk, e.g. diesel and welding fumes, motor exhaust, natural fibres (asbestos, silica, wood, or coal dust), radon, reactive chemicals (mustard gas, vinyl chloride) and solvents (benzene, toluene). adenocarcinoma subtypes are also associated with subpleural scars secondary to chronic inflammation (e.g. old infarcts, healed granuloma or pneumonitis and post-traumatic scars).21 c-reactive protein (crp) levels were documented to be higher in nsclc in a study suggestive of an aetiologic role of chronic inflammation in nsclc carcinogenesis. females with lung cancer tend to live longer compared to men because of diagnosis at a younger age, possibly diagnosis at an earlier stage, having adenocarcinoma more frequently, and perhaps due to inherent longevity. it is also possible that their superior survival in lung cancer is due to differences in nicotine metabolism, cytochrome p-450 enzymes and lifestyle.22–24 tobacco metabolism tobacco carcinogens are metabolised by cytochrome p-450 enzymes to make them readily excretable. lipoxygenase, cyclooxygenase, myeloperoxidases, and monoamine oxidases may also be involved, although infrequently. the oxygenated intermediate metabolites undergo subsequent transformations (detoxification and secretion) by glutathiones, sufatases,or uridine-5’-diphosphate-glucuronosyltransferases (u5'dpgt).25 a few of the metabolites generated during these processes react with the deoxyribonucleic acid (dna) to form covalent binding products called dna adducts in a process called metabolic activation. carcinogens like polcyclic aromatic hydrocarbons (pah) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk) require metabolic activation to exert their carcinogenic effects. the carcinogenic metabolites of pah-benzopyrenes (i.e. 7,8 diol 9,10 epioxides) and nicotine-derived nitrosamine ketone (nnk or nnal) react with dna to form adducts. alpha-hydroxylase converts methyl adducts from tobacco smoking and lung cancer perception-changing facts 348 | squ medical journal, august 2013, volume 13, issue 3 [hr] 0.87; p <0.001) is considered to be associated with poorer survival.29 in the e1594 trial, patients without weight loss (<10%) had superior survival.27 weight loss results from the release of cytokines (il-6, il-1β, interleukin-1rn, and tumour necrosis factor) with the contribution of anorexia, nausea, vomiting, diarrhoea, mediastinal lymphadenopathy compromising food passages, cytotoxic therapy and concurrent illness. the severity or burden of comorbidity has also been reported to have a clear relationship with poor survival in a variety of cancers, including lung cancer.30 tobacco smoking and lung cancer smoking is strongly linked with sclc) and squamous-cell carcinoma (scc). there has been a gradual change in the way cigarettes are manufactured which has resulted in a shift in the histology from scc which was more frequent in the 1970s to adenocarcinoma subtypes which are currently more frequent. the impact of low tar cigarettes, introduced in the 1950s, on adenocarcinoma rates has been due to the introduction of filter vents in these cigarettes, making it easier for the smoker to draw in smoke, and allowing deeper inhalation than older, unfiltered cigarettes. inhalation transports tobaccospecific carcinogens more distally toward the bronchoalveolar junction where adenocarcinoma often arises. secondly, blended reconstituted tobacco releases a higher concentration of n-nitrosamines from tobacco stems.31 a relatively older estimate of more than 26,000 cases from 17 published reports suggests that the adenocarcinoma to scc ratio is approximately 0.4 in lung cancers in smokers as compared to 3.4 in never-smokers.32 lung cancer risk increases with the duration and the former agent to form 7-methylguanine or o6 methylguanine. the damage may be repaired, or apoptosis may ensue. miscoding may result in permanent mutations, including k-ras, p53, p16, fragile histidine triad protein (f-hit), or unknown mutations, which results in either the suppression of tumour suppressor genes or the activation of oncogenes. not all smokers get lung cancer, but under 20% do. susceptibility to the development of cancer depends on the balance between metabolic activation and detoxification of potential carcinogens in smokers [figure 1].25 poor patient performance status (ps) is also associated with poorer survival outcomes. the absolute benefit of chemotherapy in metastatic disease at one year varied according to the ps. in ps 0 and 1, the absolute benefit was 8%. in ps 2, the benefit was 5%, while in ps 3 it was 4%.26 median survival fell inversely with increasing ps in the eastern cooperative oncology group (ecog) e1549 trial [table 1].27 race is also prognostic with lung cancer risk varying between different races and ethnicities. in the usa, age-adjusted surveillance, epidemiology and end results (seer) incidence rates for lung cancer in afro-americans and caucasians are higher compared to alaskans, indians, asians, pacific islanders and hispanics.28 weight loss (hazard ratio table 1: survival difference by performance status and degree of weight loss in the e1594 trial26 ecog ps median survival weight loss median survival p value 0 10.8 m nil 9.5 m 0.00011 7.1 m >10% 4.9 m 2 3.9 m ecog = eastern cooperative oncology group; ps = performance status. figure 1: link between nicotine addiction and lung cancer via tobacco smoke carcinogens and carcinogenesis. adapted from: hecht ss. tobacco smoke carcinogens and lung cancer.25 7-mg, 06-mg = 7-methylguanine, 06-methylguanine; dna = dioribonucleic acid; ner = nucleoside excision repair; ber = base excision repair. muhammad furrukh review | 349 table 2: prevalence of subtypes of lung carcinoma in smokers and never-smokers83 histologic subtype frequency (%) smokers neversmokers scc 42 33 adenocarcinoma (includes nos & bac) 39 35 carcinoids 07 16 others 08 06 prevalence of subtypes of lung cancer in smokers and never-smokers (52 patients) at squh scc 91 9 adenocarcinoma 61 39 undifferentiated ca 33 sclc 66.7 33.3 source: hecht ss. tobacco carcinogens, their biomarkers and tobacco induced cancer.83 scc = squamous-cell carcinoma; nos = not otherwise specified; bac = bronchioalveolar carcinoma; squh = sultan qaboos university hospital; ca = cancer; sclc = small-cell lung carcinoma. intensity of tobacco consumption [figure 2].33 table 2 illustrates the prevalence of various subtypes of lung carcinoma in smokers and never-smokers. approximately 20 potential carcinogens of ~3,500 chemicals have been detected in aburning cigarette. the most established are the polycyclic aromatic hydrocarbons (pah) like benzo(a) pyrenes, and the tobacco-specific n-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk), while others include asz-arenes, dibenz(a,h)acridine, inorganic compounds like cadmium, chromium, nickel, arsenic, radioactive polonium (po210) and organic compounds like butadiene.32 nitrates in the tobacco are reduced to nh2– and nh3 while smoking. air-cured tobacco contains higher concentrations of aromatic amines as compared to flue-cured tobaccos (e.g. the urinary bladder carcinogens β2-naphthylamine and 4-aminobiphenyl).34 cigarette smoke contains high levels of acrolein, which is toxic to the ciliated lining of the lungs, and other agents such as nitrogen oxides, acetaldehyde, phenols, and formaldehyde, which may contribute indirectly to pulmonary carcinogenicity in animals and humans.35 cigarette smoke also contains free radicals (fr) (e.g. hydrogen peroxide [h2o2], hydroxyl ion [oh–], sulfoxide anion) which induce oxidative damage in animal models as well as humans, while catechol and hydroquinone play their roles in single strand dna breaks caused by the release of fr.24 however, the evidence for the latter remains relatively low due to negative trials of anti-oxidant therapy in humans. total nnal and cotinine (nicotine metabolite) were measured in urine from smokers. the highest tertiles exhibited an 8.5-fold increased risk for lung cancer relative to those smokers with a comparable smoking history but possessing the lowest tertiles of these metabolites. these findings directly link nnk exposure to lung cancers in humans.36 smoking has multidimensional effects on lung cancer [figure 3]. tobacco smoking remains the most consistent causative agent in lung carcinogenesis in animal and human models, yet, over the past decade or so, it has also emerged as a prognostic and predictive clinical characteristic. proto-oncogenes, oncogenes, and cellular pathways in malignant transformation malignant transformation involves certain genetic and epigenetic changes such as hypomethylation, and methylation of the cytosine guanine promoter region (cpg) leading to the silencing of tumour suppressor genes. generally, hereditary genetic defects lead to the relatively early onset of cancers, figure 2: relative risk of lung cancer, according to duration and intensity of smoking, men. adapted from cancer research uk. tobacco and cancer risk statistics.33 tobacco smoking and lung cancer perception-changing facts 350 | squ medical journal, august 2013, volume 13, issue 3 4-anaplastic lymphoma kinase fusion gene [eml4 alk] in lung cancer).38 proto-oncogenes are turned off once the embryogenesis and developmental processes they regulate are completed. however, in cancer, proto-oncogene activity remains high, or is inappropriately reactivated later in life.39 in order to grow and divide, cells respond to outside signals through the binding of extracellular ligands (growth factors) to the extracellular region of certain trans-membrane receptors, such as egfr. when a ligand binds to a cell receptor, the receptor will frequently undergo a transformational change in its shape, which in turn leads to activation of tyrosine kinase (tk) activity in the intracellular domain and propagates the cell signal transduction pathways which regulate cell growth, proliferation, angiogenesis, apoptosis or cell death.40 in cancer, these processes may become autonomous due to overexpression of these receptors by virtue of the genetic defects mentioned above. proto-oncogenes may also code for intracellular proteins that normally act downstream of cell surface receptor pathways to stimulate cell growth and division. an example of this would be the kirsten rat sarcoma viral oncogene homolog (k-ras) in lung cancer, and some proto-oncogenes like cyclin d1 and e1, which normally act to push cells through distinct stages of the cell cycle when the cells receive the appropriate signals [figure 1].39 inactivation of apoptotic pathways may also be a step towards the accumulation of abnormal cells. molecular signalling pathways in tobacco smokers and neversmokers c e l l pat h way a c t i vat i o n i n s m o k e r s—t h e s m o k e pat h way s smokers have their own set of driver mutations which are distinct from lung cancer in neversmokers.41 common mutations in smokers include p53 (>50%), k-ras (~30%), p16 (>70%), stk11 (11%), and others like f-hit and t790m. in contrast, the incidence of egfr (4%) and eml4 alk mutations (2%) are relatively low in smokers with lung cancer. some of these are successfully targeted while others are being explored as targets for new agents [table 3].42 such as with hereditary colon carcinoma. on the other hand, sporadic genetic defects which occur after exposure to environmental mutagens such as tobacco smoke, x-γ rays, chemical, hydrocarbons, viruses, etc., usually appear after a latent period of 5–20 years and therefore at older ages, such as in lung carcinoma. a proto-oncogene is a normal gene that regulates cell growth and differentiation and is potentially capable of becoming an oncogene (mutation or increased expression) which initiates aberrant cell signal transduction pathways. an oncogene is a modified gene which codes for a protein that induces a malignant transformation. a set of 21–25 nucleosides (mirna) can control expression of these genes by downregulating them. oncogenes arise as a result of a mutation in the proto-oncogene which increases the expression level or activity of the proto-oncogene, as is the case in point mutations, deletions or insertions. gene amplification events lead to extra chromosomal copies of a proto-oncogene or translocation events that relocate a proto-oncogene to a new chromosomal site leading to higher expression of a cell surface protein receptor (e.g. epidermal growth factor receptor [egfr] overexpression).37 it can also lead to a fusion between a proto-oncogene and a second gene generating a fusion protein (e.g. echinoderm microtubule-associated protein like figure 3: impact of tobacco smoke on lung cancer. ga = general anaesthesia; adenoca = adenocarcinoma; scc = squamous-cell carcinoma; tki = tyrosine kinase inhibitor; qol = quality of life; ca = cancer; egfr mut = epidermal growth factor mutation; k-rasmut = kirsten rat sarcoma viral oncogene homolog mutation; eml4 alk = echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase fusion. muhammad furrukh review | 351 table 3: lung cancer; according to smoking status never-smokers or light ex-smokers current or ex-smokers aetiology ? unknown factors second-hand smoke environmental occupational background radiation exposure genetic predisposition scar cancers tobacco smoke n – nitorsomines pah – benzopyrenes polonium 210 inorganic compounds organic compounds age relatively younger any gender usually females either gender histology usually adenocarcinoma any *filter cigarettes adenocarcinoma unfiltered – scc cell pathways egfr; target for tkis (erlotinib/ gefitinib) p53 eml4 alk target for crizotinib (eml4 alk resistance target ldk 378) her2 neu ? herceptin ros 1 fusion target for crizotinib k-ras target mek 1 & 2 inhibitors p53 (g-t transversions at hot spots) t790m; target for afatinib (tkr) braf (v600e) target for dabrafenib stk11/lkb1 f-hit classical scc84 tp63 over expression chromosomal instability hyper-methylation 3q26 amplicon – sox2 overexpression pi3k (pik3ca gene), nrf2 pathways future ? gene signature analyses genetic linkage studies established candidate gene association studies scc = squamous-cell carcinoma; egfr = epidermal growth factor receptor; tki = tyrosine kinase inhibitor; eml4 alk = echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase fusion gene; her2-neu = human epidermal growth factor receptor 2; ros 1 = member of subfamily of tyrosine kinase insulin receptor genes; k-ras = kirsten rat sarcoma viral oncogene homolog ; tk r = tyrosine kinase resistance; stk11 = serine/threonine kinase 11, also known as liver kinase b1 (lkb1); f-hit = fragile histidine triad protein; * = usually; sox2 = sry (sex determining region y)-box 2; tp63 = tumor protein 63; pi3k = phosphatidylinositide 3 kinase akt signal transducer; nrf2 = nuclear factor erythroid related factor 2. the p53 gene is a tumour suppressor gene which controls the apoptotic pathways and keeps a check and balance on cellular proliferation and death. the mutation occurs in a variety of human cancers, including lung cancer (>50%). point mutations at guanine are common. in a sample of 550 p53 mutations in lung tumours, 33% were guanine (g)→thymine (t) transversions, while 26% were g→adenine (a) transitions. p53 mutations show a dose-dependent increase in g→t transversions at hotspots frequently after exposure to tobacco carcinogens. lung cancers have a lot of overlap between the mutation spectrum of p53 in smokers and never-smokers. as a result, p53 genotyping cannot be used to preclude different tumours solely on its basis.43,44 a trial at the massachusetts general hospital investigated the p53 gene in surgicallyresected lung cancers, and found 29% of patients (n = 85) harbouring p53 mutations. the patients with p53 mutations who were current smokers were significantly older and had smoked for significantly more years (p <0.01) than those without p53 changes. a large number (40%) of g→cytosine (c) to t→a transversion mutations were observed due to increasing cumulative exposure to smoke. interestingly, p53 mutations were also seen in patients with a history of occupational exposure to asbestos—5% for patients without versus 20% with exposure (p <0.05).45 genes in the wide ras gene superfamily, including h-ras, n-ras, and k-ras oncogenes, on chromosome 12p12.1 encodes a family of membrane-localised gtp-binding proteins that function for tk activation and subsequent downstream cell signal transduction in regulating cell growth, differentiation, and apoptosis. the ras proteins interact with multiple effectors through the mapk/stat/pi3k signalling cascades.46 wild-type k-ras has intrinsic gtpase activity, which catalyses the hydrolysis of bound gtp to gdp thereby inactivating the ras growth-promoting signal, whereas oncogenic k-ras is locked into the gtpbound state, leading to constitutive ras signalling. mutations in k-ras occurred in ~43% of nsclc cases in one study.42 it is common in mucinous adenocarcinoma, in elderly patients who are heavy smokers, and in earlier stages and grades, but not in large-cell lung cancers or bronchioloalveolar carcinoma (bac). however, its frequency falls with stage and grade progression. the occurrence in neversmokers is low (~15%) and is more likely to be transition mutations.47 in contrast, the majority of mutations from tobacco smoke exposure occur in codons 12 (g→t transversion) and 13. a trial on asian patients revealed that k-ras tobacco smoking and lung cancer perception-changing facts 352 | squ medical journal, august 2013, volume 13, issue 3 smokers, whereas it remains upregulated in normal bronchial epithelial cells from active smokers.55 there is substantial evidence that cigarette tar and nitric oxide (no) act synergistically to cause single strand dna breaks.25 the lower incidence rates of the egfr mutation and eml4 alk mean that a smoker cannot undergo equally effective and possibly less toxic oral-targeted therapies. cell signalling pathway activation in neversmokers more than 20,000 people who do not smoke tobacco eventually develop lung cancer in the us each year. cancer in never-smokers follows different cell signal transduction pathways, including egfr mutations in 37% (exon 21 l858r or exon 19) enabling targeted therapy; p53 mutations in 26%; human epidermal growth factor receptor 2 (her2/ neu) in 2%; over-expression and activation, or a higher frequency for eml4 alk fusion in 12%; enabling oral crizotinib (targeted) therapy through other unknown mutations.42,56 never-smokers with higher egfr frequency and gene copy numbers do well with tki therapy, where it has shown to be associated with improvement in rr and pfs. there is a lower frequency of p53 g→c to t→a mutations, and lower frequency of mutations at hot spots. as described earlier, never-smokers have a lower frequency of k-ras mutation (~15%), the majority of which are transition mutations with a lower frequency of k-ras transversions, and low serine/threonine kinase 11 (stk11) mutations (also known as liver kinase [lbk1] mutations).47 in a trial from east asia of 152 never-smoking nsclc patients, 75% harboured egfr mutations, 6% had her2 mutations, 5% had eml4 alk fusions, 2% had k-ras mutations, 1% harboured ros1 fusions, 0% had b raf mutations, and 10.9% had unknown mutations.57 the odds of an egfr mutation are 6.5 times higher in never smokers (p <0.0001), 4.4 times higher in those with adenocarcinoma (p <0.0001), 1.7 times higher for females (p 0.039), and 4–6 times higher in east asians.58–63 advanced age and acinar predominant subtypes were also independent predictors of egfr mutations. mutations were associated with ever-smoking status, male gender, and poor differentiation; however, western studies have not been able to validate these findings.48 in the national cancer institute of canada (ncic) br.21 study, 28% of 731 patients had a k-ras (wild) genotype that responded well to tyrosine kinase inhibitors (tkis) while 15% had mutations that conferred primary resistance to targeted therapy. data from the tribute trial reveals that egfr and k-ras mutations rarely occur together, and that survival was inferior in the group of patients with the k-ras mutation who were treated with the addition of tkis to chemotherapy. the presence of a k-ras mutation rules out an egfr mutation, and is also a marker of tki inactivity. patients harbouring the k-ras mutation are best treated with chemotherapy. in a recent trial, mek 1 and 2 inhibitors (selumetinib), which are downstream of k-ras, were given in combination with docetaxel and compared to docetaxel alone. the combination with the new agent enhanced response rates (rr) and progression-free survival (pfs), but overall survival (os) remained only numerically superior in patients harbouring the k-ras mutation.49 lkb1/stk11 (encodes a serine-threonine kinase) is a tumour suppressor which negatively regulates mammalian target of rapamycin (mtor) signalling. it is inactivated in 5–15% of primary lung adenocarcinomas. homozygous deletion or loss of heterozygosity (loh) of chromosome 19p at the lkb1 locus occurred in 90% of the tested specimen in primary lung cancers.50 the mutation is more frequent in lung cancers in smokers than neversmokers (p 0.007), and commonly occurs with k-ras mutations (p 0.042) but infrequently with egfr mutations (p 0.002). t790m (substitution of methionine for threonine at aa position 790) in tumours that progress on tkis are more common in smokers and ex-smokers than in never-smokers.51 this accounts for 50% of acquired resistance to tkis. afatinib (irreversible tki) has been approved as a targeted therapy against t790m.52 the p16 tumour suppressor gene is inactivated in >70% of human nsclc via homozygous deletion or aberrant hypermethylation of the promoter region.53 smoke carcinogens may also cause loh and chromosomal deletions in the f-hit gene.54 the downregulation of sirt1 activity has also been found to be confined to lung tumours in muhammad furrukh review | 353 impact of tobacco smoking on lung cancer outcomes smokers are prone to frequent side-effects during therapeutic courses of chemotherapy and radiotherapy (i.e. mucositis), and while under general anaesthesia (ga), and to surgical complications. their post-surgical survival is also poorer. the 10year overall and disease-specific survival rate falls as the number of cigarette packs smoked increases in patients with surgically-resected, stage i nsclc.64 multivariate analysis from a retrospective study in singapore, however, could not find a significant correlation between smoking and survival.65 smoking is also associated with poorer quality of life and predisposes patients to secondary cancers and chronic lung diseases, potentially making these patients unsuitable for or vulnerable to subsequent oncological interventions. egfr mutations in lung cancer in smokers in a relatively older trial, most patients harbouring the egfr mutation had adenocarcinomas and had smoked <100 cigarettes in his or her lifetime (never-smokers). seven of the 15 adenocarcinomas resected from untreated never-smokers harboured the mutations, in contrast to 4 of 81 nsclcs resected from untreated former or current smokers (p 0.0001).66 in 2004, lynch et al. initially described 9 patients with excellent responses to gefitinib, of whom 6 were never-smokers.67 cigarette-smoking history was used to estimate the likelihood of mutations in egfr gene exons 19 and 21 in lung adenocarcinomas at the memorial sloan kettering cancer center (mskcc); the mutation was detected in 51% of 67 never-smokers, 19% of 151 former smokers and 4% of 47 current smokers. the number of packs smoked per year (more than 15 packs/year, p <0.001) and smoke-free years (smoking cessation less than 25 years ago, p <0.02) predicted the lower prevalence of egfr mutations compared to smokers.68 a japanese trial examined egfr gene mutations within exons 18–21 and their correlations to clinico-pathological factors and other genetic alterations in 154 resected tumour specimens. egfr mutations were observed in 39%, all of which were adenocarcinomas. among the patients with adenocarcinoma, egfr mutations were more frequently observed in non-smokers than former or current smokers (83%, 50% and 15.2%, respectively); in women than men (76.3% versus 34.0%); in tumours with a bronchioalveolar component than those without (78.9% versus 42.9%), and in wellto moderately-differentiated tumours compared to their poorly differentiated counterparts (72%, 64.4% and 34.2%, respectively). tumours with egfr mutations had no k-ras codon 12 mutations, which remains a known tobacco carcinogen-induced mutation.69 patients who smoke have a lower chance of having an egfr mutation (14%) and the vast majority harbour wild-type egfr, failing to qualify them for targeted tki therapy, while current smokers who do harbour the mutations have poorer rr, pfs, and os despite tkis. however, all categories harbouring egfr mutations benefit from the targeted tkis, irrespective of their smoking status. tobacco smoke—a prognostic and predictive characteristic in an exploratory subgroup analyses of a trial using salvage erlotinib (first or second line), os was markedly increased in never-smokers (<20% of patients) on both univariate (p <0.001) and multivariate (p 0.048) analyses as compared to exsmokers.70 in a retrospective review of 139 nsclc patients at mskcc, a multivariable analysis revealed that the presence of adenocarcinoma with any bronchioalveolar features (p 0.004), and being a never-smoker (p 0.006) were independent predictors of response.71 retrospective analyses of ideal 1 and 2 studies reveal that never-smokers derive greater benefit from tki therapy compared to ever-smokers.60,72 in a phase ii iressa survival evaluation in lung cancer (isel) study, a pre-planned subgroup analysis showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n = 375; median os = 8.9 versus 6.1 months; p 0.012) in adenocarcinoma.61 a survival advantage for erlotinib compared with a placebo was demonstrated in the ncic br.21, a randomised, double-blind study of patients (n = 731) with tobacco smoking and lung cancer perception-changing facts 354 | squ medical journal, august 2013, volume 13, issue 3 patient subgroups, the range for never-smokers was 65.8–100% and the egfr mutation status was known in 33–100%. activating somatic mutations were found in a high percentage in this subgroup (49–100%), and there was a consequent superior efficacy with tkis.78 erlotinib was compared alone or with carboplatin paclitaxel in neveror light formersmokers and showed similar efficacy, but tki was less toxic in predominantly caucasian never-smokers with advanced nsclc.79 in a brazilian study comprising of nsclc patients (n = 285), the majority were ever-smokers (76%). among the never-smokers (n = 56), there were significantly more women (68%) and adenocarcinoma subtypes (70%). the os at 5 years of never-smokers and ever-smokers were significantly different (p 0.049). the median survival time was 14.9 months for ever-smokers and 22.1 months for never-smokers. multivariate analysis of factors related to os, using the cox regression for never-smokers, was highly significant (hr 0.58; p 0.047) without any influence of female gender or adenocarcinoma.80 in a subgroup analysis of the chinese optimal trial, the p value for the interaction test between various smoking statuses was 0.34, favouring the tki in never-smokers. on the contrary, a recent trial from western japan (wtog 3405) could not validate the effects of smoking status, age, sex, postoperative recurrence and mutation type on os on univariate or multivariate analyses while comparing gefitinib to cisplatin and docetaxel chemotherapy.81 a recently published trial of 1,725 patients, cisplatin and pemetrexed versus cisplatin and gemcitabine showed an interesting result among enrolled never-smokers who comprised 14–15% of the overall patient population. this trial showed that never-smokers had a superior median os in both chemotherapy arms compared to current or former smokers (15.9 versus 10.0 months in the cisplatin and pemetrexed arm; 15.3 versus 10.3 months for the cisplatin and gemcitabine arm).82 the superior survival in the preceding trials, are attributable to higher egfr mutation rates in never-smokers. therefore, tobacco smoking has indirectly emerged as a good predictor for response to tki and is generally associated with enhanced survival outcomes. advanced-stage nsclc. a marginally significant interaction was observed between smoking history and treatment (p 0.054). the hazard ratios (hr) were 0.42 among never-smokers and 0.87 for smokers, indicating that erlotinib was beneficial irrespective of the smoking status, but the tki was more useful in never-smokers. patients with egfrpositive tumours who had never smoked derived the greatest survival benefit from erlotinib relative to a placebo (hr 0.28; p 0.0007).73 in an unselected nsclc population in the talent and intact 1 and 2 studies, there was no benefit when erlotinib was combined concurrently with chemotherapy when compared to chemotherapy alone. it should be noted, however, that the endpoints of these studies were not meant for evaluating variables like smoking status.74,62,63 however, in the tribute trial, the addition of erlotinib to chemotherapy when compared to chemotherapy plus a placebo did reveal a doubling in survival in 10% of the never-smokers of the subgroups. when compared with former or current smokers, the never-smokers were relatively younger, predominantly female, and frequently harboured adenocarcinoma. while the median os of neversmokers on a placebo was similar to that of current or former smokers on a placebo (~10 months), the never-smokers on erlotinib had a doubling of median survival (22.5 months), and an improved median time to progression (ttp) (6 versus 4.3 months).75 a trial by mok et al. was carried out primarily on never-smokers (egfr mutations in 61%) or on light ex-smokers (egfr mutations in 47%). their ipass trial used oral gefitinib and compared it to paclitaxel carboplatin in east asian chemo-naive, neveror light ex-smokers (n = 261). the rr was 71% with tki and 43% with chemotherapy. the rr was 1% with tki and halved with chemotherapy in wild-type egfr. patients with an egfr mutation had a doubling in pfs with gefitinib, while in those having wild-type egfr, the pfs almost tripled with chemotherapy.76 for never-smokers in the caucasian eurtac study, the median pfs was 9.7 months in favour of erlotinib as compared to 5.1 months with chemotherapy.77 in a review of 4 randomised trials of gefitinib as first-line therapy in advanced nsclc, the majority of patients were women (63–88%) and had the adenocarcinoma subtype (90–100%). in the various muhammad furrukh review | 355 conclusion smoking has a multidimensional impact on lung cancer. it remains the most consistent causative agent for developing the disease and carries a definitive prognostic and predictive value. adenocarcinoma is more common in neversmokers and females. the rates for egfr and eml4 alk mutations are higher in never-smokers providing these individuals a chance for targeted therapy. however, tkis are ineffective in smokers with k-ras mutations. therapy optimisations should be integral while planning therapy. there is enormous room for molecular profiling of neversmokers where carcinogenesis stays presumptive. smoking during a course of therapy remains detrimental, and patients should be advised to discontinue it as soon as possible. strict regulations to control tobacco smoking can avert a number of human deaths globally, and lung cancer particularly. the fight between health authorities, the tobacco industry, and smokers continues to haunt humanity while the tobacco industry continues to pocket millions of usd in profit. a c k n o w l e d g m e n t s the author wishes to thank the following two students who helped with the literature search in epidemiology part of the review article: zainab aljabri and hanan al-shamli. references 1. wikipedia. smoking. from: http://en.wikipedia.org/ wiki/smoking#cite_ref-14 accessed: nov 2012. 2. world health organization. who report on the global tobacco epidemic, 2008. from: world health organization. from: http://www.who.int/tobacco/ mpower/mpower_report_full_2008.pdf accessed: nov 2012. 3. american cancer society. cancer facts & figures 2012. from: http://www.cancer.org/acs/groups/ content/@epidemiologysur veillance/documents/ document/acspc-031941.pdf accessed: oct 2012. 4. al-lawati ja, muula as, hilmi sa, rudatsikira e. prevalence and determinants of waterpipe tobacco. sultan qaboos univ med j 2008; 8:37–43. 5. united states department of health & human services. the health consequences of using smokeless tobacco: a report of the advisory committee to the surgeon general. from: http://www.cancer.org/ acs/groups/content/@epidemiolog ysur veilance/ documents/document/acspc-029771.pdf accessed: nov 2012. 6. world health organization international agency for research on cancer. monographs on the evaluation of carcinogenic risks to humans, volume 89: smokeless tobacco and some tobacco-specific n-nitrosamines. from: http://monographs.iarc.fr/eng/recentpub/ mono89.pdf accessed: nov 2012. 7. centers for disease control and prevention. smokingattributable mortality, years of potential life lost, and productivity losses united states, 2000-2004. mmwr morb mortal wkly rep 2008; 57:1226–28. 8. united states department of health & human services. reducing the health consequences of smoking: 25 years of progress. a report of the surgeon general. from: http://profiles.nlm.nih.gov/ ps/retrieve/resourcemetadata/nnbbxs accessed: nov 2012. 9. secretan b, straif k, baan r, grosse y, el ghissassi f, bouvard v, et al. a review of human carcinogens-part e: tobacco, areca nut, alcohol, coal smoke, and salted fish. lancet oncol 2009; 10:1033–4. 10. finnish national public health institute. smoking. from: http://www.ktl.fi/publications/ehrm/ product1/section7.htm accessed: oct 2012. 11. international agency for research on cancer. iarc monographs on the evaluation of carcinogenic risks to humans, vol. 83. from: http://monographs.iarc.fr/ eng/monographs/vol83/mono83.pdf accessed: oct 2012. 12. wikipedia. tobacco. from: http://en.wikipedia.org/ wiki/tobacco accessed: oct 2012. 13. csd of oklahoma. tobacco facts—why is tobacco so addictive? from: http://www.okladeafquit.com/ facts.html accessed: oct 2012. 14. philip morris information sheet. stanford. edu. archived from the original (www.stanford. e d u / g ro u p / si c d / ph i l i p mo r r i s / p m o r r i s . ht m l ) . from: http://web.archive.org/web/20080405204802 accessed: nov 2012. 15. proctor rn. the history of the discovery of the cigarette-lung cancer link: evidentiary traditions, corporate denial, global toll. tob control 2012; 21:87e–91. 16. luu dcn, mamet r, zornosa cc, joyce cn, d’amico ta, gregory p, et al. retrospective analyses of the impact of age on overall survival in patients with nonsmall cell lung cancer. j clin oncol 2012; 30:e18018. 17. jemal a, bray f, center mm, ferlay j, ward e, forman d, et al. global cancer statistics. ca cancer j clin 2011; 61:69–90. 18. world health organization international agency for research on cancer. globocan 2008. from: http://globocan.iarc.fr/ accessed: nov 2012. 19. tokuhata gk, lilienfeld am. familial aggregation of lung cancer in humans. j natl cancer inst 1963; 30:289–312. tobacco smoking and lung cancer perception-changing facts 356 | squ medical journal, august 2013, volume 13, issue 3 64. 35. world health organization international agency for research on cancer (iarc). tobacco smoking. from: http://monographs.iarc.fr/eng/monographs/vol38/ volume38.pdf accessed: nov 2012. 36. yuan jm, koh wp, murphy se, fan yh, wang rw, carmella sg, et al. urinary levels of tobacco-specific nitrosamine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers. cancer res 2009; 69:2990. 37. salomon ds, brandt r, ciardiello f, normmano n. epidermal growth factor-related peptides and their receptors in human malignancies. crit rev oncol hermatol 1995; 19:183–232. 38. shaw at, yeap by, mino-kenudson m, digumarthy sr, costa db, heist rs, et al. clinical features and outcome of patients with nsclc who harbor eml4 alk. j clin oncol 2009; 27:4247–53. 39. chial h. proto-oncogenes to oncogenes to cancer. nature education 2008; 1(1). from: http://www. nature.com/scitable/topicpage/proto-oncogenes-tooncogenes-to-cancer-883 accessed: feb 2013. 40. ganti ak. epidermal growth factor receptor signaling in non-small cell lung cancer. cancer invest 2010; 28:515–25. 41. begum s. molecular changes in smoking-related lung cancer. expert rev mol diagn 2012; 12:93–106. 42. paik pk, johnson ml, d'angelo sp, sima cs, ang d, dogan s. et al. driver mutations determine survival in smokers and never-smokers with stage iiib/iv lung adenocarcinomas. cancer 2012; 118:5840–7. 43. greenblatt ms, bennett wp, hollstein m, harris c. mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. cancer res 1994; 54:4855–78. 44. hussain sp, harris cc. molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. cancer res 1998; 85:4023–37. 45. wang x, christiani dc, wiencke jk, fischbein m, xu x, cheng tj, et al. mutations in the p53 gene in lung cancer are associated with cigarette smoking and asbestos exposure. cancer epidemiol biomarkers prev 1995; 4:543–8. 46. sunaga n, shames ds, girard l, peyton m, larsen je, imai h, et al. knockdown of oncogenic kras in non– small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy. mol cancer ther 2011; 10:336–46. 47. riely gj, kris mg, rosenbaum d, marks j, li a, chitale da, et al. frequency and distinctive spectrum of kras mutations in never smokers with lung adenocarcinoma. clin cancer res 2008; 14:5731–34. 48. rudin cm, avila-tang e, harris cc, herman jg, hirsch fr, pao w, et al. lung cancer in never-smokers: molecular profiles and therapeutic implications. clin 20. chlebowski rt, schwartz a, wakelee h, anderson gl, stefanick ml, manson je, et al. non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the women's health initiative randomized clinical trial. american society for clinical oncology (asco) 2009; abstr # cra1500. 21. bobba rk, holly js, loy t, perry mc. scar carcinoma of the lung: a historical perspective. clin lung cancer 2011; 12:148–54. 22. the mesothelioma center. asbestos-related lung cancer prognosis. from: http://www.asbestos. c o m / c a n c e r / l u n g c a n c e r / s u r v i v a l r a t e s . p h p accessed: nov 2012. 23. kligerman s, white c. epidemiology of lung cancer in women: risk factors, survival, and screening. am j roentgenol 2011; 196:287–95. 24. national cancer institute. seer cancer statistics review, 1975–2007. from: http://seer.cancer.gov/ csr/1975_2007/ accessed: nov 2012. 25. hecht ss. tobacco smoke carcinogens and lung cancer. j natl cancer inst 1999; 91:1194–1210. 26. burdett s, johson dh, stewart l, tierney j, le pechoux c. supportive care and chemotherapy vs supportive care alone in advanced nsclc: a meta analyses using individual patient data (ipd) from randomized controlled trials. j thorac oncol 2007; 2:s337. 27. schiller jh, harrington d, belani cp, langer c, sandler a, krook j, et al. comparision of four chemotherapy regimens for advanced nsclc. n eng j med 2002; 346:92–8. 28. national cancer institute. seer stat fact sheets: lung and bronchus. from: http://seer.cancer.gov/ statfacts/html/lungb.html accessed: feb 2013. 29. yang r, cheung mc, pedroso fe, byrne mm, koniaris lg, zimmers ta, et al. obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival. j surg res 2011; 170:e75– 83. 30. tammemagi cm, neslund-dudas c, simoff m, kvale p. impact of co-morbidity on lung cancer survival. int j cancer 2003; 103:792–802. 31. thun mj, lally ca, calle ee, heath cw jr. cigarette smoking and changes in the histopathology of lung cancer. j natl cancer inst 1997; 89:1580–6. 32. sun s, schiller jh, gazdar af. lung cancer in never smokers—a different disease. nat rev cancer 2007; 7:778–90. 33. cancer research uk. tobacco and cancer risk statistics. from: http://www.cancerresearchuk.org/ cancer-info/cancerstats/causes/lifestyle/tobacco/ tobacco-and-cancer-risk#smoking accessed: feb 2013. 34. hoffmann d, hoffmann i. the changing cigarette, 1950–1995. j toxicol environ health 1997; 50:307– muhammad furrukh review | 357 cancer res 2009; 15:5646–61. 49. janne pa, shaw at, pereira jr, jeannin g, vansteenkiste j, barrios ch, et al. phase ii doubleblind, randomized study of selumetinib (sel) plus docetaxel (doc) versus doc plus placebo as secondline treatment for advanced kras mutant non-small cell lung cancer (nsclc). j clin oncol 2012; 30:7503. 50. gill rk, yang sh, meerzaman d, mechanic le, bowman ed, jeon hs, et al. frequent homozygous deletion of the lkb1/stk11 gene in non-small cell lung cancer. oncogene 2011; 30:3784–91. 51. bell dw, gore i, okimoto ra, et al. inherited susceptibility to lung cancer may be associated with the t790m drug resistance mutation in egfr. nat genet 2005; 37:1315–16. 52. miller va, hirsh v, cadranel j, chen ym, park k, kim sw, et al. afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (lux-lung 1): a phase 2b/3 randomised trial. lancet oncol 2012; 13:528–38. 53. belinsky sa, nikula kj, palmisano wa, michels r, saccomanno g, gabrielson e, et al. aberrant methylation of p16ink4a is an early event in lung cancer and a potential biomarker for early diagnosis. proc natl acad sci usa 1998; 95:11891–6. 54. nelson hh, wiencke jk, gunn l, wain jc, christiani dc, kelsey kt. chromosome 3p14 alterations in lung cancer: evidence that fhit exon deletion is a target of tobacco carcinogens and asbestos. cancer res 1998; 58:1804–7. 55. beane j, cheng l, soldi r, zhang xh, liu g, anderlind c, et al. sirt1 pathway dysregulation in the smokeexposed airway epithelium and lung tumor tissue. cancer res 2012; 72:5702–11. 56. pfizer. pfizer announces positive results from phase 3 study profile 1007 evaluating xalkori® (crizotinib) in previously treated patients with alkpositive advanced non-small cell lung cancer. from: http://press.pfizer.com/press-release/pfizerannounces-positive-results-phase-3-study-profile1007-evaluating-xalkori-crizot accessed: jun 2012. 57. li cg, fang r, sun yh, han xk, li f, gao b, et al. spectrum of oncogenic driver mutations in lung adenocarcinomas from east asian neversmokers. from: http://www.plosone.org/article/ info:doi/10.1371/journal.pone.0028204. accessed: oct 2012. 58. douillard jy, kim e, hirsh v, mok t, socinski m, gervais r, et al. gefitinib (iressa) versus docetaxel in patients with locally advanced or metastatic nonsmall-cell lung cancer pre-treated with platinumbased chemotherapy: a randomized, open-label phase iii study (interest): prs-02. j thorac oncol 2007; 2:s305–6. 59. crino l, cappuzzo f, zatloukal p, reck m, pesek m, thompson jc, et al. gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (invite): a randomized, phase ii study. j clin oncol 2008; 26:4253–60. 60. fukuoka m, yano s, giaccone g, tamura t, nakagawa k, douillard jy, et al. a multi-institutional randomized phase ii trial of gefitinib for previously treated patients with advanced non-small cell lung cancer (the ideal 1 trial). j clin oncol 2003; 21:2237–46. 61. thatcher n, chang a, parikh p, rodrigues pereira j, ciuleanu t, von pawel j, et al. gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (iressa survival evaluation in lung cancer). lancet 2005; 366:1527–37. 62. giaccone g, herbst rs, manegold c, scagliotti g, rosell r, miller v, et al. gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase iii trial-intact 1. j clin oncol 2004; 22:777–84. 63. herbst rs, giaccone g, schiller jh, natale rb, miller v, manegold c, scagliotti g, et al. gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase iii trialintact 2. j clin oncol 2004; 22:785–94. 64. yoshino i, kawano d, oba t, yamazaki k, kometani t, maehara y, et al. smoking status as a prognostic factor in patients with stage i pulmonary adenocarcinoma. ann thorac surg 2006; 81:1189–93. 65. fujisawa t, iizasa t, saitoh y, sekine y, motohashi s, yasukawa t, et al. smoking before surgery predicts poor long-term survival in patients with stage i non-small-cell lung carcinomas. j clin oncol 1999; 17:2086–91. 66. pao w, miller v, zakowski m, doherty j, politi k, sarkaria i, et al. egf receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. proc natl acad sci usa 2004; 101:13306– 11. 67. lynch tj, bell dw, sordella r, gurubhagavatula s, okimoto ra, brannigan bw, et al. activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. n engl j med 2004; 350:2129–39. 68. pham d, kris mg, riely gj, sarkaria is, mcdonough t, chuai s, et al. use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. j clin oncol 2006 10; 24:1700–4. 69. sonobe m, manabe t, wada h, tanaka f. mutationsin the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. br j cancer 2005; 93:355–63. 70. shepherd fa, rodrigues pereira j, ciuleanu t, tan eh, hirsh v, thongprasert s, et al. erlotinib in previously treated non–small-cell lung cancer. n engl j med 2005; 353:123–32 tobacco smoking and lung cancer perception-changing facts 358 | squ medical journal, august 2013, volume 13, issue 3 78. gridelli c, de marinis f, di maio m, cortinovis d, cappuzzo f, mok t. gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer with activating epidermal growth factor receptor mutation: review of the evidence. lung cancer 2011; 72:249–57. 79. janne pa, wang x, socinski ma, crawford j, stinchcombe te, gu l, et al. randomized phase ii trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: calgb 30406 trial. j clin oncol 2012; 30:2063–9. 80. santoro il, ramos rp, franceschini j, jamnik s, fernandes alg. non-small cell lung cancer in never smokers: a clinical entity to be identified. clinics 2011; 66:1873–7. 81. mitsudomi t, morita s, yatabe y, shunichi n, isamu o, takashi s, et al. updated overall survival results of wjtog 3405, a randomized phase iii trial comparing gefitinib (g) with cisplatin plus docetaxel (cd) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor (egfr). 2012 asco annual meeting. j clin oncol 2012; 30s. abstr. 752130.. 82. scagliotti gv, parikh p, von pawel j, biesma b, vansteenkiste j, manegold c, et al. phase iii study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. j clin oncol 2008; 26:3543–51. 83. hecht ss. tobacco carcinogens, their biomarkers and tobacco induced cancer. nat rev cancer 2003; 3:733– 44. 84. daniel m, siddhartha d, ramaswamy g. genomic landscape of squamous cell carcinoma of the lung. asco educational book, 2013.pp 348-353. asco.org/ edbook. 71. miller va, kris mg, shah n, patel j, azzoli c, gomez j, et al. bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. j clin oncol 2004; 22:1103–9. 72. kris mg, natale rb, herbst rs, tj lynch jr, d prager, c p belani, et al. a phase ii trial of zd1839 (iressa) in advanced non-small cell lung cancer patients who had failed platinumand docetaxel-based regimens (ideal-2). proc am soc clin oncol 2002; 21:292a. 73. clark gm, zborowski dm, santabarbara p, ding k, whitehead m, seymour l, et al. smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the national cancer institute of canada clinical trials group study br.21. clin lung cancer 2006; 7:389–94. 74. gatzemeier u, pluzanska a, szczesna a, kaukel e, roubec j, de rosa f, et al. phase iii study of erlotinib in combination with cisplatin and gemcitabine in advanced non–small-cell lung cancer: the tarceva lung cancer investigation trial. j clin oncol 2007; 25:1545–52. 75. herbst rs, prager d, hermann r, fehrenbacher l, johnson be, sandler a, et al. tribute: a phase iii trial of erlotinib hydrochloride (osi-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. j clin oncol 2005; 23:5892–99. 76. mok ts, wu yl, thongprasert s, yang ch, chu dt, saijo n, et al. gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. n engl j med 2009; 361:947–57. 77. rosell r, carcereny e, gervais r, vergnenegre a, massuti b, felip e, et al. erlotinib versus standard chemotherapy as first-line treatment for european patients with advanced egfr mutation-positive nonsmall-cell lung cancer (eurtac): a multicentre, open-label, randomised phase 3 trial. lancet oncol 2012; 13:239. clinical & basic research sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e197-203, epub. 7th apr 14 submitted 7th jul 13 revisions req. 26th sep & 4th dec 13; revisions recd. 11th nov & 30th dec 13 accepted 16th jan 14 department of laboratory medicine, sohar hospital, sohar, oman *corresponding author e-mail: almoq96@yahoo.com مقارنة أداء ثالثة معادالت خمتلفة تستخدم للحصول على تقدير سرعة الرتشيح الكبييب لدى املرضى العمانيني املصابني بداء السكري من النوع الثاين �صليمة املقبالية و وعداهلل مل عابد abstract: objectives: estimated glomerular filtration rate (egfr) is an important component of a patient’s renal function profile. the modification of diet in renal disease (mdrd) equation and the chronic kidney diseaseepidemiology collaboration (ckd-epi) equation are both commonly used. the aim of this study was to compare the performance of the original mdrd186, revised mdrd175 and ckd-epi equations in calculating egfr in type 2 diabetes mellitus (t2dm) patients in oman. methods: the study included 607 t2dm patients (275 males and 332 females, mean age ± standard deviation 56 ± 12 years) who visited primary health centres in muscat, oman, during 2011 and whose renal function was assessed based on serum creatinine measurements. the egfr was calculated using the three equations and the patients were classified based on chronic kidney disease (ckd) stages according to the national kidney foundation kidney disease outcomes quality initiative guidelines. a performance comparison was undertaken using the weighted kappa test. results: the median egfr (ml/min/1.73 m2) was 92.9 for mdrd186, 87.4 for mdrd175 and 93.7 for ckd-epi. the prevalence of ckd stage 1 was 55.4%, 44.7% and 57% while for stages 2 and 3 it was 43.2%, 54% and 41.8%, based on mdrd186, mdrd175 and ckd-epi, respectively. the agreement between mdrd186 and ckd-epi (к 0.868) was stronger than mdrd186 and mdrd175 (к 0.753) and mdrd175 and ckd-epi (к 0.730). conclusion: the performances of mdrd186 and ckd-epi were comparable. considering that ckd-epi-based egfr is known to be close to isotopically measured gfr, the use of mdrd186 rather than mdrd175 may be recommended. keywords: diet modification; chronic renal insufficiency; epidemiology; collaboration; glomerular filtration rates; type 2 diabetes mellitus; oman. املعدل، هذا لتقدير معادلتان �رشيريا وت�صتخدم الكلى. وظائف تقييم و�صائل اأهم من )egfr( الكبيبي الرت�صيح معدل تقدير يعترب الهدف: امللخ�ص: املزمنة الكلى اأمرا�س وبائيات درا�صة من امل�صتخل�صة املعادلة هي والأخرى )mdrd( الكلى اأمرا�س يف الغذائي النمط تعديل معادلة هي الأوىل املعادلة اأداء مع )mdrd175( املعدلة ون�صختها )mdrd186( الأ�صلية املعادلة اأداء مقارنة هو الدرا�صة هذه هدف اإن .)ckd-epi( )ckd-epi( عند املر�صى امل�صابني بداء ال�صكري يف عمان. الطريقة: �صملت الدرا�صة 607 مر�صى بال�صكري من النوع الثاين )332 اإناث و275 ذكور( اأعمارهم يف املتو�صط مع انحراف معياري يبلغ 12 ± 56 عاما م�صجلني يف املراكز ال�صحية الأولية يف م�صقط ب�صلطنة عمان خلل عام 2011م، ومت تقييم وظائف الكلى عندهم با�صتخدام تركيز الكرياتنني يف الدم. مت يف هذا البحث قيا�س معدل الرت�صيح الكبيبي با�صتخدام ثلث معادلت، ومت اأي�صا ت�صنيف اأن وجد اجلودة. النتائج: مبادرات بنتائج يتعلق فيما الكلي اأمرا�س موؤ�ص�صة معايري بح�صب املر�صى هوؤلء عند )ckd( املزمن الكلوي املر�س حالة ، و بالن�صبة اإىل mdrd175 كان و�صيط egfr للمعادلت الثلث كان كالتايل بالن�صبة اإىل mdrd186 كان املعدل هو 92.9 مل دقيقة/1.73م2 املعدل هو 87.4 مل دقيقة/1.73م2، و بالن�صبة اإىل ckd-epi كان املعدل 93.7 مل دقيقة/1.73م2. ووجد اأن معدل انت�صار مرحلة ckd الأوىل -epiو mdrd175 ،mdrd186 كان %55.4، %44.7، و %57 ، يف حني كان للمرحلة الثانية والثالثة %43.2، %54 و %41.8 لكل من )mdrd175و mdrd186( كان اأقوى من التفاق بني )ckd-epiو mdrd186( على التوايل. كما لوحظ اأن التفاق بني معادلتي ckd و )mdrd175 وckd-epi(. اخلال�صة: وجد يف هذه الدرا�صة اأن اأداء معادلتي mdrd186و epi-ckd-epi لتقديرgfr كان متقاربا جدا باملقارنة مع mdrd175و epi .ckd، و للتقليل من معدل زيادة ت�صخي�س مراحل اأمرا�س الكلى املزمن ckd من امل�صتح�صن اإعادة النظر يف .mdrd175 مقارنة بckd-epi مع gfr وتقارب تقدير mdrd186 ا�صتخدام اأف�صلية مفتاح الكلمات: تعديل النظام الغذائي؛ القصور الكلوي املزمن؛ الوبائيات؛ التعاون؛ معدل الرتشيح الكبييب؛ داء السكري من النوع الثاين؛ عمان. comparison between three different equations for the estimation of glomerular filtration rate in omani patients with type 2 diabetes mellitus *salima r. s. al-maqbali and waad-allah s. mula-abed comparison between three different equations for the estimation of glomerular filtration rate in omani patients with type 2 diabetes mellitus e198 | squ medical journal, may 2014, volume 14, issue 2 serum creatinine-based equations for calculating estimated glomerular filtration rate (egfr) have an established role in the assessment of renal function; these equations have improved the detection and management of chronic kidney disease (ckd), particularly in the last decade. the egfr relates better to kidney function than serum creatinine, which is less useful as a single criterion of kidney function.1,2 several equations are available for the calculation of egfr, with the most commonly used ones being the cockroft-gault formula (1976), the modification of diet in renal disease (mdrd) equation (1999) and the chronic kidney diseaseepidemiology collaboration (ckd-epi) equation (2009).3 in order to calculate the egfr, the cockcroftgault formula requires serum creatinine levels, age, gender and weight.4 it was originally based on the 1886 jaffe assay for creatinine measurement; hence, it should be interpreted cautiously when the new creatinine methods are used. the need for weight and body surface area correction has limited its routine implementation.5 the mdrd equation is based on serum creatinine measurements, age and gender. in addition, it takes into account ethnicity (for african americans) with results adjusted to a body surface area of 1.73 m2.6–9 it is a popular equation that has been adopted for the classification of ckd in clinical practice by many international entities.1,7,8 moreover, in 2006 the department of health in england recommended all national health service laboratories to report egfr based on mdrd with every serum creatinine result, with a similar approach being adopted in north america, europe and australia.5,10,11 in the original mdrd equation (mdrd186), a constant factor of 186 was used which was later revised and re-expressed by the same authors, levey et al., to a constant factor of 175 (mdrd175). this was mainly due to the standardisation of creatinine assays against the isotope dilution-mass spectrometry reference method.7–9 the mdrd equation works reasonably well at egfr ≤60 ml/min/1.73 m2, but underestimates gfr in subjects with a gfr ≥60 ml/ min/1.73 m2; thus, it has limited accuracy in this range.9 however, despite the improved standardisation of the creatinine assay, this limitation did not improve when using the new revised mdrd175 as compared to the gold-standard isotopically-based method.12 the mdrd equation was revisited again by levey et al. in 2009, who then derived a new equation, the ckd-epi equation.12 this new equation appears to be more accurate in estimating the gfr in the range of low serum creatinine. it yields gfr values with better agreement for egfr than mdrd when compared with radio-labelled methods.12,13 the objective of this study was to compare the performance of the original mdrd186, revised mdrd175 and ckd-epi equations for the calculation of egfr, and their impact on classifying ckd stages in patients with type 2 diabetes mellitus (t2dm) attending primary health centres (phcs) in muscat, oman. methods this retrospective study was based on data from patients’ electronic records. all adult omani t2dm patients registered in phcs were considered candidates for inclusion in the study. the process involved multi-stage random selection of phcs followed by the random selection of patients. the data were mainly for omani adult patients aged ≥25 years who were diagnosed with t2dm between 1 january and 31 december 2011 (n = 607). the data included information such as age, gender, weight, height, duration of diabetes mellitus (dm), medications and serum creatinine levels. all duplicate tests were subsequently excluded. for those patients with more than one reported creatinine result, the most recent value was taken for analysis. ethical approval for advances in knowledge several estimated glomerular filtration rate (egfr) equations have been implemented and updated in clinical practice for improving diagnostic care in renal medicine. this study examines the impact of different egfr equations on the prevalence of chronic kidney disease (ckd) in diabetic patients attending primary health centres in muscat, oman. the most effective is the modification of diet in renal disease (mdrd) equation mdrd186 rather than mdrd175. application to patient care egfr in renal profiles facilitates the early detection of renal impairment which will allow for early therapy in diabetic patients. egfr equations yield comparable results in established ckd (stage 4 and 5); however, the results are usually variable in early ckd (stages 1, 2 and 3). this study provides data indicating that the most appropriate egfr equation for the classification of ckd in diabetic patients is mdrd186 rather than mdrd175. salima r. s. al-maqbali and waad-allah s. mula-abed clinical and basic research | e199 the study was obtained from the ministry of health research and ethical review & approval committee in december 2011. for all patients, the laboratory measurement of serum creatinine was performed using a synchron lx20 analyser (beckman coulter, inc., brea, california, usa). serum creatinine was analysed by the kinetic alkaline picrate methodology which is traceable to the reference method based on isotope dilution-mass spectrometry (idms). for each patient, egfr was calculated using mdrd186, mdrd175 and ckd-epi [table 1]. a factor of 1.0 was considered for ethnicity since no evidence was available for a correction factor related to the local population being studied, and there were no participants of african american ethnicity to allow the use of the factor 1.212.7–9 the patients were classified according to their egfr values (in ml/ min/1.73 m2) into five ckd stages as per the national kidney foundation kidney disease outcomes quality initiative guidelines: normal or ckd stage 1 egfr ≥90; ckd stage 2 egfr 60–89; ckd stage 3 egfr 30–59; ckd stage 4 egfr 15–29, and ckd stage 5 egfr <15.10 the data for each phc was entered separately using microsoft excel (microsoft corp., redmond, washington, usa). a final integrated excel worksheet was exported to the statistical package for the social sciences (spss), version 16 (ibm, corp., chicago, illinois, usa) for final analysis. the demographic and clinical data were expressed as mean, median, standard deviation (sd) and range (minimum–maximum). for calculating the prevalence, a pre-determined cut-off value was used to identify the abnormal levels which had been taken from the international guidelines for each parameter. the number of abnormal results were divided by the population size in that group and then multiplied by 100 to yield the prevalence percentage. a comparison between the ckd stages calculated from the three egfr equations was undertaken using the weighted kappa test for agreement: a kappa statistic (к) of 0.21–0.40 was considered fair agreement; 0.41– 0.60 a moderate agreement; 0.61–0.80 a substantial agreement, and 0.81–1.00 a near-perfect agreement.14 results the patients in this study (n = 607) included 275 males (45.3%) and 332 females (54.7%) aged 26–92 years with a mean age ± sd of 56 ± 12 years. they had a mean dm duration of 6.9 ± 0.2 years, a body mass index of 30 ± 0.34, a glycated haemoglobin (hba1c) level of 8 ± 0.09 and an albumin-to-creatinine ratio of 8.8 ± 1.97. the median value for serum creatinine (µmol/l) was 71 (range 33–339) and the egfr (ml/min/1.73 m2) was 92.9 for mdrd186, 87.4 for mdrd175 and 93.7 for ckd-epi [table 2]. the distribution of ckd stages based on the three table 1: serum creatinine-based formulae for the calculation of estimated glomerular renal filtration rate mdrd formulae: original four-variable mdrd186 formula 7: egfr (ml/min/1.73 m2) = 186 (s.cr in µmol/l x 0.011312)1.154 x (age)-0.203 x (0.742 if female) x (1.212 if african american/black) *revised four-variable mdrd175 formula 9: egfr (ml/min/1.73 m2) = 175 (s.cr in µmol/l x 0.011312)1.154 x (age)-0.203 x (0.742 if female) x (1.212 if african american/black) ckd-epi formulae12: for female with cr <62 µmol/l: egfr (ml/min/1.73 m2) = 144 x (cr/61.6)-0.329 x (0.993)age for female with cr >62 µmol/l: egfr (ml/min/1.73 m2) = 144 x (cr/61.6)-1.209 x (0.993)age for male with cr <80 µmol/l: egfr (ml/min/1.73 m2) = 141 x (cr/79.2)-0.411 x (0.993)age for male with cr >80 µmol/l: egfr (ml/min/1.73 m2) = 141 x (cr/79.2)-1.209 x (0.993)age mdrd = modification of diet in renal disease; egfr = estimated glomerular filtration rate; s.cr = serum creatinine; ckd-epi = chronic kidney disease-epidemiology; cr = creatinine. *recommended for creatinine assay standardised against isotope dilution-mass spectrometry. table 3: prevalence of chronic kidney disease stages based on egfr by mdrd and ckd-epi formulae (n = 607) egfr in ml/ min/1.73 m2 mdrd186 n (%) mdrd175 n (%) ckd-epi n (%) ≥90 337 (55.4) 271 (44.7) 346 (57) 60–89 213 (35.1) 257 (42.3) 197 (32.5) 30–59 49 (8.1) 71 (11.7) 56 (9.3) 15–29 7 (1.2) 6 (1.0) 6 (1.0) <15 1 (0.2) 2 (0.3) 2 (0.3) egfr = estimated glomerular filtration rate; mdrd = modification of diet in renal disease; ckd-epi = chronic kidney disease-epidemiology. table 2: different parameters in the diabetic population (n = 607) variables median mean ± sd range age in years 56.0 56.1 ± 12.5 26–92 creatinine in µmol/l 71.0 75.7 ± 32.0 33–399 mdrd186 in ml/ min/1.73 m2 92.9 93.8 ± 27.6 13–188 mdrd175 in ml/ min/1.73 m2 87.4 88.3 ± 25.9 13–177 ckd-epi in ml/ min/1.73 m2 93.7 89.3 ± 21.3 11–131 sd = standard deviation; mdrd = modification of diet in renal disease; ckd-epi = chronic kidney disease-epidemiology. comparison between three different equations for the estimation of glomerular filtration rate in omani patients with type 2 diabetes mellitus e200 | squ medical journal, may 2014, volume 14, issue 2 equations is shown in table 3. of the diabetic patients screened, 90.5%, 87% and 89.5% had an egfr of ≥60 ml/min/1.73 m2 (ckd stages 1 and 2) and 9.5%, 13% and 10.5% had an egfr of <60 ml/min/1.73 m2 (ckd stages 3, 4 and 5) based on mdrd186, mdrd175 and ckd-epi equations, respectively. the difference mainly involved ckd stages 1, 2 and 3. the distribution of patients was nearly the same between the three equations in ckd stages 4 and 5. based on the weighted kappa analysis (к 0.753), the agreement between mdrd186 and mdrd175 was found to be considerable. the mdrd175 overestimated 66 (19.6%) and 22 (10.3%) patients as ckd stages 2 and 3, respectively, who had been labelled as ckd stages 1 and 2, respectively, using mdrd186. the mdrd186 and ckd-epi showed near-perfect agreement (к 0.868). there were 13 (3.9%) and 8 (3.8%) patients with ckd stages 1 and 2 using mdrd186 who were reclassified into ckd stage 2 and 3 by ckd-epi, respectively. on the other hand, 22 patients (10.3%) with ckd stage 2 using mdrd186 were reclassified as ckd stage 1 using ckd-epi [table 4]. the agreement between mdrd186 and ckd-epi (к 0.868) was better than between mdrd175 and ckd-epi (к 0.730). there was also a clear underestimation of gfr using mdrd175 compared to ckd-epi and mdrd186 for patients with egfr ≥60 ml/min/1.73 m2. ckd-epi reclassified 79 (30.7%) patients from ckd stage 2 using mdrd175 into ckd stage 1, and another 15 (21.1%) patients were reclassified as ckd stage 2 from stage 3 table 4: comparison of the prevalence of chronic kidney disease stages based on egfr by mdrd186 as compared with mdrd175 and ckd-epi formulae in the study patients (n = 607) efgr in ml/ min/1.73 m2 mdrd186 n (%) ≥90 60–89 30–59 15–29 <15 total к mdrd175 ≥90 271 (80) 271 0.753 60–89 66 (20) 191 (87) 257 30–59 22 (10.3) 49 (100) 71 15–29 6 (86) 6 <15 1 (14) 1 (100) 2 totals 337 213 49 7 1 607 ckd-epi ≥90 324 (96) 22 (10.3) 346 0.868 60–89 13 (4) 183 (85.9) 1 (2) 197 30–59 8 (3.8) 48 (98) 56 15–29 6 (86) 6 <15 1 (14) 1 (100) 2 totals 337 213 49 7 1 607 egfr = estimated glomerular filtration rate; mdrd = modification of diet in renal disease; к = kappa statistic; ckd-epi = chronic kidney diseaseepidemiology. table 5: comparison of the prevalence of chronic kidney disease stages based on egfr by mdrd175 as compared with mdrd186 and ckd-epi formulae in the study patients (n = 607) efgr in ml/ min/1.73 m2 mdrd175 n (%) ≥90 60–89 30–59 15–29 <15 total к ckd-epi ≥90 267 (98.5) 79 (30.7) 346 0.753 60–89 4 (1.5) 178 (69.3) 15 (21.1) 197 30–59 56 (78.8) 56 15–29 6 (100) 6 <15 2 (100) 2 totals 271 257 71 6 2 607 mdrd186 ≥90 271 (100) 66 (25.7) 337 0.868 60–89 191 (74.3) 22 (31) 213 30–59 49 (69) 49 15–29 6 (100) 1 (50) 7 <15 1 (50) 2 totals 271 257 71 6 2 607 egfr = estimated glomerular filtration rate; mdrd = modification of diet in renal disease; к = kappa statistic; ckd-epi = chronic kidney diseaseepidemiology. salima r. s. al-maqbali and waad-allah s. mula-abed clinical and basic research | e201 [table 5]. similarly, the mdrd186 equation reclassified 66 (25.7%) and 22 (31.0%) patients as ckd stages 1 and 2 who had been in stages 2 and 3, respectively, according to the mdrd175 equation. a comparison of the data by age and gender between the three equations is shown in table 6. the misclassification mostly involved ckd stages 1, 2 and 3. apparently, the misclassification between mdrd186 and mdrd175 included an underestimation of gfr by mdrd175 within all age groups, but particularly in those above 45 years of age. ckd-epi overestimated gfr among those below 65 years of age and underestimated it in those over 65 as compared to mdrd186. similarly, ckd-epi reclassified ckd stage 2 into stage 1 within all age groups as compared to mdrd175. the misclassification of ckd stages using mdrd186 and mdrd175 involved more males than females among those above 45 years of age. however, the misclassification by ckd-epi from mdrd175 apparently involved more females in the older age groups. discussion during the last decade, there has been increasing interest in the use of creatinine-based egfr equations, with mdrd being considered the most valid formula.6,15 in its original format, the mdrd186 was recommended to be modified to the revised mdrd175 for creatinine assays standardised to the idms reference method.7–9 in the current study, the median egfr (ml/min/1.73 m2) was found to be 92.9 for mdrd186, 87.4 for mdrd175 and 93.7 for ckd-epi, with the values being almost comparable for mdrd186 and ckd-epi. only a few studies in the literature have compared the performance of mdrd186 to various other gfr equations; most of them compared mdrd175 with ckd-epi. chudleigh et al. compared the performance of mdrd186 and mdrd175 in their patient series based on the isotope gold-standard method.17 the study reported a gfr of 114.9 ± 22.4 ml/min/1.73 m2 for the isotope method, an egfr of 94.7 ± 22.0 ml/min/1.73 m2 for mdrd175 and 89.9 ± 19.0 ml/min/1.73 m2 for mdrd186 (a ckdepi equation was not available at that time). based on these results, chudleigh et al. concluded that mdrd175 is superior to mdrd186 as its egfr values were nearer to the isotope method than mdrd186. 17 these data were surprising and questionable, and the numerical results for the two mdrd equations in their study could not be verified mathematically. following the implementation of ckd-epi, several studies showed an improved agreement of egfr using ckd-epi compared to using mdrd175 based on isotope goldstandard methods.12,13,18 however, these studies did not consider or include mdrd186 in their comparison with ckd-epi. nevertheless, a comparative study involving european diabetic patients concluded a significant correlation between mdrd186 (coefficient of determination [r2] 0.818) and ckd-epi (r2 0.814) and the isotope gold-standard method.28 the difference in the prevalence of ckd using table 6: misclassification in ckd stages according to gender comparing different estimated glomerular filtration formulae in the study patients (n = 607) misclassifications of ckd stages age group in years mdrd186 and mdrd175 mdrd186 and ckd-epi mdrd175 and ckd-epi male female male female male female stage 1→2 ≤35 4 36–45 4 5 46–55 10 13 56–65 5 5 >65 3 6 1 1 stage 2→3 46–55 2 56–65 4 3 >65 5 8 3 5 1 stage 2→1 ≤35 1 5 36–45 1 6 5 11 46–55 4 5 14 18 56–65 5 9 13 >65 1 2 stage 3→2 46–55 2 56–65 4 >65 2 3 ckd = chronic kidney disease; mdrd = modification of diet in renal disease; ckd-epi = chronic kidney disease-epidemiology. comparison between three different equations for the estimation of glomerular filtration rate in omani patients with type 2 diabetes mellitus e202 | squ medical journal, may 2014, volume 14, issue 2 the three equations can mostly be attributed to the redistribution in the prevalence of ckd stages 1, 2 and 3 as seen in the agreement analysis. the agreement between mdrd186 and ckd-epi is more efficient (к 0.868) than the one between mdrd186 and mdrd175 (к 0.753) or mdrd175 and ckd-epi (к 0.730). a recent meta-analysis comparing the use of the ckd-epi equation and the mdrd equation found that, when using the revised mdrd equation, 24.4% of participants were reclassified to a higher egfr category by the ckd-epi equation and the prevalence of ckd stages 3 to 5 (egfr <60 ml/min/1.73 m2) was reduced from 8.7% to 6.3%. the reclassification mainly involved ckd stage 3a to ckd stage 2.25 the distribution of gender and age within the misclassified cases was divided into two main groups: underestimated gfr and a subsequent reclassification of ckd stage, and overestimated gfr with a subsequent reclassification of ckd to a higher stage [table 6]. when comparing mdrd175 with mdrd186, it was found that mdrd175 clearly underestimated gfr in all age groups and predominantly affected males. in contrast, when comparing ckd-epi and mdrd186, the ckd-epi predominantly underestimated gfr in those aged ≥65 years. the overestimation was much more pronounced when comparing ckd-epi and mdrd175. in a large cohort study in the uk, carter et al. reported a median egfr determined by ckdepi that was significantly higher than the median gfr determined by mdrd175 (82 versus 76 ml/min/1.73 m2,19 p <0.0001 with an overall mean bias of 5.0%) and a lower egfr in those aged ≥70 years using ckd-epi. however, kilbride et al. reported that the ckd-epi equation appears less biased and reasonably accurate in estimating gfr in both younger and older populations.20 earley et al. recently pointed out that neither mdrd nor ckd-epi may be optimal for all ages and populations despite the potential promise of the ckd-epi equation.21 moreover, the ckd-epi equation performed as inadequately as the mdrd equation in t2dm individuals.26,28 patients’ characteristics seem to account for the previously reported differences in the performance of ckd-epi and mdrd equations.27 with the good agreement between mdrd186 and ckd-epi, which is better than the agreement between mdrd175 and ckd-epi, it is worth considering the use of mdrd186 whenever mdrd equations are implemented in practice, including in primary care— particularly bearing in mind the better agreement of ckd-epi with radiolabelled methods. in addition, the ckd-epi equation requires a complicated technical procedure in order to be incorporated into electronic healthcare systems. the current cross-sectional study has some limitations. the study did not include a reference method for gfr measurements. however, comparison data were based on the status of mdrd and ckd-epi equations in relation to the reference gfr methods in the cited publications. also, the study was based mainly on single creatinine readings that might have affected the prevalence of ckd in the current diabetic population. additionally, the population data were from phcs; hence, many patients with ckd stages 4 and 5 might not have been included as these cases are usually referred to tertiary care institutions. also, the population was mainly arab-asian, and since arab ethnicity was not referred to in the mdrd or ckd-epi equation, the factor in the equation was assumed to be 1.0. further studies may be needed to validate these equations in the arab-asian population, taking into consideration that validated japanese and chinese mdrd equations have been reported in the literature.22,23 for the middle eastern community, serum creatinine, age and gender have been utilised for estimating gfr using the aforementioned equations. no correction factor for ethnicity is considered which has led to the widespread acceptance of these equations by pathologists and clinicians.7,15,24 conclusion the performance of mdrd186 and ckd-epi in the calculation of gfr was, to a great extent, in agreement. thus, calculated egfr results using both equations were comparable. the revised mdrd175 was found to underestimate gfr and thus increase the prevalence of ckd, particularly in stages 2 and 3, when compared with mdrd186 and ckd-epi. taking into consideration that ckd-epi-based egfr has been reported to be near to isotopically measured gfr, the use of mdrd186 may be recommended over mdrd175. also, before making any decision to change from mdrd175 to ckd-epi, the use of mdrd186 should be considered. references 1. astor bc, matsushita k, gansevoort rt, van der velde m, woodward m, levey as, et al. lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease: a collaborative metaanalysis of kidney disease population cohorts. kidney int 2011; 79:1331–40. doi: 10.1038/ki.2010.550. 2. walker jd. an update on diabetic renal disease. br j diabetes vasc dis 2010; 10:219–23. doi: 10.1177/1474651410371953. 3. mula-abed wa, al rasadi k. al-riyami d. estimated glomerular filtration rate (egfr): a serum creatinine-based test for the detection of chronic kidney disease and its impact on clinical practice. oman med j 2012; 27:108–13. doi: 10.5001/ salima r. s. al-maqbali and waad-allah s. mula-abed clinical and basic research | e203 omj.2012.23. 4. cockcroft dw, gault mh. prediction of creatinine clearance from serum creatinine. nephron 1976; 16:31–41. doi: 10.1159/000180580. 5. national kidney disease education program. estimating gfr. from: www.nkdep.nih.gov/ accessed: jun 2013. 6. levey as, bosch jp, lewis jb, greene t, rogers n, roth d. a more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. modification of diet in renal disease study group. ann intern med 1999; 130:461–70. doi: 10.7326/0003-4819-130-6199903160-00002. 7. levey as, greene t, kusek jw, beck gj. a simplified equation to predict glomerular filtration rate from serum creatinine. j am soc nephrol 2000; 11:155a0828. 8. levey as, eckardt ku, tsukamoto y, levin a, coresh j, rossert j, et al. definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (kdigo). kidney int 2005; 67:2089–100. doi: 10.1111/j.1523-1755.2005.00365.x. 9. levey as, coresh j, greene t, stevens la, zhang yl, hendriksen s, et al. using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. ann intern med 2006; 145:247–54. doi: 10.7326/0003-4819-145-4-200608150-00004. 10. national kidney foundation. k/doqi clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. am j kidney dis 2002; 39:s1–266. doi: 10.1016/s0272-6386(02)70084-x. 11. national kidney disease education program. laboratory evaluation. from: www.nkdep.nih.gov/lab-evaluation/gfr/ estimating.shtml accessed: feb 2014. 12. levey as, stevens la, schmid ch, zhang yl, castro af 3rd, feldman hi, et al. a new equation to estimate glomerular filtration rate. ann intern med 2009; 150:604–12. doi: 10.7326/0003-4819-150-9-200905050-00006. 13. stevens la, schmid ch, greene t, zhang yl, beck gj, froissart m, et al. comparative performance of the ckd epidemiology collaboration (ckd-epi) and the modification of diet in renal disease (mdrd) study equations for estimating gfr levels above 60 ml/min/1.73 m2. am j kidney dis 2010; 56:486–95. doi: 10.1053/j.ajkd.2010.03.026. 14. landis jr, koch gg. the measurement of observer agreement for categorical data. biometrics 1977; 33:159–74. 15. the national kidney foundation kidney disease outcomes quality initiative (nkf kdoqi). kdoqi clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. from: www.kidney.org/ professionals/kdoqi/guideline_diabetes/ accessed: jun 2013. 16. glassock rj, winearls c. diagnosing chronic kidney disease. curr opin nephrol hypertens 2010; 19:123–8. doi: 10.1097/ mnh.0b013e328335f951. 17. chudleigh ra, ollerton rl, dunseath g, peter r, harvey jn, luzio s, et al. performance of the revised ‘175’ modification of diet in renal disease equation in patients with type 2 diabetes. diabetologia 2008; 51:1714–8. doi: 10.1007/s00125-008-10869. 18. horio m, imai e, yasuda y, watanabe t, matsuo s. modification of the ckd epidemiology collaboration (ckd-epi) equation for japanese: accuracy and use for population estimates. am j kidney dis 2010; 56:32–8. doi: 10.1053/j.ajkd.2010.02.344. 19. carter jl, stevens pe, irving je, lamb ej. estimating glomerular filtration rate: comparison of the ckd-epi and mdrd equations in a large uk cohort with particular emphasis on the effect of age. qjm 2011; 104:839–47. doi: 10.1093/qjmed/ hcr077. 20. kilbride hs, stevens pe, eaglestone g, knight s, carter jl, delaney mp, et al. accuracy of the mdrd (modification of diet in renal disease) study and ckd-epi (ckd epidemiology collaboration) equations for estimation of gfr in the elderly. am j kidney dis 2013; 61:57–66. doi: 10.1053/j. ajkd.2012.06.016. 21. earley a, miskulin d, lamb ej, levey as, uhlig k. estimating equations for gloimerular filtration rate in the era of creatinine standardization: a systematic review. ann intern med 2012; 156:785–95. doi: 10.7326/0003-4819-156-6-201203200-00391. 22. ito h, takeuchi y, ishida h, antoku s, abe m, mifune m, et al. high frequencies of diabetic microand macroangiopathies in patients with type 2 dm with decreased estimated glomerular filtration rate and normoalbuminuria. nephrol dial transplant 2010; 25:1161–7. doi: 10.1093/ndt/gfp579. 23. matsuo s, imai e, horio m, yasuda y, tomita k, nitta k, et al. revised equations for estimated gfr from serum creatinine in japan. am j kidney dis 2009; 53: 982–92. doi: 10.1053/j. ajkd.2008.12.034. 24. al-khader aa, tamim h, sulaiman mh, jondeby ms, taher s, hejaili ff, et al. what is the most appropriate formula to use in estimating glomerular filtration rate in adult arabs without kidney disease? ren fail 2008; 30:205–8. doi: 10.1080/08860220701810554. 25. matsushita k, mahmoodi b, woodward m, emberson j, jafar th, jee sh, et al. comparison of risk prediction using the ckd-epi equation and the mdrd study equation for estimated glomerular filtration rate. jama 2012; 307:1941–51. doi: 10.1001/jama.2012.3954. 26. camargo eg, soares aa, detanico ab, weinert ls, veronese fv, gomes ec, et al. the chronic kidney disease epidemiology collaboration (ckd-epi) equation is less accurate in patients with type 2 diabetes when compared with healthy individuals. diabet med 2011; 28:90–5. doi: 10.1111/j.14645491.2010.03161.x. 27. dehnen d, quellmann t, herget-rosenthal s. current equations estimating glomerular filtration rate in primary care: comparison and determinants. scand j urol nephrol 2012; 46:448–53. doi: 10.3109/00365599.2012.695389. 28. rongant n, lemoine s, laville m, hadj-aïssa a, dubourg l. performance of the chronic kidney disease epidemiology collaboration equation to estimate glomerular filtration rate in diabetic patients. diabetes care 2011; 34:1320–2. doi: 10.2337/ dc11-0203. sir, i remember being a phd student in the uk some 20 years ago and being asked by the cashier at a checkout counter in one shopping mall, “are you a real doctor or a phd doctor?” this was her response to seeing my name, which was preceded by ‘dr.’ on my debit card. to many people, real doctors are those who actually write prescriptions or perform surgical procedures. any other person with the title is either a phd or does not fall within their own understanding of the role of doctors, by which they mean ‘physicians’. one could overlook this general perception of the role of physicians by a section of the general public but it would be unfortunate if this perception were to be held by physicians themselves regarding the roles some of them play in health care systems. this is because there has been a recent disturbing trend amongst some physicians to introduce a dichotomy into the role they play (i.e. medical practice) in health care delivery systems. this trend attempts to define medical (meaning clinical) practice as direct patient care, including prescribing medications, or performing surgical or invasive procedures. this writer would like to argue that it is unhelpful and restrictive to describe clinical practice in this narrow way. a passing knowledge of the workings of medical practice would reveal that physicians have many roles, including health administration, quality control and assurance, patient care, medical research, and medical education. some physicians solely perform one or a combination of the aforementioned roles. i would like to argue that clinical practice is a spectrum that encompasses the whole sphere of practising medicine starting from the education and training of doctors and continuing throughout their active practice. this spectrum obviously commences at the undergraduate stage, runs through doctors’ postgraduate training, and continues with the revalidation of those already trained.1 therefore, it is practically impossible to dissociate the education and training of medical and dental students and of doctors and dentists from the care such professionals provide to patients. the physician-educator, whose role either in basic medical sciences (‘on the bench’), the community (‘in the bush’), or the ward (‘at the bedside’) ensures that educational theory informs how s/he imparts the science and art of medicine, is as crucial a player as any other contributor to patient care. a couple of other examples may help to underscore this point. doctors working in radiology and pathology, are often regarded as working in ‘orphan specialties’ because they do not have their own patients. in spite of this, these specialties are as indispensable as the downstream end of the patient-care continuum where the prescription is written or the surgical procedure is performed! second, consider the physician-administrator who oversees the entire health system by prioritising resource allocation, planning strategic health care interventions, and ensuring that the quality of health care delivery is also essential to patient care. therefore, the attempt at separation and categorisation of doctors based on what role they play is, in my opinion, not helpful to the profession. in reality, no one single role physicians play is more important than any other. it is worthwhile to note that in its guidance on continuous professional development (cpd) of doctors, the uk’s general medical council (gmc) sets out the principles and values on which good medical practice is founded. these include all activities that doctors perform, from patient care to teaching and appraising trainees, and working with other professionals.2 the statutory requirement of cpd applies to all doctors regardless of the nature of their medical practice. in addition, it is worthwhile to learn from the experience of other countries about the effects that such sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 183-184, epub. 27th feb 13 submitted 23rd jun 12 accepted 15th aug 12 "طبيب ودكتور" اختالف اوجد انقساماً يف أدوار األطباء “there are doctors and there are ‘doctors’” creating a dichotomy between physicians’ roles letter to editor “there are doctors and there are ‘doctors’” creating a dichotomy between physicians’ roles 184 | squ medical journal, february 2013, volume 13, issue 1 a separation between patient care and the training of patient-carers has had on the whole medical practice continuum.3 in short, this separation has led to the devastation of such specialty areas as basic medical sciences, public health, health care planning and administration, etc. many medical graduates decline to take up such specialties, which are indispensable to both the training of medical practitioners of the future as well as to comprehensive health care delivery. this is because they have no incentive to take up these roles since they have been accorded less ‘professional value’ than those of their clinical colleagues. if this circumstance were to be replicated elsewhere, it would likely have an adverse effect on the implementation of any modern undergraduate or postgraduate medical training where the input of doctors is highly required. finally, i would like to submit that it may not be in the overall long-term interest of the medical profession in any setting to create an unnecessary dichotomy between physicians based on a very restrictive definition of ‘medical (clinical) practice’. this is especially so if this dichotomy is for the purposes of remuneration. i would welcome further discussion, responses, and alternative opinions on this subject. ibrahim inuwa department of anatomy, sultan qaboos university, muscat, oman e-mail: ibrahim1@squ.edu.om references 1. academy of medical educators. about aome. from:. http://www.medicaleducators.org/index.cfm/about-aome/ objectives accessed: jun 2012. 2. general medical council. good medical practice. from: http://www.gmc-uk.org/guidance/index.asp accessed: jun 2012. 3. world health organization. the training and preparation of teachers for medical schools with special reference to the needs of developing countries: 15th report. who technical report series 337. geneva: world health organization. pp. 5–26. occurence of autoantibodies in healthy omani individuals 13 abstract. objectives : to investigate the occurence of various autoantibodies in the omani population. method: sera from 392 healthy omani individuals comprising 183 pregnant women and 209 blood donors (183 men and 26 women) were investigated. autoantibodies were detected using immunofl uorescence, haemagglutination and latex agglutination techniques. result : low levels of autoantibodies were detected in approximately 50% of the subjects; very few subjects showed high autoantibody titres. anti smooth muscle autoantibodies (asma) were the most prevalent, and were detected in 31.6% of the individuals. anti thyroid microsomal autoantibodies (atma) and anti thyro globulin autoantibodies (ata) were present in 5.9% and 4.9% of indivi duals respect ively. the other autoantibodies were detected much less frequently, viz. anti nuclear auto antibodies (ana) in 1.5% , anti parietal cells autoantibodies (apca) in 1.8% , anti reticulin autoantibodies patterns (arap) in 3.0% and rheumatoid factor (rf) in 1.0% of the subjects. conclusion: the data indicate that autoantibodies do exist in healthy omani individuals and the results of clinical tests for these autoantibodies must be interpreted with caution. key words : autoantibodies, oman, healthy individuals, autoimmune diseases a utoa ntibodies can be present in sera of patients with or without autoimmune diseases. the literature clearly defi nes their role in specifi c autoimmune conditions.1–3 their presence merely supports, not confi rms the diagnosis of an autoimmune disease; for a clinical diagnosis, evidence for clinical disease and/or tissue damage should be present. the defi nition of abnormality related to autoantibody levels is usually based on abnormal quantity rather than affi nity or avidity. thus, abnormal autoantibody levels can result in clinical or sub-clinical autoimmune conditions.2 the demonstration and interpretation of autoantibodies in sera from patients is a diagnostic tool in autoimmune diseases. thus, the availability of data on the frequency and strength of autoantibodies within a normal population is important for determination of diagnostic levels.1–3 many such population studies have been performed in healthy individuals in various communities.5–9 however, such data have not been described for oman. this study aimed to establish baseline data for oman and to provide clinicians with the level of occurence of autoantibodies within this population. thus, this is the fi rst report on the distribution of different auto antibodies within the normal omani population. squ journal for scientific research: medical sciences 2001, 1, 13–19 ©sultan qaboos university occurence of autoantibodies in healthy omani individuals *ali a. al-jabri, elizabeth r. richens department of microbiology & immunology, college of medicine, sultan qaboos university, p.o. box 35, al-khod 123, muscat, sultanate of oman *to whom correspondence should be addressed. e-mail: aaljabri@squ.edu.om a l j a b r i e t a l14 table 1. the number and percentage of omani individuals positive for various autoantibodies titre range pregnant women (f=183) * blood donors (m=183, f=26) ♦ combined (n=392) auto-antibody from to number positive % number positive % number positive % asma 1:20 1:160 63 34.5 61 29.2 124 31.6 atma 1:100 1:6400 11 6.0 12 5.7 23 5.9 ata 1:10 1:1280 11 6.0 5 2.4 16 4.1 arap 1:20 1:20 3 1.6 9 4.3 12 3.1 apca 1:20 1:640 6 3.3 1 0.5 7 1.8 ama 1:20 1:20 0 0.0 5 2.4 5 1.3 ana 1:20 1:20 0 0.0 6 2.9 6 1.5 rf 1:20 1:80 4 2.2 0 0.0 4 1.0 total 98 53.6 99 47.4 197 50.3 *age range 16–46 (mean 26 years). ♦ age range 17–58 (mean 27 years); f= number of women; m= number of men asma: anti smooth muscle autoantibodies, atma: anti thyroid microsomal autoantibodies, ata: thyroglobulin autoantibodies, ama: antimitochondrial antibodies, ana: antinuclear autoantibodies arap: antireticulin autoantibodies patterns, apca: anti parietal cells autoantibodies, rf: rheumatoid factor m e t h o d two different groups were investigated, pregnant women and blood donors. individuals in both the groups, totalling 392, were all healthy with no history and/or symptoms of autoimmune diseases. all were residents of the capital area (muscat), which has the highest population density in oman. the pregnant group comprised 183 normal women, while the blood donor group numbered 209 individuals, 183 men and 26 women (figure 1). all sera were kept frozen at –20°c and thawed only at the time of testing. tests were conducted to detect the following eight autoantibodies: anti nuclear antibodies (a na) , anti smooth muscle antibodies (asm a), anti mitochondrial antibodies (a m a), anti parietal cells antibodies (a pca), anti thyroglobulin antibodies (ata), anti thyroid microsomal antibodies (atma), anti reticulin antibodies patterns (ar ap) and rheumatoid factor (rf). indirect quantafl uor fl uorescent autoantibody tests10 were used for the detection and semiquantitation of all autoantibodies except ata, atm a and r f where haemagglutination and latex agglutination assays, respectively, were used.11 indirect immunofl uorescence (iif) sera were tested at a 1:20 dilution by standard immunofl uorescence techniques (quantafl uor, kallested, usa). positive sera were titrated to determine the relative strength of the autoantibody under test. agglutination assays haemagglutination assays using turkey erythrocytes with bound microsomal antigens and bound thyroglobulin antigens were used to test for atm a and ata respectively (thymune-m and thymune t, murex, uk). sera were fi rst inactivated at 56°c for 30 minutes. positive and negative controls were included in each microtitre plate. sera and erythrocytes were mixed then incubated at room temperature out of direct sunlight for one hour in the case figure 1. age distribution of the omani individuals studied the study population, which consisted of 392 health volunteers (183 men and 209 women), was divided according to age into 5 groups. 0 30 60 90 120 <20 21-30 31-40 41-50 51-60 age groups (years) nu m be r o f s ub je ct s men women a u t o a n t i b o d i e s i n o m a n i s 15 of atm a and for 30 minutes in the case of ata tests. the end point titre was taken as the highest dilution of the sample giving approximately 50% agglutination of the test cells. ata tests were also performed by indirect immunofl uorescence using monkey thyroid as a substrate (quantafl uor, kallested, usa). rheumatoid factor was determined by the latex agglutination method (humatex rf detection kit, germany). sera were fi rst inactivated at 56°c and mixed with human gamma immunoglobulin coated latex particles. macroscopic agglutination was seen in sera where rf was present. the sera were fi rst diluted 1:20 in fresh buffer (containing glycine 0.1m sodium hydroxide 2.5mm sodium chloride 0.15m, sodium azide 0.1g/dl, ph 8.2); an equal volume of serum (50µl) was mixed with latex particles and checked for agglutination. positive and negative controls were always included. positive samples were titrated to determine their titres. r e s u l t s the results, summarized in table 1, show that asma , the most frequent autoantibody present in this population, was detected in 63/183 (34.5%) and 61/209 (29.2%) of pregnant women and blood donors respectively (p < 0.05). however, only three pregnant women (1.6%) and two blood donors (0.9%) had titres greater than 1:100 for this autoantibody [figure 2]. this titre is considered to be of clinical signifi cance in chronic autoimmune hepatitis.12–13 the remaining 60 pregnant women had low asm a titres [figure 2]. this was also the case for the blood donors, where 37/61 individuals had titres less than 1:20. thyroid antibodies occurred in 11/183 (6%) for both ata and atm a in the pregnant women and in 5/209 (2.4%) and in 12/209 (5.7%) of blood donors for ata and atm a respectively [table 1]. of the twelve blood donors who tested positive for atma , nine were men and three were women. atm a were detected at titres ranging between 1:100 and 1:1600. all men positive for atm a had lower titres compared to women among whom one case of 1:1600 and two cases of 1:400 were seen. for ata , three men and two women were shown to be positive. women showed high titre of antibodies compared to men. the other antibodies occurred generally at lower frequencies. thus a r a p occurred in 3/183 (1.6%) of the pregnant women and in 9/209 (4.3%) of the blood group donors; a m a were not detected in the pregnant women, but were found in 5/209 (2.4%) of the blood donors; a pca occurred in 6/183 (3.3%) and in 1/209 (0.5%) of pregnant women and blood donors; r f in 4/183 (2.2%) of pregnant women but was not detected amongst blood donors [table 1]. a na were absent in pregnant women but found in 6/209 (2.9%) blood donors. ten women (5.5%) tested positive for more than one of the autoantibodies [table 2]. although some of the titres were high, there were no clinical symptoms of autoimmune diseases in these persons. considering the two groups together, autoantibodies have been detected in more than half of the subjects studied (50.3%). low titre autoantibodies occurred at high frequency in both groups, having been found in 98/183 (53.6%) and in 99/209 (47.4%) of the pregnant women and the blood donors respectively (p < 0.05); [table 1]. the most common autoantibodies detected were asm a (31.6%), atm a (5.9%), ata (4.1%), a r a p (3.1%), a pca (1.8%), a na (1.5%), and r f (1%). 0 10 20 30 40 50 20 40 80 >100 titre no . o f s ub je ct s women men women (n=63), men (n=61) figure 2. the number of omani individuals positive for asma at different titres. table 2. ten pregnant omani women positive for more than one autoantibody, with their titres age ata atma asma ama apca rf 20 1:40 1:400 – – – – 21 1:1280 1:400 – – – – 23 1:20 – – – – 1:20 24 1:320 1:400 1:20 – – – 25 1:320 – 1:20 – – – 26 – – 1:20 – – 1:80 27 – 1:1600 1:20 – – – 27 1:20 1:400 – – – – 32 1:1280 1:400 – – 1:320 – 35 – 1:400 – – 1:640 – a l j a b r i e t a l16 d i s c u s s i o n autoimmune phenomena can occur when tolerance to selfcomponents fails and the immune system starts to produce autoantibodies. there is considerable evidence to suggest that autoantibodies may be present in the serum of apparently healthy individuals as well as of patients with autoimmune diseases.4–8,15–16 many factors are known to infl uence the production of autoantibodies, including genetic factors, sex, age and viral infections.14 in the present study, two groups of healthy omani individuals were investigated for different autoantibodies: pregnant women and blood donors. autoantibodies have previously been described in sera from normal pregnant women17–19 and it has been reported that there is no signifi cant difference in the frequency of autoantibodies between pregnant and non-pregnant women.20 asm a were fi rst found in the sera of patients with chronic active hepatitis and subsequently in those with other autoimmune liver diseases, viral infection, certain cancers, heroin addiction and female infertility.12 now it is known that asm a can occur at low levels in sera of healthy individuals. our study confi rms this, by showing a prevalence of 31.6% in our sample of normal omanis [figures 2 & 3]. such high level may be attributed to genetic and/or environmental factors.14 asm a occurred at a similar frequency in both pregnant females and blood donors. thus it appears that there is no gender difference in the frequency of asm a in the present study. since the vast majority of our subjects were less than 40 years old, with only fi ve above 40, [figure 1], we are unable to comment on the frequency of autoantibodies in older subjects (> 40 years). this should be addressed in future studies on this population. baig and shere,8 in their study of a saudi arabian popu lation, found a na to be more prevalent in females than in males, whereas in our study only two women and four men among the blood donors and none among the pregnant women were positive for a na [figure 4]. the titres of a na were all very low, at no more than 1:20 [tables 1 & 3]; the prevalence of 1.5% of a na in this study group is much lower than the prevalence of 4.5% found by baig and shere in their saudi arabian study.8 however, the prevalence of other autoantibodies with high titre (ata and atm a) is found higher in females than in males of a matched age group. within the blood donors group, we noted a higher frequency of autoantibodies in older subjects. these fi ndings support those of other studies.8, 21 sex and age factors are important when evaluating the presence and the titre of autoantibodies within patients.7 atm a and ata are also common autoantibodies among this group (occur in approximately 5%) and they come second after asma . females tend to have high titres of ata and atma . a na is not very common within this population and r f is rarely detected. only four pregnant omani women were positive for r f. a r a p is common within both groups. there are many reasons for performing immunological laboratory investigations for autoantibodies. occasionally , figure 3. positive immunofl uoresence of gastric smooth muscle table 3.clinically significant titres of autoantibodies among omanis autoanti body pregnant women blood donors combined asma >80 >80 >80 ana ≥ 20 ≥ 20 ≥ 20 ata > 40 > 40 > 40 atma > 400 >100 >100 ama > 20 > 20 > 20 apca >20 >20 >20 ara >20 >20 >20 rf >20 >20 >20 the table shows cut-off values (titres), of the different autoantibodies studied, that may be clinically significant among the omani population. a u t o a n t i b o d i e s i n o m a n i s 17 a diagnosis can be made from a positive test. more commonly the test may contribute signifi cantly to diag nosis, confi rm a clinical diagnosis or exclude a possible diagnosis and are valu able for monitoring treatment. low levels of many autoantibodies are not of diagnostic importance and may occur in otherwise normal individuals.4–6 for example, prevalence of autoantibodies increases steadily with age,7 and low titres of autoantibodies in the elderly are frequently of no clinical signifi cance. in general, both autoantibodies and autoimmune diseases can be found more frequently in woman, particularly caucasians, than in men.3 due to such variations, data on the frequency and strength of autoantibodies in normal individuals in a community are essential as benchmarks for interpreting the autoantibody results of patients from that community. in the absence of this knowledge, such tests may not help in the management of patients. physician seeking help from a laboratory without this knowledge must be resorting to the last refuge of the diagnostically destitute. the results of this study show clearly the existence of autoantibodies within normal healthy individuals as has been already shown by other investigators.4–8,22 the existence of autoreactive antibodies, both in healthy subjects and in patients with autoimmune diseases, is a consequence of intra-thymic selective processes during the development of the t cell repertoire. exposure of self-antigens to the thymic environment during foetal life results in the elimination of specifi c anti-self t cells; the dominant mechanism is physi cal , that is, clonal deletion. autoreactive t cells against antigens which do not passage through the thymus during developmental stages may be eliminated via functional inacti vation i.e. clonal anergy.23 failure of either of these processes will result in the maturation of autoreactive t cells.24 there are many mechanisms which result in the breakdown of self tolerance. they include alteration in the control of apoptosis, cross reactivity and molecular mimicry, anti-idiotype antibodies that function as autoantibodies and the poly clonal stimulation of natural autoantibody-producing cells that then progress via mutation and isotype switching.25 these phenomena emphasize the importance of distinguishing between autoimmune parameters and autoimmune disease. the former is benign whereas the latter is potentially fatal. autoimmunity often refl ected only by the presence of autoantibodies, a normal consequence of aging and readily inducible by drugs or infectious agents and potentially reversible, i.e., it may disappear when the offending drug or agent is eradicated. autoimmunity may be a normal physiological state: we are all probably autoimmune, but relatively few of us develop autoimmune diseases. these result when auto-reactive t and b cells, activated by genetic environmental triggers, cause actual tissue damage.26 the development of autoimmune disease is dependent on at least four factors. the two major ones are genetic and viral. a third factor is endocrine; oestrogen promotes autoimmune disease, whereas androgen acts as a natural immunosuppressive agent. these physiological effects of sex hormones on the normal immune response explain the marked female predominance of autoimmune diseases on susceptible genetic backgrounds. the fourth factor a. human epithelial (hep-2 ) cells negative for antinuclear antibodies figure 4 . indirect immunofl uoresence for the demonstration of antinuclear antibodies b. antinuclear antibodies detected by hep-2 cells a l j a b r i e t a l18 is psychoneurological i.e. the infl uence of stress and neurochemicals on the immune response. a common feature of these factors is their ability to affect gene expression.27 this study suggests that the diagnosis of an autoimmune disorder has to be made cautiously taking into consideration that, for all the above reasons, autoantibodies are present in low titres in the healthy population. the normal ranges for common autoantibodies that we have established for the omani population may be a useful guide for diagnostic purposes [table 3]. the establishment of normal cut-off values in clinically apparently healthy populations is important. further structured epidemiological studies of autoantibodies throughout oman should be undertaken. c o n c l u s i o n this study clearly shows that autoantibodies do exist in normal healthy individuals of oman. this fact should be taken into account when assessing the titres of antibodies considered to be of clinical signifi cance in this population. a c k n ow l e d g e m e n t we thank drs. said al-dahry, yaseen al-lawatia, mr. ibrahim kutty, mr. steve bishop and mrs. myrna welsh for assisting in various aspects of this study. r e f e r e n c e s 1. de rooij dj, van de putte lb, habets wj, verbeek a.l, van venrooij wj. the use of immunoblotting to detect antibodies to nuclear and cytoplasmic antigens. scand j rheu 1988, 17, 353–64. 2. tan em. antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. advanced immunol 1989, 44, 93–151. 3. de vlam k, de keyser g, verbruggen g, vandenbossche m, vanneuville b, d’haese d, veys em. detection and identifi cation of antinuclear autoantibodies in the serum of normal blood donors. clin exp rheu 1993, 11, 393–7. 4. hooper bs, whittingham s, mathew jd, mackay ir, gurnaw dh. autoimmunity in a rural community. clin exp immunol 1972, 12, 79–87. 5. serafi n u, torrigiani g, masala c. the incidence of autoantibodies in normal population. in: proceedings of the vth international congress of allergology, madrid, spain 1964. 6. whittingham s, irwin j, mackay ia, marsch s, cawling dc. autoantibodies in healthy subjects. aust ann med 1969, 18, 130–4. 7. willkens rf, whitaker rr, anderson rv, berven d. signifi cance of antinuclear factors in older persons. ann rheu dise 1967, 26, 306–10. 8. baig mm, shere sj. prevalence of autoantibodies in saudi population. j med 1989, 20, 286–90. 9. azizah mr, shahnaz m, zulkifl i mn, nasuruddin ba. anti-nuclear, anti-mitochondrial, anti-smooth muscle and anti-parietal cell antibodies in the healthy malaysian population. malaysia j pathol 1995, 17, 83–6 10. cavallaro jj, palmer df, bigazzi pe. immunofl uorescence detection of autoimmune diseases. immunology series no.7, centers for disease control, atlanta ga, 1976. 11. singer jm, plotz cm. the latex fi xation test. i. application to the serologic diagnosis of rheumatoid arthritis. am j med 1956, 21, 888. 12. toh bh. smooth muscle autoantibodies and autoantigens. clin exp immunol 1979, 72, 621–8. 13. brostoff j, scadding gk, male d, roitt i. clinical immunology, gower medical publishing, 1991, p30.6. 14. shoenefeld y, schwartz rs. genetic & immunologic factors in autoimmune diseases. n engl j med 1984, 311, 1019. 15. hawkins brr, o’connor kj, dawkins rl. autoantibodies in an australian population. j clin lab immunol 1979, 2, 211. 16. el-roeiy a, gleicher n. defi nition of normal autoantibody levels in an apparently healthy population. obstet gynecol 1988, 72, 596. 17. polishuk wz, bayth y, izak g. antinuclear factor and le cells in pregnant women. lancet 1971, 2, 270. 18. meles ka, halfon v, dobersen mj, ginsberg-fellner f, cowdery js, steinberg ad. autoantibodies in pregnancy. lancet 1983, 1, 354. 19. farrom j, lavastida mt, grant ja, reddi rc, daniles jc. antinuclear antibodies in the serum of normal women: a prospective study. j allergy clin immunol 1984, 73, 596–9. 20. patton pe, coulam cb, bergstralh e. the prevalence of autoantibodies in pregnant and nonpregnant women. am j obstet gynecol 1987, 157, 1345–50. 21. manoussakis mn, tzioufas ag, silis mp, pange pje, goudevenos j, moutsopoulos hm. high prevalence of anti-cardiolipin and other autoantibodies in healthy elderly population. clin exper immunol 1987, 69, 557–65. 22. sakata s, matsuda m, ogawa t, takuno h, matsui i, sarui h, et al. prevalence of thyroid hormone autoantibodies in healthy subjects. clin endocrinol 1994, 41, 365–70. 23. petrie ht, livak f, schatz dg, strassr a, crispe in, shortman k. multiple arrangements in tcr α-chain maximizes the production of useful thymocytes. j exp med 1993, 178, 615–22. a u t o a n t i b o d i e s i n o m a n i s 19 24. sinha aa, lopez mt, mcdevitt ho. autoimmune diseases: the failure of self-tolerance. science 1990, 248, 1380–8. 25. steinberg ad, krieg am, gourky mf. theoretical and experimental approaches to generalized autoimmunity. immunol rev 1990, 118, 129–43. 26. stevenson fk, natvig j. autoantibodies revealed: the role of b cells in autoimmune disease. immunol today 1999, 296–8. 27. bijlsma jwj, cutolo m, masi at, chickauza ic. the neuroendocrine basis of rheumatic disease. immunol today 1999, 298–301. honey medical sciences (2000), 2, 75−79 © 2000 sultan qaboos university 1department of microbiology & immunology, college of medicine, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. 2department of surgery, umm al-qura university, makkah, saudi arabia *to whom correspondence should be addressed. e-mail: basil@squ.edu.om 75 antimicrobial potential of honey on some microbial isolates *nzeako b c1, hamdi j2 الجراثيم بعض ضد حيوي آمضاد العسل صالحية حمدي جمال، آوانزي باسل مكة منطقة في تباع العسل من نوعا عشرة احدى لصالحية دراسة البحث هذا في تم لقد :الطريقة .للبكتيريا المضادة العسل فعالية تقييم :الهدف: الملخص :النتائج .الزنجارية والزائفة المعوية أألشريكية البرتقالية، العنقودية آورات22الم ضد حيوية آمضادات ) نامحلي انونوع مستوردة أنواع تسعة ( المكرمة آما العسل نوع حسب تختلف الفاعلية أن البحث وأثبت. المختبر في عزولةالم والفطريات البكتيريا من أنواع عدة على العسل من أنواع ستة فاعلية دراسة تمت درجة في حفظه أو دقيقة عشرة خمس لمدة غليه بعد حتى حيوي آمضاد فاعليته يفقد ال العسل أن البحث أثبت أيضا. العسل لمفعول مقاومة الجراثيم بعض أن زهور وعسل الترآي العسل يتبعه فاعلية أعلى على يحتوي األلماني السوداء الغابة عسل أن تبين آما. أشهر ستة ولمدة مئوية درجة 8 � 2 بين حرارة فبعض أألخرى، الحيوية للمضادات آما للحيوية مضادة خواصا للعسل أن البحث أظهر :الخالصة .الصيف زهور عسل وأخيرا الغابة وعسل البرتقال .العسل نوعية على إعتمادا الحساسية هذه وتختلف له، مقاوم غيرها بينما له حساسة الحية الكائنات abstract: ��������� – to assess the antimicrobial potential of honey against certain microbial isolates. �� �� – samples of commercial honeys sold in makkah area of saudi arabia were checked for their antimicrobial activities using standard organisms, staphylococcus aureus, escherichia coli, and pseudomonas aeruginosa. the minimal inhibitory concentration end points of six honey samples found to possess antimicrobial activities were used to determine the sensitivity patterns of some isolates from the laboratory. the temperature stabilities of the honey samples were also determined. ������ – the six honey samples had differing levels of antimicrobial activities with the standard organisms and with the laboratory isolates. black forest honey showed the highest activity followed respectively by turkish, orange flower, forest honey and summer flower. the antimicrobial activities of the samples were stable after storing at 2–8° c for six months and after boiling for 15 minutes. ���������� – the study shows that honey, like antibiotics, has certain organisms sensitive to it while others are resistant, and the sensitivity varies depending on the source of the honey.�� key words: staphylococcus aureus, escherichia coli, pseudomonas aeruginosa, honey, antibiotics, sensitivity, antimicrobial. oney was found by some workers to possess antibacterial activity where antibiotics were ineffective.1,2,13,14 some chronic debilitating conditions resulting from pressure sores, infected wounds, burns and fournier’s gas gangrene have been found to respond favourably to honey treatment.1,2,3 radwan4 attributed this antibacterial activity to specific chemicals in honey. the nature of these chemicals and the mechanisms of their action are not fully understood even though thin layer chromatography (tlc), polyacrylamide gel electrophoresis (page) or high performance liquid chromatography (hplc) have shown that honey contains seven tetracycline derivatives, fatty acids, lipids, amylases and ascorbic acid.5,6,7,8 allen9 showed that there are many types of honey with and without antibacterial activity and postulated that the type of the flower that was the source of the nectar determines the nature of the antibacterial activity of the honey. while the empirical application of honey on open wounds, burns or use of honey in syrups does show that it stops the growth of many microorganisms, the latter have seldom been isolated and identified.2,3 efem10 found that undiluted honey stopped the growth of candida species while pseudomonas aeruginosa, clostridium oedematiens, streptococcus pyogenes remained resistant. wellford11 found that some species of aspergillus did not produce aflotoxin in various dilutions of honey. radwan4 observed that honey stopped the growth of salmonella, escherichia coli, aspergillus niger and penicillium chrysogenium. however, these investigations were not conducted with standard organisms of known sensitivity to common therapeutic agents. conclusions were mostly h n z e a k o & h a m d i 76 drawn from the results from one sample of honey.9 since honey is used extensively in the arabian gulf region, the authors felt it desirable to scientifically determine the antimicrobial activities of the honeys in common use. this study was conducted to assess the antimicrobial potential of a few commercial honey samples on some laboratory isolates of known sensitivities to common antibiotics. the investigation hoped to determine the temperature stability of the active agent(s) in honey since the ambient temperature might affect both its shelf life and its killing potential. this knowledge could be effectively utilised in hospital practice and in primary health care where open skin lesions are routinely treated. method six brands of commercial honey available in saudi arabia were used in the study: black forest, orange flower and summer flowers produced by biophar, germany, black forest and forest honey produced by langaneza, germany, and turkish from turkey (figure 1). table 1 examined commercial honey samples and their sources. name source 1 black forest germany (biophar) 2 orange flower germany (biophar) 3 black forest germany (langaneza) 4 forest honey germany (langaneza) 5 summer flowers germany (biophar) 6 turkish turkey the samples were collected and marked randomly by one investigator while the experiments were performed blindly by the other. each honey sample was collected in a sterile universal container and kept at 2–8°c until tested. each sample was checked for purity on blood agar plates and was diluted to 75, 50, 40, 20, and 10% of its original concentration using physiological saline. three control organisms, staphylococcus aureus (atcc25923), escherichia coli (atcc 25922) and pseudomonas aeruginosa (atcc 27853) were used to determine the antimicrobial activity of each sample of honey. three colonies (1.1×106 organisms per ml, equivalent to brown’s opacity tube 3) of each standard organism were emulsified in 4ml of distilled water and used to swab mueller hinton sensitivity agar plates. fifty microlitres (50µl) of each honey dilution were applied on each plate using 1ml sterile syringe without the needle. each dilution was done in triplicate. the plates were left at room temperature till the honey seeped into the agar. after incubation, the inhibition zones were measured in millimetres (mm) and the average of the inhibition zones recorded. the end point of antimicrobial activity of each honey was defined as the highest dilution (lowest concentration) producing an inhibition zone with the control organisms. using stokes12 method, some multiresistant organisms isolated from hospital patients were subjected to sensitivity test using the honeys at their antimicrobial activity end points (lowest concentration end points). the sensitivities of proteus spp. to honey samples were read after 4 hours up to 12 hours duration to check for swarming activities. organisms showing inhibition zones equal to or greater than that of the control organisms were regarded as sensitive to honey samples. a stability test was also conducted as follows: each honey sample was divided into two aliquots. the first aliquots were stored for six months at 2–8° c while the second aliquots were boiled for 15 minutes and allowed to cool. each aliquot was retested for antimicrobial activity as before. results table 2 shows the zones of inhibition of the six honey samples with the standard organisms. these depended on the species of the control organism. turkish honey (sample 6) had highest activity with staph. aureus and least with pseudomonas aeruginosa while black forest honey (sample 3) had highest activity with pseudomonas and least with esch. coli. all the samples showed zones of inhibition of 10 mm or more at 50% dilution with staph. aureus, ps. aeruginosa and esch. coli except samples, 4 and 5 with staph. aureus and esch. coli respectively and sample 2 with esch. coli and pseudomonas aeruginosa respectively. all the laboratory isolates were found sensitive to the honey samples except proteus mirabilis, aspergillus niger, aspergillus fumigatus, enterococcus faecalis and streptococcus pyogenes (table 3). some pseudomonas aeruginosa and acinetobacter species found resistant to amikacin, ceftriaxone, tobramicin, aztreonam, gentamicin and imipenem were also found sensitive to all the honey samples. the honey samples retained their antimicrobial activities with the control organisms even after storage at 2– 8°c for six months and after boiling for 15 minutes, though the activity on esch. coli was destroyed at 50% dilution of honey, but retained at neat (undiluted honey). discussion the six commercial samples of honey showed differing antimicrobial activities with organisms isolated from the laboratory. commercial black forest honey, followed by turkish honey (sample 6), had the highest antimicrobial activity (tables 2 and 3). a n t i m i c r o b i a l p o t e n t i a l o f h o n e y the antimicrobial effects of the honey samples w more with pseudomonas and acinetobacter species than w the other bacteria tested. the reason for this is not cl it is possible that the low redox potential of asco acid5 in honey affects aerobic organisms such as the p domonas and acinetobacter species. jeddar15 found ho inhibitory to the growth of microorganisms at 40% d tion. this observation is not in conformity with our sults; some honey samples tested by us had no activit 40% dilution. our findings also disagree with radw who found aspergillus niger sensitive to honey and efe who found pseudomonas aeruginosa resistant. the reason staphylococcus aureus being sensitive to honey and strept cus spp. resistant is not understood. however, it is kno that streptococcus spp. are lactic acid bacteria while staph cocci are not. if lactic acid accumulates in the areas c taining honey samples as one of the microbial metab products of streptococcal growth, the activity of ho may be altered since high acidity affects the inhibit zones produced by various antibiotics.16 our findi agree with obaseiki ebor17 who found candida albi sensitive. our honey samples also exerted antimicro activities on pseudomonas and acinetobacter species, wh were resistant to some antibiotics. the ability of honey to kill microorganisms has b attributed to its high content of tetracycline derivati peroxidases, fatty acids, phenols, ascorbic acids and a lases.1,5,18–20 in this study, the antimicrobial substance the honeys were not estimated. however, the fact black forest honey had more activity than turkish other honeys, highlights the finding that the sources minimal inhibitory concentration o staphylococcus aureus� honey dilution honey samples & zones of inhibition (mm) � hone sample 1 2 3 4 5 6 1 neat 22.00 21.00 18.00 13.00 15.00 15.00 20.00 75 % 17.00 15.00 14.00 11.00 11.00 12.00 19.00 50 % 12.00 11.00 12.00 9.00 11.00 10.00 14.00 40 % 6.00 0.00 6.00 0.00 0.00 8.00 9.00 20 % 0 0 0 0 0 0 0 10 % 0 0 0 0 0 0 0 table 2 f various honey samples with control organisms escherichia coli� pseudomonas aeruginosa� y samples & zones of inhibition (mm] � honey samples & zones of inhibition (mm) 2 3 4 5 6 1 2 3 4 5 6 15.00 20.00 19.00 15.00 20.00 25.00 14.00 20.00 15.00 18.00 18.00 11.00 15.00 15.00 12.00 17.00 16.00 11.00 16.00 14.00 13.00 14.00 9.00 13.00 12.00 9.00 13.00 13.00 10.00 13.00 11.00 11.00 12.00 0.00 3.00 0.00 0.00 9.00 8.00 0 12.00 6.00 7.00 5.00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 77 ere ith ear. rbic seuney ilu rey at an5 m10 for ococwn yloonolic ney ion ngs cans bial ich een ves, mys in that or of the nectars may have contributed to the differences in their antimicrobial activities.9 the experiment showed that the antimicrobial substances in honey can withstand refrigeration temperatures for six months and are heat stable at 100°c. this shows that its antimicrobial activity is not dependent alone on its tetracycline derivatives, ascorbic acid, peroxidase or amylase activities as claimed by other workers, for these agents are heat labile. takeba19 and joerg21 attributed the antibacterial effect of honey to its phenolic content. phenol is heat stable and may be an active agent but its concentration in honey appears too low (1.3–5.0µg/l) to be solely responsible. the antimicrobial agent therefore may depend on the integrity of a particular honey sample. conclusion in this experiment, we attempted to assess the value of honey as an antimicrobial therapeutic agent. we have found some samples to have high broad-spectrum antimicrobial activity, even after the honey has been exposed to boiling or refrigerating temperatures. this makes honey unique since many topical antibiotics used in open skin lesions are heat labile. among our samples, black forest honey had the highest antimicrobial activity followed respectively by turkish, orange flower, forest honey and summer flower. the study also shows that some organisms are sensitive to some types of honey while others are resistant. however, much remains unknown, which makes this a fertile field for further research. n z e a k o & h a m d i 78 references 1. molan pc. the antibacterial activity of honey: the nature of the antibacterial activity. j bee world 1992, 73, 5– 28 2. efem se. recent advances in the management of fournier’s gangrene: preliminary observations. surgery 1993, 113, 200–4. 3. efem se. clinical observation on the wound healing properties of honey. br j surg. 1988, 75, 679–81. 4. radwan s, el-essawy a, sarhan mm. experimental evidence for the occurrence in honey of specific substances active against microorganisms. zentral mikrobiol 1984, 139, 249–55. 5. rahmanian m, khouhestani a, ghavifekr h, tersarkissian n, ionoso g, marzys ao. high ascorbic acid content in some iranian honeys: chemical and biological assays. j nutr metab 1970, 12, 131–5. 6. kapoulas vm, mastronicolis sk, galanos ds. identification of the lipid components of honey. z lebensm unters forsch 1977, 163, 96–9. 7. bergman a, yanai j, weiss j, bell d, david mp. acceleration of wound healing by topical application of honey: an animal model. am j surg 1983, 145, 374-6. 8. oka h, ihai y, kawamura n, una k, yamada m, harada k, suzuki m. improvement of chemical analysis of antibiotics: simultaneous analysis of seven tetracyclines in honey. j chromatogr 1987, 400, 253–61. 9. allen kl, molan pc, reid gm. a survey of the antibacterial activity of some new zealand honeys. j pharm pharmacol 1991, 43, 817–22. 10. efem se, udoh kt, iwara ci. the antibacterial spectrum of honey and its clinical significance. infect 1992, 20, 227–9. 11. wellford te, eadie t, llewellyn gc. evaluation of inhibitory action of honey on fungal growth, sporulation and aflotoxin production. z lebensm unters forsch 1978, 166, 280–3. 12. stokes es, ridway gi, wren mw. clinical microbiology (7th ed.) arnold london 1993. 13. subrahmanyam m. topical application of honey in treatment of burns. br j surg 1991, 78, 497–8. 14. al somal n, coley ke, molan pc, hancock bm. susceptibility of helicobacter pylori to the antibacterial activity of manuka honey. j r soc med 1994, 87, 9–12. 15. jeddar a, kharsan ya, ramsaroop ug, bhamjee a, haffejee e, moosa a. the antibacterial action of honey: an in vitro study. s afr med j 1985, 67, 257–8. 16. o’grady fw, lambert hp, finch rg, greenwood d. antibiotic and chemotherapy. anti infective agents and their use in therapy (7th ed), churchill livingstone, new york 1997. 17. obeseiki-ebor ee, afonya tc. in-vitro evaluation of the anti-candidiasis activity of honey distillate (hy1) compared with that of some antimycotic agents. j pharm pharmacol 1984, 36, 283–4. 18. bergner r, sabir dm. proteins of honey: separation of honey amylases by hydrophobic partition chromatography. z lebensm unters forsch 1977, 165, 8586. 19. takeba k, matsumoto, m, shida y, nakazawa h. table 3 effect of honey samples on different laboratory organisms. honey samples with average inhibition zones (mm) organism no. tested 1 2 3 4 5 6 pseudomonas aeruginosa 31 19.00 17.00 18.00 17.00 18.00 18.00 klebsiella pneumonia 13 14.00 16.00 20.00 15.00 15.00 16.00 acinetobacer spp. 4 16.00 15.00 20.00 22.00 18.00 19.00 candida albicans 3 12.00 10.00 19.00 12.00 12.00 13.00 staphylococcus aureus 15 10.00 17.00 20.00 15.00 19.00 18.00 escherichia coli 14 22.00 21.00 20.00 18.00 20.00 14.00 serrratia spp. 4 14.00 15.00 16.00 12.00 14.00 10.00 enterobacter cloacae 4 17.00 18.00 17.00 18.00 14.00 16.00 proteus mirabilis 4 0 0 0 0 0 0 aspergillus niger 5 0 0 0 0 0 0 aspergillus fumigatus 4 0 0 0 0 0 0 streptococcus faecalis 10 0 0 0 0 0 0 strep pyogenes 5 0 0 0 0 0 0 a n t i m i c r o b i a l p o t e n t i a l o f h o n e y 79 determination of phenol in honey by liquid chromatography with amperometric detection. j assoc anal chem 1990, 73, 602–4. 20. willix dj. molan pc. harfoot cg. a comparison of the sensitivity of wound infecting species of bacteria to the antibacterial activity of manuka honey and other honey. j appl bacteriol 1992, 73, 388–94. 21. joerg e, sontag g. multichannel coulometric detection coupled with liquid chromatography for determination of phenolic esters in honey. j chromatogr 1993, 635, 137–42. n z e a k o & h a m d i 80 antimicrobial potential of honey �on some microbial isolates method table 1 examined commercial honey samples and their sources. results discussion conclusion references sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 429-436, epub. 25th jun 13 submitted 12th dec 12 revisions req. 11th mar & 24th apr 13; revisions recd. 26th mar & 25th apr 13 accepted 1st may 13 department of community medicine, bharati vidyapeeth deemed university medical college, sangli, maharashtra, india corresponding author e-mail: vivek416416@gmail.com دراسة عن التوتر بني طالب الكليات املهنية من منطقة حضرية يف اهلند فيفيك واغا�شافري، جريي�س دميل، يوغانتارا كادام، األكا غور امللخ�ص: الهدف: اأكدت العديد من الدرا�شات يف جميع اأنحاء العامل اأن الطالب الذين يتابعون درا�شات مهنية مثل الدرا�شات الطبية و طب االأ�شنان يتعر�شون الإجهاد اأعلى. االإجهاد املفرط ميكن اأن يوؤدي اإىل م�شاكل نف�شية مثل االكتئاب والقلق. وكان الهدف من هذه الدرا�شة اإىل تقييم االإجهاد بني الطالب من خمتلف الكليات املهنية وارتباطه مع خمتلف العوامل االأكادميية واالجتماعية وال�شحية. الطريقة: اأجريت هذه الدرا�شة امل�شتعر�شة يف الفرتة من �شبتمرب 2011 اإىل فرباير 2012 بني الطالب يف كليات الطب، طب االأ�شنان والهند�شة يف املنطقة ا�شتخدام مت .1,200 العينة حجم بلغ . العينات الأخذ مب�شطة تقنية با�شتخدام الهند ايف ماهارا�شرت ال�شنغالية، املنطقة يف احل�رسية ا�شتبيان ذاتي مدرو�س قبل جمع البيانات. وقد مت حتليل النتائج با�شتخدام الن�شبة املئوية، اختبار كاي مربع، االنحدار اللوج�شتي الثنائي واالنحدار اللوج�شتي متعدد احلدود. النتائج: من بني 1,224 من امل�شتجيبني لال�شتبيان، 299 )%24.4( عانوا من االإجهاد. بينهم 115 )%38.5( و 102 )%34.1( و 82 )%27.4( من طالب طب االأ�شنان، طالب الطب ثم طالب الهند�شة على التوايل. كان هناك ارتباط ذا داللة اح�شائية بني ال�شغوط وجمال التعليم. ولوحظ التوتر يف 187 )%27.7( من االإناث و 112 )%20.4( من الذكور، وكانت العالقة مع جن�س الطالب ذات داللة اح�شائية. من خالل تطبيق االنحدار اللوج�شتي الثنائي، كانت عوامل املجال الطبي واحلالة ال�شحية و منط احلياة والعوامل االأكادميية تنبئ بداللة اح�شائية عن االإ�شابة باالإجهاد. اخلال�سة: تعر�س الطالب من املجاالت الثالثة لالإجهاد. كانت العوامل االأكادميية واحدة من اأهم ال�شغوطات. اإدخال ثقافة اإدارة االإجهاد يف املناهج ممكن اأن تكون مفيدة يف مكافحة هذه امل�شكلة. مفتاح الكلمات: ال�شغوط النف�شية؛ طالب الطب؛ طالب طب االأ�شنان؛ علم االأوبئة؛ والهند. abstract: objectives: various studies across the globe have emphasised that students undertaking professional courses, such as medical and dental studies, are subjected to higher stress. excessive stress could lead to psychological problems like depression and anxiety. the objective of the current study was to assess stress among students of various professional colleges and its association with various academic, social and health-related factors. methods: this cross-sectional study was conducted from september 2011 to february 2012 among students of medical, dental and engineering colleges from the urban area of sangli district, maharashtra, india, using a convenience sampling technique. the calculated total sample size was 1,200. a pretested self-administered questionnaire was used for the data collection. analysis was done using percentage, the chi-square test, binary logistic regression and multinomial logistic regression. results: out of the 1,224 respondents, 299 (24.4%) experienced stress. among them 115 (38.5%), 102 (34.1%) and 82 (27.4%) were dental, medical and engineering students, respectively. there was a statistically significant association between stress and the field of education. stress was observed in 187 (27.7%) females and 112 (20.4%) males; the association with gender was statistically significant. by applying binary logistic regression, medical studies, health and lifestyle factors, and academic factors were the significant predictors for stress. conclusion: students from all the three fields studied were exposed to stress. academic factors were one of the most important stressors. the introduction of stress management education into the curriculum could prove useful in combatting this problem. keywords: psychological stress; students, medical; students, dental; students, engineering; epidemiology; india. a study of stress among students of professional colleges from an urban area in india *vivek b. waghachavare, girish b. dhumale, yugantara r. kadam, alka d. gore clinical & basic research advances in knowledge studies of stress among engineering students are rare, especially in india. the research in this current study addresses the issue. this study shows that, along with academic factors, health problems and the environment of colleges and hostels can play an important role in the development of stress. application to patient care: this research highlights the need to incorporate stress management education in the curriculum, as well as to develop mechanisms for decreasing stress among students in colleges. similarly, this study highlights the importance of creating positive environments at colleges and hostels to decrease stress among students. vivek b. waghachavare, girish b. dhumale, yugantara r. kadam and alka d. gore clinical and basic research | 423 stress can be defined as ‘any challenge to homoeostasis’, or to the body’s internal sense of balance.1 it can manifest itself either as eustress or as distress. eustress, literally translated as ‘good stress’, is a positive form of stress that motivates an individual to continue working. it is when this stress is no longer tolerable and/or manageable that distress manifests. distress, or ‘bad stress’, is the point at which the good stress becomes too much to bear or cope with. some signals that this change has occurred are when tension begins to build, and there is no longer any fun in the challenge or there seems to be no relief or end in sight. this kind of stress is well-known, and may lead to poor decision-making. the general characteristics of a person in distress are: being over-aroused; tense or unable to relax; touchy, easily upset or irritable; easily startled or fidgety, and demonstrating intolerance of any interruption or delay. excessive stress results in an increased prevalence of psychological problems like depression, anxiety, substance abuse and suicide ideation.1,2 various studies around the globe have emphasised that students studying in medical and dental courses experience higher stress.3–6 however there are few studies on this topic in india, especially on populations in smaller cities. engineering students take half-yearly examinations, as compared to the annual examinations taken by medical and dental students. theoretically, the higher frequency of examinations should lead to a higher prevalence of stress among engineering students. however, there are very few studies on the prevalence of stress among engineering students, especially in india. the present study was undertaken in order to assess the prevalence of stress among students of medical, dental and engineering colleges, and the association of stress with various academic, social and health-related factors, in an urban area from the sangli district of western maharashtra, india. methods a cross-sectional study was conducted in an urban area of the sangli district of western maharashtra, india. the institutional ethical committee approved the study. the estimated sample size was 1,200, and the sampling technique used was convenience sampling. after obtaining ethical clearance, permission to conduct the study was sought from all medical, dental and engineering colleges within the study area. to ensure anonymity, no questions about the names of students or institutions were included in the questionnaire. overall, two dental colleges, two engineering colleges and one medical college participated in the study. as engineering students outnumbered the medical profession students, to ensure comparability the mechanical division from the engineering college was randomly selected and included in the study. students from all classes (grades) of each field were involved in the study. the study was conducted between september 2011 and february 2012. a pre-tested, self-administered questionnaire was used as the study instrument. it was developed with the help of published literature1,7 and finalised after a pilot study. the questionnaire was divided into three sections. the first section covered sociodemographic factors such as age, gender, educational details, area of upbringing, parents’ education and parents’ occupation. the second section comprised the short form of the depression, anxiety and stress scale (dass-21), which has been validated as a screening tool by many researchers in a variety of sociodemographic conditions.7–9 the scale of stress calculated by the dass-21 corresponds closely to the diagnostic and statistical manual of mental disorders fourth edition (dsm-iv) symptom criteria for generalised anxiety disorder (gad), and measures nervous tension, difficulty relaxing and irritability. based on the score obtained from the dass-21 guidelines, stress was classified as either absent (normal), mild, moderate or severe.7,8 the third section consisted of questions designed to identify potential stressors. possible stressors were divided into three groups, namely academic factors (8 questions), health and lifestyle factors (14 questions), and environmental and social factors (10 questions). based on the participant’s answers, each factor was awarded a maximum of 10, 14 and 10 points, respectively. after a consultation with experts in the field, the cut-off point for each stress factor was decided at 50% or higher. for example, if a respondent scored 5 or more points for academic factors, then academic problems were considered as contributing to the development of stress for this respondent. the academic factors section included information such as whether the student was taking a course by choice; if s/he had failed in any subject; a study of stress among students of professional colleges from an urban area in india 424 | squ medical journal, august 2013, volume 13, issue 3 self-satisfaction with study efforts; the quality of the educational process at the college; the presence of study-related problems; an overloaded syllabus; satisfaction with the methods of teaching, and whether the participants felt stressed concerning their studies. the section concerning health and lifestyle factors was designed to measure the participant’s perceived present health status, and if there had been any changes. depression, calculated using the dass-21, was included as a factor. other psychological problems were also included such as mood breakdown, examination phobia, frustration and self-care. health factors that were also assessed were exercise, diet, changes in sleep pattern and substance abuse. the environmental and social factors section comprised questions on the participant’s family, economic, social and emotional problems. it also included questions regarding their college and residential environment; relationship with other students; recreational activities, and their own as well as others’ expectations regarding academic achievement. questions regarding whether the students felt a need for stress management education to be included in the curriculum were additionally included in the questionnaire. following ethical approval of the study, students were contacted after their lectures. students from all classes were involved in the study, and care was taken to ensure that no participant was due to take any examinations in the month following the study. the nature and purpose of the study was explained in detail, and willing students over 18 years old were provided with questionnaires and consent forms. the principal investigator was present while the students completed the questionnaire but the teachers of each institution were requested to wait outside. absolute privacy and a mental comfort zone were maintained for each individual student while answering the questionnaire. upon completion of the questionnaire, each participant was requested to drop their questionnaire and consent form in separate drop-boxes. a total of three visits (at least one week apart) was made to each institution to ensure the inclusion of all possible participants. analysis of the data was done using percentages, chi-square tests, binary logistic regression and multinomial regression. data from the pilot study were not included in the final analysis. results out of the 1,400 distributed and collected questionnaires, 1,224 were complete and hence used in the final analysis. overall, there were 401 dental students, 417 engineering students and 406 medical students (studying for a bachelor of medicine or a bachelor of surgery [mbbs] degree). out of all the students in the study, 676 (55.23%) were female and 548 (44.77%) were male. respondents were 18–25 years old (mean ± standard deviation [sd] = 19.87 years ± 1.62 years). a total of 396 (32.3%) of the respondents were from rural areas, while 828 (67.7%) were from the urban area. a total of 939 students (76.7%) were currently residing in hostels while 285 (23.3%) were residing in other places, table 1: distribution of stress levels according to the field of education field of education stress total n absent mild moderate severe dental n (%) 286 (71.3) 47 (11.7) 35 (8.7) 33 (8.2) 401 engineering n (%) 335 (80.3) 38 (9.1) 22 (5.3) 22 (5.3) 417 medical n (%) 304 (74.9) 38 (9.4) 36 (8.9) 28 (6.9) 406 total n (%) 925 (75.6) 123 (10.0) 93 (7.6) 83 (6.8) 1,224 table 2: distribution of stress levels according to gender across the fields of education* field of education stress gender total p value female male dental n (%) absent present total 177 (67.6) 85 (32.4) 262 109 (78.4) 30 (21.6) 139 286 (71.3) 115 (28.7) 401 0.022 engineering n (%) absent present total 180 (77.6) 52 (22.4) 232 155 (83.8) 30 (16.2) 185 335 (80.3) 82 (19.7) 417 0.114 medical n (%) absent present total 132 (72.5) 50 (27.5) 182 172 (76.8) 52 (23.2) 224 304 (74.9) 102 (25.1) 406 0.325 total n (%) absent present total 489 (72.3) 187 (27.7) 676 436 (79.6) 112 (20.4) 548 925 (75.6) 299 (24.4) 1224 0.003 df = degrees of freedom. *the association of stress with field of education was statistically significant (chisquare value = 9.156, degrees of freedom = 2 and p value = 0.01). vivek b. waghachavare, girish b. dhumale, yugantara r. kadam and alka d. gore clinical and basic research | 425 for instance with parents, relatives or in rented apartments. out of the total respondents, stress was present in 299 (24.42%); of these, mild stress was present in 123 respondents (10%), while 93 (7.6%) had moderate stress and 83 (6.8%) had severe stress [table 1]. considering the results according to the participant’s field of education, 115 (28.7%) dental students, 82 (19.7%) engineering students and 102 (25.1%) medical students had stress; the association was statistically significant. concerning gender, stress was present in 187 female respondents (27.7%) as compared to 112 male respondents (20.4%). this association of stress with gender was statistically significant [table 2]. although stress was associated with age, a distinctive trend was not observed. in terms of the participant’s residence, 80 students from rural areas (20.2%) had stress as compared to 219 from the urban area (26.4%), and this association of stress with permanent residence was statistically significant. on the other hand, stress was present in 243 students living in hostels (25.9%), while among the students living elsewhere, 56 (19.6%) had stress; an association which was also statistically significant. no significant associations were observed between stress and other sociodemographic factors, such as class or parents’ education. the need to include stress management education in the curriculum was expressed by 248 (59.5%) of the engineering students, 198 (49.4%) dental and 220 (54.2%) medical students; this came to a total of 666 students (54.4%). potential stressors faced by students were divided into three groups: academic factors, health and lifestyle factors, and environmental and social factors. a total of 188 (46.9%) dental, 164 (39.3%) engineering students and 184 (45.3%) medical students scored above 50% for academic factors; this signifies that 536 respondents (43.8%) had reported scores over the cut-off point. table 3: association of stress with academic factors, health and lifestyle factors, and environmental and social factors field of education stress academic factors health and lifestyle factors environmental and social factors <50% >50% p value <50% >50% p value <50% >50% p value dental n (%) absent 192 (67.1) 94 (32.9) <0.001 258 (90.2) 28 (9.8) <0.05 231 (80.8) 55 (19.2) <0.001 present 21 (18.3) 94 (81.7) 54 (47) 61 (53) 59 (51.3) 56 (48.7) total 213 (53.1) 188 (46.9) 312 (77.8) 89 (22.2) 290 (72.3) 111 (27.7) engineering n (%) absent 233 (69.6) 102 (30.4) <0.001 290 (86.6) 45 (13.4) <0.05 261 (77.9) 74 (22.1) <0.001 present 20 (24.4) 62 (75.6) 40 (48.8) 42 (51.2) 36 (43.9) 46 (56.1) total 253 (60.7) 164 (39.3) 330 (79.1) 87 (20.9) 297 (71.2) 120 (28.8) medical n (%) absent 197 (64.8) 107 (35.2) <0.001 245 (80.6) 59 (19.4) <0.05 221 (72.7) 83 (27.3) <0.001 present 25 (24.5) 77 (75.5) 42 (41.2) 60 (58.8) 50 (49) 52 (51) total 222 (54.7) 184 (45.3) 287 (70.7) 119 (29.3) 271 (66.7) 135 (33.3) total n (%) absent 622 (67.2) 303 (32.8) <0.001 793 (85.7) 132 (14.3) <0.05 713 (77.1) 212 (22.9) <0.001 present 66 (22.1) 233 (77.9) 136 (45.5) 163 (54.5) 145 (48.5) 154 (51.5) total 688 (56.2) 536 (43.8) 929 (75.9) 295 (24.1) 858 (70.1) 366 (29.9) *for all cases, the degrees of freedom = 1. a study of stress among students of professional colleges from an urban area in india 426 | squ medical journal, august 2013, volume 13, issue 3 the difference across the three educational fields was not statistically significant. however, a higher percentage of dental and medical students reported scores above the 50% cut-off point for academic factors as compared to engineering students. scores of above 50% for health and lifestyle factors were reported by 295 respondents (24.1%), of which there were 89 (22.2%) dental, 87 (20.9%) engineering and 119 (29.3%) medical students. a higher percentage of medical students reported problems as compared to the others, and this difference was statistically significant. environmental and social factors were reported by 366 repondents (29.9%); among these, there were 111 (27.7%) dental students, 120 (28.8%) engineering students and 135 (33.3%) medical students. although a higher percentage of medical students reported scores above 50% for environmental and social factors, the difference was not statistically significant. stress was present in 299 respondents; out of these, 233 (77.9%) had a score above the 50% cut-off mark for academic factors, which was a statistically significant association. while considering the distribution according to the three fields of education, scores of above 50% for academic factors coexisted with stress in 94 (81.7%) dental, 62 (75.6%) engineering and 77 (75.5%) medical students, which are statistically significant associations for each of the three fields. the coexistence of scores over the cut-off value for health and lifestyle factors, as well as environmental and social factors, with stress was observed in 163 (54.5%) and 154 (51.5%) respondents, repectively. the statistically signifiant association was present in both cases. a total of 61 (53%) dental, 42 (51.2%) engineering and 60 (58.8%) medical students had stress along with scores of above 50% for health and lifestyle factors, which was statistically significant. similarly, 56 (48.7%) dental, 46 (56.1%) engineering and 52 (51%) medical students had a coexistence of stress and scores above the cut-off percentage for environmental and social factors. [table 3] upon further analysis using binary logistic regression, gender, academic factors, and environmental and social factors were observed to be the most important predictors for the development of stress [table 4]. furthermore, by applying multinomial logistic regression, it was observed that the development of severe stress was chiefly dependent on academic factors. [table 5] discussion in the current study, stress was observed in 24.4% of the respondents, and moderate to severe stress was present in 14.4%. considering the field of education, stress was present in 28.7% of dental students, 19.7% of engineering students and 25.1% of medical table 4: binary logistic regression for prediction of the most important factor for development of stress association of academic factors, health and lifestyle factors, and environmental and social factors with stress parameters b se wald df sig exp (b) 95% ci for exp (b) health and lifestyle factors 0.018 0.006 10.148 1 0.001 1.018 1.007–1.029 environmental and social factors 0.033 0.004 58.273 1 0.000 1.034 1.025–1.043 academic factors 0.036 0.005 45.380 1 0.000 1.036 1.026–1.047 constant -5.262 0.367 205.261 1 0.000 .005 association of sociodemographic factors with stress gender 0.331 0.142 5.429 1 0.020 1.392 1.054–1.838 medical 7.604 2 0.022 dental 0.148 0.166 0.795 1 0.373 1.159 0.837–1.605 engineering -0.310 0.174 3.185 1 0.074 0.733 0.522–1.031 present residence -0.162 0.112 2.096 1 0.148 0.851 0.683–1.059 permanent residence -0.282 0.153 3.403 1 0.065 0.754 0.559–1.018 constant -1.116 0.592 3.549 1 0.060 0.328 b = coefficient of regression; se = standard error of mean; wald = wald statistic; df = degree of freedom; sig = significance; 95% ci for exp (b) = 95% confidence interval for odds ratio. vivek b. waghachavare, girish b. dhumale, yugantara r. kadam and alka d. gore clinical and basic research | 427 students. in a study of medical students in mumbai, india, supe observed the presence of perceived stress in 73% of students.6 the observed prevalence of stress in medical students by abdulghani et al. in saudi arabia was 63.8%.10 in a study conducted on dental students by abu-ghazaleh et al. in jordan, stress was observed in 70% of the respondents.11 much lower stress levels were observed in the current study, a finding which could be attributed to geographical and social variations. additionally, it is important to note that supe considered perceived stress in the study subjects,6 whereas abdulghani et al. applied the kessler psychological distress scale (k10) inventory, which measures non-specific psychological distress,10 and abu-ghazaleh et al. applied the 12-item general health questionnaire (ghq-12), which is intended to screen for general psychiatric morbidity.11 in the current study, the scale used was the dass-21, which measures stress in a way which is quite similar to the dsm-iv diagnosis of gad.7 these different screening methods used to determine stress may have contributed to the differences in the observed prevalence of stress. in the current study, gender was found to be one of the most important factors in the development of stress, with the results indicating a female predominance; a similar trend was observed by abdulghani et al. and abu-ghazaleh et al.10,11 in the current study, stress was highest among the dental students, followed by medical students and then engineering students. thus, higher stress was observed in healthcare education branches as compared to the engineering branch. in a similar fashion al-dabal et al. observed a greater prevalence of stress in medical students in comparison with non-medical students in saudi arabia.4 barikani identified economic and accommodation-related problems as probable stressors among iranian medical students;12 consistent with those findings, environmental and social factors were identified as important stressors in this study. in the study conducted on medical students from mumbai, supe observed the association of stress with the class or semester of the respondents, and also observed that stress was independent of current residence.6 in the current study, there was no association of stress with the respondent’s class or semester; however, the respondent’s current residence was a highly significant factor as students living in hostels were more prone to stress. this may be due to the fact that a non-metropolitan lifestyle, and the nearby presence of a family support system, could be a positive method of coping with stress for students living with parents or relatives. similarly, the condition of hostels might be unsatisfactory, leading to higher stress among those living there. academic factors were one of the most important stressors in the participants of the current study, and these could be attributed to the development of stress and could also determine the severity of stress. the respondents from all three fields of education reported academic issues. researchers such as al-dabal et al., abu-ghazaleh et al. and behere et al. have studied the importance of various academic factors in the development of stress.4,11,13 hence, the results observed in the current study are in accordance with the findings of these researchers. across the three fields of education, there was no statistically significant difference in the presence of environmental and social factors, which play an important role in the development of stress. table 5: multinomial logistic regression for the association of grades of stress with academic factors, health and lifestyle factors, and environmental and social factors parameter estimates stress grades* b s.e. wald df sig. exp (b) 95% c.i. moderate intercept health and lifestyle factors academic factors environmental and social factors -3.497 0.025 0.038 -0.005 0.769 0.010 0.011 0.008 20.667 5.996 13.068 0.403 1 1 1 1 0 0.014 0 0.525 1.025 1.039 0.995 1.005–1.046 1.018–1.060 0.980–1.011 severe intercept health and lifestyle factors academic factors environmental and social factors -3.807 0.006 0.057 -0.009 0.810 0.011 0.012 0.008 22.070 0.325 23.916 1.183 1 1 1 1 0 0.569 0 0.277 1.006 1.059 0.991 0.985–1.027 1.035–1.083 0.975–1.007 * = mild category of stress; b = coefficient of regression; se = standard error of mean; wald = wald statistic; df = degree of freedom; sig = significance; 95% ci for exp (b) = 95% confidence interval for odds ratio. a study of stress among students of professional colleges from an urban area in india 428 | squ medical journal, august 2013, volume 13, issue 3 in a study by agolla et al. on undergraduate university students in botswana, social problems, like inadequate resources, and environmental problems, such as overcrowding in lecture halls, were important stressors.14 thus, the current study’s observations agree with the observations of other researchers. there is a tendency for medical students to diagnose themselves with diseases they are studying; this phenomenon is reported by some authors as the ‘medical school syndrome’.15 this ‘syndrome’ could possibly explain the reason for higher percentages of medical students reporting being affected by health and lifestyle factors in the current study, in comparison to the dental and engineering students. there are some limitations to this study. this study was based on results from a self-administered questionnaire, hence reporting bias cannot be totally eliminated. there was limited geographical coverage since the study was conducted in a single urban area. compounding factors, such as the participants’ current emotional state or personality, may be present. similarly, the difference in stress levels at different times, during pre-examination, examination and post-examination periods, was not considered in this study. conclusion students from all three fields of education are exposed to stress; however, it seems that engineering students are less prone to the development of stress compared to medical and dental students. further research needs to be done to study the differences in the academic environments of these fields, the role of a half-yearly examination pattern and the impact of these factors on the development of stress. academic, environmental, social and health problems all play an important role in the development of stress. academic factors are the most important stressors; hence the need for specific and targeted measures to decrease substantially the burden of stress on the students. teaching techniques and college environments should be adapted to the needs of the students. the productive utilisation of existing student welfare systems, development of more ‘student-friendly’ environments and regular periodic extracurricular activities with universal participation can prove to be useful stress-busters. similarly, students living in hostels were observed to be prone to develop stress; thus, a periodic review of hostels, with feedback from the students, should be conducted and the complaints of students should be promptly addressed. the majority of students were in favour of stress management education being included in the curriculum, and hence steps should be taken for its incorporation. health is a major concern of students, and therefore the promotion of healthy dietary and lifestyle habits should be encouraged. additionally, teachers, parents and even students themselves should be aware that undue expectations about academic achievement can lead to stress. finally, regular study habits and adequate preparation can help students to avoid stress. d e c l a r at i o n this research was funded by bharati vidyapeeth deemed university medical college, pune, maharashtra, india. a c k n o w l e d g e m e n t s the authors would like to thank all the students who participated in this study, and their respective institutions. references 1. bansal cp, bhave sy. stress in adolescents and its management. in: bhave sy, ed. bhave’s textbook of adolescent medicine. new delhi: jaypee brothers medical publishers, 2006. pp.844–53. 2. arria am, o’grady ke, caldeira km, vincent kb, wilcox hc, wish ed. suicide ideation among college students: a multivariate analysis. arch suicide res 2009; 13:230–46. 3. sharifirad g, marjani a, abdolrahman c, mostafa q, hossein s. stress among isfahan medical sciences students. j res med sci 2012; 17:402–6. 4. al-dabal bk, koura mr, rasheed p, al-sowielem l, makki sm. a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia. sultan qaboos univ med j 2010; 10:231–40. 5. al-dubai sa, al-naggar ra, alshagga ma, rampal kg. stress and coping strategies of students in a medical faculty in malaysia. malays j med sci 2011; 18:57–64. 6. supe an. a study of stress in medical students at seth g.s. medical college. j postgrad med 1998; 44:1–6. 7. lovibond sh, lovibond pf. manual for the depression anxiety stress scales. 2nd ed. sydney: vivek b. waghachavare, girish b. dhumale, yugantara r. kadam and alka d. gore clinical and basic research | 429 psychology foundation, 1995. 8. gloster at, rhoades hm, novy d, klotsche j, senior a, kunik m, et al. psychometric properties of the depression anxiety and stress scale-21 in older primary care patients. j affect disord 2008; 110:248– 59. 9. tran td, tran t, fisher j. validation of the depression anxiety stress scales (dass) 21 as a screening instrument for depression and anxiety in a rural community-based cohort of northern vietnamese women. bmc psychiatry 2013; 13:24. 10. abdulghani hm, alkanhal aa, mahmoud es, ponnamperuma gg, alfaris ea. stress and its effects on medical students: a cross-sectional study at a college of medicine in saudi arabia. j health popul nutr 2011; 29:516–22. 11. abu-ghazaleh sb, rajab ld, sonbol hn. psychological stress among dental students at the university of jordan. j dent educ 2011; 75:1107–14. 12. barikani a. stress in medical students. j med edu 2008; 11:41–4. 13. behere sp, yadav r, behere pb. a comparative study of stress among students of medicine, engineering, and nursing. indian j psychol med 2011; 33:145–8. 14. agolla je, ongori h. an assessment of academic stress among undergraduate students: the case of university of botswana. educ res rev 2009; 4:63–70. 15. collier r. imagined illnesses can cause real problems for medical students. can med assoc j 2008; 178:820–1. a 45-year-old woman presented with refractory pulmonary oedema secondary to a massive thrombosis of a st. jude mechanical mitral prosthetic valve. she was noncompliant with warfarin and had suffered embolic stroke 3 years earlier, from which she had recovered. she was in sinus rhythm with absent valve clicks on auscultation. a transthoracic echocardiogram revealed a high transmitral peak gradient of 34 mmhg and a mean gradient of 27 mmhg with an ejection fraction of 55% [figure 1a]. the international normalised ratio (inr) was 1.29. an urgent transesophageal echocardiogram (tee) demonstrated a large (6 cm2) left atrial thrombus attached to the mechanical valve at the discs which were stuck in a closed position [figures 1b and 1c]. the patient was advised to have emergency surgery, but she and the family refused. in spite of explaining the risks involved in thrombolysing a large clot, the patient and the family preferred thrombolytic therapy. as a life-saving measure, patient was thrombolysed with 10 units of reteplase intravenously over 2 minutes with a repeat dose of 10 units administered 30 minutes later. after an hour of thrombolysis a repeat tee showed complete disappearance of the thrombus from the left atrium with one of the discs stuck in closed position [figures 2 a and b]. the peak transmitral gradient was 7 mmhg and the mean gradient was 4 mmhg [figure 2c]. immediately, the patient started squ med j, may 2012, vol. 12, iss. 2, pp. 242-241, epub. 9th apr 2012 submitted 26th nov 11 revision req. 31st jan 12, revision recd. 8th feb 12 accepted 12th feb departments of 1cardiology, 2vascular surgery, 3radiology, 4medicine, royal hospital, muscat, oman. *corresponding author e-mail: prashanthp_69@yahoo.co.in فُِقد ُثّ َتّ العثور عليه اْنِصمام كارثي بعد عالج جلطة كبرية بصمام بديل بدواء مضاد للتخثر برا�سانت باندوراجنا، في�سل علم، الك�سمى رانتام، مطلوبة الزدجايل، حممد الديب lost and found catastrophic en block embolism of a mechanical prosthetic valve thrombus after thrombolytic therapy *prashanth panduranga,1 faisal alam,2 laxmi ratnam,3 matllooba al-zadjali,4 mohammed al-deeb1 interesting medical image figure 1: (a) transthoracic echocardiography showing mean diastolic mechanical mitral valve transvalvular gradient of 27 mmhg and a peak gradient of 34 mmhg in a patient with prosthetic valve thrombosis. (b) transesophageal echocardiography demonstrating stuck mechanical mitral valve with a large left atrial (la) thrombus attached to the prosthetic valve (arrowheads). (c) transesophageal echocardiography demonstrating close-up image of a large echogenic well defined la thrombus attached to a mechanical prosthetic valve (arrowheads). prashanth panduranga,faisal alam,laxmi ratnam,matllooba al-zadjali and mohammed al-deeb interesting medical image | 243 to complain of severe pain in the left leg with cold periphery and absent femoral pulse on both sides. an urgent computed tomography angiogram of the abdomen, pelvis and legs demonstrated complete occlusion of left common iliac artery and right common femoral artery with reformation of distal arteries [figures 3a, b and c]. an emergency open bilateral ilio-femoral embolectomy was performed and a large thrombus removed from the left common iliac artery [figure 4 a and b]. unfortunately, the patient developed refractory sepsis with acute renal shut down and died after 10 days of admission. the incidence of left-sided prosthetic valve thrombosis (pvt) ranges from 0.5% to 0.8% per patient-year.1,2 the mortality of obstructive pvt is about 10% irrespective of the treatment strategy.1 the american college of cardiology/american heart association (acc/aha) and american college of chest physicians guidelines recommend fibrinolytic therapy as first-line treatment for patients in good functional class with low thrombus burden (< 0.8 cm2) and in all other patients if they are considered to be at high risk for surgery.3,4 emergency surgery is reasonable for patients with a thrombosed left-sided prosthetic valve and new york heart association (nyha) functional class iii–iv symptoms or a large clot burden (> 0.8cm2).3,4 furthermore, in the following groups of patients figure 2: (a) transesophageal echocardiography demonstrating disappearance of a large left atrial thrombus attached to a stuck mechanical valve after thrombolysis with reteplase. note the bileaflet mechanical valve in closed position. (b) transesophageal echocardiography demonstrating residual thrombus post-thrombolysis in a bi-leaflet mechanical valve with one of the disc immobile in closed position (arrowheads). note the other disc is open. (c) transesophageal echocardiography showing mean diastolic mechanical mitral valve transvalvular gradient of 4 mmhg and a peak gradient of 7 mmhg in a patient with prosthetic valve thrombosis treated with thrombolysis. la, left atrium. figure 3: contrast-enhanced computed tomography (ct) scan in axial (a) view showing presence of contrast in the right common iliac artery (arrowheads) with absence of opacification of left common iliac artery in a patient with prosthetic valve thrombosis treated with thrombolysis. contrast-enhanced ct in three-dimensional reconstruction (b and c) demonstrates complete occlusion of left common iliac artery and right common femoral artery (arrowheads) in the patient with prosthetic valve thrombosis treated with thrombolysis. lost and found catastrophic en block embolism of a mechanical prosthetic valve thrombus after thrombolytic therapy 244 | squ medical journal, may 2012, volume 12, issue 2 surgery is advised, namely: 1) patients with large left atrial thrombus; 2) patients with any active bleeding or a history of intracranial bleeding; 3) patients with evidence of ischaemic stroke from 4 hours to six weeks, and 4) post-valve replacement within 4 days.1 the major complication of thrombolytic treatment for pvt is the risk of embolisation which occurs in 12–15% of the cases.3 a registry study demonstrated that thrombus size on tee and a past history of stroke were independent predictors of complications as seen in this patient.2 left atrial thrombi are also known to embolise at the time of, or shortly after a change in atrial rhythm.5 in this case, there was not only obstructive pvt, but it was associated with a large left atrial thrombus and hence surgery was the initial choice of treatment. however, the patient refused surgery and was thrombolysed with catastrophic embolism. references 1. cevik c, izgi c, dechyapirom w, nugent k. treatment of prosthetic valve thrombosis: rationale for a prospective randomized clinical trial. j heart valve dis 2010; 19:161–70. 2. tong at, roudaut r, ozkan m, sagie a, shahid ms, pontes júnior sc, et al. prosthetic valve thrombolysisrole of transesophageal echocardiography (protee) registry investigators. transesophageal echocardiography improves risk assessment of thrombolysis of prosthetic valve thrombosis: results of the international pro-tee registry. j am coll cardiol 2004; 43:77–84. 3. bonow ro, carabello ba, chatterjee k, de leon ac jr, faxon dp, freed md, et al. 2006 writing committee members; american college of cardiology/american heart association task force. 2008 focused update incorporated into the acc/aha 2006 guidelines for the management of patients with valvular heart disease: a report of the american college of cardiology/american heart association task force on practice guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease): endorsed by the society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, and society of thoracic surgeons. circulation 2008; 118:e523–661. 4. salem dn, o'gara pt, madias c, pauker sg. american college of chest physicians. valvular and structural heart disease: american college of chest physicians evidence-based clinical practice guidelines (8th edition). chest 2008; 133: s593–629. 5. singh a, naqvi t, marx mv, rahimtoola sh. acute thrombotic complete occlusion of the aorta: accurate, immediate clinical decision-making by echocardiography. am j med 2009; 122:e1. figure 4: (a) intra-operative image of a large thrombus protruding from left common iliac artery in a patient with prosthetic valve thrombosis treated with thrombolysis. (b) image of a large thrombus explanted en bloc from left common iliac artery in the patient with prosthetic valve thrombosis and post-thrombolysis embolism. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e134-138, epub. 27th jan 14 submitted 10th mar 13 revisions req. 14th may & 21st jun 13; revisions recd. 23rd jun & 14th sep 13 accepted 19th sep 13 pregnancy in a rudimentary uterine horn is a rare condition that can lead to a catastrophic outcome when it ruptures. the majority of cases are diagnosed late, after the rupture has occurred.the use of ultrasonography helps clinicians to diagnose uterine malformations earlier, which can then be confirmed by a magnetic resonance image (mri) or a laparoscopy. the standard treatment for a rudimentary horn pregnancy is surgical excision to prevent complications and recurrence.1 case report a 24-year-old omani female presented at 23 weeks’ gestation and was referred to the royal hospital, muscat, with a diagnosis of intrauterine fetal demise, which had been detected on a routine antenatal ultrasound. she reported an absence of fetal movements for the previous two days. there was no history of abdominal pain or vaginal blood loss at any time. the patient was gravida 2, para 1, with one previous vaginal delivery at term approximately 16 months previously. the third stage had been complicated by a retained placenta which was removed manually under general anaesthesia. there was no significant past medical or surgical history. she had had normal menstrual periods with no history of dysmenorrhoea. her current second pregnancy had previously been uneventful, with a normal fetal anomaly scan at 20 weeks’ gestation. at admission, the patient’s general condition was good and her vital signs were normal. a physical department of obstetrics & gynecology, royal hospital, muscat, oman *corresponding author e-mail: nooralqabas@hotmail.com عرض حلالة نادرة حلمل يف قرن رحم غري مكتمل النمو قمرية �أمبو�صعيدية و �صرت� جها امللخ�ص: يعد الرحم اأحادي القرن والرحم ذو القرن غري املكتمل من حاالت ت�شوهات الرحم اخللقية التي حتدث نتيجة النمو غري املكتمل لقنوات مولر. اإن احلمل يف قرن الرحم غري مكتمل النمو من احلاالت النادرة التي اإذا مل يتم ت�شخي�شها يف الوقت املنا�شب فاإنها قد توؤدي اإىل نتائج وخيمة توؤثر على حياة املري�شة عند انفجارها و متزقها. معدل حدوث احلمل يف الرحم اأحادي القرن والرحم ذي القرن غري املكتمل يقدر ب 1 يف كل 100,000 اإىل 140,000 حمل. العالج ال�شائع هو اال�شتئ�شال اجلراحي للقرن. يف هذا املقال تعر�ص حالة ملري�شة يف االأ�شبوع الثالث و الع�رشين من حملها الثاين جاءت للم�شت�شفى بعد وفاة اجلنني. ف�شل اإجراءات حتري�ص املخا�ص اأثار ال�شك يف اإمكانية وجود احلمل يف مكان غري طبيعي و هو ما اأكده الت�شوير بالرنني املغناطي�شي. لقد خ�شعت املري�شة لعملية جراحية الإزالة قرن الرحم غري املكتمل النمو. هذه احلالة ت�شلط ال�شوء عل اأهمية الفح�ص الدقيق باأ�شعة املوجات ال�شوتية يف بدايات احلمل للك�شف املبكر عن حاالت ت�شوهات الرحم. مفتاح الكلمات: ت�صوهات �لرحم �خللقية؛ �حلمل؛ �أ�صعة �ملوجات فوق �ل�صوتية؛ �لت�صوير بالرني �ملغناطي�صي؛ فتح �لبطن؛ عر�س حالة؛ عمان. abstract: a unicornuate uterus with a rudimentary horn is a uterine anomaly resulting from the incomplete development of one of the müllerian ducts and an incomplete fusion with the contralateral side. pregnancy in a rudimentary horn of the uterus is a rare clinical condition with a reported incidence of 1 in 100,000 to 140,000 pregnancies. usually the diagnosis is missed and may present as an emergency with haemoperitoneum. the standard treatment is the surgical excision of the horn. a gravida 2, para 1 patient presented at 23 weeks’ gestation with fetal demise. repeated failed attempts at induction of labour raised the suspicion of an abnormally located pregnancy which was confirmed by magnetic resonance imaging. she underwent a laparotomy with right rudimentary horn excision. the final diagnosis of a non-communicating rudimentary horn pregnancy was made intraoperatively and was confirmed by histopathology. this case highlights the importance of an early ultrasound in detecting uterine anomalies and the need for high clinical suspicion. keywords: uterus, abnormalities; pregnancy; ultrasonography; magnetic resonance imaging; laparotomy; case report; oman. pregnancy in the rudimentary uterine horn case report of an unusual presentation *qamariya ambusaidi and chitra jha online case report qamariya ambusaidi and chitra jha case report | e135 examination of the abdomen revealed a relaxed, non-tender uterus palpable to the level of the umbilicus. a transabdominal ultrasound showed a single, non-viable, intrauterine fetus with fetal parameters corresponding to 22 weeks’ gestation. the amniotic fluid was normal and the placenta was posterior in the upper segment. she was diagnosed with an intrauterine fetal death and the decision was made to induce labour. a complete blood count and coagulation profile were normal. her blood group was b positive with negative antibody screening. she was screened for torch infections (toxoplasmosis, other [syphilis, varicella-zoster and parvovirus b19], rubella, cytomegalovirus and herpes) and was negative for immunoglobulin m antibodies. a medical induction of labour with misoprostol was attempted. there was no response to the full course of 400 µg of misoprostol given vaginally every four hours for a maximum of five doses. the patient experienced uterine irritability, with minimal vaginal spotting but no cervical changes. a second course of misoprostol was repeated after 48 hours, but with no success. an abdominal ultrasound was repeated and a transvaginal ultrasound was also done. this showed a normal cervix leading to a small, normal, empty uterus just above it. the non-viable pregnancy was seen above and on the right of the uterus. pregnancy in a rudimentary horn of the uterus was suspected with a differential diagnosis of an abdominal pregnancy. an mri of the pelvis confirmed the diagnosis of pregnancy in the rudimentary horn of the uterus, as normal myometrial tissue was seen around the fetus; however, pregnancy in one horn of a bicornuate uterus could not be definitively excluded [figure 1]. the patient underwent a laparotomy through a midline infra-umbilical incision. the findings included a normal uterus with a normal ovary and fallopian tube on the left side. the pregnancy was in a rudimentary horn on the right side, with a normal ovary and fallopian tube attached to it. the horn was connected to the uterus just above the cervix by a thick fibrous band. a small incision was made over the pregnant horn and a dead female fetus weighing 450 g was delivered. the horn was then excised, along with the right fallopian tube. the patient lost 200 ml of blood [figures 2 and 3]. the post-operative period was uneventful and the patient was discharged on the fourth day. a histopathology examination confirmed the diagnosis. there was no infiltration of the chorionic figure 1 a & b: magnetic resonance images showing (a) a normal uterus (white arrows) with the pregnancy above and to the right side, and (b) with a thin myometrium all around the pregnancy (black arrow). figure 2: the uterus was exteriorised after the delivery of the fetus. the image shows the right pregnant rudimentary uterine horn (white arrow). as this image was taken after delivering the fetus, the umbilical cord can be seen emerging from the incision. figure 3: image taken after the excision of the right rudimentary horn, which was linked by a fibrous band to the uterus (white arrow). pregnancy in the rudimentary uterine horn case report of an unusual presentation e136 | squ medical journal, february 2014, volume 14, issue 1 villi into the myometrium. an intravenous urogram was done which showed an absent right kidney. discussion uterine anomalies result from the failure of complete fusion of the müllerian ducts during embryogenesis. the incidence in the general population is estimated to be 4.3%.1 a unicornuate uterus with a rudimentary horn is the rarest anomaly and results from the failure of one of the müllerian ducts to develop completely and an incomplete fusion with the contralateral side.2 the incidence of this anomaly is approximately 0.4%.1 in the majority (83%) of cases, the rudimentary horn is non-communicating.2 the anatomical variations of a rudimentary horn serve as the basis for the classification of a unicornuate uterus by the american society of reproductive medicine (asrm). acién et al. performed a systematic review to analyse the classification systems for uterine anomalies and concluded that an embryological clinical classification system seemed to be the most appropriate.3 this paper presents a case from class 1, and would be classified as class iib according to the asrm [table 1 and figure 4]. pregnancy in a rudimentary horn was first described by mauriceau and vassal in 1669.5 the reported incidence is 1 in 100,000 to 140,000 pregnancies.6 the most accepted explanation is the transperitoneal migration of the sperm cells or a fertilised ovum.1,2,6 this explanation was supported by the observation of the corpus luteum in the contralateral ovary. it is extremely uncommon for such cases to result in a viable baby. these cases usually result in the rupture of the horn in the second or third trimester, typically between the 10th and 20th week of gestation, although a rupture has been reported at 34 weeks.7,8 only 10% of cases such as these reach term, and the fetal salvage rate is only 2%.6 the rupture occurs because of the underdevelopment of the myometrium and a dysfunctional endometrium.6 a rudimentary horn pregnancy can be further complicated by placenta percreta due to the poorly developed musculature and the small size of the horn; the reported incidence is 11.9%.6 placenta percreta can be confirmed by a histopathology examination from as early as seven weeks.9 the key for diagnosis prior to the rupture is a high index of clinical suspicion. a history table 1: embryological-clinical classification for female genito-urinary malformations 1. unilateral genito-urinary agenesis or hypoplasia cases of unicornuate uterus with contralateral renal agenesis due to agenesis or hypoplasia of an entire urogential ridge. 2. uterine duplicity (bicornuate or didelphys uterus) with a blind hemivagina (or unilateral cervico-vaginal atresia) and ipsilateral renal agenesis this includes the herlyn-werner-wunderlich syndrome and there can also be cases of resorption partial of the intervaginal septum. 3. isolated or common uterine or utero-vaginal anomalies this include the anomalies in the müllerian development processes (also included in the classification of the american fertility society) without other associated anomalies; and also the transverse vaginal septum. 4. accessory uterine masses with an otherwise normal uterus, and other possible gubernaculum dysfunctions 5. anomalies of the urogenital sinus these include cases of imperforated hymen, vesico-vaginal fistulas, persistent urogenital sinus, cloacal anomalies and other external gastrointestinal or urinary anomalies. 6. malformative combinations acién et al., 2011.3 reproduced with the authors' permission. figure 4: american society of reproductive medicine (asr) classification of uterine müllerian anomalies.4 des = diethylstilbestrol. reproduced with permission. qamariya ambusaidi and chitra jha case report | e137 of severe dysmenorrhoea may be a clue for diagnosis. however, the rudimentary horn may be underdeveloped and its endometrium nonfunctional, so dysmenorrhoea may be absent. a careful pelvic examination in the first trimester showing a deviated uterus with a palpable adnexal mass should provoke suspicion of a müllerian anomaly. it can be confirmed by an ultrasound or mri. tsafrir et al. suggested the following criteria for diagnosing a pregnancy in the rudimentary horn: (1) a pseudo pattern of asymmetrical bicornuate uterus; (2) absent visual continuity between the cervical canal and the lumen of the pregnant horn, and (3) the presence of myometrial tissue surrounding the gestational sac.1,2,10 ultrasound sensitivity remains only 26%.6 the enlarging horn with the thinned myometrium can obscure the adjacent anatomical structures and the sensitivity further decreases as the gestation progresses. mri has proven to be a very useful diagnostic tool. approximately 38% of patients have coexisting renal abnormalities. unilateral renal agenesis is most commonly found; this is always ipsilateral with the rudimentary horn.11 the differential diagnosis includes a tubal, corneal or intrauterine pregnancy in a bicornuate uterus. ultrasonographical features may help to reach diagnosis, as in the following examples. a tubal pregnancy will not show a ring of the myometrium surrounding the gestational sac. a variation in the thickness of the myometrium in two horns and a marked distance between them favour the diagnosis of a rudimentary horn pregnancy. the continuity between the endometrium lining the gestational sac and the other uterine horn is typical for a pregnancy in a bicornuate uterus.10 in this case, despite the patient’s earlier ultrasound, the diagnosis was initially missed probably due to the advanced gestational age and a lack of clinical suspicion. it was only when the patient failed to respond to repeated attempts to induce labour that an abnormal pregnancy was suspected. the use of misoprostol to terminate a pregnancy in such a case can lead to the rupture of the horn. the mri was helpful in making the diagnosis of a uterine malformation, although the exact diagnosis and type of attachment was established only by a laparotomy. immediate surgery is recommended whenever a diagnosis of a pregnancy in the rudimentary horn is made. the traditional treatment is a laparotomy and the surgical removal of the pregnant horn to prevent rupture and recurrent rudimentary horn pregnancies. in recent years, several cases have been treated successfully by laparoscopies using various techniques.9 some authors have described systemic methotrexate administration or feticide with intracardiac potassium chloride as alternatives or adjuncts to surgery in early gestation.9 conservative management, until viability is established, has been advocated in selected cases with large myometrial masses. emergency surgery can be performed at any time. in all such cases, the patient should be informed of the risks of the condition as well as their management options.2 conclusion despite advances in ultrasound technology, the antenatal diagnosis of a rudimentary horn pregnancy remains difficult for inexperienced physicians. a high index of clinical suspicion for uterine malformations early in the gestation can reduce the mortality rate, along with early intervention. when a rudimentary horn pregnancy is diagnosed, the excision of the horn with ipsilateral salpingectomy is the recommended surgical treatment for the best prognosis. this case highlights the need for high clinical suspicion of this rare condition. d e c l a r at i o n written informed consent was obtained from the patient and her husband for the publication of this report, along with the mri images and photographs. references 1. buntugu k, ntumy m, ameh e, obed s. rudimentary horn pregnancy: pre-rupture diagnosis and management. ghana med j 2008; 42:92–4. 2. okonta pi, abedi h, ajuyah c, omo-aghoja l. pregnancy in a noncommunicating rudimentary horn of a unicornuate uterus: a case report. cases j 2009; 2:6624. 3. acién p, acién mi. the history of female genital tract malformation classifications and proposal of an updated system. hum reprod update 2011: 17:693–705. 4. american fertility society. the american fertility society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. fertil steril 1988; 49:944–55. 5. latto d, norman r. pregnancy in a rudimentary horn of a bicoruate uterus. br med j 1950; 2:926–7. pregnancy in the rudimentary uterine horn case report of an unusual presentation e138 | squ medical journal, february 2014, volume 14, issue 1 6. jain r, gami n, puri m, trivedi ss. a rare case of intact rudimentary horn pregnancy presenting as hemoperitoneum. j hum reprod sci 2010; 3:113–5. 7. sönmezer m, taskin s, atabekoğlu c, güngör r, unlü c. laparoscopic management of rudimentary uterine horn pregnancy: case report and literature review. jsls 2006; 10:396–9. 8. açmaz g, tayyar a, öner g, tayyar m. live birth in an unruptured communicating rudimentary horn pregnancy at 32 weeks: case report. med j bakirköy 2008; 4:170–2. 9. henriet e, roman h, zanati j, lebreton b, sabourin jc, loic m. pregnant noncommunicating rudimentary uterine horn with placenta percreta. jsls 2008; 12:101–3. 10. tsafrir a, rojansky n, sela hy, gomori jm. rudimentary horn pregnancy: first trimester prerupture sonographic diagnosis and confirmation by magnetic resonance imaging. j ultrasound med 2005; 24:219–23. 11. park jk, dominguez ce. combined medical and surgical management of rudimentary uterine horn pregnancy. jsls 2007; 11:119–22. just as general physicians have become accustomed to the concept of heart failure with preserved ejection fraction (hfpef), the latest 2016 guidelines for the diagnosis and treatment of heart failure from the european society of cardiology (esc) have introduced a new group of patients: those with heart failure with mildly reduced ejection fraction (hfmref).1 the esc has explained that this new category was needed as a means to fill the gap that existed in the knowledge and understanding of heart failure as well as stimulating research on this group of patients who have not traditionally been included in studies on heart failure with reduced ejection fraction (hfref) or hfpef.1 in the 2016 esc guidelines, the diagnostic criteria for hfmref includes signs and symptoms of heart failure, an ejection fraction (ef) of 40–49%, elevated levels of natriuretic peptides and either relevant structural heart disease (i.e. left ventricular hypertrophy and/or left atrial enlargement) or diastolic dysfunction observed during echocardiography.1 interestingly, the last two criteria are also used to diagnose hfpef; this new category could therefore be considered to constitute either pre-hfref or progressive hfpef, assuming that hfpef is a forerunner of hfref.2,3 this is supported by the fact that the ventricles of patients with hfpef are not entirely normal and have certain contractile abnormalities.4,5 previous changes in classifications in order to ascertain whether the new classification of hfmref is beneficial, it is useful to reflect on the introduction of the term ‘hfpef’. prior to the formal identification of this group of patients as a distinct entity, clinicians were aware that some patients, mainly elderly hypertensive females, presented with clinical signs of heart failure but displayed normal left ventricular function on echocardiography.6 various aetiologies were suggested and these patients were initially labelled as having diastolic heart failure, as it was believed that these hypertensive patients had stiff ventricles that did not relax.6 in the absence of any department of medicine, sultan qaboos university hospital, muscat, oman e-mail: sunilnadar@gmail.com abstract: the latest european society of cardiology (esc) guidelines for the diagnosis and management of heart failure include a new patient group for those with heart failure with mildly reduced ejection fraction (hfmref). by defining this group of patients as a separate entity, the esc hope to encourage more research focusing on patients with hfmref. previously, patients with this condition were caught between two classifications—heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. hopefully, the inclusion of new terminology will not increase confusion, but rather aid our understanding of heart failure, a complex clinical syndrome. keywords: heart failure; ventricular ejection fraction; guidelines as topic; nomenclature. امللخ�ص: �ضملت املبادئ الت�جيهية االأخرية للرابطة االأوروبية لطب القلب لت�ضخي�ص وعالج ف�ضل القلب جمم�عة جديدة من ف�ضل القلب مع انخفا�ص قليل يف الك�رس القذيف. ح�ضب تعريف هذة املجم�عة من املر�ضى ككيان منف�ضل, تاأمل الرابطة االأوروبية لطب القلب ت�ضجيع املزيد من االأبحاث التي تركز على مر�ضى ف�ضل القلب مع انخفا�ص قليل يف الك�رس القذيف. �ضابقا, املر�ضى امل�ضاب�ن بهذا املر�ص كان�ا اإدراج اأن من ناأمل القذيف. الك�رس حفظ مع القلب ف�ضل و القذيف الك�رس انخفا�ص مع القلب الت�ضنيف-ف�ضل من ن�عني حتت يدرج�ن امل�ضطلح اجلديد لن يزيد من االإرتباك بل بالعك�ص �ضي�ضاعد على فهم ف�ضل القلب والذي يعترب متالزمة �رسيرية معقدة. الكلمات املفتاحية: ف�ضل القلب؛ الك�رس القذيف البطيني؛ املبادئ الت�جيهية كم��ض�ع؛ ت�ضمية. new classification for heart failure with mildly reduced ejection fraction greater clarity or more confusion? sunil nadar sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e23–26, epub. 30 mar 17 submitted 15 sep 16 revision req. 31 oct 16; revision recd. 21 nov 16 accepted 8 dec 16 doi: 10.18295/squmj.2016.17.01.005 sounding board new classification for heart failure with mildly reduced ejection fraction greater clarity or more confusion? e24 | squ medical journal, february 2017, volume 17, issue 1 clinical evidence, clinicians often treated this group of patients in the same way as those with hfref, with varying results.7 it was gandhi et al. who first reported 38 patients presenting with hypertensive acute pulm onary oedema and preserved left ventricular func tion, both during the acute phase and after successful treatment of their acute presentation, thus demonstrating that these patients constituted a distinct entity.8 this patient group was subsequently given many labels, such as ‘diastolic heart failure’ and ‘heart failure with normal ef’.9 eventually, the american heart association and the esc formally accepted the term ‘hfpef’.10,11 the formal recognition of hfpef as a distinct entity has led to more focused research on this group of patients. it is now known that these patients are a heterogeneous group not limited to elderly hypertensive females and whose ventricles have normal systolic function with varying degrees of stiffness and diastolic abnormalities.12 in addition, evidence now shows that many of the treatment modalities for treating hfref are ineffective for patients with hfpef.12 these findings have changed the manage ment of and approach to dealing with patients with hfpef, although there are admittedly still many unanswered questions.13 in a similar manner, despite the possible initial reluctance to accept another category of heart failure patients, the decision by the esc to define hfmref may help to increase understanding of this disease and improve its treatment, particularly for patients who fall in between the two previous categories. current approaches to diagnosis and management clinicians familiar with the management of heart failure patients will know that individuals with hfmref are often difficult to treat. in a way, they are somewhat similar to hfpef patients whereby the symptoms of heart failure appear disproportional to the level of reduced ef; moreover, these patients do not often respond as well to diuretics, angiotensinconverting enzyme inhibitors or β-blockers.14 similar to the treatment that hfpef patients received prior to breakthroughs in the understanding of the disease, hfmref patients are still treated with similar management plans to those of hfref patients.15 although there is often no evidence to back up these management plans, clinicians tend to rely on their clinical experience. perhaps time will tell whether these patients are more likely to respond to conventional heart failure treatments or whether there is a need for more specific treatment modalities. currently, the esc guidelines have combined the management of patients with hfmref with that of hfpef patients.1 a major problem in the management of hfpef, and now hfmref as well, is establishing the diagnosis.16 there is still some reluctance to label a patient with preserved left ventricular function as having heart failure; as such, hfpef and hfmref patients are often underdiagnosed.16 these patients sometimes undergo multiple tests to rule out respiratory and ischaemic causes of breathlessness before ultimately being diagnosed with heart failure. moreover, hfpef and hfmref patient groups are heterogeneous and often have multiple comorbidities that can confuse the diagnosis.12 there is a danger of both the over and underdiagnosis of heart failure. epidemiological studies have shown that the incidence of hfpef appears to be on the rise.17,18 this could potentially be explained by the developing awareness of hfpef on the part of clinicians and their increased willingness to make this diagnosis now that it has been officially recognised. opportunities for further research with the previously undefined group of hfmref patients now having been legitimised with an official name, albeit one difficult to articulate properly, it can be hoped that this will spur research focusing specifically on this patient group.19 currently, it is unknown whether these patients have a milder version of hfref, if hfmref indicates those with hfpef whose ef is now deteriorating or indeed if it is simply a part of the heart failure continuum.19 along those lines, it is not clear whether aggressive treatment of hfpef would prevent patients from progressing to hfmref or whether aggressive management of hfmref would prevent patients from deteriorating to hfref. more research is therefore justified. this change in nomenclature gives rise to many questions that clinicians have perhaps always asked themselves, but never had the chance to openly query; these can hopefully now be answered, perhaps via large-scale clinical trials. alternative classifications of heart failure it must be noted that the use of ef as a method of classifying heart failure is not universally agreed upon. de keulenaer et al. argue that hfpef and hfref are overlapping phenotypes within the spectrum of heart failure and that the use of ef to classify heart failure is sunil nadar sounding board | e25 not accurate.3 they suggest that this classification came about primarily because early heart failure drug trials included patients with low ef, who were considered a high-risk group, in order to produce statistically significant results.3 subsequently, an emphasis on evidence-based medicine has automatically led to the use of cut-off values derived from the results of these trials. another suggestion is that the disease be classified based on aetiology or physiological abnormalities, as well as the clinical presentation of acute or chronic heart failure symptoms, as this affects management choices.9 furthermore, by using pathophysiology to classify heart failure, other researchers have proposed the use of biomarkers either alone or in combination with echocardiography in order to guide therapy and management choices, instead of relying entirely on ef measurements.20–22 conclusion despite the announcement by the esc of yet another category of heart failure patients with a tonguetwisting acronym, it is unlikely that the clinical management of this new hfmref patient group will change immediately. however, this new classification does define another subset of heart failure patients on whom additional and more focused research can now be conducted. ideally, this will ensure increased understanding of this patient group in order to improve and effectively tailor management approaches. references 1. ponikowski p, voors aa, anker sd, bueno h, cleland jg, coats aj, et al. 2016 esc guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (esc) developed with the special contribution of the heart failure association (hfa) of the esc. eur heart j 2016; 37:2129–200. doi: 10.1093/ eurheartj/ehw128. 2. cahill jm, ryan e, travers b, ryder m, ledwidge m, mcdonald k. progression of preserved systolic function heart failure to systolic dysfunction: a natural history study. int j cardiol 2006; 106:95–102. doi: 10.1016/j.ijcard.2004.12.096. 3. de keulenaer gw, brutsaert dl. systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum. circulation 2011; 123:1996–2004. doi: 10.1161/cir culationaha.110.981431. 4. wang j, khoury ds, yue y, torre-amione g, nagueh sf. preserved left ventricular twist and circumferential deformation, but depressed longitudinal and radial deformation in patients with diastolic heart failure. eur heart j 2008; 29:1283–9. doi: 10.1093/eurheartj/ehn141. 5. yu cm, lin h, yang h, kong sl, zhang q, lee sw. progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. circulation 2002; 105:1195–201. doi: 10.1161/hc1002.105185. 6. vasan rs, levy d. defining diastolic heart failure: a call for standardized diagnostic criteria. circulation 2000; 101:2118–21. doi: 10.1161/01.cir.101.17.2118. 7. dauterman kw, massie bm, gheorghiade m. heart failure associated with preserved systolic function: a common and costly clinical entity. am heart j 1998; 135:s310–19. doi: 10.1016/s0002-8703(98)70258-3. 8. gandhi sk, powers jc, nomeir am, fowle k, kitzman dw, rankin km, et al. the pathogenesis of acute pulmonary edema associated with hypertension. n engl j med 2001; 344:17–22. doi: 10.1056/nejm200101043440103. 9. sanderson je. hfnef, hfpef, hf-pef, or dhf: what is in an acronym? jacc heart fail 2014; 2:93–4. doi: 10.1016/j.jchf. 2013.09.006. 10. jessup m, abraham wt, casey de, feldman am, francis gs, ganiats tg, et al. 2009 focused update: accf/aha guide lines for the diagnosis and management of heart failure in adults a report of the american college of cardiology foundation/american heart association task force on practice guidelines: developed in collaboration with the international society for heart and lung transplantation. circulation 2009; 119:1977–2016. doi: 10.1161/circulatio naha.109.192064. 11. mcmurray jj, adamopoulos s, anker sd, auricchio a, böhm m, dickstein k, et al. esc guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the european society of cardiology developed in collaboration with the heart failure association (hfa) of the esc. eur j heart fail 2012; 14:803–69. doi: 10.1093/eurjhf/hfs105. 12. sharma k, kass da. heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. circ res 2014; 115:79–96. doi: 10.1161/circresaha.115.302922. 13. ferrari r, böhm m, cleland jg, paulus wj, pieske b, rapezzi c, et al. heart failure with preserved ejection fraction: uncertainties and dilemmas. eur j heart fail 2015; 17:665–71. doi: 10.1002/ejhf.304. 14. lam cs, solomon s. the middle child in heart failure: heart failure with mid-range ejection fraction (40-50%). eur j heart fail 2014; 16:1049–55. doi: 10.1002/ejhf.159. 15. maggioni ap, anker sd, dahlström u, filippatos g, ponikowski p, zannad f, et al. are hospitalized or ambulatory patients with heart failure treated in accordance with european society of cardiology guidelines? evidence from 12,440 patients of the esc heart failure long-term registry. eur j heart fail 2013; 15:1173–84. doi: 10.1093/eurjhf/hft134. 16. caruana l, petrie mc, davie ap, mcmurray jj. do patients with suspected heart failure and preserved left ventricular systolic function suffer from “diastolic heart failure” or from misdiagnosis? a prospective descriptive study. bmj 2000; 321:215–18. doi: 10.1136/bmj.321.7255.215. 17. roger vl, weston sa, redfield mm, hellermann-homan jp, killian j, yawn bp, et al. trends in heart failure incidence and survival in a community-based population. jama 2004; 292:344–50. doi: 10.1001/jama.292.3.344. 18. owan te, hodge do, herges rm, jacobsen sj, roger vl, redfield mm. trends in prevalence and outcome of heart failure with preserved ejection fraction. n engl j med 2006; 355:251–9. doi: 10.1056/nejmoa052256. 19. borlaug ba, redfield mm. diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. circulation 2011; 123:2006–13. doi: 10.1161/circulation aha.110.954388. https://doi.org/10.1093/eurheartj/ehw128 https://doi.org/10.1093/eurheartj/ehw128 https://doi.org/10.1016/j.ijcard.2004.12.096 https://doi.org/10.1161/circulationaha.110.981431 https://doi.org/10.1161/circulationaha.110.981431 https://doi.org/10.1093/eurheartj/ehn141 https://doi.org/10.1161/hc1002.105185 https://doi.org/10.1161/01.cir.101.17.2118 https://doi.org/10.1016/s0002-8703%2898%2970258-3 https://doi.org/10.1056/nejm200101043440103 https://doi.org/10.1016/j.jchf.2013.09.006 https://doi.org/10.1016/j.jchf.2013.09.006 https://doi.org/10.1161/circulationaha.109.192064 https://doi.org/10.1161/circulationaha.109.192064 https://doi.org/10.1093/eurjhf/hfs105 https://doi.org/10.1161/circresaha.115.302922 https://doi.org/10.1002/ejhf.304 https://doi.org/10.1002/ejhf.159 https://doi.org/10.1093/eurjhf/hft134 https://doi.org/10.1136/bmj.321.7255.215 https://doi.org/10.1001/jama.292.3.344 https://doi.org/10.1056/nejmoa052256 https://doi.org/10.1161/circulationaha.110.954388 https://doi.org/10.1161/circulationaha.110.954388 new classification for heart failure with mildly reduced ejection fraction greater clarity or more confusion? e26 | squ medical journal, february 2017, volume 17, issue 1 20. troughton rw, frampton cm, brunner-la rocca hp, pfisterer m, eurlings lw, erntell h, et al. effect of b-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. eur heart j 2014; 35:1559–67. doi: 10.1093/ eurheartj/ehu090. 21. troughton r, michael felker g, januzzi jl jr. natriuretic peptide-guided heart failure management. eur heart j 2014; 35:16–24. doi: 10.1093/eurheartj/eht463. 22. simioniuc a, carluccio e, ghio s, rossi a, biagioli p, reboldi g, et al. echo and natriuretic peptide guided therapy improves outcome and reduces worsening renal function in systolic heart failure: an observational study of 1137 outpatients. int j cardiol 2016; 224:416–23. doi: 10.1016/j. ijcard.2016.09.034. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 318-322, epub. 9th may 13 submitted 22th jun 12 revision req. 30th nov 12, revision recd. 30th nov 12 accepted 12th dec 12 1department of medicine, sultan qaboos university hospital and 2college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: drjayakrish@hotmail.com املضاعفات الرئوية الشديدة ملرض الربمييات املضادات احليوية و ادوية الكورتيزون بالتبادل جايا كر�شنان, فاطمة بن عابد, عبداهلل باخلري, جمعه الكعبي, عمر الروا�س, جوجي جورج, خلفان الزيدي مبر�س موبوءة الغري االماكن يف متاأخر وقت يف تكت�شف ما عادة منت�رشة, انها مع الربمييات, ملر�س الرئوية امل�شاعفات امللخ�س: الربمييات. هنا ندرج حالة ا�شابة مبر�س الربمييات مع م�شاعفات رئوية �شديدة يف م�شت�شفى جامعة ال�شلطان قابو�س عوجلت بامل�شادات احليوية املريوبنم ) واحد جرام كل ثمان �شاعات( و املوك�شيفلوك�ش�شني )400 ملي جرام مرة واحدة يف اليوم( باالإ�شافة اىل جرعات كبرية من ادوية الكورتيزون. ادوية الكورتيزون اأعطت ملدة ثالثة اأ�شهر لوجود التهابات رئوية م�شتمرة. مفتاح الكلمات: مر�س الربمييات؛ االن�شان؛ متالزمة ال�شائقة التنف�شية احلادة؛ حالة مر�شية؛ �شتريويدات؛ عمان. abstract: pulmonary complications in leptospirosis, though common, are often unrecognized in a non-endemic area. we report here a patient with leptospirosis and severe pulmonary involvement who was treated with meropenem (1 g every 8 hours), moxifloxacin (400 mg once daily), and high doses of corticosteroids. systemic steroids were continued for 3 months because of persistent pulmonary lesions. keywords: leptospirosis; human ards; steroids; case report; oman. severe pulmonary involvement in leptospirosis alternate antibiotics and systemic steroids *jayakrishnan b,1 fatma ben abid,1 abdullah balkhair,1 juma k. alkaabi,1 omar a. al-rawas,2 jojy george,1 khalfan al-zeedy1 case report leptospirosis usually presents as a non-specific anicteric myalgic febrile illness, a benign aseptic meningitis syndrome, or an icteric form with severe manifestations. pulmonary complications are common (20–70%).1,2 when a patient from a non-endemic area presents with pulmonary involvement without the classical symptoms, leptospirosis is not often suspected.3 we present a patient with severe lung involvement who responded to antibiotics other than penicillin or doxycycline, parenteral methyl prednisone and ventillatory support but needed oral prednisolone for 3 months to achieve a complete recovery. case report a 13-year-old female presented to her regional hospital in oman with a two-day history of fever, dry cough, and shortness of breath. she had been unwell for a week and had visited private clinics. on examination, the patient was febrile (39o c), tachypnoeic, and tachycardic. blood pressure was normal. the chest was clear on auscultation. liver and spleen were not enlarged but a few small cervical lymph nodes were palpable. a complete blood count, erythrocyte sedimentation rate and renal function were normal. liver enzymes were slightly raised. a chest radiograph showed bilateral symmetrical patchy opacities uniformly distributed in the middle and lower zones with a peripheral distribution. blood, urine, and sputum cultures did not grow any organisms. an autoimmune work-up and screening for h1n1 were both negative. bone marrow and lymph node biopsies were inconclusive. a skin biopsy showed features of urticarial vasculitis. since she did not respond to antibiotics, a diagnosis of miliary tuberculosis (tb) was entertained. as her liver functions were deranged she was started jayakrishnan b, fatma ben abid, abdullah balkhair, juma k. alkaabi, omar a. al-rawas, jojy george and khalfan al-zeedy case report | 319 on a modified anti-tb regimen with moxifloxacin, streptomycin, and ethambutol. the patient started to desaturate so was intubated and ventilated. a computed tomography (ct) scan of the chest revealed bilateral symmetrical interstitial infiltrates distributed predominantly in the middle and lower zones. a bronchoscopy did not reveal any abnormalities and the bronchoalveolar lavage (bal) grew klebsiella pneumoniae, for which meropenem was added. sputum and bal were negative for acid fast bacilli. her haemoglobin and platelets came down, liver enzymes showed a significant rise, and the renal function started to decline. the patient was then transferred 1,000 km from the regional hospital to sultan qaboos university hospital, muscat, a tertiary centre. basic investigations showed a haemoglobin level of 8.5 g/ dl, white blood count of 9.2 x 109/l, and a platelet count of 68 x 109/l. liver function was deranged with a serum alanine aminotransferase of 650 iu/l, a serum aspartate aminotransferase of 241 iu/l, and an alkaline phosphatase of 275 iu/l; bilirubin was 22 umol/l. the renal functions and c-reactive protein were normal. repeated antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, and anti-glomerular basement membrane antibodies were all negative. complements c3 (0.49) and c4 (0.08) were low. an echocardiogram was reported as normal. a chest radiograph showed bilateral diffuse infiltrates [figure 1a]. the ct of the chest revealed bilateral symmetrical patchy opacities with micronodularity and intralobular and centrilobular septal thickening [figure 1b]. seronegative lupus with pulmonary involvement, unexplained vasculitis, acute interstitial pneumonia, eosinophilic pneumonia, drug-induced lung disease, pneumocystis carinii infection, and viral pneumonia were the immediate differential diagnoses. she was pulsed with 250 mg of figure 1 a–d: (a) chest radiograph on admission to our centre showing bilateral uniform opacities with a peripheral distribution; (b) computed tomography (ct) image showing bilateral symmetrical opacities with interlobular and centrilobular septal thickening and micronodularities; (c) ct scan during follow-up one month after discharge showing persistent interstitial shadows; (d) ct scan showing total resolution of the opacities but with minimal localised interstitial shadows on the right side. severe pulmonary involvement in leptospirosis alternate antibiotics and systemic steroids 320 | squ medical journal, may 2013, volume 13, issue 2 methylprednisolone once daily for 3 days followed by oral prednisolone. anti-tb medications were stopped but meropenam and moxifloxacin were continued. an open lung biopsy was planned, but because of a further drop in platelets this was deferred. the patient was extubated on the second day of pulsed steroids and was then supported with non-invasive ventilation (niv). slowly the oxygen requirement came down and she was weaned from niv. this improvement was not sustained. her chest radiograph showed an increase in the opacities, she became more dyspnoeic, and her platelets and haemoglobin dropped to 4 x 109/l and 7 g/ dl, respectively. the niv was resumed and the prednisolone treatment was changed back to methylprednisolone (100 mg daily). the girl’s mother then told of a family picnic to the mountains a few days prior to the onset of her symptoms, stating that other members of the family had developed a rash and a transient febrile illness. this prompted us to do a work-up for a cryptic infection. in addition to the samples sent for legionella, mycoplasma pneumoniae, pneumocystis carinii and human immunodeficiency virus (hiv) earlier, further samples were collected for leptospira, cytomegalovirus, malarial parasite, rickettsia, and haemorrhagic fevers. fortunately, in the next 5 days the patient showed definite signs of improvement and was transferred to the general medical ward on 3 l of oxygen. almost 6 weeks after the onset of symptoms, the serology for leptospirosis was reported positive by enzyme immunoassay for genus-specific igm human antibodies against leptospira (serion elisa classic leptospira, institut virion serion gmbh, würzburg, germany) from the public health laboratory. since a microscopic agglutination test was not available, detection of igm antibodies was taken as evidence of recent infection with leptospira in this clinical context. following the report, she was started on doxycycline. when discharged after 3 weeks, she was weak and had residual pulmonary infiltrates, but was saturating well on room air and could move with support. because of the persistent pulmonary infiltrates, prednisolone was continued. when seen in the outpatient clinic one month later, the patient's chest was clear on auscultation, her sao2 on room air was 99%, her laboratory investigations were back to normal, and her chest radiograph showed total resolution. still, the ct scan showed residual linear opacities [figure 1c] so the prednisolone was continued. a ct chest done after 3 months was normal with total resolution of the opacities [figure 1d]. at that point, the prednisolone was discontinued. discussion the first publication of lung involvement in leptospirosis is attributed to moeschlin in 1943.1 the spectrum of pulmonary manifestations is wide, ranging from mild respiratory symptoms to the presence of acute respiratory distress syndrome (ards). cough, haemoptysis, and different grades of dyspnoea are the most common pulmonary symptoms. chest radiographs usually show bilateral lower lobe involvement with a peripheral distribution. nodular or reticulo nodular infiltrations, consolidations, and a ground glass appearance are the most common patterns seen.4 high-resolution ct will show bilateral ground glass opacities involving all lobes, areas of consolidations, peripheral airspace nodules, and, rarely, pleural effusions.5,6 leptospirosis is not common in oman and this is the first report of an omani national contracting the disease without travelling abroad to endemic areas. due to this, the diagnosis was not suspected in our patient on presentation. alveolar haemorrhage and ards are two of the most fatal conditions associated with leptospirosis.1,6-8 pulmonary oedema secondary to myocarditis, renal failure, or over-rehydration during resuscitation have also been reported.1 in the most severe pulmonary form of leptospirosis, where mortality rates can be as high as 30–60%, respiratory symptoms usually appear between the 4th and 6th day of disease and may lead to death in less than 72 hours.8,9 although the pathogenesis of pulmonary manifestations is poorly understood, vasculitis mediated by toxins and an exaggerated immune response in the host are believed to be responsible.1,6,9 capillary endothelial damage leads to different grades of interstitial and alveolar haemorrhage. since the bal findings were not consistent with alveolar haemorrhage, we presume that our patient developed acute lung injury (ali) and then ards, possibly with an underlying haemorrhagic pneumonitis. jayakrishnan b, fatma ben abid, abdullah balkhair, juma k. alkaabi, omar a. al-rawas, jojy george and khalfan al-zeedy case report | 321 for leptospirosis, the antibiotics treatment has to be started early, and supportive care with correction of dehydration, hypovolaemia, hypotension, and electrolyte abnormalities is essential.2 prompt management of renal and hepatic dysfunction and acute respiratory failure may decrease the mortality rate.1,7,10 human leptospirosis is generally treated with penicillin or doxycycline, but these antibiotics are not used initially if the diagnosis is not suspected.1,11 interestingly, a recent review showed that the benefit of antibiotic therapy in the treatment of leptospirosis, particularly for severe disease, remains unclear and the choice of penicillin, doxycycline, or cephalosporin did not affect mortality rates nor the duration of fever.12 as often happens with severe pulmonary involvement due to any disease, broader-spectrum antibiotics were started along with assisted ventilation and supportive care while tests were being run. our patient received meropenem and moxifloxacin which helped tide her over the crisis, thus proving that these antibiotics are active against the species. as for the laboratory proof, hospenthal and murray, while studying the susceptibilities of 11 serovars of leptospira to 14 antibiotics, found that with the exception of chloramphenicol, all tested agents, including moxifloxacin, were found to be at least as potent as penicillin and doxycycline.13 although benefits of corticosteroids in ali is known, evidence for use of corticosteroids in pulmonary leptospirosis is confined to occasional case reports or small studies.14,15 high doses or a pulse of dexamethasone or methylprednisolone have been used in patients with severe lung involvement in leptospirosis.14,16,17 in a series of 30 patients, shenoy et al. demonstrated that corticosteroids reduce mortality and change outcomes significantly.14 trivedi et al. found that mortality was higher in patients with pulmonary involvement who did not receive steroids and concluded that high dose glucocorticoids should be given as early as possible after the onset of dyspnoea to all the patients with pulmonary involvement.17 our patient received methylprednisolone, which would have influenced the recovery. not only that, since the radiological lesions persisted, oral steroids were continued leading to a total resolution. this highlights the need to use steroids for a longer time to prevent post-ards lung fibrosis. conclusion in this case, the administration of broad-spectrum antibiotics, mechanical ventilation, early supportive care, and the administration of corticosteroids led to clinical improvement and complete recovery. the clinical response suggests the utility of meropenem and moxifloxacin against leptospira and underlines the need for the use of corticosteroids in cases of pulmonary involvement. references 1. carvalho cr, bethlem ep. pulmonary complications of leptospirosis. clin chest med 2002; 23:469–78. 2. helmerhorst hj, van tol en, tuinman pr, de vries pj, hartskeerl ra, grobusch mp, et al. severe pulmonary manifestation of leptospirosis. neth j med 2012; 70:215–21. 3. assimakopoulos sf, fligou f, marangos m, zotou a, psilopanagioti a, filos ks. anicteric leptospirosisassociated severe pulmonary hemorrhagic syndrome: a case series study. am j med sci 2012; 344:326–9. 4. tanomkiat w, poonsawat p. pulmonary radiographic findings in 118 leptospirosis patients. southeast asian j trop med public health 2005; 36:1247–51. 5. marchiori e, muller nl. leptospirosis of the lung: high-resolution computed tomography findings in five patients. j thorac imaging 2002; 17:151–3. 6. marchiori e, lourenco s, setubal s, zanetti g, gasparetto td, hochhegger b. clinical and imaging manifestations of hemorrhagic pulmonary leptospirosis: a state-of-the-art review. lung 2011;189:1–9. 7. clavel m, lheritier g, weinbreck n, guerlin a, dugard a, denes e, et al. leptospirosis: an unusual cause of ards. crit care res pract 2010; 2010:408365. 8. dolhnikoff m, mauad t, bethlem ep, carvalho cr. leptospiral pneumonias. curr opin pulm med 2007; 13:230–5. 9. silva jj, dalston mo, carvalho je, setubal s, oliveira jm, pereira mm. clinicopathological and immunohistochemical features of the severe pulmonary form of leptospirosis. rev soc bras med trop 2002; 35:395–9. 10. ramachandran rj. acute lung injury and leptospirosis. br j anaesth 2007; 99:144–5. 11. griffith me, hospenthal dr, murray ck. antimicrobial therapy of leptospirosis. curr opin infect dis 2006; 19:533–7. 12. brett-major dm, coldren r. antibiotics for leptospirosis. cochrane database syst rev 2012; 2:cd008264. severe pulmonary involvement in leptospirosis alternate antibiotics and systemic steroids 322 | squ medical journal, may 2013, volume 13, issue 2 13. hospenthal dr, murray ck. in vitro susceptibilities of seven leptospira species to traditional and newer antibiotics. antimicrob agents chemother 2003; 47:2646–8. 14. shenoy vv, nagar vs, chowdhury aa, bhalgat ps, juvale ni. pulmonary leptospirosis: an excellent response to bolus methylprednisolone. postgrad med j 2006; 82:602–6. 15. minor k, mohan a. severe leptospirosis: case report of treatment with intravenous corticosteroids and supportive care. am j emerg med 2013; 31:449. 16. niwattayakul k, kaewtasi s, chueasuwanchai s, hoontrakul s, chareonwat s, suttinont c, et al. an open randomized controlled trial of desmopressin and pulse dexamethasone as adjunct therapy in patients with pulmonary involvement associated with severe leptospirosis. clin microbiol infect 2010; 16:1207–12. 17. trivedi sv, chavda rk, wadia pz, sheth v, bhagade pn, trivedi sp, et al. the role of glucocorticoid pulse therapy in pulmonary involvement in leptospirosis. j assoc physicians india 2001; 49:901–3. sir, i read with interest the article by burney and al-lamki on the accreditation of graduate medical education (gme) programmes which appeared in the may 2013 issue.1 however, i would like to raise an issue regarding their belief that the way forward for gme in oman is to seek accreditation through the accreditation council for graduate medical education international (acgme-i).1 accreditation of medical education at any level is regarded as a national responsibility by international organisations such as the united nations educational, scientific, and cultural organization (unesco), the world health organization (who) and the world federation for medical education (wfme). this implies that a national accreditation agency must have a clear mandate, and be authorised by a government entity, to conduct the accreditation. anchoring the accreditation firmly within the country reflects a fundamental regard for the specific political, socio-economic and cultural conditions, the disease patterns, the characteristics of the healthcare delivery system etc., of the nation and would thus enable the medical programmes to be relevant to the country’s needs. national conditions must be taken into account when designing the standards or criteria used in the accreditation process as the basis for evaluation, and for the decisions on accreditation. i concur with the authors regarding the notions that: (1) accreditation is a powerful tool in quality improvement and quality control, and (2) in addition to the gme “curriculum” (what is done and why; how it is done and where; how it is assessed and evaluated, using which standards), other issues central to the discussion on accreditation include the institutional culture, its state of readiness for change and other contextual parameters.1 it is in this light that i would like to draw attention to the global standards framework for quality improvement in medical education published in 2003 by the wfme as a pathway to accreditation of gme in oman.2 this framework ‘trilogy’ covers all three phases of medical education: basic medical education; postgraduate medical education, and continuing professional development [figure 1]. the global standards framework was developed by an international working party of experts from all regions of the world.2 recently, sultan qaboos university has gone through the accreditation process for basic medical education using the wfme standards framework, and is the first institution to go through this process in the region. for the sake of continuity, is it not more natural that the accreditation of postgraduate medical education should follow the same route? second, in response to the inherent question regarding gme programmes: does (or rather, sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 587-589, epub. 8th oct 13 submitted 22nd aug 13 accepted 29th aug 13 رد: اعتماد برامج الدراسات العليا للتعليم الطيب مقياس واحد يناسب اجلميع أم ال؟ re: accreditation of graduate medical education programmes one size fits all—or does it? letter to editor figure 1: the world federation for medical education framework ‘trilogy’ covering all three phases of medical education. 587 | squ medical journal, november 2013, volume 13, issue 4 ibrahim m. inuwa letter to editor | 588 should) one size fit all? i will obviously repond: ‘yes’ and ‘no’! i say yes in the sense that parameters that are globally agreed through an international organisation sanctioned by the who should guide the recognition process; and no in the sense that nation-states or closely-related regional blocks should have the final mandate to accredit (recognise) training programmes. in conclusion, i would like to posit that the road to accreditation (i prefer to use the word ‘recognition’) of gme programmes in oman should lead to the wfme and not to any other accrediting body. the oman medical specialty board (omsb)—the nationally mandated body to accredit gme programmes—could seek accreditation through the wfme’s programme for the recognition of accrediting agencies.3 ibrahim m. inuwa department of human & clinical anatomy, sultan qaboos university, muscat, oman e-mail: ibrahim1@squ.edu.om references 1. burney ia, al-lamki n. accreditation of graduate medical education programmes: one size fits all—or does it? sultan qaboos univ med j 2013; 13:198–201. 2 world federation for medical education. postgraduate medical education: wfme global standards for quality improvement. copenhagen: wfme office, university of copenhagen, 2003. 3. world federation for medical education. recognition of the accreditors: the wfme programme for recognition of accrediting agencies in medical education. copenhagen: wfme office, university of copenhagen, 2013. response from the authors sir, we read with interest the letter by ibrahim inuwa1 in response to our article, accreditation of graduate medical education programmes: one size fits all – or does it?2 we thank the author for alerting the readers to several important points, and we appreciate his contribution. the author has agreed with several of our points, for example, that the standards for accreditation process must take into account the local conditions, and that the process would be robust only if it were relevant to the socio-economic and cultural situation, and met the needs of the local healthcare delivery system. we agree with the author that local and/or national accreditation authority would be ideal for this purpose. however, the healthcare system in oman is young—there is only one medical school in the public sector and one in the private, and the oman medical specialty board (omsb) started the postgraduate residency programmes only recently. currently, there is no accreditation programme for postgraduate medical education (pgme) in oman. the oman accreditation council (oac) has so far concentrated on accrediting institutions, and has not started accrediting pgme programmes. we also agree with the author that the global standards for quality improvement of medical education, published by the world federation of medical education (wfme) are excellent,3 and in fact, the omsb has benefited from these. together with wfme standards, omsb has consulted and incorporated the standards from the general medical council (gmc), the accreditation council for graduate medical education (acgme), the royal college of physicians and surgeons of canada (rcpsc), the australian medical council (amc) and the european board guidance for training centers in creating its own booklet, quality assurance standards for omsb residency programs.4 however, we would like to point out that presently the wfme can only assist in quality improvement by providing postgraduate organisations with their standards.3 the standards set by the wfme can function as a template for local/national/regional bodies to award recognition and/or accreditation, but wfme itself does not accredit pgme programmes. thus, given that oman does not yet have its own accreditation programme for pgme, and that the wfme is not in a position to recognise programmes and offer accreditation, it is imperative that the omsb seek 589 | squ medical journal, november 2013, volume 13, issue 4 other international bodies to accredit its programmes. given the necessity of fundamental considerations for national socio-economic and cultural conditions, disease patterns and the healthcare delivery system, it is essential that omsb urge the accreditation council for graduate medical education international (acgme-i) to modify the accreditation requirements to suit the omani conditions, as it has already done in singapore. currently the choice is limited and we maintain that the time is ripe for developing countries to have a choice of accreditation agencies while they are trying to develop their own programmes. developed countries owe it to the world of medical education. clearly, as we said in our editorial,2 what is needed is a choice, to suit the needs and requirements, and that could be provided by competing accrediting bodies. one size may not fit all… *ikram a. burney1 and neela al-lamki2 1department of medicine, sultan qaboos university hospital, muscat, oman; 2oman medical specialty board, muscat, oman *corresponding author e-mail: ikramburney@hotmail.com references 1. inuwa im. re: accreditation of graduate medical education programmes: one size fits all—or does it? sultan qaboos univ med j 2013; 13: 2. burney ia, al-lamki n. accreditation of graduate medical education programmes. one size fits all—or does it? sultan qaboos univ med j 2013; 13:198‒201. 3. world foundation for medical education. global standards for quality improvement in medical education. from: http://www.eua.be/fileadmin/user_upload/files/newsletter/european-specifications-wfme-globalstandards-medical_education.pdf accessed: sep 2013. 4. oman medical specialty board. quality assurance standards for omsb residency programs. 2nd ed. muscat: omsb, june 2012. 1department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 2programme director, family medicine residency programme, oman medical specialty board, muscat, oman *corresponding author’s e-mail: asmaa_9988@hotmail.com العوامل املرتبطة ابختيار املسار الوظيفي يف طب األسرة بني األطباء املبتدئني يف عمان اأ�شماء علي ال�شلمانية، اأ�شماء ال�شيذانية، جنالء جعفر، عبدالعزيز املحرزي abstract: objectives: the number of family physicians in oman is far below that recommended by the world health organization. this study aimed to determine factors influencing junior doctors’ choice of a career in family medicine. methods: this cross-sectional study was conducted between march and june 2018 and targeted applicants to oman medical specialty board residency programmes during the 2018–2019 academic year. applicants were grouped according to their choice of either family medicine (n = 64) or other specialities (n = 81). a self-administered questionnaire was utilised to compare the applicants’ sociodemographic characteristics, factors influencing their choice of career and their myers-briggs type indicator® (mbti) personality traits. results: a total of 52 family medicine and 43 other residency applicants participated in the study (response rates: 81.3% and 53.1%, respectively). most family medicine applicants were female (86.5%), married (65.4%) and resided in rural areas (73.1%); moreover, 19.2% were ≥30 years of age. overall, emphasis on continuity of care, opportunity to deal with a variety of medical problems, the ability to use a wide range of skills and knowledge, early exposure to the discipline, opportunity to teach and perform research and the influence of family or friends were important factors in determining choice of a career in family medicine. moreover, the mbti analysis revealed that family medicine applicants were commonly extroverted-sensing-thinkingjudging personality types. conclusion: knowledge of the factors influencing career choice among junior doctors may be useful in determining future admission policies in order to increase the number of family physicians in oman. keywords: career choice; internship and residency; medical specialty; family practice; family physicians; myersbriggs type indicator; oman. امللخ�ص: الهدف: يعتربعدد اأطباء الأ�رسة يف عمان اأقل كثرياً مما اأو�شت به منظمة ال�شحة العاملية، هدفت هذه الدرا�شة اإىل حتديد العوامل التي توؤثر على اختيار الأطباء املبتدئني ملهنة طب الأ�رسة. الطريقة: مت اجراء هذه الدرا�شة املقطعية بني مار�س ويونيو 2018 حيث ا�شتهدفت املتقدمني لربامج التدريب يف املجل�س العماين للتخ�ش�شات الطبية خالل العام الدرا�شي 2019-2018. مت جتميع املتقدمني وفًقا لختيارهم اإما لطب الأ�رسة )العدد = 64( اأو لتخ�ش�شات اأخرى )العدد = 81(. مت ا�شتخدام ا�شتبيان يتم تعباأته ذاتًيا من قبل امل�شارك ملقارنة اخل�شائ�س briggs-myers الجتماعية والدميوغرافية للمتقدمني، والعوامل التي توؤثر على اختيارهم للمهن املهنية وال�شمات ال�شخ�شية ح�شب املوؤ�رس mbti( indicator® type(. النتائج: �شارك يف الدرا�شة ما جمموعه 52 من متقدمي برنامج طب الأ�رسة و 43 من املتقدمني للربامج الآخرى )معدلت ال�شتجابة: %81.3 و %53.1 على التوايل(. كما كان معظم املتقدمني لطب الأ�رسة من الإناث )%86.5(، املتزوجني )%65.4( والقاطنني يف املناطق الريفية )%73.1(؛ عالوة على ذلك، كان عمر %19.2 منهم 30 �شنة فما فوق. وب�شكل عام، كانت عوامل مثل الرتكيز على ا�شتمرارية الرعاية، وتوفر فر�شة للتعامل مع جمموعة متنوعة من امل�شاكل الطبية، والقدرة على ا�شتخدام جمموعة وا�شعة من املهارات واملعرفة، وتلقي التدريب املبكر يف التخ�ش�س، وتوفر فر�شة التدري�س وعمل بحوث طبية بالإ�شافة اإىل التاأثر بالأ�رسة اأو الأ�شدقاء هي عوامل مهمة يف حتديد اختيار م�شار التدريب يف طب الأ�رسة. عالوة على ذلك، كما ك�شف حتليل موؤ�رس mbti اأن �شخ�شية املتقدمني لطب الأ�رسة كانت غالبًا تتميز بالإنطالق واحل�س بامل�شوؤولية والتفكر. اخلال�صة: قد تكون معرفة العوامل التي توؤثر على اختيار املهنة بني �شغار الأطباء مفيدة يف حتديد �شيا�شات القبول امل�شتقبلية من اأجل زيادة عدد اأطباء الأ�رسة يف عمان. الكلمات املفتاحية: اختيار املهنة؛ التدريب والإقامة ؛ التخ�ش�س الطبي؛ ممار�شة طب الأ�رسة؛ اأطباء الأ�رسة؛ موؤ�رس myers-briggs type indicator؛ ُعمان. factors associated with choice of career in family medicine among junior doctors in oman *asma ali al-salmani,1 asma al-shidhani,1 najlaa jaafar,2 abdulaziz al-mahrezi1 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e337–343, epub. 5 oct 20 submitted 3 oct 19 revisions req. 24 nov 19 & 21 jan 20; revisions recd. 22 dec 19 & 28 jan 20 accepted 5 feb 20 advances in knowledge this study evaluates factors influencing choice of a career in family medicine compared with other specialties among omani junior doctors applying to oman medical specialty board (omsb) residency programmes. various factors were found to predict choice of a career in family medicine including age, gender, marital status and place of residence. moreover, applicants to the omsb family medicine residency programme highlighted continuity of care, the opportunity to deal with a variety of medical problems, the ability to use a wide range of skills and knowledge and early exposure to the discipline as important influences on their choice of specialty. application to patient care the findings of this study can be used by educators and omsb administrators to modify admission policies in order to encourage selection of this medical specialty and address the severe shortage of family physicians in oman. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.014 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ factors associated with choice of career in family medicine among junior doctors in oman e338 | squ medical journal, august 2020, volume 20, issue 3 using a community-oriented and collab-orative approach, family physicians provide comprehensive healthcare services to individuals and families throughout the course of their lifetime including a wide spectrum of diagnostic, treatment, maintenance, preventative, rehabilitative and palliative healthcare services.1,2 in order to meet universal health coverage targets by 2030, the world health organization (who) regional office for the eastern mediterranean (emro), together with the world organization of national colleges, academies and academic associations of general practitioners/ family physicians (wonca), recommend that a minimum of three family physicians be employed per 10,000 individuals in the population.2 in oman, family medicine was first recognised as a unique medical speciality in 1987 at the college of medicine & health sciences at sultan qaboos university in muscat.3 under the oman medical specialty board (omsb), a four-year postgraduate training programme was established in 1994 and subsequently recognised by the royal college of general practitioners in 2001 and accredited by the accreditation council for graduate medical education-international in 2017.3,4 however, as of 2015, oman had an average of 0.4 family physicians per 10,000 individuals, a number far below that recommended by the wonca and who emro.2 other countries have reported similar shortages of family physicians in their workforce.5,6 few junior doctors and medical students select family medicine as their top choice; for instance, the rate of selection of this specialty among canadian medical graduates dropped from 40% in 1982 to 32% in 2010, falling as low as 23% in some schools.7 in addition, a national survey of 39 medical schools in france indicated that the level of interest in primary care specialities was only 20%.8 in southern saudi arabia, mehmood et al. reported that the preferred specialty choices of medical students were surgery, internal medicine, paediatrics, orthopaedics and ophthalmology.9 another study from eastern saudi arabia found that only 9% of medical students and interns selected family medicine as a career choice in 2014.10 in light of these trends, medical education institutions and administrators have sought to identify factors which influence career choice among junior doctors in order to determine potential strategies to increase interest in this specialty. in canada, gill et al. identified various factors—such as emphasis on continuity of care, length of residency, influence of family, friends or community and preference for working in a rural community—as factors significantly associated with the selection of family medicine compared to other specialties.7 other factors have also been found to predict this choice of specialty, including being female, older, engaged, having a lower interest in research, an increased desire for short postgraduate training and a lower preference for medical versus social problems.7,11–16 to the best of the authors’ knowledge, no studies have yet determined factors influencing the selection of family medicine as a career choice in oman. as such, this study aimed to identify the factors influencing omani junior doctors in the selection of family medicine as opposed to other specialities when applying to residency programmes. these findings could be useful for strengthening omsb residency programmes and determining admission policies in order to encourage interest in this specialty and increase the number of family physicians in oman. methods this cross-sectional study was conducted between march and june 2018 at the omsb. the entire cohort of applicants to omsb residency programmes for the 2018–2019 academic year were contacted directly and invited to participate in the study. the applicants were subsequently divided into two groups according to their choice of career in either family medicine (n = 64) or other specialities (n = 81). a three-part self-administered english-language questionnaire was used to collect data. the first part determined the participants’ sociodemographic characteristics including age, gender, parental education level, presence of family or friends in family medicine or other medical fields and involvement in community programmes, volunteer work or research. the second part assessed factors influencing choice of speciality based on a previously validated survey from the university of alberta in canada.7 applicants were asked to rate the level of importance of each item on a scale from 1 to 5 in terms of influencing their career choice, with 1 being very unimportant and 5 being very important.7 the third part of the questionnaire aimed to determine personality type according to the myers-briggs type indicator® (mbti) personality inventory.17 the primary outcome of the study was factors influencing the choice of family medicine compared to other specialties among junior doctors. the secondary outcome was the most common personality type among those who selected family medicine as their career specialty. for the purposes of the analysis, participants’ responses to the second part of the asma ali al-salmani, asma al-shidhani, najlaa jaafar and abdulaziz al-mahrezi clinical and basic research | e339 questionnaire were grouped as either important (i.e. responses of somewhat important and very important) or not important (i.e. responses of very unimportant, somewhat unimportant and neither unimportant nor important).7 data analysis was performed using the statistical package for the social sciences (spss), version 25.0 (ibm corp., armonk, new york, usa). the results were presented using descriptive statistics. means and standard deviations were reported for continuous variables, while categorical variables were presented as frequencies and percentages. the association of the independent variables with outcome variables was calculated using non-parametric kruskal-wallis and mann-whitney-u tests. the level of two-tailed significance was set at p <0.050. the protocol for this study was approved by the research ethics committee of the omsb (rec/03/2018). informed verbal consent was obtained from all applicants prior to their participation in the study. the individual contact details of the applicants were used with permission from the omsb admissions office. results a total of 52 family medicine applicants and 43 applicants from other omsb residency programmes agreed to take part in the study (response rates: 81.3% and 53.1%, respectively). compared to those in other specialties, applicants to the family medicine programme were significantly more likely to be 30 years of age or older (19.2% versus 0%; p = 0.026), female (86.5% versus 51.2%; p <0.001), married (65.4% versus 37.2%; p = 0.021) and reside in rural areas (73.1% versus 67.4%; p = 0.005). in addition, family medicine applicants were significantly more likely to have a family member or close friend practising family medicine (61.5% versus 2.3%; p <0.001) or other medical specialties (82.7% versus 41.9%; p <0.001) [table 1]. applicants rated the perceived importance of factors contributing to their choice of career. the vast majority of family medicine applicants believed the following factors to be important when it came to choosing their preferred specialty: the ability to use a wide range of skills and knowledge in patient care (92.3%), emphasis on continuity of care (90.4%), the opportunity to deal with a variety of medical problems (90.4%) and early exposure to the discipline (90.4%). in contrast, the most important factors rated by applicants to other specialties were the opportunity to deal with a variety of medical problems (93%), whether the specialty was compatible with their personality table 1: sociodemographic characteristics of applicants to oman medical specialty board residency programmes (n = 95) characteristic n (%) p value family medicine (n = 52) other medical specialties (n = 43) age in years 0.026 <30 42 (80.8%) 43 (100) ≥30 10 (19.2%) 0 (0) gender <0.001 female 45 (86.5) 22 (51.2) male 7 (13.5) 21 (48.8) marital status 0.021 single 18 (34.6) 27 (62.8%) married 34 (65.4) 16 (37.2%) divorced/ widowed 0 (0) 0 (0) number of children 0.521 0 34 (65.4) 30 (69.8) <2 13 (25) 13 (30.2) 2–3 5 (9.6) 0 (0) maternal education level 0.009 illiterate 21 (40.4) 33 (76.7) school 23 (44.2) 7 (16.3) college 4 (7.7) 3 (7.0) postgraduate 4 (7.7) 0 (0) paternal education level <0.001 illiterate 2 (3.8) 24 (55.8) school 32 (61.5) 5 (11.6) college 9 (17.3) 3 (7) postgraduate 9 (17.3) 11 (25.6) place of residence 0.005 urban (muscat) 14 (26.9) 14 (32.6) rural (other regions) 38 (73.1) 29 (67.4) monthly income in omr 0.020 <1,000 12 (23.1) 26 (60.5) 1,000–3,000 40 (76.9) 17 (39.5) >3,000 0 (0) 0 (0) presence of a family member or friend in family medicine <0.001 yes 32 (61.5) 1 (2.3%) no 20 (38.5) 42 (97.7) omr = omani riyals. factors associated with choice of career in family medicine among junior doctors in oman e340 | squ medical journal, august 2020, volume 20, issue 3 (93%) and the ability to master a small set of skills and be an ‘expert’ (93%). there were statistically significant differences between family medicine applicants and those in other programmes with regards to the perceived importance of emphasis on continuity of care (90.4% versus 48.8%; p <0.001), early exposure to the discipline (90.4% versus 37.2%; p <0.001), opportunity for research (86.5% versus 51.2%; p <0.001), previous exposure to primary care practice (84.6% versus 0%; p <0.001), opportunity to teach (80.8% versus 34.9%; p <0.001), the influence of family or friends (71.2% versus 9.3%; p <0.001) and the intellectual content of the discipline (75% versus 30.2%; p <0.001). in contrast, fewer applicants to the family medicine programme rated income potential (51.9% versus 100%; p <0.001) and perceived prestige (59.6% versus 81.4%; p = 0.020) to be unimportant during career selection compared to applicants in other specialties. regardless of specialty, most of the applicants reported that working hours/lifestyle, the length of the residency programme and a positive experience with a teacher or clinician of the specialty were important factors in their selection [table 2]. compared to other personality archetypes within the mbti personality inventory, applicants to family medicine were most commonly extroverted-sensingthinking-judging (estj) types [figure 1]. table 1 (cont’d): sociodemographic characteristics of applicants to oman medical specialty board residency programmes (n = 95) characteristic n (%) p value family medicine (n = 52) other medical specialties (n = 43) presence of a family member or friend in other medical specialties <0.001 yes 43 (82.7) 18 (41.9) no 9 (17.3) 25 (58.1) involvement in community programmes 0.660 yes 38 (73.1) 31 (72.1) no 14 (26.9) 12 (27.9) involvement in volunteer work 0.650 yes 39 (75) 31 (72.1) no 13 (25) 12(27.9) involvement in research 0.220 yes 42 (80.8) 34 (79.1) no 10 (19.2) 9 (20.9) omr = omani riyals. table 2: importance of factors influencing career choice* among applicants to oman medical specialty board residency programmes (n = 95) item perceived importance, n (%) p value family medicine (n = 52) other medical specialties (n = 43) ui i ui i income potential 27 (51.9) 25 (48.1) 43 (100) 0 (0) <0.001 perceived prestige 31 (59.6) 21 (40.4) 35 (81.4) 8 (18.6) 0.020 emphasis on procedural skills 7 (13.5) 45 (86.5) 13 (30.2) 30 (69.8) 0.046 specialty compatible with personality 7 (13.5) 45 (86.5) 3 (7) 40 (93) 0.305 opportunity to teach 10 (19.2) 42 (80.8) 28 (65.1) 15 (34.9) <0.001 preference/ influence of family, friends or community 15 (28.8) 37 (71.2) 39 (90.7) 4 (9.3) <0.001 perceived intellectual content of discipline 13 (25) 39 (75) 30 (69.8) 13 (30.2) <0.001 opportunity for research 7 (13.5) 45 (86.5) 21 (48.8) 22 (51.2) <0.001 opportunity to work on challenging cases 10 (19.2) 42 (80.8) 6 (14) 37 (86) 0.494 opportunity to work on acute medical problems 7 (13.5) 45 (86.5) 10 (23.3) 33 (76.7) 0.215 emphasis on continuity of care 5 (9.6) 47 (90.4) 22 (51.2) 21 (48.8) <0.001 opportunity to deal with a variety of medical problems 5 (9.6) 47 (90.4) 3 (7) 40 (93) 0.645 early exposure to the discipline 5 (9.6) 47 (90.4) 27 (62.8) 16 (37.2) <0.001 length of residency 13 (25) 39 (75) 13 (30.2) 30 (69.8) 0.569 ability to use a wide range of skills and knowledge 4 (7.7) 48 (92.3) 10 (23.3) 33 (76.7) 0.033 ui = unimportant; i = important. *according to self-rated responses to a previously validated survey from the university of alberta, canada.11 each item was scored from 1 to 5, with 1 being very unimportant and 5 being very important. asma ali al-salmani, asma al-shidhani, najlaa jaafar and abdulaziz al-mahrezi clinical and basic research | e341 discussion as demonstrated by the wonca and who emro report, there is an urgent need to address the shortage of approximately 185,497 family physicians in the middle eastern region.2 nevertheless, the selection of family medicine as a career choice by junior doctors remains a complex process affected by many factors related both to individual residency programmes, the healthcare system and the sociodemographic characteristics and personalities of the doctors themselves. research examining these factors has been conducted in several countries for the purposes of modifying existing policy-building and decisionmaking processes in order to encourage more doctors to choose this specialty.7,9,12 in the current study, applicants to the omsb family medicine residency programme were significantly more likely to be female, married and over 30 years of age. it is possible that married women prefer specialties in which they can have part-time duties so that they can more easily take care of their families. similarly, a study conducted in canada involving 16 medical schools found that being older and engaged were variables which predicted selection of a career in family medicine.6 likewise, more female medical students and interns in saudi arabia selected family medicine as their top choice compared to any other specialty.10 in addition, family medicine applicants in the present study were significantly more likely to be from rural areas. this might be due to cultural differences, the presence of friends or family or the lack of family physicians in these areas compared to the capital. other studies have reported comparable results.13,14,18 as such, it is possible that increasing admission rates for female doctors from rural areas would help to eventually increase the number of family physicians in oman. the effect of role-modelling was apparent in the current study, as the majority of applicants rated a positive experience with a clinician/teacher as an important factor in their selection, regardless of specialty. similar findings have also been reported in other studies.6,7,10,15 having a family member or close friend in the field of family medicine or other medical specialties can also have an effect on career selection.7,11,14–16 in the present study, over half of this group had a friend or family member involved in this field; moreover, the influence of family, friends or community was perceived to be of great importance when making a career decision overall. generally, the core principles of family medicine as a specialty were highly rated by the family medicine applicants and included continuity of care, the ability to use a wide range of skills and knowledge and early exposure to the discipline. such factors are programme-specific and have also been rated highly elsewhere around the world.7,18,19 therefore, enabling the admission of junior doctors who have previous exposure to the field might add to the number who choose to become family physicians in future. interestingly, family medicine applicants in the current study reported being greatly influenced by the opportunity to teach and perform research; this conflicts with the findings of other studies.6,7,20 this difference might be due to the growing need for general medical research in this region, as well as research specific to the field of family medicine. in addition, just over half of the family applicants rated income potential and perceived prestige as unimportant factors; this might be because most family medicine applicants were female and thus might be more concerned about their future quality of work, career development and time spent away from their families. this finding was also observed by other researchers.21 table 2 (cont’d): importance of factors influencing career choice* among applicants to oman medical specialty board residency programmes (n = 95) item perceived importance, n (%) p value family medicine (n = 52) other medical specialties (n = 43) ui i ui i working hours/ lifestyle after completion of training 12 (23.1) 40 (76.9) 7 (16.3) 36 (83.7) 0.410 previous exposure to primary care practice 8 (15.4) 44 (84.6) 43 (100) 0 (0) <0.001 ui = unimportant; i = important. *according to self-rated responses to a previously validated survey from the university of alberta, canada.11 each item was scored from 1 to 5, with 1 being very unimportant and 5 being very important. figure 1: frequency of myers-briggs type indicator® personality traits among applicants to oman medical specialty board residency programme (n =95). factors associated with choice of career in family medicine among junior doctors in oman e342 | squ medical journal, august 2020, volume 20, issue 3 personality may play a role when it comes to career choice and the selection of a medical specialty. however, studies which have investigated the effect of personality type using the mbti personality inventory have revealed mixed results.22 the mbti inventory is used to assign one of 16 unique personality archetypes based on a sliding scale in four dichotomous categories: (1) extraversion versus introversion; (2) sensing versus intuition; (3) thinking versus feeling; and (4) judgement versus perception.17 in the present study, the predominant personality archetype among those who selected family medicine as a specialty was estj. this is similar to that observed in an older study conducted in 1976.23 however, more recent studies have since found that the family medicine specialty is chosen more frequently by those who score highly in the feeling trait compared to the thinking trait.22,24 certain limitations were present within the current study. only junior doctors who applied to different omsb residency programmes were targeted; as such, the study did not include the perspectives of medical students which would be an important addition to strengthen interest in the family medicine programme and encourage admissions. additionally, the survey might not have addressed all factors influencing career choice; moreover, as the questionnaire was not originally designed for this population, some sociocultural factors unique to oman might not have been considered. however, this limitation was partially resolved by including an option for “other” within the survey. conclusion according to international recommendations, there is a national shortage of family physicians in oman. this study identified various factors which influenced the selection of family medicine as a residency specialty among junior doctors including an emphasis on continuity of care, the ability to use a variety of skills and knowledge and early exposure to the discipline. in addition, family medicine applicants were significantly more likely to be older, female, married and reside in rural areas compared to those in other specialties. these findings may be useful in modifying admission policies and encouraging interest in this choice of specialty among future doctors in oman. a c k n o w l e d g e m e n t permission was received from the university of alberta to use the survey assessing factors influencing choice of speciality. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. boelen c. improving health systems: the contribution of family medicine a guidebook. singapore: world organization of national colleges, academies and academic association of general practitioners/family physicians, 2002. 2. world health organization regional office for the eastern mediterranean. scaling up family practice: progression towards universal health coverage. from: https://applications.emro. who.int/docs/rc_technical_papers_2016_tech_disc_1_19022_ en.pdf?ua=1&ua=1 accessed: jan 2020. 3. al-shafaee m. family medicine practice in oman: present and future. sultan qaboos univ med j 2009; 9:116–18. 4. accreditation council for graduate medical educationinternational. international benchmarking through accreditation drives oman medical specialty board (omsb) to meet worldwide standards. from: www.acgme-i.org/whatis-accreditation/accreditation-stories/accreditation-storydetails/articleid/3 accessed: jan 2020. 5. puertas eb, arósquipa c, gutiérrez d. factors that influence a career choice in primary care among medical students from high-, middle-, and low-income countries: a systematic review. rev panam salud publica 2013; 34:351–8. 6. scott i, gowans m, wright b, brenneis f, banner s, boone j. determinants of choosing a career in family medicine. cmaj 20110; 183:e1–8. https://doi.org/10.1503/cmaj.091805. 7. gill h, mcleod s, duerksen k, szafran o. factors influencing medical students’ choice of family medicine: effects of rural versus urban background. can fam physician 2012; 58:e649–57. 8. lefevre jh, roupret m, kerneis s, karila l. career choices of medical students: a national survey of 1780 students. med educ 2010; 44:603–12. https://doi.org/10.1111/j.13652923.2010.03707.x. 9. mehmood si, kumar a, al-binali a, borleffs jc. specialty preferences: trends and perceptions among saudi undergraduate medical students. med teach 2012; 34:s51–60. https://doi.org/10.3109/0142159x.2012.656753. 10. alshahrani m, dhafery b, al mulhim m, alkhadra f, al bagshi d, bukhamsin n. factors influencing saudi medical students and interns’ choice of future specialty: a self-administered questionnaire. adv med educ pract 2014; 397–402. https://doi. org/10.2147/amep.s69152. 11. senf jh, campos-outcalt d, watkins aj, bastacky s, killian c. a systematic analysis of how medical school characteristics relate to graduates’ choices of primary care specialties. acad med 1997; 72:524–33. https://doi.org/10.1097/00001888-19970 6000-00020. 12. kassebaum dg, szenas pl, schuchert mk. determinants of the generalist career intentions of 1995 graduating medical students. acad med 1996; 71:198–209. https://doi. org/10.1097/00001888-199602000-00030. 13. rabinowitz hk, diamond jj, markham fw, santana aj. the relationship between entering medical students’ backgrounds and career plans and their rural practice outcomes three decades later. acad med 2012; 87:493–7. https://doi.org/10.10 97/acm.0b013e3182488c06. https://doi.org/10.1503/cmaj.091805 https://doi.org/10.1111/j.1365-2923.2010.03707.x https://doi.org/10.1111/j.1365-2923.2010.03707.x https://doi.org/10.3109/0142159x.2012.656753 https://doi.org/10.2147/amep.s69152 https://doi.org/10.2147/amep.s69152 https://doi.org/10.1097/00001888-199706000-00020 https://doi.org/10.1097/00001888-199706000-00020 https://doi.org/10.1097/00001888-199602000-00030 https://doi.org/10.1097/00001888-199602000-00030 https://doi.org/10.1097/acm.0b013e3182488c06 https://doi.org/10.1097/acm.0b013e3182488c06 asma ali al-salmani, asma al-shidhani, najlaa jaafar and abdulaziz al-mahrezi clinical and basic research | e343 14. kondalsamy-chennakesavan s, eley ds, ranmuthugala g, chater ab, toombs mr, darshan d, et al. determinants of rural practice: positive interaction between rural background and rural undergraduate training. med j aust 2015; 202:41–45. https://doi.org/10.5694/mja14.00236. 15. borges nj, manuel rs, duffy rd, fedyna d, jones bj. influences on specialty choice for students entering person-oriented and technique-oriented specialties. med teach 2009; 31:1086–8. https://doi.org/10.3109/01421590903183787. 16. stagg p, greenhill j, worley ps. a new model to understand the career choice and practice location decisions of medical graduates. rural remote health 2009; 9:1245. https://doi. org/10.22605/rrh1245. 17. the myers & briggs foundation. mbti® basics. from: www. myersbriggs .org/my-mbti-personality-type/mbti-basics/ accessed: jan 2020. 18. alavi m, ho t, stisher c, richardson e, kelly c, mccrory ke, et al. factors that influence student choice in family medicine: a national focus group. fam med 2019; 51:143–8. https://doi. org/10.22454/fammed.2019.927833. 19. hashim mj. principles of family medicine and general practice: defining the five core values of the specialty. j prim health care 2016; 8:283–7. https://doi.org/10.1071/hc16006. 20. vanasse a, orzanco mg, courteau j, scott s. attractiveness of family medicine for medical students: influence of research and debt. can fam physician 2011; 57:e216–27. 21. senf jh, campos-outcalt d, kutob r. factors related to the choice of family medicine: a reassessment and literature review. j am board fam pract 2003; 16:502–12. https://doi. org/10.3122/jabfm.16.6.502. 22. prasad m. a test of myers-briggs type indicator in health professions: a literature review. asian j manag 2016; 7:297–306. https://doi.org/10.5958/2321-5763.2016.00045.7. 23. myers ib, davis ja. relation of medical students’ psychological type to their specialties twelve years later. gainesville, florida, usa: educational testing service, 1976. 24. mehmood si, khan ma, walsh km, borleffs jc. personality types and specialist choices in medical students. med teach 2013; 35:63–8. https://doi.org/10.3109/0142159x.2012.731104. https://doi.org/10.5694/mja14.00236 https://doi.org/10.3109/01421590903183787 https://doi.org/10.22605/rrh1245 https://doi.org/10.22605/rrh1245 https://doi.org/10.22454/fammed.2019.927833 https://doi.org/10.22454/fammed.2019.927833 https://doi.org/10.1071/hc16006 https://doi.org/10.3122/jabfm.16.6.502 https://doi.org/10.3122/jabfm.16.6.502 https://doi.org/10.5958/2321-5763.2016.00045.7 https://doi.org/10.3109/0142159x.2012.731104 sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 93-99, epub. 27th feb 13 submitted 1st may 12 revision req. 1st sep, revision recd. 12th sep & 17th oct 12 accepted 24th nov 12 departments of 1pediatrics, manipal college of medical sciences, pokhara, nepal *corresponding author e-mail: kalpana_malla@hotmail.com هل فحص الربوتني الفعال crp( c( يف السائل الدماغي الشوكي أفضل من فحصه يف الدم لتشخيص مرض السحايا يف األطفال خمربيا كالبانا مال، تيجا�ض مال، �صيجريي راو، �صاهي�ض نوتا با�صنيت، رايف �صاه امللخ�ص: الهدف: اختبار مدى كفاءة استخدام فحص الربوتني الفعالcrp( c( لتشخيص األنواع املختلفة من التهاب السحايا هبدف استخدام الفحص روتينيا. الطريقة: أجريت الدراسة على 140 طفل أدخلوا للعالج يف مستشفى مانيبال التعليمي يف خبارى, نيبال يف الفرتة يوليو/ متوز 2009 إىل يونيو/ حزيران. مت التحليل التفصيلي لعينات الدم و السائل الدماغي الشوكي متضمنا فحص الربوتني الفعالcrp( c( ألولئك املرضى. النتائج: وجد أن %31.1 لديهم سحايا صديدية )pm( و %26.2 سحايا معاجله جزئيا )ppm( و%33 سحايا فريوسيه )vm( و %9.7 سحايا السل)tbm(. %26.4 غري مرضي مت استخدامهم كضوابط للدراسة. مت عزل %12.5 من العينات املصابة بالزراعة اجلرثوميه املخربيه للدم و 25% منها بزراعة السائل الدماغي الشوكي. كانت النتائج إجيابيه ل crp يف الدم لكل أنواع السحايا يف الدراسة وكانت أعلى نسبه اجيابيه يف السحايا الصديدية )mg/dl 28.88 ± 53.12( ,السحايا املعاجلة جزئيا ولكن مل يكن الفرق معتمد إحصائيا)p = 0.08(. اما مستوى crp يف السائل الدماغي )45.75 ± 28.50 mg/dl( ,ففي السحايا الصديدية كان املستوى )p >0.001( الشوكي فقد كان أعلى من األنواع األخرى بفارق معتمد إحصائيا ويف السحايا املعاجلة جزئيا )mg/dl 28.88 ± 53.12(.احلساسية التحليلية والنوعية التحليلية لفحوصات crp يف الدم كانت كاآليت: 90.62% هي الشوكي الدماغي السائل يف crp ولفحوصات 26.12%, 24.52%, 30.97%, و32.40% 70%, 64.70%, 88.88%, %96.87, %66.66 ,%20.58,%10 و%74.73 ,%63.71 ,%50.94 ,%55.35 ألنواع السحايا الصديدية, السحايا معاجلة جزئيا, السحايا الفريوسية, وسحايا السل بالتتابع. اال�صتنتاج: بسبب احلساسية العالية لفحوصات crpيف الدم ويف السائل الدماغي الشوكي ميكن استخدامه crp يف السائل الدماغي الشوكي نتائج بنوعية حتليلية أفضل من فحص crp لفحص السحايا البكتريية )الصديدية واملعاجلة جزئيا(. لقد أظهر فحص يف الدم وهلذا ميكن استخدامة كفحص مساند مع فحوصات السائل الدماغي الشوكي املخربيه األخرى الكيميائية و اجلرثومية لتشخيص السحايا. مفتاح الكلمات: ال�صحايا، الربوتني الفعالcrp( c(، ال�صائل الدماغي ال�صوكي. abstract: objectives: this study aimed to test whether c-reactive protein (crp) measurement could differentiate between different types of meningitis and become a routine test. methods: a prospective study included 140 children admitted to manipal teaching hospital, pokhara, nepal, between july 2009 and june 2011. the subjects had a blood test and detailed cerebrospinal fluid (csf) analysis, including blood and csf crp levels. results: of those admitted, 31.1% had pyogenic meningitis (pm), 26.2% partially treated meningitis (ppm), 33% viral meningitis (vm), and 9.7% tubercular meningitis (tbm), with 26.4% controls. organisms were isolated in 12.5% of the cases by blood culture and 25% of cases through csf culture. blood crp was positive in all groups, with the highest values in pm (53.12 ± 28.88 mg/dl) and ppm (47.55 ± 34.34 mg/dl); this was not statistically significant (p = 0.08). the csf crp levels were significantly higher (p <0.001) in pm (45.75 ± 28.50 mg/dl) and ppm (23.11 ± 23.98 mg/dl). the sensitivity and specificity of blood crp was 90.62%, 88.88%, 64.7%, 70% and 32.4%, 30.97%, 24.52%, 26.12% and that of csf crp was 96.87%, 66.66%, 20.58%, 10% and 74.73%, 63.71%, 50.94%, 55.35% for pm, ppm, vm and tbm, respectively. conclusion: because of its high sensitivity, both csf crp and blood crp can be used to screen for bacterial meningitis (both pm and ppm). csf crp screening yielded results with a higher specificity than blood crp; hence, it can be a supportive test along with csf cytology, biochemistry, and microbiology for diagnosing meningitis. keywords: meningitis; c-reactive protein; cerebrospinal fluid. is cerebrospinal fluid c-reactive protein a better tool than blood c-reactive protein in laboratory diagnosis of meningitis in children? *kalpana k. malla, tejesh malla, k. seshagiri rao, sahisnuta basnet, ravi shah clinical & basic research advances in knowledge blood and cerebrospinal fluid (csf) c-reactive protein (crp) can be a simple bedside test to differentiate between different types of meningitis. both can be especially helpful in diagnosing partially treated meningitis when patients present after being prescribed antibiotics, and the csf picture is similar to viral meningitis. is cerebrospinal fluid c-reactive protein a better tool than blood c-reactive protein in laboratory diagnosis of meningitis in children? 94 | squ medical journal, february 2013, volume 13, issue 1 application to patient care: blood and csf crp help in the early diagnosis and appropriate treatment of different types of meningitis. early treatment prevents the chances of having negative sequelae. c-reactive protein (crp) and the acute phase inflammatory response were discovered in 1930 by tillett et al.1 almost any inflammatory disease will cause detectable quantities of crp to be present in serum or other body fluids closely associated with the affected tissues.2,3 in western countries, attention has been directed to the value of serum crp measurement in differentiating bacterial and viral infections.4 however, routine diagnostic use of cerebrospinal fluid (csf) crp in differentiating bacterial and non-bacterial meningitis has been evaluated in very few studies.2,5 the csf gram stain and culture still remains the gold standard in the diagnosis of meningitis, but in patients where these results are negative, there is no definitive test for diagnosing meningitis. this is especially necessary in a set up like ours where patients come after getting various antibiotics or where facilities for doing cultures are not readily available. death from meningitis is not uncommon and many who survive are left permanently disabled. hence, diagnostic tests which are readily available, easy to interpret, and simple to perform are of paramount importance. the present study was designed to evaluate the diagnostic significance of crp in csf and blood as a rapid and simple method of diagnosing and differentiating different types of meningitis in children in a developing country like nepal where there is a problem in isolating organisms. methods this hospital-based case controlled study was conducted from july 2009 to june 2011, in the paediatric ward of manipal teaching hospital in pokhara, nepal. this is the only tertiary care hospital in the western region of the country and has a 75-bed paediatric ward. therefore, mostly very sick patients with a diagnostic dilemma who are not responding to simple management are referred to this hospital; hence, most patients come after receiving a course of antibiotics. before the commencement of the study, ethical approval was obtained from the ethical committee of the hospital and informed consent from the parents/guardians. a separate proforma, which included data about clinical features and laboratory results, was completed for each case. a lumbar puncture was done on all children aged 1 month to 15 years who were included in the study. blood and csf samples were also sent for crp assay by latex agglutination test. the volume of csf used for crp analysis was 500 µl (~0.5 ml) = 8 drops, and was assessed using a series of diagnostic kits/ reagents which included biochemistry, immunology, and serology rapid tests from rfcl limited (ranbaxy fine chemicals ltd., delhi, india). other laboratory investigations included an assessment of blood sugar, and a blood culture. a csf crp titre of 4 mg/l and a blood crp of 6 mg/l were considered positive in this study.1,6 these values were the cutoff values and matched with their reference value. a csf gram stain and culture were performed as gold standard testing. in cases where the staining results were negative, csf cytology, and glucose and protein levels were considered. csf and serum crp were then evaluated against this gold standard. all 140 patients were divided into 5 groups based on clinical and csf cytochemistry.7 group 1, with pyogenic meningitis (pm), was defined by a csf leukocyte count of 100–10,000/ mm3 with polymorphonuclear neutrophils (pmns) of >50%, a csf glucose level <2/3 blood sugar level, and a csf protein level of 100–500 mg/dl. group 2, with partially treated meningitis (ppm), was defined as those who had already received oral or intravenous antibiotics before csf analysis. these patients had a csf leukocyte count of 5–10,000/ mm3 with pmns or lymphocytes predominating, protein levels of 100–500mg/dl, and normal or decreased glucose levels. group 3, with viral meningitis (vm), was defined as those with a csf pleocytosis of <100/mm3 with lymphocyte predominance, protein levels of 50–200 mg/ dl, and normal glucose levels with a negative bacterial culture and gram stain. group 4, with tubercular meningitis (tbm), was defined as those with a history of contact with a sputumpositive tuberculosis (tb) case, clinico-radiological kalpana k. malla, tejesh malla, k. seshagiri rao, sahisnuta basnet and ravi shah clinical and basic research | 95 findings consistent with tb, and a positive reaction (>20 mm in duration) to 5 tuberculin units (tu) of purified protein derivative (ppd), and a csf pleocytosis level of 10–500/mm3 with predominant lymphocytes and a high csf protein (100–3000 mg/dl), or in cases where a csf culture and/or ziehl-neelsen staining have revealed acid-fast bacilli. group 5, the control group, included those with a fever with convulsions but no meningitis. these convulsions were caused by epilepsy or febrile convulsions. excluded from the study were those patients classified as neonates, those with fungal meningitis or concomitant illnesses such as human immunodeficiency virus (hiv). patients with conditions contributing to an elevation of csf crp, such as infections other than meningitis and non-infectious conditions like rheumatic disorders, malignancies, and tissue injury, were also excluded,8 as well as those on immunosuppressive therapy. statistical analysis was done using epi-info 3.5.2 (centers for disease control and prevention, atlanta, georgia, usa). the test applied for statistics was an f-test (i.e. analysis of variance [anova] test). a p value of <0.05 was taken as statistically significant. results the csf from 140 children (32 pm, 27 ppm, 36 vm, 10 tbm, and 37 controls) was analysed. table 1 shows the distribution of ages in both cases and controls. the greatest number of meningitis cases was noted in those aged 5–10 years, with bacterial meningitis (pm and ppm) predominating in all age groups [table 1]. organisms grown in the blood cultures were enterococcus, which grew in two cultures; pseudomonas, which grew in one culture, and escherichia coli, which grew in one culture (4/32, 12.5%). organisms isolated in csf were e. coli, which was isolated in two samples; enterococcus, which was isolated in one sample; staphylococcus aureus, which was isolated in two samples; pseudomonas was isolated in one sample; and streptococcus pneumonia, which was isolated in two samples (8/32, 25%) [table 2]. blood crp was positive in all groups [table 4] with the highest values in the pm and ppm groups [table 3], but they were not statistically significant (p <0.08). csf crp was significantly (p <0.001) higher in pm (45.75 ± 28.50) [table 3]. serum crp sensitivity and specificity was 90.62% and 32.4% for pm; 88.88% and 30.97% for ppm; 64.7% and 24.52% for vm; 70% and 26.12% for tbm respectively [table 5]. csf crp sensitivity and specificity was 96.87% and 74.73%, for pm; 66.66%, and 63.71% for ppm; 20.58% and 50.94%, for vm; 10% and 55.38% for tbm, respectively [table 5]. discussion the aetiological diagnosis of meningitis remains a problem as the clinical and biochemical picture is often masked because of prior antibiotic use. this becomes even more difficult in a population like ours where patients first attend a private practitioner table 1: different types of meningitis according to age groups age pm ppm vm tbm control total <2yrs 8 5 4 0 18 34 >2–5yrs 5 4 3 1 7 20 >5–10yrs 11 13 17 2 11 55 >10–15yrs 8 5 10 7 1 31 total 32 (31.1%) 27 (26.2%) 34 (33%) 10 (9.7%) 37 (26.4%) 140 pm = pyogenic meningitis; ppm = partially treated meningitis; vm = viral meningitis; tbm = tubercular meningitis. table 2: organisms isolated in blood and cerebrospinal fluid (csf) organisms blood (n = 32) csf (n = 32) enterococcus 2 1 pseudomonas 1 1 escherichia coli 1 2 staphylococcus aureus 0 2 streptococcus pneumonia 0 2 total 4/32 (12.5%) 8/32 (25%) csf = cerebrospinal fluid. is cerebrospinal fluid c-reactive protein a better tool than blood c-reactive protein in laboratory diagnosis of meningitis in children? 96 | squ medical journal, february 2013, volume 13, issue 1 and receive a course of antibiotic. they then come to our hospital when they do not improve. in such a scenario, it becomes impossible to isolate the organisms from blood or csf. moreover, csf cultures for pyogenic organisms are positive in only 30–60% of cases, according to various researchers.9 in many places, facilities to isolate bloodor csfborne organisms is lacking and, if it is available, it can take a long time for culture reports to come. there is currently no single test to diagnose the aetiology of meningitis promptly and accurately; hence, a quick and reliable method is required for early bedside diagnosis. our results suggest that serum crp/csf crp in initial lumbar puncture is an ideal method in situations where it traditionally has been difficult to isolate organisms to aid with diagnosis. passive diffusion across the highly inflamed meninges would be a reasonable explanation as to how crp gains access to csf.10 meningitis was most frequently observed in the 5-to 10-year-old cohort. neonates were not included in this study as there is no cut-off crp titre for newborns, presumably due to the immaturity of the blood-csf barrier (b1-csf-b) during the first weeks of life.6 only 12.5% of the 32 cases of pm displayed organisms that had been isolated in blood cultures (enterococcus [2], pseudomonas [1], e. coli [1]). likewise, 25% of the csf cases displayed organisms in the blood cultures (e. coli [2], enterococcus [1], s. aureus [2], pseudomonas [1], s. pneumoniae [2]. in our study, the frequency of bacterial isolates in csf was lower than that observed in other studies where it was 36% but the isolated organisms were similar to ours.11 table 3: laboratory parameters of different types of meningitis in blood and cerebrospinal fluid variables pm mean ± sd ppm mean ± sd tbm mean ± sd vm mean ± sd control mean ± sd p value blood crp rbs 53.12 ± 28.88 106 ± 29.84 47.55 ± 34.34 98 ± 31.81 39.60 ± 41.58 98 ± 29.85 36.35 ± 38.00 88 ± 21.36 31.13 ± 35.60 100 ± 30.72 0.08 0.14 csf total count neutrophils lymphocyte sugar protein crp 903.28 ± 1419 84.18 ± 12.26 15.81 ± 12.26 29.15 ± 15.11 46.28 ± 32.89 45.75 ± 28.50 231.07 ± 303 60.37 ± 26.82 39.62 ± 26.82 47.44 ± 20.62 43.85 ± 51.89 23.11 ± 23.98 158.40 ± 133 8.90 ± 8.22 90.60 ± 8.11 40.30 ± 13.69 256.90 ± 203 1.20 ± 3.79 118.94 ± 246 10.88 ± 11.57 86.23 ± 18.75 55.00 ± 16.70 30.05 ± 19.40 4.47 ± 16.93 .1081 ± .458 .000 ± .000 5.40 ± 22.92 65.48 ± 16.75 22.21 ± 28.80 2.00 ± 8.84 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 sd = standard deviation; pm = pyogenic meningitis; ppm = partially treated meningitis; tbm = tubercular meningitis; vm = viral meningitis; crp = c-reactive protein; rbs = random blood sugar; csf = cerebrospinal fluid. the p value was determined by anova test and <0.05 was considered as statistically significant value. table 4: occurrence of different types of meningitis in blood and cerebrospinal fluid study groups blood crp csf crp positive negative positive negative pm (n = 32) 29 3 31 1 ppm (n = 27) 24 3 18 9 vm (n = 34) 22 12 7 27 tbm (n = 10) 7 3 1 9 control (n = 37) 20 17 2 35 crp = c-reactive protein; csf = cerebrospinal fluid; pm = pyogenic meningitis; ppm = partially treated meningitis; vm = viral meningitis; tbm = tubercular meningitis. table 5: sensitivity and specificity for blood and cerebrospinal fluid c-reactive protein in different groups of meningitis sensitivity (sn) specificity (sp) csf crp pm ppm vm tbm 96.87% 66.66% 20.58% 10.00% 74.73% 63.71% 50.94% 55.38% blood crp pm ppm vm tbm 90.62% 88.88% 64.47% 70 % 32.40% 23.68% 24.52% 26.12% csf = cerebrospinal fluid; crp = c-reactive protein; pm = pyogenic meningitias; ppm = partially treated meningitis; vm = viral meningitis; tbm = tubercular meningitis. kalpana k. malla, tejesh malla, k. seshagiri rao, sahisnuta basnet and ravi shah clinical and basic research | 97 in another study, the csf cultures were positive for the presence of organisms in only 16% of cases.12 the total count in csf was 903.28 ± 1419.73 and the neutrophil count was the highest, at 84.18 ± 12.26. the glucose level in csf was the lowest 29.15 ± 15.11 in pm, and was statistically significant (p <0.0001). similarly, csf lymphocyte levels (90.60 ± 8.11) and protein levels (256.90 ± 203.61) were highest in tbm cases, and were considered statistically significant (p <0.0001). similar findings were noted in other studies.12 these significant parameters may also be helpful in differentiating different types of meningitis but further studies with larger populations would be needed to assess this possibility as very little comparable data is available in this area. levels of crp in serum and csf increase as a result of invasive central nervous system infection.4 increased crp production is an early and sensitive response to most forms of microbial infections and the value of its measurement in the diagnosis of various infective conditions was established in previous studies.14,15 in this study, increased blood crp levels were noted in all groups, but the difference was statistically insignificant (p >0.05 or = 0.08). in past studies, crp levels were used to differentiate between bacterial and viral meningitis, since crp levels are found to be lowest in viral meningitis.4 similarly, in our study, blood crp level was lowest in viral meningitis (36.35 ± 38.00). additionally, blood crp was positive in 29/32 cases of pm, giving a sensitivity of 90.62%. similar findings have been reported by other researchers.16 the sensitivity for blood crp was 88.88% (24/27) for ppm, 64.47% (22/43) for vm, and 70% (7/10) for tbm. the specificity for blood crp was 32.40%, 30.97%, 24.52%, and 26.12% in pm, ppm, vm, and tbm, respectively. different findings were noted in another study where serum crp sensitivity for pyogenic meningitis was lower (76%) and specificity was higher (68%) than in our study.17 comparable data for other types of meningitis were not available. blood crp with a high sensitivity can be used as a screening test for different types of meningitis, but since the specificity was low in our study, its diagnostic accuracy has yet to be established. csf crp has been reported to be one of the most reliable and early indices to differentiate between bacterial and non-bacterial meningitis.10,18 corral et al. found positive csf crp in 24/32 patients with culture-proved bacterial meningitis, while only 2/32 children with non-bacterial meningitis had csf which was positive for crp. according to corral et al., this was a more sensitive test for differentiating bacterial from non-bacterial meningitis than any other laboratory test for csf. their study demonstrated that csf crp levels are also useful in diagnosing partially treated cases of meningitis. our results also correlate with their findings.2 the mean crp in csf in this study was significantly higher (p <0.0001) in patients with pm (45.75 ± 28.50) and ppm (23.11 ± 23.98) as compared to patients with tbm (1.20 ± 3.79), vm (4.47 ± 16.93), and controls (2.00 ± 8.84). csf crp was positive in 31/32 cases of pms and 18/ 27 of those with ppm, giving it a sensitivity rate of 96.87% and 66.66%, respectively. similar sensitivity for pyogenic meningitis was also reported in other studies.16 in viral meningitis and tbm, csf crp sensitivity was low. the specificity for pm, ppm, vm and tbm was 74.73%, 63.71 %, 50.94%, and 55.38%, respectively. for pyogenic meningitis, a sensitivity of 84% and 94%, and a specificity of 100% have been reported by other researchers.2,12 in another study, a sensitivity of 97%, which was similar to our study, and a specificity of 98% was observed.19 similarly, a sensitivity of 97% and specificity of 86% for bacterial meningitis was also reported by other researchers.20 comparable data for other types of meningitis were not available, so a definite conclusion for other types of meningitis cannot be made. in this study, csf as well as blood crp sensitivity was high (csf crp > blood crp) in pm, but in ppm, tbm, and vm, the sensitivity was higher in blood (blood crp > csf crp). this indicates that csf as well as blood crp can be a good screening test for pm and blood crp can be used as screening test for ppm, vm, and tbm. the specificity was higher in csf crp than blood crp (pm = 74.73% versus 32.40%; ppm = 63.71% versus 30.97%; tbm = 55.38 % versus 26.12%; vm = 50.94% versus 24.52%). a high specificity of 94% in csf crp was noted by other studies for differentiating bacterial meningitis from both viral and normal forms of meningitis.2,6 this indicates that csf crp is a better marker than serum crp in differentiating bacterial meningitis from ppm, vm, or tbm. a similar view has been expressed by other researchers who found raised levels of crp in csf to be a better indicator of bacterial meningitis. it also served to distinguish is cerebrospinal fluid c-reactive protein a better tool than blood c-reactive protein in laboratory diagnosis of meningitis in children? 98 | squ medical journal, february 2013, volume 13, issue 1 bacterial meningitis from viral and tubercular infections, and other central nervous system disorders.21 this study has a number of limitations. primarily, our study included a small sample size. thus, while determining csf crp levels is useful in screening for bacterial meningitis (pm, ppm), a further study with a larger population is required to assess its accuracy better in diagnosing different types of meningitis. additionally, a larger control group would yield better statistics. a lack of virological laboratory support also may have affected the results of this study as ppm is a close differential diagnosis for vm. finally, measuring crp levels before and after antibiotics would give a better interpretation. conclusion it can be concluded that assessing types of meningitis from crp levels in csf offers a high sensitivity and moderate specificity. it is a simple, rapid, and accurate method for making a laboratory diagnosis and is particularly appropriate for bacterial (both pm and ppm) meningitis. blood crp levels can also be used to screen for pm, ppm, vm, and tbm at bedside as such an assessment also offers high sensitivity. based on our results, we recommend estimating csf crp and blood crp levels in the routine evaluation of types of meningitis in children. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest in conducting this study and received no funding from any source. a c k n o w l e d g e m e n t s i thank the study patients as well as dr. ganesh bk, dr. shankar poudel, dr. prithuja puodyal, and dr. kiran panthee for assisting in this study. references 1. tillett ws, francis t jr. serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. j exper med 1980; 52:561–71. 2. corral cj, pepple jm, moxon r, hughes wt. c-reactive protein in cerebrospinal fluid in children with meningitis. j pediatr 1981; 99:365–9. 3. pepys mb. c-reactive protein-fifty years on. lancet 1981; 1:653–6. 4. peltora ho. c-reactive protein for rapid monitoring of infections of the central nervous system. lancet 1982; 1:980–2. 5. clarke d, cost k. use of serum c-reactive protein in differentiating septic from aseptic meningitis in children. j pediatr 1983; 102:718–20. 6. bengershôm e, briggeman-mol gj, de zegher f. cerebrospinal fluid c-reactive protein in meningitis: diagnostic value and pathophysiology. eur j pediatr 1986; 145:246–9. 7. prober cg, dyner ll. central nervous system infections. in: kliegman rm, stanton bf, st. geme jw, schor nf, behrman re, eds. nelson textbook of pediatrics. 19th ed. philadelphia, pa: wb saunders press, 2012. p. 2088. 8. pepys mb, gideon mh. c-reactive protein: a critical update. j clin invest 2003; 111:1805–12. 9. kumar l, chitlengiya s, ayyagiri a. the current status of pyogenic meningitis in children. indian pediatr 1980; 17:438–40. 10. vaidya ak, wagle nm, merchant sm. use of csf c-reactive protein in differentiating bacterial and nonbacterial meningitis. j postgrad med 1987; 33:58–60. 11. tankhiwale ss, jagtap pm, khadse rk, jalgaonkar sv. bacteriological study of pyogenic meningitis with special reference to c-reactive protein. indian j med microbiol 2001; 19:159–60. 12. singh n, arora s, kahlon ps. cerebrospinal fluid c-reactive protein in meningitis. indian pediatr 1995; 32:687–8. 13. abro ah, abdou as, ali h, ustadi am, hasab aah. cerebrospinal fluid analysis acute bacterial versus viral meningitis. pak j med sci 2008; 24:645–50. 14. debeer fc, kirsten gf, gie rp, beyers n, strachan af. value of c-reactive protein measurement in tuberculous, bacterial and viral meningitis. arch dis child 1984; 59:653–6. 15. mccarthy pl, frank al, ablow rc, masters sj, dolan tf jr. value of the c-reactive protein test in the differentiation of bacterial and viral pneumonia. j pediatr 1978; 92:454–6. 16. singh uk. csf crp in the diagnosis of meningitis in children. indian paediatr 1994; 31:939–42. 17. col prasad pl, brig nair mng, lt col kalghatgi at. childhood bacterial meningitis and usefulness of c-reactive protein. mjafi 2005; 61:131–5. 18. shinro m. c-reactive protein, ldh in spinal fluid of infants with meningitis. xviii international congress of pediatrics, honolulu, hawaii, usa, 1986. scientific abstracts. 19. macfarlane de, narla vr. cerebrospinal fluid c-reactive protein in the laboratory diagnosis of bacterial meningitis. acta paediatr scand 1985; 74:560–3. kalpana k. malla, tejesh malla, k. seshagiri rao, sahisnuta basnet and ravi shah clinical and basic research | 99 20. abramson js, hampton kd, babu s, wasilauskas bl, marcon mj. the use of c-reactive protein from cerebrospinal fluid for differentiating meningitis from other central nervous system diseases. j infect dis 1985; 151:854–8. 21. john m, raj is, macaden r, raghuveer ts, yeswanth m. cerebrospinal fluid c-reactive protein measurement a bedside test in the rapid diagnosis of bacterial meningitis. j trop pediatr 1990; 36:213– 7. clinical & basic research sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 315-322, epub. 15th jul 12 submitted 12th nov 11 revision req. 29th feb 12, revision recd. 17th mar 12 accepted 24th mar 12 directorate general of education & training, ministry of health, muscat, oman. e-mail: drgillianwhite@yahoo.co.nz مقارنة بني رؤساء التمريض وطالب إدارة التمريض يف سلطنة ُعمان فيما يتعلق بتوفري التعليم ملسئويل التمريض جيليان وايت �سنة يف الدبلوم لدرا�سة احلايل الدرا�سي للمنهج رئي�سية ملراجعة التح�سري خالل من التمري�ض اإدارة م�ستقبل لبحث الهدف: امللخ�ص: واحدة يف اإدارة التمري�ض مبعهد التمري�ض اخلا�ض يف ُعمان. الطريقة: درا�سة من جزاأين ملعرفة 1( الأدوار واملهارات والكفاءات املطلوبة مل�سئويل التمري�ض 2( �ساكلة القيادة مع عينتني منا�سبتني هما: م�سئويل التمري�ض وطالب اإدارة التمري�ض. وّحلل كل جزء على حدة، ثم املبني والهتمام الأدوار لو�سف عر�سة اأكرث التمري�ض روؤ�ساء كان والختالف. النتائج: الت�سابه حيث من املجموعتان مقارنة قورنت على املهام، مع الرتكيز على حل امل�ساكل، يف حني رّكز الطالب على الوظائف والعمليات. اأراد كال الفريقني اأن يكون التمري�ض معروفا بقانون لقواعد ال�سلوك املهني، واأن تكون هناك جمعية للتمري�ض ذو �سلطات قوية. واأظهرت مقارنات �ساكلة القيادة باأن م�سئويل التمري�ض يتمتعون بالن�سج واخلربة العملية، يف حني كان طالب التمري�ض مثاليني، مع نزعات متيل نحو املخاطرة. كان هناك اتفاق عام على اأّن تخ�س�ض اإدارة التمري�ض يجب اأن يكون على م�ستوى املاج�ستري، اإل اأّن على جميع املمر�سني واملمر�سات اأخذ م�ساقات للقيادة والإدارة مهنة ومتكني تقوية على يتمحور هو الآن فيها هم والذين القيادية املنا�سب لدخول يتهيئون الذين ت�سّور اإن تقدمهم. اخلال�صة: اأثناء القوة لتوفري التمري�ض اإدارة يف التعليم من عالية بدرجة متري�ض وقادة مل�سئولني حاجة هناك وبالتايل ُعمان. �سلطنة يف التمري�ض الدافعة للتغيري والتحفيز امل�ستمر. يحتاج الربنامج احلايل لإدارة التمري�ض اإىل حتديث، واأن ُيعطى على م�ستوى املاج�ستري للطالب الذين يودون التخ�س�ض يف اإدارة التمري�ض. مفتاح الكلمات: تعليم، متري�ض، منظمة، اإدارة، ُعمان. abstract: objective: to explore the future of nursing administration in preparation for a major review of the current curriculum in the one-year diploma in nursing administration at the oman specialized nursing institute (osni). methods: a two-part study explored 1) requisite roles, skills and competencies of the nurse administrator, 2) a leadership profile with two convenience samples: heads of nursing and nursing administration students. each part was analysed separately; the two groups were then compared with the latter revealing similarities and differences. results: heads of nursing were more likely to describe roles and be task-oriented, emphasising problem solving, whereas students focused on functions and processes. both groups wanted nursing to be known for its code of professional conduct, and have an empowered nursing association. leadership profile comparisons indicated heads of nursing were mature and practical whereas students were idealistic, with risk-taking tendencies. there was overall agreement that preparation for the nursing administration specialty should be at master’s level; however, all nurses should undertake a leadership and management course during their progression to senior positions. conclusion: the vision of those preparing to enter and those already in leadership positions is for empowerment of the nursing profession in oman. thus there is a need for highly educated nurse leaders and managers in nursing administration to provide the driving force for change and sustained motivation. the current nursing administration programme (nap) needs to be upgraded and delivered at the master’s level for nurses specialising in nursing administration. keywords: education; nursing; organization; administration; oman. comparison between heads of nursing and nursing administration students in the sultanate of oman regarding education for nurse administrators gillian white comparison between heads of nursing and nursing administration students in the sultanate of oman regarding education for nurse administrators 316 | squ medical journal, august 2012, volume 12, issue 3 the american organization of nurse executives (aone) has identified a set of competencies that provide a framework for nurse executives1 and in a joint meeting with the council on graduate education for administration in nursing (cgean) identified a core curriculum for graduate education in nursing leadership at the post-baccalaureate level. nursing administration is identified as a nursing role specialty that intersects with leadership and management.2 in oman, the curriculum for nurse administrators is essentially as it was when it was originally developed in 2003, with leadership and management being an adjunct to administration rather than intersecting with the role. there is no literature concerning the expected role and functions of nurse administrators in oman, yet the nursing education system continues to offer a nursing administration specialty programme. it is timely, therefore, to explore the future of the nursing administration programme (nap) within the context of ‘best fit’ and ‘best practice’ for the omani situation. the nurse administrator graduate is expected to demonstrate appropriate qualities and competencies to manage an increasingly welleducated staff and lead the transformation of the nursing/midwifery professions. the general population is also progressively more educated and they demand quality of health care service provision. therefore, highly skilled nurse managers and leaders are essential to the advancement of oman’s nurses and nursing administration has shifted to leading and managing a sophisticated nursing profession in a variety of environments from primary health to technologically challenging intensive care in tertiary hospitals. currently, the median age of the oman population is 21.1 years old 3 resulting in relatively young nurses, most under 35 years of age. this creates a bottleneck in career progression. thus, ambition for advancement is often the underlying motivator to become a nurse administrator. nursing administration students undertake a one-year diploma in nursing administration from the oman specialized nursing institute (osni). to be eligible, they must have graduated with a diploma from a nursing specialist area. graduates often return to management in tertiary and secondary hospitals or primary health care centres within their initial specialty area. thus the graduate ends up with three diplomas: a three-year general nursing diploma, a specialist nursing diploma, and a nursing administration diploma. the osni diploma includes courses in nursing administration, applied research and evidence based practice, human resources, ethics, health care finances, and leadership and management. however, objectively measurable competencies for nurse administrator graduates are lacking. the definition of curriculum ranges from the traditional ‘course of study’ to a ‘focus on multiple interactions with people.’4 contemporary omani nursing curricula aim to prepare nurses who are critical thinkers, self-motivated life-long learners, change managers, clinical decision makers, and advocates for health promotion, health education, and safer patient care. thus the omani nursing profession consists of increasing numbers of highlyqualified nurses with new health and education professional ideologies and greater sophistication in competency-based, outcome-orientated, evidence -based practice. curriculum development in nursing education is an ongoing iterative process that responds to social impetus, including the input of educators and their stakeholders. against a background of undertaking a revision of the nap, heads of nursing throughout oman and nursing administration students were asked to provide opinions about requirements for the education of nurse administrators in the future.5,6 advances in knowledge findings from this study fill a gap in knowledge about expectations of the role and functions of nurse administrators in oman. a new dimension is added to knowledge about appropriate education for nurse administrators to meet the future vision for nursing in oman. application to patient care the nurse administrator assures that nurses provide competent, safe, quality care to patients and that nursing standards are upheld. nursing administrators are in a powerful position to advocate for patients, their families and the nurses’ well-being within their agencies. gillian white clinical and basic research | 317 methods a quantitative survey design with one ‘free expression’ question about the nursing profession in the future was selected that included perspectives about roles, skills, managerial competencies of the nurse administrator, and the content of a nurse administration specialty programme. the survey questions were developed from existing nursing administration curricula, as well as literature on nursing administration and management.1,2 respondents were required to select responses and had the opportunity to comment. an adapted version of the competing values management practices survey developed by quinn was also included.7 quinn’s model8 evolved from four traditional but different management domains: the rational goal; the internal process (models from the early 1900s); the human relations; and the open systems (models from the 1950–1970s).7,8 the relationships between the models, when placed onto a larger framework, form two axes, the y axis ranging from flexibility to control and the x axis ranging from an internal to an external organizational focus. each of the four models fits into one of four quadrants which demonstrate competing values within an organisational structure [figure 1]. the tool was piloted with a small group of nurse executives, not participants in the final study. all heads of nursing (hons) attending one of their regular national meetings agreed to take part (n = 45); one survey was returned blank. no demographic data were collected as individuals within the small sample of well-known nurses may have been identifiable. all students from the nap present in class on one particular day (total 18) completed the survey (70% of the total class). the nursing administration diploma is the only programme of its kind in oman and any demographic data would certainly have identified the students. thus, the total population of hons in oman and all students enrolled in the nursing administration programme were selected. the study was approved by the osni research committee who gave face validity to the questions and accepted its ethical integrity. consent was taken as given if the participant returned the completed survey. simple descriptive analysis was used to map significant differences. as the responses indicated clear majority views, further analysis was not attempted. the managerial practices survey, was computed according to the instructions given by quinn as cited in edwards, austin and altpeter.7 participants were asked to rate 36 managerial practice statements on a scale of 1 to 7 (indicating almost never to almost always). the rankings were then transferred to a computational worksheet for self-assessment. the worksheet was divided into 8 leadership roles and instructions were given for the total category score to be marked on the corresponding spokes of the competing values wheel [figure 1]. once plotted, the profile diagram demonstrated existing strengths and priorities for further improvement. in this study, a collective profile was plotted which was useful in demonstrating competing roles and values in general. table 1: similarities and differences between heads of nursing (hons) and nursing administration programme (nap) students’ opinions on the expected broad skills of a nurse administrator clear similarities clear differences change management hons naps human relations negotiating setting goals and objectives monitoring progress financial management * motivating staff group facilitation maintaining organisational problem solving maintaining workflow organisational stability decision making mentoring maintaining structure and organizational culture *(p = 0.04) comparison between heads of nursing and nursing administration students in the sultanate of oman regarding education for nurse administrators 318 | squ medical journal, august 2012, volume 12, issue 3 comparison of the two independent groups was undertaken using the chi-square test for proportions at a 95% confidence interval (ci) and a null hypothesis that the proportions for each section (role, skills, and competencies) were equal. when comparing two proportions, the chi-square test is equivalent to the z-test. results a total of 60% of hons expected a graduate of the nursing administration diploma to be in upper and middle level management compared with 75% of students (x2 = 0.3, p >0.05). students were more likely to describe functions than roles such as “the people responsible and accountable for the success and failure of nursing practice who are good futuristic planners.” hons listed roles such as principal nurse, deputy, regional head, in charge of health centres, heads of local hospitals and senior nurses (if having to act alone). according to the students, middle level managers were expected to show an ability to lead and could be unit heads who take responsibility for a specific unit or department, or for several wards. both groups described lower management as ward level. some nap students expressed an expectation to take on an executive role as a graduate, whereas hons did not expect this (p = 0.001, 95% ci = 3.5–2.8). three students expected to be responsible for the whole of the nursing services in their organisation. executive management was defined by the students as a person assigned to look after all health services and health affairs as a director of nursing and midwifery, or to act as a principal nursing officer who reports directly to a hospital director. they were expected to have a long-term vision and to improve nursing services and affairs to gain patient and staff satisfaction. table 1 shows the similarities and differences between hons and naps regarding the expected broad skills of a nurse administrator. it uses a cutoff point (75%) representing a clear majority view for exploring similarities and differences. there was full consensus among the hons about the skill of problem solving, and full consensus among nap students about the skills of change management and motivating staff. the participants were asked what managerial competencies were important to include in a nap. the only competency on which both groups had full consensus was conflict management. competencies highly valued by both groups included communicating effectively, building teams, developing and communicating a vision, living with change, and self-improvement. the nap students also highly valued analysing core processes, fostering a productive work environment, building and maintaining a power base, negotiating agreements and commitments, and understanding development processes. the hons, on the other hand, highly valued developing employees, measuring quality and performance, designing work schedules, and thinking creatively. both groups, through free expression, indicated they wanted the nursing profession to become noted for its code of professional conduct in terms of accountability and responsibility. having an empowered nursing association was also important. however, there were also marked differences with the students urging empowerment, promotional opportunities, and leadership, while the hons focused on tasks such as clinical auditing, developing presentation skills, compiling duty rosters, writing good quality proposals and reports, using mistakes as opportunities to improve critical incident handling, and the development of nurses who can impact national health policy/education policy/nursing curricula. when asked for their recommendations about what to include in a nap curriculum, the students demonstrated much greater consensus than the table 2: four theoretical models translated in management practices focus model definition roles collaboration human relations internal flexibility facilitator/mentor competition rational goal external control producer/director creativity open systems external flexibility innovator/broker control internal process internal control monitor/coordinator gillian white clinical and basic research | 319 hons. however, both groups identified that a nap should include courses in applied ethics, evidence based practice, human resources, applied research, nursing leadership, and management. health finance was a topic strongly recommended by the nap students (88.9%) but not supported by the hons (< 40%), which is statistically significant (x2 = 12.4; p <0.001). conversely, the hons favoured a course in behavioural sciences whereas the students did not. both students and hons believed that nursing administration should be offered at master’s degree level. the hons also suggested a focus on nursing management and leadership at the post-basic diploma level. a managerial practices survey was undertaken with the two groups and the results plotted onto the competing values skills-assessment leadership role profile [figure 1].7 each quadrant represents a theoretical model (i.e. upper left = human relations, upper right = open systems, lower right = rational goal and lower left = internal process).8 to translate the four theoretical models into management practices, each quadrant is labelled according to its central focus [table 2]. a comparison of the collective leadership role profiles of the two groups showed that the students tended toward the coordination role, closely followed by mentoring and monitoring. however, the hons tended toward mentoring and directing, which demonstrates clear competing values, although the producer and coordinator roles also ranked high.5,6 discussion according to sullivan and decker, the role of the nurse administrator is to manage the daily operations of a department within a variety of health care facilities, execute the strategic objectives of the health care agency, establish and implement nursing guidelines based on research evidence, ensure the department(s) are adequately staffed over all shifts, manage the use of resources, and assist the nursing staff in delivering quality patient care.9 nurse administrator preparation includes evidence-based practice, and management and leadership development, plus organisational theory including strategic planning, quality assurance, health economics, health policy, and management of resources. the participants viewed nursing administration as mainly the middle or executive level of management. all participants believed that the nurse administrator should have a clear, longterm vision as a nursing leader. the development and articulation of vision for nursing practice flexibility innovator role broker role external producer role director role control coordinator role monitor role internal facilitator role mentor role human relations open systems rational goal internal process figure 1: competing values framework wheel (adapted from quinn7). comparison between heads of nursing and nursing administration students in the sultanate of oman regarding education for nurse administrators 320 | squ medical journal, august 2012, volume 12, issue 3 is an important ability required in the nurse administrator.10 shared opinions about skills included change management, dealing with human relations, setting goals and objectives, motivating staff, problem solving, decision making, mentoring, and maintaining the structural and organisational culture. differences were negotiating, monitoring progress, group facilitation, maintaining workflow, and maintaining organisation stability. none of these differences were statistically significant. in exploring the future of the nap, two content areas were highlighted: financial management (recommended by the students), and behavioural sciences (recommended by the hons). financial management, cost analysis, microand macroeconomics are specialty content recommended for nursing administration.10 the student group had undertaken a financial management assignment and so recognised the value of understanding the economic use of resources. the perceived need for behavioural sciences by the hon group was new. behavioural science is the study of human behavior as individuals, and in groups, societies and cultures. experiential learning strategies are very useful for teaching behavioural sciences in nursing and scenarios, case studies, role plays, and problem solving exercises can be utilised.11 the terms ‘competencies’ and ‘skills’ are sometimes used synonymously although competency is also used to mean a broad set of skills, such as managing conflict, team building, communication, developing and communicating a vision, living with change, and self-improvement. these were all identified by both groups and are in line with the joint position statement on nursing administration education.10 the addition of a managerial practices survey sought to explore the future of the nap and curriculum development from a pragmatic as opposed to a theoretical perspective. in identifying ideas about roles and functions, the two groups illuminated the deficits in the current curriculum. a comparison of the profiles demonstrated that the students’ profile consisted of the roles and functions of coordination, mentoring and monitoring. however, the hons’ profile was divided between the roles and functions of mentoring and directing, producing and coordinating. thus the hons had a greater focus on production and direction, which is a more external control authoritarian approach, compared to the students who focused more on the internal control utilising human relationships. each of the models in the competitive values framework has a perpetual opposite [figure 1]. these four opposing models generate a competing values framework appearing to carry a conflicting message. organisations need to be adaptable and flexible yet also stable and controlled; they need to value human resources at the same time as they value planning and goal setting. the opposites are not mutually exclusive. all values inherent in the framework are important because of the complexities of work which confront people every day. managers find themselves playing conflicting roles as the day-to-day and minute-by-minute context and environment of their organisation changes. effective leaders and managers often have to change roles. in figure 1, the roles of facilitator and mentor fall into the human relations model focusing on collaboration. the roles of innovator and broker fall into the open systems model focusing on creativity. the roles of producer and director fall into the rational goal model with its focus on competition, and the roles of monitor and coordinator fall into the internal process model with its focus on control. coordinators, monitors, and mentors focus on matters internal to the organisation that maintain the organisational structure through tasks such as budgeting, planning schedules, utilising systems, and implementing quality control measures and human relations. this requires technical competence, and collecting, using, and disseminating information for the smooth functioning of the organisation and the orderly flow of work, ensuring that the organisation has a competent workforce.8 the student cohort profile suggests they see the need to be flexible while maintaining a level of control; use traits for successful mentorship such as caring and empathy, and be knowledgeable and well prepared. directing falls into the dimension of external control focusing on formal structure wherein the manager deals with the interface between the organisation and its external environment.8 producing falls into the control sector, suggesting that when linked with directing, the hons function more as authorities than mentors. when balanced, however, mentoring and directing skills are as essential for the nurse manager as producing. gillian white clinical and basic research | 321 a high centralisation of authority was found in ethnographic data analysed by abdulla and al-hamoud, who argued that a paradox exists in arabian gulf cultures where dual sets of values exist as leaders and managers move from transactional to transformative leadership at the same time as they strive for change and stability.12 the practicality of the hons compared with the idealism of the students is shown when exploring the future of the nursing profession. the students show idealistic dynamism and risk taking when they advocate empowerment, promotional opportunities, and leadership. idealism defined as pursuing noble principles, purposes, or goals is not unusual among students and new graduates as they are urged to pursue higher goals and improve practice. the “honeymoon” phase after graduation, when everything is new is often followed by “culture shock” as the daily demands of nursing, devoid of the past classroom peer support, replaces idealism with realism and motivation with cynicism.13 this study is limited by its specific focus on the only nap existing in oman. however, separate analysis of the hons and nap students, followed by comparison of both groups, have strengthened the understanding of the education of nurses entering a managerial role in oman and have informed curriculum development for the existing nap. conclusion responsibility for financial management stood out as a major difference between the two groups. the hons illustrated that they do not have any responsibility for financial matters. for the students, the topic represented a vision for the future where nurse administrators can take an active role in the management of financial resources as nurses comprise the bulk of the health care workforce. internationally, nursing administration is perceived as an advanced nursing specialty; an omani master’s degree in nursing administration would prepare nurse administrators to take their rightful place in top administration with responsibility and accountability for financial and local health economies. the main purpose of this study was to gain information for the curriculum review of the only nursing administration diploma programme in oman. there was consensus that nursing administration should be offered at master’s level, which fits with the current international discussions. however, it was also strongly recommended by hons that all nurses should undertake a course in leadership and management as part of progression to senior positions, even if not going into administration. the question therefore arises whether the time has come to emphasise the development of nursing leaders and managers in all nursing specialties, and move nursing administration to the master’s level. omani nurses are facing the paradox where dual sets of values are working in parallel as the transition from the days of autocratic paternalism are transforming into the future of nursing democracy. well-educated nurse administrators will lead the way. this study leads to three main recommendations. first, a new nursing administration curriculum should promote a paradigm shift from transactional to transformative leadership. second, nursing education must meet the needs of the future generation of nursing leaders and managers. the components of leadership and management should be core courses in all post-basic specialty omani nursing programmes. third, nursing administrators should have master’s level education. this will offer greater opportunities for a career pathway in nursing administration and create competitiveness in job opportunities within the omani health care system—as currently executive positions are awarded to graduates from other health care or administrative professions. c o n f l i c t o f i n t e r e s t the author declared no conflict of interest. references 1. american organisation of nurse executives. nurse executive competencies 2005. from: http://www. aone.org/aone/resource/home.html. accessed: may 2011. 2. american nurses association. nursing: scope and standards of practice. silver springs, maryland: american nurses association, 2004. 3. ministry of health oman. annual health report 2009. from http://www.moh.gov.om. accessed: apr 2012. 4. doll we jr. ghosts and the curriculum. in: doll we jr, ed. curriculum visions. new york: peter lang. 2002. pp.23–70. comparison between heads of nursing and nursing administration students in the sultanate of oman regarding education for nurse administrators 322 | squ medical journal, august 2012, volume 12, issue 3 5. white ge. exploring the future of the nursing administration programme: perceptions of heads of nursing. unpublished report to director general of education & training, ministry of health, oman, 2011. 6. white ge. exploring the future of the nursing administration programme: perceptions of nursing administration students. unpublished report to director general of education & training, ministry of health, oman, 2011. 7. edwards rl, austin dm, altpeter ma. managing effectively in an environment of competing values. in: r. edwards rl, yankey j, altpeter ma, eds. skills for effective management of nonprofit organizations. washington: nasw press, 1998. 8. quinn re, faerman sr, thompson mp, mcgrath mr, st. clair ls. becoming a master manager: a competing values approach. danvers, massachusetts: john wiley & sons, inc. 2007. 9. sullivan e, decker p. effective leadership and management in nursing. 6th ed. upper saddle river, new jersey: prentice hall, 2005. 10. american association of critical care nurses. from: aacn.nche.edu/publications/positions/nae. htm. accessed: may 2011. 11. campbell jd. teaching the behavioural sciences: a manual of techniques. burton, michigan: association for the behavioral sciences and medical education, 2011. (published as complement to: the behavioural sciences and health care. sahler oj carr je, eds. kirkland, washington: hogrefe & huber, 2003.) 12. abdalla ia, al-hamoud ma. exploring the implicit leadership theory in the arabian gulf states. appl psychol 2001; 50:506–31. 13. culture shock and the problem of adjustment to new cultural environments. from: http://www. worldwide.edu/travel_planner/culture_shock.htm. accessed: jul 2011. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 88-92, epub. 27th feb 13 submitted 13th apr 12 revision req. 9th sep 12, revision recd. 17th sep 12 accepted 13th oct 12 departments of 1pediatrics, 2cardiology, el-minia university hospital, minia, egypt *corresponding author e-mail:sherenesammaher@yahoo.com مؤشر الكاحل العضدى ىف األطفال الذين يعانون متالزمة الكلوية مقاومة الستريويد �صريين ع�صام ماهر حممد، عبد العظيم حممد ال�صيد املزارى ،هانى طه ع�صقالنى امللخ�ص: الهدف: تهدف هذة الدرا�صة اإىل تقييم موؤ�رس الكاحل الع�صدى كموؤ�رس لأمرا�ض ال�رسايني الطرفية فى الأطفال امل�صابني مبتالزمة الكلوية امل�صادة ال�صتريويد. الطريقة: ا�صتملت هذه الدرا�صة على ع�رسين طفال من الذين يح�رسون العيادة اخلارجية لأمرا�ض الكلى لالأطفال مب�صت�صفى املنيا اجلامعى ،م�رس . فى هذة الدرا�صة كان 11 من الذكور و 9 من الإناث تراوحت اأعمارهم بني 5و 15 عام و كان بهم زلل و املر�صى جميع .تعر�ض �صابطة كمجموعة ال�صن و للجن�ض مطابق �صحيح طفال 20 اأخذ مت . بال�صتريويد للعالج يخ�صعون و بالبول الأ�صحاء لأخذ التاريخ املر�صى و للفح�ض ال�رسيرى . خ�صع جميع املر�صى فى هذة الدرا�صة لالختبارات املعملية مثل حتليل البول ،ن�صبة الربوتينات فى بول 24 �صاعة ، اليوريا والكرياتينني فى م�صل الدم ،ن�صبة اللبيومني و الكال�صيوم و الف�صفور و الفو�صفات القلوي فى م�صل عمل وكذلك الكلوية متالزمة فى املر�ض نوع لت�صخي�ض الكلى من خزعة اأخذ مت . الكولي�صتريول و الثالثية الدهون ن�صبة كذلك ،و الدم درا�صة دوبلر لتحديد موؤ�رس الكاحل الع�صدي . النتائج : اأظهرت النتائج ان موؤ�رس الكاحل الع�صدي كان اأعلى بكثري فى جمموعة املر�صى عن املجموعة ال�صابطة ، و كان هناك ارتباط اإيجابي بني موؤ�رس الكاحل الع�صدي و جرعة ال�صتريويد و مدة العالج . اخلال�صة : انتهت الدرا�صة اإىل اأن موؤ�رس الكاحل الع�صدي طريقة ب�صيطة للتنبوؤ بت�صلب ال�رسايني فى الأطفال امل�صابني مبتالزمة الكلوية امل�صادة ال�صتريويد لفرتة طويلة. مفتاح الكلمات: موؤ�رس الكاحل الع�صدي، الأطفال، مقاومة ال�صتريويد، متالزمة الكلوية، م�رس. abstract: objectives: this study aimed to assess the ankle brachial index (abi) as a predictor of peripheral arterial diseases (pad) in children with steroid-resistant nephrotic syndrome (ns). methods: twenty children (11 males and 9 females) attending the pediatric nephrology outpatient clinic of el-minia university hospital, egypt, were enrolled in this study. their age ranged between 5 and 15 years with a mean of 10.75 ± 3.31 years. they had proteinuria and were dependent on steroid therapy. twenty healthy ageand sex-matched children served as a control group. all patients and controls underwent a thorough history-taking and clinical examination. all subjects in the study underwent laboratory investigations, including a urine analysis (24-hour test for protein in urine, and levels of serum urea and creatinine, triglycerides, and cholesterol). a renal biopsy was done to diagnose the children’s histopathological type of ns. a doppler study was done to determine patients’ abi. results: abi was significantly higher in the patient group than in the control group (p <0.0001). there was a negative correlation between abi and duration of treatment (r value = 0.77 and p <0.001). conclusion: abi is simple non-invasive manoeuvre that can reliably assess arterial stiffness as an early predictor of atherosclerosis in nephrotic patients with long duration of both illness and steroid therapy. keywords: ankle brachial index; children; steroid resistant; nephrotic syndrome; egypt. ankle brachial index in children with steroid-resistant nephrotic syndrome *sheren m. mohamed,1 abdelazem elmazary,1 hany t. taha2 clinical & basic research advances in knowledge an increased risk of cardiovascular disease exists in patients with nephrotic syndrome (ns) because of hyperlipidaemia, increased thrombogenesis, and endothelial dysfunction. hypercholesterolaemia is strongly associated with severity of hypoalbuminemia, and persistent proteinuria or renal insufficiency also contributes to cardiovascular disease. the risk of premature atherosclerosis is increased due to hyperlipidaemia. the duration of nephrotic hyperlipidaemia appears to be critical to initiating vascular damage. endothelial damage from hyperlipidaemia may favor influx of lipoprotein into the mesangium, leading to proliferation and sclerosis. lipoproteins are elevated in children with long-standing and frequently relapsing ns. they are at increased risk for developing atherosclerosis, glomerular and interstitial renal disease. sheren m. mohamed, abdelazem elmazary and hany t. taha clinical and basic research | 89 patients with nephrotic syndrome (ns) are assumed to be at increased risk for peripheral arterial diseases (pad) and coronary heart diseases, probably because ns is associated with hyperlipidaemia, hypertension and steroid therapy. ns is defined by the presence of a nephrotic range of proteinuria, oedema, hyperlipidaemia, and hypoalbuminemia. primary or idiopathic nephrotic syndrome (ins) is divided into steroid-sensitive ns and steroid-resistant ns because a patient’s response to steroids has a high correlation with histological subtype and prognosis.1 ins is accompanied by a disordered lipid metabolism. apolipoprotein-b (apo-b)-containing lipoproteins are elevated with resultant increases in total cholesterol and low-density lipoprotein (ldl) cholesterol. elevations in triglyceride levels occur with severe hypoalbuminaemia. the traditional explanation for hyperlipidaemia in ins was the increased synthesis of lipoproteins that accompany increased hepatic albumin synthesis due to hypoalbuminaemia.2 high mortality from chronic kidney disease (ckd)—due to cardiovascular complications, vascular calcification induced by excess calcium and phosphate, and uremia—is a major risk factor and is independently associated with cardiovascular events and death. ckdinduced vascular disease causes stiffness of the arterial tree causing, in turn, systolic hypertension and left ventricular hypertrophy.3 management of ckd is difficult but early detection and treatment are crucial to reducing cardiovascular mortality. this study therefore aimed to assess ankle brachial index as a predictor of developing atherosclerosis in children with steroid-resistant nephrotic syndrome. methods twenty patients from the pediatric nephrology clinic of el-minia university hospital, egypt, participated in the study, which took place between april and december 2010. the study was comprised of 11 males and 9 females with a mean of age 10.75 ± 3.31 years who had been diagnosed with steroidresistant ns. their diagnosis was made according to the following criteria set forth by the international study of kidney disease in children (iskdc): no urinary remission within 4 weeks of a prednisone therapy course of 60 mg/m2/day.4 twenty apparently healthy children with no history of cardiovascular or renal diseases and matched by age and sex served as a control group. their ages ranged between 8 and 14 years with a mean age of 11 ± 2.1 years. the study was approved by the local ethical committee of elminia university in egypt and was sponsored by dr. manal ismail. written informed consent was obtained from the parents for all participating children. all patients’ medical histories were taken, and their clinical examinations included an accurate and thorough measurement of arterial pressure, an examination of oedema, and a cardiac examination. none of our patients had congenital or rheumatic heart disease. laboratory investigations included: 1) urine analysis and urinary protein measurement; 2) blood tests during which about 3 ml of venous blood was obtained by sterile vein puncture after the patients had fasted for 12–14 hours (the separated serum was then used for assessment of serum albumin, urea, creatinine, alkaline phosphatase, calcium, phosphorus, cholesterol, and triglycerides [tg]); and 3) renal ultrasonography and biopsy. the ankle brachial index (abi) is a clinical tool used for the detection of peripheral arterial disease, which in turn predicts cardiovascular morbidity and mortality.5 in this study, patients were placed supine for at least 5 minutes. the systolic blood pressure of the brachial artery of both arms and the posterior tibial artery of both ankles were then measured using a blood pressure cuff and a parks model 841-a pocket doppler probe (parks medical application to patient care peripheral artery disease (pad) can be accurately diagnosed with the ankle brachial index (abi). low values of the abi are predictive of incident cardiovascular disease (cvd), as well as total mortality. these associations hold true in both sexes and are independent of traditional cvd risk factors. abi is an independent newer biomarker for standard cvd risk factors. abi measurement can provide a simple and early prediction of patient with high risk of cvd and lead to better protection. ankle brachial index in children with steroid-resistant nephrotic syndrome 90 | squ medical journal, february 2013, volume 13, issue 1 electronics, aloha, oregon, usa). the highest arm pressure was then used to calculate abi. the ratio of ankle to arm systolic blood pressure was calculated for each leg, and the lowest ratio was recorded as the abi. abis were classified as low (≤0.9), normal (0.91–1.3), or high (>1.3).5 collected data were then tabulated. numerical data were expressed by the mean ± standard deviation (sd) and categorical data were expressed by a number and a percentage. statistical analysis was conducted by means of statistical package for social science (spss), version 15.0 (ibm, inc., chicago, illinois, usa) using an unpaired t-test for comparison of numerical data of both groups. a correlation-coefficient study between abi and laboratory data was done, with a p value considered significant at <0.05. results table 1 shows a significant increase in renal function markers in the patient group in contrast to the control group, including increases in serum urea and creatinine (p values 0.009 and 0.001, respectively). also, serum phosphorus and alkaline phosphatase were significantly higher in patients versus controls, (p values 0.03 and 0.006, respectively). serum albumin and serum calcium were significantly decreased in the patient group as compared with controls (p value 0.0001–0.01). for lipid markers, serum cholesterol was significantly higher in the patients than in the controls (p value 0.0001) but there was no significant difference in tg levels. the abi in the patient group was significantly lower (0.89 ± 0.02) than in the control group (1.04 ± 0.08) (p value 0.0001) [table 2]. also, there was a highly significant negative correlation between patients’ mean abi scores and their disease duration, serum urea, serum creatinine, and cholesterol levels (p value <0.001). additionally, there was a significant negative correlation between patients’ mean abi score and serum tg (p value <0.02). on the other hand, there was a significant positive correlation between patients’ mean abi scores and their serum albumin (p value <0.02) table 1: demographic and laboratory variables in patients and control groups data patients controls p value mean ± sd mean ± sd age (years) 10.75 ± 3.31 11 ± 4.24 0.08 sex (m/f) 9/11 9/11 disease duration (years) 3.42 ± 1.73 urea (mg/dl) 49.0 ± 34.17 21 ± 1.4 0.009 * creatinine (mg/dl) 1.13 ± 0.7 0.47 ± 0.1 0.001** calcium (mg/dl) 0.96 ± 0.17 1.09± 0.01 0.01* phosphorus (mg/dl) 5.06 ± 1.27 4.05 ± 0.78 0.03* albumin (g/dl) 2.85 ± 0.7 4.75 ± 0.35 0.0001** alkaline phosphates (u/l) 178.16 ± 109.0 81.67 ± 19.8 0.006* cholesterol (mg/dl) 248.18 ± 101.7 104.7 ± 26.2 0.0001** tg (mg/dl) 259.4 ± 152.09 173.7 ± 22.6 0.06 sd = standard deviation; m = male; f = female; tg = triglycerides; * = significant; ** = highly significant. table 2: comparison between patients and controls in regards to mean score on the ankle brachial index patients controls p value mean ± sd mean ± sd abi score 0.89 ± 0.02 1.04 ± 0.08 0.0001** sd = standard deviation; abi = ankle brachial index; ** = highly significant. table 3: correlation between mean ankle brachial index scores and different parameters in the patient group parameter r-value p value disease duration (years) -0.77 <0.001* urea (mg/dl) -0.74 <0.001 ** creatinine (mg/dl) -0.66 <0.001** calcium (mg/dl) -0.06 <0.7# albumin (g/dl) 0.35 <0.02* alkaline phosphates (u/l) -0.21 <0.2# cholesterol (mg/dl) -0.59 <0.0001** tg (mg/dl) -0.45 <0.02* tg = triglycerides; * = significant; ** = highly significant; # = nonsignificant. sheren m. mohamed, abdelazem elmazary and hany t. taha clinical and basic research | 91 [table 3]. according to renal biopsy, 17 patients had membranoproliferative glomerulonephritis, two patients had focal segmental glomerulosclerosis, and only one patient had diffuse mesangial proliferation. discussion overall, approximately 10% of patients with ins do not respond to an initial trial of steroids. additionally, about 1–3% of patients who initially do respond to steroids later become non-responders, or resistant to treatment.6 most patients who do not achieve remission of proteinuria with steroids have kidney biopsy findings other than minimal change ns. most cases fail to achieve remission with any treatment and progress to end-stage kidney disease.7,8 chronic hyperlipidaemia has been linked to an increased risk of atherosclerosis and coronary artery disease, and has also been associated with the progression of renal disease.9 however, small studies that have been done of the effects of lipidlowering agents in paediatric ins have not shown an improvement in proteinuria or the progression of renal disease.2 the abi test is a popular tool for the non-invasive assessment of pad. studies have shown the sensitivity of abi is 90% with a corresponding 98% specificity for detecting haemodynamically significant stenosis of >50% in major leg arteries as defined by angiogram.3 our study on steroid-resistant ns proved that abi scores in the patient group were significantly lower (0.89 ± 0.02) than in the control group (1.04 ± 0.08) (p <0.0001). this is related either to the nature of the disease and hyperlipidaemia, or to drugs used in treatment, such as corticosteroids. they both cause arterial stiffness and increase the risk of cardiovascular morbidity and mortality. they also predispose patients to rapid progression to end-stage kidney disease. our results were in agreement with de vinuesa et al. who investigated the prevalence of pad using the abi in 102 patients who had been referred for the first time to a nephrology clinic with ckd. the study found a high prevalence of pad (considered an abi score of <0.9) in non-dialysed patients with ckd.10 another study by willenberg et al. focused on children with a history of longterm (>5 years) corticosteroid use (group a) and a matched control group without a history of corticosteroid use (group b). abi scores showed that 80% in group a as compared to 9% in group b (p = 0.0009) were at risk of atherosclerosis. the results suggested that long-term corticosteroid therapy is associated with a distally accentuated calcifying atherosclerosis.11 in our study, abi scores correlated well with the renal function of patients (p <0.001) so abi could be a very easy way to predict early complications in these patients; for example, when renal markers (urea and creatinine) start to be affected, peripheral arterial assessment must be done. our findings also agree with those of kshirsagar et al. who found that the presence of an abi score <0.90 was associated with an estimated glomerular filtration rate (gfr) of <90 when compared to the reference group.12 in our study, serum phosphorus and alkaline phosphatase were significantly higher in the patient group versus the control group, (p value 0.01–0.03 and 0.006, respectively) this finding agrees with that of toussaint and kerr who postulated that vascular calcification induced by calcium and phosphate excesses and uremia is a major risk factor and is independently associated with cardiovascular events and death.13 they also recommended that both vascular calcification and arterial stiffness can be measured through non-invasive techniques involving computed tomography (ct), ultrasound, echocardiography, and pulse wave velocity. also in our study, there was a highly significant negative correlation between mean abi score and cholesterol levels (p <0.001). there was also a significant negative correlation between mean abi score and serum tg (p <0.02). these results were in agreement with those of an et al. who studied the relation between pad and renal insufficiency in high risk cardiovascular patients and concluded that a high prevalence of pad (defined as an abi ≤0.9) was associated with hypercholesterolaemia, cad, and cerebrovascular diseases.14 conclusion the abi is a simple, non-invasive bedside test for early detection of pad, which is a marker of cardiovascular morbidity. steroid-resistant ns patients are at high risk of developing cardiovascular complications, so early screening for pad would be useful to prevent morbid complications. ankle brachial index in children with steroid-resistant nephrotic syndrome 92 | squ medical journal, february 2013, volume 13, issue 1 references 1. anderson s, komers r, brenner bm. renal and systemic manifestations of glomerular disease. in: brenner bm. the kidney. 8th ed. philadelphia: saunders elsevier, 2008. pp. 925–50. 2. saland jm, ginsberg h, fisher ea. dyslipidemia in pediatric renal disease: epidemiology, pathophysiology, and management. curr opin pediatr 2002; 14:197–204. 3. mcdermott mm, criqui mh, liu k, guralnik jm, greenland p, martin gj et al. lower ankle/brachial index, as calculated by averaging the dorsalis pedis and posterior tibial arterial pressures, and association with leg functioning in peripheral arterial disease. j vasc surg 2000; 32:1164–71. 4. hogg rj, portman rj, milliner d, lemley kv, eddy a, ingelfinger j. evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the national kidney foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (parade). pediatrics 2000; 105:1242–9. 5. vowden p, vowden k. doppler assessment and abpi: interpretation in the management of leg ulceration. from: www.worldwidewounds.com/ wowden/doppler-assessment-abi.html accessed: mar 2001. 6. niaudet p. steroid-sensitive idiopathic nephrotic syndrome in children. in: avner e, harmon w and niaudet p, eds. pediatric nephrology. 5th ed. philadelphia: lippincott, williams & wilkins, 2004. pp. 887–917. 7. abeyagunawardena as, sebire nj, risdon ra. predictors of long-term outcome of children with idiopathic focal segmental glomerulosclerosis. pediatr nephrol 2007; 22:215–21. 8. gipson ds, chin h, presler tp. differential risk of remission and esrd in childhood fsgs. pediatr nephrol 2006; 21:344–9. 9. eddy aa, symons jm. nephrotic syndrome in childhood. lancet 2003; 362:629–39. 10. de vinuesa sg, ortega m, martinez p, goicoechea m, campdera fg, luño j. subclinical peripheral arterial disease in patients with chronic kidney disease: prevalence and related risk factors. kidney int suppl 2005; 93:s44–7. 11. willenberg t, diehm n, zwahlen m, kalka c, do dd, gretener s, et al. impact of long-term corticosteroid therapy on the distribution pattern of lower limb atherosclerosis. eur j vasc endovasc surg 2010; 39:441–6. 12. kshirsagar av, coresh j, brancati f, colindres re. ankle brachial index independently predicts early kidney disease. ren fail 2004; 26:433–43. 13. toussaint nd, kerr pg. vascular calcification and arterial stiffness in chronic kidney disease: implications and management. nephrology (carlton) 2007; 12:500–9. 14. an yc, chen yx, wang yx, zhao xj, wang y, zhang j, et al. risk factors on the recurrence of ischemic stroke and the establishment of a cox's regression model. zhonghua liu xing bing xue za zhi 2011; 32:816–20. حتديد املعادن الثقيلة يف التبغ غري املدخن "أفضل" األكثر انتشارا يف عمان نوال املخينية، طاهر باعمر، ال�سادق الطيب و عائ�سة ال�سحية abstract: objectives: afzal is an illegally sold smokeless tobacco product (stp) commonly used by youths and teenagers in oman. the aim of this study was to analyse the composition of afzal, also commonly known as sweekah, as it is believed to contain many carcinogens and toxic components. in particular, afzal’s heavy metal content includes cadmium (cd), chromium (cr), lead (pb) and nickel (ni). methods: this study was conducted between march and june 2013. three samples of afzal were first dried and then ground to form a homogenous powder. the powder was digested prior to the heavy metal analysis by inductively coupled plasma-mass spectrometry (icpms). results: afzal was shown to have high levels of all heavy metals except for ni and pb, which were detected in quantities below acceptable international limits. the concentrations of the tested metals were 15.75 µg/g, 1.85 µg/g, 1.62 µg/g and 1.57 µg/g for cr, cd, pb and ni, respectively. the estimated daily intake of heavy metals from afzal was below the maximum permissible limit accepted by the food and agriculture organization and world health organization, except for cr and ni which were found to be dangerously elevated when compared with international standards. conclusion: the results of this study showed that afzal contains a number of heavy metals that may cause health problems. therefore, urgent regulation of the illegal sale of afzal is needed at the national level in oman along with a campaign to address public health education and awareness of afzal and its health risks. keywords: smokeless tobaccos; heavy metals; spectrum analysis; oman. امللخ�ص: الهدف: اأف�سل هو الإ�سم الأكرث انت�ساراً للتبغ غري املدخن املباع بطرق غري �رسعية يف �سلطنة عمان. وي�ستعمل ب�سكل وا�سع من قبل ال�سباب واملراهقني يف عمان. الهدف: تهدف هذه الدرا�سة اىل معرفة تركيبة اأف�سل واملعروف بال�سويكة حيث يعتقد اأنه يحتوي على العديد من املركبات ال�سامة وامل�رسطنة من املعادن الثقيلة وحتديدا: الكادميوم )cd(، والكروم )cr(، والر�سا�س )pb( والنيكل )ni(. الطريقة: بداأت الدرا�سة يف مار�س وا�ستمرت حتى يونيو 2013م. مت جتفيف ثالث عينات من اأف�سل اأول ثم مت طحنها لت�سكل م�سحوقا متجان�سا ثم .)icp-ms( تفكيكها بطريقة اله�سم احلم�سي. ثم مت حتليل املعادن الثقيلة بها عن طريق جهاز احلث املقرتن ببالزما الطيف الكتلي امل�ستويات من اأقل كانا اللذين والر�سا�س النيكل عدا ما باأف�سل املحللة املعادن جلميع عالية م�ستويات النتائج اأو�سحت النتائج: الق�سوى امل�سموح بها. كانت نتيجة الرتاكيز للمعادن املحللة هي: 15.75 ميكروجم/جم، 1.85 ميكروجم/جم، 1.62 ميكروجم/جم و 1.57 ميكروجم/جم لكل من pb ،cd ،cr و ni على التوايل. عالوة على ذلك، اأو�سحت هذه الدرا�سة اأن التقدير لال�ستهالك اليومي عدا ما العاملية، ال�سحة ومنظمة الدولية والزراعة الأغذية منظمة قبل من بها امل�سموح احلدود من اأقل كان باأف�سل الثقيلة للمعادن م�ستويات الكروم والنيكل التي وجدت مب�ستويات عالية وخطرة عند مقارنتها مع املقايي�س العاملية. اخلال�صة: تبني نتائج هذه الدرا�سة اأن اأف�سل يحتوي على عدد من املعادن الثقيلة التي قد ت�سبب م�ساكل �سحية. وبالتايل، هناك حاجة ما�سة اإىل تنظيم البيع غري امل�رسوع لأف�سل على امل�ستوى الوطني يف �سلطنة عمان اإىل جانب حمالت التثقيف ال�سحي العام ون�رس الوعي مبخاطر اأف�سل ال�سحية. مفتاح الكلمات: منتجات التبغ غري املدخن؛ املعادن الثقيلة؛ احلث املقرتن ببالزما الطيف الكتلي؛ �سلطنة عمان. determination of heavy metals in the common smokeless tobacco afzal in oman nawal al-mukhaini, *taher ba-omar, elsadig eltayeb, aisha al-shehi clinical & basic research sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e349-355, epub. 24th jul 14 submitted 22nd dec 13 revision req. 6th feb 14; revision recd. 11th mar 14 accepted 23rd mar 14 department of biology, college of science, sultan qaboos university, muscat, oman *corresponding author e-mail: taher@squ.edu.om advances in knowledge this study analysed the composition of afzal, a smokeless tobacco product common in oman. it revealed high levels of certain heavy metals in afzal, including chromium, cadmium, lead and nickel. application to patient care the results of this study will help raise awareness within the omani community, especially among young people, about the danger of using afzal. smokeless tobacco products (stps) have a complex range of ingredients, from those containing only tobacco to others which include various chemicals and additives. since 1970, global tobacco companies have competed to manufacture different forms, flavours and packages of tobacco products so as to attract users.1 the use of stps has been associated with various health complications. several studies have reported cases of different cancers, mainly oral and oesophageal, associated with determination of heavy metals in the common smokeless tobacco afzal in oman e350 | squ medical journal, august 2014, volume 14, issue 3 the use of stps.2–5 other health risks that have been correlated with the use of stps include hypertension, cardiovascular diseases, diabetes, compromised platelet function and oxidative stress.6–9 moreover, the use of stps has been associated with a tendency towards alcohol consumption and lower physical activity levels, and it may also be a risk factor leading to smoking.10,11 in addition to these risks, the world health organization (who) international agency for research in cancer (iarc) has classified stps as a grou one carcinogen, i.e. substances that are definitely carcinogenic to humans.12 substances in group two a are probably carcinogenic to humans and substances in group two b are possibly carcinogenic.12 toxic heavy metal s are found in tobacco leaves and in processed tobacco products like cigarettes and stps; this is most probably due to the addition of ash, used as a binding factor for the other agents, and lime, used to alkalinise the product.13 in addition, these metals, which occur in polluted air, are absorbed from the soil.14 there are a variety of toxic metals found in stps but the main health concerns arise from cadmium (cd), nickel (ni), chromium (cr) and lead (pb). the first three have been declared by the iarc as a group one carcinogen, and the fourth one as a group two a probable human carcinogen.15 cd is very toxic to bones, the nervous system and kidneys, and can accumulate in the lenses of the eyes and cause cataracts.14 a high intake of cd can compete with zinc for biological binding sites, which affects mostly the kidney and, to a lesser extent, the reproductive system.16 pb can accumulate in bones and cause toxic developmental effects. in adults, pb is known to induce renal tumors and increase blood pressure and the risk of cardiovascular diseases. moreover, the brain is one of the organs most affected by this metal; pb exposure has been found to correlate with reduced cognitive development, decreased intelligence quotient levels and poor learning outcomes in children.17,18 ni, along with most of the metals mentioned previously, can cause inflammatory responses; in most cases, this results in allergic contact dermatitis inflammations.19 ni also causes oral allergic contact sensitisation.20 the chronic irritation-induced inflammation of epithelial tissue has long been associated with the risk of neoplastic changes.21,22 pb, cd and arsenic are toxic at much lower levels than ni.16 the analysis of heavy metals such as cd and pb in stps is an important area of study since these elements are non-biodegradable, have long biological half-lives and have the tendency to accumulate in different organs of the body, leading to unwanted toxic effects.23 hexavalent chromium (cr vi) is also considered a group one carcinogen and has been identified in cigarette smoke and ash; in contrast, low levels of chromium oxide (cr iii) are required nutritionally and, if lacking, cause people to experience immune system sensitisation.24 a who study on tobacco product regulation suggested that the cr in tobacco is oxidised as cr iii.14 out of more than 2,500 carcinogenic chemical substances, 28 have been identified in the stp snuff. however, the chemical composition of tobacco changes from year to year due to any given plant’s growth factors and geographical location, as well as the different processing methods such as curing, fermentation, mixing, packing and storage.12 different components lead to different health risks. the most dangerous components in stps are nicotine (due to its addictive nature); carcinogenic tobacco-specific nitrosamines; nitrosodimethyamine; polycyclic aromatic hydrocarbons like benzo(a) pyrene, and toxic heavy metals. the latter is the target of this study. in the last two decades, stps have started to gain popularity in oman, especially among young people. afzal is considered to be a snuff tobacco, or a type of moist stp. it is prohibited by law in oman, yet it is still sold. afzal is used by applying a pinch of the product between the lips and the upper or lower gums.12 users then sucks the juice from the afzal for varying periods of time, often up to 30 min, and subsequently spit out the rest. its composition varies due to the differences in the unmonitored and unstandardised manufacturing processes and the various additives that are mixed in with the dried tobacco [figure 1]. afzal has gained popularity in oman because of its cheap price and easy availability as well as the lack of awareness about its dangers. to the best of the authors’ knowledge, no study has been previously conducted analysing the heavy metal content of afzal in oman; thus, this report is the first of its kind. the objectives of the study were to analyse four potential toxic heavy metals (cd, pb, ni and cr) in omani afzal and compare the results with an international standard. methods this study analysed the heavy metal content of afzal between march and june 2013. a single sample of afzal weighing 4 kg was purchased personally by the investigators from one source in order to maintain uniformity. the sample was labelled with the date of purchase and the product was kept refrigerated at 4 °c in plastic bags until analysis. three samples of afzal were dried to determine nawal al-mukhaini, taher ba-omar, elsadig eltayeb and aisha al-shehi clinical and basic research | e351 their moisture content using the method developed by the centers for disease control and prevention federal register in 2009.25 subsequently, 15 g samples of afzal were measured using a weighing moisture dish and placed uncovered in an oven at 99 ± 1 °c for three hours. samples were then removed from the oven, covered and cooled to room temperature in a desiccator for approximately 30 min to prevent the reabsorption of moisture from the air. after drying, the samples were ground to form a homogenous powder. thereafter, the samples were digested prior to heavy metal analysis. the elemental analysis of the heavy metal content of the afzal was performed using an aurora m90™ inductively coupled plasma-mass spectrometry (icp-ms) system, software version v3.0 b797, firmware version 1.87 (bruker corp., billerica, massachusetts, usa) coupled with manual injection of the samples. tuning solution standards were used to calibrate the icp-ms system. all solutions were prepared with analytical reagent grade chemicals. deionised water was used exclusively throughout the study by using the milli-q integral water purification system (millipore corp., bedford, massachusetts, usa). reagent blank determinations were used to apply corrections to the instrument readings. blank and standard solutions were prepared in a similar acid matrix. three samples of 0.5 g of powdered afzal were mixed with 20 ml of 56% nitric acid of trace metal grade (merck kgaa, darmstadt, germany) for 30 min. then 4 ml of hydrochloric acid was added to each digestion vessel and the mixture was heated on a hot plate (bibby scientific ltd., staffordshire, uk) at 200 °c for 1–2 min and then allowed to cool for 30 min. the heating-cooling-reheating process was repeated until a clear solution was obtained. the contents of each digestion vessel were diluted with deionised water to obtain a final volume of 10 ml. this was then filtered with whatman® grade #42 filter paper (general electric health care, pittsburgh, pennsylvania, usa) and diluted to a volume of 50 ml with 2% nitric acid. this was subsequently injected into the icp-ms. all of the digestion processes took place in a well-ventilated fume hood and the researchers wore gloves and masks at all times when handling the acids. in order to estimate their content within the afzal product, five different concentrations of cd, pb, ni and cr solutions were prepared at 5, 10, 20, 30 and 50 parts per billion (ppb) for each metal standard using multielement calibration standards (high-purity standards, north charleston, south carolina, usa). the afzal samples and the standard solutions of cr, cd, pb and ni were aspirated into the icp-ms system using the auto-sampler. the instrumental operating conditions for the icp-ms system were as follows: the power was 1.40 kw; the cool gas flow rate was 18 l/min; the nebuliser gas flow was 1 l/min; the auxiliary gas flow rate was 1.8 l/min; the condenser temperature was 3 °c; the voltage was -12.00 v, -160.00 v and -388.00 v for extract lens 1, 2 and 3, respectively; the pole bias was 0.00 v; the fringe bias was -2.80 v and the pump rate was 5 rpm. the main run setup included peak jumping, with 100 sweeps, at a dwell time of 10,000 µsec and with a stabilisation delay of 60 sec. five replicates were made and the sampler cone identification and skimmer cone identification colour rendering index was off with a flow of 0 ml/min. there was external drift correction. the minimum daily intake afzal was estimated at 1–2 g; this was based on findings that the most common dosage of snuff or moist stps is a pinchsized amount.26 thus, the daily intake of heavy metals was calculated as follows: daily intake (µg/day) = metal concentration in a pinch-sized doze of afzal x number of times a pinch-sized dose of afzal was taken. this calculation assumed that users took a minimum figure 1 a & b: (a) a small plastic bag of afzal ready to be sold after other additives have been mixed in; (b) large package of loose afzal. determination of heavy metals in the common smokeless tobacco afzal in oman e352 | squ medical journal, august 2014, volume 14, issue 3 of a single average pinch-sized dose (2 g) per day of afzal. the average daily consumption of any stp in oman is unknown; therefore, the lowest probable daily consumption of afzal (2 g/day) was selected in calculating the lowest daily intake of metals. through 10 analyses of a blank sample and the application of the health canada official test method t-306,27 the limit of method detection and limits of detection and quantitation of the icp-ms system were calculated. other calculations using the same method were used to determine the concentration of metals in the samples on a wet weight or “as received” basis as afzal usually contains some moisture. the moisture content on this basis was 52% as determined by the following formula: analyte “as received” (µg/g) = dry matter analyte (µg/g) x 1(% moisture/100). the toxic heavy metal contents of afzal were then compared to the snus (moist powder tobacco) quality standards used by gothiatek® (swedish match, stockholm, sweden).28 appropriate quality-assurance procedures and precautions were taken to enhance the reliability of the results. samples were carefully handled to avoid cross-contamination. glassware was properly cleaned and all reagents used were of analytical grade. blank samples of deionised water were run to calculate the limits of detection and limits of quantification. blank procedural reagent samples were also used to subtract the results of all tested metal standards and samples injected into the icp-ms system. a calibration curve for each tested metal was constructed by using five different concentrations of the metal standard from the detection limit up to 5, 10, 20, 30 and 50 µg/g. excel spreadsheet software version 2007 (microsoft corp., redmond, washington, usa) and the icp-ms instrumental software were used for the statistical analysis. this study involved a chemical analysis of afzal and hence did not require ethical approval. results the method used for the icp-ms analysis of heavy metals is a validated method applied by the central analytical & applied research unit in the college of science at sultan qaboos university, oman. all analytical values of samples and metal standards obtained showed good precision and repeatability as reflected in the value of relative standard deviation percentage (rsd%), which was 8.14% [table 1]. for the same analyte level, the association of official analytical chemists sets the maximum acceptable value of rsd% at 11%.29 to further strengthen the reliability of the method and based on the calibration curves constructed for each metal standard, the r-value to determine linearity in all cases was 1 >r >0.99. the concentrations of the heavy metals (cr, ni, cd and pb) in 1 g of afzal are listed in table 2 as the mean values of the three samples of afzal and their corresponding standard deviations. the average concentrations in µg/g of the heavy metals in the three afzal samples were compared with the international gothiatek® standard, as shown in figure 2.28 table 1: relative standard deviation percentages of metal standards and afzal samples metal international standard afzal 1 at 5 ppb conc. 2 at 10 ppb conc. 3 at 20 ppb conc. 4 at 30 ppb conc. 5 at 50 ppb conc. sample 1 sample 2 sample 3 cr 1.13 0.67 0.42 0.93 0.58 1.19 1.88 1.04 ni 2.46 2.50 0.74 1.29 1.47 3.78 3.35 3.74 cd 0.85 1.87 1.28 1.09 1.03 8.13 1.78 8.14 pb 2.83 1.31 0.65 0.53 1.34 1.62 1.28 1.24 ppb = parts per billion; conc. = concentration; cr = chromium; ni = nickel; cd = cadmium; pb = lead. table 2: the concentrations of heavy metals in the tested afzal in µg/g cr ni cd pb sample 1 16.38 1.77 1.75 1.61 sample 2 15.85 1.57 1.95 1.7 sample 3 15.02 1.38 1.85 1.56 mean ± sd on a dry wt. basis 15.75 ± 0.69 1.57 ± 0.20 1.85 ± 0.10 1.62 ± 0.07 wet wt. basis* 7.56 0.75 0.89 0.78 mdl 0.0594 0.0586 0.059 0.0584 qdl 0.1782 0.1758 0.177 0.1752 cr = chromium; ni = nickel; cd = cadmium; pb = lead; sd = standard deviation; wt. = weight; mdl = method detection limit in µg/ml; qdl = quantitation detection limit in µg/ml. *weight of sample “as received”. nawal al-mukhaini, taher ba-omar, elsadig eltayeb and aisha al-shehi clinical and basic research | e353 when participants were informally questioned about their afzal use, most stated that they consumed a minimum of five doses per day; however, use patterns are also dependent on the level of addiction and the needs of the user. considering the assumption that the average pinch-sized dose of afzal is 2 g, the minimum estimated daily intake of heavy metals in afzal is shown in table 3. these were compared with the permissible daily limits set by the who and fao.30 discussion afzal consumption in oman has increased in the last two decades, especially among young people. this stp contains several heavy metals such as cr, cd, pb and ni. some of these heavy metals are carcinogenic.26 many studies have reported the presence of heavy metals in various types of stps, such as snuff and the alaskan iqmik,31 indian smokeless tobacco32 and pakistani stps.14,33 to the best of the authors’ knowledge, this is the first analysis of its kind in oman or among other arabian gulf countries. the results of this study provide very useful information about the concentrations of four heavy metals in afzal. a comparison of the contents of different stps from various countries may vary widely due to the heterogeneity of the tobacco plants, different processing techniques and storage conditions, and the additives used. however, the results of an analysis can give an idea of the most dangerous ingredients present in one particular brand of stp. from the heavy metals analysis, it was found that the cr and cd levels in the afzal sample exceeded the gothiatek® standards. in contrast, the concentrations of ni and pb were lower than the maximum levels indicated as acceptable by the standard. the order in which the elements occurred from greatest to least was as follows: cr (15.75 µg/g), ni (1.57 µg/g), pb (1.62 µg/g) and cd (1.85 µg/g). in a similar study of moist snuff and alaskan iqmik conducted in the usa, the order in which the elements occurred from greatest to least was as follows: ni (2.28 µg/g), cr (2.04 µg/g), cd (1.40 µg/g) and pb (0.45 µg/g).31 it seems that the stps in this study from the usa have lower levels of heavy metals than both the omani afzal sample of the current study and pakistani stps in a similar study.33 these types of variations are to be expected due to the aforementioned plant heterogeneity or variations in processing criteria around the world. the results of the current study can be used to formulate an idea about the indirect intake of those metals by the stp users. this was done by estimating their daily intake and then assessing whether the indirect intake of heavy metals was consistent with the permissible and acceptable daily levels set by the who and the fao.30 estimating the minimum levels of heavy metals in one dose of the selected afzal sample can help people better understand the possible health risks associated with using afzal, particularly in doses greater than the estimated intake. the estimated minimum daily intake of the selected heavy metals in this sample of afzal was below the permissible levels set by the fao and who, except for cr which was recorded in concentrations above the maximum permissible limit.30 moreover, the levels of cr found in the sample exceeded the maximum limits set by the swedish gothiatek® figure 2: the different concentrations of heavy metals in the tested afzal sample versus the swedish gothiatek® limits for snus (moist powder tobacco).28 table 3: permissible daily intake limits for the human consumption of the heavy metals according to the food and agriculture organization and world health organization and the estimated minimum daily intake of metals in single dose of the tested afzal metal permissible daily intake limit* in µg/ kg/day permissible daily intake limit for a 60 kg individual in µg/day estimated daily intake of metals in a single dose† of tested afzal per day in µg dry wt. wet wt. pb 5.0 300.0 3.24 1.56 cd 0.4–2.0 60.0 3.70 1.78 cr 0.1 6.0 31.50 15.12 ni 0.2 12.0 3.1 1.50 wt. = weight; pb = lead; cd = cadmium; cr = chromium; ni = nickel. *source: joint food and agriculture organization and world health organization expert committee. evaluation of certain food additives and contaminants.30 †for this calculation, a pinch-sized single dose of afzal was considered to be 2 g. determination of heavy metals in the common smokeless tobacco afzal in oman e354 | squ medical journal, august 2014, volume 14, issue 3 standards.28 unfortunately, the actual quantity of heavy metals ingested by a user may be higher than the minimum daily intake estimated in this study, due to variations in the blend of afzal as well as the user’s individual preferences. a single dose of afzal cannot be assigned a standard weight of 1–2 g like the tea-bag shaped swedish snus; each dose depends on the user’s level of addiction. in addition, the rate of extraction of the metals from the stps by the saliva will vary according to the individual. however, the moist form of the product fortunately has a lower metal content than that found in the dry samples analysed. nevertheless, the frequent use of this brand of stp allows the accumulation of nondegradable and dangerous elements in the user’s body.31 furthermore, excluding other potential sources of daily heavy metal intake such as from environmental and dietary sources, frequent use of afzal may put users at risk of exposure to combined metals. heavy metals have potential toxic and carcinogenic effects and some of them can cause severe health problems, even in trace amounts.16 conclusion this study gives a better understanding of the levels of selected heavy metals in afzal. the targeted metals were cr, ni, cd and pb. the results showed levels of cr and cd in afzal above the international limits, while the concentrations of ni and pb were lower than the maximum permissible limits. unfortunately, the estimated daily intake of the tested metals exceeded the allowable safe limits recommended by the fao and the who, rendering users at high risk of being poisoned or developing other undesirable side-effects. it is therefore recommended that the sale of illegal stps such as afzal be urgently regulated in oman. furthermore, it is important that education programmes aimed at the omani youth be implemented to raise awareness of the health risks and dangers of using this product. references 1. world health organization. the world health report 2002; reducing risks, promoting healthy life. from: www.who.int/ whr/2002/en/ accessed: may 2014. 2. wasnik ks, ughade sn, zodpey sp, inqole dl. tobacco consumption practices and risk of oro-pharyngeal cancer: a case control study in central india. southeast asian j trop med public health 1998; 29:827–34. 3. merchant a, husain ss, hosain m, fikree ff, pitiphat w, siddiqui ar, et al. paan without tobacco: an independent risk factor for oral cancer. int j cancer 2000; 86:128–31. doi: 10.1002/ (sici)1097-0215(20000401)86:1<128::aid-ijc20>3.0.co;2-m. 4. boffetta p, hecht s, gray n, gupta p, straif k. smokeless tobacco and cancer. lancet oncol 2008; 9:667–75. doi: 10.1016/s14702045(08)70173-6. 5. khan am, khan ms, ul haq n. oral snuff and carcinoma oesophagus. gomal j med sci 2009; 7:58–61. 6. bolinder g, de faire u. ambulatory 24-h blood pressure monitoring in healthy, middle-aged smokeless tobacco users, smokers, and nontobacco users. am j hypertens 1998; 11:1153–63. doi: 10.1016/s0895-7061(98)00137-x. 7. persson pg, carlsson s, svanström l, ostenson cg, efendic s, grill v. cigarette smoking, oral moist snuff use and glucose intolerance. j intern med 2000; 248:103–10. doi: 10.1046/j.13652796.2000.00708.x. 8. yildiz d, liu ys, ercal n, armstrong dw. comparison of pure nicotine and smokeless tobacco extract-induced toxicities and oxidative stress. arch environ contam toxicol 1999; 37:434–9. doi: 10.1007/s002449900537. 9. stegmayr b, johansson i, huhtasaari f, moser u, asplund k. use of smokeless tobacco and cigarettes: effects on plasma levels of antioxidant vitamins. int j vitam nutr res 1993; 63:195–200. 10. eliasson m, lundblad d, hägg e. cardiovascular risk factors in young snuff-users and cigarette smokers. j intern med 1991; 230:17–22. doi: 10.1111/j.1365-796.1991.tb00401.x. 11. hu fb, hedeker d, flay br, sussman s, day le, siddiqui o. the patterns and predictors of smokeless tobacco onset among urban public school teenagers. am j prev med 1996; 12:22–8. 12. world health organization international agency for research on cancer. iarc monographs on the evaluation of carcinogenic risks to humans: volume 89 smokeless tobacco and some tobacco-specific n-nitrosamines. from: www. monographs.iarc.fr/eng/recentpub/mono89.pdf accessed: nov 2013. 13. zakiullah u, saeed m, muhammad n, khan sa, gul f, khuda f, et al. assessment of potential toxicity of a smokeless tobacco product (naswar) available on the pakistani market. tob control 2012; 21:396–401. doi: 10.1136/tc.2010.042630. 14. world health organization. report on the scientific basis of tobacco product regulation: fourth report of a who study group. from: www.whqlibdoc.who.int/ publications/2012/9789241209670_eng.pdf accessed: nov 2013. 15. world health organization international agency for research on cancer. agents classified by the iarc monographs, volumes 1–109. from: www.monographs.iarc.fr/eng/ classification/classificationsgrouporder.pdf accessed: may 2014. 16. garcía-rico l, leyva-perez j, jara-marini me. content and daily intake of copper, zinc, lead, cadmium, and mercury from dietary supplements in mexico. food chem toxicol 2007; 45:1599–605. doi: 10.1016/j.fct.2007.02.027. 17. kauffman jf, westenberger bj, robertson jd, guthrie j, jacobs a, cummins sk. lead in pharmaceutical products and dietary supplements. regul toxicol pharmacol 2007; 48:128–34. doi: 10.1016/j.yrtph.2007.03.001. 18. ang hh. lead contamination in eugenia dyeriana herbal preparations from different commercial sources in malaysia. food chem toxicol 2008; 46:1969–75. doi: 10.1016/j. fct.2008.01.037. 19. linneberg a, nielsen nh, menné t, madsen f, jørgensen t. smoking might be a risk factor for contact allergy. j allergy clin immunol 2003; 111:980–4. doi: 10.1067/mai.2003.1394. 20. de rossi ss, greenberg ms. intraoral contact allergy: a literature review and case reports. j am dent assoc 1998; 129:1435–41. doi: 10.14219/jada.archive.1998.0078. 21. aggarwal bb, shishodia s, sandur sk, pandey mk, sethi g. inflammation and cancer: how hot is the link? biochem pharmacol 2006; 72:1605–21. doi: 10.1016/j.bcp.2006.06.029. nawal al-mukhaini, taher ba-omar, elsadig eltayeb and aisha al-shehi clinical and basic research | e355 22. coussens lm, werb z. inflammation and cancer. nature 2002; 420:860–7. doi: 10.1038/nature01322. 23. järup l. hazards of heavy metal contamination. br med bull 2003; 68:167–82. doi: 10.1093/bmb/ldg032. 24. sógor c, gáspár a, posta j. flame atomic absorption spectrometric determination of total chromium and cr(vi) in cigarette ash and smoke using flow injection/hydraulic highpressure sample introduction. microchem j 1998; 58:251–5. doi: 10.1006/mchj.1997.1552. 25. centers for disease control and prevention. laboratory protocol to measure the quantity of nicotine contained in smokeless tobacco products manufactured, imported, or packaged in the united states. federal register 2009; 62:24116– 19. 26. european network for smoking prevention (ensp). status report on oral tobacco. from: www.ensp.org/node/812 accessed: may 2014. 27. health canada. official methods for the collection of data on toxic constituents in chewing tobacco and snuff : official method t-306 determination of ni, pb, cd, cr, as, se and hg in whole tobacco. from: www.hc-sc.gc.ca/hc-ps/pubs/tobactabac/rc/index-eng.php accessed: may 2014. 28. swedish match. gothiatek® standard: product requirements. from: www.swedishmatch.com/en/snus-andhealth/gothiatek/gothiatek-standard/ accessed: may 2014. 29. gonzález ag, herrador ma. a practical guide to analytical method validation, including measurement uncertainty and accuracy profiles. trends analyt chem 2007; 26:227–38. doi: 10.1016/j.trac.2007.01.009. 30. joint food and agriculture organization and world health organization expert committee. evaluation of certain food additives and contaminants. from: www.whqlibdoc.who.int/ trs/who_trs_922.pdf accessed: may 2014. 31. pappas rs, stanfill sb, watson ch, ashley dl. analysis of toxic metals in commercial moist snuff and alaskan iqmik. j anal toxicol 2008; 32:281–91. doi: 10.1093/jat/32.4.281. 32. dhaware d, deshpande a, khandekar rn, chowgule r. determination of toxic metals in indian smokeless tobacco products. sci world j 2009; 9:1140–7. doi: 10.1100/ tsw.2009.132. 33. musharraf sg, shoaib m, siddiqui aj, najam-ul-haq m, ahmed a. quantitative analysis of some important metals and metalloids in tobacco products by inductively coupled plasmamass spectrometry (icp-ms). chem cent j 2012; 6:56. doi: 10.1186/1752-153x-6-56. marfan syndrome is one of the most common inherited autosomal genetic disorders of the connective tissue. the syndrome is inherited as a dominant trait, carried by the gene fbn1, which encodes the connective protein fibrillin-1. marfan has a reported incidence of 1 in 3,000 to 5,000 individuals.1–2 sufferers tend to be unusually tall, with long limbs and fingers. marfan affects many different organ systems; however, cardiovascular disease, particularly aortic root disease—leading to aneurysmal dilatation, aortic regurgitation, and dissection—is the main cause of morbidity and mortality associated with this disorder. the progressive and potentially fatal complications of marfan syndrome warrant an early diagnosis. it demonstrates the role of the family physician in making a correct diagnosis of the disease, despite late presentation, and the importance of proper follow-up, referral, and counselling. case report a 39-year-old omani man presented to the family medicine clinic of sultan qaboos university hospital complaining of a dry cough and progressive shortness of breath for 5 days. his shortness of breath was manifesting as orthopnoea and paroxysmal nocturnal dyspnoea. he reported that this was the first time he had experienced these problems. the patient denied having any chest pain and was not known to have any cardiac or respiratory disease, nor had he any history of prior hospitalisation. his four brothers had all died of sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 526-530, epub. 20th nov 12 submitted 16th oct 11 revision req. 30th apr 12, revision recd. 23rd may 12 accepted 27th jun 12 department of family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: nafisa77@squ.edu.om متالزمة مارفان تقرير ألول حالة من ُعمان التشخيص الصحيح ميكن أن ينقذ حياة نفي�صة �صمري، وفاء اآلفنة، ثورد ثيودور�صن، عبد العزيز املحرزي امللخ�ض: متالزمة مارفان ا�صطراب وراثي ي�صيب االأن�صجة ال�صاّمة ويوؤثر على العديد من اأجهزة اجل�صم. ومع ذلك، فاإن اأكرث امل�صاعفات االأَْبَهر َت�َصلُِّخ اإىل يوؤدي قد مما االأبهر، ال�رصيان جلذر التدريجي التو�صيع هو مارفان متالزمة من يعانون الذين املر�صى لدى اخلطرية ومتزقه، اأو ح�صول الَقَل�ُض االأَْبَهِرّي. اإّن الوقاية من هذه امل�صاعفات التي تهدد احلياة مهم جدا يف عالج هذه احلالة. ُندرج هنا حالة رجل ُعماين يبُلغ من الُعُمر 39 عاما م�صابا مبتالزمة مارفان، وكان بحاجة اإىل العناية الطبية نظرا الإ�صابته ب�صيق تدريجي يف التنف�ض، وقد اأجريت له عملية جراحية ُكربى ناجحة يف القلب. من املهم جدا ت�صخي�ض متالزمة مارفان مبكرا من اأجل اتخاذ اإجراءات وقائية ممكنة قبل حدوث امل�صاعفات. مفتاح الكلمات: متالزمة مارفان، َت�َصلُُّخ االأَْبَهر، اأم الدم االأبهري، مالمح متالزمة مارفان، علم جنت لت�صنيف االأمرا�ض، تقرير حالة، ُعمان. abstract: marfan syndrome is a heritable disorder of the connective tissue that affects many systems of the body. however, the most serious complication in patients with marfan syndrome is progressive enlargement of the aortic root, which may lead to aortic dissection, rupture, or aortic regurgitation. prevention of these life threatening complications is very important in the management of this condition. a 39-year-old omani man presented with progressive shortness of breath and eventually underwent major but successful cardiac surgery. it is very important to recognise marfan syndrome early as preventive actions are possible if the condition is diagnosed before complications occur. keywords: marfan syndrome; aortic dissection; aortic aneurysm; marfanoid habitus; case report; oman. marfan syndrome correct diagnosis can save lives *nafisa samir, wafa al-fannah, thord theodorson, abdulaziz al-mahrezi case report nafisa samir, wafa al-fannah, thord theodorson, abdulaziz al-mahrezi case report | 527 unknown causes before reaching their first year of life and his mother had died suddenly at the age of 64. his maternal uncle had died suddenly at age 25. the patient is the father of three children. he had no family history of hypertension, diabetes, heart disease, or any known inherited disorder. on examination, the patient’s respiratory rate was 24 breaths per minute with a collapsing pulse and a rate of 80 beats per minute. his blood pressure was 115/60 mmhg and oxygen saturation was 97%. he had a height of 182 cm and an arm span of 194 cm, giving him an arm span to height ratio of 1.06. he had hypermobile joints, a positive thumb sign, and a high arched palate with some element of teeth crowding. the patient had a pectus carinatum deformity and auscultation of the lungs revealed bilateral basal crepitations. a cardiovascular examination revealed a displaced heaving apex, dual heart sounds with palpable pulsation at the right parasternal area, a mid-systolic murmur and a grade 3–4/6 early diastolic murmur which was best heard at the right sternal area radiating to the carotid. he had no pedal oedema. an electrocardiogram (ecg) displayed a sinus rhythm with a heart rate of 80 beats per minute, but no other significant abnormality. a chest x-ray [figure 1] showed mediastinal widening and cardiomegaly with interstitial pulmonary oedema. a troponin i assay was negative. he was assessed by the cardiologist on call. left ventricular failure was suspected at that stage and intravenous furosemide was administered to the patient which led to significant improvement; therefore, he was discharged home on furosemide and carvedilol. four weeks later, a transthoracic echocardiogram (tte) was performed which showed a severely dilated left ventricle, severe aortic regurgitation, a dilated aortic root, and an ascending aorta (82 mm) with aortic dissection extending from the root to the ascending aorta. the patient was immediately sent for a contrast enhanced computed tomography (ct) of the chest. it demonstrated a large aneurysm of the ascending aorta measuring 9.9 x 9 cm with dissection and minimal pericardial effusion [figures 2 and 3]. the aortic arch and descending aorta were both normal. as a result, the patient was urgently figure 1: frontal chest x-ray showing mediastinal widening (top arrow) and dilatation of the ascending aorta (middle arrow) with signs of heart failure (bottom arrow). figure 2: axial computed tomography (ct) image through ascending (aa) and descending (da) thoracic aorta showing the aneurysmal dilatation of the ascending aorta (top-right arrow) with intimal flap (type a dissection, top-left arrow) and pericardial effusion (middle arrow). compare the diameter of ascending aorta with descending aorta (bottom arrow). figure 3: coronal reformat of the same computed tomography (ct) chest scan showing the extent of the aneurysmal dilatation of the ascending aorta as well as the dissection (both arrows). marfan syndrome correct diagnosis can save lives 528 | squ medical journal, november 2012, volume 12, issue 4 referred for surgical intervention. he underwent a bentall procedure that involved a composite graft replacement of the aortic valve, aortic root, and ascending aorta, with re-implantation of the coronary arteries into the graft. the patient recovered well from this major surgery with significant improvement of his symptoms. a postoperative chest x-ray also showed a remarkable improvement [figure 4]. the patient was discharged on the seventh postoperative day. following surgery, the patient was examined by an ophthalmologist. he was found to have myopia of -2.5 diopters but had no signs of ectopia lentis or any other ocular features of marfan syndrome. screening of other family members was arranged and two of his children, aged 4 and 5 years, were found to have marfanoid features along with aortic root dilatation on echo; they are currently being treated by a paediatric cardiologist. discussion marfan syndrome deserves particular attention by primary care physicians for two reasons. first, primary care is considered a patient’s first portal of entry into the health care system. second, there are helpful clinical clues that make it a screenable condition for primary care physicians. the ghent criteria [table 1] represent the standard for diagnosing marfan syndrome in accordance with clinical signs and family history.3–4 they employs a set of major and minor manifestations in numerous tissues, including the skeletal, ocular, cardiovascular, and pulmonary systems, and the dura, skin and integument. diagnosis is made if major criteria are identified in at least two different organ systems, and if there is involvement of a third organ system with either a major or minor manifestation. if a family history of marfan syndrome is positive then involvement table 1: major and minor ghent criteria for the diagnosis of marfan syndrome criteria major minor skeletal four of the following eight skeletal system features: • upper to lower body segment ratio <0.85 or arm span-height ratio >1.05 • scoliosis >20° or spondylolisthesis • arachnodactyly of fingers and toes, with positive thumb* and wrist signs • pes planus due to medial malleolus displacement • reduced extension at the elbows (<170º) • pectus excavatum requiring surgical intervention • pectus carinatum •protrusio acetabuli 2 of the major features, or 1 major feature and 2 of the following: • moderate pectus excavatu • joint hypermobility •high arched palate with crowding of teeth •facial features like dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, or downslanting palpebral fissures cardiovascular •dilatation of the aorta with or without aortic regurgitation •ascending aortic dissection • mitral valve prolapse • mitral regurgitation • calcification of the mitral valve before age 40 • dilatation of pulmonary artery before age 40 • dilatation/dissection of descending aorta before age 50 ocular ectopia lentis •flat cornea •increased axial length of globe • hypoplastic iris or ciliary muscle •myopia •retinal detachment. pulmonary none •spontaneous pneumothorax •apical blebs skin/integument none •cutaneous striae distensae •recurrent or incisional hernia dura •lumbosacral dural ectasia none source: ades l. csanz cardiovascular genetics working group. guidelines for the diagnosis and management of marfan syndrome.3 * = positive thumb sign: entire thumbnail protrudes beyond ulnar border of clenched fist; ¶ = positive wrist sign: thumb and fifth digit overlap when encircling the wrist. nafisa samir, wafa al-fannah, thord theodorson, abdulaziz al-mahrezi case report | 529 of only two organ systems, including one major criterion, is necessary for diagnosis.3–4 any doubt in the clinician's assessment warrants further diagnostic evaluation. over the past 30 years, advances in medical and surgical management of the cardiovascular problems, especially mitral valve prolapse, aortic dilatation, and aortic dissection, together with a reduction of physical and haemodynamic stresses have resulted in remarkable improvement in life expectancy of marfan syndrome sufferers.5–6 it is incumbent on the physicians who encounter these patients to emphasise preventive measures. these include periodic imaging of the aorta in order to evaluate its size and the progression of aortic enlargement; early administration of beta blockers mainly to delay aortic root enlargement, and prophylactic surgical repair when there is a high risk of dissection, rupture, or serious aortic regurgitation due to aortic dilatation.7 other pharmacological agents, such as angiotensin-converting enzyme inhibitors (acei), angiotensin receptor blockers (arb), and calcium-channel blockers (ccb) have all been used in patients who have unacceptable adverse events or no response to beta-blockers.7–11 initially, a biannual tte is recommended to determine the rate of aortic dilation; thereafter, an annual tte is recommended if aortic size remains stable. in instances of aortic dilatation of more than 45 mm, more frequent imaging of the aorta should be considered as rapid increase in size portends an increased risk of dissection.10 owing to these preventive measures, life expectancy has improved considerably.6,12 patients diagnosed with marfan syndrome should have appropriate counselling before choosing a career. physically demanding jobs should be avoided. these patients should also be cautioned against participating in high intensity exercise, particularly isometric exercises. instead, they should be encouraged to participate in lower intensity dynamic exercise.13 it is important for primary health care providers to be aware of the current recommendations related to physical activity in these patients.14 our case illustrates the importance of making a correct diagnosis of marfan syndrome. the initial assessment should include a comprehensive medical history that includes a personal and family history of cardiovascular disease. clinical assessment should include recognition of the physical stigmata of marfan syndrome, an eye examination, and a tte. the primary care physician can play a crucial role in the early detection of this syndrome and is also important in facilitating a multi-disciplinary approach through coordination of care with other health care professionals. in addition, the primary health care provider should be aware of the availability of pharmacological means to prevent or delay aortic dilatation. conclusion it is very important to recognise marfan syndrome early. despite the morbidity and mortality associated with marfan syndrome, early medical and surgical management can improve the life expectancy of many patients. advancing research holds the promise of further improvements. this case illustrates the importance of obtaining a complete family history, and the value of clinical correlation while assessing patients with unusual physical findings. early diagnosis of this disease by physicians will help in initiating treatment and appropriate management, including patient education and genetic counselling, and will provide an opportunity for family screening. i n f o r m e d c o n s e n t informed consent was obtained from the patient to publish this case report. a c k n o w l e d g e m e n t the authors would like to thank all squh figure 4: postoperative chest x-ray showing reduction in mediastinal widening (arrow). marfan syndrome correct diagnosis can save lives 530 | squ medical journal, november 2012, volume 12, issue 4 departments who contributed to the care of this patient. references 1. robinson pn, arteaga-solis e, baldock c, collodbéroud g, booms p, de paepe a, et al. the molecular genetics of marfan syndrome and related disorders. j med genet 2006; 43:769–87. 2. judge dp, dietz hc. marfan's syndrome. lancet 2005; 366:1965–76. 3. ades l. csanz cardiovascular genetics working group. guidelines for the diagnosis and management of marfan syndrome. heart lung circ 2007; 16:28– 30. 4. de paepe a, devereux rb, dietz hc, hennekam rc, pyeritz re. revised diagnostic criteria for the marfan syndrome. am j med genet 1996; 62:417–26. 5. pyeritz re. the marfan syndrome. annu rev med 2000; 51:481–510. 6. dean jcs. management of marfan syndrome. heart 2002; 88:97–103. 7. rossi-foulkes r, roman mj, rosen se, kramerfox r, ehlers kh, o'loughlin je, et al. phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the marfan syndrome. am j cardiol 1999; 83:1364–8. 8. shores j, berger kr, murphy ea, pyeritz re. progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in marfan’s syndrome. n engl j med 1994; 330:1335–41. 9. yetman at, bornemeier ra, mccrindle bw. usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the marfan syndrome. am j cardiol 2005; 95:1125–7. 10. brooke bs, habashi jp, judge dp, patel n, loeys b, dietz hc 3rd. angiotensin ii blockade and aorticroot dilation in marfan's syndrome. n engl j med 2008; 358:2787–95. 11. milewicz dm, dietz hc, miller dc. treatment of aortic disease in patients with marfan syndrome. circulation 2005; 11:150–7. 12. silverman di, burton kj, gray j, bosner ms, kouchoukos nt, roman mj, et al. life expectancy in the marfan syndrome. am j cardiol 1995; 75:157– 60. 13. braverman ac. exercise and the marfan syndrome. med sci sports exerc 1998; 30:387–95. زيادة مستويات الريسيستني يف حاالت اإلنتان داخل البطن ii االرتباط مع طالئع السايتوكينات االلتهابية، والفيزيلوجيا احلادة والتقييم الصحي املزمن تونق يوكتو يلمظ، مصطفى كرمي، كنان يلمظ دميرتاس، أوزق باسو قولو، اوقي تاسيالر، عمر ساكراك، كريسات ديكمن، تركان كارهان abstract: objectives: resistin, a hormone secreted from adipocytes and considered to be a likely cause of insulin resistance, has recently been accepted as a proinflammatory cytokine. this study aimed to determine the correlation between resistin levels in patients with intra-abdominal sepsis and mortality. methods: of 45 patients with intraabdominal sepsis, a total of 35 adult patients were included in the study. this study was undertaken from december 2011 to december 2012 and included patients who had no history of diabetes mellitus and who were admitted to the general surgery intensive care units of gazi university and bülent ecevit university school of medicine, turkey. evaluations were performed on 12 patients with sepsis, 10 patients with severe sepsis, 13 patients with septic shock and 15 healthy controls. the patients’ plasma resistin, interleukin-6 (il-6), tumour necrosis factor alpha (tnf-α), interleukin-1 beta (il-1β), procalcitonin, lactate and glucose levels and acute physiology and chronic health evaluation (apache) ii scores were studied daily for the first five days after admission. a correlation analysis of serum resistin levels with cytokine levels and apache ii scores was performed. results: serum resistin levels in patients with sepsis were significantly higher than in the healthy controls (p <0.001). a significant correlation was found between serum resistin levels and apache ii scores, serum il-6, il-1β, tnf-α, procalcitonin, lactate and glucose levels. furthermore, a significant correlation was found between serum resistin levels and all-cause mortality (p = 0.02). conclusion: the levels of resistin were significantly positively correlated with the severity of disease and were a possible mediator of a prolonged inflammatory state in patients with intra-abdominal sepsis. keywords: resistin; systemic inflammatory response syndrome; sepsis; shock; cytokines; apache ii; intraabdominal infections. امللخ�ص: الهدف: الري�سي�سنت هو هرمون تفرزه اخلاليا ال�سحمية، ويعترب �سببا حمتمال ملقاومة االنسولني، ويعد الآن اأحد طالئع ال�سايتوكينات اللتهابية. وتهدف هذه الدرا�سة اإىل حتديد الرتباط بني م�ستويات تركيز ري�سي�ستني عند املر�سى امل�سابني بالإنتان داخل البطن ومعدل الوفيات الطرق: �سملت هذه الدرا�سة )والتي اأجريت بني دي�سمرب 2011 ودي�سمرب 2012( 35 مري�سا من اأ�سل 45 مري�سا بالنتان داخل بق�سم املركزة الرعاية لوحدات املر�سى هوؤلء اأدخل بال�سكري. بال�سابة مر�سي تاريخ له مري�ض اأي هوؤلء بني من يكن ومل البطني، اجلراحة العامة بكليتي الطب يف جامعتي غازي وبيولنت اي�سي فيت برتكيا. ومت تقييم وت�سنيف احلالت كما يلي: 12 مري�سا بالنتان، و10 مر�سى بالنتان الوخيم، و13 مري�سا بال�سدمة النتانية، و15 من الأ�سحاء كمجموعة �سابطة. ومت قيا�ض تركيزات ري�سي�س�ستني واإنرتلوكني 6 وعامل نخر الورم الفا واإنرتلوكني -1بيتا وبرو كل�سيتونني والالكتات واجللوكوز يف م�سل الدم، اإ�سافة اإىل تقييم يومي لحراز الفيزيلوجيا احلادة والتقييم ال�سحي املزمن ii على مدي الأيام اخلم�سة الأوىل بعد الإدخال للم�ست�سفى. ومت عمل حتليل لالرتباط .ii بني تركيز ري�سي�س�ستني وتركيزات طالئع ال�سايتو كينات اللتهابية يف م�سل الدم، وتقييم الفيزيلوجيا احلادة والتقييم ال�سحي املزمن النتائج: وجد اأن م�ستويات ري�سي�ستني عند مر�سى النتان اأعلى منها يف املجموعة ال�سابطة من الأ�سحاء )p >0.001(، واأن هنالك عالقة معنوية إح�سائيا بني م�ستويات ري�سي�ستني يف م�سل الدم و الفيزيلوجيا احلادة والتقييم ال�سحي املزمن ii و تركيزات اإنرتلوكني 6 وعامل نخر الورم الفا واإنرتلوكني -1بيتا وبرو كل�سيتونني والالكتات واجللوكوز. وكذلك وجدت عالقة معنوية إح�سائيا بني تركيزات ري�سي�ستني ومعدلت الوفيات مبختلف امل�سببات )p = 0.02(. اخلال�صة: هنالك عالقة موجبة ومعنوية اإح�سائيا بني تركيزات ري�سي�ستني يف م�سل الدم ووخامة املر�ض. وميكن اأن نعد ري�سي�ستني و�سيطا حمتمال حلالة اللتهاب املتطاول عند مر�سى الإنتان داخل البطن. ال�سحي والتقييم احلادة الفيزيلوجيا �سايتوكينات؛ ال�سدمة؛ الإنتان؛ اجلهازية؛ اللتهابية ال�ستجابة متالزمة ري�سي�ستني؛ الكلمات: مفتاح املزمن ii؛ الإ�سابات داخل البطن. increased resistin levels in intra-abdominal sepsis correlation with proinflammatory cytokines and acute physiology and chronic health evaluation (apache) ii scores *tonguç u. yilmaz,1 mustafa kerem,2 canan y. demirtaş,3 özge pasaoǧlu,3 öge taşcilar,2 ömer şakrak,3 kürşat dikmen,2 tarkan karahan4 clinical & basic research sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e506−512, epub. 14th oct 14 submitted 18th jan 14 revision req. 6th mar 14; revision recd. 8th apr 14 accepted 24th apr 14 1department of general surgery, kocaeli university school of medicine, kocaeli, turkey; departments of 2general surgery, 3medical biochemistry and 4gastroenterology, gazi university, ankara, turkey *corresponding author e-mail: utku.yilmaz@kocaeli.edu.tr advances in knowledge this study provides information regarding the correlation of sepsis with blood resistin levels, using strict inclusion criteria. tonguç u. yilmaz, mustafa kerem, canan y. demirtaş, özge pasaoğlu, öge taşcilar, ömer şakrak, kürşat dikmen and tarkan karahan clinical and basic research | e507 intra-abdominal infections constitute a considerable portion of general surgery complications and their related mortality and morbidity are an important issue in intensive care (ic). patients with intra-abdominal infections have a mortality rate of approximately 30%; however, this rate exceeds 50% in cases of sepsis.1 although the prognosis of the patient depends on the underlying disease and the patient’s general condition, inflammatory responses can differ and be difficult to measure. with the onset of infection, inflammatory stimuli evoke an inflammatory response that leads to vascular permeability and chemotaxis by several activated cytokines to the inflamed area. the peritoneal surface contains many macrophages and lymphocytes.2,3 with the onset of inflammation, the inflammatory response can not only affect the peritoneal cavity, but also lead to sepsis and multi-organ dysfunction. although the aim of treatment is to resuscitate the patient and eliminate the source of infection, proinflammatory cytokines become the new therapeutic targets. even after the source of infection has been controlled, ongoing inflammation, or an increased inflammatory response in an individual, can inhibit the effectiveness of the treatment. therefore, identifying the response of the body to the sepsis would be helpful in determining the prognosis of the disease. identifying novel biomarkers for linking the state of inflammation and sepsis is crucial for the further risk evaluation and stratification of patients in ic units (icus). several approaches to risk stratification during icu admission have been applied, such as measuring inflammatory cytokines and implementing systems that rank illness severity.4,5 procalcitonin, which is a popular marker for infection and risk stratification among ic patients, is related to the severity of disease.6,7 individualised scoring systems are also gaining popularity, as an individual’s inflammatory response depends on several factors, such as their level of obesity and genetic background. adipose tissue functions not only as a fat deposit, but also as an endocrine organ, manufacturing adiponectin, resistin and proinflammatory cytokines. although resistin has been produced in adipocytes in animal models, the primary source of it in humans is in the macrophages.8 resistin also has proinflammatory properties;8,9 because of this, it has been used as an indicator of neonatal sepsis.10 in addition, longer term studies have shown correlations between resistin and inflammatory cytokines during the treatment of sepsis.11,12 the ability to predict the severity of an illness at an early stage is important. new markers of illness severity are required to ensure more accurate predictions, of which resistin may be one. as the mechanisms of intra-abdominal sepsis are related to resistin levels, the aim of this study was to determine if patients’ resistin levels were correlated with intra-abdominal sepsis and related mortality. intra-abdominal infections were targeted to achieve this as they involve large peritoneal surfaces and a variety of infections. resistin levels were also compared to common mortality prediction models used in icus, such as acute physiology and chronic health evaluation (apache) ii scores, blood procalcitonin levels and glucose levels. methods this prospective clinical study was undertaken from december 2011 to december 2012 and included 45 consecutive adult patients with intra-abdominal sepsis in the general surgery icus of gazi university and bülent ecevit university school of medicine in turkey. a control group was composed of 15 adult patients who had undergone abdominal surgery without any findings indicating a systemic inflammatory response. all patients were over 18 years old, with secondary peritonitis following intra-abdominal conditions, such as pancreatitis or a colon perforation. the patients were divided into a sepsis group and a septic shock group. sepsis was defined according to the criteria proposed by the american college of chest physicians/society of critical care medicine.13 at least three of the following criteria with an identifiable site of infection were accepted to signify sepsis: temperature of >38 or <36 °c; heart rate of >90 beats/minute; respiratory rate of >20 breaths/minute, and a white blood cell count of >12,000 or <4,000/ mm³. patients were considered to have septic shock if they had sepsis and an episode of cardiovascular collapse requiring vasopressor support. patients who had developed symptoms of sepsis less than 72 hours in this study, the levels of resistin were significantly positively correlated with the severity of the disease and were a possible mediator of a prolonged inflammatory state in patients with intra-abdominal sepsis. application to patient care this study demonstrates that measuring resistin levels may be helpful in predicting the severity of sepsis. these results highlight the need for future research on methods to decrease patients’ resistin levels. increased resistin levels in intra-abdominal sepsis correlation with proinflammatory cytokines and acute physiology and chronic health evaluation (apache) ii scores e508 | squ medical journal, november 2014, volume 14, issue 4 before their admission to the icu and those who developed symptoms of sepsis during treatment were included in the study. patients with diabetes, coronary artery disease, suspected pregnancy, acute or chronic renal failure, severe chronic liver disease or a score of less than 8 on the glasgow coma scale were not included in the study. patients who had had cardiac resuscitation or a major cardiac operation in the previous five days were also excluded. in addition, patients were excluded if it was found that the initial cause of sepsis was not intraabdominal. in total, 10 patients were excluded from the study, resulting in a sample of 35 patients. intra-abdominal infections were determined by microbiological investigations. sequential organ failure assessment (sofa) and apache ii scores for all patients were calculated daily for five consecutive days.9 the day following the diagnosis of sepsis, daily fasting venous blood samples were obtained each morning at 6 am from all patients. the blood samples were centrifuged for 10 minutes at 2,000 × g and stored at −80 °c. the patients were then kept under observation for 28 days. blood resistin levels were determined by the sandwich enzyme-linked immunosorbent assay (elisa) method using the #rd191016100 resistin human elisa immunoassay (biovendor inc., brno, czech republic) according to the manufacturer’s instructions (detection range: 0.1–50 ng/ml). serum levels of interleukin-6 (il-6), interleukin-1β (il1β) and tumour necrosis factor alpha (tnf-α) were determined using a fluorokine® multi-analyte profiling kit (r&d systems, inc., minneapolis, minnesota, usa) as described by the manufacturer and using a luminex® platform (luminex corp., austin, texas, usa). procalcitonin was assessed with a liaison® chemiluminescence analyser (diasorin, saluggia, italy) and plasma insulin levels were determined using a radioimmunoassay technique. all statistical analyses were performed using the statistical package for the social sciences (spss) version 12.0 (ibm corp., chicago, illinois, usa). parametric results were compared with analyses of variance using scheffé’s post hoc tests. results from the control group were not included in the correlation tests. non-parametric data (including the mean sofa and apache ii scores, age and body mass index [bmi] of the patients) were compared with chi-squared tests. a comparison of the mean blood resistin levels in male and female patients was also performed using chisquared tests. correlations between the serum resistin levels and the tnf-α, il-6, procalcitonin, il-1β, blood glucose and insulin levels, as well as the apache ii scores and patient ages, were analysed using bivariate pearson’s correlation coefficient tests, where p <0.05 was considered statistically significant. this study was approved by the gazi university clinical research ethic committee and written informed consent was obtained from each patient and, where relevant, their spouse. results a total of 35 patients were included in the study, of which 12 had sepsis and 23 had septic shock. among the subjects, 62% were male. the aetiology of intraabdominal sepsis among the patients included colon perforation (n = 8), infected pancreatic abscess (n = 6), gastric and duodenal perforations (n = 6), postoperative anastomotic leakage (n = 6) and biliary sepsis (n = 3), among others (n = 6). within the 28-day observation period, the mortality rate for both the sepsis and septic shock groups was 22.8%, with no fatalities occurring during the first five days of the study. the mortality table 1: comparison of the mean resistin, tnf-α, il-1β, il6, procalcitonin, blood glucose and blood insulin levels and apache ii and sofa scores among the control, sepsis and septic shock groups patient group mean ± sd p value control n = 15 sepsis n = 12 septic shock n = 23 resistin in µg/ml 3.6 ± 1.2 18.4 ± 1.2 42.1 ± 7.2 <0.001* <0.001** tnf-α in pg/ml 4.4 ± 1.0 31.0 ± 6.0 57.8 ± 6.8 <0.001* <0.001** il-1β in pg/ml 1.7 ± 0.2 7.7 ± 2.1 19.6 ± 5.2 0.001* 0.003** il-6 in pg/ml 92.0 ± 12.0 164.0 ± 28.0 389.2 ± 33.0 <0.001* <0.001** procalcitonin in ng/ml 0.42 ± 0.1 1.50 ± 0.1 3.5 ± 1.2 <0.001* <0.001** apache ii scores 11.1 ± 2.6 14.8 ± 2.9 0.03*** blood glucose in mg/dl 81.8 ± 9.2 126.2 ± 23.5 151.1 ± 29.0 0.04* 0.02** blood insulin in iu/ml 8.2 ± 2.1 10.2 ± 2.8 5.9 ± 3.3 0.04* 0.01** sofa scores 4.6 ± 2.1 8.6 ± 2.4 0.02*** tnf-α = tumour necrosis factor alpha; il-1β = interleukin-1 beta; il-6 = interleukin-6; apache = acute physiology and chronic health evaluation; sofa = sequential organ failure assessment; sd = standard deviation. *comparison between the control and sepsis groups using analysis of variance (anova) scheffé’s post hoc test; **comparison between the sepsis and septic shock groups using anova; ***comparison between the sepsis and septic shock groups using a chi-squared test. tonguç u. yilmaz, mustafa kerem, canan y. demirtaş, özge pasaoğlu, öge taşcilar, ömer şakrak, kürşat dikmen and tarkan karahan clinical and basic research | e509 rate was 16.6% in the sepsis group and 26.0% in the septic shock group; this was significantly different between the two groups (p = 0.02). the mean ages in the control, sepsis, and septic shock groups were 58.3 ± 5.6, 60.3 ± 12.3 and 64.7 ± 9.7 years, respectively. the mean bmis of the patients in the control, sepsis and septic shock groups were 26.6 ± 3.1, 24.5 ± 2.9 and 23.2 ± 4.5 kg/m2, respectively. no significant correlations were found between serum resistin levels and bmi (p = 0.87), nor did the resistin levels in the blood correlate with the patients’ ages in the sepsis or septic shock groups. there was also no significant difference in the mean resistin levels between male and female patients (p = 0.98). the mean resistin, tnf-α, il-6, procalcitonin, il-1β, blood glucose and blood insulin levels for all patients, as well as the apache ii and sofa scores, are shown in table 1. in comparison to the control group, the mean resistin, tnf-α, il-6, procalcitonin, il-1β and glucose levels were significantly elevated among the sepsis and septic shock groups (p <0.001). in addition, the mean resistin, tnf-α, il-6, procalcitonin, il-1β and glucose levels were significantly increased in the septic shock group compared to the sepsis group (p <0.001), whereas the mean blood insulin levels were significantly higher in the sepsis group than in the septic shock and control groups. a clinical comparison of the sepsis and septic shock groups using the patients’ sofa and apache ii scores (p = 0.02 and 0.03, respectively) found that these scores were significantly higher in the septic shock group than in the sepsis group. there were no significant correlations between the mean bmi and resistin levels (p = 0.92), or between the patients in the sepsis and septic shock groups with regards to their mean bmi (p = 0.987) or age (p = 0.867). there were significant positive correlations between the levels of resistin and tnf-α, il-1β, il-6 and procalcitonin [figures 1a–d], with resistin levels increasing as proinflammatory cytokine levels ncreased. the correlation between resistin levels and fasting glucose levels was also significantly positive (r = 0.44; p <0.001) [figure 2]. in contrast, blood insulin levels decreased as the disease worsened and a significant negative correlation was seen between resistin and serum insulin levels (r = 0.271; p = 0.011) [figure 3]. there was a significant positive correlation between apache ii (r = 0.51; p <0.001) and sofa (r = 0.45; p <0.001) scores with the blood resistin levels [figure 4]. the mean resistin levels in the surviving and non-surviving patients were not significantly different, at 33.4 ± 5.8 and 38.1 ± 4.5 µg/ml, respectively (p = 0.082). figure 1 a–d: the significant positive correlations between serum resistin levels and (a) tumour necrosis factor alpha levels (r = 0.753; p <0.001), (b) interleukin-6 levels (r = 0.553; p <0.001), (c) interleukin-1 beta levels (r = 0.753; p <0.001) and (d) procalcitonin levels (r = 0.715; p <0.001). tnf-α = tumour necrosis factor alpha; il-6 = interleukin-6; il-1β = interleukin-1 beta. increased resistin levels in intra-abdominal sepsis correlation with proinflammatory cytokines and acute physiology and chronic health evaluation (apache) ii scores e510 | squ medical journal, november 2014, volume 14, issue 4 discussion the findings of this study support the role of resistin as an acute-phase protein with a significant association to disease severity, as demonstrated by the the levels of proinflammatory cytokines and the sofa and apache ii scores among the studied population. as expected, no inflammatory response was seen in the control group. the blood resistin levels were significantly increased in the septic shock group in comparison to the control and sepsis groups. however, the resistin levels in the control group, which had a mean bmi of 26.6 kg/m2, were lower than those seen in a similar study from sweden by sundén-cullberg et al.11 this variation might be related to ethnic differences. in their study, sundén-cullberg et al. found no correlation between bmi and blood resistin levels.11 as with the current study, lehrke et al. observed that the blood resistin levels in non-survivors were higher than those of survivors, although this was not significant.14 both sundén-culberg et al. and lehrke et al. confirmed that adiposity appears to play no significant role in the increased levels of resistin induced by acute stress.11,14 in this regard, the results of the current study were similar to others in the literature. as mentioned earlier, the primary origin of resistin in humans is in the macrophages, as opposed to the adipose tissue.8 therefore, as expected, because human resistin is part of the inflammatory response to infection,7,15 resistin levels were not elevated among obese patients. lehrke et al. also demonstrated that the inflammatory cascade is sufficient and necessary for the production of resistin synthesis in the macrophages.14 the peritoneum is an important source of inflammatory cells, particularly macrophages. gene expression and protein expression of resistin have been shown to increase with inflammation.7 lipopolysaccharides also activate several cytokines and inflammatory pathways.8,16 after an early and short increase in the primary cytokines, secondary to lipopolysaccharide induction, the production and enhancement of resistin in macrophages is seen.11,14 it has been hypothesised that hyper-resistinaemia may be an important feature in maintaining persistent inflammation,11 as interleukins and lipopolysaccharides have been shown to also upregulate resistin levels.17 in the present study, the procalcitonin levels that increased with infection were significantly correlated with resistin levels. this finding supports the induction effect of lipopolysaccharides on resistin secretion. in addition to the laboratory findings, the patients’ clinical features, as measured by their apache ii scores, were also positively correlated with their resistin levels. therefore, increased resistin levels were associated with organ dysfunction and increased apache ii scores. the significant correlation between the apache ii scores and resistin levels demonstrates figure 2: the significant positive correlations between serum resistin levels and fasting glucose levels (r = 0.441; p <0.001). figure 3: the significant negative correlation between serum resistin levels and insulin levels (r = −0.271; p = 0.011). figure 4: the significant positive correlations between serum resistin levels and acute physiology and chronic health evaluation ii scores (r = 0.499; p <0.001). apache = acute physiology and chronic health evaluation. tonguç u. yilmaz, mustafa kerem, canan y. demirtaş, özge pasaoğlu, öge taşcilar, ömer şakrak, kürşat dikmen and tarkan karahan clinical and basic research | e511 that blood resistin levels can be used as an index in sepsis. one of the most important prognostic scoring systems in the icu is the sofa, which is usually an ongoing evaluation that uses continuous measurements.7 in contrast, the apache ii assessment is generally performed during the initial admission of the patient. both scoring systems were used throughout this study. koch et al. found no association between resistin levels at admission and the survival of patients in ic, or the disease severity as measured by apache ii scores.18 they stressed that high resistin levels were a predictor for an unfavourable prognosis only in nonsepsis cases and that these levels were independent of survival.18 however, the incidence of abdominal sepsis was only 18% in koch et al.’s study, as opposed to the current study where all of the patients had intraabdominal sepsis. in addition, the patients’ resistin levels in the current study were measured during the duration of their icu stay, rather than solely upon admission to the icu. although resistin has proven to be a reliable marker of non-septic inflammatory conditions, it has also been shown to act as a marker of septic inflammation.19 blood glucose control is an essential feature of sepsis treatment.20 in recent years, strict diet control, even for those without hypoor hyperglycaemia, has become the accepted treatment for sepsis patients.21 studies have shown that tnf-α induces insulin resistance via the ceramide accumulation in hepatic tissue.20,21 banerjee et al. found that peak cytokine and insulin resistance levels among mice began approximately six hours after the administration of lipopolysaccharides, which is close to the approximate time of resistin induction.22 as in the current study, banerjee et al. also demonstrated that increased levels of resistin were correlated with increased blood glucose levels and decreased levels of insulin.22 on the other hand, koch et al. observed that blood glucose, insulin and resistin levels were not associated in patients whose blood samples were collected promptly on admission.18 although resistin contributes to acute inflammatory responses, it may also have contributing effects within the inflammatory cascade. as such, with the induction of inflammation, macrophages would infiltrate the inflamed area and increase resistin production. the number of participants in the current study was limited due to the strict inclusion and exclusion criteria. although this appears to be a limitation, the sample size was similar to that of previous studies on resistin.10,15 the current study differed from others in that resistin levels were determined on five consecutive days in an attempt to gauge early phase changes. this extended period of observation was significant as patient risk stratification is generally only performed during admission or soon thereafter. the measurements were taken on five consecutive days in order to minimise the risk of missing the inflammatory response, thereby achieving more reliable results. the consecutive measurements of resistin level also enabled a strict evaluation of the patients’ clinical deterioration and may have increased the sensitivity of the analysis. additionally, this study included only patients with intra-abdominal sepsis. this was because it is the most frequently seen form of sepsis in general surgery clinics. although previous studies have measured resistin levels and correlated them with sepsis, those studies were performed during the treatment period as a time series.7,8 this differs to the current study, which measured resistin levels during the early phase of sepsis. conclusion in summary, blood resistin levels were significantly positively correlated with the severity of intraabdominal sepsis among this sample of patients. resistin may also have affected blood glucose metabolism among patients with sepsis. these results indicate that resistin plays an important role in sepsis. however, resistin levels were not predictive of patient survival and future studies are required to determine the clinical application of resistin levels in guiding specific therapies for intra-abdominal sepsis. acknowledgements a preliminary version of this study with a different patient population was presented at the 7th international conference on complexities in acute illness in cologne, germany, in 2008. the abstract of this preliminary study was previously published in the journal of critical care in june 2008 (vol. 23, iss. 2, p. 268). references 1. evans hl, raymond dp, pelletier sj, crabtree td, pruett tl, sawyer rg. diagnosis of intra-abdominal infection in the critically ill patient. curr opin crit care 2001; 7:117–21. 2. holzheimer rg, schein m, wittmann dh. inflammatory response in peritoneal exudate and plasma of patients undergoing planned relaparotomy for severe secondary peritonitis. arch surg 1995; 130:1314–20. doi: 10.1001/ archsurg.1995.01430120068010. 3. riese j, schoolmann s, denzel c, herrmann o, hohenberger w, haupt w. effect of abdominal infections on peritoneal and systemic production of interleukin 6 and monocyte chemoattractant protein-1. shock 2002; 17:361–4. 4. knaus wa, draper ea, wagner dp, zimmerman je. apache ii: a severity of disease classification system. crit care med 1985; 13:818–29. increased resistin levels in intra-abdominal sepsis correlation with proinflammatory cytokines and acute physiology and chronic health evaluation (apache) ii scores e512 | squ medical journal, november 2014, volume 14, issue 4 5. barriere sl, lowry sf. an overview of mortality risk prediction in sepsis. crit care med 1995; 23:376–93. 6. bülbüller n, doğru o, ayten r, akbulut h, i̇lhan ys, çetinkaya z. procalcitonin is a predictive marker for severe acute pancreatitis. ulus travma acil cerrahi derg 2006; 12:115–20. 7. meisner m, tschaikowsky k, palmaers t, schmidt j. comparison of procalcitonin (pct) and c-reactive protein (crp) plasma concentrations at different sofa scores during the course of sepsis and mods. crit care 1999; 3:45–50. doi: 10.1186/cc306. 8. patel l, buckels ac, kinghorn ij, murdock pr, holbrook jd, plumpton c, et al. resistin is expressed in human macrophages and directly regulated by ppar gamma activators. biochem biophys res commun 2003; 300:472–6. doi: 10.1016/s0006291x(02)02841-3. 9. silswal n, singh ak, aruna b, mukhopadhyay s, ghosh s, ehtesham nz. human resistin stimulates the pro-inflammatory cytokines tnf-alpha and il-12 in macrophages by nfkappab-dependent pathway. biochem biophys res commun 2005; 334:1092–101. doi: 10.1016/j.bbrc.2005.06.202. 10. aliefendioğlu d, gürsoy t, çağlayan o, aktaş a, ovalı f. can resistin be a novel indicator of neonatal sepsis? pediatr neonatol 2014; 55:53–7. doi: 10.1016/j.pedneo.2013.04.012. 11. sundén-cullberg j, nyström t, lee ml, mullins ge, tokics l, andersson j, et al. pronounced elevation of resistin correlates with severity of disease in severe sepsis and septic shock. crit care med 2007; 35:1536–42. doi: 10.1097/01. ccm.0000266536.14736.03. 12. vassiliadi da, tzanela m, kotanidou a, orfanos se, nikitas n, armaganidis a, et al. serial changes in adiponectin and resistin in critically ill patients with sepsis: associations with sepsis phase, severity, and circulating cytokine levels. j crit care 2012; 27:400–9. doi: 10.1016/j.jcrc.2012.04.007. 13. bone rc, balk ra, cerra fb, dellinger rp, fein am, knaus wa, et al. definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. the accp/sccm consensus conference committee: american college of chest physicians/society of critical care medicine. chest 1992; 101:1644–55. doi: 10.1378/chest.101.6.1644. 14. lehrke m, reilly mp, millington sc, iqbal n, rader dj, lazar ma. an inflammatory cascade leading to hyperresistinemia in humans. plos med 2004; 1:e45. doi: 10.1371/journal. pmed.0010045. 15. hillenbrand a, knippschild u, weiss m, schrezenmeier h, henne-bruns d, huber-lang m, et al. sepsis induced changes of adipokines and cytokines: septic patients compared to morbidly obese patients. bmc surg 2010; 10:26. doi: 10.1186/1471-2482-10-26. 16. cohen j. the immunopathogenesis of sepsis. nature 2002; 420:885–91. doi: 10.1038/nature01326. 17. lu sc, shieh wy, chen cy, hsu sc, chen hl. lipopolysaccharide increases resistin gene expression in vivo and in vitro. febs lett 2002; 530:158–62. doi: 10.1016/s00145793(02)03450-6. 18. koch a, gressner oa, sanson e, tacke f, trautwein c. serum resistin levels in critically ill patients are associated with inflammation, organ dysfunction and metabolism and may predict survival of non-septic patients. crit care 2009; 13:r95. doi: 10.1186/cc7925. 19. canoruç n, kale e, turhanoğlu ad, özmen ş, ogün c, kaplan a. plasma resistin and leptin levels in overweight and lean patients with rheumatoid arthritis. turk j med sci 2009; 39:447–51. 20. ali na, o’brien jm jr, dungan k, phillips g, marsh cb, lemeshow s, et al. glucose variability and mortality in patients with sepsis. crit care med 2008; 36:2316–21. doi: 10.1097/ ccm.0b013e3181810378. 21. hirasawa h, oda s, nakamura m. blood glucose control in patients with severe sepsis and septic shock. world j gastroenterol 2009; 15:4132–6. doi: 10.3748/wjg.15.4132. 22. banerjee rr, rangwala sm, shapiro js, rich as, rhoades b, qi y, et al. regulation of fasted blood glucose by resistin. science 2004; 303:1195–8. doi: 10.1126/science.1092341. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e143–145, epub. 21 jan 15 submitted 15 may 14 revision req. 3 jul 14; revision recd. 7 aug 14 accepted 19 aug 14 departments of pediatrics & neonatology, faculty of medicine, suez canal university, ismailia, egypt *corresponding author e-mail: agomran1@yahoo.com متالزمة بارت مع تشوه األذن اأحمد عمران، داليا االإمام، رمي مبارك، حممد اإبراهيم، �ضونيا ال�رضقاوي bart syndrome with ear malformation *ahmed omran, dalia elimam, reem a. e. mobarak, mohammed ibrahim, sonia el-sharkawy bart syndrome was first described by bart et al. in 1966 with a constellation of congenital localised absence of skin (clas), congenital epidermolysis bullosa (eb) and associated nail abnormalities.1 this article reports a case of bart syndrome with ear malformation in a female egyptian figure 1a–e: photographs showing a case of bart syndrome with ear malformation in a female egyptian newborn. a: well-demarcated non-inflammatory skin defects covered by a red thin translucent membrane localised to the nose, around both wrist joints, the front of the left knee, dorsum of both feet, around both ankle joints and around the lower third of the legs. b: two areas of ulcerations on the back. c: dysplastic nails and absent skin over the dorsum of the hand, sparing the fingertips. d: malformed ear with attached helix to the underlying skin and small areas of absent skin around the ear. e: dryness and extension of the old skin lesions and the appearance of multiple bullous lesions was noted over the upper and lower limbs. interesting medical image bart syndrome with ear malformation e144 | squ medical journal, february 2015, volume 15, issue 1 newborn. to the best of the authors’ knowledge, this is the first report of bart’s syndrome in an egyptian family. a female preterm newborn (with a gestational age of 35 weeks) was referred at birth to the neonatal intensive care unit of suez canal university hospital, ismailia, egypt, in february 2014. she presented with multiple areas of congenital clas associated with nail dystrophy and malformed ears. the parents were consanguineous and had previously had three daughters with the same condition who had subsequently died at the ages of three hours, four hours and seven days old, respectively. the current neonate was the sixth child born to the couple. on physical examination, the newborn showed sharply demarcated, bilateral non-inflammatory skin defects covered by a red thin translucent membrane localised to the dorsum of both hands and around both wrist joints, the dorsum of both feet and around both ankle joints, around the umbilicus, anterior aspect of the left knee and nose [figure 1a] and over the back [figure 1b]. dysplastic nails were also observed, as well as bilateral malformed ears in the form of adherent auricles attached to the underlying skin and bilateral hallux hypoplasia [figures 1c & d]. laboratory investigations revealed a total leukocyte count of 2,300/cmm, c-reactive protein levels of 28 mg/dl, normal blood chemistry and blood gases and a negative skin swab for aerobic bacteria. the newborn was managed with systemic vancomycin and ceftazidime initiated empirically in addition to local topical fusidic acid with atraumatic dressings for the skin lesions. at day of life (dol) two, the infant began to develop disseminated bullous skin lesions mainly over the upper and lower limbs and a mucous membrane of the mouth. oozing, dryness and extension were observed in the old skin lesions [figure 1e]. at dol four, the baby developed severe neonatal sepsis with depressed activity as well as extensive lesions in the lips, on the mucous membranes of the mouth and larynx with yellowish endotracheal aspirate. the neonate died on dol four due to severe neonatal sepsis, septicshock and metabolic acidosis. the rapid progression and fatal course of the disease interrupted the planned ultrastructural, immunohistological and genetic link-age investigations. comment bart syndrome is one type of dominant dystrophic eb. in some families, a link to the gene for type vii collagen has been demonstrated, suggesting that this is the mutational site.2 the diagnosis of aplasia cutis congenita, including bart syndrome, is primarily a clinical diagnosis based on the classical cutaneous findings; the extent of involvement depends on the mode of inheritance.3 in the family of the current case, only female infants were affected. this raises questions regarding whether gender is involved in the phenotypic variation and severity of bart syndrome. this case may therefore support the hypothesis of wakasugi et al., who suggested that the expression of symptoms might differ depending on the gender of the affected individual.4 the similarity of defects and symptoms in all reported cases, as well as in this patient, strongly suggests that clas in bart syndrome is not solely associated with a mechanical aetiology, but may follow blaschko’s lines, particularly with regards to the localisation of lesions to the limbs.5 other areas exposed to friction and trauma, such as the skin around the oral cavity, nose and ears, can also be affected. nail changes include congenital absence in terms of nail dystrophy or progressive loss. this reported case of bart syndrome was diagno-sed clinically, postnatally. a skin biopsy is essential in establishing an accurate postnatal classification of inherited eb. the biopsy sample should be examined for a combination of ultra structural and antigenic features by transmission electron microscopy, immunofluorescence antigenic mapping and eb-related monoclonal antibody investigations.6 fetoscopies have been performed successfully to diagnose inherited eb prenatally; fetal skin biopsy specimens for ultrastructural analysis are obtained via transmission electron microscopy in order to identify possible structural defects in the fetal skin.7 however, fetal skin biopsies have gradually been superseded by dna-based diagnostic screening using fetal dna from amniotic fluid cells or chorionic villi samples.8 despite a strong family history, a prenatal diagnosis in the current patient was not attempted due to the expense of the required tests and procedures. septicaemia, electrolyte imbalances, protein loss and failure to thrive complicate severe exudative skin lesions and often lead to death in cases of bart syndrome.9 septicaemia was also the cause of death in this case. patients with bart syndrome can be successfully treated with the use of topical antimicrobial drugs and sterile dressing pads for prophylaxis of secondary infections. in infants older than two months, the use of silver sulfadiazine cream and the early debridement of lesions with closed dressings has been shown to improve survival and quality of life for affected patients. rosmaninho et al. reported the complete healing of prominent milia after three months; however, blistering of the lesions recurred.10 extra-cutaneous involvement has also ahmed omran, dalia elimam, reem a. e. mobarak, mohammed ibrahim and sonia el-sharkawy interesting medical image | e145 been observed in survivors, commonly reported as mucosal involvement of the gastrointestinal tract, genitourinary tract and eyes. corrective gene therapy is the ideal therapy for eb, but more research is required prior to its utilisation in clinical practice. cell-based therapies using fibroblasts and bone marrow cells have recently attracted considerable attention and may lead to effective results.11 references 1. bart bj, gorlin rj, anderson ve, lynch fw. congenital localized absence of skin and associated abnormalities resembling epidermolysis bullosa: a new syndrome. arch dermatol 1966; 93:296–304. doi: 10.1001/archderm.1966.01600210032005. 2. gruis na, bavinck jn, steijlen pm, van der schroeff jg, van haeringen a, happle r, et al. genetic linkage between the collagen vii (col7a1) gene and the autosomal dominant form of dystrophic epidermolysis bullosa in two dutch kindreds. j invest dermatol 1992; 99:528–30. doi: 10.1111/1523-1747. ep12658066. 3. frieden ij. aplasia cutis congenita: a clinical review and proposal for classification. j am acad dermatol 1986; 14:646– 60. doi: 10.1016/s0190-9622(86)70082-0. 4. wakasugi s, mizutari k, ono t. clinical phenotype of bart’s syndrome seen in a family with dominant dystrophic epidermolysis bullosa. j dermatol 1998; 25:517–22. 5. duran-mckinster c, rivera-franco a, tamayo l, de la luz orozco-covarrubias m, ruiz-maldonado r. bart syndrome: the congenital localized absence of skin may follow the lines of blaschko report of six cases. pediatr dermatol 2000; 17:179– 82. doi: 10.1046/j.1525-1470.2000.01747.x. 6. pfendner eg, bruckner a, conget p, mellerio j, palisson f, lucky aw. basic science of epidermolysis bullosa and diagnostic and molecular characterization: proceedings of the iind international symposium on epidermolysis bullosa, santiago, chile, 2005. int j dermatol 2007; 46:781–94. doi: 10.1111/j.1365-4632.2007.03307.x. 7. rodeck ch, eady ra, gosden cm. prenatal diagnosis of epidermolysis bullosa letalis. lancet 1980; 1:949–52. doi: 10.1016/s0140-6736(80)91404-x. 8. fassihi h, eady ra, mellerio je, ashton gh, doppinghepenstal pj, denyer je, et al. prenatal diagnosis for severe inherited skin disorders: 25 years’ experience. br j dermatol 2006; 154:106–13. doi: 10.1111/j.1365-2133.2005.07012.x. 9. narter f, büyükbabani n, yararlı h, oztürk s, ergüven m. bart’s syndrome associated with pyloric and choanal atresia. turk j pediatr 2013; 55:214–17. 10. rosmaninho a, machado s, selores m. bart syndrome. int j dermatol 2014; 53:e54–5. doi: 10.1111/j.1365-4632.2012. 05481.x. 11. sawamura d, nakano h, matsuzaki y. overview of epidermolysis bullosa. j dermatol 2010; 37:214–19. doi: 10.1111/j.1346-8138.2009.00800.x. departments of 1physiology and 3child health, sultan qaboos university hospital, muscat, oman; 2department of child health, oman medical specialty board, muscat, oman *corresponding author e-mails: koul@squ.edu.om and roshankoul@hotmail.com اإلعتالل العصيب يف العصب الشظوي املشرتك بسبب انقباض ربطة أمنيوسية �سوزان النبهانية، حمدة العربية، انت�سار العربية، برابهاكاران فينوغوبال، رو�سان كول common peroneal nerve mononeuropathy due to an amniotic constriction band susan al-nabhani,1 hamdah al-abri,2 instisar al-abri,1 prabhakaran venugopal,1 *roshan koul3 a six-year-old boy was referred to the neurophysiology clinic at the sultan qaboos university hospital (squh), muscat, oman in january 2015 for an evaluation of right foot drop. his parents had noticed an abnormality in his right leg since birth. he had previously been diagnosed with foot drop and had undergone corrective surgery in august 2012. however, examination of the right lower limb revealed a ring-like band at the proximal end of the leg just below the knee [figure 1]. upon inspection, it was noted that the right leg was thin and there was wasting of the anterior compartment group of muscles. the child’s plantar flexion was normal with a power of grade 5/5; however, there was evidence of foot drop and ankle jerk was present. the foot was also observed to be small. a nerve conduction study revealed right common peroneal nerve neuropathy, although the tibial nerve conductions were normal. magnetic resonance imaging was not performed as additional information regarding the status of the common peroneal nerve was not required. comment amniotic constriction band syndrome (acbs) is caused by the entanglement of the fetus with fibrous strings of the amniotic membrane.1 this entanglement can cause a number of birth defects which vary depending on the affected body part; the distal portion of the extremities is most commonly involved.2 the effect of the constriction may be mild or severe, resulting in loss of body parts such as the fingers or limbs. furthermore, acbs can cause miscarriages if the band becomes wrapped around the umbilical cord. acbs is not genetic and is unlikely to recur in figure 1a & b: photographs of the (a) front and (b) side views of an amniotic constriction band (arrows) on the right leg of a six-year-old male child with associated common peroneal nerve mononeuropathy. interesting medical image sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e565–566, epub. 23 nov 15 submitted 5 feb 15 revision req. 21 apr 15; revision recd. 27 apr 15 accepted 30 apr 15 doi: 10.18295/squmj.2015.15.04.023 common peroneal nerve mononeuropathy due to an amniotic constriction band e566 | squ medical journal, november 2015, volume 15, issue 4 references 1. walter jh jr, goss lr, lazzara at. amniotic band syndrome. j foot ankle surg 1998; 37:325–33. doi: 10.1016/s10672516(98)80070-7. 2. tada k, yonenobu k, swanson ab. congenital constriction band syndrome. j pediatr orthop 1984; 4:726–30. doi: 10.109 7/01241398-198411000-00013. 3. jones nf, smith ad, hedrick mh. congenital constriction band syndrome causing ulnar nerve palsy: early diagnosis and surgical release with long-term follow-up. j hand surg am 2001; 26:467–73. doi: 10.1053/jhsu.2001.24130. 4. trojan da, cashman nr. post-poliomyelitis syndrome. muscle nerve 2005; 31:6–19. doi: 10.1002/mus.20259. future pregnancies. early surgical intervention is the treatment of choice for acbs. compression neuropathy is thought to be one form of acbs.2,3 in a case series of 83 patients with acbs, tada et al. reported club foot deformities due to compression of the common peroneal nerve in 10 patients.2 constriction bands should therefore be considered when examining children with club foot. the current patient was the first case of acbs resulting in peripheral nerve entrapment seen at squh. post-poliomyelitis foot drop is due to the involvement of anterior horn cells of the spinal cord, resulting in a wider pattern of weakness and does not follow the distribution of a single nerve.4 physiotherapy and tendon transplants are the main treatment options for this condition. http://dx.doi.org/10.1016/s1067-2516%2898%2980070-7 http://dx.doi.org/10.1016/s1067-2516%2898%2980070-7 http://dx.doi.org/10.1097/01241398-198411000-00013 http://dx.doi.org/10.1097/01241398-198411000-00013 http://dx.doi.org/10.1053/jhsu.2001.24130 http://dx.doi.org/10.1002/mus.20259 sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e292–296, epub. submitted 11 jun 14 revision req. 21 oct 14; revision recd. 10 nov 14 accepted 7 dec 14 1diagnostic imaging & radiotherapy programme, faculty of health sciences, university kebangsaan malaysia, kuala lumpur, malaysia; 2kpj healthcare university college, nilai, malaysia *corresponding author e-mail: izdiharkamal@yahoo.com تقدير اجلرعة الغدية املتوسطة بواسطة طرز ذاتية للتعرض لألشعة السينية يف الرتكيب املقطعي الرقمي للثدي اإزدهار كمال، كاناجا ك �سيال، ونوال م�سطفى abstract: objectives: the aim of this research was to examine the average glandular dose (agd) of radiation among different breast compositions of glandular and adipose tissue with auto-modes of exposure factor selection in digital breast tomosynthesis. methods: this experimental study was carried out in the national cancer society, kuala lumpur, malaysia, between february 2012 and february 2013 using a tomosynthesis digital mammography x-ray machine. the entrance surface air kerma and the half-value layer were determined using a 100h thermoluminescent dosimeter on 50% glandular and 50% adipose tissue (50/50) and 20% glandular and 80% adipose tissue (20/80) commercially available breast phantoms (computerized imaging reference systems, inc., norfolk, virginia, usa) with auto-time, auto-filter and auto-kilovolt modes. results: the lowest agd for the 20/80 phantom with auto-time was 2.28 milligray (mgy) for two dimension (2d) and 2.48 mgy for three dimensional (3d) images. the lowest agd for the 50/50 phantom with auto-time was 0.97 mgy for 2d and 1.0 mgy for 3d. conclusion: the agd values for both phantoms were lower against a high kilovolt peak and the use of auto-filter mode was more practical for quick acquisition while limiting the probability of operator error. keywords: thermoluminescent dosimetry; breast; mammography; radiation dosage. امللخ�ص: الهدف: يهدف هذا البحث لدرا�سة اجلرعة الغدية املتو�سطة )ج غ م( يف خمتلف مكونات الثدي بوا�سطة اختيار عامل الطرز الذاتية للتعر�ض. واأجريت هذه الدرا�سة بجمعية ال�رشطان القومية يف كواال المبور مباليزيا بني فرباير 2012م وفرباير 2013م، وذلك با�ستخدام الن�سف قيمة وطبقة الهواء �سطح مدخل املادة( يف املنطلقة الطاقة )وحدة كريما حتديد ومت الرقمي. اال�سعاعي الثدي ت�سوير جهاز با�ستعمال املقيا�ض اللمعي احلراري للجرعات ال�سعاعية )h 100( يف ثدي �سبحي )50/50 و20/80( متوفر جتاريا ب�رشكة اأنظمة الت�سوير املحو�سب-نورفولك-فريجينا-الواليات املتحدة االأمريكية، والذي يعمل بطراز ذاتي بالن�سبة للتوقيت والرت�سيح ونظام k-v. وتو�سلت الدرا�سة اإىل اأن اأقل ج غ م لل�سبح 20/80 ذاتي التوقيت كان 2.28 ميلي قري لبعدين و2.48 ميلي قري لثالثة اأبعاد. بينما كان اأقل ج غ م لل�سبح 50/50 ذاتي التوقيت هو 0.97 ميلي قري لبعدين و1.0 ميلي قري لثالثة اأبعاد. ووجد اأن قيم ج غ م لل�سبحني كانت اأقل على خلفية ذروة كيلو فولت، واأن ا�ستخدام طراز املر�سح الذاتي كان اأكرث عملية يف عملية االكت�ساب، واأقل احتماال حلدوث خطاأ من قبل م�سغل اجلهاز. مفتاح الكلمات: مقيا�ض اجلرعات اال�سعاعية اللمعي احلراري؛ ثدي؛ ت�سوير الثدي ال�سعاعي؛ اجلرعة اال�سعاعية. estimates of average glandular dose with auto-modes of x-ray exposures in digital breast tomosynthesis *izdihar kamal,1 kanaga k. chelliah,1 nawal mustafa2 it is generally assumed that the gland-ular tissue of the breast is most vulnerable to the induction of cancer by ionisation radiation.1 in order to calculate the average glandular dose (agd) of radiation in different breast compositions, parameters such as the half-value layer (hvl) and entrance surface air kerma (esak) have to be measured.2 the average glandular tissue dose in mammography is generally determined from published tables with knowledge of the breast entrance skin exposure, x-ray tube target material, beam quality (hvl), breast thickness and breast composition.3 in addition, the beam spectral quality, scatter control with compression and grid, detector characteristics, image processing and radiation dosage must be taken into consideration in order to optimise the agd.4 clinical trials and scientific investigations have found that, in digital mammography, a tungsten x-ray tube with rhodium (rh) and argentum (ag) filters is optimal for measuring all breast thicknesses, and will allow for important dosage reductions by approximately 30% while still maintaining excellent image quality.5 in february 2011, the food and drug administration (fda) approved tomosynthesis machines as safe for usage in the screening and diagnosis of breast cancer, as their two dimensional (2d) and three dimensional (3d) tomosynthesis images can reveal the online brief communication izdihar kamal, kanaga k. chelliah and nawal mustafa online brief communication | e293 internal breast architecture without distortion from tissue overlapping.6,7 in current clinical practice, autofilter is often used rather than the auto-time and autokilovolt (kv) modes as the latter require manual setup by the operator.8 however, there has been a need for further study to determine the best practice for screening mammography. the aim of this study was to assess the agd of radiation in two different breast compositions (50% glandular and 50% adipose [50/50] and 20% glandular and 80% adipose [20/80]) with auto-modes (auto-time, auto-filter and auto-kv) of exposure factor selection. table 1: parameters used for the assessment of the 6 cm thick 20% glandular and 80% adipose tissue (20/80) breast phantom mode of exposure hvl projection kvp mas target/ filter esak in mgy agd ± sd in mgy auto-time† 0.550 cc/2d 28 163 w/ag 5.62 2.62 ± 0.10 0.580 cc/2d 30 114 w/ag 5.48 2.60 ± 0.19 0.610 cc/2d 32 78 w/ag 4.76 2.30 ± 0.06 0.520 cc/2d 28 228 w/rh 9.16 2.82 ± 0.01 0.530 cc/2d 30 199 w/rh 7.94 2.67 ± 0.14 0.540 cc/2d 32 142 w/rh 6.83 2.28 ± 0.01* 0.580 cc/3d 32 59 w/al 6.93 2.48 ± 0.11* auto-filter 0.535 cc/2d 31 171 w/rh 7.01 2.44 ± 0.13 0.590 cc/3d 33 62 w/al 7.47 2.5 ± 0.16 auto-kv 0.535 cc/2d 31 150 w/rh 7.12 2.31 ± 0.40 0.580 cc/3d 32 62 w/al 7.34 2.61 ± 0.12 hvl = half-value layer; kvp = kilovolt peak; mas = milliampere per second; esak = entrance surface air kerma; mgy = milligray; agd = average glandular dose; sd = standard deviation; cc = craniocaudal; 2d = two dimensional; w = tungsten; ag = argentum; rh = rhodium; 3d = three dimensional; al = aluminium; auto-kv = auto-kilovolt. *lowest agd values for 2d and 3d images, respectively. †only 32 kvp available for the auto-time 3d image. table 2: parameters used for the assessment of the 4 cm thick 50% glandular and 50% adipose tissue (50/50) breast phantom mode of exposure hvl projection kvp mas target/ filter esak in mgy agd ± sd in mgy auto-time 0.550 cc/2d 28 55 w/ag 2.26 1.20 ± 0.20 0.580 cc/2d 30 65 w/ag 1.88 1.12 ± 0.04 0.610 cc/2d 32 33 w/ag 1.91 1.01 ± 0.15 0.520 cc/2d 28 96 w/rh 2.98 1.16 ± 0.03 0.530 cc/2d 30 45 w/rh 2.84 1.10 ± 0.03 0.540 cc/2d 32 33 w/rh 2.31 0.97 ± 0.32* 0.510 cc/3d 28 60 w/al 4.37 1.80 ± 0.136 0.550 cc/3d 30 38 w/al 3.32 1.28 ± 0.15 0.580 cc/3d 32 27 w/al 2.73 1.00 ± 0.01* auto-filter 0.520 cc/2d 28 91 w/rh 3.16 1.17 ± 0.01 0.522 cc/3d 29 58 w/al 3.74 1.33 ± 0.32 auto-kv 0.520 cc/2d 28 46 w/rh 3.21 1.32 ± 0.14 0.530 cc/3d 29 48 w/al 3.76 1.68 ± 0.17 hvl = half-value layer; kvp = kilovolt peak; mas = milliampere per second; esak = entrance surface air kerma; mgy = milligray; agd = average glandular dose; sd = standard deviation; cc = craniocaudal; 2d = two dimensional; w = tungsten; ag = argentum; rh = rhodium; 3d = three dimensional; al = aluminium; auto-kv = auto-kilovolt. *lowest agd values for 2d and 3d images, respectively. estimates of average glandular dose with auto-modes of x-ray exposures in digital breast tomosynthesis e294 | squ medical journal, may 2015, volume 15, issue 2 the original tabulation due to the use of a different x-ray spectrum. furthermore, in order to estimate the agd for breast tomosynthesis, dance et al. introduced t-factors for the calculation of breast dose from a single projection and t-factors for a complete exposure series from -7.5–7.5 degrees for 15 projection in less than four seconds of scanning time.13 the t-factor value for this study was between 0.93 and 1.0. the statistical analysis of the data was performed with statistical package for the social sciences (spss) version 18.0 (ibm corp., chicago, illinois, usa). the statistical significance of the overall differences between auto-modes was analysed using the one-way analysis of variance. results table 1 and table 2 show the parameters used in the experiment. the results were divided according to composition and thickness (6 cm 20/80 and 4 cm 50/50). agd values obtained from the experiment increased with the thickness of the phantom. the lowest agd for the fatty breast tissue (20/80) on auto-time was 2.28 mgy with tungsten (w)/rh anode/filter for 2d images and 2.48 mgy for 3d images [table 1]. meanwhile, for normal breast tissue (50/50), the lowest agd for the 2d images on auto-time was 0.97 mgy with w/rh anode/ filter and 1.0 mgy for 3d images [table 2]. with auto-time mode, the dosage was minimal compared with the two other modes (auto-filter and auto-kv). however for the 3d image, a tube voltage of 28 kvp and 30 kvp was insufficient to penetrate the 20/80 phantom due to the existence of a backup timer, which automatically stops the exposure when the time ends. therefore only the 32 kvp was able to penetrate the phantom.14 analysis of the 50/50 phantom was statistically significant, indicating that the agd value was influenced by different types of auto-modes (autofilter, auto-time and auto-kv) (f [2, 15] = 6.918; p <0.05). however, for the phantom 20/80, the analysis was not statistically significant, indicating that the agd values were not influenced by the different types of auto-modes (f [2, 15] = 0.495; p >0.05). discussion for the 20/80 breast phantom, the agd with autotime produced a lower dose with the rh filter, correlating with the manufacturer’s suggestion to use the w/rh combination for a breast phantom thickness between 4 and 7 cm.15 the ag filter should be considered for use on patients with fatty tissue methods between february 2012 and february 2013 a phantom study was conducted using a tomosynthesis digital mammography x-ray machine, the hologic® selenia® aws 5000 (hologic, bedford, massachusetts, usa). two types of commercially available breast phantoms (computerized imaging reference systems, inc., norfolk, virginia, usa) were used. the first tissue equivalent breast phantom was composed of 50/50 tissue with a thickness of 4 cm, while the second phantom was composed of 20/80 tissue with a thickness of 6 cm. a 100h thermoluminescent dosimeter (tld) was used to obtain the esak value. the experiment was repeated three times for each parameter in order to reduce any errors in measurement. the first experiment was conducted using the auto-filter mode to enable the automatic choice of the target, filter, kv peak (kvp) and milliampere per second (mas). for auto-time, the system automatically selected the mas but the operator manually selected the filter and kvp. for 2d images, two types of filter were used, ag and rh, while for 3d images only one filter was used, aluminium (al). each filter was used with 28, 30 and 32 kvp, respectively. finally, for auto-kv, the system automatically selected the kvp and mas while the operator selected the filter. a sachet containing three tlds was placed on the surface of the phantom, with the centre of the sachet 40 mm from the chest wall edge and centred with regards to the lateral direction. a further sachet of unexposed tlds was retained for background reading.9 tlds were calibrated in terms of air kerma at mammographic energies, using all anode/filter combinations as used in normal practice. in this study, an ionisation chamber was used to calibrate the tlds. the ionisation chamber was placed at the same effective point of the measurements and exposed to the same dose as the tlds. thus, the energy responses were consistent because they were calibrated at the same energies where the measurements were taken.10 in order to calculate the agd, the hvl for each kvp was also measured. the experimentally estimated agds were compared with theoretically calculated values based on methods indicated in earlier studies.11–13 according to methods proposed by dance et al. the agds in the current study were calculated using this equation: agd = k x g x c x s x t.11–13 in this equation, k is the esak value from the tld reading; factor g is the conversion factor of esak to agd; factor c corrects any differences in breast composition from 50% glandularity, and factor s corrects any differences from izdihar kamal, kanaga k. chelliah and nawal mustafa online brief communication | e295 and a thickness greater than 6 cm for dose reduction purposes. it is recommended that, for fatty tissue, all factors such as kvp, filter and compression should be optimised in order to obtain the lowest dose possible without compromising the image quality.16 with the breast phantom 50/50, the pattern was similar as the lowest agd was obtained using auto-time, followed by auto-filter and auto-kv. when the efficacy of different exposure modes are compared, the following factors should be considered: the radiation dose received by the patient, the image quality and the ease of use of the modes for the operator.17 in this study there was a significant dose change between the different modes of exposure, particularly for the 50/50 breast phantom. for 2d and 3d images, the 32 kvp with auto-time mode produced a low radiation dose, but when the kvp was high, the scatter radiation increased and therefore reduced the image contrast.18 therefore, unnecessary changes to the kvp should be avoided, especially for breasts with reduced thicknesses. furthermore, several research studies have shown that 28 kvp is the optimum kvp for the 50/50 breast phantom since it produces a high-quality image.4,19 in the current study, the autofilter mode automatically calculated 28 kvp as the tube output. the results of this study indicate that the autofilter mode is preferable for normal breast tissue (50/50) since this mode is automatic, fast and easy to operate. the 20/80 agd value showed no significant difference between the exposure modes. the difference between the kvp values was minimal for the 2d images. the auto-time used 32 kvp, the auto-filter used 31 kvp and the auto-kv used 31 kvp, meaning that the difference was only 1 kvp. therefore, there was no significant difference in the agd values when the exposure modes used were different. this finding was also found to be consistent with the 3d imaging. therefore the auto-mode did not have an obvious role in reducing the dose for fattier breast tissue. this is contrary to the findings of myung et al., which found differences in the agd values.17 however, their findings may have been due to the mammography system used, which could operate in three different modes of automatic optimisation of parameter: contrast (cnt), standard (std) and dose modes, which vary between low dose and high image quality.17 the cnt mode emphasised higher contrast and, therefore, higher image quality. the dose mode focused on dose reduction with acceptable image quality. the std mode was balanced between good contrast and dose reduction.17 the agd, esak, and mas were ordered as cnt mode had a higher agd than std mode and dose mode produced the lowest agd. for the phantom 50/50, the total agd value for the 2d and 3d combination mode was below the recommended dose limit of 3 mgy per projection. in order to ease the operator’s task, the auto-filter is the recommended mode for 50/50 breast types for both 2d and 3d images.20 on the other hand, the results obtained in the current study showed that the auto-kv mode produced the highest agd and, therefore, was not advisable for use with this type of breast. similarly, for the fatty type of breast tissue (20/80), auto-filter could be considered the mode of choice for both a 2d and 3d image as the kvp is high enough to penetrate thicker breast tissue and the mode is automatic. a limitation to this study was that the findings focused only on the dosage of radiation. further research on auto-modes of exposure and image quality is therefore required. conclusion this study demonstrated that the agd values for 50/50 and 20/80 breast phantoms for both 2d and 3d imaging were lower with a high kvp while using autotime mode. however, the use of auto-filter mode was found to be more practical as it was fast to use and reduced the risk of operator error. alternatively, for 20/80 breast types, it would be more suitable to choose either auto-time or auto-filter modes interchangeably since the dose does not change. however, this can be risky if the operator has insufficient training or knowledge of utilising different modes. references 1. dronkers dj, hendriks j, holland r, rosenbusch g, eds. the practice of mammography: pathology, technique, interpretation, adjunct modalities. 1st ed. germany: georg thieme verlag, 2001. pp. 59–96. 2. ng kh, jamal n, dewerd l. global quality control perspective for the physical and technical aspects of screen-film mammography: image quality and radiation dose. radiat prot dosimetry 2006; 121:445–51. doi: 10.1093/rpd/ncl051. 3. wu x, barnes gt, tucker dm. spectral dependence of glandular tissue dose in screen-film mammography. radiology 1991; 179:143–8. doi: 10.1148/radiology.179.1.2006265. 4. baldelli p, phelan n, egan g. investigation of the effect of anode/filter materials on the dose and image quality of a digital mammography system based on an amorphous selenium flat panel detector. br j radiol 2010; 83:290–295. doi: 10.1259/ bjr/60404532. 5. andrew s, biao c, alan s. minimizing dose in digital mammography: tungsten x-ray tubes with rhodium and silver filters optimize image quality. from: cdn.medicexchange.com/ images/whitepaper/minimizing%20dose%20in%20digital%20 mammography.pdf?1272615617 accessed: oct 2014. 6. united states food and drug administration. selenia dimensions 3d system p080003. from: www.fda.gov/medicaldevices/prod uctsandmedicalprocedures/deviceapprovalsandclearances/ recently-approveddevices/ucm246400.htm accessed: oct 2014. estimates of average glandular dose with auto-modes of x-ray exposures in digital breast tomosynthesis e296 | squ medical journal, may 2015, volume 15, issue 2 15. young kc, oduko jm, woolley l. technical evaluation of the hologic selenia full field digital mammography system nhsbsp equipment report 0701 january 2007.. from: www. cancerscreening.nhs.uk/breastscreen/publications/nhsbspequipment-report-0701.pdf accessed: oct 2014. 16. unavita healthcare sustainability. digital mammography and the fatty breast. from: www.una-vita.com/publications# accessed: oct 2014. 17. ko ms, kim hh, cha jh, shin hj, kim jh, kim mj. dose reduction in automatic optimization parameter of full field digital mammography: breast phantom study. j breast cancer 2013; 16:90–6. doi: 10.4048/jbc.2013.16.1.90. 18. kanaga kc, yap hh, laila se, sulaiman t, zaharah m, shantini aa. a critical comparison of three full field digital mammography systems using figure of merit. med j malaysia 2010; 65:119–22. 19. williams mb, raghunathan p, more mj, seibert ja, kwan a, lo jy, et al. optimization of exposure parameters in full field digital mammography. med phys 2008; 35:2414–23. 20. izdihar k, kanaga kc, krishnapillai v, tamanang s. determination of tube output (kvp) and exposure mode for breast phantom of various thicknesses/glandularity for digital mammography. malays j med sci 2015; 22:40–9. 7. darambara dg. digital breast tomosynthesis. presented at london quality assurance breast cancer screening study day, june 2011, london. 8. mccullagh jb, baldelli p, phelan n. clinical dose performance of full field digital mammography in a breast screening programme. br j radiol 2011; 84:1027–33. doi: 10.1259/ bjr/83821596. 9. international atomic energy agency. dosimetry in diagnostic radiology: an international code of practice. from: www-pub. iaea.org/mtcd/publications/pdf/trs457_web.pdf accessed oct 2014. 10. zeidan m. assessment of mean glandular dose in mammography. master thesis. christchurch, new zealand: university of canterbury, 2009. 11. dance dr. monte carlo calculation of conversion factors for the estimation of mean glandular breast dose. phys med biol 1990; 35:1211–9. doi: 10.1088/0031-9155/35/9/002. 12. dance dr, skinner cl, young kc, beckett jr, kotre cj. additional factors for the estimation of mean glandular breast dose using the uk mammography dosimetry protocol. phys med biol 2000; 45:3225–40. doi: 10.1088/0031-9155/45/11/308. 13. dance dr, young kc, van engen re. estimation of mean glandular dose for breast tomosynthesis: factors for use with the uk, european and iaea breast dosimetry protocols. phys med biol 2011; 56:453–71. doi: 10.1088/0031-9155/56/2/011. 14. carlton rr, adler am. principles of radiographic imaging: an art and a science. 4th ed. independence, kentucky, usa: cengage learning, 2006. pp. 606–60714. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e438–439, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.023. submitted 25 nov 14 revision req. 21 jan 15; revision recd. 29 jan 15 accepted 19 feb 15 departments of 1child health, 2surgery and 3radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: koul@squ.edu.om and roshankoul@hotmail.com نوبات األمل األذين االنتيايب يف الشريان املخيخي األمامي السفلي يف طفل رو�سان كول، رانا عبد الرحيم، راجيف كاريياتيل، ديليب �سانخال anterior inferior cerebellar artery loop-induced paroxysmal otalgia in a child *roshan koul,1 rana a. rahim,1 rajeev kariyattil,2 dilip sankhla3 figure 1: time-of-flight magnetic resonance angiography image in the axial plane showing an anterior inferior cerebellar artery loop in the left internal auditory meatus (arrow) of a seven-year-old girl with paroxysmal otalgia. interesting medical image a seven-year-old girl was referred to the child neurology outpatient clinic of sultan qaboos university hospital in muscat, oman, in june 2014 by an ear, nose and throat (ent) specialist from another hospital for an evaluation of pain in her left ear. the pain had started about two and half years previously and was paroxysmal and associated with decreased hearing and tinnitus. the pain typically lasted two to three hours at a time. initially, the child was only in pain once per month; however, more recently, the frequency had increased to two to three times a day. during episodes of otalgia, the pain was so severe that the girl could do nothing but cry out for help to relieve it. in between these episodes, there were no signs of tinnitus or hearing loss. there were no apparent triggers for the pain, such as swallowing or being touched on the face. the child had previously undergone routine ent examinations at two clinics. a computed tomography scan of the brain was performed to identify temporal bone and internal auditory canal lesions, which revealed no abnormalities. a hearing test, tympanometry and roshan koul, rana a. rahim, rajeev kariyattil and dilip sankhla interesting medical image | e439 triggers pain due to the intermediate nerve, while pain when swallowing is due to the ninth nerve. however, no such triggers were observed for the current patient. an mri scan revealed that an arterial loop of the aica was compressing the seventh nerve. neurosurgical decompression is the definitive treatment for this condition.2 this type of pain must be differentiated from that caused by a migraine; this can be difficult in younger patients as they may not be able to explain their pain clearly. for the current patient, the pain began when she was four and a half years old. there was an improvement in the severity of the pain after taking gabapentin. other causes for recurrent facial pain need to be investigated thoroughly to rule out dental and ophthalmic conditions. rarely, trigeminal neuralgia may present in a similar way.3 clinicians should therefore always attempt to determine the underlying cause of unexplained headaches or facial pain in children. references 1. smith jh, robertson ce, garza i, cutrer fm. triggerless neuralgic otalgia: a case series and systematic literature review. cephalalgia 2013; 33:914–23. doi: 10.1177/0333102413477743. 2. younes wm, capelle hh, krauss jk. microvascular decompression of the anterior inferior cerebellar artery for intermediate nerve neuralgia. stereotact funct neurosurg 2010; 88:193–5. doi: 10.1159/000313873. 3. koul r, alfutaisi a, jain r, alzri f. trigeminal neuralgia due to anterior inferior cerebellar artery loop: a case report. j child neurol 2009; 24:989–90. doi: 10.1177/0883073809332403. neurological examination were normal. a routine magnetic resonance imaging (mri) of the brain was reported to show no abnormalities. however, based on the patient’s history and the normal ent workup, the mri was reviewed with the radiologist. on reassessment, an arterial loop of the anterior inferior cerebellar artery (aica) was observed on the left side over the seventh cranial nerve in the internal auditory canal [figure 1]. the ear pain was likely caused by pressure on the intermediate nerve, a branch of the seventh cranial nerve. the child was referred to a neurosurgeon for consultation and potential decompression. she was also started on gabapentin. this was prescribed initially as a nightly dose of 25 mg which was increased twice weekly to a maximum nightly dose of 100 mg. conservative management (500 mg of paracetamol) was recommended for relief of the frequency and severity of her ear pain. a follow-up examination indicated an improvement of approximately 50% in the level of pain. comment otalgia is uncommon in children and is mainly seen in the sixth and seventh decades of life.1 there are several mechanisms which can result in ear pain, including lesions of the fifth, seventh, ninth, tenth and auricular temporal nerves.1 pain of the inner ear and tympanic membrane is due specifically to lesions of the seventh (intermediate) and ninth nerves. these two types of lesions can be differentiated clinically by their causative factors. touching the ear or face http://dx.doi.org/10.1177/0333102413477743 http://dx.doi.org/10.1159/000313873 http://dx.doi.org/10.1177/0883073809332403 graduated driver licensing an international review e432 | squ medical journal, november 2014, volume 14, issue 4 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e432−441, epub. 14th oct 14 submitted 26th feb 14 revision req. 7th may 14; revision recd. 18th may 14 accepted 5th jun 14 graduated driver licensing (gdl) systems use a public health approach to reduce the prevalence of traffic accidents by focusing on reducing the risks for new drivers as a group, rather than the risk of individual drivers.1,2 these systems minimise the exposure of novice drivers to risky situations while allowing them to obtain driving experience.3,4 the purpose of gdl is to gradually introduce new drivers to more complex driving environments as they gain experience.4,5 typically, there are three stages in a gdl system: the learner phase, the intermediate or provisional stage and the full licence stage.6 as new drivers demonstrate their experience during the less demanding stages, restrictions are lifted and new driving privileges are introduced.7 the learner phase allows the new driver to develop driving skills under the supervision of a more experienced driver, while a provisional licence allows solo driving, subject to restrictions.8,9 a gdl system is not designed to reduce deliberate risk-taking by new drivers. instead, it reduces crash risk caused by inexperience.10 new zealand introduced the first gdl system in 1987; since then, its popularity has grown, with jurisdictions within australia, the usa and canada also implementing forms of gdl.4,5 an increasing number of evaluations indicate that this countermeasure is effective in reducing crash risk.11– 14 shope et al. found that the introduction of gdl systems in the usa had reduced the crash risk of the youngest newly licensed drivers by 20–40%.15 even when a basic gdl system is introduced, research indicates that it reduces fatal crash involvement for 1school of criminology & criminal justice, griffith university, mount gravatt, queensland, australia; 2centre for accident research & road safety, school of psychology & counselling, queensland university of technology, brisbane, queensland, australia *corresponding author e-mail: l.bates@griffith.edu.au برنامج الرتخيص التدرجيي لقيادة املركبات مراجعة دولية ليندل جوديث بيت�س, �سييبوهان الني, كريي ارم�سرتوجن, باري وات�سون, مارك ج. كينج, جريمي دايف abstract: graduated driver licensing (gdl) aims to gradually increase the exposure of new drivers to more complex driving situations and typically consists of learner, provisional and open licence phases. the first phase, the learner licence, is designed to allow novice drivers to obtain practical driving experience in lower risk situations. the learner licence can delay licensure, encourage novice drivers to learn under supervision, mandate the number of hours of practice required to progress to the next phase and encourage parental involvement. the second phase, the provisional licence, establishes various driving restrictions and thereby reduces exposure to situations of higher risk, such as driving at night, with passengers or after drinking alcohol. parental involvement with a gdl system appears essential in helping novices obtain sufficient practice and in enforcing compliance with restrictions once the new driver obtains a provisional licence. given the significant number of young drivers involved in crashes within oman, gdl is one countermeasure that may be beneficial in reducing crash risk and involvement for this group. keywords: traffic accidents; public health; accident prevention; safety; automobile driving. امللخ�س: يهدف برنامج التدريجي لقيادة املركبات زيادة تعر�س ال�سائقني اجلدد إىل مواقف �سياقة معقدة والتي تتكون من مراحل رخ�سة على باحل�سول للمبتدئني لت�سمح املتعلم( )رخ�سة الأوىل املرحلة و�سممت املفتوحة. الرخ�سة مرحلة ثم املوؤقتة والرخ�سة املتعلم, على املبتدئني ت�سجع ولكنها الرتخي�س تاأخري املتعلم إيل رخ�سة توؤدي وقد اخلطورة. منخف�سة مواقف يف القيادة ممار�سة خربات تر�سخ الأبوية.بينما امل�ساركة على والت�سجيع التالية املرحلة ايل للرتقي الالزمة املمار�سة �ساعات عدد وحتديد املراقبة حتت التعلم املرحلة الثانية لقيود و�سوابط ال�سياقة وبالتايل احلد من التعر�س للمواقف عالية اخلطورة أثناء القيادة مثل القيادة أثناء الليل والقيادة مع ركاب اّخرين اأو بعد تناول امل�رصوبات الكحولية. وتعترب امل�ساركة الأبوية عن�رصا أ�سا�سيا يف م�ساعدة املبتدئني عىلاحل�سول على التدريب الكايف وت�سجيع االلتزام بالقيود وال�سوابط فور ح�سول ال�سائق حتت التمرين على الرخ�سة املوؤقتة. مفتاح الكلمات: احلوادث املرورية؛ ال�سحة العامة؛ منع احلوادث؛ الأمان؛ قيادة ال�سيارات. graduated driver licensing an international review *lyndel j. bates,1,2 siobhan allen,2 kerry armstrong,2 barry watson,2 mark j. king,2 jeremy davey2 review lyndel j. bates,siobhan allen, kerry armstrong, barry watson, mark j. king and jeremy davey review | e433 16and 17-year-old drivers when compared with slightly older drivers. correspondingly, fell et al. observed that more comprehensive gdl systems result in greater reductions in the number of crashes.11 the available evidence indicates that when gdl systems only apply to drivers aged up to 17 years old, an increase in crashes for drivers aged 18 or 19 years old can occur.16 thus, there may be advantages to implementing gdl systems for older novice drivers. research suggests that gdl programmes are beneficial both for the young licensed driver and other road users.17 evaluations of the new zealand gdl system, which were carried out immediately after its introduction, demonstrated a reduction of 25% in the number of crashes with casualties.18 however, a study carried out in the usa by romano et al. found that the reduction in young driver crashes as a result of a gdl system may differ across racial or ethnic groups.19 within the australian states of queensland and victoria, the introduction of more comprehensive gdl systems has been associated with reductions in fatal and serious injury crashes.20,21 other studies in various jurisdictions demonstrated reductions in road crashes which were attributable to gdl systems; however, these reductions were not as significant in comparison to when the systems were first introduced.22,23 road traffic crashes are an alarming public health issue throughout the world, including in oman. this issue remains of vital concern despite the nation’s on-going improvements in traffic law enforcement practices and technology.24,25 one of the main target groups for road safety among the omani population is young drivers aged 17–25 years. according to the licensing system in oman, as comprised in the traffic laws, the minimum age to apply for a driving licence is 18 years, with an exception in some cases where the minimum age may be 17 years. a recent investigation examined the characteristics of traffic accidents in oman involving young drivers over a three-year period.26 al-reesi et al. found that although young drivers aged 17–25 years old comprise around 17% of all licence holders, they also represent more than onethird of all drivers involved in road traffic accidents in oman.26 specifically, the authors reported that, of the total number of road crashes in oman between 2009 and 2011 (n = 33,172), a total of 11,101 involved a young driver. among these, 7,727 of the young drivers (69.6%) were considered to be ‘at fault’ at the time of the crash.26 these findings suggest that there is a need to consider programmes such as gdl in order to improve young driver safety in oman. while research has confirmed, to varying degrees, the effectiveness of gdl systems, there is limited evidence available regarding the mechanisms by which they successfully reduce crashes and which particular components are the most effective.3,4,14,15,27–30 however, a study by masten et al. identified that requiring drivers to hold a learner’s permit for a minimum of 12 months and having passenger and night-time restriction components were the most effective gdl mechanisms in reducing fatal crashes.31 this review is intended to provide an update on the existing literature, with special attention given to the role of parents and restriction enforcement-related issues. the learner phase the learner phase of a gdl system is designed to allow new drivers the opportunity to gain practical driving experience in terms of vehicle handling, assessing the road environment and observing the behaviour of other drivers, all the while under the supervision of a more experienced driver.2 this phase recognises that individuals need to learn how to drive and to accumulate initial driving experience in lower risk situations with an experienced supervisor.1,8 it aims to provide individuals with the experience and capabilities they will eventually need when they drive by themselves.21 while the learner phase is critical in a comprehensive gdl system, it is important to note that supervised driving is inherently different from unaccompanied driving.2,32 as scott-parker et al. noted, supervised driving is designed to effectively teach the new driver how to drive and to allow the development of driving experience.33 the benefits of the learner phase may result from the delayed licensure, supervised learning process, mandated hours of practice and the involvement of the young learner’s parents. d e l ay e d l i c e n s i n g delayed licensing occurs when learner drivers are not allowed to drive without supervision for a period of time. this limits learners’ exposure to risky driving situations and allows them time to mature, thereby reducing crashes.34 delayed licensing can include increasing the amount of time that must be spent as a learner or raising the minimum age to obtain a learner licence.35–37 in new jersey, usa, raising the licensing age from 16 to 16.5 years was found to be associated with a 7% lower fatal crash rate, while delaying the licensing age to 17 years was associated with a 13% lower fatal crash rate.3 an analysis of fatal crash rates for 15–17-yearolds in the usa revealed that jurisdictions which allow individuals to learn to drive and become licensed at an earlier age have higher crash rates.38 additionally, graduated driver licensing an international review e434 | squ medical journal, november 2014, volume 14, issue 4 a recent study by ehsani et al. suggests that a gdl system that is inclusive of all ages reduces novice driver crash risk; however, conversely, the same study concludes that a gdl system can increase the crash risk if it is only applicable to those under 18 years.39 furthermore, the length of time that the learner licence is valid for can provide another method of delaying licensing. learner licences that expire in a relatively short period of time may encourage individuals to become licensed near the expiration date due to the sense of urgency that the short time frame creates. learner licences which do not expire for a significant period of time do not create this pressure.38 s u p e r v i s e d l e a r n i n g as was observed by sagberg et al., higher-order skills— such as perception, attention and judgement—develop over several years in comparison to basic motor skills.40 the amount of practice required for learning to drive is currently not fully known.34 although a new driver’s driving ability improves over time, it does not equal the ability demonstrated by more experienced drivers in more complex driving situations. research suggests that learners who have more supervised driving practice have a reduced risk of crashing once they commence solo driving.7 the amount of practice undertaken by learner drivers may be affected by a number of factors. among an investigated sample of learner drivers, these factors included increasing self-confidence as vehicle control skills improved; time constraints, including employment; the need for personal transport to and from social events; level of education, and holding a learner’s licence.41 research has identified that learners fail to gain much experience in potentially higher-risk situations, such as driving in the rain or at night; however, they are usually confident of their driving abilities by the time they have reached the next stage of licensing.41,42 this suggests that more hours of accompanied driving results in a more positive perception of this period, as was also noted in a study of young drivers in israel.43 m a n d at e d h o u r s o f p r a c t i c e some jurisdictions require learners to undertake a fixed number of driving hours and to record these in a log book, with research suggesting that mandating a certain number of supervised practice hours increases the amount of practice undertaken.44,45 in the usa, the required number of practice hours varies from 20–65 hours.46 some states within australia require learner drivers to complete significantly more practice. for instance, learner drivers in victoria and new south wales must complete 120 hours, while those in queensland must record 100 hours.47 however, in queensland, learner drivers can record three hours within their log book for every hour completed with a professional driving instructor, for up to 10 hours of practice or 30 log book hours.33 this means that learner drivers in queensland may be able to record 100 log book hours after only 80 hours of actual practice undertaken. there appears to be little research basis for the selection of particular time limits,2,48 although there is some research support for learners obtaining close to 120 hours of practice.49 additionally, jurisdictions with 50 or more mandated hours of practice have demonstrated that there are increased levels of parental involvement in the young drivers’ learning process compared to those with fewer or no mandated hours.50 however, mandating a set number of hours may imply to learners that this is all the time needed to learn required driving skills.2 this suggests that it is a simple task that is completed as soon as the learner requirements are fulfilled.2 nevertheless, requiring new drivers to complete a certain amount of practice may delay licensing, thus further reducing their exposure to the risk of crashing.34 while parental involvement may be positive in other areas, there are a number of potential drawbacks to involving parents in ensuring that learner drivers obtain sufficient supervised practice.51 this includes the possibility that the supervised practice may lack variety and that parents may undertake many of the driving tasks requiring higher-order skills on behalf of the learner, thereby preventing the development of skills in identifying hazards and managing distractions. this concept is supported by the findings of research undertaken in north carolina, usa, which identified that parents of teenage learner drivers focussed on teaching vehicle handling skills rather than higherorder perceptual and cognitive skills.52 other potential drawbacks include little parental knowledge of the mandated number of hours and parental perceptions of supervised practice.53 a study in two australian states indicated that many parents found the log book system to be an ineffective measure of the amount of driving practice accomplished, despite reporting that their own child’s log book was accurate.54 however, the use of a log book to record hours may help structure learners’ driving practice, allowing other supervisors to be aware of how much the learner has practiced.55 research suggests that log books are not completed in voluntary systems.44,55 before the act of completing a learner log book became a compulsory requirement of the gdl system in queensland, a study found that two-thirds of participants were unaware that a voluntary log book was available for completion.42 lyndel j. bates,siobhan allen, kerry armstrong, barry watson, mark j. king and jeremy davey review | e435 the provisional phase an important component of effective gdl systems is limiting driving in high-risk situations for the first few months or years after a new driver receives their licence.38 the provisional phase is designed to reduce a new driver’s exposure to risky situations when unsupervised by limiting their driving in certain situations such as at night, with passengers or after drinking alcohol.9 younger drivers are far more likely than older drivers to crash at night.38 night-time driving restrictions have been introduced in several jurisdictions, including new zealand and numerous states in the usa.6 restricting late night driving for young drivers has proven effective in reducing crashes and young driver fatalities.4,56 a national study in the usa suggested that, when late night driving was restricted, fatal night-time crashes for 16and 17-year-old drivers was reduced by approximately 10% when compared with older peers.57 the effectiveness of night-time driving restrictions, however, is affected by the time the restriction starts, the role of parents and the availability of exemptions.37 night-time restrictions have been shown to be more effective when they restrict driving before midnight and are still effective in reducing crashes with a 50% compliance rate.58,59 pa s s e n g e r r e s t r i c t i o n s passenger restrictions also affect driving behaviour, both positively and negatively. for example, a study by lee et al. found that drivers tend to exhibit safer driving behaviours, such as wearing a seatbelt, when they are accompanied by passengers.60 the study also found that the greater the number of passengers, the greater the likelihood that safe driving behaviours would be displayed by the driver.60 conversely, younger drivers accompanied by younger passengers are more likely to cause a crash than any other age group.38,60,61 one study showed that the more young passengers that were present in a vehicle, the greater the crash risk both at night and during the day.37 passenger restrictions usually mean that individuals under a certain age are prohibited as passengers, although family members are generally exempt from the restriction and are able to ride with the provisional licence holder at all times.37 research from new zealand suggests there is a reduction in provisional licensed driver crashes when a passenger restriction is in place.18 furthermore, evaluations conducted in the usa have found positive effects relating to the implementation of passenger restrictions.4,30,37 additional research from the usa suggests that gdl laws that prohibit teenage passengers are effective in reducing fatal crashes for 16and 17-year-old drivers.57 however, provisional drivers are less likely to comply with passenger restrictions than they are with a night-time driving restriction.37 fortunately, a uk-based study by jones et al. calculated that, even with a 50% compliance rate, fatalities and serious injuries to novice drivers would be reduced if these restrictions were implemented.58 a l c o h o l r e s t r i c t i o n s while young people drive under the influence of alcohol less frequently than adults, research indicates that they have an increased crash risk when they do engage in this behaviour.61,62 while blood alcohol content (bac) restrictions for all drivers are frequently present in licensing systems, stricter bac restrictions (with permissible bac set at a much lower level) are often part of a gdl system. all australian states have bac restrictions for provisional drivers, although this restriction may sometimes only apply to drivers below a certain age.63 additionally, new zealand and jurisdictions within the usa and canada also have bac restrictions.63,64 m o b i l e p h o n e r e s t r i c t i o n s younger drivers are more likely than older drivers to use their mobile phone while driving.65,66 a survey of american college students found that they were more likely to crash or nearly crash while talking on a mobile phone than when they were dialling or answering their phone.67 mobile phone bans while driving are designed to counter the problem of distraction for new drivers.37 research suggests that those who use mobile phones (including texting) while driving have an increased risk of crashing.68,69 the incorporation of a mobile phone ban into gdl systems has also been prompted by research indicating that the use of hands-free mobile phone devices does not eliminate the crash risk.70 restrictions on mobile phone use are present in several american and australian jurisdictions. these restrictions either apply to all drivers or just newly licensed drivers.37,47 foss et al. examined mobile phone use among drivers and identified that the law had little effect on the use of these devices by young drivers.71 the method of enforcing this restriction is likely to impact on its effectiveness.71,72 further research indicates that public education campaigns which are implemented in an evidence-based manner may be useful in reducing illegal mobile phone use.73,74 v e h i c l e p o w e r r e s t r i c t i o n s a vehicle power restriction is used to limit the type of car that a newly licensed driver may drive.75 for graduated driver licensing an international review e436 | squ medical journal, november 2014, volume 14, issue 4 instance, they may be restricted to a certain number of cylinders or a power-to-weight ratio. the rationale for this restriction is that young individuals who drive an above average performance vehicle tend to have a more dangerous attitude towards driving than other young drivers, as was evidenced by clarke et al. during an in-depth study on accident causation.76 vehicle power restrictions have existed for some time in australia; however, the effectiveness of this restriction in reducing crashes is limited at best. a recent study suggests that, due to the low numbers of high-powered vehicles driven by provisional drivers, the reduction in injury rates from these restrictions ranges from 0.4% in new zealand to 2.5% in the australian states of queensland and victoria, provided there was 100% compliance with this restriction.75 p-p l at e s p-plates, also known as decals, are signs prominently displayed on a vehicle to indicate to others that the driver of the vehicle holds a provisional licence and is not yet fully licensed.77 research shows that the mandatory display of p-plates may increase compliance with, and the enforcement of, other driving restrictions.4,78,79 they also indicate to other drivers that the person holds a provisional licence and may encourage the other drivers to limit their own risk-taking behaviours.80 additionally, the removal of the requirement to display these plates may be seen as an incentive for provisional drivers.80 one study evaluated the decal law in new jersey and found that it positively affected provisional drivers’ safety and reduced their crash rates by 9%.77 however, williams et al. found that the requirement to display decals was not popular with young people in new jersey.81 e x i t t e s t s the purpose of an exit test is to assess a provisional driver before they obtain their full driving licence. it is designed to ensure that the provisional driver is capable of holding a full (unrestricted) licence and may highlight the fact that a provisional driver is still developing their driving skills and abilities.6,82 exit tests, like other tests within the licensing system, can use a range of formats, including knowledge tests, hazard perception tests or on-road driving tests.63 one north american study found that exit tests were beneficial in reducing the relative fatality risk, although another review concluded that the effectiveness of driver testing, including exit tests, is not yet known.30,83 parental involvement a key factor within gdl systems is the level of support that parents provide, with research indicating that parental involvement has a positive impact on the safety of young drivers.4,8,84 parents involved in the learning process tend to be strong supporters of gdl;4,85‒88 however, while gdl systems that implicitly encourage parental involvement are now implemented in many jurisdictions, parents tend not to be systematically involved in the process.34 a criticism of many studies on gdl was highlighted in a recent report—most studies look at novice drivers in isolation, rather than investigating the relationship between novice drivers, their peers and their parents in a holistic way.89 pa r e n ta l i n v o lv e m e n t i n t h e l e a r n e r p h a s e the involvement of parents in the learner phase is critical to the success of gdl systems.4 research has shown that the support of parents was necessary for the majority of learner drivers to accrue sufficient driving experience.41 this may be due to the expense of being taught professionally; a recent study indicated that the cost of hiring professional driving instructors was prohibitively expensive for teenage drivers.90 several studies have shown that young drivers in gdl programmes benefit from increased parental driving instruction and supervised driving during the learner phase, with parents tending to spend more time supervising driving than was required by law.45,91 research suggests that, at least for the first four months of supervised driving, parents tend to focus on vehicle handling and operation.92 according to a study based in north carolina, mothers assume most of the responsibility for supervising a teenage driver in possession of a learner’s licence.52 mothers appear to be more safety conscious than fathers and consider driving at all of the licensing stages to be riskier.87,88,93 perhaps this explains why mothers were more likely to delay driving privileges than fathers in another study based in connecticut, usa.87 further research indicates that parents continue to influence the newly licensed driver’s behaviour once they progress to solo driving.2,89,94,95 pa r e n ta l i n v o lv e m e n t i n t h e p r o v i s i o n a l p h a s e parental involvement does not cease once the new driver obtains a provisional licence. some authors argue that parental involvement is most important when young drivers are able to drive solo.51 parents can be involved by playing an active role in placing lyndel j. bates,siobhan allen, kerry armstrong, barry watson, mark j. king and jeremy davey review | e437 restrictions upon new drivers and enforcing gdl requirements.91 however, parents and their children may not agree on driving rules, with research demonstrating that parents tend to have a stricter interpretation of the rules than their children.96,97 for these reasons, parents might not become actively involved in managing their children’s driving.97 while nearly all parents place driving restrictions on their children, young drivers who have been licensed under a gdl system report more parental restrictions than those who have not.91,98 research indicates that most parents set limits on newly licensed drivers, although these limits tend not to be strict or maintained for too long.99 the restrictions may also be focussed on issues that do not directly affect crash risk, such as obtaining permission to drive the family car in the first place.51 young drivers with parents who impose stricter limits reported engaging in less risky driving behaviours and had fewer traffic violations and crashes.51,100,101 while parental limit-setting does have some safety benefits, it appears that these benefits are modest, have a limited time span and are not well enforced.51 additionally, there are often no clear consequences for young drivers when parental driving-related rules have been violated.51 p r o g r a m m e s ta r g e t i n g pa r e n t s in a study by bates et al., siblings, parents and other family members of learner drivers reported that parental involvement in supervising learners should be extensive.102 given this, the need to increase parental education regarding gdl is important. while many parent education programmes exist, the most common is the checkpoints program used in the usa, which is designed to encourage parents to limit driving under high-risk conditions when the driver is first licensed.4,103 the checkpoints program uses videos, newsletters and a parent-teen driving agreement in order to encourage parents to monitor their child’s driving. evaluations of this programme have found it effective in influencing parental limitsetting and reducing risky driving behaviours and traffic offences among participants during their first 12 months of driving.51 in connecticut, parents are now required to complete a training course when their child first begins learning to drive. an evaluation of the course suggested that parents approved of the requirement to attend the course and believed the training would help them in their role as supervisor of a learner driver.104 some parents stated that they were more likely to enforce the gdl rules as a result of this course.104 compliance and enforcement c o m p l i a n c e new drivers do not uniformly comply with all restrictions present in gdl systems, as the levels of compliance are higher for some restrictions when compared with others; for example, research indicates that new drivers are more likely to comply with a late night driving restriction than with a peer passenger restriction.105 it also appears that novice drivers become less compliant with road laws as they progress through their provisional driving licence.106 in north carolina, foss et al. found that 17% of learner drivers had driven without a supervisor present in the vehicle.107 in nova scotia, canada, and california, usa, approximately 40% of intermediate licensed drivers reported that they had occasionally violated the night-time driving restriction.108,109 however, only 12–15% of drivers on their intermediate licence reported doing so often.108,109 despite the fact that significant numbers of new drivers have, at some stage, not complied with a gdl restriction, research shows that the laws are still successful in reducing the crash risk for novice drivers.63 nevertheless, it is likely that the effectiveness of gdl systems would be enhanced by improving learner drivers’ compliance with the restrictions. accordingly, it is important to examine the factors that influence compliance rates. compliance with the gdl system is, to some extent, self-motivated. individuals are expected to conform to the laws as they represent the expected standard of behaviour. however, this will not work if the gdl laws require new drivers to comply with standards that are not considered ‘reasonable’ by the majority of new drivers. compliance with the gdl system could therefore be enhanced by ensuring that most new drivers consider the provisions contained within the gdl system to be reasonable.110 parents also appear to impact the likelihood of their children complying with traffic laws. a study by desrichard et al. found that novice drivers whose parents provided a strong supervisory role displayed a more negative attitude towards violating road rules and had less intention of violating these laws.111 t h e e n f o r c e m e n t o f r o a d l aw s generally speaking, the enforcement of traffic laws is the most common initiative used to modify driver behaviour and thus reduce the incidence of traffic accidents.112 however, the provisions within a gdl system are difficult for police officers to enforce, particularly if they are unable to recognise which driving restrictions apply to which licence.89,105 if police graduated driver licensing an international review e438 | squ medical journal, november 2014, volume 14, issue 4 officers do not have a full understanding of the gdl laws, they may be placed in difficult situations when they attempt to enforce laws amongst new drivers who have greater knowledge of the law.113 one study examined whether publicity and increased enforcement also increased compliance with gdl restrictions.113 the programme used mechanisms known to change driver behaviour in other contexts. it resulted in a modest increase in infringement notices issued to novice drivers, although virtually no tickets had been issued previously.113 gdl relies on parents to enforce its various provisions.1,87,104,110 given the difficulties involved with police enforcement, parents are implicitly expected to implement driving restrictions and monitor compliance with these restrictions; this was demonstrated during a telephone survey of parents of teenagers as well as other adults.114 research has shown that parents have a significant influence on the driving compliance of provisionally licensed drivers and that they are much more influential than the police.89 gdl programmes provide parents with support in setting limits for their children. in addition, gdl systems clearly identify the factors that are highrisk and establish readily apparent limits for parents on what is appropriate driving behaviour.98 the effective enforcement of gdl provisions requires parents to be aware of the gdl system requirements in their jurisdiction.104 conclusion gdl systems aim to gradually increase the exposure of new drivers to more complex driving situations in as safe a manner as possible. these systems typically consist of learner, provisional and open licence phases. the first phase of a gdl system, the learner licence, is designed to allow new drivers to obtain practical driving experience in a lower risk situation. benefits from this phase may result from the delayed licensure, supervised learning process, mandated hours of practice and the involvement of parents. the second phase of the gdl system, the provisional licence, reduces new drivers’ exposure to risky situations including driving at night, with passengers or after drinking alcohol. these risks are managed by putting various driving restrictions in place. the involvement of parents with gdl appears essential. they tend to be heavily involved in helping teenage drivers obtain sufficient practice and in enforcing compliance with restrictions once the new driver obtains a provisional licence. given the significant number of young drivers involved in crashes within oman, gdl is one countermeasure that may be beneficial in reducing crash risk and involvement for this group. oman has an opportunity to apply the international research reviewed above and introduce various aspects of gdl that have demonstrated crash reductions in other jurisdictions. a c k n o w l e d g e m e n t s the authors appreciate the feedback provided by the anonymous reviewers and editors as part of the peer review process. references 1. shults ra. foreword to “graduated driver licensing research, 2007-present: a review and commentary”. j safety res 2010; 41:75. doi: 10.1016/j.jsr.2010.04.001. 2. foss rd. improving graduated driver licensing systems: a conceptual approach and its implications. j safety res 2007; 38:185–92. doi: 10.1016/j.jsr.2007.02.006. 3. mccartt at, teoh er, fields m, braitman ka, hellinga la. graduated licensing laws and fatal crashes of teenage drivers: a national study. traffic inj prev 2010; 11:240–8. doi: 10.1080/15389580903578854. 4. williams af, shults ra. graduated driver licensing research, 2007-present: a review and commentary. j safety res 2010; 41:77–84. doi: 10.1016/j.jsr.2010.03.002. 5. simpson hm. the evolution and effectiveness of graduated licensing. j safety res 2003; 34:25–34. doi: 10.1016/s00224375(02)00077-4. 6. williams a, mayhew d. graduated licensing: a blueprint for north america. from: www.oninjuryresources.ca/downloads/ publications/graduated_licensing__a_blueprint_for_north_ america.pdf accessed: jan 2014. 7. gulliver p, begg d, brookland r, ameratunga s, langley j. learner driver experiences and crash risk as an unsupervised driver. j safety res 2013; 46:41–6. doi: 10.1016/j.jsr.2013.03.007. 8. mayhew dr. the learner’s permit. j safety res 2003; 34:35–43. doi: 10.1016/s0022-4375(02)00078-6. 9. preusser df, leaf wa. provisional license. j safety res 2003; 34:45–9. doi: 10.1016/s0022-4375(02)00079-8. 10. waller pf. the genesis of gdl. j safety res 2003; 34:17–23. doi: 10.1016/s0022-4375(02)00076-2. 11. fell jc, jones k, romano e, voas r. an evaluation of graduated driver licensing effects on fatal crash involvements of young drivers in the united states. traffic inj prev 2011; 12:423–31. doi: 10.1080/15389588.2011.588296. 12. masten sv, foss rd, marshall sw. graduated driver licensing and fatal crashes involving 16to 19-year-old drivers. jama 2011; 306:1098–103. doi: 10.1001/jama.2011.1277. 13. williams af, chaudhary nk, tefft bc, tison j. evaluation of new jersey’s graduated driver licensing program. traffic inj prev 2010; 11:1–7. doi: 10.1080/15389580903370047. 14. neyens dm, donmez b, boyle ln. the iowa graduated driver licensing program: effectiveness in reducing crashes of teenage drivers. j safety res 2008; 39:383–90. doi: 10.1016/j. jsr.2008.05.006. 15. shope jt. graduated driver licensing: review of evaluation results since 2002. j safety res 2007; 38:165–75. doi: 10.1016/j. jsr.2007.02.004. lyndel j. bates,siobhan allen, kerry armstrong, barry watson, mark j. king and jeremy davey review | e439 16. fell j, romano e, voas rb. a national evaluation of graduated driver licensing laws in the united states. in: 20th international council on alcohol, drugs and traffic safety conference, brisbane, australia, 25–28 august 2013. 17. kirley bb, feller a, braver e, langenberg p. does the maryland graduated driver licensing law affect both 16-year-old drivers and those who share the road with them? j safety res 2008; 39:295–301. doi: 10.1016/j.jsr.2007.12.005. 18. begg dj, stephenson s. graduated driver licensing: the new zealand experience. j safety res 2003; 34:99–105. doi: 10.1016/ s0022-4375(02)00087-7. 19. romano e, fell j, voas rb. the role of race and ethnicity on the effect of graduated driver licensing laws in the united states. ann adv automot med 2011; 55:51–61. 20. newstead s, scully m. crash effects of the new queensland graduated licensing system: a preliminary evaluation. from: acrs.org.au/files/arsrpe/paper%2023%20-%20newstead%20 -%20graduated%20licensing%20systems.pdf accessed: jan 2014. 21. healy d, catchpole j, harrison w. victoria’s graduated licensing system evaluation interim report. from: www. vicroads .vic.gov.au/~/media/files/formsandpublications / s a f e t y % 2 0 a n d % 2 0 r o a d % 2 0 r u l e s / g r a d u a t e d l i c e n s i n g systemevaluationintermreport.ashx accessed: aug 2014. 22. rouse hl, aitken me, lein sd, leath kj, halverson p, thompson jw. statewide policies for safer teen driving: an evaluation of the impact of graduated driver licensing in arkansas. j trauma acute care surg 2013; 75:s281–4. doi: 10.1097/ta.0b013e31828f9967. 23. lewis-evans b. crash involvement during the different phases of the new zealand graduated driver licensing system (gdls). j safety res 2010; 41:359–65. doi: 10.1016/j.jsr.2010.03.006. 24. mcilvenny s. road traffic accidents: a challenging epidemic. sultan qaboos univ med j 2006; 6:3–5. 25. al-lamki l. life loss and disability from traffic accidents: it is imperative we all act now. sultan qaboos univ med j 2010; 10:1–5. 26. al-reesi h, buckley l, davey j, al-adawi s, al maniri a, armstrong k, et al. analysis of young driver crashes in oman. oman: research council of oman, 2013. 27. lyon jd, pan r, li j. national evaluation of the effect of graduated driver licensing laws on teenager fatality and injury crashes. j safety res 2012; 43:29–37. doi: 10.1016/j. jsr.2011.10.007. 28. masten sv, foss rd. long-term effect of the north carolina graduated driver licensing system on licensed driver crash incidence: a 5-year survival analysis. accident anal prev 2010; 42:1647–52. doi: 10.1016/j.aap.2010.04.002. 29. pressley jc, benedicto cb, trieu l, kendig t, barlow b. motor vehicle injury, mortality and hospital charges by strength of graduated driver licensing laws in 36 states. j trauma 2009; 67:s43–53. doi: 10.1097/ta.0b013e3181937f4f. 30. vanlaar w, mayhew d, marcoux k, wets g, brijs t, shope j. an evaluation of graduated driver licensing programs in north america using a meta-analytic approach. accid anal prev 2009; 41:1104–11. doi: 10.1016/j.aap.2009.06.024. 31. masten sv, foss rd, marshall sw. graduated driver licensing program component calibrations and their association with fatal crash involvement. accid anal prev 2013; 57:105–13. doi: 10.1016/j.aap.2013.04.013. 32. bates l, watson b, king m. driving and licensing experiences of learner drivers in two australian states prior to changes in the licensing laws. j australas coll road saf 2009; 20:51–5. 33. scott-parker bj, bates l, watson bc, king mj, hyde mk. the impact of changes to the graduated driver licensing program in queensland, australia, on the experiences of learner drivers. accid anal prev 2011; 43:1301–8. doi: 10.1016/j. aap.2011.01.012. 34. simons-morton b. parent involvement in novice teen driving: rationale, evidence of effects, and potential for enhancing graduated driver licensing effectiveness. j safety res 2007; 38:193–202. doi: 10.1016/j.jsr.2007.02.007. 35. mccartt at, farmer cm, jenness jw. perceptions and experiences of participants in a study of in-vehicle monitoring of teenage drivers. traffic inj prev 2010; 11:361–70. doi: 10.1080/15389588.2010.486428. 36. williams af. licensing age and teenage driver crashes: a review of the evidence. traffic inj prev 2009; 10:9–15. doi: 10.1080/15389580802500546. 37. williams af. contribution of the components of graduated licensing to crash reductions. j safety res 2007; 38:177–84. doi: 10.1016/j.jsr.2007.02.005. 38. preusser df, tison j. gdl then and now. j safety res 2007; 38:159–63. doi: 10.1016/j.jsr.2007.02.003. 39. ehsani jp, bingham cr, shope jt. graduated driver licensing for new drivers: effects of three states’ policies on crash rates among teenagers. am j prev med 2013; 45:9–18. doi: 10.1016/j. amepre.2013.03.005. 40. sagberg f, bjørnskau t. hazard perception and driving experience among novice drivers. accid anal prev 2006; 38:407–14. doi: 10.1016/j.aap.2005.10.014. 41. harrison wa. investigation of the driving experience of a sample of victorian learner drivers. accid anal prev 2004; 36:885–91. doi: 10.1016/j.aap.2003.09.004. 42. bates l, watson b, king m. factors influencing learner driver experiences. from: www.eprints.qut.edu.au/19498/2/grant_ report.pdf accessed: jan 2014. 43. taubman-ben-ari o, lotan t. the contribution of a novel intervention to enhance safe driving among young drivers in israel. accid anal prev 2011; 43:352–9. doi: 10.1016/j. aap.2010.09.003. 44. bates l, watson b, king m. required hours of practice for learner drivers: a comparison between two australian jurisdictions. j safety res 2010; 41:93–7. doi: 10.1016/j. jsr.2010.02.006. 45. waller pf, olk ml, shope jt. parental views of and experience with michigan’s graduated licensing program. j safety res 2000; 31:9–15. doi: 10.1016/s0022-4375(99)00025-0. 46. insurance institute for highway safety. young driver licensing systems in the u.s: 2012. from: www.iihs.org/iihs/topics/laws/ graduatedlicenseintro?topicname=teenagers accessed: 18 sep 2012. 47. senserrick t. australian graduated driver licensing systems. j australas coll road saf 2009; 20:20–6. 48. bates l. the experiences of learner drivers, provisional drivers and supervisors with graduated driver licensing in two australian jurisdictions. phd thesis, queensland university of technology, brisbane, australia, 2012. 49. gregersen np, berg hy, engström i, nolén s, nyberg a, rimmö pa. sixteen years age limit for learner drivers in sweden: an evaluation of safety effects. accid anal prev 2000; 32:25–35. doi: 10.1016/s0001-4575(99)00045-7. 50. jacobsohn l, garcía-españa j, durbin dr, erkoboni d, winston fk. adult-supervised practice driving for adolescent learners: the current state and directions for interventions. j safety res 2012; 43:21–8. doi: 10.1016/j.jsr.2011.10.008. 51. simons-morton bg, ouimet mc, catalano rf. parenting and the young driver problem. am j prev med 2008; 35:s94–303. doi: 10.1016/j.amepre.2008.06.018. 52. aaa foundation for traffic safety. parents, teens and the learner stage of graduated driver licensing. from: www. aaafoundation.org/sites/default/files/parentsteensreport.pdf accessed: jan 2014. graduated driver licensing an international review e440 | squ medical journal, november 2014, volume 14, issue 4 53. o’brien np, foss rd, goodwin ah, masten sv. supervised hours requirements in graduated driver licensing: effectiveness and parental awareness. accid anal prev 2013; 50:330–5. doi: 10.1016/j.aap.2012.05.007. 54. bates l, watson b, king mj. parental perceptions of the learner driver log book system in two australian states. traffic inj prev 2014; 15:809–16. doi: 10.1080/15389588.2014.891104. 55. bates lj, watson b, king m. the structure of the learner licence affects the type of experiences novices gain during this phase: examples from queensland and new south wales. j australas coll road saf 2008; 19:36–42. 56. carpenter d, pressley jc. graduated driver license nighttime compliance in u.s. teen drivers involved in fatal motor vehicle crashes. accid anal prev 2013; 56:110–17. doi: 10.1016/j. aap.2011.12.014. 57. fell jc, todd m, voas rb. a national evaluation of the nighttime and passenger restriction components of graduated driver licensing. j safety res 2011; 42:283–90. doi: 10.1016/j. jsr.2011.06.001. 58. jones sj, begg dj, palmer sr. reducing young driver crash casualties in great britain: use of routine police crash data to estimate the potential benefits of graduated driver licensing. int j inj contr saf promot 2013; 20:321–30. doi: 10.1080/17457300.2012.726631. 59. russell kf, vandermeer b, hartling l. graduated driver licensing for reducing motor vehicle crashes among young drivers. cochrane database syst rev 2011; 10:cd003300. doi: 10.1002/14651858.cd003300.pub3. 60. lee c, abdel-aty m. presence of passengers: does it increase or reduce driver’s crash potential? accid anal prev 2008; 40:1703–12. doi: 10.1016/j.aap.2008.06.006. 61. bates lj, davey j, watson b, king mj, armstrong k. factors contributing to young driver crashes: a review. sultan qaboos univ med j 2014; 14:e297–305. 62. shope jt, bingham cr. teen driving: motor-vehicle crashes and factors that contribute. am j prev med 2008; 35:s261–71. doi: 10.1016/j.amepre.2008.06.022. 63. senserrick t, whelan m. graduated driver licensing: effectiveness of systems and individual components. from: www.monash.edu.au/miri/research/reports/muarc209.html accessed: jan 2014. 64. carpenter c. did ontario’s zero tolerance and graduated licensing law reduce youth drunk driving? j policy anal manage 2006; 25:183–95. doi: 10.1002/pam.20161. 65. gauld cs, lewis i, white km. concealing their communication: exploring psychosocial predictors of young drivers’ intentions and engagement in concealed texting. accid anal prev 2014; 62:285–93. doi: 10.1016/j.aap.2013.10.016. 66. bener a, lajunen t, özkan t, haigney d. the effect of mobile phone use on driving style and driving skills. int j crashworthiness 2006; 11:459–66. doi:10.1533/ijcr.2005.0116. 67. seo dc, torabi mr. the impact of in-vehicle cell phone use on accidents or near-accidents among college students. j am coll health 2004; 53:101–7. doi: 10.3200/jach.53.3.101-108. 68. cazzulino f, burke rv, muller v, arbogast h, upperman js. cell phones and young drivers: a systematic review regarding the association between psychological factors and prevention. traff inj prev 2014; 15:234–42. doi: 10.1080/15389588.2013.822075. 69. hafetz js, jacobsohn ls, garcía-españa jf, curry ae, winston fk. adolescent drivers’ perceptions of the advantages and disadvantages of abstention from in-vehicle cell phone use. accid anal prev 2010; 42:1570–6. doi: 10.1016/j. aap.2010.03.015. 70. mcevoy sp, stevenson mr, mccartt at, woodward m, haworth c, palamara p, et al. role of mobile phones in motor vehicle crashes resulting in hospital attendance: a case-crossover study. bmj 2005; 331:428–30. doi: 10.1136/ bmj.38537.397512.55. 71. foss rd, goodwin ah, mccartt at, hellinga la. short-term effects of a teenage driver cell phone restriction. accid anal prev 2009; 41:419–24. doi: 10.1016/j.aap.2009.01.004. 72. curry ae, hafetz j, kallan mj, winston fk, durbin dr. prevalence of teen driver errors leading to serious motor vehicle crashes. accid anal prev 2011; 43:1285–90. doi: 10.1016/j. aap.2010.10.019. 73. gauld cs, lewis i, white km. concealed texting while driving: what are young people’s beliefs about this risky behaviour? saf sci 2014; 65:63–9. doi: 10/1016/j.ssci.2013.12.017. 74. fleiter j, lewis i, watson b. promoting a more positive traffic safety culture in australia: lessons learnt and future directions. in: 2013 australasian college of road safety conference, 6–8 nov 2013, adelaide, south australia. 75. keall md, newstead s. the potential effectiveness of young driver high-performance vehicle restrictions as used in australia. accid anal prev 2013; 52:154–61. doi: 10.1016/j. aap.2012.12.005. 76. clarke d, ward p, truman w. in depth accident causation study for young drivers. uk: department of transport, 2002. 77. curry ae, pfeiffer mr, localio r, durbin dr. graduated driver licensing decal law: effect on young probationary drivers. am j prev med 2013; 44:1–7. doi: 10.1016/j.amepre.2012.09.041. 78. triggs tj, smith kb. young driver research program: digest of reports and principal findings of the research. from: www.study.monash.edu/miri/research/reports/atsb164.pdf accessed: jan 2014. 79. harrison wa. report on review of novice-driver road safety programs. sydney, australia: nrma motoring and services, 2003. 80. senserrick t, whelan m. graduated driver licensing systems. melbourne, australia: monash university accident research centre, 2002. 81. williams af, mccartt at. views of new jersey teenagers about their state’s policies for beginning drivers. j safety res 2014;.48:1–6. doi: 10.1016/j.jsr.2013.10.001. 82. ferguson sa. other high-risk factors for young drivers: how graduated licensing does, doesn’t, or could address them. j safety res 2003; 34:71–7. doi: 10.1016/s0022-4375(02)00082-8. 83. united states department of transportation, national highway traffic safety administration. from: www.safercar. gov/parents/pdf/teen/811440.pdf accessed: aug 2014. 84. taubman-ben-ari o, katz-ben-ami k. family climate for road safety: a new concept and measure. accid anal prev 2013; 54:1–14. doi: 10.1016/j.aap.2013.02.001. 85. brookland r, begg d. adolescent, and their parents, attitudes towards graduated driver licensing and subsequent risky driving and crashes in young adulthood. j safety res 2011; 42:109–15. doi: 10.1016/j.jsr.2011.01.002. 86. campbell bt, chaudhary nk, saleheen h, borrup k, lapidus g. does knowledge of teen driving risks and awareness of current law translate into support for stronger gdl provisions? lessons learned from one state. traffic inj prev 2009; 10:320–4. doi: 10.1080/15389580903020527. 87. williams af, leaf wa, simons-morton bg, hartos jl. parents’ views of teen driving risks, the role of parents, and how they plan to manage the risks. j safety res 2006; 37:221–6. doi: 10.1016/j.jsr.2006.04.002. 88. ferguson sa, williams af. parents’ views of driver licensing practices in the united states. j safety res 1996; 27:73–81. doi: 10.1016/0022-4375(96)00001-1. 89. allen s. what ‘drives’ compliance? the deterrent effects of police and parents on the driving compliance of queensland provisionally licensed drivers. mt. gravatt, queensland, australia: griffith university, 2013. lyndel j. bates,siobhan allen, kerry armstrong, barry watson, mark j. king and jeremy davey review | e441 90. scott-parker b. experiences of teen drivers and their advice for the learner licence phase. traffic inj prev 2014; [epub ahead of print]. doi: 10.1080/15389588.2014.909594. 91. beck kh, shattuck t, raleigh r, hartos j. does graduated licensing empower parents to place greater restrictions on their newly licensed teens’ driving? health educ behav 2003; 30:695– 708. doi: 10.1177/1090198103255369. 92. goodwin ah, foss rd, margolis lh, harrell s. parent comments and instruction during the first four months of supervised driving: an opportunity missed? accid anal prev 2014; 69:15–22. doi: 10.1016/j.aap.2014.02.015. 93. bates lj, watson bc, king mj. mothers vs. fathers as learner driver supervisors: time commitment, driving activities and perceptions of risk. in: proceedings of the 2013 australasian road safety research, policing & education conference, 28–30 aug 2013, brisbane, australia. 94. miller g, taubman-ben-ari o. driving styles among young novice drivers: the contribution of parental driving styles and personal characteristics. accid anal prev 2010; 42:558–70. doi: 10.1016/j.aap.2009.09.024. 95. prato cg, toledo t, lotan t, taubman-ben-ari o. modeling the behavior of novice young drivers during the first year after licensure. accid anal prev 2010: 42:480–6. doi: 10.1016/j. aap.2009.09.011. 96. brookland r, begg d, langley j, ameratunga s. parental influence on adolescent compliance with graduated driver licensing conditions and crashes as a restricted licensed driver: new zealand drivers study. accid anal prev 2014; 69:30–9. doi: 10.1016/j.aap.2013.06.034. 97. beck kh, hartos jl, simons-morton bg. parent-teen disagreement of parent-imposed restrictions on teen driving after one month of licensure: is discordance related to risky teen driving? prev sci 2005; 6:259–67. doi: 10.1007/s11121005-0001-6. 98. hartos jl, simons-morton bg, beck kh, leaf wa. parentimposed limits on high-risk adolescent driving: are they stricter with graduated driver licensing? accid anal prev 2005; 37:557–62. doi: 10.1016/j.aap.2005.01.008. 99. hartos jl, eitel p, haynie dl, simons-morton bg. can i take the car? relations among parenting practices and adolescent problem-driving practices. j adolescent res 2000; 15:352–67. doi: 10.1177/0743558400153003. 100. ginsburg kr, durbin dr, garcía-españa jf, kalicka ea, winston fk. associations between parenting styles and teen driving, safety-related behaviors and attitudes. pediatrics 2009; 124:1040–51. doi: 10.1542/peds.2008-3037. 101. simons-morton b, ouimet mc. parent involvement in novice teen driving: a review of the literature. inj prev 2006; 12:i30–7. doi: 10.1136/ip.2006.011569. 102. bates l, watson b, king mj. the role of parents and nonparents in the supervision of learner drivers in australia. accid anal prev 2014; 70:40–5. doi: 10.1016/j.aap.2014.03.004. 103. williams af, tefft bc, grabowski dj. graduated driver licensing research, 2010-present. j safety res 2012; 43:195–203. doi: 10.1016/j.jsr.2012.07.004. 104. chaudhary nk, williams af, casanova td. parents’ attitudes about connecticut’s required driver orientation course for parents. traffic inj prev 2010; 11:478–82. doi: 10.1080/15389588.2010.494695. 105. hedlund j. novice teen driving: gdl and beyond. j safety res 2007; 38:259–66. doi: 10.1016/j.jsr.2007.03.003. 106. scott-parker b, watson bc, king mj, hyde mk. young, inexperienced and on the road: do novice drivers comply with road rules? trans res rec 2012; 2318:98–106. doi: 10.3141/2318-12. 107. foss rd, goodwin ah, rodgman ea, feaganes jr. development and evaluation of the north carolina graduated driver licensing system. chapel hill, north carolina, usa: university of north carolina highway safety research center, 2002. 108. williams af, nelson la, leaf wa. responses of teenagers and their parents to california’s graduated licensing system. accid anal prev 2002; 34:835–42. doi: 10.1016/s00014575(01)00090-2. 109. mayhew d, simpson h, ferguson sa, williams a. graduated driver licensing in nova scotia: a survey of teenagers and parents. j traffic med 1998; 26:37–44. 110. foss r, goodwin a. enhancing the effectiveness of graduated driver licensing legislation. j safety res 2003; 34:79–84. doi: 10.1016/s0022-4375(02)00083-x. 111. desrichard o, roché s, bègue l. the theory of planned behavior as mediator of the effect of parental supervision: a study of intentions to violate driving rules in a representative sample of adolescents. j safety res 2007; 38:447–52. doi: 10.1016/j.jsr.2007.01.012. 112. bates l, soole d, watson b. the effectiveness of traffic policing in reducing traffic crashes. in: prenzler t, ed. policing and security in practice: challenges and achievements. london, uk: palgrave macmillan, 2012. pp. 90–109. 113. goodwin ah, wells jk, foss rd, williams af. encouraging compliance with graduated driver licensing restrictions. j safety res 2006; 37:343–51. doi: 10.1016/j.jsr.2006.05.004. 114. williams af, chaudhary nk. views of connecticut parents of teens and other adults about graduated licensing upgrades. traffic inj prev 2008; 9:503–7. doi: 10.1080/15389580802330845. sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 323-324, epub. 9th may 13 submitted 30th jan 13 revisions req. 18th nov 12 & 2nd jan 13, revisions recd. 4th dec 12 & 16th jan 13 accepted 7th jul 13 department of radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: bittanupam@gmail.com; bittanupam@yahoo.com فقد مث مت العثور عليه موقع غري عادي حلصوة يف اجملرى البويل �شخبال �شاوهني و اأنومبا كاكاريا lost and found unusual location of a urinary tract calculus *anupam k. kakaria and sukhpal sawhney interesting medical image a 41-year-old male patient presented to the emergency department (ed) of sultan qaboos university hospital (squh) complaining of left flank pain of one day’s duration which was colicky and increasing in intensity. there was no history of fever, nausea or vomiting or other significant medical history; however, a similar episode had occurred previously. the patient’s vital signs were stable and he was afebrile. physical examination of the abdomen was non-contributory; routine microscopic urinalysis was normal. in view of the suspicion of left renal figure 1 a–b: (a) oblique coronal reformation of the un-enhanced computed tomography (ct) scan shows mild left hydronephrosis (long white arrow) and left hydro-ureter with periureteric fat stranding (short white arrow). no obvious calculus is seen in the left ureter. the right-sided direct inguinal hernia is seen containing a small part of urinary bladder and a small calculus within it (arrowhead). (b) the axial unenhanced ct of the abdomen does not reveal a calculus in the left kidney or ureter, the left-sided hydroureteronephrosis with surrounding fat stranding raises a strong possibility of the recent passage of a calculus through the left-sided urinary tract. incidentally, a right direct inguinal hernia containing part of the urinary bladder and a small calculus within it (arrowhead) should be noted. lost and found unusual location of a urinary tract calculus 324 | squ medical journal, may 2013, volume 13, issue 2 colic, he was referred for a non-contrast enhanced computed tomography (ncct) scan, the gold standard at squh to assess urinary tract calculi in patients presenting with renal colic. the scan showed significant left perinephric fat stranding and mild left hydroureteronephrosis and evidence of periureteric fat stranding around the left ureter. no calculi could be identified in the left kidney or the left ureter. there was a direct inguinal hernia on the right side which contained part of the urinary bladder and a small radio-opaque calculus. these findings suggested the recent passage of a left ureteric stone into the bladder and the migration of this stone into the herniated part of the urinary bladder. it is also possible that the patient had passed out the ureteric stone via the urethra, and that the stone in the herniated bladder was an incidental finding. clinically, the pain decreased over the period of observation in the ed, and the patient was discharged. at urology clinic followups, there was no recurrence of pain, and the patient was managed conservatively. inguinal hernias can be direct or indirect; the hesselbach triangle is usually the site for direct inguinal hernias. on ct, the direct inguinal hernia lies medial to the inferior epigastric artery.1 a total of 1–3% of all inguinal hernias involve the bladder;2 in obese men aged 50–70 years, the incidence may reach 10%.3 inguinal hernias generally occur on the right side.2 urinary bladder hernias are mostly diagnosed incidentally during hernia surgeries,4 or during imaging.2 the herniated parts of the urinary bladder can contain tumors or calculi.2,5 these may migrate from upper tracts or form de novo in the hernia due to stasis. ct is the best modality for the diagnosis and evaluation of inguinoscrotal urinary bladder herniation after injection of intravenous contrast. the post-processing of the ct using 3d reconstructions can demonstrate the contents of the hernia and its relationships.6 our patient’s calculus, could possibly have passed from the left ureter. however, it is possible that it may instead have travelled to the herniated component of the urinary bladder and been overlooked, especially as the herniated part of the bladder was small and did not significantly distort the urinary bladder in the pelvis. therefore, we suggest that the protocol for the routine ncct of the kidney, ureter and bladder for urolithiasis should extend below the pubic symphysis so as not to miss posterior urethral calculi or calculi in unusual areas. references 1. shadbolt cl, heinze sbj, dietrich rb. imaging of groin masses: inguinal anatomy and pathologic conditions revisited. radiographics 2001; 21:s261– 71. 2. bacigalupo le, bertolotto m, barbiera f, pavlica p, lagalla r, mucelli r, et al. imaging of urinary bladder hernias. ajr 2005; 184:546–51. 3. kraft kh, sweeney s, fink as, ritenour cwm, issa mm. inguinoscrotal bladder hernias: report of a series and review of the literature. can urol assoc j 2008; 2:619–23. 4. izes ba, larsen cr, izes jk, malone mj. computerized tomographic appearance of hernias of the bladder. j urol 1993; 149:1002–5. 5. postma mp, smith r. scrotal cystocele with bladder calculi (case report). ajr am j roentgenol 1986; 147:287–8. 6. rifaioglu mm, bayarogullari h, akkucuk s, aydogan a, davarci m, demibras o, et al. case reports: three dimensional computerized tomography imaging of an incidentally detected inguinoscrotal bladder hernia. bju int doi: 10.1002. epub 24 mar 2012. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e139-141, epub. 27th jan 14 submitted 24th jul 13 peer-reviewed accepted 19th sep 13 department of cardiology, centre hospitalier universitaire de caen, caen, france *corresponding author e-mail: ziad_dahdouh@hotmail.com ظاهرةاألكورديون يف الشريان الكعربي هل ينبغي لنا معاجلة الشريان الكعربي مبثابة الشريان التاجي؟ زياد �صعيد دحدوح, طوين عبد �مل�صيح, �أنطو�ن �رشكي�س, جيل غروليه امللخ�ص: تعد ظاهرة �الأكورديون حاله معروفة يف جمال طب �لقلب �لتد�خلي. و هي حالة حميدة مت و�صفها ب�صورة رئي�صية يف �ل�رش�يي �لتاجية �ملتعرجة �أثناء �لتدخالت �لتاجية عن طريق �جللد. ويعتقد �أن �صببها �صلك �لتوجيه. مل تالحظ هذه �لظاهرة �صابقا يف �ل�رشيان �لكعربي. يف هذه �لدر��صة نقدم حالة لظاهرة �الأكورديون يف �ل�رشيان �لكعربي, �لتي �ختفت بعد �أن مت ��صرتجاع �لق�صطرة و�ل�صلك. وقد �ختفت �لت�صيقات �لز�ئفة متاما يف �ل�صور �لالحقة مفتاح الكلمات: �ل�رشيان �لكعربي؛ �لتدخل �لتاجي عن طريق �جللد؛ �مل�صاعفات تقرير حالة؛ فرن�صا. abstract: the accordion phenomenon is a well-known finding mechanism in the field of interventional cardiology. it is a benign condition and has mainly been described in tortuous coronary arteries during percutaneous coronary interventions. it is believed to be induced by a stiff guidewire. however, this phenomenon has not been observed previously in the radial artery. we present a case of accordion phenomenon in the radial artery, which was successfully resolved after the catheters and the wire were retrieved, with the pseudolesions found to have completely disappeared in subsequent image findings. keywords: radial artery; percutaneous coronary intervention; complications; case report; france. accordion phenomenon in the radial artery should we treat the radial as a coronary artery? *ziad s. dahdouh, tony abdel-massih, antoine sarkis, gilles grollier case report the transradial approach has been growing steadily and has become an elegant and popular technique for coronary angiography and intervention because it has been associated with a reduced incidence of vascular access complications.1 moreover, it offers early ambulation and less discomfort thus significantly improving the patient’s quality of life as compared to the femoral approach.2 we present a case of accordion phenomenon during transradial percutaneous coronary intervention. case report an 84-year-old female presented with symptoms of heart failure. a coronary catheterisation took place via the left radial access since the right radial pulse was not perceived. the operator encountered resistance while advancing the 0.35-inch wire. the forearm angiogram showed adequate calibre but a tortuous radial artery [figure 1]. under fluoroscopy guiding, a 0.014-inch soft guidewire (choice®, floppy ls, boston scientific, natick, massachusetts, usa) was successfully advanced as far as the brachial artery thus straightening the radial tortuosities [figure 2]. the second radial angiography showed a complex stenosis along the radial artery resistant to the administration of intraarterial nitrate [figure 3]. the patient did not note any pain or discomfort at the level of the forearm. then, a diagnostic judkins right coronary catheter (jr4 5 fr) was easily advanced [figure 4] and the coronary angiogram was successfully performed, showing normal coronary arteries. after the catheters and the wire were retrieved, the prior image findings of the pseudolesions were found to have completely disappeared. discussion in many interventional centres, radial access has emerged as the default strategy for both diagnostic and interventional procedures. however, anatomic variations at the level of the radial artery such as high radial artery bifurcation, loops and tortuosities, accordion phenomenon in the radial artery should we treat the radial as a coronary artery? e140 | squ medical journal, february 2014, volume 14, issue 1 are not uncommon and can be associated with prolonged procedural duration and radiation exposure, or even can generate more procedural failures.3 for these reasons, some authors have suggested a preliminary angiogram of the arteries of the forearm through the introducer inserted into the radial artery.4 our strategy consisted of performing a radial artery puncture, inserting the sheath, injecting in situ vasodilators (verapamil), and then advancing the 0.35-inch j-wire through the radial sheath with the support of the catheter with no primary forearm angiogram. if any resistance is encountered during the advancement of the wire, the operator should perform an angiogram to verify the underlying anatomy of the forearm arteries. this would enable the operator to negotiate the anatomic variations under fluoroscopy by using hydrophilic wire (terumo, tokyo, japan) or even a 0.014-inch figure 1: arterial angiogram showing the left radial tortuosities (white arrows). figure 2: fluoroscopy showing the straightening of the tortuosities of the left radial artery with the 0.014-inch guidewire. figure 3: arterial angiogram showing the accordion phenomenon (white arrows) of the left radial artery. figure 4: advancement of the judkins right catheter (jr4 5 fr) through the left radial artery over the 0.014inch guidewire. ziad s. dahdouh, tony abdel-massih, antoine sarkis and gilles grollier case report | e141 guidewire. the accordion, or concertina, phenomenon is a reversible vessel wall shortening and a deformity believed to be due to arterial telescoping. it is produced by the mechanical adaptation of the geometry and curvature of the vessel. the straightening effect, shortening of the artery at one level, lengthening at another, and the vasoconstrictive effects due to guidewire or catheter balloon manipulation lead to angiographic slit-like multiple filling defects along the longitudinal axis of the involved vessel. this pseudo-narrowing, or pseudostenosis, has been described mostly during percutaneous coronary interventions, and mainly in tortuous vessels.5 the differential diagnosis for this benign condition includes more serious conditions like dissection, spasm and thrombosis.6 three major factors contributed to this phenomenon: tortuosity of the artery, the use of a stiff guidewire, and long stenting.7 it has been also described with a soft guidewire.8 vasodilators are frequently ineffective and the suggested therapeutic management is to remove everything from the vessel, resulting in the reformation of the vessel and the re-establishment of the coronary geometry. this coronary phenomenon has also been described in the internal mammary,9 carotid10 and external iliac arteries.11,12 however, it has never been reported in the radial artery. conclusion to the best of our knowledge, this is the first reported case of the accordion phenomenon induced by a soft guidewire in the radial artery during percutaneous coronary intervention. thus, the ‘radialists’ should be aware of the possibility of intussusceptions and the twisting of the radial artery and should avoid conflicting diagnoses which may lead to unnecessary complex interventions, converting a totally reversible event into an iatrogenic complication. references 1. jolly ss, yusuf s, cairns j, niemelä k, xavier d, widimsky p, et al. radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (rival): a randomised, parallel group, multicentre trial. lancet 2011; 377:1409–20. 2. cooper cj, el-shiekh ra, cohen dj, blaesing l, burket mw, basu a, et al. effect of transradial access on quality of life and cost of cardiac catheterization: a randomized comparison. am heart j 1999; 138:430–6. 3. valsecchi o, vassileva a, musumeci g, rossini r, tespili m, guagliumi g, et al. failure of tran¬sradial approach during coronary interventions: anatomic consid¬erations. catheter cardiovasc interv 2006; 67:870–8. 4. schiano p, barbou f, chenilleau mc, louembe j, monsegu j. adjusted weight anticoagulation for radial approach in elective cor¬onarography: the aware coronarography study. eurointervention 2010; 6:247–50. 5. davidavicius g, manoharan g, de bruyne b. the accordion phenomenon. heart 2005; 91:471. 6. alvarez ja, leiva g, manavella b, cosentino jj. left main crumpling during left anterior descending angioplasty: hitherto unreported location for the ‘accordion effect’. catheter cardiovasc interv 2001; 52:363–7. 7. kim w, jeong mh, lee sr, lim sy, hong yj, ahn yk, et al. an accordion phenomenon developed after stenting in a patient with acute myocardial infarction. int j cardiol 2007; 114:e60–2. 8. dahdouh zs, roule v, labombarda f, grollier g. accordion phenomenon induced by a soft guide wire. j cardiovasc med (hagerstown) 2011;12:520–1. 9. premchand rk, loubeyre c, lefevre t, benslimane a, louvard y, morice mc. tortuous internal mammary artery angioplasty: accordion effect with limitation of flow. j invasive cardiol 1999; 11:372–4. 10. tsutsumi m, kazekawa k, onizuka m, aikawa h, iko m, kodama t, et al. accordion effect during carotid artery stenting: report of two cases and review of the literature. neuroradiology 2007; 49:567–70. 11. quinn sf, kim j, sheley rc, frankhouse jh. ‘accordion’ deformity of a tortuous external iliac artery after stent-graft placement. j endovasc ther 2001; 8:93–8. 12. joseph d, idris m. catheter-induced ‘accordion effect’ in tortuous right external iliac artery during peripheral angiography. cathet cardiovasc diagn 1995; 34:318–20. sir, the recent conclusion of saturn (study of coronary atheroma by intravascular ultrasound: effect of rosuvastatin versus atorvastatin) study,1 demonstrated that maximal suggested doses of both atorvastatin and rosuvastatin ameliorate atherosclerosis to a similar extent by facilitating the regression of percent atheroma volume. both statins, however, caused renal proteinurea, albeit to different extents. the published results of the study ephemerally state that “proteinuria was commoner in the rosuvastatin group than in the atrovastatin group (3.8% versus 1.7%)”. further, the treatment group pertaining to atrorvastatin had higher number of diabetics compared to the group on rosuvastatin (16.8% versus 13.8%). diabetes augments kidney failure,2,3 accounting for nearly 44% of new cases in the united states, therefore it is plausible the atorvastatin treatment group had more patients with renal dysfunction than the rosuvastatin treatment group whereby the actual reported percentage of patients with proteinuria on rosuvastatin might not reflect the true value. the median age of the participants in saturn-trial is ~57 years. an individual of 57 years has an average glomerular filtration rate (gfr) of 93 ml/min/1.73m2 versus 116 ml/min/1.73m2 observed in individuals 20–29 years of age, indicating a decline in renal function with advancement with age. the intriguing issue of pivotal importance remaining unanswered is “which statin should preferably be administered in patients who are elderly with declining renal function/chronic kidney disease (ckd) patients/ patients with diabetic proteinuria?” currently, with contradicting results from several trials, a conclusive answer to the above is unavailable. as a case in point, atorvastatin exhibited reno-protective effects in the treating to new targets (tnt) study, but decreased estimated (e)-gfr in planet-i and cards trials.4,5 similarly, rosuvastatin exhibited renoprotective effects in mouse-model experiments, but in planet-i it exhibited reno-deleterious effects as it significantly decreased e-gfr.6 the results of the sharp trial,7 show promise where simvastin plus squ med j, may 2012, vol. 12, iss. 2, pp. 245-246, epub. 9th apr 2012 submitted 12th feb 12 accepted 22nd feb 12 نوعية أدوية الستاتني املفضلة لعالج اضطراب اْسِتْقاَلِب الشَّْحِميَّات عند مرضى اخللل الوظيفي الكلوي )saturn( مالحظات من الدراسة العاملية statin of preference to treat dyslipidaemia in patients with renal dysfunction cues from (saturn) letter to editor statin of preference to treat dyslipidaemia in patients with renal dysfunction cues from saturn 246 | squ medical journal, may 2012, volume 12, issue 2 ezetimibe could be prescribed for patients with renal dysfunction, without plausible detrimental effects on renal health, although the trial lacked a longer follow-up period.8 future head-to-head trials with different statins or a statins plus non-statin-cholesterol lowering drug combination, conducted in a patient population with ckd and with a suitable follow up period, are essential to answer the question posed above. in the meantime, clinicians will have to choose the statin appropriate to the need of the patient. khalid al-waili,1 tamima al-dughaishi,2 khalid al-rasadi,1 riad bayoumi,3 *yajnavalka banerjee3 departments of 1biochemistry, 2obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman; 3department of biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: yaj.banerjee@gmail.com reference 1. nicholls sj, ballantyne cm, barter pj, chapman mj, erbel rm, libby p, et al. effect of two intensive statin regimens on progression of coronary disease. n engl j med 2011; 365:2078–87. 2. al-lamki l. acute coronary syndrome, diabetes and hypertension: oman must pay more attention to chronic noncommunicable diseases. sultan qaboos univ med j 2011; 11:318–21. 3. panduranga p, sulaiman k, al-zakwani i. acute coronary syndrome in oman: results from the gulf registry of acute coronary events. sultan qaboos univ med j 2011; 11:338–42. 4. shepherd j, kastelein jj, bittner v, deedwania p, breazna a, dobson s, et al. effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the treating to new targets (tnt) study. clin j am soc nephrol 2007; 2:1131–9. 5. colhoun hm, betteridge dj, durrington pn, hitman ga, neil ha, livingstone sj, et al. primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (cards): multicentre randomised placebo-controlled trial. lancet 2004; 364:685–96. 6. fellstrom bc, jardine ag, schmieder re, holdaas h, bannister k, beutler j, et al. rosuvastatin and cardiovascular events in patients undergoing hemodialysis. n engl j med 2009; 360:1395–407. 7. baigent c, landray mj, reith c, emberson j, wheeler dc, tomson c, et al. the effects of lowering ldl cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): a randomised placebo-controlled trial. lancet 2011; 377:2181–92. 8. al-rasadi k, banerjee y. benefits of lowering cholesterol in chronic kidney disease. lancet 2011; 378:1376–7. 1department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: abuheija2008@hotmail.com مرض السكري خالل احلمل وما قبل احلمل عندالنساء العمانيات مقارنة النتائج عند الوالدة وفرتة ما قبل الوالدة عادل اأبوالهيجاء، ماجدة البا�ض، مرمي ماثيو abstract: objectives: the aim of this study was to assess the prevalence of gestational diabetes mellitus (gdm) and pregestational diabetes mellitus (pgdm) among pregnant women in oman and compare their obstetric and perinatal outcomes. methods: this retrospective study assessed the obstetric and perinatal outcomes of pregnant omani women with gdm or pgdm who delivered at the sultan qaboos university hospital in muscat, oman, between january 2009 and december 2010. results: there were a total of 5,811 deliveries during the study period. of the 5,811 women who gave birth, 639 women were found to have diabetes mellitus (11.0%). a total of 581 of the diabetic women had gdm (90.9%) and only 58 (9.1%) had pgdm. women with pgdm had a significantly higher incidence of pre-eclampsia (p = 0.022), preterm deliveries (p <0.001) and caesarean sections (p <0.001). neonatal complications, such as respiratory distress syndrome (rds), neonatal hypoglycaemia, neonatal jaundice and subsequent admission to a neonatal intensive care unit (nicu) were significantly higher for neonates born to mothers with pgdm compared to those born to mothers with gdm (p <0.001). the corrected perinatal mortality rates for women with pgdm and gdm were 34.5 and 13.7 per 1,000 live births, respectively. conclusion: in this omani cohort, women with pgdm were at higher risk of developing obstetric and perinatal complications such as pre-eclampsia, preterm delivery and caesarean delivery compared to women with gdm. in addition, neonates who had mothers with pgdm had higher rates of rds, neonatal hypoglycaemia, neonatal jaundice and admission to the nicu. keywords: diabetes mellitus; gestational diabetes; perinatal care; obstetrics; complications; oman. يف احلوامل الن�ساء بني احلمل قبل ما و�سكري )gdm( احلمل �سكري انت�سار مدى تقييم هو الدرا�سة هذه من الهدف الهدف: امللخ�ص: عمان ومقارنة النتائج عند الولدة وفرتة ما قباللولدة. الطريقة: هذه درا�سة ا�ستعادية لتقييم نتائج الولدة وفرتة ما قبل الولدة للن�ساء يناير بني عمان، م�سقط، يف قابو�ض ال�سلطان جامعة م�ست�سفى يف احلمل ماقبل �سكري اأو احلمل �سكري لديهن ممن احلوامل العمانيات 2009 ودي�سمرب 2010. النتائج: كانت هناك 5,811 ولدة يف تلك الفرتة. من 5,811 امراأه ولدت يف امل�ست�سفى وجدت 639 امراأة لديها داء ال�سكري )%11.0(. منهن 581 كان لديها �سكري احلمل )%90.9(، و 58 فقط )%9.1( لديهن �سكري ماقبل الولدة. يف الن�ساء الالتي لديهن القي�رسية والولدة )p >0.001( املبكرة الولدة وكذلك ،)p = 0.022( اإح�سائيا اأكرب بن�سبة احلمل ت�سمم ح�سل الولدة ماقبل �سكري حديثي عندالأطفال الدم �سكر نق�ض ،)rds( التنف�سية ال�سائقة متالزمة مثل الولدة، حلديثي امل�ساعفات كانت وكذلك .)p >0.001(( اأمهاتهم كانت الذين للر�سع بكثري اأعلى )nicu( الولدة حلديثي املركزة العناية وحدة يف لحقا والدخول الوليدي والريقان الولدة، لديهن �سكري ما قبل احلمل مقارنة مع الذين اأمهاتهم لديهن �سكري احلمل. )p >0.001(. كانت معدلت الوفيات للر�سع ما حول الولدة للن�ساء الالتي لديهن �سكري ما قبل احلمل 34.5 وللن�ساء الالتي لديهن �سكري احلمل 13.7 لكل 1,000 ولدة حية، على التوايل. اخلال�صة: يف هذه املجموعة من الن�ساء العمانيات، كانت الن�ساء الالتي الالتي �سكري ما قبل احلمل اأكرث عر�سة مل�ساعفات الولدة مثل ت�سمم احلمل، الولدة املبكرة والولدة القي�رسية مقارنة مع الن�ساء اللواتي لديهن �سكري احلمل. بالإ�سافة اإىل ذلك، فقد كان لدى الر�سع لالأمهات الالتي لديهن �سكري احلمل ارتفاع يف معدلت متالزمة ال�سائقة التنف�سية، ونق�ض �سكر الدم يف لأطفال حديثي الولدة، والريقان الوليدي ومعدل الدخول اىل وحدة العناية املركزة حلديثي الولدة. مفتاح الكلمات: مر�ض ال�سكري؛ �سكري احلمل؛ العناية ما قبل الولدة؛ التوليد؛ م�ساعفات؛ عمان. gestational and pregestational diabetes mellitus in omani women comparison of obstetric and perinatal outcomes *adel t. abu-heija,1 majeda al-bash,2 mariam mathew2 advances in knowledge from the results of this study, omani women with pregestational diabetes mellitus (pgdm) are at higher risk of developing certain obstetric and perinatal complications in comparison to women with gestational diabetes mellitus (gdm). neonates born to omani mothers with pgdm had higher rates of respiratory distress syndrome, neonatal hypoglycaemia, neonatal jaundice and subsequent admission to a neonatal intensive care unit compared to those with gdm mothers. clinical & basic research sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e496–500, epub. 23 nov 15 submitted 15 dec 14 revision req. 5 apr 15; revision recd. 6 apr 15 accepted 19 may 15 doi: 10.18295/squmj.2015.15.04.009 adel t. abu-heija, majeda al-bash and mariam mathew clinical and basic research | e497 gestational diabetes mellitus (gdm)is defined as a carbohydrate intolerance which occurs for the first time during pregnancy and disappears by the end of the puerperium.1 if diabetes mellitus is diagnosed before pregnancy, it is classified as pregestational diabetes mellitus (pgdm). the reported prevalence of diabetes in oman is approximately 12.0%, with the disease affecting males and females equally.2 approximately 3.0% of pregnant women in oman develop gdm before delivery.3 in the united arab emirates, gdm has been reported to occur in 5.0% of pregnancies.4 a mild increase in glucose levels during pregnancy can adversely affect both the mother and fetus. increased incidences of pre-eclampsia, preterm delivery, miscarriage, fetal malformation and perinatal mortality and morbidity have been reported in diabetic pregnancies in comparison to the general population.5 hyperglycaemia during pregnancy is associated with macrosomia, which may subsequently lead to shoulder dystocia and birth trauma in addition to an increase in the rate of caesarean sections.6 additionally, research has shown that hyperglycaemia is associated with an increased risk of perinatal mortality and neonatal complications such as respiratory distress syndrome (rds), neonatal hypoglycaemia and jaundice.7–9 the majority of studies in the literature on this topic have compared the obstetric and perinatal outcomes of women with uncomplicated pregnancies to either pgdm or gdm cohorts. this study aimed to retrospectively review the obstetric and perinatal outcomes of women with pgdm or gdm who were cared for and delivered at the sultan qaboos university hospital (squh), a tertiary hospital in muscat, oman. methods this retrospective study investigated the obstetric and perinatal outcomes of pregnant omani women between 15–49 years old with gdm and pgdm who delivered at squh between january 2009 and december 2010. patient records were retrospectively reviewed for maternal data (age, parity, gestational age, labour induction and mode of delivery), antenatal or obstetric complications (e.g. pre-eclampsia, preterm delivery, polyhydramnios or oligohydramnios) and perinatal outcomes (birth weight, five minute apgar scores, admission to the neonatal intensive care unit [nicu], fetal anomalies, stillbirths and early neonatal deaths). neonatal complications, such as rds, neonatal hypoglycaemia and jaundice, were also reviewed. women were considered diabetic (positive oral glucose tolerance test [ogtt]) if either their fasting or two-hour blood glucose levels (venous plasma glucose) exceeded 5.5 or 9 mmol/l (99 or 162 mg/dl), respectively. during the study period, standard squh protocol for the diagnosis and management of diabetes during pregnancy required that all healthy pregnant omani women who were not known to be diabetic or at high-risk of developing diabetes undergo random blood sugar tests during their first official antenatal appointment (at between eight and 12 gestational weeks). if their blood sugar level was >7 mmol/l (126 mg/dl), then a two-hour 75 g ogtt was performed in order to diagnose pgdm. pregnant women who were not known to be diabetic but were classified as having a relatively high risk of developing diabetes also underwent a two-hour 75 g ogtt during their first official antenatal appointment. women were considered high-risk if they had a history of recurrent miscarriages, macrosomia, fetal malformation or unexplained intrauterine fetal death (iufd) or a family history of diabetes, previous gdm or glycosuria on at least two occasions. for pregnant women who were not at an increased risk of developing diabetes, a 50 g oral glucose challenge test was performed between 24 and 28 gestational weeks. if their blood sugar level was ≥7.8 mmol/l (140 mg/dl), a two-hour 75 g ogtt was performed. women with diabetes were treated with a diet plan and/or administration of metformin or subcutaneous insulin. glycaemic control was considered satisfactory for patients with preprandial glucose levels of <5.5 mmol/l (99 mg/dl) and two-hour postprandial levels of <8 mmol/l (144 mg/dl). long-term glycaemic control was assessed by estimating glycosylated haemoglobin levels; women with levels of <6.0% were considered to have satisfactory glycaemic control. the major indication for a caesarean delivery included cephalopelvic disproportion (cpd) or 1–2 previous caesarean section deliveries performed due to cpd. statistical analyses were performed using chisquared, mann-whitney u and fisher’s exact tests, as appropriate. differences between values were application to patient care pregnant diabetic women, particularly women with pgdm, should be monitored closely for obstetric complications. any complications should be recognised and managed effectively so that they do not adversely affect perinatal outcomes. gestational and pregestational diabetes mellitus in omani women comparison of obstetric and perinatal outcomes e498 | squ medical journal, november 2015, volume 15, issue 4 (25.9% versus 9.5%; p <0.001) and caesarean sections (60.3% versus 27.9%; p <0.001) were also significantly higher in women with pgdm compared to those with gdm. there were no differences between the groups with regards to the incidence of other obstetric complications such as polyhydramnios, oligohydramnios or labour induction. the incidence of shoulder dystocia was the same in both groups. the perinatal outcomes of women with pgdm and those with gdm are compared in table 2. there were no significant differences in mean birth weight or the incidence of macrosomia or intrauterine growth restriction between the two groups. neonatal complications such as rds (8.5% versus 2.6%; p = 0.028), hypoglycaemia (6.8% versus 1.5%; p = 0.024) and jaundice requiring phototherapy (8.5% versus 2.4%; p = 0.022) were significantly higher in babies born to pgdm women compared to their gdm counterparts. there was no significant difference in the incidence of fetal anomalies, intrapartum or unexplained iufd, stillbirths with malformations or early neonatal deaths between the groups. more babies considered significant at p ≤0.0500. ethical approval for this study was granted by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #397). results during the study period, there were 5,811 deliveries. of the 5,811 women who gave birth, 639 were diabetic (11.0%). of these, 581 had gdm (90.9%) while only 58 had pgdm (9.1%). all women with pgdm received insulin therapy. in the diabetic cohort, 42.0% of the women had had 1–2 previous caesarean section deliveries performed due to cpd. table 1 compares the demographic characteristics and obstetric outcomes of women with gdm to those with pgdm. there were no significant differences in mean maternal or gestational age between the two groups. parity was also not significant between the two groups. however, women with pgdm had a significantly higher incidence of pre-eclampsia compared to those with gdm (17.2% versus 7.8%; p = 0.022). the incidence of preterm deliveries table 1: demographic characteristics and obstetric outcomes of women with gestational diabetes and pregestational diabetes among a pregnant omani cohort (n = 5,811) characteristic n (%) p value gdm (n = 581) pgdm (n = 58) mean age in years ± sd 31.6 ± 13.6 32.6 ± 5.9 0.579 parity 0 134 (23.1) 14 (24.1) 0.871 1‒4 265 (45.6) 21 (36.3) 0.212 ≥4 182 (31.3) 23 (39.6) 0.237 mean gestational age in weeks ± sd 38.3 ± 2.1 38.6 ± 5.9 0.415 obstetric outcome pre-eclampsia 44 (7.8) 10 (17.2) 0.022 preterm delivery at <37 gestational weeks 55 (9.5) 15 (25.9) <0.001 caesarean section 162 (27.9) 35 (60.3) <0.001 shoulder dystocia 10 (1.7) 1 (1.7) >0.999 polyhydramnios 29 (4.9) 4 (6.8) 0.529 oligohydramnios 4 (0.7) 1 (1.7) 0.380 induction of labour 139 (23.9) 9 (15.5) 0.191 gdm = gestational diabetes mellitus; pgdm = pregestational diabetes mellitus; sd = standard deviation. table 2: perinatal outcomes of women with gestational diabetes and pregestational diabetes among a pregnant omani cohort (n = 5,811) perinatal outcome n (%) p value gdm (n = 581) pgdm (n = 58) mean birth weight in g ± sd 3,166 ± 597 3,135 ± 793 0.715 macrosomia >4,000 g 29 (4.9) 6 (10.3) 0.120 iugr 5 (0.8) 1 (1.7) 0.436 birth weight <2,500 g 51 (8.8) 8 (13.6) 0.231 nicu admissions 75 (12.9) 18 (31.0) <0.001 rds 15 (2.6) 5 (8.5) 0.028 neonatal hypoglycaemia 9 (1.5) 4 (6.8) 0.024 neonatal jaundice requiring phototherapy 14 (2.4) 5 (8.5) 0.022 apgar scores <7 at five minutes 25 (4.3) 5 (8.5) 0.179 fetal anomalies 11 (1.8) 2 (3.4) 0.333 intrapartum iufd 1 (0.2) 1 (1.7) 0.173 unexplained iufd 7 (1.2) 1 (1.7) 0.535 iufd with malformations 3 (0.5) 1 (1.7) 0.317 early neonatal death 1 (0.2) 1 (1.7) 0.173 gdm = gestational diabetes mellitus; pgdm = pregestational diabetes mellitus; sd = standard deviation; iugr = intrauterine growth restriction; nicu = neonatal intensive care unit; rds = respiratory distress syndrome; iufd = intrauterine fetal death. adel t. abu-heija, majeda al-bash and mariam mathew clinical and basic research | e499 born to mothers with pgdm were admitted to the nicu compared to those with gdm mothers (31.0% versus 12.9%; p <0.001). in women with gdm, obstetric and perinatal outcomes were not affected by treatment method. the uncorrected perinatal mortality rate was significantly higher in women with pgdm compared to women with gdm (68.9 and 20.6 per 1,000 live births, respectively; p = 0.041). however, when this rate was corrected for lethal fetal malformations, the difference in perinatal mortality rates between the two groups was not significant (13.7 and 34.5 per 1,000 live births; p = 0.222). discussion pregnant diabetic women have an increased risk of developing obstetric complications such as pre eclampsia and preterm delivery and perinatal complications such as miscarriages and fetal malformations. these complications are observed more frequently in women with pgdm compared to women with gdm; this may be due to the prolonged and severe fetal exposure to hyperglycaemia.10,11 in the current study, the incidence of pre-eclampsia was higher among women with pgdm compared to women with gdm. these findings are in agreement with those from a recent japanese study which reported an incidence of 10.1% and 6.1% for pgdm and gdm women, respectively (p <0.05).11 cetković et al. noted that adverse neonatal outcomes were common among women with pgdm; macrosomia occurred in 29.6% of infants born to pgdm women in their study.12 in contrast, the incidence of macrosomia was much lower in the current cohort of women with pgdm (10.3%) and those with gdm (4.9%). this may be due to early diagnosis, strict glycaemic control and labour induction (providing that there was no contraindication for vaginal delivery) between 38 and 40 gestational weeks. in the current study, women with pgdm had a considerably higher occurrence of caesarean sections and an increased risk of developing pre-eclampsia when compared to those with gdm. this may also have contributed to the higher rate of caesarean sections among the pgdm women. infants born to women with pgdm also had an increased rate of premature delivery (<37 gestational weeks) when compared to those born to gdm women. this may have been due to the relatively higher, but not statistically significant, incidence of polyhydramnios and fetal malformation in the pgdm group. additionally, infants born to women with pgdm were admitted more frequently to the nicu, mainly because of rds, neonatal hypo glycaemia and neonatal jaundice requiring phototherapy. in women with gdm, obstetric and perinatal outcomes were not affected by treatment methods. this may indicate sufficient control of blood sugar levels during treatment. the corrected perinatal mortality rate found in the current study did not differ significantly between women with pgdm and those with gdm. however, the pgdm mortality rate was lower than that reported by other studies, with perinatal mortality rates of 111.1 and 66.2 per 1,000 live births in women with pgdm, respectively.12,13 in comparison, a saudi arabian study reported a similar perinatal mortality rate for women with gdm (13.6 per 1,000 live births).14 the relatively low gdm perinatal mortality rate observed in the current study may be due to strict glycaemic control and careful follow-up during pregnancy. conclusion in the studied omani cohort, women with pgdm had a higher risk of developing obstetric complications such as pre-eclampsia or experiencing preterm or caesarean deliveries in comparison to those with gdm. although the incidence of fetal complications such as rds, neonatal hypoglycaemia and neonatal jaundice was significantly higher in women with pgdm, corrected perinatal mortality rates did not differ significantly between the two diabetic groups. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. american diabetes association. diagnosis and classification of diabetes mellitus. diabetes care 2013; 36:s67–74. doi: 10.2337/ dc13-s067. 2. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. doi: 10.1046/j.1464-5491.2002.00818.x. 3. barakat mn, youssef rm, al-lawati ja. pregnancy outcomes of diabetic women: charting oman’s progress towards the goals of the saint vincent declaration. ann saudi med 2010; 30:265–70. doi: 10.4103/0256-4947.65253. 4. rizk de. the prevalence and complications of urinary tract infections in women with gestational diabetes mellitus: facts and fantasies. int j diabetes metab 2002; 10:29–32. 5. balaji v, seshiah v. management of diabetes in pregnancy. j assoc physicians india 2011; 59:33–6. 6. poolsup n, suksomboon n, amin m. effect of treatment of gestational diabetes mellitus: a systematic review and metaanalysis. plos one 2014; 9:e92485. doi: 10.1371/journal. pone.0092485. http://dx.doi.org/10.2337/dc13-s067 http://dx.doi.org/10.2337/dc13-s067 http://dx.doi.org/10.1046/j.1464-5491.2002.00818.x http://dx.doi.org/10.4103/0256-4947.65253 http://dx.doi.org/10.1371/journal.pone.0092485 http://dx.doi.org/10.1371/journal.pone.0092485 gestational and pregestational diabetes mellitus in omani women comparison of obstetric and perinatal outcomes e500 | squ medical journal, november 2015, volume 15, issue 4 11. sugiyama t, saito m, nishigori h, nagase s, yaegashi n, sagawa n, et al. comparison of pregnancy outcomes between women with gestational diabetes and overt diabetes first diagnosed in pregnancy: a retrospective multi-institutional study in japan. diabetes res clin pract 2014; 103:20–5. doi: 10.1016/j.diabres.2013.10.020. 12. cetković a, durović m. [neonatal outcome in pregnancies complicated with pregestational diabetes mellitus]. vojnosanit pregl 2007; 64:231–4. doi: 10.2298/vsp0704231c. 13. clausen td, mathiesen e, ekbom p, hellmuth e, mandruppoulsen t, damm p. poor pregnancy outcome in women with type 2 diabetes. diabetes care 2005; 28:323–8. doi: 10.2337/ diacare.28.2.323. 14. gasim t. gestational diabetes mellitus: maternal and perinatal outcomes in 220 saudi women. oman med j 2012; 27:140–4. doi: 10.5001/omj.2012.29. 7. hapo study cooperative research group; metzger be, lowe lp, dyer ar, trimble er, chaovarindr u, et al. hyperglycemia and adverse pregnancy outcomes. n eng j med 2008; 358:1991–2002. doi: 10.1056/nejmoa0707943. 8. langer o, yogev y, most o, xenakis em. gestational diabetes: the consequences of not treating. am j obstet gynecol 2005:192:989–97. doi: 10.1016/j.ajog.2004.11.039. 9. reece ea, leguizamón g, wiznitzer a. gestational diabetes: the need for a common ground. lancet 2009; 373:1789–97. doi: 10.1016/s0140-6736(09)60515-8. 10. ray jg, vermeulen mj, shapiro jl, kenshole ab. maternal and neonatal outcomes in pregestational and gestational diabetes mellitus, and the influence of maternal obesity and weight gain: the deposit study diabetes endocrine pregnancy outcome study in toronto. qjm 2001; 94:347–56. doi: 10.1093/qjmed /94.7.347. http://dx.doi.org/10.1016/j.diabres.2013.10.020 http://dx.doi.org/10.2298/vsp0704231c http://dx.doi.org/10.2337/diacare.28.2.323 http://dx.doi.org/10.2337/diacare.28.2.323 http://dx.doi.org/10.5001/omj.2012.29 http://dx.doi.org/10.1056/nejmoa0707943 http://dx.doi.org/10.1016/j.ajog.2004.11.039 http://dx.doi.org/10.1016/s0140-6736%2809%2960515-8 http://dx.doi.org/10.1093/qjmed/94.7.347 http://dx.doi.org/10.1093/qjmed/94.7.347 590 | squ medical journal, november 2013, volume 13, issue 4 sir, the recent report on the knowledge of jordanian youths of human immunodeficiency virus (hiv) is very interesting.1 al-khasawneh et al. found that “hiv knowledge differed significantly by sources of information, with peer-acquired information associated with more accuracy, while hiv information from parents or health centres was associated with a lower score.”1 in fact, knowledge of hiv is an important issue to be investigated for the subsequent management, in any setting, of the hiv problem. one interesting finding in the present report is the source of the information. there is no doubt that youths usually acquire and rely upon information from their peers.1 luckily, the accuracy of information from peer groups in this report is satisfactory.1 knowledge provided by educational institutions contributes to the accuracy of the information that peers can pass on to each other.1 based on this information, the development of a peer-group education system might be an effective way to disseminate knowledge to focus group in rural areas, where education resources and personnel are usually limited. there are some reports of the success of using this technique—such as those from yemen2 and thailand3. nevertheless, the most important step to remember is the development of a group leader within this system to direct the group and ensure the accuracy of the information discussed within the group setting. additionally, to gather further data for the proper management of the hiv problem, a knowledge survey such as the one by al-khasawneh et al. should be followed-up by surveys on the attitudes and practices of the youths. these could employ, for instance, the knowledge, attitude and practice (kap) survey model. *beuy joob and viroj wiwanitkit department of sanitation, medical academic center, bangkok, thailand *corresponding author e-mail: beuyjoob@hotmail.com references 1. al-khasawneh em, ismayilova l, seshan v, hmoud o, el-bassel n. predictors of human immunodeficiency virus knowledge among jordanian youths. sultan qaboos univ med j 2013; 13:232–40. 2. al-iryani b, basaleem h, al-sakkaf k, kok g, van den borne b. process evaluation of school-based peer education for hiv prevention among yemeni adolescents. sahara j 2013; 10:55–64. 3. thato r, penrose j. a brief, peer-led hiv prevention program for college students in bangkok, thailand. j pediatr adolesc gynecol 2013; 26:58–65. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 590, epub. 8th oct 13 submitted 24th jul 13 accepted 25th aug 13 رد: قياس الوعي بفريوس نقص املناعة املكتسبة بني الشباب األردين re: predictors of human immunodeficiency virus knowledge among jordanian youths letter to editor sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 3-18, epub. 27th feb 13 submitted 4th jun 12 revision req. 8th aug 12, revision recd. 30th aug 12 accepted 14th oct 12 lung cancer is the most common cancer worldwide and a leading cause of cancer-related deaths (19.4%). the global cancer incidence project (globocan) estimated 12.7 million new cancers and 7.6 million cancer deaths worldwide in 2008. lung cancer accounts for 1.6 million new registered cases and 1.37 million deaths around the globe in the same year.1 the american cancer society (acs) estimated that there were 226,160 lung cancer cases and 160,340 lung cancer-related deaths in 2010 in the united states alone. the incidence of lung cancer is higher among men when compared to women, accounting for 34% and 13.5% of all cancers, respectively. the age-standardised ratio for its incidence is 33.81%, and has a 29.2% rate in men.2 the acs numbers currently place the adenocarcinoma subtype at 40% of all the reported cases.3 in 2000–2003, the us surveillance epidemiology and end results (seer) database also described it as the most prevalent (47%) lung cancer subtype regardless of race, age, or gender, and the shift in histology was attributed to department of medicine, 1sultan qaboos university hospital & 2college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: furrukh_1@yahoo.com حتسني النتائج يف سرطان الرئة املتقدم العالج املستدام يف سرطان الرئة ذي اخللية غري الصغرية حممد فروخ، اإكرام برين، �صيام كومار، فرحان خوجه، من�صور املنذري )nsclc(امللخ�ص: ظل العالج الكيميائي هو العالج التقليدي لعالج �رسطان الرئة ذي اخللية، معززا معدل البقاء على قيد احلياة يف يف و 2008م. عام اأوائل حتى اأ�صهر الع�رسة حدود يف البقاء متو�صط ا�صتقر وقد .29% اإىل الأوىل ال�صنة يف املنت�رسة ال�صغرية غري حماولة لتعزيز فر�ض احلياة يف املراحل املتقدمة من املر�ض، بداأت درا�صات العالج امل�صتدام الكيميائي والتي اأثبتت موؤخراً اإطالة اأمد البقاء �صهرين اأو ثالثة اأ�صهر اإ�صافية يف حالة املر�صى الذين كان اإجنازهم الأدائي )1-0 ( مع احتفاظهم باأداء اع�صاء ج�صمهم ب�صكل اأف�صل من واحد ي�صتخدم ثم الكيميائي العالج من دورات �صتة اإىل باأربعة الإكلينيكية ا�صتفادتهم من املرجو املر�صى عالج يتم جيد. تلك العنا�رس املكونة للعالج الكيميائي حتى الو�صول لأف�صل ا�صتجابة اأو حدوث م�صاعفات جانبية )املداومة امل�صتكملة( اأو تغريها اإىل عن�رس اآخر )املداومة املبدلة(. املقالة ت�صتعر�ض باإيجاز تطور العالج الكيميائي التقليدي وت�صف التجارب الرئي�صية من العالج امل�صتدام املتكون من العالج الكيميائي والأدوية امل�صتهدفة يف حماولة لتح�صني النتائج يف �رسطان الرئة ذي اخللية غري ال�صغرية. مفتاح الكلمات: �رسطان الرئة ذي اخللية غري ال�صغرية؛ اأورام الرئة؛ العالج امل�صتدام الكيميائي؛ العالج اجلزيئي امل�صتهدف؛ م�صتقبالت؛عامل .a منو الب�رسة؛ عامل منو بطانة الأوعية abstract: systemic chemotherapy has remained the traditional treatment for metastatic non-small-cell lung carcinoma (nsclc), enhancing survival rate at 1 year to 29%. the median survival had plateaued at around 10 months until early 2008, and in an attempt to enhance survival in advanced disease, maintenance chemotherapy trials were initiated which had recently demonstrated prolongation of survival by an additional 2–3 months in patients who had performance status (ps) 0–1 and well-preserved organ functions. suitable patients with any degree of clinical benefit are treated with 4–6 cycles, and then one of the active agents is continued until best response, or toxicity (continued maintenance), or changed to a cross non-resistant single agent (switch maintenance). the article briefly reviews the evolution of systemic therapy and describes key randomised trials of maintenance therapy instituting chemotherapy and targeted agents in an attempt to improve outcomes in advanced metastatic nsclc, based on certain clinical features, histology, and genetics. keywords: carcinoma; non-small-cell lung; lung neoplasm; maintenance chemotherapy; molecular targeted therapy; receptor; epidermal growth factor; vascular endothelial growth factor a. review improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma *muhammad furrukh,1 ikram a. burney,1 shiyam kumar,1 khwaja f. zahid,1 mansour al-moundhri2 improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 4 | squ medical journal, february 2013, volume 13, issue 1 changes in the manufacturing of cigarettes, creating filters that allow deeper inhalation, thus channelling smoke towards the distal bronchioles.4 based on a 2010 report on cancer incidence in oman, published by the ministry of health, between 1998 and 2007 lung cancer was the fifth most common cancer in oman compared to other gulf cooperation council (gcc) countries. in 2010, it was the eighth commonest cause of cancer deaths among men (4.5%).5 it was also reported to be the most common cause of cancer-related, hospital-based deaths in 2008 and the second most common cause in 2010, representing 8.78% of all cancer deaths, following stomach cancer.5,6 the age-standardised incidence rate was 4.2 and 0.7 per 100,000 per year, and the crude incidence was 1.9 and 0.3 in men and women, respectively. the disease ranks first as a cause of cancer-related deaths in qatar, the united arab emirates (uae), and bahrain. in oman, small cell lung cancer (sclc) accounted for 12% and non-small-cell lung cancer (nsclc) for 88% of all the cancers reported in those countries. among nsclcs, the adenocarcinoma subtype accounted for 34%, squamous cell carcinoma around 22%, and other specified carcinomas and not otherwise specified subtypes accounted for 16% of cases.5 traditionally, advanced metastatic nsclc was treated with palliative systemic chemotherapy, but the majority of those patients experienced disease progression shortly after the cessation of chemotherapy, including those who initially responded to such an intervention. recently, maintenance therapy has emerged as a new hope for these patients with improved outcomes and is associated with prolongation of survival by a median of two to three months. this article describes the consistent gains in survival over the past few decades and current evidence related to maintenance therapy, and also tries to identify patient subsets which are most likely to benefit from maintenance therapy. methods data was identified from searches in medscape, pubmed, google, and key cancer groups such as the american society of clinical oncology (asco), national comprehensive cancer network (nccn), and the european society for medical oncology (esmo) by using terms such as ‘chemotherapy in metastatic or advanced non-small-cell lung cancer’, ‘maintenance chemotherapy’, ‘consolidation therapy’, and ‘molecular targeted therapy’. reference was also made to key phase ii and iii trials and meta-analyses published in reputable oncology journals (e.g. journal of clinical oncology, the new england journal of medicine, oncologist, lancet oncology, journal of thoracic oncology). systemic chemotherapy in advanced non-smallcell lung carcinoma patients with untreated advanced or metastatic disease have a median survival period of ~4 months, and can expect a one-year survival period in 10% of cases when managed with best supportive care (bsc).7 systemic chemotherapy remains the standard treatment for advanced or metastatic nsclc, especially for patients who do not harbour somatic mutations of the epidermal growth factor receptor (egfr) gene. a meta-analysis in 1995 showed that the use of cisplatin-containing chemotherapy was found to be associated with a 27% reduction in the risk of death, and improvement of 10% in survival, to attain a cumulative survival of 20% at one-year when compared to bsc alone (p <0.0001).8 poly-chemotherapy with a cisplatin backbone remained the gold standard based on two meta analyses in advanced nsclc. in studies of cisplatin versus carboplatin by hotta et al., patients with metastatic lung cancer were evaluated during treatment, revealing that cisplatin was marginally superior to carboplatin. the studies also found that the addition of a third generation agent to cisplatin was associated with an 11% longer survival compared to cisplatin being used alone.9,10 large randomised phase iii trials also have shown that platinum-doublets, (with gemcitabin, docetaxel, or vinorelbine) yielded a median overall survival (os) of 8–10 months. a meta-analysis of 65 trials, including 13,601 patients, confirmed that the use of doublet chemotherapy increased the response rates (rr) and the median survival rates at one year by 20% when compared to single agent therapy. adding a third agent to platinum doublets enhanced the response rates but not the survival and were more toxic.11 muhammad furrukh, ikram a. burney, shiyam kumar, khwaja f. zahid and mansour al-moundhri review | 5 with marginal renal functions and is associated with higher rates of thrombocytopenia, especially when used in combination with gemcitabine, but needs less hydration. two separate meta-analyses of over 12,000 patients combined compared responses, survival, toxicity, and cost of the platinum versus nonplatinum doublets.22,23 the rr were higher with cisplatin but the os outcomes remained the same. one review compared platinum therapy to non-platinum agents, with a 60% increase in the odds ratio for objective rr (p <0.0001) and a 5% enhancement in patients’ 12-month survival (p <0.0003) in favour of cisplatin-based chemotherapy. it was also associated with reduced risk of death and less chemo-refractoriness, while a higher likelihood of response to platinum doublets was observed in the other trial.22,23 the rates of nausea, vomiting, delayed vomiting, myelosupression, nephrotoxicity, and gastrointestinal (gi) toxicity remained high with the platinum compounds. when cisplatin was compared with third generation agents, there was no difference in survival outcomes (p = 0.17), but it was associated with more neuropathy, more febrile neutropaenia, and toxic deaths. the third generation singlets were better tolerated, found less toxic in the case of ecog performance status (ps) 2, and may also be an option in selected ps 3 patients, or in those who are elderly or with major co-morbidity. moreover, third generation singlets remained a suitable option, when platinum compounds were contraindicated. carboplatin was not found to be superior to these agents; in fact, it was associated with 11% higher mortality in non-squamous nsclc. it is evident that the median survival of patients with advanced (iiib) or metastatic (iv) nsclc has enhanced substantially over the last few decades. for those receiving bsc, the median survival time is approximately 3–4 months, around 6 months for those receiving single agent platinum, and, when patients receive 4–6 cycles of cisplatin doublets (cisplatin plus a third generation agent), the median os reaches 8–10 months.7 the combination of cisplatin plus pemetrexed has lately emerged as standard of care in nonsquamous nsclc, with a resultant median survival of 12.6 and 11.4 months for adenocarcinoma and large cell carcinoma subtypes, respectively, while the cochrane collaboration group analysed 16 randomised trials of more than 2,700 patients with advanced nsclc.12 platinum doublets were found to be associated with higher rr with an absolute benefit of 9% improvement in median os at one year (i.e. 20%) using single agents versus 29% using doublets (p <0.0001). the eastern co-operative oncology group’s (ecog) e1594 trial compared various third generation agents (paclitaxel, doxetaxel, or gemcitabine) in combination with a platinum compound.7 the response rates were 19% and the median survival was 9.2 months in females (n = 431) and 7 months in males (n = 726) and the oneand two-year survival rates were 30% and 10%, respectively. other randomised clinical trials showed consistent results.13-17 socinski et al. reported nab paclitaxel carboplatin use in advanced squamous histology where the combination was associated with a highly significant response rate of 41% versus 24% for cremophor paclitaxel and carboplatin, but there was no improvement in survival rates except in elderly.18 in 2006, the doulliard meta-analyses comprising 7 randomised clinical trials, including 2,867 patients, compared docetaxel to vinorelbine. the study confirmed a 11% reduction in the risk of death and a 43% reduction in the risk of febrile neutropaenia in favour of docetaxel.19 the impact of third generation drugs on the activity of first-line chemotherapy in advanced nsclc was published in 2009 in a meta-analysis by francesco grossi. the study included 45 trials of 11,867 patients. the risk of immediate progression was found to be 14% lower with gemcitabine, a statistically insignificant 9% lower with docetaxel, and 22% higher with paclitaxel. no risk of immediate progression was seen with vinorelbine.20 meta-analysis of poly-chemotherapy incorporating platinum triplets certainly improved response rates (p = 0.001), but neither showed improvement in progression-free survival (pfs) or os (p = 0.88) and was certainly associated with higher toxicity.21 as a gold standard, platinum can be combined with any of the third generation agents (i.e. docetaxel, gemcitabine, vinorelbine, or irinotecan) with superior efficacy. the choice of agent generally depends on clinical parameters, drug availability, cost, patient convenience, and toxicity. carboplatin is still widely used for patients improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 6 | squ medical journal, february 2013, volume 13, issue 1 carboplatin plus gemcitabine or docetaxel has emerged as the best combination for treating the squamous subtype.24 thus, histology for the first time emerged as a predictor for response, and the impression of one chemotherapy combination as the sole therapy for all histology has started to fade away. to date, platinum doublets remain the mainstay of treatment in patients with ecog ps 0–1 [table 1], and with marginally higher toxicity in ps 2 patients.25 the absolute benefit of chemotherapy at one year varied according to the ps: in ps 0 and 1, the absolute benefit was 8%; in ps 2 the benefit was 5%, and in ps 3 it was 4%.26 lung cancer is a disease of the elderly and approximately one in every three patients is 70 years or above. an equal number of patients have a ps of 3 or 4. treatment of the elderly, and those with poor performance should be individualised.27 a third generation agent seems suitable, and there has been some evidence that these improved survival rates were as good as in younger patients when compared to bsc in the fit individuals with wellpreserved organ functions at the expense of higher toxicity.28 in the last 5 years, the plateau in survival gains prompted researchers to drift either towards molecular profiling and targeting cells at the molecular level, or towards improving survival outcomes with maintenance therapy until patients experience best response or toxicity. bsc was considered superior to chemotherapy in the frail or elderly and for those with ecog ps 3 or 4.7, 45 it had also been a matter of debate as to what constitutes the exact number of chemotherapy cycles in advanced nsclc. by 2009, it had been established that “doublet chemotherapy should be administered for no more than 6 cycles” and for patients who attain either disease stabilisation or some response to induction chemotherapy, a treatment-free interval was offered.29 initiation of a different chemotherapy prior to disease progression was not the norm. a focused update in 2009 recommended that in patients with metastatic nsclc, frontline platinum doublet should be discontinued at disease progression.29 those who attain disease stabilisation should be offered a total of 4 chemotherapy cycles while those with any degree of benefit should be continued until 6 cycles have been achieved.29 in recent times, the outcome of advanced and metastatic nsclc has improved substantially with the integration of chemotherapy with biologics either sequentially or concurrent. the targeted agents include the egfr-tyrosine kinase inhibitors (tki) (erlotinib or gefitinib) and the corresponding chimeric egfr-blocking antibody cetuximab, and the anti-angiogenic monoclonal antibody bevacizumab which targets the vascular endothelial growth factor (vegf).30‒32 these agents are used as upfront therapy in combination with platinum doublets, and were based on large randomised clinical trials where they were continued beyond chemotherapy as maintenance therapy until progression of the disease or the appearance of toxicity. maintenance therapy the biologic basis of maintenance therapy is the goldie-coldman hypothesis which states that early use of non-cross resistant agents might increase the probability of killing more cells before resistant clones arise.33 patients tolerating and responding to treatment with 4 cycles of chemotherapy may be treated with an additional two cycles. maintenance therapy using single agent chemotherapy is offered until progression of the disease or appearance of toxicity, while ensuring that the ps does not deteriorate. on the contrary, the day model indicates that the most active drug regimens should table 1: eastern co-operative oncology group (ecog) performance status25 ecog performance status grade ecog 0 fully active, able to carry on all pre-disease performance without restriction 1 restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 ambulatory and capable of all self care but unable to carry out any work activities. up and about more than 50% of waking hours 3 capable of only limited self care, confined to bed or chair more than 50% of waking hours 4 completely disabled. cannot carry on any self care. totally confined to bed or chair 5 dead muhammad furrukh, ikram a. burney, shiyam kumar, khwaja f. zahid and mansour al-moundhri review | 7 nsclc progress after initial response to induction chemotherapy. second-line chemotherapy improved pfs and enhanced the median os. soon et al. carried out a meta-analysis of 13 randomised trials between 1989 and 2008. soon’s metaanalysis was certainly influenced by a relatively large permetrexed maintenance therapy (jmen) trial (excluding atlas and saturn trials), comprised of over 3,000 patients, of which 10 of the 13 trials were done in the years after 2000.37–39 the following facts were revealed in favour of maintenance therapy: 1) the improvement in os was a statistically significant 8% reduction in the hazard of death (hr 0.92; 95%; confidence interval [ci] 0.86–0.99; p = 0.03) for continued therapy; 2) it was not dependent on chemotherapy use, either platinum or third-generation agents; 3) the pfs improved with maintenance therapy, with a 25% reduction in hazard for progression (hr 0.75; 95% ci; 0.69–0.81; p <0.00001). the use of thirdgeneration agents was associated with higher pfs (p = 0.003) when compared to the older regimens; 4) five of the 7 trials demonstrated major improvements in global quality of life (qol) scores when using the maintenance chemotherapy arm; two of the 7 favoured the standard chemotherapy arm; 5) two of the 7 trials suggested an increase in the adverse effects in the maintenance arm, especially myelotoxicity; 6) cost of the drugs and associated hospital stays were reasons for concern. there are numerous arguments against continuing chemotherapy in the palliative setting be used as a consolidation treatment to optimise results, and that treatment should be restricted to only 4–6 cycles.34 the rationale for continued intervention is simple: if one waits, allowing a chemotherapyfree interval, the disease progresses in roughly two months, with symptomatic deterioration and a possible fall in performance status. offering immediate maintenance versus delayed salvage therapy at progression has always been an area of debate.35 switch maintenance therapy refers to the continuation of systemic therapy using a different non-cross-resistant drug from the patient’s initial chemotherapy regimen before disease progression. in a meta-analysis by soon yy in 2009, patients with any degree of response or disease stabilisation were either subjected to maintenance treatment or were asked to watch and wait with intervention at progression.36 there was a 50% drop rate due to the deterioration of signs and symptoms or performance status in the watch and wait group, and only 50% were found fit enough to receive second-line therapy at progression. therefore, the benefit of such an approach was questioned and instead soon posited continuing chemotherapy until best response or toxicity. the hypothesis generated was meant to meet a primary endpoint of enhancement in pfs and an improvement in median os with acceptable toxicity and tolerability while maintaining the ps. virtually all patients with advanced, metastatic table 2: key phase iii trials of switch maintenance therapy in non-small-cell lung carcinoma clinical trials treatment arms no. patients pfs(m) os (median) fidias et al.40 2009 gemcitabine carboplatinimmediate dx gem carb → docetaxel at progression 309 5.7 2.7 (p <0.0001) 12.3 9.7 (p <0.0853) capuzzo et al. (saturn)39 platinum doublet – erlotinib (egfr mut) platinum doublet – placebo 438 451 5.7 3.7 (p <0.0001) 12 11 (p <0.0088) ciuleanu et al. (jmen)37 cg, pg, dg → pemetrexed + bsc versus placebo + bsc 441 222 5.2 2.6 (p <0.0001) *18.6 13.6 (p <0.0001) takeda et al.43 (wjtog) platinum doublets x 6 platinum doublets – gefitinib maintenance 604 higher (p <0.001) (p <0.11) ^22 vs 11 *15.5 vs 7.7 zhang et al.42 (inform c-tong 0804) platinum doublets + bsc platinum doublets – gefitinib maintenance 296 2.6 4.8 (p <0.0001) (p = ns) ^never smokers vs smokers; *adenocarcinoma vs non-adenocarcinoma. ns = not significant. improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 8 | squ medical journal, february 2013, volume 13, issue 1 as this is carried out without breaks in therapy, subjects advanced cancer patients to more toxicity, involves more trips to outpatient clinics, and increases the frequency of blood tests and/or transfusions. maintenance may also be associated with poor qol.35 the following text briefly describes trials and outcomes of effective, better-tolerated drugs that have emerged as agents to be used as maintenance therapy in selected lung cancer patients. t r i a l s o f s w i t c h m a i n t e n a n c e fidias et al. conducted a phase iii trial of 309 patients with advanced nsclc who did not show progression after first-line treatment with 4 cycles of carboplatin-gemcitabine. the patients were randomised to receive immediate docetaxel versus delayed (at progression) treatment.40 of those who enjoyed a chemotherapy holiday until progression of the disease, 37% had either deterioration of their ps or symptomatic deterioration, and therefore were not subsequent candidates for delayed docetaxel. however, of those in the maintenance arm, 95% could undergo immediate docetaxel. the two arms had similar rr, but the maintenance therapy was associated with significant improvement in pfs by three months (p = 0.0001). however, there was no difference in median os (12.5 months, p = 0.08) in the delayed docetaxel arm. though a negative trial, it is evident that a delay in salvage therapy resulted in a third of the patients falling short of subsequent intervention [table 2]. conducted by cappuzzo et al., the saturn study was a non-chemotherapy, large phase iii randomised trial of 1,949 patients.39 patients with adenocarcinoma subtypes were subjected to maintenance erlotinib after 4 cycles of standard induction chemotherapy. the trial improved pfs by two months (p = 0.0001) and median os by one month (12 versus 11 months, p = 0.0088) in favour of erlotinib. subset analyses revealed a greater benefit for patients with egfr mutations and, interestingly, patients having wild-type egfr also derived benefit with maintenance erlotinib (11.3 versus 10.2 months, p = 0.0185). all histologic subtypes benefited, but adenocarcinoma and those with stable disease benefited the most (11.9 months for erlotinib versus 9.6 months for placebo p = 0.0019). based on the saturn study39 and retrospective exploratory data from br.21 trials, patients with squamous-cell carcinoma (scc) also benefited from erlotinib after induction chemotherapy as secondor third-line salvage, but use of erlotinib as maintenance in scc remains to be defined in the context of a clinical trial.41 a manageable acne-like rash and diarrhoea were the only toxicity reported with erlotinib use, but it was not cumulative and reduced over time. the jmen 663-patient trial involved pemetrexed treatment combined with bsc versus the use of a placebo plus bsc.37 the study revealed improvement in pfs by 2.5 months and a landmark 5.2 months improvement in os in the adenocarcinoma subtypes (p = 0.0001). scc histology had a detrimental effect on survival due to differential expression of thymidylate synthase, and the survival in scc histology was indeed inferior by one month (p = 0.9). the trial included stage iiib/iv nsclc, ps 0–1 stable, or responding disease post-platinum doublets. pemetrexed also has the advantage of ease of administration (a 10 minute intravenous (iv) infusion) and therefore outpatient administration and superior tolerability with similar qol scores. pemetrexed maintenance was associated with higher but manageable toxicity (i.e. 16% in the pemetrexed arm versus 4% in the placebo arm) there was a 3% incidence of grade 3–4 neutropenia versus 0% in the placebo group, and 5% of patients felt fatigue in the treatment arm versus 1% in the placebo arm. inform, a chinese trial published by zhang l. et al. used platinum doublets in non-progressing lung cancer patients who were subsequently randomised to receive gefitinib plus bsc versus bsc only.42 the pfs was superior in favor of the tki arm but the os remained the same. in the west japan thoracic oncology group trial, 600 chemotherapy-naïve, stage iiib/iv patients with nsclc (asymptomatic brain metatstases allowed, 31% non-smokers, 78% adenocarcinoma) were randomised to 6 cycles of platinum doublets versus 3 cycles followed by gefitinib maintenance.43 the gefitinib arm revealed improvement in pfs (p = 0.001) with a trend towards improvement in os. subset analyses showed doubling in median os in non-smokers compared to smokers as well as in the adenocarcinoma subtypes in the gefitinib maintenance arm. a modest 1.2 months of improvement in median pfs was seen in a french ifc trial (eortc 08021) trial of maintenance gefitinib, but no gains muhammad furrukh, ikram a. burney, shiyam kumar, khwaja f. zahid and mansour al-moundhri review | 9 nor in the median survival (75 versus 60 weeks; p = 0.243). von plessen et al. demonstrated, in another negative trial, that 6 versus 3 cycles of vinorelbine and carboplatin did not translate into a meaningful prolongation of pfs (21 versus 16 weeks; p = 0.21) or os (32 versus 28 weeks; p = 0.75), and more blood transfusions were used in the maintenance arm.48 the use of gemcitabine as continuation therapy after initial treatment with 4 cycles of gemcitabine and cisplatin remains one of the most promising of the continuous maintenance therapies. brodowicz et al. showed that maintenance therapy with gemcitabine resulted in a longer median time to progression (6.6 versus 5.0 months; p < 0.001) without any significant improvement in median os (13 versus 11 months; p = 0.195).49 however a preplanned subgroup analysis revealed that in those with a karnofsky performance status (kps) score of greater than 80, the median survival doubled (25.3 versus 12.2 months). gemcitabine maintenance following gemcitabine carboplatin combination reported by belani et al. was a negative trial for pfs (p 0.57) and os (p 0.83), possibly because 66% of the patients had ps 2 and only 34% had a ps 0–1.50 a subgroup analysis, where patients’ kps was >80, clearly favoured the gemcitabine maintenance arm. until those studies, continuation maintenance therapy was associated with a modest improvement in pfs with no gains in os at the expense of more but manageable side-effects. kps emerged as a strong predictor for response and a clinically meaningful outcome for maintenance therapy. in the ifct-gfpc 0502 french trial of 464 were witnessed in the os.44 switch maintenance by virtue of increase in pfs and os (pemetrexed or erlotinib) has emerged as a new standard of care in adenocarcinoma patients with preserved organ function who maintain ps 0–1, and therefore has been approved by the nccn guidelines version 3.2012.45 t r i a l s o f c o n t i n o u s m a i n t e n a n c e continuous maintenance refers to the prolonged use of one or more agents which the patient has been exposed to in his/her initial regimen in the absence of disease progression. there are several published randomised and ongoing clinical trials addressing the role of continuation maintenance therapy for advanced/metastatic nsclc [table 3]. socinski et al. reported a negative trial of 230 patients with advanced nsclc.46 patients were treated with carboplatin paclitaxel doublets for a total of 4 cycles and then were either subsequently treated with weekly paclitaxel until progression or given a chemotherapy-free interval (cfi). the same agent was then given again at disease progression. the continuation paclitaxel failed to improve the rr, the median survival rate, or qol scores. however, the extended therapy arm resulted in a higher incidence of neuropathy; 40% compared to 20% in the observation arm. in 2003, belani et al. described the use of weekly maintenance paclitaxel in 390 non-progressing advanced and metastatic nsclc cases.47 using 3 different schedules of paclitaxel and carboplatin, the study revealed neither improvement in time to progression (ttp) (38 versus 29 weeks; p = 0.124) table 3: key phase ii-iii trials of continuous maintenance therapy in non-small-cell lung carcinoma clinical trials treatment arms no. of patients pfs median os (m) belani et al.47 carboplatin gemcitabine carboplatin gemcitabine → gemcitabine 390 -ive trial as 66% patients kps<80 (p <0.124) (p <0.243) brodowicz et al.9 cisplatin gemcitabine cisplatin gemcitabine → gemcitabine 519 (os for kps<80-12.2m) (os for kps>80-25.3m) 5.5 6.6 (p <0.001) 11 13 (p <0.2) perol et al.51 cisplatin gemcitabine → gemcitabine cisplatin gemcitabine → observation cisplatin gemcitabine → erlotinib 464 3.8 (p <0.0001) 1.9 2.9 (p <0.002) p = ns paz-ares et al.2 (paramount) cisplatin pemetrexed → pemetrexed + bsc cisplatinu pemetrexed – placebo + bsc 539 4.1 2.8 (p <0.0006) 13.9 11 (p <0.0195) ns = not significant. improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 10 | squ medical journal, february 2013, volume 13, issue 1 patients with stable disease or responders, 4 cycles of cisplatin gemcitabine were used and later subgroups were continued on gemcitabine or a placebo, or were switched to erlotinib maintenance.51 all patients who subsequently progressed were offered pemetrexed. pfs was superior in the erlotinib group (2.9 months; p = 0.002) versus the gemcitabine group (3.8 months; p <0.0001) versus the observation arm (1.9 months), but the os was only numerically superior in the maintenance arms. the paramount trial incorporated maintenance pemetrexed in a phase iii setting in patients receiving initial platinum pemetrexed doublets for 4 cycles. a group of 359 nonprogressive patients were randomly assigned to maintenance pemetrexed plus bsc, while 180 patients were assigned to a placebo plus bsc. the test arm revealed superior pfs (4.1 months versus 2.8 months; p = 0.0006) in all age groups, irrespective of smoking status. all responders indicated an equal qol, with 3–4% indicating grade 3 or 4 toxicity including nausea, anaemia, fatigue, etc. however, fatigue was significant (5% versus 1% in those receiving ≤12 cycles) and may be managed by increasing the cycle interval to 4 weeks. the os data were presented at the 2012 asco conference where maintenance pemetrexed plus bsc was associated with a 22% reduction in risk of death (hr 0.78; 95% ci; 0.64-0.96) and the os was 13.9 versus 11 months for the placebo plus bsc group (p = 0.0195), and was maintained when calculated from the beginning of induction therapy (17 versus 14 months). a third of the patients lived beyond 24 months.52 fast act-i was a phase ii study by tony mok et al. employing platinum gemcitabine doublets every 4 weeks for 6 cycles in untreated stage iiib/ iv nsclc, concurrent with erlotinib or a placebo followed by continuous maintenance erlotinib in non-progressing patients in the experimental arm versus erlotinib at progression in the placebo arm.53 pfs was increased, but not os in the continuous maintenance arm. based on this encouraging result, a phase iii trial (fast act-ii) with a similar design has completed patient accrual in september 2010 and the results are keenly awaited.54 some institutes, including ours, finds it reasonable to continue pemetrexed, or gemcitabine, or erlotinib in patients with adenocarcinoma subtypes and gemcitabine in scc. based on the compelling data above, the focused update in 2011 recommended that a patient with any degree of clinical benefit after 4 cycles of frontline platinum doublet therapy, an immediate alternative, or a single agent should continue maintenance treatment. this should be offered for patients with adenocarcinoma subtype having ps 0–1.55 maintenance therapy in frail and elderly patients should be individualised in the absence of controlled randomised trials. with their ease of administration at home, lack of the serious side effects that are generally seen with chemotherapy, and potential use in ecog ps ≥2 patients, oral tkis remain a viable therapeutic option in this set of patients. m o l e c u l a r ta r g e t s a n d m o n o c l o n a l a n t i b o d i e s a s m a i n t e n a n c e vascular targets and bevacizumab (monoclonal antibody targeting the vegf (vascular edothelial growth factor a) tumour angiogenesis has long been established. in 1971, folkman proposed a hypothesis regarding the presence of vascular factor, and it took almost two decades to discover vascular endothelial growth factor (vegf).56 tumours require a rich vascular supply in order to grow and metastasise. a tumour of 1–2 mm can survive without acquiring a blood supply, but as it grows it evolves an independent blood supply by the release of vegf that binds to corresponding receptors (vegfr), initiating angiogenesis, cell proliferation, invasion, and metastases. in a 2004 study whereby researchers locked vegf pathways and thus tumourigenesis by monoclonal antibodies, patients showed higher response rates and superior survival outcomes. in the initial phase ii trial of bevacizumab, two different dose schedules (7.5 and 15 mg/kg) were used, with a carboplatin paclitaxel doublet for a maximum of 6 cycles, whereas in the third arm, bevacizumab was added to the same combination therapy at disease progression and maintained until best response or toxicity.57 patients with scc were excluded in subsequent trials because of an increased risk of fatal haemoptysis (9% pulmonary haemorrhage), especially if the lesions were cavitating, central, or adherent to a mediastinal blood vessel. also excluded were patients with cns metastases, due muhammad furrukh, ikram a. burney, shiyam kumar, khwaja f. zahid and mansour al-moundhri review | 11 ecog e4599 trial [table 4], the addition of bevacizumab to the paclitaxel and cisplatin arm was associated with enhanced rr (35% versus 15%), superior pfs (6.2 versus 4.5 months), and a median os (12.3 versus 10.3 months; p = 0.003).59 the oneand two-year survival rates improved from 44% to 56%, and 17% to 27%, respectively. subgroup analyses revealed that patients with adenocarcinoma subtypes showed median survival improvement to 14.2 months (a 3.9 month improvement). for those who developed to a fear of intra-tumoural bleed. rr were enhanced from 30% with platinum doublets to 40% with doublets plus bevacizumab at 15 mg/kg weight. the median pfs (7 months versus 5.9 months; p= 0.023) and os (17.7 months versus 14.9 months; p = 0.63) were superior in the 15 mg/kg bevacizumab arm. in another phase ii japanese trial, j 019907, paclitaxel and carboplatin were used alone or with bevacizumab, and the addition improved rrs and the pfs by one month (p = 0.009).58 in an open label prospective, randomised, table 4a: key phase ii-iv trials of addition of continuous bevacizumab +m. bev – therapy in non-small-cell lung carcinoma author/ study # of patients phase regimen rr (%) pfs (m) p value os (m) p value johnson et al.57 99 ii chemo alone + m. bev 30 40 7 7.4 0.023 14.9 17.7 0.63 seiji niho58 180 ii carbo/ pac + m. bev 31 60.7 5.9 6.9 0.009 22 22 0.9 jyoti et al.64 50 ii cddp/ pem + m. bev. 8 14.6 sandler et al. (ecog e4599)59 subgroup analyses: -adenocarcinoma -developing hypertension 878 iii cddp/ pac m. bev. 15 35 4.5 6.2 10.3 12.3 14.2 15.9 0.003 0.03 reck martin et al. (avail)61 1043 iii cddp/ gem + bev 7.5 mg/ kg + bev 15 mg/ kg 22 38 35 6.1 8.5 8.2 13.1 13.6 3.4 0.76 lucio crino et al. (sail)62 2212 iv chemo + m. bev 8.3 19.3 miller et al. (atlas)38 740 iii platinum doublet + bev + m. bev + m. bev + erlotinib 3.7 4.8 ~ ns 0.0012 avaperl165 (ongoing) 362 iiib cddp pem bev. + m. bev. + m. bev. + pem 3.7 7.4 <0.001 15.7 not reached 0.23 table 4b: phase ii & iii trials of cetuximab in advanced metastatic non-small-cell lung carcinoma study/author # of patients phase regimen rr (%) pfs os (m) lucas76 rosell 86 ii cddp / vin + cetuximab 28 35 4.6 5 7.3 8.3 bms 10075 butt 130 ii cddp / gem + cetuximab 18 28 4.2 5.1 9 12 flex71 pirker 1135 iii cddp / vin + cetuximab 29 36 4.8 4.8 10.1 11.3 bms 09974 lynch 676 iii carb / taxane + cetuximab 17 26 4.4 8.4 4.2 9.7 rr = response rate; pfs = progression-free survival; os = overall survival; chemo = chemotherapy; +mbev = bevacizumab maintenance after induction with chemo + bevacizumab; carb = carboplatin; pac = paclitaxel; pem = pemetrexed; gem = gemcitabine; ccdp = cisplatin; vin = vinorelbine; ns = not significant. improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 12 | squ medical journal, february 2013, volume 13, issue 1 hypertension (defined as >150/100 mm/hg or a 20% increase in diastolic blood pressure (bp) from the baseline) because of bevacizumab, the median os was longer (15.9 months; p = 0.03).59 in retrospect, subset analyses in patients above 70 years show a trend towards higher rr and pfs with the addition of bevacizumab, but there was no increase in os (p = 0.4). it is not clear as yet if the improvement in efficacy was because of induction or because of the maintenance effects of bevacizumab. avail was a randomised phase iii trial using cisplatin, or gemcitabine and bevacizumab in three groups: group a received chemotherapy alone; group b received chemotherapy and 7.5 mg/kg of cisplatin, and group c received chemotherapy plus 15 mg/kg of bevacizumab.61 the rrs improved (group a 22%; group b 38%; group c 35%) but there was no improvement in survival with the bevacizumab addition. the primary endpoint of the trial was not an investigation of maintenance. sail, an open label phase iv trial of 2,212 patients from 40 countries, analysed the addition of bevacizumab to platinum doublets followed by maintenance bevacizumab, which suggested an improvement in time to progression (ttp) to 8+ months and a median os to a landmark 19.3 months.62 these figures were reproduced by another us-based study, aries, where the median os also approached 13.6 months.63 a phase ii trial, combining pemetrexedcarboplatin with or without bevacizumab also improved survival outcomes.64 the pfs was 8 months and there was an os of 14.6 months with the addition of bevacizumab. based on these findings, a randomised trial (avaperl 1) was initiated in patients with advanced adenocarcinoma, incorporating pemetrexed-cisplatin with or without bevacizumab and then continued with maintenance bevacizumab, with or without pemetrexed.65 the maintenance combination of bevacizumab and pemetrexed revealed better rr and a superior pfs. the median os was 15.6 months in the bevacizumab arm, which has not yet been reached in the bevacizumab-pemetrexed maintenance arm. in summary, the addition of bevacizumab to the standard platinum doublets gives a definitive hint at improving the median survival in adenocarcinoma subgroups way beyond the 12 months seen in ps 0–1 patients. information on continuing bevacizumab beyond progression came from preclinical data in animal xenografts, where it not only enhanced the effects of chemotherapy, but also delayed regrowth and improved survival.66 an observational study of bevacizumab use beyond progression in metastatic colorectal cancer has confirmed significant improvement in medial survival, from 26 months to 31 months.67 in a retrospective analysis from the electronic medical records of nsclc in the us, in a total of 498 non-squamous nsclc patients, 403 received first line chemotherapy plus bevacizumab; 154 received bevacizumab monotherapy on progression; and 249 did not. median os was 20.9 months for the bevacizumab group versus 10.2 months for the chemotherapy only group, and a pfs of 10.3 months for the bevacizumab group versus 6.5 months in the chemotherapy only group.68 a large multi-institutional, prospective, controlled randomised trial by avastin in all lung lines was initiated by roche pharmaceuticals, and is currently recruiting patients.69 it incorporates induction platinum doublets plus bevacizumab which is continued post-progression, with salvage single-agent sequential chemotherapy with each progression in an attempt to improve survival figures, without compromising qol and with acceptable toxicity. miller et al. published the atlas, a phase iii trial on advanced nsclc patients (n = 768) treated with platinum doublets for 4 cycles using bevacizumab as a third agent during induction and then continued in non-progressing patients alone or with concurrent erlotinib.38 the combination arm had a superior pfs by 1.1 months (4.8 versus 3.7 months; p = 0.0012), but there was no improvement in os; therefore, it is a struggle to find a place for the use of two targeted agents in the presence of better options [table 4]. the ongoing study design of the eracle trial (induction pemetrexed and cisplatin followed by maintenance pemetrexed versus carboplatin-paclitaxel and bevacizumab followed by maintenance bevacizumab) compares the two drug combinations in non-squamous nsclc in a maintenance setting.70 point break trial is a negative trial for os, yet the maintenance arm comprising of pemetrexed & bevacizumab revealed 1.7 & 2 months improvement in pfs and os respectively compared to bevacizumab maintenance alone. muhammad furrukh, ikram a. burney, shiyam kumar, khwaja f. zahid and mansour al-moundhri review | 13 mutation did not predict the response to cetuximab. a retrospective analysis of flex trial reveals the maintenance cetuximab arm is associated with a significant improvement in median os (1.3 months) in patients with stable disease while median survival was unchanged in patients with any kind of response.73 the us (bms-099)74 trial looked at unselected patients with nsclc to taxane plus cetuximab, and reached its primary endpoint of enhanced median os (9.7 versus 8.4 months) but not pfs. a review by pirker et al. (flex71, bms 09974, bms 10075, lucas76 [see table 4]) confirmed the consistent benefit of adding cetuximab to chemotherapy in patients with advanced nsclc of all histological subtypes in terms of os (p <0.01), pfs (p <0.03), and os rate (or 1.463, p <0.001).77 the southwest oncology group trial is a phase ii study that combined cetuximab to carboplatin, paclitaxel and bevacizumab for 6 cycles, followed by bevacizumab weekly until disease progression.78 the primary endpoint of the trial was the frequency and severity of haemorrhagic toxicity that was grade 4 or higher in advanced stage non-squamous nsclc and was found to have a tolerable safety profile with 2% incidence of haemorrhage that was grade > 4. swog 0819 is a similar, ongoing phase iii trial comparing the same 4 drug combination with the 3 drug combination of ecog 4599 trial.79 cetuximab was also evaluated concurrently with paclitaxel carboplatin or sequentially after the same regimen and then continued as maintenance. the outcomes were similar but sensory neuropathy was higher in the former (15% versus 5% p <0.036).80 acne-like rash, infusion related reactions and hypomagnesaemia were encountered in cetuximab recipients. eight trials including 3,736 patients were analysed for either maintenance therapy for patients with any clinical benefit in nsclc compared to watchful waiting or placebo. the study analyses included the os as a primary outcome and pfs and toxicity as a secondary outcome. the switch maintenance was associated with improvement in os (p <0.001), while the continuous arm showed a trend towards better os but lacked statistical significance (p = 0.124). an interaction test was applied between the two maintenance therapies (switch and continuous), yet the difference in os between the two maintenance strategies was not statistically significant (p = 0.777) and epidermal growth factor receptor and cetuximab (monoclonal antibody targeting the egfr) the first line erbitux in lung cancer (flex) trial was a phase iii, prospective, randomised trial of 1,125 patients from 155 treatment centres comparing the addition of cetuximab to cisplatin and vinorelbine given for 6 cycles.71 in the test arm, cetuximab was continued as maintenance until progression of disease or unacceptable toxicity. median os was 11.3 months in the experimental arm (n = 557) and 10.1 months in the chemotherapy alone arm (n = 558 patients; p = 0.044). interestingly, women survived longer than men (12.7 months versus 9.3 in men), asians did better compared to caucasians (19.5 months versus 9.6), and patients with a better performance status, as well as those who had never smoked, did statistically better. patients with an acne-like rash (grade 1–3 rash seen in 56%, grade 3 in 10%) had a longer overall survival than those without (15 months versus 8.8; p <0.001). the addition of monoclonal antibodies improved the rrs, which was statistically significant (36% versus 29%). adenocarcinoma subtype (46% of overall patient population) expressing egfr (defined as at least one egfr protein on immunohistochemistry (ihc) showed a survival of 20.2 months in the experimental arm and 13.6 months in the chemotherapy-only arm.72 the researchers looked at the egfr expression in a qualitative manner (i.e. product of the staining intensity [1+, 2+, 3+]) and the number of cells stained on ihc were scored between 0–300. a total of 30% of the patients had an egfr h-score >200, which was considered strongly expressive, and a median survival of 12 months was seen in the cetuximab plus chemotherapy arm as compared to those with an egfr h-score <200, which was considered negative, where the survival was 9.3 months (hr 0.75). patients with scc (34% of the patient population) had a median os of 10.2 months in cetuximab group versus 8.9 months in chemotherapy-only arm. a subgroup analysis revealed an egfr overexpression in 30% of scc patients, and when these were subjected to cetuximab and chemotherapy, the survival improved to 11.2 months for the combination arm versus 8.9 months for the chemotherapy-only arm, and also improved one-year survival to 44% in the combination arm versus 25% in the chemotherapyonly arm. unlike colon carcinoma, the k-ras improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 14 | squ medical journal, february 2013, volume 13, issue 1 an improvement in pfs was found with both maintenance strategies (p = 0.128).81 subgroup analyses could not find any differences in the survival outcome in switch maintenance using chemotherapy or that with the tki. however, maintenance therapy was associated with higher toxicity. it is therefore reasonable to consider any maintenance therapy at the expense of reasonable toxicity and tolerability. conclusion maintenance therapy has emerged as a new treatment paradigm in the management of nsclc. patients with well-preserved organ function, who are maintaining their ps and responding to chemotherapy, or who are experiencing disease stabilisation after induction chemotherapy may now be effectively treated with maintenance therapy, taking tolerability into account. others may be followed closely and therapy may be individualised according to clinical course, age, and the presence of co-morbidity. salvage chemotherapy may be instituted at any time before the ps declines to levels beyond intervention, or the patient experiences significant symptomatic deterioration. careful patient and drug selection, long term safety, and qol should all be considered while patient participation remains integral in final decision making. details of patients’ clinical features, histology, and genetics should be taken into account for optimisation of therapy [tables 5a and b]. however, retrospective data and subgroup analyses should be read with extreme caution, as the number of patients in these analyses are often table 5a: maintenance strategies in non-small-cell lung carcinoma maintenance strategies (options): adenocarcinoma subtypes: 1. switch maintenance induction chemotherapy gemcitabine + carboplatin/ or cisplatin pemetrexed + cisplatin pemetrexed + cisplatin gemcitabine/or docetaxel/ or paclitaxel + cisplatin maintenance agent docetaxel *erlotinib / or gefitinib (tki) docetaxel pemetrexed 2. continued maintenance pemetrexed + cisplatin gemcitabine + cisplatin tki pemetrexed †gemcitabine tki 3. monoclonal antibody addition: platinum doublets + ‡bevacizumab platinum doublets + cetuximab ‡bevacizumab cetuximab squamous histology: platinum + gemcitabine/ or docetaxel + §cetuximab §cetuximab †gemcitabine *may be used in frail & elderly; †kps>80; ‡in nonsquamous histology only tumor not abutting major vessel and no hemoptysis; §data favors use in cases with stable disease after post induction chemotherapy. table 5b: maintenance therapy in non-small-cell lung carcinoma who gets maintenance therapy? (non-small-cell lung carcinoma): histology: adenocarcinoma subtypes squamous cell carcinoma clinical features: age: adults 18-70 years (fit, elderly) gender: any ecog ps 0-1, †kps>80 ecog ps 2 (selected cases for tki) genetics: egfr wild type chemotherapy egfr mutant *tki (tki responders; asian, women, never smoker, having adenocarcinoma) k-ras mutation chemotherapy eml4 alk crizotinib suitable subset of patients; -clinical benefit; stable disease or regression after induction chemotherapy -well-preserved organ function -no major co-morbidity *may also be used in frail & elderly; ‡in nonsquamous histology only tumor not abutting major vessel and no hemoptysis; §data favors use in cases with stable disease after post induction chemotherapy. muhammad furrukh, ikram a. burney, shiyam kumar, khwaja f. zahid and mansour al-moundhri review | 15 single agent or a 2 agent chemotherapy regimen in advanced nsclc: a meta-analysis. jama 2004; 292:470–84. 12. nsclc meta analyses collaborative group. chemotherapy in addition to supportive care improved survival in advanced nsclc: a systematic review and meta-analysis of individual patient data for 16 randomized controlled trials. j clin oncol 2008; 26:4617–25. 13. fosella f, pereira jr, von pawel j, pluzanska a, gorbounova v, kaukel e, et al. randomized, multinational, phase iii study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced nsclc: the tax 326 study group. j clin oncol 2003; 21:3016–24. 14. kelly k, crowley j, bunn pa, presant ca, grevstad pk, moinpour cm, et al. randomized phase iii trial of paclitaxel plus carboplatin in the treatment of patients with advanced nsclc: a south west oncology group trial. j clin oncol 2001; 19:3210– 18. 15. smit ef, van meerbeeck jp, lianes p, debruyne, legrand c, schramel f, et al. three arm randomized study of two cisplatin based regimens and paclitaxel plus gemcitabine in advanced nsclc: a phase iii trial of eortc lung cancer group – eortc 08975. j clin oncol 2003; 21:3909–17. 16. ohe y, ohashi y, kubota k, tamura t, nakagawa k, negoro s, et al. randomized phase iii study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced nsclc: four-arm cooperative study in japan. ann oncol 2007; 18:317– 23. 17. scagliotti gv, de marinis f, rinaldi m, crino l, gridelli c, ricci s, et al. phase iii trial comparing three platinum based doublets in advanced nsclc. j clin oncol 2002; 20:4285–91. 18. socinski ma, bondarenko in, karaseva na, makhson a, vynnychenko i, okamoto i, et al. results of a randomized, phase iii trial of nab paclitaxel and carboplatin compared with cremophor based paclitaxel and carboplatin as first line therapy in advanced nsclc. j clin oncol 2010; 28:18s. 19. douillard jy, laporte s, fossella f, georgoulias v, pujol jl, kubota k, et al. comparison of docetaxel and vinca alkaloid-based chemotherapy in the firstline treatment of advanced non-small-cell lung cancer: a meta-analysis of seven randomized clinical trials. j thorac oncol 2007; 2:939–46. 20. grossi f, aita m, defferrari c, rosetti f, brianti a, fasola g, et al. impact of third-generation drugs on the activity of first-line chemotherapy in advanced non-small-cell lung cancer: a meta-analytical approach. oncologist 2009; 14:497-510. 21. delbaldo c, michiels s, rolland e, syz n, soria jc, le chevalier t, pignon jp, et al. second or third additional chemotherapy drug for nsclc in patients reduced and the studies are subject to biases. patient and tumour characteristics derived from molecular biology and cancer genetics continue to evolve and are helping oncology decision-makers to define subsets of patients that would derive benefit from customised maintenance therapy. the data from large numbers of randomised phase iii trials is very compelling, and the year 2012 provided a variety of options for treating any given patient, but what remains to be defined is the exact sequencing of these strategies. references 1. international agency for research on cancer. globocan 2008: estimated cancer incidence, mortality, prevalence and disability-adjusted life years (dalys) worldwide in 2008. from: http:// globocan.iarc.fr/ or www.uicc.org/general-news/ globocan-2008-launched accessed: may 2012. 2. jemal a, siegel r, ward e, hao y, xu j, thun mj, et al. cancer statistics 2009. ca cancer j clin 2009; 59:225–49. 3. american cancer society. from: www.acs.org accessed: may 2012. 4. national institute of health. seer database. from: www.cancer.gov accessed: may 2012. 5. ministry of health oman. cancer incidence in oman 2012. from: www.moh.gov.om accessed: may 2012. 6. ministry of health oman. cancer incidence in oman 2008. from: www.moh.gov.om accessed: may 2012. 7. schiller jh, harrington d, belani cp, langer c, sandler a, krook j, et al. comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. n engl j med 2002; 346:92–8. 8. nsclc collaborative group. chemotherapy in nsclc: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. bmj 1995; 311:899–909. 9. ardizzoni a, boni l, tiseo m, fossella fv, schiller jh, paesmans m, et al. cisplatinversus carboplatinbased chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. j natl cancer inst 2007; 99:847–57. 10. hotta k, matsua k, ueoka h, kiura k, tabata m, tanimoto m, et al. meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. j clin oncol 2004; 22:3852–9. 11. delbaldo c, michiels s, syz n, soria jc, le chevalier t, pignon jp, et al. benefits of adding a drug to a improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 16 | squ medical journal, february 2013, volume 13, issue 1 with advanced disease. cochrane database syst rev 2007; 4:cd00456. 22. d’addario g, pintilie m, leighi nb, feld r, cerny t, shepherd fa, et al. platinum vs non-platinum based chemotherapy in advanced non-small-cell lung cancer: a meta analyses of published literature. j clin oncol 2005; 23:2926–36. 23. pujol jl, barlesi f, daures jp. should chemotherapy combinations for advanced nsclc be platinum based? a meta analyses of phase iii randomized trials. lung cancer 2006; 51:335–45. 24. scagliotti gv, parikh p, von pawel j, biesma b, vansteenkiste j, manegold c, et al. phase iii study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy naïve patients with advanced stage nsclc. j clin oncol 2008; 26:3543–51. 25. oken mm, creech rh, tormey dc, horton j, davis te, mcfadden et, et al. toxicity and response criteria of the eastern cooperative oncology group. am j clin oncol 1982; 5:649–55. 26. burdett s, johson dh, stewart l, tierney j, le pechoux c. supportive care and chemotherapy vs supportive care alone in advanced nsclc: a metaanalysis using individual patient data (ipd) from randomized controlled trials. j thorac oncol 2007; 2:s337. 27. kelly k. challenges in defining and identifying patients with nsclc and poor performance status. semin oncol 2004; 31:3–7. 28. gridelli c, aapro m, ardizzoni a, balducci l, de marins f, kelly k, et al. treatment of advanced non-small-cell lung cancer in the elderly: results of an international expert panel. j clin oncol 2005; 23:3125–37. 29. azzoli cg, baker jr s, temin s, pao w, aliff t, brahmer j, et al. american society of clinical oncology clinical practice guideline update on chemotherapy for stage iv non–small-cell lung cancer. j clin oncol 2009; 27:6251–66. 30. yang o, ichinose y, nishiwaki y, yamamoto n, negoro s, duffield e, et al. phase iii, randomized, open-label, first-line study of gefitinib (g) versus carboplatin/paclitaxel (c/p) in selected patients (pts) with advanced non-small-cell lung cancer (nsclc) (ipass): evaluation of recruits in japan. j clin oncol 2009; 27:15s. 31. mok ts, yi long wu, thongprasert s, yang ch, chu dt, saijo n, et al. gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma (optimal trial). n engl j med 2009; 361:947–57. 32. rosell r, carcereny e, gervais r, vergnenegre a, massuti b, felip e, et al. erlotinib vs standard chemotherapy as first line treatment for european patients with advanced egfr mutation positive nonsmall-cell lung cancer (eurtac): a multicenter, open label, randomized phase iii trial. lancet oncol 2012; 13:239–46. 33. goldie jh, coldman aj. a mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. cancer treat rep 1979; 63:1727–33. 34. day rs. treatment sequencing, asymmetry, and uncertainty: protocol strategies for combination chemotherapy. cancer res 1986; 46:3876 –85. 35. linda e. coate, frances a. shepherd. maintenance therapy in advanced non-small-cell lung cancer: evolution, tolerability and outcomes. ther adv med oncol. 2011; 3(3):139–157. 36. soon yy, stockler mr, askie lm, michael j. boyer. duration of chemotherapy for advanced nsclc: a systemic review and meta-analysis of randomized trials. j clin oncol 2009; 27:3277–83. 37. ciuleanu t, brodowicz t, zielinski c, kim jh, krzakowski m, laack e, et al. maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. lancet 2009; 374:1432–40. 38. miller v, o’conner p, soh c, f. kabbinavar, et al. a randomized double blind placebo controlled phase iiib trial (atlas) comparing bevacizumab therapy with or without erlotinib after completion of chemotherapy with bevacizumab for the front line treatment of locally advanced recurrent or metastatic nsclc. j clin oncol 2009; 27:799s. 39. cappuzzo f, ciuleanu t, stelmakh l, cicenas s, szczensa a, juhasz e, et al. erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. lancet oncol 2010; 11:521–9. 40. fidias pm, dakhil sr, lyss ap, loesch dm, waterhouse dm, bromund jl et al. phase iii study of immediate compared with docetaxel after firstline therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. j clin oncol 2008; 27:591–8. 41. melosky b, agulnik j, assi h. a retrospective practice review of treatment of metastatic nonsmall-cell lung cancer with second line erlotinib. cur oncol 2008; 15:279–85. 42. zhang l, ma s, song x, han b, cheng y, huang c, et al. gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic nonsmall-cell lung cancer (inform; c-tong 0804): a multicentre, double-blind randomised phase 3 trial. lancet oncol 2012; 13:466–75. 43. takeda k, hida t, sato t, ando m, seto t, satouchi m, et al. randomized phase iii trial of platinum doublet chemotherapy followed by gefitinib compared with continued platinum doublet chemotherapy in japanese patients with advanced nsclc: result of a west japan thoracic oncology group trial (wjtog 0203). j clin oncol 2010; 28:753. 44. meerbeeck jv. a randomized phase iii study of follow up with or without adjuvant gefitinib (iressa tm) following chemotherapy in patients with advanced non-small-cell lung cancer eortc08021. from: http://www.eortc.be/protoc/details.asp?protocol =08021 accessed aug 2012. muhammad furrukh, ikram a. burney, shiyam kumar, khwaja f. zahid and mansour al-moundhri review | 17 asco clinical practice updates on chemotherapy for stage iv nsclc. j clin oncol 2011; 8:63–6. 56. ferrara n, gerber hp, lecouter i. the biology of vegf and its receptors. nat med 2003; 9:669–76. 57. johnson dh, fehrenbacher l, novotny wf, herbst rs, nemunaitis jj, jablons dm, et al. randomized phase ii trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. j clin oncol 2004; 22:2184–91. 58. niho s, kunitoh h, nokihara h, horaj t, ichinose y, hida t. randomized phase ii study of first-line carboplatin-paclitaxel with or without bevacizumab in japanese patients with advanced non-squamous non-small-cell lung cancer. lung cancer 2012; 76:362–7. 59. sandler jh, gray r, perry mc, brahmer j, schiller jh, dowlati a, et al. paclitaxel carboplatin alone or with bevacizumab for non-small-cell lung cancer. n engl j med 2006; 355:2542–50. 60. dahlberg se, sandler ab, brahmer jr, schiller jh, johnson dh, et al. clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ecog 4599. j clin oncol 2010; 6:949–54. 61. martin r, von pawel j, zaloukal p, ramlau r, gorbounova v, hirsh v, et al. phase iii trial of cisplatin gemcitabine with either placebo or bevacizumab as first line treatment of non-squamous nsclc avail. j clin oncol 2009; 27:1227–34. 62. crinò l, dansin e, garrido p, griesinger f, laskin j, pavlakis n, et al. safety and efficacy of first-line bevacizumab-based therapy in advanced nonsquamous non-small-cell lung cancer. lancet oncol 2010; 11:733–40. 63. lynch tj, brahmer j, fischbach n, garst j, kumar p, spigel dr, et al. preliminary treatment patterns and safety outcomes for non-small-cell lung cancer (nsclc) from aries: a bevacizumab treatment observational cohort study (ocs). j clin oncol 2008; 26:8077. 64. patel jd, hensing ta, rademaker a, hart e, blum m, milton, et al. phase ii study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for non-squamous nsclc. j clin oncol 2009; 27:1– 7. 65. barlesi f, de castro j, dvornichenko j, kim jh, pazzola a, rittmeyer , et al. avaperl (mo22089): final efficacy outcomes for patients with advanced nonsquamous non-small-cell lung cancer randomized to continuation maintenance with bevacizumab or bevacizumab + pemetrexed after first-line bevacizumab cisplatin + pemetrexed treatment. european multidisciplinary cancer congress 2011, 23–27 sep, stockholm, sweden. abstract 34lba. 66. o'connor jpb, carano rad, clamp ar, ross j, ho cc, jackson a, et al. quantifying anti-vascular effects of monoclonal antibodies to vascular endothelial 45. national comprehensive cancer network. clinical practice guidelines version 3. from: www.nccn.org accessed: may 2012. 46. socinski ma, schell mj, peterman a, kamal b, yates s, gitten r, et al. phase iii trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage iiib/ iv non-small-cell lung cancer. j clin oncol 2002; 20:1335–43. 47. belani cp, barstis j, perry mc, la rocca rv, nattam sr, rinaldi d, et al. multicenter, randomized trial for stage iiib or iv non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly pacitaxel or observation. j clin oncol 2003; 21:2933–9. 48. von plessen c, bergman b, andresen o, rm bremnes, s sundstrom, m gilleryd, et al. palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer. br j cancer 2006; 95:966–73. 49. brodowicz t, krzakowski m, zwitter m, tzekov v, ramlau r, ghilezn n, et al. cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small-cell lung cancer: a phase iii trial. lung cancer 2006; 52:155–63. 50. belani cp, waterhouse dm, ghazal h, ramalingam ss, bordoni r, greenberg r, et al. phase iii study of maintenance gemcitabine (g) and best supportive care (bsc) versus bsc, following standard combination therapy with gemcitabine-carboplatin (g-cb) for patients with advanced non-small-cell lung cancer (nsclc). j clin oncol 2010; 28:15s. 51. perol m, chouaid c, milleron bj, gervais r, barlesi f, westeel v, et al. maintenance with either gemcitabine or erlotinib vs observation with predefined second line treatment after cisplatin-gemcitabine induction chemotherapy in advanced nsclc ifct-gfpc 0502 phase iii study. j clin oncol 2010; 28:540. 52. paz-arers l, de marinis f, dediu m, thomas m, pujol jl, bidoli p. maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (paramount): a double-blind, phase 3, randomised controlled trial. lancet oncol 2012; 13:247–55. 53. mok ts, wu yl, yu cj, zhou cc, min cy, zhang l, et al. randomized, placebo-controlled, phase ii study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. j clin oncol 2009; 27:5080–7. 54. lee js, ignacio j, yu c, zhou c, wu y, chen y, et al. fast-act: a phase ii randomized double-blind trial of sequential erlotinib and chemotherapy as first-line treatment in patients (pts) with stage iiib/ iv non-small-cell lung cancer (nsclc). j clin oncol 2008; 26:8031. 55. azzoli cg, temin s, aliff t, baker s jr., brahmer j, johnson dh, et al. 2011 focused update of 2009 improving outcomes in advanced lung cancer maintenance therapy in non-small-cell lung carcinoma 18 | squ medical journal, february 2013, volume 13, issue 1 growth factor: insights from imaging. clin cancer res 2009; 15:6674–82. 67. grothey a, sugrue mm, purdie dm, dong w, sargent d, hedrick e, et al. bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (brite). j clin oncol 2008; 26:5326–34. 68. nadler e, yu e, ravelo a, sing a, forsyth m, gruschkus s. bevacizumab treatment to progression after chemotherapy: outcomes from a us community practice network. the oncologist 2011;16:486–96. 69. gridelli c, bennouna j, de castro j, dingemans am, griesinger f, grossi f, et al. randomized phase iiib trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the avaall (mo22097) trial. clin lung cancer 2011;12:407–11. 70. galetta d, pisconti s, cinieri s, pappagallo gl, gebbia v, borsellino n, et al. induction pemetrexed and cisplatin followed by maintenance pemetrexed versus carboplatin plus paclitaxel plus bevacizumab followed by maintenance bevacizumab: a quality of life-oriented randomized phase iii study in patients with advanced non-squamous non-small-cell lung cancer (eracle). clin lung cancer 2011; 12:402–6. 71. pirker r, pereira jr, szczesna a, von pawel j, krzakowski m, ramlau r, et al. cetuximab plus chemotherapy in patients with advanced non-smallcell lung cancer (flex): an open-label randomised phase iii trial. lancet 2009; 373:1525. 72. carillio g, montanino a, costanzo r, sandomenico c, piccirillo mc, di maio m, et al. cetuximab in non-small-cell lung cancer. expert rev anticancer therapy 2012; 12:163–75. 73. pirker r, pereira rj, pawel jv, krzakowski m, ramlau r, park k, et al. egfr expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 flex study. lancet oncol 2012; 13:33–42. 74. lynch tj, patel t, dreisbach l, mcleod m, heim wj, hermann rc, et al. cetuximab and first-line taxane/ carboplatin chemotherapy in advanced nonsmall-cell lung cancer: results of the randomized multicenter phase iii trial bms099. j clin oncol 2010; 28:911–17. 75. butts ca, bodkin d, middleman el, englund cw, ellison d, alam y, et al. randomized phase ii study of gemcitabine plus cisplatin or carboplatin, with or without cetuximab, as first-line therapy for patients with advanced or metastatic non-small-cell lung cancer. j clin oncol 2007; 25:5777–84. 76. rosell r, robinet g, szczesna a, ramlau r, constenla m, mennecier bc, et al. randomized phase ii study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in egfr-expressing advanced non-small-cell lung cancer. ann oncol 2008; 19:362–9. 77. pirker r, filipits m. cetuximab in non-small-cell lung cancer. transl lung cancer res 2012; 1:54–60. 78. gandara d, kim es, herbst rs, moon j, redman mw, dakhil sr, et al. swog s0536: carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small-cell lung cancer (nsclc): a swog phase ii study. j clin oncol 2009; 27:15s. 79. randomized, phase iii study comparing carboplatin and paclitaxel with or without bevacizumab and/ or cetuximab in treating patients with stage iv or recurrent non-small-cell lung cancer. from: http:// www.clinicaltrials.gov/ct2/show/nct00946712? term=nct00946712&rank=1 accessed: may 2012. 80. herbst rs, kelly k, chansky k, mack cp, franklin wa, hirsch fr, et al. phase ii selection design trial of concurrent chemotherapy and cetuximab vs chemotherapy followed by cetuximab in advanced stage nsclc: swog s0342. j clin oncol 2101; 28:4747–54. 81. zhang x, zang j, xu j, bai c, qin y, liu k, et al. maintenance therapy with continuous or switch strategy in advanced non-small-cell lung cancer: a systematic review and meta-analysis. chest 2011; 140:117–26. what motivates a physician to inflict disease on his own person—the tenacity to establish the truth, a passion for research whatever the cost, frustration with unbelieving peers or sheer bravado in one’s own invincibility? the history of medical discoveries is replete with tales of individuals whose pursuit of knowledge and self-belief prompted them to become human guinea pigs. the outcome of their self-experimentation ranged anywhere from mortality to a cure. accolades, including the nobel prize, were the reward for a few. one thing is certain: their feats have become the lore of medical literature that generations of physicians will remember with astonishment and admiration. this article focuses on a recent notable example of the discovery of the bacterial origin of gastritis followed by a brief mention of other heroic exploits. many of these are an inspiration to physicians when research efforts go unrequited and disappointments take their toll. dogma and disbelief demolished in 2005, the karolinska institute in stockholm, sweden, awarded the nobel prize in medicine or physiology to j. robin warren and barry j. marshall for their discovery of a bacterial cause of gastritis and peptic ulcer disease.2 the pathologist-physician duo were paid homage for the struggle they encountered in establishing a revolutionary concept—a bacterial aetiology in the pathophysiology of gastric disease. this recognition was almost an oddity in a century when awards were usually given for research on genes and subcellular biochemical processes.3 in his lecture during the nobel prize ceremony in december 2005, warren eloquently quoted the fictional detective sherlock holmes: “there is nothing more deceptive than an obvious fact”.4 he was referring to the reaction of the medical fraternity when he initially proposed that a spiral-shaped bacteria could be found in the stomach. it defied the wisdom of the centuries which stated that the acid environment of the stomach could not possibly permit bacterial growth. h2-receptor antagonists, the commercial jackpot of the 20th century pharmaceutical industry, have acid-lowering capacities, but treat rather than cure ulcers.5 warren had first observed these bacteria in a gastric biopsy on 11 june 1979 (his 42nd birthday).6 bacteria had been seen by others in the gastric mucosa but they were largely considered to be contaminants. the implication that an infection caused stomach inflammation or ulcers contradicted the firm belief that lifestyle and stomach acidity were the culprits.6 warren’s training as a pathologist, his passion for staining techniques (especially silver stains) and his persistence stood him in good stead when he doggedly pursued his discovery with other tools of the trade: electron microscopy and, later, bacterial cultures. warren’s lonely two-year quest received a boost when, in 1981, a gastroenterology registrar, marshall, became his clinical collaborator. the physicianpathologist partners took their research a step further with a systematic collection of gastric antral biopsies which allowed them to observe microscopic changes in symptomatic patients without the confounding histological changes that biopsies from ulcer edges produced. their attempts to characterise the bacteria, referred to as campylobacter-like organisms, were met with disappointment until a fortuitous failure 1department of pathology, college of medicine & health sciences, sultan qaboos university; 2department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ritu@squ.edu.om األطباء الذين جيرون التجارب على أنفسهم املتفردون أم شهداء العلم؟ ريتو لكتاكيا و اإكرام بريين medical history self-experimenting physicians mavericks or martyrs? *ritu lakhtakia1 and ikram burney2 sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e452–455, epub. 23 nov 15 submitted 22 sep 15 revision req. 21 oct 15; revision recd. 26 oct 15 accepted 27 oct 15 doi: 10.18295/squmj.2015.15.04.002 hope lies in dream, in imagination and in the courage of those who dare to make dreams into reality. jonas salk.1 ritu lakhtakia and ikram burney medical history | e453 to discard cultures over the easter holiday in april 1982 resulted in colonies appearing on the culture plate.7 this was the eureka moment following many disappointing months of collecting and delivering specimens to the microbiology laboratory with a negative outcome. routinely, culture plates had been discarded after 48 hours; however, the new bacterium needed five days to grow. the organism was later classified as helicobacter pylori.4 in 1983 and 1984, warren and marshall published their findings in a prestigious medical journal, the lancet, after stiff resistance from reviewers.8,9 initial reactions to these pioneering publications stood in sharp contrast to the laudatory interviews and expert editorials in leading scientific journals which followed when the duo’s work was recognised by the nobel committee just over two decades later.7,10,11 after the initial publications, worldwide interest grew rapidly; however, marshall still had to convince disbelievers that h. pylori was the cause of gastritis and peptic ulcers, since no effective animal model had yet proven its pathogenicity.5 in late 20th century medical practice, where ethical clearance for a human experiment was very difficult to come by, he decided to establish the disease in his own body. marshall managed to obtain a pre-experiment endoscopic biopsy to establish baseline observations. to aid the bacteria in establishing themselves in his stomach mucosa, he reduced his stomach acid by consuming cimetidine, drank the bacterial culture and fasted for the rest of the day.12 he developed bloating, nausea and vomiting with night sweats and halitosis after three days. the subsequent biopsy irrefutably established the bacterial presence on stains and cul-tures.12 after 14 days, the symptoms and the bacteria vanished from the mucosal biopsies, apparently due to his own immune response. however, marshall had fulfilled robert koch’s postulates for identifying the causative agent of a disease and proven that the bacterium was a cause of gastric inflammation.12 personal anecdotes marked this journey of discovery. warren credits the support of his wife for helping him remain on course despite the deterrence meted by his peers.10 marshall’s wife adrienne had also noted his “putrid breath” in the wake of his drinking the h. pylori cocktail without her knowledge.5 the bold experiment may have earned him marital disfavour, but was instrumental in generating an era of antibiotic treatment for gastritis disorders. h. pylori became the first bacteria to be linked to carcinogenesis (gastric adenocarcinomas and lymphomas) in the research that followed.13 the heart of the matter cardiac catheterisation appears today as a straightforward, even routine procedure for a practicing cardiologist. but when the idea first gained momentum in the mind of a young german doctor, werner forssmann, in 1929, it was nothing short of revolutionary. deriving inspiration from having witnessed the drawings of french physiologists who were able to access the heart chambers through the jugular vein in animals, he was convinced it was a workable idea.14 he tested his theory by introducing a ureteric catheter through his brachial vein and into his heart. the unconventional step needed not only personal grit but also involved considerable artifice in convincing both the head nurse to part with sterilised instruments and the radiographer to record the historical moment.14 not always for the right reasons another bacterial experiment in the 19th century did not achieve the same success that warren did with h. pylori. max von pettenkofer was koch’s antagonist and argued vociferously against contagion (infection) being the cause of disease.15 as such, he opposed the public health water hygiene measures designed to prevent water-borne infections like cholera. in a desperate attempt to prove his point, he swallowed the cholera bacillus; since he fortunately failed to develop the disease, he felt vindicated in standing his ground despite his incorrect aetiological hypothesis.15 team spirit in medical experiments from the fold of military medicine came the triumphant discovery that a mosquito, later identified as aedes aegypti, was the vector of yellow fever. in 1900, major walter reed, a surgeon in the usa army, led the u.s. army yellow fever board to cuba. although he was one of the members, reed himself did not submit to being bitten by infected mosquitoes and it was his compatriot, jesse w. lazear, who succumbed to infection in the search for truth.16 reed was hailed as a hero for saving countless lives in havana, cuba. however, the fact that many of his so-called volunteers were members of his team of health professionals casts a long shadow on the dynamic team leader who extracted a human cost from his intrepid followers. another member of this loyal band was clara maass, self-experimenting physicians mavericks or martyrs? e454 | squ medical journal, november 2015, volume 15, issue 4 for its revival in a modified form.20 she supports the practice for the accuracy of self-observation, the lack of complete replication of the human situation in animal models and the clear academic and moral arguments for doing unto oneself before inflicting others. she even emphasises a leadership element, whereby medical professionals can lead by example before seeking informed consent from patients or healthy volunteers.20 additionally, dresser points out hitherto undisclosed aspects of research she learnt as a volunteer, such as delays in treatment or the possibility of trials being prematurely stopped or remaining unfinished. in her own words, “personal exposure led me to understand the heavy burdens such a duty would impose on seriously ill patients”.20 the institutional review boards and ethics committees of today do not always include this aspect of trials in their remits and may therefore need to expand their ambit. what then is the way forward? it is our conviction that we have not seen the last of this breed of researchers who would risk all to pursue a strongly held hypothesis. it is equally certain that formal approval through ethical committees will be hard to obtain given the legal implications, with some experiments potentially being equated with suicide. yet, if the experimenters survive to tell their tale, the scientific community invariably embraces the new fact. there is another alternative—leaders of research teams may do well to pay heed to out-of-the-box ideas from their mentees and allow them the latitude to confirm or dismiss them through experimentation, rather than self-experimentation. lone rangers, however, may still make the critical decision to experiment on themselves, sometimes only to prevent an original idea from being plagiarised. therein lie the dangers of the human frailties of possession and secrecy. lessons from the history of self-experimentation altruistic, audacious or simply foolhardy, these mavericks of medicine have earned veneration from the world in general and young physicians in particular. medical pioneers and researchers who travelled this path through self-example and self-sacrifice have demonstrated the boldness and recklessness that creates legends. adversity kept them undaunted in their mission; derision and mockery by their peers pushed them to bravado. whether it earned them fame, notoriety or an untimely death, in many cases both clinical research and humankind have benefited from self-experimentation. a 25-year old american nurse-volunteer, who also succumbed to the disease in 1901.17 zealous researchers were sometimes not beyond including their family members in their crusades. jonas salk and his wife and children received the attenuated polio vaccine early in its trials, before millions of children known as ‘polio pioneers’ were officially tested in 1954 to determine the efficacy of the drug.1 inspiration and aftermath curiosity, convenience or self-conviction? perhaps they all played complementary roles in driving these explorers to what may seem to be illogical risk-taking behaviours. notably, 12 individuals who performed self-experiments—including ramsay who exposed himself to anaesthetic gases, lawrence who drank radioactive sodium, metchnikoff who self-injected relapsing fever spirochaetes and forssmann who performed self-cardiac catheterisation—were awarded nobel prizes, although not necessarily for these specific experiments. in an interesting review of autoexperimenters dating from 1800, 465 episodes came to light.18 tragically, at least eight self-experimenters died as a result of their research adventures in the field of infectious disease. geographically, the selfexperimenters were mostly from the usa (33%) followed by germany (15%); in terms of gender, there were 12 women, the majority of whom were russian.18 conclusions drawn from such misadventures were sometimes misdirected. the famous scottish surgeon, john hunter, set out to straighten the record on gonorrhoea and syphilis. these were thought to be the same disease: the first visible by its urethral discharge, the second developing more systemic manifestations.19 reports that he self-infected himself with pus derived from the genital sore of a prostitute in 1767, succeeding in contracting both gonorrhoea and syphilis simultaneously, have been controversial. nevertheless, these resulted in his putting forward a misleading conviction that these two sexually transmitted diseases were caused by a common pathogen which was later proven wrong.19 self-experimentation: the 21 st century avatar these instances detailed above beg the question—is self-experimentation relevant in the 21st century? in a recent exposition on the subject, dresser argues ritu lakhtakia and ikram burney medical history | e455 references 1. salk institute for biological sciences. about jonas salk. from: www.salk.edu/about/jonas_salk.html accessed sep 2015. 2. nobelprize.org. the nobel prize in physiology or medicine 2005. from: www.nobelprize.org/nobel_prizes/medicine/lau reates/2005/ accessed: sep 2015. 3. nobelprize.org. 15 questions and answers about the nobel prize in physiology or medicine. from: www.nobelprize.org/ nomination/medicine/questions-goran-hansson-2013.html accessed: oct 2015. 4. nobelprize.org. nobel lecture: helicobacter the ease and difficulty of a new discovery. from: www.nobelprize.org/ nobel_prizes/medicine/laureates/2005/warren-lecture.html accessed: sep 2015. 5. nobelprize.org. nobel lecture: helicobacter connections. from: www.nobelprize.org/nobel_prizes/medicine/laureates/ 2005/marshall-lecture.html accessed: sep 2015. 6. marshall b, ed. helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters 1892–1982. carlton south, australia: wiley-blackwell, 2002. pp. 150–65. 7. mégraud f. a humble bacterium sweeps this year’s nobel prize. cell 2005; 123:975–6. doi: 10.1016/j.cell.2005.11.032. 8. warren jr, marshall b. unidentified curved bacilli on gastric epithelium in active chronic gastritis. lancet 1983; 321:1273–5. doi: 10.1016/s0140-6736(83)92719-8. 9. marshall bj, warren jr. unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. lancet 1984; 323:1311–15. doi: 10.1016/s0140-6736(84)91816-6. 10. richardson r. interview: chance favours the prepared mind. lancet 2006; 368:s46–7. doi: 10.1016/s0140-6736(06)69925-x. 11. lang l. barry marshall 2005 nobel laureate in medicine and physiology. gastroenterology 2005; 129:1813–14. doi: 10.1053/j.gastro.2005.10.046. 12. marshall bj, armstrong ja, mcgechie db, glancy rj. attempt to fulfil koch’s postulates for pyloric campylobacter. med j aust 1985; 142:436–9. 13. iarc working group on the evaulation of carcinogenic risks to humans. schistosomes, liver flukes, and helicobacter pylori. iarc monogr eval carcinog risks hum 1994; 61:1–241. 14. kerridge i. altruism or reckless curiosity? a brief history of self-experimentation in medicine. intern med j 2003; 33:203–7. doi: 10.1046/j.1445-5994.2003.00337.x. 15. oppenheimer gm, susser e. invited commentary: the context and challenge of von pettenkofer’s contributions to epidemiology. am j epidemiol 2007; 166:1239–41. doi: 10.1093/ aje/kwm284. 16. altman lk. who goes first? the story of self-experimentation in medicine. berkley, california, usa: university of california press, 1998. pp. 129–58. 17. chaves-carballo e. clara maass, yellow fever and human experimentation. mil med 2013; 178:557–62. doi: 10.7205/ milmed-d-12-00430. 18. weisse ab. self-experimentation and its role in medical research. tex heart inst j 2012; 39:51–4. 19. monahan j. they called me mad: genius, madness, and the scientists who pushed the outer limits of knowledge. new york, usa: berkley, 2010. pp. 105–26. 20. dresser r. personal knowledge and study participation. j med ethics 2014; 40:471–4. doi: 10.1136/medethics-2013-101390. http://dx.doi.org/10.1016/j.cell.2005.11.032 http://dx.doi.org/10.1016/s0140-6736%2883%2992719-8 http://dx.doi.org/10.1016/s0140-6736%2884%2991816-6 http://dx.doi.org/10.1016/s0140-6736%2806%2969925-x http://dx.doi.org/10.1053/j.gastro.2005.10.046 http://dx.doi.org/10.1046/j.1445-5994.2003.00337.x http://dx.doi.org/10.1093/aje/kwm284 http://dx.doi.org/10.1093/aje/kwm284 http://dx.doi.org/10.7205/milmed-d-12-00430 http://dx.doi.org/10.7205/milmed-d-12-00430 http://dx.doi.org/10.1136/medethics-2013-101390 clinical & basic research sultan qaboos university med j, november 2013, vol. 13, iss.4, pp. 520-526, epub. 8th oct 13 submitted 20th jan 13 revision req. 26th mar & 13th may 13; revision recd. 16th apr & 26th may 13 accepted 27th jun 13 department of family & community medicine, royal college of surgeons in ireland‒medical university of bahrain, busaiteen, bahrain *corresponding author e-mail: mmb060018@rcsi-mub.com مراجعة إكلينيكية جلودة الرعاية الصحية ملرضى السكري يف مستشفى البحرين العسكري مروة منري البحارنة، ديفيد ليونارد ويتفورد امللخ�ص: الهدف: اأثبتت املراجعات االإكلينيكية للرعاية ال�سحية االأولية يف مملكة البحرين اأن الرعاية املقدمة ملر�سى ال�سكري ال ت�ستويف البحرين. م�ست�سفيات اأحد يف ال�سكري ملر�سى الرعاية جودة تقييم يف نوعها من االأوىل الدرا�سة هذه تعد . دوليا ً املعتمدة االأهداف الطريقة: مراجعة اإكلينيكية ا�ستعادية لعينة ع�سوائية من املر�سى املرتددين على عيادة الغدد ال�سماء و ال�سكري يف م�ست�سفى البحرين الع�سكري خالل 15 �سهرا ًمتتالية حتى يونيو2010. متت مراجعة ال�سجالت الطبية اإلكرتونيا ًو يدويًا ل 287 م�سابا بال�سكري لتقييم املقايي�س االأ�سا�سية ونتائج جودة الرعاية ، ومت حتليل البيانات اإح�سائيا ً. النتائج: %74 من عينة املر�سى ا�ستملت على الذكور و كان و�سيط العمر 54 عاما ً. بلغت ن�سبة االإ�سابة بالنوع االأول لل�سكري %5. متت متابعة املعدل الرتاكمي لل�سكر، �سغط الدم، ن�سبة الدهون، كرياتينني و الوزن بن�سبة تفوق %90 من املر�سى. يف حني لقت املقايي�س االأخرى كالتدخني )%8( و من�سب كتلة اجل�سم )%19( ن�سبة متابعة اأقل. كما كانت ن�سبة التحري عن م�ساعفات ال�سكري قليلة، حيث مت فح�س �سبكية العني )%42(، فح�س القدم )%22( و اختبار ي�سكل يزال ال االأدلًة على القائم اجلودة معايري تطبيق اأن الدرا�سة هذه بينت املر�سى. اخلال�صة: من )23%( الزهيدة االألبومينية البيل حتديات للممار�سات احلالية يف رعاية مر�سى ال�سكري ، حيث اأن ن�سبة التحري عن م�ساعفات ال�سكري يف عيادة ال�سكر يف هذا امل�ست�سفى منخف�سة. يوؤكد املوؤلفون على اأهمية تطبيق اأ�سلوب منهجي يف رعاية مر�سى ال�سكري يهدف اإىل حت�سني جودة الرعاية املقدمة ملر�سى ال�سكر مما يوؤدي اإىل تقليل خطر االإ�سابة باأمرا�س القلب و االأوعية الدموية وبالتايل تقليل تكاليف الرعاية ال�سحية على املدى البعيد. مفتاح الكلمات: ال�صكري، �صمان اجلودة، الرعاية ال�صحية، مراجعة اإكلينيكية، البحرين. abstract: objectives: primary care audits in bahrain have consistently revealed a failure to meet recognised standards of delivery of process and outcome measures to patients with diabetes. this study aimed to establish for the first time the quality of diabetes care in a bahraini hospital setting. methods: a retrospective clinical audit was conducted of a random sample of patients attending the diabetes and endocrine center at the bahrain defence forces hospital over a 15-month period which ended in june 2010. the medical records of 287 patients with diabetes were reviewed electronically and manually for process and outcome measures, and a statistical analysis was performed. results: of the patients, 47% were male, with a median age of 54 years, and 5% had type 1 diabetes. measured processes, including haemoglobin a1c, blood pressure, lipids, creatinine and weight, were recorded in over 90% of the patients. smoking (8%) and the patient’s body mass index (19%) were less frequently recorded. screening for complications was low, with retinal screening in 42%, foot inspection in 22% and microalbuminuria in 23% of patients. conclusion: this study shows that the implementation of recognised evidence-based practice continues to pose challenges in routine clinical care. screening levels for the complications of diabetes were low in this hospital diabetes clinic. it is important to implement a systematic approach to diabetes care to improve the quality of care of patients with diabetes which could lead to a lowering of cardiovascular risk and a reduction in healthcare costs in the long term. keywords: diabetes; quality; care; audit; bahrain. clinical audit of diabetes care in the bahrain defence forces hospital *marwa m. al-baharna and david l. whitford advances in knowledge clinical audits of diabetes care have been conducted at primary care settings in bahrain and have shown underperformance compared to evidence-based practice recommendations. this study is the first clinical audit conducted in a secondary care setting in bahrain and reveals a similar underperformance compared with international standards of diabetes care. the reasons for this need to be explored and suggestions for change made. application to patient care this study suggests that a more systematic approach to diabetes care would lead to a lowering of cardiovascular risk and improved detection of complications at an earlier stage, leading to an improvement in patient outcomes. clinical audit of diabetes care in the bahrain defence force hospital 521 | squ medical journal, november 2013, volume 13, issue 4 the rising prevalence of diabetes is placing an enormous economic and health burden on the nations of the world.1 the majority of this burden is related to the treatment of and mortality from the complications of diabetes. there is abundant evidence to indicate that good control of glycaemia, blood pressure and lipids in patients with diabetes reduces the risk of both microvascular and macrovascular complications.2–4 in addition, early detection of complications from diabetes enables early intervention leading to improved outcomes.5 there is also good evidence that the delivery of structured diabetes care to the population, combined with increased patient involvement and self-management, improves the long-term outcomes of diabetes.6–8 yet it remains a challenge to translate the wealth of research evidence into practice, although reports from some countries suggest this is being addressed.9,10 bahrain has the ninth highest prevalence of diabetes in the world, with an estimated prevalence of 22.4% in 2012.11 coping with such a high prevalence demands the involvement of both primary and secondary care. clinical audits of diabetes care within primary care in bahrain have consistently shown an underperformance compared with agreed standards.12–14 they also compare less than favourably with the clinical audits from some other countries.15–18 there have, to date, been no published clinical audits of hospital-based diabetes care in bahrain. this study aimed to establish the quality of diabetes care in a bahraini secondary care setting. methods the population of bahrain is approximately one million, 40% of whom are expatriates. the national health service provides free care at the point-ofcontact for bahraini citizens. it does not have a fully established shared care diabetes service, with many patients having direct access to secondary care services. the bahrain defence forces (bdf) hospital is the second largest hospital in bahrain, with 400 beds, and serves inpatient, outpatient and emergency patients. the main mission of the bdf hospital is to provide healthcare services for the military and interior forces and their families, emergency services for the public, and specialised medical care for referral patients, government dignitaries and the royal court. the majority of patients have an association with the military or interior forces. care for patients with diabetes is delivered in a dedicated diabetes & endocrine center with doctors, specialist nurses, dietetic and podiatry support. approximately 3,500 patients attend the diabetes & endocrine center at the bdf hospital. appointment intervals for patients with diabetes vary according to the individual need, from weekly to 6 monthly, with a median of 4 months. the study was designed as a retrospective clinical audit of the medical records of a random sample of all patients attending for diabetes care in the diabetes & endocrine center at the bdf hospital within the previous 15-month period to june 2010. permission to carry out the clinical audit was given by the bdf hospital. a sample size of 353 patients was estimated to give a 95% chance of being within 5% of the true result of establishing the prevalence of the main process measures (haemoglobin a1c test [hba1c], blood pressure and low-density lipoprotein [ldl] cholesterol) for this population size (3,500). as there is no dedicated diabetes register, a computergenerated random sample of 500 patients attending the bdf diabetes & endocrine center was taken from the hospital database, allowing for an estimated 20% of patients without diabetes (hypothyroidism, impaired glucose tolerance or gestational diabetes mellitus). some patients were excluded (n = 213) as they did not have diabetes mellitus or were aged under 18 years, leaving a sample size of 287 patients. this gives a 95% chance of being within 6% of the true result for this population. data were collected from both the electronic and manual hospital records of the patients in the sample. data collection was carried out in july and august 2010, and parameters recorded between 1st april 2009 and 30th june 2010 were searched for. this 15-month duration was chosen to allow for delayed appointments since guidelines indicate that all parameters, including retinal screening, should have been completed at least annually. however, only the latest available parameter was included in the study in order to avoid data duplication. a selection of patient records was reviewed by two researchers to ensure reliability. data were entered directly into an excel spread sheet (microsoft inc., redmond, washington, usa) from the medical records by the researcher. parameters included patients' marwa m. al-baharna and david l. whitford clinical and basic research | 522 demographic details; the presence of vascular risk factors (hyperglycaemia, hyperlipidaemia and hypertension [htn]) and their levels of control; medications, and the screening for and the presence of complications. demographics, laboratory investigations and medications were available from the electronic records; other data were collected from the manual records. complications were deemed to be present if a diagnosis was recorded in the medical records. statistical analysis was performed using the statistical package for the social sciences (spss), version 17 (ibm corp., chicago, illinois, usa). descriptive analyses were performed, and the variables were cross-tabulated using parametric and non-parametric tests of association. significance was defined as a p value of less than 0.05. results manual medical records were missing for 24 of the 287 patients, resulting in 263 full data-sets. of the 287 patients, 136 (47.4%) were male. the median age was 54 years (range 18–87 years) and the median age at diagnosis was 43 years (range 3–79 years); 14 (5.4%) patients had type 1 diabetes. screening for cardiovascular risk factors and complications of diabetes are summarised in table 1. a total of 53 (20%) patients were recorded as having ischaemic heart disease (ihd), 17 (6.5%) had cerebrovascular disease (cvd) and 10 (3.8%) had peripheral vascular disease. also, 72 (27.4%) patients were recorded as having diabetic retinopathy, 27 (10.3%) diabetic nephropathy and 26 (9.9%) diabetic neuropathy. a total of 187 (71%) patients were recorded as having htn and 181 (69%) had hyperlipidaemia (with raised ldl). on review of the medications, 182 (69%) patients were on metformin, 143 (54%) on sulfonylureas, 29 (11%) on other oral hypoglycaemic agents, 122 (46%) on combination hypoglycaemic medication, and 111 (42%) on insulin. of these 111, 14 had type 1 diabetes. the others had type 2 diabetes and were also taking oral hypoglycemic agents. a total of 138 (52%) patients were on antiplatelet agents or anticoagulants, 173 (66%) on lipid-lowering agents and 188 (71%) on antihypertensive medications. patients with established macrovascular complications were more likely to be on antiplatelet agents (82% versus 42%; χ2 = 32.1, 1 table 1: processes and outcome measures of diabetic patients at the bahrain defence forces hospital processes measured/recorded frequency, n (%) mean (± sd) hba1c 278 (96.8) <7% 91 (32) 8.2% (± 1.9) >10% 54 (19.4) *systolic bp, mmhg 260 (98.8) <130 67 (26) 146 mmhg (± 22.6) >160 65 (24.7) *diastolic bp, mmhg 260 (98.8) <70 60 (23) 77.8 mmhg (± 12.5) >90 42 (16) total cholesterol, mmol/l 275 (95.8) <4 87 (32) 4.4 mmol/l (± 1.0) >5 90 (31.4) ldl cholesterol, mmol/l 274 (95.5) <1.8 33 (12) 2.8 mmol/l (± 0.9) >2.6 177 (61.7) hdl cholesterol 274 (95.5) 1.1 mmol/l (± 0.3) triglycerides 275 (95.8) 1.8 (± 1.1) *smoking 20 (7.6) smokers 8 (40) non-smokers 9 (45) ex-smokers 3 (15) *alcohol intake 4 (1.5) *height 42 (16) *weight 240 (91.2) *bmi, kg/m2 50 (19) <25 7 (14) 33.3 kg/m2 (± 9.9) 25–29 13 (26) 30–39 19 (38) ≥40 50 (22) *retinal screening 111 (42) *foot inspection 59 (22) *podiatrist visits 7 (3) albumin:creatinine ratio 67 (23.3) 4.5 mg/g (+/-9) creatinine 278 (96.8) 77.7 mmol/l (+/-85) * n = 263 as manual medical records missing for 24 of the total 287 patients. sd = standard deviation; hbac1 = haemoglobin ac1; bp = blood pressure; ldl = low-density lipoprotein; hdl = high-density lipoprotein; bmi = body mass index. clinical audit of diabetes care in the bahrain defence force hospital 523 | squ medical journal, november 2013, volume 13, issue 4 degrees of freedom [df ], p <0.001). men aged over 50 years (66% versus 27%; χ2 = 17.0, 1 df, p <0.001) and women aged over 60 years (77% versus 40%; χ2 = 17.1, 1 df, p <0.001) were also more likely to be on antiplatelet agents. women were found to have higher high-density lipoprotein (hdl) levels (mean hdl 1.23, 95% confidence interval [ci] 1.18–1.28) compared to men (mean hdl 1.01, 95% ci 0.98–1.05). older age was associated with a lower hba1c (f-test = 7.16, 1 df, p = 0.008), higher blood pressure (f = 9.96, 1 df, p = 0.002), increased diabetic complications (f = 2.34, 56 df, p <0.001) and increased polypharmacy (f = 2.48, 56 df, p <0.001). the process and outcome measures from this study were compared with the standards of care achieved in other local and international audits [table 2].14,17,19,20 discussion this study reveals that the delivery of recognised evidence-based interventions to improve diabetes outcomes has not been fully realised in this hospital diabetes clinic in bahrain. in particular, control of hyperglycaemia and htn lags behind that achieved in other countries.10,15–20 the impact of failing to lower cardiovascular risk in patients with diabetes is likely to be considerable, with a higher progression to microand macrovascular complications, and the subsequent increased personal and economic costs associated with diabetes complications.1 the impact of the failure to achieve adequate control of cardiovascular risk factors in patients with diabetes can be determined. a 10% reduction in hba1c levels, from the population mean of 8.2% in this study to a population mean of 7.2%, would lead to a risk reduction of 15% for all adverse diabetes outcomes.21 similarly, a 10 mmhg reduction in the mean population systolic blood pressure would lead to a 22% reduction in risk of coronary heart disease events and a 41% reduction in strokes.22 lipid lowering has similar effects. the importance of striving for improved control of risk factors for the complications of diabetes not only contributes to improving the quality of patients᾿ lives but also to reducing healthcare costs. such improvements have been documented in the uk,20 the usa10 and the united arab emirates.17 however, this study has shown that many process measures are carried out for the majority of patients, and this compares favourably with the situation in other countries. it is difficult to explain the low levels of recording of lifestyle behaviours that significantly contribute to cardiovascular risk, such as smoking and alcohol consumption. cultural barriers to asking about these habits may table 2: comparison of process and outcomes measures in the diabetes clinics of the bahrain defense forces hospital (bahrain), isa town health centre (bahrain), diabetes centre (saudi arabia), al-ain health centres (united arab emirates) and wales (uk). all figures are percentages of populations with diabetes bdf, bahrain (2010) isa town hc, bahrain (2005)14 saudi arabia diabetes centre (2006)19 al-ain hc, uae (2008)17 national diabetes audit, uk (2009– 10)20 measure recorded % % % % % hba1c 96.8 65.9 88.1 76 92 bp 98.8 91.8 100 91.9 94.7 cholesterol 95.8 74.3 nr 80.3 91 creatinine 96.8 nr nr nr 91 bmi 19 nr 100 83.5 89 retinal screening 42 31.9 35.4 31.3 82 peripheral pulses 13 nr 12.7 nr 83 neuropathy testing 17 nr 12.7 nr 83 microalbumin 23.3 33.4 28.8 83.6 85 outcomes hba1c, % <7 32 20.4 8.1 45.6 nr <7.5 45.7 29.4 nr nr 63 >10 19 34.5 34.6 10 7.9 bp, mmhg <130/80 22 13.7 36.5 42.9 51.1 <140/90 43 nr 60.8 67.5 70 ldl cholesterol, mmol/l <2.6 40 24 27.7 39.4 nr total cholesterol, mmol/l <5 68.6 40.2 nr 79.6 78.3 bdf = bahrain defense forces hospital; hc = health centre; uae = united arab emirates hbac1 = haemoglobin ac1; bp = blood pressure; nr = not recorded; bmi = body mass index; ldl = low-density lipoprotein. marwa m. al-baharna and david l. whitford clinical and basic research | 524 play a part, although it is difficult to understand why doctors should not seek a smoking history from every patient when rates of smoking in bahrain are similar to most developed countries. failure to record these habits reduces cost-effective opportunities to counsel about smoking and alcohol cessation or reduction.23 the absence of height-recording in order to establish body mass index (bmi) is similarly worrying in a generally obese population, as dietary advice to encourage weight loss has been shown to improve hba1c.23,24 in addition, screening for complications in this hospital clinic may be comparable with that in other gulf countries but is much less than that achieved in england and wales.19 the delivery of diabetes care to the population in england and wales has demonstrated that screening for complications of diabetes in the majority of the population is feasible.20 the prevalence of macrovascular events in the bdf endocrinology & diabetes center are similar to those cited by the centers for disease control and prevention [cdc] (ihd: 20.2% versus 20% and cvd: 7.9% versus 6.5%, for the cdc in 2007 versus the bdf in 2010, respectively). however, the prevalence of retinopathy is higher (19.7% versus 27.4%, for the cdc in 2009 versus the bdf in 2010, respectively).25 the cdc’s rates of htn and hyperlipidaemia in 2007 are comparable to the study population (htn: 67% versus 71% and hyperlipidaemia: 62.6% versus 68.8%).26 however, the figures from the bdf endocrinology & diabetes center are based on the low rates of screening for complications; the reality is that the rates of microvascular complications are likely to be higher than those recorded in the patients’ medical records. in the context of continuing evidence of suboptimal care and poor outcomes, the question arises as to what accounts for the relative success of some systems of diabetes care. delivering highquality care to people with diabetes is challenging. a systematic review of interventions to improve diabetes care in the community underlined the need for multifaceted professional interventions to enhance the performance of health professionals in managing diabetes; organisational interventions that facilitate the recall and structured review of patients; patient-oriented interventions to improve outcomes associated with patient education and behavioural change, and enhancements in the role of nurses in the provision of diabetes care.23,27 it is increasingly clear from this existing evidence that the challenge of providing uniformly effective diabetes care has thus far defied a simple solution; multifaceted and complex interventions are necessary for the success of a diabetes care system.6,23,27 features of successful programmes include diabetes self-management education; adoption of practice guidelines; use of checklists and annual reviews; prompting; clinical audits and feedback; quality improvement programmes, and electronic medical records that allow prospective identification of those needing assessments or treatment modifications. these records can also be utilised in the waiting room to deliver questionnaires on well-being and to access data on the current condition of the patient as well as delivering patient education on diabetes.28,29 finally, teamwork that incorporates nurses or other healthcare workers in the implementation of detailed algorithms of care contributes to a successful programme. diabetes services that incorporate more of these elements demonstrated lower hba1c levels and lower cardiovascular risk scores.28 the absence of many of these features in the bdf hospital endocrinology & diabetes center likely contributes towards some aspects of the lower quality care highlighted in this study, particularly the lack of screening for smoking and for the complications of diabetes. the main strength of this study is that it is the first published clinical audit of diabetes care within a secondary care setting in bahrain. second, it reflects the current practice at the diabetes clinic, thereby highlighting deficiencies and opening doors for quality improvement. this is deemed to be an important step in improving quality.30 finally, this study will serve as a baseline for future clinical audits of the quality of diabetes care. there are several weaknesses to this study. first, the measures audited did not include dietician consultations, despite the large population of obese diabetics in bahrain. secondly, the current practice for prescribing or modifying medications for defined levels of hba1c, blood pressure and lipids was not examined. additionally, the population of patients enrolled in the study were from the bdf hospital; hence, they had an association with the military or interior forces, and thus making it difficult to generalise the findings of the study to the entire bahraini population. moreover, the final clinical audit of diabetes care in the bahrain defence force hospital 525 | squ medical journal, november 2013, volume 13, issue 4 size of the study sample was 287, which is less than the calculated required sample size of 353 patients. although this indicates that the study is slightly underpowered based on the original calculations, this is unlikely to lead to any change in the conclusions from the study. finally, as with all audits, this study measured restrospective records of data, and as such cannot ascertain whether the procedures were accurately carried out. this may lead to the under-representation of some procedures that were performed but were not recorded, or that could not be identified due to missing records. it could also lead to the over-representation of some procedures, for instance when the actual examination was cursory but recorded as being complete. conclusion overall, this study has highlighted several potential areas for improving the quality of diabetes care in the bdf hospital endocrinology & diabetes center. of particular importance is the need for improving the control of cardiovascular risk factors and screening for diabetes complications. this is most likely to occur through a systematic approach to the delivery of diabetes care, incorporating many of the key elements of chronic disease management as outlined above. this should lead to improvements in the quality of life of patients with diabetes and lower healthcare costs in the long-term. there is also a need for regular clinical audits at the primary and secondary care settings to ensure continuous monitoring and improvement of the quality of diabetes care in bahrain. there are plans to repeat this study in the future in the hope that many of the deficiencies will have been addressed, leading to an overall improvement in diabetes care. references 1. yach d, stuckler d, brownell kd. epidemiologic and economic consequences of the global epidemics of obesity and diabetes. nat med 2006; 12:62–6. 2. buse jb, ginsberg hn, bakris gl, clark ng, costa f, eckel r, et al. primary prevention of cardiovascular diseases in people with diabetes mellitus. diabetes care 2007; 30:162–72. 3. uk prospective diabetes study group. tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: ukpds 38. bmj 1998; 317:703–13. 4. uk prospective diabetes study group. intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (ukpds 33). lancet 1998; 352:837–53. 5. marshall sm, flyvbjerg a. prevention and early detection of vascular complications of diabetes. bmj 2006; 333:475–80. 6. whitford dl, roberts sh, griffin s. sustainability and effectiveness of comprehensive diabetes care to a district population. diabetic med 2004; 21:1221–8. 7. norris sl, lau j, smith sj, schmid ch, engelgau mm. self-management education for adults with type 2 diabetes. diabetes care 2002; 25:1159–71. 8. tricco ac, ivers nm, grimshaw jm, moher d, turner l, galipeau j. effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis. lancet 2012; 379:2252–61. 9. rayman g, kilvert a. the crisis in diabetes care in england. bmj 2012; 345:e5446. 10. cheung bm, ong kl, cherny ss, sham pc, tso aw, lam ks. diabetes prevalence and therapeutic target achievement in the united states, 1999 to 2006. am j med 2009; 122:443–53. 11. international diabetes federation. idf diabetes atlas. 5th ed. brussels, belgium: international diabetes federation, 2012. from: http://www.idf. org/sites/default/files/5e_idfatlasposter_2012_ en.pdf accessed: may 2013. 12. salman r. evaluation of diabetes service provision in a government health centre in bahrain. bahrain med bull 2005; 27:1–21. 13. fikree m, hanafi b, hussain za, masaudi em. glycemic control of type 2 diabetes mellitus. bahrain med bull 2006: 28:1–6. 14. nasser j. evaluation of diabetes care in a primary care setting. bahrain med bull 2007; 29:1–10. 15. mccrate f, godwin m, murphy l. attainment of canadian diabetes association recommended targets in patients with type 2 diabetes: a study of primary care practices in st. john’s, newfoundland. can fam physician 2010; 56:e13–19. 16. porter c, greenfield c, larson a, gilles m. improving gp diabetes management—a pdsa audit cycle in western australia. aust fam physician 2009; 38:939–44. 17. baynouna lm, shamsan ai, ali ta, al mukini la, al kuwiti mh, al ameri ta, et al. a successful chronic care program in al ain, united arab emirates. bmc health serv res 2010; 10:47. 18. afandi b, ahmad s, saadi h, elkhumaidi s, karkoukli ma, kelly b, et al. audit of a diabetes clinic at tawam hospital, united arab emirates, 2004-2005. ann ny acad sci 2006; 1084:319–24. 19. al-arfaj is. quality of diabetes care at armed forces marwa m. al-baharna and david l. whitford clinical and basic research | 526 hospital, southern region, kingdom of saudi arabia, 2006. j fam community med 2010; 17:129–34. 20. the national health service information centre, uk. national diabetes audit executive summary 2009-2010. from: https://catalogue.ic.nhs.uk/ publications/clinical/diabetes/nati-diab-audi-09-10/ nati-diab-audi-09-10-exec-summ.pdf accessed: dec 2012. 21. the advance collaborative group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. n engl j med 2008, 358:2560–72. 22. law mr, morris jk, wald nj. use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. bmj 2009; 338:b1665. 23. american diabetes association. standards of medical care in diabetes -2010. diabetes care 2010; 33:s11–61. 24. coppell kj, kataoka m, williams sm, chisholm aw, vorgers sm, mann ji. nutritional intervention in patients with type 2 diabetes who are hyperglycaemic despite optimised drug treatment -lifestyle over and above drugs in diabetes (loadd) study: randomised controlled trial. bmj 2010; 341:c3337. 25. centers for disease control and prevention. diabetes complications. from: http://www.cdc.gov/diabetes/ statistics/complications_national.htm accessed: dec 2012. 26. centers for disease control and prevention. risk factor for complications. from: http://www.cdc. gov/diabetes/statistics/complications_national.htm accessed: dec 2012. 27. willens d, cripps r, wilson a, wolff k, rothman r. interdisciplinary team care for diabetic patients by primary care physicians, advanced practice nurses and clinical pharmacists. clin diabetes 2011; 29:60– 8. 28. parchman ml, zeber je, romero rr, pugh ja. risk of coronary artery disease in type 2 diabetes and the delivery of care consistent with the chronic care model in primary care settings: a starnet study. med care 2007; 45:1129–34. 29. sridhar g, murali g. computerization of data in diabetes centers. int j diab dev ctries 2011; 31:48– 50. 30. rao aa, sridhar gr. quality of care: assessment. lipids in health and disease 2007. from: http:// www.lipidworld.com/content/6/1/12 accessed: apr 2013. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century squ med j, may 2012, vol. 12, iss. 2, pp. 169-176, epub. 9th apr 2012 submitted 25th feb 12 revision req. 6th mar 12, revision recd. 10th mar 12 accepted 19th mar 12 in the majority of the countries around the world, there is a variability of human lifespan, with the japanese having the longest living population.1 although it is widely assumed that ageing or longevity or senescence is not a 'disease’, and while erikson2 has portrayed old age as time of culmination of ‘wisdom’ that could be a gift for the succeeding generation, ageing does have its own unique challenges. every health practitioner will attest to the view that longevity and the resultant ageing process often herald not only decreased vitality and capability, but also increased impairment, disability and a compromised quality of life.3,4 the question is whether oman should now be concerned with the welfare of the elderly even while its population 1department of behavioral medicine, sultan qaboos university hospital, muscat, oman; 2medical students, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3oman medical specialty board, muscat, oman; departments of 4family medicine & public health, 5 behavioral medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: samir.al-adawi@fulbrightmail.org أعباء رعاية الشباب وكبار السن يف ُعمان ملن تقرع األجراس ؟ حمد ال�سناوي، حممد العلوي، رحاب اللواتية، احمد احلرا�سي، حممد ال�سافعي، �سمري العدوي امللخ�ص: اأدى التح�سن امللحوظ يف ال�سحة وزيادة م�ستوى املعي�سة يف ُعمان يف العقود االأخرية اإىل انح�سار االأمرا�س ذات ال�سلة بالبيئة واالأمرا�س املعدية. لكن ت�سهد البالد االآن حتوال وبائيا يتميز بزيادة م�سطردة الأعداد املواليد، وت�سخم قطاع ال�سباب، م�سفوعا بزيادة ُعمر الفرد. احلكمة ال�سائعة ت�سري اإىل اأنه �سوف تقل معاناة الُعمانيني من االأمرا�س، لكن درا�سة �رضيعة يف االأدبيات املوجودة ت�سري اإىل اأن االأمرا�س املزمنة غري املعدية اأ�سبحت منت�رضة وب�سكل غري متوقع. ومن املمكن اأن ُتوؤجج هذه االأمرا�س بع�س االأمناط االجتماعية والثقافية ال�سائدة يف هذا البلد، ف�سال عن التناق�س املوجود بني ال�سحة والع�رضنة. مع االأ�سف مثل هذه اأالأمرا�س اجلديدة ت�سيب �سغار �س لكبار ال�سن. اإ�سافة لذلك، وب�سبب الطبيعة ال�سمولية وامل�ستع�سية لتلك االأمرا�س ال�سن، والذي يحتاج بع�سهم نف�س الرعاية التي ُتخ�سّ املزمنة غري املعدية فاإنها تكون منيعة �سد نظام الرعاية ال�سحية املوجه نحو ال�سفاء. لذلك ت�ستدعي هذه احلالة نقلة نوعية نحو نظام رعاية �سحية يتجاوز التوجه التقليدي لل�سفاء لتوفري خدمات الرعاية للم�سابني باالأمرا�س املزمنة من كافة االعمار. مفتاح الكلمات: اعتالل مزمن، اأمرا�س غري ُمعدية، حتول دميغرايف، اإعاقة، عبء املر�س،ُعمان. abstract: recent improvements in health and an increased standard of living in oman have led to a reduction in environment-related and infectious diseases. now the country is experiencing an epidemiological transition characterised by a baby boom, youth bulge and increasing longevity. common wisdom would therefore suggest that omanis will suffer less ill health. however, a survey of literature suggests that chronic non-communicable diseases are unexpectedly becoming common. this is possibly fuelled by some socio-cultural patterns specific to oman, as well as the shortcomings of the ‘miracle’ of health and rapid modernisation. unfortunately, such new diseases do not spare younger people; a proportion of them will need the type of care usually reserved for the elderly. in addition, due to their pervasive and refractory nature, these chronic non-communicable diseases seem impervious to the prevailing ‘cure-oriented’ health care system. this situation therefore calls for a paradigm shift: a health care system that goes beyond a traditional cure-orientation to provide care services for the chronically sick of all ages. keywords: chronic disease; non-communicable diseases; transition, demographic; disability; burden of illness; oman. sounding board emerging burden of frail young and elderly persons in oman for whom the bell tolls? hamed al-sinawi,1 mohammed al-alawi,2 rehab al-lawati,2 ahmed al-harrasi,3 mohammed al-shafaee,4 *samir al-adawi5 emerging burden of frail young and elderly persons in oman for whom the bell tolls? 170 | squ medical journal, may 2012, volume 12, issue 2 there is an unusual trend whereby youth people are seeking types of health care often perceived as only relevant for the elderly. such a trend is likely to have been fostered by the following five interrelated factors. t h e c h a l l e n g e o f n o nc o m m u n i c a b l e d i s e a s e s oman has generally triumphed over communicable disease.10,11 the country now faces the challenges of a rising tide of non-communicable diseases, sometimes labelled ‘diseases of affluence’.7 these ‘elderly-onset’, intransigent, and debilitating diseases seem to be affecting oman’s youngsters.12-14 such an emerging pattern of disease would suggest the need for a different approach in order to ensure enlightened health care planning and resource allocation. as will become apparent below, many of these emerging diseases of affluence are triggered by lifestyle changes and combatting them will require concerted efforts in the domain of rehabilitation and remedial services rather than simply curative medicine.15 r o a d t r a f f i c h a z a r d s another contributor to impairment, disability and handicap in oman is what is referred to as ‘flying coffins’, the mishap that happens to motor vehicle and their occupants on the road.16 unsubstantiated data published in the media reveal that the road accident rate in oman is 28 per 100,000 of the population; if true, this is likely to be highest in the world.17 it has been well established that although an ‘accident is an accident’, road traffic injuries are a major public health problem in oman disproportionately affecting the section of the population under 40 years of age.17,18 the type of health care provision needed, if the claim of a tsunami of road traffic accidents is substantiated, would parallel that often provided for the elderly. c o n g e n i ta l d i s e a s e s new reports suggest that oman is not immune to congenital and inheritable genetic diseases as well those that are thought to be triggered by new mutations.19,20 as consanguinity is intimately embedded in omani culture (due to the practice of first cousin marriages), this is likely to exacerbate the development of diseases that owe their origin to inherited genetic traits and health impairing structure is largely youthful. in this paper, it is urged that although the elderly constitute the minority of oman’s population, nevertheless, the country is likely to be beset with a silent epidemic of medically compromised individuals (mci). this stems from the emerging trend of omani youngsters suffering from a compromised wellbeing that was previously associated with the middle-aged or elderly. such a trend would likely pose a challenge as the country moves away from the threat of environment-related and infectious diseases to the ‘potential minefield’ of impairment, disability, and handicaps arising from other conditions. these owe their origin to the modernisation and acculturation process which has taken place in the last 40 years in oman. socio-demographic pattens life expectancy in oman has increased dramatically in a little more than four decades from 50 years in 1970 to 74.22 years in 2011.5 sociodemographic patterns in oman are deemed to be in an ‘epidemiological transition’ phase marked by the ‘shift from the acute infectious and deficiency diseases characteristic of underdevelopment to the chronic non-communicable diseases characteristic of modernization and advanced levels of development’ (p.8).6 recent affluence, as well as cultural patterns, have triggered a ‘baby-boom’ and the population structure is characterised by a youth bulge,7 where ‘tomorrow’s people’ constitute the bulk of the population.8 in contrast to this youth bulge, available estimates suggest that the elderly, defined as over 60+ years, constitute barely 4.8% of the population.9 one would speculate that such a youthful population should spare society in general, and the health care system in particular, from the burden of diseases which commonly results from a large population of frail and dependent senior citizens. there might therefore seem to be less need to allocate resources to this ‘minority’ of the population. factors influencing the burden of mci in oman although oman’s populations is indeed predominantly young, the country nevertheless has many mci, some of whom are not elderly. in oman, hamed al-sinawi, mohammed al-alawi, rehab al-lawati, ahmed al-harrasi, mohammed al-shafaee and samir al-adawi sounding board | 171 care.28,29 in general, in the countries labelled ‘emerging economies’, concerted efforts to improve the welfare and care of mci due to cebd are ostensibly absent.30 instead, health care priorities are still the perceived enemies of health such as infectious diseases and reproductive, maternal, and child health conditions. this is similar to the situation in industrialised countries that have so far focused their attention on the prevention and treatment of cancer and heart diseases.31 however, such a prioritisation appears to be myopic when one considers the enormous negative repercussions of cebd. despite their protean nature, when defined using disability-adjusted life year (daly), cebd appears to outstrip all other medical conditions in term of number of years lost due to ill-health, disability or early death.32 this is consistent with the view that cebd tend to compromise the very essence of being human, namely, the capacity to think and act rationally. it is worth noting that cebd tend to peak when afflicted individuals are still at a young age, thus depriving them of meaningful existence for many years. this has obvious implications for society. in addition to impairment, disability and handicap, cebd tend affect other areas of health. for example, emotional disorders tend to have a strong link with physical illness.33 the relationship between emotional disorders and physical illness has been unequivocally shown in emerging literature, including in oman.34 in addition to this, there is strong evidence to suggest that some well known physical illnesses tend to create a psychological burden.35 for example, following diagnosis of cancer, some individuals may succumb to reactive depression which, in turn, can affect the prognosis. the omani population, with its ‘baby boom’, ‘youth bulge’ and increased longevity, should therefore expect to see an exponential increase in the number of the people succumbing to cebd. the available data are consonant with such a view. although sometimes framed in the local idioms of distress, cebd are widely recognised in oman. the magnitude of some cebd (e.g. deliberate self-harm,36 hyperkinetic disorder,37 depressive symptoms,38 factitious disorder39 and eating disorders in the form of deliberate food restriction40) is much lower compared to international standards, but oman is the ‘world leader’ in those distresses that owe their origin to social and cultural patterning (e.g. social mutations.21 this will lead to more youngsters with a dented quality of life and level of dependency that will echo those of the elderly. on such grounds, social engineering, framed in the parlance of rehabilitation and remedial intervention, would be essential. from the global perspective, the ‘potential minefield’ due to genetically determined disorders has been difficult to ascertain due to differences in case ascertainment methods, criteria definition problems, and variations due to methodology. nevertheless, the rate of genetically determined diseases reported in oman appears to be startling, if not outright alarming, with a 2% prevalence rate for beta thalassaemia trait, and 6% for sickle cell trait.22 accordingly, it has been stated that congenital anomalies and birth defects are a leading cause of morbidity and mortality in omani youngsters.23,24 h e a lt h c a r e ‘m i r a c l e’ in less than three decades, a once impoverished people has experienced such dramatic health care changes that oman was recently voted by world health organization as one of the most efficient health care systems in the world.25. this ‘miracle’ has triggered some unforeseen consequences. despite spending only 2.4% of its of gross domestic product on health,26 the health care system in oman has been equipped with versatile medical technology capable of saving lives once deemed beyond redemption.27 medical conditions that previously appeared impervious to medical treatment are now treatable to the extent that patients can survive and regain some quality of life. the paradoxical consequence of this a miracle is that people whose lives are saved by medical technology will nonetheless live with severe physical, cognitive and emotional impairment, disability and handicap. many of them will require a type of palliative care often reserved for the elderly. m e n ta l i l l n e s s by definition, mental illnesses are associated with persistent and pervasive cognitive, emotional and behavioural disorders (cebd). a sufferer is likely to have a compromised quality of life. therefore, mental illness is one of the contributory factors to the magnitude of the problem under scrutiny here, namely the growing number of mci. despite this, cebd have largely been relegated to a less prominent position in the algorithms of health emerging burden of frail young and elderly persons in oman for whom the bell tolls? 172 | squ medical journal, may 2012, volume 12, issue 2 mci who tend to ‘over-stay’ are likely to be too frail to be discharged home-as has been found in other arab countries.45-47 c a r e i n t h e fa m i ly care for mci often depends on the prevailing zeitgeist and history is full of approaches to helping those who are deemed unfit or dependent. nowadays, health care facilities are mushrooming in different parts of the world to cater to the needs of mci. these are specifically designed to provide a place of abode for mci who cannot independently undertake their activities of daily living. in the present discussion, such health care facilities aim to provide a compensatory mechanism so that mci can have a meaningful existence. thesiger fondly praised omanis for "…their sense of fellowship, … their generosity and sense of hospitality; their dignity and their regard which they have for the dignity of others as fellow human beings.” (cited in smith p.541).48 it is not clear what impact modernity (as result of acculturation) has had in recent times on such an ideal humanity. nonetheless, in family-oriented societies like oman, interdependence is still encouraged. such cultural patterning means that mci will be cared for in the realm of the family. it is a widely held belief (though one that lacks empirical support) that given this type of society the fate of mci is likely to be favourable. the question, however, is whether the modern omani family is equipped to provide the family care needed by mci. it has been indicated that recent affluence in oman has resulted in the nuclear family supplanting the traditional extended family leading to a reported emergence of socially valued individualism and the erosion of interpersonal relationships that stems from modern education systems.49,50 there are also anecdotal reports indicating that the young generation “has little time for elderly people”. 51 it is not clear, however, what implication this sociological observation has on the welfare of mci. despite such caveats, the family plays a central role in omani society. on these grounds, it would be essential to contemplate a health care model that has affinity to omani socio-cultural teaching. although, to our knowledge, there is published work, relating to the elderly, articles in the popular media indicate that the country is “not encouraging the establishment of such homes because we still phobias41 and dissociative disorders42). possible solutions to this emerging issue with the rising tide of non-communicable diseases; impairment, disability and handicap triggered by road traffic behaviour, some of consequences of the modern medical revolution, and the enduring cultural patterns that may sustain genetically determined disorders, oman needs to contemplate a new direction for its health care system. rather than focusing on environment-related and infectious diseases, an integral part of oman’s health system should be meeting the needs of mci through remedial services—since it would be an untenable aspiration to find a cure for all the causes of impairment, disability and handicap in oman. n e w t y p e s o f h e a lt h c a r e s e r v i c e s the importance of improving neurobehavioural rehabilitation in oman was previously highlighted;43 here, it is worthwhile discussing the relevance of the compensatory efforts needed to support mci with persistent and debilitating medical conditions.27 health care services should enable mci to reach and maintain their optimal levels of physical, sensory, intellectual, psychological and social functioning in order to achieve a measure of selfdetermination and meaningful and independence existence. 44 due to their focus on chronic disease, modern cure-based hospitals may be the least attractive option. rehabilitation or remedial services need multidisciplinary medical teams, with a range of skills from social work to neurosurgery, which are also supported by educational/vocational institutions and other social agencies. if the available data circulating in the media would bear scientific scrutiny, it appears that 0.3 to 0.4% of omanis are likely to incur impairment, disability and handicap arising from road accidents. this trend dovetails with the present discourse that oman is likely to experience an increased number of youngsters with mci. extrapolating from this trend, it could be thought that some mci are likely to use acute hospital beds as a ‘care home’. extended hospital stays for mci can often trigger bed shortages for other clinical populations and result in increased health care expenditure. some of the hamed al-sinawi, mohammed al-alawi, rehab al-lawati, ahmed al-harrasi, mohammed al-shafaee and samir al-adawi sounding board | 173 carried out in denmark, ireland and italy where home-based care is generally more cost-effective for such mci.54 another alternative approach is a nonresidential facility that provides activities for the mci during the day. this would mean that mci could spend 10–12 hours per day in a setting possibly with access to a medical facility. under this scheme, meals, social and recreational outings, and general supervision are provided by a team of experts. there are several advantages to such a proposal. first, regular proximity to health care delivery is likely to prevent re-hospitalizations as medical assessments and medications are readily available. second, the benefit of social stimulation will emerge. mci who would otherwise stay at home are provided with recreational activities and other social stimulations that maybe therapeutic on their own right. there are some empirical studies suggesting that social stimulation can ward off the emergence of cognitive impairment and other debilitating emotional conditions common in mci.55 relevant to this, while such centres could provide remedial education and rehabilitation for mci, in the interim, caregivers would get much needed respite to seek employment or simply to recuperate from the stress of caring for mci with their particular problems. it is worth noting in this context that many mci are marked by erratic behaviour and a rigidity of personality that may exhaust their caregivers. conclusion oman has been internationally lauded for taking vigorous action to combat disease and to improve the condition of its people such a health service ‘miracle’, associated with an increased standard of living, has led to the progressive demographic transformation of society. recent socio-economic trends have reduced the occurrence of environmentrelated and infectious diseases. instead, there is a rising tide of death, morbidity, handicap and disability due to genetically determined disorders and other sequelae of acculturation and modernisation including road traffic accidents and the very success of the medical revolution. this has occurred in the midst of a ‘baby boom’, a prevailing youth bulge and increased life expectancy. as result of such socio-demographic trends, the country is believe that the omani community will be able to take care of their elderly population as our religion and tradition teaches us to do so.52 given the lack of organised services in oman for the mci, some individual initiatives have already been seen in the community. to cope with the burden of caring for mci, with their complex physical and emotional needs, some families employ private carers who undertake the physical aspect of caring (feeding and washing). however, employing an in-house carer is limited to those who have sufficient disposable income and may not apply to the majority of omanis. nevertheless, the presence of private carers spares family members from the task of constant physical caring for their mci. s u p p o r t e d h o m e a n d c o m m u n i t y c a r e within the context of a family-oriented society, one approach that might be appropriate for mci in oman is outreach services similar to home health care, otherwise known as domiciliary care or social care. as the term implies, home health care serves the myriad needs of mci in their homes by outreach teams that include all types of health care professionals such as nurses, occupational therapists and social workers. this type of care has some subtle benefits that outweigh other approaches. first, the services will be tailor-made for the mci’s functional limitations. second, the mci not need to travel outside for help which may be difficult due to their medical complications. third, the mci will be protected from psychological trauma—the feeling of unfamiliarity that can heighten anxiety and the feeling of being uprooted from home and having to part with possessions that are usually experienced by those put in care homes. this means mci have their health needs met within their own community which mean they are likely to remain closer to their social network of friends, neighbours and family thus mitigating loneliness, depression and other existential dilemmas. international surveys show that over 95% of mci would prefer to stay in their own home for as long as possible.53 finally, for the family and society in general, such a care model is likely to be more cost effective than hospital care. there is evidence to suggest that even if mci tend to be marked by a high level of dependency, home care is likely to be cost-effective. such a view is supported by studies emerging burden of frail young and elderly persons in oman for whom the bell tolls? 174 | squ medical journal, may 2012, volume 12, issue 2 gs, al mahrooqi s, ramzy r. absence of lymphatic filariasis infection among secondary-school children in oman. east mediterr health j 2010 16:1059–63. 12. gujjar ar, william r, jacob pc, jain r, al-asmi ar. transcranial doppler ultrasonography in acute ischemic stroke predicts stroke subtype and clinical outcome: a study in omani population. j clin monit comput 2011; 25:121–8. 13. woodhouse nj, elshafie ot, al-mamari as, mohammed nh, al-riyami f, raeburn s. clinicallydefined maturity onset diabetes of the young in omanis: absence of the common caucasian gene mutations. sultan qaboos univ med j 2010; 10:80– 3. 14. asfour mg, lambourne a, soliman a, al-behlani s, al-asfoor d, bold a, et al. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabet med 1995; 12:1122–5. 15. probst-hensch n, künzli n. preventing noncommunicable diseases-beyond lifestyle. epidemiology 2012; 23:181–3. 16. nantulya vm, reich mr. the neglected epidemic: road traffic injuries in developing countries. bmj 2002; 324:1139–41. 17. al-naamani a, al-adawi s. ‘flying coffins’ and neglected neuropsychiatric syndromes in oman. sultan qaboos univ med j 2007; 7:75–81. 18. directorate general of traffic, royal oman police traffic statistics report (1971-2009). muscat: royal oman police, 2010. 19. al-futaisi am, al-kindi mn, al-mawali am, koul rl, al-adawi s, al-yahyaee sa. novel mutation of glra1 in omani families with hyperekplexia and mild mental retardation. pediatr neurol 2012; 46:89–93. 20. al-mayouf s, abdwani r, al-brawi s. familial juvenile systemic lupus erythematosus in arab children. rheumatol int 2011. doi: 10.1007/s00296011-1886-y. 21. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 9:1–24. 22. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:1–20. 23. rajab a, vaishnav a, freeman nv, patton ma. neural tube defects and congenital hydrocephalus in the sultanate of oman. j trop pediatr 1998; 44:300– 3. 24. kenue rk, raj ak, harris pf, el-bualy ms. cytogenetic analysis of children suspected of chromosomal abnormalities. j trop pediatr 1995; 41:77–80. 25. jamison dt, sandbu me. global health. who ranking of health system performance. science 2001; witnessing a rising tide of mci among both young and elderly populations. due to their persistent, pervasive and refractory nature, the emerging health conditions appear to be impervious to the benefits of the modern ‘cure-oriented’ health care system which was effective for the environmentrelated and infectious diseases of the previous era. this therefore calls for a paradigm shift: a health care system that goes beyond strict adherence to the traditional ‘comfort zone’ of cure-oriented health care system. new pragmatic solutions need to be found to meet the new challenge of the increasing numbers of mci in oman. references 1. cheung sl, robine jm. increase in common longevity and the compression of mortality: the case of japan. popul stud (camb) 2007; 61:85–97. 2. erikson h. childhood and society. new york: w. w. norton & company, 1993. 3. berlau dj, corrada mm, peltz cb, kawas ch. disability in the oldest-old: incidence and risk factors in the 90+ study. am j geriatr psychiatry 2012; 20:159–68. 4. abihabib le, chemaitelly hs, jaalouk ly, karam ne. developing capacities in aging studies in the middle east: implementation of an arabic version of the cane iv among community-dwelling older adults in lebanon. aging ment health 2011; 15:605– 17. 5. central intelligence agency. the world factbook: oman. from: https://www.cia.gov/library/ publications/the-world-factbook/geos/mu.html. accessed: feb 2012. 6. wahdan m.h. the epidemiological transition. east mediterr health j 1996; 2:8–20. 7. ganguly ss, al-lawati a, al-shafaee ma, duttagupta kk. epidemiological transition of some diseases in oman: a situational analysis. world hosp health serv 2009; 45:26–31. 8. sulaiman aj, al-riyami a, farid s, ebrahim gj. oman family health survey 1995. j trop pediatr 2001; 47:s1–33. 9. health statistics and health information systems. definition of an older or elderly person. world health organi z ation.http://w w w.who.int/he althinfo/ survey/ageingdefnolder/en/index.html. accessed march 2012. 10. al-lamki l. acute coronary syndrome, diabetes and hypertension: oman must pay more attention to chronic non-communicable diseases. sultan qaboos univ med j 2011; 11:318–21. 11. al awaidy st, bawikar s, patel pk, kurup p, sonal hamed al-sinawi, mohammed al-alawi, rehab al-lawati, ahmed al-harrasi, mohammed al-shafaee and samir al-adawi sounding board | 175 clinic in oman. int j psychiatry med 2007; 37:229– 40. 40. al-adawi s, dorvlo as, burke dt, al-bahlani s, martin rg, al-ismaily s. presence and severity of anorexia and bulimia among male and female omani and non-omani adolescents. j am acad child adolesc psychiatry 2002; 41:1124–30. 41. al-hinai ss, al-saidy o, dorvlo ass, al-riyami bms, bhargava k, northway mg, et al. culture and prevalence of social phobia in a college population in oman. in: landow mv, ed. college students: mental health and coping strategies. hauppauge, new york: nova science publishers, 2006. pp.2–19. 42. chand sp, al-hussaini aa, martin r, mustapha s, zaidan z, viernes n, et al. dissociative disorders in the sultanate of oman. acta psychiatr scand 2000; 102:185–7. 43. al-adawi s, burke dt. revamping neurorehabilitation in oman. sultan qaboos univ med j 2001; 3:61–4. 44. rehabilition. world health organization. from: http://w w w.who.int/topic s/rehabilit ation/en/ accessed: feb 2012. 45. margolis sa, reed rl. changing use of the emergency department by the elderly in the united arab emirates, 1989 and 1999. east mediterr health j 2002; 8:409–15. 46. shaltout t, bener a, al abdullah m, al mujalli z, shaltout ht. acute and transient psychotic disorders in a rapidly developing country, state of qatar. medicina 2007; 43:575–9. 47. margolis sa, reed rl. institutionalized older adults in a health district in the united arab emirates: health status and utilization rate. gerontology 2001; 47:161–7. 48. smith r. oman: leaping across the centuries. bmj. 1988;297:540-4. 49. al-barwani ta, albeelyb ts. the omani family: strengths and challenges. marriage fam rev 2007; 41:119–42. 50. al-adawi s. adolescence in oman. in: arnett jj, ed. international encyclopedia of adolescence: a historical and cultural survey of young people around the world. new york: routledge, 2006, pp. 713–28. 51. vaidya sk. state steps in to take care of elderly in oman. from: http://gulfnews.com/news/gulf/ oman/state-steps-in-to-take-care-of-elderly-inoman-1.206123. accessed: feb 2012. 52. care at hand for the elderly. omaninform.com. from: http://www.omaninfo.com/news/care-handelderly.asp accessed: feb 2012. 53. wilson a. improving life satisfaction for the elderly living independently in the community: care recipients’ perspective of volunteers. soc work health care 2012; 51:125–39. 293:1595–6. 26. alshishtawy mm. four decades of progress: evolution of the health system in oman. sultan qaboos univ med j. 2010;10:12–22. 27. al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos univ med j 2006; 6:3–9. 28. maziak w, asfar t, mzayek f, fouad fm, kilzieh n. socio-demographic correlates of psychiatric morbidity among low-income women in aleppo, syria. soc sci med 2002; 54:1419–27. 29. bass jk, bornemann th, burkey m, chehil s, chen l, copeland jr, et al. a united nations general assembly special session for mental, neurological, and substance use disorders: the time has come. plos med 2012; 9:e1001159. 30. okasha a, karam e, okasha t. mental health services in the arab world. world psychiatry 2012; 11:52–4. 31. prince m, patel v, saxena s, maj m, maselko j, phillips mr, et al. no health without mental health. lancet 2007; 370:859–77. 32. mathers c, boerma t, ma fat d. global burden of disease 2004 update. geneva: world health organization, 2008. 33. al lawati j, al lawati n, al siddiqui m, antony sx, al naamani a, martin rg, et al. psychological morbidity in primary healthcare in oman: a preliminary study. sultan qaboos univ med j 2000; 2:105–10. 34. al-maskari my, petrini k, al-zakwani i, al-adawi ssh, dorvlo ass, al-adawi s. mood dysfunction and health-related quality of life among type 2 diabetic patients in oman: preliminary study. int j nutr pharmacol, neurol dis 2011; 1:56–63. 35. kim sw, kim sy, kim jm, park mh, yoon jh, shin mg, et al. relationship between a hopeful attitude and cellular immunity in patients with breast cancer. gen hosp psychiatry 2011; 33:371–6. 36. zaidan za, burke dt, dorvlo as, al-naamani a, al-suleimani a, al-hussaini a, et al. deliberate selfpoisoning in oman. trop med int health 2002; 7: 549–56. 37. al-sharbati m, al-adawi s, ganguly s, al-lawatiya s, al-mshefri f. hyperactivity in a sample of omani schoolboys. j atten disord 2008; 12:264–9. 38. jaju s, al-adawi s, al-kharusi h, morsi m, alriyami s. prevalence and age-of-onset distributions of dsm iv mental disorders and their severity among school going omani adolescents and youths: wmh-cidi findings. child adolesc psychiatry ment health 2009; 3:29. doi: 10.1186/1753-2000-329. 39. bhargava d, al okbi mh, al-abri r, bhargava k, rizvi sga, al-adawi s. phenomenology and outcome of factitious disorders in otolaryngology emerging burden of frail young and elderly persons in oman for whom the bell tolls? 176 | squ medical journal, may 2012, volume 12, issue 2 55. woods b, aguirre e, spector ae, orrell m. cognitive stimulation to improve cognitive functioning in people with dementia. cochrane database syst rev 2012; 2:cd005562. 54. wilson a. improving life satisfaction for the elderly living independently in the community: care recipients' perspective of volunteers. soc work health care 2012; 51:125–39. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e207–212, epub. 28 may 15 submitted 9 jun 14 revisions req. 9 aug & 16 sep 14; revisions recd. 13 aug & 30 sep 14 accepted 23 oct 14 hyponatraemia is a common electro-lyte abnormality, but distinguishing its underlying cause(s) is usually challenging, and extensive laboratory investigations are commonly applied.1‒6 excluding hypothyroidism in patients with unexplained hyponatraemia has been widely attempted, but the strength of such a link has not been clearly defined and is, at times, downplayed.7–9 although 10% of patients with hypothyroidism also have hyponatraemia, clinicians often ignore its clinical significance.1 when hyponatraemia and hypothyroidism are found to coexist, the former is not necessarily a consequence of the latter, and other causes of low sodium (na) concentrations should still be investigated.7,8,10 in a patient with a marked decline of na levels and an undetermined thyroid status, clinicians must consider an evaluation of thyroid function in the patient’s work-up.10 the implication of changes in natraemia status in hypothyroidism has yet to be fully elucidated. in spite of this, an absolute link between hypothyroidism and na levels is included in standard internal medicine and subspecialty textbooks. however, such an association should be reaffirmed through individual testing.11–14 cost-effective medicine: recent medical practice a recent review suggested that about half of the most common clinical scenarios in daily practice include unnecessary testing and diagnostic approaches.15 this review documented 146 contemporary medical practices that have subsequently been reconsidered over the past 10 years. investigators assessed 1,344 original articles that studied a novel medical practice or tested a conventional one. only 27% of the articles verified an established and tested practice. of the articles that tested current medical practice, 40.2% of these practices were found to be ineffective. an additional 38% endorsed the importance of an existing 1department of internal medicine, creighton university, omaha, nebraska, usa; 2department of internal medicine, nebraska-western iowa health care system, omaha, nebraska, usa *corresponding author e-mail: ahmedabuzaid1@creighton.edu االختالفات يف تقييم نقص صوديوم الدم عند قصور الغدة الدرقية تقييم األدلة اأحمد اأبو زيد و ناثان بري�ض abstract: hyponatraemia is a common electrolyte disturbance, with moderate (serum sodium: 125–129 mmol/l) to severe (serum sodium: ≤125 mmol/l) forms of the disease occurring in 4–15% of hospitalised patients. while it is relatively common, determining the underlying cause of this condition can be challenging and may require extensive laboratory investigations. to this end, it is important to ascertain the efficacy of laboratory tests in determining the cause of hyponatraemia. up to 10% of patients with hypothyroidism also have hyponatraemia. routine evaluation of thyroid function is often advocated in cases of low serum sodium. a review and discussion of the available literature is presented here to examine this recommendation. keywords: causality; kidney disease; hypothyroidism; hyponatremia. امللخ�ص: نق�ض �سوديوم الدم هو ا�سطراب اأيوين �سائع حلاالت مر�سية ترتاوح بني املعتدلة )ال�سوديوم يف الدم: 129-125≥ مليمول/ لرت( اإىل احلادة )ال�سوديوم يف الدم: 125≥ مليمول/لرت( حتدث يف %15-4 من املر�سى املنومني يف ال�ست�سفيات. مع اأنه �سائع ن�سبيا، فاإن حتديد �سبب هذا االعتالل ي�سكل حتديا ورمبا يحتاج لفحو�ض خمربية وا�سعة النطاق. حتقيقا لهذه الغاية، فاإن من املهم التاأكد غالبا من فعالية الفحو�سات املعملية يف حتديد �سبب نق�ض �سوديوم الدم. اإن ما ي�سل اإىل %10 من املر�سى الذين يعانون من ق�سور الغدة الدم يف ال�سوديوم انخفا�ض حاالت يف الدرقية الغدة لوظيفة الروتيني التقييم فاإن ولذلك الدم. �سوديوم نق�ض اأي�سا لديهم الدرقية مطلوب. هنا نقدم عر�سا ومناق�سة لالأدبيات املتوفرة لدرا�سة هذه التو�سية. مفتاح الكلمات: ال�سببية؛ اأمرا�ض الكلى؛ ق�سور الغدة الدرقية؛ نق�ض �سوديوم الدم. sounding board the controversies of hyponatraemia in hypothyroidism weighing the evidence *ahmed s. abuzaid1 and nathan birch2 the controversies of hyponatraemia in hypothyroidism weighing the evidence e208 | squ medical journal, may 2015, volume 15, issue 2 practice while 21.8% were unconvincing.15,16 in fact, some of the most commonly utilised tests did show some beneficial evidence in previously published reports.17 however, a careful analysis of the gathered data and its clinical significance from the cochrane database in 2004 and 2011 showed insufficient evidence for the necessity of these practices, revealing that they were adding more of a load to already overburdened healthcare systems.17 non-thyroidal illness syndrome some acute and chronic medical conditions are associated with a common biochemical derangement of thyroid function, known as non-thyroidal illness syndrome (ntis). this condition is a common cause of medical costs in the absence of a causal intrinsic thyroid sickness.18 studies assessing morbidity and mortality rates in ntis subjects treated with thyroid hormones revealed no statistically significant findings.18,19 these studies found there was no need for specific therapeutic interventions, such as the administration of thyroid hormones, in patients with various forms of ntis in the context of concurrent systemic illness.18,19 this explains, in part, the futility of routine thyroid testing in hyponatraemic patients in whom thyroid aberrancy can be misleading. routine testing of the thyroid in hyponatraemic patients is based upon little evidence and results in unnecessary testing and follow-ups for sick euthyroid patients.18,19 t h e r o l e o f va s o p r e s s i n the most noticeable peculiarity in clinically significant hyponatraemia is its pathogenesis, which remains highly debatable. in general, hypothyroidism has been associated with increased total body na, proposing the vital role of water retention.6 regardless of the na levels in hypothyroid states, diminished and/or delayed free water load excretion and impaired renal dilution capacity are paramount, pointing towards a possible role for vasopressin or antidiuretic hormone (adh) and the need for effective water excretion. however, such a correlation in patients with hypothyroidism is weak. in hypothyroidism, hyponatraemia seems to be associated only with the severest cases of myxoedema where impaired cardiac function causes baroreceptormediated vasopressin secretion and total body water retention.20 in fact, the impaired excretion of water load in hypothyroidism has been demonstrated in several studies and it has been suggested that inappropriate secretion of adh might mediate water retention.13,20 elevated vasopressin levels in patients with hypothyroidism have been described in a variety of reports, yet the findings were inconsistent.12,21–23 previous studies have demonstrated that in rats with hypothyroidism, there is no upregulation of hypothalamic vasopressin gene expression; therefore the reduction in cardiac output and glomerular filtration rate (gfr) observed in severe hypothyroidism may be due to non-osmotic stimuli to vasopressin release.21,22 in 20 patients with myxoedema, raised plasma vasopressin concentrations were observed in cases of mild hyponatraemia (na levels of 130–142 mmol/l).23 surprisingly, after a water challenge, 75% of the studied individuals did not show a complete decline in elevated vasopressin concentrations and only 10% had a suppressible vasopressin response. this signifies the coexistence of an intrinsic renal mechanism unrelated to the vasopressin itself.12,23 after the achievement of euthyroidism, evaluations of urinary excretion and vasopressin inhibition were satisfactory following the oral water load.23 the expected osmotic trigger in patients with hypothyroidism seems to be normal. a study by iwasaki et al. assessed eight patients with uncontrolled myxoedema due to primary hypothyroidism after infusing them with 5% hypertonic saline.21 after the saline infusion, severe primary hypothyroidism was observed in all patients without a convincing suppression of the measured high vasopressin levels.12,21 despite the findings of additional osmotic triggering mechanisms, rising plasma osmolality and a consequent rise in measured vasopressin levels was sufficient in the entire patient group and mild hyponatraemia was observed in only two patients.21 plasma vasopressin was appropriately suppressed in each case during water loading.21 these outcomes show that an inappropriate rise in plasma vasopressin is not common in myxoedema and that compromised water elimination is predominantly due to vasopressinindependent mechanisms. this results in impaired water excretion and urine concentrations even when plasma osmolality is low, which is possibly a sequel to associated hypervolaemia.12,24 n o n-va s o p r e s s i n-r e l at e d m e c h a n i s m s intrinsic renal mechanisms reduced effective renal plasma flow and diminished proximal tubule na reabsorption have also been implicated in the pathophysiology of hypothyroidism.22,25,26 in severe cases, the effective arterial blood volume can decrease sufficiently to stimulate arginine vasopressin (avp) secretion via baroreceptor mechanisms. additionally, the impaired cardiac function that often occurs with advanced myxoedema can lead to an elevation in plasma avp levels. in ahmed s. abuzaid and nathan birch sounding board | e209 severe cases, hyponatraemia can occur secondary to thyroxine (t)3 deficiency, affecting renal na tubular reabsorption.1,10,12,27 different factors influence na handling and t3 levels in adult populations, including diet, alcohol consumption, hypertension and renal status.12 hyponatraemia and hypothyroidism have been found to coincide in a small number of selected populations.7,14 r o l e o f c e l l u l a r l o w s o d i u m / p o ta s s i u m p u m p e x p r e s s i o n a n d i n t e r s t i t i a l d e p o s i t i o n the na/potassium (k) adenosine triphosphatase (atpase) enzyme exchange process is the metabolic pacemaker of thyroid hormone-responsive tissues, leading to an increase in na pump activity.28 either directly at the messenger ribonucleic acid transcriptional level or through intermediate cellular and ionic regulators, thyroid hormones play an essential role in regulating the complex homeostatic regulation of atpase activity in the cell. na/k/atpase activity is higher in euthyroid states.12,28 reduced na/k/ atpase enzymatic activity and impaired na/hydrogen exchange activity of the proximal tubular borders and other specific segments, as part of a decline in cell metabolism in hypothyroid conditions, can contribute to the diminished proximal tubular capacity for na reabsorption in hypothyroidism.12,22 another probable influence contributing to hyponatraemia in hypothyroidism is the accumulation of interstitial mucopolysaccharides resulting in mutual solute and fluid retention, diminishing effective tissue perfusion and local lymphatic drainage, particularly in myxoedema.20 in hypothyroidism, hyponatraemia seems to be associated only with the severest cases of myxoedema as impaired cardiac function causes baroreceptor-mediated vasopressin secretion and total body water retention.20 furthermore, total body sodium is increased, evident from isotopic studies, and it is likely that the excess na is bound to the mucinous material present in the connective tissue.29 in addition, the impaired excretion of water load has been demonstrated in several studies and it has been suggested that inappropriate secretion of adh might mediate water retention.13,20 r o l e o f h y p o t h y r o i d i s m t y p e i n a d u lt s apart from myxoedema or complete hypopituitarism, primary hypothyroidism as the principal cause of hyponatraemia in either hospitalised or ambulatory patients remains questionable.13,30 reports from studies conducted on congenital hypothyroidism and adults with primary hypothyroidism did not show a definitive connection between hyponatraemia and hypothyroidism, even with a concomitant decline in the gfr among hypothyroid patients.31,32 serum creatinine levels could be elevated in patients with uncomplicated hypothyroidism without a significant decrease in serum na levels.32 despite previous reports describing hypothyroidism as a secondary cause of hyponatraemia, the evidence for such an association is poor.1 this was shown in recent studies of either congenital hypothyroidism, iatrogenic ablated cases or adults with primary hypothyroidism; all of these attempted to eliminate the influence of comorbid conditions by addressing a correlation between thyroid-stimulating hormone (tsh) and na levels and demonstrate a significant change in na concentrations as a result of normalising the hypothyroid state.14 such associations were inconclusive due to the small study populations and the presence of other confounders, together with differences in na handling mechanisms.1,14 moreover, when hyponatraemia accompanies hypopituitarism, secondary hypothyroidism is generally a sign of secondary glucocorticoid insufficiency rather than hypothyroidism itself.12 c o n g e n i ta l h y p o t h y r o i d i s m when hyponatraemia is detected in congenital hypothyroid cases, a lack of thyroid hormones is not the chief influencing factor.13,14,20,28–36 in a study conducted by asami et al., no cases of hyponatraemia were found in 32 congenital hypothyroid neonates where serum na concentrations did not statistically differ from those of 16 control neonates (median sodium level: 139 mmol/l).31 furthermore, no association was found between the measured thyroid functions and serum na. moreover, two months after thyroid hormone replacement, serum na levels in the infants had not changed significantly.31 in this study, the elimination of previously postulated factors that can affect na handling in paediatric populations, such as malnutrition, acute gastroenteritis, renal tubular disorders and syndrome of inappropriate adh secretion, did not confirm the claimed direct hyponatraemia-hypothyroidism link.31 this finding suggests other possible causes should be investigated.31,37,38 further data and related mechanisms from inpatient and outpatient settings studies involving larger numbers of patients found that serum na values were comparable in subjects with raised tsh values.10,14 however, laboratory data included hospitalised patients with raised tsh values the controversies of hyponatraemia in hypothyroidism weighing the evidence e210 | squ medical journal, may 2015, volume 15, issue 2 due to non-thyroidal illnesses such as acute hepatitis, nephrotic syndrome and depression.10,14 again, the data showed an absence of a clinically applicable relationship between newly diagnosed hypothyroidism and hyponatraemia.10,14 moreover, looking exclusively at serum samples of newly diagnosed hypothyroid patients in ambulatory settings showed a statistically significant relationship between lower na concentration in a small number of individuals and hypothyroidism; however, the relationship showed no clinically significant importance.33 it has been found that hyponatraemia was more common in patients with impaired renal function at diagnosis (serum creatinine concentrations of >1.1 mg/dl) than in those with normal renal function, which is another condition that can contribute to the progression of hyponatraemia in hypothyroid cases.32 a study involving 33,912 patients in a large urban general hospital showed matched serum na levels in euthyroid patients and hypothyroid patients (tsh >40 u/l; n = 445; na = 138.6 mmol/l). there was no significant difference between the euthyroid subjects (11.4%) and the hypothyroid subjects (12.8%) with regards to the proportion of patients with serum na lying below the reference interval of 135 mmol/l.14 a small retrospective case series studied 10 otherwise healthy ambulatory patients with primary hypothyroidism. these patients had a median tsh level of 193 µu/ml (range: 104.2–515.6 µu/ml; normal range: 0.40–5.50 µu/ml) and a median na level of 138 mmol/l (range: 136–142 mmol/l; normal range: 135–146 mmol/l).11 the lowest na level was 136 mmol/l with a concurrent tsh level of 469.7 µu/ml. no single patient was found to have a na level lower than 135 mmol/l.11 this observation suggests that hypothyroidism alone is less likely to contribute to hyponatraemia. a study conducted in an outpatient setting among individuals with hypothyroidism found that for every increase of 10 mu/l of tsh, there was a fall of only 0.14 mmol/l in the subjects’ na concentrations.33 thus, the elevation of tsh required for a clinically substantial fall in na to occur was considerable. again, none of the hypothyroid subjects and only two of the control patients had na values of <120 mmol/l. however, a relationship between lower na concentrations and hypothyroid status was statistically significant, yet unlikely to be of clinical significance.33 another retrospective study included 128 thyroidablated patients with differentiated thyroid cancers who were not receiving thyroid hormone replacement. a mean tsh level of 130.3 mu/l and a serum na level of 139.3 mmol/l was observed in hypothyroid cases. findings confirmed the infrequency of hyponatraemia in uncontrolled hypothyroidism; despite the observed elevated serum creatinine levels, there was no significant biochemically detected hyponatraemia.32 in a retrospective review of emergency room records including more than 9,000 patients, hyponatraemia was significantly more common in patients with high tsh levels than the normal tsh control group (<15% versus 9%, respectively; p <0.01).10 although serum na did not show a significant correlation with tsh and free t4 levels, a significant correlation was seen between free t3 levels and serum na levels. even though such a borderline correlation did exist, no proven practical electrolyte disturbances were confirmed.10 while there may appear to be an association between thyroid function and electrolyte disorders, it is most likely that clinically-related electrolyte derangements, such as hyponatraemia, are only established in extreme hypothyroid states. most patients with hyponatraemia have one evident cause, but there may be other contributory factors. real volume reduction can be initiated by the loss of na and water, leading to decreased tissue perfusion and provoking adh secretion. this response is facilitated by carotid sinus-related baroreceptors.20 as a consequence, water retention and hyponatraemia can develop with the depletion of effective arterial blood volume. because hypothyroidism and hyponatraemia are common findings in hospitalised patients, their cooccurrence may not necessarily be causal; therefore, other justifications for hyponatraemia should be pursued unless hypothyroidism is severe.8,10,13 a patient may not have any symptoms that indicate a thyroid illness that warrants further thyroid testing. however, an unexplained reduction in the plasma na concentration might inspire physicians to carry out further thyroid testing. recommendations overall, there is no strong evidence that supports routine thyroid testing for hyponatraemia in either hospital or outpatient encounters as compared to the general population. a history of concurrent illness and a medications list, as well as a careful physical examination, may provide clues to the pathogenesis of hyponatraemia. hyponatraemia in hypothyroidism cannot be ignored, but the clinical relevance of this association is questionable. tsh levels should be determined in challenging cases of hyponatraemia where both vasopressin-mediated and intra-renal mechanisms may be involved in the pathogenesis of the condition. thyroid assays should be ordered only when severe hypothyroidism is suspected in order to avoid unnecessary testing. ahmed s. abuzaid and nathan birch sounding board | e211 conclusion thyroid function tests are a simple and rapid way of obtaining a satisfactory diagnosis for suspected hypothyroidism. when a patient presents with typical symptoms, the diagnosis usually does not require a complex or invasive clinical investigation. although included in many diagnostic algorithms, hypothyroidism very rarely causes hyponatraemia. hyponatraemia is not a disease in and of itself, but a spectrum of diseases and/or adverse medication effects, making it a worthy clinical challenge. hypothyroidism is a possible aetiology, yet other probable causes of hyponatraemia should be sought first. the authors of this report conclude that there is no compelling evidence that suggests the need for routine thyroid testing in hyponatraemia. a thorough physical examination together with a history of the patient’s concurrent illnesses and their current medications should assist in identifying the cause of hyponatraemia. the current era of medicine demands the elimination of unnecessary testing. therefore, to avoid unessential assessments, thyroid testing should only be performed in particularly challenging cases of hyponatraemia or in possible cases of profound hypothyroidism. references 1. reynolds rm, seckl jr. hyponatraemia for the clinical endocrinologist. clin endocrinol (oxf ) 2005; 63:366–74. doi: 10.1111/j.1365-2265.2005.02318.x. 2. laczi f. [etiology, diagnostics and therapy of hyponatremias.] orv hetil 2008; 149:1347–54. doi: 10.1556/oh.2008.28409. 3. thompson c, berl t, tejedor a, johannsson g. differential diagnosis of hyponatraemia. best pract res clin endocrinol metab 2012; 26:s7–15. doi: 10.1016/s1521-690x(12)70003-9. 4. huda ms, boyd a, skagen k, wile d, van heyningen c, watson i, et al. investigation and management of severe hyponatraemia in a hospital setting. postgrad med j 2006; 82:216–9. doi: 10.1136/pmj.2005.036947. 5. adrogue hj, madias ne. the challenge of hyponatremia. j am soc nephrol 2012; 23:1140–8. doi: 10.1681/asn.2012020128. 6. adrogué hj, madias ne. hyponatremia. n engl j med 2000; 342:1581–9. doi: 10.1056/nejm200005253422107. 7. kilpatrick es. disorders of sodium balance: hypothyroidism and hyponatraemia: an old wives' tale? bmj 2006; 332:854. doi: 10.1136/bmj.332.7545.854. 8. rachoin js, cerceo ea. four nephrology myths debunked. j hosp med 2011; 6:e1–5. doi: 10.1002/jhm.703. 9. roberts cg, ladenson pw. hypothyroidism. lancet 2004; 363:793–803. doi: 10.1016/s0140-6736(04)15696-1. 10. schwarz c, leichtle ab, arampatzis s, fiedler gm, zimmermann h, exadaktylos ak, et al. thyroid function and serum electrolytes: does an association really exist? swiss med wkly 2012; 142:w13669. doi: 10.4414/smw.2012.13669. 11. sun ge, pantalone km, hatipoglu b. hypothyroidism as a cause of hyponatremia: fact or fiction? endocr pract 2012; 18:894–7. doi: 10.4158/ep12130.or. 12. hanna fw, scanlon mf. hyponatraemia, hypothyroidism, and role of arginine-vasopressin. lancet 1997; 350:755–6. doi: 10.1016/s0140-6736(05)62563-9. 13. sari r, sevinc a. life-threatening hyponatremia due to cessation of l-thyroxine. j natl med assoc 2003; 95:991–4. 14. croal bl, blake am, johnston j, glen ac, o'reilly ds. absence of relation between hyponatraemia and hypothyroidism. lancet 1997; 350:1402. doi: 10.1016/s0140-6736(05)65181-1. 15. prasad v, vandross a, toomey c, cheung m, rho j, quinn s, et al. a decade of reversal: an analysis of 146 contradicted medical practices. mayo clin proc 2013; 88:790–8. doi: 10.1016/j.mayocp.2013.05.012. 16. ioannidis jp. how many contemporary medical practices are worse than doing nothing or doing less? mayo clin proc 2013; 88:779–81. doi: 10.1016/j.mayocp.2013.05.010. 17. villas boas pj, spagnuolo rs, kamegasawa a, braz lg, polachini do valle a, jorge ec, et al. systematic reviews showed insufficient evidence for clinical practice in 2004: what about in 2011? the next appeal for the evidence-based medicine age. j eval clin pract 2013; 19:633–7. doi: 10.1111/j.13652753.2012.01877.x. 18. kaptein em, beale e, chan ls. thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. j clin endocrinol metab 2009; 94:3663–75. doi: 10.1210/jc.20090899. 19. farwell ap. nonthyroidal illness syndrome. curr opin endocrinol diabetes obes 2013; 20:478–84. doi: 10.1097/01. med.0000433069.09294.e8. 20. hierholzer k, finke r. myxedema. kidney int suppl 1997; 59:s82–9. 21. iwasaki y, oiso y, yamauchi k, takatsuki k, kondo k, hasegawa h, et al. osmoregulation of plasma vasopressin in myxedema. j clin endocrinol metab 1990; 70:534–9. doi: 10.1210/jcem-70-2-534. 22. schmitt r, klussmann e, kahl t, ellison dh, bachmann s. renal expression of sodium transporters and aquaporin-2 in hypothyroid rats. am j physiol renal physiol 2003; 284:f1097– 104. doi: 10.1152/ajprenal.00368.2002. 23. skowsky wr, kikuchi ta. the role of vasopressin in the impaired water excretion of myxedema. am j med 1978; 64:613–21. doi: 10.1016/0002-9343(78)90581-8. 24. koide y, oda k, shimizu k, shimizu a, nabeshima i, kimura s, et al. hyponatremia without inappropriate secretion of vasopressin in a case of myxoedema coma. endocrinol jpn 1982; 29:363–8. doi: 10.1507/endocrj1954.29.363. 25. ojamaa k, balkman c, klein il. acute effects of triiodothyronine on arterial smooth muscle cells. ann thorac surg 1993; 56:s61–7. doi: 10.1016/0003-4975(93)90556-w. 26. mariani lh, berns js. the renal manifestations of thyroid disease. j am soc nephrol 2012; 23:22–6. doi: 10.1681/ asn.2010070766. 27. goldberg m, reivich m. studies on the mechanism of hyponatremia and impaired water excretion in myxedema. ann intern med 1962; 56:120–30. doi: 10.7326/0003-4819-561-120. 28. mcdonough aa, brown ta, horowitz b, chiu r, schlotterbeck j, bowen j, et al. thyroid hormone coordinately regulates na+-k+-atpase alphaand beta-subunit mrna levels in kidney. am j physiol 1988; 254:c323–9. 29. macaron c, famuyiwa o. hyponatremia of hypothyroidism. appropriate suppression of antidiuretic hormone levels. arch intern med 1978; 138:820–2. doi: 10.1001/archinte.1978.03630290100035. 30. kargili a, turgut fh, karakurt f, kasapoglu b, kanbay m, akcay a. a forgotten but important risk factor for severe hyponatremia: myxedema coma. clinics (sao paulo) 2010; 65:447–8. doi: 10.1590/s1807-59322010000400015. the controversies of hyponatraemia in hypothyroidism weighing the evidence e212 | squ medical journal, may 2015, volume 15, issue 2 31. asami t, uchiyama m. sodium handling in congenitally hypothyroid neonates. acta paediatr 2004; 93:22–4. doi: 10.1111/j.1651-2227.2004.tb00668.x. 32. baajafer fs, hammami mm, mohamed ge. prevalence and severity of hyponatremia and hypercreatininemia in shortterm uncomplicated hypothyroidism. j endocrinol invest 1999; 22:35–9. doi: 10.1007/bf03345476. 33. warner mh, holding s, kilpatrick es. the effect of newly diagnosed hypothyroidism on serum sodium concentrations: a retrospective study. clin endocrinol (oxf ) 2006; 64:598–9. doi: 10.1111/j.1365-2265.2006.02489.x. 34. chelimsky g, davis id, kliegman rm. neonatal hyponatremia associated with congenital hypothyroidism. clin pediatr (phila) 1997; 36:177–80. doi: 10.1177/000992289703600310. 35. bühler uk, savary a, krauer b, stalder gr. water intoxication in a cretinoid infant. j clin endocrinol metab 1966; 26:111–6. doi: 10.1210/jcem-26-1-111. 36. robles-valdés c, ramirez mayans ja, alcántara lomeli ji. severe hyponatremia in congenital hypothyroidism. j pediatr 1979; 94: 631–2. doi: 10.1016/s0022-3476(79)80037-2. 37. gumieniak md o, farwell md ap. schmidt's syndrome and severe hyponatremia: report of an unusual case and review of the related literature. endocr pract 2003; 9:384–8. doi: 10.4158/ ep.9.5.384. 38. sert m, tetiker t, kirim s, kocak m. clinical report of 28 patients with sheehan's syndrome. endocr j 2003; 50:297–301. doi: 10.1507/endocrj.50.297. clinical & basic research sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e50-58, epub. 27th jan 14 submitted 13th may 13 revision req. 2nd jul 13; revisions recd. 1st aug 13 accepted 25th aug 13 departments of 1biochemistry and 3medicine, college of medicine & health sciences, sultan qaboos university; departments of 2pathology and 4medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: yahyatam@squ.edu.om تشكيل طفرات/عمليات احلذف ل p53 يف جمموعة صغرية من العمانيني العمانيني املصابني باألورام الليمفاوية كبرية احلجم للخاليا البائية يحيى �لتاميمي, �صيخة �حلارثي, �إبر�هيم �لهد�بي, حممد �لكندي, حمزة بابكر, من�صور �ملنذري, �إكر�م بريين abstract: objectives: mutations/deletions affecting the tp53 gene are considered an independent marker predicting a poor prognosis for patients with diffuse large b-cell lymphoma (dlbcl). a cohort within a genetically isolated population was investigated for p53 mutation/deletion status. methods: deoxyribonucleic acid (dna) samples were extracted from 23 paraffin-embedded blocks obtained from dlbcl patients, and subjected to polymerase chain reaction (pcr) amplification and sequencing of exons 4–9 of the p53 gene. results: while 35% of patients analysed displayed allelic deletions (p <0.01), immunohistochemical analysis revealed a mutation rate of 69.5%. it is noteworthy that the rate of p53 mutations/deletions in this small cohort was found to be higher than that previously reported in the literature. interestingly, patients with p53 mutations displayed a better overall survival when compared to those without. the survival of patients treated with rituximab-containing combination chemotherapy was significantly better than those who did not receive rituximab (p <0.05). furthermore, a modelling analysis of the deleted form of p53 revealed a huge structural change affecting the dna-binding domain. conclusion: the tp53 mutation/deletion status plays a role in mechanism(s) ruling the pathogenesis of dlbcl and may be useful for stratifying patients into distinct prognostic subsets. keywords: mutations; gene deletion; lymphoma, b-cell; paraffin embedding; immunohistochemistry; oman. �حلجم كبرية �للمفاوية باالأور�م �مل�صابي للمر�صى �ل�صيء للتنبوؤ م�صتقلة عالمة tp53 مت�س �لتي �حلذف �لطفر�ت/عمليات تعترب الهدف: امللخ�ص: لهذه �ختيارهم مت و�لذين ور�ثيا �ملعزولي �ملر�صي من لعينة p53 للجي �حلذف �ختبار�لطفر�ت/عمليات مت .)dlbcl( �ملنت�رشة �لبائية للخاليا �لدر��صة. الطرق: مت ��صتخر�ج مادة �حلم�س �لنووي )dna( من 23مري�س و�لتي عر�صت للم�صاعفة عن طريق تفاعل �لبلمرة �ملت�صل�صل ومن ثم مت �يجاد ,)p >0.01( النتائج: يف حي �أن %35 من �ملر�صى �لذين مت حتليلهم �أظهرو� حذفا �أليليا .p53 لت�صل�صل �لنيوكليوتيدي لالأك�صونات 9−4 من �جلي� مت �لتي �لعينة يف p53 للجي �حلذف �لطفر�ت/عمليات معدل �أن بالذكر �جلدير ومن .69.5% بن�صبة حتور معدل �لن�صيجي �ملناعي �لتحليل ك�صف در��صتها وجدت �أعلى مما هو موجود يف �لدر��صات �ل�صابقة. كما �أنه من �ملثري لالهتمام �أن �ملر�صى �لذين يحملون طفر�ت بp53 �أظهرو� فر�س يف �لبقاء علي قيد �حلياة بن�صب �أف�صل عند مقارنتهم بغريهم من �ملر�صى �لذين ال يحملون هذه �لطفر�ت. �أظهرت �لدر��صة �أي�صًا �أن �لبقاء على قيد �حلياة للمر�صى �لذين يعاجلون بعقار �لريتوك�صوماب �لعالج �لكيميائي �ملر كب �ملحتو ي �أ�صا�صا علي �لر يتو ك�صو ماب كان �أف�صل عند مقارنتهم باأولئك �لذين مل يتلقو� .dna تغيري� هيكليا كبري� يوؤثر يف جمال ربط �حلم�س �لنووي p53 عالوة على ذلك ك�صف حتليل �لنمذجة للحذف يف )p >0.05(.لريتوك�صيماب� الإ�ستنتاج: ن�صتنتج �أن �لطفر�ت/عمليات �حلذف ل p53 تلعب دور� يف �الآليات �لتي حتكم �لت�صبب ب dlbcl كما �أنها ميكن �أن تكون مفيدة لتق�صيم �ملر�صى �إىل جمموعات فرعية للتنبوؤ بحالة �ملر�س. مفتاح الكلمات: طفر�ت ور�ثية؛ عمليات �حلذف للجي؛ �الأور�م �لليمفاوية؛ �خلاليا �لليمفاوية �لبائية؛ �لتكتل بالبار�في؛ �لتحليل �ملناعي �لن�صيجي؛ عمان. the p53 mutation/deletion profile in a small cohort of the omani population with diffuse large b-cell lymphoma *yahya tamimi,1 sheikha al-harthy,1 ibrahim al-haddabi,2 mohammed al-kindi,1 hamza babiker,1 mansour al-moundhri,3 ikram burney4 advances in knowledge the tp53 mutation/deletion profile in the present study revealed a role in the mechanism(s) ruling the pathogenesis of diffuse large b-cell lymphoma (dlbcl) that might be useful for stratifying subpopulations based on their different genetic backgrounds. application to patient care the findings shed some light on the role of p53 mutations/deletions in mechanisms involved in the pathogenesis of dlbcl, which may help in stratifying affected patients into distinct prognostic subsets and in providing tailored therapies. yahya tamimi, sheikha al-harthy, ibrahim al-haddabi, mohammed al-kindi, hamza babiker, mansour al-moundhri and ikram burney clinical and basic research | e51 diffuse large b-cell lymphoma (dlbcl) is the most common type of non-hodgkin’s lymphoma (nhl) in developing countries, including those in the middle east, where it may constitute up to 60% of cases.1 it has been shown that dlbcl is morphologically a very heterogeneous disease and the affected patients usually present with an advanced stage of the disease.1–3 because of this complex heterogeneity, there is an unmet need to identify prognostic markers to help discriminate between dlbcl subgroups. the p53 protein encoded by the p53 gene is a tumour suppressor gene playing a crucial role in cell cycle control, cell growth, apoptosis and senescence, and in the response to stress signals such as deoxyribonucleic acid (dna) damage and hypoxia.4,5 mutations of the p53 gene are common and have been implicated in the disease progression of more than 50% of epithelial cancers.6 the normal functioning of the p53 gene is important for the eradication of tumours.7 tp53 mutations are responsible for an increased resistance to chemotherapy, a decrease in apoptosis, neoangiogenesis and the early progression of the disease leading to a shortened overall survival rate.8 in lymphoid malignancies, the incidence of p53 mutations is reported to have a range of 5–25% of cases, the majority of which (~90%) are clustered in the dna-binding domain of the protein.6–8 other changes, such as single-nucleotide polymorphisms (snps), allelic loss and complete deletions between exons 4–9, have been also described.9 the prognostic value of tp53 mutations has not been consistent in dlbcl, where tp53 mutations are considered a poor prognostic factor.8,10–12 this inconsistency is likely due to the tp53 mutation’s heterogeneity, the limit of mutation detection methods or the diversity in the tp53 mutation’s functions.13,14 rituximab, an anti-cd20 antibody, has improved the survival of patients with dlbcl significantly when combined with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (chop) chemotherapy, and acts through complement-mediated cytotoxicity and antibodydependent cellular cytotoxicity.15 high doses of rituximab inhibit cell growth through intracellular calcium (ca2+) mobilisation. this is independent of the cd20 antigen and the inhibition of downstream key effectors such as protein 38, nuclear factor kappa-light-chain-enhancer of activated b cells, extracellular signal-regulated kinase, protein kinase b, and the downregulation of cytokine interleukin 10 and b-cell lymphoma-2 (bcl-2).15–17 rituximab and other drugs can generate different stresses, affecting tp53 functioning. similarly, the p53independent signalling pathways induced by rituximab can affect the transcription activity of the p53 gene. thus, this lends validity to the importance of exploring the prognostic value of pt53 mutation/ deletion in patients with dlbcl treated with different drugs. studies on patients of arab ethnicity in the middle east describing p53 aberrations in dlbcl diseases are scarce; thus, this study aims to address the prognostic significance of p53 mutation/deletions in a small cohort with dlbcl. exons 4–9 of the p53 gene were analyzed using polymerase chain reaction (pcr), sequencing and immunohistochemical analysis on archival paraffinembedded material, and the mutation/deletion status was correlated with the clinical outcome. additionally, molecular modelling was used to estimate the structural changes in the affected tp53 protein. methods this study was approved by the medical ethics research committee of the college of medicine & health sciences at sultan qaboos university, muscat, oman. paraffin-embedded formalin-fixed tissue samples were obtained from sultan qaboos university hospital. all of the samples were from omanis diagnosed with stage iib dlbcl or higher, according to the ann arbor system. the ii stage indicates that either two or more lymph node regions on the same side of the diaphragm or one lymph node region and a contiguous extralymphatic site were involved, and the classification b indicates the presence of systemic symptoms. all the patients were treated between january 2001 and september 2008. table 1 outlines the histopathology and clinical data. paraffin blocks from 23 patients were examined by a pathologist and areas containing at least 95% cancer cells were marked and cut for dna extraction. serial sections of 8 μm were cut, deparaffinised in xylene and rehydrated in the p53 mutation/deletion profile in a small cohort of the omani population with diffuse large b-cell lymphoma e52 | squ medical journal, february 2014, volume 14, issue 1 decreasing ethanol concentrations of 100%, 70% and 50%. a digestion step in 20 mg/ml of proteinase k (roche diagnostic gmbh, mannheim, germany) was subsequently performed at 55 °c for at least 10 hours. the tissues were then incubated overnight at 55 °c in a lysis buffer solution (tris(hydroxymethyl) aminomethane ph 6.8, 20% sodium dodecyl sulfate (sds) and 2% glycerol) (fermentas, thermo fisher scientific, vilnius, lithuania) and subjected to phenol chloroform extraction and ethanoltable 1: clinical/pathological features of the cohort and aberrations in the p53 gene age in years and gender ipi category stage b symptoms site of the tumour ihc staining score sequencing and lom status 57 f 4 4b yes extra-nodal 3 no mutation dead 50 m 1 3b no extra-nodal 2 no mutation alive 20 m 3 4b yes extra-nodal 2 lom in exons 4, 5, 7 and 8 alive 47 f 2 3a no nodal 2 lom in exons 4 and 7–9 alive 60 f 4b yes extra-nodal 3 no mutation dead 25 f 3 4b yes extra-nodal 3 lom in exons 4, 5 and 7–9 alive 46 f 1 2b yes nodal lom in exons 4, 5 and 7–9 alive 70 m 3 3b yes nodal 1 no mutation alive 66 m 4 3b yes nodal 3 no mutation dead 50 f 3 3a no extra-nodal 3 mutation in exon 5 dead 70 m 4 4b yes nodal 2 no mutation dead 65 m 4b yes 1 no mutation dead 53 m 1 2b 1 lom in exons 4, 5 and 7–9 alive 62 m 4 3b yes nodal 0 no mutation dead 65 m 5 4a yes extra-nodal 2 no mutation dead 48 m 4 4b extra-nodal 0 lom in exons 4 and 7–9 alive 21 f nodal 2 lom in exons 4–9 alive 21 f 3 2b yes extra-nodal 2 no mutation alive 59 m 4b yes nodal 2 no mutation dead 29 m 29 m 0 no mutation alive 30 m nodal 0 mutation and deletion in exon 5 alive 70 m 5/5 4b yes extra-nodal 0 no mutation alive ipi = international prognostic index; b = presence of systemic symptoms; ihc = immunohistochemistry; lom = loss of deoxyribonucleic acid material; f = female; m = male; ipi categories: low risk (0–1 points) 5-year survival 73%; low-intermediate risk (2 points) 5-year survival 51%; high-intermediate risk (3 points) 5-year survival 43%; high risk (4–5 points) 5-year survival 26%. stage ii = cancer located in two separate regions, an affected lymph node or organ and a second affected area, and that both affected areas are confined to one side of the diaphragm. stage iii = cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen. stage iv = diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs. a = absence of constitutional (b-type) symptoms; b = presence of constitutional (b-type) symptoms. yahya tamimi, sheikha al-harthy, ibrahim al-haddabi, mohammed al-kindi, hamza babiker, mansour al-moundhri and ikram burney clinical and basic research | e53 dna precipitation. the dna concentration was estimated with the nanodrop method using a nd1000 spectrophotometer (nanodrop products, thermo scientific, wilmington, delaware, usa). due to the extremely low concentration of normal cells present in each section composed of more than 90% of cancer cells, normal tissue could not be included for the control of sequencing reactions. this was corrected by taking sequences from normal blood as a reference for the putative polymorphisms. the extracted dna was amplified by pcr using a set of designed primers covering the relevant areas of the p53 gene, including exons 4–9. an additional pair of primers was used to amplify the housekeeping gene glyceraldehyde-3phosphate dehydrogenase (gapdh) and to check for dna integrity [table 2]. in order to avoid primer mismatches that might result in negative pcr amplifications, all primers were checked for eventual mutations on their corresponding site. pcr reactions were performed in a total volume of 50 μl using optimised pcr conditions. each cycle was run through a denaturing step at 94 °c for 55 secs, an annealing step ranging between 55–60 °c for 55 secs (depending on the primers’ melting temperatures) and an elongation step of 55 secs at 72 °c. the pcr reactions were run in a thermocycler for 25 cycles, preceded by a denaturing step of 4 mins and followed by an extended elongation time of 7 mins at 72 °c. all amplification reactions were repeated at least twice to confirm the consistency of the pcr reactions. specific bands corresponding to the amplified pcr products were purified using the exosapit® enzyme clean-up method (affymetrix, inc., santa clara, california, usa), and the sequencing reactions were initiated using a bigdye terminator (applied biosystems, inc., foster city, california, usa). after the ethanol precipitation, the dna was resuspended in 10 μl of deionised formamide, covered and loaded into the sequencer abi prism® 3100 genetic analyzer (applied biosystems). sequences were analysed using the sequenchertm 4.7 software (gene codes corporation, ann arbor, michigan, usa). for immunohistochemical staining, sections of 4 μm were cut and mounted on polylysine-coated slides, dewaxed and placed in sodium perborate (0.2 m of disodium hydrogen phosphate, 0.3 m of monopotassium phosphate and 0.01 m of sodium chloride, at ph 9), then heated for 2–3 mins at 100 °c in a microwave oven to mediate antigen retrieval. the machine was set up so that heating was controlled in order to ensure only the antigen retrieval, without causing tissue damage. a mouse monoclonal anti-human p53 antibody, recognising both the wild-type and the mutant p53 protein, was applied to the sections. the secondary antibody was an anti-mouse polyclonal conjugated to horseradish peroxidase (dako a/s, glostrup, denmark) and used at 1/5000 dilution. the slides were visualised using the universal dako lsab®+ kit (code k 0679, dako a/s) and scored by a pathologist. the positive cells were characterised by a brown precipitate at the cytoplasmic level as indicated by arrows in figure 1b, whereas the negative cells were distinguished by their nuclear blue haematoxylin staining and an uncoloured cytoplasm. a cut-off value of p53 staining was set at 20% positive cells. cases with no staining or less than 20% positive cells at x 400 magnification were scored zero. cases of weak staining at x 400 magnification (more than 20% positive cells) were scored one, cases of moderate staining at x 100 magnification were scored two, and finally a score of three was given to cases with any percentage of staining recognisable at x 40 magnification. sections displaying positive immunohistochemistry (ihc) staining were considered equivalent to p53 mutations. clinicopathological variables such as age, gender, clinical stage, performance status, serum lactate dehydrogenase (ldh) levels and the site of disease were obtained from clinical reports. the number of extranodal sites was recorded and the patients were categorised using the international prognostic index (ipi). overall survival was calculated from the time of diagnosis to death or until february 2011 using the statistical package for the social sciences (spss), version 19 (ibm, corp., chicago, illinois, usa) software. the minimum follow-up period was 30 months and the maximum was nine years. median survival was estimated using the kaplan-meier method, and the log-rank test (mantel-cox test) was used for comparison among the different groups. the fisher’s exact test was applied to estimate the putative association of mutations to the disease. one of the major limitations of this study was the small size of the cohort; the statistical methods used were therefore the p53 mutation/deletion profile in a small cohort of the omani population with diffuse large b-cell lymphoma e54 | squ medical journal, february 2014, volume 14, issue 1 carefully selected for small population sizes to avoid incorrect conclusions. results paraffin blocks were available from 23 patients (15 males and 8 females) with a median age at diagnosis of 49 years (range: 20–70 years). a complete clinical profile was available for 19 of the 23 patients only. out of these 19 patients, two had stage iib (as described previously) dlbcl, eight had stage iii (indicating the involvement of lymph node regions on both side of the diaphragm), and nine had stage iv of the disease (indicating disseminated involvement of one or more extralymphatic organs). using the ipi, two patients had a low to intermediate risk, whereas eight patients had a high to intermediate risk and nine patients a high risk [table 1]. out of the 21 patients with ihc staining scores, five displayed negative, three displayed weakly positive (score = 1), eight displayed moderately positive (score = 2) and five displayed strongly positive staining (score = 3). figure 1 shows the p53 staining at different magnifications. table 1 summarises the ihc and sequencing data with the location of the aberration (mutation/deletion) and the dlbcl origin. pcr conditions were optimised using dna extracted from healthy donor blood samples. all of the tested exons displayed single bands of an expected size, implying the specificity of the pcr reactions. the housekeeping gene gapdh was run in parallel to verify the integrity of the dna. the optimised conditions were applied to amplify the dna samples [figure 2]. a gel examination revealed extracted dna of lower molecular weights and, therefore, it was difficult to amplify the large fragments (≥400 base pairs [bp]). thus, primers generating lower size products were designed for both p53 and gapdh. the pcr products were resolved using 1% agarose gel electrophoresis and all of the samples displayed specific bands of the expected sizes in exons 4, 5, 6 and 9. however, exon figure 1 a & b: a representative example of the immunohistochemistry showing the positive and the negative staining obtained for (a) samples and (b) controls, respectively. the arrows indicate the stained cells at a magnification of x 40. figure 2: the optimisation of the polymerase chain reaction (pcr) conditions for exons 4–6 of the p53 gene. the polymerase chain reaction amplification products of exon 4 (lanes 1 and 2), exon 5 (lanes 4 and 5) and exon 6 (lanes 7 and 8) of the p53 gene resolved on 1% agarose gel electrophoresis and compared to the 100 base pairs (bp) deoxyribonucleic acid marker (lane 1). samples were run in duplicate, including the negative controls (lanes 3, 6 and 9). yahya tamimi, sheikha al-harthy, ibrahim al-haddabi, mohammed al-kindi, hamza babiker, mansour al-moundhri and ikram burney clinical and basic research | e55 8 revealed either a complete absence of signals or faint bands (partial loss). in the current study, eight samples highly amplified the gapdh gene, but not the p53 gene, suggesting the presence of putative deletions [figure 3a–c]. to confirm this observation, samples were amplified from the ovca2 gene located adjacent to the p53 gene on chromosome 17 and specific bands were obtained suggesting that the deletion is specific for the p53 gene. moreover, in addition to the putative deletions observed, samples showing a high level of gapdh but weak bands for the amplified exons 4–9 were reported, representing typical examples of the partial loss of genetic material as shown in figure 3b. the electropherogram revealed missense mutations in codon 143, changing the amino acid valine (non-polar) to leucine (non-polar) (gtg to tta). in codon 145, missense mutations caused a change from the leucine (non-polar) to threonine (polar) amino acid (ctg to acg). in codons 146 and 150, there was a change from the tryptophan (non-polar) to the basic arginine (tgg to agg) and from the threonine (polar) to arginine (aca to aga), respectively. changing amino acids with different polarities may affect the functional profile of the mutated p53 protein. the amino acid sequences of the p53 protein carrying the p53 mutation w150r and the sequence harbouring the deletion in exon 5 were subjected to a modelling analysis to predict the changes that occur in the p53 structure. both aberrations (mutation and deletion) displayed an obvious change within the p53 three-dimensional structure (data not shown). while the five-year survival rate was 48%, the median overall survival time was 57 months [figure 4a]. the correlation of survival with the data obtained using ihc did not demonstrate any statistically significant difference between those with or without p53 mutations. however, patients with p53 mutations detected by sequencing demonstrated a trend of better overall survival compared to those who did not harbour mutations [figure 4b]. of the patients, 11 out of 19 received figure 3 panels a, b & c: the representative gel displaying the expression of the glyceraldehyde-3phosphate dehydrogenase (gapdh) gene and exons 4–9 of the p53 gene in samples 4, 13 and 16, respectively. the arrows indicate the obtained deletions (a & c) and partial loss (b). the partial loss is similar to gene dosage, where substantial deoxyribonucleic acid damage is obvious but not completely lost, likely resulting in farreaching repercussions on gene function. figure 4 a, b & c: the median overall survival curve. a: the overall survival plot displays the 57 months recorded for the studied cohort, while the five-year survival rate observed was 48%. b: however, the overall survival curve shows a trend towards better overall survival in patients who harboured mutations in the p53 gene, as analysed by sequence analysis. the immunohistochemistry analysis revealed no statistically significant difference between the survival of those with or without p53 mutations. c: the overall survival curve shows that patients receiving rituximab in addition to cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (r-chop) did significantly better than those who only received chop (p <0.05). the p53 mutation/deletion profile in a small cohort of the omani population with diffuse large b-cell lymphoma e56 | squ medical journal, february 2014, volume 14, issue 1 a combined therapy consisting of chop, whereas eight patients received the anti-cd20 antibody, rituximab, in addition to chop (r-chop). the survival of patients receiving r-chop was significantly better than those who received chop (p <0.05), as shown in figure 4c. discussion in this study, the entire region of the p53 gene, including exons 4–9, was screened for the presence of mutations/deletions; partial losses as well as deletions in eight of 19 patients were identified. to validate this observation, the ovca2 gene localised in the neighbouring area of the p53 gene on chromosome 17 was amplified. while no amplification of the p53 gene could be obtained using the p53 primers, specific bands were obtained systematically when the ovca2 primers were used. moreover, the p53 primers’ targeted area was meticulously scanned for the presence of any polymorphisms that might hamper the appropriate binding of the primers, resulting in non-amplified amplicons; however, no aberration was found. southern blotting would have been more appropriate to confirm the deletions and loss of genetic material. however, the amount of dna required for a southern blot is substantial (more than 5 mg), and therefore difficult to obtain from archival material. alternatively, confirming deletions by comparison of the housekeeping gene amplification of gapdh with pcr products from the exons of interest is widely used.18 faint bands were obtained by amplifying exons 4, 5, 7 and 8 using the dna from a patient with stage iv t-cell-rich dlbcl (t-dlbcl), suggesting that the loss of p53 material may be associated with the transformation of the disease. another patient with stage iib dlbcl displayed two faint bands for exons 5 and 6, while complete deletions were observed in exons 4, 7, 8 and 9 [figure 3a–c]. both patients displayed a positive staining by ihc. these data are in agreement with previous reports indicating that up to 20% of dlbcl patients harbour deletions on the short arm of chromosome 17 (chromosome 17p13) corresponding to the location of the p53 gene.19 at the structural level, both the w150r mutation and the deletion in exon 4 displayed substantial changes in the p53 gene when compared to the wild-type molecule. changing the non-polar amino acid tryptophan (w) at position 150 by the larger polar arginine amino acid (r), within a well-conserved region (from amino acid 101 to 306) containing the dna-binding domain, would likely alter the tumour-suppressing function of the p53 protein. the predicted model of the p53-exon-4-deleted form revealed an obviously disorganised structure of the p53 protein affecting several domains, including the transactivation and the binding domains. both the quantitative pcr and southern blotting methods have revealed deletions in relevant genes in dlbcl such as cdkn2 and cdkn2b.20 moreover, a substantial decrease in messenger ribonucleic acid (mrna) expression levels associated with specific gene signatures has been confirmed with gene deletion.21 interestingly, these deletions were directly associated with a poor prognosis in dlbcl.20–23 a deletion on the short arm of chromosome 17 may be a sign of transformation from other types of lymphoma to dlbcl.19 moreover, it was reported that p53 mutations and deletions are detected in t-dlbcl and predict resistance to treatment and short survival in variants of dlbcl.24,25 the transformation of follicular lymphoma can evolve through a variety of mechanisms characterised by a high proliferation rate and the mutation of the p53 gene, amplification of the rel gene, loss of cdnk2a and changes in the c-myc gene expression.26 missense mutations in exon 5 were found in two patients, one of whom presented with extranodal t-dlbcl at stage iii of the disease. the ihc analysis showed a positive staining, which is consistent with sequence analysis data. the second patient had a similar pattern with deletions in exons 4, loss of material in exon 7 and a c to t point mutation in exon 5, changing the proline amino acid to serine at position 177 (p 177 s). no positive staining, however, was revealed by ihc. this could be explained by a large deletion in the p53 gene that may hamper transcription. the missense mutation found in exon 5 was located on the dna-binding domain of the p53 protein, which is divided into three loops (l1, l2 and l3) and two loop sheet helix (lsh) regions. l1, l3 and lsh make direct contact with the dna while l2 is required for the folding and stabilisation of the dna-binding domain, with no direct contact with the dna.8 the missense mutation on exon 5 is located in the core domain within l2 and l3. therefore, this could affect both yahya tamimi, sheikha al-harthy, ibrahim al-haddabi, mohammed al-kindi, hamza babiker, mansour al-moundhri and ikram burney clinical and basic research | e57 the dna binding and the folding process of the related domain. it was found that mutations within areas of direct contact with the dna resulted in a poor survival rate, while mutations that affected the folding of the protein had no significant impact on the patient’s overall survival.8 positive staining was shown in ten patients by ihc; however, no aberrations were detected by sequencing. this contradiction is likely due to the limited area covered by the sequencing, omitting some exons (for instance exons 1–3) as well as the promoter area, also frequently targeted by mutations. moreover, the ihc technique cannot be used alone to predict mutations since the mechanisms responsible for gene overexpression may generate false-positive results.27 on the other hand, protein-stabilising factors such as the mdm2 protein could have an effect by promoting the rapid degradation of the phosphorylated form of p53.28 the p53 gene activates the expression of mdm2 in an auto-regulatory feedback loop. therefore, mutations affecting mdm2 cause a half-life increase of the p53 protein and its accumulation, allowing its detection by ihc.29 unexpectedly, a better overall survival rate for patients harbouring p53 mutations was observed when compared with patients with no mutations in the p53 gene. data concerning this matter are conflicting.9,11,30,31 for instance, ichikawa et al. demonstrated that the overall survival was inferior for an entire cohort with p53 mutations. however, this effect was not seen in patients with a high-risk ipi category.11 in the current study, at presentation all but two patients had a high to intermediate and high risk ipi category. an alternative explanation could be related to the effect of treatment. as shown in figure 4c, patients treated with r-chop had a higher overall survival compared to those who were treated with chop alone. the p53induced apoptotic pathway could be overhauled as a result of mutations in the p53 gene. conversely, rituximab inhibits the anti-apoptotic protein bcl-2, thus causing apoptosis induction. it is plausible that rituximab-induced apoptosis may override the mutant p53-mediated anti-apoptotic pathway. similarly, hussein et al. showed a negative correlation between bcl-2 and p53 protein expression in lympho-proliferative disorders.32 in a recent report, xu-monette et al. studied the prognostic significance of p53 mutations in dlbcl using a large cohort of de novo dlbcl patients treated with r-chop, and showed that those with tp53 mutations had worse overall and progressionfree survival compared to those without.33 it is worth noting that the majority of studies on the association of p53 with prognosis in dlbcl are from the pre-rituximab era. data reporting on the dlbcl incidence in the middle east and comparisons to those in western countries, including north america, are scarce. however, ameen et al. studied nhl frequency among different ethnic groups in kuwait and compared those results with studies from the western world. they found that the kuwaiti population had a higher prevalence of dlbcl and extranodal presentation.34 despite the small number of patients recruited, the data on omani patients in this study are in agreement with the increase of dlbcl frequency in the middle east region; the aberrations (mutation/deletion) of the p53 gene might be directly linked to this higher frequency. despite several tentative attempts, we were unable to increase the number of samples used for this study which was a major limitation. precautions were taken throughout and the small size of the sample was taken into account by using the appropriate statistical methods. conclusion mutations/deletions were frequently detected within the relevant region of the p53 gene. the incidence of mutations was higher than those previously reported in the literature and may suggest that the biology of the disease changes depending on ethnicity. the survival data, especially with regards to potential treatment, are intriguing and require verification in a larger cohort. the number of patients recruited for this study was very modest and analysis should be extended to a large cohort in order to draw appropriate conclusions. a c k n o w l e d g e m e n t this work was supported by the postgraduate studies & research programme at sultan qaboos university, muscat, oman. references 1. müller am, ihorst g, mertelsmann r, engelhardt m. the p53 mutation/deletion profile in a small cohort of the omani population with diffuse large b-cell lymphoma e58 | squ medical journal, february 2014, volume 14, issue 1 epidemiology of non-hodgkin’s lymphoma (nhl): trends, geographic distribution, and etiology. ann hematol 2005; 84:1–12. 2. naresh kn, advani s, adde m, aziz z, banavali s, bhatia k, et al. report of an international network of cancer treatment and research workshop on non-hodgkin’s lymphoma in developing countries. blood cells mol dis 2004; 33:330–7. 3. montoto s, fitzgibbon j. transformation of indolent b-cell lymphomas. j clin oncol 2011; 29:1827–34. 4. borrás c, gómez-cabrera mc, viña j. the dual role of p53: dna protection and antioxidant. free radic res 2011; 45:643– 52. 5. hede sm, nazarenko i, nistér m, lindström ms. novel perspectives on p53 function in neural stem cells and brain tumors. j oncol 2011; 2011:1–11. 6 gudkov av, komarova ea. the role of p53 in determining sensitivity to radiotherapy. nat rev cancer 2003; 3:117–29. 7. gaidarenko o, xu y. transcription activity is required for p53dependent tumor suppression. oncogene 2009; 28:4397–401. 8. levine aj, vosburgh e. p53 mutations in lymphomas: position matters. blood 2008; 112:2997–8. 9. bittenbring j, parisot f, wabo a, mueller m, kerschenmeyer l, kreuz m, et al. mdm2 gene snp309 t/g and p53 gene snp72 g/c do not influence diffuse large b-cell non-hodgkin lymphoma onset or survival in central european caucasians. bmc cancer 2008; 8:116. 10. zenz t, eichhorst b, busch r, denzel t, häbe s, winkler d, et al. tp53 mutation and survival in chronic lymphocytic leukemia. j clin oncol 2010; 28:4473–9. 11. ichikawa a, kinoshita t, watanabe t, kato h, nagai h, tsushita k, et al. mutations of the p53 gene as a prognostic factor in aggressive b-cell lymphoma. n engl j med 1997; 337:529–34. 12. kerbauy fr, colleoni gw, saad st, regis silva mr, correa alves a, aguiar kc, et al. detection and possible prognostic relevance of p53 gene mutations in diffuse large b-cell lymphoma. an analysis of 51 cases and review of the literature. leuk lymphoma 2004; 45:2071–8. 13. xu-monette zy, medeiros lj, li y, orlowski rz, andreeff m, bueso-ramos ce, et al. dysfunction of the tp53 tumor suppressor gene in lymphoid malignancies. blood 2012; 119:3668–83. 14. xu-monette zy, young kh. the tp53 tumor suppressor and autophagy in malignant lymphoma. autophagy 2012; 8:842–5. 15. weiner gj. rituximab: mechanism of action. semin hematol 2010; 47:115–23. 16. unruh tl, zuccolo j, beers sa, kanevets u, shi y, deans jp. therapeutic (high) doses of rituximab activate calcium mobilization and inhibit b-cell growth via an unusual mechanism triggered independently of both cd20 and fcgamma receptors. j immunother 2010; 33:30–9. 17. kheirallah s, caron p, gross e, quillet-mary a, bertrandmichel j, fournié jj, et al. rituximab inhibits b-cell receptor signaling. blood 2010; 115:985–94. 18. tamimi y, bringuier pp, smit f, van bokhoven a, debruyne fm, schalken ja. p16 mutations/deletions are not frequent events in prostate cancer. br j cancer 1996; 74:120–2. 19. stöcklein h, smardova j, macak j, katzenberger t, höller s, wessendorf s, et al. detailed mapping of chromosome 17p deletions reveals hic1 as a novel tumor suppressor gene candidate telomeric to tp53 in diffuse large b-cell lymphoma. oncogene 2008; 27:2613–25. 20. jardin f, ruminy p, kerckaert jp, parmentier f, picquenot jm, quief s, et al. detection of somatic quantitative genetic alterations by multiplex polymerase chain reaction for the prediction of outcome in diffuse large b-cell lymphomas. haematologica 2008; 93:543–50. 21. jardin f, jais jp, molina tj, parmentier f, picquenot jm, ruminy p, et al. diffuse large b-cell lymphomas with cdkn2a deletion have a distinct gene expression signature and a poor prognosis under r-chop treatment: a gela study. blood 2010; 116:1092–104. 22. grønbaek k, de nully brown p, møller mb, nedergaard t, ralfkiaer e, møller p, et al. concurrent disruption of p16ink4a and the arf-p53 pathway predicts poor prognosis in aggressive non-hodgkin’s lymphoma. leukemia 2000; 14:1727–35. 23. villuendas r, sánchez-beato m, martínez jc, saez ai, martinez-delgado b, garcía jf, et al. loss of p16/ink4a protein expression in non-hodgkin’s lymphomas is a frequent finding associated with tumor progression. am j pathol 1998; 153:887–97. 24. simonitsch-klupp i, hauser i, ott g, drach j, ackermann j, kaufmann j, et al. diffuse large b-cell lymphomas with plasmablastic/plasmacytoid features are associated with tp53 deletions and poor clinical outcome. leukemia 2004; 18:146– 55. 25. bosga-bouwer ag, van den berg a, haralambieva e, de jong d, boonstra r, kluin p, et al. molecular, cytogenetic, and immunophenotypic characterization of follicular lymphoma grade 3b; a separate entity or part of the spectrum of diffuse large b-cell lymphoma or follicular lymphoma? hum pathol 2006; 37:528–33. 26. davies aj, rosenwald a, wright g, lee a, last kw, weisenburger dd, et al. transformation of follicular lymphoma to diffuse large b-cell lymphoma proceeds by distinct oncogenic mechanisms. br j haematol 2007; 136:286–93. 27. kamata h, mitani s, fujiwara m, aoki n, okada s, mori s. mutation of the p53 tumour suppressor gene and overexpression of its protein in 62 japanese non-hodgkin’s lymphomas. clin exp med 2007; 7:39–46. 28. koduru pr, raju k, vadmal v, menezes g, shah s, susin m, et al. correlation between mutation in p53, p53 expression, cytogenetics, histologic type, and survival in patients with b-cell non-hodgkin’s lymphoma. blood 1997; 90:4078–91. 29. tokino t, nakamura y. the role of p53-target genes in human cancer. crit rev oncol hematol 2000; 33:1–6. 30. el-bolkainy tn, el-bolkainy mn, khaled hm, mokhtar nm, eissa ss, gouda hm, et al. evaluation of mib-1 and p53 overexpression as risk factors in large cell non-hodgkin lymphoma in adults. j egypt natl canc inst 2007; 19:231–8. 31. naresh kn, banavali sd, bhatia kg, magrath i, soman cs, advani sh. expression of p53 and bcl-2 proteins in t-cell lymphoblastic lymphoma: prognostic implications. leuk lymphoma 2002; 43:333–7. 32. hussein mr, al-sabae tm, georgis mn. analysis of the bcl-2 and p53 protein expression in the lymphoproliferative lesions in the upper egypt. cancer biol ther 2005; 4:324–8. 33. xu-monette zy, wu l, visco c, tai yc, tzankov a, liu wm, et al. mutational profile and prognostic significance of tp53 in diffuse large b-cell lymphoma patients treated with r-chop: report from an international dlbcl rituximab-chop consortium program study. blood 2012; 120:3986–96. 34. ameen r, sajnani kp, albassami a, refaat s. frequencies of non-hodgkin’s lymphoma subtypes in kuwait: comparisons between different ethnic groups. ann hematol 2010; 89:179– 84. sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 531-533, epub. 20th nov 12 submitted 24th jan 12 revision req. 17th apr 12, revision recd. 2nd jul 12 accepted 9th jul 12 department of pediatrics, lokmanya tilak municipal general hospital, mumbai, india *corresponding author e-mail: drzakisyed@gmail.com سل متعدد البؤر �صيد احمد زكي، �صوابنيل فوجنيد multifocal skeletal tuberculosis *syed ahmed zaki and swapnil bhongade interesting medical image a 6-year-old indian boy presented with a month-long insidious onset of pain in his back and left shoulder. he had had a low-grade fever, decreased appetite and weight loss for 2 months. there was no history of trauma, chronic cough, or bowel or bladder complaints. his father was on anti-tuberculous therapy for pulmonary tuberculosis (tb) (sputum positive). on examination, the boy had a gibbus deformity of the thoracic spine [figure 1]. tenderness was present over the upper thoracic spine and the left shoulder joint. paraspinal spasm and swelling was present. a systemic examination was normal. investigations revealed haemoglobin of 9.4 gm%; a total leucocyte count of 12,400/cumm (neutrophils 55%, lymphocyte 45%); a platelet count of 2.1 lac/cumm, and an erythrocyte sedimentation rate of 88 mm at 1 hour. a human immunodeficiency virus (hiv) enzyme linked immunosorbent assay (elisa) test was negative. a mantoux test was positive (28 mm). a chest x-ray and an ultrasound of the abdomen were normal. magnetic resonance imaging (mri) figure 1: clinical photograph of the patient showing gibbus deformity in the upper thoracic spine and paraspinal abscess. multifocal skeletal tuberculosis 532 | squ medical journal, november 2012, volume 12, issue 4 of the spine revealed multifocal skeletal tb involving the thoracic spine, the lateral end of the left clavicle, and the left acromion process. there was also evidence of prevertebral, paravertebral, and anterior epidural abscesses [figures 2–4]. surgical debridement was done and 150 ml of pus was drained. acid-fast bacilli were demonstrated in the pus by a ziehl-neelsen stain. our patient was diagnosed with multifocal tb and was started on an antituberculous therapy of isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampicin for four months. he was followed up monthly after discharge and at the end of six months showed marked improvement in symptomatology. his appetite and weight had increased, the fever had subsided, and his paraspinal abscess had decreased. in recent years, widespread immigration, hiv infection, illicit drug use, and the emergence of multi-drug resistant mycobacteria have resulted in a worldwide resurgence of tb.1 skeletal tb accounts for less than 10% of all cases of tb. multifocal tb is rare, occurring in less than 5% of cases even in endemic countries.2 multifocal skeletal tb is defined as osteoarticular lesions that occur simultaneously in two or more locations, with or without pulmonary involvement. it may affect a single bone with multifocal lytic cortical lesions or multiple sites at different bones.3 multifocal skeletal tb most often involves the axial skeleton (spine) followed by the major weight bearing joints. it is commonly seen in immunosuppressed patients, and usually associated with pulmonary tb.2,4 our patient was immunocompetent and had normal pulmonary findings. other atypical features were figure 3: coronal t2 weighted image shows bilateral paravertebral abscess. figure 2: coronal t2 weighted image shows complete destruction, with a collapse of the t3 and t4 vertebrae. marrow oedema is noted from t1 to t5 vertebral levels and also in the left lateral end of clavicle and acromion process. figure 4: sagittal t2 weighted image showing complete destruction with collapse of t3 and t4 vertebrae with decreased t3 and t4 disc height and the resultant severe gibbus deformity. there is an associated prevertebral and anterior epidural abscess, causing complete obliteration of the anterior and posterior subarachnoid space, and severe cord compression. *syed ahmed zaki and swapnil bhongade interesting medical image | 533 the involvement of the lateral end of the clavicle and the acromion process of scapula. tb of the lateral end of the clavicle and shoulder is extremely rare, occurring in less than 1% of cases.5,6 to the best of our knowledge, only two cases of tb of the acromion process and less than ten cases of tb of the lateral end of the clavicle have been reported to date.5,6 multifocal skeletal tb must be considered in the differential diagnosis of multiple destructive skeletal lesions. conventional x-rays often fail to detect early skeletal disease, resulting in a delayed diagnosis. in addition, the radiological picture is variable and the lytic bony lesions may easily be confused with osseous, or inflammatory or neoplastic diseases, either primary or metastatic.2,4 computed tomography (ct) and mri scans can usefully determine the extent of bone lesion and soft tissue involvement and differentiate between abscess and the granulation of tissue. a radionuclide bone scan is non-specific, may be negative in the early stages of the disease, and does not differentiate between lytic tuberculous lesions or malignancy. the diagnosis is confirmed by biopsy. uncomplicated tuberculous lesions of the clavicle and scapula usually resolve with anti-tubercular therapy. similarly, spinal tb is managed with bracing and anti-tb drugs. surgery is needed only if there is a neurologic deficit or spinal instability.2,4 references 1. zaki s, dadge d, shanbag p. calvarial tuberculosis. int j infect dis 2010; 14:e86–7. 2. marudanayagam a, gnanadoss jj. multifocal skeletal tuberculosis: a report of three cases. iowa orthop j 2006; 26:151–3. 3. al-tawfiq ja. multifocal systemic tuberculosis: the many faces of an old nemesis. med sci monit 2007; 13:56–60. 4. ekingen g, guvenc bh, kahraman h. multifocal tuberculosis of the chest wall without pulmonary involvement. acta chir belg 2006; 106:124–6. 5. basanagoudar pl, gupta pn, bahadur r, dhillon ms. tuberculosis of the clavicle presenting as an expansile lytic lesion: a case report. acta orthop belg 2001; 67:505–9. 6. tripathy sk, sen rk, sharma a, tamuk t. isolated cystic tuberculosis of scapula; case report and review of literature. j orthop surg res 2010; 5:7. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e357–363, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.009. submitted 23 dec 14 revision req. 29 jan 15; revision recd. 25 feb 15 accepted 30 mar 15 medical education & informatics unit, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: itmeded@gmail.com إدمان التواصل االجتماعي اإللكرتوين بني طالب العلوم الصحية يف سلطنة عمان ِكن ما�سرتز abstract: objectives: addiction to social networking sites (snss) is an international issue with numerous methods of measurement. the impact of such addictions among health science students is of particular concern. this study aimed to measure sns addiction rates among health sciences students at sultan qaboos university (squ) in muscat, oman. methods: in april 2014, an anonymous english-language six-item electronic self-reporting survey based on the bergen facebook addiction scale was administered to a non-random cohort of 141 medical and laboratory science students at squ. the survey was used to measure usage of three snss: facebook (facebook inc., menlo park, california, usa), youtube (youtube, san bruno, california, usa) and twitter (twitter inc., san francisco, california, usa). two sets of criteria were used to calculate addiction rates (a score of 3 on at least four survey items or a score of 3 on all six items). work-related sns usage was also measured. results: a total of 81 students completed the survey (response rate: 57.4%). of the three snss, youtube was most commonly used (100%), followed by facebook (91.4%) and twitter (70.4%). usage and addiction rates varied significantly across the three snss. addiction rates to facebook, youtube and twitter, respectively, varied according to the criteria used (14.2%, 47.2% and 33.3% versus 6.3%, 13.8% and 12.8%). however, addiction rates decreased when workrelated activity was taken into account. conclusion: rates of sns addiction among this cohort indicate a need for intervention. additionally, the results suggest that addiction to individual snss should be measured and that workrelated activities should be taken into account during measurement. keywords: addictive behaviors; internet; social networking; social media; students; oman. بني الإدمان هذا اأثر وي�سكل عديدة. بطرق قيا�سها ميكن والتي دولية ظاهرة الجتماعي التوا�سل مواقع إدمان يعد الهدف: امللخ�ص: بجامعة الجتماعي التوا�سل ملواقع ال�سحية العلوم طالب إدمان لقيا�س الدرا�سة هذه تهدف خا�سا. اهتماما ال�سحية العلوم طالب هي ذاتيا تعباأ عنا�رس �ست من مكون الإجنليزية باللغة إلكرتوين ا�ستبيان طبق الطريقة: عمان. �سلطنة م�سقط، يف قابو�س ال�سلطان bergen facebook addiction scale يف �سهر إبريل 2014، ب�سكل غري ع�سوائيل 141 طالبا يف تخ�س�سي الطب وعلوم املختربات يف جامعة ال�سلطان قابو�س. ا�ستخدم ال�ستبيان لقيا�س ا�ستعمال ثالث أنواع من مواقع التوا�سل الجتماعي )الفي�سبوك(، )اليوتيوب(، )التويرت(. ا�ستخدمت جمموعتان من املعايري للتحقق من ن�سبة الإدمان )عالمة 3 على اأربع من العنا�رس أو عالمة 3 على العنا�رس ال�ست(. مت قيا�س مدى ا�ستخدام مواقع التوا�سل الجتماعية ذات ال�سلة بالعمل. النتائج: تبني اأن 81 من الطالب اأكملوا ال�ستبيان )معدل ال�ستجابة 57.4%(. .)70.4%( )التويرت( واأخريا )91.4%( )الفي�سبوك( ويليه )100%( ا�ستخداما الثالثة الجتماعي التوا�سل مواقع اأكرث من اليوتيوب كان وتباينت معدلت ال�ستخدام والإدمان كثريا عرب املواقع الثالثة. معدلت الإدمان للفي�سبوك، اليوتيوب، والتويرت ح�سب املعايري امل�ستخدمة )%12.8 و %13.8، %6.3 إزاء %33.3 و %47.2، %14.2( على التوايل. وانخف�ست معدلت الإدمان عند فح�س الأن�سطة ذات ال�سلة بالعمل. اخلال�صة: دل معدل الإدمان على مواقع التوا�سل الجتماعي بني هذه الدفعة على وجوب التدخل. بالإ�سافة اإىل ذلك ت�سري النتائج على إن اإلدمان على مواقع التوا�سل الفردية يجب أن تقا�س وأن الن�سطة ذات ال�سلة بالعمل يجب أن توؤخذ بعني العتبار أثناء القيا�س. مفتاح الكلمات: �سلوكيات الإدمان؛ �سبكة؛ ال�سبكات الجتماعية؛ و�سائل التوا�سل الجتماعية؛ طالب؛ عمان. social networking addiction among health sciences students in oman ken masters advances in knowledge the results of this study confirm the existence and indicate the extent of social networking site (sns) addiction among a sample of health sciences students in oman. these findings support the argument that sns addiction should be examined for individual snss rather than in general only. work-related sns activity must be taken into account when measuring sns addiction as excluding the use of social media for work purposes was found to decrease addiction rates. application to patient care given the associations between sns addiction and certain personality traits, extended use of snss among health professionals may be indirectly harmful to patients. uncovering the extent of sns addiction among health sciences students may help to target future addiction recovery or prevention programmes, if needed. clinical & basic research social networking addiction among health sciences students in oman e358 | squ medical journal, august 2015, volume 15, issue 3 of the more than 2.5 billion active internet users worldwide, some 1.8 billion were estimated to use social networking sites (snss) in 2014, representing approximately 25% of the world’s total population.1,2 the most widely used snss are facebook (facebook, inc., menlo park, california, usa), youtube (youtube, san bruno, california, usa) and twitter (twitter, inc., san francisco, california, usa), with 1.3 billion, 1 billion and 645 million actively registered users, respectively.3–5 furthermore, the number of additional people using these snss without registering as users is unknown. within the last few years, internet usage in oman has grown dramatically; in 2014, there were more than 2 million subscribers, a trend which had been predicted in previous research according to international patterns.6,7 following global sns trends, oman currently has more than 600,000 facebook users.6 while specific national figures for other snss are not available, there is no reason to suspect that usage of these other sites in oman is not also in line with international trends. however, usage of the internet and snss per se is not alarming—the main concern lies with addiction to these forms of technology. in 1995, the psychiatrist ivan goldberg satirically introduced the term ‘internet addiction disorder’ (iad).8 by 1996, the concept of internet addiction was being taken more seriously; it was proposed to be a clinical disorder and a useful diagnostic questionnaire (based on a gambling addiction questionnaire) was developed.9 although iad is still not recognised as a clinical disorder, as opposed to internet gaming disorder, there is strong support for the concept. studies have indicated that as many as 3–4% of young people—in some cases, much more—exhibit symptoms of internet addiction, with one of the most recent cases involving a 31-year-old patient who suffered from iad with the use of google glass™ wearable technology (google, googleplex, mountain view, california, usa).10–13 the characteristics of internet addiction are similar to those of any other addiction. çam et al. summarised the condition as involving excessive mental preoccupation with the internet, coupled with repetitive thoughts of limiting or controlling this use and a subsequent failure to prevent access.14 individuals with this condition continue to use the internet despite a significant impact upon their dayto-day functionality at various levels, spending ever increasing amounts of time online and craving access when it is not available.14 in addition to generalised internet addiction, there has been focus on specific types of addiction (e.g. fixation with online games or mobile phones).8,15–17 similarly, concerns have been raised regarding the increased use of snss since the late 1990s, with an increasing number of reports of sns addiction.18 given that internet and sns usage patterns in oman conform to global trends,6 there is reason to suspect that sns addiction patterns in this country may be similar to those reported worldwide. measuring sns addiction levels is an area of some debate. some researchers believe that only levels of generalised sns addiction should be assessed.19,20 however, others have taken a more focused view; çam et al. chose to adapt and use an internet addiction scale developed by the center for internet addiction to measure facebook addiction, while the facebook addiction symptoms scale has also been implemented among a group of undergraduate students.14,21 more recently, andreassen et al. developed a shorter sixitem facebook addiction questionnaire known as the bergen facebook addiction scale (bfas), the validity and reliability of which was subsequently established.22,23 the bfas has been successfully used to measure facebook addiction rates in numerous studies and has been acknowledged as psychometrically effective.18,20,24–26 although initially designed to assess addiction to only one sns, andreassen et al. have noted that adjusting the scale to assess another sns is feasible.23 addiction can be disruptive to many aspects of life; for students, it may hinder their studies and impact their long-term career goals. excessive use of and addiction to internet activities—including snss and online games—has been negatively associated with conscientiousness, honesty/humility and agreeableness and positively associated with neuroticism, narcissism and aggression.22,27–35 for medical students aiming to develop into caring health professionals, the implications of this addiction can have wide and detrimental consequences for society as a whole. it is important, therefore, to know the scale of the problem so that appropriate measures can be taken to combat it. given the concerns outlined above, this study aimed to measure rates of sns addiction among a group of health sciences students at sultan qaboos university (squ) in muscat, oman. furthermore, this study aimed to distinguish between three main snss (facebook, youtube and twitter) rather than measuring general sns addiction only, as interventions to rectify addiction-related problems may differ depending on the specific sns. methods this study involved a non-random cohort of 141 medical and laboratory science students enrolled at the college of medicine & health sciences at squ in ken masters clinical and basic research | e359 april 2014 and taking part in the medical informatics ii course. this group of students was chosen because they had not yet studied snss in detail but still had some introductory knowledge as a result of their completion of the medical informatics i course. an anonymous english-language six-item electronic self-reporting survey was designed, based on the bfas and modified for other snss as suggested by andreassen et al.22,23 the three snss chosen for the questionnaire were facebook, twitter and youtube, as these were the most heavily used snss worldwide at the time.3–5 students were asked to report their sns usage data for the past year. although it can be argued that snss are used primarily for non-workrelated activities, research has indicated that social media sites are used in medical and other education programmes.36,37 as a result, the survey was modified in order to determine the percentage of time students reported spending on snss in the work context. although english was not the native language of all of the students in the cohort, the language of instruction of the medical informatics ii course was english; students taking the course were therefore considered to be sufficiently familiar with the language to understand the questionnaire. furthermore, a flesch reading ease and flesch-kincaid grade level test indicated that the survey could be understood by school-level students.38 students were informed of the online survey in april 2014 while in class, with two further e-mail reminders sent requesting their participation. the survey remained open for four weeks to give students enough time to complete it. after collating the survey data, rates of addiction were calculated according to two sets of criteria. the first, proposed by lemmens et al., considers a score of 3 on at least four of the bfas survey items to constitute addiction.16 however, criteria proposed by andreassen et al. requires a score of 3 on all six of the bfas items before an individual can be classified as addicted.22 when these initial addiction rates had been calculated, rates of addiction were then recalculated with regards to work-related sns usage. participants spending >50% of their sns usage time for work-related activities were excluded from the addicted group. data were entered into a microsoft excel spreadsheet (version 2010, microsoft corp., redmond, washington, usa) and descriptive statistical analyses and chisquared calculations were performed. qualitative data were themed using nvivo, version 7 (qsr international ltd., burlington, massachusetts, usa). ethical approval for this study was granted by the medical research & ethics committee at the college of medicine & health sciences at squ (mrec#869). all of the respondents gave written consent before taking part in the study. results of the 141 students included in the study, a total of 81 completed the survey (response rate: 57.4%). of these, 51 were female (63.0%); this gender ratio had no statistical significance to the rest of the class (p = 0.41). use of the three sns sites by the participants over the previous year is summarised in table 1. youtube was most commonly used (100%), followed by facebook (91.4%) and twitter (70.4%). there was no statistically significant difference between female and male sns usage (p = 0.997). the frequency of work-related sns use among the sample is summarised in table 2. while less than 15% of twitter activity was work-related, this was not the case for facebook and youtube (less than 39.4% and 41.9%, respectively). youtube was more frequently used by students for work purposes than the other social media sites (mean: 41.9%). usage patterns are shown in table 3. dependency on youtube was table 1: self-reported use of selected social networking sites during the previous year among a cohort of health sciences students in oman (n = 81) n (%) facebook* youtube† twitter‡ females 47 (92.2) 51 (100.0) 36 (70.6) males 27 (90.0) 30 (100.0) 21 (70.0) total 74 (91.4) 81 (100.0) 57 (70.4) *facebook inc., menlo park, california, usa. †youtube, san bruno, california, usa. ‡twitter inc., san francisco, california, usa. table 2: self-reported work-related use of selected social networking sites during the previous year among a cohort of health sciences students in oman (n = 81) frequency of work-related activity, % n (%) facebook* (n = 63) youtube† (n = 72) twitter‡ (n = 39) 0–20 29 (46.0) 17 (23.6) 28 (71.8) 21–40 8 (12.7) 19 (26.4) 6 (15.4) 41–60 6 (9.5) 20 (27.8) 3 (7.7) 61–80 11 (17.5) 14 (19.4) 0 (0.0) 81–100 9 (14.3) 2 (2.8) 2 (5.1) mean 39.4 41.9 14.3 *facebook inc., menlo park, california, usa. †youtube, san bruno, california, usa. ‡twitter inc., san francisco, california, usa. social networking addiction among health sciences students in oman e360 | squ medical journal, august 2015, volume 15, issue 3 table 3: self-reported usage patterns* of selected social networking sites during the previous year among a cohort of health sciences students in oman (n = 81) activity n (%) facebook† (n = 74) x youtube‡ (n = 80) x twitter§ (n = 57) x 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 spent a lot of time thinking about sns or planned to use sns 34 (45.9) 20 (27.0) 15 (23.0) 4 (5.4) 1 (1.4) 1.9 20 (25.0) 21 (26.3) 27 (33.8) 10 (12.5) 2 (2.5) 2.4 20 (35.1) 17 (29.8) 10 (17.5) 10 (17.5) 0 (0.0) 2.2 felt an urge to use sns more and more 21 (28.4) 23 (31.1) 22 (29.7) 8 (10.8) 0 (0.0) 2.2 11 (13.8) 14 (17.5) 34 (42.5) 15 (18.8) 6 (7.5) 2.9 20 (35.1) 13 (22.8) 14 (24.6) 7 (12.3) 3 (5.3) 2.3 used sns in order to forget about personal problems 40 (54.1) 14 (18.9) 14 (18.0) 4 (5.4) 2 (2.7) 1.8 13 (16.3) 14 (17.5) 35 (43.8) 13 (16.3) 5 (6.3) 2.8 22 (38.6) 14 (24.6) 15 (26.3) 4 (7.0) 2 (3.5) 2.1 tried to cut down on the use of sns without success 28 (37.8) 23 (31.1) 16 (21.6) 4 (5.4) 3 (4.1) 2.1 29 (36.3) 21 (26.3) 18 (22.5) 8 (10.0) 4 (5.0) 2.2 24 (42.1) 19 (33.3) 10 (17.5) 4 (7.0) 0 1.9 become restless or troubled if prohibited from using sns 36 (48.6) 16 (21.6) 17 (23.0) 3 (4.1) 2 (2.7) 1.9 20 (25.0) 24 (30.0) 22 (27.5) 9 (11.3) 5 (6.3) 2.4 28 (49.1) 15 (26.3) 11 (19.3) 2 (3.5) 1 (1.8) 1.8 used sns so much that it had a negative impact on academic work 37 (50.0) 23 (31.1) 5 (6.8) 6 (8.1) 3 (4.1) 1.9 26 (32.5) 23 (28.8) 22 (27.5) 7 (8.8) 2 (2.5) 2.2 24 (42.1) 18 (31.6) 11 (19.3) 4 (7.0) 0 (0.0) 1.9 mean 32.7 (44.1) 19.8 (26.8) 14.8 (20.0) 4.8 (6.5) 1.8 (2.5) 19.8 (24.8) 19.5 (24.4) 26.3 (32.9) 10.3 (12.9) 4.0 (5.0) 23.0 (40.4) 16.0 (28.1) 11.8 (20.8) 5.2 (9.1) 1.0 (1.8) sns = social networking site. *on a five-point likert scale where 1 = very rarely and 5 = very often. †facebook inc., menlo park, california, usa. ‡youtube, san bruno, california, usa. §twitter inc., san francisco, california, usa. table 4: addiction rates according to self-reported use of selected social networking sites during the previous year among a cohort of health sciences students in oman (n = 81) addiction criteria n (%) total singular combined fb† (n = 63)* yt‡ (n = 72)* tw§ (n = 39)* fb only (n = 63)* yt only (n = 72)* tw only (n = 39)* fb + yt (n = 60)* fb + tw (n = 34)* yt + tw (n = 38)* fb + yt + tw (n = 33)* lemmens et al.18 9 (14.2) 34 (47.2) 13 (33.3) 2 (3.2) 25 (34.7) 6 (15.4) 3 (5.0) 1 (2.9) 3 (7.9) 3 (9.1) andreassen et al.22 4 (6.3) 10 (13.8) 5 (12.8) 2 (3.2) 6 (8.3) 3 (7.7) 2 (3.3) 0 (0.0) 2 (5.3) 0 (0.0) fb = facebook; yt = youtube; tw = twitter. *number of students who indicated in the questionnaire the percentage of their time spent on the social networking site that was work-related. †facebook inc., menlo park, california, usa. ‡youtube, san bruno, california, usa. §twitter inc., san francisco, california, usa. ken masters clinical and basic research | e361 greater than for the other two sites. this was apparent from the means for each of the categories, which were higher for youtube than the other social media sites in every instance. there were too few qualitative comments from the students for reasonable themes and patterns to be extracted. addiction rates were calculated based on criteria by lemmens et al. and andreassen et al. [table 4].16,22 with regards to lemmens et al.’s criteria, it was found that 14.2%, 47.2% and 33.3% of the students were addicted to facebook, youtube and twitter, respectively.16 in comparison, only 6.3%, 13.8% and 12.8% of the students, respectively, were addicted to these same snss when andreassen et al.’s criteria were used to indicate addiction.22 these rates decreased when students who reported spending more than 50% of their time using snss for work-related purposes were excluded [table 5]. only 4.7%, 27.8% and 20.5% of students were still considered to be addicted to facebook, youtube and twitter, respectively, according to the criteria proposed by lemmens et al.16 with andreassen et al.’s criteria, rates of addiction dropped to 3.2%, 6.9% and 7.7% for facebook, youtube and twitter, respectively.22 this showed an important drop in addiction rates when work-related sns activities were taken into account, with a 41.2% reduction (34 versus 20 students) in those classified as addicted to youtube according to lemmens et al.’s criteria and a 80% reduction (10 versus two students) according to andreassen et al.’s criteria.16,22 discussion this study attempted to measure addiction rates to three snss (facebook, youtube and twitter) among a group of health sciences students in oman. in addition, the study acknowledged that students might use these sites for work-related purposes and took this into account when calculating addiction rates. one issue raised in the literature is whether addiction rates should be measured to snss in general, or whether a more focused breakdown of addiction to specific snss is warranted.19,22,23 results from the current study indicated a wide range of usage across the three selected snss, with all students using youtube, but not facebook or twitter. immediately, this result serves to warn against grouping all snss together; if this were the case, it would appear that the entire cohort used an sns, which would be misleading given the wide range of usage and purposes served by these snss. in addition, figures regarding addiction and work-related activities varied across the snss, supporting the contention that snss should be examined individually. as snss inevitably evolve and the popularity of a particular site waxes and wanes over time, individual examination of snss will become even more important. previous research has demonstrated the importance of the internet in general to the work-related activities of health professionals.39,40 similarly, profess ional usage of mobile applications and snss by students and qualified health professionals is wellestablished.36,41–44 it is for this reason that usage rates must be seen in light of students’ use of snss for work-related activities. in terms of the current study, generalisations about work-related sns usage were difficult—not only was twitter used less than the other two snss, it was also used far less for work-related activities than the other sites. the same difficulty applies in determining general and non-workrelated addiction rates. nonetheless, rates of general addiction observed in this study were similar to those determined in other studies.17,24,25 importantly, however, addiction rates were much lower when the results were adjusted to exclude work-related social media activity. unfortunately, only one of the comparative studies mentioned above considered work-related activities when calculating addiction rates, so further comparisons were not possible.25 interpretations of sns usage and addiction may be a pessimistic indictment of the way in which students are viewed by the rest of society. abnormal dependence on social media for personal activities is generally considered an addiction, while the same dependence on social media for work-related activities may instead be considered to denote an admirable work ethic. as such, future studies on this topic might consider the pressures placed on students. these pressures are of such magnitude that their time and dedication spent on these activities could be considered an addiction, were it not for the fact that their academic performance is so highly valued. from the results of the current table 5: addiction rates according to self-reported use of selected social networking sites during the previous year among a cohort of health sciences students in oman who spent <50% of usage time on work-related activities addiction criteria n (%) facebook* (n = 63) youtube† (n = 72) twitter‡ (n = 39) lemmens et al.18 3§ (4.7) 20¶ (27.8) 8¶ (20.5) andreassen et al.22 2 (3.2) 5§ (6.9) 3\\ (7.7) *facebook inc., menlo park, california, usa. †you tube, san bruno, california, usa. ‡twitter inc., san francisco, california, usa. §in addition to this, three students did not indicate the amount of time spent on work-related activities. ¶in addition to this, four students did not indicate the amount of time spent on work-related activities. \\in addition to this, two students did not indicate the amount of time spent on work-related activities. social networking addiction among health sciences students in oman e362 | squ medical journal, august 2015, volume 15, issue 3 study, it could easily be argued that several of the students were addicted, not to snss, but to their studies; snss were merely one of the means to feed their addiction to high academic performance. nevertheless, as far as sns addiction can be discussed, data from the present study indicate that this sample of health sciences students in oman appeared inappropriately dependent on snss. this is especially disquieting considering that the majority of these students will graduate and become health professionals in the near future. given the association between internet or sns addiction and certain personality traits, it is possible that there will be an impact on patient care.22,27–35 indeed, studies have shown that these same personality traits impact directly on work performance;45,46 in health-related fields, this will have affect the quality of patient care. therefore, it would be beneficial for future research to focus on the possibility of a direct link between these addictions and negative repercussions on patient care. additionally, these studies should also consider measures to reduce the potential consequences that this may have on the delivery of healthcare in oman. apart from the standard limitations of a selfreported survey, it is important to note that this study was conducted with a single class of students at a single institution. as a result, generalisations are difficult, although the comparisons made with other studies conducted under similar circumstances remain valid. this study chose to investigate only three of the hundreds of existing snss. in addition, there is currently debate regarding whether youtube should be considered an sns, as some sites—including reddit (reddit inc., san francisco, california, usa), snapchat (snapchat, venice, california, usa), wikipedia (wikipedia, san francisco, california, usa) and whatsapp (whatsapp inc., mountain view, california, usa)—may not easily fit a narrow definition of an sns and yet are still frequently included in this category.47 future studies should take this into account. finally, although administrative data indicated high homogeneity among the cohort with respect to age (all students were between the ages of 20–25 years old), it would have been useful to confirm this information for further analysis. this should be corrected in future studies. conclusion overall addiction rates among this group of health sciences students in oman were found to be similar to rates reported in other studies. the implications of this finding need to be addressed in terms of future healthcare delivery in oman. the variety of usage rates observed strongly indicates that snss should not be combined into one group, but rather be examined individually. furthermore, addiction rates decreased notably when work-related activity was taken into account which demonstrates that rates need to be adjusted according to purpose. these two key points should be considered when conducting similar studies. a c k n o w l e d g e m e n t s the author would like to thank the following individuals for their assistance in preparing this manuscript: professor andreassen of bergen university, norway, for permission to use and adapt the bfas for this research and for literature suggestions; ms. buthaina m. baqir for the arabic translation; all of the students who participated in the survey; and, finally, the anonymous reviewers of a previous version of this paper for their comments. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. references 1. internet world stats. internet users of the world: distribution by world regions 2014 q4. from: www.internetworldstats. com/stats.htm accessed: feb 2015. 2. emarketer. social networking reaches nearly one in four around the world. from: www.emarketer.com/article/ so cial-networking-reaches-nearly-one-four-aroundworld/1009976 accessed: feb 2015. 3. statistics brain research institute. facebook statistics. from: www.statisticbrain.com/facebook-statistics/ accessed: feb 2015. 4. youtube. statistics. from: www.youtube.com/yt/press/ statistics.html accessed: feb 2015. 5. statistics brain research institute. twitter statistics. from: www.statisticbrain.com/twitter-statistics/ accessed: feb 2015. 6. internet world stats. internet users in the middle east and the world: 2014 q4. from: www.internetworldstats.com/stats5. htm accessed: feb 2015. 7. masters k, ng’ambi d, todd g. “i found it on the internet”: preparing for the e-patient in oman. sultan qaboos univ med j 2010; 10:169–79. 8. boyd d. it’s complicated: the social lives of networked teens. new haven, connecticut, usa: yale university press, 2014. 9. young ks. internet addiction: the emergence of a new clinical disorder. cyberpsychol behav 1998; 1:237–44. doi: 10.1089/ cpb.1998.1.237. 10. beard kw. internet addiction: a review of current assessment techniques and potential assessment questions. cyberpsychol behav 2005; 8:7–14. doi: 10.1089/cpb.2005.8.7. 11. kuss dj, griffiths md, binder jf. internet addiction in students: prevalence and risk factors. comput human behav 2013; 29:959–66. doi: 10.1016/j.chb.2012.12.024. 12. pezoa-jares re, espinoza-luna il, vasquez-medina ja. internet addiction: a review. j addict res ther 2012; s6:004. doi: 10.4172/2155-6105.s6-004. http://dx.doi.org/10.1089/cpb.1998.1.237 http://dx.doi.org/10.1089/cpb.1998.1.237 http://dx.doi.org/10.1089/cpb.2005.8.7 http://dx.doi.org/10.1016/j.chb.2012.12.024 http://dx.doi.org/10.4172/2155-6105.s6-004 ken masters clinical and basic research | e363 13. yung k, eickhoff e, davis dl, klam wp, doan ap. internet addiction disorder and problematic use of google glass™ in patient treated at a residential substance abuse treatment program. addict behav 2015; 41:58–60. doi: 10.1016/j. addbeh.2014.09.024. 14. çam e, i̇şbulan o. a new addiction for teacher candidates: social networks. turk online j educ tech 2012; 11:14–9. 15. petry nm, rehbein f, gentile da, lemmens js, rumpf hj, mößle t, et al. an international consensus for assessing internet gaming disorder using the new dsm-5 approach. addiction 2014; 109:1399–406. doi: 10.1111/add.12457. 16. lemmens js, valkenburg pm, peter j. development and validation of a game addiction scale for adolescents. media psych 2009; 12:77–95. doi: 10.1080/15213260802669458. 17. lee eb. too much information: heavy smartphone and facebook utilization by african american young adults. j black stud 2015; 46:44–61. doi: 10.1177/0021934714557034. 18. kuss dj, griffiths md. online social networking and addiction: a review of the psychological literature. int j environ res public health 2011; 8:3528–52. doi: 10.3390/ijerph8093528. 19. griffiths md. facebook addiction: concerns, criticism and recommendations a response to andreassen and colleagues. psychol rep 2012; 110:518–20. doi: 10.2466/01.07.18. pr0.110.2.518-520. 20. griffiths md, kuss dj, demetrovics z. social networking addiction: an overview of preliminary findings. in: rosenberg km, feder lc, eds. behavioral addictions: criteria, evidence and treatment. 1st ed. new york, usa: academic press, 2014. pp. 119–41. 21. alabi of. a survey of facebook addiction level among selected nigerian university undergraduates. new media mass commun 2013; 10:70–80. 22. andreassen cs, torsheim t, brunborg gs, palleson s. development of a facebook addiction scale. psychol rep 2012; 110:501–17. doi: 10.2466/02.09.18.pr0.110.2.501-517. 23. andreassen cs, palleson s. facebook addiction: a reply to griffiths (2012). psychol rep 2013; 113:899–902. doi: 10.24 66/02.09.pr0.113x32z6. 24. akter t. social media addiction, resistance, and influence of awareness: measurement of psychology students’ resistance to facebook addiction. mediterr j soc sci 2014; 5:456–64. doi: 10.5901/mjss.2014.v5n8p456. 25. ozer i. facebook® addiction, intensive social networking site use, multitasking, and academic performance among university students in the united states, europe, and turkey: a multigroup structural equation modeling approach. dissertation submitted to the kent state university college of education, health, & human services. from: etd.ohiolink.edu/!etd.send_ file?accession=kent1403276756&disposition=inline accessed: feb 2015. 26. volpi b, tambelli r, baiocco r, marconi p. epa-1276: internet use and abuse attachment and new forms of psychopathology. eur psychiatry 2014; 29:1. doi: 10.1016/s0924-9338(14)78507-4. 27. gnisci a, perugini m, pedone r, di conza a. construct validation of the use, abuse and dependence on the internet inventory. comput human behav 2011; 27:240–7. doi: 10.10 16/j.chb.2010.08.002. 28. wilson k, fornasier s, white km. psychological predictors of young adults’ use of social networking sites. cyberpsychol behav soc netw 2010; 13:173–7. doi: 10.1089/cyber.2009.0094. 29. collins e, freeman j, chamarro-premuzic t. personality traits associated with problematic and non-problematic massively multiplayer online role playing game use. pers individ diff 2012; 52:133–8. doi: 10.1016/j.paid.2011.09.015. 30. cao f, su l. internet addiction among chinese adolescents: prevalence and psychological features. child care health dev 2007; 33:275–81. doi: 10.1111/j.1365-2214.2006.00715.x. 31. cole sh, hooley jm. clinical and personality correlates of mmo gaming: anxiety and absorption in problematic internet use. soc sci comput rev 2013; 31:424–36. doi: 10.11 77/0894439312475280. 32. huh s, bowman n. perception of and addiction to online games as a function of personality traits. j media psychol 2008; 13:1–31. 33. mehroof m, griffiths md. online gaming addiction: the role of sensation seeking, self-control, neuroticism, aggression, state anxiety, and trait anxiety. cyberpsychol behav soc netw 2010; 13:313–16. doi: 10.1089/cyber.2009.0229. 34. nerguz bs. an examination of predictor variables for problematic internet use. turk online j educ technol 2011; 10:54–62. 35. mehdizadeh s. self-presentation 2.0: narcissism and selfesteem on facebook. cyberpsychol behav soc netw 2010; 13:357–64. doi: 10.1089/cyber.2009.0257. 36. cheston cc, flickinger te, chisolm ms. social media use in medical education: a systematic review. acad med 2013; 88:893–901. doi: 10.1097/acm.0b013e31828ffc23. 37. seaman j, tinti-kane h. social media for teaching and learning. from: www.meducationalliance.org/sites/default/files/social_ media_for_teaching_and_learning.pdf accessed: feb 2015. 38. flesch r. a new readability yardstick. j appl psychol 1948; 32:221–33. 39. masters k. for what purpose and reasons do doctors use the internet: a systematic review. int j med inform 2008; 77:4–16. doi: 10.1016/j.ijmedinf.2006.10.002. 40. masters k. access to and use of the internet by south african general practitioners. int j med inform 2008; 77:778–86. doi: 10.1016/j.ijmedinf.2008.05.008. 41. masters k. health professionals as mobile content creators: teaching medical students to develop mhealth applications. med teach 2014; 36:883–9. doi: 10.3109/0142159x.2014.916783. 42. campbell bc, craig cm. health professions students academic and personal motivations for using social media. from: www. communicationandhealth.ro/upload/number3/britannycampbell-clay-craig.pdf accessed: feb 2015. 43. hollinderbäumer a, hartz t, uckert f. education 2.0: how has social media and web 2.0 been integrated into medical education? a systematical literature review. gms z med ausbild 2012; 30:14. doi: 10.3205/zma000857. 44. masters k, al-rawahi z. the use of mobile learning by 6th-year medical students in a minimally-supported environment. int j med educ 2012; 3:92–7. doi: 10.5116/ijme.4fa6.f8e8. 45. barrick mr, mount mk, judge ta. personality and performance at the beginning of the new millennium: what do we know and where do we go next? int j select assess 2001; 9:9–30. doi: 10.1111/1468-2389.00160. 46. hurtz gm, donovan jj. personality and job performance: the big five revisited. j appl psychol 2000; 85:869–79. doi: 10.1037/0021-9010.85.6.869. 47. bbc news. mainstream media ‘still dominate online news’. from: www.bbc.co.uk/news/technology-27772070 accessed: feb 2015. http://dx.doi.org/10.1016/j.addbeh.2014.09.024 http://dx.doi.org/10.1016/j.addbeh.2014.09.024 http://dx.doi.org/10.1111/add.12457 http://dx.doi.org/10.1080/15213260802669458 http://dx.doi.org/10.1177/0021934714557034 http://dx.doi.org/10.3390/ijerph8093528 http://dx.doi.org/10.2466/01.07.18.pr0.110.2.518-520 http://dx.doi.org/10.2466/01.07.18.pr0.110.2.518-520 http://dx.doi.org/10.2466/02.09.18.pr0.110.2.501-517 http://dx.doi.org/10.2466/02.09.pr0.113x32z6 http://dx.doi.org/10.2466/02.09.pr0.113x32z6 http://dx.doi.org/10.5901/mjss.2014.v5n8p456 http://dx.doi.org/10.1016/s0924-9338%2814%2978507-4 http://dx.doi.org/10.1016/j.chb.2010.08.002 http://dx.doi.org/10.1016/j.chb.2010.08.002 http://dx.doi.org/10.1089/cyber.2009.0094 http://dx.doi.org/10.1016/j.paid.2011.09.015 http://dx.doi.org/10.1111/j.1365-2214.2006.00715.x http://dx.doi.org/10.1177/0894439312475280 http://dx.doi.org/10.1177/0894439312475280 http://dx.doi.org/10.1089/cyber.2009.0229 http://dx.doi.org/10.1089/cyber.2009.0257 http://dx.doi.org/10.1097/acm.0b013e31828ffc23 http://dx.doi.org/10.1016/j.ijmedinf.2006.10.002 http://dx.doi.org/10.1016/j.ijmedinf.2008.05.008 http://dx.doi.org/10.3109/0142159x.2014.916783 http://dx.doi.org/10.3205/zma000857 http://dx.doi.org/10.5116/ijme.4fa6.f8e8 http://dx.doi.org/10.1111/1468-2389.00160 http://dx.doi.org/10.1037/0021-9010.85.6.869 sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e297–298, epub. submitted 10 sep 14 accepted 6 nov 14 departments of 1haematology and 2medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: arwa.alriyami@gmail.com عرض نادر ملريض عماين مصاب بلمفوما اخلاليا اللمفاويه الطبعيه القاتله اروى الرياميه، خليل الفار�سي، �ساهيمه املعمريه، احمد الفرقاين، مرت�سى اخلابوري rare presentation of aggressive t/natural killer lymphoproliferative disorder in a leukaemic phase in an omani patient *arwa z. al-riyami,1 khalil al-farsi,1 sahimah al-mamari,1 ahmed al-farqani,2 murtadha al-khabori1 natural killer (nk) cells are cytotoxic cells that target tumour, bacteriaand virus-infected cells.1 they produce cytokines such as interferon-γ and tumour necrosis factor-α. morphologically, nk cells appear as large granular lymphocytes with abundant pale cytoplasm with azurophilic granules. they are negative for surface cd3; positive for cd16, cd56 and cd57, and variably express some t cell antigens like cd2, cd7 and cd8.2 nk and t/nk lymphomas are very rare, and are mainly described in areas of east asia, where they account for 7–10% of all lymphomas.3 they are commonly associated with the presence of epstein-barr virus in the neoplastic cells. to the best of the authors’ knowledge, no cases from the gulf region have been reported in the medical literature. herein, is a description of a presentation of this rare disease in an omani patient. a 46-year-old omani female with schizophrenia presented to the department of haematology at the sultan qaboos university hospital in muscat, oman, in january 2013. she was referred for evaluation of bilateral adrenal masses, abdominal lymphadenopathy, hepatosplenomegaly, transaminitis and elevated lactate dehydrogenase levels at 540 u/l (normal range: 135–225 u/l). she had a two-week history of vomiting, abdominal pain and jaundice. a complete blood count revealed a total white cell count of 17.0 x 109/l (normal range: 2.4–9.5 x 109/l), lymphocytosis of 11.4 x 109/l (1.2–3.8 x 109/l), haemoglobin of 6.6 g/dl (11.0–14.5 g/dl) and a platelet count of 48 x 109/l (150–450 x 109/l). the patient’s blood film showed medium to large lymphoid cells with prominent nucleoli and deep basophilic cytoplasm with occasional vacuolation and cytoplasmic granulation [figure 1]. online interesting medical image figure 1: blood film showing large lymphoid cells with prominent nucleoli and deep basophilic cytoplasm. rare presentation of aggressive t/natural killer lymphoproliferative disorder in a leukaemic phase in an omani patient e298 | squ medical journal, may 2015, volume 15, issue 2 negative nk lymphomas are very rare, with only three cases described in the medical literature from east asia of extranodal nk/t cell lymphoma-nasal type, with nasal cavity involvement.3 the current case represents the first described case of cd45-negative t/nk lymphoproliferative disorder in the leukaemic phase. references 1. spits h, lanier ll, phillips jh. development of human t and natural killer cells. blood 1995; 85:2654–70. 2. kwong yl. natural killer-cell malignancies: diagnosis and treatment. leukemia 2005; 19:2186–94. doi: 10.1038/ sj.leu.2403955. 3. au wy, ma sy, chim cs, choy c, loong f, lie ak, et al. clinicopathologic features and treatment outcome of mature t-cell and natural killer-cell lymphomas diagnosed according to the world health organization classification scheme: a single center experience of 10 years. ann oncol 2005; 16:206–14. doi: 10.1093/annonc/mdi037. peripheral blood flow cytometry showed that t/ nk cells made up 25–30% of the patient’s blood count. the t/nk cells were uniformly positive for cd56, cd16, cd2, cd7, cd8 (dim) and α/β. however, they were negative for surface cd3, cd4, cd5 and γ/δ. interestingly, the cells were also cd45-negative. the diagnosis of t/nk lymphoproliferative disorder in a leukaemic phase was made and a bone marrow aspiration and biopsy procedure were planned. however, the patient deteriorated rapidly with increasing oxygen requirements. she eventually went into cardiac arrest and died. comment this case illustrates the leukaemic phase of a disseminated t/nk lymphoproliferative disorder. the presentation and the rapid deterioration of the patient were consistent with aggressive disease. cd45department of andrology, kasr el aini faculty of medicine, cairo university, cairo, egypt *corresponding author e-mail: dr.osama@alrijal.com الرأب الظهري للقضيب للحفاظ على طول القضيب عند زرع البدلة اأ�ضامه �ضعري, كمال �ضعري, اإ�ضالم عبد الرحمن abstract: objectives: following penile prosthesis implantation (ppi), patients may complain of a decrease in visible penis length. a dorsal phalloplasty defines the penopubic junction by tacking pubic skin to the pubis, revealing the base of the penis. this study aimed to evaluate the efficacy of a dorsal phalloplasty in increasing the visible penis length following ppi. methods: an inflatable penile prosthesis was implanted in 13 patients with severe erectile dysfunction (ed) at the kamal shaeer hospital, cairo, egypt, from january 2013 to may 2014. during the surgery, nonabsorbable tacking sutures were used to pin the pubic skin to the pubis through the same penoscrotal incision. intraoperative penis length was measured before and after the dorsal phalloplasty. overall patient satisfaction was measured on a 5-point rating scale and patients were requested to subjectively compare their postoperative penis length with memories of their penis length before the onset of ed. results: intraoperatively, the dorsal phalloplasty increased the visible length of the erect penis by an average of 25.6%. the average length before and after tacking was 10.2 ± 2.9 cm and 13.7 ± 2.8 cm, respectively (p <0.002). postoperatively, seven patients (53.8%) reported a longer penis, five patients (38.5%) reported no change in length and one patient (7.7%) reported a slightly shorter penis. the mean overall patient satisfaction score was 4.9 ± 0.3. none of the patients developed postoperative complications. conclusion: a dorsal phalloplasty during ppi is an effective method of increasing visible penis length, therefore minimising the impression of a shorter penis after implantation. keywords: penile implantation; penile prosthesis; pubis; erectile dysfunction; egypt. امللخ�ص: الهدف: ي�ضتكي املر�ضى بعد زراعة بدلة الق�ضيب من انخفا�ص الط�ل الظاهري للق�ضيب. الراأب الظهري للق�ضيب يحدد الفا�ضل ما بني الع�ض� والعانة بتثبيت جلد العانة لعظام احل��ص الإظهار قاعدة الق�ضيب. يهدف هذا البحث لتقييم كفاءة الراأب الظهري يف زيادة ط�ل الق�ضيب عند زرع البدلة. الطريقة: مت زرع بدالت قابلة للنفخ بالق�ضيب لعدد 13 مري�ضا يعان�ن من �ضعف يف االنت�ضاب و ذلك يف م�ضت�ضفي كمال �ضعري, يف القاهرة مب�رس, يف الفرتة من يناير 2013 اإىل ماي� 2014. خالل اجلراحة, مت ا�ضتخدام خيط جراحي غري قابل لالمت�ضا�ص لتثبيت جلد العانة اإىل عظام احل��ص من فتح جراحي مابني قاعدة الق�ضيب و كي�ص ال�ضفن. مت قيا�ص ط�ل الق�ضيب اأثناء العملية قبل و بعد الراأب الظهري. مت تقييم ر�ضى املر�ضى عن الط�ل بعد اجلراحة ح�ضب مقيا�ص راأى ذو 5 درجات, و كذلك راأيهم يف ط�ل بن�ضبة للق�ضيب الظاهري الط�ل من الظهري الراأب زاد اجلراحة, اأثناء النتائج: االنت�ضاب. �ضعف حدوث قبل كان مبا مقارنة الق�ضيب %25.6 يف املت��ضط. كان مت��ضط الط�ل قبل و بعد جراحة تثبيت جلد العانة اإىل عظام احل��ص 2.9 ± 10.2 �ضم و 2.8 ± 13.7 �ضم على الت�ايل )p >0.002(. بعد اجلراحة, ذكر �ضبعة مر�ضى )%53.8( باأن الق�ضيب اأ�ضبح اأط�ل, و اأقر خم�ص )%38.5( باأن الط�ل مل يتغري, بينما اأ�ضار مري�ص واحد )%7.7( اإىل ق�رس ب�ضيط للق�ضيب. كان املت��ضط العام للر�ضى ه� 0.3 ± 4.9. مل ي�ضتكي اأي من املر�ضى من م�ضاعفات ما بعد اجلراحة. اخلال�صة: الراأب الظهري للق�ضيب اأثناء زرع البدلة ه� و�ضيلة فعالة لزيادة الط�ل الظاهري للق�ضيب و بذلك ينخف�ص اإنطباع ق�رس الق�ضيب بعد زرع البدلة. الكلمات املفتاحية: زرع الق�ضيب؛ بدلة الق�ضيب؛ العانة؛ ال�ضعف اجلن�ضي؛ م�رس. dorsal phalloplasty to preserve penis length after penile prosthesis implantation *osama shaeer, kamal shaeer, islam a. rahman sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e27–30, epub. 30 mar 17 submitted 26 sep 16 revision req. 28 nov 16; revision recd. 29 nov 16 accepted 15 dec 16 clinical & basic research doi: 10.18295/squmj.2016.17.01.006 advances in knowledge combining a penile prosthesis implantation (ppi) with a dorsal phalloplasty can minimise the possibility of perceived shorter penis length and improve postoperative patient satisfaction rates. application to patient care surgeons should consider performing a dorsal phalloplasty in combination with a ppi as the procedure was found to significantly increase the visible length of the penis and resulted in high patient satisfaction scores. combining these procedures allows both surgeries to be performed without an increase in the postoperative complication rate or the need for a secondary incision. penile prosthesis implantation (ppi) results in high long-term patient satisfaction rates in comparison to non-surgical treatments. 1–4 however, some patients may complain of a decrease in penis length following ppi; wang et al. reported a mean penile shortening of dorsal phalloplasty to preserve penis length after a penile prosthesis implantation e28 | squ medical journal, february 2017, volume 17, issue 1 0.74 ± 0.15 cm following ppi while salem et al. found that ppi resulted in a decrease in erect penis length of 9.5%.3,4 when comparing postoperative and preoperative impressions of penis length after ppi, 72% of patients reported a decrease in penis length, 19% reported no change and 9% reported a slight increase in length.2 this study aimed to describe and evaluate the use of a new minimally invasive procedure—a dorsal phalloplasty—in increasing the visible length of the penis. during this procedure, the penopubic junction (ppj) is defined by tacking the pubic skin to the pubis, revealing the base of the penis and increasing the visible length of the penis from the pubic skin surface to the glans. methods this study included 13 male patients with severe refractory erectile dysfunction (ed) who underwent a combined ppi and dorsal phalloplasty at the kamal shaeer hospital, cairo, egypt, between january 2013 and may 2014. before surgery, each patient was stood before a mirror and the ppj was pressed down to mimic the effects of the dorsal phalloplasty. if the patient decided that the procedure would improve their visible penis length and agreed to undergo the combined surgery, they were included in the study. patients presenting with scarred corporal bodies following neglected priapism, extrusions of infected prostheses or severe peyronie’s disease requiring intraoperative incisions and grafts were excluded. the combined ppi and dorsal phalloplasty procedure was performed under general anaesthesia via a penoscrotal incision. the dartos muscle was split open until the tunica albuginea of the corpora cavernosa. the penis was retracted to one side and the space lateral to the base of the penis was bluntly dissected down to the pubis. the undersurface of the pubic skin in the midline was approximated to the pubis and a large needle was passed through the periosteum into the undersurface of the pubic skin, tacking in an adequate bulk of subcutaneous tissue and dermis at the ppj using a tacking suture made of braided polyester (trubond™ polyester sutures, sutures india private ltd., bangalore, karnataka, india) [figure 1]. without pulling down or tethering the skin of the penis, the optimum location for the placement of the tacking suture on the undersurface of the pubic skin was determined by palpitating several potential points around the base of the stretched penis and choosing the point that revealed the penis the most. to avoid puncturing the implant components, a corporotomy was performed and a three-piece girth-expanding inflatable prosthesis (titan® otr, coloplast group, minneapolis, minnesota, usa) was inserted after the tacking sutures had been placed. the tacking suture was subsequently tied, defining the ppj and anchoring it to the pubis, revealing the base of the penis. intraoperatively, visible penis length from the pubic skin surface to the glans was measured with the prosthesis inflated both before and after tying the tacking suture [figure 2]. following the completion figure 2: photographs showing the surgical procedure of a dorsal phalloplasty to increase penis length during penile prosthesis implantation. initially, the (a) tacking suture was placed and the (b) pre-tacking visible penile length recorded. following this, the (c) tacking suture was tied, the (d) penopubic junction defined and the (e) visible penis length measured again. figure 1: illustration of a dorsal phalloplasty to increase visible penis length after a penile prosthesis implantation showing the placement of the (a) pubic and (b) penopubic junction arms of the tacking suture. osama shaeer, kamal shaeer and islam a. rahman clinical and basic research | e29 of the procedure, the penoscrotal incision was closed in layers. postoperatively, the patients were discharged on the same day and allowed to resume intercourse 45 days after the surgery. each patient was followedup for between 12–18 months (mean: 15.4 ± 1.3 months) via quarterly phone interviews and clinical examinations. patients were requested to rate their overall satisfaction with visible penile length on a 5-point scale, with a score of 1 indicating severe dissatisfaction and 5 indicating high satisfaction. at their final follow-up appointment, they were also asked to subjectively assess their postoperative visible penile length in comparison to their memory of their erect penis length before the onset of ed. the development of any postoperative complications was documented. statistical analysis was performed using an excel spreadsheet, version 2010 (microsoft inc., redmond, washington, usa) and the statistical package for the social sciences (spss), version 19 (ibm corp., chicago, illinois, usa). results were expressed as means and standard deviations or frequencies and percentages, as appropriate. means were compared using the paired sample t-test and continuous numerical values were assessed using the student’s t-test. a p value of <0.050 was considered statist ically significant. this study was approved by the ethics committee of the department of andrology at the faculty of medicine of cairo university. participants were assured of the confidentiality of their data. all patients provided informed written consent before their inclusion in the study. results the mean age of the patients was 57.1 ± 6.2 years old. intraoperatively, the dorsal phalloplasty resulted in an average increase of 25.6% in the visible length of the erect penis. before tacking, the average length of the visible penis was 10.2 ± 2.9 cm in comparison to an average length of 13.7 ± 2.8 cm after tacking (p <0.002). postoperatively, seven patients (53.8%) reported a longer penis, five patients (38.5%) reported no change in penis length and one patient (7.7%) reported a slightly shorter penis at their final followup in comparison with recalled erect length before the onset of ed [table 1]. the mean overall satisfaction score was 4.9 ± 0.3. none of the patients reported any infections, extrusions, prosthesis malfunctions or persistent penile pain lasting more than two months after the surgery. moreover, none of the patients reported experiencing any pain at the tacking suture sites, instability of the erect penis during intercourse or a decrease in their perception of penis length over the duration of the follow-up period. discussion patient dissatisfaction with penis length following ppi can be addressed in various ways, including pre and postoperative counselling, implantation of lengthexpanding prostheses and adjuvant pre-, intraor postoperative augmentation techniques.5 previous studies have evaluated the efficacy of several months of penile traction before implantation as a method of increasing postoperative penis length.6,7 suspensory ligament release, with or without v-y skin plasty, may also potentially increase post-implantation penis length.7 another option is a suprapubic lipectomy, which can reveal a buried penis among patients with an overhanging fat pad.8 ventral phalloplasties may also enhance patient satisfaction via removal of the penoscrotal web, thereby revealing the ventral aspect of the penis hidden within the scrotal sac.9,10 a combination of various post-implantation augmentation techniques have also been previously reported to enhance patient satisfaction.5 in the current study, a combined dorsal phalloplasty and ppi procedure was found to significantly increase intraoperative penis length and enhance table 1: visible penis length before and after a dorsal phalloplasty postoperative impression of length and patient satisfaction scores among male patients with severe erectile dysfunction (n = 13) patient age in years visible penis length in cm postoperative patient satisfaction before dorsal phalloplasty after dorsal phalloplasty impression of length satis faction score* 62 9.5 12.0 longer 5 59 10.6 12.2 longer 5 52 14.0 17.3 same 5 55 7.2 12.2 longer 5 57 9.0 15.0 shorter 5 54 8.0 12.2 same 5 52 13.0 16.8 same 5 48 11.0 15.1 same 5 55 13.0 14.8 longer 5 70 7.0 11.3 same 4 60 7.0 11.3 longer 5 66 15.4 18.5 longer 5 52 7.5 9.0 longer 5 *satisfaction was self-assessed by patients using a 5-point rating scale, with a score of 1 indicating severe dissatisfaction and 5 indicating high satisfaction. dorsal phalloplasty to preserve penis length after a penile prosthesis implantation e30 | squ medical journal, february 2017, volume 17, issue 1 postoperative patient satisfaction, without an increase in morbidity. a dorsal phalloplasty reveals the length of the penis hidden within the suprapubic fat pad; moreover, tacking the pubic skin at the ppj is a relatively simple procedure, allowing both surgeries to be performed through the same incision and during the same session. as such, other augmentation techniques requiring a secondary incision or a second surgical session are unnecessary. furthermore, a dorsal phalloplasty circumvents the possible complications of other length enhancement procedures, such as wound dehiscence, infections, oedema or a downward erection angle.6,7,11,12 although a dorsal phalloplasty can be combined with other techniques for further length gain, these techniques cannot correct an ill-defined ppj on their own.6,13 in comparison to memories of their penis length before ed onset, more patients in the current study perceived their postimplantation erect length to be longer (53.8% versus 9%) or the same (38.5% versus 19%) and fewer patients perceived their length to be shorter (7.7% versus 72%) following ppi with dorsal phalloplasty compared to patients in a previous study who underwent ppi without dorsal phalloplasty, respectively.2 this study is subject to certain limitations. there is a theoretical possibility that the tacking sutures may loosen over subsequent years and that patients may lose visible penis length accordingly. as a result, further studies with longer follow-up periods are required to determine the sustainability of length gain from a dorsal phalloplasty. in addition, patients were asked to subjectively assess their impression of penis length gain by comparing their postoperative penis length with memories of their penis length before onset of ed, which may have resulted in inaccurate recollections of previous penis length. conclusion a dorsal phalloplasty is a minimally invasive surgical technique which involves defining the ppj using tacking sutures. the findings of this study indicate that it is an effective method for revealing the penis and increasing the visible penile length following ppi, minimising impression of a shorter penis and increasing postoperative patient satisfaction. a c k n o w l e d g m e n t s the data of some of the patients included in this study were presented among those of a larger cohort at the 19th congress of the european society for sexual medicine on 2–4 february 2017 in nice, france. an abstract of this presentation will be published in the journal of sexual medicine at a later date. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. akin-olugbade o, parker m, guhring p, mulhall j. determinants of patient satisfaction following penile prosthesis surgery. j sex med 2006; 3:743–8. doi: 10.1111/j.1743-6109.2006.00278.x. 2. deveci s, martin d, parker m, mulhall jp. penile length alterations following penile prosthesis surgery. eur urol 2007; 51:1128–31. doi: 10.1016/j.eururo.2006.10.026. 3. wang r, howard ge, hoang a, yuan jh, lin hc, dai yt. prospective and long-term evaluation of erect penile length obtained with inflatable penile prosthesis to that induced by intracavernosal injection. asian j androl 2009; 11:411–15. doi: 10.1038/aja.2009.35. 4. salem a, shaeer o, abdel-aal a, younes m. comparative study of penile size before and after penile prosthesis implantation. hum androl 2012; 2:42–4. doi: 10.1097/01. xha.0000415084.67485.67. 5. shaeer o. supersizing the penis following penile prosthesis implantation. j sex med 2010; 7:2608–16. doi: 10.1111/j.17436109.2010.01723.x. 6. shaeer o, shaeer k. revealing the buried penis in adults. j sex med 2009; 6:876–85. doi: 10.1111/j.1743-6109.2008.01162.x. 7. borges f, hakim l, kline c. surgical technique to maintain penile length after insertion of an inflatable penile prosthesis via infrapubic approach. j sex med 2006; 3:550–3. doi: 10.11 11/j.1743-6109.2006.00232.x. 8. hakky ts, suber j, henry g, smith d, bradley p, martinez d, et al. penile enhancement procedures with simultaneous penile prosthesis placement. adv urol 2012; 2012:314612. doi: 10.1155/2012/314612. 9. carrion r. ventral phalloplasty. j sex med 2010; 7:2914–17. doi: 10.1111/j.1743-6109.2010.01983.x. 10. caso j, keating m, miranda-sousa a, carrion r. ventral phalloplasty. asian j androl 2008; 10:155–7. doi: 10.1111/j. 1745-7262.2008.00365.x. 11. li cy, kayes o, kell pd, christopher n, minhas s, ralph dj. penile suspensory ligament division for penile augmentation: indications and results. eur urol 2006; 49:729–33. doi: 10.10 16/j.eururo.2006.01.020. 12. shaeer o, shaeer k, el-sebaie a. minimizing the losses in penile lengthening: “v-y half-skin half-fat advancement flap” and “t-closure” combined with severing the suspensory ligament. j sex med 2006; 3:155–60. doi: 10.1111/j.17436109.2005.00105.x. 13. alter gj, ehrlich rm. a new technique for correction of the hidden penis in children and adults. j urol 1999; 161:455–9. doi: 10.1016/s0022-5347(01)61922-0. https://doi.org/10.1111/j.1743-6109.2006.00278.x https://doi.org/10.1016/j.eururo.2006.10.026 https://doi.org/10.1038/aja.2009.35 https://doi.org/10.1097/01.xha.0000415084.67485.67 https://doi.org/10.1097/01.xha.0000415084.67485.67 https://doi.org/10.1111/j.1743-6109.2010.01723.x https://doi.org/10.1111/j.1743-6109.2010.01723.x https://doi.org/10.1111/j.1743-6109.2008.01162.x https://doi.org/10.1111/j.1743-6109.2006.00232.x https://doi.org/10.1111/j.1743-6109.2006.00232.x https://doi.org/10.1155/2012/314612 https://doi.org/10.1111/j.1743-6109.2010.01983.x https://doi.org/10.1111/j.1745-7262.2008.00365.x https://doi.org/10.1111/j.1745-7262.2008.00365.x https://doi.org/10.1016/j.eururo.2006.01.020 https://doi.org/10.1016/j.eururo.2006.01.020 https://doi.org/10.1111/j.1743-6109.2005.00105.x https://doi.org/10.1111/j.1743-6109.2005.00105.x https://doi.org/10.1016/s0022-5347%2801%2961922-0 sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century sultan qaboos university med j, august 2013, vol. 13, iss.3, pp. 437-441, epub. 25th jun 13 submitted 23rd dec 12 revision req. 9th mar 13; revision recd. 3rd apr 13 accepted 1st may 13 department of biochemistry, gulf medical university, ajman, united arab emirates *corresponding author e-mail: gomathikg@gmu.ac.ae and gomathikg@hotmail.com أسباب التوتر النفسي واالسرتاتيجيات املعتمدة ملواجهتها من قبل طلبة املرحلة اجلامعية األوىل للمهن الطبية يف إحدى اجلامعات يف دولة اإلمارات العربية املتحدة كادايام كوماثي، �شوفيا اأحمد، جاياديفان �رسيدهاران طلبة من عينة اعتمدتها والتي عليها للتغلب املتبعة واال�شرتاتيجيات التوتر اأ�شباب مقارنة اإىل الدرا�شة هذه هدفت الهدف: امللخ�ص: ا�شتطالعي م�شح اإجراء مت الطريقة: املتحدة. العربية االإمارات دولة الطبية، اخلليج جامعة يف الطبية للمهن االأوىل اجلامعية املرحلة تطوعي جمهول اال�شم خالل الفرتة من يناير اإىل يوليو 2011، لتحديد اأ�شباب التوتر بني طلبة املرحلة اجلامعية االأوىل والثانية للطب العام، وطب االأ�شنان، وال�شيدلة، وطالب العالج الطبيعي )عدد=212(. كذلك متت درا�شة االإ�شرتاتيجيات املعتمدة با�شتخدام خال�شة اجلرد الذي اعتمد. النتائج: كان قلق توقعات امل�شتقبل )%54.2( وتلبية توقعات االأهل )%40.1( اأكرث اأ�شباب التوتر. كان �شوء التغذية متعددة، ا�شرتاتيجيات الطلبة اأ�شتخدم للتوتر. امل�شببة االأخرى االأ�شباب من )36.3%( الريا�شية التمارين ممار�شة وعدم )36.8%( منها وب�شورة اأ�شا�شية الدين/ال�شالة )%74.5(، التخطيط )%70.5(، واتخاذ اخلطوات املنا�شبة )%70.5( للتعامل مع التوتر. كما اأ�شارت الدرا�شة اإىل اأنه ال توجد فروقات ملحوظة يف ا�شرتاتيجيات الت�شدي لعوامل التوتر بني اجلن�شني اأوبني الربامج املختلفة. اعتمد ا�شتنتجت )%48.5(. اخلال�سة: الثانية ال�شنة طلبة من )p >0.05( اأكرب ب�شورة املعنوي الدعم على )62.5%( االأوىل ال�شنة طلبة الدرا�شة اأن االأ�شباب الرئي�شية للتوتر هو القلق ب�شاأن امل�شتقبل وتلبية توقعات االأهل. اأغلب الطلبة اتبعوا ا�شرتاتيجيات اإيجابية للتغلب على التوتر وذلك باللجوء للدين وال�شالة والتي كانت االأكرث �شيوعًا. مفتاح الكلمات: التوتر؛ �شيكولوجي؛ املهن ال�شحية؛ التعليم الطبي؛ املرحلة اجلامعية االأوىل؛ �شلوك التعامل؛ دولة االإمارات العربية املتحدة. abstract: objectives: this study aimed to compare causes of stress and coping strategies adopted by a sample of undergraduate health-profession students at the gulf medical university, united arab emirates. methods: an anonymous voluntary questionnaire-based survey was conducted, from january to july 2011, among firstand second-year medicine, dentistry, pharmacy and physiotherapy students (n = 212) to identify causes of stress. coping strategies were studied using the brief cope inventory. results: worries regarding the future (54.2%) and parental expectations (40.1%) were the major stressors. poor diet (36.8%) and a lack of exercise (36.3%) were also reported to cause stress. students used multiple strategies, mainly religion/praying (74.5%), planning (70.5%) and taking action (70.5%) to cope with stress. there were no significant differences observed in the stressors or coping strategies between genders or programmes. first-year students (62.5%) relied on emotional support significantly more (p <0.05) than second-year students (48.5%). conclusion: the main causes of stress were worries regarding future and parental expectations. the majority of the students used positive coping strategies, with religion/ praying found to be the most frequently used strategy. keywords: stress, psychological; health professions; medical education, undergraduate; coping behavior; united arab emirates. brief communication causes of stress and coping strategies adopted by undergraduate health professions students in a university in the united arab emirates *kadayam g. gomathi, soofia ahmed, jayadevan sreedharan students in undergraduate health-professions are subjected to many different kinds of stresses. studies indicate high stress levels in students of medicine,1,2,3 dentistry,4 pharmacy5 and physiotherapy6 programmes. a high prevalence of depression and anxiety has also been reported in medical students, especially females, compared to age-matched peers in the general kadayam g. gomathi, soofia ahmed and jayadevan sreedharan brief communication | 431 population.1 students cope with stress in different ways. while some studies on medical students have shown more usage of positive coping strategies such as positive reframing, planning and religion,7,8 others have identified the use of alcohol, tobacco and drugs to cope with stress.1 very few studies regarding coping behaviour in students of health professions have been reported from the arab region.9 studying causes of stress and coping strategies used can help in designing appropriate interventions and planning modifications in the curricula to reduce stress and enhance students’ wellbeing and learning abilities. this study compared the causes of stress and coping strategies adopted by first and secondyear undergraduate health-profession students at the gulf medical university in the united arab emirates (uae). methods between january and july 2011, a cross-sectional survey was carried out using a voluntary, anonymous, self-administered questionnaire, among first and second-year undergraduate medicine, dentistry, pharmacy and physiotherapy students at the gulf medical university in the uae. ethical approval was obtained from the research & ethics committee of the university (4rc/17/13th oct 2010). students were informed about the purpose of the study and verbal student consent was obtained. factors causing stress were identified using a 22-item questionnaire as described earlier.10 stressors were classified into three domains: academic-related, psychosocial and health-related. the brief cope inventory11 was administered to assess coping behaviours spread over 14 dimensions, including self-distraction, active coping, denial, substance use, emotional support (family and friends), instrumental support (faculty and other institutional resources), behavioural disengagement (giving up coping), venting anger/ frustration, positive reframing, planning, humour, acceptance, religion and self-blame. students were asked to rate items on a 4-point scale, ranging from ‘not been doing this at all’, ‘doing this a little bit’, to ‘doing this a medium amount’ and ‘doing this a lot’. for the purpose of analysis, ‘not doing this at all/ doing this a little bit’ were taken as not using the coping strategy while ‘doing this a medium amount/ doing this a lot’ were taken as adopting the strategy. data were entered into the predictive analytics software, version 18 (statistical package for the social sciences, ibm corp., chicago, illinois, usa) and analysed by a statistician. pearson’s chi-square test was used for testing significance. a total of 4 questionnaires were found to be incomplete and so were excluded from the analysis. results all 238 first and second-year undergraduate health-profession students were contacted for the survey. a total of 212 students (112 first-year students and 100 second-year students) completed the survey giving a response rate of 89%. a total of 46.7% of the students were studying medicine, 22.2% dentistry, 16.5% pharmacy and 14.6% were in the physiotherapy programme. the age of the students ranged from 16 to 28 years with 95% of the students aged ≤23 years. the student population was 72% female and the rest was male. just over half the students (51%) were living at home with their families, and the rest were living in hostels or apartments. as shown in table 1, the stressors were found to be very similar in first and second-year students. among the academic-related stressors, frequency of examinations, time-management and academic workload were identified as the main stressors by both first and second-year students. among the psychosocial stressors, the main concerns identified were ‘worries regarding the future’, ‘high parental expectations’ and ‘lack of recreation’. a total of 19.3% of the students were found to be anxious; 18.4% of the students reported ‘difficulty relating to members of the opposite sex’. poor eating habits, lack of exercise and sleep-related problems were the main health-related issues identified by the students. tobacco/alcohol abuse was reported by very few students. there were no statistically significant differences in stressors between the genders, and between students in the different programmes or years. multiple coping strategies were being used by students to handle stressful situations. as shown in table 2, the majority of the students were using positive coping strategies. religion/praying were very important coping strategies for students in both the first (78%) and second (71%) years. other important coping strategies were planning (76% causes of stress and coping strategies adopted by undergraduate health professions students in a university in the united arab emirates 432 | squ medical journal, august 2013, volume 13, issue 3 and 65%), active coping (71% and 70%), positive reframing (68% and 62%) and seeking instrumental support (56% and 57%) for firstand second-year students, respectively. however, many students in the first and second year were also attempting selfdistraction (52% and 51%), blaming themselves (50% and 42%), coping by venting their anger/ frustration (35% and 30%) and some (28% and 25%) of the students had even given up coping. there were no statistically significant differences in coping strategies used between the genders or between students in different programmes. no significant association was seen between stress and any specific coping strategy. the only significant difference (p <0.05) was the higher numbers of first-year students (62.5%) seeking emotional support compared to second-year students (48.5%). discussion students in the health-profession programmes are not only required to adjust to the challenges of the academic environment but also usually lack time for recreation. stress among health-profession students has been reported, in earlier studies, to be associated with psychological morbidity.6,7,10 students’ own expectations and motivation are known to be affected by parental expectaions.12 in this study, psychosocial causes such as worries regarding the future, and high parental expectations were the main stressors for both firstand secondyear health-profession students. high parental expectations were also identified as an important stressor for medical students in nepal.7 students in health-profession programmes are preparing for specific careers and thus should feel confident about their future. however ‘worries about the future’ were reported by both firstand secondyear students and were found to be higher among second-year students (though not statistically significant). this finding could not be explained and needs to be probed further. the lack of recreation reported by students is probably due to a lack of time due to the academic workload. poor eating habits table 1: comparison of stressors in first and second -year health-profession students at gulf medical university item firstyear (n = 112) n (%) secondyear (n = 100) n (%) both years (n = 212) n (%) academic-related high academic workload 21 (18.7) 12 (12) 33 (15.6) dissatisfaction with classes 11 (9.8) 9 (9) 20 (9.4) high frequency of examinations 25 (22.3) 26 (26) 51 (24.1) poor performance in examinations 19 (17) 7 (7) 26 (12.3) lack of learning material 13 (11.6) 13 (13) 26 (12.3) difficulty reading textbooks 17 (15.2) 12 (12) 29 (13.7) inability to manage time 21(18.7) 20 (20) 41 (19.3) inability to concentrate 11 (9.8) 7 (7) 18 (8.5) psychosocial anxiety 24 (21.4) 17 (17) 41 (19.3) high parental expectations 50 (44.6) 35 (35) 85 (40.1) worries about future 56 (50) 59 (59) 115 (54.2) problems adjusting with classmates 11 (9.8) 11 (11) 22 (10.4) loneliness 9 (8) 12 (12) 21 (9.9) financial problems 7 (6.2) 6 (6) 13 (6.1) family problems 6 (5.4) 9 (9) 15 (7.1) difficulty relating to members of the opposite sex 20 (17.9) 19 (19) 39 (18.4) lack of recreation 31 (27.7) 22 (22) 53 (25) health-related lack of healthy diet/ irregular eating habits 44 (39.3) 34 (34) 78 (36.8) sleep problems 28 (25) 24 (24) 52 (24.5) illness/health problem 6 (5.4) 6 (6) 12 (5.7) tobacco/ alcohol/ substance abuse 4 (3.6) 2 (2) 6 (2.8) lack of exercise 39 (34.8) 38 (38) 77 (36.3) kadayam g. gomathi, soofia ahmed and jayadevan sreedharan brief communication | 433 are often seen among university students especially those living alone in hostels/apartments and is not surprising. difficulties in dealing with members of the opposite sex may be due to the fact that most students come from single-gender high schools. the same problem has also been reported in saudi students studying in australia.13 sleep-related problems are a worrying finding since lack of sleep is known not only to impair academic performance but also to be associated with a higher incidence of psychological disorders including suicide ideation.14 multiple coping strategies were adopted by the students. most of them were positive and included praying, taking action to negate the stressor, planning and learning from the experience. religion or praying as a coping mechanism is not unexpected since most of the students are muslim and the uae offers ample opportunities to practice this religion. these findings are similar to reports from malaysia8 and jordan15 on medical students. the strategies of active coping, positive reframing and seeking help have also been identified as the major strategies used by medical students in nepal7 and malaysia.8 it was interesting to note that emotional support was an important coping mechanism for students in the first year but significantly fewer students in the second year adopted it as a coping strategy. this could be an indication of students' maturation. many students in the first year are away from their family for the first time and may need more emotional support compared to secondyear students. while self-blame, which was used by many students is a negative coping mechanism, self-distraction and venting can also be negative if used exclusively. psychological help and counselling may help students handle stress and anger better. substance abuse was identified by very few students as a health-related concern or as a coping table 2: coping strategies used by firstand second-year health-professions students at gulf medical university coping strategy details percentage of students who adopt the strategy first-year (n = 112) second-year (n = 100) both years (n = 212) active coping doing something about the situation, taking action to negate the stressor 71 70 70.5 emotional support* getting emotional support/advice from friends and family 62.5 48.5 55.5 instrumental support getting help and advice from faculty members, student advisors, counsellors or peers 56 57 56.5 selfdistraction doing something to take your mind off the situation such as going to movies, watching tv, shopping, sleeping, listening to music 52 51 51.5 alcohol/tobacco/substance abuse using tobacco/alcohol/drugs to feel better 5.5 6 5.75 denial refusing to believe it happened, not accepting the situation 15 16 15.5 given up coping given up the attempt to do anything about the situation, giving up trying to deal with it 28 25 26.5 venting expressing negative feelings: showing anger at things/ people, swearing, bad language 35 30 32.5 positive reframing seeing something good in what is happening, learning from the experience 68 62 65 planning planning a strategy on what to do, how to deal with the situation 76 65 70.5 humour making fun of the situation 38 29 33.5 acceptance learning to live with the situation, accepting it 65 58 61.5 religion praying/meditating 78 71 74.5 self-blaming blaming yourself for getting into the situation or for handling it badly 50 42 46 *significantly different (p<0.05) between the two years. causes of stress and coping strategies adopted by undergraduate health professions students in a university in the united arab emirates 434 | squ medical journal, august 2013, volume 13, issue 3 strategy. these findings are similar to reports from nepal7 where 3.4% of students reported abusing alcohol/tobacco, but are much lower than reports from usa and canada1 where up to 20% of students have reported tobacco and alcohol abuse. however, it is also possible that students may not have disclosed such issues for cultural reasons. the limitations of this study are its crosssectional nature and the fact that it was based entirely on student responses. the conclusions drawn are from the experience of one university and may not be applicable to other universities. conclusion firstand second-year undergraduate healthprofessions students at the gulf medical university in the uae reported worries about the future, high parental expectations, lack of recreation and frequency of examinations as the major causes of stress. irregular eating habits, a lack of exercise and sleep problems were the main health-related concerns. while the majority of the students were using positive coping strategies such as praying/ meditating, planning and taking action to resolve the problem, many were also blaming themselves and some had given up coping entirely. interventions such as teaching students about stress management and developing student-support groups led by trained individuals may help health-profession students to learn self-care and cope better with stress. a c k n o w l e d g e m e n t s the authors would like to thank the students for their cooperation. references 1. dyrbye ln, thomas mr and shanafelt td. systematic review of depression, anxiety, and other indicators of psychological distress among us and canadian medical students. acad med 2006; 81:354–73. 2. al-dabal bk, koura mr, rasheed p, al-sowielem l, makki sm. a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia. sultan qaboos univ med j 2010; 10:231–40. 3. al-lamki l. stress in the medical profession and its roots in medical school. sultan qaboos univ med j 2010; 10:156–9. 4. abu-ghazaleh sb, rajab ld, sonbol hn. psychological stress among dental students at the university of jordan. j dent educ 2011; 75:1107–14. 5. frick lj, frick jl, coffman re, dey s. student stress in a three-year doctor of pharmacy program using a mastery learning educational model. am j pharm educ 2011; 75:64. 6. walsh jm, feeney c, hussey j, donnellan c. sources of stress and psychological morbidity among undergraduate physiotherapy students. physiotherapy 2010; 96:206–12. 7. sreeramareddy ct, shankar pr, binu vs, mukhopadhyay c, ray b, menezes rg. psychological morbidity, sources of stress and coping strategies among undergraduate medical students of nepal. bmc med educ 2007; 7:26. 8. al-dubai sa, al-naggar ra, alshagga ma, rampal kg. stress and coping strategies of students in a medical faculty in malaysia. malaysian j med sci 2011; 18:57–64. 9. elzubeir ma, elzubeir ke, magzoub me. stress and coping strategies among arab medical students: towards a research agenda. educ health (abingdon) 2010; 23:355. from: http://www.educationforhealth. n e t / p u b l i s h e d a r t i c l e s / a r t i c l e _ p r i n t _ 3 5 5 . p d f accessed: dec 2012. 10. gomathi kg, ahmed s, sreedharan j. psychological health of first-year health professional students in a medical university in the united arab emirates. sultan qaboos univ med j 2012; 12:206–13. 11. carver, c. s. you want to measure coping but your protocol's too long: consider the brief cope. int j behav med 1997; 4:92–100. 12. wang l-f, heppner pp. assessing the impact of parental expectations and psychological distress on taiwanese college students. couns psychol 2002; 30:582–608. 13. alhazmi a, nyland b. the saudi arabian international student experience: from a gendersegregated society to studying in a mixed-gender environment. compare: j compar int educ 2012; 43:346–65. from: http://dx.doi.org/10.1080/030579 25.2012.722347 accessed: apr 2013. 14. wong ml, lau ey, wan jh, cheung sf, hui ch, mok ds. the interplay between sleep and mood in predicting academic functioning, physical health and psychological health: a longitudinal study. j psychosom res 2013; 74:271–7. 15. bataineh zm, hijazi ta, hijleh mf. attitudes and reactions of jordanian medical students to the dissecting room. surg radiol anat 2006; 28:416–21. 1department of radiology, gata haydarpaşa training hospital, istanbul, turkey; 2division of radiology, kasımpaşa military hospital, istanbul, turkey *corresponding author e-mail: draksivrioglu@gmail.com ظهور األستبدال الشحمي الكلوي يف التصوير املقطعي شبه ورم نادر كمال كارا، علي كمال �سيفريوجلو، كو�سكون اأوزتوركر، جاهد كافادار appearance of renal replacement lipomatosis on computed tomography rare pseudotumour kemal kara,1 *ali k. sivrioglu,2 coskun oztürker,1 cahit kafadar1 an 81-year-old male patient presented to the urology department of gata haydarpaşa training hospital, istanbul, turkey, in may 2014 complaining of left lumbar pain and a sense of abdominal fullness. on physical examination, left lumbar tenderness and a palpable mass were observed. a urine analysis showed an increased number of red blood cells. plain abdominal radiography demonstrated soft tissue density at the left upper quadrant pushing the colon segments medially [figure 1]. abdominal ultrasonography revealed a significant increase in the size and echogenicity of the left kidney and its margin could not be clearly differentiated from the surrounding fat tissue. in addition, a decrease in the left renal parenchymal thickness was noted. computed tomography (ct) and magnetic resonance imaging (mri) were performed without the administration of intravenous contrast due to elevated serum creatinine levels. the ct scan [figure 2] and axial t2-weighted mri images revealed a fatty mass in the left kidney (approximately 22 x 18 x 14 cm in figure 1: plain abdominal radiograph showing a mass with soft tissue density in the left upper quadrant pushing the colon segments medially (arrows) in a patient with renal replacement lipomatosis. interesting medical image sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e567–568, epub. 23 nov 15 submitted 5 nov 14 revision req. 11 jan 15; revision recd. 22 feb 15 accepted 11 may 15 doi: 10.18295/squmj.2015.15.04.024 appearance of renal replacement lipomatosis on computed tomography rare pseudotumour e568 | squ medical journal, november 2015, volume 15, issue 4 interesting medical image | e568 liposarcomas and angiomyolipomas should be considered in the differential diagnosis for rrl. xgp is defined as a chronic granulomatous inflammatory disorder of the kidney that is characterised by microscopic lipid-laden foamy macrophages.4 for patients with this condition, ct scans show xantho granulomatous hypodense regions in the renal cortex and medulla, reduced renal function, detection of staghorn calculi, hydronephrosis and pyonephrosis.4 malakoplakia is a rare inflammatory disorder that may affect the kidneys. this condition is characterised by foamy histiocyte accumulation in the renal parenchyma and may represent a variant of xgp.2 lipomas and liposarcomas are generally seen in the intrarenal or extrarenal regions, outside of the renal sinus. liposarcomas should be considered if the lesion has irregular borders and invasion of the surrounding structures or if heterogeneity or a mass effect are present.5 angiomyolipomas are generally seen in patients with tuberous sclerosis; they are differentiated by the presence of normal renal function and the absence of renal calculi on ct scans. the complications of rrl generally include perirenal abscesses and fistulae.1 in conclusion, rlr is a rare condition that should be considered in the presence of significant perirenal and intrarenal fatty infiltration. early recognition of this condition would avoid unnecessary medical and surgical treatment. ct scans are an effective imaging modality in the diagnosis and follow-up of this condition. references 1. tunçbilek i̇, ünlübay d, kacar m, bilaloğlu p. [lipomatous of renal replacement: us and ct findings.] diagn interv radiol 2002; 8:82–4. 2. ginat dt, bhatt s, dogra vs. replacement lipomatosis of the kidney: sonographic features. j ultrasound med 2008; 27:1393–5. 3. sönmez g, mutlu h, özturk e, sıldıroğlu o, akyol i̇, başekim cç, et al. replacement lipomatosis of the kidney: mri features. eur j gen med 2008; 5:184–6. 4. başara i, akın y, serter s, bozkurt a, nuhoğlu b. [renal sinus lipomatosis.] kafkas j med sci 2013; 3:48–54. doi: 10.5505/ kjms.2013.72473. 5. nicholson da. case report: replacement lipomatosis of the kidney unusual ct features. clin radiol 1992; 45:42–3. doi: 10.1016/s0009-9260(05)81469-2. size) with areas of linear and patchy fibrous tissue. the mass caused significant enlargement of the left kidney and distortion of the surrounding structures. there were no areas of restricted diffusion within the lesion on diffusion-weighted images. a biopsy of the mass was performed and a pathological examination revealed mature fat tissue. as a result of these findings, the left renal mass was considered to indicate renal replacement lipomatosis (rrl). ultrasonography performed three months after the initial diagnosis revealed no changes in the size and imaging characteristics of the lesion. comment rrl is a marked proliferation of fat within the renal sinus and perirenal region where the renal parenchyma is replaced by fatty tissue.1 while renal sinus lipomatosis is a mild proliferation of fatty tissue in the renal sinus, rrl is considered to be an advanced or aggressive form of renal sinus lipomatosis.2,3 the condition is the result of severe atrophy of the renal parenchyma and fatty proliferation and is usually accompanied by chronic infections, obstructive kidney stones and long-standing hydronephrosis. it generally occurs unilaterally, contrary to renal sinus lipomatosis, and extends to the perirenal and periureteral areas.3,4 calculi are also seen in approximately 70% of cases.3 xanthogranulomatous pyelonephritis (xgp), malakoplakia and tumours including fat-like lipomas, figure 2: non-contrast computed tomography showing a fatty renal mass (arrows) in a patient with renal replacement lipomatosis. the mass caused significant left renal enlargement and distortion on the surrounding structures. kemal kara, ali k. sivrioglu,coskun oztürker and cahit kafadar http://dx.doi.org/10.5505/kjms.2013.72473 http://dx.doi.org/10.5505/kjms.2013.72473 http://dx.doi.org/10.1016/s0009-9260%2805%2981469-2 sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 198-201, epub. 9th may 13 submitted 1st apr 13 revision reqd. 6th apr 13, revision recd. 8th apr 13 accepted 8th apr 13 worldwide, medical education, both at the undergraduate and postgraduate levels, is in a process of evolution. oman has adopted outcomeand competency-based curricula in graduate medical education programmes, and is currently seeking accreditation with the accreditation council for graduate medical education international (acgme-i).1 we believe that is the way forward. in fact, many medical schools have adopted and are currently adopting outcomeand competencybased curricula, while many others employ the timetested methods of apprenticeship and mentorship in their graduate medical education programmes. not only are the two models of teaching and learning different, but efforts at ‘fine-tuning’ have led to a whole range of different options along the spectrum. thus, while the medical education systems vary from one country to the other, from one region to the other in the same country, and even from one medical school to the other, there are advantages in each system. it is evident that many of the ‘core competencies’ of medical graduates and postgraduate doctors are developed by different training methods, and stimulated by a variety of accreditation systems. the process of refining methods in teaching, learning, and assessment in undergraduate and postgraduate education dates back to the 19th century, and is the result of either systematic reforms introduced, and/or a response to societal demands. from the 19th century apprenticeship model, through the systems-based model introduced as a result of the flexner report2,3 in the earlier part of the 20th century, and onto the outcomebased curriculum straddling the start of the 21st century, there has been a continuous process of refinement. at the heart of the continuous desire for improvement, is the need to produce medical practitioners who can use both scientific knowledge and appropriate clinical reasoning to provide medical care with character, compassion and integrity. the strengths of the apprenticeship model, such as role-modelling and story-telling, are still important today, especially at the fellowship training level. they are considered the cornerstone for developing and polishing some very important outcomes, such as professionalism. subsequently, the flexner’s report2,3 stressed the need for formal analytic reasoning, and considered this to be one of the most important requirements for the intellectual training of physicians. the ‘think much; publish little’ dictum was then replaced by a ‘publish or perish’ culture4 in response to the then emerging standard, against which the faculty accomplishments were judged. the introduction of the discovery-care continuum in academic health institutions,5 leading to the integration of research with patient care and teaching, contributed immensely to the current state of development of healthcare. unfortunately, the pendulum swung too far in some institutions, as the medical research became increasingly molecular, leading to polarisation between clinicalteachers and top-notch researchers. another leap 1department of medicine, sultan qaboos university hospital; 2department of radiology & molecular imaging, sultan qaboos university, and oman medical specialty board, muscat, oman *corresponding author e-mail: ikramburney@hotmail.com اعتماد برامج الدراسات العليا للتعليم الطيب مقياس واحد يناسب اجلميع أم ال؟ اإكرام بريين و نيال ملكي editorial accreditation of graduate medical education programmes one size fits all—or does it? *ikram a. burney1 and neela al-lamki2 ikram a. burney and neela al-lamki editorial | 199 forward that impacted medical education can be attributed to the current healthcare environment, and the need for the generation of revenue; ‘clinical productivity’ became a benchmark for the clinician’s performance.4 this necessitated the incorporation into curricula of inter-professional skills, teamwork, population health, and health service organisation. for example, ‘managerial’ competency is now defined as yet another important outcome in being a competent doctor. clearly the various competencies, as defined by the world federation of medical education (wfme),6 canmeds (from the royal college of physicians and surgeons of canada),7 the uk general medical council (gmc) competencies8 and those from the accreditation council for graduate medical education (acgme)9 are a reflection of the ever-changing standards of medical education. life-long learning is more important today, as an outcome of our medical education, than ever before. indeed most accreditation systems today insist on achieving various competencies, including life-long learning. whereas more and more postgraduate medical education programmes throughout the world are adopting ‘structured’ curricula (such as competencyand outcome-based curricula), there is still an enormous amount of variability in the way that graduate medical programmes are conducted and monitored. there appears to be a trans-atlantic divide, with most of the postgraduate training programmes in north america being based on structured clinical teaching, compared to the vast majority of programmes outside of north america, which are still based on the apprenticeship method. however, in some of these countries, these postgraduate programmes have now begun to undergo changes and reforms. whereas there are merits in both systems, it is difficult for one system to claim absolute superiority. prima facie, the structured clinical training and competencybased curricula appear superior and seem more attractive. however, the final result is far from clear as the outcome measurement tools are still in their infancy. the residency programmes in the usa and canada have started applying the concept of outcome-based and competency-based assessment. utilising such assessment tools provides a level playing field for the accreditation system of residency training programmes. the process of accreditation helps to evaluate, improve and recognise the programmes by complying with certain standards of education; it also improves healthcare by assessing and enhancing the quality of graduate resident physicians for the benefit of the public. the standards are set independently by the accrediting bodies, conformity to which helps to boost the confidence of the public in the physicians graduating from the programme. thus, accreditation is seen to safeguard the rights of the public on the one hand, and the interests of residents on the other. furthermore, it creates an environment conducive to research and optimal professional practice, as well as creating opportunities to integrate clinical practice, education and research. the concept of the ‘discovery-care continuum’5 is therefore also encouraged by accreditation. moreover, it is a positive driver of market forces, as accredited programmes attract better residents than non-accredited programmes, and the jobmarket seeks graduates of accredited programmes; hence, the need for accreditation becomes clearer. the question is, which system should be adopted by oman and other countries in the region, or by countries with health systems like oman? is there a choice, and what are the options? accreditation of graduate medical education started in the usa in the 1940s for individual programmes such as surgery. it gradually became popular and, nearly 40 years later, the acgme9 was established in the 1970s. more recently, the acgme piloted the international provision of accreditation, to programmes outside the usa and thus acgme-i1 was created in 2009, almost a further 40 years later. in canada, the royal college of physicians and surgeons of canada, since its inception in 1929, has accredited only the canadian medical residency training programmes.7 in 2009, the royal college canada international (rcci)10 was established; however, it still does not accredit residency programmes outside canada. we wonder what the delay is. why not share what they have with developing countries, where there is a dire need for an accreditation system? the gmc monitors the quality of training, etc., of the residency programmes in the uk deaneries but not international programmes as yet.8 the australian medical council11 accredits only the residency-training programmes in australia and accreditation of graduate medical education programmes one size fits all—or does it? 200 | squ medical journal, may 2013, volume 13, issue 2 new zealand. a great majority of specialists and healthcare managers in countries like oman have been trained in canada, the uk, australia or new zealand, and hence the healthcare systems in some developing countries have much in common with those systems. the ability to choose from the validated accrediting programmes of those systems could be immensely helpful. the concept of training doctors in specialties and subspecialties using ‘structured training’ and ‘measurable outcomes’ is relatively recent in many countries, and hence full acceptance by all trainers and trainees might be slow. accreditation is a good stimulus for acceptance of change and unification amongst staff and students. the basic mandate of acgme-i1 is to provide a strategic overview and make recommendations of standards for international accreditation similar to the acgme standards, albeit modified by removing those standards required by us government policies, and after accommodating for regional differences in types of diseases, their prevalence and burden, etc. as a result, the requirements to comply with the standards are not less rigorous, but may be somewhat different. at the level of the educational programme, the standards seek to ensure an adequate number and quality of faculty and facilities, as well as a structured curriculum and learner-centered environment providing a humanistic experience and patientcentered care which takes into account local culture and patient safety. at the institutional level, however, the standards seek to develop a residentcentered learning environment, prioritising education, but balancing this with the provision of service. these demanding standards of acgme-i1 are clearly beneficial for graduate medical training, but can all healthcare systems comply with them? or should they? is that what we want—for all international graduate medical education to be almost identical in all countries? clearly, what is needed is a choice to suit the varying needs and requirements, and that could be provided by competing accrediting bodies. one size may not fit all—and it is not necessary that it should do so! the strength of the acgme/acgme-i1,9 is that the system has been running in the usa for several years, is validated, and is well-received by the stakeholders. importantly, the programmes need to comply with competencyand proficiencybased structured training programme even though the length of training experience or the number of procedures performed during training do not equate to proficiency. rather, each resident’s competency needs to be assessed using multiple tools and various methods of assessment. the challenge outside the usa is to align the training programmes with the accreditation standards, especially where the programmes are still heavily dependent on apprenticeship and when change is not always easy or readily accepted. there needs to be a change in culture in the medical field in many developing countries. in oman, we have adopted a structured training system in the residency programmes, even before inviting an accreditation agency, and the oman medical specialty board (omsb)12 has also recently adopted competency-based training. thus, it is reasonably easy to comply with the acgme-i accreditation standards for possible accreditation, and for now the acgme-i may be an appropriate choice. however, specialist training is provided in six different hospitals across the capital, and these places have strong, long-standing institutional cultures, especially the priority of the provision of clinical services. it is the responsibility of the trainees and the trainers to meet the requirements for certification, with respect to achieving the required competencies, but also to keep in mind the philosophy of the institution, and the constraints of resources. accreditation involves acceptance of change and readiness to compromise! whereas it may be possible to make the graduate programmes compliant with the requirements of acgme-i, it would be difficult to change the institutional culture over a short period. the change needs to be accepted and embraced not only by residents, but also by the faculty and the leadership, i.e. the affiliated institutions, and that amounts to a paradigm shift. we believe that one size may not fit all. while accreditation is the need of the hour, it is imperative to assess the culture of the individual institution, and its state of readiness for change. the alternative would be to create an accreditation programme which is conducive and aligned to the prevalent culture. such a development, however, would involve several built-in stages with multiple checks and balances, in order to comply with the concept that an ideal accreditation system should be structured, valid, reliable and have measurable outcomes. the time is ripe for developing countries ikram a. burney and neela al-lamki editorial | 201 to have a choice of accreditation agencies. developed countries owe it to the world of medical education. references 1. accreditation council for graduate medical education-international. from: www.acgme-i.org accessed: mar 13. 2. flexner a. medical education in the united states and canada: a report to the carnegie foundation for the advancement of teaching. new york: carnegie foundation for the advancement of teaching, 1910. 3. tanira m. medical education is on the move once more. sultan qaboos university med j 2010; 10:310– 11. 4. cooke m, irby dm, sullivan w, ludmerer km. american medical education 100 years after the flexner report. n eng j med 2006; 355:1339–44. 5. dzau vj, ackerly dc, sutton-wallace p, merson mh, williams rs, krishnan kr, et al. the role of academic health science systems in the transformation of medicine. lancet 2010; 375:949–53. 6. world federation for medical education. basic medical education. wfme global standards for quality improvement. from: http://www.wfme.org accessed: mar 13. 7. royal college of physicians and surgeons of canada. from: www.royalcollege.ca/ accessed mar 13. 8. general medical council (uk). from: www.gmc-uk. org accessed: mar 13. 9. accreditation council for graduate medical education. from: www.acgme.org accessed: mar 13. 10. royal college canada international. from: http:// www.royalcollege.ca/portal/page/portal/rc/about/ international accessed: mar 13. 11. australian medical council. from: http://www.amc. org.au accessed: mar 13. 12. oman medical specialty board. from: www.omsb. org accessed: mar 13. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e146–147, epub. 21 jan 15 submitted 5 may 14 revisions req. 4 jun & 23 jul 14; revisions recd. 2 jul & 1 aug 14 accepted 7 aug 14 االعتالل العضلي الناجم عن صوديوم فالربويت يف طفل sodium valproate-induced myopathy in a child sir, an eight-year-old saudi male child presented to the department of paediatric neurology at king fahad military hospital, jeddah, saudi arabia, in may 2013. he was diagnosed with childhood onset epilepsy with absence seizures on the basis of clinical seizure semiology and classical electroencephalography findings. baseline haematological and biochemical investigations, including serum lactate and ammonia tests, performed prior to the administration of any medication proved to be normal. the patient was subsequently started on 250 mg of sodium valproate in two divided doses (20 mg/kg). as his response to the treatment was inadequate, the dose of the medication was gradually increased over the following few weeks to the maximum permissible dose of 500 mg twice daily (40 mg/kg/day). at this dose, the absence seizures were controlled. six months later, it was observed that the patient had slowly developed progressive weakness of the lower limbs. he found it difficult to rise from a sitting position, climb stairs, run or play games. there was no pain in the legs or any diurnal variation in weakness. there was no difficulty in using the upper limbs. since the symptoms were progressive, the child’s parents sought medical advice. a clinical examination at this time revealed predominant weakness of the proximal limb muscles, particularly in the lower rather than the upper limbs, with retained deep tendon reflexes and a normal sensory examination. there was no weakness of the neck, chest or abdominal muscles and no sensory involvement or calf muscle hypertrophy. he walked with exaggerated lumbar lordosis and had a waddling gait. the findings of this clinical examination were consistent with the diagnosis of a form of myopathy, predominantly proximal. routine investigations were normal, including tests for serum lactate, creatinine kinase and serum valproate levels. a nerve conduction study was normal, however needle electromyography (emg) in the lower limb muscles revealed action potentials of short duration and with a low amplitude which were consistent with the myopathic pattern. a muscle biopsy was planned but not performed as the parents did not give consent for the procedure. there was no history of preceding neurological illness and the family history was negative. additionally, the valproate therapy was determined to have been of sufficient duration. a diagnosis of valproate-induced myopathy was concluded from the available clinical and emg findings. further investigations revealed low serum carnitine levels at 13 micromoles/l (normal range: 25–54 micromoles/l). a diagnosis of secondary carnitine deficiency due to valproate was considered. the patient’s medication was changed to lamotrigine at a dose of 50 mg twice daily (5 mg/kg). oral carnitine was also prescribed at a dose of 500 mg four times daily (100 mg/kg/day). he showed good clinical response to the therapy; in three weeks, he had regained power in the skeletal muscles. furthermore, his gait improved considerably with limited waddling and no lordosis. a repeat emg was normal after six months, as were his serum carnitine levels. these factors were suggestive of transient secondary valproate-induced myopathy. the drug of choice for childhood absence seizures is ethosuximide; however, due to its potential haemato logical side-effects and lack of availability in many countries, sodium valproate has become an equivalent choice because of its efficacy and improved safety profile.1 many clinicians prefer sodium valproate as opposed to ethosuximide because of the use of the former in controlling myoclonic and generalised tonic-clonic seizures, although this may not be a cause of concern in childhood absence epilepsy.2 carnitine synthesis takes place in the liver and kidney from amino acids (lysine and methionine). it functions as a transporter of fatty acids from the mitochondria to the matrix for the purposes of lipid breakdown and generation of metabolic energy. prolonged valproate therapy can induce transient carnitine deficiency due to either renal loss of carnitine esters or inhibition of plasmalemmal carnitine uptake.3,4 although decreased carnitine levels may not induce major pathological changes in children, cardiac dysfunction, encephalopathy, hepatic toxicity and cerebral oedema have been reported in the literature as complications of long-term valproate therapy.5,6 shapira et al. described six patients who presented with hypotonia with low carnitine levels.7 muscle biopsy studies have also showed ultrastructural abnormalities in the muscles with lipid droplet accumulation by electron microscopy.7,8 letter to the editor riaz ahmed letter to editor | e147 beversdorf et al. illustrated several risk factors for the development of valproate-induced encephalopathy, including hyperammonaemia, metabolic acidosis and multiple neurological disabilities.9 patients of a younger age (less than two years old) and those who were non-ambulatory, underweight or on multiple anticonvulsants were also considered to be at higher risk.9 in addition, valproic acid was also considered to be the cause of myopathy and rhabdomyolysis among patients with lipid storage disorders and carnitine palmitoyltransferase deficiencies.10,11 the current patient presented here was not subject to any of the aforementioned risk factors and a muscle biopsy was not performed. in this case, low serum carnitine levels and the observed clinical recovery following supplementation of oral carnitine were enough to confirm the diagnosis of valproate-induced myopathy. this case clearly illustrates that secondary carnitine deficiency should be considered for children developing muscle weakness while on valproate therapy. riaz ahmed department of pediatric neurology, king fahad military hospital, jeddah, saudi arabia e-mail: nodisability@yahoo.com references 1. glauser ta, charin a, cnaan a, shinnar s, hirtz dg, dlugos d, et al.; childhood absence epilepsy study group. ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. new eng j med 2010; 362:790–9. doi: 10.1056/nejmoa0902014. 2. panayiotopoulos cp. absence epilepsies. in: engel jj, pedley ta, eds. epilepsy: a comprehensive textbook. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 1997. pp. 2327–46. 3. van wouwe jp. carnitine deficiency during valproic acid treatment. int j vitam nutr res 1995; 65:211–14. 4. zelnik n, fridkis i, gruener n. reduced carnitine and antiepileptic drugs: cause relationship or co-existence? acta paediatr 1995; 84:93–5. doi: 10.1111/j.1651-2227.1995.tb13494.x. 5. bratton sl, garden al, bohan tp, french jw, clarke wr. a child with valproic acid-associated carnitine deficiency and carnitineresponsive cardiac dysfunction. j child neurol 1992; 7:413–16. doi: 10.1177/088307389200700416. 6. triggs wj, gilmore rl, millington ds, cibula j, bunch ts, harman e. valproate-associated carnitine deficiency and malignant cerebral edema in the absence of hepatic failure. int j clin pharmacol ther 1997; 35:353–6. 7. shapira y, gutman a. muscle carnitine deficiency in patients using valproic acid. j pediatr 1991; 118:646–9. doi: 10.1016/s00223476(05)83396-7. 8. melegh b, trombitás k. valproate treatment induces lipid globule accumulation with ultrastructural accumulation of mitochondria in skeletal muscle. neuropediatrics 1998; 28:257–61. doi: 10.1055/s-2007-973710. 9. beversdorf d, allen c, nordgren r. valproate induced encephalopathy treated with carnitine in an adult. j neurol neurosurg psychiatry 1996; 61:211. 10. papadimitriou a, servidei s. late onset lipid storage myopathy due to multiple acyl coa dehydrogenase deficiency triggered by valproate. neuromuscul disord 1991; 1:247–52. doi: 10.1016/0960-8966(91)90097-c. 11. kottlors m, jaksch m, ketelsen up, weiner s, glocker fx, lücking ch. valproic acid triggers acute rhabdomyolysis in a patient with carnitine palmitoyltransferase type ii deficiency. neuromuscul disord 2001; 11:757–9. doi: 10.1016/s0960-8966(01)00228-0. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century sultan qaboos university med j, november 2012, vol. 12, iss. 4, pp. 411-421, epub. 20th nov 12 submitted 26th nov 11 revision req. 31st jan 12, revision recd. 8th feb 12 accepted 12th feb 12 interstitial cells of cajal (icc) are specialised mesenchymal cells that were first described in the tunica muscularis of the gastrointestinal tract (git) by ramon y cajal in the 19th century.1 they form networks in the muscular layers of the alimentary tract, with their location in the git being organ and species specific.2 icc originate slow wave intestinal pacemaker activity and mediate input from the enteric nervous system.1–3 studies on these cells have lead to the discovery of c-kit expression by icc, a protein that is as important as insulin and insulinlike growth factor-1 for icc development and maintenance.4–9 similar to other cells in the body, icc are affected by various insults to the git such as inflammation, obstruction, diabetes mellitus (dm), and ageing.3,7,10,11 this can cause a decrease in their number and/or disruption in structural or functional abnormalities which ultimately affect gastrointestinal (gi) motility.6,7 on the other hand, harbouring a c-kit mutation causes icc to grow into hyperplastic sheets and even transform into malignant gastrointestinal stromal tumours (gist).12 however, icc have the ability to recover and repopulate after removal of injury.3,10,13,14 this review will discuss icc development; the effect of dm, diabetic gastropathy, and ageing on icc as examples of an icc injury; the possible mechanisms 1department of pathology & molecular medicine and 2farncombe family digestive health research institute, mcmaster university, hamilton, ontario, canada *corresponding author e-mail: d.alsaji@yahoo.co.uk خاليا كاجال اخلاللية علم األمراض واإلصابات واإلصالح �صحى ال�صاجي، يان هيوزنكا امللخ�ص: خاليا كاجال اخلاللية من كاجال هي خاليا متخصصة تقع داخل عضالت اجلهاز اهلضمي، وعلى الرغم من أهنا تشكل %5 فقط من اخلاليا يف عضالت اجلهاز اهلضمي، اال أّن لديها دور حاسم يف تنظيم وظيفة العضالت امللساء وحركة اجلهاز اهلضمي وذلك بالتنسيق مع اجلهاز العصيب املعوي. )c-kit( هو عبارة عن بروتني سكري يعرب الغشاء وهو يلعب دورا حامسا يف تطور خاليا كاجال اخلاللية ونضوجها. الظروف اضطراب أو غياب وارتبط اخلاللية. خاليا كاجال ووظيفة شبكة على سلبا تؤثر املختلفة املرضية احلاالت وكذلك الشيخوخة، مثل الفسيولوجية شبكات خاليا كاجال اخلاللية باضطرابات يف حركة اجلهاز اهلضمي. هذا االستعراض يسلط الضوء على آلية إصالح خاليا كاجال اخلاللية من خمتلف أنواع اإلصابات، واليت تستلزم فهم تطورها والعوامل املؤثرة فيه. ويناقش حتول خاليا كاجال اخلاللية إىل أورام خبيثة )أورام انسجة اجلهاز اهلضمي(، واملسامهة احملتملة للمقاومة العالجية. مفتاح الكلمات: خاليا كاجال اخلاللية، اجلهاز اله�صمي، داء ال�صكر، ال�صيخوخة، اأورام اجلهاز اله�صمي. abstract: interstitial cells of cajal (icc) are specialised cells located within the musculature of the gastrointestinal tract (git). although they form only 5% of the cells in the musculature of the git, they play a critical role in regulating smooth muscle function and git motility in coordination with the enteric nervous system. c-kit is a transmembrane glycoprotein that plays a critical role in icc development and maturation. physiological conditions such as ageing, as well as pathological conditions that have different disease processes, negatively affect icc networks and function. absent or disordered icc networks can be associated with disorders in git motility. this review highlights the mechanism of icc recovery from various types of injury which entails understanding the development of icc and the factors affecting it. icc transformation into malignant tumours (gastrointestinal stromal tumours) and their potential as contributors to therapeutic resistance is also discussed. keywords: cajal interstitial cells; gastrointestinal tract; diabetes mellitus; c-kit; ageing; gastrointestinal stromal tumors. review interstitial cells of cajal pathology, injury and repair *dhuha al-sajee1 and jan d. huizinga2 interstitial cells of cajal pathology, injury and repair 412 | squ medical journal, november 2012, volume 12, issue 4 u lt r a s t r u c t u r e according to electron microscopy results, all icc classes probably share the following features: the presence of numerous mitochondria, abundant intermediate filaments, the presence of surface caveolae, and partially (variably) developed basal lamina. icc also have well-developed smooth and rough endoplasmic reticulum, and gap junctions connecting them to smooth muscles and other adjacent icc.19 the lack of thick myofilaments is an important differentiating point from smooth muscle cells. icc are also thought to be non-contractile. another cell that may have similar ultrastructural features to icc is the fibroblast; however, fibroblasts do not show caveolae, and rarely have smooth cisternae, intermediate filaments, or a partial basal lamina.2,18,19 i c c m a r k e r s icc were identified by their morphology until the discovery of c-kit, which is considered its defining marker.1,3–6 c-kit is a tyrosine kinase that is a 145 kd transmembrane glycoprotein.20 it is a member of the type iii tyrosine kinase receptors.20,21 c-kit is related to platelet derived growth factor (pdgf), which belongs to the same family of tyrosine kinases. c-kit acts as a receptor for stem cell factor (scf), which serves as its ligand. in its normal state, c-kit is present as a monomer in the cell membrane. upon binding to its scf ligand, a dimerisation of the protein takes place thus activating itself through autophosphorylation of the tyrosine residues. this will activate intracellular signaling pathways that are important for normal cellular growth and development.20 a negative regulatory effect is mediated by sh2 domain-containing protein tyrosine phosphatase that inhibits the excessive signalling and cellular transformation, as occurs in malignancy.21,22 thus, certain mutations in c-kit can lead to oncogenic transformation and scfindependent activation causing kinase activity and cancer development, or gist.12,20,21 the other cell that expresses c-kit in the git is the mast cell.11 this led to the need to search for other specific markers to detect icc. one recently discovered marker is the transmembrane protein 16a (tmem16a) which encodes anoctamin-1 (ano1), a calcium-activated chloride channel. antibodies against ano1 identified it as a selective biomarker for all classes of icc at all levels of the git in humans and animals, of recovery, and finally icc transformation into gist. icc classes and localisation in the git icc are found in the git, from the oesophagus to the internal anal sphincter.15 this distribution varies in different organs within the git and in different species.2 icc associated with the myenteric plexus (icc-mp), also called icc in the myenteric region (icc-my), or icc associated with auerbach’s plexus (icc-ap), icc-intramuscular, is an icc network within the circular muscle (cm) and longitudinal muscle (lm) layers. icc-submuscular plexus (icc-smp) indicates icc at the submucosal border of the cm layer in the colon. icc-deep muscular plexus (icc-dmp) is the presence of icc in the deep muscular plexus in the inner surface of the cm in the small intestine. icc-septa (iccsep) are found in the septa separating the cm bundles and are described in humans and larger animals.2,4,14,15 icc-sep are considered a part of the icc-im by some while others recognise them as a separate entity.2,4,14,15 in general, icc-mp are present at all levels of the git14,15 except in the oesophagus, where only icc-im are present.14–16 icc-im and icc-smp are described as existing in the stomach, while icc-mp, icc-im, and icc-dmp are present in the small intestine.2,10,15,17 icc-mp, icc-im and icc-smp are generally identified in the colon.2,10,15 stellate subserosal icc have been found outside the lm layer in the subserosa in mouse colons.18 characterisation of icc m o r p h o l o g y icc are variable in their morphology in accordance to their location and function.2,18,19 icc-im are spindle-shaped cells with bipolar processes that run parallel to the longitudinal axis of smooth muscle cells. icc-im and icc-smp show a resemblance to the smooth muscle cells, while icc-mp are more multipolar and have more cytoplasmic processes.10,18 this variation in shape has been explained by the effect of the surrounding microenvironment, such as the type of nerve supply and the relation to the smooth muscle cells, in addition to the type of food passing through that part of the git.2 dhuha al-sajee and jan d. huizinga review | 413 animals deficient in c-kit and kit-ligand (kl) have shown a marked reduction in the icc network despite the normal density of the associated enteric nerves.1,6,8,28–30 a neural crest origin was excluded by young b (1996). thus far, studies have provided evidence that icc originated from a common mesenchymal precursor cell instead of a neural crest-derived cell.1,6,8,28,29 development of icc t h e i m p o r ta n c e o f c-k i t a n d s t e m c e l l fa c t o r i n i c c d e v e l o p m e n t the stimulation of c-kit by kl or stem cell factor (scf) is an important step in the development of icc; hence, mice lacking c-kit (w/wv) or kit ligand (sl/sld) have disrupted icc networks.1,4,5,6,8 since the common progenitor of icc and smooth muscles express c-kit, it has been postulated that a subset of these precursors will respond to kl and differentiate into icc, while the rest of the precursor cells will develop into smooth muscle cells. sources of kl in the gut are either neuronal or non-neuronal.6,11,30 the non-neuronal sources include smooth muscle cells, mast cells, and fibroblasts, while the neuronal sources are provided by the enteric neurons as well as extrinsic nerves of the gut.6,11 scf is found in soluble and membrane bound forms (sol-scf and mb-scf, respectively). the sol-scf is needed for the maintenance of icc progenitors.25 mb-scf is required later on for icc progenitors to be fully differentiated into mature icc.25 whether neuronal membrane-bound kl has a role in icc maintenance has been precluded by the ability of icc to develop in cultures of a murine bowel that is devoid of extrinsic nerves, schwann cells, or neurons.6 however, it has been suggested that neuronal kl is important for the development of icc-mp, while non-neuronal kl, which is provided by the smooth muscle cells, is required for the development of icc-im.6 this could explain the loss of icc-mp from the aganglionic segment of sl/sl deficient mice. another observation is that in crohn’s disease the diffuse injury to the nerves is associated with a remarkable loss of icc-mp, more so than icc-im.11 although this contradicts previously stated evidence in the literature, and that there is the possibility that icc loss in crohn’s can as well as primates.23 ano1 is more specific for icc and, unlike c-kit it does not stain mast cells.16,23 a recent study found that ano1 plays an important role in pacemaking activity by affecting the conductance of icc and slow wave generation; however, it was found that ano1 played no role in icc development.17,23 another much less specific marker of icc is cd34, an 11 kd transmembrane glycoprotein. cd34 is a marker for endothelial cells and haematopoietic cells, as well as fibroblasts. its expression within the icc has been debated.24–26 a study by robinson et al. using a single-cell reverse transcription and polymerase chain reaction (rt-pcr) on cultured murine intestinal cells and immunohistochemistry on the human small intestine could identify a small subset of icc expressing c-kit and cd34.24 cd34 is also a marker for icc progenitor cells, which have been found to lose their cd34 expression and acquire more of c-kit expression as they mature into icc.25 cd34’s role in icc function is of little significance.25 cd44 is another marker for icc. it is also a transmembrane glycoprotein that is expressed by mesenchymal stem cells and tumours. it has been found to be expressed in icc progenitor cells, and in immature as well as mature icc. the role of cd44 in icc development has been studied but does not show any significant impact.12,25,27 other markers include vimentin gamma enteric actin, alpha-type platelet-derived growth factor receptor (pdgfra), and others.10,24,28 embryological origin of icc when icc were first discovered by cajal, he thought that they were nerve cells.6 later, it was believed that icc were specialised smooth muscle cells based on previously mentioned ultrastructural features between them.2 with the discovery of c-kit expression in these cells, a neural crest origin for the icc was suggested.6 however, ultrastructural features such as basal laminae, scarcity of rough endoplasmic reticulum, the presence of gap junction contacts between icc and smooth muscle, and close contacts with the nerve endings made a neural origin less likely.6,28 in addition, studies on the embryological development of icc in the murine small intestine and colon have revealed that interstitial cells of cajal pathology, injury and repair 414 | squ medical journal, november 2012, volume 12, issue 4 insulin-like growth factor-1 (igf-1) where they acquired more expression of kit positivity with electrophysiological detection of low-amplitude slow waves. thus, another phenotype expressing more c-kit than progenitor cells, in addition to expressing cd34+ cd44+ ins+ ingfr+, was defined as committed progenitor cells in this study. interestingly, these cells were able to differentiate into a mature icc phenotype in terms of acquiring more intense expression of c-kit, and losing cd34, insr and igfr expressions in response to mb-scf produced under the control of insulin and igf-1. the cells grew in networks similar to icc networks, and normal slow waves could be detected at that time. it is interesting to compare this recent study with a study by faussone-pellegrini et al. who studied the morphogenesis of developing icc in different areas of mice small intestines. they described the presence of icc-blasts at birth. these icc-blasts had an oval shape with small processes. they were present in the myenteric plexus and in between the cm and lm layers. these cells acquired the ultrastructure of mature icc by day 17. however, electrical slow wave activity developed before day 17.31 this suggests that the functional maturity of icc preceded their morphological development. interestingly, these observations were similar to the observations of lornicz et al. in 2008.25 a further study by bardsley et al. considered kitlowcd34+cd44+insrigfr+ cells to be icc stem cells (icc-sc). this is because the derived icc progenitor cell lines from two mouse strains, the transgenic immortomice and the wild type c57bl/6j mice, had the ability to preserve their phenotype and develop into mature icc. in addition, the ability of these cells to differentiate in vitro as well as in vivo into mature icc could be due to endogenous production of igf-1 and scf acting in an autocrine loop manner.12 although kit signalling is important for the proliferation of icc stem cells, c-kit was not important to their survival since in mice hypomorphic for kit and kl, icc-sc were not reduced compared to an obvious reduction in mature icc networks.12 neither antibodies to kit, nor scf, nor tyrosine kinase inhibitors could inhibit the proliferation of these cells, while mature icc were greatly affected.12 be due to the effect of inflammation, it is important to investigate further the possible role of neuronally derived kl in icc maintenance.6,11 the importance of c-kit in the development of icc has been studied using c-kit deficient mice, the so-called w/wv mutant mice. at five days postnatal, these mice showed normal c-kit positive icc networks; however, the network density starts to decrease thereafter, suggesting that c-kit is important only in the later postnatal development of icc in the small intestine, and that determination of the icc lineage in embryos does not require c-kit.1,6 interestingly, in these mice the only classes of icc which were lost were icc-mp in the small intestine, and icc-im in the stomach, lower oesophageal sphincter, and pyloric sphincter. there was a mixed loss in the colon. in the small intestine, loss of icc-mp correlated with the loss of electrical slow waves, which indicates that these classes are more important for the characteristic pacemaking activity than other classes of icc that were preserved. thus, icc may differ in their sensitivity to the reduced levels of c-kit, and icc dependence on c-kit is age-related.6,25,28 i c c p r e c u r s o r s a n d i c c s t e m c e l l s recently, lornicz et al. examined a postnatal murine stomach (aged 7–14 days) for the presence of icc precursors.25 using flow cytometry and immunohistochemistry, they could identify a small subset of cells that expressed a very small amount of c-kit along with cd44 and cd34. these cells were oval to round in shape and had few or no cytoplasmic processes. they were detected as small clusters in the myenteric region, in between the muscle fibres as well as in the subserosa outside the lm. culturing these cells in unsupplemented serum-free basal media resulted in a complete loss of icc, as well as their presumed progenitors. however, small networks of c-kit-negative cd44+ cells showing a similar morphology to icc were recognised. these were described as senescent icc only in this study.25 thus, a well-defined phenotype for an icc progenitor was concluded as follows: kitlowcd34+cd44 insulin receptor and insulinlike growth factor receptor (insrigfr+) positive cells. the mature phenotype expressed only kit+cd44+ and was negative for cd34. these progenitor cells may have been stimulated directly by sol-scf and dhuha al-sajee and jan d. huizinga review | 415 participate in alimentary tract motility.33 similar icc loss has been observed in the small intestines and the colons of diabetic animals.34,35 w h y a r e i c c l o s t i n d i a b e t e s? loss of icc results from the imbalance between factors that injure, and factors that regenerate and maintain icc.3,10 the effects of both factors on icc were investigated by hovarth et al.7 in this study, icc showed better tolerance in terms of maintaining their densities to hyperglycemia than normoglycemia in the absence of insulin or igf-1 supplements. thus, absence or relative deficiency of insulin may be the main factor contributing to icc loss in dm, and leading to abnormal gastric motility and gastroparesis. since icc do not have insulin receptors, this points to the indirect effect of insulin on icc.7 smooth muscle atrophy and enteric nerve loss are other factors contributing to icc loss in dm. scf, which is produced by the smooth muscle and enteric nerves, mediates the effect of insulin and igf-1 on icc.7,9,14 thus, when the smooth muscle atrophies, the resulting decrease in the scf results in a loss of icc. in dm there is a loss of neuronal nitric oxide synthase-(nnos) derived nitric oxide that maintains icc proliferation.32,36 as icc can tolerate hyperglycemia, this suggests an endogenous ability to remove reactive oxygen species (ros). alternatively, this might be due to the presence of other factors.7 carbon monoxide produced by the stress-induced enzyme heme oxygenase-1(ho-1) is a cytoprotective for icc. ho-1 is upregulated mainly in macrophages residing in the muscle layer in close contact with icc and enteric nerves. ho-1 increases the expression of c-kit and nnos and reverses the delay in gastric emptying.37 i c c i n i d i o pat h i c g a s t r o pat h y studies comparing the cellular and ultrastructural changes in diabetic and idiopathic gastropathy found that at the light microscopy level, there were no differentiating features between the two except that in idiopathic gastropathy the damage to the icc was more diffuse in nature.38,39 in general, both conditions share the following features: loss of icc density, especially in icc-mp; an inflammatory infiltrate mainly of cd45+ cells in the myenteric plexus and macrophages; loss of nnos expression, which was more evident in idiopathic gastropathy than in diabetic gastropathy; ultrastructural response of icc to injury icc are affected in several diseases that directly or indirectly involve the bowel, such as inflammation, obstruction, and dm. in these conditions, there is either a disruption in ultrastructure only, which is an early event, or a decrease in icc networks leading, in severe cases, to loss of function. in the following sections, icc in the diseases such as dm, idiopathic gastropathy, and ageing will be discussed. i c c i n d i a b e t e s m e l l i t u s one of the most important complications of dm is gastrointestinal dysfunction, in particular diabetic gastropathy. it occurs in 30–50% of individuals with type i or ii dm.7,9,14 since gi motility requires the interaction between enteric nerves, smooth muscles, and icc, gi dysfunction generally involves changes in all of these factors.14 many dm studies which use animal models as well as human samples are found in the literature.3,7,9,14 ordög et al.9 and wang et al.32 studied icc densities in two types of diabetic animals: non-obese diabetic (nod) mice and streptozotocin-(stz) induced diabetic rats respectively. in both studies, icc loss was patchy and not uniform throughout the stomach. ordög demonstrated that icc density loss started midcorpus and worsened towards the antrum, mainly involving icc-mp. although slow waves could still be detected in these areas, they were abnormal in amplitude as well as in frequency, and these slow waves could not propagate throughout the stomach. the remaining icc displayed changes in ultrastructure such as increased cell processes and loss of contact with adjacent enteric ganglia. the fundus did not show loss of icc-im but there was excess extracellular space separating the icc from the adjacent enteric nerves. in contrast, wang et al. showed that the loss of icc density in the stomach of stz-diabetic rats mainly involved icc-im and icc-sm. also notable was an associated ultrastructural change in nerves and the loss of enteric nerves.32 an interesting finding was the presence of fibroblast-like cells in the iccim surrounding the enteric ganglia. they were described by the authors as representing immature or recovering icc which might be involved in tissue healing and repair. other investigators have considered these fibroblast-like cells to be a distinct subset of cells in the alimentary tract that might interstitial cells of cajal pathology, injury and repair 416 | squ medical journal, november 2012, volume 12, issue 4 to icc were mentioned in this study. collectively, one may think of icc as dynamic cells that are adaptable to changes in their microenvironment, thus acquiring a more protective phenotype upon injury so that they can differentiate back to the usual icc when the insult is removed. r o l e o f m a s t c e l l s i n i c c i n j u r y a n d r e pa i r one of the cells that may play a role in icc repair is the mast cell. mast cells have been identified in the inflammatory content of gastrointestinal diseases such as crohn’s disease, ulcerative colitis, and achalasia.11,16 mast cells also express c-kit and in non-pathological conditions they are present in the mucosa and submucosa but rarely within the musculature.16 in conditions such as crohn’s disease and achalasia, mast cells were found to be more concentrated in the gut musculature. these immunologically activated cells closely adhere to the injured icc. selective degranulation was observed to be towards icc. these granules, which contain various cytokines, have been described in neighbouring cells including icc, either through fusion of the cell membranes or transgranulation.11,16 mast cells, which have been identified as an additional source of membrane-bound and soluble scf, are a major source of fibroblast growth factor, and fibroblasts are another source of membrane bound scf.11,30 all these data are conclusive of the importance of mast cells in providing factors for survival and maintenance of icc in disease states. r o l e o f m a c r o p h a g e s i n i n j u r y a n d r e pa i r macrophages establish close contacts with icc in normal states as resident macrophages, and during disease states as activated and phagocytic macrophages. this is true for macrophages in the small intestine at the level of the myenteric region, deep muscular plexus, and serosa, but not in mice colons. in human colons, macrophages were also found in close contact to icc. resident tissue macrophages provide cytoprotection for icc through the ho-1 pathway, a mechanism presumed to protect icc during hyperglycemia.37 in disease states, such as in infections like trichinella spiralis and in response to injury such as surgery, the macrophages’ influence on icc depends on the activation pathway. for example, changes in icc such as swollen mitochondria and intracytoplasmic vacuoles; thickened basal lamina; loss of contact with the nerves, smooth muscle cells and with other icc, and increased spacing of the smooth muscle by increased fibrous tissue. nerves also showed more diffuse ultrastructural changes in idiopathic gastroparesis, such as increased filaments and empty nerve endings.38 as the most constant feature in these two disorders, icc loss is most likely responsible for the disturbed gastric motility in both diabetic and idiopathic gastropathy and in other conditions that present as gi dysmotility.3,7,9,14,34, 35–39 possible mechanisms for icc recovery and repair i c c h av e t h e a b i l i t y t o r e c o v e r f o l l o w i n g i n j u r y studies have found that icc have the ability to re-differentiate into other cell types upon injury, and that those redifferentiated cells retain their kit-positive phenotype.10,13,28 in one study where c-kit was blocked, icc-mp dramatically decreased in number and the ones remaining showed ultrastructural features similar to smooth muscle cells in terms of developing myofilaments, and in expressing desmin (a smooth muscle marker) and c-kit.13 in another study, fibroblast-like cells or fibroblast-like icc cells were found in the area of icc-im and were associated with the enteric nerves. these cells could represent recovering or immature icc that would be involved in repair and recovery of icc. these cells were also found in the areas of icc following injury to the gut, as in obstruction or inflammation, and their number decreased following recovery of icc and removal of the insult.40,41 in contrast, a study by horiguchi et al. comparing the ultrastructure of the small intestine in wild type and c-kit deficient mice detected fibroblast-like cells in the small intestine of both strains in equal distributions. these cells showed a similar ultrastructure in all regions of the small intestine which contrasts with the diversity expressed by icc.33 the fibroblast-like cells described in this study had small gap junctions with smooth muscle cells as well as nerves. unfortunately, no immunohistochemical studies to identify the immunophenotype of these cells and their relation dhuha al-sajee and jan d. huizinga review | 417 effect of ageing on icc networks had been studied recently on human and animal samples.36,46 to date it appears that only two studies have focused on the effect of ageing on icc in animal models as well as in human samples. the first study included human stomach and colon samples surgically resected for non-obstructive colon cancer in age ranges of 25– 70 and 36– 92 years respectively. although patients did not have any dysmotility problems, there was a significant decrease in icc network density and icc cell bodies in stomach samples in relation to age. the colon showed similar results. the decrease in icc numbers was found to be approximately 13% per 10 years of life after the age of 25 years in the stomach and 12% per 10 years in the colon.36 the icc cell volume was also decreased. unfortunately, this study did not demonstrate the icc senescent phenotype (kit-cd44+)25 that was described in previous studies although these human samples could represent a good model of senescent icc. the second study used progeric mice that are deficient in klotho protein, which suppresses the ageing process.46 in this study, it was demonstrated that icc networks are decreased in the tunica muscularis in the corpus and antrum. icc-sc were also decreased significantly. in contrast, myenteric neurons and smooth muscle cells showed no changes.46 these prematurely aged mice had additional factors that affected icc development and maintenance such as low insulin and igf-1, low mband sol-scf and significantly higher ros.46 t h e m e c h a n i s m o f l o s s o f i c c d u r i n g a g e i n g the inability of the senescent icc-sc to selfrenew is one of the causes of icc-loss in ageing.46 in a t. spiralis infection, macrophages which are alternatively activated through il4/il-13 produce fibrogenic factors such as fibronectin, igf-1, and platelet derived growth factor (pdgf), which all provide signals for tissue proliferation and repair. fibroblasts proliferated in response to macrophage fibrogenic factors provide a source of igf-1 as well. taken together, these factors help to repair injured icc.42,43 thus the close contact between activated macrophages and icc would eventually affect icc both when pro-inflammatory or antiinflammatory cytokines and growth factors are produced by macrophages in response to infection, inflammation, and surgical manipulation. i c c p r o g e n i t o r c e l l s another source for replenishing icc in disease states is the local reserve of icc progenitor or stem cells.25 these icc progenitor/stem cells (icc-sc) differ from mature icc in having low levels of c-kit expression and receptors for insulin and igf-1; hence, they can be directly activated by these factors and do not need mb-scf for survival.12,25 they can also be stimulated by sol-scf unlike mature icc. interestingly, these cells can cause tumours such as gist when the control mechanisms are lost; they can also lose their ability for self-renewal during ageing.36,44,45 effect of ageing on icc ageing associated disturbance in gastrointestinal function has been attributed to neurodegenerative changes. however, with the knowledge that icc play a fundamental role in gastrointestinal motility, the figure 1: a small gastrointestinal stromal tumour (gist) from the subserosal surface, dissected from the first part of the duodenum. figure 2: a stomach, opened to show a large gastrointestinal stromal tumour (gist) protruding into the gastric lumen. interstitial cells of cajal pathology, injury and repair 418 | squ medical journal, november 2012, volume 12, issue 4 in the oncogenesis of gist further linked these tumours to icc.48–50 tumours that do not express c-kit were found to express pdgfra.55 pdgfra tumours are usually composed of epithelioid cells and they are gastric in location. of pdgfra mutant tumours, 30–40% occur in c-kit negative gist, which suggests that a mutation in pdgfra can substitute for c-kit mutation in the development of gist.55 treatment of these tumours includes surgery followed by the administration of a tyrosine kinase inhibitor such as imantinib. in a percentage of c-kit negative gists, imantinib can still be used to target the pdgfra mutation.53,55 however, a subset of c-kit positive tumours does not respond to imantinib. a recent study found that icc-sc could be the source of resistance in these tumours.56 in imantinib treatment, antibodies against kit and scf could not prevent the proliferation of icc-sc while at the same time inhibiting mature icc.12,25 this resistance is due to a low expression of c-kit. a recently published abstract by asuzu et al. showed that there is an epigenetic control leading to low kit expression in icc-sc and thus resistance to treatment in gist. this control is mediated by the polycomb group (pcg) of proteins that control gene expression and differentiation of stem cells and, at the same time, repress kit through methylation. thus, sensitivity to imantinib can be achieved by reversal of this methylation.56 conclusion icc are unique cells that are heterogeneous in their distribution, morphology, structure, and function. several factors affect icc development, its response a recent study by asuzu et al. showed that the icc-sc actually become senile.44 the wnt signalling pathway is important for sc renewal and regeneration.48 it has been found that elevated wnt signalling, measured by beta-catenin levels, can lead to hyperproliferation of icc-sc and eventually to their senescence. another probable mechanism for icc loss in ageing is the increase in oxidative stress or an increased apoptosis combined with the inability of icc-sc to replenish the injured or lost icc.36,49 t r a n s f o r m at i o n o f i c c gist are common mesenchymal tumours in the git, accounting for 1% of all gi neoplasms. the most common site of these tumours is the stomach (60%), compared to 30% in the small intestine and 10% elsewhere.48 they can occur in other parts of the abdomen and can be small and asymptomatic [figure 1], or large and produce symptoms ranging from abdominal pain to complete obstruction of the viscus [figure 2]. they also undergo malignant transformation. histologically, these tumours are quite variable and this creates a problem for pathologists in providing accurate diagnoses.51 the tumour cells can be spindle [figure 3] or epithelioid [figure 4] in shape, or a mixture of both.50–52 with the introduction of immune markers in the diagnosis of these tumours, it was found that they express c-kit, cd34, and cd44, as well as ano1 discovered on gist (dog) 1.1,1.3 and pdgfr.24,50–55 almost all of these markers present with icc; thus, icc is implicated in the development of these tumours. the finding that a c-kit mutation is the most important pathway figure 3: sections of gastrointestinal stromal tumour (gist) mainly composed of spindle cells. haematoxylin and eosin stain (x 200). figure 4: microscopic view of gastrointestinal stromal tumour (gist) showing epitheloid cell components. haematoxylin and eosin stain (x 200). dhuha al-sajee and jan d. huizinga review | 419 epperson a, shen l, et al. development of interstitial cells of cajal and pacemaking in mice lacking enteric nerves. gastroenterology 1999; 117:584–94. 9. ordög t, takayama i, cheung wk, ward sm, sanders km. remodeling of networks of interstitial cells of cajal in a murine model of diabetic gastroparesis. diabetes 2000; 49:1731–9. 10. huizinga jd, zarate n, farrugia g. physiology, injury, and recovery of interstitial cells of cajal: basic and clinical science. gastroenterology 2009; 137:1548– 56. 11. wang xy, zarate n, soderholm jd, bourgeois jm, liu lw, huizinga jd. ultrastructural injury to interstitial cells of cajal and communication with mast cells in crohn's disease. neurogastroenterol motil 2007; 19:349–64. 12. bardsley mr, horváth vj, asuzu dt, lorincz a, redelman d, hayashi y, et al. kitlow stem cells cause resistance to kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors. gastroenterology 2010; 139:942–52. 13. torihashi s, nishi k, tokutomi y, nishi t, ward s, sanders km. blockade of kit signaling induces transdifferentiation of interstitial cells of cajal to a smooth muscle phenotype. gastroenterology 1999; 117:140–8. 14. kashyap p, farrugia g. diabetic gastroparesis: what we have learned and had to unlearn in the past five years. gut 2010; 59:1716–26. 15. hagger r, gharaie s, finlayson c, kumar d. distribution of the interstitial cells of cajal in the human anorectum. j auton nerv syst 1998; 73:75–9. 16. zarate n, wang xy, tougas g, anvari m, birch d, mearin f, et al. intramuscular interstitial cells of cajal associated with mast cells survive nitrergic nerves in achalasia. neurogastroenterol motil 2006; 18:556–68. 17. sanders km, zhu mh, britton fc, koh sd, ward sm. anoctamins and gastrointestinal smooth muscle excitability. exp physiol 2012; 97:200–6. 18. komuro t. structure and organization of interstitial cells of cajal in the gastrointestinal tract. j physiol 2006; 576:653–8. 19. komuro t, seki k, horiguchi k. ultrastructural characterization of the interstitial cells of cajal. arch histol cytol 1999; 62:295–316. 20. yuzawa s, opatowsky y, zhang z, mandiyan v, lax i, schlessinger j. structural basis for activation of the receptor tyrosine kinase kit by stem cell factor. cell 2007; 130:323–4. 21. liu h, chen x, focia pj, he x. structural basis for stem cell factor-kit signaling and activation of class iii receptor tyrosine kinases. embo j 2007; 26:891– 901. 22. you m, yu dh, feng gs. she-2 tyroisne phosphatase functions as a negative regulator of the interferonto injury as well as its repair and healing. icc loss or reduction in density seems to be a constant factor in different pathological conditions, and in physiological conditions such as ageing. however, a reduced icc network is not always accompanied by gastrointestinal dysmotility and the number of icc that need be lost in order to produce functional abnormalities remains to be proven. repopulation of the injured icc is proposed to occur from local reserves represented by icc-sc or progenitor cells. whether the fibroblast-like cells that appear at icc locations after injury are actually immature icc that participate in replenishment of reduced icc population, or whether they are a distinct cell population, would be an interesting research subject. although icc-sc serve in maintaining icc networks and, hence, git function, they starts to lose this ability during ageing, and their uncontrolled proliferation causes gi tumours that are treatment-resistant. references 1 kluppel mj, huizinga jd, malysz j, bernstein a. developmental origin and kit-dependent development of the interstitial cells of cajal in the mammalian small intestine. devel dynamics 1998; 211:60–71. 2. komuro t. comparative morphology of interstitial cells of cajal: ultrastructural characterization. microsc res tech 1999; 47:267–85. 3. ordög t. interstitial cells of cajal in diabetic gastroenteropathy. neurogastroenterol motil 2008; 20:8–18. 4. ward sm, burns aj, torihashi s, sanders km. mutation of the protooncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. j physiol (lond) 1994; 480:91–7. 5. huizinga jd, thuneberg l, kluppel m, malysz j, mikkelsen hb, bernstein a. w/kit gene required for interstitial cells of cajal and for intestinal pacemaker activity. nature 1995; 373:347–9. 6. wu jj, rothman tp, gershon md. development of the interstitial cells of cajal: origin, kit dependence and neuronal and nonneuronal sources of kit ligand. j neurosci res 2000; 59:384–401. 7. horvath vj, vittal h, ordög t. reduced insulin and igf-i signaling, not hyperglycemia, underlies the diabetes-associated depletion of interstitial cells of cajal in the murine stomach. diabetes 2005; 54:1528–33. 8. ward sm, ordög t, bayguinov jr, horowitz b, interstitial cells of cajal pathology, injury and repair 420 | squ medical journal, november 2012, volume 12, issue 4 mice. am j physiol gastrointest liver physiol 2010; 298:g241–7. 36. gomez-pinilla pj, gibbons sj, sarr mg, kendrick ml, shen kr, cima rr, et al. changes in interstitial cells of cajal with age in the human stomach and colon. neurogastroenterol motil 2011; 23:36–44. 37. choi km, gibbons sj, nguyen tv, stoltz gj, lurken ms, ordög t, et al. heme oxygenase-1 protects interstitial cells of cajal from oxidative stress and reverses diabetic gastroparesis. gastroenterology 2008; 135:2055–64. 38. grover m, farrugia g, lurken ms, bernard ce, faussone-pellegrini ms, smyrk tc, et al. niddk gastroparesis clinical research consortium: cellular changes in diabetic and idiopathic gastroparesis. gastroenterology 2011; 140:1575–85. 39. faussone-pellegrini ms, grover m, pasricha p, bernard c, lurken m, smyrk t, parkman h, et al. ultrastructural differences between diabetic and idiopathic gastroparesis: the niddk gastroparesis clinical research consortium (gpcrc). j cell mol med 2012; 16:1573–81. 40. wang xy, berezin i, mikkelsen hb, der t, bercik p, collins sm, et al. pathology of interstitial cells of cajal in relation to inflammation revealed by ultrastructure but not immunohistochemistry. am j pathol 2002; 160:1529–40. 41. chang iy, glasgow nj, takayama i, horiguchi k, sanders km, ward sm. loss of interstitial cells of cajal and development of electrical dysfunction in murine small bowel obstruction. j physiol 2001; 536:555–68. 42. mikkelsen hb. icc,macrophages and mast cells in the gut musculature: morphology, distribution, spatial and possible functional interaction. j cell mol med 2010; 14:818–32. 43. yanagida h, yanase h, sanders km, ward sm. intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. gastroenterology 2004; 127:1748–59. 44. asuzu dt, hayashi y, bardsley mr, farrugia g, ordög t. persistent β-catenin activation underlies senescence of interstitial cell of cajal (icc) stem cells in naturally aging mice. gastroenterology 2011; 140:s-139. 45. kindblom lg, remotti he, alsenborg f, meiskindblom jm. gastrointestinal pacemaker cell tumor (gipact): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of cajal. am j pathol 1998; 152:1259–69. 46. izbeki f, asuzu dt, lorincz a, bardsley mr, popko ln, choi km, et al. loss of kitlow progenitors, reduced stem cell factor, and high oxidative stress underlie gastric dysfunction in progeric mice. j physiol 2010; 15:3101–17. 47. kuro-o m. klotho and the aging process. korean j intern med 2011; 26:113–22. stimulated jak//stat pathway. mol cell biol 1999; 19:2416–24. 23. hwang sj, blair pj, britton fc, o'driscoll ke, hennig g, bayguinov yr, et al. expression of anoctamin 1/ tmem16a by interstitial cells of cajal is fundamental for slow wave activity in gastrointestinal muscles. j physiol 2009; 587:4887–904. 24. robinson tl, sincar k, hewlett br, chornevko k, riddell rh, huizinga jd. gastrointestinal stromal tumors may originate from a subset of cd34positive interstitial cells of cajal. am j pathol 2000; 156:1157–63. 25. lornicz a, redelman d, horvath vj, bardsley mr, chen h, ordög t. progenitors of interstitial cells of cajal in postnatal murine stomach. gastroenterology 2008; 1053:1083–93. 26. vanderwinden jm, rumessen jj, de laet mh, vanderhaeghen jj, schiffmann sn. cd34 immunoreactivity and interstitial cells of cajal in the human and mouse gastrointestinal tract. cell tissue res 2000; 302:145–53. 27. yu b, han j, he yt, guo s, li sf, mei f. immunohistochemical study of cd44 immunopositive cells in the muscular layers of the gastrointestinal tract in adult guinea pigs and mice. acta histochem 2009; 111:382–90. 28. sanders km, ordög t, koh sd, torihashi s, ward sm. development and plasticity of interstitial cells of cajal. neurogastroenterol motil 1999; 11:311–38. 29. young hm. embryological origin of interstitial cells of cajal. microsc res tech 1999; 47:303–8. 30. de paulis a, minopoli g, arbustini e, de crescenzo g, dal piaz f, pucci p, et al. stem cell factor is localized in, released from, and cleaved by human mast cells. j immunol 1999; 163:2799–808. 31. faussone-pellegrini ms. cytodifferentiation of the interstitial cells of cajal related to the myenteric plexus of mouse intestinal muscle coat. an e.m. study from foetal to adult life. anat embryol (berl) 1985; 171:163–9. 32. wang xy, huizinga j, diamond j, liu l. loss of intramuscular and submuscular icc and associated enteric nerves is related to decreased gastric emptying in streptozotocin-induced diabetes. neurogastroenterol motil 2009; 21:1095–e92. 33. horiguchi k, komuro t. ultrastructural observations of fibroblast-like cells forming gap junctions in the w/w (nu) mouse small intestine. j auton nerv syst 2000; 80:142–7. 34. lammers wj, al-bloushi hm, al-eisaei sa, aldhaheri fa, stephen b, john r, et al. slow wave propagation and plasticity of interstitial cells of cajal in the small intestine of diabetic rats. exp physiol 2011; 96:1039–48. 35. lin l, xu lm, zhang w, ge yb, tang yr, zhang hj, et al. roles of stem cell factor on the depletion of interstitial cells of cajal in the colon of diabetic dhuha al-sajee and jan d. huizinga review | 421 53. kitamura y. gastrointestinal stromal tumors: past, present, and future. j gastroenterol 2008, 43:499– 508. 54. west rb, corless cl, chen x, rubin bp, subramanian s, montgomery k, et al. the novel marker, dog1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of kit or pdgfra mutation status. am j pathol 2004; 165:107–13. 55. rossi g, valli r, bertolini f, marchioni a, cavazza a, mucciarini c, et al. pdgfr expression in differential diagnosis between kit-negative gastrointestinal stromal tumours and other primary soft-tissue tumours of the gastrointestinal tract. histopathology 2005; 46:522–31. 56. asuzu dt, mcgehee cd, hayashi y, bardsley mr, grzenda al, lomberk ga, et al. epigenetic control of kit expression in murine kitlow interstitial cell of cajal (icc) stem cells and gastrointestinal stromal tumors (gist). gastroenterology 2011; 140:s119– 120. 48. katoh m. wnt signaling in stem cell biology and regenerative medicine. curr drug targets 2008; 9:565–70. 49. gibbons sj, de giorgio r, pellegrini ms, garritypark mm, miller sm, schmalz pf, et al. apoptotic cell death of human interstitial cells of cajal. neurogastroenterol motil 2009; 21:85–93. 50. sircar k, hewlett br, huizinga jd, chornevok k, berezin i, riddell rh. interstitial cells of cajal as precursors of gastrointestinal stromal tumors. am j surg path 1999; 23:377–89. 51. wong na. gastrointestinal stromal tumours-an update for histopathologists. histopathology 2011; 59:807–21. 52. mazur mt, clark hb: gatric stroma tumors: reappraisal of histogenesis. am j surg pathol 1983; 7:507–19. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e440–441, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.024. submitted 7 dec 14 revision req. 29 jan 15; revision recd. 29 jan 15 accepted 26 feb 15 1department of pediatrics, madras institute of orthopaedics & traumatology in chennai, india; 2department of neonatology, fernandez hospital, hyderabad, india; 3department of pathology, nkp salve institute of medical sciences & research centre, nagpur, maharashtra, india *corresponding author e-mail: dr.deepak.rohtak@gmail.com الطاخة اخللقية الصبغية يف اللسان مرض نادر يف األطفال الرضع جيتان كومار، ديبا �سارما، اأكا�س بانديتا، �سويتا �سا�سرتي congenital lingual melanotic macule rare entity in infants chetan kumar,1 *deepak sharma,2 aakash pandita,2 sweta shastri3 a five-month-old male infant presented to the department of pediatrics at the madras institute of orthopaedics & traumatology in chennai, india, in june 2014 with a pigmented lesion on the tongue that had been observed since birth. the baby was healthy, accepting feeds well and was not taking any medication. there was no associated family history of melanomas, polyposis or mucosal pigmentation. the mother reported that the size of the lesion had been increasing gradually since birth. an oral cavity examination revealed a solitary 6 x 6 mm black macule on the right lateral aspect of the surface of the tongue [figure 1]. there were no other pigmented lesions found anywhere else on the infant’s body. a dermatological opinion was sought and a diagnosis of a congenital lingual melanotic macule was made. a biopsy was recommended; however, the family moved away and the patient was lost to follow-up. comment hyperpigmentation of the oral cavity is usually seen after the second decade of life and can be caused by the intake of certain drugs, smoking or by carcinomatous changes.1 however, it is very rarely seen in the neonatal and infantile period.2 in adults, congenital oral and labial melanotic macules are among the most common cause of hyperpigmented lesions of the oral mucosa.2 there are very few case reports of congenital lingual melanotic macules presenting in newborns and infants.3 these macules are now recognised as a unique and benign cause of hyperpigmentation of the tongue.2 congenital oral and labial melanotic macules are the most common causes of hyperpigmented lesions of the oral mucosa in the elderly population; however, they are rarely observed in the neonatal period.2 oral melanotic macules usually present at a median age of 40 figure 1: five-month-old male infant with a solitary black congenital lingual melanotic macule measuring 6 x 6 mm on the right lateral aspect of the surface of the tongue (arrow). interesting medical image chetan kumar, deepak sharma, aakash pandita and sweta shastri interesting medical image | e441 melanotic macule can be made: (1) the presence of single or multiple melanotic lesions on the tongue; (2) the presence of the lesion since birth and which continues to grow in size; and (3) no family history of any disease known to cause mucosal pigmentation.4 patients with congenital lingual melanotic macules need to be followed up regularly to note any changes in the size, shape or colour of the lesion. long-term outcomes of patients with congenital lingual melanotic macules are not known, as fewer than ten cases have been reported and the cause of origin of the lesion remains uncertain.6 there is no specific treatment for oral melanotic macules, although many researchers recommend complete excision and histological examination of the lesion.7 references 1. ho kk, dervan p, o’loughlin s, powell fc. labial melanotic macule: a clinical, histopathologic, and ultrastructural study. j am acad dermatol 1993; 28:33–9. doi: 10.1016/01909622(93)70005-e. 2. marque m, vabres p, prigent f, guillot b, bessis d. [congenital melanotic macules of the tongue.] ann dermatol venereol 2008; 135:567–70. doi: 10.1016/j.annder.2008.07.012. 3. menni s, boccardi d. melanotic macules of the tongue in a newborn. j am acad dermatol 2001; 44:1048–9. doi: 10.1067/ mjd.2001.113687. 4. dohil ma, billman g, pransky s, eichenfield lf. the congenital lingual melanotic macule. arch dermatol 2003; 139:767–70. doi: 10.1001/archderm.139.6.767. 5. eisen d, voorhees jj. oral melanoma and other pigmented lesions of the oral cavity. j am acad dermatol 1991; 24:527–37. doi: 10.1016/0190-9622(91)70077-f. 6. rapini rp, golitz le, greer ro jr, krekorian ea, poulson t. primary malignant melanoma of the oral cavity: a review of 177 cases. cancer 1985; 55:1543–51. doi: 10.1002/1097-014 2(19850401)55:7<1543::aid-cncr2820550722>3.0.co;2-f. 7. shen zy, liu w, bao zx, zhou zt, wang lz. oral melanotic macule and primary oral malignant melanoma: epidemiology, location involved, and clinical implications. oral surg oral med oral pathol oral radiol endod 2011; 112:e21–5. doi: 10.1016/j.tripleo.2011.02.040. years, whereas labial melanotic macules usually present at a median age of 27.5 years.4 the most common localisation of the macule is a single lesion at the vermillion border of the lower lip near the midline, with the size of the lesion rarely exceeding 5 mm in diameter.4 congenital lingual melanotic macules usually have benign histological features; however, biopsies are recommended to ascertain that the lesion is not malignant. a biopsy of the lesion is characterised by excess deposition of melanin in the basal cell layer and lamina propria of the skin.3 histopathological examination of the lesion shows an increase in melanin pigmentation of the basal epidermal layer and hyperkeratosis of a varying nature with an abundance of subepidermal pigment-laden macrophages.3 there is usually a normal number of melanocyte cells; junctional nests of melanocytes and atypical cells are also noted. congenital lingual melanotic macules are differentiated from melanocytic naevi and melanomas by the lack of melanocyte nests and by negative melanosome antibody staining (homatropine methyle bromide-45), respectively.3 the differential diagnosis for congenital lingual melanotic macules includes physiological melanin pigmentation; drug-associated pigmentation (e.g. from chloroquine); toxin-associated pigmentation; pigmented fungiform papillae; laugier-hunziker syndrome; pigmented naevi; malignant melanomas; smoker’s melanosis; amalgam tattoos; post-inflammatory pigmentation; addison’s disease; and peutzjeghers syndrome.5 a detailed patient history and thorough physical examination of the lesion are needed to rule out other possible causes of pigmentation of the oral cavity, such as smoking and the intake of certain drugs. toxin tests and a biopsy should be performed to rule out conditions like malignant or metastatic melanomas, which can also present in a similar manner. three criteria need to be fulfilled before a clinical diagnosis of congenital lingual http://dx.doi.org/10.1016/0190-9622%2893%2970005-e http://dx.doi.org/10.1016/0190-9622%2893%2970005-e http://dx.doi.org/10.1016/j.annder.2008.07.012 http://dx.doi.org/10.1067/mjd.2001.113687 http://dx.doi.org/10.1067/mjd.2001.113687 http://dx.doi.org/10.1001/archderm.139.6.767 http://dx.doi.org/10.1016/0190-9622%2891%2970077-f http://dx.doi.org/10.1002/1097-0142%2819850401%2955:7%3c1543::aid-cncr2820550722%3e3.0.co%3b2-f http://dx.doi.org/10.1002/1097-0142%2819850401%2955:7%3c1543::aid-cncr2820550722%3e3.0.co%3b2-f http://dx.doi.org/10.1016/j.tripleo.2011.02.040 practical proof of the validity of the target theory by simulating cellular targets medical sciences (2000), 2, 81–86 © 2000 sultan qaboos university department of clinical and biomedical physics, college of medicine, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. e-mail: fadhil@squ.edu.om. 81 practical proof of the validity of the target theory by simulating cellular targets salih f m الهدف نظرية صالحية على عملي برهان مقلدةخلوية أهداف بأستخدام صالح مهدي فاضل . المؤينة لألشعة القاتل التأثير آليات وفهم لوصف موضوع رياضي آنموذج الهدف نظرية صالحية عمليا ألثبات يهدف البحث : الهدف :الملخص منها آل يحوي مجاميع تعريض تم وقد ، ميغاتيريوم عصيات بكتيريا) سبورات (ابواغ باستخدام تجريبيا الهدف نظرية صالحية إثبات محاولة تمت :الطريقة واعتبرت. األوآسجين وجود وعدم بوجود غاما أشعة من مختلفة جرع إلى ،قنينة لكل غوب،500,50,5,2,1على مجموعة آل ني قنا احتوت قنينة، 100 على التشبيه ولغرض. اإلشعاعية الجرعة مقاومة استطاع اآثر أو واحد بوغ على حتويي أيام ستة لمدة حضنها بعد بكتيريا نموا أظهرت التي ني للقنا المئوية النسبة إلى الحاجة افتراض اعتمد وقد فاعليته، يفقد آي واحدة ضربة إلى يحتاج منها آل) ابواغ (األهداف من عددا حويت متكاملة حية خلية تمثل قنينة آل اعتبرت . صفر قيمتها التي اإلشعاعية الجرعة في انحدار على احتوائه مدبع اتصف حيث المستعملة باالبواغ الخاص البقاء منحنى شكل إلى هذه الواحدة الضربة ، قنينة آل في االبواغ عدد بزيادة يزداد الكتف حجم آان أسي، انحدار يليه آتف على باحتوائها الحالي العمل من اشتقت التي البقاء نياتمنح اتصفت :النتيجة هذه من ليهاع حصل التي البيانات فان التشبيه عملية لتسهيل وضعت التي االفتراضات بعض من بالرغم :الخالصة. ثابتا بقي األسى الجزء انحدار إن حين في :التالي الواحدة الضربة ذات المتعددة األهداف لنظرية الرياضي النموذج باستخدام حسبت التي تلك مع جيدا تتطابق الدراسة p =1 – (1 – e–kd)n إن حيثp و ، المتبقي الجزء هو k و ، اإلشعاعي الفاعلية فقدان ثابت هوd و ، اإلشعاعية الجرعة هي n إن. هدافاأل عدد هو .افضل بصورة المؤذية اإلشعاعية التأثيرات فهم من تمكننا آأداة الهدف نظرية نموذج صالحية يثبت التطابق هذا abstract: objective – to practically prove the validity of the target theory as a mathematical model to describe and understand the mechanisms involved in cell killing by ionising radiation. method – experimental validation of the target theory was attempted using bacillus megaterium spores. sets of 100 vials containing averages of 1, 2, 5, 50 and 500 spores per vial was exposed to varying gamma radiation doses in presence (oxic) and absence (anoxic) of oxygen (o2). the percentage of the vials that exhibited bacterial growth after 6 days of incubation was taken as containing one spore or more, which survived a given dose. for the purpose of simulation each vial was considered to represent one living cell, as a unit, containing a given number of targets (spores) each of which needed a single hit to be inactivated. the need for single hit was assumed depending on the shape of the dose ln-survival curve of b. megaterium spores, which has a nonzero slope at zero dose. result – the dose ln-survival curves derived from these radiation experiments are characterized by a shoulder followed by an exponential part. the size of the shoulder increases with increasing number of spores per vial. however, the slope of the exponential parts stays the same. conclusion – despite some assumptions imposed to easily manipulate the simulation process, the data obtained from the present study correlate well with those calculated using the multitarget single hit (mtsh) equation: p = 1 – (1 – e–kd)n where p is the surviving fraction, k is the radiation inactivation constant, d is the radiation dose and n is the number of target. this proves the validity of the target theory model as a tool to provide a better understanding of the observed notorious effects of radiation. key words: target theory, bacterial spore, gamma radiation, simulation t is a long time since lea1 proposed his interpretive models for cell killing by radiation, generally known as the “target theory of cell killing”. the theory was developed using microorganism inactivation data and bioactive molecules. although there have been debates about the validity of the target theory as a general model of cellular radiation inactivation that characterizes cellular death, it has wide applicability to mammalian clonogenic survival.2,3 target theory has taken into consideration a number of variables that can possibly modify the inactivation capacity of ionising radiation such as chemical additives, temperature, type of test organism and its physiological status, type of radiation and many others. nevertheless, there are still insurmountable shortcomings that prevent the generalization of the applicability and validity of the theory. the physiological dormancy of bacterial spores renders them unable to perform biological activities,4–6 i s a l i h 82 including repair of radiation damage.7 this could be justified on the basis that bacterial spores that survived a given radiation dose (both in presence or absence of o2) demonstrated no change in the number of surviving spores even after a long period of holding in distilled water and in buffer prior to plating out.8 in addition, exposure of spores to harsh conditions normally damaging to vegetative cells does not alter their viability.9–12 radiation inactivation of bacterial spores in presence and absence of o2 has been extensively studied and the shapes of the survival curves have been very well characterized.13–16 generally, spores irradiated in the absence of o2 exhibited non-shoulder dose ln-survival curves with an extrapolation number (the intercept of the back extrapolated linear portion of the dose ln-surviving curve with the y-axis), n, of 1.0. however, the presence of o2 slightly increased this value to about 1.2. this small increase in the value of n may be attributed to the dose modifying action of o2,17 which alters mainly the slope (k) of the exponential part of the survival curve. in addition, the experimental design of the dose ln-survival curve adopted in most of the previous studies was not good enough to determine the exact values of both k and n; the major part of the curve was determined by very small numbers of viable cells at higher doses.18 therefore, in the present investigation, the small shoulder of the oxic cells was not considered as a change in number of targets. there has always been an application of target theory to explain the effect of radiation on biological systems.17–26 based on the mtsh mathematical formulation, a relationship between the number of cellular targets and the value of the extrapolation number was assumed,17,27 i.e., as the value of extrapolation number increases, the shoulder of the survival curve widens. such increase in width can also be obtained if the number of targets per cell (values of n) is increased. therefore, spores exhibiting a value of extrapolation number close to 1.0 can be assumed to represent cells that have one target which requires a single hit to be inactivated. it should be noted, however, that this assumption could not be extended to fully describe the effects of radiation on other biological systems such as mammalian cells. some of these systems respond to radiation in a multiphase fashion and the relationship between cell survivors and radiation dose deviates from the usual trend, i.e., a shoulder followed by an increasingly curving exponential part.3 the relationship is rather well described by a linear quadratic model which assumes two components of cell killing by radiation, one proportional to the dose and the other proportional to the square of the dose.2 based on the above assumption, it was hoped in the present investigation to study the possibility of using vials containing bacterial spores, with a particular experimental design, to simulate cells with varying number of targets. each spore was considered as a single target that required a single hit to become inactivated. pp method test microorganism and growth media spores of bacillus megaterium atcc 8245 were suspended in distilled water to make a stock suspension of 2 × 107 spores/ml. the spores were prepared and washed as previously described.28 in order to activate the spores and to kill the vegetative cells, the spore suspension was heat shocked at 80°c for 15 minutes. plating efficiency of the nutrient medium (nutrient broth and agar; oxoid, hampshire, uk) was determined to be 100% by comparing the total number of spores (counted with the aid of a platelet counting chamber) with the number of spores capable of forming visible colonies on the nutrient agar. the latter (viable count) was done weekly to follow the degree of spore batch stability during storage at 4oc. the selection of spores as the biological indicator was made on the basis of their physiological dormancy. this characteristic allowed their storage in distilled water for a long period without noticeable loss of viability, which permitted the use of the same spore suspension over the entire experimentation period. irradiation technique for the purpose of determining the regular oxic and anoxic radiation response, spore suspensions were exposed at 24°c to 137cs gamma radiation (nordion international inc., ontario, canada), at a dose rate of 0.035 kgy/minute in the presence and absence of o2. for anoxic experiments, 5 ml of spore suspension (105 spores/ml) was purged with nitrogen (n2) (99.995%; british oxygen co.) for 10 minutes prior to the commencement of irradiation and then vials were held tightly closed during the irradiation periods. however, for the oxic experiment, vials were irradiated in equilibrium with air. caps were kept slightly loosened to allow for air equilibration. the oxygen enhancement ratio (oer) was determined to be 2.16. two sets of experiments were carried out with vials (capacity 2 ml) containing 1 ml of spore suspension: one set was purged with n2 for one minute only prior to irradiation (to deoxygenate suspension), and the other set was irradiated in equilibrium with air. equilibrium with air was maintained without any additional air flow or stirring. no direct measurement of the concentration of o2 was performed. however, the efficiency of deoxygenation was predicted simply by comparing the oer value (2.21) obtained from these experiments with that derived from the regular survival curves (2.16). diluted spore suspension was prepared to have an average number of 1, 2, 5, 50 and 500 spore/ml of nutrip r a c t i c a l a s s e s s m e n t o f t a r g e t t h e o r y 83 ent broth. aliquots of 1 ml of the diluted suspension were introduced into 100 screw capped, 2 ml capacity vials so that each vial contained the given average number of spores. test of spore distribution among vials was performed. vials containing average of 1 and 2 spores per vial exhibited only 71 and 90% growth, respectively, i.e. the number of vials which exhibited growth among the 100 vials used in each test. vials containing average of more than 2 spores each exhibited 100% growth. for ease of comparison, percentage of the vials containing 1 and 2 spores per vial was made up to 100%. radiation exposure was carried out by arranging vials in a beaker and exposing the beaker to gamma radiation. to ensure homogeneous exposure, the beaker was rotated throughout the irradiation period. no specific radiation dosimetry was performed. dose rate calculation was performed using the theoretical decay scheme of 137cs and the isodose distribution provided by the manufacturer. irradiated vials were then incubated at 37°c for 6 days. the presence of growth, which was detected by the presence of turbidity, was used as an indication of the presence of one or more spores surviving the given radiation dose. in each experiment, two vials containing the same number of spores, but without irradiation, were used as controls. results figure 1 shows typical dose ln-survival curves for spores in 5 ml suspensions irradiated in presence and absence of o2. the calculated values of k and n were 7.30 ± 0.22 × 10–4 gy–1 and 1.03 ± 0.027 for anoxic spores and 17.30 ± 0.38 × 10–4 gy–1 and 1.24 ± 0.028 for oxic spores, respectively. these values were derived from 6 replicated experiments. using the value of k given above (7.30 × 10–4 gy–1) as the inactivation constant, k, and varying values of extrapolation number, n, as the number of target, to range between 0–500 and radiation doses, d, to range between 0–12 kgy, a set of theoretical survival curves for anoxic condition was constructed using the mtsh equation: p = 1 – (1 – e–kd)n as depicted by the solid lines in figure 2. these curves are characterized by the same slope at the exponential regions and increasing size of shoulders and hence increasing extrapolation numbers. similar theoretical set of curves was also constructed for spores irradiated in the presence of o2 using a value of k derived from the typical oxic survival curve (17.30 × 10–4 gy–1), as depicted by the solid line in figure 3. again all curves exhibited the same slope but increasing size of shoulder. figure 2. the numbers of vials that exhibited growth after gamma irradiation in the absence of o2. symbols represent vials contained averages of 1 (closed circles), 2 (open diamonds), 5 (closed triangles), 50 (closed squares) and 500 (open circles) spores/ vial. solid lines represent curves derived from the mtsh formula in which the values of n varied, in multiple fashion, according to the corresponding value of extrapolation number of the dose ln-survival curve. survival curves derived from the present investigation in which vials containing varying number of spores and exposed to gamma radiation in the absence of o2 are presented as symbols in the composite figure 2. for clarity purposes and to avoid overlapping of data, and to allow easy comparison the lines are not shown. curves are also characterized by having the same slope at the exponential regions and varying size of shoulder corresponding to the number of spores in each vial in a manner similar to the theoretical ones. figure 1. typical dose ln-survival curves for spores irradiated in presence (closed squares) and in the absence of (open squares) of o2. 0 2 4 6 8 10 dose (kgy) s ur vi vi ng f ra ct io n 10 -1 10-3 10-2 10-4 100 1 10 100 dose (kgy) % v ia ls w ith g ro w th 2 4 6 8 10 120 s a l i h 84 similarly, data derived from oxic experiments are given as symbols in figure 3. again the slopes of the curves at the exponential regions are the same and the shoulders increase in size with increasing the number of spores per vial. apparently, data derived from these experiments agree totally with the theoretically calculated. discussion assuming b. megaterium spore as a cell having a single target that requires a single hit to be inactivated based on the value of extrapolation number (n) derived from the survival curves reported previously by many investigators.9,12,15 such a characteristic was considered in the present attempt to simulate a living cell by a vial containing nutritive medium in which varying numbers of spores were introduced to represent the bioactive molecules. the number of spore in each vial represents the number of target (target multiplicity), each of which requires a single hit to be inactivated. figure 3. numbers of vials exhibited growth after gamma irradiation in the presence of o2. symbols represent vials contained averages of 1 (closed circles), 2 (open diamonds), 5 (closed triangles), 50 (closed squares) and 500 (open circles) spores/vial. solid lines represent curves derived from the mtsh formula in which the values of n varied, in multiple fashion, according to the corresponding value of extrapolation number of the dose ln-survival curve. in order to test the validity of the present assumption theoretical data were obtained by substituting the value of n in the mtsh formula by the numbers 1, 2, 5, 50 and 500 for both oxic and anoxic condition. when the value of the extrapolation numbers, 1.03, and its multiples was used for anoxic spores, a set of curves is obtained (solid lines in figures 2). however, in this set it is apparent (as it should be) that the change in the value of n influenced the size of the shoulders without changing the slope of the exponential part of the survival curves. similar findings were obtained when the number of spore in each set of vials was changed. the survival curves derived from anoxic experiments exhibited changes in the shoulders comparable with those of the theoretical survival curves and the values of extrapolation number correspond to their values of n. the two sets of survival curves superimpose, as shown in figure 2. support to the above findings comes from the work done by khan and tallentire29 in their attempt to verify a model relating frequency of contaminated items and increasing radiation dose. theoretical (using mtsh mathematical model) and practical (using b. pumilus spores and serratia marcescens cells) findings agree. this adds more to the present assumption in that these two microorganisms and b. megaterium spores behaved similarly regarding the validity and applicability of the mtsh model. typically, the presence of o2 seems to have no effect on the observed values of n although the initial value of extrapolation number as calculated from the regular survival curve (1.24) was higher than that in the absence of o2 (1.03). this relatively high value of n seemed to also affect the observed values of extrapolation number in a multiple fashion, i.e. the values of the extrapolation numbers increased by a factor of about 1.25 multiplied by the number of spores per vial. the present findings support very well the role of targets in cell killing by radiation. however, the generalization of the present validity of the simulation is subject to a lot of questioning regarding the structure of the cell and the use of a vial, of a completely different composition, to represent the cell. but spore(s) present in a vial, no matter what the surrounding medium is, needed to be inactivated for the vial to show no growth. in addition, the large distances separating spores (targets) in the vial cannot, by no means, be compared with that in the cell. and the nature of the cellular targets vary from one cell to the other. nevertheless, these shortcomings cannot be considered disproving factors for the simulation purpose since the ultimate end point is the same, i.e. the inactivation of the cell as the usual parameter and the absence of growth in the vial as the present investigation parameter. the most encouraging aspect of the present finding is the similarity between the shapes of the theoretical survival curves and those derived from the present investigation. similarly, the values of extrapolation number and slope derived from the present work correspond with those theoretically calculated. a major limitation reported earlier in the target theory17 was that it has never been possible experimentally to obtain a zero slope at zero dose. in the present investigation, however, a zero slope was obtained even at high doses, particularly when larger numbers of spores per vial were used. the latter adds 1 10 100 dose (kgy) % v ia ls w ith g ro w th 0 2 4 6 p r a c t i c a l a s s e s s m e n t o f t a r g e t t h e o r y 85 one more support to the validity of the present experimental design, which substantiates our findings and supports the simulation process. based on the current molecular understanding of subcellular structures and the size of the elements affecting cellular radiation response,30 target theory seems more complicated than can simply be justified by a simple simulation process. more work is needed to draw a solid conclusion about its general applicability. hyperthermia,2,31 radiation dose rate,32 repair of radiation damage23,33 and presence of chemical additives17 have been so far studied and their effects on the validity of target theory were considered. yet a generalized formula is far from being produced due to the diversity of factors involved in the modification of radiation damage. moreover, systems other than microorganisms, such as mammalian cells, impose difficulties in applying the target theory to describe the effect of radiation despite that the survival curves derived from mammalian cells experiments are characterized by having an initial shoulder followed by a portion that tends to become straight. however, for some cell lines the survival curve appears to bend continuously so that the conventional target theory model cannot be applied and therefore, the linear quadratic relationship is a better fit and the extrapolation number (n) has no meaning.2 conclusion the present data coincide very well with those calculated using the mtsh formula. this implies that the simulation of cell by vial containing a given number of spores to represent the bioactive molecules (targets), needed to be inactivated for the cell to die, is valid. references 1. kiefer j. biological radiation effects. springer-verlag, berlin 1990. 2. hall ej. radiobiology for the radiologist. (4th ed.), lippincott, philadelphia 1994. 3. nias ahw. an introduction to radiobiology 2nd ed., wiley, chichester 1998. 4. hopson jl, wessells nk. essentials of biology, mcgrawhill publishing co. new york 1990. 5. popham dl, gilmore me, setlow p. roles of low molecular weight penicillin-binding proteins in bacillus subtilis spore peptidoglycan synthesis and spore properties. j bacteriol 1999, 181, 126–32. 6. atrih a, foster sj. the role of peptidoglycan structure and structural dynamics during endospore dormancy and germination. antonie van leeuwenhoek 1994, 75, 299–307. 7. tallentire a. symposium on bacterial spores: xi. radiation resistance of spores. j appl bacteriol 1970, 33, 141–6. 8. salih fm. modification of liquid holding recovery of gamma irradiated bacillus megaterium cells by chemicals and heat. j biol sci res 1986, 17, 127–46. 9. tallentire a, jones ab. radiosensitization of bacterial spores by potassium permanganate. int j radiat biol 1973, 24, 345–54. 10. tallentire a, jacobs gp. radiosensitization of bacterial spores by ketonic agents of differing electron affinities. int j radiat biol 1972, 21, 205–13. 11. tallentire a, schiller nl, powers el. 2,3-butanedione, an electron-stabilizing compound, as a modifier of sensitivity of bacillus megaterium spores to x-rays. int j radiat biol 1968, 14, 397–402. 12. salih fm. radioensitization of bacillus megaterium spores by combinations of oxygen and misonidazole. j radiat res 1984, 25, 160–9. 13. stratford ij, maughan rl, michael bd, tallentire a. the decay of potentially lethal oxygen-dependent damage in fully hydrated spores exposed to pulsed electron irradiation. int j radiat biol 1977, 32, 447–55. 14. stratford ij, tallentire a. a comparative study of the gamma radiation responses of bacillus megaterium spores suspended in aqueous solutions of ethanol and ethylene glycol. j pharm phamacol 1974, 26, 103. 15. purdie jw, ebert m, tallentire a. increased response of anoxic bacillus megaterium spores to radiation at high dose rate. int j radiat biol 1974, 26, 435–43. 16. stratford ij, tallentire a. inactivation by gamma-rays of bacillus megaterium spores suspended in aqueous solutions of ethanol, acetone and 1,4-dioxane of widely varying concentrations. j pharm pharmacol 1973, 25, 130. 17. alpen el. radiation biophysics. (2nd ed.), academic press san diago 1998. 18. chadwick kh, leenhouts hp. a molecular theory of cell survival. phys med biol 1973, 18, 78–87. 19. kiefer j. target theory and survival curves. j theor biol 1971, 30, 307–17. 20. alper t. mechanisms of cell killing in the light of formal target theory. br j radiol 1975, 48, 415–26. 21. gilbert cw. target-type models for survival curves. br j radiol 1975, 48, 1045–56. 22. domon m. a biological variability model of cell survival curves. radiat res 1980, 82, 611–5. 23. louw wk, van rensburg ej, izatt h, engelbrecht ri. nucleoid sedimentation analysis of dna superstructure, gamma radiation induced damage and repair in human and chacma baboon (pupia ursinus) peripheral lymphocytes. int j radiat biol 1991, 59, 951–62. 24. katz r, zachariah r, cucinotta fa, zhang c. survey of cellular radiosensitivity parameters. radiat res 1994, 140, 356–65. 25. deshpande a, goodwin eh, baily sm, marrone bl, lehnert be. alpha particle-induced sister chromatid exchange in normal human lung fibroblasts: evidence for an extra nuclear target. radiat res 1996, 145, 260–7. 26. briden pe, holt pd, simmons ja. the track structures of ionizing particles and their application to radiation biophysics, i. a new analytical method for investigating two biophysical models. radiat environ biophys 1999, 38, 175–84. 27. tallentire a, dwyer j, ley ft. microbiological quality control of sterilized products: evaluation of a model relating frequency of contaminated items with increasing ras a l i h 86 diation treatment. j appl bacteriol 1971, 34, 521–34. 28. powers el, ehret cf, bannon a. the membrane filter technique in radiation studies of spores of bacillus megaterium. appl microbiol 1957, 5, 61–4. 29. khan aa, tallentire a, dwyer j. quality assurance of sterilized products: verification of a model relating frequency of contaminated items and increasing radiation dose. j appl bacteriol 1977, 43, 205–13. 30. savage jr. update on target theory applied to chromosomal aberrations. environ mol mutagen 1993, 22, 198–207. 31. petin vg, komarov vp. mathematical description of synergistic interaction of hyperthermia and ionizing radiation. math biosci 1997, 146, 115–30. 32. goodhead d. track structure considerations in low dose and low dose rate effects of ionizing radiation. adv radiat biol 1992, 16, 7–44. 33. gordon at, mcmillan tj. a role for the molecular biology in radiotherapy. clin oncol 1997, 9, 70–78. practical proof of the validity of �the target theory by simulating cellular targets method test microorganism and growth media irradiation technique results discussion conclusion references brca2 و brca1 سري عمل التحري التشخيصي لطفرات جينات �ضتيل الي، كلري بروكز، ديربا اأو برو�ضري، �ضوان–�ضينج الن، اليني دوهريتي ودوناالد ر. لوف abstract: objectives: screening for mutations in large genes is challenging in a molecular diagnostic environment. sanger-based dna sequencing methods are largely used; however, massively parallel sequencing (mps) can accommodate increasing test demands and financial constraints. this study aimed to establish a simple workflow to amplify and screen all coding regions of the brca1 and brca2 (brca1/2) genes by sanger-based sequencing as well as to assess a mps approach encompassing multiplex polymerase chain reaction (pcr) and pyrosequencing. methods: this study was conducted between july 2011 and april 2013. a total of 20 patients were included in the study who had been referred to genetic health services new zealand (northern hub) for brca1/2 mutation screening. patients were randomly divided into a mps evaluation and validation cohort (n = 10 patients each). primers were designed to amplify all coding exons of brca1/2 (28 and 42 primer pairs, respectively). primers overlying known variants were avoided to circumvent allelic drop-out. the mps approach necessitated utilisation of a complementary fragment analysis assay to eliminate apparent false-positives at homopolymeric regions. variants were filtered on the basis of their frequency and sequence depth. results: sanger-based sequencing of pcramplified coding regions was successfully achieved. sensitivity and specificity of the combined mps/homopolymer protocol was determined to be 100% and 99.5%, respectively. conclusion: in comparison to traditional sangerbased sequencing, the mps workflow led to a reduction in both cost and analysis time for brca1/2 screening. mps analysis achieved high analytical sensitivity and specificity, but required complementary fragment analysis combined with sanger-based sequencing confirmation in some instances. keywords: massively parallel sequencing; brca1 gene; brca2 gene; hboc syndrome; detection, heterozygote. امللخ�ص: الهدف: ي�ضعب يف بيئة الت�ضخي�س اجلزيئي حتري الطفرات يف اجلينات الكبرية. وعادة ما يقا�س ت�ضل�ضل احلم�س النووي بطرق �ضانقر. غري اأن طرق الت�ضل�ضل املوازي وا�ضع النطاق )mps( ميكنها ا�ضتيعاب الطلب املتزايد من القيا�ضات حتت ظروف قيود مالية كبرية. تهدف هذه الدرا�ضة اإىل تقدمي خطة �ضري عمل ت�ضخيم وحتري كل مناطق ال�ضفرات يف جينات brca1 و brca2 بوا�ضطة طريقة �ضانقر يوليو 2011 بني الدرا�ضة هذه البايرو. الطريقة: أجريت و�ضل�ضلة )pcr( املت�ضل�ضل البلمرة تفاعل ت�ضمل التي mps طريقة تقييم وكذلك .brca1/2 واأبريل 2013، و�ضملت 20 مري�ضا مت حتويلهم اإىل اخلدمات ال�ضحية الوراثية يف نيوزلندا )املحور ال�ضمايل( لتحري طفرات ومت تق�ضيم املر�ضى ع�ضوائيا لق�ضمني مت�ضاويني، ق�ضم لتقييم طرق الـ mps، وق�ضم لتوثيق املصداقية. ومت حتديد مناطق بدء العمل لت�ضخيم �ضفرة كل اك�ضونات )حموارات( جينات brca1 و brca2 )28 و 42 زوجا من مناطق بدء العمل، على التوايل(. ومت حتا�ضي مناطق العمل التي تعلو املتغريات املعروفة للروغان من اال�ضقاط االأليلي. وتطلب ا�ضتخدام طرق الـ mps ا�ضتعمال مقاي�ضة مكملة لتحليل ال�ضدفة حتى ميكن التخل�س من النتائج االإيجابية الكاذبة الظاهرية حول املناطق البلومرية املتماثلة. ومت تر�ضيح )فلرتة( املتغريات بناء على تواترها وت�ضل�ضل عمقها. النتائج: مت بنجاح قيا�س ال�ضفرات بوا�ضطة تسلسل احلم�س النووي امل�ضخم بوا�ضطة الـ pcr واملبني على طريقة �ضانقر. وبلغت نسبتا احل�ضا�ضية والنوعية لطريقة mps %100 و %99.5، على التوايل. اخلال�صة: عند املقارنة مع طريقة �ضانقر التقليدية لقيا�س الت�ضل�ضل جند اأن باإمكان �ضري عمل الـ mps اأن يقلل تكلفة التحري الت�ضخي�ضي لـ brca1/2 ويخت�رض من زمنه. وميتاز حتليل الـ mps بن�ضبة عالية من احل�ضا�ضية والنوعية، اإال اأنه يتطلب يف بع�س احلاالت ا�ضتخدام مقاي�ضة مكملة لتحليل ال�ضدفة اإ�ضافة اإىل التثبت بوا�ضطة الت�ضل�ضل املبني على طريقة �ضانقر. مفتاح الكلمات: طرق الت�ضل�ضل املوازي وا�ضع النطاق؛ جني brca1؛ جني brca2؛ متلزمة hboc؛ اكت�ضاف، زيجوت متغرية االأالئل. diagnostic screening workflow for mutations in the brca1 and brca2 genes stella lai, clare brookes, debra o. prosser, chuan-ching lan, elaine doherty, *donald r. love sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e58–70, epub. 21 jan 15 submitted 23 mar 14 revision req. 29 apr 14; revision recd. 4 sep 14 accepted 2 oct 14 department of diagnostic genetics, labplus, auckland city hospital, auckland, new zealand *corresponding author e-mail: donaldl@adhb.govt.nz advances in knowledge the research described in this study allows for capillary-based sequencing as well as massively parallel sequencing (mps) of the brca1 and brca2 (brca1/2) genes for disease-causing mutations in patients with apparent hereditary breast and ovarian cancer. the results of this study have determined parameters for assessing sequence quality in order to reduce the number of false-positive calls using mps and a pyrosequencing platform. application to patient care the use of mps enables sequence-detectable mutations to be identified quickly, which is a significant advantage to all patients, regardless of their results. furthermore, the mps approach used in the current study was found to improve turn-around time for screening brca1/2 genes and reduce the cost of diagnostic screening. clinical & basic research stella lai, clare brookes, debra o. prosser, chuan-ching lan, elaine doherty and donald r. love clinical and basic research | e59 conventional sanger dideoxynucleo-tide (ddntp) dna sequencing is the most commonly used method of routine mutation screening.1–3 this method was developed in the 1970s and has become the gold standard for diagnostic sequencing.1,4 however, the cost of sanger-based sequencing is relatively high and the procedure is time-consuming, making it impractical for screening large genes such as brca1 and brca2 (brca1/2). the increasing demand for diagnostic genetic testing in a clinical setting has created the need for an alternative technology that can accommodate high throughput, while reducing costs and turnaround times. the development of massively parallel sequencing (mps), also known as next-generation sequencing, enables the sequencing of millions of dna fragments in a single run.5,6 mps technology has been readily adopted in research settings and has recently moved into the diagnostic environment; however, this has led to issues regarding sequence quality parameters and the need for comprehensive bioinformatic analysis. in new zealand, breast cancer is the most frequently registered cancer and the second leading cause of cancer-related deaths among women. compared to the second half of last century, the incidence of breast cancer has increased in new zealand.7 germline mutations in the brca1/2 genes account for approximately 10–15% of all breast and ovarian cancers; these are known as hereditary breast and ovarian cancers (hboc).8,9 the brca1/2 genes, which were identified by positional cloning during the 1990s, encode for proteins that are responsible for controlling cellular growth and differentiation.8 the majority of germline mutations in the brca1/2 genes are either nonsense or frame-shift mutations, which result in truncated proteins.8,9 exonic deletions or duplications have also been reported but are rare. in view of the above, together with the large number of reported mutations, screening the coding regions of the brca1/2 genes for mutations has largely involved denaturing high-performance liquid chromatography or direct sequencing.10–14 in contrast, targeted mutation analysis using conventional sanger-based sequencing is a common initial testing strategy for individuals of ashkenazi jewish ancestry with hboc. three founder mutations have been described in this population: c.68_69delag and c.5266dupc in the brca1 gene and c.5946delt in the brca2 gene, with a combined frequency of approximately 2%.15,16 the brca1/2 genes are classic examples of the difficulties commonly encountered in a diagnostic setting: they are large autosomal genes with a wide spectrum of mutations, rich in homopolymeric regions and are highly polymorphic, complicating primer designs for polymerase chain reaction (pcr) amplification.17 the objective of this study was to investigate the diagnostic potential of the more cost-effective mps approach in screening for mutations in the brca1/2 genes, compared to conventional sanger-based sequencing. this strategy involved a pyrosequencing approach in order to develop a rapid, inexpensive and rigorous assay for identifying disease-causing mutations in the brca1/2 genes. methods this study was carried out between july and april 2013. a total of 20 patients who had been referred to genetic health services new zealand (northern hub) for brca1/2 gene mutation screening were selected for inclusion. of the patients, 16 carried known diseasecausing mutations. these patients carried a range of brca1/2 gene variants, including missense, nonsense, duplication, insertion-deletion and deletion variants. the analysis of whole exon deletion events was excluded from the current study as it concerned only the ability to detect intra-exonic and splice site mutations. a total of 10 patients were randomly assigned to comprise the mps evaluation cohort. genomic dna from the evaluation group was subjected to two sequencing strategies. the first comprised exontargeted amplification and subsequent sanger-based sequencing of the coding regions of brca1/2 while the second comprised the mps approach described below. a comparison of the latter data against the former allowed mps analysis parameters to be determined. identified parameters were then applied to the genomic dna of the 10 patients in the mps validation cohort in order to identify sequence variants. variants were identified using seqnext, sequence pilot software, version 3.4.2 (jsi medical systems gmbh, kippenheim, germany). all identified variants, as well as amplicons with insufficient coverage (set at 30x coverage), were subjected to sanger-based sequencing to determine the sensitivity and specificity of the mps approach. a fragment analysis approach was also used in conjunction with mps to reduce the frequency of the false-positive (fp) calls that required sanger-based sequencing confirmation. dna was extracted from peripheral ethylenediaminetetraacetic acid (edta) blood samples using the gentra® puregene® blood kit (3 ml) (qiagen, venlo, limburg, netherlands), according to the manufacturer’s instructions. these dna samples were assessed by an accredited overseas laboratory to validate the local gene screening strategy used in the study. diagnostic screening workflow for mutations in the brca1 and brca2 genes e60 | squ medical journal, february 2015, volume 15, issue 1 in order to offer local brca1/2 gene screening, primers were designed for the simple amplification of all coding regions of the two genes. the design process used, which allows for amplification using a standard reaction condition and cycling protocol, has been previously described.18 critically, the primer designs involved extensive analysis of the single nucleotide polymorphism database (dbsnp)19 and an iterative design process in order to ensure that primers did not overlie known single nucleotide polymorphisms (snps) using snpcheck (national genetics reference laboratory, manchester, uk).20 in the case of sangerbased sequencing, 70 pairs of primers were designed to flank all of the coding and adjacent splice junction regions of the brca1/2 genes for pcr amplification [appendix 1].21,22 in total, 140 fragments were generated with amplicon lengths of 218–745 base pairs (bp). the amplicon lengths were short enough to allow complete bi-directional sequencing of the coding regions of the brca1/2 genes. in order to allow the unambiguous sequencing of amplicons containing repetitive sequences, eight nested primers were also designed [appendix 2]. the coding regions of the brca1/2 genes were then amplified in a reaction volume of 25 μl containing 50 ng of genomic dna, 0.4 mm of ddntp (ge healthcare ltd., little chalfont, uk), 0.8 μm each of forward and reverse primers, 2 mm of magnesium chloride (mgcl2) and one unit of pcr reaction buffer without mgcl2 together with one unit of faststart taq dna polymerase (roche applied science, penzberg, upper bavaria, germany). the thermal cycling conditions consisted of a denaturation step of 95 °c for five minutes, 35 cycles of 94 °c for 45 seconds, 60 °c for 30 seconds and 72 °c for 30 seconds, followed by a final extension of 72 °c for 10 minutes. purification of each 5 μl of pcr product was performed using usb® exosap-it® (affymetrix inc., santa clara, california, usa). the purified pcr product was then diluted to 2.5 ng per 100 bp and sequenced bi-directionally using m13 forward and reverse primers and bigdye® terminator version 3.1 cycle sequencing kit (applied biosystems, life technologies, thermo fisher scientific corp., carlsbad, california, usa). sequenced products (5 μl) were purified using the bigdye® xterminator™ purification kit (applied biosystems) and then subjected to capillary electrophoresis using a 3130xl genetic analyser (applied biosystems) with a 50 cm capillary array. sequence traces were analysed using kb™ basecaller sequencing analysis software, version 1.4, and variant reporter™ software, version 1.0 (applied biosystems), with a minimum trace score of 35, which corresponds to an average fp base call frequency of 0.031%. mps library amplification involved the amplification of the coding regions of the brca1/2 genes using the brca mastr™ dx assay (multiplicom, niel, belgium) in a reaction volume of 15 μl containing 50 ng of genomic dna. this molecular diagnostic assay allows for multiplex pcr amplification of 93 amplicons in five separate pcrs for each patient. the thermal cycling conditions consisted of a denaturation step of 95 °c for 10 seconds, 20 cycles consisting of 95 °c for 45 seconds, 60 °c for 45 seconds and 68 °c for two minutes, followed by a final extension of 72 °c for 10 minutes. secondary pcr used the 454 mid dx kit (multiplicom) to tag the amplicons with patientspecific molecular barcodes and 454 sequencing adaptors (a and b) for downstream sequencing. the multiplex identifier (mid) sequences consist of six unique nucleotides and are used to index each brca library, allowing multiple patient libraries to be multiplexed in a single mps run. the primary pcr products were diluted in sterile water (1:1000) and 1 μl of this product was used as a template for the secondary pcr with indexing adapters in a total reaction volume of 25 μl. the thermal cycling conditions consisted of a denaturation step at 98 °c for 10 seconds, 20 cycles consisting of 95 °c for 45 seconds, 64 °c for 45 seconds and 68 °c for two minutes, followed by a final extension of 72 °c for 10 minutes. subsequent pooling of tagged amplicons for each patient was followed using a predefined mixing protocol (multiplicom). each patient’s ampliconpooled library was purified using agencourt ampure xp (beckman coulter inc., beverly, massachusetts, usa) to remove small residual dna fragments such as primer dimers. the concentration of each patient’s amplicon-pooled library was determined using quantit™ picogreen® dsdna reagent and assay kit (invitrogen, life technologies) and normalised to 10 nm in tris-edta buffer (ph 8). in each experiment, five patients’ amplicon-pooled libraries were pooled in an equimolar ratio to generate a sequencing library, which contained a total of 465 amplicons for sequencing on the mps platform. emulsion pcr using the gs junior titanium empcr lib-a kit (roche diagnostics corp., indianapolis, indiana, usa) was performed to clonally amplify single dna molecules in their own microreactors. this was achieved by hybridising the dna library onto primer-coated beads together with emulsification through vigorous shaking of an oilwater mixture and amplification reagents to achieve emulsion micro-reactors. after subsequent pcr amplification, the micro-reactors were broken and stella lai, clare brookes, debra o. prosser, chuan-ching lan, elaine doherty and donald r. love clinical and basic research | e61 dna-positive beads were deposited onto a picotiter plate for subsequent pyrosequencing. data processing was carried out using a predefined amplicon pipeline program, genome sequencer run processor (roche applied science). sequence data were aligned against the reference sequences nc_000017.10 (nm_007294.3; brca1) and nc_000013.10 (nm_000059.3; brca2) from the human genome assembly (hg19; genome bioinformatics group, university of california santa cruz, usa). nomenclature from the human genome variation society (hgvs), version 2.0,23 was used to describe all variants with nucleotide numbering starting from the first nucleotide of the translated sequence. amplicons with flanking regions of 3–20 bp upstream and downstream were analysed using seqnext. settings were customised to achieve a phred quality score equivalent to 33, as described in others studies.24–26 seqnext sorts the sequence data for each patient according to the attached mid and variant calling is achieved based on a defined variant frequency, which was set at 20%. as pyrosequencing errors commonly arise in homopolymeric regions, a secondary threshold for these regions of 35% was set to filter out apparent fps. currently, a minimum read depth of 20x is widely adopted in research settings as not all targeted regions are evenly sequenced by mps.25,27,28 this threshold, termed the minimum base coverage threshold, is necessary in order to avoid possible variant miscalling.29 the minimum base coverage threshold was set at 30x (combined forward and reverse reads) [table 1]. an initial variant frequency (vf) of 20% allowed reliable variant calling. subsequent vf ranges of 40–60% and 90–100% were used for calling heterozygotes and homozygotes, respectively. brca1/2 genes are homopolymer (hp)-rich and sequencing homopolymeric regions is a known limitation of pyrosequencing technology which can hamper its effective use.24,30,31 for this reason, a commercially available fragment analysis assay was used (brca hp kit, version 2.0, multiplicom) to screen for variants in targeted homopolymeric regions in the brca1/2 genes. a fragment analysis approach was used in conjunction with mps to reduce the frequency of the fp calls that required sangerbased sequencing confirmation. this assay targets 29 homopolymeric regions (stretches of 6 bp or more) within the coding regions of the brca1/2 genes. two multiplex pcrs were set up in reaction volumes of 15 μl containing 30 ng of genomic dna. the thermal cycling conditions consisted of a denaturation step at 98 °c for 10 minutes, 24 cycles consisting of 95 °c for 45 seconds, 60 °c for 45 seconds and 68 °c for two minutes, followed by a final extension of 72 °c for 10 minutes. the pcr products were electrophoresed in the 3130xl genetic analyzer and the data were analysed using maq-s software, version 1.4.0 (multiplicom). three strategies were established to reduce the number of fp calls. first, mps using a pyrosequencing approach required a complementary strategy to screen homopolymeric regions. regions not covered by the fragment analysis assay were therefore subjected to sanger-based sequencing. second, literature searches and bioinformatic splice site analyses using the berkeley drosophila genome project program (bdgp)32,33 were used in the case of intronic single base insertions or deletions occurring in homopoly-meric tracts of ≥6 bp or outside of ±3 bp of the exon-intron boundaries. these putative variants would be filtered out if they were determined highly unlikely to be of pathogenic significance, as reporting them would be of no clinical significance. third, it was decided not to report variants in the following untranslated regions (utrs) of the brca2 gene: c.-26g>a (5’ utr) and c.*105a>c (3’ utr). while these variants are listed in the breast cancer information core (bic) database,34 they have no known clinical significance and thus fall outside the regions of interest (roi) of the current study. these exclusion strategies were applied to the mps analysis of the validation cohort. all patients gave informed consent to be included in this study. results sanger-based sequencing was applied to the evaluation cohort (n = 10) who carried a range of brca1/2 gene variants, including missense, nonsense, insertiondeletion and deletion variants. table 2 summarises the variants that were detected. external laboratory table 1: custom settings applied to seqnext, sequence pilot software, version 3.4.2 (jsi medical systems gmbh, kippenheim, germany) to identify sequence variants in the genomic dna of 10 patients setting parameter analyse/ignore region: minimum absolute coverage off low coverage warning 30 mutations: minimum absolute coverage off mutations: minimum % coverage 20% per direction mutations sorting: distinct/other % coverage 20% per direction mutations sorting: distinct/homopolymer coverage 35% per direction diagnostic screening workflow for mutations in the brca1 and brca2 genes e62 | squ medical journal, february 2015, volume 15, issue 1 reports on the same dna samples confirmed the mutations reported. in total, 128 variants were identified, of which 80 variants were true-positives (tps) and 48 variants were apparent fps. the latter were identified by comparing the variant calls against the sanger-based sequencing data. of these 48 apparent fps, 43 lay in homopolymeric regions. of the 43 apparent fp variants in homopolymeric regions, 17 were in exons (13 were covered by the brca hp kit and four lay in homoploymeric tracts of five bases only) and 26 were in introns. of the remaining five apparent fps, three corresponded to the same intronic deletion of one base in a homopolymeric tract that was three bases upstream of a splice acceptor site and two were sequenced at insufficient read depth. table 2: variants detected in the brca1 and brca2 genes of 20 patients using sanger-based sequencing nucleotide codon type patient 1 2 3 4 5 6 7 8 9 10 brca1 c.140g>a p.cys47tyr m het* c.1067a>g p.gln356arg m het het het c.1175_1214del40 p.leu392glnfs*5 f het* c.2077g>a p.asp693asn m het c.2082c>t p.ser694ser s het het het hom hom c.2311t>c p.leu771leu s het het het hom hom c.2315t>c p.val772ala m het c.2612c>t p.pro871leu m het het het hom hom c.3113a>g p.glu1038gly m het het het hom hom c.3548a>g p.lys1183arg m het het het hom hom c.3756_3759delgtct p.ser1253argfs*10 f het* c.4065_4068deltcaa p.asn1355lysfs*10 f het* c.4308t>c p.ser1436ser s het het het hom hom c.4837a>g p.ser1613gly m het het het hom hom brca2 c.68-7t>a i het c.865a>c p.asn289his m het c.1114a>c p.asn372his m het het het hom het het het c.1365a>g p.ser455ser s het c.1395a>c p.val465val s het c.2229t>c p.his743his s het c.2971a>g p.asn991asp m het c.3396a>g p.lys1132lys s het het het het c.3807t>c p.val1269val s het het het c.7242a>g p.ser2414ser s het het het het c.7655_7658delttaa p.ile2552thrfs*95 f het* c.7762_7764delatainstt p.ile2588phefs*60 f het* c.7806-14t>c i het het hom het het het het hom c.8297delc p.thr2766asnfs*11 f het* c.8575delc p.gln2859lysfs*4 f het* m = missense; het = heterozygote; het* = heterozygote disease-causing mutation; fs = frame-shift; s = synonymous; hom = homozygous; i = intronic. stella lai, clare brookes, debra o. prosser, chuan-ching lan, elaine doherty and donald r. love clinical and basic research | e63 the mps analysis parameters and the exclusion strategies derived from the evaluation cohort were applied to the mps analysis of the validation cohort (n = 10). a total of 115 variants were identified using the mps analysis parameters; however, 66 calls remained after applying the exclusion strategies. sanger sequencing confirmed 62 of these 66 calls to be tps. the remaining four calls were localised to homopolymeric regions not covered by the fragment analysis assay. importantly, two pathogenic mutations in the brca2 gene (c.1813dupa and c.2957dupa) were not detected by mps analysis. these mutations occurred in the homopolymeric regions comprising eight and seven adenosines, respectively. however, these two duplications were clearly identified using the fragment analysis assay and maq-s software [figures 1a & b]. the sensitivity and specificity of the combined mps/hp protocol was determined to be 100% and 99.5%, respectively. combining the results of the two cohorts, there were 17 true mutations, 11 fps that were not filtered out using the exclusion criteria, four with a vf out of the acceptable range and two with insufficient base coverage of less than 30 reads. as two of these confirmations occurred in the same amplicon of one patient, a total of 33 amplicons required sequencing confirmation. a summary of the variants detected in all 20 patients is presented in appendix 3, together with conclusions regarding their pathogenic status based on the bic database and the human genome mutation database (biobase hgmd® professional, biobase biological databases, beverly, massachusetts, usa).23,34,35 overall, the sequence data showed variations of approximately 10,000–26,700 total read counts per patient. in terms of read counts per amplicon, the variation was 30–1,900. the sangerbased sequencing approach achieved a phred score of 35 with a base call accuracy of 99.97%. the mps/hp mutation screening strategy for brca1/2 genes resulted in significant savings in terms of both the cost of consumables and time by three-fold and two-fold, respectively [appendix 4]. discussion in this study, a simple workflow was established using a benchtop mps platform to perform comprehensive mutation screening of the brca1/2 genes [figure 2]. the mps analysis achieved high analytical sensitivity and specificity, but required complementary fragment analysis combined with sanger-based sequencing confirmation in some instances. this complementary approach eliminated some of the concerns about the inherent limitations of pyrosequencing technology. the mps/hp mutation screening strategy for brca1/2 genes resulted in significant savings in terms of both the cost of consumables and time. these advantages are important criteria for diagnostic laboratories.36 an added advantage of this study was the identification of all variants within the roi, which comprised the coding regions and flanking 20 bp of the brca1/2 genes. figure 1 panel a & b: fragment analysis of homopolymeric regions. a: electropherograms of selected fragments amplified using a commercially available fragment analysis assay. heterozygotes are identified by arrows. b: sequence electropherograms of the heterozygous regions of the brca1 and brca2 genes shown in panel a. the arrows indicate that length heterozygosity is due to a differing number of adenosines. diagnostic screening workflow for mutations in the brca1 and brca2 genes e64 | squ medical journal, february 2015, volume 15, issue 1 the quality of sequencing data is the major concern when implementing mps in a diagnostic setting. the phred score system has been widely adopted as a quality measure for automated sequencing approaches.24 phred scores of 20 for bi-directional sequence data and 30 for uni-directional data have been recommended as rigorous quality control parameters.37 the sangerbased sequencing approach utilised had a phred score of 35 and a 99.97% base call accuracy; it is crucial for a diagnostic laboratory to maintain this score quality when implementing mps. in order to achieve a similar mps phred score, a depth of coverage of 30x and a vf of 20% were implemented. these measures were chosen based on the results of the evaluation cohort and the findings of de leeneer et al.25 also referred to as the allelic fraction, vf is the proportion of individual reads containing the variant call.25 a vf of 100% for homozygotes and 50% for heterozygotes is ideal. however, cut-off frequencies for heterozygous and homozygous calls have been reported from 23–74% and 78–100%, respectively.25 according to jones et al., variant calls of <85% for homozygous variants and <40% for heterozygous variants should be discarded.38 from the mps data in the current study, a homozygous variant with a vf of 81% was observed; sanger-based sequencing determined that this variant was a true heterozygote. based on jones et al.’s findings, a false-negative result would have been generated if this call was discarded.38 as a result, cut-off ranges were defined as 90–100% and 40–60% for homozygotes and heterozygotes, respectively. genotypes of variants that fell outside of the stated thresholds were confirmed by sanger based sequencing. in the current study, a total of 33 amplicons required sequencing confirmation. however, this sequence load reflects samples that were biased towards positive mutations. in the case of a mutation-negative patient, a sanger-based sequence load of approximately one amplicon would be expected, which would include the confirmation of any non-pathogenic or missense variants with unknown clinical significance detected for the first time. the ability to multiplex samples is one of the main advantages of mps, allowing for cost-effective sequencing with a high sample throughput. the current study was largely confined to analysing five patients per single experiment. an experiment where seven samples were multiplexed was performed to improve cost savings; however, both sensitivity and specificity decreased with less than 10,000 reads generated for each sample. this is lower than the manufacturer’s recommendation of 11,000 reads per sample. in addition, the average base coverage was 106 ± 58 bp, which indicated that multiplexing seven samples decreased the confidence of variant calls due to lower coverage across the roi. mps technology is rapidly evolving and further developments and improvements will continue to reduce costs. while the current study has presented an introduction to mps in the context of a small diagnostic laboratory, the possibility of whole exome sequencing and even whole genome sequencing is attractive, albeit requiring a significant increase in data storage and processing. however, these developments suggest that screening a defined number of genes in a targeted approach, as shown in this study, will be superseded by filtering sequence data to identify variants in a defined gene list that is relevant to the clinical referral. the validation of the approach described here was limited in scope due to the number of patients analysed; hence, the current study could be considered under-powered.39 in order to mitigate this feature, further work has been undertaken assessing an additional 70 patients referred for brca1/2 gene sequencing by mps. these data (not shown here) comprise the identification of approximately 500 variants, all of which are either known exonic and intronic snps (averaging seven per patient), known mutations (eight patients) or novel mutations (two patients). all mutations were confirmed as correct by sanger-based sequencing. importantly, the exonspecific primer designs have provided a critical resource for the confirmation of variants detected by mps and for predictive testing. the fact that the figure 2: flowchart of massively parallel sequencing/ homopolymer workflow for brca1 and brca2 referrals. mps = massively parallel sequencing ; hp = homopolymer; vf = variant frequency; fp = false-positive; utr = untranslated region. stella lai, clare brookes, debra o. prosser, chuan-ching lan, elaine doherty and donald r. love clinical and basic research | e65 primers do not overlie known snps has reduced the likelihood of allelic drop-out. conclusion in comparison to traditional sanger-based sequencing, the mps workflow led to a reduction in cost, analysis time and turn-around time for the screening of brca1/2 genes. the analysis used achieved high analytical sensitivity and specificity, but required complementary fragment analysis combined with sanger-based sequencing confirmation in some instances. mps technology is rapidly evolving and further developments and improvements will continue to reduce costs. the current study presented an introduction to mps in the context of a small diagnostic laboratory. a p p e n d i c e s primer sequences, nested primers for sequencing selected exons, brca1/2 gene variants detected and a brief cost-efficiency analysis of the methods used are available in four supplementary tables included in the online version of this article. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. frança lt, carrilho e, kist tb. a review of dna sequencing techniques. q rev biophys 2002; 35:169–200. doi: 10.1017/ s0033583502003797. 2. metzker ml. sequencing technologies: the next generation. nat rev genet 2010; 11:31–46. doi: 10.1038/nrg2626. 3. zhou x, ren l, meng q, li y, yu y, yu j. the next-generation sequencing technology and application. protein cell 2010; 1:520–36. doi: 10.1007/s13238-010-0065-3. 4. sanger f, nicklen s, coulson ar. dna sequencing with chain-terminating inhibitors. proc natl acad sci u s a 1977; 74:5463–7. doi: 10.1073/pnas.74.12.5463. 5. wheeler da, srinivasan m, egholm m, shen y, chen l, mcguire a, et al. the complete genome of an individual by massively parallel dna sequencing. nature 2008; 452:872–6. doi: 10.1038/nature06884. 6. voelkerding kv, dames sa, durtschi jd. next-generation sequencing: from basic research to diagnostics. clin chem 2009; 55:641–58. doi: 10.1373/clinchem.2008.112789. 7. cunningham r, shaw c, blakely t, atkinson j, sarfati d. ethnic and socioeconomic trends in breast cancer incidence in new zealand. bmc cancer 2010; 10:674. doi: 10.1186/1471-240710-674. 8. taylor mr. genetic testing for inherited breast and ovarian cancer syndromes: important concepts for the primary care physician. postgrad med j 2001; 77:11–15. doi: 10.1136/ pmj.77.903.11. 9. michils g, hollants s, dehaspe l, van houdt j, bidet y, uhrhammer n, et al. molecular analysis of the breast cancer genes brca1 and brca2 using amplicon-based massive parallel pyrosequencing. j mol diagn 2012; 14:623–30. doi: 10.1016/j.jmoldx.2012.05.006. 10. kim by, lee dg, lee kr, han sh, surendran s, han cw, et al. identification of brca1 and brca2 mutations from korean breast cancer patients using denaturing hplc. biochem biophys res commun 2006; 349:604–10. doi: 10.1016/j. bbrc.2006.08.086. 11. ou j, wu t, sijmons r, ni d, xu w, upur h. prevalence of brca1 and brca2 germline mutations in breast cancer women of multiple ethnic region in northwest china. j breast cancer 2013; 16:50–4. doi: 10.4048/jbc.2013.16.1.50. 12. ratajska m, brozek i, senkus-konefka e, jassem j, stepnowska m, palomba g, et al. brca1 and brca2 point mutations and large rearrangements in breast and ovarian cancer families in northern poland. oncol rep 2008; 19:263–8. doi: 10.3892/ or.19.1.263. 13. riahi a, kharrat m, ghourabi me, khomsi f, gamoudi a, lariani i, et al. mutation spectrum and prevalence of brca1 and brca2 genes in patients with familial and early-onset breast/ovarian cancer from tunisia. clin genet 2013. doi: 10.1111/cge.12337. [epub ahead of print]. 14. vuttariello e, borra m, calise c, mauriello e, greggi s, vecchione a, et al. a new rapid methodological strategy to assess brca mutational status. mol biotechnol 2013; 54:954– 60. doi: 10.1007/s12033-012-9646-0. 15. struewing jp, hartge p, wacholder s, baker sm, berlin m, mcadams m, et al. the risk of cancer associated with specific mutations of brca1 and brca2 among ashkenazi jews. n engl j med 1997; 336:1401–8. doi: 10.1056/nejm199705153362001. 16. roa bb, boyd aa, volcik k, richards cs. ashkenazi jewish population frequencies for common mutations in brca1 and brca2. nat genet 1996; 14:185–7. doi: 10.1038/ng1096-185. 17. tarabeux j, zeitouni b, moncoutier v, tenreiro h, abidallah k, lair s, et al. streamlined ion torrent pgm-based diagnostics: brca1 and brca2 genes as a model. eur j hum genet 2014; 22:535–41. doi: 10.1038/ejhg.2013.181. 18. doherty e, marquis-nicholson r, love jm, brookes c, prosser d, love dr. primer design to sequence analysis: a pipeline for a molecular genetic diagnostic laboratory. in: ivanov o, ed. applications and experiences of quality control. rijeka, croatia: intech, 2011. pp. 257–72. 19. national center for biotechnology information. dbsnp. from: www.ncbi.nlm.nih.gov/snp accessed: sep 2014. 20. national genetics reference laboratory manchester. snpcheck. from: www.ngrl.org.uk/manchester/projects/ snpcheck accessed: sep 2014. 21. messing j. new m13 vectors for cloning. methods enzymol 1983; 101:20–78. doi: 10.1016/0076-6879(83)01005-8. 22. yanisch-perron c, vieira j, messing j. improved m13 phage cloning vectors and host strains: nucleotide sequences of the m13mp18 and puc19 vectors. gene 1985; 33:103–19. doi: 10.1016/0378-1119(85)90120-9. 23. human genome variation society (hgvs). nomenclature for the description of sequence variants. from: www.hgvs.org/ mutnomen accessed: sep 2014. 24. mardis er. the impact of next-generation sequencing technology on genetics. trends genet 2008; 24:133–41. doi: 10.1016/j.tig.2007.12.007. 25. de leeneer k, de schrijver j, clement l, baetens m, lefever s, de keulenaer s, et al. practical tools to implement massive parallel pyrosequencing of pcr products in next generation molecular diagnostics. plos one 2011; 6:e25531. doi: 10.1371/ journal.pone.0025531. diagnostic screening workflow for mutations in the brca1 and brca2 genes e66 | squ medical journal, february 2015, volume 15, issue 1 26. ewing b, green p. base-calling of automated sequencer traces using phred: ii error probabilities. genome res 1998; 8:186– 94. doi: 10.1101/gr.8.3.175. 27. ellard s, charlton r, lindsay h, camm n, watson c, abbs s, et al.; clinical molecular genetics society. practice guidelines for targeted next generation sequencing analysis and interpretation. from: www. cmgsweb.shared.hosting.zen.co.uk/ bpgs/bpg%20for%20targeted%20next%20generation%20 sequencing%20final.pdf accessed: feb 2014. 28. craig dw, pearson jv, szelinger s, sekar a, redman m, corneveaux jj, et al. identification of genetic variants using barcoded multiplexed sequencing. nat methods 2008; 5:887–93. doi: 10.1038/nmeth.1251. 29. gargis as, kalman l, berry mw, bick dp, dimmock dp, hambuch t, et al. assuring the quality of next-generation sequencing in clinical laboratory practice. nat biotechnol 2012; 30:1033–6. doi: 10.1038/nbt.2403. 30. balzer s, malde k, lanzén a, sharma a, jonassen i. characteristics of 454 pyrosequencing data: enabling realistic simulation with flowsim. bioinformatics 2010; 26:i420–5. doi: 10.1093/bioinformatics/btq365. 31. balzer, s, malde k, jonassen i. systematic exploration of error sources in pyrosequencing flowgram data. bioinformatics 2011; 27:i304–9. doi: 10.1093/bioinformatics/btr251. 32. berkeley drosophila genome project (bdgp). splice site prediction by neural network. from: www.fruitfly.org/seq_ tools/splice.html accessed: sep 2014. 33. reese mg, eeckman fh, kulp d, haussler d. improved splice site detection in genie. j comput biol 1997; 4:311–23. doi: 10.1145/267521.267766. 34. national human genome research institute, national institutes of health. breast cancer information core: an open access on-line breast cancer mutation data base. from: www. research.nhgri.nih.gov/bic/ accessed: sep 2014. 35. biobase biological databases. hgmd® human gene mutation database. from: www.biobase-international.com/ product/hgmd accessed: sep 2014. 36. alansari a, al-rawahi s, ba-omar t, al-nabhani m, date a. the identification of pompe disease mutations in archival tissues and development of a rapid molecular-based test. sultan qaboos univ med j 2013; 13:502–9. 37. ellard s, charlton r, lindsay h, camm n, watson c, abbs s, et al.; clinical molecular genetics society. practice guidelines for targeted next generation sequencing analysis and interpretation. from: www.cmgsweb.shared.hosting.zen.co.uk/ bpgs/bpg%20for%20targeted%20next%20generation%20 sequencing%20final.pdf accessed: feb 2014. 38. jones ma, bhide s, chin e, ng bg, rhodenizer d, zhang vw, et al. targeted polymerase chain reaction-based enrichment and next generation sequencing for diagnostic testing of congenital disorders of glycosylation. genet med 2011; 13:921– 32. doi: 10.1097/gim.0b013e318226fbf2. 39. mattocks cj, morris ma, matthijs g, swinnen e, corveleyn a, dequeker e, et al. a standardized framework for the validation and verification of clinical molecular genetic tests. eur j hum genet 2010; 18:1276–88. doi: 10.1038/ejhg.2010.101. appendix 1: primer sequences for amplifying the coding regions of the brca1 and brca2 genes exon forward primer sequences reverse primer sequences brca1 2 tgtaaaacgacggccagtggacgttgtcattagt tctttgg caggaaacagctatgaccagaggcagagtgg atggaga 3 tgtaaaacgacggccagtaaatattgaacgaact tgaggc caggaaacagctatgaccggtgtttcctgggt tatgaag 4 tgtaaaacgacggccagtggctcttaagggcag ttgtg caggaaacagctatgaccaaactttcaggaaa ataactttgg 5 tgtaaaacgacggccagtttgattatagaggttt tctactgttgc caggaaacagctatgaccaaaaggtcttatca ccacgtcatag 6 tgtaaaacgacggccagttgtcttaacacaacaa agagcatac caggaaacagctatgaccgaggactgcttcta gcctgg 7 tgtaaaacgacggccagtttctcttcaggagga aaagcac caggaaacagctatgaccttggcaaaactata agataaggaatc 8 tgtaaaacgacggccagtctagcattgtacctg ccacag caggaaacagctatgacctgcacatacatccc tgaacc 9 tgtaaaacgacggccagtcccagcaaccatttc atttc caggaaacagctatgaccaacgaaagggcaa caatcag 10-1 tgtaaaacgacggccagtggttgatttccacct ccaag caggaaacagctatgacccagactccccatca tgtgag 10-2 tgtaaaacgacggccagttgccatgctcagaga atcc caggaaacagctatgaccagctttcgttttga aagcag 10-3 tgtaaaacgacggccagtcaagaaagcagattt ggcag caggaaacagctatgacctttcttctcttgga aggctagg 10-4 tgtaaaacgacggccagtgagccaagaagagta acaagcc caggaaacagctatgaccttgtttctttaagg acccagag 10-5 tgtaaaacgacggccagtgcagaatacattcaag gtttcaaag caggaaacagctatgacctcattaatactgga gcccacttc stella lai, clare brookes, debra o. prosser, chuan-ching lan, elaine doherty and donald r. love clinical and basic research | e67 10-6 tgtaaaacgacggccagtacagtgagcacaatt agccg caggaaacagctatgaccaagcagggaagct cttcatc 10-7 tgtaaaacgacggccagtggagtcctagccctt tcacc caggaaacagctatgacctgctccccaaaagc ataaac 11 tgtaaaacgacggccagtaatccagtcctgcca atgag caggaaacagctatgaccaatgcaaaggaca ccacaca 12 tgtaaaacgacggccagtttaaaaggtgttcagc tagaacttg caggaaacagctatgaccggacaagaaccaa ggctcc 13 tgtaaaacgacggccagtttgtgtatcatagatt gatgcttttg caggaaacagctatgaccgcaataaaagtgta taaatgcctg 14 tgtaaaacgacggccagttctgatctctctgaca tgagctg caggaaacagctatgaccacaccaagactccc tcatcc 15 tgtaaaacgacggccagtaattcttaacagagac cagaactttg caggaaacagctatgacctgacaatacctacat aaaactctttcc 16 tgtaaaacgacggccagtcactttaaatagttcc aggacacg caggaaacagctatgacccgcctcatgtggtt ttatgc 17 tgtaaaacgacggccagttccagattgatcttg ggagtg caggaaacagctatgacctggtaactcagact cagcatcag 18 tgtaaaacgacggccagtagggaaggacctctc ctctg caggaaacagctatgaccggtgcattgatgga aggaag 19 tgtaaaacgacggccagttgtctgctccacttc cattg caggaaacagctatgacctggaatacagagtg gtgggg 20 tgtaaaacgacggccagtgcagcagaaatcatc aggtg caggaaacagctatgaccttcagcaatctgag gaaccc 21 tgtaaaacgacggccagtaccattgtcctttgg agcag caggaaacagctatgaccatggagtcttttgg cacagg 22 tgtaaaacgacggccagttgaagtgacagttcc agtagtcc caggaaacagctatgaccaaaccaaacccatg caaaag 23 tgtaaaacgacggccagtaggaccctggagtcg attg caggaaacagctatgaccaaataatgaatcag catcttgctc brca2 2 tgtaaaacgacggccagtaatgcatccctgtgta agtgc caggaaacagctatgaccagcaacactgtgac gtactgg 3 tgtaaaacgacggccagttgccttaacaaaagta atccatagtc caggaaacagctatgaccgatttgcccagcat gacac 4 tgtaaaacgacggccagtaaacacttccaaaga atgcaaa caggaaacagctatgacctctaccaggctctt agccaaa 5/6 tgtaaaacgacggccagtccagcagctgaaatt tgtgag caggaaacagctatgacctctcagggcaaag gtataacg 7 tgtaaaacgacggccagtagcgttatacctttg ccctg caggaaacagctatgaccttgacaccactgga ctaccac 8 tgtaaaacgacggccagtttcactgtgttgattg acctttc caggaaacagctatgaccgacagcagagtttc acaggaag 9 tgtaaaacgacggccagttccatttccattttcc tttcc caggaaacagctatgacctcacgaccatttga gaccag 10-1 tgtaaaacgacggccagttgtttctatgagaaag gttgtgaga caggaaacagctatgaccacaggccaaagac ggtacaa 10-2 tgtaaaacgacggccagtggaaccaaatgatac tgatcc caggaaacagctatgacctttccagtccactt tcagagg 10-3 tgtaaaacgacggccagtgtggcttcttcattt caggg caggaaacagctatgacccagaaggaatcgtc atctataaaac 11-a tgtaaaacgacggccagtcactgtgcccaaaca ctacc caggaaacagctatgaccgcacatacatcttg attcttttcc diagnostic screening workflow for mutations in the brca1 and brca2 genes e68 | squ medical journal, february 2015, volume 15, issue 1 11-b tgtaaaacgacggccagtcaaggatgttctgtca aacctagtc caggaaacagctatgaccttggacctaagagt cctgcc 11-c tgtaaaacgacggccagtaagtagctaatgaaa ggaataa caggaaacagctatgaccgtaaatgtgcagat acagtatta 11-d tgtaaaacgacggccagtacaaatgggcaggac tcttaggtc caggaaacagctatgaccgatcagcatctctg cattcctcagaag 11-e tgtaaaacgacggccagtcagatgttattttcca agcagg caggaaacagctatgacccccctaaaccccac ttcatt 11-f tgtaaaacgacggccagtgaggaatgcagagat gctga caggaaacagctatgaccttgaatcactgcca tcaaattc 11-g tgtaaaacgacggccagttcttcaagtaaatgtc atgattctg caggaaacagctatgacctccattttgttcttt cttatgtcag 11-h tgtaaaacgacggccagtgccagtttatgaagg aggg caggaaacagctatgaccgtcactagttgatt tccagtacc 11-i tgtaaaacgacggccagttcagactgcaagtgg gaaaa caggaaacagctatgaccaagttgcaggactt tttgctg 11-j tgtaaaacgacggccagtaaaaccttgtttctat tgagactgtg caggaaacagctatgacccagtttgtgggtat gcatttg 11-k tgtaaaacgacggccagtaatgattcaggatatc tctcaaa caggaaacagctatgaccactttctccaatcc agacatat 11-l tgtaaaacgacggccagtggccacctgcattta ggata caggaaacagctatgacccttgcgttttgtaa tgaagca 11-m tgtaaaacgacggccagttgccaaacgaaaatt atggc caggaaacagctatgaccagatgaatttacca cattatatg 11-n tgtaaaacgacggccagtgcttcataagtcagtc tcatctgc caggaaacagctatgaccgctctgggtttct cttatc 11-o tgtaaaacgacggccagtaatactgctatacgta ctccaga caggaaacagctatgaccccaaaacatgaatg ttctca 11-p tgtaaaacgacggccagtttcacctacgtctaga caaaatgtatc caggaaacagctatgaccacactttaaaaata gtgattggcaac 12 tgtaaaacgacggccagtctgactttactctttc aaacattagg caggaaacagctatgaccaaatgctcttttag gtcctcagt 13 tgtaaaacgacggccagttgctgatttctgttgt atgcttg caggaaacagctatgaccttggcttccaaact tttgttg 14 tgtaaaacgacggccagtatgagggtctgcaac aaagg caggaaacagctatgaccgggaaaaccatca ggacatt 15 tgtaaaacgacggccagtgcctcagcctgctga ata caggaaacagctatgaccccattcctgcacta atgtgttc 16 tgtaaaacgacggccagttttggtaaattcagtt ttggtttg caggaaacagctatgaccgagaagaaagagg gatgaggg 17 tgtaaaacgacggccagtaccatgctcagcaat gaag caggaaacagctatgacccactgacaactggc ttgtgc 18 tgtaaaacgacggccagtgtttaaacagtggaat tctagagtca caggaaacagctatgacccagtacatctaaga aattgagcatcc 19 tgtaaaacgacggccagtggcagttctagaagaa tgaaaactc caggaaacagctatgaccggcaagagaccga aactcc 20 tgtaaaacgacggccagtgcctggcctgataca attaac caggaaacagctatgacctgtcccttgttgct attctttg 21 tgtaaaacgacggccagttgcttggttctttagt tttagttgc caggaaacagctatgaccccttgaataatcatc aagcctca 22 tgtaaaacgacggccagtgctctaattttgttgt atttgtcctg caggaaacagctatgaccaatcattttgttagt aaggtcattttt 23/24 tgtaaaacgacggccagtgcaaaatccactacta atgccc caggaaacagctatgacctgccaactggtagc tccaac stella lai, clare brookes, debra o. prosser, chuan-ching lan, elaine doherty and donald r. love clinical and basic research | e69 appendix 2: nested primers for sequencing selected exons of the brca1 and brca2 genes exon primer sequence brca1 6 internal reverse gaagaagaaaacaaatgg 8 internal forward acccttttaattaagaaa brca2 3 internal forward gatttaggaccaataag 9 internal reverse caacaacaacaaaaaaacc 10-3 internal reverse gtactatttacaaaaaaaaaaa 13 internal reverse gggaagtgttaacttct 15-1 internal forward gctaagtatttattctttg 15-1 internal reverse ccatcagtattgtagac appendix 3: brca1 and brca2 gene variants* detected in 20 dna samples mutation protein mutation type variant class† clinical importance‡ detection method count§ brca1 c.140g>a p.cys47tyr missense dm mps 1 c.212+1g>t intronic ivs dm yes mps 1 c.213-11t>g intronic ivs dm yes mps 1 c.1067a>g p.gln356arg missense dp unknown mps 3 c.1175_1214del40 p.leu392glnfsx5 frame-shift dm yes mps 1 c.2077g>a p.asp693asn missense dp no mps 2 c.2082c>t p.ser694ser synonymous unknown mps 9 c.2311t>c p.leu771leu synonymous unknown mps 9 c.2315t>c p.val772ala missense dm unknown mps 1 c.2612c>t p.pro871leu missense dfp no mps 8 c.2612delcinstt p.pro871leufsx32 frame-shift dm mps 1 c.3113a>g p.glu1038gly missense dp no mps 9 c.3119g>a p.ser1040asn missense dm? unknown mps 1 c.3548a>g p.lys1183arg missense dp no mps 9 c.3706_3707delaa p.asn1236tyrfsx7 frame-shift dm yes mps 1 25 tgtaaaacgacggccagtaagcaacaggtcatt ttggaa caggaaacagctatgaccccccatctcctgag gttcat 26 tgtaaaacgacggccagttccctatcagctagat tcccc caggaaacagctatgacccccagagtttcata tcttgcttc 27-1 tgtaaaacgacggccagttaggggagggagact gtgtg caggaaacagctatgaccaccagacaaaaga gcttggg 27-2 tgtaaaacgacggccagtacagaaggcatttca gccac caggaaacagctatgaccaaacgctgaggtaa atttgaaac blue = 5’ tails for forward primers taken from the m13 bacteriophage genome. 21,22 red = 5’ tails for reverse primers taken from the m13 bacteriophage genome.21,22 diagnostic screening workflow for mutations in the brca1 and brca2 genes e70 | squ medical journal, february 2015, volume 15, issue 1 c.3756_3759delgtct p.ser1253argfsx10 frame-shift dm yes mps 1 c.4065_4068deltcaa p.asn1355lysfsx10 frame-shift dm yes mps 1 c.4308t>c p.ser1436ser synonymous unknown mps 9 c.4837a>g p.ser1613gly missense dm? no mps 9 brca2 c.68-7t>a intronic ivs dm unknown mps 1 c.865a>c p.asn289his missense dp no mps 1 c.1114a>c p.asn372his missense dfp c>a mps 11 c.1365a>g p.ser455ser synonymous no mps 1 c.1395a>c p.val465val synonymous unknown mps 1 c.1813dupa p.ile605asnfsx11 frame-shift dm yes hp kit 1 c.1938c>t p.ser646ser synonymous no mps 1 c.2229t>c p.his743his synonymous no mps 1 c.2957dupa p.asn986lysfsx2 frame-shift dm yes hp kit 1 c.2971a>g p.asn991asp missense dm? no mps 1 c.3396a>g p.lys1132lys synonymous no mps 10 c.3807t>c p.val1269val synonymous no mps 5 c.4478_4481delaaag p.glu1493valfsx10 frame-shift dm yes mps 1 c.7242a>g p.ser2414ser synonymous no mps 6 c.7655_7658delttaa p.ile2552thrfsx95 frame-shift dm yes mps 1 c.7762_7764delatainstt p.ile2588phefsx60 frame-shift dm mps 1 c.7806-14t>c intronic ivs unknown mps 17 c.7977-1g>c intronic ivs dm yes mps 1 c.8149g>t p.ala2717ser missense dm? no mps 1 c.8297delc p.thr2766asnfsx11 frame-shift dm yes mps 1 c.8575delc p.gln2859lysfsx4 frame-shift dm yes mps 1 c.9257-16t>c intronic ivs unknown mps 1 c.9976a>t p.lys3326x nonsense dp no mps 1 dm = disease-causing mutation; = not reported; mps = massively parallel sequencing ; ivs = intervening sequence; dp = disease-associated polymorphism; dfp: disease-associated polymorphism with additional supporting functional evidence; dm? = potential disease-causing mutation; c>a = reported as base pair change from cytosine to adenine; hp = homopolymer. *variants are named according to human genome variation society nomenclature, version 2.0.23 †according to the human genome mutation database (biobase hgmd® professional, biobase biological databases, beverly, massachusetts, usa) in february 2013.35 ‡according to the 2014 breast cancer information core database.34 §number of times the variant was observed in the dna samples. appendix 4: cost-efficiency of massively parallel sequencing/homopolymer mutation screening strategy for brca1 and brca2 genes sanger sequencing multiplexing five samples sequenced by mps savings cost per sample in nzd 2,700 820 1,880 time per sample in minutes 510 284 226 nzd = new zealand dollars; mps = massively parallel sequencing. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e204-210, epub. 7th apr 14 submitted 10th nov 13 revision req. 6th jan 14; revision recd. 1st feb 14 accepted 18th feb 14 departments of 1obstetrics & gynaecology and 4child health, sultan qaboos university hospital; 2oman medical specialty board; 3department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university; muscat, oman *corresponding author e-mail: gowri@squ.edu.om نتائج احلمل ثالثي التوائم يف األمهات واألجنة يف مستشفى رعاية ثالثي يف سلطنة عمان مرمي ال�صكرية، دردانا خان، عاتكة احل�رشمية، نهال الريامية، فاديانثان جوري ، رحمة الهدابية، حممد عبد اللطيف، متيمة الدغي�صية abstract: objectives: the aim of this study was to describe the fetal and maternal outcomes of triplet gestation and to report on the maternal characteristics of those pregnancies in a tertiary care centre in oman. methods: a retrospective study was undertaken of all triplet pregnancies delivered at sultan qaboos university hospital, muscat, oman, between january 2009 and december 2011. results: over the three-year study period, there were 9,140 deliveries. of these, there were 18 triplet pregnancies, giving a frequency of 0.2%. the mean gestational age at delivery was 31.0 ± 3.0 weeks, and the mean birth weight was 1,594 ± 460 g. the most common maternal complications were preterm labour in 13 pregnancies (72.2%), gestational diabetes in 7 (39%) and gestational hypertension in 5 (28%). of the total deliveries, there were 54 neonates. neonatal complications among these included hyaline membrane disease in 25 neonates (46%), hyperbilirubinaemia in 24 (43%), sepsis in 18 (33%) and anaemia in 8 (15%). the perinatal mortality rate was 55 per 1,000 births. conclusion: the maternal and neonatal outcomes of triplet pregnancies were similar to those reported in other studies. keywords: triplet pregnancies; morbidity; perinatal mortality; fetus, complications; preterm births; fertility; oman. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل و�صف نتائج الأمهات والأجنة للحمل ثلثي التوائم وبيان اخل�صائ�س ال�رشيرية للأمهات يف هذا النوع من احلمل يف م�صت�صفى رعاية ثالثي يف �صلطنة عمان. الطريقة: هذه الدرا�صة ال�صتعادية �صمت جميع حالت احلمل ثلثية التوائم التي متت ولدتها يف م�صت�صفى جامعة ال�صلطان قابو�س ، م�صقط ، �صلطنة عمان يف الفرتة مابني يناير 2009 و دي�صمرب 2011. النتائج: خلل فرتة الدرا�صة كان هناك 9,140 حالة ولدة. من تلك احلالت كانت هناك 18 ولدة ثلثية التوائم بن�صبة %0.2. متو�صط عمر احلمل عند الولدة كان 3.0 ± 31.0 ا�صبوع ومتو�صط وزن الطفال عند الولدة 460 ± 1,594 غ. اأكرث امل�صاعفات �صيوعا بني المهات كانت الولدة املبكرة يف 13 حمل )%72.2(، �صكري احلمل يف 7 حاالت )39%( وارتفاع �صغط الدم احلملي يف 5 حاالت )%28( . �صملت الدرا�صة 54 مولوداً. ت�صمنت امل�صاعفات عند هوؤلء املواليد مر�س الغ�صاء الزجاجي يف )46%( 25، الريقان يف )%43( 24، اإنتان الدم يف )%33( 18 وفقر الدم يف )%15( 8 مواليد. بلغ معدل الوفاة يف الفرتة املحيطة بالولدة 55 لكل 1,000 ولدة. اخلال�صة: نتائج درا�صتنا اخلا�صة بالأمهات واملواليد للحمل ثلثي التوائم متاثل النتائج املن�صورة يف درا�صات اأخرى. مفتاح الكلمات: احلمل ثلثي التوائم؛ مر�صية؛ معدل الوفاة يف الفرتة املحيطة بالولدة؛ جنني؛ م�صاعفات؛ ولدة مبكرة؛ خ�صوبة؛ �صلطنة عمان. maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman maryam al-shukri,1 durdana khan,1 atka al-hadrami,2 nihal al-riyami,1 *vaidyanathan gowri,3 rahma haddabi,1 mohammed abdellatif,4 tamima al-dughaishi1 clinical & basic research advances in knowledge this is one of the first studies in oman on the prevalence of triplet pregnancies. this study also provides information on iatrogenic triplet pregnancies due to the use of fertility medications. application to patient care the results of this study will help in counselling couples on the neonatal outcomes of triplet pregnancies in oman. the incidence of triplet and higherorder multi-fetal gestation has risen several hundred percent since 1980, primarily due to the increasingly widespread availability of fertility therapies.1 the natural incidence of spontaneous triplet pregnancy is approximately 1 in 6,000 to 8,000 births.2 by comparison, triplet births accounted for 153.5 per 100,000 live births in 2009 in the usa, which is approximately 1 in 651 live births;1 fewer than 20% of these were naturally conceived. in 2008, 15.5 per 1,000 women giving birth in england and wales had multiple births compared with 9.8 per 1,000 in 1980. up to 24% of successful in vitro fertilisation (ivf) procedures result in multiple pregnancies and maryam al-shukri, durdana khan, atka al-hadrami, nihal al-riyami, vaidyanathan gowri, rahma haddabi, mohammed abdellatif and tamima al-dughaishi clinical and basic research | e205 currently account for 3% of live births.3 triplet pregnancies are associated with significantly increased risks of maternal and neonatal morbidity. these pregnancies have a significantly higher incidence and risk of diabetes, anaemia, amniotic fluid abnormalities, pregnancy-associated hypertension, eclampsia, incompetent cervix, antepartum haemorrhaging, the use of tocolytic drugs, caesarean deliveries, placental abruption and placenta praevia. overall maternal mortality associated with multiple births is 2.5 times the rate for single births.3 about 75–100% of triplets are born prematurely with an average gestational duration of 32 weeks.3 the overall stillbirth rate is 27.9 per 1,000 triplet births compared with 4.8 per 1,000 single births.3 additional risks to the babies include intrauterine growth restriction with major congenital abnormalities; this is more common in multiple pregnancies (4.9%) than in singleton pregnancies.3 the present retrospective descriptive study was conducted to describe the fetal and maternal outcomes of triplet gestation and to report on the maternal characteristics of these pregnancies in a tertiary care centre in muscat, oman. it is hoped that the results of this study will assist in the future counselling of expectant couples regarding the outcomes of triplet pregnancies in this setting. methods sultan qaboos university hospital (squh) is one of three centres in oman that provides tertiary maternity and neonatal care. data were collected on all triplet pregnancies managed at squh from january 2009 to december 2011; they were gathered from the hospital information system, the labour ward registry and the neonatal unit records. all patients with triplet pregnancies who were followed-up antenatally and delivered in squh were included. unless indications called for admittance, all patients were followed-up on an outpatient basis until almost their third trimester. in women with regular periods, gestational age was calculated from the date of their last menstrual period if they were certain of this date. in cases of ovulation induction, the age was calculated by the known treatment dates and in patients who had undergone ivf by the date of embryo transfer. all of these calculations were complemented by early ultrasound dating in the first trimester.4 first trimester scans were performed to determine chorionicity and second trimester scans were used to identify anomalies. serial growth scans and cervical length assessments by transvaginal ultrasounds were also performed. cervical cerclage was performed where indicated in patients with a short cervix (<2.5 cm) or a history suggestive of cervical incompetence. in some patients, a prophylactic cerclage was performed in the centres where they had received assisted reproductive technology (art). prophylactic steroid administration at 24–28 gestational weeks and admission for bed rest in the third trimester was offered to all patients, with an elective caesarean section at 36–37 gestational weeks. in cases where there was a clinical indication of a fetal or maternal condition, an early delivery was planned. the total hospital stay was calculated from the date of admission to the date of discharge, including any antenatal and postnatal inpatient stays. the number of days spent immediately following the birth of a neonate was determined to be the neonatal hospital stay.4 in order to identify clinically relevant maternal and neonatal complications of triplet gestation, the following definitions were utilised.4 preterm labour was defined as progressive cervical dilatation combined with uterine contractions at <37 weeks’ gestation.4 pre-eclampsia was defined according to national institute for health and clinical excellence (nice) guidelines.5,6 the cut-off value to label a patient as anaemic was a haemoglobin level of less than 10.5 g/ dl. women were diagnosed with gestational diabetes mellitus (gdm) by glucose tolerance testing according to the royal college of obstetricians & gynaecologists and nice guidelines.3 a maternal temperature of 38 °c or more, persisting for more than 24 hours postpartum and requiring investigation and/or treatment was considered as febrile morbidity.4 blood loss of more than 500 ml during vaginal delivery and more than 1,000 ml during caesarean section was defined as post-partum haemorrhage.4 all neonates born were initially assessed by neonatologists; the ones requiring care were admitted to the neonatal intensive care unit (nicu) for further appropriate evaluation and management. chest radiography was the investigation of choice by the neonatologists in the diagnoses of hyaline membrane disease and chronic lung disease. transient tachypnoea of the newborn was defined as respiratory distress lasting <24 hours, after hyaline membrane disease had been ruled out by chest x-ray.4 the assessment and grading of intraventricular haemorrhage was done by a cranial ultrasound examination of the neonate. sepsis was suspected on the basis of a clinical deterioration combined with either a raised c-reactive protein or an abnormal immature white cell count.4 subsequently, sepsis was confirmed on the basis of the above investigations as well as positive cultures from wound swabs/fluids from otherwise sterile sites.4 maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman e206 | squ medical journal, may 2014, volume 14, issue 2 necrotising enterocolitis (nec) was diagnosed based on a clinical diagnosis by a neonatologist. if phototherapy was required, the neonate was labelled as having jaundice (hyperbilirubinaemia).4 if patent ductus arteriosus (pda) was clinically significant and required either medical or surgical therapy, it was also added to the data.4 retinopathy of prematurity was diagnosed and graded according to the standard international classifications7,8 by a paediatric ophthalmologist.4 a blood glucose level of less than 4 mmol/l requiring dextrose therapy was defined as hypoglycaemia and a body temperature of <36 °c was defined as hypothermia. descriptive statistics were undertaken using the statistical package for the social sciences (spss) version 16.0 (ibm, corp., chicago, illinois, usa). this study was approved by the college of medicine research & ethics committees of sultan qaboos university, 4th november 2012 (erc#625). results from january 2009 to december 2011, 18 sets of triplets over 20 weeks’ gestation were delivered at squh. the frequency of triplet pregnancy was 0.2% (18 triplets out of 9,140 total deliveries) [table 1]. the gestational age at delivery varied from <24 weeks to 37 weeks [figure 1]. there was a significant association between triplet pregnancy and infertility and the increased use of art and ovulation induction. of the 18 sets of triplets, 33% (6/18) were conceived via ivf, 28% (5/18) were conceived using gonadotropin stimulation, follicle-stimulating hormone (fsh) and intrauterine insemination (iui), 28% (5/18) with clomiphene and iui and 11% (2/18) were the result of spontaneous conception. the maternal characteristics of the subjects are shown in table 2. the mean maternal age was 29 ± 6 years. mean gravidity was 2 ± 1 and parity was 1 ± 1. the mean gestational age at delivery was 31.0 ± 3.0 weeks and the mean antenatal hospital stay was 27 ± 20 days. the most common maternal prenatal complications were preterm labor (72.2%), gdm (39%) and gestational hypertension (28%) [figure 2]. out of the 18 pregnancies, 16 mothers had at least one antenatal complication. fourteen had emergency caesarean deliveries due to preterm labour occurring much earlier than their previously planned elective caesarean sections. only three patients (16.6%) had elective caesarean deliveries and one (5.5%) had a vaginal delivery because she presented with preterm labour at <23 weeks’ gestation. all 18 mothers received antenatal steroids at a mean gestational age of 26 ± 2 weeks [table 2]. regarding postnatal maternal complications, five women (27%) required blood transfusions; two (11%) were due to post-partum haemorrhaging with blood losses in excess of 1,000 ml. three of the five women had pre-existing antenatal anaemia which was aggravated by the blood loss during their caesarean delivery. post-partum febrile morbidity occurred in one woman (5.5%) which required an extended hospital stay and resulted in endometritis and wound infection. the mean postnatal hospital stay was 6 ± 3 days. the neonatal outcomes of the triplet pregnancies are shown in table 3. among the 54 neonates, the mean birth weight was 1,594 ± 460 g and the mean weight at the time of discharge from the nicu was 1,715 ± 415 g. fifty (90%) neonates were admitted to the nicu and 34 (63%) required surfactants. the mean neonatal hospital stay was 24 ± 10 days [table 3]. there were 3 (5%) neonatal deaths and the perinatal mortality rate was 55 per 1,000. the neonates who had early neonatal death were delivered at <23 weeks’ gestation. antenatal counselling was given to the parents regarding the poor prognosis of survival at this gestational age. among the 54 neonates, neonatal complications included hyaline membrane disease in 25 babies (46%), hyperbilirubinaemia in 23 (43%), sepsis in 18 (33%), anaemia in 8 (15%), pda/atrial septal defect in 5 [9%] and nec in 2 (4%) [figure 3]. figure 1: gestational age group of the neonates at delivery. table 1: frequency of triplet pregnancies by year year total deliveries triplets n (%) 2009 2,414 3 (0.12) 2010 3,396 7 (0.21) 2011 3,330 8 (0.24) maryam al-shukri, durdana khan, atka al-hadrami, nihal al-riyami, vaidyanathan gowri, rahma haddabi, mohammed abdellatif and tamima al-dughaishi clinical and basic research | e207 discussion the majority of the triplet pregnancies in this study were conceived as a result of art. preterm labour of <34 gestational weeks (13/18) was the most common antenatal complication (72.2%) noted in this study. the mean antenatal hospital stay was 27 ± 20 days, which is very similar to other reports where the average antenatal stay was approximately 11–42 days.9,10 in squh, routine antenatal admission for bed rest in the third trimester is offered despite the fact that retrospective analyses have not clearly demonstrated the benefit of bed rest for the prevention of preterm delivery. however, in a study of 20 triplet pregnancies, women with restricted activity delivered at a later mean gestational age than women with unrestricted activity (34.3 and 31.3 weeks, respectively).11 furthermore, a randomised prospective study of 19 triplet gestations compared inpatient bed rest after 24 gestational weeks with outpatient management. bed rest was associated with an additional week’s pregnancy duration, reduced frequency of pre-eclampsia (9% versus 31%) and a lower rate of neonatal intraventricular haemorrhage (1% versus 10%).12 similar findings were noted in nonrandomised studies.13 the mean cervical length of women with triplet pregnancies is reported to be less than that of women with singleton pregnancies.14 in one study, women with triplet pregnancies delivering prior to 33 gestational weeks had shorter cervixes at 28, 30 and 32 weeks than those delivering after 33 weeks.14 the policy at squh during the present study was to monitor cervical length by ultrasound; when cervical length was found to be less than 25 mm (11/18), cervical cerclage was performed to reduce the risk of pregnancy loss and preterm labour. the mean gestational age for the cervical cerclage procedure was 16 weeks. in this study, five emergency cervical cerclages were performed. six women had had prophylactic cerclage performed by the centres where they had received art. the effectiveness of prophylactic cerclage is unproven, despite at least one small series suggesting efficacy.13 the largest study addressing this issue used a national database to compare the outcome of triplet pregnancies with cerclage (n = 248) to those without cerclage (n = 3,030).15 both groups had similar rates of table 3: neonatal outcomes of the triplet pregnancies (n = 18) neonatal outcome mean ± sd n (%) birth weight in g 1,594 ± 460 gestational age in weeks 31 ± 3 apgar score 1 min 7 ± 2 5 mins 9 ± 1 neonatal death 3 (5) intubation 40 (74) surfactant 34 (63) nicu admission 50 (90) total nicu admission 24 ± 10 weight at discharge in g 1,715 ± 415 sd = standard deviation; nicu = neonatal intensive care unit. table 2: maternal characteristics of the triplet pregnancies (n = 18) characteristic mean ± sd n (%) age in years 29 ± 6 gravidity 2 ± 1 parity 1 ± 1 history of infertility 16 (88) duration of infertility in years 6 ± 4 gestational age at first visit in years 18 ± 9 cervical length at first visit in mm 34 ± 9 cervical cerclage 11 (61) gestational age at cerclage in weeks 16 ± 3 cervical length at cerclage in mm 23 ± 7 gestational age at steroid administration in weeks 26 ± 2 gestational age at admission in weeks 28 ± 4 gestational age at delivery in weeks 31 ± 3 mode of delivery emergency caesarean 14 (78) elective caesarean 3 (16.6) vaginal delivery 1 (5.5) postoperative complications post-partum haemorrhage 2 (11) fever 1 (5.5) total hospital stay in days 27 ± 20 postoperative stay in days 6 ± 3 sd = standard deviation. figure 2: maternal complications of the triplet pregnancies. dm = diabetes mellitus; htn = hypertension; pupps = pruritic urticarial papules and plaques of pregnancy. maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman e208 | squ medical journal, may 2014, volume 14, issue 2 preterm birth at <28 and <32 weeks, respectively. available evidence suggests that the effects of glucocorticoids on respiratory distress syndrome are influenced by plurality, with increasing plurality associated with a decreasing effect of the steroids. in a study of 906 triplet infants, 2,460 twin infants and 4,754 singletons, the odds ratios for respiratory distress syndrome among infants who received a complete course of antenatal steroids compared with singletons were 1.4 and 1.8 for twins and triplets, respectively.16 while these findings suggest that the appropriate dose of steroids might be higher in triplets than singletons, there are no data evaluating the efficacy of higher doses in multi-fetal gestations. furthermore, in another study, plurality did not appear to influence the effect of glucocorticoids on the risk of intraventricular haemorrhage.17 it has been observed that the administration of one course of glucocorticoids is most helpful for fetuses who are delivering in the 28–32 gestational week window.4,16,17 in the current study, the mean gestational age for prophylactic steroid administration was 26 ± 2 weeks, although there were three sets of triplets who received steroids at less than 26 gestational weeks as they were preterm. the most common maternal complications were gdm (39%) and gestational hypertension (28%). the results of the current study show that the prevalence of gdm appears to be increased in triplet compared to singleton pregnancies, although this has not been a consistent finding in all studies.18,19 in the current study, seven women developed gdm; five were managed using diet control and exercise and two required insulin for glycaemic control. the prevalence of pregnancy-associated hypertension is significantly increased in triplets compared to singletons (adjusted odds ratio of 2.8).19 five women in the current study developed gestational hypertension. pre-eclampsia complicates 20–46% of triplet pregnancies compared to 5% of singleton pregnancies.13,20–22 pre-eclampsia occurs earlier and is more severe in multi-fetal gestations and the hellp syndrome (haemolysis, elevated liver enzymes and low platelet count) is also more likely. fortunately, no patients in the current study developed pre-eclampsia. in the current study, 17 sets of triplets (94.6%) were delivered by lower segment caesarean section; of these, 14 (78%) were by emergency lower segment caesarean section and 3 (16.%) were by elective caesarean section. one woman (5.4%) spontaneously delivered vaginally because she presented in preterm labour at >23 weeks’ gestation. this shows that the caesarean section was the recommended mode of delivery in this tertiary centre for triplets.4 lipitz et al. reported increased perinatal morbidity—in particular low apgar scores—as well as asphyxia and respiratory complications among vaginally-delivered triplets;23 however, such complications were rarely observed in studies where caesarean sections were the chosen mode of delivery.8 a study from the netherlands suggested that the safety of vaginal delivery is similar to that of caesarean delivery.24 however, there are no randomised controlled studies comparing the safety of caesarean and vaginal deliveries. at present, there is no concrete evidence to justify changes in the existing practices regarding the mode of delivery for triplet pregnancies. post-partum haemorrhage was the most common complication in addition to post-partum pyrexia most probably due to endometritis in 5% of the women in figure 3: neonatal complications of the triplet pregnancies (n = 18). rop = retinopathy of prematurity; gerd = gastroesophageal reflux disease; nec = necrotising enterocolitis; pda = patent ductus arteriosus; asd = atrial septal defect; rds = respiratory distress syndrome of the newborn. maryam al-shukri, durdana khan, atka al-hadrami, nihal al-riyami, vaidyanathan gowri, rahma haddabi, mohammed abdellatif and tamima al-dughaishi clinical and basic research | e209 the current study, which was similar to reports from other studies.25,26 the perinatal mortality rate in the current study was similar to that in the existing literature,27 at 55 per 1,000 live births. the major reason for the high perinatal mortality rate was linked to the low birth weight and very low birth weight of the infants. the mean birth weight was 1,594 ± 460 g and the mean weight at discharge from the nicu was 1,715 ± 415 g. the prevalence of chronic lung disease and retinopathy of prematurity for babies born at 28 gestational weeks or more were consistent with earlier reports.4 although there are no reported rates of sepsis in the existing literature of triplet births, sepsis was the third major cause of neonatal morbidity in the current study, affecting 18 neonates (33%). it is a relevant and important finding, as sepsis is a known cause of death in very preterm infants. the outcomes for triplets born after 28 gestational weeks in squh were favourable. it is hoped that these data will be useful for the counselling of couples planning to use art and also in the management of women with triplet pregnancies. additionally, this study highlights the maternal and fetal outcomes of this high-risk type of pregnancy under the current levels of obstetric and neonatal care. it will give some information to help care providers counsel patients based on their local data. however, this study is limited by its retrospective nature. the patients in the study were referred at different gestational ages from different centres. this means that they had received variable care before the referral, which makes it difficult to correlate the maternal and neonatal outcome with the care provided. furthermore, the small sample size of the study and the fact that it is a single-centre experience makes it difficult to generalise the study outcomes to all triplets pregnancies in oman. further research in the area of multi-fetal gestations and their outcomes is strongly recommended to improve the understanding of the outcomes of these pregnancies and standardise early obstetric care. this research should ideally take the form of a prospective study with a larger sample size. conclusion the maternal and neonatal outcomes of triplet pregnancies in squh are similar to those reported in other studies. it is hoped that these results will reassure healthcare providers that their outcomes are in line with other international centres. it should also help to provide local information about maternal and neonatal outcomes of higher order births to those practioners counselling couples planning assisted reproduction and those counselling women with triplet pregnancies. references 1. martin ja, hamilton be, ventura sj, osterman mj, kirmeyer s, mathews tj, et al. births: final data for 2009. natl vital stat rep 2011; 60:1−70. 2. guttmacher af. the incidence of multiple births in man and some of the other unipara. obstet gynecol 1953; 2:22−35. 3. national institute for health and clinical excellence. clinical guideline 129 multiple pregnancy: the management of twin and triplet pregnancies in the antenatal period. from: www. publications.nice.org.uk/multiple-pregnancy-cg129 accessed: feb 2014. 4. barkehall-thomas a, woodward l, wallace em. maternal and neonatal outcomes in 54 triplet pregnancies managed in an australian tertiary centre. aust n z j obstet gynaecol 2004; 44:222–7. doi: 10.1111/j.1479-828x.2004.00214.x. 5. national institute for health and clinical excellence. clinical guideline 107 hypertension in pregnancy: the management of hypertensive disorders during pregnancy. from: www. guidance.nice.org.uk/cg107 accessed: feb 2014. 6. national institute for health and clinical excellence. clinical guideline 62 antenatal care: routine care for the healthy pregnant woman. from: www.guidance.nice.org.uk/cg62 accessed: feb 2014. 7. international committee for the classification of retinopathy of prematurity. the international classification of retinopathy of prematurity revisited. arch ophthalmol 2005; 123:991–999. doi: 10.1001/archopht.123.7.991. 8. kaufman ge, malone fd, harvey-wilkes kb, chelmow d, penzias as, d’alton me. neonatal morbidity and mortality associated with triplet pregnancy. obstet gynecol 1998; 91:342–38. 9. blickstein i, keith lg. outcome of triplets and high-order multiple pregnancies. curr opin obstet gynecol 2003; 15:113– 7. 10. weissman a, yoffe n, jakobi p, brandes jm, paldi e, blazer s. management of triplet pregnancies in the 1980s: are we doing better? am j perinatol 1991; 8:333–7. doi: 10.1055/s-2007999408. 11. syrop ch, varner mw. triplet gestation: maternal and neonatal implications. acta genet med gemellol (roma) 1985; 34:81–8. 12. crowther ca, verkuyl da, ashworth mf, bannerman c, ashurst hm. the effects of hospitalization for bed rest on duration of gestation, fetal growth and neonatal morbidity in triplet pregnancy. acta genet med gemellol (roma) 1991; 40:63–8. 13. adams dm, sholl js, haney ei, russell tl, silver rk. perinatal outcome associated with outpatient management of triplet pregnancy. am j obstet gynecol 1998; 178:843–7. 14. ramin kd, ogburn pl jr, mulholland ta, breckle rj, ramsey ps. ultrasonographic assessment of cervical length in triplet pregnancies. am j obstet gynecol 1999; 180:1442–5. 15. rebarber a, roman as, istwan n, rhea d, stanziano g.. prophylactic cerclage in the management of triplet pregnancies. am j obstet gynecol 2005; 193:1193–6. doi: 10.1016/j. ajog.2005.05.076. 16. blickstein i, shinwell es, lusky a, reichman b; israel neonatal network. plurality-dependent risk of respiratory distress syndrome among very-low-birth-weight infants and antepartum corticosteroid treatment. am j obstet gynecol 2005; 192:360–4. doi: 0.1016/j.ajog.2004.10.604. maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman e210 | squ medical journal, may 2014, volume 14, issue 2 17. blickstein i, reichman b, lusky a, shinwell es; israel neonatal network. plurality-dependent risk of severe intraventricular hemorrhage among very low birth weight infants and antepartum corticosteroid treatment. am j obstet gynecol 2006; 194:1329–33. doi: 10.1016/j.ajog.2005.11.046. 18. american college of obstetricians and gynecologists committee on practice bulletins-obstetrics; society for maternal-fetal medicine; acog joint editorial committee. acog practice bulletin #56: multiple gestation: complicated twin, triplet, and high-order multifetal pregnancy. obstet gynecol 2004; 104:869–83. 19. luke b, brown mb. contemporary risks of maternal morbidity and adverse outcomes with increasing maternal age and plurality. fertil steril 2007; 88:283–93. doi: 10.1016/j. fertnstert.2006.11.008. 20. holcberg g, biale y, lewenthal h, insler v. outcome of pregnancy in 31 triplet gestations. obstet gynecol 1982; 59:472–6. 21. albrecht jl, tomich pg. the maternal and neonatal outcome of triplet gestations. am j obstet gynecol 1996; 174:1551–6. doi: 10.1016/s0002-9378(96)70605-1. 22. alamia v jr, royek ab, jaekle rk, meyer ba. preliminary experience with a prospective protocol for planned vaginal delivery of triplet gestations. am j obstet gynecol 1998; 179:1133–5. doi: 10.1016/s0002-9378(98)70119-x. 23. lipitz s, reichman b, paret g, modan m, shalev j, serr dm, et al. the improving outcome of triplet pregnancies. am j obstet gynecol 1989; 161:1279–84. doi: 10.1016/0002-9378(89)906832. 24. wildschut hi, van roosmalen j, van leeuwen e, keirse mj. planned abdominal compared with planned vaginal birth in triplet pregnancies. br j obstet gynaecol 1995; 102:292–6. doi: 10.1111/j.1471-0528.1995.tb09134.x. 25. gibbs rs. clinical risk factors for puerperal infection. obstet gynecol 1980; 55:178s–84s. 26. henderson e, love ej. incidence of hospital-acquired infections associated with caesarean section. j hosp infect 1995; 29:245– 55. doi: 10.1016/0195-6701(95)90271-6. 27. joseph ks, marcoux s, ohlsson a, kramer ms, allen ac, liu s, et al. preterm birth, stillbirth and infant mortality among triplet births in canada, 1985-96. paediatr perinat epidemiol 2002; 16:141–8. doi: 10.1046/j.1365-3016.2002.00413.x. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 100–106, epub. 27th feb 13 submitted 6th mar 12 revision req. 4th jun 12, revision recd. 10th jun 12 accepted 30th jul 12 departments of 1family medicine, 2psychiatry and 3medical education, united arab emirates university, al ain, united arab emirates *corresponding author e-mail: jhashim@uaeu.ac.ae تعلم مهارات التواصل بلغه ثانية عند طالب الطب التعاطف والتوقعات حممد ها�صم ، �صتيال ميجور، دين مريزا، اجنيال برن�صلو، اأ�صامة عثمان، لينا اأمريي، مي�صيل مكالين امللخ�ص: الهدف: التدريب على مهارات التواصل للفحص الطيب يف األغلب يكون باللغة اإلجنليزية يف املؤسسات التعليمية الطبية على مستوى العامل. يف هذه الدراسة سعينا ملعرفة إذا كان طالب الطب الناطقني باللغة العربية يواجهون صعوبة يف املكونات املختلفة للتدريب على مهارات التواصل باللغة اإلجنليزية. الطريقة: مت تسجيل شريط فيديو لطالب السنة الثالثة )n=45(كل على حدة أثناء فحصهم ملمثلني دور املرضى. قام كل طالب بتقييم أدائه يف استمارة تقييم تتضمن 13 بنداً )كل بند حيوي 5 مقاييس(. كما مت التقييم من قبل األستاذ وطالب آخرين يف اجملموعة. النتائج: من واقع 13 بنداً من بنود تدريب مهارات التواصل كان أقل البنود تقييما من قبل األساتذة هو مقدرة الطالب على إبداء التعاطف مع املرضى, السؤال عن أحاسيسهم, سالسة تداول املعلومات و استنباط توقعات املرضى )p >0.001(. اخلال�صة: من الصعوبة تطوير مهارة التعبري عن التعاطف واستنباط توقعات املرضى لدى طالب الطب الذين يدرسون بلغة ثانية. مفتاح الكلمات: التوا�صل، التاريخ الطبي، لغة، طالب الطب، عناية املري�ض املركزية، الإمارات العربية املتحدة. abstract: objectives: communications skills (cs) training for medical interviewing is increasingly being conducted in english at medical schools worldwide. in this study, we sought to identify whether arabic-speaking medical students experienced difficulty with the different components of the cs training that were conducted in english. methods: individual third-year preclinical medical students (n = 45) were videotaped while interviewing simulated patients. each student assessed his/her performance on a 13-item (5-point scale) assessment form, which was also completed by the tutor and other students in the group. results: of the 13 components of their cs training, tutors awarded the lowest marks for students’ abilities to express empathy, ask about patients’ feelings, use transition statements, ask about functional impact, and elicit patients’ expectations (p <0.001). conclusion: the expression of empathy and the ability to elicit patients’ feelings and expectations are difficult to develop in medical students learning cs in a second language. keywords: communication; medical history taking; language; medical students; patient-centered care; united arab emirates. medical students learning communication skills in a second language empathy and expectations *muhammad j. hashim,1 stella major,1 deen m. mirza,1 engela a. m. prinsloo,1 ossama osman, leena amiri,2 michelle mclean3 clinical & basic research advances in knowledge preclinical medical students learning communication skills in a second language experience difficulty in demonstrating empathy, and eliciting feelings and expectations from simulated patients. application to patient care when supervising medical students in clinical rotations, instructors should be aware of the difficulty that arab medical students trained in english-medium programmes may have with expressing empathy, and in eliciting patients’ feelings and expectations in a crosscultural clinical context. muhammad j. hashim, stella major, deen m. mirza, engela a.m. prinsloo, ossama osman, leena amiri and michelle mclean clinical and basic research | 101 accumulating evidence suggests that a patient-centred approach to communication in the clinical consultation improves health outcomes, reduces costs, and leads to higher patient satisfaction.1–3 key skills in patientcentred communication skills (cs) include eliciting and prioritising patients’ problems, exploring their ideas, concerns and expectations, and recognising and responding to emotions.4–6 based on his work in rural clinics in nepal, moore has, however, raised the concern that patient-centred communication may be contextually bound to culture and language.7 although research into patient-physician communication in the arab context is limited, social sciences literature does explore cross-cultural communication in such a setting.8,9 observational research suggests that arab patients have certain culture-specific customs, such as restrictions based on gender, or an individual’s status in the family and community. additionally, patterns of acculturation differ from those in western societies.10 within the mental health context, specific guidelines have been suggested including “an emphasis on short-term, directive treatment; communication patterns that are passive and informal; patients' understanding of external loci of control and their use of ethnospecific idioms of distress; and, where appropriate, the integration of modern and traditional healing systems”.10 as some of the observations of arab patients' preferences depart from the patientcentred communication approach, the development of a workable model for teaching patient-physician communication in arab cultures must take these into account. arab physicians’ attitudes, however, seem to vary across the spectrum from paternalistic to patient-centred. when presented with scenarios of diagnosis disclosure and decision-making, physicians and patients favoured a family-oriented over a patient-centred approach.11 a tension thus exists between some traditions of arabic culture and the individual-oriented, patient-centred model currently in vogue in western settings. while the literature reveals only a few studies relating to the difficulty of learning cs in the context of a language difference, it is even more scant for the arab region.12–14 to the best of our knowledge, no studies have been published relating to aspects of patient-centred communication that may be culturally incongruous or challenging during cs training. therefore, this study set out to evaluate the ability of third-year arabic-speaking medical students to develop patient-centred cs in an english-medium programme. methods the faculty of medicine and health sciences (fmhs) at the united arab emirates university (uaeu) was established in 1984 and has an annual intake of 60–80 students, with females comprising at least 60% of each cohort. training is gender-segregated. to prepare medical students for postgraduate studies abroad, the language of instruction is english in all courses, including cs training. the model of cs training is based on generally accepted theoretical frameworks for undergraduate medical education.15–18 extensive use is made of simulated patients (sps). ethical approval for the study was obtained from the uaeu research affairs ethics committee. students were verbally informed in class about the study and participation was voluntary, except in the case of tutor assessments of student performance, which was part of the course requirements. this observational cohort study comprised 45 third-year medical students in the 2009–10 academic year, with females accounting for 78% (n = 35) of the learners. all students were emirati nationals and by implication were native arabicspeakers. as english is the university’s medium of instruction, cs training was conducted in english. english language proficiency amongst students varied, often reflecting their secondary schooling experience (i.e. english-medium teaching if they had studied at private schools or arabic at public schools). the course of cs for medical history-taking involved six weeks of a year-long clinical skills module in the third year of a six-year undergraduate degree. after the first four weeks, students received two additional weeks of cs instruction later in the year. the weekly student contact time was about 6 hours (two hours on each of 3 days) per week. each week was designed to provide a consistent learning structure across the three sessions, addressing different components of patient-centred medical interviewing: orientation on day 1, a videorecording session of individual students with an sp without a faculty tutor on day 2, and finally, on day 3, a video review of the day 2 session with a medical students learning communication skills in a second language empathy and expectations 102 | squ medical journal, february 2013, volume 13, issue 1 faculty tutor in a small group [table 1]. specific skills were introduced sequentially over the first 4 weeks of the course, progressing from basic cs such as introduction and eliciting an agenda to more advanced skills, including exploring feelings and expressing empathy. in weeks 5 and 6, the complete set of cs were revised and assessed in role-plays. prior to the start of the cs training sessions, faculty members and sps jointly attended a workshop to orient them to the objectives of the cs course as well as to provide guidance on providing students with feedback. in addition, sps attended workshops in which they were coached in roleplaying and providing feedback. written patient scenarios were distributed to sps a week in advance but were not revealed to students. on the scheduled cs training days, sps arrived an hour earlier to discuss the week’s patient scenarios with the course organisers. assessment was achieved based on the framework described above using a global rating as well as a cs assessment instrument comprising 13 items. the assessment form included keywords from a lexicon for medical communication.19 each item was scored on a 5-point likert scale, from 5 (excellent) to 1 (not done). all items were based on positive characteristics; thus, higher scores represented a better performance. on day 3 of each week videos from day 2 were reviewed, and students self-assessed their performance using this assessment form. they also received a rating from the tutor and their peers in the group. as empathy forms part of a patient-centred approach, students were asked, prior to the commencement of the cs sessions, to complete an abbreviated version of davis’ interpersonal reactivity index (iri), a self-reported empathy scale.20 this abbreviated inventory, comprising 14-item empathic concern and perspective-taking scales only, has been validated among medical students elsewhere as a reliable measure of selfreported empathy.21 items have a limited-response on a 5-point scale ranging from ‘describes me very well’ to ‘does not describe me well’. we studied one complete cohort of students. post-hoc analysis revealed that a mean difference of one point on the rating scale of 1 to 5 with the observed standard deviations of less than 1.0 would have been detected with a power of 96% with samples as small as 50 assessments. we analysed 207 tutor assessments. the data collected, which included tutor, self, and peer ratings for each student on the 13 cs components and the global score, were analysed using the statistical package for the social sciences, version 18 (ibm, spss inc., chicago, il, usa 2009). standard descriptive statistics were used. as tutor ratings were not normally distributed (kolmogorov-smirnov test, p < 0.05), nonparametric tests were used instead, including the mann-whitney u-test and the spearman’s rankcorrelation coefficient. two-sided statistical testing was applied using a cut-off of 0.05 for significance. sub-group analyses included a comparison between male and female students with a one-way analysis of variance (anova) test. results figure 1, which provides the average tutor rating of four sessions by male and female students for the different components of a patient-centred cs approach, including the global score, suggests that students were generally adept at introducing themselves but were less competent with more patient-centred aspects such as asking about functional impact and patients’ expectations. although male and female students generally scored similarly, some significant differences were measured. specifically, tutors considered male table 1: details of the weekly communication skills training sessions day description outcomes 1 interactive large-group sessions (males and females separate) with live demonstration by faculty tutors with an sp or a review of a professionally recorded video overview of communication skills 2 video-recording of individual interviews with trained sps with different scenarios each week verbal feedback from sp 3 review of individual student videos in small groups facilitated by a faculty tutor verbal feedback: student reflection, peers and tutor 13-item assessment form completed by student, peers, and tutor sp = simulated patient. muhammad j. hashim, stella major, deen m. mirza, engela a.m. prinsloo, ossama osman, leena amiri and michelle mclean clinical and basic research | 103 students more skilled at introducing themselves, and eliciting the patient’s agenda, feelings, and expectations, while females were rated more highly at using silent pauses and showing appropriate body language (p <0 .05). a comparison between self-assessment and peer and tutor ratings over the first 4 weeks of the training, indicated that except for week 2 when there was congruence between the three ratings, peer and self-evaluations were generally higher than the tutor rating [figure 2]. the exception, however, was in week 1, when students generally underestimated their performances while their peers overestimated their abilities. only tutors were asked to score weeks 5 and 6, which took place several weeks after the initial training. basic skills introduce* build rapport elicit agenda* start with open-ended questions use silent pauses* summarize use transition statements advanced skills ask about feelings* ask about ideas of causation ask about functional impact ask about expectations* emphatize skillfully global score (overall rating) show appropriate body language* 0 1 2 3 4 5 mean rating males females 4.8 4.7 4.2 4.2 4.7 4.6 4.5 4.3 4 4.4 4.2 4.4 4.2 4 4.1 4 4 3.8 4.2 3.9 3.9 3.6 3.2 3.9 3.8 4.1 4.1 3.9 figure 1: mean faculty ratings of components of communication skills for male and female medical students n = 44 students (34 females, 10 males, data missing for 1 female student). these data reflect the first four weeks of training only. * = statistically significant difference between male and female students. 5 4 3 2 1 1 0 gl ob al sc or e (m ea n) 1 2 3 4 5 6 video review session assessed by tutor self peer figure 2: tutor, peer and self-ratings of overall interviewing skills over the communication skills training period. medical students learning communication skills in a second language empathy and expectations 104 | squ medical journal, february 2013, volume 13, issue 1 forty students (89%) completed the iri administered at the start of the course. although the mean self-reported empathy score was slightly higher for female students (54.9 ± 5.6) compared with their male colleagues (51.8 ± 7.1), this difference was not statistically significant (p = 0.172) [figure 3]. only 40% of males as compared with 60% of females considered themselves to be empathetic. their self-reported empathy did not, however, correlate with the tutor's rating of the students' ability to empathise with sps (r = -0.099; data for 34 students only). discussion this study explored the learning of patientcentred cs in a second language. based on tutor ratings, students appeared to be able to introduce themselves adequately, elicit an agenda, and begin with open-ended questions, with the more complex skills of expressing empathy and eliciting patients’ feelings, which are key elements of a patientcentred clinical encounter, being less developed, or difficult to acquire, and/or requiring more practice. more practice in these skills is advocated. the need for practice is indicated by the increase in tutor ratings for weeks 5 and 6 after a plateau in weeks 2–4. during weeks 5 and 6, students were practising all 13 components. although zick et al. found that american medical students generally did not report any difficulty mastering the skills of eliciting a patient’s agenda or building rapport, or mastering even more complex skills such as expressing concern and empathy, it must be remembered that those students were learning cs in their native language, and in a western context which subscribes to a patient-centred approach.22 language and culture are intimately linked and, in the present study, both may be influencing the acquisition of more complex patient-centred cs skills. additionally, our course did not include student reflections on empathy and compassion in medical interviewing, which may have hampered the acquisition of these skills. gender differences were found in terms of tutor ratings, with males generally scoring higher on many of the cs components. this contradicts the results of the empathy inventory in which more males reported low-moderate empathy than did females. this discordance between self-reported empathy and observed skills has been reported elsewhere and appears to be a generalisable finding.23 cs educators should therefore not assume that students with more empathetic tendencies will necessarily have the skills to express their concerns to patients. gender differences are possibly due to culture-dependent characteristics in the way female and male students interact with sps, and may be independent of second language effects. the context of the present study raises two issues that have not been addressed to any great extent in the cs literature: learning to communicate in a language different from one’s mother tongue, and the validity or appropriateness of a patientcentred model in a middle eastern/arabic setting. not surprisingly, just as the lack of colloquial english language fluency among medical students 100 90 80 70 60 50 40 30 20 10 0 pe rce nt of ma le or fe ma le stu de nts males females 20 4 40 41 40 55 low (<45) median (45-54) high (55+) iri score figure 3: self-reported empathy among male and female medical students using the abbreviated interpersonnal reactivity index questionnaire. n = 40 students (5 students did not return the questionnaire). the possible score range was 14–70 (higher scores indicate greater self-reported empathy). muhammad j. hashim, stella major, deen m. mirza, engela a.m. prinsloo, ossama osman, leena amiri and michelle mclean clinical and basic research | 105 from non-english speaking backgrounds was a barrier to learning cs in australia, teaching native arabic-speaking medical students to communicate with patients in english poses challenges such as student anxiety and the need for remedial instruction.12–14,24,25 degen and absalom have described barriers to teaching and learning across chinese and australian universities that are in some respects parallel our findings of arab students being taught by international teachers.26 our finding that students appeared reluctant to ask about patients’ expectations may reflect the cultural context. the fact that sps were generally middle-aged western women and unknown to students may have inhibited the exploration of emotions. it may also be that as preclinical students, their difficulty in addressing emotional issues might reflect a lack of understanding of the relationship between psychosocial issues and medical conditions.27 within the arab culture, the value attached to empathy in the doctorpatient relationship certainly warrants further investigation. standard english expressions of empathy are not commonplace in everyday conversation in arab society, unlike utterances of hope and prayers, which may not translate easily into english.29 traditional norms such as saying inshallah, meaning “god be willing”, indicate the strong need to instill hope in patients while implicitly conveying uncertainty about, and yet acceptance of, the outcome. others have argued that expressions of compassion have to be adapted to cultural differences.28 lastly, cross-cultural health care may require the rethinking of existing models of collaborative, participatory, patient-physician communication.29 future studies in this area should explore the benefit of making simulations in cs training more context-specific. this study was limited by the small cohort size and potential bias of the observers, who were mostly western expatriates. among the seven tutors, only three were native arabic-speakers. we did not assess tutors’ abilities to recognise advanced cs in a standardised manner. as we were limited to arab medical students from the uae, generalisation to other arab sub-cultures may not be valid. english language proficiency can affect medical interviewing and may explain some of our findings. further research should compare the performance of students when they interview in arabic to their cs in english, while adjusting for language proficiency. although the iri has been validated, concerns have been raised about the reliability and validity of selfreported empathy.30 the use of this questionnaire in english to assess empathy in arab medical students may have further reduced its validity. despite these limitations, to the best of our knowledge this is the first empirical study using video-recording and structured assessment of cs amongst medical students learning in a second language. conclusion the results of this study suggest that medical students learning cs in an english-medium programme may encounter difficulty with complex communications skills, especially in expressing empathy and eliciting patients’ expectations and feelings. while this may reflect uncertainty in terms of learning cs in a foreign language within the middle eastern context, this observation may also be influenced by cultural factors. cs tutors and clinicians supervising medical students may regard these findings as useful when observing arab students who are interviewing patients in english. a c k n o w l e d g e m e n t s this study, which was conducted between september 2009 and may 2010 at uaeu, was supported through a grant from the uaeu (individual research grant 1520-08-01-10). ethical approval for the study was obtained from the uaeu research affairs ethics committee (ref. 163/10). the authors report no conflict of interest and they alone are responsible for the content and writing of this article. references 1. stewart m, brown jb, donner a, mcwhinney ir, oates j, weston ww, et al. the impact of patientcentered care on outcomes. j fam pract 2000; 49:796–804. 2. beck rs, daughtridge r, sloane pd. physicianpatient communication in the primary care office: a systematic review. j am board fam pract. 2002; 15:25–38. 3. takemura yc, atsumi r, tsuda t. which medical interview behaviors are associated with patient satisfaction? fam med 2008; 40:253–8. 4. de haes h, bensing j. endpoints in medical medical students learning communication skills in a second language empathy and expectations 106 | squ medical journal, february 2013, volume 13, issue 1 communication research, proposing a framework of functions and outcomes. patient educ couns 2009; 74:287–94. 5. arora nk, street jr rl, epstein rm, butow pn. facilitating patient-centered cancer communication: a road map. patient educ couns 2009; 77:319–21. 6. mccormack la, treiman k, rupert d, williamspiehota p, nadler e, arora nk, et al. measuring patient-centered communication in cancer care: a literature review and the development of a systematic approach. soc sci med 2011; 72:1085–95. 7. moore m. what does patient-centred communication mean in nepal? med educ 2008; 42:18–26. 8. dwairy ma. counseling and psychotherapy with arabs and muslims: a culturally sensitive approach. new york: teachers college press; 2006. 9. nasir ls, abdul-haq ak. caring for arab patients: a biopsychosocial approach. milton keynes: radcliffe publishing; 2008. 10. al-krenawi a, graham jr. culturally sensitive social work practice with arab clients in mental health settings. health soc work 2000; 25:9-22. 11. mobeireek af, al-kassimi f, al-zahrani k, alshimemeri a, al-damegh s, al-amoudi o, et al. information disclosure and decision-making: the middle east versus the far east and the west. j med ethics 2008; 34:225–9. 12. hays rb, pearse p, cooper cw, sanderson l. language background and communication skills of medical students. ethn health 1996;1:383–8. 13. mirza dm, hashim mj. communication skills training in english alone can leave arab medical students unconfident with patient communication in their native language. educ health (abingdon) 2010; 23:450. 14. ryan ca, walshe n, gaffney r, shanks a, burgoyne l, wiskin cm. using standardized patients to assess communication skills in medical and nursing students. bmc med educ 2010;10:24. 15. makoul g, schofield t. communication teaching and assessment in medical education: an international consensus statement. netherlands institute of primary health care. patient educ couns 1999; 37:191–5. 16. association of american medical colleges. contemporary issues in medicine: communication in medicine medical school objectives project. 1999. from: https://members.aamc.org/eweb/ upload/contemporary%20issues%20in%20med%20 commun%20in%20medicine%20report%20iii%20. pdf accessed: may 2012. 17. makoul g. essential elements of communication in medical encounters: the kalamazoo consensus statement. acad med 2001; 76:390–3. 18. von fragstein m, silverman j, cushing a, quilligan s, salisbury h, wiskin c. uk consensus statement on the content of communication curricula in undergraduate medical education. med educ 2008; 42:1100–7. 19. arnold rw, losh dp, mauksch lb, maresca tm, storck mg, wenrich md, et al. lexicon creation to promote faculty development in medical communication. patient educ couns 2008; 74:179– 83. 20. davis mh. measuring individual differences in empathy: evidence for a multidimensional approach. j personality soc psych 1983; 44:113–26. 21. hojat m, mangione s, kane gc, gonnella js. relationships between scores of the jefferson scale of physician empathy (jspe) and the interpersonal reactivity index (iri). med teach 2005; 27:625–8. 22. zick a, granieri m, makoul g. first-year medical students’ assessment of their own communication skills: a video-based, open-ended approach. patient educ couns 2007; 68:161–6. 23. berg k, majdan jf, berg d, veloski j, hojat m. a comparison of medical students’ self-reported empathy with simulated patients’ assessments of the students’ empathy. med teach 2011; 33:388–91. 24. chur-hansen a, vernon-roberts j, clark s. language background, english language proficiency and medical communication skills of medical students. med educ 1997; 31:259–63. 25. chur-hansen a, barrett rj. teaching colloquial australian english to medical students from nonenglish speaking backgrounds. med educ 1996; 30:412–7. 26. degen t, absalom d, australia c. teaching across cultures: considerations for western efl teachers in china. hong kong j applied linguistics 1998; 3:117–32. 27. lumma-sellenthin a. talking with patients and peers: medical students’ difficulties with learning communication skills. med teach 2009; 31:528–34. 28. kim s, flaskerud jh. cultivating compassion across cultures. issues in mental health nursing 2007; 28:931. 29. hamilton j. the collaborative model of doctor-patient consultation--is it always culturally appropriate? what do doctors and patients need to know to make it work in intercultural contexts? med teach 2009 ; 31:163–5. 30. pedersen r. empirical research on empathy in medicine--a critical review. patient educ couns 2009; 76:307–22. 31. hofstede g. cultural differences in teaching and learning. int j intercultural relations 1986; 10:301– 20. sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e356-360, epub. 24th jul 14 submitted 18th dec 13 revision reqd. 4th feb 14; revision recd. 28th feb 14 accepted 18th mar 14 department of community medicine, hawler medical university, erbil, iraq *corresponding author e-mail: tariq.hadithi@hmu.edu.iq توزع نوع البيولوجيا الزمنية لدى عينة من طالب الطب الكرد العراقيني اورنك معروف روؤوف، يا�سني اأحمد اأ�سعد، طارق �سلمان احلديثي abstract: objectives: the aim of this study was to assess the distribution of chronotypes in a sample of iraqi kurdish medical students. methods: a descriptive cross-sectional study was conducted at the hawler medical university college of medicine in erbil city, iraq, between 1st january and 31st march 2013. a total of 580 students were given the reduced version of the horne and ostberg morningness-eveningness questionnaire (meqr), a close-ended self-administered questionnaire. results: of the 580 students, 130 (22.4%) were male and 450 (77.6%) were female. the mean age ± standard deviation was 20.3 ± 1.45 years, with a range of 17‒24 years. most of the students (52.6%) were in the intermediate class, followed by morning type (24.1%) and evening type (23.3%). significant gender differences were detected in the proportion of morning, intermediate and evening types (p <0.001). the mean scores for the female students were 14.8 ± 2.2 and the mean scores for the male students were 14.6 ± 7.3, with no statistically significant differences (p = 0.45). conclusion: students in the college of medicine were mostly classified as intermediate types. the morning type was more common among this student population, particularly male students, than has been reported in similar age groups in some western countries. there was a significant gender difference in the proportion of meqr types. keywords: chronobiology phenomena; circadian rhythm; sleep; iraq. العراقيني. الكرد الطب طالب من عينة لدى الزمنية البيولوجيا نوع توزع تقييم الدرا�سة هذه من الهدف كان الهدف: امللخ�ص: مت مار�س 2013. و 31 يناير بني 1 اأربيل مدينة يف الطبية هولري جامعة من الطب كلية يف و�سفية مقطعية درا�سة اأجريت الطريقة: الإكمال. ذاتي و النهاية مغلق ا�ستبيان هو الذي ،horne and ostberg ل�ستبيان املخت�رس الإ�سدار طالبًا 580 جمموع اإعطاء النتائج: من جمموع 580 طالبًا، 130 )%22.4( كانوا ذكورا و 450 )%77.6( كانوا من الإناث. كان معدل عمرهم 20.3 ± 1.45 �سنة، و تراوحت اأعمارهم بني 17 اإىل 24 عاما. كان معظم الطالب من نوع املتو�سط ) %52.6(، يليها النوع ال�سباحي )%24.1( و النوع امل�سائي )%23.3(. مت الك�سف عن فرق مهم بني اجلن�سني يف ن�سبة اأنواع ال�سباحية، املتو�سطة، وامل�سائية )p >0.001(. كان معدل الدرجات للطالب الإناث )14.8 ± 2.2(، و معدل الدرجات للطالب الذكور )14.6 ± 7.3( مع عدم وجود فروق ذات دللة اإح�سائية بني معدل الدرجات )p = 0.45(. اخلال�صة: ي�سنف الطالب يف كلية الطب يف الغالب من النوع املتو�سط. كان النوع ال�سباحي اأكرث �سيوعا عند هذا اجلمع من الطالب، و بالأخ�س الطالب الذكور، باملقارنة مع درا�سات اأخرى يف الدول الغربية. كان هناك فرق مهم بني اجلن�سني .meqr يف ن�سبة نوع مفتاح الكلمات: ظواهر علم البيولوجيا الزمني؛ الإيقاع اليومي؛ النوم؛ العراق. distribution of chronotypes among a sample of iraqi kurdish medical students awring m. raoof, yasin a. asaad, *tariq s. al-hadithi clinical & basic research advances in knowledge this study found that this sample of iraqi kurdish medical students were mostly classified as intermediate circadian types. kurdish iraqi college students, particularly males, were more often classified as morning types than similar groups in some western countries. female kurdish iraqi students were significantly more oriented towards the evening type than male students. application to patient care the chronotype studies performed on this sample of college students cannot be generalised to the rest of the iraqi population. however, clinicians need to take into consideration chronotype behavioural variations when treating disorders in young adults, for example in complaints of generalised weakness, fatigue and even tension headaches. the term chronotype, or morning/evening preference, is used to describe individual differences in sleepingwaking patterns that most clearly explain variations in the rhythmic expression of biological or behavioural patterns.1 individuals who go to sleep early, get up early and feel and perform better in the morning are classified as morning types, whereas individuals who go to bed late, wake up late and perform better in the afternoon are classified as evening types.2 humans awring m. raoof, yasin a. asaad and tariq s. al-hadithi clinical and basic research | e357 show large inter-individual differences in their behaviours and activities within a 24-hour day. this is most obvious in their preferred timings of sleeping and wakefulness, with extreme morning and evening types often called ‘larks’ and ‘owls’, respectively. sleep and wake times show a near-gaussian distribution in a given population, with extreme early types waking up when extreme late types fall asleep. this distribution is predominantly based on differences in individuals’ circadian clocks.3 systematic investigations of individual circadian rhythm preferences have been stimulated by the publication of the horne and ostberg morningnesseveningness questionnaire (meq).4 the meq is the most widely used subjective tool for identifying individual chronotypes and the physiological variations of circadian rhythms in diverse cultures.3,5,6 however, the meq has been criticised for its excessive length (19 questions); thus, a reduced version (meqr) with just five questions was developed.7 many western studies have assessed the chronotypes of college-aged students.5,8 however, such studies are scarce in the middle east,6,9 with no comparable studies investigating the chronotypes of young people in the kurdistan regions of iraq. students of other population groups are more frequently included in research on circadian typology. the current study chose a sample of kurdish students because this ethnic group has had fewer constraints to social synchronisers, for example work schedules, and can express with greater freedom their circadian rhythmic preferences.10 the aim of this study, therefore, was to assess the distribution of chronotypes in a sample of iraqi kurdish medical students in erbil, the main city of the iraqi kurdistan region. methods this cross-sectional study was conducted in the hawler medical university college of medicine, erbil, iraq, between 1 january and 31 march 2013. the total number of medical students for the academic year 2012‒13 was 900, with a male to female ratio of 0.58:1. a random student sample was selected and the sample size was calculated to detect a prevalence of 26.9% evening types according to a saudi study,6 with a confidence interval (ci) of 95% and a precision of 10%. the estimated sample size was 484 out of 900 students. a target sample of 580 students was chosen to account for non-response.11 students at all academic levels were recruited using a systematic random sampling technique, whereby every third name on the class list was skipped. participation in the study was anonymous and voluntary. the reduced version of the horne and ostberg meq was used.7 this version has been validated and shown to successfully identify human circadian typology.12,13 the meqr was independently translated into the kurdish language by four different lecturers from the department of english of the faculty of education at salahaddin university, hawler, iraq. the translations were then reviewed in collaboration with the investigators and translators from the department of kurdish language and literature of the faculty of education of salahaddin university. any differences in translation were expressed in joint statements. following this, a pilot study was performed on a group of 20 subjects in order to evaluate the comprehensiveness of the questionnaire. the questionnaire was adapted according to the findings, distributed to the selected students at the end of each class session and collected the day after. the five questions on the meqr established the chronotypes within a score range of 4‒25. these questions determined each individual’s preferred time to wake up; preferred time to go to bed; the hour of the day when they felt their “best”; the extent of their tiredness within the first half hour after waking in the morning, and what circadian type each respondent considered themselves to be. in this study, a simpler classification was used which included three behavioural categories: morning type (score 18‒25), intermediate type (score 12‒17) and evening type (score 4‒11). this simpler classification has been used previously.5,6,9,14 information was also collected regarding the students’ gender. the data was transferred to the statistical package for the social sciences (spss), version 18 (ibm, corp., chicago, illinois, usa). pearson’s chi-squared test and the z-test were used for the analysis of gender and circadian typology results. the student’s t-test and analysis of variance (anova) accompanied by post-hoc tests were used to analyse gender and mean scores in respect to the meqr items. the study was approved by the research ethics committee of the hawler medical university college of medicine. results of the 580 students, 130 (22.4%) were male and 450 (77.6%) were female. the mean age ± sd was 20.3 ± 1.45 years, ranging from 17‒24 years. although the distribution of the meqr scores (range = 5‒22, mean ± standard deviation [sd] = 14.2 ± 3.8) did not show skewness (value = 0.15, error = 0.10) or kurtosis (value = 0.63, error = 0.20), it was distribution of chronotypes among a sample of iraqi kurdish medical students e358 | squ medical journal, august 2014, volume 14, issue 3 significantly different from the normal curve (z = 2.37, p <0.001) [figure 1]. a total of 24.3% of the participants were classified as morning types, 52.6% were intermediate type sand 23.1% were evening types. significant gender differences were detected in the proportion of morning, intermediate and evening types (chisquared = 13.80, p = 0.001). female students showed a tendency towards eveningness (26.4%) while male students had a tendency towards morningness (30.8%) [table 1]. there was no statistically significant difference between the mean scores of the behavioural categories in respect to gender after using anova (f = 0.54, p = 0.45) [table 2]. table 3 displays the mean, sd and number of subjects in each group according to age and gender. in order to study gender differences in more detail, the meqr questionnaire items were analysed with the z-test. there were no significant differences in any of the following items: time getting out of bed (z = -1.38 , p = 0.16); feeling refreshed during the first half hour of the morning (z = -1.62, p = 0.10); feeling tired in the evening and needing to sleep (z = -1.50, p = 0.13); feeling their “best” during the day (z = -1.6, p = 0.09), and which circadian typology the respondent considered themselves to be (z = 0.08, p = 0.93). anova was also used to analyse the age differences in respect to mean scores, considering age as an independent variable. age differences were statistically significant (f = 7.89, p <0.001) and the age-gender interaction was highly significant (f = 21.98, p <0.001). the multiple post-hoc comparisons among the different age groups revealed differences in the 17‒18 (p = 0.02), 18‒19 (p = 0.001) and 19‒20 age groups (p = 0.003). discussion this study showed that 24.3% of the subjects were morning types, 52.6% were intermediate types and 23.1% were evening types. a saudi arabian study reported a lower figure for morning types (18.2%) and similar figures of 54.9% and 26.9% for both ‘neither’ (intermediate) types and evening types, respectively.6 studies in western countries have reported lower figures for morningness, with an overall proportion of 20% and 15% in spain,15,16 9% in italy,17 15.6% for males and 20.3% for females in germany,18 and 5.9% for males and 9.7% for females in the usa.13 in contrast with those findings, the saudi arabian investigators postulated that, as the majority of their population was muslim, waking up each day for dawn prayers might explain the higher prevalence of morningness among their participants.6 it is worth noting that both the saudi arabian and iraqi populations have similar religious beliefs and cultural traditions, which may explain the similar findings. most participants in the current study were intermediate types (52.6%), which is in agreement with the circadian typology reported in western table 1: distribution of the studied sample of kurdish medical students according to circadian type and gender (n = 580) circadian type students n (%) total male female morning 141 (24.3) 40 (30.8) 101 (22.4) intermediate 305 (52.6) 75 (57.7) 230 (51.1) evening 134 (23.1) 15 (11.5) 119 (26.4) total 580 (100.0) 130 (100.0) 450 (100.0) gender variation was significant according to pearson’s chi-squared = 13.80 and p <0.001. table 2: distribution of the studied sample of kurdish medical students by mean meqr scores and range (n = 580) circadian type students mean ± sd (range) total male female morning 13.9 ± 2.7 (18‒22) 11.7 ± 2.6 (19‒22) 14.8 ± 2.3 (18‒22) intermediate 14.8 ± 4.0 (12‒16) 15.8 ± 4.2 (12‒16) 14.5 ± 3.9 (13‒16) evening 13.1 ± 4.0 (5‒11) 14.7 ± 7.4 (5‒11) 13.1 ± 3.5 (6‒11) total 14.2 ± 3.8 (5‒22) 14.5 ± 4.7 (5‒22) 14.2 ± 3.6 (6‒22) meqr = reduced version of the horne and ostberg morningnesseveningness questionnaire; sd = standard deviation. figure 1: frequency distribution of the meqr scores among a sample of kurdish medical students (n = 580). meqr = reduced version of the horne and ostberg morningnesseveningness questionnaire. awring m. raoof, yasin a. asaad and tariq s. al-hadithi clinical and basic research | e359 countries: an overall proportion of 61% and 59.6% in spain,15,16 69.1% in italy,17 55.5% for males and 58.9% for females in germany,18 and 63.7% for males and 61.6% for females in the usa.13 the figures reported in western countries on eveningness were as follows: an overall proportion of 19% and 24% in spain,15,16 21.9% in italy,17 28.9% for males and 20.8% for females in germany,18 and 30.4% for males and 28.6% for females in the usa.13 once again, these findings are similar to those of the current study (23.1%). the mean meqr scores obtained in this study were lower than those obtained in the usa,13 france,19 spain20 and taiwan.21 variations in culture and ethnicity could be responsible for disparities in morning/evening preferences, in addition to sampling variations in age range and gender distributions. as for gender differences, the current study revealed significant variations in circadian distribution, with male students displaying morningness significantly more often than female students, who exhibited greater eveningness. however, there was no gender difference in the mean scores. the findings of other studies on the effect of gender on chronotypes have been inconsistent. the saudia arabian study revealed no gender differences in the frequency of any category of chronotypes or in the mean scores.6 in western countries, some investigators have reported a higher proportion of morningness in females while others have found no gender differences.16,18,22 regarding gender differences in the mean scores, while some researchers did not find significant differences between male and female participants,15,23 others did when using larger samples.16,24 these results underscore the need for further and more detailed investigation regarding gender and circadian typology. there have been reports that personality characteristics are affected by the morningnesseveningness pattern. morning types were found to be more conscientious and have higher self-esteem and internal locus of control than evening types.25 in contrast, evening types have been reported to have irregular sleeping patterns.25‒27 irregular nocturnal sleeping patterns and increased daytime sleepiness have been found to be associated with lower academic performance in medical students.28,29 educators and college authorities need to encourage students to control their sleeping patterns through orientation sessions. one of the methodological limitations of this study was that a cross-sectional design is not the most appropriate method to test for a direct relationship between factors. this means that further controlled studies are needed to test these relationships. the validity of results gathered from self-reported questionnaires is another limitation to be considered when interpreting the results of this study. in addition, chronotype studies performed with college students cannot be generalised to the rest of the population. as the study was only done on kurdish students, the findings of this study cannot be generalised to all medical students in iraq, or to the iraqi population in general. these findings are limited to kurdish iraqi medical students. finally, various other aspects such as lifestyle habits, social/gender demands, family schedules, academic performance, or psychological and physical issues have not been considered in this study. however, despite these limitations, this study provides useful baseline data on the age differences, gender variations and distribution of chronotypes among a sample of college students. table 3: mean meqr scores, standard deviation and number of kurdish medical students as a function of their age and gender (n = 580) students age in years female male total n mean ± sd n mean ± sd n mean ± sd 17 5 0 ± 11.0 5 12.0 ± 0 10 11.3 ± 0 18 45 3.8 ± 16.1 5 19.0 ± 0 50 16.4 ± 3.7 19 55 4.1 ± 15.3 10 17 ± 1.05 65 15.6 ± 3.8 20 211 3.3 ± 13 20 13 ± 2.4 231 13.5 ± 3.2 21 89 3.5 ± 13.7 30 12.6 ± 5.07 119 13.4 ± 3.9 22 20 0.7 ± 15 30 15.8 ± 4.6 50 15 ± 3.6 23 10 4.7 ± 14.5 25 14.6 ± 6.1 35 14.5 ± 5.7 24 10 3.6 ± 15.5 5 15 ± 0 15 15.3 ± 2.9 totals 445 3.6 ± 14.2 130 14.5 ± 4.7 580 14.2 ± 3.8 meqr = reduced version of the horne and ostberg morningness-eveningness questionnaire; sd = standard deviation. distribution of chronotypes among a sample of iraqi kurdish medical students e360 | squ medical journal, august 2014, volume 14, issue 3 conclusion in this study investigating the chronotypes of a sample of kurdish medical students, most were classified as intermediate types. however, the morning type was more common, particularly among males, than has been reported in similar age groups in some western studies. as determined by the meqr scores, chronotypology differed significantly according to gender. in the light of these findings, future studies are recommended to determine circadian typology and to identify factors that influence circadian typology among different age groups and populations. references 1. daan s, beersma dg, borbély aa. timing of human sleep: recovery process gated by a circadian pacemaker. am j physiol 1984; 246:r161‒78. 2. kerkhof ga. inter-individual differences in the human circadian system: a review. biol psychol 1985; 20:83‒112. doi: 10.1016/0301-0511(85)90019-5. 3. roenneberg t, kuehnle t, juda m, kantermann t, allebrandt k, gordijn m, et al. epidemiology of the human circadian clock. sleep med rev 2007; 11:429‒38. doi: 10.1016/j. smrv.2007.07.005. 4. horne ja, ostberg o. a self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. int j chronobiol 1976; 4:97‒110. 5. laberge l, carrier j, lespérance p, lambert c, vitaro f, tremblay re, et al. sleep and circadian phase characteristics of adolescent and young adult males in a naturalistic summer time condition. chronobiol int 2000; 17:489‒501. doi: 10.1081/ cbi-100101059. 6. bahammam as, almistehi w, albatli a, alshaya s. distribution of chronotypes in a large sample of young adult saudis. ann saudi med 2011; 31:183‒6. doi: 10.4103/02564947.78207. 7. adan a, almirall h. horne and östberg morningnesseveningness questionnaire: a reduced scale. pers individ dif 1991; 12:241‒53. doi: 10.1016/0191-8869(91)90110-w. 8. randler c. morningness-eveningness comparison in adolescents from different countries around the world. chronobiol int 2008; 25:1017‒28. doi: 10.1080/07420520802551519. 9. bahammam a. assessment of sleep patterns, daytime sleepiness, and chronotype during ramadan in fasting and nonfasting individuals. saudi med j 2005; 26:616–22. 10. kim s, dueker gl, hasher l, goldstein d. children’s time of day preference: age, gender and ethnic differences. pers indiv dif 2002; 33:1083‒90. doi: 10.1016/s0191-8869(01)00214-8. 11. naing l, winn t, rusli bn. practical issues in calculating the sample size for prevalence studies. arch orofacial sci 2006; 1:9‒14. 12. natale v, esposito mj, martoni m, fabbri m. validity of the reduced version of the morningness-eveningness questionnaire. sleep biol rhythms 2006; 4:72‒4. doi: 10.1111/j.1479-8425.2006.00192.x. 13. chelminski i, petros tv, plaud jj, ferraro fr. psychometric properties of the reduced horne and ostberg questionnaire. pers indiv dif 2000; 29:469‒78. doi: 10.1016/s01918869(99)00208-1. 14. taillard j, philip p, bioulac b. morningness/eveningness and the need for sleep. j sleep res 1999; 8:291‒5. doi: 10.1046/j.13652869.1999.00176.x. 15. adan a, almirall h. adaptation and standardization of a spanish version of the morningness-eveningness questionnaire: individual differences. pers indiv dif 1990; 11:1123‒30. doi: 10.1016/0191-8869(90)90023-k. 16. adan a, natale v. gender differences in morningnesseveningness preference. chronobiol int 2002; 19:709‒20. 17. fabbri m, antonietti a, giorgetti m, tonetti l, natale v. circadian typology and style of thinking differences. learn individ differ 2007; 17:175–80. doi: 10.1016/j.lindif.2007.05.002. 18. lehnkering h, siegmund r. influence of chronotype, season, and sex of subject on sleep behavior of young adults. chronobiol int 2007; 24:875‒88. doi: 10.1080/07420520701648259. 19. caci h, robert p, dossios c, boyer p. [morningnesseveningness for children scale: psychometric properties and month of birth effect]. encephale 2005; 31:56‒64. doi: 10.1016/ s0013-7006(05)82372-3. 20. adan a, caci h, prat g. reliability of the spanish version of the composite scale of morningness. eur psychiatry 2005; 20:503‒9. doi: 10.1016/j.eurpsy.2005.01.003. 21. gau ss, soong wt, merikangas kr. correlates of sleep-wake patterns among children and young adolescents in taiwan. sleep 2004; 27:512‒19. 22. reyner la, horne ja, reyner a. genderand age-related differences in sleep determined by home-recorded sleep logs and actimetry from 400 adults. sleep 1995; 18:127‒34. 23. caci h, nadalet l, staccini p, myquel m, boyer p. psychometric properties of the french version of the composite scale of morningness in adults. eur psychiatry 1999; 14:284‒90. doi: 10.1016/s0924-9338(99)00169-8. 24. randler c. gender differences in morningness–eveningness assessed by self-report questionnaires: a meta-analysis. pers indiv dif 2007; 43:1667‒75. doi: 10.1016/j.paid.2007.05.004. 25. jackson la, gerard da. diurnal types, the “big five” personality factors, and other personal characteristics. j soc behav pers 1996; 11:273–84. 26. park ym, matsumoto k, seo yj, shinkoda h, park kp. sleep in relation to age, sex, and chronotype in japanese workers. percept mot skills 1998; 87:199‒215. doi: 10.2466/pms.1998.87.1.199. 27. roenneberg t, wirz-justice a, merrow m. life between clocks: daily temporal patterns of human chronotypes. j biol rhythms 2003; 18:80‒90. doi: 10.1177/0748730402239679. 28. medeiros ald, mendes dbf, lima pf, araujo jf. the relationships between sleep-wake cycle and academic performance in medical students. biol rhythm res 2001; 32:263‒70. doi: 10.1076/brhm.32.2.263.1359. 29. bahammam as, alaseem am, alzakri aa, almeneessier as, sharif mm. the relationship between sleep and wake habits and academic performance in medical students: a cross-sectional study. bmc med educ 2012; 12:61. doi: 10.1186/1472-6920-1261. sir, recently, during a routine histopathological examination, an excisional biopsy of a squamous cell carcinoma, on the lateral border of the tongue of a 70-year-old male patient, was evaluated and revealed a remarkable feature. in a haematoxylin and eosin (h&e) stained slide, numerous well defined polygonal isomorphous tiny structures, the majority of them stained with eosin and a few unstained, filled a lumen-like structure formed by the folding of the thin stratified squamous epithelium [figure 1a]. my fellow postgraduates suspected them to be some sort of desquamated epithelial cells, ghost cells, cross-sections of muscle fibres, keratin flakes, red blood corpuscles or inclusion dust, glass or metal particles. moreover, in another field, a few elongated well defined semi-transparent structures, resembling candidal hyphae were seen interspersed with the numerous above mentioned structures [figure 1b]. since candidal hyphae hardly persist in formalin fixed tissue and can easily be differentiated by its pseudomycelium forms, we excluded this possibility. an artefact (latin ‘ars’art + ‘factum’made) in histology means any non-natural feature or structure accidentally introduced into something being observed or studied.1 suture material is an occasional inclusion in histological specimens. it may consist of isolated fragments or complete fibre-bundles cut in transverse, oblique or longitudinal planes. detail of the fibre structure can sometimes be seen upon careful examination of h&e stained sections. silk sutures exhibit strong birefringence under polarised light and can be useful in their identification.2,3 our suspicion in this case was confirmed when we observed the same sections under a polarising microscope. the sections of mysterious foreign material exhibited a strong birefringence under a polarised light [figure 2]. hence we concluded that the foreign material was polyfilament silk suture material (cross-sections and longitudinal sections). other artefacts with structures almost similar to suture filament include cellulose fibre and hair. cellulose fibres arising from cotton gauze can be encountered as a contaminant during specimen collection and processing. it is recognised by the characteristic appearance of plant cells with their strongly staining cell walls and square shape. very rarely a hair can also contaminate the tissue during processing; it can be squ med j, may 2012, vol. 12, iss. 2, pp. 247-248, epub. 9th apr 2012 submitted 13th jan 12 accepted 7th mar 12 خداع خيط اجلراحة استكشافه من خالل جمهر مستقطب suture artefacts explored through polarising microscope letter to editor figures 1a and 1b: cross-sections (a) and longitudinal sections (b) of the polyfilament silk suture material when viewed under a bright field microscope (haematoxylin and eosin stain, x 20) suture artefacts explored through polarising microscope 248 | squ medical journal, may 2012, volume 12, issue 2 clearly differentiated by its characteristic tubular structure and black/brown colour. moreover, in contrast to polyfilament sutures, and in the case of, too many cross-sections, hair will not be seen in a single section.2,3 the purpose of this letter is to call the attention to this artefact, which may be found during a histopathology routine, and needs to be kept in mind for an accurate diagnosis. *sonal grover, rashmi naik, jayadeva hm, ahmed mujib br department of oral pathology & microbiology, bapuji dental college & hospital, davangere, karnataka, india *corresponding author e-mail: sonalgrvr@yahoo.com references 1. jadhav kb, gupta n, ahmed mbr. maltese cross: starch artifact in oral cytology, divulged through polarized microscopy. j cyt 2010; 27:40–1. 2. rolls og, farmer nj, hall jb. artifacts in histological and cytological preparations. scientia, leica microsystem education series. from: http://www.leica-microsystems.com accessed: dec 2012. 3. wallington ea. artifacts in tissue sections. med lab sci 1979; 36:3–61. figures 2a and 2b: cross-sections (a) and longitudinal sections (b) of the polyfilament silk suture material when viewed under a polarising microscope (haematoxylin and eosin stain, x 20) department of dermatology & venereology, virgen de las nieves hospital, granada, spain *corresponding author e-mail: gonzaloblascomorente@gmail.com املليساء املعدية على اجللد املوشوم جونزالو بال�سكو-مورينتى، ماريا خو�سيه ناراجن-دياز، اإ�رسائيل برييز-لوبيز، اأنطونيو مارتينيز لوبيز، كري�ستينا غاريدو-كوملينريو molluscum contagiosum over tattooed skin *gonzalo blasco-morente, maria jose naranjo-díaz, israel pérez-lópez, antonio martínez-lópez, cristina garrido-colmenero a 33-year-old spanish male presented to the department of dermatology & venereology at the virgen de las nieves hospital, granada, spain, in february 2015 with pruritic skin lesions located over a tattoo on his right arm. the tattoo had been completed three months earlier without protective measures by the patient’s friend at his home. at presentation, the patient was not suffering from any known illnesses. a physical examination showed several pearled papules of 0.3–0.5 cm located over the tattoo [figure 1a]. the papules were umbilicated and occurred over the lines of the tattoo [figure 1b]. biochemical tests and a haemogram were normal. serology for hepatitis b and c, human immunodeficiency virus (hiv) and syphilis was negative. the patient was diagnosed with molluscum contagiosum (mc) and treated with curettage, with a subsequent healing time of three weeks. figure 1a & b: a: photograph showing several pearled molluscum contagiosum papules of 0.3–0.5 cm (arrows) located over a tattoo on the arm of a 33-year-old male patient. b: dermoscopic image showing the umbilicated papules occurring on the inked lines of the tattoo. interesting medical image sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 257–258, epub. 15 may 16 submitted 23 jul 15 revision req. 16 sep 15; revision recd. 3 oct 15 accepted 29 oct 15 doi: 10.18295/squmj.2016.16.02.022 molluscum contagiosum over tattooed skin 258 | squ medical journal, may 2016, volume 16, issue 2 however, these conditions were not detected in the current patient. the differential diagnosis for mc includes common warts, condylomata acuminata and granulomatous or inflammatory reactions, such as lichen planus, lichenoid reactions or cutaneous lupus erythematosus-like reactions.1,2,4 deep fungal infections should also be excluded in immunocompromised patients as they can have a similar presentation.3 to confirm a diagnosis of mc, a skin biopsy should be performed.2 treatment options include curettage, cryotherapy, topical keratolytics, topical potassium hydroxide and imiquimod.2,4 otherwise, papules may spontaneously resolve in certain cases.4 references 1. molina l, romiti r. molluscum contagiosum on tattoo. an bras dermatol 2011; 86:352–4. doi: 10.1590/s0365-0596201100 0200022. 2. grillo e, urech m, vano-galvan s, jaén p. lesions on tattooed skin: a case study. aust fam physician 2012; 41:308–9. 3. de giorgi v, grazzini m, lotti t. a three-dimensional tattoo: molluscum contagiosum. cmaj 2010; 182:e382. doi: 10.1503/ cmaj.091480. 4. ruiz-villaverde r, sánchez-cano d. pearled papules over tattoo: molluscum cotagiosum. pan afr med j 2013; 16:49. doi: 10.11604/pamj.2013.16.49.3442. 5. thappa dm. the isomorphic phenomenon of koebner. indian j dermatol venereol leprol 2004; 70:187–9. comment mc is an infection caused by a virus of the poxviridae family; it occurs commonly in children although only occasionally in adults.1,2 it presents as small, umbilicated, rose-coloured pearly papules generally located on the trunk and within body folds.2 on certain occasions, mc may occur over tattoos in the form of a pseudo-koebner phenomenon, affecting the ink lines weeks after the tattoo’s completion.1‒4 the koebner or isomorphic phenomenon occurs when identical clinical and histological lesions develop on traumatised uninvolved areas of skin among patients who already have cutaneous diseases such as psoriasis, vitiligo or lichen planus.2,5 when these lesions develop with infections such as mc, it is deemed a pseudo-koebner phenomenon.2,5 in the present case, the patient’s tattoo was performed at home by an unqualified tattoo artist; it is very likely that the instruments used were not sterilised which would have increased the risk of secondary infections. the mc virus may have been transmitted via instruments used during the tattooing process or through contaminated ink.2 furthermore, black pigment has been suggested to reduce cellular and humoural immunity.1 syphilis, atypical mycobacteria, hepatitis, hiv, tuberculosis and viral warts may potentially be transmitted during the application of a tattoo.2 http://dx.doi.org/10.1590/s0365-05962011000200022 http://dx.doi.org/10.1590/s0365-05962011000200022 http://dx.doi.org/10.1503/cmaj.091480 http://dx.doi.org/10.1503/cmaj.091480 http://dx.doi.org/10.11604/pamj.2013.16.49.3442 sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 323-329, epub. 15th jul 12 submitted 24th aug 11 revision req. 8th jan 12, revision recd. 28th mar & 27th apr 12 accepted 2nd may 12 1research center of pharmaceutical nano technology, tabriz university (medical sciences), tabriz, iran; 2department of oral and maxillofacial pathology, dental faculty, tabriz, iran; 3kamal asgar research center (karc), azad university, dental branch, tehran, iran; 4department of endodontics, dental faculty, tabriz university (medical sciences), tabriz, iran; 5department of endodontics, dental branch, islamic azad university, tehran, iran, 6department of endodontics/dental research center, school of dentistry, tehran university of medical sciences, tehran, iran. *corresponding author e-mail: svosough.rare@yahoo.com تأثري سائل النسيج الصناعي يف التسرب اجملهري جملموع األكاسيد الثالثية املعدنية الرمادية والبيضاء كمواد تعبئة لنهاية اجلذر دراسة خمربية مهرداد لطفي، �سيبيداه يو�سف ح�سيني، حممد علي �سغريي، �سعيد رحيمي، وحيد زند ، حممد فروغ ريحاين، حممد �سميع، جنني قا�سمي، باميان مهرفارظفر، �سهرام عظيمي ، نو�سني �سوكيهينجاد كمية �سعف الرمادية املعدنية الأكا�سيد جمموع عن ينتج القّمة. ختم على جزئيا يعتمد اللبية اجلراحة جناح اأن ظهر امللخ�ص: الهدف: هيدروك�سيباتيت الناجتة عن جمموع الأكا�سيد املعدنية البي�ساء عندما تكون معلقة يف حملول الفو�سفات امللحي. هدف هذه الدرا�سة التي اأجريت يف املخترب يتمحور على مقارنة ظاهرة الت�رسب املجهري من جمموع الأكا�سيد املعدنية الرمادية والبي�ساء كمواد ح�سو لنهاية اجلذر بعد غمرها يف �سائل الن�سيج ال�سناعي. الطريقة: مت تق�سيم 55 من اأ�سنان الفك العلوي الأمامية الب�رسية اأحادية اجلذور اإىل جمموعتني جتريبيتني من 20 �سنًا لكل منهما، بالإ�سافة اإىل 3 جمموعات من 5 اأ�سنان لكل منها، كعينات �سابطة، اثنان منها �سلبية وواحدة اإيجابية: مت تنظيف قنوات اجلذور وترتيب �سكلها ومت دمج اأطرافها بجوتا-بريجا. مت ملء نهايات اجلذور باملجاميع التجريبية مبجموع الأكا�سيد الثالثية املعدنية الرمادية والبي�ساء.مت حتديد الت�رسب با�ستخدام طريقة اخرتاق ال�سبغ. مت حتليل البيانات با�ستخدام حتليل التباين على م�ستوى دللة 0.05. النتائج: كان متو�سط ت�رسب ال�سبغ 0.40 ± 0.1 ملم ملجموع الأكا�سيد الثالثية املعدنية الرمادية و 0.50 ± 0.1 ملم ملجموع الأكا�سيد الثالثية املعدنية البي�ساء. مل يكن هناك فرق معتّد بني املجموعتني )p = 0.14(. اخلال�صة: على الرغم من اختالف اختالفات هناك تكن مل كما ال�سناعي، الن�سيج �سائل يف والبي�ساء الرمادية املعدنية الثالثية الأكا�سيد ملجموع و�سلوكيات خ�سائ�ض معتّدة يف الت�رسب املجهري عند ا�ستخدام اأيا من الأك�سيد الثالثية املعدنية. مفتاح الكلمات: ت�رسب الأ�سنان، جمموع الأكا�سيد الثالثية املعدنية، ح�سو الأ�سنان. abstract: objectives: the success of endodontic surgery has been shown to depend partly on the apical seal. grey mineral trioxide aggregate (gmta) produces hydroxyapatite twice as often as white mineral trioxide aggregate (wmta) when suspended in a phosphate buffered saline (pbs) solution. the aim of this in vitro study was to compare the microleakage phenomenon of gray and white mineral trioxide aggregates as root-end filling materials after immersion in synthetic tissue fluid (stf). methods: 55 single-rooted extracted maxillary anterior human teeth were divided into two experimental groups of 20 teeth each, plus 3 groups of 5 teeth each as two negative and one positive control groups. the root canals were cleaned, shaped, and laterally compacted with gutta-percha. the root ends were resected and 3 mm deep cavities were prepared. the root-end preparations were filled with gmta or wmta in the experimental groups. leakage was determined using a dye penetration method. data were analysed using analysis of variance (anova) at the 0.05 level of significance. results: the mean dye leakage was 0.40 ± 0.1 mm for gmta and 0.50±0.1 mm for wmta groups, respectively. there was no significant difference between the two experimental groups (p = 0.14). conclusion: despite the different properties and behaviours of gmta and effect of synthetic tissue fluid on microleakage of grey and white mineral trioxide aggregate as root-end filling materials an in vitro study mehrdad lotfi,1,4 *sepideh vosoughhosseini,2 mohammad ali saghiri,3 saeed rahimi,4 vahid zand,4 mohammad forough reyhani,4 mohammad samiei,4 negin ghasemi,4 payman mehrvarzfar,5 shahram azimi,5 noushin shokohinejad6 clinical & basic research effect of synthetic tissue fluid on microleakage of grey and white mineral trioxide aggregate as root-end filling materials an in vitro study 324 | squ medical journal, august 2012, volume 12, issue 3 endodontic surgery may be indicated if conventional root canal therapy cannot treat complex anatomy, procedural misadventures, or inflammatory processes.1,2 root-end filling materials are used in periapical surgery to seal the root canal from the periapical tissues.1 an ideal root-end filling material should be biocompatible and able to seal, insoluble in tissue fluids, non-resorbable, radiopaque, and dimensionally stable.3 increasing the sealing ability of materials can lead to more successful endodontic treatments.3 mineral trioxide aggregate (mta) was first introduced in 1993 as a root repair material and is a mixture of portland cement, gypsum, bismuth oxide, and trace amounts of metallic oxides.4–7 the first generation of mta was grey in colour. white mta (wmta) was introduced in 2002 as an alternative to grey mta (gmta) which does not match with the colour of the anterior teeth.8 the measured chemical composition of gmta and wmta revealed that al2o3 (122%), mgo (130%), and especially feo (1000%) are more abundant in gmta.9 wmta contains smaller and finer particles with a narrower range of size distribution and has less tetracalcium aluminoferrate as compared to gmta.10 regardless of these differences, the success of endodontic materials mainly depends on provision of an acceptable apical seal.11 the sealing abilities of gmta and wmta, when applied at a thickness of 3 mm, were similar when used as a root-end filling material in the presence of water.12 set mta contains many voids in the form of air bubbles, pores, and capillary channels. these voids within mta and at the interface of mta and dentin, if sufficiently large, might promote an increased potential for leakage of fluids, bacteria, and endotoxins beyond the mta.13 however, mta as a bioactive material can exchange calcium ions with an environment that contains phosphate ions; therefore, after placement of mta in the root canal in the presence of synthetic tissue fluid (stf), and after its gradual dissolution, hydroxyapatite (ha) crystals nucleate and grow, filling the microscopic spaces between mta and the dentinal wall through a physicochemical reaction.5 initially, this seal is mechanical; however, with time, a diffusioncontrolled reaction between the apatite layer and dentin leads to their chemical bonding, creating a seal at the mta-dentine interface.14,15 the reaction between mta and stf results in the formation of precipitates in the form of ha following the combination of ca from mta and phosphates from stf. the chemical aspect is the result of mta coated with ha, forming a chemical bond to dentin. in fact, stf or any phosphate-containing solution such as phosphate buffered saline (pbs) or hank’s balanced salt solution (hbss) has the potential to produce ha crystals adjacent to the mta due to calcium hydroxide production from mta after mixing with water.16 on the other hand, gmta has been shown advances in knowledge root-end filling materials play a crucial rule in the success of periapical surgery. using bioactive materials for root-end filling purposes has demonstrated promising treatment in periapical surgery to increase success rates, as shown in this study. on the basis of available information, it appears that mineral trioxide aggregate (mta) is the material of choice for periapical surgery. however, the difference between using white or grey mta has not been adequately studied. therefore, more studies are needed to confirm mta’s efficacy as compared with other materials. more studies should be conducted to show the advantages and disadvantages of grey or white mta. application to patient care inadequate apical sealing is the most common cause of failure in periapical surgery. therefore, the root-end filling material used should prevent ingress of potential contaminants into periapical tissue. mta was developed because existing materials did not have the ideal characteristics necessary for retrograde root-end fillings. however, mta has two versions: white and grey, and choosing one over the other to use as retrofill material is still under question. this study will help in choosing an appropriate root-end filling material for patients needing periapical surgery. wmta in stf, there were no significant differences in microleakage when using gmta or wmta. keywords: dental leakage; mineral trioxide aggregate; endontics. mehrdad lotfi, sepideh vosoughhosseini, mohammad ali saghiri, saeed rahimi, vahid zand, mohammad forough reyhani, mohammad samiei, negin ghasemi, payman mehrvarzfar, shahram azimi, noushin shokohinejad clinical and basic research | 325 to expand significantly more than wmta when immersed in either water or hbss.17 gmta produced 0.82 g of ha-like crystals as compared with 0.47 g for wmta (i.e. wmta produced 43% less ha than gmta).17 therefore, gmta produces ha almost twice as often as wmta when suspended in a pbs solution.18 more ha formation and a greater expansion of gmta as compared to wmta has led to the speculation that gmta and wmta may not exhibit the same microleakage properties; therefore, the hypothesis is that gmta and wmta should not demonstrate the same microleakage phenomenon. the aim of this study was to compare microleakage of gmta and wmta when used as root-end filling materials in stf. methods the ethics committee of tabriz university of medical sciences, iran, approved the proposal of this study. a total of 55 single-rooted human upper anterior teeth (centrals and laterals) with straight canals and mature apices which were extracted for periodontal reasons, and were without cracks or calcified canals, were collected for the experiment and stored in phosphate buffered saline (pbs) solution (merck kgaa, darmstadt, germany) until use. pbs, containing sodium chloride, sodium phosphate, potassium chloride and potassium phosphate was used as a buffer solution as the buffer’s phosphate groups help maintain a constant ph and the osmolarity and ion concentrations of the solution mimic those of the human body. the surface of the roots was cleaned using an ultrasonic device (joya electronic, tehran, iran). the teeth were randomly divided into 2 experimental groups with 20 teeth each and 2 negative and 1 positive control group, each with 5 teeth. standard access cavities were prepared with figure 1: stereomicroscopic images at ×16 magnification of dye leakage in root-end cavity preparations after immersion in synthetic tissue fluid. (a) positive control; (b) negative control; (c) white mineral trioxide aggregate; (d) grey mineral trioxide aggregate. effect of synthetic tissue fluid on microleakage of grey and white mineral trioxide aggregate as root-end filling materials an in vitro study 326 | squ medical journal, august 2012, volume 12, issue 3 a round diamond bur under water spray. the root canals were prepared with the conventional stepback technique using k-files (maillefer, ballaigues, switzerland).19 the master apical file was #35. after each instrument, the root canals were irrigated with 2 ml of 2.5% naocl (golrang, tehran, iran) solution. gates-glidden drills (maillefer, ballaigues, switzerland) #2 and #3 were used in the coronal third of the canals. the canals were dried with paper points (apadanatak, tehran, iran). the root canals were obturated with gutta-percha (vdw gmbh, munich, germany) without sealer, using a cold lateral compaction technique. the apical 3 mm of each root was resected perpendicular to the long axis of the tooth using a fissure bur (caulk superbru, ld caulk division, dentsply international inc., milford, de, usa) in a high-speed hand piece under a continuous water spray. the root apices were prepared with a kis-3d microsurgical ultrasonic instrument (spartan, missouri, usa). a circular preparation 3 mm in depth was created in each root. preparations were checked to ensure that the lc-1 condenser tip (grand industries, california, usa) would fit the length and then it was rinsed with saline (samen, mashhad, iran) and dried with paper points. the apical preparations in one experimental group were filled with wmta (tooth-colored formula, dentsply, tulsa dental, tulsa, ok, usa) and the other with gmta (dentsply, tulsa dental, tulsa, ok, usa). a total of 5 teeth in the negative control groups were filled with wmta and 5 teeth with gmta. the materials were prepared according to the manufacturers’ instructions. all the roots were mounted in red wax with the buccal surfaces facing upward. an x-ray tube was adjusted perpendicular to the buccal surfaces and radiographs were taken. then the teeth were mounted again in the mesiodistal direction in the red wax and radiographed in the same position to ensure the adequacy of the root-end fillings. apical preparation in the positive control groups was left unfilled. all the teeth were incubated for 4 hours at 37º c in 100% relative humidity and then immersed in one liter of stf for 3 days at 37º c. the stf had been prepared as follows: 1.7 g of kh2po4, 11.8 g of na2hpo4, 80.0 g of nacl, and 2.0 g of kcl in 10 l of h2o (ph = 7.2). 4 the stf was renewed every day. the roots in the experimental and positive control groups were coated with two layers of nail varnish. the resected apical roots were left uncoated. the entire root surfaces of the negative control group samples were covered with 2 layers of nail varnish. sticky wax was placed over all the surfaces of the teeth that were coated with nail varnish, and allowed to dry. the roots were then submerged in india ink for 48 hours and then rinsed in water. the roots in all the groups were grooved on the buccal and lingual surfaces and split longitudinally into two sections. retrofill materials were removed, and the extent of dye penetration was measured separately in mm, using a calibrated stereomicroscope (carl zeiss ag, oberkochen, germany) at ×16 magnification. linear dye penetration was measured independently by three observers at three different times under the same conditions; the mean value of the recorded measurements was selected as the extent of dye penetration into each specimen. statistical analysis was performed by statistical package for the social sciences software package, version 13.0 for windows (spss inc., chicago, il, usa). quantitative values are presented as mean ± standard deviation (sd). one-way analysis of variance (anova) was used to determine statistical differences between the groups. results all the preparations in the positive control group demonstrated leakage throughout the entire root lengths [figure 1a]. the root-end preparations in 0.60 0.50 0.40 0.30 0.20 le ak ag e mta wmta gmta figure 2: box plot of dye leakage (in millimetres) of white and grey mineral trioxide aggregate (wmta and gmta) after immersion in synthetic tissue fluid, which illustrates the minimum and maximum amount of leakage, as well as the variance in each experimental group. mehrdad lotfi, sepideh vosoughhosseini, mohammad ali saghiri, saeed rahimi, vahid zand, mohammad forough reyhani, mohammad samiei, negin ghasemi, payman mehrvarzfar, shahram azimi, noushin shokohinejad clinical and basic research | 327 the negative control groups, filled with wmta or gmta, did not exhibit any leakage [figure 1b]. the mean dye leakage values for the gmta and wmta groups were 0.40 ± 0.1 mm and 0.50 ± 0.1 mm, respectively [figures 1c & 1d]. there were no significant differences between the two experimental groups (p = 0.14) [figure 2]. figure 2 illustrates dye leakage in the gmta and wmta groups after immersion in stf, which shows the minimum and maximum amounts of leakage, as well as the variance in each experimental group. discussion the ability of dye penetration technique to demonstrate microleakage has been emphasised in different studies.20,21 moreover, many methods such as bacterial penetration, glucose leakage, and fluid filtration have been reported as methods to evaluate microleakage.11,22–24 in fact, there is no standard method to investigate microleakage. for instance, the amount of leakage in a bacterial leakage study might be influenced by the kind of bacteria and the culture medium that has been used as an indicator.25 the reliability of any glucose leakage study is questionable because mta produces calcium hydroxide after hydration, which can react with glucose.25 fluid filtration using active pressure to measure leakage does not mimic the actual leakage phenomenon.26 in the present study, a dye penetration method was used for assessing the degree of microleakage because it is a common method, and the dye has a molecular weight even less than that of bacterial toxins. however, the limitation of dye leakage studies is that they measure the extent of leakage in only one plane, making it impossible to evaluate the total amount of leakage. despite its disadvantages, the dye penetration method is popular and has been used in many studies;26 therefore, this method was used in this study. no sealer was used in this study because the aim of this study was to evaluate leakage through retrofilling materials, not through obturating materials within the root canal. moreover, many studies have demonstrated that sealers can penetrate into the dentinal tubules, occluding them and influencing leakage phenomenon.27,28 therefore, in this study no sealer was used. other studies have measured microleakage after 24 hours of incubation; in this study, a 72-hour period was used to allow more time for interaction between the stf and the mta. some previous leakage studies on mta as a root-end filling material did not mention the storage media, while others used tap water or saline.11,29,30 moreover, some researchers have used phosphatecontaining solution as a storage medium before leakage studies to mimic an in vivo situation.31-33 parirokh et al. showed that placing mta in a pbs storage medium caused a significant decrease in coronal leakage.34 they postulated that future in vitro studies should use pbs as a storage medium to simulate an in vivo condition.34 mta, as a bioactive material, can develop hydroxiapatite on its surface in a synthetic tissue fluid such as pbs.5,18 however, long-term studies have been recommended to demonstrate any interaction between pbs or any phosphate-containing medium, and mta. it might be noteworthy that hbss, pbs, and stf, as phosphate-containing solutions, have similarities with inorganic components of tissue fluids to some extent. however, stf does not contain organic elements and only maintains the mineral contents of tissue fluid. it is recommended that more studies should be carried out in the presence of blood to closely simulate real conditions. lack of dye leakage in the negative control and its presence in the positive control groups showed that the test design was reliable. this study showed that there were no significant differences between the leakage observed with gmta and wmta when used as retrofill materials in contact with stf after the initial setting. no study has compared leakage of gmta and wmta in the presence of stf. despite different amounts of ha formation with gmta and wmta, the microleakage phenomenon was the same. it seems that more expansion and more ha formation of gmta, in comparison with wmta, did not influence leakage.16–17 this effect might have two explanations: first, the expansion of gmta, even if it is greater than that of wmta, was not sufficient to fill the gaps and create differences in the leakage phenomenon; second, the ha crystals that are created in microscopic gaps between both kinds of mta and the dentinal wall were sufficient to prevent leakage. conclusion in conclusion, within the limitations of this in vitro study on the microleakage phenomenon of effect of synthetic tissue fluid on microleakage of grey and white mineral trioxide aggregate as root-end filling materials an in vitro study 328 | squ medical journal, august 2012, volume 12, issue 3 gmta and wmta, the results appear to support the use of both of them, although further longterm microleakage studies in the presence of blood should be undertaken. c o n f l i c t o f i n t e r e s t the authors declared no conflcit of interest. references 1. chong bs. a surgical alternative. in: chong bs, ed. managing endodontic failure in practice. chicago: quintessence publishing co. ltd., 2004. pp. 123–47. 2. rahimi s, shahi s, lotfi m, zand v, abdolrahimi m, es’haghi r. root canal configuration and the prevalence of c-shaped canals in mandibular second molars in an iranian population. j oral sci 2008; 50:9–13. 3. johnson br. considerations in the selection of a root-end filling material. oral surg oral med oral pathol oral radiol endod 1999; 87:398–404. 4. lee sj, monsef m, torabinejad m. sealing ability of a mineral trioxide aggregate for repair of lateral root perforations. j endod 1993; 19:541–4. 5. sarkar nk, caidedo r, tirwik p, moiseyeva r, kawashima i. physicochemical basis of the biologic properties of mineral trioxide aggregate. j endod 2005; 31:97–100. 6. camilleri j, montesin fe, brady k, sweeney r, curtis rv, pitt ford tr. the constitution of mineral trioxide aggregate. dent mater 2005; 21:297–303. 7. dammaschke t, gerth huv, zuchner h, schafer e. chemical and physical surface and bulk material characterization of white proroot mta and two portland cements. dent mater 2005; 1:731–8. 8. glickman gn, koch ka. 21st century endodontics. j am dent assoc 2000; 131:39–46s. 9. asgary s, parirokh m, eghbal mf, brink f. chemical differences between white and gray mineral trioxide aggregate. j endod 2005; 31:101–3. 10. komabayashi t, spangberg ls. comparative analysis of the particle size and shape of commercially available mineral trioxide aggregates and portland cement: a study with a flow particle image analyzer. j endod 2008; 34:94–8. 11. torabinejad m, rastegar a, kettering jd, pitt ford tr. bacterial leakage of mineral trioxide aggregate as a root-end filling material. j endod 1995; 21:109–12. 12. shahi s, rahimi s, yavari hr, shakouie s, nezafati s, abdolrahimi m. sealing ability of white and gray mineral trioxide aggregate mixed with distilled water and 0.12% chlorhexidine gluconate when used as root-end filling materials. j endod 2007; 33:1429–32. 13. friedland m, rosado r. mineral trioxide aggregate (mta) solubility and porosity with different waterto-powder ratios. j endod 2003; 29:814–17. 14. reyes-carmona jf, felippe ms, felippe wt. biomineralization ability and interaction of mineral trioxide aggregate and white portland cement with dentin in a phosphate-containing fluid. j endod 2009; 35:731–6. 15. dreger la, felippe wt, reyes-carmona jf, felippe gs, bortoluzzi ea, felippe mc. mineral trioxide aggregate and portland cement promote biomineralization in vivo. j endod 2012; 38:324–9. 16. lotfi m, vosoughhosseini s, saghiri ma, mesgariabbasi m, ranjkesh b. effect of white mineral trioxide aggregate mixed with disodium hydrogen phosphate on inflammatory cells. j endod 2009; 35:703–5. 17. storm b, eichmiller fc, tordik pa, goodell gg. setting expansion of gray and white mineral trioxide aggregate and portland cement. j endod 2008; 34:80–2. 18. bozeman tb, lemon rr, eleazer pd. elemental analysis of crystal precipitation from gray and white mta. j endod 2006; 32:425–8. 19. goodman a, reader a, beck m , melfi r, meyers w. an in vitro comparison of the efficacy of the step back technique versus a step-back/ultrasonic technique in human mandibular molars. j endod 1985; 11:249–56. 20. tamse a, katz a, kablan f. comparison of apical leakage shown by four different dyes with two evaluating methods. int endod j 1998; 31:333–7. 21. ahlberg km, assavanop p, tay wm. a comparison of the apical dye penetration patterns shown by methylene blue and india ink in root-filled teeth. int endod j 1995; 28:30–4. 22. maltezos c, glickman gn, ezzo p, he j. comparison of the sealing of resilon, pro root mta, and supereba as root-end filling materials: a bacterial leakage study. j endod 2006; 32:324–7. 23. zou l, liu j, yin s, li w, xie j. in vitro evaluation of the sealing ability of mta used for the repair of furcation perforations with and without the use of an internal matrix. oral surg oral med oral pathol oral radiol endod 2008; 105:e61. 24. martin rl, monticelli f, brackett ww, et al. sealing properties of mineral trioxide aggregate orthograde apical plugs and root fillings in an in vitro apexification model. j endod 2007; 33:272–5. 25. torabinejad m, parirokh m. mineral trioxide aggregate: a comprehensive literature review-part ii: leakage and biocompatibility investigations. j endod 2010; 36:190–202. 26. wu mk, wesselink pr. endodontic leakage studies reconsidered. part i: methodology, application and relevance. int endod j 1993; 26:37–43. 27. chadha r, taneja s, kumar m, gupta s. an in mehrdad lotfi, sepideh vosoughhosseini, mohammad ali saghiri, saeed rahimi, vahid zand, mohammad forough reyhani, mohammad samiei, negin ghasemi, payman mehrvarzfar, shahram azimi, noushin shokohinejad clinical and basic research | 329 vitro comparative evaluation of depth of tubular penetration of three resin-based root canal sealers. j conserv dent 2012; 15:18–21. 28. ravindranath m, neelakantan p, karpagavinayagam k, subba rao cv. the influence of obturation technique on sealer thickness and depth of sealer penetration into dentinal tubules evaluated by computer-aided digital analysis. gen dent 2011; 59:376–82. 29. fischer ej, arens de, miller ch. bacterial leakage of mineral trioxide aggregate as compared with zincfree amalgam, intermediate restorative material, and super-eba as a root-end filling material. j endod 1998; 24:176–9. 30. de-deus g, petruccelli v, gurgel-filho e, coutinhofilho t. mta versus portland cement as repair material for furcal perforations: a laboratory study using a polymicrobial leakage model. int edod j 2006; 39:293–8. 31. rahimi s, shahi s, lotfi m, yavari hr, charehjoo me. comparison of microleakage with three different thicknesses of mineral trioxide aggregate as root-end filling material. j oral sci 2008; 50:273–7. 32. saghiri ma, lotfi m, saghiri am, vosoughhosseini s, fatemi a, shiezadeh v, et al. effect of ph on sealing ability of white mineral trioxide aggregate as a root-end filling material. j endod 2008; 34:1226–9. 33. lotfi m, vosoughhosseini s, saghiri m, zand v, yavari hr, kimyai s, et al. effect of alkaline ph on sealing ability of white mineral trioxide aggregate. med oral patol oral cir bucal 2011; 16:1014–6e. 34. parirokh m, askarifard s, mansouri s, haghdoost aa, raoof m, torabinejad m. effect of phosphate buffer saline on coronal leakage of mineral trioxide aggregate. j oral sci 2009; 51:187–91. sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e299–300, epub. submitted 16 jun 14 accepted 27 aug 14 department of cardiology, royal hospital, muscat, oman e-mail: prashanthp_69@yahoo.co.in القلب والرئة اخلزفيني برا�سانث باندوراجنا porcelain heart and lung prashanth panduranga figure 1a–d: a: transthoracic echocardiogram (tte) in parasternal long-axis view showing calcification (arrow heads) of mitral valve prosthesis without involving the discs, extensive calcification of the mitral valve chordae and multiple pedunculated calcific nodular masses seen subvalvularly. b: tte in the short-axis view showing calcification (arrow heads) of the left ventricular myocardium and part of the interventricular septum. c: computed tomography (ct) scan of the chest demonstrating cardiac calcification (arrow heads). d: ct scan of the chest showing a lung parenchyma mass of ground-glass nodular calcification (arrow heads) in the right lower lobe. online interesting medical image a 24-year-old male presented withacute heart failure to the department of medicine at royal hospital, muscat, oman, in october 2011. he had undergone a mechanical mitral valve (mv) replacement in 2005 after a mitral valve prolapse and severe mitral regurgitation. he was diagnosed with systemic lupus erythematosus in 2006, end-stage renal disease on haemodialysis in 2008 and prosthetic valve endocarditis in february 2011. a transthoracic echocardiogram showed calcification of the mv prosthesis without involving the discs and extensive calcification of the mv chordae with multiple pedunculated calcific nodular masses which were seen subvalvularly. this was suggestive of old healed calcific vegetation [figure 1a]. there was calcification of the adjacent left ventricular myocardium and part of the interventricular septum [figure 1b]. the aorta and aortic valve were calcific with severe stenosis. a computed tomography scan of the chest confirmed cardiac calcification [figure 1c] along with a lung parenchyma mass of ground-glass nodular calcification in the right lower porcelain heart and lung e300 | squ medical journal, may 2015, volume 15, issue 2 metastases or destruction. non-calcium-containing phosphate binders, paricalcitol (vitamin d receptor agonists), cinacalcet (to lower parathormone levels) and a parathyroidectomy need to be considered to prevent the development of secondary hyperparathyroidism and cardiac calcification.3,4 references 1. matsui m, okayama s, takitsume a, morimoto k, samejima k, uemura s, et al. heart failure associated with metastatic myocardial calcification in a hemodialysis patient with progressive calcification of the hand. cardiorenal med 2012; 2:251–5. doi: 10.1159/000343497. 2. lee hu, youn hj, shim bj, lee sj, park my, jeong ju, et al. porcelain heart: rapid progression of cardiac calcification in a patient with hemodialysis. j cardiovasc ultrasound 2012; 20:193–6. doi: 10.4250/jcu.2012.20.4.193. 3. mazzaferro s, pasquali m, cozzolino m. treatment of cardiovascular calcification in uremia. curr vasc pharmacol 2011; 9:741–9. 4. bellasi a, reiner m, pétavy f, goodman w, floege j, raggi p. presence of valvular calcification predicts the response to cinacalcet: data from the advance study. j heart valve dis 2013; 22:391–9. lobe [figure 1d]. laboratory investigations revealed secondary hyperparathyroidism suggesting metastatic calcification. the patient’s parathyroid hormone level was 49.1 pmol/l (normal range: 1.6–6.9 pmol/l) with an adjusted calcium level of 2.78 mmol/l (normal range: 2.1–2.6 mmol/l) and a phosphate level of 2.72 mmol/l (normal range: 0.75–1.5 mmol/l). he underwent a successful aortic valve replacement procedure with decalcification of the mv and the subvalvular apparatus nodular masses without the need for a further mv replacement. comment metastatic calcification is the deposition of calcium salts in previously normal tissue due to an elevated calcium-phosphate product.1,2 in contrast, dystrophic calcification indicates calcium deposition in damaged tissue in the presence of normal levels of serum calcium and phosphate.1,2 common causes of metastatic calcification are hyperparathyroidism, secondary hyperparathyroidism as in end-stage renal disease, hypervitaminosis d/sarcoidosis and extensive bone 1department of adult health nursing, hashemite university, zarqa, jordan; 2department of nursing, school of nursing, california state university, california, los angeles, usa; 3department of adult health & critical care, college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mail: aliammouri@yahoo.com معرفة عوامل اخلطر ألمراض القلب التاجية لدى عينة من اجملتمع احمللي يف عمان دراسة جتريبية علي اأحمد عموري، اأمين طيلخ، �سندراين ا�سحق، جوي كابا�سيندي، جو�سوا موليريا، �رسيدييفي بال�ساندران abstract: objectives: the aim of this study was to assess the knowledge of omani adults regarding conventional coronary heart disease (chd) risk factors and to identify demographic variables associated with these knowledge levels. methods: this descriptive cross-sectional pilot study was carried out among a convenience sample of 130 adults attending a health awareness fair held in a local shopping mall in muscat, oman, in november 2012. a modified version of the heart disease facts questionnaire in both english and arabic was used to assess knowledge of chd risk factors. scores were calculated by summing the correct answers for each item (range: 0–21). inadequate knowledge was indicated by a mean score of <70%. descriptive and multivariate logistic regression analyses were performed to establish the participants’ knowledge levels and identify associated demographic variables. results: a total of 114 subjects participated in the study (response rate: 87.7%). of these, 69 participants (60.5%) had inadequate mean chd knowledge scores. knowledge of chd risk factors was significantly associated with body mass index (odds ratio [or] = 0.739; p = 0.023), marital status (or = 0.057; p = 0.036) and education level (or = 9.243; p = 0.006). conclusion: low knowledge levels of chd risk factors were observed among the studied community sample in oman; this is likely to limit the participants’ ability to engage in preventative practices. these findings support the need for education programmes to enhance awareness of risk factors and prevention of chd in oman. keywords: coronary heart disease; knowledge; risk factors; prevention; oman. امللخ�ص: اأهداف: هدفت هذه الدرا�سة لتقييم معرفة البالغني العمانيني بعوامل اخلطر لأمرا�س القلب التاجية التقليدية وحتديد املتغريات الدميوغرافية املرتبطة مب�ستويات هذه املعرفة. منهجية: اأجريت هذه الدرا�سة الو�سفية امل�ستعر�سة على عينة مالئمة من 130 من البالغني ا�ستخدام مت .2012 نوفمرب يف عمان، م�سقط، يف املحلية التجاريه املراكز اأحد يف عقد الذي ال�سحية التوعية معر�س يح�رسون الذين مت الوعائية. القلبية اخلطر بعوامل العينة معرفة لتقييم والعربية الإجنليزية باللغتني القلب" اأمرا�س حقائق من "ا�ستبيان معدلة ن�سخة احت�ساب النقاط عن طريق جمع الإجابات ال�سحيحة لكل بند )املدى: 21–0(. مت حتديد احل�سول على نقاط اأقل من %70 كدليل علي عدم كفاية املعرفة من قبل امل�ساركني. اأجريت حتليالت النحدار اللوج�ستي الو�سفية متعددة املتغريات لتحديد م�ستويات معرفة امل�ساركني و املتغريات الدميوغرافية املرتبطة بها. نتائج: �سارك 114 �سخ�س يف الدرا�سة وبلغ معدل ال�ستجابة %87.7. من هوؤلء، ح�سل 69 م�ساركا باأمرا�س ال�سابة خطر بعوامل املعرفة ارتبطت التاجية. ال�رسايني باأمرا�س املعرفة عدم على يدل مما غريكافية نقاط علي )60.5%( )p = 0.036 ؛or = 0.057( احلالة الجتماعية ،)p = 0.023 ؛]or[ = 0.739 القلب ب�سكل كبري مع موؤ�رس كتلة اجل�سم )ن�سبة الأرجحية وم�ستوى التعليم )or = 9.342؛ p = 0.006(. خامتة: لوحظت م�ستويات معرفة منخف�سة عن عوامل خطر اإل�سابة باأمرا�س القلب بني عينة جمتمعية يف �سلطنة عمان. هذا اإلنخفا�س املعريف قد يحد من قدرة امل�ساركني على النخراط يف املمار�سات الوقائية. تدعم هذه النتائج احلاجة اإىل برامج تعليمية لتعزيز الوعي بعوامل اخلطر والوقاية من اأمرا�س ال�رسايني التاجية يف عمان. كلمات مفتاحية: مر�س القلب التاجي؛ معرفة؛ عوامل اخلطر؛ الوقاية؛ عمان. knowledge of coronary heart disease risk factors among a community sample in oman pilot study *ali a. ammouri,1 ayman tailakh,2 chandrani isac,3 joy k. kamanyire,3 joshua muliira,3 shreedevi balachandran3 sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 189–196, epub. 15 may 16 submitted 12 may 15 revisions req. 5 jul, 3 sep & 28 oct 15; revisions recd. 3 aug, 20 sep & 9 nov 15 accepted 10 dec 15 clinical & basic research doi: 10.18295/squmj.2016.16.02.009 advances in knowledge this is the first study in oman to highlight deficits in knowledge of coronary heart disease (chd) risk factors among a community sample of omani adults. several factors—including a high body mass index, low education levels and being married—were associated with low levels of chd risk factor knowledge among the sample. application to patient care the findings of this study contribute to existing knowledge regarding chd in oman and should be considered when planning and implementing targeted chd health education and other preventative measures. programmes to address the increasing burden of chd in oman should take into account the low levels of knowledge of chd risk factors observed among the omani community. the results of this study highlight certain psycho-cognitive factors that require further exploration by healthcare services and researchers to enhance chd risk factor knowledge and preventative lifestyle behaviours in oman. knowledge of coronary heart disease risk factors among a community sample in oman pilot study 190 | squ medical journal, may 2016, volume 16, issue 2 coronary heart disease (chd) is an increasing worldwide health burden. according to the world health organization (who), there were 7.4 million deaths due to ischaemic heart disease in 2012, with high-income countries and upper-middle-income countries accounting for 158 and 107 deaths per million, respectively.1,2 while the prevalence of chd has stabilised in developed countries, the condition has recently begun to impact developing countries due to increasing life expectancy, urbanisation and lifestyle changes; certain middle eastern countries (e.g. bahrain, kuwait, oman, qatar and the united arab emirates) are examples of areas experiencing this epidemiological transition.3 modifiable risk factors such as hypertension, diabetes mellitus, hyperlipidaemia, a sedentary lifestyle, obesity and smoking are considered to be the main precursors of chd.4 the increasing trend of chd and its related risk factors has highlighted the need to strengthen national surveillance schemes and efforts to reduce chd-related morbidity and mortality. many countries have implemented a primary prevention approach; however, a key aspect affecting the success of this method is the knowledge of the individuals at risk regarding a specific health problem.5 greater knowledge of chd risk factors helps individuals to correctly assess their personal risk, motivates them to increase prevention-seeking behaviours and has been associated with increased action to lower risks.6–8 estimating knowledge of traditional chd risk factors among a population is therefore crucial in the prevention and treatment of this condition and continues to serve as the baseline for most screening programmes.9 inherent psycho-cognitive factors such as the perceived risk of a disease or the importance of behavioural change as well as barriers to the adoption of preventative behaviours or chd screening may contribute to lack of knowledge.6,7,10 the population of oman is currently approximately four million and life expectancy has recently increased (76.2 years in 2012 versus 73.3 years in 2010).11,12 lifestyle changes, including an increase in sedentary lifestyles and a greater caloric intake, have contributed to a rapid rise in the incidence of chd; diseases of the circulatory system accounted for 32.5% of hospital deaths in oman in 2012 versus 29.4% of hospital deaths in 2010.12 the prevalence of diabetes, hypertension and high serum cholesterol levels among omani adults was 12.3%, 40.3% and 33.6%, respectively, in 2008.13 other surveys conducted in oman have estimated the prevalence rates of overweight individuals, obesity and smoking in adults to be 67.4%, 30.9% and 13.5%, respectively.14 despite this threat, awareness and understanding of chd are low in oman and there is a significant lack of surveillance data for populations in the middle eastern region.15–17 recent studies in this region have focused on screening for obesity, dietary patterns and diabetes mellitus.18–20 there is therefore an urgent need to understand baseline knowledge levels of chd among the omani population before designing appropriate and effective interventions to promote awareness. this study aimed to assess the knowledge of omani adults regarding conventional chd risk factors and to identify demographic variables associated with these knowledge levels. methods this descriptive cross-sectional pilot study was carried out on a convenience sample of 130 omani adults attending a health awareness fair held at a large shopping mall in muscat, oman, in november 2012. the fair was organised by faculty members of the college of nursing at sultan qaboos university (squ), muscat, and provided community awareness activities and services with the goal of increasing public awareness about chd. omani adults ≥18 years old who were not disabled or suffering from any medical conditions that prevented them from answering questions and who were not working in the healthcare profession were included in the study. cohen’s table was used to estimate a sample size allowing for the detection of a medium effect with a power of 0.80 and alpha of 0.05 with a regression analysis for seven variables.21 a sample of 107 participants was thus deemed adequate to ensure a description of variables in a single group and allow the researchers to control for type ii errors. the effect size was estimated to be medium to account for the possibility that some participants had previously acquired chd knowledge while seeking healthcare or from other sources. in order to assess self-reported knowledge of chd risk factors, participants were invited to complete the modified version of the heart disease facts questionnaire (hdfq).22,23 the hdfq was originally designed by wagner et al. to measure chd knowledge among diabetic patients utilising 25 true/ false questionnaire items and has demonstrated good psychometric properties, test-retest reliability (r = 0.89), internal consistency (kuder-richardson r = 0.77) and excellent discriminant validity.22 the modified hdfq contains 21 items measuring knowledge of chd risk factors and methods of decreasing chd risk.23 each item on the modified hdfq scale has three available responses: true, false or unknown. scores were ali a. ammouri, ayman tailakh, chandrani isac, joy k. kamanyire, joshua muliira and shreedevi balachandran clinical and basic research | 191 calculated by summing the correct answers (range: 0–21). statements with scores of <70% and ≥70% were deemed to indicate low and adequate knowledge, respectively.22 the modified hdfq instrument has also shown high internal consistency, with a cronbach’s alpha of 0.84.23 in this study, the cronbach’s alpha coefficient was 0.86. the questionnaire was administered in both arabic and english. the arabic version was independently translated from the english instrument by three different postgraduate nurses who were proficient in both languages. they discussed and agreed on one version which was then back-translated by a bilingual expert. both the translated and backtranslated forms were validated by two bilingual doctorate nurses specialising in cardiovascular care. the demographic characteristics of the participants were recorded, including age, gender, marital and employment status, level of education and annual income. body mass index (bmi) was calculated by dividing the participants’ weight by their height. weight was measured to the nearest 0.1 kg with portable digital scales and height was measured to the nearest 0.1 cm with a portable stadiometer. during these measurements, participants were requested to take off their shoes and any heavy clothing and to stand upright. participants were then categorised according to their bmi as underweight (<18.5 kg/m2), normal (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) or obese (≥30.0 kg/m2), according to who standards.24 data were entered into the statistical package for the social sciences (spss), version 19, (ibm corp., chicago, illinois, usa). descriptive analyses were conducted and results presented as means ± standard deviation and percentages. a multivariate logistic regression analysis was used to determine the associations between predictive variables (age, gender, bmi, education level, marital status, monthly income and employment) and the dichotomous dependent variable (knowledge of chd). these results were presented as odds ratios (ors) and 95% confidence intervals. a p value of <0.050 was considered statistically significant. this study received ethical approval from the research & ethics committee of the squ college of nursing (#crc/2012/20.9.2012). individuals who expressed an interest in participating in the study were provided with detailed information about the study’s purpose and procedures. participants were assured that no information pertaining to their identity would be collected. written consent was obtained from each of the subjects before their participation in the study. results a total of 114 subjects participated in the study (response rate: 87.7%). the demographic characteristics of the participants are presented in table 1. participants ranged in age from 18–80 years old. the majority of the participants were male (63.2%). the mean bmi was 27.47 ± 4.12 kg/m2 and the majority of the participants were categorised as overweight table 1: demographic characteristics and knowledge of coronary heart disease risk factors* among a community sample of omani adults (n = 114) characteristic n (%) mean age in years (iqr) 37.36 (13.50) bmi† in kg/m2 <18.5 2 (2.0) 18.5–24.9 27 (27.3) 25.0–29.9 42 (42.4) ≥30.0 28 (28.3) mean ± sd 27.47 ± 4.12 gender male 72 (63.2) female 42 (36.8) marital status single 32 (28.1) married 82 (71.9) education level primary school 10 (8.8) high school 36 (31.6) diploma 26 (22.8) baccalaureate degree 30 (26.3) graduate degree 12 (10.5) employment status unemployed 27 (23.7) employed 87 (76.3) monthly income in usd† <$1,300 46 (46.5) >$1,300 53 (53.5) chd knowledge score <69.9% 69 (60.5) ≥70.0% 45 (39.5) mean ± sd 13.52 ± 4.59 iqr = interquartile range; bmi = body mass index; sd = standard deviation; chd = coronary heart disease. *knowledge was self-assessed by participants using the modified version of the heart disease facts questionnaire.22,23 †total dataset was 99 due to missing data for 15 participants. knowledge of coronary heart disease risk factors among a community sample in oman pilot study 192 | squ medical journal, may 2016, volume 16, issue 2 (42.4%). in terms of education level, a large proportion of the participants possessed a diploma qualification or higher (59.6%). a total of 69 participants (60.5%) had chd knowledge scores <70%, indicating a low level of knowledge. the mean chd knowledge score was 13.52 ± 4.59 and the mean percentage of correct answers was 64.4%. participants showed adequate knowledge of certain chd risk factors, such as smoking (n = 112; 98.3%), high blood pressure (n = 100; 87.7%), being overweight (n = 100; 87.7%), high cholesterol levels (n = 97; 85.1%) and age (n = 81; 71.1%). the majority also demonstrated adequate knowledge regarding several chd prevention measures, such as regular physical activity (n = 104; 91.2%), blood pressure control (n = 101; 88.6%) and smoking cessation (n = 100; 87.7%). however, fewer participants demonstrated correct knowledge of other chd risk factors, including diabetes (n = 72, 63.2%), stress (n = 72; 63.2%), a family history of chd (n = 68; 59.7%) and abdominal obesity (n = 61; 53.5%). fewer subjects were aware of high-density lipoproteins (hdl) and low-density lipoproteins (ldl) as risk factors (n = 39; 34.2% and n = 59; 51.8%, respectively). only 39 participants correctly responded that individuals with chd might not be aware of their condition (34.2%). while two of the three questionnaire items relating to physical activity were identified correctly by over 80% of the cohort, 59.6% of the participants believed that exercising in a gym or class was the only for of physical actively which lowers the risk of chd [table 2]. a multiple logistic regression analysis was performed to predict chd knowledge. the model fit the data well (chi-squared value = 23.42, p <0.001; goodness of fit = 6.38, p = 0.609). the only modifiable factor that was significantly associated with knowledge of chd risk factors was a bmi of ≥25 kg/m2 (or = 0.739; p = 0.023), indicating that participants with a bmi of ≥25 kg/m2 had 73.9% less knowledge than participants with a bmi of <25 kg/m2. demographic variables significantly associated with knowledge of chd risk factors included being married (or = 0.057; p = 0.036) and having a diploma, baccalaureate or graduate educational qualification (or = 9.243; p = 0.006). this indicates that married participants had 5.7% less knowledge than unmarried participants and participants with a diploma or higher education level had knowledge scores which were 9.2% higher than those with less education [table 3]. discussion the purpose of this study was to assess knowledge of chd risk factors and identify demographic variables associated with knowledge levels among a community sample of adult omanis. the mean score obtained table 2: levels of accurate* knowledge of coronary heart disease risk factors† among a community sample of omani adults (n = 114) questionnaire item n (%) a person always knows when they have chd 39 (34.2) if you have a family history of chd, you are at risk of developing heart disease 68 (59.7) the older a person is, the greater their risk of developing chd 81 (71.1) smoking is a risk factor for chd 112 (98.3) a person who stops smoking will lower their risk of developing chd 100 (87.7) high blood pressure is a risk factor for developing chd 100 (87.7) keeping blood pressure under control will reduce a person’s risk for developing chd 101 (88.6) high cholesterol is a risk factor for developing chd 97 (85.1) if your ‘good’ cholesterol (hdl) is high, you are at risk for heart disease 39 (34.2) if your ‘bad’ cholesterol (ldl) is high, you are at risk for heart disease 59 (51.8) eating fatty foods does not affect blood cholesterol levels 86 (75.4) being overweight increases a person’s risk of chd 100 (87.7) regular physical activity will lower the risk of developing heart disease 104 (91.2) only exercising at a gym or in an exercise class lowers the risk of developing heart disease 46 (40.4) walking and gardening are considered exercise that will help lower the risk of developing heart disease 94 (82.5) diabetes is a risk factor for developing chd 72 (63.2) high blood sugar makes the heart work harder 66 (57.9) a person who has diabetes can reduce their risk of developing chd if they keep their blood sugar levels under control 77 (67.5) abdominal obesity is a risk factor for developing chd 61 (53.5) stress may cause an increase in blood sugar, blood pressure and cholesterol levels 72 (63.2) slow deep breaths, counting to 10 before speaking and going for a walk are examples of stress inhibitors 73 (64.0) chd = coronary heart disease; hdl = high-density lipoproteins; ldl = low-density lipoproteins. *using correct responses only. †knowledge was self-assessed by participants using the modified version of the heart disease facts questionnaire.22,23 ali a. ammouri, ayman tailakh, chandrani isac, joy k. kamanyire, joshua muliira and shreedevi balachandran clinical and basic research | 193 on the hdfq scale by the participants indicated an inadequate level of chd risk factor knowledge among adult omanis. studies from other parts of the world have similarly reported low levels of knowledge and awareness of chd risk factors.7,25 a study conducted in kuwait to assess public knowledge of cardiovascular disease (cvd) risk factors reported similar findings, while another conducted in jordan reported higher levels of knowledge among their cohort.15,16 smoking, high blood pressure and high cholesterol have been rated as factors posing the greatest risk for chd.8 pereira et al. reported that the prevalence, awareness, treatment and control of these risk factors in developing countries are coming closer to those in developed countries.26 the aggressive nature and consequences of these risk factors have prompted healthcare providers to give them more emphasis whilst advising patients.27 in the current study, the majority of the participants were familiar with common chd risk factors, such as smoking, high blood pressure and high cholesterol levels. awad et al. also reported sufficient knowledge levels among their kuwaiti cohort regarding the risks associated with smoking, obesity, an unhealthy diet and physical inactivity; these similarities could be attributed to the frequent and comprehensive dissemination of information on the ill-effects of these risk factors by various media sources globally.16,28 however, hypercholesterolaemia, hypertension, diabetes mellitus, stress and a family history of cvd were less frequently identified as chd risk factors among the kuwaiti cohort.16 this may be due to inter-country variations in information provided by the mass media. health education and guidance are necessary to allow the general population to gain adequate knowledge from reliable sources.29 among the cohort in the current study, the level of knowledge regarding age as a risk factor for chd was close to the cut-off point designating adequate knowledge, reflecting a limited understanding of age as a non-modifiable risk factor for chd. furthermore, while the majority of the participants knew that being overweight increased the risk of chd, fewer realised that carrying higher levels of abdominal fat imposes the greatest risk. ford et al. noted an increasing prevalence of abdominal obesity in the usa.30 this may indicate the existence of intra-personal inhibitory factors preventing individuals from instituting measures to address this chd risk factor. in the current study, levels of knowledge regarding hdl and ldl were low. these scores were consistent with those reported among a sample in india.31 additionally, the participants’ knowledge of stress, diabetes and a family history of chd as risk factors was inadequate in the present study. type 2 diabetes mellitus was found to be an independent risk factor for cvd among individuals of middle eastern descent living in sweden.20 fernandez et al. noted that the only 46% of their australian cohort recognised diabetes to be a risk factor for heart disease.32 lack of awareness about family history as a chd risk factor has also been documented in the literature.33 as a result, the risk factors which were less known to the current study’s cohort may be fuelling the prevalence of chd in oman; this indicates an urgent need for these factors to be addressed in health education and public awareness campaigns. in the present study, a bmi of ≥25 kg/m2 was significantly associated with lower chd knowledge levels. this finding is similar to that reported in a study of overweight and obese individuals in romania which showed that participants were usually not aware of their sub-optimal health.34 like many arab countries, oman has witnessed an alarming rise in its obesity rate in the last three decades, largely due to increased industrialisation, urbanisation, westernisation, adop tion of a sedentary lifestyle and improved socioeconomic status.35 unfortunately, many obese individuals do not understand the necessity of making lifestyle changes due to a lack of knowledge about the cardiovascular implications of obesity.36 this supports the need for educational interventions to increase awareness of chd-associated risk factors and required lifestyle changes related to eating habits and physical activity.37 critically, a sizable number of participants in the present study believed that only physical activity performed at a gym or in an exercise class could prevent chd. female participants in a similar table 3: multivariate logistic regression analysis* of associations between predictive variables and knowledge of coronary heart disease risk factors† among a community sample of omani adults (n = 114) variable beta estimate p value or 95% ci intercept 9.460 0.010 age‡ 0.041 0.304 1.041 0.964–1.130 bmi of ≥25 kg/m2 -0.302 0.023 0.739 0.570–0.959 gender 0.621 0.506 0.537 0.086–3.353 employment -2.099 0.064 0.123 0.013–1.123 diploma education or higher 2.224 0.006 9.243 1.872–45.632 married -2.871 0.036 0.057 0.004–0.825 income 0.910 0.259 2.483 0.512–12.056 or = odds ratio; ci = confidence interval; bmi = body mass index. *all variables were entered into the model. †knowledge was self-assessed by participants using the modified version of the heart disease facts questionnaire.22,23 ‡continuous variable. knowledge of coronary heart disease risk factors among a community sample in oman pilot study 194 | squ medical journal, may 2016, volume 16, issue 2 study from india were aware that engaging in physical activity and losing weight were important lifestyle changes required for preventing chd.38 a study from the usa found that college-level students who exercised regularly rated their chd risk as lower than those who did not;32 this may indicate that knowledge of chd risk factors can influence behaviour. education level was also found to have a significant association with chd knowledge in the current study. this finding is consistent with results reported by wagner et al. and highlights the need for multilateral interventions in order to enhance chd awareness.22 many of these interventions could be based in the health sector; however, others are needed at the societal level in order to increase the level of general education among the community.39 in the current study, married participants also had significantly less knowledge about chd compared to their single counterparts. similar results were found in a study conducted in egypt.40 specific marital-related factors, such as family obligations, have been found to result in a lack of time to engage in preventative actions and may therefore contribute to a lack of knowledge about chd.7 in contrast, no significant association between chd knowledge and gender was noted among the present cohort. this result was inconsistent with previous research by jensen et al. which indicated that women were more aware of chd risk factors than their male counterparts.41 sampling bias and the larger proportion of male participants in the current study could explain this inconsistency. the results of this study should be considered by health policy-makers when designing and implementing interventions to enhance awareness and prevention of chd in oman, including mass media and other community awareness campaigns. these findings could also be used to identify individuals who are likely to possess lower knowledge levels so that they can be targeted with tailored education strategies. however, further studies using larger samples and a longitudinal design are needed to validate the findings of this study. the knowledge gaps identified in this study need to be explored in greater depth by healthcare service providers and researchers to determine psycho-cognitive factors affecting lifestyle behaviours. culturally and ethnically diverse groups and rural communities have been a common focus for studies identifying chd risk factors.42,43 while ethnicity was beyond the scope of the current study, this factor may potentially be explored in later studies which include both the local and expatriate populations of oman. the current study had a number of limitations which may have impacted its findings. the crosssectional nature of the study hindered the ability to draw inferences or generalise the findings to the larger omani population. the use of a small convenience sample with a larger proportion of male participants, the self-selection of the group and the use of self-reported data may also have introduced inherent biases. furthermore, the participants for the current study were attending a health awareness fair, indicating some degree of interest in health-related topics. it should also be noted that the original hdfq questionnaire was created for diabetic patients with high health awareness, rather than to assess the general public on knowledge of chd risk factors. as a result, the findings of this study may overor underestimate knowledge of chd risk factors in oman. conclusion low levels of knowledge regarding chd risk factors were reported among the studied group of omani adults. while knowledge of certain chd risk factors was adequate, fewer participants were aware of other risk factors, such as diabetes, stress, a family history of chd, abdominal obesity, hdl and ldl. marital status, bmi and education levels were significantly associated with knowledge levels. health policymakers should therefore consider these findings when preparing education programmes to enhance awareness of risk factors and prevention of chd in oman. further studies are needed to determine the causative factors behind the identified knowledge gaps. in addition, studies using larger sample sizes and a longitudinal design are necessary to substantiate the results of this pilot study. a c k n o w l e d g m e n t s the authors wish to thank the study subjects for their cooperation. in addition, the authors are grateful for the support of the students and faculty who participated in the health awareness fair. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. world health organization. cardiovascular diseases (cvds). from: www.who.int/mediacentre/factsheets/fs317/en/ accessed: nov 2015. 2. world health organization. the top 10 causes of death: the 10 leading causes of death by country income group (2012). from: www.who.int/mediacentre/factsheets/fs310/en/index1.html accessed: nov 2015. ali a. ammouri, ayman tailakh, chandrani isac, joy k. kamanyire, joshua muliira and shreedevi balachandran clinical and basic research | 195 3. yusuf s, hawken s, ounpuu s, dans t, avezum a, lanas f, et al. effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the interheart study): case-control study. lancet 2004; 364:937–52. doi: 10.1016 /s0140-6736(04)17018-9. 4. world health organization. global status report on noncommunicable diseases: 2010. from: apps.who.int/iris/ bitstream/10665/44579/1/9789240686458_eng.pdf accessed: nov 2015. 5. perk j, de backer g, gohlke h, graham i, reiner z, verschuren m, et al. [european guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts)]. eur heart j 2012; 33:1635–701. doi: 10.1093/ eurheartj/ehs092. 6. claassen l, henneman l, van der weijden t, marteau tm, timmermans dr. being at risk for cardiovascular disease: perceptions and preventive behavior in people with and without a known genetic predisposition. psychol health med 2012; 17:511–21. doi: 10.1080/13548506.2011.644246. 7. haidinger t, zweimüller m, stütz l, demir d, kaider a, strametz-juranek j. effect of gender on awareness of cardiovascular risk factors, preventive action taken, and barriers to cardiovascular health in a group of austrian subjects. gend med 2012; 9:94–102. doi: 10.1016/j.genm.2012.02.001. 8. mosca l, hammond g, mochari-greenberger h, towfighi a, albert ma, et al. fifteen-year trends in awareness of heart disease in women: results of a 2012 american heart association national survey. circulation 2013; 127:1254–63. doi: 10.1161/cir.0b013e318287cf2f. 9. wagner j, lacey k, abbott g, de groot m, chyun d. knowledge of heart disease risk in a multicultural community sample of people with diabetes. ann behav med 2006; 31:224–30. doi: 10.1207/s15324796abm3103_3. 10. juwita s, norwati d, harmy my, alina ti, siti hawa a. barriers to cardiovascular screening among malay women in east coast malaysia. int j collab res intern med public health 2013; 5:67–78. 11. national centre for statistics and information, sultanate of oman. data analysis. from: www.data.gov.om/en/data analysis/ accessed: nov 2015. 12. oman ministry of health. health facts report 2012. from: www. moh.gov.om/documents/274609/274943/health_fact2012. pdf/0b5a636f-e2e8-4400-9ef9-e1ab0d39df82 accessed: nov 2015. 13. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1 methodology, sociodemographic profile and epidemiology of noncommunicable diseases in oman. oman med j 2012; 27:425–43. 14. world health organization. eastern mediterranean region: framework for health information systems and core indicators for monitoring health situation and health system performance – 2015. from: applications.emro.who.int/dsaf/ emropub_2015_en_1904.pdf?ua=1 accessed: nov 2015. 15. mukattash tl, shara m, jarab as, al-azzam si, almaaytah a, al hamarneh yn. public knowledge and awareness of cardiovascular disease and its risk factors: a cross-sectional study of 1000 jordanians. int j pharm pract 2012; 20:367–76. doi: 10.1111/j.2042-7174.2012.00208.x. 16. awad a, al-nafisi h. public knowledge of cardiovascular disease and its risk factors in kuwait: a cross-sectional survey. bmc public health 2014; 14:1131. doi: 10.1186/1471-2458-14-1131. 17. shara nm. cardiovascular disease in middle eastern women. nutr metab cardiovasc dis 2010; 20:412–18. doi: 10.1016/j. numecd.2010.01.013. 18. barakat h, barakat h, baaj mk. cvd and obesity in transitional syria: a perspective from the middle east. vasc health risk manag 2012; 8:145–50. doi: 10.2147/vhrm.s28691. 19. khosravi-boroujeni h, sarrafzadegan n, mohammadifard n, sajjadi f, maghroun m, asgari s, et al. white rice consumption and cvd risk factors among iranian population. j health popul nutr 2013; 31:252–61. doi: 10.3329/jhpn.v31i2.16390. 20. bennet l, agardh cd, lindblad u. cardiovascular disease in relation to diabetes status in immigrants from the middle east compared to native swedes: a cross-sectional study. bmc public health 2013; 13:1133. doi: 10.1186/1471-2458-13-1133. 21. cohen j. a power primer. psychol bull 1992; 112:155–9. doi: 10.1037/0033-2909.112.1.155. 22. wagner j, lacey k, chyun d, abbott g. development of a questionnaire to measure heart disease risk knowledge in people with diabetes: the heart disease fact questionnaire. patient educ couns 2005; 58:82–7. doi: 10.1016/j.pec.2004.07.004. 23. dalusung-angosta a. chd knowledge and risk factors among filipino-americans connected to primary care services. j am assoc nurse pract 2013; 25:503–12. doi: 10.1002/23276924.12039. 24. world health organization. bmi classification. from: apps.who. int/bmi/index.jsp?intropage=intro_3.html accessed: nov 2015. 25. reiner z, sonicki z, tedeschi-reiner e. public perceptions of cardiovascular risk factors in croatia: the percro survey. prev med 2010; 51:494–6. doi: 10.1016/j.ypmed.2010.09.015. 26. pereira m, lunet n, azevedo a, barros h. differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries. j hypertens 2009; 27:963–75. doi: 10.1097/hjh.0b013e3283282f65. 27. abdullah a, husten c. promotion of smoking cessation in developing countries: a framework for urgent public health interventions. thorax 2004; 59:623–30. doi: 10.1136/ thx.2003.018820. 28. mosca l, ferris a, fabunmi r, robertson rm; american heart association. tracking women’s awareness of heart disease: an american heart association national study. circulation 2004; 109:573–9. doi: 10.1161/01.cir.0000115222.69428.c9. 29. van bekkum je, hilton s. primary care nurses’ experiences of how the mass media influence frontline healthcare in the uk. bmc fam pract 2013; 14:178. doi: 10.1186/1471-2296-14-178. 30. ford es, li c, zhao g, tsai j. trends in obesity and abdominal obesity among adults in the united states from 1999-2008. int j obes (lond) 2011; 35:736–43. doi: 10.1038/ijo.2010.186. 31. saeed o, gupta v, dhawan n, streja l, shin js, ku m, et al. knowledge of modifiable risk factors of coronary atherosclerotic heart disease (cashd) among a sample in india. bmc int health hum rights 2009; 9:2. doi: 10.1186/1472-698x-9-2. 32. fernandez rs, salamonson y, griffiths r, juergens c, davidson p. awareness of risk factors for coronary heart disease following interventional cardiology procedures: a key concern for nursing practice. int j nurs pract 2008; 14:435–42. doi: 10.1111/j.1440-172x.2008.00717.x. 33. karthik s, tahir n, thakur b, nair u. risk factor awareness and secondary prevention of coronary artery disease: are we doing enough? interact cardiovasc thorac surg 2006; 5:268–71. doi: 10.1510/icvts.2005.120956. 34. rada c. body mass index: knowledge, practice and health evaluation. int j collab res intern med public health 2012; 4:1276–84. 35. badran m, laher i. obesity in arabic-speaking countries. j obes 2011; 2011:686430. doi: 10.1155/2011/686430. 36. andersson p, sjöberg rl, ohrvik j, leppert j. knowledge about cardiovascular risk factors among obese individuals. eur j cardiovasc nurs 2006; 5:275–9. doi: 10.1016/j.ejcnu rse.2006.02.005. 37. mooney la, franks am. evaluation of community health screening participants’ knowledge of cardiovascular risk factors. j am pharm assoc (2003) 2009; 49:529–37. doi: 10.1331/japha.2009.08120. http://dx.doi.org/10.1016/s0140-6736%2804%2917018-9 http://dx.doi.org/10.1016/s0140-6736%2804%2917018-9 http://dx.doi.org/10.1093/eurheartj/ehs092 http://dx.doi.org/10.1093/eurheartj/ehs092 http://dx.doi.org/10.1080/13548506.2011.644246 http://dx.doi.org/10.1016/j.genm.2012.02.001 http://dx.doi.org/10.1161/cir.0b013e318287cf2f http://dx.doi.org/10.1207/s15324796abm3103_3 http://dx.doi.org/10.1111/j.2042-7174.2012.00208.x http://dx.doi.org/10.1186/1471-2458-14-1131 http://dx.doi.org/10.1016/j.numecd.2010.01.013 http://dx.doi.org/10.1016/j.numecd.2010.01.013 http://dx.doi.org/10.2147/vhrm.s28691 http://dx.doi.org/10.3329/jhpn.v31i2.16390 http://dx.doi.org/10.1186/1471-2458-13-1133 http://dx.doi.org/10.1037/0033-2909.112.1.155 http://dx.doi.org/10.1016/j.pec.2004.07.004 http://dx.doi.org/10.1002/2327-6924.12039 http://dx.doi.org/10.1002/2327-6924.12039 http://dx.doi.org/10.1016/j.ypmed.2010.09.015 http://dx.doi.org/10.1097/hjh.0b013e3283282f65 http://dx.doi.org/10.1136/thx.2003.018820 http://dx.doi.org/10.1136/thx.2003.018820 http://dx.doi.org/10.1161/01.cir.0000115222.69428.c9 http://dx.doi.org/10.1186/1471-2296-14-178 http://dx.doi.org/10.1038/ijo.2010.186 http://dx.doi.org/10.1186/1472-698x-9-2 http://dx.doi.org/10.1111/j.1440-172x.2008.00717.x http://dx.doi.org/10.1510/icvts.2005.120956 http://dx.doi.org/10.1155/2011/686430 http://dx.doi.org/10.1016/j.ejcnurse.2006.02.005 http://dx.doi.org/10.1016/j.ejcnurse.2006.02.005 http://dx.doi.org/10.1331/japha.2009.08120 knowledge of coronary heart disease risk factors among a community sample in oman pilot study 196 | squ medical journal, may 2016, volume 16, issue 2 38. green js, grant m, hill kl, brizzolara j, belmont b. heart disease risk perception in college men and women. j am coll health 2003; 51:207–11. doi: 10.1080/07448480309596352. 39. kang y, yang is, kim n. correlates of health behaviors in patients with coronary artery disease. asian nurs res (korean soc nurs sci) 2010; 4:45–55. doi: 10.1016/s19761317(10)60005-9. 40. seef s, jeppsson a, stafström m. what is killing? people’s knowledge about coronary heart disease, attitude towards prevention and main risk reduction barriers in ismailia, egypt (descriptive cross-sectional study). pan afr med j 2013; 15:137. doi: 10.11604/pamj.2013.15.137.1628. 41. jensen la, moser dk. gender differences in knowledge, attitudes, and beliefs about heart disease. nurs clin north am 2008; 43:77–104. doi: 10.1016/j.cnur.2007.10.005. 42. artac m, dalton ar, majeed a, car j, millett c. effectiveness of a national cardiovascular disease risk assessment program (nhs health check): results after one year. prev med 2013; 57:129–34. doi: 10.1016/j.ypmed.2013.05.002. 43. kandula nr, patel y, dave s, seguil p, kumar s, baker dw, et al. the south asian heart lifestyle intervention (saheli) study to improve cardiovascular risk factors in a community setting: design and methods. contemp clin trials 2013; 36:479–87. doi: 10.1016/j.cct.2013.09.007. http://dx.doi.org/10.1080/07448480309596352 http://dx.doi.org/10.1016/s1976-1317%2810%2960005-9 http://dx.doi.org/10.1016/s1976-1317%2810%2960005-9 http://dx.doi.org/10.11604/pamj.2013.15.137.1628 http://dx.doi.org/10.1016/j.cnur.2007.10.005 http://dx.doi.org/10.1016/j.ypmed.2013.05.002 http://dx.doi.org/10.1016/j.cct.2013.09.007 department of clinical sciences, princess nourah bint abdulrahman university, riyadh, saudi arabia e-mail: mahaabdulrahman@hotmail.com املعرفة والنظرة جتاه اإلنعاش احليوي األساسي بني طالبات الكليات الصحية يف جامعة نسائية سعودية مها عبدالرحمن املحي�ضن abstract: objectives: awareness of basic life support (bls) is paramount to ensure the provision of essential life-saving medical care in emergency situations. this study aimed to measure knowledge of bls and attitudes towards bls training among female health students at a women’s university in saudi arabia. methods: this prospective cross-sectional study took place between january and april 2016 at five health colleges of the princess nourah bint abdulrahman university, riyadh, saudi arabia. all 2,955 students attending the health colleges were invited to participate in the study. participants were subsequently asked to complete a validated englishlanguage questionnaire which included 21 items assessing knowledge of bls and six items gauging attitudes to bls. results: a total of 1,349 students completed the questionnaire (response rate: 45.7%). the mean overall knowledge score was very low (32.7 ± 13.9) and 87.9% of the participants had very poor knowledge scores. a total of 32.5% of the participants had never received any bls training. students who had previously received bls training had significantly higher knowledge scores (p <0.001), although their knowledge scores remained poor. overall, 77.0% indicated a desire to receive additional bls training and 78.5% supported mandatory bls training. conclusion: overall knowledge about bls among the students was very poor; however, attitudes towards bls training were positive. these findings call for an improvement in bls education among saudi female health students so as to ensure appropriate responses in cardiac arrest or other emergency situations. keywords: basic cardiac life support; health occupations students; medical education; knowledge; attitudes; saudi arabia. امللخ�ص: الهدف: الت�عية باالإنعا�ص احلي�ي االأ�ضا�ضي اأمر بالغ االأهمية ل�ضمان ت�فري الرعاية الطبية االأ�ضا�ضية املنقذة للحياة يف حاالت الط�ارئ. هدفت هذه الدرا�ضة اإىل قيا�ص مدى املعرفة والنظرة اإىل التدريب على االإنعا�ص احلي�ي االأ�ضا�ضي بني طالبات الكليات ال�ضحية يف جامعة للبنات يف اململكة العربية ال�ضع�دية. الطريقة: هذه درا�ضة م�ضتقبلية م�ضتعر�ضة اأجريت يف الفرتة ما بني يناير واأبريل 2016 يف خم�ص كليات �ضحية يف جامعة االأمرية ن�رة بنت عبد الرحمن, الريا�ص, اململكة العربية ال�ضع�دية. دعيت جميع طالبات الكليات ال�ضحية 2,955 طالبة للم�ضاركة يف الدرا�ضة. طلب من امل�ضاركات ا�ضتكمال ا�ضتبيانات باللغة االجنليزية ت�ضمنت 21 بندا تهدف اىل تقييم املعرفة طالبة 1,349 اال�ضتبيان اأكمل النتائج: االأ�ضا�ضي. احلي�ي االإنعا�ص جتاه الطالبات نظرة تقي�ص بن�د و�ضتة االأ�ضا�ضي احلي�ي باالإنعا�ص )معدل اال�ضتجابة: %45.7(. كانت نتيجة مت��ضط املعرفة ال�ضاملة منخف�ضة جدا )13.9 ± 32.7( وكانت نتيجة املعرفة �ضيئة للغاية عند %87.9, من امل�ضاركات. كما اأن )%32.5( من امل�ضاركات مل يتلق�ن اأي تدريب على االإنعا�ص احلي�ي االأ�ضا�ضي. كان مدى املعرفة اأف�ضل �ضيئا ظل معرفتهن م�ضت�ى اأن من الرغم على ,)p >0.001( �ضابقا االأ�ضا�ضي احلي�ي االإنعا�ص على التدريب تلقني الالتي الطالبات لدى للغاية. وعم�ما, اأبدت %77.0 من امل�ضاركات رغبتهن يف تلقي تدريب اإ�ضايف على االإنعا�ص احلي�ي االأ�ضا�ضي بينما اأيد %78.5 منهن جعل التدريب اإلزاميا. اخلال�صة: كانت املعرفة ال�ضاملة ح�ل االإنعا�ص احلي�ي االأ�ضا�ضي بني الطالبات �ضيئة للغاية. ومع ذلك, كانت النظرة اإىل التدريب علية اإيجابية. تدع� هذه النتائج للت��ضع يف تعليم االإنعا�ص احلي�ي االأ�ضا�ضي لطالبات الكليات ال�ضحية ال�ضع�ديات وذلك ل�ضمان اال�ضتجابة املنا�ضبة لهن يف حاالت ال�ضكتة القلبية اأو غريها من حاالت الط�ارئ. الكلمات املفتاحية: االإنعا�ص القلبي احلي�ي االأ�ضا�ضي؛ طالب املهن ال�ضحية؛ التعليم الطبي؛ املعرفه؛ الت�جه؛ اململكة العربية ال�ضع�دية. knowledge and attitudes towards basic life support among health students at a saudi women’s university maha a. al-mohaissen clinical & basic research sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e59–65, epub. 30 mar 17 submitted 5 sep 16 revision req. 9 oct 16; revision recd. 31 oct 16 accepted 17 nov 16 doi: 10.18295/squmj.2016.17.01.011 advances in knowledge to the best of the author’s knowledge, this is the largest study to investigate knowledge and attitudes towards basic life support (bls) among women in saudi arabia. the findings of this study revealed that the majority of saudi female health students had positive attitudes towards bls but poor bls knowledge. knowledge and attitudes towards basic life support among health students at a saudi women’s university e60 | squ medical journal, february 2017, volume 17, issue 1 adequate awareness of basic life support(bls) and cardiopulmonary resuscitation (cpr) is an important global issue to ensure that individuals can provide necessary life-saving care in emergency situations.1–3 in saudi arabia, there is a lack of data regarding awareness and attitudes towards bls; however, current evidence suggests that individuals in saudi arabia have low levels of bls knowledge, but positive attitudes towards bls training.4–8 although several studies have highlighted this important issue, they are subject to several limitations, including small sample sizes, a lack of validated tools to assess bls knowledge, infrequent exploration of attitudes towards bls training and imprecise definitions of factors associated with low bls knowledge levels.5–7 furthermore, there is currently no detailed information regarding bls knowledge and attitudes among women in saudi arabia, as either gender was not specified or female participants were underrepresented in previously published studies.5–7 female health students represent a primary target for bls education in the community.9–12 this study therefore aimed to evaluate knowledge and attitudes towards bls among saudi female health students at the princess nourah bint abdulrahman university (pnu) in riyadh, the largest female-only university in saudi arabia. in particular, bls knowledge was compared according to college and year of study and the effects of prior bls training on bls knowledge and attitudes towards training was investigated. methods this prospective, cross-sectional study took place between january and april 2016 and involved all 2,955 students attending the five health colleges (medicine, dentistry, nursing, pharmacy and health & rehabilitation sciences) at pnu. these colleges share a common preparatory year known as the basic health sciences year. previous research has indicated average bls knowledge scores of 38–45% among allied health medical students; as such, the minimum required sample size was calculated to be 614 using a test value of 45% with a 5% margin of error, 95% confidence level (α = 0.05), beta value of 0.20 and 80% power.6 previously validated questionnaires to assess knowledge of cpr and bls were updated according to recent american heart association guidelines, where appropriate.9,13,14 attitudes towards bls were evaluated using another previously validated questionnaire.3 as such, the final self-administered questionnaire contained 27 questions assessing bls knowledge and skills (21 multiple choice questions) and attitudes towards bls (six multiple choice questions). as the majority of courses at pnu are taught in english, the questionnaire was distributed in its original english-language format. the final questionnaire was pilot-tested among a group of 30 female health students which resulted in an overall cronbach’s alpha value of 0.81 (0.76 for the knowledge section and 0.74 for the attitudes section). no changes were made to the questionnaire as a result of the pilot study. subsequently, the questionnaire was distributed to all female health students at pnu by two research coordinators during class at the end of scheduled lectures. the importance of the study for improving bls education at pnu was explained verbally during distribution of the questionnaire. the participants who had previously taken part in the pilot study were subsequently included in the main study. data were analysed using the statistical analysis system software, version 9.4 (sas institute inc., cary, north carolina, usa). categorical variables were reported as numbers and percentages while continuous variables were expressed as means and standard deviations. responses to knowledge questions were analysed according to an answer key developed from the original questionnaires; subsequently, the percentage of accurate responses for each multiple choice question was calculated.9,13,14 the overall knowledge score for the entire sample was expressed as the percentage of correct answers out of all 21 knowledge questions. accordingly, knowledge levels were classified as excellent (90–100%), very good (80–89%), good (70–79%), acceptable (60–69%), poor (50–59%) or very poor (<50%). associations were calculated using analysis of variance, fisher’s exact, chi-squared or tukey’s multiple comparison tests, as appropriate. a p value of ≤0.050 was considered statistically significant. ethical approval for this study was obtained from the institutional review board of pnu before data collection (irb #08121504). the study was conducted in accordance with the principles of the declaration of helsinki. all of the participants gave informed verbal consent and were assured that completion of the questionnaire was voluntary and anonymous. application to patient care this study emphasises the importance of improving current bls education programmes among health students at a saudi women’s university, particularly as this population is likely to be actively involved in patient care in the future and may need to demonstrate appropriate bls skills in emergency situations. maha a. al-mohaissen clinical and basic research | e61 results a total of 1,349 students returned completed questionnaires (response rate: 45.7%). the response rates from the individual colleges were 56.4%, 83.4%, 83.2%, 40.1%, 34.3% and 29.6% for the basic health sciences, medicine, dentistry, nursing, pharmacy and health & rehabilitation sciences colleges, respectively. the mean age was 20.2 ± 1.5 years. the distribution of the participants according to college and year of study is shown in table 1. overall, the mean knowledge score for the entire cohort was very low (32.7 ± 13.9; 95% confidence interval: 32.0–33.4) and the majority of participants (87.9%) demonstrated very low bls knowledge levels. when analysed by year of study, basic health sciences students had a mean knowledge score of 27.1 ± 13.2, which was significantly lower than the mean scores of the first-, second-, third-, fourthand fifth-year students (34.5 ± 14.4, 38.8 ± 12.5, 31.6 ± 12.6, 34.2 ± 14.6 and 35.6 ± 12.4, respectively; p <0.001). second-year students had significantly higher scores compared to students in other years (p <0.010), with the exception table 1: characteristics of health students attending a women’s university in saudi arabia (n = 1,349) characteristic n (%) year of study basic health sciences* 362 (26.8) 1st year 237 (17.6) 2nd year 242 (17.9) 3rd year 260 (19.3) 4th year 197 (14.6) 5th year 51 (3.8) college medicine 231 (17.1) dentistry 129 (9.6) nursing 159 (11.8) pharmacy 208 (15.4) health & rehabilitation sciences 260 (19.3) *a common preparatory year for students in all health colleges. table 2: basic life support knowledge levels and scores according to college and year of study among health students attending a women’s university in saudi arabia (n = 1,349) mean total score ± sd p value* median score (iqr) range knowledge levels, n (%) p value* good acceptable poor very poor college medicine 34.3 ± 14.1† <0.001‡ 33.3 (23.8–42.9) 0.0–71.4 1 (0.4) 9 (3.9) 19 (8.2) 202 (87.4) <0.001 dentistry 33.6 ± 13.0† 33.3 (23.8–38.1) 4.8–71.4 1 (0.8) 4 (3.1) 10 (7.8) 114 (88.4) nursing 35.9 ± 13.8† 33.3 (28.6–42.9) 4.8–66.7 0 (0.0) 10 (6.3) 19 (11.9) 130 (81.8) pharmacy 35.6 ± 12.5† 35.7 (28.6–42.9) 4.8–66.7 0 (0.0) 6 (2.9) 25 (12.0) 177 (85.1) hrs 34.4 ± 14.4† 33.3 (23.8–47.6) 4.8–66.7 0 (0.0) 9 (3.5) 32 (12.3) 219 (84.2) year of study bhs§ 27.1 ± 13.2¶ 28.6 (19.0–38.1) 0.0–66.7 0 (0.0) 3 (0.8) 15 (4.1) 344 (95.0) 1st year 34.5 ± 14.4\\ <0.001 33.3 (23.8–42.9) 0.0–66.7 0 (0.0) 8 (3.4) 31 (13.1) 198 (83.5) <0.001 2nd year 38.8 ± 12.5 38.1 (28.6–47.6) 4.8–61.9 0 (0.0) 10 (4.1) 40 (16.5) 192 (79.3) 3rd year 31.6 ± 12.6§ 28.6 (23.8–38.1) 4.8–66.7 0 (0.0) 7 (2.7) 14 (5.4) 239 (91.9) 4th year 34.2 ± 14.6§ 33.3 (23.8–42.9) 4.8–71.4 2 (1.0) 12 (6.1) 14 (7.1) 168 (85.7) 5th year 35.6 ± 12.4 33.3 (26.2–47.6) 14.3–61.9 0 (0.0) 1 (1.9) 6 (11.5) 45 (86.5) total 32.7 ± 13.9 33.3 (23.8–42.9) 0.0–71.4 2 (0.1) 41 (3.0) 120 (8.9) 1,186 (87.9) sd = standard deviation; iqr = interquartile range; hrs = health & rehabilitation sciences; bhs = basic health sciences. *p values are based on an analysis of variance test for continuous scores and fisher’s exact test for categorical scores. †p = 0.491 for comparison among the five groups. ‡p <0.001 for comparison between the five groups. §a common preparatory year for students in all health colleges. ¶p <0.001 in comparison with the other five groups individually in paired comparisons. \\p <0.010 in comparison with second-year students. no statistically significant difference was observed between secondand fifth-year students based on tukey’s multiple comparison test (p = 0.626). knowledge and attitudes towards basic life support among health students at a saudi women’s university e62 | squ medical journal, february 2017, volume 17, issue 1 table 3: frequency of correct responses to questionnaire items assessing basic life support knowledge among health students attending a women’s university in saudi arabia (n = 1,349) correct response n (%) ems stands for emergency medical services 672 (49.8) cpr stands for cardiopulmonary resuscitation 905 (67.1) if a 50-year-old man complains of retrosternal chest pain and nausea, contact ems, administer aspirin and allow him to rest 513 (38.0) if a colleague displays slurring of speech and right upper limb weakness, it could be a stroke which would require thrombolysis, so you should contact ems 342 (25.4) if you see a person collapse on the road, check if he is conscious, breathing and has a pulse 1,012 (75.0) to find out if a person is unconscious, shake them and shout at them 244 (18.1) to find a person’s carotid pulse, feel their neck 743 (55.1) after confirming that a person is unconscious, not breathing and has no pulse, you should contact ems 162 (12.0) the phone number for ems is 997 969 (71.8) the location of chest compressions in cpr is the mid-chest 659 (48.9) the correct rate of chest compressions for adults and children is 100–120 times/minute 249 (18.5) the correct depth of chest compressions for adults is 5–6 cm 285 (21.1) the correct ratio of chest compressions to rescue breaths is 30:2 503 (37.3) the correct depth of chest compressions for children and infants is at least two-thirds of the depth of the chest 60 (4.4) the correct location for chest compressions for infants is one finger breadth below the nipple line 393 (29.1) rescue breathing in infants is given mouth-to-mouth and mouth-to-nose 340 (25.2) if you do not want to give mouth-to-mouth cpr, not administering cpr is not an appropriate course of action 346 (25.6) the chance of survival for individuals experiencing an out-of-hospital cardiac arrest increases two-fold if the patient receives sufficient bls before the arrival of ems personnel 90 (6.7) if you come across an unresponsive adult who has been removed from fresh water and is breathing spontaneously, keep him in the recovery position 109 (8.1) if someone appears to be choking, confirm foreign body aspiration by talking to them 131 (9.7) if an infant shows symptoms of foreign body aspiration and you have confirmed that they are unable to cry/cough, perform back blows and chest compressions of five cycles each, then open the mouth and remove the foreign body only if it can be seen 536 (39.7) ems = emergency medical services; cpr = cardiopulmonary resuscitation; bls = basic life support. table 4: frequency and attitudes towards basic life support training among health students attending a women’s university in saudi arabia (n = 1,349) questionnaire item n (%) have you had previous bls training? yes, in college 293 (21.7) yes, outside college 154 (11.4) yes, both in and outside college 119 (8.8) no 438 (32.5) i don’t know 345 (25.6) do you want more bls training? yes 1,039 (77.0) no 81 (6.0) i don’t know 229 (17.0) if yes, why do you want more bls training?* a family history of heart disease 52 (5.0) avoiding unnecessary deaths in the community 446 (42.9) important for my future work 369 (35.5) other reasons 78 (7.5) no answer 94 (9.0) if you have had no bls training outside of college, what was the reason?† little interest 20 (1.9) little time 312 (29.0) not sure where courses are held 346 (32.2) cost 77 (7.2) no answer 321 (29.8) do you think bls training should be mandatory and, if so, where should it be provided? yes, in health colleges only 100 (7.4) yes, in all colleges 456 (33.8) yes, in all workplaces regardless of occupation 503 (37.3) no, bls training should be optional 42 (3.1) i don’t know 248 (18.4) when do you think bls training should first be provided? high school 562 (41.7) 1st year of college 318 (23.6) 3rd year of college 115 (8.5) just before graduation 127 (9.4) i don’t know 227 (16.8) bls = basic life support. *total dataset for this variable was 1,039 as the question was targeted only at those students who wanted more bls training. †total dataset for this variable was 1,076 as the question was targeted only at those students who had not previously received bls training outside of college. maha a. al-mohaissen clinical and basic research | e63 of fifth-year students (p = 0.626) [table 2]. the frequency of correct responses to all of the knowledge questions is displayed in table 3. a total of 32.5% of the students had never received any bls training. overall, attitudes towards bls were positive; most participants reported that they wanted more bls training (77.0%) and supported mandatory bls training (78.5%) [table 4]. students who had previously received bls training in college had significantly greater bls knowledge scores compared to those who had received bls training outside college, those who had received bls training both in and outside college and those who never received bls training (41.7 ± 13.0 versus 32.4 ± 10.9, 33.3 ± 12.6 and 32.7 ± 13.1, respectively; p < 0.001). there was no significant difference in knowledge scores between those who had never received bls training before and those who had received training outside college or both in and outside college (p = 0.856) [table 5]. according to their previous history of bls training, 98.3% of students with no prior bls training wanted further bls training in comparison to 87.9% of the students who had prior bls training (p <0.001). in addition, students without prior training also favoured earlier bls training (i.e. training provided in high table 5: basic life support knowledge levels and scores according to previous training history among female health students attending a women’s university in saudi arabia (n = 1,349) previous training mean total score ± sd p value* median score (iqr) range knowledge levels, n (%) p value* good acceptable poor very poor none 32.7 ± 13.1† <0.001 33.3 (23.8–38.1) 0.0–61.9 0 (0.0) 13 (3.0) 40 (9.1) 385 (87.9) <0.001 in college 41.7 ± 13.0 42.9 (33.3–52.4) 4.8–71.4 1 (0.3) 23 (7.8) 54 (18.4) 215 (73.4) outside college 32.4 ± 10.9† 33.3 (23.8–38.1) 4.8–71.4 1 (0.6) 2 (1.3) 3 (1.9) 148 (96.1) both in and outside college 33.3 ± 12.6† 33.3 (23.8–42.9) 9.5–66.7 0 (0.0) 2 (1.7) 14 (11.8) 103 (86.6) sd = standard deviation; iqr = interquartile range. *p values are based on an analysis of variance test for continuous scores and fisher’s exact test for categorical scores. †p = 0.856 for comparison between the three groups. table 6: attitudes to basic life support training according to previous training history among health students attending a women’s university in saudi arabia (n = 1,349) previous training, n (%) p value* none (n = 438) any previous training (n = 566) in college (n = 293) outside college (n=154) both in and outside college (n = 119) p1† p2‡ p3§ p4¶ p5\\ p6** do you want more bls training? yes 398 (98.3) 437 (87.9) 260 (91.2) 99 (90.8) 78 (75.7) <0.001 <0.001 <0.001 0.900 <0.001 <0.001 no 7 (1.7) 60 (12.1) 25 (8.8) 10 (9.2) 25 (24.3) do you think bls training should be mandatory? yes 389 (97.7) 506 (94.6) 281 (97.6) 125 (89.9) 100 (92.6) <0.001 0.885 0.008 <0.001 0.021 0.016 no 9 (2.3) 29 (5.4) 7 (2.4) 14 (10.1) 8 (7.4) when do you think bls training should first be provided? high school or 1st year of college 348 (82.5) 392 (73.1) 217 (75.6) 87 (62.1) 88 (80.7) <0.001 0.026 0.674 0.004 0.279 <0.0013rd year of college or just before graduation 74 (17.5) 144 (26.9) 70 (24.4) 53 (37.9) 21 (19.3) bls = basic life support. *p values are based on chi-squared or fisher’s exact tests, as appropriate. †comparison among all four groups. ‡comparison between no training and in college training. §comparison between no training and both in and outside college training. ¶comparison between in college training and outside college training.\\comparison between in college training and both in and outside college training. **comparison between no training and any previous training. knowledge and attitudes towards basic life support among health students at a saudi women’s university e64 | squ medical journal, february 2017, volume 17, issue 1 school or first year of college) more frequently than those with any prior training (p <0.001). a significantly larger percentage of students without prior training supported mandatory training compared with students who had received training outside of college or both in and outside of college (97.7% versus 89.9% and 92.6%, respectively; p = 0.008); however, they did not support mandatory training significantly more than students who had received training in college (97.7% versus 97.6%; p = 0.885) [table 6]. discussion to the best of the author’s knowledge, this is the largest study to evaluate bls knowledge and attitudes towards training among saudi women. unfortunately, although the results of the study indicated that female health students had overall positive attitudes towards bls training, the majority of the students were severely deficient in bls knowledge. these findings are in agreement with those of previous research from saudi arabia, which have consistently shown poor bls awareness but favourable attitudes towards bls training.4,5,8 in addition, the knowledge scores observed in the current study were similar to those reported among dental students in riyadh; however, the current cohort more frequently demonstrated very poor knowledge levels in comparison to two other studies from saudi arabia (87.9% versus 49.6% and 67%, respectively).6–8 the lower scores observed in the present sample may be due to the lack of bls training in the pnu colleges’ curricula, even though bls education is strongly encouraged. in contrast, alotaibi et al. found that female students achieved significantly higher scores than male students when comparing bls knowledge levels by gender among saudi dental students.8 reddy et al. similarly observed higher mean knowledge scores among female dental students compared to their male counterparts.15 interestingly, alotaibi et al. have also shown that saudi men are more reluctant to perform cpr on a stranger in comparison to women; however, this factor was not evaluated in the present study.8 poor bls knowledge scores among health students have been reported in many countries.9,16–20 perceived barriers to bls competency—including a lack of adequate education (i.e. knowledge acquisition) and educational reinforcement (i.e. knowledge retention)—should be addressed in order to improve bls knowledge and skills among healthcare trainees. in the current study, internal bls training performed in college resulted in better outcomes than external training, including better knowledge scores and more favourable attitudes towards bls. therefore, integrating a bls training programme into the undergraduate curricula could be beneficial; this recommendation has been previously advocated in order to improve students’ resuscitation skills.16 early exposure to bls training in college with subsequent refresher courses for reinforcement is essential to improve bls knowledge acquisition and retention among students.10,13,21 another proposed recommendation to improve bls knowledge among saudi female health students is to simplify bls training to be more appropriate and cost-effective.13 for example, poorly executed and inefficient chest compressions and rescue breaths prevent effective cpr, whereas high-quality standard cpr produces 25– 33% of normal cardiac output and oxygen delivery; as such, competency in these two basic skills is vital.14,22,23 in the present study, only 18.5% of the students knew the correct rate of chest compressions and 21.1% were aware of the recommended chest compression depth. this observation is alarming considering the simple, yet critical, value of chest compression skills.14 peer-led training may also serve to increase the number of female bls educators at pnu, which could further disseminate bls knowledge in both the university itself and the wider community.24 there are several limitations to this study. while this study measured bls knowledge and attitudes, it did not evaluate actual bls skills among the students. as many of the participants had not previously received bls training and the majority had poor knowledge levels, their practical bls skills are expected to be poor. further research evaluating students’ bls skills in practice is required but should accompany effective bls educational programmes. in addition, although the number of participants was large, there was a low response rate from some of the colleges. this may be because the questionnaires were manually distributed after lectures when some of the senior students and interns may have been based in teaching hospitals for their practical training. consequently, future studies should consider distributing questionnaires by e-mail in order to reach a larger cohort. conclusion the findings from this study suggest that more bls training is necessary among saudi female health college students at pnu. despite having very positive attitudes towards bls training, many of the students had never received bls training; moreover, very poor bls knowledge levels were observed, even amongst the trained students. as students who had received bls training in college had higher knowledge scores, it is advised that bls training be incorporated into the maha a. al-mohaissen clinical and basic research | e65 university curricula, preferably for first-year students and with refresher courses offered in subsequent years. a c k n o w l e d g e m e n t s the author would like to thank ms anita choco and ms waad al-negaimshi for their invaluable help with data collection during this study. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bhanji f, donoghue aj, wolff ms, flores ge, halamek lp, berman jm, et al. part 14: education 2015 american heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. circulation 2015; 132:s561–73. doi: 10.1161/cir.0000000000000268. 2. aroor ar, saya rp, attar nr, saya gk, ravinanthanan m. awareness about basic life support and emergency medical services and its associated factors among students in a tertiary care hospital in south india. j emerg trauma shock 2014; 7:166–9. doi: 10.4103/0974-2700.136857. 3. kanstad bk, nilsen sa, fredriksen k. cpr knowledge and attitude to performing bystander cpr among secondary school students in norway. resuscitation 2011; 82:1053–9. doi: 10.1016/j.resuscitation.2011.03.033. 4. al-turki ya, al-fraih ys, jalaly jb, al-maghlouth ia, al-rashoudi fh, al-otaibi af, et al. knowledge and attitudes towards cardiopulmonary resuscitation among university students in riyadh, saudi arabia. saudi med j 2008; 29:1306–9. 5. alanazi a, bin-hotan m, alqahtani h, alhalyabah a, alanazi a, al-oraibi s. community awareness about cardiopulmonary resuscitation among secondary school students in riyadh. world j med sci 2013; 8:186–9. doi: 10.5829/idosi.wjms.2013. 8.3.7337. 6. alanazi a, alsalmeh m, alsomali o, almurshdi am, alabdali a, al-sulami m, et al. poor basic life support awareness among medical and college of applied medical sciences students necessitates the need for improvement in standards of bls training and assessment for future health care providers. middle east j sci res 2014; 21:848–54. doi: 10.5829/ idosi.mejsr.2014.21.05.82335. 7. almesned a, almeman a, alakhtar am, alaboudi aa, alotaibi az, al-ghasham ya, et al. basic life support knowledge of healthcare students and professionals in the qassim university. int j health sci (qassim) 2014; 8:141–50. doi: 10.12816/0006080. 8. alotaibi oa, alamri f, almufleh l, alsougi w. basic life support: knowledge and attitude among dental students and staff in the college of dentistry, king saud university. saudi j dent res 2016; 7:51–6. doi: 10.1016/j.sjdr.2015.06.001. 9. chandrasekaran s, kumar s, bhat sa, saravanakumar, shabbir pm, chandrasekaran v. awareness of basic life support among medical, dental, nursing students and doctors. indian j anaesth 2010; 54:121–6. doi: 10.4103/0019-5049.63650. 10. pande s, pande s, parate v, pande s, sukhsohale n. evaluation of retention of knowledge and skills imparted to first-year medical students through basic life support training. adv physiol educ 2014; 38:42–5. doi: 10.1152/advan.00102.2013. 11. choi hs, lee dh, kim cw, kim se, oh jh. peer-assisted learning to train high-school students to perform basic lifesupport. world j emerg med 2015; 6:186–90. doi: 10.5847/ wjem.j.1920-8642.2015.03.004. 12. perkins gd, hulme j, shore hr, bion jf. basic life support training for health care students. resuscitation 1999; 41:19–23. doi: 10.1016/s0300-9572(99)00037-4. 13. celenza t, gennat hc, o’brien d, jacobs ig, lynch dm, jelinek ga. community competence in cardiopulmonary resuscitation. resuscitation 2002; 55:157–65. doi: 10.1016/ s0300-9572(02)00201-0. 14. neumar rw, shuster m, callaway cw, gent lm, atkins dl, bhanji f, et al. part 1: executive summary 2015 american heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. circulation 2015; 132:s315–67. doi: 10.1161/cir.0000000000000252. 15. reddy s, doshi d, reddy p, kulkarni s, reddy s. awareness of basic life support among staff and students in a dental school. j contemp dent pract 2013; 14:511–17. doi: 10.5005/jp-journ als-10024-1353. 16. zaheer h, haque z. awareness about bls (cpr) among medical students: status and requirements. j pak med assoc 2009; 59:57–9. 17. lami m, nair p, gadhvi k. improving basic life support training for medical students. adv med educ pract 2016; 7:241–2. doi: 10.2147/amep.s102111. 18. tan ec, severien i, metz jc, berden hj, biert j. first aid and basic life support of junior doctors: a prospective study in nijmegen, the netherlands. med teach 2006; 28:189–92. doi: 10.1080/01421590500312847. 19. price cs, bell sf, janes se, ardagh m. cardio-pulmonary resuscitation training, knowledge and attitudes of newlyqualified doctors in new zealand in 2003. resuscitation 2006; 68:295–9. doi: 10.1016/j.resuscitation.2005.07.002. 20. mac giolla phadraig c, ho jd, guerin s, yeoh yl, mohamed medhat m, doody k, et al. neither basic life support knowledge nor self-efficacy are predictive of skills among dental students. eur j dent educ 2016; epub ahead of print. doi: 10.1111/ eje.12199. 21. abbas a, bukhari si, ahmad f. knowledge of first aid and basic life support amongst medical students: a comparison between trained and un-trained students. j pak med assoc 2011; 61:613–16. 22. berg ra, hemphill r, abella bs, aufderheide tp, cave dm, hazinski mf et al. part 5: adult basic life support 2010 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. circulation 2010; 122:s685–705. doi: 10.1161/circulationaha.110. 970939. 23. perkins gd, handley aj, koster rw, castrén m, smyth ma, olasveengen t, et al. european resuscitation council guidelines for resuscitation 2015: section 2 adult basic life support and automated external defibrillation. resuscitation 2015; 95:81–99. doi: 10.1016/j.resuscitation.2015.07.015. 24. harvey pr, higenbottam cv, owen a, hulme j, bion jf. peer-led training and assessment in basic life support for healthcare students: synthesis of literature review and fifteen years practical experience. resuscitation 2012; 83:894–9. doi: 10.1016/j.resuscitation.2012.01.013. https://doi.org/10.1161/cir.0000000000000268 https://doi.org/10.4103/0974-2700.136857 https://doi.org/10.1016/j.resuscitation.2011.03.033 https://doi.org/10.5829/idosi.wjms.2013.8.3.7337 https://doi.org/10.5829/idosi.wjms.2013.8.3.7337 https://doi.org/10.5829/idosi.mejsr.2014.21.05.82335 https://doi.org/10.5829/idosi.mejsr.2014.21.05.82335 https://doi.org/10.12816/0006080 https://doi.org/10.1016/j.sjdr.2015.06.001 https://doi.org/10.4103/0019-5049.63650 https://doi.org/10.1152/advan.00102.2013 https://doi.org/10.5847/wjem.j.1920-8642.2015.03.004 https://doi.org/10.5847/wjem.j.1920-8642.2015.03.004 https://doi.org/10.1016/s0300-9572%2899%2900037-4 https://doi.org/10.1016/s0300-9572%2802%2900201-0 https://doi.org/10.1016/s0300-9572%2802%2900201-0 https://doi.org/10.1161/cir.0000000000000252 https://doi.org/10.5005/jp-journals-10024-1353 https://doi.org/10.5005/jp-journals-10024-1353 https://doi.org/10.2147/amep.s102111 https://doi.org/10.1080/01421590500312847 https://doi.org/10.1016/j.resuscitation.2005.07.002 https://doi.org/10.1111/eje.12199 https://doi.org/10.1111/eje.12199 https://doi.org/10.1161/circulationaha.110.970939 https://doi.org/10.1161/circulationaha.110.970939 https://doi.org/10.1016/j.resuscitation.2015.07.015 https://doi.org/10.1016/j.resuscitation.2012.01.013 sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e142-144, epub. 27th jan 14 submitted 17th jun 13 revision req. 17th sep 13; revision recd. 3rd oct 13 accepted 31st oct 13 mosul college of medicine, mosul, ninevah, iraq e-mail: ahmed_khalil5@yahoo.com حصاة مثانة تعرقل حتويلة بطينية مثانية �أحمد خليل �إبر�هيم امللخ�ص: تكمن �لطريقة �لقيا�صية لعالج ��صت�صقاء �لدماغ يف �لتحويلة �لبطينية �ل�صفاقية �أو �لبطينية �الأذينية. لكن هذه �لتحويالت �لتقليدية قد ترتبط حلالة تقرير� نعر�س هنا �ملر�صى. من معينة ملجموعة منا�صبة غري �ملاألوفة �لتحويالت هذه يجعل �لذي �الأمر مرتفع تعديل معدل و ملحوظة بتعقيد�ت نادرة مرتبطة باأجر�ء غري معتاد المر�أة تبلغ من �لعمر 42 عاما لديها حتويله بطينية مثانية منذ �أربع �صنو�ت. تعر�صت �ملري�صة اللتهابات �مل�صالك �لبولية �ملتكررة, بيلة دموية و �صل�س بويل ��صطر�ري. مت �كت�صاف وجود ح�صاة كبرية يف �ملثانة فوق �لنهاية �ملثانية للتحويلة. مت عالج �ملري�صة با�صتخر�ج ح�صاة �ملثانة بعملية فتح فوق �لعانة و�إعادة توجيه �لتحويلة �إىل جوف �ل�صفاق. و�أخ�صعت �ملري�صة للمر�قبه ملدة �ثني ع�رش �صهر� بعد �لعملية وكانت �لنتيجة خلوها من �أية �أعر��س للم�صالك �لبولية. مفتاح الكلمات: ح�صاة �ملثانة؛ �لتحويلة �لبطينية �ل�صفاقية؛ �صل�س �لبول؛ بيلة دموية؛ �لعر�ق. abstract: the standard treatment for hydrocephalus is either a ventriculoperitoneal or a ventriculo-atrial shunt. however, these conventional shunts may be associated with considerable complications and high revision rates which make these familiar shunts inappropriate for a certain subset of patients. a rare complication is reported associated with an unusual procedure in a 42-year-old woman who had had a ventriculovesical shunt for four years. she presented with recurrent urinary tract infections, haematuria and urge incontinence, and was discovered to have a large vesical stone over the vesical end of the shunt. she was treated with open suprapubic cystolithotomy and the redirection of the shunt to the peritoneal cavity. the patient was followed up for 12 months postoperatively and remained free of any urinary tract symptoms. keywords: urinary bladder calculi; ventriculoperitoneal shunt, surgical; urinary incontinence; hematuria; surgical procedures, operative; case report; iraq. urinary bladder stone complicating ventriculovesical shunt ahmed k. ibrahim case report hydrocephalus due to various causes is typically managed with the diversion of the cerebrospinal fluid (csf) via either ventriculoperitoneal or ventriculo-atrial shunts. nevertheless, there are still patients who are no longer candidates for these conventional shunts and for them other more creative solutions must be considered. diversion of the csf into the genitourinary system was first tried as early as 1925 when heile used ureterodural anastomosis for the treatment of communicating hydrocephalus. heile sutured the renal pelvis to the lumbar dura to drain the csf.1,2 since then many similar procedures have been tried and revised as alternatives for the management of complicated conventional shunts. foreign bodies are well-recognised causes for vesical stones formation where they act as a nidus for stone aggregation.3 case report the patient was a 42-year-old-woman with a history of a brain tumour that had been resected a few years previously. she had initially been managed with a ventriculoperitoneal (vp) shunt which became obstructed at the peritoneal end, and therefore conversion to a ventriculo-atrial shunt was performed; this also became complicated by infection. eventually, a ventriculovesical shunt (vvs) was inserted as a last resort four years prior to the current presentation. the patient did well for the first year and then failed to return for follow-up; she presented three years later complaining of dysuria, suprapubic pain, haematuria, urgency, frequency and urge incontinence over the previous few weeks. she had been treated as a case of recurrent urinary tract infections (utis) by her general practitioner without any clinical response, following which she ahmed khalil ibrahim case report | e143 was referred to our centre. a urine analysis and culture revealed a uti and appropriate antibiotic therapy was instituted. renal function tests and haematological examinations were normal. a plain pelvic x-ray and an ultrasound examination revealed the presence of a large vesical stone that had formed around the lower end of the vvs without hydronephrosis [figure 1]. clinical examination confirmed the presence of a functioning valve. the patient was evaluated and prepared for intervention under general anaesthesia. after obtaining consent, a cystoscopy was performed under general anaesthesia; this showed a vesical stone that had formed over and engulfed the lower end of the shunt. cystolitholapaxy was an appealing treatment option, but the stone size and the presence of the shunt tube within the stone necessitated open cystolithotomy. during the procedure a solitary vesical stone about 4 cm in diameter was removed with the lower end of the shunt attached to it. the lower segment of the shunt tube was disconnected and the shunt tube was redirected to the peritoneal cavity. the patient was discharged the next morning and a urinary catheter was removed after five days. the patient was followed up clinically and radiologically for 12 months postoperatively and did well in respect to her bladder and shunt functions. discussion in spite of the long history of csf shunting procedures, there is as yet no ideal procedure. vp shunt surgery is the predominant mode of therapy for patients with hydrocephalus. however, it has potential complications which may require surgical procedures. conventional ventricular diversion surgeries are reported to have a complication rate of about 20%.4 in another recent study, the rate of surgical complications, which required revision among patients with vp shunts, was 17%. these complications included: catheter malfunction or obstruction; shunt infection; extrusion of the catheter (from the anus, neck, chest and abdominal wall); ventricular end displacement; subcutaneous collection, and a csf pseudocyst.5 in 1980, west reported on the use of vvs as a unique solution for patients with previously complicated standard shunts. he inserted the distal end of the shunt tubing at an oblique angle through the bladder wall.6 in 2001, ames et al. performed a vvs using a distal shunt catheter with a polyester cuff 5 cm from the tip of the catheter with the creation of a serosal tunnel around the shunt tubing aiming to provide stabilisation and infection control.2 another unusual site for csf diversion in complicated cases is the gall bladder as a ventriculo-cholecystic shunt.7 the vvs has its own advantages and disadvantages. with regard to its advantages, the insertion of the distal shunt catheter into the bladder is, first, a technically simple procedure that can be performed rapidly, i.e. through a pfannenstiel incision, where the shunt is pulled subcutaneously and introduced at an oblique angle to the bladder; the intravesical part of the shunt tube is kept to a minimum and fixed with non-absorbable sutures. second, the risk of obstruction to the shunt is low. on the other hand, there are disadvantages. the continuous drainage of the csf through the urine may be associated with an increased risk figure 1: plain pelvic x-ray showing the bladder stone attached to the ventriculovesical shunt. figure 2: the removed urinary bladder stone with the attached lower end of the ventriculovesical shunt. urinary bladder stone complicating ventriculovesical shunt e144 | squ medical journal, february 2014, volume 14, issue 1 of fluid-electrolyte depletion, especially in young children and in patients with high csf output, as in choroid plexus papilloma. moreover, the presence of a foreign body in the urinary bladder may increase the risk of recurrent utis and calculus formation; this has led some authors to discourage the use of this shunt.8 lastly, patients may have bothersome irritative voiding symptoms due to the presence of the distal shunt within the bladder. vesical stones usually develop secondary to underlying problems such as voiding dysfunction and/or the presence of intravesical foreign bodies. various types of intravesical foreign bodies have been described,2,9 but a vvs as the cause of a vesical stone has previously been reported only once in the literature.8 other related case reports have described vesical stone formation over the lower end of a migrated vp shunt which perforated the urinary bladder.10,11 according to the modified claviendindo classification system, this complication is regarded as grade iiib.12 this patient was managed with open cystolithotomy and the shunt was redirected to the peritoneal cavity to prevent the occurrence of this complication. many factors may have contributed to stone formation in this patient, but the most significant of these is the length of the intravesical part of the shunt. by reducing its length as much as possible the risk of future vesical stone formation and the related irritative symptoms may have minimised. conclusion the vvs technique may offer a unique solution for patients with complicated conventional shunts. it is a relatively simple and rapid procedure; on the other hand, it may be associated with particular complications like vesical stone formation. the modification of the procedure by proper patient selection, keeping the length of the intravesical part of the shunt as short as possible and a strict follow-up are mandatory steps to reduce the related complications. d e c l a r at i o n this case report was approved by the authorities of the department of surgery at mosul college of medicine and a consent form was signed by the patient. references 1. heile b. anastomosis between ureter and spinal dura to drain congenital hydrocephalus. zbl chir 1925; 52:2229– 36. 2. ames cd, jane ja jnr, jane ja snr, campbell fg, howards ss. a novel technique for ventriculovesical shunting of congenital hydrocephalus. j urol 2001; 165:1169–71. 3. kamal f, clark at, lavallée lt, roberts m, watterson j. intravesical foreign body–induced bladder calculi resulting in obstructive renal failure. can urol assoc j 2008; 2:546–8. 4. sinha a, sharma a, gupta c. pediatric hydrocephalus: does the shunt device pressure selection affect the outcome? j indian assoc pediatr surg 2012; 17:54–7. 5. ghritlaharey rk, budhwani ks, shrivastava dk, srivastava j. ventriculoperitoneal shunt complications needing shunt revision in children: a review of 5 years of experience with 48 revisions. afr j pediatric surg 2012; 9:32–9. 6. west cg. ventriculovesical shunt. technical note. j neurosurg 1980; 53:858–60. 7. demetriades ak, haq iz, jarosz j, mccormick d, bassi s. the ventriculo-cholecystic shunt: two case reports and a review of the literature. br j neurosurg 2013; 27:505–8. 8. shahul hameed as, yousaf i, choudhari ka. urinary bladder calculi complicating ventriculo-vesical shunt. br j neurosurg. 2005; 19:449–50. 9. chae jy, kim jw, yoon cy, park hs, moon du g, oh mm. bladder stone due to accidentally intravesically inserted intrauterine device. urol res 2012; 40:429–30. 10. eichel l, allende r, mevorach ra, hulbert wc, rabinowitz r. bladder calculus formation and urinary retention secondary to perforation of a normal bladder by a ventriculoperitoneal shunt. urology 2002; 60:344. 11. ramana murthy kv, jayaram reddy s, prasad dv. perforation of the distal end of the ventriculoperitoneal shunt into the bladder with calculus formation. pediatr neurosurg 2009; 45:53–5. 12. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004; 240:205–13. sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. e593-596, epub. 8th oct 13 submitted 24th apr 13 revision req. 10th jun 13; revision recd. 9th jul 13 accepted 5th aug 13 departments of 1obstetrics & gynecology, 2child health and 3pathology, sultan qaboos university hospital, muscat, oman; 4department of paediatric surgery, hamad general hospital, doha, qatar *corresponding author e-mail: drshahila@gmail.com الكيسات املعوية املضاعفة املتعددة يف جنني توأم التشخيص و العالج �شهيال ال�شيخ، مرمي ماثيو، حممد عبد اللطيف، عا�شم قر�شي، براكا�ش ماندهان امللخ�ص: الكي�شات املعوية امل�شاعفة املتعددة هي من الت�شوهات اخللقية النادرة يف اجلهاز اله�شمي. وميكن اأن ي�شتبه فيها اإذا لوحظت االآفات الكي�شية يف بطن اجلنني اأثناء الت�شوير باملوجات فوق ال�شوتية قبل الوالدة. وي�شمل الت�شخي�ش التفريقي لالآفات الكي�شية داخل البطن للجنني على كي�شات ثربية جنينية، وكي�شات م�شاريقية جنينية، وكي�شات العقي الكاذبة و كي�شات املبي�ش اجلنيني . نحن نعر�ش تقرير عن الكي�شات املعوية امل�شاعفة التي مت ت�شخي�شها قبل الوالدة يف واحدة من االأجنة التواأم و التي مت عالجها بنجاح. �شوء �شافقي؛ ورم الوالدة؛ قبل الت�شخي�ش ال�شوتية، فوق باملوجات الت�شوير تواأمي؛ حمل كي�شات، اخللقية؛ الت�شوهات الكلمات: مفتاح اال�شتدارة املعوية؛ عائلي، تقرير حالة؛ عمان. abstract: enteric duplication cysts are rare congenital anomalies of the gastrointestinal tract. these can be suspected if cystic lesions are noted in the fetal abdomen during an antenatal ultrasonogram. the differential diagnoses of fetal intra-abdominal cystic lesions include fetal omental cysts, fetal mesenteric cysts, meconium pseudocysts and fetal ovarian cysts. we report an antenatally diagnosed enteric duplication cyst in one of a set of twin fetuses which was managed successfully. keywords: congenital abnormalities; cysts; twin pregnancy; ultrasonography; prenatal diagnosis; peritoneal neoplasm; intestinal malrotation, familial; case report; oman. multiple enteric duplication cysts in a twin fetus diagnosis and management *shahila sheik,1 mariam mathew,1 mohamed abdellatif,2 asim qureshi,3 prakash mandhan4 online case report enteric duplication cysts are rare congenital anomalies that occur anywhere in the gastrointestinal tract, with a greater predilection towards the ileal region.1,2 the reported incidence is 1:4,500 newborns, and the embryogenesis of these anomalies remains controversial.2 they may be either cystic or tubular and present at the mesenteric border of the bowel. these can be suspected antenatally if cystic lesions are noted in the fetal abdomen during an anatomy or growth scan. the differential diagnosis of fetal intraabdominal cystic lesions includes gastrointestinal and urogenital anomalies such as choledochal, hepatic or mesenteric cysts, meconium pseudocysts and fetal ovarian cysts. prenatal diagnosis of these cystic lesions allows planning for appropriate postnatal work-up and screening for associated malformations. only a few cases of antenatally diagnosed duplication cysts are mentioned in english medical literature.3 we report a case of an antenatally diagnosed enteric duplication cyst in one of a set of twins which was managed successfully after birth. a literature review is also included. case report a 25-year-old gravida 2, para 1, woman with a twin pregnancy presented to sultan qaboos university hospital, muscat, oman, in early labour at 35 weeks of gestation. her antenatal care had been at a private healthcare facility. her first pregnancy had ended with an intrauterine fetal death at 26 weeks of gestation but had not been investigated further. the current pregnancy was a spontaneous conception. an early pregnancy scan revealed shahila sheik, mariam mathew, mohamed abdellatif, asim qureshi and prakash mandhan case report | 594 a dichorionic diamniotic twin pregnancy. some anomaly was suspected in the second twin during an anatomy scan which would need an evaluation after delivery. a follow-up scan at 29 weeks reported corresponding growth, with the second fetus showing two intra-abdominal cystic structures likely to be related to a duplication cyst and mild polyhydramnios [figure 1]. the patient had been normotensive and normoglycemic during this pregnancy. an ultrasound scan, done on admission to the sultan qaboos university hospital, oman, confirmed a twin pregnancy with the first twin in a cephalic presentation. the second twin, in breech presentation, had two anechoic intra-abdominal cystic lesions that were separate from normal hollow structures (i.e. the bladder and stomach). there was evidence of polyhydramnios. a decision was made to allow for a trial of vaginal delivery after detailed counselling about the risks to the second twin. the mother progressed to spontaneous vaginal delivery of the first twin but an emergency caesarean section had to be performed for the second twin due to the transverse lie and prolonged fetal bradycardia. both neonates were moved to the neonatal intensive care unit (nicu) for observation and monitoring. the initial assessment of the second twin in the nicu was unremarkable. however, the neonate later started to have persistent green aspirates and an abdominal x-ray showed a dilated stomach, duodenum and proximal small bowel with no gas in the rest of the abdomen, suggesting a small bowel obstruction [figure 2]. the patient underwent laparotomy soon after stabilisation. a 5 × 7 cm fluid-filled cyst was noted in the mesentery of the proximal jejunum compressing the small bowel lumen, causing a complete obstruction [figure 3]. further exploration revealed another 6 × 3 cm fluid-filled isolated cyst in the right upper quadrant, extending into the retroperitoneum thereby displacing the duodenum and pushing the extrahepatic biliary system forward. the second cyst also had its blood supply from the mesenteric vessels. the caecum and appendix were positioned in the midline. the cysts were excised completely and ladd’s procedure was carried out to correct the malrotation. the patient had a smooth postoperative course. an abdominal ultrasound performed before discharge to outline the hepatobiliary anatomy and to rule out any residual retroperitoneal cysts was normal. the histology revealed cyst walls lined by well-formed small bowel type mucosa, submucosa, and circular and longitudinal layers of muscularis mucosa confirming small bowel duplication cysts [figure 4]. upon the one-year follow-up, the affected child was doing well and achieving normal milestones. discussion prenatal detection of enteric duplication was first reported by van dam et al. in 1984.4 the factors that distinguish enteric duplication cysts from other cystic lesions include thickness of the muscular wall, peristalsis evident in the cystic wall of the enteric duplication and intimate contact of the figure 1: antenatal scan of fetal abdomen showing two cystic structures. figure 2: plain x-ray of the abdomen showing the gas distended stomach and duodenum but no evidence of gas filled bowel loops distal to it. multiple enteric duplication cysts in a twin fetus diagnosis and management 595 | squ medical journal, november 2013, volume 13, issue 4 cyst wall with the mesenteric border. antenatal scans have been reported to identify only 20–30% of such cases, and ours was one of these cases.5,6 the neonate in this case was symptomatic for bowel obstruction from the first day of life and a plain x-ray of the abdomen supported the clinical diagnosis. if the enteric duplication is antenatally undiagnosed and asymptomatic at birth, symptoms usually start during infancy and vary according to the location, size and presence or absence of the heterotopic gastric mucosa. enteric duplications could act as the lead point for volvulus or intussusceptions.2 gastrointestinal haemorrhage leading to haemodynamic instability, due to ulcerating gastric mucosa within a duplication cyst, has been reported.7 therefore, intestinal duplication cysts should be included in the differential diagnosis for paediatric surgical abdominal emergencies.8 although rare, cases of intestinal carcinomas arising within duplication cysts in adulthood have also been reported.9,10 hence, asymptomatic duplication cysts, when diagnosed incidentally during a surgical procedure, should be excised to prevent future complications as described.7,9 retroperitoneal enteric duplication cysts are even rarer and most of the reports mention these arising from the left side.11 however, the retroperitoneal cyst in the right upper quadrant in our case causing anterior displacement of the extrahepatic biliary system is, to the best of our knowledge, the first one reported in the literature. malrotation of the gut, as seen in this case has been reported as a rare associated anomaly with mid-gut duplication cysts.12,13 a complete resection of the enteric duplication cyst along with the adjacent bowel segment and primary reanastomosis is the recommended treatment for small enteric duplications. if duplication cysts are extensive and involve large segments of the bowel, mucosal stripping is indicated to avoid the risk of short bowel syndrome.1,2,12 conclusion although intestinal duplications are benign lesions in children, they can cause significant morbidity and even mortality if left untreated. with the increasing accuracy of prenatal ultrasounds, intraabdominal enteric duplication cysts are much more likely to be detected antenatally. duplication cysts should be considered in the differential diagnosis of abdominal cystic lesions. surgical excision of the enteric duplications is required to make a definitive diagnosis and to prevent future complications. in our case, prenatal detection of the enteric duplication allowed close neonatal surveillance and timely surgical intervention. references 1. zahir i, yusuf s, zada f, asif m, akhtar n, abbasi mz. duplication cyst in a newborn. int j pathol 2010; 8:84–6. 2. arias mp, lorenzo fg, sanchez mm, vellibre rm. enteric duplication cyst resembling umbilical cord cyst. j perinatol 2006; 26:368–70. 3. correia-pinto j, tavares m.l, monteiro j, moura n, guimaraes h, estevao-costa j. prenatal diagnosis of abdominal enteric duplications. prenat diagn 2000; 20:163–7. 4. van dam lj, degroot cj, hazelbrock fw, figure 3: enteric duplication cyst located at the mesenteric border of the proximal jejunum. figure 4 a & b. a: haematoxylin & eosin stained slide (10 x magnification) showing a duplication cyst in the wall of the intestine; b: haematoxylin & eosin stained slide (20 x magnification) showing the cyst lined by intestinal type epithelium. shahila sheik, mariam mathew, mohamed abdellatif, asim qureshi and prakash mandhan case report | 596 wladimiroff jw. case report: intrauterine demonstration of bowel duplication by ultrasound. gynecol reprod biol 1984; 18:229–32. 5. gul a, tekoglu g, asian h, cebeci a, erol o, unal m et al. prenatal sonographic features of esophageal and ileal duplications at 18 weeks of gestation. prenatal diagn 2004; 24:969-71. 6. foley pt, sithasanan n, mcewing r, lipsett j, ford wda, furness m et al. enteric duplications presenting as antenatally detected abdominal cysts: is delayed resection appropriate? j pediatr surg 2003; 38:1810-13. 7. holcomb gw, gheissari a, o’neill ja, jr. surgical management of alimentary tract duplications. ann surg 1989; 209:167–72. 8. dombale v, patil bv, kadam sa, kerudi bh. enteric duplication cyst of caecum presenting with intestinal obstruction—a case report. jkimsu (j krishna institute of medical sciences university) 2012; 1:147–9. 9. blank g, königsrainer a, sipos b, ladurner r. adenocarcinoma arising in a cystic duplication of the small bowel: case report and review of literature. world j surg oncol 2012; 10:55. 10. kuraoka k, nakayama h. adenocarcinoma arising from a gastric duplication cyst with invasion to the stomach: a case report with literature review. j clin pathol 2004; 57:428–31. 11. lo ys, wang js, yu cc, chou cp, chen cj, lin sl, et al. retroperitoneal enteric duplication cyst. j chin med assoc 2004; 67:479–82. 12. ildstad st, tollerud dj, weiss rg, ryan dp, mcgowan ma, martin lw. duplications of the alimentary tract. clinical characteristics, preferred treatment, and associated malformations. ann surg 1988; 208:184–9. 13. somuncu s, cakmak m, caglayan f, unal b. intestinal duplication cyst associated with intestinal malrotation anomaly: report of a case. acta chir belg 2006; 106:611–12. advancing tobacco dependence treatment services in the eastern mediterranean region international collaboration for training and capacity-building e442 | squ medical journal, november 2014, volume 14, issue 4 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e442−447, epub. 14th oct 14 submitted 13th feb 14 revisions req. 11th mar & 22nd apr 14; revisions recd. 6th & 27th apr 14 accepted 1st may 14 smoking tobacco-based products harms nearly every organ in the body and has been linked causally to a diminished health status in general. specifically, smoking is linked to several non-communicable diseases (ncds) which have recently advanced their ranking among the most frequently reported causes of death in the arab world.1 tobacco-related cancers include lung cancer, head and neck cancers, bladder cancers and leukaemia.2 new evidence has emerged suggesting that colorectal and liver cancers are also caused by smoking.2 in addition, smoking is a common risk factor for other ncds, namely cardiovascular diseases and respiratory illnesses and is an independent risk factor for diabetes mellitus; in fact, smoking raises an individual’s risk of developing diabetes by 30–40% compared to nonsmokers.2 the annual death toll caused by tobacco use, which stood in 2008 at five million, is expected to rise to eight million by 2030, with individuals from lowand middle-income countries making up approximately 80% of these deaths.3 tobacco smoking, including second-hand smoke inhalation, ranked third in terms of the global burden of disease in 1990; today, it is now ranked second within an array of risk factors.4 in north africa and the middle east, tobacco smoking, including second-hand smoke inhalation, ranked third in 2010 only after high blood pressure and a high body mass index (bmi), based on the attributable burden of disease.4 results from the world health cancer control office, king hussein cancer center, amman, jordan *corresponding author e-mail: fhawari@khcc.jo النهوض باخلدمات العالجية إلدمان التبغ يف منطقة شرق املتوسط تعاون دويل للتدريب وبناء القدرات فرا�س الهواري و ر�شا بدر abstract: tobacco use negatively affects health and is a major risk factor for non-communicable diseases (ncds). today, tobacco use ranks third among risk factors in north africa and the middle east in terms of disease burden. despite the established need for these services, tobacco dependence treatment (tdt) services are still inadequate in the eastern mediterranean region (emr). among the main challenges hindering their expansion is the current lack of training opportunities. the provision of training and capacity-building—a key enabler of tdt—offers an excellent catalyst to launch tdt services in the region. this review discusses the need for tdt training in the emr and describes a model for providing regional evidence-based training in line with international standards. the king hussein cancer center in amman, jordan, is the regional host for global bridges, a worldwide tdt initiative. using this model, they have trained 1,500 professionals and advocates from the emr over the past three years. keywords: chronic diseases; tobacco dependence; smoking cessation; education; capacity building; eastern mediterranean region. لعوامل الثالثة املرتبة التبغ يحتل ال�شارية. غري للأمرا�س كبري خطر عامل و ال�شحة على �شلبية تاأثريات ذا التبغ يعترب امللخ�ص: الخطرمن ناحية عبء املر�س يف �شمال اأفريقا و ال�رشق الأو�شط. بالرغم من احلاجة املعتمدة لهذه اخلدمات، تعترب خدمات علج اإدمان التبغ يف الوقت احلايل غري كافية يف منطقة �رشق املتو�شط. ويعترب النق�س احلايل يف فر�س التدريب من اأهم التحديات التي تعيق تو�شع هذه اخلدمات. اال�شتعداد امل�شبق للتدريب وبناء القدرات هام املفتاح لتمكني علج اإدمان التبغ حيث تعطي حافزا ممتازا النطلق اخلدمات املتو�شط �رشق منطقة يف التبغ اإدمان علج يف للتدريب احلاجة االستعرايض املقال هذا يناق�س املنطقة. يف التبغ لإدمان العلجية م�شيف هو الأردن، بعمان، لل�رشطان مركزاحل�شني الدولية. للمعايري موازي و الأدلة على قائم اإقليمي تدريب اعطاء منوذج وت�شف اإقليمي ملبادرة اجل�شور العاملية، كاملبادرة العاملية لعلج اإدمان التبغ. باإ�شتخدام هذا النموذج، مت تدريب 1500 من املهنيني وموؤيدي املبادئ من منطقة �رشق املتو�شط خلل الثلث �شنوات املا�شية. مفتاح الكلمات: الأمرا�س غري ال�شارية؛ التدريب؛ اإدمان التبغ؛ الإقلع عن التدخني؛ بناء القدرات؛ �رشق املتو�شط. review advancing tobacco dependence treatment services in the eastern mediterranean region international collaboration for training and capacity-building *feras i. hawari and rasha k. bader feras i. hawari and rasha k. bader review | e443 world bank estimated that 200 million deaths could be prevented by 2050 if adult tobacco consumption were to be halved by 2020.9 in comparison, halving the number of young people who take up smoking would have a negligible effect on short-term mortality rates.9 the inclusion of smoking cessation advice in primary healthcare settings has proven to be a low-cost strategy since the only major investment required is in training providers and availing informational materials to tobacco users.3 however, pharmacotherapy, while more expensive than offering cessation advice, has been shown to double or triple quit rates.3 in general, tdt interventions are extremely cost-effective when compared to the treatment of other chronic diseases. for example, compared to treatments for hypertension, tdt saves three times as many lives and takes on average only around two hours of a specialist’s time, which is much quicker than the time required to treat a case of hypertension.10 in general, the costeffectiveness of tdt exceeds that of other commonly provided clinical preventative services, including pap tests, mammographies and screening for colon cancer, as well as treatment for high serum cholesterol levels and mild to moderate hypertension.11 different countries have adopted different systems for offering tdt, building on variables such as income level, as was observed in a case series on tdt implementation in brazil, england, india, south africa and uruguay.12 not all of the studied countries had national policies mandating that this treatment be offered, and furthermore, while some of the countries’ tdt policies relied on offering broadly available brief advice, others were dependent on specialist support which was often limited in availability. in addition, the extent of medication coverage and reimbursement of provider time varied from one country to another.12 however, training and skill-building are integral to various models of tdt provision. for example, england, a high-income country, offers tdt as part of their national health service (nhs) plan. both widely available brief advice and more intensive specialist support are offered to smokers, with the majority of the costs covered by the nhs. in this model, significant emphasis is placed on the training and skills of service providers and england has accordingly established a national centre to address training, certification and performance evaluation for tdt providers.12 in uruguay, an upper-middle-income country of 3.5 million, 100 tdt programmes were established by 2010. these programmes offer training to hcps and provide free tdt medication to smokers. moreover, uruguayan law mandates that public and private service providers record the smoking status of all patients in their medical notes, incorporate a diagnosis organization (who) report on the global tobacco epidemic in 2008 indicate that the age-standardised prevalence of tobacco smoking among men in the eastern mediterranean region (emr) ranged from 63% in jordan and 51% in tunisia to 25% in oman.3 in 2012, the estimated age-standardised prevalence of daily smoking among men in the emr ranged from 43% in jordan and 45% in tunisia to 13% in oman.5 for an individual, quitting smoking brings about immediate health benefits, including the normalisation of heart rate and blood pressure and a decrease in coughing and the production of phlegm.6 in the long term, quitting tobacco generally reduces the risk of disease and premature death by 90% for those who quit before the age of 30 and by 50% for those who quit before the age of 50.6 five years after quitting, the risk of stroke falls to that of a non-smoker and the risk of head, neck and bladder cancers is reduced by half.7 one of the six policies recommended by the who to counter the tobacco epidemic is a countrylevel initiative in offering help to smokers in quitting tobacco use; these measures are intended to assist in reducing the demand for tobacco.3 however, despite this policy and the documented shortand long-term benefits of quitting smoking, tobacco dependence treatment (tdt) services continue to be scarce and inconsistent across the emr. many factors contribute to this shortage of tdt services, including the lack of training opportunities for healthcare providers (hcps) in the basic skills needed to deliver these services. this review justifies the urgent need for establishing tdt services across the emr and describes a model of international collaboration that addresses one of the most important limitations for establishing these services—the training of hcps in delivering effective and relevant tdt to interested smokers. tobacco dependence treatment tdt is an integral component of any comprehensive tobacco control effort. in article 14 of their framework convention on tobacco control (fctc), the who mandates that parties should design and implement effective programmes to promote the cessation of tobacco use and provide adequate treatment for tobacco dependence.8 they furthermore recommend the inclusion of cessation advice in primary healthcare services, establishing accessible and free ‘quitlines’ and making low-cost pharmacotherapy available to interested smokers.3,8 likewise, in a report issued in 1999, the world bank urged governments seeking health and economic gains to encourage smokers to quit.9 building on previously published data, the advancing tobacco dependence treatment services in the eastern mediterranean region international collaboration for training and capacity-building e444 | squ medical journal, november 2014, volume 14, issue 4 of tobacco dependence and offer relevant treatment through primary care programmes.12 national guidelines are in place and efforts are underway to ensure that the national treatment programmes have complete population coverage.12 brazil and india, two lower-middle-income countries, have focused on establishing a limited number of specialised treatment units.12 these services, while not necessarily wide-reaching, act as training hubs for hcps. although only brazil currently has a national tdt policy, both countries have developed and adopted national tdt guidelines.12,13 medication is available through treatment units in both countries but is only reimbursed in brazil.12 the situation in the emr is similar to that in other parts of the world; while a significant number of smokers have shown interest in quitting, the availability of tdt services continues to be limited and grows only marginally from year to year.3,14‒16 accordingly, tdt services are not consistently available across the emr and are not yet integrated within the healthcare system. while some countries, including kuwait, the united arab emirates (uae) and iran, offer a ‘quitline’ and cover costs for cessation services and nicotine replacement therapies (nrts), most emr countries offer partial to no coverage for smokers attempting to quit.14 correspondingly, the data on screening for tobacco use demonstrate that there is insufficient screening and advice for smokers. for example, data from 2009 indicated that only 22% of smokers in egypt had visited an hcp in the previous 12 months.17 among smokers, only 74% were screened for smoking and, of those screened, only 67% were advised to quit smoking.17 in qatar, data from 2013 revealed that only 71% of smokers in the country had been advised in the previous 12 months to quit smoking.16 training and capacity-building the training and capacity-building of service providers is a key measure in developing an infrastructure that supports smoking cessation and tdt, as highlighted by the guidelines for the implementation of article 14 of the fctc.8 at a minimum, the guidelines recommend that hcps be trained to record tobacco use among patients, provide brief advice, encourage attempts to quit and refer smokers to specialised tdt services. additionally, the fctc states that cessation training be incorporated into the curricula of all health professions as well as within continuous professional development programmes.8 muramoto et al. noted that training and education in general enhances physicians’ confidence and their readiness to offer tdt services as well as advise and counsel patients on smoking cessation.18 in spite of the clear need for such programmes, there continues to be a lack of education and training programmes concerning tdt in healthcare disciplines. this was demonstrated during a survey of 171 countries in 2009 which found that only 27% of medical schools taught a specific module on tobacco.19 specifically in the emr countries, results from the global health professions student survey indicated a shortage of formal training in smoking cessation approaches in medical schools.20 the percentage of medical students who reported receiving training ranged from approximately 40% in kuwait, tunisia and bahrain to approximately 9% in morocco.20 similar gaps in training and education were revealed in other healthcare disciplines.20 in a survey of medical students in the usa, respondents who reported receiving instruction, modelling and feedback on tdt by their preceptors in medical school had a higher self-reported skill level compared to those who recalled receiving less comprehensive training.21 however, a lack of staff, incentive and financial resources to support tdt teaching appears to present major barriers to its implementation, preventing less developed countries from incorporating a tobacco module into their medical curricula.19 to that end, developing the capacity of faculty members becomes critical in attempts to institutionalise tdt education and training for students in health professions.18 a systematic review of educationaland practicebased programmes concluded that hcps could be better engaged in tdt if they were intercepted both during their education and once they became healthcare professionals; while the first affects quit rates among their patients, the latter is effective in increasing screening rates.22 a recent cochrane review looked at randomised trials with interventions involving the training of hcps in smoking cessation techniques.23 the review concluded that such training had a measurable effect on the continuous tobacco abstinence among patients and the point prevalence of smoking. additionally, trained hcps were more likely to make follow-up appointments, provide smoking cessation counselling and ask patients to set a quit date.23 yet, and despite the proven value of such training progammes, an international survey of tdt training programmes could identify only four programmes in the emr, training a total of 98 individuals in 2007.24 model for tobacco dependence treatment: king hussein cancer center the king hussein cancer center (khcc) is a comprehensive cancer care facility in amman, jordan. since 2008, khcc has offered tdt services to feras i. hawari and rasha k. bader review | e445 tdt services. the methods employed vary between teaching, interactive exercises and case studies derived from the trainers’ own treatment practices. preand post-workshop tests are utilised to gauge the benefits of the training while a workshop evaluation is used to collect feedback in order to inform any updates and upgrades to the curriculum. workshops are conducted in close coordination with in-country partners who understand the situation within the local context and can influence the programme’s design and execution, in addition to providing continuing medical education accreditation for the workshops. the international collaboration demonstrated within the global bridges initiative is testimony to how a regional problem can be successfully addressed through global partnerships. to date, khcc has trained over 1,500 hcps and advocates from the emr on tobacco control and tdt [figure 1]. a total of 20 workshops and conferences have been held in six cancer patients and the general public, endeavouring to address the gaps in capacity and competence that limit the reach of tdt services and patients’ access to help. realising the importance of training hcps in evidence-based treatment, khcc started offering tdt training to hcps in emr countries in 2011. this was done via a collaboration with global bridges, an international healthcare tdt alliance that was cofounded by the mayo clinic, the american cancer society and the university of arizona. the global bridges initiative seeks to create opportunities to share treatment and advocacy expertise and to provide state-of-the-art training to countries around the world in order to help them fulfill article 14 of the fctc. while other organisations represent global bridges throughout latin america, africa and europe, khcc is the regional host and partner for this initiative in the emr. in this capacity, khcc developed a standard tdt curriculum designed to respond to the identified needs and gaps in the region. the training curriculum content was built on internationally recognised standards and is implemented during a three-day workshop which aims to enhance the participants’ understanding of tdt as an integral component of tobacco control and to equip trainees to practice tdt and handle various cases. the topics covered include a general introduction to tobacco and its products; tobacco and ncds; the process of addiction, withdrawal and relapse; conducting counselling and motivational interviews; pharmacotherapies, and building individualised treatment plans. additional training sessions seek to present tdt in the context of tobacco control in general; highlight ethical issues in tdt; present the water-pipe as a regional and global health hazard, and guide participants through establishing and sustaining figure 1: graph indicating the recent cumulative growth in the number of trained healthcare providers and advocates attending tobacco dependence treatment training conducted by the king hussein cancer centre in the eastern mediterranean region. figure 2: distribution map representing the geographic reach of the tobacco dependence treatment training conducted by the king hussein cancer centre in the eastern mediterranean region (emr). jordan, tunisia and the united arab emirates have hosted three or more workshops to date. most countries in the emr region have been represented at these workshops. advancing tobacco dependence treatment services in the eastern mediterranean region international collaboration for training and capacity-building e446 | squ medical journal, november 2014, volume 14, issue 4 countries in the emr; participants attended from a total of 19 countries, spanning morocco to the uae, as well as iran and afghanistan [figure 2]. additionally, the participants had varying professional backgrounds, including cardiology, oncology, pulmonology, general medical practice, nursing and pharmacology, among others. this diversity highlights the level of interest in such training and the enthusiasm for establishing these programmes across the region. other challenges facing tobacco dependence treatment in the eastern mediterranean region while training programmes such as the one described above seek to bring about significant progress, the emr continues to face other challenges that hinder service expansion. political commitment across the region to tobacco control is not uniform and the tobacco industry has been gaining traction in some emr countries.25–27 as developed nations around the world tighten their regulations on the tobacco industry, the developing nations of the emr, with their relaxed tobacco control regulations, may present a safe haven for this industry.25–27 tobacco companies are state-owned in eight emr countries, while multinational corporations have recently established operations in other middle eastern countries, such as in jordan and egypt.26‒28 another challenge that may hinder the expansion of tdt services in the region is the prevalence of tobacco use among physicians and other healthcare workers. in 2010, 24–42% of medical students in the emr were either current smokers or had previously been smokers.20 this undermines the role that hcps should play in diminishing the social acceptability of tobacco use; it also reduces their credibility in promoting tdt services.8 it is therefore imperative that teaching and training programmes for hcps address tobacco control and tdt early on and that special attention is given to first helping these professionals quit tobacco use themselves. in general, the infrastructure necessary to enable tdt services is not yet available in many emr countries, particularly as there are no national policies to promote tobacco cessation. screening for and recording tobacco use is not yet common practice among hcps and the availability of tdt medication may be interrupted. inadequate accessibility to services and treatment coverage present more barriers. in particular, the lack of treatment coverage is a key obstacle that needs to be addressed in parallel to any attempts to increase tdt services. experiences in other countries have shown that the extent of treatment coverage influences the utilisation rate of cessation services; the rate of usage has the potential to quadruple if full coverage is provided.29‒31 finally, population-level strategies that promote cessation and encourage smokers to quit, such as price measures and pictorial warnings on tobacco products, are either not in place or are only in the early stages of implementation, adding to the challenges facing the expansion of tdt services in this region.32 conclusion in summary, the rise in the prevalence of tobacco use in the region is alarming and calls for quick and decisive action in emr countries, specifically the implementation of who-recommended strategies for tobacco control. in the short term, helping smokers to quit is highly feasible. enabling and training hcps, potentially through international collaborations, should help build the skills needed to deliver effective tdt measures to smokers throughout the emr. acknowledgements khcc is a grantee of the mayo clinic in the usa for conducting global bridges work in the emr. references 1. mokdad ah, jaber s, aziz mi, albuhairan f, alghaithi a, alhamad nm, et al. the state of health in the arab world, 1990-2010: an analysis of the burden of diseases, injuries, and risk factors. lancet 2014; 383:309–20. doi: 10.1016/s01406736(13)62189-3. 2. united states department of health and human services. the health consequences of smoking—50 years of progress: a report of the surgeon general, 2014. from: www. surgeongeneral.gov/library/reports/50-years-of-progress/ accessed: jan 2014. 3. world health organization. who report on the global tobacco epidemic, 2008: the mpower package. from: www.who.int/tobacco/mpower/mpower_report_full_2008.pdf accessed: jan 2014. 4. lim ss, vos t, flaxman ad, danaei g, shibuya k, adairrohani h, et al. a comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010. lancet 2012; 380:2224– 60. doi: 10.1016/s0140-6736(12)61766-8. 5. ng m, freeman mk, fleming td, robinson m, dwyerlindgren l, thomson b, et al. smoking prevalence and cigarette consumption in 187 countries, 1980-2012. jama 2014; 311:183–92. doi: 10.1001/jama.2013.284692. 6. national cancer institute. harms of smoking and health benefits of quitting. from: www.cancer.gov/cancertopics/ factsheet/tobacco/cessation accessed: feb 2014. 7. american cancer society. guide to quitting smoking benefits. from: www.cancer.org/healthy/stayawayfromtobacco/ guidetoquittingsmoking/guide-to-quitting-smoking-benefits accessed: feb 2014. feras i. hawari and rasha k. bader review | e447 21. geller ac, hayes rb, leone f, churchill lc, leung k, reed g, et al. tobacco dependence treatment teaching by medical school clerkship preceptors: survey responses from more than 1,000 us medical students. prev med 2013; 57:81–6. doi: 10.1016/j.ypmed.2013.04.006. 22. anderson p, jané-llopis e. how can we increase the involvement of primary health care in the treatment of tobacco dependence? a meta-analysis. addiction 2004; 99:299–312. doi: 10.1111/j.1360-0443.2004.00672.x. 23. carson kv, verbiest me, crone mr, brinn mp, esterman aj, assendelft wj, et al. training health professionals in smoking cessation. cochrane database syst rev 2012; 5:cd000214. doi: 10.1002/14651858.cd000214.pub2. 24. rigotti na, bitton a, richards ae, reyen m, wassum k, raw m. an international survey of training programs for treating tobacco dependence. addiction 2009; 104:288–96. doi: 10.1111/j.1360-0443.2008.02442.x. 25. bollyky tj, glassman a; center for global development. incentives for life: cash-on-delivery aid for tobacco control in developing countries. from: www.cgdev.org/publication/ incentives-life-cash-delivery-aid-tobacco-control-developingcountries accessed: feb 2014. 26. eriksen m, mackay j, ross h. the tobacco atlas. 4th ed. atlanta, georgia, usa: american cancer society, 2012. pp. 54–7, 66–82. 27. awraq investments. al-eqbal investment company equity report. from: www.awraq.com/uploads/research/033a1e112 edd533f5ef22504ed856594740a1c88.pdf accessed: feb 2014. 28. japan tobacco international. jt completes acquisition of a leading waterpipe tobacco (shisha) company. from: www.jti. com/media/news-releases/jt-completes-acquisition-leadingwater-pipe-tobacco-company/ accessed: feb 2014. 29. gollust se, schroeder sa, warner ke. helping smokers quit: understanding the barriers to utilization of smoking cessation services. milbank q 2008; 86:601–27. doi: 10.1111/j.14680009.2008.00536.x. 30. curry sj, grothaus lc, mcafee t, pabiniak c. use and cost effectiveness of smoking-cessation services under four insurance plans in a health maintenance organization. n engl j med 1998; 339:673–9. doi: 10.1056/nejm199809033391006. 31. land t, rigotti na, levy de, paskowsky m, warner d, kwass ja, et al. a longitudinal study of medicaid coverage for tobacco dependence treatments in massachusetts and associated decreases in hospitalizations for cardiovascular disease. plos med 2010; e1000375. doi: 10.1371/journal.pmed.1000375. 32. borland r, li l, driezen p, wilson n, hammond d, thompson me, et al. cessation assistance reported by smokers in 15 countries participating in the international tobacco control (itc) policy evaluation surveys. addiction 2012; 107:197–205. doi: 10.1111/j.1360-0443.2011.03636.x. 8. world health organization framework convention on tobacco control. guidelines for implementation of article 14. from: www.who.int/fctc/guidelines/adopted/article_14/en/ accessed: feb 2014. 9. jha p, chaloupka fj; the world bank. curbing the epidemic: governments and the economics of tobacco control. tob control 1999; 8:196–201. doi:10.1136/tc.8.2.196. 10. hughes jr. tobacco treatment specialists: a new profession. j smok cessat 2007; 2:2–7. doi: 10.1375/jsc.2.supp.2. 11. centers for disease control and prevention. 2000 surgeon general’s report: reducing tobacco use. from: www. surgeongeneral.gov/library/reports/50-years-of-progress/ accessed: aug 2014. 12. raw m, mcneill a, murray r. case studies of tobacco dependence treatment in brazil, england, india, south africa and uruguay. addiction 2010; 105:1721‒8. doi: 10.1111/j.13600443.2010.03043.x. 13. national tobacco control programme, india ministry of health & family welfare. tobacco dependence treatment guidelines. from: www.treatobacco.net/en/uploads/documents/treatment %20guidelines/india%20treatment%20guidelines%20in%20 english%202011.pdf accessed: feb 2014. 14. world health organization. who report on the global tobacco epidemic, 2013: enforcing bans on tobacco advertising, promotion and sponsorship. from: www.who.int/tobacco/ global_report/2013/en/ accessed: jan 2014. 15. world health organization regional office for the eastern mediterranean. global adult tobacco survey: egypt fact sheet. from: www.emro.who.int/images/stories/tfi/documents/ gats%20fs%20egy%202009.pdf accessed: feb 2014. 16. world health organization regional office for the eastern mediterranean. global adult tobacco survey: qatar fact sheet. from: www.emro.who.int/images/stories/tfi/documents/ fact_sheets/fs_gats_qatar_2013.pdf accessed: feb 2014. 17. centers for disease control and prevention. morbidity and mortality weekly report: health-care provider screening for tobacco smoking and advice to quit: 17 countries, 2008-2011. from: www.cdc.gov/mmwr/preview/mmwrhtml/mm6246a4. htm accessed: feb 2014. 18. muramoto ml, lando h. faculty development in tobacco cessation: training health professionals and promoting tobacco control in developing countries. drug alochol rev 2009; 28:498–506. doi: 10.1111/j.1465-3362.2009.00106.x. 19. richmond r, zwar n, taylor r, hunnisett j, hyslop f. teaching about tobacco in medical schools: a worldwide study. drug alcohol rev 2009; 28:484–97. doi: 10.1111/j.14653362.2009.00105.x. 20. world health organization regional office for the eastern mediterranean. global health professions student survey fact sheets and country reports. from: www.emro.who.int /tobacco/gtss-matrix/ghpss-factsheets-reports.html accessed: feb 2014. التقييم األذين العصيب و الوضعي لدى الغواصني املكفوفني otoneurological and postural assessment in blind scuba divers sir, the visual system provides approximately 80% of the sensory perception required to maintain static and dynamic balance; this means that those who are visually impaired often have poor balance control.1 in congenital (cdg) as opposed to acquired (adg) visual impairment, the visual system relies on other stimuli from birth which leads to higher postural control in situations where vision is ineffectual.2 when blurred vision is induced in sighted subjects, the result is poor postural control and a predisposition to falling.3 visual feedback is essential for dynamic tasks and low-vision/blind subjects have poorer postural stability than normal sighted subjects.4 congenitally blind subjects have significantly faster reaction times than healthy controls to somatosensory stimuli triggered by random movements.5 a study was conducted between december 2012 and march 2013 in siena, italy, to examine results of the sensory organisation test (sot) and otoneurological tests among blind scuba divers in comparison to blind sedentary subjects. it was hypothesised that blind divers would have better motor and balance control than sedentary blind individuals due to the acquisition of postural control skills from the scuba diving. a total of 10 divers with adg (n = 7) or cdg (n = 3) visual impairment and 10 sedentary subjects with adg (n = 7) or cdg (n = 3) visual impairment were recruited from the otoneurology unit of the ear, nose & throat department at the university of siena in siena, italy. subjects were defined as visually impaired if their visual acuity was ≤20/200 and their visual field was <10° from a fixed point. participants were classified as divers if they had participated in >30 dives per year and sedentary if they did not play sports and needed a guide dog. subjects underwent a complete otoneurological examination including an otoscopy, pure tone audiometry and tympanometry as well as tubaric function, head shaking, positional and caloric tests as described by fitzgerald et al.6 evidence of spontaneous or gaze-evoked nystagmus was also noted. the sot was carried out using the neurocom® smart equitest® computerised dynamic posturography (cdp) machine (neurocom international inc., clackamas, oregon, usa) to evaluate the contributions of the three sensory systems to standing balance control. participants were evaluated under the following sot conditions: (1) eyes open on a firm surface with fixed visual surroundings; (2) eyes closed on a firm surface; (3) eyes open with a firm surface but with sway-referenced visual surroundings; (4) eyes open on a sway-referenced surface with fixed visual surroundings; (5) eyes closed on a swayreferenced surface; and (6) eyes open on a sway-referenced surface and with sway-referenced surroundings. these conditions were performed while subjects were standing without shoes on a duel force plate platform of 45.7 cm2, with their arms by their sides, eyes looking forward and feet positioned according to height. participants wore safety harnesses to prevent falls. the cdp machine generated an equilibrium score (es) for each test using values from 0 (falling) to 100 (balanced) by comparing the anteroposterior centre of pressure sway with the theoretical limit of stability (12.50° in the anteroposterior direction). composite scores and three sensory ratios (somatosensory, visual and vestibular) were calculated for each participant. mean results were analysed using the student’s t-test with a significance level of p <0.050. all subjects gave written informed consent and the study was approved by the university of siena committee for the protection of human subjects. the demographic and clinical characteristics of the study population is reported in table 1. unilateral vestibular paresis was detected in one scuba diver with letter to the editor sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e569–571, epub. 23 nov 15 submitted 7 feb 15 revision req. 24 may 15; revision recd. 8 jun 15 accepted 2 jul 15 doi: 10.18295/squmj.2015.15.04.025 table 1: demographic characteristics of blind scuba divers and blind sedentary subjects (n = 20) characteristic mean ± sd p value divers (n = 10) sedentary subjects (n = 10) age in years 31.85 ± 6.57 33.35 ± 6.35 0.468 years of blindness 18.9 ± 7.13 16.65 ± 6.29 0.297 height in cm 167.9 ± 10.89 170.9 ± 14.36 0.619 weight in kg 63.33 ± 12.33 64.78 ± 10.43 0.751 male-to-female ratio 1:1 3:2 >0.050 sd = standard deviation. otoneurological and postural assessment in blind scuba divers e570 | squ medical journal, november 2015, volume 15, issue 4 adg blindness and one sedentary subject, both of whom were well-compensated with regards to high and low stimulation frequencies. signs of previous tympanic perforation were noted in three subjects (two sedentary subjects and one diver with adg blindness), while two divers (one with adg and one with cdg blindness) had bilateral exostosis in the external auditory canal. spontaneous eye movements due to chronic deprivation of visual feedback, such as disjunctive and conjugate gaze instability (drifts and nystagmus), were observed in six divers (60%). there was no evidence of nystagmus or vertigo in any of the subjects. no statistically significant differences were noted in composite cdp or sot 1, 2 or 3 values between the divers or sedentary subjects. divers showed superior sot 4, 5 and 6 results compared to sedentary subjects. their somatosensory, visual and vestibular ratios were also significantly higher [table 2]. subjects with cdg blindness had better sot 1, 2 and 3 results compared to those with adg blindness; however, these differences were not statistically significant due to the small sample size. the sot provides information regarding which input system (somatosensory, visual or vestibular) is being utilised to maintain postural control. in a population of blind subjects, sight is not used and thus the exercises are changed. in the current study, sot 1 results were very similar to sot 2 because only a few subjects could perceive faint light; this meant there was little visual contrast between having their eyes open or closed. this suggests that impaired vision does not affect static balance in blind subjects. additionally, the results of sot 3 were similar to those for the first two tests; this may be because the blind individuals could not perceive the simulated movement of their surroundings. finally, the scores of sot 4, 5 and 6 were similar. this could be because the blind subjects could not use sight to compensate for the movements induced by the platform. in the blind divers, input from the somatosensory and vestibular systems played a crucial role in postural control as there was a significant difference in the vestibular ratio between the divers and sedentary subjects. this may indicate that blind divers can substitute information from their missing visual system.4 values obtained in the first two sot tests were exceptionally high when compared with reference values for normal sighted subjects, potentially indicating that blind subjects recover postural control more quickly than sighted subjects.7 this is likely due to modified sensorimotor integration processes which control body orientation in space. the visual ratio was significantly higher among the divers than the sedentary subjects. no significant difference was noted between the divers and sedentary subjects with regards to their somatosensory ratios. for blind subjects, the conditions used to calculate this ratio (sot 1 and 2) are exactly the same; as such, a very high somatosensory ratio is to be expected. table 2: sensory organisation test results among blind scuba divers and blind sedentary subjects (n = 20) sot test condition sensory input mean ± sd p value divers sedentary subjects 1 eyes open on a firm surface with fixed visual surroundings somatosensory, visual and vestibular 91.83 ± 3.65 93.01 ± 2.49 0.436 2 eyes closed on a firm surface somatosensory and vestibular 94.08 ± 2.05 92.72 ± 1.75 0.130 3 eyes open on a firm surface with swayreferenced visual surroundings somatosensory and vestibular 92.62 ± 3.01 91.23 ± 2.94 0.338 4 eyes open on a sway-referenced surface with fixed visual surroundings visual and vestibular 61.13 ± 8.92 51.18 ± 6.97 0.023* 5 eyes closed on a sway-referenced surface vestibular 66.90 ± 9.20 56.06 ± 11.27 0.040* 6 eyes open on a sway-referenced surface with sway-referenced visual surroundings vestibular 66.83 ± 10.08 55.92 ± 8.40 0.024* composite 73.56 ± 6.89 73.22 ± 3.61 0.900 somatosensory ratio† 1.025 ± 0.02 0.9975 ± 0.03 0.052 visual ratio‡ 0.6667 ± 0.10 0.5513 ± 0.09 0.022* vestibular ratio§ 0.7300 ± 0.10 0.6039 ± 0.12 0.037* sot = sensory organisation test; sd = standard deviation. *statistically significant at p <0.05. †calculated by dividing the mean equilibrium score (es) of sot 2 with the mean es of sot 1. ‡calculated by dividing the mean es of sot 4 with the mean es of sot 1. §calculated by dividing the mean es of sot 5 with the mean es of sot 1. jacopo cambi, ludovica livi, michele loglisci and walter livi letter to the editor | e571 divers may have a more effective central vestibular response, as evidenced by their superior performance in sot conditions 4, 5 and 6. repetitive stimuli cannot affect the peripheral inner ear but may lead to plasticity in areas of the brain delegated to vestibular control among sedentary blind subjects.8 among blind subjects who take part in sports, these are replaced by links to vestibular and proprioceptive areas.9 this mechanism could explain the results of the current study. however, further research with magnetic resonance imaging is needed to confirm this. the main limitations of this study were the small sample size and the non-blinded methodology which may have biased the results. in conclusion, in visually impaired divers, the vestibular and somatosensory systems play a fundamental role in balance control and compensate for the lack of visual input. *jacopo cambi, ludovica livi, michele loglisci, walter livi department of ear, nose & throat, università degli studi di siena, siena, italy *corresponding author e-mail: ishajacopo@hotmail.it references 1. friedrich m, grein hj, wicher c, schuetze j, mueller a, lauenroth a, et al. influence of pathologic and simulated visual dysfunctions on the postural system. exp brain res 2008; 186:305–14. doi: 10.1007/s00221-007-1233-4. 2. schwesig r, goldich y, hahn a, müller a, kohen-raz r, kluttig a, et al. postural control in subjects with visual impairment. eur j ophthalmol 2011; 21:303–9. 3. mohapatra s, krishnan v, aruin as. the effect of decreased visual acuity on control of posture. clin neurophysiol 2012; 123:173–82. doi: 10.1016/j.clinph.2011.06.008. 4. tomomitsu ms, alonso ac, morimoto e, bobbio tg, greve jm. static and dynamic postural control in low-vision and normal-vision adults. clinics (sao paulo) 2013; 68:517–21. doi: 10.6061/clinics/2013(04)13. 5. nakata h, yabe k. automatic postural response systems in individuals with congenital total blindness. gait posture 2001; 14:36–43. doi: 10.1016/s0966-6362(00)00100-4. 6. fitzgerald g, hallpike cs. studies in human vestibular function i: observations on the directional preponderance of caloric nystagmus resulting from cerebral lesions. brain 1942; 62:115–37. doi: 10.1093/brain/65.2.115. 7. goebel ja, sataloff rt, hanson jm, nashner lm, hirshout ds, sokolow cc. posturographic evidence of nonorganic sway patterns in normal subjects, patients, and suspected malingerers. otolaryngol head neck surg 1997; 117:293–302. doi: 10.1016/s0194-5998(97)70116-5. 8. klinge c, eippert f, röder b, büchel c. corticocortical connections mediate primary visual cortex responses to auditory stimulation in the blind. j neurosci 2010; 30:12798–805. doi: 10.1523/jneurosci.2384-10.2010. 9. collignon o, vandewalle g, voss p, albouy g, charbonneau g, lassonde m, et al. functional specialization for auditory-spatial processing in the occipital cortex of congenitally blind humans. proc natl acad sci u s a 2011; 108:4435–40. doi: 10.1073/pnas.1013928108. http://dx.doi.org/10.1007/s00221-007-1233-4 http://dx.doi.org/10.1016/j.clinph.2011.06.008 http://dx.doi.org/10.6061/clinics/2013%2804%2913 http://dx.doi.org/10.1016/s0966-6362%2800%2900100-4 http://dx.doi.org/10.1093/brain/65.2.115 http://dx.doi.org/10.1016/s0194-5998%2897%2970116-5 http://dx.doi.org/10.1523/jneurosci.2384-10.2010 http://dx.doi.org/10.1073/pnas.1013928108 sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e442–443, epub. 24 aug 15. doi: 10.18295/ squmj.2015.15.03.025. submitted 20 apr 15 accepted 14 may 15 رد: االعتالل العضلي الذي يسببه دواء صوديوم فالربويت يف طفل re: sodium valproate-induced myopathy in a child sir, we read with interest the article by ahmed published in the squmj february 2015 issue.1 the author reports an eight-year-old male weighing 25 kg who developed myopathy with carnitine deficiency after valproate therapy.1 this case is not the only one of its kind; kasturi et al. reported a similar case in 2005 of a four-year-old boy developing neurocysticercosis proximal muscle weakness and carnitine deficiency after long-term valproate therapy due to symptomatic epilepsy.2 upon discontinuation of valproate and the addition of l-carnitine, the clinical manifestations completely resolved.2 ahmed attributes the development of myopathy in his patient to the administration of valproate (1,000 mg/ day or 40 mg/kg/day).1 however, valproate-induced myopathy may not only be due to carnitine deficiency, but also due to the primary mitochondrion-toxic effect of the drug.3 valproate not only inhibits complexes i and iv of the respiratory chain, but also restricts oxidative phosphorylation and thus adenosine triphosphate synthesis and β-oxidation.4,5 as a consequence, oxygen consumption is reduced, coenzyme a (coa) and cytochrome c are sequestered, the structure of the inner mitochondrial membrane is impaired and there is vacuolar fragmentation of mitochondria. additionally, valproate has been reported to unmask mitochondrial disorders (mids). chaudhry et al. reported a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (melas) syndrome, in whom the mid became evident after the administration of valproate.6 valproate has also been shown to cause myopathy in patients with acyl-coa dehydrogenase deficiency, rhabdomyolysis in neonates with chromosomal defects and rhabdomyolysis in patients with carnitine palmitoyltransferase ii deficiency.7 mitochondrial toxicity of valproate was further documented to induce severe acute liver failure in patients with a mitochondrial depletion syndrome.8 valproate-induced myopathy has additionally been observed in a patient with schizoaffective disorder, although this patient was also taking quetiapine, nifedipine, torsemide, levothyroxine and acetylsalicylic acid.9 the mitochondrion-toxic effect of valproate was also confirmed in a patient with melas syndrome, in whom valproate aggravated epilepsy.10 mitochondrion-toxicity of valproate may be the reason why the compound is often ineffective as an anti-epileptic drug in mid patients.11 concerning the case presented by ahmed, it would be helpful to know: if there was consanguinity between the parents; if the family history was positive for epilepsy; if myopathy developed in any first-degree relative; if muscle cramps, easy fatigability, double vision, exercise intolerance, muscle weakness or myalgia were reported by the parents, grandparents or siblings; if there were complications during general anaesthesia in the individual or his family; the results of neurological investigations by specialists familiar with metabolic myopathies; and if there were elevated creatine kinase or lactate levels or myoglobinuria in any of the relatives.1 overall, there is evidence that valproate may cause mitochondrial myopathy due to its mitochondrion-toxic effect. however, this seems to predominantly affect patients with subclinical or clinical manifestations of mid. the interesting case reported by ahmed would thus profit from an extensive work-up for mid or a β-oxidation defect.1 the question as to whether valproate myopathy is a mitochondrial disorder would have to be answered with “yes”. *josef finsterer1 and marlies frank2 departments of 1neurology and 2first medical, krankenanstalt rudolfstiftng, vienna, austria *corresponding author e-mail: fifigs1@yahoo.de references 1. ahmed r. sodium valproate-induced myopathy in a child. sultan qaboos univ med j 2015; 15:e146–7. 2. kasturi l, sawant sp. sodium valproate -induced skeletal myopathy. indian j pediatr 2005; 72:243–4. doi: 10.1007/bf02859266. letter to the editor http://dx.doi.org/10.1007/bf02859266 josef finsterer and marlies frank letter to the editor | e443 3. finsterer j, zarrouk mahjoub s. mitochondrial toxicity of antiepileptic drugs and their tolerability in mitochondrial disorders. expert opin drug metab toxicol 2012; 8:71–9. doi: 10.1517/17425255.2012.644535. 4. hroudova j, fisar z. activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers. neuro endocrinol lett 2010; 31:336–42. 5. luís pb, ruiter jp, aires cc, soveral g, de almeida it, duran m, et al. valproic acid metabolites inhibit dihydrolipoyl dehydrogenase activity leading to impaired 2-oxoglutarate-driven oxidative phosphorylation. biochim biophys acta 2007; 1767:1126–33. doi: 10.1016/j. bbabio.2007.06.007. 6. chaudhry n, patidar y, puri v. mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes unveiled by valproate. j pediatr neurosci 2013; 8:135–7. doi: 10.4103/1817-1745.117847. 7. kottlors m, jaksch m, ketelsen up, weiner s, glocker fx, lücking ch. valproic acid triggers acute rhabdomyolysis in a patient with carnitine palmitoyltransferase type ii deficiency. neuromuscul disord 2001; 11:757–9. doi: 10.1016/s0960-8966(01)00228-0. 8. pronicka e, weglewska-jurkiewicz a, pronicki m, sykut-cegielska j, kowalski p, pajdowska m, et al. drug-resistant epilepsia and fulminant valproate liver toxicity: alpers-huttenlocher syndrome in two children confirmed post mortem by identification of p.w748s mutation in polg gene. med sci monit 2011; 17:cr203–9. doi: 10.12659/msm.881716. 9. sarlon j, hess e, krasnianski a. valproate-induced hyperammonemic encephalopathy followed by benzodiazepine withdrawal in a patient with schizoaffective disorder: a differential diagnosis. j neuropsychiatry clin neurosci 2013; 25:e69–70. doi: 10.1176/appi. neuropsych.12090218. 10. lin cm, thajeb p. valproic acid aggravates epilepsy due to melas in a patient with an a3243g mutation of mitochondrial dna. metab brain dis 2007; 22:105–9. doi: 10.1007/s11011-007-9056-3. 11. pérez lópez-fraile mi, barrena r, montoya j, marta e. [evolution until death of two members of a family with a3243g mutation and melas phenotype versus diabetes mellitus.] neurologia 2006; 21:327–32. http://dx.doi.org/10.1517/17425255.2012.644535 http://dx.doi.org/10.1016/j.bbabio.2007.06.007 http://dx.doi.org/10.1016/j.bbabio.2007.06.007 http://dx.doi.org/10.4103/1817-1745.117847 http://dx.doi.org/10.1016/s0960-8966%2801%2900228-0 http://dx.doi.org/10.12659/msm.881716 http://dx.doi.org/10.1176/appi.neuropsych.12090218 http://dx.doi.org/10.1176/appi.neuropsych.12090218 http://dx.doi.org/10.1007/s11011-007-9056-3 clinical & basic research العدوى االنتهازية واملضاعفات عنداإلصابه بفريوس نقص املناعة البشرية-1 يف األطفال واالرتباط مع احلالة املناعية جيفندر ياداف، �شاجنيف ناندا، ديباك �شارما abstract: objectives: the aim of this study was to ascertain the correlation between various opportunistic infections and complications in human immunodeficiency virus (hiv)-1-infected children and the immune status of these patients, evaluated by absolute cluster of differentiation 4 (cd4) count and cd4 percentage. methods: this study was conducted from january 2009 to june 2010 at the antiretroviral treatment centre of the pt. b.d. sharma post graduate institute of medical sciences, a tertiary care hospital in rohtak, haryana, in northern india. a total of 20 hiv-1-infected children aged 4–57 months were studied. demographic and baseline investigations were performed prior to the start of highly active antiretroviral therapy (haart). a fixed-dose combination of haart was given based on the patient’s weight. baseline investigations were repeated after six months of haart. results: there was a significant increase in the patients’ haemoglobin, weight, height and cd4 count after six months of haart. significant improvements (p <0.05) were also noted in the patients’ immune status, graded according to the world health organization. conclusion: this study observed that the severity and frequency of opportunistic complications in paediatric patients with hiv-1 increased with a fall in the cd4 count. the treatment of opportunistic infections, along with antiretroviral therapy, may lead to both clinical and immunological recovery as well as a decreased incidence of future opportunistic infections. the cd4 count may give treating physicians an initial idea about the immune status of each child and could also be used as a biological marker of haart efficacy. patient compliance must be ensured during haart as this is a key factor in improving outcomes. keywords: aids; highly active antiretroviral therapy; aids-related opportunistic infections; cd4 lymphocyte count; india. امللخ�ص: الهدف: الهدف من الدرا�شة هو التاأكد من العالقه بني االأمرا�ض االنتهازية املختلفه وامل�شاعفات املر�شيه يف االطفال امل�شابني بفريو�ض نق�ض املناعة الب�رشية -1 واحلالة املناعية، عن طريق التقييم العددي ملجموعة التمايز )cd4( و ن�شبة خاليا cd4 الطريقه: اأجريت هذه الدرا�شة خالل الفرتة من يناير 2009 اإىل يونيو 2010 يف مركز العالج امل�شاد للفريو�شات يف معهد �شارما العايل للعلوم بني اأعمارهم ترتاوح hiv-1-ب م�شابا طفال 20 على الدرا�شه متت الهند. �شمال يف الثالثه للرعاية وهوم�شت�شفى )روتاك(، الطبية احلثيث العالج بدء قبل املر�شى لالأطفال االأ�شا�شيه الت�شخي�شية والقيا�شات الدميوغرافية املعلومات على احل�شول مت اأ�شهر. 4-157 بامل�شاد للفريو�شات )haart(. اأعطيت جرعة ثابتة من haart اعتمادا على وزن املري�ض و متت اعادة القيل�شات بعد �شتة اأ�شهر من عالج haart. النتائج: كانت هناك زيادة كبرية يف م�شتوى خ�شاب الدم والوزن والطول وعدد خاليا cd4 بعد �شتة اأ�شهر من العالج بhaart ولوحظ حت�شن كبري ) p >0.05( يف احلالة املناعية للمر�شى وفقا ملنظمة ال�شحة العاملية اخلال�صة: هذه cd4 ارتفع مع االنخفا�ض يف تعداد hiv-1 الدرا�شة ت�شري اىل اأن �شدة وتواتر امل�شاعفات االنتهازية يف طب االأطفال املر�شى مع . ان عالج العدوى االنتهازية، جنبا اإىل جنب مع العالج امل�شاد للفريو�شات، قد يوؤدي اإىل االنتعا�ض ال�رشيري واملناعي وانخفا�ض معدل االإ�شابة بااللتهابات االنتهازية امل�شتقبليه. ان اأعداد cd4 قد تعطي فكرة اأولية للطبيب املعالج عن احلالة املناعية لكل طفل وميكن اأي�شا اأن ت�شتخدم كعالمة بيولوجية لفاعلية عالج haart. يجب �شمان امتثال املري�ض خالل عالج haart الأن هذا ي�شكل عامال رئي�شيا يف حت�شني النتائج. مفتاح الكلمات: االإيدز؛ العالج امل�شاد للفريو�شات الن�شط للغاية؛ العدوى االنتهازية املرتبطه باالإيدز؛ عدد اللمفاويات cd4؛ الهند. opportunistic infections and complications in human immunodeficiency virus-1-infected children correlation with immune status jaivinder yadav, sanjeev nanda, *deepak sharma sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e513−521, epub. 14th oct 14 submitted 23rd feb 14 revision req. 17th apr 14; revision recd. 6th may 14 accepted 28th may 14 department of paediatrics, pt. b. d. sharma post graduate institute of medical sciences, rohtak, haryana, india *corresponding author e-mail: dr.deepak.rohtak@gmail.com advances in knowledge the results of this study show that while specific infections cannot be predicted based upon the cluster of differentiation 4 (cd4) count and percentage, the frequency and severity of opportunistic infections increase as the cd4 count falls. this study demonstrated that highly active antiretroviral therapy (haart) has significant positive effects on the health of patients with human immunodeficiency virus (hiv)-1, including their weight and immunological status. opportunistic infections and complications in human immunodeficiency virus-1-infected children correlation with immune status e514 | squ medical journal, november 2014, volume 14, issue 4 acquired immune deficiency syndrome (aids) was first recognised in the usa in 1981 due to an unexplained pneumocystis jiroveci infection in a previously healthy man. ever since its appearance, the disease has progressed rapidly and is now being reported from every corner of the globe.1 aids is caused by the human immune deficiency virus (hiv) types 1 and 2. the disease is present worldwide, but mainly concentrated in subsaharan africa and asia. the number of hiv patients in india is growing fast, and the total number of infected people in this country is second only to that in africa.1 there is an increasing number of paediatric hiv patients worldwide, with an estimated 2.5 million cases (7.5%) in 2007.2 in the developed world, paediatric patients constitute 2% of the hiv-infected population, whereas in developing countries, 15–20% of the total hiv-infected population are children.3 ever since hiv was first registered in india in 1986, the country has reported a hiv seropositivity prevalence of 2.5%.4 in india, aids is rapidly increasing among the hiv population; with the current rate of increase, india will soon have the highest aids prevalence worldwide.4 hiv is most commonly contracted through vertical transmission, as observed by rogers et al. when investigating an american paediatric population.5 cluster of differentiation 4 (cd4) cells are the primary cellular target for hiv.1 a diagnosis of hiv can be made by detecting viral antibodies, ribonucleic acid or antigens, for example by using a protein 24 antigen assay. the hiv deoxyribonucleic acid (dna) polymerase chain reaction (pcr) test is the preferred virology assay among developed countries.6 opportunistic infections occur in hiv-positive individuals as their immune system weakens and the aetiology of the infectious organism is affected by the immunological status of the patient.7,8 in more economically developed countries, due to the extensive use of highly active antiretroviral therapy (haart), infections like cytomegalovirus (cmv), cryptosporidiosis and toxoplasmosis predominate.4,9 however, in developing countries, infections due to mycobacterium tuberculosis are more common.4,9 the present study aimed to find a correlation between various hiv-related complications, both infectious and non-infectious, and immune status, measured by cd4 count. the study also examined changes in growth and opportunistic infections among patients after they began treatment with haart. methods this prospective study was undertaken in clinical and laboratory settings for an 18-month period between january 2009 and june 2010. a total of 20 paediatric patients with hiv-1 infections were observed. the subjects were either inpatients or outpatients at the antiretroviral treatment centre of the pt. b.d. sharma post graduate institute of medical sciences, a tertiary care hospital in rohtak, haryana, in northern india. all patients tested positive for hiv1 infections confirmed by three positive enzymelinked immunosorbent assay tests. to be included in the study, subjects also had to fulfil the world health organization (who) revised clinical staging system for hiv/aids in children,10 and have one or more opportunistic infections or complications. children under 18 months of age were excluded from the study, unless the diagnosis of hiv-1 had been confirmed by dna pcr assay and they were already being treated for an opportunistic infection. the patients’ clinical parameters prior to the beginning of the study were considered to be the control values. all children enrolled in this study were followedup monthly for six months. clinical and nutritional examinations were done at each visit to identify any opportunistic infections. each child underwent detailed general physical and systemic examinations at the time of their enrolment in the study. at this time, a record was made of their baseline data, including demographic details, nutritional status and malnutrition classification according to the indian academy of pediatrics.11 the possible modes of hiv transmission were also recorded via a thorough patient history, focusing on the patients’ antenatal and perinatal history. any suggestion of risk behaviours among the parents, the hiv status of the parents, if the patient had undergone previous blood transfusions and whether the patient had been breastfed were also documented. laboratory investigations were application to patient care this study supports the benefits of haart in improving the nutritional status of patients, leading to decreased hospitalisation and a reduction in the healthcare costs associated with this. however, haart is known to have high dropout rates and patient complicance must be emphasised in order to achieve the best results. as the results of this study demonstrate that specific infections cannot be predicted based upon the cd4 count alone, physicians should consistently test for opportunistic infections in hiv-1 patients. in resource-limited settings where cd4 count tests are not available, opportunistic infections may be used as a guide for the patient’s immunological status and to inform the prescription of haart. jaivinder yadav, sanjeev nanda and deepak sharma clinical and basic research | e515 subsequently performed to estimate haemoglobin (hb) concentration, absolute lymphocyte count, serum glutamic oxaloacetic transaminase to pyruvic transaminase ratio, serum creatinine and cholesterol. additionally, all of the children underwent chest radiography and ultrasound abdomen scans. the cd4 count was measured using a fully automated fluorescence-activated cell sorting cytometer (s3™ cell sorter, bio-rad laboratories, inc., hercules, california, usa). the cd4 percentage was calculated as follows: cd4 percentage = (absolute cd4 t-lymphocyte count divided by total lymphocyte count) x 100. the cd4 and absolute lymphocyte counts were repeated six months after their first visit. viral opportunistic infections like herpes simplex, herpes zoster and molluscum contagiosum were identified clinically. suspected bacterial and fungal infections were confirmed by culture, serology and gram staining, or with special stains like indian ink. the children were investigated for tuberculosis if they had any of the following symptoms: a fever and cough lasting more than one month; marked weight loss or marasmus; multiple lymphadenopathy; meningeal syndrome; a positive tuberculin skin test (with induration of more than 10 mm), or pulmonary infiltrates with or without lymph nodes as identified on a chest radiograph. anthropometry and a detailed nutritional examination were performed to identify any signs of wasting. smear testing and cultures were performed on samples obtained from the subjects by early gastric aspiration after overnight fasting for three consecutive days. patients with a history of oral thrush or other fungal infections underwent fungal swab testing and cultures using axillary, inguinal, rectal, throat swabs, urine (for fungal hyphae) and blood samples. patients with persistent diarrhoea underwent three stool examinations and cultures to identify the microbes responsible for this symptom. all of the patients enrolled in the study were graded according to the revised who clinical staging system for hiv/aids in children.10 immunological staging was determined according to the who classifications of hiv-associated immunodeficiency in infants and children.8 children who were in clinical stages 3 or 4 were candidates for haart. children who were in stages 1 and 2 were also candidates if they fulfilled the following criteria according to their age group: <11 months (if cd4 <1,500 cells/mm3 or <25%); 12– 35 months (if cd4 <750 cells/mm3 or <20%); 36–59 months (if cd4 <350 cells/mm3 or <15%), or >5 years (if cd4 <200 cells/mm3). if applicable, patients were prescribed a dispersible fixed-dose combination of haart, containing stavudine (30 mg or 40 mg), lamivudine (150 mg) and nevirapine (200 mg). these drugs were provided free of charge from the antiretroviral treatment centre at the pt. b.d. sharma post graduate institute of medical sciences. patients with tuberculosis were started on haart after the completion of antitubercular therapy (att); in severely immunosuppressed patients, haart was prescribed only after 2–8 weeks of att. opportunistic infections were treated according to guidelines issued by the national aids control organization for hiv care and treatment for infants and children in india.7 in this study, analysed variables included the child’s nutritional status, absolute lymphocyte count, cd4 percentage, cd4 count and any changes in this count, as well as the child’s immune status after undergoing specific therapy for various opportunistic infections and complications. all the data were inserted in patient proformas. the statistical analysis was carried out using the statistical package for the social sciences (spss), version 16 (ibm, corp., chicago, illinois, usa). the student’s t-test and fisher’s exact test were applied to the data. before each child was enrolled in the study, informed consent was obtained from their parents. in cases where the patient had lost both parents, consent was obtained from the child’s guardians. the study was approved by the ethical & scientific committee of the pt. b.d. sharma post graduate institute of medical sciences in december 2008. results a total of 20 paediatric patients with hiv-1 infections ranging in age from 4 to 157 months were observed during the study period, with a mean age at presentation of 72.4 ± 46.18 months. none of the patients dropped out of the study during the study period. among the children, the predominant mode of hiv transmission was vertical. a total of 50% of the patients had experienced the loss of one or both parents. this posed great difficulty in maintaining the care of these patients, especially as it was not always clear who was responsible for them. a total of 19 patients (95%) were prescribed haart; of these, 95% were compliant with the treatment and did not miss any doses. one patient (5.3%) developed a skin rash following the commencement of haart; however, the rash subsided without treatment and the patient was able to continue the therapy for the required duration. at the beginning of the study, the majority of the patients (75%) suffered from wasting, with a weightfor-age measurement in the <3rd percentile, as per the opportunistic infections and complications in human immunodeficiency virus-1-infected children correlation with immune status e516 | squ medical journal, november 2014, volume 14, issue 4 centers for disease control and prevention (cdc) growth charts.12 however, 45% of the patients had a length-for-age measurement that was between the 10th and 50th percentiles, which demonstrated that wasting was more prevalent in hiv patients than stunted growth [table 1]. fevers, anorexia and weakness were the most common symptoms noticed in the study (95%), followed by weight loss/failure to thrive (85%) [table 2]. following six months of haart, a significant increase was noted in the mean hb, height and weight measurements of the hiv-1-infected children. upon admission to the study, the mean hb was 7.78 ± 2.36 g %, mean weight was 13.95 ± 7.63 kg and mean height was 105.72 ± 27.06 cm. following haart, these values increased to 9.28 ± 1.13 g % (p <0.05), 18.8 ± 7.32 kg (p <0.01) and 110 ± 25.66 cm (p <0.01), respectively. these results suggest that the treatment for opportunistic infections and haart significantly improved clinical outcomes among the patients [table 3]. additionally, the rate of hospital admissions decreased during the study period. a total of 16 patients (80%) were hospitalised at the beginning of the study, but only 3 (15%) were admitted to the hospital during the six-month follow-up period, demonstrating that combined therapy for opportunistic infections and haart were effective in decreasing the hospital admission rate for this group of hiv-positive children. table 1: weight-for-age and height-for-age percentiles of human immunodeficiency virus-1-infected children before and after six months of highly active antiretroviral therapy (n = 20) percentile12 weight-for-age* in kg height-for-age* in cm before therapy after therapy before therapy after therapy <3rd 15 4 4 3 3–10th 4 3 5 1 10–50th 1 11 9 15 >50th 0 2 2 1 *divided by the number of patients. table 2: clinical manifestations of opportunistic infections or complications among human immunodeficiency virus-1-infected children (n = 20) manifestation n % fever 19 95 cough 11 55 diarrhoea 8 40 generalised weakness/anorexia 19 95 weight loss/failure to thrive 17 85 abdomen distension 5 25 generalised lymphadenopathy 15 75 hepatomegaly 14 70 splenomegaly 6 30 other skin lesions 3 15 otitis 3 15 oral thrush 4 20 chelosis/apthous ulcer/stomatitis 6 30 seizures 5 25 pleural effusion 1 5 table 3: comparison of clinical parameters, immunological markers, world health organization clinical stage and immunological stage for human immunodeficiency virus-1-infected children at diagnosis and following six months of highly active antiretroviral therapy and treatment for opportunistic infections (n = 20) at diagnosis* after therapy p value clinical parameter mean hb in g % 7.78 ± 2.36 9.28 ± 1.13 <0.05 mean weight in kg 13.95 ± 7.63 18.8 ± 7.32 <0.01 mean height in cm 105.72 ± 27.06 110 ± 25.66 <0.01 immunological marker mean total lymphocyte count in mm3 3,061 ± 1,723 2,931 ± 1,169 >0.05 mean cd4 count in cells/ mm3 391 ± 274 720 ± 356 <0.01 mean cd4 percentage 12.86 ± 7.54 25.53 ± 15.03 <0.01 clinical stage10 1 0 0 <0.05 2 1 17 3 12 1 4 7 2 immunological stage8 not significant 2 10 <0.05 mild 1 6 advanced 8 3 severe 9 1 hb = haemoglobin; cd4 = cluster of differentiation 4. *upon diagnosis of an opportunistic infection. jaivinder yadav, sanjeev nanda and deepak sharma clinical and basic research | e517 there was a significant increase in cd4 count and cd4 percentage among the patients after six months of haart, as well as a statistically significant (p <0.05) change in clinical stage. the majority of patients initially categorised as stages 3 and 4 were subsequently reclassified to stage 2 following treatment. an improvement in immunological stage was also observed, with the majority of patients promoted to the ‘not significant’ group after six months of treatment [table 3]. furthermore, the results showed a statistically significant improvement in the mean weight, height, cd4 count and cd4 percentage of patients when the data was compared by age group (<60 versus >60 months). additionally, there was a significant improvement in weight, height and hb among tuberculosis patients following six months of haart and a significant increase in hb and height among patients with oral thrush [table 4]. the most commonly observed opportunistic infections in this study were tuberculosis and thrush. other opportunistic infections seen included persistent diarrhoea, bacteremia, meningitis, hiv encephalopathy, disseminated cmv and systemic thrush [table 5]. at the time of presentation, eight (40%) patients had persistent diarrhoea and 11 (55%) patients had a cough. the distribution of various opportunistic infections were noted in relation to the patients’ immunological status. it was observed that six patients (30%) had cd4 counts <200 cells/mm3 and 14 (70%) had cd4 counts >200 cells/mm3. similarly, eight patients (40%) had a cd4 percentage <20% and 12 (60%) had a cd4 percentage >20%. infections occurring with cd4 counts <200 cells/mm3 included tuberculosis (33.3%), oral thrush (25%), persistent diarrhoea (25%), bacteremia (25%) and disseminated cmv [table 6]. discussion the global aids epidemic is one of the greatest challenges facing the current generation and the extent of this problem among children is growing rapidly. the aim of this study was to determine the correlation between opportunistic infections and complications among hiv-1-infected children and immune status, evaluated by cd4 count and percentage. upon enrolment in the present study, the majority of the patients had a weight-for-age below the 3rd percentile and 20% had a height-for-age below the 3rd percentile. another 20% and 25% of the patients were between the 3rd and 10th percentiles, for weightand height-for-age, respectively. only two patients had a table 4: comparison of the clinical parameters of human immunodeficiency virus-1-infected children at diagnosis and following six months of highly active antiretroviral therapy by age group and the two most common opportunistic infections (n = 20) clinical parameter age group <60 months >60 months before therapy after therapy p value before therapy after therapy p value mean weight in kg 8.05 ± 3.30 13.1 ± 2.56 <0.01 20.05 ± 5.55 25.5 ± 5.88 <0.01 mean height in cm 83.55 ± 16.83 88.85 ± 15.06 <0.01 127.9 ± 12.5 131.25 ± 12.81 <0.01 mean cd4 count in cells/mm3 544 ± 286 910 ± 348 <0.05 238 ± 158 550 ± 293 <0.05 mean cd4 percentage 16.84 ± 7.99 28.25 ± 8.23 <0.05 11.5 ± 9.06 23.94 ± 11.58 <0.05 tuberculosis patients at diagnosis after therapy p value mean hb in g/dl 8.08 ± 1.88 9.83 ± 1.50 <0.05 mean weight in kg 16.5 ± 9.54 21.08 ± 10.18 <0.01 mean height in cm 112.67 ± 22.21 116.33 ± 21.79 <0.01 oral thrush patients at diagnosis after therapy p value mean hb in g/dl 5.9 ± 0.93 8.45 ± 0.70 <0.05 mean weight in kg 11 ± 6.48 16.3 ± 6.54 >0.05 mean height in cm 102 ± 25.39 106 ± 23.51 <0.05 cd4 = cluster of differentiation 4; hb = haemoglobin. opportunistic infections and complications in human immunodeficiency virus-1-infected children correlation with immune status e518 | squ medical journal, november 2014, volume 14, issue 4 height-for-age above the 50th percentile, while none of the patients had a weight-for-age above the 50th percentile. these results are similar to those found among other studies based in india, with lodha et al. describing growth failure among all of the observed paediatric hiv-infected patients (n = 27) in their study and shah reporting weight loss and failure to thrive in 35.6% out of 317 children with hiv infections.13,14 in this study, fever, anorexia and weakness were the most commonly observed symptoms, followed by weight loss/failure to thrive. furthermore, a sizeable percentage of the patients had persistent diarrhoea and a cough at the time of presentation. similar manifestations of hiv infection have also been reported elsewhere in india. verghese et al. studied the clinical manifestations of hiv infection among 88 children and reported hepatomegaly in 72%, lymphadenopathy in 60%, splenomegaly in 43%, failure to thrive in 58%, recurrent diarrhoea in 36%, m. contagiosum in 4% and pulmonary tuberculosis in 14%.15 dhurat et al. noted non-specific presenting symptoms in 41 children with perinatally transmitted table 5: distribution of opportunistic infections or complications observed among human immunodeficiency virus1-infected children by mean age at presentation and immunological indicators (n = 20) opportunistic infection/complication n mean age in months mean total lymphocyte count in mm3 mean cd4 count in mm3 (range) mean cd4 percentage (range) tuberculosis 6 78 ± 42.76 3,391 ± 2,535 333 ± 302 (21–839) 9.2 ± 6.88 (2.9–21.4) oral thrush 4 60.2 ± 48.91 3,041 ± 1,680 541 ± 296 (98–716) 17.46 ± 3.82 (14.1–21.78) persistent diarrhoea 3 88.33 ± 66.6 3,765 ± 880 521 ± 406 (171–967) 15.76 ± 15.71 (4.4–33.7) bacteremia 3 72 ± 54.99 2,481 ± 2,002 356 ± 280 (98–654) 14.4 ± 0.30 (14.1–14.7 meningitis 2 66 ± 42.42 2,171 ± 612 295 ± 9.19 (289–302) 14.10 ± 3.53 (11.6–16.6) hiv encephalopathy 2 91 ± 76.36 3,605 ± 1,391 3,322 ± 178 (206–458) 11.24 ± 1.78 (9.98–12.5) disseminated cmv 1 4 467 19 4 systemic thrush 1 96 3,268 510 15.6 cd4 = cluster of differentiation 4; cmv = cytomegalovirus. table 6: distribution of various opportunistic infections or complications among human immunodeficiency virus-1infected children in relation to clinical markers of immune status (n = 20) opportunistic infection/ complication cd4 count <200 cells/mm3 cd4 count >200 cells/mm3 cd4 percentage <20% cd4 percentage >20% tuberculosis yes 2 4 4 2 no 4 10 4 10 thrush yes 1 1 no 6 13 7 12 oral thrush yes 1 3 2 2 no 5 11 6 10 persistent diarrhoea yes 1 2 2 1 no 5 12 6 11 bacteremia yes 1 2 3 0 no 5 12 5 12 hiv encephalopathy yes 0 2 2 0 no 6 12 6 12 meningitis yes 0 2 2 0 no 6 12 6 12 disseminated cmv yes 1 1 cd4 = cluster of differentiation 4; cmv = cytomegalovirus. jaivinder yadav, sanjeev nanda and deepak sharma clinical and basic research | e519 hiv, such as tuberculosis (67.5%), failure to thrive (48.6%), hepatomegaly (51.9%), splenomegaly (48.6%), lymphadenopathy (35%), recurrent fever (29.3%) and diarrhoea (27.2%).16 among 58 hiv-infected children, madhivanan et al. reported the following manifestations: oral thrush (43%), tuberculosis (43%), hepatosplenomegaly (14%), lymphadenopathy (14%), papulopruritic dermatitis (10%) and chronic diarrhoea (7%).17 these manifestations and infections have a very high incidence in aids patients and it is advisable that paediatric patients presenting with one or more of these conditions be evaluated for the syndrome. among the patient population of the current study, significant increases in mean hb, weight and height were noted by the end of the study, following treatment with haart. consequently, it can be inferred that the combined treatment of opportunistic infections and haart significantly improved the patients’ clinical outcomes. similar results were reported in studies conducted by puthanakit et al. in thailand and wamalwa et al. in kenya.18,19 additionally, there was a significant increase in the mean total lymphocyte count, cd4 count and cd4 percentage after the sixmonth follow-up and treatment period of the current study. puthanakit et al. identified that mean cd4 percentage increased to 21%, from a baseline of 3%, while cd4 count increased from 126 to 532 cells/mm3 after 72 weeks of haart.18 wamalwa et al. and pensi also recorded significant increases in cd4 count after their patients underwent antiretroviral therapy.19,20 the hiv-infected children in the present study were categorised into four clinical stages using the who criteria.10 there was a statistically significant (p <0.05) change in clinical stage after six months of therapy. several studies have reported comparable improvements in clinical stage after antiretroviral therapy.20,21 the change in immunological classifications for the current patient population after six months of therapy was also found to be statistically significant. this indicates that an immunological improvement is seen in hiv-infected children after treatment with haart. similar results were reported by natu et al. while studying the effectiveness of haart in relation to cdc immunological classifications.21 in the present study, the predominant opportunistic infections were tuberculosis and oral thrush. van dyke reported that the most common opportunistic infections among children with hiv included serious bacterial infections (pneumonia and bacteremia), pneumocystis pneumonia, tuberculosis, non-tuberculous mycobacterial infections and cmv.22 tuberculosis was the most commonly occurring opportunistic infection in indian children in two separate studies.14,17 balkhair et al. found that pneumocystis jiroveci pneumonia was the most frequently observed opportunistic infection among their study population, followed by cryptococcal meningitis, cmv retinitis, disseminated tuberculosis and cerebral toxoplasmosis.23 among the studied hiv-infected paediatric population, 30% had a cd4 count <200 cells/mm3 and 40% had a cd4 percentage <20% upon diagnosis of an opportunistic infection. the swiss hiv cohort study reported that the risk of developing opportunistic infections is increased by 2.5 if the cd4 count is between 51–200 cells/mm3; this risk increases to 5.8 for counts <50 cells/mm3 in comparison to those >200 cells/mm3.24 various studies have demonstrated that lower cd4 counts are associated with an increased prevalence of opportunistic infections.13,25,26 while these infections can occur at any cd4 count, the severity and frequency of opportunistic infections increases when the count falls below 200 cells/mm3. the organisms responsible for causing opportunistic infections also differ with changes in immune status. a hierarchy of severity can therefore be proposed for opportunistic infections in relation to cd4 values as follows: oral thrush <tuberculosis <disseminated cmv infection. the mean cd4 count and percentage among tuberculosis patients at the time of diagnosis was 333 cells/mm3 and 9.2%, respectively, while for the patients with oral thrush it was 541 cells/mm3 and 17.46%, respectively. similar results were found by laufer et al. and shah.14,27 the swiss hiv cohort study found a median cd4 count of 6 cells/mm3 in patients newly-diagnosed with tuberculosis, while those with a diagnosis of cmv had a median cd4 count of 28 cells/ mm3.24 the above studies reported a variety of cd4 counts and percentages upon diagnosis of different opportunistic infections. this makes it difficult to define specific cd4 count cut-off values for different opportunistic infections. individual opportunistic infections were analysed separately for changes to the patients’ immunological and clinical profiles after six months of haart and treatments for the relevant opportunistic infection. all of the studied patients experienced a gain in both weight and height along with an increase in their cd4 count. guillén et al. reported that there was a significant decrease in hiv-related complications (infectious as well as non-infectious) among their study population after the introduction of haart.28 the authors also found that patients who benefited from haart had higher cd4 counts than those who had not yet been treated; furthermore, those who were not treated with haart had a 2.77% incidence of wasting syndrome, opportunistic infections and complications in human immunodeficiency virus-1-infected children correlation with immune status e520 | squ medical journal, november 2014, volume 14, issue 4 compared to an incidence of only 0.24% among those who underwent the treatment.28 similar results were found by puthanakit et al.18 all but one of the patients in the current study were prescribed haart and the vast majority (95%) of these children were compliant with the treatment requirements. nischal et al. suggested that the minimum adherence to art should be 95%.29 as with the present study, minor skin rashes have been observed on some patients during the first two weeks of treatment with nevirapine, which then subsided completely.30 in the same cohort, one child developed pancreatitis while on haart, which improved with conservative management. no other significant sideeffects were noticed.30 in developing countries like india, it is common for paediatric patients without hiv infections to present with certain health concerns, including a failure to thrive, severe acute malnutrition, lower respiratory infections and gastrointestinal problems (such as recurrent diarrhoea). unfortunately, these symptoms are also frequently seen among children with hiv infections. these overlapping symptoms make it difficult to ensure an early diagnosis of hiv, often leading to a delay in the start of treatment. this raises a dilemma as to whether all children presenting with such complaints should be screened for hiv. nevertheless, it is prudent to conduct an hiv screening for children presenting with severe malnutrition, recurrent or persistent diarrhoea, recurrent pneumonia, disseminated tuberculosis (like tubercular meningitis) or pulmonary tuberculosis. consequently, this will allow the early allocation of treatment and significantly improve patient outcomes. these findings should be interpreted with caution as the study was subject to certain limitations, including the relatively small sample size and the short duration of follow-up. further studies of longer duration and with a larger cohort are recommended. conclusion among 20 hiv-infected children, increased hb, weight, height and cd4 cell counts were observed following six months of treatment with haart. improvements in clinical stage and immunological status were also observed among the patients. the most frequently noted opportunistic infections were tuberculosis followed by oral thrush. the severity and frequency of opportunistic infections increased with a decrease in the cd4 count. treatment of opportunistic infections, in addition to haart, led to both clinical and immunological recovery, as well as a decreased incidence of future opportunistic infections. these findings indicate that healthcare professionals may be able to use a patient’s cd4 count as one of the first indications of their immunological status, in association with an understanding of the opportunistic infection in question. the cd4 count could also potentially be used as a biological marker of haart efficacy. however, compliance to haart must be ensured as it is a key factor in achieving optimal results from this type of treatment. c o n f l i c t o f i n t e r e s t the authors report no conflicts of interest. no funding was received during the completion of this study. references 1. malkani m. pediatric hiv disease. in: parthasarathy a, menon psn, eds. iap textbook of pediatrics. 4th ed. new delhi, india: jaypee brothers medical publishers ltd., 2009. pp. 414–18. 2. unaids. aids epidemic update: december 2007. from: www.data.unaids.org/pub/epislides/2007/2007_epiupdate_ en.pdf accessed: aug 2014. 3. newell ml, peckham cs. hiv infection in europe. in: pizzo p, wilfert cm, eds. pediatric aids: the challenge of hiv infection in infants, children, and adolescents. 2nd ed. baltimore, maryland, usa; lippincott william & wilkins, 1994. pp. 21–30. 4. merchant rh, oswal js, bhagwat v, karkare j. clinical profile of hiv infection. indian pediatr 2001; 38:239–46. 5. rogers mf, caldwell mb, gwinn ml, simonds rj. epidemiology of pediatric human immunodeficiency virus infection in the united states. acta pediatr suppl 1994; 400:5–7. doi: 10.1111/ j.1651-2227.1994.tb13324.x. 6. yogev r, chadwick eg. acquired immunodeficiency syndrome (human immunodeficiency virus). in: kliegman rm, behrman re, jenson hb, stanton bf, eds. nelson textbook of pediatrics. 18th ed. philadelphia, pennsylvania, usa: elsevier saunders, 2007. pp. 1427–42. 7. national aids control organisation. guidelines for hiv care and treatment in infants and children. from: www.naco.gov. in/upload/policies%20&%20guidelines/4-%20guidelines%20 for%20hiv%20care%20and%20treatment%20in%20infants%20 and%20children.pdf accessed: aug 2014. 8. world health organization. antiretroviral therapy of hiv infection in infants and children in resource limited settings: towards universal access recommendations for a public health approach, 2006. from: www.who.int/hiv/pub/guidelines/ whopaediatric.pdf accessed: feb 2014. 9. bhargava a, singh dk, rai r. sero-prevalence of viral coinfections in hiv infected children of northern india. indian j pediatr 2009; 76:917–9. doi: 10.1007/s12098-009-0142-x. 10. world health organization. who case definitions of hiv for surveillance and revised clinical staging and immunological classification of hiv-related disease in adults and children. from: www.who.int/hiv/pub/guidelines/hivstaging150307.pdf accessed: jan 2014. 11. mantan m, bagga a. nutrition and nutritional disorders. in: kabra sk, srivastava sn, eds. pediatrics: a concise text. new delhi, india: reed elsevier private ltd., 2011. pp. 47–60. 12. centers for disease control and prevention. growth charts. from: www.cdc.gov/growthcharts/ accessed: apr 2014. jaivinder yadav, sanjeev nanda and deepak sharma clinical and basic research | e521 13. lodha r, singhal t, jain y, kabra sk, seth p, seth v. pediatric hiv infection in tertiary care center in north india: early impression. indian pediatr 2000; 37:982–6. 14. shah i. age related clinical manifestations of hiv infection in indian children. j trop pediatr 2005; 51:300–3. doi: 10.1093/ tropej/fmi018. 15. verghese vp, cherian t, cherian aj, babu pg, john tj, kirubakaran c, et al. clinical manifestations of hiv-1 infection. indian pediatr 2002; 39:57–63. 16. dhurat r, manglani m, sharma r, shah nk. clinical spectrum of hiv infection. indian pediatr 2000; 37:831–6. 17. madhivanan p, mothi sn, kumarasamy k, yepthomi t, venkatesan c, lambert js, et al. clinical manifestations of hiv infected children. indian j pediatr 2003; 70:615–21. doi: 10.1007/bf02724249. 18. puthanakit t, oberdorfer a, akarathum n, kanjanavanit s, wannarit p, sirisanthana t, et al. efficacy of highly active antiretroviral therapy in hiv-infected children participating in thailand’s national access to antiretroviral program. clin infect dis 2005; 41:100–7. doi: 10.1086/430714. 19. wamalwa dc, farquhar c, obimbo em, selig s, mboringacha da, richardson ba, et al. early response to highly active antiretroviral therapy in hiv-1-infected kenyan children. j acquir immun defic syndr 2007; 45:311–17. doi: 10.1097/qai.0b013e318042d613. 20. pensi t. fixed dose combination of lamivudine, stavudine and nevirapine in the treatment of pediatric hiv infection: a preliminary report. indian pediatr 2007; 44:519–21. 21. natu sa, daga sr. antiretroviral therapy in children: indian experience. indian pediatr 2007; 44:339–43. 22. van dyke rb. opportunistic infections in pediatric hiv disease. ann n y acad sci 1993; 693:158–65. 23. balkhair aa, al-muharrmi zk, ganguly s, al-jabri aa. spectrum of aids defining opportunistic infections in a series of 77 hospitalised hiv-infected omani patients. sultan qaboos univ med j 2012; 12:442–8. 24. ledergerber b, egger m, erard v, weber r, hirschel b, furrer h, et al. aids-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the swiss hiv cohort study. jama 1999; 282:2220–6. doi: 10.1001/ jama.282.23.2220. 25. moore rd, chaisson re. natural history of opportunistic disease in an hiv-infected urban clinical cohort. ann intern med 1996; 124:633–42. doi: 10.7326/0003-4819-124-7-19960 4010-00003. 26. agarwal d, chakravarty j, sundar s, gupta v, bhatia bd. correlation between clinical features and degree of immunosuppression in hiv infected children. indian pediatr 2008; 45:140–3. 27. laufer mk, van oosterhout jj, perez ma, kanyanganlika j, taylor te, plowe cv, et al. observational cohort study of hivinfected african children. pediatr infect dis j 2006; 25:623–7. doi: 10.1097/01.inf.0000220264.45692.a0. 28. guillén s, garcía san miguel l, resino s, bellón jm, gonzález i, jiménez de ory s, et al. opportunistic infections and organspecific diseases in hiv-1-infected children: a cohort study (1990-2006). hiv med 2010; 11:245–52. doi: 10.1111/j.14681293.2009.00768.x. 29. nischal kc, khopkar u, saple dg. improving adherence to antiretroviral therapy. indian j dermatol venereol leprol 2005; 71:316–20. doi: 10.4103/0378-6323.16780. 30. lodha r, upadhyay a, kabra sk. antiretroviral therapy in hiv-1 infected children. indian pediatr 2005; 42:789–96. 1department of dermatology, alcalá la real high resolution hospital, jaén, spain; 2department of dermatology, university hospital complex of granada, granada, spain *corresponding author e-mail: gonzaloblascomorente@gmail.com فحص تألقي بلون أمحر مرجاين لرتسبات الوذح اجللدي غونزالو بال�صكو-مورينتى، �صلفادور اأريا�ض-�صانتياغو، اإ�رضائيل برييز-لوبيز، اأنطونيو مارتينيز-لوبيز coral-red fluorescence of erythrasma plaque *gonzalo blasco-morente,1 salvador arias-santiago,2 israel pérez-lópez,2 antonio martínez-lópez2 a 50-year-old man presented to the department of dermatology, university hospital complex of granada, granada, spain, in 2015 with a slightly pruritic rash on the left groin, which he had had for two years. he had attended the hospital previously and been diagnosed with eczema and tinea cruris. this had been treated with topical steroids and antifungal drugs (methylprednisolone and sertaconazole) for several months without improvement. a physical examination of the patient showed a diffuse, brownish, well-defined, scaly plaque in the left inguinal region [figure 1a]. a potassium hydroxide preparation of tissue scrapings was negative for fungal elements or cultures. the coralred fluorescence of the plaque under a wood’s lamp (wl) examination was characteristic of erythrasma [figure 1b]. the patient was treated with 500 mg of oral erythromycin every 12 hours for 14 days, with progressive healing observed over three weeks. comment erythrasma is a localised and chronic skin infection caused by corynebacterium minutissimum.1–3 it appears as patches that are either asymptomatic and well-defined or irregular in shape and size and red/ brown in colour.3–5 the diagnosis is usually clinical, but a wl examination can show characteristic fluorescence due to coproporphyrin iii produced by the bacteria.2,3 the wl emits ultraviolet a radiation with figure 1a & b: a: diffuse, brownish, well-defined, scaly plaque in the left inguinal region of a 50-year-old man. note the ‘cigarette paper’ appearance. b: wood’s light skin examination of the plaque showing bright coral-red fluorescence characteristic of erythrasma. interesting medical image sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e381–382, epub. 19 aug 16 submitted 10 jan 16 revision req. 1 feb 16; revision recd. 1 mar 16 accepted 13 mar 16 doi: 10.18295/squmj.2016.16.03.023 coral-red fluorescence of erythrasma plaque e382 | squ medical journal, august 2016, volume 16, issue 3 references 1. klatte jl, van der beek n, kemperman pm. 100 years of wood’s lamp revised. j eur acad dermatol venereol 2015; 29:842–7. doi: 10.1111/jdv.12860. 2. blasco morente g, martínez peinado c, martínez garcía e, tercedor sánchez j. [wood’s lamp in congenital erythropoietic porphyria]. an pediatr (barc) 2014; 81:403–4. doi: 10.1016/j. anpedi.2014.01.005. 3. wilson bb, wagenseller a, noland mm. an atypical presentation of erythrasma. j am acad dermatol 2012; 67:e217–18. doi: 10.1016/j.jaad.2012.04.004. 4. chodkiewicz hm, cohen pr. erythrasma: successful treatment after single-dose clarithromycin. int j dermatol 2013; 52:516–18. doi: 10.1111/j.1365-4632.2011.05005.x. 5. holdiness mr. erythrasma and common bacterial skin infections. am fam physician 2003; 67:254. wavelengths between 320–400 nm and is useful in the diagnosis of disorders of pigmentation, skin infections (such as erythrasma) and porphyrias.2 however, microscopic examinations (e.g. gram staining of an epidermis scraping to reveal gram-positive filaments and rods) and cultures on different types of media (e.g. 20% fetal bovine serum, 2% agar and 78% tissue culture medium #199) may be required in certain cases.4,5 a potassium hydroxide preparation of tissue scrapings can rule out concomitant infections, especially in patients with interdigital involvement.4 the differential diagnosis of erythrasma includes candidiasis, psoriasis and dermatophytosis.1–5 the most effective treatment is 500 mg of erythromycin twice daily for 14 days, with cure rates as high as 100%; however, other treatments with topical antibiotics and antifungals have also demonstrated good responses.1–5 http://dx.doi.org/10.1111/jdv.12860 http://dx.doi.org/10.1016/j.anpedi.2014.01.005 http://dx.doi.org/10.1016/j.anpedi.2014.01.005 http://dx.doi.org/10.1016/j.jaad.2012.04.004 http://dx.doi.org/10.1111/j.1365-4632.2011.05005.x sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e213–217, epub. 28 may 15 submitted 3 jul 14 revisions req. 10 aug & 21 oct 14; revisions recd. 28 sep & 9 nov 14 accepted 4 dec 14 in many parts of the world, prior tothe introduction of modern healthcare and social and economic improvements, vulnerable children were often prone to an early death.1 more recently, countries such as oman have witnessed a dramatic decline in child mortality. out of 230 countries, oman is ranked 48th in the global population growth rate with a demographic profile characterised by a younger population; 44.7% of the population is under the age of 20 years.2 population growth means that the number of people afflicted by cognitive, emotional and social deficits is likely to be on the rise. furthermore, oman’s population is characterised by large family sizes and a preponderance of consanguineous marriages.3,4 the latter is thought to trigger many developmental anomalies, including those that are likely to cause social and intellectual disabilities.4 autism spectrum disorders (asd) encompass five pervasive developmental disorders that are characterised by impairments in social interaction, impediments in communication skills and behavioural and emotional problems.3 according to the available nomenclature, diagnoses of asd are only made if symptoms are persistent and pervasive prior to the departments of 1genetics, 2family medicine & public health, 3behavioural medicine and 5obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university; 4department of food science & nutrition, college of agricultural & marine sciences, sultan qaboos university, muscat, oman; 6vice dean for clinical affairs, oman medical college, sohar, oman *corresponding author e-mail: aouhtit@squ.edu.om العوامل الكامنة وراء اخنفاض معدل انتشار طيف اضطراب التوحد يف ُعمان منظور اجتماعي وثقايف عالل اوهتيت، يحيى الفار�سي، مروان ال�رشبتي، م�سطفى وايل، اي�سيتا غوبتا، عمر الفار�سي، مها اخل�سورية، حممدال�سافعي، �سمري العدوي abstract: epidemiological surveys from various countries indicate an increased prevalence of autism spectrum disorders (asd), leading researchers to debate whether there are now ‘more affected’ or ‘more detected’. the epidemiology of asd in developing countries, such as oman, has generally indicated a lower prevalence compared to developed countries in the west. in oman, the prevalence is low; however, this article highlights some of the factors that could contribute to the appearance of a low asd rate: cross-cultural variations in the presentation of distress; a lack of reliable biological markers for diagnosing asd, and a lack of health services for children with asd, thus limiting the number of participants in epidemiological surveys. while the defining features of asd have yet to be established, pilot studies in oman indicate a substantial number of children with these disorders. therefore, it is important that these discrepancies be addressed and the need for appropriate services for this patient population in oman be highlighted. keywords: autism; prevalence; culture; oman. اذهان يف ت�ساوؤال يطرح مما التوحد، طيف ا�سطرابات انت�سار زيادة اإىل البلدان خمتلف من الوبائي امل�سح درا�سات اأ�سارت امللخ�ص: الباحثني حول ما اإذا كان ذلك ناجتا عن زيادة معدل حدوث اال�سطراب، اأم زيادة الك�سف عنه. اأظهرت الدرا�سات الوبائية يف البلدان النامية، مثل ُعمان، قلة انت�سار ا�سطراب التوحد باملقارنة مع الدول املتقدمة يف الغرب. هذا املقال ي�سلط ال�سوء على بع�ض العوامل التي ميكن اأن ت�سهم يف ظهور ذلك املعدل املنخف�ض؛ االختالفات بني الثقافات يف عر�ض ال�سدة، عدم وجود ’’عالمات بيولوجية‘‘ ميكن االعتماد عليها لت�سخي�ض اال�سطراب، وعدم وجود اخلدمات ال�سحية لالأطفال امل�سابني باال�سطراب، مما يحّد من عدد امل�ساركني يف درا�سات امل�سح الوبائي. يف حني مل يتم بعد تاأ�سي�ض ال�سمات املميزة لالأ�سطراب، اأظهرت الدرا�سات التجريبية يف ُعمان وجود عدد كبري من االأطفال الذين يعانون من هذه اال�سطرابات. ولذلك نرى من االأهمية مبكان اأن يتم االلتفات اىل هذه التناق�سات، واحلاجة اإىل تقدمي اخلدمات املنا�سبة لهذه الفئة من املر�سى يف ُعمان. مفتاح الكلمات: التوحد؛ انت�سار؛ الثقافة؛ عمان. sounding board underlying factors behind the low prevalence of autism spectrum disorders in oman sociocultural perspective *allal ouhtit,1 yahya al-farsi,2 marwan al-sharbati,3 mostafa waly,4 ishita gupta,1 omar al-farsi,2 maha al-khaduri,5 mohammed al-shafaee,2,6 samir al-adawi3 underlying factors behind the low prevalence of autism spectrum disorders in oman sociocultural perspective e214 | squ medical journal, may 2015, volume 15, issue 2 age of three years old.5 while autism-like conditions may have always existed,3 autism has only recently been featured in diagnostic nomenclatures such as the diagnostic and statistical manual of mental disorders (dsm).6 according to a review on the history of ideas surrounding autism, a child with symptoms akin to autism was previously perceived as a “soulless mass of flesh possessed by the devil”.5 as with any condition that is culturally devalued, the societal perception of children with autism is often akin to ‘madness’ and demonic possession.7 in recent history, various studies have explored the ignorance (knowledge), prejudice (attitude) and discrimination (behaviour) of the general public towards those with autism.8 many studies have indicated that the general public regard children with autism as less affable.9 however, those who have previously had contact with autism sufferers—such as family members or those who provide them with social, education or medical care—have a less pervasively negative attitude towards such children.9 on the whole, attitudes towards any culturally-devalued condition tends to be greatly influenced by the prevailing zeitgeist.8 despite the increased awareness that autism is marked by both maladaptive behaviour as well as proficiency, there is little evidence that the concept of autism has not suffered effects of the ‘euphemism treadmill’ as in the case of those with marked intellectual disabilities.8 although it has been widely broadcast that asd, like other neurodevelopmental disorders, are debilitating and impervious to available medical interventions,10 there is a strong indication that early diagnosis, coupled with early intervention, can be good prognostic indicators.11 against such a background, the focus has been on lessening the associated impairments and disabilities of those with asd while improving their quality of life and facilitating functional independence and psychosocial skills.10,12 this means that early recognition is essential, if not paramount, in order to safeguard the path of such children to a meaningful and comfortable future. furthermore, in order to improve the educational, social and medical remedial services for these children, it is essential to quantify the magnitude of the problem in order to allocate appropriate resources. it is well known that an incentive for establishing services for those affected by asd will stem from the recognition that there is an increasing number of children with asd in oman. thus, quantifying the rate of asd in the community is crucial for ensuring the welfare of this patient population. the aim of the present discourse, therefore, is to highlight some of the factors that could contribute to a lower prevalence of asd in oman. prevalence of autism spectrum disorders asd constitute a global challenge as it appears that a proportion of children in all societies will be affected by these disorders in the future.13 in a recent systematic review of asd epidemiological surveys conducted in various parts of the world, it was estimated that the worldwide prevalence was 77/10,000.13,14 the review also noted both an increasing prevalence as well as variations among different populations.14 without making a blanket generalisation, most studies from emerging-economy countries have reported prevalence estimates that, with a few exceptions,15 are skewed towards the lower limit.16 the prevalence of asd in oman was estimated to be 1.4 cases per 10,000 0–14-year-old children.16 on the other hand, in saudi arabia, the prevalence of autism was 18 per 10,000 children,17 while in the united arab emirates, from a representative random sample of three-year-old emirati children, 29 per 10,000 children had autism.18 in libya, of 38,508 children who attended a paediatric clinic in tripoli, 128 children were autistic, thus giving a prevalence of one in 300.19 furthermore, in egypt and tunisia, the autism frequency rate among children with developmental disorders was documented as 33.6% and 11.5%, respectively.20 it appears that there is a wide discrepancy in the magnitude of asd, even among countries with similar sociocultural characteristics; therefore, it is essential to discuss factors that may have contributed to such variations. potential factors underlying the low prevalence of autism in oman compared to the international trend, an asd prevalence of 1.4 cases per 10,000 in oman would likely convince policymakers that oman has been spared the global ‘epidemic’ of asd. although differing study methodologies could have led to this variability, other factors may have significantly contributed to the lower prevalence of autism in oman. these are summarised in the following sections. c r o s s-c u lt u r a l va r i at i o n s studies from populations outside of north america and western europe have indicated that some of the core symptoms of asd do not mimic the asd symptoms linked to african populations.21,22 this suggests that there are cultural variations in the expression of asd. a study carried out in sub-saharan africa demonstrated that there was a lack of non-verbal aspects within the expressive language of predominantly suballal ouhtit, yahya al-farsi, marwan al-sharbati, mostafa waly, ishita gupta, omar al-farsi, maha al-khaduri, mohammed al-shafaee and samir al-adawi sounding board | e215 saharan children diagnosed with asd.23 this means, as has been shown in other psychiatric conditions, that distress, disability or illness are often expressed within sociocultural contexts.23 it has been wellestablished that applying euro-american expectations of human nature to people in other parts of the world constitutes a ‘category of fallacy’ or, simply put, like using the same yardstick to measure two different situations.21 this is an example of the pan-human predisposition to neurogenetic determinism that is often applied to such developmental disorders. the argument that asd should display a similar degree of prevalence worldwide stems from the misconception that these disorders are rooted in biology.24 another view is that the phenotypical features of asd stem from pathoplastic cultural factors and individual idiosyncrasies.25 therefore, the high variability of the rate of asd in different populations suggests that both sociocultural and ecological factors play a substantial role in shaping the features of asd, while existing evidence points to complex interactions between the nature versus nurture dichotomy.26 r e l i a b i l i t y o f d i a g n o s t i c t o o l s diagnosing asd is challenging as there are no biochemical tests or neuro-imaging techniques that can be reliably employed to establish the presence of autism. there are, however, many symptom checklists that are largely accepted as accurate in ensuring improved diagnoses of asd.27 one important point about these available checklists is their tendency not to detect higher-functioning individuals with autism, as opposed to moderate and severe cases.24 in such cases, the experience and skills of the clinician are the sole influential factors in determining the accuracy of the diagnosis. there is a dearth of studies examining the psychometric properties of these symptom checklists.28,29 it is possible, therefore, that there is be a conceptual issue in adopting verbal or nonverbal scales from euro-american populations for cross-cultural populations. this issue is relevant for studies examining the epidemiology of asd. related to this, estimating the ‘true’ prevalence of asd is likely to be hampered by the fact that the ‘true’ signs and symptoms of asd may be submerged by their resemblance to other childhood conditions. the very fact that some of the hallmark symptoms of asd are without central features means that diagnoses of asd are often confused with mental retardation. the difficulty of distinguishing between ‘true’ mental retardation and asd is compounded by the fact that a significant number of children with autism are also likely to have mental retardation.17 similarly, many psychiatric disorders have been reported as the ‘twin sisters’ of asd, including social anxiety disorder, oppositional defiant disorder, childhood-onset schizophrenia and social communication disorder, as well as those child disorders characterised by inattention and hyperactivity.15,16 one way to circumvent such a problem is to establish a genetic marker for asd. as yet, identifying a genetic signature for asd has remained an elusive search. most experts agree that biological markers for autism are likely to owe their origin to spontaneous mutation.16 therefore, without a validated genotype, diagnoses of asd often hinge on a phenotypical presentation such as the symptom checklist which is featured in some of the common nomenclatures, including the dsm and the international statistical classification of diseases (icd). it is worth noting that some critics have indicated that both dsm and icd fail to recognise that disease, distress and disability is often expressed in a sociocultural context. in the available literature, there is a lack of discussion on how sociocultural context may shape the ‘content’ of asd.30 such issues are likely to contribute to the disparity in reported rates of asd in different parts of the world. s e r v i c e m i s d i s t r i b u t i o n a n d s o c i e ta l c o p i n g ideally, appropriate developmental evaluation an early intervention by a team of dedicated multidisciplin ary professionals can aid in providing services to children with special needs. in oman, however, services for children with special needs generally do not exist or are only rudimentary. despite the fact that oman has a geographical area of 310,000 km2 and a population of 3.5 million, to date, there is only one child and adolescent mental health service unit in the country (located in a tertiary care setting in an urban area of oman).31 in the rest of the country, there are no dedicated centres for diagnosing children with developmental disorders. this is likely to contribute both to the under-diagnosis and to the under-reporting of asd cases. with no one to address affected children’s symptoms, ‘doctor-shopping’ is a common method for parents to find a ‘cure’ for their children.32 since the modern healthcare system often cannot meet their needs, alternative or traditional healing systems are filling the vacuum. there is evidence to suggest that pathways to care for people with behavioural and emotional disorders in oman are often seen as the prerogative of traditional healers.18,19 in the omani community, emotional and cognitive impairments are often perceived as a manifestation of possession underlying factors behind the low prevalence of autism spectrum disorders in oman sociocultural perspective e216 | squ medical journal, may 2015, volume 15, issue 2 by spirits or supernatural forces, such as hassad (contemptuous envy), sihr (sorcery) or the ‘evil eye’. 4,18 little documentation exists regarding the role of traditional healing processes in families caring for children with asd. in reference to other conditions, the traditional healing system tends to allay the ‘guilt’ often found among caregivers of children with intractable conditions. the family caregiver may resort to any means at their disposal to find a ‘cure’ for their autistic child. the use of traditional healers may also result from the frequent lack of mental healthcare services available in most omani communities. given this situation, it is difficult to quantify the true prevalence of children with asd in the country. conclusion in the available literature on asd in populations from north america and western europe, there is debate regarding whether the rising tide of children with asd is because there are more children affected or more cases detected others have pointed out that the recent increase may stem from a broadening of the diagnostic criteria, greater service availability and an increased awareness among both professionals and the general public. on the other hand, although conditions akin to asd have been reported in different parts of the world, including oman, the prevalence of asd varies from culture to culture. in oman, the lower reported rate of asd could be directly related to various sociocultural factors. this potential discrepancy in the prevalence rate of asd may stem from cross-cultural variations in the manifestation of behavioural and emotional disorders. if the current, apparently low prevalence in oman is in fact just a consequence of under-diagnosis and under-reporting, a concerted effort is needed to increase public awareness of asd. additionally, an attempt should be made to institute services for the welfare of such children. this would require training healthcare practitioners to provide the necessary services and remedial interventions for children with asd. a c k n o w l e d g e m e n t s this work was supported by his majesty’s strategic research fund (sr/med/fmco/11/01), at the college of medicine & health sciences, sultan qaboos university, muscat, oman. references 1. fink g, günther i, hill k. slum residence and child health in developing countries. demography 2014; 51:1175–97. doi: 10.1007/s13524-014-0302-0. 2. al-sinawi h, al-alawi m, al-lawati r, al-harrasi a, alshafaee m, al-adawi s. emerging burden of frail young and elderly persons in oman: for whom the bell tolls? sultan qaboos univ med j 2012; 12:169–76. 3. shi l, zhang x, golhar r, otieno fg, he m, hou c, et al. whole-genome sequencing in an autism multiplex family. mol autism 2013; 4:8. doi: 10.1186/2040-2392-4-8. 4. al-farsi y, waly mi, al-sharbati mm, al-shafaee m, al-farsi o, al-fahdi s, et al. variation in socio-economic burden for caring of children with autism spectrum disorder in oman: caregiver perspectives. j autism dev disord 2013; 43:1214–21. doi: 10.1007/s10803-012-1667-9. 5. wing l. the history of ideas on autism: legends, myths and reality. autism 1997; 1:13–23. doi: 10.1177/1362361397011004. 6. american psychiatric association. diagnostic and statistical manual of mental disorders. 5th ed. arlington, virginia, usa: american psychiatric association, 2013. 7. waltz m. from changelings to crystal children: an examination of ‘new age’ ideas about autism. j religion disabil health 2009; 13:114–28. doi: 10.1080/15228960802581511. 8. durand-zaleski i, scott j, rouillon f, leboyer m. a first national survey of knowledge, attitudes and behaviours towards schizophrenia, bipolar disorders and autism in france. bmc psychiatry 2012; 12:128. doi: 10.1186/1471-244x-12-128. 9. wright rh, cummings na, eds. destructive trends in mental health: the well intentioned path to harm. new york, usa: routledge, 2005. 10. myers sm, johnson cp; american academy of pediatrics council on children with disabilities. management of children with autism spectrum disorders. pediatrics 2007; 120:1162–82. doi: 10.1542/peds.2007-2362. 11. boyse k. autism, autistic spectrum disorders (asd) and pervasive developmental disorders (pdd). from: www.med. umich.edu/yourchild/topics/autism.htm accessed: jun 2014. 12. seida jk, ospina mb, karkhaneh m, hartling l, smith v, clark b. systematic reviews of psychosocial interventions for autism: an umbrella review. dev med child neurol 2009; 51:95–104. doi: 10.1111/j.1469-8749.2008.03211.x. 13. elsabbagh m, divan g, koh yj, kim ys, kauchali s, marcín c, et al. global prevalence of autism and other pervasive developmental disorders. autism res 2012; 5:160–79. doi: 10.1002/aur.239. 14. insel t; national institute of mental health. director’s blog: autism prevalence: more affected or more detected? from: www.nimh.nih.gov/about/director/2012/autism-prevalencemore-affected-or-more-detected.shtml accessed: jun 2014. 15. al-sharbati m, al-farsi ym, al-sharbati zm, ouhtit a, waly mi, al-khaduri mm, et al. autistic spectrum disorder (asd) among omani children below 6 years: a five-year retrospective descriptive study. from: imfar.confex.com/imfar/2012/ webprogram/paper10828.html accessed: jun 2014. 16. simonoff e, pickles a, charman t, chandler s, loucas t, baird g. psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. j am acad child adolesc psychiatry 2008; 47:921–9. doi: 10.1097/chi.0b013e318179964f. 17. al-sharbati mm, al-farsi ym, ouhtit a, waly mi, al-shafaee m, al-farsi o, et al. awareness about autism among school teachers in oman: a cross-sectional study. autism 2015; 19:6– 13. doi: 10.1177/1362361313508025. 18. al-adawi s, al-busaidi z, al-adawi s, burke dt. families coping with disability due to brain injury in oman: attribution to belief in spirit infestation and ensorcellment. sage open 2012; 3:1–8. doi: 10.1177/2158244012457400. 19. al-mandhari a, al-adawi s, al-zakwani i, al-shafaee m, eloul l. relatives’ advice and health care-seeking behaviour in oman. sultan qaboos univ med j 2009; 9:264–71. allal ouhtit, yahya al-farsi, marwan al-sharbati, mostafa waly, ishita gupta, omar al-farsi, maha al-khaduri, mohammed al-shafaee and samir al-adawi sounding board | e217 20. zeglam am, maouna a. is there a need for a focused health care service for children with autistic spectrum disorders? a keyhole look at this problem in tripoli, libya. autism 2012; 16:337–9. doi: 10.1177/1362361310393535. 21. belhadj a, mrad r, halayem mb. [a clinic and a paraclinic study of tunisian population of children with autism. about 63 cases.] tunis med 2006; 84:763–7. 22. seif eldin a, habib d, noufal a, farrag s, bazaid k, al-sharbati m, et al. use of m-chat for a multinational screening of young children with autism in the arab countries. int rev psychiatry 2008; 20:281–9. doi: 10.1080/09540260801990324. 23. american psychiatric association. glossary of cultural concepts of distress. diagnostic and statistical manual of mental disorders. arlington, viriginia, usa: american psychiatric association, 2013. 24. cosmides l, tooby j. evolutionary psychology: a primer. available from: www.cep.ucsb.edu/primer.html accessed: jun 2014. 25. ardhanareeswaran k, coppola g, vaccarino f. the use of stem cells to study autism spectrum disorder. yale j biol med 2015; 88:5‒16. 26. lewkowicz dj. the biological implausibility of the naturenurture dichotomy & what it means for the study of infancy. infancy 2011; 16:331–67. doi: 10.1111/j.1532-7078.2011.00079.x. 27. eloul l, ambusaidi a, al-adawi s. silent epidemic of depression in women in the middle east and north africa region: emerging tribulation or fallacy? sultan qaboos univ med j 2009; 9:5–15. 28. mcleod tcv, leach c. psychometric properties of self-report concussion scales and checklists. j athl train 2012; 47:221–3. 29. pirkis j, burgess p, kirk p, dodson s, coombs t, williamson m. a review of the psychometric properties of the health of the nation outcome scales (honos) family of measures. health qual life outcomes 2005; 3:76. doi: 10.1186/14777525-3-76. 30. zhao x, leotta a, kustanovich v, lajonchere c, geschwind dh, law k, et al. a unified genetic theory for sporadic and inherited autism. proc natl acad sci u s a 2007; 104:12831–6. doi: 10.1073/pnas.0705803104. 31. al-salehi sm, al-hifthy eh, ghazziuddin m. autism in saudi arabia: presentation, clinical correlates and comorbidity. transcult psychiatry 2009; 46:340–7. doi: 10.1177/1363461509105823. 32. nichter m. idioms of distress revisited. cult med psychiatry 2010; 34:401–16. doi: 10.1007/s11013-010-9179-6. according to the world health organization, the annual tuberculosis (tb) burden in india was 2.2 million in 2012; this figure constitutes one quarter of global tb cases per year.1 genitourinary tb is a common form of extrapulmonary tb, accounting for 27% (range: 14–41%) of all cases of extrapulmonary tb in developed countries.2 usually, genitourinary tb is a complication in 3–4% of pulmonary tb cases.3 active genitourinary tb generally occurs between five and 15 years after a primary pulmonary infection with mycobacterium tuberculosis.4 despite its status as the most common form of genitourinary tb, renal tb is very rare in the paediatric population.5 genitourinary tb mostly presents with irritative voiding symptoms, haematuria and flank pain.6 presentation as a mass lesion is extremely rare and few cases have been published in the literature to date.7–10 this report describes a two-year-old child who presented with a renal mass and was diagnosed with renal tb via a post-nephroureterectomy histopathological examination. case report a two-year-old girl presented to a private health clinic in kolkata, india, with non-specific abdominal pain of three months’ duration. as she did not improve with symptomatic management and anthelmintic therapy, she was referred to the nil ratan sircar medical college, kolkata, india, in june 2014 for further evaluation. there was no history of fever, vomiting, altered bowel habits, abdominal distension or changes in urinary frequency or colour over the preceding three months. in addition, no appetite or weight loss had been observed by the parents. the child departments of 1chest medicine and 2pathology, nil ratan sircar medical college, kolkata, india *corresponding author e-mail: dravradip@gmail.com ظهور السل الكلوي كآفة كتلة يف طفلة عمرها سنتان عرض حلالة نادرة اأفراديب �شنرتا، فالجوين مندي، اأبهي�شك ب�ندى اأوب�دي� abstract: genitourinary tuberculosis usually occurs in young adults and the middle-aged and is very uncommon in the paediatric population. it generally presents with haematuria, pyuria, irritative voiding symptoms and flank pain; presentation as a renal mass is highly unusual. we report a two-year-old girl who was referred to the nil ratan sircar medical college, kolkata, india, in june 2014 with abdominal pain. subsequent radiological investigations revealed a left renal hypoechoic mass lesion. a left nephroureterectomy was performed on suspicion of a wilms’ tumour. histopathology indicated an epithelioid granuloma with lymphocytic infiltration, suggestive of a tubercular aetiology. a mantoux tuberculin skin test was positive; however, there was no evidence of tuberculosis detected elsewhere in the body and the source of the infection could not be identified. a diagnosis of renal tuberculosis was made and the child was treated with antitubercular drugs. the patient was asymptomatic at a six-month follow-up. keywords: renal tuberculosis; urogenital tuberculosis; abdominal pain; granuloma; case report; india. امللخ�ص: ال�شل البويل التن��شلي يظهر ع�دة عند ال�شب�ب ومتو�شطى العمر وهو ن�در احلدوث عند االأطف�ل. وع�دة م� يظهرمع وجود بيلة دموية، بيلة قيحية، اأعرا�ص تهيج عند االأ�شتفراغ واأمل اخل��رضة، لكن الظهور ككتلة كلوية يعترب غري ع�دي للغ�ية. نعر�ص هن� تقرير ح�لة الفحو�ش�ت معوي. ب�أمل م�ش�بة ،2014 يونيو يف ب�لهند كلكت� يف للطب �شريك�ر رات�ن نيل كلية اإىل حتويله� مت �شنت�ن عمره� لطفلة اإل�شع�عية اأظهرت وجود كتلة آفة ن�ق�شة ال�شدى. مت ا�شت�ش�ل الكلية الي�رضى مع احل�لب وذلك ال�شتب�ه وجود ورم وملز. تقرير الت�رضيح املر�شي بني وجود حبيب ب�رضاين مع ارت�ش�ح ملف�وي يوحى مب�شبب�ت مر�شية لل�شل. ك�ن فح�ص م�نتو �شلني للجلد اإيج�بيا، لكن مل يتم العثور على وجود لل�شل يف االأجزاء االأخرى من اجل�شم وكذلك عدم التمكن من العثور على م�شدر االألته�ب. مت ت�شخي�ص احل�لة ب�ل�شل الكلوي ومت عالج الطفلة مب�ش�دات ال�شل.وك�نت الطفلة خ�لية من االأعرا�ص عند املت�بعة بعد 6 اأ�شهر. مفتاح الكلمات: ال�شل الكلوي؛ ال�شل البويل التن��شلي؛ اأمل البطن؛ حبيب؛ تقرير ح�لة؛ الهند. renal tuberculosis presenting as a mass lesion in a two-year-old girl report of a rare case *avradip santra,1 falguni mandi,1 abhishek bandyopadhyay2 case report sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e105–108, epub. 2 feb 16 submitted 20 jul 15 revision req. 26 aug 15; revision recd. 4 sep 15 accepted 17 sep 15 doi: 10.18295/squmj.2016.16.01.020 renal tuberculosis presenting as a mass lesion in a two-year-old girl report of a rare case e106 | squ medical journal, february 2016, volume 16, issue 1 however, her chest x-ray was normal and a gastric lavage was negative for m. tuberculosis. morning urine samples taken on three consecutive days were afb-negative and a urine culture was also negative for m. tuberculosis. there was no evidence of active tb on chest x-rays or afb in sputum examinations for any of the patient’s family members. an endometrial biopsy was requested from the child’s mother; however, this was not performed as she was completely asymptomatic and did not give consent for the investigation. the patient was diagnosed with renal tb based on the findings of the renal histopathology and ancillary investigations. she subsequently underwent two months of intensive phase antitubercular therapy with isoniazid, rifampicin, pyrazinamide and ethambutol, followed by four months of continuation phase therapy with isoniazid and rifampicin, as per the guidelines of the revised national tuberculosis control programme (rntcp).11 she improved symptomatically and the abdominal pain subsided within one month of beginning the treatment. by the end of the six-month antitubercular therapy, she was completely asymptomatic. at the time of writing, the patient was being followed up at regular intervals. discussion genitourinary tb is most commonly encountered between the second and fourth decade of life.3,6 this form of tb represents less than 5% of paediatric extrapulmonary cases worldwide and is very infrequently reported in the literature.12,13 chattopadhyay et al. observed only nine cases of paediatric genitourinary tb over a span of seven years among patients aged 5–12 years old.14 a case of congenital renal tb was reported in a 34-day-old infant presenting with exsanguinating haematuria.13 another report described miliary tb with focal had been delivered at full term at home and was not immunised. she had no prior significant illnesses and her developmental history was normal. there were no signs of pallor, icterus, palpable lymphadenopathy or malnutrition. an abdominal examination revealed no palpable organomegaly or tenderness. the results of routine biochemical tests and a complete haemogram were within normal ranges and the child was negative for human immunodeficiency virus infection. ultrasonography of the abdomen revealed a hypoechoic mass lesion in the left kidney along with mild hepatomegaly without any abdominal lymphadenopathy, splenomegaly or ascites. subsequently, a computed tomography scan of the abdomen was performed with intravenous and oral contrast. a well-defined hypodense space-occupying lesion (28 x 23 x 32 mm) with heterogeneous enhancement was observed at the mid-pole of the left kidney compressing the left renal pelvis [figure 1]. no other abnormalities were observed. the liver was mildly enlarged, but otherwise normal in terms of position, shape and contour. the intrahepatic biliary radicles were also normal. these findings were suggestive of a wilms’ tumour and a left nephroureterectomy was deemed necessary. following the surgery, a histopathological examination of the excised mass revealed granulomatous interstitial nephritis with central areas of caseous necrosis. an epithelioid granuloma was observed along with langhans giant cells and dense lymphoplasmacytic infiltrate with lymphoid follicle formation. the granuloma was found within the perinephric fat [figure 2]; however no evidence of acid-fast bacilli (afb) was found with ziehl-neelsen staining. a mantoux tuberculin skin test using two tuberculin units of purified protein derivative rt-23 was positive with an induration of 12 mm. the patient underwent further evaluations for congenital tb; figure 1: contrast-enhanced abdominal computed tomography scan showing a well-defined hypodense mass lesion in the left kidney of a two-year-old girl with renal tuberculosis. figure 2: haematoxylin and eosin stain at x10 magnification showing a caseating epithelioid granuloma and lymphoid follicle within the perinephric fat of a two-year-old girl with renal tuberculosis. avradip santra, falguni mandi and abhishek bandyopadhyay case report | e107 renal involvement in a five-month old male infant.15 commonly, patients with renal tb present with dysuria, haematuria, sterile pyuria, flank pain, recurrent urinary tract infections and constitutional symptoms.6,13 however, the radiographic appearance of the condition is variable and depends on the stage of infection.16 an enhancing renal mass is a rare presentation; in such cases, renal cell carcinomas, renal metastasis, lymphomas or abscesses are usually considered in the differential diagnosis.17 similarly to the present case, dhua et al. noted a well-defined hypodense renal mass in a case of renal tb.13 kumar et al. reported a pseudotumoural manifestation of genitourinary tb in a 34-year-old woman, which was initially suspected to be a renal cell carcinoma.7 a solid tubercular large mass mimicking a tumour in a horseshoe kidney has also been described in the literature.8 haematogenous dissemination from an active tb infection site usually results in the formation of metastatic tubercles in the kidney which either heal spontaneously or as a result of antitubercular therapy. renal lesions may sometimes progress during primary infection or enlarge after several years.3 in the current case, the route of infection could not be ascertained. there was no evidence of active tb elsewhere in the body or among family members. additionally, the case did not meet the revised criteria for a diagnosis of congenital tb as described by cantwell et al.18 nevertheless, it is often very difficult to differentiate congenital tb from acquired neonatal tb when the baby is infected after birth. unfortunately, a maternal endometrial biopsy could not be performed to rule out this possible source of infection. renal tb can be cured without surgical intervention; however, this requires timely diagnosis and a high degree of clinical suspicion.6 unfortunately, the tubercular aetiology of the tumour-like mass in the current case was not suspected preoperatively and early radical surgery was performed. fine-needle aspiration cytology (fnac) is a recommended diagnostic procedure to avoid surgical intervention and retain the affected kidney.7 additionally, the interferon gamma release assay (igra) test, which can detect m. tuberculosis infection anywhere in the body, is generally considered a more effective diagnostic tool than a conventional tuberculin skin test.19 however, this test was not carried out in the present case due to a lack of igra performance data in paediatric populations below five years of age.19 in addition, certain nontuberculous mycobacteria—including m. kansasii, m. szulgai and m. marinum—may produce false-positive results which could complicate the diagnostic procedure.19 short-course chemotherapy is the standard pharmacological treatment for genitourinary tb, as per the rntcp guidelines.1,2 a six-month course of category i therapy can be highly efficacious; singh et al. described positive urinary afb, mycobacterial cultures or polymerase chain reaction tests in 86.4% of genitourinary tb cases which became negative within three months of antitubercular therapy.6 nevertheless, surgery still plays an important role in genitourinary tb management despite the advent of modern antitubercular therapy. a partial nephrectomy is recommended for localised polar lesions containing calcification which fail to respond to six weeks of intensive chemotherapy or for areas of calcification which slowly increase in size and threaten to gradually destroy the entire kidney.6 complete nephrectomies are indicated only for non-functioning tubercular kidneys with calcification or for cases of extensive disease involving the whole kidney occurring with other complications (e.g. hypertension or a coexistent renal cell carcinoma).20 a minimum of four weeks of antitubercular therapy is recommended before any major surgical intervention as it stabilises the lesion and allows greater accuracy during recon structive surgery.6,21 conclusion renal tb should be considered in the differential diagnosis of a paediatric renal mass. a high degree of suspicion is warranted, especially for patients from countries with a high prevalence of tb. close family members should be thoroughly investigated in cases of suspected congenital tb to determine the source of infection. preoperative diagnosis is recommended to avoid the need for radical surgery. references 1. directorate general of health services, government of india. tb india 2014: revised national tb control programme annual status report. from: www.tbcindia.nic.in/showfile. php?lid=3142 accessed: sep 2015. 2. eastwood jb, corbishley cm, grange jm. tuberculosis and the kidney. j am soc nephrol 2001; 12:1307–14. 3. hemal ak. genitourinary tuberculosis. in: sharma sk, mohan a, eds. tuberculosis. 1st ed. new delhi, india: jaypee brothers medical publishers, 2001. pp. 325–37. 4. wallgren a. the time-table of tuberculosis. tubercle 1948; 29:245–51. doi: 10.1016/s0041-3879(48)80033-4. 5. hatzenbuehler la, starke jr. tuberculosis (mycobacterium tuberculosis). in: kliegman rm, stanton bm, st. geme j, schor nf, eds. nelson textbook of paediatrics. 20th ed. philadelphia, pennsylvania, usa: elsevier, 2015. pp. 1445–60. 6. singh jp, priyadarshi v, kundu ak, vijay mk, bera mk, pal dk. genito-urinary tuberculosis revisited: 13 years’ experience of a single centre. indian j tuberc 2013; 60:15–22. http://dx.doi.org/10.1016/s0041-3879%2848%2980033-4 renal tuberculosis presenting as a mass lesion in a two-year-old girl report of a rare case e108 | squ medical journal, february 2016, volume 16, issue 1 15. kay aw, mccarthy ca. renal and miliary tuberculosis in an internationally adopted infant. pediatr infect dis j 2009; 28:751–3. doi: 10.1097/inf.0b013e31819c6bfb. 16. merchant s, bharati a, merchant n. tuberculosis of the genitourinary system: urinary tract tuberculosis renal tuberculosis: part i. indian j radiol imaging 2013; 23:46–63. doi: 10.4103/0971-3026.113615. 17. mcdougal ws, wein aj, kavoussi lr, novick ac, partin aw, peters ca, et al. campbell-walsh urology. 10th ed. philadelphia, pennsylvania, usa: saunders, 2012. pp. 1417–18. 18. cantwell mf, shehab zm, costello am, sands l, green wf, ewing ep, et al. brief report: congenital tuberculosis. n engl j med 1994; 330:1051–4. doi: 10.1056/nejm199404143301505. 19. mazurek gh, jereb j, vernon a, lobue p, goldberg s, castro k, et al. updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection: united states, 2010. mmwr recomm rep 2010; 59:1–25. 20. krishnamoorthy s, gopalakrishnan g. surgical management of renal tuberculosis. indian j urol 2008; 24:369–75. doi: 10.41 03/0970-1591.42620. 21. gupta np, kumar r, mundada op, aron m, hemal ak, dogra pn, et al. reconstructive surgery for the management of genitourinary tuberculosis: a single center experience. j urol 2006; 175:2150–4. doi: 10.1016/s0022-5347(06)00310-7. 7. kumar s, shankaregowda sa, choudhary gr, singla k. rare presentation of genitourinary tuberculosis masquerading as renal cell carcinoma: a histopathological surprise. j clin imaging sci 2014; 4:26. doi: 10.4103/2156-7514.133259. 8. gupta h, kone k, pandey s, dorairajan ln, kumar s. tubercular mass mimicking a tumour in a horseshoe kidney: a unique presentation. int urol nephrol 2004; 36:323–4. doi: 10.1007/s11255-004-0925-y. 9. sood r, mukhopadhyay s. unusual imaging features in a case of renal tuberculosis presenting as fever of unknown origin. j indian acad clin med 2001; 2:87–90. 10. dinolfo m. renal tuberculosis presenting as renal mass. proc ucla healthcare 2013; 17:1. 11. verma r, khanna p, mehta b. revised national tuberculosis control program in india: the need to strengthen. int j prev med 2013; 4:1–5. 12. starke jr, smith kc. tuberculosis. in: feigin rd, cherry j, demmler g, kaplan s, eds. textbook of pediatric infectious diseases. philadelphia, pennsylvania, usa: saunders, 2003. pp. 1337–79. 13. dhua ak, borkar n, ghosh v, aggarwal sk. renal tuberculosis in infancy. j indian assoc pediatr surg 2011; 16:69–71. doi: 10.4103/0971-9261.78136. 14. chattopadhyay a, bhatnagar v, agarwala s, mitra dk. genitourinary tuberculosis in pediatric surgical practice. j pediatr surg 1997; 32:1283–6. doi: 10.1016/s0022-3468 (97)90302-x. http://dx.doi.org/10.1097/inf.0b013e31819c6bfb http://dx.doi.org/10.4103/0971-3026.113615 http://dx.doi.org/10.1056/nejm199404143301505 http://dx.doi.org/10.4103/0970-1591.42620 http://dx.doi.org/10.4103/0970-1591.42620 http://dx.doi.org/10.1016/s0022-5347%2806%2900310-7 http://dx.doi.org/10.4103/2156-7514.133259 http://dx.doi.org/10.1007/s11255-004-0925-y http://dx.doi.org/10.4103/0971-9261.78136 http://dx.doi.org/10.1016/s0022-3468%2897%2990302-x http://dx.doi.org/10.1016/s0022-3468%2897%2990302-x departments of 1radiology & molecular imaging and 2medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drshoaib.rad@gmail.com سالمة ومضاعفات القساطري الوريدية املركزية النفقية املكممة اخلاصة بالديلزة الدموية منظور سريري وشعاعي من مركز واحد يف عمان رنا �سعيب حميد، اأنوبام كومار كاكاريا، �سيف اأحمد خان، �سجى حممد، را�سد ال�سكيتي، داود الريامي، يا�رس وعد اهلل املال عبد abstract: objectives: this study aimed to assess the technical success, safety and immediate and delayed complications of double-lumen tunnelled cuffed central venous catheters (tvcs) at the sultan qaboos university hospital (squh), muscat, oman. methods: this retrospective study took place between january 2012 and october 2013. the clinical records and radiological data of all patients who underwent ultrasoundand fluoroscopy-guided tvc placement at squh during the study period were reviewed. demographic data and information regarding catheter placement, technical success and periand post-procedure complications (such as catheter-related infections or thrombosis) were collected. results: a total of 204 tvcs were placed in 161 patients. of these, 68 were female (42.2%) and 93 were male (57.8%). the mean age of the patients was 54.4 ± 17.3 years. the most common reason for catheter placement was the initiation of dialysis (63.4%). a total of 203 procedures were technically successful (99.5%). the right internal jugular vein was the most common site of catheter placement (74.9%). mild haemorrhage which resolved spontaneously occurred in 11 cases (5.4%). no other complications were observed. subsequent follow-up data was available for 132 catheters (65.0%); of these, thrombosis-related catheter malfunction was observed in 22 cases (16.7%) and catheter-related infection in 29 cases (22.0%). conclusion: radiological-guided placement of tunnelled haemodialysis catheters can be performed safely with excellent technical success. the success rate of catheter insertion at squh was favourable in comparison with other studies reported in the literature. keywords: central venous catheters; interventional radiology; thrombosis; catheter-related infections; renal dialysis; oman. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل تقييم النجاح التقني وعن�رس ال�سالمة وامل�ساعفات الآنية واملتاأخرة للق�ساطري الوريدية املركزية الدرا�سة هذه الطريقة: عمان. يف م�سقط يف قابو�ض ال�سلطان جامعة م�ست�سفى يف الوريدية( )الق�ساطري املكممة النفقية اجلوف ثنائية ال�ستعرا�سية ال�ستعادية اأجريت ما بني �سهر 2012 و �سهر اكتوبر 2013. من خالل مراجعة ال�سجالت ال�رسيرية والبيانات ال�سعاعية جلميع ال�سعاعي والتنظري )ال�سونار( ال�سوتية فوق بالمواج الفح�ض جهاز من بتوجيه لهم وريدية ق�ساطري ق�ساطري و�سع مت الذين املر�سى )الفلورو�سكوبي( يف م�ست�سفى جامعة قابو�ض يف فرتة الدرا�سة. مت جمع ومراجعه كافه البيانات الدميوغرافية واملعلومات اخلا�سة بادخال الق�ساطري والنجاح التقني وم�ساعفات مابعد العملية )مثل النتانات املتعلقة بالق�سطار، والتخرث(. النتائج: خالل فرتة الدرا�سة مت ادخال 204 ق�سطارا وريديا يف 161 مري�سا. من بني هوؤلء املر�سى كان عدد الإناث 68 بن�سبة )%42.2( والذكور 93 بن�سبة )%57.8(. معدل اأعمار املر�سى كان يرتواح مابني 17.3 ± 54.4 �سنة. من خالل هذه الدرا�سة وجدنا اأن ال�سبب الأكرث �سيوعا لإدخال الق�سطار كان لغر�ض ابتداء الديلزة الدموية بن�سبه )%63.4(. 203 حالة )%99.5( اأجريت بتقنية ناجحة. الوريد الوداجي الداخلي الأمين كان املو�سع الأكرث �سيوعا لإدخال الق�سطار بن�سبة )%74.9(. حدوث نزف ب�سيط مع التوقف التلقائي �سجلت يف 11 حالة و بن�سبة )%5.4(. مل ت�ساهد اأي م�ساعفات اأخرى، معلومات عن املتابعة للم�ساعفات املتاأخرة كانت متوفرة من 132 ق�سطارا )%65.0(، من بينها 22 حالة )%16.7( عطل يف عمل الق�سطار ناجت عن التخرث، واإنتانات متعلقة بالق�سطار يف 29 حالة )%22.0(. اخلال�صة: و�سع ق�ساطري الديلزة الدموية النفقية بالتوجيه ال�سعاعي ميكن اإجراوؤه باأمان و بنجاح تقني ممتاز. معدل النجاح يف اإدخال الق�ساطري يف م�ست�سفى جامعة ال�سلطان قابو�ض كان مر�سيا مقارنة بالدرا�سات الأخرى امل�سجلة واملن�سورة. مفتاح الكلمات: ق�سطار وريدي مركزي؛ علم ال�سعة التداخلية؛ تخرث؛ اإنتانات متعلقة بالق�سطار؛ ديلزة دموية؛ عمان. safety and complications of double-lumen tunnelled cuffed central venous dialysis catheters clinical and radiological perspective from a tertiary centre in oman *rana s. hamid,1 anupam k. kakaria,1 saif a. khan,2 saja mohammed,2 rashid al-sukaiti,1 dawood al-riyami,2 yasser w. al-mula abed2 sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e501–506, epub. 23 nov 15 submitted 12 jan 15 revision req. 4 may 15; revision recd. 31 may 15 accepted 25 jun 15 clinical & basic research doi: 10.18295/squmj.2015.15.04.010 safety and complications of double-lumen tunnelled cuffed central venous dialysis catheters clinical and radiological perspective from a tertiary centre in oman e502 | squ medical journal, november 2015, volume 15, issue 4 the provision of adequate haemodia-lysis depends on reliable access to large blood vessels capable of providing rapid blood flow.1 currently, the three forms of long-term access most commonly used are the native arteriovenous (av) fistula, synthetic graft and double-lumen tunnelled cuffed central venous catheter (tvc).2 first developed in 1987, these catheters are radio-opaque and made of soft silicone or polyurethane and are widely used to either provide bridging access before the creation and maturation of a high-flow av fistula/graft or permanent access when a creation of a fistula/graft is not possible.3,4 at the sultan qaboos university hospital (squh) in muscat, oman, tvcs are available in 12.5–14.5 french catheter sizes. they are placed in the distal superior vena cava and right atrium, usually using an internal jugular vein puncture after the creation of a subcutaneous tunnel superior to the breast along the lateral chest wall. compared to a temporary dialysis catheter, tvcs have a softer polymer and therefore carry a reduced risk of subsequent vessel injury or erosion.5 additionally, the larger diameter of the lumen allows increased blood flow during dialysis.5 they have a special antimicrobial cuff which serves to anchor the catheter in its tunnel using the ingrowth of fibrous tissue. these catheters are normally placed by nephrologists or surgeons depending on local expertise. however, there is an increasing global trend for these catheters to be placed by interventional radiologists with very low incidences of procedure-related complications.2 nevertheless, late complications—particularly infection and thrombosis—remain problematic and can lead to catheter dysfunction and significant morbidity.6–8 to the best of the authors’ knowledge, no local data yet exist from oman regarding the safety of radiological catheter placement and the prevalence of catheter-related complications. this study therefore aimed to assess the technical success, safety and immediate and delayed complications of ultrasoundand fluoroscopy-guided tvcs at squh. methods this retrospective study was carried out between january 2012 and october 2013 at the departments of radiology & molecular imaging and medicine at squh. all patients who underwent tvc placement during this 22-month period were included in the study. demographic data for all patients were recorded on a structured form along with information about catheter placement, technical success, complications of the catheter placement procedure and the development of any subsequent complications, such as catheter-related infections or thrombosis. all catheters were inserted by an interventional radiologist while the patient was in a supine position and under local anaesthesia. coagulation parameters were checked before the procedure, including the prothrombin time, partial thromboplastin time and platelet count. a platelet count of ≥100 x 109/l and an international normalised ratio of <1.5 were considered acceptable. the procedures were performed using ultrasound and fluoroscopic guidance in the interventional radiology suite using a sterile technique. ultrasonography was used to verify the patency of the internal jugular or femoral veins and to mark an appropriate puncture site. the vein was accessed with an 18-gauge needle with real-time ultrasound guidance and a 0.038-inch j-shaped flexible wire. subsequently, a peel-away sheath was introduced over the guide wire following serial dilatation. after the patient had received lidocaine injected into either the upper chest or thigh (according to the puncture site), a subcutaneous tract was created using a tunnelling trocar. the catheter was attached to the threaded end of the trocar and pulled through the tunnel and out via the exit site. the tvc was then introduced through the peel-away sheath under fluoroscopy. the catheter hubs were flushed with heparinised saline solution and sterile caps were attached. a chest or pelvic radiograph was taken at the end of the procedure to confirm the position of the catheter tip. when required, the catheter was removed using a sterile technique. using advances in knowledge to the best of the authors’ knowledge, this study provides the first local data from oman regarding the clinical safety of interventional radiological placement of double-lumen tunnelled cuffed central venous catheters (tvcs). this study presents the initial experience of this procedure at a tertiary care hospital. application to patient care as the number of patients requiring dialysis continues to grow, the creation and maintenance of haemodialysis access remains a vital healthcare issue worldwide. this retrospective study assessed the safety and performance of tvcs at a tertiary care hospital in oman to identify the nature and frequency of problems related to catheter insertion and usage. this will aid catheter placement and handling practices and ultimately improve patient care. rana s. hamid, anupam k. kakaria, saif a. khan, saja mohammed, rashid al-sukaiti, dawood al-riyami and yasser w. al-mula abed clinical and basic research | e503 meticulous blunt dissection, the cuff was freed and the catheter was gently pulled out. statistical analysis was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa). ethical permission for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university, muscat, oman (mrec #840). results a total of 161 patients were referred to squh for tvc insertion during the study period. of these, 68 were female (42.2%) and 93 were male (57.8%). the mean age of the patients was 54.39 ± 17.3 years (range: 13–90 years old). in total, 204 catheter placement procedures were performed on these patients; four patients had between 3–8 catheters inserted, 26 patients had two catheters inserted and 131 patients had one catheter inserted. the most common indication for catheter placement was the initiation of dialysis in newly diagnosed patients (63.4%) [table 1]. catheter placement procedures were successful in 203 cases (99.5%). only one procedure failed; the catheter could not be placed due to bilateral internal jugular vein stenosis. the patient was restless and had respiratory distress due to pulmonary oedema. however, after his condition had stabilised, he returned the next day and a tvc was successfully placed in the right femoral vein. of the successfully-placed catheters, 201 (99.0%) were placed during the first puncture. in the remaining two cases, the first puncture was unsuccessful and the catheters were placed during a second puncture within the same session. the right internal jugular vein was accessed in 152 cases (74.9%) while 32 catheters were placed through the left internal jugular vein (15.8%), 15 catheters were placed through the right femoral vein (7.4%) and four catheters were placed through the left femoral vein (2.0%). a total of 193 catheters (95.1%) were inserted in a satisfactory position with optimal placement and without any kinks in the catheter lumen and 10 catheters (4.9%) had suboptimal placement with kinks, malposition or both. the majority of the successful procedures (n = 193; 95.1%) were completed uneventfully without any complications. mild bleeding at the skin entry site in the chest wall occurred during 11 procedures (5.4%); all of these resolved following manual compression for 10–15 minutes. these patients did not require any blood transfusions and were placed under observation to ensure their haemodynamic stability. there were no instances of haemo/pneumothorax, air embolisms or any other complications. after catheter placement, 114 patients (70.8%) continued dialysis outside of squh at other governmental facilities. the remaining 47 patients (29.2%) continued receiving dialysis at squh. clinical follow-up information regarding catheter status was only available for 132 catheters placed in 100 patients [figure 1]. the remaining 61 patients were lost to follow-up and no clinical records were therefore available for the remaining 71 catheters (35.0%). of the patients who were lost to follow-up, 52 patients (85.3%) were receiving dialysis at other governmental facilities and nine patients (14.7%) had had their initial dialysis session at squh but did not return after being discharged. out of the 132 catheters with followup data, 10 (7.6%) were accidentally pulled out after placement and three (2.3%) were found to have cuts. table 1: indications for double-lumen tunnelled cuffed central venous dialysis catheter insertion among patients at the sultan qaboos university hospital, muscat, oman (n =161) indication n (%) dialysis initiation 102 (63.4) replacement of temporary catheter 34 (21.1) failed av fistula/graft 17 (10.6) failed transplant 4 (2.5) replacement of blocked tvc 3 (1.9) not available in records 1 (0.6) total 161 (100.0) av = arteriovenous; tvc = tunnelled cuffed central venous catheter. figure 1: catheter status at follow-up of double-lumen tunnelled cuffed central venous dialysis catheter catheters inserted among 161 patients at the sultan qaboos university hospital, muscat, oman (n = 204). follow-up information was only available for 132 catheters placed in 100 patients. blood-borne and exit site infections were observed at follow-up in 29 catheters (22.0%) placed in 22 patients. thrombosis-related catheter malfunctions were observed in 22 cases (16.6%) leading to subsequent problems during dialysis. safety and complications of double-lumen tunnelled cuffed central venous dialysis catheters clinical and radiological perspective from a tertiary centre in oman e504 | squ medical journal, november 2015, volume 15, issue 4 all of these catheters were not suitable for reuse and had to be replaced. of the 132 catheters placed in the patients who were not lost to follow-up, thrombosis-related malfunctions were observed in 22 catheters (16.6%) leading to subsequent problems during dialysis. these 22 catheters were placed in 15 patients [table 2]. the highest frequency of catheter-related thrombosis was seen in two patients. one of these patients had thrombosis in six out of eight catheters placed during the study period. as a result, this patient had multiple access problems, bilateral central venous stenosis and a thrombosed fistula. a routine thrombophilic screening test was negative. for the other patient, thrombosis was observed in three out of six catheters placed. this patient was in a hypercoagulable state and had a previous history of deep venous thrombosis of the lower limbs. he also had protein c and protein s deficiencies and there were pre-existing venous stenoses in the right internal jugular vein and the veins of right lower limb which were believed to be responsible for the recurrent thrombosis. the stenoses in the lower limb veins were treated by angioplasty. among the thrombosed catheters, the patency of five catheters was successfully restored via the injection of thrombolytic agents into the catheter lumen. however, 17 catheters were still non-functioning after this treatment and were removed. table 3: catheter-related infections of double-lumen tunnelled cuffed central venous dialysis catheter procedures among patients at the sultan qaboos university hospital, muscat, oman (n = 22) catheters placed per patient infected catheters per patient route of infection causative organism 6 2 blood-borne exit site staphylococcus aureus staphylococcus aureus 4 3 blood-borne blood-borne blood-borne pseudomonas enterobacter enterobacter 2 2 blood-borne blood-borne staphylococcus aureus pseudomonas 2 2 blood-borne blood-borne acinetobacter no growth 2 2 blood-borne both routes staphylococcus aureus staphylococcus aureus 2 2 both routes both routes staphylococcus aureus staphylococcus aureus 2 1 blood-borne pseudomonas 2 1 both routes acinetobacter 2 1 blood-borne staphylococcus aureus 1 1 exit site staphylococcus aureus 1 1 blood-borne staphylococcus aureus 1 1 exit site staphylococcus aureus 1 1 blood-borne acinetobacter 1 1 blood-borne staphylococcus aureus 1 1 blood-borne staphylococcus aureus 1 1 both routes klebsiella 1 1 both routes proteus mirabilis 1 1 blood-borne enterococcus 1 1 blood-borne staphylococcus aureus 1 1 both routes staphylococcus aureus 1 1 blood-borne staphylococcus epidermidis 1 1 exit site staphylococcus aureus table 2: thrombosis-related malfunctions of doublelumen tunnelled cuffed central venous dialysis catheter procedures among patients at the sultan qaboos university hospital, muscat, oman (n =15) catheters placed per patient thrombosed catheters per patient 8 6 6 3 2 1 2 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 rana s. hamid, anupam k. kakaria, saif a. khan, saja mohammed, rashid al-sukaiti, dawood al-riyami and yasser w. al-mula abed clinical and basic research | e505 infection was observed at follow-up in 29 catheters (22.0%) placed in 22 patients [table 3]. two of the patients with infected catheters also had thrombosis but it was not possible to determine which condition occurred first. of the infections, there were 18 cases of blood-borne infections (62.1%), four cases (13.8%) of exit site infections in the skin of the chest and seven cases (24.1%) of both blood-borne and exit site infections. one elderly male patient had blood-borne infections which occurred in three out of four catheters placed during the study period. he was diabetic and hypertensive and had coronary artery disease. his dialysis sessions were held at another facility outside of squh. four patients had catheters placed twice during the study period, with all of these catheters developing infections. culture results indicated that the most common bacteria causing infections was staphylococcus aureus in 16 cases (55.2%), followed by bacteria of the acinetobacter and pseudomonas genera which were each seen in three cases (10.3% each). infections in five catheters (17.2%) were successfully treated with antibiotics while 24 infections (82.8%) did not respond well to antibiotics and persisted, leading to the catheters being removed. discussion dialysis as a modality of renal replacement therapy is generally required in patients with acute kidney injury or end-stage renal disease. haemodialysis accounts for 89% of all patients who receive dialysis, with the rest receiving peritoneal dialysis.9 although the av fistula is the preferred mode of access for haemodialysis, tvcs can help patients awaiting maturation of an av fistula or those for whom an av fistula is not possible. the success rate of catheter insertion in the current study was favourable in comparison with other studies reported in the literature.10,11 this may be because all of the procedures were performed using ultrasound and fluoroscopic guidance, which is known to increase the success rate of insertion.11,12 additionally, the procedure was very safe for the majority of patients with a very low procedure-related immediate complication rate. all of the immediate complications were related to local bleeding and could be controlled by manual compression. none of the patients required additional procedures for management and there were no cases of haemo/pneumothorax or air embolism detected. these findings are similar to those reported elsewhere.10,11 catheter-related thrombosis in the form of a fibrin sheath or a thrombus in the catheter is a frequent complication of indwelling catheters and accounts for up to 40.0% of catheter failures.2 in the present study, the rate of thrombus-related catheter malfunctions (16.7%) was lower than those reported in the literature.2,4 in particular, one patient had eight catheters inserted of which six thrombosed and an av fistula which also thrombosed without ever being used for dialysis. although a routine thrombophilic screen was negative, it is likely that the patient was suffering from an unknown thrombophilic disorder. another patient had a previous history of deep venous thrombosis and protein c and protein s deficiencies which probably contributed to the multiple catheter failures. however, although the overall thrombosisrelated catheter failure rate was lower than previously reported, and several affected catheters were salvaged by intracatheter thrombolysis, the majority of the affected catheters had to be removed. another serious complication with significant morbidity and mortality in patients undergoing haemodialysis is catheter-related infection. the risk of bacteraemia with a cuffed tunnelled catheter is nearly 10 times that of an av fistula.13 the overall infection rate in the current study (21.9%) was much lower than that reported in the literature; catheterrelated infection rates of 54.0% have been reported, with up to two-thirds of catheters requiring removal.2,3 despite the low catheter-related infection rate, the majority of infected catheters in the current study required removal and very few infections were cleared satisfactorily with antibiotics. cuffed tunnelled catheters provide a temporary alternative to av fistulae for haemodialysis patients. nevertheless, while patient acceptance is particularly high with catheters as no needles are required for the purposes of the dialysis, significant complications and failure rates remain higher than for av fistulae.14 further research into catheter materials and construction is needed to reduce the rates of these complications and prolong the useful life span of catheters. conclusion radiology-guided placement of tunnelled haemodialysis catheters at squh was performed safely with excellent technical success (99.5%). mild haemorrhage which resolved spontaneously was the only procedurerelated immediate complication (5.4%). additionally, low rates of subsequent thrombosis-related catheter malfunction (16.7%) and catheter-related infection (22.0%) were observed. these rates compared favourably with the international literature. safety and complications of double-lumen tunnelled cuffed central venous dialysis catheters clinical and radiological perspective from a tertiary centre in oman e506 | squ medical journal, november 2015, volume 15, issue 4 c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. butterly dw, schwab sj. catheter access for hemodialysis: an overview. semin dial 2001; 14:411–15. doi: 10.1046/j.1525139x.2001.00104.x. 2. trerotola so. hemodialysis catheter placement and manage ment. radiology 2000; 215:651–8. doi: 10.1148/radiology. 215.3.r00jn23651. 3. schwab sj, buller gl, mccann rl, bollinger rr, stickel dl. prospective evaluation of a dacron cuffed hemodialysis catheter for prolonged use. am j kidney dis 1988; 11:166–9. doi: 10.1016/s0272-6386(88)80206-3. 4. moss ah, mclaughlin mm, lempert kd, holley jl. use of a silicone catheter with a dacron cuff for short-term vascular access. am j kidney dis. 1988; 12:492–8. doi: 10.1016/s02726386(88)80100-8. 5. schwab sj, beathard g. the hemodialysis catheter conundrum: hate living with them, but can’t live without them. kidney int 1999; 56:1–17. doi: 10.1046/j.1523-1755.1999.00512.x. 6. lok ce, mokrzycki mh. prevention and management of catheter-related infection in hemodialysis patients. kidney int 2011; 79:587–98. doi: 10.1038/ki.2010.471. 7. liangos o, gul a, madias ne, jaber bl. long-term management of the tunneled venous catheter. semin dial 2006; 19:158–64. doi: 10.1111/j.1525-139x.2006.00143.x. 8. bruno s, remuzzi g. vascular access-related thrombotic complications: research hypotheses and therapeutic strategies. j nephrol 2006; 19:280–5. 9. grassman a, gioberge s, moeller s, brown g. esrd patients in 2004: global overview of patient numbers, treatment modalities and associated trends. nephrol dial transplant 2005; 20:2587–93. doi: 10.1093/ndt/gfi159. 10. wivell w, bettmann ma, baxter b, langdon dr, remillard b, choabanian m. outcomes and performance of tesio twin catheter system placed for hemodialysis access. radiology 2001; 221:697–703. doi: 10.1148/radiol.2213991994. 11. sayani r, anwar m, tanveer-ul-haq, al-qamari n, bilal ma. outcome of radiologically placed tunneled haemodialysis catheters. j coll physicians surg pak 2013; 23:837–41. doi: 12.2013/jcpsp.837841. 12. bishop l, dougherty l, bodenham a, mansi j, crowe p, kibbler c, et al. guidelines on the insertion and management of central venous access devices in adults. int j lab hematol 2007; 29:261–78. doi: 10.1111/j.1751-553x.2007.00931.x. 13. wilcox ta. catheter-related bloodstream infections. semin intervent radiol 2009; 26:139–43. doi: 10.1055/s-0029-1222458. 14. rehman r, schmidt rj, moss ah. ethical and legal obligation to avoid long-term tunneled catheter access. clin j am soc nephrol 2009; 4:456–60. doi: 10.2215/cjn.03840808. http://dx.doi.org/10.1046/j.1525-139x.2001.00104.x http://dx.doi.org/10.1046/j.1525-139x.2001.00104.x http://dx.doi.org/10.1148/radiology.215.3.r00jn23651 http://dx.doi.org/10.1148/radiology.215.3.r00jn23651 http://dx.doi.org/10.1016/s0272-6386%2888%2980206-3 http://dx.doi.org/10.1016/s0272-6386%2888%2980100-8 http://dx.doi.org/10.1016/s0272-6386%2888%2980100-8 http://dx.doi.org/10.1046/j.1523-1755.1999.00512.x http://dx.doi.org/10.1038/ki.2010.471 http://dx.doi.org/10.1111/j.1525-139x.2006.00143.x http://dx.doi.org/10.1093/ndt/gfi159 http://dx.doi.org/10.1148/radiol.2213991994 http://dx.doi.org/12.2013/jcpsp.837841 http://dx.doi.org/10.1111/j.1751-553x.2007.00931.x http://dx.doi.org/10.1055/s-0029-1222458 http://dx.doi.org/10.2215/cjn.03840808 radiation exposure levels in relatives of patients after radioiodine therapy medical sciences (2000), 2, 87–90 © 2000 sultan qaboos university department of clinical and biomedical physics, college of medicine, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. e-mail: haddiab@omantel.net.om. *to whom correspondence should be addressed. 87 radiation exposure levels in relatives of patients after radioiodine therapy *bererhi h, constable a r مستوى األشعاعية ألقارب المرضى بعد العالج باليود المشع أنتوني آونستابل، هاديا البريحي المستشفى بمغادرة للمرضى يسمح واطئ بمستوى هو ،وهل المشــع باليود عالجا تلقوا الذين ىالمرض ألقارب االشعاعي النشاط مستوى تقييم :الهدف :الملخص الدرقية الغدة بسرطان المرضى أقارب من 23 و الدرقية الغدة نشاط بفرط المصابين المرضى أقارب من 47 مراقبة تمت :الطريقة. رقادهم فترة يقلل وبذلك مبكرا :النتائج .المشع اليود بقايا من mbq 30 مستوى على المستشفى في المرضى خروج بعد أشعاعيتهم لقياس أيام، سبعة لمدة المشع باليود المرضى أقاربهم عولج والذين لها ىتعرضالت القليلة االشعاعية للجرعة بالنظر :الخالصة 1msvر46 أستلم واحدًا طفًال ماعدا msv 1 من أقل واألطفال األزواج في المقاسة الجرع آانت المستشفى في هم بقاء مدة نختزل وبذلك مبكرا المرضى بخروج يسمح مما صرامة أقل التعليمات جعل الممكن فمن ، األقارب abstract: objective – to assess whether the level of radioactivity received by relatives of patients treated with radioiodine (131i) is low enough to allow the patients leave the hospital earlier, thus reducing their hospital stay. method – forty seven relatives of thyrotoxic patients and 23 relatives of thyroid cancer patients treated with 131i therapy were monitored for 7 days for radiation after discharging the patients at 30 mbq residual 131i. results – the doses measured in spouses and children were less than 1 msv except for one child who received 1.46 msv. conclusion – in view of the low radiation doses received by the relatives, regulations could be made less stringent, thus reducing the hospital stay of the patients. key words: radioiodine, relatives, radiation, dosimeter adioiodine (131i) is widely accepted as the treatment of choice for thyrotoxicosis.1 it is also used for whole body scans and in high doses for therapy in differentiated thyroid carcinoma.2 in the united kingdom, patients receiving 131i therapy are nowadays treated as outpatients with some restrictions on their contact with others if they receive a dose less than 800 mbq. this corresponds to the limit for travel by private transport.3 in the united states, an internally retained activity of 1110 mbq4 is permitted for a patient to be discharged from hospital with timed restrictions for contact with others. now the us regulations are less stringent since they have been updated. 5 for social and cultural reasons regulations in oman require that patients remain in hospital until the radiation level at one metre from the patient drops to 2 µsv/h. this practice was derived from the uk guidance notes,3 which allow an internal body activity limit of 30 mbq of 131i for returning to radiosensitive work and contact with children. this corresponds to a radiation level at one metre from the patient of about 2 µsv/h. buchan and brindle have shown that contamination6 and radiation doses7 to relatives of patients receiving up to 800 mbq and discharged as outpatients with appropriate instructions, are negligible. the present study was planned to measure the radiation dose received by relatives of patients with 30 mbq of 131i in the body at discharge from hospital and without imposing any restrictions on them. the study was undertaken as a first step towards relaxing our rather stringent regulations. method fourteen patients treated with 131i for thyrotoxicosis and five treated for differentiated carcinomas of the thyroid (3 therapeutic doses and 2 whole body scans) were selected. the mean (±sd) dose administered for thyrotoxic patients was 489 (±117) mbq (range, 300–670 mbq) and for cancer patients was 2920 (±2500) mbq (range 300–5740 mbq). the duration of hospitalisation varied from 2 to 9 days (mean 5 days) for patients with cancer r b e r e r h i a n d c o n s t a b l e 88 and 9 to 15 days (mean 12 days) for thyrotoxic patients. the patient was discharged when the activity in the body fell below 30 mbq and this was deemed to have occurred when the radiation level at one metre from the erect patient was less than 2 µsv/h. on discharge, all patients in this study were well and self-dependent. the main selection criteria were (a) the patient and family must consent to wearing the dosimeter at all times for 7 days, (b) the patient and relatives should live together during the whole week the dosimeter was worn. in other respects, families were to assume their normal habits and sleeping arrangements, which were recorded. the ages of the relatives monitored ranged from 6 months to 60 years. for the dosimeters, harshaw tld 200 rods (6 mm x 1 mm dia) made of cadmium fluoride dysprosium were used. for every subject three rods were inserted into a flexible black tube made of silicon rubber with one sealed end. the open end was sealed with a removable plug of black rubber. the tube was then put into a watertight painted capsule with a screw-in end piece and a cord was threaded into two holes at the extremities of the capsule, designed in such a way that, once the cord was in place, the capsule could not be opened (figure 1). the lengths of the cord were individually adjusted to bring the capsules to the level of the supra-sternal notch. the capsules were placed in individually labelled lead pots, which were then fitted into a wooden box (figure 2) together with a dosimeter for background measurement. patients were asked to keep the background dosimeter in a place remote from general living activities. after the capsules were returned the radiation doses were measured with a harshaw 6600 tld reader. the ethical committee of our institution approved the study and, after discussion with their relatives, all patients agreed to participate. results the cumulative radiation dose (µsv) over 7 days received by the relatives of patients treated with 131i for thyrotoxicosis and carcinoma from the time the patient arrived home are shown in table 1 and table 2 respectively. the results are presented as mean plus and minus one standard deviation. statistical significance was determined by applying the student’s t-test. a p value <0.05 was considered statistically significant. one patient was eliminated from the study because he left home for a 7-day period. children slept in separate rooms from their parents except for one 7 year-old child who slept in the same bed as her parents. the spouse of each patient slept in the same bed in all cases. in the families of cancer and thyrotoxicosis patients, the spouses received a higher mean dose than the rest of the relatives. in the families of the thyrotoxic patients the spouses received the maximum dose. however, among the families of the cancer patients, it was a child who received the maximum dose (1.46 µsv). the lowest dose of zero was received by a child looked after by a maid, who also received zero dose. there was no significant difference between the means of the cumulative radiation doses received by relatives of our patients with 30 mbq over a 7 day period and the cumulative radiation dose per 30 mbq received by the relatives of buchan and brindles’s patients over 21 days. buchan and brindle7 measured the cumulative dose figure 1. capsules showing one mounted on a necklace. figure 2. a wooden box that houses the lead pots containing the capsules. r a d i a t i o n e x p o s u r e t o r e l a t i v e s 89 to family members for 21 days from the time the patient arrived home after administration of 131i doses of 148592 mbq on an outpatient basis and to whom no instructions were given to minimise radiation hazards. the results of buchan and brindle7 were analysed by wasserman and klopper8 and were found to be, on average, for 21 days, 5.6±3.7 µsv.mbq-1 for spouses and 1.5±0.87 µsv.mbq-1 for other family members. using these figures, the radiation dose to the families if, like ours, their patients had 30 mbq of 131i in their bodies at the time of discharge would be 168±110 µsv for spouses and 45±26 µsv for other family members (table 3). discussion there is no evidence that radiation from patients treated with 131i causes problems to other people. moreover, a long-term study9 did not detect any harmful effect in 103 persons, who, when children had been treated with 131i for thyroid carcinoma with a mean dose of 17 gbq and a maximum dose of 26 gbq and were followed for a mean period of 22 years (maximum: 45 years). nevertheless, precautions should be taken to avoid unnecessary radiation to others who may come into the vicinity of the patient. to achieve this, patients are usually kept in hospital until their retained activity satisfies the adopted regulations: 30 mbq in oman, 800 mbq for england3 and 1110 mbq for usa.4 since 1997, the activity retained by the patient in the usa has been unspecified provided no other individual receives a dose exceeding 5 msv. this means that a patient, treated with more than 7000 mbq of 131i, could leave the hospital subject to certain restrictions.5 in our institution patients are kept in hospital until they are considered safe for close contact with children. our study shows that even with this strict restriction the radiation doses to relatives of patients with thyrotoxicosis or carcinoma of the thyroid showed a measurable radiation dose. for most relatives this was lower than the icrp recommended annual limit of 1 msv except for a one year-old child who received a cumulative dose over 7 days of 1.46 msv. this child was the youngest in a family we visited on the day of discharge. the entire time we were there (about one hour), the patient held the child in her lap or her shoulder. apart from this child, spouses received the highest radiation, evidently due to the time they spent close to the patient, particularly during sleep. the fact that the lowest dose was sustained by a child cared by a maid suggests that families with infants should preferably appoint a childminder. this study shows that although we retained our patients until they were considered safe to be with children, the relatives still received doses comparable to the doses documented as received from outpatients,7 in another study, even though that study recorded doses over a period approximately thrice as long as ours. unlike in other countries, our patients are not released immediately from hospital, mainly because of the uncertainty regarding their compliance to hospital instructions in a climate of social and cultural traditions totally different from those of western urban communities. traditional close physical contact between mothers and young children cannot be minimised by mere instructions. conclusion while the restrictions practised in our study were intentionally more stringent than necessary, these enabled us to observe and measure the radiation doses to relatives table 1 cumulative radiation doses received over 7 days by relatives of patients treated with 131i for thyrotoxicosis with 30 mbq body retained activity. radiation dose (µsv) relatives no. minimum maximum mean sd spouses 13 1 728 221 246 other 34 0 (child & maid) 253 68 60 table 2. cumulative radiation doses received over 7 days by relatives of patients treated with 131i for differentiated thyroid carcinoma with 30 mbq body retained activity radiation dose (µsv) relatives no. minimum maximum mean sd spouses 4 8 665 195 314 other 19 819 1460 (child) 167 347 table 3 cumulative radiation doses received by relatives of buchan and brindle’s patients treated with 131i for thyrotoxicosis6 calculated for 30 mbq body retained radioactivity. radiation dose (µsv) relatives number mean sd spouses 29 168 110 other 25 45 26 b e r e r h i a n d c o n s t a b l e 90 at extreme conditions. our findings enable us to recommend significant shortening of the hospital stay of patients treated with 131i. acknowledgements we thank mr. hugh wilkins for his contribution to the implementation of this study. we are also grateful to mr. afkar nadhim al-farsi and mr. kirthi jayasekera for their meticulous technical assistance. references 1. solomon b, glinoer d, lgasse r, wartofsky l. current trends in the management of grave’s disease. j clin endocrinol metab 1990, 70, 1518–24. 2. freitas je, grass md, ripley s, shapiro b. radionuclide diagnosis and therapy of thyroid cancer. current status report. semin nucl med 1985, 15, 122–5. 3. hmso. guidance notes for the protection of persons against ionizing radiations arising from medical and dental use. london. 1988. 4. us regulatory title 10 cfr 35.75. 1986. 5. us regulatory title 10 cfr 35.75 1997. 6. buchan rct, brindle jm. radioiodine therapy to outpatients: the contamination hazard. brit j radiol 1970, 43, 479–83. 7. buchan rct, brindle jm. radioiodine therapy to outpatients: the radiation hazard. brit j radiol 1971, 44, 973–5. 8. wasserman hj, klopper jf. analysis of radiation doses received by public from 131i treatment of thyrotoxic outpatients. nucl med commun 1993, 14, 756–60. 9. shapiro b, beierwaltes wh, guz e et al. 131i treatment of thyroid carcinoma in children. endocrinology. 1986, 119, 119. 10. **grigsby pw, siegal ba, baker s, eichling jo. radiation exposure from outpatient radioactive iodine (131i) therapy for thyroid carcinoma. jama 2000, 283, 2272–4. radiation doses glossary µsv – microsievert msv millisievert mbq megabecqueral gbq – gigabecqueral mci millicuries **editor’s note: this recent study (ref: 10) has vindicated the leniency of the us regulations by finding the radiation doses received by relatives of 30 outpatients treated with large doses of 131.i for thyroid cancer to be well below the permitted limit of 5.0 msv. (reference added at editor’s discretion.). radiation exposure levels in relatives of patients �after radioiodine therapy method results discussion table 1 cumulative radiation doses received over 7 days by relatives of patients treated with 131i for thyrotoxicosis with �30 mbq body retained activity. table 2. cumulative radiation doses received over 7 days by relatives of patients treated with 131i for differentiated thyroid �carcinoma with 30 mbq body retained activity conclusion acknowledgements references sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e301–302, epub. submitted 3 jan 15 accepted 19 feb 15 رد: اجتاهات وصف املضادات احليوية يف عينة من األطفال العمانيني re: antibiotic prescribing trends in an omani paediatric population sir, i read with interest the study by al-balushi et al. published in the squmj november 2014 issue.1 interestingly, although most of the children included in al-balushi et al.’s study were outpatients (64.3%) attending the paediatric outpatient clinic at sultan qaboos university hospital (squh), the authors mentioned that there was a trend towards more antibiotic prescriptions (aps) among inpatients (58%; 80/138) than outpatients (42%; 58/138).1 i presume that al-balushi et al.’s study would be more constructive if the authors had considered listing the percentages of aps in various paediatric units at squh, such as the respiratory, gastroenterology, haematology and nephrology units, and addressed the diagnoses of the health problems encountered in these units. moreover, the authors could not ascertain whether the studied aps were scientifically or irrationally based. it is important to stress that the misuse of antibiotics still represents a major concern for health authorities, particularly in developing countries. irrational use is often noticed in the improper selection of an antibiotic and in over-prescribing. though no studies on antibiotic misuse are yet present in oman, i presume that its magnitude is substantial. this could be indirectly concluded from the observation that in al-balushi et al.’s study there was an increasing trend of aps among inpatients (58%) in comparison to outpatients (42%). this is despite the notion that antibiotics tend to be more judiciously prescribed among inpatients pending the results of sound laboratory and imaging investigations.1 however, various factors like the postgraduate qualifications and experience of the paediatricians; sources and methods for updating knowledge; inpatient practice settings, and the presence of fever, together with a paediatrician’s perception of parental expectations, are strong determinants of aps in the clinical setting.2,3 i do stress that increasing the alertness of paediatricians in oman on the judicious prescription of antibiotics is fundamental. moreover, antimicrobial stewardship programmes (asps) have been adopted in various developed countries to optimise antimicrobial use for hospitalised patients through focusing on discontinuing antibiotics appropriately and promoting local antibiograms in the proper clinical setting.4 current evidence has demonstrated that neonatal and paediatric asps appear to be safe, practical to implement, generally cost-effective and possibly associated with a reduction in the antimicrobial resistance rates.5 i, therefore, suggest that the implementation of neonatal and paediatric asps in oman should be seriously considered as an effective means to contain unnecessary aps. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq email: mdalmendalawi@yahoo.com references 1. al-balushi k, al-ghafri f, al-sawafi f, al-zakwani i. antibiotic prescribing trends in an omani paediatric population. sultan qaboos univ med j 2014; 14:466–70. 2. bharathiraja r, sridharan s, chelliah lr, suresh s, senquttuvan m. factors affecting antibiotic prescribing pattern in pediatric practice. indian j pediatr 2005; 72:877–9. doi: 10.1007/bf02731121. 3. ciofi degli atti ml, massari m, bella a, boccia d, filia a, salmaso s, et al. clinical, social and relational determinants of pediatric ambulatory drug prescriptions due to respiratory tract infections in italy. eur j clin pharmacol 2006; 62:1055–64. doi: 10.1007/s00228-0060198-8. 4. bowes j, yasseen as 3rd, barrowman n, murchison b, dennis j, moreau ka, et al. antimicrobial stewardship in pediatrics: focusing on the challenges clinicians face. bmc pediatr 2014; 14:212. doi: 10.1186/1471-2431-14-212. 5. brett a, bielicki j, newland jg, rodrigues f, schaad ub, sharland m. neonatal and pediatric antimicrobial stewardship programs in europe: defining the research agenda. pediatr infect dis j 2013; 32:e456–65. doi: 10.1097/inf.0b013e31829f0460. online letter to the editor re: antibiotic prescribing trends in an omani paediatric population e302 | squ medical journal, may 2015, volume 15, issue 2 response from the authors sir, we thank you for your interest and comments on our recently published article on the subject of antibiotic prescribing trends in an omani paediatric population.1 with regards to the comment on listing percentages of antibiotic prescriptions (aps) by disease type, this information is already mentioned in the first paragraph of the results on page 496, namely, ‘‘among the children who were prescribed antibiotics, the most common diseases were respiratory diseases (n = 62; 44.9%) followed by haematological conditions (n = 18; 13.0%) and gastrointestinal diseases (n = 8; 5.8%)’’.1 the second comment was about the rational use of aps in our study. we would like to inform you that the aim of our study, which was mentioned in the last paragraph of the introduction on page 496, was only to describe the antibiotic prescribing patterns for paediatric patients at sultan qaboos university hospital in oman. the rational use of antibiotics could very well be the scope for future studies. *khalid al-balushi1 and ibrahim al-zakwani1,2 1department of pharmacology & clinical pharmacy, college of medicine & health sciences, sultan qaboos university; 2department of pharmacy, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mme51@squ.edu.om reference 1. al-balushi k, al-ghafri f, al-sawafi f, al-zakwani i. antibiotic prescribing trends in an omani paediatric population. sultan qaboos univ med j 2014; 14:466–70. تقييم مستويات جلوبيولني املناعي a املفرز يف اللعاب لدى مرضى السكري وعالقته مع أعراض الفم واألسنان �سهال كاكوي، بهاره ح�سيني، علي اأكرب حاجدو�ست، مويجن �سنجاري، اأحمد غالم ح�سينيان ، وحيد اف�سار abstract: objectives: oral and dental manifestations in diabetic patients can arise due to numerous factors, including elevated salivary secretory immunoglobulin a (s-iga) levels. this study aimed to evaluate s-iga concentrations in patients with type 2 diabetes mellitus (t2dm) and to investigate the association between s-iga levels and oral and dental manifestations of t2dm. methods: this cross-sectional descriptive study was carried out between october 2011 and september 2012 in kerman, iran, and included 260 subjects (128 patients with t2dm and 132 healthy controls). unstimulated salivary samples were collected from all subjects and s-iga levels were determined using the immunoturbidimetric method. the oral cavities and teeth of t2dm patients were evaluated for oral and dental manifestations. results: both diabetic and control subjects with higher concentrations of s-iga had significantly higher numbers of decayed, missing or filled teeth (dmft) and periodontal index (pdi) scores (p <0.050). s-iga levels were significantly higher in subjects with oral candidiasis (p <0.050). among diabetic patients, significantly higher s-iga levels were concomitant with xerostomia and denture stomatitis (p ≤0.050). there were no significant differences between s-iga concentrations and other oral or dental manifestations in either group. conclusion: individuals with a greater number of dmft, a higher pdi score and oral candidiasis had significantly higher s-iga levels. s-iga levels were not significantly higher among diabetic patients in comparison to the control group. however, significantly higher s-iga levels occurred with xerostomia and denture stomatitis in diabetic patients. in addition, s-iga was significantly higher in patients with uncontrolled diabetes compared to those with controlled diabetes. keywords: diabetes mellitus; saliva; secretory immunoglobulin a; oral manifestations; iran. امللخ�ص: الهدف: اأعرا�ض الفم والأ�سنان يف مر�سى ال�سكري ميكن اأن تن�ساأ نتيجة لعوامل عديدة، مبا يف ذلك ارتفاع م�ستويات جلوبيولني املناعي a املفرز يف اللعاب. هدفت هذه الدرا�سة اإىل تقييم تركيز جلوبيولني املناعي a املفرز يف لعاب املر�سى الذين يعانون من النوع 2 من داء ال�سكري ولتقييم ارتباط م�ستويات جلوبيولني املناعي a املفرز واأعرا�ض الفم والأ�سنان. الطريقة: اأجريت هذه الدرا�سة الو�سفية من و 132 النوع 2 من ال�سكري مر�سى من 128( �سخ�سا و�سملت 260 اإيران، كرمان، يف و�سبتمرب 2012 اأكتوبر 2011 بني امل�ستعر�سة ال�سحاء(. مت جمع عينات اللعاب غرياملحفز من جميع امل�ساركني ومت حتديد م�ستويات جلوبيولني املناعي a با�ستخدام طريقة قيا�ض التعكر املناعي. مت تقييم جتاويف الأ�سنان والفم ملر�سى ال�سكري. النتائج: كان ال�سحاء ومر�سى ال�سكري الذين لديهم تركيزات اأعلى من م�ستويات جلوبيولني املناعي a لديهم ن�سبة اأعلى اإح�سائيا من الأ�سنان النخرة واملفقودة اأو بها ح�سو اأ�سنان ودرجات موؤ�رس اللثة اأعلى )p >0.050(. وكانت م�ستويات جلوبيولني املناعي a اأعلى بكثري يف امل�ساركني الذين لديهم داء املبي�سات الفموي )p >0.050(. ويف مر�سى .)p ≤0.050( املرتفعة اإح�سائيا م�ساحبة جلفاف الفم والتهاب الفم امل�ساحب لطقم الأ�سنان a ال�سكري، كانت م�ستويات جلوبيولني املناعي مل توجد فروق اخرى ذات دللة اإح�سائية بني م�ستويات جلوبيولني املناعي a و اأعرا�ض الفم اأو الأ�سنان يف اأي من املجموعتني )ال�سكري والأ�سحاء(. اخلال�صة: ال�سخا�ض الذين لديهم اأ�سنان نخرة اأومفقودة اأو بها ح�سو اأ�سنان ودرجات موؤ�رس اللثة مرتفعة ولديهم داء املبي�سات الفموي لديهم ن�سبة اأعلى بكثري يف م�ستويات جلوبيولني املناعي a. ولكن لي�ض هناك فرق اإح�سائي يف م�ستويات جلوبيولني املناعي a املناعي جلوبيولني م�ستويات يف اإح�سائية زيادة فهناك ذلك، ومع الأ�سحاء. التحكم جمموعة مع مقارنة ال�سكري مر�سى لدى a عند الأ�سخا�ض امل�سابني بجفاف الفم والتهاب الفم امل�ساحب لطقم الأ�سنان يف مر�سى ال�سكري. بالإ�سافة اإىل ذلك، فاإن التهاب الفم امل�ساحب لطقم الأ�سنان اأعلى بكثري يف املر�سى الذين يعانون من مر�ض ال�سكري غري املن�سبط مقارنة مع اأولئك امل�سابني بداء ال�سكري املن�سبط بالعالج. مفتاح الكلمات: مر�ض ال�سكري؛ اللعاب؛ جلوبيولني املناعي a؛ اأعرا�ض الفم؛ اإيران. evaluation of salivary secretory immunoglobulin a levels in diabetic patients and association with oral and dental manifestations shahla kakoei,1,2 *bahareh hosseini,1,3 ali-akbar haghdoost,4 mojgan sanjari,5 ahmad gholamhosseinian,6 vahid f. n. afshar2 departments of 1oral medicine and 6biochemistry and centers for 2oral & dental diseases research, 3endontology research, 4modeling in health research and 5endocrinology & metabolism diseases research, institute of basic & clinical physiology sciences, kerman university of medical sciences, kerman, iran *corresponding author e-mail: bhd_1362@yahoo.com clinical & basic research sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e507–511, epub. 23 nov 15 submitted 28 dec 14 revisions req. 10 mar & 6 may 15; revisions recd. 13 apr & 19 may 15 accepted 24 may 15 doi: 10.18295/squmj.2015.15.04.011 evaluation of salivary secretory immunoglobulin a levels in diabetic patients and association with oral and dental manifestations e508 | squ medical journal, november 2015, volume 15, issue 4 advances in knowledge to the best of the authors’ knowledge, little information exists regarding the probable association between salivary secretory immunoglobulin a (s-iga) levels and oral and dental manifestations in patients with type 2 diabetes (t2dm). advances in patient care determination of the salivary components of patients with t2dm could play a fundamental role in predicting, detecting and managing oral and dental manifestations of the disease. based on the results of this study, it is recommended that patients exhibiting a change or decrease in their s-iga levels undergo periodic oral health evaluations. type 2 diabetes mellitus (t2dm) is one of the most prevalent metabolic disorders worldwide; by 2025, approximately 320 million people will have the disease.1 the disease has a wide range of signs and symptoms and manifests differently in various organs. in the oral cavity, manifestations of diabetes can include a dry or burning mouth, periodontal diseases, bone loss, dental abscesses, fungal and bacterial infections, oral lichen planus and delayed wound healing.1,2 immunoglobulin a (iga) and immunoglobulin g affect oral cavity microorganisms in the saliva, gingival sulcular fluid and plasma.3 these antibodies prevent bacterial metabolism and adhesion of microorganisms to the oral tissue.3 although there are many nonspecific defensive elements in the saliva, such as lactoferrin and lysozymes, salivary secretory iga (s-iga) is the foremost protective mechanism against bacterial colonisation of the oral mucous membranes. as s-iga plays an important role in protecting against these pathogens, the antibody might also protect against periodontal diseases.4 changes in salivary iga concentrations in diabetic patients could have an effect on their oral health. several studies have sought to determine salivary flow rates and components that can affect the progression, symptoms and varieties of oral changes in diabetic patients.1,2,5 overall, determining the salivary components of diabetic patients can be useful in detecting and managing their oral manifestations.5 previous research has assessed s-iga levels and oral conditions among diabetic patients. a brazilian study reported that diabetic patients with lower s-iga levels had more severe and frequent periodontal disease.4 however, two iranian studies yielded different results: mohiti-ardekani et al. recorded significantly higher s-iga levels in diabetic patients while bakianian vaziri et al. found no significant differences between diabetic and non-diabetic groups.1,5 other studies have also reported conflicting results with regards to s-iga levels and their relationship to various diseases.6,7 the current study aimed to compare s-iga levels between healthy subjects and t2dm patients and determine the association between s-iga levels and various oral and dental manifestations in diabetic patients. this relationship could help determine the prognosis of oral diseases in diabetic patients and serve as a guide for their dental care. methods this cross-sectional descriptive study was carried out between october 2011 and september 2012 in kerman, iran, and included 260 subjects divided into two groups. the first group consisted of 128 patients with t2dm who routinely attended followup appointments at the diabetes center of shahid bahonar hospital in kerman. the non-diabetic control group was composed of 132 healthy individuals with no history of dm who attended annual check-ups at either the razi laboratory or the besat clinical laboratory in kerman. information regarding the subjects’ gender, age, diabetes type and medical results (including assessments of glycated haemoglobin [hba1c] and fasting blood sugar [fbs] levels) was compiled by a trained dental student. smokers and subjects <20 years old were excluded from the study. control subjects were included only if they had fbs levels of <100 mg/dl, no systemic disorders and did not take medications that affected either iga secretion or its levels in the saliva. a diagnosis of t2dm was made with a hba1c level of ≥6.5%, fasting plasma glucose (pg) level of ≥126 mg/dl and a two-hour pg level of ≥200 mg/dl. for patients exhibiting classic symptoms of hyperglycaemic crises, a random pg measurement of ≥200 mg/dl met the criteria for a diagnosis of t2dm.8 known diabetic patients who were already taking medicine for lowering blood glucose and who had a hba1c level of ≥6.5% were determined to have uncontrolled t2dm. the oral mucosa of all subjects was checked for abnormalities, including manifestations of oral candidiasis (erythematous candidiasis, thrush, angu lar cheilitis, median rhomboid glossitis and denture stomatitis), lichenoid reactions and frequent abscesses. the characteristics of any noted lesions and their locations were recorded. in addition, a tongue blade test was performed on all participants to detect xerostomia. the guidelines of the world health organization for assessing dental cavities were used to calculate the number of decayed, missing or filled teeth (dmft).9 the periodontal disease index (pdi) were used to evaluate the effect of any periodontal disease on the supporting tissues of the oral mucosa. xerostomia was assessed using fox et al.’s standardised questionnaire.10 shahla kakoei, bahareh hosseini, ali-akbar haghdoost, mojgan sanjari, ahmad gholamhosseinian and vahid f. n. afshar clinical and basic research | e509 unstimulated salivary samples were collected from all subjects in the morning (between 7:30 and 9:30 a.m.) after fasting for eight hours and having cleaned their mouths and teeth 90 minutes beforehand.1 participants were requested to keep their mouths closed for a few moments in order for saliva to pool and then hold their heads over a container and release, resulting in a sample of 1‒2 ml of saliva.3 samples were then frozen to -20 °c and sent to a laboratory for testing.11 concentrations of s-iga were determined using the immunoturbidimetric method with measurements obtained from a commercial kit (pars azmoon co., tehran, iran) and an automated continuous flow analyser (autoanalyzer, technicon systems inc., oakland, california, usa).12 data were analysed using the statistical package for the social sciences (spss), version 17 (ibm corp., chicago, illinois, usa). pearson’s correlation coefficient test was used to determine the relationship between s-iga levels and age, hba1c and fbs. the independent t-test was used to compare dmft and pdi indices between the groups. this study was approved by the ethics committee of kerman university of medical sciences (#k/91/05). all subjects gave informed consent before participating in the study. results a total of 128 t2dm patients and 132 healthy adults were included in the study. the mean age of the subjects was 47.96 years (range: 20–83 years old). mean s-iga levels in the diabetic and control groups were 45.40 ± 6.87 mg/dl and 41.17 ± 7.66 mg/dl, respectively; this difference between the two groups was not significant (p >0.050). there was no significant difference in s-iga levels between genders or with age. however, there was a significant increase in s-iga levels among patients with uncontrolled t2dm compared to those with controlled disease (p <0.050). both the dmft and pdi indices showed significant increases among the diabetic patients in comparison with the control group (p <0.050). between the two groups, s-iga levels were significantly higher among subjects with a higher pdi index. correlations between s-iga levels and other variables are shown in table 1. table 2 shows the distribution of various oral and dental manifestations among the two groups. s-iga levels were significantly higher in subjects with oral candidiasis in both the diabetic and control groups. tongue blade signs were positive for two subjects in the control group and 38 patients in the diabetic group. s-iga levels were significantly higher for diabetic patients with xerostomia in comparison to the control subjects (p = 0.050). diabetic patients also suffered from denture stomatitis more frequently than control subjects with significantly higher s-iga levels (p ≤0.050). discussion as patients with systemic diseases such as dm become better educated regarding self-management table 1: correlation between salivary secretory immunoglobulin a concentrations and other variables among control and diabetic subjects in kerman, iran (n = 260) variable correlation with s-iga concentration r (p value) control group (n = 132) diabetic group (n = 128) total age 0.05 (0.520) 0.15 (0.070) 0.10 (0.080) hba1c 0.30 (0.009)* fbs -0.07 (0.370) -0.06 (0.460) -0.01 (0.830) dmft 0.06 (0.510) 0.22 (0.040)† 0.14 (0.04)† pdi 0.40 (0.001)* 0.50 (0.004)* 0.12 (0.001)* s-iga = salivary secretory immunoglobulin a; hba1c = glycated haemoglobin; fbs = fasting blood sugar; dmft = decayed, missing or filled teeth; pdi = periodontal index. *highly statistically significant at p <0.001. †statistically significant at p <0.050. table 2: comparison between salivary secretory immunoglobulin a levels and oral and dental manifestations among control and diabetic subjects in kerman, iran (n = 260) oral/dental manifestation control group diabetic group mean iga in mg/dl ± se p value mean iga in mg/dl ± se p value oral candidiasis 79.5 ± 16.5 0.010* 67.5 ± 10.6 0.006* erythematous candidiasis 74.0 ± 16.8 0.160 thrush 49.0 ± 11.7 0.630 median rhomboid glossitis 35.7 ± 15.9 0.810 denture stomatitis 64.1 ± 22.9 0.280 71.4 ± 14.7 0.002 angular cheilitis 95.0 ± 25.0 0.010* 89.2 ± 27.9 0.110 lichenoid reactions 34.6 ± 6.6 0.880 126.5 ± 76.5 0.460 frequent abscesses 35.0 ± 6.5 0.650 xerostomia 35.0 ± 15.0 0.890 51.8 ± 7.5 0.050* iga = immunoglobulin a; se = standard error. *statistically significant at p ≤0.05. evaluation of salivary secretory immunoglobulin a levels in diabetic patients and association with oral and dental manifestations e510 | squ medical journal, november 2015, volume 15, issue 4 and beneficial lifestyle choices, they are increasingly seeking to address their oral health issues.13 while various research has focused on diabetic subjects, few studies have evaluated salivary immunoglobulin levels among this patient population. unlike other body fluids, saliva is easily accessible and there is therefore no need for aggressive sampling techniques in order to make a diagnosis or determine the prognosis of a disease. as such, many researchers prefer to use saliva instead of blood for sampling purposes.14,15 saliva is a complex biological fluid and conditions which affect saliva production—such as xerostomia and saliva excretion dysfunction—decrease its buffering and cleansing capacity. in addition, neuropathic disturbances in diabetic patients can influence the development of dental caries and periodontal diseases.16 within the oral cavity, s-iga can act as the first line of defence against pathogens that affect mucous membranes by preventing the aggregation and adhesion of bacteria to the mucosa and neutralising enzymes, toxins and viruses.10 the concentrations of various salivary elements, such as s-iga, have been investigated in a number of systemic diseases as well as many oral conditions, including periodontitis, xerostomia, lichen planus and smoking-induced oral diseases.14,17–21 immune suppression or disturbances have been observed in diabetic patients;2 it is possible that t2dm affects the secretion of iga in the saliva and, consequently, the defence reaction of the mucosa. in the present study, s-iga levels in diabetic patients were not significantly higher in comparison with non-diabetic individuals. this result is similar to those seen in previous studies.5–7,9,22 in contrast, mohiti-ardekani et al. demonstrated that s-iga levels in diabetic patients were higher than in non-diabetics.1 other studies have also found higher s-iga levels in diabetic patients.1,22 discrepancies between these results could be attributed to differences in study designs and sampling and measuring techniques (e.g. the use of stimulated versus unstimulated saliva or immunoturbidimetric versus immunonephelometric methods).5 s-iga levels were considerably higher in patients with uncontrolled t2dm in the current study. harrison et al. and malicka et al. found similarly high s-iga levels in patients with poorly controlled diabetes.10,24 in the current research, there was a significant positive relationship between s-iga and pdi and dmft indices in both groups, suggesting that the innate immune system tries to synthesise high levels of iga to reduce periodontal tissue infections.10 in addition, kakoei et al. also noted a positive association between high salivary glucose levels and dmft and pdi indices in diabetic patients.25 this is compatible with other findings showing that s-iga levels were significantly higher in diabetic patients with periodontitis.10,18,26 using the gingival and modified sulcus bleeding indices, malicka et al. reported that the periodontal status of diabetic patients was significantly worse than that of healthy subjects.12 ranadheer et al. showed that s-iga levels were significantly higher among individuals with more than three dmft.15 in studies by bakianian vaziri et al. and lopez et al., diabetic patients had significantly increased numbers of dmft in comparison with healthy subjects.5,27 in the current study, the prevalence of oral candidiasis was significantly higher in the subjects with higher s-iga levels in both groups; this is consistent with the results observed by jaganathan et al.28 however, no significant relationship between s-iga and oral lichen planus was found. this correlates with previous research by divya et al., who did not report any significant association between s-iga levels and pre-cancerous lesions like lichen planus.20 in contrast, ghalayani et al. found higher s-iga levels in patients with oral lichen planus in comparison with normal individuals.21 in the present study, a significant increase in s-iga levels was found in diabetic patients with denture stomatitis. a study by papova et al. also showed that s-iga levels in patients with denture stomatitis were significantly higher in comparison to a control group.29 the results of the current study differed from those observed in a study by wilson et al., who found that that s-iga levels were significantly lower in denture wearers with denture stomatitis in comparison to healthy subjects.30 changes in the function and components of saliva as a result of different conditions among diabetic patients (e.g. dental caries, periodontitis, burning mouth and sensory problems) are not yet fully understood. previous investigations have shown the efficacy of the buffering capacity and cleansing effect of saliva in negating some of these changes.16 however, the differences in s-iga levels in different studies could be attributed to different sampling techniques or detection methods. one of the limitations of the current study was an inability to assess oral hygiene among the subjects. further investigations are recommended to detect salivary immunoglobulins among diabetic patients in order to determine a precise and more reliable technique to predict and manage oral manifestations of the disease. conclusion the s-iga levels of the diabetic patients were not significantly higher than those of the control group among the studied population. in both groups, subjects with a higher number of dmft, greater pdi scores and oral candidiasis were found to have significantly shahla kakoei, bahareh hosseini, ali-akbar haghdoost, mojgan sanjari, ahmad gholamhosseinian and vahid f. n. afshar clinical and basic research | e511 higher s-iga levels. among diabetic patients, significantly higher s-iga levels were concomitant with xerostomia and denture stomatitis. furthermore, s-iga levels were found to be significantly elevated in patients with uncontrolled t2dm compared to those with controlled t2dm. further research is needed to investigate s-iga concentrations among diabetic patients in order to aid in the prediction and management of oral manifestations. a c k n o w l e d g e m e n t s this article was based on a thesis submitted to the kerman dental school (no. 753). the authors wish to thank the research committee of the kerman university of medical sciences for their financial support. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. mohiti-ardekani a, karbassi mh, mohiti-ardekani j, akhondinasab f, mohammad mh. evaluation of salivary iga in diabetic and non-diabetic patients: a case-control study. iran j diabetes obes 2012; 4:167–71. 2. petrou-amerikanou c, markopoulos ak, belazi m, karamitsos d, papanayotou p. prevalence of oral lichen planus in diabetes mellitus according to the type of diabetes. oral dis 1998; 4:37–40. doi: 10.1111/j.1601-0825.1998.tb00253.x. 3. marcotte h, lavoie mc. oral microbial ecology and the role of salivary immunoglobulin a. microbiol mol biol rev 1998; 62:71–109. 4. branco-de-almeida ls, alves cm, lopes ff, pereira ade f, guerra rn, pereira al. salivary iga and periodontal treatment needs in diabetic patients. braz oral res 2011; 25:550–5. doi: 10.1590/s1806-83242011000600013. 5. bakianian vaziri p, vahedi m, mortazavi h, abdollahzade sh, hajilooi m. evaluation of salivary glucose, iga and flow rate in diabetic patients: a case-control study. j dent (tehran) 2010; 7:13–18. 6. bonamico m, nenna r, luparia rp, perricone c, montuori m, lucantoni f, et al. radioimmunological detection of antitransglutaminase autoantibodies in human saliva: a useful test to monitor coeliac disease follow-up. aliment pharmacol ther 2008; 28:364–70. doi: 10.1111/j.1365-2036.2008.03720.x. 7. yap g, sil bk, ng lc. use of saliva for early dengue diagnosis. plos negl trop dis 2011; 5:e1046. doi: 10.1371/journal.pntd.0001046. 8. american diabetes association. diagnosis and classification of diabetes mellitus. diabetes care 2010; 33:s62–9. doi: 10.2337/ dc10-s062. 9. world health organization. oral health surveys: basic methods. 3rd ed. geneva, switzerland: who press, 1987. 10. fox pc, busch ka, baum bj. subjective reports of xerostomia and objective measures of salivary gland performance. j am dent assoc 1987; 115:581–4. doi: 10.1016/s0002-8177(87)54012-0. 11. belazi ma, galli-tsinopoulou a, drakoulakos d, fleva a, papanayiotou ph. salivary alterations in insulin-dependent diabetes mellitus. int j paediatr dent 1998; 8:29–33. doi: 10.1046/j.1365-263x.1998.00057.x. 12. malicka b, kaczmarek u, skośkiewicz-malinowska k. selected antibacterial factors in the saliva of diabetic patients. arch oral biol 2015; 60:425–31. doi: 10.1016/j.archoralbio.2014.07.010. 13. parirokh m, eghbal mj, ghoddusi j, kakoei s, haghdoost aa, kakooei s. the frequency of medically compromised patients in endodontic offices in iran. iran endod j 2013; 8:48–51. doi: 10.7508/10.7508/iej. 14. castagnola m, picciotti pm, messana i, fanali c, fiorita a, cabras t, et al. potential applications of human saliva as diagnostic fluid. acta otorhinolaryngol ital 2011; 31:347–57. 15. ranadheer e, nayak ua, reddy nv, rao va. the relationship between salivary iga levels and dental caries in children. j indian soc pedod prev dent 2011; 29:106–12. doi: 10.4103/09704388.84681. 16. al-maskari a, al-maskari m, al-sudairy a. oral manifestations and complications of diabetes mellitus: a review. sultan qaboos univ med j 2011; 11:179–86. 17. ohyama k, moriyama m, hayashida jn, tanaka a, maehara t, ieda s, et al. saliva as a potential tool for diagnosis of dry mouth including sjögren’s syndrome. oral dis 2015; 21:224–31. doi: 10.1111/odi.12252. 18. brito e cabral p, júnior je, de macedo ac, alves ar, gonçalves tb, brito e cabral tc, et al. anti-pgl1 salivary iga/igm, serum igg/igm, and nasal mycobacterium leprae dna in individuals with household contact with leprosy. int j infect dis 2013; 17:e1005–10. doi: 10.1016/j.ijid.2013.05.011. 19. olayanju oa, rahamon sk, joseph io, arinola og. salivary immunoglobulin classes in nigerians with periodontitis. j contemp dent pract 2012; 13:163–6. doi: 10.5005/jpjournals-10024-1114. 20. divya vc, sathasivasubramanian s. estimation of serum and salivary immunoglobulin g and immunoglobulin a in oral precancer: a study in oral submucous fibrosis and oral lichen planus. j nat sci biol med 2014; 5:90–4. doi: 10.4103/0976-9668.127294. 21. ghaleyani p, sardari f, akbari m. salivary iga and igg in oral lichen planus and oral lichenoid reactions diseases. adv biomed res 2012; 1:73. doi: 10.4103/2277-9175.102977. 22. ben-aryeh h, cohen m, kanter y, szargel r, laufer d. salivary composition in diabetic patients. j diabet complications 1988; 2:96–9. doi: 10.1016/0891-6632(88)90011-6. 23. dodds mw, yeh ck, johnson da. salivary alterations in type 2 (non-insulin-dependent) diabetes mellitus and hypertension. community dent oral epidemiol 2000; 28:373–81. doi: 10.1034/j.1600-0528.2000.028005373.x. 24. harrison r, bowen wh. flow rate and organic constituents of whole saliva in insulin-dependent diabetic children and adolescents. pediatr dent 1987; 9:287–91. 25. kakoei s, hosseini b, haghdoost aa, sanjari m, hashemipour ma, gholamhosseinian a. the detection of salivary glucose, caries and periodontal status in diabetes mellitus patients. j oral health oral epidemiol 2014; 3:79–84. 26. bachrach g, muster z, raz i, chaushu g, stabholz a, nussbaum g, et al. assessing the levels of immunoglobulins in the saliva of diabetic individuals with periodontitis using checkerboard immunodetection. oral dis 2008; 14:51–9. doi: 10.1111/j.16010825.2006.01345.x. 27. lópez me, colloca me, páez rg, schallmach jn, koss ma, chervonagura a. salivary characteristics of diabetic children. braz dent j 2003; 14:26–31. doi: 10.1590/s0103-64402003000100005. 28. jeganathan s, ufomata d, hobkirk ja, ivanyi l. immunoglobulin a1 and a2 subclass of salivary antibodies to candida albicans in patients with oral candidosis. clin exp immunol 1987; 70:316–21. 29. popova e, stankova g, dermendzieva s. [quantitative determination of immunoglobulins in serum and saliva of patients with denture stomatitis]. stomatologiia (sofiia) 1989; 71:23–7. 30. wilson j, wilton jm, sterne ja. comparison of secretory iga and igg isotype levels in palatal secretions of denture stomatitis patients with denture wearers having clinically healthy palates. eur j prosthodont restor dent 2007; 15:50–4. http://dx.doi.org/10.1111/j.1601-0825.1998.tb00253.x http://dx.doi.org/10.1590/s1806-83242011000600013 http://dx.doi.org/10.1111/j.1365-2036.2008.03720.x http://dx.doi.org/10.1371/journal.pntd.0001046 http://dx.doi.org/10.2337/dc10-s062 http://dx.doi.org/10.2337/dc10-s062 http://dx.doi.org/10.1016/s0002-8177%2887%2954012-0 http://dx.doi.org/10.1046/j.1365-263x.1998.00057.x http://dx.doi.org/10.1016/j.archoralbio.2014.07.010 http://dx.doi.org/10.7508/10.7508/iej http://dx.doi.org/10.4103/0970-4388.84681 http://dx.doi.org/10.4103/0970-4388.84681 http://dx.doi.org/10.1111/odi.12252 http://dx.doi.org/10.1016/j.ijid.2013.05.011 http://dx.doi.org/10.5005/jp-journals-10024-1114 http://dx.doi.org/10.5005/jp-journals-10024-1114 http://dx.doi.org/10.4103/0976-9668.127294 http://dx.doi.org/10.4103/2277-9175.102977 http://dx.doi.org/10.1016/0891-6632%2888%2990011-6 http://dx.doi.org/10.1034/j.1600-0528.2000.028005373.x http://dx.doi.org/10.1590/s0103-64402003000100005 clinical & basic research squ med j, may 2012, vol. 12, iss. 2, pp. 177-183, epub. 9th apr 2012 submitted 23rd sep 11 revision req. 18th jan 12, revision recd. 10th & 18th feb 12 accepted 17th mar 12 departments of 1anaesthesia & intensive care and 2pathology, sultan qaboos university hospital muscat, oman; 3intensive care unit, royal adelaide hospital, australia. *corresponding author e-mail: drqutaibaamir@yahoo.com فقر الدم املنجلي لدى البالغني جتربة مخس سنوات من العناية املركزة يف مستشفى جامعي يف ُعمان. قتيبة عامر توفيق، راجيني كوزاليا، �سحى حممود علوان، جوتي براد، اأحمد خمي�س حممد، اأرفند نرايانان االأكرث الوراثية الدم ا�سطرابات من واحد وهو الهيموغلوبني، من طبيعي غري نوع عن ناجم وراثي مر�س املنجلي الدم فقر امللخ�ص: �سيوعا يف منطقة اخلليج، مبا يف ذلك ُعمان. قد يح�سل م�ساعفات تتطلب العالج يف وحدة العناية املركزة. هذه الدرا�سة تبحث االأ�سباب التي اأدت اإىل اإدخال املر�سى امل�سابني بفقر الدم املنجلي وحدة العناية املركزة. الطريقة: هذه درا�سة ا�ستعادية جلميع املر�سى البالغني )12 �سنة اأو اأكرث( امل�سابني بفقر الدم املنجلي الذين رقدوا يف وحدة العناية املركزة مب�ست�سفى جامعة ال�سلطان قابو�س بني يناير 2005 ودي�سمرب 2009. النتائج: مت اإح�ساء 56 حالة رقود ل 49 مري�سا يف وحدة العناية املركزة. �سملت اأ�سباب الرقود متالزمة ال�سدر احلادة )%69.6(، واالأزمات املوؤملة )%16.1(، ف�سل االأع�ساء املتعددة )%7.1( واأ�سباب اأخرى )%7.2(. كان معدل وفيات مر�سى فقر الدم العناية وحدة دخول حني اأ�س والهيموجلوبني الهيموجلوبني م�ستويات درا�سة مّت .)16.1%( املركزة العناية يف الراقدين املنجلي املركزة لكن مل تظهر اأية داللة اإح�سائية معتّدة لهما يف فح�س )تي( لتوقع الوفاة. مت ا�ستخدام ن�سبة االأرجحية مع فرتة الثقة )95%( موؤ�رض امليكانيكي والتنف�س الدوران جهاز دعم على للح�سول احلاجة كانت بالوفيات. للتكّهن اأع�ساء ل�ستة داعمة اأخرى تدابري لدرا�سة جيد للوفيات، يف حني اأن احلاجة اإىل التنف�س غري الغازي وتر�سيح الدم وعمليات نقل الدم وتبديل الدم ال تعترب ذات داللة كبرية للتكهن باحتماالت الوفاة. اخلال�صة: متالزمة ال�سدر احلادة هي ال�سبب الرئي�سي الإدخال مري�س فقر الدم املنجلي يف وحدة العناية املركزة. خالفا لغريها من االإجراءات الداعمة، ا�ستخدام الدعم جلهاز الدوران و/اأو التنف�س امليكانيكي هو موؤ�رض على ارتفاع معدل وفيات هوؤالء املر�سى. مفتاح الكلمات: فقر الدم، خلية منجلية، متالزمة ال�سدر احلادة، ُعمان. abstract: objectives: sickle cell disease (scd) is an inherited disease caused by an abnormal type of haemoglobin. it is one of the most common genetic blood disorders in the gulf area, including oman. it may be associated with complications requiring intensive care unit (icu) admission. this study investigated the causes of icu admission for scd patients. methods: this was a retrospective analysis of all adult patients ≥12 years old with scd admitted to sultan qaboos university hospital (squh) icu between 1st january 2005 and 31st december 2009. results: a total number of 49 sickle cell patients were admitted 56 times to icu. the reasons for admission were acute chest syndrome (69.6%), painful crises (16.1%), multi-organ failure (7.1%) and others (7.2%). the mortality for scd patients in our icu was 16.1%. the haemoglobin (hb) and hb s levels at time of icu admission were studied as predictors of mortality and neither showed statistical significance by student’s t-test. the odds ratio, with 95% confidence intervals, was used to study other six organ supportive measures as predictors of mortality. the need for inotropic support and mechanical ventilation was a good predictor of mortality. while the need for noninvasive ventilation, haemofiltration, blood transfusions and exchange transfusions were not significant predictors of mortality. conclusion: acute chest syndrome is the main cause of icu admission in scd patient. unlike other supportive measures, the use of inotropic support and/or mechanical ventilation is an indicator of high mortality rate scd patient. keywords: anemia; sickle cell; acute chest syndrome; oman. adult sickle cell disease a five-year experience of intensive care management in a university hospital in oman *qutaiba amir tawfic,1 rajini kausalya,1 dhuha al-sajee,2 jyoti burad,1 ahmed k mohammed,1 aravind narayanan3 advances in knowledge this study gives a descriptive analysis for sickle cell patients admitted to an intensive care unit. it validates the rate and causes of sickle cell patients’ admission to intensive care unit. the need for inotropic support and mechanical ventilation are the main mortality predictors for sickle cell patient in an intensive care unit. adult sickle cell disease a five-year experience of intensive care management in a university hospital in oman 178 | squ medical journal, may 2012, volume 12, issue 2 sickle cell disease (scd) is an autosomal recessive disease caused by an abnormal type of haemoglobin, termed haemoglobin s (hb s).this haemoglobin is caused by the substitution of valine for glutamic acid at the sixth amino acid position of the beta chain.1, 2 there is more than one form of sickle cell disease resulting from coinheritance of hb s with other abnormal hb variants. sickle cell anaemia (hb ss) is the commonest form in the usa. other forms include, hb sβ+-thalassaemia, hb sd hb sc. there are rare forms result from coinheritance of other hb variants such as d-punjab and o-arab with hb s.1 scd is much more common in certain ethnic groups and it is considered as one of the most common genetic blood disorders in the gulf area, including oman.2 in oman, the incidence of sickle cell disease and sickle cell trait in omani neonates was 0.3% and 4.8% respectively.3although the scd manifestations per se do not typically necessitate critical care management, several lifethreatening complications may require intensive care unit (icu) admission. some patients have repeated crises, which can result in damage to different organs or systems. the most common complications associated with scd include vasoocclusive pain crises (voc), acute chest syndrome, severe anaemia, infection, cerebral vascular accidents, and multiorgan failure.4,5 because of the fact that there has been little progress in fully understanding the pathophysiology of scd and finding a cure for it, our management is primarily focusing on treating the negative sequelae and complications of the disease.6,7 this study was a descriptive analysis of sickle cell patients who were admitted with complications to the icu at sultan qaboos university hospital, oman, over five years and investigated the predictive factors for sickle cell mortality. methods this study was a retrospective analysis of all adult patients ≥12 years with scd admitted to the squh icu between 1st january 2005 and 31st december 2009. the study was approved by both the institution’s medical research committee and its ethics committee. squh is a tertiary care, teaching hospital with a 12-bed icu and haematology ward. data were collected from the squh information system (his) and its electronic patient records (epr) as well as the squh intensive care database. information collected included presentation, co-morbidities, organ failure, organ support, length of stay in the icu, and final outcome. eight factors were studied as predictors for mortality for scd in icu. these included hb and hb s levels in addition to six methods of organ support: inotropes, invasive ventilation, noninvasive positive pressure ventilation (nippv), haemodialysis/ haemofiltration, blood transfusion and exchange transfusions. the student’s t-test was used for continuous/ordinary variables, while odds ratios (ors), with 95% confidence intervals (cis) were used to assess binary variables. results a total of 49 sickle cell patients were admitted 56 times to the icu; 25 of those admissions (44.6%) were female patients. two patients had three admissions while three patients had two admissions each. the range of patients’ ages was 12 and 52 years, with median of 27 years. our icu admits patients ≥ 16 years old, but our protocol allows admission of specific surgical cases and trauma down to the age of 12 years. acute chest syndrome was the commonest reason for admission (n = 39, 69.6%) [table 1]. painful crises were the principal cause of admission for 9 patients (16.1%). however, voc was present in another 16 cases in association with other major complaints like acute chest syndrome (acs). multiorgan failure (mof) was the cause of admission in 4 patients (7.1%). neurological complications related to scd were found in 2 patients (3.57%). one patient application to patient care this study will improve sickle cell patient care in intensive care units by understanding causes of admission, complications, length of stay and mortality. it helps in realising the modes of organ support required for those patients. qutaiba amir tawfic, rajini kausalya,dhuha al-sajee, jyoti burad,ahmed k mohammed and aravind narayanan clinical and basic research | 179 was transferred intubated from another hospital with radiological features of cerebral ischaemia and anoxic brain injury. the other patient had a subarachnoid haemorrhage. one patient was admitted with hepatic failure associated with hepato-renal shutdown and features of hepatic encephalopathy (1.8%). another 12-year-old patient was admitted to our adult icu as a surgical case after laparoscopic splenectomy and cholecystectomy with sever intra-operative haemorrhage. eight patients were admitted through the emergency department (14.28%) in comparison to 46 admissions (83.9%) from the ward. only one patient (1.78%) was referred, intubated, from another hospital directly to our icu. the mortality for scd in our icu was 16.07% (9 patients), comparable to an icu-overall mortality of 21.1% during the same period in the same institute. five cases were admitted with acs and four cases with mof. the length of stay in the icu ranged from 1 to 23 days. for survivors, the mean lengths of icu stay was 5 days, while for non-survivors it was 2.7 days. this is considered to be statistically significant (p = 0.04). a total of 27 admissions for those who survived were with those with no co-morbidities (57.4%) in comparison to 4 admissions among those who died (44 %). the survivors’ co-morbidities can be classified into: behcet’s disease (1); autoimmune disease (1); hepatitis (c and/or b) virus (5); liver cirrhosis (1); osteoporosis with avascular necrosis of one or more joint (6); glucose-6-phosphate dehydrogenase (g6pd) deficiency (4); nephrotic syndrome (2); asthma (2); chronic renal failure (2), and protein c deficiency with cerebral ischaemia (1). four admissions were pregnant patients. it should be taken in consideration that some patients had more than one medical problem or comorbidity at the time of admission. co-morbidities in non-survivors can be classified into: congenital neutropenia (1); dilated cardio-myopathy (1); systemic lupus erythematosus associated with chronic renal failure (2), and nephrotic syndrome (1). in the icu, the level of hb and hb s at the time of admission was studied as a predictor of mortality. the mean hb for both, survivors and non-survivors were similar (8.3mg/dl and 8.6mg/dl, respectively). the range of hb was (4.4–12.5 gm/dl) for those who survived and (6.4–11.2gm/dl) for non survivors. this result is not statistically significant (p = 0.8). for those who survived, the hb s mean for 36 cases was 63% with standard deviation (sd) 21.5 (11 not available), while for non-survivors the mean hb s for 7 admissions was 54.5% (2 not available) with sd 25.5. this result is also not statistically significant by t-test (p = 0.4). high-performance liquid chromatography (hplc) was used to study hb s through bio-rad variant ii (bio-rad laboratories, inc., hercules, california, usa). most of the patients in this study were admitted for some time in the ward and received simple or exchange blood transfusions before coming to the icu. the odds ratio (or), with 95% cis, was used to study the six organ supportive measures as a predictive for the increase in mortality [table 2]. these supportive measures include the use of inotropes, invasive ventilation, nippv, haemodialysis/ haemofiltration, exchange transfusion and top-up blood transfusions. requirement for inotropes was a good predictive for mortality (or 117.3). it means that mortality is much more likely in scd patient who require cardiovascular support in the form of inotropes. eight of the 9 patients who died required inotropes. four of those patients had mof and another 4 acs. three of 47 patients who survived required inotropic support. all the three were admitted with acs. invasive mechanical ventilation (mv) was similarly a good predictive for mortality as 8 of 9 patients who died required mv while another 8 required mv among those who survived (or 39). regarding those who required intubation and table 1: causes of intensive care unit admission for sickle cell patients. cause of admission number (n = 56) percentage acute chest syndrome 39 69.6 painful crises 9 16.1 multi-organ failure 4 7.1 brain insult 2 3.6 hepatic failure 1 1.8 surgical cause 1 1.8 adult sickle cell disease a five-year experience of intensive care management in a university hospital in oman 180 | squ medical journal, may 2012, volume 12, issue 2 mechanical ventilation among non-survivors, 4 of them had mof and the other 4 had acs. of those who survived, one patient was admitted for subarachnoid haemorrhage, one patient for cerebral ischaemia and anoxic brain injury (ended with tracheostomy), another patient post laparoscopic surgery, and all others with acs. nippv was studied as a predictor for mortality (or 0.09). this ratio illustrates that mortality was very unlikely in those patients who have scd and do require nippv. nippv was required in 28 admissions (27 survived). the only patient who died was a case of acs who had a sudden cardiac arrest while he was on nippv. simple blood transfusion was used to support 35 scd admissions in icu (62.5%). a total of 29 of them survived while 6 died. the need for blood transfusion was not considered as a very good predictor for mortality (or 1.2). blood exchange transfusion was used in 45 admissions (80.4%), 7 of them died. the need for exchange transfusion does not predict mortality (or 0.8). continuous veno-venous haemodialysis (cvvhd) was used in 8 admissions; four of them died (or 8.6). two of those who died were admitted because of acs as a part of generalised voc and they developed acute renal failure. the other two were admitted with systemic lupus erythmatosus and chronic renal failure. for the 4 admissions that had acute renal failure and survived, 3 had acs and one had hepato-renal shutdown. as haemodialysis was used for both acute and chronic renal failure, it was not considered a good indicator of severe acute illness and mortality discussion sickle cell vaso-occlusion may involve both the microand macrovasculature. it is the most important pathophysiologic event in scd and explains most of its clinical manifestation. the median age at death in patient with scd is 42 years for males and 48 years for females.8 acute chest syndrome (acs) is a common cause of admission and death among patients with sickle cell disease. acs is usually caused by infection, pulmonary infarction or fat embolism. painful crisis is the main cause of admission in those patients (90%). to reach a diagnosis of acs, we need a triad of fever, respiratory distress and new interstitial infiltrates on chest x-ray.9,10,11 this study represents the first data collection and analysis of sickle cell patients admitted to an icu in oman. in squh, the adult 12 bed icu admits both medical and surgical cases including trauma patients. we admit some of those patients who require non-invasive ventilation (niv) as well because our high dependency units (hdu) setting is not completed. we also sometimes accept paediatric trauma or post surgical patients ≥ 12 years for specific reasons. over five years there were 56 scd admissions which represent 3.5% of total admissions in our icu. we referred to our patients as sickle cell disease patients depending on their high hb s level, although genotyping studies are required for all patients to confirm the hb ss or other sickle cell types of hb. a retrospective study in the uk reported that hb ss was found in 84% of their icu admission while the other 16% was hb sc.12 this might possibly refer to the severity of disease expression in patients having this type of haemoglobin. all sickle cell patients’ admissions, except one, were for medical reasons. two patients had 3 repeated admissions while three patients had 2 admissions each. these repeated admissions were divided between acs and painful crisis. no mortality was reported among those who had repeated admissions. it was sometimes difficult to choose a single reason for admission as some patients may have a complex clinical presentation with more than one complaint and more than one organ involved. this complexity may be related to the nature of scd and the sickling process. acs was the most common cause of admission (69.6% in our icu) compared to table 2: types of organ support needed by patients admitted to the intensive care unit. organ support survivors nonsurvivors odd ratio inotropic support 3:44 8:1 117.3 mechanical ventilation 8:39 8:1 39 non-invasive ventilation 27:20 1:8 0.09 blood transfusion 21:26 6:3 1.2 exchange transfusion 38:9 7:2 0.8 haemodialysis\ haemofiltration 4:43 4:5 not identified qutaiba amir tawfic, rajini kausalya,dhuha al-sajee, jyoti burad,ahmed k mohammed and aravind narayanan clinical and basic research | 181 30% in gardner’s study.12 all those patients required ventilatory support whether it was invasive or noninvasive. in our study, mof (4 patients) was the third cause of admission after painful crisis with a rate of 7.1%, compared to 17% in gardner’s study.12 the mortality rate for sickle cell patients in our study was less than the overall mortality in our icu (16.1% versus 21.1%). gardner et al. reported a higher icu sickle cell patient mortality compared to overall icu mortality in the same period and same institute (19.6% versus 17.6%).12 we can explain this difference by the cases of painful crises (9 admissions) in our study in which no death was reported, while in the british study there were no painful crises as a cause of admission. in fact, cases of painful crisis can be treated in the ward or in hdu if no other organ support measures are required. according to our hospital protocol, patients who require icu admission are those on very high doses of opioid infusion with no response, those with compromised cardiovascular or respiratory functions, and those who require additional ketamine infusion. we agree that if there is a well-structured hdu, admission of those cases to an icu can be avoided. two main causes of death in icu sickle cell patients were found in our study [table 3]: acs (5 patients, 55.6%) and mof (4 patients, 44.4%). three of those acs patients stayed for less than one day and one patient died after 3 days after admission. regarding the four mof patients who died, two deaths were triggered by acs while another two were associated with sepsis. gardner et al. found that mof and stroke (haemorrhage/ischaemia) were the main causes of death in sickle cell patients in their icu, 33.3% for each condition. acs was next commonest cause with a rate of 22.2% while trauma caused death in 11.1% of cases.12 a review of the causes of death in adult patients (age >20 years) with sickle-cell disease in jamaica by thomas et al. showed that acs was responsible for 22% of death in those patients. other common causes of death in jamaican sickle cell patients were renal failure 15.7%, pregnancyrelated problems 7.4% and sepsis 3.7%.13 the length of stay in the icu ranged from 1 to 23 days. for non-survivors, 4 of 9 patients (44%) stayed for less than 24 hours. one patient with a history of dilated cardiomyopathy was admitted from the emergency department with mof. the other 3 patients were admitted from the ward with voc/ acs and suddenly deteriorated. one of them had clinical and echocardiographic features suggestive of pulmonary embolism (no spiral computed tomography [ct]). the other two had an element of sepsis in addition to acs. this result can be referred to the nature and complexity of the disease with possibility of rapid deterioration in some cases. the other explanation may be the possibility of delay of icu admission to give intensive supportive measures especially for patient with features of sepsis. the majority of the cases (83.9%) had been table 3: clinical data for non-survivors among sickle cell patients admitted to intensive care unit (icu) age(years)/ gender admission hb gm/dl admission haemglobin s % co-morbidities days of icu stay cause of admission types of support 19/m 8.8 48.4 nil 2 sepsis, mof i, v, b, e 28/f 8.7 36.2 nil 8 acs, mof i,v,b, h 19/m 9.6 na sle, crf, congenital neutropenia 1 acs/pe? i,v, e 22/f 7.2 36.5 sle, crf 2 sepsis, mof i, v, b, e, h 31/f 6.4 na sle, nephrotic syndrome 1 acs, sepsis i, v, b, e 53/f 7.9 33.2 nephrotic syndrome. 3 acs/pe? i, v, b, h 19/f 7.7 91.9 nil 3 acs, sepsis i, v, b, e, h 28/f 9.9 77.8 nil 1 acs niv, e 30/m 11.2 89.6 dilated cardiomyopathy 1 acs, mof i, v, e legend: m = male; f = female; mof = multi organ failure; i = inotropes; v = mechanical ventilation; b = blood transfusion; e = exchange transfusion; acs = acute chest syndrome; h = haemodialysis; sle = systemic lupus erythematosus; crf = chronic renal failure; pe = pulmonary embolism; nil = no co-morbidities, niv = non-invasive ventilation. adult sickle cell disease a five-year experience of intensive care management in a university hospital in oman 182 | squ medical journal, may 2012, volume 12, issue 2 admitted to the ward for some time before being moved to our icu. those patients received all necessary supportive measures in the ward including blood transfusion and exchange transfusion depending on their length of stay. this may mask the role of hb and hb s level at the time of icu admission as an indicator for severity of the crises or even mortality. however, simple and exchange transfusions were performed as supportive measures in 62.5% and 80.4% of icu admissions respectively depending on base line hb and hb s levels and the patient’s general condition. the main aim of red blood cell (rbc) transfusion in scd is to prevent and resolve vasoocclusive events that result in acs, stroke, and other ischaemic organ damages. this transfusion can be chronic or intermittent. the effect of rbc transfusion is improving the oxygen-carrying capacity; lowering blood viscosity; diluting the concentration of hb s, and suppressing production of sickle rbcs due to the improvement in tissue oxygenation.14,15 the indications for intermittent rbc transfusion include: acute symptomatic anaemia; sequestration crisis; aplastic crisis; acute stroke; acs; sepsis; acute multiorgan failure, and preparation for general anesthesia or ophthalmic surgeries.14 simple transfusion is more convenient and easier than exchange transfusion and it is more frequently used for acute transfusion, but exchange transfusion is a good option in an acute crisis patient with a higher pretransfusion hb level or when volume overload and hyperviscosity are of particular concern.16 one of the therapeutic aims of exchange transfusion in vaso-occlusive event like acs is to decrease the proportion of erythrocytes containing hb s to less than 30%, thereby improving microvascular perfusion. two volumes of red cell exchange transfusion decrease hbs containing red blood cells to less than 20%. however, a reduction in hb s levels may not be the only explanation for the early and dramatic clinical improvement often demonstrated in patients with acs after exchange transfusion. this is because neutrophils and platelets, which are inflammation markers, may contribute to venous stasis in the pulmonary microcirculation.14,15 alhashimi d et al., during their cochrane review, found that there is no reliable evidence to support or refute the effectiveness of simple or exchange blood transfusions in treating acs.17 inotropic support was required in 88.9% of those who did not survive in comparison to 6.4% in survivors. it is clear that this difference is basically related to the seriousness of the clinical condition and the presence of elements of sepsis and mof in most of non-survivors. the same facts can be applied to invasive ventilation as it was required in 88.9% in non-survivors compared with 17% for those who survived. patients who required one or both of these organ supports have a significant higher risk of mortality. by contrast, non-invasive ventilation (niv) does not carry that risk as it is usually used for more stable patients with acs who require some ventilatory support. acs may be triggered in scd by infection. usually the clinical presentation is similar whether it is due to infectious or non-infectious causes. therefore, antibiotics can be considered as one of the supportive measures for those patients. antibiotic cover as a line of treatment for those patients was not included in detail in our study.18 finally, there are some limitations to this retrospective study. the sample size was not large; this might be overcome in future research by including multicentre data. the other point was the difficulty in assessing the direct effect of the co-morbidities on mortality. the third point was related to our hospital icu protocol, which led to admitting some categories of sickle cell patients who would normally be treated in an hdu rather than an icu. conclusion scd is a common haematological problem in oman. acs was the main reason for icu admissions in our study. the mortality for scd was slightly less than the overall icu mortality during the same period. the need for inotropes and invasive ventilation were considered the main predictors of mortality. on the other hand, the need for non-invasive ventilation, haemofiltration, blood transfusions and exchange transfusions were not significant predictors of mortality. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest. qutaiba amir tawfic, rajini kausalya,dhuha al-sajee, jyoti burad,ahmed k mohammed and aravind narayanan clinical and basic research | 183 references 1. bender ma, hobbs w. sickle cell disease. in: pagon ra, bird td, dolan cr, stephens k, eds. genereviews [internet]. seattle (wa): university of washington, seattle, 2012. 2. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 3. alkindi s, al zadjali s, al madhani a, daar s, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. 4. chiang ey, frenette ps. sickle cell vaso-occlusion. hematol oncol clin north am 2005; 19:771–84. 5. jaiyesimi f, pandey r, bux d, sreekrishna y, zaki f, krishnamoorthy n. sickle cell morbidity profile in omani children. ann trop paediatr 2002; 22:45–52. 6. chiang ey, frenette ps. sickle cell vaso-occlusion. hematol oncol clin north am 2005; 19:771–84. 7. odièvre mh, verger e, silva-pinto ac, elion j. pathophysiological insights in sickle cell disease. indian j med res 2011; 134:532–7. 8. platt os, brambilla dj, rosse wf, milner pf, castro o, steinberg mh, et al. mortality in sickle cell disease. life expectancy and risk factors for early death. n engl j med 1994; 330:1639–44. 9. ballas sk. current issues in sickle cell pain and its management. hematology am soc hematol educ program 2007:97–105. 10. laurie ga. acute chest syndrome in sickle cell disease. intern med j 2010; 40:372–6. 11. vichinsky ep, neumayr ld, earles an, williams r, lennette et, dean d, et al. causes and outcomes of acute chest syndrome in sickle cell disease. n engl j med 2000; 342: 1855–65. 12. gardner k, bell c, bartram jl, allman m, awogbade m, rees dc, ervine m, thein sl. outcome of adults with sickle cell disease admitted to critical care experience of a single institution in the uk. br j haematol 2010; 150:610–13. 13. thomas an, pattison c, serjeant gr. causes of death in sickle-cell disease in jamaica. br med j 1982; 285:633–5. 14. josephson cd, su ll, hillyer kl, hillyer cd. transfusion in the patient with sickle cell disease: a critical review of the literature and transfusion guidelines. transfus med rev 2007; 21:118–33. 15. liem ri, o’gorman mr, brown dl. effect of red cell exchange transfusion on plasma levels of inflammatory mediators in sickle cell patients with acute chest syndrome. am j hematol 2004; 76:19– 25. 16. wahl s, quirolo kc. current issues in blood transfusion for sickle cell disease. curr opin pediatr 2009; 21:15–21. 17. alhashimi d, fedorowicz z, alhashimi f, dastgiri s. blood transfusions for treating acute chest syndrome in people with sickle cell disease. cochrane database syst rev 2010; 20:cd007843 18. martí-carvajal aj, conterno lo, knight-madden jm. antibiotics for treating acute chest syndrome in people with sickle cell disease. cochrane database syst rev 2007; apr 18:cd006110. sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 19-25, epub. 27th feb 13 submitted 6th jun 12 revision req. 8th sep 12, revision recd. 10th oct 12 accepted 26th nov 12 systemic lupus erythematosus (sle) is a multisystem autoimmune disorder which commonly affects the nervous system. it affects around 130:100,000 people in the united states.1 females are affected 7 times more than males.2 in the united states, african american, hispanic, and asian populations are most commonly affected.1 the overall survival of sle patients has significantly improved over the last 50 years, from 74.8 to 94.8% and from 63.2 to 91.4% for 5-year and 10-year survival, respectively.3 recent data has suggested that both renal and neuropsychiatric involvement negatively affects the overall 5-year survival rate, whereas the neuropsychiatric involvement did not change for the 10-year survival rate.3 the involvement of the nervous system is due primarily to the disease process, secondarily, to infection, or metabolic or drug-related effects. the aim of this review is to discuss the clinical picture, pathogenesis, evaluation, and treatment of neuropsychiatric sle. clinical picture and epidemiology the american college of rheumatology (acr) diagnostic criteria for sle includes only psychosis and seizures as nervous system manifestations. in spite of this, different neuropsychiatric manifestations are recognised in patients with sle. because of the variable presentation, in 1999 the acr established 19 different neuropsychiatric sle syndromes (npsle). the classification of npsle takes into consideration the part of the nervous system that is affected—the central or the peripheral nervous system [table 1]. the prevalence of npsle varies from 40.3% to 91.0%.4–6 the difference in the reported prevalence depends on the case definition used and the use of formal neuropsychological testing for patient evaluation. recent data show that npsle affects the central nervous system in around 93.1% of patients and the peripheral nervous system in 6.9% of patients.4 diffuse npsle accounted for 79% of the events and only 21% were focal in nature.4 most patients will department of medicine, umm al-qura university, makkah, saudi arabia e-mail: dr.amalalkhotani@hotmail.com املتالزمة العصبية-النفسية ملرض الذئبة احلمامية اأمل اخلوتاين امللخ�ض: مر�ض الذئبة احلمامية املجموعية )sle( مر�ض مناعة ذاتية لأجهزة اجل�صم. م�صاركة اجلهاز الع�صبي الأويل اأو الثانوي �صائع الع�صبية الأمرا�ض هذه تتطور احلمامية. الذئبة مر�ض مع تتالزم والنف�صية الع�صبية الأمرا�ض من ع�رس ت�صعة فهناك املر�ض هذا فى والنف�صية املتالزمة مع sle اأوما ي�صمى npsle عن طريق عدة اآليات منها ما ين�صاأ من ت�رسر الأوعيه الدمويه او نتيجة لالأج�صام امل�صادة الذاتيه او ما ينتج عن ا�صابة الن�صجة بعوامل ال�صايتوكني امل�صببة لاللتهاب. مطلوب تقييم دقيق للمري�ض ل�صتبعاد الأ�صباب npsle. الثانوية قبل اأن تعزى الأعرا�ض ملر�ض الذئبة احلمامية. والعالج يعتمد على طبيعة و�صدة متالزمة مفتاح الكلمات: الذئبة احلمامية املجموعية )sle(؛ اجلهاز الع�صبي؛ املتالزمة.الع�صبية-النف�صية. abstract: systemic lupus erythematosus (sle) is a multisystem autoimmune disease. involvement of the nervous system, either primary or secondary, is common in sle, and 19 different neuropsychiatric clinical syndromes have been recognised in association with the disease. several pathophysiological mechanisms have been implicated in the pathogenesis of neuropsychiatric sle (npsle), including vasculopathy, autoantibodies, and cytokine-mediated tissue injury. careful evaluation of the patient is required to rule out secondary causes before attributing the neurological symptoms to sle. treatment depends on the nature and severity of npsle syndrome. keywords: systemic lupus erythematosus (sle); nervous system; neuropsychiatric; syndrome. review neuropsychiatric lupus amal alkhotani neuropsychiatric lupus 20 | squ medical journal, february 2013, volume 13, issue 1 have one neuropsychiatric event, while only 17.4% of the patients have two or more events.4 around 24% of nervous system involvement occurs as an initial presentation.7 in general, around 50–60% of npsle occurrs at disease onset or within the first 5 years after sle onset.8 the reported prevalence of specific npsle is as follows: headache (47.1–57%), seizure (7.5–16%), cerebrovascular disease (4.7–17%), and polyneuropathy (2.4–22%).4–7 the prevalence of cognitive impairment ranges from 5.1–81%, depending on the study.4–6 the same observation has been noted for mood disorders, with the prevalence ranging from 16.5–51%.4,6 the major difference that contributes to this finding is the screening modality in each study. in studies where patients were screened with formal neuropsychiatric and sensitive psychiatric testing, the prevalence of mood disorder and cognitive impairment was high. mild cognitive impairment was the most frequent abnormality among these patients, with only 3–5% exhibiting severe cognitive impairment.8 other npsle syndromes are rarer. for example, the reported prevalence for movement disorders and transverse myelitis is around 1% in each case. in comparison to western data, npsle was uncommon in the data from the arab gulf region. the reported prevalence was around 15.6–19%.9-10 in those studies, seizures were reported in 10% of cases, whereas the incidence of stroke ranged from 4–11%.9-10 the other reported npsle syndromes were movement disorders, myelitis, neuropathy, and psychosis. the low prevalence of npsle in these data is related to the case definition used. in these two studies, there were no reports of cognitive impairment or mood disorders, both of which are considered common npsle syndromes in the data where higher prevalence is reported. there has been no specific study done in the region looking specifically for the prevalence of npsle syndromes. different risk factors are associated with the development of npsle. patients with generalised disease activity, prior history, or concurrent npsle, as well as those with antiphospholipid antibodies are at higher risk of developing npsle. skin lesions were the most frequently reported disease activity in association with nervous system involvement. pathogenesis several pathophysiological mechanisms have been implicated in the pathogenesis of npsle. these include vasculopathy, autoantibodies, blood brain barrier and the cytokine effect [table2]. in post-mortem studies, vascular occlusion is universally found. the most common findings on pathological examinations were multiple infarct, cortical atrophy, microhaemorrhages, and gross infarction. the most commonly reported vasculopathy is small vessel non-inflammatory vasculopathy.11 in several autopsy case reports of patients who died during an acute lupus flare, small vessel occlusions were secondary to leukocyte aggregates in the absence of immune complex deposition. this was most likely secondary to complement activation that resulted in increased leukocyte adhesiveness to the subendothelial table 1: neuropsychiatric syndromes associated with systemic lupus erythematosus npsle associated with the central nervous system npsle associated with the peripheral nervous system aseptic meningitis acute inflammatory demyelinating cerebrovascular disease syndromes (guillain-barré syndrome) demyelinating syndromes autonomic neuropathy headaches mononeuropathy, single or multiplex movement disorders (chorea) myasthenia gravis myelopathy cranial neuropathy seizure disorders plexopathy anxiety disorders polyneuropathy cognitive dysfunction mood disorders psychosis npsle = neuropsychiatric systemic lupus erythematosus. table 2: pathogenic mechanisms in neuropsychiatric systemic lupus erythematosus vasculopathy small vessel non-inflammatory vasculopathy vascuilitis (rare) autoantibodies procoagulant effect direct cytotoxic effect cytokines promotion of antibodies production recruitment of immune cells alteration of blood brain barrier amal alkhotani review | 21 meta-analysis of the utility of anti-ribosomal p antibodies in the diagnosis of npsle or for specific npsle did not find a significant relation between them.25 proinflammatory cytokines and chemokines also play a role in the pathogenesis of npsle. elevated levels of several cytokines, including interleukin-6 (il-6), il-1, il-8, il-10, tumour necrosis factoralpha (tnf-α)-, interferon (ifn)-ϒ, monocyte chemotactic protein 1 (mcp-1)/ccl2, interferon gamma-inducible protein 10 (ip-10)/cxcl10, and fractalkine (cx3cl1) have been found in the csf of patients with npsle.26 they have different effects, including the promotion of intrathecal antibody production, immune cell recruitment, affecting the blood-brain barrier permeability by modifying the neuroendocrine response, and neurotransmitter release.27 evaluation when dealing with sle patients with neurological presentation, careful assessment is necessary to exclude other potential causes [table 3]. a detailed medical history, past history and medication review are mandatory. laboratory evaluation is required to rule out secondary causes, such as infection and metabolic abnormalities. there is no gold standard diagnostic test for npsle. in general, the diagnostic approach will be the same as for non-sle patients. different diagnostic tests can be helpful when assessing patients with possible npsle. the use of different tests should be individualised according to the patient's presentation. an examination of csf is indicated when infection is suspected. to date, there is no role for csf autoantibody testing. it remains mainly of research interest. in the presence of focal deficit, neuroimaging is indicated. magnetic resonance imaging (mri) can assist with the diagnosis of cerebrovascular disease [figure 1], transverse myelitis, and demyelinating syndromes. it is also required in patients presenting with seizure, acute confusional states, or movement disorders. an mri scan will help to exclude other causes of neurological impairment, for example, progressive multifocal leukoencephalopathy. in general, most reported abnormalities on mri are white matter lesions and cerebral atrophy.28–30 advanced imaging modalities might be beneficial in patients with normal mri results. magnetic surface of the blood vessels.11–13 multiple autoantibodies have been reported in association with npsle. the most frequently reported antibodies are antiphospholipid antibodies, a subset of anti-double-stranded dna (dsdna) and anti-ribosomal antibodies. the autoantibodies either obtain access to the nervous system through the permeable blood brain barrier or through direct intrathecal production.14 antiphospholipid antibodies are a group of antibodies that target the phospholipid binding protein, therefore altering the expression and secretion of procoagulants and promoting thrombosis. they have been associated with different npsle syndromes, including stroke, epilepsy. transverse myelitis, and cognitive impairment.15–18 the pattern of cognitive impairment was consistent with subcortical deficit.19 n-methyl-d-aspartate (nmda) receptors are glutamate receptors, which are present throughout brain tissue. a subset of anti-dsdna antibodies were found to react with the nr2 subunit of nmda receptors, which are present in the amygdala and hippocampus. in animal models, anti-nr2 receptors antibodies induced apoptotic cell death of the hippocampus and amygdala in the presence of permeable blood brain barrier.20–22 in human studies, in which both serum and cerebrospinal (csf) levels of anti-nr2 receptors correlated with npsle, no relation between npsle and the serum level was found. in contrast, a significant relation was found between diffuse npsle and csf antinrs, but none with focal npsle or peripheral npsle.23 anti-ribosomal p antibodies cross-react with a protein on neuronal membrane, initiating apoptotic cell death.24 the role of anti-ribosomal p antibodies in the pathogenesis of npsle is controversial. a table 3: secondary causes of nervous system involvement in systemic lupus erythematosus patients infection hypertension metabolic abnormalities e.g. renal failure, electrolyte abnormalities, hypoxia drugs thrombotic thrombocytopenic purpura sleep apnea thyroid disorders neuropsychiatric lupus 22 | squ medical journal, february 2013, volume 13, issue 1 resonance spectroscopy (mrs) has shown neurometabolic abnormalities during both active and quiescent npsle.29 different neurophysiological studies can be beneficial in the diagnosis of subsets of npsle syndromes. in patients presenting with seizure, an electroencephalogram (eeg) will help to identify those at high risk of seizure recurrence. in patients presenting with acute confusional state, an eeg study is required to rule out the presence of seizure disorder. nerve conduction studies (ncs) and electromyography (emg) are indicated in patients presenting with symptoms of peripheral nervous system involvement. these examinations can help diagnose different types of neuropathy (mononeuropathy versus polyneuropathy/ demyelinating versus axonal), plexopathy, and neuromuscular disorders. management the management of patients with npsle consists of correcting the aggravating factors, providing symptomatic treatment, and applying specific measures related to the disease process. one should try to identify and correct possible aggravating factors, which include metabolic or blood pressure abnormalities, and possible offending drugs. symptomatic treatment will be required depending on the nature of npsle, and it may be initiated before disease-specific therapy. symptomatic treatment for patients with npsle is similar to symptomatic treatment of the same condition in non-sle patients. this includes antipsychotic treatment for psychosis, antiepileptic treatment for patients with seizure conditions, and antidepressants for patients with depression. the severity and nature of the underlying neurological manifestation will direct the treatment decision. some patients with mild forms will only require symptomatic treatment such as in the case of patients with headaches. in 2010, the european league against rheumatism (eular) developed recommendations for the management of npsle. the treatment of npsle depends on whether the process is more likely secondary to an inflammatory or thrombotic process.8 in inflammatory processes like transverse myelitis, peripheral neuropathy, refractory seizures, or psychosis, treatment with immunosuppressive therapy is indicated. treatment should include glucocorticoids with or without more potent immunosuppressive treatment for maintenance. the most commonly used immunosuppressive therapy includes azathioprine and cyclophosphamide. in cases of poor response or failure of conventional treatment, other modalities can be used like plasma exchange, intravenous immunoglobulin, or rituximab. in severe cases like transverse myelitis, early treatment with glucocorticoids in combination with cyclophosphamide can provide a better outcome than glucocorticoids alone.31 the combination of three modalities comprising glucocorticoids, cyclophosphamide, and plasma exchange has been used in severe cases of transverse myelitis.32–35 in the presence of antiphospholipid antibodies, the use of antiplatelets/anticoagulants can be considered in addition to immunosuppressive therapy.32,34 rituximab is an anti-cd20 antibody that targets the b-cell directly. it induces antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity and apoptosis. data on the use of rituximab in npsle are mostly derived from case reports and open-labelled studies. tokunaga et al. reported 10 patients with severe npsle who failed to achieve improvements with conventional treatment modalities but had favourable outcomes with rituximab treatment.36 in their series, all of the treated patients showed improvement in their neurological statuses. a recent randomised controlled trial evaluated the efficacy of rituximab figure 1: diffusion-weighted image in a 50-year-old male patient with systemic lupus erythematosus and antiphospholipid syndrome showing right cerebellar infarction. amal alkhotani review | 23 should be individualised according to the patients’ conditions. a c k n o w l e d g e m e n t s this work was sponsored by al zaidi’s chair for research in rheumatic diseases at umm al-qura university. references 1. danchenko n, satia ja, anthony ms. epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. lupus 2006; 15:308–18. 2. chakravarty ef, bush tm, manzi s, clarke ae, ward mm. prevalence of adult systemic lupus erythematosus in california and pennsylvania in 2000: estimates obtained using hospitalization data. arthritis rheum 2007; 56:209. 3. mak a, cheung mw, chiew hj, liu y, ho rc. global trend of survival and damage of systemic lupus erythematosus: meta-analysis and meta-regression of observational studies from 1950s to 2000s. semin arthritis rheum 2012; 41:830–9. 4. hanly jg, urowitz mb, su l, bae sc, gordon c, wallace dj, et al. retrospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. ann rheum dis 2010; 69:529–35. 5. ainiala h, loukkola j, peltola j, korpela m, hietaharju a. the prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. neurology 2001; 57:496–500. 6. brey rl, holliday sl, saklad ar, navarrete mg, hermosillo-romo d, stallworth cl, et al. neuropsychiatric syndromes in lupus: prevalence using standardized definitions. neurology 2002; 58:1214–20. 7. joseph fg, lammie ga, scolding nj. cns lupus: a study of 41 patients. neurology 2007; 69:644–54. 8. bertsias gk, ioannidis jp, aringer m, bolen e, bombardieri s, bruce in, et al. eular recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the eular standing committee for clinical affairs. ann rheum dis 2010; 69: 2074–82. 9. heller t, ahmed m, siddiqqi a, wallrauch c, bahlas s. systemic lupus erythematosus in saudi arabia: morbidity and mortality in multiethnic population. lupus 2007; 16:908–914. 10. alsaleh j, jassim v, elsayed m, saleh n, harb d. clinical and immunological manifestations in 151 sle patients living in dubai. lupus 2008;17:62–6. 11. ellison d, gatter k, heryet a, esiri m. intramural platelet deposition in cerebral vasculopathy of versus placebo in moderate to severe active sle. the study included 32 patients with neurological sle. there was no difference between the treated and placebo groups.37 further clinical trials are required before making a recommendation regarding the use of rituximab in npsle. in spite of this, rituximab should still be considered in patients with severe cases who have failed to improve using other treatments. the treatment of patients with acute thrombotic events is similar to that in non-sle patients. thrombolytic therapy should be considered in the absence of contraindications. secondary causes of stroke like carotid stenosis and endocarditis should be ruled out before attributing them to sle. further treatment should depend on the presence of antiphospholipid antibodies. in patients with positive antiphospholipid antibodies, anticoagulation therapy is indicated.8 in the absence of antiphospholipid antibodies, patients should receive antiplatelet therapy and cardiovascular risk factor modifications. outcome in spite of recent advances in understanding and managing npsle, it remains a major cause of morbidity and impaired quality of life (qol). in a swedish cohort consisting of patients with npsle, it was found that the patients had higher levels of work incapacity compared to the normal population, although there was no increase in mortality.38 in a large cohort of sle patients, the development of neuropsychiatric events was associated with significant reduction of patients’ self-reported health-related qol.4 conclusion nervous system involvement with sle remains poorly understood. there is currently no gold standard test that can diagnose npsle, and the diagnosis of the disease remains an exercise of exclusion. different diagnostic tests can be helpful, but are not specific to the disease itself. the mainstay of treatment includes the correction of possible aggravating factors, symptomatic treatment, immunosuppressive therapy, and anticoagulation/antiplatelet treatment in a subset of patients with thrombotic events. the treatment neuropsychiatric lupus 24 | squ medical journal, february 2013, volume 13, issue 1 systemic lupus erythematosus. j clin pathol 1993; 46:37–40. 12. hammad a, tsukada y, torre n. cerebral occlusive vasculopathy in systemic lupus erythematosus and speculation on the part played by complement. ann rheum dis 1992; 51:550–2. 13. ellis sg, verity ma. central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 19561977. semin arthritis rheum 1979; 8:212–21. 14. hopkins p, belmont hm, buyon j, philips m, weissmann g, abramson sb. increased levels of plasma anaphylatoxins in systemic lupus erythematosus predict flares of the disease and may elicit vascular injury in lupus cerebritis. arthritis rheum 1988; 31:632–41. 15. afeltra a, garzia p, mitterhofer ap, vadacca m, galluzzo s, del porto f, et al. neuropsychiatric lupus syndromes: relationship with antiphospholipid antibodies. neurology 2003; 61:108–10. 16. syuto t, shimizu a, takeuchi y, tanaka s, hasegawa m, nagai y, et al. association of antiphosphatidylserine/prothrombin antibodies with neuropsychiatric systemic lupus erythematosus. clin rheumatol 2009; 28:841–5. 17. herranz mt, rivier g, khamashta ma, blaser ku, hughes gr. association between antiphospholipid antibodies and epilepsy in patients with systemic lupus erythematosus. arthritis rheum 1994; 37:568– 71. 18. liou hh, wang cr, chen cj, chen rc, chuang cy, chiang ip, et al. elevated levels of anticardiolipin antibodies and epilepsy in lupus patients. lupus 1996; 5:307–12. 19. denburg sd, carbotte rm, ginsberg js, denburg ja. the relationship of antiphospholipid antibodies to cognitive function in patients with systemic lupus erythematosus. j int neuropsychol soc 1997; 3:377– 86. 20. huerta pt, kowal c, degiorgio la, volpe bt, diamond b. immunity and behavior: antibodies alter emotion. proc natl acad sci usa 2006; 103:678–83. 21. kowal c, degiorgio la, nakaoka t, hetherington h, huerta pt, diamond b, et al. cognition and immunity: antibody impairs memory. immunity 2004; 21:179–88. 22. aranow c, diamond b, mackay m. glutamate receptor biology and its clinical significance in neuropsychiatric systemic lupus erythematosus. rheum dis clin north am 2010; 36:187–201. 23. arinuma y, yanagida t, hirohata s. association of cerebrospinal fluid anti-nr2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus. arthritis rheum 2008; 58:1130–5. 24. matus s, burgos pv, bravo-zehnder m, kraft r, porras oh, farías p, et al. antiribosomal-p autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis. j exp med 2007; 204:3221–34. 25. karassa fb, afeltra a, ambrozic a, chang dm, de keyser f, doria a, et al. accuracy of anti-ribosomal p protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-analysis. arthritis rheum 2006; 54:312–24. 26. okamoto h, kobayashi a, yamanaka h. cytokines and chemokines in neuropsychiatric syndromes of systemic lupus erythematosus. j biomed biotechnol 2010; 2010:268436. 27. rhiannon j. systemic lupus erthematosus involving the nervous system: presentation, pathogenesis, and management. clinic rev allergy immunol 2008; 34:356–60. 28. bosma gp, huizinga tw, mooijaart sp, van buchem ma. abnormal brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus. ajnr am j neuroradiol 2003; 24:850–4. 29. brey rl. neuropsychiatric lupus: clinical and imaging aspects. bull nyu hosp j dis 2007; 65:194– 9. 30. appenzeller s, pike gb, clarke ae. magnetic resonance imaging in the evaluation of central nervous system manifestations in systemic lupus erythematosus. clin rev allergy immunol 2008; 34:361–6. 31. barile-fabris l, ariza-andraca r, olguín-ortega l, jara lj, fraga-mouret a, miranda-limón jm, et al. controlled clinical trial of iv cyclophosphamide versus iv methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. ann rheum dis 2005; 64:620–5. 32. d'cruz dp, mellor-pita s, joven b, sanna g, allanson j, taylor j, et al. transverse myelitis as the first manifestation of systemic lupus erythematosus or lupus-like disease: good functional outcome and relevance of antiphospholipid antibodies. j rheumatol 2004; 31:280–5. 33. łukjanowicz m, brzosko m. myelitis in the course of systemic lupuserythematosus: review. pol arch med wewn 2009; 119:67–72. 34. kovacs b, lafferty tl, brent lh, dehoratius rj. transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. ann rheum dis 2000; 59:120–4. 35. kimura ky, seino y, hirayama y, aramaki t, yamaguchi h, amano h, et al. systemic lupus erythematosus related transverse myelitis presenting longitudinal involvement of the spinal cord. intern med 2002; 41:156–60. 36. tokunaga m, saito k, kawabata d, imura y, fujii t, nakayamada s, et al. efficacy of rituximab (anticd20) for refractory systemic lupus erythematosus amal alkhotani review | 25 of rituximab trial. arthritis rheum 2010; 62:222–33. 38. jönsen a, bengtsson aa, nived o, ryberg b, sturfelt g. outcome of neuropsychiatric systemic lupus erythematosus within a defined swedish population: increased morbidity but low mortality. rheumatology (oxford) 2002; 41:1308–12. involving the central nervous system. ann rheum dis 2007; 66:470–5. 37. merrill jt, neuwelt cm, wallace dj, shanahan jc, latinis km, oates jc, et al. efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase ii/iii systemic lupus erythematosus evaluation clinical & basic research sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e59-64, epub. 27th jan 14 submitted 23rd aug 12 revisions req. 18th sep 12 & 10th mar 13; revisions recd. 19th jan & 20th mar 13 accepted 18th jun 13 1università di siena, siena, italy; 2università cattolica del sacro cuore, rome, italy; 3università degli studi dell'aquila, l'aquila, italy; 4università degli studi di roma tor vergata, rome, italy *corresponding author e-mail: d.passali@virgilio.it التهاب األذن الوسطى واألرجية األنفية عالقة حقيقية؟ دزيدوريو� ب�صايل, جيوليو �صي�صار بي�صايل, ماريا ليوريالو�, �أنتونيو� رومانو, ليو�صا بيلو�صي, فر�ن�صي�صكو ماريا ب�صايل abstract: objectives: the correlation between middle ear pathology and nasal allergy has been debated for almost 30 years. this study aimed to evaluate the relationship between otitis media with effusion (ome) and persistent allergic rhinitis symptoms versus intermittent rhinitis in children. methods: the study included 100 atopic children (52 boys, 48 girls) aged 5‒9 years with otological symptoms who were patients of the university of siena hospital, italy. ear, nose and throat evaluations, tympanometry, skin prick tests (spts), mucociliary transport time (mctt) and eustachian tube function tests were performed. results: the spts revealed 50 children sensitised to dermatophagoides pteronyssinus, 34 to grass pollen and 16 to parietaria. of all patients, mild symptoms were intermittent in 19 children and persistent in 18; moderate/severe symptoms were intermittent in 22 and persistent in 41. tubal dysfunction was present in 25 children, whereas middle ear effusion was present in 45 children undergoing myringotomy. the mctt was slower in the persistent group (21 ± 2 mins) versus the intermittent group (16 ± 2 mins) with a significant difference (p <0.01). mean eosinophil cationic protein (ecp) values in the middle ear effusions of children who had undergone myringotomy were 251 ± 175.2 μg/l, and mean ecp blood values were 25.5 ± 16.3 μg/l, with significant differences (p < 0.001). conclusion: there was a significant association between ome, delayed mctt, ecp values in middle ear effusion and persistent symptoms of allergic rhinitis. these results suggest a direct involvement of the middle ear mucosa as a target organ in persistent forms. keywords: otitis media; nasal allergy; children; genetic predisposition; eustachian tubes; italy. �لعالقة تقييم �إىل �لدر��صة هذة تهدف �صنة. 30 تقارب لفرتة نقا�س مو�صع كانت �الأنف و�أرجية �لو�صطى �الأذن �أمر��س بي �لعالقة الهدف: امللخ�ص: بي �لتهاب �الأذن �لو�صطى مع �الن�صباب و�لتهاب �الأذن �الأرجي �مل�صتدمي �إز�ء�لتهاب �الأذن �ملتقطع عند �الأطفال. �لطريقة: �صملت �لدر��صة 100 طفال منتبذ )52 �صبيا, 48 بنتا( �أعمارهم 9-5 �صنو�ت عندهم �أعر��س باالأذن, وهم من مر�صى م�صت�صفى جامعة �رشدينيا, �إيطاليا. مت عمل فحو�صات �صملت تقييم �إىل ح�صا�صا طفال 50 وجود بي �لوخز فح�س �لنتائج: �لنفري. عمل وفح�س �لهدبي, �ملخاط نقل وقت �جللد, وخز �لطبلة, قيا�س و�حللق, و�الأنف �الأذن dermatophagoides pteronyssinus, �إىل 34 �إىل طلع �لع�صب, و 16 �إىل parietaria. من كل �ملر�صى, �الأعر��س �ملتقطعة �خلفيفة كانت عند 19 طفال, �مل�صتدمية �خلفيفة عند 18, و�ملتو�صطة �إىل �ل�صديدة �ملتقطعة عند 22 و�مل�صتدمية عند 41. خلل �الأد�ء �الأنبوبي كان موجود عند 25 طفال بينما �أن�صباب �الأذن �لو�صطى كان موجود عند 45 طفال ممن خ�صعو� لعملية ب�صع �لطبلة. وقت نقل �ملخاط �لهدبي كان �أبطاأ عند �ملجموعة �مل�صتدمية )2 ± 21 mins( �إز�ء �ملجموعة �ملتقطعة )mins 2 ± 16( مع فارق معتد به )p >0.01(. متو�صط قيم �لربوتي �لكاتيوين لليوزينية عند �ن�صباب �الأذن �لو�صطى لالأطفال �لذين خ�صعو� لب�صع �لطبلة كانت μg/l 175.2 ± 251. ومتو�صط قيم دم ecp كانت μg/l 16.3 ± 25.5 مع فارق معتد به )0.001< p(. �خلال�صة: كان هناك تر�بط معتد به بي �لتهاب �الأذن �لو�صطى مع �الن�صباب, تاأخر �أوقات نقل �ملخاط �لهدبي, قيم ecp الن�صباب �الأذن �لو�صطى و �الأعر��س �مل�صتد�مة اللتهاب �الأنف �الأرجي. هذة �لنتائج ت�صري �إىل عالقة مبا�رشة للغ�صاء �ملخاطي يف �الأذن �لو�صطى كع�صو �ل�صدمة عند �الأعر��س �مل�صتد�مة. مفتاح الكلمات: �لتهاب �الأذن �لو�صطى؛ �أرجية �الأنف؛ �الأطفال؛ �أهبة ور�ثية؛ �لنفري؛ �إيطاليا. nasal allergy and otitis media a real correlation? *desiderio passali,1 giulio c. passali,2 maria lauriello,3 antonio romano,1 luisa bellussi,1 francesco m. passali4 advances in knowledge this research demonstrated the close relationship between persistent rhinitis and otitis media with effusion (ome). the mucosa of the nasal cavities and the pharyngeal portion of the tube have the same histological structure and thus, the same physiological target. the defense of the middle ear comes not only from the valve mechanism of the eustachian tube (et), but also from the effectiveness of mucociliary clearance. the minimal persistent inflammation affecting the rhinopharynx and the et in persistent allergic rhinitis prevents the middle ear from returning to a stable physiological state. in these cases, the middle ear mucosa, subjected to continuous allergenic stimulation, can develop a specific hyperactivity with local production of specific immunoglobulin e and mediators of the allergic reaction such as eosinophil cationic protein. nasal allergy and otitis media a real correlation? e60 | squ medical journal, february 2014, volume 14, issue 1 nose and middle ear are correlated entities, which belong to a system called the rhinopharyngotubal unit or the “unified airspace”.1 the key element to middle ear disease, in both physiological and pathological conditions, is the eustachian tube (et), whose functions are middle ear ventilation, clearance, and mechanical and immunological defence.2 the et opens during swallowing (once per min during waking hours and once every five mins during sleep), chewing and yawning to balance the mucosal reabsorption of air (0.5‒1 mm3 per min). the drainage of secretions from the middle ear is carried out by the mucociliary transport (mct) system, which is localised in the cartilaginous portion of the et. the functioning of the mct system of the et is enhanced by the surface tension lowering substance (stls), which allows the rolling of the mucus. the periodical opening of the et fibro-cartilaginous portion prevents the aspiration of inflammatory or infectious secretions from the rhinopharynx. furthermore, the et is provided with specific defence mechanisms by antimicrobial substances such as lysozymes and by resident microbial flora which compete with pathogens. the local lymphoid tissue is scattered in the superficial layer of the chorion of the cartilaginous portion and is particularly plentiful around the pharyngeal ostium.3 studies on the pathogenesis of otitis media (om) have identified interactions between infection, allergic reactions and et dysfunction.4,5 in particular, martines et al., who studied the audiological characteristics of otitis media with effusion (ome) in two cohorts of children (atopic and non-atopic), found that atopic children are more prone to developing bilateral ome, to present with a type b tympanogram (flat, clearly abnormal) and to have a lower hearing threshold compared to non-atopic children.6,7 the link between om and nasal allergy was also confirmed through the study of the joint effect of atopy and upper respiratory tract infection (urti) in the development and/or maintenance of middle ear effusion. in fact, the relative risk for om, in presence of urti, increases 271 times among the allergic population.8 in a previous study, we showed that specific immunogobulin e (ige) are significantly increased, when compared with blood values, in middle ear effusion in patients allergic to dermatophagoides pteronyssinus (der. pt.).9 to elucidate whether allergy plays a role in the pathogenesis of om, the aims of the present study were to evaluate the relationship between ome—defined as the presence of middle ear fluid without signs and/or symptoms of infection (otalgia, fever)—and persistent allergic rhinitis symptoms versus intermittent rhinitis in children methods the present study, conducted between september 2008 and may 2010, was approved by the hospital and research committees of the university of siena, italy. it received no financial support from any source. after obtaining informed consent from the parent/caregiver of each child, we enrolled 100 atopic children (52 boys and 48 girls), aged between five and nine years, who had otological symptoms (aural fullness, hearing loss) and persistent or intermittent nasal allergic symptoms according to the allergic rhinitis and its impact on asthma (aria) classification.10 the classification of allergic rhinitis into seasonal, perennial and occupational types has the merit of being simple and didactic; however, it does not always correspond to the clinical picture of allergic rhinitis. for example, in pollinosis the respiratory symptomatology is conditioned by latitude, climatic conditions and atmospheric pollution; these factors can all influence the environmental pollen load and hyperactivity of the exposed subjects.11 in the last decade, a classification has been added to the aria guidelines that makes reference to the intensity and the duration of the symptoms. this allows a application to patient care the ear nose and throat specialist, as well as the general practitioner, need to be made well aware of the data from this study. in the presence of a middle ear effusion, particularly if it is resistant to common medical and surgical approaches, the state of the nose should be carefully evaluated to detect a possible allergic predisposition or pathology. if such a chronic disease is present, it should be treated to avoid repeated acute episodes and the sequelae of chronic middle ear effusion. desiderio passali, giulio c. passali, maria lauriello, antonio romano, luisa bellussi and francesco m. passali clinical and basic research | e61 stepwise therapeutic approach for the treatment of “persistent minimal inflammation” involving the respiratory mucosa which is often present in the absence of symptoms. this classification was used in the selection of the patients. the term ‘intermittent’ was defined as symptoms present for less than four days a week or for less than four weeks; ‘persistent’ was defined as symptoms present more than four days a week and longer than four weeks. the severity of the symptoms was classified as ‘mild’ (absence of sleep disturbance, no impairment of daily activities, of school or work, no troublesome symptoms) or ‘moderate-severe’ (when one or more of the previous factors were present).10 for each child, a clinical evaluation of the ear, nose and throat (ent), a skin prick test (spt), a mucociliary transport time (mctt) test, a tympanometry and an et function test were performed. eosinophil cationic protein (ecp) values were measured only in the middle ear effusions of the 45 children with bilateral type b tympanogram, undergoing myringotomy after six month’s follow-up. patients with both ear and nasal symptoms were selected because the intention was not to demonstrate the relationship between ome and nasal allergy which has already been demonstrated by several studies.2,4,5,12 rather, the present research aimed to increase the knowledge about the relationship between ome and chronic versus intermittent nasal allergenic symptoms. for the same reason, monosensitised subjects to three different allergens responsible for persistent or intermittent nasal symptoms independent of the season or climatic changes were selected. spts were performed on the volar side of the forearm. allergen-containing vials for a standardised panel of respiratory allergens were used (lofarma s.p.a., milano, italy). they were adapted for the spts by means of disposable plastic skin needles. allergens were standardised and titrated in diagnostic biological units (dbu). the patients’ nasal symptoms were treated on demand with oral antihistamines or leukotrienes according to the suggestion of their family paediatrician. the et function was evaluated as follows: (1) after a baseline tympanogram with a gsi tympstar impedenzometer (grason-stadler inc., eden prairie, minnesota, usa), the patient was asked to drink a glass of water in order to reduce middle ear pressure (toynbee manoeuvre) and then another tympanometric recording was carried out; (2) the patient was instructed to close their mouth, occlude the nostrils with two fingers, and try to blow air through the nose in order to create positive pressure in the middle ear (valsalva manoeuvre). a final tympanometric recording was then taken. the et was considered ‘completely occluded’ when no changes in the tympanometric curve were registered after both the toynbee and valsalva manoeuvres, or ‘partially occluded’ when only the valsalva manoeuvre had obtained positive effects. all the tests were performed randomly by two trained ent specialists. to determine the nasal mctt, a mixture of charcoal powder and 3% saccharine was used. as charcoal powder is an insoluble tracer, it efficiently monitors the transport of the particles entrapped into the outer gel layer; saccharine, on the other hand, is a soluble marker and gives the time of clearance into the inner sol layer of ciliated epithelium.12 the mctt was evaluated as follows: a small quantity of charcoal powder and 3% saccharine mixture was applied into the nose on the head of the inferior turbinate by cotton swab. the time needed to detect the presence of the charcoal powder on the oropharynx wall, checked by using a tongue depressor every minute, was considered the mctt. this method is simple to execute, noninvasive and inexpensive. it furnishes reliable results in adults and children on the efficiency of the clearance system and on the eutrophic condition of the respiratory mucosa.13 it can also be usefully employed to follow-up any medical therapy, including local nasal immunotherapy, as we have previously reported.14 a total of 45 children, allergic to der. pt. and who, on follow-up six months after enrolment, had a type b tympanogram, were selected for a myringotomy with insertion of a ventilation tube. blood and middle ear effusion samples were collected to measure ecp, a marker of eosinophil activation, by fluorescent-enzyme immunoassay (feia) (cap system ecp-feia method, pharmacia biosystems gmbh, freiburg, germany). the statistical analysis was performed using the student’s t-test. the mctt times were reported in mins ± standard deviation (sd). ecp concentration values were reported in μgr/l ± sd. nasal allergy and otitis media a real correlation? e62 | squ medical journal, february 2014, volume 14, issue 1 results a total of 50 children (50% of the cohort) were found by spts to be sensitised to der. pt. among them, 41 (82%) reported persistent symptoms from moderate to severe and nine (18%) had intermittent moderate to severe nasal obstruction. of the 34 children found to be sensitised to grass pollen, 20 (58.8%) had intermittent symptoms, whereas the other 14 (41.2%) had mild to moderate persistent nasal obstruction and watery rhinorrhoea. finally, among 16 children allergic to parietaria, only four subjects (25%) reported persistent mild symptoms. mild intermittent symptoms were present in 10 subjects (62.5%), whereas two children (12.5%) reported intermittent symptoms from moderate to severe [table 1]. the mctt was significantly delayed in the persistent rhinitis group of all subjects (21 ± 2 mins) compared to the intermittent group (16 ± 2 mins) with a significant difference (p <0.01) [figure 1]. both groups of children with ome and either persistent or intermittent allergic rhinitis exceeded normal values for the charcoal powder mctt (8 ± 3 mins in children and 13 ± 2 mins in adults).13 all children with ome were followed up every six months after their enrolment. among the children allergic to der. pt. (all on monthly followup visits), 45 had a bilateral type b tympanogram. at the end of the six-month follow-up period, they all underwent a myringotomy with ventilation tube insertion. five (10%) of the children allergic to der. pt. had a type c tympanogram. among the 34 children allergic to grass pollen, nine cases (26.5%) had a type a tympanogram (normal), and 25 children (73.5%) had type c (indicating a significantly negative figure 1: mean values of mucociliary transport time (charcoal powder) in allergic children reporting persistent or intermittent symptoms and otologic complaints. figure 2: eosinophil cationic protein mean levels (μgr/l) in blood and middle ear effusion in 45 children allergic to dermatophagoides pteronyssinus and reporting a type b tympanogram at follow-up six months after enrolment. table 1: allergic sensitisation, symptoms severity-duration and tympanograms pts intermittent rhinitis* n (%) persistent rhinitis** n (%) mild moderate/severe mild moderate/severe der. pt. 50 5 (10.0) 4 (8.0) c b 41 (82.0) b grass 34 9 (26.5) a 11 (32.3) c 14 (41.2) c parietaria 16 10 (62.5) a 2 (12.5) c 4 (25.0) c der. pt. = dermatophagoides pteronissinus; pts = patients; a = tympanogram classification type a/normal; b = tympanogram classification type b/flat, clearly abnormal; c = tympanogram classification type c/indicates significantly negative pressure. * the presence of the symptoms for less than four days a week or for less than four weeks. ** the presence of the symptoms for more than four days a week and longer than four weeks. mild symptoms = absence of sleep disturbance, no impairment of daily activities, including school or work, no troublesome symptoms; moderate/severe symptoms = one or more of the previous symptoms are present. desiderio passali, giulio c. passali, maria lauriello, antonio romano, luisa bellussi and francesco m. passali clinical and basic research | e63 pressure). among the parietaria-positive children, the tympanograms were classified as type a in 10 cases (62.5%) and type c in six (37.5%) [table 1]. tubal dysfunction was present in 25% of all patients; in particular the et tubes were completely occluded in 16 der. pt.-positive children, in five grass pollen-positive patients and in four parietariapositive ones. the mean ecp values in the middle ear effusions of children undergoing myringotomy were 251 ± 175.2 μg/l and were significantly elevated as comp ared to the mean ecp blood values at 25.5 ± 16.3 μg/l (p <0.001) [figure 2]. discussion as far as allergy is concerned, raised levels of eosinophils, basophils and histamine have been found in the nasal mucosa of young children with chronic otitis, and chronic or recurrent ome. this seems to be associated with allergic rhinitis in 24% to 89% of cases.6‒8 several studies have underlined a correlation between allergic inflammation and alteration of the mucociliary clearance. the mediators released by the nasal mucosa during allergic inflammation influence mct, modify the cilia function and structure15 and the production and rheological characteristics of the secretion.16 the results of the current study have demonstrated a statistically significant difference between the mctt of subjects reporting perennial allergic symptoms compared to those who complained only about intermittent mild symptoms. in a recent study, kirtsreesakul et al.17 described alterations to the mucociliary clearance in subjects affected by allergic and non-allergic rhinitis; these changes are more evident in allergic patients and they are proportional to the cutaneous reactivity during skin tests to the alteration of parameters of respiratory functionality (peak expiratory flow index), and to symptom severity (total nasal symptoms score), but not to the number of sensitising allergens. the results of the present study concur and affirm that the mct is impaired in patients with ome and allergic rhinitis. this is an expression of the underlying mucosal inflammation and should lead physicians to adopt a stepwise therapeutic approach. data from the literature show that allergy is a risk factor for ome18 and that atopic children are more prone to ome recurrence after medical therapy19 and/or adenoidectomy versus non-atopic children (p <0.005) and that immunotherapy significantly improves middle ear disease.20 in the current study, children with persistent ome and nasal allergy were found to have tympanograms positive for et dysfunction more frequently than children complaining of intermittent symptoms. this study has established a significant association between ome and persistent allergic rhinitis whereas the correlation between ome and intermittent allergic forms was less significant. it may be that the continuous allergic inflammation affecting the rhinopharynx and the et in patients with persistent allergic rhinitis prevents the middle ear from returning to a physiologically stable state. the oedema and vessel congestion of the respiratory mucosa in allergic inflammation hinder the ventilation function of the et; rhinorrhoea and abundant secretions alter the function of drainage and of the et aeration of the middle ear. on the ground of these considerations, it can be hypothesised that the middle ear mucosa, subjected to continuous allergenic stimulation, can sensitise itself to develop a specific local hyperactivity with the accumulation of eosinophils, t helper type 2 (th2) lymphocytes, and positive cells for interleukin 4 (il-4) and il-5, with local production of specific ige and mediators of the allergic reaction.21 in the patients examined, mean blood ecp values far above normal values proved and confirmed that the patients were atopic. however, higher levels of ecp in middle ear effusions, when compared with those measured in the blood (with a statistically significant difference), together with our previous identification of high specific ige values in middle ear effusion from patients allergic to der. pt.,9 strongly suggest the direct involvement of middle ear mucosa as a target organ in om—in patients affected by persistent allergic rhinitis with local production of specific ige and release of ecp in the middle ear effusion. only the 45 subjects who had a bilateral type b tympanogram over the six-month follow-up period (corresponding to the 90% of the examined sample) underwent transtympanic drainage and the measurement of ecp, as a marker for the allergic inflammation, in the blood and in the secretions from the middle ear. this could be considered a limitation of our study. nevertheless, nasal allergy and otitis media a real correlation? e64 | squ medical journal, february 2014, volume 14, issue 1 the myringotomy and the transtympanic drainage with the possible measurement of the inflammatory mediators in the endotympanic effusion, have to be considered invasive procedures, especially because ome has a fluctuating course and a high rate of spontaneous resolution.22 conclusion the findings of this study suggest that children affected with persistent nasal allergy and auricular symptoms should be accurately assessed. in these cases, the objective evaluation of the rhinopharyngotubal area, performed by flexible endoscope, may reveal a pale and swollen mucosa. the nasal mucociliary function can be easily evaluated by an mct test which, if delayed, would suggest allergy as an aetiology for the child’s middle ear disease. tympanometry and tubal tests are useful to study the tubal opening, but they are not useful for providing data about clearance and tubal defensive functions. in children with ome, tympanometric dysfunction correlates more significantly with the delay of nasal mctt than with tubal function tests. this study's findings of increased middle ear ecp and delayed mctt in persistent allergic rhinitis supports the hypothesis that chronic ome is related to the patient’s allergic disease. references 1. marple bf. allergic rhinitis and inflammatory airway disease: interactions within the unified airspace. am j rhinol allergy 2010; 24:249‒54. 2. pelikan z. role of nasal allergy in chronic secretory otitis media. curr allergy asthma rep 2009; 9:107‒13. 3. skoner ar, skoner kr, skoner dp. allergic rhinitis, histamine, and otitis media. allergy asthma proc 2009; 30:470‒81. 4. caruso g, damiani v, salerni l, passali fm. atopy: pediatric ent manifestations in children. int j pediatr otorhinolaryngol 2009; 73:s19‒25. 5. pelikan z. audiometric changes in chronic secretory otitis media due to nasal allergy. otol neurotol 2009; 30:868‒75. 6. martines f, bentivegna d. audiological investigation of otitis media in children with atopy. curr allergy asthma rep 2011; 11:513‒20. 7. martines f, martines e, sciacca v, bentivegna d. otitis media with effusion with or without atopy: audiological findings on primary school children. am j otolaryngol 2011; 32:601‒6. 8. martines f, bentivegna d, maira e, sciacca v, martines e. risk factors for otitis media with effusion: case-control study in sicilian school children. int j pediatr otorhinolaryngol 2011; 75:754‒9. 9. passali d, bellussi l. ige and secretory otitis media. in: mogi g, honig i, ishii t, takasaka t, eds. recent advances in otitis media. proceedings of the 2nd extraordinary international symposium on otitis media, oita, japan, 31 march – 3 april 3 1993. amsterdam-new york: kegler publications, 1994. p. a:543. 10. bousquet j, van cauwenberge p, khaltaev n. allergic rhinitis and its impact on asthma. j allergy clin immunol 2001; 108:s147–334. 11. bauchau v, durham sr. epidemiological characterization of the intermittent and persistent types of allergic rhinitis. allergy 2005; 60:350‒3. 12. alles r, parikh a, hawk l, darby y, romero jn, scadding g. the prevalence of atopic disorders in children with chronic otitis media with effusion. pediatr allergy immunol 2001; 12:102-106 13. passali d, bellussi l, bianchini ciampoli m, de seta e. experiences in the determination of nasal mucociliary transport time. acta otolaryngol 1984; 97:319‒23. 14. passali d, bianchini-ciampoli m. normal values of mucociliary transport time in young subjects. int j ped otorhinolaryngol 1985; 9:151‒6. 15. passali d, bellussi l. monitoring methods for local nasal immunotherapy. allergy 1997; 52:22‒5. 16. maurizi m, paludetti g, todisco t, almadori g, ottaviani f, zappone c. ciliary ultrastructure and nasal mucociliary clearance in chronic allergic rhinitis. rhinology 1984; 22:233‒40. 17. kirtsreesakul v, somjareonwattana p, ruttanaphol s. impact of ige mediated hypersensitivity on nasal mucociliary clearance. arch otolaryngol head neck surg 2010; 136:801‒6. 18. gultekin e, develioğlu on, yener m, ozdemir i, külekçi m. prevalence and risk factors for persistent otitis media with effusion in primary school children in istanbul, turkey. auris nasus larynx 2010; 37:145‒9. 19. lack g, caulfield h, penagos m. the link between otitis media with effusion and allergy: a potential role for intranasal corticosteroids. pediatr allergy immunol 2011; 22:258‒66. 20. hurst ds. efficacy of allergy immunotherapy as a treatment for patients with chronic otitis media with effusion. int j pediatr otorhinolaryngol 2008; 72:1215‒23. 21. tewfik tl, mazer b. the links between allergy and otitis media with effusion. curr opin otolaryngol head neck surg 2006; 14:187‒190. 22. de ru ja, grote jj. otitis media with effusion: disease or defense? a review of the literature. int j pediatr otorhinolaryngol 2004; 68:331‒9. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e364–369, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.010. submitted 19 nov 14 revisions req. 15 dec 14 & 24 mar 15; revisions recd. 20 jan & 31 mar 15 accepted 9 apr 15 departments of 1child health, 2radiology & molecular imaging, 3pathology and 4genetics, sultan qaboos university hospital, muscat, oman corresponding author e-mails: koul@squ.edu.om and roshankoul@hotmail.com متالزمة تصلب العمود الفقري لدى األطفال يف سلطنة عمان رو�سان كول، دليب �سانكالة، �سعاد اجله�سمية، رجنيت ماين، رنا عبد الرحيم، �سيف اليعربي، ح�سني الكندي، خالد الذهلي، اآمنة الفطي�سية abstract: objectives: rigidity of the spine is common in adults but is rarely observed in children. the aim of this study was to report on rigid spine syndrome (rss) among children in oman. methods: data on children diagnosed with rss were collected consecutively at presentation between 1996 and 2014 at the sultan qaboos university hospital (squh) in muscat, oman. a diagnosis of rss was based on the patient’s history, clinical examination, biochemical investigations, electrophysiological findings, neuro-imaging and muscle biopsy. atrophy of the paraspinal muscles, particularly the erector spinae, was the diagnostic feature; this was noted using magnetic resonance imaging of the spine. children with disease onset in the paraspinal muscles were labelled as having primary rss or rigid spinal muscular dystrophy. secondary rss was classified as rss due to the late involvement of other muscle diseases. results: over the 18-year period, 12 children were included in the study, with a maleto-female ratio of 9:3. a total of 10 children were found to have primary rss or rigid spinal muscular dystrophy syndrome while two had secondary rss. onset of the disease ranged from birth to 18 months of age. a family history was noted, with two siblings from one family and three siblings from another (n = 5). on examination, children with primary rss had typical features of severe spine rigidity at onset, with the rest of the neurological examination being normal. conclusion: rss is a rare disease with only 12 reported cases found at squh during the study period. cases of primary rss should be differentiated from the secondary type. keywords: rigid spine syndrome; rigid spine muscular dystrophy; selenoprotein; children; magnetic resonance imaging; oman. امللخ�ص: الهدف: ت�سلب العمود الفقري مر�س �سائع لدى الكبار و لكنه نادر احلدوث عند الأطفال. الهدف من هذه الدرا�سة هو اكت�ساف حالت ت�سلب العمود الفقري لدى الأطفال العمانيني. الطريقة: مت ا�ستخراج املعلومات عن الأطفال الذين مت ت�سخي�سهم مبتالزمة ت�سلب ت�سلب متالزمة ت�سخي�س مت عمان. �سلطنة مب�سقط، قابو�س ال�سلطان جامعة م�ست�سفى يف 2014 و 1996 بني الفرتة يف الفقري العمود العمود الفقري اعتمادا على التاريخ املر�سي، و الفح�س ال�رسيري، و الفحو�سات الألكرتوف�سيولوجية، و �سور الأ�سعة و حتليل عينة من الع�سلة. ما مييز هذه املتالزمة هو وجود �سمور يف الع�سلة املحيطة بالنخاع بالتحديد وهو ما ميكن ت�سخي�سه عن طريق اأ�سعة الرنني املغناطي�سي للعمود الفقري. و�سفت اإ�سابات الأطفال باأولية او ثانوية بناءا على الع�سلة امل�سابة اأول. النتائج: خالل فرتة 18 �سنة، مت ت�سخي�س 12 طفال مبتالزمة ت�سلب العمود الفقري، بن�سبة الذكور اإىل الإناث 9 اإىل 3. مت ت�سخي�س متالزمة ت�سلب العمود الفقري الأويل يف 10 من الأطفال اأما الثنان املتبقيان فتم ت�سخي�سهم مبتالزمة ت�سلب العمود الفقري الثانوي. مت مالحظة اأن اأعرا�س املر�س تبداأ عادة يف الفرتة ما بني الولدة و حتى عمر 18 �سهرا. كان هناك تاريخ عائلي للمر�س يف حالتني من الأطفال امل�سابني. الفح�س ال�رسيري اأو�سح اأن الأطفال امل�سابني مبتالزمة ت�سلب العمود الفقري الأويل لديهم ت�سلب �سديد يف ع�سالت العمود الفقري. اأما بقية فحو�سات الأع�ساب ال�رسيرية فكانت �سليمة. اخلال�صة: متالزمة ت�سلب العمود الفقري مر�س نادر احلدوث، و قد مت ت�سجيل 12 حالة فقط يف م�ست�سفى جامعة ال�سلطان قابو�س خالل فرتة الدرا�سة. الكلمات املفتاحية: متالزمة ت�سلب العمود الفقري؛ ت�سلب العمود الفقري احلثلي؛ �سلينوبروتني؛ الأطفال؛ اأ�سعة الرنني املغناطي�سي؛ عمان. rigid spine syndrome among children in oman *roshan koul,1 dilip sankhla,2 suad al-jahdhami,3 renjith mani,1 rana a. rahim,1 saif al-yaarubi,1 hussein al-kindy,1 khalid al-thihli,4 amna al-futaisi1 clinical & basic research advances in knowledge rigid spine syndrome (rss) is common in adults but is infrequently seen among children. this study presents a large series of paediatric patients with this rare condition in oman. application to patient care the results of this study support the implementation of support groups and family counselling services for the parents and guardians of children suffering from rss in oman. genetic tests were available for only three patients during the study period. the development of genetic testing facilities in oman is recommended for diagnosing this condition among those with a family history of rss. paediatricians and physicians should learn to recognise this rare entity, particularly as diagnosed rss patients will require multidisciplinary care. roshan koul, dilip sankhla, suad al-jahdhami, renjith mani, rana a. rahim, saif al-yaarubi, hussein al-kindy, khalid al-thihli and amna al-futaisi clinical and basic research | e365 rigidity or stiffness of the spine is common in adults and among the elderly but is rarely seen in children.1,2 in adults, the disease mainly results in a bent spine (forward bending), often with a bent or drooping head. in children, while the spine may also be bent, the head remains upright and the neck becomes so stiff that the child cannot look to the ground. differences have been noted between the underlying aetiopathology of a rigid spine in children and adults, although the usual causes are bone, neuromuscular and brain disorders.3,4 inheritance patterns also differ between adults and children as the condition is generally autosomal dominant in the former and recessive in the latter.5 the disease presents between the 4–6th decade of life for adults and during the first decade for children.5 for adults, this condition is known as axial myopathy, camptocormia, rigid spine syndrome (rss) and, more recently, paraspinal neuromuscular syndrome.4,6,7 rigidity of the spine is noted in the late stages of several childhood muscular dystrophies and myopathies. in these diseases, the rigid spine is due to the spread of the disease to the muscles and the late involvement of the paraspinal muscles.5 this is known as secondary rss; a specific muscle disease is usually the underlying cause. rigid spinal muscular dystrophy syndrome (primary rss) develops when the onset of the disease occurs in the paraspinal muscles and then spreads to the other muscles of the body.5,8 in the primary form of rss, the muscle disease is often of non-specific origin or is due to congenital myopathies such as multicore disease or desmin-related myopathy with mallory body-like inclusions. in these cases, the disease originates outside the dystrophin, glycoprotein or extracellular matrix.9 the muscle histopathology is therefore non-specific as the myopathy changes with fibro-fatty accumulation.10–12 the diagnosis of rss is based on the clinical course of the illness as well as biochemical, electrophysiological, histopathological, genetic and radiological findings. in cases of primary rss, a magnetic resonance imaging (mri) scan of the spine will reveal atrophy of the paraspinal muscles, particularly the erector spinae.13 selenoprotein dysfunction has been recognised as the main defect in the muscles of children with primary rss; mutations in the selenoprotein n1 (sepn1) gene-related myopathy were found to be associated with this disease and primary rss was mapped to the 1p35–36 chromosome in four siblings.9,13 this study aimed to report on the characteristics of rss among children in oman. methods children diagnosed with rss were enrolled in the study consecutively at presentation between 1996 and 2014 at the sultan qaboos university hospital (squh) in muscat, oman. after their initial presentation, the children were followed over the study period. children were suspected of having rss if there was restricted neck movement and bending of the spine. a diagnosis of rss was based on the following clinical features: an inability to look down due to limited neck movement; restriction of overall spine mobility and normal limb strength which did not affect day-to-day activities; no difficulty in swallowing, breathing or speaking; and no bone or joint involvement. results from biochemical tests, imaging and muscle biopsies, as well as electrophysiological findings, were also used to make a diagnosis. genetic tests were available for only three patients during the study period. these children did not have features of other dystrophinopathies so associated tests were not performed. formal consent for inclusion in this study was obtained from the parents or guardians of the children. this study was approved by the medical research & ethics committee at the college of medicine & health sciences of sultan qaboos university (mrec#675). results a total of 12 children with rss presented to squh over the 18-year study period. seven of these children had been previously reported in a case series.5 the estimated prevalence of rss in oman was therefore one per 170,000 of the general population or six per one million, based on a national population of approximately two million.14 there were nine male and three female patients. onset of the disease ranged from birth to 18 months old (mean age: eight months and five days), although the parents of one child could not remember the exact time of disease onset. seven of the children (58.3%) had delayed gross motor skill development; the remaining five patients (41.7%) had normal milestones. a family history was noted, with two siblings from one family and three siblings from another (n = 5). the remainder of the patient group were single cases (n = 7). a total of 10 children were found to have primary rss (83.3%) while the remaining two had the secondary form of the disease (16.7%). muscle biopsies were performed in 41.7% of the children rigid spine syndrome among children in oman e366 | squ medical journal, august 2015, volume 15, issue 3 (three patients with primary rss and two with secondary rss). histopathological findings were available for five patients (three with primary rss and two with secondary rss) and genetic information was available for two children with primary rss and one with secondary rss. one child with primary rss was previously diagnosed with stiff person syndrome. a summary of the clinical and imaging features of all patients is available in table 1. on examination, the children with primary rss had typical features of severe spine rigidity although their other neurological findings were normal. gowers’ table 1: clinical, laboratory and imaging features of children diagnosed with rigid spine syndrome (n = 12) disease type age at onset in months development age at presentation in years creatine kinase level* in iu/l emg ecg muscle biopsy findings spine mri findings primary 6 n 12 94 myo normal myo, fat and collagen muscle wasting, hypointensity and fibro-fatty infiltration primary 6 n not seen not performed not performed not performed not performed not performed primary unknown n 7 150 myo normal none muscle wasting, hypointensity and fibro-fatty infiltration primary 18 n 5 145 myo normal none muscle wasting, hypointensity and fibro-fatty infiltration primary 8 n 5 151 myo normal patient did not consent muscle wasting, hypointensity and fibro-fatty infiltration secondary† 10 motor delay 2 856 myo normal mitochondrial changes in shape and size normal primary‡ 5 motor delay 6 147 myo normal non-specific myo muscle wasting, hypointensity and fibro-fatty infiltration primary 12 motor delay 11 200 myo normal patient did not consent muscle wasting, hypointensity and fibro-fatty infiltration primary 15 motor delay 9 187 myo normal patient did not consent muscle wasting, hypointensity and fibro-fatty infiltration primary 15 motor delay 8 230 myo normal patient did not consent muscle wasting, hypointensity and fibro-fatty infiltration primary† 6 motor delay 10.4 123 myo normal multicore disease not performed secondary at birth motor delay 5.6 800 myo normal congenital myo of uncertain type not performed emg = electromyography; ecg = echocardiography; mri = magnetic resonance imaging ; myo = myopathy. *normal range: 62–302 iu/l. †genetically confirmed. ‡genetically negative. roshan koul, dilip sankhla, suad al-jahdhami, renjith mani, rana a. rahim, saif al-yaarubi, hussein al-kindy, khalid al-thihli and amna al-futaisi clinical and basic research | e367 sign was negative in all 10 of these children. mri scans of the spine were diagnostic in cases of primary rss. these scans revealed typical features of muscle mass loss in the paraspinal muscles and low signals of fibrofatty infiltration were seen replacing the muscle tissue. two children with primary rss had non-specific myopathy while a third child had a multicore type of congenital myopathy. the following case may serve as a representative example of primary rss observed in this study. a 10-year-old boy with breathing difficulties and repeated chest infections was referred to squh from a peripheral hospital. initial signs of the disease began in the first year of life with motor developmental delay; his parents noted that, compared to his siblings, the child was slower in learning to sit. however, he was able to walk by the time he was two years old and all social and mental milestones were achieved in an appropriate timeframe compared to his siblings. after the age of six years, the child contracted repeated chest infections requiring ventilatory support and was admitted multiple times to the intensive care unit (icu) of a peripheral hospital. in 2014, primary muscle disease was suspected and the patient was referred to the squh icu. on examination, the boy had normal higher mental and cranial nerve function. however, he had wasting of the spine muscles and could not bend his spine or neck [figure 1]. his intercostal muscles were weak and he had mild difficulty in getting up, although after standing he was able to walk normally. all deep tendon reflexes were elicited and his serum creatine kinase levels were normal. an electrocardiogram (ecg) and an echocardiography scan showed normal results; however, myopathy was observed in an electromyogram (emg). a muscle biopsy was performed and the diagnosis was confirmed by electron microscopy to be a multicore disease in the form of congenital myopathy [figure 2]. nicotinamide adenine dinucleotide staining is diagnostic in rss; however, histochemistry and light microscopy was not possible as the muscle biopsy had very limited muscle tissue. genetic testing for sepn1 was positive. unfortunately, an mri scan of the spine could not be arranged before the child was referred back to the peripheral hospital. however, an mri scan performed on a similarly affected male patient revealed wasting of the paraspinal muscles [figure 3]. the two children with secondary rss had mild neck rigidity but demonstrated typical features of the underlying disease with positive gowers’ signs. both patients were female. one of the secondary rss patients had mitochondrial myopathy features and was found to have mitochondrial deletion. she had a single heterozygous mutation in the polymerase gamma (polg) gene (c.803g>c, p.268glyc>ala), indicating polg-related mitochondrial depletion syndrome. serum creatine kinase levels were elevated in the first child and normal in the second. the former was initially diagnosed by electron microscopy to have mitochondrial myopathy with a mitochondrial deletion. an emg was myopathic and nerve conduction was normal. the second patient had features of congenital myopathy although the exact type could not be ascertained. mri scans of the brain and spine were normal in both cases of secondary rss. figure 1: photograph of a child diagnosed with primary rigid spine syndrome showing wasted neck muscles and an inability to bend the neck. respiratory difficulties required him to be on nasal oxygen supplementation. figure 2: electron microscopy showing multicore bodies in the muscle (arrows). this confirmed the diagnosis of primary rigid spine syndrome. rigid spine syndrome among children in oman e368 | squ medical journal, august 2015, volume 15, issue 3 a representative secondary rss patient is detailed below. a five-year-old girl was referred to squh from a local orthopaedic hospital in 2014 for an evaluation of foot deformities. although she had a normal birth and mental and social milestones, her parents noted a delay in motor skill development. on examination, the cranial nerves were normal. her face had a myopathic look with jaw drop. she had proximal muscle weakness and was positive for gowers’ sign. she had difficulty in bending and turning her neck fully. both upper and lower limb strength was grade 4/5. bilateral mild foot inversion with mild weak dorsiflexion of both feet was observed. her serum creatine kinase level was normal. ecg and echocardiography showed no abnormal findings. the emg was myopathic and nerve conduction was normal. a muscle biopsy resulted in an initial diagnosis of congenital myopathy, awaiting confirmation via electron microscopy. discussion there are several childhood muscle dystrophies and congenital myopathies that may present with a rigid spine in the late stages of the primary disease. this is due to the progression of the disease to the paraspinal muscles and is referred to as secondary rss.5 in these cases, serum creatine kinase levels may be elevated and the respiratory muscles affected in the terminal stage of the disease.15 muscle biopsies and genetic studies help to confirm the diagnosis of the original disease. an mri scan of the spine does not show the same changes as those seen in primary rss.15 of the two children with secondary rss in the current study, one had congenital myopathy while the other had mitochondrial myopathy. the latter was found to have polg-related mitochondrial depletion syndrome; this mutation is pathogenic and has been reported elsewhere.16 in primary rss, the disease starts in the paraspinal muscles and then spreads to the other muscles.8 serum creatine kinase levels and echocardiography scans are usually normal in these children.13 there is no proximal weakness at the onset of the disease and the diagnosis is usually made by features of spine stiffness, an inability for the patient to bend their neck and imaging evidence of the loss of muscle mass in the erector spinae muscles.13 primary rss appears to have a genetic basis as mutations in the sepn1 gene have been found to be associated with primary rss, with four siblings mapped to the 1p35-36 chromosome bands.9,13 however, in a previous cases series of seven children with rss in oman, sepn1 testing was negative in one patient.5 in the current study genetic testing for sepn1 for one patient was positive. primary rss among children is rarely reported in the literature.12,13 a regional genetic factor may be responsible for the number of primary rss cases observed in this current single centre study from oman. differential diagnosis of secondary rss is not difficult as the underlying primary condition often dominates the clinical picture. however, primary rss needs to be differentiated from other rare conditions such as x-linked emery-dreifuss muscular dystrophy, generalised dystonia and stiff person syndrome.15,17 in cases of emery-dreifuss muscular dystrophy, there is proximal wasting of the upper limb muscles with contractures and early cardiac involvement. serum creatine kinase levels are high and an ecg usually shows abnormal findings.15 muscle biopsies and genetic testing are used to confirm the diagnosis. dystonia can be differentiated from rss due to the figure 3: low signal intensity magnetic resonance image of the spine in a case of paediatric primary rigid spine syndrome. there was wasting of the back muscles of the spine, particularly the erector spinae. the muscle tissue was replaced by fibro-fatty tissue (arrowheads). roshan koul, dilip sankhla, suad al-jahdhami, renjith mani, rana a. rahim, saif al-yaarubi, hussein al-kindy, khalid al-thihli and amna al-futaisi clinical and basic research | e369 rigidity of the entire body—as opposed to the localised stiffness seen in rss—and abnormal posture.17 stiff person syndrome may be the initial diagnosis given in cases of primary rss; indeed, one of the patients in the current study was initially diagnosed with stiff person syndrome while abroad. generalised body stiffness involving even the abdominal muscles helps in making the correct diagnosis. stiff person syndrome is very uncommon in children.17 physiotherapy and occupational therapy are the main treatments currently available for rss. the early involvement of the respiratory muscles in children with primary rss can be rapid and fatal. in these cases, prompt respiratory care with pulmonary bi-level positive airway pressure non-invasive ventilation—a common mode of respiratory support for patients with respiratory muscle weakness—can prolong life expectancy.18 a possible limitation of this study was the fact that histopathological and genetic testing was only performed for a few patients. further studies are recommended to confirm the histopathological and genetic findings of cases of paediatric rss in oman. the development of local advanced genetic facilities is recommended. conclusion this study aimed to report on cases of rss among children in oman. only 12 children who presented to squh during the 18-year study period were reported to have this condition. a total of 10 patients were found to have primary rss while the remaining two had the secondary form of the disease. as the two forms of this disease have different aetiologies, cases of primary rss should be differentiated from the secondary type. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. serratrice g. axial myopathies: an elderly disorder. acta myol 2007; 26:11–13. 2. oerlemans wg, de visser m. dropped head syndrome and bent spine syndrome: two separate clinical entities or different manifestations of axial myopathy? j neurol neurosurg psychiatry 1998; 65:258–9. doi: 10.1136/jnnp.65.2.258. 3. azher sn, jankovic j. camptocormia: pathogenesis, classification, and response to therapy. neurology 2005; 65:355–9. doi: 10.1212/01.wnl.0000171857.09079.9f. 4. lenoir t, guedj n, boulu p, guigui p, benoist m. camptocormia: the bent spine syndrome, an update. eur spine j 2010; 19:1229–37. doi: 10.1007/s00586-010-1370-5. 5. koul r, al-yarubi s, al-kindy h, al-futaisi a, al-thihli k, chacko pa, et al. rigid spinal muscular dystrophy and rigid spine syndrome: report of 7 children. j child neurol 2014; 29:1436–40. doi: 10.1177/0883073813479173. 6. mahjneh i, marconi g, paetau a, saarinen a, salmi t, somer h. axial myopathy: an unrecognised entity. j neurol 2002; 249:730–4. doi: 10.1007/s00415-002-0701-9. 7. clovstok t, hirano m. clinical summary: paraspinal neuromuscular syndromes. from: www.medlink.com/cip. asp?uid=mlt002qb&src=search&ref=41623889 accessed: mar 2015. 8. dubowitz v. 50th enmc international workshop: congenital muscular dystrophy 28 february to 2 march 1997, naarden, the netherlands. neuromuscul disord 1997; 7:539–47. 9. flanigan km, kerr l, bromberg mb, leonard c, tsuruda j, zhang p, et al. congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and genetic study. ann neurol 2000; 47:152–61. doi: 10.1002/ 1531-8249(200002)47:2<152::aid-ana4>3.0.co;2-u. 10. reed uc. congenital muscular dystrophy: part i a review of phenotypical and diagnostic aspects. arq neuropsiquiatr 2009; 67:144–68. doi: 10.1590/s0004-282x2009000100038. 11. isozaki e, fujimoto y, kawata a, matsubara s, hirai s. [clinical and myopathological studies on rigid spine syndrome.] rinsho shinkeigaku 1996; 36:1136–42. 12. schara u, kress w, bönnemann cg, breitbach-faller n, korenke cg, schreiber g, et al. the phenotype and longterm follow-up in 11 patients with juvenile selenoprotein n1related myopathy. eur j paediatr neurol 2008; 12:224–230. doi: 10.1016/j.ejpn.2007.08.011. 13. sponholz s, von der hagen m, hahn g, seifert j, richard p, stoltenburg-didinger g, et al. selenoprotein n muscular dystrophy: differential diagnosis for early-onset limited mobility of the spine. j child neurol 2006; 21:316–20. doi: 10.1177/08830738060210041401. 14. national centre for statistics & information. population clock. from: www.ncsi.gov.om/pages/ncsi.aspx accessed: mar 2015. 15. escolar dm, leshner rt. muscular dystrophies. in: swaiman kf, ashwal s, ferriero dm, schor nf, eds. swaiman’s pediatric neurology: principles and practice. 5th ed. philadelphia, pennsylvania, usa: saunders, 2012. pp. 1570–606. 16. di fonzo a, bordoni a, crimi m, sara g, del bo r, bresolin n, et al. polg mutations in sporadic mitochondrial disorders with multiple mtdna deletions. hum mutat 2003; 22:498–9. doi: 10.1002/humu.9203. 17. munhoz rp, moscovich m, araujo pd, teivi ha. movement disorders emergencies: a review. arq neuropsiquiatr 2012; 70:453–61. doi: 10.1590/s0004-282x2012000600013. 18. hill ns. ventilator management for neuromuscular dieases. semin respir crit care med 2002; 23:293–305. doi: 10.1055/s2002-33038. http://dx.doi.org/10.1136/jnnp.65.2.258 http://dx.doi.org/10.1212/01.wnl.0000171857.09079.9f http://dx.doi.org/10.1007/s00586-010-1370-5 http://dx.doi.org/10.1177/0883073813479173 http://dx.doi.org/10.1007/s00415-002-0701-9 http://dx.doi.org/10.1002/1531-8249%28200002%2947:2%3c152::aid-ana4%3e3.0.co%3b2-u http://dx.doi.org/10.1002/1531-8249%28200002%2947:2%3c152::aid-ana4%3e3.0.co%3b2-u http://dx.doi.org/10.1590/s0004-282x2009000100038 http://dx.doi.org/10.1016/j.ejpn.2007.08.011 http://dx.doi.org/10.1177/08830738060210041401 http://dx.doi.org/10.1002/humu.9203 http://dx.doi.org/10.1590/s0004-282x2012000600013 http://dx.doi.org/10.1055/s-2002-33038 http://dx.doi.org/10.1055/s-2002-33038 sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 527-533, epub. 8th oct 13 submitted 6th apr 13 revisions req. 2nd jun & 30th jun 13; revisions recd. 10th jun & 2nd jul 13 accepted 4th jul 13 انتشار وعالقة فريوس الورم البشري احلُليمي وأنواعه مبؤشرات الورم املعروفة بني مرضى أورام الثدي يف الكويت ع�سام فرن�سي�س, ب�رشى العيا�سي, �سفيقه العو�سي, كو�سم كابيال, فهد املال امللخ�ص: الهدف: تهدف الدرا�سة اإىل توثيق العالقة بني فريو�س الورم احلليمي الب�رشي واأنواعه باأورام الثدي يف عينات من اأن�سجة الثدي امل�سابهة من الن�ساء الكويتيات وعالقته مبوؤ�رشات التنبوؤ بالورم املعروفة. الطريقه: متت درا�سة 144 عينه من الأن�سجة املحفوظة من حالت �رشطان الثدي الأقنية الغازية واأخذ البيانات املتاحة اإكلينيكيا وباثولوجيا وتت�سمن العمر, وحجم الورم, وانت�سار املر�س يف العقد الليمفاوية, وحالة م�ستقبالت الإ�سرتوجني و الربوج�سرتون وعامل منو الب�رشة 2. وقد مت توثيق تكرار تواجد فريو�س الورم احلليمي الب�رشي با�ستخدام الكيمياء اله�ستولوجية املناعية و و�سيلة التهجني اللونية.مت توثيق الأنواع الفرعية من فريو�س الورم احلليمي الب�رشي با�ستخدام امل�سابر لفريو�س الورم احلليمي الب�رشي cish وقورنت نتائج cish و ihc وارتباط فريو�س الورم احلليمي الب�رشي مع موؤ�رشات التنبوؤ بالورم. النتائج: كان انت�سار فريو�س الورم احلليمي الب�رشي ح�سب cish و ihc 51 من احلالت )%35.4( و 24 )16.7%( حالة تواترا. كانت احل�سا�سية للك�سف عن فريو�س الورم احلليمي الب�رشي با�ستخدام cish %37.3, واخل�سو�سية كانت %94.6. وجد اأن املقارنة الإح�سائية للح�سا�سية واخل�سو�سية بني cish وihc يف الك�سف عن فريو�س الورم احلليمي الب�رشي يعتد بها اإح�سائيا )p >0.001( با�ستخدام اختبار في�رش. )hpv-cish( وجدت يف 51 من احلالت و مزيج من فريو�س الورم احلليمي الب�رشي 18 .)13.7%( احلالت من يف 7 6, 11, 31, الب�رشي 33 احلليمي الورم فريو�س ومزيج )%3.9(؛ حالتني يف وجدت 6, 11, 16, فريو�س الورم احلليمي الب�رشي من الثالث اأنواع 18 ,16 ,11 ,6 و كذلك/33 ,13 كانت موجودة يف حالتني )%3.9(. وكان مدى انت�سار hpv-cish يف الكويتيني وغري الكويتيني )%52.9( 27 و )%37.2( 19، على التوايل. مل تالحظ اأية رابطة مع موؤ�رشات الورم. اخلال�صة: كان تواتر فريو�س الورم احلليمي الب�رشي يف حالت �رشطان الثدي يف الكويت cish( 35.4%( ومن هوؤلء 52.9% من الكويتيني ممن وجد عندهم فريو�س الورم احلليمي الب�رشي منخف�س وعايل اخلطر. مفتاح الكلمات: فريو�س الورم احُلليمي؛ �رشطان الثدي؛ الكيمياء اله�ستولوجية املناعية؛ التهجني املو�سعي؛الكويت. abstract: objectives: this study aimed to document the association of human papilloma virus (hpv) and its types in breast carcinoma tissues in kuwaiti women, and correlate this with known prognostic markers. methods: the clinicopathological data of archived tissue from 144 cases of invasive ductal breast carcinoma were studied (age, histological grade, size of tumour, lymph node metastases, oestrogen/progesterone receptors and human epidermal growth factor receptor 2 status). hpv frequency was documented using immunohistochemistry (ihc) and chromogenic in-situ hybridisation (cish). hpv types were documented by cish using hpv probes. cish and ihc techniques were compared and hpv correlated with prognostic parameters. results: the hpv prevalence as determined by cish and ihc was 51 (35.4%) and 24 (16.7%) cases, respectively. the sensitivity of hpv by ihc was 37.3% and specificity was 94.6%. the sensitivity and specificity of hpv-cish compared to hpvihc was statistically significant (p <0.001). hpv-cish was seen in 51 cases. a combination of hpv 6 and 11, and 16 and 18 was seen in 2 (3.9%) cases, and a combination of hpv 6, 11, 31 and 33 was seen in 7 (13.7%) cases. all three hpv probes: 6 and 11, 16 and 18, as well as 31 and 33 were present in 2 (3.9%) cases. the prevalence of hpvcish in the kuwaiti and non-kuwaiti populations was 27 (52.9%) and 19 (37.2%), respectively. no correlation was observed with the prognostic parameters. conclusion: the frequency of hpv in breast carcinoma cases in kuwait was 35.4% (cish). of those, 52.9% were kuwaitis in whom both lowand high-risk hpv types were detected. keywords: human papillomavirus; breast neoplasm; immunohistochemistry; in situ hybridization; kuwait. prevalence and correlation of human papilloma virus and its types with prognostic markers in patients with invasive ductal carcinoma of the breast in kuwait *issam m. francis, bushra al-ayadhy, shafiqa al-awadhi, kusum kapila, fahd al-mulla department of pathology, faculty of medicine, kuwait university, kuwait city, kuwait *corresponding author e-mail: issamfrancis@gmail.com clinical & basic research issam m. francis, bushra al-ayadhy, shafiqa al-awadhi, kusum kapila and fahd al-mulla clinical and basic research | 528 breast cancer is the most common form of cancer among women in kuwait. in 2001, the breast cancer age-standardised incidence rate (asr) was 36 among kuwaiti and 39.5 among non-kuwaiti female residents.1 since then, its incidence has increased rapidly. alshaibani et al. noticed that in kuwait the majority of breast cancer patients were 40–49 years of age, and increased breast carcinoma risk was correlated with the menopause, recent hormone replacement therapy and family history.2 well-known breast cancer risk factors associated with the development of breast cancer are age, familial history, hormonal intake, early menarche, late menopause, multiparity, first pregnancy at >30 years, obesity and personal history. nevertheless, in 50–80% of cases, known risk factors have not been identified which has generated an interest in identifying new factors related to this cancer.2,3 the three most studied viruses found to cause breast cancer in humans are mouse mammary tumour virus (mmtv), the epstein-barr virus (ebv) and the human papilloma virus (hpv), with mmtv and ebv occurring in up to 37% and 50% of breast carcinoma cases, respectively.4 hpv is accepted as carcinogenic in human cervical, anogenital, and head and neck cancers. molecular and epidemiological studies have shown that a persistent infection with high-risk types of hpv is the most important risk factor for both cervical cancer and its precursors.5 recently, the possibility of hpv being aetiologically-related to breast cancer has been debated. however, the causal role of hpv infection in the development of breast carcinoma remains controversial.6 reports on the distribution of hpv infection in breast cancer are not only limited but also highly controversial.7 several authors have reported the absence of hpv deoxyribonucleic acid (dna) in breast cancer and suggested that it is improbable that integrated hpv is aetiologically-associated with the development of breast carcinoma.8–11 however, a moderate frequency of 20–48% hpv infection and as high as 60–85% of hpv infection in breast carcinomas has been reported.7 the suspicion that hpv may also play a role in human breast cancer is based on the identification of hpv in human breast tumours and the immortalisation of normal human breast cells by hpv 16 and 18.12 previous studies have demonstrated the presence of hpv types 16, 18 and 33 in breast cancer specimens from diverse populations around the world: italy, norway, china, japan, usa, austria, brazil, australia, taiwan, turkey, greece, korea, mexico, hungary and syria.6,13–23 the prevalence of hpv-positive breast cancer in these studies was reported to vary from 4% in mexican to 86% in american women.13 in all the studies, high-risk hpv was found in tumour tissue only and not in the surrounding normal tissue, with the exception of the study from turkey where the virus was also detected in normal tissue but at a lower expression than in the cancerous tissue.20 most of the studies have used standard and nested polymerase chain reaction (pcr) techniques. the disadvantage of this technique is its inability to confirm whether or not a positive reaction is in the mammary epithelial cells.24 very few studies have used in-situ molecular methods for the demonstration of hpv, and in three of them a comparison between solution pcr and in-situ hybridisation methods for the same set of specimens was made and identified oncogenic hpv in mammary epithelium of 12% of the collective total versus 22% using standard or nested pcr.18,13– 15,22,24 in-situ methods have the potential to establish advances in knowledge reports on the distribution of human papilloma virus (hpv) infection in breast cancer patients are limited and highly controversial. this manuscript describes the prevalence of hpv in breast carcinoma cases in kuwait and the distribution of the low risk (hpv 6 and 11) high risk (hpv 16 and 18) and intermediate risk (hpv 31 and 33) types in kuwaiti and non-kuwaiti women. previous to this study, hpv and its subtypes in breast carcinoma in the middle east had only been described in turkey and syria. applications to patient care molecular and epidemiological studies have shown that persistent infection with high-risk hpv is an important risk factor for cervical cancer. the causal role of hpv in the development of breast carcinoma remains controversial. the association of hpv and breast carcinoma, the commonest cancer in kuwait, has not been studied before. very few studies are available which correlate the presence of hpv with prognostic parameters in cases of breast carcinoma. the frequency of hpv-positivity in breast carcinoma could help guide the hpv vaccination policy. prevalence and correlation of human papilloma virus and its types with prognostic markers in patients with invasive ductal carcinoma of the breast in kuwait 529 | squ medical journal, november 2013, volume 13, issue 4 more accurately the frequency of hpv in breast cancer tissue because of their ability to localise the signals in individual cells which can be categorised as benign or malignant. the association of breast carcinoma with hpv has yet not been studied in kuwait. the aim of this study was to document the association of hpv and its types (6, 11, 16, 18, 31 and 33) with breast carcinoma cases in kuwait, both in kuwaitis and non-kuwaitis. the study also aimed to identify the correlation of hpv and its types with known prognostic and predictive markers, namely age, histological grade, tumour size, lymph node metastases, oestrogen (er) and progesterone (pr) receptor expression and human epidermal growth factor receptor 2 (her2/neu) amplification status. the secondary aim of this study was to compare hpv detection with immunohistochemistry (ihc) versus chromogenic in-situ hybridisation (cish). methods archived formalin-fixed paraffin-embedded tissue from 144 cases of invasive ductal breast carcinoma, from the department of pathology at hussain makki al-juma center for specialized surgery (hmjcss) in kuwait, were studied over a 3-year period (2009 to 2011). the study was performed according to the guidelines of the local ethics committee which conforms to the helsinki declaration. cases were selected in which the following clinicopathological data were available: age of the patient at the time of diagnosis, histological grade and size of tumour, lymph node status, er, pr and her2/neu status. histology slides were reviewed and histological grading of the tumour was done using the modified scarff-bloom-richardson grading system.25 the size of the tumour, the number of lymph nodes involved, and the er, pr and her2/neu status were reviewed for uniformity. paraffin-embedded tissue sections of the 144 breast cancer cases were analysed for hpv status by ihc and cish. for ihc, the prefixed unstained tissue sections were used to demonstrate hpv by the standard ihc methodology using antibody from dako (carpinteria, california, usa), dilution of antibody (1:100) and the detection system, dako envision, flex/hrp, high ph (dako global r & d, glostrup, denmark). positive and negative controls were run with each batch. hpv staining was considered positive when there was distinct nuclear staining. for cish, a cish implementation kit ap-nbt/ bcip (zytovision, bremerhaven, germany) was used. in cish, all the cases were first screened for hpv status using the zytovision biotin labelled hpv screening probe that allows the simultaneous screening of 7 hpv types (6, 11, 16, 18, 31, 33 and 35) without determination of specific hpv types. positive and negative controls were run with each batch. hpv staining was considered positive when there was distinct nuclear staining. for hpv typing, all positive cases were tested for the specific hpv types, namely the low-risk: 6 and 11; intermediate-risk: 31 and 33, and high-risk: 16 and 18, types using the specific biotin labelled 6 and 11, 31 and 33, and 16 and 18 zytofast hpv dna probes by the cish technique. the hpv types detected were correlated with the prognostic markers, namely age, histological grade, tumour size, lymph node metastases, er, pr and her2/neu. data were analysed using statistical package for social sciences (spss), version 17 (ibm, corp., chicago, illinois, usa). univariate analysis was used to compare the clinical and pathological features with the hpv types. fisher’s exact test was used to find the association between the two techniques of cish and immunostaining. for all analyses, p <0.05 was considered statistically significant. results of 144 cases of invasive ductal breast carcinoma, 67 (46.5%) were kuwaitis and 66 (45.9%) were nonkuwaitis, comprising both non-kuwaiti arabs and non-arabs including asians and caucasians. in 11 cases (7.6%), information on nationality was not available. the age range was 27–84 years with a median age of 52. there were 42 cases (29.2%) in the fourth and fifth decades of life. a histological grade of 1, 2 and 3 was documented in 5 (3.5%), 47 (32.6%) and 86 (59.7%) of the cases, respectively. of the 144 cases, tumour sizes were documented in 139 (96.5%) cases and the size was less than 2 cm, 2–5 cm and 5 cm or more in 19 (13.2%), 98 (68.1%) and 22 (15.3%) cases, respectively. lymph nodes were involved in 75 (52.1%) cases but not involved in 56 (38.9%) cases, and data were not available in 13 (9%) cases. for the 144 cases of breast carcinoma, issam m. francis, bushra al-ayadhy, shafiqa al-awadhi, kusum kapila and fahd al-mulla clinical and basic research | 530 er status was available for 137 (95.1%) cases; 103 (75.2%) cases were er-positive and 34 (24.8%) cases er-negative. the pr status was available in 134 cases, of which 88 (61.1%) cases were pr-positive and 46 (31.9%) cases were pr-negative. her2/ neu, determined by ihc, was available in 135 cases of which 21 (15.6%) cases were positive and 114 (84.4%) cases were negative. hpv was detected by cish in 51 (35.4%) cases and by ihc in 24 (16.7%). the correlation of the hpv status in breast carcinoma cases by cish and ihc. a good correlation was seen in 19 (13.2%) and 88 (61.1%) cases, being positive and negative, respectively, for hpv by both methods. the sensitivity and specificity of hpv-ihc was 37.3% and 95.6%. the sensitivity and specificity of hpv-cish was 79.2% and 73.3%. this association was found to be significant by fisher’s exact test (p <0.001). hpv typing performed on 51 cases found positive by cish were hpv 6 and 11 positive in 23 (45.1%) cases, hpv 16 and 18 positive in 6 (11.8%) cases, and hpv 31 and 33 positive in 11 (21.6%) cases. a combination of hpv 6 and 11, and 16 and 18 was seen in 2 (3.9%); and a combination of hpv 6 and 11, and 31 and 33 was seen in 7 (13.7%) cases. the distribution by nationality of hpv types in breast carcinoma cases determined positive for hpv-cish is shown in table 1. in the kuwaiti population, hpv 6 and 11 were present alone in 11 of 27 (40.7%) cases. in 9 cases, hpv 6 and 11 were found in combination with hpv 16 and 18 (2 cases, 7.4%) and hpv 31 and 33 (6 cases, 22.3%). all three types were detected in one kuwaiti woman. high risk hpv 16 and 18 were detected in 2 (7.4%) kuwaiti women while the intermediate-risk hpv 31 and 33 alone were detected in 5 (18.5%) kuwaiti women [table 1]. the distribution of hpv types and the age groups of the cases with breast carcinoma are shown in table 2. the low-risk hpv types 6 and 11 were seen in all decades of life. the prevalence was higher in patients greater than 30 years of age. the high-risk hpv types 16 and 18, and intermediaterisk hpv 31 and 33 were detected in the fifth, sixth and seventh decades of life. the correlation of hpv types determined by cish according to age, histological grade, tumour size, lymph node metastases, er, pr and her2/ neu status is shown in table 3. univariate analysis between the hpv status determined by cish was done with the histological grade of the tumour, size of the tumour, lymph node metastases, er, pr and her2/neu. no statistically significant differences were observed. linear-by-linear association did not show significant correlation with the prognostic parameters although a trend was observed in that hpv types 16 and 18 were associated with lymphnodal metastases; however, the numbers were too limited to come to a definitive conclusion. discussion this study documented hpv and the various types (6, 11, 16, 18, 31 and 33) in kuwaiti and non-kuwaiti women. we found hpv determined by cish in 51 (35.41%) cases of invasive ductal carcinoma of the breast. the reported prevalence of hpv in breast tissue between 1992 and 2012 varies between 4% in mexico to 86% in the usa.26 hpv prevalence as determined by the pcr method was seen in 61.1% cases in syria.23 simoes et al. conducted a comprehensive systematic review of studies table 1: distribution by nationality of human papilloma virus (hpv) types in breast cancer cases testing positive for hpv by chromogenic in-situ hybridisation hpv types hpv status as determined by cish total number of cases n = 51 nationality kuwaiti n = 27 non-kuwaiti n = 19 n/a n = 5 arabs n = 9 nonarabs n = 10 6, 11 11 [40.7] 3 [33.3] 5 [50] 4 [80] 23 [45.2] 16, 18 2 [7.4] 2 [22.3] 2 [20] 6 [11.7] 31, 33 5 [18.5] 3 [33.3] 2 [20] 1 [20] 11 [21.6] 6, 11 & 16, 18 2 [7.4] 0 0 0 2 [3.9] 6, 11 & 31, 33 6 [22.3] 1 [11.1] 0 0 7 [13.7] 6, 11, 16, 18 & 31, 33 1 [3.7] 0 1 [10] 2 [3.9] hpv = human papilloma virus; cish = chromogenic in situ hybridisation; n/a = not applicable; [ ] = percentage within hpv types. prevalence and correlation of human papilloma virus and its types with prognostic markers in patients with invasive ductal carcinoma of the breast in kuwait 531 | squ medical journal, november 2013, volume 13, issue 4 addressing worldwide hpv prevalence rates.27 in this meta-analysis of 29 studies comprising of 2,211 samples, the overall prevalence of hpv in breast carcinoma was 23% with great variation worldwide, ranging from 13.4–42.8%.27 this large worldwide variability could be related to methodology. most studies utilise the pcr technique, which is more sensitive but less specific as compared to in-situ hybridisation techniques, which show the virus location.24 the hpv types found in our study, as determined by cish, were hpv 6 and 11 (45.1%); hpv 16 and 18 (11.8%); and hpv 31 and 33 (21.6%). more than one hpv type was seen in 11 cases (21.6%). a combination of hpv 6 and 11 and hpv 16 and 18 was seen in two cases (3.9%) while a combination of hpv 6 and 11 and hpv 31 and 33 was seen in 7 cases (13.7%). in two cases (3.9%), all hpv types examined were identified [table 1]. in the kuwaiti population, the distribution of hpv types 6 and 11; 16 and 18, and 31 and 33 were 40.7%, 7.4% and 18.5%, respectively, while in nonkuwaitis it was 42.1%, 21.1% and 26.2%, respectively [table 1]. a combination of hpv 6 and 11, and 16 and 18 was seen in 7.4% of the kuwaiti women while a combination of hpv 6 and 11, and 31 and 33 was found in 22.3%. all three hpv types were seen in one woman. in the non-kuwaitis, only one (5.3%) case had a combination of hpv 6, 11, 31, 33 [table 1]. the highand intermediate-risk hpv types were found in 16 of the 27 (59.3%) kuwaiti women and 11 of the 19 (47.9%) non-kuwaitis table 3: distribution of human papilloma virus types in breast cancer cases with prognostic parameters (n = 51) hpv types hpv positive cases n = 51 *tumour size (cm) <2/2–5/>5 n = 50 **histological grade 1/2/3 n = 51 †lymph node metastasis n = 48 ‡er (ihc) n = 50 §pr (ihc) n = 48 ¶her2/neu (ihc) n = 49 6, 11, n (%) 23 (45.1) 4/16/3 0/7/16 12 (52.2) 17 (73.9) 15 (65.2) 4 (17.4) 16, 18, n (%) 6 (11.8) 0/4/2 1/3/2 6 (100) 4 (80) 2 (66.7 0 (0) 31, 33, n (%) 11 (21.6) 1/8/2 0/6/5 7 (77.8) 10 (90.9) 10 (90.9) 2 (8.7) 6, 11 & 16, 18, n (%) 2 (3.9) 0/1/1 0/0/2 2 (100) 0 (0) 0 (0) 1 (50) 6, 11 & 31, 33, n (%) 7 (13.7) 1/4/1 0/3/4 3 (50) 4 (57.1) 3 (42.9) 1 (14.3) 6, 11 16, 18 & 31, 33, n (%) 2 (3.9) 0/2/0 0/0/2 2 (100) 1 (50) 1 (50) 0 (0) total 51 6/35/9 1/19/31 32(62.7) 36 (72) 31 (64.6) 8 (16.3) *p = 0.895, ** p = 0.225, †p = 0.134, ‡p = 0.129, §p = 0.125, ¶p = 0.400. hpv = human papilloma virus; er = oestrogen receptors; ihc = immunohistochemistry; pos = positive; neg = negative; pr = progesterone receptors; her2/neu = human epidermal growth factor receptor 2. table 2: distribution of age according to human papilloma virus (hpv) types in breast cancer cases (n = 51) age group in years total number of hpv-positive cases hpv types 6 & 11 16 & 18 31 & 33 6 & 11 + 16 & 18 6 & 11 + 31 & 33 6 & 11 + 16 & 18 + 31 & 33 n (% within hpv types); n [% within age groups] 21–30 2 [3.9] 2 [8.7] 31–40 8 [15.7] 3 [13] 1 [16.7] 3 [27.3] 1 [50] 41–50 8 [15.7] 4 [17.4] 1 [9.1] 1 [50] 2 [28.6] 51–60 15 [29.4] 8 [34.8] 2 [33.3] 2 [18.2] 1 [50] 1 [14.3] 1 [50] 61–70 12 [23.5] 4 [17.4] 2 [33.3] 3 [27.3] 3 [42.8] ≥71 6 [11.8] 2 [8.7] 1 [16.7] 2 [18.2] 1 [14.3] total 51 23 (45.2) 6 (11.7) 11 (21.6) 2 (3.9) 7 (13.7) 2 (3.9) issam m. francis, bushra al-ayadhy, shafiqa al-awadhi, kusum kapila and fahd al-mulla clinical and basic research | 532 [table 1]. this is the first time that the association of hpv types with breast carcinoma has been documented in kuwaitis and non-kuwaitis in kuwait. we have no explanation for these differences, and more research work needs to be undertaken. di lonardo et al. were the first to report hpv 16 dna using pcr in 29.4% of 40 breast cancer specimens.14 using pcr, hpv types 11, 16 and 18 have been reported with increasing frequency from women living in usa and brazil, while hpv type 18 was present in the majority of australian women.12,16,17 hpv 33 was seen in 34.1% of breast carcinoma cases in japan.28 studies from the middle east reveal that hpv types 18, 33 and 35 were present in cancerous and normal breast tissue in turkish women.20 in syria, a prevalence of hpv 16 (9%), hpv 33 (56%) and hpv 35 (37%) was observed.23 in 24 (34.78%) women, more than one hpv type was detected.23 only two studies have been reported where in-situ pcr (is-pcr), which involves amplification to detect hpv in breast tissue, was used.13,24 very few studies have tried to correlate the presence of hpv in breast carcinoma cases with other prognostic markers.12,29,30 in our study, 51 hpv dna-positive cases, as determined by cish, were correlated with the age of the patients, histological grades, tumour sizes, lymph nodal metastases, er, pr and her2/neu expression. we did not find any significant correlation as our numbers were limited; thus, more work needs to be done in this regard. kan et al. using pcr for detecting hpv, did not find any significant correlation between grade of tumour, mortality of patients, er, pr, erb-b2, p53 expression and the presence of p53 mutations.12 cantu de leon, using pcr for hpv determination, found that the greater the tumour size the greater the probability of finding viral dna in the tumour, but not in tumours larger than 4 cm where the viral dna appeared to be lost.29 however, there was no correlation with the histological grade, er, pr or clinical stage.29 mou et al., in a retrospective study from china of 62 breast cancer patients tested for hpv status by nested pcr, did not find any significant correlation between the presence of hpv and patient age, tumour size, metastases, or er and pr status.30 there are several limitations to this study apart from the limited sample size. while the nucleic acid is degraded in archival paraffin-embedded tissue, cish should still be considered a relevant technique when used on such material. although ihc is not as sensitive a technique as pcr, we did not perform pcr in this study as in-situ methods have the advantage of detecting hpv in individual cells, which can be categorised as benign or malignant under conventional light microscopy. conclusion the frequency of hpv in breast carcinoma cases in kuwait was 35.4% when determined by the cish method. the cish method was useful in detecting hpv in malignant cells and should be considered as part of a standard investigation. of the 51 hpvpositive cases, 27 (52.9%) were kuwaitis. both low-risk and high-risk hpv types, along with a combination of hpv types, were detected in the kuwaiti population. no correlation was observed with the prognostic parameters. declaration this research was supported by kuwait university (research grant mg01/10). references 1. motawy m, el hattab o, fayaz s, oteifa m, ali j, george t, et al. multidisciplinary approach to breast cancer management in kuwait, 1993-1998. j egyptian natl cancer inst 2004; 16:85–91. 2. al-shaibani h, bu-alayyan s, habiba s, sorkhou e, al-shamali n, al-qallaf b. risk factors of breast cancer in kuwait: case-control study. iran j med sci 2006; 31:61–4. 3. hortobagyi gn, de la garza salazar j, pritchard k, amadori d, haidinger r, hudis ca, et al. abreast investigators: the global breast cancer burden: variations in epidemiology and survival. clin breast cancer 2005; 6:391–401. 4. mant c, hodgson s, hobday r, d’arrigo c, cason j. a viral aetiology for breast cancer: time to reexamine the postulate. intervirology 2004; 47:2–13. 5. cuschieri ks, cubie ha, whitley mw, gilkison g, arends mj, graham c, et al. persistent high risk hpv infection associated with development of cervical neoplasia in a prospective population study. j clin pathol 2005; 58:946–50. 6. khan na, castillo a, koriyama c, kijima y, umekita y, ohi y, et al. human papillomavirus detected in female breast carcinomas in japan. brit j cancer 2008; 99:408–14. prevalence and correlation of human papilloma virus and its types with prognostic markers in patients with invasive ductal carcinoma of the breast in kuwait 533 | squ medical journal, november 2013, volume 13, issue 4 7. hedau s, kumar u, hussain s, shukla s, pande s, jain n, et al. breast cancer and human papillomavirus infection: no evidence of hpv etiology of breast cancer in indian women. bmc cancer 2011; 11:27– 9. 8. lindel k, forster a, altermatt hj, greiner r, gruber g. breast cancer and human papillomavirus (hpv) infection: no evidence of a viral etiology in a group of swiss women. breast 2007; 16: 172–7. 9. de cremoux p, thioux m, lebigot i, sigal-zafrani b, salmon r, sastre-garau x. no evidence of human papillomavirus dna sequences in invasive breast carcinoma. breast cancer res treat 2008; 109:55–8. 10. rodrigues fr, rochael mc. the possible involvement of hpv in breast cancer. j bras doenças sex transm 2011; 23:182–5. 11. silva rg, silva bb. no evidence for an association of human papilloma virus and breast carcinoma. breast cancer res treat 2011; 125:261–4. 12. kan cy, iacopetta bj, lawson js, whitaker nj. identification of human papillomavirus dna gene sequences in human breast cancer. br j cancer 2005; 93:946–8. 13. heng b, glenn wk, ye y, tran b, delprado w, lutzemann l, et al. human papilloma virus is associated with breast cancer. br j cancer 2009; 101:1345–50. 14. di lonardo a, venuti a, marcante ml. human papilloma virus in breast cancer. breast cancer res treat 1992; 21:95–100. 15. hennig em, di lonardo a, venuti a, holm r, marcante ml, nesland jm. hpv-16 in multiple neoplastic lesions in women with cin iii. j exp clin cancer res 1999; 18:369–77. 16. liu y, klimberg vs, andrews nr, hicks cr, peng h, chiriva-internati m, et al. human papilloma virus dna is present in a subset of unselected breast cancers. j hum virol 2001; 4:329–34. 17. damin a, karam r, zettler cg, caleffi m, alexandre co. evidence for an association of human papillomavirus and breast carcinomas. breast cancer res treat 2004; 84:131–7. 18. de villiers e-m, sandstrom re, zur hausen h, buck ce. presence of papillomatous sequences in condylomatous lesions of the mamillae and in invasive carcinoma of the breast. breast cancer res 2005; 7:r1–11. 19. tsai j, tsai ch, cheng mh, lin sj, xu fl, yang cc. association of viral factors with non-familial breast cancer in taiwan by comparison with noncancerous, fibroadenoma and thyroid tumor tissues. j med virol 2005; 75:276–81. 20. gumus m, yumuk pf, salepci t, aliustaoglu m, dane f, ekenel m, et al. hpv dna frequency and subset analysis in human breast cancer patients’ normal and tumoral tissue samples. j exp clin cancer res 2006; 25:515–21. 21. kroupis c, markou a, vourlidis n, dionyssiouasteriou a, lianidou es. presence of high-risk human papillomavirus sequences in breast cancer tissue and association with histopathological characteristics. clin biochem 2006; 39:727–31. 22. choi yl, cho ey, kim jh, nam sj, oh yl, song sy, et al. detection of human papillomavirus dna by dna chip in breast carcinomas of korean women. tumor biol 2007; 28:327–32. 23. akil n, yasmeen a, kassab a, ghabreau l, darnel ad, al moustafa ae. high-risk human papillomavirus infections in breast cancer in syrian women and their association with id-1 expression: a tissue microarray study. br j cancer 2008; 99:404–7. 24. baltzell k, buehring gc, krishnamurthy s, kuerer h, shen hm, sison jd. limited evidence of human papillomavirus in breast tissue using molecular in situ methods. cancer 2012; 118:1212–20. 25. elston cw, ellis io. pathological prognostic factors in breast cancer. the value of histologic grade in breast cancer: experience from a large study with long term follow-up. histopathology 1991; 19:403– 10. 26. mykyskova i, turcios e, villavicencio v, cetina l, coronel a, hes o. human papilloma virus (hpv) in breast tumors: prevalence in a group of mexican patients. bmc cancer 2009; 9:26–32. 27. simoes pw, medeiros lr, pires pds, edelweiss mi, rosa dd, silva fr, et al. prevalence of human papillomavirus in breast cancer: a systemic review. int j gynecol cancer 2012; 22:343–7. 28. yu y, morimoto t, sasa m, okazaki k, harada y, fujiwara t, et al. human papillomavirus type 33 dna in breast cancer in chinese. breast cancer 2000; 7:33–6. 29. cantu de leon d, montiel dp, nemcova j, mykyskova i, turcios e, villavicencio v, et al. human papillomavirus (hpv) in breast tumors: prevalence in a group of mexican patients. bmc cancer 2009; 9:26–32. 30. mou x, chen l, liu f, shen y, wang h, li y, et al. low prevalence of human papillomavirus (hpv) in chinese patients with breast cancer. j int med res 2011; 39:1636–44. 1department of marine science & fisheries, college of agricultural & marine sciences, sultan qaboos university; 2centre of excellence in marine biotechnology, sultan qaboos university; departments of 3biochemistry and 4pathology, college of medicine & health sciences, sultan qaboos university; 5department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: sergey@squ.edu.om الكشف عن املكونات البيولوجية اليت حتتوي عليها الكائنات البحرية واليت تتسم بأنشطة مضادة للسرطان يف عمان �رسجي دوبريت�سوف، يحيي التاميمي، حممد الكندي، اأكرام بريين abstract: objectives: marine organisms are a rich source of bioactive molecules with potential applications in medicine, biotechnology and industry; however, few bioactive compounds have been isolated from organisms inhabiting the arabian gulf and the gulf of oman. this study aimed to isolate and screen the anti-cancer activity of compounds and extracts from 40 natural products of marine organisms collected from the gulf of oman. methods: this study was carried out between january 2012 and december 2014 at the sultan qaboos university, muscat, oman. fungi, bacteria, sponges, algae, soft corals, tunicates, bryozoans, mangrove tree samples and sea cucumbers were collected from seawater at marina bandar al-rowdha and bandar al-khayran in oman. bacteria and fungi were isolated using a marine broth and organisms were extracted with methanol and ethyl acetate. compounds were identified from spectroscopic data. the anti-cancer activity of the compounds and extracts was tested in a michigan cancer foundation (mcf)-7 cell line breast adenocarcinoma model. results: eight pure compounds and 32 extracts were investigated. of these, 22.5% showed strong or medium anti-cancer activity, with malformin a, kuanoniamine d, hymenialdisine and gallic acid showing the greatest activity, as well as the soft coral sarcophyton sp. extract. treatment of mcf-7 cells at different concentrations of sarcophyton sp. extracts indicated the induction of concentration-dependent cell death. ultrastructural analysis highlighted the presence of nuclear fragmentation, membrane protrusion, blebbing and chromatic segregation at the nuclear membrane, which are typical characteristics of cell death by apoptosis induction. conclusion: some omani marine organisms showed high anti-cancer potential. the efficacy, specificity and molecular mechanisms of anti-cancer compounds from omani marine organisms on various cancer models should be investigated in future in vitro and in vivo studies. keywords: anticancer agents; cancer screening; breast cancer; marine organisms; biological products; apoptosis; oman. الطب يف تطبيقات لها تكون قد التي النا�سطة واجلزيئات احليوية باملكونات غني م�سدر البحرية تعتربالكائنات اأهداف: امللخ�ص: والتكنولوجيا احليوية وال�سناعة. وقد مت ا�ستخراج عدد قليل فقط من املركبات واملكونات احليوية النا�سطة. من كائنات بحرية تعي�س يف منطقة اخلليج العربي وبحر عمان. يهد ف هذا البحث إىل عزل وا�ستخال�س مركبات طبيعية والتحري عن الن�ساط امل�ساد لل�رسطان فيها يف 40 من املنتجات الطبيعية التي مت جمعها من بحر عمان منهجية: اأجريت هذه الدرا�سة بني يناير 2012 و دي�سمرب 2014 يف جامعة ال�سلطان قابو�س يف م�سقط/�سلطنة عمان. مت جمع الفطريات والبكترييا والإ�سفنج واملرجان البحري الناعم و اخليار البحري من منطقة مارينا بندر الرو�سة ومنطقة بند اخلريان ب�سلطنة عمان. عملية عزل البكترييا والفطريات متت با�ستخدام مرق البحر. اأما املكونات احليوية متت املطيافية. بالتحاليل عليها احل�سول مت التي البيانات اأ�سا�س على حتديدها ومت اأ�سيتيت والإيثيل بامليثانول ا�ستخال�سها مت فقد .mcf-7 جتربة الأن�سطة امل�سادة لل�رسطان املتواجدة يف الكائنات البحرية على خاليا �رسطانية من�سقة من الثدي واملعروفة بالنموذج نتائج: عدد 8 مركبات نقية و 32 م�ستخل�سات من الكائنات البحرية قد مت درا�ستها. اأظهرت %22.5 من جميع العينات التي مت فح�سها sarcophyton بكميات خمتلفة من م�ستخل�سات كائنات ال�ساركوفايتون mcf-7 نتائج ايجابية م�سادة لل�رسطان. التجربة علي خاليا ت�سرياإىل اأن موت اخلاليا ال�رسطانية خا�سع اىل الكمية امل�ستعملة من املواد اخلا�سعة للتجربة. ي�سري الفح�س الدقيق للخاليا اخلا�سعة للتجربة ايل وجود جتزئة يف نواة اخللية، مع بروز على الغ�ساء وتكوين فقاعات اىل جانب انعزال الكروماتني عند الغ�ساء النووي والتي تعترب من ال�سمات املميزة يف حالة موت اخللية املربمج. خامتة: حتتوي بع�س الكائنات البحرية العمانية على مواد م�سادة لل�رسطان عالية الفعالية. الدرا�سات امل�ستقبلية ينبغي اأن ت�سلط ال�سوء على فعالية هذه املواد، وخ�سو�سياتها، والطالع علي اآليات التحكم اجلزيئية للمواد م�سادة لل�رسطان من الكائنات البحرية العمانية وذلك با�ستخدام مناذج �رسطانية خمتلفة يف جتارب معملية وعلى فئران التجارب. كلمات مفتاحية: مواد مكافحه لل�رسطان؛ فح�س ال�رسطان؛ �رسطان الثدي؛ الكائنات البحرية؛ املنتجات البيولوجية؛ املوت اخللوي؛ عمان. screening for anti-cancer compounds in marine organisms in oman *sergey dobretsov,1,2 yahya tamimi,3 mohamed a. al-kindi,4 ikram burney5 clinical & basic research sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 168–174, epub. 15 may 16 submitted 8 sep 15 revision req. 19 nov 15; revision recd. 2 dec 15 accepted 3 jan 16 doi: 10.18295/squmj.2016.16.02.006 advances in knowledge this is the first study from oman showing the anti-cancer potential of omani marine organisms. very few studies of this kind have been conducted in the gulf cooperative council region. the greatest activity against the breast adenocarcinoma model was observed with the malformin a, kuanoniamine d, hymenialdisine and gallic acid compounds as well as the soft coral sarcophyton sp. extract. sergey dobretsov, yahya tamimi, mohamed a. al-kindi and ikram burney clinical and basic research | e169 the marine ecosystem covers two-thirds of the earth’s surface and has diverse environmental conditions, facilitating the specialisation and diversity of marine organisms; as such, these organisms are a rich source of as-yetuntapped bioactive molecules.1‒3 soft-body sessile marine organisms—such as algae, sponges, soft corals and tunicates—are important sources of bioactive compounds.4‒6 this is due to the fact that sessile organisms often accumulate toxic and repellent compounds in their body, not only to compensate for their lack of mechanical defences and protective structures, but also to protect themselves from predators, pathogens and the accumulation of unwanted material on their surfaces.7 few secondary metabolites have yet been isolated from marine organisms and transformed into pharmaceuticals, but it is expected that novel drugs will be isolated from marine organisms in the future.4,8–11 cancer remains one of the major causes of mortality worldwide; unsurprisingly, many research groups are currently focusing on finding novel anti-cancer drugs to enhance chemotherapy treatment and increase survival rates.12 a significant number of anti-cancer compounds have been isolated from marine organisms but only a few have been approved for treatment, for example the chemotherapy drugs cytosine arabinoside (isolated from the sponge cryptotethya crypta) and eribulin (halichondrin b isolated from the sponge halichondria okadai) and the anti-tumour drug trabectedin (ecteinascidin isolated from the tunicate ecteinascidia turbinata).12–14 bryostatin-1 is a macrolide compound produced by endosymbiotic bacteria of the bryozoan bugula neritina which induces apoptosis at nanomolar concentrations in cancer cells and is enhanced by protein kinase c overexpression; it is currently in phase ii clinical trials.13 another product, didemnin b, was isolated from the tunicate trididemnum solidum and revealed high activity against myelomas and breast, ovarian, cervical and lung cancers; unfortunately, it was excluded from any further consideration as an anti-cancer agent after it was found to be highly toxic.7,13 data are limited regarding natural products from marine organisms and their application as traditional medications in the arabian gulf area, particularly oman. while the activity of pure anti-cancer compounds isolated from marine organisms has been reported previously, it is possible that new anti-cancer compounds can be isolated from omani organisms. several novel natural products have been isolated from spatoglossum variabile and dictyota dichotoma algae gathered from the coast of the arabian sea in karachi, pakistan, but their pharmaceutical activity has not yet been investigated.15,16 an antifungal phenolic compound with aromatic unsaturation was produced from the bacterium pseudomonas aeruginosa cmg1055, also isolated from the arabian sea coast of pakistan.17 gelliodes spp. and spheciospongia spp.1 and spp.2 sponges from the persian gulf coast in bushehr, iran, were identified as the most active against a panel of bacterial pathogens such as bacillus subtilis, staphylococcus aureus, p. aeruginosa and escherichia coli; unfortunately, no bioactive compounds were identified.18 in a previous study in oman, researchers screened the anti-microbial, antidiatom and antilarval properties of holothuria atra and h. edulis sea cucumbers collected from the bandar al-khayran region; their findings suggested the presence of cytotoxic compounds.19 to the best of the authors’ knowledge, there is no information in the literature about anti-cancer compounds derived from marine organisms in oman. therefore, the aim of this study was to screen the anti-cancer activity of natural products and extracts of marine organisms collected from the gulf of oman. methods this study was carried out between january 2012 and december 2014 at the sultan qaboos university, muscat, oman. a total of 40 natural products were obtained from different species of fungi, bacteria, marine sponges, algae, soft corals, tunicates, bryozoans, mangrove tree samples and sea cucumbers collected from seawater at marina bandar al-rowdha (23º 34.55' north, 58º 36.27' east) and bandar alkhayran (23º 75' north, 58º 75' east) in oman.20 bacteria and fungi were isolated from the seawater using a marine broth (oxoid ltd., basingstoke, uk) according to previously described methods.21 all macroorganisms were freeze-dried and extracted with methanol and ethyl acetate solvents (sigma-aldrich corp., st. louis, missouri, usa). for microbes, ultrastructural analysis and staining of the michigan cancer foundation-7 cell line indicated the role of the apoptotic pathway in triggering cell death. application to patient care the results of this study indicate possibilities for the development of new treatments for breast adenocarcinomas and other cancers. screening for anti-cancer compounds in marine organisms in oman e170 | squ medical journal, may 2016, volume 16, issue 2 cultures were centrifuged at 5,000 g and the bacterial cell pellets and fungi mycelium were extracted using the methanol and ethyl acetate solvents. all extracts were filtered using filtration paper (whatman® grade 1 filtration paper, sigma-aldrich corp.) and the solvents were removed by evaporation under reduced pressure using a rotary evaporator (büchi labortechnik ag, flawil, switzerland). the extracts were separated and purified using open-air silica for non-polar extracts or c18 columns for polar extracts. highperformance liquid chromatography was performed using a shimadzu system (shimadzu corp., kyoto, japan) in order to further purify the fractions. finally, the structure of pure secondary metabolites was elucidated on the basis of spectroscopic data, including infrared and ultraviolet radiation, high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. the novelty of the isolated compounds was assessed using the royal society of chemistry marinlit® database of marine natural products.22 the dry extracts and pure compounds were then redissolved either in dimethyl sulfoxide (dmso; sigmaaldrich corp.) or methanol. a breast adenocarcinoma cell line, michigan cancer foundation (mcf)-7 (atcc® htb-22™, american type culture collection, manassas, virginia, usa), and a control line of human fibroblasts were cultured in dulbecco’s modified eagle medium (dmem; gibco®, thermo fisher scientific inc., waltham, massachusetts, usa). this was supplemen ted with 10% fetal bovine serum (fbs) and a 1% anti biotic antimycotic cocktail (gibco®, thermo fisher scientific inc.) containing 10,000 units/ml of penicillin, 10,000 µg/ml of streptomycin and 25 µg/ ml of amphotericin b. the cells were maintained in a humidified incubator at 37 ºc with a 5% carbon dioxide atmosphere. extracts or solutions of pure compounds (1 µl) were applied to each well of a 96-well plate (nunc™ microwell™ plate, thermo fisher scientific inc.). the mcf-7 cells or human fibroblasts were then seeded in the 96-well plate at a density of 1,500 cells per well in 100 μl of dmem supplemented with 10% fbs before being incubated for 24 hours. at the end of the experiment, the cells were observed with an inverted microscope and the status of the cells was determined. the experiment was repeated three times. due to its activity and availability, the crude extract of sarcophyton sp. was selected for further analysis to determine the mode of its anti-cancer action. the mcf-7 cells were treated for 24 hours with different concentrations (12.5, 25.0, 50.0, 100.0, 150.0, 200.0, 300.0, 350.0 and 400.0 μg/ml) of the crude extract prepared in dmem, without phenol red solution or fbs. cells treated with dmso were included as negative controls for each concentration. cells were seeded in a six-well plate and treated with the determined inhibitory concentration 50% (ic50) of sarcophyton sp. extract on attainment of 70–80% confluence. the cells were subsequently stained with hoechst dye in order to identify the mode of cell death induced by the bioactive extracts of sarcophyton sp. in the mcf-7 breast cancer model. treated cells were harvested, suspended in 40 μl of hoechst-formalin solution (ratio: 1:50) and incubated overnight in the dark at 4 ºc. hoechst-stained cells were then mounted on a glass slide and examined under the microscope using the 4’,6-diamidino-2-phenylindole filter (excitation: 350 nm; emission: 461 nm). cells treated with dmso were included as a negative control. following the cell viability assay, electron microscopy analysis of the treated cells was used to elucidate the mechanism by which the extracts destroyed the cells. the mcf-7 cell lines were visualised using a transmission electron microscope (tem; jeol, peabody, massachusetts, usa).23 briefly, the cell samples were fixed, dehydrated using an alcohol series and embedded in epoxy resin. ultra-thin sections were obtained using an ultramicrotome and stained with uranyl acetate and reynolds’ lead citrate. results a total of eight pure compounds and 32 extracts of marine organisms in oman were investigated, with 22.5% showing strong or medium anti-cancer activity against the mcf-7 cells, including 62.5% of the compounds and 12.5% of the extracts [table 1]. the greatest anti-cancer activity was observed for malformin a, kuanoniamine d, hymenialdisine and gallic acid compounds, as well as the soft coral sarcophyton sp. extract. medium activity was observed for the aaptamin compound and the bryozoan schizoporella unicornis, gorgonian coral acanthogorgia sp. and sponge mycale sp. extracts. no quantifiable activity on the control human fibroblast cells was detected. treatment of mcf-7 cells with different concentrations of sarcophyton sp. extract indicated a gradual increase in anti-cancer bioactivity as observed from escalating levels of cell death with increasing treatment concentration. the ic50 was 97 µg/ml; concentrations of cell death induction were most potent at doubled ic50. the presence of fragmented nuclei was observed in treated cells in comparison to the negative control cells [figure 1]. this highlighted the role of the apoptotic pathway in triggering cell sergey dobretsov, yahya tamimi, mohamed a. al-kindi and ikram burney clinical and basic research | e171 table 1: pure compounds* and extracts isolated from omani marine organisms and their activity against the breast cancer michigan cancer foundation-7 cell line isolate organism species phylum solvent aca† c om po un d aaptamin sponge hemiasterella sp. porifera dmso medium hymenidin sponge halichondria sp. porifera dmso weak 2-bromoaldisine sponge thethya sp. porifera dmso none hymenialdisine sponge hemiasterella sp. porifera dmso strong malformin a fungus aspergillus niger ascomycota dmso strong kojic acid fungus aspergillus sp. ascomycota meoh none kuanoniamine d tunicate didemnum sp. chordata dmso strong gallic acid mangrove tree avicennia marina tracheophyta meoh strong ex tr ac t methanol soft coral sarcophyton sp. cnidaria dmso none ethyl acetate soft coral sarcophyton sp. cnidaria dmso strong methanol soft coral sinularia sp. cnidaria dmso none ethyl acetate soft coral sinularia sp. cnidaria dmso none methanol soft coral cladiella sp. cnidaria dmso weak ethyl acetate soft coral cladiella sp. cnidaria dmso weak methanol soft coral scleronephthya sp. cnidaria dmso none ethyl acetate soft coral scleronephthya sp. cnidaria dmso weak methanol soft coral dendronephthya sp. cnidaria dmso none ethyl acetate soft coral dendronephthya sp. cnidaria dmso none methanol tunicate phallusia nigra chordata dmso none ethyl acetate tunicate phallusia nigra chordata dmso none methanol sponge chondrosia sp. porifera dmso none ethyl acetate sponge chondrosia sp. porifera dmso none ethyl acetate fungus penicillium sp. ascomycota dmso none methanol fungus penicillium sp. ascomycota dmso none methanol sea cucumber holothuria edulis echinodermata dmso weak ethyl acetate sea cucumber holothuria atra echinodermata dmso weak methanol gorgonian coral acanthogorgia sp. cnidaria dmso weak ethyl acetate gorgonian coral acanthogorgia sp. cnidaria dmso medium methanol bryozoan schizoporella unicornis bryozoa dmso none ethyl acetate bryozoan schizoporella unicornis bryozoa dmso medium methanol sponge mycale sp. porifera dmso medium ethyl acetate sponge mycale sp. porifera dmso none methanol bacterium halomonas sp. proteobacteria dmso none ethyl acetate bacterium halomonas sp. proteobacteria dmso none methanol bacterium marinobacter sp. proteobacteria dmso none ethyl acetate bacterium marinobacter sp. proteobacteria dmso none methanol green alga ulva sp. chlorophyta meoh none ethyl acetate green alga ulva sp chlorophyta meoh none ethyl acetate bryozoan bugula sp. bryozoa meoh none methanol bryozoan bugula sp. bryozoa meoh weak control dmso and meoh none aca = anti-cancer activity; dmso = dimethyl sulfoxide; meoh = methanol. *all compounds were dissolved either in meoh or dmso prior to the experiments and meoh solutions were also evaporated beforehand. correspondent meoh and dmso controls were included. †anti-cancer activity was classified as either none (no activity), weak (<1,000 µg/ml), medium (100–1,000 µg/ml) or strong (>100 µg/ml). screening for anti-cancer compounds in marine organisms in oman e172 | squ medical journal, may 2016, volume 16, issue 2 death. furthermore, the tem ultrastructural analysis of the sarcophyton sp.-treated cells indicated the presence of cell membrane blebbing, intense vacuolisation and chromatic segregation at the periphery of the nucleus [figure 2]. these changes confirmed the activation of apoptosis in the treated mcf-7 cells. discussion numerous studies have indicated the benefits of marine flora and fauna extracts in various fields, including improvement in the prognosis of several diseases such as cancer.24–26 the complexity, poor prognosis and patient-, typeand stage-specificity of cancer requires the investigation and identification of novel compounds with effective clinical utility. in this study, the aim was to investigate the anti-cancer activity of extracts and compounds isolated from marine organisms in oman. almost a quarter of the investigated extracts and compounds showed medium or strong anti-cancer activity. the strongest activity against the mcf-7 breast adenocarcinoma model was observed for the malformin a, kuanoniamine d, hymenialdisine and gallic acid compounds and the soft coral sarcophyton sp. extract. hagimori et al. observed that malformin can disrupt the cell cycle at the g2 figure 1a & b: hoechst stains at x40 magnification of michigan cancer foundation-7 breast cancer cells treated with (a) 97 µg/ml of sarcophyton sp. extract for 24 hours and (b) dimethyl sulfoxide as a negative control. note the presence of nuclear fragmentation in the cells treated with the sarcophyton sp. extract (arrows). figure 2a–d: transmission electron microscopy ultrastructural analysis at x4,000 magnification of (a–c) michigan cancer foundation (mcf)-7 breast cancer cells treated with 97 µg/ml of sarcophyton sp. extract for 24 hours and (d) control cells treated with solvents. intensive blebbing, vacuolisation and chromatic segregation (arrows) due to apoptosis were observed in the mcf-7 cells. n = nucleus. sergey dobretsov, yahya tamimi, mohamed a. al-kindi and ikram burney clinical and basic research | e173 checkpoint in cancer cells.27 similarly, kuanoniamine a and c isolated from sponges has been found to inhibit the growth of tumour and non-tumour cell lines, as well as an oestrogen-dependent breast cancer cell line.28 smith et al. revealed that hymenialdisine has anti-cancer properties against human colorectal carcinomas.29 furthermore, gallic acid has been shown as a potent compound with antimicrobial, antioxidant, quorum-sensing inhibitory and anti-cancer properties.30–32 in the current study, the tested compounds had no measurable effects on human fibroblast cells. this may suggest that these compounds are non-toxic, although alternatively this could indicate that fibroblasts are very resistant compared to the mcf-7 breast cancer cell line. this observation is in agreement with earlier findings regarding the resistance of fibroblasts to several toxic compounds.32 moreover, mcf-10a cells are not considered a good control model since they have a transformed phenotype and are abnormal epithelial cells.33 new epithelial non-transformed cells are commercially available; however, they are difficult to handle and propagate.33 as such, there is a need for future in vivo studies to be carried out in order to assess the toxicity of marine natural products using immunosuppressed mice. analysis of the anti-cancer activity of sarcophyton sp. extracts in the present study indicated the potency of this extract in inducing cell death in the mcf-7 breast cancer model at the ic50 of 97 µg/ml. moreover, tem microscopic analysis and hoechst staining indicated the presence of fragmented nuclei within the treated cells. typical characteristics of cell death induction by apoptosis were noted, such as nuclear fragmentation, membrane blebbing and increased vacuolisation. the anti-cancer activity of soft coral extracts has been previously reported.34,35 for example, diterpenes from the soft coral xenia elongata were found to induce apoptosis in a genetically engineered mouse cell line which was d3-deficient in the bak1 and bax genes.35 the preliminary results of the current study therefore indicate the potential benefit of sarcophyton sp. extracts in cancer treatment. an in-depth analysis of the molecular effects, specificity and efficacy of the extract for breast, ovarian, colon and prostate cancers is required through further in vitro and in vivo studies; this may potentially lead to the development of new treatments for breast adenocarcinomas and other cancers. conclusion the results of this study highlight the anti-cancer potential of various marine organisms in oman. the active anti-cancer compound extracted from sarcophyton sp. is of particular interest and should be isolated in future experiments. the compound should be tested on in vitro models of various cancers to determine the specificity of its anti-cancer activity. finally, the molecular mechanism and pathways activated in response to treatment with this compound should be investigated. such an investigation will provide possibilities for the development of new cancer treatments. a c k n o w l e d g e m e n t s this study was funded by an internal grant from the sultan qaboos university (#ig/agr/fish/12/01). the authors would like to acknowledge the support given to them by sultan qaboos university. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. fenical w, jensen pr. developing a new resource for drug discovery: marine actinomycete bacteria. nat chem biol 2006; 2:666–73. doi: 10.1038/nchembio841. 2. cooper el, yao d. diving for drugs: tunicate anticancer compounds. drug discov today 2012; 17:636–48. doi: 10.1016 /j.drudis.2012.02.006. 3. blunt jw, copp br, keyzers ra, munro mh, prinsep mr. marine natural products. nat prod rep 2013; 30:237–323. doi: 10.1039/c2np20112g. 4. proksch p, edrada ra, ebel r. drugs from the seas: current status and microbiological implications. appl microbiol biotechnol 2002; 59:125–34. doi: 10.1007/s00253-002-1006-8. 5. thoms c, schupp p. biotechnological potential of marine sponges and their associated bacteria as producers of new pharmaceuticals (part i). j inter biotech law 2005; 2:217–20. doi: 10.1515/jibl.2005.2.5.217. 6. penesyan a, kjelleberg s, egan s. development of novel drugs from marine surface associated microorganisms. mar drugs 2010; 8:438–59. doi: 10.3390/md8030438. 7. paul vj, arthur ke, ritson-williams r, ross c, sharp k. chemical defenses: from compounds to communities. biol bull 2007; 213:226–51. doi: 10.2307/25066642. 8. schwartsmann g, ratain mj, cragg gm, wong je, saijo n, parkinson dr, et al. anticancer drug discovery and development throughout the world. j clin oncol 2002; 20:47s–59s. doi: 10.1200/jco.2002.07.122. 9. newman dj, cragg gm. natural products as sources of new drugs over the last 25 years. j nat prod 2007; 70:461–77. doi: 10.1021/np068054v. 10. abraham i, el sayed k, chen zs, guo h. current status on marine products with reversal effect on cancer multidrug resistance. mar drugs 2012; 10:2312–21. doi: 10.3390/ md10102312. 11. terlau h, olivera bm. conus venoms: a rich source of novel ion channel-targeted peptides. physiol rev 2004; 84:41–68. doi: 10.1152/physrev.00020.2003. http://dx.doi.org/10.1038/nchembio841 http://dx.doi.org/10.1016/j.drudis.2012.02.006 http://dx.doi.org/10.1016/j.drudis.2012.02.006 http://dx.doi.org/10.1039/c2np20112g http://dx.doi.org/10.1007/s00253-002-1006-8 http://dx.doi.org/10.1515/jibl.2005.2.5.217 http://dx.doi.org/10.3390/md8030438 http://dx.doi.org/10.2307/25066642 http://dx.doi.org/10.1200/jco.2002.07.122 http://dx.doi.org/10.1021/np068054v http://dx.doi.org/10.3390/md10102312 http://dx.doi.org/10.3390/md10102312 http://dx.doi.org/10.1152/physrev.00020.2003 screening for anti-cancer compounds in marine organisms in oman e174 | squ medical journal, may 2016, volume 16, issue 2 12. sawadogo wr, schumacher m, teiten mh, cerella c, dicato m, diederich m. a survey of marine natural compounds and their derivatives with anti-cancer activity reported in 2011. molecules 2013; 18:3641–73. doi: 10.3390/molecules18043641. 13. simmons tl, andrianasolo e, mcphail k, flatt p, gerwick wh. marine natural products as anticancer drugs. mol cancer ther 2005; 4:333–42. 14. hussain sm, fareed s, ansari s, khan ms. marine natural products: a lead for anti-cancer. indian j geomarine sci 2012; 41:27–39. 15. hayat s, atta-ur-rahman, chouldhary mi, khan km, abbaskhan a. two new cinnamic acid esters from marine brown alga spatoglossum variabile. chem pharm bull (tokyo) 2002; 50:1297–9. doi: 10.1248/cpb.50.1297. 16. ali ms, pervez mk, ahmed f, saleem m. dichotenol-a, b and c: the c-16 oxidized seco-dolastanes from the marine brown alga dictyota dichotoma (huds.) lamour. nat prod res 2004; 18:543–9. doi: 10.1080/14786410310001622059. 17. uzair b, ahmed n, mohammad fv, ahmad vu. detection, isolation and partial characterization of antifungal compound(s) produced by pseudomonas aeruginosa cmg1055. j chem soc pak 2008; 30:649–53. 18. safaeian s, hosseini h, asadolah aa, farmohamadi s. antimicrobial activity of marine sponge extracts of offshore zone from nay band bay, iran. j mycol med 2009; 19:11–16. doi: 10.1016/j.mycmed.2008.11.003. 19. dobretsov s, al-mammari im, soussi b. bioactive compounds from omani sea cucumbers. j agricultural mar sci 2009; 14:49–53. 20. riguera r. isolating bioactive compounds from marine organisms. j mar biotech 1997; 5:187–93. 21. dobretsov sv, qian py. effect of bacteria associated with the green alga ulva reticulata on marine microand macrofouling. biofouling 2002; 18:217–28. doi: 10.1080/08927010290013026. 22. royal society of chemistry. marinlit: a database of the marine natural products literature. from: pubs.rsc.org/marinlit/ accessed: jan 2016. 23. skalli o, boykins lg, coons l. electron microscopy. in: dobretsov s, williams dn, thomason jc, eds. biofouling methods. london, uk: wiley-blackwell, 2014. pp. 26–43. doi: 10.1002/9781118336144. 24. lee jc, hou mf, huang hw, chang fr, yeh cc, tang jy, et al. marine algal products with anti-oxidative, anti-inflammatory, and anti-cancer properties. cancer cell int 2013; 13:55. doi: 10.1186/1475-2867-13-55. 25. sithranga boopathy n, kathiresan k. anticancer drugs from marine flora: an overview. j oncol 2010; 2010:214186. doi: 10.1155/2010/214186. 26. cooper el, albert r. tunicates: a vertebrate ancestral source of antitumor compounds. in: kim sk, ed. handbook of anticancer drugs from marine origin. geneva, switzerland: springer, 2015. pp. 383–96. doi: 10.1007/978-3-319-07145-9_18. 27. hagimori k, fukuda t, hasegawa y, omura s, tomoda h. fungal malformins inhibit bleomycin-induced g2 checkpoint in jurkat cells. biol pharm bull 2007; 30:1379–83. doi: 10.1248/ bpb.30.1379. 28. kijjoa a, wattanadilok r, campos n, nascimento ms, pinto m, herz w. anticancer activity evaluation of kuanoniamines a and c isolated from the marine sponge oceanapia sagittaria, collected from the gulf of thailand. mar drugs 2007; 5:6–22. doi: 10.3390/md502006. 29. smith v, raynaud f, workman p, kelland lr. characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol. mol pharmacol 2001; 60:885–93. doi: 10.1124/mol.60.5.885. 30. choubey s, varughese lr, kumar v, beniwal v. medical importance of gallic acid and its ester derivatives: a patent review. pharm pat anal 2015; 4:305–15. doi: 10.4155/ppa.15.14. 31. singh bn, singh br, singh rl, prakash d, dhakarey r, upadhyay g, et al. oxidative dna damage protective activity, antioxidant and anti-quorum sensing potentials of moringa oleifera. food chem toxicol 2009; 47:1109–16. doi: 10.1016/j. fct.2009.01.034. 32. wang k, zhu x, zhang k, zhu l, zhou f. investigation of gallic acid induced anticancer effect in human breast carcinoma mcf-7 cells. j biochem mol toxicol 2014; 28:387–93. doi: 10.1002/jbt.21575. 33. imbalzano km, tatarkova i, imbalzano an, nickerson ja. increasingly transformed mcf-10a cells have a progressively tumor-like phenotype in three-dimensional basement membrane culture. cancer cell int 2009; 9:7. doi: 10.1186/14752867-9-7. 34. byju k, anuradha v, vasundhara g, nair sm, kumar nc. in vitro and in silico studies on the anticancer and apoptosisinducing activities of the sterols identified from the soft coral, subergorgia reticulata. pharmacogn mag 2014; 10:s65–71. doi: 10.4103/0973-1296.127345. 35. andrianasolo eh, haramaty l, white e, lutz r, falkowski p. mode of action of diterpene and characterization of related metabolites from the soft coral, xenia elongata. mar drugs 2014; 12:1102–15. doi: 10.3390/md12021102. http://dx.doi.org/10.3390/molecules18043641 http://dx.doi.org/10.1248/cpb.50.1297 http://dx.doi.org/10.1080/14786410310001622059 http://dx.doi.org/10.1016/j.mycmed.2008.11.003 http://dx.doi.org/10.1080/08927010290013026 http://dx.doi.org/10.1002/9781118336144 http://dx.doi.org/10.1186/1475-2867-13-55 http://dx.doi.org/10.1155/2010/214186 http://dx.doi.org/10.1007/978-3-319-07145-9_18 http://dx.doi.org/10.1248/bpb.30.1379 http://dx.doi.org/10.1248/bpb.30.1379 http://dx.doi.org/10.3390/md502006 http://dx.doi.org/10.1124/mol.60.5.885 http://dx.doi.org/10.4155/ppa.15.14 http://dx.doi.org/10.1016/j.fct.2009.01.034 http://dx.doi.org/10.1016/j.fct.2009.01.034 http://dx.doi.org/10.1002/jbt.21575%20 http://dx.doi.org/10.1186/1475-2867-9-7 http://dx.doi.org/10.1186/1475-2867-9-7 http://dx.doi.org/10.4103/0973-1296.127345 http://dx.doi.org/10.3390/md12021102 sultan qaboos university med j, august 2015, vol. 15, iss. 3, p. e444, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.026. submitted 5 apr 15 accepted 14 may 15 رد: االعتالل العضلي الذي يسببه دواء صوديوم فالربويت يف طفل re: sodium valproate-induced myopathy in a child sir, i read with interest the letter to the editor by ahmed published in the squmj february 2015 issue.1 the patient, after a diagnosis of childhood-onset epilepsy with absence seizures, was started on 250 mg of sodium valproate in two divided doses (20 mg/kg). as response to treatment was inadequate, the dose of the drug was gradually increased over the following weeks to the maximum permissible dose of 500 mg twice daily.1 six months later, slowly developing myopathy was observed. based on the clinical picture, a myopathic needle electromyography pattern and low serum carnitine levels, the author attributed the myopathy to carnitine deficiency secondary to valproate therapy.1 nakajima et al. reported that the long-term treatment of paediatric patients with sodium valproate could have an impact on specific acylcarnitines and proposed that this effect is augmented by simultaneous use of other anticonvulsants.2 however, they also noted that valproylcarnitine formation through the use of therapeutic sodium valproate seems insufficient for the development of severe carnitine deficiency.2 hence, such biochemical changes in acylcarnitines in children are not clinically significant.2,3 i presume that the development of myopathy in the patient described by ahmed cannot be solely attributed to valproate therapy, as the drug was prescribed at permissible doses.1 the myopathy in the studied patient may be due to a carnitine palmitoyltransferase (cpt) ii deficiency. this condition leads to a disorder of long-chain fatty-acid oxidation.4 there are several clinical presentations of cpt ii deficiency, including the myopathic form, which is usually mild and can manifest from infancy to adulthood. myopathic cpt ii deficiency can be associated with myoglobinuria and manifest as exercise-induced muscle pain and weakness.4 there is evidence that valproate is among the factors that trigger myopathy in cpt ii-deficient patients.4 tandem mass spectrometry are used to measure serum and plasma acylcarnitines.3 reduced cpt enzyme activity indicate a definitive diagnosis. however, new advances in molecular genetic testing have provided an improved non-invasive diagnostic method with the presence of the carnitine palmitoyltransferase 2 gene (the only gene associated with cpt ii deficiency).4 although, to the best of my knowledge, no studies yet exist which investigate cpt ii deficiency in saudi arabia, the high prevalence of consanguinity in this region might be a strong indicator of its potential existence.5 consanguinity is significantly associated with various patterns of inborn errors of the metabolism.6 a myopathic form of cpt ii deficiency ought to be seriously considered for this reported patient and suitable laboratory tests employed.1 however, the patient reported by ahmed could still be included among the paediatric valproate-associated myopathy cases reported in the literature.1 valproate is a broad-spectrum antiepileptic drug. in high-risk patients, carnitine supplementation with combined antiepileptic drug therapy, carnitine-free enteral tube feeding and the maintenance of a healthy body weight have been recently recommended to prevent epilepsy-related complications.7 however, controlled, randomised and multicentre studies are needed to investigate the therapeutic and prophylactic roles and the optimal administration of carnitine supplementation during valproate therapy. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. ahmed r. sodium valproate-induced myopathy in a child. sultan qaboos univ med j 2015; 15:e146–7. 2. nakajima y, ito t, maeda y, ichiki s, kobayashi s, ando n, et al. evaluation of valproate effects on acylcarnitine in epileptic children by lc-ms/ms. brain dev 2011; 33:816–23. doi: 10.1016/j.braindev.2010.12.003. 3. cansu a, serdaroglu a, biberoglu g, tumer l, hirfanoglu tl, ezgu fs, et al. analysis of acylcarnitine levels by tandem mass spectrometry in epileptic children receiving valproate and oxcarbazepine. epileptic disord 2011; 13:394–400. doi: 10.1684/epd.2011.0478. 4. wieser t. carnitine palmitoyltransferase ii deficiency. in: pagon ra, adam mp, ardinger hh, wallace se, amemiya a, bean lj, et al., eds. genereviews. from: www.ncbi.nlm.nih.gov/books/nbk1253/ accessed: apr 2015. 5. warsy as, al-jaser mh, albdass a, al-daihan s, alanazi m. is consanguinity prevalence decreasing in saudis? a study in two generations. afr health sci 2014; 14:314–21. doi: 10.4314/ahs.v14i2.5. 6. al bu ali wh, balaha mh, al moghannum ms, hashim i. risk factors and birth prevalence of birth defects and inborn errors of metabolism in al ahsa, saudi arabia. pan afr med j 2011; 8:14. 7. fukuda m, kawabe m, takehara m, iwano s, kuwabara k, kikuchi c, et al. carnitine deficiency: risk factors and incidence in children with epilepsy. brain dev 2014; pii: s0387–7604(14)00289–7. doi: 10.1016/j.braindev.2014.12.004. letter to the editor e444 | squ medical journal, august 2015, volume 15, issue 3 http://dx.doi.org/10.1016/j.braindev.2010.12.003 http://dx.doi.org/10.1684/epd.2011.0478 http://dx.doi.org/10.4314/ahs.v14i2.5 http://dx.doi.org/10.1016/j.braindev.2014.12.004 التشخيص و التحليل الوراثي جللوتاريك امحضاض الدم النوع 1 خطأ استقاليب وراثي نادرا جدا diagnosis and genetic analysis of glutaric acidaemia type i very rarely seen inborn error of metabolism sir, a 10-month-old female child with delayed milestones presented to the genetic clinic of the fernandez hospital in hyderabad, india, in january 2008. she had been delivered at full term via a lower segment caesarean section due to non-progressive labour. the head circumference at birth was 33 cm and the baby cried immediately after birth with apgar scores of 8, 9 and 9 at one, five and 10 minutes, respectively. the family were muslim and of indian descent and the child had been raised in india. the parents reported a history of stiffness in the child’s hands occurring intermittently for the previous two months; a cold, cough and fever over the preceding eight days; and regression of developmental milestones. a physical examination revealed that the child was conscious and alert with a head circumference of 54.5 cm (>90th percentile). neurological examination of the infant revealed increased muscle tone in all of the limbs with exaggerated deep reflexes. the complete blood count and serum electrolyte and serum calcium levels were normal. an electroencephalogram displayed a normal pattern. the metabolic work-up revealed elevated glutaric, glutaconic and 3-hydroxyglutaric acids in the urine. magnetic resonance imaging of the brain showed bilateral hyperintense signal abnormalities in the basal ganglia with symmetrical involvement of the lenticular and caudate nuclei and thalamic hypointensity. there was evidence of diffuse cerebral cortical atrophy with wide extraaxial cerebrospinal fluid spaces in the frontal and temporal regions. superior centrum semiovale white matter hypointense foci were also observed. magnetic resonance spectroscopy showed patterns of high glutamate and minimal lactate production and a normal choline/creatinine ratio. sanger sequencing of the glutaryl-coenzyme a dehydrogenase (gcdh) gene revealed that the child had a homozygous mutation c.1119t>g (p. n373k) in exon 10. both of the infant’s parents were heterozygous for the same mutation. during their subsequent pregnancy, the couple were followed-up by the clinic staff and the fetus was tested for the gcdh gene. the results suggested that the fetus was heterozygous for the mutation. the pregnancy was continued and further screening after birth indicated that the infant was not affected. had the genetic testing revealed that their second child did have a homozygous mutation, the option of terminating the pregnancy would have been discussed with the parents. genetic counselling would also have been offered to aid the parents in their decision-making. the early diagnosis of inborn errors of metabolism (iems) is important not only to ensure rapid treatment of the index case but also to inform subsequent pregnancies.1,2 glutaric acidaemia type i (gai) is an iem whereby the body is unable to completely break down the lysine, hydroxylysine and tryptophan amino acids, resulting in the accumulation of intermediate breakdown products (such as glutaric acid, glutaryl-coenzyme a, 3-hydroxyglutaric acid and glutaconic acid) in bodily fluids and various organs, particularly the brain.3,4 gai sometimes results in mental retardation and is also known to cause secondary carnitine deficiency.5 the estimated prevalence of gai is one in 100,000 newborns.1 the presentation of gai is variable and appears unrelated to biochemical phenoor genotypes. most affected neonates are asymptomatic initially, gradually developing macrocephaly as they get older, with frontal bossing from birth or during the first six months of life.6,7 they typically present with symptoms of acute encephalopathy, usually secondary to a concurrent infection or due to other acute catabolic states such as diarrhoea or vomiting. this normally leads to a misdiagnosis of viral encephalopathy secondary to encephalitis or acute disseminated encephalomyelitis.6,7 after the acute course, extrapyramidal symptoms will develop corresponding to the striatal involvement; this is usually seen as necrosis on neuroimaging. however, gai can also have an insidious onset without episodes of acute deterioration; rarely, the condition presents in adulthood asymptomatically or with progressive encephalopathy.6,7 letter to the editor sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e572–573, epub. 23 nov 15 submitted 12 jan 15 revisions req. 8 apr & 25 may 15;revisions recd. 14 apr & 21 jun 15 accepted 26 jul 15 doi: 10.18295/squmj.2015.15.04.026 madhavi vasikarla, aakash pandita, deepak sharma, oleti t. pratap and srinivas murki letter to the editor | e573 episodes of decompensation and encephalopathy are mild or absent in approximately 25% of children affected by gai.8 typically, these patients develop dystonia (usually diagnosed as cerebral palsy), motor delay and intellectual disability.9,10 some children present with an acute subdural haemorrhage or chronic subdural effusions that may be erroneously attributed to child abuse or shaken baby syndrome. a possible explanation for acute haemorrhage is the increased fragility of bridging veins that are stretched due to cerebral atrophy.9,10 medical professionals should consider the wide presentation of this condition when assessing patients with suspected gai.11 clinicians should be aware of the clinical spectrum of iem and consider these rare disorders in cases of unexplained illness, delayed milestones, global developmental delay or unexplained neonatal death as well as among patients with a family history of iem. early diagnosis of these conditions through newborn screening programmes can lead to improved neurodevelopmental outcomes. genetic analysis is currently the gold standard for diagnosing iem. all affected iem patients should be closely followed up and comply with necessary dietary management. in cases of developmental delay, early stimulation is advisable. treatment with carnitine and riboflavin are also beneficial treatment options.12 madhavi vasikarla,1 aakash pandita,2 *deepak sharma,2 oleti t. pratap,2 srinivas murki2 departments of 1genetics and 2neonatology, fernandez hospital, hyderabad, india *corresponding author e-mail: dr.deepak.rohtak@gmail.com references 1. pfeil j, listl s, hoffmann gf, kölker s, lindner m, burgard p. newborn screening by tandem mass spectrometry for glutaric aciduria type 1: a cost-effectiveness analysis. orphanet j rare dis 2013; 8:167. doi: 10.1186/1750-1172-8-167. 2. lindner m, kölker s, schulze a, christensen e, greenberg cr, hoffmann gf. neonatal screening for glutaryl-coa dehydrogenase deficiency. j inherit metab dis 2004; 27:851–9. doi: 10.1023/b:boli.0000045769.96657.af. 3. harting i, neumaier-probst e, seitz a, maier em, assmann b, baric i, et al. dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type i. brain 2009; 132:1764–82. doi: 10.1093/brain/awp112. 4. hoffmann gf, trefz fk, barth pg, böhles hj, biggemann b, bremer hj, et al. glutaryl-coenzyme a dehydrogenase deficiency: a distinct encephalopathy. pediatrics 1991; 88:1194–203. 5. hedlund gl, longo n, pasquali m. glutaric acidemia type 1. am j med genet c semin med genet 2006; 142c:86–94. doi: 10.1002/ ajmg.c.30088. 6. wen p, wang gb, liu xh, chen zl, shang y, cui d, et al. [analysis of clinical features and gcdh gene mutations in four patients with glutaric academia type i]. zhonghua yi xue yi chuan xue za zhi 2012; 29:642–7. doi: 10.3760/cma.j.issn.1003-9406.2012.06.004. 7. strauss ka, puffenberger eg, robinson dl, morton dh. type i glutaric aciduria, part 1: natural history of 77 patients. am j med genet c semin med genet 2003; 121:38–52. doi: 10.1002/ajmg.c.20007. 8. strauss ka, morton dh. type i glutaric aciduria, part 2: a model of acute striatal necrosis. am j med genet c semin med genet 2003; 121:53–70. doi: 10.1002/ajmg.c.20008. 9. funk cb, prasad an, frosk p, sauer s, kölker s, greenberg cr, et al. neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. brain 2005; 128:711–22. doi: 10.1093/brain/awh401. 10. mühlhausen c, ergün s, strauss ka, koeller dm, crnic l, woontner m, et al. vascular dysfunction as an additional pathomechanism in glutaric aciduria type i. j inherit metab dis 2004; 27:829–34. doi: 10.1023/b:boli.0000045766.98718.d6. 11. wang q, ding y, liu y, li x, wu t, song j, et al. [clinical and laboratory studies on 28 patients with glutaric aciduria type 1]. zhonghua er ke za zhi 2014; 52:415–19. 12. kölker s, greenberg cr, lindner m, müller e, naughten er, hoffmann gf. emergency treatment in glutaryl-coa dehydrogenase deficiency. j inherit metab dis 2004; 27:893–902. doi: 10.1023/b:boli.0000045774.51260.ea. http://dx.doi.org/10.1186/1750-1172-8-167 http://dx.doi.org/10.1023/b:boli.0000045769.96657.af http://dx.doi.org/10.1093/brain/awp112 http://dx.doi.org/10.1002/ajmg.c.30088 http://dx.doi.org/10.1002/ajmg.c.30088 http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2012.06.004 http://dx.doi.org/10.1002/ajmg.c.20007 http://dx.doi.org/10.1002/ajmg.c.20008 http://dx.doi.org/10.1093/brain/awh401 http://dx.doi.org/10.1023/b:boli.0000045766.98718.d6 http://dx.doi.org/10.1023/b:boli.0000045774.51260.ea sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. e597-600, epub. 8th oct 13 submitted 25th dec 12 revisions req. 1st apr & 13th may 13; revisions recd. 20th apr & 28th may 13 accepted 4th jul 13 department of diagnostic radiology, the university of jordan hospital, amman, jordan *corresponding author e-mail: drmahasennajjar@yahoo.com ورم أرومي وعائي فردي يف البطني الوحشي ظهر بنزف داخل البطني و نزف حتت العنكبوتية حما�سن النجار، عزمي احلديدي، اأالء �سالح، اأحمد التميمي، اأ�سعد الدراوي�ش، فاطمة عبيدات امللخ�ص: مت االإبالغ عن عدد قليل من حاالت الورم االأرومي الوعائي داخل البطني يف االأدب الطبي اإما ب�سكل فردي اأو مرتبطا مبر�ش فون هيبيل لينداوز . ف�سال عن ذلك، فاإن حدوث النزف البطيني من ذلك الورم يبدو ا�ستثنائيا. نعر�ش هنا حالة نادرة لورم اأرومي وعائي فردي يف البطني الوح�سي االأمين ظهر ب�سكل نزف يف داخل الورم و داخل البطني، باالإ�سافة اإىل وجود بقع حداد �سطحية متعددة داخل اجلمجمة و التي ت�سري اإىل حدوث نزف حتت العنكبوتية اأي�سا. مل يتم االإبالغ عن مثل ذلك االرتباط من قبل. اإن اإيجاد ورم داخل البطني مع وجود نزف بطيني مع او بدون نزف حتت العنكبوتية ، �سوف يجعلنا ن�سع الورم االأرومي الوعائي �سمن القائمة الت�سخي�سية، خا�سة اإذا مل تطابق املظاهر االإ�سعاعية االورام االأخرى االأكرث �سيوعا. abstract: intraventricular hemangioblastoma (hb) is very rare; few cases of intraventricular hb have been reported in the literature, either sporadically or in association with von hippel-lindau disease. furthermore, the incidence of ventricular haemorrhage from hb seems to be uncommon. we report a unique case of sporadic hb of the right lateral ventricle presenting with intratumoural and intraventricular haemorrhage in addition to multifocal intracranial superficial siderosis, indicating the presence of a subarachnoid haemorrhage (sah) as well. such a combination has not been reported before. in the future, the detection of an intraventricular mass in association with ventricular haemorrhage, with or without sah, should include hb as a differential diagnosis, particularly when the imaging appearances are not typical of the more common intraventricular tumours. keywords: hemangioblastoma; lateral ventricle; subarachnoid hemorrhage; von hippel-lindau disease; case report; jordan. sporadic lateral ventricular hemangioblastoma presenting with intraventricular and subarachnoid haemorrhage *mahasen al-najar, azmy al-hadidy, alaa saleh, ahmad al-tamimi, asaad al-darawish, fatima obeidat hemangioblastoma (hb) of the central nervous system occurs usually in the infratentorial structures, but it may occur in supratentorial structures. however, hb of the lateral ventricle is very rare. the first case of intraventricular hb was incidentally discovered during a postmortem examination and, since then, only a few other cases have been reported.1 spontaneous haemorrhage is so uncommon among hb cases that, when it happens, it usually presents with a subarachnoid haemorrhage (sah) or intracerebral bleeding. an intraventricular haemorrhage from hb seems to be rare, and only one case of intraventricular hb was previously reported to cause direct haemorrhage into the ventricular system.² we believe that our case is the second one worldwide. case report a 70-year-old man presented to the emergency room with severe headache, vomiting and dizziness. he had had no seizures, changes in level of consciousness, fever, or a history of trauma. the patient had had recurrent headaches during the previous 3 months which were attributed to uncontrolled hypertension. his blood pressure was 150/70 mmhg. other vital signs were stable and a online case report mahasen al-najar, azmy hadidy, alaa saleh, ahmad tamimi, asaad al-darawish and fatima obeidat case report | 598 physical examination was unremarkable. neurological examinations revealed disorientation and an unsteady gait in addition to left upper motor neuron facial palsy and left-sided hemiparesis. laboratory investigations, including complete blood count, coagulation profile, and liver and renal function tests were all normal, with a haemoglobin level of 12.5 g/dl. a fundoscopic examination was also normal. an unenhanced computed tomography (ct) scan showed evidence of haemorrhage in the right ventricular trigone and occipital horn, surrounded by vasogenic oedema with suspicion of an underlying mass lesion. a blood level was also noted in the left occipital horn [figure 1]. magnetic resonance imaging (mri) confirmed the presence of a mass lesion in the trigone and occipital horn of the right lateral ventricle, which appeared isointense to grey matter on t1-weighted images and markedly hyperintense on t2-weighted and fluid attenuated inversion recovery (flair) images. these images also showed internal haemorrhagic foci. intraventricular bleeding was again noted in addition to multifocal superficial siderosis particularly around the brainstem and in both sylvian fissures [figure 2a]. this was best visualised on the gradient-recalled echo images (gre), indicating the presence of sah. gadolinium-enhanced t1-weighted images demonstrated a solitary, solid, mildly heterogeneously enhancing intraventricular mass about 3.3 cm in diameter [figure 2b]. the approximate volume of this lesion was 12.4 cm3 which was calculated by a modified ellipsoid formula (length × width × height × 0.5). magnetic resonance angiography did not show any abnormal vascularity. four-vessel conventional angiography was also normal. a frameless stereotactic brain biopsy was performed and a histopathologic examination showed hb. the tumour cells were arranged in nests separated by fine fibrovascular septae with occasional mitotic figures and bizarre nuclei. based on this result, the patient underwent an abdominal ultrasound examination to check for possible figure 1: axial non-enhanced brain computed tomography scan showing the haemorrhagic tumoral mass occupying the right occipital horn (black arrow, left) with surrounding vasogenic oedema (black star). a blood level is seen in the left one (black arrow, right). figures 2 a & b. a: axial t2-weighted image. note the superficial siderosis, particularly in the sylvian fissures (white arrow) in addition to the hemosiderin rim around the tumour (black star). again note the blood level in the left occipital horn (black arrow). b: contrast enhanced t1-weighted image demonstrating heterogenous mild enhancement within the right ventricular mass (white arrow). sporadic lateral ventricular hemangioblastoma presenting with intraventricular and subarachnoid haemorrhage 599 | squ medical journal, november 2013, volume 13, issue 4 stigmata of von hippel-lindau (vhl) disease such as renal tumours, but it was unremarkable. the patient’s family history was also negative for any relevant illnesses. a craniotomy with complete excision of the tumour was performed. a histopathologic examination again confirmed the diagnosis of hb. the postoperative course was uneventful. discussion hbs are benign vascular tumours of uncertain origin (world health organization grade 1) that comprise 2% of all intracranial tumours and present equally in both sexes.3 they usually present sporadically, but approximately 20–30% of cases are linked to vhl, which is an autosomal dominant inherited disorder with incomplete expression and penetrance.3 headache is the most common complaint followed by ataxia. less frequent presentations include motor palsies, visual disturbances and seizures. polcythaemia can be seen in 10–50% of patients with infratentorial hb but rarely in supratentorial hb.4 the most common locations of hb are infratentorial, particularly in the cerebellum (80– 85%), but they have been described throughout the central nervous system (cns). supratentorial hbs are rare, accounting for 4% of sporadic cases and 13% of cases with vhl.4,5 intraventricular hb and, in particular, the lateral ventricle form are very rare. only a few cases have been reported in medical literature, some of them associated with vhl and others not [table 1]. all reported intraventricular hbs have been solid and larger than those located elsewhere in the body, likely because of the space available to accommodate such masses before they produce symptoms.5 lateral ventricular tumours include a wide variety of benign and malignant types. the most relevant differential diagnosis of a mass in the lateral ventricle in this particular age group includes subependymoma, which is commonly associated with hydrocephalus and often shows cystic components and calcifications but rarely haemorrhage; central neurocytoma that commonly demonstrates calcifications and cyst-like spaces but rarely is associated with ventricular or parenchymal haemorrhage, and metastasis, particularly from table 1: summary of the reported cases of intraventricular hemangioblastoma* author age in years/ sex site number vhl rho et al.9 1969 58/m third ventricle + cerebellum + spinal cord multiple yes diehl et al.1 1981 20/m lateral ventricle + cerebellum + medulla multiple yes loftus et al.10 1984 63/m third ventricle solitary no murakami et al.11 1985 31/m lateral ventricle + cerebellum multiple positive family history katayama et al.12 1987 30/m third ventricle solitary no fujii et al.2 1987 70/f fourth ventricle solitary no ho et al.13 1990 44/f lateral ventricle solitary positive family history isaka et al.14 1999 47/f third ventricle + cerebellum multiple no prieto et al.5 2005 73/m lateral ventricle solitary yes son et al.4 2009 55/m fourth ventricle solitary no jaggi et al.15 2009 30/m lateral ventricle solitary no present case 2011 70/m lateral ventricle solitary no all reported cases were solid in nature vhl = von-hippel-lindau disease; m = male; f = female. renal and lung cancers, which can be associated with haemorrhage. it usually shows intense enhancement. the imaging appearance in our case did not fit any of these more common lesions. our case is also different from the other reported intraventricular hb cases because it showed only mild heterogeneous enhancement instead of the reported intense homogenous enhancement. hb most commonly presents as a cystic lesion with a mural nodule (60%) and less commonly as a solid lesion (20‒29%), which tends to bleed more than cystic hb.3,6,7 spontaneous macroscopic haemorrhage is uncommon among hbs despite their known vascular nature but, when it happens, it usually presents like a sah or intracerebral mahasen al-najar, azmy hadidy, alaa saleh, ahmad tamimi, asaad al-darawish and fatima obeidat case report | 600 bleeding with less frequent occurrence in cerebral ventricles and the spinal cord. this has only been confirmed from spinal hbs, according to the review by prieto et al., with no cases among their intracranial counterparts.5 interestingly, the current case showed extensive superficial siderosis indicating the presence of sah which seemed to originate from the intraventricular haemorrhage by the circulating cerebrospinal fluid. parenchymatous haemorrhage was reported in the cerebrum, spinal cord and intratumoural. intratumoural bleeding was very prominent in our case; this was previously reported in only one spinal hb which was also associated with sah.8 ventricular haemorrhage from hb appears to be uncommon. only a few cases have been reported; these have referred to ventricular bleeding as the spread of a parenchymatous clot or as a reflux from the subarachnoid space. however, a pure ventricular haemorrhage from hb was reported by fujii et al.2 in this case, a ct scan showed the presence of blood within the third and fourth ventricles, but the tumour was unnoticed. brainstem hb was diagnosed at autopsy. the average diameter of the hb nodules that bled was 2.57–3 cm, which is in accordance with our case. in fact, the risk of haemorrhage was found to increase with the increasing size of the hb.3,5 to our knowledge, our case is the second one reported with a direct haemorrhage, but is the first case of a sporadic lateral ventricular hb combined with overt ventricular haemorrhage and sah as well. conclusion tumours of the lateral ventricle include a large variety of benign and malignant lesions such as subependymoma, neurocytoma and metastatic cancers. although intraventricular, hb is very rare and is increasingly being reported in the literature. our case is unique because it was sporadic and caused direct ventricular haemorrhage as well as sah. we recommend that hb should be included in the differential diagnosis of intraventricular tumours, especially when associated with haemorrhage and when the imaging appearances do not fit those of the more common intraventricular tumours. references 1. diehl pr, symon l. supratentorial intraventricular hemangioblastoma: case report and review of literature. surg neurol 1981; 15:435–44. 2. fujii h, higashi s, hashimoto m, shouin k, hiyase h, kimura m, et al. hemangioblastoma presenting with fourth ventricular bleeding: case report. neurol med chir 1987; 27:545–9. 3. pedro jr, rodriguez fa, niguez bf, sanchez jf, lopez-guerrero al, murcia mf. massive hemorrhage in hemangioblastomas.literature review. neurosurg rev 2010; 33:11–26. 4. son rc, byun wm, lee hj, jang hw, choi jh. hemangioblastoma of the fourth ventricle. j korean soc radiol 2009; 61:211–4. 5. prieto r, roda jm. hemangioblastoma of the lateral ventricle: case report and review of the literature. neurocirugía 2005; 16:58–62. 6. iyigün öl, cokluk c, aydin k, yildiz l, rakunt c, celik f. supratentorial leptomeningeal hemangioblastoma mimicking a meningioma without von hippel-lindau complex. turkish neurosurg 2004; 14:25–7. 7. choyke pl, glenn gm, walther mm, patronas nj, linehan wm, zbar b. von hippel-lindau disease: genetics, clinical and imaging features. radiology 1995; 146:629–42. 8. kormos rl, tucker ws, bilbao jm, gladstone rm, bass ag. subarachnoid hemorrhage due to a spinal cord hemangioblastoma: case report. neurosurgery 1980; 6:657–60. 9. rho ym. von hippel-lindau's disease: a report of five cases. can med assoc j 1969; 101:135–42. 10. loftus cm, marquradt md, stein bm. hemangioblastoma of the third ventricle. neurosurgery 1984; 15:67–72. 11. murakami h, toya s, otani m, sato s, ohiera t, takenaka n, et al. a case of concomitant posterior fossa and supratentorial hemangioblastoma. no shinkei geka 1985; 13:175–9. 12. katayama y, tsubokawa t, miyagi a, goto, t., miyagami, m., and suzuki, k.. solitary hemangioblastoma within the third ventricle. surg neurol 1987; 27:157–62. 13. ho ys, plets c, goffin j, dom r. hemangioblastoma of the lateral ventricle. surg neurol 1990; 33:407–12. 14. isaka t, horibe k, nakatani s, maruno m, yoshimine t. hemangioblastoma of the third ventricle. neurosurg rev 1999; 22:140–4. 15. jaggi rs, premsagar ic, abhishek. hemangioblastoma of the lateral ventricle. neurol india; 2009:677–9. osteomas are rare, benign, osteogenic tumours characterised by the production of mature bone and slow growth.1 the lesion usually remains asymptomatic unless there is obvious disfigurement or discomfort to the patient.2,3 osteomas can be central (intraosseous or endosteal), peripheral (periosteal) or extra-skeletal in location,4 and occur mainly in the cranio-facial bones, with the most common location being paranasal sinuses.5 solitary peripheral osteomas of the jaws are a rare entity. they involve the mandible more frequently than the maxilla with the sites of greatest predilection being the lingual aspect of the body, the angle, and the inferior border of the mandible.2,5,6 case report a 42-year-old woman reported to the department of oral pathology at nair hospital dental college, mumbai, india, with a complaint of a bony, hard, asymptomatic swelling on the buccal aspect of the left side of the mandible. over the previous 20 years, the lesion had progressed from a peasized mass to a hard, globular, well-circumscribed swelling measuring 2 x 2 cm [figure 1]. she gave no history of facial trauma. her medical, family and social histories were unremarkable. a clinical examination revealed a swelling producing obvious facial asymmetry. the overlying skin was normal, showing no signs of induration, erythema or inflammation. regional lymph nodes were not palpable. an intra-oral examination revealed a pedunculated swelling when the mucosa in the left canine-premolar region was stretched. no similar bony hard swellings where found anywhere else in the body. the mandibular occlusal radiograph showed a well-circumscribed, pedunculated, radio-opaque mass in the canine-premolar region on the buccal sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e145-148, epub. 27th jan 14 submitted 31st mar 13 revision req. 20th jun 13; revision recd. 21st aug 13 accepted 15th sep 13 department of oral pathology, nair hospital dental college, mumbai, india *corresponding author e-mail: bshivani2000@gmail.com ورم عظمي مسحاقي منفرد للفك السفلي تقرير حالة رميا ميهتا, �أركانا ياد�ف, �صيفاين بان�صال, موهان دي�صباندي امللخ�ص: يعد ورم عظم �لفك حاله نادرة وت�صري �الأدبيات �لطبية �إىل حاالت قليلة جد� يف هذ� �ملجال. ويعترب �لورم �لعظمي ورما حميد� بطيء �لنمو يف �لهيكل �لعظمي �لقحفي ويت�صم بانت�صار �لعظم �مل�صغوط �أو �الإ�صفنجي. وميكن �أن يكون �لورم مركزيا, متطرفا �أو خارج �لهيكل �لعظمي. يف منطقة �لوجه, حتدث هذه �الأور�م �لعظمية �ل�صمحاقيه �أكرث يف �جليوب �الأنفية, ولكن �الأور�م �لعظمية �ل�صمحاقيه �ملنفرده لعظام �لفك نادرة جد�. ويتاأثر �لفك �ل�صفلي بهذه �الأور�م �أكرث من �لفك �لعلوي مع �مليل نحو �لل�صا ن, و�لزو�يا و�حلدود �ل�صفلية. هنا نعر�س حالة ورم عظمي �صمحاقي �نفر�دي على جانب �ل�صدق �ل�صفلي لفك �مر�أة تبلغ من �لعمر 42 عاما. كلمات البحث: �لفك �ل�صفلي٬ ورم عظمي٬ �صمحاقي٬ تقرير حالة٬ �لهند abstract: osteoma of the jaw bones is a rare entity with very few cases reported in the literature. osteomas are benign, slow-growing osteogenic tumours of the bone commonly encountered in the craniofacial skeleton and characterised by the proliferation of compact or cancellous bone. they can be central, peripheral or extra-skeletal in their location. in the facial region, periosteal osteomas occur more frequently in the paranasal sinuses, but solitary periosteal osteomas of the jaw bones are quite rare. the mandible is more commonly affected than the maxilla, with the sites of predilection being the lingual aspect of the body, the angle and the inferior border. we report a case of a solitary periosteal osteoma on the buccal aspect of the mandible in a 42-year-old woman. keywords: mandible; osteoma; periosteal; case report; india. solitary periosteal osteoma of the mandible a case report reema mehta, archana yadav, *shivani p. bansal, mohan d. deshpande case report solitary periosteal osteoma of the mandible a case report e146 | squ medical journal, february 2014, volume 14, issue 1 aspect of the left side. computed tomography (ct) imaging showed a well-defined, pedunculated bony mass arising from the left side of the mandible, measuring 1.8 x 1.8 cm in maximum dimension. the pedicle was 1 cm wide [figure 2]. based on clinico-radiological findings, a working diagnosis of an osteoma was made. the lesion was surgically excised under general anaesthesia through a crevicular incision and surgical flap reflection [figure 3]. the gross specimen was smooth and ivory-type in appearance. a histopathological examination revealed a wellcircumscribed, unencapsulated, normal-appearing, extremely dense cortical bone with minimal marrow tissue suggestive of a periosteal osteoma of the mandible (compact type) [figure 4]. discussion according to lichtenstein, an osteoma is a benign osteogenic lesion composed essentially of osteoblastic connective tissue forming an abundant osteoid and new bone, which may eventually become compact over a period of time.7 osteomas may be grouped on the basis of their site of derivation as peripheral, central or extra-skeletal lesions.1 central osteomas arise from the endosteum, peripheral osteomas arise from the periosteum, and extra skeletal soft tissue osteomas evolve within muscle tissue.8 the most common locations of osteomas are the paranasal sinuses including frontal, ethmoidal and maxillary sinuses.4 the lesions rarely affect the jaws.2,4 sayan et al. reported that 22.85% of periosteal osteomas occurred in the mandible as compared to 81.3% reported by kaplan et al.5,8 osteomas are classified as: compact/ivory, cancellous/spongy, or mixed on histopathological figure 1: clinical photograph showing a bony, hard swelling on the left side of the mandible. figure 2: computed tomography images showing welldefined, pedunculated mass arising in the left side of the mandible (arrow). figure 3: surgical clinical photograph showing the lesion exposed surgically via a crevicular incision and reflected flap. figure 4: photomicrograph showing hard tissue composed of benign dense bone with minimal marrow spaces, and haversian canals (haematoxylin & eosin stain x 10). reema mehta, archana yadav, shivani p. bansal and mohan d. deshpande case report | e147 and clinical grounds.9,10 peripheral (periosteal) osteomas are infrequently encountered as solitary lesions.5 the compact osteoma is comprised of dense, compact bone with some marrow space and osteons. the cancellous osteoma shows bony trabeculae and fibrofatty marrow.10 kaplan et al. reported an increased occurrence of periosteal osteomas between the ages of 15 and 75 years, with a mean age of 25 years.5 osteomas do not show any sex predilection; however, cases favouring the cancellous variant in females and the compact form in males have been reported.6,10 the pathogenesis of periosteal osteomas is not well-understood.3 kaplan et al. proposed three possible aetiologies for periosteal osteomas: developmental, neoplastic and reactive.5 however, it is unlikely that periosteal osteomas, either located in the mandible or the sinuses, are developmental anomalies as, in most cases, they develop during adulthood. furthermore, as the majority of cases of periosteal osteoma are slow growing, it is likely that they are non-neoplastic in origin. kaplan et al. and others have reported that most periosteal osteomas of the mandible occur on the lower border or on the buccal aspect, and this site is more susceptible to trauma than the lingual aspect.4,5,11 a combination of trauma and muscle traction may provide the best explanation of the pathogenesis of mandibular periosteal osteomas. it is suggested that osteomas are initiated following minor traumas which are unlikely to be remembered by the patient years later.5 the patient in this report did not recall any history of trauma. bony hyperplasia associated with muscle traction is also a documented phenomenon.4,5 other aetiologies mentioned in the literature are that of a reilly-finkel-biskis osteoma virus (ecotropic type c retrovirus) and their clones which have shown to induce osteomas in mice.12 their frequent relationship to gardner’s syndrome is of crucial clinical significance.2 this autosomal dominant syndrome is characterised by the development of multiple osteomas and these may present as the initial clinical signs of the syndrome. osteomas can be confused with a plethora of lesions. exostoses and peripheral osteomas are distinguished on the basis of history and clinical appearance. they are bony excrescences, reactive or developmental in origin, which cease to grow by puberty.2,3,8 other pathological entities, including peripheral ossifying fibroma, tori and osteochondroma, should be considered as differential diagnoses.2 also, torus mandibularis are hamartomas lesions with a predilection for the lingual region of the mandible.8 the peripheral ossifying fibroma is a reactive focal overgrowth that occurs mostly in the maxilla anteriorly and histologically shows prominent collagenous highly cellular stroma. it is radioopaque but does not intrude into the osseus cortex like an osteoma.13 in sessile osteochondroma, the cortex of the lesion merges imperceptibly with the cortex of the bone. microscopically, it is composed of areas of endochondral ossification, calcified cartilage and fatty or haematopoetic marrow in the trabecular spaces.10 fibrous dysplasia is most commonly confused clinically and radiographically with osteomas.2 it is usually possible to differentiate the two conditions on the basis of radiographic structure alone. fibrous dysplasia does not often reveal the same homogenous density as osteomas and, while osteomas may present a suggestion of granularity, it is not likely to be so definite in fibrous dysplasia.14 osteomas can also be radiographically mistaken for odontomas or sclerosing osteitis.8,14 odontomes are usually surrounded by a radiolucent soft tissue capsule, differentiating it from osteomas.14 sclerosing osteitis can be differentiated by margins that are ill-defined radiographically. the aetiology is generally an infected tooth or retained root.8,12 osteoblastomas and osteoid osteomas are more frequently painful and grow more rapidly than peripheral osteomas.10 microscopically, an osteoid osteoma shows highly vascular cellular tissue containing osteoid trabeculae, whereas a periosteal osteoblastoma is composed of trabeculae of woven bone with osteoblasts and osteoclasts.8,10 sialoliths may also mimic osteomas on panoramic and lateral radiographs but they can be differentiated by further radiographic examination, clinical signs and symptoms.2 particular consideration should be given to osteochondroma because some of these tumours can undergo malignant transformation.2 malignant transformation within an osteoma has not been reported. recurrence has been reported, but is rare.2 the overall prognosis of osteomas is considered to be good.2 solitary periosteal osteoma of the mandible a case report e148 | squ medical journal, february 2014, volume 14, issue 1 conclusion solitary periosteal osteomas of the jaws are uncommon bony tumours. this case report describes a solitary periosteal osteoma that occurred on the posterior buccal aspect of the left side of the mandible. the lesion had grown slowly for 20 years, causing obvious facial asymmetry. early diagnosis and surgical excision of this slow-growing benign osteogenic lesion helps in alleviating subsequent facial asymmetry. although rare, the possibility of a periosteal osteoma should be considered as a differential diagnosis for any peripheral, solitary, slow-growing, non-tender, bony hard, non-compressible, non-fluctuant and non-pulsatile swelling encountered in the oral and maxillofacial region. even if recurrence is rare, it is appropriate to provide both periodic clinical examination and radiographic follow-up after the surgical excision of such lesions. references 1. walker dg. benign nonodontogenic tumors of the jaws. j oral surg 1970; 28:39–57. 2. noren gd, roche wc. huge osteoma of the mandible: report of case. j oral maxillofac surg 1978; 36:375–9. 3. swanson ks, guttu rl, miller me. gigantic osteoma of the mandible: report of a case. j oral maxillofac surg 1992; 50:635–8. 4. bodner l, galot a, sion vardy n, fliss dm. peripheral osteoma of the mandibular ascending ramus. j oral maxillofac surg 1998; 56:1446–9. 5. kaplan i, calderon s, buchner a. peripheral osteoma of the mandible : a study of 10 new cases and analysis of the literature. j oral maxillofac surg 1994; 52:467–70. 6. bosshardt l, gordon rc, westerberg m, morgan a. recurrent peripheral osteoma of mandible : report of case. j oral surg 1971; 29:446–50. 7. lichtenstein l. bone tumors, 1st ed. st. louis: c.v. mosby company, 1952. p. 20. 8. sayan nb, ucok c, karasu ha, gunhan o. peripheral osteoma of the oral and maxillofacial region: a study of 35 new cases. j oral maxillofac surg 2002; 60:1299–301. 9. das ak, kashyap rc. osteoma of the mastoid bone: a case report. mjafi 2005; 61:86–7. 10. johann ac, freitas jb, aguiar mc, de araujo ns, mesquita ra. peripheral osteoma of the mandible: case report and review of the literature. j craniomaxillofac surg 2005; 33:276–81. 11. schneider lc, dolinsky hb, grodjesk je. solitary peripheral osteoma of the jaws: a report of case and review of literature. j oral surg 1980; 38:452–5. 12. veera sd, jayanthi k, dayanand b. solitary peripheral osteoma at a curious site with an ambiguous etiopathogenesis : a case report and review of literature. int j oral & maxillofac pathol 2012; 3:50–5. 13. dayan bl. growth potential of peripheral ossifying fibroma. j clin periodontol 1987; 14:551–4. 14. worth hm. principles and practice of oral radiologic interpretation. 1st ed. chicago: year book medical publishers, 1963. p. 536. sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century sultan qaboos university med j, august 2013, vol. 13, iss.3, pp. 442-449, epub. 25th jun 13 submitted 7th nov 12 revisions req. 2nd feb & 23rd mar 13; revisions recd. 11th feb & 24th mar 13 accepted 27th apr 13 college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mail: rhodam@squ.edu.om حتسني مهارة الفحص املهبلي للقابالت رودا �شووبي مولريا، فيديا �شي�شان، �شانتي راما�شوبرامانيام امللخ�س: اإجراء الفح�س املهبلي هو جزء اأ�شا�شي من رعاية القبالة، وتتم ب�شكل روتيني عند تقييم التقدم املحرز خالل مراحل الوالدة. وتبني االأدلة اأن الفح�س املهبلي خالل مراحل الوالدة مزعج وحمرج وموؤمل يف بع�س االأحيان؛ وال يدرك الكثريون مدى االأمل واال�شطراب العاطفي الذي ي�شببه هذا الفح�س. وت�شري نتائج البحوث والدرا�شات اإىل اأن على القابلة االهتمام لعدم تكرار هذا الفح�س اإال عند ال�رسورة امللّحة، وتاليف االأمل واالإحراج واإدارة طريقة اأخذ املعلومات ومراعاة االأولويات ملنح االأم احلامل ال�شعور باأنها املتحكمة بهذا الفح�س. ميكن حتقيق هذه التدخالت من خالل التوا�شل واأخذ موافقة االأم، وتوفري الرعاية التي تركز على املراأة وعالج االأم، ودعم العمل املكثف وا�شتخدام اأ�شاليب بديلة ملراقبة تقدم مراحل الوالدة. مفتاح الكلمات: القابلة؛ مراحل الوالدة؛ التوليد؛ فح�س املهبل. abstract: a vaginal examination (ve) is an essential part of midwifery care, and is routinely performed when assessing the progress of labour. as evidence shows that during labour women may find ves unpleasant, embarrassing and sometimes painful, the aim of this article is to review literature on the use of ves during labour and to synthesise information from the available literature on how to provide an effective ve. the studies considered were retrieved from three databases (the cumulative index to nursing and allied health literature [cinahl], scopus and medline) using the following search terms: “ves in labour”, “midwives and use of ves” and “women experiences of ves in labour”. the literature reviewed suggests that midwives are not careful about ves. therefore, a concerted effort is needed to pay attention to the frequency of ves, the management of pain and distress, information-giving and the preferences of the patient, so that the patient can feel in control during a ve. keywords: midwifery; labour; midwifery care; vagina; vaginal examination. technical note improving vaginal examinations performed by midwives *rhoda s. muliira, vidya seshan, shanthi ramasubramaniam a vaginal examination (ve) is an extremely intimate examination which is performed regularly and accepted as a routine procedure by midwives during labour.1,2 a ve can be performed digitally, or by using instruments such as a speculum.3 in midwifery care, a woman in labour is often subjected to at least one ve, and often these are repeated every 4 hours on obstetric orders or according to the practice requirements of the birth unit.4 as the average labour lasts between 8 and 12 hours, most women can expect to have at least two or three ves during their labour.4,5 the woman in labour and her labour companions often rely solely on the ve as the indicator of labour progress.6 in midwifery care, a ve is used to assess the degree of opening of the cervix so that the labour progress and time of birth can be estimated.7 in addition, a thorough ve can determine the location of the presenting fetal part (the relationship of the presenting fetal part to an imaginary line drawn between the ischial spines of the pelvis, the status of the membranes) and fetal well-being through scalp stimulation.6,7 this information gives some guidance as to whether the woman is in true labour, how long the labour will last and whether the plan of care needs to be changed. during the process of undergoing a ve, some women have reported feelings of powerlessness, physical pain, unsympathetic attitudes on the part of the healthcare provider and difficulty obtaining adequate information about the procedure.7–9 it is also alleged that ves are used as an unnecessary procedure by which healthcare providers demonstrate that they are in control of both the woman in labour and the process of labour.8,9 this is evidenced by the frequency of ves performed by healthcare providers; the reasons given by healthcare providers for performing ves; the usage of verbal and physical strategies to distance oneself from ves, and the healthcare provider’s distrust that a woman will dilate on her own without medication.8–11 a ve is an interesting procedure which represents a structured interaction in which ‘private areas’ no longer remain private; this raises problematic issues of the body and of being touched.10,12 midwives therefore need to consider how they discuss ves with women during pregnancy and labour, so that they can inform them of their purpose and rationale, and provide sensitive woman-centred care so that patients can be involved in decisions about how and when ves should be performed.10,13 the purpose of this literature review is to explore the use of ves during labour and to discuss important interventions that midwives can adopt in order to provide sensitive and appropriate care during this intimate examination. methods the authors aimed to identify articles reporting primary studies relevant to the subject of ves during pregnancy and labour. trial searches were conducted to finalise the search terms and to maximise the number of articles identified. the terms used to conduct the search were “ve in labour”, “midwives and use of ve” and “women’s experiences of ve in labour”. after finalising the search terms, articles concerning ves during pregnancy/labour were researched on the medline, scopus and the cumulative index to nursing and allied health (cinhal) databases. other databases were not searched as it was observed that several of the articles were repeated in the three databases. a total of 6 articles based on primary studies, reporting about ves during labour, and published between 2002–2012, were used to formulate the foundation for this narrative review. the 6 articles were included regardless of the methods and instruments used in each study. the search yielded 60 articles in medline, 43 articles in scopus and 34 articles in cinhal. after the initial screening, it was established that only 40 articles from the three databases had titles and abstracts focusing on ve during labour, using different combinations of the search terms. these 40 articles were reviewed for relevance to the subject matter. a total of 34 articles were excluded because they did not meet the inclusion criteria. the reasons for exclusion included either the format of the article, as several of the articles were letters to the editor (n = 5), literature reviews (n = 8) or commentaries (n = 8), or that the article was found to be based on personal opinion (n = 5), or was not a primary research study (n = 8). results the findings of this review [table 1] show that ves were conducted too frequently and by many providers, and that the most common reason given by midwives for performing a ve was to assess the progress and commencement of labour. in addition, pain, discomfort and embarrassment were frequently experienced during ves; there was low satisfaction in the management of associated pain; opportunities to refuse examinations were minimal; there was insufficient information about the ve process, and many women felt embarrassment and discomfort when being examined by a male healthcare professional. some midwives also used verbal and physical strategies to distance themselves from ves as an attempt to establish power differentials between themselves and the women—resulting in the women feeling vulnerable. however, some studies reported that healthcare providers had shown improvement, conducting ves with sensitivity and maintaining the dignity of the patient in a supportive, informative and reassuring environment. this review of the literature also emphasised some interventions that can make the experience of a ve more comfortable for the patient; for example, using sensitive woman-centred care; judging the necessity of ves based on individual patients; the management of pain and distress; giving sufficient information on the procedure to the patient; giving the patient a choice in preferred options; increased communication skills, and treating the women with courtesy and respect. this literature review discusses the important interventions that midwives can adapt when performing ves. improving vaginal examinations performed by midwives 436 | squ medical journal, august 2013, volume 13, issue 3 rhoda s. muliira, vidya seshan and shanthi ramasubramaniam technical note | 437 table 1: primary studies on vaginal examinations during labour author sample size (n), gender, location, type, design/ instrument study purpose main findings and conclusions shepherd et al.11 2013 144 female patients nhs hospital, uk cross-sectional survey self-reported data collection forms to investigate the number of ves performed in relation to the length of labour, and the reasons given by midwives for performing ves. • the number of ves carried out (mean 2.9, sd 1.5, range 1–7) increased as the labour time increased. • almost 70% of women had more ves than expected when the procedure of 4-hourly ves was applied. • the most common reason given by midwives for performing a ve was to assess labour progress and the commencement of labour. • women received more ves than was consistent with the guidelines. hassan et al.9 2012 176 female patients public hospital, palestine cross-sectional survey semi-structured questionnaires and faceto-face interviews to explore women’s feelings opinions, knowledge and experiences of ves during normal childbirth. • ves were conducted too frequently, and by too many different providers. • 82% of the women reported feeling pain or severe pain during ves. • 68% reported feeling discomfort during ves. • some women reported being treated insensitively by their healthcare providers, a lack of privacy and being treated with little respect or dignity. dixon7 2005 6 female and male midwives, new zealand small, qualitative, descriptive study in-depth unstructured interviews to explore midwives’ use of ves during labour. • a knowledge of the patient helps guide the midwife in the use of ves. • midwives use their judgment on the necessity for a ve based on each individual woman and each situation. • the midwives used ves more frequently when they needed to gain a fuller understanding of the labour, particularly when the observed signs were unclear or a problem was developing. lewin et al.13 2005 104 female patients three midwifery units, cambridgeshire, uk prospective, analytic survey postal survey; 20-item likert-type scale to investigate women’s perception of and their experiences of ves during labour. • women were most satisfied (74%) concerning ves in areas such as privacy, dignity, sensitivity, support and the frequency of ves. • the women were least satisfied in areas such as associated pain with ves, lack of opportunities to refuse examinations and the lack of detailed information-giving. • ves have become a routine element of care-giving that merits some attention, particularly regarding the management of pain and distress, informationgiving and allowing alternative patient-preferred options. stewart10 2005 10 midwives and 6 patients south-west england, uk in-depth interviews and non-participant observation analytical memos, a reflective diary and textual data to explore the qualitative experiences of midwives and women in relation to ves in labour, focusing on how ves are discussed and on the wash-down procedure performed by some midwives. • midwives used persistent abbreviations or euphemisms as a means of distancing themselves from the reality of the procedure. • some midwives were observed washing women's genitalia in a ritualised manner prior to ves as a strategy of establishing power differentials between the midwife and the woman. this resulted in feelings of vulnerability on the part of the woman. • healthcare professionals and students need to be taught specific communication skills to enable them to discuss ves more openly with women. • it is important to carry out ves in a way that is not demeaning and does not reinforce notions that women’s bodies are dirty. ying lai et al.3 2002 8 female patients maternity unit of a university-affiliated district general hospital, hong kong qualitative study with a phenomenological approach tape-recorded openended interviews to explore women’s experiences of ves during labour. • women accepted the necessity for ves. • some women felt embarrassed when examined by a male doctor but the attitude and approach of the examiner was considered more important than the gender. • pain and embarrassment were frequently experienced during ves. • participants expressed the need to be able to trust that the examiner would respect them as individuals, maintain their dignity, perform the ve skillfully and communicate their findings. • every woman should be treated with courtesy and respect by the examiner, and her modesty should be protected by minimal exposure. ve = vaginal examination; sd = standard deviation. improving vaginal examinations performed by midwives 438 | squ medical journal, august 2013, volume 13, issue 3 discussion many women dislike ves because they are often painful, and can be performed with little accompanying information in a sometimes ritualistic or intimidating manner.9,14 expressions of pain or discomfort during the examination could be an individual’s response to fear and anxiety rather than actual physical trauma, and therefore the pain may be more psychological than physical.3 pain during a ve could also be related to the inadequate skill of the examiner.9 during labour, pain is part of the normal physiological process and may be influenced by psychological, spiritual and cultural factors.15 hence the experience of undergoing a ve can cause further pain during what is often already an extremely vulnerable and painful time for the woman.8 furthermore, the frequency of ves may suggest a distrust or fear in the patient’s ability to give birth unaided on the part of the healthcare professional.8,9 in addition to the invasiveness of the procedure and the negative perceptions of ves by the patients,7 a high frequency of ves raises concerns regarding the increased risk of infection, with chorioamnionitis occurring in 8–12 women per 1,000 births.8,9 this increased rate of infection in women who have had ves after a premature rupture of the membranes, can put their babies at risk of ascending infections.8 a vaginal examination may cause negative reactions such as embarrassment over genital exposure, which may in turn lead to feelings of helplessness and vulnerability, dehumanisation and a violation of privacy.3,10 in addition, the verbal and physical strategies displayed by some midwives to distance themselves from ves, for example by using abbreviations or euphemisms, or ritualised methods of washing genitalia, can cause feelings of humiliation.8,10 in addition, if the healthcare provider is male, the process of a ve may cause significant embarrassment for both the woman and healthcare provider, particularly in more conservative cultures.3,9,10 several studies revealed that women seem to have more ves than expected during labour, despite the presence of institutional policy guidelines on performing ves at certain institutions.2,8–11,16 one study found that midwives also frequently perform ves which are not officially recorded, often referred to in the case notes as ‘quickies’.17 a study conducted by bergstorm et al. found there was a variation between 2–17 in the number of ves conducted during labour; for one woman, a ve was performed following every contraction.16 the main reasons given by midwives for performing ves during labour were to assess the progress and onset of labour, to assess the patient’s contractions of the abdominal muscles and diaphragm during labour, and to teach the woman the correct way of forcefully contracting the muscles and diaphragm during labour.2,8,16 this lack of consistency regarding the frequency of ves may demonstrate that the individual midwives are in control of both the woman in labour and the process of labour itself,8,10 without an institutional policy or the presence of guidelines to aid them in their management of the patient. the experience of a difficult ve could also result in the patient developing post-traumatic stress disorder (ptsd).18,19 certain variables are highly related to the occurrence of ptsd after such procedures; these included feelings of powerlessness, a lack of information concerning the procedure and its necessity, experiencing physical pain, a perceived unsympathetic attitude by the examiner and the lack of patient consent to the procedure.18–20 hence, the propensity to develop ptsd after birth is associated with how women felt they were treated during labour; whether they felt in control; whether they panicked or felt angry during labour; whether they experienced dissociation, and whether they suffered ‘mental defeat’.20–22 other risk factors for developing birth-related ptsd include having a history of unresolved sexual and emotional trauma, which would make undergoing a ve a difficult experience.13,20,22,23 during the procedure, the patient may experience strong discomfort and flashbacks triggered by the feelings of a loss of control over the situation and their body.23 without a previous awareness of the patient’s history of emotional or sexual trauma, the patient’s reaction may seem incomprehensible to the midwives.23 i n t e r v e n t i o n s m i d w i v e s c a n a d o p t d u r i n g va g i n a l e x a m i n at i o n s judging the necessity of vaginal examinations a ve is an important and essential tool by which midwives assess the establishment and progress of labour, and perform procedures such as the artificial rupture of membranes.3,24 a ve can provide vital rhoda s. muliira, vidya seshan and shanthi ramasubramaniam technical note | 439 information on many aspects, such as the fetal presentation position (the relationship of a reference point on the presenting part of the fetus, such as the occiput, sacrum, chin, or scapula to its location to the front or back or side of the maternal pelvis and descent of the presenting part of the fetus that lies closest to the internal os of the cervix) as well as cervical effacement, consistency and dilatation.8,9,25 knowing this information can help to reassure the patient, her partner and the midwife that labour is progressing well.6 in cases of difficult labour, ves can help midwives to understand when and why labour has deviated from the normal course.8 therefore, midwives can use ves when they need to gain a fuller understanding of the woman’s labour or when a problem is felt to be developing.7,9 this entails the midwives using their judgment on the necessity for a ve based on each individual woman and situation.8 using effective communication skills communication skills are crucial in establishing trust between the healthcare providers and the patients, and will aid in ensuring that ves do not cause unnecessary distress.9,13 according to lai et al., healthcare providers should introduce themselves first while the woman is sitting upright and clothed before the examination starts so as to establish a rapport, and the women should be provided with private, warm, comfortable and secure changing facilities.3 the women should not be assisted in the removal of their clothing unless it has been clarified that assistance is required.13 furthermore, midwives should be encouraged to inform the patient adequately about the necessity of the procedure, and what to expect; additionally, healthcare providers should address the patient’s fears and anxieties, and give them the opportunity to ask questions.3,13 specific nonverbal communication skills, such as maintaining eye contact and allowing the woman to adopt a semi-sitting position, can also be used during the examination to decrease any feelings of vulnerability.3,10,26 utilising honest and effective communication skills before, during and after the ve will enable midwives to become more comfortable during the procedure. in addition, midwives should be discouraged from using abbreviations or euphemisms to refer to different body parts during the procedure.9,10 informed consent the informed consent of the patient is essential before proceeding with a ve.12,27 informed consent is only valid if the patient has the mental capacity to consent, after being given sufficient information about the procedure, and if they subsequently voluntarily consent to undergo the procedure.9,28 the essence of good midwifery care lies in valuing women as individuals, providing essential information about the plan of care and offering them choices regarding their options during care.9,10,12 the importance of informed consent is further affirmed by the uk royal college of nursing, which has issued guidelines on the conduct of intimate examinations, focusing particularly on issues of consent, necessity, explanation, privacy, dignity and indicators of distress.29 exploring the patient’s preferences and choices establishing a good relationship between the midwife and the patient is important for the continuity of care, as the patient and midwife can build a trusting relationship.7,30 the patient’s beliefs and expectations can be discussed during the antenatal period, along with her preferences regarding ves during labour.7,8,31 during labour, the healthcare provider can negotiate with the patient, bearing in mind both the wishes and beliefs of the patient, as well as using his/her medical judgment and knowledge on the necessity of a ve during each individual situation.7,30,31 by understanding and respecting the beliefs of the patient, the midwife is able to provide sensitive woman-centred care.30,31 the key element of this patient-centred care is continuity of care based on a trusting relationship; the midwives will then be able to utilise both their knowledge of the patient, by demonstrating sensitivity towards the woman’s beliefs, expectations and wishes, and also their medical experience and judgment during the assessment of labour.7 providing sensitive woman-centred care the importance of demonstrating sensitivity towards the patient’s feelings during a ve cannot be underrated, and it is possible that the gender of the examiner may have some effect.3,9 a study carried out by elderen et al. concluded that female healthcare providers were perceived as showing improving vaginal examinations performed by midwives 440 | squ medical journal, august 2013, volume 13, issue 3 significantly more caring behaviour during ves.9,32 in comparison, some women, particularly those from more conservative cultures, felt embarrassed when examined by a male healthcare provider. nevertheless, the attitude and approach of the examiner was generally found to be more important than gender.3,9 another explanation of the difference in attitude may involve medico-legal concerns, in that men are far more prone to accusations of sexual harassment or misbehaviour during intimate examinations, particularly if the patient perceives a disrespectful attitude on their part.3 minimising variability during vaginal examinations the uk royal college of midwives suggests that all ves be conducted by the same midwife during labour to reduce inter-observer variability and inaccuracy.2,33 a ve is an imprecise measure of labour progress, especially when undertaken by different examiners.34 the practice of having different healthcare providers conducting ves could be related to poor organisation, an overloading of staff responsibilities, shift organisation and educational purposes.9 buchmann et al. noted that, in a group of 508 women, two clinicians differed in dilatation measurements by two cm or more on 11% of occasions.2,8,35 similarly, in another study done by tuffnell et al., cervical measurement was both overand underestimated by obstetricians and midwives.7,36 inconsistent findings between examiners have been noted to cause distress in women and have resulted in the patient losing confidence in their healthcare provider.8 tufnell et al. also suggested that having an inaccuracy rate of over 50% in cervical measurements could lead to increased interventions, as decisions to augment labour or perform a caesarean section are influenced by cervical assessment.7,36 paying attention to the frequency of vaginal examinations the frequency of ves is often dependent on the individual healthcare provider and the guidelines of the institution.37 however, different studies advocate various frequencies, ranging from every 3 hours, 4 hours, 6 hours or at the midwives’ discretion.4,8,38,39 these different recommendations reveal a lack of agreement on the ideal times to perform ves during labour.40 there is limited evidence to determine the average rate of ves during a normal labour, or indeed what the ideal rate should be.17 the world health organization recommends that ves be conducted at 4-hour intervals and by the same provider if possible; preferably there should be only one examination to establish active labour.41 similarly, borders et al. agree that experienced healthcare providers can sometimes limit the number of ves to one if the labour is progressing well.6 most authorities agree that ves should be performed only if the information obtained will alter the management of labour.6 in addition, midwives should use ves when they need to gain a clear understanding of the patient’s labour, for instance when the observable labour signs are unclear, or when a problem seems to be developing.7 therefore, the frequency of ves should be individualised to meet the needs of each patient and each situation, with healthcare providers using their own judgment on the necessity of an examination.7 using alternative ways to measure the progress of labour there are a number of alternative ways to measure labour progress, including assessing the descent of the fetal head by abdominal palpation; monitoring the frequency, length and strength of contractions, and by observing the appearance, vocalisation and behaviour of the mother, however, these methods are currently often used only as an adjunct to a ve rather than as a replacement.8,11,41 burvill stresses that the stage of labour must be determined by observable events and the patient’s experiences, and not be based on cervical dilatation alone because the process of labour is unique to each individual woman and therefore cannot be defined by physiological measurements, time restrictions or other medical criteria alone.42 in addition, there has been some recent discussion about whether the emergence of the ‘purple line’ can be used as a possible measure of labour.2,11 this involves the appearance of a line of red/purple discolouration arising from the anal margin and extending between the buttocks, and reaching the intergluteal cleft at the onset of the second stage of labour.2,11 however this method has yet to be validated by further research before it can be accepted as a reliable measurement of labour progress.2 it has been suggested that over-reliance on ves may have influenced the confidence midwives have in rhoda s. muliira, vidya seshan and shanthi ramasubramaniam technical note | 441 alternative methods of assessment.43 in addition, midwives may lack the necessary skills, knowledge or confidence in their diagnostic abilities when facing less invasive alternatives.12 nevertheless, if midwives routinely discuss with their patients alternative ways of assessing labour progress, this would enable the patients to feel empowered, and therefore take a stronger position to either decline ves or at least to reduce the frequency with which they are conducted.13 managing unresolved traumatic experiences healthcare providers should elicit their patient’s psychosocial and medical history, and if there is evidence of previous unresolved physical, sexual or emotional trauma, they should discuss a plan of care with the patient; this will help maximise the feeling of being supported by their healthcare provider, as well as of being in control. this will also minimise the likelihood of excessive pain or feelings of depersonalisation.21,44 unresolved trauma is a risk factor for developing birth-related ptsd.21,22 in attempting to determine the patient’s psychological and medical history, healthcare professionals should avoid asking specific questions but rather ask open-ended questions such as, “do you have any issues, concerns, fears that you'd like to tell me about to help me provide better care for you?”21 even though unresolved previous traumas are unlikely to be healed during pregnancy, most of the other variables associated with ptsd such as feelings of powerlessness, lacking important information, experiencing physical pain, perceived unsympathetic attitudes on the part of the examiner, and a lack of consent by the patient for the procedure, can be prevented through the provision of sensitive care in labour that enhances perceptions of control and support.21–23,45 the uk royal college of gynaecologists recommends that women who experience difficulties with ves be given the opportunity to discuss any underlying sexual, marital or trauma-related issues.29 conclusion this study has reviewed the available literature on the use of ves during labour and the interventions that midwives should adopt in order to provide sensitive care. a number of publications supported the view that women receive more ves than is necessary during labour; ves can cause pain, discomfort and embarrassment to the women; ves are sometimes conducted without consent, respect or dignity, and women are rarely given preferences or choices during ves. therefore ves during labour require attention on the part of the midwife, particularly regarding the management of the patient’s discomfort or pain, the provision of information and acceptance of alternative options. when treated with sensitivity and respect, the patients will be able to develop a positive relationship with the midwives, allowing a discussion of the plan of care and their preferred options regarding ves, so that they can remain comfortable throughout the examination. considering the centrality of ve to labour and obstetric care, there is a need to enhance best practice for ves. references 1. buchmann e, libhaber e. interobserver agreement in intrapartum estimation of fetal head station. int j gynecol obstet 2008; 101:285–9. 2. shepherd a, cheyne h, kennedy s, mcintosh c, styles m, niven c. the purple line as a measure of labour progress: a longitudinal study. bmc pregnancy childbirth 2010; 10:54. 3. ying lai c, levy v. hong kong chinese women’s experiences of vaginal examinations in labour. midwifery 2002; 18:296–303. 4. lowdermilk dl, perry se. maternity nursing. 7th ed. missouri: mosby, 2006. p. 414. 5. lowdermilk dl, perry se, cashion mc. maternity nursing. 8th ed. missouri: mosby, 2010. pp. 85–90. 6. borders n, lawton r, martin sr. a clinical audit of the number of vaginal examinations in labour: a novel idea. j midwifery womens health 2012; 57:139–44. 7. dixon l. building a picture of labour: how midwives use vaginal examinations during labour. new zealand midwives j 2005; 33:22–6. 8. dixon l, foureur m. the vaginal examination during labour. is it of benefit or harm? new zealand midwives j 2010; 42:21–6. 9. hassan sj, sundby j, husseini a, bjertness e. the paradox of vaginal examination practice during normal childbirth: palestinian women’s feelings, opinions, knowledge and experiences. reprod health 2012; 9:16. 10. stewart m. ‘i’m just going to wash you down’: sanitizing the vaginal examination. j adv nurs 2005; 51:587–94. improving vaginal examinations performed by midwives 442 | squ medical journal, august 2013, volume 13, issue 3 11. shepherd a, cheyne h. the frequency and reasons for vaginal examination in labour. women birth 2013; 26:49–54. 12. o’loughlin e. critical incident analysis: informed consent and the use of vaginal examinations during labour. rcm midwives 2003; 6:352–5. 13. lewin d, fearon b, hemmings v, johnson g. women’s experiences of vaginal examinations in labour. midwifery 2005; 21:267–77. 14. lewin d, fearon b, hemmings v, johnson g. informing women during vaginal examinations. br j midwifery 2005; 13:26–9. 15. leap n, vague s. working with pain in labour. in: pairman s, pincombe j, tracy s,thorogood c, eds. midwifery: preparation for practice. 1st ed. sydney: elsevier, 2006. p. 416. 16. bergstrom l, roberts j, skillman l, seidel j. “you'll feel me touching you sweetie”: vaginal examinations during the second stage of labour. birth 1992; 19:10– 18. 17. stewart m. midwives’ discourses on vaginal examination in labour. phd thesis. bristol: university of the west of england, 2008. 18. menage j. post-traumatic stress disorder following obstetric/gynaecological procedures. br j midwifery 1996; 4:532–3. 19. wijma k, söderquist j, wijma b. posttraumatic stress disorder after childbirth: a cross sectional study. j anxiety disord 1997; 11:587–97. 20. simkin p. pain, suffering and trauma in labour and prevention of subsequent posttraumatic stress disorder. j perinat educ 2011; 20:166–76. 21. ayers s. thoughts and emotions during traumatic birth: a qualitative study. birth 2007; 34:253–63. 22. modarres m, afrasiabi s, rahnama p, montazeri ali. prevalence and risk factors of childbirth-related post-traumatic stress symptoms. bmc pregnancy childbirth 2012; 12:88. 23. swahnberg k, wijma b, siwe k. strong discomfort during vaginal examination: why consider a history of abuse. eur j obstet gynecol reprod biol 2011; 157:200–5. 24. cheyne h, dowding dw, hundley v. making the diagnosis of labour: midwives’ diagnostic judgment and management decisions. j adv nurs 2006; 53:625–35. 25. thorpe j, anderson j. supporting women in labour. in: pairman s, pincombe j, tracy s, thorogood c, eds. midwifery: preparation for practice. 1st ed. sydney: elsevier, 2006. 26. henderson c, jones k. essential midwifery. london: mosby, 1997. p. 285. 27. ouj u, igberase go, eze jn, ejikeme bn. perception of intimate pelvic examination by gynaecological clinic attendees in rural southeast nigeria. arch gynecol obstet 2011; 284:637–42. 28. kulkielka m. supervision in action: developing a guidance paper on consent and treatment of minors. rcm midwives j 2002; 5:204–7. 29. royal college of nursing. vaginal and pelvic examination: guidance for nurses and midwives. london: royal college of nursing, 2006. 30. freeman lm, timperley h, adair, v. partnership in midwifery care in new zealand. midwifery 2004; 20:2–14. 31. kennedy hp, shannon mt, chuahorm u, kravetz mk. the landscape of caring for women: a narrative study of midwifery practice. j midwifery womens health 2004; 49:14–23. 32. van elderen t, maes s, rouneau c, seegers g. perceived gender differences in physician consulting behaviour during internal examination. fam pract 1998; 15:147–52. 33. royal college of midwives. evidence based guidelines for midwifery-led care in labour: assessing progress in labour. from: http://www.rcm.org.uk/ college/policy-practice/evidence-based-guidelines/ accessed: sep 2012. 34. munro j, spiby h. evidence based guidelines for midwifery-led care in labour: midwifery practice guideline. sheffield: royal college of midwives, 2005. 35. buchmann ej, libhaber e. accuracy of cervical assessment in the active phase of labour. bjog 2007; 144:833–7. 36. tuffnell dj, bryce f, johnson n, lilford rj. simulation of cervical changes in labour: reproducibility of expert assessment. lancet 1989; 2:1089–90. 37. albers l. rethinking dystocia: patience please. midirs midwifery digest 2001; 11:351–3. 38. fraser dm, cooper ma, eds. myles’ textbook for midwives. 14th ed. london: churchill livingstone, 2003. p.502. 39. varney h, kriebs jm, gegor cl. varney’s midwifery. 4th ed. boston: jones & bartlett learning, 2004. p. 585. 40. enkin m, keirse m, neilson j, crowther c, duley l, hodnett e, hofmeyr j. a guide to effective care in pregnancy and childbirth. oxford: oxford university press, 2000. 3rd ed. pp. 281–9. 41. world health organisation. care in normal birth: a practical guide. geneva: world health organization, 1996. 42. burvill s. midwifery diagnosis of labour onset. br j midwifery 2002; 10:600–5. 43. sookhoo ml, biott c. learning at work: midwives judging progress in labour. learn health soc care 2002; 1:75–85. 44. alehagen s, wijma b, lundberg u, wijma k. fear, pain and stress hormones during childbirth. j pyschosom obstet gynaecol 2005; 26:153–65. 45. czarnocka j, slade p. prevalence and predictors of post-traumatic stress symptoms following childbirth. br j clin psychol 2000; 39:35–51. 1dermatology unit, complejo hospitalario torrecárdenas, almería, spain; 2department of dermatology, virgen de las nieves university hospital, granada, spain; 3dermatology unit, hospital universitario san cecilio, granada, spain *corresponding author e-mail: cristinagarrido86@gmail.com احلزاز املسطح املصطبغ مع البالشكويد ماريا خو�صيه األون�صو-كورال، كري�صتينا غاريدو-كوملنريو، اآنا املودوفار-ريال، ريكاردو رويز-فيالفريدي lichen planus pigmentosus with blaschkoid distribution maría j. alonso-corral,1 *cristina garrido-colmenero,2 ana almodovar-real,3 ricardo ruiz-villaverde2 interesting medical image a 57-year-old woman presented at a dermatology unit in granada, spain, in 2015 with a two-month history of slightly pruritic brown-coloured macular lesions on the trunk and right arm. she was not taking any medications or using cosmetics and had not been exposed to the sun before the onset of the rash. on examination, clearly defined hyperpigmented brown macules were seen on the right submammary region, right hemithorax, right abdomen and right buttock [figure 1] with an s-shaped appearance, compatible with the pattern of blaschko lines. tests for hepatitis b and hepatitis c were negative. a histological examination showed rich lymphocytic infiltrate and melanin incontinence with slight epidermal atrophy and lichenoid reaction with hypergranulosis [figure 2]. considering these features, a diagnosis of lichen planus pigmentosus (lpp) with blaschkoid distribution was proposed. the patient was prescribed topical clobetasol propionate for four weeks. the lesions responded well to the treatment, with significant pigment reduction and improvement of the associated pruritus. comment various triggering factors, ranging from viral infections and vaccinations to trauma, have been implicated in the aetiology of lichen planus.1 a rare variant of lichen planus, lpp is distinguished by hyperpigmented macules or papules. the histological characteristics of lpp include epidermal atrophy, vacuolar degeneration of the basal cell layer and rich dermal lichenoid infiltrate.2 kanwar et al. suggested that lpp may represent a lichenoid reaction to an unknown agent or stimuli, with regards to the histological concordance between lpp and lichen planus.3 the differential diagnosis of lpp includes conditions such as lichen striatus, erythema dyschromicum perstans, incontinentia pigmenti, linear and whorled nevoid hypermelanosis, occupational sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e383–384, epub. 19 aug 16 submitted 24 feb 16 revision req. 13 apr 16; revision recd. 20 apr 16 accepted 28 apr 16 doi: 10.18295/squmj.2016.16.03.024 figure 1a–c: hyperpigmented brown macules on the (a) right submammary region, (b) right hemithorax, right abdomen and (c) right buttock of a 57-year-old woman. lichen planus pigmentosus with blaschkoid distribution e384 | squ medical journal, august 2016, volume 16, issue 3 lesions of classical lichen planus can also occur over the blaschko lines.7 the majority of lpp lesions are usually distributed in areas exposed to the sun; trunk lesions, such as those observed in the present case, are rarely observed.8 both topical and oral treatments for lpp have been used with varying results, including topical steroids, keratolytics, tacrolimus, griseofulvin, prednisone, etretinate and chloroquine.3,4 references 1. rosenblatt ae, stein sl. cutaneous reactions to vaccinations. clin dermatol 2015; 33:327–32. doi: 10.1016/j. clindermatol.2014.12.009. 2. lehman js, tollefson mm, gibson le. lichen planus. int j dermatol 2009; 48:682–94. doi: 10.1111/j.1365-4632.2009. 04062.x. 3. kanwar aj, dogra s, handa s, parsad d, radotra bd. a study of 124 indian patients with lichen planus pigmentosus. clin exp dermatol 2003; 28:481–5. doi: 10.1046/j.13652230.2003.01367.x. 4. sharma a, białynicki-birula r, schwartz ra, janniger ck. lichen planus: an update and review. cutis 2012; 90:17–23. 5. akarsu s, ilknur t, özer e, fetil e. lichen planus pigmentosus distributed along the lines of blaschko. int j dermatol 2013; 52:253–4. doi: 10.1111/j.1365-4632.2011.04872.x. 6. taniguchi y, minamikawa m, shimizu m, ando k, yamazaki s. linear lichen planus mimicking creeping eruption. j dermatol 1993; 20:118–21. doi: 10.1111/j.1346-8138.1993.tb03843.x. 7. grosshans em. acquired blaschkolinear dermatoses. am j med genet 1999; 85:334–7. doi: 10.1002/(sici)1096-8628(1999 0806)85:4<334::aid-ajmg4>3.0.co;2-f. 8. das a, mishra v, podder i, kumar p, das d, das nk. linear lichen planus pigmentosus: a rare entity with an illusory presentation. pigment int 2014; 1:100–2. doi: 10.4103/23495847.147048. dermatosis with hyperpigmentation and drug-related melanoses.4 in the current case, these differential diagnoses were not considered as there was no history of inflammatory processes before the beginning of the hyperpigmentation. the most frequent variant of lpp is linear, as was observed in the current case, with zosteriform or blaschkoid lpp being much less common.5 the distribution of lpp along the blaschko lines was first described by taniguchi et al. in 1993.6 dispersed figure 2: haematoxylin and eosin stain at x10 magnification showing rich lymphocytic infiltrate and melanin incontinence with light epidermal atrophy and lichenoid reaction with hypergranulosis. http://dx.doi.org/10.1016/j.clindermatol.2014.12.009 http://dx.doi.org/10.1016/j.clindermatol.2014.12.009 http://dx.doi.org/10.1111/j.1365-4632.2009.04062.x http://dx.doi.org/10.1111/j.1365-4632.2009.04062.x http://dx.doi.org/10.1046/j.1365-2230.2003.01367.x http://dx.doi.org/10.1046/j.1365-2230.2003.01367.x http://dx.doi.org/10.1111/j.1365-4632.2011.04872.x http://dx.doi.org/10.1111/j.1346-8138.1993.tb03843.x http://dx.doi.org/10.1002/%28sici%291096-8628%2819990806%2985:4%3c334::aid-ajmg4%3e3.0.co%3b2-f http://dx.doi.org/10.1002/%28sici%291096-8628%2819990806%2985:4%3c334::aid-ajmg4%3e3.0.co%3b2-f http://dx.doi.org/10.4103/2349-5847.147048 http://dx.doi.org/10.4103/2349-5847.147048 1department of biobehavioral health & population sciences, university of minnesota medical school, duluth, minnesota, usa; 2department of community medicine, faculty of medicine, university of monastir, monastir, tunisia; 3department of epidemiology & preventive medicine, university hospital of monastir, monastir, tunisia; 4department of psychology, goethe university frankfurt, frankfurt, germany *corresponding author e-mail: malabsi@umn.edu إختبار قياس العمليات النفسية لنسخة عربية من مقياس مسة وحالة الغضب واساليب التعبري عنه موتوهريو ناكاجيما، اإينا�ض بوعنان، �صناء املحمدي، حممد �صلطاين، �صتيفن بوجنارد، م�صطفى العب�صي abstract: objectives: this study aimed to examine the psychometric properties of an arabic version of the trait anger and anger expression scales of the state-trait anger expression inventory (staxi). methods: this study took place between april 2005 and august 2014. adults in yemen (n = 334) and tunisia (n = 200) were recruited from university campuses and a smoking cessation clinic, respectively. the staxi was translated into arabic using backtranslation methods. an explanatory principal component analysis was conducted to explore the factor structure of the anger expression scale, utilising parallel analyses to determine the number of retained factors. results: good internal consistency of the trait anger scale was observed among the yemeni (cronbach’s alpha = 0.76) and tunisian (cronbach’s alpha = 0.86) samples. the parallel analysis suggested a three-factor solution for the anger expression scale (anger in, anger out and anger control), in accordance with the original staxi. the internal consistency of anger in, anger out and anger control factors ranged between 0.51–0.79 in the yemeni sample and 0.66–0.81 in the tunisian sample. overall, items loaded on the anger control factor included all items proposed by the original authors and this factor had higher reliability than the other two factors in both samples. conclusion: the results of the current study provide initial support for the use of the trait anger and anger expression scales of the staxi in arabic-speaking countries. keywords: psychometrics; anger; reliability and validity; translations; yemen; tunisia. امللخ�ص: اأهداف: تهدف هذه الدرا�صة اإىل فح�ض اخل�صائ�ض ال�صيكومرتية للن�صخة العربية من مقيا�ض �صمة الغ�صب و التعبري عن الغ�صب )n = 220(و تون�ض )n = 334( منهجية: اأجريت هذه الدرا�صة بني اأبريل 2005 و اأغ�صط�ض 2014. مت تقييم مفحو�صني بالغني من اليمن .)staxi( من حرم اجلامعة وعيادة االإقالع عن التدخني، على التوايل. مت ترجمة staxi اإىل اللغة العربية عن طريق الرتجمة املرجعية. مت حتليل عوامل عدد لتحديد املوازي التحليل با�صتخدام الغ�صب، عن التعبري مقيا�ض عامل هيكل ال�صتك�صاف الرئي�صي املكون باإ�صتخدام النتائج املقيا�ض املرتجم. نتائج: لوحظ وجود تنا�صق داخلي جيد يف مقيا�ض �صمة الغ�صب عند عينات اليمنيني )cronbach's alpha = 0.76( و التون�صيني )cronbach's alpha = .086(. التحليل املوازي او�صح ثالثة عوامل حل ملقيا�ض التعبري عن الغ�صب )الغ�صب الداخلي، الغ�صب اخلارجي، التحكم يف الغ�صب(. تراوح التنا�صق الداخلي لعوامل الغ�صب الداخلي، الغ�صب اخلارجي و التحكم يف الغ�صب بني 0.51-0.79 يف عينة اليمنيني و 0.81-0.66 يف عينة التون�صيني. عموما، ت�صمنت البنود التي مت حتميلها على عامل التحكم يف الغ�صب جميع البنود املقرتحة من املوؤلفني االأ�صليني وكان هذا العامل اأكرث موثوقية من العاملني االآخرين يف كال العينتني. خامتة: توفر نتائج الدرا�صة احلالية الدعم االأويل الإ�صتخدام مقايي�ض �صمة الغ�صب و التعبري عن الغ�صب staxi يف الدول الناطقة بالعربية. كلمات مفتاحية: �صيكومرتية؛ الغ�صب؛ املوثوقية وامل�صداقية؛ الرتجمة؛ اليمن؛ تون�ض . psychometric examination of an arabic version of the state-trait anger expression inventory motohiro nakajima,1 ines bouanene,2,3 sana el-mhamdi,2,3 mohamed soltani,2,3 stephan bongard,4 *mustafa al’absi1 sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e322–328, epub. 19 aug 16 submitted 21 feb 16 revision req. 29 mar 16; revision recd. 27 apr 16 accepted 19 may 16 clinical & basic research doi: 10.18295/squmj.2016.16.03.010 advances in knowledge validated instruments to assess trait anger levels are helpful in elucidating the relationship between anger and various negative health outcomes, such as cardiovascular diseases. to date, most research on anger and anger expression has been conducted in western countries. there has been no attempt to validate a tool to assess anger in arabic-speaking countries. to the best of the authors’ knowledge, this study is the first to test the psychometric properties of an arabic version of the state-trait anger expression inventory (staxi). as the current study was conducted in two arabic-speaking countries, the results provide initial support for the usefulness of the staxi in this region of the world. application to patient care anger is a commonly expressed emotion that plays an important role in physical and mental health. research to elucidate individual differences in anger expression therefore has clinical implications for patient care, as well as potentially improving patient-provider relationships and affecting the quality of treatment programmes. motohiro nakajima, ines bouanene, sana el-mhamdi, mohamed soltani, stephan bongard and mustafa al’absi clinical and basic research | e323 anger is a common emotional state that becomes more pronounced in stressful circumstances.1 anger expression has been associated with numerous physical and mental negative health outcomes, including cardiovascular mortality and morbidity.2–8 valid assessments of anger therefore have an important impact on research related to health and psychological well-being. the statetrait anger expression inventory (staxi) is one of the most frequently used instruments to assess anger and anger expression.9 several studies have shown the sound psychometric properties of the staxi in various populations.10–14 however, to the best of the authors’ knowledge, no study has yet examined the validity of utilising the staxi in arabic-speaking countries. the current study was therefore designed to develop and assess the properties of an arabic version of the trait anger and anger expression scales of the staxi. to enhance the generalisability of the findings, samples from tunisia in north africa and yemen in the middle east were included. methods this study was conducted between april 2005 and august 2014 among adults living in yemen and tunisia. a total of 334 male and female participants were recruited between april 2005 and march 2010 from taiz university, taiz, yemen, and sana’a university, sana’a, yemen, by posting flyers around the campuses and within communities. participants were included in the study if they were not currently taking any prescribed medications and had completed their high school education. individuals were contacted by trained research staff and were scheduled for a laboratory appointment. additionally, 200 male smokers who visited the smoking cessation clinic at the monastir university hospital, monastir, tunisia, were recruited between february and august 2014. potential participants were briefed regarding the objectives of the study and asked if they were interested in participating. smokers who were over 15 years old, interested in smoking cessation and who did not have current depression were considered eligible for this study. participants from both yemen and tunisia were requested to complete a series of questions which included demographic information and items from the staxi.9 all data were collected during face-toface interviews. the staxi contains 44 items measuring state anger (10 items), trait anger (10 items) and three anger expression factors: anger in (ai; eight items), anger out (ao; eight items) and anger control (ac; eight items).9 these scales assess how individuals generally react or behave when they feel angry: trait anger measures how prone individuals are to experiencing anger, while ai assesses how frequently an individual suppresses their anger, ao gauges how often an individual expresses their anger towards other people and ac determines how often an individual tries to regulate their anger. a general index of anger expression can also be calculated from anger expression factors (i.e. ai plus ao minus ac plus 16).9 in this study, only trait anger and anger expression items of the staxi were included since the primary purpose was to explore dimensions of habitual anger dispositions in a new population. furthermore, although a newer version of the inventory is available (staxi-2™), the original version was used due to its established validity and reliability across different populations.14–19 for the original english version of the staxi, internal consistency has been reported as 0.82 and 0.83 for trait anger, 0.73 and 0.74 for ai, 0.75 and 0.77 for ao and 0.85 and 0.84 for ac among male and female college students, respectively.9 for the purposes of the current study, the staxi was first translated into arabic and then back-translated into english by two independent translators. in cases of discrepancy between the translations, the translators discussed the respective items until they agreed on one version. as no data yet exist to determine the consistency of underlying dimensions of the staxi across different cultures—and, more specifically, no studies testing anger constructs among individuals in arabicspeaking countries—an exploratory, rather than confirmatory, data analysis method was deemed appropriate. in order to determine the appropriate number of components/factors to be retained, a parallel analysis was conducted using raneigen software.20,21 a number of correlation matrices were constructed based on random data but with the same sample size and number of variables relative to those from empirical data. eigenvalues obtained from the empirical dataset were then compared to those obtained from the random dataset. the number of retained components was then restricted to those which showed eigenvalues above what was expected by a principal component analysis based on random data generated by monte carlo methods.22 a varimax rotation was used and the kaiser-meyer-olkin (kmo) index was calculated to test the adequacy of the sampling. a factor loading of 0.30 or above was employed as an a priori criterion for an item to be included in a factor. cronbach’s alpha was obtained to test internal consistency. as only the yemeni sample included both male and female participants, a one-way analysis of variance was conducted in this sample to examine gender differences in trait anger and anger psychometric examination of an arabic version of the state-trait anger expression inventory e324 | squ medical journal, august 2016, volume 16, issue 3 expression scales. due to occasional missing data, variations existed between sample size and degrees of freedom for the reported variables. this study was approved by the research and ethical committees of sana’a university and taiz university as well as the monastir university hospital in tunisia. all subjects provided written consent before participating in the study. results a total of 334 and 200 participants from yemen and tunisia, respectively, were included in the study. among the yemeni sample, 139 (42%) were female. the mean age was 23.7 ± 5.3 years for men and 23.8 ± 5.0 years for women. all of the tunisian participants were male, the majority (68%) were employed and 8% were students. in the tunisian sample, 74% had attended high school. the mean age was 42.9 ± 14.2 years (range: 15–75 years old). descriptive statistics associated with the anger scales are shown in table 1. for both the yemeni and tunisian samples, the parallel analysis suggested a three-factor structure. the eigenvalues for three factors were greater for the empirical data than expected based on random data [figure 1]. these factors were labelled according to the original three-factor solution: ai, ao and ac.9 factor structures of the anger expression items are described in table 2. for the yemeni sample, the sample size was adequate (kmo index = 0.73 and 0.72 for men and women, respectively). men and women reported comparable scores on the trait anger scale (f[1,331] = 0.81; p = 0.37), with an internal consistency of 0.76 (0.77 versus 0.74 for men and women, respectively). item-to-total correlations ranged from 0.34–0.52. cronbach’s alpha was 0.63, 0.68 and 0.75 for the ai, ao and ac factors, respectively. men reported higher scores for ao (f[1,331] = 3.97; p <0.05) and ac (f[1,331] = 6.37; p <0.05) compared to women. gender differences were not observed for ai or anger expression scores (fs <1.0; p >0.64). the total variance accounted for by the three-factor solution was 37.6% and 36.5% in men and women, respectively. among men, the internal consistency was 0.67, 0.63 and 0.79 for ai, ao and ac, respectively. item-total correlations were between 0.28–0.46 for ai, 0.15–0.44 for ao and 0.41–0.57 for ac. the reliability of ao improved to 0.65 when the item with the lowest itemtotal correlation was removed (item #23). for women, internal consistency was 0.51, 0.73 and 0.68 for ai, table 1: trait anger and anger expression factor scores* among adults from yemen (n = 334) and tunisia (n = 200) factor mean score ± se yemen tunisia men (n = 195) women (n = 139) total (n = 334) p value men (n = 200) trait anger 21.9 ± 0.4 21.3 ± 0.4 21.9 ± 0.3 0.37 23.2 ± 0.5 anger in 17.1 ± 0.3 16.9 ± 0.3 17.0 ± 0.2 0.64 16.7 ± 0.3 anger out 15.6 ± 0.3 14.7 ± 0.3 15.2 ± 0.2 0.05 16.4 ± 0.3 anger control 21.6 ± 0.4 20.1 ± 0.4 20.9 ± 0.3 0.01 18.3 ± 0.4 anger expression† 27.1 ± 0.6 27.5 ± 0.8 27.3 ± 0.5 0 .74 30.8 ± 0.6 se = standard error. *assessed using an arabic version of the trait anger and anger expression scales of the state-trait anger expression inventory.9 †calculated as anger in plus anger out minus anger control plus 16.9 figure 1a & b: parallel analyses of eigenvalues based on empirical data regarding anger expression* gathered from adults in (a) yemen (n = 334) and (b) tunisia (n = 200) compared to eigenvalues based on random data generated by monte carlo methods. *assessed using an arabic version of the trait anger and anger expression scales of the state-trait anger expression inventory.9 motohiro nakajima, ines bouanene, sana el-mhamdi, mohamed soltani, stephan bongard and mustafa al’absi clinical and basic research | e325 ao and ac, respectively. item-total correlations were between 0.15–0.32 for ai, 0.30–0.48 for ao and 0.20–0.61 for ac. the reliability of ac increased to 0.75 when the least correlated item (item #20) was deleted; table 2: factor structure and internal consistency of anger expression factors* (anger in, anger out and anger control) among adults from tunisia (n = 200) and yemen (n = 334) yemen (n = 334) tunisia (n = 200) ai ao ac ai ao ac men women men women men women variance in % 6.3 6.9 13.0 10.5 18.2 19.0 10.5 15.9 15.6 eigenvalue 1.52 1.67 3.13 2.53 4.37 4.57 2.02 4.98 3.06 original scale cronbach’s alpha8 0.67 0.51 0.63 0.73 0.79 0.68 0.66 0.69 0.81 current scale cronbach’s alpha 0.68 0.51 0.73 0.53 0.66 0.57 0.59 0.70 0.70 item 3. keeps things in 0.62† 0.33† -0.30§ 0.31§ 0.38§ 0.61† 5. pouts or sulks 0.26‡ 0.41† 0.57§ -0.32§ -0.45§ 0.37† 0.47§ 6. withdraws 0.41† 0.50† 0.36§ -0.30§ 0.61† 10. boils inside 0.75† 0.53† -0.32§ 0.35§ 0.70† 13. harbours grudges 0.48† 0.44† 0.58† 16. secretly critical 0.21‡ 0.52† 0.47§ 0.40† 0.38§ 17. angrier than admits 0.53† 0.56† 0.30§ 0.12‡ 0.72§ 21. irritated 0.61† 0.36† 0.43§ 0.32† 0.45§ 2. expresses anger 0.52† 0.58† 0.71† 7. sarcastic 0.53† 0.51† 0.22‡ 9. slams doors 0.32§ 0.47† 0.55† 0.46† 12. argues with others 0.49† 0.59† 0.35† 0.42§ 14. strikes out 0.31† 0.59† 0.48† 19. says nasty things 0.60† 0.64† 0.73† 22. loses temper 0.44§ 0.38† 0.61† -0.32§ 0.69† -0.34§ 23. tells feelings to others 0.35† 0.49† -0.35§ 0.44† 0.32§ 1. controls temper 0.53† 0.56† 0.55† 4. patient 0.63† 0.68† 0.31§ 0.53† 8. keeps cool -0.36§ 0.74† 0.53† -0.39§ 0.58† 11. controls behaviour 0.72† 0.73† 0.66† 15. prevents temper loss 0.62† 0.68† 0.63† 18. calms down quickly 0.56† 0.39† 0.57† 20. tolerant 0.63† 0.33† 0.66† 24. controls anger 0.66† 0.63† 0.73† ai = anger in; ao = anger out; ac = anger control. *assessed using an arabic version of the trait anger and anger expression scales of the state-trait anger expression inventory.9 †factor proposed by the authors of the original scale for that specific item.9 ‡items proposed by the authors of the original scale that did not reach the criteria of factor loading (0.30).9 §items proposed by the authors of the original scale that met the criteria of factor loading (0.30).9 psychometric examination of an arabic version of the state-trait anger expression inventory e326 | squ medical journal, august 2016, volume 16, issue 3 however, deleting the least correlated item (item #3) in ai did not improve the reliability of the scale. for both men and women, ai was positively correlated with ao (r >0.17; p <0.05) and ac was inversely related to ao (r = -0.24; p <0.01). there was no relationship between ai and ac (p >0.63). for both men and women, items loaded under the ao and ac factors included all items proposed by the original authors of the staxi and most of them loaded uniquely on the expected component.9 in addition, three to four items loaded on these components. internal consistency for these items was 0.73 and 0.66 among men and 0.53 and 0.57 among women for ao and ac, respectively. items loaded under the ai factor among women were identical to those from the original staxi.9 however, the data for ai among men did not replicate those from the original staxi;9 two expected items (items #5 and #16) loaded weakly under this construct. cronbach’s alpha for items that met the loading criteria was 0.68. for the tunisian sample, the kmo index (0.79) indicated the adequacy of the sample size. the internal consistency for the trait anger scale was 0.86. item-tototal correlations ranged from 0.44–0.68. cronbach’s alpha was 0.66, 0.69 and 0.81 for ai, ao and ac, respectively. item-total correlations were between 0.25–0.46 for ai, 0.19–0.60 for ao and 0.39–0.63 for ac. the reliability of ao improved to 0.70 when the item with the lowest item-total correlation was removed (item #7). the reliability of ac was almost the same (0.81) when the least correlated item (item #18) was deleted. however, deleting the least correlated item (item #3) in ai did not improve the reliability of the scale. moreover, ai was positively correlated with ao (r = 0.23; p <0.01) and ac (r = 0.17; p <0.05). in contrast, ac was inversely related to ao (r = -0.28; p <0.01). items loaded under ac included all items proposed by the original authors of the scale and most of them loaded uniquely on the expected component.9 in addition, three items loaded under these components. internal consistency with these items was 0.70. however, ai and ao did not replicate those from the original staxi;9 one expected item loaded weakly under each construct (items #17 and #7, respectively). cronbach’s alpha for items that met the loading criteria was 0.59 for ai and 0.70 for ao. discussion the results of the current study provide initial evidence for the use of the trait anger and anger expression scales of the staxi among individuals of arabicspeaking countries. trait anger was found to have good internal consistency among both yemeni and tunisian samples, confirming data from the original staxi.9 results on anger expression items were predominantly in agreement with the original structures.9 among both yemeni men and women, items loaded on each component included all of those proposed by the authors of the original scale.9 moreover, items loaded on ai among women were identical to those from the original scale.9 the internal consistency of the ac factor with original items was 0.79 in men and 0.68 in women, with cronbach’s alpha improving up to 0.75 with the removal of the least correlated item. similar trends were observed among the sample of tunisian male smokers: items loaded under the ac factor included all items that were proposed by the authors of the original scale and all but one item were loaded under ai and ao factors proposed by the authors of the original scale.9 the high reliability of ac (0.81 with the original items) among the tunisian sample is consistent with that of the yemeni sample, which adds strength to the generalisability of the findings and suggests the potential usefulness of ac items to assess anger in arab individuals of both genders. in the present study, several items which were expected to load exclusively under ai also loaded on ao or ac. additionally, the inclusion of items that met the loading criteria did not improve internal consistency of these scales; this trend was observed in both samples. a similar lack of psychometric properties in ai has been reported among hispanics, african americans and russians.11,16,18 although this finding may be related to the difficulty in translating or wording certain items, it is also possible that some items are not sensitive enough to identify or differentiate underlying dimensions of anger expression. for example, items such as “keeps things in” and “pouts or sulks” (items #3 and #5) loaded on both ai and ac and partly on ao in the yemeni sample. items such as “pouts or sulks”, “secretly critical” and “irritated” (items #5, #16 and #21) loaded on ai and ac, whereas “tells feelings to others” (item #23) loaded on all three constructs in the tunisian sample. it is possible that these items may have been misunderstood as either the suppression or regulation of anger among yemeni and tunisian individuals. unexpected loading of items such as “pouts or sulks” has been found in other studies.10,11,23 future studies should therefore exercise caution in the interpretation or translation of these items.14 to the best of the authors’ knowledge, the current study is the first to show gender differences in anger expression among middle eastern adults. higher ao, as well as lower ac, was found in yemeni men compared to women; however, the extent to which gender moderates anger expression is not clear. two previous studies have reported gender differences motohiro nakajima, ines bouanene, sana el-mhamdi, mohamed soltani, stephan bongard and mustafa al’absi clinical and basic research | e327 in item loadings of anger expression scales.10,11 for example, certain items (i.e. “secretly critical” and “pouts or sulks”) considered to be part of ai actually loaded on ao among women but not men, while another study observed that the item “i pout or sulk” loaded on both ai and ao for men only.10,11 these findings suggest the possibility that anger expression is different in men and women. other research has shown no gender differences in anger expression among caucasians and african americans, although one study involving individuals from multiple ethnic backgrounds found higher ac and lower anger expression among women.8,16,19 recent data suggest the role of situational determinants in gender differences in anger expression; using a domain-specific strategy, men and women were found to express anger differently in various circumstances (e.g. women were more likely to report ao at home than men, while men reported greater ao at work than women).24–26 however, this theory has not been directly tested among arabic-speaking adults. in the current study, gender differences were noted in the internal consistency of anger expression items; in general, reliability scores for ai, ao and ac were lower among women compared to men. it is possible that men and women interpreted or perceived some items differently. future research should take into account the role of sociocultural setting on gender differences in anger expression. fischer et al. found that women living in countries where females were more empowered to engage in economic and political life were more likely to report anger expression.27 accounting for these factors may help improve the usefulness of the staxi across different populations. the results of the current study suggest that trait anger and ac scales can be used in arabic-speaking regions; this would subsequently help to assess correlates with health and psychological risks in these countries. haukkala et al. reported that ac levels can predict cardiovascular mortality and morbidity.3 another study showed that smokers with high trait anger suffered from increased withdrawal symptoms during acute nicotine withdrawal and had a greater risk of relapse within a week of cessation.28 due to the tobacco epidemic causing serious concern in many arab countries, including yemen and tunisia, investigating the role of trait anger in emotion regulation and drug consumption behaviour may have important clinical implications within these populations.29,30 the current study had several limitations; as such, these results should be considered preliminary. future work should examine the validity of using the staxi in larger arabic-speaking samples. results from yemen and tunisia were difficult to compare because of differences in sample characteristics, as the sample from yemen consisted of young adult men and women whereas the sample from tunisia included only male smokers who were seeking treatment. furthermore, these countries have different geographical, socioeconomic and cultural influences. these might explain differences in reliability and validity in comparison to the original staxi.9 moreover, this study did not test the state anger scale as the purpose of this study focused on validating the trait anger and anger expression scales, which may have direct health consequences.3 further research should examine other components of validity (e.g. concurrent or discriminant validity) and reliability (e.g. test-retest reliability) of arabic versions of the inventory and use the latest version of the scales (staxi-2™).15 despite these limitations, the study included participants from two different countries, yemen and tunisia, which strengthens the generalisability of the findings. conclusion this study provides initial support for the structural validity and reliability of the staxi trait anger and anger expression scales among adults in arabicspeaking countries. the internal consistency of trait anger and ac items in the current study were comparable to data from the original staxi scales. preliminary gender differences in ac and ao suggest the role of social and cultural influences in anger expression. accounting for these influences may help to improve the usefulness of the inventory in elucidating the relationship between anger expression and health risks in these populations. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was supported in part by grants from the national institutes of health/fogarty international center (#r03tw007219), the national institute for drug abuse (#da024626) and the office of international programs at the university of minnesota, duluth, minnesota, usa. a c k n o w l e d g e m e n t s the authors would like to thank dr anisa dokam, dr abed n. kasim and dr mohammed al-soofi at the taiz university as well as dr najat s. khalil and dr molham al-habori at the sana’a university for their efforts in developing the research programme and coordinating the study. in addition, ms basma psychometric examination of an arabic version of the state-trait anger expression inventory e328 | squ medical journal, august 2016, volume 16, issue 3 a. thabe and mr khaled al-sahmiry are thanked for their help with data collection and dr volker hodapp is also thanked for his support with the preliminary data analysis. references 1. averill jr. studies on anger and aggression: implications for theories of emotion. am psychol 1983; 38:1145–60. doi: 10.1037/0003-066x.38.11.1145. 2. everson sa, goldberg de, kaplan ga, julkunen j, salonen jt. anger expression and incident hypertension. psychosom med 1998; 60:730–5. doi: 10.1097/00006842-199811000-00014. 3. haukkala a, konttinen h, laatikainen t, kawachi i, uutela a. hostility, anger control, and anger expression as predictors of cardiovascular disease. psychosom med 2010; 72:556–62. doi: 10.1097/psy.0b013e3181dbab87. 4. gonzalez oi, novaco rw, reger ma, gahm ga. anger intensification with combat-related ptsd and depression comorbidity. psychol trauma 2016; 8:9–16. doi: 10.1037/ tra0000042. 5. smith tw, glazer k, ruiz jm, gallo lc. hostility, anger, aggressiveness, and coronary heart disease: an interpersonal perspective on personality, emotion, and health. j pers 2004; 72:1217–70. doi: 10.1111/j.1467-6494.2004.00296.x. 6. deffenbacher jl, oetting er, lynch rs, morris cd. the expression of anger and its consequences. behav res ther 1996; 34:575–90. doi: 10.1016/0005-7967(96)00018-6. 7. erwin ba, heimberg rg, schneier fr, liebowitz mr. anger experience and expression in social anxiety disorder: pretreatment profile and predictors of attrition and response to cognitive-behavioral treatment. behav ther 2003; 34:331–50. doi: 10.1016/s0005-7894(03)80004-7. 8. al’absi m, bongard s. neuroendocrine and behavioral mechanisms mediating the relationship between anger expression and cardiovascular risk: assessment considerations and improvements. j behav med 2006; 29:573–91. doi: 10.1007/ s10865-006-9077-0. 9. spielberger cd. state-trait anger expression inventory: professional manual. odessa, florida, usa: psychological assessment resources, 1996. 10. forgays dg, forgays dk, spielberger cd. factor structure of the state-trait anger expression inventory. j pers assess 1997; 69:497–507. doi: 10.1207/s15327752jpa6903_5. 11. reyes lr, meininger jc, liehr p, chan w, mueller wh. anger in adolescents: sex, ethnicity, age differences, and psychometric properties. nurs res 2003; 52:2–11. doi: 10.1097/00006199200301000-00002. 12. azevedo fb, wang yp, goulart ac, lotufo pa, benseñor im. application of the spielberger’s state-trait anger expression inventory in clinical patients. arq neuropsiquiatr 2010; 68:231–4. doi: 10.1590/s0004-282x2010000200015. 13. fuqua dr, leonard e, masters ma, smith rj, campbell jl, fischer pc. a structural analysis of the state-trait anger expression inventory. educ psychol meas 1991; 51:439–46. doi: 10.1177/0013164491512018. 14. kassinove h, sukhodolsky dg, eckhardt ci, tsytsarev sv. development of a russian state-trait anger expression inventory. j clin psychol 1997; 53:543–57. doi: 10.1002/ (sici)1097-4679(199710)53:6<543::aid-jclp3>3.0.co;2-l. 15. spielberger cd. staxi-2™: state-trait anger expression inventory-2™ professional manual. odessa, florida, usa: psychological assessment resources, 1999. 16. armstead ca, clark r. assessment of self-reported anger expression in preand early-adolescent african americans: psychometric considerations. j adolesc 2002; 25:365–71. doi: 10.1006/jado.2002.0481. 17. knight rg, chisholm bj, paulin jm, waal-manning hj. the spielberger anger expression scale: some psychometric data. br j clin psychol 1988; 27:279–81. doi: 10.1111/j.20448260.1988.tb00792.x. 18. eckhardt ci, kassinove h, tsytsarev sv, sukhodolsky dg. a russian version of the state-trait anger expression inventory: preliminary data. j pers assess 1995; 64:440–55. doi: 10.1207/ s15327752jpa6403_4. 19. musante l, treiber fa, davis hc, waller jl, thompson wo. assessment of self-reported anger expression in youth. assessment 1999; 6:225–34. doi: 10.1177/107319119900600303. 20. lautenschlager gj. a comparison of alternatives to conducting monte carlo analyses for determining parallel analysis criteria. multivariate behav res 1989; 24:365–95. doi: 10.1207/ s15327906mbr2403_6. 21. enzmann d. raneigen: a program to determine the parallel analysis criterion for the number of principal components. appl psychol meas 1997; 21:232. doi: 10.1177/01466216970213003. 22. hayton jc, allen dg, scarpello v. factor retention decisions in exploratory factor analysis: a tutorial on parallel analysis. organ res methods 2004; 7:191–205. doi: 10.1177/109442810 4263675. 23. lievaart m, franken ih, hovens je. anger assessment in clinical and nonclinical populations: further validation of the state-trait anger expression inventory-2. j clin psychol 2016; 72:263–78. doi: 10.1002/jclp.22253. 24. bongard s, martin nm, seip m, al’absi m. evaluation of a domain-specific anger expression assessment strategy. j pers assess 2011; 93:56–61. doi: 10.1080/00223891.2010.513705. 25. bongard s, al’absi m. domain-specific anger expression and blood pressure in an occupational setting. j psychosom res 2005; 58:43–9. doi: 10.1016/j.jpsychores.2004.04.370. 26. bongard s, al’absi m. domain-specific anger expression assessment and blood pressure during rest and acute stress. pers individ dif 2003; 34:1383–402. doi: 10.1016/s01918869(02)00106-x. 27. fischer ah, rodriguez mosquera pm, van vianen ae, manstead as. gender and culture differences in emotion. emotion 2004; 4:87–94. doi: 10.1037/1528-3542.4.1.87. 28. al’absi m, carr sb, bongard s. anger and psychobiological changes during smoking abstinence and in response to acute stress: prediction of smoking relapse. int j psychophysiol 2007; 66:109–15. doi: 10.1016/j.ijpsycho.2007.03.016. 29. al’absi m, grabowski j. concurrent use of tobacco and khat: added burden on chronic disease epidemic. addiction 2012; 107:451–2. doi: 10.1111/j.1360-0443.2011.03684.x. 30. fakhfakh r, hsairi m, maalej m, achour n, nacef t. tobacco use in tunisia: behaviour and awareness. bull world health organ 2002; 80:350–6. doi: 10.1590/s0042-96862002000500004. http://dx.doi.org/10.1037/0003-066x.38.11.1145 http://dx.doi.org/10.1097/00006842-199811000-00014 http://dx.doi.org/10.1097/psy.0b013e3181dbab87 http://dx.doi.org/10.1037/tra0000042 http://dx.doi.org/10.1037/tra0000042 http://dx.doi.org/10.1111/j.1467-6494.2004.00296.x http://dx.doi.org/10.1016/0005-7967%2896%2900018-6 http://dx.doi.org/10.1016/s0005-7894%2803%2980004-7 http://dx.doi.org/10.1007/s10865-006-9077-0 http://dx.doi.org/10.1007/s10865-006-9077-0 http://dx.doi.org/10.1207/s15327752jpa6903_5 http://dx.doi.org/10.1097/00006199-200301000-00002 http://dx.doi.org/10.1097/00006199-200301000-00002 http://dx.doi.org/10.1590/s0004-282x2010000200015 http://dx.doi.org/10.1177/0013164491512018 http://dx.doi.org/10.1002/%28sici%291097-4679%28199710%2953:6%3c543::aid-jclp3%3e3.0.co%3b2-l http://dx.doi.org/10.1002/%28sici%291097-4679%28199710%2953:6%3c543::aid-jclp3%3e3.0.co%3b2-l http://dx.doi.org/10.1006/jado.2002.0481 http://dx.doi.org/10.1111/j.2044-8260.1988.tb00792.x http://dx.doi.org/10.1111/j.2044-8260.1988.tb00792.x http://dx.doi.org/10.1207/s15327752jpa6403_4 http://dx.doi.org/10.1207/s15327752jpa6403_4 http://dx.doi.org/10.1177/107319119900600303 http://dx.doi.org/10.1207/s15327906mbr2403_6 http://dx.doi.org/10.1207/s15327906mbr2403_6 http://dx.doi.org/10.1177/01466216970213003 http://dx.doi.org/10.1177/1094428104263675 http://dx.doi.org/10.1177/1094428104263675 http://dx.doi.org/10.1002/jclp.22253 http://dx.doi.org/10.1080/00223891.2010.513705 http://dx.doi.org/10.1016/j.jpsychores.2004.04.370 http://dx.doi.org/10.1016/s0191-8869%2802%2900106-x http://dx.doi.org/10.1016/s0191-8869%2802%2900106-x http://dx.doi.org/10.1037/1528-3542.4.1.87 http://dx.doi.org/10.1016/j.ijpsycho.2007.03.016 http://dx.doi.org/10.1111/j.1360-0443.2011.03684.x http://dx.doi.org/10.1590/s0042-96862002000500004 department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: mariamm1762@gmail.com قرارات إجراء عمليات قيصرية طارئة يف مستشفى جامعي هل أخصائيو التوليد متفقون؟ �شلج� بيالي، ج�وري فيدي�ن�ث�ن، مرمي ال�شكرية، متيمة الدغي�شية، �ش�هيال ت�شنيم، دردانة خ�ن، �شنية الطيب، مرمي م�ثيو abstract: objectives: this study was undertaken to assess the degree of agreement amongst obstetricians regarding decisions to perform emergency caesarean section (cs) procedures at a university hospital. methods: this retrospective clinical audit was carried out on 50 consecutive emergency cs procedures performed between november 2012 and march 2013 on women with singleton pregnancies at the sultan qaboos university hospital in muscat, oman. data on each procedure were collected from electronic patient records and independently reviewed by six senior obstetricians to determine agreement with the decision. results: of the 50 women who underwent cs procedures, the mean age was 28.9 ± 5.1 years and 48% were primigravidae. a total of 65% of the cs procedures were category i. the most common indications for a cs was a non-reassuring fetal heart trace (40%) and dystocia (32%). there was complete agreement on the decision to perform 62% of the cs procedures. five and four obstetricians agreed on 80% and 95% of the procedures, respectively. the range of disagreement was 4–20%. disagreement occurred primarily with category ii and iii procedures compared to category i. additionally, disagreement occurred in cases where the fetal heart trace pattern was interpreted as an indication for a category ii cs. conclusion: the majority of obstetricians agreed on the decisions to perform 94% of the emergency cs procedures. obstetric decision-making could be improved with the implementation of fetal scalp ph testing facilities, fetal heart trace interpretation training and cardiotocography review meetings. keywords: caesarean section; emergency; decision making; consensus; clinical audit; cardiotocography; fetal monitoring; oman. ط�رئة قي�رضية عملي�ت اإجراء بقرار يتعلق فيم� التوليد اأخ�ش�ئي بني االتف�ق درجة لتقييم الدرا�شة هذه اإجراء مت الهدف: امللخ�ص: واحد بجنني حلوامل متوالية ط�رئة قي�رضية عملية 50 على املرجعية ال�رضيرية الدرا�شة هذه اأجريت الطريقة: اجل�معة. م�شت�شفى يف من ح�لة لكل البي�ن�ت جمع مت عم�ن. �شلطنة م�شقط، يف ق�بو�ص ال�شلط�ن ج�معة مب�شت�شفى 2013 م�ر�ص اإىل 2012 نوفمرب في�لفرتة �شجالت املري�ص االإلكرتونية ومتت مراجعته� ب�شكل م�شتقل من قبل �شتة من اأخ�ش�ئيي التوليد لتحديد موافقتهم على القرار املتخذ ب�إجراء العملي�ت القي�رضية. النتائج: من الن�ش�ء اخلم�شني اللواتي اأجرين العملية القي�رضية واللواتي ك�ن متو�شط اأعم�رهن 5.1 ± 28.9 �شنة. 48% من ال�شيدات كن يف حملهن االأول. م� جممله %65 من هذه العملي�ت القي�رضية ك�ن من الفئة االأوىل. اأكرث دواعي اإجراء العملية القي�رضية ك�ن عدم االطمئن�ن اإىل تخطيط قلب اجلنني اأثن�ء الوالدة بن�شبة )%40( يتبعه تعرث تقدم الوالدة بن�شبة )%32(. االأخ�ش�ئيون ال�شتة وافقوا على اإجراء العملية يف %62 من احل�الت. خم�شة اأخ�ش�ئييني وافقوا على اجراء العملية القي�رضية يف %80 من احل�الت واأربعة يف %95 من احل�الت. مدى االختالف ك�ن %20-4. اأكرث االختالف ك�ن يف العملي�ت القي�رضية من الفئة الث�نية والث�لثة مق�رنة ب�لفئة االوىل. اإ�ش�فة اإىل ذلك ف�إن االختالف يف املق�م االأول حدث يف العملي�ت التي اجريت بداعي ا�شطراب�ت يف تخطيط �رضب�ت قلب اجلنني وهي عملي�ت قي�رضية من الفئة الث�نية. اخلال�صة: وافق غ�لبية االأطب�ء امل�ش�ركون يف هذه الدرا�شة على قرار اإجراء عملية قي�رضية يف %94 من احل�الت. وحتليل ميكن حت�شني عملية اتخ�ذ القرار بوجود معدات لقي��ص معدل حمو�شة فروة راأ�ص اجلنني، عمل دورات منتظمة يف كيفية قراءة نت�ئج جه�ز قي��ص ت�أثر نب�ش�ت قلب اجلنني واجتم�ع�ت ملراجعة تخطيط قلب اجلنني. مفتاح الكلمات: والدة قي�رضية؛ الطوارئ؛ اتخ�ذ القرار؛ ااّلراء؛ مراجعة �رضيرية؛ تخطيط قلب اجلنني؛ مراقبة اجلنني؛ عم�ن. decisions to perform emergency caesarean sections at a university hospital do obstetricians agree? silja a. pillai, gowri vaidyanathan, maryam al-shukri, tamima r. al-dughaishi, shahila tazneem, durdana khan, saniya el-tayeb, *mariam mathew clinical & basic research advances in knowledge this study is the first formal audit to assess peer agreement on the indications for performing emergency caesarean section (cs) procedures at a university hospital in oman. a high degree of agreement among peer obstetricians was noted for the majority of emergency cs decisions carried out during the study period. the findings of this study may serve to educate peers, junior colleagues and medical students on evidence-based indications for performing cs procedures. sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e42–46, epub. 2 feb 16 submitted 2 mar 15 revisions req. 25 may & 23 aug 15; revisions recd. 26 jul & 2 sep 15 accepted 10 sep 15 doi: 10.18295/squmj.2016.16.01.008 silja a. pillai, gowri vaidyanathan, maryam al-shukri, tamima r. al-dughaishi, shahila tazneem, durdana khan, saniya el-tayeb and mariam mathew clinical and basic research | e43 over the past two decades, there has been an increase in the caesarean section (cs) rate in the usa.1 this increase was noted among all women regardless of age, race, risk of complications, history of prior cs deliveries and among both preterm and full-term pregnancies.1 in 2010, the cs rate levelled off at 32.8% after steeply increasing for more than a decade.2 currently, approximately one in three mothers gives birth by cs delivery.2 an increase in cs rates is not necessarily beneficial to either the mother or fetus; in fact, the surgery may have harmful effects.3–5 according to althabe et al., cs rates of over 15% may increase maternal and neonatal morbidity.6 the findings of a report by a national non-profit organisation in the usa overwhelmingly support vaginal birth, particularly spontaneous vaginal birth, in the absence of compelling reasons to utilise other delivery methods.7 nevertheless, cs procedures have become more widely accepted due to advances in anaesthesia, newborn care and blood transfusions as well as in order to avoid litigation.8 the most common indications for a cs procedure include a nonreassuring fetal heart trace, labour dystocia, previous uterine scarring and fetal malpresentation.9 in oman, the cs rate gradually increased from 9.7% in 2000 to 15.7% in 2009.10,11 at the sultan qaboos university hospital (squh), a tertiary care university hospital in muscat, oman, the annual delivery rate was approximately 3,800 in 2013, with a cs rate of 18%.12 the cs rate is a key performance indicator for the department of obstetrics & gynaecology at squh; the aim is to keep the rate at 15%, if possible. this study aimed to assess the degree of agreement among six senior peer obstetricians regarding emergency cs decisions at squh. methods this retrospective clinical audit was conducted in squh between november 2012 and march 2013. a total of 50 consecutive emergency cs procedures performed in squh during the study period for women with singleton pregnancies were reviewed by six senior obstetricians to determine agreement with the decision to perform the procedure. women with multiple pregnancies and those who underwent elective cs procedures or emergency cs procedures due to malpresentation were excluded from the study. informed consent for the cs procedure was obtained from all patients prior to the surgery. all of the patients included in the study were monitored using continuous cardiotocography (ctg) at a speed of 1 cm/minute during the active phase of labour. fetal heart rate traces were categorised as normal, suspicious or pathological by the delivery ward team according to the royal college of obstetricians and gynaecologists (rcog) guidelines on intrapartum fetal monitoring.13 the cs procedures were categorised by urgency as per rcog guidelines as follows: category i (immediately life-threatening to mother or fetus), category ii (no immediate threat to mother or fetus) or category iii (requiring early delivery).14 the decision to perform a category i cs was made with a pathological trace, while a decision for a category ii cs was made by the senior registrar/ consultant on call following suspicious traces which did not respond to conservative measures. category iii procedures were performed when early delivery was indicated, as per the availability of resources. nonprogress of labour was defined as a failure to achieve progressive cervical dilatation and descent despite four hours of adequate uterine activity or six hours of oxytocin administration with inadequate uterine activity.15 electronic patient records were reviewed by four consultants and two senior registrars from the department of obstetrics & gynaecology at squh. each individual assessor collected and analysed information from each case, including maternal age, parity, body mass index (bmi), umbilical artery ph and past obstetric history as well as the ctg tracings, gestational age at delivery and apgar scores of the fetus. maternal and fetal outcomes and data on the cs indications and category were also reviewed. following their analysis, each of the six peer obstetricians were asked to answer either “yes” or “no” to the following question: “do you agree with the decision for performing the cs?” the range of agreement was calculated by a simple count of how many agreed or disagreed on the indications for each cs procedure. the obstetricians were not blinded and had full access to the hospital records. analysis of the data was performed using descriptive statistics. this study was approved by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #991). application to patient care the results of this study may help to reduce the cs rate and its associated morbidity in oman, which will subsequently reduce future costs within the healthcare sector. decisions to perform emergency caesarean sections at a university hospital do obstetricians agree? e44 | squ medical journal, february 2016, volume 16, issue 1 results of the 50 women included in the study, 48% were primigravidae and the rest were multiparae. the majority (66%) of the women were 21–30 years old (mean age: 28.9 ± 5.1 years). only one of the women was over 40 years old. most of the women (92%) delivered at full-term, while 8% had preterm deliveries. labour occurred spontaneously in 62% of the women; the remaining women either underwent induced labour (24%) or did not go into labour at all (14%). the birth weight of the neonates ranged from 1,500– 4,200 g (mean: 2,990 ± 700 g). one of the neonates had an umbilical artery ph of <7 and required a short period of observation after birth, although they recovered without any sequelae. the majority of the women (90%) had an uneventful postoperative period and were discharged on the third postoperative day. the most common morbidity was postpartum haemorrhage (10%). a blood transfusion was required for three women who were operated on for placenta praevia. there were two cases of postoperative pyrexia and one case each of pneumonic consolidation and wound infection. the categorisation of cs procedures based on urgency is shown in figure 1. the most common indications for emergency cs procedures were fetal distress as evidenced by a non-reassuring fetal heart trace (40%) and dystocia (32%). other indications included antepartum haemorrhage (8%), severe preeclampsia (6%) and fetal macrosomia (2%). of the 20 cases of fetal distress, 60% had pathological traces and 40% had suspicious traces. for cases of labour dystocia, 63% were operated on during the active phase of the first stage of labour while the remaining women underwent the cs procedure at full dilation. out of the 16 cases of labour dystocia, 15 women received oxytocin prior to the cs procedure. the mean time interval between the decision to perform the cs procedure and the delivery was 40.7 minutes for cases with non-reassuring fetal heart traces and 47.4 minutes for those with dystocia. complete agreement with the decision to perform cs procedures was reported by all six obstetricians for 62% of cases. five obstetricians agreed with 80% and four agreed with 95% of the decisions. there was a higher degree of agreement for category i cs procedures compared to categories ii and iii. the majority of the disagreements amongst peer obstetricians occurred when the indication for the cs procedure was a non-reassuring fetal heart trace (one obstetrician disagreed in three cases, two in three cases and three in one case), dystocia (one obstetrician disagreed in three cases and two in three cases) or fetal macrosomia (three obstetricians disagreed in one case). figure 2 shows the number of peer obstetricians who disagreed with the decision to perform a cs procedure according to selected cs indications. the frequency of disagreement with indications to perform cs procedures for each peer obstetrician is shown in figure 3. discussion several studies have shown an inverse association between cs rates and maternal and perinatal mortality at the population level in low-income countries where figure 1: categorisation by urgency* of consecutive emergency caesarean sections carried out at the sultan qaboos university hospital in muscat, oman, during the study period (n = 50). *category i procedures were performed due to immediate life-threatening indications to the mother or fetus, category ii procedures were performed when there was no immediate threat and category iii procedures were performed when early delivery was indicated.14 figure 2: disagreement among peer obstetricians according to the indication for a caesarean section (cs) among consecutive emergency cs procedures carried out at the sultan qaboos university hospital in muscat, oman, during the study period (n = 50). cs = caesarean section. silja a. pillai, gowri vaidyanathan, maryam al-shukri, tamima r. al-dughaishi, shahila tazneem, durdana khan, saniya el-tayeb and mariam mathew clinical and basic research | e45 large sectors of the population lack access to basic obstetric care.3,4,16,17 the world health organization (who) estimated the average cost of a cs procedure to be approximately usd $373 in countries with an excessive cs rate and usd $135 in countries with an optimal cs rate.18 as a result, cs procedures are approximately 2.8 times more expensive in countries which utilise the procedure excessively.18 the current cs rate at squh exceeds the recommended cs rate advocated by the who.19 this may be a result of the referral of high-risk patients to squh from primary and secondary care hospitals in oman. the current study was therefore undertaken as a measure of quality and to assess the scope for reducing the cs rate at squh, consequently reducing the morbidity and costs associated with this procedure. in the current study, cs procedures were classified into three categories according to the degree of urgency.14 the majority of the disagreements amongst peer obstetricians regarding decisions to perform emergency cs procedures occurred when the indication for the cs was a non-reassuring fetal heart trace or dystocia. this often occurred in cases where the fetal heart trace pattern was interpreted as an indication for a category ii cs. unnecessary cs procedures performed due to suspicious fetal heart traces generally occur because of limited knowledge regarding the ctg patterns that predict neonatal outcomes or due to the fear of medicolegal liability.20 review meetings designed to correctly interpret ctg traces may help to reduce the cs rate. in cases with non-reassuring fetal heart traces, resuscitative measures like maternal positioning, oxygen supplementation, correction of maternal hypotension and uterine hyperstimulation should be tried before the decision to perform a cs procedure is made. fetal heart rate acceleration in response to scalp stimulation is a recommended procedure to confirm that the fetus does not have acidosis.13,14 some evidence exists to indicate that fetal scalp sampling reduces the cs rate when the fetal heart trace is suspicious.21 however, fetal scalp ph testing is not favoured in certain institutions.15,20 additionally, scalp ph test kits are not easily available and many hospitals do not have the facilities to perform scalp ph estimations. although scalp ph estimation was previously performed at squh, it was stopped due to difficulties in obtaining the test kits. the american congress of obstetricians and gynecologists recommends that cs procedures performed due to active-phase labour arrest during the first stage of labour should be reserved for women with ruptured membranes who are at least 6 cm dilated and “who fail to progress despite 4 hours of adequate uterine activity, or at least 6 hours of oxytocin administration with inadequate uterine activity and no cervical change”.15 in the current study, 94% of the labour dystocia cases received a trial of oxytocin before the cs procedure was performed. according to delivery ward protocol at squh, partograms are maintained for all women in labour. four hours’ delay from the alert line of the partogram with good uterine contractions is considered to indicate arrest of labour in the active phase. however, this policy may not have been followed for all cases in the current study, as fetal heart tracing was perceived to be non-reassuring for some cases with dystocia. some of the other indications for cs observed in the current study included placenta praevia, severe pre-eclampsia and fetal macrosomia. fetal macrosomia was the third most common indication for a cs decision where the assessors had disagreement. the difficulties in estimating fetal weight clinically or by ultrasound are well-known. ultrasonography performed late in pregnancy to estimate fetal weight is associated with an increase in cs deliveries with no evidence of neonatal benefit.22 at squh, cs deliveries based on late-pregnancy ultrasonography are mostly performed to avoid medicolegal issues like shoulder dystocia and erb’s palsy in cases of suspected macrosomia. although a cs is indicated in cases where the estimated birth weight is ≥5,000 g or 4,500 g for babies born to non-diabetic and diabetic women, respectively, an accurate estimation of fetal weight is difficult, particularly in late gestation.22 patients should be made aware that shoulder dystocia can also occur with much smaller babies—especially among diabetic women—and that this may subsequently affect the decision to perform a cs for women with pregestational or gestational diabetes.22 as the number of cases in this audit was small, it was not possible to reach a clinically significant result. further studies with larger samples are recommended. figure 3: frequency of disagreement among individual peer obstetricians regarding decisions to perform emergency caesarean sections carried out at the sultan qaboos university hospital in muscat, oman, during the study period (n = 50). decisions to perform emergency caesarean sections at a university hospital do obstetricians agree? e46 | squ medical journal, february 2016, volume 16, issue 1 conclusion this audit was carried out to analyse emergency cs procedures performed at a university hospital in oman and to assess the degree of agreement among peer obstetricians with the decisions to perform these procedures. notably, disagreement mostly occurred with decisions to perform category ii cs procedures due to non-reassuring fetal heart traces. accordingly, fetal scalp ph testing facilities, cardiotocography review meetings and staff education and training sessions on the correct interpretation of fetal heart rate traces in labour are recommended to reduce cs rates. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. menacker f, declercq e, macdorman mf. cesarean delivery: background, trends, and epidemiology. semin perinatol 2006; 30:235–41. doi: 10.1053/j.semperi.2006.07.002. 2. hamilton be, martin ja, ventura sj. births: preliminary data for 2010. natl vital stat rep 2011; 60:1–26. 3. betrán ap, merialdi m, lauer ja, bing-shun w, thomas j, van look p, et al. rates of caesarean section: analysis of global, regional and national estimates. paediatr perinat epidemiol 2007; 21:98–113. doi: 10.1111/j.1365-3016.2007.00786.x. 4. althabe f, sosa c, belizán jm, gibbons l, jacquerioz f, bergel e. cesarean section rates and maternal and neonatal mortality in low-, medium-, and high-income countries: an ecological study. birth 2006; 33:270–7. doi: 10.1111/j.1523536x.2006.00118.x. 5. belizán jm, althabe f, cafferata ml. health consequences of the increasing caesarean section rates. epidemiology 2007; 18:485–6. doi: 10.1097/ede.0b013e318068646a. 6. althabe f, belizán jm. caesarean section: the paradox. lancet 2006; 368:1472–3. doi: 10.1016/s0140-6736(06)69616-5. 7. childbirth connection. vaginal or cesarean birth: what is at stake for women and babies? from: childbirthconnection.org/ pdfs/vaginalorcesareanbirth.pdf accessed: sep 2015. 8. sachs bp, kobelin c, castro ma, frigoletto f. the risks of lowering the cesarean-delivery rate. n engl j med 1999; 340:54–7. doi: 10.1056/nejm199901073400112. 9. barber el, lundsberg ls, belanger k, pettker cm, funai ef, illuzzi jl. indications contributing to the increasing cesarean delivery rate. obstet gynecol 2011; 118:29–38. doi: 10.1097/ aog.0b013e31821e5f65. 10. al busaidi i, al-farsi y, ganguly s, gowri v. obstetric and non-obstetric risk factors for cesarean section in oman. oman med j 2012; 27:478–81. doi: 10.5001/omj.2012.114. 11. directorate general of planning, oman ministry of health. annual health report 2009: chapter 7 utilisation of health services. muscat, oman: oman ministry of health, 2010. p. 2. 12. sultan qaboos university college of medicine & health sciences & sultan qaboos university hospital. annual report 2013. muscat, oman: sultan qaboos university printing press, 2014. p. 13. 13. royal college of obstetricians and gynaecologists. the use of electronic fetal monitoring: the use and interpretation of cardiotocography in intrapartum fetal surveillance. london, uk: rcog press, 2001. pp. 11–13. 14. royal college of obstetricians and gynaecologists. classi-fication of urgency of caesarean section: a continuum of risk. from: www.rcog.org.uk/globalassets/documents/guidelines/good practice11classificationofurgency.pdf accessed: sep 2015. 15. american congress of obstetricians and gynecologists. obstetric care consensus: safe prevention of the primary cesarean delivery. from: www.acog.org/resources-and-publi cations/obstetric-care-consensus-series/safe-prevention-ofthe-primary-cesarean-delivery accessed: sep 2015. 16. ronsmans c, holtz s, stanton c. socioeconomic differentials in caesarean rates in developing countries: a retrospective analysis. lancet 2006; 368:1516–23. doi: 10.1016/s0140-6736 (06)69639-6. 17. villar j, valladares e, wojdyla d, zavaleta n, carroli g, velazco a, et al. caesarean delivery rates and pregnancy outcomes: the 2005 who global survey on maternal and perinatal health in latin america. lancet 2006; 367:1819–29. doi: 10.1016/s0140-6736(06)68704-7. 18. gibbons l, belizán jm, lauer ja, betrán ap, merialdi m, althabe f. the global numbers and costs of additionally needed and unnecessary caesarean sections performed per year: overuse as a barrier to universal coverage. from: www. who.int/healthsystems/topics/financing/healthreport/30csectioncosts.pdf accessed: sep 2015. 19. world health organization. appropriate technology for birth. lancet 1985; 2:436–7. doi: 10.1016/s0140-6736(85)92750-3. 20. cahill ag, roehl ka, odibo ao, macones ga. association and prediction of neonatal acidemia. am j obstet gynecol 2012; 207:206.e1–8. doi: 10.1016/j.ajog.2012.06.046. 21. skupski dw, rosenberg cr, eglinton gs. intrapartum fetal stimulation tests: a meta-analysis. obstet gynecol 2002; 99:129–34. doi: 10.1016/s0029-7844(01)01645-3. 22. little se, edlow ag, thomas am, smith na. estimated fetal weight by ultrasound: a modifiable risk factor for cesarean delivery? am j obstet gynecol 2012; 207:309.e1–6. doi: 10.1016/j.ajog.2012.06.065. http://dx.doi.org/10.1053/j.semperi.2006.07.002 http://dx.doi.org/10.1111/j.1365-3016.2007.00786.x http://dx.doi.org/10.1111/j.1523-536x.2006.00118.x http://dx.doi.org/10.1111/j.1523-536x.2006.00118.x http://dx.doi.org/10.1097/ede.0b013e318068646a http://dx.doi.org/10.1016/s0140-6736%2806%2969616-5 http://childbirthconnection.org/pdfs/vaginalorcesareanbirth.pdf http://childbirthconnection.org/pdfs/vaginalorcesareanbirth.pdf http://dx.doi.org/10.1056/nejm199901073400112 http://dx.doi.org/10.1097/aog.0b013e31821e5f65 http://dx.doi.org/10.1097/aog.0b013e31821e5f65 http://dx.doi.org/10.5001/omj.2012.114 http://www.rcog.org.uk/globalassets/documents/guidelines/good%0apractice11classificationofurgency.pdf http://www.rcog.org.uk/globalassets/documents/guidelines/good%0apractice11classificationofurgency.pdf http://www.acog.org/resources-and-publications/obstetric-care-consensus-series/safe-prevention-of-the-primary-cesarean-delivery http://www.acog.org/resources-and-publications/obstetric-care-consensus-series/safe-prevention-of-the-primary-cesarean-delivery http://www.acog.org/resources-and-publications/obstetric-care-consensus-series/safe-prevention-of-the-primary-cesarean-delivery http://dx.doi.org/10.1016/s0140-6736%2806%2969639-6 http://dx.doi.org/10.1016/s0140-6736%2806%2969639-6 http://dx.doi.org/10.1016/s0140-6736%2806%2968704-7 http://www.who.int/healthsystems/topics/financing/healthreport/30c-sectioncosts.pdf http://www.who.int/healthsystems/topics/financing/healthreport/30c-sectioncosts.pdf http://www.who.int/healthsystems/topics/financing/healthreport/30c-sectioncosts.pdf http://dx.doi.org/10.1016/s0140-6736%2885%2992750-3 http://dx.doi.org/10.1016/j.ajog.2012.06.046 http://dx.doi.org/10.1016/s0029-7844%2801%2901645-3 http://dx.doi.org/10.1016/j.ajog.2012.06.065 1department of forensic medicine, legal medicine research center, tehran, iran; departments of 2anatomy and 3forensic medicine, tehran university of medical sciences, tehran, iran *corresponding author e-mail: bbehnoush@tums.ac.ir مضاعفات القلب واألوعية الدموية الناجتة عن إساءة تعاطي منبهات األمفيتامني دراسة مستعرضة اإلهام بازمي, فاريناز م��ضايف, ليلى جيا�ضن, تهمينة خمتاري, بهنام بهن��ص abstract: objectives: this study aimed to evaluate cardiovascular complications among patients who abuse amphetamines. methods: this cross-sectional study took place between april 2014 and april 2015 among 3,870 patients referred to the toxicology emergency department of baharlou hospital, tehran university of medical sciences, tehran, iran. those with clinical signs of drug abuse and positive urine screening tests were included in the study, while cases of chronic abuse were excluded. cardiac complications were evaluated via electrocardiography (ecg) and transthoracic echocardiography. results: a total of 230 patients (5.9%) had a history of acute amphetamine abuse and positive urine tests. of these, 32 patients (13.9%) were <20 years old and 196 (85.2%) were male. in total, 119 (51.7%) used amphetamine and methamphetamine compounds while 111 (48.3%) used amphetamines with morphine or benzodiazepines. the most common ecg finding was sinus tachycardia (43.0%), followed by sinus tachycardia plus a prolonged qt interval (34.3%). mean creatine kinase-mb and troponin i levels were 35.9 ± 4.3 u/ml and 0.6 ± 0.2 ng/ml, respectively. a total of 60 patients (26.1%) were admitted to the intensive care unit. the majority (83.3%) of these patients had normal echocardiography results. the mean aortic root diameter (ard) was 27.2 ± 2.8 mm. abnormalities related to the ard were found in 10 patients (16.7%), three of whom subsequently died. conclusion: according to these findings, cardiac complications were common among iranian patients who abuse amphetamines, although the majority of patients had normal echocardiography and ecg findings. keywords: amphetamines; substance abuse; cardiovascular abnormalities; tachycardia; echocardiography; electrocardiography; iran. االأمفيتامينات. يتعاط�ن الذين املر�ضى لدى الدم�ية واالأوعية القلب جهاز م�ضاعفات تقييم اإىل الدرا�ضة هذه هدفت الهدف: امللخ�ص: الطريقة: متت هذة الدرا�ضة امل�ضتعر�ضة يف الفرتة ما بني اأبريل 2014 واأبريل 2015 وت�ضمنت 3,870 مري�ضًا مت حت�يلهم اإىل ق�ضم ط�ارئ ال�ضم�م يف م�ضت�ضفى باهارل� بجامعة طهران للعل�م الطبية باإيران. وقد مت قب�ل املر�ضى يف هذه الدرا�ضة اإذا كان لديهم عالمات �رسيرية لتعاطي املخدرات وفح��ضات اإيجابية للب�ل, بينما مت ا�ضتبعاد حاالت التعاطي املزمن. مت فح�ص امل�ضاعفات القلبية عن طريق جهاز تخطيط القلب الكهربائي وتخطيط القلب عن طريق ال�ضدر بال�ضدى. النتائج: كان هناك اجمايل 230 مري�ضًا ي�ضكل�ن ن�ضبة )%5.9( من جميع املر�ضى ِمن َمن يتعاط�ن االأمفيتامني وكانت فح��ضات الب�ل عندهم اإيجابية, من بني ه�ؤالء كان عدد 32 )%13.9(مري�ضًا منهم االأمفيتامني م�ضتخدمي من مري�ضًا )51.7%( 119 عدد جمماًل هناك وكان الذك�ر. من مري�ضًا )85.2%( 196 وعدد الع�رسين �ضن دون ومركبات امليثامفيتامني, بينما كان 111 )%48.3( مري�ضًا ِمن َمن ي�ضتخدم�ن االأمفيتامينات اإ�ضافًة اإىل امل�رفني اأو البنزوديازيبينات. اأظهرت النتائج اأن اأكرث م�ضاعفات القلب �ضي�عًا ح�ضب تخطيط القلب هي ت�رّسع القلب اجليبي بن�ضبة )%43.0(, يليها ت�رّسع القلب اجليبي امل�ضاحب با�ضتطالة فرتة qt الفا�ضلة )%34.3(. كان مت��ضط الكرياتني كاينيز-mb مقداره 4.3 ـ± 35.9 وحدة والرتوب�نني 0.2 ـ± 0.6 مليليرت. مت اإدخال ما جمم�عه )%26.1( 60 مري�ضًا اإىل وحدة العناية املركزة. وكانت نتائج فح��ضات القلب بال�ضدى طبيعية الأغلبية ه�ؤالء املر�ضى )%83.3(. كما كان مت��ضط قطر جذر ال�رسيان االأبهر مقداره 2.8 ± 27.2 مليمرت. وقد وجدت ت�ض�هات متعلقة بجذر ال�رسيان االأبهر يف 10 مر�ضى )%16.7(, ت�يف ثالثة منهم الحقا. اخلال�صة: وفقًا لهذه النتائج ي�ضتنتج اأن امل�ضاعفات القلبية هي االأكرث �ضي�عًا بني املر�ضى االإيرانيني الذين ي�ضي�ؤون تعاطي االأمفيتامينات, لكن بالرغم من ذلك فاإن اأغلبية املر�ضى كان نتائج فح��ضات القلب بالتخطيط الكهربائي وبال�ضدى عندهم طبيعية. بال�ضدى؛ القلب تخطيط القلب؛ دقات ت�رّسع الدم�ية؛ واالأوعية القلب ت�ض�هات الكيميائية؛ امل�اد تعاطي االأمفيتامينات؛ املفتاحية: الكلمات تخطيط القلب الكهربائي؛ اإيران. cardiovascular complications of acute amphetamine abuse cross-sectional study elham bazmi,1 farinaz mousavi,1 leila giahchin,1 tahmineh mokhtari,2 *behnam behnoush3 clinical & basic research advances in knowledge among iranian patients, the most common cardiac abnormality following acute amphetamine abuse was sinus tachycardia followed by sinus tachycardia plus prolonged qt intervals. application to patient care the findings of this study may be used by emergency physicians to increase awareness of the potential cardiovascular complications of acute amphetamine abuse. sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e31–37, epub. 30 mar 17 submitted 9 aug 16 revisions req. 5 sep & 20 oct 16; revisions recd. 5 & 27 oct 16 accepted 10 nov 16 doi: 10.18295/squmj.2016.17.01.007 cardiovascular complications of acute amphetamine abuse cross-sectional study e32 | squ medical journal, february 2017, volume 17, issue 1 psychoactive drug dependence/abusehas become an increasing problem worldwide, with adverse physical, familial, social, mental and financial consequences.1 in iran, patterns of drug abuse have changed immensely in recent years, with drug use shifting from traditional opioids to new artificial opioids.2 moreover, the incidence of drug poisoning and toxicity due to the abuse of psychoactive drugs—such as amphetamines—has increased among younger individuals.3 acute use of amphetamines results in increased brain activity and a feeling of euphoria; however, chronic use of these compounds can lead to psychological dependency, loss of appetite, depression, aggressive behaviour, irritability and sleep, memory and mood disorders.1 in addition, amphetamine abuse may lead to increased stimulation of the sympathetic nervous system, which could in turn lead to hypertension, hyperthermia, subarachnoid haemorrhage and ventricular dysrhythmias, sometimes resulting in death.4 depending on the type and form of the drug, central nervous system stimulants can be imbibed orally, injected, smoked or snorted. direct injection of the stimulant into the blood stream or inhalation into the lungs enables the more rapid onset of the drug’s effects.5 the stimulants increase the synaptic concentration of neural mediators (especially adrenaline, dopamine and serotonin), stimulating these mediators and inhibiting their reuptake. amphetamine compounds stimulate the central and peripheral nervous systems, increasing catecholamine secretion and inhibiting their reuptake. at the synapse, the catecholamines lead to excessive cardiac stimulation and an increased heart rate.1 amphetamine compounds have good oral absorption and a wide range of distribution sizes (3–33 l/kg); they are primarily metabolised by the liver and excreted in acidic urine.1 cardiac complications are an important issue in the context of drug toxicity. hypertension is the most common cardiovascular result of central nervous system stimulants.1 with oral amphetamines, systolic and diastolic blood pressure increases, while heart rate decreases. the cardiovascular effect of the laevus isomer in amphetamines is greater than that of the dexter isomer.6 chest pains, dysrhythmias, acute coronary syndrome, acute cardiac infarctions, vasospasms, irreversible cardiomyopathy and acute pulmonary oedema are among the cardiovascular manifestations of toxicity arising from psycho active drugs.7 this study aimed to evaluate cardiovascular complications among iranian patients who abuse amphetamines. methods this descriptive cross-sectional study took place between april 2014 and april 2015 among 3,870 patients referred to the toxicology emergency department of baharlou hospital, tehran university of medical sciences, tehran, iran. only those individuals with positive urine drug screening test results and a history of acute amphetamine abuse were included in the study. patients with a history of underlying cardiovascular disease or a family history of cardiac disease and those with diabetes mellitus, proven hypertension or hyperlipidaemia were excluded from the study. in addition, chronic drug users without any evidence of recent abuse were not included. a predesigned checklist was used to collect existing data, including the demographic characteristics and laboratory and clinical findings of the patients. rapid urine drug screening tests (acon laboratories inc., san diego, california, usa) were performed. following this, blood samples were taken from each patient. patients were evaluated using cardiac and vital sign monitoring, routine laboratory examinations and cardiac biomarker tests, including levels of troponin i (aia-360 benchtop immunoassay analyser, tosoh bioscience, san francisco, california, usa) and creatinine kinase (ck)-mb (architect system stat ck-mb chemiluminescent microparticle immunoassay, abbott diagnostics, wiesbaden, germany). normal cut-off troponin i and ck-mb levels were set at 0.1 ng/ml and 24.0 u/ml respectively, as per the manufacturers’ recommendations. cardiac complications were evaluated via electrocardiography (ecg) and transthoracic echocardiography (tte). all ecg and tte scans were performed by an emergency physician. each patient underwent three ecg recordings to measure the following variables: heart rate, rhythm, qt interval (intervals of >0.44 milliseconds were considered prolonged), supraventricular and ventricular arrhythmias, atrioventricular and ventricular cardiac blocks, tall t-waves and myocardial ischaemia (i.e. st segment and t-wave changes).8 tachycardia was defined as a heart rate of >100 beats/minute.1 moreover, for patients admitted to the intensive care unit (icu) due to tachycardia or very abnormal ecg findings, additional echocardiography was performed to measure their ejection fraction (ef), regional wall motion abnormalities, aortic root diameter (ard), cardiac wall size (including right ventricular enddiastolic volume, left ventricle end-systolic volume, left ventricular end-diastolic volume, left ventricular elham bazmi, farinaz mousavi, leila giahchin, tahmineh mokhtari and behnam behnoush clinical and basic research | e33 end-diastolic pressure [lvedp], left ventricular enddiastolic diameter [lvedd] and left ventricle endsystolic diameter [lvesd]) and other abnormalities. data were analysed using the statistical package for the social sciences (spss), version 22 (ibm corp., chicago, illinois, usa). chi-squared, analysis of variance, student’s t-test, mann-whitney u and kruskal-wallis tests were performed, as appropriate. a p value of <0.050 was considered statistically significant. interquartile ranges and correlations were also calculated. ethical approval for this study was granted by the tehran university of medical sciences. prior to being enrolled in the study, all of the patients gave conscious informed consent. if the competency of the patient was in doubt, informed consent was given by a relative. data confidentiality and security were ensured throughout the study period. results of the 3,870 patients referred to the toxicology emergency department during the study period, 460 (11.9%) had a history of amphetamine use. among these, 395 cases (10.2%) had positive urine drug screening results; however, 165 cases (4.3%) were excluded due to a history of chronic abuse. therefore, a total of 230 patients (5.9%) were enrolled in the study. the mean age of the participants was 34.4 ± 11.4 years (range: 15–68 years old) and the majority were male (85.2%). amphetamines were smoked by 161 patients (70.0%), taken orally by 20 patients (8.7%), injected by 10 patients (4.3%) and taken via a combination of methods by 39 patients (17.0%). a total of 119 patients (51.7%) used amphetamines in combination with methamphetamine compounds while 111 (48.3%) used amphetamines with morphine or benzodiazepines. the referral time to the emergency ward was ≤6 hours of use for 174 patients (75.7%) and >6 hours of use for 56 patients (24.3%) [table 1]. the ecg results were normal for 104 patients (45.2%). sinus tachycardia was observed in 99 patients (43.0%), while 34.3% of patients had sinus tachycardia plus a prolonged qt interval. arrhythmias were table 1: characteristics of patients referred to a toxicology emergency department following acute amphetamine abuse in tehran, iran (n = 230) characteristic n (%) age in years <20 32 (13.9) 21–30 86 (37.4) 31–40 62 (27.0) 41–50 33 (14.3) >50 17 (7.4) gender male 196 (85.2) female 34 (8.7) drugs taken amphetamine and methamphetamine 119 (51.7) amphetamine and morphine/benzodiazepines 111 (48.3) method of drug administration smoking 161 (70.0) oral 20 (8.7) injection 10 (4.3) combination 39 (17.0) time to admission in hours 0–6 174 (75.7) >6 56 (24.3) agitation present 131 (57.0) absent 99 (43.0) ecg finding* normal 104 (45.2) sinus tachycardia 99 (43.0) sinus tachycardia plus prolonged qt interval 79 (34.3) arrhythmia 8 (3.5) arrhythmia plus first-degree atrioventricular block 6 (2.6) tall t-wave 4 (1.7) arrhythmia, st segment elevation plus anterior mi 4 (1.7) arrhythmia plus st segment elevation 3 (1.3) st segment elevation 1 (0.4) anterior mi 1 (0.4) mean bp ± sd systolic bp in mmhg 129.9 ± 4.2 diastolic bp in mmhg 82.1 ± 3.4 mean hr in beats/minute 109.1 ± 9.3 mean ck-mb level in u/ml 35.9 ± 4.3 mean troponin i level in ng/ml 0.6 ± 0.2 ecg = electrocardiography; mi = myocardial infarction; bp = blood pressure; sd = standard deviation; hr = heart rate; ck-mb = creatinine kinase-mb. *patients with more than one abnormality have been included in several categories. cardiovascular complications of acute amphetamine abuse cross-sectional study e34 | squ medical journal, february 2017, volume 17, issue 1 observed in eight patients (3.5%). other cardiac abnormalities included arrhythmias plus a first-degree atrioventricular block (2.6%), tall t-waves (1.7%), arrhythmias, st segment elevation plus anterior myocardial infarctions (1.7%), arrhythmias plus st segment elevation (1.3%), anterior myocardial infarctions (0.4%) and st segment elevation (0.4%). mean ck-mb and troponin i levels were 35.9 ± 4.3 u/ml and 0.6 ± 0.2 ng/ml, respectively [table 1]. for the patients with arrhythmias, this complication was followed by ventricular tachycardia, premature atrial contractions, paroxysmal supraventricular tachycardia and premature ventricular contractions. a total of 60 patients were admitted to the icu; of these, the majority were 21–30 years old (28.3%). mean lvedd and lvesd measurements were 45.4 ± 4.4 mm (range: 39–56 mm) and 29.2 ± 3.5 mm (range: 22–36 mm), respectively. mean lvedd measurements were significantly higher in patients who were >50 years old (p = 0.034). although there was no significant difference in lvesd measurements among age groups (p = 0.433), the highest value was observed in patients between 41–50 years old. the mean lvedp value was 8.5 ± 3.5 mmhg (range: 6–10 mmhg) and there was a significant difference in lvedp value according to age group (p = 0.042), with the highest values noted in patients <20 years old and >50 years old. the highest mean ef was observed in patients <20 years old and the lowest mean ef was found in patients aged 31–40 years old (p = 0.012). the mean ard was 27.2 ± 2.8 mm (range: 22–32 mm) with a significant difference according to age group (p = 0.032). patients >50 years of age had the highest mean ard and patients <20 years old had the lowest mean ard [table 2]. of the 60 patients admitted to the icu, the majority had normal echocardiography findings (83.3%). however, four patients (6.7%) had left ventricular systolic and/or diastolic dysfunction. the most common abnormality of the cardiac valves was related to the mitral valve (mv); 21.7% of patients had mild mv regurgitation, 3.3% had moderate mv regurgitation and 3.3% had mv prolapse. tricuspid regurgitation and mild aortic regurgitation were found in 3.3% and 1.7% of patients, respectively. right ventricular function was abnormal in two patients (3.3%). anterior akinaesia and pulmonary hypertension plus cor pulmonale were each reported table 2: selected echocardiographic measurements according to age group among patients admitted to an intensive care unit following acute amphetamine abuse in tehran, iran (n = 60) mean ± sd age in years p value <20 (n = 6) 21–30 (n = 17) 31–40 (n = 15) 41–50 (n = 5) >50 (n = 17) rvesv in ml/m2 24.3 ± 3.2 25.1 ± 3.4 28.1 ± 3.4 26.6 ± 3.5 26.2 ± 3.7 0.144 lvedd in mm 43.2 ± 4.4 43.5 ± 4.3 46.6 ± 4.5 43.8 ± 4.6 47.7 ± 4.7 0.034 lvesd in mm 28.8 ± 3.2 29.8 ± 3.4 29.1 ± 3.6 30.4 ± 3.5 28.6 ± 3.7 0.433 ef in % 54.2 ± 5.8 50.6 ± 5.6 48.2 ± 5.5 50.1 ± 5.5 48.8 ± 5.2 0.012 lvedp in mmhg 8.8 ± 3.4 8.3 ± 3.7 8.4 ± 3.5 8.4 ± 3.2 8.8 ± 3.5 0.042 ard in mm 24.8 ± 2.4 26.3 ± 2.7 25.7 ± 2.6 28.8 ± 2.9 29.7 ± 3.3 0.032 sd = standard deviation; rvesv = right ventricle end-systolic volume; lvedd = left ventricular end-diastolic diameter; lvesd = left ventricle endsystolic diameter; ef = ejection fraction; lvedp = left ventricular end-diastolic pressure; ard = aortic root diameter. table 3: cardiac function according to echocardiography among patients admitted to an intensive care unit following acute amphetamine abuse in tehran, iran (n = 60) finding n (%) normal 50 (83.3) lvs or lvd dysfunction alone 5 (8.3) lvs and lvd dysfunction combined 1 (1.7) anterior akinaesia 3 (5.0) pah plus cor pulmonale 1 (1.7) rv function normal 58 (96.7) abnormal 2 (3.3) mv dysfunction normal 43 (71.7) mild regurgitation 13 (21.7) moderate regurgitation 2 (3.3) prolapse 2 (3.3) other valvular dysfunctions none 57 (95.0) tricuspid regurgitation 2 (3.3) mild aortic regurgitation 1 (1.7) lvs = left ventricular systolic; lvd = left ventricular diastolic; pah = pulmonary artery hypertension; rv = right ventricular; mv = mitral valve. elham bazmi, farinaz mousavi, leila giahchin, tahmineh mokhtari and behnam behnoush clinical and basic research | e35 in 1.7% of patients, respectively [table 3]. right ventricular wall movement abnormalities was noted only among patients who were 30–39 years old and >50 years old. in addition, abnormal right ventricular function was seen only among those aged 30–39 years old [table 4]. unfortunately, 10 patients (16.7%) died among those admitted to the icu. while left ventricular end-diastolic volume and diameter values were normal in all of the admitted patients, two living patients (3.3%) and one deceased patient (1.7%) had abnormal interventricular systolic diameters. moreover, abnormal ef was noted in four of the patients who died (6.7%) and three living patients (5.0%), with abnormal ef significantly more prevalent among the deceased patients (p = 0.011). the ard was abnormal in seven living patients and three deceased patients (11.7% versus 5.0%; p = 0.211) [table 5]. the frequency of severe right ventricle end-diastolic volume disorder was higher among the deceased patients than the survivors (10.0% versus 2.0%) [table 6]. discussion according to the findings of the current study, amphetamine abuse occurred mostly among individuals aged 21–40 years old (64.4%), with fewer participants being <20 years old (13.9%) or >41 years old (21.7%). other studies have shown that drug abuse is more prevalent among young people.9,10 barooni et al. found that 18.5% of young adults who went to coffee shops in tehran had a history of psychoactive drug abuse, in the form of ecstasy abuse.3 as with the present study, previous research has indicated that the mean age of drug abusers is low in iran.11,12 a study of drug abuse cases in taiwan reported a mean age of 26.7 years among those who abused drugs for the first time.13 in a study of methamphetamine-related fatalities in australia, kaye et al. found that the mean age of patients was 32.7 years and that 77% were male.14 in the current study, the vast majority of the subjects were male (85.2%). other researchers have also reported more frequent drug abuse practices among men.13,15,16 in the current study, approximately half of the patients exclusively used amphetamine and methamphetamine, while the rest used other drugs in combination with amphetamines. in addition, most patients administered the drugs via inhalation. kaye et al. found that 89% of their subjects had used drugs other from methamphetamine, including benzodiazepines (41%) and morphine (36%).14 moreover, administration of amphetamine is usually reported to be intravenous.14,17 in the current study, 10 patients (4.3%) died after being admitted to the icu, presumably due to drug-related toxicity. knudsen et al. reported an amphetamine-related mortality rate of 12.3% among γ-hydroxybutyrate poisoning cases in sweden.18 troponin i and ck-mb levels were very high among amphetamine users in the present study, indicating table 4: right ventricular wall mobility and function abnormalities according to age group among patients admitted to an intensive care unit following acute amphetamine abuse in tehran, iran (n = 60) n (%) right ventricular wall motion abnormalities right ventricular function normal abnormal normal abnormal age in years <20 6 (10.0) 0 (0.0) 6 (10.0) 0 (0.0) 21–29 17 (28.3) 0 (0.0) 17 (28.3) 0 (0.0) 30–39 13 (21.7) 2 (3.3) 13 (21.7) 2 (3.3) 40–41 5 (8.3) 0 (0.0) 5 (8.3) 0 (0.0) >50 16 (26.7) 1 (1.7) 17 (28.3) 0 (0.0) total 57 (95.0) 3 (5.0) 58 (96.7) 2 (3.3) table 5: echocardiographic findings among deceased and living patients admitted to an intensive care unit following acute amphetamine abuse in tehran, iran (n = 60) finding n (%) p value living patients (n = 50) deceased patients (n = 10) lvedv 0 (0.0) 0 (0.0) ivsd 2 (3.3) 1 (1.7) 0.427 lvedd 0 (0.0) 0 (0.0) abnormal ef 3 (5.0) 4 (6.7) 0.011 ard 7 (11.7) 3 (5.0) 0.212 lvedv = left ventricle end-diastolic volume; ivsd = interventricular systolic diameter, lvedd = left ventricular end-diastolic diameter; ef = ejection fraction; ard = aortic root diameter. table 6: frequency of right ventricle end-diastolic volume disorder among deceased and living patients admitted to an intensive care unit in tehran, iran, following acute amphetamine abuse (n = 60) classification n (%) living patients (n = 50) deceased patients (n = 10) normal 42 (84.0) 9 (90.0) fair 7 (14.0) 0 (0.0) moderate 0 (0.0) 0 (0.0) severe 1 (2.0) 1 (10.0) cardiovascular complications of acute amphetamine abuse cross-sectional study e36 | squ medical journal, february 2017, volume 17, issue 1 cardiac damage; these findings were consistent with those of various previously published research.19–22 in a case report, khattab et al. described a 54-year-old man with chest pains after amphetamine use, increased troponin i and ck-mb levels and complete obstruction of the left circumflex coronary artery due to acute thrombosis.23 the most commonly observed abnormal ecg findings in the current study were sinus tachycardia (43.0%) and sinus tachycardia plus a prolonged qt interval (34.3%). haning et al. observed prolonged qt intervals among 27.2% of patients abusing methamphetamines in the usa.24 other researchers have reported various arrhythmias associated with the use of amphetamines or other psychoactive drugs, such as qt interval fluctuations, right bundle branch block and st segment changes, particularly st segment elevation.25–28 westover et al. found a significant relationship between acute myocardial infarction and amphetamine abuse.29 moreover, kaye et al. found use of amphetamines to be associated with high pathological cardiac risk; however, this was possibly due to the presence of preexisting chronic disorders and hence not limited to amphetamine use.14 according to tte findings in the current study, left ventricular systolic dysfunction was noted in three cases, abnormal ef in seven cases and abnormal ard in 10 cases; additionally, right ventricle enddiastolic volume disorder was observed among both living and deceased patients admitted to the icu. to the best of the authors’ knowledge, no similar studies have been published in which amphetamine users were evaluated using echocardiographical parameters. however, various case reports have shown different cardiac abnormalities following abuse of amphetamine, such as reverse takotsubo cardiomyopathy.30 yeo et al. reported that cardiomyopathy was related to methamphetamine use among young adults in hawaii.31 moreover, wijetunga et al. found that 84% of crystal methamphetamine users had cardiomyopathy and global ventricular disorders.32 in another study, maeno et al. found that methamphetamine use directly led to cellular hypertrophy and could potentially result in disorders of cardiac function among adult rats.33 varner et al. demonstrated that methamphetamine administration could significantly change cardiovascular responses and lead to severe cardiac pathology; moreover, they also showed that methamphetamine elicited biphasic heart rate responses consisting of initial bradycardia followed by tachycardia.34 according to a review of methamphetamine-induced cardiac complications by paratz et al., dilated, hypertrophic and stress cardiomyopathies are the most common methamphet amine-associated cardiomyopathies.35 additionally, intranasal administration of d-amphetamine reportedly lead to a more rapid response compared with oral administration.5 this study is subject to certain limitations. although the statistical significance of the findings in this study could not be determined due to the small sample size, these findings may pave the way for future research focusing on echocardiography findings among amphetamine users. also, as there are few studies in the current literature on this topic, it was difficult to compare the findings of this study with those of previous research. in the current study, most of the subjects were referred to the hospital in the acute phase of drug abuse and the researchers did not have access to each patient’s prior medical history relating to heart disease. as such, distinguishing heart problems due to drug abuse from those resulting from pre-existing cardiac disorders was not possible. in addition, most of the patients who were admitted did not consent to undergo echocardiography. another limitation of this study was the lack of a control group with which to compare results. more studies are needed to assess the true pathogenicity of amphetamine abuse. conclusion although the majority of patients had normal tte and ecg scans, cardiac complications were common among iranian patients who abuse amphetamines, particularly sinus tachycardia and sinus tachycardia plus prolonged qt intervals. emergency physicians should therefore be aware of these as potential cardiovascular complications of acute amphetamine abuse. a c k n o w l e d g e m e n t s this study was based on findings from a thesis submitted to the tehran university of medical sciences in 2015 (giahchin l. evaluation of cardiovascular complications of acute amphetamine abuse in bahailoo hospital: cross-sectional study. thesis, 2015, tehran university of medical sciences, tehran, iran.) c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. elham bazmi, farinaz mousavi, leila giahchin, tahmineh mokhtari and behnam behnoush clinical and basic research | e37 references 1. hoffman rs, howland ma, lewin na, nelson ls, goldfrank lr. goldfrank’s toxicologic emergencies, 10th ed. new york, usa: mcgraw-hill, 2014. pp. 2429–56. 2. baheiraei a, hamzehgardeshi z, mohammadi mr, nedjat s, mohammadi e. alcohol and drug use prevalence and factors associated with the experience of alcohol use in iranian adolescents. iran red crescent med j 2013; 15:212–17. doi: 10. 5812/ircmj.4022. 3. barooni sh, mehrdad r, akbari e. [survey of ecstasy use among 15-25 year-olds in five areas of tehran]. tehran univ med j 2008; 11:49–54. 4. dimaio vj, dimaio d. forensic pathology, 2nd ed. boca raton, florida, usa: crc press, 2001. pp. 501–26. 5. kirkpatrick mg, gunderson ew, johanson ce, levin fr, foltin rw, hart cl. comparison of intranasal methamphetamine and d-amphetamine self-administration by humans. addiction 2012; 107:783–91. doi: 10.1111/j.13600443.2011.03706.x. 6. shannon mw, borron sw, burns mj. haddad and winchester’s clinical management of poisoning and drug overdose, 4th ed. amsterdam, netherlands: saunders, 2007. p. 782. 7. karch sb, drummer o. karch’s pathology of drug abuse, 4th ed. boca raton, florida, usa: crc press, 2008. pp. 261–312. 8. simonson e, cady ld jr, woodbury m. the normal q-t interval. am heart j 1962; 63:747–53. doi: 10.1016/00028703(62)90059-5. 9. gonzales r, mooney l, rawson ra. the methamphetamine problem in the united states. annu rev public health 2010; 31:385–98. doi: 10.1146/annurev.publhealth.012809.103600. 10. mcketin r, kozel n, douglas j, ali r, vicknasingam b, lund j, et al. the rise of methamphetamine in southeast and east asia. drug alcohol rev 2008; 27:220–8. doi: 10.10 80/09595230801923710. 11. momtazi s, rawson r. substance abuse among iranian high school students. curr opin psychiatry 2010; 23:221–6. doi: 10.1097/yco.0b013e328338630d. 12. amiri zm, shakib aj, moosavi ak. prevalence and risk factors of ecstasy use among college students in astara, islamic republic of iran. east mediterr health j 2009; 15:1192–200. 13. hsu j, lin jj, tsay wi. analysis of drug abuse data reported by medical institutions in taiwan from 2002 to 2011. j food drug anal 2014; 22:169–77. doi: 10.1016/j.jfda.2014.01.019. 14. kaye s, darke s, duflou j, mcketin r. methamphetamine‐ related fatalities in australia: demographics, circumstances, toxicology and major organ pathology. addiction 2008; 103:1353–60. doi: 10.1111/j.1360-0443.2008.02231.x. 15. vollenweider fx, liechti me, gamma a, greer g, geyer m. acute psychological and neurophysiological effects of mdma in humans. j psychoactive drugs 2002; 34:171–84. doi: 10.1080/ 02791072.2002.10399951. 16. becker jb, hu m. sex differences in drug abuse. front neuroendocrinol 2008; 29:36–47. doi: 10.1016/j.yfrne.2007. 07.003. 17. kaye s, mcketin r, duflou j, darke s. methamphetamine and cardiovascular pathology: a review of the evidence. addiction 2007; 102:1204–11. doi: 10.1111/j.1360-0443.2007.01874.x. 18. knudsen k, greter j, verdicchio m. high mortality rates among ghb abusers in western sweden. clin toxicol (phila) 2008; 46:187–92. doi: 10.1080/15563650701263633. 19. pozoga j, snopek g, dabrowski m. [acute coronary syndrome after amphetamine use in a young male with myocardial bridging: a case report]. kardiol pol 2005; 62:381–2. 20. chen jp. methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary arteries: refractory global coronary microvascular spasm. j invasive cardiol 2007; 19:e89–92. 21. brennan k, shurmur s, elhendy a. coronary artery rupture associated with amphetamine abuse. cardiol rev 2004; 12:282–3. doi: 10.1097/01.crd.0000132372.38506.45. 22. wang q, michiue t, ishikawa t, zhu bl, maeda h. combined analyses of creatine kinase mb, cardiac troponin i and myoglobin in pericardial and cerebrospinal fluids to investigate myocardial and skeletal muscle injury in medicolegal autopsy cases. legal med (tokyo) 2011; 13:226–32. doi: 10.1016/j. legalmed.2011.05.002. 23. khattab e, shujaa a. amphetamine abuse and acute thrombosis of left circumflex coronary artery. int j case rep imag 2013; 4:698–701. doi: 10.5348/ijcri-2013-12-414-cr-8. 24. haning w, goebert d. electrocardiographic abnormalities in methamphetamine abusers. addiction 2007; 102:70–5. doi: 10.1111/j.1360-0443.2006.01776.x. 25. sinha a, lewis o, kumar r, yeruva sl, curry bh. amphetamine abuse related acute myocardial infarction. case rep cardiol 2016; 2016:7967851. doi: 10.1155/2016/7967851. 26. samuels si, maze a, albright g. cardiac arrest during cesarean section in a chronic amphetamine abuser. anesth analg 1979; 58:528–30. doi: 10.1213/00000539-197911000-00021. 27. awudu ga, besag fm. cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder: an update. drug saf 2014; 37:661–76. doi: 10.1007/s40264-0140201-8. 28. chia-yu chang j, peng cz, how ck, huang ms. an unusual case of silent acute st-elevation myocardial infarction following amphetamine use. pak j med sci 2013; 29:1059–61. doi: 10.12669/pjms.294.3500. 29. westover an, nakonezny pa, haley rw. acute myocardial infarction in young adults who abuse amphetamines. drug alcohol depend 2008; 96:49–56. doi: 10.1016/j.drugalcdep. 2008.01.027. 30. movahed mr, mostafizi k. reverse or inverted left ventricular apical ballooning syndrome (reverse takotsubo cardiomyopathy) in a young woman in the setting of amphetamine use. echocardiography 2008; 25:429–32. doi: 10.1111/j.1540-8175.2007.00604.x. 31. yeo kk, wijetunga m, ito h, efird jt, tay k, seto tb, et al. the association of methamphetamine use and cardiomyopathy in young patients. am j med 2007; 120:165–71. doi: 10.1016/j. amjmed.2006.01.024. 32. wijetunga m, seto t, lindsay j, schatz i. crystal methamphetamine-associated cardiomyopathy: tip of the iceberg? j toxicol clin toxicol 2003; 41:981–6. doi: 10.1081/ clt-120026521. 33. maeno y, iwasa m, inoue h, koyama h, matoba r, nagao m. direct effects of methamphetamine on hypertrophy and microtubules in cultured adult rat ventricular myocytes. forensic sci int 2000; 113:239–43. doi: 10.1016/s0379-0738 (00)00216-4. 34. varner kj, ogden ba, delcarpio j, meleg-smith s. cardiovascular responses elicited by the “binge” administration of methamphetamine. j pharmacol exp ther 2002; 301:152–9. doi: 10.1124/jpet.301.1.152. 35. paratz ed, cunningham nj, macisaac ai. the cardiac complications of methamphetamines. heart lung circ 2016; 25:325–32. doi: 10.1016/j.hlc.2015.10.019. https://doi.org/10.5812/ircmj.4022 https://doi.org/10.5812/ircmj.4022 https://doi.org/10.1111/j.1360-0443.2011.03706.x https://doi.org/10.1111/j.1360-0443.2011.03706.x https://doi.org/10.1016/0002-8703%2862%2990059-5 https://doi.org/10.1016/0002-8703%2862%2990059-5 https://doi.org/10.1146/annurev.publhealth.012809.103600 https://doi.org/10.1080/09595230801923710 https://doi.org/10.1080/09595230801923710 https://doi.org/10.1097/yco.0b013e328338630d https://doi.org/10.1016/j.jfda.2014.01.019 https://doi.org/10.1111/j.1360-0443.2008.02231.x https://doi.org/10.1080/02791072.2002.10399951 https://doi.org/10.1080/02791072.2002.10399951 https://doi.org/10.1016/j.yfrne.2007.07.003 https://doi.org/10.1016/j.yfrne.2007.07.003 https://doi.org/10.1111/j.1360-0443.2007.01874.x https://doi.org/10.1080/15563650701263633 https://doi.org/10.1097/01.crd.0000132372.38506.45 https://doi.org/10.1016/j.legalmed.2011.05.002 https://doi.org/10.1016/j.legalmed.2011.05.002 https://doi.org/10.5348/ijcri-2013-12-414-cr-8 https://doi.org/10.1111/j.1360-0443.2006.01776.x https://doi.org/10.1155/2016/7967851 https://doi.org/10.1213/00000539-197911000-00021 https://doi.org/10.1007/s40264-014-0201-8 https://doi.org/10.1007/s40264-014-0201-8 https://doi.org/10.12669/pjms.294.3500 https://doi.org/10.1016/j.drugalcdep.2008.01.027 https://doi.org/10.1016/j.drugalcdep.2008.01.027 https://doi.org/10.1111/j.1540-8175.2007.00604.x https://doi.org/10.1016/j.amjmed.2006.01.024 https://doi.org/10.1016/j.amjmed.2006.01.024 https://doi.org/10.1081/clt-120026521 https://doi.org/10.1081/clt-120026521 https://doi.org/10.1016/s0379-0738%2800%2900216-4 https://doi.org/10.1016/s0379-0738%2800%2900216-4 https://doi.org/10.1124/jpet.301.1.152 https://doi.org/10.1016/j.hlc.2015.10.019 sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 330-335, epub. 15th jul 12 submitted 5th dec 11 revision req. 10th mar 12, revision recd. 7th may 12 accepted 9th may 12 department of oral and maxillofacial surgery, kle vishwanath katti institute of dental sciences, belgaum, karnataka, india. *corresponding author e-mail: tejrajkale@yahoo.com فعالية ضماد هيمكون لألسنان مقابل الطريقة التقليدية املتبعة يف ختثر الدم يف 40 مريضا يتناولون األدوية املضادة للصفيحات عن طريق الفم تيجراج كايل، اأميت كومار �سينغ، ا�ض ام كوترا�سيتي، ابهي�سيك كابور امللخ�ص: الهدف: تقييم فعالية �سماد هيمكون لالأ�سنان يف ال�سيطرة على النزيف بعد خلع ال�سن والتاأكد من دوره يف �سفاء اجلروح باملقارنة مع الطريقة التقليدية. الطريقة: كان جميع امل�ساركني يف الدرا�سة )وعددهم 40( يتلقون العالج امل�ساد لل�سفيحات عن طريق الفم. مت قلع ما جمموعه 80 من الأ�سنان دون تغيري عالج املر�سى، ومت تق�سيم مواقع القلع اإىل جمموعتني: املجموعة الأوىل عوجلت ب�سماد هيمكون، واملجموعة الثانية عوجلت بالطريقة التقليدية املتبعة يف ال�سغط مع �سا�ض معقم حتت �سغط الع�ض )تليها خياطة اإذا لزم الأمر( لتحقيق مواقع من ثانية( 53 = )املتو�سط للدم �رسيعا تخرثا الهيمكون ب�سماد عالجها مت التي القلع مواقع جميع حققت النتائج: الدم. تخرث القلع التي عوجلت بالطريقة التقليدية )املتو�سط = 918 ثانية( وكان الفرق ذات دللة اإح�سائية معتدة )p <0.001(. كما كان الأمل بعد اجلراحة يف جمموعة �سماد الهيمكون )1.74( اأي�سا اأقل بكثري مما كانت عليه يف املجموعة ال�سابطة )p<0.001()5.26(. واأظهرت من بكثري اأف�سل ب�سكل اجلراحية العملية بعد لل�سفاء متاثلوا الهيمكون ب�سماد املعاجلة املواقع من %72.5 من يقرب ما اأن الدرا�سة املوقع املعاجلة تقليديا )p <0.001(. اخلال�صة: ثبت اأن �سماد الهيمكون عامال ممتازا لتخرث الدم حيث اخت�رس كثريا من وقت نزيف ما بعد قلع الأ�سنان عند املر�سى الذين يتناولون الأدوية امل�سادة لل�سفيحات. بالإ�سافة اإىل ذلك، حت�سن اللتئام بعد اجلراحة يف قلع الأ�سنان ب�سكل ملحوظ ، وكان الأمل اأقل كذلك. مفتاح الكلمات: مثبطات تكد�ض ال�سفيحات، ال�سيتوزان، نزف، التئام اجلروح. abstract: objectives: the purpose of the study was to evaluate the effectiveness of the hemcon dental dressing (hdd) in controlling post extraction bleeding and to ascertain its role in healing of extraction wounds, as compared to control. methods: the 40 participants in the study were all receiving oral antiplatelet therapy (oat). a total of 80 extractions were conducted without altering the patients’ drug therapy. the extraction sites were divided into 2 groups: one group received a hdd, and the control group where the conventional method of pressure pack with sterile gauze under biting pressure (followed by suturing if required) was used to achieve haemostasis. results: all hemcon treated sites achieved haemostasis sooner (mean = 53 seconds) than the control sites (mean = 918 seconds) which was statistically significant (p <0.001). postoperative pain in the hdd group (1.74) was also significantly lower than in the control group (5.26) (p <0.001). approximately 72.5% of hdd-treated sites showed significantly better postoperative healing when compared to the control site (p <0.001). conclusion: hdd proved to be an excellent haemostatic agent that significantly shortened the bleeding time following dental extraction in patients on oat. additionally, hdd offered significantly improved post-operative healing of the extraction socket and less postoperative pain. keywords: platelet aggregation inhibitors; chitosan; hemorrhage; wound healing. effectiveness of hemcon dental dressing versus conventional method of haemostasis in 40 patients on oral antiplatelet drugs *tejraj p. kale, amit kumar singh, s.m. kotrashetti, abhishek kapoor clinical & basic research advances in knowledge for patients undergoing simple extractions, the study outcome supports no change in patient’s oral antiplatelet drug regimen. expected results regarding the effectiveness of chitosan were observed. this clinical study supports the use of advances in technology (chitosan) to improve patient care. application to patient care health professionals still prefer to alter drug regimens for patients receiving oral antiplatelet therapy (oat) prior to minor surgical procedures. this places patients at risk of developing thromboembolism. tejraj p. kale, amit kumar singh, s.m. kotrashetti and abhishek kapoor clinical and basic research | 331 medical problems are one of the roadblocks for oral and maxillofacial surgeons; they are expected to manage patients with such ailments with utmost care.1 excessive bleeding in patients on oral antiplatelet therapy (oat) is currently one of the most commonly encountered complications in dentistry, making oat patients some of the most challenging patients to treat.2 although the prevalence of bleeding disorders in patients being treated by dentists and oral surgeons appears to be small, a study in 1994 showed that 2.3% of 1500 adults seeking dental treatment were on oat and, indeed, bleeding disorders were more prevalent than cancer, renal disease, or joint replacement.3 when encountering such a patient, a dental surgeon has the choice of either altering or stopping the oat, which presents a risk of thromboembolism, or continuing the oat and risking uncontrolled bleeding.4–9 a common approach to managing such patients is suspension of the oat for 3 to 4 days before surgery, which exposes the patients to a higher risk of thromboembolism, myocardial infarction, and cardiovascular accidents.10,11 intraoperative or postoperative bleeding is not significantly reduced by this regimen. other authors have suggested the use of local haemostatic measures to control intraand postoperative bleeding without altering a patient’s oat regimen.12–14 many styptics such as the gelatin sponge, fibrin glue, and tranexamic acid have been used in the past to control intraand postoperative haemorrhage. the hemcon dental dressing (hdd) (hemcon medical technologies, portland, oregon, usa) is an usa food and drug administration (fda) approved material which has been used extensively under the name hemcon bandage to stop bleeding in combat wounds and other severe trauma.15,16 the hdd is a new generation medical device which offers self-adhesion and provides a protective layer that can be custom cut according to a patient’s need. although haemostasis proceeds rapidly, there is no heat generated that might cause thermal injury to the wound site.17 hdd is chitin, which is manufactured from freeze dried shrimp shells. chitin is an insoluble polysaccharide polymer of glucosamine that is purified and partially deacetylated to form soluble chitosan aqueous gel.18,19 chitosan gel is then freeze dried in moulds to make a highly electropositive sponge-like material that is haemostatic and adapts well to oral surgical wounds. chitosan is a food grade material which can be safely ingested, and its accidental inhalation risk is almost zero as it undergoes dissolution. chitosan has a positive charge and attracts red blood cells (rbc) and platelets, which are negatively charged through ionic interaction; thus, a strong seal is formed at the wound site.16 this supportive, primary seal allows the body to activate its coagulation pathway effectively, initially forming organised platelets. hdds are designed to maintain this seal and serve as a frontline support structure as the platelets and rbc continue to aggregate until haemostasis is achieved. hdds do not rely solely on the clotting cascade to maintain haemostasis.20 the strong sealing action allows the body to form a clot naturally. hdd can also be used in haemophiliac patients as clot formation is based on electrostatic charge attraction instead of the normal quantities and functioning of clotting factors. in addition to providing haemostasis, hdd also offers an antibacterial barrier. the purpose of this study was to evaluate the effectiveness of hdd in controlling postextraction bleeding and its role in the healing of extraction wounds as compared to more conventional methods such as pressure gauze, followed by suturing if required. for our study, we hypothesised that, in oat patients, hdd would yield better outcomes as compared to more conventional measures used after tooth extractions. methods a total of 40 adult oat patients undergoing extractions were chosen randomly for this study after institutional review board approval was the study results showed earlier haemostasis, less discomfort, and better healing without changing a patient’s oat regimen when undergoing minor surgical procedures using hdd. the study results also support early treatment without repeated evaluations of international normalised ratios in patients receiving oat regimens. effectiveness of hemcon dental dressing versus conventional method of haemostasis in 40 patients on oral antiplatelet drugs 332 | squ medical journal, august 2012, volume 12, issue 3 obtained. all patients underwent extractions without any alteration to their antiplatelet medication regimens. included in the study were oat patients undergoing multiple tooth extractions who were between the ages of 35 and 75 years, and had international normalised ratio (inr) values ≤3 (1–3). diabetic patients with wellcontrolled sugar levels were also included. patients undergoing a single tooth extraction or multiple extractions limited to one quadrant; those with an allergy to seafood; those indicating that they were smokers, and those with genetic bleeding disorders were excluded from the study. all patients underwent various investigations preoperatively such as haemoglobin estimation (hb), bleeding time (bt), clotting time (ct), inr, and platelet count (pc). bt measures the primary phase of haemostasis—the interaction of the blood vessel wall and the formation of a haemostatic plug. ct indicates the time interval from the formation of a platelet plug to the completion of vasoconstriction and clot formation. similar and identical extraction sites were selected within each patient (for example, extraction of the first molars in the right and left quadrants of the lower jaw). a split-mouth study design was used. by this method, a patient would receive hdd on one side of the mouth (study site). on the other side (control side), the conventional method of pressure packing with a sterile piece of gauze under biting pressure, followed by suturing, if required, was used to achieve haemostasis after extraction. to reduce study variability, similar contralateral or counterpart teeth were extracted wherever possible (32 patients). in the other 8 patients, similar sized teeth were selected (i.e. single rooted tooth for single rooted tooth and molar for molar). neither the surgeon nor the patients could be blinded to the use of hdd versus the control method; however, every second patient’s left side/ upper arch was used as a study site. after obtaining consent, each patient underwent atraumatic simple extractions under local anaesthesia using lignocaine with adrenaline (1:80,000). the procedure was completed on a single visit by a single surgeon. surgical sites were randomly selected for treatment either by a complete or custom-cut hdd in one quadrant and a control consisting of biting pressure on a sterile cotton gauze dressing followed by suturing if required in the other quadrant in each patient. custom-cut hdds were used to fit loosely into extraction sockets that were smaller than the size of a complete hdd (10 mm x 12 mm x 5.5 mm). a hdd was placed into the extraction socket at the height of the crestal bone wherever possible. direct finger pressure was placed over the extraction site for 40–60 seconds after placement of the hdd. sutures were placed whenever haemostasis was not achieved under biting pressure over the sterile gauze piece after 900 seconds (15 minutes). timing to haemostasis was noted for both the hdd and control surgical sites using a stopwatch. all patients were prescribed a diclomol tablet (diclofenac sodium 50 mg + paracetamol 500 mg) every 8 hours for 3 days. all patients were reviewed by another surgeon on the 7th postoperative day for assessment of pain and healing. relative pain scores were assessed 1 week postoperatively. self-reported pain scores on a scale of 0–10 were taken into account to estimate postoperative pain. healing was assessed on the basis of epithelization using the visual analogue scale, the presence of liver clots, pus discharge, dry socket, and the extent of the sinus opening. healing was compared between the study and control sites and was assessed on a scale of 1–3 with 1 representing the healing of the study site being significantly worse than the control; 2 representing the healing of the study site being the same as the control, and 3 meaning the healing table 1: details of patient age and various investigations (n = 40) variables mean sd minimum maximum age (years) 56.2 9.61 38 74 hb (gm %) 13.2 0.92 11.6 15.8 pc (mm3) 2,46,900 48,113 1,14,000 3,28,000 bt (seconds) 192 24 150 240 ct (seconds) 324 30 240 390 legend: sd = standard deviation; hb = haemoglobin estimation; pc = platelet count; bt = bleeding time; ct = clotting time. tejraj p. kale, amit kumar singh, s.m. kotrashetti and abhishek kapoor clinical and basic research | 333 of the study site was significantly better than the control. secondary bleeding was assessed through patients’ self-reporting and/or by the presence or absence of liver clots. secondary bleeding/venous haemorrhage is usually characterised by the slow oozing of dark red blood and can manifest as liver clots. liver clots, which are also known as currant jelly clots, are defined as red, jelly-like clots that are rich in haemoglobin from erythrocytes within the clot. statistical analysis through a paired t-test and the wilcoxon signed-rank test was applied for testing statistical significance. results out of the 40 patients, there were 33 males and 7 females. the mean bt was 192 seconds and the mean pc was 246,000/cc [table 1]. hdds that had adhered to the soft/hard tissue adjacent to the extraction site were easily removed after wetting with sterile normal saline, and there was no adherence to the sterile gauze piece used on the control site postoperatively. time to haemostasis was noted for both the hdd and control surgical sites using a stopwatch. the study site achieved haemostasis at 53 seconds, which was a considerably shorter time than the control site at 918 seconds [table 2]. there was statistically improved haemostasis with the use of hdd. the postoperative pain experienced by patients throughout the week while performing day-to-day activities such as eating, tooth brushing, etc. were recorded as 0 being no pain and 10 being the worst pain the patient had ever experienced. the average pain score at the study site (1.74) was considerably less than the control site (5.26) [table 2]. although we did not experience any cases of liver clots, sinus opening, pus discharge, or dry socket, there was comparatively better epithelialization with the use of hdd. the 29 study sites showed significantly better healing as compared to the control sites [table 2]. discussion clopidogrel and ticlopidine inhibit adenosine diphosphate (adp)-induced platelet fibrinogen binding whereas aspirin inhibits the activity of cyclooxygenase. platelets are affected for the life of the cell, and complete reversal of antiplatelet activity does not occur for approximately 2 weeks. in this study, the hdd was used to control bleeding in extraction wounds in patients receiving oat. the results show that in every patient the time to haemostasis was shorter when using hdd than when using the control. shen et al. showed a release of growth factor from human platelets stimulated by chitosan exposure, which may help explain our positive findings.21 cunha-reis et al. showed cell adhesion consistent with the nature of the hdd material used in this study.22 in our study, sites receiving the hdd had improved postoperative healing with minimal complications when compared to the control site. this may be attributed to the antibacterial properties of chitosan, which have been investigated in vitro studies.23,24 results demonstrated that chitosan increased permeability of the inner and outer membranes and ultimately disrupted the bacterial cell membranes, releasing their contents. thus hdd provides an antibacterial barrier against a wide range of gram positive and gram negative organisms, including methicillin-resistant staphylococcus aureus (mrsa), vancomycinresistant enterococcus (vre), and acinetobacter baumannii.23,24 in an animal study, azargoon et al. found hdd to be as efficacious ferric sulfate in haemostasis and wound healing.25 the self-adhesive nature of hdd is caused by the electrostatic attraction of rbc to the hemcon material. as the rbcs bind to the hdd surface, it forms a dense viscous mass that provides adhesion, and also adapts to the alveolar bone’s irregularities under digital pressure, thereby providing frictional locking with the bony socket. considering the competency of hdd in forming a barrier that seals the wound from exposure to the environment, we can state that only a small amount of hdd (i.e. about ½ of a 10 mm x 12 mm piece) is required to attain complete haemostasis [figure 1]. there was table 2: comparison of bleeding time, pain score and quality of healing study site control site p value bleeding time 53 ± 13 seconds 918 ± 769 seconds <0.0001 pain score 1.74 ± 0.65 5.26 ± 1.33 <0.0001 healing 29 0 <0.0001 effectiveness of hemcon dental dressing versus conventional method of haemostasis in 40 patients on oral antiplatelet drugs 334 | squ medical journal, august 2012, volume 12, issue 3 no clinical indication of the necessity to pack the extraction socket fully, and the excess was easily trimmed chair side, according to the patients’ needs. additionally, we observed initial slightly raised pain scores in sites with hdd, which subsided once the acetic acid was fully dissolved in oral fluids. to work, hdd material requires active bleeding; thus, the more bleeding takes place, the better the hdd material performs which is quite useful during surgical procedures. conclusion the results of this study fully support our hypothesis regarding the effectiveness of hdd in patients receiving oat. they show that hemcon is a new generation haemostatic agent which facilitates early haemostasis of extraction wounds, along with improved healing and reduces postoperative pain.25 the use of hdd eliminates or minimises the risk of thromboembolism by allowing the patient to continue his/her antiplatelet medication regimens; however, the haemostatic properties of the hdd do not obviate the need for thorough preand postoperative evaluation and management of a patient’s inr status. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest f u n d i n g this research was funded by hemcon inc., usa. references 1. henderson jm, bergman s, salama a, koterwas g. management of the oral and maxillofacial surgery patient with thrombocytopenia. j oral maxillofac surg 2001; 59:421–7. 2. yacabucci je, kramer hs jr. platelet defects of importance in oral surgery. j oral surg 1972; 30:478– 85. 3. patton ll, ship ja. treatment of patients with bleeding disorders. dent clin north am 1994; 38:465–82. figure 1: intraoperative photograph of study site with hemcon dental dressing in situ (loosely placed). tejraj p. kale, amit kumar singh, s.m. kotrashetti and abhishek kapoor clinical and basic research | 335 4. anavi y, sharon a, gutman d, laufer d. dental extractions during anticoagulant therapy. refuat hapeh vehashinayim 1981; 28:9–12. 5. blinder d, martinowitz u, ardekian l, peleg m, taicher s. oral surgical procedures during anticoagulant therapy. harefuah 1996; 130:681–3. 6. campbell jh, alvarado f, murray ra. anticoagulation and minor oral surgery: should the anticoagulation regimen be altered? j oral maxillofac surg 2000; 58:131–5. 7. blinder d, manor y, martinowitz u, taicher s. dental extractions in patients maintained on oral anticoagulant therapy: comparison of inr value with occurrence of postoperative bleeding. int j oral maxillofac surg 2001; 30:518–21. 8. conti cr. aspirin and elective surgical procedures. clin cardiol 1992; 15:709–10. 9. handin ri. disorders of the platelet and vessel wall. in: harrison i, randolph t, isselbacher k, eds. harrison’s principle of internal medicine. 13th ed. new york: mcgraw-hill, 1994. pp. 1798–803. 10. beirne or. evidence to continue oral anticoagulant therapy for ambulatory oral surgery. j oral maxillofac surg 2005; 63:540–5. 11. us army medical department. high-tech bandages. from: www.armymedicine.army.mil/ about/tl/factsbandages.html. accessed: may 2012. 12. blinder d, manor y, martinowitz u, taicher s, hashomer t. dental extractions in patients maintained on continued oral anticoagulant: comparison of local hemostatic modalities. oral surg oral med oral pathol oral radiol endod 1999; 88:137–40. 13. cannon pd, dharmar vt. minor oral surgical procedures in patients on oral anticoagulants--a controlled study. aust dent j 2003; 48:115–8. 14. madan ga, madan sg, madan g, madan ad. minor oral surgery without stopping daily low-dose aspirin therapy: a study of 51 patients. j oral maxillofac surg 2005; 63:1262–5. 15. della valle a, sammartino g, marenzi g, tia m, espedito di lauro a, ferrari f, et al. prevention of postoperative bleeding in anticoagulated patients undergoing oral surgery: use of platelet-rich plasma gel. j oral maxillofac surg 2003; 61:1275–8. 16. wedmore i, mcmanus jg, pusateri ae, holcomb jb. a special report on the chitosan-based hemostatic dressing: experience in current combat operations. j trauma 2006; 60:655–8. 17. chou tc, fu e, wu cj, yeh jh. chitosan enhances platelet adhesion and aggregation. biochem biophys res commun 2003; 302:480–3. 18. kumar mn, muzzarelli ra, muzzarelli c, sashiwa h, domb aj. chitosan chemistry and pharmaceutical perspectives. chem rev 2004; 104:6017–84. 19. yang j, tian f, wang z, wang q, zeng yj, chen sq. effect of chitosan molecular weight and deacetylation degree on hemostasis. j biomed mater res b appl biomater 2008; 84:131–7. 20. malmquist jp, clemens sc, oien hj, wilson sl. hemostasis of oral surgery wounds with the hemcon dental dressing. j oral maxillofac surg 2008; 66:1177–83. 21. shen ec, chou tc, gau ch, tu hp, chen yt, fu e. releasing growth factors from activated human platelets after chitosan stimulation: a possible biomaterial for platelet-rich plasma preparation. clin oral implants res 2006; 17:572–8. 22. cunha-reis c, tuzlakoglu k, baas e, yang y, el haj a, reis rl. influence of porosity and fibre diameter on the degradation of chitosan fibre-mesh scaffolds and cell adhesion. j mater sci mater med 2007; 18:195–200. 23. burkatovskaya m, tegos gp, swietlik e, demidova tn, p castano a, hamblin mr. use of chitosan bandage to prevent fatal infections developing from highly contaminated wounds in mice. biomaterials 2006; 27:4157–64. 24. speechley ja, rugman fp. some problems with anticoagulants in dental surgery. dent update 1992; 19:204–6. 25. azargoon h, williams bj, solomon es, kessler hp, he j, spears r. assessment of hemostatic efficacy and osseous wound healing using hemcon dental dressing. j endod 2011; 37:807–11. evidence-based caring research center, department of medical-surgical nursing, school of nursing & midwifery, mashhad university of medical sciences, mashhad, iran *corresponding author e-mail: heidarya@mums.ac.ir ُمَعوَّلِيَّة مؤشر شدة الطوارئ التحليل التلوي اأمري مريحقي، عبا�س حيدري، ر�ضا مظلوم، فرزانه ح�ضن زاده abstract: objectives: although triage systems based on the emergency severity index (esi) have many advantages in terms of simplicity and clarity, previous research has questioned their reliability in practice. therefore, the aim of this meta-analysis was to determine the reliability of esi triage scales. methods: this metaanalysis was performed in march 2014. electronic research databases were searched and articles conforming to the guidelines for reporting reliability and agreement studies were selected. two researchers independently examined selected abstracts. data were extracted in the following categories: version of scale (latest/older), participants (adult/paediatric), raters (nurse, physician or expert), method of reliability (intra/inter-rater), reliability statistics (weighted/unweighted kappa) and the origin and publication year of the study. the effect size was obtained by the z-transformation of reliability coefficients. data were pooled with random-effects models and a meta-regression was performed based on the method of moments estimator. results: a total of 19 studies from six countries were included in the analysis. the pooled coefficient for the esi triage scales was substantial at 0.791 (95% confidence interval: 0.787‒0.795). agreement was higher with the latest and adult versions of the scale and among expert raters, compared to agreement with older and paediatric versions of the scales and with other groups of raters, respectively. conclusion: esi triage scales showed an acceptable level of overall reliability. however, esi scales require more development in order to see full agreement from all rater groups. further studies concentrating on other aspects of reliability assessment are needed. keywords: triage; emergency treatment; algorithm; reliability and validity; meta-analysis. امللخ�ص: الهدف: على الرغم من اأن الأنظمة الفرز على اأ�ضا�س موؤ�رض �ضدة الطوارئ )esi( العديد من املزايا من حيث الب�ضاطة والو�ضوح، اإال اأن االأبحاث ال�ضابقة قد �ضككت يف م�ضداقيتها عند املمار�ضة. ولهذا كان الهدف من هذا التحليل التلوي )البعدي( معرفة معولية مقيا�س الفرز م. �س. ط. الطريقة: مت البحث يف قواعد البيانات االلكرتونية منذ تاريخ اإن�ضائها اإىل مار�س 2014م، ومت اختيار املواد مطابقة للدالئل االإر�ضادية لدرا�ضات التبليغ واملعولية واملوافقة )grras(. وقام باحثان م�ضتقلن بفح�س ملخ�ضات خمتارة وا�ضتخرجا البيانات يف الفئات التالية: ن�ضخة مقيا�س )االآخر / االأكرب( وامل�ضاركون )الكبار / االأطفال(، املقيمون )ممر�ضة، طبيب اأو خبري( اأو اأ�ضلوب املعولية )و�ضط / بني املقيمني(، واالإح�ضاءات املعولية )املوزونة / غري املوزونة كابا( وامل�ضدر وعام ن�رض الدرا�ضة. ومت احل�ضول على حجم التاأثري من قبل حتويل معاملت املعولية. ومت جتميع البيانات مع مناذج االآثار الع�ضوائية، ومت اإجراء التحوف التايل اإح�ضائيا على اأ�ضا�س طريقة كبريا esi الفرز ملوازين التجميعي املعامل وكان التحليل. يف دول �ضت من درا�ضة 19 جمموعه ما اإدراج مت النتائج: اللحظات. تقدير ويعادل 0.791 )فا�ضل املوثوقية عند %95 يرتاوح بني 0.787–0.795(. وكان التوافق اأكرب بني العايل واأحدث اإ�ضدارات والكبار احلجم واملقيمني بني اخلرباء، مقارنة باالتفاق مع االإ�ضدارات القدمية واالأطفال من املقايي�س ومع جمموعات اأخرى من املقيمني، على التوايل. اخلال�صة: اأظهرت جداول الفرز esi وعلى وجه العموم م�ضتوى مقبوال من املعولية ا. ومع ذلك، فاإن موازين esi تتطلب املزيد من التطوير حتى ميكن الو�ضول التفاق كامل عند جميع الفئات املقيمة. وهناك حاجة اإىل مزيد من الدرا�ضات التي تركز على جوانب اأخرى من تقييم املعولية. مفتاح الكلمات: الفرز؛ علج حاالت الطوارئ؛ اخلوارزمية؛ املعولية التحليل التلوي )البعدي(. reliability of the emergency severity index meta-analysis amir mirhaghi, *abbas heydari, reza mazlom, farzaneh hasanzadeh clinical & basic research advances in knowledge it is important to determine the reliability of triage scales as this reveals the consistency of patient prioritisation within emergency departments. the results of this meta-analysis demonstrate that the emergency severity index (esi) triage scale has substantial agreement and shows acceptable overall reliability when implemented in emergency departments within and outside of the usa. however, the esi was also found to have a tendency to allocate patients to level 2. application to patient care a triage scale enables emergency departments to allocate resources to the most critically ill patients. it is therefore important for medical personnel to be aware of the reliability of the scale as inconsistent triage decisions may result in under-triage and put patients’ health in danger. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e71–77, epub. 21 jan 15 submitted 13 may 14 revision req. 8 jul 14; revision recd. 20 jul 14 accepted 25 sep 14 reliability of the emergency severity index meta-analysis e72 | squ medical journal, february 2015, volume 15, issue 1 in emergency departments (eds), patients are categorised based on their clinical acuity; thus, the more critically ill the patient, the sooner treatment is delivered and care needs are addressed.1 the emergency severity index (esi) is a five-level ed triage algorithm designed to stratify patients into groups based on clinical need. the esi is continuously developed by physicians in the usa and has been adopted by several other developed countries.2,3 it has also been endorsed by the american college of emergency physicians and the emergency nurses association.4 many studies have investigated the validity and reliability of the esi triage scale in both adult and paediatric populations.2,3,5–10 however, the extent to which the esi triage scale is used in triage nurses’ decision-making outside of the usa is still unclear, especially considering the wide variety of healthcare systems currently in existence around the world.11 with regards to this, andersson et al. addressed contextual influences on the triage decision-making process in rural sweden.12 the reliability of triage scales outside of the usa should therefore be assessed for internal consistency, repeatability and interrater agreement.1,11 while the kappa statistic is most commonly used to measure inter-rater agreement, this statistic can be influenced by incidence, bias and levels of scale, potentially generating misleading results.13–15 additionally, weighted kappa statistics have been reported to reveal deceivingly high reliability coefficients.11 therefore, a pooled estimate of a reliability coefficient is more practical in the identification of significant differences among reliability methods. a meta-analysis is a systematic approach for the introduction, evaluation, synthesis and unification of results with reference to a specific research question. it also produces the strongest evidence for intervention and is therefore an appropriate method to gain insight regarding the reliability of triage scales.16 a review by christ et al. on the reliability of the esi scale demonstrated kappa statistics ranging from 0.46 (moderate) to 0.98 (almost perfect).17 this considerable variation in kappa statistics indicates a discernable gap in the reliability of the triage scale. thus, the aim of this meta-analysis was to review the reliability of the esi triage scale in a variety of contexts. methods this study was performed in march 2014. the first phase consisted of a literature search using the cumulative index to nursing and allied health literature (cinahl), scopus, medline®/pubmed, google scholar and cochrane library databases. studies published before 1 march 2014 in these databases and found using the following search terms were included: reliability; triage; system; scale; agreement; emergency, and emergency severity index. all studies in english identified by the database search were examined by two researchers to identify eligible articles regarding the reliability of the esi. irrelevant or duplicate results were eliminated. reference lists of acceptable publications were also examined to identify further articles for inclusion in the study. articles were chosen for inclusion according to the guidelines for reporting reliability and agreement studies.18 according to these guidelines, studies were only included in the analysis if they reported more than six of the following eight items in sufficient detail: sample size; number of raters; number of subjects; sampling method; rating process; statistical analysis, and reliability coefficient. disagreements were resolved by consensus with a third researcher. articles that did not report the type of reliability (either inter-rater reliability, intra-rater reliability or internal consistency) were excluded from the analysis. researchers also recorded moderator variables relating to participants, raters and the origin and year of publication of the study as well as studies which were conducted based on the latest version (2012) of the esi triage scale. in the next phase, further information was retrieved from the articles, including: age group of participants and size of cohort; raters’ professions and overall number of raters; instruments used (e.g. live or scenario-based cases); country of origin and year of publication of study; reliability coefficient, and type of reliability. reliability was determined by inter-rater reliability (weighted or unweighted kappa coefficients), intra-rater reliability (reliability statistics including intraclass correlation coefficient, pearson correlation coefficient or spearman’s rank correlation coefficient) and internal consistency (alpha coefficients) statistics. authors of research articles were contacted for supplementary information if necessary. in the meta-regression, each rater sample was considered to be a unit of analysis. if the same sample was reported in two or more articles, it was included only once in the analysis. in contrast, if several samples with different populations were reported in one study, each sample was included as a separate unit of analysis. data were pooled for all three types of reliability. many articles reported a reliability coefficient using the kappa statistic; it could be considered an r-type coefficient ranging from −1.00 to +1.00. standard agreement was categorised as poor (κ = 0.00–0.20), fair (κ = 0.21–0.40), moderate (κ = 0.41–0.60), substantial (κ = 0.61–0.80) or almost perfect (κ = amir mirhaghi, abbas heydari, reza mazlom and farzaneh hasanzadeh clinical and basic research | e73 0.81–1.00).13 the kappa statistic can be treated as a correlation coefficient in meta-analyses.19 in order to obtain the correct interpretation, back-transformation (z to r transformation) of pooled effect sizes to the level of primary coefficients was performed.20,21 fixed and random-effect models were applied. data were analysed using comprehensive meta-analysis (cma) software, version 2.2.050 (biostat inc., englewood, new jersey, usa). a simple meta-regression analysis was performed according to the method of moments estimator.22 in the meta-regression model, effect size was a dependent variable while studies and subject characteristics were considered independent variables in order to discover potential predictors of reliability coefficients. z-transformed reliability coefficients were regressed based on variables of country origin and year of publication as well as studies based on the latest version of triage scale versus those of a prior version. distance was defined as the distance from each study's country of origin to the city of boston, massachusetts, in the usa (where the esi triage scale originated). meta-regression was performed using a randomeffects model due to the presence of significant interstudy variation.23 this study received ethical approval from the research & ethics committee of mashhad university of medical science in mashhad, iran. results a total of 260 primary citations relevant to the reliability of the esi triage scale were identified during the literature search. however, only 19 unique citations (7.3%) met the inclusion criteria.2,3,5–10,24–34 the studies were organised into subgroups according to participants (adult/paediatric); raters (nurses/ physicians/experts); method of reliability (intra-/ inter-rater); reliability statistics (weighted/unweighted kappa statistics), and by country of origin and publication year. the level of agreement among the researchers regarding the final selection of articles for the meta-analysis was almost perfect (κ = 1.0). a total of 40,579 cases (both paper-based case scenarios and live triage cases) were included in the initial analysis. among the 19 studies meeting the required criteria, the reliability of the esi triage scale had been assessed in six different countries with publication years ranging from 2000–2013 (median year of publication: 2009). in addition, 70% had been conducted using the latest version of the triage scale. the inter-rater reliability method was used in all studies except for one, which used intra-rater reliability. none of the studies in the analysis had used the alpha coefficient to report internal consistency. the weighted kappa coefficient was the most commonly utilised statistic [table 1]. the overall pooled coefficient for the esi triage scale was substantial, at 0.791 (95% confidence interval [ci]: 0.752–0.825). participants’ pooled coefficients ranged from substantial (0.732; 95% ci: 0.625–0.812) for nurse-expert agreement to almost perfect (0.900; 95% ci: 0.570–0.980) for expert-expert agreement [figures 1 and 2]. agreement regarding adult/ paediatric versions of the esi triage scale was almost perfect for both adult (0.815; 95% ci: 0.753–0.862) and paediatric patients (0.769; 95% ci: 0.747–0.837). additionally, almost perfect agreement was noted for paper-based scenario assessments (0.824; 95% ci: 0.778–0.861) and substantial agreement was observed for live case assessments (0.694; 95% ci: 0.575–0.784). interand intra-rater reliability agreement was 0.786 (95% ci: 0.745–0.821) and 0.873 (95% ci: 0.801– 0.921), respectively. substantial agreement was found for both weighted (0.796; 95% ci: 0.751–0.834) and unweighted kappa statistics (0.770; 95% ci%: 0.674– 0.841). agreement for the latest version of the esi was 0.833 (95% ci: 0.774–0.878), whereas it was 0.808 (95% ci: 0.762–0.846) for previous versions. only six studies presented a 5 x 5 contingency table to show the frequency distribution of triage decisions for each esi level between two raters [table 2].2,3,5,7,9,24 the overall agreement in these studies was 78.55%. agreement for each esi level was 1.12%, 23.40%, 19.55%, 18.81% and 15.67% for levels 1 to 5, respectively, while disagreement was 0.25%, 4.07%, 6.10%, 6.90% and 4.12%, respectively. a total of 80% of all disagreements concerned levels 3 to 5 (17.12% out of 21.44%). only esi level 2 decisions showed a wide distribution across all levels [table 2]. table 3 shows the meta-regression analysis based on the method of moments for moderators (distance from esi origin, year of publication and esi version). studies using the latest version of the esi scale and which had been published more recently showed significantly higher pooled coefficients. however, higher pooled coefficients were not indicated for studies conducted closest in geographical distance to boston, usa [figure 3]. discussion the results of this study indicate that the overall reliability of the esi triage scale is substantial. the esi showed an acceptable level of reliability which guarantees consistent decisions regarding the allocation of patients to appropriate categories; thereby supporting evidence-based practice in eds.17,35 reliability of the emergency severity index meta-analysis e74 | squ medical journal, february 2015, volume 15, issue 1 table 1: studies on the reliability of the emergency severity index triage scale included in the meta-analysis (n = 19) author and year of study participant raters instrument method statistic co wuerz et al.5 2000 adult adult ee np scenario live cases inter inter κw usa wuerz et al.25 2001 adult adult nn np scenario scenario inter inter κw usa travers et al.26 2002 adult ne scenario inter κw usa eitel et al.27 2003 adult adult ne nn scenario live cases inter inter κw usa tanabe et al.24 2004 adult adult ne ne scenario scenario inter inter κw usa worster et al.6 2004 adult nn scenario inter κw canada travers et al.28 2002 adult paediatric nn nn scenario scenario inter inter κw usa choi et al.29 2009 adult adult ne np live cases live cases inter inter κw κw korea storm-versloot et al.3 2009 adult adult adult adult nn nn nn nn scenario scenario scenario scenario intra inter intra inter κuw κuw κw κw netherlands grossman et al.2 2011 adult adult adult adult ee ee ne ne scenario scenario scenario scenario inter inter inter inter r kw r kw switzerland platts-mills et al.30 2010 adult adult ne np live cases live cases inter inter kw usa grossmann et al.31 2012 adult ee scenario inter κw switzerland baumann et al.7 2005 paediatric paediatric paediatric paediatric paediatric ne ne nn np pe live cases scenario scenario scenario scenario inter inter inter inter inter kw usa durani et al.32 2007 paediatric paediatric paediatric nn np pp scenario scenario scenario inter kw usa durani et al.8 2009 paediatric paediatric paediatric paediatric paediatric paediatric nn nn np np pp pp scenario scenario scenario scenario scenario scenario inter kuw kw kuw kw kuw kw usa travers et al.9 2009 paediatric paediatric ne nn live cases scenario inter kw usa green et al.10 2012 paediatric paediatric paediatric paediatric nn nn np np live cases live cases live cases live cases inter icc kuw icc kuw usa jafari-rouhi et al.33 2013 paediatric paediatric paediatric nn np np scenario scenario scenario inter kuw r kuw iran ho et al.34 2007 adult ee live cases inter κw usa co = country of origin; inter = inter-rater reliability; kw = weighted kappa; np = nurse-physician; nn = nurse-nurse; ne = nurse-expert; intra = intra-rater reliability; kuw = unweighted kappa; ee = expert-expert; r = correlation coefficient; pe = physician-expert; pp = physician-physician. amir mirhaghi, abbas heydari, reza mazlom and farzaneh hasanzadeh clinical and basic research | e75 figure 1: fisher’s z-transformation showing pooled estimates of participants’ reliability (random-effect model) among studies relating to the reliability of the emergency severity index.2,3,5–10,24–34 ee = expert-expert; ne = nurse-expert; nn = nurse-nurse; np = nurse-physician; pe = physician-expert; pp = physician-physician. in the esi, levels 3 to 5 are generally defined by the requirement and availability of resources; because this varies from one setting to another, most disagreements are to do with these levels. this was reflected in the current study. fortunately, these levels indicate semito non-urgent patients which means that misclassifications rarely occur among those who are critically ill. another interesting observation of the current meta-analysis was the strong tendency towards level 2 categorisation. although this may prevent the under-triaging of certain patients, it could also create a significant disturbance in the patient flow and interfere with the overall functioning of the ed. diverse pooled reliability coefficients were observed regarding participants, patients, raters, reliability methods and statistics among the studies. the results of the meta-analysis found that agreement with the latest and the adult versions of the esi and among experts was higher than those with previous or paediatric versions and among the other groups of raters. the different results determined by these moderator variables could lead to further studies to explore these variables in more depth. the reliability and consistency of the esi across eds in different countries has been documented and supported by scientific evidence.35 this could be due to the fact that the simplicity and objectivity of the esi algorithm plays a pivotal role in helping clinicians reach optimal agreement.36 in the current study, the analysis of reliability in studies of non-american origin show that the esi triage scale can be adopted successfully in countries outside of the usa in spite of cultural differences. studies using the latest version of the esi scale and those which were published more recently showed higher agreement. as the esi triage scale has been updated several times and its reliability has improved over the years, this indicates that revisions have been effective. additionally, this emphasises the need for eds to update their triage systems according to the latest versions of the chosen triage scale. in general, intra-rater reliability is more satisfactory than inter-rater reliability.37 this was highlighted in the current study, which revealed almost perfect agreement in the former as compared to the substantial agreement yielded by the latter. while intraand inter-rater reliability are intended to report the degree to which measurements taken by the same and different observers are similar, other methods of examining reliability have remained uncommon in studies regarding triage reliability.38 the current study’s analysis demonstrated that the weighted kappa coefficient showed substantial agreement. in fact, the weighted kappa coefficient reveals higher reliability than the unweighted kappa coefficient because it places more emphasis on the larger differences between ratings than on the smaller ones.39 in practical terms, the misallocation of critically-ill patients by even a single esi level can endanger their clinical outcomes; unweighted kappa statistics therefore provide a more realistic estimation of triage scale reliability.11 a number of limitations of this study must be noted. while the esi showed an acceptable level of reliability, it is important to remember that there is a considerable gap between research and clinical practice even at the best of times.40 in addition, almost all of the studies used weighted kappa statistics to report reliability coefficients. as weighted kappa statistics generally overestimate the reliability of a triage scale, it is necessary to interpret these results with caution.11 therefore, it is likely that the esi is in fact only moderately reliable. furthermore, none of the studies in the analysis reported raw agreement for each figure 2: pooled estimates of measures of raters’ reliability (random-effect model) using weighted kappa statistics among studies relating to the reliability of the emergency severity index.2,3,5–10,24–34 ci = confidence interval. reliability of the emergency severity index meta-analysis e76 | squ medical journal, february 2015, volume 15, issue 1 the authors declare no conflicts of interest. references 1. mirhaghi ah, roudbari m. a survey on knowledge level of the nurses about hospital triage. iran j crit care nurs 2011; 3:167–74. 2. grossmann ff, nickel ch, christ m, schneider k, spirig r, bingisser r. transporting clinical tools to new settings: cultural adaptation and validation of the emergency severity index in german. ann emerg med 2011; 57:257–64. doi: 10.1016/j.annemergmed.2010.07.021. 3. storm-versloot mn, ubbink dt, chin a choi v, luitse js. observer agreement of the manchester triage system and the emergency severity index: a simulation study. emerg med j 2009; 26:556–60. doi: 10.1136/emj.2008.059378. 4. fernandes cm, tanabe p, gilboy n, johnson la, mcnair rs, rosenau am, et al. five-level triage: a report from the acep/ena five-level triage task force. j emerg nurs 2005; 31:39–50. doi: 10.1016/j.jen.2004.11.002. 5. wuerz rc, milne lw, eitel dr, travers d, gilboy n. reliability and validity of a new five-level triage instrument. acad emerg med 2000; 7:236–42. doi: 10.1111/j.15532712.2000.tb01066.x. 6. worster a, gilboy n, fernandes cm, eitel d, eva k, geisler r, et al. assessment of inter-observer reliability of two fivelevel triage and acuity scales: a randomized controlled trial. cjem 2004; 6:240–5. 7. baumann mr, strout td. evaluation of the emergency severity index (version 3) triage algorithm in pediatric patients. acad emerg med 2005; 12:219–24. doi: 10.1197/j. aem.2004.09.023. 8. durani y, brecher d, walmsley d, attia mw, loiselle jm. the emergency severity index version 4: reliability in pediatric patients. pediatr emerg care 2009; 25:504–7. doi: 10.1097/pec.0b013e3181b0a0c6. 9. travers da, waller ae, katznelson j, agans r. reliability and validity of the emergency severity index for pediatric triage. acad emerg med 2009; 16:843–9. doi: 10.1111/j.15532712.2009.00494.x. 10. green na, durani y, brecher d, depiero a, loiselle j, attia m. emergency severity index version 4: a valid and reliable tool in pediatric emergency department triage. pediatr emerg care 2012; 28:753–7. doi: 10.1097/pec.0b013e3182621813. 11. göransson ke, ehrenberg a, marklund b, ehnfors m. accuracy and concordance of nurses in emergency department triage. scand j caring sci 2005; 19:432–8. doi: individual esi level and only a few studies presented a contingency table for inter-rater agreement. since this study was limited to overall reliability, some inconsistencies may exist across each esi level. finally, research has indicated that raters’ experiences could affect the reliability and validity of triage decisionmaking; these experiences were not reported among any of the studies in this analysis.41 conclusion overall, the esi triage scale was shown to display an acceptable level of reliability in this meta-analysis. however, there is a need for further development of the scale in order to reach almost perfect agreement. the reliability of triage scales requires a more comprehensive approach, including a thorough assessment of all aspects of reliability. in light of this, further studies should concentrate on the reliability of triage scales in terms of specific moderator variables, such as the version of the esi used. c o n f l i c t o f i n t e r e s t table 2: distribution of triage decision-making relating to each emergency severity index triage category among emergency department raters in six studies2,3,5,7,9,24 rater 2 esi category rater 1 esi category n (%) 1 2 3 4 5 total 1 35 (1.12) 9 0 0 0 44 2 7 730 (23.39) 102 26 3 868 3 0 82 610 (19.55) 91 12 795 4 0 18 77 587 (18.81) 85 767 5 0 7 16 134 489 (15.67) 646 total 42 846 805 838 589 3,120 (100.00) esi = emergency severity index. table 3: meta-regression of fisher’s z-transformed kappa coefficients on predictor variables* independent variable b seb p latest esi version 0.302 0.018 0.00 distance from esi origin** −0.00 0.000 0.53 publication year 0.015 0.002 0.00 seb = simultaneous equation bias; esi = emergency severity index. *using studies relating to esi reliability with weighted kappa coefficients.2,3,5–10,24–34 **the esi triage scale originated in boston, massachusetts, usa. figure 3: fisher’s z-transformation of kappa coefficients regarding the year of publication among studies relating to the reliability of emergency severity index.2,3,5–10,24–34 amir mirhaghi, abbas heydari, reza mazlom and farzaneh hasanzadeh clinical and basic research | e77 10.1111/j.1471-6712.2005.00372.x. 12. andersson ak, omberg m, svedlund m. triage in the emergency department: a qualitative study of the factors which nurses consider when making decisions. nurs crit care 2006; 11:136–45. doi: 10.1111/j.1362-1017.2006.00162.x. 13. sim j, wright cc. the kappa statistic in reliability studies: use, interpretation, and sample size requirements. phys ther 2005; 85:257–68. 14. van der wulp i, van stel hf. calculating kappas from adjusted data improved the comparability of the reliability of triage systems: a comparative study. j clin epidemiol 2010; 63:1256–63. doi: 10.1016/j.jclinepi.2010.01.012. 15. viera aj, garrett jm. understanding interobserver agreement: the kappa statistic. fam med 2005; 37:360–3. 16. petitti d. meta-analysis, decision analysis, and costeffectiveness analysis. 1st ed. new york, usa: oxford university press, 1994. p. 69. 17. christ m, grossmann f, winter d, bingisser r, platz e. modern triage in the emergency department. dtsch arztebl int 2010; 107:892–8. doi: 10.3238/arztebl.2010.0892. 18. kottner j, audige l, brorson s, donner a, gajewski bj, hróbjartsson a, et al. guidelines for reporting reliability and agreement studies (grras) were proposed. j clin epidemiol 2011; 48:661–71. doi: 10.1016/j.ijnurstu.2011. 01.016. 19. rettew dc, lynch ad, achenbach tm, dumenci l, ivanova my. meta-analyses of agreement between diagnoses made from clinical evaluations and standardized diagnostic interviews. int j methods psychiatr res 2009; 18:169–84. doi: 10.1002/mpr.289. 20. hedges lv, olkin i. statistical methods for meta-analysis. san diego, california, usa: academic press, 1985. pp. 76–81. 21. rosenthal r. meta-analytic procedures for social research. newbury park, california, usa: sage publications inc., 1991. pp. 43–89. 22. chen h, manning ak, dupuis j. a method of moments estimator for random effect multivariate meta-analysis. biometrics 2012; 68:1278–84. doi: 10.1111/j.1541-0420.20 12.01761.x. 23. riley rd, higgins jp, deeks jj. interpretation of random effects meta-analyses. bmj 2011; 342:d549. doi: 10.1136/bmj. d549. 24. tanabe p, gimbel r, yarnold pr, kyriacou dn, adams jg. reliability and validity of scores on the emergency severity index version 3. acad emerg med 2004; 11:59–65. doi: 10.1197/j.aem.2003.06.013. 25. wuerz rc, travers d, gilboy n, eitel dr, rosenau a, yazhari r. implementation and refinement of the emergency severity index. acad emerg med 2001; 8:170–6. doi: 10.1111/j.15532712.2001.tb01283.x. 26. travers da, waller ae, bowling jm, flowers d, tintinalli j. five-level triage system more effective than three-level in tertiary emergency department. j emerg nurs 2002; 28:395– 400. doi: 10.1067/men.2002.127184. 27. eitel dr, travers da, rosenau am, gilboy n, wuerz rc. the emergency severity index triage algorithm version 2 is reliable and valid. acad emerg med 2003; 10:1070–80. doi: 10.1197/s1069-6563(03)00350-6. 28. travers da, agans r, eitel d, mecham n, rosenau a, tanabe p, et al. reliability evaluation of the emergency severity index version 4. acad emerg med 2006; 13:s126. doi: 10.1111/j.1553-2712.2006.tb02227.x. 29. choi m, kim j, choi h, lee j, shin s, kim d, et al. reliability of emergency severity index version 4. ann emerg med 2009; 54:s95–6. doi: 10.1016/j.annemergmed.2009.06.336. 30. platts-mills tf, travers d, biese k, mccall b, kizer s, lamantia m, et al. accuracy of the emergency severity index triage instrument for identifying elder emergency department patients receiving an immediate life-saving intervention. acad emerg med 2010; 17:238–43. doi: 10.1111/j.1553-2712.2010.00670.x. 31. grossmann ff, zumbrunn t, frauchiger a, delport k, bingisser r, nickel ch. at risk of undertriage? testing the performance and accuracy of the emergency severity index in older emergency department patients. ann emerg med 2012; 60:317–25. doi: 10.1016/j.annemergmed.2011.12.013. 32. durani y, brecher d, walmsley d, attia m, loislle j. the emergency severity index (version 4): reliability in pediatric patients. acad emerg med 2007; 14:s95. doi: 10.1197/j. aem.2007.03.704. 33. jafari-rouhi ah, sardashti s, taghizadieh a, soleimanpour h, barzegar m. the emergency severity index, version 4, for pediatric triage: a reliability study in tabriz children’s hospital, tabriz, iran. int j emerg med 2013; 6:36. doi: 10.1186/1865-1380-6-36. 34. ho a, tintinalli j, travers d. emergency severity index for psychiatric triage. acad emerg med 2007; 14:s135. doi: 10.1197/j.aem.2007.03.704. 35. van veen m, moll ha. reliability and validity of triage systems in paediatric emergency care. scand j trauma resusc emerg med 2009; 17:38. doi:10.1186/1757-7241-17-38. 36. agency for healthcare research and quality, united states department of health & human services. emergency severity index (esi): a triage tool for emergency department 2012 edition of the implementation handbook, version 4. from: www.ahrq.gov/professionals/systems/hospital/esi/ esihandbk.pdf accessed: apr 2014. 37. eliasziw m, young sl, woodbury mg, fryday-field k. statistical methodology for the concurrent assessment of interrater and intrarater reliability: using goniometric measurements as an example. phys ther 1994; 74:777–88. 38. hogan tp, benjamin a, brezinski kl. reliability methods: a note on the frequency of use of various types. educ psychol meas 2000; 60:523–31. doi: 10.1177/00131640021970691. 39. cohen j. weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit. psychol bull 1968; 70:213–20. doi: 10.1037/h0026256. 40. le may a, mulhall a, alexander c. bridging the research practice gap: exploring the research cultures of practitioners and managers. j adv nurs 1998; 28:428–37. doi: 10.1046/j.1365-2648.1998.00634.x. 41. göransson ke, ehrenberg a, marklund b, ehnfors m. emergency department triage: is there a link between nurses’ personal characteristics and accuracy in triage decisions? accid emerg nurs 2006; 14:83–8. doi: 10.1016/j. aaen.2005.12.001. department of radiology, armed forces hospital, muscat, oman *corresponding author e-mail: drphilipsgm@yahoo.com قيلة ملفية حوضية أعراضية ثنائية اجلانب وكبرية عقب استئصال َجْذرِيَّ للربوستاتة فيليب�س مي�شيل, راكي�س ج�خم�نديك�ر, ج�ير�س كوك�دي, �شعيد الأغربي large bilateral symptomatic pelvic lymphoceles following a radical prostatectomy *philips g. michael, rakesh jamkhandikar, girish l. kukade, said k. s. al-aghbari a 55-year-old male presented to the accident & emergency department of the armed forces hospital, muscat, oman, in 2012 with increased micturition, dysuria, bilateral loin pain and progressive bilateral lower limb swelling. two months previously, he had undergone an open radical prostatectomy with open pelvic lymph node dissection for an adenocarcinoma with a gleason score of 7 (3 + 4). there was no other relevant prior medical history. on physical examination, the patient was afebrile with normal vital signs. an abdominal examination revealed a 7 cm vertical healed surgical scar in the midline suprapubic region with lower abdominal tenderness. mild bilateral pitting pedal oedema was noted. all preliminary routine investigation results were within normal limits. ultrasonography and non-contrast computed tomography (ct) of the kidney and urinary bladder region revealed two large well-defined cystic lesions in the lower pelvis, along the inner aspect of the iliopsoas muscles. the lesions were compressing the bladder from either side, resulting in a significant narrowing of the bladder lumen [figures 1a & b]. the right lesion had a volume of 131 ml, while the left lesion was 193 ml in volume. intravenous urography confirmed the extrinsic compression of the bladder, resulting in an hourglass appearance [figure 1c]. in order to relieve the patient’s urinary symptoms, ct-guided percutaneous catheter drainage and aspir ation of the cystic collections was performed, which confirmed the diagnosis of large bilateral postoperative pelvic lymphoceles. a six-month follow-up ct scan revealed complete regression of the leftsided lymphocele, while the one on the right side had recurred and required repeated drainage [figure 2]. during this period, the patient’s urinary symptoms and bilateral pedal oedema gradually abated. subsequently, there was complete resolution of the right-sided lymphocele and the patient recovered fully. figure 1: a: ultrasound image showing large hypoechoic pelvic collections (arrows) with compression on the bladder lumen of a 55-year-old male following an open radical prostatectomy with concomitant pelvic lymph node dissection. b: axial computed tomography of the bladder revealing lymphoceles (arrows) in the form of bilateral large hypodense fluid attenuation collections along the inner aspect of the iliopsoas muscle. c: an intravenous urogram of the contrastfilled bladder demonstrating the degree of extrinsic compression by the lymphoceles (arrows). note the bilateralmetallic surgical clips adjacent to the inferior aspect of the bladder. ub = urinary bladder. interesting medical image sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e525–526, epub. 30 nov 16 submitted 12 jun 16 revision req. 21 jun 16; revision recd. 3 aug 16 accepted 31 aug 16 doi: 10.18295/squmj.2016.16.04.023 large bilateral symptomatic pelvic lymphoceles following a radical prostatectomy e526 | squ medical journal, november 2016, volume 16, issue 4 patients with symptomatic lymphoceles rarely require open surgery; uniloculated lesions are usually managed successfully via simple interventions such as ultrasound or ct-guided percutaneous drainage with or without sclerotherapy, while multiloculated lesions can be treated laparoscopically.3,5 according to gust et al., asymptomatic lymphoceles of less than 100 ml do not require treatment; however, prophylactic or early interventions should be considered for larger lymphoceles in order to prevent complications like deep vein thrombosis or the formation of pelvic abscesses.1 stolzenburg et al. recommended that peritoneal fenestration be routinely performed after a concomitant radical prostatectomy and pelvic lymph node dissection, as this significantly reduces the incidence of both symptomatic and asymptomatic lymphoceles, without an increase in postoperative morbidity.3 this procedure involves the surgical creation of a peritoneal window to drain fluid from the lymphocele into the peritoneal cavity, after which a tongue of omentum is brought down and placed through the window to prevent it from closing. references 1. gust km, engel o, schertl u, kuefer r, rinnab l. clinical significance of postoperative lymphoceles following pelvic lymph node dissection in prostate cancer disease. nephrourol mon 2009; 1:94–102. 2. heers h, laumeier t, olbert pj, hofmann r, hegele a. lymphoceles post-radical retropubic prostatectomy: a retrospective evaluation of epidemiology, risk factors and outcome. urol int 2015; 95:400–5. doi: 10.1159/000381463. 3. stolzenburg ju, wasserscheid j, rabenalt r, do m, schwalenberg t, mcneill a, et al. reduction in incidence of lymphocele following extraperitoneal radical prostatectomy and pelvic lymph node dissection by bilateral peritoneal fenestration. world j urol 2008; 26:581–6. doi: 10.1007/s00345008-0327-3. 4. keskin ms, argun öb, öbek c, tufek i, tuna mb, mourmouris p, et al. the incidence and sequela of lymphocele formation after robot-assisted extended pelvic lymph node dissection. bju int 2016; 118:127–31. doi: 10.1111/bju.13425. 5. treiyer a, haben b, stark e, breitling p, steffens j. univs. multiloculated pelvic lymphoceles: differences in the treatment of symptomatic pelvic lymphoceles after open radical retropubic prostatectomy. int braz j urol 2009; 35:164–9. doi: 10.1590/s1677-55382009000200006. comment a lymphocele is a collection of lymphatic fluid occurr ing after surgical dissection as a result of inadequate closure of the afferent lymphatic vessels.1 pelvic lymphoceles are a known complication of concomitant pelvic lymph node dissection and radical prostatectomy.2 while up to 15% of patients treated by radical prostatectomy may develop postoperative pelvic lymphoceles, only 2.6% of these are symptomatic.2 symptomatic patients usually present with pelvic bloating, lower abdominal pain, increased urinary frequency and lower limb oedema, all of which can be attributed to the mass effect of the lymphoceles on the adjacent pelvic organs and veins.3 the risk of developing symptomatic lymphoceles is lower after laparoscopic surgery in comparison to open surgery.2 in the current case, the patient had undergone open surgery, which likely contributed to the formation of large symptomatic lymphoceles. the possibility of lymphocele formation following a radical prostatectomy should therefore be considered among patients who present with lower abdominal and urinary symptoms. in a retrospective study of 521 patients who had undergone robot-assisted extended pelvic lymph node dissection, keskin et al. found that only 2.5% of patients developed symptomatic lymphoceles that required intervention; however, patients with diabetes mellitus had a signifi cantly higher risk of developing symptomatic or infected lymphoceles.4 figure 2: axial computed tomography scan of a 55-year-old male with large bilateral pelvic lymphoceles six months after percutaneous catheter drainage and aspiration. the left-sided lymphocele showed complete regression, although the lymphocele on the right side had recurred (arrow) and required an in situ drain. clinical & basic research sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e361-368, epub. 24th jul 14 submitted 25th nov 13 revision req. 21st jan 14; revision recd. 20th feb 14 accepted 6th mar 14 departments of 1pediatrics and 3medical education, college of medicine & health sciences, united arab emirates university, al ain, united arab emirates; 2faculty of health sciences & medicine, bond university, gold coast, queensland, australia *corresponding author e-mail: e.aburawi@uaeu.ac.ae تقييم أعضاء هيئة التدريس هل طالب الطب وهيئة التدريس متفقان؟ الهادي اأبوراوي، مي�سيل ماكلن و�سامي �سعبان abstract: objectives: student evaluation of individual teachers is important in the quality improvement cycle. the aim of this study was to explore medical student and faculty perceptions of teacher evaluation in the light of dwindling participation in online evaluations. methods: this study was conducted at the united arab emirates university college of medicine & health sciences between september 2010 and june 2011. a 21-item questionnaire was used to investigate learner and faculty perceptions of teacher evaluation in terms of purpose, etiquette, confidentiality and outcome on a five-point likert scale. results: the questionnaire was completed by 54% of faculty and 23% of students. faculty and students generally concurred that teachers should be evaluated by students but believed that the purpose of the evaluation should be explained. despite acknowledging the confidentiality of online evaluation, faculty members were less sure that they would not recognise individual comments. while students perceived that the culture allowed objective evaluation, faculty members were less convinced. although teachers claimed to take evaluation seriously, with medical sciences faculty members in particular indicating that they changed their teaching as a result of feedback, students were unsure whether teachers responded to feedback. conclusion: despite agreement on the value of evaluation, differences between faculty and student perceptions emerged in terms of confidentiality and whether evaluation led to improved practice. educating both teachers and learners regarding the purpose of evaluation as a transparent process for quality improvement is imperative. keywords: evaluation studies; faculty; feedback; medical students; undergraduate medical education; united arab emirates. امللخ�ص: الهدف: تقييم املتعلم للمعلمني ب�سكل فردي اأمر مهم يف دورة حت�سني اجلودة. هدف البحث اإىل ا�ستك�ساف روؤية طلبة الطب واأع�ساء هيئة التدري�س نحو تقييم املعلم. الطريقة: اأجريت هذه الدرا�سة يف كلية الطب والعلوم ال�سحية يف جامعة الإمارات يف دولة الإمارات العربية املتحدة. مت ا�ستخدام ا�ستبيان يحتوي على اإحدى وع�رسين بندا على مقيا�س بخم�سة نقاط )ليكرت( لتقييم روؤية كال من املتعلم و اأع�ساء هيئة التدري�س يف تقييم املعلمني من حيث الغر�س والآداب وال�رسية النتائج: اأكمل ال�ستبيانات %54 من اأع�ساء هيئة التدري�س و%23 من الطالب. اتفق هيئة التدري�س والطالب عموما على اأهمية تقييم املعلمني من قبل الطالب فرديا ، ولكن بعد �رسح واف للغر�س من التقييم. على الرغم من اإقرار الكلية على �رسية التقييم عرب الإنرتنت كان املعلمون اأقل ثقة من اإمكانية تعرفهم على �سخ�سية املتعلمني من خالل التعليقات الفردية. اأقر الطالب على اأن الثقافة احلالية ت�سمح بتقييم مو�سوعي، اإل اأن اأع�ساء هيئة التدري�س كانوا اأقل اقتناعا. على الرغم من اأن املعلمني ادعوا باأنهم ياأخذون التقييم على حممل اجلد، وبالذات معلمو املراحل الأوىل ويقومون باإحداث حت�سينات يف املنهاج ويف تدري�سهم بناء على هذه التعليقات، اإل اأن الطالب كانوا اأقل اقتناعا بذلك. اخلال�صة: على الرغم من التفاق العام ب�ساأن قيمة تقييم املعلم، برزت خالفات بني اأع�ساء هيئة التدري�س والطالب من حيث التحقق من ال�رسية ورد فعل املعلمني للتقييم، واإن ما كان �سيوؤدي اإىل حت�سني العملية التعليمية اأم ل. نو�سي بتثقيف املعلمني واملتعلمني بخ�سو�س الغر�س من التقييم مع اأهمية ال�سفافية و�سمان ال�رسية لتح�سني اجلودة و ت�سجيع امل�ساركة. مفتاح الكلمات: التقييم؛ اأع�ساء هيئة التدري�س؛ ردود فعل؛ طالب الطب؛ التعليم الطبي للمرحلة اجلامعية الأوىل؛ دولة الإمارات العربية املتحدة. evaluation of faculty are medical students and faculty on the same page? *elhadi aburawi,1 michelle mclean,2 sami shaban3 advances in knowledge this study confirmed that there was reasonable agreement between teachers and students on the value of teacher evaluation. the study also found, however, that faculty and student perceptions differed in terms of confidentiality, what teachers do with evaluation feedback and whether the process of evaluation leads to improved practice. application to patient care improvements in the medical education of students will indirectly improve patient care once the students have completed their studies. the evaluation of individual teachers should be a transparent process for quality improvement; educating teachers and learners regarding the purpose of evaluation is vital. evaluation of faculty are medical students and faculty on the same page? e362 | squ medical journal, august 2014, volume 14, issue 3 academic faculty members are generally not appointed for their teaching prowess; instead, their publication history and grant records are often the deciding factors for their appointment. increasingly, however, it is being recognised that teaching is a scholarly activity requiring specific skills and deliberate practice.1 the evaluation of teachers by learners as well as peers is therefore a valuable tool, serving as both a formative (e.g. feedback to improve practice) and summative (e.g. promotion or tenure) measure.2,3 feedback from learners is also an important part of the quality improvement cycle, not only in terms of courses and programmes but also for the professional development of individual educators.3‒5 as students are at the coalface of the delivered and the informal or ‘hidden’ curriculum, their perceptions of learning provide feedback to improve the ‘experienced’ curriculum.6 successful quality assurance in teaching and learning, however, has several requirements, not least of which is establishing a culture of continuous improvement in which learners and teachers develop a sense of ownership of and commitment to a transparent evaluation process.4,5,7‒9 the college of medicine & health sciences (cmhs) at the united arab emirates university (uaeu) is a federal institution providing medical training for emirati students. faculty members, who are generally recruited internationally, are mostly male even though female students outnumber their male counterparts at a ratio of approximately 4:1. the cmhs curriculum consists of three courses each of two years’ duration: the medical sciences course (msc), organ systems course (osc) and clinical sciences course (csc). during the msc, osc and csc, students complete 10 units, 11 modules (including clinical skills) and 10 clerkships, respectively. in msc, the teaching format is largely didactic, while osc comprises a hybrid problem-based learning (pbl) approach. in csc, approximately six students rotate through several specialties over a period of two years. units, modules and clerkship rotations usually run for six weeks. one week prior to the end-of-course examination in each unit, module or clerkship, students are informed of the availability of an anonymous online evaluation, which comprises 10 short statements relating to the unit, module or clerkship they have just completed. two open-ended items are included: what contributed the most to your personal and professional development during this unit/module/rotation? and what can be improved in this unit/module/rotation? students also evaluate their teachers or tutors and these evaluations are used for annual professional development as well as for re-contracture and promotion purposes. student participation in online evaluation has steadily declined to below 30% over the past few years. although regularly discussed at various committees, students and faculty are divided on how to address this issue. reservation has been expressed about the confidentiality of online evaluation. faculty members have also complained about receiving personal, sometimes derogatory, comments. in light of the dwindling student responses to the regular evaluation of courses in the six-year medical programme at uaeu, this study set out to investigate teachers’ and learners’ perceptions of individual teacher evaluation. it was hoped that the survey would provide insight into why students do not participate in evaluation, a common phenomenon in higher education.9‒11 the present study therefore sought to identify student and academic perceptions of and concerns about evaluation. methods all academics and students at the cmhs were invited by email to participate in a web-based survey between september 2010 and june 2011, with two follow-up reminder e-mails being sent to encourage participation. on the opening screen of the survey, participants were informed that completion was taken as consent to participate. the 21-item online questionnaire was adapted from schmelkin et al.’s 16-item pen and paper faculty rating inventory and used to canvas student and faculty perceptions about evaluation in terms of its purpose, value, confidentiality, the etiquette required and the academics’ response to the evaluation.6,12 two items were removed from the original inventory as the survey was web-based; six items were added relating to local context and based on informal faculty and student comments about evaluation. the staff version of the questionnaire mirrored the student version. the english language instructor read the questionnaire to check its suitability for students with english as a second language. a five-point likert scale was used with 1 = strongly disagree and 5 = strongly agree. two to this end, findings from the study indicated that guaranteeing the confidentiality of students’ comments would encourage their participation in the feedback process. furthermore, evaluation should be rationalised, with the recognition that student input is only one part of the evaluation process. elhadi aburawi, michelle mclean and sami shaban clinical and basic research | e363 open-ended items were included to allow students and faculty to comment on any issue relating to evaluation and to provide suggestions for improvement. participants were assured of the anonymity of their data. data were downloaded to a microsoft excel file and imported into the statistical package for the social sciences (spss), version 19 (ibm, corp., chicago, illinois, usa). given the categorical nature of these variables, non-parametric tests were chosen. the mann-whitney u test was used for two-group comparisons (i.e. staff versus students; males versus females; medical science versus clinical courses; years in academia, etc.) and the kruskal-wallis test was used to compare more than two groups (i.e. student level and academic rank). significance was adjusted for multiple testing using the holm-bonferroni method.13 the sample size was too small to perform factor analysis. cronbach’s alpha was 0.38 for the learner survey and 0.30 for the faculty survey. this low internal consistency is probably due to the small sample size of the students and the diverse background of the faculty. ethical approval for this study was obtained from the al ain medical district human research ethics committee, uaeu (protocol no. 2010/30) in may 2010. results in total, 52 (54%) faculty members and 80 (23%) students completed the questionnaire. by course, the response rates were as follows: msc (47.5%), osc (35%) and csc (17.5%) [table 1]. while the results of the study suggest general agreement in terms of the need for evaluation and who should perform the evaluation, faculty and student perceptions were not always congruent with respect to its purpose and process and issues concerning confidentiality [table 2]. both faculty and students (seniors, in particular) were unanimous that the purpose of evaluation should be explained to students at the outset of their studies. responses to the two open-ended items indicated that evaluation etiquette was a crucial factor. some faculty members (17%), mainly in the msc, indicated that they had received derogatory comments, while some students (9%), particularly juniors, admitted to making such comments [tables 2 and 3]. while respondents were generally comfortable with the security and confidentiality of the online evaluation, with 61% agreeing or strongly agreeing, faculty members (particularly clinicians [50%], assistant professors [53%] and academics in academia less than eight years [53%]) were less convinced than the students (59% agreeing or strongly agreeing) [tables 2 and 3]. interestingly, the timing of the evaluation was questioned by students, who suggested that it should be more rather than less frequent. this was mostly because they believed that teachers would be more likely to make changes during the semester if the students could comment during the semester, rather than at the end. in this way, the students themselves would benefit from any changes rather than the next cohort of students. as one second-year male msc student commented, “mid-unit evaluations that the teachers will look at is better for the student because it may help us during the unit not that it will help students in the next year. this will give the students the hope that it will be useful for them.” in addition, evaluation just prior to an examination was not ideal, according to students, as they were too busy and would either hurry through it or not even attempt it. another interesting comment was that evaluation should take place immediately following the final examination so that both the teachers and the assessment itself could be evaluated. in terms of evaluation outcome, students were less convinced than faculty that teachers responded to student feedback [tables 2 and 3], with responses from osc and csc learners suggesting that students table 1: demographic details of the faculty and students participating in the survey participants demographic information n faculty 52 title assistant professor 15 associate professor 22 professor 15 academic responsibility premedical (msc and osc) 20 csc 32 teaching experience >8 years 34 <8 years 18 students 80 gender male 14 female 66 course msc 38 osc 28 csc 14 msc = medical sciences course; osc = organ systems course; csc = clinical sciences course. evaluation of faculty are medical students and faculty on the same page? e364 | squ medical journal, august 2014, volume 14, issue 3 table 2: faculty (n = 52) and student (n = 80) responses on a five-point likert-scale to the adapted 21-item questionnaire in terms of confidentiality, purpose, outcome and etiquette (1 = strongly disagree, 5 = strongly agree) item faculty/ student mean score ± sd mann-whitney u confidentiality student comments/evaluation of individual instructors/teachers are confidential and should be for his/her/my eyes only. student 3.20 ± 1.39 0.002* faculty 2.46 ± 1.18 teachers/instructors can recognise individual student comments in the evaluation they receive. student 3.23 ± 0.95 0.000* faculty 2.35 ± 1.12 i am comfortable with the security (i.e. confidentiality) of the online evaluation system. student 3.59 ± 1.20 0.863 faculty 3.67 ± 1.01 evaluators faculty members should not be evaluated by students. student 1.63 ± 1.06 0.370 faculty 1.67 ± 0.93 in general, student evaluations do not provide any useful feedback to individual teachers/instructors. student 2.20 ± 0.89 0.185 faculty 2.02 ± 0.86 peers (i.e. other faculty members) are better than students at evaluating teaching ability. student 1.98 ± 0.93 0.005* faculty 2.59 ± 1.22 the culture allows students to objectively evaluate an individual’s teaching ability. student 3.56 ± 0.73 0.000* faculty 2.83 ± 1.11 students are not sufficiently qualified to judge teaching ability. student 2.18 ± 1.10 0.443 faculty 2.30 ± 1.06 evaluation process students write comments only when they feel very positively about the teacher/ instructor. student 2.66 ± 1.18 0.134 faculty 2.37 ± 1.17 most students take evaluation seriously.† student 2.80 ± 1.11 0.819 faculty 2.72 ± 1.04 the purpose of evaluation should be explained to students at the outset of their studies. student 4.21 ± 0.84 0.479 faculty 4.28 ± 0.92 evaluation of individual units/modules/clerkships does not need to be done every unit/module/clerkship. student 2.00 ± 0.98 0.022 faculty 2.48 ± 1.24 individual teacher evaluations for each unit/module/clerkship are timeconsuming for students to complete. student 2.78 ± 1.09 0.618 faculty 2.67 ± 1.20 the current fmhs criteria against which students evaluate instructors is adequate. student 3.06 ± 0.85 0.767 faculty 3.09 ± 1.03 response to evaluation teachers frequently make changes to their teaching in response to student evaluations. student 3.40 ± 0.92 0.000* faculty 3.91 ± 1.01 instructors do not take the students’ written feedback/comments seriously. student 2.76 ± 0.93 0.000* faculty 1.69 ± 0.87 it is difficult to get students to complete evaluations because they believe that the faculty does not respond to their feedback. student 3.41 ± 1.12 0.037 faculty 3.04 ± 1.08 teachers should view student comments collectively rather than responding to individual student comments. student 3.80 ± 1.21 0.383 faculty 3.70 ± 1.09 student comments should not be used for a teacher’s promotion. student 3.10 ± 1.27 0.719 faculty 3.02 ± 1.30 etiquette faculty members can manipulate their ratings (i.e. receive high scores) through certain behaviours and interactions with students. student 3.09 ± 1.11 0.057 faculty 3.43 ± 1.34 i have made a derogatory (insulting) personal comment about a teacher in an evaluation. student 1.93 ± 1.03 0.062 faculty 2.28 ± 1.14 sd = standard deviation; fmhs = faculty of medicine & health sciences. *significant using the holm-bonferroni method starting at alpha 0.05/21, then 0.05/20, etc.13 †only 79 students responded to this question. elhadi aburawi, michelle mclean and sami shaban clinical and basic research | e365 table 3: responses of the faculty of the medical sciences (n = 20) and clinical sciences (n = 32) courses on a fivepoint likert-scale to the adapted 21-item questionnaire in terms of confidentiality, purpose, outcome and etiquette (1 = strongly disagree, 5 = strongly agree) item course mean ± sd mann-whitney u confidentiality student comments/evaluations are confidential and are for my eyes only. msc 2.30 ± 1.08 0.581 csc 2.53 ± 1.27 teachers/instructors can recognise individual student comments in their evaluation. msc† 2.26 ± 1.05 0.606 csc 2.44 ± 1.11 i am comfortable with the security (i.e. confidentiality) of the online evaluation system. msc 4.25 ± 0.64 0.001* csc 3.34 ± 1.06 evaluators faculty members should not be evaluated by students. msc 1.95 ± 1.05 0.048 csc 1.47 ± 0.80 in general, student evaluations do not provide useful feedback to me as an individual teacher/instructor. msc 2.00 ± 1.03 0.540 csc 2.03 ± 0.74 peers (i.e. other faculty members) are better than students at evaluating teaching ability. msc 2.95 ± 1.57 0.239 csc 2.38 ± 0.87 the culture allows students to objectively evaluate an individual's teaching ability. msc 2.70 ± 1.22 0.442 csc 2.91 ± 1.06 students are not sufficiently qualified to judge teaching ability. msc 2.50 ± 1.28 0.361 csc 2.16 ± 0.85 evaluation process students write comments only when they feel positive about/happy with the teacher/instructor. msc 2.30 ± 1.30 0.475 csc 2.44 ± 1.13 most students take evaluation seriously. msc 2.60 ± 1.19 0.380 csc 2.84 ± 0.95 the purpose of evaluation should be explained to students at the outset of their studies. msc 4.50 ± 0.61 0.243 csc 4.13 ± 1.07 evaluation of individual units/modules/clerkships does not need to be done for every unit/module/clerkship. msc 2.75 ± 1.37 0.518 csc† 2.45 ± 1.09 individual teacher evaluations for each unit/module/clerkship are timeconsuming for students to complete. msc 2.90 ± 1.37 0.395 csc† 2.58 ± 0.99 the current fmhs criteria against which students evaluate instructors is adequate. msc 3.20 ± 1.06 0.774 csc 3.06 ± 1.05 response to evaluation i frequently make changes to my teaching in response to student evaluations. msc 4.30 ± 0.80 0.017 csc 3.72 ± 1.05 i don't take students’ feedback/comments seriously. msc 1.75 ± 0.91 0.594 csc 1.63 ± 0.87 it is difficult to get students to complete evaluations because they believe that the faculty does not respond to their feedback. msc 3.15 ± 1.18 0.618 csc 2.94 ± 1.05 teachers should view student comments collectively rather than responding to individual student comments. msc 3.55 ± 1.28 0.598 csc 3.78 ± 1.01 student comments should not be used for promotion (i.e. should not be summative). msc 3.25 ± 1.48 0.271 csc 2.84 ± 1.14 etiquette faculty members can manipulate their ratings (i.e. receive high scores) through certain behaviours and interactions with students. msc 3.60 ± 1.47 0.308 csc 3.35 ± 1.14 i have received a personal comment that i consider derogatory (insulting) from students in evaluations. msc 2.80 ± 1.28 0.007 csc 1.84 ± 0.77 sd = standard deviation; msc = medical sciences course; csc = clinical sciences course; fmhs = faculty of medicine & health sciences. *significant using the holm-bonferroni method starting at alpha 0.05/21, then 0.05/20, etc.;13 †one response missing. evaluation of faculty are medical students and faculty on the same page? e366 | squ medical journal, august 2014, volume 14, issue 3 do not complete evaluations if they think faculty do not respond to the feedback, with 85% agreeing or strongly agreeing. in terms of teachers making changes to their practice as a result of evaluation feedback, clinical teachers (81%) appeared to be less likely to do so [table 3]. only a single student made a comment about how an academic might respond to negative feedback. according to that commenter, a first-year female msc student, “the teacher might not like what he/she reads therefore might develop some kind of ‘grudge’ or whatever against a certain batch [cohort] due to evaluation because they are incapable of accepting criticism”. in this study, all students were emirati nationals while the academics were mainly expatriates. although students strongly agreed that the ‘culture’ allowed them to evaluate their teachers objectively (63% agreeing or strongly agreeing), faculty members were less convinced (31% agreeing or strongly agreeing) [tables 2 and 3]. the following comments offer some insight into their responses from both student and staff perspectives. one member of the medical sciences faculty wrote, “student evaluation is often used for re-contracture, promotion. in this culture, faculty who are ‘tough’ on students, make them work, etc. are sometimes punished by students in the evaluation.” one member of the clinical faculty commented on the cultural difficulties students might face in evaluating professors: “students worry about evaluating people badly out of cultural respect and out of worry that this will come back to them in the future.” discussion in general, the findings of this survey indicate that the learners and faculty of the cmhs at uaeu were “on the same page” in terms of the purpose and process of evaluation, with both parties viewing evaluation as a valuable tool for improving courses and programmes and for informing teachers’ professional development. the process, however, needs to be transparent and the feedback received needs to be seen to be acted upon.4 this study identified several issues that should be addressed if evaluation is to serve its purpose better; this may in turn translate into improved learner participation. while these issues have emerged in a particular institutional context and perhaps ‘culture’, the authors believe that these issues are not unique to this setting as they address the foundations of quality evaluation. a clear message that emerged from the findings was the need for a common understanding of the purpose, process and etiquette of evaluation. this could be achieved by explaining the evaluation process, including confidentiality, at the outset of a learner’s studies. being transparent about the anonymity of responses might encourage participation, while being informed of the expectations of the evaluation process might obviate the derogatory comments some students indicated they had made and some faculty indicated they had received. a first-year female csc student suggested a further way of addressing this problem: “maybe some students use this evaluation to insult teachers. so, maybe someone should filter the comments before giving it to the teachers because they work hard and it is not ‘ethical’ to use the evaluation to convey personal opinions about a person rather than their way of teaching and i am sure that receiving such comments is disturbing!” in addition, although only one student commented on the potential of a negative response by the faculty member towards their evaluation, it is a reminder that such a reaction is possible on the part of the individual being evaluated. this reaffirms the need for confidentiality to be emphasised in all aspects of the evaluation process. furthermore, academics need to understand that evaluation is a two-way process: if learners provide quality feedback, teachers need to be seen responding appropriately.9 in addition, teachers need to view student comments collectively rather than taking umbrage at individual comments. how the institution uses evaluation is also important, as one medical science faculty member commented, “it will be beneficial to us only if faculty know it is not punitive and also accept some of the comments at face value.” unfortunately, evaluation is too often perceived and used as a wedge to obstruct advancement and not as a tool for improving teaching practice.3 collectively, the findings of this study translate into a plan of action—to develop an appropriate institutional culture of mutual trust and respect where transparency of the evaluation purpose and outcomes obviate the fear of retribution, both from the perspective of the givers as well as the receivers of feedback. this culture should be one in which students can be honest, courteous and objective and teachers can reflect on the broader implications of the feedback received. this requires moving from an ethos of ‘reporting’ to one of ‘dialogue’.4 undoubtedly, the institutional context—perhaps reflecting the local ‘culture’—should be taken into consideration. the context of this study, in which the students were local emiratis and the faculty were mostly expatriate, may be considered somewhat unusual at face value. globalisation and the increasing emergence of higher education as a business mean, however, that both learners and faculty are now elhadi aburawi, michelle mclean and sami shaban clinical and basic research | e367 being recruited internationally.14 in situations where different worldviews abound, unless learners and teachers are “on the same page”, the purpose and value of evaluation needs to be explicitly stated and welladvertised. the timing of the evaluation was also found to have implications. the results suggest that the common practice of scheduling evaluations just prior to a final examination may not be the best strategy as learners are busy and distracted. while there is no consensus in terms of the timing, berk is of the opinion that the window needs to be narrow and should meet the desired purpose.15 the suggestion from the learners to allow the evaluation to remain open until after the assessment was interesting and not unusual.15 while this would allow more time for students to respond, it may be used by some students to comment on specific teachers whose examinations questions they had considered “difficult”. a common complaint from students was that they did not benefit from improvements implemented as a result of feedback if the evaluation was at the end of the course. evaluation performed mid-way through the semester would address this. an alternate suggestion was to have the evaluation system open throughout the duration of the course, allowing students to provide continuous feedback and encouraging the instructor to address issues as they arose. as academic managers, it is imperative to rationalise how, when and why evaluation is undertaken. for example, the following questions should be posed: what is the purpose of the evaluation? do we need to evaluate every module or course every year? do we need to evaluate every teacher each year? when is the best time to evaluate? from where do we gather additional evidence? if evaluation becomes a planned strategy of quality improvement with clear aims which are agreed to by all stakeholders, faculty evaluations might then be held on an “as-needed” basis (e.g. for new appointments or promotions). in addition, it is important to also decide upon what constitutes a “reliable response”.7,10,15,16 a lower response rate might provide more valid feedback than a 90% response rate in which students hurriedly complete evaluation in order to receive their grades. qualitative approaches such as interviews and focus groups by an independent facilitator may provide a richer and more in-depth perspective on learners’ experiences.14,15,17 the benefit of a more focussed and reduced sample is that less commitment is required from each student. as a result, students can take part in a single targeted evaluation rather than all of them, which may encourage participation.17‒19 this should, however, not exclude students who wish to partipate voluntarily.16 goldfarb and morrison’s model of continuous curricular feedback with a small group of trained students and faculty is appealing as it addresses many of the issues discussed.18 as feedback on teaching is often used summatively, it is important to acknowledge that students are not always best qualified to judge a teacher’s methodology and expertise. as berk clarifies, when student ratings are the only method being used, this runs the risk of unfair decisions about a faculty member’s abilities. ratings need to be supported by other evidence, such as peer and self-evaluation.15 a step in the quality improvement cycle which is often omitted is that of providing participants with feedback on the evaluation. this should not only be in terms of what changes are to be implemented as a result of their feedback but also on the quality of their individual evaluation.9,17 this will allow for an open dialogue between course coordinators, designers and learners as well as between learners and their teachers. it would also lend credibility to the overarching purpose of evaluation, that of quality improvement, and will also hopefully encourage participation. this study has certain limitations. only 23% of students responded, which more or less reflects evaluation response rates reported in the literature.9‒11 in addition, students who completed the survey were probably those individuals who regularly complete such evaluations. as stated earlier, a low response to evaluation is a common phenomenon in higher education. despite this, and also considering that these results reflect the perceptions of students and faculty at one institution in the middle east and so may not be generalisable outside of this context, the authors believe that several important messages have emerged from this study that are applicable to the wider higher education community. conclusion the aim of this research was to gain insight into the declining student response to teacher evaluations in one faculty in the middle east. while there was reasonable consensus on the value of teacher evaluations, faculty and students differed in their responses, particularly in terms of perceptions regarding confidentiality, what teachers did with feedback and whether evaluation led to improved practice. several important messages emerged from these results. evaluation, with evidence from multiple sources, must be undertaken as a transparent quality improvement exercise. this requires fostering a culture of trust amongst the stakeholders. new teachers and learners therefore need to be informed as to whether evaluation of faculty are medical students and faculty on the same page? e368 | squ medical journal, august 2014, volume 14, issue 3 the evaluation is a formative or summative measure. furthermore, participants should be educated on acceptable evaluation etiquette and the importance of critiquing the instructor’s actions and methods rather than personality. providing students with evidence of the outcomes of their feedback, preferably with more immediate, tangible benefits, would go a long way to developing the appropriate institutional culture. ensuring anonymity, such as with an online system, is also key to participation. a c k n o w l e d g e m e n t s the authors wish to thank the cmhs faculty and students at the uaeu for their participation in this study. references 1. mclean m. how to professionalise your practice as a health professions educator. med teach 2010; 32:953–5. doi: 10.3109/0142159x.2010.506563. 2. snell l, tallett s, haist s, hays r, norcini j, prince k, et al. a review of the evaluation of clinical teaching: new perspectives and challenges. med educ 2000; 34:862‒70. doi: 10.1046/j.13652923.2000.00754.x. 3. elzubeir m, rizk d. evaluating the quality of teaching in medical education: are we using the evidence for both formative and summative purposes? med teach 2002; 24:313‒9. doi: 10.1080/01421590220134169. 4. dolmans d, stalmeijer r, van berkel h, wolfhagen i. quality assurance of teaching and learning: enhancing the quality culture. in: dornan t, mann kv, scherpbier ajj, spencer ja, eds. medical education: theory and practice. edinburgh: churchill livingston, elsevier ltd., 2011. pp. 257‒64. 5. woloschuk w, coderre s, wright b, mclaughlin k. what factors affect students’ overall ratings of a course? acad med 2011; 86:640–3. doi: 10.1097/acm.0b013e318212c1b6. 6. hafferty fw, franks r. the hidden curriculum, ethics teaching, and the structure of medical education. acad med 1994; 69:861‒71. 7. kreiter cd, lakshman v. investigating the use of sampling for maximising the efficiency of student-generated faculty teaching evaluations. med educ 2005; 39:171‒5. doi: 10.1111/j.13652929.2004.02066.x. 8. macdougall cf. evaluation: the educational context. arch dis child educ pract ed 2010; 95:28‒32. doi: 10.1136/adc.2008.142240. 9. anderson j, brown g, spaeth s. online student evaluations and response rates reconsidered. from: www.rugby.ou.edu/content/ dam/provost/documents/evaluations/evaluate-online-studentevaluations-and-response-rates.pdf accessed: oct 2011. 10. cohen-schotanus j, schönrock-adema, schmidt hg. quality of courses evaluated by ‘predictions’ rather than opinions: fewer respondents needed for similar results. med teach 2010; 32:851‒6. doi: 10.3109/01421591003697465. 11. veerapen k, mcaleer s. students’ perception of the learning environment in a distributed medical programme. med educ online 2010; 15. doi: 10.3402/meo.v15i0.5168. 12. schmelkin lp, spencer kj, gellman es. faculty perspectives on course and teacher evaluations. res high educ 1997; 38:575‒92. doi: 10.1023/a:1024996413417. 13. holm s. a simple sequentially rejective multiple test procedure. scand stat theory appl 1979; 6:65‒70. 13. harden rm. international medical education and future directions: a global perspective. acad med 2006; 81:s22‒9. doi: 10.1097/01.acm.0000243411.19573.58. 15. berk ra. top five flashpoints in the assessment of teaching effectiveness. med teach 2013; 35:15‒26. doi: 10.3109/0142159x.2012.732247. 16. morrison j. abc of learning and teaching in medicine: evaluation. bmj 2003; 326:385‒7. doi: 10.1136/bmj.326.7385.385. 17. richardson jte. instruments for obtaining student feedback: a review of the literature. assess eval high educ 2005; 30:387‒415. doi: 10.1080/02602930500099193. 18. goldfarb s, morrison g. continuous curricular feedback: a formative evaluation approach to curricular improvement. acad med 2014; 89:264‒9. doi: 10.1097/acm.0000000000000103. 19. pelsang re, smith wl. comparison of anonymous student ballots with student debriefing for faculty evaluations. med educ 2000; 34:465‒7. doi: 10.1046/j.1365-2923.2000.00565.x. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 368-370, epub. 25th jun 13 submitted 21st may 13 peer reviewed accepted 3rd jun 13 origins, symptoms and signs a disease characterised by the ‘too great emptying of urine’ finds its place in antiquity through egyptian manuscripts dating back to 1500 b.c.1 indian physicians called it madhumeha (‘honey urine’) because it attracted ants. the ancient indian physician, sushruta, and the surgeon charaka (400–500 a.d.) were able to identify the two types, later to be named type i and type ii diabetes.2,3 recognised for the last three millennia, recorded history attributes the first complete descriptions in the first century a.d. to aretaeus the cappadocian, who coined the word diabetes (greek, ‘siphon’) and dramatically stated “… no essential part of the drink is absorbed by the body while great masses of the flesh are liquefied into urine,,.4–6 avicenna (980–1037 a.d.), the great persian physician, in the canon of medicine not only referred to abnormal appetite and observed diabetic gangrene but also concocted a mixture of seeds (lupin, fenugreek, zedoary) as a panacea.7 the term mellitus (latin, ‘sweet like honey’) was coined by the british surgeon-general, john rollo in 1798, to distinguish this diabetes from the other diabetes (insipidus) in which the urine was tasteless.1 pathophysiology through experimentation in 1869, paul langerhans, then aged 22 and working on his medical doctorate, identified the cells that came to be known as the ‘islets of langerhans’.8 however, the name insulin for the secretions of the islets (latin, insula = island), which could bring down blood glucose levels, was coined only in 1909 and 1910, individually by de mayer and schaefer, respectively.9,10 in 1889, von mering and minkowski, when experimenting on dogs, found that removal of the pancreas led to diabetes.11 in 1921, banting, best and collip, working in macleod’s laboratory, ligated the pancreatic duct, causing the destruction of the exocrine pancreas while leaving the islets intact. in their elegant animal experiments, by using canine insulin extracts to reverse induced diabetes, they conclusively established that the deficiency of insulin was the cause of diabetes.12 diagnosis willis, a london physician, epitomised the true spirit of scientific enquiry by his bold action of tasting the urine of his patients—possibly because the passage of copious urine seemed to be the hallmark of the disease! this was a supreme and extreme example of bedside testing leading to labelling a patient as diabetic if his urine was ‘honeyed’.13 urine strips in the 1960s and the automated ‘doit-yourself ’ measurement of blood glucose through glucometers, produced by ames diagnostics in 1969, brought glucose control from the emergency room to the patient’s living room. it imbued diabetic patients with a new sense of freedom, making the disease more comprehensible and manageable. department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ritu@squ.edu.om نظرة تارخيية عن مرض السكري ريتو الكتكيا medical history the history of diabetes mellitus ritu lakhtakia “… no essential part of the drink is absorbed by the body while great masses of the flesh are liquefied into urine.,, aretaeus of cappadocia ritu lakhtakia medical history | 369 routine blood sugar tests at prescribed intervals continued for a long time until the introduction of the glycosylated haemoglobin (hba1c) estimation. that test, which measured blood glucose control over the previous three months (linked to the life of red blood cells), defined an extremely important aspect of diabetes management—tight control of blood glucose levels.14 the latter directly determined the risk of the occurrence of devastating complications of target organs like the eyes, vessels, nerves and kidneys that ultimately influenced morbidity and mortality. treatment with little understanding of pathophysiology, early remedies for diabetes included diverse and interesting prescriptions like “oil of roses, dates, raw quinces and gruel, jelly of viper’s flesh, broken red coral, sweet almonds and fresh flowers of blind nettles” representing a variety of beliefs and practices of the times.4 later, in the pre-insulin era, calorie restriction reigned supreme, and graphic accounts of the terminal gasping and sighing and sweet smell (ketosis) surrounding the patient in a diabetic coma abound in the volumes written on the disease. diet and exercise advocacy was the hallmark of treatment by 19th century physicians led by joslin and fitz from the massachusetts general hospital, among others.15 this advice still remains an important component of diabetic management. it may sound bizarre today, but opium (‘syrup of poppies’) was prescribed liberally for the malady for over two hundred years from willis (1675) to joslin (1898).15,16 the rationale could only have been an easing of the symptoms originating from complications like gangrene. the 19th and 20th centuries heralded galloping advances in medicine in general and in diabetes treatment in particular. one of the miracles of the last century was the discovery of insulin by canadian surgeon banting and his assistant best. following experimentation on dogs, their life-saving infusion of a bovine extract of insulin (made by their biochemist colleague, collip) to a 14-year-old boy, leonard thompson, in 1922 at the toronto general hospital, proved to be a sensation in the world of diabetic therapy.12 it galvanised research into and the commercial production of several modifications of insulin with various durations of action, that changed the entire course of life of a significant proportion of the world populace.17 it won banting and macleod the nobel prize in physiology and medicine in 1923.18 the hat trick of nobel prizes for this important molecule was complete with subsequent winners in chemistry and medicine, respectively for its aminoacid sequence (sanger, 1958) and radioimmunoassay (yallow, 1977).19,20 however, it was not until the 1950s that the first oral antidiabetic drugs (sulphonylureas) were added to the treatment armamentarium. others, including metformin, glucosidase inhibitors and insulin sensitisers, followed in the succeeding decades with different sites of action to enable better handling and metabolic assimilation of ingested carbohydrates.1,13 traditional spices, herbs and indigenous plants used through centuries have provided supportive alternatives and potential for future research.21 in 1980, the first human insulin was manufactured by graham bell.22 in 1982, the first biosynthetic insulin (humulin) was developed. syringes appeared in 1961 but, being made of glass, brought with them the attendant hazards of infections until they were replaced with disposable plastic ones. it was only 15 years later that the introduction of the first needle-free insulin delivery system by derata in 1979 provided relatively painfree, metered doses. insulin pumps, inhaled insulin and oral sprays in recent times have shown the way ahead for ease of administration.13,23,24 history in the making in the new millennium, pancreatic transplantation, first performed in 1966,25,26 exists as a radical therapy for especially intractable type i diabetes with advanced complications. still in experiment mode, gene therapy with molecules like leptin and insulin may one day be a reality.27,28 lessons from the history of diabetes 1. the antiquity of early descriptions of diabetes underscores the importance of the observation and recording of medical conditions as humans evolve. early physicians used whatever was in their capacity (smell or even taste!) in pursuit of knowledge, skills and diagnosis. 2. age is no bar to contributing significantly to the profession; langerhans, was a 22 year old student when he wrote a thesis identifying the cells that were the history of diabetes mellitus 370 | squ medical journal, august 2013, volume 13, issue 3 26:371–87. doi:10.1007/bf01831214. 12. banting fg, best ch, collip jb, campbell wr, fletcher aa. pancreatic extracts in the treatment of diabetes mellitus: preliminary report. cmaj 1922; 12:141–6. 13. barnett dm, krall lp. the history of diabetes. in: joslin’s diabetes mellitus. 14th ed. boston, massachusetts: lippincott williams & wilkins, 2005. 14. the diabetes control and complications trial research group. the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. new engl j med 1993; 329:977–86. 15. allan fn. the writings of thomas willis: diabetes 300 years ago. diabetes,1953; 2:74–8. 16. holms ow, hall m. principles of the theory and practice of medicine. boston, massachusetts: little & brown, 1839. 17. allan fl. diabetes before and after insulin. med hist 1972;16:266–73. 18. nobel prize laureates, medicine, 1923. from: http://www.nobelprize.org/nobel_prizes/medicine/ laureates/1923/ accessed: may 2013. 19. nobel prize laureates, chemistry, 1958. from: http://www.nobelprize.org/nobel_prizes/chemistr y/ laureates/1958/ accessed: may 2013. 20. nobel prize laureates, medicine, 1977. from: http://www.nobelprize.org/nobel_prizes/medicine/ laureates/1977/ accessed: may 2013. 21. gilani ah. medicinal value of food and dietary supplements. diab endoc j 2007; 35:4. 22. bell gi. pictet rl, rutter wj, cordell b, tischer e, goodman hm. sequence of the human insulin gene. nature 1980; 284:26–32. 23. dunn c, curran mp. inhaled human insulin (exubera): a review of its use in adult patients with diabetes mellitus. drugs 2006; 66:1013–32. 24. generex biotechnology. oral-lyn – oral insulin for types 1 and 2 diabetes. industry project. from: http:// www.drugdevelopmenttechnology.com/projects/orallyn/2007 accessed: may 2013. 25. pancreas transplant. from: http://www.mayoclinic.com/ health/pancreas-transplant/my00762 accessed: may 2013. 26. kelly wd, lillehei rc, merkel fk, idezuki y, goetz fc. allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. surgery 1967; 61:827–37. 27. amitani m, asakawa a, amitani h, inui a. the role of leptin in the control of insulin-glucose axis. front neurosci 2013; 7:51. epub. 8 apr 2013. doi:10.3389/ fnins.2013.00051. 28. gene therapy in dogs to treat diabetes. from: http:// www.diabetes.org/for-media/2013/gene-therapy-usedin-dogs-to-treat-type1-diabetes.html accessed: may 2013. 29. louis rosenfeld. insulin: discovery and controversy. clin chem 2002; 48:2270–88. later known to be the source of insulin production. 3. despite accounts of the acrimonious ‘team’ interactions building up to and following the groundbreaking discovery of insulin, the acknowledgement of fellow professionals is illustrated in banting and macleod’s (noble laureates) recognition of best and collip’s immense contributions by sharing their noble prize money with them.29 4. the refusal to patent insulin but to share this miraculous therapy freely with the world will remain an outstanding example of unreserved generosity towards mankind in the history of medical disease. banting’s colossal contribution has been globally recognised by the declaration, since 2007, of his birthday (14th november) as world diabetes day. from unrecorded accounts to published knowledge, this human scourge is, simply put, a modern day epidemic. we, and future generations of medical professionals, share the task of taking this history forward. references 1. maccracken j, hoel d. from ants to analogues: puzzles and promises in diabetes management. postgrad med 1997;101:138–40, 143–5, 149–50. 2. tipton mc. susruta of india, an unrecognized contributor to the history of exercise physiology. j appl physiol 2008;108:1553–6. 3. frank ll. diabetes mellitus in the texts of old hindu medicine (charaka, susruta, vagbhata). am j gastroenterol 1957;27:76–95. 4. sattley melissa. the history of diabetes. from: http:// diabeteshealth.com/read/2008/12/17/715/the-historyof-diabetes/ accessed: may 2013. 5. ahmed am. history of diabetes mellitus. saudi med j 2002; 23:373–8. 6. sanders lj. from thebes to toronto and the 21st century: an incredible journey. diabetes spectr 2002;15:56–60. 7. dobson m. experiments and observations on the urine in diabetes. med obs inq 1776; 5:298–316. 8. sakula a. paul langerhans (1847-1888): a centenary tribute. j r soc med 1988; 81:414–5 9. schafer e. an introduction to the study of the endocrine glands and internal secretions. palo alto, california: stanford university, 1914. pp. 84, 86. 10. de meyer j. action de la sécrétion interne du pancéras sur différents organes et en particulier sur la sécrétion rénale. arch fisiol 1909; 7:96–9. 11. von mehring j, minkowski o. diabetes mellitus nach pankreasexstirpation. arch exp pathol pharmakol 1890. clinical & basic research sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 107-114, epub. 27th feb 13 submitted 26th jun 12 revision req. 8th sep 12, revision recd. 12th sep 12 accepted 18th oct 12 universiti sains malaysia, kota bharu, kelantan, malaysia author e-mail: msaiful@kb.usm.my العالقة بني نتائج النجاح الفشل والصحة النفسية لطالب سنة أوىل طب يف كلية للطب مباليزيا حممد يو�صف امللخ�ص: الهدف: احلاجة والبيئة احلادة للتدريب الطبي قد يخلف �صغوطًا �صديدة على طلبة الطب، الأمر الذي قد يوؤدي بدوره اإىل نتائج الدرا�صة هذه املعرفية. القدرة يف واعتالل الأكادميي الداء �صعف هذا ي�صمل قد املهني. اأو ال�صخ�صي الو�صع من كال على اإيجابية غري �صملت الطريقة: الكاآبة(. واعرا�ض )التوتر،القلق، النف�صية ال�صحه ومتغريات الف�صل النجاح نتائج بني الرتابط اكت�صاف على اأعتمدت -21( تقييم وحدة ذو 21 التوتر القلق الكاآبه مقيا�ض مباليزيا. للطب كلية يف طب اأوىل �صنة طالب من جماعة املقطعية الدرا�صة هذه dass( مت اإعطاوؤه فور انتهاء من اآخر ورقة امتحان لطلبة ال�صنة الأوىل. مت تتبع نتائج المتحانات )جناح-ف�صل( للطلبة با�صتخدام رمز الطالب التعريفي عن طريق املكتب الأكادميي بجامعة �صاين�ض املاليزية. النتائج: اإجمايل194 )%98( من طالب الطب ا�صتجاب ل dass-21. اختبارtامل�صتقل اأظهر اأن الطالب الذين جنحوا كان لديهم ن�صبة قليلة معتربة من التوتر، القلق واأعرا�ض الكاآبة مقارنة باأولئك الذين ف�صلوا يف المتحان النهائي لل�صنة الأوىل )p >0.05(. اأولئك الذين يعانون من توتر متو�صط اإىل حاد كانوا بن�صبة 2.43 اأعلى عر�صة للف�صل يف المتحانات من اأولئك الذين كانوا يعانون من توتر عادي اإىل ب�صيط. اخلال�صة: طالب الطب الذين ف�صلوا يف المتحان النهائي كان لديهم معدل اأعلى من القلق النف�صي مقارنة باأولئك الذين جنحوا يف المتحان. اأولئك الذين يعانون من م�صتوى اأعلى من القلق كانوا اأكرث عر�صة للف�صل من غريهم. خف�ض القلق النف�صي لطالب الطب قبل المتحان قد ي�صاعدهم على تقدمي اأداء اأف�صل يف المتحانات. مفتاح الكلمات: التوتر النف�صي; القلق; الكاآبة; طلبة الطب; تقييم الطلبة; ماليزيا. abstract: objectives: the demanding and intense environment of medical training can create excessive pressures on medical students that eventually lead to unfavorable consequences, either at a personal or professional level. these consequences can include poor academic performance and impaired cognitive ability. this study was designed to explore associations between pass-fail outcome and psychological health parameters (i.e. stress, anxiety, and depression symptoms). methods: a cross-sectional study was conducted on a cohort of first-year medical students in a malaysian medical school. the depression anxiety stress scale 21-item assessment (dass-21) was administered to them right after the final paper of the first-year final examination. their final examination outcomes (i.e. pass or fail) were traced by using their student identity code (id) through the universiti sains malaysia academic office. results: a total of 194 (98.0%) of medical students responded to the dass-21. an independent t-test showed that students who passed had significantly lower stress, anxiety, and depression symptoms than those who failed the first-year final examination (p <0.05). those who experienced moderate to high stress were at 2.43 times higher risk for failing the examination than those who experienced normal to mild stress. conclusion: medical students who failed in the final examination had higher psychological distress than those who passed the examination. those who experienced high stress levels were more likely to fail than those who did not. reducing the psychological distress of medical students prior to examination may help them to perform better in the examination. keywords: psychological stress; anxiety; depression; medical students; student assessment; malaysia. associations of pass-fail outcomes with psychological health of first-year medical students in a malaysian medical school muhamad s. b. yusoff advances in knowledge this study showed that there was an association between pass-fail outcomes and the psychological health status of medical students during a summative assessment. efforts to reduce psychological distress of medical students prior to a summative assessment might improve their performance on the assessment. associations of pass-fail outcomes with psychological health of first-year medical students in a malaysian medical school 108 | squ medical journal, february 2013, volume 13, issue 1 many studies have revealed that the environment of medical training programmes are not optimal to medical students’ psychological health as the reported prevalence of psychological disorders among them was higher than that of the general population and of students taking other courses.1-13 the prevalence of medical student psychological distress, which broadly encompasses anxiety, stress, depression and mental health-related problems, ranged from 21% to 56% in two different studies.14–15 the prevalence was found to have doubled at the end of first-year medical training and during the final examination period.8,16 some aspects of medical training cause unwanted consequences for medical students’ psychological health, therefore hampering the noble aims of medical training. the reported sources of stress for medical students seem to be linked with medical training and are related particularly to academic requirements.2,10,11,17 the demanding and intense environment of medical training creates excessive pressures on medical students that eventually leads to unfavorable consequences either at personal or professional levels, possibly resulting in poor academic performance and/or impaired cognitive ability.2,3 many studies have revealed that the greatest source of stress for medical students is the medical curriculum.2,10,11,15,16,18 the top three sources of stress found in previous studies were examinations, learning large amounts of content, and lack of time to review what had been learnt.10,11 these studies showed that medical students were overloaded with the tremendous amount of information to be learnt in a limited time for examinations. the overload of information created feelings of academic disappointment because most medical students never perceived themselves as being able to revise sufficiently in the subjects they had studied in order to attain personal examination performance goals. therefore, many medical students struggle with questions about their ability to meet the demands of medical curricula.19 the mismatch that occurs between demands and perceived ability to meet the demands may worsen stressful feelings in medical students.20 it is possible that these feelings of academic disappointment may be most prevalent among those students who have poor previous academic performance.21 previous studies reported that the prevalence of medical students with unfavourable stress levels was found to double during final examinations.16 many studies have shown that female medical students face more stressors than their male peers.1,3,22,23 it was also reported that women experience a greater degree of anxiety and depressive symptoms than men do.3,9,12,19 in contrast, several studies have found no asso ciation between gender and psychological distress.10,11,24 a few studies also have found an association between race and psychological distress among medical students.23,24 however, other studies have found that there is no significant association between race and psychological distress.10–12,25,26 other research studies have shown that minority medical students experience higher stresses than their counterparts.27–29 several studies have reported that psychological distress is associated with poor academic achievement.2,3,30,31 in contrast, a number of studies have reported that there is no association between stress and academic achievement.11,13,32 a previous study reported that there was also no association between depressive symptoms and academic qualifications upon entry to university.12 these studies have suggested that race, sex, entry qualifications, and academic achievement might have a significant relationship to stress, anxiety, and depression. however, a review of this literature reveals that the relationship between the psychological health parameters to pass-fail outcomes in summative assessments have been largely unexplored. this study was therefore designed to explore possible associations between psychological health parameters (i.e. stress, anxiety, and depression) and pass-fail outcomes in a cohort of first-year applications to patient care academically weak medical students should be monitored by medical schools since they might experience significant psychological problems. early intervention by medical schools may help to improve their students’ psychological health. doctors with healthy minds will provide better quality patient care. muhamad s. b. yusoff clinical and basic research | 109 medical students at the universiti sains malaysia (usm) school of medical sciences (sms) during a summative assessment. the working hypothesis for this study was that medical students who passed their examinations would experience a lower degree of stress, anxiety, and depression symptoms than those who failed. after controlling for race, entry qualifications, and gender, those who experienced a high degree of psychological distress would be at high risk of failing their examination. methods a cross-sectional study was conducted on a cohort of 196 new first-year medical students in the sms at usm. ethical approval was obtained from the human ethical committee of usm prior to the start of the research. the sms offers an integrated, problem-based, and community-oriented medical curriculum. this five-year programme is divided into three phases. phase i (year 1) is the fundamental year focusing on organ-based systems. phase ii (years 2 and 3) continues the system-based approach and introduces the basics of clinical clerkship. phase iii (years 4 and 5) is the clinical phase where the students are rotated through all clinical disciplines. the medical school grades student performance in assessments based on a pass/fail grading. year 1 medical students have to go through three continuous assessments tests and one final examination before they can progress to the second year of study. the final examination (i.e. summative assessment) is constituted of three main tests—an objective structured practical examination (ospe), an essay section, and multiple choice questions (mcqs). the examinations are administered over a week and constitute 70% of the total marks. the other 30% of marks are based on the 3 continuous assessments, each of them contributing 10%. the students must obtain a total examination mark of more than 50% to pass and progress to the second year. otherwise, they have to repeat the whole year. the depression anxiety stress scale 21-item (dass-21) questionnaire was administered to a cohort of 196 new medical students in the 2009– 2010 academic session right after the final paper of the first-year final examination in the examination hall.33 participants were asked to write down their matrix number on the dass-21 form as an identity code (id) for follow-up purposes. they were also asked to tick boxes regarding basic demographic information pertaining to gender, race (malay, chinese, indian, or other), and entry qualifications (matriculation, high school certificate [hsc], or a-level). instructions and information about the study were given to them. they were clearly informed that the results of this study would not have any influence on their examination results. they were informed that they would be referred to and further assessed by the student medical academic response team (smart), (constituting the deputy dean of academics, the chairman of personnel and the professional development programme, a medical educationist, a clinical psychologist, and a psychiatrist), if they were found to be experiencing high to severe psychological distress. their final examination outcomes (i.e. pass or fail) were traced by using their id through the usm academic office. the students did not know the results of their summative examination at the time they completed the dass-21. the dass-21 was developed to measure depression, anxiety and stress levels.33-35 its validity and reliability among student samples was wellestablished, among others, by mcdowell in 2006. the reliability coefficient of depression, anxiety, and stress subscales range from 0.81 to 0.97, and the three subscales demonstrated a satisfactory discriminative ability to differentiate between psychiatric and non-psychiatric patients.36 the dass manual for student samples,33‒35 categorises 1) stress subscale scores as normal (0–14), mild (15–18), moderate (19–25), severe (26–33), and extremely severe (34 and above); 2) anxiety subscale scores as normal (0–7), mild (8–9), moderate (10– 14), severe (15–19) and extremely severe (20 and above), and 3) depression subscale scores as normal (0–9), mild (10–13), moderate (14–20), severe (21–27) and extremely severe (28 and above).33–35 the dass-21 was chosen for this study because it can be administered rapidly, is a well-validated and reliable instrument, and further is superior and more consistent than the full-scale version.36 a high score on each subscale indicated poor psychological health.33 data were analysed by predictive analysis software (pasw), version 18 (ibm, inc., chicago, il, usa). descriptive statistics were used to report on frequency and percentage of variables. an associations of pass-fail outcomes with psychological health of first-year medical students in a malaysian medical school 110 | squ medical journal, february 2013, volume 13, issue 1 independent t-test was applied to determine the mean difference of stress, anxiety, and depression scores between the pass and fail groups. binary logistic regression was applied to determine the factors that contributed to a pass-fail outcome and its odds ratio. for analysis purposes, stress, anxiety, and depression scores were categorised as ‘normal to mild’ and ‘moderate to extremely severe’. results a total of 194 (98%) medical students responded to the dass-21. the majority of them were female, had matriculated from high school and were malay [table 1]. the total number of students who passed and failed in the final examination were 161 and 33, respectively. a majority of the medical students experienced a high degree of anxiety (67.5%), followed by depression (29.9%) and stress (24.2%) [table 1]. an independent-t test showed that students who passed had experienced significantly lower stress, anxiety, and depression symptoms than those who failed [table 2]. these results indicated that students who failed in the examination experienced a high degree of stress, anxiety, and depression symptoms during the final examination. binary logistic regression (forward: lr method) was applied to determine factors which contributed to the medical students’ pass-fail outcomes in the final examination. a logistic regression model indicated that one factor significantly contributed to the pass-fail outcomes—the stress status (x2 = 4.58; p value <0.032; -2 log likelihood = 172.37; nagelkerke r2 = 0.039) [table 3]. this result indicated that those who experienced moderate to extremely severe stress were at a 2.43 times higher risk of failing the final examination than those who experienced normal to mild stress. the passfail outcomes among medical students were not affected by gender, race, entry qualification, anxiety status, or depression status. discussion prior to medical training, approximately 14.4% and 1.1% of entering medical students suffered from mild and moderate anxiety symptoms, respectively. in contrast, during medical training approximately 11.5% of medical students suffered from anxiety disorder.19,37 these facts suggested that both before table 1: demographic profiles of respondents variable frequency n (%) sex male female 066 (34.0) 128 (66.0) entry qualification matriculation high school certificate others 172 (88.7) 13 (6.7) 9 (4.6) race malay chinese indian others 104 (53.6) 60 (30.9) 24 (12.4) 6 (3.1) examination outcome passed failed 161 (83.0) 33 (17.0) stress status normal to mild moderate to extremely severe 147 (75.8) 47(24.2) anxiety status normal to mild moderate to extremely severe 63 (32.5) 131 (67.5) depression status normal to mild moderate to extremely severe 136 (70.1) 58 (29.9) table 2: association between pass-fail outcomes of the final examination with stress, anxiety, and depression scores dass phase 1 final exam status* n mean sd mean difference (95% ci) t-test p value stress passed failed 161 033 12.18 16.12 9.44 8.75 3.93 (0.42, 7.45) 2.306 0.029 anxiety passed failed 161 033 13.06 17.39 9.25 9.17 4.34 (0.86, 7.35) 2.457 0.015 depression passed failed 161 033 08.76 12.79 9.24 9.03 4.03 (0.56, 7.50) 2.292 0.023 dass = depression anxiety stress scale; n = number; sd = standard deviation; ci = confidence interval. independent t-test: a p-value <0.05 was considered significant. parametric assumptions were met as the levene’s test was not significant (p value >0.05) and histogram showed data were normally distributed. *the pass and fail outcomes were based on the official results from the examination board of phase i, universiti sains malaysia. muhamad s. b. yusoff clinical and basic research | 111 and after medical training, medical students experience a substantial degree of anxiety. our study found a far greater percentage of medical students experienced significant anxiety disorders (67.5%) during the final examination than those figures reported either before or during medical training, but relatively similar to figures reported by a few previous studies which ranged from 60% to 70%.19,37–39 the huge increase in anxiety disorders among medical students found in this study is, perhaps, due to the impact of the final examination on psychological well-being as reported by a previous study.16 even so, the percentage of medical students who experienced significant symptoms of stress (24.2%) and depression (29.9%) were similar to previous studies, ranging from 21% to 56% for stress, and 5% to 37.5% for depression.3,4,6,12,15,40 also of great interest in this study, is the fact that a far greater percentage of medical students scored moderate to severe on the anxiety scale (67.5% of the students) than on either the stress scale (24.2% of the students) or the depression scale (29.9% of the students), but yet, only the stress scale showed a statistically significant correlation with examination performance. apparently, a majority of the students were expressing anxiety, but the higher performers on the assessment were expressing as much anxiety as the low performers. a logical reason behind this finding could be due to the consequences of the pass-fail outcomes to the students, whereby if they failed they could not progress to phase ii and would have to repeat the first year of medical training. the consequence creates a great worry among the students regardless of their real performance. results showed that students who passed had significantly lower symptoms of stress, anxiety, and depression than those who failed during the examination period. these findings were similar to previous studies that reported that medical students who had significant mental health problems achieved low academic results.1-3,30,40 for example, a nationwide study conducted on medical students across medical schools in korea revealed that medical students with major depressive disorder had significant lower cumulative grade point average (cgpa) as an expression of academic achievement, than those who were not depressed.40 however, a previous study conducted on students from various courses, including a medical course, found a weak negative correlation between cgpa and stress levels.13 another study that was conducted on pre-diploma science students reported a similar finding where students’ cgpas weakly correlated with stress levels.32 in a nutshell, based on findings from the literature and our study, it could be said that a substantial association might exist between psychological health and the examination performance of medical students. there are short-term and long-term postulations for a correlation between a psychological wellbeing factor and examination performance. the short-term postulation is that if the students are anxious, stressed, or depressed at the time that they are taking the examination, their performance may be affected regardless of how well they have learnt the material. the long-term postulation is that if a student is chronically anxious, stressed, or depressed through their first year of medical training, then this may have affected their ability to learn properly and/or retain the material necessary for successful performance on the final examination. continued research is required to verify these postulations. one important lesson learnt from these findings is that medical schools should be aware that students who performed poorly in examinations might need psychological support, as seen in a study conducted in oman by a committee that deals with students who were under academic probation.41 table 3: factors that contributed to failure of medical students in the final examination variables b-coefficient wald-x2 statistics (df ) p value* odds ratio (95% ci) stress status normal to mild stress (reference group) 2.43 (1.10, 5.37) moderate to extremely severe stress 0.887 4.79 (1) 0.029 constant -1.848 59.04 (1) <0.001 ci = confidence interval. *binary logistic regression test (forward: lr method); a p value <0.05 was considered significant at 95% ci. variables included in the analysis were sex, race, entry qualification, stress status, anxiety status, depression status. pass was coded as 0 and fail was coded as 1. associations of pass-fail outcomes with psychological health of first-year medical students in a malaysian medical school 112 | squ medical journal, february 2013, volume 13, issue 1 introducing peer-group support might serve as effective psychological support to academically weak students.42,43 optimal levels of stress (i.e. favourable stress) will enhance the learning abilities of students; however, excessive stress (i.e. unfavourable stress) may lead to unfavourable consequences.2,3,44 our study revealed that medical students who experienced moderate to extremely severe stress were at a 2.43 times higher risk of failing in the final examination than those who experienced normal to mild stress. this finding was relatively similar to those of a previous study which reported that medical students with a major depressive disorder were at a 1.8 times higher risk to get cgpas below 2.0 as compared to those who were not depressed.40 our study failed to demonstrate any significant risks posed by anxiety and depression status after controlling for gender, race, and academic qualifications upon entry to university. these findings suggested that the stress status of medical students was the main risk factor for pass-fail outcomes. two important lessons can be learnt from these findings. the first would be to introduce a programme that induces favourable stress and reduces the unfavourable stress experienced by medical students prior to examination. this might improve students’ outcomes in examinations. the second would be to provide faculty mentoring to academically weak students which might help to improve students’ psychological health. people who feel well-supported are less likely to burn out, giving credence to these postulations.45 apart from that, stress management interventions should be introduced to help medical students cope positively with the stressors related to medical training.46-48 such an intervention might be a medical student well-being workshop; this was reported to be a well-accepted intervention and showed promise in positively impacting medical students’ psychological health.49-52 it is worth highlighting the finding that unfavourable stress in medical students was associated with low self-esteem, difficulties in solving interpersonal conflicts, sleeping disorders, cynicism, decreased attention spans, reduced concentration, academic dishonesty, and alcohol and drug abuse.52,53–58 likewise, many medical students suffered from symptoms of depression during medical training.3,4,6,12 approximately 10 to 14% of them had suicidal thoughts and 6% planned to commit suicide during medical training.1,3,59 in contrast, prior to medical training the reported prevalence of depression was less than 1% which is comparable with the general population’s prevalence of depression ranging from 2.1 to 3.1%.9,19 these facts indicate that some aspects of medical training, such as academic requirements, can cause unfavourable stress that might lead to an unintentional adverse impact on students’ academic performance. this study has several limitations which would need to be considered in future studies. first, the study design was cross-sectional and so would not reflect the cause-effect relationship between factors and outcomes. second, the purposive sampling method may have led to a sample bias that might have compromised the accuracy of the results. third, this study did not control other potential confounding factors such as intelligent quotient (iq), age as an indicator of maturity level, or previous academic achievement that might have influenced pass-fail outcomes. fourth, this study did not measure or control the coping strategies of the students as a potential confounding factor that might have influenced the psychological well-being of the students. fifth, the psychological health measurement was done during the examination period and, therefore, might not truly reflect the state of the students’ psychological health prior to the examination. therefore, future studies should administer this psychological health measurement at entry into medical school and halfway through the first and second semesters as well as at the end of the first year. finally, the study population was confined to first-year medical students in a medical school so the results may not be generalised to other years of study or other medical schools. considering all of these limitations, the results of this study should be interpreted and applied cautiously. conclusion medical students who failed their final examinations had higher psychological distress than those who passed. those who experienced high stress levels were more likely to fail than those who experienced optimal stress levels. reducing psychological distress in medical students prior to examinations may help them perform better in examinations. muhamad s. b. yusoff clinical and basic research | 113 references 1. dyrbye ln, thomas mr, massie f, power dv, eacker a, harper w, et al. burnout and suicidal ideation among us medical students. ann intern med 2008; 149:334–9. 2. dyrbye ln, thomas mr, shanafelt td. medical student distress: causes, consequences, and proposed solutions. mayo clin proc 2005; 80:1613– 22. 3. dyrbye ln, thomas mr, shanafelt td. systematic review of depression, anxiety, and other indicators of psychological distress among us and canadian medical students. acad med 2006; 81:354–73. 4. given jl, tjia j. depressed medical students' use of mental health services and barrier to use. acad med 2002; 77:918–21. 5. guthrie e, black d, bagalkote h, shaw c, campbell m, creed f. psychological stress and burnout in medical students: a five-year prospective longitudinal study. j r soc med 1998; 91:237–43. 6. mohd sidik s, kaneson n. the prevalence of depression among medical students. malays j psychiatry 2003; 11:12–17. 7. mohd sidik s, rampal l, kaneson n. prevalence of emotional disorders among medical students in a malaysian university. asia pac fam med 2003; 2:213–7. 8. vitaliano pp, maiuro rd, russo j, mitchell es. medical student distress: a longitudinal study. j nerv ment dis 1989; 177:70–6. 9. world health survey. country report for malaysia: mental health condition. volume i-v. kuala lumpur: institute for health system research, 2002. 10. yusoff msb, liew yy, ling hw, tan cs, loke hm, lim xb, et al. a study on stress, stressors and coping strategies among malaysian medical students. int j student res 2011; 1:45–50. 11. yusoff msb, rahim afa, yaacob mj. prevalence and sources of stress among universiti sains malaysia medical students. malays j med sci 2010; 17:30–7. 12. yusoff msb, rahim afa, yaacob mj. the prevalence of final year medical students with depressive symptoms and its contributing factors. int med j 2011; 18:305–9. 13. elias h, ping ws, abdullah mc. stress and academic achievement among undergraduate students in universiti putra malaysia. proced soc behav sci 2011; 29:646–55. 14. dyrbye ln, szydlo dw, downing sm, sloan ja, shanafelt td. development and preliminary psychometric properties of a well-being index for medical students. bmc med educ 2010; 10:1–9. 15. yusoff msb, rahim afa. stress, stressors and coping strategies: first year medical students in malaysian public universities. saarbrucken: vdm verlag dr muller gmbh & co. kg; 2011. p. 92. 16. yusoff msb. impact of summative assessment on first year medical students' mental health. int med j 2011; 18:172–5. 17. kaufman dm, mensink d, day v. stressors in medical school: relation to curriculum format and year of study. teach learn med 1998; 10:138–44. 18. firth j. levels and sources of stress in medical students. br med j (clin res ed) 1986; 292:1177–80. 19. smith ck, peterson df, degenhardt bf, johnson jc. depression, anxiety, and perceived hassles among entering medical students. psychol health med 2011;12:31–9. 20. van harrison r. person-environment fit and job stress. in: cooper cl, payne r, eds. stress at work. chichester: wiley, 1978. 21. stewart sm, lam t, betson c, wong c, wong a. a prospective analysis of stress and academic performance in the first two years of medical school. med educ 1999; 33:243–50. 22. grossman hy, salt p, nadelson c, notman m. coping resources and health responses among men and women medical students. soc sci med 1987; 25:1057–62. 23. kressin n. race and sex differences in medical students’ experienced stress. 100th annual convention american psychological association. washington, d.c., usa, 1992. 24. henning k, ey s, shaw d. perfectionism, the impostor phenomenon and psychological adjustment in medical, dental, nursing and pharmacy students. med educ 1998; 32:456–64. 25. dyrbye ln, thomas mr, eacker a, harper w, massie jr f, power dv, et al. race, ethnicity, and medical student well-being in the united states. arch intern med 2007; 167:2103–09. 26. zaid z, chan s, ho j. emotional disorders among medical students in a malaysian private medical school. singapore med j 2007; 48:895–9. 27. pyskoty ce, richman ja, flaherty ja. psychosocial assets and mental health of minority medical students. acad med 1990; 65:581–5. 28. strayhorn g, frierson h. assessing correlations between black and white students' perceptions of the medical school learning environment, their academic performances, and their well-being. acad med 1989; 64:468–73. 29. tjia j, givens jl, shea ja. factors associated with undertreatment of medical student depression. j am coll health 2005; 53:219–24. 30. elliott aj, shell mm, henry kb, maier ma. achievement goals, performance contingencies, and performance attainment: an experimental test. j educ psychol 2005; 97:630–40. 31. bennett r. determinants of undergraduate student associations of pass-fail outcomes with psychological health of first-year medical students in a malaysian medical school 114 | squ medical journal, february 2013, volume 13, issue 1 drop out rates in a university business studies department. j further high educ 2003; 27:12341. 32. rafidah k, azizah a, norzaidi md, chong sc, salwani mi, noraini i. stress and academic performance: empirical evidence from university students. acad educ leadership j 2009; 13:1–7. 33. lovibond sh, lovibond pf. manual for the depression anxiety stress scales. sydney: pscyhology foundation, 1995. 34. crawford jr, henry jd. the depression anxiety stress scales (dass): normative data and latent structure in a large non-clinical sample. brit j psychol soc 2003; 42:111–31. 35. henry jd, crawford jr. the short-form version of the depression anxiety stress scales (dass-21): construct validity and normative data in a large nonclinical sample. br j clin psychol 2005; 44:227–39. 36. mcdowell i. measuring health: a guide to rating scales and questionnaires. new york: oxford university press, 2006. 37. chandavarkar u, azzam a, mathews ca. anxiety symptoms and perceived performance in medical students. depress anxiety 2007; 24:103–11. 38. khan ms, mahmood s, badshah a, ali su, jamal y. prevalence of depression, anxiety and their associated factors among medical students in karachi, pakistan. j pak med assoc 2006; 56:583–6. 39. inam s, saqib a, alam e. prevalence of anxiety and depression among medical students of private university. j pak med assoc 2003; 53:1–7. 40. roh ms, jeon hj, kim h, han sk, hahm bj. the prevalence and impact of depression among medical students: a nationwide cross-sectional study in south korea. acad med 2010; 85:1384–90. 41. al-sharbati m, al-jabri a. the experience of the committee for students under probation in the college of medicine and health sciences, squ (oman). 6th congress asian medical education association. kuala lumpur, malaysia, 2011. 42. yusoff msb, rahim afa, noor ar, yaacob na, hussin zam. the bigsib students' peer group mentoring programme. med educ 2009; 43:1106. 43. yusoff msb, rahim afa, noor ar, azwany n, yaacob zamh. evaluation of medical students' perception towards the bigsib programme in the school of medical sciences, usm. educ medicine j 2010; 2:e2–e11. 44. kaplan hi, saddock bj. learning theory. sypnosis of psychiatry: behavioural sciences/clinical psychiatry. 8th ed. philadelphia: lippincott williams & wilkins, 2000. p. 148–54. 45. payne r, fletcher b. job demands, supports, and constraints as predictors of psychological strain among school teachers. j vocat behav 1983; 22:136– 47. 46. yusoff msb, esa ar. stress management for medical students: a systematic review. in: azcarate malv, ed. social sciences and humanities: applications and theories. vol. 3. rijeka: intech open access publisher, 2012. 47. shapiro sl, shapiro de, schwartz ger. stress management in medical education: a review of the literature. acad med 2000; 75:748–59. 48. al-sharbati m, al-jabri a. exam stress and emotional disorders in medical students under probation. in: landow mv, ed. stress and mental health of college students. usa: nova science publishers, inc., 2006. pp. 62–80. 49. yusoff msb, rahim afa. the impact of medical students well-being workshop on medical students’ stress level: a preliminary finding. asian j psychiatr 2010; 11:1–8. 50. yusoff msb, rahim afa. experiences from a medical students' well-being workshop. med educ 2009; 43:1108–9. 51. yusoff msb. effects of a brief stress reduction intervention on medical students' depression, anxiety and stress level during stressful period. asian j psychiatr 2011; 12:1–14. 52. yusoff msb, rahim afa. descriptive study on medical students' well-being workshop. educ med j 2009; 1:1–6. 53. silver hk, glicken ad. medical student abuse. jama 1990; 263:527–32. 54. clark ej, rieker pp. gender differences in relationships and stress of medical and law students. j med educ 1986; 61:32–40. 55. niemi p, vainiomaki p. medical students' distressquality, continuity and gender differences during a six-year medical programme. med teach 2006; 28:136–41. 56. flaherty ja, richman ja. substance use and addiction among medical students, residents, and physicians. psychiatr clin north am 1993; 16:189– 97. 57. newbury-birch d, white m, kamali f. factors influencing alcohol and illicit drug use amongst medical students. drug alcohol depend 2000; 59:125–30. 58. pickard m, bates l, dorian m, greig h, saint d. alcohol and drug use in second year medical students at the university of leeds. med educ 2000; 34:148–50. 59. hem e, gronvold nt, aasland og, ekeberg o. the prevalence of suicidal ideation and suicidal attempts among norwegian physicians: results from a cross-sectional survey of a nationwide sample. eur psychiatry 2000;15:183–9. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e211-217, epub. 7th apr 14 submitted 26th sep 13 revisions req. 12th nov 13 & 26th jan 14; revisions recd. 1st jan & 11th feb 14 accepted 18th feb 14 1department of obstetrics & gynaecology, nizwa hospital, oman; 2ministry of health, oman *corresponding author e-mail: hansad10@rediffmail.com دراسة عدوى اجلروح ملا بعد الوالدة القيصرية يف مستشفى إحالة إقليمي، عمان هان�صا دهار، اإبراهيم البو�صعيدي، وبهاونا راثي،واإميان اليون منر،فيبها �صا�صديفا،اإلهام حمدي abstract: objectives: the aim of this study was to determine the incidence of surgical site infections (ssi) in patients undergoing a caesarean section (cs) and to identify risk factors, common bacterial pathogens and antibiotic sensitivity. ssi significantly affect the patient’s quality of life by increasing morbidity and extending hospital stays. methods: a retrospective cross-sectional study was conducted in nizwa hospital, oman, to determine the incidence of post-caesarean (pcs) ssi from 2001 to 2012. this was followed by a case-control study of 211 pcs cases with ssi. controls (220) were randomly selected cases, at the same hospital in the same time period, who had undergone cs without any ssi. data was collected on cs type, risk factors, demographic profile, type of organism, drug sensitivity and date of infection. results: the total number of pcs wound infections was 211 (2.66%). there was a four-fold higher incidence of premature rupture of the membranes (37, 17.53%) and a three-fold higher incidence of diabetes (32, 15.16%) in the pcs cases compared with controls. the most common organisms responsible for ssi were staphylococcus aureus (66, 31.27%) and the gram-negative escherichia coli group (40, 18.95%). the most sensitive antibiotics were aminoglycoside and cephalosporin. polymicrobial infections were noted in 42 (19.90%), while 47 (22.27%) yielded no growth. a high incidence of associated risk factors like obesity, hypertension, anaemia and wound haematoma was noted. conclusion: measures are recommended to reduce the incidence of ssi, including the implementation of infection prevention practices and the administration of antibiotic prophylaxis with rigorous surgical techniques. keywords: caesarean section; surgical wound infections; wounds and injuries; antibiotics; risk factors; nosocomial infections; oman. امللخ�ص: الهدف: تهدف هذه الدرا�صة اإىل حتديد معدل انت�صار العدوى يف املوقع اجلراحي للمر�صى اللواتي اأجريت لهن عمليات قي�رشية، وحتديد عوامل الختطار وم�صببات الأمرا�س البكتريية ال�صائعة وح�صا�صية امل�صادات احليوية. انت�صارالعدوى يف املوقع اجلراحى له تاأثري كبري على نوعية احلياة للمر�صى عن طريق زيادة املرا�صة ومتديد الإقامة يف امل�صت�صفى. الطريقة: اأجريت درا�صة ا�صتعادية م�صتعر�صة يف م�صت�صفى نزوى، عمان، لتحديد مدى انت�صار عدوى جرح الولدة القي�رشية من 2001 اإىل 2012. اأتبعت هذة الدرا�صة بدرا�صة ملراقبة 211 حالة من العمليات القي�رشية امل�صابة بالتهاب اجلرح اجلراحي. نف�س يف اجلراحي اجلرح التهاب حدوث دون من قي�رشية عمليات لهن اأجريت ملن ع�صوائيًا اختيارها مت التي احلالت من )220( املرجعية املجموعة امل�صت�صفى ولنف�س الفرتة الزمنية. �صملت البيانات التي مت جمعها تفا�صيل نوع العملية القي�رشية، وعوامل الختطار، التوزيع الدميوغرايف ، نوع امليكروب امل�صبب وح�صا�صية العقاقري و يوم ظهور العدوى من تاريخ عمل القي�رشية. النتائج: كان العدد الإجمايل لعدوى جرح القي�رشية 211 )%2.66(. ووجد اأن هناك اأربعة ا�صعاف الزيادة يف حالت الإ�صابة بالتمزق املبكر للأغ�صية )37، %17.53( وثلثة اأ�صعاف الزيادة يف ال�صكري )32، %15.16( من حالت بعد العمليات القي�رشية مقارنة باملجموعة املرجعية. امليكروب الأكرث �صيوعًا امل�صوؤول عن عدوى اجلرح كان العنقودية الذهبية )66، 31.27%(، لوحظ ال�صيفالو�صبورين. و الأمينوغليكوزيد هي ح�صا�صية احليوية امل�صادات اأكرث اأن ووجد .)18.95% ،40 )عدد= الغرام �صلبية القولونية والإ�رشيكّية اأن اإ�صابة اجلرح متعدد امليكروبات وجد يف 42 )%19.90( واأنه يف 47 )%22.27( مل يوجد اأي منو بكتريي. لوحظ اأنه يوجد ن�صبة عالية من عوامل �صاأنها من والتي بها املو�صى التدابري الدموي. اخلال�صة: والورم الدم وفقر الدم �صغط وارتفاع ال�صمنة مثل القي�رشى اجلرح بعدوى الختطاراملرتبطة التقليل من الإ�صابة بعدوى املوقع اجلراحي ت�صمل تنفيذ ممار�صات الوقاية والتقاء بامل�صادات احليوية مع تقنية جراحية جيدة. مفتاح الكلمات: العمليات القي�رشية؛ عدوى اجلرح اجلراحى؛ اجلروح والإ�صابات؛ امل�صادات احليوية؛ عوامل الختطار؛ عدوى امل�صت�صفيات؛ عمان. a study of post-caesarean section wound infections in a regional referral hospital, oman *hansa dhar,1 ibrahim al-busaidi,2 bhawna rathi,2 eman a. nimre,2 vibha sachdeva,2 ilham hamdi2 clinical & basic research advances in knowledge the results of this retrospective study revealed that obesity, diabetes, prolonged labour with premature rupture of the membranes and wound haematoma were the main contributory risk factors for post-caesarean section wound infections in an omani regional referral hospital. the commonest infections were nosocomial infections, particularly hospital-acquired infections. the commonest bacteria grown were staphylococcus aureus and escherichia coli sensitive to the cephalosporin and aminoglycoside drug classes. application to patient care surgical site infections have a clinical and economic impact by significantly increasing maternal morbidity and prolonging hospital stays. the results of this study emphasise the need to implement infection control policies. antibiotic prophylaxis, improved surgical techniques, sterilisation of medical equipment, proper personal hygiene and hand-washing on the part of the hospital staff, as well as a study of post-caesarean section wound infections in a regional referral hospital, oman e212 | squ medical journal, may 2014, volume 14, issue 2 caesarean section (cs) wound infections represent a substantial burden to the health system and the prevention of such infections should be a healthcare priority in developing countries.1 the global estimates of surgical site infections (ssi) are from 0.5–15%.2 ssi can be attributed to a perioperative bacterial load in the tissue at the site of surgery and the diminished integrity of the host’s defenses.3 some of the risk factors observed for cs wound infections are obesity, diabetes, immunosuppressive disorders, chorioamnionitis, a previous caesarean delivery, certain medications like steroids, the lack of pre-incision antimicrobial care, lengthy labour and surgery.4,5 any infection of the abdominal wound complicating cs should be minimised through strict preventative measures, such as antisepsis, preoperative preparation, a reduction in the duration of surgery, a reduction in blood loss, the use of absorbable sutures and avoiding crossinfection. many studies have proved that antimicrobial prophylaxis is effective in reducing the incidence of postoperative wound infections as it reduces the risk of resident bacteria overcoming the immune system in the immediate postoperative period.6–8 as infection continues to be a common postoperative complication in both the developed and developing world, there is a need to implement ssi surveillance during and after surgeries so as to obtain a standardised incidence.9 the delivery of high-quality services with early interventions to reduce wound infections is an important aspect of patient safety measures. therefore, the aim of this study was to determine the incidence of ssi in patients undergoing a cs at a regional referral hospital in oman, and to identify risk factors, common bacterial pathogens and antibiotic sensitivity. methods this retrospective cross-sectional study included all post-caesarean (pcs) wound infections recorded from 2001 to 2012 at the nizwa regional referral hospital, oman. nizwa hospital provides tertiary care service to all extended hospitals and health centres in the al dakhiliyah governorate, a region in northern central oman. wound infections were defined as inflammation or sepsis with or without positive bacterial cultures. with ssi, there may be fever, redness, swelling and/or pain in the area around the incision site. the centers for disease control and prevention (cdc) state that ssi should be suspected within 30 days of a surgical procedure if at least one of the following symptoms are present: localised swelling, with or without purulent discharge from the wound, pain or tenderness, redness, malodour or fever. data concerning all patients with wound infections after a cs procedure from 2001 to 2012 were retrieved from the electronic patient records system of the hospital. this formed the study group (n = 211). inclusion criteria included infections occurring within 30 days of the surgery which involved the skin, subcutaneous tissues and the fascia and muscle layers of the incision site. the cases diagnosed with wound infections during their hospital stay accounted for 62 (29.38%) patients. the remaining 149 (70.61%) patients were readmitted 6–10 days after discharge, with evidence of wound induration and soakage, either with or without fever. a case-control study was then undertaken of the 211 pcs cases with wound infection. the control group (220) consisted of pcs cases randomly selected during the same period, who were routinely discharged on their third postoperative day without any symptoms of wound infections. all patients with wound infections underwent swab cultures in accordance with hospital policy and all cases of suspected ssi had swabs taken prior to the commencement of antibiotics. both culture-positive and -negative cases were included in the study. where the culture was positive, an antibiotic sensitivity tests of the organism was carried out using standard microbiology techniques. the wound swabs of the culture-negative cases yielded no organism growth of any kind after 24 hours of incubation. the cases and controls were reviewed in detail with respect to the type of cs, the characteristics of the antecedent labour, the duration of the rupture of membranes and other associated risk factors. the organisms isolated from the incision sites were investigated and antibiotic sensitivity was measured. data collected included details of the wound infections, any organisms grown in the cultures, the drug sensitivity of those organisms as well as the risk factors contributing to infections, like obesity, premature rupture of the membranes (prom), prolonged labour and comorbid medical conditions like diabetes, hypertension and anaemia. a p value of 0.05 or less was considered statistically significant. ethical clearance was obtained from the nizwa hospital ethical committee. post-discharge surveillance programmes for obstetric cases, are recommended to prevent nosocomial infections among women having a caesarean section. hansa dhar, ibrahim al-busaidi, bhawna rathi, eman a. nimre, vibha sachdeva and ilham hamdi clinical and basic research | e213 results this retrospective case-control cross-sectional study showed the incidence of wound infections in pcs cases in a regional hospital. a cumulative total of 7,923 cs surgeries were performed from 2001 to 2012 in nizwa hospital [table 1]. pcs wound infections occurred in 211 (2.66%) cases and were confirmed by positive bacteriology in 164 (77.72%) cases. the highest rate of infections during these years was 4.01%. overall, 149 (70.61%) women were diagnosed with wound infections following discharge. a higher infection rate was noted in emergency (119, 1.50%) in comparison with elective (92, 1.16%) cs procedures. a comparison of the case and control groups for pre-existing risk factors can be seen in table 2. a calculation of the odds ratio showed that those women who already had more than six children were 1.4 times more likely to contract a wound infection compared to those women who were delivering for the first time or had only one child. however, the association between wound infections and parity was not significant (p = 0.077). women with diabetes were three times more likely to develop wound infections and the association between diabetes and wound infections was significant (p = 0.001). a four-fold increase was noted in the rate of prom among the case group compared to the rate among controls. the association between prom and wound infections was highly significant (p <0.001). the risk of wound infections among those women who were mildly, moderately or severely anaemic was higher compared to those without anaemia and the association with wound infections was significant (p = 0.035). calculating the odds ratio showed that those women who had hypertension and pre-eclampsia were three times more likely to develop a wound infection compared to women without these conditions. there was a significant association between hypertension, preeclampsia and wound infections (p = 0.007). likewise, women who were morbidly obese, with a body mass index (bmi) of >35, were three times more likely to develop a wound infection compared to non-obese women and the association was significant (p = 0.018). the majority of ssi cases yielded growth of staphylococcus aureus (66, 31.27%) followed by escherichia coli (40, 18.95%) [table 3]. polymicrobial infections were found in 42 (19.90%) cases. the main organisms found to be growing together were: klebsiella and e. coli; klebsiella and proteus; klebsiella and s. aureus; e. coli and coagulase-negative staphylococcus, and e. coli and proteus. a few cultures yielded the growth of organisms such as morganella morganii, acinetobacter and methicillin-resistant s. aureus (mrsa). there were 47 (22.27%) cases where the culture did not yield any organisms. this was probably due to the use of broad-spectrum antibiotics prior to the wound swab; however, other features of ssi were present, such as wound soakage, induration and sepsis. the aminoglycoside drug class constituted the most sensitive antibiotic and was used whenever indicated by the culture sensitivity [table 4]. cephalosporin is frequently used in nizwa hospital as it is the second most sensitive antibiotic of choice and also the most convenient one. quinolone, like ciprofloxacin, is the least used drug class in the antenatal and postpartum period, followed by combined amoxicillin and table 1: total caesarean section procedures and surgical site infections in nizwa hospital between 2001 and 2012 (n = 7,923) year deliveries per annum total cs ssi elective cs ssi emergency cs ssi n (%) n (%) n (%) n (%) n (%) n (%) 2001 2,557 240 (9.38) 8 (3.33) 32 (13.33) 3 (1.25) 208 (86.66) 5 (2.08) 2002 2,831 349 (12.32) 14 (4.01) 59 (16.90) 6 (1.71) 290 (83.09) 8 (2.29) 2003 3,191 427 (13.38) 11 (2.57) 109 (25.52) 7 (1.63) 318 (74.47) 4 (0.93) 2004 3,218 464 (14.41) 11 (2.37) 127 (27.37) 7 (1.50) 337 (72.62) 4 (0.86) 2005 3,679 497 (13.50) 8 (1.60) 160 (32.19) 2 (0.40) 337 (67.80) 6 (1.20) 2006 4,014 631 (15.71) 25 (3.96) 175 (27.73) 13 (2.06) 456 (72.26) 12 (1.90) 2007 4,090 618 (15.11) 14 (2.26) 194 (31.39) 6 (0.97) 424 (68.60) 8 (1.29) 2008 4,486 748 (16.67) 12 (1.60) 198 (26.47) 6 (0.80) 550 (73.52) 6 (0.80) 2009 4,989 930 (18.64) 18 (1.93) 255 (27.41) 9 (0.96) 675 (72.58) 9 (0.96) 2010 5,022 896 (17.84) 27 (3.01) 267 (29.79) 13 (1.45) 629 (70.20) 14 (1.56) 2011 5,268 998 (18.98) 37 (3.70) 284 (28.45) 10 (1.00) 714 (71.54) 27 (2.70) 2012 5,409 1,099 (20.31) 26 (2.36) 281 (25.56) 10 (0.90) 818 (74.43) 16 (1.45) cumulative totals 48,754 7,923 (16.25) 211 (2.66) 2,141 (27.11) 92 (1.16) 5,756 (72.88) 119 (1.50) cs = caesarean section; ssi = surgical site infections. a study of post-caesarean section wound infections in a regional referral hospital, oman e214 | squ medical journal, may 2014, volume 14, issue 2 clavulanate, which was not used at all due to the risk of neonatal side-effects, particularly for preterm cases. few cases were sensitive to the antipseudomonal penicillin group of drugs, for instance tazobactam and piperacillin. antibiotics like meropenem and imipenem were used for the enterobacteriaceae which were highly resistant to cephalosporin (e. coli, klebsiella and enterobacter). discussion developing ssi is a traumatic experience.10 smyth et al. reported ssi to be the third most common type of nosocomial infection, accounting for 14–16%.11 cs surgery has a 5–20 times higher risk of postpartum infection as compared to vaginal deliveries, mainly with regards to wound infections, endometritis, pelvic peritonitis or pelvic abscesses.10 wound infections are still regarded as the most common nosocomial infections in patients undergoing surgery. the most common pathogens were s. aureus, pseudomonas aeruginosa and e. coli,12 as was also observed in the current study. staphylococcus is the most common cause of nosocomial infections and is often the cause of postsurgical wound infections; the gram-positive cocci are often found living on the skin and in the nose. table 2: comparison of pre-existing risk factors between the study and control groups of caesarean section patients (n = 431) characteristics study group (n = 211) n (%) controls (n = 220) n (%) or (95% ci) p value parity 0–1 60 (28.43) 44 (20.00) 1.0 0.077 2–5 97 (45.97) 122 (55.45) 0.58 (0.36–0.93) ≥6 54 (25.59) 54 (24.54) 1.4 (0.79–2.34) diabetes mellitus no 179 (84.83) 208 (94.54) 1.0 0.001* yes 32 (15.16) 12 (5.45) 3.09 (1.55–6.19) prom of ≥6 hours duration no 174 (82.46) 208 (94.54) 1.0 <0.001* yes 37 (17.53) 10 (4.54) 4.46 (2.16–9.20) anaemia normal 173 (81.99) 198 (90.00) 1.0 0.035* †mild to moderate 27 (12.79) 20 (9.09) 1.52 (0.82–2.82) ‡severe 10 (4.73) 02 (0.90) 5.09 (1.08–23.88) htn/pre-eclampsia no 191 (90.52) 213 (96.81) 1.0 0.007* yes 20 (9.47) 07 (3.18) 3.19 (1.30–7.70) bmi of >35 no 193 (91.46) 213 (96.81) 1.0 0.018* yes 18 (8.53) 07 (3.18) 2.83 (1.16–6.94) or = odds ratio; ci = confidence interval; prom = premature rupture of the membranes; htn = hypertension; bmi = body mass index. *significant; †haemoglobin levels of 7–10 g/dl; ‡haemoglobin levels of ≤6 g/dl. table 3: organisms causing caesarean section wound infections in the study group (n = 211) g+ n (%) gn (%) other n (%) s. aureus 66 (31.27) e. coli 40 (18.95) no growth 47 (22.27) mrsa 3 (1.42) klebsiella 19 (9.00) mixed growth* 42 (19.90) α-h streptococci 3 (1.42) p. aeruginosa 18 (8.53) β-h streptococci 1 (0.47) enterobacter 5 (2.36) proteus 3 (1.42) gbacilli 1 (0.47) m. morganii 1 (0.47) acinetobacter 1 (0.47) esblp e. coli 3 (1.42) g+ = gram-positive organisms; g= gram-negative organisms; s. aureus = staphylococcus aureus; e. coli = escherichia coli; mrsa = methicillin-resistant staphylococcus aureus; h = haemolytic; p. aeruginosa = pseudomonas aeruginosa; m. morganii = morganella morganii; esblp = extended-spectrum beta-lactamase-producing. *polymicrobial organisms. table 4: antibiotics prescribed for post-caesarean wound infections in the study group (n = 211)* antibiotic n % penicillin, amoxycillin, ampicillin and coamoxiclav 30 14.21 cloxacillin 20 9.47 cephalosporin (cephalexin, cefuroxime, ceftriaxone, cefotaxime and ceftazidime) 48 22.74 aminoglycoside (gentamicin) 52 24.64 ciprofloxacin 15 7.10 meropenem 20 9.47 sulfamethoxazole/trimethoprim 10 4.73 fusidic acid 16 7.58 total 211 100 *antibiotics were prescribed as per culture sensitivity. hansa dhar, ibrahim al-busaidi, bhawna rathi, eman a. nimre, vibha sachdeva and ilham hamdi clinical and basic research | e215 to avoid any infections from staphylococcus bacteria, it is important to implement regular hand-washing and ensure that wounds are kept covered with clean, dry bandages until they are fully healed. shittu et al. recommended collaboration with a microbiologist and wound-care practitioners, and patient education on personal hygiene to help control wound infections.12 even though the annual number of cs procedures at nizwa hospital has consistently risen, from 240 in 2001 to 1,099 in 2012, the rate of wound infection has remained more or less constant. this may be due to high compliance among the infection control team and medical personnel in the hospital regarding its infection control rules and policies. these include hand-washing, the use of alcohol rubs, avoiding crossinfection by restricting visitors and routine education among health workers regarding infection control measures. the rate of cs wound infections was 2.66% in the current study. rates of 2.8% were reported by mah et al.13 and mathew et al.,14 respectively, and these are comparable to similarly low rates of 2.8% and 2–5% in the usa and certain european countries.15 higher rates were noted in other studies, at 9.3%, 9.1% and 9.6% respectively.16–18 the rate of ssi has been reported to be from 5.7–9.0%10 and many other studies in various centres reported infection rates ranging from 6.09–38.7%.1,3,19,20 satyanarayan et al. reported rates of wound infections as high as 25.2% in emergency cs compared to 7.6% in elective cases.21 in the current study, 119 (1.50%) suffered wound infections after emergency surgeries compared to 92 (1.16%) in elective cases. the probable reason for this difference may be that less time was available for preoperative preparation in the emergency surgeries. in the current study, a difficult case was reported where the ssi was so severe that it had progressed to necrotising fasciitis. a similar case of wound infection progressing to necrotising fasciitis was reported by mathew et al., which was successfully treated with wound debridement and antibiotics.14 an independent risk factor for ssi in the current study was the development of subcutaneous wound haematomas in 15 (7.10%) patients. this suggests lapses in complete haemostasis during the wound closure as a haematoma may provide a medium for bacterial growth. the meticulous closure of potential spaces and good haemostatic techniques would reduce the frequency of haematomas leading to wound infections. postoperative wound haematoma was the strongest independent risk factor for ssi in a study conducted at a 1,250-bed tertiary care hospital in the usa, where ssi were identified in 5.0% of women undergoing low transverse cs.20 obesity is a major and rapidly growing health problem. the incidence of infections in patients who are obese with a bmi of 30 or more is higher than that of the general population. this is due to the poor penetration of antibiotics into the skin because of the avascularity of adipose tissue. moreover, obesity places greater mechanical stress on the wound and thus delays healing.22 wloch et al. observed that being overweight with a bmi >35 was a major risk factor for infection compared with cases who had a bmi 18.5–25 (or 3.7, 95% confidence interval [ci] 2.6–5.2).18 this was also observed in the current study as the rate of wound infections was 18 (8.53%) in women with bmi >35 as compared to 7 (3.18%) with normal body weight (or 2.83, 95% ci: 1.16–6.94). vertical incisions, which have to be used for overweight or obese patients, are more likely to lead to complications than the typical transverse incisions.23 women should be encouraged to eat healthily, have a well-balanced diet and take adequate exercise to avoid the risks of ssi associated with obesity. the incidence of infections in patients with gestational diabetes, either controlled by diet or insulin, was significantly higher (32, 15.16%) than among the non-diabetic patients (12, 5.45%). in other studies, the incidence of wound infections was noted to be six times higher in diabetic patients.1,24 uncontrolled blood glucose levels increase the infection rate and impairs wound healing as it enables the leukocytes to control the harmful proliferation of bacteria. prolonged labour, after a full trial of vaginal delivery, was observed in 20 (9.47%) cases of wound infections in the current study and similar findings were reported by ezechi et al.16 frequent vaginal examinations may be a contributory factor for the increased infection rate in such cases. most infections in the female genital area or the gastrointestinal tract can contaminate the normally sterile amniotic fluid. an associated risk factor, prom, increases the risk of chorioamnionitis as the protective effect of the intact fetal membranes is lost. the culture reports in such cases showed polymicrobial growth of both grampositive and gram-negative organisms. only three (1.42%) cultures showed extended-spectrum betalactamase-producing e. coli resistant to quinolones and aminoglycosides. such infections were controlled with carbapenems (meropenem and imipenem). the length of time between the rupture of the membranes and surgical intervention influences the cs wound infection rate as once the membranes have ruptured, the amniotic fluid is no longer sterile and may act as a transport medium, allowing bacteria to come into contact with any uterine and/or skin incisions.9 a total of 11 (5.21%) cases with wound infections underwent surgery in other health institutions but a study of post-caesarean section wound infections in a regional referral hospital, oman e216 | squ medical journal, may 2014, volume 14, issue 2 were admitted to nizwa hospital for wound care as they belonged to al dakhiliyah governorate and preferred the more convenient location of nizwa hospital. these cases were initially screened for mrsa and acinetobacter and were treated accordingly. the majority of the cultures in this study yielded growth of s. aureus (31.27%); similar results (71.4%) were documented in nisa et al.’s study.25 departmental policy at nizwa hospital strongly advocates using prophylactic antibiotics, for example a second-generation cephalosporin (such as cefuroxime 750–1500 mg), at cord clamping. however, recent evidence suggests that pre-incisional antibiotics reduce maternal morbidity with no disadvantage to the neonate.8,26 in a number of cases, the infection was polybacterial and warranted the use of combination drugs, mostly ceftriaxone with metronidazole and sometimes an addition of aminoglycoside. even though quinolones, like ciprofloxacin, were sensitive in 15 (7.10%) cases and showed low resistance, they are avoided in breastfeeding women in nizwa hospital. gentamicin was observed to be highly effective against most of the organisms, with the least drug resistance. resistant gram-negative bacteria like enterobacter, e. coli and klebsiella were treated with thirdand fourthgeneration drugs such as cephalosporin, imipenem and meropenem. however, consistent efforts were made to use narrow-spectrum drugs so as to avoid the emergence of drug-resistant strains of bacteria. cultures of the bacteria were found to be highly resistant to penicillin groups like the ampicillins and amoxicillins in comparison to the sulphonamide group, which was found to have the least resistance. however, this drug was minimally used in this centre due to the risk of undiagnosed cases of glucose-6-phosphate dehydrogenase deficiency which has a high incidence in the middle east. riyami et al., in a communitybased survey on genetic disorders, found that the prevalence of glucose-6-phosphate dehydrogenase (g6pd) enzyme deficiency was highest (29%) in the al dakhiliyah region as compared to other regions of oman.27 cs wound infection increases maternal morbidity and prolongs hospital stays. in nizwa hospital, women undergoing cs are routinely discharged on the third postoperative day. however, women suffering ssi stayed in the hospital for an average of 5–8 days. most of the women developing wound infections following discharge returned 6–10 days later, with complaints of fever, pain, and wound discharge and redness. the frequency of cs wound infections can be prevented by educational programmes designed to raise public and clinical awareness. modifiable risk factors like bmi and associated comorbid medical problems, such as diabetes and hypertension, should be closely monitored and controlled in the prepregnancy period. some of the cases with wound infections in the current study were noted to have poor personal hygiene. standards of personal hygiene, such as bathing every day, are culture-dependent and may also differ according to the individual patient. women opting for a cs for non-medical reasons should be informed about the risks of ssi as a complication.2,6 measures should be taken in the pre-, intraand postoperative phases to reduce the risk of infection. in the preoperative phase, certain measures can be beneficial—for example, bathing on the day of the surgery, avoiding the unnecessary shaving of hair, the use of electric clippers, the proper sterilisation of instruments, antibiotic prophylaxis and patientspecific theatre-wear. additionally, hand-washing, the antiseptic preparation of the surgical site and the use of appropriate staff theatre-wear should be encouraged. intraoperative infection prevention can be aided by one of the latest practices worldwide which is the use of monofilament sutures. the use of subcuticular sutures buried in the wound is also very unlikely to cause infection.9 gregson suggested the use of a hydrofiber® and hydrocolloid combination dressing (conva tec inc., new jersey, usa) for control of wound infection.10 nevertheless, despite all of these precautions, surgical wound infections may occur in the operating theatre when the tissues are exposed. postoperative wound infection can be greatly reduced and controlled by rigorous surgical techniques. furthermore, covering surgical incisions with an interactive dressing able to absorb exudates, placed so as to ease pain and to ensure that they remain in place for a minimum of 48 hours after the operation, is another practice to avoid wound infections.6 a satisfactory surveillance system is essential in all hospitals to reduce the rate of sepsis, with reliable feedback to clinicians.28 in this context, the infection control unit of nizwa hospital is currently adopting measures to establish this system. until now, no wound surveillance office has been established to gather information and tabulate wound infection rates according to surgical specialty. a surgical wound infection task force is recommended to enforce measures and expedite the control of wound infections in this healthcare institution. there were several limitations to this study. this retrospective study covered a long time period and the accuracy of information regarding the risk factors is limited by several cases with incomplete data. however, it is possible to confirm that all cases of pcs wound infections post-discharge were recorded, as this hospital was the only secondary care institution for such cases in the region. hansa dhar, ibrahim al-busaidi, bhawna rathi, eman a. nimre, vibha sachdeva and ilham hamdi clinical and basic research | e217 conclusion even though the rate of cs procedures consistently rose in the study period, the rate of wound infections remained consistent. the rate of cs wound infections was 2.66% between 2001 and 2012. the most common pathogens observed were s. aureus, p. aeruginosa and e. coli, which is in agreement with the results of other studies. the most sensitive antibiotics were aminoglycoside and cephalosporin. obesity, diabetes, prolonged labour with prom and wound haematoma were the main contributory risk factors responsible for pcs wound infections. the need to reduce ssi is currently receiving considerable attention and requires more research. reducing the rate of ssi will help to reduce the unnecessary morbidity and associated socioeconomic consequences for the patient and her family. recommendations include addressing modifiable risks factors in the preconception period, ensuring a sterile environment, aseptic surgeries, meticulous haemostatic techniques and the use of antimicrobial prophylaxis to reduce the incidence of infection. additionally, an organised system of wound surveillance and reporting may help to reduce the wound infection rate to an attainable minimum. references 1. nwankwo eo, ibeh i, enabulele oi. incidence and risk factors of surgical site infection in a tertiary health institution in kano, northwestern nigeria. int j infect control 2012; 8:1−6. doi: 10.3396/ijic.v8i4.035.12. 2. arabashahi ks, koohpayezade j. investigation of risk factors for surgical wound infection among teaching hospital in tehran. int wound j 2006; 3:59−62. doi: 10.1111/j.17424801.2006.00186e.x. 3. yohannes y, mengesha y, tewelde y. timing, choice and duration of perioperative prophylactic antibiotic use in surgery: a teaching hospital based experience from eritrea, in 2009. j eritrean med assoc 2009; 4:65−7. doi: 10.4314/jema. v4i1.52126. 4. amenu d, belachew t, araya f. surgical site infection rate and risk factors among obstetric cases of jimma university specialized hospital, southwest ethiopia. ethiop j health sci 2011; 21:91−100. 5. gong sp, guo hx, zhou hz, chen l, yu yh. morbidity and risk factors for surgical site infection following cesarean section in guangdong province, china. j obstet gynaecol res 2012; 38:509–15. doi: 10.1111/j.1447-0756.2011.01746.x. 6. national institute of health and clinical excellence. clinical guideline 74: surgical site infection: prevention and treatment of surgical site infection. from: www.nice.org.uk/nicemedia/ pdf/cg74niceguideline.pdf accessed: mar 2014. 7. scottish intercollegiate guidelines network. national clinical guideline 104: antibiotic prophylaxis in surgery. from: www. sign.ac.uk/pdf/sign104.pdf accessed: mar 2014. 8. young bc, hacker mr, dodge le, golen th. timing of antibiotic administration and infectious morbidity following cesarean delivery: incorporating policy change into workflow. arch gynecol obstet 2012; 285:1219−24. doi: 10.1007/s00404011-2133-1. 9. gould d. caesarean section, surgical site infection and wound management. nurs stand 2007; 21:57−62. doi: 10.7748/ ns2007.04.21.32.57.c4498. 10. gregson h. reducing surgical site infection following caesarean section. nurs stand 2011; 25:35−40. doi: 10.7748/ ns2011.08.25.50.35.c8655. 11. smyth et, emmerson am. surgical site infection surveillance. j hosp infect 2000; 45:173−84. doi: 10.1053/jhin.2000.0736. 12. shittu ao, kolawole do, oyedepo ear. a study of wound infections in two health institutions in ile-ife , nigeria. afr j biomed res 2002;5:97–102. 13. mah mw, pyper am, oni ga, memish za. impact of antibiotic prophylaxis on wound infection after cesarean section in a situation of expected higher risk. am j infect control 2001; 29:85−8. doi: 10.1067/mic.2001.111372. 14. mathew m, kumari r, vaclavinkova v, krolikowski a. caesarean sections at sultan qaboos university hospital: a three year review. j sci res med sci 2002; 4:29−32. 15. mahesh cb, shivakumar s, suresh bs, chidanand sp, vishwanath y. a prospective study of surgical site infections in a teaching hospital. j clin diagn res 2010; 4:3114−19. 16. ezechi oc, edet a, akinlade h, gab-okafor cv, herbertson e. incidence and risk factors for caesarean wound infection in lagos nigeria. bmc res notes 2009: 2:186. doi: 10.1 1186/1756-0500-2-186. 17. jido t, garba i. surgical-site infection following cesarean section in kano, nigeria. ann med health sci res 2012; 2:33−6. doi: 10.4103/2141-9248.96934. 18. wloch c, wilson j, lamagni t, harrington p, charlett a, sheridan e. risk factors for surgical site infection following caesarean section in england: results from a multicentre cohort study. bjog 2012; 119:1324−33. doi: 10.1111/j.14710528.2012.03452.x. 19. dyrkorn oa, kristoffersen m, walberg m. reducing postcaesarean surgical wound infection rate: an improvement project in a norwegian maternity clinic. bmj qual saf 2012; 21:20–10 20. olsen ma, butler am, willers dm, devkota p, gross ga, fraser vj. risk factors for surgical site infection after low transverse cesarean section. infect control hosp epidemiol 2008; 29:477−84. doi: 10.1086/587810. 21. satyanarayana v, prashanth hv, basavaraj b, kavyashree an. study of surgical site infections in abdominal surgeries. j clin diagn res 2011; 5:935−39. 22. vuolo jc. assessment and management of surgical wounds in clinical practice. nurs stand 2006: 20:46−58. doi: 10.7748/ ns2006.09.20.52.46.c4494. 23. wall pd, deucy ee, glantz jc, pressman ek. vertical skin incisions and wound complications in the obese parturient. obstet gynecol 2003; 102:952−6. doi: 10.1016/s00297844(03)00861-5. 24. alsaimary iea. bacterial wound infections in diabetic patients and their therapeutic implications. med pract rev 2010; 1:12−15. 25. nisa m, naz t, afzal i, hassan l. scope of surgical site infections (ssi) in obstetrics and gynaecology. j postgrad med inst 2005; 19:438−41. 26. macones ga, cleary kl, parry s, stamilio dm, cahill ag, odibo ao, et al. the timing of antibiotics at cesarean: a randomized controlled trial. am j perinatol 2012: 29:273−6. doi: 10.1055/s-0031-1295657. 27. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 28. chadli m, rtabi n, alkandry s, koek jl, achour a, buisson y, et al. incidence of surgical wound infections: a prospective study in the rabat mohamed-v military hospital, morocco. med mal infect 2005; 35:218−22. doi: 10.1016/j.medmal.2005.03.007. aneurysmal dilatation of a dissected ascending aortic aneurysm (aa) is an uncommon phenomenon in contrast to an isolated dissection or aneurysm. the incidence of this complication is even rarer following aortic valve replacement (0.2% and 2%).1 the combination of dissected ascending aa with multiple fistulae to the surrounding structures such as the pulmonary artery and left atrium, along with the concomitant presence of paravalvular leaks, is an exceedingly rare complication of prosthetic aortic valve endocarditis.1 research has shown that aortic valve replacement is an independent variable for the development and progression of ascending aas that may lead to dissection or rupture.2 predisposing factors for the occurrence of postaortic valve replacement aneurysms are well described in the literature. the infected medial aortic wall may be dilated by the haemodynamic burden of aortic regurgitation and a paravalvular leak may be a risk factor for the occurrence of prosthetic aortic valve infective endocarditis (ie).3 by inducing a high flow velocity, these paravalvular leaks produce a turbulent flow across the aortic valve which collides with the aortic wall and leads to the gradual dilatation of the ascending aorta.2 related mechanisms can cause ascending aas in other native valve pathologies such as aortic stenosis or aortic regurgitation, even in the absence of a haemodynamic gradient in patients with preventive cardiovascular research centre, kermanshah university of medical sciences, kermanshah, iran *corresponding author e-mail: r.faraji61@gmail.com وجود متد تشرحيي عمالق يف غشاء الشريان األورطي الصاعد مع عدة نواسري إيل حجرات القلب ناجته عن التهاب الشغاف يف الصمام األورطي االصطناعي فرييدون �ش�بزي و ر�ش� فرجي abstract: the combination of a dissected ascending aortic aneurysm (aa) with multiple fistulae to the periaortic root structures is a life-threatening complication that occurs rarely after infective endocarditis of the prosthetic aortic valve. many risk factors are potentially associated with this complication, including aortic diameter, connective tissue disease of the aortic wall, hypertension and infection. we report a rare case of dissected ascending aa with fistulae to the left atrium and pulmonary artery and a paravalvular leak in a 47-year-old woman with a history of an aortic valve replacement. the patient had presented to the imam ali hospital, kermanshah, iran, in january 2015 with clinical features of heart failure. after initially being treated for congestive heart failure, she underwent open-heart surgery via a classic bentall procedure and double fistula closure. she was discharged 23 days after the operation in good condition. a six-month follow-up showed normal functioning of the composite conduit prosthetic valve and no fistulae recurrence. keywords: aneurysm; aortic valve; fistula; case report; iran. تهدد التي امل�ش�عف�ت من ال�رضي�ن جذور يف نوا�شري عدة مع ال�ش�عد االأورطي ال�رضي�ن غ�ش�ء يف ت�رضيحي متد وجود يعترب امللخ�ص: اأن ميكن اخلطر عوامل من العديد اأن املعروف من اال�شطن�عي. االأورطي ال�شم�م يف ال�شغ�ف الته�ب بعد م�حتدث ن�درا والتي احلي�ة واالإلته�ب�ت الدم �شغط وارتف�ع جدارال�رضي�ن يف ال�ش�م الن�شيج واأمرا�ص االأورطي، ال�رضي�ن قطر ذلك يف مب� التعقيد، هذا مع ترتافق امليكروبية.هذا تقرير عن عن ح�لة ن�درة من وجود متد ت�رضيحي يف غ�ش�ء ال�رضي�ن االأورطي ال�ش�عد مع عدة نوا�شري اإيل االأذين االأي�رض وال�رضي�ن الرئوي، وت�رضب جم�ور لل�شم�م يف امراأة تبلغ من العمر 47 ع�م� مع ت�ريخ مر�شي ال�شتبدال ال�شم�م االأورطي. وقدمت املري�شة اإىل م�شت�شفىاالإم�م علي يف كرم�ن�ش�ه، اإيران بت�ريخ ين�ير 2015. نظرا لوجود مظ�هر �رضيرية لق�شور القلب. بعد العالج املبداأي لق�شور القلب االحتق�ين، خ�شعت املري�شة لعملية قلب مفتوح بوا�شطة طريقة bentall التقليدية واإغالق الن��شور املزدوج. مت خروج املري�شة من امل�شت�شفى بعد 32 يوم من العملية يف ح�لة ع�مة جيدة. بعد �شتة اأ�شهر من املت�بعة مل يوجد اأي ارتداد للنوا�شري وك�ن ال�شم�م اال�شطن�عي يعمل بكف�ءة. مفتاح الكلمات: متدد االأوعية الدموية؛ �شم�م االأورطي؛ ن��شور؛ تقرير ح�لة؛ اإيران. combination of a giant dissected ascending aortic aneurysm with multiple fistulae into the cardiac chambers caused by prosthetic aortic valve endocarditis feridoun sabzi and *reza faraji sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e109–112, epub. 2 feb 16 submitted 18 jun 15 revisions req. 3 aug & 20 sep 15; revisions recd. 17 aug & 28 sep 15 accepted 8 oct 15 doi: 10.18295/squmj.2016.16.01.021 case report combination of a giant dissected ascending aortic aneurysm with multiple fistulae into the cardiac chambers caused by prosthetic aortic valve endocarditis e110 | squ medical journal, february 2016, volume 16, issue 1 bicuspid aortic valve. the high volume of regurgitated blood by paravalvular leakage causes turbulent flow in the weakened area of the aortic root and subsequent fistula formation.4 this case report describes the successful surgical repair of a giant dissected ascending aa associated with double fistulae to the pulmonary artery and left atrium and the concomitant presence of a small paravalvular leak to the left ventricle. case report a 47-year-old woman who had undergone an aortic and mitral valve replacement 10 years previously was admitted to the emergency room of the imam ali hospital, kermanshah, iran, in january 2015 with severe dyspnoea and cold perspiration. a physical examination showed pitting oedema on the lower extremities, pulmonary rales and elevated jugular venous pressure. in addition, the patient’s skin was cold and damp. the patient history revealed two separate admissions to local hospitals two years earlier for incidences of high fever. she had been treated with appropriate antibiotics during these previous hospital admissions; however, no echocardiographic results were available. she had received oral warfarin and her international normalised ratio was 3–3.5 iu. the patient had had an uneventful postoperative course following her previous primary aortic and mitral valve replacement. at the time of her initial surgery, her native aortic valve was calcified and the diameter of the aa at the sinotubular junction was 4 cm. at admission, the patient’s chest radiography exhibited enlargement of the cardiac silhouette and pulmonary congestion. an electrocardiogram showed atrial fibrillation rhythm with rapid ventricular response. a physical examination revealed an irregular heart rhythm, low blood pressure (100/30 mmhg), tachycardia (120 beats per minute), tachypnoea, cyanosis, a prominent jugular vein and a diastolic 3/6 murmur along the left sternal border. the rales were heard diffusely in both lung fields. a transthoracic echocardiogram (tte) revealed normal functioning of the prosthetic mitral and aortic valve and a giant ascending aa involving the sinuses of valsalva. the dissection flap was not detected by tte. the aneurysm’s transverse diameter was measured as 7.5 cm with an aortic root contrast injection [figure 1]. a transoesophageal echocardiogram (toe) showed a highand low-velocity continuous pulse conforming with fistulae from the right and left valsalva sinuses to the left atrium and pulmonary artery, respectively. pulmonary artery angiography docu mented a large left-to-right shunt with a pulmonarysystemic flow ratio of 2:5. angiography revealed that the coronary arteries were normal. the aortic root angiogram detected the path of the fistulae. the patient was intubated due to severe respiratory dysfunction. she was prepared for urgent cardiac surgery and immediately taken to the operating room. due to abnormal preoperative coagulation tests, the patient received fresh frozen plasma. before the sternotomy, the femoral artery was cannulated; a cardiopulmonary bypass was established after reopening the sternum and right atrial cannulation. a giant aa with severe inflammatory adhesion to the neighbouring organs was observed. the normal diameter of the aa was just below the innominate artery and it was encircled with a tape. after establishing the cardiopulmonary bypass by inducing systemic and local hyperthermia, the giant aorta was transected just above the sinotubular junction. although a preoperative tte did not reveal figure 1: contrast medium angiograph showing fistulae to the left atrium (white arrow) and pulmonary artery (black arrow) in a 47-year-old woman with a dissected ascending aortic aneurysm. figure 2: an image showing the fistula to the pulmonary artery (arrow) in a 47-year-old woman with a dissected ascending aortic aneurysm. feridoun sabzi and reza faraji case report | e111 root may become flaccid following the disruption of supporting tissues by primary surgical procedures, such as the releasing of tissue in the aortopulmonary groove, iatrogenic trauma to the aortic wall due to the tip of the needle, extensive decalcification of the aortic ring, calcification of the aortic wall, coronary ostium vault perforation by turbulent flow of the cardioplegia catheter’s tip, aortic-mitral fibrous continuity disruption in the primary valve replacement, uncontrolled traction on the aortic wall by the surgeon’s assistants or infection of the prosthetic valve and aortotomy suture line.5,6 the current patient had three interrelated cardiac characteristics: fistulae, an aneurysm and a history of ie. these complications could be attributed to the patient’s previous aortic valve replacement. complications of the aortic root apparatus following aortic valve replacement is a well-known event and may be associated with high morbidity and mortality. a key complication of aortic valve replacement is ascending aorta dissection, which can lead to various cardiac problems, including ruptures, aneurysms, fistulae formation to a cardiac chamber, haemolytic anaemia, stroke, peripheral emboli and endocarditis. aorto-cardiac fistulae may be a rare complication of ie.7,8 aortic root ie has been associated with a myriad of complications such as congestive heart failure, stroke, emboli, respiratory failure, pneumonia and dehiscence of a prosthetic valve.5 the frequency and type of complications caused by ie have changed with advances in diagnosis and modern antibiotic therapy. previously common complications of extravalvular cardiac complications of ie—such as fistulae to the cardiac chamber—are infrequent today.8 only 3% of prosthetic valve ie with staphylococcus aureus (confirmed by autopsies and retrospective studies) have been associated with cardiac fistulae. it has been postulated that the formation of aorto-cardiac fistulae are caused by a bacterial invasion following a valve replacement; the spread of bacteria from the infected prosthetic valves into the surrounding organs and structures can lead to periannular abscess formation.9,10 the invasion of an abscess into the adjacent tissues can be facilitated by surgical handling or iatrogenic injuries to the aortic wall.6 periprosthetic aortic valve infections with involvement of the aortic ring and valsalva sinuses may extend upwardly and cause infectious aortitis and a subsequent dilatation or rupture of the aorta, erosion of the fibrous trigone or interventricular septum, which could lead to the formation of aorto-left atrial or left ventricular fistulae.11 a periannular abscess in the left valsalva sinus can sometimes erode into the aortopulmonary groove and lead to an aortopulmonary fistula.7 it is a dissection flap, intraoperative inspection revealed a flap in the posterior aortic wall. the prosthetic aortic valve was functionally normal but had a small paravalvular leak to the left ventricle [figures 2 & 3]. the orifice of both fistulae tracts in the right and left sinuses of valsalva and their entrance to the left atrium and pulmonary artery was defined intraoperatively. the fistula tract to the pulmonary artery ended at the main pulmonary artery. the aorto-left atrial fistula was located just over the left atrial roof and opened into the left atrial chamber via the fibrous trigone. both fistulae were repaired with two interrupted 4–0 pledgeted polypropylene sutures. intraoperative toe confirmed that the suture lines of sewing rings on the native fibrous ring were intact. the previous prosthetic aortic valve was removed. a classic bentall operation was performed using a carbomedics number 25 valve conduit (sorin group, rome, italy). distal anastomosis was performed with a proximal aortic cross-clamp and the patient was weaned from the cardiopulmonary bypass. the postoperative course was complicated by respiratory and renal failure which was managed accordingly with a tracheostomy, respiratory care, physiotherapy and peritoneal dialysis. on the ninth postoperative day, a tracheotomy was performed and the patient was weaned from the ventilator two days later. she was discharged 23 days after the operation in a good general condition. discussion aortic valve replacement is a risk factor for postoperative ie, aortic dilatation, dissection and paravalvular leaks. on the other hand, the presence of a paravalvular leak may be a predisposing factor for ie and subsequent fistulae formation.4 the aortic figure 3: an image showing the left atrial fistula in a 47-year-old woman with a dissected ascending aortic aneurysm. the prosthetic mitral valve was seen deep in the cavity (arrow). the upper curved line shows the native aortic ring after the removal of the prosthetic aortic valve. combination of a giant dissected ascending aortic aneurysm with multiple fistulae into the cardiac chambers caused by prosthetic aortic valve endocarditis e112 | squ medical journal, february 2016, volume 16, issue 1 known that no cardiac chamber can be excluded by ie-induced fistulae and no preponderance from any type of aortic sinus to a specific cardiac chamber can be predicted.3,4,8–11 conclusion the combination of aorto-cardiac fistulae with a dissected ascending aa is a very rare and fatal complication of aortic valve replacement. both complications may be caused by ie or they may each have a specific aetiology. the diagnosis of aorto-cardiac fistulae with a dissected ascending aa should be considered in patients with a history of aortic valve replacement and in those admitted with a diastolic murmur, congestive heart failure or shock in the setting of a post-aortic valve replacement aa. prompt surgical intervention is necessary for patient survival. references 1. holmes dr jr, brennan jm, rumsfeld js, dai d, o’brien sm, vemulapalli s, et al. clinical outcomes at 1 year following transcatheter aortic valve replacement. jama 2015;313:1019-28. doi: 10.1001/jama.2015.1474. 2. sreedharan m, baruah b, dash pk. aorta-right atrial tunnel: a novel therapeutic option. int j cardiol 2006; 107:410–12. doi: 10.1016/j.ijcard.2005.01.056. 3. girdauskas e, disha k, borger ma, kuntze t. long-term prognosis of ascending aortic aneurysm after aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. j thorac cardiovasc surg 2014; 147:276–82. doi: 10.1016/j.jtcvs .2012.11.004. 4. tsutsumi k, inoue y, hashizume k, kimura n, takahashi r. risk factor analysis for acute type a aortic dissection after aortic valve replacement. gen thorac cardiovasc surg 2010; 58:601–5. doi: 10.1007/s11748-010-0658-z. 5. vahanian a, baumgartner h, bax j, butchart e, dion r, filippatos g, et al. guidelines on the management of valvular heart disease: the task force on the management of valvular heart disease of the european society of cardiology. eur heart j 2007; 28:230–68. 6. yilmaz a, dessing t, botta l. ascending aorta impending rupture: successful surgical management in a patient with type iv ehlers-danlos syndrome. j cardiovasc med (hagerstown) 2010; 11:610–12. doi: 10.2459/jcm.0b013e3283314176. 7. roseborough gs, williams gm. marfan and other connective tissue disorders: conservative and surgical considerations. semin vasc surg 2000; 13:272–82. 8. benedik j, pilarzcyk k, wendt d, price v, tsagakis k, perrey m, et al. is there any difference in aortic wall quality between patients with aortic stenosis and those with regurgitation? eur j cardiothorac surg 2013; 44:754–9. doi: 10.1093/ejcts/ezt123. 9. tzemos n, therrien j, yip j, thanassoulis g, tremblay s, jamorski mt, et al. outcomes in adults with bicuspid aortic valves. jama 2008; 300:1317–25. doi: 10.1001/jama.300.11. 1317. 10. mckellar sh, michelena hi, li z, schaff hv, sundt tm 3rd. long-term risk of aortic events following aortic valve replacement in patients with bicuspid aortic valves. am j cardiol 2010; 106:1626–33. doi: 10.1016/j.amjcard.2010.07.043. 11. matsuhisa h, obo h, nakagiri k, mokohara n, shida t. aortoright atrial fistula caused by type a aortic dissection. ann thorac surg 2004; 78:2173–5. doi: 10.1016/j.athoracsur.2003. 08.007. http://dx.doi.org/10.1001/jama.2015.1474 http://dx.doi.org/10.1016/j.ijcard.2005.01.056 http://dx.doi.org/10.1016/j.jtcvs.2012.11.004 http://dx.doi.org/10.1016/j.jtcvs.2012.11.004 http://dx.doi.org/10.1007/s11748-010-0658-z http://dx.doi.org/10.2459/jcm.0b013e3283314176 http://dx.doi.org/10.1093/ejcts/ezt123 http://dx.doi.org/10.1001/jama.300.11.1317 http://dx.doi.org/10.1001/jama.300.11.1317 http://dx.doi.org/10.1016/j.amjcard.2010.07.043 http://dx.doi.org/10.1016/j.athoracsur.2003.08.007 http://dx.doi.org/10.1016/j.athoracsur.2003.08.007 1department of surgery, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2general surgery residency program, oman medical specialty board, muscat, oman; 3department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: kadhim.lawati@gmail.com مقارنة وضع أنبوب النزح وعدم وضعه بعد عمليات استئصال الغدة الدرقية دراسة اسرتجاعية بني احلاالت والشواهد يف مستشفى جامعة السلطان قابوس٬ مسقط٬ عمان اأ�شمى �شعيد احلب�شية, العنود خلف�ن ال�شليم�نية, ك�ظم م�شطفى تقي, ه�ين اأحمد الق��شي abstract: objectives: a thyroidectomy is a frequently performed surgical procedure which can result in lifethreatening complications. the insertion of a drain after a thyroidectomy has been suggested to prevent such complications. this study aimed to evaluate the use of surgical drains following thyroidectomies in relation to postoperative complications and mass sizes. methods: this retrospective case-control study included all thyroidectomies conducted at the sultan qaboos university hospital, muscat, oman, from january 2011 to december 2013. length of hospital stay, readmission, postoperative complications and mass size were evaluated. results: during the study period, 250 surgeries were carried out on 241 patients. the majority of patients were female (87.2%). drains were inserted postoperatively after 202 surgeries (80.8%) compared to 48 surgeries (19.2%) without drains. a total of 32 surgeries (12.8%) were conducted on patients with thyroid masses <1 cm, 138 (55.2%) on those with masses between 1–4 cm and 80 (32.0%) on those with masses >4 cm. the association between drain use and mass size was not significant (p = 0.439). although postoperative complications were more prevalent in patients with drains, the relationship between these factors was not significant (p >0.050). length of hospital stay was significantly longer among patients with postoperative drains (p <0.010). conclusion: the routine insertion of drains after thyroid surgeries was found to result in longer hospital stays and did not reduce rates of postthyroidectomy complications. thyroid mass size should not be used as an indicator for the insertion of a drain after thyroidectomy. keywords: thyroidectomy; drainage; length of stay; postoperative complications; oman. امللخ�ص: الهدف: تعترب عملي�ت ا�شتئ�ش�ل الغدة الدرقية من العملي�ت ال�ش�ئعة ولكنه� قد توؤدي حلدوث م�ش�عف�ت ت�شكل خطرا على احلي�ة. ويعترب و�شع اأنبوب النزح بعد عملي�ت ا�شتئ�ش�ل الغدة الدرقية اأ�شلوبً� مقرتحً� ملنع حدوث هذه امل�ش�عف�ت. وتهدف هذه الدرا�شة اإىل تقييم و�شع اأنبوب النزح اجلراحي بعد عملي�ت ا�شتئ�ش�ل الغدة الدرقية وعالقته مب�ش�عف�ت العملية وحجم الورم. الطريقة: ت�شمل هذه الدرا�شة ال�شرتج�عية بني احل�لت وال�شواهد, جميع عملي�ت ا�شتئ�ش�ل الغدة الدرقية يف م�شت�شفى ج�معة ال�شلط�ن ق�بو�س, م�شقط, عم�ن, منذ ين�ير 2011 اإىل دي�شمرب 2013. وي�شمل التقييم كذلك مدة الإق�مة يف امل�شت�شفى, واإع�دة الرتقيد, وم�ش�عف�ت العملية وحجم الورم. النتائج: خالل فرتة الدرا�شة, مت اإجراء 250 عملية جراحية على 241 مري�شً�. معظم املر�شى ك�نوا اإن�ثً� )%87.2(. مت و�شع اأن�بيب النزح بعد 202 عملية جراحية )%80.8( مق�رنة بـ48 عملية جراحية مل يتم و�شع اأنبوب النزح فيه� )%19.2(. جمموع العملي�ت اجلراحية التي اأجريت ملر�شى حجم الورم لديهم 1< �شم هو 32 عملية )%12.8(, و 138 )%55.2( عملية جراحية على مر�شى حجم الورم لديهم بني 4-1 �شم, و 80 عملية جراحية .)p = 0.439( �على مر�شى حجم الورم لديهم 4> �شم. العالقة بني ا�شتعم�ل اأنبوب النزح وحجم الورم مل تكن معنوية اإح�ش�ئي )32.0%( على الرغم من اأن امل�ش�عف�ت ك�نت اأعلى لدى املر�شى الذين مت و�شع اأنبوب النزح لهم, اإل اأن العالق�ت بني هذه العوامل مل تكن معنوية .)p >0.010( فرتة الإق�مة يف امل�شت�شفى ك�نت اأعلى لدى املر�شى الذين و�شع اأنبوب النزح لهم بعد العملية اجلراحية .)p <0.050( �اإح�ش�ئي اخلال�صة: اأدى ال�شتعم�ل الروتيني لأنبوب النزح بعد عملي�ت ا�شتئ�ش�ل الغدة الدرقية اإىل اإط�لة فرتة الإق�مة يف امل�شت�شفى ومل يوؤدى اإىل خف�س معدلت امل�ش�عف�ت بعد عملي�ت ا�شتئ�ش�ل الغدة الدرقية. ينبغي عدم اعتب�رحجم الورم يف الغدة الدرقية موؤ�رسا لو�شع اأنبوب النزح بعد عملي�ت ا�شتئ�ش�ل الغدة الدرقية. الكلمات املفتاحية: ا�شتئ�ش�ل الدرقية؛ نزح؛ مدة الإق�مة؛ م�ش�عف�ت ت�لية للجراحة؛ عم�ن. comparison of postoperative drain insertion versus no drain insertion in thyroidectomies retrospective case-control study from the sultan qaboos university hospital, muscat, oman asma s. al-habsi,1 al-anood k. al-sulaimani,1 *kadhim m. taqi,2 hani a. al-qadhi3 clinical & basic research advances in knowledge in the current study, the association between drain insertion and mass size was not significant. drain insertion was not found to prevent post-thyroidectomy complications and was associated with significantly longer hospital stays. application to patient care the findings of the current study indicate that preoperative thyroid mass size should not be used as an indicator for postoperative drain insertion following a thyroidectomy. sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e464–468, epub. 30 nov 16 submitted 12 apr 16 revision req. 15 may 16; revision recd. 11 jun 16 accepted 30 jun 16 doi: 10.18295/squmj.2016.16.04.010 asma s. al-habsi, al-anood k. al-sulaimani, kadhim m. taqi and hani a. al-qadhi clinical and basic research | e465 thyroidectomies are considered one of the most commonly performed procedures in endocrine surgery.1,2 in recent years, the number of thyroidectomies has increased due to a rise in the incidence of thyroid malignancies, which now account for 1.7% of the total number of malignancies worldwide.3,4 despite improvements in surgical techniques, many patients who undergo a thyroidectomy develop postoperative complications, including haemorrhage (0.3–6.5%), haematoma formation (1–1.2%), recurrent laryngeal nerve injuries (0.5–4.4%) and hypocalcaemia (3.1–11%).1–3,5–10 many surgeons insert a drain post-thyroidectomy in order to prevent haematomas, alert surgeons to early postoperative bleeding or in cases of large dead spaces where the chance of seroma formation is high.6,11–13 however, the findings of multiple studies and randomised clinical trials have indicated against the routine use of drains.8,14,15 even though the insertion of a postoperative drain has proven significantly beneficial for patients suffering from bleeding disorders, research has shown that postoperative drain placement can have a negative impact on patients and lead to scarring, pain, increased susceptibility to infection and prolonged hospital stay.1,3,8,14,15 in addition, the placement of a post-thyroidectomy drain may be a causative factor for haematoma formation, which can turn into a life-threatening complication as a result of airway obstruction.14 although many studies have been conducted to assess the necessity of postoperative drainage, no official guidelines or recommendations have yet been proposed; the personal preference of the surgeon therefore remains the main deciding factor regarding drain placement.5,11,16,17 in oman, thyroid cancer was ranked in 2011 as the fifth most common cancer in the country, accounting for 11.3% of all cancers with an incidence of approximately 67 per 100,000 females and 10 per 100,000 males; hence, thyroidectomies are commonly performed in oman.18 however, there is currently no national consensus regarding the insertion of drains after a thyroidectomy. the current study aimed to evaluate the use of surgical drains following a thyroidectomy in relation to postoperative complications and tumour mass size at the sultan qaboos university hospital (squh), muscat, oman. to the best of the authors’ knowledge, this study is the first of its kind in oman. methods this retrospective case-control study was conducted from january 2011 to december 2013 and included all thyroidectomies performed at squh during the study period. surgeries on patients ≤12 years old as well as cases of modified radical neck dissection were excluded from the study. clinical and descriptive data were collected from both paper and electronic records, including length of hospital stay, readmission, mass size and the occurrence of any post-thyroidectomy complications, including haemorrhage, haematoma and/or seroma formation, hypocalcaemia, recurrent laryngeal nerve injuries and wound infection. the type of surgery—either a total thyroidectomy (tt), hemi-thyroidectomy (ht) or complete thyroidectomy (ct)—was also noted. re-admission was defined as admission within one month of discharge. the size of the thyroid mass was calculated from the most recent ultrasound scan before the surgery. one patient was excluded from the study due to an inability to accurately assess the thyroid mass size. patients whom had had a drain inserted were considered cases and patients without a drain were considered controls. data were analysed using the statistical package for social sciences (spss), version 23 (ibm corp., chicago, illinois, usa). a chi-squared test was used to evaluate the significance of the associations between variables. continuous variables were displayed as means and standard deviations. a p value of ≤0.050 was considered significant. this study obtained ethical approval from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #946). results a total of 250 thyroidectomies were performed on 241 patients over the three-year period. the majority of patients were female (87.2%). the mean age was 40.8 ± 13.8 years (range: 14–83 years old). the majority of the surgeries were tts (75.6%), while 16.8% and 7.6% of the surgeries were hts and cts, respectively. the majority of patients were euthyroid prior to surgery (84%); of these, 74.7% underwent tts, 18.6% underwent hts and 6.7% underwent cts. most patients with hyperthyroidism or hypothyroidism prior to surgery underwent a tt (85.1% and 69.2%, respectively). drains were placed in 83.5% of patients undergoing a tt, 69.0% of those undergoing a ht and 79.0% of those receiving a ct. a total of 202 patients (80.8%) had single or multiple drains inserted after the surgery, while 48 patients (19.2%) had no drain inserted. the drains were kept in place for between 0–9 days, with a mean duration of 2.3 ± 1.3 days. comparison of postoperative drain insertion versus no drain insertion in thyroidectomies retrospective case-control study from the sultan qaboos university hospital, muscat, oman e466 | squ medical journal, november 2016, volume 16, issue 4 in terms of mass size, 32 surgeries (12.8%) were performed on patients with a thyroid mass <1 cm, while 138 (55.2%) were performed on those with a mass between 1–4 cm and 80 (32.0%) were performed on patients with a mass >4 cm. there was no significant association between the use of a drain and thyroid mass size (p = 0.439) [table 1]. length of hospital stay ranged between 1–10 days, with a mean duration of 2.5 ± 1.4 days. the majority of patients who stayed in hospital for 2–4 days after the surgery (85.2%) had drains, while the majority of patients who stayed less than two days (60.4%) did not have drains. moreover, of the 14 patients who stayed for ≥5 days, 13 patients (92.9%) had drains while only one patient (7.1%) had no drain [figure 1]. the average length of hospital stay for patients with drains was 2.7 ± 1.4 days in comparison to 1.8 ± 1.3 days for those without drains (p <0.010). there was no statistically significant difference in the rate of postoperative complications between those with drains and those without [table 2]. overall, 5.6% of patients developed postoperative bleeding, with a higher incidence among those with drains versus those without (5.2% versus 0.4%). of the 20 patients (8.0%) who developed respiratory distress, 18 (90.0%) had drains. postoperative haematoma formation was noted in three patients (1.2%) and seroma formation in one patient (0.4%), all of whom had drains. wound infection was noted in nine patients (3.6%), of which eight (88.8%) had drains. a total of 13 patients were readmitted (5.2%); readmissions occurred mostly among patients with drains (n = 10; 76.9%). only one patient died postoperatively (0.4%); this patient had a drain and died from sepsis with an anaplastic thyroid carcinoma. discussion the use of post-thyroidectomy drains remains a controversial subject and an area of active discussion and research. many surgeons still use drains after thyroid and parathyroid surgeries, despite the large body of evidence suggesting that they may be associated with negative outcomes.19 although the prophylactic use of postoperative drains to decrease the incidence of postoperative haematomas may seem logical, most studies and clinical trials have failed to demonstrate any advantage to this procedure.11,12 drains often become blocked by clotted blood.19 suslu et al. studied 135 thyroid surgery patients, two of whom developed severe postoperative respiratory symptoms requiring a second operation; they found that although the amount of blood was not significant, one patient developed the respiratory symptoms after their drain became blocked by a clot.20 thus, the use of a neck drain did not prevent life-threatening haemorrhage and the decision to re-operate was made only after the development of dyspnoea and not according to the amount of blood in the drain. similarly, hurtado-lópez et al. found that the presence or absence of drains did not affect the incidence of seromas or haematomas in an analysis of 150 patients.13 figure 1: length of hospital stay among patients with and without postoperative drains following thyroidectomies performed at the sultan qaboos university hospital, muscat, oman (n = 250). table 1: use of postoperative drains in relation to presurgical thyroid mass size among thyroidectomies performed at the sultan qaboos university hospital, muscat, oman (n = 250) mass size in cm n (%) p value patients with drains patients without drains <1 28 (87.5) 4 (12.5) 0.4391–4 108 (78.3) 30 (21.7) >4 66 (82.5) 14 (17.5) table 2: postoperative complications among patients with and without postoperative drains following thyroidectomies performed at the sultan qaboos university hospital, muscat, oman (n = 250) complication n (%) p value total patients with drains patients without drains haemorrhage 14 (5.6) 13 (5.2) 1 (0.4) 0.238 respiratory distress 20 (8.0) 18 (7.2) 2 (0.8) 0.276 haematoma 3 (1.2) 3 (1.2) 0 (0.0) 0.396 seroma 1 (0.4) 1 (0.4) 0 (0.0) 0.625 readmission 13 (5.2) 10 (4.0) 3 (1.2) 0.715 wound infection 9 (3.6) 8 (3.2) 1 (0.4) 0.530 asma s. al-habsi, al-anood k. al-sulaimani, kadhim m. taqi and hani a. al-qadhi clinical and basic research | e467 the current study was conducted to assess the efficacy of drains in terms of the incidence of postoperative complications and the relationship between mass size and drain insertion in a hospital setting in oman. while there was no statistically significant difference in the rate of postoperative complications between patients with drains and those without, inserting a postoperative drain did not reduce the incidence of respiratory distress and haematoma or seroma formation. similarly, ozlem et al. reported that drainage of the thyroidectomy bed did not effectively decrease the rate of post-thyroid surgery complications in 1,066 patients.12 in the current study, preoperative thyroid mass size was not significantly related to the use of postoperative drains; many surgeries on patients with large thyroid masses did not result in drain insertion, while other surgeries on patients with small thyroid nodules did. mass size was therefore not considered a factor influencing drain insertion. dunlap et al. compared the use of drains in 100 patients undergoing lobectomies and total thyroidectomies and reported that type of surgery and mass size could not be used as indicators for drain insertion or predictors of postoperative bleeding.11 hurtado-lópez et al. also presented evidence that gland size, diagnosis, type of surgery and intraoperative bleeding were invalid arguments for the use of an external drain.13 hospital stays were significantly longer among patients with drains in comparison to those without drains in the current study. the wound infection rate was also found to be higher in patients with drains; however, this was not statistically significant. nevertheless, this finding is in agreement with previous studies.12,20 a recent meta-analysis showed that the use of drains after routine thyroid surgery was not beneficial to patients; drain insertion was associated with a higher risk of wound infection, a higher pain score on the first postoperative day and longer hospital stays.19 furthermore, hurtado-lópez et al. found that hospital stay was significantly shorter for patients without drains compared to those with drains, leading to a reduction in costs and minimising the risk of intrahospital infections.13 one of the factors contributing to longer hospital stays is the higher incidence of complications and wound infection in patients with drains compared to patients without drains.12,19,20 in the current study, the mean amount of time a postoperative drain was kept in situ was approximately 55 hours; however, most haematomas usually occur 2–6 hours after surgery.11,21 these findings call into question the need for prolonged in situ drains as these devices further increase the risk of infection and prolonged hospital stays. it is important to emphasise that the prevention of haematomas and seromas can be achieved through other means, such as the identification of risk factors and utilisation of proper intraoperative techniques. harding et al. identified multiple risk factors for the development of haematomas, broadly categorised into patient-related, thyroid pathology-related and surgeryrelated factors.22 patient-related factors include a history of bleeding disorders, the use of anticoagulant medications and smoking. moreover, there is no clear evidence that high vascularity in toxic multinodular glands and grave’s disease are associated with a higher risk of postoperative bleeding.22 the most effective way to prevent complications associated with haematoma and seroma formation is to use adequate surgical techniques, handle tissues carefully and ensure adequate haemostasis intraoperatively.13,22 the current study has a number of limitations. due to the retrospective nature of this study, it was difficult to accurately assess thyroid mass sizes in some patients, which resulted in the exclusion of one patient from the study. another limitation was the small sample size, as only surgeries conducted at a single hospital over a three-year period were included. in addition, the type of haemostasis device used in the surgeries was sometimes difficult to determine due to the lack of a unified format for intraoperative notes. finally, due to the lack of clear hospital practice guidelines, there was a difference in the sample size between the two groups. further randomised control trials are needed to establish definitive recommendations and practice guidelines in this area. however, this study was the first of its kind to be carried out in oman; these findings may therefore act as a reference for future research. conclusion in the current study, post-thyroidectomy drain insertion was not significantly associated with thyroid mass size and did not reduce the rate of postoperative complications, including haematoma or seroma formation. moreover, the insertion of a drain resulted in significantly longer hospital stays. further research is required to inform recommendations and practice guidelines regarding the insertion of postoperative drains following a thyroidectomy. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. comparison of postoperative drain insertion versus no drain insertion in thyroidectomies retrospective case-control study from the sultan qaboos university hospital, muscat, oman e468 | squ medical journal, november 2016, volume 16, issue 4 references 1. colak t, akca t, turkmenoglu o, canbaz h, ustunsoy b, kanik a, et al. drainage after total thyroidectomy or lobectomy for benign thyroidal disorders. j zhejiang univ sci b 2008; 9:319–23. doi: 10.1631/jzus.b0720257. 2. majid ma, siddique mi. major post-operative complications of thyroid surgery: preventable or not? bangladesh med res counc bull 2008; 34:99–103. 3. kalemera ssenyondo e, fualal j, jombwe j, galukande m. to drain or not to drain after thyroid surgery: a randomized controlled trial at a tertiary hospital in east africa. afr health sci 2013; 13:748–55. doi: 10.4314/ahs.v13i3.33. 4. nikiforov ye, biddinger pw, thompson ld. diagnostic pathology and molecular genetics of the thyroid, 2nd ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2012. pp.108–11. 5. güngör b, polat ak, polat c, yurtseven i, erzurumlu k. role of drainage of the thyroid bed. world j endocrine surg 2011; 3:15–19. doi: 10.5005/jp-journals-10002-1048. 6. alexiou k, konstantinidou e, papagoras d. the use of drains in thyroid surgery. hell cheirourgike 2015; 87:97–100. doi: 10.10 07/s13126-015-0191-8. 7. christou n, mathonnet m. complications after total thyroidectomy. j visc surg 2013; 150:249–56. doi: 10.1016/j. jviscsurg.2013.04.003. 8. morrissey at, chau j, yunker wk, mechor b, seikaly h, harris jr. comparison of drain versus no drain thyroidectomy: randomized prospective clinical trial. j otolaryngol head neck surg 2008; 37:43–7. 9. deveci u, altintoprak f, sertan kapakli m, manukyan mn, cubuk r, yener n, et al. is the use of a drain for thyroid surgery realistic? a prospective randomized interventional study. j thyroid res 2013; 2013:285768. doi: 10.1155/2013/285768. 10. farling pa. thyroid disease. br j anaesth 2000; 85:15–28. doi: 10.1155/2013/285768. 11. dunlap ww, berg rl, urquhart ac. thyroid drains and postoperative drainage. otolaryngol head neck surg 2010; 143:235–8. doi: 10.1016/j.otohns.2010.04.024. 12. ozlem n, ozdogan m, gurer a, gomceli i, aydin r. should the thyroid bed be drained after thyroidectomy? langenbecks arch surg 2006; 391:228–30. doi: 10.1007/s00423-006-0048-2. 13. hurtado-lópez lm, lópez-romero s, rizzo-fuentes c, zaldívar-ramírez fr, cervantes-sánchez c. selective use of drains in thyroid surgery. head neck 2001; 23:189–93. doi: 10.1002/1097-0347(200103)23:3<189::aid-hed1017>3.0. co;2-y. 14. neary pm, o’connor oj, shafiq a, quinn em, kelly jj juliette b, et al. the impact of routine open nonsuction drainage on fluid accumulation after thyroid surgery: a prospective randomised clinical trial. world j surg oncol 2012; 10:72. doi: 10.1186/1477-7819-10-72. 15. memon za, ahmed g, khan sr, khalid m, sultan n. postoperative use of drain in thyroid lobectomy: a randomized clinical trial conducted at civil hospital, karachi, pakistan. thyroid res 2012; 5:9. doi: 10.1186/1756-6614-5-9. 16. minami s, sakimura c, hayashida n, yamanouchi k, kuroki t, eguchi s. timing of drainage tube removal after thyroid surgery: a retrospective study. surg today 2014; 44:137–41. doi: 10.1007/s00595-013-0531-7. 17. panda nk, sood m, kaushal d, bakshi j, verma rk. how long to keep the surgical drains: looking for evidence. j otolaryngol ent res 2015; 2:00021. doi: 10.15406/joentr.2015.02.00021. 18. al-lawati ja, al-lawati na, al-siyabi nh, al-ghabri do, al-wehaibi s. cancer incidence in oman 2011. oman: ministry of health, 2011. pp. 29–31. 19. woods rs, woods jf, duignan es, timon c. systematic review and meta-analysis of wound drains after thyroid surgery. br j surg 2014; 101:446–56. doi: 10.1002/bjs.9448. 20. suslu n, vural s, oncel m, demirca b, gezen fc, tuzun b, et al. is the insertion of drains after uncomplicated thyroid surgery always necessary? surg today 2006; 36:215–18. doi: 10.1007/s00595-005-3129-x. 21. herranz j, latorre j. [drainage in thyroid and parathyroid surgery]. acta otorrinolaringol esp 2007; 58:7–9. doi: 10.1016/ s0001-6519(07)74868-9. 22. harding j, sebag f, sierra m, palazzo ff, henry jf. thyroid surgery: postoperative hematoma prevention and treatment. langenbecks arch surg 2006; 391:169–73. doi: 10.1007/s00423 006-0028-6. 1department of community medicine, gulf medical university, ajman, united arab emirates; 2mushairef health center, ministry of health, ajman, united arab emirates; 3department of medicine, gulf medical college hospital, ajman, united arab emirates *corresponding author e-mail: shathaalsharbatti@gmail.com التوافق يف مرض السكري عند النساء املتزوجات املراجعات للمؤسسات الصحية يف عجمان، اإلمارات العربية املتحدة �سذى �سعيد ال�رسبتي، يا�سمني اإبراهيم عبد، جلني متعب الهيتي، �سيخ األطاف با�سا abstract: objectives: spousal concordance is defined as similar behaviours and associated health statuses between spouses. this study aimed to identify the concordance of diabetes mellitus (dm) and related variables among genetically unrelated couples in ajman, united arab emirates (uae). methods: this cross-sectional study included 270 married women attending either the mushairef health center or the gulf medical college hospital in ajman between may and november 2012. a validated questionnaire was designed to determine sociodemographic characteristics and a history or family history of dm, hypertension, coronary artery disease or dyslipidaemia among the women and their husbands. the weight, height, body mass index, waist circumference, fasting blood sugar and glycated haemoglobin (hba1c) levels of all women were measured. results: of the women, 39.3% of those with diabetic husbands and 39.9% of those with non-diabetic husbands were diabetic themselves (p >0.050). the prevalence of dm spousal concordance was 17.8%. a history of hypertension, coronary artery disease and dyslipidaemia was significantly more frequent among women whose husbands had a history of the same conditions (p = 0.001, 0.040 and 0.002, respectively). spousal concordance of abnormal glycaemia among non-diabetic women with diabetic husbands was significant (p = 0.001). having a diabetic husband (p = 0.006) and being obese (p = 0.009) were the only significant predictors of hyperglycaemia among non-diabetic women after controlling for confounding factors. conclusion: there was significant concordance of abnormal glycaemia among non-diabetic women with diabetic husbands. the spouses of diabetic patients may therefore be a target population for regular hyperglycaemia and dm screening. keywords: spouses; women; diabetes mellitus; hyperglycemia; united arab emirates. هذه هدفت الزوجني. بني ال�سحية الأو�ساع من بها يرتبط ما و ال�سلوكيات يف الت�سابه باأنه الزوجي التوافق يعرف اأهداف: امللخ�ص: الدرا�سه اإىل التعرف على وجود التوافق يف مر�س ال�سكري و املتغريات ذات ال�سله بني الأزواج الغري مرتبطني وراثيا يف عجمان، الإمارات العربية املتحدة. منهجية: �سملت هذه الدرا�سة املقطعية 270 �سيدة متزوجة من املراجعات اإىل مركز م�سريف للرعاية ال�سحية اأو م�ست�سفى كلية اخلليج الطبية يف عجمان بني �سهري مايو ونوفمرب 2012. مت ت�سميم ا�ستمارة ا�ستبيان باللغة العربية مت التحقق منها لتحديد احلالة الإجتماعية و الدميوغرافية والتاريخ العائلي و ال�سخ�سي ملر�س ال�سكري، ارتفاع �سغط الدم، مر�س ال�رسيان التاجي و اإ�سطراب الدهون يف الدم بني الن�ساء و اأزواجهن. مت قيا�س الوزن والطول و موؤ�رس كتلة اجل�سم، وحميط اخل�رس و م�ستوى ال�سكر يف الدم يف حالة ال�سيام ون�سبة الهيموغلوبني الغليكوزيالتي )hba1c( جلميع الن�ساء. نتائج: من بني الن�ساء، كانت %39.3 من اللواتي يعاين أزواجهن من مر�س ال�سكري و %39.9 من اللواتي ل يعاين أزواجهن من مر�س ال�سكري م�سابات مبر�س ال�سكري )p <0.050(. كان اإنت�سار التوافق الزوجي ملر�س ال�سكري %17.8. كان تاريخ ارتفاع �سغط الدم و مر�س ال�رسيان التاجي و ا�سطراب الدهون يف الدم الأكرث �سيوعا وب�سكل ملحوظ اأهمية ذو زوجي توافق هناك كان التوايل(. على 0.002 و 0.040 ،p = 0.001( احلالت لنف�س تاريخ اأزواجهن لدى اللواتي الن�ساء عند زوج وجود .)p = 0.001( بال�سكري امل�سابني اأزواجهن مع بال�سكري امل�سابات غري الزوجات عند لل�سكري الطبيعي غري املن�سوب بني م�ساب بال�سكري )p = 0.006( و ال�سمنة )p = 0.009( هما املتغريان الوحيدان ذوي الأهمية املتنباأن بوجود فرط �سكر الدم عند الزوجات للزوجات الدم �سكر فرط جود و بني هام زوجي توافق هناك كان خامتة: الأخرى. التدقيق عوامل �سبط بعد بال�سكري امل�سابات غري غري امل�سابات بال�سكري مع اأزواجهن امل�سابني بال�سكري. لذلك فاإن اأزواج الأ�سخا�س امل�سابني بال�سكري ميكن اأن يكونوا من ال�سكان امل�ستهدفني بامل�سوحات ال�سحية ملر�س ال�سكري وفرط �سكر الدم. كلمات مفتاحية: الأزواج؛ الن�ساء؛ مر�س ال�سكري؛ فرط �سكر الدم؛ الإمارات العربية املتحدة. spousal concordance of diabetes mellitus among women in ajman, united arab emirates *shatha s. al-sharbatti,1 yasmeen i. abed,1 lujain m. al-heety,2 shaikh a. basha3 advances in knowledge in the current study, there was significant spousal concordance of abnormal glycaemic levels. non-diabetic women with diabetic husbands were 2.5 times more likely to have abnormal glycaemic levels than those with non-diabetic husbands. clinical & basic research sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 197–202, epub. 15 may 16 submitted 12 sep 15 revisions req. 25 oct 15 & 22 dec 15; revisions recd. 24 nov 15 & 5 jan 16 accepted 24 jan 16 doi: 10.18295/squmj.2016.16.02.010 spousal concordance of diabetes mellitus among women in ajman, united arab emirates e198 | squ medical journal, may 2016, volume 16, issue 2 diabetes mellitus (dm) is currently one of the most common health concerns worldwide, with a potentially detrimental effect on the everyday life of those affected by the condition.1,2 in 2010, 190 million people had dm; this is estimated to increase to 330 and 366 million by 2025 and 2030, respectively.2 although genetic factors are important in the development of type 2 dm, they alone cannot explain the rapid rise of this disease and it is believed that the condition results from an interaction between genetic and environmental factors.3,4 spousal association/concordance has been identified as a similar connection between spouses in behaviour and in health status.5 studies have found that married couples often have associated or concordant health statuses.6,7 spouses often share a common living environment, social habits, eating patterns, physical activity levels and other health-related behaviours, but are usually genetically unrelated; thus, similarities in disease patterns between spouses mainly reflect underlying environmental aetiologies.6,8 previous re search has shown that the marital relationship influences the health of spouses living within the same household.9 it has been found that social support— particularly spousal support—has a positive impact on patient outcomes, health behaviours and selfcare management strategies.6,10,11 simple lifestyle modifications have proven effective in the prevention of type 2 dm and interventions targeting married couples are reportedly more effective than those aimed at individuals.12,13 targeting both patients and their spouses may enhance the collective efficacy of behavioural interventions for chronic illnesses in comparison to patient-oriented approaches. in addition, interventions aimed at couples enhance long-term maintenance of behavioural changes.9 in the united arab emirates (uae), the prevalence of dm is 24% among citizens and 17.4% among expatriates.14 in 2013, the international diabetes federation (idf) ranked the prevalence of type 2 dm in the uae as the fifth highest in the middle eastern and north african region.15 however, no literature yet exists regarding the spousal concordance of dm or abnormal glycaemic levels in the uae. the objective of the current study was therefore to investigate the spousal concordance of dm among married women in ajman, uae. methods this cross-sectional study was conducted at two health centres in ajman, the gulf medical college hospital and mushairef health center, between may and november 2012. the inclusion criteria included all women between 30 and 75 years old who been married for at least one year to a man who was not their genetic relative and who were attending either of these two health institutions during the study period. pregnant women, women who were related to their husbands and those who could not communicate adequately in arabic or english were excluded. the sample size was determined according to a 20% prevalence of dm in the uae using the following formula: where p was 0.2 and q was 0.8, with a marginal error of 5% and a significance level of 95%.3,16 according to this, the required sample size was 246 participants. a consecutive sampling technique was used to recruit 270 women for the study according to the inclu sion criteria. data collection was carried out during direct interviews with the participants by a member of the research team. a pilot-tested questionnaire was designed to determine the participants’ sociodemographic and other health-related variables. specific items on the questionnaire required the women to report a history or family history of dm, gestational dm, hypertension, coronary artery disease (cad) or dyslipidaemia for both themselves and their husbands. participants also reported their own and their husband’s smoking status and physical activity level (mild, moderate/vigorous or none). the global tobacco surveillance system definition for a current tobacco smoker was used to identify current smokers.17 the recommendations of the world health organization (who) were used to define physical activity levels.18 the content of the questionnaire was validated by two specialists in internal medicine and community medicine. the questionnaire was then translated from english into arabic and the arabic version subsequently validated. weight, height, waist circumference (wc), fasting blood glucose (fbg) and glycated haemoglobin (hba1c) measurements were taken for all of the women. abnormal glycaemia was defined as application to patient care the concept of spousal concordance provides an insight into which conditions or lifestyle behaviours may put the spouses of diabetic patients at risk of developing diabetes mellitus (dm) themselves. this information can then be utilised as a supportive measure in dm awareness, education and screening interventions. the findings of this study indicate that the spouses of diabetic patients should be targeted for routine hyperglycaemia screening. n = z2 pq/l2 shatha s. al-sharbatti, yasmeen i. abed, lujain m. al-heety and shaikh a. basha clinical and basic research | e199 hba1c levels of ≥5.7%.19 pre-diabetes and dm were diagnosed according to the criteria of the who, idf and american diabetes association.19,20 weight and height measurements were used to determine body mass index (bmi). obesity and abdominal obesity were defined as a bmi of ≥30 kg/m2 and a wc of ≥88 cm, respectively. statistical analysis was carried out using the statistical package for the social sciences (spss), version 19 (ibm corp., chicago, illinois, usa). data were described using means ± standard deviations for continuous variables and proportions for categorical variables. comparisons between group characteristics were made with chi-squared, zand t-tests. a logistic regression analysis was used to assess the odds of abnormal glycaemic levels among non-diabetic women according to the diabetic status of their husbands. univariate logistic regression analyses were performed as potential predictors of abnormal glycaemia among non-diabetic women. all potential predictors were entered into a multivariable regression analysis and the variables that most accurately predicted outcomes were identified. a p value of <0.05 was considered statistically significant. this study was approved by the ethics committee of the gulf medical university and the uae ministry of health. the ministry of health ethics committee approved data collection from the mushairef health center, while the gulf medical university ethics committee approved data collection from the gulf medical university hospital. the nature and procedures of the study and the rights of the participants were explained to all women enrolled in the study. all of the subjects gave informed consent before participating in the study. results the sociodemographic data of the participants and their husbands are presented in table 1. in comparison to the women, a history of dm (45.2% versus 39.6%), hypertension (44.8% versus 35.9%), cad (13.0% versus 4.8%) and dyslipidaemia (41.5% versus 36.7%) was more common among the husbands. in addition, more husbands were current smokers (26.3% versus 1.9%) and undertook moderate/vigorous physical activity (17.4% versus 8.5%). a total of 107 women (39.6%) and 122 husbands (45.2%) were diabetic. the mean duration of dm was 6.2 ± 5.9 years among diabetic women and 7.4 ± 5.9 years among diabetic husbands. the frequency of obesity among diabetic and non-diabetic women was 61.7% (n = 66) and 57.7% (n = 94), respectively. the frequency of dm among women with diabetic and non-diabetic husbands was 39.3% (n = 48) and 39.9% (n = 59), respectively (z = 0.1; p >0.050). spousal concordance of dm was found among 48 couples, resulting in a prevalence rate of 17.8%. a history of table 1: self-reported characteristics of women and their husbands according to married women attending primary health centres in ajman, united arab emirates (n = 270) characteristic n (%) women husbands age in years 30–39 77 (28.5) 45 (16.7) 40–49 87 (32.2) 59 (21.9) 50–59 71 (26.3) 75 (27.8) ≥60 35 (13.0) 91 (33.7) history of dm yes 107 (39.6) 122 (45.2) no 163 (60.4) 148 (54.8) treatment for dm diet and oral hypoglycaemic drugs 79 (73.8) 100 (82.0) oral hypoglycaemic drugs and insulin 22 (20.6) 21 (17.2) diet only 6 (5.6) 1 (0.8) history of htn yes 97 (35.9) 121 (44.8) no 173 (64.1) 149 (55.2) history of cad yes 13 (4.8) 35 (13.0) no 257 (95.2) 235 (87.0) history of dyslipidaemia yes 99 (36.7) 112 (41.5) no 171 (63.3) 158 (58.5) smoker status current smoker 5 (1.9) 71 (26.3) ex-smoker 0 (0.0) 23 (8.5) never smoker 265 (98.2) 176 (65.2) level of physical activity mild 148 (54.8) 134 (49.6) moderate/vigorous 23 (8.5) 47 (17.4) none 99 (36.7) 89 (33.0) dm = diabetes mellitus; htn = hypertension; cad = coronary artery disease. spousal concordance of diabetes mellitus among women in ajman, united arab emirates e200 | squ medical journal, may 2016, volume 16, issue 2 hypertension (46.3% versus 27.5%; z = 3.2; p = 0.001), cad (11.4% versus 3.8%; z = 2.0; p = 0.040) and dyslipidaemia (47.3% versus 29.1%; z = 3.1; p = 0.002) was significantly more frequent among women whose husbands also had these conditions in comparison to those whose husbands did not. women whose husbands currently smoked were more frequently current smokers themselves compared to those with non-smoker husbands (3.3% versus 1.1%; z = 1.3; p >0.050). a greater number of the women with diabetic husbands undertook no physical activity than those with non-diabetic husbands (53.3% versus 32.4%). furthermore, fewer women with diabetic husbands undertook mild (41.8% versus 56.1%) or moderate/vigorous (4.9% versus 11.5%) in comparison to those with non-diabetic husbands. there were no significant differences between mean fbg, hba1c, bmi and wc measurements among women with non-diabetic husbands compared to those with diabetic husbands (p <0.050 each). however, women with diabetic husbands had slightly higher mean fbg values (6.7 ± 6.3 mmol/l versus 6.0 ± 1.8 mmol/l) than those married to nondiabetics [table 2]. table 3 shows the glycaemic levels of the non-diabetic women. the total prevalence of abnormal glycaemia among non-diabetic women was 46.0% (n = 75). the rates of abnormal glycaemia among non-diabetic women with diabetic husbands was significantly more frequent than those with non-diabetic husbands (56.8% versus 37.1%; z = 3.2; p = 0.001). an unadjusted logistic regression analysis for independent predictors of abnormal glycaemia in non-diabetic women demonstrated a significant increase in the probability of abnormal glycaemia among those with diabetic husbands (p = 0.013) and those with general and abdominal obesity (p = 0.001 each). other factors, including age, duration of marriage and smoking status, were not significant [table 4]. however, the adjusted odds ratio (or) for abnormal glycaemia was only significant for women with a diabetic husband (or = 2.5, 95% confidence interval [ci]: 1.31–4.86; p = 0.006) and for those who were obese (or = 1.06, 95% ci: 1.01–1.12; p = 0.009). non-diabetic women with diabetic husbands were 2.5 times more likely to have abnormal glycaemic levels in comparison to those with non-diabetic husbands, although this was not significant (or: 2.5, 95% ci: 1.3–4.8; p <0.050). in addition, there was a 6% increase in the rate of abnormal glycaemic levels among obese women. table 3: proportion of non-diabetic married women attending primary health centres in ajman, united arab emirates, according to their glycaemic level and the diabetic status of their husbands (n = 163) glycaemic level non-diabetic women with diabetic husbands (n = 74) non-diabetic women with non-diabetic husbands (n = 89) total abnormal* 42 33 75 normal 32 56 88 *glycated haemoglobin levels of >5.7%.19 table 4: predictors of abnormal glycaemic levels* among non-diabetic married women attending primary health centres in ajman, united arab emirates (n = 163) predictor or (95% ci) p value age 1.01 (0.98–1.04) 0.362 duration of marriage 1.01 (0.98–1.04) 0.341 duration of stay in the uae 1.01 (0.98–1.02) 0.536 being a housewife 1.37 (0.71–2.66) 0.343 having a diabetic husband 2.22 (1.18–4.18) 0.013 obesity† 3.08 (1.60–5.94) 0.001 abdominal obesity‡ 2.99 (1.57–5.68) 0.001 history of gdm 0.94 (0.69–1.28) 0.685 family history of dm 0.83 (0.44–1.55) 0.570 smoking 1.18 (0.07–19.12) 0.900 or = odds ratio; ci = confidence interval; uae = united arab emirates; gdm = gestational diabetes mellitus; dm = diabetes mellitus. *glycated haemoglobin levels of >5.7%.19 †body mass index of ≥30 kg/m2. ‡waist circumference of ≥88 cm. table 2: clinical variables of married women attending primary health centres in ajman, united arab emirates, according to the diabetic status of their husbands (n = 270) variable mean ± sd women with diabetic husbands (n = 122) women with nondiabetic husbands (n = 148) fbg in mmol/l 6.7 ± 6.3 6.0 ± 1.8 hba1c % 6.2 ± 1.3 6.2 ± 1.2 bmi in kg/m2 31.7 ± 6.6 32.0 ± 6.4 wc in cm 90.5 ± 14.2 91.0 ± 12.3 sd = standard deviation; fbg = fasting blood glucose; hba1c = glycated haemoglobin; bmi = body mass index; wc = waist circumference. shatha s. al-sharbatti, yasmeen i. abed, lujain m. al-heety and shaikh a. basha clinical and basic research | e201 discussion type 2 dm results from defective insulin secretion and response (e.g. insulin resistance) as well as a range of environmental factors.21 evidence suggests that environmental factors could modulate the phenotypic expression of dm and disease progression in high-risk individuals with impaired glucose tolerance.22 spousal concordance may reflect environmental and lifestyle factors relating to dm diagnoses among genetically unrelated couples; the concept has been attributed to a shared environment, common behaviours and the tendency of individuals to choose a spouse with similar characteristics.23 the current study showed significant spousal concordance of abnormal glycaemic levels among non-diabetic women. this is in agreement with the findings of khan et al., who found a significantly increased risk of developing type 2 dm among the spouses of diabetic patients as compared to those with non-diabetic spouses.24 furthermore, the prevalence of dm concordance among the couples in khan et al.’s study was lower than that of the current study (7.8% versus 17.8%).24 in the present study, a history of hypertension, cad and dyslipidaemia was significantly more frequent among women whose husbands had the same conditions. this is consistent with findings from a systematic review which revealed significant spousal concordance for many cad risk factors, including hypertension, dm, obesity and smoking.23 stimpson et al. revealed significant spousal concordance of hypertension, dm, arthritis and cancer among older mexican-american couples, after adjusting for other factors such as age, bmi and smoking habits.25 suarez et al. suggested that age, duration of cohabitation and the extent of shared activities among married or cohabiting couples should be considered when interpreting familial aggregation of blood pressure.26 however, age and duration of marriage did not show a significant correlation with abnormal glycaemia in the current study. nevertheless, a high prevalence of abnormal glycaemia was noted among the nondiabetic women; this could be attributed to the similarly high prevalence of obesity among this group. evidence has linked obesity with multiple endocrine, inflammatory, neural and cell-intrinsic changes associated with insulin resistance; it is also a major risk factor for cardiovascular disease and type 2 dm.27 some researchers have advocated for regular hyperglycaemia screening among high-risk groups in developing countries.28 in the present study, having a diabetic husband and being obese were the only significant predictors of hyperglycaemia among nondiabetic women after controlling for confounding factors. this finding is important as it indicates that both the spouses of diabetic patients and obese individuals should be included in hyperglycaemia and dm screening programmes. clinical trial data recommends that obese patients undergo lifestyle modifications with regards to diet and exercise; this is known to help prevent and reduce rates of dm by attenuating insulin resistance and subsequent hyperinsulinaemia, reflecting the importance of promoting preventative strategies to tackle the growing dm epidemic.29 with regards to spousal concordance, lifestyle modification interventions should be targeted at both diabetic patients and their spouses in order to eliminate risk factors for both individuals. sexton et al. have indicated the effectiveness of this strategy for patients with cardiovascular diseases.30 in the uae, current management strategies directed at type 2 dm patients include pharmacological therapy for hyperglycaemia, medical nutrition therapy and psychosocial assessment and care.31 the researchers suggest including the spouses of diabetic patients in dm management strategies in order to reduce the risk of dm spousal concordance. the present study has a number of limitations. first, only female participants were included in the study due to logistical issues; however, the authors believe that spousal concordance can be observed in both genders. second, the findings of this study cannot be generalised to the wider population of the uae because of the nonprobability sampling method used to recruit the participants. third, with regards to the multicultural society of the uae, more evidence is needed to show the role of spousal concordance in lifestyle-related and chronic diseases, including dm. fourth, selection bias may have been possible due to the study design, although the authors tried to reduce this bias by employing a consecutive sampling technique. finally, the random effect of spousal concordance of abnormal glycaemia was not calculated, which could have had an effect on the results of the multi variable analysis. conclusion there was significant concordance of abnormal glycaemia among non-diabetic women with diabetic husbands in the current study. the spouses of diabetic patients may therefore be a target population for regular hyperglycaemia and dm screening. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. spousal concordance of diabetes mellitus among women in ajman, united arab emirates e202 | squ medical journal, may 2016, volume 16, issue 2 references 1. alavi nm, ghofranipour f, ahmadi f, emami a. developing a culturally valid and reliable quality of life questionnaire for diabetes mellitus. east mediterr health j 2007; 13:177–85. 2. waly mi, essa mm, ali a, al-shuaibi ym, al-farsi ym. the global burden of type 2 diabetes: a review. int j biol med res 2010; 1:326–29. 3. shanker j, kanjilal s, rao vs, perumal g, khadrinarasimhiah nb, mukherjee m, et al. adult nontwin sib concordance rates for type 2 diabetes, hypertension and metabolic syndrome among asian indians: the indian atherosclerosis research study. vasc health risk manag 2007; 3:1063–8. 4. lee ym, yon hj, lee y, lee bj, koh jh, chung ch. development of diabetes mellitus in married couples according to environmental factors. j korean diabetes assoc 2005; 29:133–9. 5. falba ta, sindelar jl. spousal concordance in health behavior change. health serv res 2008; 43:96–116. doi: 10.1111/j.14756773.2007.00754.x. 6. meyler d, stimpson jp, peek mk. health concordance within couples: a systematic review. soc sci med 2007; 64:2297–310. doi: 10.1016/j.socscimed.2007.02.007. 7. wilson se. the health capital of families: an investigation of the inter-spousal correlation in health status. soc sci med 2002; 55:1157–72. doi: 10.1016/s0277-9536(01)00253-2. 8. leong a, rahme e, dasgupta k. spousal diabetes as a diabetes risk factor: a systematic review and meta-analysis. bmc med 2014; 12:12. doi: 10.1186/1741-7015-12-12. 9. martire lm, schulz r, helgeson vs, small bj, saghafi em. review and meta-analysis of couple-oriented interventions for chronic illness. ann behav med 2010; 40:325–42. doi: 10.1007/ s12160-010-9216-2. 10. trivedi rb, piette j, fihn sd, edelman d. examining the interrelatedness of patient and spousal stress in heart failure: conceptual model and pilot data. j cardiovasc nurs 2012; 27:24–32. doi: 10.1097/jcn.0b013e3182129ce7. 11. tang ts, brown mb, funnell mm, anderson rm. social support, quality of life, and self-care behaviors among african americans with type 2 diabetes. diabetes educ 2008; 34:266–76. doi: 10.1177/0145721708315680. 12. world health organization. diabetes: fact sheet n°312. from: www.who.int/mediacentre/factsheets/fs312/en/ accessed: jan 2016. 13. macken lc, yates b, blancher s. concordance of risk factors in female spouses of male patients with coronary disease. j cardiopulm rehabil 2000; 20:361–8. doi: 10.1097/00008483200011000-00005. 14. al-maskari f, el-sadig m, norman jn. the prevalence of macrovascular complications among diabetic patients in the united arab emirates. cardiovasc diabetol 2007; 6:24. 15. international diabetes federation. idf diabetes atlas, 6th ed. brussels, belgium: international diabetes federation, 2013. 16. bennett s, woods t, liyanage wm, smith dl. a simplified general method for cluster-sample surveys of health in developing countries. world health stat q 1991; 44:98–106. 17. global tobacco surveillance system (gtss). global adult tobacco survey (gats) indicator guidelines: definition and syntax. from: www.who.int/tobacco/surveillance/en_tfi_gats_ indicator_guidelines.pdf accessed: jan 2016. 18. world health organization. global strategy on diet, physical activity and health: physical activity and adults. from: www. who.int/dietphysicalactivity/factsheet_adults/en/ accessed: jan 2016. 19. american diabetes association. standards of medical care in diabetes: 2012. diabetes care 2012; 35:s11–63. doi: 10.2337/ dc12-s011. 20. world health organization and international diabetes federation. definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. from: apps.who.int/iris/ bitstream/10665/43588/1/9241594934_eng.pdf accessed: jan 2016. 21. murea m, ma l, freedman bi. genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. rev diabet stud 2012; 9:6–22. doi: 10.1900/ rds.2012.9.6. 22. knowler wc, barrett-connor e, fowler se, hamman rf, lachin jm, walker ea, et al. reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. n engl j med 2002; 346:393–403. doi: 10.1056/nejmoa012512. 23. di castelnuovo a, quacquaruccio g, donati mb, de gaetano g, iacoviello l. spousal concordance for major coronary risk factors: a systematic review and meta-analysis. am j epidemiol 2009; 169:1–8. doi: 10.1093/aje/kwn234. 24. khan a, lasker ss, chowdhury ta. are spouses of patients with type 2 diabetes at increased risk of developing diabetes? diabetes care 2003; 26:710–12. doi: 10.2337/diacare.26.3.710. 25. stimpson jp, peek mk. concordance of chronic conditions in older mexican american couples. prev chronic dis 2005; 2:a07. 26. suarez l, criqui mh, barrett-connor e. spouse concordance for systolic and diastolic blood pressure. am j epidemiol 1983; 118:345–51. 27. qatanani m, lazar ma. mechanisms of obesity-associated insulin resistance: many choices on the menu. genes dev 2007; 21:1443–55. doi: 10.1101/gad.1550907. 28. echouffo-tcheugui jb, mayige m, ogbera ao, sobngwi e, kengne ap. screening for hyperglycemia in the developing world: rationale, challenges and opportunities. diabetes res clin pract 2012; 98:199–208. doi: 10.1016/j.diabres.2012.08.003. 29. kashyap sr, louis es, kirwan jp. weight loss as a cure for type 2 diabetes? fact or fantasy. expert rev endocrinol metab 2011; 6:557–61. doi: 10.1586/eem.11.42. 30. sexton m, bross d, hebel jr, schumann bc, gerace ta, lasser n, et al. risk-factor changes in wives with husbands at high risk of coronary heart disease (chd): the spin-off effect. j behav med 1987; 10:251–61. doi: 10.1007/bf00846539. 31. uae national diabetes committee. national diabetes guidelines united arab emirates: 2009. from: cms.wounds-uk.com/media/ nationaldiabetesguidelinesuae.pdf accessed: jan 2016. http://dx.doi.org/10.1111/j.1475-6773.2007.00754.x http://dx.doi.org/10.1111/j.1475-6773.2007.00754.x http://dx.doi.org/10.1016/j.socscimed.2007.02.007 http://dx.doi.org/10.1016/s0277-9536%2801%2900253-2 http://dx.doi.org/10.1186/1741-7015-12-12 http://dx.doi.org/10.1007/s12160-010-9216-2 http://dx.doi.org/10.1007/s12160-010-9216-2 http://dx.doi.org/10.1097/jcn.0b013e3182129ce7 http://dx.doi.org/10.1177/0145721708315680 http://dx.doi.org/10.1097/00008483-200011000-00005 http://dx.doi.org/10.1097/00008483-200011000-00005 http://dx.doi.org/10.2337/dc12-s011 http://dx.doi.org/10.2337/dc12-s011 http://dx.doi.org/10.1900/rds.2012.9.6 http://dx.doi.org/10.1900/rds.2012.9.6 http://dx.doi.org/10.1056/nejmoa012512 http://dx.doi.org/10.1093/aje/kwn234 http://dx.doi.org/10.2337/diacare.26.3.710 http://dx.doi.org/10.1101/gad.1550907 http://dx.doi.org/10.1016/j.diabres.2012.08.003 http://dx.doi.org/10.1586/eem.11.42 http://dx.doi.org/10.1007/bf00846539 to the editor, we comment on the recent reports on vitamin d deficiency in oman both in pregnant women1 and those of childbearing age.2 our objective is to share the utility of an enzyme-linked immunosorbent assay (elisa) for an in-house assay of vitamin d3 levels that will eliminate any outside evaluation.1 vitamin d3 deficiency is being evaluated at sant parmanand hospital, a 140-bed, tertiary care, multidisciplinary private hospital in delhi, india. with effect from april 2010, 25-hydroxy vitamin d [25(oh)d] levels are measured in the hospital laboratory using commercially available elisa kits. we use the 25(oh)d direct elisa kit (immundiagnostik ag, bensheim, germany), based on a competitive elisa technique with a selected monoclonal antibody that recognises 25(oh)d. the results are expressed, after point-to-point calculation, as nmol/l (with 1 nmol/l being equivalent to 2.5 ng/ml). values ≥80 nmol/l correspond to a sufficient level of vitamin d, while those of <50 nmol/l to a deficient, and 50–75 nmol/l to an insufficient level. among 20 pregnant women in delivery more than 75% were deficient in 25(oh)d. vitamin d3 levels exceeded 75 nmol/l in three, while in two the respective values were between 50–74 nmol/l, and 15 had levels below 25 nmol/l.3 future plans to address vitamin d deficiency in oman1,2 should, in our opinion, include both vitamin d3 supplementation and a watch on post-supplementation vitamin d3 levels. a daily supplementation of 1000 iu of vitamin d3 may fail to bring levels to a minimum of 75 nmol/l in 20–30% cases.4 in view of the global prevalence of vitamin d deficiency among women of childbearing age,1,2,3 it would be desirable to initiate simple and rapid point-of-care assays for quantification of vitamin d3 levels in the general population, both in rural and urban areas. *subhash c. arya and nirmala agarwal sant paramanand hospital delhi, india corresponding author email: subhashbhapaji@gmail.com references 1. al kalbani m, elshafie o, rawahi m, al-mamari a, al-zakwani a, woodhouse n. vitamin d status in pregnant omanis: a disturbingly high proportion of patients with low vitamin d stores. sultan qaboos univ med j 2011; 11:52–5. 2. al-kindi mk. vitamin d status in healthy omani women of childbearing age: study of female staff at the royal hospital, muscat, oman. sultan qaboos univ med j 2011; 11:56–61. 3. agarwal n, arya sc. vitamin d(3) levels in pregnant women and newborns at a private tertiary care hospital in delhi, india. int j gynaecol obstet 2011; 113:240-1. 4. schwalfenberg gk. a step in the right direction. cmaj 2010; 182:1763. doi:10.1503/cmaj.110-2118. squ med j, august 2011, vol. 11, iss. 3, pp. 418-419, epub. 15th aug 11 submitted 24th apr l^èfi^€�√÷]<^äfl÷]<çfl¬<dåe<∞⁄^jè <ìœfi<vó◊¬<åö  re: vitamin d deficiency in omani women letter to editor subhash c. arya and nirmala agarwal letter to editor | 419 author's response i read with interest the comments raised by dr subhash concerning my article.1 at the time of conducting my work in 2006, the 25-hydroxy vitamin d assay was neither available at the royal hospital laboratory, nor in many other hospitals in oman so samples were sent for testing to referral laboratories outside the country. however, during the last 3–4 years there has been an increasing awareness of and interest in the physiological, pathological and therapeutic aspects of vitamin d. this has led to a tremendous increase in vitamin d testing worldwide. at the royal hospital, the vitamin d testing workload has increased several-fold, and still continues to expand. hence, we have been performing the measurement in-house since mid-2009 using the elisa technique (ids uk healthcare marketing). in order to keep pace with the rising demand, we now hope to adopt an automated assay using a well validated method. finally, for the interpretation of vitamin d results, we are using the following cut-off points: <50 nmol/l = deficient, 50–75 nmol/l = insufficient and >75 nmol/l = sufficient. manal al-kindi department of chemical pathology directorate of medical laboratories royal hospital, oman email: manal.kalifa@moh.gov.oom reference 1. al-kindi mk. vitamin d status in healthy omani women of childbearing age: study of female staff at the royal hospital, muscat, oman. sultan qaboos univ med j 2011; 11:56–61. departments of 1child health and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mails: koul@squ.edu.om and roshankoul@hotmail.com ظهور عقيدات البطانة العصبية على شكل ’بذور مثرة البابايا‘ بتصوير الرنني املغناطيسي يف مرضى التصلب اجللدي رو�صان كول، اآمنة الفطي�صية، ديليب �صانخال، في�صل العزري ‘papaya seed’ appearance of subependymal nodules on magnetic resonance imaging in a patient with tuberous sclerosis *roshan koul,1 amna al-futaisi,1 dilip sankhla,2 faisal al-azri2 a 14-month-old male was referred tothe department of child health at the sultan qaboos university hospital (squh), muscat, oman, in 2014 with a two-week history of frequent abnormal movements of the body. a video, recorded by the patient’s father, revealed that the patient suffered from typical flexor body spasms and left side partial motor seizures. on physical examination, the patient had several cutaneous features of tuberous sclerosis, including depigmented skin lesions and shagreen patches. a neurological examination was unremarkable. sleep electroencephalography displayed interictal generalised and focal discharges from the left frontocentral region. there was no evidence of hypsarrhythmia. magnetic resonance imaging (mri) of the brain revealed multifocal cortical and subcortical tubers with subependymal nodules (sen) which had a ‘papaya seed’ appearance [figure 1a]. four to five rhabdomyomas in both ventricles were visible on echocardiography. ophthalmological examination revealed an astrocytoma along the inferior vascular arcade close to the optic nerve of the left eye. the figure 1a & b: t1-weighted axial magnetic resonance images showing subependymal nodules (arrows) with a ‘papaya seed’ appearance in two patients with tuberous sclerosis. interesting medical image sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e385–386, epub. 19 aug 16 submitted 4 nov 15 revision req. 26 jan 16; revision recd. 27 jan 16 accepted 25 feb 16 doi: 10.18295/squmj.2016.16.03.025 ‘papaya seed’ appearance of subependymal nodules on magnetic resonance imaging in a patient with tuberous sclerosis e386 | squ medical journal, august 2016, volume 16, issue 3 scans performed on children with tuberous sclerosis has shown that mri imaging of multiple sen attached to the ventricular wall closely resemble papaya seeds attached to the interior of the fruit [figure 1b]. observations of clinical features of tuberous sclerosis combined with the ‘papaya seed’ appearance of sen on an mri scan could obviate the need for additional ct imaging among patients with tuberous sclerosis. references 1. holmes gl, stafstrom ce; tuberous sclerosis study group. tuberous sclerosis complex and epilepsy: recent developments and future challenges. epilepsia 2007; 48:617–30. doi: 10.11 11/j.1528-1167.2007.01035.x. 2. jóźwiak s, kotulska k, domańska-pakieła d, lojszczyk b, syczewska m, chmielewski d, et al. antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. eur j paediatr neurol 2011; 15:424–31. doi: 10.1016/j. ejpn.2011.03.010. 3. northrup h, krueger da; international tuberous sclerosis complex consensus group. tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. pediatr neurol 2013; 49:243–54. doi: 10.1016/j. pediatrneurol.2013.08.001. 4. crino pb, mehta r, vinters hv. pathogenesis of tsc in the brain. in: kwiatkowsi dj, whittermore vh, thiele ea, eds. tuberous sclerosis complex: genes, clinical features and therapeutics. weinheim, germany: wiley-blackwell, 2010. pp. 161–86. 5. pinto gama hp, da rocha aj, braga ft, da silva cj, maia ac jr, de campos meirelles rg, et al. comparative analysis of mr sequences to detect structural brain lesions in tuberous sclerosis. pediatr radiol 2006; 36:119–25. doi: 10.1007/s00247005-0033-x. 6. avrahami e, cohn df, feibel m, tadmor r. mri demonstration and ct correlation of the brain in patients with idiopathic intracerebral calcifications. j neurol 1994; 241:381–4. doi: 10.1007/bf02033355. patient’s father had a possible skin lesion on his back, while the rest of the family had normal examinations. the child was diagnosed with tuberous sclerosis and epilepsy. he was initially prescribed the antiepileptic medication vigabatrin; due to a lack of response, this was changed to topiramate and levetiracetam after two weeks. comment tuberous sclerosis is a neurocutaneous disease characterised by skin lesions, often in association with epilepsy (80–90% of cases) and mental retardation (40–70% of cases).1,2 the disease may affect any organ of the body, but predominantly involves the brain. the diagnostic criteria of tuberous sclerosis have recently been revised with the new criteria emphasising clinical elements of the disease based on 11 major and nine minor features.3 for a diagnosis of definite tuberous sclerosis, evidence of two major features or one major feature with two or more minor features is essential. the presence of one major feature or two minor features is labelled as possible tuberous sclerosis.3 subependymal giant cell astrocytoma and sen are considered two major features; the latter are seen in 80% of patients with tuberous sclerosis and can be detected antenatally or at birth.4 these benign growths develop along the ependymal lining of the lateral and third ventricles. computed tomography (ct) of the brain allows easy visualisation of sen due to calcification.5 an mri scan alone can easily miss calcific lesions and hence a ct scan is also often performed to confirm the calcification.6 at squh, analysis of ct and mri http://dx.doi.org/10.1111/j.1528-1167.2007.01035.x http://dx.doi.org/10.1111/j.1528-1167.2007.01035.x http://dx.doi.org/10.1016/j.ejpn.2011.03.010 http://dx.doi.org/10.1016/j.ejpn.2011.03.010 http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.001 http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.001 http://dx.doi.org/10.1007/s00247-005-0033-x http://dx.doi.org/10.1007/s00247-005-0033-x http://dx.doi.org/10.1007/bf02033355 املؤمتر الدويل األول للتطورات يف ختصص النسائية والتوليد اجلزء الثاين ملصقات جامعة ال�صلطان قابو�س و 4-6 دي�صمرب 2013 1st international conference on advances in obstetrics & gynaecology part ii posters sultan qaboos university, 4–6 december 2013 abstracts subtotal abdominal hysterectomy versus laparoscopic assisted supra-cervical hysterectomy: will austerity promote a rethink? dr. t. thomas and m. oak. obstetrics & gynaecology, wishaw general hospital, lanarkshire, uk. e-mail: tonythom@gmail.com since its introduction in 1948, spending on the uk national health service (nhs), as a share of national income, has more than doubled, rising by an average of 4% a year in real terms. this period of rapid growth has now ended, but funding pressures on the nhs continue to rise igniting a debate on the most cost-effective way of offering treatment. in this context, we audited subtotal abdominal hysterectomy (stah) and laparoscopic-assisted supra-cervical hysterectomy (lash) for benign gynaecological indications in a large district general hospital. a retrospective audit was undertaken of records of patients who had stah or lash for benign conditions at wishaw general hospital between august and july 2012. twenty-five patients for each procedure were identified from the theatre information system. as three sets of notes could not be traced, there were 22 patients in the stah group and 25 in lash group. the mean operating time for stah was 61 min (34–85 min) and 145 min (75–237 min) for the lash group. there was one major complication in the stah group (1,000 ml blood loss) compared to five in the lash group (a pelvic infection, two wound infections and two patients with neuropathic pain at port sites). the mean hospital stay in the stah group was 2.5 nights (2–4 nights) and 2 nights for patients undergoing lash (1–4 nights). costs were £2,213.40 (= omr 1420) for stah and £2,613.80 (= omr 1677) for lash. in this study, complication rates and apparent costs seemed comparable. shorter hospital stays and possibly quicker recovery are areas where the laparoscopic approach scores over open surgery. in days of austerity for the nhs, surgery options need careful consideration. open surgery’s shorter operating times will help tackle long waiting lists but, if the impact on post-operative recovery and time off work are considered, the laparoscopic approach might be better. audit of clinical coding: a neglected aspect of practice with significant impact on clinical care! dr t. thomas and dr b. wilkes walsall health care nhs trust, uk. e-mail: tonythom@gmail.com clinical coding is the translation of medical terminology describing a patient's complaint, problem, diagnosis, treatment or reason for seeking medical attention, into a nationally and internationally recognised coded format. it is used to support many functions both clinical and statistical. this audit looked at the quality and depth of the coding by the clinical coder compared to what is documented by the clinical staff in the patient record. we also checked with clinical staff that the right information is being extracted for coding and is understood in the right context. three dimensions of coding accuracy were reviewed: (1) individual codes – that each statement of diagnosis and operative procedure had the correct code; (2) totality of codes – all codes gave an accurate clinical picture of the patient’s stay in hospital; (3) sequencing of codes – that codes were organised according to the rules and conventions. a retrospective review of case notes was undertaken by a consultant obstetrician/gynaecologist and a clinical coding auditor. all patients admitted under a randomly selected consultant in april 2013 were included. 42 case notes were reviewed; six amendments were made to the original coding giving a 14.28% amendment rate. however, the primary diagnosis was right in 100% of cases; amendments affected secondary diagnosis and procedure codes. this related to the coder difficulty in extracting information from the notes; particular problem areas were poor handwriting, information being in a random order, and occasionally conflicting information. an amendment rate of 14.28% to initial coding is high and can have significant implications with regards to clinical governance/evaluation of a patient’s clinical care and comparison of outcomes. it also adversely affects epidemiology data and can adversely impact hospital finances. moving to electronic case notes might be the way forward in effectively addressing this issue which has profound implications for patient care. guidelines in obstetrics & gynaecology: should we universalise them? maarof h. m. mahroof and mohaynisah n. madali consultant obstetrician and gynecologist, 20 ibn jarir al tabari street, al faisalia district jeddah 21433, saudi arabia. e-mail: hmmahroof@gmail.com guidelines are considered today as the backbone of best clinical practice. they are mainly built on evidence and clinical experience. a search on google gives 106 million hits for clinical guidelines and 3.79 million for guidelines in obstetrics and gynaecology. interestingly, the clinical practice guidelines of the society of obstetricians and gynaecologists (sogc) comes first in the search category and the e276 | squ medical journal, may 2014, volume 14, issue 2 1st international conference on advances in obstetrics & gynaecology part ii posters royal college of obstetricians & gynaecologists (rcog) takes the second place with the royal australian new zealand college guidelines coming fourth. despite the enthusiasm to produce guidelines for every clinical situation there is an overwhelming number of overlaps and differences, leading to confusion. in the uk, virtually every hospital has “customised” these guidelines, giving less flexibility for its use in practice. they are all developed based on the rcog and national institute for health and care excellence (nice) guidelines. recent trends are shown in the merging of nice and the rcog guidelines in certain conditions like obesity, diabetes and hypertension. we believe the huge evidence-based knowledge base should be cultivated to produce simple, clear, but comprehensive guidelines for management of various clinical conditions. the guidelines usually have an algorithmic design and flow. such algorithms help in making appropriate analysis and design based on clinical evidence and experience. an added advantage is that these analytic processes can be captured online especially using artificial intelligence programs like neural networks. thereafter they could be validated, following appropriate clinical audits, to provide best practice opportunities for all clinicians and support staff. more importantly, when we use a single or uniform guideline across the world utilising modern day e-documentation technology, we are able to develop a flexible management guideline for very important situations like postpartum haemorrhage. instead of having protocols from the world health organization, rcog, the federation of gynecology and obstetrics (figo), the american college of obstetricians and gynecologists (acog), nice and many more, we could have an international set of guidelines that could be effectively used in both de-veloped and developing countries. such a guideline would bring an effective electronic clinical management system to the world while still accommodating individual but safe variations. prevalence of multiple gestations and their maternal and perinatal outcomes in dubai hospital in 2012 dr heba i. adan dubai hospital, united arab emirates. e-mail: dr.heba.adan@gmail.com twins and higher order multiple pregnancies are becoming increasingly common. this is due to the increasing availability and affordability of assisted reproductive techniques in the united arab emirates. this study aimed to determine the prevalence of multiple pregnancies in dubai hospital in 2012 and to analyse the associated adverse maternal, perinatal and neonatal outcomes. this retrospective study involved all multiple pregnancies followed and delivered in dubai hospital between 1 january and 31 december 2012. there were a total of 106 multiple gestations in this period including 97 twins and 9 triplets. this gives a multiple gestation rate of 65.2 per 1000 live births which is much higher than other rates worldwide. the mean maternal age was 30.5 years. the commonest comorbidity was prematurity (72.6%) followed by diabetes (22.6%). in contrast, almost 60% had no associated comorbidities. growth discordance was seen in approximately 7.5% of patients; hypertensive disorders occurred in 6.6%; antepartum haemorrhage in 5.7% and postpartum haemorrhage in 3.8%. half of these multiple gestations were conceived spontaneously and around a third were conceived through in vitro fertilisation or intracytoplasmic sperm injection. the mean gestational age of delivery for twins in our study was 34.3 weeks ± 3.7 and for triplets it was 31 weeks ± 3.5. a total of 72.6% were delivered via caesarean section, the main indication (32.1%) being maternal request; 25.5% were delivered vaginally. regarding neonatal outcome, most were of low birth weight (58.4%). the vast majority (93.2%) had a 5 minute apgar score of ≥7 but the nicu admission rate was around 38%, and these were mainly in the triplet category (77% versus 33% in twins). this study suggests a multiple-gestation prevalence rate much higher than in other developed countries such as the usa. it was even higher than nigeria which previously had the highest multiple-gestation rate worldwide. both mothers and fetuses in these pregnancies are at increased risk and this warrants increased awareness of the associated complications. improving knowledge of urinary incontinence among community-dwelling women using a video-assisted teaching programme mrs. vidya seshan college of nursing, sultan qaboos university, muscat, oman. e-mail: vidya69@squ.edu.om urinary incontinence (ui) is a common health problem among women of all ages, cultures and races across the world with rates ranging from 4.8–58.4%. by the year 2018, it is projected that 423 million people worldwide will be affected by ui and the burden of this condition will be greatest in asia and other developing regions. due to lack of knowledge of available treatments and women’s tendency to consider ui as a normal part of ageing, affected women do not readily seek treatment. the aim of this study was to assess women’s knowledge and attitude about ui and the effectiveness of a video-assisted teaching programme for improving their knowledge. the study was conducted in coimbatore, tamil nadu, india. a cross-sectional design was used to collect data from 598 women aged 20 to 60 years. a preand post-test design was then used to assess the effectiveness of the video-assisted teaching. data were analysed using a paired sample t-test. ui was self-reported by 33.8% of women while 66% denied having ui. the majority of women with ui (90%) and without ui (90%) had inadequate knowledge levels. the attitudes of women with and without ui were mostly negative. more than 80% reported that they agreed with statements such as: accidental loss of urine is a common problem that every woman faces; women should not go for social events if they have ui; there is no treatment available for ui; ui cannot be prevented or cured. the differences in preand post-test knowledge level scores of both women with and without ui were statistically significant (p <0.001). many women suffer from ui; this warrants significant public health consideration especially health education given that the life expectancy of females is increasing. delay in seeking medical care to manage ui effectively can lead to a worsening of the condition and of overall life quality. effectiveness of antenatal exercises on fetal outcome mrs. emi prince clinical facilitator, university of queensland, brisbane, australia. e-mail: emijohnprince@gmail.com maternal and reproductive health is a global issue in today’s world. childbirth educators can significantly improve the safety of mothers and babies during labour and birth. childbirth preparation classes provide women with information on what care will be provided and what they need to know to complete their labour safely. this study aimed to determine the effectiveness of antenatal exercises on fetal outcome such as fetal distress, asphyxia neonatorum and birth trauma. a quasi-experimental study was conducted in a maternity hospital in karnataka, india with 600 primigravid women (300 + 300 controls). education on antenatal exercises was provided with the help of 3-d animation and the practice was monitored. the chi-squared test was applied for comparing the groups against fetal distress, birth trauma, and asphyxia neonatorum. the primigravid women performed exercises for between 15 and 34 days. the chi-squared value showed a statistically significant difference in fetal outcomes in both the groups. fetal distress was assessed by the colour of the abstracts | e277 sultan qaboos university, 4—6 december 2013 amniotic fluid; it was green for 4.3% in experimental group versus 12.3% in the control group. this was highly significant at p <0.001. asphyxia neonatorum was found in 96.7% of newborns in the experimental group, while 93.3% of the controls had mild asphyxia at 1 minute. moderate and severe asphyxia were present in 2% and 2% of newborns in experimental group and 4% and 2.7 % in the control group, respectively (p <0.005). birth trauma was absent for 97.3% and 8.33% of newborns in the experimental and control groups, respectively. caput succedaneum was found in 7% and 25 % of the experimental and control groups, respectively (p <0.005). there was no significant difference in cephalhaematoma between the two groups. healthcare providers should be aware of the benefits of a prenatal exercise programme and promote it as a routine, non-pharmacological measure to improve maternal and fetal wellbeing. ectopic pregnancy: experience in a tertiary care hospital in oman raniga hs, shanker up, date yr, sheika al-abri, department of obstetrics & gynecology, armed forces hospital, muscat, oman. e-mail: yogitadate@gmail.com ectopic pregnancy is a leading cause of maternal morbidity in first trimester, occurring in 1 in every 100 pregnancies from natural conception cycles. the rates of ectopic pregnancies have recently risen due to the increasing incidence of sexually-transmitted diseases and of in vitro fertilisation techniques. transvaginal ultrasonography along with beta-human chorionic monitoring are the standard methods for evaluating suspected ectopic pregnancies. the availability of these diagnostic modalities has led to early diagnosis and improved the management of this life-threatening condition. systemic methotrexate has emerged as an effective and low-cost treatment with minimal side-effects for unruptured ectopic pregnancy. this study aimed to find the incidence and prevalence of ectopic pregnancy and the effectiveness of its medical management at the armed forces hospital (afh), a tertiary care hospital in muscat, oman. a retrospective analysis was carried out of all cases of ectopic pregnancies diagnosed from july 2007 to june 2012. the demographics and management of each case was analysed and statistical tests applied. a total of 92 cases of ectopic pregnancies were diagnosed at the afh in this period. most of the cases were in the younger age group; 13 (14%) cases were primigravida and the rest multigravida, while 25 (27%) cases presented with a ruptured ectopic pregnancy. systemic methotrexate was offered according to protocol to 55 cases as the primary management. out of the 55 cases, 50 (91%) cases were treated successfully with medical management. there were two cases each of cervical and cornual pregnancy and one case of misdiagnosed interstitial pregnancy reaching 34 weeks. early referral and increased vigilance, in order to rule out ectopic pregnancy, can lead to successful outcomes with medical management. the diagnosis of rare types of ectopic pregnancies should be kept in mind when monitoring pregnancies of unknown location. medical management has a 80–90% success rate and should be offered whenever the criteria are met. third and fourth degree perineal tears: can they be predicted or prevented? nalini mohan and chitra jha department of obstetrics & gynecology, royal hospital, muscat, oman. e-mail: naliman@hotmail.co.uk third degree obstetric perineal tears are defined as a partial or complete disruption of anal sphincter muscles, involving either or both external and internal anal sphincter muscles. fourth degree perineal tears are a disruption of the anal sphincter muscles with a breach of the rectal mucosa. the overall risk of obstetric anal sphincter injury is 1% of all vaginal deliveries. this study aimed to analyse the risk factors for obstetric anal sphincter injury and determine whether these injuries can be predicted or prevented. an audit was conducted at the royal hosptial, oman, a tertiary care hospital, using the hospital database to review patient records. the initial audit was from 1 june to 31 december 2012, and the re-audit was undertaken from 1 march to 31 august 2013. the number of women who delivered vaginally in this period was noted and the number of cases with third/fourth degree perineal tears was determined as per the royal college of obstetricians & gynecologists greentop guideline no. 27, 2007. risk factors for anal sphincter injuries were listed and it was determined how each factor was incriminated in the study. the re-audit analysed how the recommendations of the audit had improved the incidence, management and follow-up of these patients. the incidence of anal sphincter injuries in the audit was 0.87% but in the re-audit only 0.36%. the incidence was higher in primigravidas in both groups (63%, 59%), with pregnancies being postdated in 35% and 20% cases, respectively. the incidence of fetal macrosomia was 21% and 8% in the two audits, respectively, with 12% cases of shoulder dystocia in the audit and none in the re-audit. the incidence of instrumental deliveries and episiotomies was identical in both audits. tears were repaired by senior doctors in 64% in first group, but in 100% in the re-audit group. the end-to-end method of repair was more often used. obstetric anal sphincter injuries cannot be predicted but can be prevented to some extent by an awareness of the risk factors. adequate perineal support and supervised delivery by a senior obstetrician, especially where fetal macrosomia is suspected, may help. senior doctors should repair the tears and carry out the postoperative review and follow-up. accuracy of optium xceed glucose meter for measuring blood glucose levels in pregnancy mariam mathew,1 seema zulfiker,1 noura al-amri,2 tamima al-duguhaishi1 departments of 1obstetrics & gynaecology, 2biochemistry, sultan qaboos university hospital, muscat, oman. e-mail: mariamm1762@gmail.com the glucose meter is used as a point-of-care testing device to follow up patients for diabetes control. there is a difference in the glucose values obtained by the glucose meter compared to the central laboratory measurements. this study aimed to evaluate the accuracy of the optium xceed glucose meter with optium h strips for measuring glucose levels in capillary and venous whole blood, in comparison with the plasma glucose measurement by the roche cobas integra 800 analyzer in pregnant women. a total of 74 pregnant women were included in this study, with a total of 120 samples collected for fasting/post-prandial glucose measurments; 43 patients (58%) were gestational diabetic; 14 (19%) type 2 diabetic; 1 (1%) type 1 diabetic and 16 (22%) were normal. glucose measurements for all samples were done using both types of analyser. capillary and venous whole blood samples in the fasting and post-prandial state were used for glucose meter measurement using optium h strips. venous samples were sent to the laboratory for plasma glucose measurement, using glucose hk liquid reagent by the enzymatic reference method with hexokinase. statistical evaluation of the data was performed using the statistical package for the social sciences software and the stata programme. analysis of variation, correlation and the paired t-test were used to ascertain the relationship between continuous variables. a very high correlation between capillary and venous glucometer measurements and laboratory measurements were observed in both fasting and postprandial states. the difference between the capillary whole blood glucose and plasma glucose results from the laboratory were 12% and 13% respectively and within the acceptable range. this study demonstrates that the optium xceed glucose meter gives accurate results for glucose levels in capillary and venous samples in a few seconds. home blood glucose monitoring can therefore replace laboratory testing thus saving resources. e278 | squ medical journal, may 2014, volume 14, issue 2 1st international conference on advances in obstetrics & gynaecology part ii posters an audit of caesarean sections by peer review silja a. pillai,1 mariam shukri,1 mariam mathew,1 tamima al-dughaishi,1 saniya eltayeb,1 shahila sheik,1 durdana khan,1 vaidyanathan gowri2 department of 1obstetrics and gynaecology, sultan qaboos university hospital; 2department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman. the rising caesarean section (cs) rate worldwide is a subject of concern. cs leads to an increase in maternal mortality and morbidity as well as having considerable financial implications. the changing trends in the rates of cs section may be partly explained by the change in the expectations of the obstetric population coupled with improved anaesthetic and neonatal techniques. fear of litigation is another major factor affecting cs rates. this study aimed to audit 50 consecutive emergency cs done for singleton pregnancies and assess the degree of agreement among peers for the decision to perform each cs. a retrospective audit with peer review of emergency singleton cs was done from november 2012 to march 2013 in sultan qaboos university hospital. fifty consecutive women undergoing emergency cs were included. the peer review was undertaken by four consultants and two senior registrars. the cs were stratified according to the indication and the auditors were asked to answer the question: do you agree with the decision for performing the cs? out of the 50 emergency cs, 20 (40%) cases were done due to a non-reassuring fetal trace while labour dystocia accounted for 16 cases (32%). the mean decision to delivery interval was 40.7 mins in patients who had a cs for a non-reassuring trace in contrast to a mean of 47.4 in patients with labour dystocia. in 31 cases (62%), there was complete agreement among all auditors. there were only 3 cases where all three auditors disagreed. at least one auditor disagreed in 9 cases (18%) and two in 7 (14%) cases. overall there was 94% agreement in two-thirds of the cases. the range of disagreement between auditors varied from 4–20%. the agreement among the auditors were comparable to international standards though there is scarcity of data in this area. letrozole versus tamoxifen in clomiphene citrate-resistant women with polycystic ovarian syndrome m. n. el-gharib, a. e. mahfouz, m. a. farahat department of obstetrics & gynecology, faculty of medicine, tanta university,tanta, egypt. e-mail: mohgharib@hotmail.com this study aimed to compare the effects of letrozole versus tamoxifen (tmx) in ovulation induction in clomiphene citrate (cc)-resistant women with polycystic ovarian syndrome (pcos). this prospective randomised study was carried out at the department of obstetrics & gynecology of tanta university hospital, egypt. the study included a total of 60 infertile women (175 cycles) with cc-resistant pcos. the patients were randomised to treatment with 2.5 mg of letrozole daily (30 patients, 86 cycles) or 20 mg of tamoxifen daily (30 patients, 89 cycles) for 5 days from day 5 of menses and 10,000 iu human chorionic gonadotropin (hcg) when mature follicles become ≥18 mm. the total number of follicles was ≥ 18 mm more in the letrozole group. the endometrial thickness at the time of hcg administration was significantly greater in the letrozole than in the tmx group (10.2 ± 0.7 versus 9.1 ± 0.2 mm). ovulation occurred in 23.33% in the letrozole group versus 8.89%) in the tmx group, whereas pregnancy occurred in 5.56% in the letrozole group versus 2.22% in the tmx group. both letrozole and tmx should be considered as optional therapies for cc-resistant women. salivary versus serum approaches in the assessment of biochemical hyperandrogenaemia in women with polycystic ovarian syndrome m. n. el-gharib and s. m. e. hazaa department of obstetrics & gynecology, faculty of medicine, tanta university,tanta, egypt. e-mail: mohgharib@hotmail.com the aim of this prospective randomised observational cohort study was to study the likelihood of using saliva rather than serum in diagnosing biochemical hyperandrogenemia in women with polycystic ovarian syndrome (pcos). the study was conducted on 75 women with pcos who were patients of the department of obstetrics & gynecology, tanta university hospital, egypt, in the period november 2011 to april 2012 and a control group of 20 normal fertile women. venous blood and salivary samples were taken on the third day of their cycle to measure luteinising hormone (lh), free testosterone (ft) and dehydroepiandrosterone sulfate (dhea-s) levels. the study found that biochemical hyperandrogenemia prevailed in 40% of cases with pcos. salivary levels of lh, ft and dheas correlated with their corresponding serum values with the salivary approach having a higher sensitivity than the serum approach. therefore, this study shows that saliva provides a sensitive, simple, reliable, non-invasive and uncomplicated diagnostic approach for biochemical hyperandrogenemia. fetal distress in labour and cesarean section rate: how reliable is the ctg? veena paliwal and tsabiyah ali department of obstetrics & gynecology, sultan qaboos hospital, salalah, oman. e-mail: paliwal@omantel.net.om cardiotocography (ctg) is a screening tool used to detect fetal hypoxia during labour. variable interpretations of the tracing by clinician may affect patient management. diagnosis of fetal jeopardy based on ctg alone has led to an increase in the caesarean section (cs) rate over the last 40 years; however, there has been virtually no change in cerebral palsy rates and high cs section rates have contributed to maternal morbidity and mortality, including a rising incidence of morbidly adherent placenta. this study aimed to estimate the relationship between fetal distress in labour and the rate of cs and to test ctg as a non-invasive method for diagnosising and managing fetal distress in labour. this prospective observational study included patients who underwent emergency cs for suspected fetal distress following changes in the ctg pattern in the obstetrics & gynecology department of sultan qaboos hospital, salalah, oman, from january–june 2013. the following were recorded: maternal age; parity; any associated risk factors; specific types of abnormal fetal heart rate tracing; adverse immediate neonatal outcomes in terms of apgar score <7 at 5 minutes; umbilical cord ph <7.0; neonates requiring immediate ventilation and neonatal intensive care unit (nicu) admissions. the correlation between non-reassuring fetal heart and neonatal outcome were analysed. out of 2,909 patients delivered during the study period, 586 (20.1%) patients underwent a cs; 396 (67.5%) of these had an emergency cs, while 109 (27.5 %) patients underwent a cs during labour primarily for suspected fetal distress. the most common fetal heart abnormality was non-reassuring traces in 63 (57.8%) cases followed by variable deceleration in 14 (12.8%) cases and unclassified decelerations in 10 (9.2%) cases, suspicious traces in 7 (6.4%) cases, reduced variability in 7(6.4%) cases, and pathological traces in 2 (1.8%) cases. in 4 (3.6%) babies the 5 min apgar score was <7; 21 (19.3%) babies required admission to the nicu for observation. out of these, 3 (14.2%) babies required intubation and 2 (9.5%) babies had cord blood ph <7.0. the rest of the neonates (88, 80.7%) were born healthy. in this study, the non-reassuring fetal heart rate detected by ctg did not correlate well with abstracts | e279 sultan qaboos university, 4—6 december 2013 adverse neonatal outcome. understanding the types of hypoxia, fetal reserves and other intrapartum risk factors as well as the human factors affecting ctg interpretation may help improve perinatal outcomes and reduce unnecessary interventions, even in centres where additional tests of fetal wellbeing are not available. evaluation of diagnostic ability of novel techniques in endometrial biopsy maha al-khaduri,1 yayha al farsi,2 a. al-alawi2 departments of 1obstetrics & gynaecology, 2family medicine and public health,sultan qaboos university hospital, muscat, oman. e-mail: m.khaduri@gmail.com in endometrial sampling a tissue sample is taken from the lining of the uterus and examined under the microscope to look for abnormal cells and identify the cause of abnormal bleeding, pelvic pain, thickened uterine lining seen on ultrasound and infertility. this study aimed to investigate women who underwent endometrial sampling by pipelle and sonobiopsy catheters at sultan qaboos university hospital (squh), oman, as well as the adequacy of sonobiopsy and pipelle specimens in detecting endometrial pathology. this retrospective cohort study included all women who underwent endometrial biopsy at squh by the above methods between january 2010 and december 2011. the data was collected from squh electronic records system. a total of 61 cases were selected among 108 women who underwent endometrial biopsy by sonobiopsy and pipelle catheters at the obstetrics & gynaecology outpatient department. participants’ ages ranged from 27–66 years. the majority of cases were from the muscat region, married (52) and omani (55), with c. 48% of women having menorrhagia as the main compliant. a total of 50.8% of samples were obtained by sonobiopsy catheter of which 87.1% were adequate, while 49.2% were obtained by pipelle catheter of which 73.3% were adequate. fibroids were common in younger patients (26.3% of those less than 39 years old), while endometrial polyp was common in older women (31.3% of those over 47 years old). this study showed that sonobiopsy and pipelle catheters produced similar results for detecting endometrial pathology. women who underwent endometrial biopsy for menorrhagia were more likely to have fibroids if under 39 years old and polyps if over 47 years old. the study highlights the need for future research using prospective trials to compare the adequacy of sonobiopsy and pipelle catheters. clinical profile of women diagnosed with polycystic ovarian syndrome in a tertiary hospital in oman: a case-control study fatema y. sabt,1 iman j. al-afifi,1 maryam i. al-kiyumi,1 yahya al-farsi,2 maha al-khaduri3 1college of medicine & health sciences and 2department of family medicine & public health, college of medicine & health sciences, sultan qaboos university; 3department of obstetrics gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: m.khaduri@gmail.com data about polycystic ovary syndrome (pcos) in arab countries is scarce despite increasing rates of obesity, diabetes, and infertility among the female population. this study aimed to assess the risk factors and clinical profiles of pcos in oman, a developing arab country. a retrospective hospital-based case control study was undertaken from july 2006 to june 2012 among omani women aged 16–45 years old. it included 85 women diagnosed with pcos (rotterdam 2003 criteria) and 85 randomly-selected controls without pcos and matched for age, ethnicity, and quality of healthcare received. socio-demographic data, anthropometric measurements, hormonal assays, lipid and glucose profiles, hyperandrogenism, a detailed fertility history and ultrasound findings of polycystic ovaries were collected for both study groups at baseline and over the follow-up period at the antenatal care clinic. compared to the controls, the pcos group had higher risk of obesity (or 3.1; 95% ci 2.8–4.3), diabetes (or 2.6; 95% ci 1.9–4.7), hypertension (or 1.8; 95% ci 1.02–4.8) and hyperandrogenism (or 3.6; 95% ci 2.1–5.2). moreover, a positive family history of pcos, diabetes, and hypertension were also positively associated with pcos. further prospective studies are required to confirm these results; however, the risk factors and clinical profiles identified lay the groundwork for developing a screening and early detection programme for pcos in oman. assessment of awareness about polycystic ovary syndrome among female university students maha al-khaduri,1 yayha al-farsi,2 h. al-hajri1 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: m.khaduri@gmail.com this study aimed to assess the level of awareness about polycystic ovary syndrome (pcos) among female university students. a prospective cross-sectional study was conducted from october to december 2010 at sultan qaboos university, oman. a total of 500 female university students were contacted of which 468 (93.6%) completed a questionnaire which had been previously tested in a pilot study. of the 468 respondents, 44.4% had never heard the term pcos, while 55.6% had heard about it. the latter group was classified into: minimally aware (63%), moderately aware (16.5%) and highly aware (3.6%). the most common reported source of information was friends (57.7%) followed by the media (10.8%), school (10%), doctors (4.6%) and family (1.6%). those aware of pcos reported the following signs and symptoms: difficulty in conceiving (58.1%), unpredictable menstrual periods (17.1%), obesity (6.1%), hirsutism (4.7%) and acne (3.6%). these findings imply that in oman most young women have a low level of awareness about pcos. female students who were aware of it reported that the first source of knowledge was a friend. medical treatment of etcopic pregnancy with systemic methotrexate: a review of 17 cases at buraimi hopsital, oman kaukab naheed department of obstetrics & gynecology, buraimi hospital, oman. e-mail: naheedkaukab@yahoo.com historically, the treatment of ectopic pregnancy was limited to surgery. methotrexate has revolutionised the treatment of selected cases of ectopic pregnancy. methotrexate is an antimetabolite that interferes with dna synthesis and disrupts cell proliferation. medical therapy is preferable to surgery for various reasons including eliminating morbidity from surgery and general anaesthesia, potentially less tubal damage and lower cost. successful medical treatment with methotrexate has been associated with good subsequent pregnancy outcomes.this study aimed to assess the effectiveness of systemic methotrexate for the treatment of selected cases of ectopic pregnancy through a retrospective review of 17 cases of ectopic pregnancy at buraimi hospital, oman, from january 2010 to september 2013. the cases selected were haemodynamically stable patients without any contraindication to the use of methotrexate (such as deranged liver or renal function tests or known sensitivity to the drug) and who had serum beta human chorionic gonadotrophin (hcg) levels e280 | squ medical journal, may 2014, volume 14, issue 2 1st international conference on advances in obstetrics & gynaecology part ii posters <5000iu/l and an adnexal mass of <4 cm with <300 ml of free fluid in the pod. patients were hospitalised, informed consent taken and they were counselled about the side-effects of the drug, the incidence of treatment failure and the need for further injection or surgery. the methotrexate dose was calculated by 50 mg/m2 body surface area and injected intramuscularly. the patients were observed for abdominal pain and signs of tubal rupture. transvaginal ultrasonography and serum beta hcg levels were done on 4th and 7th days after the injection. if serum beta hcg levels fell by >15% between 4th and 7th day, patients were followed with weekly beta hcg tests until the levels became non-pregnant. if the beta hcg level increased or fell less than 15% a second dose of methotrexate was given. treatment was described as successful if no surgical intervention was needed. surgical intervention was undertaken in cases of tubal rupture or persistently higher levels of beta hcg in the absence of intrauterine gestation. a total 13 out of 17 (71.5%) cases were successfully treated with methotrexate of which 4 (23.5%) required an additional dose of methotrexate, while 4 (23.5%) cases required surgery for rupture of the ectopic pregnancy. pretreatment beta hcg levels were <3,000 iu/l (mean value 910 iu/l and range 100–2020) in 15 cases and >3,000 iu/l in 2 cases. average hcg resolution time was 16 days (range 8–37 days). with early diagnosis and the adoption of proper selection criteria, the medical treatment of an ectopic pregnancy with systemic methotrexate is an effective and safe alternative to surgical intervention. medical induction in first trimester miscarriages: the experience at the royal hospital, oman qamariya ambusaidi department of obstetrics & gynecology, royal hospital, muscat. e-mail: nooralqabas@hotmail.com medical methods for the induction of miscarriages have emerged over the last two decades as safe, effective and feasible alternatives to surgical evacuation. misoprostol is one of the drugs used to induce miscarriage. this study aimed to evaluate the effectiveness of misoprostol as an agent for medical termination in first trimester miscarriages, in particular the complete miscarriage rate—defined as successful cases that did not required surgical evacuation after receiving misoprostol. this prospective study included all patients who were admitted in the gynecology ward of the royal hospital (rh), oman, from 1 october 2009 to 30 september 2010 for termination of first trimester miscarriages. misoprostol was administered according to the rh protocol. data were analysed using the statistical package for the social sciences. medical management with misoprostol was successful in 61.21% of patients while 38.79 % required surgical evacuation. failed medical termination was the indication for surgical evacuation in 59% of patients. most of the patients tolerated the misoprostol well and the pain was controlled by simple analgaesia in 70.1%. misoprostol is well-tolerated drug which reduced the rate of surgical evacuation by > 60%. misoprostol can be used safely for management of incomplete miscarriages, while more studies for its effect on missed miscarriages are needed. misoprostol had a patient acceptance and satisfaction rate of 95%. maternal and perinatal morbidity and mortality in twin pregnancies alya y. a. al-madhani oman medical specialty board and department of obstetrics & gynecology, khoula hospital, oman. e-mail: alyaa81@hotmail.com the diagnosis of multiple gestations is frequently met with joy and excitement by families; however, the happiness is tempered when it is realised that this places the mother and the fetuses at significantly increased risk for morbidity and mortality. the incidence of multiple gestations varies in different parts of the world. in developed countries, it has increased during the past 20 years mainly due to the widespread availability of ovulation-inducing agents, assisted reproduction techniques and delayed childbearing. multiple gestations warrant special attention as they have been associated with an increased incidence of adverse outcomes, including premature delivery, pre-eclampsia, respiratory distress syndrome and malpresentations. preterm delivery increases the risk for the baby. this study was conducted to evaluate the risks of pregnancy complications and adverse perinatal outcome in women with twin pregnancies. a 5-year retrospective study was undertaken at the department of obstetrics & gynecology, khoula hospital, muscat, oman, between january 2008 and august 2012. all women admitted to the antenatal and labour ward with multiple pregnancies after 24 weeks gestation were included in the study. the main outcomes measures were maternal complications (anaemia, gestational diabetes mellitus, preeclampsia, preterm labour, preterm prelabour rupture of membranes and postpartum haemorrhage), perinatal morbidity and mortality. all data were analysed using the statistical package for the social sciences, version 16. a total of 85 (52%) women presented with preterm labour, 79 (48%) were delivered at ≥ 37 weeks of gestation. anaemia was found in 17 cases (10%) and pre-eclampsia in 39 (24%) cases; 101 (62%) cases ended in caesarean sections. prematurity was the major problem in 52%, and about half of twins were admitted to the neonatal intensive care unit. a total of 21 (12.5%) babies had congenital anomalies. multiple pregnancies are associated with increasing risk for the mother and fetus. preterm delivery increases the risk for the neonates. recurrent miscarriage and consanguinity among omani women: a case control study fatma al hoqani,¹ safaa ambusaidi,¹ wadha al-ghafri,² yahya al-farsi,3 vaidyanathan gowri,4 saniya el tayeb² 1college of medicine & health sciences and departments of 3family medicine & public health, and 4obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: wghafri@hotmail.com the aim of this case-controlled study was to determine the prevalence of unexplained recurrent miscarriages (rm) at sultan qaboos university hospital, oman and to find out if there was a significant relationship between recurrent miscarriages and consanguinity. the case group included all women with unexplained rm attending the outpatient clinic at sultan qaboos university hospital between july 2006 and april 2012. the control group included women with no history of rm after matching them with the cases for age and parity (case to control ratio was 1:2). during study period a total of 290 women with rm were seen of which 150 (51.7%) had unexplained rm. the consanguinity rate among cases of rm (60.7%) was higher than for the controls (53.7%). consanguineous couples were 1.39 times more likely to have rm compared to non-consanguineous couples. however, this observed increase in the risk of rm was not statistically significant (95% confidence interval [ci] 0.93–2.07; p = 0.11). this study found that more than half of the rm cases were unexplained and there was no significant association between rm and consanguinity. abstracts | e281 sultan qaboos university, 4—6 december 2013 aetiology of recurrent miscarriage among omani women presenting to sultan qaboos university hospital, oman safaa ambusaidi,¹ fatma al hoqani,¹ saniya el tayeb,² yahya al-farsi,3 vaidyanathan gowri,4 wadha al-ghafri ² 1college of medicine & health sciences and departments of 3family medicine & public health, and 4obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: saniya.eltayeb@gmail.com recurrent pregnancy loss (rpl) is defined as the occurrence of three or more consecutive losses of clinically recognised pregnancies prior to the 20th week of gestation. the well-known aetiologies of rpl include: chromosomal abnormalities (like parental translocations, inversions, sex chromosome mosaicism or ring chromosome); thrombotic tendency (as a result of thrombophilia or immunologic problems); anatomical problems (e.g. congenital uterine malformation, uterine synechiae and fibroids), endocrine factors (e.g. thyroid disease, uncontrolled diabetes mellitus, elevated luteinising hormones or luteal phase insufficiency); infectious causes, and environmental factors (e.g. smoking, alcohol consumption, exposure to chemicals and radiation). several studies indicate that in more than 50% of cases of rpl the cause of miscarriage is unknown. this retrospective study aimed to investigate the different aetiological causes of recurrent miscarriage among omani women presenting to the recurrent abortion clinic, obstetrics & gynaecology outpatient department, sultan qaboos university hospital (squh), a tertiary care hospital in oman between june 2006 and march 2012. women were included if they had a history of two or more consecutive miscarriages in the first or second trimester. the data were collected from the hospital information system (his) in squh. the sample size gathered during the study period was 290 women. a total of 140 (48%) of patients had an identifiable cause for their rpl while in 150 (52%) of the patients, no cause was identified. the most common cause of rpl was immunological aetiologies found in 35.4% of patients and the least common cause was environmental factors (1.7%). the other aetiological factors implicated were: chromosomal abnormalities (8.3%), anatomical factors (9.4%), endocrine disorders (29.8%), infectious causes (3%) and thrombotic causes (12.71%). this study found that 48% of women had an identifiable cause of rpl, while in 52% of them no causes was identified. 2-hour postload serum glucose levels and maternal blood pressure as independent predictors of birth weight in appropriate for gestational age neonates in healthy nondiabetic pregnancies lovina machado,1 jumana saleh,2 zahra razvi3 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2department of biochemistry department, college of medicine & health sciences; 3college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: lovina1857@gmail.com increased neonatal birth weight (nbw), often associated with diabetic pregnancies, is a recognised indicator of childhood obesity and future metabolic risk. predictors of nbw in healthy non-diabetic pregnancies are not yet established. in this study, the association was investigated between the maternal parameters of healthy non-diabetic non-hypertensive omani women at late gestation and the delivery of appropriate-for-gestational age babies with increased nbw. this cross-sectional prospective study involved 36 healthy mother/infant pairs. parameters examined included nbw, maternal age, first and last trimester body mass index, weight gain, fasting serum lipids and glucose, 2-hour postload glucose levels and blood pressure. analysis of variance (anova) and regression analysis methods were used to correlate and predict the effects of the studied variables. maternal postload-glucose levels were significantly higher in mothers of heavier neonates. anova results indicated that a 15% increase in postload-glucose levels corresponded to a more than 0.5 kg increase in nbw in the third tertile. nbw correlated positively with postload glucose levels and negatively with systolic blood pressure. regression analysis showed that the main predictors of nbw were postload glucose levels (b = 0.455, p = 0.003), followed by systolic blood pressure (b = -0.447, p = 0.004), together predicting 31.7% nbw variation. insulin resistance that normally develops at late gestation directs maternal glucose towards the fetal circulation increasing fetal insulin production; this accelerates fetal growth. this study highlights the fact that increased maternal postload glucose levels and blood pressure, within the normal range, highly predicts the nbw of their babies. these findings may provide the focus for early dietary intervention measures to avoid future risks to the mother and baby. this study was published as: saleh j, machado l, razvi z. 2-hour postload serum glucose levels and maternal blood pressure as independent predictors of birth weight in "appropriate for gestational age" neonates in healthy nondiabetic pregnancies.biomed res int 2013; 2013:757459. doi: 10.1155/2013/757459. epub sep 18 2013. giant borderline mucinous cystadenoma presenting as an acute abdomen in early buerperium lovina s.m. machado,1 diya omer,1 aneeta bai,1 ibrahim al-haddabi2 departments of 1obstetrics & gynaecology and 2pathology, sultan qaboos university hospital, muscat, oman. e-mail: lovina1857@gmail.com the incidence of adnexal masses in pregnancy is 0.5‒2 per 1,000 pregnancies. more than 90% of these are benign. about 28% of adnexal masses diagnosed during pregnancy are serous or mucinous cystadenomas and torsion is the commonest complication followed by rupture of the cyst. mucinous cystadenomas may attain a large size during pregnancy and may also tend to be hormonally responsive. we present a rare case of a giant mucinous cystadenoma presenting as acute abdomen on the 7th postpartum day following a normal vaginal delivery. a 26-year-old, para 3 woman presented to the emergency room seven days after a spontaneous normal vaginal delivery with acute generalised abdominal pain. examination revealed a huge soft mass with a smooth surface arising from the pelvis and extending to the xiphisternum. the uterus was not separately palpable. ultrasound and computed tomography scans of the abdomen revealed a very large multiseptate cystic lesion, 40 x 38 cm, occupying the whole abdomen with extensive internal septae. both ovaries and the appendix were not visualised and the uterus was bulky. at laparotomy, a massive left-sided ovarian tumour c. 38 x 30 cm in diameter was found weighing 4,000 gm; it was mostly cystic with some areas haemorrhagic while the capsule was intact. peritoneal cytology, left salpingoovariotomy, and right ovarian, peritoneal and omental biopsies were taken and an appendectomy performed. the frozen section showed a left ovarian benign mucinous cystadenoma. however, the histopathology report revealed a left ovarian borderline mucinous cystadenoma with no evidence of microinvasion. the patient is on regular close follow-up in the outpatient clinic. on six month follow-up, the ovarian cancer test ca-125 and the scans were normal. most adnexal masses are discovered incidentally during pregnancy on routine scans. giant cysts are found in less than 1% of all ovarian cysts complicating pregnancy. though there are case reports of mucinous cystadenomas complicating pregnancy, which have been surgically removed during pregnancy or during e282 | squ medical journal, may 2014, volume 14, issue 2 1st international conference on advances in obstetrics & gynaecology part ii posters caesarean sections, to our knowledge, this is the first report of a giant borderline mucinous cystadenoma not interfering with normal delivery and presenting for the first time with acute abdominal pain on the 7th postpartum day. ovarian cysts in pregnancy must be diagnosed early and treated in time to optimise maternal and fetal outcomes. evidence for assessing effectiveness of calcium supplementation in reducing risk of hypertensive disorders during pregnancy iman al-hashmi, et al. college of nursing, sultan qaboos university, muscat, oman, e-mail: eiman@squ.edu.om high blood pressure, either with or without proteinuria, is one of the most commonly seen medical problems during pregnancy and complicates c. 5–10% of all pregnancies. it is associated with substantial maternal and neonatal mortality worldwide accounting for up to 40,000 maternal deaths annually. for this reason, interventions to reduce the risk of hypertensive disorders of pregnancy have received significant attention. a relationship between high calcium intake and low incidence of preeclampsia has been noted in ethiopian women and mayan indians women of guatemala. this hypothesis was tested in several studies which suggested a promising beneficial effect for calcium supplementation—although the impact varies according to the baseline calcium intake of the population and preexisting risk factors. it is possible that calcium supplementation reduces parathyroid release and intracellular calcium and thus reduces vasoconstriction. this review examined the effectiveness of calcium supplementation on reducing high blood pressure risk during pregnancy and so promoting maternal and infant health. searches were made in the cochrane data base of systematic reviews, pubmed and cinahl and meta-analyses, systematic reviews, randomised controlled trials in english since 2005 were reviewed. six studies were appraised; two of them were meta-analysis studies with level i evidence, two were systematic review studies with level i evidence and two were randomised control trials (rcts) with level ii evidence. five out of the six studies attested that calcium supplementation is significantly effective in reducing risk of gestational hypertension as well as risk of pre-eclampsia in pregnant women. the effectiveness of calcium supplementation was greater in high-risk pregnant women and in women with a low baseline calcium intake. these findings are significant enough to guide clinical practice. this author therefore recommends 1–2 mg of calcium tablets daily for high-risk pregnant women and for women with a calcium intake of less than 1,000 mg/day. patient should be advised to take it 3 hours after taking iron tablets and to avoid taking calcium tablets with food rich in iron or caffeine. diet – a new approach to treating endometriosis: what is the evidence? deepa thomas, et al. college of nursing, sultan qaboos university, muscat, oman, e-mail: deepash@squ.edu.om endometriosis affects over 70 million women worldwide and is more common than breast cancer and diabetes. endometriosis is a gynecological disorder characterised by the presence and growth of endometrial tissue outside the uterine cavity. considering the high prevalence of the disease and its difficult diagnosis and therapeutic management as a result of its complex pathogenesis, which is yet to be fully clarified, a question has been raised as to whether women affected by endometriosis have certain nutritional peculiarities. the purpose of this review was to assess a possible association between dietary components and endometriosis from the existing literature. a search for relevant studies was conducted in cinahl, medline plus, science direct, scopus and pubmed for the period 2003–2013 using the following search terms: endometriosis and related factors like diet, fat, dairy products, fish, coffee and antioxidants. twelve articles were included for the review. the findings revealed that there is an association between endometriosis and dietary fat intake, calcium fibre, antioxidants and caffeine. based on these results, we can suggest that health education should be improved in regard to dietary management in endometriosis in order to improve the quality of life of women with this condition. nurses and other health professionals in primary care play an essential role in health promotion through disease management and infertility prevention by providing support and much needed information to the patient with endometriosis. there is an urgent need to improve the understanding of the impact of dietary components on the risk of endometriosis in order to modify and/or prevent this prevalent gynaecological disease. mature cystic teratoma: a rare histopathologic presentation of mucinous cystadenoma in an appendix in the ovarian teratoma wadha al-ghafri,1 maryam al-shukri,1 marwa al-riyami,1 khalfan al-amrani2 departments of 1obstetrics & gynaecology and 2emergency, sultan qaboos university hospital, muscat, oman. e-mail: wghafri@hotmail.com mature cystic teratomas, conventionally known as dermoid cysts, are common benign ovarian tumours occurring most commonly in women of reproductive age. the majority are composed of disorganised, neoplastic, mature tissues of one or more of the embryonic germ layers: ectoderm, mesoderm, and endoderm. these tumours are the third most common benign tumors next to serous and mucinous cystadenomas and the commonest germ cell tumor. they range in size but the majority is 5–10 cm in diameter and they are filled with thick sebaceous material and hair. in 30–50% of the cases formed teeth are present. the other cellular elements present are skin with its appendages, gastrointestinal epithelium, salivary gland, thyroid tissue, cartilage, bone, muscle, nervous tissue, choroid plexus, etc. we report a 35-year-old woman, para 11 abortion 1, living 10, who underwent a laparoscopic bilateral ovarian cystectomy for bilateral dermoid cysts. operative findings were a normal-looking uterus and tubes, normal-looking bowel liver and hemidiaphragm. the left ovary was enlarged with a dermoid cyst c. 8 x 7 cm and the right ovary enlarged with a dermoid cyst c. 3 x 4 cm. the postoperative course was uneventful and she was discharged home the next day. the histopathologic examination of the right ovarian cyst showed it was largely lined by keratinising squamous epithelium with skin adnexa in its wall. in one area, prostatic tissue including acinar glands and fibromuscular stroma were noted. mature glial tissue and ganglion cells are also present. a smaller locule was lined by urothelium with squamous metaplasia. there was a cystic area filled with mucoid material proven histologically to be like an appendix with an epithelial lining of a benign mucinous cystadenoma. the wall of this appendicular structure had an inner and outer muscle coat with intervening nerve bundles and ganglion cells identical to the architecture of a gastro-intestinal appendix. no dysplasia or malignancy was found. the other ovarian cyst was typical of a mature cystic teratoma. to the best of our knowledge, there have been no previously reported cases of finding tissue resembling the appendix in mucinous cystadenoma tumours. in addition, we have reported a rare ovarian neoplasm composed of an admixture of mature teratoma and a benign mucinous cystadenoma in an appendix to the teratoma. abstracts | e283 sultan qaboos university, 4—6 december 2013 silent spontaneous uterine rupture in early third trimester of pregnancy following myomectomy sharifa al-farsi1 and thuria al-rawahi2 1oman medical specialty board and department of obstetrics & gynecology, royal hospital; 2department of obstetrics & gynecology, royal hospital, muscat, oman. e-mail: dralfarsi@ hotmail.com uterine rupture is a life threatening condition which can affect both the mother and the fetus. spontaneous uterine rupture during pregnancy following myomectomy is a rare complication but can occur—especially if the uterine cavity was opened during either laparoscopic or abdominal surgery. we report a case of a silent spontaneous uterine rupture in a woman 29 weeks pregnant with a previous myomectomy. it demonstrates the difficulties in diagnosing uterine rupture in a patient with a previous myomectomy presenting with abdominal pain. a primigravida at 29 weeks gestation presented with sudden-onset, continuous right-sided abdominal pain with no vaginal bleeding. one year previously, she has undergone a laparoscopic converted to an open myomectomy where she was diagnosed to have severe endometriosis. she had in vitro fertilisation and was on metformin for gestational diabetes. on presentation, she looked sick and in pain with stable vital signs. an abdominal examination showed tenderness on superficial palpation mainly in the right lumbar region, with positive rebound tenderness. the uterine size was appropriate for gestational age and the uterus was relaxed. cardiotocography was reactive. the scan showed an active viable fetus with no evidence of placental separation. the vaginal examination showed she was not in labour. she received corticosteroids. investigations showed normal blood counts, amylase, and renal and liver function. the urine dipstick was negative. an ultrasound scan could not visualise the appendix but revealed minimal fluid collected was collected in the pelvis. the patient underwent an emergency diagnostic laparoscopy which revealed that the peritoneal cavity was full of blood clots of about 2,300 ml at both the paracolic gutters covering the omentum and below the diaphragm. there was a linear 6 cm uterine rupture at the fundus toward the left side where the placenta implanted with 5 x 5 cm placental tissue protruding through it which was actively bleeding. the surgery was converted to a midline laparotomy and the fetus was delivered by lower segment caesarean section. repair of the uterine rupture site was performed in two layers and homeostasis was secured. the postoperative period was uneventful. uterine rupture can complicate pregnancies following myomectomy. it should always been suspected if they present with abdominal pain as it can occur without symptoms or signs of maternal or fetal compromise. any pregnancy after myomectomy should be closely monitored with respect to uterine rupture. cesarean scar pregnancy with intrauterine death at 23 weeks: case presentation and review of the literature b. k. wittmann1 and a. kaznacheyeva2 1starcare hospital, muscat, oman; 2saad specialist hospital, khobar, saudi arabia. e-mail: bkwittmann@gmail.com caesarean scar pregnancy (csp) is a type of ectopic pregnancy which is usually managed in the first trimester, and rarely goes beyond it. we present a case of csp with delayed diagnosis and intrauterine death at 23 weeks. a gravida 3 women with two previous cesarean sections (cs) conceived 7 weeks after the last cs. the first ultrasound examination (us) showed a 6-week gestation sac implanted at the cs scar site. a follow-up us confirmed a low implantation only. the us at 17 weeks was normal; however, at 23 weeks intrauterine death was diagnosed. termination attempts with vaginal, oral, intravenous prostaglandins, oxytocin and transcervical catheter failed, and on reevaluation, the earlier concerns about csp were noted. at laparotomy, a 20-week-sized mass, covered by large blood vessels and containing the fetus, replaced the lower segment. attached to the mass above was the uterus, which connected posteriorly to the cervix. the abnormally implanted placenta was removed with difficulty, and bleeding from multiple vessels controlled. the paper-thin lower segment was resected and the uterus closed. the postoperative course was unremarkable. patients with previous cs should have a first trimester us, with special attention paid to the scar area. if csp is confirmed, then medical treatment at this time provides the best results, and avoids the serious complications that can be seen later. maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman maryam al-shukri,1 durdana khan,1 atka al-hadrami,2 nihal al-riyami,1 vaidyanathan gowri,3 rahma al-hadabi,1 mohammed abdellatif,4 tamima al-dughaishi1 departments of 1obstetrics & gynaecology and 4child health, sultan qaboos university hospital; 2oman medical specialty board; 3department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university; muscat, oman. e-mail: gowri@squ.edu.om the aim of this study was to describe the fetal and maternal outcomes of triplet gestation and to report on the maternal characteristics of those pregnancies in a tertiary care centre in oman. a retrospective study of all triplet pregnancies delivered at sultan qaboos university hospital, muscat, oman, between january 2009 and december 2011 was undertaken. over the three-year study period, there were 9,140 deliveries. of these, there were 18 triplet pregnancies, giving a frequency of 0.2%.the mean gestational age at delivery was 31.0 ± 3.0 weeks, and the mean birth weight was 1,594 ± 460 g. the most common maternal complications were preterm labour in 13 pregnancies (72.2%), gestational diabetes in 7 (39%) and gestational hypertension in 5 (28%). of the total deliveries, there were 54 neonates. neonatal complications among these included hyaline membrane disease in 25 neonates (46%), hyperbilirubinaemia in 24 (43%), sepsis in 18 (33%) and anaemia in 8 (15%). the perinatal mortality rate was 55 per 1,000 births. the maternal and neonatal outcomes of triplet pregnancies were similar to those reported in other studies. this study was published as: maryam al-shukri, durdana khan, atka al-hadrami, nihal al-riyami, vaidyanathan gowri, rahma haddabi, mohammed abdellatif, tamima al-dughaishi. maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman. sultan qaboos university med j 2014; 14:190–6. audit of vaginal birth after caesarean section nihal abdu department of obstetrics & gynecoloy, sultan qaboos hospital, salalah, oman. e-mail: nihalsalah@hotmail.com the royal college of obstetricians & gynaecologists recommends that women with a prior history of one uncomplicated lowersegment transverse caesarean section (cs), in an otherwise uncomplicated pregnancy at term, with no contraindication to vaginal birth, should be able to discuss the option of planned vaginal birth after cs (vbac) and the alternative of a repeat caesarean section (ercs). this prospective re-audit, done between january and june 2013, aimed to compare the practice in south tyneside foundation e284 | squ medical journal, may 2014, volume 14, issue 2 1st international conference on advances in obstetrics & gynaecology part ii posters trust, uk, against the local guideline of january 2013 (which originated from the rcog guideline no.45, feb 2007). the number of patients was 49. a proforma was originated from the guideline. for a standard to be met, we expected 100% adherence to all the criteria. guidelines: women with history of cs will be referred to a consultant. the vbac proforma should document the discussion of the risks and benefits of vbac versus ercs and regarding the place of birth, the management plan of labour—including, if a preterm labour, an appointment with a consultant at 41 weeks. an ultrasound scan (uss) for estimated fetal weight (efw) should be offered between 36–38 weeks. a cervical sweep should be offered at 40 weeks with the community midwife. the woman should be seen by the consultant on call at 41 weeks gestation for cervical assessment, sweep and discussion and to decide on the feasibility of induction of labour (iol) accord¬ing to the bishop score. in the case of spontaneous labour, an artificial rupture of membranes should be performed 2 hours after starting the partogram, and the subsequent vaginal examinations should be at least 4 hours apart. during labour, continuous fetal monitoring should be done by intravenous access, blood group information should also be obtained. if augmentation is needed, the consultant should be involved. the audit showed excellent adherence to most of the criteria, including consultant booking, performing uss for efw between 36–38 weeks gestation, and reviewing the woman at 41 weeks in the antenatal clinic if not delivered and offering iol or ercs on a case basis. good adherence was also noted in management of labour. the audit highlighted some areas that needed improvement, mainly in regard to documentation. we recommend that staff should be aware that the proforma should be completed at booking and at 38 weeks.we also suggest to alter the guideline so at the 41-week appointment a consultant or an experienced representative is present to a assess the cervix. recurrent aggressive angiomyxoma of vulvula manjunath a. p.,1 girija s.,1 pratap kumar2 1department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman, 2department of obstetrics & gynaecology, kasturba medical college manipal, india. e-mail: manjunathattibele@gmail.com aggressive angiomyxoma is an extremely uncommon mesenchymal tumor of the female pelvis and perineum. the lesion has a tendency for slow growth and local recurrence. the term aggressive emphasises the potential of this tumor to recur locally. primary clinical diagnosis is rarely made. hence it is important to understand its clinical presentation and the available modalities of treatment. a 38-year-old, para 3 woman presented with a vulval mass, which had gradually progressed in size over 6 months. two years previously, she had had a similar mass arising from the vulva for which she underwent excision. on examination a 16 x 10 x 10 cm, soft, non-tender, pedunculated mass was visible arising from right labia majora. the lesion had extended up to the fourchette and right lateral vagina. wide surgical excision was performed under general anaesthesia. the upper end of the tumour pedicle extended paravaginally up to the right uterine cornu in the pelvis. primary reconstruction of the wide vulval defect was performed. the histopathology examination revealed recurrent aggressive angiomyxoma. immunohistochemistry showed high oestrogen and progesterone receptor positivity. postoperatively, there was wound disruption which healed by secondary intension. aggressive angiomyxoma is a rare neoplasm of the perineum and lower pelvic soft tissues. it is a slow growing neoplasm occurring almost exclusively in women of reproductive age. misdiagnosis is common, as the clinical presentation may resemble other benign conditions. the tumour is locally aggressive with a tendency to recurrence although it rarely metastasises. surgery in the form of wide local excision is the treatment of choice. the definitive diagnosis is made by histopathology and immunohistochemistry analysis. whenever soft tissue masses in the pelvic and perineal region are encountered in a reproductive-age woman, one should suspect a possible clinical diagnosis of recurrent aggressive angiomyxoma. live fallopian tube twin gestation diagnosed preoperatively and managed surgically maysea tageldin,1 aneeta b. jayakumari,1 vaidyanathan gowri,2 kuntal rao1 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: maysaco21@gmail.com a twin pregnancy in the fallopian tube is rare and even rarer is the live gestation of twins in the fallopian tube. we present a case of live twin gestation diagnosed by ultrasound and managed surgically. 36-year-old, gravida 3, para 0, woman with a history of miscarriage and right-sided ectopic pregnancy managed by right salpingectomy, presented to the emergency department with severe lower abdominal pain and 9 weeks amenorrhoea. she was vitally stable and there was mild tenderness in the lower abdomen. on bimanual examination there was cervical excitation and the uterus was normal size. serum beta human chorionic gonadotropin (beta-hcg) was 61,798 iu. endovaginal ultrasound showed an empty uterus, live twin gestation in the left adnexa and some free fluid in the pelvis. laparotomy was performed and it confirmed two live embryos in the left ampullary part of the fallopian tube. the mass measured about 5 cm and there were adhesions in the pelvis. left salpingectomy was performed and she recovered well and was advised to have in vitro fertilisation. live twin ectopic gestation is rare and can be picked up on endovaginal ultrasound with good technology if the physician is experienced. early diagnosis will help in proper management. management of amniotic fluid embolism: case presentation vandana pandit and arif jahan new sohar hospital, ministry of health, oman. e-mail: vandsu@hotmail.com an amniotic fluid embolism is a rare obstetric emergency (1/8,000 to 1/80,000 cases) associated with life-threatening complications. it is also known as an anaphylactoid reaction in pregnancy and needs early diagnosis and treatment with early management by a skilled obstetrician. a 41-year-old female, gravida 13, para10, aborted 4, at 39 weeks gestation presented with epigastric pain, blurring of vision, and headache for the previous 2 days. on presentation, the vital signs were normal: blood pressure 135/90, pulse 90/min with no oedema. laboratory results were within normal limits. on physical examination, the uterus was relaxed, 38 weeks and the fetal heart sounds were 140/min. the vaginal examination revealed the cervix was 2 cm dilated, 1.5 cm long, station at -1. in view of the history and above findings, the patient was admitted for interruption of labour. an artificial rupture of membranes (arm) was performed. a few minutes after the arm, the patient collapsed, was non-responsive to verbal and painful stimuli, and no vitals could be recorded. the patient was suspected to have an amniotic fluid embolism, (laboratory investigations later confirmed disseminated intravascular coagulation with haemoglo-bin 5.4 gm %, coagulation profile deranged prothrombin time >130, activated partial thromboplastin time aptt >180, international normalized ratio 10). while undergoing resuscitation, an urgent perimortem lower segment caesarean section with hysterectomy was performed. the patient required massive transfusions and survived through five cardiac arrests and underwent five laparotomies with multiorgan failure. the patient had serial monitoring of investigations for multiorgan failure. in spite abstracts | e285 sultan qaboos university, 4—6 december 2013 of these insults, the outcome was successful and the mother and child survived. both were discharged home after 35 days of hospital stay without any residual damage and with follow-up advice. this rare case of amniotic fluid embolism emphasises the need for the effective management and treatment of patients with suspected amniotic fluid embolism. urgent decisions and prompt action after consultation with senior doctors are essential. it is important to conduct drills for the management of sudden maternal collapse and be trained in basic life-support skills. a multidisciplinary team approach and aggressive management can potentially improve outcomes in such cases. effect of childbirth education on maternal satisfaction among primigravid women girija madhavanprabhakaran,1 k. a. kumar,2 k. r. sivadasan2 1department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman; 2victoria hospital kollam, kerala, india. e-mail: km_girija@squ.edu.om the objective of the study was to assess the effect of childbirth education on intranatal self-care practices and maternal satisfaction among primigravid women. a quasi-experimental approach with a pretest post-test control group design was used. the study was carried out in the labour room and antenatal ward of victoria hospital, kollam, kerala, india. a total of 100 primigravid women were recruited by convenience sampling (50 in the control and 50 in the experimental group). each woman was interviewed using a questionnaire to collect their sociodemographic data and their knowledge on childbirth. the experimental group received two to three sessions of childbirth education which include the process of labour, nutrition during labour, non-pharmacological pain relieving measures (especially breathing and relaxation techniques), common medical procedures and care during labour, bearing down efforts and the initiation of breast feeding. their childbirth knowledge was reassessed a week before childbirth. on day one after 6 hours of labour, women were asked to self-rate their satisfaction over their childbirth experience using the maternal satisfaction scale. the study revealed that childbirth education has improved the knowledge of primigravid women (t = 155, p < 0.001). the experimental group had significantly greater maternal satisfaction (t = 84.20, p < 0.001) compared with the control group. the pearson correlation coefficient test indicated a positive correlation between knowledge of childbirth and maternal satisfaction (r = 0.78, p < 0.001). the childbirth education programme appears to be a very promising intervention for promoting maternal satisfaction in primigravid women. implementing childbirth education as routine during antenatal check-ups will improve women’s knowledge and attitudes towards childbirth and subsequent childrearing. molar pregnancies in a tertiary care hospital bindu sethumadhavan, thuraiya r. s. al-rawahi. department of obstetrics & gynaecology, royal hospital, muscat,oman. e-mail: bindurajeev1996@yahoo.co.in a retrospective descriptive analysis was undertaken of cases at the royal hospital (rh), oman with a diagnosis of gestational trophoblastic disease (gtd) during the period 1st january 2006 to 30th september 2013. all cases registered in the rh as outpatient or inpatient in obstetrics and gynaecology and medical oncology were included and studied retrospectively. data was collected from electronic hospital records. the total number of deliveries in 7 years was 53,504 and the total number of molar pregnancies was 112 giving an incidence of 2 per 1,000 deliveries. of the 112 cases, 49 were complete moles, 63 partial moles and 3 had invasive moles. all patients were managed and followed-up according to the hospital protocol. a total of 38.7 % of patients with complete and 6.3 % of patients with partial moles required chemotherapy, while 56% of patients who developed gtd were over 35 years old. the incidence of gtd and partial mole requiring chemotherapy was higher than described in literature. all patients with partial mole should be followed-up more vigilantly. age more than 35 years was a significant risk factor for developing persistent gtd. pregnancy with anemia and severe thrombocytopenia: a rare presentation youssef a. elwan and waleed husain hera general hospital, makkah, saudi arabia. e-mail: aboelwan@yahoo.com a 24-year-old saudi patient, gravida 3, para 2 and 35 weeks pregnant, was admitted as an emergency case complaining of dizziness and fatigability. she had suffered nausea throughout her pregnancy. she had history of delivery of anencephaly and was a known case of hypothyroidism. upon admission, she was pale but not jaundiced. her hb was 4.9 gm/dl, mean corpuscular volume 82.30 fl (80–101), mean corpuscular hemoglobin 28.80 pg (27–33), retics % 0.18 (0.2–2), her platelet count dropped from 40,000 to 27,000/ mm3 3 days after admission. the lactate dehydrogenase was 5175 and blood pressure 120/80 with no proteinurea; the aspartate aminotransferase and alanine aminotransferase were within normal limits. she received three units of packed red blood cells on admission. based on the thrombocytopenia, high esr and splenomegaly, the diagnosis was connective tissue disease and the patient received pulse methylprednisolone for three days, but with no response. later, the repeated blood film and serum b12 level showed hypersegmented neutrophil and serum b12 (31.9 pmol/l; n = 148–616). the cause of severe thrombocytopenia was vitamin b12 deficiency. so cyanocobalamine injections were started which led, after less than 10 days from starting the vitamin b12 injections, to marked improvement in the platelet count up to 260.000/ mm3, hb 11.7 g/dl, retics % 10.9. the patient continued her pregnancy and delivered spontaneously a 2,270 gm baby with a good apgar score. it is concluded that vitamin b12 deficiency should be considered as a possible though rare cause of severe thrombocytopenia. conservative management of twisted ischaemic adnexa in early pregnancy somaiah a. mubarak,1 sunita k jesrani,2 mariam mathew2 1oman medical specialty board and department of obstetrics & gynaecology, sultan qaboos university hospital; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: sumeya_84@hotmail.com adnexal torsion is the fifth most common gynaecological emergency. diagnosing torsion can be difficult especially in cases of intermittent torsion. delay in diagnosis can lead to necrosis and loss of the affected ovary compromising the reproductive capacity. the ovarian function can be safely preserved by untwisting and conserving the affected adnexa regardless of the necrotic appearance. a 22-year-old primigravida at 10 weeks of gestation presented with severe left iliac fossa pain associated with nausea of one day’s duration. on examination, she was afebrile and tachycardic with marked tenderness in the left iliac fossa. an ultrasound examination showed a live fetus of 10 week’s size, an enlarged and oedematous left ovary with a clear cyst of 76 x 63 mm, with flow to the ovary. the right ovary appeared normal. with a provisional diagnosis of left adnexal torsion she was taken for emergency surgery. the left adnexa was found twisted twice with dark purplish discoloration. torsion was successfully managed by detorsion and cystectomy conserving the tube and e286 | squ medical journal, may 2014, volume 14, issue 2 1st international conference on advances in obstetrics & gynaecology part ii posters the ovary. serial scans showed normal sized ovaries with good flow and an appropriately growing fetus. ovarian torsion usually presents with acute onset pelvic pain, nausea, vomiting, tachycardia and low grade fever. the diagnosis of torsion can be difficult due to the atypical presentation in many cases leading to misdiagnosis or delay resulting in the loss of ovarian function. the ultrasound appearance of torsion can be highly variable. though abnormal doppler signals are common, a complete absence of perfusion may be a late sign and the presence of flow within the ovary does not exclude ovarian torsion. diagnosis of ovarian torsion requires a meticulous approach: a thorough history taking, examination and investigation with a high index of suspicion. delay in diagnosis can lead to necrosis and loss of the affected ovary thus compromising the reproductive capacity. the clinical appearance of a torted adnexa does not correlate well with the residual function. the affected ovary can be preserved by untwisting, even if ovary appears dark purple or blackish in colour. ruptured rudimentary horn pregnancy diagnosed by preoperative magnetic resonance imaging resulting in fetal salvage silja a. pillai,1 mariam mathew,1 noreen ishrat,1 anupam kakaria,2 asim qureshi,3 vaidyanathan gowri4 departments of 1obstetrics & gynaecology, 2radiology, 3pathology, sultan qaboos university hospital; 4department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: siljarenjit@gmail.com pregnancy in a rudimentary horn is extremely rare with a reported incidence of 1 in 76,000–150,000. rudimentary horn pregnancies result in rupture of the horn in 80–90% of cases in the second trimester and only 10% reach term and fetal salvage is very rare. a 31-year-old, gravida 5 para 2 woman at 32weeks of gestation presented with generalised abdominal pain of one week’s duration. she was haemodynamically stable with diffuse abdominal tenderness. the uterine contour appeared globular and the height of uterus corresponded to the gestation. a cardiotocogram revealed a reactive fetal heart with no uterine contractions. vaginal examination showed a long closed cervix. an abdominal ultrasound revealed an appropriately grown fetus, the presence of free fluid and a possible cervical fibroid. an urgent magnetic resonance imaging (mri) scan suggested pregnancy in a rudimentary horn/abdominal pregnancy. her hb dropped from 9 gm/dl to 7.8 gm/dl and an emergency laparotomy was performed. there was haemoperitoneum of 800 ml with clots. the rudimentary left horn harboured the pregnancy with active bleeding from a 1 cm rent in the posterior surface. the unicornuate uterus with the right tube and ovary was normal and connected to the left horn through a fibrous band. a baby girl weighing 1,510 gm with good apgar score was delivered by incising the horn. the rudimentary horn with the placenta was excised along with left salpingoophorectomy. the patient received 4 units of packed red blood cells, 4 units fresh frozen plasma and 4 units of cryoprecipitate. the postoperative period was uneventful. the histopathology report of the placenta was consistent with placenta increta. rupture of a rudimentary horn pregnancy is an obstetric emergency which can be life threatening for the mother and the fetus. preoperative diagnosis of such pregnancies can be quite challenging and they are usually diagnosed intraoperatively. mri is a very useful diagnostic tool especially in patients presenting in advanced pregnancy. the advent of mri has resulted in preoperative diagnosis of conditions which were usually diagnosed during laparotomy. a definite preoperative diagnosis helps in counselling the couple and preparing them for appropriate surgical intervention. distress during the menopausal transition: a review of literature jansi r. natarajan, college of nursing, sultan qaboos university, muscat, oman. e-mail: jrj.jrn@gmail.com the menopause is a time in a woman’s life when biological and social changes can adversely influence their quality of life. while most women traverse the menopausal transition with little difficulty, others may undergo significant stress. it is a challenge to the healthcare professionals to appreciate and manage the symptoms experienced by women during the menopause. even in developed countries, there is limited focus on menopausal related research and hence it is challenging to meet the demands of menopausal women. the purpose of this review was to assess the literature concerning the menopausal symptoms experienced by women in various countries worldwide. a database search was conducted in cinahl, pubmed, google scholar, and medline for the period 2007–2013 using the specific terms “menopause”, “perimenopause”, “menopause symptoms”, “midlife and quality of life”. a total of 15 studies were identified which met the inclusion criteria. the results revealed that the burden of menopausal symptoms experienced by women worldwide, which were vasomotor, somatic and urogenital, were found to be affecting their quality of life. there is a great diversity across cultures both in symptom frequencies and ways of coping with them. there is a need to explore the current perceptions of menopause among women, the prevalence of menopausal symptoms and the coping strategies adopted by them. based on these findings, healthcare professionals can use various culturally-relevant approaches to educate and treat women with menopausal symptoms and concerns. successful strategies for coping with the menopause across cultures are self-care practices, education, having an accepting and positive attitude toward life transitions, and medication including herbs. with appropriate counselling, health information and an understanding of the menopause and its dimensions, menopause can become a time of beginning, rather than an end. a rare case of twin pregnancy with a live fetus and co-existing hydatidiform mole shahila sheik,1 mathew n. r.,2 rashid al-sukaiti,3 nihal al-riyami,1 vaidyanathan gowri,4 mariam mathew1 departments of 1obstetrics & gynaecology, 3radiology, sultan qaboos university hospital; 2medical student elective, kasturba medical college, manipal, india; 4department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: drshahila@yahoo.co.in a hydatidiform mole co-existing with a normal live fetus in a twin pregnancy presents a significant management dilemma for the physicians in charge of the patient. this is an extremely rare phenomenon with the incidence ranging from 1 in 22,000–100,000 pregnancies. a gravida 3, para 2, woman at 13 weeks gestation was diagnosed with a twin pregnancy on ultrasound scan. one fetus was normal with its placenta covering the os, and the other one was a molar pregnancy. both ovaries were enlarged with large theca lutein cysts. the serum beta human chorionic gonadotropin (hcg) level was 1386570.0 iu/l. after detailed counselling, the couple opted to continue the pregnancy with close follow-up. the patient presented at 17 weeks of gestation with vaginal bleeding, tachycardia and a significant drop in haemoglobin levels. after placing uterine artery balloon catheters, a hysterotomy was performed. molar tissue weighing 1,040 gm was evacuated with a fetus weighing 105 gm and a normal placenta of 65 gm. the histopathology report confirmed a complete hydatidiform mole with a co-existing normal fetus. her serum beta hcg level returned to normal three months after the surgery and, one year later, there was no evidence of any persistent trophoblastic disease. in dizygotic twins with one hydatidiform mole, the live fetuses are chromosomally normal and potentially viable. traditionally, termination of pregnancy was indicated due to abstracts | e287 sultan qaboos university, 4—6 december 2013 the very high risk of complications such as haemorrhage, early onset pre-eclampsia, thyrotoxicosis and an increased risk of persistent trophoblastic disease. in the past decade, however, some authors have supported the option of conservation under strict hospital-based observation and follow-up which has resulted in a few live births. clinicians should rely on thorough counselling and close follow-up of the patients, being ready to deal with any emergency situation as and when it arises while managing this rare clinical entity. as seen with our case, conservative management with close surveillance in a tertiary care centre can be offered to patients with this rare presentation, although the chances of delivering a live fetus after the period of viability is low. idiopathic intracranial hypertension: an unusual cause of postpartum headache ayesha salaluddin,1 namitha r. mathew,2 raman nandagopal,3 mariam mathew1 departments of 1obstetrics & gynaecology and 3medicine, sultan qaboos university hospital, muscat, oman; 2medical student elective. kasturba medical college, manipal, india. e-mail: ashi_saro@yahoo.com headache is a common symptom in the postpartum period affecting up to 39% of parturients. common causes of postpartum headaches include tension headaches, migraine, pre-eclampsia/eclampsia, post-dural puncture headache, cortical vein thrombosis, subarachnoid haemorrhage, space-occupying lesions, cerebral infarction and meningitis. idiopathic intracranial hypertension (iih) or benign intracranial hypertension (bih) is a rare condition with the triad of headache, papilloedema and elevated intracranial pressure in the absence of focal neurologic deficit/pathology. the diagnosis is made when the lumbar cerebral spinal fluid (csf) opening pressure is >25cm of water. a 32-year-old, para 1, woman underwent caesarean section for prolonged second stage of labour under spinal anaesthesia. she was discharged on the fourth day but readmitted on 18th day with severe headache. a detailed history revealed generalised headache with no associated vomiting, convulsions visual or hearing disturbances. the headache was not affected by changes in posture or with straining. the patient had previously had infrequent episodes of headache. on examination, she was afebrile, normotensive and complete blood counts, urea electrolytes, liver function tests and c-reactive protein were normal. anti-nuclear antibody, anti-nuclear cytoplasmic antibodies and anticardiolipin antibodies were negative. a fundoscopic examination revealed papilloedema. a computed tomography scan of the brain was normal with no signs of venous thrombosis or intracranial lesions. a lumbar puncture showed clear csf with opening pressure >40cm of water; cytology, biochemistry and viral serology tests were negative; hence, the diagnosis of iih was made. she responded well to acetazolamide and mannitol. to date, the patient is on regular follow-up to date with a neurologist and the asymptomatic papilloedema has subsided. iih is a rare cause of postpartum headache and needs to be diagnosed by exclusion. pregnancy, obesity, polycystic ovarian disease, certain drugs and hormones can promote or worsen the condition. no adverse effect on the fetus is reported. the aim of treatment is to relieve pain and prevent visual loss, as blindness may occur in up to 10% of cases. there is no convincing evidence that either the vaginal or caesarean mode of delivery is advantageous in cases of iih. regional anaesthesia is a better choice than general anaesthesia for caesarean delivery as general anaesthesia can increase csf pressure. iih should be considered as one of the differential diagnoses of postpartum headache. teenage pregnany in oman: maternal and neonatal outcomes lovina machado,1 shabnam saquib,1 seema zulfikar,1 syed g. rizvi2 1department of obstetrics & gynaecology, sultan qaboos university hospital and 2epidemiology & statistics unit, family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: lovina1857@gmail.com adolescents between 15–19 years give birth to approximately 13 million children annually; over 90% of these births occur in low-income countries. teenage pregnancy has major social and financial implications. the young mothers are financially dependent, their school drop-out rate is high and the possibilities of further resumption of education usually remote. teenagers face greater risks of pregnancy complications than their adult counterparts. conflicting results regarding maternal and neonatal outcomes are presented by several studies including an increased incidence of maternal and perinatal mortality, preterm birth, pre-eclampsia, cephalopelvic disproportion, low birthweight, anaemia and an increased risk of abortion-related morbidity and mortality. this study aimed to evaluate the obstetric and perinatal outcome in teenage pregnant omani girls at a tertiary care university hospital in oman. a retrospective case control study was conducted at the sultan qaboos university hospital, muscat, between 2007 and 2011. all teenage mothers aged 13–19 years at the time of delivery were the study group. the following two consecutive deliveries in the age group 20–30 years served as controls for each case. data retrieved from the computerised hospital database and maternity register were analysed using the statistical package for the social sciences, version 17. a p value <0.05 was considered statisti-cally significant. maternal, fetal and neonatal outcomes were compared. the incidence of teenage pregnancies was 2.2%. a total of 252 teenage mothers formed the study group and 504 mothers, the controls. there was a statistically significant increase in anaemia, pre-eclampsia, eclampsia, preterm premature rupture of membranes (pprom) and low birthweight in the teenage group. in the control group, gestational diabetes mellitus and polyhydramnios were significantly increased. teenage pregnancy is an important social and public health issue in developing countries and also in oman. an increasing incidence in recent years could be attributed to the early onset of puberty, early sexual activity in girls and relative lack of awareness of birth spacing. adolescent marriage is still a common practice in some countries including oman. conflicting results have been published regarding maternal and neonatal outcomes. adolescents are also at increased risk of abortion-related morbidity and mortality due to unsafe abortion practices. teenage pregnancy in omani girls is associated with anaemia, pre-eclampsia, low birth weight and pprom. creating public awareness and increasing the health education of girls would optimise outcomes. intramural ectopic pregnancy following ivf-et successfully managed with systemic methotrexate lovina machado, nihal al-riyami n, h. al-sayeed department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: lovina1857@gmail.com intramural ectopic pregnancy is one of the rarest forms of ectopic gestation, characterised by a gestation within the uterine wall completely surrounded by the myometrium and separated from the uterine cavity and fallopian tube. to date, less than 30 cases have been reported in the literature. intramural ectopics are difficult to diagnose, may not have unusual presenting symptoms, rarely go beyond 12 weeks gestation and if they do, may present with bleeding and uterine rupture between 11–30 weeks gestation often necessitating a hysterectomy. we present a case of intramural ectopic pregnancy following in vitro fertilisation and embryo transfer (ivf-et) diagnosed early by ultrasound and successfully managed with systemic methotrexate. a 28-year-old omani woman with primary infertility underwent ivf-et at another centre. she presented at 7 + weeks gestation, asymptomatic for follow-up. the pelvic examination revealed an 8-week sized uterus. a vaginal ultrasound scan showed an endometrial thickness of 16 mm, an intramyometrial e288 | squ medical journal, may 2014, volume 14, issue 2 1st international conference on advances in obstetrics & gynaecology part ii posters gestational sac in the fundus, fetal pole crown-rump length = 7 + 4 weeks, no cardiac activity. magnetic resonance imaging confirmed the findings of a sac within the fundus 4.4 x 4.6 cm with marked thinning of the fundal myometrium. serum beta human chorionic gondatropin (hcg) was 20,797 iu/l. she was treated with two doses of systemic methotrexate one week apart. the beta-hcg levels regressed to normal in 7 weeks and serial scans showed the intramural ectopic decreasing in size with no vascularity. the patient is well to date and has resumed normal periods. ivf-et is associated with an increased risk of intramural ectopic pregnancy. early ultrasound diagnosis and intervention can preserve fertility. an unusual presentation of gartner’s duct cyst jayasree santhosh, abdul r. al-farsi, thuria al-rawahi department of obstetrics & gynaecology, royal hospital, sultanate of oman. e-mail: santhosh.jayasree@hotmail.co.uk gartner’s duct cyst is a rare condition consequent to an unfinished disappearance of the mesonephric duct in females. usually, they present as a lateral vaginal wall cyst in the upper third of vagina. we report the case of a 27-year-old woman who was referred with a suspected an anterior vaginal wall tumour. clinically and radiologically the tumour had solid and cystic components and was infiltrating to the anterior vaginal wall. the histopathological examination after excision of the tumour revealed a gartner’s duct cyst. the clinical, radiological and histopathological features are presented and correlated with a literature review. controversies on abortion and the period of ensoulment: an islamic perspective badawy a. k. khitamy national committee for bioethics, oman and department of microbiology & immunology, sultan qaboos university hospital,muscat, oman. e-mail: khitamy@yahoo.com a 16-week pregnant muslim woman was informed that the ultrasound scan was showing spina bifida, the laboratory results, showing raised maternal serum alpha-fetoprotein, confirmed the diagnosis. the child would have various complications and most probably need medical care for life. with the consent of her husband she decided to terminate the pregnancy. her decision sparked controversies among the muslim clerics of her community. there were those who were against abortion after 40 days from conception, for whatever reason, unless the life of the mother was seriously threatened. in their opinion “ensoulment” occurs at about 40 days after conception. hence, abortion after “ensoulment”, as in this case, is a serious crime, the perpetrator being liable to pay diya (full blood money). a second group of clerics held contrary views regarding the period of “ensoulment”. in their opinion “ensoulment” occurs at about 120 days after conception. therefore, the clinical results of the diagnosis justified the abortion. the third group was of the opinion that the clinical picture presented above is not convincing enough to justify abortion. the fetus has a right to life, and destroying the 16-week-old fetus holds the parent liable to pay 1/10 of the full diya referred as al ghurrah. this paper first reviews the philosophical and theological arguments of the pro-life group which emphasises that human life should be preserved from conception regardless of circumstances involved, giving absolute priority to the life of the fetus over the life of the mother. second, the paper examines the pro-choice arguments that a woman should have the right to control her body to the point of absolutising her right over the natural phenomenon of development of the fetus. third, the paper examines the views of the “delayed ensoulment theory” and the “immediate ensoulment theory” and their correlation to the beginning of life concept—and how theologians apply the moment of ensoulment as the cut-off point in determining the legislation on abortion. finally, the paper expounds on the three views presented above of the 16week pregnant woman who terminated her pregnancy for medical reasons. what is the islamic position regarding different categories of abortion, the woman’s autonomy and ‘fetal rights’ or the fetus as a patient? this work was published as: khitamy b. a. b. divergent views on abortion and the period of ensoulment. sultan qaboos university med j 2013; 13:26–31. permission has been granted by squmj to reproduce this material. rectovaginal and bladder involvement in stage four endometriosis maha m. al-khaduri,1 issa al-qarshoobi,2 hani al-qadhi,3 shahid aquil3 departments of 1obstetrics & gynaecology, 2medicine and 3surgery, sultan qaboos university hospital, muscat, oman. e-mail: m.khaduri@gmail.com we report a case of stage four endometriosis with rectovaginal and bladder endometriosis which was managed operatively. a 31-yearold nulliparous woman known to have stage four endometriosis with bilateral endometriomas was followed-up and managed to relieve her symptoms and improve her fertility. she presented with history of primary infertility, postcoital bleeding and dysparunia in addition to constipation and bloody stools. she was found to have microscopic haematuria. symptoms improved after receiving the gonadotropin-releasing hormone agonist (gnrh) agonist, triptorelin. the patient underwent laparoscopy, laparotomy, bilateral ovarian cystectomy, adhesiolysis, hysteroscopy, colonoscopy and cystoscopy with retrograde pyelogram and stenting of the right ureter. the pathology of the bladder and rectal mucosal biopsies confirmed endometriosis. advanced endometriosis requires a multidisciplinary approach. colonoscopy and cystoscopy are indicated in cases where patients are symptomatic or have evidence of rectovaginal septum endometriosis on magnetic resonance imaging. pregnancy outcome following bariatric surgery seema zulfikar, aneeta bai, shahnaz b. patul, mariam mathew department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. e-mail: seemazulfi@gmail.com obesity is defined as a body mass index (bmi) of ≥30 kg/m2 and is a growing health problem globally. about 25% of women are affected by obesity. pregnancy with obesity has increased the incidence of complications like gestational diabetes mellitus, gestational hypertension, pre-eclampsia, fetal macrosomia, caesarean deliveries and anesthesia-related complications. with bariatric surgery and subsequent weight loss, these morbidities related to obesity can be reduced. we report two cases of pregnancy following bariatric surgery. a 39-year-old woman, gravida 3 para 2 both vaginal deliveries, had gastric stapling and abdominoplasty for cosmetic purpose. her bmi prior to surgery was 32 and dropped to 22 after surgery. she became pregnant two years after surgery. throughout the pregnancy she had vomiting and a feeling of fullness but no electrolyte imbalance. the weight gain during pregnancy was 5 kg. serial scans showed a small for gestational age fetus. at 37 weeks, she delivered a baby girl of 2.63 kg with a good apgar score. a 28-year-old woman, gravida 4, para 3, with two previous lower segment caesarean sections had had laparoscopic gastric banding 8 years previously for morbid obesity. her bmi prior to surgery was 47 which then dropped to 35. this was her second pregnancy after bariatric surgery. the weight gain during pregnancy was 5.5 kg. she developed gestational diabetes and was on metformin. she had difficulty in eating, abstracts | e289 sultan qaboos university, 4—6 december 2013 shortness of breath and vomiting requiring intravenous fluids throughout the pregnancy. she had an elective caesarean section at 38 weeks and delivered a baby girl of 2.790 kg with a good apgar score. an increasing number of women in the reproductive age group are undergoing bariatric surgery for obesity. complications associated with obesity and diabetes can be reduced after bariatric surgery. with nutritional supplements and careful monitoring, pregnancies following bariatric surgery can be managed well. delaying pregnancy for 12 to 18 months is advisable after weight-loss surgery. this minimises the complications related to nutrition, miscarriage, preterm labour and lower mean birth weight. pregnancy after bariatric surgery is safe and not associated with an adverse perinatal outcome. such pregnancies should be managed in a multidisciplinary setting with proper nutrition and prenatal vitamin supplementation. angular ectopic pregnancy diagnosed intraoperatively at 33 + weeks of gestation upma p. shanker, sheikha al-abri, hetal s. raniga department of obstetrics & gynaecology, armed forces hospital, muscat, oman. e-mail: drupmashanker@gmail.com interstitial pregnancy is a major therapeutic challenge which can have fatal consequences if not diagnosed in time. it accounts for 2–4% of all ectopic pregnancies. we report the case of a gravida 2, para 1 woman who was diagnosed with placenta previa and was being followed-up both in the armed forces hospital and a ministry of health hospital. she underwent a lower segment caesarean section at 33+ weeks due to poor fetal doppler results. intraoperatively, the patient was diagnosed as a case of angular pregnancy which had slowly ruptured and was growing into the abdominal cavity with a normal uterus lying separately lower down in the abdominal cavity. this is an extremely rare finding as there are only three reported cases in the literature of angular pregnancies reaching such an advanced stage gestation. clinicians should be aware of the difficulties they might encounter in dealing with such cases and the benefit of early diagnosis and careful prenatal care as the condition can have disastrous outcomes. the patient even had a magnetic resonance imaging scan at 27 weeks of gestation due to chronic pelvic pain but no definitive diagnosis could be made at that time. this condition and its management are a surgical challenge. الندوة الوطنية الثانية للصحة العامة الغذاء و التغذية من أجل كوكب صحي الرابطة �لعمانية للصحة �لعامة، 18 �أكتوبر 2014 2nd national public health symposium food and nutrition for a healthy planet oman public health society, 18 october 2014 abstracts keynote: food policy for a healthy planet geof rayner centre for food policy, city university london, london, uk. e-mail: geof.rayner@gmail.com the title of this presentation might be the cause of consternation. isn’t the health of people more important than the health of the planet? the roman philosopher cicero stated that people’s health is the highest law. the philosopher john locke agreed—cicero’s statement, he said, should be the fundamental rule for government. many of us in public health would agree, but we have a problem. we homo sapiens are not alone on the planet. if our needs always come first, what priority do we accord other species? are they simply food or an entertainment source? in 1788, the economist and demographer thomas malthus, at a time when the world’s population stood at one billion, argued that food availability places limits on human expansion. today’s population of seven billion places a greater demand on resources than ever before. the world’s population eats more meat than in previous years and, in order to boost production, the variety of crops grown has been reduced. in malthus’ day, food production was sustainable; today, it is not, as fossil energy is used to grow and transport our food. a modern malthus might tell us that we have pushed the capacity of the planet to its limits. indeed, our rate of urbanisation or conversion of land from wilderness to a farming or habitation landscape means that there is little wilderness left. consequently, biodiversity is in rapid decline, our energy requirements are changing the climate and agriculture is threatened by soil erosion and water stress. our social relations are also suffering; a billion of us are underfed, but this number is now exceeded by those who are overweight or obese. how can we shift towards sustainable diets and food systems? furthermore, can we obtain a balance between the demands of equitable public health and the need to secure a healthy planet? sustainable food policy: lessons from europe geof rayner centre for food policy, city university london, london, uk. e-mail: geof.rayner@gmail.com for hundreds of years, the vast majority of europeans did not have enough to eat. after the world war ii, the european economic community and subsequently the european union was formed to ensure that this situation would never occur again. with a revolution in farming methods, the supply problems of the past have eased. today, the quest for sustainable food policies requires a better balance between environment, social justice and the need for healthy sustainable diets. europe may have come a long way—with lessons for elsewhere—but much more needs to be done. oman national nutrition strategy amel i. ahmed department of nutrition, ministry of health, muscat, oman. e-mail: amarania66@yahoo.com between 1970 and 2005, oman’s per capita gross domestic product rose 30-fold from 158 omani riyals (omr) to 8,289 omr, bringing with it promises of modernity. that 35-year span marked a period of remarkable growth accompanied by demographical, epidemiological and nutritional changes, including the overconsumption of processed foods, low exercise levels and limited access to organic produce. in addition, the pre-pregnancy nutritional needs of women are often neglected, sometimes resulting in low birth weight babies. other issues include disappointing rates of exclusive breastfeeding until six months; poor nutrition in utero and in the first two years of life; and micronutrient deficiencies in part from limited dietary diversity. higher rates of overweight and obese individuals accompanied by non-communicable diseases (such as cardiovascular and coronary artery disease, diabetes and cancer) are imposing great costs. the challenge is to identify the areas of greatest need, increase the national health system’s ability to improve public nutrition and mobilise relevant resources to serve these needs. this strategy aims to define trends and issues and suggest future public health achievement possibilities over the next three and a half decades in order to reach the country’s health vision goals of 2050. before any programmes can be planned, implemented or evaluated, the public’s capacity to better their nutrition must be improved. additionally, a multisectoral approach must be developed to establish a core system for proceeding with national public nutrition policies and interventions. finally, a public nutrition knowledge base must be encouraged and issues and disparities must be identified and prioritised in order to target programmes appropriately. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e445–446, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.027. oman public health society board members: *yahya m. al-farsi, deena h. al-asfoor, ruth mabry and sabah al-bahlani. *conference organiser e-mail: ymfarsi@gmail.com e446 | squ medical journal, august 2015, volume 15, issue 3 2nd national public health symposium food and nutrition for a healthy planet nutrition and food security in the arab world fatima hachem food & agriculture organization regional office, cairo, egypt. e-mail: fatima.hachem@fao.org over the last four decades, arab countries in the near east and north african (nena) region have made long strides in increasing the food supply to their population despite structural constraints—mainly water and land limitations—to increasing food production. in arab countries in nena, data from food balance sheets show that the energy supply has increased by 36%, protein supply by 39.3% and fat supply by 56.6% since the early 1970s. notwithstanding this increase in food availability, these countries have not made parallel improvements in reducing malnutrition. the prevalence of malnutrition in both its manifestations, underand over-nutrition, has been increasing in some of these countries, placing them high on the world list of countries with malnutrition problems. underand over-nutrition exists in all arab countries of nena, but their degree of prevalence varies from one country to another depending on many factors, including income and development levels. nutritional transition, which is marked by the double burden of malnutrition and micronutrient deficiencies, especially anaemia, is common to all countries. the long-term impact these nutritional problems have on the human and economic capitals of individuals and nations and the multisectoral nature of nutrition calls for the adoption of an intersectoral approach for addressing nutritional challenges and the implementation of nutrition-sensitive policies in different societal sectors (e.g. agriculture, health, trade and education) for achieving positive nutritional outcomes. obesity and its risk factors in the arab world omar obeid department of nutrition & food science, faculty of agriculture & food sciences, american university of beirut, beirut, lebanon. e-mail: oo01@aub.edu.lbnau evidence from epidemiological studies reveals that the increased consumption of refined carbohydrates (cereals), sugars, sweeteners (especially high fructose corn syrup), oils and fats can be implicated in the increased prevalence of obesity. during the past few decades, major changes in dietary habits have mainly been related to a dramatic increase in the intake of macromineral (potassium, phosphorus and magnesium)-free commodities such as oils, sugar and sweeteners, which contain negligible amounts of the above macrominerals, and refined cereal commodities, where refinement has reduced macromineral content by about 70%. in developed and transitional countries, the consumption of these commodities is known to be inversely related to socioeconomic status, mainly because of their high energy density (kcal/g food) and low energy cost. increased urbanisation is reportedly associated with an increased consumption of vegetable fats and sugars. a high per capita gross national product is associated with higher consumption of vegetable and animal fats and sugars, with a sharp decrease in the consumption of complex carbohydrates. it can therefore be deduced that the high intake of refined carbohydrates, fats and sweeteners accompanied by the lower intake of fruit and vegetables, leads to a diet that is deficient or suboptimal in vitamins and minerals, including potassium, phosphorus and magnesium. thus, the increased prevalence of obesity among people consuming high quantities of commodities with low macromineral levels may implicate these macrominerals in the development of obesity. world health organization response to address the double burden of malnutrition in the eastern mediterranean region ayoub al-jawaldeh department of nutrition, world health organization eastern mediterranean region, cairo, egypt. e-mail: aljawaldeha@who.int malnutrition remains a major health problem in the eastern mediterranean region (emr), where it contributes to more than onethird of the child mortality rate, as well as the prevalence of stunting and underweight among children under five years of age. in many emr countries, the high prevalence of wasting is due to natural disasters, food insecurity and political instability. among under-fiveyear-olds, low levels of breastfeeding and poor feeding practices have led to an increase in the prevalence of overweight children from 5.6% in 1991 to 8.1% in 2010. non-communicable diseases (ncds) account for 57% of all deaths in the region, with cardiovascular disease, cancer, diabetes and chronic respiratory diseases responsible for the largest proportion. in 2012, the world health organization (who) adopted a comprehensive plan to reduce stunting, wasting, overweight, anaemia and low birth weight in children while improving breastfeeding rates in women. technical support has been provided to member states to develop a national action plan for implementation. in 2013, the who agreed to nine global voluntary targets for the prevention and control of ncds, which include a halt in the rise of diabetes and obesity and a reduction in salt intake by 2025. the global action plan for the prevention and control of noncommunicable diseases provides guidance and policy options for member states to achieve targets, focusing on salt, sugar and fat reduction strategies to address ncd risk factors at global and regional levels. food security in oman: challenges of a desert state naufal rasheed ministry of agriculture, muscat, oman. e-mail: naufalhrasheed@gmail.com this study highlights the issue of food security (fs) in oman, defines certain fundamentals, contemplates challenging issues, diagnoses certain constraints, describes features of the agricultural sector, analyses economic indicators, scrutinises food groups and proposes a road map for fs achievement along with expected outcomes. fs in oman is a multidimensional issue, with many elements involved in its definition. prior to oil exploration in the 1960s, oman was considered a nearly food-secure country. however, due to urbanisation and the growth of modern food businesses, food imports have gradually increased. currently, wheat, rice, sugar, vegetable oils and legumes, considered essential food commodities, are 100% imported. poultry, meat, eggs, red meat and produce are produced at a rate of semi-self-sufficiency. date and fish production is self-sufficient. while there is still potential to achieve better fs in certain plant and livestock products, water scarcity is a limiting constraint facing agricultural development. the oman ministry of agriculture & fisheries has taken serious steps toward finalising and implementing a realistic, long-term strategic plan for agricultural development. the plan includes a strategy for the development of and investment in fisheries, with more than 10 such projects under preparation. under this plan, small and medium enterprises and cooperatives are likely to replace current traditional farming systems, resulting in modernised farming systems, increased productivity and improved fs, ultimately improving contributions to gross domestic product. agriculture is the backbone of all food commodities and a marriage between food and agriculture has become a necessity as access to sufficient, safe and nutritious food must be available at all times for a healthy population. departments of 1pediatrics and 4statistics and centres for 2cellular & molecular research and 3metabolic diseases research, qazvin university of medical sciences, qazvin, iran *corresponding author e-mail: abolfazl473@yahoo.com مستوى معدن الزنك يف مصل دماء األطفال املصابني بإسهال َدَموّي أو مائي حاد اأبو الفا�سل مهيار، بارفيز اأبازي، فيكتوريا فقيني، مهدي �ساهماين، �سونيا اأوفيزي، �سيفا اإ�سماعيلي abstract: objectives: the role of zinc in the pathogenesis of diarrhoea is controversial. this study was conducted to compare serum zinc levels in children with acute diarrhoea to those found in healthy children. methods: this case-control study was carried out at the qazvin children’s hospital in qazvin, iran, between july 2012 and january 2013. a total of 60 children with acute diarrhoea (12 children with bloody diarrhoea and 48 children with watery diarrhoea) and 60 healthy children were included. zinc levels for all subjects were measured using a flame atomic absorption spectrophotometer and data were analysed and compared between groups. results: mean serum zinc levels in the patients with acute bloody diarrhoea, acute watery diarrhoea and the control group were 74.1 ± 23.7 µg/dl, 169.4 ± 62.7 µg/dl and 190.1 ± 18.0 µg/dl, respectively (p = 0.01). hypozincaemia was observed in 50.0% of children with acute bloody diarrhoea and 12.5% of those with acute watery diarrhoea. none of the patients in the control group had hypozincaemia (p = 0.01). conclusion: children with acute bloody diarrhoea had significantly reduced serum zinc levels in comparison to healthy children. however, a study with a larger sample size is needed to examine the significance of this trend. keywords: zinc; diarrhea; children; case-control study; iran. دماء م�سل يف الزنك م�ستوى ملقارنة الدرا�سة هذه هدفت خالفيا. اأمرا الإ�سهال فيمر�ض الزنك يلعبه الذي الدور يعد الهدف: امللخ�ص: الأطفال امل�سابني باإ�سهال َدَموّي اأو مائي حاد مع م�ستواه عند الأطفال الأ�سحاء. الطريقة: اأجريت هذه الدرا�سة ال�ستعادية يف م�ست�سفى و12 مائي باإ�سهال 48( حاد مائي اأو َدَموّي باإ�سهال م�سابني طفال 60 الدرا�سة و�سملت .2013 ويناير 2012 يوليو بني باإيران قزوين الذري، المت�سا�ض لهب مطياف جهاز طريق عن الأطفال هوؤلء م�سل يف الزنك تركيز قيا�ض ومت �سحيحا. طفال و60 دموي( باإ�سهال وحللت النتائج ومتت املقارنة بني املجموعات. النتائج: وجد اأن متو�سط تركيز الزنك يف م�سل دماء الأطفال امل�سابني بالإ�سهال الدموي، وبالإ�سهال املائي، والأ�سحاء كان µg/dl 23.7 ± 74.1 و µg/dl 62.7 ± 169.4 و µg/dl 18.0 ± 190.1، على التوايل )p = 0.01( . ولوحظ اأن %50.0 من الأطفال امل�سابني باإ�سهال َدَموّي حاد، و %12.5 من الأطفال امل�سابني باإ�سهال مائي حاد كانوا يعانون من حالة قلة الزنك تركيز يف اإح�سائيا معنوي نق�ض من حاد دموي باإ�سهال امل�سابون الأطفال يعاين اخلال�صة: .)p = 0.01( الدم يف الزنك تركيز يف م�سل الدم عند مقارنتهم بالأطفال الأ�سحاء. غري اأنه ملعرفة اأهمية هذه النتيجة ودللتها، يجب القيام بدرا�سة اأخرى بعدد اأكرب من العينات. مفتاح الكلمات: زنك؛ اإ�سهال؛ درا�سة حالة �سابطة؛ الأطفال؛ اإيران. serum zinc concentrations in children with acute bloody and watery diarrhoea *abolfazl mahyar,1 parviz ayazi,1 victoria chegini,1 mehdi sahmani,2 sonia oveisi,3 shiva esmaeily4 clinical & basic research advances in knowledge the results of the present study confirm the role of zinc in the pathophysiology of acute diarrhoea, particularly for patients with acute bloody diarrhoea. application to patient care the findings of this study may inform treatment regimens for children with diarrhoea, as the addition of zinc supplementation may help children recover more rapidly. sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e512–516, epub. 23 nov 15 submitted 15 dec 14 revisions req. 9 mar & 21 may 15; revisions recd.23 mar & 22 may 15 accepted 22 jul 15 doi: 10.18295/squmj.2015.15.04.012 diarrhoea is defined by the world health organization as the excretion of loose or watery stool at least three times within 24 hours.1 acute diarrhoea occurs over a few hours or days with a total duration of less than 14 days. it is divided into two types: watery and bloody diarrhoea (dysentery). the main causes of acute diarrhoea include rotavirus, enteroinvasive escherichia coli, shigella and salmonella.1–3 diarrhoea is a common condition in children. based on available data, 2.5 billion diarrhoea cases occur per year among children under five years of age in developing countries.4 more than 80% of these cases are observed in asia and africa, where the incidence of diarrhoea abolfazl mahyar, parviz ayazi, victoria chegini, mehdi sahmani, sonia oveisi and shiva esmaeily clinical and basic research | e513 is 3.6 episodes annually per child.1,3,4 diarrhoea is a significant cause of child mortality worldwide, particularly in developing countries; boschi-pinto et al. estimated that approximately 1.8 million deaths each year are diarrhoea-related, with most of these deaths occurring in children under five years old.5 micronutrient deficiency is still a notable cause of mortality among patients with diarrhoea despite the introduction of oral rehydration salts (ors).6–12 furthermore, micronutrient deficiency is known to exacerbate diarrhoea and delay recovery time, causing the condition to become chronic.6–12 zinc is one of the most important micronutrients and is crucial for free radical detoxification, antioxidant defence and immune system function in humans.13,14 zinc levels have been found to be reduced in patients with acute diarrhoea.6,15 despite these findings, there is disagreement regarding the efficacy of zinc supplementation for children with acute diarrhoea. some studies have reported that zinc supplementation accelerates recovery and reduces the duration and severity of diarrhoea, consequently reducing mortality;16–18 however, other studies do not support these findings.19–23 due to this controversy and the high prevalence of acute diarrhoea in iranian children, this study was conducted to determine serum zinc levels in children with acute diarrhoea in qazvin, iran. methods this case-control study was carried out at the qazvin children’s hospital in qazvin between july 2012 and january 2013. inpatients ≤5 years old who were admitted to the emergency or paediatric wards of the qazvin children’s hospital due to severe/ acute diarrhoea, diarrhoea with vomiting and/or a fever during the study period were included. acute diarrhoea was defined as the excretion of loose or watery stools at least three times within 24 hours, developing over a few hours or days and lasting fewer than 14 days.1 patients with chronic diarrhoea lasting more than 14 days and occurring in conjunction with other underlying diseases such as malnutrition, diabetes, urinary tract infections, septicaemia, pneumonia and other skin or metabolic diseases were excluded from the study. group matching was used to select the control group from healthy children who were referred to the health centre of the same hospital for evaluation of their growth. children in both groups resided in qazvin province and were similar in age and gender. the sample size was calculated according to the following formula:24 where α is 0.05, 1-α/2 is 0.95, β is 0.2, 1-β2 is 0.8, σ is 8, µ1 is 79 µg/dl and µ2 is 83 µg/dl. consecutive sampling was used until the desired sample size was reached. a total of 60 children with acute diarrhoea and 60 healthy children were included. the children with acute diarrhoea were divided into watery (n = 48) and bloody (n = 12) diarrhoea groups. the children with acute diarrhoea were also subdivided according to dehydration severity into mild (<5%), moderate (5–10%) and severe (>10%) groups.3,25 the demographic information and symptoms of all subjects were recorded. prior to beginning treatment for diarrhoea, blood samples from the experimental group were analysed to measure erythrocyte sedimentation rates and c-reactive protein levels and white blood cell, neutrophil and platelet counts. all tests were performed in the laboratory department of qazvin children’s hospital using standard methods. to measure serum zinc levels, 3 ml of blood were drawn from the peripheral vessels of all of the children. serum was obtained by centrifugation at 3,000 revolutions per minute for five minutes at 4 °c. the serum was then poured into acid-washed tubes and stored in a freezer at -20 °c until the serum zinc assays were completed. serum zinc levels were then measured using a flame atomic absorption spectrophotometer (gbc scientific equipment pty ltd, braeside, victoria, australia) in the biochemistry department of qazvin university of medical sciences in qazvin. levels of 70–120 µg/dl were considered to indicate a normal range and levels of less than 70 µg/dl were considered to indicate hypozincaemia.26 data were entered into the statistical package for the social sciences (spss), version 16 (ibm corp., chicago, illinois, usa). the results were analysed using chi-squared and tukey’s post hoc tests and spearman’s rank correlation coefficient and pearson’s correlation coefficient analyses. a value of p <0.05 was considered statistically significant. this study was approved by the ethics committee of the research department at the qazvin university of medical sciences (project #303). the parents of all subjects gave written informed consent for their inclusion in the study. n = 2(z[1]+z[1-β])2σ2 (µ1-µ2) 2 α 2 serum zinc concentrations in children with acute bloody and watery diarrhoea e514 | squ medical journal, november 2015, volume 15, issue 4 table 1: demographic data of children with acute diarrhoea in comparison to an ageand gendermatched control group in qazvin, iran (n = 120) variable acute diarrhoea group (n = 60) control group (n = 60) p value male-to-female ratio* 37:23 38:22 0.99 mean age in months ± sd† 28.8 ± 15.2 30.1 ± 15.5 0.65 mean weight in kg ± sd† 12.3 ± 3.1 12.8 ± 2.9 0.80 height in cm ± sd† 88.9 ± 12.1 89.3 ± 11.6 0.90 median head circumference in cm ± iqr‡ 46 ± 2.0 46 ± 3.0 0.73 sd = standard deviation; iqr = interquartile range. *calculated using the chi-squared test. †calculated using the student’s t-test. ‡calculated using the mann-whitney u-test. table 2: characteristics of diarrhoeal illness among children with acute diarrhoea in qazvin, iran (n = 60) characteristic n (%) type of diarrhoea* watery 48 (80.0) bloody 12 (20.0) mean frequency ± sd† 6.0 ± 1.5 mean duration of illness in days ± iqr‡ 2.1 ± 1.0 dehydration severity*§ mild 17 (28.3) moderate 30 (50.0) severe 13 (21.7) symptoms fever 48 (80.0) vomiting 34 (56.7) abdominal pain 21 (35.0) lack of appetite 16 (26.7) stool culture results no growth 32 (53.3) pathogenic escherichia coli 15 (25.0) shigella 10 (16.7) salmonella 3 (5.0) sd = standard deviation; iqr = interquartile range. *calculated using the chi-squared test. †calculated using the student’s t-test. ‡calculated using the mann-whitney u test. §dehydration severity was classified into mild (<5%), moderate (5–10%) and severe (>10%) categories. table 3: mean serum zinc levels and hypozincaemia among children with acute diarrhoea in comparison to an ageand gendermatched control group in qazvin, iran (n = 120) acute diarrhoea group control group (n = 60) p value bloody (n = 12) watery (n = 48) mean zinc ± sd in µg/dl* 74.1 ± 23.7 169.4 ± 62.7 190.1 ± 18.0 0.01 hypozincaemia,† n (%)‡ 6 (50.0) 6 (12.5) 0 (0.0) 0.01 sd = standard deviation. *calculated using the tukey’s post hoc test. †serum zinc levels of <70 µg/dl. ‡calculated using the chi-squared test. table 4: serum zinc levels according to causative organism of bacterial acute diarrhoea among children in qazvin, iran (n = 28) zinc in µg/dl causative organism p value pathogenic escherichia coli (n = 15) shigella (n = 10) salmonella (n = 3) minimum 50.0 50.0 155.0 0.01 maximum 95.0 120.0 180.0 mean ± sd 74.0 ± 13.2 74.0 ± 25.0 170.0 ± 13.2 sd = standard deviation. table 5: correlation between serum zinc levels and inflammatory and non-inflammatory variables among children with acute diarrhoea in qazvin, iran (n = 60) variables serum zinc levels acute diarrhoea (n = 60) acute watery diarrhoea (n = 48) acute bloody diarrhoea (n = 12) r p value r p value r p value inflammatory fever -0.43 0.01 -0.26 0.06 -0.20 0.40 wbc -0.68 0.01 -0.52 0.01 -0.24 0.40 neutrophils -0.74 0.01 -0.62 0.01 -0.42 0.16 esr -0.83 0.01 -0.78 0.01 -0.50 0.06 crp -0.82 0.01 -0.75 0.01 -0.27 0.30 non-inflammatory dehydration severity 0.52 0.01 0.6 0.01 -0.24 0.40 type of diarrhoea -0.52 0.01 causative organism -0.86 0.01 wbc = white blood cell count; esr = erythrocyte sedimentation rate; crp = c-reactive protein. abolfazl mahyar, parviz ayazi, victoria chegini, mehdi sahmani, sonia oveisi and shiva esmaeily clinical and basic research | e515 results a total of 60 children with acute diarrhoea and 60 healthy children were included. there were 37 males (61.7%) and 23 females (38.3%) among the acute diarrhoea group, while the control group had 38 males (63.3%) and 22 females (36.7%). subjects in the diarrhoea group ranged from 3–60 months old while those in the control group ranged from 3–57 months old. there was no significant difference between the groups in terms of age, gender, weight, height or head circumference (p >0.05) [table 1]. diarrhoeal illness characteristics of the patients with acute diarrhoea are shown in table 2. of the 60 children with acute diarrhoea, 12 had bloody diarrhoea and 48 had watery diarrhoea. the mean serum zinc levels among those in the acute bloody diarrhoea, acute watery diarrhoea and control groups were 74.1 ± 23.7 µg/dl, 169.4 ± 62.7 µg/dl and 190.1 ± 18.0 µg/dl, respectively (p = 0.01). hypozincaemia was observed in 50.0% of the children with acute bloody diarrhoea and 12.5% of the children with acute watery diarrhoea. however, none of the children in the control group had hypozincaemia (p = 0.01) [table 3]. among the children with acute diarrhoea, 28 were found to have bacterial diarrhoea caused by the following organisms: e. coli (n = 15), shigella (n = 10) and salmonella (n = 3). a significant difference was observed in the mean serum zinc levels of these patients (p = 0.01) [table 4]. correlations between serum zinc levels and inflammatory and noninflammatory variables among children with acute diarrhoea is shown in table 5. discussion zinc is an essential nutrient for humans and plays an important role in immunological processes and the adequate functioning of many macromolecules. hypozincaemia can cause various diseases, including acute diarrhoea, by disrupting the defence system and reducing antioxidant activity.27 some researchers believe that the administration of zinc to patients with diarrhoea accelerates their recovery by facilitating rapid regeneration of the intestinal epithelium and increasing brush border (apical) enzymes.18,27 this provides a zinc transporter for enterocytes and enhances the immune response. the result of these pathophysiological changes is the improvement of water and electrolyte absorption, as well as the faster removal of pathogenic organisms from the intestine.18,27 although the exact mechanism of zinc in water and electrolyte transportation in the intestine is not clear, this effect may be due to the inhibition of adenosine 3’,5’-cyclic monophosphate-induced chloride-dependent fluid secretion in the small intestine.27 in the current study, children with acute bloody diarrhoea had significantly lower serum zinc levels in comparison with healthy children. additionally, hypozincaemia was observed in half of the children with acute bloody diarrhoea and some of those with acute watery diarrhoea while none of the control group had hypozincaemia. this reduction in serum zinc levels may be related to either the excretion of zinc following acute diarrhoea or metabolic reactions against the infections (known as acute phase responses) or both.15,20,28,29 many studies have reported contradictory results on the effect of zinc in the treatment of acute diarrhoea. a study of 3–59-month-old children affected with acute diarrhoea in bangladesh indicated that the daily administration of 20 mg of zinc reduced the duration and frequency of diarrhoea.16 al-sonboli et al. also found that the administration of zinc reduced the duration of diarrhoea among brazilian children <5 years old.17 a study by bahl et al. in india revealed that the administration of zinc along with ors reduced the severity of acute diarrhoea among children between 6–35 months old.18 in contrast, patel et al. demonstrated that the administration of zinc did not affect the duration of or rate of complications arising from acute diarrhoea among children aged 6–59 months receiving either ors and zinc or ors and a placebo.20 the researchers suggested that the inefficacy of zinc in their study may have been attributable to a low dose of zinc, poor compliance and the failure of the supplements to replenish the zinc loss.20 other studies have confirmed these results.21–23 the primary limitation of the current study was the failure to measure serum zinc concentrations after patients had completed their course of treatment. additionally, the sample size was small. as a result, future studies with a larger sample size are recommended to assess the efficacy of zinc supplementation among patients with acute diarrhoea. conclusion the results of this study showed a trend towards reduced serum zinc levels in children with acute bloody diarrhoea as compared with healthy children in a control group. however, a study with a larger sample size is needed to study the significance of this trend and to resolve the on-going controversy regarding the efficacy of zinc supplementation as a treatment option for individuals with acute diarrhoea. serum zinc concentrations in children with acute bloody and watery diarrhoea e516 | squ medical journal, november 2015, volume 15, issue 4 a c k n o w l e d g e m e n t s the researchers would like to thank the participants and their parents for their cooperation in this study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. world health organization. the treatment of diarrhoea: a manual for physicians and other senior health workers. from: www.who.int/maternal_child_adolescent/documents/9241 593180/en/ accessed: may 2015. 2. black re, cousens s, johnson hl, lawn je, rudan i, bassani dg, et al. global, regional, and national causes of child mortality in 2008: a systematic analysis. lancet 2010; 375:1969–87. doi: 10.1016/s0140-6736(10)60549-1. 3. bhutta za. acute gastroenteritis in children. in: kliengman rm, stanton bm, st geme j, schor nf, behrman re, eds. nelson textbook of pediatrics. 19th ed. philadelphia, pennsylvania, usa: saunders, 2011. pp. 1323–37. 4. united nations international child emergency fund and the world health organization. diarrhoea: why children are still dying and what can be done. from: www.who.int/maternal_ child_adolescent/documents/9789241598415/en/ accessed: may 2015. 5. boschi-pinto c, velebit l, shibuya k. estimating child mortality due to diarrhoea in developing countries. bull world health organ 2008; 86:710–17. 6. fischer walker cl, black re. micronutrients and diarrheal disease. clin infect dis 2007; 15:s73–7. doi: 10.1086/518152. 7. brown kh. diarrhea and malnutrition. j nutr 2003; 133:328s–32s. 8. kossmann j, nestel p, herrera mg, el amin a, fawzi ww. undernutrition in relation to childhood infections: a prospective study in the sudan. eur j clin nutr 2000; 54:463–72. doi: 10.1038/sj.ejcn.1600998. 9. ortiz j, van camp j, wijaya s, donoso s, huybregts l. determinants of child malnutrition in rural and urban ecuadorian highlands. public health nutr 2014; 17:2122–30. doi: 10.1017/s1368980013002528. 10. wierzba tf, el-yazeed ra, savarino sj, mourad as, rao m, baddour m, et al. the interrelationship of malnutrition and diarrhea in a periurban area outside alexandria, egypt. j pediatr gastroenterol nutr 2001; 32:189–96. doi: 10.1097/00005176200102000-00018. 11. black re, sazawal s. zinc and childhood infectious disease morbidity and mortality. br j nutr 2001; 85:s125–9. doi: 10.1079/bjn2000304. 12. black re. zinc deficiency, infectious disease and mortality in the developing world. j nutr 2003; 133:1485s–9s. 13. gallagher ml. vitamins. in: mahan lk, escott-stump s, eds. krause’s food, nutrition, & diet therapy. 11th ed. philadelphia, pennsylvania, usa: saunders, 2004. pp. 75–119. 14. king jc, cousins rj. zinc. in: shils me, shike m, ross ac, caballero b, cousins rj, eds. modern nutrition in health and disease. 10th ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2005. pp. 271–85. 15. arora r, kulshreshtha s, mohan g, singh m, sharma p. estimation of serum zinc and copper in children with acute diarrhea. biol trace elem res 2006; 114:121–6. doi: 10.1385/ bter:114:1:121. 16. baqui ah, black re, el arifeen s, yunus m, chakraborty j, ahmed s, et al. effect of zinc supplementation started during diarrhoea on morbidity and mortality in bangladeshi children: community randomised trial. bmj 2002; 325:1059. doi: 10.1136/bmj.325.7372.1059. 17. al-sonboli n, gurgel rq, shenkin a, hart ca, cuevas le. zinc supplementation in brazilian children with acute diarrhoea. ann trop paediatr 2003; 23:3–8. 18. bahl r, bhandari n, saksena m, strand t, kumar gt, bhan mk, et al. efficacy of zinc-fortified oral rehydration solution in 6 to 35-month-old children with acute diarrhea. j pediatr 2002; 141:677–82. doi: 10.1067/mpd.2002.128543. 19. valery pc, torzillo pj, boyce nc, white av, stewart pa, wheaton gr, et al. zinc and vitamin a supplementation in australian indigenous children with acute diarrhoea: a randomised controlled trial. med j aust 2005; 182:530–5. 20. patel ab, dhande la, rawat ms. therapeutic evaluation of zinc and copper supplementation in acute diarrhea in children: double blind randomized trial. indian pediatr 2005; 42:433–42. 21. brooks wa, santosham m, roy sk, faruque as, wahed ma, nahar k, et al. efficacy of zinc in young infants with acute watery diarrhea. am j clin nutr 2005; 82:605–10. 22. fischer walker cl, bhutta za, bhandari n, teka t, shahid f, taneja s, et al. zinc supplementation for the treatment of diarrhea in infants in pakistan, india and ethiopia. j pediatr gastroenterol nutr 2006; 43:357–63. doi: 10.1097/01. mpg.0000232018.40907.00. 23. long kz, montoya y, hertzmark e, santos ji, rosado jl. a double-blind, randomized, clinical trial of the effect of vitamin a and zinc supplementation on diarrheal disease and respiratory tract infections in children in mexico city, mexico. am j clin nutr 2006; 83:693–700. 24. cesur s, kocaturk pa, kavas go, aksaray s, tezeren d, ciftci u. serum copper and zinc concentrations in patients with brucellosis. j infect 2005; 50:31–3. doi: 10.1016/j. jinf.2004.05.001. 25. farthing m, lindberg g, dite p, khalif il, salazar-lindo e, ramakrishna bs, et al. world gastroenterology organisation practice guideline: acute diarrhea. milwaukee, wisconsin, usa: world gastroenterology organisation, 2008. pp. 7–12. 26. burtis ca, ashwood er, eds. tietz fundamentals of clinical chemistry. 5th ed. philadelphia, pennsylvania, usa: saunders, 2001. pp. 1137–41. 27. lukacik m, thomas rl, aranda jv. a meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. pediatrics 2008; 121:326–36. doi: 10.1542/peds.20070921. 28. kassu a, yabutani t, mahmud zh, mohammad a, nguyen n, huong bt, et al. alterations in serum levels of trace elements in tuberculosis and hiv infections. eur j clin nutr 2006; 60:580–6. doi: 10.1038/sj.ejcn.1602352. 29. cuevas le, koyanagi a. zinc and infection: a review. ann trop paediatr 2005; 25:149–60. doi: 10.1179/146532805x58076. http://dx.doi.org/10.1016/s0140-6736%2810%2960549-1 http://dx.doi.org/10.1086/518152 http://dx.doi.org/10.1038/sj.ejcn.1600998 http://dx.doi.org/10.1017/s1368980013002528 http://dx.doi.org/10.1097/00005176-200102000-00018 http://dx.doi.org/10.1097/00005176-200102000-00018 http://dx.doi.org/10.1079/bjn2000304 http://dx.doi.org/10.1385/bter:114:1:121 http://dx.doi.org/10.1385/bter:114:1:121 http://dx.doi.org/10.1136/bmj.325.7372.1059 http://dx.doi.org/10.1067/mpd.2002.128543 http://dx.doi.org/10.1097/01.mpg.0000232018.40907.00 http://dx.doi.org/10.1097/01.mpg.0000232018.40907.00 http://dx.doi.org/10.1016/j.jinf.2004.05.001 http://dx.doi.org/10.1016/j.jinf.2004.05.001 http://dx.doi.org/10.1542/peds.2007-0921 http://dx.doi.org/10.1542/peds.2007-0921 http://dx.doi.org/10.1038/sj.ejcn.1602352 http://dx.doi.org/10.1179/146532805x58076 outcome of pregnancy in patients possessing anticardiolipin antibodies medical sciences (2000), 2, 91−95 © 2000 sultan qaboos university 1department of obstetrics and gynaecology, armed forces hospital, muscat, sultanate of oman. 2department of obstetrics and gynaecology, sultan qaboos university hospital, p o box 38 al-khod, muscat 123, sultanate of oman. 3department of microbiology & immunology, college of medicine, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. e mail: erichens@squ.edu.om 91 outcome of pregnancy in patients possessing anticardiolipin antibodies al abri s1, vaclavinkova v2, *richens e r3 الحامل المرأة على للكارديوليبين المضادة األجسام أثر رتيشثن اليزابيث ,فاآالثينكوفا فالستا, العبري شيخه المذآورة المضادة األجسام يحملن اللواتي الحوامل النساء من عينة دراسة عند الحمل على للكارديوليبين المضادة جساماأل وجود أثر تحليل: الهدف:الملخص من الالزمة المعلومات معتج :الطريقة.الحاالت تلك مثل في البريدتيزولون أو باألسبرين المعالجة فاعلية تحليل . الحمل لفقدان يمرض تاريخ وجود بشرط وجود مع الطبيعي المعدلن ب للكارديوليبي المضادة األجسام وجود على الحاالت تلك اختيار ترآز . أسيوي أصل من أخرى حاالت بعأرو عربية ةمريض 21 آان نوع ج فقط،وجود أألجسام المضادة من عند أنه تبين:نتائجال إحصائيا المعلومات بتحليل قمنا ذلك بعد ثم . أآثر أو واحدة لمرة باالجهاض مرضي تاريخ و ج نوع من مضادة أجسام وجود حالة في أما ، األخير الثلث عن مهمة زيادة ويزيد ي من الحمل، والثان يا للثلثين األول و متسا الجنين وفقدان اإلجهاض معدل هذه لعالج األسبرين من القليلة الجرعة بإستعمال أنه وتبين . الحمل في والثالث الثاني الثلثين زيادة مهمة عن زادت األول الثلث في اإلجهاض نسبة فإن معا م النسبة آانت عالج أي إعطاء عدم وعند . فقط األسبرين استعمال عند% 54 عليه آانت عما% 75 الحمل نجاح نسبة أصبحت البريدثيزولون بجانب الحاالت تبين وآذلك الحمل فقدان إحتمال من يزيد الحامل المرأة عند ج نوع من للكارديوليبين المضادة األجسام وجود أن فيه الشك مما : الخالصة . فقط% 17 المرأة عند المضادة األجسام وجود حالة في الحمل نجاح نسبة من يزيد معه الستيرويد إستخدام عن النظر بغض القليلة بالجرعة باألسبرين العالج أن إحصائيا .الحامل abstract: objective – to analyse the outcome of pregnancy in a sample of patients with a history of fetal loss, and possessing anticardiolipin antibodies (acas), and to assess the effectiveness of therapy with aspirin and prednisolone. method – data on a cohort of 21 arab and 4 other asian patients who had one or more episodes of fetal loss associated with raised levels of acas were analysed retrospectively. statistical analysis was performed using χ2 test for assessment of isotype data and the fischer test for assessment of the effects of therapeutic intervention. results –where immunoglobulin g (igg) acas were found alone, abortion rates occurred at the same rate in the first and second trimesters, which was significantly higher than in the third trimester. in the few cases where igg and immunoglobulin m (igm) acas coexisted, the rate of pregnancy loss was significantly higher in the first trimester than the second and the third. in the group who had received both aspirin and prednisolone, 75% pregnancies were successful compared to 54% in the group receiving aspirin alone and 17% in those who received no therapy. conclusion – the presence of igg antibodies appears to increase the risk of abortions. low dose aspirin, either alone or with prednisolone, appears to significantly improve the chances for successful pregnancies in patients with acas. further clinical trials are needed to ascertain optimal therapeutic protocols. key words: anticardiolipin, antibody, aspirin, prednisolone, pregnancy nticardiolipin antibodies (acas) are strongly associated with venous and arterial thrombosis, thrombocytopenia and recurrent fetal loss.1 these findings were first observed during studies of systemic lupus erythematosus (sle), a disease whose many symptoms include thrombosis. of the spectrum of auto antibodies described in sle, two were found to be directed against most negatively charged phospholipids, including cardiolipin.2 anti-phospholipid antibodies are known to prolong in vitro phospholipid-dependent coagulation tests, and have been historically referred to as the lupus anticoagulant (lac). in addition to their occurrence in patients with sle, acas are found in patients with other autoimmune diseases, as well as in some with no apparent previous underlying disease.3 the term �antiphospholipid syndrome� is used to describe patients who present with the clinical manifestations described above, in association with acas or the lac.4 acas may bind independently to the negatively charged phospholipid (in which case, they are called �authentic� acas) or they may require a cofactor, beta 2 glycoprotein-i (β2gpi).5 the role of β2gpi antibodies in fetal loss is under study.6 a a l a b r i e t a l 92 in pregnancy, the antibodies may react against the trophoblast resulting in sub-placental clots and interfere with further placentation. necrotizing descidual vascular lesions are seen in the placenta.7 thrombosis may occur in all trimesters of pregnancy resulting in complications such as spontaneous abortions and intrauterine growth retardation (iugr). in this retrospective study, the outcome of pregnancy in patients with a history of fetal loss, and possessing acas, who were attending the outpatient clinic of the obstetrics department of sultan qaboos university hospital, has been analysed. sle is common is this country and a minority of the patients presented with this condition also. the patients received therapy either with aspirin or with aspirin combined with prednisolone. due to noncompliance, six patients received no therapy. like other corticosteroids, prednisolone suppresses antibody production. low-dose aspirin acts by inhibiting the production of thromboxane a2, a vasoconstrictive prostaglandin associated with platelet aggregation and thrombocytopenia. the data has been further examined to determine the effect of these therapeutic modalities on fetal survival. method during the period 1995�97, 25 patients with acas and pregnancy losses were seen in the outpatient clinic of squ hospital. their ages ranged from 20�40 years; 21 were omani whilst 4 were asian expatriate. patients who sustained pregnancy losses from other causes, such as genetic, endocrine or gynaecological abnormalities, rhesus incompatibility or sperm antibodies were excluded from the study. table 1 shows the obstetric history of the patients; they had lost from 1�6 (mean ± sd: 2.3 ± 1.9) pregnancies, the abortions occurring mainly in the first and second trimester. all the patients possessed acas, and four patients, in addition, possessed antinuclear antibodies (anas). all patients were put on therapy as soon as the pregnancy was diagnosed. none had received treatment in previous pregnancies. the therapy was either aspirin, 80 mg daily, alone or in combination with prednisolone, 10�20 mg daily, according to the presence of antibodies and, in some patients, the coexistence of connective tissue disease. of the 21 patients with acas alone, five were treated with aspirin and prednisolone and 11 with aspirin alone. due to non-compliance the remaining five patients received no therapy. of the four patients with both acas and anas, three received both aspirin and prednisolone (one with the addition of cyclophosphamide) and the fourth received no therapy, again due to non-compliance (table 2). acas were measured using the kallestad system where the normal range for igg aca was < 23 gpl and for igm aca was < 11 mpl. statistical analysis was performed using χ2 test for assessment of isotype data and the fischer test for assessment of the effects of therapeutic intervention. results the patients were first analysed to assess the effect of therapeutic modality on the outcome of the pregnancies (table 2). among the 7 patients receiving both aspirin and prednisolone (five with acas only and two with both acas and anas), there were six (84%) successful pregnancies. one further aca and ana positive patient, who received cyclophosphamide in addition to aspirin and prednisolone, underwent an abortion. among the 11 table 1 obstetric history of patients stage of losses no. of pregnancies no. of losses no. of live births 7 3 4 1 1 0 2 2 0 3 2 1 3 3 0 4 4 0 3 3 0 2 2 0 6 3 3 3 3 0 10 2 8 3 2 1 t1 3 2 1 8 2 6 5 4 1 3 2 1 4 4 0 t2 6 3 3 2 2 0 7 4 3 t3 3 3 1 8 5 3 6 3 3 t1 &t2 7 5 2 t2 & t3 12 6 6 p r e g n a n c y a n d a n t i c a r d i o l i p i n a n t i b o d i e s patients receiving aspirin alone, all of whom possessed acas only, there were five (45%) successful pregnancies. among the 6 patients receiving no therapy, 5 with acas only and one with acas and anas, there was only one (16%) successful pregnancy. despite the low numbers this suggests that combined aspirin and prednisolone therapy gives better outcome than aspirin alone, and that treatment with either modality is superior to no treatment. indeed, the advantage attained with combined aspirin and prednisolone therapy is significantly better (χ2 =5.82, p<0.05) than with no therapy. the patients were secondly analysed to determine the relation of the aca isotype to the stage of pregnancy disaster. this data is summarized in table 3. it shows that overall, throughout pregnancy, the coincidence of igm and igg acas led to the highest rate of abortions and stillbirths, 78%, compared with 71% and 55% respectively when igm and igg acas were found separately. these differences were significant (χ2 = 3.98, p<0.05) when the presence of igg acas alone is compared with the coincident presence of igg and igm acas. analysis of the effect of aca isotype on the trimester of the pregnancy disaster shows that where igg and igm acas coincided in patients, 78% of the total abortions for that group occurred in the first trimester. where igm acas and igg acas occurred separately in a patient, 30% and 42% of the abortions respectively were in the first trimester. by contrast, where igm and igg acas were found separately in patients, 70% and 47% respectively of all abortions occurred in the second trimester, whereas only 11% of all abortions in the patient group with coincident igg and igm acas occurred in this trimester. disasters in the third trimester of pregnancy were uncommon and occurred in 6% of pregnancies where igg aca occurred alone and in 9% where igm and igg aca were found together. in summary, the presence of igg acas led to a similar frequency of unsuccessful pregnancies in the first and second trimester, the rates being significantly higher than in the third trimester (χ2 = 12.26, p<0.001 and χ2 = 5.02, p<0.001 respectively). where igm acas occurred alone, more abortions occurred in the second than in the first trimester. the sample size was very small (3 patients, 14 pregnancies) and the increase was not significant (χ2 = 3.20, p>0.05). however, where both igg and igm acas coincided, the rate of pregnancy losses was significantly higher in the first trimester than in either the second trimester (χ2 = 16:20, p<0.001) or the third trimester (χ2 = 16:20, p<0.001). discussion acas are associated with recurrent abortion and fetal wastage occurs in more than 90% of untreated patients with antiphospholipid syndrome and in those with autoimmune disease.8 microinfarction of the placenta, the relationship of autoantibodies an outcome of pregnancy a. aca only (n=21) aspirin + prednisolone (n=5) 4 normal deliveries 1 abortion 5 normal deliveries 4 abortions 1 stillbirth at 29 weeks aspirin only (n=11) 1 delivery at 32 weeks with c abnormalities – died 1 normal delivery no therapy 4 abortions b. aca and ana (n=4) aspirin + prednisolone (n=2) 2 normal deliveries aspirin + prednisolone + cyclophosphamide (n=1) 1 abortion no therapy (n=1) 1 abortion table 2 d therapeutic modality to the outcome of pregnancy gestation period / trimester of abortion birthweight 38–40 weeks t1 3.00 – 3.41 kg 36–39 weeks 2.60 – 3.40 kg t1 t1 ongenital t1 40 weeks 3.50 kg t1 37 – 39 weeks 3.20 – 3.45 kg t1 t1 93 a l a b r i e t a l 94 possibly related to interference in prostaglandin metabolism, maybe responsible for the fetal loss, but the role of antiphospholipid antibodies, including acas, is not yet definitely ascertained.9 the antibody involved appears to be the �authentic� antiphospholipid antibody since aca and lac negative patients do not possess antibodies to (β2gpi )6 and animal models of aps in pregnancy can be induced by infusion of acas.10 in this study, we have examined the clinical and serological characteristics of patients specifically selected for the presence of igm and igg acas and multiple fetal losses. the majority were categorized as having the antiphospholipid syndrome, but four of the subjects were also diagnosed with sle and possessing anas. we have investigated the effect of therapeutic intervention on subsequent pregnancies and whether the aca isotype was implicated in the trimester of the fetal loss. previous trials reported successful pharmacological prevention of recurrent fetal loss using heparin,7 prednisolone and heparin11 prednisolone and azathioprine,12 corticosteroids either alone13 or with low-dose aspirin14 and high dose intravenous immunoglobulins.15 the clinical significance of the different aca isopes is still under investigation. igg-acas are generally considered to have broader pathological sequelae.17 the isotypes occur with variable frequency and in individual patients each isotype may occur exclusively or in combination with another isotype. previous studies of fetal losses indicate that the majority have the igg isotype (+/� igm) with a minority having igm alone.17 it has been suggested that where igm aca occurs alone, the only complaint is pregnancy loss.18 we have not been able to confirm this. in this study, we have found that 78% of all abortions occur in the first trimester and in these cases, the igg and igm aca isotype are generally both present. where the igg isotype occurs alone, abortions occur at the same frequency in the first and second trimester, whereas, on the very limited data available, where the igm isotype occurs alone, more abortions occur in the second trimester. conclusion in our study, we used low-dose aspirin, either alone or with prednisolone. the patient numbers were low, but both in patients with the antiphospholipid syndrome and with sle, the highest frequency of successful of pregnancies occurred with the combined therapy. the use of aspirin alone was encouraging and it may be that aspirin is playing the most important role in the prevention of fetal loss. however, a randomised prospective controlled trial is necessary to determine the optimum therapy for pregnancy conservation and prophylaxis.16 further clinical trials should give more precise information about optimal therapeutic protocols for the prevention of fetal loss and the management of patient at risk needs to be standardized. acas are rarely found in healthy populations: one study indicates 22 in 1000.8 hence there is little benefit in the routine screening of healthy pregnant women for the presence of acas. references 1. ascherson ra, harris en. anticardiolipin antibodies�clinical associations. postgraduate med j 1986, 62, 1081�7. 2. buchanan rrc, woodlaw jr, riglar rj, littlejohn go, miller mh. antiphospholipid antibodies in connective tissue diseases: their relation to the antiphospholipid syndrome and forme fruste diseases. j rheumatol 1989, 16, 757�61. 3. fields ra, toubbeh h, searles rp, bankhurst ad. the prevalence of anticardiolipin antibodies in a healthy table 3 the relationship of anticardiolipin isotype to the trimester (t) where abortion occurred igg aca igm aca igg & igm acas no of women 14 3 8 no of pregnancies 85 14 23 no abortions over entire pregnancy (t1t2t3) 47 10 18 % abortion 55 71 78 trimester 1 number of abortions 20 3 14 % t1 abortions/pregnancies 23 21 61 % t1 abortions/t123 abortions 42 30 78 trimester 2 number of abortions 22 7 2 % t2 abortions/pregnancies 26 50 9 % t2 abortions/t123 abortions 42 70 11 trimester 3 number of abortions 5 0 2 % t3 abortions/pregnancies 6 9 % t3 abortions/t123 abortions 11 11 p r e g n a n c y a n d a n t i c a r d i o l i p i n a n t i b o d i e s 95 elderly population and its association with antinuclear antibodies. j rheumatol 1989, 16, 623�5. 4. khamashta ma, hughes grv. antiphospholipid syndrome. bmj 1993, 307, 883�4. 5. forastiero rr, martinuzzo me, kordich lc, carreras lo. reactivity to β2 glycoprotein i clearly differentiates anticardiolipin antibodies from antiphospholipid syndrome and syphilis. thromb haemostat 1996, 75, 717� 20. 6. balasch j, revertor jc, creus m, tassies d, fabreques f, et al. human reproductive failure is not a clinical feature associated with β2 glycoprotein-i antibodies in anticardiolipin and lupus anticoagulant seronegative patients (the antiphospholipid.cofactor syndrome). human reprod 1999, 14, 1956�9. 7. gardlund b. the lupus inhibitor in thromboembolic disease and intrauterine death in the absence of systemic lupus. acta med scand 1984, 215, 293�8. 8. lockwood cj, romero r, feinberg rf, clyne lp, coster b, hobbins jc. the prevalence and significance of lupus anticoagulant and cardiolipin antibodies in a general obstetric population. am j obstet gynecol 1989 161, 369�74. 9. branch dw, dudley dj, murray md. immunoglobulin g fractions from patients with antiphospholipid antibodies cause fetal death in balb/c mice: a model for autoimmune fetal loss. am j obstet gynecol 1990, 163, 210�6. 10. shoenfeld y, sherer y, blank m. antiphospholipid syndrome in pregnancy-animal models and clinical implications. scand j. rheumatol suppl 1999, 107, 33�6. 11. parke a, maier d, hakim c, randolph j, andreoli j. subclinical autoimmune disease and recurrent spontaneous abortion. j rheumatol 1986, 13, 1178�80. 12. lockshin md, druzin ml, goei s, qamar t, magid ms, jovanovic l, et al. antibody to cardiolipin as a predictor of fetal distress in pregnancy patients with systemic lupus erythematosus. n eng j med 1985, 313, 152�6. 13. hedfers e, lindatol g, lindbland s. anticardiolipin antibodies during pregnancy. j rheumatol 1987, 14, 160-1. 14. norberg r. nived o, sturfelt g. anticardiolipin and complement activation: relation to clinical symptoms. j rheumatol 1987, 14, 149�54. 15. carreras co, perez gn, vega hr, casavilla f. lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. lancet 1988, 2, 393�4. 16. granger ka, farquharson rg. obstetric outcome in phospholipid syndrome. lupus 1997, 6, 509�13. 17. lopez lr, santos me, espinosa lr, rosa fgl. clinical significance of immunoglobulin a versus immunoglobulins g and m anticardiolipin antibodies in patients with systemic lupus erythematosus. am j clin path 1992, 98, 449�54. 18. brown hl. antiphospholipid antibodies and recurrent pregnancy loss. clin obstet gynecol 1991, 34, 17�26. outcome of pregnancy in patients possessing �anticardiolipin antibodies method results table 1 table 1 stage of losses t1 discussion table 3 the relationship of anticardiolipin isotype to the �trimester (t) where abortion occurred trimester 1 trimester 2 trimester 3 conclusion references 1department of nursing & midwifery and 2student research committee, torbat heydariyeh university of medical sciences, torbat-e heydariyeh, iran *corresponding author e-mail: azmoudehe@gmail.com املعرفة وفاعلية العناية والتفعيل الذايت املعتمدة علی الدليل لدی القابالت القانونيات يف شرقي إيران الهام اآزم�ده, فر�ضته فرخنده, مرمي اآه�ر, مرمي كابرييان abstract: objectives: the successful implementation of evidence-based practice (ebp) can lead to appropriate and effective midwifery care during pregnancy, childbirth and in the postnatal period. however, levels of knowledge and confidence in one’s ability to apply ebp are related to its effective implementation. this study aimed to investigate levels of knowledge, practice of and self-efficacy towards the use of ebp among midwives in east iran. methods: this cross-sectional study took place between january and february 2016 and involved 98 midwives employed at two hospitals and all four urban health care centres in torbat-e heydariyeh, iran. two subscales of the evidence-based practice questionnaire were used to assess participants’ knowledge and practice of ebp, respectively, while a modified version of a previously described scale was used to determine self-efficacy. results: a total of 76 midwives participated in the study (response rate: 77.6%). mean knowledge, practice and self-efficacy scores were 4.48 ± 0.94, 3.53 ± 0.68 and 2.80 ± 0.81, respectively. significant relationships were found between mean selfefficacy, practice and knowledge scores and proficiency in english language (p = 0.001 each) and statistical methods (p <0.050 each). additionally, significant relationships were found between knowledge and practice of ebp and proficiency in the use of databases (p <0.050 each). knowledge and self-efficacy scores were significantly correlated with practice (p = 0.001 each). conclusion: these findings demonstrate a need for improvement in the self-efficacy, practice and knowledge of ebp among midwives in east iran. interventions that promote these factors may help increase the use of ebp in this population. keywords: evidence-based practice; knowledge; self efficacy; nurse midwives; iran. امللخ�ص: الهدف: اإّن التنفيذ الناجح لعملية العناية املعتمدة على الدليل ي�ؤدي اإىل ت�فري وعر�ص خدمات منا�ضبة للعناية باحل�امل يف فرتات احلمل, وال�الدة, وما بعد ال�الدة. هذا و ت�جد عالقة وثيقة بني م�ضت�ى املعرفة والثقة بالنف�ص لدى القابالت القان�نيات و بني تنفيذ عملية العناية املعتمدة على الدليل. هدف هذا البحث اإىل درا�ضة م�ضت�ى املعرفة, و التفعيل الذاتي يف تنفيذ تلك العملية لدى القابالت القان�نيات يف �رسقّي اإيران. الطريقة: اأجريت هذه الدرا�ضة على 98 قابلة قان�نية يعملن يف م�ضت�ضفيني و جميع املراكز ال�ضحّية يف مدينة تربة حيدرية وذلك خالل الفرتة مابني �ضهر يناير حتى �ضهر فرباير عام 2016 م. مّت حت�ضري ا�ضتمارتني ا�ضتخدمت االأوىل لدرا�ضة و تقييم فاعلية العناية القائمة على الدليل, واالأخرى لدرا�ضة كمية التفعيل الذاتي. النتائج: �ضارکت يف الدرا�ضة 76 قابلة قان�نية )ن�ضبة االإجابات على الرتتيب: 0.94 كاالأتي هي الذاتي والتفعيل والفاعلية, املعريف, من اجلانب كل يف امل�ضرتكات درجات مت��ضطات وكانت .)77.6% ± 4.48, 0.68 ± 3.53 و 0.81 ± 2.80. کان هناك ارتباط ذو داللة اأح�ضائية بني درجات املعرفة, والفاعلية, والتفعيل الذاتي, مع اإتقان اللغة االإجنليزية, و اأ�ضاليب االإح�ضاء على الرتتيب )p >0.050( )p = 0.001(. وجد اأي�ضا ارتباط ذو داللة اأح�ضائية بني م�ضت�ى املعرفة, و الفاعلية بالن�ضبة لتنفيذ عمليات العناية املعتمدة على الدليل واتقان ا�ضتخدام ق�اعد البيانات )p >0.050(. وقد كان هناك اأي�ضا ارتباط ذو داللة اأح�ضائية بني املعرفة والتفعيل الذاتي بالن�ضبة لفاعلية ال�ضخ�ص )p = 0.001(. اخلال�صة: تدّل هذه النتائج على �رسورة حت�ضني التفعيل الذاتي, والفاعلية, واملعرفة بالن�ضبة للعناية القائمة على اأ�ضا�ص الدليل لدى القابالت القان�نيات �رسقّي اإيران. �ضتلعب االآلّيات التي تت�ضبب يف حت�ضني هذه امل�ضت�يات دوراً ملح�ظًا يف ارتفاع م�ضت�ى ت�ظيف العناية القائمة على الدليل. الكلمات املفتاحية: العناية املعتمدة على الدليل؛ املعرفة؛ التفعيل الذاتي؛ القابالت القان�نيات؛ اإيران. knowledge, practice and self-efficacy in evidence-based practice among midwives in east iran *elham azmoude,1 fereshteh farkhondeh,2 maryam ahour,2 maryam kabirian1 clinical & basic research sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e66–73, epub. 30 mar 17 submitted 24 jul 16 revision req. 1 sep 16; revision recd. 24 sep 16 accepted 23 oct 16 doi: 10.18295/squmj.2016.17.01.012 advances in knowledge the findings of this study indicate that midwives in east iran have poor levels of practice and moderate levels of knowledge and selfefficacy regarding evidence-based practice (ebp). significant relationships were observed between ebp knowledge, practice and self-efficacy and proficiency in english, statistical methods and using databases. knowledge and self-efficacy were also significantly correlated with practice. elham azmoude, fereshteh farkhondeh, maryam ahour and maryam kabirian clinical and basic research | e67 application to patient care the implementation of ebp is a vital competency for midwives. the moderate levels of ebp knowledge and self-efficacy and poor levels of practice reported among the iranian midwives in the current study have alarming implications for future patient care. as such, interventions to promote ebp implementation are recommended in this population. pregnancy-related complications are the second global leading cause of death among women of reproductive age.1 in 2015, approximately 303,000 maternal deaths occurred worldwide, most of which could have been prevented; in the same year, 340 women in iran died from pregnancyrelated complications, resulting in a maternal mortality ratio of 25 deaths per 100,000 live births.2 evidence-based practice (ebp) plays an integral role in high-quality healthcare by promoting a problemsolving approach that emphasises implementation of the current best available research within a clinical context, helping healthcare professionals to remain up-to-date and make better healthcare decisions.3–7 the national academy of medicine in the usa recognises ebp as an essential skill for healthcare providers in the 21st century.8 several studies have also indicated that ebp improves the quality and safety of patient care.6,7,9 nevertheless, many healthcare decisions are still based on traditional practices, assumptions, personal experiences and individual opinions and skills.10,11 the possession of adequate knowledge and skills is essential for gathering and appraising evidence and implementing best practices in a clinical setting.4 however, numerous studies have revealed that most healthcare professionals do not have sufficient knowledge and skills for the effective implementation of ebp.4,11–14 in a study analysing perceptions of ebp among nurses, melnyk et al. found that fewer than half of the participants believed that their colleagues consistently used ebp in patient care.5 similarly, zhou et al. indicated that most chinese nurses lacked practice in many ebp-related skills.15 another important variable affecting the implementation of ebp is self-efficacy, which is defined as an individual’s belief in their own ability to execute skills at a designated level of performance.11,16–18 several studies have indicated that the majority of healthcare professionals do not have the desired level of selfefficacy in the implementation of ebp.11,19 to the best of the authors’ knowledge, few studies have focused on the knowledge, practice and selfefficacy of ebp among iranian midwives. as health policies in iran are based on population growth, the role of midwives is becoming more prominent, due to their importance in the pregnancy and childbirth process. this study therefore aimed to determine levels of knowledge, practice and self-efficacy towards ebp in clinical decision-making among midwives working in hospitals and healthcare centres in torbat-e heydariyeh, iran. methods this descriptive cross-sectional study took place from january to february 2016 and included 98 midwives employed at two public hospitals and all four urban health centres in torbat-e heydariyeh. only those midwives with at least six months of work experience at the time of the study were included. midwives who were sick or on maternity leave during this period were excluded from the study. a convenience sampling method was used to recruit the midwives. all midwives in the hospitals and health centres were informed of the study goals and were invited to participate at the beginning of each work shift. a questionnaire was designed to collect information regarding the participants’ sociodemographic and professional characteristics, including age, education level, number of years of work experience, previous participation in ebp courses, proficiency in english, statistical methods and use of databases, participation in conferences or congresses and number of previously published articles in national and international journals. the frequency of use of various print (five items), electronic (eight items) or human (six items) health information sources was scored on a 5-point likert scale, with a score of 1 indicating never and 5 indicating always.11 in order to assess ebp knowledge and practice, the 14-item and 6-item subscales of the evidence-based practice questionnaire were used; items were scored on 7-point likert scales ranging from 1 to 7, indicating poor and best knowledge for knowledge items and never and frequently for practice items, respectively.20 a modified version of a previously described ebp self-efficacy scale was used to determine the participants’ self-efficacy towards implementing ebp.11 these eight items were scored on a 5-point likert scale, with scores of 1 and 5 indicating poor and best efficacy, respectively.11 all of the questionnaire items were translated from the original english into persian, after which two linguists made revisions to ensure the validity of the translations. subsequently, the content and face validity of all questionnaire items was confirmed by knowledge, practice and self-efficacy in evidence-based practice among midwives in east iran e68 | squ medical journal, february 2017, volume 17, issue 1 a group of experts. additionally, cronbach’s alpha values indicated good internal consistency reliability of the knowledge (0.81), self-efficacy (0.88), practice (0.70), print information sources (0.72) electronic information sources (0.88) and human information sources (0.72) questionnaire items. the various questionnaire subscales were compiled into one survey which was distributed individually to each midwife. the researchers then collected the completed surveys from midwives at each hospital and healthcare centre. the entire survey took approximately 15 minutes to complete. data were analysed using the statistical package for the social sciences (spss), version 19.0 (ibm corp., chicago, illinois, usa). means, standard deviations and frequencies were calculated for the descriptive data. to determine relationships between variables, pearson and spearman’s correlation tests were performed. a p value of <0.050 was considered statistically significant. this study was approved by the ethical board committee of torbat heydariyeh university of medical sciences (#ir.thums.rec.1394.2). all of the midwives provided written informed consent before participating in the study. midwives were assured of the confidentiality of the data before recruitment. once analysed, the results of this study were provided to the midwives and officials of the participating health centres and hospitals. results a total of 76 midwives participated in the study (response rate: 77.6%); of these, 42 (55.3%) were employed by hospitals and 34 (44.7%) by health centres. the mean age of the participants was 29.30 ± 4.86 years (range: 22–43 years old). the percentage of midwives with a bachelor’s or master’s qualification was 93.4% and 6.6%, respectively. the mean number of years of work experience was 5.22 ± 4.21 years (range: 6 months–18 years). overall, 44.7% of the midwives had previously taken part in ebp training courses. most of the participants were moderately proficient in english (63.2%) but had low proficiency in statistics (48.7%) [table 1]. mean knowledge, practice and self-efficacy scores were 4.48 ± 0.94, 3.53 ± 0.68 and 2.80 ± 0.81, respectively. mean scores for individual items in the knowledge subscale ranged from 3.78–5.29. determining the validity and usefulness of material were the knowledge items with the lowest mean table 1: sociodemographic and professional characteristics of midwives in torbat-e heydariyeh, iran (n = 76) characteristic n (%) experience in years* <5 39 (51.3) 5–10 27 (35.5) >10 9 (11.8) previous participation in ebp courses yes 34 (44.7) no 42 (55.3) proficiency in english low 25 (32.9) moderate 48 (63.2) high 3 (3.9) proficiency with statistical methods* none 14 (18.4) low 37 (48.7) moderate 22 (28.9) high 2 (2.6) proficiency in database use† none 3 (3.9) low 22 (28.9) moderate 41 (53.9) high 6 (7.9) previous participation in conferences or congresses yes 58 (76.3) no 18 (23.7) number of previously published articles in national journals* 0 66 (86.8) 1–2 3 (3.9) ≥3 6 (7.9) number of previously published articles in international journals 0 73 (96.1) 1 1 (1.3) ≥2 2 (2.6) *due to missing data in the completed questionnaire of one participant, the total cohort for this variable was 75. †due to missing data in the completed questionnaires of four participants, the total cohort for this variable was 72. elham azmoude, fereshteh farkhondeh, maryam ahour and maryam kabirian clinical and basic research | e69 scores (3.78 ± 1.36 and 3.97 ± 1.36, respectively) [table 2]. in the self-efficacy subscale, mean scores ranged from 3.26–3.88, indicating that the midwives had above-average self-efficacy. however, conversion of a clinical problem into a well-formulated clinical question resulted in a lower mean self-efficacy score in comparison to the other items (3.26 ± 0.98) [table 3]. for the practice subscale, mean scores ranged from 3.94–4.97. the most practiced items included sharing information with colleagues (4.97 ± 1.53), integrating evidence with expertise (4.67 ± 1.30) and formulating clear questions (4.43 ± 1.42), whereas critically appraising literature was the least frequently practised item (3.94 ± 1.34) [table 4]. in terms of health information sources, print sources were most frequently employed, closely followed by electronic sources (3.43 ± 0.86 and 3.13 ± 0.97, respectively). among print information resources, textbooks and instructions/handouts produced by the iranian ministry of health (moh) were the most frequently used (3.96 ± 1.15 and 3.92 ± 1.06, respectively). websites identified via an internet browser search engine were the most frequently used electronic source (3.50 ± 1.43), followed by online tutorials provided by professional associations, medical libraries or overseas hospitals (3.36 ± 1.28). finally, the most common human sources of health information were colleagues (3.41 ± 1.27) and physicians (3.32 ± 1.24) [table 5]. a bivariate correlational analysis was performed to determine relationships between ebp knowledge, self-efficacy and practice scores and the demographic and professional characteristics of the midwives. significant relationships were observed between education level and knowledge, self-efficacy and practice (p = 0.001, 0.010 and 0.013, respectively). moreover, significant correlations between know ledge, self-efficacy and practice were observed with table 3: self-efficacy towards evidence-based practice* among midwives in torbat-e heydariyeh, iran (n = 76) questionnaire item mean score ± sd ability to identify clinical problems 3.88 ± 0.92 ability to overcome barriers of evidencebased care 3.47 ± 0.78 ability to convert a clinical problem into a well-formulated clinical question 3.26 ± 0.98 ability to conduct online searches using databases and web search engines 3.55 ± 1.01 ability to relate research findings to clinical practice and point out similarities and differences when reading research articles 3.57 ± 0.91 ability to read research reports and form general notions of strengths and weaknesses 3.57 ± 0.91 ability to apply interventions based on the most applicable evidence 3.44 ± 0.87 ability to evaluate the application of interventions and use this to improve clinical decisions 3.51 ± 0.96 sd = standard deviation. *self-efficacy was self-assessed by participants using a persian version of a previously described evidence-based practice self-efficacy scale.11 responses were scored on a 5-point likert scale, with scores of 1 and 5 indicating poor and best efficacy, respectively. table 4: practice of evidence-based practice* among midwives in torbat-e heydariyeh, iran (n = 76) item mean score ± sd critical appraisal of literature 3.94 ± 1.34 integration of evidence with expertise 4.67 ± 1.30 formulation of clear questions 4.43 ± 1.42 tracking down of relevant evidence 4.39 ± 1.47 evaluation of outcomes of practice 4.36 ± 1.41 sharing of information with colleagues 4.97 ± 1.53 sd = standard deviation. *practice was self-assessed by participants using a persian version of the practice subscale of the evidence-based practice questionnaire.20 responses were scored on a 7-point likert scale, with scores of 1 and 7 indicating never and frequently, respectively. table 2: knowledge of evidence-based practice* among midwives in torbat-e heydariyeh, iran (n = 76) questionnaire item mean score ± sd converting information queries into a question 4.21 ± 1.56 research skills 4.06 ± 1.40 awareness of information types/sources 4.45 ± 1.28 ability to determine the validity of material 3.78 ± 1.36 ability to critically appraise material 4.05 ± 1.29 knowledge of how to retrieve evidence 4.20 ± 1.34 it skills 4.24 ± 1.34 monitoring and reviewing practice skills 4.44 ± 1.39 ability to identify gaps in own practice 4.44 ± 1.33 ability to determine usefulness of material 3.97 ± 1.36 discussion of new ideas with colleagues 5.08 ± 1.14 application of information to individual cases 5.25 ± 1.18 sharing ideas/information with colleagues 5.29 ± 1.20 ability to review own practice 5.26 ± 1.27 sd = standard deviation; it = information technology. *knowledge was self-assessed by participants using a persian version of the knowledge subscale of the evidence-based practice questionnaire.20 responses were scored on a 7-point likert scale, with scores of 1 and 7 indicating poor and best knowledge, respectively. knowledge, practice and self-efficacy in evidence-based practice among midwives in east iran e70 | squ medical journal, february 2017, volume 17, issue 1 proficiency in english (p = 0.001 each) and statistical methods (p = 0.002, 0.016 and 0.015, respectively). similarly, knowledge and practice had statistically significant relationships with proficiency in the use of databases (p = 0.015 and 0.005, respectively). midwives with a higher number of published articles in national journals also had significantly higher self-efficacy scores (p = 0.023). no correlation was noted between previous ebp training and knowledge, self-efficacy or practice. finally, significant relationships were found between mean knowledge scores and self-efficacy and practice (p = 0.001 each) and between mean selfefficacy scores and practice (p = 0.001) [table 6]. discussion overall, different levels of ebp knowledge, practice and self-efficacy have been reported among health professionals.6,11,21,22 these findings may be useful in developing a comprehensive and appropriate strategy for promoting ebp, leading to more effective patient care.23 in the current study, levels of knowledge and self-efficacy among the midwives were slightly higher than average, while their practice scores were below average. previous research has also demonstrated moderate mean knowledge scores among nurses and nursing faculty.5,13,24,25 brown et al. reported that practice scores among nurses were higher than average while farokhzadian et al. previously reported a low mean self-efficacy score among nurses (2.93 ± 1.06).19,24 appropriate interventions should be performed targeting priorities among the items in the three subscales utilised in the current study to increase knowledge and practice of and self-efficacy towards ebp among midwives in east iran. as per the findings of the present study, the ability to determine the validity (i.e. truthfulness) and usefulness (i.e. clinical application) of information should have the highest priority in the knowledge context when planning an intervention. consequently, midwives should be able to identify reliable and applicable information within a large volume of medical research in order to bridge the gap between empirical evidence and clinical practice. participants of the current study demonstrated the least self-efficacy when it came to their ability to convert a clinical problem into a well-formulated question and to apply an intervention based on the most applicable evidence. similarly, mohsen et al. found that most clinical nurse specialists had no confidence in their ability to translate clinical problems into well-formulated questions.26 the ability to apply interventions based on the most applicable evidence was also one of the highest priorities identified in another iranian study.19 in general, ebp should begin with a precise and structured clinical question; it is therefore important that midwives develop the necessary skills to convert informational needs into questions. subsequently, evidence can be applied to a clinical decision.27 in the current study, mean scores for the remaining self-efficacy items were comparable, indicating moderate levels of confidence among the midwives for other aspects of ebp self-efficacy. other studies have reported mean self-efficacy scores of 2.5–3.5 among nurses.11,19 in terms of mean practice scores, results from the current study indicated that the ability to critically table 5: frequency of use of health information sources* among midwives in torbat-e heydariyeh, iran (n = 76) source of information mean score ± sd print 3.43 ± 0.86 textbooks 3.96 ± 1.15 journal articles 3.05 ± 1.27 magazines/newspapers 2.96 ± 1.46 instructions/handouts from the iranian moh 3.92 ± 1.06 other 3.16 ± 1.13 electronic 3.13 ± 0.97 e-books 3.20 ± 1.30 digital medical/nursing libraries 2.81 ± 1.30 medical/nursing databases (e.g. cinahl) 3.11 ± 1.36 websites found via browser search engines 3.50 ± 1.43 online tutorials 3.36 ± 1.28 medical blogs 2.92 ± 1.18 uptodate (wolters kluwer health, alphen aan den rijn, netherlands) and clinicalkey (elsevier, amsterdam, netherlands) databases 2.92 ± 1.24 other 2.97 ± 1.37 human 3.01 ± 1.05 colleagues 3.41 ± 1.27 supervisors 2.82 ± 1.36 research groups within an organisation 2.72 ± 1.32 physicians 3.32 ± 1.24 professional friends working in other hospitals/clinics 2.98 ± 1.24 other 2.92 ± 1.31 sd = standard deviation; moh = ministry of health; cinahl = cumulative index to nursing and allied health literature. *frequency of use of health information sources was self-assessed by participants using a persian version of a previously described questionnaire.11 responses were scored on a 5-point likert scale, with scores of 1 and 5 indicating never and always, respectively. elham azmoude, fereshteh farkhondeh, maryam ahour and maryam kabirian clinical and basic research | e71 appraise literature, evaluate outcomes of practice and track down relevant evidence were the most important priorities for an ebp intervention among midwives in east iran. these findings are consistent with those of shafiei et al. and brown et al.24,25 therefore, educational interventions would be useful to familiarise midwives with the entire ebp process, from formulating answerable questions to finding recent and relevant material, critically evaluating evidence and applying that evidence in practice. in the current study, midwives with a higher level of education had significantly greater knowledge, self-efficacy and practice of ebp. this may be because midwives with more advanced academic degrees had more knowledge and experience in practicing ebp and were therefore more likely to be confident in their ebp skills. farokhzadian et al. observed no significant relationship between self-efficacy and academic degree in another study of iranian nurses; in contrast, weng et al. also reported that healthcare professionals with more advanced academic degrees more frequently implemented ebp.12,19 similarly, several studies have confirmed the positive effects of higher education levels on patient outcomes through the implementation of ebp.26,28–30 in the present study, midwives who were older and had more work experience were not significantly more likely to have greater ebp knowledge, self-efficacy or practice. this finding was supported by a previous study which found no relationships between age or clinical experience with ebp knowledge among nurses.13 however, both majid et al. and ferguson et al. have suggested that new nurses have limited practical knowledge and experience and are less confident in the implementation of ebp.11,31 nearly half of the participants in the current study reported previously taking part in ebp training courses; however, relationships between this variable and ebp knowledge, practice or self-efficacy were not significant, which is inconsistent with previous findings from iran and singapore.11,19 significant relationships were noted in the present study between proficiency in english language and the use of databases with ebp knowledge, self-efficacy and practice. previous studies have considered lack of familiarity with english to be a barrier to ebp implementation among non-english speakers.12,32,33 this may be because the majority of up-to-date medical resources are in english. unfortunately, table 6: correlations between demographic and professional characteristics and evidence-based practice knowledge, self-efficacy and practice scores* among midwives in torbat-e heydariyeh, iran (n = 76) variable knowledge self-efficacy practice r p r p r p age 0.086 0.468 0.130 0.297 0.246 0.036‡ education level 0.369 0.001‡ 0.314 0.010‡ 0.289 0.013‡ work experience 0.082 0.489 0.151 0.228 0.170 0.150 previous ebp training 0.142 0.224 -0.070 0.572 0.191 0.102 proficiency in english 0.419 0.001‡ 0.423 0.001‡ 0.410 0.001‡ proficiency in statistics 0.354 0.002‡ 0.294 0.016‡ 0.285 0.015‡ proficiency in the use of databases 0.288 0.015‡ 0.215 0.088 0.329 0.005‡ previous participation in conferences/congresses 0.153 0.190 0.103 0.408 0.140 0.233 number of published articles in national journals 0.113 0.339 0.280 0.023‡ 0.056 0.638 number of published articles in international journals 0.191 0.100 0.203 0.100 0.088 0.458 print information sources† 0.384 0.008 ‡ 0.464 0.002‡ 0.386 0.009‡ electronic information sources† 0.274 0.066 0.261 0.099 0.265 0.075 human information sources† -0.077 0.593 0.160 0.292 -0.080 0.586 knowledge score 0.625 0.001‡ 0.739 0.001‡ self-efficacy score 0.638 0.001‡ ebp = evidence-based practice. *knowledge and practice were self-assessed by participants using persian versions of the knowledge and practice subscales of the evidence-based practice questionnaire while self-efficacy was self-assessed by participants using a persian version of a previously described ebp self-efficacy scale.11,20 †frequency of use of health information sources was self-assessed by participants using a persian version of a previously described questionnaire.11 ‡significant at p <0.050. knowledge, practice and self-efficacy in evidence-based practice among midwives in east iran e72 | squ medical journal, february 2017, volume 17, issue 1 most midwives in the current study had a low under standing of statistical methods; this is important as significant relationships were identified between proficiency in statistics and ebp knowledge, selfefficacy and practice. numerous ebp studies have reported that an inadequate understanding of statistical terms and difficulties in understanding statistical analysis are two of the most notable barriers to adopting ebp.11,24,34,35 therefore, welldesigned education and training courses focusing on familiarity with the english language, database searching skills and statistical methods are potential approaches to increasing knowledge and facilitating the implementation of ebp among iranian midwives. according to farokhzadian et al., iranian nurses use more human and print resources than electronic resources to gain information.36 similarly, more than half of the nurses in a study by yoder et al. utilised physicians or nursing peers as their primary information sources.37 print materials were the most frequently used source of health information in the current study, in particular textbooks and instructions/handouts from the iranian moh. due to the structure, peer review process and legal aspects associated with the publication of these resources, their use in clinical decision-making is justifiable. a significant relationship was observed between use of print resources and ebp knowledge, self-efficacy and practice; this may be due to the continuous updating of printed medical resources. electronic sources were the second most commonly used source of health information, particularly online tutorials and websites identified via an internet browser search engine; however, no significant relationships were found between this factor and ebp knowledge, self-efficacy or practice. this may be because browser search engines do not solely provide results from evidencedbased websites. use of medical e-books and medicinespecific databases was infrequent among midwives in the current study; this may be due to limited internet access and access to valid databases at home. midwives in the current study least frequently utilised people as a source of health information; among those who did, colleagues and physicians were the most common information sources. as with electronic sources, no significant relationships were identified between frequency of use of human information sources and ebp knowledge, self-efficacy and practice. in the present study, significant associations were observed between knowledge of and self-efficacy towards ebp, both of which were associated with practice. recent quantitative studies have demonstrated that interventions to promote knowledge can improve ebp implementation.24,25 adequate training may therefore be helpful in increasing confidence and engagement in ebp among iranian midwives; additionally, the findings of the present study may aid hospital managers and policy-makers in the development of strategies to promote ebp in this population. employing midwives with more advanced academic degrees, providing advanced education programmes—including statistics training—and holding journal clubs to improve midwives’ confidence in appraising medical literature are potential strategies to encourage ebp implementation in east iran. the results of the present study are subject to certain limitations. first, the findings were based on responses to self-administered questionnaire items and may therefore be inaccurate or biased; data collection using interviews and focus groups might have generated more objective results. second, since the study was cross-sectional, a causal relationship could not be established. as a result, interventional studies are recommended to confirm these findings. in addition, there is a need for further research to investigate other variables affecting the use of ebp among iranian midwives. conclusion the findings of the current study indicate that there is a need to improve ebp knowledge, self-efficacy and practice among iranian midwives. in addition, there was significantly greater knowledge, practice and self-efficacy in ebp among participants with more advanced academic degrees, those with increased proficiency in english, statistics and the use of databases and among midwives who more frequently used print sources of health information. consequently, interventions and training that support these factors may help to increase the use of ebp among midwives in east iran. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the torbat-e heydariyeh university of medical sciences (grant number #132). references 1. world health organization. women’s health. from: www.who. int/mediacentre/factsheets/fs334/en/ accessed: sep 2016. 2. world health organization. trends in maternal mortality: 1990 to 2015. from: www.who.int/reproductivehealth/publications/ monitoring/maternal-mortality-2015/en/ accessed: sep 2016. elham azmoude, fereshteh farkhondeh, maryam ahour and maryam kabirian clinical and basic research | e73 3. hughes rg, ed. patient safety and quality: an evidence based handbook for nurses. from: https://archive.ahrq. gov/professionals/clinicians-providers/resources/nursing/ resources/nurseshdbk/nurseshdbk.pdf accessed: sep 2016. 4. ashktorab t, pashaeypoor sh, rassouli m, alavi-majd a. nursing students’ competencies in evidence-based practice and its related factors. nurs midwifery stud 2015; 4:e23047. doi: 10.17795/nmsjournal23047. 5. melnyk bm, fineout-overholt e, gallagher-ford l, kaplan l. the state of evidence-based practice in us nurses: critical implications for nurse leaders and educators. j nurs adm 2012; 42:410–17. doi: 10.1097/nna.0b013e3182664e0a. 6. stichler jf, fields w, kim sc, brown ce. faculty knowledge, attitudes, and perceived barriers to teaching evidencebased nursing. j prof nurs 2011; 27:92–100. doi: 10.1016/j. profnurs.2010.09.012. 7. decleene huber ke, nichols a, bowman k, hershberger j, marquis j, murphy t, et al. the correlation between confidence and knowledge of evidence-based practice among occupational therapy students. open j occup ther 2015; 3:5. doi: 10.15453/2168-6408.1142. 8. greiner ac, knebel e, eds. health professions education: a bridge to quality, 1st ed. washington dc, usa: national academies press, 2003. p. 153. 9. bahammam ma, linjawi ai. knowledge, attitude, and barriers towards the use of evidence based practice among senior dental and medical students in western saudi arabia. saudi med j 2014; 35:1250–6. 10. kermanshahi s, parvinian am. barriers to implementation of evidence-based care: viewpoints of nursing staff. iran j med educ 2012; 12:84–92. 11. majid s, foo s, luyt b, zhang x, theng yl, chang yk, et al. adopting evidence-based practice in clinical decision making: nurses’ perceptions, knowledge, and barriers. j med libr assoc 2011; 99:229–36. doi: 10.3163/1536-5050.99.3.010. 12. weng yh, kuo kn, yang cy, lo hl, chen c, chiu yw. implementation of evidence-based practice across medical, nursing, pharmacological and allied healthcare professionals: a questionnaire survey in nationwide hospital settings. implement sci 2013; 8:112. doi: 10.1186/1748-5908-8-112. 13. mehrdad n, joolaee s, joulaee a, bahrani n. nursing faculties’ knowledge and attitude on evidence-based practice. iran j nurs midwifery res 2012; 17:506–11. 14. stokke k, olsen nr, espehaug b, nortvedt mw. evidence based practice beliefs and implementation among nurses: a cross-sectional study. bmc nurs 2014; 13:8. doi: 10.1186/14726955-13-8. 15. zhou f, hao y, guo h, liu h. attitude, knowledge, and practice on evidence-based nursing among registered nurses in traditional chinese medicine hospitals: a multiple center cross-sectional survey in china. evid based complement alternat med 2016; 2016:5478086. doi: 10.1155/2016/5478086. 16. karp s. the effects of maternal psychological factors on maternal competence for infant feeding. thesis, 2008, vanderbilt university, nashville, tennessee, usa. 17. adib-hajbaghery m. factors facilitating and inhibiting evidence-based nursing in iran. j adv nurs 2007; 58:566–75. doi: 10.1111/j.1365-2648.2007.04253.x. 18. koehn ml, lehman k. nurses’ perceptions of evidence-based nursing practice. j adv nurs 2008; 62:209–15. doi: 10.11 11/j.1365-2648.2007.04589.x. 19. farokhzadian j, khajouei r, ahmadian l. evaluating factors associated with implementing evidence-based practice in nursing. j eval clin pract 2015; 21:1107–13. doi: 10.1111/jep. 12480. 20. upton d, upton p. development of an evidence-based practice questionnaire for nurses. j adv nurs 2006; 53:454–8. doi: 10.1111/j.1365-2648.2006.03739.x. 21. martis r, ho jj, crowther ca; sea-orchid study group. survey of knowledge and perception on the access to evidencebased practice and clinical practice change among maternal and infant health practitioners in south east asia. bmc pregnancy childbirth 2008; 8:34. doi: 10.1186/1471-2393-8-34. 22. heiwe s, kajermo kn, tyni-lenné r, guidetti s, samuelsson m, andersson il, et al. evidence-based practice: attitudes, knowledge and behaviour among allied health care professionals. int j qual health care 2011; 23:198–209. doi: 10.1093/ intqhc/mzq083. 23. enkin m, keirse mj, neilson j, crowther c, duley l, hodnett e, et al. a guide to effective care in pregnancy and childbirth, 3rd ed. oxford, uk: oxford university press, 2000. p. 218. 24. brown ce, wickline ma, ecoff l, glaser d. nursing practice, knowledge, attitudes and perceived barriers to evidence-based practice at an academic medical center. j adv nurs 2009; 65:371–81. doi: 10.1111/j.1365-2648.2008.04878.x. 25. shafiei e, baratimarnani a, goharinezhad s, kalhor r, azmal m. nurses’ perceptions of evidence-based practice: a quantitative study at a teaching hospital in iran. med j islam repub iran 2014; 28:135. 26. mohsen mm, safaan na, okby om. nurses’ perceptions and barriers for adoption of evidence based practice in primary care: bridging the gap. am j nurs res 2016; 4:25–33. doi: 10.12691/ajnr-4-2-1. 27. akobeng ak. principles of evidence based medicine. arch dis child 2005; 90:837–40. doi: 10.1136/adc.2005.071761. 28. brown ce, kim sc, stichler jf, fields w. predictors of knowledge, attitudes, use and future use of evidence-based practice among baccalaureate nursing students at two universities. nurse educ today 2010; 30:521–7. doi: 10.1016/j. nedt.2009.10.021. 29. eberhart a. quality improvement needs assessment for evidence-based-practice readiness in primary care. thesis, 2014, ohio state university, columbus, ohio, usa. 30. eizenberg mm. implementation of evidence-based nursing practice: nurses’ personal and professional factors? j adv nurs 2011; 67:33–42. doi: 10.1111/j.1365-2648.2010.05488.x. 31. ferguson lm, day ra. challenges for new nurses in evidence-based practice. j nurs manag 2007; 15:107–13. doi: 10.1111/j.1365-2934.2006.00638.x. 32. khammarnia m, haj mohammadi m, amani z, rezaeian s, setoodehzadeh f. barriers to implementation of evidence based practice in zahedan teaching hospitals, iran, 2014. nurs res pract 2015; 2015:357140. doi: 10.1155/2015/357140. 33. chiu yw, weng yh, lo hl, shih yh, hsu cc, kuo kn. comparison of accessing online databases between physicians and nurses in taiwan. inform health soc care 2012; 37:230–41. doi: 10.3109/17538157.2012.654842. 34. hutchinson am, johnston l. bridging the divide: a survey of nurses’ opinions regarding barriers to, and facilitators of, research utilization in the practice setting. j clin nurs 2004; 13:304–15. doi: 10.1046/j.1365-2702.2003.00865.x. 35. o’connor s, pettigrew cm. the barriers perceived to prevent the successful implementation of evidence-based practice by speech and language therapists. int j lang commun disord 2009; 44:1018–35. doi: 10.1080/13682820802585967. 36. farokhzadian j, khajouei r, ahmadian l. information seeking and retrieval skills of nurses: nurses’ readiness for evidence based practice in hospitals of a medical university in iran. int j med inform 2015; 84:570–7. doi: 10.1016/j. ijmedinf.2015.03.008. 37. yoder lh, kirkley d, mcfall dc, kirksey km, stalbaum al, sellers d. staff nurses use of research to facilitate evidencebased practice. am j nurs 2014; 114:26–37. doi: 10.1097/01. naj.0000453753.00894.29. https://doi.org/10.17795/nmsjournal23047 https://doi.org/10.1097/nna.0b013e3182664e0a https://doi.org/10.1016/j.profnurs.2010.09.012 https://doi.org/10.1016/j.profnurs.2010.09.012 https://doi.org/10.15453/2168-6408.1142 https://doi.org/10.3163/1536-5050.99.3.010 https://doi.org/10.1186/1748-5908-8-112 https://doi.org/10.1186/1472-6955-13-8 https://doi.org/10.1186/1472-6955-13-8 https://doi.org/10.1155/2016/5478086 https://doi.org/10.1111/j.1365-2648.2007.04253.x https://doi.org/10.1111/j.1365-2648.2007.04589.x https://doi.org/10.1111/j.1365-2648.2007.04589.x https://doi.org/10.1111/jep.12480 https://doi.org/10.1111/jep.12480 https://doi.org/10.1111/j.1365-2648.2006.03739.x https://doi.org/10.1186/1471-2393-8-34 https://doi.org/10.1093/intqhc/mzq083 https://doi.org/10.1093/intqhc/mzq083 https://doi.org/10.1111/j.1365-2648.2008.04878.x https://doi.org/10.12691/ajnr-4-2-1 https://doi.org/10.1136/adc.2005.071761 https://doi.org/10.1016/j.nedt.2009.10.021 https://doi.org/10.1016/j.nedt.2009.10.021 https://doi.org/10.1111/j.1365-2648.2010.05488.x https://doi.org/10.1111/j.1365-2934.2006.00638.x https://doi.org/10.1155/2015/357140 https://doi.org/10.3109/17538157.2012.654842 https://doi.org/10.1046/j.1365-2702.2003.00865.x https://doi.org/10.1080/13682820802585967 https://doi.org/10.1016/j.ijmedinf.2015.03.008 https://doi.org/10.1016/j.ijmedinf.2015.03.008 https://doi.org/10.1097/01.naj.0000453753.00894.29 https://doi.org/10.1097/01.naj.0000453753.00894.29 sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 26-31, epub. 27th feb 13 submitted 11th dec 11 revision req. 10th apr 12, revision recd. 26th aug 12 accepted 6th oct 12 abortion remains one of the most hotly debated social and moral issues today. both the pro-life and pro-choice groups present powerful arguments for and against abortion. the pro-life group emphasises the argument of preserving human life from conception at any cost, to the point of giving absolute priority to the life of the unborn fetus over the life of the mother. the pro-choice group emphasises the argument that a woman should have the right to control her body to the point of absolutising her right over the natural phenomenon of the development of a new being. according to peter singer, the issue of abortion is currently one of the most bitterly disputed of all ethical issues. the debate has been long-running, and neither side has had much success in altering the opinions of its opponents.1 this paper explores how the advent of parental screening and genetic testing have shifted the focus of the abortion debate from a woman’s reproductive freedom and her autonomous right to choose, to the concept of human dignity, personhood, and the fetus’s right to life. philosophical arguments on abortion from the western perspective some of the philosophers on the abortion debate propose the following syllogism. first premise: it is wrong to take the life of an innocent human being intentionally. second premise: the unborn is an innocent human being. conclusion: it is wrong to take the life of the unborn human being intentionally. national committee for bioethics, oman and department of microbiology & immunology, sultan qaboos university hospital, muscat, oman e-mail: khitamy@yahoo.com تباعد اآلراء حول اإلجهاض وفرتة نفخ الروح اأحمد بدوي امللخ�ض:امراأة م�صلمة حامل يف الأ�صبوع 16 مت اإعالمها باأن فح�ض املوجات فوق ال�صوتية للجنني بنّي وجود ال�صننة امل�صقوقة، والنتائج املخربية اأكدت هذا الت�صخي�ض. واأن الطفل �صيعاين من عدة م�صاعفات ويف الأغلب �صيحتاج لعناية طبية مدى احلياة. مبوافقة الزوج مت اإقرار اإنهاء احلمل. هذا القرار اأثار جدًل بني علماء الدين يف املجتمع، �رسارة اجلدل كانت بني من هم موافقني على الإجها�ض لأ�صباب طبية وبني معار�صني له لأي �صبب. هذه الورقة تقدم عر�ض حلجج وبراهني فل�صفية وطبية عن املعار�صني لالإجها�ض واملنا�رسين له وكذلك نظرة الإ�صالم جتاه ا�صتقالل املراأة على جهازها التنا�صلي، حرمة اجلنني، الإجها�ض العالجي و وقت نفخ الروح. مفتاح الكلمات: معار�صة الإجها�ض، حق احلياة، ال�صتقالل، قد�صية احلياة، اجلنني، امل�صغة، عالقة العقل-اجل�صم، ما وراء الطبيعة، عمان. abstract: a muslim woman in her sixteenth week of pregnancy was informed that her ultrasound scan showed spina bifida, and laboratory results confirmed the diagnosis. the child would have various complications and, most probably, would need medical care for life. with the consent of her husband she decided to terminate the pregnancy. her decision sparked controversy among muslim clerics in her community, sparking debate between those who would allow abortion for medical reasons and those who oppose abortion for any reason. this paper will review the philosophical and theological arguments of the pro-life and pro-choice groups as well as the islamic perspective concerning a woman’s autonomy over her reproductive system, the sanctity of the fetus and the embryo, therapeutic abortion, and ensoulment. keywords: anti-abortion; right to life; autonomy; sanctity of life; fetus; embryo; mind-body relations, metaphysical; oman. special contribution divergent views on abortion and the period of ensoulment badawy a. b. khitamy badawy a. b. khitamy special contribution | 27 thomson’s paper, a defense of abortion, has stirred reactions and criticisms from many different philosophers and bioethicists from both sides of the abortion debate. john finnis and patrice lee are among a number of philosophers who rebutted thomson’s thought experiment as flawed and her hypothetical cases justifying abortion as lacking parallelism to abortion.5,6 first, her opponents argued that the principle of respect of autonomy in the case of a pregnant woman intending to terminate her pregnancy for no medical reasons is in conflict with the principles of justice and non-maleficence. according to the principle of justice, the fetus is denied the right to life. it has the same fundamental right as that of a human being after birth. the principle of respect of autonomy also contradicts the principle of non-maleficence by harming the fetus. hence, in this case, the principles of justice and non-maleficence take precedence over the principle of respect of autonomy. second, they argued that the hypothetical case of a violinist in justifying abortion is not truly analogous to most situations in which a woman finds herself pregnant. this is, at best, analogous to cases of rape only. therefore, thomson’s hypothetical case of a woman who woke up in the morning to find herself connected to the violinist through no fault of hers and without her consent fits with a rape case, but not with induced abortion for social non-medical reasons. on the other hand, thomson’s proponents praised her imaginative examples and controversial conclusions in defense of induced abortion. they concede that her thought experiments and arguments in support of abortion have made her paper the most widely reprinted essay in all of contemporary philosophy.7 peter singer, a controversial, secular, philosopher of preference utilitarianism, argues that any debate about abortion should be based on a utilitarian calculation which weighs the preferences of a woman against the preferences of the fetus.8 he argues that a fetus, at least up to around eighteen weeks, has no capacity to suffer or feel satisfaction; hence, it is not possible for such a fetus to hold any preferences at all. based on this premise of a utilitarian calculation, there is nothing to weigh against a woman's preference to have an abortion. singer concludes that abortion is morally permissible. don marquis and philippa foot are amongst the philosophers who argue that abortion, except in rare cases, is seriously immoral.2,3 first, they consider the fetus as a potential moral person who has the right to life like anyone else, and is entitled to protection against homicide. they argue that a fetus’ right to life outweighs the mother’s right to decide to terminate the pregnancy. second, the fetus and the mother are not the only persons involved in the abortion conflict. there is also the father who has contributed as much genetically to its existence as the mother. then there are the family members and the community who have substantial influence and bearing on the question of the moral permissibility of abortion. most western critics for or against abortion disregard the importance and the supremacy of society and the extended family which, in some communities, can be more important than that of an individual. if the principle of utilitarianism is applied, where the moral worth of an action is determined solely by its usefulness in maximising utility and minimising negative utility, then abortion will not be warranted except in rare cases of serious congenital abnormalities or when carrying the pregnancy to term would endanger the life of the mother. the abortion-rights campaigners take a liberal stand. they argue that the mother has the right to decide what will happen to her body. she has the right to control the use of her body. this is an expression of her autonomy, and she is at liberty either to bear the pregnancy to term if she chooses, or to have it aborted. these arguments have been supported by judith thomson who argues that a fetus is not yet a person and, even if the fetus were to be considered a person, it does not necessarily deprive a woman of her right to abortion.4 she presented a number of thought experiments to argue her case. one of these is the implausible yet thought-provoking story of a world famous violinist with a fatal kidney ailment who has been attached, without her consent and for a term of nine months, to a kidnapped woman, as the woman happened to be the only one with the blood type that could save the life of the violinist. thomson asks if it would be incumbent upon the woman to stay in bed with the violinist for nine months in order to save him, likening this to a woman’s situation during pregnancy. divergent views on abortion and the period of ensoulment 28 | squ medical journal, february 2013, volume 13, issue 1 person with rights. the argument of don marquis, a noted american philosopher, hinges on the premise of the ‘future-of-value’ as crucial for the right of the fetus not to be killed. marquis argues that the immorality of killing children and adults is that killing them will deprive them of their futureof-value, which includes all things that are good in life that they would have experienced had they not been killed.10 the same premise holds for the fetus, which has enough future-of-value to deserve not to be killed. patrick lee, arguing from the premise of aristotelian metaphysics of substances and essences, contends that the right to life is an essential property of a human being, and this intrinsically valuable property begins at conception. fetuses and adult humans are in different phases of an identical substance.6 he argues that the development phases from zygote to adult human being are only quantitative, and not a change of substance. the moral status of the fetus is a consequence of its essential property or properties. it is wrong to kill an unborn human being because she or he is identical to an entity which it would be wrong to kill at some time later in her or his development. philosophers like singer, mary anne warren, thomson, and many others consider the argument of ‘potentiality’ to be invalid and weak.4,8,11 they argue that if the fetus has the potential to become a person, then it is not yet a person and we need not treat it like one. an acorn has the potential to become a large oak tree, but acorns are not oak trees. as the australian philosopher stanley benn puts it, “a potential president of the united states is not on that account commander-in-chief of the u.s. army and navy”.12 the argument that the fetus has the right to life is a reality in life. first, in islam as well as in the world’s communities and governments, people recognise that infants have human rights that must be respected. in fact, the infants’ rights are held in trust until such a time that they are capable of exercising them themselves. second, there is already legal precedent for the recognition of personhood in those who yet have to develop the ability to perform personal acts. eric t. olson, an american philosopher who specialises in metaphysics and philosophy of the mind, argues that personhood begins at the moment that an ovum is fertilised by the sperm in the uterus to form a zygote, leading a n t e n ata l s c r e e n i n g a n d a b o r t i o n d u e t o f e ta l a b n o r m a l i t i e s the advent of prenatal screening and genetic testing has made it possible to predict the risk of genetic diseases or disabilities in the developing fetus. these technological advances have created an ethical and theological dilemma for a number of women who initially, willingly, and excitedly decided to become pregnant. they then later on decided to terminate their late-stage pregnancies after detecting unforeseen fatal anomalies during a routine antenatal screening. these women argue that it is their autonomous right to bear a healthy child instead of a deformed child. they are the ones who will carry the burden of raising a handicapped child if they decide not to abort. hence, the focus of the abortion debate now shifts from a woman’s reproductive freedom and her autonomous right to choose, to the concept of human dignity, personhood, and the right to life. t h e c o n c e p t o f h u m a n d i g n i t y daryl pullman, a prominent canadian professor of medical ethics, examines female infanticide (which has become an increasingly common practice in obstetric centres globally) in light of the concept of human dignity.9 he argues that human beings have an innate and inviolable basic dignity which must be respected and protected. he argues that people have rights because they have dignity. any human being and even other non-persons/non-agents, including human gametes, embryos, fetuses, and those who are in a state of severe, advanced dementia enjoy a prima facie claim of moral consideration simply by virtue of their biological connection to the rest of the human species. pullman argues that with this concept of human dignity, the fetus should enjoy this same legal protection as a newborn baby or adult human being and that infanticide is morally impermissible. p o t e n t i a l p e r s o n h o o d a n d t h e r i g h t t o l i f e one of the most famous and most derided arguments against the morality of abortion is the argument which says that the fetus has the potential to become a person. this argument maintains that abortion is morally wrong as it is wrong to kill the fetus. if left alone, it has the potential to become a badawy a. b. khitamy special contribution | 29 illegal. s a n c t i t y o f t h e f e t u s a n d t h e e m b r y o fetal rights in islam start from the moment of conception. if the pregnant mother is attacked and the fetus is injured or aborted, then the assailant will have to pay al ghurrah, or full diya (blood money) depending upon the age of the fetus. the al ghurrah blood money is levied as a compensation for destroying the fetus in the womb before ensoulment. the value of al ghurrah is 1/10th of the full diya blood money of homicide. once the spirit is breathed in after 120 days, the fetus acquires perception and volition, (i.e. becomes a person), and is entitled to the same rights as a living being. in another scenario, a pregnant woman commits homicide, and the court has ruled for the death penalty. the court order cannot be executed until after she gives birth and provisions have been made for the newborn baby to be suckled by a wet nurse. in a third scenario where the pregnant mother dies and there are indications that the fetus is alive in the womb, then it is mandatory according to the shafi’i school to dissect the woman to remove the fetus. with modern technology, this dissection would be in the form of a caesarean operation, and would uphold the fetus’s right to life. further, the fetus has also full rights of inheritance. if the husband dies while his wife is pregnant, the disposal of his estate cannot be inherited by testators until the pregnancy is brought to term and the baby’s share is allocated. this demonstrates the sharia’s consideration for the fetus’s right of inheritance. finally, in the case of miscarriage or abortion, the fetus is given full burial rights including prayers for the dead. but if the fetus is less than 4 months old, it is granted all the burial rights of the dead person, except that prayers for the dead are not offered. t h e r a p e u t i c a b o r t i o n many jurists, including the muslim world league fiqh council, allow abortion prior to 120 days of pregnancy if the fetus is grossly malformed, the ailment cannot be treated, and both parents have agreed to the procedure.16,17 abortion after ensoulment is strictly forbidden by all authorities, but the vast majority do make an exception to preserve the mother's life. if a choice has to be made to save either the fetus or the mother, but not both, to the formation of a blastocyst. olson holds that the continuous existence of a human biological organism from the blastocyst stage is necessary and sufficient for personhood.13 philosophical arguments on abortion from the islamic perspective the case of the muslim woman who terminated her pregnancy raises four issues: 1) a woman’s autonomy over her reproductive system in islam; 2) the sanctity of the fetus and the embryo; 3) therapeutic abortion; 4) the ensoulment period. t h e i s s u e o f w o m e n’s a u t o n o m y o v e r h e r r e p r o d u c t i v e s y s t e m islam holds high the principal of respect of autonomy. the rule of autonomy entails a competent major who can decide for him/herself what is best for him/her. if an adult competent patient has no desire to eat, it is improper to provide him/her with food. the prophet said, “do not force your sick to eat or drink”.14 abu-bakr siddiq, the first caliph of islam, and muadh ibn jabal were among the eminent companions of the prophet who exercised their principle of respect of autonomy by refusing therapy at their last illness as they felt it would be futile to receive treatment. an adult patient is free to choose loyalties or a system of religious belief. the qur’an is explicit in this issue: “no compulsion in religion. truth stands out clear from error”.15 it is clear that an ailing person who is mentally competent should have full control over consent to his/her medical treatment. however, the concept that individuals have unlimited autonomy with respect to their reproductive systems, as long as they do not breach the autonomy of others, is unacceptable in islam. in the case of abortion for social reasons, islamic sharia gives priority to the principle of justice over the principle of autonomy. the fetus and the embryo have the right to life and the same fundamental right as that of a human being after birth. the principle of respect of autonomy in this case also contradicts the principle of non-maleficence by harming the fetus. hence, in the scenario of the abortion for other than medical reasons case, the principles of justice and nonmaleficence take precedence over the principle of respect of autonomy, and abortion is considered divergent views on abortion and the period of ensoulment 30 | squ medical journal, february 2013, volume 13, issue 1 perception and volition i.e. becomes a person”.27 therefore, abortion with no medical reasons is a crime in islam, and “the degree of crime”, affirmed imam ghazali, “increases from phase to phase. the first stage is when the sperm in the uterus mixes with the woman’s fluid (ova) and becomes ready to receive life. destroying it (i.e. the zygote) is a crime. the crime becomes more serious when aborting the alaqa or mudh’gha (clot).3,4 the degree of crime becomes even more serious when aborting the fetus after ensoulment or before its birth (as it is considered homicide)”.28 conclusion a moral answer concerning the abortion issue is not simple. a response to the abortion issue should be a dynamic and rich dialogue between different classes of our society, one in which political terms are avoided. it has become a chronic tendency for proponents and opponents of abortion to show their own philosophical arguments in the best possible light, while at the same time describing their opponents in the worst possible light. for example, those who oppose abortion would refer to those who hold the alternative view as pro-death and call themselves pro-life, while those who support abortion say their opponents are anti-choice and refer to themselves as pro-choice. secondly, most of the philosophers and ethicists on both sides of the debate fail to acknowledge that the abortion debate is of religious or philosophical nature. our ideas about life, ensoulment, personhood, and the value of the human being are shaped by various religious and philosophical influences. it is unfortunate to see some secular humanists viewing religions as superstitions, repressive, or close-minded. in conclusion, there is bad news and good news as far as the abortion debate is concerned. the bad news is that the controversies and conflicts are far from over. however, the good news is that, irrespective of all hurdles, as affirmed by peter singer, both sides can reach a level of understanding and respect of one another’s opinions if both sides—both pro-life and pro-choice—show good will and work together for a common good and take a rational and moral stand, avoiding labels and rhetoric. then the mother's life would take precedence. she is seen as the root and the fetus as an offshoot.18 in the case of rape, a number of jurists would also allow abortion during the first 40 days computed from fertilisation.19,20 t h e e n s o u l m e n t p e r i o d ensoulment refers to the moment the human being gains a soul. the teachings of judaism, christianity, and islam affirm that what makes one a person with full moral rights is the possession of the soul, and they apply the moment of ensoulment as the cut-off point in determining legislation on abortion. there are two theories regarding the period of ensoulment: immediate or delayed ensoulment. according to the immmediate ensoulment theory, the soul begins to exist at conception, when the sperm fuses with the ovum. professor jones produced a wealth of historical scholarship to prove that the belief in delayed ensoulment among mediaeval western christians was founded on mistranslation of scriptures and on an outmoded embryology.21 the delayed ensoulment theory dates back to the time of aristotle, who argued that ensoulment for males is 40 days and 90 days for females.22 thomas aquinas was among the christian philosophers who affirmed delayed ensoulment.21 the view of allowing abortion prior to the ensoulment period was practised in the usa in the 19th century, when abortion was generally regarded as morally acceptable during the first trimester of pregnancy on the grounds that the fetus had not yet acquired a soul.23 the qur’an and the tradition of the prophet muhammad declared the ensoulment period to be about 120 days (4 lunar months plus 10 days) computed from the moment of conception, which is equivalent to 19 weeks and one day, or 134 days from a woman’s last menstrual period.17,24–26 prior to this period, the human embryo has sanctity which gradually increases with its development. it is considered as a person after ensoulment. ibn qayyim al-jawziyyah, an eminent muslim jurist, has this to say regarding different stages of the embryo in the uterus: “the embryo and the fetus before ensoulment has the life of growth and nourishment like that of the plant. its movement and perception is not voluntary. but once the spirit is breathed unto the fetus, the movement and perception becomes voluntary, thus acquiring badawy a. b. khitamy special contribution | 31 15. ali ay. the holy qur'an, yusuf ali. ware, herts: wordsworth editions, 2001. sura 2:256 16. muslim world league conference of jurists, 12th session mecca, 10–17 feb 1990. fatwa (islamic ruling) no. 4. 17. albar m. human development as revealed in the qur’an and hadith: the creation of man between medicine and the quran. jeddah: saudi publishing house. 4th ed., 1996. 18. daar as, khitamy a. bioethics for clinicians: 21. islamic bioethics. can med assoc j 2001; 164:60–3. 19. al booty ms. masaalat tahdid al naslwiqayatan wailaqan. damascus: maktabat al farabi, 1996. pp. 135– 53. 20. al mashoor ar. ghaiat talkhisal murad min fatwa ziyad. cairo: dar al-ma’arif, 1980. p. 247. 21. jones da. the human embryo in the christian tradition: a reconsideration. j med ethics 2005; 31:710–13. 22. aristotle. history of animals, books vii–x. in: balm dm, ed. london: loeb classical library, 1991. pp. 7.3, 583b, 3–23. 23. glannon w. tracing the soul: medical decisions at the margins of life. christ bioeth 2000; 6:49–69. 24 ali ay. the holy qur'an, yusuf ali. ware, herts: wordsworth editions, 2001. suras 22:5, 23:12-14, 25. al-bukhari, imam m. sahih al-bukhary (hadith),vol. 3. beirut: dar al maarifah, 1995. 26. al-hajjaj, imam m. sahih muslim (hadith) vol. 4. beirut: dar al maarifah, 1955. 27. al-jawziyya iq. tibyan fi ahkam al-qur’an. beirut: dar al-fikr, 2000. p. 255. 28. ghazali, imam ahm. ihya ulum al-din, vol. 2. beirut: dar al maarifah, 2000. p. 51. references 1. singer p. taking life: the embryo and the foetus. in: practical ethics, cambridge: cambridge university press, 1993. p. 135. 2. marquis d. why abortion is immoral. j philos 1989; 66:183–202. 3. foot p. killing and letting die in: cahn sm and markie p, eds. ethics history, theory, and contemporary issues. 4th edition. oxford: oxford university press, 1984. p. 788. 4. thomson jj. a defense of abortion. philos public aff 1971; 1:47–66. 5. finnis j. the rights and wrongs of abortion: a reply to judith thomson. philos public aff 1973; 2:117– 145. 6. lee p. the pro-life argument from substantial identity: a defence. bioethics 2004; 18:249–63. 7. thomson jj. rights, restitution, and risk: essays in moral theory. cambridge, massachusetts: harvard university press, 1986. 8. peter singer. from: http://en.wikipedia.org/wiki/ peter_singer accessed: dec 2011. 9. pullman d. human non-persons, feticide, and the erosion of dignity. j bioeth inq 2010; 7:353–64. 10. marquis d. deprivations, futures and the wrongness of killing. j med ethics 2001; 27:363–9. 11. warren ma. on the moral and legal status of abortion. monist 1973; 57:43–61. 12. benn si. abortion, infanticide, and respect for persons. in: feinberg j, ed. the problem of abortion. belmont, ca: wadsworth publishing, 1973. p.102. 13. eberl jt. the beginning of personhood: a thomistic biological analysis. bioethics 2000; 14:134–57. 14. al-nishaburi h. hadith no 1296. in: mustadrak alaa sahihain (hadith collection). beirut: dar al kitab al arabi, 2008. عروض املؤمترات اإلكلينيكية الباثولوجية املنعقدة يف جامعة السلطان قابوس كلية الطب والعلوم الصحية يف جامعة السلطان قابوس، ومستشفى جامعة السلطان قابوس، 2014-2015 presentations of sultan qaboos university clinico-pathologic conferences sultan qaboos university college of medicine & health sciences and sultan qaboos university hospital, 2014–2015 abstracts paroxysmal nocturnal haemoglobinurea arwa al-riyami,1 fehmida zia,1 sahimah al-mamari,1 yarab al-bulushi,2 saja mahmood,3 *salam al-kindi4 departments of 1haematology, 2radiology & molecular imaging and 3medicine, sultan qaboos university hospital; 4department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: sskindi@yahoo.com paroxysmal nocturnal haemoglobinuria (pnh) is a rare disorder characterised by deficiency of glycosylphosphatidylinositol-anchored complement regulatory proteins. manifestations range from indolent to life-threatening, including coombs’-negative intravascular haemolysis, abdominal pain associated with smooth muscle dystonia, renal impairment, cytopaenia and thrombosis (typically affecting the portal and mesenteric veins and occasionally the arterial veins). testing should be done in cases with such manifestations and in those with bone marrow failure or cytopaenia of unknown aetiology. flow cytometry is the gold-standard test for this condition. management includes observation for asymptomatic cases, transfusion, anticoagulation, eculizumab administration and bone marrow transplantation (bmt). pnh is rare in oman and only six cases have been diagnosed at the sultan qaboos university hospital in muscat, oman. of these cases, four underwent bmt, while two were prescribed eculizumab. we present a complicated case of flow cytometry-diagnosed pnh presenting with thrombosis during pregnancy and progressing to renal impairment and bone marrow failure. this case was presented at the sultan qaboos university clinico-pathological conference on 13 november 2014 with the title “go with the flow”. percutaneous transvenous mitral commissurotomy hatim al-lawati, *mohammed misbah, mohammed mujtaba, zaheer siddiqui department of medicine, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: mohammedmisbah75@gmail.com percutaneous transvenous mitral commissurotomy (ptmc) is the preferred alternative to surgical commissurotomy among suitable patients with severe rheumatic mitral stenosis. ptmc is a minimally invasive procedure to correct an uncomplicated mitral stenosis by dilating the valve using a balloon. pregnancy in women with mitral stenosis is associated with a marked increase in maternal morbidity and adverse fetal outcomes. a multidisciplinary approach reduces mortality and morbidity during the peripartum stage of pregnancy. if symptoms persist despite optimal medical treatment, ptmc should be considered. we report a case of a woman who presented at the sultan qaboos university hospital (squh) in muscat, oman, with symptomatic severe mitral stenosis during pregnancy. she was managed medically after refusing intervention. however, after delivery she underwent a successful ptmc as the first case in squh. one month after the procedure, the patient showed dramatic improvement, both clinically and on echocardiography. this case was presented at the sultan qaboos university clinico-pathological conference on 20 november 2014 with the title “risky business”. developmental consequences of 22q11.2 microdeletion syndrome adila al-kindy, *nazreen b. kamarus, zandre bruwer department of genetics, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: nazreenarif@hotmail.com raising awareness of 22q11.2 deletion syndrome amongst physicians is crucial. the clinical phenotype of this syndrome is due to haploinsufficiency of multiple dosage-sensitive genes, resulting in the disruption of numerous embryonic developmental processes. these include cardiovascular/palatal anomalies, immunodeficiencies, hypocalcaemia and cognitive/psychiatric disorders. although 22q11.2 deletion syndrome is the most common microdeletion condition in humans, it remains the most underdiagnosed because of its remarkable variability and expression among affected individuals. we present a case series of six children with 22q11.2 deletion syndrome seen at the genetics clinic of the sultan qaboos university hospital in muscat, oman. these patients had molecularlyconfirmed 22q11.2 deletion which was diagnosed by either fluorescence in situ hybridisation or array-comparative genomic hybridisation in three cases each. this series highlights a holistic approach to the diagnosis and management of 22q11.2 deletion, including the use of a multidisciplinary team. an early diagnosis also provides the best opportunity to optimise patient care. this case series was presented at the sultan qaboos university clinico-pathological conference on 11 december 2014 with the title “fishing for a good catch”. sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e574–577, epub. 23 nov 15 doi: 10.18295/squmj.2015.15.04.027 abstracts | e575 sultan qaboos university college of medicine & health sciences and sultan qaboos university hospital, 2014–2015 development of obstructive sleep apnoea in patients with pierre robin sequence *abdulaziz bakathir,1 hussein al-kindi,2 hamdoon al-naamani,3 mohammed rashid,4 said al-rashidi5 departments of 1oral health and 2child health, sultan qaboos university hospital, muscat, oman; departments of 3ear, nose & throat and 4anaesthesia, al-nahda hospital, muscat oman; 5oral & maxillofacial surgery programme, oman medical specialty board, muscat, oman. *corresponding author e-mail: abakathir@squ.edu.om pierre robin sequence (prs) is a condition characterised by the triad of micrognathia/retrognathia, glossoptosis and a ‘v’-shaped palate with or without a cleft palate. it occurs in approximately one in 8,500 births. infants in the immediate and early postnatal period may experience varying degrees of upper airway obstruction leading to the development of obstructive sleep apnoea (osa). mandibular distraction osteogenesis (mdo) has a high success rate and is now the gold standard in the management of moderate to severe osa in prs patients. we present a case of prs with severe osa that was managed surgically with mdo and resulted in the immediate successful elimination of the osa. this case highlights the clinical appearance and pathogenesis of the condition, as well as the importance of preoperative full airway and anaesthetic assessments. in addition, prs cases that were managed with mdo in oman between 2008‒2014 are also reviewed. this case was presented at the sultan qaboos university clinico-pathological conference on 25 december 2014 with the title “whoever saves a life, it is as if he saved the life of all mankind”. lung transplantation: first patient from oman since the early 1990s *jayakrishnan b.,1 dawar m. rizavi,1 jojy george,1 saif m. al-mubaihsi,1 imran y. nizami2 1department of medicine, sultan qaboos university hospital, muscat, oman; 2organ transplant center, king faisal specialist hospital & research centre, riyadh, saudi arabia. *corresponding author e-mail: drjayakrish@hotmail.com we report a 19-year-old omani male who was the first patient from oman to undergo a lung transplant since the early 1990s. he was born to consanguineous parents and was diagnosed with bilateral bronchiectasis at three years old. his mother and sister had been diagnosed with the same condition, leading to his mother’s early death. computed tomography performed at the sultan qaboos university hospital in muscat, oman, showed extensive cystic bronchiectasis as well as areas of air trapping and partial volume loss. in march 2013, he underwent bilateral lung transplantation at the king faisal specialist hospital in riyadh, saudi arabia. his postoperative course was protracted with episodes of acute rejection. to date, he has recovered well, despite several respiratory infections. the unique features of this transplant included short cold preservation time (4‒8 hours), continuous external exposure of the organ, complex surgery (six anastomoses) and damaged donor lungs. lung transplantation challenges include costs/logistics, cultural/religious aspects, donor shortages, long waiting lists and the need for frequent follow-up. this case was presented at the sultan qaboos university clinico-pathological conference on 8 january 2015 with the title “a new breath, a new life”. intraoperative pulmonary embolism *jyoti burad,1 mohamed ismaili,1 babji kalapati,1 hilal al-sabti,2 sunil nadar3 departments of 1anaesthesia & intensive care, 2surgery and 3medicine, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: jyotiburad@yahoo.com an intraoperative pulmonary embolism (ipe) can be catastrophic. risk factors include major surgery as well as pelvic and lower extremity trauma. thromboprophylaxis is recommended and inferior vena cava filters are reserved for patients with contraindications to prophylaxis. whenever possible, neuraxial anaesthesia should be considered. specific electrocardiogram changes are seen in approximately 25% of affected patients. echocardiography findings of a massive ipe include acute right ventricular dilatation and dysfunction with leftward septal displacement. the initial treatment comprises cardiorespiratory support. definitive treatment with anticoagulants and thrombolysis carry the risk of bleeding while conservative approaches can result in life-threatening obstructive shock. surgical embolectomies and direct catheter-based approaches are rare. early extracorporeal membrane oxygenation (ecmo) should be considered in order to reduce pulmonary vascular resistance and improve haemodynamics and tissue oxygenation. however, ecmo requires systemic anticoagulation as well. prevention and a high index of suspicion in high-risk patients cannot be overemphasised. this case was presented at the sultan qaboos university clinico-pathological conference on 15 january 2015 with the title “walking on the tightrope”. syndromic hypoparathyroidism with septic shock saif al-yaarubi and *irfan ullah department of child health, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: irfanullahdr@gmail.com a six-week-old male baby was transferred from a peripheral hospital to the sultan qaboos university hospital (squh) in muscat, oman, after having hypocalcaemic seizures. the baby was born to consanguineous parents at 35 gestational weeks with intrauterine growth retardation. a physical examination revealed dysmorphic features suggestive of sanjad-sakati syndrome. he was subsequently found to have severe hypocalcaemia and hyperphosphataemia and was diagnosed with hypoparathyroidism. his condition was managed by intravenous calcium infusion but this was interrupted due to difficulties with intravenous access. his treatment was further complicated by right femoral line displacement into the abdominal cavity, requiring an urgent laparotomy. the child then developed septic shock resulting from klebsiella and candida albicans infections. he was prescribed broad-spectrum antibiotics and antifungal medication and was successfully extubated after five weeks. he developed cholestasis, which gradually improved, and underwent an operation for bilateral cataracts before being discharged. this case was presented at the sultan qaboos university clinico-pathological conference on 22 january 2015 with the title “outwit, outplay and outlast”. e576 | squ medical journal, november 2015, volume 15, issue 4 presentations of sultan qaboos university clinico-pathologic conferences phosphaturic mesenchymal tumour treated with octreotide and cured by surgical removal *omayma el-shafie,1 samir hussein,2 norman machado,3 asim qureshi,4 nicholas woodhouse5 departments of 1medicine, 2radiology & molecular imaging, 3surgery and 4pathology, sultan qaboos university hospital; 5department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: omayma0@hotmail.com tumour-induced osteomalacia (tio) is a rare disorder associated with the development of osteomalacia as a result of renal phosphate wasting. the latter results from increased circulating levels of fibroblast growth factor 23 which is secreted by a variety of different mesenchymal tumours that may be very small and difficult to find. this association was first reported by mccance in 1947. we report a case of tumour-induced hypophosphataemia and severe osteomalacia presenting to the sultan qaboos university hospital, muscat, oman, whereby the tumour was localised with the use of positron emission tomography and octreotide scintigraphy. the patient responded clinically and biochemically to a short trial of octreotide and was cured by the surgical removal of the tumour. this case was presented at the sultan qaboos university clinico-pathological conference on 5 february 2015 with the title “seen, but again, not observed”. commercial kidney transplant complicated by severe infection *marwa al-riyami,1 ahmed naeim,1 lateefa al-mutawea,1 yarab al-bulushi,2 badria al-ghaithi,3 naifain al-kalbani,3 badriya al-adawi,4 mohamed al-riyami3 departments of 1pathology and 4microbiology & immunology, sultan qaboos university hospital, muscat, oman; 2radiology programme, oman medical specialty board, muscat, oman; 3department of paediatrics, royal hospital, muscat, oman. *corresponding author e-mail: marwariyami@hotmail.com a seven-year-old boy received a commercial renal transplant due to chronic renal failure secondary to congenital posterior urethral valves and bilateral hydronephrosis. the immediate post-transplant period was uneventful. however, over the course of the following six months he had several episodes of diarrhoea associated with rising creatinine levels. his parents refused a renal biopsy and the child was managed conservatively with dosage modifications to his immunosuppression medication and antibiotic treatment. six months after the transplant, his condition deteriorated. he developed persistent fever, respiratory distress and a reduced urine output necessitating admission to the intensive care unit. an ultrasound showed an oedematous graft kidney with multiple hypoechoic regions while a computer tomography angiogram confirmed multiple renal infarcts. he underwent a life-saving graft nephrectomy which showed widespread parenchymal and angioinvasive mucormycosis with infarction. following a six-month postoperative period that included several surgical debridements for mucormycosis, the child was alive and undergoing dialysis again. this case was presented at the sultan qaboos university clinico-pathological conference on 19 february 2015 with the title “for sale”. traumatic brain injury leading to cognitive and behavioural impairment in a 69-year-old man mandhar al-maqbali,1 ahmed al-harrasi,1 ammar al-obaidy,2 *hamed al-sinawi1 departments of 1behavioural medicine and 2medicine, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: senawi@squ.edu.om the geriatric age group is rapidly growing in oman and cognitive and behavioural challenges should be recognised among the various disorders affecting these individuals. we report a 69-year-old male who was referred to the memory clinic at sultan qaboos university hospital in muscat, oman. the patient was suffering from behavioural changes of one month’s duration following recovery from a coma after a road traffic accident. he became increasingly irritable, argumentative and forgetful. he was easily provoked, had threatened to kill himself and reported visual and auditory hallucinations as well as visuospatial disorientation. he could no longer recognise close family members and experienced functional impairment in daily activities. this case highlights the neuropsychiatric manifestations of traumatic brain injuries. in addition, it emphasises the importance of comprehensive assessment to differentiate between the sequelae of traumatic brain injuries and a neurodegenerative disorder like alzheimer’s disease, which can also be triggered by head trauma. this case was presented at the sultan qaboos university clinico-pathological conference on 5 march 2015 with the title “a walk down memory lane”. overview of cystic fibrosis in sultan qaboos university hospital with focus on ivacaftor therapy *hussein al-kindi,1 amer qais,1 alaa elmanzalawy2 departments of 1child health and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: husseink30@yahoo.com we present four patients with cystic fibrosis (cf) with full manifestations of the disease and different outcomes modified by available therapies. all four patients were diagnosed with cf in infancy, presenting at the sultan qaboos university hospital in muscat, oman, with failure to thrive and chronic respiratory symptoms. their sweat chloride levels were above 60 mmol/l and they were prescribed enzyme replacement therapy (pancrelipase), high-caloric diet supplement vitamins and daily chest physiotherapy. subsequently, the patients developed persistent pseudomonas lung infections with bronchiectasis. they were administered regular nebulised tobramycin, 7% saline and dornase alfa but deteriorated clinically. two of the patients passed away due to irreversible respiratory failure and severe lung infections at eight and 14 years old, respectively. the remaining two patients were given ivacaftor which improved their lung function by 20% and their weight by an average of 5 kg. they subsequently experienced an overall improvement in quality of life. this case was presented at the sultan qaboos university clinico-pathological conference on 12 march 2015 with the title “a new dawn for cystic fibrosis patients”. abstracts | e577 sultan qaboos university college of medicine & health sciences and sultan qaboos university hospital, 2014–2015 blood cultures *badriya al-adawi,1 hilal al-shibli,2 sulien al-khalili,3 ismail el-beshlawi4 departments of 1microbiology & immunology, 2anaesthesia & intensive care and 4child health, sultan qaboos university hospital, muscat, oman; 3department of medical microbiology, oman medical specialty board, muscat, oman. *corresponding author e-mail: badriyak@squ.edu.om blood cultures are essential diagnostic tools and blood samples are arguably the most critical samples in the microbiology laboratory. once a blood culture bottle reaches the laboratory, it is processed through a series of tests involving different types of equipment. this process takes a minimum of three days. sometimes, a blood culture grows organisms that are not really present in the patient’s blood. this is known as blood culture contamination, which can adversely affect patient management, prolong hospital stay and incur unnecessary costs. this presentation describes how blood cultures are processed in the microbiology laboratory. three different clinical cases are presented to highlight key learning points. in particular, blood culture contamination is discussed, emphasising the adverse effects it causes and how it can be prevented. this case was presented at the sultan qaboos university clinico-pathological conference on 2 april 2015 with the title “blood cultures: what happens in the dark tower?”. acquired haemophilia a *anil pathare,1 khalil al-farsi,1 zainab al-hosni,2 zeba jabeen,1 karima al-farsi,1 salam al-kindi3 1department of haematology, sultan qaboos university hospital, muscat, oman; 2department of haematopathology, oman medical specialty board, muscat, oman; 3department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: pathare@squ.edu.om acquired haemophilia a is characterised by the presence of autoantibodies against endogenous factor viii and presents with spontaneous bleeding diathesis associated with an isolated prolonged activated partial thrombosis time (aptt). we report a 54-year-old man who presented at the sultan qaboos university hospital in muscat, oman, with a history of progressive left elbow swelling associated with skin discolouration and limited movement. investigations revealed an isolated prolonged aptt of 154 seconds, which did not correct during mixing studies; very low factor viii levels (<0.01 iu/ml); and high bethesda anti-factor viii antibody titres of 33.92 bethesda units. the patient was given factor viii:c concentrates along with recombinant factor viiic daily for a week to control the underlying bleeding diathesis. eradication of factor viii inhibitor was achieved with combined prednisolone/cyclophosphamide over one month along with four weekly 375 mg/m2 doses of rituximab. this resulted in aptt and factor viii:c normalisation without the inhibitor. this case was presented at the sultan qaboos university clinico-pathological conference on 9 april 2015 with the title “the enemy within”. awareness of early symptoms of colorectal cancer *mohammed al-azri,1 issa al-qarshoubi,2 humoud al-dhuhli,3 hani al-qadhi,4 khawaja f. zahid,2 hassan al-thani1 departments of 1family medicine & public health, 2medicine, 3radiology & molecular imaging and 4surgery, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: mhalazri@squ.edu.om colorectal cancer (crc) is the third most commonly diagnosed cancer in males and the second in females worldwide. the survival rate from crc depends on the stage at which the diagnosis is made; in many developing countries, there is often a delay in diagnosis. the delay can occur due to patients, doctors and/or the healthcare system. primary care is the first point of contact for patients with crc, however early-stage patients may delay presenting or present with non-specific symptoms. this presentation highlights the importance for doctors in primary care facilities to be alert for suspicious symptoms of crc and investigate or refer cases as early as possible. doctors should also follow national or international crc guidelines to manage such patients. furthermore, it is crucial that a national healthcare strategy be developed to increase public awareness about crc risk factors and early symptoms. this case was presented at the sultan qaboos university clinico-pathological conference on 16 april 2015 with the title “be alert before it is too late”. clinical & basic research squ med j, november 2011, vol. 11, iss. 4, pp. 492-496, epub. 25th oct 11 submitted 27th apr 11 revision req. 18th jul 11, revision recd. 29th jul 11 accepted 24th sep 11 السيطرة على املعلومات، الرعاية الصحية الفعالة، املمارسة املبنية على الدليل وجرّاح األنف واألذن واحلنجرة ديبا بهارجافا، يو�ضف ال�ضعيدي، كاملي�س بهارجافا، را�ضد العربي امللخ�ص: الهدف: درا�ضة �ضلوك احل�ضول على املعلومات لدى جّراحي الأنف والأذن واحلنجرة يف ُعمان، ورغبتهم للتعلم واكت�ضاب مهارات املمار�ضة املبنية على الدليل. الطريقة: اأجريت هذه الدرا�ضة املقطعية عرب توزيع ا�ضتبيان على 63 من اجلراحني العاملني بجراحة الأنف والأذن الأنف جلراحة وطنيا موؤمترا ح�ضورهم اأثناء ال�ضت�ضاري( اإىل املقيم من التخ�ض�س درجات خمتلف )ت�ضمل ُعمان يف واحلنجرة 10 عن تزيد خربة امل�ضاركني من %57 لدى وكان كامل، ا�ضتبيانا واأربعني ت�ضعة ا�ضتلم مت النتائج: .2010 يناير يف واحلنجرة �ضنوات، وكان 60% منهم يعملون يف م�ضت�ضفيات الرعاية الثالثية. ظهر باأن 38.8% منهم على اتفاق تام و 36.7% على اتفاق جزئي من اأكرث لدى كان للمر�ضى. فعالة �ضحية رعاية تقدمي وبالتايل الرعاية، نوعية حت�ضني �ضاأنها من الدليل على املبنية املمار�ضة باأن اأبدى الطبية. الرعاية اأداء اأثناء الأ�ضبوع يف اأكرث اأو �ضوؤال )11( 18.4% منهم لدى كان بينما الأ�ضبوع، يف اأ�ضئلة )1-5( %46.9 69.4% من اجلراحني ا�ضتعدادا لكت�ضاب مهارات ال�ضيطرة على املعلومات. كانت هناك علقة ارتباط اإح�ضائية بني عدد �ضنوات اخلربة، وعدد الأ�ضئلة، والرغبة يف اكت�ضاب مهارات ال�ضيطرة على املعلومات. اخلال�صة: تبني ازدياد اأهمية م�ضادر ال�ضبكة الدولية اأثناء املمار�ضة اكت�ضاب من التمكن ال�رسوري من اأنه يعتقدون ل ُعمان يف واحلنجرة الأنف جراحة يف العاملني اجلراحني معظم اليومية. ال�رسيرية مهارات املعلومات فح�ضب، بل اإن الرعاية ال�ضحية الفعالة تعتمد على هذه املهارات وعلى املمار�ضة املبنية على الدليل. واأظهر غالبية تقدمي على الخت�ضا�س بهذا اجلراحني مل�ضاعدة امل�ضتقبل يف حيوية �ضتكون املهارات هذه املهارات. هذه لكت�ضاب الرغبة امل�ضاركني حلول فعالة يف الرعاية ال�ضحية. مفتاح الكلمات: اإدارة املعلومات، رعاية �ضحية فعالة، ُعمان، طب مبني على الدليل، ممار�ضة قائمة على الدليل، ال�ضبكة الدولية. abstract: objectives: the objectives of this study were to study the information-seeking behaviour of otolaryngologists in oman, and their willingness to learn and acquire evidence-based practice (ebp) skills. methods: a cross-sectional survey was carried out by distribution of a questionnaire to 63 otolaryngologists (ranging from residents to consultants) employed in oman who attended a national otolaryngology meeting in january 2010. results: forty-nine completed questionnaires were received; 57% of the respondents had more than 10 years’ experience, and 60% were from tertiary care; 38.8% “totally agreed”, and 36.7% “partially agreed” that ebp would improve the quality of care and thus provide effective health care to patients. more than 46.9% had 1–5 questions per week, 18.4% had 11 or more questions per week at the point-of-care; 69.4% were willing to acquire information mastery skills. there was a statistical correlation between the number of years of experience, the number of questions, and willingness to acquire information mastery skills. conclusion: in day-to-day clinical practice, web-based resources are of increasing significance. most otolaryngologists in oman not only believed that it is essential to acquire information mastery skills, but also that effective health care depends on such skills and on ebp. most were willing to acquire these skills. in the future, these skills will be vital in helping otolaryngologists deliver effective health care solutions. keywords: information management; effective health care; oman; evidence-based medicine; evidence-based practice; internet; point-of-care. information mastery, effective health care, evidence-based practice and the otolaryngologist *deepa bhargava,1 yousef al-saidi,1 kamlesh bhargava,2 rashid al-abri1 clinical & basic research departments of 1surgery and 2family medicine & public health, sultan qaboos university hospital, muscat, oman. *corresponding author email: deepaent@gmail.com advances in knowledge 1. in medical literature there are very few studies on information mastery in general and none in the field of otolaryngology. 2. the results of this study revealed that most otolaryngologists are aware of the relevance of information mastery, effective health care and deepa bhargava, yousef al-saidi, kamlesh bhargava and rashid al-abri clinical and basic research | 493 the goal of medicine has always been to provide care to patients in a way that will help them live to their fullest capacity with the minimum amount of pain and discomfort. not only has the identification of ways to provide better medical care improved, but also this information is coming to us at an accelerated pace. new treatments are constantly being found, and older approaches are continually becoming obsolete. physicians and surgeons are being asked to retool their whole approach to information. now they have to be information managers, continually learning and updating their approach to medical care as medical knowledge continues to evolve. information mastery has been defined as “applied science that allows clinicians to harness resources in the information age”. it is a set of skills that will help medical professional be as up-to-date as their patients by obtaining the most valid and relevant information in the least amount of time.1 information mastery was defined as: usefulness of an information = relevance x validity work the usefulness of any information is directly proportional to its relevance and its validity; however, if too much work is required to obtain that information its usefulness diminishes.1 information mastery is an outgrowth of the movement towards evidence-based medicine (ebm), which first started in 1981.2 the constant increase in the body of medical knowledge is a source of frustration and anxiety amongst health professionals in general and medical students in particular. every day new diagnostic tests and treatments are being introduced. patients are also becoming better informed through the media and the internet stimulating a new passion for life-long learning in academia, professional environments, work place and at home.3 there is a need for evidence-based knowledge at the point-of-care as most physicians and surgeons have unmet information needs, besides day-today clinical dilemmas and differences in opinions. medical research continues to expand at an exponential rate. the task of clinicians striving to practice ebm medicine seems to be getting bigger with doctors increasingly having to rely on internetbased resources.4 today otolaryngologists are not expected to know everything, but should be able to access and assess information when required, to be information masters rather than encyclopedias of medical information. the aim of this study is therefore to examine the information-seeking behaviour and attitudes of otolaryngologists in oman and the impact of information technology on their day-today practice. methods this cross-sectional study was carried out in january 2010 at the annual meeting of otolaryngologists in oman. all sixty-three otolaryngologists present were requested to participate in the study by completing a questionnaire which was distributed to them. the questionnaire was created and designed by two co-authors of this article (db and kb). it comprised 4 sections and 15 statements/questions. questions covered demographics (including number of years of experience); information mastery needs; availability of information mastery tools, and attitudes to information mastery and ebm. the questionnaire was subjected to internal and external validation. internal validation included evidence-based practice (ebp) in day-to-day practice. 3. the knowledge that 69% would like to acquire skills for practising ebp would help in determining the educational needs of this cohort. 4. the study revealed a direct statistical correlation between otolaryngologists with less than 5 years clinical experience and a reluctance to acquire ebp skills; this cohort also had fewer questions arising from their day-to-day practice of otolaryngology. this needs to be addressed if effective health care is to be provided to patients in oman by future otolaryngologists. applications to patient care 1. this study showed that otolaryngologists, faced by information overload, lack of time, assessments of quality of care and patients informed by internet research, can improve their knowledge, the quality of their care, and protect themselves from litigation by acquiring information mastery skills. 2. information mastery skills can help in solving day-to-day clinical dilemmas and differences of opinion, and meet currently unmet information needs at the point of patient care. information mastery, effective health care, evidence-based practice and the otolaryngologist 494 | squ medical journal, november 2011, volume 11, issue 4 piloting the questionnaire with four experts who analysed its linguistic, face, and content validity. following internal validation, the questionnaire was edited and arranged in a logical, brief, simple, clear, concise, unambiguous and user-friendly format; unnecessary and repetitive questions were detected and deleted. the effectiveness of the questionnaire was determined by the survey itself and its reliability was found to be satisfactory. the data were analysed using the statistical package for the social sciences (spss, chicago, il, usa, version 16) and correlations were studied. the significant differences in the percentages between the groups were studied using the chi-square test. a p value (two tailed) of less than 0.05 was considered statistically significant. results a total of 49 completed questionnaires were received. the demographic data is shown in table 1. a total of 57% of respondents had more than 10 years experience, while 60% were from tertiary care. a total of 38.8% “totally agreed” and 36.7% “partially agreed” that ebp would improve the quality of care [figure 1]. “questions” were defined as questions which required the otolaryngologists to undertake further investigations during the care of a specific patient. more than 46.9% had 1-5 questions per week at the point-of-care; 18.4% had 11 or more questions per week. a significant finding was that 12% had less than one question per week; all these responders had less than 5 years of experience [figure 2]. on the topic of information mastery skills, 69.4% of respondents were willing to acquire them. there was a statistical correlation between the number of years of experience, the number of questions, and willingness to acquire information mastery skills. these results reveal that more experienced otolaryngologists had higher information needs, and vice versa [figure 3]. discussion this study examined the impact of information technology, with a ebp focus, on the way otolaryngologists in oman sought to answer clinical queries. most of the otolaryngologists (75.5%) agreed partially or totally that the quality of health care depended on evidence at point-of-care and that ebp would improve the quality of care. it would have been interesting to know the thoughts of the respondents regarding factors other than ebp that influenced the quality of patient care, but that was outside the scope of the present study. there was a positive correlation between the number of years of experience and the number of questions which occurred each week. this finding is in contradiction to the expectation that lesserexperienced surgeons would have more questions. some of the possible explanations for the junior otolaryngologists’ small number of weekly questions and low interest in developing information mastery skills could be lack of time, other priorities, a preoccupation with developing surgical skills and the need to study for examinations. this attitude 0 10.0% 20.0% 30.0% 40.0% 50.0% questions p e r c e n t < 1 per week 1-5 per week 6-10 per week 11 or more per week 12.2% 46.9% 22.5% 18.4% figure 2: number of questions arising in daily practice of otolaryngologists in oman. 36.78 6.1218.37 36.73 totally agree totally disagree partially disagree partially agree quality care and ebm figure 1: percentage response to question on belief that quality of care depends on evidence-based practice correlated to number of years experience. deepa bhargava, yousef al-saidi, kamlesh bhargava and rashid al-abri clinical and basic research | 495 needs to be addressed in the interest of the quality of their education and patient care with the ultimate goal of enhancing their skills in both knowledgeacquisition and surgery. in a study carried out in 1994, covell et al. found that physicians had two questions for every three patients seen, and that 40% of clinical questions raised during in-patient consultations were on medical facts.6 these findings appear similar to those found in the present study where more than 46.9% of respondents had 1-5 questions per week. translating knowledge into practice can close the gap between good and best care. no matter what source we choose, we would like to spend the least amount of time and energy to find the best information.7 the problem with using clinical experience alone is its validity although certainly using one’s own experience to meet information needs involves minimal work. a study conducted in the usa showed that 49% of causes of family physician errors, as perceived by physicians, were due to a lack of knowledge about the medical aspects of the case.8 in another study, it was also found that family physicians do not pursue answers to 64% of their clinical questions, but when answers are pursued, they can be found for 80% questions.8 we have a very similar experience in our team as invariably as we have been able to retrieve answers to most of the clinical questions asked. the imperative of training junior doctors to utilise information technology resources competently was found to be a strongly held belief among responders in a somewhat similar study of paediatricians;9 however, the provision of access to online resources may not result in the application of ebm to patient care. in a survey of uk paediatricians carried out while they were on call, riodan et al. found that very few of them used ebm resources to make on call decisions although they had access them.10 they concluded that a better utilisation of resources might be to train doctors to be ‘practitioners of ebm’ and so to know where to find preprocessed evidence and how to apply it— rather than be able to perform complex critical appraisal through training in clinical epidemiology. in a review of online evidence-based resources, krupski et al. commented that the use of electronic databases of pre-appraised evidence can greatly expedite the search for high quality evidence. this can then be integrated with the patient’s individual circumstances to provide translational research at the point-of-care.11 the study had some limitations: the small number of otolaryngologists in oman, and a limited representation of them at the meeting where the data was gathered. another limitation was that the survey respondents ranged from junior to senior otolaryngologists. conclusion in day-to-day clinical practice at the pointof-care, internet resources are of increasing significance. in this study, most otolaryngologists believed that quality of care depended on ebp and information mastery skills. the number of clinical queries at the point-of-care was directly correlated to the number of years of clinical practice experience of the respondents. most of the 0 10% 20% 30% 40% 50% years experience p e r c e n t less than 1 year no ebp yes 1-5 years 6-10 years more than 10 years 2.0% 6.2% 10.2%12.2% 12.2% 44.4% 6.1% 6.1% figure 3: relationship between number of years of experience and willingness to acquire information mastery skills for evidence=based practice (ebp). table 1: demographic data on the survey respondents demographic category percentage of respondents grade consultants 37 specialists 22 postgraduate trainees 41 age group >40 years 57 < 40 years 43 gender female 47 male 53 information mastery, effective health care, evidence-based practice and the otolaryngologist 496 | squ medical journal, november 2011, volume 11, issue 4 otolaryngologists surveyed were willing to acquire information mastery skills. the reluctance of junior otolaryngologists to acquire these skills in addition to surgical skills needs to be addressed. to address the ever changing world of medical knowledge and to keep up with the advances in medicine, we propose that otolaryngologists should incorporate into their practice the skills of information mastery in order to keep updated, and provide the best possible care thus improving the quality of care and the patients’ heath-related quality of life. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. shaughnessy af, slawson dc. introduction to information mastery in: rosser ww, slawson dc, shaughnessy af, eds. information mastery: evidence-based family medicine. 2nd ed. london: bc decker hamilton, 2004. pp. 1–4. 2. department of clinical epidemiology and biostatistics, mcmaster university health science center. how to read clinical journals: why to read them and how to start reading them critically. can med assoc j 1981; 124:555–8. 3. sedory hse. internet platform for life long learning: a continuum of opportunity. otolaryngol clin north am 2007; 40:1275–93. 4. hurwitz sr, slawson dc. should we be teaching information management instead of evidence-based medicine? clin orthop relat res 2010; 10:468. 5. slawson dc, shaughnessy af, bennett jh. becoming a medical information master: feeling good about not knowing everything. j fam pract 1994; 38:505– 13. 6. covell dg, uman gc, manning pr. information needs in office practice: are they being met? ann intern med 1985; 103:596–9. 7. ely jw, levinson w, elder nc, mainous ag, vinson dc. perceived causes of family physicians’ errors. j fam prac 1995; 40:37–44. 8. ely jw, osheroff ja, ebell mh, bergus gr, levy bt, chambliss ml, et al. analysis of questions asked by family doctors regarding patient care. bmj 1999; 319:358–61. 9. prendiville tw, saunder j, fitzsimons j. information seeking behavior of paediatricians accessing web based resources. arch dis child 2009; 94:633–5. 10. riordan fai, boyle em, philips b. best paediatric evidence; is it accessible and used on call? arch dis child 2004; 89:469–71. 11. krupski tl, dahm p, fesperman sf, schardt cm. how to perform a literature search j urol 2008; 179:264–70. sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 451-453, epub. 25th jun 13 submitted 25th apr 12 revision req. 16th oct 12; revision recd. 2nd dec 12 accepted 8th jan 13 linitis plastica denotes a diffuse type of carcinoma which accounts for 3–19% of gastric adenocarcinomas.1 it is characterised by a rigidity of a major portion, or all of the stomach, with the absence of a filling defect or extensive ulceration. gastric carcinoma is notorious for its failure to cause early symptoms so that patients do not present themselves for diagnosis until late in the course of the disease. because of the rich lymphatic supply, the cancer rapidly disseminates beyond the reach of surgical resection. consequently, the patients with symptoms generally have far-advanced malignancy.2 we report our experience of managing patients who were diagnosed with linitis plastica over a period of 18 months in 2011–2012 at barnsley district general hospital, uk. patients diagnosed with linitis plastica were identified from the cancer database, and their clinicopathological findings were retrieved from medical case notes. all cases were discussed in multidisciplinary meetings at a tertiary referral centre, and their clinical progress and outcomes were noted. case series in this series, 8 patients diagnosed with linitis plastica are discussed. their demographic details, symptoms, endoscopic and computed tomography (ct) findings, treatment details, and survival statistics are given in table 1. the average age upon presentation was 75 years (range 59–87 years). all patients were symptomatic at presentation. one patient (case 7) was scoped 3 times as the first endoscopy showed diffuse mucosal inflammation, and biopsies showed only chronic inflammation with no evidence of dysplasia. her ct scan was suspicious for linitis plastica but, in the absence of histological diagnosis, she underwent a repeat endoscopy and had negative biopsies. a diagnostic laparoscopy did not show serosal or peritoneal disease and she remained under close observation. department of general surgery, barnsley general hospital national health service foundation trust, barnsley, uk *corresponding author e-mail: sjafferbhoy@doctors.org.uk عالج التهاب املعدة املصنع اترك املشرط بالغمد �شدف جعفربوي، حنيف �شيواين، قوة اهلل ر�شتم امللخ�ص: يعترب التهاب املعدة امل�شنع �رشطاناً ذي طبيعة منت�رشة، ويتميز ب�شماكة وت�شلب بطانة جدار املعدة، وي�شتهر بعجزه عن اإبراز الأعرا�ص يف املراحل املبتدئة، واملر�شى الذين لديهم اأعرا�ص يكونون عادة م�شابني بدرجة متقدمة من املر�ص. نعر�ص هنا خربة 18�شهراً يف معاجلة التهاب املعدة امل�شنع يف م�شت�شفى مقاطعة بارن�شلي العام باململكة املتحدة. يف جمموعتنا املكونة من 8 حالت، مت عر�ص اجلراحة على مري�ص واحد فقط، وبقية املر�شى مت عر�ص العالج امللطف اأو الداعم. نتائج جمموعتنا كانت متالئمة مع الرباهني املتوفرة والتي ت�شري اإىل اأن العالج ال�شايف ل يعترب خياراً يف اأغلبية حالت التهاب املعدة امل�شنع. مفتاح الكلمات: �رسطان املعدة، التهاب املعدة امل�شنع، االأعرا�س، اإدارة املر�س، تقارير حاالت، بريطانيا العظمى. abstract: gastric linitis plastica is a diffuse type of cancer which is characterised by a thickening and rigidity of the stomach wall. it is notorious for its failure to cause early symptoms, and patients with symptoms generally have a more advanced form of the disease. we report our 18-month-long experience of managing gastric linitis plastica at barnsley district general hospital, uk. in our series of 8 patients, only one patient was offered surgery; the rest were offered palliative or supportive treatment. the findings in our series were consistent with the available evidence that curative treatment is not an option for the majority of cases with linitis plastica. keywords: gastric cancer; linitis plastica; symptoms; disease management; case reports; great britain. managing gastric linitis plastica keep the scalpel sheathed *sadaf jafferbhoy, hanif shiwani, quatullah rustum case series managing gastric linitis plastica keep the scalpel sheathed 444 | squ medical journal, august 2013, volume 13, issue 3 case series | 444 however, 10 months after presentation, she started having dyspepsia despite being on proton-pump inhibitors. a repeat endoscopy and biopsy showed an intramucosal adenocarcinoma. four patients with metastatic disease and two patients with extensive local disease were not offered surgery. one patient had local lymph node involvement and was not known to have any major comorbidities table 1: charateristics of each of the 8 linitis plastica cases age symptoms comorbidities endoscopic findings ct scan findings treatment offered treatment received outcome time since diagnosis 70 dyspepsia; dysphagia htn prominent gastric folds; non-distending stomach [figure 1]. thick-walled stomach with extensive local disease. palliative chemotherapy none alive 6 months 83 upper abdominal discomfort, postprandial vomiting, weight loss htn, ihd, pvd, ckd thickened area of irregular gastric mucosa at greater curvature. diffusely thickened gastric wall affecting the whole stomach [figure 2]; suspicious lung nodules. supportive care supportive care dead 3 months 87 early satiety; weight loss none circumferential thickening of proximal gastric mucosa. local lymphadenopathy; lung nodules; enlarged mediastinal nodes. supportive care supportive care dead 3 months 69 early satiety; dyspepsia; dysphagia dementia, ihd, pvd thickened gastric mucosa; polypoidal growth in proximal stomach. enlarged local lymph nodes; liver metastases. palliative radiotherapy palliative radiotherapy alive 4 months 76 vomiting; weight loss dm, ihd fungating lesion extending from og junction to antrum [figure 3]. enlarged local lymph nodes; liver metastases. supportive care supportive care dead 5 months 59 dysphagia none suspicious lesion at the cardia; thick mucosal folds; non-distending stomach. thick-walled stomach; perigastric stranding; extensive local involvement. palliative chemotherapy none dead 4 months 80 dyspepsia; weight loss none diffuse gastric mucosal inflammation with normal biopsy. repeat endoscopic biopsy showed intramucosal carcinoma. thick-walled stomach. surgery none dead 5 months 78 dyspepsia; vomiting none prominent and rigid gastric folds. diffuse gastric wall thickening; perigastric stranding; local lymph node involvement [figure 4]. palliative chemotherapy none alive 6 weeks ct = computed tomography; htn = hypertension; ihd = ischaemic heart disease; pvd = peripheral vascular disease; ckd = chronic kidney disease; dm = diabetes mellitus; og = oesophagogastric. sadaf jafferbhoy, hanif shiwani and quatullah rustum case series | 445 but, because of poor functional status, he was deemed unfit for surgery. only one patient was offered surgery in this cohort, but she declined the treatment. out of 8 patients, 5 patients died within 5 months of follow-up. the maximum survival recorded so far in this cohort of patients has been 6 months. discussion gastric linitis plastica is a diffuse type of cancer in which the cells invade throughout the stomach, resulting in the thickening and rigidity of the stomach wall. most of the patients presenting with symptoms have an advanced form of the disease, with the reason being the limited sensory qualities of the stomach. all the patients in these series were symptomatic. dyspepsia was the commonest feature of presentation (55%), followed by dysphagia (33%), vomiting (33%) and weight loss (33%). the infiltration of malignant cells reduces the volume of the stomach and interferes with peristalsis so that the stomach acts as a funnel between the oesophagus and duodenum. as a result, food is easily regurgitated into the oesophagus. this was the commonest presentation in these series. linitis plastica generally arises from the lower third of the mucosa without destroying the architecture of the stomach wall. the mucosa is often spared malignant infiltration, making endoscopic diagnosis extremely difficult. since macroscopic features do not permit the distinction between benign and malignant lesions, multiple endoscopic biopsies are required. the characteristic stroma reaction of the tissue is especially apparent in the submucosa, although it can also be noted in the muscle layer and subserosa.3 in most typical cases, the cells appear in a signet-ring form. the standard endoscopic biopsy specimens which contain only mucosa may result in a negative yield. one patient in these series had a negative first biopsy. in such patients with endoscopic suspicion, a diathermic snare can be used which will allow the acquisition figure 2: computed tomography scan showing the grossly thickened wall (oblique arrow) and the perigastric extension of tumour (horizontal arrow). figure 4: computed tomography scan showing grossly thickened gastric wall (white arrow) and early perigastric involvement (arrowhead). figure 1: endoscopy showing thickened gastric folds. figure 3: endoscopy showing a circumferential tumour with gross stomach contraction. managing gastric linitis plastica keep the scalpel sheathed 446 | squ medical journal, august 2013, volume 13, issue 3 of larger and deeper tissue, but this procedure has a higher risk of perforation. the diagnostic yield can also be increased by taking multiple forceps biopsies from the same site. the preoperative work-up involves an assessment of the spread of the disease. a ct scan of the abdomen may reveal thickening of the stomach wall with poor definition of the plane between the stomach and adjacent organs, or the involvement of surrounding nodes. sometimes an endoscopic ultrasound is useful to establish the diagnosis and in guiding treatment. the treatment for linitis plastica is a controversial issue. some authors have proposed using more radical multimodality treatments such as systemic and/or intraperitoneal chemotherapy in addition to radical surgery, whereas others suggest that these patients should be treated with primary chemotherapy even in the absence of unfavourable parameters, as the overall survival rate has been reported to be low in patients undergoing curative surgery.4–6 aranha et al. reported a slightly improved survival rate, with an average of 11 months, in patients who received palliative chemotherapy or radiotherapy when compared to those patients who did not receive any treatment.7 during their 21-year experience, moreaux et al. reported a 5-year survival rate of 11% after curative resection, but this was only possible in a small number of cases.8 in the series reported by schauer et al., only one-third of their cases had complete resection despite undergoing multivisceral resection and metatsatectomy.9 although a survival advantage was reported in this series, the median survival only increased from 8 to 17 months with complete resection. in contrast, kodera et al. reported an improved survival from 7.8 months in patients who did not receive any treatment to 30.2 months with complete resection, with no survival advantage in those undergoing palliative resection.10 in our series, the patients with locally advanced disease had poor physiological or functional status and were deemed unfit for major local resection. our findings are limited by the small number of patients in the series, the majority of whom were elderly and unfit for extensive local resections. conclusion in conclusion, gastric linitis plastica is one of the forms of adenocarcinoma which usually presents at a later stage, where curative treatment is not an option for the majority of cases. the prognosis may be ameliorated with complete resection. surgery should only be offered where complete resection is anticipated. in the era of modern medicine, we are increasingly being faced with an ageing population where surgery may not be a viable option. references 1. sah bk, zhu jg, chen mm, yan m, yin hr, zhen ly. gastric cancer surgery and its hazards: postoperative infection is the most common complication. hepatogastroenterology 2008; 55:2259–63. 2. yu j, yang d, wei f, sui y, li h, shao f, et al. the staging system of metastatic lymph node ratio in gastric carcinoma. hepatogastroenterology 2008; 55:2287–90. 3. karila-cohen p, petit t, aparicio t, teissier j, merran s. linitis plastica. j radiol 2005; 86:37–40. 4. komorowski ra, caya jg, geenen je. the morphological spectrum of large gastric folds: utility of snare biopsy. gastrointest endosc 1986; 32:190–2. 4. macdonald js, smalley sr, benedetti j, hundahl sa, estes nc, stemmerman gn, et al. chemotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. new engl j med 2001; 345:725–30. 5. yonemura y, de aretxabala x, fujimura t, fushida s, katayama k, bandou e, et al. intraoperative chemo hyperthermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomised controlled study. hepatogastroenterology 2001; 48:1776–82. 6. sasaki t, koizumi w, tanabe s, higuchi k, nakayama n, saigenji k. ts-1 as first line therapy for gastric linitis plastica: historical control study. anti-cancer drugs 2006; 17:581–6. 7. aranha gv, georgen r. gastric linitis plastica is not a surgical disease. surgery 1989; 106:758–62. 8. moreaux j, barratt f, msika s. linitis plastica of stomach: study of 102 cases surgically treated. results of the surgical treatment. chirurgie 1986; 112:485–92. 9. schauer m, peiper m, theisen j, knoefel w. prognostic factors in patients with diffuse type gastric cancer (linitis plastica) after operative treatment. eur j med res 2011; 16:29–33. 10. kodera y, seiji i, yoshinari m, yoshitaka y, kazunari m, norifumi o, et al. the number of metastatic lymph nodes is a significant risk factor for bone metastasis and poor outcome after surgery for linitis plastic-type gastric carcinoma. world j surg 2008; 32:2015–20. 1student research committee and 2emergency room & division of medical toxicology, hazrat-e ali asghar hospital, shiraz university of medical sciences, shiraz, iran *corresponding author e-mail: marashi@sums.ac.ir تشوه الصورة البيانية الكهربائية للقلب مرتبطة جبرعة زائدة من امليثادون مه�ش� آكاهي، وحيد �شكوري، �شيد مهدي مرع�شي electrocardiogram abnormality associated with methadone overdose mahsa agahi,1 vahid shakoori,1 *sayed mahdi marashi2 a 19-year-old male patient presented to the emergency department at hazrat-e ali asghar hospital, shiraz, iran, in may 2015 four hours after ingesting 200 mg of methadone in a suicide attempt. his past medical and family history were negative for any hereditary diseases. he had a history of opium addiction but had been abstinent for the preceding six months; he had previously been prescribed 40 mg of methadone per day as treatment for his opiate dependence. on examination, the patient was conscious, well-oriented and had stable vital signs. laboratory tests and arterial blood gas analysis were within normal limits. a 12-lead electrocardiogram (ecg) was performed [figure 1a]. although the ecg initially seemed normal, further inspection revealed that the qtc interval in the patient was approximately 500 milliseconds (ms). moreover, the pr interval exceeded 200 ms and a small deflection after the t wave (known as the u wave) was detected. interestingly, another ecg performed 48 hours later, just before the patient was discharged, revealed the complete normalisation of these abnormalities without the administration of antiarrhythmic agents [figure 1b]. figure 1a & b: 12-lead electrocardiograms (ecgs) in a patient with methadone intoxication (a) within the first hour of admission showing t (black arrowheads) and u (white arrowheads) waves and (b) 48 hours later. note the complete normalisation of the abnormalities in the second ecg which occurred without the use of antiarrhythmic agents. interesting medical image sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e113–114, epub. 2 feb 16 submitted 14 jul 15 revision req. 27 aug 15; revision recd. 3 sep 15 accepted 22 sep 15 doi: 10.18295/squmj.2016.16.01.022 electrocardiogram abnormality associated with methadone overdose e114 | squ medical journal, february 2016, volume 16, issue 1 tachycardia (also known as torsade de pointes). this is especially important when the qtc interval is more than 500 ms, as this may adversely lead to syncope or sudden cardiac death.1,4 patients who have been prescribed methadone should be assessed in order to identify those who are at potential risk of qtc interval prolongation. baseline ecgs before treatment and routine ecgs on a biannual basis and upon hospital admission are recommended.5 furthermore, as an acute increase in methadone dosage induces prolongation of the qtc interval, a 12-lead ecg should be considered during routine evaluation of these patients. moreover, close inspection of the ecg is necessary, as prolonged qtc intervals may lead to severe complications. references 1. lionte c, bologa c, sorodoc l. toxic and drug-induced changes of the electrocardiogram. in: millis rm, ed. advances in electrocardiograms: clinical applications. 1st ed. rijeka, croatia: intech, 2012. pp. 271–96. doi: 10.5772/22891. 2. brown r, kraus c, fleming m, reddy s. methadone: applied pharmacology and use as adjunctive treatment in chronic pain. postgrad med j 2004; 80:654–9. doi: 10.1136/pgmj.2004.022988. 3. krantz mj, lewkowiez l, hays h, woodroffe ma, robertson ad, mehler ps. torsade de pointes associated with veryhigh-dose methadone. ann intern med 2002; 137:501–4. doi: 10.7326/0003-4819-137-6-200209170-00010. 4. roden dm. drug-induced prolongation of the qt interval. n engl j med 2004; 350:1013–22. doi: 10.1056/nejmra032426. 5. d’arcy y. compact clinical guide to acute pain management: an evidence-based approach for nurses. 1st ed. new york, usa: springer publishing company, 2011. p. 211. comment acquired long qtc intervals are associated with the use of certain medications, including antihistamines, class i and class iii antiarrhythmics, antidepressants, antipsychotics, antibiotics and antifungals.1 genetic factors, the co-administration of the aforementioned drugs or hepatic enzyme inhibitors can also increase the risk of developing a long qtc interval.1 methadone is a long-acting opioid usually prescribed for opiate withdrawal or as an analgaesic for patients suffering from side-effects due to narcotics. methadone exerts its effects through μ-opioid receptors and has an antagonistic effect on n-methyl-d-aspartate receptors which results in the relief of neuropathic pain. considering its long half-life, methadone is considered an optimal medication for chronic pain management in opioid-tolerant cancer patients.2 despite being in use for more than 40 years, the cardiovascular effects of methadone have only recently been identified.2,3 methadone use, either chronic use or an acute increase in dosage, leads to the blockage of the voltage-activated delayed potassium current (the ik channel) and causes prolonged repolarisation of the ventricular myocardium. as a result, methadone use is associated with prolonged qtc intervals on ecgs.1,3 moreover, interruption of the repolarisation causes a decrease in the charge difference across the myocardial cell membrane, resulting in early postdepolarisation; thus, signifying an association with the u wave.1 as the prominent u wave and prolonged qtc interval are signs of early post-depolarisation, doctors should be wary of triggering polymorphic ventricular http://dx.doi.org/10.5772/22891 http://dx.doi.org/10.1136/pgmj.2004.022988 http://dx.doi.org/10.7326/0003-4819-137-6-200209170-00010 http://dx.doi.org/10.1056/nejmra032426 assessment of breast cancer awareness among female university students in ajman, united arab emirates تقييم وعي الطالبات اجلامعيات حول سرطان الثدي يف عجمان، اإلمارات العربية املتحدة �شذى �شعيد �أل�رشبتي, رزو�نه برهان �ألدين �شيخ, �أل�شيبا ماثيو, مو�هب �ألبياتي abstract: objectives: the aim of this study was to assess female university students’ knowledge of breast cancer and its preventative measures and to identify their main misconceptions regarding breast cancer. methods: this cross-sectional study was conducted between april 2011 and june 2012 and included female students from three large universities in ajman, united arab emirates (uae). a stratified random sampling procedure was used. data were collected through a validated, pilot-tested, self-administered questionnaire. the questionnaire included 35 questions testing knowledge of risk factors, warning signs and methods for the early detection of breast cancer. participants’ opinions regarding breast cancer misconceptions were also sought. results: the participants (n = 392) were most frequently between 18 and 22 years old (63.5%), non-emirati (90.1%) and never married (89%). a family history of breast cancer was reported by 36 (9.2%) of the students. the percentage of participants who had low/below average knowledge scores regarding risk factors, warning signs and methods for early detection of breast cancer was 40.6%, 45.9% and 86.5%, respectively. significantly higher knowledge scores on risk factors were noticed among participants with a family history of breast cancer (p = 0.03). the misconception most frequently identified was that “treatment for breast cancer affects a woman’s femininity” (62.5%). conclusion: a profound lack of knowledge about breast cancer was noted among female university students in the three uae universities studied. the most prominent gaps in knowledge identified were those concerning breast cancer screening methods. keywords: breast cancer; awareness; students; united arab emirates. امللخ�ص: الهدف: تهدف �لدر��شة �ىل تقييم معرفة �لطالبات �جلامعيات ب�رشطان �لثدي وتد�بريه �لوقائية وحتديد �أهم �ملفاهيم �خلاطئة فيما يتعلق ب�رشطان �لثدي الطريقه: �أجريت در��شة مقطعية بني ني�شان/�أبريل 2011 حزير�ن/يونيو 2012, و�شملت �لدر��شة �لطالبات يف ثالث جامعات كبرية يف عجمان. مت ��شتخد�م �لعينة �لع�شو�ئية �لطبقية. جمعت �لبيانات من خالل ��شتبيان مت �لتحقق من �شحته و �خترب جتريبيا. �شمل �ال�شتبيان 35 �شوؤ�ل الختبار�ملعرفة عن عو�مل �خلطر, عالمات �لتحذير, وطرق �لك�شف �ملبكر عن �رشطان �لثدي. وقد مت �أي�شا �أخذ �آر�ء �مل�شاركات ب�شاأن �ملفاهيم �خلاطئة �ملتعلقة ب�رشطان �لثدي. النتائج: كانت �مل�شاركات )�لعدد 392( يف �أغلب �الأحيان بني 22 و 18 �شنة )%63.5(, غري �إمار�تيات )%90.1(, وغريمتزوجات )%89(. وذكر تاريخ عائلي ل�رشطان �لثدي من قبل 9.2% )�لعدد 36( من �مل�شاركات. وكانت �لن�شبة �ملئوية للطالبات �لالتي �أحرزن م�شتوى معرفة منخف�ض/دون �ملتو�شط فيما يتعلق بعو�مل �خلطورة, وعالمات �لتحذير, وطرق �لك�شف �ملبكر عن �رشطان �لثدي هي %40.6 و %45.9 و %86.5 على �لتو�يل. لوحظ �حر�ز م�شتوى �أعلى و بن�شبة معنوية للمعرفة �ملتعلقة بعو�مل �خلطورة بني �مل�شاركات ذو�ت �لتاريخ �لعائلي ل�رشطان �لثدي )p = 0.03(. لوحظ �ن حول للمعرفة كبري نق�ض وجود لوحظ )%62.5(.اخلال�صة: �ملر�أة" �أنوثة على يوؤثر �لثدي �رشطان "عالج هو �الأكرث �خلاطئ �العتقاد �رشطان �لثدي بني �لطالبات �جلامعيات يف �جلامعات �الإمار�تية �لثالث �ملدرو�شة. كانت �لثغرة �الأبرز يف �ملعرفة تخ�ض طرق �لك�شف �ملبكر عن �رشطان �لثدي . مفتاح الكلمات: �رشطان �لثدي؛ �لوعي؛ طالبات؛ �الإمار�ت �لعربية �ملتحدة. assessment of breast cancer awareness among female university students in ajman, united arab emirates *shatha s. al-sharbatti,1 rizwana b. shaikh,1 elsheba mathew,1 mawahib a. al-biate2 clinical & basic research sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e522−529, epub. 14th oct 14 submitted 13th feb 14 revision req. 2nd apr 14; revision recd. 29th apr 14 accepted 9th jun 14 1department of community medicine, gulf medical university, ajman, united arab emirates; 2department of obstetrics & gynaecology, gulf medical college hospital, ajman, united arab emirates *corresponding author e-mail: shatha_alsharbatti@yahoo.com advances in knowledge this study found that female university students in the united arab emirates (uae) showed a profound lack of knowledge about breast cancer. this was particularly the case with regards to knowledge about breast cancer screening methods. given the lack of published data about female university students’ knowledge of breast cancer in the uae, the results of this study could be used as a baseline for planning future breast cancer education programmes for young women. these programmes should reflect the specific needs of this population, taking into account all of the identified barriers and misconceptions noted in this study. application to patient care the findings of this study highlight the need to raise awareness of breast cancer among female university students. self-awareness can shatha s. al-sharbatti, rizwana b. shaikh, elsheba mathew and mawahib a. al-biate clinical and basic research | e523 breast cancer is the most common cancer in women; in 2004, it comprised 16% of all female cancers and was the cause of death for 519,000 women worldwide.1 available data from the usa show that between 2005 and 2006 the highest incidence rate of breast cancer was among women aged 75–79 years and the median age at the time of diagnosis was 61 years.2 in the uk, approximately 80% of cases occur in women over the age of 50 years, with the peak ages being 50–64 years.3 in the eastern mediterranean region (emr), breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer-related deaths.4 in the united arab emirates (uae), breast cancer is the most common female cancer, accounting for 22.8% of diagnosed cases.5 however, 12% of these patients were less than 35 years of age at their first diagnosis, while 74% were less than 54 years of age.5 this average age at first diagnosis is earlier than those observed in the usa and uk. these data suggest that it is necessary to raise breast cancer awareness among young women in the uae. in the uae, there is a marked underutilisation of existing public screening services for breast cancer. in 2007, only 12% of the targeted female population underwent screening using a mammography.6 an inadequate awareness of and widespread misconceptions about breast cancer were identified as barriers that affect the utilisation of the existing public screening services.6 it has been suggested that the enhancement of knowledge and the correction of misconceptions among young women will stimulate positive attitudes towards breast cancer education and make them more ‘breast aware’, which in turn may promote the earlier detection of breast cancer.7 the present study aimed to assess the knowledge of female university students in the uae regarding breast cancer and its preventive measures and to identify the main misconceptions regarding breast cancer among this population. methods this cross-sectional study was conducted between april 2011 and june 2012 and included female students from three large universities in ajman, uae. these universities were the gulf medical university (u1), ajman university of science & technology (u2) and preston university ajman (u3). one of the universities offers only medical/health-related programmes (u1), while the other two offer mainly science and technology programmes (u2 and u3). female participants of 18 years of age or older, who were registered students in any of the three selected universities and who were available during the data collection period were included in the study. students who were male or who were attending other universities were excluded from the study. in order to overcome variability in the various curricula regarding health-related knowledge and obtain adequate representation from all programmes offered in the three universities, a stratified random sampling procedure was adopted to recruit the participants. a minimum of 10 samples were therefore selected from each programme taught in the three universities. an equal number of questionnaires (n = 150) were distributed among the three universities (n = 450) so as to have an equal representation of the female students from all three universities. a validated, pilot-tested and self-administered questionnaire was used as a data collection tool. the questionnaire included knowledge questions in three subdomains: risk factors, signs of and methods for the early detection of breast cancer. the first subdomain, concerning knowledge of breast cancer risk factors, was based on guidelines and information published by the world health organization (who) regional office for the eastern mediterranean and the american cancer society.8,9 using cronbach’s alpha coefficient, the internal consistency and reliability of this subdomain was 0.85. the second and third knowledge subdomains were warning signs of breast cancer and methods for the early detection of breast cancer.10 a scoring system was used to analyse the students’ knowledge: a score of one was given for a correct response while a score of zero was given for an incorrect answer or if the participant responded ‘i don’t know’. to compare the participants’ knowledge in the three subdomains, quartiles of correct total scores in the subdomains were used to categorise participants’ scores as either low (quartile 1), below average (quartile 2), above average (quartile 3) or high (quartile 4). the frequency and percentage of correct answers in these categories for each subdomain was help prevent the late detection of breast cancer and thereby improve survival rates. students are an easily accessible target group for breast cancer education and it is important that they be included in educational programmes. increased knowledge of breast cancer among female university students would be an asset in disseminating correct information among the community. assessment of breast cancer awareness among female university students in ajman, united arab emirates e524 | squ medical journal, november 2014, volume 14, issue 4 subsequently calculated. knowledge scores were compared in relation to the participants’ demographic characteristics (age, nationality, university, marital status and family history of breast cancer). the questionnaire also aimed to determine the participants’ breast self-examination (bse) practices, their main sources of breast cancer information and their opinions regarding breast cancer and its effect on women. these latter questions were based on misconceptions concerning breast cancer identified in a previous survey.7 data were entered into an excel spreadsheet, version 2011 (microsoft corp., redmond, washington, usa) and analysed using the statistical package for the social sciences (spss), version 19 (ibm, corp., chicago, illinois, usa). the kruskalwallis test for independent samples, mann-whitney u test and pearson’s chi-squared test were used to analyse the data. this study was funded by the who and the research adhered to ethical conduct guidelines. the study was approved by the ethics review committees of the gulf medical university and the who regional office for the eastern mediterranean. informed consent was taken from the participants before their enrolment in the study and the confidentiality of information was respected. results a total of 392 students took part in the study (response rate = 87%), with 142, 137 and 113 students from u1, u2 and u3, respectively. participants were mostly between 18 and 22 years of age (63.5%), expatriates (90.1%) and never married (89%). the age of the participants ranged from 16–47 years, with a median age of 21 years and a mean of 21.2 ± 3.5 years. none of the participants reported currently having breast figure 1: the percentage of correct answers among participants regarding breast cancer risk factors (n = 392). figure 2: the percentage of correct answers among participants regarding warning signs for breast cancer (n = 392). shatha s. al-sharbatti, rizwana b. shaikh, elsheba mathew and mawahib a. al-biate clinical and basic research | e525 cancer, although a family history of breast cancer was reported by 36 students (9.2%), mostly in seconddegree relatives (n = 23, 63.9%). the percentage of participants who had scores indicating correct knowledge regarding risk factors and warning signs for breast cancer are shown in figures 1 and 2. more than 50% of the participants did not have correct knowledge regarding the majority of the risk factors and warning signs. only 49% knew that never breastfeeding could be a risk factor for breast cancer. the proportion of those who knew that obesity, cigarette smoking and a lack of physical activity figure 3: the percentage of correct answers among participants regarding methods for the early detection of breast cancer (n = 392). cbe = clinical breast examination; bse = breast self-examination; mg = mammography. table 1: knowledge scores of participants in the three breast cancer subdomains by age, nationality, marital status, university and family history of breast cancer (n = 392) demographic variables n knowledge scores, median (range) risk factors p value warning signs p value early detection methods p value age in years* <18 57 10.0 (0–18) 0.598 5 (0–8) 0.421 3 (1–6) 0.002 18–20 133 10.0 (0–18) 5 (0–8) 3 (0–6) 20–22 116 11.0 (0–18) 5 (0–8) 3 (1–6) 22–24 48 11.0 (0–18) 5 (0–7) 4 (2–7) ≥25 38 10.5 (0–18) 5 (0–8) 4 (2–8) nationality** emirati 39 11.0 (0–18) 0.680 5 (0–8) 0.502 3 (0–6) 0.779 non-emirati 353 11.0 (0–18) 5 (0–8) 3 (1–8) marital status** never married 349 11.0 (0–18) 0.796 5 (0–8) 0.994 3 (0–7) 0.13 married or previously married 43 11.0 (0–17) 5 (0–8) 4 (2–8) university* 1 142 12.0 (0–18) <0.001 5 (0–8) 0.01 3 (0–7) 0.0012 137 11.0 (0–18) 5 (0–8) 3 (1–8) 3 113 8.0 (0–17) 4 (0–8) 3 (1–6) family history of breast cancer** yes 36 12.5 (2–18) 0.03 5 (0–8) 0.629 3 (2–7) 0.469 no 356 11.0 (0–18) 5 (0–8) 3 (0–8) *kruskal-wallis test; **mann-whitney u test. assessment of breast cancer awareness among female university students in ajman, united arab emirates e526 | squ medical journal, november 2014, volume 14, issue 4 increased the risk of breast cancer were 53%, 65% and 55%, respectively. figure 3 shows the percentage of correct answers regarding methods for the early detection of breast cancer. only 69 participants (17.6%) correctly identified mammography as a method for the early detection of breast cancer. additionally, approximately half of the students had never heard of bses and clinical breast examinations (cbes), at 46.2% and 55.9%, respectively. the vast majority of the participants did not have any knowledge regarding the recommended frequency of bse (98%) or its timing in relation to their menstrual cycle (94%). the median knowledge scores of participants by age, nationality, university, marital status and family history of breast cancer and the significance of these median differences are shown in table 1. the variability between participants’ knowledge scores (as observed in the wide standard deviation) made the mean an unreliable measure in reflecting the knowledge of the group. in consequence, median scores were used for comparison [table 1]. significantly higher knowledge scores regarding risk factors for breast cancer were noted among participants from the university offering only medical/health-related programmes and those with a family history of breast cancer, compared to their respective counterparts. with regards to knowledge about methods for the early detection of breast cancer, significant differences by age and university were also observed. an analysis of the knowledge scores in the three subdomains is shown in table 2. the percentage of students who had low or below average knowledge scores in the three knowledge subdomains was 40.6%, 45.9% and 86.5%, for the risk factors, warning signs and early detection methods domains, respectively. this demonstrated that the most evident gap in knowledge among the participants concerned methods for the early detection of breast cancer. table 3 shows the participants’ median knowledge scores when divided according to their bse practice. participants were asked how often they practiced bse and were categorised according to their response: no practice, rarely, sometimes and every month. only 89 participants (22.7%) admitted to having ever conducted a bse and only 13 (3.3%) of the students practiced monthly bses. the median knowledge scores of participants who conducted bses were significantly higher in all three subdomains compared to those who indicated that they did not practise bse. the most frequent breast cancer misconceptions reported by the study participants were that: treatment for breast cancer affects a woman’s femininity (62.5%); herbal remedies can treat breast cancer (56.4%); there is little that can be done to prevent cancer (49.7%); breast cancer inevitably results in death (44.4%); men do not get breast cancer (38%); they were too young to worry about breast cancer (35.5%); individuals can only get breast cancer if they have a family history of breast cancer (21.4%), and that breast cancer is the result of a curse or due to the ‘evil eye’ (19.4%). the reported sources of information for breast cancer were, in descending order, the media (72.4%), the internet (59.9%), doctors/nurses/health workers (37%), previous lectures in college/curriculum materials (31.6%), relatives (27%) and scientific journals/ meetings (24.5%). table 3: breast cancer knowledge scores of participants among breast self-examination practice groups (n = 392) bse practice n knowledge scores, median (range) risk factors p value warning signs p value early detection methods p value none 303 10.0 (0–18) 0.02 4.0 (0–8) <0.001 3.0 (0–6) <0.001 rarely 42 11.5 (0–18) 6.0 (0–8) 4.0 (2–7) sometimes 34 11.0 (1–18) 5.0 (0–7) 4.0 (2–7) every month 13 13.0 (0–18) 6.0 (4–8) 5.0 (3–8) bse = breast self-examination. table 2: participants’ scores in the three breast cancer knowledge subdomains by quartile (n = 392) score knowledge subdomain risk factors warning signs early detection methods quartile, n (%)* 1 54 (13.8) 120 (30.6) 138 (35.2) 2 105 (26.8) 60 (15.3) 201 (51.3) 3 165 (42.1) 140 (35.7) 48 (12.2) 4 68 (17.3) 72 (18.4) 5 (1.3) mean ± sd 9.8 ± 4.8 3.9 ± 2.7 3.2 ± 1.2 median 11.0 5.0 3.0 range 0–18 0–8 0–8 sd = standard deviation. *quartiles of correct total scores in the subdomains were used to categorise participants’ scores as either low (quartile 1), below average (quartile 2), above average (quartile 3) or high (quartile 4). shatha s. al-sharbatti, rizwana b. shaikh, elsheba mathew and mawahib a. al-biate clinical and basic research | e527 discussion in the uae, breast cancer is the most common form of cancer in females among both citizens and noncitizens.3 the annual report of the uae ministry of health in 2008 showed that 28% of deaths attributed to breast cancer occurred in women less than 45 years of age.11 data regarding breast cancer knowledge and preventative practices among female university students in the uae are limited. several factors affect an individual’s risk of developing breast cancer, some of which are modifiable and largely related to lifestyle, social, economic and environmental factors.12 a study conducted in 2010 showed that 26.8% of breast cancer cases in the uk were attributable to lifestyle and environmental factors.13 it is essential for women to know about these factors early in life so they can make the right lifestyle choices concerning these risk factors, since an increase in women’s awareness can change their risk perceptions and behaviours.14 the current study found that there was a profound lack of knowledge regarding breast cancer among a group of female university students at three universities in the uae. in this study, many participants correctly identified that a personal and family history of breast cancer was a risk factor, which correlates with other researchers’ findings.15 however, a lack of knowledge was noted among a large proportion of the participants regarding modifiable risk factors for breast cancer, such as the risk of never breastfeeding. this is thought to be a risk factor because various physiopathological mechanisms are involved in the protective effect of breastfeeding: anovulation, cellular differentiation of the mammary cells and excretion in the milk of breast carcinogens.16 obesity, cigarette smoking and a lack of physical activity also increase the risk of breast cancer; however, only 53%, 65% and 55% of participants, respectively, were aware of this. a similar study in turkey reported that the percentage of their participants who were aware of these three risk factors was 23%, 64% and 43%, respectively.7 a study from buraidah, saudi arabia, showed that the most frequently reported risk factors for breast cancer were not breastfeeding and the use of female sex hormones.17 it should be noted here that an increase in awareness about risk factors and risk-reducing strategies are important for the primary prevention of breast cancer. having adequate knowledge of the warning signs and symptoms of breast cancer, and being able to report any noticed abnormalities to healthcare providers, is part of what is known as “breast awareness”. this selfawareness can help in preventing the late detection of breast cancer and thereby improve survival rates.18 in this study, the percentage of participants who had correct knowledge scores regarding breast cancer warning signs was <60% for the majority of the signs mentioned in the questionnaire. low levels of knowledge about breast cancer warning signs were also reported in a study of university students in saudi arabia.19 in nigeria, only 70.7% of observed undergraduate females knew that there were warning signs of breast cancer.20 with regards to knowledge regarding measures for the early detection of breast cancer, it was worrying to find that most of the participants (86.5%) in the current study had low or below average knowledge regarding methods for early detection of breast cancer. a greater emphasis is required to address this knowledge gap in future educational campaigns directed at the female university population. specifically, the majority of the participants were unaware that mammography is a useful method for the early detection of breast cancer. additionally, approximately half of the students had never heard of bse and cbe practices. in contrast, a study among female health workers in nigeria reported that 81% of the participants mentioned mammography as a breast cancer diagnostic method, although only 46% mentioned bse and cbe as diagnostic techniques.21 in saudi arabia, only 51.8% of the female university students studied by habib et al. knew of mammography as a screening tool for breast cancer.19 the vast majority of the current study’s participants were unaware of the recommended frequency of bse (98%) or its timing in relation to their menstrual cycle (94%). this finding is in agreement with data from saudi arabia, where approximately 86% of the female university students questioned did not know about the recommended frequency of bse.19 in this study, age was found to be a significant determinant of knowledge related to methods for the early detection of breast cancer. it was found that younger participants had significantly lower knowledge scores in comparison to older participants. this finding is similar to that of a study from australia.22 it should be noted that the confounding effect of maturity cannot be excluded in this study and that the observed improvement in the knowledge scores of older female students may not be related to the effect of the curriculum; especially as only 31% of the students considered the curriculum to be the main source of their information. concerning nationality, no significant differences between knowledge scores were noted between emirati and non-emirati participants, which may indicate the possibility that cultural and ethnic factors have no significant effect on breast cancer awareness. however, a study in singapore by sim et al. found that that race was a assessment of breast cancer awareness among female university students in ajman, united arab emirates e528 | squ medical journal, november 2014, volume 14, issue 4 significant independent factor affecting breast cancer knowledge.23 another explanation, therefore, could be that the participants of the current study all had similar levels of education, likely diminishing the effect of cultural and ethnic factors. the difference in the knowledge scores of participants from different universities may be attributed to the types of courses or programmes offered at each university and their basic curriculums. a similar observation was made in another study of university students from angola.24 however, basic information about breast cancer should be provided to all young female students, irrespective of their educational programmes, in order to enhance overall awareness and influence positive behaviours related to breast cancer screening and prevention. a family history of breast cancer was reported by 9% of the participants, which is very close to findings from a saudi arabian study by sait et al. (9.8%) and from the lebanese national mammography campaign in 2009 (8.9%).25,26 interestingly, participants with a family history of breast cancer had significantly higher knowledge scores on breast cancer risk factors. this is consistent with a logistic regression model from another saudi arabian study among adult women in a primary healthcare setting.27 researchers have identified misconceptions as an independent factor associated with a delay in seeking healthcare.28 misconceptions also affect how women assess screening efficacy and make decisions about pursuing breast cancer screening.28 there were many misconceptions reported by the participants of the current study. for example, just over 44% of the participants thought that developing breast cancer inevitably resulted in death. a study from pennsylvania in the usa showed that a fatalistic attitude influenced the breast cancer knowledge and screening practices of the participants since it led them to believe that there was little they could do to prevent cancer and death.29 communication channels for health information have changed greatly in recent years. selecting the right channels and materials based on the required behavioural change and knowledge of the target audience is essential in influencing health behaviours. in this study, the media was the major contributor to the participants’ knowledge of breast cancer. other researchers have reported similar findings from lebanon,26 saudi arabia17 and iran.30 greater attention should be directed to this medium to ensure that correct information regarding breast cancer reaches the target population. female university students are an easily accessible target group that should be included in breast cancer educational programmes. in addition, female university students may help in disseminating correct information and developing positive attitudes towards breast cancer detection among relatives, family members and friends. this approach would amplify the benefits of breast cancer education in the community as a whole. conclusion a high proportion of female university students in the uae have inadequate knowledge about breast cancer. in this study, the percentage of students who had low or below average knowledge scores in the three knowledge subdomains was similar to the percentages reported in similar studies conducted in the region. this suggests that a lack of knowledge regarding breast cancer is a regional issue and is not limited to ajman or the uae. more than half of the participants falsely believed that the treatment for breast cancer affects a woman’s femininity and held inaccurate beliefs regarding treatment and prevention. in light of this study’s findings, female university students in ajman should be targeted for educational campaigns that take into consideration specific and relevant gaps in breast cancer knowledge. acknowledgements the authors would like to thank the who for funding this study and the centre for advanced biomedical research and innovation and the statistical support unit of the gulf medical university in ajman for their help and support. the authors would also like to thank the participants and their universities for their cooperation during the study. references 1. world health organization. the global burden of disease: 2004 update. from: www.who.int/healthinfo/global_burden_ disease/gbd_report_2004update_full.pdf accessed: jan 2014. 2. american cancer society. breast cancer facts & figures, 2005-2006. from: www.cancer.org/acs/groups/content/@nho / d o c u m e nt s / d o c u m e nt / c a ff 2 0 0 5 b r f a c s p d f 2 0 0 5 p d f . p d f accessed: jan 2014. 3. office for national statistics. cancer statistics registrations: registrations of cancer diagnosed in 2006, england. from: www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations-england--series-mb1-/no--37--2006/index.html accessed: jan 2014. 4. world health organization. global status report on noncommunicable diseases 2010. from: www.who.int/nmh/ publications/ncd_report_full_en.pdf?ua=1 accessed: jan 2014. 5. united arab emirates ministry of health. cancer incidence report: uae 1998-2001. from: www.tawamhospital.ae/ccr/ reports/annual/cancerincidencereportuae19982001.pdf accessed: aug 2014. shatha s. al-sharbatti, rizwana b. shaikh, elsheba mathew and mawahib a. al-biate clinical and basic research | e529 6. global initiative for breast cancer awareness team abu dhabi. 2008 community profile: summary of findings. from: www.haad.ae/haad/portals/0/cp-28-1-2009_jalaa[1].pdf accessed: jan 2014. 7. karayurt o, ozmen d, cetinkaya a. awareness of breast cancer risk factors and practice of breast self examination among high school students in turkey. bmc public health 2008; 8:359. doi: 10.1186/1471-2458-8-359. 8. world health organization regional office for the eastern mediterranean. guidelines for the early detection and screening of breast cancer. from: www.emro.who.int/dsaf/ dsa696.pdf accessed: jan 2014. 9. american cancer society. breast cancer facts & figures, 20072008. from: www.bcdcofalaska.org/pdf/aca%20breast%20 cancer%20facts%202009.pdf accessed: jan 2014. 10. osteen rt. breast cancer. in: lenhard re jr, osteen rt, gansler t, eds. clinical oncology. atlanta, georgia: american cancer society, 2001. pp. 251–68. 11. abu dhabi ministry of health. annual report of health policy sector. abu dhabi: ministry of health, 2008. 12. world cancer research fund and the american institute for cancer research. policy and action for cancer prevention: food, nutrition and physical activity, with an added us perspective. from: www.aicr.org/assets/docs/pdf/advocacypapers/wcrf_ policy_us_summary_final.pdf accessed: jan 2014. 13. parkin dm, boyd l, walker lc. the fraction of cancer attributable to lifestyle and environmental factors in the uk in 2010. br j cancer 2011; 105:s77–81. doi: 10.1038/bjc.2011.489. 14. spector d, mishel m, skinner cs, deroo la, vanriper m, sandler dp. breast cancer risk perception and lifestyle behaviors among white and black women with a family history of the disease. cancer nurs 2009; 32:299–308. doi: 10.1097/ ncc.0b013e31819deab0. 15. pöhls ug, renner sp, fasching pa, lux mp, kreis h, ackermann s, et al. awareness of breast cancer incidence and risk factors among healthy women. eur j cancer prev 2004; 13:249–56. 16. freund c, mirabel l, annane k, mathelin c. [breastfeeding and breast cancer]. gynecol obstet fertil 2005; 33:739–44. doi: 10.1016/j.gyobfe.2005.07.030. 17. dandash kf, al-mohaimeed a. knowledge, attitudes, and practices surrounding breast cancer and screening in female teachers of buraidah, saudi arabia. int j health sci (qassim) 2007; 1:61–71. 18. sharma k, costas a, damuse r, hamiltong-pierre j, pyda j, ong ct, et al. the haiti breast cancer initiative: initial findings and analysis of barriers-to-care delaying patient presentation. j oncol 2013; 2013:206367. doi: 10.1155/2013/206367. 19. habib f, salman s, safwat m, shalaby s. awareness and knowledge of breast cancer among university students in al madina al munawara region. mid east j cancer 2010; 1:159– 66. 20. salaudeen ag, akande tm, musa oi. knowledge and attitudes to breast cancer and breast self examination among female undergraduates in a state in nigeria. eur j soc sci 2009; 7:157– 65. 21. akhigbe ao, omuemu vo. knowledge, attitudes and practice of breast cancer screening among female health workers in a nigerian urban city. bmc cancer 2009; 9:203. doi: 10.1186/1471-2407-9-203. 22. johnson n, dickson-swift v. ‘it usually happens in older women’: young women’s perceptions about breast cancer. health educ j 2008; 67:243–57. doi: 10.1177/0017896908097068. 23. sim hl, seah m, tan sm. breast cancer knowledge and screening practices: a survey of 1,000 asian women. singapore med j 2009; 50:132–8. 24. sambanje mn, mafuvadze b. breast cancer knowledge and awareness among university students in angola. pan afr med j 2012; 11:70. 25. sait wa, al-amoudi sm, tawtai da, abduljabbar hs. the knowledge of breast cancer among young saudi females. saudi med j 2010; 31:1242–4. 26. kobeissi l, hamra r, samari g, koleilat l, khalifeh m. the 2009 lebanese national mammography campaign: results and assessment using a survey design. epidemiol 2012; 2:112. doi: 10.4172/2161-1165.1000112. 27. amin tt, al mulhim ar, al meqihwi a. breast cancer knowledge, risk factors and screening among adult saudi women in a primary health care setting. asian pac j cancer prev 2009; 10:133–8. 28. rauscher gh, ferrans ce, kaiser k, campbell rt, calhoun ee, warnecke rb. misconceptions about breast lumps and delayed medical presentation in urban breast cancer patients. cancer epidemiol biomarkers prev 2010; 19:640–7. doi: 10.1158/10559965.epi-09-0997. 29. luquis rr, villanueva cruz ij. knowledge, attitudes, and perceptions about breast cancer and breast cancer screening among hispanic women residing in south central pennsylvania. j community health 2006; 31:25–42. doi: 10.1007/s10900-0058187-x. 30. montazeri a, vahdaninia m, harirchi i, harirchi am, sajadian a, khaleghi f, et al. breast cancer in iran: need for greater women awareness of warning signs and effective screening methods. asia pac fam med 2008; 7:6. doi: 10.1186/1447056x-7-6. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e370–375, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.011. submitted 24 oct 14 revision req. 4 dec 14; revision recd. 19 dec 14 accepted 30 apr 15 1department of obstetrics & gynecology, kasturba medical college, manipal, karnataka, india; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: deekshiiiobg@gmail.com نسخة معدلة من مؤشر األعراض جوف أداة بسيطة لتصنيف حاالت سرطان املبيض جيوثي �ستي، بريادار�سيني، ديك�سا باندي، ماجنوناث abstract: objectives: ovarian cancer often goes undiagnosed or misdiagnosed in the early stages. the present study aimed to validate a modified version of the goff symptom index (gsi) in an indian population. methods: this prospective case-control study was conducted between july 2010 and june 2012 in a university hospital in manipal, karnataka, india. a total of 305 inpatients admitted for ovarian pathology investigations and outpatients undergoing routine gynaecological check-ups were included in the study. the modified gsi (mgsi) was used to investigate the presence, severity, frequency and duration of 10 ovarian cancer symptoms on a scale of 1–5. four additional symptoms were included with those of the original gsi (two symptoms from a previous mgsi and two new symptoms). patients were regarded as positive for ovarian cancer if symptoms occurred >12 times per month and time since onset was <1 year. histopathology confirmed the diagnosis of ovarian tumours. results: a total of 13 patients were excluded. the final sample (n = 292) was divided into a test group (n = 74) and a control group (n = 218) based on histopathology. within the controls, 144 women were found to have benign tumours. the mgsi was positive in 71.6% of the test group as opposed to only 11.5% of the control group. the addition of two symptoms (loss of appetite and weight) to the gsi increased the test’s sensitivity from 71.6% to 77% without compromising specificity (88.5%). conclusion: based on these findings, the addition of two new symptoms (loss of appetite and weight) to the gsi is proposed in order to increase the test’s sensitivity. however, the addition of urinary symptoms to the gsi requires further validation. keywords: ovarian cancer; diagnosis; symptom assessment; triage; algorithm; reliability and validity; india. امللخ�ص: الهدف: غالبا ما ل يتم ت�سخي�س �رسطان املبي�س اأو ي�سخ�س ب�سكل خاطئ يف املراحل املبكرة. تهدف هذه الدرا�سة اإىل التحقق من �سحة ا�ستخدام ن�سخة معدلة من موؤ�رس الأعرا�س جوف )gsi( يف ال�سكان الهنود. الطريقة: اأجريت هذه الدرا�سة على حالت مر�سية و�سوابط بني يوليو 2010 ويونيو 2012 يف م�ست�سفى اجلامعة يف مانيبال، كارناتاكا، الهند. اأدرجت يف هذه الدرا�سة 305 حالة من حالت اأمرا�س املبي�س املختلفة و�سوابط ت�سمل ن�ساء ياأتني لفحو�سات اأمرا�س ن�ساء روتينية يف العيادات اخلارجية. ا�ستخدمت ن�سخة معدلة من موؤ�رس الأعرا�س جوف )mgsi( للتاأكد من وجود و�سدة وتكرار ومدة 10 اأعرا�س من �رسطان املبي�س على مقيا�س من 5-1. واأدرجت الأعرا�س حدثت اإذا املبي�س ل�رسطان اإيجابية احلالت اعتربت .gsi جوف موؤ�رس األعرا�س على املدرجة تلك مع جديدة اأعرا�س اأربعة الدرا�سة من مري�سة ا�ستبعاد 13 مت املبي�س. النتائج: اأورام املجهري الت�سخي�س �سنة.واأكد الأعرا�س 1< بداية منذ ال�سهر يف مرة <12 �سمن املجهري. الت�سخي�س اأ�سا�س على 218 عدد ال�سابطة واملجموعة 74 عدد اختبار جمموعة اإىل 292 عدد النهائية العينة تق�سيم ثم ال�سوابط، مت العثور على 144 من الن�ساء لديهم اأورام حميدة. كان mgsi اإيجابيا يف %71.6 من جمموعة الختبار يف مقابل %11.5 فقط من املجموعة ال�سابطة. اإ�سافة اثنني من الأعرا�س )فقدان ال�سهية والوزن( اإىل gsi زادت ح�سا�سية الختبار من %71.6 اإىل %77 دون امل�سا�س بخ�سو�سية الختبار )%88.5(. اخلال�صة: ا�ستنادا اإىل هذه النتائج، يقرتح اإ�سافة اثنني من الأعرا�س اجلديدة وهي )فقدان ال�سهية والوزن( اإىل gsi من اأجل زيادة ح�سا�سية الختبار. واإ�سافة الأعرا�س البولية ملوؤ�رس الأعرا�س يتطلب مزيدا من التحقق من �سحة الختبار. مفتاح الكلمات: �رسطان املبي�س؛ الت�سخي�س؛ تقييم اأعرا�س؛ ت�سنيف؛ النظم؛ ال�سحة والدقة؛ الهند. modified goff symptom index simple triage tool for ovarian malignancy jyothi shetty,1 priyadarshini p.,1 *deeksha pandey,1 manjunath a. p.2 advances in knowledge early-stage ovarian malignancies often go unnoticed or misdiagnosed. this study emphasises the importance of using a simple index based on the common non-specific symptoms of ovarian cancer. this study may be a platform for further population-based studies to determine the benefit of this simple index in screening women for early-stage ovarian malignancies. applications to patient care the modified symptom index was found to be helpful in identifying women with early-stage ovarian cancer among a sample in india. the identified clusters of non-specific symptoms in the proposed symptom index can assist women in self-screening and help family physicians to make timely patient referrals. health workers and the general population should be made aware of the common non-specific symptoms of ovarian cancer in order to minimise delay in diagnosis. clinical & basic research jyothi shetty, priyadarshini p., deeksha pandey and manjunath a. p. clinical and basic research | e371 ovarian cancer remains a majorhealth concern worldwide, with more than 225,000 new cases annually leading to 140,000 deaths.1,2 ovarian cancer often goes unnoticed or misdiagnosed in its early stages. hence, many researchers have evaluated the predictive value of ovarian cancer symptoms.3–5 recent research has also emphasised the highly stressful effect of a late ovarian cancer diagnosis on quality of life.6 screening strategies like sonography and cancer antigen (ca) 125 tests have failed to prove their efficacy in early detection among the general population.7 the recognition of non-specific symptoms of the disease may minimise diagnostic delays, facilitate early management and improve survival rates. a thorough understanding of the spectrum of nonspecific symptomatology in ovarian malignancies can help in making an early diagnosis. the other advantage of using a symptom-based screening tool is to create awareness among the general public. thus, the potential utility of recognising unique patterns of non-specific symptoms is two-fold—such recognition can alert both patients and healthcare providers to potential ovarian malignancies.8 the present study was conducted with the aim of validating kim et al.’s modified version of the goff symptom index (gsi) in an indian population.9,10 furthermore, this study sought to validate the addition of two new symptoms to kim et al.’s modified gsi (mgsi).10 methods this prospective case-control study was conducted between july 2010 and june 2012 in a university hospital in manipal, karnataka, india. a total of 305 women were enrolled in this study. this included both women who were admitted to the hospital for evaluation and management of ovarian tumour pathology and those with an intact uterus and at least one intact ovary who visited the outpatient department for a routine gynaecological check-up during the study period. the latter patients formed the control-clinic group. all of the participants were given a survey to complete. the survey instrument was specifically designed for the current study and included questions eliciting demographic information, such as age, number of children and body mass index. the remainder of the survey investigated the presence, severity, frequency and duration of 10 ovarian cancer symptoms. these included six symptoms (pelvic pain, abdominal pain, increased abdominal size, bloating, difficulty in eating and a feeling of fullness) from the original symptom index proposed by goff et al.9 two other symptoms (urinary urgency and frequency) were included, as proposed by kim et al. in the mgsi.10 finally, two new symptoms (loss of weight and loss of appetite) were also included, based on the authors’ past experience with ovarian cancer cases. the participants were asked to rate the severity of each of these 10 symptoms on a scale of 1–5, with a score of 1 being mild and 5 being intolerable. similar scales were used to determine the frequency and duration of each symptom. eight symptoms, excluding the two new symptoms, were combined into four symptom clusters (abdominal/pelvic pain, increased abdominal size/bloating, difficulty in eating/feeling full and urinary frequency/urgency). the symptom index was considered to be positive for ovarian cancer if any of these symptoms occurred >12 times a month and the total duration since the onset of the symptom was <1 year. in order to avoid bias, the investigator involved with data collection remained unaware of the patients’ diagnoses during the survey period. following their completion of the survey, all of the participants who presented with ovarian pathology underwent post-surgical histopathological assessment of their ovarian tumours. as the control-clinic group had no ovarian pathology, they did not undergo any histological assessment. if a post-surgical (following a cystectomy, ovariotomy or staging laparotomy) histopathology report revealed a borderline ovarian tumour, these patients were excluded from the final analysis. participants with ovarian malignancies revealed by histopathology were assigned to the test group, while those with benign ovarian neoplasms or endometriomas were classified as the control-benign group. participants were therefore assigned to one of two groups (test group or control group), with those in the control group further classified according to two subgroups (control-benign and control-clinic groups). the inclusion of a control-clinic group helped ensure the test and control-benign groups were comparable. a comparative analysis was performed between the results of the survey and the final diagnoses for all participants. as no histological examinations were performed for the control-clinic group, transvaginal sonography suggestive of a normal ovarian architecture was taken to indicate no pathology. statistical analysis was performed using the statistical package for the social sciences, version 16.0 (ibm corp., chicago, illinois, usa). symptoms were compared using a chi-squared test. the odds ratio of each symptom was calculated by logistic regression analysis. a multivariate logistic regression was performed to determine which of the four symptom clusters remained independently significant. for all analyses, p <0.05 was considered statistically significant. modified goff symptom index simple triage tool for ovarian malignancy e372 | squ medical journal, august 2015, volume 15, issue 3 ethical approval for this study was granted by the institutional ethics committee of kasturba hospital, manipal, india (#iec124/2010). written informed consent was obtained from all participants before inclusion in the study. results of the 305 women enrolled in the study, 304 completed the survey (response rate: 99.7%). a total of 12 patients were excluded from the final analysis (seven from the test group and five from the control-benign group) as their final histopathology assessments revealed borderline ovarian tumours. thus, the final cohort consisted of 292 women [figure 1]. of these, 74 made up the test group while 218 made up the control group. for the latter group, the women were subdivided into a control-benign subgroup (n = 144) and control-clinic subgroup (n = 74). the demographic characteristics of the cohort are presented in table 1. the symptom index was positive for ovarian cancer for 71.6% of women in the test group as opposed to only 11.5% of women in the control group. this difference was statistically significant (p <0.001). the majority of clustered symptoms were reported to occur more frequently among the test group in comparison to the control group, including abdomen/pelvic pain figure 1: figure 1: consort (consolidated standards of reporting trials) flow chart detailing the population of the current hospital-based prospective case-control study. *diagnosis of malignant ovarian tumours were based on clinical features. table 1: demographic characteristics reported among test and control groups at an indian university hospital (n = 292) characteristic n (%) test group (n = 74) control group (n = 218) controlbenign group (n = 144) controlclinic group (n = 74) median age in years (range) 47 (12–75) 34 (14–75) 48 (25–81) parity nulliparous primiparous multiparous 17 (23) 11 (14.9) 46 (62.2) 64 (44.4) 29 (20.1) 51 (35.4) 6 (8.1) 6 (8.1) 62 (83.8) bmi in kg/m2 <18 18–24.9 25–29.9 ≥30 4 (5.4) 47 (63.5) 21 (28.4) 2 (2.7) 3 (2) 112 (84.7) 27 (18.8) 2 (1.4) 0 61 (82.4) 12 (16.2) 1 (1.4) menstrual status pre menopausal menopausal 35 (47.3) 39 (52.7) 115 (79.9) 29 (20.1) 35 (47.3) 39 (52.7) bmi = body mass index. jyothi shetty, priyadarshini p., deeksha pandey and manjunath a. p. clinical and basic research | e373 (44.6% versus 7.8%), increased abdominal size/bloating (55.4% versus 6.0%) and difficulty in eating/feeling full (45.9% versus 3.2%). these three symptom clusters were statistically significant predictors of ovarian cancer according to the histopathological findings [table 2]. urinary symptoms were not indicated among any women in the test group. in contrast, three women in the control group complained of urinary frequency/urgency. while one patient in the test group complained of increased urinary frequency, the total duration since the onset of the symptom was >1 year. as urinary symptoms were absent from the test group, this symptom cluster was excluded from the logistic regression analysis. all of the other symptom clusters were independent predictors of ovarian cancer according to the logistic regression analysis [table 3]. in the test group, there were six patients with stage iv ovarian cancer, 43 with stage iii, six with stage ii and 17 with stage i. two patients were not staged as one had a krukenberg tumour and the other had synchronous endometrial cancer. a total of 60 patients had epithelial cancer, seven had germ cell cancer, six had sex cord-stromal tumours and one had a krukenberg tumour. the results of the symptom index were analysed according to cancer stage among individuals in the test group. the symptom index was found to be positive in 83.3% of stage iv patients and 76.7% of stage iii patients. however, it was also positive in 64.7% and 50% of those with stage i and stage ii cancer, respectively. on correlating the symptom index with histology findings, the symptom index was found to be positive among 78% of those with epithelial cancer, 71.5% of those with germ cell cancer and 16.6% of those with sex cord-stromal tumours. a total of 21 patients in the test group had negative symptom index results. of these, seven experienced abdominal pain and one had bloating; however, these symptoms occurred <12 times a month. four patients experienced a loss of appetite and weight, four presented with menstrual irregularities, two presented with postmenopausal bleeding, one reporting having backache and two developed features of hyperandrogenism. in terms of histology, a negative symptom index was reported by 16.3% of those with epithelial cancer, 28.6% of those with germ cell tumours, 83.3% of those with sex cord-stromal tumours and 100% of those with a krukenberg tumour. the clinical significance of each symptom cluster was calculated in terms of sensitivity, specificity and positive and negative predictive values. increased abdominal size and bloating were the most sensitive symptoms (55.4%). although the sensitivity of individual clusters was approximately 50%, adding them together resulted in the sensitivity of the index increasing to 71.6% [table 4]. the new symptom cluster added to the mgsi (loss of appetite and weight) was one of the most common clusters reported among women with ovarian cancer. a total of 34 women (45.9%) in the test group reported having these symptoms. the addition of these two symptoms to the mgsi was therefore compared to the mgsi in terms of sensitivity and specificity [table 5]. adding this symptom cluster to the modified symptom index increased the sensitivity of the test from 71.6% to 77%, without compromising the specificity, which remained at 88.5%. table 2: positive modified goff symptom index10 for ovarian malignancy and distribution of symptom clusters reported among test and control groups at an indian university hospital (n = 292) variable n (%) p value test group (n = 74) control group (n = 218) symptom cluster abdominal pain/pelvic pain 33 (44.6) 17 (7.8) <0.001 increased abdominal size/bloating 41 (55.4) 13 (6.0) <0.001 difficulty in eating/ feeling full 34 (45.9) 7 (3.2) <0.001 increased urinary frequency/urgency 0 (0.0) 3 (1.4) 0.573 positive* modified goff symptom index10 53 (71.6) 25 (11.5) <0.001 *the symptom index was considered to be positive for ovarian cancer if any symptoms were reported to have occurred >12 times a month and total duration since the onset of the symptom was <1 year. table 3: independent logistic regression analysis of the goff symptom index9 for ovarian malignancy and symptom clusters reported among test and control groups at an indian university hospital (n = 292) variable or 95% ci p value symptom cluster abdominal pain/pelvic pain 09.5 04.84–18.68 <0.001 increased abdominal size/ bloating 19.6 09.49–40.41 <0.001 difficulty in eating/feeling full 26.6 10.61–61.82 <0.001 positive* goff symptom index9 19.5 10.12–37.50 <0.001 or = odds ratio; ci = confidence interval. *the symptom index was considered to be positive for ovarian cancer if any symptoms were reported to have occurred >12 times a month and total duration since the onset of the symptom was <1 year. modified goff symptom index simple triage tool for ovarian malignancy e374 | squ medical journal, august 2015, volume 15, issue 3 was considered positive for ovarian cancer if any of those six symptoms occurred >12 times per month and had been present for <1 year. in the confirmatory sample, the index had a sensitivity of 56.7% and 79.5% for earlyand advanced-stage cases, respectively.9 specificity was 90% for women >50 years of age and 86.7% for women <50 years of age.9 this original symptom index was found to be an effective triage tool for ovarian malignancies in the current studied cohort of indian women. patients with a positive symptom index should therefore be referred to an appropriate medical centre for an evaluation of potential ovarian cancer. kim et al. supported the efficacy and validity of the gsi in a korean population, with sensitivity and specificity rates of 65.5% and 84.7%, respectively.10 two urinary symptoms (urgency/frequency) were added to the original gsi and found to be an independent predictor of ovarian cancer.10 however, the two urinary symptoms added by kim et al. in the mgsi were not an important predictor of ovarian malignancy in the current study. urinary symptoms were not common among the studied indian cohort, perhaps due to the younger median age of the test group and smaller tumour sizes. urinary symptoms were also not included by goff et al. in their index as addition of these symptoms did not result in improved sensitivity of the index.9 thus, further research is required to find the significance of this particular symptom cluster before including it among future ovarian cancer symptom indexes. in the current study, the two new symptoms added—loss of appetite/weight—were found to be significantly present in the test group. furthermore, when this symptom cluster was included, the sensitivity of the index increased by 5.4% without compromising the specificity of the test. these results suggest that this variable should be added to the original index proposed by goff et al.9 although borderline ovarian tumours were excluded from the final analysis, a discussion ovarian cancer cases have a high frequency of late diagnosis and associated mortality.11 as a result, there is a dire need to focus research on effective methods of screening for and detecting ovarian cancer at an early stage. unfortunately, no screening test or surveillance strategy to date has achieved this goal. van nagell et al. determined that neither sonography nor ca 125 testing were cost-effective or practical for ovarian cancer screening in the general population, revealing that 5,200 ultrasound scans were needed in order to detect one case of invasive cancer.12 furthermore, even when assessing cancer incidence among a highrisk cohort, liede et al. reported that the combination of sonography and ca 125 testing did not prove efficacious in reducing mortality or morbidity.13 after exploring the symptomatology of ovarian cancer patients, goff et al. noted that women with ovarian cancer frequently reported symptoms prior to diagnosis, although these symptoms were usually nonspecific.14,15 based on the hypothesis that recognition of this symptom pattern would serve as a simple and cost-effective screening tool, goff et al. proposed their original symptom index in 2007.9 the original gsi included six symptoms clustered into three groups (pelvic/abdominal pain; increased abdominal size/ bloating; and difficulty in eating/feeling full).9 the gsi table 4: clinical efficacy of individual symptom clusters and the modified goff symptom index10 in predicting ovarian malignancy among test and control groups at an indian university hospital (n = 292) variable percentage sensitivity specificity ppv npv symptom cluster abdominal pain/pelvic pain 44.6 92.2 66.6 83.0 increased abdominal size/bloating 55.4 94.0 75.9 86.1 difficulty in eating/ feeling full 45.9 96.8 82.9 84.0 increased urinary frequency/ urgency 0.0 98.6 0.0 74.3 positive* modified goff symptom index10 71.6 88.5 67.9 90.1 ppv = positive predictive value; npv = negative predictive value. *the symptom index was considered to be positive for ovarian cancer if any symptoms were reported to have occurred >12 times a month and total duration since the onset of the symptom was <1 year. table 5: clinical efficacy of the modified goff symptom index10 for ovarian malignancy and the same index with two new additional symptoms (loss of appetite and weight) among test and control groups at an indian university hospital (n = 292) symptom index percentage sensitivity specificity ppv npv mgsi10 71.6 88.5 67.9 90.1 current index* 77.0 88.5 69.5 91.9 mgsi = modified goff symptom index; ppv = positive predictive value; npv = negative predictive value. *addition of two new symptoms (loss of appetite and loss of weight) to the mgsi proposed by kim et al.10 jyothi shetty, priyadarshini p., deeksha pandey and manjunath a. p. clinical and basic research | e375 subanalysis of this group showed the symptom index to be positive in 11 out of 12 cases (91.6%). to the best of the authors’ knowledge, this is the first study to correlate a symptom index with histological types of ovarian malignancies. the symptom index used in the current study was found to hold well for epithelial cancer and, to some extent, for germ cell tumours. however, the role of this symptom index in detecting sex cord-stromal and krukenberg tumours was found to be limited. this may be because sex cord-stromal tumours present early due to bleeding and symptoms related to an altered hormonal milieu, unlike epithelial ovarian cancers.16 hoskins et al. reported that only 15% of women in their study were familiar with the symptoms of ovarian cancer.17 creating awareness of these symptoms with an emphasis on the frequency and duration of individual symptoms could influence women to seek healthcare advice earlier, thus minimising diagnostic delays and reducing mortality related to late diagnoses. the early detection of ovarian cancer will be much less difficult when well-informed women work in tandem with clinicians. the results of the current study should be interpreted in light of some limitations. the population was heterogeneous and included a small number of patients. additionally, this was a hospital-based study and the results may therefore not be representative of the indian population in general. conclusion the original gsi was an effective triage tool in the studied cohort of indian women and the results supported the value of an ovarian cancer symptom index which can be used among women with nonspecific symptoms. furthermore, the addition of two new symptoms (loss of appetite/weight) to the mgsi increased the sensitivity of the test, without diminishing specificity. however, the two urinary symptoms of the mgsi were not found to be an important predictor of ovarian malignancy. further research is needed to assess the efficacy of including these symptoms in the gsi. awareness of ovarian cancer symptoms should be promoted among health workers as well as the general population in order to minimise delays in diagnosis and treatment of ovarian cancer. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. siegel r, naishadham d, jemal a. cancer statistics, 2013. ca cancer j clin 2013; 63:11–30. doi: 10.3322/caac.21166. 2. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin 2011; 61:69–90. doi: 10.3322/caac.20107. 3. lurie g, wilkens lr, thompson pj, matsuno rk, carney me, goodman mt. symptom presentation in invasive ovarian carcinoma by tumor histological type and grade in a multiethnic population: a case analysis. gynecol oncol 2010; 119:278–84. doi: 10.1016/j.ygyno.2010.05.028. 4. black ss, butler sl, goldman pa, scroggins mj. ovarian cancer symptom index: possibilities for earlier detection. cancer 2007; 109:167–9. doi: 10.1002/cncr.22414. 5. andersen mr, lowe ka, goff ba. value of symptom-triggered diagnostic evaluation for ovarian cancer. obstet gynecol 2014; 123:73–9. doi: 10.1097/aog.0000000000000051. 6. mangone l, mandato vd, gandolfi r, tromellini c, abrate m. the impact of epithelial ovarian cancer diagnosis on women’s life: a qualitative study. eur j gynaecol oncol 2014; 35:32–8. 7. van nagell jr jr, hoff jt. transvaginal ultrasonography in ovarian cancer screening: current perspectives. int j womens health 2014; 6:25–33. doi: 10.2147/ijwh.s38347. 8. markman m. development of an ovarian cancer symptom index: possibilities for earlier detection. cancer 2007; 110:226–7. doi: 10.1002/cncr.22749. 9. goff ba, mandel ls, drescher cw, urban n, gough s, schurman km, et al. development of an ovarian cancer symptom index: possibilities for earlier detection. cancer 2007; 109:221–7. doi: 10.1002/cncr.22371. 10. kim mk, kim k, kim sm, kim jw, park nh, song ys, et al. a hospital-based case-control study of identifying ovarian cancer using symptom index. j gynecol oncol 2009; 20:238–42. doi: 10.3802/jgo.2009.20.4.238. 11. rauh-hain ja, krivak tc, del carmen mg, olawaiye ab. ovarian cancer screening and early detection in the general population. rev obstet gynecol 2011; 4:15–21. 12. van nagell jr jr, depriest pd, reedy mb, gallion hh, ueland fr, pavlik ej, et al. the efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. gynecol oncol 2000; 77:350–6. doi: 10.1006/ gyno.2000.5816. 13. liede a, karlan by, baldwin rl, platt ld, kuperstein g, narod sa. cancer incidence in a population of jewish women at risk of ovarian cancer. j clin oncol 2002; 20:1570–7. doi: 10.1200/jco.20.6.1570. 14. goff ba, mandel l, muntz hg, melancon ch. ovarian carcinoma diagnosis. cancer 2000; 89:2068–75. doi: 10.1002 /1097-0142(20001115)89:10<2068::aid-cncr6>3.0.co;2-z. 15. goff ba, mandel ls, melancon ch, muntz hg. frequency of symptoms of ovarian cancer in women presenting to primary care clinics. jama 2004; 291:2705–12. doi: 10.1001/ jama.291.22.2705. 16. vijayraghwan m. sex cord-stromal tumors: pathological considerations. indian j med paediatr oncol 2004; 25:32–7. 17. hoskins wj, mcguire wp, brady mf, homesley hd, creasman wt, berman m, et al. the effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. am j obstet gynecol 1994; 170:974–9. doi: 10.1016/s0002-9378(94)70090-7. http://dx.doi.org/10.3322/caac.21166 http://dx.doi.org/10.3322/caac.20107 http://dx.doi.org/10.1016/j.ygyno.2010.05.028 http://dx.doi.org/10.1002/cncr.22414 http://dx.doi.org/10.1097/aog.0000000000000051 http://dx.doi.org/10.2147/ijwh.s38347 http://dx.doi.org/10.1002/cncr.22749 http://dx.doi.org/10.1002/cncr.22371 http://dx.doi.org/10.3802/jgo.2009.20.4.238 http://dx.doi.org/10.1006/gyno.2000.5816 http://dx.doi.org/10.1006/gyno.2000.5816 http://dx.doi.org/10.1200/jco.20.6.1570 http://dx.doi.org/10.1002/1097-0142%2820001115%2989:10%3c2068::aid-cncr6%3e3.0.co%3b2-z http://dx.doi.org/10.1002/1097-0142%2820001115%2989:10%3c2068::aid-cncr6%3e3.0.co%3b2-z http://dx.doi.org/10.1001/jama.291.22.2705 http://dx.doi.org/10.1001/jama.291.22.2705 http://dx.doi.org/10.1016/s0002-9378%2894%2970090-7 sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e65-71, epub. 27th jan 14 submitted 16th may 13 revision req. 5th sep 13; revision recd. 3rd oct 13 accepted 31st oct 13 college of medicine & health sciences, united arab emirates university, al-ain, united arab emirates *corresponding author e-mail: suleiman.alhammadi@uaeu.ac.ae مسية األفالتوكسني يف اخلاليا البشرية اللمفاوية �صليمان �حلمادي, فريدة �ملرزوقي, عائ�صة �ملن�صوري, �ألن �صاهي, مرمي �ل�صم�صي, �إريك من�صه بر�ون, عبد �لقادر �صويد abstract: objectives: aflatoxin b1 (afb1) is a naturally occurring carcinogenic and immunosuppressive compound. this study was designed to measure its toxic effects on human peripheral blood mononuclear cells (pbmc). methods: the study recruited 7 healthy volunteers. pbmc were isolated and cellular respiration was monitored using a phosphorescence oxygen analyser. the intracellular caspase activity was measured by the caspase-3 substrate n-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin. phosphatidylserine exposure and membrane permeability to propidium iodide (pi) were measured by flow cytometry. results: cellular oxygen consumption was inhibited by 2.5 µm and 25 µm of afb1. intracellular caspase activity was noted after two hours of incubation with 100 µm of afb1. the number of annexin v-positive cells increased as a function of afb1 concentration and incubation time. at 50 µm, a significant number of cells became necrotic after 24 hours (annexin v-positive and pi-positive). conclusion: the results show afb1 is toxic to human lymphocytes and that its cytotoxicity is mediated by apoptosis and necrosis. keywords: aflatoxin b1; oxygen analyzer; cellular respiration; mitochondria; caspases; leukocytes, mononuclear. امللخ�ص: الهدف: �الأفالتوك�صي هو مركب طبيعي م�صبب لل�رشطان ولنق�س �ملناعة. هذه �لدر��صة تقّيم �الآثار �ل�صامة لالأفالتوك�صي على �خلاليا �لب�رشية عزلت خاليا دموية ملفاوية من �صبعة متطوعي �أ�صحاء. ر�صد �لتنف�س �للمفاوية. متت هذه �لدر��صة بي ت�رشين ثاين 2008 وحزير�ن 2012. الطريقة: �خللوي بو��صطة �ملوؤ�رش �لف�صفوري لك�صف �الأك�صجي. وك�صف ن�صاط �نزمي �لكا�صبي�س د�خل �خللية با�صتخد�م �ملادة �لف�صفورية �مل�صتقة من كومارين �لقادرة �يود�يد لربوبدمي �خللية غ�صاء نفاذية زيادة و �صريين �لفو�صفاتيديل ملادة �لتعر�س قيا�س طريق عن �خللية موت قيا�س مت �الإنزمي. ن�صاط قيا�س على با�صتخد�م تقنية �لتدفق �خللوي. النتائج: �الأفالتوك�صي )μm 2.5 و μm 25( ثبط �ال�صتهالك �خللوي لالأك�صجي. ظهرت فعالية �لكا�صبي�س د�خل �خلاليا بعد �صاعتي من �إ�صافة �الأفالتوك�صي. عدد �خلاليا �مليتة �اليجابية ملادة �النيكزن-v �رتفع بزيادة جرعة �الأفالتوك�صي وبزيادة زمن تعر�س �خلاليا لهذ� �ل�صم. عند �إ�صافة μm 50 من �الأفالتوك�صي �أ�صبحت ن�صبة معتربة من �خلاليا نخرية بعد 24 �صاعه )�نيكزن )+v+pi(. اخلال�سة: �الأفالتوك�صي مادة �صامة للخاليا �لب�رشية �للمفاوية و�صميته تتم عرب �ملوت �خللوي �ملربمج و�لنخر. مفتاح الكلمات: �الأفالتوك�صي؛ موؤ�رش ك�صف �الأك�صجي؛ �لتنف�س �خللوي؛ �مليتوكوندريا؛ كا�صبي�س؛ �لدم؛ �خلاليا �للمفاوية. the cytotoxicity of aflatoxin b 1 in human lymphocytes *suleiman al-hammadi, farida marzouqi, aysha al-mansouri, allen shahin, mariam al-shamsi, eric mensah-brown, abdul-kader souid clinical & basic research advances in knowledge aflatoxin b1 (afb1) is a potent immunosuppressant. afb1 induces apoptosis and necrosis in human lymphocytes. afb1 inhibits lymphocyte respiration (mitochondrial oxygen consumption). application to patient care the cytotoxicities of aflatoxin in humans include immunosuppression, mediated by lymphocyte apoptosis and necrosis. public awareness of the potential immunotoxicity of aflatoxins is needed. effective health regulations are required to minimise the exposure to aflatoxins, especially in immunocompromised hosts. aflatoxin b1 (afb1) is a mycotoxin commonly found in food contaminated by organisms, such as aspergillus flavus.1,2 exposure to afb1 is linked to several human diseases, including hepatocellular carcinoma,3,4 mutagenesis,5 immunosuppression,6–8 impaired infant growth,9–12 and adverse birth outcomes.12,13 synergistic interactions with hepatitis b and human immunodeficiency viruses have also been reported.14,15 the toxin is activated by hepatic cytochrome p450 3a4, and its active form (afb1-exo-8,9 the cytotoxicity of aflatoxin b 1 in human lymphocytes e66 | squ medical journal, february 2014, volume 14, issue 1 epoxide) rapidly reacts with cellular deoxyribonucleic acid (dna) and proteins.16,17 most of the information regarding its immunotoxicity has been derived from animal studies.18–20 the exposure of young children to dietary aflatoxin and its toxic effects on human lymphocytes are also well established,14,21–24 including the inhibition of lymphocyte respiration.25 the term apoptosis describes the caspase(or apoptosome)-mediated cytotoxic processes that cause mitochondrial dysfunction, membrane damage and dna fragmentation.26 the apoptotic pathways that are independent of apoptosomes are also known.27 this study explores the mechanisms (biomarkers) of the toxic effects of afb1 in human lymphocytes. methods this study was carried out from november 2008 to june 2012. the pbmc were isolated from the whole blood of 7 healthy adult volunteers as previously described.28 the institutional review board for the protection of human subjects of the united arab emirates university approved the collection of blood from the healthy volunteers. informed consent was obtained from the participating volunteers. the reagents and solutions used were as follows. the pd(ii) complex of meso tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin ([pd phosphor] at molecular weight [mr]~1300) was purchased from porphyrin products (frontier scientific, inc., logan, utah, usa). the dactinomycin was purchased from merck & co., inc. (whitehouse station, new jersey, usa). the benzyloxy-carbonyl-val-aladl-asp-fluoromethylketone (zvad-fmk) was a calbiochem® product (emd millipore, billerica, massachusetts, usa). the n-acetyl-asp-glu-valasp-7-amino-4-methylcoumarin (ac-devd-amc) was purchased from alexis biochemicals (enzo life sciences, inc., farmingdale, new york, usa). the afb1 (produced by aspergillus flavus), glucose oxidase, d(+)-glucose and remaining reagents were from sigma-aldrich co. (st. louis, missouri, usa). the pd phosphor (at 2.5 mg/ml and 2.0 mm), glucose oxidase (at 10 mg/ml) and sodium cyanide (at 1.0 m) solutions were prepared in distilled water (dh2o) and stored at -20 °c. the phosphate buffered saline (pbs) solution was made daily. the afb1, dactinomycin, zvad-fmk (at 2.14 mm) and ac-devd-amc (at 7.4 mm) solutions were prepared and stored as previously described.29–31 oxygen detection was based on the principle described previously,32 and the phosphorescence oxygen (o2) analyser used as reported elsewhere.33–36 for the fluorescence-activated cell sorting (facs) analysis, an aliquot of 106 of pbmc for each subject were cultured with 0, 5, 10, 50 or 165 µm of afb1. the cells were harvested after 2, 16, and 24 hours, and analysed as previously described.37 the afb1 was prepared and measured as described.38 the reaction mixtures contained 1.5 x 106 cells in pbs, 10 mm of glucose and 68 µm of acdevd-amc, with and without zvad-fmk (at 20 µm). the mixtures were incubated at 37 °c in glass vials (in the dark with continuous agitation) for two hours, with and without afb1 or dactinomycin. the suspensions were then diluted with 1.0 ml of ice-cold pbs-glucose, sonicated for 60 secs and passed through 23-g needles. the supernatants were collected by centrifugation (12,300 x g for 10 mins) and separated on high-performance liquid chromatography (hplc) as described.37 the released 7-amino-4-methylcoumarin (amc) moiety (peak retention time of ~8.7 mins) was detected by fluorescence. a control reaction mixture containing pbs-glucose, 68 µm of ac-devd-amc and 5 µl of dimethyl sulfoxide (dmso) (the vehicle for zvad-fmk) without added cells was monitored periodically at 37 °c for the spontaneous release of amc moieties; in these control reactions, the amc peak areas at 0.5, 1, 2 and 3 hours were negligible. the hplc analysis of the released amc moieties was done on a waters corporation (milford, massachusetts, usa) reversed-phase hplc system (excitation wavelength of 380 nm and emission wavelength of 460 nm). solvent a was acetonitrile (ch3cn) and water (h2o) at a ratio of 1:3 and solvent b was dh2o. the column, a 4.6 x 250 mm ultrasphere® ion pair column (beckman coulter, inc., brea, california, usa), was operated at 25 °c at 1.0 ml/min (0.5 ml/min of each pump). the run time was 15 mins and the injection volume was 20 µl.37 results the cellular respiration results were as follows. the suleiman al-hammadi, farida marzouqi, aysha al-mansouri, allen shahin, mariam al-shamsi, eric mensah-brown and abdul-kader souid clinical and basic research | e67 representative o2 consumption runs are shown in figure 1 and 2. in figure 1, the pbmc (2.5 x 107 cells/ ml) were incubated with 12 µl/ml of dmso or 25 µm of afb1. at t = 154 mins, 1.0 ml of each mixture was simultaneously placed in the instruments for the o2 measurements. the respiration rate, zeroorder rate (constant for cellular mitochondrial o2 consumption (k) in µm o2 min -1) for untreated cells was 3.6 and 1.2 for afb1-treated cells (67% inhibition). in figure 2, the pbmc (107 cells/ml) were incubated with 1.2 µl/ml of dmso or 2.5 µm of afb1. at t = 95 mins, 1.0 ml of each mixture was simultaneously placed in the instruments for the o2 measurements. the k values were 1.6 and 1.3 µm of o2/min, respectively (19% inhibition). in four separate experiments, the values of k for untreated lymphocytes were 2.2 ± 1.1 µm o2 min-1 per 107 cells. the corresponding values for lymphocytes treated with afb1 (cells exposed to 2.5–75 µm of afb1 for 60–154 mins) were 1.3 ± 0.6 µm o2 min -1 per 107 cells; the inhibition was dosedependent and ranged from 19–67%. the caspase activity was monitored after incubation for two hours at 37 °c with 100 µm of afb1 (which was added as a powder), with and without 20 µm of zvad-fmk, using the caspase-3 substrate analogue ac-devd-amc. caspase-3 cleaved ac-devd-amc, releasing the fluorogenic figure 1: the afb1 (25 µm in dmso) inhibited the pbmc respiration. the pbmc (2.5 x 107 cells/ml in pbs-glucose, 3 µm of pd phosphor and 0.5% of fatfree albumin) were incubated at 37 °c with 12 µl/ ml of dmso or 25 µm of afb1 (in dmso). min zero corresponded to the addition of afb1. at t = 154 mins, 1.0 ml of each mixture was simultaneously placed in the phosphorescence o2 analysers for o2 measurements at 37 °c. the rates of respiration (k) were calculated from the best fit curves. the additions of 5.0 mm of nacn and 50 µg/ml of glucose oxidase are shown. o2 = oxygen; dmso = dimethyl sulfoxide; k = zero-order rate constant for cellular mitochondrial o2 consumption; r 2 = regression coefficient; nacn = sodium cyanide; afb1 = aflatoxin b1 ; pbmc = human peripheral blood mononuclear cells; pbs = phosphate buffered saline; pd phosphor = pd(ii) complex of meso-tetra-(4sulfonatophenyl)-tetrabenzoporphyrin. figure 2 a & b: the afb1 (2.5 µm in dmso) inhibited the pbmc respiration. the pbmc (10 7 cells/ml in pbs-glucose, 3 µm of pd phosphor and 0.5% of fat-free albumin) were incubated at 37 °c with 1.2 µl/ml of dmso (a) or 2.5 µm of afb1 (b). min zero corresponded to the addition of the afb1. at t = 95 mins, 1.0 ml of each mixture was simultaneously placed in the phosphorescence o2 analysers for o2 measurements at 37 °c. the rates of respiration (k) were calculated from the best-fit curves. the additions of 5.0 mm of nacn and 50 µg/ml of glucose oxidase are shown. o2 = oxygen; k = zero-order rate constant for cellular mitochondrial o2 consumption; r 2 = regression coefficient; nacn = sodium cyanide; afb1 = aflatoxin b1; dmso = dimethyl sulfoxide; pbmc = the human peripheral blood mononuclear cells; pbs = phosphate buffered saline; pd phosphor = pd(ii) complex of meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. the cytotoxicity of aflatoxin b 1 in human lymphocytes e68 | squ medical journal, february 2014, volume 14, issue 1 moiety amc. after cell disruption, the amc was separated on hplc and detected by fluorescence. for untreated cells [figure 3a], the amc peak area (in arbitrary units) was 273,367 and abolished by zvad-fmk. for cells treated with afb1 alone [figure 3b], the amc peak area was 32,347,746 (118-fold higher). for cells treated with afb1 and zvad-fmk [figure 3b], the amc peak area was 3,522,589 (89% inhibition). similar results were obtained in two additional experiments. for comparison, the cells were also treated with 20 µm of dactinomycin, which is well known to activate caspases. the amc peak area in the presence of dactinomycin alone was 54,679,510; in the presence of dactinomycin and zvad-fmk, the peak area was 4,561,062 (92% inhibition) [figure 3c]. the caspase activation was monitored as a function of the time of incubation with afb1. three conditions were tested: untreated cells, cells treated with 100 µm of afb1 alone and cells treated with 100 µm of afb1 and 20 µm of zvad-fmk. the acdevd-amc cleavage was monitored at 15, 30, 60 and 120 mins after treatment. the amc moiety appeared only after two hours of incubation with afb1; zvad-fmk blocked ~94% of the amc peak area. this profile of caspase activation was similar to that described for dactinomycin and doxorubicin in human immortalised t-lymphocytes.28,29 the induction of the lymphocyte apoptosis by afb1 was monitored by flow cytometry, using the cell membrane’s permeability to propidium iodide (pi) and the phosphatidylserine exposure. there were 10 independent experiments performed, and the results of these are summarised in figure 4. the pbmc were isolated from the blood of 7 healthy volunteers and exposed to 0, 5, 10 or 50 µm of afb1. the facs analysis was performed at 2, 16 and 24 hours. with the total number of mononuclear cells isolated at 2.5 x 106, the number of annexin v-positive cells increased with incubation time; this increase was statistically significant (p <0.05) after 16 hours of incubation for each concentration. although the difference in the effect of 5 µm and 10 µm was not significant (p = 0.082), the increase in the number of apoptotic cells after treatment with 50 µm was significant [figure 4 a and b]. it is noteworthy that 50 µm of afb1 also produced a significant number of necrotic cells (annexin v-positive and pi-positive), which became more evident at 24 hours [figure 4c]. thus, the results of this study show that afb1 inhibits cyanide-sensitive cellular respiration. the toxin also induces apoptosis and necrosis. discussion the phosphorescence o2 analyzer, caspase assay and flow cytometry were used here to confirm the toxic effects of afb1 on human lymphocytes. 25 the results show that afb1 impairs human lymphocyte figure 3 a‒c: the intracellular caspase activation by afb1 and dactinomycin. each mixture (final volume of 0.5 ml) contained 1.5 x 106 cells in pbs-glucose and 68 µm of ac-devd-amc, with and without 20 µm of zvad-fmk. the suspensions were incubated at 37 °c for two hours without addition (a), with the addition of 100 µm of afb1 (b) or with the addition of 20 µm of dactinomycin (c). at the end of the incubation period, the cells were disrupted and their supernatants were separated via hplc. the amc moiety was monitored by fluorescence. the retention time for the acdevd-amc was ~2.4 mins and ~8.7 mins for the amc. pbmc = the human peripheral blood mononuclear cells; zvad-fmk = benzyloxy-carbonyl-val-ala-dl-asp-fluoromethylketone; amc = 7-amino-4-methylcoumarin; afb1 = aflatoxin b1 ; pbs = phosphate buffered saline; ac-devd-amc = n-acetylasp-glu-val-asp-7-amino-4methylcoumarin; hplc = high-performance liquid chromatography. suleiman al-hammadi, farida marzouqi, aysha al-mansouri, allen shahin, mariam al-shamsi, eric mensah-brown and abdul-kader souid clinical and basic research | e69 mitochondrial function [figure 1 and 2] and activates intracellular caspases [figure 3]. the afb1 also produces lymphocyte apoptosis and necrosis [figure 4]. the caspases become active in the cells within two hours of the afb1 addition [figure 3]. this period is similar to that needed to inhibit cellular respiration [figure 1 and 2]. in one study, 32 µm of afb1 had a minimum effect on human lymphocyte proliferation following phytohaemagglutinin-p stimulation.39 however, an earlier study on human lymphocytes showed less lymphocyte proliferation in the presence of 16 µm of afb1. 40 the afb1 also inhibited concanavalin a-promoted lymphocyte proliferation (50% inhibition at 60 nm).20 moreover, afb1 was shown to induce apoptosis in human lymphocytes.41,42 the concentrations of afb1 used here were relatively high, especially since the average human exposure in eastern china is only ~0.5 mmol/day.3 it is important, however, to emphasise that the stability of afb1 in solutions is poor and the bulk of the toxin is deactivated by the rapid reaction with h2o. 43 thus, the data presented here mainly point to the potential immunotoxicity of afb1. the caspase activity reaction described was previously calibrated using recombinant human caspase-3.28 the amc was expressed as peak areas (in arbitrary units) per number of cells. the reactions were conducted in the presence and absence of the pan-caspase inhibitor zvad-fmk. it is of note that the substrate ac-devd-amc can be cleaved by several caspases, including caspase-3 (turnover number [kcat]/ michaelis constant [km] = 218,000 s-1); caspase-7 (kcat/km = 37,000 s-1); caspase-1/interleukin-1 converting enzyme (kcat/km = 30,000 s-1); caspase-6 (kcat/km = 2,000 s-1), and caspase-4 (kcat/km = 1,800 s-1). 44 figure 4 a–c: the flow cytometry analysis of the apoptosis. a: the percentages of the annexin v-positive cells; data are representative of samples from 7 healthy individuals. b: the quantification of the facs analysis of the apoptotic (annexin v-positive) cells from 7 healthy donors stained with pi and annexin v at 24 hours (horizontal lines), 16 hours (vertical lines) and two hours (no lines). c: the quantification of the facs analysis of the necrotic (annexin v-positive and pi-positive) cells after treatment with 50 µm of afb1. pi = propidium iodide; facs = fluorescence-activated cell sorting ; afb1 = aflatoxin b1 . *p <0.05; **p <0.005. the cytotoxicity of aflatoxin b 1 in human lymphocytes e70 | squ medical journal, february 2014, volume 14, issue 1 conclusion human lymphocytes exposed in vitro to afb1 exhibit impairments in cellular respiration, caspase activation and necrosis. the results underscore the immunosuppressive activity of aflatoxins in humans exposed to this natural fungal toxicant. references 1. eaton dl, gallagher ep. mechanisms of aflatoxin carcinogenesis. annu rev pharmacol toxicol 1994; 34:135–72. 2. williams jh, phillips td, jolly pe, stiles jk, jolly cm, aggarwal d. human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions. am j clin nutr 2004; 80:1106–22. 3. wang ly, hatch m, chen cj, levin b, you sl, lu sn, et al. aflatoxin exposure and risk of hepatocellular carcinoma in taiwan. int j cancer 1996; 67:620–5. 4. montesano r, hainaut p, wild cp. hepatocellular carcinoma: from gene to public health. j natl cancer inst 1997; 89:1844–51. 5. aguilar f, hussain sp, cerutti p. aflatoxin b1 induces the transversion of g-->t in codon 249 of the p53 tumor suppressor gene in human hepatocytes. proc natl acad sci u s a 1993; 90:8586–90. 6. corrier de. mycotoxicosis: mechanisms of immunosuppression. vet immunol immunopathol 1991; 30:73–87. 7. cusumano v, costa gb, seminara s. effect of aflatoxins on rat peritoneal macrophages. appl environ microbiol 1990; 56:3482–4. 8. rossano f, ortega de luna l, buommino e, cusumano v, losi e, catania mr. secondary metabolites of aspergillus exert immunobiological effects on human monocytes. res microbiol 1999; 150:13–19. 9. gong yy, cardwell k, hounsa a, egal s, turner pc, hall aj, et al. dietary aflatoxin exposure and impaired growth in young children from benin and togo: cross sectional study. bmj 2002; 325:20–1. 10. gong yy, egal s, hounsa a, turner pc, hall aj, cardwell kf, et al. determinants of aflatoxin exposure in young children from benin and togo, west africa: the critical role of weaning. int j epidemiol 2003; 32:556–62. 11. gong y, hounsa a, egal s, turner pc, sutcliffe ae, hall aj, et al. postweaning exposure to aflatoxin results in impaired child growth: a longitudinal study in benin, west africa. environ health perspect 2004; 112:1334–8. 12. turner pc, collinson ac, cheung yb, gong y, hall aj, prentice am, et al. aflatoxin exposure in utero causes growth faltering in gambian infants. int j epidemiol 2007; 36:1119–25. 13. shuaib fmb, jolly pe, ehiri je, yatich n, jiang y, funkhouser e, et al. association between birth outcomes and aflatoxin b1 biomarker blood levels in pregnant women in kumasi, ghana. trop med int health 2010; 15:160–7. 14. jiang y, jolly pe, preko p, wang js, ellis wo, phillips td, et al. aflatoxin-related immune dysfunction in health and in human immunodeficiency virus disease. clin devel immunol 2008; 2008:790309. 15. stern mc, umbach dm, yu mc, london sj, zhang zq, taylor ja. hepatitis b, aflatoxin b(1), and p53 codon 249 mutation in hepatocellular carcinomas from guangxi, people’s republic of china, and a meta-analysis of existing studies. cancer epidemiol biomarkers prev 2001; 10:617– 25. 16. guengerich fp, johnson ww, shimada t, ueng yf, yamazaki h, langouët s. activation and detoxification of aflatoxin b1. mutat res 1998; 402:121–8. 17. johnson ww, harris tm, guengerich fp. kinetics and mechanism of hydrolysis of aflatoxin b1 exo-8,9-epoxide and rearrangement of the dihydrodiol. j am chem soc 1996; 118:8213–20. 18. reddy rv, taylor mj, sharma rp. studies of immune function of cd-1 mice exposed to aflatoxin b1. toxicology 1987; 43:123–32. 19. reddy rv, sharma rp. effects of aflatoxin b1 on murine lymphocyte functions. toxicology 1989; 54:31–44. 20. stec j, żmudzki j, rachubik j, szczotka m. effects of aflatoxin b1, ochratoxin a, patulin, citrinin, and zearalenone on the in vitro proliferation of pig blood lymphocytes. bull vet inst pulawy 2009; 53:129–34. 21. methenitou g, maravelias c, koutsogeorgopoulou l, athanaselis s, koutselinis a. immunomodulative effects of aflatoxins and selenium on human peripheral blood lymphocytes. vet hum toxicol 1996; 38:274–7. 22. maenetje pw, de villiers n, dutton mf. the use of isolated human lymphocytes in mycotoxin cytotoxicity testing. int j mol sci 2008; 9:1515–26. 23. turner pc, moore se, hall aj, premtice am, wild cp. modification of immune function through exposure to dietary aflatoxin in gambian children. environ health perspect 2003; 111:217–20. 24. polychronaki n, wild cp, mykkänen h, amra h, abdelwahhab m, sylla a, et al. paul c. urinary biomarkers of aflatoxin exposure in young children from egypt and guinea. food chem toxicol 2008; 46:519–26. 25. al-jasmi f, al suwaidi ar, al-shamsi m, marzouqi f, al mansouri a, shaban s, et al. phosphorescence oxygen analyzer as a measuring tool for cellular bioenergetics. from: www.intechopen.com/books/bio energetics accessed: dec 2013. 26. green dr, kroemer g. the pathophysiology of mitochondrial cell death. science 2004; 305:626–9. 27. hao z, duncan gs, chang cc, elia a, fang m, wakeham a, et al. specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement of cytochrome c and apaf-1 in apoptosis. cell 2005; 121:579– 91. 28. al samri mt, biradar av, alsuwaidi ar, balhaj g, alhammadi s, shehab s, et al. in vitro biocompatibility of calcined mesoporous silica particles and fetal blood cells. int j nanomedicine 2012; 7:3111–21. 29. tao z, goodisman j, penefsky hs, souid ak. caspase activation by anticancer drugs: the caspase storm. mol pharm 2007; 4:583–95. suleiman al-hammadi, farida marzouqi, aysha al-mansouri, allen shahin, mariam al-shamsi, eric mensah-brown and abdul-kader souid clinical and basic research | e71 30. tao z, ahmad ss, penefsky hs, goodisman j, souid ak. dactinomycin impairs cellular respiration and reduces accompanying atp formation. mol pharm 2006; 3:762–72. 31. al-jasmi f, penefsky hs, souid ak. the phosphorescence oxygen analyzer as a screening tool for disorders with impaired lymphocyte bioenergetics. mol genet metab 2011; 104:529–36. 32. lo lw, koch cj, wilson df. calibration of oxygendependent quenching of the phosphorescence of pdmeso-tetra (4-carboxyphenyl) porphine: a phosphor with general application for measuring oxygen concentration in biological systems. anal biochem 1996; 236:153–60. 33. souid ak, tacka ka, galvan ka, penefsky hs. immediate effects of anticancer drugs on mitochondrial oxygen consumption. biochem pharmacol 2003; 66:977–87. 34. shaban s, marzouqi f, al mansouri a, penefsky hs, souid ak. oxygen measurements via phosphorescence. comput methods programs biomed 2010; 100:265–8. 35. al-salam s, balhaj g, al-hammadi s, sudhadevi m, tariq s, biradar av, et al. in vitro study and biocompatibility of calcined mesoporous silica microparticles in mouse lung. toxicol sci 2011; 122:86–99. 36. al-jasmi f, pramathan t, swid a, sahari b, penefsky hs, souid ak. mitochondrial oxygen consumption by the foreskin and its fibroblast-rich culture. sultan qaboos univ med j 2013; 13:411–16. 37. al-shamsi m, shahin a, mensah-brown ep, souid ak. derangements of liver tissue bioenergetics in concanavalin a-induced hepatitis. bmc gastroenterol 2013; 13:6. 38. nesheim s, trucksess mw, page sw. molar absorptivities of aflatoxins b1, b2, g1, and g2 in acetonitrile, methanol and toluene-acetonitrile (9 + 1) (modification of aoac official method 971.22): collaborative study. j aoac int 1999; 82:251–8. 39. meky fa, hardie lj, evans sw, wild cp. deoxynivalenolinduced immunomodulation of human lymphocyte proliferation and cytokine production. food chem toxicol 2001; 39:827–36. 40. savel h, forsyth b, schaeffer w, cardella t. effect of aflatoxin b1 upon phytohemagglutinin-transformed human lymphocytes. proc soc exp biol med 1970; 134:1112–15. 41. sun xm, zhang xh, wang hy, cao wj, yan x, zuo lf, et al. effects of sterigmatocystin, deoxynivalenol and afaltoxin g1 on apoptosis of human blood lymphocytes in vitro. biomed environ sci 2002; 15:145–52. 42. wang h, sun x, zhang x, zuo l. [effect of deoxynivalenol and aflatoxins g1 on apoptosis of human blood lymphocytes in vitro]. wei sheng yan jiu 1999; 30:102–4. 43. johnson ww, guengerich fp. reaction of aflatoxin b1 exo8,9-epoxide with dna: kinetic analysis of covalent binding and dna-induced hydrolysis. proc natl acad sci u s a 1997; 94:6121–5. 44. talanian rv, quinlan c, trautz s, hackett mc, mankovich ja, banach d, et al. substrate specificities of caspase family proteases. j biol chem 1997; 272:9677–82. 1department of dermatology, complejo hospitalario de granada, granada, spain; 2department of internal medicine, hospital santa ana, motril, spain *corresponding author e-mail: ismenios@hotmail.com تقيح اجللد الغرغريين املتعدد املرتبط مبعاقرة الكوكايني ريك�ردو روي�س-فيالفريدي و داني�ل �ش�ن�شيز-ك�نو multiple pyoderma gangrenosum ulcers associated with cocaine abuse *ricardo ruiz-villaverde1 and daniel sánchez-cano2 a 38-year-old male was admitted to thedepartment of dermatology, complejo hospitalario de granada, granada, spain, in 2016 with inflamed papules, plaques and nodules in the armpits, chest, pubis and lumbar region [figure 1]. he had a history of poorly-controlled type 2 diabetes, which was being treated with insulin, and dyslipidaemia, treated with 40 mg of simvastatin per day. the skin lesions were associated with abscess formation and spontaneous drainage. the patient acknowledged a past history of cocaine abuse, but denied any recent drug use. the results of a laboratory work-up were normal, including a complete blood count, general biochemistry tests, an autoimmune profile, an antinuclear antibody panel, a lupus anticoagulant and cryoglobulin work-up, a c-reactive protein test, complement levels and erythrocyte sedimentation rate. the patient tested negative for hepatitis b, hepatitis c and human immunodeficiency virus infections. a computed tomography scan showed neither pulmonary nor abdominal anomalies. cutan eous tissue cultures for bacteria, fungi and mycobacteria were all negative. the initial differential diagnosis included cutaneous chronic lupus and atypical mycobacteriosis. an excisional biopsy was performed on an active lesion on the right side of the chest. histopathology revealed a dense neutrophilic inflammatory infiltrate involving the entire dermis, without granulomas or vasculitis [figure 2]. direct immunofluorescence test ing was negative. urine toxicology screening was positive for cocaine and levamisole. as a result of the clinical and pathological findings, a diagnosis of pyoderma gangrenosum (pg) was made. the patient was advised to stop using cocaine and was prescribed prednisone at a dose of 60 mg daily for a month, reduced by 5 mg per week until cessation. unfortunately, due to patient noncompliance, optimal control of the dermatological condition could not be achieved. continued use of cocaine resulted in ongoing pg flare-ups. the patient was subsequently prescribed 0.5 mg/kg/day of prednisone, although figure 1: a: erythematous-violaceous ulcerated plaques on the right armpit and chest of a 38-year-old male cocaine user. b: erythematous plaques with serous crusts on the back of the patient, with small disseminated ulcers surrounding the major lesions. interesting medical image sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e527–528, epub. 30 nov 16 submitted 10 aug 16 revision req. 22 aug 16; revision recd. 23 aug 16 accepted 1 sep 16 doi: 10.18295/squmj.2016.16.04.024 multiple pyoderma gangrenosum ulcers associated with cocaine abuse e528 | squ medical journal, november 2016, volume 16, issue 4 lupus and granulomatosis with polyangiitis. infectious diseases such as atypical mycobacteriosis, an emerging disease in spain, were also considered.2 keith et al. previously reported an association between pg and the use of levamisole-adulterated cocaine.3 endothelial damage due to the direct toxic effect of cocaine and vasculopathy caused by levamisole have been postulated to be the major pathophysiological mechanisms in these types of cases.4 the therapeutical approach may be complicated; the severity of pg influences the choice of the initial therapy. systemic therapy—such as corticosteroids, immunosuppressive therapy or even biological therapy—is needed to achieve remission in cases of extensive pg; cessation of cocaine use is also imperative.5 references 1. roche e, martínez-menchón t, sánchez-carazo jl, oliver v, alegre de miquel v. [two cases of eruptive pyoderma gangrenosum associated with cocaine use]. actas dermosifiliogr 2008; 99:727–30. doi: 10.1016/s1578-2190(08)70351-2. 2. esteban j, ortiz-pérez a. current treatment of atypical mycobacteriosis. expert opin pharmacother 2009; 10:2787–99. doi: 10.1517/14656560903369363. 3. keith pj, joyce jc, wilson bd. pyoderma gangrenosum: a possible cutaneous complication of levamisole-tainted cocaine abuse. int j dermatol 2015; 54:1075–7. doi: 10.1111/ijd.12212. 4. baliu-piqué c, mascaró jm jr. multifocal and refractory pyoderma gangrenosum: possible role of cocaine abuse. australas j dermatol 2016. doi: 10.1111/ajd.12498. 5. jeong hs, layher h, cao l, vandergriff t, dominguez ar. pyoderma gangrenosum (pg) associated with levamisoleadulterated cocaine: clinical, serologic, and histopathologic findings in a cohort of patients. j am acad dermatol 2016; 74:892–8. doi: 10.1016/j.jaad.2015.11.040. he never completed treatment cycles for longer than three weeks. after one year, the patient was lost to follow-up. comment pg is an uncommon neutrophilic dermatosis that presents as an inflammatory and ulcerative disorder of the skin. most cases are associated with an underlying immunological condition, such as inflam matory bowel disease, rheumatological diseases, haematological disorders or metabolic syndrome.1 in the current patient, all of the laboratory tests were negative apart from the toxicology screening, which distinguishes this case from others reported in the literature. the differential diagnosis included connective tissue diseases such as chronic cutaneous figure 2: haematoxylin and eosin stain at x40 magnification showing a dense neutrophilic inflammatory infiltrate involving the entire dermis, without evidence of granulomas or vasculitis. 1department of technology of radiology & radiotherapy, allied medical sciences school and 2cancer research center, cancer institute of iran, tehran university of medical sciences, tehran, iran; 3department of toxicology & pharmacology, international campus and 4razi drug research center, iran university of medical sciences, tehran, iran *corresponding author e-mail: shetab.v@iums.ac.ir الوقاية من أضرار اإلشعاع على احلمض النووي يف اخلاليا الليمفاوية البشرية باستخدام خليط من كربيتات السريين واملغنيسيوم وحيد ت�ساجنيزي، مونا بهرامي، مهبد ا�سفهاين، وحيد �ستاب بو�سهري abstract: objectives: ionising radiation has deleterious effects on human cells. n-acetylcysteine (nac) and cysteine, the active metabolite of nac, are well-known radioprotective agents. recently, a serine-magnesium sulfate combination was proposed as an antidote for organophosphate toxicity. this study aimed to investigate the use of a serine-magnesium sulfate mixture in the prevention of γ-radiation-induced dna damage in human lymphocytes as compared to nac and cysteine. methods: this study was carried out at the iran university of medical sciences, tehran, iran, between april and september 2016. citrated blood samples of 7 ml each were taken from 22 healthy subjects. each sample was divided into 1 ml aliquots, with the first aliquot acting as the control while the second was exposed to 2 gy of γ-radiation at a dose rate of 102.7 cgy/minute. the remaining aliquots were separately incubated with 600 μm concentrations each of serine, magnesium sulfate, serine-magnesium sulfate, nac and cysteine before being exposed to 2 gy of γ-radiation. lymphocytes were isolated using a separation medium and methyl-thiazole-tetrazolium and comet assays were used to evaluate cell viability and dna damage, respectively. results: the serine-magnesium sulfate mixture significantly increased lymphocyte viability and reduced dna damage in comparison to serine, magnesium sulfate, nac or cysteine alone (p <0.01 each). conclusion: the findings of the present study support the use of a serine-magnesium sulfate mixture as a new, non-toxic, potent and efficient radioprotective agent. keywords: ionizing radiation; gamma rays; dna damage; radioprotective agents; serine; magnesium sulfate; n-acetylcysteine; cysteine. امللخ�ص: الهدف: االإ�سعاعات املوؤينة مثل االأ�سعة جاما واالأ�سعة ال�سينية لها العديد من االآثار ال�سارة على اخلاليا الب�رشية. من املعروف اأن ال ن-اأ�سيتيل �سي�ستئني وال�سي�ستئني، وامل�ستقلب الفعال لل ن-اأ�سيتيل �سي�ستئني، مواد حماية �سد االإ�سعاع. وحديثا اقرتح خليط كربيتات املغني�سيوم وال�سريين كم�ساد للت�سمم مببيدات االآفات الفو�سفاتية الع�سوية. يف هذا العمل، وهدفت هذه الدرا�سة ايل التحقق من ا�ستخدام كربيتات �سريين املغني�سيوم ملنع التاأثريات ال�سارة لالإ�سعاع جاما على احلم�س النووي يف اخلاليا الليمفاوية لالإن�سان ومقارنتها مع ا�ستخدام ال ن-اأ�سيتيل �سي�ستئني وال�سي�ستني. الطريقة: وقد اأجريت هذه الدرا�سة يف كلية ال�سيدلة، يف احلرم اجلامعي الدويل جلامعة ايران �سخ�سا 22 من بال�سيرتات معاجله أنابيب يف الدم من مل 7 �سحب مت .2016 و�سبتمرب اأبريل �سهري بني اإيران، طهران، الطبية، للعلوم من 2 gy اإىل الثاين اجلزء تعري�س مت �سابطه. جمموعه االأول اجلزء واعترب مل. 1 منها كل اأجزاء اإىل العينات جميع تق�سيم مت �سليما. اإ�سعاع جاما مبعدل جرعة دقيقة/cgy 102.7. اأما بالن�سبه ايل االأجزاء من الثالثة اإىل ال�سابعة فتم حفظها ب�سكل منف�سل مع μm 600 من مواد ال�سريين وكربيتات املغني�سيوم و�سريين-كربيتات املغني�سيوم، ال ن-اأ�سيتيل �سي�ستئني، وال�سي�ستني قبل تعري�سها على ل gy 2 غراي من اإ�سعاع جاما. مت ف�سل اخلاليا الليمفاوية من العينات بوا�سطة و�سيط و مادة ال مثيل ثيازول تيرتازوليوم وا�ستحدم مقيا�س كوميت لتقييم �سالمة اخللية واحلم�س النووي. النتائج: اأظهرت النتائج اأن خليط كربيتات املغني�سيوم وال�سريين هو االأف�سل بكثري يف تقليل التلف يف احلم�س النووي وحيوية اخلاليا الليمفاوية من مركبات ال�سريين، كربيتات املغني�سيوم، ال ن-اأ�سيتيل �سي�ستئني ، وال�سي�ستني لوحدها (p <0.01، كل واحد) اخلال�صة: تدعم نتائج هذا البحث اأ�ستخدام خليط كربيتات املغني�سيوم وال�سريين كعامل جديد قوي، وفعال يف احلماية �سد خطر االإ�سعاع. املغني�سيوم؛ كربيتات ال�سريين؛ االإ�سعاع؛ �سد حماية مواد النووي؛ احلم�س تلف جاما؛ اأ�سعة املوؤينة؛ االإ�سعاعات املفتاحية: الكلمات ن -اأ�سيتيل �سي�ستني؛ ال�سي�ستني. prevention of γ-radiation-induced dna damage in human lymphocytes using a serine-magnesium sulfate mixture vahid changizi,1 mona bahrami,1 mahbod esfahani,2 *seyed v. shetab-boushehri3,4 clinical & basic research sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e162–167, epub. 20 jun 17 submitted 28 dec 16 revision req. 12 feb 17; revision recd. 26 feb 17 accepted 23 mar 17 advances in knowledge the findings of the present study demonstrated that a serine-magnesium sulfate mixture reduced γ-radiation cytotoxicity and genotoxicity in isolated human lymphocytes. moreover, the radioprotective effects of a serine-magnesium sulfate mixture were greater than that of n-acetylcysteine and its active metabolite, cysteine. as such, these findings indicate that a mixture of serine and magnesium sulfate mixture may be a new and nontoxic radioprotective agent. doi: 10.18295/squmj.2016.17.02.005 vahid changizi, mona bahrami, mahbod esfahani and seyed v. shetab-boushehri clinical and basic research | e163 both γand x-rays are forms of ionising radiation with sufficient energy to displace electrons from molecules; these released electrons can subsequently have deleterious effects on human cells, particularly highly proliferating cells, with one of the most important cellular effects being dna damage.1–3 lymphocytes are among the most radiosensitive cells which can be used to evaluate the effect of ionising radiation on humans.1–3 a simple, sensitive, versatile, rapid and economical method of assessing dna damage is comet assay or single-cell gel electrophoresis; this involves embedding cells in a low-melting-point agarose (lmpa), lysis of the cells in neutral or alkaline conditions (ph >13) and electrophoresis of the suspended lysed cells.4–6 a methyl-thiazole-tetrazolium (mtt) assay is a colour imetric assay for assessing cell viability and metabolic activity in which a yellow water-soluble tetrazolium dye is reduced by mitochondrial nicotinamide adenine dinucleotide phosphatedependent oxidoreductase enzymes of live, but not dead, cells to a purple formazan product that is insoluble in aqueous solutions. under defined conditions, a mtt assay therefore reflects the number of viable cells present.7,8 serine is an analogue of cysteine, a well-known radioprotective agent.9–11 a serine-magnesium sulfate combination was recently proposed as an antidote for organophosphate pesticide poisoning by an ionradical mechanism.12 this study therefore aimed to investigate the prevention of γ-radiation-induced dna damage in human lymphocytes using a serine magnesium sulfate mixture in comparison to n-acetylcysteine (nac) and cysteine. comet and mtt assays were used to evaluate dna damage and cell viability, respectively, in isolated lymphocytes. methods this study was carried out at the school of pharmacy of the iran university of medical sciences, tehran, iran, between april and september 2016. a total of 22 healthy human subjects were recruited to participate. the sample size was determined according to the following formula for continuous variables:13 where the constant c is dependent on the values of α (false-positive) and β (false-negative). for α = 0.05 and 1 β = 0.9, c is 10.51, s is the standard deviation of a variable and d is the magnitude of the difference. accordingly, for d = s, the sample size was calculated as 22. each recruited participant was subsequently asked to fill out a questionnaire design to elicit information on their health status, use of medications, occupational history and exposure to pesticides. individuals with a history of diabetes mellitus, hypertension, liver disease, anaemia, malnutrition, cancer or other chronic illnesses, cigarette smoking, alcohol or drug use and a history of radiotherapy were excluded. the following chemicals and solutions were purchased: l-serine, nac, l-cysteine, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, potassium chloride, sodium hydroxide, trisodium citrate dihydrate, absolute ethanol, tris(hydroxymethyl)aminomethane hydrochloride (tris-hcl), ethylenediaminetetraacetic acid (edta) and its disodium salt dihydrate (na2edta), trypan blue, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (hepes), dimethyl sulfoxide (dmso), glycine and mtt (merck kgaa, darmstadt, germany); normal melting agarose (nma), lmpa, fetal bovine serum (fbs) and sybr green (sigma-aldrich co. ltd., dorset, uk); and lymphosep® (biowest, nuaillé, france). stock solutions of nac, l-cysteine, l-serine, magnesium sulfate and an l-serine-magnesium sulfate mixture were stored in the dark at 4 °c. each solution was then separately prepared in 0.9% of weight/volume (w/v) sodium chloride in distilled water (i.e. normal saline) to produce 60 mm concentrations. a 7-ml blood sample was obtained from each participant by venipuncture and immediately citrated with trisodium citrate at a concentration of 3.8% w/v in a ratio of 1:9 parts of blood to prevent clot formation.14 all samples were divided into 1 ml aliquots. the first aliquot was considered the control. the second aliquot was exposed to 2 gy of γ-radiation at a dose rate of 102.7 cgy/minute using a theratron® 780 cobalt-60 therapy unit (theratronics ltd., ottawa, canada). the remaining aliquots were pre-incubated for 60 minutes with 10 μl each of the nac, l-cysteine, l-serine, magnesium sulfate and l-serine-magnesium sulfate mixture solutions at a final concentration of 600 μm application to patient care the results of this study may potentially be utilised at emergency medicine, radiotherapy and radiology centres to prevent and/or reduce γ-radiation toxicity among personnel; however, extensive in vivo studies are needed to confirm the safety and efficacy of this new radioprotective agent among both animals and humans. (n = 1+2c )2 s d prevention of γ-radiation-induced dna damage in human lymphocytes using a serine-magnesium sulfate mixture e164 | squ medical journal, may 2017, volume 17, issue 2 each in a 37 °c water bath before being exposed to 2 gy of γ-irradiation at a dose rate of 102.7 cgy/minute. lymphocytes were isolated from the blood samples using the lymphosep® (biowest) separation medium according to the manufacturer’s instructions. the samples were diluted at a ratio of 1:1 with a phosphatebuffered saline (pbs) solution and then carefully layered on the separation medium in a 1:1.5 ratio. lymphocytes were separated by centrifugation at 400 x g for 20 minutes at room temperature. buffy coats containing lymphocytes were removed and washed twice more with a pbs solution and then centrifuged at 200 x g for 10 minutes. cell count and viability were determined using the trypan blue exclusion method.15 the lymphocytes were then diluted to 1,000 cells/µl with a pbs solution containing 10 mm of hepes at a ph of 7.4. isolated lymphocytes were analysed using mtt and comet assays for cell viability and dna damage, respectively. for the mtt assay, isolated lympho cytes were incubated for four hours at 37 °c with 5% carbon dioxide (co2) and humidified. 16 a total of 50 μl of mtt in a pbs solution at a concentration of 3 mg/ml was added to 200 μl of suspended lymphocytes. the samples were wrapped in aluminium foil and incubated for four hours at 37 °c. the pbs solution and mtt was removed by centrifugation at 300 x g for 10 minutes. a total of 200 μl of dmso and 25 μl of a glycine buffer at a ph of 10.5 was added to each sample and mixed. the lymphocytes of each sample were then transferred to a 48-well plate and the corresponding absorbances were measured with a multi-mode microplate reader (synergy™ ht, bio-tek instruments inc., highland park, illinois, usa) at 570 nm. for the comet assay, lymphocytes were first centrifuged at 300 x g for 10 minutes and suspended in a roswell park memorial institute (rpmi) 1640 culture medium containing 10% fbs. they were cultured and incubated for 24 hours at 37 °c with 5% co2 and humidified. cells were then collected in microtubes, centrifuged at 300 x g for 10 minutes at 4 °c and then resuspended in the rpmi 1640 medium and diluted to 100 cells/µl. the comet assay was performed in alkaline conditions as previously described by singh et al.17 a total of 10 µl of lymphocytes were mixed with 100 µl of 0.5% lmpa at 37 °c. then, 75 µl of the mixture was placed on a precleaned microscope slide which had been covered with a thin layer of 0.5% nma and allowed to solidify to promote even and firm attachment of the second layer. the suspension was spread on the surface with a coverslip. the slides were then refrigerated at 4 °c for five minutes to allow solidification of the agarose. without coverslips, the slides were subsequently immersed in a freshly prepared cold lysing solution consisting of 2.5 m of sodium chloride, 100 mm of na2edta, 10 mm of tris-hcl at a ph of 10.0 and 1% triton™ x-100 (sigma-aldrich co. ltd.). the solution was refrigerated for one hour to lyse the cells and permit dna unfolding. slides were then immersed in an alkaline buffer of 300 mm of sodium hydroxide and 1 mm of na2edta at a ph of 13.0 for 20 minutes to allow unwinding of the dna. electrophoresis was conducted for 20 minutes at a voltage of 25 v. slides were then drained and immersed in a neutralisation buffer of 0.4 m of tris-hcl at a ph of 7.5 for five minutes. they were dried and stained with 50 μl of diluted sybr green (sigma-aldrich co. ltd.) at a ratio of 1:10 with a buffer of 1 mm of edta and 10 mm tris-hcl at a ph of 7.5 on each circle of dried agarose. the slides were again refrigerated for five minutes, gently tapped to remove the excess sybr green (sigma-aldrich co. ltd.) and allowed to dry completely at room temperature in the dark. they were then viewed under a fluorescence microscope (dp72 digital color camera, olympus, tokyo, japan) equipped with an ultravioletwg filter cube with an excitation filter of 510–560 nm and a barrier filter of 590 nm. a total of 200 individual cells were screened for each aliquot. undamaged cells were defined as cells with an intact nucleus without a tail while cells were considered damaged if they had visible tails (i.e. cells with a ‘comet’-like appearance). all statistical analyses were performed using the statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa). the cell viability of each sample was divided by that of the control sample and presented as a percentage of cell viability. a one-sample t-test was used to analyse differences in cell viability between samples that received only γ-radiation and the control group (deemed to have 100% viability). differences in cell viability between experimental groups were analysed using a one-way analysis of variance (anova) test followed by scheffe post hoc analysis. the dna damage for each cell was quantified by calculating the tail moment (i.e. the product of tail length and fraction of total dna in the tail) using opencomet software, version 1.3.18 differences between the tail moments of experimental groups were also analysed using a one-way anova test followed by scheffe post hoc analysis. charts comparing the differences between the experimental groups were rendered using sigmaplot software, version 12.0 (systat software inc., san jose, california, usa). levene’s test was used to determine the homogeneity of variance of tail moments and cell viabilities. a p value of <0.05 was considered statistically significant. vahid changizi, mona bahrami, mahbod esfahani and seyed v. shetab-boushehri clinical and basic research | e165 all procedures performed during this study were in accordance with the ethical guidelines of the declaration of helsinki. all of the subjects provided informed written consent prior to their inclusion in the study. results all variances for cell viabilities were homogeneous (p >0.05). the γ-irradiation significantly reduced lymphocyte viability in comparison to the control group (45.1% ± 3.0% of the control group; p <0.01). in contrast, nac significantly increased lymphocyte viability over that of the γ-irradiated group (65.1% ± 3.7% of the control group; p <0.01). cysteine significantly increased lymphocyte viability over that of the γ-irradiated, serine and nac groups (75.1% ± 2.2% of the control group; p <0.01 each). serine significantly increased lymphocyte viability over that of the γ-irradiated group (59.4% ± 3.2% of the control group; p <0.01); however, there was no statistical difference in cell viability between the nac and serine groups (p >0.05). magnesium sulfate did not significantly increase lymphocyte viability in comparison to the γ-irradiated group (42.7% ± 1.7% of the control group; p >0.05). the serine-magnesium sulfate mixture significantly increased lymphocyte viability in comparison to the γ-irradiated, nac, cysteine and serine groups (89.7% ± 1.6% of the control group; p <0.01 each) [figure 1]. all variances for tail moments were homogeneous (p >0.05). the mean tail moment of the control group was 4.7 ± 0.4. the γ-irradiation signifi cantly increased tail moments in comparison to the control group (34.1 ± 2.2; p <0.01). both nac and cysteine significantly reduced tail moments compared to the γ-irradiated group (24.8 ± 1.8 and 19.2 ±1.9, respectively; p <0.01 each); however, cysteine also significantly reduced tail moments in comparison to the nac group (p <0.05). serine significantly reduced tail moments below those of the γ-irradiated group (29.1 ± 1.3; p <0.05), although cysteine was significantly stronger than serine in reducing tail moments (p <0.01). there was no statistical difference between nac and serine in terms of tail moment reduction (p >0.05). magnesium sulfate did not significantly reduce tail moments in comparison to the γ-irradiated group (33.2 ± 1.9; p >0.05). the serine-magnesium sulfate mixture significantly reduced tail moments in comparison to the γ-irradiated, nac, cysteine and serine groups (12.4 ± 1.4; p <0.01) [figure 2]. discussion the deleterious effects of ionising radiation on peripheral lymphocytes—such as dna fragmentation—are commonly observed at least 24 hours after exposure to radiation.19 moreover, nucleotide pool levels are generally lower in lymphocytes than other cell types, which may account for the observed increased sensitivity of lymphocytes to radiation.20 low nucleotide pool levels hinder dna double-strand rejoining, leading to more detectable strand breaks than other cell types.20 peripheral human lymphocytes are quiescent cells, meaning that they are in the g0 phase; thus, there is no need to rule out cell cycle arrest.21,22 since lymphocytes do not undergo normal mitosis, different phases of the cell cycle (i.e. g1, s, m and g2) were not defined in the current study. 21,22 figure 1: chart showing mean lymphocyte viability in different experimental groups as a measure of radioprotection against γ-irradiation in human lymphocytes (n = 22). nac = n-acetylcysteine; mgso4 = magnesium sulfate. *statistically significant difference in comparison to the control group (p <0.01). †statistically significant difference in comparison to the γ-irradiation group (p <0.01). ‡statistically significant difference in comparison to the serine group (p <0.01). §statistically significant difference in comparison to the nac group (p <0.01). ¶statistically significant difference in comparison to the cysteine group. figure 2: chart showing mean tail moment in arbitrary units in different experimental groups as a measure of radioprotection against γ-irradiation in human lymphocytes (n = 22). nac = n-acetylcysteine; mgso4 = magnesium sulfate. *statistically significant difference in comparison to the control group (p <0.01). †statistically significant difference in comparison to the γ-irradiation group (p <0.05). ‡statistically significant difference in comparison to the serine group (p <0.01). §statistically significant difference in comparison to the nac group (p <0.01). ¶statistically significant difference in comparison to the cysteine group. prevention of γ-radiation-induced dna damage in human lymphocytes using a serine-magnesium sulfate mixture e166 | squ medical journal, may 2017, volume 17, issue 2 the median lethal oral doses of cysteine, nac and serine in rats are 1,890 mg/kg, 5,050 mg/kg and 14,000 mg/kg, respectively; thus, these substances are classified as moderately toxic, slightly toxic and practically non-toxic, respectively.23–26 currently, the mucolytic agent nac is used for the treatment of acetaminophen overdoses, hepatotoxic mushroom poisoning and as an adjuvant antidote for organophosphate pesticide poisoning.27–29 other medical uses for nac include the treatment of radiocontrastinduced nephropathy, cyclophosphamide-induced haemorrhagic cystitis and a number of psychiatric disorders; it also has significant antiviral activity against influenza type a viruses.30 moreover, nac has been shown to replenish glutathione stores in cells and has free radical scavenging properties.30 it is a prodrug which is enzymatically metabolised (i.e. deacetylated) to its active metabolite cysteine by the liver and serves as a cysteine donor. the thiol group is reactive toward xenobiotics and seems to be responsible for the beneficial effects of cysteine in poisoning cases.11,30 both nac and cysteine are known radioprotective agents whose radioprotective properties are attributable to the antioxidant and free radical scavenging characteristics of the thiol group.10,11 the pka values—the values at which half of the functional group are ionised—of the thiol group have been shown to play an important role in the radioprotective properties of these agents, in that the more the thiol is ionised, the greater the radioprotection.31 although comparable in reactivity to thiol for the scavenging of hydroxyl radicals, the thiolate ion (the ionised form of thiol) is more reactive in the repair of dna.31 the pka values of nac and cysteine are 9.5 and 8.3, respectively.10,32 according to the henderson-hasselbalch equation, the nac and cysteine thiol groups are 0.8% and 11.2% ionised, respectively, at a ph of 7.4, which is the physiological ph of the human body.9 serine is an analogue of cysteine which differs in that the sulphur atom in cysteine is replaced by an oxygen atom in serine hydroxyl; the pka of the serine hydroxyl group is approximately 13.0 and is only 0.00025% ionised at a ph of 7.4.9 magnesium sulfate has been shown to reduce the pka value of high-pka groups of oxygen nucleophiles, such as the serine hydroxyl group.9 in the present study, the radioprotective effect of an equimolar therapeutic concentration of a serine-magnesium sulfate mixture on γ-radiationinduced dna damage was compared with nac, cysteine, serine and magnesium sulfate alone. the concentrations of nac, cysteine and magnesium sulfate were selected on the basis of their therapeutic plasma concentrations in humans.27,33,34 the results indicated that the serine and magnesium sulfate mixture had a greater radioprotective effect than nac and cysteine alone. this may be related to the pka reduction of the serine hydroxyl group by magnesium sulfate and the production of a more ionised hydroxyl group. an oxygen ion has a smaller ionic radius than sulphur and is therefore smaller in size; thus, the density of a negative charge is greater on the smaller-sized oxygen ion in comparison to the larger-sized sulphur ion.35 this may result in greater reactivity of the hydroxyl group compared to the thiol group. the results of the current study also demonstrated that cysteine provided greater protection against γ-radiation-induced dna damage and cell death in isolated human lymphocytes in comparison to nac. this may be due to the fact that nac needs to be metabolised by the liver, a process which was not conducted in the present in vitro study. the findings also showed that serine alone protected the lymphocytes against γ-radiation-induced dna damage and cell death, although to a lesser degree than nac or cysteine. this may be related to the presence of a small amount of the intracellular magnesium ion which partially reduces the pka of the serine hydroxyl group, thereby resulting in a more ionised form of the hydroxyl group.12,36 lymphocytes are among the most useful radiosensitive cells for studying the biological effects of radiation. their advantages over other human cells include the fact that they can be easily obtained in large numbers, do not require cell culture facilities, are diploid and are almost all in the same phase of the cell cycle (g0). 21,22 they are highly specialised and potentially reflect the overall state of the organism as they circulate throughout the entire body.35 while the findings of the current study indicate a potential new radioprotective agent, further in vivo studies are needed to confirm the safety and efficacy of serinemagnesium sulfate in terms of preventing γ-radiationinduced dna damage. conclusion the findings of this study propose the use of a serinemagnesium sulfate mixture as a new, non-toxic and more potent and efficient radioprotective agent against γ-radiation cytotoxicity and genotoxicity. however, extensive human as well as animal studies are needed to confirm the safety and efficacy of this agent. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. vahid changizi, mona bahrami, mahbod esfahani and seyed v. shetab-boushehri clinical and basic research | e167 f u n d i n g this study was funded by the iran university of medical sciences & health services (grant #27817). references 1. international atomic energy agency. effects of ionizing radiation on blood and blood components: a survey. vienna, austria: international atomic energy agency, 1997. pp. 7–17. 2. international atomic energy agency. cytogenetic analysis for radiation dose assessment: a manual. vienna, austria: international atomic energy agency, 2001. pp. 4–12. 3. international atomic energy agency. radiation biology: a handbook for teachers and students. vienna, austria: international atomic energy agency, 2010. pp. 13–32. 4. el yamani n, collins ar, rundén-pran e, fjellsbø lm, shaposhnikov s, zielonddiny s, et al. in vitro genotoxicity testing of four reference metal nanomaterials, titanium dioxide, zinc oxide, cerium oxide and silver: towards reliable hazard assessment. mutagenesis 2017; 32:117–26. doi: 10.1093/mutage/ gew060. 5. collins ar, azqueta a. dna repair as a biomarker in human biomonitoring studies: further applications of the comet assay. mutat res 2012; 736:122–9. doi: 10.1016/j.mrfmmm. 2011.03.005. 6. speit g, rothfuss a. the comet assay: a sensitive genotoxicity test for the detection of dna damage and repair. methods mol biol 2012; 920:79–90. doi: 10.1007/978-1-61779-998-3_6. 7. nikzad s, baradaran-ghahfarokhi m, nasri p. dose-response modeling using mtt assay: a short review. life sci j 2014; 11:432–7. 8. nikzad s, hashemi b. mtt assay instead of the clonogenic assay in measuring the response of cells to ionizing radiation. j radiobiol 2014; 1:3–8. doi: 10.15171/jrb.2014.02. 9. kennelly pj, rodwell vw. amino acids and peptides. in: rodwell vw, bender da, botham km, kennelly pj, weil pa, eds. harper’s illustrated biochemistry, 30th ed. new york, usa: mcgraw-hill, 2015. pp. 15–24. 10. gudkov sv, popova nr, bruskov vi. radioprotective substances: history, trends and prospects. biophys 2015; 60:659–67. doi: 10.1134/s0006350915040120. 11. demirel c, kilçilksiz s, ay oi, gürgül s, ay me, erdal n. effect of n-acetylcysteine on radiation-induced genotoxicity and cytotoxicity in rat bone marrow. j radiat res 2009; 50:43–50. doi: 10.1269/jrr.08066. 12. shetab-boushehri sv, shetab-boushehri sf, abdollahi m. possible role of mg2+ ion in the reaction of organophosphate (dichlorvos) with serine. j med hypotheses ideas 2012; 6:53–7. doi: 10.1016/j.jmhi.2012.05.001. 13. dell rb, holleran s, ramakrishnan r. sample size determination. ilar j 2002; 43:207–13. doi: 10.1093/ilar.43.4.207. 14. young ds, bermes ew. specimen collection and processing: sources of biological variation. in: burtis ca, ashwood er, eds. tietz textbook of clinical chemistry, 3rd ed. philadelphia, pennsylvania, usa: saunders, 1999. pp. 42–72. 15. freshney ri. culture of animal cells: a manual of basic technique and specialized applications, 6th ed. hoboken, new jersey, usa: wiley-blackwell, 2010. p. 367. 16. wilson ap. cytotoxicity and viability assays. in: masters jr, ed. animal cell culture: a practical approach, 3rd ed. oxford, uk: oxford university press, 2010. pp. 175–220. 17. singh np, mccoy mt, tice rr, schneider el. a simple technique for quantitation of low levels of dna damage in individual cells. exp cell res 1988; 175:184–91. doi: 10.1016/ 0014-4827(88)90265-0. 18. gyori bm, venkatachalam g, thiagarajan ps, hsu d, clement mv. opencomet: an automated tool for comet assay image analysis. redox biol 2014; 2:457–65. doi: 10.1016/j.redox.2013.12.020. 19. wilkins rc, kutzner bc, truong m, sanchez-dardon j, mclean jr. analysis of radiation-induced apoptosis in human lymphocytes: flow cytometry using annexin v and propidium iodide versus the neutral comet assay. cytometry 2002; 48:14–19. doi: 10.1002/cyto.10098. 20. fairbairn dw, olive pl, o’neill kl. the comet assay: a comprehensive review. mutat res 1995; 339:37–59. doi: 10.1016/ 0165-1110(94)00013-3. 21. vignon c, debeissat c, georget mt, bouscary d, gyan e, rosset p, et al. flow cytometric quantification of all phases of the cell cycle and apoptosis in a two-color fluorescence plot. plos one 2013; 8:e68425. doi: 10.1371/journal.pone.0068425. 22. yusuf i, fruman da. regulation of quiescence in lymphocytes. trends immunol 2003; 24:380–6. doi: 10.1016/s14714906(03)00141-8. 23. sprince h, parker cm, smith gg, gonzales lj. protection against acetaldehyde toxicity in the rat by l-cysteine, thiamin and l-2-methylthiazolidine-4-carboxylic acid. agents actions 1974; 4:125–30. doi: 10.1007/bf01966822. 24. goldenthal ei. a compilation of ld50 values in newborn and adult animals. toxicol appl pharmacol 1971; 18:185–207. doi: 10.1016/0041-008x(71)90328-0. 25. tada y, yano n, takahashi h, yuzawa k, ando h, kubo y, et al. a 90-day feeding toxicity study of i-serine in male and female fischer 344 rats. j toxicol pathol 2010; 23:39–47. doi: 10.1293/ tox.23.39. 26. keller rj. principles of toxicology. in: luttrell we, jederberg ww, still kr, eds. toxicology principles for the industrial hygienist. fairfax, virginia, usa: american industrial hygiene association, 2008. pp. 7–13. 27. prescott l. oral or intravenous n-acetylcysteine for acetaminophen poisoning? ann emerg med 2005; 45:409–13. doi: 10.10 16/j.annemergmed.2004.09.028. 28. enjalbert f, rapior s, nouguier-soulé j, guillon s, amouroux n cabot c. treatment of amatoxin poisoning: 20-year retrospective analysis. j toxicol clin toxicol 2002; 40:715–57. doi: 10.1081/clt-120014646. 29. shadnia s, ashrafivand s, mostafalou s, abdollahi m. n-acetylcysteine a novel treatment for acute human organophosphate poisoning. int j pharmacol 2011; 7:732–5. doi: 10.3923/ijp.2011.732.735. 30. asevedo e, mendes ac, berk m, brietzke e. systematic review of n-acetylcysteine in the treatment of addictions. rev bras psiquiatr 2014; 36:168–75. doi: 10.1590/1516-4446-2013-1244. 31. zheng s, newton gl, gonick g, fahey rc, ward jf. radioprotection of dna by thiols: relationship between the net charge on a thiol and its ability to protect dna. radiat res 1988; 114:11–27. doi: 10.2307/3577140. 32. moffat ac, osselton md, widdop b, eds. clarke’s analysis of drugs and poisons, 4th ed. london, uk: pharmaceutical press, 2011. p. 823. 33. pajoumand a, shadnia s, rezaie a, abdi m, abdollahi m. benefits of magnesium sulfate in the management of acute human poisoning by organophosphorus insecticides. hum exp toxicol 2004; 23:565–9. doi: 10.1191/0960327104ht489oa. 34. prescott lf, donovan jw, jarvie dr, proudfoot at. the disposition and kinetics of intravenous n-acetylcysteine in patients with paracetamol overdose. eur j clin pharmacol 1989; 37:501–6. doi: 10.1007/bf00558131. 35. silberberg m. principles of general chemistry, 2nd ed. new york, usa: mcgraw-hill, 2009. p. 273. 36. romani am. cellular magnesium homeostasis. arch biochem biophys 2011; 512:1–23. doi: 10.1016/j.abb.2011.05.010. https://doi.org/10.1093/mutage/gew060 https://doi.org/10.1093/mutage/gew060 https://doi.org/10.1016/j.mrfmmm.2011.03.005 https://doi.org/10.1016/j.mrfmmm.2011.03.005 https://doi.org/10.1007/978-1-61779-998-3_6 https://doi.org/10.15171/jrb.2014.02 https://doi.org/10.1134/s0006350915040120 https://doi.org/10.1269/jrr.08066 https://doi.org/10.1016/j.jmhi.2012.05.001 https://doi.org/10.1093/ilar.43.4.207 https://doi.org/10.1016/0014-4827%2888%2990265-0 https://doi.org/10.1016/0014-4827%2888%2990265-0 https://doi.org/10.1016/j.redox.2013.12.020 https://doi.org/10.1002/cyto.10098 https://doi.org/10.1016/0165-1110%2894%2900013-3 https://doi.org/10.1016/0165-1110%2894%2900013-3 https://doi.org/10.1371/journal.pone.0068425 https://doi.org/10.1016/s1471-4906%2803%2900141-8 https://doi.org/10.1016/s1471-4906%2803%2900141-8 https://doi.org/10.1007/bf01966822 https://doi.org/10.1016/0041-008x%2871%2990328-0 https://doi.org/10.1293/tox.23.39 https://doi.org/10.1293/tox.23.39 https://doi.org/10.1016/j.annemergmed.2004.09.028 https://doi.org/10.1016/j.annemergmed.2004.09.028 https://doi.org/10.1081/clt-120014646 https://doi.org/10.3923/ijp.2011.732.735 https://doi.org/10.1590/1516-4446-2013-1244 https://doi.org/10.2307/3577140 https://doi.org/10.1191/0960327104ht489oa https://doi.org/10.1007/bf00558131 https://doi.org/10.1016/j.abb.2011.05.010 sultan qaboos university med j, may 2013, vol. 13, iss. 2, pp. 202-217, epub. 9th may 13 submitted 19th jul 12 revision req. 10th sep 12, revision recd. 18th oct 12 accepted 27th oct 12 according to the global cancer incidence report, lung cancer is the most common malignancy and a leading cause of cancer-related death worldwide.1 in the usa, non-small-cell lung carcinoma (nsclc) accounts for approximately 87% of all the cases of lung cancer with adenocarcinoma as the most prevalent subtype (40%).2 in oman, nsclc accounts for 88% of all lung cancers, with adenocarcinoma in 34% of cases, and squamous cell carcinoma (scc) in 22%.3 despite diagnostic advances, lung cancer continues to present in advanced stages and as many as 50% of the patients have unresectable disease (stages iiib– iv), and perhaps an even higher percentage in the developing world [table 1].2 certain clinical parameters have an impact on the outcome of the disease. gender affects outcomes as females generally are diagnosed at a younger age and earlier stage, and perhaps have an inherent greater longevity. different races also have different 5-year relative survival rates. in a study done between 2001–07, the 5-year survival rates were as follows: white men 13.7%; white women 18.3%; black men 11.6%; black women 14.5%.2 weight loss, 1department of medicine, sultan qaboos university hospital; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3oncology department, shaukat khanum memorial cancer hospital & research center, lahore, pakistan *corresponding author e-mail: furrukh_1@yahoo.com العالج الفردي و املخصص لسرطان الرئة املنتشر من اخلاليا غري الصغرية حممد فروخ، من�شور املنذري، فرحان خوجة زاهد، �شيام كومار، و اإكرام برين املتقدمة املراحل مر�شى اأن موؤخرا اأكدت واأوروبا اآ�شيا يف الع�شوائية الثالثة واملرحلة الثانية، املرحلة درا�شات من �شل�شلة امللخ�ص: من �رسطان الرئة من اخلاليا الغري �شغرية من النوع الفرعي الغدي الآوي لطفرات حمددة عندما تتعر�ض للعالج امل�شتهدف تظهر نتائج بقاء م�شاوية للذين عوجلوا بالعالج الكيميائي ومبناأى عن اإثارة الأعرا�ض اجلانبية. ان مفهوم العالج الكيميائي للجميع بداأ بالتال�شي، والو�شول للعالج الأمثل يربز كنقلة نوعية يف العالج. تو�شح هذه املقالة باإيجاز الآليات اخللوية امل�شاهمة يف �رسطنة الرئة و التي توفر اأ�شا�ض جزيئي للعالج امل�شتهدف. اإن التقدم يف علم الأحياء اجلزيئي ح�شنت فهمنا لالآليات التي ت�شارك يف مقاومة الأدوية البتدائية اأو الثانوية. يورد هذا املقال باإيجاز التطورات يف املوؤ�رسات احليوية ذات األأهمية التكهنية والتنبوؤية، واأثر البحوث املتعدية على نتائج العالج. اإن عالمة ما تعترب تكهنية اإذا توقعت النتائج، بغ�ض النظر عن العالج، وتنبوؤية اإذا توقعت نتائج عالج حمدد الأوعية بطانة منو عامل الب�رسة؛ منو عامل الرئة؛ يف اخلبيثة الأورام �شغرية؛ الغري اخلاليا من الرئة �رسطان �رسطان؛ الكلمات: مفتاح الدموية؛ عالمات بيولوجية؛ مثبطات الربوتني كينيز. abstract: a series of phase ii and randomised phase iii trials in asia and europe have confirmed recently that advanced stage non-small-cell lung carcinoma patients with adenocarcinoma subtypes harbouring specific mutations when subjected to targeted therapy experience equivalent survival outcomes as those treated with chemotherapy and are spared from its side effects. the concept of chemotherapy for all is fading, and therapy optimisation has emerged as a paradigm shift in treatment. this article briefly describes cellular mechanisms involved in lung carcinogenesis which provide a molecular basis for targeted therapy. advances in molecular biology have improved our understanding of mechanisms involved in primary or secondary drug resistance. evolving biomarkers of prognostic and predictive importance, and the impact of translational research on outcomes are also covered. a marker is considered prognostic if it predicts the outcome, regardless of the treatment, and predictive if it predicts the outcome of a specific therapy. keywords: carcinoma; non-small-cell lung; lung neoplasm; receptor, epidermal growth factor; vascular endothelial growth factor; biological markers; protein kinase inhibitors, bevacizumab, erlotinib. review customised, individualised treatment of metastatic non-small-cell lung carcinoma (nsclc) *muhammad furrukh,1 mansour al-moundhri,2 khawaja f. zahid,3 shiyam kumar,1 ikram burney1 muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 203 poor performance status, advancing age, and the presence of concomitant illness may also adversely affect patient outcomes.4–7 smoking has emerged as a prognostic and predictive marker. in addition, it also has certain significance, i.e. never smokers have epidermal growth factor receptor (egfr) mutations at a rate of 37% compared to 14% in current and former smokers; k-ras mutations in 4% of never smokers as compared to 43% in current and former smokers, and echinoderm microtubule-associated protein-like4 anaplastic lymphoma kinase (eml4alk) in 12% of never smokers as compared to 2% of current and former smokers. the prevalence of p53 mutation was the same in never smokers and current and former smokers (26% each).8 methods data were identified from searches of pubmed, medscape, google, and key cancer groups (american society for clinical oncology, national comprehensive cancer network, european society for medical oncology) using search terms such as “chemotherapy in advanced nsclc”, and various biomarkers of prognostic and predictive markers in lung cancer, egfr, egfr mutation (egfrmut), k-ras mutation, eml4-alk mutation, met, and t790m mutations. reference was also made to key phase ii and iii trials and meta-analyses published in oncology journals including chest, clinical advances in hematology & oncology, journal of clinical oncology, new england journal of medicine, the lancet oncology, oncologist, and cancer. information acquired from international scientific conferences was confirmed through computer searches. evolution of systemic chemotherapy in advanced/metastatic nsclc patients with advanced or metastatic nsclc have traditionally been treated with systemic therapy if they carry a performance status of zero to two. untreated, these patients have a median survival time of 3–4 months, and only one in 10 patients survives 12 months on best supportive care (bsc).9–10 cisplatin or carboplatin is the cytotoxic backbone when considering palliative chemotherapy.11 in 1995, a large meta-analysis revealed a 27% risk reduction in death and one year survival enhancement of 10% when comparing chemotherapy to best supportive care (bsc).12 the cochrane collaboration group upheld the advantage of platinum doublets which were associated with higher response rates (rr) and an absolute benefit of 5% improvement in one-year survival.13 the eastern cooperative oncology group (ecog) e1594 study is regarded as a reference trial of advanced nsclc comparing four different chemotherapy regimens with each other (i.e. cisplatin combined in three arms with paclitaxel, gemcitabine, and docetaxel, respectively and the fourth arm comprising carboplatin and paclitaxel). the rr improved from 10 to 19%, and the median survival improved to 9.1 months for 431 females, and 7.4 months for 726 males. the survival increased to approximately 33% in the first year and 11% in the second year. essentially, all arms revealed similar median survival, but the regimen comprising cisplatin and gemcitabine was associated with longer time to progression (ttp), whereas carboplatin and paclitaxel was the least toxic amongst the four arms, and regarded as their reference doublet combination for future studies.10 other large phase iii trials validated the results table 1: stage, distribution, and 5-year survival rate by stage at diagnosis: 2001–07 (adapted from seer2) stage at diagnosis stage distribution (%) 5-year relative survival (%) localised 15 52 regional (lymph nodes) 22 24 distant (metastases) 56 <4 not staged 07 08 *stage at diagnosis stage distribution (%) 5-year relative survival (%) **nsclc (82.7%) i 4.6 100 ii 13 66.7 iii 21.7 20 iv 60.4 10 * = stage, distribution, and survival rate by stage of 43/52 patients with non-small-cell lung carcinoma at sultan qaboos university hospital: 2002–2011 (unpublished data); **nsclc = non-small-cell lung carcinoma. customised, individualised treatment of metastatic non-small cell lung carcinoma (nsclc) 204 | squ medical journal, may 2013, volume 13, issue 2 by 2008, chemotherapy for nsclc reached a plateau with median survival approaching 10–12 months, while scientific research drifted towards molecular profiling with the evolution of cancer genetics and translational work. researchers started to study the cell signalling pathways and evaluate means to target cancer cells at the molecular level. others started to use maintenance therapy in their effort to enhance the median survival time in this aggressive disease. molecular targets and targeted therapy in metastatic nsclc t u m o u r a n g i o g e n e s i s a n d va s c u l a r ta r g e t s: b e va c i z u m a b vascular endothelial growth factor (vegf) was discovered by harold dvorak and donald senger in 1983, and subsequently sequenced by napoleone ferrara's group in 1989.15,16 it was well-established that small tumours fail to thrive after attaining sizes as small as a few millimeters until they derive their independent vasculature. this in fact is carried out by the release of vegf-a and other ligands that bind to the extracellular domain on the tumour cell vegf receptors [figure 1]. this initiates of the platinum doublets used in the e1594 trial and these doublets emerged as a standard of care for patients with well-preserved organ function in performance status (ps) 0–1, and with slightly higher toxicity in selected ps 2 cases. towards the end of the last decade, histology emerged as a strong predictor for response and enhanced survival in non-squamous nsclc. data from phase ii and randomised phase iii trials of patients having the adenocarcinoma subtype, including large cell carcinoma and bronchioalveolar carcinoma (bac), confirmed improvement in median survival beyond 10 months after the addition of pemetrexed. a phase iii study revealed survival approaching a statistically significant 12.6 months in the pemetrexed cisplatin arm compared to 11 months in gemcitabine cisplatin arm in adenocarcinoma subtypes.14 the survival was 10.4 versus 6.7 months for the experimental arm in large cell carcinoma. scc, however, did poorly with the addition of pemetrexed where median overall survival (os) remained at <10 months. the combination therefore emerged as an option for non-squamous subtypes, reaching a median survival time in excess of 12 months, while cisplatin plus gemcitabine or docetaxel remained the standard treatment for scc. figure 1: the egfr and vegfr cell signal transduction pathways and site of blockade by targeted therapies 1–3. egfr = epidermal growth factor receptor; tki = tyrosine kinase inhibitor; vegfr = vascular endothelial growth factor receptor; vegf = vascular endothelial growth factor; mut = mutation. muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 205 downstream cell signalling through activation of ras/raf/mek/erk or pi3k/akt/mtor pathways leading to cell proliferation, endothelial migration, angiogenesis, invasion, and metastases. the vegf-a and platelet-derived growth factor (pdgf) binding to platelet-derived growth factor receptor (pdgfr) also complements the regulation of angiogenesis indirectly providing targets for dualor multi-tyrosine kinase inhibitors (tkis). bevacizumab blocks the vegf-a and prevents binding to the vegf receptor while the complex is recognised and eliminated by the immune system. bevacizumab exerts its action through the following proposed mechanisms. antivascular effects lead to the regression of the tumour vasculature and reduce tumour size. antiangiogenesis inhibits neo-angiogenesis and recurrent blood vessel growth in the tumour. antipermeability decreases vascular permeability, and oedema in the tumour microenvironment, reducing pleural fluid volume. after promising results from a us phase ii trial by johnson et al. in 2004, a series of large randomised phase iii trials of bevacizumab were initiated [figure 2].17 a subset analysis of a phase iii trial by sandler et al. revealed interesting findings: patients with an adenocarcinoma subtype had a survival advantage of 3.9 months.18 additionally, patients who developed hypertension on bevacizumab had a superior os.19 also, elderly patients (>70 years) showed a trend of higher rr and (progression-free survival) pfs but no gains in os. they also experienced more toxicity. the outcome of patients on maintenance bevacizumab showed promise on retrospective review and, therefore, a series of successful phase iii maintenance trials were initiated to test its relevance. the addition of bevacizumab to pemetrexed and platinum improved survival outcomes in adenocarcinoma histology in two phase ii trials.20,21 a randomised phase iii maintenance trial (avaperl 1) in ps 0–1 advanced adenocarcinoma patients was initiated using pemetrexed-cisplatin plus bevacizumab followed by continuation bevacizumab with or without pemetrexed.22 the interim results seem promising, as the addition of bevacizumab was well tolerated and associated with a superior pfs of 3.6 months. the median os for the bevacizumab arm was 15.7 months, but for the pemetrexed bevacizumab arm; an os level has not yet been reached. the pointbreak study (900 patients) with advanced non-squamous nsclc used pemetrexed + carboplatin + bevacizumab induction followed by pemetrexed + bevacizumab maintenance (arm a) and compared it with paclitaxel + carboplatin + bevacizumab induction followed by bevacizumab maintenance (arm b). though it failed to reach the primary endpoint of enhancing os, the maintenance arm a improved the survival outcomes (pfs and os) compared to maintenance arm b.23 whether the gain in survival is because of pemetrexed or bevacizumab remains to be defined. the ecog e 5508 trial is underway to address this question.24 in a meta-analysis of 2,252 patients from 5 randomised trials with advanced nsclc, andre et al. reported that the addition of bevacizumab to platinum doublets increased rr, enhanced pfs by 1.4 months, extended os by 1 month, and was associated with a significant 11% reduction in death. however, the combination was associated with slightly higher toxicity and mortality and therefore warrants careful patient selection.25 based on promising survival gains from a colorectal study (brite),26 the aries trial27 in nsclc, and another american retrospective analysis of non-squamous nsclc,28 a large multi institutional, randomised trial called avastin in all lung lines (avall) was initiated and is currently recruiting patients to evaluate the role of post-progression bevacizumab.29 nearly all key trials exploring the efficacy of the addition of bevacizumab to standard platinum doublets showed a consistent improvement in rr, pfs, and median survival rates in adenocarcinoma subtypes figure 2: continued survival benefit with bevacizumab: 2006 to 2011 showing the major trials undertaken. -the yellow bars show the subset analysis for ecog4599 trial. -the red bar is the control (chemotherapy arm) of ecog 4599 trial. customised, individualised treatment of metastatic non-small cell lung carcinoma (nsclc) 206 | squ medical journal, may 2013, volume 13, issue 2 e p i d e r m a l g r o w t h fa c t o r r e c e p t o r (e g f r) egfr is a trans-membrane cellular protein receptor located on the cell surface. the gene that codes for egfr protein is located in 7p11-13. it consists of 26 exons, of which the first 14 code for the extracellular ligand binding domain, exon 15 for the transmembrane domain, and the last 11 for the intracellular domain. the atp-binding site and intrinsic tk activity is also coded by exons 16–26.43 it is generally expressed at low levels in a wide variety of normal tissues. excessive expression or activation of egfr is able to induce malignant transformation. over-expression has been observed in 40–80% of nsclc.44-46 a form of egfrmut (egfrviii) is implicated in carcinogenesis with tk activity.47 receptor activation is generally initiated by the binding of egf or related ligands, leading to receptor homodimerisation or heterodimerisation, which activates intrinsic tk activity of the receptors leading to autophosphorylation of tyrosine residues. mutations or over-expression in the tk domain of the egfr gene increase the activity of the intracellular signalling cascades through ras/raf/ mapk and pi3k/akt/mtor pathways [figure 1], leading to events which result in over-proliferation, differentiation, enhanced survival, inhibition of apoptosis, neo-angiogenesis, and metastases, and is associated with a poorer prognosis.48,49 determination of egfr gene mutations has clinical relevance as it allows the optimisation of therapy and has emerged as one of the most important single predictive molecular markers in clinical oncology. patients with certain egfrmut derive significant benefit after the addition of gefitinib or erlotinib.50–52 these agents inhibit the tk and adversely compete with atp for the critical atp-binding site located in the intracellular domain inhibiting the intrinsic tyrosine kinase enzyme activity. cetuximab is a monoclonal antibody that binds the extracellular domain of egfr effectively and prevents the subsequent intracellular cascade of events and the inhibition of malignant transformation [figure 1]. certain clinical subgroups of patients derive a greater benefit from tyrosine kinase inhibitors (tki) therapy by virtue of the presence of an egfrmut. these include patients of east asian origin, never smokers, females, and those having an adenocarcinoma.53–54 the egfrmut are found in exons 18–21 of the egfr gene.43 with ps 0–1 [figure 2]. however, the 4,000 patients (>65 years) from the seer database were recently analysed and the addition of bevacizumab was not found to be advantageous in the elderly population.30 when a single cellular target is blocked, the cancer cell finds an alternative pathway to proliferate and hence provides a rationale for dual or multitargeted therapy. phase ii and iii trials, using dual tki (vandetanib) after multi-line chemotherapy failure in advanced nsclc, provided a hint of activity and efficacy in favour of the combination of chemotherapy with vandetanib.31–34 multi-tki (i.e. sorafenib, which inhibits tk, vegfr, pdgfr, and the raf signalling pathway when compared to a placebo) failed to enhance the efficacy of the treatment.35–36 in the mission trial, sorafenib failed to improve the os, but the pfs, ttp, rr, and disease control rate (dcr) improved substantially.37 battle, a phase ii study, incorporated heavily pretreated nsclc patients with ps 0–2 (2–5 lines failures, brain metastases allowed). the study compared the effects of erlotinib in the egfr mutation-positive group, which validated results of earlier randomised trials, versus vandetanib and erlotinib, which showed enhanced activity in the vegfr2-expressing subsets versus erlotinib and bexarotene showing activity in cyclin d1 expressing and egfr amplified patients with improved outcomes versus. sorafenib which was associated with a dismal outcome in egfr-mutation positive subsets.38,39 multi-tki roles in the metastatic setting remain under investigation. however, there is emerging data of multi-tki use in ret translocations (1%) in adenocarcinoma subtype. bibf 1120, a triple angio-kinase inhibitor (active against fgfr, pdgfr, and vegfr) in the secondor third-line setting was found to be associated with tumour shrinkage in patients with adenocarcinoma.40 its use is being explored in combination with docetaxel and pemetrexed.41,42 with advances in molecular biology and genetics, newer markers of significance are being explored to determine their prognostic or predictive value, and non-squamous nsclc has emerged as a classical model of studying cancer genetics. discovery of key cellular markers and their targeting has started to bring a paradigm shift in the management of advanced adenocarcinoma subtypes and will be the focus of the following discussion. muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 207 ta r ge t i n g t h e e pi d e r m a l gr ow t h fa c t o r r e c e p t o r ( e gfr) lu n g the different types of egfr mutations provide information on whether patients with these mutations are likely to benefit from tkis (erlotinib or gefitinib)50–52,56 [table 2]. an individual matching the clinical criteria above carries a 50% chance of harbouring the mutation, but this is not the sole criteria used to commence tki therapy. egfrmut are present in 30–50% of east asians and approximately 10% of caucasians having nsclc. its exact incidence in arabian gulf countries or oman is not known. well to moderately differentiated tumours have more frequent egfrmut than their poorly differentiated counterparts.57 adenocarcinoma, which is thyroid transcription factor 1 (ttf1) negative, will usually harbour a wild-type (normal) egfr (egfrwt). 58,59 around 30% of sccs overexpress the egfr protein (not the gene) on immune-staining, and tki provides a similar advantage to this subtype. the evidence of adding a tki in scc comes from the subset analysis of the saturn study and the exploratory retrospective analyses from the ncic br.21 trial according to which these agents enhance pfs and os irrespective of histology when used as maintenance and second-line salvage therapy, respectively.60,61 similarly, data from the flex trial recommend use of cetuximab with induction chemotherapy in scc expressing the egfr protein. egfr mutations rarely occur in never smoking scc patients, and therefore are not routinely determined. ta r ge t i n g t h e e gfr i n t r a c e l lu l a r d om a i n : t y r o si n e k i n a se i n h i b i t o r s (t k i s) after successful preclinical studies, evidence that the egfrmut correlated with response to tki in clinical practice first emerged in 2004 from phase ii trials in previously treated nsclc patients. trials of salvage tkis have been undertaken. in the ideal 1 trial, gefitinib was used in patients pretreated with two or fewer previous chemotherapy regimens, while in ideal 2 the same agent was used in pretreated nsclc patients who received more than two regimens.62,63 in 210 patients, the rr were 18–19% and there were median survival gains of 7.6–8 months in the ideal 1 trial. the rr was 11.8% and median os was 6.5 months in the ideal 2 trial. the subset analyses revealed that asian, never smoking females having adenocarcinoma (especially bac) reacted with a predictable response to gefitinib. the isel, a phase iii study, used gefitinib as first salvage in nsclc after one or more prior chemotherapy failures. survival was increased in patients who were asians or never smokers.53 interest, a phase iii trial, utilised gefitinib versus docetaxel in a second-line salvage setting. the tki was associated with a superior quality of life (qol) and fewer side effects.64 erlotinib was also used as a monotherapy in patients with nsclc who progressed on 1–2 previous chemotherapies in the phase iii br.21 trial against bsc, and was associated with improvement in disease-related symptoms, superior ttp, and median os enhancement by 2 months.61 phase iii trials of concurrent use of tkis with chemotherapy have also been conducted. talent was a negative trial (>1,172 patients) with two arms that used carboplatin and paclitaxel with or without erlotinib.65 the rr, pfs, and os remained unchanged when the tki was used concurrent with chemotherapy as compared to chemotherapy alone. the tribute study utilised cisplatin and gemcitabine alone or concurrent with erlotinib and validated the results of the talent trial.66 however, subset analyses revealed increased survival in never smokers. intact 1 and intact 2 also used carboplatin and paclitaxel alone or concurrent table 2: epidermal growth factor receptor mutation types, incidence, and sensitivity to tyrosine kinase inhibitors sr. no. egfr mutation type known mutations % sensitivity to tki 1 exon 19 del(del 746-a750) exon 21 point mutation(l858r) 45 45 + yes 2 dual mutationst790m/exon19del t790m/l858r/others 5–7 ? no, data limited 3 exon 20 insertion(t790m) exon 18(g719s) 5 5 no egfr = epidermal growth factor receptor; tki = tyrosine kinase inhibitor. customised, individualised treatment of metastatic non-small cell lung carcinoma (nsclc) 208 | squ medical journal, may 2013, volume 13, issue 2 the optimal trial was conducted by the chinese thoracic oncology group, and involved 23 centres using erlotinib.51,52 the trial also validated results from the ipass study. in subgroup analyses, pfs was 15.3 months in exon 19 del and 12.5 months in l585r mutation. table 3 shows the key phase iii, prospective randomised clinical trials of upfront tkis in non-squamous nsclc with almost similar outcomes.50–52,55,72–74 at disease progression on tkis, patients may still be treated with salvage platinum doublets. the torch trial revealed that in unselected advanced nsclc patients, first-line erlotinib (followed by cisplatin gemcitabine at progression) was inferior in terms of os compared with the standard sequence of first-line chemotherapy followed by erlotinib at progression.75 tailor is another phase iii trial, where 218 evaluable patients (egfrwt) were subjected to second-line docetaxel or erlotinib. the pfs was superior in the docetaxel arm with an absolute difference in 6 months pfs of 12% and remains a negative trial for tki in wild type egfr.76 ta r ge t i n g t h e e gfr e xt r a c e l lu l a r d om a i n : c e t u x i m a b after encouraging results from phase ii trials of the addition of cetuximab to induction chemotherapy in metastatic nsclc, phase iii trials were initiated. the monoclonal antibody binds to the extracellular ligand binding domain of the egfr, blocking the intracellular cell signalling [figure 1]. flex (first line erbitux in lung cancer trial) is a key phase iii, randomised trial comparing the addition of cetuximab to cisplatin and vinorelbine, given for 6 cycles and cetuximab continued as maintenance therapy until progression of disease or unacceptable toxicity versus chemotherapy alone. the median os was superior.77 moreover, a high egfr expression was associated with a better survival with the addition of cetuximab. survival figures were also superior for females, those of asian ethnicity, in those who developed acne, and in those having adenocarcinoma. the addition of cetuximab to chemotherapy was found to be as effective in scc with a prolongation of one year survival by 19%.78 another usa-based trial looked at unselected nsclc patients treated with taxane plus cetuximab, which enhanced median os.79 the addition of cetuximab to platinum doublets remains a reasonable option in distinct ps 0–1 patients, as erlotinib without improvement in efficacy.67,68 calgb 30406, presented in asco 2012, reveals erlotinib efficacy as singlet or concurrent with paclitaxel carboplatin in never or light smokers, harboring adenocarcinoma. erlotinib was found to have similar efficacy in egfrmut in this phase ii setting whether used as a singlet, and with higher toxicity or when used in combination with chemotherapy.69 there is a hint of tki continuation concurrent with chemotherapy in some nsclc cases associated with flare-up of the disease on discontinuation of the tki. tki use concurrent with chemotherapy remains investigational and necessitates further study in the context of a phase iii trials. trials comparing tkis to chemotherapy as initial therapy have also been carried out. when tki was used as frontline therapy in adenocarcinoma harbouring the egfrmut, the rr and pfs improved substantially but with similar os gains to those seen with chemotherapy.50–52,56,70–74 similar efficacy, superior tolerability, and less toxicity made tki a new therapeutic option for adenocarcinoma subtypes, as well as its potential use in ps 3 and selected ps 4 cases. certain clinical subgroups of patients with an egfrmut had a substantial enhancement in median survival, including those having an adenocarcinoma, never smokers, females, ethnic asians, and those who developed a high-grade, acne-like rash with tki.64–68,70–74 in the iressa pan-asia study (ipass), a phase iii, multicentre, randomised trial of advanced nsclc, 1,217 patients from east asia were randomly assigned to receive daily tki orally versus a platinum doublet every 3 weeks for 6 cycles.50 crossover was allowed. one-third of the patients had an egfrmut. the objective rr was statistically and numerically superior in the gefitinib arm in all clinical subgroups, with marked improvement of rr in the egfrmut-positive subgroup. however, the median os remained similar, and mutationnegative patients benefited from chemotherapy but did extremely poorly with gefitinib (rr = 1%). the tki are therefore not indicated in egfrwt. the os was similar in the egfrmut positive or negative groups and is possibly due to crossover in the two arms. the survival was also superior in patients with a high egfr gene copy number, however, at the expense of mild toxicity. muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 209 shown in the algorithm in figure 3. it is reasonable to consider adding cetuximab to platinum doublets in patients with scc (30% of these express the egfr protein) and then use it as maintenance in those stablising after induction therapy, where it adds 1 month to os. molecular markers of significance in targeted therapy with advances in molecular biology and translational research, molecular targets are evolving which are potential targets of newer drugs [tables 3 and 4]. some key markers of prognostic and predictive value are described below. m e t a m p l i f i c at i o n met is a cell surface receptor with tk activity expressed by normal cells as well as malignant cells.80 it is amplified in 10–20% of nsclc. ligand-like hepatocyte growth factor/scatter factor binds to met, activating downstream cell signalling and leading to cell proliferation, angiogenesis, invasion and metastases. high expression is defined on immunostaining, when >50% cells stain strongly (>3+) or, by an increased gene copy number (>5 copies/cell) as detected by fluorescent in situ hybridisation (fish). met and egfr coamplification occurs rarely—in only 1% of cases. the incidence of met mutation was highest in asians (13%), 0% in blacks, and n375s was the commonest mutation.81 met amplification may lead to acquired resistance to tki therapy through activation of alternate cell signalling pathways like pi3k in up to 20% of patients.82,83 it is also associated with reduced ttp. the pfs varies inversely with met overexpression. patients with high met had superior survival with chemotherapy (p 0.25). several met inhibitors, with or without dual inhibition of egfr and met as a potential mechanism to overcome resistance, are currently undergoing trials. met inhibitors like metmab plus erlotinib versus placebo plus erlotinib were compared in a phase ii trial and showed 50% enhancement in pfs and os in patients with high met expression.84 patients with low met expression fared worse with the same combination. arq 197 is another mek inhibitor that showed superior pfs when combined with erlotinib in a phase ii trial with a trend towards increased os.85 the metlung trial is a global phase iii randomised trial recruiting patients with metastatic or recurrent disease after one previous chemotherapy failure in met-positive nsclc. patients are being randomised to erlotinib plus onartuzumab (metmab) versus erlotinib plus placebo.86 k-r a s m u tat i o n mutations in the kirsten rat sarcoma virus oncogene homologue gene (k-ras) occurs in approximately 20–30% of nsclc cases. they are common in mucinous adenocarcinoma (but not in large-cell carcinoma or bac), in the elderly, in heavy smokers, in stage i and tumour grade i but frequently fall with stage and grade progression, while the table 3: phase iii, prospective, randomised clinical trials of upfront tyrosine kinase inhibitorerlotinib (e), and gefitinib (g) study no. of patients orr % dcr % median pfs (months) median os (months) hr/p value for pfs tki trials egfrmut p value ns ipass50(g) china 261; 132 71.2 91.7 9.8 vs. 6.4 21.3 vs. 23.3 0.48 optimal51,52(e) asia 154; 82 82.9 96.3 13.7 vs. 4.6 18.8 vs. 17.4 0.16 eurtac56(e) europe 1275; 174 54.5 10.5 10.4 vs. 5.1 22.9 vs. 18.8 0.34 first-signal70(g) korea 42; 26 84.6 88.5 8.4 vs. 6.7 21.3 vs. 23.3 0.613 nejsg 00271(g) japan 228; 114 73.7 89.5 10.8 vs. 5.4 30.5 vs. 23.6 0.30 wjtog 340572(g) japan 172; 86 62.1 93.1 9.2 vs. 6.3 36.3 vs. 39 0.489 slcg73(e) spain 217; 217 70.6 89.8 14.0 27 -calgb 3040669(e) us 181; 164 71 nr 14.1 vs. 2.6 os 31 vs.18 orr = objective response rate; dcr = disease control rate; pfs = progression free survival; os = overall survival; hr = hazard ratio; tki = tyrosine kinase inhibitor; egfrmut = epidermal growth factor mutation; ns = not significant; nr = not reported. customised, individualised treatment of metastatic non-small cell lung carcinoma (nsclc) 210 | squ medical journal, may 2013, volume 13, issue 2 only rules out egfr mutation, but is also a marker of tki inactivity. to date, patients harbouring the k-ras mutation are best treated with chemotherapy. in a recent trial comparing docetaxel with or without selumetinib (mek 1 and 2 inhibitor downstream of k-ras), the combination resulted in superior rr, pfs, and os in patients with the k-ras mutation.87 e c h i n o d e r m m i c r o t u b u l ea s s o c i at e d p r o t e i n-l i k e 4 a n a p l a s t i c ly m p h o m a k i n a s e (e m l 4-a l k) m u tat i o n eml4-alk was isolated from a surgically resected lung adenocarcioma specimen, but originally identified in anaplastic large-cell lymphoma (alcl).88,89 it occurs in 4–11% of nsclc. eml4alk exhibits activating mutations or translocations of the anaplastic lymphoma kinase aberrant fusion gene (result of a small inversion within short arm of chromosome 2p, in which the eml4 becomes fused to the intracellular kinase domain of alk). it leads to the activation of downstream cell signalling through pi3k and stat pathways. the gene encodes a cytoplasmic chimeric protein with kinase activity, and typically tested positive in younger subjects, having adenocarcinoma of a predominantly signet ring subtype, and in never or occurrence in non-smokers is low. the majority of mutations occur in codon 12 (>90%—guanine to thymine transversion) and 13, and the gene leads to impaired gtpase activity, located towards the inner surface of the cell membrane. this leads to subsequent constitutive activation of ras signalling, which is downstream of the egfr, leading to activation of proliferative and antiapoptotic pathways such as erk. in the early 1990s, it was considered a negative prognostic marker, and perhaps a negative predictive marker responsible for chemo-resistance. however, data from recent trials like tribute and flex negates it.66,77 unlike colorectal cancers, where k-ras mutation is a strong predictor of response to cetuximab, its status in nsclc could not confirm it to be so on retrospective analyses of flex and bms 099 trials.77,79 in the ncic br.21 study, 28% of 731 patients had k-ras genotype.61 the majority was wild type that responded well to tki, while 15% had a mutation that conferred primary resistance to tki therapy. data from tribute reveals that egfr and k-ras mutations rarely occur together, and that survival was inferior in the group of patients with k-ras mutation who were treated with chemotherapy plus tki.66 hence, the presence of k-ras mutation not figure 3: evolving treatment algorithm of non-small-cell lung carcinoma in 2012. nsclc = non-small-cell lung carcinoma; egfr = epidermal growth factor receptor; ca = carcinoma; bac = bronchioalveolar carcinoma; ihc = immunohistochemistry; vegf = vascular endothelial growth factor; eml4-alk = echinoderm microtubule-associated protein-like4 anaplastic lymphoma kinase; ps = performance status; *bsc = best supportive care. muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 211 light smokers who did not harbour egfr mutations. immunohistochemistry (ihc) could detect the protein, and reverse transcription polymerase chain reaction (rt-pcr), gene sequencing, and fish could detect the break-apart rearrangement.90 the break removes the inhibitory effect of eml4 and alk initiates carcinogenesis due to its inherent oncogenic activity. eml4-alk positivity mutually rules out egfr and k-ras mutations. currently, patients with this distinct expression have a similar rr and os to platinum-based chemotherapy compared to the wild type patients. crizotinib, an oral alk inhibitor which produced a 90% clinical benefit (57% objective response rate [orr]) when used as a second-line compared favourably to salvage second-line chemotherapy which produced a rr of 10% in a phase ii trial.91 another phase ii trial (profile 1005) is assessing salvage crizotinib in adenocarcinoma patients treated with one previous platinum, with the finding that the orrs were 54% and the dcrs were 74%, which was considered safe and tolerable.92 recently, profile 1007 data were presented to the european society for medical oncology. alkpositive patients who failed one previous platinum doublet were treated with crizotinib compared with chemotherapy (docetaxel or pemetrexed). crizotinib enhanced pfs (7.7 versus 3 months; p <0.0001), rr (60% versus 20%; p <0.001), and qol.93 the exact sequencing of the drug still needs to be defined. currently all patients harbouring wild type egfr are treated with chemotherapy doublets and crizotinib is reserved as salvage in those who have the eml4-alk mutation. the new agent is being tested in metastatic setting as frontline treatment. crizotinib has also been found effective against ros1 (~1%) mutation in nsclc. r e s i s ta n c e t o e p i d e r m a l g r o w t h fa c t o r r e c e p t o r (e g f r) t y r o s i n e k i n a s e i n h i b i t o r s (t k i s) at some point during the course of disease, nsclc progresses, despite therapy, because of the emergence of resistance due to underlying table 4: personalised therapy in 2012 for non-small cell lung carcinoma factors featurers/ molecular targets targeted therapy/chemotherapy options clinical female, never smoker, asian, adenocarcinoma treated cns metastases, no hemoptysis, controlled hypertension, no tumor near great vessels, no vte, no therapeutic anticoagulant therapy tki bevacizumab histologic non mucinous adenocarcinoma(egfr mutation+) mucinous adenocarcinoma(k ras mutation/ egfr wild) mucinous adenocarcinoma(eml4 alk+) nonsquamous subtypes squamous(30% egfr protein expression) tki platinum doublets (pemetrexed) crizotinib 1st line or after induc chemo pemetrexed/ cisplatin/ or both bevacizumab, pemetrexed + platinum gemcitabine or taxanes + platinum + cetuximab no pemetrexed/ no bevacizumab molecular (markers in targeted therapy) egfr mutation + (fish) k ras +ive , egfr wild type egfr overexpression on (for scc) cmet mutation t790m mutation eml4 alk mutation/ ros 1 mutation ret translocation tki chemotherapy, suitable combination? cetuximab chemotherapy, (?arq 197, metmab) afatinib, (?aee788+everolimus) crizotinib pemetrexed/ cisplatin/ or both ?multi-tki (sorafenib/ sunitinib) unanswered triple negative lung cancer*(egfr-, k ras -, eml4 alk-) primary vs metastases do poorly with standard chemotherapy, best regimen? do these harbour same mutations? biomarkers in chemotherapy** ercc1 low ercc1 high rrm1 high β tubulin platinum sensitive disease gemcitabine docetaxel (cisplatin resistance) non-gemcitabine doublets (gemcitabine resist) non taxane combination (taxane resistance) * = retrospective subgroup analyse; ** = markers undergoing research; cns = central nervous system; vte = venous thromboembolism; tki = tyrosine-kinase; egfr = epidermal growth factor reactor; fish = fluorescence in situ hybridization; scc = squamous cell carcinoma; eml4 alk = echinoderm microtubule-associated protein-like4 anaplastic lymphoma kinase; ercc1 = excision repair cross-complementation group 1; rrm1 = ribonucleotide reductase m1 gene inhibitor. customised, individualised treatment of metastatic non-small cell lung carcinoma (nsclc) 212 | squ medical journal, may 2013, volume 13, issue 2 30% of acquired resistance.101 it has also been shown that patients who have developed resistance to tki, when subjected to chemotherapy, may respond again to the re-introduction of tki.102 conclusion bevacizumab and cetuximab have emerged as targeted agents to be used with cisplatin doublets in metastatic adenocarcinoma in patients with ps 0–1 and well preserved organ function. those harbouring the egfrmut in ps 0–3 and highly selected ps 4 are now candidates for oral tki therapy which offers equal efficacy, superior tolerability, and a lesser and different side effect profile, bringing a paradigm shift in the management of these cancers. there are compelling data for using more or prolonged therapy, and optimising therapy based on histology and genetic mutations, while resistance patterns continue to be recognised. the era of one chemotherapy that fits all is fading as patients’ median survival is improving gradually under customised individualised therapy. references 1. union for international cancer control. agency for research on cancer. globocan 2008 fast stats. from: http://globocan.iarc.fr/factsheet.asp. accessed: may 2012. 2. howlader n, noone am, krapcho m, neyman n, aminou tatalovich z, cho h, et al. seer cancer statistics review 1975-2008 nci bethesda. from: http : / / s e e r. c a n ce r. go v / c s r ? 1 9 7 5 2 0 0 8 / p o s te d . accessed: may 2012. 3. ministry of health. cancer incidence in oman. from: www.moh.gov.om. accessed: may 2012. 4. yang r, cheung mc, pedroso fe, byrne mm, koniaris lg, zimmers ta. obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival. j surg res 2011; 170:e75–83. 5. burdett s, johnson dh, stewart l, tierney j, le pechoux c for the nsclc collaborative group. supportive care and chemotherapy vs supportive care alone in advanced nsclc: a meta analysis using individual patient data (ipd) from randomized controlled trials. j thorac oncol 2007; 2:s337. 6. luu dcn, mamet r, zornosa cc, niland jc, d'amico ta, kalemkerian gp, et al. retrospective analyses of the impact of age on overall survival in patients with non-small cell lung cancer. j clin oncol 2012; e18018. genetic alterations. primary resistance affects patients who are refractory to tki therapy at the time of initiation. molecular factors identified as predictive of an egfr tki response are often egfr-related due to an increased egfr gene copy number; activating mutations within the egfr tki domain; or resistant egfr mutants. for example, the presence of insertions in egfr’s exon 20 (5% of all known mutations) precludes the binding of gefitinib or erlotinib to the egfr tki domain, conferring resistance.94 exon 18 (g719s) or exon 21 mutations (t854a), the presence of the k-ras mutation, and the loss of pten, b raf mutations, or overexpression of mapk and bcl2 also confer primary resistance. secondary or acquired resistance generally affects patients who initially respond to tki therapy but experience a loss of response after 6–12 months. acquired resistance generally occurs with changes in met over-expression, which accounts for 20% of resistance to the tki.82,83 a t790m mutation (substitution of methionine for threonine at position 790) in progressing tumours accounts for 50% of resistance, and interferes with the binding of tkis to the atp-kinase binding pocket leading to continued activation of downstream signalling.95–97 this mutation is responsible for acquired drug resistance in patients receiving tki therapy over a period of time. patients harbouring this mutation have an indolent course as the disease is not rapidly fatal and metastasises late. the lux1 trial used irreversible tki (afatinib) that inhibits t790m after failure of first-line tki with a dcr of 58% versus 19% and a 2.2 month improvement in pfs in favour of the agent.98 the agent was subsequently used in chemo-naive metastatic nsclc patients in the lux lung 3 trial, revealing a superior rr and enhanced pfs of 11.1 months in patients with an exon 19 del and 13.6 months in the l585r mutation when the agent was compared to pemetrexed and cisplatin.99 the lux lung 7 and 8 trials compare afatinib versus tkis (gefitinib and erlotinib) respectively. aee788 is a multiple rtk inhibitor that blocks egfr, vegfr, and human epidermal growth factor receptor 2 (her2) pathways and, when combined with a mtor inhibitor (everolimus), was found to be effective against the t790m mutation.100 numerous unknown mechanisms (e.g. rare d761y, l747s, t854a mutations, igf-1r, etc.) account for muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 213 7. tammemagi cm, neslund-dudas c, simoff m. impact of co-morbidity on lung cancer survival. int j cancer 2003;103:792-802. 8. paik pk, johnson ml, d'angelo sp, sima cs, ang d, dogan s, et al. driver mutations determine survival in smokers and never-smokers with stage iiib/iv lung adenocarcinomas. cancer 2012; 118:5840–7. 9. ganz pa, figlin ra, haskell cm, la soto n, siau j. supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer. cancer 1989; 63:1271–8. 10. schiller jh, harrington d, belani cp, langer c, sandler a, krook j, et al. comparison of four chemotherapy regimens for advanced nsclc. n engl j med 2002; 346:92–8. 11. ardizzoni m, boni l, tiseo m, fossella fv, schiller jh, paesmans m. cisplatinversus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. j natl cancer inst 2007; 99:847– 57. 12. nsclc collaborative group. chemotherapy in nonsmall cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. bmj 1995; 311:899–909. 13. nsclc meta-analyses collaborative group. chemotherapy in addition to supportive care improved survival in advanced nsclc: a systematic review and met analyses of individual patient data for 16 randomized controlled trials. j clin oncol 2008; 26:4617–25. 14. scagliotti gv, parikh p, von pawel j, biesma b, vansteenkiste j, manegold c, et al. phase iii study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced stage nsclc. j clin oncol 2008; 26:3543–51. 15. ferrara n, gerber hp, lecouter i. the biology of vegf and its receptors. nat med 2003; 9:669–76. 16. leung dw, cachianes g, kuang wj, goeddel dv, ferrara n. vascular endothelial growth factor is a secreted angiogenic mitogen. science 1989; 246:1306–9. 17. johnson dh, fehrenbacher l, novotny wf, herbst rs, nemunaitis jj, jablons dm, et al. randomized phase ii trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. j clin oncol 2004; 22:2184–91. 18. sandler a, gray r, perry mc, brahmer j, schiller jh, dowlati a, et al. paclitaxel carboplatin alone or with bevacizumab for non-small cell lung cancer. n engl j med 2006; 355:2542–50. 19. dahlberg se, sandler ab, brahmer jr, schiller jh, johnson dh. clinical course of advanced non-smallcell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin & paclitaxel on ecog 4599. j clin oncol 2010; 28:949–54. 20. jyoti dp, thomas ah, alfred r, eric mh, mathew gb, daniel tm, et al. phase ii study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsqamous nsclc. j clin oncol 2009; 27:1–7. 21. stevenson jp, langer cj, somer ra, evans tl, rajagopalan k, krieger k, et al. phase 2 trial of maintenance bevacizumab alone after bevacizumab plus pemetrexed and carboplatin in advanced, non-squamous non-small cell lung cancer. cancer 2012;118:5580–7. 22. barlesi f, de castro j, dvornichenko v, kim jh, pazzola a, rittmeyer a, et al. avaperl1 (mo22089): final efficacy outcomes for patients with advanced nonsquamous non-small cell lung cancer (nsnsclc) randomised to continuation maintenance (mtc) with bevacizumab (bev) or bev+pemetrexed (pem) after first-line (1l) bev-cisplatin (cis)-pem treatment (tx). european multidisciplinary cancer congress. euro j cancer 2011; 47:s16. 23. patel jd, bonomi p, socinski ma, govindan r, hong s, obasaju c, et al. treatment rationale and study design for the pointbreak study: a randomized,openlabel phase iii study of pemetrexed/carboplatin/ bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/ bevacizumab followed by maintenance bevacizumab in patients with stage iiib or iv nonsquamous nonsmall-cell lung cancer. clin lung cancer 2009; 10:252–6. 24. eastern cooperative oncology group and national cancer institute. bevacizumab or pemetrexed disodium alone or in combination after induction therapy in treating patients with advanced nonsquamous non-small cell lung cancer. from: http : / / cl i n i c a l t r i a l s . go v / s h o w / n c t 0 1 1 0 7 6 2 6 accessed: jun 2012. 25. lima abc, macedo lt, sasse ad. addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis. from: http://www.plosone. org/article/info%3adoi%2f10.1371%2fjournal. pone.0022681. accessed: may 2012. 26. grothev a, sugrue mm, purdie dm, dong w, sargent d, hedrick e, et al. bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (brite). j clin oncol 2008; 26:5326–34. 27. lynch tj, brahmer j, fischbach n, garst j, kumar p, spigel dr, et al. preliminary treatment patterns and safety outcomes for non-small cell lung cancer (nsclc) from aries, a bevacizumab treatment observational cohort study (ocs). j clin oncol 2008; 26:8077. 28. nadler ee, yu ee, ravelo aa, sing aa, forsythe customised, individualised treatment of metastatic non-small cell lung carcinoma (nsclc) 214 | squ medical journal, may 2013, volume 13, issue 2 therapy for lung cancer. cancer discov 2011; 1:44– 53. 39. herbst rs, blumenschein gr, jr, kim es, lee j, tsao as, alden cm, et al. sorafenib treatment efficacy and kras biomarker status in the biomarkerintegrated approaches of targeted therapy for lung cancer elimination (battle) trial. j clin oncol 2010; 28:7609. 40. gori b, ricciardi s, fulvi a, intagliata s, del signore e, de filippo m, et al. new antiangiogenics in nonsmall cell lung cancer treatment: vargatef (bibf 1120) and beyond. ther clin risk manag 2011; 7:429–40. 41. boehringer ingelheim pharmaceuticals. lumelung 1. bibf 1120 plus docetaxel as compared to placebo plus docetaxel in 2nd line non-small cell lung cancer. from: http://clinicaltrials.gov/show/ nct00805194. accessed: may 2012. 42. boehringer ingelheim pharmaceuticals. lume lung 2. bibf 1120 plus pemetrexed compared to placebo plus pemetrexed in 2nd line nonsquamous nsclc. from: http://clinicaltrials.gov/show/nct00806819. accessed: may 2012. 43. haley j, whittle n, bennet p, kinchington d, ullrich a, waterfield m, et al. the human egf receptor gene: structure of the 110 kb locus and identification of sequences regulating its transcription. oncogene res 1987; 1:375–96. 44. salomon ds, brandt r, ciardiello f, normanno n. epidermal growth factor-related peptides and their receptors in human malignancies. crit rev onco hematol 1995; 19:183–232. 45. herbst rs, shin dm. monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. cancer 2002; 94:1593–611. 46. sridhar ss, seymour l, shepherd fa. inhibitors of epidermal-growth factor receptors: a review of clinical research with a focus on non-small cell lung cancer. lancet oncol 2003; 4:397–406. 47. pederson mw, meltorn m, damstrup l, poulsen hs. the type iii egfr mutation. biological significance and potential target for anticancer therapy. ann oncol 2001; 12:745–60. 48. janmaat ml, giaccone g. the epidermal growth factor receptor pathway and its inhibition as anticancer therapy. drugs today (barc) 2003; 39:61– 80. 49. ennis bw, lippman me, dickson rb. the egf receptor system as a target for antitumor therapy. cancer invest 1991; 9:553–62. 50. fukuoka m, wu yl, thongprasert s, sunpaweravong p, leong ss, sriuranpong v, et al. biomarker analyses and final overall survival results from a phase iii, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in mm, gruschkus ss. bevacizumab treatment to progression after chemotherapy: outcomes from a us community practice network. oncologist 2011; 16:486–96. 29. f. hoffmann la roche ltd. an open label, randomized, phase iiib trial evaluating the efficacy and safety of standard of care + continuous bevacizumab treatment beyond progression of disease in patients with advanced nsclc after first line treatment with bevacizumab plus a platinum doublets containing chemotherapy – avaall (mo22097); from: http://clinicaltrials.gov/show/nct01351415 accessed: may 2012. 30. zhu j, sharma db, gray sw, chen ab, weeks jc, schrag d. carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced nonsmall cell lung cancer. jama 2012; 307:1593–601. 31. herbst rs, sun y, eberhardt we, germonpre p, saijo n, zhou c, et al. vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (zodiac): a double-blind, randomised, phase 3 trial. lancet oncol 2010; 11:619–26. 32. de boer rh, arrieta ó, yang ch, gottfried m, chan v, raats j, et al. vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase iii trial. j clin oncol 2011; 29:1067–74. 33. natale rb, thongprasert s, greco fa, thomas m, tsai cm, sunpaweravong p, et al. phase iii trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. j clin oncol 2011; 29:1059–66. 34. lee j, hirsh v, park k, qin s, blajman cr, perng r, et al. vandetanib versus placebo in patients with advanced non-small cell lung cancer (nsclc) after prior therapy with an egfr tyrosine kinase inhibitor (tki): a randomised, double-blind phase iii trial (zephyr). j clin oncol 2010; s28:7525. 35. scagliotti g, govindan r. targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. oncologist 2010; 15:436–46. 36. gatzemeier u, eisen t, santoro a, paz-ares l, bennouna j, liao m, et al. sorafenib (s) + gemcitabine/cisplatin (gc) vs gc alone in the first-line treatment of advanced non-small cell lung cancer (nsclc): phase iii nsclc research experience utilizing sorafenib (nexus) trial. transl lung cancer res 2012; 1:72–7. 37. bayer health care pharmaceuticals. a 3rd/4th line placebo-controlled trial of sorafenib in patients with predominantly non squamous nonsmall cell lung cancer nsclc. (mission). from: www.clinicaltrials.gov/show/nct00863746 accessed: jun 2012. 38. kim es, herbst rs, wistuba ii, lee jj, blumenschein gr, jr, tsao a, et al. the battle trial: personalizing muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 215 asia (ipass). j clin oncol 2011; 29:2866. 51. mok ts, wu yl, thongprasert s, yang ch, chu dt, saijo n, et al. gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. optimal trial. n eng j med 2009; 361:947–57. 52. zhou c, wu yl, chen g, feng j, liu xq, wang c, et al. erlotinib versus chemotherapy as firstline treatment for patients with advanced egfr mutation-positive non-small-cell lung cancer (optimal, ctong-0802): a multicentre, openlabel, randomised, phase 3 study. lancet oncol 2011; 12:735. 53. thatcher n, chang a, parikh p, rodrigues pereira j, ciuleanu t, von pawel j, et al. gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (iressa survival evaluation in lung cancer). lancet 2005; 366:1527–37. 54. d'angelo sp, pietanza mc, johnson ml, riely gj, miller va, sima cs, et al. incidence of egfr exon 19 deletions and l858r in tumor specimens from men and cigarette smokers with lung adenocarcinomas. j clin oncol 2011; 29:2066–70. 55. shigematsu h, gazdar af. somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. int j cancer 2006; 118:257–62. 56. rosell r, carcereny e, gervais r, vergnenegre a, massuti b, felip e, et al. erlotinib versus standard chemotherapy as first-line treatment for european patients with advanced egfr mutation-positive nonsmall-cell lung cancer (eurtac): a multicentre, open-label, randomised phase 3 trial. lancet oncol 2012; 13:239. 57. leary af, castro dg, nicholson ag, ashley s, wotherspoon a, o'brien me, et al. establishing an egfr mutation screening service for non-small cell lung cancer – sample quality criteria and candidate histological predictors. eur j can 2012; 48:61–7. 58. somaiah n, garrett-mayer e, huang x, wahlquist ae, danenberg k, simon gr, et al. use of negative thyroid transcription factor (ttf-1) status to predict for negative epidermal growth factor receptor (egfr) mutations (mts) status with a high negative predictive value (npv) in patients (pts) with adenocarcinomas (ac) of the lung. j clin oncol 2011; 29:7530. 59. gazdar af. activating and resistance mutations of egfr in non-small-cell lung cancer: role in clinical response to egfr tyrosine kinase inhibitors. oncogene 2009; s24–31. 60. coudert b, ciuleanu t, park k, wu yl, giaccone g, cappuzzo f. survival benefit with erlotinib maintenance therapy relative to prior chemotherapeutic response: a subanalysis of the phase iii saturn study in nsclc. from: https:// w w w.webges .com/cslide/e6388cc/public/play_ video/500. accessed: may 2012. 61. shepherd fa, rodrigues pereira j, ciuleanu t, tan eh, hirsh v, thongprasert s, et al. ncic br.21 trial. erlotinib in previously treated non–small cell lung cancer. n engl j med 2005; 353:123–32. 62. fukuoka m, yano s, giaccone g, tamura t, nakagawa k, douillard jy, et al. a multi-institutional randomised phase ii trial of gefitinib for previously treated patients with advanced non-small cell lung cancer (the ideal 1 trial). j clin oncol 2003; 21:2237–46. 63. kris mg, natale rb, herbst rs, tj lynch jr, d prager, c p belani, et al. a phase ii trial of zd1839 (iressa) in advanced non-small cell lung cancer patients who had failed platinumand docetaxel-based regimens (ideal-2). proc am soc clin oncol 2002; 21:292a. 64. douillard jy, kim e, hirsh v, mok t, socinski m, gervais r, et al. gefitinib (iressa) versus docetaxel in patients with locally advanced or metastatic nonsmall-cell lung cancer pre-treated with platinumbased chemotherapy: a randomised, open-label phase iii study (interest): prs-02. j thorac oncol 2007; 2:s305–6. 65. gatzemeier u, pluzanska a, szczesna a, kaukel e, roubec j, de rosa f, et al. phase iii study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the tarceva lung cancer investigation trial. j clin oncol 2007; 25:1545–52. 66. herbst rs, prager d, hermann r, fehrenbaher l, johnson be, sandler a, et al. tribute: a phase iii trial of erlotinib hcl combined with carboplatin and paclitaxel chemotherapy in advanced nsclc. j clin oncol 2005; 23:5892–9. 67. giaccone g, herbst rs, manegold c, scagliotti g, rosell r, miller v, et al. gefitinib in combination with gemcitabine and cisplatin in advanced nonsmall-cell lung cancer: a phase iii trial-intact 1. j clin oncol 2004; 22:777–84. 68. herbst rs, giaccone g, schiller jh, natale rb, miller v, manegold c, et al. gefitinib in combination with paclitaxel and carboplatin in advanced non-smallcell lung cancer: a phase iii trial-intact 2. j clin oncol 2004; 22:785–94. 69. janne pa, wang x, socinski ma, crawford j, stinchcombe te, gu l, et al. randomized phase ii trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: calgb 30406 trial. j clin oncol 2012; 30:2063–9. 70. lee js, park k, kim sw, lee dh, kim ht, han jy, et al. a randomised phase iii study of gefitinib (iressa) versus standard chemotherapy (gemcitabine plus cisplatin) as a first-line treatment for never-smokers with advanced or metastatic adenocarcinoma of the lung. j thor oncol 2009; 4:abstrprs4. 71. maemondo m, inoue a, kobayashi k, sugawara s, oizumi s, isobe h, et al. gefitinib or chemotherapy for non-small-cell lung cancer with mutated egfr. customised, individualised treatment of metastatic non-small cell lung carcinoma (nsclc) 216 | squ medical journal, may 2013, volume 13, issue 2 oncol 2008; 19:1605–12. 83. engelman ja, zejnullahu k, mitsudomi t, song y, hyland c, park jo, et al. met amplification leads to gefitinib resistance in lung cancer by activating erbb3 signaling. science 2007; 316:1039–43. 84. spigel dr, ervin t, ramlau r, daniel db, goldschmidt jh, blumenschein gr, et al. final efficacy result from a randomized phase ii study (oam4558g) evaluating metmab or placebo in combination with erlotinib in advanced nsclc. j clin oncol. 2011; 29:7505. 85. schiller jh, akerley wl, brugger w, ferrari d, garmey eg, gerber de, et al. results from arq 197-209: a global randomized placebo-controlled phase ii clinical trial of erlotinib plus arq 197 versus erlotinib plus placebo in previously treated egfr inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (nsclc). j clin oncol 2012; 28:7502. 86. genentech with hoffmann-la roche. a study of onartuzumab (metmab) in combination with tarceva (erlotinib) in patients with met diagnosticpositive non-small cell lung cancer who have received chemotherapy for advanced or metastatic disease (metlung) trial. from: http://clinicaltrials. gov/show/nct01456325. accessed: sep 2012. 87. jänne pa, shaw at, pereira jr, gaelle j, johan v, et al. phase ii double-blind, randomized study of selumetinib (sel) plus docetaxel (doc) versus doc plus placebo as second-line treatment for advanced kras mutant non-small cell lung cancer (nsclc). j clin oncol 2012; 30:7503. 88. mano h. nonsolid oncogenes in solid tumors; eml4-alk fusion genes in lung cancer. cancer sci 2008; 99:2349–55. 89. manabu s, shuji t, kengo t, young lc, munehiro e, toshihide u, et al. eml4 alk mutations in lung cancer that confers resistance to alk inhibitors. n engl j med 2010; 313:18:1734–9. 90. shaw at, yeap by, mino-kenudson m, digumarthy sr, costa db, heist rs, et al. clinical features and outcomes of patients with nsclc who harbor eml4 alk. j clin oncol 2009; 27:424. 91. kwak el, bang yj, camidge dr, shaw at, solomon b, maki rg, et al. anaplastic lymphoma kinase inhibition in non-small cell lung cancer. n engl j med 2010; 363:1693–703. 92. riely g. phase 2 data for crizotinib (pf-02341066) in alk-positive advanced non-small cell lung cancer (nsclc): profile 1005. international association for the study on lung cancer, 14th world conference on lung cancer, amsterdam, the netherlands, 3–7 jul 2011. abstr 031.05. 93. pfizer oncology. profile 1007: a phase iii trial of crizotinib (pf-02341066) versus standard of care in patients with nsclc with a specific alterationof the anaplastic lymphoma kinase (alk) gene. npu00315. from: http://www.pfizer.com/files/news/ n engl j med 2010; 362:2380–8. 72. mitsudomi t, morita s, yatabe y, shunichi n, isamu o, takashi s, et al. updated overall survival results of wjtog 3405, a randomized phase iii trial comparing gefitinib (g) with cisplatin plus docetaxel (cd) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor (egfr). j clin oncol 2012; 30:7521. 73. massuti b, morán t, porta r, queralt c, cardenal f, mayo c, et al. multicenter prospective trial of customized erlotinib for advanced nsclc patients with epidermal growth factor receptor mutations: final results of spanish lung cancer group (slcg) trial. j clin oncol 2009; 7;8023. 74. jänne pa, wang xf, socinski ma, crawford j, capelletti m, edelman mj, et al. randomized phase ii trial of erlotinib (e) alone or in combination with carboplatin/ paclitaxel (cp) in never or light former smokers with advanced lung adenocarcinoma: calgb 30406. j clin oncol 2010; 28:7503. 75. gridelli c, ciardiello f, gallo c, feld r, butts c, gebbia v, et al. first-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the torch randomized trial. j clin oncol. 2012; 30:3002–11. 76. garassino mc, martelli o, bettini a, floriani a, copreni e, calogero l, et al. tailor: a phase iii trial comparing erlotinib with docetaxel as the second-line treatment of nsclc patients with wildtype (wt) egfr. j clin oncol 2012: 30:7501. 77. pirker r, pereiera jr, szezesna a, von pawel j, krzakowski m, ramlau r, et al. cetuximab plus chemo in patients with advanced nsclc (flex): an open label phase iii trial. lancet 2009; 373:1525– 31. 78. carillio gg, montanino a, costanzo r, sandomenico c, piccirillo mc, di maio m, et al. cetuximab in non-small-cell lung cancer. expert rev anticancer therapy 2012; 12:163–75. 79. lynch tj, patel t, dreisbach l, heim wj, hermann rc, paschold e, et al. cetuximab and first-line taxane/carboplatin chemotherapy in advanced nonsmall-cell lung cancer: results of the randomized multicenter phase iii trial bms099. j clin oncol 2010; 28:911–7. 80. christensen jg, burrows j, salgia r. cmet as a target for human cancer and characterization of inhibitors for therapeutic intervention. cancer lett 2005; 225:1–26. 81. krishnaswamy s, kanteti r, duke-cohan js, loganathan s, liu w, ma pc, et al. ethnic differences and functional analysis of met mutations in the lung cancer. clin cancer res 2009; 15:5714–23. 82. zucali pa, ruiz mg, giovannetti e, destro a, varella-garcia m, floor k, et al. role of cmet expression in non-small-cell lung cancer patients treated with egfr tyrosine kinase inhibitors. ann muhammad furrukh, mansour al-moundhri, khawaja f. zahid, shiyam kumar and ikram burney review | 217 ash/crizotinib_study_1007_backgrounder_2010.pdf. accessed: jun 2012. 94. greulich h, chen th, feng w, jänne pa, alvarez jv, zappaterra m, et al. oncogenic transformation by inhibitor-sensitive and resistant egfr mutants. plos med 2005; 2:e313. 95. pao w, miller v, politi ka, riely gj, samwar r, zakowski mf, et al. acquired resistance of lung adenocarcinoma to gefitinib or erlotinib is associated with a second mutation in the egfr kinase domain. plos med 2005; 2:e73. 96. kobayashi s, boggon tj, dayaram t, jänne pa, kocher o, meyerson m, et al. egfr mutation and resistance of non-small-cell lung cancer to gefitinib. n engl j med 2005; 352:786–92. 97. engelman ja, mukohara t, zejnullahu k, lifshits e, barras am, gale cm, et al. allelic dilution obscures detection of a biologically significant resistance mutation in egfr amplified lung cancer. j clin invest 2006; 116:2695–706. 98. boehringer ingelheim pharmaceuticals. bibw 2992 and bsc versus placebo and bsc in non-small cell lung cancer patients failing erlotinib or gefitinib (lux-lung 1) from: http://clinicaltrials.gov/show/ nct00656136. accessed: jun 2012. 99. yang jc, schuler mh, yamamoto n, o'byrne kj, hirsh v, mok t, et al. a multicentre, randomised, open-label phase iii trial of bibw 2992 versus chemotherapy (cisplatin /pemetrexed) as firstline treatment for patients with advanced and metastatic nonsmall cell lung cancer (nsclc) harboring an egfr mutation. j clin oncol 2012; 30:7500. 100. nakachi i, naoki k, soejima k, kawada i, watanabe h, yasuda h, et al. the combination of multiple receptor tyrosine kinase inhibitor and mammalian target of rapamycin inhibitor overcomes erlotinib resistance in lung cancer cell lines. mol cancer res 2010; 8:1142–51. 101. nguyen ks, kobayashi s, costa db. acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. clin lung cancer 2009; 10:281–9. 102. gua rh, chen xf, wang ts, zhang zy, sun j, shu yq, et al. subsequent chemotherapy reveals acquired tki resistance and restores response to tki in advanced nsclc. bmc cancer 2011; 11:9. departments of 1obstetrics & gynaecology and 2statistics, nizwa hospital, nizwa, oman *corresponding author e-mail: drkaukab2010@gmail.com الوقت ما بني اختاذ القرار وإجراء العملية القيصرية العاجلة دراسة متكررة ملقطع عرضي من عمان ك�كب ت�ضفني, ماليني باتيل, الهام م��ضى حمدي, اإبراهيم علي الب��ضعيدي, من�ض�ر نا�رس اليعربي abstract: objectives: in cases of fetal intolerance to labour, meeting the standard decision-to-delivery time interval (ddi) of ≤30 minutes is challenging. this study aimed to assess ddis in emergency caesarean section (cs) cases to identify factors causing ddi delays and the impact of a delayed ddi on perinatal outcomes. methods: this repeated cross-sectional study included all emergency cs procedures performed due to acute fetal distress, antepartum haemorrhage or umbilical cord prolapse at the nizwa hospital, nizwa, oman. three audit cycles of three months each were conducted between april 2011 and june 2013, including an initial retrospective cycle and two prospective cycles following the implementation of improvement strategies to address factors causing ddi delays. poor perinatal outcomes were defined as apgar scores of <7 at five minutes, admission to the special care baby unit (scbu) or a stillbirth. results: in the initial cycle, a ddi of ≤30 minutes was achieved in 23.8% of 84 cases in comparison to 44.6% of 83 cases in the second cycle. in the third cycle, 60.8% of 79 women had a ddi of ≤30 minutes (p <0.001). no significant differences in perinatal outcomes for cases with a ddi of ≤30 minutes versus 31–60 minutes were observed; however, a ddi of >60 minutes was significantly associated with poor neonatal outcomes in terms of increased scbu admissions and low apgar scores (p <0.001 each). factors causing ddi delays included obtaining consent for the cs procedure, a lack of operating theatre availability and moving patients to the operating theatre. conclusion: the identification of factors causing ddi delays may provide opportunities to improve perinatal outcomes. keywords: obstetric delivery; medical decision-making; cesarean section; clinical audit; fetal death; apgar score; oman. حتمل عدم حاالت يف اأقل اأو دقيقة ≤30 خالل العاجلة القي�رسية العملية واإجراء القرار اتخاذ بني ال�قت قيا�ص مت الهدف: امللخ�ص: اجلنني للمخا�ص وذلك لتقييم هذه الفرتة ملعرفة االأ�ضباب التي ت�ؤخر العملية وما ه� تاأثري ذلك على حالة اجلنني قبل ال�الدة وبعدها. الطريقة: �ضملت هذه الدرا�ضة جميع العمليات القي�رسية العاجلة التي اإجريت يف م�ضت�ضفى نزوى بعمان يف حاالت اجلنني احلرجة احلادة ونزف ما قبل ال�الدة اأو نزول احلبل ال�رسي قبل اجلنني. اإجريت ثالثة حلقات تدقيق مدة كل منها ثالثة اأ�ضهر خالل الفرتة بني �ضهر اإبريل 2011 وحتى ي�ني� 2013. ت�ضمنت احللقة االأوىل منها درا�ضة احلاالت ال�ضابقة على فرتة التدقيق اأما احللقتني الثانية والثالثة كانتا لعمل تدقيق م�ضتقبلي. مت بعدهما اجراء تعديل يف ا�ضرتاتيجيات معاجلة االأ�ضباب التي ادت اإىل التاأخري يف اإجراء العملية. مت التدليل على تده�ر ميتًا. والدته اأو املركزة الرعاية غرفة يف ال�ليد ترقيد مت اأو ال�الدة من دقائق خم�ص بعد 7 من اأقل اأبجار معدل كان اذا اجلنني حالة النتائج: يف احللقة االأوىل اأظهرت النتائج اإجراء العملية القي�رسية يف %23.8 من بني 84 حالة يف اأقل من 30≥ دقيقة. ويف احللقة الثانية حالة 79 من 60.8% يف دقيقة ≤30 من اأقل يف العملية اأجريت فقد الثالثة احللقة يف واأما حالة 83 من 44.6% يف العملية اإجراء مت )p >0.001( تبني عدم وج�د اختالف ملح�ظ يف حالة اجلنني ما قبل وبعد ال�الدة يف احلاالت التي اأجريت فيها العملية يف اأقل من 30≥ دقيقة. بينما ل�حظ وج�د تده�ر يف حاالت امل�اليد حديثي ال�الدة عند تاأخري العملية القي�رسية بني 60–31 دقيقة, بينما كان ال�قت بني اتخاذ القرار و اإجراء العملية الأكرث من 06 دقيقة مرتبطا ب�ضكل كبري بتده�ر حالة املري�ص ويت�ضح ذلك من وج�د زيادة ملح�ظة اأح�ضائيا اىل اأدت التي الع�امل اأهم وكانت حالة( لكل p >0.001( اأبجـاـر معــدل يف هبــ�ط مع املركزة للعناية ادخل�ا الذين امل�اليد عدد يف التاخري هي التاخري يف م�افقة املري�ضة وذويها على اإجراء العملية القي�رسيةوعدم جاهزية غرفة العمليات الأ�ضباب عدة واأي�ضا التاأخري يف نقل املري�ضة اإىل �ضالة العمليات. اخلال�صة: اأن معرفة االأ�ضباب امل�ؤدية لتاأخري العلمية القي�رسية قد تخلق فر�ضا ت�ؤدي ايل حت�ضني حالة الطفل ال�ليد. الكلمات املفتاحية: والدة؛ قرار طبي؛ عملية قي�رسية؛ تدقيق كلينيكي؛ م�ت اجلنني؛ مقيا�ص االأبجار؛ عمان. decision-to-delivery time intervals in emergency caesarean section cases repeated cross-sectional study from oman *kaukab tashfeen,1 malini patel,1 ilham m. hamdi,1 ibrahim h. a. al-busaidi,2 mansour n. al-yarubi2 clinical & basic research sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e38–42, epub. 30 mar 17 submitted 25 jul 16 revisions req. 6 sep & 7 nov 16; revisions recd. 6 oct & 27 nov 16 accepted 8 dec 16 doi: 10.18295/squmj.2016.17.01.008 advances in knowledge the target decision-to-delivery interval (ddi) in cases of emergency caesarean section (cs) is ≤30 minutes. in the current study, the implementation of improvement strategies—such as the introduction of a pro forma timesheet and an obstetric crash code procedure—significantly increased the rate of satisfactory ddis in emergency cs cases. factors affecting ddi delays in the current study included obtaining consent for emergency cs procedures from patients, transferring patients from the ward to the operating theatre and a lack of operating theatre availability. kaukab tashfeen, malini patel, ilham m. hamdi, ibrahim h. a. al-busaidi and mansour n. al-yarubi clinical and basic research | e39 application to patient care in the current study, it was found that a ddi of >60 minutes led to an increased risk of adverse perinatal outcomes, in terms of admissions to the special care baby unit and low apgar scores. this finding may help raise awareness of the importance of a swift delivery in cases of acute fetal hypoxia. healthcare institutions should implement improvement strategies to reduce ddi delays in emergency cs cases so as to improve perinatal outcomes. acute intrapartum fetal hypoxia affects 1% of all women in labour and leads to fetal death in 0.5 out of 1,000 births and cerebral palsy in 1 out of 1,000 deliveries.1 this complication necessitates immediate intervention via caesarean section (cs) or instrumental vaginal delivery so as to prevent birth asphyxia and fetal death.2,3 a nonreassuring fetal heart rate during labour is considered a major indicator for prompt delivery via an emergency cs procedure.3 the decision-todelivery time interval (ddi) indicates the period of time between the clinical decision to carry out a cs procedure and the delivery of the baby.4 the american academy of pediatrics, american college of obstetricians and gynecologists and the royal college of obstetricians and gynaecologists recommend a ddi of ≤30 minutes following a diagnosis of acute intrapartum fetal hypoxia.5,6 other studies have also emphasised the importance of a 30-minute interval for safe neonatal outcomes.7,8 however, there is currently little evidence that a ddi of ≤30 minutes is the norm in emergency cs cases.9 in particular, achieving a ddi of ≤30 minutes in cases of fetal intolerance to labour can be very challenging. nizwa hospital is a 308-bed secondary care institution which serves as a regional referral centre for primary healthcare centres in the al-dakhylia region of oman. there are approximately 5,500 deliveries per year, of which an estimated 21% are delivered via cs procedure.10 the delivery suite is well equipped and fully staffed with qualified nurses, trained midwives, operating theatre (ot) staff nurses, specialist obstetricians, anaesthesiologists and neonatologists. in addition, the hospital has its own labour ward ot with 24-hour emergency staff. this study aimed to assess ddis among emergency cs cases at nizwa hospital in order to identify causative factors in ddi delays, plan improvement strategies accordingly and determine the impact of a delayed ddi on perinatal outcomes. methods this repeated cross-sectional study took place between april 2011 and june 2013 at nizwa hospital and included all women with singleton pregnancies delivered by emergency cs procedures due to fetal distress, antepartum haemorrhage or umbilical cord prolapse. women with multiple pregnancies or preterm deliveries were excluded from the study. as per the international classification of diseases, acute fetal distress was defined as an abnormal fetal heart rate pattern on cardiotocography (ctg)—such as persistent bradycardia, late decelerations, complicated tachycardia or persistent poor variability—either with or without the presence of meconium-stained amniotic fluid.11 category i cs cases in which there was an immediate threat to the life of the woman or her baby were defined as ‘crash’ emergencies, for instance due to cord prolapse, severe antepartum haemorrhage or alarming pathological ctg results.12 perinatal outcomes were recorded for all cases, including the incidence of stillbirths, specific apgar scores and number of admissions to the special care baby unit (scbu). as per hospital protocol, criteria for admission to the scbu was defined as an apgar score of <7 at five minutes. for the sake of analysis, ddi was categorised as either 0–30 minutes, 31–60 minutes or >60 minutes. three audit cycles were carried out, with each cycle lasting three months. initially, the data collection for the first cycle was performed retrospectively. after analysis of the results for this cycle, factors causing ddi delays were identified. interand intradepartmental meetings were held to discuss these issues and improvement strategies were designed and implemented accordingly. staff were taught to transfer patients to the ot within 10 minutes of the cs decision. it was also recommended that the second ot be fully prepared at all times in case another cs procedure was required at the same time for a different patient. a pro forma timesheet starting from the delivery decision and ending at delivery was designed to further identify factors causing ddi delays and to encourage a sense of accountability and team work among members of the delivery team. in addition, patient counselling and staff education were provided in order to obtain rapid consent for the cs procedure. following the implementation of these strategies, a second prospective cross-sectional audit cycle was performed. an interdepartmental meeting was subsequently held to again discuss the results of the preceding cycle and encourage interdepartmental decision-to-delivery time intervals in emergency caesarean section cases repeated cross-sectional study from oman e40 | squ medical journal, february 2017, volume 17, issue 1 communication. an obstetric crash code (occ) procedure was implemented which, when activated, identified the exact location of an emergency so that relevant healthcare providers could assemble more quickly. the third and final cycle was then undertaken. data from each of the three audit cycles were subsequently analysed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). a chi-squared test was used to analyse discrete variables. a p value of <0.050 was considered statistically significant. ethical permission for this study was granted by the research & ethics committee of nizwa hospital (#3011/2011). results during the study period, there were 3,940 deliveries, of which 553 (14.0%) were delivered by cs procedure. of these, 469 (84.8%) were classified as emergency cs cases. cord prolapse alone accounted for 44.4% of the emergency cs cases. overall, a total of 246 women underwent emergency cs procedures due to acute fetal distress, antepartum haemorrhage or cord prolapse. the first audit cycle included 84 emergency cs cases; of these, only 23.8% achieved a ddi of ≤30 minutes. in the second cycle, after the initiation of improvement strategies, 44.6% of 83 emergency cs cases had a ddi of ≤30 minutes. in the third cycle, after the introduction of the occ procedure, 60.8% of 79 emergency cs cases had a ddi of ≤30 minutes. the increase in the rate of cases with target ddis between each cycle was statistically significant (p <0.001; χ2 = 28.812) [table 1]. out of 67 cs cases defined as ‘crash’ emergencies, a ddi of ≤30 minutes was achieved for 54 patients (80.6%). a total of 35 women delivered babies who were subsequently admitted to the scbu; of these, 24 (68.5%) had a ddi of >60 minutes. there was an apparent positive and statistically significant relationship between number of admissions to the scbu and increased ddis (p <0.001) [table 2]. table 3 shows a comparison of perinatal outcomes in terms of apgar scores at five minutes, scbu admissions and neonatal convulsions according to ddi category. there was a strong and statistically significant relationship between apgar scores of <7 and ddi (p <0.001). apgar scores of >7 more frequently occurred with lower ddis. unfortunately, it was not possible to calculate associations between the frequency of neonatal convulsions and ddi because data for the 0–30 and 31–60 minute intervals were not available. figure 1 shows the main reasons for delays table 1: decision-to-delivery time intervals by audit cycle among emergency caesarean section cases* performed at the nizwa hospital, nizwa, oman (n = 246) audit cycle total ddi in minutes, n (%) p value 0–30 31–60 >60 first 84 20 (23.8) 30 (35.7) 34 (40.5) <0.001second 83 37 (44.6) 30 (36.1) 16 (19.3) third 79 48 (60.8) 21 (26.6) 10 (12.7) total 246 105 (42.7) 81 (32.9) 60 (24.4) ddi = decision-to-delivery time interval. *due to acute fetal distress, antepartum haemorrhage or umbilical cord prolapse. table 2: admissions to the special care baby unit according to decision-to-delivery time interval among emergency caesarean section cases* performed at the nizwa hospital, nizwa, oman (n = 246) ddi in minutes total scbu admissions, n (%) p value admitted not admitted 0–30 105 3 (2.9) 102 (97.1) <0.00131–60 81 8 (9.9) 73 (90.1) >60 60 24 (40.0) 36 (60.0) total 246 35 (14.2) 211 (85.8) ddi = decision-to-delivery time interval; scbu = special care baby unit. *due to acute fetal distress, antepartum haemorrhage or umbilical cord prolapse. table 3: perinatal outcomes according to decision-todelivery time interval among emergency caesarean section cases* performed at the nizwa hospital, nizwa, oman (n = 246) ddi in minutes total perinatal outcomes, n (%) apgar score at five minutes scbu admissions nc <7 >7 0–30 105 2 (1.9) 103 (98.1) 3 (2.9) 0 (0.0) 31–60 81 4 (4.9) 77 (95.1) 8 (9.9) 0 (0.0) >60 60 35 (58.3) 25 (41.7) 24 (40.0) 5 (8.3) total 246 41 (16.7) 205 (83.3) 35 (14.2) 5 (2.0) ddi = decision-to-delivery time interval; scbu = special care baby unit; nc = neonatal convulsions. *due to acute fetal distress, antepartum haemorrhage or umbilical cord prolapse. kaukab tashfeen, malini patel, ilham m. hamdi, ibrahim h. a. al-busaidi and mansour n. al-yarubi clinical and basic research | e41 among the 60 cases with a ddi of >60 minutes; over all three cycles, the most frequent reasons for delayed deliveries were obtaining patient consent for the cs procedure (38.3%), lack of ot availability (25.0%) and moving the patients to the ot (18.3%). discussion the current study sought to assess ddis among emergency cs cases at nizwa hospital during three audit cycles, the results of each of which evidenced an improvement in optimal ddi rates. after the first cycle, several weak areas were identified and remedial strategies were implemented to improve ddis before the second cycle began, including the introduction of a timesheet and staff education regarding the importance of a ≤30-minute ddi, rapid preparation of the ot room, dealing with staff shortages and ways to move patients to the ot more efficiently. unfortunately, the second cycle indicated that the rate of cases with optimal ddis was still substandard. at this point, poor interdepartmental communication was deemed to be the main causative factor for ddi delays and an occ procedure was implemented. overall, the implemented strategies resulted in a significant improvement in the frequency of cases with ≤30-minute ddis and a decrease in the rate of poor perinatal outcomes. these results are consistent with those of a similar study of decisionto-incision time intervals among cs deliveries at a community hospital.13 although there is still room for improvement, the findings of the current study have indicated areas for future countermeasures to reduce ddi delays at nizwa hospital. fortunately, 80.6% of deliveries in ‘crash’ emergencies were achieved within the 30-minute target ddi. similarly, dunn et al. reported that 100% of ‘crash’ emergency cs procedures in their retrospective cohort study were performed within the recommended time interval.14 in the present study, difficulties in obtaining patient consent for a cs procedure was identified as the main factor causing delayed ddis of >30 minutes. in oman, the majority of the local population have large families; however, it is a common belief that undergoing a cs procedure can limit family size.15 it is possible that patients may be reluctant to consent to the surgical procedure for this reason. in addition, the husband and mother-in-law of an omani female patient may have more influence in terms of healthcare decision-making than the patient herself. in the current study, obtaining patient consent for the surgery was challenging, despite counselling efforts by social workers, public relations officers, patient educators, midwives and doctors. raising awareness of reproductive health, perhaps through nursing and midwifery programmes, may help to change attitudes and beliefs in the omani community. other factors resulting in delayed ddis included delays in contacting obstetricians by the nursing staff and delays in arrival and presurgical preparation by the anaesthesiology team. similar difficulties have been reported in a previous study.16 among the 35 babies admitted to the scbu in the current study, three showed signs of hypoxic ischaemic encephalopathy with convulsions. in one case, the fetus had severe prolonged bradycardia with meconium aspiration and the mother had had a prolonged pregnancy. in this case, the ddi was 75 minutes due to difficulties in obtaining patient consent for the procedure. in the second case, a cs procedure was indicated at 40 gestational weeks due to fetal distress; there was a 65-minute ddi due mainly to a refusal on the part of the patient to consent to the procedure. after delivery, the baby had an apgar score of 5 at five minutes. the third baby developed hypoxic ischaemic encephalopathy as the mother had uncontrolled diabetes at 38 gestational weeks; the cs surgery was indicated due to pathological ctg findings and moderate meconium aspiration. there was a delay of 70 minutes in getting consent for the procedure and the baby had an apgar score of 4 at five minutes. no stillbirths were reported during the study period and there was no difference between the perinatal outcomes among cases with a ddi of figure 1: reasons for decision-to-delivery time interval delays of >60 minutes among emergency caesarean section cases* performed at the nizwa hospital, nizwa, oman (n = 60). ot = operating theatre. *due to acute fetal distress, antepartum haemorrhage or umbilical cord prolapse. decision-to-delivery time intervals in emergency caesarean section cases repeated cross-sectional study from oman e42 | squ medical journal, february 2017, volume 17, issue 1 ≤30 minutes versus those with 31–60 minutes. these findings are consistent with those of singh et al.17 this study is subject to certain limitations. ideally, the most valid immediate measures to determine perinatal outcome include the five-minute apgar score, umbilical cord acid-base balance and the presence of neonatal encephalopathy; use of five-minute apgar scores alone is a relatively restricted measure of fetal hypoxia.7,18 unfortunately, in the current study, perinatal outcomes were assessed by apgar scores and scbu admissions, as there were no facilities available to assess cord ph. in addition, the rate of neonatal convulsions could not be compared according to ddi category as data were not available for the 0–30 minutes and 31–60 minutes groups. conclusion an optimal ddi of ≤30 minutes is an important predictor of neonatal outcomes, particularly for acutely compromised fetuses. in the current study, the introduction of corrective strategies to reduce ddi delays resulted in a significant improvement in optimal ddi rate among emergency cs cases at nizwa hospital. although the standard ddi target was not achieved in all cases, awareness of the factors causing ddi delays are important to help improve future patient outcomes. in particular, difficulty in obtaining patient consent for the surgery was identified as a major setback in prolonging ddis among emergency cs cases. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. james d. caesarean section for fetal distress: the 30 minute yardstick is in danger of becoming a rod for our backs. bmj 2001; 322:1316–17. doi: 10.1136/bmj.322.7298.1316. 2. oladapo ot, sotimehin sa, ayoola-sotubo o. predictors of severe neonatal compromise following caesarean section for clinically diagnosed foetal distress. west afr j med 2009; 28:327–32. 3. weiner e, bar j, fainstein n, ben-haroush a, sadan o, golan a, et al. the effect of a program to shorten the decisionto-delivery interval for emergent cesarean section on maternal and neonatal outcome. am j obstet gynecol 2014; 210:224. e1–6. doi: 10.1016/j.ajog.2014.01.007. 4. rashid n, nalliah s. understanding the decision-delivery interval in cesarean births. int ej sci med educ 2007; 1:61–8. 5. american academy of pediatrics, american college of obstetricians and gynecologists. guidelines for perinatal care, 6th ed. chicago, illinois, usa: american academy of pediatrics, 2007. p. 159. 6. royal college of obstetricians and gynaecologists. the use of electronic fetal monitoring: the use and interpretation of cardiotocography in intrapartum fetal surveillance. london, uk: rcog press, 2001. pp. 8–15. 7. leung ty, chung pw, rogers ms, sahota ds, lao tt, hung chung tk. urgent cesarean delivery for fetal bradycardia. obstet gynecol 2009; 114:1023–8. doi: 10.1097/ aog.0b013e3181bc6e15. 8. ajah lo, ibekwe pc, onu fa, onwe oe, ezeonu tc, omeje i. evaluation of clinical diagnosis of fetal distress and perinatal outcome in a low resource nigerian setting. j clin diagn res 2016; 10:qc08–11. doi: 10.7860/jcdr/2016/17274.7687. 9. chukwudi oe, okonkwo ca. decision delivery interval and perinatal outcome of emergency caesarean sections at a tertiary institution. pak j med sci 2014; 30:946–50. doi: 10. 12669/pjms.305.5470. 10. ministry of health oman. birth & death facts report: 2015. from: www.moh.gov.om/en_us/web/statistics/birth-death accessed: nov 2016. 11. world health organization. international classification of diseases (icd) 10. geneva, switzerland: world health organization, 2004. 12. lucas dn, yentis sm, kinsella sm, holdcroft a, may ae, wee m, et al. urgency of caesarean section: a new classification. j r soc med 2000; 93:346–50. 13. de regt rh, marks k, joseph dl, malmgren ja. time from decision to incision for cesarean deliveries at a community hospital. obstet gynecol 2009; 113:625–9. doi: 10.1097/aog. 0b013e31819970b8. 14. dunn cn, zhanq q, sia jt, assam pn, taqore s, sng bl. evaluation of timings and outcomes in category-one caesarean sections: a retrospective cohort study. indian j anaesth 2016; 60:546–51. doi: 10.4103/0019-5049.187782. 15. times of oman. avoid caesarean births, advises an expert in oman. from: http://timesofoman.com/article/66464/oman/ health/avoid-caesarean-section-advises-an-expert-in-oman accessed: nov 2016. 16. bloom sl, leveno kj, spong cy, gilbert s, hauth jc, landon mb, et al. decision-to-incision times and maternal and infant outcomes. obstet gynecol 2006; 108:6–11. doi: 10.1097/ 01.aog.0000224693.07785.14. 17. singh r, deo s, pradeep y. the decision-to-delivery interval in emergency caesarean sections and its correlation with perinatal outcome: evidence from 204 deliveries in a developing country. trop doct 2012; 42:67–9. doi: 10.1258/td.2012.110315. 18. kamoshita e, amano k, kanai y, mochizuki j, ikeda y, kikuchi s, et al. effect of the interval between onset of sustained fetal bradycardia and cesarean delivery on long-term neonatal neurologic prognosis. int j gynaecol obstet 2010; 111:23–7. doi: 10.1016/j.ijgo.2010.05.022. https://doi.org/10.1136/bmj.322.7298.1316 https://doi.org/10.1016/j.ajog.2014.01.007 https://doi.org/10.1097/aog.0b013e3181bc6e15 https://doi.org/10.1097/aog.0b013e3181bc6e15 https://doi.org/10.7860/jcdr/2016/17274.7687 https://doi.org/10.12669/pjms.305.5470 https://doi.org/10.12669/pjms.305.5470 https://doi.org/10.1097/aog.0b013e31819970b8 https://doi.org/10.1097/aog.0b013e31819970b8 https://doi.org/10.4103/0019-5049.187782 https://doi.org/10.1097/01.aog.0000224693.07785.14 https://doi.org/10.1097/01.aog.0000224693.07785.14 https://doi.org/10.1258/td.2012.110315 https://doi.org/10.1016/j.ijgo.2010.05.022 sultan qaboos university med j, november 2013, vol. 13, iss. 4, pp. 486-490, epub. 8th oct 13 submitted 25th aug 13 peer-reviewed accepted 3rd sep 13 tuberculosis (tb) has occupied pride of place throughout the history of disease as a scourge with an unparalleled impact on humankind in terms of morbidity, mortality and economic cost. until robert koch’s revolutionary elucidation of its aetiology in 1882,1 this disease inspired awe, social stigma, a variety of wide-ranging but largely ineffective remedies, and even stimulated artistic fervour in prose, poetry and paintings. it therefore behooves both current and future physicians to look back, recognise and remember the multitude of individuals and disciplines that contributed to (and sometimes detracted from) the understanding of this disease, which was famously alluded to by john bunyan in 1680 as “the captain of all these men of death…consumption”.2 this article casts a spotlight on tuberculosis during the pre-koch era, from its semantics and eponyms, to a host of individuals (acknowledged or forgotten) who form part of the narrative of this disease as either discoverers or sufferers. these glimpses of past eons, preceding koch’s landmark discovery of the tubercle bacillus, offer a deeper insight into the complex interactions between disease, discoveries and societal interpretations. antiquity and semantics tuberculous deformities and lesions have been identified both by macroscopic appearances and by molecular analyses in the spinal columns of egyptian mummies from 2,400 bc.3 the terms ‘phthisis’ (greek phthinein, wasting) and ‘consumption’ (greek, to eat up or devour) typified a terminal disease that caused a ‘drying’ or ‘consuming’ of the body. the hopeless prognosis of the disease prompted hippocrates to warn physicians to keep away from tb patients so as to preserve their professional reputation! franciscus dele boë sylvius (in his opera medica in 1679) and richard morton independently described ‘tubercles’ (latin tuberculum = a small firm nodule or swelling; a diminutive of tuber, potato).4 in 1839, johann lukas schönlein first used the word ‘tuberculosis’ in reference to this disease.5 the term ‘miliary’ tb was derived from the appearance of 1–5 mm millet-like lesions visible in chest radiographs when there was disseminated involvement of both lungs. the japanese refer to the disease by varying names: kekkaku (tuberculosis), rogai (consuming and coughing) and haibyo (lung disease).6 scrofula referred to the enlargement of the tubercular cervical glands, but is often loosely used to refer to tubercular infections of other tissues, like the bones.7,8 the degeneration of infected tissue into a cheese-like mass, ‘caseation’, became a byword in classical pathologic descriptions of the disease.9 eponyms, euphemisms and metaphors the ‘great white plague’, as distinct from the infamous ‘black plague’ which also took its toll on the human race, is a metaphorical reference to the epidemic prevalence of tb in europe between the 17th and 19th century, associated with inevitable mortality. we know now, of course, that the two diseases had only one common theme—bacterial department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ritu@squ.edu.om of animalcula, phthisis and scrofula نظرة تارخيية عن السل يف فرتة ما قبل كوخ ريتو الكتكيا medical history of animalcula, phthisis and scrofula historical insights into tuberculosis in the pre-koch era ritu lakhtakia of animalcula, phthisis and scrofula historical insights into tuberculosis in the pre-koch era 487 | squ medical journal, november 2013, volume 13, issue 4 infection—and that they were vastly different in epidemiology and in the acuteness of clinical manifestations. at the same time, references to tb as the ‘king’s evil’ implied that the panacea lay in the healing powers of the ‘royal touch’.7 anton ghon (1866–1936), an austrian pathologist, lent his name to the terms ‘ghon’s focus’ and ‘ghon’s complex’ (the subpleural primary pulmonary lesion in children and its draining lymph node, respectively).10 on calcification, its radiological appearance is referred to as ‘ranke’s complex’. sir percival pott, a pioneering surgeon in 18th century england, described the gibbuslike deformity of collapsed adjoining tubercular vertebrae, which indelibly wrote his name in the annals of medicine when this deformity was eponymously named ‘pott’s disease of the spine’.11 a tubercular granuloma in the cortex of the brain, which can rupture into the subarachnoid space causing tubercular meningitis, came to be known as rich’s focus after the american pathologist arnold rice rich (1893–1968).12 the term lupus for the ulcerated tubercular lesion of the skin epitomises its wolf-like rapacity, virulence and its capacity for destruction.13 the occupational hazard of implantation-tb (tuberculosis verrucosa cutis) is exemplified by the term ‘prosector’s wart’ which could be acquired with equal ease by such diverse professionals as anatomists, pathologists, butchers or veterinarians.14 in the pre-antibiotic era, one of the lifethreatening complications was massive haemoptysis due to the rupture of a pseudo-aneurysm of the bronchial or pulmonary vessels; this complication eponymously came to be known as rasmussen’s aneurysm after fritz rasmussen, a danish physician, described its appearance in 11 autopsy cases.15 pathophysiology and clinical manifestations while hippocrates considered tb a hereditary disease, aristotle and ibn sina,16 perhaps more accurately, ascribed it as being a contagion. the republic of lucca in tuscany, italy, issued an edict in 1699 that emphasised the infective nature of the disease, the need for notification and the disinfection procedures required for the mortal remains.17 centuries later, in 1546, girolamo fracastoro brought the communicable nature of the disease to the forefront again in his treatise de contagione.18 araeteus of cappadoccia provided grotesque, but accurate, descriptions of the physiognomy of a phthisic patient: voice hoarse; neck slightly bent, tender, not flexible, somewhat extended; fingers slender, but joints thick; of the bones alone the figure remains, for the fleshy parts are wasted; the nails of the fingers crooked, their pulps are shriveled and flat... nose sharp, slender; cheeks prominent and red; eyes hollow, brilliant and glittering; swollen, pale or livid in countenance; the slender parts of the jaws rest on the teeth as, as if smiling; otherwise of cadaverous aspect...19 in 1720, long before the advent of microscopy and koch’s visualisation of the bacillus, the english physician benjamin marten first raised the possibility of “wonderfully minute creatures”, animalcula, causing the disease.20 the french physician, gaspard bayle (1774–1816) classified 6 kinds of pulmonary consumption: chronic ulcerative; granular; melanotic; ulcerous; calculous, and cancerous (corresponding to fibrocaseous; miliary; anthracotic; abscess; calcified lesions, and true cancers in modern terms, respectively).21 his colleague, rené laennec, invented the stethoscope in 1816, which enabled the auscultation of the tubercular chest, anointing him as an authority on lung pathology and diagnosis. inevitably, this contact with tb patients caused his demise at only 46 years of age.18,21,22 he thus joined the ranks of many physicians who died after prolonged attendance on their tb patients. epidemiology and sociopolitical dynamics in different eras of social evolution in japan, groups susceptible to tb included upper-class young women, highly-talented young men (18th century) or female mill-hands (during the industrial revolution).6 a well-known universal predisposition was crowded living in unhygienic surroundings, often, but not always, an accompaniment of poverty. more specifically, occupational lung diseases (silicosis) and metabolic conditions (diabetes) provided breeding grounds for the infection to thrive. political movements were often founded on and contributed to denouncing ‘infection’ as the cause of tb. the syndicalist movement in 19th ritu lakhtakia medical history | 488 benefits of the fresh air, such practices encouraged the isolation of tb cases that curtailed the human spread of disease, and provided better nutrition and closer supervision of the patients. even today, when the ‘specific’ aetiological agent and its therapy have been known for more than a century, supportive measures like nutrition, hygiene and environment still play a vital conjunctive role in achieving a cure and reducing morbidity. pneumothorax or plombage were surgical options deemed to give rest to the infected lung and allow it to heal. artistic romanticism versus societal demonisation in the 18th century, a wealth of literature elevated the sick pallor of tubercular facies to a poetic and romantic condition. victor hugo’s les misérables and puccini’s opera la bohème depicted accurate portraits of consumptive characters. the delicate allure of these afflicted yet fair women imbued the audience with a morbid fascination for this incomprehensible and seemingly unconquerable disease. the victims of this slow death were considered to be ‘redeemed’ or ‘condemned’ by this fate, depending on whether society perceived them as innocent or evil. john keats’s tubercular affliction and his extraordinary poetic creations, were even attributed in some bizarre manner to an igniting of the mind while the body wasted of the disease.28 this glorification contrasted sharply with the social ostracism of entire families once the understanding of tb’s communicable nature took root. the expulsion of the tuberculosis-afflicted frédéric chopin from palma, majorca (where he had gone to benefit from the fresh air), by an intolerant and fearful citizenry reflected the opposing views of aetiology within the continent. while northern europeans considered it hereditary, the south considered it contagious.29 king tutankhamun, emily brontë, elisabeth browning, anton chekov, robert burns, john keats, d. h. lawrence and frédéric chopin are just a few of the hundreds of famous and talented historical figures whose extraordinary contributions to civilisation were cut short by consumption. century france, used the disease as a rallying point to call for shorter labour hours, which were held as the preeminent cause of the working-class’ inability to fight chronic diseases.22 the clashes for supremacy of one aetiological theory over another can today be dispassionately resolved; the wealth of knowledge indicates that, in most chronic infectious diseases, nutrition, occupation, personal habits, hygiene and immunity are inextricably linked. the telling adage that ‘‘history repeats itself ’’ is evident in a recent commentary on the increased number of tb cases in london that points the finger at two populations groups: immigrants inhabiting boroughs with similar living conditions to victorian england, and prisons with abhorrent environs. it warns of a resurgence of the ‘white plague’ in the absence of timely political and financial commitment.23 closely following these predisposed populations are victims of geopolitical circumstance or human frailties such as migrants, refugees, homeless people, drug users, and human immunodeficiency virus (hiv)-infected groups. all of this calls for socio-political action since it is certain that the end of the ‘white plague’ is nowhere in sight.24 treatment and prevention a variety of diets purporting to cure tb—including vegetables, fruits and meats—have been proposed by physicians throughout the ages. one ‘cure-forall-ills’ was blood-letting, a practice that stood strong for centuries. as mentioned previously, in the 18th century the ‘royal touch’ of kings was touted as a panacea, with anecdotal success.25 the first tb sanatorium was opened in 1854 by hermann brehmer in görbersdorf, germany (now poland), after his own disease was ‘cured’ by a sojourn in the himalayas.26 such incidents of recovery, after exposure to fresh mountain air, heralded a faith in sanatorium treatment that reigned supreme for centuries. the choices ranged from ‘enjoying the mountain air’ or ‘taking the waters’ at spas in badenbaden (germany), royal tunbridge wells (uk) and kusatsu or atami (japan). additionally, tb inspired a new wave of architectural (flat roofs and terraces) and furniture designs in modernistic housing, which allowed the victims and their healthy contacts the beneficial effects of sunshine and air.27 whatever the of animalcula, phthisis and scrofula historical insights into tuberculosis in the pre-koch era 489 | squ medical journal, november 2013, volume 13, issue 4 oblivion versus stardom in 1865, the french military physician, jeanantoine villemin, demonstrated the contagious nature of the disease through his experiments on animal pathogenicity. however, his observations were doomed to obscurity because of vehement opposition by his vocal contemporary herman pidoux, who expressed disdain for a theory that challenged classic knowledge. pidoux expressed fear for the social stigma that would victimise sufferers if this concept was allowed to take ground. the prevalent notions of epidemiology attributed ‘consumption of the rich’ to chronic diseases, laziness, flabbiness, overeating and ambition; ‘consumption of the poor’ was instead attributed to ignorance, overwork, malnutrition and a lack of hygiene. this contrasting list of habits and behavioural practices questions the veracity of the scientific enquiry that allowed it to stand ground. in 1882, koch’s brilliant exposition at the berlin physiological society—endorsing beyond doubt his predecessor’s often maligned ‘germ theory’— secured his place in history. he thus received the recognition for endorsing villemin’s astute conclusions that was denied to villemin himself.30 the germ theory proven: koch raises the curtain koch’s identification of the tubercle bacillus in 1882—an achievement for which he was awarded the nobel prize in physiology or medicine in 1905— and koch’s postulates became the gold standard for establishing a causal relationship between an infectious agent and the resultant disease.1,31 that watershed discovery, and the rapid advances in diagnosis, prevention and therapy that followed over the next 100 years, deserve to be addressed in another exposition on the subject in a subsequent issue. lessons from the history of tuberculosis this short history of tb in the pre-koch era offers a panoramic view of an unenviable struggle in the understanding of a formidable infectious disease. men of science waded through a jigsaw puzzle of facts and myths; ironically, many were ‘consumptives’ themselves. prosection procedures (regrettably, a dying practice today) and a study of pathological anatomy provided much of the wealth of knowledge of this period. the creative arts represented the public notions of the time regarding the disease, and many socio-political policies were themselves disease-influenced. numerous contributions enhanced, and disputes enriched, the inexorable progress leading to koch’s landmark identification of the tubercle bacillus. however, there is no doubt that the knowledge of past experiences enlightens us to face yet unknown challenges in the future of medicine—because history often repeats itself! references 1. carter kc (ed). essays of robert koch: contributions in medical studies. westport: greenwood press, 1987. pp. ix–xxv. 2. meyer ja. tuberculosis, the adirondacks, and coming of age for thoracic surgery. ann thorac surg 1991; 52:881–5. 3. salo wl, aufderheide ac, buikstra j, holcomb ta. identification of mycobacterium tuberculosis dna in a pre-columbian peruvian mummy. proc natl acad sci usa 1994; 91:1091–4. 4. trail rr. richard morton (1637-1698). med hist 1970; 14:166–74. 5. tomashefski jf, farver cf, fraire ae, cagle pt (eds). dail and hammar’s pulmonary pathology volume 1: nonneoplastic lung disease. new york: springer. p. 316. 6. fukuda m. a cultural history of tuberculosis in modern japan. from: http://www.lang.nagoya-u. ac.jp/~mfukuda/english.html accessed: jun 2013. 7. encyclopædia britannica online academic edition. scrofula. from: http://www.britannica.com/ ebchecked/topic/530041/scrofula> accessed: aug 2013. 8. merriam-webster. scrofula. from: http://www. m e r r i a m w e b s t e r. c o m / d i c t i o n a r y / s c r o f u l a accessed: aug 2013. 9. world english dictionary. caseation. from: http://dictionary.reference.com/browse/caseation accessed: aug 2013. 10. ober wb. ghon but not forgotten: anton ghon and his complex. pathol annu 1983; 18 pt 2:79–85. 11. dobson j. percivall pott. ann r coll surg engl 1972; 50:54–65. 12. rice ra, mccordock ha. the pathogenesis of tuberculous meningitis. bull johns hopkins hosp 1933; 52:5–37. 13. james wd, berger tg, dirk m. andrews’ diseases of ritu lakhtakia medical history | 490 22. laennec rth. de l’auscultation médiate ou traité du diagnostic des maladies des poumons et du coeur. paris: brosson & chaudé, 1819. 23. zumla a. the white plague returns to london--with a vengeance. lancet 2011; 377:10–11. 24. rubin sa. tuberculosis: captain of all these men of death. radiol clin north am 1995; 33:619–39. 25. maulitz rc, maulitz sr. the king's evil in oxfordshire. med hist 1973; 17:87–9. 26. mccarthy or. the key to the sanatoria. j r soc med 2001; 94:413–17. 27. campbell m. what tuberculosis did for modernism: the influence of a curative environment on modernist design and architecture. med hist 2005; 49:463–88. 28. morens dm. at the deathbed of consumptive art. emerg infect dis 2002; 8:1353–8. 29. daniel tm. the history of tuberculosis. respir med 2006; 100:1862–70. 30. barnes ds. historical perspectives on the etiology of tuberculosis. microbes infect 2000; 2:431−40. 31. nobelprize.org. the nobel prize in physiology or medicine 1905. from: http://www.nobelprize.org/ nobel_prizes/medicine/laureates/1905/ accessed: aug 2013. the skin: clinical dermatology. 10th ed. amsterdam: elsevier health sciences, 2006. p. 335. 14. golden rl. sir william osler and the anatomical tubercle. j am acad dermatol 1987; 16:1071–4. 15. rasmussen fv. on haemoptysis, especially when fatal, in its anatomical and clinical aspects. edinburgh med j 1868; 14:385–401 16. avicenna (ibn sina). the canon of medicine. from: http://www.unani.com/avicenna%20story%203.htm accessed: jul 2013. 17. new jersey medical school global tuberculosis institute. a history of tuberculosis treatment. from: http://www.umdnj.edu/ntbc/tbhistory.htm accessed: jun 2013. 18. brock td (ed). milestones in microbiology: 1546 to 1940. new jersey: prentice hall inc., 1961. pp. 69– 75. 19. porter r. the greatest benefit to mankind: a medical history of humanity from antiquity to the present. new york: w. w. norton & company, 1999. 20. doetsch rn. benjamin marten and his “new theory of consumptions”. microbiol rev 1978; 42:521–8. 21. long er. a history of pathology. london: ballière tindall & cox., 1928. pp. 131–3. to the editor, the review paper by jeremy d. davey and james e. freeman on improving road safety through deterrencebased initiatives, published in squmj in february 2011, is an interesting discussion and overview of this important topic.1 the clarity of the presentation and the balanced view provided by the authors add much value to the paper. in addition, stressing the aspects of culture and cultural change in relation to road safety practices is of particular importance. as asserted by the authors, the deterrence-based approach is not the magic panacea for road traffic accidents, nor does it provide lasting behavioural changes. despite the theoretical appeal of deterrence as a control measure for the performance of the drivers, evidence shows repeatedly that legislation and deterrencebased approaches to change behavior of road users produce weak, marginal or transient results.2,3,4 studies over several decades have shown inconsistent results. it appears that what is more potentially important in this context than deterrence-based legislations is a deeper understanding of required changes in the social atmosphere.5 successful law enforcement is based on its capacity to build an effective deterrent peril to road users and its appeal to the culture. in this letter, we would like to share with you a basic analysis of the offences and crashes data reported by the royal oman police (rop) in the last 10 years, viz. 2000 to 2009.6 in the year 2000, rop ticketed around 230,000 offences which is equivalent to around a half offence per registered vehicle during that year. by 2009, the number of offences had increased almost eight-fold exceeding 1,800,000 offences with around 2.5 offences per vehicle. during all those years, omani male drivers were responsible for more than 90% of all offences. if we focus on speeding, which is the highly cited cause of death from road traffic incidents (rti) in oman and elsewhere,7-9 we see that speeding related offences as a percentage of all traffic offences have increased from around 32% in 2000 to over 85% in 2009. at the same time, the number of crashes attributed to speeding increased from 39% to around 51% during the same period. elsewhere, longitudinal research has shown that receiving speeding fines is actually associated with increased risk of getting ensuing speeding tickets.10 this may indicate that enforcing speeding tickets alone may not be effective. there is, therefore, a need to consider other deterrence strategies that considers the context. quoting davey jd and freeman je, "the effectiveness of any deterrence-based enforcement practice is heavily dependent upon increasing motorists’ perceptions regarding the risk of being apprehended for an offence, e.g., general deterrence". however, the question is what are the perceptions of "risk" and "speeding" of our young drivers? culturally determined bias is an important factor in the perception of risk and the causes of accidents.11 as such, it is of paramount importance to address the socio-cultural aspects of accidents. for example, the core component of speed, i.e. time, needs to be considered within the broader social context. traditional communities, like oman and other gulf countries, lived previously in a more relaxed manner as their time was squ med j, august 2011, vol. 11, iss. 3, pp. 420-423, epub. 15th aug 11 received 28th may <l]öå^f⁄<ÿ¯}<‡⁄<–ëü�÷]<ì⁄¯â<∞ä†<vó◊¬<åö ≈åü÷]<ó◊¬<ìèflf⁄  re: improving road safety through deterrence-based initiatives letter to editor nasser al-azri and abdullah al-maniri letter to editor | 421 not dictated by the clock, but by social and religious events, such as daily prayers.12 the rapid modernisation process has created a new perception of time with clock-time dominating some daily activities (e.g. work) and event-driven time continuing to play a role in some other parts of people’s daily lives such as prayers and social affairs.13 vehicles themselves have contributed to this profound change in the perception and collapse of time.14,15 such socio-cultural dimensions of the speeding problem should not escape analysis when seeking deterrence strategies for this problem in our region. nasseral-azri and *abdullah al-maniri epidemiology & statistics unit department of family medicine & public health college of medicine and health sciences sultan qaboos university, muscat, oman corresponding author email: almaniri@gmail.com references 1. davey jd, freeman je. improving road safety through deterrence-based initiatives. squ med j 2011; 11:29–37. 2. bertelli am, richardson le. the behavioral impact of drinking and driving laws. policy stud j 2008; 36:545–69. 3. houston dj, richardson le. drinking-and-driving in america: a test of behavioral assumptions underlying public policy. polit res quart 2004; 57:57–63. 4. wilde gjs. target risk 2: a new psychology of safety and health. 2nd ed. ontario: pde publications, 2001. 5. evans l. traffic safety and the driver. new york: van nostrand reinhold, 1991. 6. royal oman police. traffic statistics report, muscat, sultanate of oman, directorate general of traffic. muscat: royal oman police, 2009. 7. al-lamki l. life loss and disability from traffic accidents: it is imperative we all act now. squ med j 2010; 10:1–5. 8. suriyawongpaisal p, kanchanasut s. road traffic injuries in thailand: trends, selected underlying determinants and status of intervention. inj control saf promot 2003; 10:95–104. 9. moore vm, dolinis j,woodward aj. vehicle speed and risk of a severe crash. epidemiol 1995; 6:258–62. 10. lawpoolsri s, li j, braver er. do speeding tickets reduce the likelihood of receiving subsequent speeding tickets? a longitudinal study of speeding violators in maryland. traffic inj prev 2007; 8:26–34. 11. kauoabenan dr. beliefs and the perception of risks and accidents. risk analy 1998; 18:243–52. 12. d’avanzo ce, geissler em. pocket guide to cultural health assessment. 3rd ed. st. louis: mosby, 2003. 13. aboelenein m. time use in a changing arab culture: a study in the united arab emirates. paper accepted for presentation at the 99th annual meeting, american sociological association, san francisco, california, usa, 14–17 august 2004. 14. featherstone m. automobilities: an introduction. theory, cult & soc 2004; 21:1–24. 15. knowles rd. transport shaping space: differential collapse in time-space. jtransp geog 2006; 14:407-425. authors’ response firstly, the authors would like to thank the editor for the opportunity to respond to dr. al-azri’s and dr. almaniri’s letter. secondly, while the current authors also accept that deterrence-based approaches should act as only one cornerstone of a suite of interventions and public policy initiatives designed to improve road safety, deterrence-based approaches have nonetheless consistently proven to be a valuable resource to improve road safety.1,2 dr. al-azri and dr. al-maniri reinforce their assertion about the limited utility of deterrence by citing drink driving research, and the issue of drink driving is particularly relevant within the current context given that the problem of driving after drinking has historically been addressed through deterrence-based approaches. while the effectiveness of deterrence-based approaches to reduce drink driving will always be dependent upon a range of situational and contextual factors (including police enforcement practices, re: improving road safety through deterrence-based initiatives 422 | squ medical journal, august 2011, volume 11, issue 3 cultural norms, etc.), the utilisation of this approach has proven particularly effective within queensland, australia. for example, a relatively recent comprehensive review of random breath testing in queensland demonstrated that this initiative not only had a deterrent impact upon self-reported intentions to drink and drive, but was also found to have significantly reduced alcohol-related fatalities in the state.2 however, the authors agree that deterrence-based approaches can be particularly transient and thus require constant “topping up” not least through sustained public reinforcement, which was clearly articulated in the seminal work by homel.1 dr. al-azri and dr. al-maniri reinforce their assertion regarding the weak link between deterrence-based approaches and positive road safety outcomes by focusing on speeding-related research, which is another central road safety concern that has been historically addressed through the application of deterrence-based sanctions e.g., speeding fines, loss of licence, etc. additionally, the issue of utilising deterrence approaches to reduce speeding offences is arguable more relevant (compared to drink driving) for the current context in oman. the authors cite a 10-year evaluation of speeding offences in oman3 which demonstrated a sizeable increase in the number of recorded speeding offences and speeding-related crashes (even after considering offences per registered vehicle) as well as a maryland study that provided preliminary evidence that receiving speeding fines may increase the risk of receiving further fines.4 in regards to the former, this study is similar to other research that has failed to find a positive relationship between fixed speeding penalties and improvements in driving behaviour,5 although it is noted that an opposing body of research does exist that has demonstrated that increases in the severity of penalties can lead to a decrease in accidents and injury rates.6 what remains evident is that a range of factors are likely to impact also upon what would seem a relatively simple analysis between speeding offences and crash outcomes, not least changes in policing activities and enforcement styles, modernisation of vehicles, improvements in road conditions, improvements in speeding detection procedures, etc. additionally, the origins of this counter-intuitive effect may be found within a wider social sphere, as “cultural norms” may dilute any deterrent effect that is produced through the threat of sanctions, such as the cultural acceptance of speeding-related practices in order to meet increasing modern day deadlines. additionally, researchers are beginning to demonstrate that there are a range of personal and social rewards that appear to contribute to speeding, which may ultimately have a counterproductive impact upon deterrent processes.7 another particularly salient factor is the issue of punishment avoidance (e.g., committing an offence and avoiding detection) and it is noteworthy that recent speeding-related research has also demonstrated that the effectiveness of the severity of the penalty is also dependent upon the perceived certainty of punishment.8,9 in short, the effectiveness of any deterrence-based initiative to reduce speeding related offences will be heavily dependent upon its capacity to detect offences regularly, which will initially prove a particularly daunting task when a community increasingly embraces vehicles as a primary mode of transport. in regards to the later study, the maryland research also demonstrated that those who initially received a speeding fine during the sample period were significantly more likely to be younger males who were also more likely to be cited for a drink driving offence.4 this finding provides further evidence that sanctions are not an equally effective deterrent for all motorists, and may yet prove to be least effective among younger cohorts who are less inclined to calculate consequences associated with a utilitarian model. this is also in line with current research that continues to demonstrate that younger drivers are at an increased risk of engaging in other forms of deviant driving behaviour and thus are also overrepresented in crash statistics.10 this central issue also relates to dr. al-azri’s and dr. al-maniri’s question of what are the perceptions of "risk" and "speeding" of younger drivers? it is noted that both understanding and changing perceptions of risk has proven particularly difficult among younger cohorts, and thus a considerable amount of research is still required in this area to reduce crash-involvement among this high need group. however, similar to the central tenet of dr. al-azri’s and dr. al-maniri’s letter, the current authors agree that it is likely that researchers and practitioners will need to look beyond purely deterrence-based approaches to create change. for example, emerging research is beginning to illuminate the fact that younger drivers’ speeding behaviours may be more influenced by their peer support network than the threat of sanctions.11 as a result, the current authors also assert that both research and policy increasingly need to consider nasser al-azri and abdullah al-maniri letter to editor | 423 the wider socio-cultural factors that influence driving behaviours as well as crash risk. however, this will no doubt continue to prove a difficult task as it is widely accepted that a plethora of factors can influence any driving decision. these include the array of factors associated with both the modernisation of communities as well as technological improvements in vehicle design and performance. therefore, it is imperative that deterrence-based approaches are complemented with well-informed and targeted media campaigns (as well as other public policy initiatives) that clearly highlight the heightened dangers which are associated with increased reliance on vehicles to meet the demands of modern living. finally, one of the greatest challenges that remains for road safety practitioners (that was not considered in the review paper or the corresponding letter) is the need to develop better methods to bridge the gap between theoretical understandings of behaviour modification (e.g., principles of deterrence) and the corresponding practical application of theory-based interventions to create lasting change among motorists. additionally, there is a need to identify the conditions under which lasting deterrent effects can be achieved. despite this substantial challenge, such efforts are clearly worthwhile when considering the tremendous personal and economic cost of road crashes worldwide.12 such efforts will also no doubt take the form of scientific inquiry as well as active debate, both of which have a complementary place in the pursuit of improvements in road safety. jeremy davey and *james freeman centre for accident research and road safety institute of health & biological innovation queensland university of technology, australia corresponding author email: je.freeman@qut.edu.au references 1. homel rj. policing and punishing the drinking driver. a study of specific and general deterrence. new york: springer-verlag, 1988. 2. watson b, hart s, freeman j, tay r, davey j, madden j, goff a. review of random breath testing (rbt) in queensland. queensland university of technology, 2005. 3. royal oman police. traffic statistics report, muscat, sultanate of oman, directorate general of traffic. muscat: royal oman police, 2009. 4. lawpoolsri s, li j, braver er. do speeding tickets reduce the likelihood of receiving subsequent speeding tickets? a longitudinal study of speeding violators in maryland. traffic inj prev 2007; 8:26–34. 5. elvik r, christensen p. the deterrent effect of increasing fixed penalties for traffic offences: the norwegian experience. j safety res 2007; 38:689–95. 6. tavares a, mendes s, costa c. the impact of deterrence policies on reckless driving: the case of portugal. eur j crim policy res 2008; 14:417–29. 7. fleiter j, watson b, lennon a, king m, shi k. speeding in australia and china: a comparison of the influence of legal sanctions and enforcement practices on car drivers. in: proceedings of the 2009 australasian road safety research, policing and education conference: smarter, safer directions. sydney convention & exhibition centre, sydney, new south wales, australia, 2009. 8. fleiter j, watson b. the speed paradox: the misalignment between driver attitudes and speeding behaviour. j australasian coll road safety 2006; 17:23–30. 9. ritchey m, nicholson-crotty s. deterrence theory and the implementation of speed limits in the american states. policy stud j 2011; 39:329–46. 10. mccartt a, mayhew d, braitman k, ferguson s, simpson h. effects of age and experience on young driver crashes: review of recent literature. traffic inj prev 2009; 10:209–19. 11. matthews k, agnew r. extending deterrence theory: do delinquent peers condition the relationship between perceptions of getting caught and offending? j res crime delinq 2008; 45:91–118. 12. world health organization. global status report on road safety: time for action. from: http://whqlibdoc.who.int/ publications/2009/9789241563840_eng.pdf, 2009. accessed mar 2011. 1department of community medicine, college of medicine, university of basrah, basrah, iraq; 2department of community medicine ,college of medicine, university of misan, maysan, iraq; 3general directorate of health, basrah, iraq *corresponding author e-mail: snasrah@hotmail.com معدل انتشار ومستويات االكتئاب بني آباء وأمهات األطفال املصابني بالسرطان يف البصرة، العراق �صكرية كامل املالكي، جا�صم االأ�صدي، عقيل الوائلي، �صباح اأغا abstract: objectives: cancer in a family member can be a major source of psychological disorders, especially for the parents of children diagnosed with cancer. this study aimed to determine the prevalence and levels of depression among parents of children with cancer in basrah, iraq. methods: this cross-sectional study was conducted between november 2014 and april 2015 at the specialist paediatric hospital in basrah city, iraq. one parent each of 384 children with cancer admitted to the hospital for treatment or follow-up during the study period were invited to participate in the study. age, gender, years of education, occupation, monthly income, place of residence and the overall number of children in a family were recorded. the center for epidemiologic studies depression scale was used to identify depression and assess levels of depression. results: a total of 336 parents participated in the study (response rate: 87.5%). of these, 70.5% were depressed, 54.1% of which had major depression. depression was significantly more common (77.2% versus 57.1%) and more severe (60.7% versus 41.1%) among mothers compared to fathers (p = 0.001). parents with fewer years of education were more likely to be depressed; this association was significant for mothers but not fathers (p = 0.001 and 0.814, respectively). depression was significantly inversely associated with monthly income (p = 0.001). conclusion: the prevalence of depression among the parents of children with cancer was high. depression was significantly more severe among mothers compared to fathers and among mothers who were less educated. income also had a significant association with levels of depression among parents. keywords: cancer; children; parents; depression; prevalence; iraq. امللخ�ص: اأهداف: ال�رضطان يف اأحد اأفراد االأ�رضة ميكن اأن يكون م�صدراً رئي�صيًا لل�صدمة النف�صية، خا�صة بالن�صبة الآباء واأمهات االأطفال امل�صابني، تهدف هذه الدرا�صة اإىل حتديد معدل انت�صار وم�صتويات االكتئاب بني اآباء واأمهات االأطفال امل�صابني بال�رضطان يف الب�رضة مدينة يف التخ�ص�صي االأطفال طب م�صت�صفى يف 2015م اأبريل و 2014م نوفمرب بني املقطعية الدرا�صة هذه اأجريت منهجية: بالعراق. الب�رضة بالعراق. متت دعوة اأحد والدي كل من 384 من االأطفال امل�صابني بال�رضطان الذين اأدخلوا اإىل امل�صت�صفى للعالج اأو املتابعة خالل فرتة الدرا�صة للم�صاركة يف هذه الدرا�صة، مت ت�صجيل بيانات العمر، واجلن�ض، و�صنوات التعليم، والعمل، والدخل ال�صهري، ومكان االإقامة، م�صتويات وتقييم االكتئاب على للتعرف الوبائية الدرا�صات ملركز االكتئاب مقيا�ض ا�صتخدام مت االأ�رضة، يف لالأطفال االإجمايل والعدد كانوا امل�صاركني من 70.5% .)87.5% اال�صتجابة )معدل 336 هو الدرا�صة يف امل�صاركني واالمهات االآباء عدد اإجمايل االكتئاب.نتائج: م�صابني باالكتئاب، منهم %54.1 م�صابني باكتئاب �صديد .االكتئاب كان اإىل حد كبري اأكرث �صيوعًا )%77.2 مقابل %57.1( و اأكرث �صدًة )%60.7 مقابل %41.1( بني االأمهات مقارنة باالآباء )p = 0.001(، االآباء و االأمهات مع �صنوات اأقل من التعليم كانوا اأكرث عر�صًة لال�صابة حد اإىل االكتئاب وارتبط التوايل(، على ،0.814 و p = 0.001( لالآباء لي�ض ولكن لالأمهات بالن�صبة هامًا كان الرتابط هذا باالكتئاب، كبريعك�صيًا مع الدخل ال�صهري )p = 0.001(. خامتة: كان انت�صار االكتئاب بني اآباء واأمهات االأطفال امل�صابني بال�رضطان مرتفعًا، كما كان االكتئاب اإىل حد كبري اأكرث حدًة بني االأمهات مقارنًة باالآباء وبني االأمهات اللواتي كنَّ اأقل تعليمًا، الدخل ال�صهري كان له ارتباٌط كبرٌي مع م�صتويات االكتئاب بني االآباء واالأمهات. كلمات مفتاحية: ال�رضطان؛ االأطفال؛ االآباء واالأمهات؛ االكتئاب؛ انت�صار؛ العراق. prevalence and levels of depression among parents of children with cancer in basrah, iraq *shukrya k. al-maliki,1 jasim al-asadi,1 akeel al-waely,2 sabah agha3 clinical & basic research sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e329–334, epub. 19 aug 16 submitted 1 feb 16 revision req. 29 mar 16; revision recd. 10 may 16 accepted 2 jun 16 doi: 10.18295/squmj.2016.16.03.011 advances in knowledge psychological disorders among the parents or family members of a child with cancer constitute an important health problem. the results of this study showed that the prevalence of depression among parents of children with cancer in basrah, iraq, was very high. to the best of the authors’ knowledge, this is the first study from basrah, iraq, to explore this health problem. application to patient care it is critical to consider the mental health of parents of children with cancer, not only for the sake of the parents but also because depressed parents may often not be able to adequately care for their children. the results of this study may encourage the implementation of preventative interventions to reduce levels of depression among the parents of children with cancer in this region. prevalence and levels of depression among parents of children with cancer in basrah, iraq e330 | squ medical journal, august 2016, volume 16, issue 3 diagnosed with cancer. due to the scarcity of studies regarding this important health issue, this study was conducted to shed light on the prevalence and levels of depression among the parents of children with cancer in this region and the factors which affect these levels. this study sought to investigate potential associations between levels of depression and various parental and child sociodemographic factors. methods this cross-sectional study was conducted between november 2014 and april 2015 at the inpatient and outpatient clinics of the specialist paediatric hospital in basrah, iraq. either the mother or father of 384 children diagnosed with cancer and admitted to the hospital for treatment or follow-up during the study period were invited to participate in the study. the inclusion criteria included parents with children younger than 16 years old who had been diagnosed with any type of cancer at least two months’ previously but still within the last year.15 parents with a past or current diagnosis of psychiatric illness or those who were undergoing treatment for depression were excluded from the study. those who had suffered a death in the family within six months of the study were also excluded. consecutive parents who fulfilled the inclusion criteria and agreed to participate were included in the study. the sample size was calculated assuming a prevalence rate of 50%, with a precision degree of 0.05 at the 95% confidence interval.2,4,14,16 a two-part english-language questionnaire was designed for use during face-to-face interviews with the participants. it was translated into arabic by one of the researchers. all of the interviews were conducted by a single researcher. the first part of the questionnaire focused on the sociodemographic characteristics of the parents, including age, gender, number of years of education, occupation, monthly income, number of children overall and place of residence. in addition, characteristics of the children diagnosed with cancer were also elicited, including age, gender, type of cancer and time since diagnosis. the second part of the questionnaire sought to measure the presence and level of depression among the parents using the center for epidemiological studies depression scale (ces-d), which consists of 20 self-reported items.17 to minimise recall bias, the items focused on symptoms that the parents had experienced within the previous week. each ces-d item was scored from 0–3, with higher scores suggesting depressive symptoms. the potential total score was out of 60, with a score of <15 indicating no depression, 15–21 mild to moderate depression and >21 major depression. a diagnosis of cancer in a familymember, especially a child, is often a source of stress to the entire family and can have a psychological effect on the patient’s parents; in contrast, children diagnosed with cancer tend to be affected physically rather than psychologically.1 research conducted on this subject has indicated that parents of cancer patients go through predictable and permanent lifestyle changes after their children are diagnosed with cancer.2 these changes can have a negative impact on employment, daily routines and relationships with other family members.3 some parents of cancer patients may be able to cope adequately with the diagnosis, but a significant number suffer from mental weariness, nervousness, post-traumatic stress and feelings of hopelessness.4,5 factors which can lead to depression or other psychological conditions among the parents of children diagnosed with cancer include the deterioration of the child’s health, any behavioural or conduct problems on the part of the child, frequent visits to hospitals and a previous diagnosis of cancer in the family.5,6 looking after a child with cancer can also result in health problems that do not usually occur among parents with healthy children.7 one study investigating the parents of children or adolescents in chronic pain noted that the parents were required to pay exceptionally close attention to their sick child’s healthcare needs, a factor which notably increased their stress levels.8 depression among parents of children with cancer has been strongly associated with conduct problems/externalising disorders on the part of the sick child; in addition, the degree of family cohesiveness may also play a role in sustaining symptoms of depression.9 common symptoms of depression include help lessness, hopelessness, feelings of guilt, reduced energy, restlessness, an inability to sleep or oversleeping and problems concentrating or making decisions.10,11 levels of depression among the parents of children with cancer have been reported as high, even very soon after the diagnosis.12 further research indicates that when symptoms of depression start at a moderate to high level, depression may affect the parent for a longer time.13 unfortunately, depressed parents are often not able to adequately care for children who require intensive cancer treatment and health management.14 kostak et al. reported that the parents of children with cancer who have predisposing factors to developing depression require support from expert consultants in order to make the required lifestyle adjustments to suitably manage the diagnosis.3 to the best of the authors’ knowledge, there is limited information from basrah, iraq, with regards to depression levels among the parents of children shukrya k. al-maliki, jasim al-asadi, akeel al-waely and sabah agha clinical and basic research | e331 data were analysed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). frequencies and percentages were calculated for the categorical variables (demographic characteristics of the parents and children). chi-squared or fisher’s exact tests were used for the assessment of differences between variables. quantitative data were expressed in means and standard deviations. a p value of <0.050 was considered statistically significant. a logistic regression analysis was performed to examine independent predictors of depression with depression categorised as either none, mild to moderate or severe. the ethical committees of the college of medicine at the university of basrah and the iraqi general directorate of health approved this study. verbal consent was taken from all participants before they were enrolled in the study. results of the 384 parents of children with cancer invited to take part in this study, 336 participated (response rate: 87.5%). the mean age of the fathers was 37.1 ± 5.9 years, while the mean age of the mothers was 31.9 ± 5.3 years. a total of 67.9% of the parents had four children or more, including the child with cancer [table 1]. the mean age of the children with cancer was 7.7 ± 2.6 years, with a mean time since diagnosis of 8.7 ± 3.5 months. the majority of the children were female (69.0%). the most common type of cancer was acute lymphoblastic leukaemia (44.6%), followed by lymphomas (32.4%) [table 2]. the overall prevalence of depression among the parents was 70.5% (95% confidence interval [ci]: 65.5–75.3). of these, 16.4% had mild to moderate depression, while 54.1% had major depression. mothers had a higher prevalence of depression than fathers (77.2% and 57.1%, respectively). in total, 60.7% of the mothers had major depression, while only 16.5% had mild to moderate depression. in contrast, 16.0% of the fathers exhibited signs of mild to moderate depression table 1: characteristics of parents* of children with cancer in basrah, iraq (n = 336) characteristic n (%) gender of parent male 112 (33.3) female 224 (66.7) mean age in years ± sd fathers 37.1 ± 5.9 mothers 31.9 ± 5.3 education of father in years <12 110 (32.7) ≥12 226 (67.3) education of mother in years <12 204 (60.7) ≥12 132 (39.3) occupation of father government employee 220 (65.5) private sector employee 86 (25.6) retired 3 (0.9) unemployed 27 (8.0) occupation of mother housewife 304 (90.5) employed 32 (9.5) monthly income in iqd <500,000 136 (40.5) 500,000–1,000,000 70 (20.8) >1,000,000 130 (38.7) residence urban 137 (40.8) rural 199 (59.2) number of children 1–3 108 (32.1) ≥4 228 (67.9) sd = standard deviation; iqd = iraqi dinar. *either the mother or father of each child with cancer but not both. table 2: characteristics of children with cancer in basrah, iraq (n = 336) characteristic n (%) mean age in years ± sd 7.7 ± 2.6 mean time since diagnosis in months ± sd 8.7 ± 3.5 gender female 232 (69.0) male 104 (31.0) type of cancer acute lymphoblastic leukaemia 150 (44.6) lymphoma 109 (32.4) neuroblastoma 28 (8.3) other* 49 (14.6) sd = standard deviation. *including sarcomas, wilms’ tumours and retinoblastomas. prevalence and levels of depression among parents of children with cancer in basrah, iraq e332 | squ medical journal, august 2016, volume 16, issue 3 and 41.1% showed signs of major depression. this gender difference was significant (p = 0.001). no signi-ficant associations were found between levels of parental depression and the age, place of residence or occupation of the parents or the age, gender or type of cancer of the children. years of education were inversely and significantly associated with depression for the mothers (p = 0.001); however, no significant association with this variable was observed among the fathers (p = 0.814). major depression was more frequent among parents with a lower monthly income compared to those with higher incomes (73.5% versus 33.1%), which was a highly significant difference (p = 0.001) [table 3]. after logistic regression analysis, the association of depression with parental gender (odds ratio [or]: 1.96; 95% ci: 1.14–3.37; p = 0.017) and monthly income (or: 5.6; 95% ci: 2.7–11.6; p = 0001) remained significant. discussion this study found a high prevalence of depression among the parents of children with cancer in basrah, iraq; these findings are consistent with those of previous studies.2,3,18,19 significant gender differences in the levels of depression among parents of children with cancer were also noted in the current study, especially with regards to major depression. in particular, mothers of children with cancer at any stage table 3: associations between parental and child characteristics and levels of depression among parents* of children with cancer in basrah, iraq (n = 336) n (%) p value no depression mild to moderate depression major depression parental characteristic gender of parent 0.001 male 48 (42.9) 18 (16.0) 46 (41.1) female 51 (22.8) 37 (16.5) 136 (60.7) age of father in years 0.679 <30 9 (36.0) 6 (24.0) 10 (40.0) 30–39 57 (30.0) 28 (14.7) 105 (55.3) 40–49 27 (25.7) 18 (17.1) 60 (57.1) ≥50 6 (37.5) 3 (18.8) 7 (43.8) age of mother in years 0.885 <30 30 (30.9) 18 (18.6) 49 (50.5) 30–39 62 (28.6) 33 (15.2) 122 (56.2) 40–49 7 (31.8) 4 (18.2) 11 (50.0) education of father in years 0.814 <12 30 (27.3) 18 (16.4) 62 (56.4) ≥12 69 (30.5) 37 (16.4) 120 (53.1) education of mother in years 0.001 <12 43 (21.1) 36 (17.6) 125 (61.3) ≥12 56 (42.4) 19 (14.4) 57 (43.2) occupation of father 0.286 government employee 74 (33.6) 36 (16.4) 110 (50.0) private sector employee 19 (22.1) 14 (16.3) 53 (61.6) retired 6 (22.2) 4 (14.8) 17 (63.0) unemployed 0 (0.0) 1 (33.3) 2 (66.7) occupation of mother 0.078 housewife 88 (28.9) 46 (15.1) 170 (55.9) government employee 11 (34.4) 9 (28.1) 12 (37.5) monthly income in iqd 0.001 <500,000 17 (12.5) 19 (14.0) 100 (73.5) 500,000 –1,000,000 12 (17.10) 19 (27.1) 39 (55.7) >1,000,000 70 (53.8) 17 (13.1) 43 (33.1) residence 0.072 urban 46 (33.6) 27 (19.7) 64 (46.7) rural 53 (26.6) 28 (14.1) 118 (59.3) number of children 0.111 1–3 32 (29.6) 24 (22.2) 52 (48.1) ≥4 67 (29.4) 31 (13.6) 130 (57.0) child characteristic age in years 0.584 <5 22 (33.3) 14 (21.2) 30 (45.5) 5–10 64 (28.2) 35 (15.4) 128 (56.4) 11–15 13 (30.2) 6 (14.0) 24 (55.8) gender 0.217 male 35 (33.7) 12 (11.5) 57 (54.8) female 64 (27.6) 43 (18.5) 125 (53.9) type of cancer 0.062 all 45 (30.0) 21 (14.0) 84 (56.0) lymphoma 28 (25.7) 16 (14.7) 65 (59.6) neuroblastoma 5 (17.9) 8 (28.6) 15 (53.6) other† 21 (42.9) 10 (20.4) 18 (36.7) iqd = iraqi dinar; all = acute lymphoblastic leukaemia. *either the mother or father of each child with cancer but not both. †including sarcomas, wilms’ tumours and retinoblastomas. shukrya k. al-maliki, jasim al-asadi, akeel al-waely and sabah agha clinical and basic research | e333 of treatment or off treatment demonstrated a higher level of depressive symptoms than the fathers; this result is in agreement with other studies.2,3,11,20–22 this gender difference could be due to variations in stress reactions to childhood cancer or because women may be more likely to report their problems compared with men.12,23 mothers of children with cancer also often spend greater amounts of time caring for a sick child compared to fathers; due to cultural and economic obligations, fathers often spend more time at work, enabling them greater access to sources of external support, and they may hence feel less depressed.3 in the current study, the majority of parents had four children or more; this factor may also contribute to increased stress among the mothers, who may need to balance care of their other children in addition to their responsibilities caring for the sick child. however, no significant association was noted between the number of children in the family and levels of depression. in the current study, rates of depression decreased significantly in relation to the number of years the mothers had been educated. thus, women with higher educational attainment reported fewer depressive symptoms, a finding which is in agreement with other research.4,24–26 in contrast, several studies have shown no significant association between depression levels and education.3,27 in iraq, women with more advanced educational qualifications may have reduced depression levels due to the protective effect of education against depression and anxiety, for which a gender difference has been noted.28,29 education itself can also bestow an enhanced sense of control over an individual’s surroundings.2 in the present study, a significant difference was also noted between depression levels and monthly income. other studies are in agreement with this finding;3,4 however, erkan et al. did not find a statistically significant association between family income and parents’ levels of depression.27 iqbal et al. also showed no significant relationship between parents’ depression levels and their socioeconomic status.2 however, kupst et al. reported that coping mechanisms are affected by income and educational levels.30 low income, along with the financial burden of expensive medical treatments, cause added strain on families in addition to the trauma resulting from the devastating diagnosis of cancer in a child. depression levels among poorer families may therefore increase following a diagnosis of cancer in a child, as depression is already more prevalent among families of lower socioeconomic status.31,32 in contrast, no significant association was found between depression levels and the parents’ occupations in the current study. similarly, no significant associations were found between levels of depression among parents and the ages of the parents and the age, gender or type of cancer of the child, which is in agreement with previous studies.2–4,27 based on the findings of this study, specialist healthcare providers in basrah should assess parents at risk of developing depression after their child has been diagnosed with cancer and consider enrolling them in intervention programmes. parents should also receive support from social workers and perhaps financial aid from social security in order to help prevent further psychological deterioration, which would affect their ability to care for their sick child. however, an additional community-based study is indicated to determine base levels of depression among parents of healthy children in basrah as, due to the cross-sectional nature of this study, the lack of a control group precludes inferences of causality among the variables. nevertheless, despite this limitation, the results of the current study are comparable to published findings. conclusion this study showed a high prevalence of depression, particularly major depression, among the parents of children diagnosed with cancer in basrah. depression was significantly more common and more severe among mothers and among parents with a lower income; as such, gender and income were significant independent predictors of depression. based on these findings, parents at risk of developing depression after their child has been diagnosed with cancer should be enrolled in intervention programmes. moreover, they should receive additional social and financial support. levels of depression among the parents of healthy children in basrah should be assessed in future community-based studies. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. klassen af, gulati s, granek l, rosenberg-yunger zr, watt l, sung l, et al. understanding the health impact of care giving: a qualitative study of immigrant parents and single parents of children with cancer. qual life res 2012; 21:1595–605. doi: 10.1007/s11136-011-0072-8. 2. iqbal a, siddiqui ks. depression among parents of children with acute lymphoblastic leukemia. j ayub med coll abbottabad 2002; 14:6–9. http://dx.doi.org/10.1007/s11136-011-0072-8 prevalence and levels of depression among parents of children with cancer in basrah, iraq e334 | squ medical journal, august 2016, volume 16, issue 3 19. magni g, silvestro a, carli m, de leo d. social support and psychological distress of parents of children with acute lymphocytic leukaemia. br j med psychol 1986; 59:383–5. doi: 10.1111/j.2044-8341.1986.tb02708.x. 20. allen r, newman sp, souhami rl. anxiety and depression in adolescent cancer: findings in patients and parents at the time of diagnosis. eur j cancer 1997; 33:1250–5. doi: 10.1016/s09598049(97)00176-7. 21. dockerty jd, williams sm, mcgee r, skegg dc. impact of childhood cancer on the mental health of parents. med pediatr oncol 2000; 35:475–83. doi: 10.1002/1096-911x (20001101)35:5<475::aid-mpo6>3.0.co;2-u. 22. norberg al, lindblad f, boman k. coping strategies in parents of children with cancer. soc sci med 2005; 60:965–75. doi: 10.1016/j.socscimed.2004.06.030. 23. sloper p. predictors of distress in parents of children with cancer: a prospective study. j pediatr psychol 2000; 25:79–91. doi: 10.1093/jpepsy/25.2.79. 24. al-homaidan ht. depression among women with primary infertility attending an infertility clinic in riyadh, kingdom of saudi arabia: rate, severity, and contributing factors. int j health sci (qassim) 2011; 5:108–15. 25. ramezanzadeh f, aghssa mm, abedinia n, zayeri f, khanafshar n, shariat m, et al. a survey of relationship between anxiety, depression and duration of infertility. bmc womens health 2004; 4:9. doi: 10.1186/1472-6874-4-9. 26. noorbala aa, ramezanzadeh f, abedinia n, yazdi sa, jafarabadi m. study of psychiatric disorders among fertile and infertile women and some predisposing factors. j fam reprod health 2007; 1:6–11. 27. erkan s, kaplan y. a study on the depression levels of mothers of leukemic children. pak j soc sci 2009; 6:42–7. 28. ross ce, mirowsky j. sex differences in the effect of education on depression: resource multiplication or resource substitution? soc sci med 2006; 63:1400–13. doi: 10.1016/j. socscimed.2006.03.013. 29. bjelland i, krokstad s, mykletun a, dahl aa, tell gs, tambs k. does a higher educational level protect against anxiety and depression? the hunt study. soc sci med 2008; 66:1334–45. doi: 10.1016/j.socscimed.2007.12.019. 30. kupst mj. family coping: supportive and obstructive factors. cancer 1993; 71:3337–41. doi: 10.1002/1097-0142 (19930515)71:10+<3337::aid-cncr2820711733>3.0.co;2-7. 31. kessler rc, berglund p, demler o, jin r, koretz d, merikangas kr, et al. the epidemiology of major depressive disorder: results from the national comorbidity survey replication (ncs-r). jama 2003; 289:3095–105. doi: 10.1001/ jama.289.23.3095. 32. elcigil a, conk z. determining the burden of mothers with children who have cancer. deuhyo ed 2010; 3:175–81. 3. kostak ma, avci g. hopelessness and depression levels of parents of children with cancer. asian pac j cancer prev 2013; 14:6833–8. doi: 10.7314/apjcp.2013.14.11.6833. 4. kholasehzadeh g, shiryazdi s, neamatzadeh h, ahmadi n. depression levels among mothers of children with leukemia. iran j ped hematol oncol 2014; 4:109–13. 5. maurice-stam h, oort fj, last bf, grootenhuis ma. emotional functioning of parents of children with cancer: the first five years of continuous remission after the end of treatment. psychooncology 2008; 17:448–59. doi: 10.1002/pon.1260. 6. boman kk, kjällander y, eksborg s, becker j. impact of prior traumatic life events on parental early stage reactions following a child’s cancer. plos one 2013; 8:e57556. doi: 10.1371/journal. pone.0057556. 7. hoekstra-weebers je, jaspers jp, kamps wa. klip ec. risk factors for psychological maladjustment of parents of children with cancer. j am acad child adolesc psychiatry 1999; 38:1526–35. doi: 10.1097/00004583-199912000-00014. 8. palermo tm, eccleston c. parents of children and adolescents with chronic pain. pain 2009; 146:15–7. doi: 10.1016/j.pain. 2009.05.009. 9. manne sl, lesanics d, meyers p, wollner n, steinherz p, redd w. predictors of depressive symptomatology among parents of newly diagnosed children with cancer. j pediatr psychol 1995; 20:491–510. doi: 10.1093/jpepsy/20.4.491. 10. norberg al, lindblad f, boman kk. parental traumatic stress during and after paediatric cancer treatment. acta oncol 2005; 44:382–8. doi: 10.1080/02841860510029789. 11. barrera m, d’agostino nm, gibson j, gilbert t, weksberg r, malkin d. predictors and mediators of psychological adjustment in mothers of children newly diagnosed with cancer. psychooncology 2004; 13:630–41. doi: 10.1002/pon.765. 12. yeh ch. gender differences of parental distress in children with cancer. j adv nurs 2002; 38:598–606. doi: 10.1046/j.13652648.2000.02227.x. 13. vrijmoet-wiersma cm, van klink jm, kolk am, koopman hm, ball lm, maarten egeler r. assessment of parental psychological stress in paediatric cancer: a review. j pediatr psychol 2008; 33:694–706. doi: 10.1093/jpepsy/jsn007. 14. ghufran m, andrades m, nanji k. frequency and severity of depression among mothers of children with cancer: results from a teaching hospital in karachi, pakistan. br j med pract 2014; 7:a701. 15. kendler ks, myers j, zisook s. does bereavement-related major depression differ from major depression associated with other stressful life events? am j psychiatry 2008; 165:1449–55. doi: 10.1176/appi.ajp.2008.07111757. 16. naing l, winn t, rusli bn. practical issues in calculating the sample size for prevalence studies. arch orofac sci 2006; 1:9–14. 17. radloff ls. the ces-d scale: a self-report depression scale for research in the general population. appl psychol meas 1977; 1:385–401. doi: 10.1177/014662167700100306. 18. sharan p, mehta m, chaudhry vp. psychiatric disorders among parents of children suffering from acute lymphoblastic leukemia. pediatr hematol oncol 1999; 16:43–7. doi: 10.1080/ 088800199277588. http://dx.doi.org/10.1111/j.2044-8341.1986.tb02708.x http://dx.doi.org/10.1016/s0959-8049%2897%2900176-7 http://dx.doi.org/10.1016/s0959-8049%2897%2900176-7 http://dx.doi.org/10.1002/1096-911x%2820001101%2935:5%3c475::aid-mpo6%3e3.0.co%3b2-u http://dx.doi.org/10.1002/1096-911x%2820001101%2935:5%3c475::aid-mpo6%3e3.0.co%3b2-u http://dx.doi.org/10.1016/j.socscimed.2004.06.030 http://dx.doi.org/10.1093/jpepsy/25.2.79 http://dx.doi.org/10.1186/1472-6874-4-9 http://dx.doi.org/10.1016/j.socscimed.2006.03.013 http://dx.doi.org/10.1016/j.socscimed.2006.03.013 http://dx.doi.org/10.1016/j.socscimed.2007.12.019 http://dx.doi.org/10.1002/1097-0142%2819930515%2971:10%2b%3c3337::aid-cncr2820711733%3e3.0.co%3b2-7 http://dx.doi.org/10.1002/1097-0142%2819930515%2971:10%2b%3c3337::aid-cncr2820711733%3e3.0.co%3b2-7 http://dx.doi.org/10.1001/jama.289.23.3095 http://dx.doi.org/10.1001/jama.289.23.3095 http://dx.doi.org/10.7314/apjcp.2013.14.11.6833 http://dx.doi.org/10.1002/pon.1260 http://dx.doi.org/10.1371/journal.pone.0057556 http://dx.doi.org/10.1371/journal.pone.0057556 http://dx.doi.org/10.1097/00004583-199912000-00014 http://dx.doi.org/10.1016/j.pain.2009.05.009 http://dx.doi.org/10.1016/j.pain.2009.05.009 http://dx.doi.org/10.1093/jpepsy/20.4.491 http://dx.doi.org/10.1080/02841860510029789 http://dx.doi.org/10.1002/pon.765 http://dx.doi.org/10.1046/j.1365-2648.2000.02227.x http://dx.doi.org/10.1046/j.1365-2648.2000.02227.x http://dx.doi.org/10.1093/jpepsy/jsn007 http://dx.doi.org/10.1176/appi.ajp.2008.07111757 http://dx.doi.org/10.1177/014662167700100306 http://dx.doi.org/10.1080/088800199277588 http://dx.doi.org/10.1080/088800199277588 departments of 1microbiology and 2medicine, kasturba medical college, mangalore, india *corresponding author e-mail: jyoti.kumari1985@rediffmail.com البكترييا العنقودية الذهبية املقاومة للميثيسيلني املرتبطة بالرعلية الصحية b اخلصائص السريرية و مقاومة املضادات احليوية مع الرتكيز على مقاومة املاكروليد واللينكوساميد-سرتبتوغرامني جيوتي كوماري، �ساليني �سينوي، �رسيكال باليغا، �ساكرباين م.، جوبالكري�سنا باهت abstract: objectives: healthcare-associated methicillin-resistant staphylococcus aureus (mrsa) is a common pathogen worldwide and its multidrug resistance is a major concern. this study aimed to determine the clinical characteristics and antibiotic susceptibility profile of healthcare-associated mrsa with emphasis on resistance to macrolide-lincosamide-streptogramin b (mlsb) phenotypes and vancomycin. methods: this cross-sectional study was carried out between february 2014 and february 2015 across four tertiary care hospitals in mangalore, south india. healthcare-associated infections among 291 inpatients at these hospitals were identified according to the centers for disease control and prevention guidelines. clinical specimens were collected based on infection type. s. aureus and mrsa isolates were identified and antibiotic susceptibility tests performed using the kirby-bauer disk diffusion method. the minimum inhibitory concentration of vancomycin was determined using the agar dilution method and inducible clindamycin resistance was detected with a double-disk diffusion test (d-test). results: out of 291 healthcare-associated s. aureus cases, 88 were mrsa (30.2%). of these, 54.6% were skin and soft tissue infections. all of the isolates were susceptible to teicoplanin and linezolid. four mrsa isolates exhibited intermediate resistance to vancomycin (4.6%). of the mrsa strains, 10 (11.4%) were constitutive mlsb phenotypes, 31 (35.2%) were inducible mlsb phenotypes and 14 (15.9%) were macrolide-streptogramin b phenotypes. conclusion: healthcare-associated mrsa multidrug resistance was alarmingly high. in routine antibiotic susceptibility testing, a d-test should always be performed if an isolate is resistant to erythromycin but susceptible to clindamycin. determination of the minimum inhibitory concentration of vancomycin is necessary when treating patients with mrsa infections. keywords: healthcare associated infections; antibiotic resistance; methicillin-resistant staphylococcus aureus; phenotypes; clindamycin; vancomycin. الأمرا�س م�سببات من )mrsa( مري�سا ال�سحية بالرعاية املرتبطة للميثي�سيلني العنقودية املكورات مقاومة تعترب اأهداف: امللخ�ص: الأكرث �سيوعا يف جميع اأنحاء العامل ومقاومتها لالأدوية املتعددة م�سدر قلق كبري. هدفت هذه الدرا�سة اإىل حتديد اخل�سائ�س ال�رسيرية وخ�سائ�س احل�سا�سية للم�سادات احليوية لهذه اجلرثومة املتعلقة بالرعاية ال�سحية مع الرتكيز على مقاومتها ملاكرومليد لينكو�ساميد اأربع يف 2015 وفرباير 2014 فرباير بني ما الفرتة يف امل�ستعر�سة الدرا�سة هذه اأجريت منهجية: الفانكوماي�سني. و b �سرتبتوغرامني املر�سى من 291 بني من ال�سحية بالرعاية املتعلقة العدوى حتديد مت وقد الهند. بجنوب ماجنالور يف الثالثية للرعاية م�ست�سفيات نوع على بناءا ال�رسيرية العينات جمع مت منها. والوقاية الأمرا�س على ال�سيطرة مراكز لتعليمات وفقا امل�ست�سفيات هذه يف املنومني الإ�سابة. وقد مت حتديد بكرتيا املكورة العنقودية واملري�سا واأجريت اختبارات احل�سا�سية با�ستخدام طريقة كريبي باور باأقرا�س امل�سادات الك�سف ومت الكلينداماي�سني ومقاومة الآجار تخفيف طريقة با�ستخدام للفانكوماي�سني املثبط للرتكيز الأدنى احلد حتديد مت احليوىة. .)30.2%( مري�سا ب�سبب كانت حالة 88 ال�سحية، بالرعاية متعلقة حالة 291 من d-. نتائج: لأقرا�س املزدوج النت�سار باختبار عنها منها %54.6 حالة التهابات جلدية واأن�سجة رخوة. وكانت جميع العينات املعزولة ح�سا�سة للتيكوبالنني وينزوليد. اأظهرت اأربعة عينات جرثومية معزولة مقاومة متو�سطة للفانكوماي�سني )%4.6(. 10 )%11.4( من عينات مري�سا كانت من نوع mlsb الأ�سا�سية، و 31 )35.2%( من نوع mlsb املحر�س و 14 )%15.9( كانوا من النوع املقاوم ملاكروليد �سرتبتوغرامنيb. خامتة: اإن ن�سبة مقاومة املكورات العنقودية احليوية للم�سادات احل�سا�سية اختبارات يف دائما d فح�س يوؤدي اأن ينبغي ومقلقة: عالية ال�سحية بالرعاية املرتبطة للميثي�سيلني الروتينية اإذا كانت العينة املعزولة مقاومة لالإريرثومي�سني لكن ح�سا�سة لكلينداماي�سني. حتديد احلد الأدنى لرتكيز مثبط للفانكوماي�سني �رسوري عند عالج املر�سى الذين يعانون من التهابات مري�سا. الظواهر؛ للميثي�سيلني؛ املقاومة الذهبية العنقودية املكورات احليوية؛ امل�سادات مقاومة ال�سحية؛ بالرعاية املرتبطة العدوى مفتاحية: كلمات كلينداماي�سني؛ فانكوماي�سني. healthcare-associated methicillin-resistant staphylococcus aureus clinical characteristics and antibiotic resistance profile with emphasis on macrolide-lincosamide-streptogramin b resistance *jyoti kumari,1 shalini m. shenoy,1 shrikala baliga,1 chakrapani m.,2 gopalkrishna k. bhat1 clinical & basic research sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 175–181, epub. 15 may 16 submitted 6 jan 16 revision req. 2 feb 16; revision recd. 3 feb 16 accepted 10 feb 16 doi: 10.18295/squmj.2016.16.02.007 healthcare-associated methicillin-resistant staphylococcus aureus clinical characteristics and antibiotic resistance profile with emphasis on macrolide-lincosamide-streptogramin b resistance e176 | squ medical journal, may 2016, volume 16, issue 2 methicillin-resistant staphylococcus aureus (mrsa) was first identified in the 1960s and continues to be a significant pathogen worldwide, causing a variety of infections from minor skin and soft tissue infections to severe osteomyelitis, bacteraemia and sepsis.1 healthcareassociated mrsa spreads through direct or indirect contact and normally exhibits multidrug resistance.1 the distribution of healthcare-associated mrsa varies geographically; rates in the western pacific region, latin america, the usa and europe are 46.0%, 34.9%, 34.2% and 26.3%, respectively.2 in contrast, northern european countries such as denmark, the netherlands, iceland and sweden have reported rates of <1.0%.3 in asia, the prevalence varies from 22.6–86.5%, with the highest rate reported in sri lanka and the lowest in india.4 nevertheless, the rate of healthcare-associated mrsa in india has steadily increased over the past few years, from <20.0% in 2002 to 39.6% in 2012.5–8 the rise of multidrug-resistant healthcareassociated mrsa cases has reduced the number of available therapeutic options for these infections. potential antibiotics include daptomycin, linezolid, quinupristin/dalfopristin, trimethoprim/sulfamethoxazole and vancomycin.9 glycopeptides, in particular vancomycin, are the treatment of choice for serious infections.9 the macrolide-lincosamide-streptogra min b (mlsb) group of antibiotics can be used to treat less severe skin and soft tissue infections.9 the lincosamide antibiotic clindamycin is often preferred because of its low cost and pharmacokinetic properties, including significant tissue penetration, an extended half-life and the ability to inhibit toxin production.9,10 unfortunately, the widespread use of mlsb antibiotics has resulted in increased resistance which occurs either due to an efflux mechanism encoded by the methionine sulfoxide reductase a gene or a ribosomal target site modification encoded by the erythromycin ribosomal methylase gene.10 constitutive mlsb (cmlsb) resistance can be detected in routine susceptibility testing by its resistance to both erythromycin and clindamycin; in contrast, bacteria with inducible mlsb (imlsb) resistance appear resistant to erythromycin but susceptible to clindamycin in routine testing, thereby posing a problem in detection.10 as a result, if clindamycin is used for the treatment of infections caused by these strains, the treatment will fail. it is therefore important to detect this kind of resistance. the available literature does not reveal precise data on mlsb-resistant phenotypes and the susceptibility profile to vancomycin among healthcare-associated mrsa-affected populations from south india. consequently, the present study was conducted to determine the clinical characteristics and antibiotic susceptibility patterns of mrsa isolates from clinical specimens taken from a south indian cohort, with emphasis on the aforementioned factors. methods this cross-sectional study was conducted from february 2014 to february 2015 among four tertiary care hospitals in mangalore, south india. two of the hospitals were governmental hospitals with 600 and 250 beds, respectively, while the other two were private hospitals with 510 and 251 beds, respectively. the governmental hospitals had general surgery and neurosurgical departments, burn units, general intensive care units (icus) and urology, nephrology, dermatology, gynaecology and paediatric wards. in addition to the aforementioned departments, the private hospitals also had oncology, haematology, cardiothoracic and nephrosurgery departments as well as general, nephrosurgery, neurosurgery and cardiothoracic icus. the inclusion criteria included inpatients presenting to one of the four hospitals with localised or systemic conditions resulting from the presence of an infectious agent or its toxins which was not present or incubating at the time of admission to the hospital but only became evident 48 hours after admission or longer. in addition, patients with a history of hospitalisation, haemodialysis, surgery or admission to a long-term healthcare facility within the previous advances in knowledge a high rate of inducible macrolide-lincosamide-streptogramin b (mlsb) phenotypes were found among healthcare-associated methicillin-resistant staphylococcus aureus (mrsa) isolates identified from clinical specimens in the current study. four cases of healthcare-associated mrsa with intermediate resistance to vancomycin were detected. this finding challenges the efficacy of vancomycin in cases of serious multidrug-resistant healthcare-associated mrsa infections. application to patient care the results of this study indicate the necessity of performing double-disk diffusion tests to identify inducible mls b resistance to prevent the therapeutic failure of clindamycin in healthcare-associated mrsa cases. additionally, these findings suggest that the minimum inhibitory concentration of vancomycin should be determined in order to guide therapy. jyoti kumari, shalini m. shenoy, shrikala baliga, chakrapani m. and gopalkrishna k. bhat clinical and basic research | e177 year and those with indwelling catheters, intravenous lines or other percutaneous medical devices at the time of culture collection were included. outpatients and those with no healthcare-associated mrsa risk factors who were diagnosed with an s. aureus infection within 48 hours of hospitalisation were excluded.11,12 the sample size was calculated using the following formula:13 where z1-α is 1.96 (95% confidence interval), p is 0.37 (expected proportion), q is 0.63 (1-p) and d is 0.0555 (relative precision of 15% of p, i.e. allowable error). the expected proportion was selected based on a previous study.14 the total sample size required was therefore 291 patients. the criteria of the centers for disease control and prevention were used to identify healthcare-associated infections due to s. aureus.12 a structured pro forma was used to collect the demographic and clinical details of the patients. based on the type and site of infection, clinical specimens such as pus/exudates, blood, sputum and indwelling medical devices (i.e. central line tips, peripheral intravenous catheters, endotracheal tubes and urinary catheters) were collected from the patients and processed by the department of microbiology at the kasturba medical college in mangalore. gram staining of the specimens was performed followed by blood agar and macconkey’s agar cultures using standard bacteriological procedures.15 s. aureus bacteria were identified by colony morphology, gram staining and catalase, slide and tube coagulase and deoxyribonuclease tests.15 the cefoxitin (30.00 µg) disk diffusion method was used to detect methicillin resistance in s. aureus isolates.16 antibiotic susceptibility was tested using the kirby-bauer disk diffusion method and the results interpreted using the guidelines of the clinical and laboratory standards institute (clsi).16 the following antibiotics were tested: ciprofloxacin (5.00 µg), clindamycin (2.00 µg), trimethoprim/ sulfamethoxazole (1.25 µg/23.75 µg), erythromycin (15.00 µg), gentamicin (10.00 µg), linezolid (30.00 µg), penicillin (10 u), rifampicin (5.00 µg) and teicoplanin (30.00 µg). all antibiotics were purchased from himedia laboratories ltd. (mumbai, maharashtra, india). an s. aureus strain (atcc® 25923™, american type culture collection, manassas, virginia, usa) was used as the control. the minimum inhibitory concentration (mic) of vancomycin was determined by the agar dilution method using clsi guidelines.17 gradient plates of mueller-hinton agar were prepared with vancomycin (0.062–128.000 µg/ml). three or four mrsa colonies grown on blood agar were picked and inoculated in mueller-hinton broth (mhb) and incubated at 35 °c for 4–6 hours. the turbidity of the broth culture was matched with a 0.5 mcfarland standard (bacterial count ≈ 1.5 x 108 colony-forming unit [cfu]/ml) and then diluted at a ratio of 1:10 in sterile mhb to ensure a concentration of 1.5 x 107 cfu/ml. from this culture, 2 µl of the suspension was spotinoculated on each plate and incubated at 35 °c for 24 hours. mrsa strains with mics of ≤2.00 µg/ml, 4.00–8.00 µg/ml and ≥16.00 µg/ml were considered susceptible, intermediate and resistant to vancomycin, respectively.16 s. aureus (atcc® 29213™, american type culture collection) and enterococcus faecalis (atcc® 29212™, american type culture collection) strains were used as vancomycin-susceptible controls. another e. faecalis strain (atcc® 51299™, american type culture collection) was used as the vancomycinresistant control. the mlsb phenotypes were identified as described previously.16,18 mrsa strains resistant to both erythromycin and clindamycin in routine antibiotic susceptibility testing were considered cmlsb phenotypes. a double-disk diffusion test (d-test) was performed to determine mrsa strains which were resistant to erythromycin but sensitive to clindamycin (imlsb phenotypes). erythromycin (15.00 µg) and clindamycin (2.00 µg) disks were placed on a muellerhinton agar plate containing a lawn culture of the test isolate at a distance of 15 mm edge to edge. the plate was incubated at 35 °c for 16–18 hours. any flattening of the zone of inhibition (d-shape) around the clindamycin disk adjacent to the erythromycin disk was subsequently observed; strains with a d-shaped zone of inhibition were considered imlsb phenotypes. strains of mrsa which were resistant to erythromycin, susceptible to clindamycin and were also d-test negative (had no d-shaped zone of inhibition) were considered macrolide-streptogramin b (msb) phenotypes. the statistical package for the social sciences (spss), version 16.0 (ibm corp., chicago, illinois, usa) was used to analyse the data. rates of mrsa infections were presented as percentages. the pearson’s chi-squared test was used to analyse results between the two groups of categorical variables. a p value of ≤0.050 was considered statistically significant. this study was approved by the institutional ethics committee of kasturba medical college (#ieckmcmlr01-14/14). informed consent was collected from all patients prior to their participation in the study. z2 pq 1-α d2 n = healthcare-associated methicillin-resistant staphylococcus aureus clinical characteristics and antibiotic resistance profile with emphasis on macrolide-lincosamide-streptogramin b resistance e178 | squ medical journal, may 2016, volume 16, issue 2 results a total of 291 non-repetitive healthcare-associated-s. aureus cases were isolated during the study period; 119 and 12 cases were from the two governmental hospi tals and 95 and 65 cases were from the two private hospitals, respectively. the rates of healthcareassociated mrsa in the two government hospitals and two private hospitals were 41.2%, 33.3%, 22.1% and 21.5%, respectively. no statistically significant differences were observed between male and female patients. patients aged 31–40 and 41–50 years old were most likely to be infected with mrsa. the different types of s. aureus infections found are shown in table 1. of the s. aureus cases, 95 (32.7%) were isolated from surgical site infections, 42 (14.4%) from cellulitis cases, 25 (8.6%) from blood stream infections (including bacteraemia and catheter-associated bacteraemia infections) and 15 (5.2%) from osteomyelitis cases. a total of 88 s. aureus cases (30.2%) were methicillinresistant. of the mrsa cases, 54.6% were skin and soft tissue infections, comprising cellulitis, bed sore, ulcer, burn wound, toxic epidermal necrolysis and psoas abscess infections. mrsa was significantly more frequent in bacteraemia infections while methicillinsensitive s. aureus (mssa) was significantly more frequent in surgical site infections (p <0.005). the antibiotic resistance patterns of the mrsa and mssa isolates are shown in table 2. all of the mrsa and mssa isolates were susceptible to teicoplanin and linezolid, while the majority of mrsa isolates were resistant to ciprofloxacin (75.0%), clindamycin (51.1%), trimethoprim/sulfamethoxazole (59.1%) and erythromycin (62.5%). in comparison to mssa isolates, mrsa isolates were significantly more resistant to ciprofloxacin, clindamycin, trimethoprim/ sulfamethoxazole, erythromycin, gentamicin and tetracycline (p <0.005). of the mrsa strains, 84 (95.5%) were susceptible to vancomycin while four (4.6%) demonstrated inter mediate resistance. none of the strains were resistant to vancomycin. the mic 90 and mic50 values of vancomycin were 2.00 µg/ml and 1.00 µg/ml, respectively. the four mrsa strains with intermediate resistance to vancomycin were isolated from four patients with osteomyelitis, an infected wound, a psoas abscess and catheter-associated bacteraemia, respectively; three of the isolates were from patients in a governmental hospital and the remaining isolate was from a patient in a private hospital. two of the isolates with intermediate resistance to vancomycin were of the cmlsb phenotype and two were of the table 1: type of healthcare-associated methicillinresistant staphylococcus aureus and methicillinsensitive staphylococcus aureus infections (n = 291) type of infection n (%) p value* mrsa (n = 88) mssa (n = 203) surgical site 18 (20.5) 77 (37.9) 0.004† cellulitis 17 (19.3) 25 (12.3) 0.118 bed sore 11 (12.5) 16 (7.9) 0.212 catheter-associated bacteraemia 14 (15.9) 3 (1.5) <0.001† ulcer 8 (9.1) 23 (11.3) 0.569 burn wound 8 (9.1) 28 (13.8) 0.263 ten 3 (3.4) 5 (2.5) 0.665 bacteraemia 6 (6.8) 2 (1.0) 0.005† psoas abscess 1 (1.1) 0 (0.0) 0.665 empyema 1 (1.1) 0 (0.0) 0.665 pneumonia 0 (0.0) 8 (3.9) 0.134 osteomyelitis 1 (1.1) 14 (6.9) 0.041 catheter-associated uti 0 (0.0) 2 (1.0) 0.350 ten = toxic epidermal necrolysis; mrsa = methicillin-resistant staphylococcus aureus; mssa = methicillin-sensitive staphylococcus aureus; uti = urinary tract infection. *determined using the chi-squared test. †statistically significant at p ≤0.050. table 2: antibiotic resistance patterns of healthcareassociated methicillin-resistant staphylococcus aureus and methicillin-sensitive staphylococcus aureus isolates (n = 291) antibiotic n (%) p value* resistant mrsa isolates (n = 88) resistant mssa isolates (n =203) ciprofloxacin 66 (75.0) 68 (33.5) <0.001† clindamycin 45 (51.1) 33 (16.3) <0.001† trimethoprim/ sulfamethoxazole 52 (59.1) 59 (29.1) <0.001† erythromycin 55 (62.5) 64 (31.5) <0.001† gentamicin 37 (42.1) 22 (10.8) <0.001† linezolid 0 (0.0) 0 (0.0) penicillin 88 (100.0) 181 (89.2) 0.001† rifampicin 1 (1.1) 0 (0.0) 0.128 teicoplanin 0 (0.0) 0 (0.0) tetracycline 33 (37.5) 37 (18.2) <0.001† mrsa = methicillin-resistant staphylococcus aureus; mssa = methicillin-sensitive staphylococcus aureus. *determined using the chi-squared test. †statistically significant at p ≤0.050. jyoti kumari, shalini m. shenoy, shrikala baliga, chakrapani m. and gopalkrishna k. bhat clinical and basic research | e179 msb phenotype. a total of 10 mrsa isolates (11.4%) were resistant to both erythromycin and clindamycin (cmlsb phenotype), while 45 (51.1%) were resistant to erythromycin but susceptible to clindamycin. of these 45 strains, 31 (68.9%) were d-test positive (imlsb phenotype) and 14 (31.1%) were d-test negative (msb phenotype). the remaining 33 mrsa isolates (37.5%) were sensitive to both clindamycin and erythromycin. the mlsb phenotypes of the mrsa isolates from the four hospitals are shown in table 3. discussion considerable geographical variation exists in the prevalence of healthcare-associated mrsa infections.2–4 the present study revealed a high cumulative rate of health-associated mrsa infections among patients admitted to four tertiary care hospitals in mangalore. however, the rate was lower than the 41% national prevalence rate reported by the indian network for surveillance of antimicrobial resistance (insar) group based on data collected from 15 tertiary centres.8 nevertheless, the rate in the present study was higher than that that reported from the same four hospitals in a previous study in 2011 (25.25%).7 akoğlu et al. reported a higher rate of healthcare-associated mrsa in turkey (71.5%) while the australian group on antimicrobial resistance reported a similar rate (30.3%) to that of the current study.19,20 however, it is important to note that the current study included patients with potential predisposing risk factors to healthcare-associated mrsa infections, including previous surgeries/trauma, the presence of indwelling devices such as catheters and lengthy hospital stays.12 in terms of gender predilection, no significant difference was found between male and female patients in the current study; this observation is in agreement with previous research.21 a significantly greater number of healthcareassociated mrsa isolates in the current study were resistant to non-β-lactam antibiotics in comparison with healthcare-associated mssa isolates. a similar observation was made by the insar group.8 this could be due to the unique molecular properties of mrsa bacteria—these strains carry the staphylococcal cassette chromosome mec (sccmec), a mobile genetic element which includes the meca gene that codes for methicillin resistance.22 healthcare-associated mrsa carries sccmec types i, ii or iii; these elements are relatively large and are associated with resistance to many other non-β-lactam antibiotics.22 this kind of multidrug resistance is challenging for clinicians when selecting an appropriate antibiotic for treatment. among different phenotypes of mlsb resistance, detection of cmlsb does not pose a problem because these strains are resistant to both erythromycin and clindamycin in routine susceptibility testing; however, the detection of imlsb and msb phenotypes is not possible with standard methods because these strains appear resistant to erythromycin but susceptible to clindamycin.10 hence, clindamycin treatment will fail with imlsb mrsa strains. 10 conversely, if clindamycin is not considered as a treatment option due to the suspicion that the strain might be resistant, patients with clindamycin-susceptible infections would be deprived of the correct antibiotic. in the present study, more than a third of the mrsa isolates were of the imlsb phenotype; this finding is higher than those reported from previous indian studies.7,23 studies from other parts of the world have shown imlsb phenotype rates ranging from 7.1–56%.24–26 these results clearly support the use of a d-test to identify healthcareassociated mrsa strains with imlsb resistance. vancomycin is considered an appropriate antibiotic for the treatment of serious mrsa infections and its use has increased dramatically over the past 20 years due to the emergence of multidrug-resistant healthcare-associated mrsa.9,27 however, the recent emergence of vancomycin-intermediate s. aureus (visa) and vancomycin-resistant s. aureus (vrsa) infections has added to the difficulty in selecting the appropriate antibiotic for these bacteria.1 several reports of mrsa infections with reduced susceptibility to vancomycin have been reported from france, japan, korea, germany and the usa.27 while vrsa infections are not yet a problem in india, visa strains have been reported from some centres.28,29 there were four visa cases observed in the present study; however, routine testing does not differentiate between visa and vancomycin-susceptible strains.16,17 in the table 3: macrolide-lincosamide-streptogramin b phenotypes among patients with healthcare-associated methicillin-resistant staphylococcus aureus infections (n = 88) hospital n (%) cmlsb phenotype imlsb phenotype msb phenotype government hospital 1 6 (6.8) 23 (26.1) 8 (9.1) government hospital 2 1 (1.1) 1 (1.1) 0 (0.0) private hospital 1 1 (1.1) 4 (4.5) 3 (3.4) private hospital 2 2 (2.3) 3 (3.4) 3 (3.4) total* 10 (11.4) 31 (35.2) 14 (15.9) mls b = macrolide-lincosamide-streptogramin b; cmlsb = constitutive mlsb ; imlsb = inducible mlsb ; msb = macrolide-streptogramin b. *the remaining 33 isolates were sensitive to both clindamycin and erythromycin. present study, it was observed that agar dilution was useful in determining the vancomycin mic and also contributed to differentiating visa from vancomycinsusceptible strains. tandel et al. have previously shown that the etest® (biomérieux, marcy-l’étoile, lyon, france) can also be used for this purpose.30 determining the mic of vancomycin is required before selecting this antibiotic for the treatment of a healthcare-associated mrsa infection. fortunately, all mrsa strains were susceptible to linezolid, leaving it as the choice of treatment in these cases. molecular testing was not performed on the mrsa isolates and was therefore a limitation of the present study. there is an urgent need for further studies on the judicious use of vancomycin and the surveillance of antibiotic resistance. in addition, strategies need to be implemented in order to prevent healthcareassociated infections in india. conclusion a high rate of healthcare-associated mrsa infections was observed, indicating that this type of infection is a significant concern for the four hospitals included in this study. a greater number of mrsa cases were multidrug-resistant as compared with mssa. a d-test should be performed before selecting clindamycin to treat cases of mrsa that appear susceptible to clindamycin but are resistant to erythromycin according to standard antibiotic susceptibility testing. the mic of vancomycin should be determined and susceptibility should be proven before considering this antibiotic for the treatment of serious mrsa infections. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. deleo fr, chambers hf. reemergence of antibiotic-resistant staphylococcus aureus in the genomics era. j clin invest 2009; 119:2464–74. doi: 10.1172/jci38226. 2. diekema dj, pfaller ma, schmitz fj, smayevsky j, bell j, jones rn, et al. survey of infections due to staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the united states, canada, latin america, europe, and the western pacific region for the sentry antimicrobial surveillance program, 1997-1999. clin infect dis 2001; 32:s114–32. doi: 10.1086/320184. 3. tiemersma ew, bronzwaer sl, lyytikäinen o, degener je, schrijnemakers p, bruinsma n, et al. methicillin-resistant staphylococcus aureus in europe, 1999-2002. emerg infect dis 2004; 10:1627–34. 4. song jh, hsueh pr, chung dr, ko ks, kang ci, peck kr, et al. spread of methicillin-resistant staphylococcus aureus between the community and the hospitals in asian countries: an ansorp study. j antimicrob chemother 2011; 66:1061–9. doi: 10.1093/jac/dkr024. 5. tahnkiwale ss, roy s, jalgaonkar sv. methicillin resistance among isolates of staphylococcus aureus: antibiotic sensitivity pattern & phage typing. indian j med sci 2002; 56:330–4. 6. bouchiat c, el-zeenni n, chakrakodi b, nagaraj s, arakere g, etienne j. epidemiology of staphylococcus aureus in bangalore, india: emergence of the st217 clone and high rate of resistance to erythromycin and ciprofloxacin in the community. new microbes new infect 2015; 7:15–20. doi: 10.1016/j. nmni.2015.05.003. 7. sharma nk, garg r, baliga s, bhat kg. nosocomial infections and drug susceptibility patterns in methicillin sensitive and methicillin resistant staphylococcus aureus. j clin diagn res 2013; 7:2178–80. doi: 10.7860/jcdr/2013/6750.3463. 8. indian network for surveillance of antimicrobial resistance (insar) group, india. methicillin resistant staphylococcus aureus (mrsa) in india: prevalence & susceptibility pattern. indian j med res 2013; 137:363–9. 9. liu c, bayer a, cosgrove se, daum rs, fridkin sk, gorwitz rj, et al. clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children: executive summary. clin infect dis 2011; 52:285–92. doi: 10.1093/cid/cir034. 10. leclercq r. mechanism of resistance to macrolides and lincosamides: nature of the resistant elements and their clinical implications. clin infect dis 2002; 34:482–92. doi: 10.1086/324626. 11. david mz, daum rs. community-associated methicillinresistant staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. clin microbiol rev 2010; 23:616–87. doi: 10.1128/cmr.00081-09. 12. centers for disease control and prevention. cdc/nhsn surveillance definition for specific types of infection. from: w w w.cdc .gov/nhsn/pdfs/ps cmanual/17ps cnosinfd ef_ current.pdf accessed: feb 2016. 13. mahajan bk. methods in biostatistics: for medical students and research workers, 8th ed. new delhi, india: jaypee brothers medical publishers ltd., 2016. pp. 113–27. doi: 10.50 05/jp/books/12646. 14. rashid a, rashid h, qureshi ur, rashid a. conquering methicillin resistant staphylococcus aureus: prespectives and treatment options. int arch med 2015; 8:1–7. doi: 10.3823/1666. 15. bannerman tl. staphylococci, micrococcus, and other catalase positive cocci that grow aerobically. in: murray pr, baron ej, jorgenson jh, pfaller ma, yolken rh (eds). manual of clinical microbiology, 8th ed. washington dc, usa: asm press, 2003. pp. 384–404. 16. clinical and laboratory standards institute. m100-s25: performance standards for antimicrobial susceptibility testing twenty-fifth informational supplement. from: http://shop.clsi. org/microbiology-documents/ accessed: feb 2016. 17. clinical and laboratory standards institute. m100-s22: performance standards for antimicrobial susceptibility testing twenty-second informational supplement. from: http://shop. clsi.org/microbiology-documents/ accessed: feb 2016. 18. steward cd, raney pm, morrell ak, williams pp, mcdougal lk, jevitt l, et al. testing for induction of clindamycin resistance in erythromycin-resistant isolates of staphylococcus aureus. j clin microbiol 2005; 43:1716–21. doi: 10.1128/jcm.43.4.17161721.2005. healthcare-associated methicillin-resistant staphylococcus aureus clinical characteristics and antibiotic resistance profile with emphasis on macrolide-lincosamide-streptogramin b resistance 180 | squ medical journal, may 2016, volume 16, issue 2 http://dx.doi.org/10.1172/jci38226 http://dx.doi.org/10.1086/320184 http://dx.doi.org/10.1093/jac/dkr024 http://dx.doi.org/10.1016/j.nmni.2015.05.003 http://dx.doi.org/10.1016/j.nmni.2015.05.003 http://dx.doi.org/10.7860/jcdr/2013/6750.3463 http://dx.doi.org/10.1093/cid/cir034 http://dx.doi.org/10.1086/324626 http://dx.doi.org/10.1128/cmr.00081-09 http://dx.doi.org/10.5005/jp/books/12646 http://dx.doi.org/10.5005/jp/books/12646 http://dx.doi.org/10.3823/1666 http://dx.doi.org/10.1128/jcm.43.4.1716-1721.2005 http://dx.doi.org/10.1128/jcm.43.4.1716-1721.2005 jyoti kumari, shalini m. shenoy, shrikala baliga, chakrapani m. and gopalkrishna k. bhat clinical and basic research | e181 19. akoğlu h, zarakolu p, altun b, ünal s. [epidemiological and molecular characteristics of hospital-acquired methicillinresistant staphylococcus aureus strains isolated in hacettepe university adult hospital in 2004-2005.] mikrobiyol bul 2010; 44:343–55. 20. coombs gw, nimmo gr, pearson jc, collignon pj, bell jm, mclaws ml, et al.; australian group on antimicrobial resistance. australian group on antimicrobial resistance hospital-onset staphylococcus aureus surveillance programme annual report, 2011. commun dis intell q rep 2013; 37:e210–18. 21. abbas a, nirwan ps, srivastava p. prevalence and antibiogram of hospital acquired-methicillin resistant staphylococcus aureus and community acquired-methicillin resistant staphylococcus aureus at a tertiary care hospital national institute of medical sciences. community acquir infect 2015; 2:13–15. doi: 10.4103/2225-6482.153857. 22. hiramatsu k, katayama y, yuzawa h, ito t. molecular genetics of methicillin-resistant staphylococcus aureus. int j med microbiol 2002; 292:67–74. doi: 10.1078/1438-4221-00192. 23. chadha t, kulsum sn, adlekha s, mailapur pc. comparison of antibiotic susceptibility pattern of communityand hospitalassociated methicillin-resistant staphylococcus aureus with special reference to inducible clindamycin resistance in a tertiary care hospital in southern india. med j d y patil univ 2014; 7:439–42. doi: 10.4103/0975-2870.135257. 24. schmitz fj, sadurski r, kray a, boos m, geisel r, köhrer k, et al. prevalence of macrolide-resistance genes in staphylococcus aureus and enterococcus faecium isolates from 24 european university hospitals. j antimicrob chemother 2000; 45:891–4. doi: 10.1093/jac/45.6.891. 25. schreckenberger pc, ilendo e, ristow kl. incidence of constitutive and inducible clindamycin resistance in staphylococcus aureus and coagulase-negative staphylococci in a community and a tertiary care hospital. j clin microbiol 2004; 42:2777–9. doi: 10.1128/jcm.42.6.2777-2779.2004. 26. patel m, waites kb, moser sa, cloud ga, hoesley cj. prevalence of inducible clindamycin resistance among communityand hospitalassociated staphylococcus aureus isolates. j clin microbiol 2006; 44:2481–4. doi: 10.1128/ jcm.02582-05. 27. loomba ps, tanjea j, mishra b. methicillin and vancomycin resistant s. aureus in hospitalized patients. j glob infect dis 2010; 2:275–83. doi: 10.4103/0974-777x.68535. 28. thati v, shivannavar ct, gaddad sm. vancomycin resistance among methicillin resistant staphylococcus aureus isolated from intensive care units of tertiary care hospitals in hyderabad. indian j med res 2011; 134:704–8. doi: 10.4103/0971-5916. 91001. 29. dhawan b, gadepalli r, rao c, kapil a, sreenivas v. decreased susceptibility to vancomycin in methicillin-resistant staphylococcus aureus: a 5 year study in an indian tertiary hospital. j med microbiol 2010; 59:375–6. doi: 10.1099/jmm. 0.011940-0. 30. tandel k, praharaj ak, kumar s. differences in vancomycin mic among mrsa isolates by agar dilution and e test method. indian j med microbiol 2012; 30:453–5. doi: 10.4103/02550857.103768. http://dx.doi.org/10.4103/2225-6482.153857 http://dx.doi.org/10.1078/1438-4221-00192 http://dx.doi.org/10.4103/0975-2870.135257 http://dx.doi.org/10.1093/jac/45.6.891 http://dx.doi.org/10.1128/jcm.42.6.2777-2779.2004 http://dx.doi.org/10.1128/jcm.02582-05 http://dx.doi.org/10.1128/jcm.02582-05 http://dx.doi.org/10.4103/0974-777x.68535 http://dx.doi.org/10.4103/0971-5916.91001 http://dx.doi.org/10.4103/0971-5916.91001 http://dx.doi.org/10.1099/jmm.0.011940-0 http://dx.doi.org/10.1099/jmm.0.011940-0 http://dx.doi.org/10.4103/0255-0857.103768 http://dx.doi.org/10.4103/0255-0857.103768 الندوة الوطنية الثانية لطب النوم مجعية اجلهاز التنفسي الُعمانية ومستشفى جامعة السلطان قابوس 5-4 مايو 2011 abstracts 2nd national symposium on sleep medicine oman respiratory society and sultan qaboos university hospital 4-5th may 2011 squ med j, november 2011, vol. 11, iss. 4, pp. 534-539, epub. 25th oct 11 overview of obstructive sleep apnoea including historical background, pathophysiology and clinical presentations abdulaziz al-hashemi hamad general hospital, doha, qatar. email: sleepmed@gmail.com obstructive sleep apnoea (osa) is a common disorder characterised by repetitive narrowing or collapse of the pharyngeal airway during sleep. estimates of disease prevalence are in the range of 2% to 4%, with certain subgroups of the population bearing higher risk. the disorder is associated with major co-morbidities including excessive daytime sleepiness and increased risk of cardiovascular disease. the underlying pathophysiology is multifactorial and may vary considerably between individuals. important risk factors include age, male sex, obesity, family history, menopause, craniofacial abnormalities, and certain health behaviours such as alcohol use. despite the numerous advancements in our understanding of the pathogenesis and clinical consequences of the disorder, a majority of those affected remain undiagnosed. in this presentation, the historical background of obstructive sleep apnoea will be briefly covered. the current understanding of osa pathophysiology in adults, the potential mechanisms underlying the principal risk factors and various clinical presentations of this disease will be discussed. diagnosis of obstructive sleep apnoea nasser al-busaidi, royal hospital, muscat, oman. email: enhsa@hotmail.com obstructive sleep apnoea (osa) is a disorder characterised by obstructive apnoeas and hypopnoeas caused by repetitive collapse of the upper airway during sleep. according to american academy of sleep medicine, the criteria for definition of obstructive apnoea are (all 3): 1) cessation of air flow; 2) continued respiratory effort, and 3) apnoea lasting 10 seconds or longer. a central apnoea occurs when both airflow and ventilatory efforts are absent. mixed apnoea occurs when there is an interval during which there are no respiratory efforts and an interval during which there are obstructed respiratory efforts. diagnosis of osa is suspected from history and physical examination and confirmed by a sleep study using polysomnography (psg). snoring and excessive daytime sleepiness are the most important symptoms. interestingly, it has been noted that women report symptoms of osa less frequently. the epworth sleepiness scale (ess), a subjective test, measures sleepiness as it occurs in ordinary life situations. it can be used as a screening test for excessive sleepiness, or to follow an individual's subjective response to an intervention. physical examination is frequently normal. obesity and crowded oro-pharynx are the most important findings. hypertension or uncontrolled hypertension is also a significant observation. the mallampati score (ms) is an important tool to assess the upper airway; ms 3 and 4 have good sensitivity and specificity. the differential diagnosis of osa include periodic limb movements of sleep, sleep pattern of rotating shift workers, narcolepsy, upper airway resistance syndrome and simple snoring. for diagnosis, full-night or split-night, attended, in-laboratory polysomnography is suggested for most of the patients. unattended portable monitoring is an alternative test for patients in whom there is a high likelihood of moderate or severe osa. the severity of osa is graded using the apnoea hypopnoea index (ahi) which equals the number of apnoeas and hypopnoeas occurring per hour of sleep. ahi of 5–15 defines mild osa, 15–30 moderate osa and ahi > 30 severe osa. complications of obstructive sleep apnoea/hypopnoea syndrome mohammed a. al-abri sultan qaboos university hospital, muscat, oman. email: malabri@squ.edu.om the obstructive sleep apnoea/hypopnoea syndrome (osahs) is a common disorder, affecting around 2–4% of the middle-aged population. there is a strong association between osahs and hypertension, ischaemic heart diseases stroke and type 2 diabetes. different mechanisms play a role in the process of developing complications in osahs. abstracts | 535 4-5th may 2011 sympathetic activity is increased in osahs patients during sleep and wakefulness. this increase in sympathetic activity is probably due to activation of baroreflexes and chemoreflexes by frequent arousals and also due to hypoxaemia resulting from apnoea or hypopnoea events. altered endothelial function may also have a role in the pathogenesis of hypertension as well as cardiovascular and cerebrovascular diseases in osahs subjects. reduction of nitric oxide production and increase in the formation of free radicals may be responsible for the impairment of the vasodilatation of micro-vasculature in these subjects. furthermore, disturbed sleep in obstructive sleep apnoea may cause insulin resistance and impaired glucose tolerance. continuous positive airway pressure (cpap) therapy has been shown to have a reversible effect on endothelial dysfunction and sympathetic hyperactivity. it has also been shown to improve insulin sensitivity and glucose tolerance in those patients who are compliant with the treatment. psychosocial and economic impact of obstructive sleep apnoea nabil m al-lawati royal hospital, muscat, oman. email: nabil.allawati@gmail.com obstructive sleep apnoea (osa) is a common under diagnosed disorder characterised by recurrent upper airway obstruction during sleep. the prevalence of osa is estimated to be around 4% in middle aged men and 2% in females in the same age group. in addition to its numerous medical consequences, osa has it is own effects on the psychosocial well being of the affected individuals and can adversely impact health care economics. daytime sleepiness, one of the main symptoms of osa, adversely affects cognition which impairs the work performance. it can also result in deficits in neurocognitive performance which in turn leads to errors while driving and result in increased risks of motor vehicle crashes, including a high rate of collisions in patients who drive as part of their occupation. in one of the studies, the risk of occupational accidents was found to be 50% higher in those with osa compared to normal controls. osa appears to cause a huge economic burden. the economic burden of osa-related automobile collisions alone is enormous. to illustrate this, patients with sleep apnoea have a three to seven fold increased risk of motor vehicle crashes and cpap reduces these risks substantially. sassani et al. reported that in the year 2000 there were 810,000 collisions and 1,400 fatalities attributable to osa in the usa with a total cost of 15.9 billion dollars. treatment with cpap would have prevented 567,000 of these crashes, saved approximately 1,000 lives, and resulted in an overall savings of 7.9 billion dollars after costs associated with treatment were taken into account. untreated osa leads to multiple medical problems (such as systemic hypertension, cardiovascular disease, injuries and mood disorders) that increase health care utilisation. patients with sleep apnoea can consume 1.7 times more health care resources than controls matched for age, gender, area of residency and family physician. the total economic burden of sleep disorders in australia (a country with a population of 20.1 million) was substantial: $7.494 billion in 2004. the financial costs, excluding the cost of suffering, were $4.524 billion, representing 0.8% of australia’s gross domestic product. cpap therapy for osa appears to reduce health care utilisation. more importantly, it is cost effective—more so than fluticasone for asthma and primary angioplasty after myocardial infarction as assessed by the incremental cost-effectiveness ratio (icer), which is the ratio of the incremental cost and incremental change in quality-adjusted life years (qaly) that follows from the adoption of a treatment (cpap in case of osa). medical treatment of obstructive sleep apnoea issa al-jahdami armed forces hospital, muscat, oman. email: essajah111@yahoo.co.uk obstructive sleep apnoea is a disease characterised by obstructive apnoeas and hypopnoeas due to upper airway collapse. medical therapy involves mainly the use of continuous positive airway pressure (cpap) devices that basically work by blowing air into the upper airways under constant pressure to prevent or correct the collapse of the airways during sleep. there is high quality evidence that cpap therapy improves daytime sleepiness, cognitive function and quality of life. treatment also improves the cardiovascular consequences of osa. cpap machines either deliver a constant pressure throughout the night (fixed cpap), or variable pressure depending on a specific algorithm (auto cpap). there is no consensus on the optimal duration for using cpap, but use for more than five hours every night is preferred. compliance with cpap therapy remains an issue with most patients having poor adherence. this might be improved with proper patient counselling and trial of various forms of masks that will fit the particular patient best. medical therapy in terms of using pharmacological agents has not been shown to be effective; however, it can be used as an adjunctive therapy in patients who continue to have daytime sleepiness despite proper and adequate use of cpap. role of oral and maxillofacial surgery in the management of obstructive sleep apnoea ahmed khamis al-hashmi al nahdha hospital, muscat, oman. email: abufatami@ymail.com oral and maxillofacial specialty plays an important role in the management of patients with sleep apnoea. the oral and maxillofacial surgeon can screen the patients in the outpatient clinic, manage associated orofacial symptoms (bruxism, tempero mandibular disorders, etc), provide mandibular advancement devices and offer maxillofacial surgeries to improve the airflow at the oropharynx area. usually patients are referred to the maxillofacial surgeon after the diagnosis and severity of their apnoea are established by a sleep study. in addition, endoscopic airway assessment by an ent 536 | squ medical journal, november 2011, volume 11, issue 4 2nd national symposium on sleep medicine oman respiratory society and sultan qaboos university hospital surgeon confirms the obstructive nature of the apnoea and will define its level (nasal, palatal, tongue). a mandibular advancement device (mad) is made of acrylic and keeps the mandible in forward relation to the maxilla. this opens the posterior airway at the level of the tongue base. the device is worn during sleep and most of the patients tolerate it well. it is useful in the management of mild to moderate obstructive sleep apnoea and in patients who snore. this is an alternative for patients who cannot tolerate continuous positive airway pressure (cpap). it is gaining popularity because of its simplicity and reversibility. recent reviews show a positive outcome in 60–75% and superior results when compared to upper airway surgery. most commonly performed maxillofacial surgeries are genioplasty (chin advancement), mandibular advancement osteotomy, maxillomandibular advancement (mma) and distraction osteogenesis (do). these surgical procedures are based on the fact that soft tissues follow the bone. bringing the jaws surgically forward will bring with it associated soft tissues (tongue base or soft palate), which in turn will open the airways. these are now routine procedures in the oral and maxillofacial surgery unit at al nahdha hospital with good and predictive results. finally, close interaction between the respiratory physician, ent surgeon and oral and maxillofacial surgeon will secure optimal results in the management of patients with sleep apnoea. surgical approach for obstructive sleep apnoea rashid al-abri sultan qaboos university hospital, muscat, oman. email: ralabri@gmail.com obstructive sleep apnoea (osa) syndrome is a potentially serious disorder affecting millions of people around the world. it involves periodic partial or total collapse of the pharyngeal airway during sleep. this results in progressive asphyxia, which increasingly stimulates breathing efforts against the collapsed airway, typically until the patient is awakened from sleep. the intention of surgery in osa is to open the airway sufficiently to eliminate or to reduce obstructions to a clinically insignificant level. the most commonly performed procedures include nasal reconstruction, adenotonsillectomy, uvulopalatopharyngoplasty (uppp), advancement genioplasty, mandibular osteotomy with genioglossus advancement, and hyoid myotomy and suspension. in more severe cases, maxillomandibular advancement (mma) with advancement genioplasty or even tracheostomy may be indicated. in osa, the success of surgery is generally measured by achieving a respiratory disturbance index (rdi) of less than 5, improvement of oxygen saturation to 90 per cent or more and quality of life improvements with elimination or significant reduction of osa symptoms. it is extremely difficult in practice to achieve these goals without the cooperation of the patient, especially weight loss and maintenance of a healthy lifestyle. finally, continuous positive airway pressure (cpap) is the gold standard treatment for osa, surgical management only being an adjuvant. insomnia, assessment and treatment abdulaziz al-hashemi hamad general hospital, doha, qatar. email: sleepmed@gmail.com insomnia is the most prevalent sleep disorder in the general population and is commonly encountered in medical practices. its prevalence is estimated to be around 20%. insomnia is defined as a subjective perception of difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity for sleep leading to some form of daytime impairment. insomnia may present with a variety of specific complaints and aetiologies, making the evaluation and management of this disorder demanding on a clinician’s time. in this presentation, the epidemiology, risk factors, pathophysiology, and consequences of insomnia will be briefly discussed. the different types of insomnia, its evaluation and available effective treatments will also be highlighted. non-invasive ventilation: practical aspects jayakrishnan b sultan qaboos university hospital, muscat, oman. email: drjayakrish@hotmail.com noninvasive ventilation (niv) is a form of assisted ventilation without an invasive artificial airway. it is now increasingly used in the first line management of both acute and chronic respiratory failure in the hospital as well as in the home setting. ventilation is delivered through a noninvasive interface like a nasal mask, facemask, total face mask or nasal pillows. the key to the successful application of noninvasive ventilation is in recognising its capabilities and limitations. patients who require immediate intubation should not be offered niv. relative contraindications include cardiac or respiratory arrest, inability to cooperate, inability to protect the airway or clear secretions, severely impaired level of consciousness, facial surgery, trauma or deformity, high risk for aspiration and recent oesophageal anastamosis. many patients are provided with the most basic level of support, the continuous positive airway pressure (cpap). cpap may be especially useful in patients with pulmonary oedema or obstructive sleep apnoea. bi-level positive airway pressure (bpap) is probably the most common mode of support and requires provision of inspiratory positive airway pressure (ipap) and expiratory positive airway pressure (epap) separately. another mode, proportional-assist ventilation (pav) provides flow and volume assistance with each breath. it is better to start with low pressure in spontaneously triggered mode with backup rate, applying 8 to 12 cm h2o of ipap and 3 to 5 cm h2o of epap. the mask should be first held in place by the therapist to familiarise the patient with the flow. then the straps should be applied to hold the mask in place, with care to minimise excess pressure on the face or nose. the pressures can then be gradually increased in increments of 2 cm h2o or as tolerated (ipap 20-25 and epap 10-15 cm h2o maximum) to achieve alleviation of dyspnoea, decreased respiratory rate, increased tidal volume and a good patient-ventilator synchrony. oxygen is supplemented as abstracts | 537 4-5th may 2011 needed to keep sao2 around 90%. subsequent adjustments are based on arterial blood gas values. if hypercapnia persists, ipap and, if it is hypoxia, epap are increased. once the acute event is tided over, weaning may be accomplished by progressively decreasing the amount of positive airway pressure, permitting the patient to be disconnected from the niv for progressively longer durations, or a combination of both. conditions known to respond well to this treatment include exacerbations of chronic obstructive pulmonary disease, cardiogenic pulmonary oedema and hypoxaemic respiratory failure and, in the chronic setting, obstructive sleep apnoea and chronic type ii respiratory failure due to diverse causes. it is also useful in preventing post extubatuion respiratory failure and in selected cases of asthma exacerbations. sleep from an islamic perspective ahmed bahammam king saud university, riyadh, saudi arabia. email: ashammam2@gmail.com sleep medicine is a relatively new scientific specialty. sleep is an important topic in islamic literature, and the quran and hadith discuss types of sleep, the importance of sleep, and good sleep practices. islam considers sleep as one of the signs of the greatness of allāh (god) and encourages followers to explore this important sign. the quran describes different types of sleep, and these correspond with sleep stages identified by modern science. the quran discusses the beneficial effects of sleep and emphasises the importance of maintaining a pattern of light and darkness. a mid-day nap is an important practice for muslims, and the prophet muhammad peace be upon him (pbuh) promoted naps as beneficial. in accordance with the practice and instructions of muhammad (pbuh), muslims have certain sleep habits and these sleep habits correspond to some of the sleep hygiene rules identified by modern science. details of how to sleep include sleep position—like encouraging sleep on the right side and discouraging sleep in the prone position. dream interpretation is an established science in the islamic literature and islamic scholars have made significant contributions to the theories of dream interpretation. we suggest that sleep scientists examine religious literature in general, and islamic literature in particular, to understand the views, behaviours, and practices of ancient people about sleep and sleep disorders. such studies may help to answer some unresolved questions in sleep science or lead to new areas of inquiry. restless leg syndrome and periodic limb movement abdullah al-asmi sultan qaboos university hospital, oman. email: alasmi@gmail.com restless leg syndrome (rls) is a chronic neurological disorder which is underreported; various reported prevalence rates range from 2–15%. four diagnostic criteria are being identified in order to diagnose rls, including an urge to move the legs associated with unpleasant sensation in the legs which begin or worsen at rest, in particular at night. the symptoms are relieved partially or completely by movement. it is at times associated with period limb movement (plm) during sleep. rls and plm can lead to significant sleep disturbance and poor quality of life. both conditions are chronic with 45% of patients experiencing their first symptoms before the age of 20. the frequency and severity of symptoms worsen with time and most of the patients will start feeling their symptoms on daily basis between the ages of 40–60. the pathophysiology is still not well understood, but the dopamine pathway system, brain iron metabolism and endogenous opioids system are being implicated. most of the time, the aetiology is unknown. however, both rls and plm are reported in patients with anaemia, uraemia, and neuropathy. it is important to differentiate rls and plm from other conditions like akathisia, nocturnal leg cramps, painful legs and moving toes, peripheral vascular disease and peripheral neuropathy. there are various scales available to assess the severity and quality of life of these patients as well as how to quantify the symptoms in sleep laboratory. most patients respond well to one of the dopamine agonists. in severe cases, other options may be considered including opioids and anitiepileptics. narcolepsy nabil m al-lawati royal hospital, muscat, oman. email:nabil.allawati@gmail.com narcolepsy is the second most common cause of disabling daytime sleepiness after sleep apnoea. descriptions of the disorder appeared as early as 1862. the term narcolepsy was first applied by gélineau to a clinical syndrome of daytime sleepiness with cataplexy, hypnagogic hallucinations, and sleep paralysis. the prevalence of narcolepsy with cataplexy is estimated to be 25–50 cases per 100,000. it is equally common in both genders. it typically begins in the teens and early twenties, but can occur as early as five years of age or after 40 years of age. the symptoms may worsen during the first few years and then persist for life. narcolepsy is a disorder of sleep-wake state control in which elements of sleep intrude into wakefulness and vice versa. only about one third of the affected patients will have the four classic symptoms of daytime sleepiness, hypnagogic hallucinations, sleep paralysis, and cataplexy. thus diagnosis of narcolepsy should be considered even in patients with sleepiness alone. patients with untreated narcolepsy typically have epworth sleepiness scale (ess) scores greater than 15. loss of orexin signalling, genetic factors, and rare brain lesions can cause or contribute to narcolepsy. diagnostic testing for narcolepsy includes an overnight polysomnogram (psg) followed by a multiple sleep latency test (mslt). the psg evaluates sleep quality and can identify coexisting causes of sleepiness such as obstructive sleep apnoea, periodic limb movements of sleep, or rem behaviour disorder that are common in narcolepsy and may warrant specific treatment. mslt is performed the day after the psg. during the mslt, the patient is given four or five opportunities to nap every two hours. on average, healthy subjects fall asleep in about 10 to 15 minutes, whereas people with narcolepsy often fall asleep in less than five minutes, providing objective evidence of their 538 | squ medical journal, november 2011, volume 11, issue 4 2nd national symposium on sleep medicine oman respiratory society and sultan qaboos university hospital sleep propensity. the naps of narcoleptics often include rem sleep, and the occurrence of two or more of these sleeponset rem periods (sorems) is an essential feature in establishing the diagnosis of narcolepsy. narcolepsy without cataplexy can be confirmed if a) chronic sleepiness is accompanied by a mslt showing an average sleep latency less than eight minutes and/or at least two sorems and b) alternative aetiologies have been excluded by history, clinical examination and psg (e.g., untreated sleep apnoea, periodic limb movements of sleep, insufficient sleep, or sedating medications). patients with narcolepsy can benefit from a regular and adequate sleep schedule, scheduled daytime naps, avoidance of drugs that produce daytime sleepiness or insomnia, and joining a psychosocial support group. coexisting sleep disorders need to be treated if present. patients with sleepiness severe enough to require medication can be treated with stimulant medications, such as modafinil. rem sleep-suppressing drugs which can selectively inhibit the reuptake of norepinephrine or serotonin such as venlafaxine, atomxetine and fluoxetine may substantially reduce cataplexy with relatively few side effects. approach to sleep disorders in children adel s. al-harbi riyadh military hospital, riyadh, saudi arabia. email: drasra55@yahoo.com identification of sleep problems in children is important because there is very strong evidence from the literature to suggest a link between sleep disorders and physical, cognitive, emotional, and social development. children with neurodevelopmental problems, learning differences, or behaviour problems may be at heightened risk for sleep problems compared with the general paediatric population. paediatricians, paediatric subspecialists, and other health care practitioners are in an ideal position to identify sleep problems and disorders in children. parents may not volunteer information about their child's sleep, or they may not appreciate the potential relationship between sleep problems and daytime behaviour. for these reasons, clinicians should incorporate questions about sleep into routine health assessment for children of all ages. sleep problems present most commonly in the outpatient setting, but the hospitalised child may develop sleep problems during an acute illness, or chronic sleep disorders may come to medical attention during hospitalisation. this presentation will discuss the approach to taking a structured sleep history, describe specific sleep problems that may present during childhood, and explain indications for further diagnostic testing. this will enable the participants to understand the basic parameters, epidemiology and classification of sleep disorders in children, know how to take a structured sleep history and explain indications for further diagnostic testing. sleep-disordered breathing in children hussein al kindy sultan qaboos university hospital, muscat, oman. email: husseink30@yahoo.com children of all ages can have a sleep-disordered breathing (sdb), just like adults; however, there are some differences in the pattern of causes and symptoms. sleep in children with sleep-disordered breathing is very different from sleep in normal children. the increase in upper airway resistance during sleep can be extreme, and can lead to a markedly increased work of breathing associated with snoring, obstructive sleep apnoea and/or obstructive hypoventilation resulting in sleep disruption, hypoxia, and hypercarbia. the definition of sdb in children and the range of manifestations including the most common cause adenotonsillar hypertrophy will be discussed in detail. other causes such as generalised hypotonia, as in patients with prader-willi syndrome, congenital central hypoventilation syndrome, and finally the treatment of sdb in children including surgery and cpap will also be discussed. parasomnias: common sleep disorders in children adel s. al-harbi riyadh military hospital, riyadh, saudi arabia. email: drasra55@yahoo.com parasomnia is a common sleep problem in children. parasomnia can be sub-classified into disorders of arousal from non-rapid eye movement (nrem) sleep and parasomnias associated with rapid eye movement (rem) sleep. arousal disorders from nrem sleep consist of several common disorders in children such as confusional arousals, sleep terror and sleep walking. parasomnias associated with rem sleep include a common disorder like nightmares and a rare condition in children such as rem sleep behaviour. these episodes can be precipitated by stress, sleep deprivation, anxiety and environmental noises. diagnosis of parasomnia is done by obtaining a standard clinical history with emphasis on detailed description, timing, and response to intervention. there is no need for a sleep study in children with simple parasomnias. a referral to a sleep centre is indicated in children with unusual presentations, persistent parasomnia, violent behaviours or symptoms of other sleep disorders. polysomnography may demonstrate precipitous arousals from slow-wave sleep. in addition, a sleep study can help to identify co-existing sleep disorders which could potentially precipitate arousals, e.g. obstructive sleep apnoea. treatment is reassurance and good sleep hygiene in mild cases. this presentation will enable participants to define and classify parasomnias as well as to differentiate between parasomnias and seizure/epilepsy in children. abstracts | 539 4-5th may 2011 acute ventilatory failure complicating obesity hypoventilation: update on a “critical care syndrome” ahmed bahammam king saud university, riyadh, saudi arabia. email: ashammam2@gmail.com obesity can result in serious complications, including obesity hypoventilation syndrome (ohs). ohs patients may present with acute-on-chronic ventilatory failure, necessitating acute care management. this presentation will discuss the recent literature on acute ventilatory failure in ohs patients. obese subjects can develop acute hypercapnic respiratory failure (ahrf) and sleep hypoventilation due to disorders in lung mechanics, ventilatory drive, and neurohormonal and neuro-modulators of breathing. although there are no clearly defined predictors for ohs patients who are likely to develop ahrf, most such patients are middle-aged (mid-50s), morbidly obese, and have daytime hypercapnia, hypoxaemia, and low serum ph values. immediate ventilatory support, without sleep study confirmation, is necessary in most such patients. patients with respiratory acidaemia (ph <7.30) or altered mental status may require intensive care unit monitoring. non-invasive positive pressure ventilation (nippv) is the recommended initial ventilatory support which must be closely monitored. prompt initiation of nippv reduces the need for invasive mechanical ventilation and rapidly improves the levels of blood gases. obese patients with sleep hypoventilation have an increased risk of ahrf. early diagnosis and implementation of nippv is recommended for these patients. central sleep apnoea issa al-jahdami armed forces hospital, muscat, oman. email: essajah111@yahoo.co.uk central sleep apnoea (csa) occurs when both airflow and respiratory effort are absent. recurrent central apnoeas are the main finding in central sleep apnoea syndrome (csas). these occur when the inhibitory input to the respiratory centre exceeds the excitatory input. csas is uncommon, occurring in approximately 4% of the population. the mechanism causing csa is primarily related to removal of the wakefulness drive to breath as well as unmasking of a pco2 sensitive apnoeic threshold. in normal sleep, the ventilation decrease and hence pco2 level slightly rise. the main control of ventilation during sleep is through the pco2 level. in patients with csa, pco2 levels decrease to below the apnoeic threshold leading to temporary cessation of breathing which in turn raises the pco2 to the normal level when the ventilation starts again. csa could occur physiologically at sleep onset, but most often is a pathological process. causes include heart failure, stroke, brain stem disorders, congenital alveolar hypoventilation syndrome and muscle disorders. clinically, patients present with features similar to obstructive sleep apnoea with poor sleep, morning headache, daytime somnolence and nocturnal shortness of breath. in sleep study, csa is diagnosed when more than 50% of the apnoeic events are central. management of csa includes finding the underlying cause like heart failure, hypothyroidism, brain stem lesions or muscle disease and managing it. cpap therapy is used if csa is associated with a significant amount of obstructive apnoea. patients with hypercapnic csa will benefit from bi-level ventilation. optimising the treatment of heart failure in patients with csa will improve the associated sleep disordered breathing. the role of oxygen and respiratory stimulants is less clear. polysomnography rajesh p poothrikovial sultan qaboos university hospital, muscat, oman. email: rajeshthrissur@yahoo.com polysomnography (psg) is an excellent tool for evaluating sleep and sleep related disorders which utilises multiple physiological measures. these include brain waves (eeg), ocular movements (eog), skeletal muscle activities (emg), respiratory monitoring (airflow, effort, snoring), cardiac activity (ecg) and pulse oximetry (sao2). in addition, audio and video recordings are made during the test. psg gives an opportunity to correlate a variety of events occurring in separate physiological systems during different sleep stages and wakefulness. scoring of sleep stages (nrem – n1, n2, n3 and rem) and wakefulness can be performed with the help of eeg, eog and chin-emg activities which can be recorded by means of small surface electrodes through a conductive medium (gel). appropriate sensors are used to monitor respiration. this includes thermal sensors for oro-nasal airflow, strain gages for respiratory effort (chest/ abdomen movements) and dynamic snore microphones for snoring signals. alternatively, a nasal pressure transducer can be used to register nasal airflow and snoring. leg movements can be monitored by recording tibialis anterior muscle activity (emg). ecg monitoring is essential to detect abnormal arrhythmias and cardiac activity. sleep disordered breathing (sdb) such as apnoeas and hypopnoeas can be detected by a series of abnormally diminished airflow or cessation of airflow for a minimum duration of 10 seconds. these need to be correlated with other physiologic variations (to fulfil the criteria) such as drop in sao2, arousal in eeg and other skeletal muscle movements along with abnormally heavy snoring. audio/video recording is always advised for a better understanding of different types of parasomnias and nocturnal seizures. clinical & basic research sultan qaboos university med j, may 2015, vol. 15, iss. 2 pp. e218–225, epub. 28 may 15 submitted 11 sep 14 revision req. 4 nov 14; revision recd. 13 nov 14 accepted 3 dec 14 department of diagnostic genetics, labplus, auckland city hospital, auckland, new zealand *corresponding author e-mail: donaldl@adhb.govt.nz brca2 و brca1 توقع امكانية حدوث األمراض للمتغريات اجلينية ل احملددة يف الفحص اجليين السريري كلري بروك�ض، �ستيال الي، الني دوروثي، دونالد لوف abstract: objectives: missense variants are very commonly detected when screening for mutations in the brca1 and brca2 genes. pathogenic mutations in the brca1 and brca2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. this study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. methods: between july 2011 and april 2013, an analysis was undertaken of 13 missense brca gene variants that had been detected in patients referred to the genetic health services new zealand (northern hub) for brca gene analysis. the analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three brca gene databases. results: in most of the variants, the analysis showed different in silico interpretations. this illustrates the interpretation challenges faced by diagnostic laboratories. conclusion: unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the brca genes. this discordance leads to complexities in interpreting and reporting these variants in a clinical context. the authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. as a consequence, the clinical value of some reports may be negligible. keywords: genes, brca1; genes, brca2; hboc syndrome; in silico. امل�سببة والطفرات .brca2 و brca1 جينات يف الطفرات فح�ض عند �سائعة ب�سورة املغلوطة املتغريات تكت�سف امللخ�ص: الهدف: لالأمرا�ض يف جيني brca1 و brca2 توؤدي ايل زيادة خطورة حدوث �رشطانات الثدي واملباي�ض والربو�ستاتا والبنكريا�ض. وهدفت هذه الدرا�سة ايل تقييم القدرة التنبوؤية لقواعد بيانات وبرامج "انسيليكو" مل�ساعدة املعامل الت�سخي�سية يف حتيد قدرة الطفرات الت�سل�سلية علي الت�سبب يف االأمرا�ض. الطريقة: مت حتليل 13 متغري مغلوط يف جينات ال brca يف الفرتة مابني يوليو 2011 ايل ابريل 2013 يف عينات برنامج 13 التحليل يف وا�ستخدم .brca ال جينات لتحليل )northern hub( النيوزيالندية ال�سحية اخلدمات ايل املحولة املر�سي "انسيليكو" التنبوؤى للربوتني، واثنني برنامج "انسيليكو" للتحليل الن�سي وفح�ض ثالثة قواعد بيانات جلني ال brca. النتائج: اأظهرت نتائج هذه تف�سري يف الت�سخي�سية املعامل تواجه التي التحديات يو�سح وهذا املتغريات. ملعظم "انسيليكو" تف�سري يف ملحوظا اختالفا التحليل النتائج. اخلال�صة: لالأ�سف فانه يحدث الكثري من االأختالف عند ت�سنيف املتغريات املغلوطة يف جني ال brca باأ�ستخدام قواعد بيانات ال�سبكة العنكبوتية لتنفيذ حتليل "انسيليكو". وقد اأدي هذا االأختالف ايل حدوث تعقيدات كبرية يف تف�سري هذه املتغريات يف ال�سياق ال�رشيري. وقد طور الباحثون طريقة ب�سيطة لتحليل املتغريات ولكن بالرغم من ذلك فانه اليزال هناك الكثري منها غري معلوم الداللة. وبالتايل فاأن القيمة ال�رشيرية لبع�ض هذه التقارير ميكن اإهمالها. مفتاح الكلمات: اجلينات، brca1؛ واجلني، brca2؛ متالزمة hboc؛ "انسيليكو". predicting the pathogenic potential of brca1 and brca2 gene variants identified in clinical genetic testing clare brookes, stella lai, elaine doherty, *donald r. love advances in knowledge the analysis of sequence-detectable variants in the brca1 and brca2 (brca1/2) genes is critical in establishing if these variants are disease-causing. the analysis presented here shows the challenges posed by in silico programmes. diagnostic laboratories may therefore have to rely on familial segregation studies or the development of better in silico programmes possibly based on advanced neural network modelling requiring phenotypic as well as genotypic data. appication to patient care the analysis in this study shows the advantages and disadvantages of database searching and in silico analyses in predicting the pathogenicity of gene variants. in the case of brca1/2 gene variants, evolving analytical tools offer an improved outcome for guiding counselling of patients at risk of hereditary breast and ovarian cancer. clare brookes, stella lai, elaine doherty and donald r. love clinical and basic research | e219 pathogenic mutations in the brca1 and brca2 (brca1/2) genes predispose patients to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer; these genes are two of the genes most commonly tested for cancer predisposition. in the usa, a known pathogenic mutation is detected in approximately 10–15% of patients who undergo sequencing of the entire coding regions of the brca genes.1 however, a variant of uncertain significance (vus) is detected in more than 5% of patients, with higher frequencies seen in less commonly tested ethnic groups.2 patients with known pathogenic brca gene mutations are offered preventative strategies including enhanced surveillance, chemoprevention and irreversible surgical interventions. a study of patients in the usa, surveyed two years after being given either an uninformative (un) brca gene-negative or vus result by trained genetic counsellors, found that a vus result did not result in excessive surgeries, exaggerated distress or increased risk perception compared to patients with a un result.3 the riskreducing mastectomy rate was 7% in both groups and the oophorectomy rate was 5% for vus patients and 3% for un patients.3 a pathogenic mutation refers to a genetic variant that has been shown to cause or contribute to disease. a benign variant does not significantly impact on the function of the protein or increase disease risk, and it includes polymorphisms which are seen in over 1% of the general population. a vus is a variant where the effect on protein function and disease risk is unknown.4 in the case of the brca genes, vus are largely missense substitutions where a single nucleotide change results in an altered amino acid. the terms, vus and unclassified variant (uv) are often used interchangeably in the literature; however, they have slightly different interpretations. the term uv is suggestive of an unstudied variant, whereas a vus may or may not have been studied but still has unknown clinical relevance.5 providing a clear interpretation of a vus is a complex challenge for a diagnostic laboratory. common methods used to predict pathogenicity can include literature and database searches, in silico analyses, segregation analyses and functional studies. the requesting clinician may be faced with the difficult task of deciphering the ambiguity of the vus and communicating the result to the patient along with clinical recommendations. furthermore, it is imperative that the classifications of vus are regularly checked and any changes to their classifications are relayed to the patients and their family. the majority of missense mutations in the brca genes are classified as vus. the exceptions include missense mutations that lie within the highly conserved brca1 ring and the brca1 carboxyl-terminal domains.6 known pathogenic missense mutations in the brca2 gene are less common but may occur in the dna-binding domain.7 the difficulty in the interpretation of missense variants in the brca genes arises due to the discordance in the classification of variants in the breast cancer databases and the variety of predictions based on in silico analyses. recently, lindor et al. used a quantitative posterior probability model to reclassify vus in the brca1/2 genes into five classes as defined by the international agency for research on cancer (iarc) working group on unclassified genetic variants.8 these classes range from class 1 (not pathogenic) through to class 5 (definitely pathogenic). this reclassification attempts to combine a range of information regarding each vus in the literature and convert this into a useful posterior probability. this study analysed nine brca1 and four brca2 gene missense variants identified in the diagnostic genetics labplus, auckland city hospital, auckland, new zealand, where the interpretation was hampered by the diversity of classifications in international databases and online in silico predictions. methods this study was carried out between july 2011 and april 2013 and included 20 patients referred to genetic health services new zealand (northern hub) for brca1/2 gene mutation screening. dna was extracted from peripheral blood samples in ethylenediaminetetraacetic acid (edta) using the gentra puregene dna extraction kit (qiagen gmbh, hilden, germany). genomic dna from 20 patients were subjected to brca1/2 gene sequencing as described elsewhere;9 any identified variants were subsequently confirmed by exon-targeted polymerase chain reaction amplification and bi-directional sanger-based sequencing.10 sequence traces were analysed using kb basecaller version 1.4 (applied biosystems inc., foster city, california, usa), on variant reporter™ software version 1.0 (applied biosystems inc.), with a minimum trace score of 35, which corresponds to an average false base-call frequency of 0.031%. the analysis of sequence data and the subsequent investigation of databases and bioinformatic programmes used the relevant reference sequence (refseq) transcript, refseq protein and uniprot accession numbers for the brca1 (nm_007294.3; np_009225.1; p38398) and predicting the pathogenic potential of brca1 and brca2 gene variants identified in clinical genetic testing e220 | squ medical journal, may 2015, volume 15, issue 2 brca2 (nm_000059.3; np_000050.2; p51587) genes. all variants were checked for splicing effects using two in silico splice prediction programmes: the splice site prediction by neural network online tool of the berkeley drosophilia genome project and the alternative splice site predictor (assp) tool.11–14 all of the patients included in the study gave informed consent. the new zealand multi-region ethics committee has ruled that cases of patient management do not require formal ethical approval from a committee. results the missense brca gene variants identified are shown in table 1. these variants were checked for pathogenicity in six databases (three of which were specific to the brca genes)[figure 1 and table 2].8,15‒19 the missense variants were also scored for predicted pathogenicity using 13 online in silico protein analysis programmes [figure 2 and table 3].20‒43 when all variants were checked for splicing effects using the two aforementioned in silico splice prediction programmes, both of the programmes predicted that each variant would have no effect on splicing (data not shown). apart from four of the variants, the results of the in silico protein analysis programmes varied depending on which programme was used. the frequency with which variants were predicted to be pathogenic varied significantly between programmes [table 4].22‒43 a total of 13 missense brca gene mutations were identified and only one was identified as probably pathogenic (brca1: c.140g>a) based on the combined results achieved from databases and in silico programmes. however, this variant was predicted to be benign using the polymorphism phenotyping, version 2 (polyphen-2), humvar database and the protein variation effect analyzer (provean).20,37 in addition, a further three variants appeared to be probably benign (brca1: c.2612c>t, c.3548a>g and brca2: c.2971a>g). however, the remaining nine variants could not be interpreted even though minor allele frequencies on the database of single nucleotide polymorphisms (dbsnp) ranged from 0.01 to 0.327.19 table 1: missense brca gene mutations identified in the dna of 20 patients mutation predicted amino acid change detection frequency brca1 c.140g>a p.cys47tyr 0.05 c.1067a>g p.gln356arg 0.14 c.2077g>a p.asp693asn 0.10 c.2315t>c p.val772ala 0.05 c.2612c>t p.pro871leu 0.38 c.3113a>g p.glu1038gly 0.48 c.3119g>a p.ser1040asn 0.05 c.3548a>g p.lys1183arg 0.43 c.4837a>g p.ser1613gly 0.43 brca2 c.865a>c p.asn289his 0.05 c.1114a>c p.asn372his 0.52 c.2971a>g p.asn991asp 0.05 c.8149g>t p.ala2717ser 0.05 figure 1: diagrammatic representation of the pathogenicity calls of 13 brca gene missense variants in six databases, including the (1) human gene mutation database professional 2013;15 (2) breast cancer information core;16 (3) universal mutation database;17 (4) leiden open variation database;18 (5) international agency for research on cancer,8 and (6) database of single nucleotide polymorphisms.19 clare brookes, stella lai, elaine doherty and donald r. love clinical and basic research | e221 table 2: database listings for brca gene missense mutations variant hgmd class bic clinically important lovd summary umd biological significance iarc class dbsnp dbsnp maf brca1 c.140g>a dm not listed not listed 5 – causal not listed not listed c.1067a>g dp unknown mixed 1 – neutral 1 not path rs1799950 c = 0.028 c.2077g>a dp no mixed 1 – neutral 1 not path rs4986850 t = 0.039 c.2315t>c dm unknown neutral 1 – neutral 1 not path rs80357467 c.2612c>t dfp1 no mixed 1 – neutral 1 not path rs799917 a = 0.483 c.3113a>g dp2 no mixed 1 – neutral 1 not path rs16941 c = 0.303 c.3119g>a dm? unknown neutral 1 – neutral 1 not path rs4986852 t = 0.012 c.3548a>g dp1 no mixed 1 – neutral 1 not path rs16942 c = 0.324 c.4837a>g dm? no mixed 1 – neutral 1 not path rs1799966 c = 0.327 brca2 c.865a>c dp1 no mixed 1 neutral not listed rs766173 c = 0.058 c.1114a>c dfp listed as c>a neutral listed as c>a listed as c>a rs144848 c = 0.240 c.2971a>g dm? no neutral polymorphism not listed rs1799944 g = 0.062 c.8149g>t dm? no neutral 1 neutral 1 not path rs28897747 t = 0.001 hgmd = human gene mutation database professional 2013;15 bic = breast cancer information core database;16 lovd = leiden open variation database;18 umd = universal mutation database;17 iarc = international agency for research on cancer;8 dbsnp = database of single nucleotide polymorphisms;19 maf = minor allele frequency; dm = disease-causing mutation; dp = disease-associated polymorphism; path = pathogenic; dfp = disease-associated polymorphism with additional supporting functional evidence; 1 = associated with a decreased risk; 2 = comments included “polymorphism”; dm? = potential disease-causing mutation. figure 2: diagrammatic representation of the pathogenicity calls of 13 brca gene missense variants using 13 online in silico analysis programmes (all used in default online mode). these prediction programmes included: both the (1) humdiv and (2) humvar predictions of polymorphism phenotyping, version 2;20,21 (3) mutation assessor, release 2;22,23 (4) i-mutant, version 3.0, for the prediction of disease-associated single point mutations from protein sequence;24,25 (5) mutpred, version 1.2;26,27 (6) snps&go;28,29 (7) protein analysis through evolutionary relationships evolutionary analysis of coding snps, version 6.1;30,31 (8) align-grantham variation grantham deviation used with the supplied brca1 and brca2 alignments;32,33 (9) snap;34,35 (10) predictor of human deleterious single nucleotide polymorphisms;36 (11) protein variation effect analyzer, version 1.1.3, and sorting intolerant from tolerant;37–39 (12) sorting intolerant from tolerant blink,40,41 and (13) mutation taster.42,43 predicting the pathogenic potential of brca1 and brca2 gene variants identified in clinical genetic testing e222 | squ medical journal, may 2015, volume 15, issue 2 ta bl e 3: o nl in e in si lic o pr ed ic ti on s* r eg ar di ng th e pa th og en ic it y of b r c a g en e m is se ns e m ut at io ns v ar ia nt p ol yp he n 2 h um d iv p ol yp he n 2 h um v ar m ut a ss im ut an t m ut p re d sn p s& g o pa n t h e r a li gn g v g d sn a p p hd sn p si f t p r o v e a n m ut t as sc or e sc or e fi s co re r i sc or e r i su bs pe c c la ss r i, a cc ur ac y r i se qr ep sc or e pr ob ab ili ty b r c a 1 c. 14 0g >a po ss ib ly 0. 67 7 b en ig n 0. 22 3 h ig h 4. 02 5 d 2 d 0. 98 9 d 10 -4 .6 20 3 c 65 n on -n 6, 9 3% d 7 n ot to le ra te d 0. 23 n -1 .5 88 d is ea se 0. 97 5 c. 10 67 a >g pr ob ab ly 0. 99 8 pr ob ab ly 0. 98 8 h ig h 3. 63 5 n 6 n 0. 23 2 d 7 -1 .9 15 24 c 0 n on -n 3, 7 8% d 4 n ot to le ra te d 0. 98 d 3. 30 2 po ly 0. 99 9 c. 20 77 g >a b en ig n 0. 00 0 b en ig n 0. 01 0 n eu tr al 0. 55 n 5 n 0. 13 5 d 3 -1 .6 36 02 c 0 n on -n 2, 7 0% n 6 n ot to le ra te d 1. 00 n 0. 03 2 po ly 0. 99 9 c. 23 15 t >c po ss ib ly 0. 84 8 pr ob ab ly 0. 92 8 m ed iu m 2. 63 n 4 d 0. 84 7 d 8 -2 .2 58 07 c 0 n on -n 4, 8 2% d 3 n ot to le ra te d 1. 00 d 3. 61 2 po ly 0. 99 9 c. 26 12 c >t b en ig n 0. 00 0 b en ig n 0. 00 0 n eu tr al -3 .3 95 n 4 n 0. 23 2 n 6 -2 .7 18 72 c 0 n 0, 5 3% n 8 to le ra te d 1. 00 n 5. 74 2 po ly 0. 99 6 c. 31 13 a >g po ss ib ly 0. 93 6 po ss ib ly 0. 60 6 m ed iu m 2. 54 n 3 n 0. 19 2 d 2 -2 .4 87 8 c 0 n on -n 4, 8 2% n 3 n ot to le ra te d 0. 98 d -5 .6 87 po ly 0. 99 9 c. 31 19 g >a pr ob ab ly 0. 97 4 po ss ib ly 0. 83 1 m ed iu m 2. 78 5 n 6 n 0. 12 3 d 7 -3 .4 63 89 c 0 n on -n 4, 8 2% n 3 to le ra te d 0. 98 n -1 .6 83 po ly 0. 99 9 c. 35 48 a >g b en ig n 0. 00 0 b en ig n 0. 00 1 n eu tr al -1 .0 85 n 8 n 0. 09 6 n 6 -0 .8 26 66 c 0 n 4, 8 5% n 7 to le ra te d 1. 00 n 0. 39 8 po ly 1 c. 48 37 a >g b en ig n 0. 25 5 b en ig n 0. 03 8 lo w 1. 04 n 5 n 0. 12 7 d 2 -1 .5 78 16 c 0 n on -n 2, 7 0% n 6 n ot to le ra te d 0. 26 n -0 .5 09 po ly 0. 99 9 b r c a 2 c. 86 5a >c b en ig n 0. 27 8 b en ig n 0. 03 4 lo w 1. 44 5 n 0 n 0. 19 4 d 10 er ro r c 0 n on -n 4, 8 2% n 4 to le ra te d 0. 37 n -0 .5 09 po ly 0. 99 9 c. 11 14 a >c c al le d as h a t 3 72 h re si du e n 4 n 0. 05 8 er ro r er ro r er ro r n on -n 0, 5 8% n 9 to le ra te d 0. 33 n -0 .5 99 po ly 0. 99 9 c. 29 71 a >g b en ig n 0. 00 0 b en ig n 0. 00 0 n eu tr al -1 .1 5 n 0 n 0. 32 5 d 7 -0 .4 52 25 c 0 n 3, 7 8% n 9 to le ra te d 0. 99 n 2. 12 7 po ly 0. 99 9 c. 81 49 g >t po ss ib ly 0. 95 5 po ss ib ly 0. 76 3 m ed iu m 1. 96 5 d 1 d 0. 78 3 d 9 -2 .3 92 9 c 0 n 1, 6 0% n 8 to le ra te d 0. 37 n -0 .4 41 po ly 0. 96 1 po ly ph en 2 = po ly m or ph ism p he no ty pi ng , v er sio n 2, p re di ct io n an d sc or e s ho w n; 20 ,2 1 m ut a ss = m ut at io n a ss es so r, re le as e 2 , p re di ct ed f i ( hi gh o r m ed iu m ) o r n on -f i ( lo w o r n eu tr al ) a nd co m bi ne d sc or e i s s ho w n; 22 ,2 3 i -m ut an t = v er sio n 3. 0, p re di ct io n of d is ea se -a ss oc ia te d sin gl e p oi nt m ut at io n fr om p ro te in se qu en ce a nd r i s ho w n; 24 ,2 5 m ut pr ed = v er sio n 1. 2, p re di ct io n of a n am in o ac id su bs tit ut io n as d o r n a nd sc or e s ho w n; 26 ,2 7 s n ps & g o = p re di ct io n of h um an d is ea se re la te d m ut at io ns in p ro te in s w ith fu nc tio na l a nn ot at io ns , p re di ct ed e ffe ct a nd r i s co re fr om 0 (u nr el ia bl e) to 1 0 (r el ia bl e) sh ow n; 28 ,2 9 p a n t h er = p ro te in a na ly sis th ro ug h ev ol ut io na ry r el at io ns hi ps , v er sio n 6. 1, e vo lu tio na ry a na ly sis o f co di ng si ng le n uc le ot id e p ol ym or ph ism s, su bs pe c sc or es o f c on tin uo us v al ue s f ro m 0 (n eu tr al ) t o -1 0 (m os t l ik el y to b e d el et er io us ) s ho w n* *;3 0, 31 a lig ng v g d = a lig ng ra nt ha m v ar ia tio n g ra nt ha m d ev ia tio n, u sin g s up pl ie d al ig nm en ts , cl as s s ho w n (c la ss c 65 m os t l ik el y an d c 0 le ss li ke ly ;32 ,3 3 s n a p = pr ed ic tio n of e ffe ct o f n on -s yn on ym ou s p ol ym or ph ism s o n fu nc tio n, r i a nd e xp ec te d ac cu ra cy sh ow n; 34 ,3 5 p hd -s n p = pr ed ic to r o f h um an d el et er io us s in gl e n uc le ot id e po ly m or ph ism s, pr ed ic tio n an d ri sh ow n; 36 s if t = s or tin g i nt ol er an t f ro m t ol er an t b li nk , t ol er at ed o r n ot to le ra te d pr ed ic tio n an d se qr ep sc or e s ho w n; 40 ,4 1 p ro v ea n = p ro te in v ar ia tio n eff ec t a na ly ze r, v er sio n 1. 1. 3, u sin g t he h um an pr ot ei n ba tc h to ol , p re di ct io n an d sc or e ( sc or e o f ≤ -2 .5 si gn ifi ed a “d el et er io us ” e ffe ct a nd sc or e o f > -2 .5 si gn ifi ed a “n eu tr al ” e ffe ct ) s ho w n; 37 –3 9 m ut ta st = m ut at io n ta st er , p re di ct io n an d pr ob ab ili ty (u sin g p v al ue s, w ith a v al ue cl os e t o 1 in di ca tin g t he h ig h se cu ri ty o f t he p re di ct io n; th e p v al ue u se d he re is n ot th e p ro ba bi lit y of e rr or a s u se d in tte st st at is tic s) sh ow n; 42 ,4 3 f i = fu nc tio na l i m pa ct ; r i = re lia bi lit y in de x; s eq re p = fra ct io n of se qu en ce s t ha t c on ta in o ne o f t he b as ic am in o ac id s, w he re a lo w fr ac tio n in di ca te s t he p os iti on is e ith er se ve re ly g ap pe d or u na lig na bl e a nd h as li ttl e i nf or m at io n, a p oo r p re di ct io n is e xp ec te d at th es e p os iti on s; d = d is ea se -a ss oc ia te d; n = n eu tr al ; p ol y = po ly m or ph ism ; h = hi st id in e. *a ll pr og ra m m es w er e u se d in d ef au lt on lin e m od e. ** a sc or e o f 3 is th e p re vi ou sly id en tifi ed cu to ff po in t f or fu nc tio na l s ig ni fic an ce . clare brookes, stella lai, elaine doherty and donald r. love clinical and basic research | e223 discussion the results presented here illustrate a major problem in interpreting missense brca1/2 gene variants. the classifications from various databases and the predictions from a variety of online in silico analysis programmes can vary widely. this highlights the risk of relying on information obtained from just one database or from using only a few in silico programmes when reporting missense variants, as the outcome can affect clinical surveillance and prevention decisions. of the 13 missense brca gene mutations identified, only one was shown to be probably pathogenic, although the same variant was predicted to be benign by the polyphen-2 humvar database and provean.20,37 lindor et al. classified nine of the variants in their study as iarc class 1 (not pathogenic).8 their reclassification uses a model based on prior probabilities derived from evolutionary predictions combined with a likelihood component from segregation information, co-occurrence in ‘trans’, personal and family history and a histopathology profile to give a posterior probability of causality. the outcome of this analysis is based on combining a wide range of information, which is clearly different from the predictions made from individual databases and single in silico programmes, and again highlights the importance of an over-reliance on one source of information to determine the disease causality of a variant. the clinical molecular genetics society (cmgs) in the uk states in their 2007 guidelines for interpreting and reporting uvs that it is unacceptable to rely solely on in silico predictions to assign pathogenicity to a previously unclassified variant.44 furthermore, the association for clinical genetic science states in their 2013 practice guidelines for the reporting of sequence variants in clinical molecular genetics that “the classification generated from the prediction tools must not be considered definitive”.45 the american college of medical genetics (acmg) guidelines state that all variants of unknown clinical significance must be included in a laboratory’s report and be followed by an interpretation of their likely clinical significance.46 acmg recommend categorising uncertain sequence variants as either “previously unreported and of the type which may or may not be causative of the disorder” or “previously unreported and probably not causative of disease”.46 the cmgs 2007 guidelines also state that it is “essential to report all uvs where the clinical significance is uncertain” and furthermore that it is “essential that reports of uvs should be issued to appropriately trained clinicians”.44 the european molecular genetics quality network’s best practice guidelines for genetic analysis in hereditary breast ovarian cancer recommend that the identification of brca gene vus do not “provide a basis for changing the clinical management of the patient or for offering predictive testing to at risk relatives”.6 the protocol which the authors have established for interpreting brca gene missense variants includes: (1) checking the breast cancer information core (bic)and iarc databases;8,16 (2) checking the dbsnp for classification and minor allele frequency;19 (3) undertaking splice site predictions using the online splice site prediction by neural network and assp tools,11,13 and (4) undertaking in silico protein analysis using the grantham score polyphen sift blink, snps&go and provean.2,20,28,32,40 in the event that a database search is conflicting, or there is no entry, the authors recommend that dbsnp and splice site/in silico protein analysis programmes are also used. apart from the bic and iarc databases, other databases are not as comprehensive, or provide little value in assigning benign/disease-causing status to a missense variant. the in silico programmes use a variety of approaches to achieve a prediction: sequence and table 4: percentage of brca1 and brca2 gene missense variants predicted to be pathogenic using online in silico analysis programmes programme % predicted to be pathogenic snps&go 83 snap 69 polyphen humdiv 50 sift 46 polyphen humvar 42 mutpred 23 phd-snp 23 provean 23 panther 18 mutass 17 i-mutant 15 align-gvgd 8 muttas 8 snp&go = predicts human disease-related mutations in proteins with functional annotations;28,29 snap = predicts effect of non-synonymous polymorphisms on function;34,35 polyphen = polymorphism phenotyping, version 2;20,21 sift = sorting intolerant from tolerant blink;40,41 mutpred = version 1.2, classifies an amino acid substitution as disease-associated or neutral;26,27 phd-snp = predictor of human deleterious single nucleotide polymorphisms;36 provean = protein variation effect analyzer, version 1.1.3;37–39 panther = protein analysis through evolutionary relationships, version 6.1;30,31 mutass = mutation assessor programme, release 2;22,23 i-mutant = version 3.0;24,25 align-gvgd = align-grantham variation grantham deviation;32,33 muttast = mutation taster.42,43 predicting the pathogenic potential of brca1 and brca2 gene variants identified in clinical genetic testing e224 | squ medical journal, may 2015, volume 15, issue 2 evolutionary conservation-based methods, protein sequence and structure-based methods and machine learning methods. the data from this study support using a number of programmes to achieve a consensus prediction rather than relying on only one programme. the authors suggest that, when results are uncertain, a report of the cascade approach used should be recorded and a detailed work-up should be archived for the clinician to refer to if necessary. the authors recommend that their conclusions are reviewed by clinicians to determine their continuing validity. the predictions have varying levels of confidence, but are considered as an aid to clinical interpretation, although the work described here shows that the value of these predictions may be largely ambivalent at best, or misleading at worst. the authors recommend that the testing of additional family members and a correlation with clinical findings would be helpful to determine the significance of the result. this recommendation for segregation analysis is not entirely fool-proof, especially in light of the predominance of breast cancer in families with brca1/2 gene mutations, and that cancer risk may involve an appreciation of familial context rather than a population-based calculation.47 critically, the authors suggest only accepting referrals from trained genetic counsellors or clinicians with a sufficient understanding of interpreting complicated genetic results. in the event of brca gene missense mutations that are reliably benign (stated as such in bic/iarc databases or when all in silico predictions agree), then these should be relegated to an ancillary table in the report with a footnote indicating how the benign status was determined. this study highlights the complexity of interpreting and reporting missense brca1/2 gene variants where the results will be used in genetic counselling, screening and disease prevention. it demonstrates that some brca gene missense variants cannot be clearly interpreted with the tools and data available today; however, these variants must be included in laboratory reports so that if future information becomes available regarding their classification then this can be passed on to the patient and their family. this future information could be provided by international developments under the auspices of the enhancing neuro imaging genetics through meta analysis consortium which is involved in coordinating the development of algorithms for the classification of variants in the brca1/2 genes.48 recent work reported by this consortium has embraced functional assays of brca2 gene variants and has attempted to translate functional outcomes into a probability of pathogenicity.49 conclusion the findings of this study show that there is significant discordance in the classification of some missense variants in the brca genes when using online mutation databases and carrying out in silico analyses. this discordance leads to complexities in interpreting and reporting these variants in a clinical context. as such, it is vital that laboratories have agreed guidelines for determining the pathogenicity of a given variant based on a wide range of information and for reporting an uncertain result to the referring clinician. importantly, the complexity of interpreting and communicating vus findings highlights the importance of sequencing results being conveyed to patients in a specialist genetic counselling environment. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. vallée mp, francy tc, judkins mk, babikyan d, lesueur f, gammon a, et al. classification of missense substitutions in the brca genes: a database dedicated to ex-uvs. hum mutat 2012; 33:22–8. doi: 10.1002/humu.21629. 2. saam j, burbidge la, bowles k, roa b, pruss d, schaller j, et al. decline in rate of brca1/2 variants of uncertain significance: 2002-2008. poster. 27th annual education conference of the national society of genetic counselors, los angeles, usa, 24–28 oct 2008. 3. culver jo, brinkerhoff cd, clague j, yang k, singh ke, sand sr, et al. variants of uncertain significance in brca testing: evaluation of surgical decisions, risk perception, and cancer distress. clin genet 2013; 84:464–72. doi: 10.1111/cge.12097. 4. lindor nm, goldgar de, tavtigian sv, plon se, couch fj. brca1/2 sequence variants of uncertain significance: a primer for providers to assist in discussions and in medical management. oncologist 2013; 18:518–24. doi: 10.1634/ theoncologist.2012-0452. 5. iversen es jr, couch fj, goldgar de, tavtigian sv, monteiro an. a computational method to classify variants of uncertain significance using functional assay data with application to brca1. cancer epidemiol biomarkers prev 2011; 20:1078–88. doi: 10.1158/1055-9965. 6. larsson n, borg å, hodgson s, sinilnikova o, loman n, mcdevitt t, et al. emqn best practice guidelines for molecular genetic analysis in hereditary breast/ovarian cancer, 2008. from: www. emqn.org/emqn/best+practice accessed: oct 2013. 7. easton df, deffenbaugh am, pruss d, frye c, wenstrup rj, allen-brady k, et al. a systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the brca1 and brca2 breast cancer-predisposition genes. am j hum genet 2007; 81:873–83. doi: 10.1086/521032. 8. lindor nm, guidugli l, wang x, vallée mp, monteiro an, tavtigian s, et al. a review of multifactorial probability-based model for classification of brca1 and brca2 variants of uncertain significance (vus). hum mutat 2012; 33:8–21. doi: 10.1002/humu.21627. 9. lai s, brookes c, prosser do, lan cc, doherty e, love dr. diagnostic screening for mutations in the brca1 and brca2 genes. sultan qaboos univ med j 2015; 15:58‒66. clare brookes, stella lai, elaine doherty and donald r. love clinical and basic research | e225 10. doherty e, marquis-nicholson r, brookes c, love jm, prosser d, love dr. from primer design to sequence analysis: a pipeline tool for use in a diagnostic genetics laboratory. in: ivanov o, ed. applications and experiences of quality control. rijeke, bosnia and herzegorvina: intech, 2011. pp. 257–72. doi: 10.5772/612. 11. berkeley drosophilia genome project. splice site prediction by neural network online tool. from: www.fruitfly.org/seq_tools/ splice.html accessed: oct 2013. 12. reese mg, eeckman fh, kulp d, haussler d. improved splice site detection in genie. j comput biol 1997; 4:311–23. doi: 10.1089/ cmb.1997.4.311. 13. wang computing. alternative splice site predictor (assp). from: www.wangcomputing.com/assp/index.html accessed: oct 2013. 14. wang m, marín a. characterization and prediction of alternative splice sites. gene 2006; 366:219–27. 15. biobase biological databases. human gene mutation database (hgmd), professional 2013.3 database. from: www.biobaseinternational.com/product/hgmd accessed: october 2013. 16. national human genome research institute. breast cancer information core (bic). from: research.nhgri.nih.gov/bic/ accessed: oct 2013. 17. aix merseille university, inserm. the universal mutation database (umd). from: www.umd.be/ accessed: oct 2013. 18. leiden open variation database (lovd). from: chromium.liacs. nl/lovd2/cancer/home.php accessed: oct 2013. 19. national center for biotechnology information. single nucleotide polymorphism database (dbsnp). from: www.ncbi.nlm.nih.gov/ projects/snp/ accessed: oct 2013. 20. department of genetics, harvard university, brigham & women’s hospital. polymorphism phenotyping v2.2.2 (polyphen-2) humvar database. from: genetics.bwh.harvard.edu/pph2/ accessed: oct 2013. 21. adzhubei ia, schmidt s, peshkin l, ramensky ve, gerasimova a, bork p, et al. a method and server for predicting damaging missense mutations. nat methods 2010; 7:248–9. doi: 10.1038/ nmeth0410-248. 22. computational biology, memorial sloan kettering cancer center. mutation assessor, release 2. from: www.mutationassessor.org accessed: oct 2013. 23. reva b, antipin y, sander c. predicting the functional impact of protein mutations: application to cancer genomics. nucleic acids res 2011; 39:e118. doi: 10.1093/nar/gkr407. 24. biocomputing group, university of bologna. i-mutant suite, i-mutant 3.0. from: gpcr2.biocomp.unibo.it/cgi/predictors/imutant3.0/i-mutant3.0.cgi accessed: oct 2013. 25. capriotti e, fariselli p, casadio r. i-mutant 2.0: predicting stability changes upon mutation from the protein sequence or structure. nucleic acids res 2005; 33:w306–10. doi: 10.1093/nar/gki375. 26. mooney laboratory, buck institute, indiana university. mutpred v1.2. from: mutpred.mutdb.org accessed: oct 2013. 27. li b, krishnan vg, mort me, xin f, kamati kk, cooper dn, et al. automated inference of molecular mechanisms of disease from amino acid substitutions. bioinformatics 2009; 25:2744–50. doi: 10.1093/bioinformatics/btp528. 28. biocomputing group, university of bologna. snps&go. from: snps-and-go.biocomp.unibo.it/snps-and-go/ accessed: oct 2013. 29. calabrese r, capriotti e, fariselli p, martelli pl, casadio r. functional annotations improve the predictive score of human disease-related mutations in proteins. hum mutat 2009; 30:1237– 44. doi: 10.1002/humu.21047. 30. mooney laboratory, buck institute, indiana university. protein analysis through evolutionary relationships (panther) v6.1. from: www.pantherdb.org/tools/csnpscoreform.jsp accessed: oct 2013. 31. thomas pd, campbell mj, kejariwal a, mi h, karlak b, daverman r, et al. panther: a library of protein families and subfamilies indexed by function. genome res 2003; 13:2129–41. doi: 10.1101/ gr.772403. 32. international agency for research on cancer. align-grantham variation grantham deviation (agvgd). from: www.agvgd.iarc. fr/about.php accessed: oct 2013. 33. tavtigian sv, deffenbaugh am, yin l, judkins t, scholl t, samollow pb, et al. comprehensive statistical study of 452 brca1 missense substitutions with classification of eight recurrent substitutions as neutral. j med genet 2006; 43:295–305. doi: 10.1136/jmg.2005.033878. 34. rost lab, columbia university. screening for non-acceptable polymorphisms (snap). from: www.rostlab.org/services/snap/ accessed: oct 2013. 35. bromberg y, rost b. snap: predict effect of non-synonymous polymorphisms on function. nucleic acids res 2007; 35:3823–35. doi: 10.1093/nar/gkm238. 36. biofold unit, university of alabama at birmingham. predictor of human deleterious single nucleotide polymorphisms (phd-snp). from: snps.biofold.org/phd-snp/phd-snp.html accessed: oct 2013. 37. j. craig venter institute. protein variation effect analyzer (provean) database. from: provean.jcvi.org accessed: oct 2013. 38. choi y, sims ge, murphy s, miller jr, chan ap. predicting the functional effect of amino acid substitutions and indels. plos one 2012; 7:e46688. doi: 10.1371/journal.pone.0046688. 39. j. craig venter institute. sorting intolerant from tolerant (sift). from: sift.jcvi.org/ accessed oct 2013. 40. j. craig venter institute. sorting intolerant from tolerant (sift) blink. from: sift.jcvi.org/www/sift_blink_submit.html accessed: oct 2013. 41. ng pc, henikoff s. predicting deleterious amino acid substitutions. genome res 2001; 11:863–74. doi: 10.1101/gr.176601. 42. charité–universitätsmedizin berlin. mutation taster. from: www.mutationtaster.org/ accessed: oct 2013. 43. schwarz jm, rödelsperger c, schuelke m, seelow d. mutationtaster evaluates disease-causing potential of sequence alterations. nat methods 2010; 7:575–6. doi: 10.1038/nmeth0810-575. 44. bell j, bodmer d, sistermans e, ramsden sc. practice guidelines for the interpretation and reporting of unclassified variants (uvs) in clinical molecular genetics. from: cmgsweb.shared. hosting .zen.co.uk/bp gs/p dfs%20cur rent%20bpgs/u v%20 guidelines%20ratified.pdf accessed: oct 2013. 45. wallis y, payne s, mcanulty c, bodmer d, sistermans e, robertson k, et al. practice guidelines for the evaluation of pathogenicity and the reporting of sequence variants in clinical molecular genetics. from: www.acgs.uk.com/media/774853/ e v a l u at i o n _ a n d _ r e p o r t i n g _ o f _ s e q u e n ce _ v a r i a nt s _ b p g s _ june_2013_-_finalpdf.pdf accessed: oct 2013. 46. richards cs, bale s, bellissimo db, das s, grody ww, hegde mr, et al. acmg recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. genet med 2008; 10:294–300. doi: 10.1097/gim.0b013e31816b5cae. 47. evans dg, shenton a, woodward e, lalloo f, howell a, maher er. penetrance estimates for brca1 and brca2 based on genetic testing in a clinical cancer genetics service setting: risks of breast/ ovarian cancer quoted should reflect the cancer burden in the family. bmc cancer 2008; 8:155. doi: 10.1186/1471-2407-8-155. 48. spurdle ab, healey s, devereau a, hogervorst fb, monteiro an, nathanson kl, et al. enigma—evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in brca1 and brca2 genes. hum mutat 2012; 33:2–7. doi: 10.1002/humu.21628. 49. guidugli l, carreira a, caputo sm, ehlen a, galli a, monteiro an, et al. functional assays for analysis of variants of uncertain significance in brca2. hum mutat 2014; 35:151–64. doi: 10.1002/ humu.22478. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e78–84, epub. 21 jan 15 submitted 23 apr 14 revision req. 24 jun 14; revision recd. 25 aug 14 accepted 25 sep 14 1department of family medicine, king fahd university hospital, al khobar, saudi arabia; departments of 2family & community medicine and 3psychiatry, college of medicine, dammam university, dammam, saudi arabia *corresponding author e-mail: dr.esraa_almaddah@yahoo.com معدل انتشار احلرمان من النوم وعالقته باالكتئاب لدى األطباء املقيمني العاملني يف مستشفى امللك فهد اجلامعي يف مدينة اخلرب باململكة العربية السعودية اإ�رضاء حممد املداح، بدرية خالد الدبل، حممد �ضلح خليل abstract: objectives: sleep deprivation is common among medical residents of all specialties. this study aimed to determine the prevalence of sleep deprivation and depressive symptoms among medical residents in king fahd university hospital (kfuh) in al khobar, saudi arabia. furthermore, the association between sleep deprivation, sleepiness and depressive symptoms was examined. methods: this cross-sectional study took place between february and april 2012 and involved 171 kfuh medical residents of different specialties. data were collected using a specifically designed questionnaire eliciting demographic information, working hours and number of hours of sleep. in addition, validated arabic versions of the epworth sleepiness scale and the beck depression inventory-2 (bdi-2) were used. results: the prevalence of acute sleep deprivation and chronic sleep deprivation among residents in kfuh was 85.9% and 63.2%, respectively. the prevalence of overall sleepiness was 52%; 43.3% reported being excessively sleepy in certain situations while 8.8% reported being excessively sleepy regardless of the situation. based on the bdi-2, the prevalence of mild, moderate and severe depressive symptoms was 43.3%, 15.2% and 4.7%, respectively. significant associations were found between sleep deprivation and depressive symptoms; depressive symptoms and sleepiness, and depressive symptoms and being a female resident. conclusion: the vast majority of medical residents had acute sleep deprivation, with more than half suffering from chronic sleep deprivation. the number of hours and quality of sleep among the residents were strongly associated with depressive symptoms. new regulations are recommended regarding the number of working hours and night duties for medical residents. further studies should assess these new regulations on a regular basis. keywords: sleep deprivation; depression; drowsiness; physicians; saudi arabia. امللخ�ص: الهدف: ي�ضود احلرمان من النوم بني االأطباء املقيمني العاملني يف جميع التخ�ض�ضات الطبية، لذا هدفت هذه الدرا�ضة اإىل حتديد مدى انت�ضار احلرمان من النوم واأعرا�س االكتئاب لدى االأطباء املقيمني العاملني يف م�ضت�ضفى امللك فهد اجلامعي يف مدينة اخلرب باململكة العربية ال�ضعودية. ومت كذلك فح�س العلقة بني احلرمان من النوم والنعا�س واأعرا�س االكتئاب. الطريقة: اأجريت هذه الدرا�ضة املقطعية يف الفرتة ما بني فرباير واأبريل 2012، و�ضملت املعلومات ال�ضتنباط الدرا�ضة لهذه خ�ضي�ضا �ضمم ا�ضتبيان با�ضتخدام البيانات جمع مت وقد الطبية. التخ�ض�ضات خمتلف يف املقيمني االأطباء من 171 العامة، وعدد �ضاعات النوم والعمل، كما ا�ضتخدمت االأ�ضئلة يف مقيا�ضي اإبوورث للنعا�س وبيك للجرد واالكتئاب بعد توثيق م�ضد اقيتهما يف ن�ضختهما العربية. النتائج: كان معدل انت�ضار احلرمان من النوم احلاد واملزمن لدى االأطباء املقيمني العاملني يف م�ضت�ضفى امللك فهد اجلامعي يعادل %85.9 و %63.2 على التوايل. وكان انت�ضار النعا�س ب�ضكل عام مبعدل %52؛ %43.3 منهم يعانون من النعا�س يف حاالت معينة بينما %8.8 منهم يعانون من النعا�س ب�ضكل مفرط بغ�س النظر عن الو�ضع. و بناء على مقيا�س بيك للجرد واالكتئاب املوثق امل�ضد اقية كان معدل انت�ضار اأعرا�س االكتئاب الب�ضيط واالكتئاب املعتدل واالكتئاب ال�ضديد بن�ضب %43.3 و %15.2 و %4.7 على التوايل. وكان هناك ارتباط ذا داللة اإح�ضائية بني احلرمان من النوم واأعرا�س االكتئاب، وبني اأعرا�س االكتئاب والنعا�س، وبني اأعرا�س االكتئاب عند الطبيبات املقيمات. اخلال�صة: تعاين الغالبية العظمى من االأطباء املقيمني من احلرمان من النوم احلاد، ويعاين اأكرث من ن�ضفهم من احلرمان من النوم املزمن. و يرتبط عدد �ضاعات النوم ونوعيته بقوة مع اأعرا�س االكتئاب. نو�ضي بتوفري اأنظمة جديدة فيما يتعلق بعدد �ضاعات العمل واملناوبات الليلية للأطباء املقيمني. كما يجب اإجراء مزيد من الدرا�ضات لتقييم هذه االأنظمة ب�ضكل دوري. مفتاح الكلمات: احلرمان من النوم؛ االكتئاب؛ النعا�س؛ االأطباء؛ اململكة العربية ال�ضعودية. prevalence of sleep deprivation and relation with depressive symptoms among medical residents in king fahd university hospital, saudi arabia *esraa m. al-maddah,1 badria k. al-dabal,2 mohammad s. khalil3 advances in knowledge to the best of the authors’ knowledge, no study has yet been carried out in saudi arabia to examine the prevalence of sleep deprivation and its relation to depression among medical residents. the results of this study suggest that there is a strong association between depressive symptoms and acute sleep deprivation, working hours, sleepiness and gender among medical residents in a university hospital in saudi arabia. application to patient care sleep deprivation among medical residents may affect the quality of their patient care. this study may improve awareness of sleep deprivation and depression in residents and contribute to new guidelines concerning the number of working hours and night duties assigned to residents. clinical & basic research esraa m. al-maddah, badria k. al-dabal and mohammad s. khalil clinical and basic research | e79 the amount of sleep obtained bymedical residents can have a significant impact on their work performance and, in turn, the safety of the patients they are interacting with. it is well known that residency training is very stressful, particularly as a result of the long working hours and heavy work load; these challenges often lead to sleep deprivation and limited personal time for residents.1,2 these conditions may be related to a high incidence of depression and anxiety among interns and residents.3,4 sleep deprivation occurs when an individual has had insufficient sleep to function adequately in terms of their alertness, performance and health.5 the two main types of sleep deprivation are known as acute and chronic sleep deprivation. an individual will experience acute sleep deprivation if they have not slept over a period of one or two days while chronic sleep deprivation occurs as a result of sleeping less than 5–6 hours for several consecutive nights.5,6 medical residents may experience acute sleep loss during night shifts when they are on-call. in addition, they may also experience chronic sleep loss as a long-term effect of regular night shifts. many studies have demonstrated the negative effects of acute and chronic sleep deprivation on the health of an individual.7,8 in addition, previous research has examined the association between sleep deprivation and depression among physicians. one such study found that chronic sleep deprivation increased the incidence of moderate depression by seven-fold.9 balch et al. studied the relationship between working hours, night duties and surgeon distress. they found that depression was significantly associated with long working hours as well as an increased number of nights on-call.10 to the best of the authors’ knowledge, no studies have yet been carried out in saudi arabia to examine the prevalence of sleep deprivation and its relation to depression among residents. therefore, the objective of this study was to determine the extent of sleep deprivation and depressive symptoms among medical residents of all specialties in king fahd university hospital (kfuh) in al khobar, saudi arabia. furthermore, the association between sleep deprivation, sleepiness and depressive symptoms was examined. methods this cross-sectional study was conducted from february to april 2012 among residents at kfuh in al khobar, saudi arabia. medical residents of both genders working in all specialties and with night duties were included in the study population (n = 185). both saudi and non-saudi participants were included. residents who participated in the pilot study, those who did not respond and those who failed to complete the entire questionnaire were excluded from the study. three instruments were used to collect data from the participants, including a specifically designed questionnaire and validated versions of the epworth sleepiness scale (ess) and the beck depression inventory-2 (bdi-2).11,12 the first questionnaire was designed for the study and was composed of two sections. the first section collected demographic data including age, gender, nationality, marital status, number of family members/ children, pregnancy/nursing status for females, place of residence, living situation, income, specialty, level of residency and years of experience. the second section aimed to measure sleep deprivation, specifically the resident’s number of sleeping hours over their last night duty and in the previous seven days, number of working hours over one night duty and per week and the overall number of night duties per month. following this, an arabic version of the ess was used.13 this self-administered eight-item questionnaire was translated by riachy et al. from the original english version.11,13 the ess has been shown to have good internal consistency with a cronbach’s alpha value of 0.762.14 an overall score of 10 or more from the eight individual scores reflects above average daytime sleepiness and a need for further evaluation.11 the third instrument used was the bdi-2, a 21-item self-reported test translated into arabic by ghareeb in 2000.12,15 alpha values for this instrument range from 0.82–0.93, indicating high reliability and internal consistency.16 a total score of 0–9 is considered to indicate minimal depression, while 10–19, 20–29 and 30–63 indicate mild, moderate and severe depression, respectively.15 a pilot study utilising the above instruments was carried out on 21 medical residents who were working in king fahd medical military city and specialising in either obstetrics and gynaecology, family medicine or surgery. three participants faced some difficulties in understanding a number of the sentences in the arabic bdi-2 and therefore did not complete it. the overall response to the two scales (the arabic versions of the bdi-2 and ess) was that there was some ambiguity in the questions and participants had difficulties scoring themselves in the case of the arabic bdi-2. some alterations were made to both scales under the supervision of two consultants (one family physician and one psychologist) to resolve any ambiguity and clarify each question. the entire questionnaire (including the main questionnaire and the arabic versions of the bdi-2 and epss) was then tested again prevalence of sleep deprivation and relation with depressive symptoms among medical residents in king fahd university hospital, saudi arabia e80 | squ medical journal, february 2015, volume 15, issue 1 on 30 participants with a positive response. after data collection, all variables were processed using the statistical package for the social sciences (spss), version 16.0 (ibm corp., chicago, illinois, usa). a p value of ≤0.05 was considered statis tically significant. ethical approval for this study was obtained from the medical director of kfuh. verbal consent was taken from the participants after the purpose of the study was explained and confidentiality of the data was assured. results out of the 185 residents in the study population, 171 completed the questionnaire in its entirety, giving a response rate of 92.4%. approximately 80% of the residents were between 25–30 years old while 16% were between 30 and 35. a total of 58% of the participants were female. the vast majority of the residents were saudi arabian (85%). more than half of the residents were married and less than 3% were divorced or separated. the majority of the residents (64%) were working in non-surgical specialties and 23% were working in family medicine. the residents were well distributed in terms of the different residency levels, with the exception of fifth-year (5%) and sixth-year residents (0%). more than 8% of the residents were service residents, i.e. residents who were working in a certain speciality department but were not part of the residency program for that speciality. about half of the participants had less than three years of experience and approximately 10% had more than five years of experience. table 1 shows the prevalence of sleep deprivation as indicated by direct indices (sleeping hours per night duty and sleeping hours per week). a total of 147 respondents (85.9%) reported that they had slept for less than six hours during their last night duty and thus were considered to be acutely sleep-deprived. moreover, 63.2% of the residents were considered to be chronically sleep-deprived as they had slept for less than 42 hours in the previous seven days. table 1 also shows the association between depressive symptoms and the direct indices of sleep deprivation. the association between acute sleep deprivation and depressive symptoms among residents was statistically significant (p = 0.009), with 45.9% of acutely sleep deprived residents showing mild depressive symptoms and 21.2% reporting moderate to severe depressive symptoms. there were no significant associations between chronic sleep deprivation and depressive symptoms among residents (p = 0.115). table 2 shows the prevalence of sleep deprivation as indicated by indirect indices (working hours per week and the number of night duties per month). the lowest frequency was represented by residents working 8–18 hours (<3%) in one night shift, while the highest frequency was for those who worked 19–24 hours (≥40%). residents who worked 40–76 hours a week were slightly more common than those who worked 77–90 hours. approximately half of the residents had more than five night duties a month while only 9.4% had less than three night shifts. furthermore, the association between the number of working hours per night duty and depressive symptoms was statistically significant (p = 0.003). as shown in table 2, 54.8% of residents who worked more than 24 hours per onenight duty had mild depressive symptoms while 20.2% of those working more than 24 hours had moderate to severe symptoms. depressive symptoms in residents were also shown to be significantly associated with the number of working hours per week (p = 0.047). of the 74 residents who worked more than 76 hours per week, 28.4% reported symptoms of moderate to severe depression compared to 13.4% of those who worked less than 77 hours. no significant association was found between the number of night duties per month and depressive symptoms among residents (p = 0.780). the reported prevalence of sleepiness among the studied kfuh residents is depicted in figure 1. a total of 89 residents (52%) experienced sleepiness; of those, 43.3% experienced excessive sleepiness in specific circumstances for which they might consider seeking medical attention, while 8.8% reported continuous excessive sleepiness requiring medical attention. figure 2 shows the prevalence of depressive symptoms among the cohort. according to their responses to the table 1: prevalence of sleep deprivation measured by direct indices and the association with depression among surveyed medical residents at king fahd university hospital (n = 171) direct index n (%) percentage of residents p value no depression depression† sleeping hours per night duty <6‡ 147 (85.9) 32.9 67.1 0.009* >6 24 (14) 60 40 sleeping hours in the previous 7 days <42§ 108 (63.2) 32.4 67.6 0.115 >42 63 (36.8) 44.4 55.6 †depression was scored using a validated arabic version of the beck depression inventory-2.13,16 *statistically significant. ‡indicating acute sleep deprivation. §indicating chronic sleep deprivation. esraa m. al-maddah, badria k. al-dabal and mohammad s. khalil clinical and basic research | e81 bdi-2 instrument, 108 residents (63%) had depressive symptoms. the majority of those (43.3%) had mild symptoms, while 15.2% reported moderate symptoms and symptoms of severe depression. moreover, 4.7% admitted to having suicidal thoughts. the relationship between depression and sleepiness among the residents can be seen in figure 3. a significant association was found between sleepiness and depressive symptoms among the cohort (p = 0.003). of the residents who reported excessive daytime sleepiness, 50.6% had mild depressive symptoms while 23.6% had symptoms of moderate to severe depression. there were no significant associations between depressive symptoms and sociodemographic factors, with the exception of gender (p = 0.033). a significant increase in the prevalence of depressive symptoms among female residents (68.7%) was noted in comparison to male residents (55.5%). additionally, the percentage of female residents showing moderate to severe depressive symptoms was more than double that of the male residents. no significant relationship was found between the prevalence of depressive symptoms and choice of specialty; however, it was interesting to note that the prevalence of depressive symptoms was highest among general surgery, internal medicine, neurology and urology residents. additionally, although no significant relationship was found between the prevalence of depressive symptoms and residency levels in general, the prevalence of depressive symptoms rose slightly among third-year residents and doubled among fourth-year residents in comparison to non-depressed residents at the same level. the results also revealed that the rates of depression among service residents were double that of non-service residents. figure 1: prevalence of sleepiness among surveyed medical residents at king fahd university hospital (n = 171). sleepiness was scored using a validated arabic version of the epworth sleepiness scale.12,14 figure 2: prevalence of depression among surveyed medical residents at king fahd university hospital (n = 171). depression was scored using a validated arabic version of the beck depression inventory-2.13,16 critically, 4.7% of the cohort admitted to having suicidal thoughts. table 2: prevalence of sleep deprivation measured by indirect indices and the association with depression among surveyed medical residents at king fahd university hospital (n = 171) indirect index n (%) percentage of residents p value minimal depression† mild depression† moderate/severe depression† working hours per night duty ≤24 76 (44.4) 48.7 30.3 21.1 0.003* >24 84 (49.2) 25 54.8 20.2 working hours per week 40–76 97 (56.7) 41.2 45.4 13.4 0.047* 77–90 74 (43.3) 31.1 40.5 28.4 night duties per month 0 7 (4.1) 42.9 42.9 14.3 0.780 <3 9 (5.3) 55.6 33.3 11.1 3–5 66 (38.6) 40.9 40.9 18.2 >5 89 (52) 31.5 46.1 22.5 †depression was scored using a validated arabic version of the beck depression inventory-2.13,16 *statistically significant. prevalence of sleep deprivation and relation with depressive symptoms among medical residents in king fahd university hospital, saudi arabia e82 | squ medical journal, february 2015, volume 15, issue 1 discussion residency training is known to be a challenging and demanding period and many studies have investigated issues related to residents’ performance, mood changes, sleep deprivation and sleepiness. however, few studies have examined the possible relationship between sleep deprivation and depressive symptoms.9,10 the current study revealed that the majority of kfuh residents were acutely sleep-deprived (85.9%). this result was similar to those reported in both local and international studies. sleep deprivation among medical residents in chicago, usa, was reported to be extremely high (over 92%).17 additionally, the prevalence of acute sleep deprivation among medical residents at kfuh was very similar to that observed among junior doctors in jeddah, saudi arabia (87%).18 chronic sleep deprivation among kfuh residents was also high (63.2%). a study conducted at the university of pennsylvania in the usa found a much lower rate (43%).9 however, wada et al. conducted a national survey on japanese physicians which indicated a higher prevalence of total chronic sleep deprivation (85%).19 the frequency of night duties among kfuh residents did not differ from the norm when compared to similar studies around the world. of the kfuh residents, 52% had an average of more than five night duties per month as compared to japanese residents (58.9%) and german physicians (48.2%) with more than five and six night duties per month, respectively.19,20 however, the current study’s findings indicated a high number of working hours per week. at kfuh, 43.3% of the residents worked more than 76 hours per week; this is comparable to a study in germany which reported 48.1% of physicians working over 70 hours per week.20 in contrast, less than 17% of the residents in the american college of surgeons were reported to work more than 80 hours a week.10 the reason for this finding may be due to variations in working hours, night duty and on-call policies at individual institutions. furthermore, the current study found a significant association between working hours and the prevalence of depression. however, the number of night duties worked by the residents did not affect the severity of their depressive symptoms. balch et al. found a significant increase in the prevalence of depression with an increase in working hours among american surgeons.10 a significant association was observed between sleepiness and depressive symptoms among the residents in the current study. excessive daytime sleepiness as a normal consequence of sleep loss was elevated (52%). this is higher than findings reported among pennsylvania medical residents which ranged from 11% at the beginning of the academic year to 36% towards the end.9 in addition, the prevalence of depressive symptoms among the kfuh residents was particularly high (63%) in comparison to other studies. in japan, the prevalence of depression among physicians was only 8.8%.19 moreover, goebert et al. examined depressive symptoms in medical students and residents in six different states in the usa; this study found that 11.9% of the medical residents were depressed, with 4.7% reporting mild to moderate depression and 7.2% with major depression, including 3.9% indicating suicidal ideation.21 the high prevalence of depressive symptoms among kfuh residents may potentially be explained by work-related stressors, such as difficulties with the nature of the work, patient care, career planning, poor interpersonal/ interdisciplinary relationships, inadequate learning environments, a lack of adequate mentoring and information overload. a number of cultural factors or non-work-related stressors could also play a part, such as financial concerns or a lack of emotional support. a strong association between sleep deprivation and depression was noted in the current study, akin to findings in the literature.10,22 however, while the significant relationship between depressive symptoms and acute sleep deprivation was confirmed, the relationship between depressive symptoms and chronic sleep deprivation was not significant. wali et al. studied the effect of on-call-related sleep deprivation on junior physicians’ moods in jeddah. in sleepdeprived physicians, mood status scores were high and were related to acute sleep deprivation and long on-call periods.18 depression scores were significantly higher in the post-on-call period than in the pre-oncall period.18 in contrast to the current study, some research has shown a significant association between depressive symptoms and chronic sleep deprivation. rosen et al. found a strong association between figure 3: prevalence of sleepiness among surveyed medical residents at king fahd university hospital (n = 171). sleepiness was scored using a validated arabic version of the epworth sleepiness scale.12,14 esraa m. al-maddah, badria k. al-dabal and mohammad s. khalil clinical and basic research | e83 depression and chronic sleep deprivation among junior doctors in pennsylvania.9 among japanese physicians, wada et al. also found an association between depression and routinely sleeping less than five hours in a 24-hour period.19 although the proportion of male to female participants differed, the results of the current study showed a significantly greater prevalence of depressive symptoms among female residents than their male counterparts. this finding could be due to several reasons. women may be subject to additional stressors such as familial responsibilities (e.g. household tasks and child care), a lack of personal time, exhaustion and hormonal changes. other studies have also observed that female physicians have a higher prevalence of depression. the prevalence of depression among physicians in primary healthcare settings in jeddah was greater among women (53.3%) than men (28.6%).23 wada et al. also found that depression among female japanese physicians was more frequent than among men (10.5% and 8.3%, respectively).19 the outcome of this research may increase awareness about the need for sufficient sleep among medical professionals, as well as the need to regulate medical residents’ work hours. the number of working hours and night duties per month at kfuh is determined by the saudi arabian ministry of civil services; however, it was observed that within many of the specialities these regulations were not being followed. therefore, the authors of the current study recommend that a clear detailed guideline be set stating the number of working hours and night duties for residents. specific guidelines for pregnant female residents should also be included. these new guidelines should be assessed on a regular basis by further studies. additionally, the authors recommend that all medical residents be educated on the importance of sleep and its relationship to depression. residents should be capable of predicting symptoms of sleep deprivation and depression and amend their sleeping patterns accordingly. furthermore, a well-trained mentor for each resident is necessary to help minimise stress in the professional setting. regular meetings should also be organised for all residents, including newly graduated specialists, in order for them to share their knowledge and experiences with one another. the present study included some limitations. a few residents faced difficulties in answering the questions that depended on recalling their frequency of sleep. furthermore, self-reported values may have been biased or inaccurate. certain residents did not respond due to either a lack of time or interest and therefore were not included in the study. as the study was cross-sectional, it was difficult to determine causality. the simple random sampling technique was difficult to apply due to the limited time frame of the study and the number of residents in the study population. finally, potential comorbidities and medications among the residents were not evaluated, which may have affected the results. conclusion the vast majority of the studied kfuh residents were found to have acute sleep deprivation and more than half of them had chronic sleep deprivation. daytime sleepiness was prevalent in almost half of the cohort. approximately two-thirds of the participants reported mild or moderate to severe depressive symptoms. strong associations were found between depressive symptoms and acute sleep deprivation, working hours (either per night duty or per week), sleepiness and gender. new regulations are recommended regarding the number of working hours and night duties for medical residents. a c k n o w l e d g e m e n t the authors would like to extend special thanks to dr. ammar khamis, statistical advisor, for his constant guidance and support. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. shapiro sl, shapiro de, schwartz ge. stress management in medical education: a review of the literature. acad med 2000; 75:748–59. 2. public citizen foundation. petition requesting medical residents work hour limits. from: www.publiccitizen.org/ publications/release.cfm?id=6771 accessed: feb 2014. 3. kirsling ra, kochar ms, chan ch. an evaluation of mood states among first-year residents. psychol rep 1989; 65:355–66. doi: 10.2466/pr0.1989.65.2.355. 4. girard de, elliot dl, hickman dh, sparr l, clarke ng, warren l, et al. the internship: a prospective investigation of emotions and attitudes. west j med 1986; 144:93–8. 5. cirelli c. definition and consequences of sleep deprivation. from: www.uptodate.com/contents/definition-and-consequences -of-sleep-deprivation accessed: feb 2014. 6. carskadon ma, dement wc. cumulative effects of sleep restriction on daytime sleepiness. psychophysiology 1981; 18:107–13. doi: 10.1111/j.1469-8986.1981.tb02921.x. 7. kramer m. sleep loss in resident physicians: the cause of medical errors? front neurol 2010; 1:128. doi: 10.3389/ fneur.2010.00128. 8. national sleep foundation. white paper: how much sleep do adults need? from: www.sleepfoundation.org/article/whitepapers/how-much-sleep-do-adults-need accessed: apr 2012. prevalence of sleep deprivation and relation with depressive symptoms among medical residents in king fahd university hospital, saudi arabia e84 | squ medical journal, february 2015, volume 15, issue 1 9. rosen im, gimotty pa, shea ja, bellini lm. evolution of sleep quantity, sleep deprivation, mood disturbances, empathy, and burnout among interns. acad med 2006; 81:82–5. 10. balch cm, shanafelt td, dyrbye l, sloan ja, russell tr, bechamps gj, et al. surgeon distress as calibrated by hours worked and nights on call. j am coll surg 2010; 211:609–19. doi: 10.1016/j.jamcollsurg.2010.06.393. 11. johns mw. a new method for measuring daytime sleepiness: the epworth sleepiness scale. sleep 1991; 14:540–5. 12. beck at, steer ra, ball r, ranieri w. comparison of beck depression inventories -ia and -ii in psychiatric outpatients. j pers assess 1996; 67:588–97. doi: 10.1207/ s15327752jpa6703_13. 13. riachy m, juvelikian g, sleilaty g, bazarbachi t, khayat g, mouradides c. [validation of the arabic version of the epworth sleepiness scale: multicenter study]. rev mal respir 2012; 29:697–704. doi: 10.1016/j.rmr.2011.12.017. 14. johns mw. reliability and factor analysis of the epworth sleepiness scale. sleep 1992;15:376–81. 15. ghareeb ag. manual of arabic bdi-ii. cairo, egypt: angle press, 2000. 16. alansari bm. internal consistency of an arabic adaptation of the beck depression inventory-ii with college students in eighteen arab countries. soc behav pers 2006; 34:425–30. doi: 10.2224/sbp.2006.34.4.425. 17. baldwin dc jr, daugherty sr. sleep deprivation and fatigue in residency training: results of a national survey of firstand second-year residents. sleep 2004; 27:217–23. 18. wali s, abushanab l, quotah k, krayem a. effect of on-call related sleep deprivation on physicians’ mood and level of alertness. chest 2011; 140:809a. doi: 10.1378/chest.1117573. 19. wada k, yoshikawa t, goto t, hirai a, matsushima e, nakashima y, et al. national survey of the association of depressive symptoms with the number of off duty and oncall, and sleep hours among physicians working in japanese hospitals: a cross sectional study. bmc public health 2010; 10:127. doi: 10.1186/1471-2458-10-127. 20. rosta j, gerber a. excessive working hours and health complaints among hospital physicians: a study based on a national sample of hospital physicians in germany. ger med sci 2007; 5:doc09. 21. goebert d, thompson d, takeshita j, beach c, bryson p, ephgrave k, et al. depressive symptom in medical students and residents: a multischool study. acad med 2009; 84:236–41. doi: 10.1097/acm.0b013e31819391bb. 22. khuwaja ak, qureshi r, azam si. prevalence and factors associated with anxiety and depression among family practitioners in karachi, pakistan. j pak med assoc 2004; 54:45–9. 23. al-harby nm. prevalence of depression and its associated factors among physicians in the primary health care centers, jeddah, saudi arabia. from: www.ssfcm.org/public/english/ artical/index/secid/867/artid/1748#1748 accessed: feb 2014. clinical & basic research sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 115-120, epub. 27th feb 13 submitted 6th jun 12 revision req. 6th aug 12, revision recd. 10th aug 12 accepted 2nd sep 12 department of physiology & pharmacology, school of medicine, al-quds university, jerusalem, palestine e-mail: yasin.tayem@gmail.com أثر التعلم املبين على احلاالت السريرية يف جمموعات صغرية لتدريس علم األدوية على الطريقة التقليدية يا�صني تيم امللخ�ص: الهدف: هتدف هذه الدراسة إىل قياس مدى رضا طلبة الطب عن استخدام التعلم يف جمموعات صغرية املبين على احلاالت السريرية يف مساق احملاضرات التقليدية لعلم األدوية. الطريقة: مت مجع البيانات من طلبة السنة الثالثة يف كلية الطب جبامعة القدس، فلسطني )عدد = 68, %57 ذكور, %43 إناث(. مت عرض تدريس الطالب مساق علم األدوية -2 على طريقة مكونة من العمل ضمن جمموعات صغرية بعدما قام الطالب بدراسة مساق علم األدوية -1 بالطريقة التقليدية خالل الفصل الدراسي السابق. مت استخدام استبانه تعبأ ذاتيا ملعرفة رأي الطلبة يف الربامج املعاد هيكلتها .النتائج: غالبية الطلبة اعتقدوا أن الطريقة اجلديدة كانت أداة تعليمية فعالة بالنسبة هلم )%82( و أهنا حسنت مهاراهتم التعلمية )%83(، مهارات التعلم الذايت لديهم )%74(، مهاراهتم التحليلية )%70( و مستوى التحضري لالمتحانات )%75(. ذكر معظم الطلبة أن نقاش احلاالت السريرية قد متحور حول أهداف احملاضرات )%84(.بالنسبة للحاالت السريرية قال معظم الطلبة أهنا كانت مالئمة ملواضيع احملاضرات )%96( وبأن الوقت املخصص ملناقشتها كان كافيا )%86(. اعتقد غالبية املستطلعة آراؤهم أن األسلوب اجلديد قد ساهم يف حتسني مهارات االتصال لديهم )%68( و رغبتهم يف مساعدة زمالئهم ضمن اجملموعة )%80( و قدرهتم على العمل بروح الفريق الواحد )%79(. اخلال�صة: إعادة هيكلة مساق علم األدوية -2 قد أدى ىل حتسن هام يف الرضا الذايت للطلبة وكذلك حتمسهم واندماجهم يف العملية التعليمية. مفتاح الكلمات: التعلم �صمن جمموعات �صغرية، التعلم القائم على احلالت ال�رسيرية، علم الأدوية. abstract: objectives: this study aimed to measure medical students’ perceptions of incorporating small group case-based learning (cbl) in traditional pharmacology lectures. methods: data were collected from third-year students (n = 68; 57% males, 43% females) at al quds university medical school, palestine. the students were offered a cbl-incorporated pharmacology-2 course after they had been taught pharmacology-1 in the traditional format during the preceding semester. student attitudes towards the restructured course were examined by a self-administered structured questionnaire. results: the majority of students thought that cbl was an effective learning tool for them (82%) and that it improved their learning skills (83%), independent learning skills (74%), analytical skills (70%), and their level of preparation for exams (75%). most students reported that team discussions addressed lecture objectives (84%). regarding cases discussed, most responders said that the cases were appropriate to the lecture topics (96%) and that the time allocated for case discussion was sufficient (86%). a large proportion of students thought that cbl improved their communication and collaborative skills (68% and 80%, respectively) and ability to work within a team (79%). conclusion: pharmacology-2 course restructuring led to a significant improvement of self-reported student satisfaction, motivation, and engagement. keywords: small group learning; case-based learning; pharmacology. the impact of small group case-based learning on traditional pharmacology teaching yasin i. tayem advances in knowledge students prefer case-based learning (cbl) over the traditional approach for learning pharmacology and other basic medical sciences. cbl enhances students’ self-reported analytical and communication skills. cbl improves students’ self-reported collaborative and team work skills. application to patient care cbl develops students’ ability to become life-long, self-learners. this is crucial since. once they join the medical workforce, these students will be expected to remain up-to-date in their knowledge in order to provide better care for their patients. cbl-induced improvement of students’ analytical skills is expected to promote their ability to analyse patients' clinical pictures and reach a diagnosis. the impact of small group case-based learning on traditional pharmacology teaching 116 | squ medical journal, february 2013, volume 13, issue 1 there can be no single best way of learning in medicine since each method has its own advantages and disadvantages. although the didactic lecture format may be effective for disseminating a large body of information to a large number of students, it presents many challenges to both teachers and learners because it often promotes passive learning and fails to motivate students.1 therefore, over the past few decades, a lot of attention has been paid to promoting active learning by adopting interactive student-centred approaches in undergraduate medical education, including problem-based learning (pbl), and casebased learning (cbl).2,3 active learning is a studentcentred rather than a teacher-centred process; it makes learners responsible for their own learning by self-directed, peer-assisted seeking of new information.4 cbl is an interactive, student-centred, instructor-led learning approach that is closely related to pbl.5 this innovative learning approach was first applied in medical education by the anatomy department of a medical school in newfoundland, canada. cbl promotes active learning by utilising clinical case scenarios which reflect real life experiences that students will face during the clinical phase of their medical education.5 cases are generally written as problems that provide students with the history, physical findings and laboratory results of a patient. active learning happens when students are given the opportunity to develop a more interactive relationship with the case, encouraging them to generate rather than simply receive knowledge, organising it in a meaningful manner and developing skills to share with other learners in a group. cbl has several advantages, including promoting self-directed life-long learning; introducing basic medical sciences in a coherent manner closely related to topics in clinical sciences, and reinforcing the reasoning, collaborative and communication skills of students.6-8 at al-quds university school of medicine, palestine, the 6-year programme is divided into independent courses in basic sciences in the first year, basic medical sciences in the second and third years, and clinical sciences in the fourth to sixth years. the challenges facing medical education which our faculty experiences, are similar to other medical schools in the region. the learning process is still problematic with large classes, and most of the curriculum time is spent on traditional lectures. moreover, student assessment is limited to summative methods which often fail to address the analytical and reasoning skills a medical student needs. pharmacology is taught to our preclinical undergraduates during their third year of the medical curriculum in two separate courses, namely pharmacology-1 and pharmacology-2, which are offered in the fall and spring semesters, respectively. in this study, we describe medical students` attitudes towards implementing an innovative instructional design that incorporates cbl into a traditional lecture-based pharmacology-2 course. methods ethical approval was provided by the al-quds university human research ethics committee in compliance with the helsinki declaration for ethical principles of medical research involving human subjects. oral consent was sought from participants after the purpose and nature of the study were explained. the course restructuring we describe in this study pertains to the lecture portion of pharmacology-2, a spring semester course that typically enrolls around 70 third-year medical students. this course was offered during the 2011–12 academic year. the same students were enrolled in the pharmacology-1 course during the preceding semester. the hypothesis we considered in this study was that students would have a positive attitude towards pharmacology-2 compared to pharmacology-1 in response to the new instructional design we introduced. our pharmacology-2 course focused on cardiovascular, respiratory, gastrointestinal cbl improves students’ ability to work as a team with the medical staff. this collaborative work is considered a cornerstone for improving patient care. cbl-induced improvement in students’ communication skills is expected to enhance their ability to communicate with their patients in the future. yasin i. tayem clinical and basic research | 117 tract (git) and, central nervous system (cns) pharmacology. pharmacology-1, on the other hand, addressed the basic principles of pharmacology, including pharmacokinetics, pharmacodynamics, autonomic pharmacology, general and local anaesthetics, antibiotics, and chemotherapeutic agents. in both courses, lectures traditionally consisted of two-hour face-to-face sessions twice weekly. assessment for the lecture portion of the courses consisted of a midterm and final examination, with each exam containing a mixture of quantitative problem solving, short answer, and short essay questions. lectures in pharmacology-1 were purely didactic. in our pharmacology-2 course redesign, we incorporated small-group cbl into every lecture. students were organised into groups of 7–9 on the first lecture and were requested to work as a team throughout the semester. lecture notes, along with their clinical case scenarios and accompanying questions, were sent to the students a few days before each lecture so that they could prepare. for each lecture objective, a brief explanation was presented by the facilitator followed by an introduction of a clinical case scenario accompanied by questions addressing the objectives of this part of the lecture. thereafter, the groups were given 10–15 minutes to discuss the case and answer the questions. during discussion, the facilitator would move from group to group to monitor student progress, facilitate discussion, and offer suggestions if a group experienced difficulty. the same cycle was repeated for the next objective and so on. we also placed increased emphasis on formative assessment at the end of lectures so that students would receive feedback designed to improve their performance. at the end of each session, two groups were selected and enrolled into a short individual quiz focusing on the objectives of the lecture. we examined students’ attitudes towards implementing the cbl methodology in the newly designed pharmacology-2 lectures by administering a two-page self-administered questionnaire to the participating students (n = 68; 57% males, 43% females; mean age 21 years). the survey was administered inside the classroom on the last day of the academic year before the pharmacology-2 final examination. all participating students had been enrolled in the same pharmacology-1 and pharmacology-2 courses, and there were no failing or repeating students. the questionnaire focused on the impact of cbl on student’ selfreported changes in their learning, collaborative abilities, and teamwork and communication skills, and the quality of cases discussed [table-1]. each participant was requested to answer all questions in the survey using a scale that reflected to what degree he or she agreed or disagreed with the statement. the scale was composed of three main categories: agree, disagree, or not sure. furthermore, the agree and disagree categories were subcategorised into strongly agree or agree, and strongly disagree or disagree. to ensure questionnaire reliability, an internal consistency technique was utilised. these methods ensured that, on the one hand, the students had been exposed to both teaching approaches before they completed the questionnaire and, on the other hand, potential bias due to the stress of the examination was avoided. results students' attitudes towards the implementation of cbl were examined in this study [table 1]. our data showed that the majority of students accepted the incorporation of cbl into traditional pharmacology teaching. when we asked the students about their view of implementing this teaching methodology in other basic medical sciences, most of them responded positively to this question (45% strongly agreed, 38% agreed). a large proportion of students thought that cbl was an effective learning tool for them (82%), out of which 32% strongly agreed, 50% agreed, and 13% disagreed. a similar percentage of respondents said that cbl improved their learning skills (24% strongly agreed, 59% agreed). most participating students believed that cbl improved their independent learning skills (24% strongly agreed, 51% agreed), analytical skills (16% strongly agreed, 54% agreed), ability to retain information (28% strongly agreed, 45% agreed) and preparation for examinations (27% strongly agreed, 48% agreed). moreover, 79% of the students reported that their attendance and engagement in pharmacology-2 lectures were better than it had been in pharmacology-1 (46% strongly agreed, 33% agreed). regarding students’ views of the case scenarios discussed within the groups, almost all responders said that these cases were appropriate for the lecture topics (48% the impact of small group case-based learning on traditional pharmacology teaching 118 | squ medical journal, february 2013, volume 13, issue 1 strongly agreed, 48% agreed). most responders thought that the group discussions addressed the objectives of the lectures (42% strongly agreed, 42% agreed). a similar proportion of responders thought that time allocated for case discussion was sufficient (37% strongly agreed, 49% agreed). the majority of responders believed that cbl improved their communication skills (19% strongly agreed, 49% agreed) and ability to work as part of a team (19% strongly agreed, 60% agreed). concerning the effect of cbl on students’ collaborative skills, a high percentage of students said that group discussion allowed them to help other peers to understand difficult cases (26% strongly agreed, 54% agreed). although the participants were requested to answer all questions in the survey, a minority of them decided to leave some of the questions blank [table 1]. discussion teaching methods which increase student motivation and enhance learning have evolved throughout history. however, the introduction of an interactive student-centred approach in medical education has dramatically changed the way students learn. our primary goal of introducing team-based case-oriented assignments in traditional pharmacology-2 lectures was to promote student learning by improving their motivation and engagement. the present investigation was carried out to describe medical students’ perceptions after incorporating cbl into a traditionally didactic pharmacology-2 lecture-based course. by and large, our data demonstrated that the majority of the students not only accepted this innovative technique but were also satisfied about the quality of cases discussed in the lectures. a large proportion of the participating students thought that cbl should be implemented in other basic medical sciences table 1: third year medical students’ perceptions of implementing case-based learning into traditional pharmacology-2 lectures (n = 68; 57% males, 43% females) statement strongly agree (%) agree (%) strongly disagree (%) disagree (%) not sure (%) no. of responders cbl should be utilised in other basic medical sciences 25 (45) 21 (38) 3 (5) 4 (7) 3 (5) 56 cbl was an effective learning tool for me 22 (32) 34 (50) 4 (6) 5 (7) 3 (4) 68 cbl improved my learning skills 16 (24) 40 (59) 2 (3) 3 (4) 7 (10) 68 cbl improved my independent learning skills 16 (24) 35 (51) 3 (4) 7 (10) 7 (10) 67 cbl improved my analytical skills 11 (16) 36 (54) 2 (3) 9 (13) 9 (13) 67 cbl improved my ability to retain information 18 (28) 29 (45) 5 (8) 5 (8) 8 (12) 65 cbl helped me prepare for exams 18 (27) 32 (48) 6 (9) 4 (6) 7 (10) 67 cbl improved my attendance and participation in lectures 26 (46) 19 (33) 3 (5) 5 (9) 4 (7) 57 case scenarios were appropriate for the lecture topics 32 (48) 32 (48) 1 (1) 1 (1) 1 (1) 67 student discussion addresses lecture objectives 28 (42) 28(42) 4 (6) 1 (2) 5 (8) 66 time allowed for case discussion was sufficient 25 (37) 33 (49) 7 (10) 5 (7) 10 (15) 68 cbl improved my communication skills 13 (19) 33 (49) 7 (10) 5 (7) 10 (15) 68 cbl improved my ability to work within a team 13 (19) 40 (60) 2 (3) 4(6) 8 (12) 67 cbl allowed me to help other students in my group understand difficult cases 16 (26) 33 (54) 1 (2) 3 (5) 8 (13) 61 cbl = case-based learning. yasin i. tayem clinical and basic research | 119 indicating that our students warmly welcomed the new methodology. most of them also reported that cbl improved their general and independent learning skills, ability to prepare for examinations, and reasoning skills. the findings of the current investigation are consistent with positive results demonstrated by other studies which examined the impact of cbl on medical education.9,10 in a maxillofacial radiology course, kumar et al. reported that the majority of students felt that case-based instruction helped them learn course contents in a more comprehensive manner and increased their knowledge of radiographic interpretation.11 our data showed that students' reaction to cbl was overwhelmingly positive as most students believed that this interactive approach boosted their learning and should be implemented in other basic medical sciences disciplines. most students thought that their motivation as assessed by self-reported lecture attendance and participation improved as a result of increased engagement in the small group discussions. yoo et al. examined the effects of cbl on learning motivation in nursing students and found that it was significantly higher in the cbl group than in the non-cbl one.12 another benefit of cbl reported by the respondents was the development of their collaborative skills as reflected by an improved desire to help their group members to understand difficult cases. they also reported improved team-work and communication skills as a result of participating in the small group discussions. in line with our findings, ciraj et al. reported that student communication skills and ability to work within a team were significantly improved due to cbl implementation in a microbiology course.13 our data indicated that this innovative pedagogical approach not only improved students’ learning but also reinforced their self-reported engagement and motivation, communication and collaborative skills, and their ability to work as part of a team. there are certain limitations pertaining to this study which should be taken in consideration when interpreting these findings. first, the instrument utilised to assess students’ perceptions was only designed to be administered on a single occasion at the end of the pharmacology-2 course, rather than assessing students’ perceptions of both courses separately and comparing the results. a multi-stage assessment of changes in student perceptions would have been more reliable for measuring student attitudes towards course restructuring. second, a comparison of students’ grades before and after the introduction of cbl, to gauge the effect of this pedagogy on their academic performance, was not possible in this investigation. the reasons for this were related to the differences in the materials that each course covered and the lack of a control group. finally, we relied on self-reported changes in student attendance and engagement before and after introducing cbl. comparing actual attendance records in both courses would have been a more accurate way to detect changes in these measures. conclusion in summary, we developed and implemented an instructional design which focused on incorporating active learning and a group-based case-oriented pedagogy into what was previously a traditional lecture-based pharmacology course. these changes were appreciated by students and led to a significant improvement in students’ self-reported satisfaction, engagement and motivation. a c k n o w l e d g e m e n t s we express our appreciation to the third-year medical students for their cooperation with the investigator. the valuable support of the deanship of al-quds university school of medicine is also gratefully acknowledged. c o n f l i c t o f i n t e r e s t the author reports no financial or other conflicts of interest pertaining to the subjects or products discussed in this article. this research received no specific grant from any funding agency in the public, commercial, or non-profit sectors. references 1. sprawls p. evolving models for medical physics education and training: a global perspective. biomed imaging intervention j 2008; 4:e16. 2. husain a. problem-based learning: a current model of education. oman med j 2011; 26:295. 3. srinivasan m., wilkes m, stevenson f, nguyen t, slavin s. comparing problem-based learning with case-based learning: effects of a major curricular shift at two institutions. acad med 2007; 82:74–82. 4. ozbicakci, s, bilik o, intepeler ss. assessment of the impact of small group case-based learning on traditional pharmacology teaching 120 | squ medical journal, february 2013, volume 13, issue 1 goals in problem-based learning. nurse educ today 2012; 32:e79–82. 5. thistlethwaite je, davies d, ekeocha s, kidd jm, macdougall c, matthews p, et al. the effectiveness of case-based learning in health professional education. a beme systematic review: beme guide no. 23. med teach 2012; 34:e421–4. 6. tsou ki, cho sl, lin cs, sy lb, yang lk, chou ty, et al. short-term outcomes of a near-full pbl curriculum in a new taiwan medical school. kaohsiung j med sci 2009; 25:282–93. 7. malher x, bareille n, noordhuizen jp, seegers h. a case-based learning approach for teaching undergraduate veterinary students about dairy herd health consultancy issues. j veterin med educ 2009; 36:22–9. 8. engel fe and hendricson wd. a case-based learning model in orthodontics. j dental educ 1994; 58:762– 7. 9. blewett el and kisamore jl. evaluation of an interactive, case-based review session in teaching medical microbiology. bmc med educ 2009; 9:56. 10. hirshbein ld, gay t. case-based independent study for medical students in emergency psychiatry. acad psychiatry 2005; 29:96–9. 11. kumar v, gadbury-amyot cc. a case-based and team-based learning model in oral and maxillofacial radiology. j dental educ 2012; 76:330–7. 12. yoo, ms, park jh, lee sr. the effects of case-based learning using video on clinical decision making and learning motivation in undergraduate nursing students. j korean acad nursing 2010; 40:863–71. 13. ciraj am, vinod p, ramnarayan k. enhancing active learning in microbiology through case-based learning: experiences from an indian medical school. indian j pathol microbiol 2010; 53:729–33. 1medical imaging unit, faculty of medicine, universiti teknologi mara, selangor, malaysia; 2radiology department, kuala lumpur general hospital, kuala lumpur, malaysia *corresponding author e-mail: drbushra@salam.uitm.edu.my متدد الوريد البايب داخل الكبد بالتزامن مع سرطان خاليا الكبد حممد حن�فية، ب�رضى جوه�ري، مريميول كو�شي، حممد م�شني intrahepatic portal vein aneurysm with concurrent hepatocellular carcinoma mohammad hanafiah,1,2 *bushra johari,1 marymol koshy,1 mohamed n. misni2 a 70-year-old male with a nine-year history of chronic hepatitis b infection and liver cirrhosis was admitted to the kuala lumpur general hospital in kuala lumpur, malaysia, in november 2012 with chills and jaundice. a physical examination revealed a distended abdomen without tenderness or masses. there were no other signs of chronic liver disease and the patient was haemodynamically stable. liver function tests revealed elevated total bilirubin (172.0 μmol/l), alkaline phosphatase (163.0 u/l) and gamma-glutamyl transferase (134.0 u/l) levels. alanine aminotransferase, white cell count and c-reactive protein levels were within normal limits. however, the patient’s serum α-fetoprotein levels were elevated (919.3 ng/ml). an ultrasound examination of the abdomen showed a cirrhotic liver with fusiform dilatation of the right portal vein. contrast-enhanced abdominal computed tomography (ct) confirmed the presence of a fusiform aneurysm of the distal right portal vein [figure 1]. the aneurysm measured 2.2 cm in diameter and the remainder of the right portal vein was also diffusely dilated. the main portal vein and its left branch, as well as the hepatic veins, were not dilated. these veins were patent with no filling defects to suggest thrombosis. the spleen was mildly enlarged (14.5 cm) and there were multiple varices in the perigastric region and splenic hilum. an illdefined mass in segment v of the liver was observed which demonstrated heterogeneous enhancement in the arterial phase and relative contrast washout in the portal venous phase. the greatest diameter of the enhancing component of the lesion in the arterial phase was 4.0 cm. there was extrinsic compression of the mass on the adjacent right intrahepatic duct resulting in dilatation of the proximal biliary system. a figure 1a & b: selected axial computed tomography images showing a concurrent portal venous aneurysm (asterisks) and a mass in segment v of the liver, most likely a hepatocellular carcinoma, in a 70-year-old male. the mass (white arrows) demonstrated (a) typical heterogeneous enhancement in the arterial phase and (b) washout in the portal venous phase. additionally, it caused dilatation of the proximal intrahepatic biliary ducts (black arrows). interesting medical image sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e115–116, epub. 2 feb 16 submitted 19 may 15 revision req. 11 aug 15; revision recd. 11 sep 15 accepted 8 oct 15 doi: 10.18295/squmj.2016.16.01.023 intrahepatic portal vein aneurysm with concurrent hepatocellular carcinoma e116 | squ medical journal, february 2016, volume 16, issue 1 however, the incidence of portal hypertension and pva is disproportionate, suggesting the existence of other contributory factors. other secondary causes of pva include pancreatitis, trauma and invasive malignancy.1,5 to the best of the authors’ knowledge, no data yet exist in the available english scientific literature evidencing a direct relationship between hcc and pva. as such, this remains an exciting avenue to be explored. it is likely these two conditions have an indirect relationship as both are related to chronic liver disease and cirrhosis. the present case demonstrates the imaging appearances of pva on ct scans. doppler ultrasonography and contrast-enhanced abdominal ct scans are reliable methods of diagnosing pva; furthermore, these imaging techniques can help identify complications and are useful during the follow-up period.1 contrast-enhanced ct allows multi-planar 3d image reconstruction and can clearly demonstrate the size, location and extent of an aneurysm.5 within the pva, ct or magnetic resonance imaging differentiate slow-flowing blood from thromboses.1 more invasive imaging techniques such as direct or indirect portography are other potential confirmatory investigations, particularly if a portocaval fistula is suspected. however, these procedures are not usually necessary.1 in general, pvas require no treatment and careful follow-up is adequate.2,5 the decision to treat a pva depends on its size and location, the existence of symptoms and the presence of thrombosis.2 it is important to be familiar with the imaging appearance and nature of pvas to allow for appropriate management of the condition. references 1. schwope rb, margolis dj, raman ss, kadell bm. portal vein aneurysms: a case series with literature review. j radiol case rep 2010; 4:28–38. doi: 10.3941/jrcr.v4i6.431. 2. iimuro y, suzumura k, ohashi k, tanaka h, iijima h, nishiguchi s, et al. hemodynamic analysis and treatment of an enlarging extrahepatic portal aneurysm: report of a case. surg today 2015; 45:383–9. doi: 10.1007/s00595-014-0882-8. 3. rafiq sa, sitrin md. portal vein aneurysm: case report and review of the literature. gastroenterol hepatol (n y) 2007; 3:296–8. 4. labgaa i, lachenal y, allemann p, demartines n, schäfer m. giant extra-hepatic thrombosed portal vein aneurysm: a case report and review of the literature. world j emerg surg 2014; 9:35. doi: 10.1186/1749-7922-9-35. 5. laurenzi a, ettorre gm, lionetti r, meniconi rl, colasanti m, vennarecci g. portal vein aneurysm: what to know. dig liver dis 2015; 47:918–23. doi: 10.1016/j.dld.2015.06.003. complementary three-dimensional (3d) ct volumerendered image was constructed to provide a clearer view of the aneurysm [figure 2]. given the patient’s history of chronic hepatitis b infection, liver cirrhosis and elevated α-fetoprotein levels, as well as the enhancement pattern of the mass, a diagnosis of hepatocellular carcinoma (hcc) was made. the patient unfortunately deteriorated clinically while in hospital and died due to complications arising from hospital-acquired pneumonia, cholangitis and hepatic encephalopathy. comment portal vein aneurysms (pvas) are extremely rare, with a worldwide prevalence of 0.43%; however, the condition is increasingly detected with modern imaging technology.1 in most cases, patients are asymptomatic and the pva is discovered incidentally during routine imaging.1 the aneurysm is located most frequently in the main portal vein and the confluence of the splenic and superior mesenteric veins.2 generally, pva is divided into congenital and acquired forms; however, the exact aetiology is unclear and remains controversial. the most common cause of acquired pva is portal hypertension related to chronic liver disease, such as cirrhosis.3–5 long-standing portal hypertension causes intimal thickening with compensatory medial hypertrophy of the portal vein.3 with time, the medial hypertrophy is replaced with fibrous tissue leading to a weakening of the vein wall, thus making it susceptible to aneurysmal dilatation.3 figure 2: complementary three-dimensional computed tomography volume-rendered image showing fusiform aneurysmal dilatation at the distal part of the right portal vein (arrow) in a 70-year-old male with concurrent hepatocellular carcinoma. the remainder of the right portal vein was also diffusely dilated. http://dx.doi.org/10.3941/jrcr.v4i6.431 http://dx.doi.org/10.1007/s00595-014-0882-8 http://dx.doi.org/10.1186/1749-7922-9-35 http://dx.doi.org/10.1016/j.dld.2015.06.003 squ med j, february 2012, vol. 12, iss. 1, pp. 93-96, epub. 7th feb 12. submitted 1st may 11 revision req. 10th oct 11, revision recd. 24th oct 11 accepted 16th nov 11 department of 1obstetrics & gynaecology and 2family medicine & public health, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: m.khaduri@gmail.com ُمَعّدل الّتقنية كُمؤّشر جودة للّتمّيز يف أمراض الّنساء مها اخل�سوري، يحيى الفار�سي هذه الطريقة: ُعمان. يف جامعي ثالثي رعاية م�ست�سفى يف الّرحم ا�ستئ�سال لعمليات الّتقنية معّدل ح�ساب درا�سة الأهداف: امللخ�س: درا�سة ا�ستعادية �سملت املري�سات اللواتي خ�سعن لعمليات ا�ستئ�سال الّرحم يف م�ست�سفى جامعة ال�سلطان قابو�س املرجعي للفرتة من 2003 اإىل 2009. مت اإح�ساء الرتددات الرتاكمية جلميع اأنواع عمليات ا�ستئ�سال الرحم، كما مّت ح�ساب موؤ�رص التقنية لكل عام. النتائج: َبَلَغ جمموع عمليات ا�ستئ�سال الرحم 258 عملّية، منها 6 )%2.3( عن طريق ا�ستخدام املنظار، 42 )%16.3( عن طريق امِلهَبل، و 208 )%80.6( عن طريق فتح البطن. كان متو�سط ُمَعّدل التقنية %19 )258/84( وتراوحت بني %11 اإىل %24. وتراوحت نزعة مرة النخفا�س اإىل لتعود ثم من 2004–2006، الفرتة خالل تدريجيا �سنة 2003 لرتتفع فكانت %16 يف ال�سنني، ح�سب التغيري اأخرى خالل �سنتي 2007 – 2008 ب�سكل معتّد اإح�سائيا )p=0.02(. ُتعزى هذه النزعة املنخف�سة واملتذبذبة ب�سكل رئي�سي اإىل عدم قابو�س ال�سلطان جامعة مب�ست�سفى التقنية معدل حت�سني ميكن اخلال�صة: املنظار. واأجهزة امُلَدّربني اجلّراحني من كافية اأعداد توفر بزيادة َعدد عملّيات ا�ستئ�سال الرحم عن طريق املنظار وذلك عن طريق توفري اأدوات املنظار وتوفري اجلّراحني امُلدّربني. مفتاح الكلمات: َمن�َسب )دليل( التقنية، ا�ستئ�سال الرحم، موؤ�رص اجلودة، علم اأمرا�س الن�ساء، ُعمان. abstract: objectives: the objective of this study was to calculate the technicity index (ti) for hysterectomies at a tertiary care university hospital in oman. methods: this is a retrospective chart review of patients who had hysterectomies at sultan qaboos university hospital (squh), a tertiary care university hospital. profiles were reviewed for all patients who had hysterectomies at squh in the period 2003–2009. the cumulative frequencies for all types of hysterectomies were tallied and the year-specific ti was calculated. results: overall, we enumerated a total of 258 hysterectomies, of which 6 (2.3%) were laparoscopic assisted hysterectomies, 42 (16.3%) vaginal hysterectomies, and 208 (80.6%) total abdominal hysterectomies. the average ti was 19% (48/258), and it ranged from 11% to 24%. the trend of change fluctuated over the years starting with 16% (2003) and increasing gradually during 2004–2006, but then declining again during 2007–2008 (trend p value 0.02). this low and fluctuating trend was mainly attributed to the inconsistency in the availability of trained surgeons and laparoscopic equipment. conclusion: ti at our institution can be improved by increasing the number of minimally invasive hysterectomies through providing more trained surgeons and laparoscopic equipment. keywords: technicity index; hysterectomy; quality indicator; gynaecology; oman. brief communication technicity as a quality indicator of excellence in gynaecology *maha al-khaduri1 and yahya alfarsi2 in recent years, international and national health regulatory bodies have been advocating the use of indicators as a means of improving the quality of patient care.1 quality indicators are defined as specific and measurable elements of practice that can be used to assess the quality of patient care. they are usually derived from retrospective reviews of medical records or routine information sources.2 with the advancement of minimally invasive surgery (mis) in gynaecology, new quality and performance indicators are required to evaluate the use of procedures which benefit patients and may be more cost effective as a result of a reduced hospital stay.3,4 one such indicator is the technicity index (ti) which is a relatively new quality metric in gynaecology. it was initially proposed for hysterectomies and is defined as the percentage of minimally invasive hysterectomies which includes vaginal hysterectomies (vh), laparoscopic assisted hysterectomies (lah), laparoscopic assisted vaginal hysterectomies (lavh), total laparoscopic hysterectomies (tlh), and supracervical hysterectomies (lsh) over the total number of hysterectomies (total abdominal hysterectomies (tah), vh and lah), performed in a single hospital in one technicity as a quality indicator of excellence in gynaecology 94 | squ medical journal, february 2012, volume 12, issue 1 year. the ti provides a comparative benchmark which may help in implementing strategies to improve performance which can be defined as an increase in mis and decrease in the proportion of tah. it was first used in france to rank gynaecology departments’ performance of hysterectomy. the highest ti in 2008 in france was reported as 90%, meaning that only 10% of hysterectomies were done by laparotomy.4 in canada, the average ti has been reported to be approximately 30% and the highest estimate was 60% in one hospital during the period 2008–2009.5 to our knowledge, no prior report about technicity has been published from developing countries. this ti research project aims at assessing the practice of hysterectomy in oman, an upper-middle income country in the arabian peninsula, with an approximate population of 3.5 million.6,7 there is a planned future extension of the project to assess the practice of hysterectomy in other hospitals in the country and the region. the objective of this study was to calculate ti as a quality indicator of excellence at our hospital. methods we conducted a retrospective chart review of all hysterectomies performed at sultan qaboos university hospital (squh), a 524 bed tertiary care hospital, in the period 2003 to 2009. the cumulative frequencies for all types of hysterectomies were tallied and the ti was calculated for each year. the statistical package for social sciences (spss) software (version 16.0, ibm, chicago, illinois, usa) was used for data analysis. chisquare analyses were used to evaluate the statistical significance of differences among proportions of categorical data, and a p value of <0.05 was used for all tests of statistical significance. the fisher’s exact test (two-tailed) replaced the chi-square test if the assumptions underlying chi-square were violated, namely in the case of small sample size and where the expected frequency was less than five in any of the cells. the study protocol was evaluated and approved by the medical research ethics committee at sultan qaboos university, muscat, oman. results table 1 shows the frequency distribution and yearspecific ti for hysterectomies at squh throughout the period 2003–2009. overall, we enumerated a total of 258 hysterectomies, of which 6 (2.3%) were lah, 42 (16.3%) vh, and 208 (80.6%) tah. the average ti was 19% (48/258), and it ranged from 11% to 24%. the trend of change fluctuated over the years. it started with 16% (year 2003) and increased gradually during 2004–2006, but then declined gradually during 2007–2008 (trend p value 0.02). the fluctuating trend of ti is depicted schematically in figure 1. discussion the development of minimally invasive hysterectomy procedures in gynaecology has created a need for the development of quality table 1: year-specific technicity index (ti) for hysterectomies at sultan qaboos university hospital, muscat, oman during the period 2003–2009. year lah vh tah total technicity index % 2003 0 7 36 43 16 2004 5 4 43 62 15 2005 0 10 32 42 24 2006 0 2 8 10 20 2007 0 2 17 19 11 2008 1 7 37 45 18 2009 0 4 33 38 11 total 6 42 208 258 19 legend: lah = laparoscopic abdominal hysterectomy; vh = vaginal hysterectomy; tah = total abdominal hysterectomy. 0% 5% 10% 16 15 24 20 11 11 18 15% 20% 25% 30% 2003 2004 2005 2006 2007 2008 2009 figure 1: trend of technicity index (ti) for hysterectomies at sultan qaboos university hospital, oman, in the period 2003–2009. maha al-khaduri and yahya alfarsi brief communication | 95 indicators in order to assess the performance of gynaecology departments. the ti provides a comparative benchmark which may help implement strategies to improve performance based on available evidence. the higher the ti in a department the better the quality of care for the procedure performed. the quality of care is determined by five criteria. these are complication rate, length of stay in the hospital, duration of surgery, hospital cost and quality of life. however, there is a need to decide on an acceptable ti level for hysterectomies for the region based on the available resources. the overall ti was found to be low at our institution which is due to the low number of lah and vh performed. the low and fluctuating trend in ti was mainly attributed to the inconsistency in the availability of trained gynaecologists and laparoscopic equipment in the different years. the increase in ti in 2005 is explained by a greater number of lavh procedures compared to other years which is likely due to the availability of a gynaecologist trained in lavh. the lowest ti in 2007 was due to a decrease in the number of vh performed. it can also be argued that the type of cases at different times would influence the type of procedure performed and may partially explain the changing trend. there are several reasons for caution in extrapolating conclusions from this study. we were unable to compare our ti results with ti in other institutions in the region as there is as yet no published data. to our knowledge, we are the first to report ti for hysterectomy in the region. the ti at our institution is lower than the reported ti from canada and france; however, these ti values are not comparable due to the difference in resources and training of gynaecologists in north america, europe and the middle east. additionally, we could identify the following limitations to our study. first, the numbers of hysterectomy procedures performed per year at our institution are small with an annual incidence of 0.87%. although we attempted to compensate for that by looking at the overall number of hysterectomies performed over seven years, the sample size remained small. second, when looking at the different indications for hysterectomies, we found that 2.7% of cases were malignant conditions and the rest were benign. the details of the cases would not change the ti, but could shed light on possible reasons for not choosing the minimally invasive approach. for example, in the case of advanced uterine and ovarian cancer, the minimally invasive hysterectomy procedure may not be the standard of care. a more detailed analysis of the indications for hysterectomies during the period of study should be carried out in order to explain the results. we plan to include this in future expansions of our research project. conclusion with the emphasis on moving towards minimally invasive procedures in gynaecology, it will be imperative to develop quality and performance indicators in order to measure the quality of patient care. the ti indicator is one of the first to be developed for minimally invasive procedures and can be perceived as a quality indicator of excellence in gynaecology. knowing where we stand in terms of providing the best care for our patients is important. in addition, acknowledging that transparency in quality is the first step towards achieving excellence will improve acceptance of accountability. in this study, we were able to establish that the ti for hysterectomy at our institution can be improved by increasing the number of minimally invasive hysterectomies through providing more trained gynaecologists, operating theatre nurses trained in endoscopy procedures and availabitlity of appropriate laparoscopic equipment. as a result we expect that the ti at our institution will increase in the near future. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g m e n t s an abstract of this study was accepted by the american association of gynecologic laparoscopists (aagl) for the 39th global congress on minimally invasive gynecology, 8–12 november 2010 in las vegas, nevada and published in the journal of minimally invasive gynaecology in november 2010 (17:s73). references 1. mclaughlin v, leatherman s, fletcher m, owen jw. improving performance using indicators. recent experiences in the united states, the united kingdom, and australia. int j qual health care technicity as a quality indicator of excellence in gynaecology 96 | squ medical journal, february 2012, volume 12, issue 1 2001; 13:455-62. 2. women’s health care physicians (committee on patient safety and quality improvement). quality and safety in women’s health care. 2nd ed. danvers, ma: american college of obstetricians and gynecologists, 2010. 3. garry r, fountain j, mason s, hawe j, napp v, abbott j, et al. the evaluate study: two parallel randomised trials, one comparing laparoscopic with abdominal hysterectomy, the other comparing laparoscopic with vaginal hysterectomy. bmj 2004; 328:129-33. 4. le point. hôpitaux le palmarès 2008. from : w w w.lepoint.fr/html/hopitaux-2008/chirurgiegynecologique.jsp. accessed: aug 2010. 5. laberge py, singh ss. surgical approach to hysterectomy: introducing the concept of technicity. j obstet gynaecol can 2009; 31:1050-3. 6. annual health report. ministry of health, sultanate of oman, 2008. muscat: ministry of health, 2008. clinical & basic research sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e218-222, epub. 7th apr 14 submitted 2nd sep 13 revisions req. 30th oct & 31st dec 13; revisions recd. 20th nov 13 & 4th jan 14 accepted 19th jan 14 department of nursing, hawler medical university, erbil, iraq author e-mail: d.sallih@yahoo.com معارف ومواقف مديري املدارس االبتدائية حنو مرض الصرع لدى األطفال يف مدينة أربيل، العراق �صالح احمد عبداهلل abstract: objectives: this study aimed to determine the knowledge and attitudes of primary school managers regarding epilepsy among school children in erbil city, iraq. methods: a cross-sectional study was conducted in primary schools between 18 june and 18 august 2013. a total of 80 primary school managers were selected to answer a questionnaire covering three domains: socio-demographical characteristics, knowledge of epilepsy and attitudes towards epilepsy. results: more than half of the participants (55%) had spent less than 10 years in school administration. more than one-third (37.5%) of the participants believed that epilepsy was an infectious disease, and over half of the respondents (53.75%) stated that epilepsy cannot be treated or prevented. conclusion: although the respondents’ attitudes towards pupils with epilepsy were generally positive, their knowledge of epilepsy was imperfect; thus, an epilepsy education campaign is required. this should focus on the causes of epilepsy and its management. keywords: epilepsy; health knowledge; attitudes; practice; iraq. امللخ�ص: الهدف: الت�صنج هوالنوبة املر�صية ال�صديدةوالتي ي�صاحبها الإطلق الكهربائي الذي ل ميكن ال�صيطرة عليه من اخلليا الع�صبية يف الدماغ. وهي قد حتدث ب�صورة عفوية دون اأي �صبب وا�صح. وهدفت الدرا�صة اإىل معرفة املعارف واملواقف من مديري املدار�س البتدائية بخ�صو�س ال�رشع بني اأطفال املدار�س يف مدينة اأربيل. الطريقة: اأجريت درا�صة مقطعية يف املدار�س البتدائية يف مدينة اأربيل/العراق بني 18 يونيو و 18 اأغ�صط�س 2013. مت اختيار ثمانني من مديري املدار�س البتدائيةلإجابة ثلثة ا�صتبيانات يف ثلثة جمالت خمتلفة: املجال الأول عن اخل�صائ�س الجتماعية والدميوغرافية و املجال لديهم الدرا�صة �صملتهم ممن )55%( اأن النتائج اأظهرت اأ�صئلة(. النتائج: 10( ال�رشع مر�س حول املواقف الثالث واملجال اأ�صئلة( املعرفة )10 الثاين خربة اأقل من 10 �صنوات يف الإدارة وكان اأكرث من ثلث )%37.5( امل�صاركني لديهم مفهوم خاطىء اأن ال�رشع هو مر�س معد. اأكرث من ن�صف امل�صاركني جتاه الدرا�صة يف امل�صاركني مواقف اإيجابية اإىل الدرا�صة نتائج اأ�صارت عليه. اخلال�صة: ال�صيطرة اأو منه ال�صفاء ميكن ل ال�رشع اأن ذكروا )53.75%( التلميذ الذين يعانون من ال�رشع ولكن كانت هناك اأوجه ق�صور مهمة من حيث املعرفة العامة حول ال�رشع. ونو�صي بتدريب وتوعية مديري املدار�س البتدائية عن مر�س ال�رشع وطرق علجة. مفتاح الكلمات: ال�رشع؛ املعرفة ال�صحية؛ املواقف؛ املمار�صة؛ العراق. primary school managers’ knowledge of and attitude towards epilepsy among children in erbil city, iraq salih a. abdulla advances in knowledge a large segment of the primary school manager population in the city of erbil in northern iraq know very little about epilepsy. regardless of their understanding of epilepsy, primary school managers in erbil demonstrate incorrect attitudes towards children with this disorder. application to patient care this research emphasises the need to include epilepsy management education in school curricula. health education should focus on improving knowledge of epilepsy among school managers. epilepsy is a chronic disorder ofabnormal, recurring, excessive and self-terminating electrical discharge of neurons in the brain in which a person has recurrent seizures.1 seizures are paroxysmal, uncontrolled electrical discharges of neurons in the brain that interrupt normal function.2 a seizure (sometimes called a convulsion) is a single event of abnormal electrical discharge in the brain resulting in an abrupt and temporary altered state of cerebral function.3 the incidence of epilepsy is 0.3–0.5% in different populations throughout the world, with the prevalence salih a. abdulla clinical and basic research | e219 of epilepsy estimated at 5–10 people per 1,000.4 epilepsy can influence behaviour in many different ways; these changes in behaviour can be either due to the underlying cause of the epilepsy; a side-effect of the seizures; the drugs used to treat the epilepsy, or the management of the disorder.5 the frequent need for continuous medical care in epilepsy, in addition to the availability of antiepileptic drugs, justifies the careful planning of an epilepsy awareness programme. persons suffering from epilepsy are often stigmatised, mainly as a result of fear of the unexpected and public loss of self-control.6 therefore, primary school managers’ knowledge of and attitudes towards epilepsy should be considered as an important issue since their knowledge and attitudes will have a significant impact on the learning outcomes of their students. this study aimed to assess the knowledge and attitudes of primary school managers in erbil, iraq, concerning epilepsy among schoolchildren and to find relationships between the managers’ demographical data and their knowledge and attitudes. methods this cross-sectional study was performed in erbil city in northern iraq from 18th june to 18th august 2013. this is a wealthy region (population 1,000,000) with an economy based on natural resources, industry and commercial activities and services. in erbil city, primary school managers are administrators in schools while retaining some limited teaching responsibilities. out of the 525 primary schools, 80 primary school managers were selected by a purposive sampling method. this sample size was chosen because it reduced cost and time while still allowing for an estimation of information about the whole population. the sample size calculation indicated that a sample of 80 managers was appropriate, considering a 95% confidence interval. a questionnaire was designed based on the general knowledge, attitude, practice (kap) questionnaires used in many previous studies with slight modifications adapted to iraqi society. the aim of the questionnaire was to measure the knowledge and attitude of primary school managers toward epilepsy among children.7,8 questions covered three domains: socio-demographic characteristics (including age, gender, years of formal education, years of experience in administration, marital status and religion); knowledge of epilepsy (10 questions) and attitudes towards epilepsy (10 questions). the content validity of the questionnaire was tested after getting comments from specialists in the field. test-retest reliability was employed to determine the questionnaire’s reliability by collecting data from questionnaires completed by 10 primary school managers. the pearson correlation coefficient was then computed. the findings indicated that r = 0.96 for the test-retest reliability. a total of 105 questionnaires were distributed, with a 76.2% response rate. frequency tables were developed to display the frequencies of responses to each of the 20 questions. the respondents were notified of the aims of the study and assured of the confidentiality of the data. verbal permission was received before data collection, keeping in mind that verbal consent is easier to obtain in the iraqi culture as a request for written consent creates fear among expected participants which often results in non-participation in prospective studies. the questionnaires were filled out anonymously to encourage the respondents to participate actively. the scientific & ethical committee of the college of nursing of hawler medical university granted approval for the study on 13th may 2013. results the mean age of the managers was 44.62 years (standard deviation [sd] = 8.57, range = 24‒63). table 1 shows that nearly half (45%) of the respondents were aged 40–49 years. males constituted 62.5% of the respondents. with respect to formal years of education, 67.5% had 14 years of formal education and 2.5% had 12 years of formal education. more than half of the respondents (55%) had less than 10 years in administration. regarding the marital status of the studied sample, 68.8% were married. table 2 shows that more than one-third (37.5%) of the participants believed that epilepsy was an infectious disease. more than half of the participants (53.8%) stated that epilepsy cannot be treated or prevented. high percentages of the respondents knew or believed that epilepsy is a chronic neurological disorder (93.8%); epilepsy affects people of all races and genders (95.0%); children who have epilepsy cannot perform any physical exercises (92.5%), and children with epilepsy have difficulties in acquiring knowledge (65.0%). more than half of the subjects (58.8%) knew that epilepsy can be hereditary and more than onethird knew that brain tumours and malnutrition can cause epilepsy. table 3 shows that more than half (55.0%) of the participants thought that children who have epilepsy should be taught separately and in a different classroom from non-epileptic children. more than two-thirds (72.5%) of the subjects believed that children with primary school managers’ knowledge of and attitude towards epilepsy among children in erbil city, iraq e220 | squ medical journal, may 2014, volume 14, issue 2 epilepsy have equal privileges to other citizens. more than half of the respondents thought that children with epilepsy are: mentally underdeveloped; a threat to the community; should be separated from others who do not have epilepsy, and can be expected to demonstrate illegal behaviours more often than non-epileptic pupils. the majority of primary school managers believed that children who have epilepsy do not have a normal life expectancy, wish to live with others who have epilepsy and have an undesirable impact on the other children in a regular class. table 4 shows the correlation between total knowledge and attitude scores with some variables in the study. the results show a positive statistically significant correlation between knowledge and attitude with age, years of formal education and number of years in administration. discussion the analysis of the primary school managers’ demographic characteristics revealed that most of the primary school managers were between 40–49 years; this result agrees with a study conducted by dantas et al. in brazil to assess teachers’ knowledge and attitudes towards epilepsy which indicated that 69.0% of teachers were between 30–49 years.6 in the iraqi educational system, especially that of erbil city, those who wish to become school managers are required to have at least 10 years of teaching and learning experience. concerning the managers’ level of education, this study revealed that 67.5% of the respondents had 14 years of formal education (with an institutional qualification), while the study in northeast brazil demonstrated that 70.0% of their participants had 14 years of education.6 among those surveyed, 37.5% believed that epilepsy is an infectious disease; this is in agreement with a study of schoolteachers in both urban and rural settings in nigeria which found that 45.5% of the 60 respondents felt that seizure disorders were infectious.9 the current study indicated that 53.8% of the participants supposed that epilepsy cannot be treated or prevented; similarly, a study of 360 schools in thailand indicated that approximately half of the table 1: demographic data of primary school managers (n = 80) demographic characteristic n % age in years 20–29 4 5 30–39 17 21.3 40–49 36 45 50–59 18 22.5 >60 5 6.3 formal years of education 12 2 2.5 14 54 67.5 16 24 30 number of years in administration <10 44 55 10–19 27 33.8 20–29 6 7.5 30–39 2 2.5 >40 1 1.3 marital status single 17 21.3 married 55 68.8 widowed 2 2.5 separated 6 7.5 table 2: knowledge of epilepsy among primary school managers (n = 80) questionnaire item response n (%) yes no don’t know epilepsy is an infectious disease 30 (37.5) 48 (60) 2 (2.5) epilepsy cannot be treated or prevented 43 (53.8) 28 (35) 9 (11.3) convulsions take place after an abnormal electric discharge occurs 77 (96.3) 1 (1.3) 2 (2.5) epilepsy is a chronic neurological disorder 75 (93.8) 1 (1.3) 4 (5) epilepsy affects people of all races and genders 76 (95) 1 (1.3) 3 (3.8) children who have epilepsy cannot perform any physical exercise 74 (92.5) 1 (1.3) 5 (6.3) children who have epilepsy have difficulties in acquiring knowledge 52 (65) 18 (22.5) 10 (12.5) epilepsy can be hereditary 47 (58.8) 23 (28.8) 10 (12.5) brain tumours can cause epilepsy 39 (48.8) 16 (20) 25 (31.3) malnutrition is one cause of epilepsy 32 (40) 26 (32.5) 22 (27.5) salih a. abdulla clinical and basic research | e221 schoolteachers (46.6%) thought that epilepsy was a chronic, incurable disease.10 the present study shows that 65% of primary school managers believed that epileptic children have difficulties in acquiring knowledge; correspondingly, in a study by thacker et al. in india assessing knowledge, attitude and practice towards epilepsy among schoolteachers, nearly half of the subjects (47.7%) stated that epileptics have normal intelligence.11 however, 31.7% of teachers believed that their intelligence was below average. the results of the current study show that 55% of managers believed that schools should separate epileptic children into another classroom, while thacker et al. demonstrated that only 32.2% of the indian schoolteachers were troubled by having epileptic pupils in their classrooms.11 this is in contrast to a study that demonstrated that more than 70% of nigerian secondary schoolteachers did not feel that epileptic patients could be placed in regular classrooms.12 the results of the current study found that school managers perceived that epilepsy can have a hereditary cause (58.75%). this result was in agreement with a study conducted in iran in 2012, which stated that 41% of biology teachers were aware that the aetiology of epilepsy was genetic.13 however, most iraqis traditionally consider that the majority of diseases have a genetic cause. the majority of primary school managers in the current study believed that children with epilepsy cannot perform any physical exercise (92.5%). this is in contrast to a 2013 study in zimbabwe where three-quarters of the respondents (74%) indicated that epileptic pupils should do active sports for interaction and socialisation purposes.14 less than half (40%) of the participants in the current study indicated that malnutrition is a cause of epilepsy; whereas, in humans, restricted nutrition does increase the risk of neurological disorders such as epilepsy.15 an important limitation of the current study was the non-response bias. school managers with high workloads may not have responded to the survey due to a lack of time. table 3: attitudes among primary school managers regarding epilepsy (n = 80) questionnaire item response n (%) agree uncertain disagree children who have epilepsy should be put into separate classrooms 44 (55.0) 5 (6.3) 31 (38.8) children who have epilepsy have equal privileges like all citizens 58 (72.5) 12 (15.0) 10 (12.5) children who have epilepsy do not have a normal life expectancy 69 (86.2) 6 (7.5) 5 (6.3) children who have epilepsy are mentally underdeveloped 49 (61.2) 5 (6.3) 26 (35.5) children who have epilepsy are a threat to the community 62 (77.5) 9 (11.3) 9 (11.3) epileptic children should not mix with others from their age group 45 (56.3) 11 (13.7) 24 (30.0) children who have epilepsy are expected to demonstrate illegal behaviours more often than normal pupils 46 (57.5) 9 (11.3) 25 (31.2) epileptic pupils who take medications that stop seizures are like anyone else 50 (62.5) 13 (16.2) 17 (21.2) epileptic children wish to live with others who have epilepsy 64 (80.0) 8 (10.0) 8 (10.0) children who have epilepsy have an undesirable impact on other children in regular classes 69 (86.3) 10 (12.5) 1 (1.3) table 4: correlations of primary school managers’ knowledge and attitude scores with their age, formal years of education and number of years in administration (n = 80) demographic characteristic r value p value age knowledge scores 0.360* 0.012 attitude scores 0.271* 0.043 years of formal education knowledge scores 0.279 0.051 attitude scores 0.248 0.081 number of years in administration knowledge scores 0.422** 0.003 attitude scores 0.796* 0.031 **correlation is significant at the 0.01 level; *correlation is significant at the 0.05 level. primary school managers’ knowledge of and attitude towards epilepsy among children in erbil city, iraq e222 | squ medical journal, may 2014, volume 14, issue 2 conclusion although the respondents’ attitudes towards pupils with epilepsy were generally positive, primary school managers’ knowledge of epilepsy was inaccurate; thus, an epilepsy education campaign is required and should focus on the causes of epilepsy as well as its management. such a campaign would increase teachers’ knowledge, create understanding among the epileptic students’ classmates as well as within the epileptic community and improve the quality of life for all. a c k n o w l e d g e m e n t s this study was supported by kerman university of medical sciences. the authors would like to thank the research deputy for their financial support. references 1. lowenstein dh. seizures and epilepsy. in: fauci as, braunwald e, kasper dl, hauser sl, longo dl, jameson jl, et al., eds. harrison’s principles of internal medicine. 17th ed. new york, usa: mcgraw-hill professional, 2008. pp. 2357‒71. 2. lewis sm, heitkemper mm, dirkson sr, o’brien pg, dirksen sr, eds. medical-surgical nursing: assessment and management of clinical problems, volume 2. 6th ed. st. louis, missouri: elsevier health sciences, 2003. p. 1555. 3. hickey jv. the clinical practice of neurological and neurological nursing. 4th ed. philadelphia, usa: lippincott williams & wilkins, 2003. p. 1547. 4. lowestein dh. seizures and epilepsy. in: fauci as, braunwald e, hauser sl, kasper dl, hauser sl, longo dl, et al., eds. harrison’s principles of internal medicine. 17th ed. mcgrawhill professional, 2008. pp. 2498‒512. 5. shorvon sd. handbook of epilepsy treatment. 1st ed. london, uk: wiley-blackwell, 2000. p. 1555. 6. dantas fg, cariri ga, cariri ga, ribeiro filho ar. knowledge and attitudes toward epilepsy among primary, secondary and tertiary level teachers. arq neuropsiquiatr 2001; 59:712‒6. doi: 10.1590/s0004-282x2001000500011. 7. jensen r, dam m. public attitudes toward epilepsy in denmark. epilepsia 1992; 33:459‒63. doi: 10.1111/j.1528-1157.1992. tb01691.x. 8. rwiza ht, matuja wb, kilonozo gp, haule j, mbena p, mwang’ombola r, et al. knowledge, attitude, and practice toward epilepsy among rural tanzanian residents. epilepsia l993; 34:1017‒23. doi: 10.1111/j.1528-1157.1993.tb02127.x. 9. akpan mu, ikpeme ee, utuk eo. teachers’ knowledge and attitudes towards seizure disorder: a comparative study of urban and rural school teachers in akwa ibom state, nigeria. niger j clin pract 2013; 16:365‒70. doi: 10.4103/11193077.113465. 10. kankirawatana p. epilepsy awareness among school teachers in thailand. epilepsia 1999; 40:497‒501. doi: 10.1111/j.15281157.1999.tb00747.x. 11. thacker ak, verma am, ji r, thacker p, mishra p. knowledge awareness and attitude about epilepsy among schoolteachers in india. seizure 2008; 17:685‒90. doi: 10.1016/j. seizure.2008.04.007. 12. mustapha af, odu oo, akande o. knowledge, attitudes and perceptions of epilepsy among secondary school teachers in osogbo south-west nigeria: a community based study. niger j clin pract 2013; 16:12‒18. doi: 10.4103/1119-3077.106709. 13. asadi-pooya aa, torabi-nami m. knowledge and attitude towards epilepsy among biology teachers in fars province, iran. iran j child neurol 2012; 6:13‒18. 14. goronga p, gatsi r, gatahwi l, dozva m. primary school teachers’ attitudes towards pupils living with epilepsy: the zimbabwean experience and implications for practice. am based res j 2013; 2:41‒50. 15. gomes tk de c, oliveira sl de, castro rm de. malnutrition and experimental epilepsy. j epilepsy clin neurophysiol 2011; 17:24‒9. doi: 10.1590/s1676-26492011000100006. clinical & basic research sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 336-343, epub. 15th jul 12 submitted 30th oct 11 revision req. 31st jan 12, revision recd. 11th feb 12 accepted 24th mar 12 department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, oman. e-mail: ibrahim1@squ.edu.om اجتاهات طلبة السنة األوىل بكلية الطب إلسرتاتيجية دراسة مادة علم التشريح بطريقة معدلة تعتمد على ) tbl ( الدراسة يف جمموعات اإبراهيم حممد اأنووا امللخ�ص: على الرغم من اأن الدرا�سة يف جمموعات )tbl( ت�ستخدم على نطاق وا�سع يف التعليم الطبي، فاإن تقييمها كان حمدوداً ح�سب ال�سحية والعلوم الطب بكلية الأوىل ال�سنة طالب لتقبل ونوعي كمي تقييمًا الورقة ت�ستعر�سهذه لها. خ�سعوا الذين الطالب نظر وجهة للدرا�سة يف جمموعات ) tbl (. الطريقة: مت حتويل حما�رسات دورات علم الت�رسيح اإىل �سل�سلة من ) tbl ( اجلل�سات لدفعتني من طالب ال�سنة الأوىل بكلية الطب والعلوم ال�سحية. كل جل�سة حتتوي على مرحلة ماقبل القراءة واختبارات للتاأكد من ال�ستيعاب داخل الف�سل و حل امل�ساكل و امل�سائل ال�رسيرية من خالل جمموعات طالبية. ويف نهاية كل برنامج درا�سي، يجري اإ�ستبيان للطالب با�ستخدام الأدوات cronbach’s ( النوعية والكمية لتقييم تقبلهم لالإ�سرتاتيجية.التوافق الداخلي لبنود هذا الإ�ستبيان يتم التاأكد منه بتحليل امل�سداقية بطريقة املفتوحة الأ�سئلة درا�سة متت كما كمي. نهج على اأجريت قد املوازية التحاليل و التحليل لعوامل الرئي�سية املكونات .)alpha التحليل املو�سوعي. النتائج: اأ�سارت تقييمات الطالب اإىل اأن ) tbl(،كما مت تطبيقها يف هذه الدرا�سة، بديل مرحب به عو�سًا عن نظام حدد الدرا�سة. قاعات داخل النقا�ض اإثراء يف ثمره اآتى و ال�رسيرية للمع�سالت حلول اإيجاد على ذلك �سجع فقد باملحا�رسات، التدري�ض على يوافقوا مل الطالب معظم فاإن كل وعلى )cronbach’s alpha 0.602–0.875( عوامل خم�سة للتحاليل الرئي�سي املعامل زيادة وولدت درا�ستهم، تنظيم يف اأ�سهمت الإ�سرتاتيجية هذه اأن على الطالب معظم اتفق اجلن�سني. من خمتلطة جمموعات يف الدرا�سة يف الوعي للتعلم املوجه ذاتيا، مما كان له اأثر اإيجابي على توجهاتهم يف التعلم. اخلامتة: الدرا�سة يف جمموعات )tbl( هي اإ�سرتاتيجية تعليمية مرحب بها كما ورد عن طلبتنا يف ال�سنة الأوىل بكلية الطب والعلوم ال�سحية. ومت تقبلها كطريقة مثلى مقارنة بالطريقة املعتمدة على حمتوى املحا�رسات. ويتم الآن التحقق من تاأثريها الفعلي على م�ستوى حت�سيل الطالب. مفتاح الكلمات: التعلم الن�سط، حل امل�ساكل، �سلوكيات، �سلوك تعاونى، عمان abstract: objectives: although team-based learning (tbl) is widely used in medical education, its evaluation from the perspectives of the students exposed to it has been limited. this paper reports on a quantitative and qualitative evaluation of perceptions of first year medical students towards tbl. methods: lectures in an anatomy course were transformed into a series of tbl sessions for two cohorts of first-year medical students. each session consisted of pre-class reading, in-class readiness assurance tests, and problem-solving of clinical cases by student teams. at the end of each course, students were surveyed using qualitative and quantitative instruments to assess their perceptions of the strategy. internal consistency of questionnaire items was determined by a reliability analysis (cronbach’s alpha). principal component factor analysis and correspondence analysis were conducted on the quantitative data. open-ended questions were explored by thematic analysis. results: students’ evaluations indicated that tbl is a welcome alternative to lecture-based teaching; as implemented in this study, it encouraged clinical problem solving and fruitful in-class discussion. principal component factor analysis identified five factors (cronbach’s alpha 0.602–0.875). however, the majority of students disapproved of mixed gender tbl teams. most students agreed that the strategy facilitated consistency in their study, generated an increased awareness about selfdirected learning, and had a positive impact on their learning attitudes. conclusion: tbl is a welcome instructional strategy as reported by our first-year medical students. it was perceived to be a better approach compared to content-based lectures. the effect on actual student performance is currently being investigated. keywords: active learning; problem solving; attitudes; cooperative behavior; oman. perceptions and attitudes of first-year medical students on a modified team-based learning (tbl) strategy in anatomy ibrahim m inuwa ibrahim m inuwa clinical and basic research | 337 “i wish all our lectures will be like this tbl.” first year medical student. one of the global trends in teaching in medical schools has been a move towards more student-centered, integrated, clinical application models.1–3 in addition, teaching strategies that promote active learning and problem-solving are increasingly being advocated.4–7 an example of such a strategy that combines features of student-centeredness and problem-solving attributes is team-based learning (tbl).8 in its classical format, tbl employs a structured three-phase sequence during which learners study an advanced assignment defined by faculty, demonstrate knowledge through individual and group readiness assurance tests (irats, grats), and apply course concepts to problemsolving exercises designed by faculty and analysed by teams.9 the method employs strategies that incorporate the effectiveness of small group learning methods like problem-based learning (pbl) into large-group, lecture-oriented sessions.10,11 adequate knowledge of basic sciences such as anatomy, with a strong emphasis on ‘clinical application’, logical learning, and developing effective problem solving skills is considered crucial for effective and safe clinical practice.12,13 although numerous strategies have been employed to develop these skills, implementing them early in the curriculum can be a great challenge. this is especially so in cases where the students have had little or no previous exposure to active learning and teamwork.14–16 in many medical curricula, the teaching methodology in basic sciences is largely characterised by content-based, tutor-centered lectures with hardly any problem-based or studentcentered activities.17 this is despite the increasing recognition of the importance of early student introduction to clinical application, active learning, and group problem solving.15,16,18,19 one of the newer methods to develop these skills is the tbl method, first introduced by michaelsen et al. for teaching large classes in business schools.10 other significant motivators for implementing tbl were to introduce peer teaching and learning, keep students more engaged during in-class activities, and encourage students to take responsibility for their own learning. however, unlike other wellestablished teaching strategies, such as pbl, tbl has only recently been employed as an active learning strategy in medical education.20–23 in its classical format [figure 1], tbl employs a structured three-phase sequence: preparation, during which learners study an advance assignment defined by faculty; readiness assurance, where learners demonstrate knowledge through individual and group readiness assurance tests (irats and grats), and application, where learners apply course concepts to problem-solving exercises designed by faculty and analysed by teams.9 in this study, we evaluated the implementation of the tbl strategy over two semesters in the first year of a medical curriculum by using a survey that elicited student perceptions of both the process and its facilitation of their learning. methods the college of medicine & health sciences (com&hs) at sultan qaboos university (squ) has recently adopted an integrated, presentationbased, outcome-based and student-centered curriculum. the six-year curriculum is organised into three phases: foundation of medical sciences (one year), integrated organ-system phase (2.5 years), and clerkship phase (2.5 years). teaching methods during the first two phases include didactic lectures, laboratory sessions (including clinical skills) and tutor-led seminars. the majority of students have had 12 years of secondary education which is an entry qualification to squ. advances in knowledge the implementation of tbl is feasible in the early years of undergraduate training, especially in a setting similar to that of sultan qaboos university’s college of medicine & health sciences. team-based learning is a refreshing alternative to lectures as a method of teaching large groups. application to patient care although this strategy was implemented in the basic sciences, there are implications for patient care. through tbl, students begin to learn about teamwork, peer assessment, and clinical reasoning, which have positive implications for their ability to provide quality patient care in the future. a cross-sectional study of perceptions and attitudes of first-year medical students on a modified team-based learning (tbl) strategy in anatomy 338 | squ medical journal, august 2012, volume 12, issue 3 although the implementation of the tbl strategy is part of the ongoing innovation in teaching within the medical school, this study was conducted as part of a teaching scholarship in medicine. as such, ethical approval was sought and granted by the com&hs medical ethics & research committee. before photographs were taken of students engaged in the tbl activity, they were informed of the intention to publish some of the images as part of a journal article. therefore, consent was sought and permission given by the students. in place of lectures in the introduction to anatomy course during the foundation phase, a modified tbl strategy was employed during two semesters of the academic year.24 the remaining contact time was utilised for laboratory practical sessions in the dissecting room. teams of six to seven students were formed by random sorting at the beginning of the semester and the students remained on the same teams throughout the course.25 in view of cultural sensitivities regarding mixing of genders, each group consisted of members of the same gender. the students remained in the same group throughout each semester. reading materials, multiple choice questions (mcqs) for readiness assurance (irat and grat) were prepared well before the semester started.26 such reading materials were uploaded onto the moodletm learning management software accessible to all students. additional study materials included readings from recommended textbooks, prosected specimens in the anatomy laboratory, as well as an image bank created on the learning management platform. the contents of all the reading materials were linked to a list of learning objectives for each of the eleven tbl sessions. each of the modified tbl sessions consisted of 3 phases: pre-class preparation, readiness assurance testing (including application of concepts to patient cases) and tutor wrap-up [figure 1]. a trial tbl session was held to familiarise students with the entire concept. the first phase occurred prior to the tbl session and was completed by each student individually. the second and third phases occurred during the two-hour tbl session and involved individual students, their tbl teams, and the entire class [figures 2a to 2d]. a final post-tbl reflection preparation readiness assurance application exercise 1. individual study 2. individual test (irat) 3. group test (grat) 4. team appeals 5. tutor feedback 6. application of concepts and problem-solving exercises 40-60 minutes of class time 40-60 minutes of class time figure 1: the sequence of activities in a classical team-based learning (tbl) strategy figure 2: after individual study, the second and third phases were conducted in the computer laboratory and lecture theatre. (a) the individual readiness assurance test (irat) was administered in the computer laboratory. (b) the group readiness assurance test (grat). ibrahim m inuwa clinical and basic research | 339 occurred at the end of the course consisting of peer evaluation where students within each team assessed one another with respect to teamwork and interpersonal skills. the whole tbl activity accounted for 20% of the overall course grade. this was distributed as 16%, 3% and 1% for individual quizzes (irat), group quizzes (grat), and peer evaluation, respectively. the whole process strategy was evaluated both qualitatively and quantitatively. students were asked about their perceptions through a six-point likerttype questionnaire consisting of 22 items. their responses were rated on a scale of 1–6 (1 = strongly disagree, 2 = disagree, 5 = agree, and 6 = strongly agree). the neutral (undecided) scale was split into two (3 = undecided but leaning towards disagree, and 4 = undecided but leaning towards agree) to increase the chance of obtaining either a positive or negative perception of the activity. in addition, the students were also asked a number of open-ended questions to solicit comments on the positive and negative aspects of tbl, and to garner suggestions as to where improvements could be made. to aid in the identification of items to be included in the questionnaire, the course faculty conducted focus group meetings with students to explore aspects of the strategy they valued and appreciated. themes from the focus groups were used to create a formal questionnaire to elicit student feedback about their experiences with tbl. to ensure face and content validity, the questionnaire was initially pilot-tested on 10 students before being administered to the whole class. the questions were directed at probing students’ level of preparation for rats, the usefulness of learning issues for acquiring knowledge, the perceived importance of group discussion for deeper understanding, and students’ attitudes about the facilitation of the strategy. quantitative data analysis was carried out with statistical package for the social sciences (spss, version 16.0, polar engineering and consulting, chicago, illinois, usa, 2007). a principal components factor analysis with varimax rotation (kaiser normalisation) was conducted on the complete quantitative data set. the internal consistency of questionnaire items was determined by reliability analysis (cronbach’s alpha). correspondence analysis based on gender was carried out on items with the highest mean score. all open-ended responses were categorised into common themes. results a total of 125 out of 170 students completed the online questionnaire (response rate = 73.5%). a principal components factor analysis with varimax rotation (kaiser normalisation) yielded five factors (subscales) with eigen values greater than 1.0. the five factors, comprising 22 items, accounted for 66.7% of the overall variance and were determined to represent motivation (43.6%), teamwork (4.8%), learning objectives (6.9%), knowledge application (6.1%), and facilitation (5.1%), each with 3–5 items [table 1]. internal consistency (cronbach’s alpha) for the 22-item questionnaire response was 0.933. within each subscale, internal consistency of items is shown in table 2. the motivation subscale had the highest rating (0.833) whilst teamwork had the lowest (0.602). correspondence analysis by gender on items with the highest mean score in each of the five subscales is shown in table 2. the teamwork item had the lowest percentage of positive perception by both male and female students (58.6% and 67.1% respectively). male students felt more motivated by the strategy than females (82.3% and 68.4% respectively). in contrast, more female students agreed that the strategy helped them achieve the set objectives of the sessions than males (88.1% and 79.3% respectively). a total of 50 students (40%) responded to the open-ended questions. they provided 75 responses, out of which four themes emerged from content analysis [table 4]. most students agreed that the strategy promoted deeper learning and was an enjoyable experience. the strategy also helped nurture self-directed learning. although the composition of each tbl group was of the same gender, interestingly, the majority of students (70%) was opposed to the possibility of having mixed gender tbl groups in the future. discussion tbl was introduced early in the medical curriculum with a view to improving upon the teachinglearning experience and to create an active learning environment for our students. in addition, it was a cross-sectional study of perceptions and attitudes of first-year medical students on a modified team-based learning (tbl) strategy in anatomy 340 | squ medical journal, august 2012, volume 12, issue 3 table 1: mean score and percentage of students responding 1–6 (strongly disagree–strongly agree) to items in the quantitative questionnaire (n = 125) item percent responding* strongly disagree strongly agree mean score 1 2 3 4 5 6 motivation 5.2 i prefer tbl to normal lectures 0.8 3.2 2.4 15.2 28.0 50.4 5.1 tbl strategy motivated me to study hard 1.9 2.8 2.8 17.6 40.7 34.3 5.4 i look forward to learn again in a tbl course. 2.4 0 5.6 14.4 26.4 51.2 5.1 tbl challenged me to give my best. 2.4 2.4 6.4 9.6 23.2 56.0 5.3 i felt sad when i missed a tbl session. 4.0 0 4.0 1.6 32.8 57.6 4.9 tbl had a positive impact on my learning. 1.6 0.8 2.4 8.0 42.4 44.8 5.1 teamwork 4.1 tbl helped me learn how to study in a group. 12.0 16.0 11.2 13.6 23.2 24.0 4.5 i would prefer to be in a mixed gender tbl team. 16.8 18.4 8.8 4.8 7.6 3.6 3.1 i frequently studied with my colleagues. 5.6 2.4 2.4 14.4 34.4 40.8 3.5 discussion during grats helped me comprehend better. 4.0 4.8 9.6 18.4 28.0 35.2 4.9 tbl required more hard work by the students. 4.0 1.6 9.6 12.0 41.6 31.2 4.7 learning objectives 5.1 the irat was a good test of my knowledge. 0.8 3.2 2.4 9.6 34.4 49.6 5.0 the course materials were essential for the tbl. 0.8 3.2 2.4 9.6 34.4 49.6 5.2 i understood the learning objectives of the tbl. 2.4 0.8 0.8 12.8 39.2 44.0 5.2 i was able to achieve the learning objectives set. 5.6 4.8 12.0 20.8 26.4 30.4 5.2 knowledge application 5.1 the grat was useful for applying knowledge. 2.4 0.8 0.8 11.2 42.4 42.4 5.1 tbl promoted understanding rather than memorisation. 3.2 0 0 18.4 33.6 44.8 5.1 tbl made me apply what i learned. 3.2 0.8 8.8 20.0 35.2 32.0 5.0 facilitation 5.0 the tbl course is well-organised. 2.4 1.6 6.4 17.6 35.2 36.8 4.9 i was satisfied with this tbl approach. 0.8 3.2 2.4 14.4 44.8 34.4 5.0 the venue of the tbl was comfortable. 1.6 3.2 12.8 17.6 27.2 37.6 4.8 the duration of the tbl was just right. 1.6 1.6 0 13.6 18.4 64.8 5.4 legend: tbl = team-based learning; grat = group readiness assurance test; irat = individual readiness assurance test ibrahim m inuwa clinical and basic research | 341 thought advantageous to introduce the concept of self-directed learning and team working very early in the curriculum. the combination of the quantitative and qualitative approaches in this evaluation helped to complement the findings of each approach. the five factors identified by factor analysis explained a good percentage (66.7%) of the variance. qualitative analysis of students’ responses to open-ended questions supported the quantitative data and added valuable information to be considered in future improvements in using tbl. the main strengths of the strategy, as perceived by the students, were related to considering tbl an enjoyable learning experience, with the invaluable potential to enhance students’ learning attitudes. tbl advocates self-directed learning of course content and student application of this new knowledge within small collaborative teams and full classroom discussions, thus promoting deeper learning. being aware that the irat will be administered at the beginning of a tbl session motivated students to prepare well by attempting to master independently the knowledge contained in the advanced assignment. nieder et al. have used the tbl method for teaching gross anatomy and embryology. their first experience with this method was positive. the students felt that working in teams was an effective way of learning content and applying this to practice clinical reasoning skills.27 other studies have shown that student perception of knowledge acquisition with the tbl method compared favourably with more traditional methods such as lectures.24,28–30 for example, parmelee et al. recently assessed the attitudes of medical students to tbl in the pre-clinical curriculum. they reported high rates of agreement in response to a questionnaire assessing overall satisfaction with the impact of tbl on learning quality.31 we made two interesting observations during this study: first, our students seem not to value team-work as much as the other aspects of tbl and, second, they were reluctant to accept mixed gender teams. this lack of enthusiasm for teamwork could be related to the competitive atmosphere in secondary school. during secondary education, ranking of students is widely used as a means of selection and reward. this competitive atmosphere usually results in students being reluctant to share information. with regards to their opposition to mixed groups, this could be related to the fact than many of the students have been nurtured in a fairly traditional society where secondary education is segregated and mixing with the opposite genders is generally frowned upon. as the university is the first setting where both genders share a common learning environment, it appears that they are not ready yet to accept this change. it will be interesting table 2: internal consistency analysis (cronbach’s alpha) for component factors (subscales) identified in the questionnaire factor cronbach’s alpha motivation 0.875 teamwork 0.602 learning objectives 0.861 knowledge application 0.806 facilitation 0.768 table 3: correspondence analysis by gender of items with the highest mean score in each factor (subscale) *percentage responding (n) (factor) item males n = 58 females n = 67 (motivation) tbl strategy motivated me to study harder 82.3 (48) 68.4 (46) (teamwork) discussion during grats helped me comprehend better 58.6 (34) 67.1 (45) (learning objectives) i was able to achieve the learning objectives set 79.3 (46) 88.1 (59) (knowledge application) tbl promoted understanding rather than memorisation 81.0 (47) 76.1 (51) (facilitation) the duration of the tbl session was just right 81.0 (47) 85.0 (57) * percentage of students who responded ‘agree’ or ‘strongly agree’ legend: tbl = team-based learning; grat =group readiness assurance test. a cross-sectional study of perceptions and attitudes of first-year medical students on a modified team-based learning (tbl) strategy in anatomy 342 | squ medical journal, august 2012, volume 12, issue 3 to find out how these attitudes develop as they mature in the university environment. in addition, the finding that significantly more male students felt motivated by the strategy than females might be related to gender differences in learning styles. student learning style is based on the sensory preference of the individual. these sensory modalities are defined by the neural system that is preferred when receiving information: visual (v), aural (a), mixed read-write (r), and kinaesthetic (k), collectively known as vark.32 students with a v preference learn best by seeing or observing (drawings, pictures, diagrams, demonstrations, etc). learners that prefer a are best suited to learn by listening to or recording lectures, discussing material, and talking through material with themselves or others. r-type learners learn through interactions with textual materials. k-style learners perform best by using physical experiences: touching, performing an activity, moving, doing things within a lesson, and manipulating objects. student learners are capable of using all of these sensory modes of learning; however, each individual has a unique preference, or set of preferences, in which one mode is often dominant.33 the fact that we found females to be less motivated than males could possibly be because more of them dislike the a nature of tbl learning compared to males. indeed, some studies have shown that majority of females prefer mixed r and k learning styles and dislike a styles.34 admittedly, this study suffers from some limitations. first, because the study was crosssectional, we could not determine the long-term effects of tbl in changing students’ attitudes towards self-directed learning and teamwork. second, it remains to be seen how the experience will translate into improved learning as evidenced by better examination scores. third, its impact on future collaborative medical practice remains to be evaluated. these issues will be the focus of our future studies on this teaching strategy. conclusion in summary, our initial experience with a modified tbl process adopted for our first year medical students demonstrated that they perceived the strategy to be more rewarding and enjoyable than regular lecture-based teaching. despite their initial misgivings regarding team work and the mixing of genders during group learning, we believe that with time and experience, tbl has the potential to be an effective and highly valued learning strategy in settings similar to squ’s, thus providing an environment that promotes active learning and deeper understanding of the subject matter. c o n f l i c t o f i n t e r e s t the author declared no conflict of interest. references 1. harden rm, davis mh, crosby jr. the new dundee medical curriculum: a whole that is greater than the sum of the parts. med educ 1997; 31:264–71. 2. hook km, pfeiffer ca. impact of a new curriculum on medical students’ interpersonal and interviewing skills. med educ 2007; 41:154–9. 3. wijnen-meijer m, ten cate tj, van der schaaf m, borleffs jc. vertical integration in medical school: effect on the transition to postgraduate training. med educ 2010; 44:272–9. 4. harden rm. twelve tips to encourage better teaching. med teach 1992; 14:5–9. 5. harden rm, sowden s, dunn wr. educational strategies in curriculum development: the spices model. med educ 1984; 18:284–97. 6. hook km, pfeiffer ca. impact of a new curriculum on medical students’ interpersonal and interviewing skills. med educ 2007; 41:154–9. 7. wijnen-meijer m, ten cate tj, van der schaaf m, borleffs jc. vertical integration in medical school: effect on the transition to postgraduate training. med educ 2010; 44:272–9. table 4: open-ended questionnaire responses categorised into common themes theme percentage (n) of comments* sample comment deep learning 88 (110) “… it is a good way to remember information for long time” team formation 70 (88) “i do not agree to mixed gender tbl group” motivated learning 82 (103) “i really like tbl and hope to have it again and again” self-directed learning 74 (93) “i spend a lot of time for preparing for the tbl …, it helped me a lot” * most students wrote comments that touched on multiple themes. legend: tbl = team-based learning ibrahim m inuwa clinical and basic research | 343 8. michaelsen l, black r. building learning teams: the key to harnessing the power of small groups in higher education. in: kadel s, keener j, eds. collaborative learning: a sourcebook for higher education, vol 2. state college, pensylvania: national center for teaching, learning, and assessment, 1994. pp. 65– 81. 9. michaelsen l, knight a, fink l. team-based learning: a transformative use of small groups in college teaching. sterling (va): stylus publishing, 2004. pp. 85–9. 10. michaelsen l, fink l, knight a. designing effective group activities: lessons for classroom teaching and faculty development. in: dezure d, ed. to improve the academy: lessons for classroom teaching and faculty development. stillwater (ok): new forums press, 1997. pp. 1–19 11. michaelsen l. getting started with team-based learning. in: michaelsen l, knight a, fink l, eds. team-based learning: a transformative use of small groups. westpoint (cn): praeger, 2002. pp. 27–51. 12. boon jm,meiring jh, richards pa. clinical anatomy as the basis for clinical examination: development and evaluation of an introduction to clinical examination in a problem-oriented medical curriculum. clin anat 2002; 15:45–50. 13. heylings dj. anatomy 1999-2000: the curriculum, who teaches it and how? med educ 2002; 36:702–10. 14. geuna s, giacobini-robecchi mg. the use of brainstorming for teaching human anatomy. anat rec 2002; 269:214–6. 15. miller sa, perrotti w, silverthorn du, dalley af, rarey ke. from college to clinic: reasoning over memorization is key for understanding anatomy. anat rec 2002; 269:69–80. 16. holla sj, selvaraj kg, isaac b, chandi g. significance of the role of self-study and group discussion. clin anat 1999; 12:277–80. 17. schwartz pl. active, small group learning with a large group in a lecture theatre: a practical example. med teach 1989; 11:81–6. 18. scott tm. a case-based anatomy course. med educ 1994; 28:68–73. 19. michael j. where’s the evidence that active learning works? adv physiol educ 2006; 30:159–67. 20. haidet p, o’malley kj, richards b. an initial experience with “team learning” in medical education. acad med 2002; 77:40–4. 21. seidel cl, richards bf. application of team learning in a medical physiology course. acad med 2001; 76:533–4. 22. nieder gl, parmelee dx, stolfi a, hudes pd. teambased learning in a medical gross anatomy and embryology course. clin anat 2005; 18:56–63. 23. koles p, nelson s, stolfi a, parmelee d, destephen d. active learning in a year 2 pathology curriculum. med educ 2005; 39:1045–55. 24. dunaway ga. adaption of team learning to an introductory graduate pharmacology course. teach learn med 2005; 17:56–62. 25. mcmahon k. team formation. in: michaelsen l, parmelee d, mcmahon k, levine r, eds. teambased learning for health professions education. sterling (va): stylus publishing, 2008. pp. 85–8. 26. michaelsen l, sweet m. fundamental principles and practices of team-based learning. in: michaelsen l, parmelee d, mcmahon k, levine r, eds. teambased learning for health professions education. sterling, virginia: stylus publishing, 2008. pp. 9–34. 27. nieder gl, parmelee dx, stolfi a, hudes pd. teambased learning in a medical gross anatomy and embryology course. clin anat 2005; 18:56–63. 28. koles p, nelson s, stolfi a, parmelee d, destephen d. active learning in a year 2 pathology curriculum. med educ 2005; 39:1045–55. 29. hunt dp, haidet p, coverdale jh, richards b. the effect of using team learning in an evidence-based medicine course for medical students. teach learn med 2003; 15:131–9. 30. levine re, o’boyle m, haidet p, lynn dj, stone mm, wolf dv, et al. transforming a clinical clerkship with team learning. teach learn med 2004; 16:270–5. 31. parmelee dx, destephen d, borges nj. medical students attitudes about team-based learning in a pre-clinical curriculum. med educ online 2009; 14:1–7 32. fleming n. i’m different; not dumb. modes of presentation (vark) in the tertiary classroom. in: zelmar a, ed. research and development in higher education. canterbury, new zealand: lincoln university, 1995. pp. 308–13. 33. coffield f, moseley d, hall e, ecclestone k. learning styles and pedagogy in post-16-year old learning: a systematic and critical review. learn skills res centre 2004; pp. 1–5. 34. wehrwein e, lujan h, dicarlo s. gender differences in learning preferences amongst undergraduate physiology students. adv physiol educ 2007; 31:153– 7. the term ‘cardiovascular disease’ (cvd) encompasses a wide spectrum of diseases—including ischaemic heart disease (ihd), congenital structural heart disease and various inherited arrhythmias and cardiomyopathies—each of which has its own aetiology and pathogenesis. ihd continues to be a leading cause of morbidity and mortality worldwide and its incidence is increasing in the developing world.1 it is estimated that 17.5 million people die each year from cvd, accounting for 31% of all deaths worldwide; more than three-quarters of these deaths occur in lowand middle-income countries.1 our understanding of the pathogenesis of cvd as a whole, and ihd in particular, has changed over the years and many risk factors have been identified. risk scores can predict a person’s cardiovascular risk over 10 years and identify those at high risk for whom intensive preventive measures would help.2 many new modalities of treatment, both pharmacological and interventional, have been established as the mainstay of treatment over the last few years. however, most of these advances seek to treat or prevent so-called modifiable risk factors. it is important to note that many of these risk factors have a genetic predisposition, thereby limiting the extent to which they can be modified. a genetic basis to most disease processes is now widely accepted and genetic associations have been described for hypertension, obesity, hypercholesterolaemia and diabetes.3 understandably, attention is now focused towards understanding the genetic basis of cvd and ihd in particular. perhaps one of the most remarkable discoveries of the last century is our understanding of genes and our genetic make-up. indeed, it is not surprising that most of the nobel prizes awarded for medicine have been in the field of genetic research.4 the importance of a strong family history as a risk factor for ihd has been engrained into the minds of most medical students. however, despite our advances in knowledge, our understanding of the genes behind cvd is still limited, apart from a few genetic lineages. interestingly, more than 100 different cardiovascular loci have been described in the human genome.3 however, the effects of these loci are still unknown as most studies have only shown associations.3 the current issue of squmj includes two studies investigating the association of certain genes with cardiovascular risk factors. in the first study, rizvi et al. assessed the association of angiotensin converting enzyme and glutathione s-transferase gene polymorphisms with body mass index (bmi) among hypertensive north indians; they found that these gene polymorphisms were not associated with bmi but were significantly associated with hypertension.5 interestingly, other genes that control the reninangiotensin-aldosterone system (raas) have also been implicated in the pathogenesis of hypertension.6 the raas is responsible for salt and water balance and consequently blood pressure. therefore, it is understandable that changes in genes controlling this system could affect blood pressure. in the second study, al-balushi et al. observed the frequencies of arg16gly, gln27glu and thr164ile polymorphisms in the adrenergic β-2 receptor (adrb2) gene in the omani population.7 it is interesting to note that the frequency of these genetic variants in the omani population was similar to that seen in caucasian populations.7 this demonstrates that there does not appear to be an ethnic variation in the polymorphism of this gene. leineweber et al. have suggested that variations in this gene do not directly cause disease processes.8 however, other researchers have noted that variations can affect patients’ responses to drugs that 1department of medicine, sultan qaboos university hospital, muscat oman; 2department of cardiology, university hospitals of north midlands, stoke-on-trent, uk *corresponding author e-mail: sunilnadar@gmail.com اجلينات وأمراض القلب ماهي اخلطوة التالية؟ �سونيل نادر و كويل �ساندو editorial genes and cardiovascular disease where do we go from here? *sunil k. nadar1 and kully sandhu2 sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e448–451, epub. 23 nov 15 submitted 27 sep 15 revision req. 21 oct 15; revision recd. 25 oct 15 accepted 26 oct 15 doi: 10.18295/squmj.2015.15.04.001 sunil k. nadar and kully sandhu editorial | e449 target adrb2, such as those used in the treatments of asthma and hypertension.9,10 where do we go from here? despite our understanding of the genetic basis of these conditions, we are still a long way from applying this knowledge to either the prevention or treatment of ihd. human genetic engineering is still a very contentious and divisive topic. however, an enhanced understanding of these genes and the genetic basis of various risk factors would still enable us to identify high-risk populations, to ensure that high-intensity prophylactic and primary prevention measures can be undertaken. oncology is one such field where the identification of people with high-risk alleles can lead to preventative surgery, although the benefit of such a course of action is controversial.11 many candidate gene studies have also been performed to assess asthma susceptibility; however, no significant correlation has been found between adrb2 gene mutations and response to asthma medications.12,13 in the cardiovascular field, identifying high-risk patients through genetic studies has been helpful for those susceptible to developing cardiomyopathies and channelopathies causing certain arrhythmias. prophylactic interventions, such as implantable cardiac defibrillators, can now help prevent sudden cardiac death in high-risk patients with known pathogenic mutations.14 within the field of ihd, the benefits of genetic studies are yet to be seen. there was a considerable amount of interest 20 years ago, following the identification of certain alleles that were found to be associated with cvd.15 however, despite significant research in this field, longitudinal studies have failed to show any prognostic value for these gene variants in risk-stratifying patients. furthermore, we are still no closer to producing risk models for predicting cardiovascular risk using genetic information.16 one of the main reasons for this is due to the multifactorial nature of ihd pathogenesis. there is a significant degree of interaction between the environment and the genetic make-up of an individual; as a result, whether individuals with a particular genotype eventually contract the disease is another matter. our present understanding seems to suggest that it is not one gene on its own that leads to cvd, but rather an interaction between the effects of various genes.16,17 single nucleotide polymorphisms (snps) are single base changes in an individual’s genome that differ from the usual base at that location. the estimated relative risks associated with snps are very small and individually confer between 1.0–1.2 times the risk of developing the associated disease—a person would therefore need to have dozens or even hundreds of at-risk snps to double or triple the risk of a complex disease such as ihd.17 thus, we would need to test a large number of candidate snps and conduct longitudinal long-term follow-ups before we could obtain any meaningful results for clinical application. the elucidation of epigenetic factors is also critical for our understanding of disease predisposition in ihd.18 epigenetics refers to heritable changes in gene expression that do not require changes in the dna sequence and which are instead mediated by chromatin-based mechanisms. these changes explain why individuals with similar genetic backgrounds and risk factors for a particular disease can have different clinical manifestations and responses to therapy. does this mean that despite the initial excitement we have hit the proverbial ‘brick wall’? are these gene association studies useless? in our opinion, we should not be pessimistic about the future of genetics in the field of cvd and ihd. we are still a long way from fully understanding the true effect of multiple gene variants. genetic testing is still in its infancy and various genome-wide association studies form the foundation of future research. the 1,000 genomes project and the encyclopedia of dna elements (encode) project are two worldwide initiatives that will certainly help improve our understanding of genes.19,20 the encode project was established in 2003 by the national human genome research institute in the usa with the aim of studying the functional elements in the human genome, their tissue distribution and the ways in which changes in dna sequences affect gene function.20 the 1,000 genomes project is an international programme launched in 2008 tasked with cataloguing variations in human genomes across different ethnicities.19 pharmacogenetics is another field in which our knowledge of genes can help us to manage diseases. genes can affect a person’s response to medications and thereby affect the overall outcome of treatment. for example, mutations in the cytochrome p-450 enzyme gene, cy2c19, are associated with decreased responsiveness to the antiplatelet agent clopidogrel and an increased likelihood of complications following coronary stenting.21 identifying patients with these mutations can lead to tailored therapy. however, at the present moment, studies investigating genotypepersonalised antiplatelet therapy have failed to show any prognostic benefit.22,23 this may be due to the process of stent thrombosis and the complexity of antiplatelet responses. nevertheless, this is still a promising aspect of genetic testing which should be studied more extensively.24 genes and cardiovascular disease where do we go from here? e450 | squ medical journal, november 2015, volume 15, issue 4 o’donnell et al. summarised the pathway needed for the application of cvd genomics knowledge: large-scale cross-sectional studies are required to show the associations of candidate genes or mutations with particular cardiovascular risk factors and longitudinal studies are required to show causation.3 from there, risk prediction models can be generated.3 however, this would not be easy as most cvd risk factors are polygenic, with environmental factors also playing a significant role. studies of this nature are time-consuming, expensive and difficult to conduct due to the sheer number of patients required to achieve statistical significance. once a causative effect is found, then preventative interventions can be studied. in addition, one must be aware of the legal and privacy issues that come with genetic testing as well as the potential emotional and social effects of predictive genetic testing, especially in asymptomatic individuals.25,26 all centres that offer genetic testing should have well-trained genetic counsellors who can provide patients with an objective explanation of the potential benefits and risks of testing.27 another potential drawback of genetic testing is the likely misuse of sensitive information for insurance and employment purposes. as such, the usa government has passed legislation that bans the discrimination of individuals based on their genetic make-up.27 in conclusion, the impact of the field of genetics in cvd is extensive and promising. it is also fairly complicated in view of the various risk factors and the important role of environmental and lifestyle factors. multiple genetic variations have an association with cvd, but the advent of routine genetic testing for patients with this condition is still far-removed. at present, perhaps the greatest benefit of genetic testing is in pharmacogenetics, whereby genotyping would help us in identifying patients who are less likely to respond to particular drugs in order to tailor their therapies accordingly. furthermore, it is imperative that clinicians and scientists be aware of the various social, ethical and moral implications of genetic testing before advising these tests for their patients. references 1. world health organization. cardiovascular diseases. from: www.who.int/cardiovascular_diseases/en/ accessed: sep 2015. 2. jbs3 board. joint british societies’ consensus recommendations for the prevention of cardiovascular disease (jbs3). heart 2014; 100:ii1–67. doi: 10.1136/heartjnl-2014-305693. 3. o’donnell cj, nabel eg. genomics of cardiovascular disease. n engl j med 2011; 365:2098–109. doi: 10.1056/nejmra1105239. 4. nobelprize.org. facts on the nobel prize in physiology or medicine. from: www.nobelprize.org/nobel_prizes/facts/med icine/index.html accessed: sep 2015. 5. rizvi s, raza st, siddiqi z, abbas s, mahdi f. association of angiotensin-converting enzyme and glutathione s-transferase gene polymorphisms with body mass index among hypertensive north indians. sultan qaboos univ med j 2015; 15:426–34. doi: 10.18295/squmj.2015.15.04.006. 6. caulfield m, lavender p, farrall m, munroe p, lawson m, turner p, et al. linkage of the angiotensinogen gene to essential hypertension. n engl j med 1994; 330:1629–33. doi: 10.1056/ nejm199406093302301. 7. al-balushi k, zadjali f, al-sinani s, al-zajdali a, bayoumi r. frequencies of the arg16gly, gln27glu and thr164ile adrenoceptor β-2 polymorphisms among omanis. sultan qaboos univ med j 2015; 15:435–9. doi: 10.18295/squmj.2015.15.04.007. 8. leineweber k, heusch g. beta 1and beta 2-adrenoceptor poly morphisms and cardiovascular diseases. br j pharmacol 2009; 158:61–9. doi: 10.1111/j.1476-5381.2009.00187.x. 9. johnson ad, newton-cheh c, chasman di, ehret gb, johnson t, rose l, et al. association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. hypertension 2011; 57:903–10. doi: 10.1161/ hypertensionaha.110.158667. 10. salvi e, kutalik z, glorioso n, benaglio p, frau f, kuznetsova t, et al. genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial no synthase. hypertension 2012; 59:248–55. doi: 10.1161/ hypertensionaha.111.181990. 11. you yn, lakhani vt, wells sa jr. the role of prophylactic surgery in cancer prevention. world j surg 2007; 31:450–64. doi: 10.1007/s00268-006-0616-1. 12. meyers da, bleecker er, holloway jw, holgate st. asthma genetics and personalised medicine. lancet respir med 2014; 2:405–15. doi: 10.1016/s2213-2600(14)70012-8. 13. bleecker er, postma ds, lawrance rm, meyers da, ambrose hj, goldman m. effect of adrb2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. lancet 2007; 370:2118–25. doi: 10.1016/s0140-6736(07)61906-0. 14. charron p, arad m, arbustini e, basso c, bilinska z, elliott p, et al. genetic counselling and testing in cardiomyopathies: a position statement of the european society of cardiology working group on myocardial and pericardial diseases. eur heart j 2010; 31:2715–26. doi: 10.1093/eurheartj/ehq271. 15. geisterfer-lowrance aa, kass s, tanigawa g, vosberg hp, mckenna w, seidman ce, et al. a molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosium heavy chain gene missense mutation. cell 1990; 62:999–1006. doi: 10.1016/0092-8674(90)90274-i. 16. johansen ct, hegele ra. predictive genetic testing for coronary artery disease. crit rev clin lab sci 2009; 46:343–60. doi: 10.3109/07388550903422075. 17. kraft p, hunter dj. genetic risk prediction: are we there yet? n engl j med 2009; 360:1701–3. doi: 10.1056/nejmp0810107. 18. schiano c, vietri mt, grimaldi v, picascia a, pascale mr, napoli c. epigenetic-related therapeutic challenges in cardiovascular disease. trends pharmacol sci 2015; 36:226–35. doi: 10.1016/j.tips.2015.02.005. 19. 1000 genomes. about the 1000 genomes project. from: www.1000genomes.org/home accessed: sep 2015. http://dx.doi.org/10.1136/heartjnl-2014-305693 http://dx.doi.org/10.1056/nejmra1105239 http://dx.doi.org/10.18295/squmj.2015.15.04.006 http://dx.doi.org/10.1056/nejm199406093302301 http://dx.doi.org/10.1056/nejm199406093302301 http://dx.doi.org/10.18295/squmj.2015.15.04.007 http://dx.doi.org/10.1111/j.1476-5381.2009.00187.x http://dx.doi.org/10.1161/hypertensionaha.110.158667 http://dx.doi.org/10.1161/hypertensionaha.110.158667 http://dx.doi.org/10.1161/hypertensionaha.111.181990 http://dx.doi.org/10.1161/hypertensionaha.111.181990 http://dx.doi.org/10.1007/s00268-006-0616-1 http://dx.doi.org/10.1016/s2213-2600%2814%2970012-8 http://dx.doi.org/10.1016/s0140-6736%2807%2961906-0 http://dx.doi.org/10.1093/eurheartj/ehq271 http://dx.doi.org/10.1016/0092-8674%2890%2990274-i http://dx.doi.org/10.3109/07388550903422075 http://dx.doi.org/10.1056/nejmp0810107 http://dx.doi.org/10.1016/j.tips.2015.02.005 sunil k. nadar and kully sandhu editorial | e451 20. encode project consortium. an integrated encyclopedia of dna elements in the human genome. nature 2012; 489:57–74. doi: 10.1038/nature11247. 21. mega jl, close sl, wiviott sd, shen l, hockett rd, brandt jt, et al. cytochrome p-450 polymorphisms and response to clopidogrel. n engl j med 2009; 360:354–62. doi: 10.1056/nejmoa0809171. 22. price mj, berger pb, teirstein ps, tanguay jf, angiolillo dj, spriggs d, et al. standardvs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the gravitas randomized trial. jama 2011; 305:1097–105. doi: 10.1001/jama.2011.290. 23. collet jp, hulot js, cuisset t, rangé g, cayla g, van belle e, et al. genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the arcticgene study. eur j clin pharmacol 2015; 71:1315–24. doi: 10.1007/s00228-015-1917-9. 24. roden dm, wilke ra, kroemer hk, stein cm. pharmaco genomics: the genetics of variable drug responses. circulation 2011; 123:1661–70. doi. 10.1161/circulationaha.109.91 4820. 25. fulda kg, lykens k. ethical issues in predictive genetic testing: a public health perspective. j med ethics 2006; 32:143–7. doi: 10.1136/jme.2004.010272. 26. broadstock m, michie s, marteau t. psychological consequences of predictive genetic testing: a systematic review. eur j hum genet 2000; 8:731–8. doi: 10.1038/sj.ejhg.5200532. 27. ashley ea, hershberger re, caleshu c, ellinor pt, garcia jg, herrington dm, et al. genetics and cardiovascular disease: a policy statement from the american heart association. circulation 2012; 126:142–57. doi: 10.1161/ cir.0b013e31825b07f8. http://dx.doi.org/10.1038/nature11247 http://dx.doi.org/10.1056/nejmoa0809171 http://dx.doi.org/10.1001/jama.2011.290 http://dx.doi.org/10.1007/s00228-015-1917-9 http://dx.doi.org/10.1161/circulationaha.109.914820 http://dx.doi.org/10.1161/circulationaha.109.914820 http://dx.doi.org/10.1136/jme.2004.010272 http://dx.doi.org/10.1038/sj.ejhg.5200532 http://dx.doi.org/10.1161/cir.0b013e31825b07f8 http://dx.doi.org/10.1161/cir.0b013e31825b07f8 تشخيص العدوى بالركيتسيات يف سياق سريري يف عمان rickettsial infection diagnosed in a clinical context in oman dear sir, an 11-year-old boy presented to the sultan qaboos university hospital (squh), muscat, oman, in 2016 with a one-week history of scattered nodular-like erythematous lesions over the arms, petechial rashes over the dorsa of both feet and itchy maculopapular urticarial rashes over both thighs [figure 1]. he had a high-grade fever which reached 39.5 °c as well as a headache, generalised body pain and swelling around the joints. the patient lived in muscat and had no known history of tick bites, travel or contact with animals. a systemic examination revealed hepatomegaly and splenomegaly (both organs enlarged to 3 cm below the costal margin) as well as generalised body tenderness, myalgia and meningism. the bilateral knee and ankle joints were swollen with some restriction in movement, mainly flexion with partial extension. all vital signs were stable and normal, except for the persistent high-grade fever, which responded only partially to antipyretic medications. initial investigations showed mild proteinuria (700 mg/dl over a 24-hour period) and microscopic haematuria (1+). a complete blood count revealed normal amounts of haemoglobin cells and platelets; however, the patient had leukocytosis (white blood cell count: 24,000/m3) and neutrophilia (absolute neutrophil count: 21,400/m3). his coagulation profile was normal. further investigations indicated high c-reactive protein levels (125 mg/l), a high erythrocyte sedimentation rate (58 mm/hour), persistent unexplained low sodium levels (128 mmol/l), low chloride levels (89 mmol/l), very high creatine kinase levels (781 u/l), low serum albumin levels (29 g/l), normal renal function, normal complement levels, elevated alanine aminotransferase levels (190 iu/l) and elevated aspartate aminotransferase levels (250 u/l). an initial chest x-ray, ultrasound of the abdomen and gallium scan were normal. autoimmune causes, including vasculitis, immune deficiency, malignancy and pyrexia of unknown origin, were ruled out with various investigations, including antinuclear antibody, anti-double-stranded dna, antineutrophil cytoplasmic autoantibody, antimyeloperoxidase antibody and antiproteinase 3 antibody tests, skin and bone marrow aspirate biopsies, cultures and lumbar punctures. however, the patient had persistently high inflammatory markers. serology screening for brucella, leishmania, mycoplasma, malaria and leptospira infections was negative. a bronchoalveolar lavage for tuberculosis resulted in a negative acid-fast bacilli smear with normal cytology and negative cultures. virology screening was negative for cytomegalovirus, epstein-barr virus and acute hepatitis infections. virology screening of nasopharyngeal aspirate was negative for influenza a and b viruses and subtype a h1n1 as well as enteroviruses, coxsackieviruses, human immunodeficiency virus and coxiella burnetii bacteria. the patient was treated with several combinations of antibiotics, including ceftriaxone and piperacillin/ tazobactam, vancomycin and meropenem, vancomycin and erythromycin as well as ciprofloxacin and gentamicin. however, he did not respond to these treatments. at this point, his fever had persisted for 35 days. a funduscopic letter to the editor sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e529–530, epub. 30 nov 16 submitted 4 jul 16 revision req. 4 aug 16; revision recd. 18 aug 16 accepted 25 aug 16 doi: 10.18295/squmj.2016.16.04.025 figure 1: photographs of an 11-year-old boy with (a) scattered nodular-like erythematous lesions over the arms, (b) a petechial rash over the dorsa of both feet and (c) itchy maculopapular urticarial rashes over the thighs. rickettsial infection diagnosed in a clinical context in oman e530 | squ medical journal, november 2016, volume 16, issue 4 examination revealed white preretinal infiltrates with a cheese-like appearance, extending up to the macula and obscuring the retinal vessels [figure 2]. no haemorrhage was observed. finally, a weil-felix test using the ox2 (titre 160) and oxk (titre 80) antigens was positive; combined with the clinical features, this was suggestive of a rickettsial infection. the patient was subsequently prescribed doxycycline. within four days, he showed a marked reduction in fever and his serological titre decreased after 10 days of treatment. regular follow-up ophthalmological examinations showed substantial improvement. despite the presence of potential tick vectors in oman, clinical rickettsial infections were not reported until the late 1990s.1 however, a serological survey in the dhofar province of southern oman revealed that these infections are common among the rural population.2 the patient in the current case was diagnosed with a rickettsial infection following observation of typical clinical features, including rashes, headaches, hepatosplenomegaly, myalgia, meningism, hyponatremia, and elevated liver transaminase levels.3 moreover, evidence of retinal changes supported the diagnosis as ocular manifestations have been a key element in previous reports of similar conditions.4–6 although the weil-felix test is considered to have low specificity, the clinical features, exclusion of other differential diagnoses and the improvement of symptoms after treatment with doxycycline are suggestive of a rickettsial infection.3 testing of the ox2 and oxk antigens was positive. unfortunately, further testing to confirm the diagnosis could not be carried out due to the unavailability of indirect immunofluorescence antibody and polymerase chain reaction assays at squh at the time. in addition, national public health laboratories were not consulted due to the delay in serological test results and the patient’s prompt clinical response to treatment. despite these factors, the current case is indicative of the existence of rickettsial infections in oman. ophthalmological examinations for characteristic features of rickettsial infection can aid in diagnosis, within the context of clinical presentation and response to treatment. *mohamed a. el-naggari,1 ahmed idris,1 zakariya al-muharrmi,2 ibtisam el-nour1 1department of child health, sultan qaboos university hospital; 2department of microbiology & immunology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mails: mnaggari@squ.edu.om, mnaggari@yahoo.com and mnaggari@hotmail.com references 1. scrimgeour em, mehta fr, suleiman aj. infectious and tropical diseases in oman: a review. am j trop med hyg 1999; 61:920–5. 2. idris ma, ruppel a, petney t. antibodies against rickettsia in humans and potential vector ticks from dhofar, oman. j sci res med sci 2000; 2:7–10. 3. mittal v, gupta n, bhattacharya d, kumar k, ichhpujani rl, singh s, et al. serological evidence of rickettsial infections in delhi. indian j med res 2012; 135:538-41. 4. agahan al, torres j, fuentes-páez g, martínez-osorio h, orduña a, calonge m. intraocular inflammation as the main manifestation of rickettsia conorii infection. clin ophthalmol 2011; 5:1401–7. doi: 10.2147/opth.s21257. 5. smith tw, burton tc. the retinal manifestations of rocky mountain spotted fever. am j ophthalmol 1977; 84:259–62. doi: 10.1016/00029394(77)90860-1. 6. abroug n, khairallah-ksiaa i, kahloun r, khochtali s, zaouali s, khairallah m. parinaud’s oculoglandular syndrome revealing subclinical rickettsia conorii infection. int ophthalmol 2015; 35:717–19. doi: 10.1007/s10792-015-0094-2. figure 2: funduscopy image showing white preretinal infiltrates with a cheese-like appearance, extending up to the macula. programmes of 1physiotherapy, school of rehabilitation science and 3dietetics, school of healthcare sciences, faculty of health sciences, universiti kebangsaan malaysia, bangi, malaysia; 2physiotherapy department, faculty of allied health sciences, cyberjaya university college of medical sciences, cyberjaya, malaysia *corresponding author e-mail: dina_physio@hotmail.com فعالية اجلمع بني الرقص واالسرتخاء يف احلد من القلق واالكتئاب وحتسني نوعية احلياة بني مرضى الضعف اإلدراكي يف املسنني دين� اآدم، اأي�شة رملي، �شوزان� �ش�ه�ر abstract: objectives: cognitive impairment is a common problem among the elderly and is believed to be a precursor to dementia. this study aimed to explore the effectiveness of a combined dance and relaxation intervention as compared to relaxation alone in reducing anxiety and depression levels and improving quality of life (qol) and cognitive function among the cognitively impaired elderly. methods: this quasi-experimental study was conducted between may and december 2013 in peninsular malaysia. subjects from four government residential homes for older adults aged ≥60 years with mild to moderate cognitive function as assessed by the mini-mental state examination were included in the study. subjects were divided into an intervention group and a control group; the former participated in a combined poco-poco dance and relaxation intervention whilst the latter participated in relaxation exercises only. both groups participated in two sessions per week for six weeks. anxiety and depression were self-assessed using the hospital anxiety and depression scale and qol was self-assessed using the quality of life in alzheimer’s disease questionnaire. results: a total of 84 elderly subjects were included in the study; 44 were in the intervention group and 40 were in the control group. when compared to control subjects, those in the intervention group showed significantly decreased anxiety (p <0.001) and depression (p <0.001) levels as well as improved qol (p <0.001) and cognitive impairment (p <0.001). conclusion: dance as a form of participationbased physical exercise was found to reduce anxiety and depression levels and improve qol and cognitive function among the studied sample of cognitively impaired elderly subjects in malaysia. keywords: mild cognitive impairment; dance therapy; quality of life; anxiety; depression; malaysia امللخ�ص: الهدف: ال�شعف االإدراكي م�شكلة �ش�ئعة بني كب�ر ال�شن، ويعتقد اأن يكون من مقدم�ت اخلرف. هدفت هذه الدرا�شة اإىل ا�شتك�ش�ف فع�لية اإدراج الرق�ص و اال�شرتخ�ء مع� مق�رنة مع اال�شرتخ�ء وحده يف احلد من القلق واالكتئ�ب وحت�شني جودة احلي�ة ووظيفة االدراك جزيرة �شبه يف ودي�شمرب 2013 م�يو بني م� التجريبية �شبه الدرا�شة هذه اأجريت ال�شن. الطريقة: كب�ر يف االإدراكي ال�شعف مر�شى بني م�ليزي�على اأ�شخ��ص اأعم�رهم فوق ال�شتني ع�م يقطنون يف اأربع من�زل �شكنية لكب�ر ال�شن الت�بعة للحكومة. ك�ن امل�ش�ركون يف الدرا�شة جمموعة اإىل امل�ش�ركني تق�شيم مت العقلية. للقدرة م�شغر اختب�ر على بن�ء معتدلة إىل خفيفة االإدراكية الوظيفة يف �شعف من يع�نون اختب�ر وجمموعة �ش�بطة. جمموعة االختب�ر �ش�ركت يف رق�شة بوكو بوكو مع مت�رين اال�شرتخ�ء يف حني �ش�ركت املجموعة ال�ش�بطة واالكتئ�ب للقلق الذاتي التقييم جرى اأ�ش�بيع. �شتة ملدة االأ�شبوع يف جل�شتني يف املجموعتني كلت� �ش�ركت فقط. اال�شرتخ�ء مت�رين يف ب��شتخدام مقي��ص القلق واالكتئ�ب اخل��ص ب�مل�شت�شفى و مت التقييم الذاتي لنوعية احلي�ة بتعبئة ا�شتبي�ن خ��ص بجودة احلي�ة ملر�شى ال�ش�بطة، ب�ملجموعة ب�ملق�رنة ال�ش�بطة(. املجموعة يف 40 و االختب�ر جمموعة يف 44( م�شن� 84 الدرا�شة �شملت النتائج: الزه�مير. اأظهرت جمموعة االختب�ر انخف��ش� ملحوظ� ذا قيمة اح�ش�ئية يف القلق )p >0.001( واالكتئ�ب )p >0.001( ف�شال عن حت�شني نوعية احلي�ة )p >0.001( واالإدراك. )p >0.001( النتيجة: وجد اأن الرق�ص ميكن اإ�ش�فته ك�شكل من اأ�شك�ل مم�ر�شة الري��شة البدنية للحد من القلق واالكتئ�ب وحت�شني جودة احلي�ة ووظيفة االدراك يف العينة املدرو�شة للم�شنني الذين لديهم �شعف اإدراكي يف م�ليزي�. مفتاح الكلمات: ال�شعف اإلدراكي املعتدل؛ العالج ب�لرق�ص؛ جودة احلي�ة؛ القلق؛ االكتئ�ب؛ م�ليزي�. effectiveness of a combined dance and relaxation intervention on reducing anxiety and depression and improving quality of life among the cognitively impaired elderly *dina adam,1,2 ayiesah ramli,1 suzana shahar3 clinical & basic research sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e47–53, epub. 2 feb 16 submitted 23 apr 15 revision req. 8 jun 15; revision recd. 10 jul 15 accepted 18 aug 15 doi: 10.18295/squmj.2016.16.01.009 advances in knowledge the results of the current study indicate that a combination of dance and relaxation exercises improves quality of life (qol) and cognitive impairment and reduces anxiety and depression among cognitively impaired elderly residents of government institutions as compared to relaxation alone. application to patient care combined dance and relaxation interventions are recommended for elderly individuals as a form of enjoyable physical activity which can improve cognitive function and qol and reduce anxiety and depression. effectiveness of a combined dance and relaxation intervention on reducing anxiety and depression and improving quality of life among the cognitively impaired elderly e48 | squ medical journal, february 2016, volume 16, issue 1 mild cognitive impairment occurs on a spectrum between normal ageing proc-esses and the development of dementia.1 the deterioration of cognitive function is more predominant in anxious or depressed individuals.2 according to nikmat et al., delays in the early detection of cognitive impairment can lead to depression, functional dependence and poor quality of life (qol).3 decreased physical activity can contribute significantly to increased levels of depression.4 physically active individuals have demonstrated less cognitive decline than sedentary subjects, as well as improved cardiovascular fitness, muscle strength, range of motion, posture, balance and mental health.5,6 more than one in six residents of homes for older adults have anxiety and depression problems.7 this is likely due to the lack of a supportive environment, societal stigma, depersonalisation, sleep disturbances, communication problems and illnesses that affect their qol and functional abilities.7 dance interventions, multi-modal training and progressive muscle relaxation therapy have been identified as measures that can significantly reduce anxiety and depression levels and improve qol in older adults.5,8,9 dance as a form of physical activity can be performed in a range of environments.10 it is safe and more likely to be adopted by older adults as part of their lifestyle compared to other more structured and/ or expensive exercises.11 dance interventions engage the elderly in everyday life by encouraging enjoyment of the activity and improving their psychosocial qol.6 the therapeutic benefits therefore motivate individuals at all levels of fitness to adhere to the interventions.2 besides dance therapy, relaxation exercises using the imagination method are useful in treating stress and anxiety, especially among older adults.12 these exercises are believed to be beneficial in releasing physical and mental stress, decreasing depressive symptoms and enhancing qol. many types of relaxation exercises—including breathing techniques, meditation, progressive muscle relaxation and autogenic training—have a positive impact on anxiety.13 however, very few studies have investigated the beneficial effects of a combination of dance and relaxation exercises in improving the psychological status of older adults. therefore, this study aimed to determine the effectiveness of a combined dance and relaxation intervention in reducing anxiety and depression and improving cognitive impairment and qol among elderly individuals with cognitive impairment residing in publicly-funded institutions. methods this quasi-experimental study was carried out between may and december 2013 in four government residential homes for older adults in peninsular malaysia (rumah seri kenangan seremban, negeri sembilan; rumah seri kenangan cheras, klang valley; rumah seri kenangan cheng, melaka; and rumah seri kenangan taiping, perak). these institutions represent major publicly-funded institutions in the southern, central and northern areas of peninsular malaysia. subjects between 60–80 years old who could walk independently and had mild (18/30) to moderate (28/30) cognitive impairment as categorised by the mini-mental state examination (mmse) were included.14 exclusion criteria included uncontrolled hypertension or terminal illness; severe cognitive and musculoskeletal impairments; cardiovascular disease; mental illness; stroke; administration of antipsychotic or anticholinergic drugs; hearing or vision deterioration; speech disturbances; difficulties in performing daily routines; and severe pain.10 subjects were divided into an intervention group and a control group; the intervention group undertook a combination of poco-poco dance and relaxation exercises whilst the control group participated only in the relaxation exercises. both groups had sessions twice per week for six weeks resulting in a total of 12 sessions. dance sessions were facilitated by an experienced physical therapist, with each 60-minute session beginning with 10 minutes of warm-up and stretching activities followed by a 20-minute pocopoco dance session. the dance routine included two sidewalk steps to the right, left and back to the midpoint position repeated twice, followed by three backward steps from the mid-point forwards and then backwards repeated twice before a forward-backward weight transfer in walking stance repeated twice. the whole cycle was then repeated several times. at baseline and during the first two weeks, lower limb movements were incorporated with slow simple reciprocal armswinging. from the third week onwards, the intensity of the limb movements increased to include extension of the arms straight upward and forward-backward arm-swinging three times to both sides. in the fifth and sixth weeks, circular arm motions were added three times to both sides. all dance sessions concluded with a 10-minute cool-down period. participants in the intervention group undertook a 30-minute relaxation session following their dance session. in the control group, subjects took part in a 40-minute relaxation session without any physical intervention. in the relaxation sessions, subjects were requested to sit comfortably on a chair in a quiet area and loosen any tight clothing before closing their eyes dina adam, ayiesah ramli and suzana shahar clinical and basic research | e49 and focusing on slow deep breathing, emphasising their exhalations. relaxing music was played on a compact disc player and subjects were asked to visualise a peaceful and calming environment. using the progressive muscle relaxation technique, participants were encouraged to tense and hold certain muscles for five seconds and then relax the muscles for 30 seconds, starting with their foot, calf and thigh, hand and arm, buttocks and stomach muscles and progressing up to their neck and head muscles.15 subjects were then asked to lift their shoulders up to the ears for five seconds before lowering them. for facial muscles, the subjects had to yawn and pout, frown and wrinkle their nose and raise and lower their eyebrows. finally, subjects had to wriggle their fingers and toes before opening their eyes. this process was carried out three times with deep breathing exercises interspersed throughout each session.16 among the subjects, anxiety, depression and qol were evaluated at baseline and during the third and sixth week of the intervention. anxiety and depression were evaluated using the hospital anxiety and depression scale (hads), a brief selfadministered questionnaire designed to assess the presence of general anxiety and depression disorders.17,18 a score of <7 was considered normal, 8–10 borderline abnormal and ≥11 abnormal out of a total score of 21. qol was assessed using the quality of life in alzheimer’s disease (qol-ad) questionnaire. the qol-ad questionnaire is considered a valid, reliable and appropriate instrument for assessing qol in individuals with cognitive impairment, particularly as the completion time is relatively short and the completion rate is high.19,20 scores are rated on a 4-point scale, with 1 indicating poor and 4 indicating excellent qol. total scores range from 13–52 with higher scores indicating a better qol. cognitive impairment was measured at baseline and during the third and sixth weeks using the mmse. statistical analysis was performed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). results were expressed as means ± standard deviations. a repeated-measures analysis of variance (anova) model was used to compare the effects of the interaction (time*group) with anxiety and depression levels and qol-ad scores at three intervals (at baseline and during the third and sixth week). if the sphericity assumption was not violated (p <0.05 using mauchly’s test of sphericity), the huynhfeldt correction was used to estimate p values.21 cognitive impairment, anxiety and depression levels and qol were compared between the two groups at each interval using a repeated-measures anova model with the bonferroni correction for multiple outcomes. a partial eta-squared statistic (η2) was used to measure the effect size as either small (0.01 ≤η2 <0.06), medium (0.06 ≤η2 <0.14) or large (η2 ≥0.14).22 the level of statistical significance was set at p <0.050. this study was approved by the researchers ethics committee at universiti kebangsaan malaysia, bangi, malaysia (#ukm1.5.3.5/244/nn-086-2013). informed consent was obtained from all of the subjects prior to their participation in the intervention. table 1: demographic variables of elderly malaysian subjects undergoing a combined dance and relaxation intervention as compared to controls undergoing relaxation exercises alone (n = 84) variable n (%) p value control group (n = 40) intervention group (n = 44) cognitive impairment* 0.185 mild 30 (75.0) 38 (86.4) moderate 10 (25.0) 6 (13.6) age in years 0.287 >60 21 (52.5) 18 (40.9) >70 19 (47.5) 26 (59.1) gender 0.662 male 21 (52.5) 21 (47.7) female 19 (47.5) 23 (52.3) education level 0.693 none 11 (27.5) 9 (20.5) primary 22 (55.0) 25 (56.8) secondary/ tertiary 7 (17.5) 10 (22.7) anxiety† 0.433 borderline abnormal 33 (82.5) 32 (72.7) abnormal 7 (17.5) 12 (27.3) depression† 0.073 borderline abnormal 32 (80.0) 36 (81.8) abnormal 8 (20.0) 8 (18.2) qol‡ 0.915 low 25 (62.5) 27 (61.4) high 15 (37.5) 17 (38.6) qol = quality of life. *cognitive impairment was assessed using the mini-mental state examination with scores of 21–28 and 10–20 out of 30 indicating mild and moderate cognitive impairment, respectively.14 †anxiety and depression were self-assessed using the hospital anxiety and depression scale with scores of <7, 8–10 and ≥11 out of 21 considered normal, borderline abnormal and abnormal, respectively.17,18 ‡qol was selfassessed using the quality of life in alzheimer’s disease questionnaire with scores of <33 and >34 out of 52 indicating low and high qol, respectively.19,20 effectiveness of a combined dance and relaxation intervention on reducing anxiety and depression and improving quality of life among the cognitively impaired elderly e50 | squ medical journal, february 2016, volume 16, issue 1 results a total of 84 subjects were included in the study and were divided into an intervention group (n = 44) and control group (n = 40). the mean age of the subjects was 70.87 ± 8.19 years. at baseline, there were no significant differences in cognitive impairment, age, gender or education level between the groups (p >0.050). however, a lower percentage of subjects in the intervention group had moderate cognitive impairment as compared to the control group (13.6% versus 25.0%; p >0.050) [table 1]. there was a significant interaction between time interval and group for cognitive impairment (p <0.001), anxiety (p <0.001), depression (p <0.001) and qol (p <0.001), with subjects in the intervention group showing improved cognitive impairment, reduced anxiety and depression levels and improved qol. this represented a large effect (partial η2 = 0.42, 0.26, 0.35 and 0.29, respectively) [table 2]. furthermore, a significant difference was noted between the third and sixth week of the intervention for all of the subjects, regardless of group, for cognitive impairment (p <0.001), anxiety (p <0.001), depression (p <0.001) and qol (p <0.001) [table 3]. at baseline, there were equal rates of borderline abnormal anxiety (22.7% ; n = 10) and abnormal anxiety (22.7%; n = 10) in the intervention group. at the same time interval, rates of borderline abnormal depression and abnormal depression in the intervention group were 34.1% (n = 7) and 18.2% (n = 8), respectively. a drastic improvement was observed following six weeks of the intervention, with the majority of subjects in the intervention group reporting normal anxiety levels (90.9%; n = 40) and only 6.8% (n = 3) reporting borderline abnormal anxiety. a similar trend was observed for depression, with 95.5% (n = 42) of subjects in the intervention group reporting normal depression levels after six weeks of the intervention; in contrast, only 57.5% (n = 23) and 37.5% (n = 15) of those in the control group reported normal anxiety and normal depression levels by the sixth week [figure 1]. table 3: comparison of cognitive impairment, anxiety, depression and quality of life according to time interval among elderly malaysian subjects (n = 84) interval cognitive impairment* anxiety† depression† qol‡ mean (95% ci) p value§ mean (95% ci) p value§ mean (95% ci) p value§ mean (95% ci) p value§ baseline 23.5 (22.8–24.1) <0.001 6.7 (6.0–7.4) <0.001 7.0 (6.4–7.6) <0.001 32.0 (30.9–33.0) <0.001 week 3 23.8 (23.1–24.5) <0.001 6.3 (5.7–6.9) <0.001 6.4 (5.7–7.0) <0.001 32.4 (31.4–33.3) <0.001 week 6 23.5 (22.8–24.2) <0.001 6.4 (5.8–7.0) <0.001 6.7 (6.1–7.3) <0.001 32.2 (31.2–33.2) <0.001 qol = quality of life; ci = confidence interval. *cognitive impairment was assessed using the mini-mental state examination with scores of 21–28 and 10–20 out of 30 indicating mild and moderate cognitive impairment, respectively.14 †anxiety and depression were self-assessed using the hospital anxiety and depression scale with scores of <7, 8–10 and ≥11 out of 21 considered normal, borderline abnormal and abnormal, respectively.17,18 ‡qol was self-assessed using the quality of life in alzheimer’s disease questionnaire with scores of <33 and >34 out of 52 indicating low and high qol, respectively.19,20 §p values were adjusted for multiple comparisons using the bonferroni correction procedure. table 2: comparison of variables among elderly malaysian subjects undergoing a combined dance and relaxation intervention (n = 44) as compared to controls (n = 40) undergoing relaxation exercises alone (n = 84) variable mean ± sd p value partial η2* baseline week 3 week 6 cognitive impairment† <0.001 0.42 ig 23.7 ± 3.4 25.0 ± 3.3 26.6 ± 3.0 cg 22.6 ± 3.2 22.5 ± 3.2 21.2 ± 3.7 anxiety‡ <0.001 0.26 ig 7.5 ± 3.5 6.1 ± 3.6 4.4 ± 2.7 cg 6.2 ± 3.7 7.1 ± 3.3 7.6 ± 3.1 depression‡ <0.001 0.35 ig 7.6 ± 3.1 5.3 ± 3.0 3.7 ± 2.7 cg 7.1 ± 3.1 8.1 ± 3.3 8.4 ± 3.4 qol§ <0.001 0.29 ig 32.0 ± 7.0 34.1 ± 5.1 36.4 ± 4.1 cg 31.6 ± 4.8 30.2 ± 4.6 28.8 ± 4.4 sd = standard deviation; ig = intervention group; cg = control group; qol = quality of life. *partial η2 was used to measure the effect size as either small (0.01 ≤η2 <0.06), medium (0.06 ≤η2 <0.14) or large (η2 ≥0.14).22 †cognitive impairment was assessed using the mini-mental state examination with scores of 21–28 and 10–20 out of 30 indicating mild and moderate cognitive impairment, respectively.14 ‡anxiety and depression were self-assessed using the hospital anxiety and depression scale with scores of <7, 8–10 and ≥11 out of 21 considered normal, borderline abnormal and abnormal, respectively.17,18 §qol was self-assessed by subjects using the quality of life in alzheimer’s disease questionnaire with scores of <33 and >34 out of 52 indicating low and high qol, respectively.19,20 dina adam, ayiesah ramli and suzana shahar clinical and basic research | e51 slightly fewer subjects in the intervention group re-ported low baseline qol scores compared to those in the control group (61.4% versus 62.5%; n = 27 versus 25). however, during the sixth week, 81.8% (n = 36) of those in the intervention group reported high qol scores. in comparison, 87.5% (n = 35) of those in the control group reported low qol scores during the sixth week with only 12.5% (n = 5) reporting high qol scores [figure 2]. discussion in the current study, the combined dance and relaxation intervention was found to significantly improve cognition and qol and decrease anxiety and depression symptoms among elderly malaysian subjects. additionally, the large effect size supported the magnitude of the findings. this was consistent with a pilot study which demonstrated that music therapy and physical relaxation were beneficial in improving physical and mental function.23 the duration of the six-week intervention period was chosen to minimise figure 1: anxiety and depression levels according to time interval among elderly malaysian subjects undergoing a combined dance and relaxation intervention (n = 44) as compared to control subjects (n = 40) undergoing relaxation exercises alone (n = 84). anxiety and depression were self-assessed using the hospital anxiety and depression scale with scores of <7, 8–10 and ≥11 out of 21 considered normal, borderline abnormal and abnormal, respectively.17,18 subjects were evaluated at baseline and during the third and sixth week of the intervention. figure 2: quality of life (qol) according to time interval among elderly malaysian subjects undergoing a combined dance and relaxation intervention (n = 44) as compared to control subjects (n = 40) undergoing relaxation exercises alone (n = 84). qol was self-assessed using the quality of life in alzheimer’s disease questionnaire with scores of <33 and >34 out of 52 indicating low and high qol, respectively.19,20 subjects were evaluated at baseline and during the third and sixth week of the intervention. effectiveness of a combined dance and relaxation intervention on reducing anxiety and depression and improving quality of life among the cognitively impaired elderly e52 | squ medical journal, february 2016, volume 16, issue 1 drop-outs among the studied sample, particularly considering potential health problems among the participants. gottlieb et al. found that a shorter intervention period could still have significant effects while also encouraging adherence.24 as a result of the six-week intervention, participants in the intervention group in the current study experienced improvements in cognitive impairment, anxiety, depression and qol as measured by mmse, hads and qol-ad scores, respectively. the intensity of the dance activities increased progressively in order to encourage balance, focus and engagement with the activities, with simple reciprocal arm swings progressing to forward and backward arm movements which were then later augmented with circular motions. gradually increasing the intensity and biomechanical movements within dance sessions may further improve aspects of cognitive function, balance and qol.25 listening to music and dancing stimulates the parietal lobe and provides somatosensory input; these may increase the neurotrophic factor that improves cognitive and visuospatial function.26 pocopoco is a commonly enjoyed dance among the local population of malaysia.27 subjects taking part in pocopoco dance sessions may favour this type of dance because it is non-competitive. anxiety and depression levels among control subjects in the current study were slightly lower during the third week compared to the sixth week. the leading factor contributing to depression is a perceived lack of control in life; other possible contributors include a lack of harmony with the surrounding environment, limited physical ability and various family, social and economic issues.8,28 gottlieb et al. found that females had higher rates of borderline abnormal anxiety levels and depression compared to males; however, they also demonstrated greater improvement than their male counterparts.24 this may have been because they were more naturally inclined to enjoy dance-like activities.24 in the current study, anxiety and depression levels were reduced among the intervention group and higher among the control group; these findings were consistent with previous studies.23,29 relaxation therapy alone without the physical movements encouraged by the dance intervention was not as effective in decreasing anxiety or depression among studied participants with a low quality of life. on the other hand, those undergoing a combined dance and relaxation intervention had reduced levels of anxiety and depression regardless of quality of life. relaxation therapy alone may more effectively reduce anxiety and depression symptoms if sessions are conducted more frequently (i.e. if the participants engage in at least 50 sessions).17 the effect of relaxation therapy is generally minimal among elderly residents receiving standard care in institutions.30 in malaysia, government policies ensure that elderly residents receive continuous support and care to prevent loss of functionality.25 older adults in institutions therefore have ample and equal opportunities to take part in institutional activities.25 the significant improvement in cognitive function observed among subjects in the intervention group in the current study was consistent with the findings of middleton et al.6 improvements in qol following physical interventions such as dance are potentially related to increased cognitive and physical function as well as an enhanced sense of wellbeing.8 these factors may also be linked with enhanced coping strategies when facing difficult situations within the residence and an increased sense of independence.31 this study has several limitations. as the subjects were neither randomised nor blinded, it is possible that those who agreed to participate may have been more motivated to engage in the intervention. additionally, the study was limited by the small sample size, the absence of a no-treatment control group and the heterogeneity of the groups. further studies to evaluate the effects of exercise intensity, frequency and duration on cognitive function are needed to verify the improvements observed in the present study. despite these limitations, the findings of this study provide evidence of the positive effects of dance exercise on cognitive status among elderly people. dance interventions should therefore be encouraged as an enjoyable and beneficial leisure activity in institutions for elderly residents. such interventions should be conducted on a larger scale for longer periods of time. conclusion participation in a six-week combined dance and relaxation intervention was found to significantly reduce anxiety and depression levels and improve cognitive function and qol among studied elderly malaysian subjects. furthermore, significant improvement in qol were reported by the participants during the third week of the intervention, after only six dance and relaxation sessions. dance interventions are therefore recommended for elderly residents among government institutions as a method of improving mental health and qol. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. dina adam, ayiesah ramli and suzana shahar clinical and basic research | e53 references 1. petersen rc. mild cognitive impairment as a diagnostic entity. j int med 2004; 256:183–94. doi: 10.1111/j.1365-2796.2004. 01388.x. 2. jorm af, christensen h, korten ae, henderson as, jacomb pa, mackinnon a. do cognitive complaints either predict future cognitive decline or reflect past cognitive decline? a longitudinal study of an elderly community sample. psychol med 1997; 27:91–8. 3. nikmat aw, hawthorne g, al-mashoor sh. dementia in malaysia: issues and challenges. asean j psychiatr 2011; 12:95–101. 4. vanková h, holmerová i, andel r, veleta p, janecková h. functional status and depressive symptoms among older adults from residential care facilities in the czech republic. int j geriatr psychiatry 2008; 23:466–71. doi: 10.1002/gps.1905. 5. douglas s, james i, ballard c. non-pharmacological interventions in dementia. adv psychiatr treat 2004; 10:171–7. doi: 10.1192/apt.10.3.171. 6. middleton le, yaffe k. promising strategies for the prevention of dementia. arch neurol 2009; 66:1210–15. doi: 10.1001/ archneurol.2009.201. 7. reynolds cf 3rd, frank e, perel jm, imber sd, cornes c, miller md, et al. nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. jama 1999; 281:39–45. doi: 10.1001/jama.281.1.39. 8. de silva borges eg, de souza vale rg, cader sa, leal s, miguel f, pernambuco cs, et al. postural balance and falls in elderly nursing home residents enrolled in a ballroom dancing program. arch gerontol geriatr 2014; 59:312–16. doi: 10.1016/j.archger.2014.03.013. 9. dehdari t, heidarnia a, ramezankhani a, sadeghian s, ghofranipour f. effects of progressive muscular relaxation training on quality of life in anxious patients after coronary artery bypass graft surgery. indian j med res 2009; 129:603–8. 10. hauer k, specht n, schuler m, bärtsch p, oster p. intensive physical training in geriatric patients after severe falls and hip surgery. age ageing 2002; 3:49–57. doi: 10.1093/ageing/31.1.49. 11. peri k, kerse n, robinson e, parsons m, parsons j, latham n. does functionally based activity make a difference to health status and mobility? a randomised controlled trial in residential care facilities (the promoting independent living study; pils). age ageing 2008; 37:57–63. doi: 10.1093/ageing/afm135. 12. manzoni gm, pagnini f, castelnuovo g, molinari e. relaxation training for anxiety: a ten-years systematic review with metaanalysis. bmc psychiatry 2008; 8:41. doi: 10.1186/1471-244x8-41. 13. malchiodi ca. handbook of art therapy, 1st ed. new york, usa: guilford press, 2003. pp. 5–24. 14. ibrahim nm, shohaimi s, chong ht, rahman ah, razali r, esther e, et al. validation study of the mini-mental state examination in a malay-speaking elderly population in malaysia. dement geriat cogn disord 2009; 27:247–53. doi: 10.1159/000203888. 15. jacobson e. progressive relaxation. am j psychol 1987; 100:522–37. doi: 10.2307/1422693. 16. ip-winfield v, grocke d. group music therapy methods in cross-cultural aged care practice in australia. aus j music ther 2011; 22:59–80. 17. conrad p. the medicalization of society: on the transformation of human conditions into treatable disorders, 1st ed. baltimore, usa: johns hopkins university press, 2007. pp. 133–45. doi: 10.1056/nejmbkrev58828. 18. zigmond as, snaith rp. the hospital anxiety and depression scale. acta psychiatr scand 1983; 67:361–70. doi: 10.1111/ j.1600-0447.1983.tb09716.x. 19. logsdon rg, gibbons le, mccurry sm, teri l. assessing quality of life in older adults with cognitive impairment. psychosom med 2002; 64:510–19. doi: 10.1097/00006842200205000-00016. 20. moyle w, gracia n, murfield je, griffiths sg, venturato l. assessing quality of life of older people with dementia in longterm care: a comparison of two self-report measures. j clin nurs 2012; 21:1632–40. doi: 10.1111/j.1365-2702.2011.03688.x. 21. weerahandi s. generalized inference in repeated measures: exact methods in manova and mixed models, 1st ed. oxford, uk: wiley-interscience, 2004. pp. 39–88. 22. cohen j. statistical power analysis for the behavioral sciences, 2nd ed. hillsdale, new jersey, usa: routledge, 1988. pp. 273–88. 23. castelino a. the effect of single sessions of music therapy on the level of anxiety in older persons with psychiatric disorders: a pilot study. thesis, 2009, new zealand school of music, wellington, new zealand. 24. gottlieb ss, khatta m, friedmann e, einbinder l, katzen s, baker b, et al. the influence of age, gender, and race on the prevalence of depression in heart failure patients. j am coll cardiol 2004; 43:1542–9. doi: 10.1016/j.jacc.2003.10.064. 25. ministry of women, family and community development. national policy for the elderly. from: www.kpwkm.gov.my/ documents/10156/576479be-3a70-4dc0-82dd-0ee30cc83ea8 accessed: jul 2015. 26. cotman cw, engesser-cesar c. exercise enhances and protects brain function. exerc sport sci rev 2002; 30:75–9. doi: 10.1097/00003677-200204000-00006. 27. khan a, brown wj, burton nw. what physical activity contexts do adults with psychological distress prefer? j sci med sport 2013; 16:417–21. doi: 2010.1016/j.jsams.2012.10.007. 28. pinniger r, brown rf, thorsteinsson eb, mckinley p. argentino tango dance compared to mindfulness meditation and a waiting list control: a randomised trial for treating depression. complement ther med 2012; 20:377–84. doi: 10.1016/j.ctim. 2012.07.003. 29. masomeh at, mehdi s, monire mn. the effect of selected relaxation training with physical activity on mental well-being. ann biol res 2012; 3:2893–9. 30. horgas al, yoon sl, grall m. pain management. in: boltz m, capezuti e, fulmer t, zwicker d, eds. evidence-based geriatric nursing protocols for best practice, 4th ed. new york, usa: springer publishing company. pp. 246–67.31. 31. lagacé m, tanguay a, lavallée ml, laplante j, robichaud s. the silent impact of ageist communication in long term care facilities: elders’ perspectives on quality of life and coping strategies. j aging stud 2012; 26:335–42. doi: 10.1016/j. jaging.2012.03.002. http://dx.doi.org/10.1111/j.1365-2796.2004.01388.x http://dx.doi.org/10.1111/j.1365-2796.2004.01388.x http://dx.doi.org/10.1002/gps.1905 http://dx.doi.org/10.1192/apt.10.3.171 http://dx.doi.org/10.1001/archneurol.2009.201 http://dx.doi.org/10.1001/archneurol.2009.201 http://dx.doi.org/10.1001/jama.281.1.39 http://dx.doi.org/10.1016/j.archger.2014.03.013 http://dx.doi.org/10.1093/ageing/31.1.49 http://dx.doi.org/10.1093/ageing/afm135 http://dx.doi.org/10.1186/1471-244x-8-41 http://dx.doi.org/10.1186/1471-244x-8-41 http://dx.doi.org/10.1159/000203888 http://dx.doi.org/10.2307/1422693 http://dx.doi.org/10.1056/nejmbkrev58828 http://dx.doi.org/10.1111/j.1600-0447.1983.tb09716.x http://dx.doi.org/10.1111/j.1600-0447.1983.tb09716.x http://dx.doi.org/10.1097/00006842-200205000-00016 http://dx.doi.org/10.1097/00006842-200205000-00016 http://dx.doi.org/10.1111/j.1365-2702.2011.03688.x http://dx.doi.org/10.1016/j.jacc.2003.10.064 http://www.kpwkm.gov.my/documents/10156/576479be-3a70-4dc0-82dd-0ee30cc83ea8 http://www.kpwkm.gov.my/documents/10156/576479be-3a70-4dc0-82dd-0ee30cc83ea8 http://dx.doi.org/10.1097/00003677-200204000-00006 http://dx.doi.org/2010.1016/j.jsams.2012.10.007 http://dx.doi.org/10.1016/j.ctim.2012.07.003 http://dx.doi.org/10.1016/j.ctim.2012.07.003 http://dx.doi.org/10.1016/j.jaging.2012.03.002 http://dx.doi.org/10.1016/j.jaging.2012.03.002 sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e369-374, epub. 24th jul 14 submitted 1st dec 13 revisions req. 15th jan & 10th feb 14; revisions recd. 29th jan & 15th feb 14 accepted 20th mar 14 maternity nursing unit, college of nursing, hawler medical university, erbil, iraq e-mail: hamdia76@gmail.com األسباب السريرية إلجراء عملية قص العجان من قبل القابالت ىف إقليم كردستان هل هي مستندة على األدلة العلمية؟ حمدية مريخان اأحمد abstract: objectives: an episiotomy is one of the most common obstetric surgical procedures and is performed mainly by midwives. the decision to perform an episiotomy depends on related clinical factors. this study aimed to find out midwives’ reasons for performing episiotomies and to identify the relationship between these reasons and the demographic characteristics of the midwives. methods: this cross-sectional study was conducted between 1st july and 30th september 2013 in three governmental maternity teaching hospitals in the three main cities of the kurdistan region of iraq. all of the midwives who had worked in the delivery rooms of these hospitals for at least one year were invited to participate in the study (n = 53). data were collected through interviews with midwives as well as via a questionnaire constructed for the purpose of the study. the questionnaire sought to determine: midwives’ demographic characteristics; type of episiotomy performed; authority of the decision to perform the procedure, and reasons for performing episiotomies. results: the main clinical reasons reported by midwives for performing an episiotomy were: macrosomia/large fetus (38, 71.7%), breech delivery (31, 58.5%), shoulder dystocia (29, 54.7%), anticipated perineal tear (27, 50.9%) and fetal distress (27, 50.9%). there was a significant association between the frequency of these reasons and midwives’ total experience in delivery rooms as well as their levels of education. conclusion: most of the reasons given by the midwives for performing episiotomies were not evidencebased. age, years of experience, specialties and level of education also had an effect on midwives’ reasons for performing episiotomies. keywords: episiotomy; nurses; midwives; iraq. امللخ�ص: الهدف: اإن عملية ق�س العجان هى من اأكرث العمليات اجلراحية انت�سارا و جترى عادة من قبل القابالت و يعتمد قرار اإجراء العملية على الأ�سباب ال�رسيرية املتعلقة بذلك و تهدف هذه الدرا�سة اىل اإيجاد اأ�سباب اإجراء عملية ق�س العجان من قبل القابالت و التعرف على العالقة بني هذه الأ�سباب و ال�سفات الدميوغرافية للقابالت. الطريقة: اأجريت درا�سة مقطعية يف الفرتة مابني 07/01–2013/09/30 فى ثالث م�ست�سفيات تعليمية حكومية للولدة فى املدن الرئي�سية الثالث لإقليم كرد�ستان فى العراق. و�سملت الدرا�سة جميع القابالت العامالت فى �سالت الولدة اللواتي لديهن خربة ل تقل عن �سنة واحدة يف هذه امل�ست�سفيات )عدد = 53(. وقد جمعت املعلومات عن طريق املحاورة مع القابالت و كذلك عن طريق ا�ستمارات ال�ستبيان و التى مت اإعدادها لهذا الغر�س وقد احتوت ال�ستمارة على معلومات تتعلق باخلوا�س الدميوغرافية للقابالت و اأنواع عمليات ق�س العجان و �سالحية اتخاذ القرار لإجراء هذه العمليات و الأ�سباب املوجبة لإجرائها. النتائج: اأظهرت نتائج الدرا�سة باأن الأ�سباب ال�رسيرية حول قرار اإجراء عملية ق�س العجان كانت التايل: )71.7% ,38( لكرب حجم اجلنني و )%58.5 ,31( ولدة مقعدية و)%54.7 ,29( �سعوبة ولدة الكتف و %50.9 ,27( ملنع متزق منطقة العجان و)50.9% ,27( ب�سبب كرب اجلنني. و كانت هناك عالقه اإيجابية بني الأ�سباب املذكورة اأعاله مع �سنوات اخلدمة يف �سالت الولدة و امل�ستوى التعليمى للقابالت. اخلال�صة: ن�ستنتج من هذه الدرا�سة اأن القابالت مل يجرين عملية ق�س العجان ا�ستنادا على الأدلة العلمية. و اأن اأهم العوامل التى اأثرت على اإجراء عمليات ق�س العجان هي العمر و �سنوات اخلربة و الخت�سا�س و امل�ستوى التعليمي. مفتاح الكلمات: ق�س العجان؛ ممر�سات؛ قابالت؛ العراق. midwives’ clinical reasons for performing episiotomies in the kurdistan region are they evidence-based? hamdia m. ahmed clinical & basic research advances in knowledge this study provides baseline data for the first time on the clinical reasons of performing episiotomies among kurdish midwives in northern iraq. knowing the clinical reasons for performing episiotomies and comparing them with evidence-based reasons may help in decreasing the rate of episiotomies and restricting their use. application to patient care the results of this study may help to decrease the number of patients undergoing unnecessary episiotomies. midwives’ knowledge and practice regarding this procedure should be updated through the establishment of training courses and new policies. midwives’ clinical reasons for performing episiotomies in the kurdistan region are they evidence-based? e370 | squ medical journal, august 2014, volume 14, issue 3 an episiotomy is a surgical incision of the perineum performed to increase the diameter of the vaginal outlet during childbirth.1 episiotomies are controversial and recent studies show that the common indications for performing this procedure are based on limited data.2 in addition, there is a general underestimation of the potential adverse consequences of this procedure, including thirdor fourth-degree tears due to extension of the incision, anal sphincter dysfunction and painful intercourse.2 other complications can include bleeding, infection, swelling, wound closure complications, localised pain and the possibility of short-term sexual dysfunction.1,3 episiotomies increase perineal pain on the first postpartum day as well as perineal pain and woundhealing problems during the third postpartum week.4 routine episiotomies are unfortunately very common, both in under-resourced settings and in some developed countries.5 they have been associated with an increased risk of severe perineal trauma and can also significantly increase the risk of anal sphincter tears rather than reducing this complication.6,7 the incidence of anal sphincter injuries was shown to be higher in patients undergoing a routine episiotomy, compared to patients who underwent a selective episiotomy according to certain criteria, including the state of the perineum (normal or tight), the size of the baby and the length of the second stage of labour.9 indeed, the cochrane review article regarding episiotomies for vaginal birth showed that, compared with routine use, restrictive use of episiotomies resulted in less severe perineal trauma and suturing as well as fewer healing complications.8 in line with the best available evidence, the world health organization (who) has taken a clear stand against the routine use of episiotomies, recommending an average episiotomy rate of 10% for normal deliveries.1,10 clinical guidelines regarding intrapartum care recommend that episiotomies should only be performed if there is a clinical need, such as during an instrumental vaginal birth or in cases of suspected fetal compromise.11 midwifery practice in iraq suffers from the absence of up-to-date and evidenced-based clinical guidelines; there is no research-based information regarding midwifery practice, especially regarding episiotomies, which are one of the most common surgical procedures used in obstetric care. almost all primigravida women in maternity teaching hospitals in the kurdistan region have an episiotomy and multigravida women also routinely undergo an episiotomy to shorten the length of the second stage of labour. an analysis of the reasons behind the use of an episiotomy is an important step in the reduction of episiotomy rates.12 thus this study aimed to determine the clinical reasons why midwives working in delivery rooms performed episiotomies and whether these reasons matched with evidence and recent research findings. the specific objectives of the present study were to determine the midwives’ clinical reasons for performing episiotomies, identify relationships between midwives’ demographic characteristics and their reasons for performing episiotomies and to compare the midwives’ clinical reasons for performing episiotomies between the three main cities in the kurdistan region. methods a cross-sectional study was conducted between 1st july and 30th september 2013 in the kurdistan region of iraq. kurdistan is an autonomous region of iraq that consists of the three governorates of erbil, dohuk and sulaymaniyah. the study was conducted in the biggest maternity teaching hospitals of these three governorates; these three hospitals provide comprehensive maternity care to the whole region. the study population included all of the midwives working in the hospitals’ delivery rooms. the midwives who had less than one year’s experience of working in delivery rooms (n = 9) were excluded from the study. all participants (n = 53) had nursing or midwifery qualifications, but those qualifications differed between individuals. in kurdistan, even though the primary and secondary nursing school has closed, older nurses with primary or secondary education in nursing are still practising. currently, erbil has one active secondary school of midwifery. in spite of these different qualifications, there is no difference between the job descriptions of midwives with nursing qualifications and those with midwifery qualifications. therefore all participants in this study were referred to as “midwives”. the purpose of the study was explained to all participants during personal interviews and informed verbal consent was obtained. data were collected evidence-based practice and national guidelines should be prepared for midwives in order to restrict the use of episiotomies and to decrease the rate of this procedure. it is recommended that these guidelines be created according to the recommendations of the world health organization. hamdia m. ahmed clinical and basic research | e371 through interviews with the midwives. a threepart questionnaire was constructed for the purpose of the study and was also completed during the interviews. the questionnaire sought to determine the participants’ demographic characteristics; their level and type of training; the type of episiotomy given; the authority of the decision to perform an episiotomy, and the midwives’ reasons for performing episiotomies (an open-ended question). these reasons are referred to in this article as “clinical reasons”. only the five most frequent clinical reasons (≥50%) were selected for investigation of their relationship with midwives’ demographic characteristics; these included the midwives’ number of years of experience in the delivery room and their level of education. data were analysed using the statistical package for the social sciences (spss), version 18 (ibm, corp., chicago, illinois, usa). the f-test and chi-squared test were also used for analysing data. a p value ≤0.05 was considered statistically significant and a p value ≤0.01 was considered highly significant. this study was approved by the directorate of health of erbil, dohuk and sulaymaniyah as well as the scientific and ethical committees of the nursing college of hawler medical university. results the mean age ± standard deviation (sd) of the study sample was 37.79 ± 7.01 years (range: 23‒57 years). the mean number of years of experience in the delivery room ± sd was 13.66 ± 9.25. a high percentage of the study participants (43.4%) were graduates of nursing or midwifery secondary schools and the majority of them were working morning, evening and night shifts. all midwives performed medio-lateral episiotomies but the majority of the study sample (83%) had received no training course on performing episiotomies. the majority of the midwives (71.7%) mentioned that performing an episiotomy was their own decision, while the rest (29.3%) stated that physicians helped make the decision. the midwives reported 16 clinical reasons for performing episiotomies, with the major clinical reason being macrosomia (large fetus) (71.7%). more than half of midwives stated that a breech delivery (58.5%) was a clinical reason for performing an episiotomy, followed by shoulder dystocia (54.7%), the prevention of perineal tearing (50.9%) and fetal distress (50.9%) [table 1]. there was a highly significant association between the midwives’ number of years of experience in the delivery room and choosing shoulder dystocia as a table 1: clinical reasons for performing episiotomies among midwives in three governorates in the kurdistan region (n = 53) clinical reasons total n (%) governorate n (%) p value hawler n = 17 duhok n = 18 sulaymaniyah n = 18 maternal factors better healing 12 (22.6) 9 (52.9) 0 (0) 3 (16.7) <0.001* anticipated perineal tear 27 (50.9) 11 (64.7) 3 (16.7) 13 (72.2) 0.001 previous pelvic surgery 13 (24.5) 2 (11.8) 2 (11.1) 9 (50) 0.014 poor maternal effort during labour 4 (7.5) 1 (5.9) 0 (0) 3 (16.7) 0.207 thick or inelastic perineum 22 (41.5) 1 (5.9) 9 (50) 12 (66.7) 0.001 fetal factors fetal distress 27 (50.9) 16 (94.1) 6 (33.3) 5 (27.8) <0.001 to decrease pressure on the fetal head 13 (24.5) 4 (23.5) 0 (0) 9 (50) 0.001* shoulder dystocia 29 (54.7) 14 (82.4) 0 (0) 15 (83.3) <0.001 shortening the second stage of labour 6 (11.3) 1 (5.9) 0 (0) 5 (27.8) 0.025* fetal malposition 10 (18.9) 2 (11.8) 1 (5.9) 7 (38.9) 0.047 instrumental delivery 11 (20.8) 0 (0) 0 (0) 11 (61.1) <0.001 breech delivery 31 (58.5) 13 (76.5) 5 (27.8) 13 (72.2) 0.005 macrosomia/large fetus 38 (71.7) 16 (94.1) 8 (44.4) 14 (77.8) 0.004 other factors routine due to primiparity 16 (30.2) 1 (5.9) 15 (83.3) 0 (0) <0.001 easier to repair for the physician 8 (15.1) 1 (5.9) 0 (0) 7 (38.9) 0.002* by order of the physician 15 (28.3) 5 (29.4) 2 (11.8) 8 (44.4) 0.020* *fisher’s exact test was applied. midwives’ clinical reasons for performing episiotomies in the kurdistan region are they evidence-based? e372 | squ medical journal, august 2014, volume 14, issue 3 clinical reason for performing an episiotomy [table 2]. there was also a highly significant association between the midwives’ level of education and choosing perineal tear and shoulder dystocia as clinical reasons, as well as a significant association between the level of education and choosing breech delivery and macrosomia as reasons for performing an episiotomy [table 3]. furthermore, there was a statistically significant difference in the midwives’ demographic characteristics between the governorates of erbil, duhok and sulaymaniyah. discussion currently, continuing controversy prevents a consensus regarding justifiable clinical reasons for performing an episiotomy.6 the primary results of this study indicate that the main clinical reasons of midwives in the kurdistan region of iraq for performing episiotomies were due to the delivery of a large fetus, shoulder dystocia, fetal distress and a likely perineal tear or injury. these fetal and maternal factors accounted for more than 50% of the identified reasons in this study. this finding is congruent with a number of national guidelines and recent studies that recommend using episiotomies to aid in deliveries when the perineum is tight and causing poor progress during the second stage of labour.13,14 in addition, an episiotomy also allows more space during operative or manipulative deliveries, such as in forceps-assisted or breech deliveries or in cases of shoulder dystocia.11,15 further reasons include preventing damage to the fetus during a face or breech presentation or during instrumental delivery, or shortening the second stage of labour due to fetal distress or a maternal medical condition. in some countries, an episiotomy is indicated to accommodate issues associated with female genital mutilation.16 an episiotomy is also indicated for preventing perineal trauma in women with a history of surgical repair to the pelvic floor, bladder or fistula, and in cases when the perineal body is unusually short.17 other indications, such as buttonholing (a short straight incision into a cavity or organ), a rigid perineum or previous scarring have been found by gibbon not to be justifiable reasons to perform an episiotomy.15 in addition, de tayrac et al. recommended the routine use of episiotomies to prevent perineal tears, urinary incontinence, fecal incontinence and genital prolapse should be abandoned.18 with regards to the actual number of clinical reasons for performing an episiotomy, the present study identified 16 reasons in total. a study in singapore by wu et al. identified 12 midwife-reported reasons for performing episiotomies, of which only one reason—fetal distress—was supported by the international guidelines.19 the primary reasons for performing episiotomies in primiparous women were primiparity and fetal distress; among multiparous table 2: association between the midwives’ years of experience in the delivery room and the top five clinical reasons for performing an episiotomy (n = 53) clinical reasons years of experience n (%) p value ≤5 6–15 16–25 >25 likely perineal tear yes 9 (60) 9 (60) 7 (41.2) 2 (33) 0.544* no 6 (40) 6 (40) 10 (58.8) 4 (66.7) fetal distress yes 9 (60) 7 (46.7) 7 (41.2) 4 (66.7) 0.641* no 6 (40) 8 (53.3) 10 (58.8) 2 (33.2) shoulder dystocia yes 14 (93.3) 10 (66.7) 3 (17.6) 2 (33.3) <0.001* no 1 (6.7) 5 (33.3) 14 (82.4) 4 (66.7) breech delivery yes 11 (73.3) 10 (66.7) 6 (35.3) 4 (66.7) 0.133* no 4 (26.7) 5 (33.3) 11 (64.7) 2 (33.3) macrosomia yes 14 (93.3) 11 (73.3) 10 (58.8) 3 (50) 0.079* no 1 (6.7) 4 (26.7) 7 (41.2) 3 (50) *fisher’s exact test was applied. table 3: association between midwives’ levels of education and their top five clinical reasons for performing an episiotomy (n = 53) clinical reasons level of education† n (%) p value primary secondary institute college likely perineal tear yes 3 (18.8) 15 (65.2) 7 (77.8) 2 (40) 0.007* no 13 (81.3) 8 (34.8) 2 (22.2) 3 (60) fetal distress yes 6 (37.5) 14 (60.9) 3 (33.3) 4 (80) 0.200* no 10 (62.5) 9 (39.1) 6 (66.7) 1 (20) shoulder dystocia yes 3 (18.8) 13 (56.5) 8 (88.9) 5 (100) <0.001* no 13 (81.3) 10 (43.5) 1 (11.1) 0 (0) breech delivery yes 4 (25) 17 (73.9) 6 (66.7) 4 (80) 0.011* no 12 (73) 6 (26.1) 3 (33.3) 1 (20) macrosomia yes 7 (43.8) 18 (78.3) 8 (88.9) 5 (100) 0.025* no 9 (56.3) 5 (21.7) 1 (11.1) 0 (0) †both nursing or midwifery qualifications were considered appropriate as there is no difference between midwives with nursing qualifications and those with midwifery qualifications in iraq. *fisher’s exact test was applied. hamdia m. ahmed clinical and basic research | e373 women, the leading reasons were fetal distress and poor maternal effort.19 another study by wu et al. examining 20 midwives’ reasons for performing episiotomies showed that primiparity was the most frequently cited factor in addition to fetal bradycardia (distress) and macrosomia.20 in the current study, midwives in the three governorates reported different numbers of reasons for performing episiotomies. the midwives in duhok reported only 10 reasons for performing an episiotomy in comparison to the 16 given by midwives in other cities. this may be due to the significant difference between demographic characteristics and the lack of uniform training in the region. all midwives in the current study performed medio-lateral episiotomies. studies have shown a decreased rate of deep perineal tears and trauma in this type of episiotomy and a high level of protection from severe perineal lacerations in cases where vacuum and forceps deliveries are used.6,21–23 in general, the majority (71.7%) of the midwives in the present study had the authority to make the decision to perform episiotomies, which is consistent with the results of a nigerian study in which the vast majority (75.6%) of episiotomies were authorised and performed by midwives.24 according to the international confederation of midwives, midwives should hold the responsibility of determining and performing episiotomies.25 however, the majority (85.7%) of midwives in duhok did not make the decision to perform episiotomies. in these cases, the decision was made either by the physician alone or in cooperation with the midwife. it is evident that the midwives’ education, experience and knowledge influence their decisions on episiotomy practice; this should be updated through continuous education.26 however, the vast majority of nurse/midwives in the present study had received no training course on episiotomies; this may have affected their technique and the type of episiotomy performed, in addition to their knowledge of indications for performing an episotomy. the strongest predictor of episiotomy use was found to be the type of care provider (either physician, midwife or faculty member), with weaker associations found to be the baby’s birth weight, the length of the second stage of labour or the use of epidural analgaesia.27 conclusion the findings of this study indicate that the midwives’ clinical reasons for performing episiotomies were not evidence-based or uniform in the three governorates of kurdistan. the midwives’ age, number of years of experience in the delivery room, specialties and levels of education affected their reasons for performing episiotomies. training courses and continuing education for midwives, in addition to developing regional clinical policies and guidelines, are essential to unify the practice of evidence-based surgical procedures. further research is recommended to analyse the reasons for performing episiotomies in individual deliveries. a c k n o w l e d g e m e n t s the author would like to express deep gratitude to ms. sazan tawfiq rashid, mrs. chya talia hamdi and ms. safia jamil piro in the erbil, sulaymaniah and duhok maternity teaching hospitals, respectively, for their advice and assistance in conducting this study. references 1. holmes d, baker pn, eds. midwifery by ten teachers. london, uk: crc press, 2006. pp.. 239‒41. 2. the american congress of obstetricians and gynecologists. acog recommends restricted use of episiotomies. from: www.acog.org/about_acog/news_room/news_ releases/2006/acog_recommends_restricted_use_of_ episiotomies accessed: nov 2013. 3. fraser dm, cooper ma, eds. myles’ textbook for midwives, 15th ed. london, uk: churchill-livingstone, 2009. p. 523. 4. karaçam z, ekmen h, çalişir h, şeker s. prevalence of episiotomy in primiparas, related conditions, and effects of episiotomy on suture materials used, perineal pain, wound healing 3 weeks postpartum in turkey: a prospective followup study. iran j nur midwifery res 2013; 18:237‒45. 5. sleep j, roberts j, chalmers i. care during the second stage of labour. in: chalmers i, enkin m, keirse mjnc, eds. effective care in pregnancy and childbirth. oxford, uk: oxford university press, 1989. pp. 1129–41. 6. dudding tc, vaizey cj, kamm ma. obstetric anal sphincter injury: incidence, risk factors, and management. ann surg 2008; 247:224–37. doi: 10.1097/sla.0b013e318142cdf4. 7. darves b. risks for anal sphincter injury at delivery increase with interventions. from: www.docguide.com/risks-analsphincter-injury-delivery-increase-interventions-presentedaugs?tsid=5 accessed: nov 2013. 8. carroli g, mignini l. episiotomy for vaginal birth. cochrane database syst rev 2009; 1:cd000081. doi: 10.1002/14651858. cd000081.pub2. 9. alnakash ah, jafar s, abdul-raheem y. whether selective or routine episiotomy is more useful to protect anal sphincter in primiparous women. iraqi postgrad med j 2012; 11:26–32. 10. maduma-butshe a, dyall a, garner p. routine episiotomy in developing countries: time to change a harmful practice. bmj 1998; 316:1179–80. doi: 10.1136/bmj.316.7139.1179. 11. national institute for health and clinical excellence. clinical guideline 55 intrapartum care: care of healthy women and their babies during childbirth. from: www.publications.nice. org.uk/intrapartum-care-cg55/guidance accessed: nov 2013. 12. rusavý z1, kalis v, landsmanová j, kasová l, karbanová j, dolejsová k, et al. [perineal audit: reasons for more than one thousand episiotomies]. ceska gynekol 2011; 76:378–85. midwives’ clinical reasons for performing episiotomies in the kurdistan region are they evidence-based? e374 | squ medical journal, august 2014, volume 14, issue 3 13. american college of obstetricians and gynecologists (acog). episiotomy. acog practice bulletin no. 71. washington dc: american college of obstetricians & gynecologists (acog), 6 apr 2006. 14. national health service uk. nhs choices. pregnancy and baby: episiotomy. from: http://www.nhs.uk/conditions/ pregnancy-and-baby/pages/episiotomy.aspx, accessed: apr 2014. 15. royal college of obstetricians and gynaecologists. shoulder dystocia (green-top 42). from: www.rcog.org.uk/womenshealth/clinical-guidance/shoulder-dystocia-green-top-42 accessed: nov 2013. 16. gibbon k. how to perform an episiotomy. from: www.rcm. org.uk/midwives/features/how-to-perform-an-episiotomy/ accessed: nov 2013. 17. women and newborn health service, king edward memorial hospital. obstetrics and midwifery guidelines 5.9.3.1: infiltration of the perineum and cutting an episiotomy. from: kemh.health.wa.gov.au/development/manuals/o&g_ guidelines/sectionb/5/5430.pdf accessed: nov 2013. 18. de tayrac r, panel l, masson g, mares p. [episiotomy and prevention of perineal and pelvic floor injuries] j gynecol obstet biol reprod (paris) 2006; 35:1s24–31. 19. wu lc, malhotra r, allen jc jr, lie d, tan tc, østbye t. risk factors and midwife-reported reasons for episiotomy in women undergoing normal vaginal delivery. arch gynecol obstet 2013; 288:1249‒56. doi: 10.1007/s00404-013-2897-6. 20. wu lc, lie d, malhotra r, allen jc, tay js, tan tc, et al. what factors influence midwives’ decision to perform or avoid episiotomies? a focus group study. midwifery 2013; 29:943–9. doi: 10.1016/j.midw.2012.11.017. 21. mckinney es, james sr, murray ss, ashwill jw. maternalchild nursing, 3rd ed. toronto, canada: saunders, 2009. pp. 445–6. 22. lappen jr, gossett dr. changes in episiotomy practice: evidence-based medicine in action. expert rev obstet gynecol 2010; 5:301–9. doi: 10.1586/eog.10.21. 23. sooklim r, thinkhamrop j, lumbiganon p, prasertcharoensuk p, pattamadilok j, seekorn k, et al. the outcome of midline versus medio-lateral episiotomy. reprod health 2007; 4:10. doi: 10.1186/1742-4755-4-10. 24. shahraki ad, aram s, pourkabirian s, khodaee s, choupannejad s. a comparison between early maternal and neonatal complications of restrictive episiotomy and routine episiotomy in primiparous vaginal delivery. j res med sci 2011; 16:1583–9. 25. international confederation of midwives. essential competencies for basic midwifery practice. from: www. i n t e r n a t i o n a l m i d w i v e s . o r g / w h a tw e d o / e d u c a t i o n coredocuments/essential-competencies-basic-midwifer ypractice/ accessed: sep 2013. 26. teckla n, omoni g, mwaura j, omuga b. evaluation of evidence-based episiotomy practice by midwives. afr j midwifery womens health 2010; 4:80–7. 27. robinson jn, norwitz er, cohen ap, lieberman e. predictors of episiotomy use at first spontaneous vaginal delivery. obstet gynecol 2000; 96:214–8. doi: 10.1016/s1526-9523(01)00103-9. surgical-site infections (ssis) are one of the most common healthcare-associated infections, accounting for 31% of all healthcareassociated infections worldwide.1 it is estimated that 2–5% of patients undergoing surgery develop ssis, with a higher percentage estimated in resourcelimited healthcare settings.2 the impact of ssis on healthcare delivery systems is very severe, resulting in prolonged hospitalisation, complex medical treatments, increased readmissions and outpatient visits as well as increased direct and indirect medical costs.3,4 in addition, these factors result in significant morbidity and mortality.3,4 previous research indicates that approximately 60–80% of ssis are preventable through the implementation of evidence-based practices such as surgical antimicrobial prophylaxis (sap) guidelines.5 the key to preventing ssis lies in the understanding and careful implementation of sap guidelines. choosing the right antibiotic for each case is of particular importance, as the right antibiotic will produce adequate serum and tissue drug levels and exceed the minimal inhibitory concentration for any organisms that are likely to be encountered during the operation. optimal timing of the antibiotic prophylaxis administration is considered to be 30–60 minutes before the first incision is made, except for certain antibiotics (e.g. vancomycin and ciprofloxacin) which are administered 120 minutes beforehand.6 bratzler et al. have confirmed that a single dose of an antimicrobial agent is sufficient for most surgical operations.6 although the principles of antimicrobial prophylaxis in surgery are clearly established and several guidelines have been published, the implementation of these guidelines remains problematic and controversial among surgeons.7 the overprescription and inappropriate timing and duration of antimicrobials remains a significant issue in the practice of surgical prophylaxis. in addition, the incidence of ssis has increased and new antimicrobialresistant bacteria have emerged due to poor adherence to sap guidelines.8,9 the aforementioned challenges have been widely addressed in many developed countries,10 although very little attention has been given to this issue in developing countries and the middle eastern region. in the november 2015 issue of squmj, telfah et al. published a report on the impact of a multidisciplinary quality improvement project on the adherence to sap guidelines in the treatment of surgical oncology patients.10 a clinical pharmacist was noted to play a key role in updating the sap guidelines and providing the surgeons with required prophylaxis education. telfah et al. concluded that there was significant improvement in the adherence to sap guidelines following the implementation of the multidisciplinary quality improvement project.10 this approach demonstrates the important role of both clinical pharmacists and surgeons in engaging with and improving adherence to sap guidelines.7,11 a review of studies evaluating guideline implementation strategies found only modest-to-moderate effects and noted that healthcare organisations’ resources for guideline implementation were usually insufficient to allow much more than the dissemination of educational materials or lunchtime educational meetings, interventions whose effects were usually only short-lived.12 barlow et al. found that education and audit-based interventions used before the implementation of guidelines resulted in a significant increase in appropriate antibiotic prescriptions after the introduction of a multifaceted education programme.13 audit feedback systems to improve the quality of care have also been shown to be feasible and effective in hospital settings in low-income countries.14 consequently, successful guideline implementation 1department of medicine, royal hospital, muscat, oman; 2central department of infection prevention & control, directorate general for disease surveillance & control, ministry of health, muscat, oman *corresponding author e-mail: salabri@gmail.com الوقاية باملضادات احليوية يف اجلراحة التحديات يف ترمجة األدلة إىل ممارسة �شيف �ش�مل العربي و م�أمون ال�شيخ editorial surgical antimicrobial prophylaxis challenges in translating evidence to practice *seif s. al-abri1 and mamoun elsheikh2 sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e1–2, epub. 2 feb 16 submitted 23 nov 15 revision req. 10 dec 15; revision recd. 12 dec 15 accepted 13 dec 15 doi: 10.18295/squmj.2016.16.01.001 surgical antimicrobial prophylaxis challenges in translating evidence to practice e2 | squ medical journal, february 2016, volume 16, issue 1 programmes need to understand local barriers, incorporate multiple-component interventions and proceed within a framework of continuous quality improvement.12 although sap plays an important role in reducing the rate of ssis, other factors must be taken into consideration. these include attention to basic infection control strategies; the experiences and techniques of the surgeon; the duration of a procedure; hospital and operating room environments; instrument-sterilisation procedures; preoperative preparation techniques (e.g. surgical scrubs, skin antisepsis and appropriate hair removal); perioperative management of patient temperature and glycaemic control; and the underlying medical condition of the patient.6 in conclusion, drafting sap guidelines without addressing the implementation process will not necessarily decrease ssi rates. to achieve optimal adherence, antibiotic policy-makers should develop evidence-based guidelines in collaboration with surgeons, guarantee an effective distribution of those guidelines, perform periodic audits on adherence to the guidelines and provide feedback from these audits to surgeons and the appropriate authorities. hospitals also need to establish a ssi surveillance system, formulate a multidisciplinary implementation team and monitor antimicrobial consumption related to surgical procedures. moreover, education and training on ssi prevention and management, including sap guidelines, should be integrated in all undergraduate and postgraduate surgical training programmes. references 1. burke jp. infection control: a problem for patient safety. n engl j med 2003; 348:651–6. doi: 10.1056/nejmhpr020557. 2. mu y, edwards jr, horan tc, berrios-torres si, fridkin sk. improving risk-adjusted measures of surgical site infection for the national healthcare safety network. infect control hosp epidemiol 2011; 32:970–86. doi: 10.1086/662016. 3. de lissovoy g, fraeman k, hutchins v, murphy d, song d, vaughn bb. surgical site infection: incidence and impact on hospital utilization and treatment costs. am j infect control 2009; 37:387–97. doi: 10.1016/j.ajic.2008.12.010. 4. leaper dj, van goor h, reilly j, petrosillo n, geiss hk, torres aj, et al. surgical site infection: a european perspective of incidence and economic burden. int wound j 2004; 1:247– 73. doi: 10.1111/j.1742-4801.2004.00067.x. 5. anderson dj. surgical site infections. infect dis clin north am 2011; 25:135–53. doi: 10.1016/j.idc.2010.11.004. 6. bratzler dw, dellinger ep, olsen km, perl tm, auwaerter pg, bolon mk, et al. clinical practice guidelines for antimicrobial prophylaxis in surgery. am j health syst pharm 2013; 70: 195–283. doi: 10.2146/ajhp120568. 7. tourmousoglou ce, yiannakopoulou ech, kalapothaki v, bramis j, st papadopoulos j. adherence to guidelines for antibiotic prophylaxis in general surgery: a critical appraisal. j antimicrob chemother 2008; 61:214–8. doi: 10.1093/jac/ dkm406. 8. kernodle ds, barg nl, kaiser ab. low-level colonization of hospitalized patients with methicillin-resistant coagulasenegative staphylococci and emergence of the organisms during surgical antimicrobial prophylaxis. antimicrob agents chemother 1988; 32:202–8. doi: 10.1128/aac.32.2.202. 9. terpstra s, noordhoek gt, voesten hg, hendriks b, degener je. rapid emergence of resistant coagulase-negative staphylococci on the skin after antimicrobial prophylaxis. j hosp infect 1999; 43:195–202. doi: 10.1053/jhin.1999.0636. 10. telfah s, nazer l, dirani m, daoud f. improvement in adherence to surgical antimicrobial prophylaxis guidelines after implementation of a multidisciplinary quality improvement project. sultan qaboos univ med j 2015; 15:e523–7. doi: 10.18295/squmj.2015.15.04.014. 11. ozgun h, ertugrul bm, soyder a, ozturk b, aydemir m. perioperative antibiotic prophylaxis: adherence to guidelines and effects of educational intervention. int j surg 2010; 8:159–63. doi: 10.1016/j.ijsu.2009.12.005. 12. al-abri ss, al-maashani s, memish za, beeching nj. an audit of inpatient management of community-acquired pneumonia in oman: a comparison with regional clinical guidelines. j infect public health 2012; 5:250–6. doi: 10.1016/j.jiph.2012.03.002. 13. barlow g, nathwani d, myers e, sullivan f, stevens n, duffy r, et al. identifying barriers to the rapid administration of appropriate antibiotics in community-acquired pneumonia. j antimicrob chemother 2008; 61:442–51. doi: 10.1093/jac/ dkm462. 14. wahlström r, kounnavong s, sisounthone b, phanyanouvong a, southammavong t, eriksson b, et al. effectiveness of feedback for improving case management of malaria, diarrhoea and pneumonia: a randomized controlled trial at provincial hospitals in lao pdr. trop med int health 2003; 8:901–9. doi: 10.1046/j.1365-3156.2003.01105.x. http://dx.doi.org/10.1056/nejmhpr020557 http://dx.doi.org/10.1086/662016 http://dx.doi.org/10.1016/j.ajic.2008.12.010 http://dx.doi.org/10.1111/j.1742-4801.2004.00067.x http://dx.doi.org/10.1016/j.idc.2010.11.004 http://dx.doi.org/10.2146/ajhp120568 http://dx.doi.org/10.1093/jac/dkm406 http://dx.doi.org/10.1093/jac/dkm406 http://dx.doi.org/10.1128/aac.32.2.202 http://dx.doi.org/10.1053/jhin.1999.0636 http://dx.doi.org/10.18295/squmj.2015.15.04.014 http://dx.doi.org/10.1016/j.ijsu.2009.12.005 http://dx.doi.org/10.1016/j.jiph.2012.03.002 http://dx.doi.org/10.1093/jac/dkm462 http://dx.doi.org/10.1093/jac/dkm462 http://dx.doi.org/10.1046/j.1365-3156.2003.01105.x 1ministry of health, muscat, oman; 2department of information systems & technology, sur university college, sur, oman *corresponding author e-mail: falfannah@gmail.com منوذج افرتاضي للتنبؤ بتصورات طالب التمريض للفائدة من تدريب ما قبل اخلدمة يف جمال تدابري الرعاية املتكاملة ألمراض الطفولة فنة العرميية و �شتوات عثم�ن لنجري�ل abstract: objectives: this study aimed to test a hypothetical model to predict nursing students’ perceptions of the usefulness of pre-service integrated management of childhood illness (imci) training and their intention to apply this training in clinical practice. methods: this study was carried out at the sur nursing institute, sur, oman, in may 2015. using six predefined constructs, a hypothetical structural model was created. the constructs were used as latent variables to highlight their probable impact on intention to apply imci-related knowledge and skills in practice. a structured validated questionnaire was subsequently developed to assess the perceptions of nursing students. factor loadings and calculated variances were examined to ensure convergent validity. cronbach’s alpha was used to calculate internal consistency reliability. results: factor loadings for each item in the model were above 0.70. all of the constructs had cronbach’s alpha values over 0.700, except for enhanced assessment skills (cronbach’s alpha: 0.694). the variance extracted value was 0.815 for perceived usefulness, 0.800 for enhanced assessment skills, 0.687 for enhanced knowledge, attitudes and skills, 0.697 for enhanced confidence, 0.674 for enhanced counselling skills and 0.805 for future intention to use imci in a clinical setting. conclusion: overall, the results support the hypothetical model and indicate that nursing students perceive imci training to be beneficial and intend to apply imci-related knowledge and skills in clinical practice. keywords: statistical model; nursing; perceptions; disease management; oman. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل اختب�ر منوذج افرتا�شي للتنبوؤ بت�شورات طالب التمري�س للف�ئدة من تدريب م� قبل اخلدمة يف هذه اأجريت الطريقة: ال�رسيرية. املم�ر�شة يف التدريب هذا تطبيق على عزمهم ومدى الطفولة لأمرا�س املتك�ملة االرع�ية تدابري جم�ل حمددة بني�ت �شت طريق عن الهيكلي الفرتا�شي النموذج اإن�ش�ء مت .2015 م�يو يف عم�ن يف �شور مبدينة التمري�س معهد يف الدرا�شة التدابري على املكت�شبة وامله�رات املعرفة تطبيق لنية املحتمل الت�أثري على ال�شوء لت�شليط ك�منة كمتغريات بني�ت وا�شتخدمت م�شبق�, عن التمري�س طلبة ت�شورات لتقييم لحق وقت يف التحقق ا�شتب�نة تطوير مت وقد اال�رسيرية. املم�ر�شة يف الطفولة لأمرا�س املتك�ملة حل�ش�ب كرونب�خ األف� مع�مل ا�شتخدم وقد املتق�ربة. ال�شحة ل�شم�ن املح�شوبة والفروق الع�مل �شحن�ت فح�س ومت املرجوة. الف�ئدة موثوقية الت�ش�ق الداخلي. النتائج: ك�نت �شحن�ت ع�مل لكل عن�رس يف النموذج اأكرث من 0.70. وك�ن كل قيم بني�ت األف� كرونب�خ اأكرث ,0.815 هي املت�شورة للف�ئدة امل�شتخرج التب�ين متو�شط وك�ن .)0.694 األف�: )كرونب�خ املح�شنة التقييم مه�رات ب��شتثن�ء ,0.700 من 0.800 ب�لن�شبة مله�رات التقييم املح�شنة, 0.687 للمعرفة والجت�ه�ت وامله�رات املح�شنة, 0.697 للثقة املح�شنة, 0.674 مله�رات الإر�ش�د والتوجيه و 0.805 للنية امل�شتقبلية ل�شتخدام تدابري االرع�ية املتك�ملة لأمرا�س الطفولة �رسيري� يف امل�شتقبل. اخلال�صة: على وجه العموم تدعم النت�ئج منوذج الفر�شية التي در�شت, وت�شري اإىل اأن طالب التمري�س يت�شورون اأن تدريب م�قبل اخلدمة للتدابري املتك�ملة لأمرا�س الطفولة �شيكون مفيدا, وينون تطبيق املعرفة وامله�رات املتعلقة به� يف املم�ر�شة ال�رسيرية. الكلمات املفتاحية: النموذج الإح�ش�ئي؛ التمري�س؛ الت�شورات؛ عالج الأمرا�س؛ عم�ن. a hypothetical model to predict nursing students’ perceptions of the usefulness of pre-service integrated management of childhood illness training *fannah a. al-araimi1 and sitwat u. langrial2 clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e469–474, epub. 30 nov 16 submitted 16 jun 16 revision req. 14 jul 16; revision recd. 23 aug 16 accepted 8 sep 16 doi: 10.18295/squmj.2016.16.04.011 advances in knowledge the current study uses a quantitative approach for developing and validating a predictive structural data model. the findings of this study add to the current knowledge base by highlighting nursing students’ positive perceptions of integrated management of childhood illness (imci) training and their intentions to apply imci-related skills in clinical settings. application to patient care although there is rich evidence of the strengths of imci training, the extent to which imci-trained healthcare professionals apply these skills has not been reported. this is important as the application of imcirelated skills may have a positive influence on paediatric health. a hypothetical model to predict nursing students’ perceptions of the usefulness of pre-service integrated management of childhood illness training e470 | squ medical journal, november 2016, volume 16, issue 4 childhood illnesses continue to increase the global disease burden, especially in lowto middle-income countries.1 in the mid-1990s, the world health organization and united nations international children’s fund initiated the integrated management of childhood illness (imci) strategy in order to improve the health standards of children under five years of age.1,2 this approach focuses on improving health worker skills, refining healthcare systems, enhancing knowledge of child health among families and communities and disease-specific interventions.3 imci relies on trained healthcare professionals to improve symptom assessments, illness classifications and treatment needs and provide better counselling to caregivers.1,2 since its introduction, imci has been implemented in several countries, including uganda, bangladesh, brazil, tanzania and peru.1,4–8 in tanzania, imci implementation resulted in a 13% reduction in the child mortality rate.5 furthermore, imci training is believed to have improved the quality of child health in a number of countries.6–10 these promising findings have resulted in the implementation of imci in over 100 countries.11 in oman, imci was introduced into the healthcare system in 1999. since its implementation, a number of studies have examined the epidemiology and burden of specific conditions, such as diarrhoea, urinary tract infections, antimicrobial resistance and influenza; a few studies have also focused on other factors, such as patient-physician interactions and antibiotic policies.12–17 there are evident benefits of imci implementation for families and communities. in nigeria, imci implementation was reported to be a cost-effective intervention.18 the positive effects of imci on case management and in improving illness classifications and enhancing skills in managing childhood illness are frequently reported.7,10,18 however, limitations of healthcare systems, long duration of training courses, extended consultations and resistance from experienced doctors have been identified as barriers to the acceptance and practice of imci.19 in order to predict the effectiveness of imci implementation, it is essential to understand how imci-trained healthcare workers perceive imci training and whether they intend to use imci-related skills and knowledge in clinical practice. however, there is a lack of research on how healthcare professionals perceive imci training; this is important, as imci emphasises a new role for both doctors and nurses as educators as well as healthcare professionals.19 moreover, healthcare professionals, such as nurses, play a vital role in paediatric health management.20 this study therefore aimed to test a hypothetical model to predict the perceived benefits of preservice imci training among nursing students and their intentions of applying imci-related skills and knowledge in future. it was hypothesised that imcitrained nursing students would perceive imci training to useful in improving knowledge, skills and confidence, leading to the use of these skills in future clinical practice. this hypothesis was based on the theory of reasoned action, which suggests that the decision to perform a specific behaviour is strongly linked with the expected outcome or benefit of the behaviour.21,22 methods this study was carried out in may 2015 at the sur nursing institute in sur, oman. a hypothetical structural model was developed with the help of six healthcare professionals, including two imci experts. the following six predefined constructs were used: perceived usefulness, enhanced assessment skills, enhanced knowledge, attitudes and skills (kas), enhanced confidence, enhanced counselling skills and future intention to use imci in a clinical setting. these constructs were used as latent variables to highlight their probable impact on a formative variable (i.e. intention to apply imci-related knowledge and skills in practice). the model was designed to indicate relationships between the constructs. subsequently, a total of 114 nursing students were recruited via the distribution of posters at the sur nursing institute. all of the nursing students had received pre-service imci training via workshops, lectures, laboratory sessions and field trips for a mean duration of 3.155 ± 0.361 years. the minimum sample size for this type of analysis was calculated using the heuristic method by multiplying by 10 the largest number of independent constructs influencing the dependent construct (i.e. six).23 thus, the minimum sample size for the current study was calculated to be 60. an english-language structured questionnaire was created to assess the students’ actual perceptions of imci training and intention to use this training in future practice. the questionnaire was developed and validated with the help of six practicing healthcare professionals to ensure that the language and terminology used in the questionnaire could be easily understood. the items were pretested by the healthcare professionals to ensure that each construct was loaded with three items. participants completed and returned the questionnaires in sealed envelopes. fannah a. al-araimi and sitwat u. langrial clinical and basic research | e471 the reliability and validity of the model was analysed using smart partial least square software, version 3.2.5 (smartpls gmbh, bönningstedt, germany). this software was chosen because it is appropriate for exploratory research aiming to test a new predictive model rather than re-examining existing models or theories.24 in the analysis, a twostep approach was applied (i.e. assessment of reliability and validity of the hypothetical model).25 the properties of the constructs were assessed in terms of factor loadings, discriminant validity and internal consistency. factor loadings and calculated variances were examined to ensure convergent validity; factor loading and internal consistency values of over 0.700 were considered adequate. cronbach’s alpha was used to calculate the internal consistency reliability of the items. the fornell-larcker criterion was used to determine discriminant validity between the studied constructs.24 however, as previous research has indicated that the fornell-larcker criterion may not necessarily detect discriminant validity reliably, the heterotrait-monotrait (htmt) ratio of correlations was also assessed.26 a htmt value of below 0.90 indicated satisfactory discriminant validity.26 the effect sizes indicated by the path coefficients were noted to be either small (0.02), medium (0.15) or large (0.35). ethical approval for this study was obtained from the ministry of health of oman. each student gave written informed consent before participating in the study. the students were not offered any financial rewards or incentives for participating in the study. results of the 114 students invited to participate in the study, 110 completed the entire questionnaire (response rate: 96.5%). there were 77 females (70%) and 33 males (30%). figure 1 shows the relationships between the constructs in the hypothetical model. factor loadings and calculated variances for each item exceeded 0.70 and 0.50, respectively, indicating that all of the items loaded well. the average variance extracted value was above 0.607. all of the constructs had cronbach’s alpha values over 0.700, except for enhanced assessment skills (cronbach’s alpha: 0.694). the composite reliability of all of the constructs in the model exceeded 0.821 [table 1]. the discriminant validity of all of the correlations was below the threshold htmt ratio value of 0.90. upon analysis of the path coefficients, enhanced assessment skills (p <0.010), enhanced confidence (p <0.050), enhanced counselling (p <0.050) and perceived usefulness (p <0.001) had a significant influence on future intention to use imci in a clinical setting. finally, the cross-loadings of the items on their assigned latent variables were larger than any other loading. therefore, the reliability and validity of the constructs in the model were acceptable. the studied constructs were complexly interrelated. there was a 36.2% variance in the enhanced kas construct. the enhanced kas construct predicted 14.6% variance in enhanced confidence and 20.1% variance in future intention to apply imci-related figure 1: a hypothetical structural model to predict nursing students’ perceptions of the usefulness of pre-service integrated management of childhood illness training and their intention to apply this training in future clinical practice. kas = knowledge, assessment and skills. a hypothetical model to predict nursing students’ perceptions of the usefulness of pre-service integrated management of childhood illness training e472 | squ medical journal, november 2016, volume 16, issue 4 knowledge and skills. the main direct contributors of the variance in future intention to apply imcirelated knowledge and skills were enhanced kas (36.2%), enhanced confidence (14.7%) and enhanced counselling skills (17.1%). when taken together, enhanced confidence and enhanced counselling skills resulted in a 31.8% variance in future intention to apply imci-related knowledge and skills. the r2 values were 36.2 for enhanced kas, 14.7 for enhanced confidence, 17.1 for enhanced counselling and 14.0 for future intention to use imci. the constructs expressed significant variance (60%) in future intention to apply imci-related knowledge and skills (p <0.010). the significance of the total effects are displayed in table 2. based on these statistical findings, the central hypothesis of the study was supported. discussion the current study was performed to test a hypothetical model to predict perceived benefits of preservice imci training among trainee nurses and their subsequent intentions of using learned skills in clinical settings. to the best of the authors’ knowledge, this is the first imci-related hypothetical model in the available literature. the results from the analysis substantially supported the hypothetical structural model. factor loadings for each item in the model were above the minimum required threshold;27 moreover, the majority of the constructs had cronbach’s alpha values above the minimum cut-off level.25,28 indeed, previous research has indicated that even reliability ranges of 0.5–0.6 can be regarded as significant for experimental studies.29 overall, the composite reliability of all constructs in the model exceeded the recommended value of 0.700.29 while the r2 values were relatively low, lower r2 values can nevertheless still indicate some level of significance.30 this is particularly true in any research work seeking to predict human behaviours and intentions.31 as the central assumption in the presented model was future intentions of healthcare professionals to use imcirelated knowledge and skills, even a lower r2 value should be viewed as significant. the current study revealed strong correlations between the studied constructs and intentions of using imci-related knowledge and skills in the future. importantly, the current study found that the table 1: latent variable coefficients and correlations of a hypothetical structural model to predict nursing students’ perceptions of pre-service integrated management of childhood illness training construct future intention to use imci 0.925 0.879 0.804 2.1 1.000 enhanced assessment skills 0.821 0.694 0.607 3.4 0.075 1.000 enhanced confidence 0.873 0.795 0.698 1.9 -0.006 0.527 1.000 enhanced counselling 0.861 0.763 0.674 1.5 0.080 0.295 0.506 1.000 enhanced kas 0.865 0.765 0.685 2.6 0.254 0.933 0.457 0.511 1.000 perceived usefulness 0.930 0.887 0.815 2.7 0.256 0.826 0.682 0.106 0.572 1.000 ave = average variance extracted; vif = variance inflation factor; imci = integrated management of childhood illness; kas = knowledge, assessment and skills. c om po si te r el ia bi lit y c ro nb ac h’ s al ph a fu tu re in te nt io n to u se i m c i en ha nc ed as se ss m en t s ki lls en ha nc ed co nfi de nc e en ha nc ed co un se lli ng pe rc ei ve d us ef ul ne ss en ha nc ed k a s a v e v if table 2: total effect of constructs in a hypothetical structural model to predict nursing students’ perceptions of pre-service integrated management of childhood illness training construct 1 construct 2 total effect p value enhanced assessment skills enhanced confidence 0.231 <0.001 enhanced assessment skills enhanced counselling 0.095 0.008 enhanced assessment skills enhanced kas 0.602 <0.001 enhanced confidence future intention to use imci -0.263 0.016 enhanced confidence enhanced counselling 0.414 <0.001 enhanced kas enhanced confidence 0.383 <0.010 enhanced kas enhanced confidence 0.158 0.002 kas = knowledge, assessment and skills; imci = integrated management of childhood illness. fannah a. al-araimi and sitwat u. langrial clinical and basic research | e473 constructs expressed significant variance in future intention to apply imci-related knowledge and skills. in other words, this implies that nursing students are more likely to plan to apply imci-related skills in future if they perceive imci to be useful in helping improve their assessment skills, counselling skills, selfconfidence and kas. all of the studied constructs were found to be contributors towards a positive intention to use the imci-related skills and knowledge. based on this finding, it is likely that imci-trained nurses will actually apply the skills learned from pre-service imci training. however, it is critical to note that improved knowledge of caregivers and the synchronised func-tioning of the entire health system is necessary for the successful integration of imci.1,2 the findings of the current study add to the existing literature by highlighting the importance of imci among nursing students who will go on to practice in clinical settings after their graduation. to the best of the authors’ knowledge, no previous studies have examined how nursing students perceive the useful ness of imci training. moreover, this study is important in terms of furthering efforts to implement imci training in oman. although the findings from this study may not have a direct impact on practices, public health policy-makers are advised to take appropriate steps to integrate imci training at all medical and nursing institutions in the country. governmental institutions and policies may help establish healthcare systems that embrace imci as a holistic approach. healthcare policy-makers and senior medical professionals should consider the potential benefits of imci and encourage its implementation, allowing for sick children to receive timely, accurate and effective treatment. future studies are recommended to identify factors that contribute to the high mortality rate of children under five years old.32 this study is subject to certain limitations. first, the studied sample was taken from a single educational institution so there may be potential selection bias. second, due to the small sample size, it is hard to generalise the results. third, while the statistical results indicate that imci-trained nursing students intend to apply their acquired skills in clinical settings, further investigation is necessary to establish whether these intentions hold true in the future. in future research, the authors recommend that efforts are made to investigate the extent to which imci-trained nurses apply their skills and knowledge in clinical settings and the factors which hinder them from doing so. conclusion an imci-related hypothetical model was developed and evaluated for the first time. perceived benefits of imci training were found to lead to an intention to apply related skills and knowledge in future clinical practice among nursing students. overall, nursing students perceived imci to be a useful approach that could improve their skills, knowledge and confidence; as such, they intended to apply skills and knowledge learnt as result of this training in the future. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors would like to thank all of the participants for their cooperation, as well as the relevant authorities of the ministry of health and mr mohammad m. bahwan for their extended support. in addition, the authors appreciate the efforts of the healthcare professionals who aided in the development and validation of the questionnaire items. finally, the authors wish to thank the management of sur nursing institute for their support in carrying out this research. references 1. bryce j, el arifeen s, pariyo g, lanata c, gwatkin d, habicht jp, et al. reducing child mortality: can public health deliver? lancet 2003; 362:159–64. doi: 10.1016/s0140-6736 (03)13870-6. 2. gove s. integrated management of childhood illness by outpatient health workers: technical basis and overview the who working group on guidelines for integrated management of the sick child. bull world health organ 1997; 75:7–24. 3. bryce j, boschi-pinto c, shibuya k, black re; who child health epidemiology reference group. who estimates of the causes of death in children. lancet 2005; 365:1147–52. doi: 10.1016/s0140-6736(05)71877-8. 4. bryce j, victora cg, habicht jp, vaughan jp, black re. the multi-country evaluation of the integrated management of childhood illness strategy: lessons for the evaluation of public health interventions. am j public health 2004; 94:406–15. doi: 10.2105/ajph.94.3.406. 5. armstrong schellenberg jr, adam t, mshinda h, masanja h, kabadi g, mukasa o, et al. effectiveness and cost of facilitybased integrated management of childhood illness (imci) in tanzania. lancet 2004; 364:1583–94. doi: 10.1016/s01406736(04)17311-x. 6. amaral j, leite aj, cunha aj, victora cg. impact of imci health worker training on routinely collected child health indic ators in northeast brazil. health policy plan 2005; 20:i42–8. doi: 10.1093/heapol/czi058. a hypothetical model to predict nursing students’ perceptions of the usefulness of pre-service integrated management of childhood illness training e474 | squ medical journal, november 2016, volume 16, issue 4 7. pariyo gw, gouws e, bryce j, burnham g; uganda imci impact study team. improving facility-based care for sick children in uganda: training is not enough. health policy plan 2005; 20:i58–68. doi: 10.1093/heapol/czi051. 8. arifeen se, hoque dm, akter t, rahman m, hoque me, begum k, et al. effect of the integrated management of childhood illness strategy on childhood mortality and nutrition in a rural area in bangladesh: a cluster randomised trial. lancet 2009; 374:393–403. doi: 10.1016/s0140-6736(09)60828-x. 9. wagstaff a, bustreo f, bryce j, claeson m; who-world bank child health and poverty working group. child health: reaching the poor. am j public health 2004; 94:726–36. doi: 10.2105/ajph.94.5.726. 10. naimoli jf, rowe ak, lyaghfouri a, larbi r, lamrani la. effect of the integrated management of childhood illness strategy on health care quality in morocco. int j qual health care 2006; 18:134–44. doi: 10.1093/intqhc/mzi097. 11. chopra m, binkin nj, mason e, wolfheim c. integrated management of childhood illness: what have we learned and how can it be improved? arch dis child 2012; 97:350–4. doi: 10.1136/archdischild-2011-301191. 12. patel pk, mercy j, shenoy j, ashwini b. factors associated with acute diarrhoea in children in dhahira, oman: a hospitalbased study. east mediterr health j 2008; 14:571–8. 13. world health organization department of child and adolescent health and development. urinary tract infections in infants and children in developing countries in the context of imci. from: whqlibdoc.who.int/hq/2005/who_fch_ cah_05.11.pdf accessed: aug 2016. 14. prakash kp. epidemiology and antimicrobial resistance of enteric pathogens in dhahira region, oman. iran j public health 2008; 37:60–9. 15. al-awaidy s, hamid s, al obaidani i, al baqlani s, al busaidi s, bawikar s, et al. the burden of influenza-associated hospitalizations in oman, january 2008-june 2013. plos one 2015; 10:e0144186. doi: 10.1371/journal.pone.0144186. 16. abdulhadi n, al-shafaee am, ostenson cg, vernby a, wahlström r. quality of interaction between primary healthcare providers and patients with type 2 diabetes in muscat, oman: an observational study. bmc fam pract 2006; 7:72. doi: 10.1186/1471-2296-7-72. 17. al-fannah f, khandekar r, kurup p, shah s. preferral antibiotic treatment policy to be adopted in the integrated management of childhood illness strategy in all the developing countries? oman med j 2009; 24:248–55. doi: 10.5001/omj.2009.51. 18. ebuehi om. health care for under-fives in ile-ife, south-west nigeria: effect of the integrated management of childhood illness (imci) strategy on growth and development of underfives. afr j prim health care fam med 2009; 1:029. doi: 10.41 02/phcfm.v1i1.29. 19. saloojee h. integrated management of childhood illness (imci): traditional versus new approaches to clinical care. contin med educ 2007; 25:172–5. 20. fujimori e, higuchi ch, carneiro ta, borges al, chiesa am, veríssimo md, et al. integrated management of childhood illness (imci): knowledge and practice of nurses who have graduated from school of nursing at university of são paulo a case study. online braz j nurs 2010; 9:1. doi: 10.5935/16764285.20102657. 21. fishbein m. a theory of reasoned action: some applications and implications. nebr symp motiv 1980; 27:65–116. 22. madden tj, ellen ps, ajzen i. a comparison of the the theory of planned behavior and the the theory of reasoned action. personal soc psychol bull 1992; 18:3–9. doi: 10.1177/0146167292181001. 23. chin ww, marcolin bl, newsted pr. a partial least squares latent variable modeling approach for measuring interaction effects: results from a monte carlo simulation study and an electronic-mail emotion/adoption study. inf syst res 2003; 14:189–217. doi: 10.2753/mtp1069-6679190202. 24. hair jf, ringle cm, sarstedt m. pls-sem: indeed a silver bullet. j mark theory pract 2011; 19:139–52. 25. anderson jc, gerbing dw. structural equation modeling in practice: a review and recommended two-step approach. psychol bull 1988; 103:411–23. doi: 10.1037/0033-2909.103. 3.411. 26. henseler j, ringle cm, sarstedt m. a new criterion for assessing discriminant validity in variance-based structural equation modeling. j acad mark sci 2015; 43:115–35. doi: 10.1007/s11747-014-0403-8. 27. langrial s. persuasive subtleties of social networking sites: design implications for behavior change interventions. in: theng lb, ed. assistive technologies for physical and cognitive disabilities. hershey, pennsylvania, usa: igi global, 2014. pp. 191–210. doi: 10.4018/978-1-4666-7373-1.ch010. 28. gliem ja, gliem rr. calculating, interpreting, and reporting cronbach’s alpha reliability coefficient for likert-type scales. from: scholarworks.iupui.edu/handle/1805/344 accessed: aug 2016. 29. nunnally jc, bernstein ih. psychometric theory, 3rd ed. new york, usa: mcgraw-hill, 1994. pp. 248–92. 30. vinzi ve, trinchera l, amato s. pls path modeling: from foundations to recent developments and open issues for model assessment and improvement. in: vinzi ve, chin ww, henseler j, wang h, eds. handbook of partial least squares: concepts, methods and applications. berlin, germany: springer, 2010. pp. 47–82. doi: 10.1007/978-3-540-32827-8_3. 31. onditi aa. relationship between customer personality, service features and customer loyalty in the banking sector: a survey of banks in homabay county, kenya. int j bus soc sci 2013; 4:132–50. 32. black re, cousens s, johnson hl, lawn je, rudan i, bassani dg, et al. global, regional, and national causes of child mortality in 2008: a systematic analysis. lancet 2010; 375:1969–87. doi: 10.1016/s0140-6736(10)60549-1. the treatment of cancer is going through a phase of evolution and rapid progress. the last few years have seen a paradigm shift, and targeted therapy is now considered a cornerstone in cancer management. despite this progress, cytotoxic chemotherapy plays a pivotal role in the medical management of various cancers. cancer chemotherapy and biotherapy: principles and practice highlights the importance of this subject. this hard-back 5th edition, with fully searchable online text and image bank, should be considered as a useful source of reference, especially with regards to cytotoxic chemotherapy, for any medical library, in the vicinity of which cancer is treated, or cancer management taught and learnt. section i deals with the basic principles of cancer treatment, including areas such as, drug discovery, development and marketing approval, in the present day setting of fierce competition amongst the pharmaceutical companies, this section provides guidelines as to how a molecule travels the journey from target identification to marketing and even post-marketing surveillance. another important ‘innovation’ in this section is the chapter on “pharamacogenomics”. with the rapidly evolving indications and guidelines, these drugs are being used increasingly commonly across the globe. nevertheless, the vast majority of the clinical trials are still conducted in north america, western europe and japan. however, there are important genetic differences in various ethnic groups resulting in differential responses and toxicities, and the chapter highlights this aspect of drug development and disposition. section ii deals in detail with the conventional cytotoxic chemotherapeutic agents and it is this section which could serve as a repository. the drugs are classified according to their mechanism of action, and the chapters include not only a detailed discussion of the compounds, but are also replete îáè£]ê<îê^€è”÷]<·^õü �ä÷]<t¯¬ ìâö^€π]ê<ùå^fπ]<  book review cancer chemotherapy and biotherapy principles and practice authors: bruce a chabner and dan l longo publisher: wolters kluwer: lipincott williams & wilkins, 5th edition, 2011 isbn: 13: 978-1-60547-431-1 and 10: 1-60547-431-2 squ med j, august 2011, vol. 11, iss. 3, pp. 424-425, epub. 15th aug 11 submitted 16th may bruce a chabner and dan l longo book review | 425 with tables, figures and diagrammes. some sections are supported by more than 600 references; this alone testifies to the amount of detailed research that has gone into some of the chapters. for quick reference, the table of “key features” of almost all the compounds discussed in this section provides useful information in a nutshell. section iii deals with the molecularly targeted therapies, referred to as ‘biotherapy’ in the title. over the 160 pages of the section, compounds used regularly in routine clinical practice over the past dozen years are admixed with those still in the phase of investigation and phase iii trials, such as the histone deacetylase inhibitors and some of the signalling inhibitors. whereas this section provides details of the origins of the compounds, the rapidly evolving data in pivotal phase ii and phase iii trials over the past few years has made this information slightly outdated. moreover, one would have liked to see more emphasis on compounds such as, imatinib mesylate, which changed the paradigm of treatment for cancer in 1999, to the extent that reputable journals indeed spoke about the ‘treatment of cancers in the imatinib era’, and rituximab which again changed the way lymphomas and many other benign and malignant conditions have been treated in the past decade. also the section on conjugation of monoclonal antibodies with either immunotoxins or radiotherapy could have contained more details. section iv deals with ‘immunologic agents’, including cytokines, vaccines, and adoptive cellular therapies. the chapter on cytokines is detailed, with results of some of the landmark clinical trials, which may or may not form the backbone of routine clinical practice these days, but nevertheless are considered important steps in the journey of advancing the treatment of cancer. the sections on vaccines and adoptive therapy are relatively short, even by the standards of the book, but do provide the essentials which underpin the use of such therapies. section v deals with hormonal treatment of breast and prostate cancers. although the two chapters explain the basis of use of several types of hormones/strategies, the rapid development and evolving data in the field means that the reader would be best advised to combine this section with the results of some of the recently concluded clinical trials in order to comprehend the overall picture in this form of cancer treatment. section vi deals with "supportive care". whereas, chapters on pain management, haematopoietic growth factors, treatment of nausea and vomiting and bisphosphonates are comprehensive, one would have liked to see some of the other topics, such as, psycho-social care, treatment of anxiety and depression, fatigue, and the management of common side effects of cytotoxic chemotherapy and targeted therapies in a reference book of this size. section vii deals with survivorship issues such as late effects of chemotherapy including infertility. the chapter on infertility summarises the results of salvage treatments to preserve/treat infertility, and provides the reader with some up-to-date results in the field. in this section, one would have liked to see something about chemoprevention, especially for those who are at high or very high risk of developing cancer. in summary, this is a useful reference book; however, in some areas, the information it provides should be combined with other rapidly evolving data in order to obtain a full picture of the exciting times of cancer treatment in which we live! r e v i e w e r ikram burney department of medicine, sultan qaboos university hospital, muscat, oman email: ikramburney@hotmail.com sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 454-459, epub. 25th jun 13 submitted 2nd nov 12 revisions req. 6th jan & 20th mar 13; revisions recd. 4th feb & 22nd mar 13 accepted 30th mar 13 1department of oral & maxillofacial surgery, rishiraj college of dental sciences & research centre, bhopal, india; 2kle pk hospital, kle university, belgaum, india; 3department of dentistry, all india institute of medical sciences, raipur, india *corresponding author e-mail: jshru23@gmail.com افرتاق التكون العظمي للفاصل األمامي يف مرضى نقص تنسج فلج الفك العلوي عرض خلمس حاالت �رسوثي راو، اأ�س كوترا�شيتي، جي لنجراج، بي بنتو، كي كيلو�شكار، �شيدراث جان، بيو�س �شوين، �شانتو�س راو امللخ�ص: جراحات تقومي الفك وافرتاق التكون العظمي تلعب دورا اأ�شا�شيا يف ت�شحيح نق�س تن�شج الفك العلوي ملر�شى فلج ال�شفة واحلنك. التقدمي االأمامي للفك العلوي بدون التداخل مع م�رسة ال�رساع البلعومي قد تكون مفيدة ملر�شى الفلج الذين دائما ما يعانون من عجز يف الكالم وتزاحم يف االأ�شنان. نعر�س هنا جمموعة خلم�شة مر�شى م�شابني بنق�س تن�شج الفك العلوي الذين خ�شعوا لعمليات افرتاق التكون باالجتاه املركب الوبر مفك مع ال�شني التثبيت لغر�س م�شنع افرتاق جهاز ا�شتخدام مت �شنة. ملدة متابعة مع االأمامي للفا�شل العظمي االأمامي واخللفي. مت تقييم حتليل االأن�شجة اللينة وال�شلبة وكذلك تقومي الكالم. بعد مرور �شنة على عملية اقرتان تكون العظم، مت ا�شتقرار تطابق االأ�شنان والرتاكب االأفقي االإيجابي وكذلك ت�شحيح تزاحم االأ�شنان بدون احلاجة لقلع االأ�شنان.مت حت�شني املظهر اجلانبي للوجه وال�شفة ومل يكن هناك اأي تدهور يف الكالم. مفتاح الكلمات: تكون العظم؛ افرتاق؛ جراحة تقومي الفك؛ فلج احلنك؛ قطع عظم الفك العلوي؛ تقرير حاالت؛ الهند. abstract: orthognathic surgery and distraction osteogenesis play a prime role in the correction of maxillary hypoplasia in patients with cleft lip and palate (clp). advancement of the anterior maxilla alone without interfering with the velopharyngeal sphincter may be advantageous in cleft patients, who more commonly have speech deficits and dental crowding. we present a case series of anterior maxillary segmental distraction for maxillary hypoplasia in 5 clp patients with a one-year follow-up. a custom-made tooth-borne distraction device with a hyrax screw positioned anteroposteriorly was used. the evaluation comprised of hard and soft tissue analysis and speech assessment. a stable occlusion with positive overjet and correction of dental-crowding without extraction was achieved at one year post-distraction. facial profile and lip support improved. there was no deterioration in speech. keywords: distraction osteogenesis; orthognathic surgeries; cleft palate; maxillary osteotomy; case reports; india. anterior segmental distraction osteogenesis in the hypoplastic cleft maxilla report of five cases *sruthi rao (janardhan),1 s. m. kotrashetti,2 j. b. lingaraj,2 p. x. pinto,2 k. m. keluskar,2 siddharth jain,2 piyush sone,2 santhosh rao3 case series of all patients born with cleft lip and/or palate (clp), 25–60% require maxillary advancement to correct the maxillary hypoplasia and improve aesthetic facial proportions.1 this can be accomplished with the help of orthognathic surgery or distraction osteogenesis, or both of these.2 the first successful clinical application of anterior maxillary segmental distraction (amsd) using an intraoral tooth-borne distractor on dogs was reported in 1994 by block and brister and on humans in 2003 by dolanmaz.3,4 subsequent clinical research was carried out to determine the optimal protocols for amsd.5–10 here we present a series of five clp cases treated with amsd. case series a total of 5 patients with hypoplastic maxilla secondary to clp and anterior crossbite with dental-crowding underwent amsd at our centre. they were from karnataka and maharashtra, india, anterior segmental distraction osteogenesis in the hypoplastic cleft maxilla report of five cases 448 | squ medical journal, august 2013, volume 13, issue 3 with a mean age of 16.8 years (range: 13–26 years; 4 male, 1 female). all patients had permanent dentition. none of them had previously undergone alveolar bone grafting. three of the 5 patients had an anterior palatal fistula, one had a tongue flap and one had undergone fistula repair. written informed consent was taken from the patients and ethical permission was obtained. the patients were followed-up for a period of one year postdistraction. the patients were prepared using extraoral and intraoral photographs, study casts and digital radiographs, including lateral cephalogram, orthopanthomograph, and intraoral periapical radiographs. in order to standardise the cephalograms, the patients’ heads were placed in a natural position with lips in repose and in centric occlusion. lateral cephalograms were traced using dolphin imaging software, version 11.0 (dolphin imaging and management solutions, chatsworth, california, usa). a treatment simulation was performed in order to calculate the amount of advancement required in each case. based on the root angulation assessed from preoperative radiographs and the size of the premaxilla, the osteotomy site was chosen as mesial to the first molar in 4 patients and between the two premolars in one patient. with the use of preoperative casts, the appliance was custommade for each patient. a 12 mm hyrax expansion screw number 140–005 (great lakes orthodontics ltd, tonawanda, new york, usa) was used in an anteroposterior direction, parallel to the sagittal plane. this was soldered to a unit with complete tooth coverage using acrylic in two patients, nickel chromium alloy in two patients, and titanium in one patient [figure 1]. all of the patients underwent presurgical oral prophylaxis, restoration of dental caries and speech assessment by a speech pathologist. divergence of the roots orthodontically at the osteotomy site was not required for any of the patients. anterior maxillary osteotomy was carried out under general anaesthesia with nasoendotracheal intubation. a modified cupar technique was used with a maxillary buccal vestibular incision from the lateral incisor to the first molar on either side, maintaining the central pedicle. the anterior maxillary segment was mobilised adequately and the prefabricated distractor device was then placed. it was tested to ensure the anterior segment was moving without resistance, and the appliance was then cemented intraoperatively using glass ionomer luting cement (gc fujicem™, gc corporation, tokyo, japan). in two patients, the posterior component of the distractor had only a single tooth, and additional palatal screws were fixed to secure the appliance. postoperatively, all the patients were kept on regular antibiotics, analgesics, and steroids. a latency phase of 2 to 4 days was given varying proportionately with the age of the patient. distraction was carried out at a rate of 1 mm/ day with a twice daily rhythm. two of the five patients experienced pain and showed mucosal inflammatory changes at a distraction rate of 1 mm/ day due to premature consolidation. when the rate was increased to 1.5 mm/day, these effects ceased. the activation was stopped once the required advancement predicted from the simulation was achieved. this amounted to a 10–12 mm distraction [figure 1]. the distractor was sealed and retained through a consolidation period of 6–8 weeks. at the end of the consolidation phase, the distractor was removed and orthodontic treatment was started with banding and bonding carried out at the same sitting. follow-up records were repeated at the end of activation phase, after the consolidation phase, and at three months, 6 months and one year after the distraction. each speech analysis was rated according to the universal parameters ratings of speech outcomes in cleft palate.11 statistical analysis was carried out using a paired t–test. figure 1: distraction appliance in situ showing regenerate (patient 3). sruthi rao (janardhan), s. m. kotrashetti, j. b. lingaraj, p. x. pinto, k. m. keluskar, siddharth jain, piyush sone and santhosh rao case series | 449 results the interdental space created by distraction at the osteotomy site was utilised orthodontically to erupt partially-erupted lateral incisors in two patients and correct dental-crowding in the anterior maxilla in all patients, without the need for dental extractions. a functionally stable occlusion with alignment of teeth in the arch and a positive overjet was established at the end of one year [figure 2]. no patient reported any clinical worsening of the anterior palatal fistula. hard and soft tissue parameters were evaluated using the cephalometrics for orthognathic surgery (cogs) analysis for hard and soft tissue, and steiner analysis [table 1].12–14 the preoperative and oneyear follow-up values were taken into consideration. on studying the landmarks, there appeared to be an anticlockwise rotation of the maxillary plane together with an increase in the maxillary horizontal length. there was a concomitant opening of the mandibular plane angle. the mean value of the nasion-a pointpogonion angle (n-a-pg) improved by 12.9º (p = 0.006). the nasion-a point linear measurement (na) of the horizontal plane value improved by 8.56 mm (p = 0.008). the mandibular plane to horizontal plane angle increased by 2.62º (p = 0.001). the posterior nasal spine-anterior nasal spine linear measurement (pns-ans) distance increased by 9.82 mm (p = 0.00). the mean sellanasion-a point angle (s-n-a) increased from 71.56º to 78.2º with an average increase of 6.64º (p = 0.03). the facial soft tissue contour showed an average decrease in concavity of 7.14º (p = 0.022), thereby establishing a straight to convex profile from the preexisting concave profile. clinically, there was a significant improvement in the appearance of the patients [figure 3]. the facial balance was restored and the previously retruded upper lips attained normal protrusion. the results of the speech analysis were not statistically significant. however, in two cases there was an improvement in speech understandability, and in two there was an improvement in speech acceptability [table 2]. in one case, where a high anterior maxillary osteotomy was carried out as directed by the cephalometric tracing, extension prongs were adapted and soldered to the intraoral distractor. two-hole titanium plates (synthes, inc., sydney, australia) were fixed bilaterally at the upper end of the osteotomised segment, in the infraorbital region. a pull-through wire was secured around the plate on either side, which exited the skin and was connected to the prongs. this enabled the bodily distraction of the anterior maxilla. the transcutaneous wires were removed along with the intraoral distractor at the end of the consolidation period. there was minimal scarring. in one patient, the appliance fractured during the consolidation period. thereafter, an acrylic retention appliance was immediately fabricated and retained in situ until the end of consolidation. discussion various treatment modalities have been used and recommended by different authors for the correction of secondary deformities in clp patients. the literature reveals that about 25% of patients with maxillary hypoplasia secondary to clp do not respond to orthodontic-orthopaedic therapy alone and require further intervention.15 orthognathic surgery consists of single stage corrective procedures accompanied by internal fixation. distraction osteogenesis consists of slow regeneration of the bone following corticotomy or figure 3: profile pre-distraction and one year postdistraction (patient 5). figure 2: occlusion pre-distraction and one year postdistraction (patient 1). anterior segmental distraction osteogenesis in the hypoplastic cleft maxilla report of five cases 450 | squ medical journal, august 2013, volume 13, issue 3 osteotomy after vector planning. in clp patients, the relapse after orthognathic surgery is greater due to tense scar tissue from multiple previous surgeries. larger advancements with better stability can be achieved with the help of distraction.15 block et al. carried out a pilot study on the distraction of the anterior maxilla in dogs and described the use of a tooth-borne distractor.3,16 sagittal advancement of the entire maxilla in clp patients has the risk of shortening the soft palate and inducing velopharyngeal incompetence. the use of amsd is recommended as an alternative table 1: cephalometric analysis for orthognathic surgery preoperative mean 1 year postoperative mean preoperative sd 1 year postoperative sd paired differences mean paired differences sd significance hard tissue analysis horizontal skeletal n-a-pg (º) -14.36 -1.46 5.34 0.92 -12.90 5.29 0.006 n-a (hp) (mm) -9.06 -0.50 3.99 0.94 -8.56 3.95 0.008 n-b (hp) (mm) -1.72 -1.66 0.94 1.43 -0.06 0.60 0.834 n-pg (hp) (mm) -0.38 -0.24 1.31 1.18 -0.14 0.27 0.311 vertical (skeletal, dental) n-ans (perp hp) (mm) 40.60 40.50 5.27 5.28 0.10 0.85 0.806 ans-me (perp hp) (mm) 62.96 63.90 6.91 6.49 -0.94 0.63 0.03 pns-n (perp hp) (mm) 40.00 39.80 5.46 5.25 0.20 0.23 0.13 mandibular plane-hp (º) 21.42 24.04 1.52 1.63 -2.62 0.76 0.001 maxilla, mandible pns-ans (hp) (mm) 40.74 50.56 4.10 4.45 -9.82 1.05 0.00 soft tissue analysis ul protrusion (mm) 2.30 3.60 2.43 2.74 -1.30 1.85 0.19 ll protrusion (mm) 6.68 5.70 2.43 2.86 0.98 1.29 0.17 nasolabial angle (º) 96.54 96.00 22.76 17.10 0.54 12.57 0.93 steiner analysis selected parameters sna (º) 71.56 78.20 4.45 4.70 -6.64 2.32 0.003 snb (º) 75.62 78.74 3.83 4.23 -3.12 4.09 0.16 soft tissue convexity (º) 144.1 136.96 3.11 3.04 7.14 4.36 0.02 sn-gogn(º) 34.64 32.62 3.84 6.04 2.02 5.96 0.49 sd = standard deviation; n-a-pg = nasion-a point-pogonion angle; hp = horizontal plane; n-a = nasion-a point; n-b = nasion-b point; n-pg = nasion-pogonion; n-ans = nasion-perpendicular-anterior nasal spine; ans-me = anterior nasal spine-menton; pns-n = posterior nasal spine-nasion perpendicualr; ul = upper lip; ll = lower lip; s-n-a = sella-nasion-a point angle; s-n-b = sella-nasion-b point angle; sn-gogn = angle between sella-nasion and gonion-gnathion. sruthi rao (janardhan), s. m. kotrashetti, j. b. lingaraj, p. x. pinto, k. m. keluskar, siddharth jain, piyush sone and santhosh rao case series | 451 method to conventional le fort i osteotomy and rigid external distraction systems for clp patients with severe velopharyngeal incompetence as it does not affect the velopharyngeal sphincter.7 patients who have a class i molar relationship, negative or zero overjet, or impacted or malaligned anterior teeth are ideal candidates.5,17,18 in these patients, the treatment objective should be to create space for the eruption of impacted anterior teeth or for their alignment by increasing the arch length while maintaining the class i molar relationship. an anterior crossbite and a concave profile can also be addressed using this technique. external and internal distractors like the dynaform system, modified hyrax appliance and the hybrid distractors have been described in relation to an anterior maxillary distraction.8,10,19 the distractor used in this case series had the advantage of easy fabrication, minimal expense and good patient tolerance. the modified cupar technique used for these cases was intended to prevent vascular compromise to the previously operated-upon cleft maxillae.20 the rate of distraction was planned according to age and executed based on the resistance of the maxilla to easy distraction, which would be related to the consolidation changes taking place.21 in the consolidation phase, the patients had minimal discomfort and psychological trauma in retention of the intraoral tooth borne distractor, in contrast to the conspicuous extraoral distractors. similar to previous studies on soft tissue changes in maxillary distraction, in the current case series there appeared to be a clinically significant improvement in facial balance, with positive soft tissue changes produced by increasing the nasal projection, normalising the nasolabial angle and making the upper lip more prominent.15,17,22,23 the results of this case series were in accordance with the study by ho et al. who reported stable occlusion results after 3 years’ follow-up.17 there has been no previous study on speech outcomes after amsd. in this case series, there was no worsening of speech in any patient, possibly attributable to there being no change in the velopharyngeal sphincter. the speech analysis revealed no clinically or statistically significant changes in speech. improvement in speech understandability and acceptability may be attributed to the improved dental alignment and incisor relationship. conclusion anterior segmental distraction osteogenesis of the hypoplastic cleft maxilla improves facial balance and aesthetics, and achieves stable occlusion while correcting dental-crowding without any detrimental effect on speech. references 1. polley jw, figueroa aa. management of severe cleft maxillary deficiency with distraction osteogenesis: procedure and results. am j orthod dentofacial orthop 1999; 115:1–12. 2. precious ds. treatment of retruded maxilla in cleft lip and palate – orthognathic surgery versus distraction osteogenesis: the case for orthognathic surgery. j oral maxillofac surg 2007; 65:758–61. 3. block ms, brister gd. use of distraction osteogenesis for maxillary advancement: preliminary results. j oral maxillofac surg 1994; 52:262–6. 4. dolanmaz d, karaman ai, ozyesil ag. maxillary anterior segmental advancement by using distraction osteogenesis: a case report. angle orthod 2003; 73:201–5. 5. wang xx, wang x, li zl, yi b, liang c, jia yl, et al. anterior maxillary segmental distraction for correction of maxillary hypoplasia and dental table 2: speech analysis preoperative mean 1 year postoperative mean preoperative sd 1 year postoperative sd paired differences mean paired differences sd significance hypernasality 1.4 0.8 1.1402 0.4472 0.6 0.8944 .208 speech understandability 1.6 1.2 0.8944 0.8367 0.4 0.5477 .178 speech acceptability 1.8 1.2 1.0954 0.8367 0.6 0.5477 .07 sd = standard deviation. anterior segmental distraction osteogenesis in the hypoplastic cleft maxilla report of five cases 452 | squ medical journal, august 2013, volume 13, issue 3 crowding in cleft palate patients: a preliminary report. int j oral maxillofac surg 2009; 38:1237–43. 6. alkan a, bas b, ozer m, bayram m, yuzbasioglu e. maxillary anterior segmental advancement of hypoplastic maxilla in cleft patients by distraction osteogenesis: report of 2 cases. j oral maxillofac surg 2008; 66:126–32. 7. bengi o, karacay s, akin e, okqu km, olmez h, mermut s. cephalometric evaluation of patients treated by maxillary anterior segmental distraction: a preliminary report. j craniomaxillofac surg 2007; 35:302–10. 8. gualini c. advancement of maxillary anterior segment by distraction osteogenesis (do): a case report. prog orthod 2007; 8:54–61. 9. gunaseelan r, cheung lk, krishnaswamy r, veerabahu m. anterior maxillary distraction by tooth-borne palatal distractor. j oral maxillofac surg 2007; 65:1044–9. 10. karakasis d, hadjipetrous l. advancement of the anterior maxilla by distraction (case report). j craniomaxillofac surg 2004; 32:150–4. 11. henningsson g, kuehn dp, sell d, sweeney t, judith et, whitehill tl. universal parameters for reporting speech outcomes in individuals with cleft palate. cleft palate craniofac j 2008; 45:1–17. 12. burstone cj, james rb, legan h, murphy ga, norton la. cephalometrics for orthognathic surgery. j oral surg 1978; 36:269–77. 13. legan hl, burstone cj. soft tissue cephalometric analysis for orthognathic surgery. j oral surg 1980; 38:744–51. 14. steiner cc. cephalometrics in clinical practice. angle orthod 1959; 1:8–29. 15. rachmiel a. treatment of maxillary cleft palate: distraction osteogenesis versus orthognathic surgery part one: maxillary distraction. j oral maxillofac surg 2007; 65:753–7. 16. block ms, cervini d, chang a, gottsegen gb. anterior maxillary advancement using toothsupported distraction osteogenesis. j oral maxillofac surg 1995; 53:561–5. 17. ho ct, heller f, lo lj, liou ejw, huang cs, chen yr. distraction osteogenesis in adolescents with maxillary arch deficiency and dental crowding: a 3-year follow-up. plast reconstr surg 2006; 117:2337–46. 18. okcu km, sencimen m, karacay s, bengi ao, ors f, dogan n, et al. anterior segmental distraction of the hypoplastic maxilla by a tooth borne device: a study on the movement of the segment. int j oral maxillofac surg 2009; 38:817–22. 19. aikawa t, haraguchi s, tanaka s, uematsu s, ishibashi m, kogo m, et al. rotational movement of the anterior maxillary segment by hybrid distractor in patients with cleft lip and palate. oral surg oral med oral pathol oral radiol endod 2010; 110:292– 300. 20. bell wh. correction of maxillary excess by anterior maxillary osteotomy. a review of three basic procedures. oral surg oral med oral pathol 1977; 43:323–32. 21. van sickels je. distraction osteogenesis: advancements in the last 10 years. oral maxillofac surg clin north am 2007; 19:565–74. 22. molina f, ortiz monasterio f, de la paz aguilar m, barrera j. maxillary distraction: aesthetic and functional benefits in cleft lip-palate and prognathic patients during mixed dentition. plast reconstr surg 1998; 101:951–63. 23. wen-ching ko e, figueroa aa, polley jw. soft tissue profile changes after maxillary advancement with distraction osteogenesis by use of a rigid external distraction device: a 1-year follow-up. j oral maxillofac surg 2000; 58:959–69. the epitome of humility and hard work obituary professor christopher sapara grant mb.chb, frcs, facs 1942–2013 professor grant, head of the department of surgery at sultan qaboos university (squ) for 15 years, died in squ hospital on friday 4th october aged 71. prof. grant, who joined the college of medicine & health sciences just four years after squ opened in 1986, was one of the pioneers who made immense contributions to both medical education and the healthcare sector in oman. many of his former students now occupy senior positions in the ministry of health and the medical colleges in the country. after medical studies in ghana and the uk, and then teaching and clinical work at king faisal university college of medicine and king fahd hospital of the university in saudi arabia, prof grant was appointed as associate professor of surgery and consultant surgeon at squ in 1990. he became full professor in 1997 and head of department a year later. his clinical interests included gastrointestinal, thyroid and parathyroid surgery. he played a key role in developing the general surgery department at squ into a state-of-the-art facility with a number of specialisations including cardiothoracic, trauma, orthopaedic, paediatric, ent, and urology surgery. dr. hilal al-sabti, a former student and now cardiothoracic surgeon at squ hospital said: “he was a skillful surgeon with a sound knowledge of the discipline. many physicians approached him for his expert opinion on various medical and surgical issues. his wisdom and his dedication to his profession were amazing.” dr. al-sabti added, “as a medical educator, prof. grant played a key role in creating excellent physicians. he helped a lot of omani graduates to go abroad for higher studies at prestigious medical schools. he was also a well-recognised researcher. as an individual, he was humble and modest, showing great respect to his colleagues and students. he treated them as equals without even a hint of arrogance.” for dr. abdullah al-harthy, trauma surgeon and deputy director general of squ hospital, prof. grant was instrumental in his choice to specialise in trauma surgery. “prof. grant was a great role model. he taught us that surgery is the medical specialty which has a direct effect on the patients—where the doctor can see immediate results.” he added, “prof. grant dealt with patients in an exemplary manner. originally a paediatric surgeon, he dealt affectionately with child patients and maintained the same courtesy with adult and geriatric patients. he always tried to understand the problems of each of his patients and never belittled their concerns”. according to dr. hani al-qadhi, head of the department of surgery at squ and also a former student, prof. grant was someone who showed the utmost selflessness in all his duties and responsibilities. “as a medical educator, prof. grant taught us how to face the stressful work situations of a surgeon with calmness and patience. when we did our higher studies abroad, he called us quite often to check on our welfare and study progress. he was a legendary figure who offered great services to patients, students, medical students, and the healthcare sector of oman at large”. prof. grant is survived by edith, his wife of 45 years, and his son, cobby. this obituary is based on an article published in the squ horizon magazine in september 2013. photograph courtesy of amir hussain, office of the deputy vice chancellor for postgraduate studies & research, squ. department of pharmacology & therapeutics, arabian gulf university, manama, bahrain *corresponding author e-mail: dr.hj@live.com فهم أداء طالب الطب يف املرحلة ما قبل الدراسة السريرية ضعف األداء يف كتابة الوصفات الطبية هرني جيم�س، خالد اأحمد جا�سم اخلاجة، يا�سني اإبراهيم تيم، �سندان فرياموثو، ريجنالد �سكويرا abstract: objectives: this study aimed to explore reasons for poor performance in prescription writing stations of the objective structured practical examination (ospe) and absenteeism in prescription writing sessions among preclerkship medical students at the arabian gulf university (agu) in manama, bahrain. methods: this descriptive study was carried out between september 2014 and june 2015 among 157 preclerkship medical students at agu. data were collected using focus group discussions and a questionnaire with closedand open-ended items. results: all 157 students participated in the study (response rate: 100.0%). the most frequently cited reasons for poor performance in ospe stations were an inability to select the correct drugs (79.6%), treatment duration (69.4%), drug quantity (69.4%) and drug formulation (68.2%). additionally, students reported inadequate time for completing the stations (68.8%). during focus group discussions, students reported other reasons for poor performance, including examination stress and the difficulty of the stations. absenteeism was attributed to the length of each session (55.4%), lack of interest (50.3%), reliance on peers for information (48.4%) and optional attendance policies (47.1%). repetitive material, large group sessions, unmet student expectations and the proximity of the sessions to summative examinations were also indicated to contribute to absenteeism according to open-ended responses or focus group discussions. conclusion: this study suggests that agu medical students perform poorly in prescription writing ospe stations because of inadequate clinical pharmacology knowledge. participation in prescription writing sessions needs to be enhanced by addressing the concerns identified in this study. strategies to improve attendance and performance should take into account the learner-teacher relationship. keywords: medical students; medical education; drug prescriptions; inappropriate prescribing; absenteeism; formularies; bahrain. حمطات يف ال�رسيرية الدرا�سة قبل ما املرحلة يف الطب طالب اأداء �سعف اأ�سباب عن البحث اإىل الدرا�سة هذه تهدف اأهداف: امللخ�ص: الو�سفة كتابة درو�س عن الطالب تغيب اأ�سباب ولدرا�سة ،)ospe( العملية املو�سوعية الطبية الإمتحانات يف الطبية الو�سفة كتابة ويونيو 2014 �سبتمرب بني ما الفرتة يف الو�سفية الدرا�سة هذه اأجريت البحرين. منهجية: املنامة، يف العربي اخلليج جامعة يف الطبية حلقات با�ستخدام البيانات جمع مت العربي. اخلليج جامعة يف ال�رسيرية الدرا�سة قبل ما املرحلة يف الطب طالب من 157 على 2015 نقا�س مركزة وا�ستبانات تت�سمن اأ�سئلة منتهية وغري منتهية. نتائج: �سارك جميع الطالب يف الدرا�سة )معدل ال�ستجابة: %100.0(. كانت مدة ال�سحيحة )79.6%(، الأدوية اختيار على القدرة عدم اإىل تعود الدرا�سة هذه من الناجتة الطبية الو�سفة كتابة �سعف اأ�سباب معظم العالج )%69.4(، كمية الدواء )%69.4( و�سيغته )%68.2(. بالإ�سافة اإىل ذلك، اأفاد الطالب اأن الوقت مل يكن كافيا ل�ستكمال الإمتحان يف حمطات الإمتحان )%68.8(. وخالل حلقات النقا�س، اأ�سار الطلبة اىل اأ�سباب اأخرى منها التوتر عند الفح�س و�سعوبة الإمتحان. ويعزى الغياب عن املحا�رسات لطول فرتتها )%55.4(، عدم اإهتمام الطالب )%50.3(، الإعتماد على الزمالء للح�سول على املعلومات )48.4%( �سيا�سة احل�سور الختياري )%47.1(. كذلك فاإن التكراراملت�سمن يف املادة املعطاة، عدد الطالب الكبري يف الف�سل الدرا�سي، عدم ارتقاء املادة لتوقعات الطالب وقرب مواعيد الدرو�س من اأوقات المتحانات الأ�سا�سية كانت اأي�سا من م�سببات غياب الطالب عن الدرو�س ح�سب اأداء طلبة الطب يف جامعة اخلليج العربي اإجابات الأ�سئلة املفتوحة وحلقات النقا�س اخلا�سة. خامتة: ت�سري هذه الدرا�سة اإىل اأن �سعف يف حمطات الإمتحانات الطبية املو�سوعية العملية لكتابة الو�سفة الطبية هو ب�سبب عدم الإملام الكايف بعلم العقاقري ال�رسيري. وبالتايل فاإن امل�ساركة يف درو�س كتابة الو�سفة الطبية حتتاج اإىل التعزيز من خالل معاجلة الأ�سباب املو�سوفة يف هذه الدرا�سة. الإ�سرتاتيجيات لتح�سني ح�سور الطالب واأدائهم وينبغي اأن تؤخذ بعني العتبار عالقة املتعلم مع املعلم. كلمات مفتاحية: طالب الطب؛ التعليم الطبي؛ و�سفات الأدوية؛ و�سف الأدوية الغريمنا�سب؛ الغياب؛ معجم الأدوية؛ البحرين. understanding preclerkship medical students’ poor performance in prescription writing *henry james, khalid a. j. al khaja, yasin i. tayem, sindhan veeramuthu, reginald p. sequeira advances in knowledge this study sheds light on reasons for poor performance in drug-related components of prescription writing and absenteeism in prescription writing sessions among medical students at a university in bahrain. this information is important to make any necessary changes in the medical curriculum so as to improve student participation, training and performance as rational drug prescribers. clinical & basic research sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 203–209, epub. 15 may 16 submitted 1 oct 15 revision req. 18 nov 15; revision recd. 7 dec 15 accepted 31 dec 15 doi: 10.18295/squmj.2016.16.02.011 understanding preclerkship medical students’ poor performance in prescription writing e204 | squ medical journal, may 2016, volume 16, issue 2 rational drug prescribing is one of the most important competencies of health professionals as most patients require prescriptions.1,2 however, prescriptions written by qualified health professionals and medical students are sometimes irrational and contain various errors.3–5 it has been suggested that medical schools do not adequately train students in prescribing drugs and this can compromise patient safety.6,7 a typical drug prescription has standard components which fall into three categories: patient-related (name, age and gender), physician-related (identity of the prescriber) and drug-related (drug name, dose, formulation, route and frequency of administration, quantity to be dispensed, duration of treatment and directions for use).8 the college of medicine & medical sciences at the arabian gulf university (agu) in manama, bahrain, offers a six-year degree programme divided into three phases: phase i (premedical), phase ii (preclerkship) and phase iii (clerkship).9 there is a dedicated programme for teaching prescription writing to students within the nine-unit preclerkship phase; typically, at the end of a unit or subunit, a dedicated 1.5–2-hour interactive prescription writing session is conducted relating to the topics addressed in the unit. such programmes have been found to enhance rational prescribing skills among medical students.10 during prescription writing sessions, students are trained in medication prescribing and learn about the various components of a prescription and chart order. at the beginning of each session, a general introduction is given about rational therapeutic decision-making processes and the prescription format. this is followed by discussion of 5–6 clinical case scenarios with emphasis resting on why a particular drug is prescribed or not prescribed. to foster this understanding, theoretical aspects are discussed which necessitate the repetition of concepts the students have studied in the previous weeks of that unit. the rational therapeutic decision-making process and the prescription format are also repeated in every unit. at agu, students are taught self-regulated learning and are provided with the british national formulary (bnf) as a reference for relevant prescribing information.11 at the end of each unit, students’ prescription writing skills are tested at the pharmacotherapy stations of an objective structured practical examination (ospe). this examination is followed by a review session where model answers are discussed; students are then given feedback on their examination results and advice on how to improve their performance. an earlier study indicated that preclerkship students at agu perform particularly poorly in the drug-related components of a prescription.5 moreover, another study from agu found a positive correlation between students’ attendance at prescription writing classes and their examination performance, with students who had attended the two-hour interactive prescription writing sessions performing better in the summative examinations than the absentees.12 at agu, the medical programme is continuously evaluated with regards to examination performance based on staff and student feedback so that necessary changes in the curriculum can be made to improve agu students’ participation, learning and performance. the present study aimed to identify the reasons for students’ poor performance in the drugrelated components of prescription writing, as well as the high rates of absenteeism in prescription writing sessions. methods this descriptive study was carried out at agu in the academic year september 2014 to june 2015 and included 157 thirdand fourth-year medical students. second-year medical students were not included in the study because of their limited exposure to prescription writing sessions and the ospes. as the study was focused on phase ii preclerkship students, first-year students (premedical, phase i) and fifthand sixth-year students (clerkship, phase iii) were also not included. a 24-item english-language questionnaire was designed to collect information from the students, with 12 questions exploring reasons for poor performance in the drug-related components of prescription writing in the ospe and the remaining 12 items focusing on reasons for absenteeism from interactive prescription writing sessions. all questions were closed-ended (yes/no) although sections were provided for openended responses. the key knowledge and skill competencies required for writing a prescription were taken into account when preparing all questionnaire items. the questionnaire was tested on a pilot group of 10 fourth-year students who later participated application to patient care irrational drug prescribing and prescribing errors are common and complicate patient care by causing preventable suffering. this study may help to minimise these problems by enhancing the training of medical students in rational drug prescribing. henry james, khalid a. j. al khaja, yasin i. tayem, sindhan veeramuthu and reginald p. sequeira clinical and basic research | e205 following their completion of the questionnaire, students were invited to participate in two focus group discussions according to academic year group. to ensure uniform representation, male and female medical students from each nationality present in the class were included. the discussions were led by a faculty member from the department of pharmacology & therapeutics at agu who had not previously been involved in teaching or evaluating the students. during the discussions, the faculty member asked the students for comments on each of the 24 items of the questionnaire, in addition to any other comments, and recorded their responses in writing. data were compiled and analysed using microsoft excel, version 2010 (microsoft corp., redmond, washington, usa). qualitative data, including information collected from questionnaires and the focus group discussion, were thematically clustered and configured to a single specified unit of analysis. this study was approved by the research & ethics committee of the college of medicine & medical sciences at agu. informed verbal consent was obtained from all participants following an explanation of the study’s purpose and confirmation of the voluntary nature of participation. results a total of 157 students participated in this questionnaire-based study; of these, 51 were male and 106 were female. a total of 82 students were in their third year and 75 were in their fourth year. all of the participants originated from gulf cooperation council (gcc) countries. there was no significant difference in responses according to gender. the students’ closedand open-ended responses regarding their poor performance in drug-related components of the ospe are presented in table 1. according to responses to closed-ended questions, the most frequently cited reasons for poor performance were an inability to correctly select the drugs (79.6%), duration of treatment (69.4%), quantity of drug to be dispensed (69.4%) and drug formulation (68.2%). moreover, the majority of students stated that the time allowed for the completion of assigned tasks at the prescription writing ospe stations was inadequate (68.8%). the open-ended statements revealed that students also expected a greater number of training sessions, needed more information on correctly using the bnf and would prefer small group prescription writing sessions over large group sessions. during the focus group feedback, 12 comments were given by students regarding reasons for their poor performance. several of the comments confirmed in the full study. the pilot questionnaire obtained a cronbach’s alpha value of 0.85 using the statistical package for the social sciences (spss), version 19 (ibm corp., chicago, illinois, usa). the validated questionnaire was then administered to all thirdand fourth-year agu medical students present in the class. participating students filled in and returned the questionnaires anonymously. table 1: reasons for poor performance in prescription writing components of the objective structured practical examination according to preclerkship students at the arabian gulf university, manama, bahrain (n = 157) reasons n (%) closed-ended responses difficulty in selecting a particular drug(s) 125 (79.6) inability to decide on duration of treatment 109 (69.4) inability to decide on quantity of drug to be dispensed 109 (69.4) lack of time 108 (68.8) inability to decide on drug formulation 107 (68.2) difficulty in deciding on drug class 106 (67.5) inability to decide on drug dose/strength 105 (66.9) inadequate theoretical knowledge of therapeutic reasoning 98 (62.4) insufficient prescription writing sessions per unit 85 (54.1) difficulty in diagnosing the clinical case 78 (49.7) difficulty in using the bnf 59 (37.6) inability to differentiate between generic and brand drug names 50 (31.9) open-ended responses need for more prescription writing sessions 15 (9.6) lack of time during examination 12 (7.6) inability to decide on drug/drug dose/duration of treatment according to bnf 11 (7.0) preference for smaller groups in prescription writing sessions 5 (3.2) differences between questions in examinations compared to prescription writing sessions 4 (2.6) lack of interest 2 (1.3) unclear questions 2 (1.3) difficulty of clinical cases 2 (1.3) lack of feedback on mistakes made in previous examinations 2 (1.3) lack of clarity on which topics to study 2 (1.3) lack of model answers discussed during sessions 2 (1.3) bnf = british national formulary. understanding preclerkship medical students’ poor performance in prescription writing e206 | squ medical journal, may 2016, volume 16, issue 2 similar views to those identified by the questionnaire responses. however, other comments revealed additional reasons for poor performance: stress and exhaustion due to the number of ospe stations; the overall difficulty level of the ospe; confusion regarding the duration of drug therapy; wasted time due to having to reopen the bnf at the second station; difficulty in utilising the printed rather than elec tronic version of the bnf to find drug information; and confusion as a result of other students’ notes on the bnf, or after the bnf was left open by the previous student. the students’ closedand open-ended responses regarding absenteeism from prescription writing sessions are presented in table 2. the most cited reasons for absenteeism according to responses to the closed-ended questionnaire items were the length of each session (55.4%), a lack of interest (50.3%), reliance on peers to learn prescription writing (48.4%) and optional attendance policies (47.1%). openended responses suggested that the repetitiveness of the material, focus on large-group instruction, lack of model examination answers provided, unsuitable timings of the sessions and the instructor’s individual teaching style were also contributory to the students’ absenteeism. comments made during the focus group discussion (n = 12 each for thirdand fourth-year students) supported these findings. other reasons for student absenteeism included the proximity of the sessions to summative examinations; instruction on material which would not appear in the examination; emphasis on theoretical rather than practical skills in sessions; lack of focus in sessions on the drug selection process and the prescription; lack of usefulness of the sessions; and the limited priority given to the pharmacology ospe stations. discussion this descriptive study sought to identify possible reasons for poor performance in the drug-related components of prescription writing among agu medical students. according to the responses, the majority of students expressed difficulty in various aspects of prescription writing, including choosing a particular drug from a class, identifying the appropriate dose and duration of treatment, calculating the quantity to be dispensed and deciding on the drug formulation to be used. these difficulties reflect insufficient clinical pharmacology knowledge about drugs and their use in treating various conditions. medical students may be overwhelmed with the heavy course content as well as have difficulties remembering specific information, particularly drug names. other reasons for poor performance identified in the present study included difficulty in using the bnf, a lack of time or stress when attempting to complete the examination and issues with the prescription writing sessions. at agu, students are trained either in groups or individually on how to use the bnf to seek relevant prescribing information. nevertheless, in the authors’ experience based on informal student feedback, some table 2: reasons for absenteeism in prescription writing sessions according to preclerkship students at the arabian gulf university, manama, bahrain (n = 157) reasons n (%) closed-ended responses length of each session 87 (55.4) lack of interest 79 (50.3) reliance on peers to learn prescription writing 76 (48.4) optional attendance policies 74 (47.1) availability of prescription writing booklet 67 (42.7) reliance on medical professional relatives to learn prescription writing 66 (42.0) prescription writing can be learnt after graduation 62 (39.5) lack of priority for studying* 43 (27.4) prescription writing is not important during the preclerkship phase 34 (21.7) sessions are not useful 32 (20.4) peers have said that the sessions are not useful 31 (19.8) senior students have said that the sessions are not useful 26 (16.6) open-ended responses repetitive material 9 (5.7) preference for smaller groups in sessions 7 (4.5) lack of model answers provided 7 (4.5) lack of interest 6 (3.8) timing of sessions is not suitable 6 (3.8) length of sessions 5 (3.2) lack of teaching focus on how to choose drugs in sessions 5 (3.2) individual teaching style of the session instructor 3 (1.9) differences between questions in examinations compared to sessions 3 (1.9) the prescription writing booklet is sufficient for self-study 2 (1.3) *prescription writing comprises only 1–3 out of 30–35 of the objective structured practical examination stations. henry james, khalid a. j. al khaja, yasin i. tayem, sindhan veeramuthu and reginald p. sequeira clinical and basic research | e207 absenteeism from prescription writing sessions among participants in the current study was reported to be primarily due to the nature of the sessions and optional attendance policies. approximately half of the respondents perceived the sessions to be too long or uninteresting. additionally, several students indicated that the sessions were repetitive; however, in the opinion of the authors, reinforcement of previously covered material is important to enhance learning. nearly half of the students reported that they did not attend the sessions because of optional attendance policies. as the pbl curriculum at agu involves a student-centred self-study approach, atten dance is optional across the curriculum for certain educational activities. however, attendance at prescription writing sessions has been shown to be an important determinant of performance and the acquisition of rational therapeutic decision-making and prescription writing skills.12 certain participants in the current study seemed to follow an examinationoriented approach, with some students commenting during the focus group discussion on the inadequate timing of the sessions in relation to the examinations. furthermore, some students noted in open-ended responses that cases discussed in the sessions did not appear in the examination; however, it is important to note that the ospe tests students on the same concepts as those covered in the sessions, although the clinical scenarios differ. studying the same cases as those provided in the examination would only encourage rote learning. previous research has found that medical students who do not learn the basic concepts and principles of prescription writing find it difficult to apply their knowledge in similar situations, known as the transfer effect.17 it is likely that this problem is further compounded when students do not attend interactive prescription writing sessions. the results of this study suggest that changes should be made to the prescription writing sessions at agu to ensure that the classes are held more frequently, are more interesting and that the material is delivered in smaller groups and in a vertically integrated manner during the subsequent clinical clerkship training in phase iii of the medical programme. however, the authors of the current study also recommend that agu medical students should be encouraged to improve their approach to learning— moving from examination-oriented strategies to those that will facilitate the understanding of fundamental concepts and their application to different therapeutic scenarios. although this was not investigated in the current study, another possible reason for lack of attendance at prescription writing sessions may have been due to a mistaken belief among the students that passing each ospe station is not necessary students do not practice using the bnf before their examination. previous knowledge of which classes of drugs are appropriate for a particular clinical condition will enable the student to choose specific drugs from the bnf with relative ease. however, when individualising therapy, not all drugs within a class may be suitable. avoiding these drugs requires an in-depth understanding of the mechanisms of their adverse effects and contraindications. this understanding is acquired through a deep learning approach and the ability to integrate learning with practical experience.1,2 rather than memorising information, students therefore need to focus on understanding the basics of clinical pharmacology and applying these to individual patients. in order to minimise information overload, there should be greater emphasis on the personal drug (p-drug) concept, in line with the recommendations of the world health organization.13–15 developing and maintaining a personal formulary has also been shown to increase student competence in rational prescribing.16 at agu, medical students are encouraged to implement a personal formulary. in the current study, many students reported that the time allocated for the prescription writing stations of the ospe was insufficient to search for relevant information in the bnf and complete the task. at agu, the time allocated for prescription writing stations is double that of the other stations (six versus three minutes). nevertheless, this concern could be addressed by the provision in electronic format of the bnf or other relevant formulary, as this may reduce time needed during the ospe station. in addition, students also revealed during the focus group discussion that they were stressed and exhausted during the ospe as they had to complete more than 30 stations from various disciplines during a single examination. the stress and performance anxiety involved with summative examinations such as the ospe could adversely affect decision-making abilities and the students’ ability to use the bnf effectively. as such, perhaps prescription writing skills are best assessed in a continuous assessment format whereby each student is required to complete the task in a nonclassroom setting until a satisfactory result is achieved and certified by an instructor. during focus group sessions, several students felt that more prescription writing sessions were required. some students suggested these sessions be conducted in a small group setting. while increasing the number of sessions and decreasing the student-to-teacher ratio per session would be desirable, both physical and faculty resources at agu are limited and these suggestions may therefore not be feasible. furthermore, it has been previously observed that some students do not attend the sessions already being held.12 understanding preclerkship medical students’ poor performance in prescription writing e208 | squ medical journal, may 2016, volume 16, issue 2 because their final grade is based on an aggregate score. in reality, final grades are based on multiple assessments that involve knowledge, skills and attitude components derived from written examinations, the ospe, objective structured clinical examinations and on-going evaluation of student performance in small-group tutorials. further research is needed to determine whether this mistaken belief influences absenteeism; if so, there is a need to revisit assessment policies in a broader context to address such concerns without compromising integration, a central aspect of problem-based learning (pbl). in an editorial, kanter critiqued the reasons for student absenteeism, including generational and technological issues, values and etiquette.18 in his view, issues of absenteeism arise due to factors involving the learner-teacher relationship, rather than problems of attendance. hence, a key priority in combatting absenteeism is to investigate factors which drive student engagement within the learnerteacher relationship. focusing on the learner-teacher relationship may therefore “broaden the discussion to learners at all levels and to all forms of the learnerteacher relationship, including advising and mentoring sessions”.18 further research has also confirmed that solutions for student absenteeism should take into account the learner-teacher relationship.19,20 the findings of the current study should therefore be interpreted in this broader perspective in order to find solutions for student absenteeism and to enhance learning. although student absenteeism in classroom acti vities is a universal problem, the generalisability of the current findings may be somewhat limited. enforcement of attendance policies may differ across various institutions. however, one of the tenets on which pbl relies is the adult learning principle, which necessitates that the learner is motivated enough to realise that certain professional skills require the supervision of a mentor rather than solely self-regulated learning. as an increasing number of healthcare programmes in the gcc region are considering implementing curriculum innovations, the insights pro vided by this study may inform policy decisions regarding student attendance as well as determine the most appropriate stage in the undergraduate medical curriculum to introduce drug prescribing skills.21–24 conclusion the results of this study suggest that agu medical students performed poorly in the drug-related components of prescription writing due to inadequate clinical pharmacology knowledge. lack of participation in interactive prescription writing sessions was attributed to optional attendance policies and because students felt that the sessions were too long and uninteresting. based on these findings, efforts are recommended to improve student participation, learning and performance at prescription writing sessions. greater emphasis should be placed on the p-drug concept and the development of a personal formulary. in addition, absenteeism should be considered in the context of the learner-teacher relationship. a c k n o w l e d g e m e n t s the authors are grateful to the agu medical students for their participation in this study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. maxwell s, walley t; bps clinical section committee. teaching safe and effective prescribing in uk medical schools: a core curriculum for tomorrow’s doctors. br j clin pharmacol 2003; 55:496–503. doi: 10.1046/j.1365-2125.2003.01878.x. 2. richir mc, tichelaar j, geijteman ec, de vries tp. teaching clinical pharmacology and therapeutics with an emphasis on the therapeutic reasoning of undergraduate medical students. eur j clin pharmacol 2008; 64:217–24. doi: 10.1007/s00228007-0432-z. 3. dornan t, ashcroft d, heathfield h, lewis p, miles j, taylor d, et al. an in depth investigation into causes of prescribing errors by foundation trainees in relation to their medical education: equip study. from: www.gmc-uk.org/final_report_prev alence_and_causes_of_prescribing_errors.pdf_28935150.pdf accessed: dec 2015. 4. al khaja ka, sequeira rp, al-ansari tm, damanhori ah. prescription writing skills of residents in a family practice residency programme in bahrain. postgrad med j 2008; 84:198–204. doi: 10.1136/pgmj.2007.062547. 5. al khaja ka, handu ss, james h, mathur vs, sequeira rp. assessing prescription writing skills of pre-clerkship medical students in a problem-based learning curriculum. int j clin pharmacol ther 2005; 43:429–35. doi: 10.5414/cpp43429. 6. general medical council. tomorrow’s doctors: outcomes and standards for undergraduate medical education. from: www. gmc-uk.org/tomorrow_s_doctors_1214.pdf_48905759.pdf accessed: dec 2015. 7. sequeira rp. patient safety in medical education: medication safety perspectives. indian j pharmacol 2015; 47:135–6. doi: 10. 4103/0253-7613.153417. 8. lofholm pw, katzung bg. rational prescribing and prescription writing. in: katzung bg, masters sb, trevor aj, eds. basic and clinical pharmacology. 12th ed. new york, usa: mcgraw-hill medical, 2012. pp. 1139–48. 9. james h, al khaja ka, sequeira rp. effective use of real-life events as tools for teaching-learning clinical pharmacology in a problem-based learning curriculum. indian j pharmacol 2015; 47:316–21. doi: 10.4103/0253-7613.157131. http://dx.doi.org/10.1046/j.1365-2125.2003.01878.x http://dx.doi.org/10.1007/s00228-007-0432-z http://dx.doi.org/10.1007/s00228-007-0432-z http://dx.doi.org/10.1136/pgmj.2007.062547 http://dx.doi.org/10.5414/cpp43429 http://dx.doi.org/10.4103/0253-7613.153417 http://dx.doi.org/10.4103/0253-7613.153417 http://dx.doi.org/10.4103/0253-7613.157131 henry james, khalid a. j. al khaja, yasin i. tayem, sindhan veeramuthu and reginald p. sequeira clinical and basic research | e209 17. de vries tp. presenting clinical pharmacology and therapeutics: evaluation of a problem based approach for choosing drug treatments. br j clin pharmacol 1993; 35:591–7. doi: 10.1111/ j.1365-2125.1993.tb04187.x. 18. kanter sl. to be there or not to be there: is attendance really the question? acad med 2012; 87:679. doi: 10.1097/acm. 0b013e31825a5a2a. 19. cornelius-white j. learner-centered teacher-student relationships are effective: a meta-analysis. rev educ res 2007; 77:113–43. doi: 10.3102/003465430298563. 20. bin abdulrahman ka. students’ views on student-teacher relationship: a questionnaire-based study. j family community med 2007; 14:81–7. 21. world federation for medical education. wfme global standards for quality improvement: the 2015 revision. from: http://wfme.org/standards/bme/78-new-version-2012-quality -improvement-in-ba sic-me dic al-e duc ation-english/file accessed: dec 2015. 22. al-muhanna fa, subbaroa vv. standards in medical education and gcc countries. j family community med 2003; 10:15–17. 23. yudkowsky r, park ys, lineberry m, knox a, ritter em. setting mastery learning standards. acad med 2015; 90:1495–500. doi: 10.1097/acm.0000000000000887. 24. dreyfus se. the five-stage model of adult skill acquisition. bull sci technol soc 2004; 24:177. doi: 10.1177/0270467604264992. 10. richir mc, tichelaar j, stanm f, thijs a, danner sa, schneider aj, et al. a context-learning pharmacotherapy program for preclinical medical students leads to more rational drug prescribing during their clinical clerkship in internal medicine. clin pharmacol ther 2008; 84:513–16. doi: 10.1038/ clpt.2008.82. 11. british national formulary. bnf publications. from: www.bnf. org/ accessed: dec 2015. 12. al khaja ka, james h, sequeira rp. effectiveness of an educational intervention on prescription writing skill of preclerkship medical students in a problem-based learning curriculum. j clin pharmacol 2013; 53:483–90. doi: 10.1002/ jcph.68. 13. de vries tp, henning rh, hogerzeil hv, fresle da; world health organization action programme on essential drugs. guide to good prescribing: a practical manual. from: http://apps.who.int/medicinedocs/pdf/whozip23e/whozip23e. pdf accessed: dec 2015. 14. khan aa, bagewadi hg. medical students’ task based learning of p-drug concept: a study to know its effectiveness and participant feedback. int j pharmacol res 2015; 5:8–11. doi: 10.7439/ijpr.v5i1.1418. 15. keijsers cj, segers ws, de wildt dj, brouwers jr, keijsers l, jansen pa. implementation of the who-6-step method in the medical curriculum to improve pharmacology knowledge and pharmacotherapy skills. br j clin pharmacol 2015; 79:896–906. doi: 10.1111/bcp.12575. 16. de vries tp, daniels jm, mulder cw, groot oa, wewerinke l, barnes ki, et al. should medical students learn to develop a personal formulary? an international, multicentre, randomised controlled study. eur j clin pharmacol 2008; 64:641–6. doi: 10.1007/s00228-008-0465-y. http://dx.doi.org/10.1111/j.1365-2125.1993.tb04187.x http://dx.doi.org/10.1111/j.1365-2125.1993.tb04187.x http://dx.doi.org/10.1097/acm.0b013e31825a5a2a http://dx.doi.org/10.1097/acm.0b013e31825a5a2a http://dx.doi.org/10.3102/003465430298563 http://dx.doi.org/10.1097/acm.0000000000000887 http://dx.doi.org/10.1177/0270467604264992 http://dx.doi.org/10.1038/clpt.2008.82 http://dx.doi.org/10.1038/clpt.2008.82 http://dx.doi.org/10.1002/jcph.68 http://dx.doi.org/10.1002/jcph.68 http://dx.doi.org/10.7439/ijpr.v5i1.1418 http://dx.doi.org/10.1111/bcp.12575 http://dx.doi.org/10.1007/s00228-008-0465-y 1department of medicine, kolkata medical college, kolkata, west bengal, india; 2department of gynaecology, chittaranjan seva sadan hospital, kolkata, west bengal, india *corresponding author e-mail: docr89@gmail.com حالة مايلوما متعددة تصاحب مرض السكري الكاذب رودراجيت بول، اأديتيا فيكرام رويا، عا�سم �ساها، جاياتي موندال، تي جى �ساو، اإندرانيل ثاكور، كونال هالدار abstract: multiple myeloma (mm) can present with involvement of the central nervous system in the form of nerve palsy, plasma cell masses or, rarely, with endocrinological effects due to involvement of the pituitary gland. usually, in such cases, the disease has a rapid progression and poor prognosis. we report a 52-year-old man who was admitted to the kolkata medical college, kolkata, india, in 2016 with a prolonged low-grade fever and hypernatremia. shortly afterwards, the patient began to complain of increased urinary frequency and drowsiness. the hypernatremia was treated with intranasal desmopressin and free water replacement. serum protein electrophoresis and an immunofixation study revealed an immunoglobulin g-κ monoclonal band. magnetic resonance imaging of the pituitary gland revealed the absence of a posterior bright spot and spotty infiltration of the pituitary fossa. a bone marrow biopsy confirmed a diagnosis of cranial diabetes insipidus due to posterior pituitary mm infiltration. keywords: multiple myeloma; diabetes insipidus; pituitary gland; hypernatremia; case report, india. امللخ�ص: املايلوما املتعددة من املمكن اأن ت�ساحب خلل يف اجلهاز الع�سبي املركزي يظهر ك�سلل ع�سبي، اأو كتل خاليا البالزما اأونادرا هنا ن�سجل �سلبية. نتائج اىل يوؤدي �رشيع ب�سكل املر�س يتطور احلاالت هذه مثل يف عادة، النخامية. الغدة تورط ب�سبب هرموين خلل يف وزيادة املدى طويلة منخف�سة حمى ومعه 2016 عام الهند يف الطبية كولكاتا كلية اىل اأدخل عاما 52 العمر من يبلغ رجل حالة ن�سبة ال�سوديوم يف الدم. وبعد فرتة ق�سرية، بداأ املري�س ي�سكو من تكرار التبول والنعا�س. مت عالج زيادة ن�سبة ال�سوديوم باعطاء بعقار ديزموبري�سني من خالل االأنف واال�ستبدال باملياه املقطرة. ك�سف التحليل الكهربائي لربوتني م�سل الدم والدرا�سة بالتثبيت املناعي وجود خلفية م�سيئه بقعة وجود عدم املغناطي�سي بالرنني النخامية الغدة ت�سوير وك�سف االأحادي. كابا( )ج اجللوبيولني املناعي الربوتني ووجود بقع متخلله للحفرة النخامية. واأكدت خزعة نخاع العظم ت�سخي�س مر�س ال�سكري الكاذب يف اجلمجمة ب�سبب تغلغل املايلوما يف الغدة النخامية اخللفية. الكلمات املفتاحية: ميولوما متعددة؛ مر�س ال�سكري الكاذب؛ الغدة النخامية؛ ازدياد ن�سبة ال�سوديوم بالدم؛ تقرير حالة؛ الهند. a case of multiple myeloma presenting with diabetes insipidus *rudrajit paul,1 aditya v. ruia,1 asim saha,1 jayati mondal,2 t. j. sau,1 indranil thakur,1 kunal haldar1 sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e221–224, epub. 20 jun 17 submitted 3 sep 16 revision req. 17 oct 16; revision recd. 10 nov 16 accepted 1 dec 16 case report doi: 10.18295/squmj.2016.17.02.015 multiple myeloma (mm) is a haemato-logical malignancy of the plasma cells which can affect multiple organs; in cases of neuro logical involvement in mm, this may take different forms.1–3 while both the central and peripheral nervous systems may be affected, involvement of the central nervous system (cns) is rare and the prognosis is usually quite poor.2 usually, cns involvement is observed in cases of established residual mm or during a subsequent relapse.3 this case report describes a patient with mm which manifested initially with cranial diabetes insipidus. case report a 52-year-old man was admitted to the kolkata medical college, kolkata, india in 2016 with a low-grade fever of one month’s duration. he had been treated several times for a recurrent respiratory tract infection over the previous month. upon admission, a clinical examination revealed pallor and mild dehydration. there was no evidence of organomegaly, bone tenderness or lymphadenopathy. the patient had no urinary complaints and weighed approximately 61 kg. as he had a fever with scattered crepitations in the chest cavity, he was initially treated for a respiratory tract infection. initial blood investigations revealed haemoglobin levels of 6 g/dl, a total leukocyte count of 9,000/µl (neutrophils: 59%; lymphocytes: 30%; eosinophils: 6%) and a platelet count of 80,000/µl. his erythrocyte sedimentation rate was 110 mm in the first hour and his urea and creatinine levels were 72.1 mg/dl and 1.6 mg/dl, respectively. his serum albumin level was 2.9 g/dl, his globulin level was 10.4 g/dl and his serum calcium level was 8.6 mg/dl (corrected: 9.5 mg/dl). at admission, his blood serum sodium and potassium levels were 148 meq/l and 4 meq/l, respectively. on the second day following admission, the patient suddenly complained of increased urinary a case of multiple myeloma presenting with diabetes insipidus e222 | squ medical journal, may 2017, volume 17, issue 2 frequency both during the day and at night. his total daily urinary output was approximately 9 l while drinking a normal amount of water ad libitum. his 24-hour urinary creatinine level was 1,100 mg and urinary osmolality was 250 mosm. there was no evidence of increased thirst and the patient was not currently taking any diuretics or mannitol. his blood and urine glucose levels were also normal. a microscopic analysis of a urine sample did not reveal any evidence of infection. by the third day of admission, the patient had become drowsy. his blood sodium level was 170 meq/l and urine osmolarity was 100 mosm. as a result, free water replacement was immediately initiated at 100 ml/hour. following a desmopressin challenge as per standard protocols, a dose of 10 µg of desmopressin was administered intranasally thrice daily, as the intramuscular form of the drug was not available.4 subsequently, the patient’s blood serum sodium levels gradually fell from 160 meq/l on day four to 152 meq/l on day five and 145 meq/l on day six [figure 1]. his urinary output decreased to 5 l/day and then 3 l/day, respectively, on the first and second days after the administration of desmopressin. the patient’s consciousness level also improved. his blood pressure remained normal throughout the admission period. on the second day following admission, the patient underwent serum protein electrophoresis which revealed a monoclonal band in the γ-globulin region. according to an immunofixation study performed on day six, the monoclonal globulin was an immunoglobulin g κ-light chain. the patient’s serum β2-microglobulin level was 1,800 µg/ml. skeletal x-rays did not reveal any lytic lesions. a t1weighted magnetic resonance imaging (mri) scan of the pituitary gland region on the seventh day revealed the absence of a posterior pituitary bright spot along with some infiltrations, likely from the underlying malignancy [figure 2]. although a cerebrospinal fluid (csf) analysis was performed twice (on days three and seven), no plasma cells were seen. levels of plasma cortisol and thyroid-stimulating hormone were also normal. a bone marrow biopsy performed on the 10th day following admission showed approximately 30% plasma cells with depressed erythropoiesis. the patient was thus diagnosed with mm and cranial diabetes insipidus due to posterior pituitary infiltration. a pituitary biopsy was not performed as the patient did not agree to the procedure. additionally, in view of his severe dehydration and hypernatremia, a water deprivation test was not attempted, although the patient continued using an intranasal desmopressin spray. however, after being informed of the diagnosis, the patient refused further treatment and was subsequently lost to follow-up. discussion in cases of mm, involvement of the cns can manifest in different forms, including carcinomatous meningitis, cranial nerve palsy, quadriparesis or higher-function abnormalities such as dysphasia.3 these effects can occur as a result of the direct infiltration of the malignant plasma cells, the development of plasmacytomas in the skull or because of metabolic derangements caused by the malignancy.3 generally, most patients with cns myelomas have a very poor prognosis.3 it is postulated that malignant plasma cells acquire certain molecular characteristics which enable them to invade the cns and which also confer drug resistance; hence, any form of therapy is largely ineffective.3 figure 1: line graph showing changes in the blood serum sodium levels and urine osmolality of a 52-yearold man with a prolonged low-grade fever and hypernatremia from the day of admission (day 0) onwards. intranasal desmopressin was administered from the third day onwards. the patient was subsequently diagnosed with diabetes insipidus. figure 2: t1-weighted magnetic resonance imaging of a 52-year-old man with a prolonged low-grade fever and hypernatremia showing the absence of a posterior pituitary bright spot (arrow) with spotty infiltration of the pituitary fossa (asterisk), likely due to multiple myeloma. rudrajit paul, aditya v. ruia, asim saha, jayati mondal, t. j. sau, indranil thakur and kunal haldar case report | e223 not all mm cases with pituitary masses are associated with diabetes insipidus. mandagere et al. reported a 53-year-old woman with a sellar plasmacytoma which had only mass effects and no endocrine effects; this was resected completely with a relatively good outcome in which the patient remained disease free for the following seven years.11 in the present case, the presence of features of diabetes insipidus indicated extension of the tumour beyond the sella turcica and thus surgical resection was not feasible. patients with both mm and diabetes insipidus generally have a poorer prognosis.5 one unusual feature of the present case was the absence of increased thirst at the onset of diabetes insipidus. this feature is very rarely reported and is often associated with increased mortality.12 in the present case, this may have been due to simultaneous damage to the hypothalamic thirst centre, although there was no evidence of this on mri. management of diabetes insipidus without increased thirst is more complex because patients require daily assessments to ensure adequate water intake.12 although the present case report is limited by a lack of definitive evidence from a pituitary biopsy, a few other cases of mm with pituitary involvement have been reported in which the diagnosis was also made presumptively.8 taking a biopsy sample from the posterior pituitary gland is a technically demanding procedure and often not feasible in certain institutions. a csf analysis is an indirect method of diagnosing mm, especially to rule out alternative diagnoses like infection.3 however, in the present case, a repeated csf analysis was normal. conclusion this case report describes a patient with mm which manifested initially as cranial diabetes insipidus. in mm cases, involvement of the cns is rare and generally has a very poor prognosis for affected patients; clinicians should therefore be aware of this potential manifestation. in addition, abnormally increased urinary output in a patient with mm should prompt investigations for concomitant diabetes insipidus. references 1. kashyap r, kumar r, kumar s. cranial nerve palsy in multiple myeloma and solitary plasmacytoma. asia pac j clin oncol 2010; 6:251−5. doi: 10.1111/j.1743-7563.2010.01327.x. 2. méndez ce, hwang bj, destian s, mazumder a, jagannath s, vesole dh. intracranial multifocal dural involvement in multiple myeloma: case report and review of the literature. clin lymphoma myeloma leuk 2010; 10:220−3. doi: 10.3816/ clml.2010.n.035. usually, mm infiltrates the cns via leptomeningeal spread; however, direct cns involvement due to plasma cell deposit may rarely occur.5 in such circumstances, repeated csf samples may be negative for plasma cells, as in the current case; yi et al. reported a case of mm with brain parenchymal involvement from korea wherein the frontal lobe space-occupying lesion was detected after a negative csf analysis.5 however, adjacent bony destruction and other punched out lesions of the skull were also present, features which were not seen in the present case.5 in a report from japan, harada et al. described a 71-year-old male who was diagnosed with massive intracerebral plasma cell metastasis without skull involvement.6 nevertheless, the cerebral metastasis occurred almost two years after the initial diagnosis of mm; in the present case, the cerebral involvement was evident from first presentation.6 this may indicate that the patient in the current case had plasma cells with a de novo aggressive phenotype. diabetes insipidus in mm is very rare and can have several aetiologies.7,8 first, tubular toxicity due to excreted light chains may cause nephrogenic diabetes insipidus which is resistant to desmopressin, although potentially responsive to myeloma chemotherapy.7 in the current case, a diagnosis of nephrogenic diabetes insipidus was excluded as the patient was not currently taking drugs known to cause this condition and both his serum calcium and potassium levels were normal. second, cranial diabetes insipidus may be caused by infiltration into the posterior pituitary region. cranial diabetes insipidus is extremely rare in mm, with only two cases reported to date.8 in one of these cases, a plasma-cytoma of the sella turcica led to panhypopituitarism which did not respond to therapy.8 in the present case, there were no features of anterior pituitary dysfunction to suggest panhypopituitarism. in the other reported case of cranial diabetes insipidus, mm chemotherapy treatment led to a resolution of the diabetes insipidus-related symptoms.8 additionally, mm has been associated with auto immune phenomena.9 thus, autoimmune involvement of the pituitary gland is theoretically a possibility; however, neural autoimmune phenomena are very rare.9 in addition, autoimmune hypophysitis usually involves the anterior pituitary first.10 however, in the present case, the patient’s serum cortisol levels were normal. as such, autoimmune pituitary involvement was deemed unlikely to have caused the diabetes insipidus. moreover, the rise in urine osmolality above 300 mosm following the administration of desmopressin was deemed to further confirm a diagnosis of central cranial diabetes insipidus.4 https://doi.org/10.1111/j.1743-7563.2010.01327.x https://doi.org/10.3816/clml.2010.n.035 https://doi.org/10.3816/clml.2010.n.035 a case of multiple myeloma presenting with diabetes insipidus e224 | squ medical journal, may 2017, volume 17, issue 2 3. schluterman ko, fassas ab, van hemert rl, harik si. multiple myeloma invasion of the central nervous system. arch neurol 2004; 61:1423−9. doi: 10.1001/archneur.61.9.1423. 4. barts health nhs trust centre for endocrinology. barts endocrine e-protocols for pituitary function. from: www. bartsendocrinology.co.uk/resources/pituitary_barts_ protocol_$5bfinal$5d.pdf accessed: nov 2016. 5. yi hj, hwang hs, moon sm, shin iy, choi yh. a case of multiple myeloma with brain parenchyme involvement. brain tumor res treat 2013; 1:103−6. doi: 10.14791/btrt.2013.1.2.103. 6. harada k, yoshida j, wakabayashi t, sugita k, ichihara m, hotta t, et al. [a case of multiple myeloma with intracerebral metastasis]. no shinkei geka 1992; 20:1113−17. 7. goranov s, hristova i, pencheva k. nephrogenic diabetes insipidus: prodromal phase of multiple myeloma. folia med (plovdiv) 1994; 36:63−6. 8. shand ja, mcgrath n. reversible diabetes insipidus in a patient with multiple myeloma. n z med j 2015; 128:52−4. 9. shimanovsky a, alvarez argote j, murali s, dasanu ca. autoimmune manifestations in patients with multiple myeloma and monoclonal gammopathy of undetermined significance. bba clin 2016; 6:12−18. doi: 10.1016/j.bbacli.2016.05.004. 10. dhanwal dk, dharamshaktu p. autoimmune hypophysitis. indian j med res 2013; 137:995–6. 11. mandagere ka, schimke rn, kyner jl, bhatia ps. an unusual sellar mass: solitary plasmacytoma. endocr pract 1998; 4:382−6. doi: 10.4158/ep.4.6.382. 12. eisenberg y, frohman la. adipsic diabetes insipidus: a review. endocr pract 2016; 22:76−83. doi: 10.4158/ep15940.ra. https://doi.org/10.1001/archneur.61.9.1423 https://doi.org/10.14791/btrt.2013.1.2.103 https://doi.org/10.1016/j.bbacli.2016.05.004 https://doi.org/10.4158/ep.4.6.382 https://doi.org/10.4158/ep15940.ra psychological morbidity in primary health care in oman medical sciences (2000), 2, 105–110 © 2000 sultan qaboos university 1department of medicine, 2department of obstetrics and gynaecology, 3department of behavioural medicine, 4department of family & community health, college of medicine, sultan qaboos university, p o box 35, al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. e-mail: adawi@squ.edu.om 105 psychological morbidity in primary health care in oman a preliminary study al-lawati j1, al-lawati n2, al-siddiqui m1, antony s x3, al-naamani a3, martin r g3, kolbe r4, theodorsson t4, osman y4, al-hussaini a a3, *al-adawi s3 عمان في أألولية الصحية الرعاية في النفسية المراضة مارتن، روجرالنعماني، عزيز أنتوني، سجيفالصديقي، مزون اللواتيا، نواراللواتيا،جليلة العدوي وسمير الحسيني الدين عالء عثمان، يوسف ثيودورسون، ورت آولبي، الفر مؤشرات بين التوافق وفحص عمان، في أألولية الصحية الرعاية مراآز في النفسية والمراضة يدالتجس أنتشار مدى تقييم إلى البحث يهدف :الهدف: الملخص الجسمي برادفورد مقياس أستخدم. عمان في أألولية الرعاية مراآز راجعوا ممن متتابعين مريض 100 مسح تم :الطريقة. النفسية وأألضطرابات التجسيد برادفورد عرفها آما التجسيد تاأضطراب بان الدراسة أظهرت :النتائج .النفسي الكرب لقياس ذاتي اقرار انوأستبي النفسجسمية، المراضة يقيس والذي يعاني ::الخالصة. النفسية والمراضة التجسيد مؤشرات بين احصائيا مهم ايجابي ترابط وظهر أألولية، الصحية الرعاية مرضى بين شائعة النفسية والمراضة في المرضى بأن القديمة الفكرة الدراسة هذه نتائج تتحدى .والجسماني النفسي الكرب من أألولية الصحية رعايةزالآين يراجعون مرا الذ العمانيون المرضى .فقط جسماني شكل على فيهم الكرب يظهر النامية الدول abstract: objective – to assess the prevalence of somatization and psychological morbidity presenting to primary health care in oman and to examine the correlation between the indices of somatization and psychological disorders. method – consecutive primary care patients (n = 100) were screened with bradford somatic inventory which gauges psychosomatic morbidity, and self reporting questionnaire, which measures psychological distress. result – somatization disorder as defined by bradford, and psychological morbidity were relatively common in primary care settings. there was significant positive correlation between indices of somatization and psychological morbidity. conclusion – omani patients seeking primary health care equally experience both psychological distress as well as somatic ones. this finding challenges the old notion that people in developing countries generally express distress somatically. key words: somatization, cross-cultural, psychological distresses, primary-health care, oman octors often meet patients who insist they are diseased despite repeated assurances to the contrary. such patients who frequently seek care in primary as well as tertiary medical settings, and account for a large number of consultations, �doctor shopping�, unnecessary tests and multiple surgeries, cause what is sometimes called �fat file syndrome�.1 patients, in their turn, come to believe that they receive neither clear diagnosis nor effective treatment.1,2 since doctors tend to prescribe medication symptomatically, iatrogenic illnesses might ultimately result.3,4 although it is possible that such patients might be suffering from unidentifiable physical illnesses,5�7 empirical evidence suggests that they might be somatizing.8 as a clinical entity, somatization is a chronic, disabling syndrome that presents a physical facade hiding significant psychopathology. somatic symptoms are common in affective and anxiety disorders.9,10 it is usually assumed that somatization occurs in response to psychological stresses on a background of predisposing personality factors, but in adopting the sick role, psychological equilibrium is achieved. clinical and epidemiological surveys over the past two decades suggest that acute forms of somatoform disorders are invariably present in all primary care settings.11�14 naturalistic observations of somatization disorders have revealed that the condition begins before age 30, and most often during teenage. the disorder is inversely related to social position, occurs most often in communities with little urbanisation and literacy, and affects more women than men.15,16 using screening instruments thought to be sensitive to local idioms of emotional distress, ohaeri & odejide17 and mumford et al18 have found the incidence of psychological morbidity to range from 20% to 80% in various cultures among the developing countries. complementing d a l l a w a t i e t a l 106 surveys from developing countries, goldberg and blackwell19 in uk, giel & le nobel20 in the netherlands, and katon et al3 in usa found similar patterns. the frequent association of somatization and affective disorders suggests that the latter is a predisposing factor and not simply a reaction to disability.21 in the arab world, el-rufaie et al22 and alsubaie et al23 have reported high incidences of patients complaining of depression and anxiety and a variety of somatic symptoms, confirming previous anecdotal reports.24�26 however, these reports have relied on clinical impression and psychological scales that lack items to elicit somatic symptoms.8 since various commentators in the field have suggested that non-western patients tend to use �somatopsychic� idiom of distress rather than verbalize their distress in psychological concepts,27�29 it remains to be established whether omanis, arab/muslim, follow this generalization. the world over, psychological morbidity has been found to be very high among patients seeking primary healthcare.14,30 in oman, such research has not been conducted despite the nearly 12 million visits per year to primary healthcare facilities, representing an average of 5.4 visits per year per person, in a population of slightly above two million.31 the interrelated aims of this study are to (a) determine the rate of psychological morbidity among omani patients attending primary health care in muscat urban conglomeration, the national capital region of oman, (b) determine the prevalence of somatization in those patients and (c) explore whether there is a relationship between psychological distress and somatization. method this research forms part of the studies conducted at the department of behavioural medicine, college of medicine, sultan qaboos university, with the aims to examine the rate of psychological disorders in oman. the study was conducted in the newly built bowsher health care centre, serving mostly residents of suburban areas of muscat. subjects this is a prospective, cross-sectional, study drawn from patients attending in a polyclinic for both male and female outpatient care. consecutive patients, 52 females and 48 males, who were able to speak arabic and attending the clinics on a self-initiated visit for a new problem, were invited to participate in the study. patients known to have sensory or cognitive impairments that would affect proper completion of the study questionnaires were excluded from the sample. all subjects were able to speak arabic. a brief explanation of the study was given to the patients and their oral consent taken. some degree of privacy for the subjects was attempted whilst administering the questionnaires. assessment experienced staff members had produced arabiclanguage versions of the questionnaires by the method of back-translation.32 in the pilot phase, interviewers (7th year medical students) were trained to reliably read out the items of the questionnaire in the local dialect of spoken arabic, and rate the patients� responses accordingly. in order to accommodate for illiteracy among some subjects, questions were read to all the patients. as a result, there was substantial inter-rater agreement on the various items of the questionnaires. somatization bradford somatic inventory (bsi)8 is a 44-item inventory for psychosomatically expressed psychological distress. it has cross-cultural validity as shown by studies carried out in great britain, pakistan, india, nepal, and russia.18,33 the bsi asks the subject on a wide range of somatic symptoms during the previous month, and whether or not the subject has experienced a particular symptom, on more or fewer than 15 days during the month (scoring 1 or 2 respectively). for the present purpose, the scoring was based on mumford,18 where a score >40 is considered to be the �high� range, 26�40, �middle� range and 0�25, �low� range. psychological morbidity psychological morbidity was assessed using selfreporting questionnaire (srq),30 consisting of 24 short questions concerning key phenomena related to mental disorders. the srq requires only a simple �yes� or �no� answer to each question. srq has been established to be a psychiatric case-finding instrument for detection of psychiatric patients among visitors of health care facilities23 and most of its questions had been selected from existing psychiatric questionnaires such as the symptom sign inventory,34 the general health questionnaire35 and the present state examination.36 designed by the world health organisation, srq has been validated in various developing countries23,30,37 to determine the prevalence of �conspicuous psychiatric morbidity� (cpm), without specific diagnoses.38 for the present analysis, the scores were categorised as follows: high range = 10�20; middle range = 6�9; lower range = 0�5. results socio-demographic features the interview sample consisted of 100 patients with a mean age of 26.03 ± 9.62, (52 females with mean age 25.65 ± 10.48 and 48 males with mean age 26.44 ± 8.68). there was no statistically significant age difference between males and females (t = 0.41, df = 96.89, p > 0.05). p s y c h o l o g i c a l m o r b i d i t y i n p r i m a r y h e a l t h c a r e 107 of the patients, 54% were single; 41% married and the remainder (5%) either divorced or widowed. as regards education, 7% each had university degrees 7% or professional diplomas, 39% had secondary school education, 34% primary education and 13% were illiterate, except one patient who had a cursory knowledge of koran. while 42% were working, 15% were unemployed, 20% were students and 24% were housewives. the patients complained of the following types of illnesses: musculoskeletal (23%), gastrointestinal (17%), respiratory (17%) cardiovascular (16%), genitourinary (10%), central nervous system (8%), and infectious (5%). prevalence of somatization using cut-off points of 40 and above as �high� , 26� 40 as �middle� and 0�25 �low� range, figure 1 shows the percentage scores on bsi of whole sample as well as for males and females separately. 7% of the sample scored �high�, among whom there were more females (9.6%) than males (4.2%). 16% of the whole sample scored in the �middle� range. again females (21%) outnumbered the males (10.5%). the bulk of the subjects (77%) were in the �low� range. here males (88%) outnumbered females (68%). in terms of gender differences, women showed a trend towards somatization (χ2, p = 0.05). figure 1. performance on bradford somatic inventory prevalence of psychological disorders using a cut-off point of 10�20 as �high� range, 6�9 as �middle� range and 0-5 as �lower� range, figure 2 shows the percentage scores of srq for the whole sample, male and female patients. 18% of total sample scored in the �high� range, 14% in the �middle� and 48% in the �lower� range. this means 32% were in psychiatric caseness. among females, 15% were in the �high� range, 11% in the �middle� range and 20% in the �lower� range. among males, the figures were respectively 3%, 3% and 28%. in terms of gender differences, women appeared to have a higher propensity towards psychological distress (χ2, p<0.0001). figure 2. performance on self-reporting questionnaire relationship between psychological and somatization indices the association between the srq and bsi were explored using bivariate correlation. the result shows a significant inverse correlation between somatization and psycho logic indices (r = 0 .77, p <0.001, n = 76). discussion the principal aim of this study was to assess the prevalence of somatization and psychiatric morbidity in patients seeking treatment in a typical urban primary health care centre. the study also aimed to be a pilotscreening instrument with multicultural validity. the study found that somatization (as defined by bradford somatic inventory) was present in 17% patient sample, a trend similar to those reported elsewhere.39,40 it is often reported that women are more susceptible to somatization than men, no matter where these studies are conducted.41 prima facie, our present finding substantiates such view. however, this difference could also be due to the manner in which either sex responded to the screening questionnaires, as suggested by other researchers.42,43 future studies need to examine how gender shapes responses. 0 10 20 30 40 50 60 70 80 90 high range middle range low range p er ce nt ag e sc or e total female male 0 10 20 30 40 50 60 70 80 90 high range middle range low range p er ce nt ag e sc or e total female male a l l a w a t i e t a l 108 in conjunction with the rate of somatic syndromes, this study also explored psychological morbidity using who�s screening scale, self-reporting questionnaires. it was found that 32% of the sample was identified as psychiatric cases, a finding compatible with the earlier studies23 suggesting a high incidence of psychiatric morbidity in patients seeking treatment in primary health care. again, women were the majority with the tendency towards conspicuous psychiatric disturbances. it has generally been assumed that somatization is a subjective state, disguising distress in psychological idiom. such conceptualisation has been an integral part of the theoretical model of somatization.44,45 from this perspective, an inverse relationship between the indices of somatization and psychiatric morbidity should be expected. contrary to this, the present data suggests a significant and positive relationship between the indices of somatization and psychiatric morbidity and close association exists between the somatic and psychological scales, i.e., both scales are possibly measuring similar dimensions of emotional distress and psychological pathology.46,47 mumford et al48 have suggested that somatic and psychological symptoms are �two sides of the same coin of dysphoria� and therefore it is viable to use either somatic or psychological items to screen for psychiatric morbidity depending on local idioms of emotional distress. alternatively, the situation in oman may be parallel to those in the other developing countries where improved education has coincided with reduction of somatization.49 in the past decades, oman has drastically improved education. however, it remains to be established whether rapid acculturation has affected how omanis verbalise their emotional distress. the limitation of this study was that it was conducted in a cultural setting where research is not usual and among patients who are not often studied. indeed, it is difficult to show how representative is this patient sample of the general population in oman; for example, �doctor-shoppers� might have been over-represented. secondly, the design of this study did not take into account the prevalence of major mental illnesses and did not obtain qualitative data that might shed light on the reasons for the patterns we observed. thirdly, it is possible that some of these patients were suffering from some hitherto unsuspected physical disturbances, rather than presenting merely depression or anxiety.50�52 therefore, before one can regard the symptoms as index of psychic distress, one needs to rule out myriads of other possibilities including whitlock�s53 notion that manifestation of acute somatization is built into the central nervous system in order to protect it from overwhelming stress. lastly, the present study relied on questionnaires. although questionnaires are easy to apply, they might also elicit inflated number of positive responses. in a study conducted in rural ethiopia, korthmann36 noted that the participants often confused simple �yes� or �no� answer to each question on srq. although both bsi and sri have been previously established to have multicultural validity,8,23,54 one possible way to rule out this problem was to design a two-phase study in order to evaluate both sensitivity and specificity of the questionnaires. however, it was not logistically feasible in the present study, which was a �one-shot� design. the study therefore should be viewed as preliminary and with cautions. conclusion the present study suggests that people seeking treatment at primary health care in oman, especially women, might also be suffering from psychological disorders. inquiring about psychological symptoms in primary health care centres in oman in patients who present initially with somatic symptoms is worthwhile, in their own language and idioms of distress. also, screening scales consisting of only somatic symptoms is as effective as psychologically based questionnaires when screening for psychiatric morbidity. the findings of the study also suggest that the generally held view that in non-western countries psychological distress tends to be expressed exclusively in somatic language might not be true. acknowledgements we are grateful to the men and women who voluntarily acted as subjects for this research. . references 1. kirmayer lj, robbins j m. current concepts of somatization: research and clinical perspectives. american psychiatric press, washington 1991. 2. epstein rm, quill te, mcwhinney ir. somatization reconsidered � incorporating the patient's experience of illness. arch intern med 1999, 159, 215�22. 3. katon w, ries rk, kleinman a. the prevalence of somatization in primary care. compr psychiatry 1984, 25, 208�15. 4. mehl-madrona le. frequent users of rural primary care: comparisons with randomly selected users. j am board fam pract 1998, 11, 105�15. 5. simon ge, vonkorff m. somatization and psychiatric disorders in the nimh epidemiological catchment area study. am j psychiatry 1991, 148, 1494�500. 6. katon wj, walker ea. medically unexplained symptoms in primary care. j clin psychiatry 1998, 59, 15�21. 7. tokunaga m, ida i, higuchi t, mikuni m. alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123iiomazenil spect. radiat med 1997, 3, 163�69. 8. mumford db, bavington jt, bhatnagar ks, hussain y, mirza s, naraghi mm. the bradford somatic inventory: a multi-ethnic inventory of somatic symptoms reported by anxious and depressed patients in britain and the indo-pakistan subcontinent. br j psyp s y c h o l o g i c a l m o r b i d i t y i n p r i m a r y h e a l t h c a r e 109 chiatry 1991, 158, 379�86. 9. thurston-hicks a, paine s, hollifield m. functional impairment associated with psychological distress and medical severity in rural primary care patients. psychiatr serv 1998, 49, 951�55. 10. escobar ji, gara, m, silver rc, waitzkin h, holman a, compton w. somatization disorder in primary care. br j psychiatry 1998, 173, 262�66. 11. ndetei dm, muhangi j. the prevalence and clinical presentation of psychiatric illness in a rural setting in kenya. br j psychiatry 1979, 135, 269�72. 12. giel r, de arango mv, hafeiz ba, bonifacio m, climent ce, harding tw, et al. the burden of mental illness on the family. results of observations in four developing countries. a report from the who collaborative study on strategies for extending mental health care. acta psychiatr scand 1983, 68, 186�201. 13. goldberg dp, bridges k. somatic presentations of psychiatric illness in primary care setting. j psychosom res 1988, 32, 137�44. 14. gureje o, simon ge, ustun tb, goldberg dp. somatization in cross-cultural perspective: a world health organisation study in primary care. am j psychiatry 1997, 154, 989�95. 15. hartung cm, widiger ta. gender differences in the diagnosis of mental disorders: conclusions and controversies of the dsm-iv. psychol bull 1998, 123, 260�78. 16. desjarlais r, eisenberg l, good b, kleinman a. world mental health: problems and priorities in low-income countries. oxford university press, new york 1995. 17. ohaeri ju, odejide oa. somatization symptoms among patients using primary health care facilities in a rural community in nigeria. am j psychiatry 1994, 151, 728�31. 18. mumford db, saeed k, ahmad i, latif s, mubbashar m. stress and psychiatric disorder in rural punjab: a community survey. br j psychiatry 1997, 170, 473�78. 19. goldberg dp, blackwell b. psychiatric illness in general practices: a detailed study using new methods of identification. bmj 1970, 2, 439�43. 20. giel r, le nobel cpj. neurotic instability in a dutch village. acta psychiatr scand 1971, 47, 462�72. 21. cope h, ron m. conversion disorders. in: contemporary behavioural neurology: m. r. trimble & j.l. cummings (eds.) butterworth-heinemann, oxford 1997, pp: 311-�26. 22. el-rufaie oe, absood gh, abou-saleh mt. the primary care anxiety and depression (pcad) scale: a culture-oriented screening scale. acta psychiatr scand 1997, 95, 119�24. 23. alsubaie as, mohammed k, al n malik, t. the arabic self-reporting questionnaire (srq) as a psychiatric screening instrument in medical patients. annals of saudi medicine 1998, 18, 308�10. 24. hamdi ti, al-hasani l, mahmood a, al-husaini a. hysteria: a large series in iraq. br j psychiatry 1981, 138, 177�78. 25. racy j. somatization in saudi women: a therapeutic challenge. br j psychiatry 1980, 137, 212�16. 26. pu t, mohamed e, imam k, el-roey am. one hundred cases of hysteria in eastern libya�a sociodemographic study. br j psychiatry 1986, 148, 606�9. 27. leff j. the cross-cultural study of emotions. cult med psychiatry 1977, 1, 317�50. 28. kleinman a. anthropology and psychiatry: the role of culture in cross-cultural research on illness. br j psychiatry 1987, 151, 447�54. 29. littlewood r, lipsedge m. alien and alienists. ethnic minorities and psychiatry (2nd edition). unwin london. 1989. 30. harding tw, de arango mv, baltazar j, climent ce, ibrahim hh, ladrido-ignacio l et al. mental disorders in primary health care: a study of their frequency and diagnosis in four developing countries. psychol med, 1980, 2, 231�41. 31. directorate general of planning. annual statistical report. ministry of health, sultanate of oman 1997. 32. el-rufaie oef, daradkeh tk. psychiatric screening in primary health care: transcultural application of psychiatric instruments. primary care psychiatry 1997 3, 37� 43. 33. havenaar jm, poelijoe nw, kasyanenko ap, vanden-bout j, koeter mw, filipenko vv. screening for psychiatric disorders in an area affected by the chernobyl disaster: the reliability and validity of three psychiatric screening questionnaires in belarus. psychol med 1996, 26, 837�44. 34. foulds ga, hope k. manual of the symptom sign inventory (ssi). university of london press, london 1968. 35. goldberg dp, cooper je, eastwood mr, kedward hb, shephard m. a standardized psychiatric interview for use in community surveys. br j prev soc med 1970, 1, 18�23. 36. wing jk, cooper je, sartorious n. the description and classification of psychiatric symptoms: an introductory manual of the pse and catego. cambridge university press, london 1974. 37. korthmann f. problems in practising psychiatry in ethiopia. ethiopia medical journal 1988, 26, 77�84. 38. harding tw, climent ce, diop m, giel r, ibrahim hh, murthy r s, suleiman ma, wig nn. the who collaborative study on strategies for extending mental health care, ii. the development of new research methods. am j psychiatry 1983, 140, 1474�80. 39. bhatt a, tomerson b, benjamine s. transcultural patterns of somatization in primary health care: a preliminary report. j psychosom res 1989, 33, 671�80. 40. kisely sr, goldberg dp. physical and psychiatric comorbidity in general practice. br j psychiatry 1996, 169, 236�42. 41. keating jj, dinan tg, chua a, keeling pwn. hysterical paralysis. lancet 1990, 336, 1506�7. 42. stanfeld sa, marmot mg. social class and minor psychiatric disorder in british civil servants: a validated screening survey using the general health questionnaire. psychol med 1992, 22, 739�49. 43. piccinelli m, simon g. gender and cross-cultural differences in somatic symptoms associated with emotional distress. an international study in primary care. psychol med 1997, 27, 433�44. a l l a w a t i e t a l 110 44. pilowsky i. the concept of abnormal illness behaviour. psychosomatics 1990, 31, 207�13. 45. kellner r. somatization theories and research. j nerv ment dis 1990, 178, 150�60. 46. farooq s, gahir ms, okyere e, sheikh aj, oyebode f. somatization: a transcultural study. j psychosom res 1995, 39, 883�8. 47. hamdi e, amin y, abou-saleh mt. performance of the hamilton depression rating scale in depressed patients in the united arab emirates. acta psychiatr scand 1997, 96, 416�23. 48. mumford db, nazir m, jilani fum, baig iy. stress and psychiatric disorder in the hindu kush a community survey of mountain villages in chitral, pakistan. br j psychiatry 1996, 168, 299�307. 49. nandi dn, banerjee g, nandi s, nandi p. is hysteria on the wane? a community survey in west bengal, india. br j psychiatry 1992, 160, 87�91. 50. merskey h, buhrish na. hysteria and organic brain disease. br j med psychol 1975, 48, 359�66. 51. shurbini la, ayad fs. overviews of influences of sociocultural factors on mental illness in arabic culture. interdisciplinary psychological culture 1997, 29, 70�8. 52. maier w. anxiety and somatization disorders. fortschr neurol psychiatr 1998, 66, s3�8. 53. whitlock fa. the aetiology of hysteria. acta psychiatr scand 1967, 43, 144�62. 54. el-rufaie oef, absood gh. validity study of the self-reporting questionnaire (srq-20) in primary health care in the united arab emirates. international journal of methods in psychiatric research 4, 45�5. psychological morbidity in primary health care in oman a preliminary study method subjects assessment somatization psychological morbidity results socio-demographic features prevalence of somatization prevalence of psychological disorders figure 2. performance on self-reporting questionnaire relationship between psychological and somatization indices discussion conclusion acknowledgements references 1department of dermatology, hospital alto guadelquivir, andújar, jaén, spain; 2department of dermatology, complejo hospitalario de granada, granada, spain *corresponding author e-mail: ismenios@hotmail.com لوحات صبغية مثل الرتاب على الرقبة واخلط األبيض لفتاه عمرها أثين عشر عاما بابلو فرنانديز-كريهيو و ريكاردو رويز فيالفريدي dirt-like hyperpigmented plaques on the neck and linea alba of a 12-year-old girl pablo fernández-crehuet1 and *ricardo ruiz-villaverde2 interesting medical image a 12-year-old girl was referred to the outpatient dermatology department at the hospital alto guadalquivir, andújar, spain, in april 2015 with a five-month history of asymptomatic dirt-like hyperpigmented plaques on her neck and linea alba [figure 1]. the patient had been previously treated with adapalene 0.1% cream twice a day for one month after the eruption was diagnosed as pseudoacanthosis nigricans by a general paediatrician. however, no response to treatment was observed. diabetes mellitus and insulin resistance were ruled out as causative factors and the patient’s medical history was unremarkable. a dermoscopic examination using the dermlite dl3 (3 gen inc, san juan capistrano, california, usa) revealed polygonal areas of brownish pigmentation affecting the dermatoglyphs [figure 2]. complete and immediate resolution of the plaques was noted after firm rubbing with a 70% isopropyl alcohol swab [figure 3]. comment terra firma-forme dermatosis (tffd), also known as duncan’s dirty dermatosis, has a distinctive clinical presentation as it generally appears as an eruption of dirt-like hyperpigmented brown plaques. tffd is relatively common and usually occurs on the neck or posterior malleolus of children and young adults.1 there is currently some debate as to whether tffd and dermatosis neglecta are the same entity; however, patients with tffd generally have satisfactory hygiene habits, whereas dermatosis neglecta usually results from inadequate cleansing.2 delay in the maturation of keratinocytes—with melanin retention and a sustained accumulation of sebum, sweat and corneocytes in areas of the body where hygiene measures may be less rigorous—might explain the appearance of tffd. vigorous but unsuccessful attempts at cleaning the affected areas have previously been described in the literature.2 pathological examination of the plaques sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 259–260, epub. 15 may 16 submitted 25 oct 15 revision req. 7 dec 15; revision recd. 9 dec 15 accepted 3 jan 15 doi: 10.18295/squmj.2016.16.02.023 figure 1a & b: photographs showing asymptomatic dirt-like hyperpigmented plaques on the (a) neck and (b) linea alba of a 12-year-old girl. dirt-like hyperpigmented plaques on the neck and linea alba of a 12-year-old girl e260 | squ medical journal, may 2016, volume 16, issue 2 ethyl or isopropyl alcohol—although salicylic acidbased exfoliants or other keratolytic agents are sometimes recommended to accelerate normalisation of the skin.7 unfortunately, topical corticosteroids, antimycotics and retinoids are sometimes prescribed inappropriately for cases of tffd.8 physicians should therefore be aware of this entity to avoid performing unnecessary skin biopsies and to ensure that they prescribe appropriate treatment. references 1. berk dr. terra firma-forme dermatosis: a retrospective review of 31 patients. pediatr dermatol 2012; 29:297–300. doi: 10.1111/j.1525-1470.2011.01422.x. 2. martín-gorgojo a, alonso-usero v, gavrilova m, jordácuevas e. dermatosis neglecta or terra firma-forme dermatosis. actas dermosifiliogr 2012; 103:932–4. doi: 10.1016/j.adengl. 2011.12.006. 3. dalton sr, pride h. the histopathology of terra firma-forme dermatosis. j cutan pathol 2011; 38:537–9. doi: 10.1111/j.16000560.2011.01731_1.x. 4. erkek e, sahin s, çetin ed, sezer e. terra firma-forme dermatosis. indian j dermatol venereol leprol. 2012; 78:358–60. doi: 10.4103/0378-6323.95455. 5. thomas rs, collins j, young rj, bohlke a. atypical presentations of terra firma-forme dermatosis. pediatr dermatol 2015; 32:e50–3. doi: 10.1111/pde.12505. 6. kaminska-winciorek g, wydmanski j, scope a, argenziano g, zalaudek i. “neglected nipples”: acanthosis nigricans-like plaques caused by avoidance of nipple cleansing. dermatol pract concept 2014; 4:81–4. doi: 10.5826/dpc.0403a17. 7. choudhary sv, bisati s, koley s. dermatitis neglecta. indian j dermatol venereol leprol 2011; 77:62–3. doi: 10.4103/03786323.74986. 8. ratcliffe a, williamson d, hesseling m. terra firma-forme dermatosis: it’s easy when you know it. arch dis child 2013; 98:520. doi: 10.1136/archdischild-2012-303499. is not usually necessary unless another condition is suspected. in cases of tffd, lamellar orthokeratotic hyperkeratosis and intra-corneal orthokeratotic whorls may be observed and dermoscopic examination will show a ‘stone pavement’ pattern characterised by polygonal areas of brownish pigmentation.3 in addition, endocrinological evaluation should be performed to rule out skin diseases associated with insulin resistance, such as acanthosis nigricans.4 the differential diagnosis of tffd includes acanthosis nigricans, confluent and reticular papillomatosis, tinea versicolor, ‘dirty neck’ lesions of atopic dermatitis, epidermal naevi, epidermolytic hyperkeratosis, granular parakeratosis and ichthyosis vulgaris.5,6 treatment for these conditions is similar to that prescribed for tffd—swabbing with 70% figure 2: dermoscopic image at x10 magnification showing polygonal areas of brownish pigmentation affecting the dermatoglyphs of a 12-year-old girl with asymptomatic dirt-like hyperpigmented plaques on her neck and linea alba. figure 3a & b: photographs of the (a) neck and (b) linea alba of a 12-year-old girl showing the complete resolution of asymptomatic dirt-like hyperpigmented plaques after firm rubbing with a 70% isopropyl alcohol swab. http://dx.doi.org/10.1111/j.1525-1470.2011.01422.x http://dx.doi.org/10.1016/j.adengl.2011.12.006 http://dx.doi.org/10.1016/j.adengl.2011.12.006 http://dx.doi.org/10.1111/j.1600-0560.2011.01731_1.x http://dx.doi.org/10.1111/j.1600-0560.2011.01731_1.x http://dx.doi.org/10.4103/0378-6323.95455 http://dx.doi.org/10.1111/pde.12505 http://dx.doi.org/10.5826/dpc.0403a17 http://dx.doi.org/10.4103/0378-6323.74986 http://dx.doi.org/10.4103/0378-6323.74986 http://dx.doi.org/10.1136/archdischild-2012-303499 1department of special surgery, faculty of medicine, jordan university of science and technology, irbid, jordan; 2department of pathology and laboratory medicine, jordan university of science and technology, irbid, jordan *corresponding author’s e-mail: aialomari@just.edu.jo nodular fasciitis and myxolipoma of the larynx a rare case report with brief literature review *ahmad al omari,1 wisam qarqaz,1 rasha a. alrhman,1 ra’ed al-ashqar,1 samir al bashir,2 mohammed alorjani2 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 574–577, epub. 7 nov 22 submitted 28 apr 21 accepted 29 jun 21 case report a 61-year-old male patient, who is a heavy smoker, presented to the ent outpatient clinic of a tertiary care hospital in ar ramtha, jordan, in 2020, complaining of a change in his voice, which had started few months earlier, associated with dysphagia, intermittent dyspnoea and choking. his surgical history was unremarkable except for a laparoscopic cholecystectomy one year ago. there was no history of trauma and head and neck examination was unremarkable. a large right supraglottic mass was identified by flexible nasolaryngoscopy. radiological findings were suggestive of a locally advanced laryngeal cancer measuring 5.1 × 3.8 × 3.7 cm [figure 1]. biopsy was taken by suspension microlaryngoscopy for precise diagnosis and the results were suggestive of a benign/borderline spindle cell neoplasm. due to its benign nature, the lesion was debulked trans-orally via laser and histologic diagnosis was in favour of laryngeal nf. shortly after surgery, the mass rapidly enlarged. a tracheostomy was performed and he underwent complete mass excision with right partial laryngectomy through an open surgical approach [figure 2]. repeated pathological examination of microscopic sections and an immunohistochemistry study revealed the same findings which were in agreement with the aforementioned diagnosis of laryngeal nf, along with incidental myxolipoma nodular fasciitis (nf), a subtype of benign mesenchymal spindle cell tumor-like lesions, is a non-cancerous, reactive fibrous proliferation which makes up almost 11% of all benign soft tissue tumours.1 although konwaler et al. first described this condition as ‘pseudosarcomatous fasciitis’ in 1955, it was not until 1961 that shuman used the term ‘nodular fasciitis’ for the first time and since then it has been broadly adopted by authors.2 nf arises mostly in the extremities and trunk, with the larynx being a very rare location;3 diagnosis of nf is challenging in this region. in most cases, the patient presents with a painless, rapidly expanding subcutaneous mass. however, unlike other locations, laryngeal nf may cause life-threatening symptoms by obstructing the respiratory tract. in contrast, lipoma is a common slow developing benign mesenchymal tumour, with approximately 15% of lipomas being found in the head and neck.4 due to the presence of scant amounts of adipose tissue in the larynx, laryngeal occurrence is infrequent.5 myxolipoma is a rare variant which has prominent myxoid areas. to the best of the authors’ knowledge, only four cases of laryngeal myxolipomas, one of them being juvenile, have been reported in the english literature.6–9 this case report describes a patient with laryngeal nodular fasciitis coexisting with myxolipoma. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.112 case report abstract: nodular fasciitis (nf) is a peculiar, rapid-growing soft tissue lesion, typically appearing in subcutaneous tissue. approximately 20% of nf occurs in the head and neck region, where they can involve any anatomic site. laryngeal involvement, however, is quite rare. lipoma is recognised as a slow growing, benign mesenchymal tumour; myxolipoma is a rare variant which has a prominent myxoid background. laryngeal lipoma is infrequent, accounting for only 0.6% of all benign laryngeal lesions. we report a 61-year-old male patient with laryngeal nodular fasciitis coexisting with myxolipoma who presented to a tertiary care hospital in ar ramtha, jordan, in 2020. radiological and histological findings were indicative of laryngeal nodular fasciitis and myxolipoma was incidentally diagnosed. following trans-oral debulking of the lesion the mass enlarged rapidly and the patient underwent a tracheostomy with complete mass excision and right partial laryngectomy through an open surgical approach. the patient had an uneventful recovery with no evidence of recurrence. the purpose of this report is to broaden the differential diagnosis of rapid-growing laryngeal masses that cause airway obstruction and to stress the significance of integrative interdisciplinary collaboration to establish an accurate diagnosis, thereby allowing proper management for benign pathologies and avoid futile aggressive treatment. keywords: nodular fasciitis; larynx; stridor; neck; case report; jordan. https://creativecommons.org/licenses/by-nd/4.0/ ahmad al omari, wisam qarqaz, rasha a. alrhman, ra’ed al-ashqar, samir al bashir and mohammed alorjani case report | 575 [figures 3 and 4]. postoperatively, the patient recovered uneventfully with no evidence of recurrence. his health improved and he is currently under regular follow-up. written informed consent was obtained from the patient for publication purposes. discussion nf is a rare, but distinct, benign self-limited mesen chymal neoplasm of fibroblastic/myofibroblastic derivation that resembles soft tissue sarcoma. the aetiology is still not fully understood. although not documented in the vast majority of patients, traumatic insult may trigger this reactive inflammatory response.3 while occurring at all ages, this condition is most often diagnosed in adults 20–40 years of age, with no gender predilection.5 clinically, when appearing in the larynx, the main presenting symptoms are related to the degree of laryngeal obstruction. this may include hoarseness of voice, foreign body sensation, dysphagia, as well as dyspnoea and stridor that may require urgent medical attention. despite most of the lesions being less than 2 cm in its greatest dimension at the time of diagnosis, the size can vary from 0.5–10 cm.6 lipoma is a benign tumor consisting of adipose tissue. it is considered the most common mesenchymal figure 1: computed tomography scan of the neck of a 61-year-old male patient in an (a) axial, (b) sagittal view showing a heterogenous laryngeal mass with thick-enhancing rim, measuring approximately 5.1 × 3.8 × 3.7 cm starting at the level of the hyoid bone and extending caudally reaching the right cricoid cartilage. magnetic resonance image in the (c) coronal view of a t1-weighted image showing the same mass causing compression effect on the adjacent vessels with significant stenosis on supra-glottic region and minimal invasion of the right thyroid cartilage. positron emission tomography scan showing a (d) hypermetabolic laryngeal mass. figure 2: intraoperative photographs showing (a & b) the cystic lesion with an extra-laryngeal extension which was incidentally found, mimicking laryngocele (arrow). in addition, (c) another smooth, well circumscribed, firm mass which seemed to involve the right thyroid cartilage and reach the false vocal cords was identified (arrow). excised specimen (d) including parts of the larynx with a cystic structure attached to a well-defined mass. nodular fasciitis and myxolipoma of the larynx a rare case report with brief literature review 576 | squ medical journal, november 2022, volume 22, issue 4 tumor, constituting 16% of soft tissue tumours.6 lipoma of larynx can be subdivided according to the site of origin into intrinsic (endolaryngeal) type, or more commonly the extrinsic type. it has a male predominance and occurs over a wide age range (mean age: 40 years) with a supraglottic predisposition.4 the aetiology of laryngeal lipomas is unclear. unlike other locations, laryngeal lipomas may occasionally cause fatal airway obstruction with dyspnoea and dysphonia being the most frequent presenting symptoms. grossly, it can be sessile or pedunculated, usually appearing as a smooth, well-encapsulated mass. the size typically ranges from 1–3 cm, but sometimes it may exceed 10 cm.7 on ct scan most nf lesions appear as a welldefined homogeneous mass with low or isodensity and show moderate to strong enhancement. on mri, lesions will exhibit hypointense or isointense signals on t1-weighted sequences and show heterogeneous intermediate-to-high signal on t2-weighted sequences.8,9 for lipomas, imaging serves a vital role in diagnosis. on ct scan, it mostly simulates fatty tissue characteristics, thus lipomatous lesions appear as a homogenous mass with low attenuation. on mri, lipoma has predominantly low signal intensity on t1weighted images and markedly high signal intensity on t2-weighted images.10 lesions of nf are often composed of undulating short, intersecting fascicles of haphazardly arranged plump, immature fibroblasts and myofibroblasts in a loose myxoid and/or fibrous stroma which resembles the feathery or tissue culture-like appearance. the cells have uniform, elongated non-pleomorphic nuclei with pale, fine chromatin and small but prominent nucleoli. some typical mitotic activity is commonly seen. numerous extravasated red blood cells, scattered lymphocytes, chronic inflammatory cells and multinucleated osteoclast-like giant cells are also present within the background.11 likewise, lipomas have some distinctive histological features, being generally composed of mature adipocytes bound by thin fibrous capsules. myxolipoma demonstrates similar features, but with abundant extracellular mucoid matrix.12 myofibroblasts often stain for smooth muscle actin, muscle-specific actin and vimentin. meanwhile, none of lesional cells express s100 protein, β-catenin, cluster of differentiation 34, keratin, caldesmon and desmin. the proliferation index with ki67 can be high in reactive lesions such as nf.13 it should be noted that immunohistochemistry is not of much help in diagnosing myxolipoma. in regard to the post-genomic era and cytogenetic tests, few studies have established the molecular and cytogenetic abnormalities or proven the neoplastic nature of nf. for example, erikson-johnson et al. described the usp6 rearrangement with the formation of the fusion gene myh9-usp6, which is commonly observed in these lesions, and referred to nf as “transient neoplasia” due to its self-limiting nature.14 given the paucity of cases of nf involving the larynx, their natural course is not fully understood. however, assuming that the behaviour would be similar to nf in other anatomic sites and as this lesion figure 3: haematoxylin and eosin stains at (a) ×20 magnification showing spindled and plump cells exhibiting fascicular arrangement in myxofibrotic background (lesional cells demonstrate storiform architecture); at (b) ×40 magnification showing benignlooking, uniform, stellate fibroblasts resembling a tissue culture-like appearance and; at (c) ×40 and (d) ×10 magnification showing mature-appearing adipocytes with prominent myxoid areas. no evidence of atypia, plexiform vascular network or lipoblasts. figure 4: haematoxylin and eosin stains at ×40 magnification showing (a) numerous extravasated red blood cells and scattered chronic inflammatory cells and (b) lesional cells of nodular fasciitis which typically have ovoid nuclei and prominent nucleoli. immunohistochemistry study showing diffuse expression of smooth muscle antibody immunohistochemical marker in the (c) lesional cells and (d) cluster of differentiation 10 positive immunostaining of nodular fasciitis. ahmad al omari, wisam qarqaz, rasha a. alrhman, ra’ed al-ashqar, samir al bashir and mohammed alorjani case report | 577 references 1. kransdorf mj. benign soft-tissue tumors in a large referral population: distribution of specific diagnoses by age, sex, and location. ajr am j roentgenol 1995; 164:395–402. https://doi. org/10.2214/ajr.164.2.7839977. 2. price eb jr, silliphant wm, shuman r. nodular fasciitis: a clinicopathologic analysis of 65 cases. am j clin pathol 1961; 35:122–36. https://doi.org/10.1093/ajcp/35.2.122. 3. dickson bc. nodular fasciitis. from: https://www.pathologyoutlines.com/topic/softtissuenf.html accessed: jun 2021. 4. de bree e, karatzanis a, hunt jl, strojan p, rinaldo a, takes rp, et al. lipomatous tumours of the head and neck: a spectrum of biological behaviour. eur arch otorhinolaryngol 2015; 272:1061–77. https://doi.org/10.1007/s00405-014-3065-8. 5. azandaryani ar, eftekharian m, taghipour m. large laryngeal lipoma with extra laryngeal component mimics mixed form laryngocele: a case report. adv j emerg med 2019; 3:e45. https://doi.org/10.22114/ajem.v0i0.196. 6. singhal sk, virk rs, mohan h, palta s, dass a. myxolipoma of the epiglottis in an adult: a case report. ear nose throat j 2005; 84:728,730,734. https://doi.org/10.1177/014556130508401117. 7. rozas aristy f, espino durán m, zapateiro j. [myxoid lipoma of the larynx]. rev med panama 1991; 16:33–8. https://doi. org/10.22206/cys.1991.v16i4.pp359-75. 8. verma r, sardana n, verma rr. multiple myxoid lipomas supraglottic region, int j phonosurg laryngology 2011; 1:88–90. https://doi.org/10.5005/jp-journals-10023-1023. 9. dinsdale rc, manning sc, brooks dj, vuitch f. myxoid laryngeal lipoma in a juvenile. otolaryngol head neck surg 1990; 103:653–7. https://doi.org/10.1177/019459989010300423. 10. çelik sy, dere y, çelik öi̇, derin s, şahan m, dere ö. nodular fasciitis of the neck causing emergency: a case report. oman med j 2017; 32:69–72. https://doi.org/10.5001/omj.2017.13. 11. razek aa, huang by. soft tissue tumors of the head and neck: imaging-based review of the who classification. radiographics 2011; 31:1923–54. https://doi.org/10.1148/rg.317115095. 12. ma y, zhou b, wang s. large lipoma in the subglottic larynx: a case report. j int med res 2020; 48:300060520928786. https:// doi.org/10.1177/0300060520928786. 13. khuu a, yablon cm, jacobson ja, inyang a, lucas dr, biermann js. nodular fasciitis: characteristic imaging features on sonography and magnetic resonance imaging. j ultrasound med 2014; 33:565–73. https://doi.org/10.7863/ultra.33.4.565. 14. lu l, lao iw, liu x, yu l, wang j. nodular fasciitis: a retro spective study of 272 cases from china with clinicopathologic and radiologic correlation. ann diagn pathol 2015; 19:180–5. https://doi.org/10.1016/j.anndiagpath.2015.03.013. 15. gupta p, potti ta, wuertzer sd, lenchik l, pacholke da. spectrum of fat-containing soft-tissue masses at mr imaging: the common, the uncommon, the characteristic, and the sometimes confusing. radiographics 2016; 36:753–66. https:// doi.org/10.1148/rg.2016150133. has neither a high local recurrence propensity nor metastatic potential, adequate surgical excision of the lesion with negative margins could be sufficient as was seen in the current patient. yet, due to anatomical factors and critical structures, laryngeal nf lesions can be unamenable to simple complete laryngoscopic local excision. hence, a partial laryngectomy, whether endoscopic or open (based on the lesion, surgeon’s skills and patient factors) could be an appropriate choice in favour of vocal function preservation. total laryngectomy should be performed in selected cases with advanced diseases or reserved as salvage surgery. other controversial conservative methods such as intralesional corticosteroid injection can be considered when there are no substantial symptoms and spontaneous regression is expected. surgical excision is recommended in the case of laryngeal lipoma. depending on the size, endoscopic approach is preferred in small lipomas, whereas open surgical approach must be used if the lesion’s dimension is greater than 2 cm. as for benign lesions, the prognosis for laryngeal lipoma is very good. recurrence is rare and is mostly due to hidden malignancy or inadequate excision; because of this, long-term follow-up is recommended.15 conclusion nf of the larynx can mimic malignant tumors, thus reaching an exact diagnosis is very challenging. although it has a favorable prognosis compared to other aggressive laryngeal lesions, simple lesional resection in this unique location might be difficult and laryngectomy could be unavoidable. laryngeal myxolipoma is rare but must be considered in the differential diagnosis of laryngeal masses. a u t h o r’s c o n t r i b u t i o n ao and raa performed the literature review. all authors contributed to the drafting of the manuscript. all authors approved the final version of the manuscript. https://doi.org/10.2214/ajr.164.2.7839977 https://doi.org/10.2214/ajr.164.2.7839977 https://doi.org/10.1093/ajcp/35.2.122 https://doi.org/10.1007/s00405-014-3065-8 https://doi.org/10.22114/ajem.v0i0.196 https://doi.org/10.1177/014556130508401117 https://doi.org/10.22206/cys.1991.v16i4.pp359-75 https://doi.org/10.22206/cys.1991.v16i4.pp359-75 https://doi.org/10.5005/jp-journals-10023-1023 https://doi.org/10.1177/019459989010300423 https://doi.org/10.5001/omj.2017.13 https://doi.org/10.1148/rg.317115095 https://doi.org/10.1177/0300060520928786. https://doi.org/10.1177/0300060520928786. https://doi.org/10.7863/ultra.33.4.565 https://doi.org/10.1016/j.anndiagpath.2015.03.013 https://doi.org/10.1148/rg.2016150133 https://doi.org/10.1148/rg.2016150133 departments of 1medicine and 2pathology, nile valley university, atbara, sudan; 3department of medicine, milton keynes university hospital nhs foundation trust, eaglestone, buckinghamshire, uk *corresponding author e-mail: elziber@yahoo.com تغري منط التنومي لعنابر الباطنية يف املستشفيات عبء األمراض غري املعدية يف مستشفى يف بلد نام �سفيان نور، وديع املدهون، �ساره ب�ساره، حممد اأحمد abstract: objectives: this study aimed to determine the pattern of hospital admissions and patient outcomes in medical wards at atbara teaching hospital in river nile state, sudan. methods: this retrospective cross-sectional study was conducted from august 2013 to july 2014 and included all patients admitted to medical wards at the atbara teaching hospital during the study period. morbidity and mortality data was obtained from medical records. diseases were categorised using the world health organization’s international classification of diseases (icd) coding system. results: a total of 2,614 patient records were analysed. the age group with the highest admissions was the 56‒65-year-old age group (19.4%) and the majority of patients were admitted for one week or less (86.4%). non-communicable diseases constituted 71.8% of all cases. according to icd classifications, patients were admitted most frequently due to infectious or parasitic diseases (19.7%), followed by diseases of the circulatory (16.4%), digestive (16.4%) and genito-urinary (13.8%) systems. the most common diseases were cardiovascular disease (16.4%), malaria (11.3%), gastritis/peptic ulcer disease (9.8%), urinary tract infections (7.2%) and diabetes mellitus (6.9%). the mortality rate was 4.7%. conclusion: the burden of non-communicable diseases was found to exceed that of communicable diseases among patients admitted to medical wards at the atbara teaching hospital. keywords: patient admissions; patient outcome assessment; international classification of diseases; hospital mortality; sudan. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل حتديد منط التنومي لعنابر الأمرا�ض الباطنية ونتائج العالج يف م�ست�سفى عطربة التعليمي يف ولية نهر النيل بال�سودان. الطريقة: اأجريت هذه الدرا�سة امل�ستعر�سة الراجعة من اأغ�سط�ض 2013 اإىل يوليو 2014، و�سملت جميع املر�سى املرقدين يف الأجنحة الطبية يف م�ست�سفى عطربة التعليمي اأثناء فرتة الدرا�سة. مت احل�سول على بيانات معدلت العتالل والوفيات من ما حتليل مت النتائج: العاملية. ال�سحة ملنظمة تبعا لالأمرا�ض الدويل الرتميز نظام با�ستخدام الأمرا�ض ت�سنيف مت الطبية. ال�سجالت جمموعه 2,614 قي �سجالت املر�سى. كانت الفئة العمرية الأعلى تنوميا يف امل�ست�سفى هي البالغة من العمر 65-56 عام بن�سبة مئوية بلغت %19.4 ومت ترقيد غالبية املر�سى ملدة اأ�سبوع اأو اأقل )%86.4(. �سكلت الأمرا�ض غري املعدية %71.8 من جميع حالت التنومي. وفقا اأمرا�ض تليها ،)19.7%( الطفيلية اأو املعدية الأمرا�ض ب�سبب الأحيان معظم يف املر�سى ترقيد مت لالأمرا�ض، الدويل الرتميز لت�سنيف الدورة الدموية )%16.4(، ثم اجلهاز اله�سمي )%16.4(، و اجلهاز البويل التنا�سلي )%13.8(. كانت اأكرث الأمرا�ض �سيوعا هي اأمرا�ض القلب والأوعية الدموية )%16.4( تليها املالريا )%11.3(، ثم التهاب املعدة / مر�ض القرحة اله�سمية )%9.8(، والتهابات امل�سالك البولية )7.2%( ومر�ض البول ال�سكري )%6.9(. بلغت ن�سبة الوفيات %4.7. اخلال�صة: لقد وجد اأن عبء الأمرا�ض غري املعدية تزيد على الأمرا�ض املعدية بني املر�سى الذين مت ترقيدهم بعنابر الباطني يف م�ست�سفى عطربة التعليمي. مفتاح الكلمات: تنومي املري�ض؛ تقييم نتائج املري�ض؛ الت�سنيف الدويل لالأمرا�ض؛ وفيات امل�ست�سفى؛ ال�سودان. the changing pattern of hospital admission to medical wards burden of non-communicable diseases at a hospital in a developing country sufian k. noor,1 wadie m. elmadhoun,2 sarra o. bushara,1 *mohamed h. ahmed3 advances in knowledge this study explores the most common causes of hospital admission and inpatient death among medical wards at a health facility in the developing country of sudan. the changing trend from communicable to non-communicable diseases (ncds) is documented. application to patient care health policies concerning patient care should be formulated according to the most common diseases encountered in health facilities. the findings of this study indicate that preventive measures should be directed towards ncds as well as communicable diseases at the atbara teaching hospital in north sudan. clinical & basic research sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e517–522, epub. 23 nov 15 submitted 20 feb 15 revisions req. 4 may & 5 jul 15; revision recd. 27 may & 9 jul 15 accepted 30 jul 15 doi: 10.18295/squmj.2015.15.04.013 in general, communicable diseases arethe main causes of admission to medical wards in developing countries, while non-communicable diseases (ncds) are the main causes in developed countries.1 the exact pattern of illness among adults in sub-saharan africa has not been well studied;2,3 the changing pattern of hospital admission to medical wards burden of non-communicable diseases at a hospital in a developing country e518 | squ medical journal, november 2015, volume 15, issue 4 however, the world health organization (who) predicts that by the year 2020 the causes of diseases and deaths in sub-saharan africa will have undergone a significant transition towards ncds and away from infectious diseases.4 this shift could be attributed to the increasing urbanisation and westernisation of populations in developing countries.4 the admission of patients to a medical ward is generally determined by age, coexisting illnesses, physical and laboratory findings, patient compliance with oral medication regimens and the resources available to the patient outside of the hospital.5 in sudan, as in many other african countries, epidemiological information on disease profiles is very limited; until 2013, there were no data available on the pattern of medical admissions.6 recently, a study by el bingawi et al. determined that communicable diseases were the predominant cause of admission in sudan.7 in sudan, the river nile state lies to the north of the capital of khartoum and extends to the border of egypt, covering an area of 124,000 m2 with a total estimated population of 1,309,129 in 2013.8 the atbara teaching hospital is the main tertiary hospital in the river nile state with a very wide catchment area and a capacity of 350 beds. the available specialties include internal medicine, surgery, obstetrics and gynaecology, paediatrics, orthopaedics, ear, nose and throat surgery, ophthalmology, dermatology and psychiatry. routine laboratory, radiology, haematology and histopathology investigations are the main diagnostic modalities. it is known that identifying patterns of disease can help improve policy-making and facilitate the prioritisation of healthcare needs, as well as effectively influence the appropriate allocation of resources.4 as such, the main objectives of this study were to assess the most common causes of admission to the medical wards at atbara teaching hospital, the average duration of hospital stay and the in-hospital mortality rate. methods this observational retrospective cross-sectional study was conducted from august 2013 to july 2014 on all patients admitted to the medical wards of atbara teaching hospital. patients under 16 years old and without complete medical records were excluded from the study. the records of all of the admitted patients were reviewed by three medical students and validated by two consultants. the data collectors were trained in completing the structured data collection format prepared for the study. the dependent variables in this study were: reason(s) for admission (i.e. principal/ provisional diagnosis), body system involved and outcome of admission. other variables included age, gender, residence and comorbidities. the diseases were categorised using version 10.0 of the who international classification of diseases (icd) coding system.9 the classification of diseases into communicable and non-communicable categories were based on the definitions used by the centers for disease control and prevention and the who.10,11 data were entered into the statistical package for the social sciences (spss), version 16.0 (ibm corp., chicago, illinois, usa). analyses were performed to obtain descriptive measures. ethical permission for this study was obtained from the ethical committee of the faculty of medicine & health sciences at nile valley university, atbara, sudan (#nvu/fm/ ea34/14). no patient consent was necessary as the records were reviewed following permission from the administration of atbara teaching hospital. all information obtained was kept confidential and was used only for the purposes of this study. results a total of 2,614 patients were admitted to medical wards during the study period. of these, 1,316 were male and 1,298 were female (ratio: 1:1). the age of the patients ranged from 16‒89 years with a mean age of 52.06 ± 18.9 years. the most common age group was table 1: sociodemographic characteristics of patients admitted to medical wards at atbara teaching hospital, river nile state, sudan (n = 2,614) characteristic n (%) gender male 1,316 (50.3) female 1,298 (49.7) age group in years* 15‒25 338 (12.9) 26‒35 284 (10.9) 36‒45 361 (13.8) 46‒55 429 (16.4) 56‒65 507 (19.4) 66‒75 451 (17.3) >75 235 (9.0) residence urban 1,449 (55.4) rural 1,165 (44.6) *total number of patients for this variable was 2,605 due to missing data. sufian k. noor, wadie m. elmadhoun, sarra o. bushara and mohamed h. ahmed clinical and basic research | e519 the majority of patients stayed in the hospital for short periods, with 1,470 patients (56.2%) staying between one and three days and 788 patients (30.1%) staying between four and seven days. during the study period, the outcome of hospital admission was favourable in most cases with 78.0% of the patients showing improvement and being subsequently discharged. the rate of referral to other betterequipped centres was only 3.8%. there were 123 inhospital deaths, constituting 4.7% of all admissions [table 4]. the most common causes of death were septicaemia/sepsis (n = 31; 25.2%), cerebrovascular accidents/strokes (n = 23; 18.7%) and complications due to renal failure (n = 18; 14.6%) [table 5]. the 56‒65-year-old group, which constituted 19.4% of all patients. the patients were predominantly from urban areas (n = 1,449; 55.4%) [table 1]. according to icd classifications, patients were admitted most frequently due to infectious or parasitic diseases (n = 516; 19.7%), followed by diseases of the circulatory (n = 429; 16.4%), digestive (n = 428; 16.4%), genito-urinary (n = 361; 13.8%) and respiratory (n = 317; 12.1%) systems [table 2]. the most common diseases were cardiovascular disease (n = 429; 16.4%), malaria (n = 296; 11.3%), gastritis/peptic ulcer disease (n = 255; 9.8%), urinary tract infections (n = 188; 7.2%) and diabetes mellitus (n = 181; 6.9%). additionally, 167 patients were admitted due to renal failure (6.4%), of which chronic kidney disease was the predominant cause. of the patients admitted to medical wards, 720 had communicable diseases (27.5%), whereas 1,878 had ncds (71.8%) [table 3]. table 2: reasons for admission by disease category* to medical wards at atbara teaching hospital, river nile state, sudan (n = 2,614) icd category reason for admission n (%) total male female a or b infectious or parasitic diseases 516 (19.7) 273 (52.9) 243 (47.1) c malignant neoplasms 46 (1.8) 30 (65.2) 16 (34.8) d diseases of the blood 97 (3.7) 43 (44.3) 54 (55.7) e endocrine, nutrition and metabolic diseases 190 (7.3) 85 (44.7) 105 (55.3) g diseases of the nervous system 192 (7.4) 90 (46.9) 102 (53.1) i diseases of the circulatory system 429 (16.4) 190 (44.3) 239 (55.7) j diseases of the respiratory system 317 (12.1) 170 (53.6) 147 (46.4) k diseases of the digestive system 428 (16.4) 229 (53.5) 199 (46.5) m spondylopathies and musculoskeletal disorders 22 (0.8) 7 (31.8) 15 (68.2) n diseases of the genito-urinary system 361 (13.8) 188 (52.1) 173 (47.9) o miscellaneous conditions 16 (0.6) 11 (68.8) 5 (31.2) icd = international classification of disease. *categorised using version 10.0 of the world health organization’s icd coding system.8 table 3: diseases causing admission to medical wards at atbara teaching hospital, river nile state, sudan (n = 2,614) disease n (%) total male female cardiovascular disease* 429 (16.4) 190 (44.3) 239 (55.7) malaria 296 (11.3) 162 (54.7) 134 (45.3) gastritis/peptic ulcer disease* 255 (9.8) 114 (44.7) 141 (55.3) urinary tract infection* 188 (7.2) 88 (46.8) 100 (53.2) diabetes mellitus* 181 (6.9) 83 (45.9) 98 (54.1) pneumonia 180 (6.9) 96 (53.3) 84 (46.7) renal failure* 167 (6.4) 98 (58.7) 69 (41.3) septicaemia* 167 (6.4) 79 (47.3) 88 (52.7) cerebrovascular accident* 131 (5.0) 57 (43.5) 74 (56.5) gastroenteritis 85 (3.3) 51 (60.0) 34 (40.0) anaemia* 79 (3.0) 36 (45.6) 43 (54.4) tuberculosis 69 (2.6) 49 (71.0) 20 (29.0) hepatitis 44 (1.7) 28 (63.6) 16 (36.4) bronchial asthma* 40 (1.5) 15 (37.5) 25 (62.5) typhoid fever 37 (1.4) 21 (56.8) 16 (43.2) other 266 (10.2) 149 (56.0%) 117 (44.0%) *non-communicable disease. the changing pattern of hospital admission to medical wards burden of non-communicable diseases at a hospital in a developing country e520 | squ medical journal, november 2015, volume 15, issue 4 discussion to the best of the authors’ knowledge, this is the first study on the pattern of hospital admissions in the river nile state and the second of its kind in sudan as a whole.5 identifying the most common causes of hospital admission and in-hospital deaths is essential for policy-making and healthcare planning. communicable diseases were previously believed to constitute the main burden of hospital admissions in developing countries.1 the results of this study, however, demonstrate that there has been a considerable change; 71.8% of the admissions at the studied hospital were due to ncds. this finding is in agreement with similar studies on hospital admission patterns conducted in nigeria and south africa.12–14 however, findings from studies carried out in ethiopia, sudan and pakistan indicated that communicable diseases were more prevalent.1,6,15 the change from communicable diseases to ncds in the hospital admission patterns observed in the current study could be explained by the fact that more than half of the admitted patients were from urban areas. increasing urbanisation can result in reduced physical activity, dietary changes and a rise in the rate of obesity.4 in addition, the adoption of westernised lifestyles and habits by many rural communities may have played a role, as well as potential improvements in personal hygiene, environmental sanitation, health awareness and vaccine programmes. these factors, or a combination of them, may explain the reduced burden of communicable diseases in the river nile state. health professionals, policy-makers and health planners should be informed of the higher prevalence of ncds over communicable diseases in this community. overall, cardiovascular diseases, when considered as a single disease entity, were the most common causes of hospital admission in the present study. this could potentially be explained by the increased prevalence of cardiovascular risk factors since there were many individuals with diabetes and/or hypertension. this explanation is supported by findings from a previous study carried out in the river nile state that reported a high prevalence of undiagnosed hypertension (38.2%).16 since smoking is a common habit in developing countries such as sudan, it could also be implicated in the high incidence of cardiovascular disease.17 renal diseases were also noted among the hospital admissions in the current study. this may be attributed to the high prevalence of diabetes and hypertension, but could also reflect an increased use of over-the-counter nonsteroidal anti-inflammatory drugs. the in-hospital mortality rate of the current study (4.7%) was lower than that found in similar studies in ethiopia (12.0%) and nigeria (12.3%).1,18 this low mortality rate may, in part, reflect the comprehensive health services offered at atbara teaching hospital. the most commonly reported causes of death (sepsis, stroke and renal failure) could likewise be explained by the high prevalence of hypertension and diabetes mellitus and the high percentage of older subjects in the current study population. furthermore, a lack of access to early computed tomography scans and table 4: duration of hospital stay and outcome of patients admitted to medical wards at atbara teaching hospital, river nile state, sudan (n = 2,614) variable n (%) duration of stay in days 1‒3 1,470 (56.2) 4‒7 788 (30.2) 8‒14 251 (9.6) 15‒21 50 (1.9) 22‒29 14 (0.6) 30‒60 1 (<0.1) not documented 40 (1.5) outcome improved and discharged 2,039 (78.0) not improved 11 (0.4) left against medical advice 157 (6.0) died 123 (4.7) discharged at patient request 3 (0.1) referred to other centre 98 (3.8) not documented 183 (7.0) table 5: causes of death among patients admitted to medical wards at atbara teaching hospital, river nile state, sudan (n = 123) cause of death n (%) septicaemia 31 (25.2) cerebrovascular accident 23 (18.7) renal failure 18 (14.6) tuberculosis 6 (4.9) cardiovascular disease 5 (4.1) hepatitis 5 (4.1) hiv/aids 4 (3.3) diabetes mellitus 3 (2.4) malaria 2 (1.6) other 26 (21.1) hiv = human immunodeficiency virus; aids = acquired immunodeficiency syndrome. sufian k. noor, wadie m. elmadhoun, sarra o. bushara and mohamed h. ahmed clinical and basic research | e521 conclusion the pattern of hospital admission to medical wards at the atbara teaching hospital indicated a predominance of ncds over communicable diseases. policy-makers and health planners should be made aware of the changing patterns of disease in this community. a c k n o w l e d g e m e n t s the authors are grateful to the staff of the department of statistics at atbara teaching hospital for their role in the data collection. in addition, they are also indebted to m. scarborough for assistance with editing this article. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. ali e, woldie m. reasons and outcomes of admissions to the medical wards of jimma university specialized hospital, southwest ethiopia. ethiop j health sci 2010; 20:113–20. 2. rajaratnam jk, marcus jr, levin-rector a, chalupka an, wang h, dwyer l, et al. worldwide mortality in men and women aged 15-59 years from 1970 to 2010: a systematic analysis. lancet 2010; 375:1704–20. doi: 10.1016/s01406736(10)60517-x. 3. koyanagi a, shibuya k. what do we really know about adult mortality worldwide? lancet 2010; 375:1668‒70. doi: 10.1016/ s0140-6736(10)60629-0. 4. world health organization. global status report on noncommunicable diseases 2010: description of the global burden of ncds, their risk factors and determinants. from: www.who.int/nmh/publications/ncd_report2010/en/ accessed: jul 2015. 5. mandell la, wunderink r. pneumonia. in: fauci as, braunwald e, kasper dl, hauser sl, longo dl, jameson jl, et al., eds. harrison’s principles of internal medicine. 17th ed. new york, usa: mcgraw-hill professional, 2008. pp. 1619–28. 6. etyang ao, scott ja. medical causes of admissions to hospital among adults in africa: a systematic review. global health action 2013; 6:1‒14. doi: 10.3402/gha.v6i0.19090. 7. el bingawi hm, hussein mb, bakheet my. characteristics of patients admitted to medical ward of a referral hospital in a developing country. int j sci basic appl res 2014; 14:86–92. 8. republic of sudan central bureau of statistics. summary of projected population. from: www.cbs.gov.sd/en/files. php?id=7#&panel1-4 accessed: jul 2015. 9. world health organization. international statistical classification of diseases and related health problems 10th revision. from: apps.who.int/classifications/icd10/browse/2015 /en accessed: jul 2015. 10. centers for disease control and prevention. menu of suggested provisions for state tuberculosis prevention and control laws: definitions for consideration. from: www.cdc.gov/tb/ programs/laws/menu/definitions.htm accessed: jul 2015. 11. world health organization. noncommunicable diseases: fact sheet. from: www.who.int/mediacentre/factsheets/fs355/en/ accessed: jul 2015. fibrinolytic agents and poor stroke unit facilities may also have contributed to the high stroke mortality. interestingly, although malaria was a common cause of admission, it was not a common cause of death, with only two malaria-related fatalities during the study period. this may reflect effective malaria management protocol and case management or other factors that have yet to be determined. additionally, human immunodeficiency virus (hiv)/acquired immune deficiency syndrome (aids) was not a common cause of morbidity or mortality in the current study, despite the fact that the atbara teaching hospital is a regional centre for the diagnosis and management of these conditions. this finding differs from the current hiv/aids situation in many neighbouring african countries.1 high rates of case improvement and patient discharge were observed in the current study. this could be attributed to a number of factors, for example the quality of services, follow-up and number of physicians at the atbara teaching hospital as compared to other state hospitals in sudan. the rate of improved and discharged patients (78.0%) was similar to the rate reported in a tertiary health centre in nigeria, but lower than rates reported from hospitals in ethiopia and sudan.1,6,18 in most cases, the average duration of hospital stay in the current study was one week or less (86.3%), which is consistent with similar studies carried out in khartoum and pakistan.6,15 this could be explained by the fact that most acute communicable diseases, as well as uncomplicated ncds, are treatable within this short timeframe. the current study had several limitations; as it was a retrospective hospital-based study, problems associated with incomplete medical recordkeeping, missing data and under-reporting were encountered. these limitations were overcome as much as possible via a meticulous search and retrieval of the available data and the exclusion of patients with missing data. while acknowledging this shortcoming, in resourcepoor countries such as sudan where access to reliable epidemiological data is not always feasible, data such as those reported here constitute the best available alternative. another limitation was the short one-year duration of the study period; conducting such studies for a longer period of time would provide stronger evidence for these findings. in view of the above, this study may not necessarily reflect the actual disease pattern in the community as a whole. however, in spite of these limitations, this study is novel and constitutes a basis for further studies on hospital admission patterns in river nile state and across sudan. http://dx.doi.org/10.1016/s0140-6736%2810%2960517-x http://dx.doi.org/10.1016/s0140-6736%2810%2960517-x http://dx.doi.org/10.1016/s0140-6736%2810%2960629-0 http://dx.doi.org/10.1016/s0140-6736%2810%2960629-0 http://dx.doi.org/10.3402/gha.v6i0.19090 the changing pattern of hospital admission to medical wards burden of non-communicable diseases at a hospital in a developing country e522 | squ medical journal, november 2015, volume 15, issue 4 12. odenigbo cu, oguejiofor oc. pattern of medical admissions at the federal medical centre, asaba: a two year review. niger j clin pract 2009; 12:395–7. 13. ike so. the pattern of admissions into the medical wards of the university of nigeria teaching hospital, enugu (2). niger j clin pract 2008; 11:185–92. 14. tollman sm, kahn k, sartorius b, collinson ma, clark sj, garenne ml. implications of mortality transition for primary health care in rural south africa: a population-based surveillance study. lancet 2008; 372:893–901. doi: 10.1016/ s0140-6736(08)61399-9. 15. ashraf m, zakria m. disease patterns: admitted patients in medical ward of independent university hospital, marzipura, faisalabad. prof med j 2014; 21:570–4. 16. noor sk, bushara so, sulaiman aa, elmadhoun wm. a preliminary survey of un-diagnosed hypertension among nubians and coptics in atbara and eldamer cities, sudan: does ethnicity affect prevalence? arab j nephrol transplant 2013; 6:193–5. 17. world health organization western pacific region. smoking statistics: fact sheet. from: www.wpro.who.int/mediacentre/ factsheets/fs_20020528/en/ accessed: jul 2015. 18. ogunmola oj, oladosu oy. pattern and outcome of admissions in the medical wards of a tertiary health center in a rural community of ekiti state, nigeria. ann afr med 2014; 13:195–203. doi: 10.4103/1596-3519.142291. http://dx.doi.org/10.1016/s0140-6736%2808%2961399-9 http://dx.doi.org/10.1016/s0140-6736%2808%2961399-9 http://dx.doi.org/10.4103/1596-3519.142291 departments of 1employee health and 2research, king khaled eye specialist hospital, riyadh, saudi arabia *corresponding author e-mail: rajiv.khandekar@gmail.com حَتَرِّي اإلبصار عند ممرضات وممرضي قسم العيون يف مستشفى رعاية ثالثية النتائج والسلوكيات الساعية للحصول على رعاية صحية للعيون روحي خان, �ضي�ص �ض�رو, �ضيج� فاقي�ص, زيااول يا�رس, راجيف خانديكار abstract: objectives: this study aimed to evaluate ocular healthcare-seeking behaviours and vision screening outcomes of nursing staff at a tertiary eye care hospital. methods: this study was conducted between april and september 2016 among all 500 nurses employed at the king khaled eye specialist hospital, riyadh, saudi arabia. data were collected on age, gender, use of visual aids, the presence of diabetes, a history of refractive surgery and date of last ocular health check-up. participants were tested using a handheld spot™ vision screener (welch allyn inc., skaneateles falls, new york, usa). results: a total of 150 nurses participated in the study (response rate: 30.0%). the mean age was 41.2 ± 8.9 years old. distance spectacles, reading spectacles and both types of spectacles were used by 37 (24.7%), 32 (21.3%) and 10 (6.7%) nurses, respectively. a total of 58 nurses (38.7%) failed the vision screening test. visual defects were detected for the first time in 13 nurses (8.7%). with regards to regular eye checkups, 77 participants (51.3%) reported acceptable ocular healthcare-seeking behaviours; this factor was significantly associated with age and the use of visual aids (p <0.01 each). conclusion: a high proportion of participants failed the vision screening tests and only half displayed good ocular healthcare-seeking behaviours. this is concerning as ophthalmic nurses are likely to face fewer barriers to eye care services than the general population. keywords: vision screening; refractive errors; health care seeking behavior; nurses; saudi arabia. كل عند االإب�ضار حتري ونتائج للعي�ن, �ضحية رعاية على للح�ض�ل ال�ضاعية ال�ضل�كيات لتق�مي الدرا�ضة هذه هدفت الهدف: امللخ�ص: طاقم التمري�ص يف م�ضت�ضفى للرعاية ال�ضحية للعي�ن. الطريقة: اأجريت هذه الدرا�ضة, بني �ضهري يناير و�ضبتمرب من عام 2016م, على كل الطاقم الطبي العامل يف م�ضت�ضفى امللك خالد بالريا�ص يف اململكة العربية ال�ضع�دية وعددهم 500 ممر�ص وممر�ضة. وجمعت يف الدرا�ضة معل�مات عن العمر واجلن�ص واملعينات الب�رسية, واالإ�ضابة مبر�ص ال�ضكري, واأي تاريخ مر�ضي الأي جراحة اإنك�ضارية, وتاريخ اآخر فح�ص طبي اأجراه/اأجرته املمر�ص اأو املمر�ضة على العي�ن. مت فح�ص كل امل�ضاركني يف البحث عن طريق فاح�ص كا�ضف �ض�ئي حمم�ل باليد البحث هذا يف �ضارك النتائج: املتحدة(. بال�اليات ي�رك ني� يف ف�لز ا�ضكانيتيلز مدينة املحدودةيف االآلني ويبي�ص �رسكة انتاج )من من ون�ضب اأعداد بلغت �ضنة. 41.2 ± 8.9 امل�ضاركني اأعمار مت��ضط بلغ .)30.0% م�ضاركة )بن�ضبة بامل�ضت�ضفى التمري�ص طاقم من 150 كان�ا ي�ضتخدم�ن نظارات لالإب�ضار البعيد, وللقراءة, اأو الن�عني معا 37 )%24.7(, 32 )%21.3( و 10 )%6.7(, على الت�ايل. ومل ينجح يف اختبار االإب�ضار 58 ممر�ص/ممر�ضة )اأي ما ن�ضبته %38.7(. ووجد كذلك اأن 13 ممر�ضا/ممر�ضة )اأي ما ن�ضبته %8.7( لديهم عي�ب ب�رسية اأكت�ضفت الأول مرة يف الفح�ص احلايل. وبلغ عدد امل�ضاركني وامل�ضاركات يف الدرا�ضة الذين اأبدوا �ضل�كيات مقب�لة �ضاعية للح�ض�ل على رعاية �ضحية للعي�ن 77 م�ضاركا وم�ضاركة اأي ما ن�ضبته )%51.3(. وكان ذلك العامل مرتبط على نح� معن�ي بالعمر وا�ضتخدام املعينات الب�رسية )p >0.01 يف كل حالة(. اخلال�صة: مل تنجح ن�ضبة كبرية من امل�ضاركني يف اختبارات االإب�ضار, ومل يظهر اإال ن�ضف عدد امل�ضاركني وامل�ضاركات �ضل�كيات جيدة لل�ضعي للح�ض�ل على رعاية �ضحية للعي�ن, وهذا اأمر مقلق اإذ اأن ممر�ضى طب العي�ن ي�اجه�ن �ضع�بات اأقل من عامة ال�ضكان يف احل�ض�ل على خدمات الرعاية ال�ضحية للعي�ن. اململكة املمر�ضني؛ �ضحية؛ رعاية على للح�ض�ل ال�ضاعية ال�ضل�كيات االإنك�ضارية؛ االأخطاء االإب�ضار؛ رِّي حَتَ املفتاحية: الكلمات العربية ال�ضع�دية. vision screening of ophthalmic nursing staff in a tertiary eye care hospital outcomes and ocular healthcare-seeking behaviours ruhi a. khan,1 ches souru,2 sejo vaghese,2 ziaul yasir,2 *rajiv khandekar2 clinical & basic research sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e74–79, epub. 30 mar 17 submitted 8 jun 16 revision req. 20 jul 16; revision recd. 12 aug 16 accepted 22 sep 16 doi: 10.18295/squmj.2016.17.01.013 advances in knowledge the findings of this study indicate that the rate of refractive errors among nurses working at a tertiary eye care hospital in saudi arabia was high; moreover, many nurses did not have healthy ocular healthcare-seeking behaviours. application to patient care nurses should be encouraged to undergo periodic vision testing in order to ensure adequate patient care as well as for their own benefit. ruhi a. khan, ches souru, sejo vaghese, ziaul yasir and rajiv khandekar clinical and basic research | e75 although preschooland school-aged children undergo regular eye care tests, the vision screening of healthy adults is not standard practice.1–3 in many countries, vision screening is a component of comprehensive physical assessments which prospective employees undergo during job recruitment.4 in addition, the increasing number of senior citizens who continue to drive past 65 years of age has compelled many licensing agencies to incorporate vision screening into their relicensing requirements.5 some professions also have specialised visual needs with regards to their employees; the role of eye testing in relation to altered refractive status has been highlighted previously in a cohort of pilots.6 however, healthy asymptomatic individuals rarely present for regular vision tests. for young adults, the visual demands of precise near work has increased significantly due to the extensive use of smartphones and computers for communication, entertainment and work-related tasks.7 this constant strain on the visual system can cause symptoms of asthenopia and changes in the refractive status of the eyes.8 for healthcare staff, untreated or undiagnosed defective vision could compromise the quality of patient care and potentially result in early retirement.9 hence, even asymptomatic healthcare workers should ensure any visual issues are appropriately addressed in order to function effectively within the patient care environment and in daily life activities. in 2016, the world health organization initiated a worldwide campaign to increase public awareness of important health issues for healthcare workers, as well as the general population.10 this study consequently aimed to determine the refractive status and ocular healthcare-seeking behaviours of ophthalmic nurses at a tertiary eye care hospital in central saudi arabia. methods this study was conducted between april and september 2016 at the king khaled eye specialist hospital, riyadh, saudi arabia. using a convenience sampling method, all 500 ophthalmic nurses working in different departments of the hospital were invited to participate in a three-day refractive error screening campaign via a personalised email sent by the head of the nursing department. the demographic data of the participants was collected, including age, gender, use of visual aids such as spectacles or contact lenses, a previous history of refractive surgery and the presence/absence of diabetes. participants were considered diabetic based on their fasting blood sugar and glycated haemoglobin levels over the previous year and a confirmed diagnosis by a physician. nurses following medical advice to use distance or reading spectacles or both were considered to be regular users of visual aids. if they used visual aids sparingly or not at all, they were considered to be irregular users. for each participant, the spot™ vision screener (welch allyn inc., skaneateles falls, new york, usa) was used to determine the refractive status of each eye without visual aids. the instrument was held 1 m from the eyes during measurement; if a message was displayed stating that the eyes were too far or too close, the distance was adjusted accordingly until a successful measurement was acquired. at the end of the measurement, the screening instrument displayed a message within 10 seconds indicating if the subject had passed or failed the test. failure indicated the presence of a substantial visual defect requiring assessment by an ophthalmologist or optometrist, either due to refractive error, corneal opacity, lenticular opacity, nystagmus or miotic pupils. a pass indicated that the participant was bilaterally emmetropic, either had no or marginal refractive errors and that their vision was probably >20/40. if the display indicated that the pupils were too miotic, the ambient room lighting was reduced and the test was repeated. the average time taken to perform the screening test was one minute. refractive errors were documented as spherical, cylindrical or axial. if the cylindrical error was <1 d, the spherical equivalent of the refractive error was calculated using the following equation:11 where sph is the spherical value and cyl is the cylindrical value as determined by the screening instrument. the eye with the greatest refractive error was used to determine the refractive status of the participant. the nurses were diagnosed as anisometropic if there was a >1 d difference in the refractive error between each eye.12 mild and moderate myopia was defined as -0.5 d to -3 d and -3 d to -6 d in the worse eye, respectively. severe myopia was defined as >-6 d in the worse eye.13 ocular healthcare-seeking behaviours were deter mined using a questionnaire and confirmed via ophthalmic or optometric health records. healthcareseeking behaviour was deemed acceptable if the participants reported having undergone an eye/vision assessment in the preceding two years. participants who had not undergone an ocular examination since being recruited or those who had undergone an examination more than two years prior to their sph + (cyl/2) vision screening of ophthalmic nursing staff in a tertiary eye care hospital outcomes and ocular healthcare-seeking behaviours e76 | squ medical journal, february 2017, volume 17, issue 1 participation in the study were considered to have poor ocular healthcare-seeking behaviour. data were collected using an excel spreadsheet, version 2003 (microsoft corp., redmond, washington, usa). the statistical package for the social sciences (spss), version 22 (ibm corp., chicago, illinois, usa), was used to analyse the data. for qualitative data, frequencies and percentages were calculated. if quantitative data were normally distributed, means and standard deviation were calculated for each variable. associations between the outcome variables and determinants were assessed using odds ratios, 95% confidence intervals and two-sided p values. a p value of <0.05 was considered statistically significant. this study was approved by the institutional research & ethics board of the king khaled eye specialist hospital (local project #1641-r). verbal informed consent to use their data for research purposes was obtained from all participating nurses. participants who failed the screening test were advised to consult an optometrist and/or ophthalmologist for further management. results a total of 150 nurses participated in the study (response rate: 30.0%). most participants were over 40 years old (n = 78; 52.0%) and just over half were using visual aids on the day of the screening (n = 81; 54.0%). in addition, 36 nurses (24.0%) had never undergone vision testing after being recruited to their current place of employment. none of the participants had previously undergone refractive surgery and two were irregular users of contact lenses for optical and cosmetic purposes [table 1]. the outcomes of the vision screening tests are shown in table 2. a total of 58 nurses (38.7%) failed the test; of these, 13 (8.7%) with distance vision defects were unaware that they required visual aids. very few table 1: demographic characteristics and ocular healthcare-seeking behaviours among ophthalmic nurses at a tertiary eye care hospital in saudi arabia (n = 150) variable n (%) age in years ≤30 22 (14.7) 31–40 50 (33.3) 41–50 55 (36.7) ≥51 23 (15.3) mean ± sd 41.2 ± 8.9 gender male 20 (13.3) female 130 (86.7) diabetes present 11 (7.3) absent 139 (92.7) use of visual aids distance spectacles 37 (24.7) reading spectacles 32 (21.3) both distance and reading spectacles 10 (6.7) contact lenses 2 (1.3) none 69 (46.0) date of last ocular check-up within one year 12 (8.0) within two years 65 (43.3) more than two years ago 37 (24.7) never* 36 (24.0) *after being recruited to their current place of employment. table 2: vision screening outcomes and ocular healthcareseeking behaviours among ophthalmic nurses at a tertiary eye care hospital in saudi arabia (n = 150) variable outcome of vision screening, n (%) 95% ci pass fail gender male 15 (75.0) 5 (25.0) 6.0–44.0 female 77 (59.2) 53 (40.8) 32.4–49.2 diabetes present 6 (54.5) 5 (45.5) 16.1–74.9 absent 86 (61.9) 53 (38.1) 30.0–46.2 date of last ocular check-up within two years 34 (44.2) 43 (55.8) 44.7–66.9 more than two years ago 25 (67.6) 12 (32.4) 17.3–47.5 never* 33 (91.7) 3 (8.3) 0.0–17.3 age in years ≤30 17 (77.3) 5 (22.7) 5.2–40.2 31–40 35 (70.0) 15 (30.0) 17.3–42.7 41–50 30 (54.5) 25 (45.5) 32.3–58.7 ≥51 10 (43.5) 13 (56.5) 36.2–76.8 total 92 (61.3) 58 (38.7) 18.0–28.4 ci = confidence interval. *after being recruited to their current place of employment. ruhi a. khan, ches souru, sejo vaghese, ziaul yasir and rajiv khandekar clinical and basic research | e77 participants under 30 years old failed the test (n = 5; 22.7%). while more than half of the participants had refractive errors, no participants were found to have severe myopia or anisometropia [figure 1]. the ocular healthcare-seeking behaviour of the nurses and associations with different variables is presented in table 3. an acceptable level of healthcare-seeking behaviour was noted in 77 participants (51.3%). age and the use of visual aids were significantly associated with a higher rate of acceptable healthcareseeking behaviour in terms of more frequent vision check-ups (p <0.01 each). discussion due to the increased visual demands of the modern digital era, universal vision and refractive error screening is not recommended as individuals are more motivated to actively seek out an eye care professional to maintain optimal vision. hence, recommendations for vision screening in adults remain debatable.14 however, evidence from developing countries indicates that unmet visual needs remain high, perhaps due to cost-related barriers to care.14–16 kumah et al. reported that 68.1% of ghanaian teachers who underwent vision screening were presbyopic; 29.6% of these individuals did not wear corrective aids.15 studies from zanzibar and kenya also indicated that while 89.2% and 85.4% of adults were presbyopic, only 17.6% and 5.4% of these individuals wore spectacles, respectively.16,17 although the current study was performed in a country with a rapidly evolving economy, the vision screening of nurses working at a tertiary eye care hospital indicated that several participants were unaware that they had a refractive error requiring an optical aid for optimal vision. moreover, just under half of the ophthalmic nursing staff demonstrated poor healthcare-seeking behaviours in that they had not undergone an ocular assessment in the previous two years. these results indicate that proactive vision and refractive error screening is needed even for individuals with fewer barriers to adequate eye care, such as cost, distance and lack of access. public health and education initiatives are therefore necessary to ensure the provision of rapid vision screening services to healthcare professionals in saudi arabia. in the present study, none of the participants had previously undergone refractive surgery and just over half regularly wore distance or reading spectacles at the time of screening. this may be due to the fact that just over half of the participants were over 40 years old; at this age, hyperopia can manifest due to a loss of ciliary muscle tone.18 initially, hyperopic individuals may compensate for the refractive error by decreasing the distance of far objects to view them more clearly or simply ignoring the effect of the error. for near-sighted table 3: determinants of acceptable ocular healthcareseeking behaviours* among ophthalmic nurses at a tertiary eye care hospital in saudi arabia (n = 150) variable healthcare-seeking behaviour, n (%) or (95% ci) p value acceptable (n = 77) unacceptable (n = 73) gender male 7 (9.1) 13 (17.8) 0.5 (0.2–1.2) 0.13 female 70 (90.9) 60 (82.2) diabetes present 4 (5.2) 7 (9.6) 0.5 (0.2–1.9) 0.34 absent 73 (94.8) 66 (90.4) visual aids using 56 (72.7) 25 (34.2) 5.1 (2.5–10.3) <0.01† none 21 (27.3) 48 (65.8) age in years‡ ≤30 9 (11.7) 13 (17.8) 0.61 (0.2–1.5) 0.30 31–40 18 (23.4) 32 (43.8) 0.4 (0.2–0.8) 0.01† 41–50 36 (46.8) 19 (26.0) 2.5 (1.3–5.0) 0.01† ≥51 14 (18.2) 9 (12.3) 1.6 (0.6–3.9) 0.33 or = odds ratio; ci = confidence interval. *acceptable ocular healthcare-seeking behaviour was defined as having had an eye care check-up within the previous two years. †a p value of <0.05 was considered statistically significant. ‡healthcare-seeking behaviour was not significantly correlated to age group (χ2 = 6.2; degrees of freedom = 3). figure 1: distribution of refractive status* among ophthalmic nurses at a tertiary eye care hospital in saudi arabia (n = 150). *using data from the worst eye. vision screening of ophthalmic nursing staff in a tertiary eye care hospital outcomes and ocular healthcare-seeking behaviours e78 | squ medical journal, february 2017, volume 17, issue 1 individuals, a reading distance of >25 cm should be ensured. however, female nurses may avoid or delay wearing spectacles for aesthetic reasons.19 contact lens use was also found to be very low among participants of the current study; this is surprising as the prevalence of contact lens use has been noted to be as high as 70.2% in saudi arabia.20 this low rate of use might be due to the hot, dry and dusty climate and the widespread use of air conditioners in saudi arabia, which can cause tears or film abnormalities in contact lenses.21 in the current study, the prevalence of diabetes was appreciably higher than that reported among danish nurses (7.3% versus 4.4%).22 a high prevalence of diabetes has been previously reported among saudi arabian adults (12.1%).23 a high prevalence of risk factors for diabetes—such as obesity, poor diet and a sedentary lifestyle—could be the underlying cause of the high prevalence of diabetes in riyadh.24 rapid vision screening methods have previously been proposed for adults.25 however, such methods often involve computer-assisted tools and are not portable. in contrast, the spot™ vision screener (welch allyn inc.) is a handheld unit that provides rapid measurements and has been validated in the detection of risk factors for amblyopia and uncorrected refractive errors in children.26,27 in the clinical experience of the authors, significant uncorrected refractive errors are regularly identified in adults using the spot™ vision screener (welch allyn inc.); moreover, individuals with distance spectacles often fail the screening test and their prescriptions are outdated. however, in the majority of patients, the outcomes of the screening test using the spot™ vision screener (welch allyn inc.) are similar to that of their current prescriptions. the current study is subject to some limitations. vision screening was performed on a voluntary basis; as such, the findings of the current sample may differ from those who opted not to undergo screening and cannot be extrapolated for all nurses working at this tertiary eye care hospital. moreover, to the best of the authors’ knowledge, the spot™ vision screener (welch allyn inc.) has not been validated for use in adults. further studies are recommended to validate this instrument for adult vision screening in comparison with other conventional tests or instruments. lastly, the grading of refractive errors was not confirmed by other methods. conclusion a high proportion of ophthalmic nurses failed the vision screening tests; furthermore, only half reported adequate ocular healthcare-seeking behaviours. as nurses working at a tertiary eye care hospital are less likely to face barriers to eye care, the detection of uncorrected refractive errors among these individuals is concerning. these findings indicate the need for enhanced public health and education initiatives in saudi arabia to ensure the provision of rapid vision screening services to healthcare professionals. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. solebo al, cumberland pm, rahi js. whole-population vision screening in children aged 4-5 years to detect amblyopia. lancet 2015; 385:2308–19. doi: 10.1016/s0140-6736(14)60522-5. 2. sharma a, congdon n, patel m, gilbert c. schoolbased approaches to the correction of refractive error in children. surv ophthalmol 2012; 57:272–83. doi: 10.1016/j. survophthal.2011.11.002. 3. hopkins s, sampson gp, hendicott p, wood jm. review of guidelines for children’s vision screenings. clin exp optom 2013; 96:443–9. doi: 10.1111/cxo.12029. 4. pradeep tg, bhandary a. visual health assessment amongst in service police personnel. indian j clin exp ophthalmol 2016; 2:141–5. 5. desapriya e, harjee r, brubacher j, chan h, hewapathirane ds, subzwari s, et al. vision screening of older drivers for preventing road traffic injuries and fatalities. cochrane database syst rev 2014; 2:cd006252. doi: 10.1002/14651858.cd006252.pub4. 6. nakagawara vb, montgomery rw, wood kj. changing demographics and vision restrictions in civilian pilots and their clinical implications. aviat space environ med 2004; 75:785–90. 7. he m, abdou a, ellwein lb, naidoo ks, sapkota yd, thulasiraj rd, et al. age-related prevalence and met need for correctable and uncorrectable near vision impairment in a multi-country study. ophthalmology 2014; 121:417–22. doi: 10.1016/j.ophtha.2013.06.051. 8. toomingas a, hagberg m, heiden m, richter h, westergren ke, tornqvist ew. risk factors, incidence and persistence of symptoms from the eyes among professional computer users. work 2014; 47:291–301. doi: 10.3233/wor131778. 9. neal-boylan l, fennie k, baldauf-wagner s. nurses with sensory disabilities: their perceptions and characteristics. rehabil nurs 2011; 36:25–31. doi: 10.1002/j.2048-7940.2011. tb00062.x. https://doi.org/10.1016/s0140-6736%2814%2960522-5 https://doi.org/10.1016/j.survophthal.2011.11.002 https://doi.org/10.1016/j.survophthal.2011.11.002 https://doi.org/10.1111/cxo.12029 https://doi.org/10.1002/14651858.cd006252.pub4 https://doi.org/10.1016/j.ophtha.2013.06.051 https://doi.org/10.3233/wor-131778 https://doi.org/10.3233/wor-131778 https://doi.org/10.1002/j.2048-7940.2011.tb00062.x https://doi.org/10.1002/j.2048-7940.2011.tb00062.x ruhi a. khan, ches souru, sejo vaghese, ziaul yasir and rajiv khandekar clinical and basic research | e79 10. world health organization. world health day 2016: who calls for global action to halt rise in and improve care for people with diabetes. from: www.who.int/mediacentre/news/ releases/2016/world-health-day/en/ accessed: aug 2016. 11. millodot m. dictionary of optometry and visual science, 7th ed. oxford, uk: butterworth-heinemann elsevier, 2009. p. 116. 12. gupta m, rana sk, mittal sk, sinha rn. profile of amblyopia in school going (5-15 years) children at state level referral hospital in uttarakhand. j clin diagn res. 2016 nov;10(11):sc09-sc11. doi: 10.7860/jcdr/2016/16026.8866. 13. american academy of ophthalmology. refractive errors & refractive surgery ppp: 2013. from: www.aao.org/preferredpractice-pattern/refractive-errors--surgery-ppp-2013 accessed: aug 2016. 14. jessa z, evans b, thomson d, rowlands g. vision screening of older people. ophthalmic physiol opt 2007; 27:527–46. doi: 10.1111/j.1475-1313.2007.00525.x. 15. kumah db, lartey sy, amoah-duah k. presbyopia among public senior high school teachers in the kumasi metropolis. ghana med j 2011; 45:27–30. doi: 10.4314/gmj.v45i1.68919. 16. laviers hr, omar f, jecha h, kassim g, gilbert c. presbyopic spectacle coverage, willingness to pay for near correction, and the impact of correcting uncorrected presbyopia in adults in zanzibar, east africa. invest ophthalmol vis sci 2010; 51:1234–41. doi: 10.1167/iovs.08-3154. 17. sherwin jc, keeffe je, kuper h, islam fm, muller a, mathenge w. functional presbyopia in a rural kenyan population: the unmet presbyopic need. clin exp ophthalmol 2008; 36:245–51. doi: 10.1111/j.1442-9071.2008.01711.x. 18. schachar ra. the mechanism of accommodation and presbyopia. int ophthalmol clin 2006; 46:39–61. 19. [no authors listed]. women need reading glasses for different reasons than men. harv womens health watch 2012; 20:8. 20. abahussin m, alanazi m, ogbuehi kc, osuagwu ul. prevalence, use and sale of contact lenses in saudi arabia: survey on university women and non-ophthalmic stores. cont lens anterior eye 2014; 37:185–90. doi: 10.1016/j. clae.2013.10.001. 21. [no authors listed]. the epidemiology of dry eye disease: report of the epidemiology subcommittee of the international dry eye work shop (2007). ocul surf 2007; 5:93–107. doi: 10.1016/s1542-0124(12)70082-4. 22. hansen ab, stayner l, hansen j, andersen zj. night shift work and incidence of diabetes in the danish nurse cohort. occup environ med 2016; 73:262–8. doi: 10.1136/ oemed-2015-103342. 23. bahijri sm, jambi ha, al raddadi rm, ferns g, tuomilehto j. the prevalence of diabetes and prediabetes in the adult population of jeddah, saudi arabia: a community-based survey. plos one 2016; 11:e0152559. doi: 10.1371/journal. pone.0152559. 24. jessa z, evans bj, thomson dw. the development & evaluation of two vision screening tools for correctable visual loss in older people. ophthalmic physiol opt 2012; 32:332–48. doi: 10.1111/j.1475-1313.2012.00919.x. 25. peterseim mm, papa ce, wilson me, davidson jd, shtessel m, husain m, et al. the effectiveness of the spot vision screener in detecting amblyopia risk factors. j aapos 2014; 18:539–42. doi: 10.1016/j.jaapos.2014.07.176. 26. aljohani nj. metabolic syndrome: risk factors among adults in kingdom of saudi arabia. j family community med 2014; 21:170–5. doi: 10.4103/2230-8229.142971. 27. harvey em. development and treatment of astigmatismrelated amblyopia. optom vis sci 2009; 86:634–9. doi: 10.1097/ opx.0b013e3181a6165f. https://doi.org/10.7860/jcdr/2016/16026.8866 https://doi.org/10.1111/j.1475-1313.2007.00525.x https://doi.org/10.4314/gmj.v45i1.68919 https://doi.org/10.1167/iovs.08-3154 https://doi.org/10.1111/j.1442-9071.2008.01711.x https://doi.org/10.1016/j.clae.2013.10.001 https://doi.org/10.1016/j.clae.2013.10.001 https://doi.org/10.1016/s1542-0124%2812%2970082-4 https://doi.org/10.1136/oemed-2015-103342 https://doi.org/10.1136/oemed-2015-103342 https://doi.org/10.1371/journal.pone.0152559 https://doi.org/10.1371/journal.pone.0152559 https://doi.org/10.1111/j.1475-1313.2012.00919.x https://doi.org/10.1016/j.jaapos.2014.07.176 https://doi.org/10.4103/2230-8229.142971 https://doi.org/10.1097/opx.0b013e3181a6165f https://doi.org/10.1097/opx.0b013e3181a6165f squ med j, november 2011, vol. 11, iss. 4, pp. 497-502, epub. 25th oct 11 submitted 17th may 11 revision req. 19th jul 11, revision recd. 20th aug 11 accepted 14th sep 11 departments of 1anatomical sciences & neurobiology, 2behavioural & social science and 3physiology, oman medical college, sohar, oman. corresponding author email: drpakumar@yahoo.com تسجيل جراحة البطن باملنظار كمكمل لطرق ّ يانيِ التدريس التقليدية يف علم التشريح العيِ بانانغات كومار، مارك نوري�س، توما�س هيمنج امللخ�س: الأهداف: حتتاج اأ�ضاليب تدري�س العلوم املورفولوجية من اأجل زيادة فعاليتها اإىل تنقيح لدمج التقدم التكنولوجي احلديث ه تف�ضل يف كثري من يٌح امُلَوجَّ مبيدان الطب فيها. تدري�س الرتكيبة الب�رسية بالطرق التقليدية لوحدها بوا�ضطة ا�ضتخدام عينة من الَت�رسرْ اأ�ضلوب التعلم الذاتي ثلثي الأبعاد املكانية ودمج الت�رسيح الأحيان لإعداد الطلب ب�ضكل كاف لتدريبهم ال�رسيري. املطلوب ا�ضتخدام لعملية ملدة 30 دقيقة بطيء ب�ضكل فيديو ت�ضجيل مت العتبار، يف التحديات هذه اأخذ مع الطريقة: ال�رسيري. الإعداد مع اأوثق ب�ضكل اأجريت وقد واحلو�س. البطن لت�رسيح التقليدي التعليم لتكملة وا�ضتعماله 54 عاما عمرها ل�ضيدة املنظار بجراحة املرارة ا�ضتئ�ضال هذه الدرا�ضة يف اأكتوبر 2010. النتائج: كان عدد امل�ضاركني يف هذه الدرا�ضة 48 طالبا يف ال�ضنة الوىل من درا�ضتهم الطبية يف م�ضاق الت�رسيح يف كلية طب ُعمان اخلا�ضة. مت احل�ضول على ملحظاتهم من خلل ا�ضتبيان، وتبني اأن عر�س الفيديو �ضاعد الطلب على اإدراك اأهمية تعلم التفا�ضيل الت�رسيحية خلل م�ضاق الت�رسيح. اخلال�صة: يعترب ت�ضجيل عمليات البطن اجلراحية باملنظار طريقة فعالة لتدري�س للت�رسيح ال�رسيرية الأهمية مدى تقدير على الطلب ت�ضاعد اأنها كما للطالب. الذاتي التعلم يف مهم وم�ضدر ال�رسيري قبل ما الت�رسيح العياين وتعزيز دوافعهم للتعلم. الكلمات الرئيسية : ت�ضجيل جراحة البطن باملنظار، ت�ضجيل فيديو، جتويف البطن، التعليم الطبي. abstract: objectives: in order to increase their effectiveness, methods of teaching morphological sciences need to be revised to incorporate the recent technological advances made in the field of medicine. teaching human structure with conventional methods of prosections using dissected cadaveric specimen alone quite often fails to prepare students adequately for their clinical training. a learner-oriented method, incorporating three dimensional spatial anatomy and more closely mirroring the clinical setting, is required. methods: with these challenges in mind, a 30-minute slow-paced video recording of a cholecystectomy performed laproscopically on a 45 year-old lady was adapted to supplement the conventional teaching of anatomy of the abdomen and pelvis. this study was carried out in october 2010. results: the subjects of this study were 84 students in a first year preclinical md course in human structure at the private oman medical college. their feedback was obtained via questionnaire and revealed that the video presentation helped the students to realise the significance of the anatomical details learnt during the human structure course. conclusion: recordings of laparoscopic surgeries are an effective preclinical anatomy teaching resource in student-centred learning. they also help the students to appreciate the clinical relevance of gross anatomy and enhance their motivation to learn. keywords: laparoscopic surgery recordings; video recording; abdominal cavity; medical education. brief communication laparoscopic surgery recording as an adjunct to conventional modalities of teaching gross anatomy *pananghat a. kumar,1 mark norrish,2 thomas heming3 recent technological advances have revolutionised the realm of patient care and led to remarkable changes in the nature of anatomical knowledge required by a clinician. it has therefore become necessary to review teaching strategies to ensure that these newly desired learning outcomes are addressed. although the curricula used in medical schools worldwide are diverse, the level of anatomical knowledge required to become an efficient clinician remains agreed upon. until recently, the conventional method of learning the subject by dissection of human cadavers and didactic lectures has served its purpose. with the advent of modern surgical techniques and interventional devices, the nature of living anatomy required for a medical laparoscopic surgery recording as an adjunct to conventional modalities of teaching gross anatomy 498 | squ medical journal, november 2011, volume 11, issue 4 student has changed immensely.1 there has also been a growing tendency to replace the hours of dissection with prosected specimens, anatomical models and simulated procedures as a result of the dearth of conventional learning resources including cadaveric material, and the reduction in time allotted to anatomy teaching. it has been suggested that this reduced attention to anatomy has resulted in a situation, in many medical schools, where undergraduate education in anatomy is below the minimum necessary for safe medical practice.2 this has led to calls for the 21st century curriculum to move from the passive, didactic and highly detailed courses that used to be taught towards more functionally and clinically relevant modes of teaching.3 the introduction of a laparoscopic video presentation into a preclinical anatomy course is one example of this trend. whatever the methods used to teach anatomy, it is very clear that the learner needs to comprehend the three-dimensional structure and the spatial relations of the organs in as live a manner as possible in order to apply this knowledge in later clinical practice.4 radiological images and videos of laparoscopic procedures seem to be resources of choice to address this issue. laparoscopic training using embalmed cadavers has been used in some schools of medicine,5 but it has mainly been centered on reviewing basic anatomy for clinical students and residents in specific specialities and principally designed to develop laparoscopic skills in surgical trainees.6,7 the main hindrance to this method has been the fact that the cadaveric material does not show the flexibility of tissue and the liveliness of the organs. to circumvent this problem, thiel embalmed cadavers that maintain the colour, consistency and flexibility of a live body, and avoid rigor mortis changes, have been used to simulate minimally invasive techniques and to review the clinical trainees’ knowledge of anatomy.6,8 however, information regarding the structured use of laparoscopic surgery to teach preclinical students seems to be scanty. in an attempt to enhance the learning outcomes of preclinical students, it was decided to test the use of a video of a laparoscopic procedure to supplement the conventional methods employed in teaching anatomy of the abdomen and pelvis to preclinical students in a private medical school in oman. methods eighty-four students took part in this study as part of their regular teaching programme: a mandatory course in human structure (anatomy) in their first preclinical year of medical studies. all of the students were enrolled in a full time degree in medicine (md), after three years of premedical studies. the study was carried out during october 2010. it was part of ongoing research into improving teaching and learning in medical education and, as such, conformed to all of the ethical requirements and had the approval of the institutional review panel for ethics. a video of a cholecystectomy performed laparoscopically on a 45 year-old lady was used to supplement the module on the anatomy of the abdomen and pelvis. the laparoscopic procedure had previously been explained to the patient and informed consent obtained to use the video for teaching medical students. the video presentation, which lasted approximately thirty minutes, was preceded by a lecture introducing laparoscopic surgery and the steps involved in it. in the first part of the video, prior to the surgery and soon after establishing the pneumoperitoneum, the consultant surgeon scanned the abdomen of the patient with the camera to provide a ‘laparoscopic excursion’ of the abdominal cavity thereby demonstrating the general anatomy of the region and the disposition of the viscera in situ. the video showed the abdominal surface of the diaphragm and subsequently the anterior abdominal wall, the general outlay of the peritoneum and the disposition of the abdominopelvic organs. the video was presented at a slow pace, with frequent pauses and with a live commentary on the structures seen, allowing time for the students to observe and appreciate all the major structures within the abdominal cavity in situ. these included the greater omentum, the lesser omentum and the abdominal organs and also the major pelvic organs. peristalsis of the intestines, the ureter and the pulsations of the mesenteric arteries were all clearly visible and well appreciated in the video. in the second part of the video, the gall bladder surgery highlighted the detailed anatomy of the extra hepatic biliary system. thus the anatomy of the cystic duct, biliary duct and common bile duct as well as the cystic artery was clearly visualised. pananghat a. kumar, mark norrish and thomas heming brief communication | 499 feedback from the students regarding the effectiveness of this presentation as a means of enhancing the understanding of the normal anatomy of the abdomino-pelvic cavity was obtained by means of a questionnaire with four sections. three were in the form of direct questions on: 1) appreciation of specific organs; 2) functional anatomy of some abdominal structures, and 3) general comments on the overall effectiveness of the programme. the students were requested to register their understanding on a five point likert scale ranging from ‘not at all’ to ‘excellently well’. in the fourth part of the questionnaire, students provided written comments on the programme itself. the responses were analysed and the data are presented below. results the majority of students felt that this teaching paradigm had broadened their perspective (excellent = 51%), had contributed to different areas of study (excellent = 56%), and had improved the quality of the module on the abdomen and pelvis (excellent = 57%) [figure 1]. as to their ability to appreciate the individual structures, students also had a very positive response, with outcomes of ‘very well’ or ‘excellently well’ for all 16 structures in the video. particularly high scores were given for the structures of concern in this surgery with the vast majority of students considering them as ‘very well’ or ‘excellently well’ appreciated, for example liver (89%) and gall bladder (85%). figure 2 shows the composite responses for the groups of structures involved at the site of surgery, the structures seen during the ‘laparoscopic excursion’ and the examples of ‘living anatomy’. of particular importance was the opportunity for students to see ‘living anatomy’ in the case of peristalsis of the intestines (excellent = 58%), pulsation of the mesenteric arteries (excellent = 27%) and peristalsis of the ureter (excellent = 39%). the complete set of responses can be seen in table 1. the written feedback from students was very supportive of these findings. forty of the 84 students (48%) provided written feedback. content analysis on the responses to these open questions revealed four main content categories. the most common was the general theme of “thank you” or “it was very good”. the next most frequent content category was comments requesting that laparoscopic video teaching be used more frequently in the course and repeated in the future (45% of respondents). the third content category was that the activity had provided them with clear insight into functional anatomy in a living patient (40% of respondents). the final category was that the activity had helped them to understand the relative positions and spatial relations of the various structures better (23% of respondents). in addition to these four main categories which emerged from the content analysis, there was a variety of individual comments, for example that the activity “provided some variety” to the usual didactic teaching and that the activity “was motivating”. one of the most insightful comments was that this “was the only time there has been complete silence in the lecture hall”. discussion this programme provided the preclinical students with the opportunity to observe in situ the live position and spatial relations of abdominopelvic 0 10 20 30 40 50 60 70 not at all fairly well well very well excellently well broadens your perspective contributes to different areas of study improves quality of the module pe rce nta ge of st ud en ts figure 1: student responses for overall opinions on the video. 0 10 20 30 40 50 60 70 not at all fairly well well very well excellently well site of surgery laparoscopic excursion living anatomy pe rce nta ge of st ud en ts figure 2: composite student responses for the items related to the surgery, the 'laparoscopic excursion' and the 'living anatomy' items. laparoscopic surgery recording as an adjunct to conventional modalities of teaching gross anatomy 500 | squ medical journal, november 2011, volume 11, issue 4 organs. additionally, the students could visualise the peristalsis of the intestines and the ureter and the pulsations of the arteries thus appreciating the dynamic anatomy of these regions. routine cadaveric dissections do not offer the unique aspects which this programme provides to the learner. the conventional method of teaching anatomy through cadavers, either by dissections or prosections, helps them to understand the interrelationships of the structures. nevertheless, it does not give the learner the correct concept regarding the nature and appearance of these structures as living structures. in the conventional learning setting, the preclinical students must wait until they begin their surgery rotation before getting the opportunity to appreciate this all-important aspect of the human body. in the present context, an exposure to the annotated video-surgery has provided these students with the opportunity of appreciating the clinical relevance of the details of anatomy that are learned during the course of human structure. in this respect, this programme has achieved the goals of present day teaching of anatomy, as spelt out by shaffer.1 to our knowledge, laparoscopic surgery has not previously been used in an organised way to augment the learning outcomes of preclinical students. it is clear that students rated this exercise very highly as is reflected by both their numeric responses and their written feedback. this programme broadened their perspective and improved their learning of the anatomy of the abdomen as well as enhancing the quality of the module. the written comments of students were very supportive of the use of laparoscopic surgery recordings. invariably all of them appreciated the efforts taken to show them the video where they could ‘peek into’ the abdominal cavity of a patient. many of them wanted to see videos of other anatomical areas during their course on human structure as it would help them to appreciate living anatomy better. in the past, attempts have been made to review the anatomical knowledge of clinical trainees using laparoscopy on embalmed cadavers.5,9,10 although those learners had the privilege of developing dexterity using the tools on the cadaver, the programme lacked the effects achieved by viewing the live organs in situ, which is attained through the video demonstration of a surgical procedure. table 1: student responses for each item in the questonnaire structure/ item not at all fairly well well very well excellently well structure at the site of surgery liver 0 1 8 30 45 gall bladder 1 2 10 21 50 cystic duct 5 3 19 22 32 stomach 1 2 9 24 45 coils of the intestine 11 12 15 19 24 appendicitis piploicae 9 9 15 22 23 taneai coli 9 9 15 22 23 ascending coli 5 6 16 26 26 vermiform appendix 9 6 6 26 34 cecum 5 5 13 22 26 transverse colon 5 6 14 26 27 sigmoid colon 10 12 12 27 18 structures seen on 'laparoscopic excursion' urinary bladder 15 5 12 26 20 fallopian tube 7 8 6 27 33 ovary 7 7 5 28 31 falciform ligament 10 13 9 20 30 living anatomy peristalsis of the intestines 2 5 6 18 49 pulsation of the mesenteric arteries 10 14 15 14 23 peristalsis of the ureter 9 12 9 13 33 student's views of the video broadens your perspective 0 0 8 32 41 contributes to different areas of study 0 0 6 29 45 improves quality of the module 0 0 0 26 45 pananghat a. kumar, mark norrish and thomas heming brief communication | 501 academic use of laparoscopic surgery recordings has previously been restricted to those used for training surgeons and quite often these procedures have been performed on laboratory animals in an effort to impart the techniques and dexterity to the surgeons in the making.11 the possibility of using laparoscopic recordings for academic purposes was suggested in a review article, but so far there have been no reports of their organised use in an academic setting for preclinical medical training.12 nowadays, there is a need to use innovative teaching methods to instill enthusiasm and positive learning attitudes in students. videos of laparoscopic procedures, a valuable teaching resource, can be obtained without inconveniencing the patient since almost all such procedures are routinely recorded by surgical teams; it therefore requires neither extra time and effort nor any additional cost. routinely recorded surgeries can be used in emphasising the spatial relationship of organs. moreover, exposure to such surgical procedures enables the preclinical students to appreciate the relevance of anatomy learnt during the course of human structure to the practice of clinical medicine. such awareness renders the learning process more useful and meaningful. this learning experience also provides an opportunity early in their career, for students to consider their future speciality and the field for their residency programme. overall, this programme has proved to be a useful adjunct to the conventional method of learning morphological sciences. the entire course content of the anatomy of abdomen and pelvis cannot, however, be taught through laparoscopic videos alone. it is understood that these videos, when properly used, become a valuable adjunct to the conventional teaching of gross anatomy, enhancing the appreciation of living anatomy of the region. it should be possible to choose appropriate laparoscopic surgery recordings to supplement the understanding of the anatomy of specific areas such as: laparoscopic cholecystectomy, herniorrhaphy, appendectomy, salpingectomy, and removal of the fibroids from the uterus. recordings of such surgeries are available on the internet and could be readily used to supplement conventional teaching;13 however, the video used in the present context was unique since it was specifically recorded to enhance the learning of preclinical students. it amply served its purpose. with the advent of recent technological advances in the field of medicine, it becomes necessary for medical educators to equip the students with tools for self-directed learning. this will help them to keep pace with the current trends in clinical sciences and to stay abreast of the developments in continuing medical education once they graduate. conclusion the students’ responses in the present study were positive enough to recommend that selected videos of laparoscopic procedures be used more widely in order to make the teaching of anatomy more interesting and relevant to clinical medicine. encouraged by this experience, it is tempting to suggest that this modality of teaching may be incorporated as a standard element into the preclinical academic programme. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g e m e n t we gratefully acknowledge the help of dr p. vasudevan, consultant laparoscopic surgeon, coimbatore, india, who provided us with the recording of laparoscopic surgery that was used in this research. references 1. shaffer k. teaching anatomy in the digital world. n engl j med 2004; 351:1279–81. 2. waterston sw, stewart ij. survey of clinicians’ attitudes to the anatomical teaching and knowledge of medical students. clin anat 2005; 18:380–4. 3. turney bw. anatomy in a modern medical curriculum. ann r coll surg engl 2007; 892: 104–7. 4. collins jp. modern approaches to teaching and learning anatomy. student bmj 2008; 16:402–3. 5. fitzpatrick cm, kolesari gl, brasel kj. teaching anatomy with the surgeons’ tools: use of laparoscope in clinical anatomy. clin anat 2001; 14:349–53. 6. gogalniceanu p, madani h, paraskeva pa, darzi a. a minimally invasive approach to undergraduate anatomy teaching. anat sci edu 2008; 1:46–7. 7. cundiff gw, weider ac, visco ag. effectiveness of laparoscopic cadaveric dissection in enhancing resident comprehension of pelvic anatomy. j am coll surg 2001; 192:492–7. laparoscopic surgery recording as an adjunct to conventional modalities of teaching gross anatomy 502 | squ medical journal, november 2011, volume 11, issue 4 8. pattanshetti vm, pattanshetti sv. laparoscopic surgery on cadavers: a novel teaching tool for surgical residents. anz j surg 2010; 80:676–8. 9. anderson d, duggan n, al-ali s, windsor j. a study of different methods for visualizing anatomy laparoscopically in embalmed cadavers. j anat 2004; 204:238. 10. glasgow sc, tiemann d frisella mm, conroy g, klingensmith m. laparoscopy as an educational and recruiting tool. am j surg 2006; 191:542–4. 11. jimenez am, aquilar jf. laparoscopy: learning a new surgical anatomy? anat sci educ 2009; 2:81–3. 12. ganguly pk, chan lk. living anatomy in the 21st century: how far can we go? south east j med ed 2008; 2:52–7. 13. laparoscopic surgery videos. from: http://www. onlinemedical.com.au/ and http://videosurgery. com/ accessed: sep 2011. sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e376–381, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.012. submitted 30 dec 14 revision req. 19 mar 15; revision recd. 22 mar 14 accepted 19 apr 15 departments of 1pharmacology & therapeutics, 2physiology and 3anatomy, arabian gulf university, manama, bahrain *corresponding author e-mail: yasin.tayem@gmail.com رأي طالب الطب بتقييم زمالئهم ضمن منهاج مبين على حل املشكالت يا�سني تيم، هرني جيم�س، خالد اخلاجة، رميا عبد الرزاق، بهاجاث بوتو، ريجينالد �سكويرا abstract: objectives: peer assessment (pa) is believed to support learning and help students develop both professionally and personally. the aim of this study was to examine medical students’ perceptions of intragroup pa in a problem-based learning (pbl) setting. methods: this study was carried out between september and november 2014 and involved six random groups of fourth-year undergraduate medical students (n = 60) enrolled at the arabian gulf university in manama, bahrain. while working on set tasks within a curriculum unit, each student evaluated a randomly selected peer using an english language adapted assessment tool to measure responsibility and respect, information processing, critical analysis, interaction and collaborative skills. at the end of the unit, students’ perceptions of pa were identified using a specifically-designed voluntary and anonymous selfadministered questionnaire in english. results: a total of 55 students participated in the study (response rate: 92%). the majority of students reported that their learning (60%), attendance (67%), respect towards group members (70%) and participation in group discussions (71%) improved as a result of pa. regarding problem analysis skills, most participants believed that pa improved their ability to analyse problems (65%), identify learning needs (64%), fulfil tasks related to the analysis of learning needs (72%) and share knowledge within their group (74%). lastly, a large proportion of students reported that this form of assessment helped them develop their communication (71%) and self-assessment skills (73%), as well as collaborative abilities (75%). conclusion: pa was well accepted by the students in this cohort and led to self-reported improvements in learning, skills, attitudes, engagement and other indicators of personal and professional development. pa was also perceived to have a positive impact on intragroup attitudes. keywords: peer group; educational assessment; self-assessment; perception; medical students; problem-based learning; bahrain. امللخ�ص: الهدف: يعترب تقييم الطلبة ألقرانهم حمفزا لهم على تنمية مهاراتهم ال�سخ�سية و املهنية. الهدف: درا�سة ت�سورات طالب الطب لعملية تقييم أداء زمالئهم �سمن جمموعات يف منهاج يعتمد على حل امل�سكالت. الطريقة: مت إجراء هذه الدرا�سة من �سهر �سبتمرب حتى نوفمرب2014 حيث مت جمع البيانات من �ست جمموعات من طلبة ال�سنة الرابعة يف كلية الطب الب�رسي يف جامعة اخلليج العربي، املنامة، مملكة البحرين )عدد= 60(. خالل التعلم �سمن جمموعاتهم يف وحدة معينة من املنهاج طلب من كل طالب يف املجموعة تقييم أداء زميله با�ستخدام أداة تقييم باللغة الجنليزية مت ت�سميمها خ�سي�سا لهذا الهدف. ا�ستملت األداة على تقييم الطلبة من حيث امل�سوؤولية والحرتام، معاجلة املعلومات، التحليل النقدي، التفاعل، و التعاون مع املجموعة. يف نهاية الوحدة التجريبية قام الطلبة امل�ساركون بتعبئة ا�ستبانة باللغة اإلجنليزية عربوا من خاللها عن رأيهم يف هذه التجربة. النتائج: غالبية الطلبة اعتقدوا أن هذا التقييم �ساهم يف حت�سن التعلم لديهم )%60(، ن�سبة ح�سورهم اللقاءات )%67(، احرتامهم لزمالئهم )%70( و م�ساركتهم يف النقا�س �سمن جمموعاتهم )%71(. معظم امل�ساركني اعتربو أن هذا التقييم أدى اىل تطور يف قدرتهم على حتليل املع�سالت )%65(، حتديد األهداف التعلمية )%64(، الوفاء باملهام املتعلقة بتحليل أهداف التعلم املن�سودة )%72(، و تبادل املعلومات مع جمموعاتهم )%74(. اأخريا ن�سبة كبرية من امل�ساركني أعتربو ان تقييمهم عرب اخلال�صة: .)73%( الذاتي التقييم و )75%( التعاونية القدرات ،)71%( الت�سال مهارات يف لديهم ملحوظ حت�سن إىل أدى لزمالئهم الطالب امل�ساركون عن ر�ساهم عن هذه التجربة و اأن تقييمهم ألقرانهم أدى إىل تقدم كبري يف عملية التعلم واملهارات وال�سلوك لديهم و مدى انخراطهم يف جمموعاتهم، و تطور على امل�ستوى ال�سخ�سي و املهني وتاأثري ايجابي على �سلوك املجموعات. مفتاح الكلمات: جمموعة الطلبة؛ التقييم الرتبوي؛ التقييم الذاتي؛ الت�سور؛ طالب الطب؛ التعلم املبني على حل امل�سكالت؛ البحرين. medical students’ perceptions of peer assessment in a problem-based learning curriculum *yasin i. tayem,1 henry james,1 khalid a. j. al-khaja,1 rima l. a. razzak,2 bhagath k. potu,3 reginald p. sequeira1 advances in knowledge peer assessment (pa) could be a valuable approach to improving self-directed learning and engagement in the educational process among medical students. the results of this study found that pa helped groups of fourth-year undergraduate medical students in bahrain develop their analytical, collaborative and communication skills in a problem-based learning curriculum. clinical & basic research yasin i. tayem, henry james, khalid a. j. al-khaja, rima l. a. razzak, bhagath k. potu and reginald p. sequeira clinical and basic research | e377 application to patient care different types of learning models need to be investigated to determine which are most effective in medical education, as this will affect future patient care. information processing, critical analysis, communication and collaborative skills are important in the medical profession. pa is likely to improve the interpretation of patient complaints, physical findings and results of investigations in future clinical practice. problem-based learning (pbl) has rapidly found its way into all health science-related education. currently, the vast majority of medical schools worldwide have integrated pbl into their curricula.1 the worldwide implementation of this student-centred approach has opened an avenue to the development of innovative methods of evaluation, including self-assessment and peer assessment (pa).2 in higher education, pa is a strategy whereby students actively engage in evaluating their peers using standard assessment criteria.3 in most cases, this type of assessment takes place in a group context and typically takes one of three forms: intragroup (each member of a group assesses the performance of another individual within the same group), intergroup (one or more members in a group evaluate the performance of another group) and extra group (individuals who are not group members assess the performance of a group).4 since pa and pbl both emphasise a student-centred approach, student peer evaluation seems to be an appropriate assessment tool for a pbl-based curriculum. kritikos et al. evaluated pa in an undergraduate pharmacy curriculum and found that it provided an opportunity for the development of a variety of skills, including self-directed learning, collaboration, critical analysis, professional judgment and teamwork.5 selfassessment may also be learnt concurrently with pa, since the skills needed to evaluate a colleague’s performance may also be applied to oneself; this creates a unique opportunity for students to evaluate their own strengths and weaknesses.6 despite growing evidence of the benefits of pa in education, some studies have shown that this form of assessment is negatively received by students.7 other investigations have criticised the reliability of pa and raised doubts about its contribution to the overall assess ment process.6,8 pbl is the primary learning approach used to teach students undertaking a six-year medical programme at the arabian gulf university (agu) in manama, bahrain.9 however, the use of pa in the context of small group learning has not yet been introduced at agu or among any other medical schools in the unique cultural setting of the gulf cooperative council (gcc) region. this study therefore aimed to develop and implement a process of intragroup pa among groups of medical students taking part in pbl tutorials at agu. students’ self-reported perceptions of pa and its impact on skill development were assessed, including any improvements in self-directed learning, critical analysis, professional growth, teamwork, collaboration and self-assessment. methods this study was conducted between september and november 2014. at the time of the study, there were approximately 950 students enrolled in the six-year agu undergraduate medical programme during the academic year 2014–2015; of these, 140 were in their fourth year of study and were divided into 14 groups of 10 students each. six groups were randomly chosen for inclusion in the study as they were considered representative of all 14 groups in this year. fourthyear students were selected for the study since they had experienced pbl for three preceding years and were thus deemed capable of assessing their peers in a pbl context. fifthand sixth-year students were not suitable for the purposes of the study as they were clinical students and no longer took pbl tutorials. all students were accepted into the undergraduate medical programme after successfully completing high school in their countries of residence with excellent grade point averages and passing an english language test and a personal interview. pa was introduced to the participating groups in the last four problems of the musculoskeletal and integumentary unit of the curriculum. this course typically enrols approximately 120–140 fourth-year medical students every academic year; these students are divided into small groups of 10 students. a total of 140 students participated in this unit between october and november 2014, engaging in twice weekly pbl tutorials. during the first tutorial of the week, students discuss a clinical case scenario and reach their learning needs facilitated by a tutor. during the second session, the group gathers and students present the information they have collected over that week to address their learning requirements. at the end of their second pbl tutorial, students were asked to evaluate the weekly performance of a randomly selected peer in their group using an evaluation form. by the end of each problem, every medical students’ perceptions of peer assessment in a problem-based learning curriculum e378 | squ medical journal, august 2015, volume 15, issue 3 this study was granted ethical approval by the agu research & ethics committee. all participants were informed of the purpose and nature of the study before inclusion and were advised that their participation was anonymous and voluntary. results a total of 55 medical students in six groups participated in the study (response rate: 92%); of these, 57% were female and 43% were male. the mean age of the students was 22 years old. all participants originated from one of four gcc countries (saudi arabia, bahrain, kuwait or oman). most students reported positive feelings towards the integration of pa in their pbl tutorials [table 1]. of the students, 60% either agreed or strongly agreed that their learning had improved due to pa. with regards to the perceived effect of pa on their own performance, the vast majority of respondents agreed or strongly agreed that pa had improved their self-assessment (73%). students reported that their engagement had improved as a result of their participation in the pa process. most respondents agreed or strongly agreed that their attendance (67%), participation in group discussions (71%) and desire to use more resources to achieve learning needs (64%) had improved. changes in attitudes as a response to pa were also examined. a large proportion of participants agreed or strongly agreed that their respect towards the other group members (70%) and desire to share information with them (74%) had improved. participants also agreed or strongly agreed that they had become more dependable (75%) as a result of pa. the role of pa in the development of problem analysis skills was also investigated. a large percentage of participants agreed or strongly agreed that pa had increased their analytical skills (65%) as well as their ability to achieve their learning objectives (64%) and fulfil tasks related to the analysis of problems (72%). regarding the impact of pa on the development of personal and professional skills, a large percentage of respondents agreed or strongly agreed that their communication skills (71%), collaborative skills (75%) and ability to work as part of a team (69%) had improved as a result of pa. discussion assessment is a major driving force for learning, since it supports and enhances the integration of knowledge and skill acquisition within the educational process. following the introduction of pbl in medical education, several methods of student evaluation have student had evaluated one of their peers and had themselves been evaluated by one of the other group members. assessment criteria used in the peer evaluation form were based on those of das et al. and an assessment tool currently in use by the college of medicine & medical sciences at agu.10 input was also received from experts in the university’s medical education unit. a total of 22 items in the assessment tool covered all of bloom’s taxonomy of learning domains and were divided into four key areas: clinical reasoning skills (cognitive), reflection on practice (cognitive/ affective), teamwork (affective) and presentation (psychomotor).11 specifically, participants evaluated the performance of group members in the following areas: responsibility towards and respect for the tutorial process; information processing and ability to achieve learning requirements; critical analysis of the week’s problem; ability to handle different learning resources; and interaction and collaboration. group members were assessed by their peers in each category on a scale of 1 to 5, with 1 graded as very poor and 5 graded as excellent. to avoid bias, it was emphasised to participants that the outcomes of pa would be used for research purposes only and would not be taken into consideration for their assessment at the end of the experimental unit. after participants had completed their last group member assessments with a facilitator present, they were asked to complete a modified voluntary anonymous self-administered questionnaire.12 this questionnaire sought their opinions on changes in attitudes, learning, analytical and communication and collaborative skills as well as engagement in the learning process as a result of the pa experience. students were given a series of statements to which they had to score their opinions on a 5-point scale, with 1 indicating strongly disagree and 5 indicating strongly agree. a pilot study was conducted to test the appropriateness and comprehensibility of the assessment tool and perception questionnaire. three groups of fourth-year students who were engaged in the experimental unit (n = 10 students each) were asked to read both the assessment form and the questionnaire and identify any unclear terms. no significant modifications were needed except for one unclear word which was clarified accordingly. these three groups were subsequently excluded from participation in the rest of the study. data were entered into a microsoft excel spreadsheet, version 10 (microsoft corp., redmond, washington, usa) and analysed using simple descriptive statistics. yasin i. tayem, henry james, khalid a. j. al-khaja, rima l. a. razzak, bhagath k. potu and reginald p. sequeira clinical and basic research | e379 table 1: self-reported perceptions of the effects of peer assessment among fourth-year medical students in bahrain undergoing a problem-based learning curriculum (n = 55) item n (%) strongly agree agree unsure disagree strongly disagree overall improved learning 14 (25) 19 (35) 15 (27) 2 (4) 4 (7) improved self-assessment 23 (42) 17 (31) 7 (13) 2 (4) 3 (5) learning and engagement improved tutorial attendance 23 (42) 14 (25) 8 (15) 4 (7) 5 (9) improved participation in discussions 24 (44) 15 (27) 8 (15) 4 (7) 4 (7) began to use more resources for finding relevant information 16 (29) 19 (35) 10 (18) 4 (7) 5 (9) attitude more respectful towards group members 25 (45) 14 (25) 9 (16) 4 (7) 2 (4) more keen to share information with group members 20 (36) 21 (38) 6 (11) 4 (7) 3 (5) more dependable 23 (42) 18 (33) 7 (13) 5 (9) 2 (4) problem analysis improved ability to analyse problems 15 (27) 21 (38) 10 (18) 6 (11) 3 (5) more able to reach learning objectives 16 (29) 19 (35) 11 (20) 4 (7) 3 (5) more able to fulfil tasks related to problem analysis 14 (25) 26 (47) 9 (16) 4 (7) 2 (4) communication, teamwork and collaboration improved communication skills 22 (40) 17 (31) 8 (15) 4 (7) 4 (7) improved teamwork 23 (42) 15 (27) 8 (15) 5 (9) 3 (5) more willing to help other group members understand difficult issues 24 (44) 17 (31) 6 (11) 4 (7) 4 (7) evolved including tutor-, peer and self-assessment. however, as wagner et al. reported, it is difficult to demonstrate the value and reliability of the latter two methods of assessment.6 the primary aim of the current study was to examine perceptions of a four-week pa course among six groups of medical students in bahrain. the criteria used for pa in this study focused on peer responsibility and respect as well as information processing, critical analysis and collaborative skills. overall, and in line with previous reports, the results of the current study demonstrated that the vast majority of participating students accepted pa and perceived this method to add value to their learning, motivation and personal and professional growth.13 the majority of participants in the current study believed that their learning improved as a result of pa; this is in agreement with the findings of maas et al., who explored the impact of pa on the acquisition of clinical skills among students in an undergraduate physical therapy course.14 the authors concluded that, despite the fact that participants ranked pa to be less useful than expert assessment, it was still a powerful tool in improving clinical performance.14 the majority of pharmacy students in another study by basheti et al. agreed that anonymous assessment of a peer was a useful learning experience.15 in support of this, garner et al. investigated medical students’ views on pa and found that students were generally positive about the usefulness of pa for their formative learning.16 data from both the current study and the literature therefore clearly demonstrate that pa plays an important role in promoting self-directed learning among students. with respect to motivation and participation in the tutorial process, most students in the current study believed that taking part in pa improved their attendance and engagement in group discussions. these findings were in line with those of casey et al., who reported that the implementation of pa in an undergraduate nursing programme promoted student engagement in the learning process.17 in the current study, a large number of participants believed that pa made them more dependable, respectful to their colleagues and keen to share knowledge with them. in accordance with this, nofziger et al. investigated the professional and personal reactions of students medical students’ perceptions of peer assessment in a problem-based learning curriculum e380 | squ medical journal, august 2015, volume 15, issue 3 conclusion among the studied group of medical students in bahrain, pa was perceived positively and led to selfreported progress in learning and analytical skills. pa also boosted engagement and motivation in the educational process as well as students’ personal and professional development. moreover, pa was believed to have a positive impact on the students’ attitudes towards other members of their group. a c k n o w l e d g e m e n t s the authors would like to express their appreciation to the fourth-year medical students at agu for their cooperation in this study. the valuable support of the facilitators is also gratefully acknowledged. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. azer sa, mclean m, onishi h, tagawa m, scherpbier a. cracks in problem-based learning: what is your action plan? med teach 2013; 35:806–14. doi: 10.3109/0142159x.2013.826792. 2. papinczak t, young l, groves m, haynes m. an analysis of peer, self, and tutor assessment in problem-based learning tutorials. med teach 2007; 29:e122–32. doi: 10.10 80/01421590701294323. 3. falchikov n. involving students in assessment. psych learn teach 2003; 3:102–8. doi: 10.2304/plat.2003.3.2.102. 4. ballantyne r, hughes k, mylonas a. developing procedures for implementing peer assessment in large classes using an action research process. assess eval high educ 2002; 27:427–41. doi: 10.1080/0260293022000009302. 5. kritikos vs, woulfe j, sukkar mb, saini b. intergroup peer assessment in problem-based learning tutorials for undergraduate pharmacy students. am j pharm educ 2011; 75:73. doi: 10.5688/ajpe75473. 6. wagner ml, suh dc, cruz s. peerand self-grading compared to faculty grading. am j pharm educ 2011; 75:130. doi: 10.5688/ ajpe757130. 7. papinczak t, young l, groves m. peer assessment in problembased learning: a qualitative study. adv health sci educ theory pract 2007; 12:169–86. doi: 10.1007/s10459-005-5046-6. 8. machado jl, machado vm, grec w, bollela vr, vieira je. self and peer assessment may not be an accurate measure of pbl tutorial process. bmc med educ 2008; 8:55. doi: 10.1186/14726920-8-55. 9. hamdy h, anderson mb. the arabian gulf university college of medicine and medical sciences: a successful model of a multinational medical school. acad med 2006; 81:1085–90. doi: 10.1097/01.acm.0000246680.82786.76. 10. das m, mpofu d, dunn e, lanphear jh. self and tutor evaluations in problem-based learning tutorials: is there a relationship? med educ 1998; 32:411–18. doi: 10.1046/j.13652923.1998.00217.x. 11. bloom bs, engelhart md, furst ej, hill wh, krathwohl dr. taxonomy of educational objectives: the classification of educational goals. new york, usa: david mckay co., 1956. towards pa and found that two-thirds reported associated changes in their awareness, attitudes or behaviours.18 these findings demonstrated that the evaluation experience helped students to develop personally and professionally and supported their motivation and engagement.18 regarding the impact of pa on critical analysis abilities, the majority of participants in the current study thought that pa helped them improve their problem analysis skills and identification of their learning needs. moreover, most students reported improvement in their collaborative, teamwork and communication skills. kritikos et al. reported that pa helped undergraduate pharmacy students to learn from each other and become more engaged, attentive, reflective, analytical, critical, confident and self-aware.5 ramakrishna et al. described significant progress in students’ professionalism, collaboration, communication and group work in response to the implementation of an evaluation tool that involved pa in addition to selfand faculty assessment.19 these findings emphasise the role of pa in the development of students’ critical analysis skills and integration within their groups. while pa has been shown to be a valuable tool for promoting student learning and professional accountability, many questions related to this evaluation strategy remain unanswered. indeed, concerns about the reliability of pa have been raised.20 therefore, it is of the utmost importance that the implementation of this evaluation process be formally organised so as to maximise its benefits to students and institutions. this may include training students to increase their competence in the pa process, integrating this form of evaluation in the institution’s assessment scheme and encouraging facilitators to support the use of this approach. however, further research is needed to determine whether pa has a significant impact on academic performance. there are several limitations pertaining to this study. first, although the sample was representative of the entire student body of the university, conducting this study with a larger sample might yield more informative results. second, the students’ exposure to pa in this study occurred over a relatively short period of time and during only one unit of their course. a longitudinal study involving the utilisation of pa on multiple occasions and over several years would be potentially more enlightening. finally, the evaluation of learning among the students was only performed at level 1 of kirkpatrick et al.’s learning evaluation model and the effects of pa on future student activities and outcomes were not investigated.21 this may be a focus of future research. http://dx.doi.org/10.3109/0142159x.2013.826792 http://dx.doi.org/10.1080/01421590701294323 http://dx.doi.org/10.1080/01421590701294323 http://dx.doi.org/10.2304/plat.2003.3.2.102 http://dx.doi.org/10.1080/0260293022000009302 http://dx.doi.org/10.5688/ajpe75473 http://dx.doi.org/10.5688/ajpe757130 http://dx.doi.org/10.5688/ajpe757130 http://dx.doi.org/10.1007/s10459-005-5046-6 http://dx.doi.org/10.1186/1472-6920-8-55 http://dx.doi.org/10.1186/1472-6920-8-55 http://dx.doi.org/10.1097/01.acm.0000246680.82786.76 http://dx.doi.org/10.1046/j.1365-2923.1998.00217.x http://dx.doi.org/10.1046/j.1365-2923.1998.00217.x yasin i. tayem, henry james, khalid a. j. al-khaja, rima l. a. razzak, bhagath k. potu and reginald p. sequeira clinical and basic research | e381 12. tayem yi. the impact of small group case-based learning on traditional pharmacology teaching. sultan qaboos univ med j 2013; 13:115–20. 13. burgess a, mcgregor d, mellis c. medical students as peer tutors: a systematic review. bmc med educ 2014; 14:115. doi: 10.1186/1472-6920-14-115. 14. maas mj, sluijsmans dm, van der wees pj, heerkens yf, nijhuis-van der sanden mw, van der vleuten cp. why peer assessment helps to improve clinical performance in undergraduate physical therapy education: a mixed methods design. bmc med educ 2014; 14:117. doi: 10.1186/1472-692014-117. 15. basheti ia, ryan g, woulfe j, bartimote-aufflick k. anonymous peer assessment of medication management reviews. am j pharm educ 2010; 74:77. doi: 10.5688/aj740577. 16. garner j, mckendree j, o’sullivan h, taylor d. undergraduate medical student attitudes to the peer assessment of professional behaviours in two medical schools. educ prim care 2010; 21:32–7. 17. casey d, burke e, houghton c, mee l, smith r, van der putten d, et al. use of peer assessment as a student engagement strategy in nurse education. nurs health sci 2011; 13:514–20. doi: 10.1111/j.1442-2018.2011.00637.x. 18. nofziger ac, naumburg eh, davis bj, mooney cj, epstein rm. impact of peer assessment on the professional development of medical students: a qualitative study. acad med 2010; 85:140–7. doi: 10.1097/acm.0b013e3181c47a5b. 19. ramakrishna j, valani r, sriharan a, scolnik d. design and pilot implementation of an evaluation tool assessing professionalism, communication and collaboration during a unique global health elective. med confl surviv 2014; 30:56–65. doi: 10.1080/13623699.2014.874088. 20. langendyk v. not knowing that they do not know: selfassessment accuracy of third-year medical students. med educ 2006; 40:173–9. doi: 10.1111/j.1365-2929.2005.02372.x. 21. kirkpatrick dl, kirkpatrick jd. transferring learning to behavior: using the four levels to improve performance. 1st ed. san franscisco, california, usa: berrett-koehler publishers inc., 2005. http://dx.doi.org/10.1186/1472-6920-14-115 http://dx.doi.org/10.1186/1472-6920-14-117 http://dx.doi.org/10.1186/1472-6920-14-117 http://dx.doi.org/10.5688/aj740577 http://dx.doi.org/10.1111/j.1442-2018.2011.00637.x http://dx.doi.org/10.1097/acm.0b013e3181c47a5b http://dx.doi.org/10.1080/13623699.2014.874088 http://dx.doi.org/10.1111/j.1365-2929.2005.02372.x sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e530−536, epub. 14th oct 14 submitted 28th feb 14 revision reqd. 16th apr 14; revision recd. 3rd may 14 accepted 15th may 14 departments of 1fundamentals & administration and 2maternal & child health, college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mail: gamandu@squ.edu.om التحديات واالسرتاتيجيات املستخدمة لبناء واستدامة العالقة الفعالة بني املدرس والدارس العالقة ما بني املمرضات جريالد اأماندو ماتوا، فيدايا �سي�سان، رامان �سافيرثاي، دين�س كايابان فروندا abstract: objectives: this study aimed to determine the challenges encountered and strategies used by nurse preceptors to build effective professional relationships during the preceptorship of final year nursing students. methods: this study was conducted in november 2012 at the college of nursing in sultan qaboos university, muscat, oman. a qualitative research design consisting of focus group discussions was used to investigate the challenges that preceptors encounter and the strategies that they use to build effective relationships with preceptees. a total of 21 preceptors from sultan qaboos university hospital participated in the study as part of a training workshop for nurse preceptors. the interviews were audio recorded, transcribed verbatim and thematically analysed. results: the main challenges faced by preceptors included discrepancies in applying theory to practice; lack of trust; lack of time, and perceived lack of knowledge. the effective strategies identified by the preceptors to be used in building a healthy preceptor-preceptee relationship were proper orientation; effective communication; preparation for complex situations; appreciation and acknowledgment; positive feedback; assurance of support; spending time together; knowing preceptors personally; giving breaks, and encouraging self-commitment. conclusion: preceptors should be encouraged to identify challenges that hinder the building of effective relationships with preceptees early during their preceptorship. the incorporation of appropriate and evidenced-based strategies, such as those identified in this study, can transform the preceptorship experience into one that is fulfilling for both preceptors and preceptees. this may lead to greater job satisfaction, personal and professional growth as well as higher self-esteem levels for preceptors and the realisation of clinical objectives for preceptees. keywords: preceptorship; nursing students; mentorship; socialization; communication barriers; oman. امللخ�ص: الهدف: تهدف هذه الدرا�سة اإىل تقدير التحديات واال�سرتاتيجيات املتبعة من قبل مدر�سي التمري�س لبناء عالقات مهنية فعالة خالل مرحلة التدري�س لطلبة ال�سنة االأخرية من التمري�س. الطريقة: اأجريت هذة الدرا�سة يف نوفمرب 2012 بكلية التمري�س، جامعة ال�سلطان قابو�س، م�سقط، عمان. �سمل ت�سميم البحث الكيفي على مناق�سات جماعية للتحقق من التحديات التي تواجه املدر�سني واال�سرتاتيجيات امل�ستخدمة من قبلهم لبناء عالقات فعالة مع الدار�سني. جمموع 21 مدر�س من م�ست�سفى جامعة ال�سلطان قابو�س �ساركوا يف هذه الدرا�سة التي التحديات اأكرث النتائج: وحتليلها. مبح�رض ون�سخها �سوتيا ت�سجيلها مت املقابالت التمري�س. ملدر�سي التدريب ور�سة من كجزء واجهت املدر�سني �سملت التباين يف تطبيق املمار�سات النظرية اإىل عملية، انعدام الثقة، غياب الوقت، اإدراك انعدام املعرفة. اال�سرتاتيجيات والعرفان، والتقدير ال�سكر املعقدة، لالأو�ساع اجليد التح�سري الفعال، التوا�سل اجليد، التوجيه هي املدر�سني عليها تعرف التي الفعالة ال�سخ�سي. االلتزام وت�سجيع ا�سرتاحة فرتات اأعطاء �سخ�سيا، املدر�س معرفة م�سرتكة، اأوقات ق�ساء الدعم، �سمان االإيجابي، االإرجتاع اخلال�صة: يجب ت�سجيع املدر�سني على اإدراك التحديات التي تعيق بناء عالقات فعالة مع الدار�سني يف املراحل االأوىل من التدري�س. دمج اال�سرتاتيجيات املنا�سبة واملبنية على االأدلة مثل امل�سار اإليها يف هذه الدرا�سة �سي�ساعد على حتويل جتربة التدري�س اإىل جتربة متكاملة بالن�سبة للمدر�س والدار�س. هذا �سيوؤدي اإىل زيادة الر�سا الوظيفي، والنمو املهني وال�سخ�سي، واأرتفاع معدل الثقة عند املدر�س و اإدراك اأهداف التدريب ال�رضيري لدى الدار�سني. مفتاح الكلمات: مرحلة التدري�س؛ طلبة التمري�س؛ االإر�ساد؛ التن�سئة االجتماعية؛ موانع االت�سال؛ عمان. challenges and strategies for building and maintaining effective preceptor-preceptee relationships among nurses *gerald a. matua,1 vidya seshan,2 raman savithri,2 dennis c. fronda1 clinical & basic research advances in knowledge this study highlights the challenges encountered in establishing preceptor-preceptee relationships. these obstacles negatively affect clinical teaching practices for the preceptors and skill acquisition on the part of the preceptees. remedial strategies are presented in this study to encourage relationship-building efforts between preceptors and preceptees within the prevailing sociocultural environment of oman. application to patient care understanding and addressing preceptors’ unique challenges in preceptorship relationship-building is vital for patient care. preceptees gerald a. matua, vidya seshan, raman savithri and dennis c. fronda clinical and basic research | e531 preceptorship refers to the transitional process that many final year nursing students undergo as they enter into the workplace and is designed to help them function as qualified professionals in a clinical setting.1,2 this has become an alternative teaching method to the traditional clinical approach that is still used in some nursing programmes.3 within nursing, preceptorship occurs as part of the regular clinical working hours.4 senior students are assigned to experienced nurses who guide, act as role models for and support the students on a one-to-one basis.5,6 preceptorship facilitates the development of the preceptees’ clinical knowledge and skills as well as their attainment of professional competencies, to ensure they are fit to enter professional practice after they have concluded their supervised clinical practice.2,4 this approach bridges the gap between theory and practice and reduces the potential ‘reality shock’ that occurs when preceptees enter the work force for the first time.7,8 preceptorship is effective if it promotes learning and supports the development of future generations of health professionals by exposing preceptees to unique learning opportunities. it also helps to orientate them to the prevailing work environment and its culture.8 successful preceptorship programmes enable preceptees to settle into clinical placements quickly and gain greater confidence in their clinical skills.9 if successfully implemented, the preceptorship experience is rewarding for both preceptors and preceptees. a successful preceptorship experience may positively influence preceptees to remain in the nursing profession for the entire length of their careers, while for preceptors it may enhance the enjoyment of their role and bring greater job satisfaction.10,11 success for both preceptors and preceptees may also mean personal and professional growth as well as higher self-esteem and confidence levels.12,13 effective preceptorship has also been linked to more positive patient outcomes through the carryover effect of enhanced student competencies.14 additionally, a rewarding preceptorship experience may also result in the continued mentorship of the preceptee by the preceptor, maintaining their support and contributing to the preceptee’s long-term professional growth and development.4 however, any significant challenges encountered during the preceptorship period tend to undermine the realisation of the full potential of this approach for both the preceptors and preceptees.5,8 the literature on this topic has highlighted a number of challenges encountered by preceptors, including high workload; lack of support from peers; inadequate preparation for taking on the role of preceptor; lack of time spent with the student; lack of support from and ineffective communication with the faculty, and being made to feel responsible for the preceptee’s success or failure.8,14–16 in oman, preceptorship in nursing is implemented at the sultan qaboos university hospital (squh) in muscat, a tertiary hospital that emphasises teaching, service, research and leadership development within the country and surrounding region. squh is accredited by both the international organization for standardization and accreditation canada international. the hospital is served by over 1,200 registered nurses. as a teaching hospital for medical, nursing and health science students, preceptors play an important role in facilitating clinical training for the students. in the case of nursing, preceptors are selected on the basis of their educational qualifications and experience; the minimum requirements include a diploma and at least three years of clinical experience. through the use of a specially designed course known as the advanced clinical nursing course, the preceptors at squh play an important role in aiding final year nursing students at the college of nursing of sultan qaboos university (squ) to transition from the role of student to professional. each student is assigned to a preceptor during their last semester and squh and the college of nursing at squ mutually collaborate to ensure these preceptors are supported and trained for this vital role. although preceptorship arrangements at squh have been in place since 2003, there are no published studies in oman to date highlighting the challenges preceptors encounter when implementing this approach. understanding such challenges is vital because problems experienced during this period can negatively affect the clinical teaching and preceptorship experience, leading to preceptor fatigue, frustration and burnout as well as insufficient support and guidance for preceptees.8,16 this study therefore who have supportive preceptor-preceptee relationships often become more competent nurses, leading to better patient outcomes. the results of this study will help identify areas for improvement in the preceptorship of final year nursing students. this study indicates that when challenges hindering preceptorship relationships are identified, preceptors should implement evidencebased strategies to build or improve their relationships with preceptees. furthermore, improving preceptorship will have a beneficial effect for preceptors as well as preceptees. preceptors who have rewarding preceptee relationships will be motivated to continue providing exemplary patient care, as they act as role models for their preceptees. challenges and strategies for building and maintaining effective preceptor-preceptee relationships among nurses e532 | squ medical journal, november 2014, volume 14, issue 4 sought to explore the challenges nurse preceptors at squh encounter and the strategies they could use to establish and maintain effective professional relationships with their preceptees. methods this study was conducted in november 2012 at the college of nursing at squ and used a two-group modified focus group discussion method. this qualitative research design allowed participants to discuss their ideas and experiences more easily by using their own words.17 in addition, this technique is inexpensive, flexible and stimulating and facilitates information recall, resulting in rich data.18 this method is also known to promote self-disclosure among participants, especially when sensitive topics are discussed, as they were in this study.18,19 while there are no general guidelines on the optimal number of focus groups, even a single focus group may be enough, depending on the circumstances, as long as group homogeneity and data saturation or redundancy have been accounted for.17 participation in the study was limited to preceptors working in either the neonatal and intensive care units or the departments of emergency medicine, medicine and surgery of squh (n = 21). as preceptors, all of the participants either had a bacclaureate degree or a nursing diploma and at least three years of clinical experience. the data collection occurred in two phases. initially, the following questions were asked to a small group of preceptors (n = 5): what issues have you encountered when initiating relationships with preceptees at the start of the clinical rotation? and what strategies do you use to build and maintain an effective relationship with the preceptees? only five participants were included in this initial group in order to accommodate the sensitive nature of the questions and to ensure an orderly discussion and facilitate idea generation. after two hours of analysis, the main findings from this initial discussion were then shared with and examined by the second group of preceptors (n = 21); this group included the five preceptors from the initial group. modifications were then made to these findings to ensure agreement from the whole group. this allowed the initial interviews to be validated and provided a second opportunity for participants to express new ideas. following this, the original questions were paraphrased as follows: of the issues identified above, what issues have you encountered when initiating relationships with preceptees at the start of the clinical rotation? and in addition to the strategies already identified, what strategies do you use to build and maintain an effective relationship with the preceptees? these questions were then the subject of the remaining discussion period among the large group of preceptors. in both groups, prompts were used to facilitate information flow and to ensure the consistency of the data. the same researcher led the discussion sessions for both focus groups. these discussions lasted for a total of 66 minutes; 46 minutes for the first group and 20 minutes for the second group. the group discussions were audio recorded and field notes were also taken to ensure data security and accuracy. the data was analysed after the verbatim transcription of the focus group audio recordings. initially, the analysis involved the individual reading and re-reading the transcripts several times in order to become familiar with the data and enable the comprehension of any unfamiliar concepts. thematic statements were then isolated using van manen’s lineby-line and highlighting approaches.20 these thematic statements were then compared and discussed in-depth by two doctoral-level researchers until a consensus emerged, at which point the given theme was finalised. no outlier themes emerged as a result of this comparison and discussion. prior to the data collection, details of the study (including the study’s purpose and methods) were explained to the participants and written consent was obtained from each participant. in addition, participating preceptors were assured of complete confidentiality, anonymity and the right to withdraw from the study without penalty. ethical approval for the study was received from the research & ethics committee at the college of nursing at squ (crc#2012/11.07.2012). results a total of 21 preceptors participated in the study. of these, 86% were female and 14% were male. the majority (76%) had over ten years of clinical experience and 71% had worked at squh for more than three years. approximately half (52.5%) of the preceptors were qualified at the diploma level of nursing education, while the remaining 47.5% had baccalaureate degrees. the participants had an average of four years of preceptorship experience at squh. the study identified four challenges to preceptorship and ten strategies to encourage relationship-building between preceptors and preceptees. the challenges included discrepancies related to the application of theory to practice; lack gerald a. matua, vidya seshan, raman savithri and dennis c. fronda clinical and basic research | e533 of trust and readiness to commit to a preceptorship relationship; insufficient time to invest in relationshipbuilding, and a perceived lack of knowledge in nursing trends. preceptees often disagreed with the way their preceptors carried out certain clinical procedures, maintaining that such approaches were different from what they had expected or were not consistent with what they had learnt previously. such disagreements hindered relationship-building efforts. as one participant (p1) observed, “sometimes there will be differences in the way we are doing [certain tasks]... it is not that we are wrong, but it is because sometimes there are good reasons. so we expect the student to understand”. moreover, preceptees were noted for their lack of trust and readiness to commit to the relationship, with some preferring to perform given tasks on their own. this frustrated preceptors’ attempts to build professional relationships. a participant (p4) explained that “there are some students who prefer to do things different from you, they will search and sometimes they will fight... some become confrontational, talking simultaneously… as you advise them”. time constraints were a major challenge faced by preceptors: the participants claimed that they were frequently preoccupied with patient care duties. in view of this, they were unable to devote sufficient time to the preceptees, thereby hindering relationshipbuilding. this was evident from a comment by one of the preceptors (p4): “we have a lot of work. also you find… you need time to know each other first, what is expected from them… all these take time and yet we have other responsibilities… you do not find enough time”. lastly, the final challenge identified by the focus group was a perceived lack of knowledge. some preceptors perceived themselves as being less knowledgeable than their preceptees, especially with regards to the latest trends in nursing practice. this negatively influenced their self-confidence and interfered with their relationship-building efforts. as one preceptor (p2) admitted, “i never blame the students… they are more trained than us… our knowledge is old now. what we do, we learned 10 years back… and… i cannot say i am not doing anything wrong”. remedial strategies that preceptors could use with their preceptees during preceptorship were also identified. these included thorough orientation; effective communication; preparing for complex situations; appreciating and acknowledging preceptee success; offering positive feedback; assurance of support; spending time together; knowing preceptees personally; allowing recess periods, and encouraging preceptees to commit themselves to the nursing profession. preceptors reported that thoroughly orientating preceptees to their clinical environments enabled them to cultivate friendly relationships with the preceptees and was also noted for minimising the likelihood of preceptees feeling lost. as a preceptor (p1) noted, “we should orientate [them], then the student is clear what we expect from them, so they will not be lost and there will be no problems later on”. ensuring open communication throughout the preceptorship period was also considered to be a critical strategy in preceptor-preceptee relationship-building. allowing preceptees to be open about their feelings was emphasised by one of the preceptors (p3): “we should give them the freedom to express their feelings... this makes them [feel more] comfortable with us, which is good for supervision”. preparing preceptees in advance with regards to unfamiliar and complex clinical nursing situations was another strategy identified by the preceptors. preceptors believed that this would help increase preceptees’ confidence levels, motivate them to take their assignments seriously as well as cultivate positive relationships between preceptees and preceptors. a participant (p4) observed, “yes, before we do a complex procedure we explain... this way they will know what to do when they are doing the actual procedure”. preceptors found that appreciating preceptees and acknowledging their successes facilitated the building of a healthy and supportive relationship with the preceptees: “we should praise them if they are doing good things. we should appreciate [them]... they will be happy... [and] will do more next time” (p4). preceptors also observed that giving positive feedback to preceptees led to better relationships and improved supervision outcomes: “when you give them quality feedback… they are normally happy to hear that and they will have more initiative in performing their duties” (p4). additionally, assuring preceptees of their preceptor’s support was thought to be helpful in gaining their trust and increasing their interest in learning, leading to better student learning outcomes. specifically, one preceptor (p4) stated that “students are more interested in their evaluation. if we show interest in what the student is going to be assessed [on]... they will do even better next time.” furthermore, spending sufficient time with preceptees was emphasised as a way of maintaining a friendly relationship as well as ensuring close follow-up while preceptees were performing their duties: “when students are placed under your care, it is important not to leave the student alone but you have to watch what she [or he] is doing... this adds to [their] confidence…as a kind of follow-up” challenges and strategies for building and maintaining effective preceptor-preceptee relationships among nurses e534 | squ medical journal, november 2014, volume 14, issue 4 (p1). additionally, one preceptor (p4) reported that getting to know preceptees on a personal level would aid in gaining a deeper understanding of their personal attributes and ensure a better exchange of information: “we also sometimes share personal things like about parents and siblings. we found that by knowing the student personally also it kind of helps to build a good relationship and makes you… go along well”. allowing preceptees to rest and refresh between shifts was considered by the preceptors to be a good strategy. this evidence of flexibility made them more comfortable, leading to better professional relationships, as noted by one of the preceptors (p5), “we as preceptors are working continuously but they are new to the ward so we tell them to go for a break in between... by giving [them a] break they kind of feel comfortable and it works”. encouraging preceptees to commit to and show interest in their profession was also thought to strengthen their interest in bedside learning, which would result in improved preceptorpreceptee relationships in the long term: “i used to tell them about the commitment to nursing… to learn to take care of.. [their] own people—parents, brothers and sisters” (p4). discussion nurturing supportive relationships with preceptees may be both a challenging and rewarding experience for preceptors.8,21 in this study, various challenges, such as discrepancies in knowledge or in the application of theory to practice, were found to have a negative impact on preceptor-preceptee relationships. these findings are consistent with earlier studies; such difficulties were noted to delay the formation or hasten the breakdown of preceptor-preceptee relationships.8,22 when these challenges persist, preceptees may even fail to achieve their learning objectives, thereby increasing the likelihood of have a strained relationship with their preceptor.5,23 while these challenges exist, several strategies were identified by the preceptors in the current study to help create and maintain healthy relationships with preceptees. for instance, preceptors reported that appropriate orientation procedures would help integrate preceptees into a specific clinical setting. remedies such as these have been shown to enable preceptees to relate positively with their preceptors, as a result of a supportive learning environment and a beneficial and educative relationship.24 other strategies identified, for instance communicating with preceptees in a friendly manner and allowing them to express their feelings without fear of compromising their relationship with the preceptor, also appear to have a positive impact on learning and should be encouraged.25,26 research shows that advance preparation for unfamiliar or complex situations enables preceptees to develop professional competencies, which in turn prepares them for professional practice.26 this preparation, when provided through a strong preceptorship programme, also nurtures positive preceptor-preceptee relationships by progressively building the preceptees’ confidence during the learning process. furthermore, spending more time with preceptees and endeavouring to know them on a personal level also helps in building and sustaining positive relations between preceptors and preceptees.11 these approaches were identified by preceptors in the current study as methods to improve preceptorpreceptee relations. carlson found that the allotment of ‘protected time’ to preceptees by preceptors was supportive of their overall learning, leading to greater trust among the preceptees.26 a study by dewolfe et al. revealed that appreciating and acknowledging the success of preceptees through positive feedback and support also resulted in more productive professional relationships.27 the results of the current study were consistent with those of a study by atack et al. which reported that treating students as colleagues created a positive relationship with clinical staff, resulting in open communication, mutual courtesy and respect.28 the focus group discussions of the current study identified that the strategy of encouraging preceptees’ commitment and interest in their profession enhanced the development of supportive relationships with preceptors by facilitating the professional socialisation of preceptees. research has shown that this professional socialisation occurs best when students are made to feel part of the nursing team, which helps them to gain confidence and interest in their profession.26,29 while it is true that the aforementioned strategies would have different success rates depending on the people involved, previous studies show that using these strategies appropriately, either individually or in combination, can help to build and maintain healthy and effective preceptorships in the clinical setting.5,8,30 these positive relationships have the potential to make the clinical learning experience more rewarding and fulfilling for all those involved.5,8,30 in order to enhance preceptorship outcomes, the authors of this study recommend that preceptees undergo a half-day workshop prior to clinical allocation, during which former preceptees and preceptors share their past experiences. it would also be beneficial to explore the views of preceptees involved in existing preceptorship programmes. gerald a. matua, vidya seshan, raman savithri and dennis c. fronda clinical and basic research | e535 further studies are recommended to explore preceptors’ expectations of preceptees as this could help to strengthen future preceptorship programmes. in addition, clinical nurse managers at squh should encourage preceptors to identify any challenges they face in building or maintaining a positive relationship with their preceptees and then implement relevant remedial strategies. preceptors should be trained on a regular basis to ensure that they are prepared for the role, especially with regard to building and maintaining effective relationships with preceptees. the proper implementation of training will likely lead to a stronger preceptorship programme. in the long-term, this would benefit the organisation or hospital by reducing the period of acclimatisation for new graduates and limiting potential errors in patient care. furthermore, a strong preceptorship programme is likely to lessen the need for a lengthy internship programme, with the further advantage of reducing the workloads of both staff nurses and managers. this would allow nurses more time to focus on other roles, potentially leading to improved patient outcomes. as this study involved a group of preceptors from a single teaching hospital, the findings cannot be generalised to the overall population. additionally, due to the small sample size, the views expressed in this study may not reflect those of all preceptors within squh. however, despite these limitations, the researchers believe that the results of this study still offer significant insight into preceptorship relationships. conclusion building and maintaining professional relationships during preceptorship is vital and both preceptors and preceptees should be adequately prepared for the experience. to this end, educational institutions need to thoroughly equip preceptees for the preceptorship experience in order to avoid discrepancies when they enter clinical practice. as with the current study, preceptors should be encouraged to identify any challenges impeding their relationship-building efforts and adopt appropriate remedial strategies. to better understand the dynamics of preceptor-preceptee relationships and to improve preceptorship experiences, further studies are recommended exploring the views of preceptees as well as examining preceptors’ expectations of preceptees during preceptorship. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest that may have inappropriately influenced this research. a c k n o w l e d g e m e n t s the authors of this study wish to thank the squ college of nursing for making this study possible and dr. joshua k. muliira for coordinating the advanced clinical nursing course and helping to bring the preceptors together. the authors are also grateful to the preceptors for sharing their views and experiences. a u t h o r s tat e m e n t gerald a. matua, vidya seshan and raman savithri contributed to the study design. gerald a. matua, raman savithri , vidya seshan and dennis c. fronda were involved in the data collection and analysis. gerald a. matua, vidya seshan, raman savithri and dennis c. fronda took part in the manuscript preparation. references 1. yonge o, billay d, myrick f, luhanga f. preceptorship and mentorship: not merely a matter of semantics. int j nurs educ scholarsh 2007; 4:19. doi: 10.2202/1548-923x.1384. 2. bourbonnais ff, kerr e. preceptoring a student in the final clinical placement: reflections from nurses in a canadian hospital. j clin nurs 2007; 16:1543–9. doi: 10.1111/j.13652702.2006.01828.x. 3. billay d, myrick f. preceptorship: an integrative review of the literature. nurse educ pract 2008; 8:258–66. doi: 10.1016/j. nepr.2007.09.005. 4. watson lc, raffin-bouchal s, melnick a, whyte d. designing and implementing an ambulatory oncology nursing peer preceptorship program: using grounded theory research to guide program development. nurs res pract 2012; 2012:451354. doi: 10.1155/2012/451354. 5. haitana j, bland m. building relationships: the key to preceptoring nursing students. nurs prax n z 2011; 27:4–12. 6. epstein i, carlin k. ethical concerns in the student/preceptor relationship: a need for change. nurse educ today 2012; 32:897–902. doi: 10.1016/j.nedt.2012.03.009. 7. charleston r, happell b. coping with uncertainty within the preceptorship experience: the perceptions of nursing students. j psychiatr ment health nurs 2005; 12:303–9. doi: 10.1111/j.1365-2850.2005.00837.x. 8. duteau j. making a difference: the value of preceptorship programs in nursing education. j contin educ nurs 2012; 43:37–43. doi: 10.3928/00220124-20110615-01. 9. zilembo m, monterosso l. towards a conceptual framework for preceptorship in the clinical education of undergraduate nursing students. contemp nurse 2008; 30:89–94. 10. bradbury-jones c, sambrook s, irvine f. the meaning of empowerment for nursing students: a critical incident study. j adv nurs 2007; 59:342–51. doi: 10.1111/j.13652648.2007.04331.x. 11. gopee n. mentoring and supervision in healthcare. 2nd ed. london, uk: sage publications ltd., 2011. pp. 8–13. 12. glass n, walter r. an experience of peer mentoring with student nurses: enhancement of personal and professional growth. j nurs educ 2000; 39:155–60. 13. greene mt, puetzer m. the value of mentoring: a strategic approach to retention and recruitment. j nurs care qual 2002; 17:63–70. challenges and strategies for building and maintaining effective preceptor-preceptee relationships among nurses e536 | squ medical journal, november 2014, volume 14, issue 4 14. kim kh. clinical competence among senior nursing students after their preceptorship experiences. j prof nurs 2007; 23:369– 75. doi: 10.1016/j.profnurs.2007.01.019. 15. barker er, pittman o. becoming a super preceptor: a practical guide to preceptorship in today’s clinical climate. j am acad nurse pract 2010; 22:144–9. doi: 10.1111/j.17457599.2009.00487.x. 16. national nursing research unit and kings college london. preceptorship for newly qualified nurses: impacts, facilitators and constraints. from: www.kcl.ac.uk/nursing/research/nnru/ publications/reports/preceptorshipreview.pdf accessed: aug 2014. 17. mclafferty i. focus group interviews as a data collecting strategy. j adv nurs 2004; 48:187–94. doi: 10.1111/j.13652648.2004.03186.x. 18. streubert hj, carpenter dr. qualitative research in nursing: advancing the humanistic imperative. 5th ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2011. p. 37. 19. freeman t. ‘best practice’ in focus group research: making sense of different views. j adv nurs 2006; 56:491–7. doi: 10.1111/j.1365-2648.2006.04043.x. 20. van manen m. researching lived experience: human science for an action sensitive pedagogy. new york, usa: state university of new york press, 1990. p. 93. 21. yonge o. meaning of boundaries to rural preceptors. online j rural nurs health care 2009; 9:15–21. 22. mccarthy b, murphy s. preceptors’ experiences of clinically educating and assessing undergraduate nursing students: an irish context. j nurs manag 2010; 18:234–44. doi: 10.1111/j.1365-2834.2010.01050.x. 23. kelly m. preceptorship in public health nursing. j comm nurs 2011; 25:10–15. 24. poirier ti, santanello cr, gupchup gv. a student orientation program to build a community of learners. am j pharm educ 2007; 71:13. doi: 10.5688/aj710113. 25. rogers b. nurse preceptor program builder: tools for a successful preceptor program. marblehead, massachusetts, usa: hcpro inc., 2007. pp. 39–45. 26. carlson e. precepting and symbolic interactionism: a theoretical look at preceptorship during clinical practice. j adv nurs 2013; 69:457–64. doi: 10.1111/j.1365-2648.2012.06047.x. 27. dewolfe j, laschinger s, perkin c. preceptors’ perspectives on recruitment, support, and retention of preceptors. j nurs educ 2010; 49:198–206. doi: 10.3928/01484834-20091217-06. 28. atack l, comacu m, kenny r, labelle n, miller d. student and staff relationships in a clinical practice model: impact on learning. j nurs educ 2000; 39:387–92. 29. feng rf, tsai yf. socialisation of new graduate nurses to practising nurses. j clin nurs 2012; 21:2064–71. doi: 10.1111/j.1365-2702.2011.03992.x. 30. chisengantambu c, penman j, white f. preceptors central to nursing workforce. aust nurs j 2005; 13:35. 1department of histopathology, armed forces hospital, muscat, oman; 2department of pathology, ministry of defense, muscat, oman *corresponding author e-mail: sunithamanjunath98@yahoo.co.in تكيس جلدي زاليل متحول �شونيث� رام��ش�ندرا، الك�شمي راو، م�شعود الكندي cutaneous metaplastic synovial cyst *sunitha ramachandra,1 lakshmi rao,2 masoud al-kindi2 interesting medical image a 31-year-old male patient presented to the surgical outpatient department at the armed forces hospital, muscat, oman, in september 2014 with a swelling on the left side of his forehead that had been on-going for 10 months. a clinical examination showed a subcutaneous, mobile and non-tender swelling. he had a past history of a similar swelling at the same site, which had been operated on four years previously at another hospital. no reports were available regarding the nature of this previous swelling. at presentation, the swelling was diagnosed clinically as a recurrent dermoid cyst and was excised and sent for histopathological examination. the pale grey firm nodular mass (1.2 x 1.0 x 0.8 cm) showed a solid cystic mass when sliced. an irregular cyst lined by hyperplastic synoviocytes forming broad villi and papillae with hyalinised cores infiltrated by lymphocytes and plasma cells was observed on microscopic examination [figure 1]. foci of chondroid metaplasia, haemorrhage and pigment-laden macrophages surrounded by skeletal muscle with atrophic changes and giant cell formation were noted. a histopathological diagnosis of cutaneous metaplastic synovial cyst (cmsc) was made. immunohistochemistry (ihc) showed vimentinpositive [figure 2a] and cluster of differentiation (cd) 68-positive [figure 2b] synoviocytes. however, ihc was negative for pan-cytokeratin and cd34. comment also known as synovial metaplasia of the skin, cmsc is a rare cystic tumour first described in 1987 by gonzalez et al.1 the tumour is located intradermally or subcutaneously and is lined by a hyperplastic synovium-like membrane associated with transepidermal fistulae.2 the aetiology remains unknown, although a history of trauma or surgery is noted in most cases, suggesting that surgical or sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e117–118, epub. 2 feb 16 submitted 21 may 15 revision req. 30 jun 15; revision recd. 29 jul 15 accepted 13 aug 15 doi: 10.18295/squmj.2016.16.01.024 figure 1: haematoxylin and eosin stain at x4 magnification showing the cyst wall with broad papillae and villi lined by synoviocytes (red arrow) with hyalinised cores (black arrow) in a 31-year-old patient with a cutaneous metaplastic synovial cyst. cutaneous metaplastic synovial cyst e118 | squ medical journal, february 2016, volume 16, issue 1 composed of hypoand hypercellular areas with a mixture of fibroblasts, epithelioid cells, mononuclear inflammatory cells and occasional multinucleated giant cells.1,3 hypocellular areas show fibrin deposits and hyalinisation. when located close to a joint cavity, these lesions need to be differentiated from the fluid-filled sacs of bursitis, which are deeper in the subcutaneous tissue and located over the bony prominences.1 ihc testing in cmsc cases shows positive staining for vimentin and negative staining for the s100 protein, carcinoembryonic antigen and cd34. cd68 shows a variable reaction. however, ihc is not mandatory for the diagnosis, as cmsc can be diagnosed histologically.3 references 1. kim bc, choi wj, park ej, kwon ih, cho hj, kim kh, et al. cutaneous metaplastic synovial cyst of the first metatarsal head area. ann dermatol 2011; 23:s165–8. doi: 10.5021/ad.2011.23. s2.s165. 2. rosai j. rosai and ackerman’s surgical pathology. 9th ed. st louis, missouri, usa: mosby, 2004. pp. 202. 3. yang hc, tsai yj, hu sl, wu yy. cutaneous metaplastic synovial cyst: a case report and review of literature. dermatol sinica 2003; 21:275–9. 4. weedon d. weedon’s skin pathology. 3rd ed. london, uk: churchill livingstone, 2010. pp. 454. 5. shim wh, jwa sw, song m, kim hs, ko hc, kim bs, et al. cutaneous metaplastic synovial cyst of the cheek generated by repetitive minor trauma. ann dermatol 2011; 23:s235–8. doi: 10.5021/ad.2011.23.s2.s235. non-surgical trauma is the precipitating cause.3 the spontaneous development of these cysts in ehlers-danlos syndrome indicates the occurrence of cutaneous fragility and anomalous scarring after microtrauma.4 cases of cmsc have been associated with basal cell carcinomas, rheumatoid arthritis and arthrosis.3 within the embryo, the normal synovium develops from a mechanical disruption of the connective tissue; cmscs form due to the disruption of connective tissue following trauma or surgery.5 the cyst develops between a few weeks to several years following the trauma. it has no predilection for site, gender or age.5 clinically, cmscs are tender, erythematous, cutaneous or dermal nodules with or without drainage.3 cmsc remains a lesser known entity in clinical dermatology.5 it is commonly misdiagnosed and the lack of clinical awareness is an impediment to establishing its true incidence. the swelling is commonly misdiagnosed as a suture granuloma or an epidermal inclusion cyst following surgery or trauma.5 other differential diagnoses include foreign body granulomas, leiomyomas, eccrine poromas and other cutaneous cysts.3 epidermal cysts are distinguished from cmscs as they are true cysts with an epithelial lining. in comparison, cmscs lack a true epithelial lining and are pseudocysts with papillary and villous projections towards the centre of the cavity. the lining is similar to a synovial membrane and is figure 2a & b: immunohistochemistry stains at x20 magnification showing (a) vimentin-positive (arrows) and (b) cluster of differentiation 68-positive (arrows) synoviocytes in a 31-year-old patient with a cutaneous metaplastic synovial cyst. http://dx.doi.org/10.5021/ad.2011.23.s2.s165 http://dx.doi.org/10.5021/ad.2011.23.s2.s165 http://dx.doi.org/10.5021/ad.2011.23.s2.s235 squ med j, february 2012, vol. 12, iss. 1, pp. 1-4, epub. 7th feb 12 submitted 14th jan 12 accepted 17th jan 12 in this issue of squmj, dr. muna al saadoon and her colleagues report a series of 6 cases, which demonstrate different types of child abuse or child maltreatment.1 dr. al saadoon and her colleagues describe clearly the disgraceful way that some children in oman are treated. there are no statistics to indicate the frequency of such treatment, but clearly it does exist, as evidenced by the six reported cases. unfortunately, this is, most likely, just the tip of the iceberg and the scope of the problem is likely to be much greater. in most countries, the rate of child abuse cases that are reported to the authorities is much smaller than the real incidence. it is possible that in oman, because of culture and religion, the magnitude of child maltreatment is lower, but, such a conclusion would require substantiation by research employing rigorous methodology. there is an indication that what is deemed child abuse in one culture may be perceived as ‘parenting style’ in other cultures. however, this is no reason for tolerating any form of child maltreatment in any country in the world. unfortunately, children are deprived of their rights in many ways, and it is a universal problem. child abuse, or taking away the child’s rights, has a very long history. confucius, the chinese philosopher (551 to 479 bc), stressed children’s obedience to their parents, and parents used various measures to ensure such forms of socialisation.2 the greek philosopher, plato, in stressing the importance of education, suggested state ownership of children in his famous book, the republic, thus depriving them of their rights. he also suggested that only healthy men and women should be allowed to consummate in order to produce healthy children, thus resulting in a noble generation. thus, he effectively suggested that the life of a child should be used as a tool to further the ambitions of the state.2 another greek philosopher, aristotle, although he disagreed with plato, endorsed abortion as a tool to control the child population and suit the needs of the state—yet another piece of evidence from ancient history of the mass deprivation of child rights.2 roman law authorised a father to sell a child like a slave, or even to sacrifice the child’s life as a punishment (ius vitae necisque), an example of the father’s power of life and death (patria potestas).2 in pre-islamic times, the arab man often regarded a child and wife as his property. in some other societies, children were used as ‘bait’ to lure animals in hunting or even sacrificed to the gods.2 sadly, maltreatment of children is not limited to ancient history, but is prevalent today—in maybe even more abhorrent forms—as demonstrated in the movie, slumdog millionaire. that film shows the actions of organized crime gangs which are allegedly still current practice in india. they amputated the hands of children and blinded the friends of jamal malik, so the children had no option but to beg in the streets for their bosses. a similar action was reported in cairo as narrated by the egyptian nobel laureate, naguib mahfouz.3 until this day, in some countries, female circumcision, also referred to as female genital mutilation, is still being practised. the infringement of child rights varies according to editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, oman. *e-mail: mjournal@squ.edu.om حقوق الطفل ماذا نستطيع عمله يف ُعمان؟ ملك اللمكي editorial child rights what can we do in oman? lamk al-lamki child rights what can we do in oman? 2 | squ medical journal, february 2012, volume 12, issue 1 cultures and the education level of the society, but almost all countries have cases of child abuse and other forms of deprivation of child rights. in june 2002, on the world day against child labor, the international labor organization (ilo) announced that 70 million children under the age of 10 are working, and 10 million under the age of 15 were coerced into hazardous work that would likely dent their growth and prevent a meaningful existence.2 according to the ilo, at one time, there were 13 million children working as labourers in the middle east and north africa (mena region) alone.2 the paucity of data on the degree of child abuse in oman, and, for that matter, the rest of the world, hinders the implementation of evidence-based prevention and intervention. gathering more data on the prevailing situation in oman would be an essential first step. the research council of oman (trc) should perhaps consider calling for more research on the different types and causes of child abuse in oman. trc has now received, and is considering, one research proposal on this topic. we hope more research studies will be conducted to shed light on the situation in oman that would have direct bearing on prevention of harm to children, and also lead to the treatment of the adults involved. the basic principle of quality assurance calls for 'measurements' to be taken before any effort is undertaken to improve quality. in the case of child rights, that will include collecting information on the prevalence and extent of the abuse so that further studies on treatment and prevention can be carried out. in 2006, the united nations (un) tried to carry out a study on violence against children in various locations, and came to the conclusion that we are lacking the tools to elicit accurately the extent of child abuse.4 as a result of that failure, 122 experts from 28 different countries, under the auspices of the international society for the prevention of child abuse and neglect (ispcan), developed the international child abuse screening tools (icast). this instrument is considered a culturally free assessment tool. icast has been translated into many languages as well as back translated to ensure accuracy. it has been tried out in several countries and it has adequate psychometric properties including for arab speaking populations. icast is basically three types of questionnaire: 1) icast-p (parental version); 2) icast-r (retrospective) for young adults aged 19–24, and 3) icast-c for children. the latter has both home and institution versions.4,5 the availability of icast should mean it can be employed to quantify the situation in oman. with the creation of the united nations organization (uno) in 1945, children appeared in the international human rights agenda as a separate group. that was a major step towards the comprehensive introduction of rights for children, but the international fight for child rights goes back to 1923 with the child rights declaration of the international save the children union.2,6 this was endorsed in 1924 by the league of nations as the world child welfare charter.2,6 the un’s 1948 universal declaration of human rights followed this.7 in 1959, the un general assembly adopted the 10 principles of the declaration of rights of the child and declared that a child should be among the first to be protected.2,6,7 all these efforts culminated in the adoption of convention on the rights of the child (crc) in 1989 by the un general assembly, the fruit of 10 years of comprehensive negotiations between experts from governments, non-governmental organisations (ngos), various advocates of human rights and lawyers, as well as health specialists, social workers, and educators. the crc has 54 articles and is supplemented by 2 optional protocols. it recognises the rights of all children (persons under 18) to develop physically, mentally and socially to their fullest potential, to express their opinions freely, and to participate in decisions affecting their future. it also ensures that they develop their personalities, abilities and talents to the fullest.4,6 "the crc is a legally binding international instrument that incorporates the full range of human rights, civil, cultural, economic, political and social”.4,6 it provides a vision of children as individuals, and as members of the family and community, with their rights, and responsibilities, appropriate to their age and stage of development and assures that children have access to education and health care and have the right to nationality, to a name, to freedom of speech and thought, and to freedom from exploitation, torture and abuse.4,6 the governments that have ratified the crc have to send periodic reports to the un on the progress on their efforts related to child rights. the crc is the most respected international agreement and has been signed by all nations lamk al-lamki editorial | 3 in the world, except the united states and somalia. the current us president, barack obama, has described the us failure to ratify the convention as “embarrassing” and has promised to review this.7 oman acceded to the convention in 1996, but with five reservations. after extensive discussion with the un, oman has finally withdrawn its objection to all but one clause—article 14, which gives the child a right to choose his/her own religion. otherwise, oman had fully ratified the treaty as of 22 september 2011. in 2004, oman signed agreements to both of the optional protocols of the crc, and the government established a national committee to follow-up both the implementation of the crc and the optional protocols. there are several ways a child can lose his/her rights. this can be in a form of child abuse which includes “doing anything that results in harm to a child or puts a child at risk”.1 child abuse can be physical, sexual, or emotional; neglect, i.e. not providing for the child’s needs, is also a form of abuse as it deprives the child of the basic rights delineated in the crc. among the cases reported to child protection services, neglect is by far the most commonly observed child abuse, followed by physical and sexual abuse. approximately 5.5 million children are neglected annually, and 3 million cases of other incidents of child abuse are reported each year.1,8 most abused children suffer greater emotional than physical damage.1 this can range from being withdrawn to being severely depressed. sometimes emotional abuse subsequently triggers drug or alcohol abuse, or running away from home. unfortunately, a study in united states has shown that the majority of children who run away, are taken into a prostitution ring within 48 hours. a declaration of the world congress against commercial sexual exploitation (csex) of children held in stockholm in 1996, defined csex as “sexual abuse by adults and remuneration in cash or kind to the child or a third person/s. the child is treated as a sexual object and as a commercial object.”9,10 commercial sexual exploitation, where children are forced into prostitution and child pornography, appears to be increasingly common in several societies. the crc explicitly rejects any form of sexual harassment of children. one of the most horrifying statistics is that 75% of minors that are engaged in prostitution have a pimp.9,10 the united nations children's fund (unicef) estimates that 2 million children are exploited in prostitution and pornography every year.9–11 as far as we know, this is not a problem in oman,12 but nevertheless, we have to be very resolute and diligent, in protecting our children against all forms of exploitation, as our society is rapidly changing with young children increasingly spending hours on the internet and in internet chat rooms. what else can we do to ensure the preservation and improvement of child rights in oman? much is already being done, but we need to make more diligent efforts both individually and also collectively. the country needs to promote a public education campaign (e.g. tv shows) that openly discuss the issue of child abuse and how it can be prevented or avoided. such a campaign should target both parents and children. the ministry of social development (mosd) has formed executive figure 1: elements of the protective environment for children. (reproduced with permision from unicef.18) child rights what can we do in oman? 4 | squ medical journal, february 2012, volume 12, issue 1 committees to celebrate 2012 as the ‘year of the child’ in oman, and will establish a cultural centre for children to enhance children's capabilities and polish their skills.13,14 clearly, this is great news and should be met with rejoicing by all of us in oman. ngos need to work on, or support, others’ efforts in improving the acceptance of child rights in oman. more individual effort is also overdue. the mosd is playing its role, e.g. they have opened a child help line which both children and adults can access, but is this help line getting calls all from the children who need help? annually, child help lines worldwide receive 11.3 million calls from children and youth needing care and protection,15 thus more public education about child rights is needed. teachers, nurses and daycare workers need to be educated. the mosd has also organised a child rights seminar in muscat to discuss combatting violence against children.16 oman is currently preparing a draft law of the child. also, the law on juvenile accountability (royal decree 30/2008) has significantly advanced guarantees for juveniles. clearly, we are getting somewhere in oman with all the efforts of the mosd and some ngos. for example, “there are no reports of child prostitution and child labor is not a problem in oman” according to a us report.17 nevertheless, more individual efforts and efforts by the media, both electronic and print, is urgently needed to stop cases like those reported by dr. al saadoon et al. in this issue of squmj.1 children need a fully protective environment in order to thrive. figure 1 shows the 8 protective elements (circle) and the 6 threats (arrows). therefore, we need more enthusiasm by everybody concerned to live up to the spirit of the crc.4 references 1. al-saadoon m, al-sharbati m, el nour i, al-said b. child maltreatment—types and effects: series of six cases from a university hospital in oman. sultan qaboos university med j 2012; 12:455–60. 2. ghassan khalil. child rights – the historical evolution. beirut: chemaly & chemaly printing press, 2002. 3. mafouz n. midaq alley. colorado springs: knopf doubleday publishing group (random house), 1991. 4. unicef. convention on the rights of the child. from: http://www.unicef.org/crc accessed: jan 2012. 5. international society for the prevention of child abuse (ispcan). un study on violence against children. from: http://www.ispcan. org/?page=icast accessed: jan 2012. 6. convention on the rights of the child from: http:// childrightscampaign.org accessed: jan 2012. 7. us ratification of the convention on the rights of a child. from: http://en.wikipedia.org/wiki/ us_ratification_of_the_convention_on_the_rights_ of_a_child accessed jan 2012. 8. healthy children. safety & prevention at home. from: http://www.healthychildren.org/ english/safety-prevention-at-home accessed: jan 2012. 9. commercial sexual exploitation of children (csec). from:http://en.wikipedia.org/wiki/commercial_ sexual_exploitation_of_children. accessed: jan 2012. 10. kristi house and the orlowitz-lee children's advocacy center. from: http://www.kristihouse.org accessed: jan 2012. 11. gudzer d. pulitzer center on crisis reporting. unicef: protecting children from commercial sexual exploitation. from: http://www.pulitzercenter. typepad.com accessed: jan 2012. 12. al-adawi s. adolescence in oman. in: arnett jj, ed. international encyclopedia of adolescence: a historical and cultural survey of young people around the world. new york: routledge, 2006. 13. oman daily observer. focus on child rights, skill development, 2 jan 2012. from: http://omanobserver. om/node/77765 accessed jan 2012. 14. williams e. year of the child. the week, 11 jan 2012. from: http://www.theweek.co.om/discon. aspx?cval=5935 accessed jan 2012. 15. billimoria j. child helpline international. recommendations to the un committee on the rights of the child – 43rd session, oman. from: http://w w w.cr in.org/do c s/oman_c h i_n g o_ report.doc accessed jan 2012. 16. seminar on child rights begins. muscat daily, 16 jan 2012. from: http://www.muscatdaily.com/archive/ oman/seminar-on-child-rights-begins accessed jan 2012. 17. us department of state, bureau of democracy, human rights, and labor. oman. pub. 8 march 2005. from: http://www.state.gov/g/drl /rls/hrrpt/2005/61696.htm accessed jan 2012. 18. unicef oman. charting progress towards child protection in sultanate of oman–findings of a national consultative workshop muscat: unicef 2009,p.6. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e72-79, epub. 27th jan 14 submitted 8th may 13 revision req. 21st jun 13; revision recd. 30th jul 13 accepted 25th aug 13 1department of internal medicine, al nahdha hospital, muscat; 2ministry of health, muscat, oman *corresponding author e-mail: mag_alosali@yahoo.com تقييم سرعة الرتشيح الكبييب ىف املرضى العمانيني باستخدام معادلة كوككروفت-جولت و معادلة تعديل النظام الغذائى ملرضى الكلى جمدي عيد �لع�صيلي و �صامل �صعيد �لق�صابى و �صعود حممد �حلارثي abstract: objectives: glomerular filtration rate (gfr) is the best index of renal function and is frequently assessed by corrected creatinine clearance (cclcr). the limitations of cclcr have inspired researchers to derive easy formulas to estimate gfr, with cockcroft-gault (c-g) and the modification of diet in renal disease (mdrd) being the most widely used. this study aimed to evaluate the validity of these equations by finding the relation between cclcr and estimated gfr (egfr) by c-g, modified c-g and mdrd equations. methods: from 2007 to 2011, 158 subjects were analysed for serum creatinine and cclcr at bowsher polyclinic, muscat, oman. the c-g equation was used to obtain egfrc-g which was adjusted to body surface area (bsa) to obtain egfrmc-g, and the mdrd equation was used to obtain egfrmdrd. the egfrmdrd, egfrmc-g and egfrc-g were then compared to cclcr. results: the egfrmdrd, egfrmc-g and egfrc-g significantly correlated with cclcr, with a slightly stronger correlation with egfrmdrd (r = 0.701, 0.658 and 0.605, respectively). a receiver operating characteristic curve analysis showed that the diagnostic accuracy of egfrmdrd for diagnosing chronic kidney disease (ckd) was higher than that of egfrmc-g, which in turn was higher than that of egfrc-g (area under the curve was 0.846, 0.831, and 0.791; cut-off limits were 61.9, 58.3 and 59.5, respectively). conclusion: c-g and mdrd equations can be an alternative to the cclcr test for assessing gfr, thus avoiding the need for the cumbersome and expensive gfr test. the mdrd formula had greater validity than the c-g equation and the c-g equation validity was improved by an adjustment to bsa. keywords: creatinine; glomerular filtration rate; diet modification; chronic kidney disease; oman. امللخ�ص: الهدف: يعد ح�صاب �رشعة �لرت�صيح �لكبيبي و�لذي يقا�س عن طريق ��صتخال�س �لكرياتيني من �أف�صل �ملوؤ�رش�ت لوظائف �لكليتي. ونظر� ل�صلبيات معادلة تعد و �لكرياتيني. ��صتخال�س على تعتمد ال �لكبيبي �لرت�صيح �رشعة حل�صاب معادالت ال�صتقاق ��صطر�لباحثون �لكرياتيني, ��صتخال�س طريقة عن �ملعادالت هذه تقييم هو �لدر��صة هذه من �لغر�س �صيوعا. �ملعادالت هذه �أكرث من �لكلى ملر�صى �لغذ�ئي �لنظام تعديل ومعادلة كوككروفت-جولت طريق �إيجاد �لعالقة بي ��صتخال�س �لكرياتيني وكل من �رشعة �لرت�صيح �لكبيبي عن طريق معادلة كوككروفت-جولت و �رشعة �لرت�صيح �لكبيبي عن طريق لقد الطريقة: �لكلى. ملر�صى �لغذ�ئي �لنظام تعديل معادلة طريق عن �لكبيبي �لرت�صيح �رشعة و �جل�صم �صطح مل�صاحة �ملعدلة كوككروفت-جولت معادلة �أجريت هذه �لدر��صة يف جممع بو�رش �لتخ�ص�صي يف حمافظة م�صقط يف عمان )�لفرتة من عام 2007و حتى عام 2011(. و مت قيا�س ن�صبة �لكرياتيني بالدم و كمية ��صتخال�س �لكرياتيني يف بول 24 �صاعة يف �ملر�صى �مل�صاركي يف �لدر��صة و عددهم مائة و ثمانية و خم�صون مري�صا. مت ح�صاب �رشعة �لرت�صيح �لكبيبي عن طريق معادلة كوككروفت-جولت و�رشعة �لرت�صيح �لكبيبي عن طريق معادلة كوككروفت-جولت �ملعدلة مل�صاحة �صطح �جل�صم و �رشعة �لرت�صيح �لكبيبي عن طريق معادلة تعديل �لنظام �لغذ�ئي ملر�صى �لكلى جلميع �ملر�صى ثم مت در��صة �لعالقة بي ��صتخال�س �لكرياتيني و بي و �رشعة �لرت�صيح �لكبيبي عن طريق �ملعادالت �لثالثة. النتائج: تبي �نه يوجد �رتباط كبريبي كل من �رشعة �لرت�صيح �لكبيبي عن طريق معادلة تعديل �لنظام �لغذ�ئي ملر�صى �لكلى و�رشعة �لرت�صيح �لكبيبي عن طريق معادلة كوككروفت-جولت �ملعدلة و�رشعة �لرت�صيح �لكبيبي عن طريق معادلة كوككروفت-جولت و بي ��صتخال�س �لكرياتيني)معامل �الرتباط= 0.701 و0.658 و0.605 بالرتتيب( و �أظهر منحنى خ�صائ�س �لت�صغيل �أن قدرة �رشعة �لرت�صيح �لكبيبي عن طريق معادلة تعديل �لنظام �لغذ�ئى ملر�صى �لكلى لت�صخي�س مر�س �لكلى �ملزمن �أعلى من قدرة �رشعة �لرت�صيح �لكبيّب عن طريق معادلة كوككروفت-جولت �ملعدلة مل�صاحة �صطح �جل�صم و �لذي بدوره �أعلى من �رشعة �لرت�صيح �لكبيبي عن طريق معادلة كوككروفتجولت )�ملنطقه حتت �ملنحنى كانت 0.846و 0.831و0.791و حدود �لقطع كانت 61.9 و58.3 و59.5 بالرتتيب( اخلال�سة: تعد معادلة كوككروفت-جولت و معادلة تعديل �لنظام �لغذ�ئى ملر�صى �لكلى بديل عن �ختبار ��صتخال�س �لكرياتيني لقيا�س �رشعة �لرت�صيح �لكبيبي مما يوؤدي �إىل جتنب �صعوبة و تكلفة هذ� �الختبار. وتعد معادلة تعديل �لنظام �لغذ�ئى ملر�صى �لكلى �أكرث دقة من معادلة كوككروفت-جولت �ملعدلة مل�صاحة �صطح �جل�صم و �لتي بدورها �أكرث دقة من معادلة كوككروفت-جولت �الأ�صلية. مفتاح الكلمات: �لكرياتيني؛ �رشعة �لرت�صيح �لكبيبي؛ تعديل �لنظام �لغذ�ئي؛ مر�س �لكليتي �ملزمن؛ عمان. assessment of glomerular filtration rates by cockcroft-gault and modification of diet in renal disease equations in a cohort of omani patients *magdi e. al-osali,1 salim s. al-qassabi,2 saud m. al-harthi2 clinical & basic research magdi e. al-osali, salim s. al-qassabi and saud m. al-harthi clinical and basic research | e73 glomerular filtration rate (gfr) is considered the best index of renal function as it assesses the progression of kidney dysfunction. the normal value is ~130 and 120 ml/min/1.73 m² for men and women, respectively, depending on age, sex and body size.1 gfr can be determined by measuring the clearance of exogenous (inulin, 125-iothalamate, 51 crethylene diamine tetra acetic acid [edta], 99mtcdiethylene triamine penta acetic acid [dtpa] and iohexol) or endogenous (creatinine) substances.2 methods using exogenous substances are expensive, time-consuming, risky and cannot be easily implemented in clinical practice. nevertheless, inulin clearance is the gold standard test for gfr as it is freely filtered and is not secreted, reabsorbed, synthesised or metabolised by the kidney.3 creatine clearance (clcr) is an alternative to inulin clearance. creatinine is freely filtered and is not metabolised by the kidney; however, it is secreted by the renal tubules.4 if the effect of secretion is ignored, then all of the filtered creatinine will be excreted and this will reflect the gfr. thus the gfr and clcr will be equal: [ucr x v]/scr,5 where ucr is urine creatinine, v is the 24hour urine volume and scr is the serum creatinine. however, clcr tends to exceed the true gfr due to tubular secretion.5 it should therefore be adjusted to body surface area (bsa) so as to obtain the corrected creatinine clearance (cclcr) in ml/min/1.73 m² by the following equation:6 the normal value of cclcr is 95 ± 20 ml/min per 1.73 m² in women and 120 ± 25 ml/min per 1.73 m2 in men.5 scr varies inversely with gfr and is used to assess stable kidney function, as a rise in scr represents a reduction in gfr. however, in acute renal failure, gfr is markedly reduced and there is no time for creatinine to accumulate.6 the mean scr values for men and women are 100 and 82 µmol/l, respectively. these values vary by race and differ according to its production, secretion, extrarenal excretion and assay.7,8 the limitations of clcr and inulin clearance have inspired researchers to seek out easy formulas to estimate gfr (egfr).9 the most widely used formulas are cockcroft-gault (c-g)10 and the modification of diet in renal disease (mdrd).11 these formulas include variables such as age, sex, race, weight and scr. in adults, normal egfr is ≥90 ml/min/1.73m². chronic kidney disease (ckd) is defined by an egfr of <60 ml/min/1.73 m2.9 as for scr, the proper interpretation of these equations requires stable kidney function, and its accuracy is also limited as scr is affected by factors other than creatinine filtration.12,13 in the c-g equation, clcr can be estimated by the following formula:10 this formula should be adjusted for bsa to increase its accuracy and compare normal values.14 it appears to be less accurate in the obese, those of different ethnicities, different age groups, children and pregnant women.1 the original mdrd equation has six variables, including urea and albumin which was a limitation advances in knowledge methods using exogenous substances to assess renal function are expensive, time-consuming, risky and cannot be easily implemented in clinical practice. additionally, creatinine clearance (clcr) has some limitations. due to the limitations of the clearance tests, they are frequently replaced by estimation equations such as cockcroft-gault (c-g) and the modification of diet in renal disease (mdrd) formulas. in this study, the mdrd formula had greater validity than the c-g equation and the c-g equation validity was improved by an adjustment to body surface area. applications to patient care the knowledge that c-g and mdrd equations can be used as an alternative to the clcr test for assessing gfr will enable the patient to avoid the time-consuming, cumbersome and expensive clcr test. it will be easier for the clinician to follow the progress of kidney disease by assessing egfr with these equations, depending on patient age, weight and serum creatinine. it will also circumvent the need for 24-hour urine collection. the mdrd formula is recommended to assess egfr in patients with chronic kidney disease as it has greater validity than the c-g equation. cclcr = (clcr x 1.73) bsa clcr (ml/min) = (140 age in years ) x (weight in kg) x 1.23 if male (1.04 if female)/scr in µmol/l assessment of glomerular filtration rates by cockcroft-gault and modification of diet in renal disease equations in a cohort of omani patients e74 | squ medical journal, february 2014, volume 14, issue 1 egfr (ml/min per 1.73 m2) = 1.75 x scr-1.154 x age0.203 x 1.212 (if of african descent) x 0.742 (if female), where scr is in µmol/l and age in years for the added cost and analytical variation.13 recognising this, the mdrd-4 variable equation was developed based on scr, age, gender and ethnicity by the following formula:15 this study was conducted primarily to evaluate the performance of c-g and mdrd equations in omani patients by finding out the relation between cclcr and egfr by using c-g (egfrc-g), modified c-g (egfrmc-g ) and mdrd (egfrmdrd) equations. secondly, we sought to replace the clcr test with egfr for the assessment of kidney function in clinical practice, thereby avoiding the need for the time-consuming, cumbersome and expensive clcr test. methods this cross-sectional analytical study was carried out at bowsher polyclinic, muscat, oman, by auditing the files of subjects reporting to the internal medicine clinic for a clcr test to assess kidney function from 1 january 2007 to 30 april 2011. ethical approval was received from the regional research & ethics committee of the directorate general & health services of the muscat region. the inclusion criteria included adult patients who reported to the internal medicine clinic at polyclinic for a clcr test. however, patients who had incomplete data or dialysis therapy were excluded; thus 97 of the 255 files reviewed could not be considered, leaving a total of 158 subjects. demographic data, such as age, gender, weight, height, body mass index (bmi) and bsa, were recorded. all subjects were analysed for scr and subjected to 24-hour urine collection to estimate urine volume (v) and urine creatinine (ucr). the clcr was calculated by the following equation:5 the clcr was then adjusted to bsa to get cclcr in ml/min per 1.73 m² by the following formula, where bsa equals the square root ([height in cm x weight in kg]/3600):8,16 depending on a patient’s gender, age and scr, c-g was used to obtain the predicted clcr, which was abbreviated as egfrc-g, as in the following formula:10 the egfrc-g (ml/min) was adjusted to bsa (modified c-g) to obtain egfrmc-g (ml/min per 1.73 m²): egfrmc-g = egfrc-g x 1.73/bsa. the mdrd-4 variable equation was used to obtain egfrmdrd in ml/min per 1.73 m² by the following formula:15 the egfrc-g, egfrmc-g and egfrmdrd were compared to cclcr and statistical analysis was done to find out the correlation between them and to estimate an agreement between them. data were coded using the statistical package for the social sciences (spss), version 15 (ibm, corp., chicago, illinois, usa) and summarised using the mean, standard deviation (sd), minimal and maximum values for quantitative variables and number and percentage for qualitative values. correlations were done to test for linear relations between variables. logistic regression analysis was done to test for significant predictors of dependent variables. a receiver operating characteristic (roc) curve was used to test the validity of scores calculated by regression equations. a p value of ≤0.05 was considered statistically significant. results the subjects in the study (n = 158) were predominantly <70 years of age (n = 115), although 43 were ≥70 years. the gender distribution was nearly equal (85 males and 73 females) and 42 were obese while 116 were not considered obese. of those included in the study, 99 had diabetes (dm) and 59 were non-diabetic. the mean ± sd (range) age was 61.65 ± 10.46 (34.0–82.0); bmi was 27.93 ± 5.89 (16.6–54.6); scr was 108.23 ± 47.12 (28.0–373.0); cclcr was 69.52 ± 37.28 (10.30–196.5); egfrmdrd was 62.89 ± 27.52 (14.0–206.0); egfrmc-g was 66.37 ± 28.09 (18.3–154.3), and egfrc-g was 66.87 ± cclcr =(clcr x 1.73) bsa cclcr (ml/min)=(ucr x v) scr egfrc-g (ml/min) = (140 age in years) x (weight in kg) x 1.23 if male (1.04 if female )/scr in µmol/l. egfrmdrd = 175 x scr-1.154 x age-0.203) x 1.212 (if of african descent) x 0.742 (if female), where scr is in µmol/l and age in years. none of our patients were of african descent. magdi e. al-osali, salim s. al-qassabi and saud m. al-harthi clinical and basic research | e75 30.54 (20.21–163.92) of the studied subjects. the egfrmdrd, egfrmc-g and egfrc-g correlated significantly with cclcr, with a slightly stronger correlation with egfrmdrd (r = 0.701, 0.658 and 0.605, respectively; p <0.001). studying egfrmdrd, egfrmc-g and egfrc-g at a known cut-off value of 90 found that egfrmc-g had a higher validity than egfrc-g and that egfrmdrd had a higher sensitivity and lower specificity than either egfrmc-g or egfrc-g (sensitivity = 97.4, 93.6 and 92.3; specificity = 22.5%, 27.5% and 26.3%, respectively). the roc curve analysis showed that the diagnostic accuracy of egfrmc-g for a diagnosis of ckd was higher than that of egfrc-g. the egfrmdrd had a higher area under the curve (auc) and higher sensitivity and lower specificity than either egfrc-g or egfrmc-g [figure 1 and table 1]. regression analysis was performed to predict renal impairment by using egfrc-g adjusted for age, sex, obesity and dm. a regression equation was applied to calculate the predicted score for each patient (ranging from 0–100). the predicted score was entered in a roc curve to detect its validity as well as to determine the best cut-off value for diagnosing renal impairment. the same was done for egfrmc-g and egfrmdrd for comparison. a roc curve analysis showed that the egfrmc-g score had a higher auc, sensitivity, negative predictive value (npv) and total accuracy (ta), and lower specificity and positive predictive value (ppv) than the egfrc-g score. additionally, the egfrmdrd score had a higher validity than the egfrmc-g score [figure 2 and table 2]. regarding the validity among the studied groups, the egfrmdrd had a higher validity than either egfrc-g or egfrmc-g in the obese, diabetic, male or the ≥70-year-old subjects. comparing the validity of egfrmc-g and egfrc-g, this study also showed that egfrmc-g had higher validity in the table 1: the validity of egfrc-g, egfrmc-g and egfrmdrd as a diagnostic tool for renal impairment after receiver operating characteristic curve analysis auc p value cut-off values* sensitivity specificity ppv npv ta egfrc-g 0.791 <0.001 ≤59.5 73.1 80.0 78.1 75.3 76.6 egfrmc-g 0.831 <0.001 ≤58.3 75.6 85.0 83.1 78.2 80.4 egfrmdrd 0.846 <0.001 ≤61.9 82.1 72.5 74.4 80.6 77.2 auc = area under the curve; ppv = positive predictive value; npv = negative predictive value; ta = total accuracy; egfrc-g = estimated glomerular filtration rate by cockcroft-gault equation; egfrmc-g = estimated glomerular filtration rate by modified cockcroft-gault equation; egfrmdrd = estimated glomerular filtration rate by modification of diet in renal disease. *mg/min for egfrc-g and mg/min/1.73 m2 for egfrmc-g and egfrmdrd . figure 1: the validity of egfrc-g , egfrmc-g and egfrmdrd as a diagnostic tool for renal impairment after receiver operating characteristic curve analysis. egfrc-g = estimated glomerular filtration rate by cockcroftgault equation; egfrmc-g = estimated glomerular filtration rate by modified cockcroft-gault equation; egfrmdrd = estimated glomerular filtration rate by modification of diet in renal disease. figure 2: receiver operating characteristic curve for egfrc-g , egfrmc-g and egfrmdrd for the assessment of kidney function after adjustment for age, sex, weight and diabetes mellitus*. egfrc-g = estimated glomerular filtration rate by cockcroftgault equation; egfrmc-g = estimated glomerular filtration rate by modified cockcroft-gault equation; egfrmdrd = estimated glomerular filtration rate by modification of diet in renal disease. *predicted probability 1 by egfrc-g ; predicted probability 2 by egfrmc-g ; predicted probability 3 by egfrmdrd . assessment of glomerular filtration rates by cockcroft-gault and modification of diet in renal disease equations in a cohort of omani patients e76 | squ medical journal, february 2014, volume 14, issue 1 ≥70-year-old, male and diabetic subjects; however, in the obese subjects, egfrmc-g was more sensitive but had less specificity, ppv, npv and ta than in egfrc-g [table 3]. discussion gfr is the best index of renal function in health and disease. it can be estimated by measuring the renal clearance of certain substances using exogenous (radioisotopic and non-radioisotopic) filtration markers. however, these methods are impractical and expensive.17 endogenous markers such as creatinine have also been used to assess gfr. the accuracy of clcr may be limited by inaccurate urine collection and creatinine secretion. not only is urine collection time-consuming and cumbersome, but incomplete collection leads to a reduced clcr while over-collection leads to an increased clcr.8 moreover, clcr overestimates the gfr due to tubular creatinine secretion.5 to compensate for these previous limitations, investigators have devised equations that predict gfr based on scr, gender, body size, race and age. the most widely used equations are the c-g equation, which produces gfr values in ml/min, and the mdrd equation, which produces gfr values in ml/min per 1.73 m².18 the c-g equation should be adjusted for bsa to increase its accuracy and enable a comparison with normal values.14 in this study, we evaluated the performance of the c-g and mdrd equations for estimating the gfr in a cohort of 158 subjects. an important characteristic of the cohort is that it included subjects whose cclcr ranged from 10.3–196.5 ml/ min per 1.73 m² with sufficient numbers of subjects having cclcr >60 and <60 (84 and 74, respectively). thus, the performance of these equations could be assessed over a wide range of kidney function. furthermore, because all patients included in this study were arab, the performances of the c-g and mdrd equations could be assessed in a group of subjects whose anthropometric characteristics are slightly different from those of american or european subjects. with these different anthropometric characteristics in mind, we compared egfrmdrd, egfrmc-g and egfrc-g with cclcr. it was found that these equations underestimated gfr in comparison to cclcr (mean cclcr, egfrmdrd, egfrmc-g and egfrc-g were 69.52, 62.89, 66.37 and 66.87, respectively). this can be explained by the fact that cclcr exceeds the true gfr by 19% because of tubular secretion.5 in their study, froissart et al. showed that there was a very good global agreement between measured gfr and both egfrmdrd and egfrmc-g. on average, egfrmdrd was only 1.0 ml/ min per 1.73 m² less than measured gfr; egfrmc-g was only 1.9 ml/min per 1.73 m² greater than measured gfr. however, froissart et al.’s study compared egfrmdrd and egfrmc-g against gfr measured by 51cr-edta renal clearance, and not cclcr, and did not evaluate egfrc-g.19 similarly, in 1999, levey et al. documented that the c-g formula largely overestimated measured gfr.13 the current study demonstrated that egfrmdrd, egfrmc-g and egfrc-g can replace cclcr in practice, avoiding the limitations of cclcr, as evidenced by the significant correlation between them, with a stronger correlation with egfrmdrd (r = 0.701, 0.658 and 0.605, respectively; p <0.001). these results are supported by a pakistani study which compared egfrmdrd and egfrc-g with cclcr in 369 cases, revealing a significant correlation between them, with a stronger correlation with egfrmdrd (r = 0.788 for egfrmdrd and r = 0.775 for egfrc-g). however, that study did not evaluate egfrmc-g.18 in 2006, shoker et al. compared table 2: the validity of egfrc-g, egfrmc-g and egfrmdrd as a diagnostic tool for the assessment of kidney function after adjustment for age, sex, weight and diabetes auc p value cut-off values* sensitivity specificity ppv npv ta egfrc-g 0.806 <0.001 ≥48.7 80.8 73.8 75.0 79.7 77.2 egfrmc-g 0.841 <0.001 ≥46.3 84.6 71.3 74.2 82.6 77.8 egfrmdrd 0.853 <0.001 ≥48.4 84.6 73.8 75.9 83.1 79.1 auc = area under the curve; ppv = positive predictive value; npv = negative predictive value; ta = total accuracy; egfrc-g = estimated glomerular filtration rate by cockcroft-gault equation; egfrmc-g = estimated glomerular filtration rate by modified cockcroft-gault equation; egfrmdrd = estimated glomerular filtration rate by modification of diet in renal disease. *mg/min for egfrc-g and mg/min/1.73 m2 for egfrmc-g and egfrmdrd . magdi e. al-osali, salim s. al-qassabi and saud m. al-harthi clinical and basic research | e77 egfrmc-g and egfrc-g with cclcr, documenting that egfrmc-g gave superior results compared to egfrc-g, with an overall accuracy in the general and subgroup analysis.14 similarly, our results showed that egfrmc-g had a stronger correlation with cclcr than egfrc-g emphasising that the correction for bsa increases the validity of the c-g equation. the difference between the two studies is that egfrmc-g and egfrc-g were compared with clcr in the shoker et al. study, but in our study they were compared with cclcr, which is more accurate. in 2012, alcântara et al. compared egfrc-g with cclcr and no significant difference was found between the mean egfrc-g (64.7 ± 27.4) and the mean cclcr (68.4 ± 32.6) and a correlation between them was found (r = 0.68; p <0.001). using lean body weight instead of total body weight to obtain the egfrc-g, the correlation coefficient was increased to 0.75 (p <0.001).20 however, alcântara et al.’s study did not evaluate egfrmc-g and egfrmdrd, as in our study. in studying egfrmdrd, egfrmc-g and egfrc-g as a diagnostic tool for renal impairment, as table 3: the validity of egfrc-g, egfrmc-g and egfrmdrd in diagnosing renal impairment among different studied groups variable egfr group sensitivity specificity ppv npv ta age egfrc-g <70 76.5 84.4 79.6 81.8 80.9 egfrmc-g <70 82.4 81.3 77.8 85.2 81.7 egfrmdrd <70 82.4 79.7 76.4 85.0 80.9 egfrc-g ≥70 88.9 31.3 68.6 62.5 67.4 egfrmc-g ≥70 88.9 31.3 68.6 62.5 67.4 egfrmdrd ≥70 88.9 50.0 75.0 72.7 74.4 sex egfrc-g f 83.8 72.2 75.6 81.3 78.1 egfrmc-g f 83.8 72.2 75.6 81.3 78.1 egfrmdrd f 83.8 72.2 75.6 81.3 78.1 egfrc-g m 78.0 75.0 74.4 78.6 76.5 egfrmc-g m 85.4 70.5 72.9 83.8 77.6 egfrmdrd m 85.4 75.0 76.1 84.6 80.0 bmi egfrc-g not 81.8 78.7 77.6 82.8 80.2 egfrmc-g not 85.5 77.0 77.0 85.5 81.0 egfrmdrd not 83.6 77.0 76.7 83.9 80.2 egfrc-g obese 78.3 57.9 69.2 68.8 69.0 egfrmc-g obese 82.6 52.6 67.9 71.4 69.0 egfrmdrd obese 87.0 63.2 74.1 80.0 76.2 dm egfrc-g dm 87.3 56.8 71.6 78.1 73.7 egfrmc-g dm 89.1 56.8 72.1 80.6 74.7 egfrmdrd dm 89.1 61.4 74.2 81.8 76.8 egfrc-g no dm 65.2 94.4 88.2 81.0 83.1 egfrmc-g no dm 73.9 88.9 81.0 84.2 83.1 egfrmdrd no dm 73.9 88.9 81.0 84.2 83.1 egfr = estimated glomerular filtration rate; ppv = positive predictive values; npv = negative predictive value; ta = total accuracy; egfrc-g = estimated glomerular filtration rate by cockcroft-gault equation; egfrmc-g = estimated glomerular filtration rate by modified cockcroft-gault equation; egfrmdrd = estimated glomerular filtration rate by modification of diet in renal disease; bmi = body mass index; f = female; m = male; dm = diabetes mellitus. assessment of glomerular filtration rates by cockcroft-gault and modification of diet in renal disease equations in a cohort of omani patients e78 | squ medical journal, february 2014, volume 14, issue 1 detected by cclcr and at a known cut-off value of 90, it was found that egfrmc-g had a higher validity than egfrc-g. this emphasises that correction for bsa increases the validity of the c-g equation and that egfrmdrd had a higher sensitivity and lower specificity than either egfrmc-g or egfrc-g. a roc curve analysis showed that the diagnostic accuracy of egfrmc-g for diagnosing ckd was higher than that of egfrc-g, and that egfrmdrd had a higher sensitivity, higher auc and a lower specificity than either egfrc-g or egfrmc-g. by doing a regression analysis to predict renal impairment, using egfrc-g, egfrmc-g and egfrmdrd adjusted for age, sex, obesity and dm, the roc curve analysis showed that the egfrmc-g score had a higher auc, sensitivity, npv and ta, and a lower specificity and ppv than that of the egfrc-g score. additionally, it showed that the egfrmdrd score had a higher validity than the egfrmc-g score. our results supported those of srinivas et al., whose study compared egfrmdrd and egfrmc-g with gfr measured by 99mtc-dtpa renal clearance in 599 renal donors; this study demonstrated that egfrmdrd performed better in terms of global bias, precision, correlation and accuracy than egfrmc-g.21 regarding the validity among studied groups, our study showed that egfrmdrd had a higher validity than either egfrc-g or egfrmc-g in males, those with dm, individuals ≥70 years of age and those who were obese. the egfrmc-g had higher validity in diabetics, males and those ≥70 years of age than egfrc-g; however, in the obese subjects, egfrmc-g was more sensitive but had less specificity, ppv, npv and ta than egfrc-g. this was similar to froissart et al.’s study, which showed that egfrmc-g had the lowest level of precision for obese subjects.19 in 2005, rigalleau et al. compared egfrmdrd and egfrmc-g with measured gfr in 160 diabetic patients, and revealed that egfrmdrd and egfrmc-g correlated well with measured gfr, while egfrmdrd underestimated and egfrmc-g overestimated it. the roc curve analysis showed that the maximum diagnostic accuracy of egfrmc-g for diagnosing ckd was lower than that of egfrmdrd. it was concluded that the mdrd equation is more accurate for the diagnosis of renal failure in diabetic patients.22 however, egfrmdrd and egfrmc-g were evaluated against measured gfr by 51cr-edta clearance and not against cclcr. the egfrc-g was not evaluated. based on the current study, as well as other studies, it is clear that the measurement of clcr using a 24-hour urine collection system does not improve the estimate of gfr compared to that provided by the c-g and mdrd equations. nevertheless, this system provides useful information for the estimation of gfr in individuals with unsual dietary intake (for example in subjects with vegetarian diets or those taking creatine supplements), or abnormal muscle mass (for instance as a result of amputation, malnutrition or muscle wasting). it is also useful for the assessment of diet and nutritional status, and for assessing the patient’s status when there is a need to start dialysis.9 there are several limitations to this study. first, clcr was used as the reference method for gfr although the measurement of clcr has many theoretical and practical difficulties. ideally it should be substituted by inulin or isotope clearances as a reference to verify the accuracy of the results. second, it would be more relevant to compare c-g and mdrd formulas in a multicentre environment. conclusion c-g and mdrd equations can be used as an alternative to the clcr test for assessing gfr, thereby avoiding the cumbersome, time-consuming and expensive gfr test. the mdrd formula had better validity in this study than the c-g equation and the validity of the c-g equation was improved by an adjustment to the bsa. references 1. stevens la, levey as. measurement of kidney function. med clin north am 2005; 89:457–73. 2. gaspari f, perico n, remuzzi g. application of newer clearance techniques for the determination of glomerular filtration rate. curr opin nephrol hypertens 1998; 7:675– 80. 3. rahn kh, heidenreich s, brückner d. how to assess glomerular function and damage in humans. j hypertens 1999; 17:309–17. 4. shemesh o, golbetz h, kriss jp, myers bd. limitations of creatinine as a filtration marker in glomerulopathic patients. kidney int 1985; 28:830–8. 5. doolan pd, alpen el, theil gb. a clinical appraisal of the plasma concentration and endogenous clearance of creatinine. am j med 1962; 32:65–79. magdi e. al-osali, salim s. al-qassabi and saud m. al-harthi clinical and basic research | e79 6. rule ad, bergstralh, ej, slezak jm, bergert j, larson ts. glomerular filtration rate estimated by cystatin c among different clinical presentations. kidney int 2006; 69:399– 405. 7. jones ca, mcquillan gm, kusek jw, eberhardt ms, herman wh, coresh j et al. serum creatinine levels in the us population: third national health and nutrition examination survey. am j kidney dis 1998; 32:992–9. 8. inker la, perrone rd. assessment of kidney function. from: www.uptodate.com/contents/assessment-of-kidneyfunction accessed: mar 2012. 9. national kidney foundation. k/doqi clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. am j kidney dis 2002; 39:s1–266. 10. cockcroft dw, gault mh. prediction of creatinine clearance from serum creatinine. nephron 1976; 16:31–41. 11. levey as, greene t, kusek jw, beck gj. a simplified equation to predict glomerular filtration rate from serum creatinine. j am soc nephrol 2000; 11:155a. 12. levin a. the advantage of a uniform terminology and staging system for chronic kidney disease (ckd). nephrol dial transplant 2003; 18:1446–51. 13. levey as, bosch jp, lewis jb, greene t, rogers n, roth d. a more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. modification of diet in renal disease study group. ann intern med 1999; 130:461–70. 14. shoker a, hossain ma, koru-sengul t, raju dl, cockcroft d. performance of creatinine clearance equations on the original cockcroft-gault population. clin nephrol 2006; 66:89–97. 15. levey as, coresh j, greene t, stevens la, zhang yl, hendriksen s, et al. using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. ann intern med 2006; 145:247–54. 16. mosteller rd. simplified calculation of body surface area. new engl j med 1987; 317:1098. 17. lin j, knight el, hogan ml, singh ak. a comparison of prediction equations for estimating glomerular filtration rate in adults without kidney disease. j am soc nephrol 2003; 14:2573–80. 18. zubairi am, hussain a. the glomerular filtration rate: comparison of various predictive equations based on serum creatinine with conventional creatinine clearance test in pakistani population. j pak med assoc 2008; 58:182– 5. 19. froissart m, rossert j, jacquot c, paillard m, houillier p. predictive performance of the modification of diet in renal disease and cockcroft-gault equations for estimating renal function. j am soc nephrol 2005; 16:763–73. 20. alcântara p, gonçalves f, moreira c, gonzalez ma. [assessment of glomerular filtration rate in a hospital population. comparison of two methods]. acta med port 1998; 11:767–72. 21. srinivas s, annigeri ra, mani mk, rao bs, kowdle pc, seshadri r. estimation of glomerular filtration rate in south asian healthy adult kidney donors. nephrology (carlton) 2008; 13:440–6. 22. rigalleau v, lasseur c, perlemoine c, barthe n, raffaitin c, liu c, et al. estimation of glomerular filtration rate in diabetic subjects: cockcroft formula or modification of diet in renal disease study equation? diabetes care 2005; 28:838–43. first published in 1989, this book has sold over 15 million copies. the reason for its success would seem to because the book ignores trends and pop psychology for proven principles of fairness, integrity, honesty, and human dignity. after a positive overview of the seven habits of highly effective people, the book is divided into four parts: in part one, paradigms and principles, the author discusses personality and character ethics, primary and secondary greatness. he also explains the power of a paradigm in which the seven habits of highly effective people embody many of the fundamental and primary principles of human effectiveness. part two, private victory, discusses the first three of the seven habits. habit 1 is be proactive, principles of personal vision. this means that selfawareness enables us to stand apart and examine the way we see ourselves, our self-paradigm. imagination, conscience and independence are other principles of this proactive model. habit 2 is begin with the end in mind. here principles of personal leadership are explained. leaders may be very busy people, but in order to be both efficient and truly effective, their goals need to be foremost in their mind. this habit is based on the principle that all things are created twice. there is a mental or first creation, and a physical or second creation of all things. in order to write a personal mission statement, we must begin at the very centre of our circle of influence; that centre is comprised of our most basic paradigms, the lens through which we see the world. habit 3 is put first things first. this is my favourite habit as it provides the principles of personal management. it teaches that the things which matter most must never be at the mercy of vìë^«◊÷<∞÷^ �√à÷]<î^~ç˙÷<ì√f �ä÷]<l]å^√÷] íí~ �é÷]<4è«j◊÷<ìëáœ<åêöå<  book review the seven habits of highly effective people author: stephen r. covey publisher: fireside books, simon & schuster, free press, 15th anniversary edition, 2004 isbn-13: 978-0-7432-6951-3 and isbn-10: 0-7432-6951-94 orders: https://www.stephencovey.com/7habits/7habits.php squ med j, august 2011, vol. 11, iss. 3, pp. 426-427, epub. 15th aug 11 submitted 13th mar stephen r. covey book review | 427 things which matter least. the author provides a description of the time management matrix which divides activities into four types: 1. urgent and important; 2. important and not urgent; 3. urgent and not important, and 4. not urgent and not important, i.e. things which can be considered for delegation. in part three, public victory, the author covers the next three habits, focusing on the paradigms of interdependence. habit 4 is think win/win. here principles of interpersonal leadership are explained.‘win/win’ is a frame of mind and heart that constantly seeks mutual benefit in all human interactions. this principle sets the stage for life in a cooperative, not competitive arena. habit 5 is entitled seek first to understand, then to be understood. this habit covers the principles of empathetic communication. it introduces five important responses: listening, evaluating, probing, advising, and interpreting. habit 6 is synergize. this leads to the principles of creative cooperation where we communicate synergistically by opening our mind and heart to new possibilities, alternatives, and options. the final part of the book is entitled renewal and covers the seventh habit sharpen the saw. here the four dimensions of balanced self-renewal are described, corresponding to the four elements of human nature: physical, spiritual, mental, and social/emotional. the strengths of this popular book are that it is concise and informative with plenty of examples and realistic stories to demonstrate the philosophy of the seven habits of highly effective people. it also contains tables, pictures and figures which help to illustrate ideas. the message is further underlined as the description of every habit starts with a proverb and ends with suggestions for applications. the book has, however, some weaknesses. some sections of the text are difficult to understand, especially for ‘english as a second language’ readers. also, surprisingly, the figures and tables are not labelled in the text. not withstanding these minor weaknesses, i recommend this book to all faculty members, teachers, leaders, managers, especifically to those strive for effectiveness and efficiency in leadership. r e v i e w e r thuraya a al-shidhani oman medical specialty board and department of family & community medicine university of toronto, canada email: shidhanitutu@yahoo.com acknowledgment: i wish to thank vinita arora for editing this article sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 32-42, epub. 27th feb 13 submitted 24th apr 12 revision req. 8th aug 12, revision recd. 15th sep12 accepted 18th oct 12 1department of mathematics & statistics, sultan qaboos university, muscat, oman; 2directorate general of planning, ministry of health, muscat, oman *corresponding author e-mail: mislam@squ.edu.om األمناط املتعلقة بزواج اإلناث يف عمان مظهر اإ�صالم، ات�صوا �ض دورفلوا، اأحمد القا�صمي امللخ�ص: الهدف: تهدف هذه الدرا�صة اإىل درا�صة الأمناط العمانية املتعلقة بزواج الإناث، مبا يف ذلك �صن الزواج والعوامل املوؤثرة يف حتديد ال�صن الذي تتزوج فيه املراأة لأول مرة. الطريقة: ا�صتخدمت الدرا�صة بيانات من امل�صح الوطني لل�صحة عام 2000. وقد مت حتليل البيانات با�صتخدام التحليالت الإح�صائية الأحادية والثنائية ومتعددة املتغريات، مبا يف ذلك حتليل النحدار اللوج�صتي. النتائج: يعد زواج الأقارب اأحد اأهم اأمناط الزواج املنت�رسة يف عمان، حيث ي�صكل زواج الأقارب اأكرث من ن�صف اإجمايل الزيجات يف عمان )%52(، الزواج من ابن العم هو النوع الأكرث �صيوعا يف زواج الأقارب، حيث ي�صكل %39 من جميع حالت الزواج و %75 من جميع حالت زواج الأقارب. �صكل تعدد الزوجات حوايل %11 من اإجمايل الزيجات. كما ل يزال الزواج املبكر وا�صع النت�صار يف عمان. اأما بالن�صبة ل�صن الزواج، فاإن %75من الن�صاء الالتي �صملتهن الدرا�صة وتراوحت اأعمارهن بني 44-20 �صنة قد تزوجن قبل �صن الع�رسين، واأن متو�صط ال�صن عند زواجهن الأول كان 16 �صنة. ومع ذلك فاإن متو�صط �صن املراأة عند الزواج يتزايد تدريجيا، حيث اأن هذا التغيري اأ�صبح وا�صحا ب�صكل خا�ض يف الآونة الأخرية يف زواج اجليل الأ�صغر من الإناث، ويف فئات اجتماعية وثقافية معينة. اأظهر التحليل متعدد املتغريات اأن تعليم الإناث، الفئة العمرية، احلالة ال�صكنية، منطقة الإقامة، اأنواع الزواج، والتوظيف، تعد من اأهم العوامل التي حتدد �صن املراأة العمانية عند الزواج. اخلال�صة: اإن التزايد امللحوظ يف عدد ال�صباب يف عمان مع ميولهم اإىل تاأخري الزواج قد ي�صكل ظاهرة دميوغرافية خطرية ذات تداعيات اجتماعية واقت�صادية و�صيا�صية، مما يربز احلاجة املا�صة لفهم خ�صائ�ض اجليل اجلديد من ال�صباب واهتماماتهم ومتطلباتهم وذلك لو�صع ال�صيا�صات املالئمة ملعاجلة هذه الق�صايا والتحديات التي تواجه ال�صباب غري املتزوجني. مفتاح الكلمات: ال�صن عند الزواج الأول، زواج الأقارب؛ الزواج؛ تعدد الزوجات؛ عمان. abstract: objectives: the purpose of this study was to examine omani patterns of female nuptiality, including the timing of marriage and determinants of age at a woman’s first marriage. methods: the study utilised data from the 2000 oman national health survey. univariate, bivariate, and multivariate statistical methods, including logistic regression analysis, were used for data analysis. results: one of the most important aspects of the marriage pattern in oman is the high prevalence of consanguineous marriages, as more than half (52%) of the total marriages in oman are consanguineous. first cousin unions are the most common type of consanguineous unions, constituting 39% of all marriages and 75% of all consanguineous marriages. about 11% of the marriages are polygynous. early and universal marriage is still highly prevalent in oman. three-quarters (75%) of married women respondents aged 20–44 years were married by age 20, with their median age at their first wedding being 16 years. however, women’s average age upon marriage is gradually increasing. the change is especially apparent in more recent marriages or among younger cohorts of women, and for certain socio-cultural groups. multivariate analysis identified female education, age cohort, residential status, region of residence, types of marriage, and employment as strong predictors of omani women’s age at marriage. conclusion: the growing number of young adults, accompanied by their tendency to delay marriage, may have serious demographic, social, economic, and political ramifications for oman, highlighting the need to understand the new situation of youth, their unique characteristics, and their interests and demands. culturally appropriate policies need to be implemented to address the issues and challenges of unmarried young adults. keywords: nuptial; consanguinity; marriage; polygyny; oman. the pattern of female nuptiality in oman *m. mazharul islam,1 atsu s. dorvlo,1 ahmed m. al-qasmi2 clinical & basic research advances in knowledge this study sheds light on the pattern of female nuptiality in oman which has implications for an evidence-based approach for all spheres of women’s reproductive health. understanding the determinants of the timing of a woman’s first marriage is very important from a population policy perspective. application to patient care studying omani patterns of female nuptiality has a direct impact on the allocation of resources and the laying of groundwork for evidence-based family planning and the formulation of health policy, planning, and management. m. mazharul islam, atsu s. dorvlo and ahmed m. al-qasmi clinical and basic research | 33 oman is an oil-rich arab muslim country, located in the southeast of the arabian peninsula. according to the 2010 population census, the population is about 2.7 million, of which 27% are non-omanis, occupying a land area of 309,500 square kilometers (about 8 persons per km2). the country had a turbulent past, characterised by internal tribal strife in the 19th and early 20th centuries. prior to the commercial exploitation of oil in late 1960s, the economy of oman consisted of subsistence agriculture and fishing. social and economic infrastructure was almost non-existent. by late 1980s, oman had been transformed into a modern state with modern facilities and infrastructure. the standard of living, women’s education, and the status of omanis have all improved enormously since the mid-1980s.1 women’s participation in the paid labour force is also increasing in oman.2 the social system in oman is structured around the family and linked to traditional and religious teachings that consider family formation to be the basic function of society. the family is the unit in which reproduction is authorised; reproduction is expected to occur through marriage. marriage and establishing a family are treated as essential and sacred. hashemi gives the legal minimum age at which boys and girls can marry as 18 years.3 in the past, the primary role of women was to bear and raise children. today, this role is still central, but has been modified somewhat given the increasing participation of women in higher education and in the labour force.4 like most other countries in the arab world, oman is in the midst of social, economic, and cultural transformations that are dramatic in pace and effect. families are undergoing major changes as new patterns of marriage and family formation emerge across the arab world.5 arab and muslim countries of the region have traditionally been characterised by women marrying in their teens. traditionally, men have married later. there has been an expectation of universal marriage for both sexes, a large age difference between spouses, high levels of consanguineous marriage or endogamy (particularly marriages between maternal and paternal cousins), and the presence of polygyny.6–10 however, this tradition of early and universal marriage has been diminishing and the mean age of marriage rising. in oman, the singulate mean age at marriage (smam) for females increased from 19.2 years in 1988 to 23.5 years in 2000.11,12 more arab women are staying single longer or not marrying at all.5,8 all of these changes are introducing new issues and challenges into arab societies. changes in marriage patterns have been seen as precursors of demographic transition in most societies.13 changes in nuptiality patterns have played a very significant role in many european demographic transitions.14 in western europe, people typically stay single longer, leading to later first marriages. the combination of widespread celibacy and the trend of later marriage has led to lower fertility rates. female age at marriage is becoming an important demographic variable due to its influence on fertility and population growth, especially in countries like oman where rates of contraceptive use are still low.15 oman’s universality of marriage and relatively early marriages, coupled with the onset of childbearing soon after marriage, makes it imperative, from a population policy perspective, to understand the determinants and correlates of the timing of marriage. thus, the objective of this study was to analyse oman’s marriage patterns and examine the levels, trends, and determinants of age at first marriage. methods this study utilised data extracted from the 2000 oman national health survey (onhs). the details of the survey may be seen elsewhere.12 the survey was conducted by the ministry of health (moh) of oman with technical support from united nations (un) organisations such as the united nations population fund (unfpa) and the united nations children’s fund (unicef), the world health organization (who), and the un statistics division. the survey considered households of omani nationals only. women who were under 50 years of age and were or had ever been married were eligible respondents. the onhs 2000 covered a nationally representative sample of 2,013 omani households and 2,037 eligible women were successfully interviewed. the survey contained a wide range of data on general health of the household members and reproductive health characteristics of women including their nuptiality patterns. the moh allowed researchers access to the pattern of female nuptiality in oman 34 | squ medical journal, february 2013, volume 13, issue 1 the data set for the present study. the data were analysed using univariate (frequency distribution), bivariate, and multivariate methods. the results of the bivariate analyses were tested for statistical significance by a chi-square test for categorical data, and analysis of variance (anova) was used for the continuous level data. a value of significance was set at p <0.05. the analysis was based on complete information given by the 2,037 ever-married. first, the characteristics of marriage were examined using univariate and bivariate analysis. this was followed by an examination of age patterns in marriage, and those patterns’ trends, differentials, and determinants. median age at first marriage, a commonly used summary measure of age at first marriage, was calculated based on retrospective reporting of age at first marriage by women who had been married in the past. it describes the age by which 50% of the women have experienced marriage and has an advantage in that we could use cohorts that still had not stopped “getting married". it is based on the age at first marriage reported by the women interviewed in a survey, and is accordingly a cohort measure. the well-known demographic and health surveys (dhss) are using the measure to report the age at fist marriage throughout the world. however, this measure typically results in an average age that is lower than mean age, due to selection bias. this is because it considers only the men or women who have been ever married and thus includes only those who have been married early, excluding those who remain single but might marry in later years. however, the differential analysis of age at marriage usually remains unaffected by this selection bias. the determinants of early marriage, defined as marriage before age 20, were estimated using a logistic regression model. however, a logistic regression model requires a dichotomous dependent variable. since our dependent variable, or age at marriage, is a continuous variable, we dichotomized table 1: distribution of respondents by selected background characteristics (oman, 2000) background characteristics number percent age <20 95 4.7 20–29 851 41.8 30–39 7 55 37.1 40–49 336 16.5 mean age 31.02 years birth cohort before 1965 711 34.9 1965–1974 823 40.4 1975 or after 503 24.7 residential setting urban 1492 73.2 rural 545 26.8 geographic region muscat 446 21.9 al-batinah 644 31.6 dhofar 259 12.7 al-sharqiyah 226 11.1 al-dhakhliya 310 15.2 al-dhahirah 152 7.5 education no education 879 43.2 some primary 203 10.0 primary or preparatory 567 27.8 secondary or higher 388 19.0 work status work for remuneration 266 13.1 do not work for remuneration 1771 86.9 occupation professional/administrative 158 7.8 clerical 39 1.9 sales and service 34 1.7 manual worker 35 1.7 housewife 1771 86.9 live births 0 199 9.8 1–2 460 22.6 3–5 561 27.5 6–8 424 20.8 9+ 393 19.3 mean 4.94 children total n = 2037 100.0 m. mazharul islam, atsu s. dorvlo and ahmed m. al-qasmi clinical and basic research | 35 it as follows: y = 1, if the respondent married before age 20, and y = 0, when a respondent married at age 20 or above. thus, we used the following regression model: logit where )........,,2,1(')1( kisbandyprobp i === are the linear regression coefficients, indicating the effect of the predictor variables xis and b0 is the intercept. however, in logistic regression analysis, the effects of the predictors on original variables are measured by odds ratio (or) defined by eb. an odds ratio of 1.000 indicates the reference category of a predictor variable. an odds ratio greater than 1.000 for a category of the predictor variable indicates a higher likelihood of getting married early in that category as compared with that of the reference category. some of the covariates that affect when couples marry are a woman’s birth cohort, place of birth and/or residence, parents’ education levels, and a respondent’s education level, family background, work status, and type of marriage.16–19 year of birth is included in the models to estimate the secular trend. place of birth, place of residence and region of residence partially explain the socialisation process of the respondents since people born in rural areas tend to display more traditional behaviours such as early marriage, higher consanguinity rates, and polygyny, even if they later live in urban areas.6 also, the longer a woman stays in school, the less likely it is for her to marry early. a number of covariates are thought to affect the timing of marriage. it has been observed that young men and women who have higher levels of education are likely to develop higher levels of autonomy by having better knowledge and better opportunities for paid employment and economic independence, which usually results in later marriage.16,17 furthermore, young women with a higher level of education are more likely to be employed and employment is likely to delay marriage. results table 1 shows the distribution of the sample respondents by selected background characteristics. most of the respondents in the sample (~80%) were in their prime reproductive ages (20–39 years) while about 17% were at the end of their childbearing ages (40–49 years). women aged 15–19 years comprised about 5% of the sample. the average age of the respondents was 31 years. a total of 75.3% of respondents were born before 1975. about 73% of the respondents lived in urban areas. among the six major geographical regions in oman, over half of the respondents came from the al-batinah (32%) and muscat (22%), both regions on the northern table 2: distribution of women aged 15 and above by age and marital status, based on enumerated household population (oman, 2000) age group female marital status (n) percentage evermarried single married widowed divorced/ separated 15–19 92.0 7.6 0.1 0.3 8.0 20–24 53.1 44.9 0.4 1.8 46.9 25–29 18.8 75.3 0.9 5.0 81.2 30–34 5.1 86.3 2.8 5.8 94.9 35–39 2.3 88.9 3.5 5.3 97.7 40–44 0.9 89.3 7.1 2.7 99.1 45–49 0.8 85.1 5.8 8.3 99.2 50–54 0.6 72.8 20.5 6.1 99.4 55–59 1.5 67.3 25.5 5.7 98.5 60–64 0.8 48.5 43.2 7.5 99.2 65+ 0.8 31.4 58.8 9.0 99.2 total 36.7 51.6 8.1 3.6 63.3 0 1 1 2 2( ) log .....1 k k p p b b x b x b x p   = = + + + + −  the pattern of female nuptiality in oman 36 | squ medical journal, february 2013, volume 13, issue 1 coast. a total of 43% of women had never attended school; 10% had some primary education; 28% had completed primary education, while 19% had secondary or higher level education. most of the respondents (87%) were housewives; only 13% of the women were engaged in paid work. most of the latter were working as professionals or administrators with high levels of education. nearly 19% had a very high parity of 9 or more children [table 1]. in contrast, 23% of the women had only one or two children, while three-quarters had 3 or more children, and about 10% still had none. the distribution of women by live births indicated very high fertility in oman, reflected by their high average number of children (~5 children); 32% of the married women were using family planning methods. table 2 shows the distribution of the female population aged 15 and above enumerated by current age and marital status, calculated from the household population in the 2000 onhs. it is evident that 8% of women aged 15 and above were married between ages 15 and 19. the proportion of married women increased rapidly with age. by age 50, almost 100% of women had been or were married, indicating universal marriage in oman. the proportion of currently married women increased rapidly to ages 40–44 and then declined due to the effects of widowhood and/or divorce [table 2]. about 8% of women aged 15 and above were widowed and another 4% were divorced. between ages 25 and 49, the proportion of divorcees ranged from 3–8%, while the proportion of widows ranged from 1–7%. overall, 37% of the women aged 15 and above were single in 2000. the corresponding figure in 1995 was 29%, indicating a rising trend in the proportion of single women in oman.20 the 2000 onhs documented a similar pattern of divorced and widowed women as had been observed in the 1995 oman family health survey (ofhs). as in other parts of the arab and muslim world, consanguineous marriage is very common in oman. according to the 2000 onhs data, more than half of married women under 50 years of age (52%) reported that they had a blood relationship with their husbands. first cousin marriages, both maternal and paternal, constituted 38.5% of all marriages and more distant forms of blood relation constituted 13% of all marriages. specifically, paternal first-cousin marriages constituted 27.7% of all marriages and 72% (565/786) of all first-cousin marriages, while maternal first-cousin marriages constituted 10.8% of all marriages and 28% table 3: prevalence of consanguineous marriage (oman, 2000) types of marriage 2000 onhs 1995 ofhs number of women prevalence (%) number of women prevalence (%) consanguineous paternal first cousin 565 27.7 1,635 25.5 maternal first cousin 221 10.8 525 8.2 other relation 266 13.1 1,319 20.6 non-consanguineous 985 48.4 2,927 45.7 total 2037 100.0 6,405 100.0 onhs = oman national health survey; ofhs = oman family health survey. table 4: prevalence of polygynous marriages among currently married women (oman 2000) polygyny 2000 onhs 1995 ofhs number (n) prevalence (%) number prevalence (%) yes 215 11.5 666 11.3 no 1,658 88.5 5,238 88.7 total 1,873 100.0 5,904 100.0 onhs = oman national health survey; ofhs = oman family health survey. m. mazharul islam, atsu s. dorvlo and ahmed m. al-qasmi clinical and basic research | 37 (221/786) of all first-cousin marriages. although the overall prevalence of consanguineous marriages declined slightly from 54% in 1995 to 52% in 2000, the prevalence of first-cousin marriages increased from 33.7% in 1995 to 38.5% in 2000 [table 3]. this pattern of consanguineous marriage may be related to deeply rooted cultural practices as well as the social and economic advantages of first cousin marriages.6 polygyny is when a man is simultaneously married to more than one wife. table 4 presents the prevalence of polygynous marriages among married women in oman as observed in the 1995 ofhs and the 2000 onhs. the data indicated that 1 in 9 marriages (11%) in oman is polygynous. over the study period, the rate of polygamous marriages remained stable. table 5 presents the median age at first marriage for women responding to the 2000 onhs according to select background characteristics. overall, the median age at first marriage was 16 years, indicating that early female marriages are still prevalent in oman. it also indicates that most of the female marriages took place before age 20. however, the age of women when they first marry is increasing in oman, as indicated by the rising trends in median age at first marriage across the age cohorts and birth cohorts. women’s age at first marriage is significantly higher for the younger cohort than their older counterparts (p <0.01). for women aged 45–49 years, the median age at first marriage was found to be 15.68 years, which increased to 17.70 years for women aged 20–24 years. birth year cohorts also showed a significant rising trend in age at first marriage (p <0.01). the median age at first marriage increased from 15.21 years for women born before 1975 to 17.29 years for women born after 1975—an increase of two years. urban women were more likely to marry at a later age than rural women (p < 0.05), and women’s ages at marriage varied significantly (p <0.01) across the geographical regions. the muscat and al-dhahirah urbanised regions showed a later age at marriage (about 17 years) while the aldhakhlia central region showed the youngest (15.5 years). age at marriage in other regions was closer to 16 years. female education had a strong positive, statistically significant effect on age at first marriage (p <0.001). for example, the median age at marriage was about 16 years among women with table 5: median age at first marriage according to selected characteristics (oman, 2000) characteristics no. of cases median p value total 2,037 16.10 age 0.008 20–24 401 17.70 25–29 450 17.01 30–34 372 15.51 35–39 383 15.14 40–44 218 15.45 45–49 118 15.68 birth year cohort 0.003 before 1965 711 15.21 1965–1974 823 16.18 after 1975 503 17.29 residential setting 0.010 urban 1,492 16.28 rural 545 15.77 region of residence 0.005 muscat 446 17.25 al-batina 644 15.84 dhofar 259 15.82 al-sharqiah 226 15.73 al-dhakhlia 310 15.57 al-dhahirah 152 17.00 educational level 0.000 no education 879 15.57 some primary 203 15.43 primary 345 15.81 preparatory 222 16.40 secondary or higher 388 18.58 work status 0.000 work for remuneration 266 18.05 not working for remuneration 1,771 15.93 have say in family decision 0.015 yes 444 16.78 no 1,593 15.43 types of marriage 0.001 consanguineous 1,052 15.47 nonconsanguineous 985 16.86 the pattern of female nuptiality in oman 38 | squ medical journal, february 2013, volume 13, issue 1 no education, while it was about 19 years among women with an educational level of secondary or above. women’s work status also showed significant differential effects on median age at marriage (p <0.001). women who were employed married later. age at marriage was likely to be higher among the women who felt empowered and could participate in the decision-making process regarding family matters. the type of marriage, specifically whether it was consanguineous or non-consanguineous, had a statistically significant effect on the timing of the marriage with consanguineous marriages likely to occur at an earlier age (median age 15 years), but about 17 years for non-consanguineous marriages (p <.001). table 6 shows the age cohort trend at omani women’s first marriage. nuptiality cohort trends were examined by comparing the distribution of the proportion of ever-married women by age for successive age cohorts. in the 25–29 year old cohort, one-third of women were married by age 15, 58% were married by age 19, and 79% by age 25. overall, nearly 30% of the women aged 20–44 were married by 15 years old. by age 19, 62% of the women aged 20–44 were married and only 25% were married after age 20 indicating a long tradition of early female marriage in oman. however, recently there has been a substantial shift towards later marriage among women. for example, the proportion married by age 20 fell steadily from the oldest to youngest age groups. the proportion fell from 92% for women aged 40–44 to 38% for women aged 20–24. the differential analysis of age at first marriage showed that all the selected background variables had a statistically significant effect on age at marriage. however, these are unadjusted effects and encounter complications due to the influence of other variables which may be correlated. to disentangle the effects on the dependent variable of each of the inter-correlated variables, a multivariate logistic regression model was applied to the data in order to assess the effects of various background characteristics more fully and to provide a succinct summary of the effects. table 7 shows the effects (odds ratios) of selected background characteristics of women by age at marriage. the logistic regression analysis suggests that women’s age, residential status, region of residence, education, types of marriage, and family size as measured by number of children born were significant determinants of age at first marriage. as expected, the age of women has a strong negative effect (p <0.001) on the likelihood of early marriage. today’s young women are less likely to marry early than their older counterparts. three additional factors are associated with delaying early marriage: 1) residential status; 2) being born or brought up in urban areas (urban women were about 30% less likely to marry early than rural women), and region of residence. except for muscat, the other 6 regions had a higher likelihood of early marriage than the al-dhahirah western urbanised region. the effects are statistically significant for dhofar, the southernmost region (p <0.01) and the al-sharqiah eastern desert region (p <0.05). attainment of a level of education beyond primary had a strong negative effect on early marriage. women with primary, preparatory, table 6: percentage of marriages by exact ages, listed by age cohort (oman, 2000) age cohort percentage who were married by exact age percentage never married15 18 19 20 22 25 15–19 3.1 92.0 20–24 13.2 29.3 33.3 38.3 53.1 25–29 33.7 53.0 57.7 61.8 70.3 78.7 18.8 30–34 54.1 75.6 78.7 82.5 88.8 92.6 5.1 35–39 65.4 82.3 84.3 88.4 90.7 94.4 2.3 40–44 62.5 86.2 89.7 92.4 96.4 97.3 0.9 45–49 28.9 62.4 70.3 75.7 2.7 = not applicable. m. mazharul islam, atsu s. dorvlo and ahmed m. al-qasmi clinical and basic research | 39 secondary, or a higher level of education had a lower risk of getting married early than the women with no education. this may be due to time spent in schooling, an increased interest in finding an appropriate match, or an increased interest in getting employment. working women were 23% less likely to marry early than their non-working counterparts. the type of marriage, consanguineous or non-consanguineous, appeared to be a strong determinant of marital timing. consanguinity is one of the key cultural factors mediating marriage timing. the data indicated that women who had a consanguineous marriage are 37% more likely to have married early. discussion this study analysed female marriage patterns and timing of marriage in oman by utilising recent national level survey data. the results indicate that marriage is universal in oman, as by age 50 almost all women (99.4%) are or have been married at least once. many aspects of the nuptial behaviour of omani women continues to follow traditional patterns. a key aspect of marriage patterns is the high prevalence of consanguineous marriage, as more than half (52%) of married women are blood relatives of their husbands. this is a very similar pattern to that in other arab countries. however, the overall prevalence of consanguineous marriage in oman is higher than in most arab and middle east countries, except saudi arabia (58%), mauritania (60%) and sudan (65%).6,9,21 this reflects table 7: logistic regression analysis showing the extent of the effect (odd ratios) of selected correlates on women younger than 20 at first marriage (oman, 2000) variables coefficient (β) se of β p-value odds ratio (or) age -.116 .013 .000 0.890 residential setting urban -.363 .152 .012 0.695 rural (ref.) 1.000 region of residence muscat -.011 .241 .180 0.989 al-batina .232 .232 .287 1.261 dhofar .915 .290 .001 2.496 al-sharqiah .662 .292 .015 1.940 al-dhakhlia .353 .263 .152 1.424 al-dhahirah (ref.) 1.000 educational level no education (ref.) 1.000 some primary -.012 .226 .952 0.988 primary/preparatory -.354 .166 .014 0.702 secondary or higher -.561 .185 .001 0.571 work status work for remuneration -.260 .195 .015 0.771 not working for remuneration (ref.) 1.000 type marriage consanguineous -.467 .126 .000 0.627 non-consanguineous (ref.) 1.000 ref. = reference category. the pattern of female nuptiality in oman 40 | squ medical journal, february 2013, volume 13, issue 1 both prevailing religious and cultural practices in the region. although the overall prevalence of consanguineous marriages declined slightly, from 54% in 1995 to 52% in 2000, the prevalence of first-cousin marriages increased from 33.7% in 1995 to 38.5% in 2000. this is mainly due to a decline in second cousin or more distant cousin marriages. women’s increasing education levels, their declining fertility resulting in lower numbers of suitable relatives to marry, participation in paid employment, cultural empowerment, and urbanisation may have caused the decline in overall consanguineous marriage. the apparent increasing trend in first cousin marriages may be related to deeply rooted cultural practice as well as the significant social and economic advantages of first cousin marriages in oman.6 consanguineous marriages, particularly the first cousin marriages, promote family ties, reduce dowry or bridewealth payment requirements, simplify premarital negotiations, offer a greater compatibility between spouses and other family members, offer a lesser risk of hidden financial and health issues, and keep family property within the parental families.22,23 the data reveals that about 12% of ever-married women have one or more co-wife, indicating that the rate of polygynous marriage is also quite high in oman. over the period analysed, the rate of polygynous marriages remained more or less stable. as residents of an islamic state, oman’s men are legally allowed to have up to four wives if they can afford it. we speculate that the stability of this rate may be attributed to the affluence in the country. these findings indicate a trend in rising age at women’s first marriage in oman, even though marriage remains virtually universal. the change was apparent especially for more recent marriages and among younger cohorts of women and for certain sociocultural groups. this was evidenced by the fact that 33% of women aged 20–24 were married by their age 19 compared with 58% of those aged 25–29 years and 79% by age 30–34 years. the proportion of single females of reproductive age doubled (from 18 to 36%) between 1988 and 1995 and was 44% in 2000.11,12 over that period, the proportion of single women increased in almost all age groups. the most remarkable rise occurred in the younger age groups, particularly in 15 to 29 year olds. thus, the pattern of women’s age at first marriage in oman is changing from an early and universal pattern to one of delayed but universal marriage, which is similar to the eastern european marriage pattern.24–26 such a change is expected to continue and as a consequence the fertilityinhibiting effect of oman’s changing nuptiality pattern will increase over time.27 the results of the multivariate analysis indicate that women’s educational levels, age cohorts, residential status, region of residence, and types of marriage were the most important factors affecting age at marriage and had both direct and indirect effects on participation in the labour force. respondents’ residential status (i.e. rural or urban) in general reflects their cultural background, marriage norms, and family system. urban females tend to marry later compared to rural ones. this phenomenon is a possible consequence of modernisation, which has already resulted in an expansion of educational opportunities and changes in the work force and occupational activities, particularly for females in oman. however, occupational effects on marriage are largely a function of education. the results of this study are consistent with the findings of other studies which indicate that educational attainment and employment reduce women’s’ likelihood of early marriage.18,28 women in school are likely to postpone marriage either because of the time spent in school or because of exposure to western middle class ideals and norms, which influence preferences and lifestyle choices. women who work are likely to postpone marriage due to greater social independence from their families and communities, and thus a less exposure to pressures to marry. financial independence as well as control over earnings also allow working women to postpone marriage. as mentioned earlier, marriage type is also one of the key factors affecting timing. the data showed that women who have non-consanguineous marriages are more likely to marry late. it is possible that this is because consanguineous marriages are easier to arrange and may cost less in terms of dowry payments. it is speculated that the increasing costs of marriage: bridal cost and gifts, ceremony, furniture, and appliances might be related to the rising marriage age for both males and females. few studies in the arab region or other developing countries, m. mazharul islam, atsu s. dorvlo and ahmed m. al-qasmi clinical and basic research | 41 with the exception of india and bangladesh, have linked delays in marriage to increases in the cost of marriage.29,30 the cost of marriage is considered the “hidden variable in the new arab demography.”29 changes in fertility, age composition, and family demography are clearly associated with nuptiality changes. the future direction of fertility change is very much related to the ongoing changes in nuptiality as well as possible changes in marital fertility patterns to offset the fertility-inhibiting effects of later marriages in oman.27 understanding determinants of nuptiality change, the response of married females to shorter fecund periods of life, and the health consequences of different reproductive patterns are all areas for future research needed to guide future planning. conclusion changing demographic patterns of marriage in oman reflect broader social and economic changes that are taking place throughout the arab world. the majority of the arab world’s population, including oman, now lives in cities and is involved in the industrial or service sectors. arab youth are more educated compared with previous generations, and young educated women are more likely to work outside their homes. these changes challenge women’s traditional roles in the household and society as a whole and have a positive impact on rising trends in age at first marriage. the delay in marriage among recent female omani cohorts may also be related to the persistence of traditional cultural attitudes and gender norms, combined with the increasing cost of marriage, which is related to increasing bridal and living costs, and higher expectations of living standards. women’s rising age at marriage in recent years in oman not only stimulates the demographic transition but also gives rise to many issues and challenges. due to delayed marriage, fertility is declining and changing the age structure. the population of oman is moving from a very young age structure to one where young adults aged 10–24 constitute more than one-third of the population. this growing young adult population, accompanied by delayed marriage, and the growing autonomy of females, gender equality, and exposure to western media will have serious social, economic and political ramifications for oman, highlighting the need to understand the new situation of youth, and their characteristics, problems, and demands. the consequences of these demographic transitions are evident today in many arab countries, and expected to be even more pronounced in the coming years. the arab spring may be one of the symptoms of such consequences. there is a demographic window of opportunity due to a notable decline in fertility, but oman’s potential success in benefiting from this demographic bonus will depend on good national population policy. better understanding young people’s sexuality is another area of concern. the social transition to later marriage in oman, however, is unlikely to be painless for oman’s society, families, or the government, since delayed marriage means prolonged exposure to at least the possibility of premarital sex and its consequences. culturally appropriate policies need to be undertaken to address the issues and challenges of unmarried young adults in oman. despite recent trends in delayed age at first marriage, a substantial proportion of oman’s marriages are still undertaken by young women. the negative health, demographic, social, and economic consequences of these types of marriages are well-documented in literature. this study therefore underscores the need for government policies to support the reduction of teen marriages in oman. considering that a large proportion of women of reproductive age, particularly the women from older marriage cohorts, have never gone to school, information and education stressing the disadvantages of early marriage and motherhood should be made available to all girls and women in their community. this could be done through mass media programmes. in view of the ever-increasing proportion of girls that are attending school due to universal free education in oman, schoolbased reproductive health programmes need to be introduced to raise awareness about reproductive health. a c k n o w l e d g e m e n t s the authors would like to thank the omani ministry of health, and especially the director of planning and research, for providing raw data files from the onhs 2000. the pattern of female nuptiality in oman 42 | squ medical journal, february 2013, volume 13, issue 1 references 1. al-riyami a, afifi m. determinants of women’s fertility in oman. saudi med j 2003; 24:748–53. 2. al-lamki sm. women in the labor force: the case of the sultanate of oman. int j manage 2000; 17:166– 74. 3. hashemi k. religious legal traditions, muslim states and the convention on the rights of the child: an essay on the relevant un documentation. hum rights quart 2007; 29:194–227. 4. eickelman c. oil, fertility, and women’s status in oman. in: da bowen, ea early, eds. everyday life in the muslim middle east. bloomington, indiana: indiana university press, 2002. pp. 128–35. 5. rashad h, osman m, roudi-fahimi f. marriage in the arab world. from: www.prb.org/pdf05/ marriageinarabworld_eng.pdf accessed: mar 2012. 6. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571–94. 7. fargues p. the decline of arab fertility. population 1989; 44:147–75. 8. tabutin d, schoumaker b. the demography of the arab world and the middle east from 1950s to the 2000s. population-e 2005; 60:505–616. 9. bener a, alali ka. consanguineous marriage in a newly developed country: the qatari population. j biosoc sci 2006; 38:239–46. 10. sueyoshi s, ohtsuka r. effects of polygyny and consanguinity on high fertility in the rural arab population in south jordan. j biosocial sci 2003; 44:513–26. 11. oman ministry of health. oman child health survey 1988–89. muscat: ministry of health, 1989. 12. oman ministry of health. national health survey 2000, vol. 2, reproductive health survey. muscat: ministry of health, 2000. 13. caldwell jc. the asian fertility revolution: its implication for transition theories. in: leete r, alam i, eds. the revolution in asian fertility: dimensions, causes and implications. oxford: claredon press, 1993. pp. 299–316. 14. van de walle e. marriage and marital fertility. in: glass dv, revelle r, eds. population and social change. london: edward arnold, 1972. 15. al riyami a, afifi m, mabry rm. women’s autonomy, education and employment in oman and their influence on contraceptive use. reprod health matter 2004; 12:144–54. 16. gupta n, mahy m. adolescent child bearing in subsaharan africa: can increased schooling alone raise ages at first birth? demographic res 2003; 8:93–105. 17. hogan d. the effect of demographic factors, family background, and job achievement on age at marriage. demography 1978; 15:161–75. 18. choe mk, thapa s, mishra v. early marriage and early motherhood in nepal. j biosoc sci 2004; 37:143–62. 19. aryal t. r. age at first marriage in nepal: differentials and determinants. j biosoc sci 2007; 39:693–706. 20. oman ministry of health. oman family health survey 1995, final report. muscat: ministry of health, 1995. 21. jurdi r, saxena pc. the prevalence and correlates of consanguineous marriages in yemen: similarities and contrasts with other arab countries. j biosoc sci 2003; 35:1–13. 22. bittles ah. the role and significance of consanguinity as a demographic variable. popul dev rev 1994; 20:561–83. 23. bittles ah. a background summary of consanguineous marriage. perth: edith cowan university, 2001. 24. united nations. pattern of first marriage: timing and prevalence. new york: united nations, 1990. 25. hajnal j. age at marriage and proportion marrying. popul studies 1953; 2:111–36. 26. hajnal j. european marriage patterns in perspective. in: glass dv, eversle dec, eds. population history. chicago: aldine, 1965. 27. islam mm, dorvlo ass, al-qasmi am. proximate determinants of declining fertility in oman in 1990s. can studies popul 2011; 38:133–52. 28. fargues p. women in arab countries: challenging the patriarchal system? reprod health matter 2005; 13:43–8. 29. singermann d, ibrahim b. the cost of marriage in egypt: a hidden dimension in the new arab demography. in: hopkins ns, ed. the new arab family, cairo: american university of cairo press, 2003. pp. 80–117. 30. mensch bs, susheela s, john bc. trends in the timing of first marriage among men and women in the developing world. policy research division working papers #202. new york: population council, 2005. املؤمتر الدويل الثاين للتطورات يف طب التوليد وأمراض النساء اجلزء األولملخص املطويات املعروضة جامعة السلطان قابوس، 22-24 يناير 2016 2nd international conference on advances in obstetrics and gynaecology part i poster presentations sultan qaboos university, 22–24 january 2016 audit on improving measurement of the quality of maternal and neonatal care at a regional referral hospital in oman *hansa dhar, asha santosh, ilham hamdi department of obstetrics & gynecology, nizwa hospital, nizwa, oman. *corresponding author e-mail: hdhar16@gmail.com objectives: this study aimed to determine causes of maternal and neonatal morbidity and mortality at nizwa hospital, nizwa, oman, in order to improve the quality of healthcare. methods: a prospective self-audit was conducted by the maternal morbidity working group to critically analyse secondary healthcare lapses during the management of all obstetric cases at nizwa hospital in order to highlight possible strategies to avoid such errors in future. results: major obstetric morbidity occurred in 3.97% of cases. leading causes of death were obstetric haemorrhages caused by placenta accreta and rupture of the uterus, followed by eclampsia, vaginal tears and wound haematomas. sickle cell disease and h1n1 influenza type a-associated pneumonia were the main indirect causes of maternal mortality. in some cases, uncontrolled diabetes led to birth asphyxia, stillbirths and an increased rate of congenital anomalies. conclusion: auditing morbidity and mortality can help in recognising, anticipating and managing risks to maternal and neonatal health. impact of androgens on symptoms in omani women with polycystic ovarian syndrome *maha al-khaduri,1 reem al-jahwari,2 maha suleiman,2 yahya al-farsi3 departments of 1obstetrics & gynaecology and 3family medicine & public health, college of medicine & health sciences, sultan qaboos university; 2medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: m.khaduri@gmail.com objectives: polycystic ovarian syndrome (pcos) is an endocrine disorder affecting 6–7% of women of reproductive age. the prevalence of pcos among omani women was 2.8% in 2010. symptoms include irregular menstruation, hirsutism, acne, weight gain and infertility. this study aimed to evaluate the effects of increased testosterone and dehydroepiandrosterone sulphate (dhea-s) levels on hormonal, metabolic and clinical features of obese and non-obese omani women with pcos. methods: a retrospective case-control study was conducted at the sultan qaboos university hospital in muscat, oman. data were collected from the medical records of 175 omani women of reproductive age with pcos treated between 2007–2014. results: of the women with pcos, 43% showed biochemical hyperandrogenemia, 39% were obese, 35% had increased testosterone and 32% had high dhea-s levels. conclusion: obesity was common among omani women with pcos. there were significant associations between hyperandrogenemia, hirsutism and anovulation. elevated dhea-s levels were associated with non-obesity in pcos women. risk factor profile for the early detection of women with polycystic ovarian syndrome in primary care in oman: case-control study maha sulaiman,1 yahya al-farsi,2 mostafa waly,3 jumana saleh,4 *maha al-khaduri5 1medical student, college of medicine & health sciences, sultan qaboos university; departments of 2family medicine & public health, 4biochemistry and 5obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university; 3department of food science & nutrition, college of agricultural & marine sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: m.khaduri@gmail.com objectives: polycystic ovarian syndrome (pcos) data from developing countries is scarce. this study aimed to assess the pcos risk factor profile in oman with the aim of improving screening and early detection. methods: a hospital-based case-control study was conducted at the sultan qaboos university hospital, muscat, oman. a total of 53 women with pcos (diagnosed according to the rotterdam 2003 criteria) and 55 female control subjects without pcos were recruited and their sociodemographic, anthropometric, clinical and biochemical data collected. results: selected clinical characteristics were significantly higher among the pcos group in comparison to the control group, including nulliparity (p = 0.02) and infertility (p = 0.01). additionally, the waist-to-hip ratio was significantly higher in the pcos group than the control group (p <0.01). levels of testosterone and dehydroepiandrosterone sulphate (p <0.01) were higher in women with pcos, indicating hyperandrogenism. fasting insulin was higher among pcos patients, indicating insulin resistance. conclusion: these findings highlight the need for early pcos detection at the primary healthcare level in oman. abstracts doi: 10.18295/squmj.2016.16.03.026 sultan qaboos university med j, august 2016, vol. 16, iss. 3, p. e387–395, epub. 19 aug 16 e388 | squ medical journal, august 2016, volume 16, issue 3 2nd international conference on advances in obstetrics and gynaecology part i poster presentations attitudes of women with cancer towards oocyte cryopreservation maha al-khaduri,1 o. al-kalbani,2 yahya al-farsi3 departments of 1obstetrics & gynaecology and 3family medicine & public health, college of medicine & health sciences, sultan qaboos university; 2medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: m.khaduri@gmail.com objectives: oocyte cryopreservation is a process involving the freezing of oocytes to preserve fertility. it frequently takes place before treatments that damage oocytes, such as chemotherapy and radiotherapy. this study aimed to assess awareness, knowledge, attitudes and opinions on oocyte cryopreservation among female gynaecology and oncology patients. methods: a cross-sectional study was undertaken at the sultan qaboos university hospital (squh), muscat, oman. data were collected through patient interviews. results: significantly higher awareness of oocyte cryopreservation was noted among oncology patients compared to gynaecology patients, with the former showing 1.69 times greater awareness. both groups demonstrated a high acceptance of oocyte cryopreservation for medical reasons; however, there was greater acceptance among oncology patients. awareness levels and attitudes were influenced by sociodemographic characteristics. conclusion: significant differences exist in levels of awareness and attitudes towards oocyte cryopreservation between oncology and gynaecology patients. obstetric intensive care unit indications and outcomes: seven-year study at nizwa hospital, oman *bhawna rathi and hansa dhar department of obstetrics & gynecology, nizwa hospital, nizwa, oman. *corresponding author e-mail: jrth392@gmail.com objectives: this study aimed to determine reasons for and outcomes of admissions to an intensive care unit (icu) at a secondary care hospital in oman. methods: the admission records of critically ill obstetric patients admitted to the icu at nizwa hospital, nizwa, oman, between 2008–2014 were retrospectively reviewed. results: out of 37,066 deliveries, 75 obstetric patients (0.2%) were admitted to the icu during the study period. reasons for admission included massive obstetric postpartum haemorrhages (n = 24; 32.0%), pre-eclampsia or eclampsia (n = 11; 14.7%), post-caesarean section anaesthesia-related complications (n = 6; 8.0%), suspected pulmonary embolisms (n = 3; 4.0%), postoperative cardiac complications (n = 7; 9.3%), postoperative pneumonia (n = 4; 5.3%), malignant hypertension (n = 1; 1.3%), hellp (haemolysis, elevated liver enzyme levels and low platelet levels) syndrome (n = 2; 2.7%), spaceoccupying intracranial lesions (n = 2; 2.7%) and postoperative sickle cell crises (n = 8; 10.6%). there were four antenatal admissions due to sickle cell crises and two due to h1n1 influenza type a infections. three patients were transferred to tertiary care facilities (4.0%). maternal mortality occurred in seven postpartum cases (9.3%). conclusion: few obstetric patients required icu care. timely intensive care with a multidisciplinary approach increases the likelihood of positive outcomes. acceptance of oocyte cryopreservation by omani females maha al-khaduri,1 raya al-busaidi,2 yahya al-farsi3 departments of 1obstetrics & gynaecology and 3family medicine & public health, college of medicine & health sciences, sultan qaboos university; 2medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: m.khaduri@gmail.com objectives: although oocyte cryopreservation was initially developed for medical indications, it later became available for individuals with non-medical indications. this study aimed to assess awareness and acceptance of oocyte cryopreservation among omani females. methods: a prospective cross-sectional study was conducted at the sultan qaboos university, muscat, oman, between september 2013 and april 2014. a questionnaire was randomly distributed to 437 female students studying either science or humanity subjects. the survey included items relating to demographic factors as well as awareness of and attitudes towards fertility and oocyte cryopreservation. results: fertility awareness was adequate, with no differences between the groups. science students were more aware of oocyte cryopreservation (p = 0.005). of all students surveyed, only 7.2% reported that they would consider oocyte cryopreservation for non-medical reasons in contrast to 45.4% who would consider undergoing the process for medical reasons. conclusion: while there was high awareness regarding female fertility among omani females, there was low awareness of oocyte cryopreservation. the students demonstrated greater acceptance of the procedure for medical reasons rather than for non-medical reasons. peer review and audit of abdominal hysterectomies performed at a teaching hospital *shahila sheik,1 l. jeyaseelan,2 saba mubbashir1 departments of 1obstetrics & gynaecology and 2hospital director general's office, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: drshahila@hotmail.com objectives: this study aimed to review the outcomes of patients undergoing total abdominal hysterectomies performed by five consultant gynaecologists at a tertiary referral and teaching hospital. methods: all patients who underwent total abdominal hysterectomies for benign gynaecological conditions at the sultan qaboos hospital, muscat, oman, over a period of eight years were included. retrospective data was collected and various operative parameters compared. results: the most common indication for a hysterectomy was heavy menstrual bleeding (63%). the most frequent histopathological finding was leiomyomas (61%), followed by adenomyosis (33%). unexpected neoplasia was found in 4% of cases. there were significant differences in the preferred incision (transverse versus vertical) and duration of surgery amongst the five surgeons (p <0.001). rates of intraand postoperative morbidity were comparable with international standards. conclusion: very few audits are conducted in gynaecological practice. this needs to change in order to demonstrate commitment to improving patient care. the relationship between cardiotocography, umbilical cord artery ph and early neonatal outcomes at nizwa hospital, oman *mona fakhry, hansa daher, aisha mumtaz department of obstetrics & gynecology, nizwa hospital, nizwa, oman. *corresponding author e-mail: monafakhry18@yahoo.com objectives: this study sought to evaluate the relationship between abnormal fetal heart rate, umbilical artery ph, apgar score (at 0 and 5 minutes) and the early perinatal morbidity and mortality outcomes of neonates. methods: a total of 200 participants were recruited abstracts | e389 sultan qaboos university, 22–24 january 2016 from nizwa hospital, nizwa, oman, including a control group of 100 patients with reactive cardiotocography (ctg) findings and a case group of 100 patients with abnormal ctg findings. all ctg assessments were conducted in the delivery suite one hour before delivery. cord ph was measured from umbilical artery samples collected after delivery. results: there was a significant association between abnormal ctg findings and low apgar scores at 0 minutes (p = 0.004) and umbilical artery ph. additionally, the relationship between abnormal ctg findings and umbilical cord artery ph was significant (p <0.001). conclusion: a combination of intra-partum ctg findings, cord blood ph and apgar scores is a more effective measure for assessing neonatal outcomes than any of these parameters alone. arterial ph can be used to diagnose birth asphyxia in newborns with neonatal respiratory depression. analysis of the best evidence available to midwives for perineal protection *frincy francis and sheeba e. john department of maternal & child health, college of nursing, sultan qaboos university, muscat, oman. *corresponding author e-mail: frincy.s@squ.edu.om objectives: midwives are regularly held responsible for a torn perineum following childbirth. as an intact perineum is a key goal in current childbirth practice, there is a clear motivation for midwives to research the best available practices to reduce perineum tearing. methods: a comprehensive literature search of perineal protection techniques was undertaken with five publication databases using the following search terms: “methods of protecting the perineum”, “perineal massage”, “hands-on” and “hands poised”. results: a total of 225 studies from 2006 onwards were identified. of these, 165 studies were eliminated due to irrelevance to the topic. of the 60 studies which were potentially relevant, 18 studies were duplicates. the remaining 35 studies comprised randomised controlled trials, quasiexperimental research and systematic reviews. conclusion: the effectiveness of various techniques in perineal protection needs to be analysed and the best methods put into practice. prevalence of maternal risk factors associated with intrauterine growth restriction at a tertiary referral centre in oman *silja pillai,1 reham al-hinai,2 sunita kumari,1 lovina machado1 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: siljarenjit@gmail.com objectives: intrauterine growth restriction (iugr) is a major neonatal health issue associated with increased perinatal morbidity and mortality. there is a lack of data on this issue in oman. this study aimed to examine the prevalence of and risk factors for iugr among omani women delivering at the sultan qaboos university hospital (squh), muscat, oman. methods: a retrospective cohort study was conducted of all women antenatally diagnosed with iugr who delivered at squh between 24 and 37 gestational weeks from april 2012 to march 2014. results: the prevalence of iugr was 7.4%. major risk factors for iugr included haematological disorders (12.1%), diabetes (9.9%), hypertensive disorders (8.0%), placental and cord abnormalities (7.8%), a previous history of iugr (2.5%) and previous caesarean section deliveries (12.4%). conclusion: the prevalence of iugr in omani women was comparable with other studies reporting prevalence rates of 6–10%. this is the first omani study addressing this issue and serves as a baseline for future research. perinatal outcomes of babies with intrauterine growth restriction at a tertiary healthcare centre in oman *lovina machado,1 silja pillai,1 noof al-essaei,2 sunita kumari1 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: lovina1857@gmail.com objectives: intrauterine growth restriction (iugr) is associated with increased perinatal morbidity and mortality. this study aimed to evaluate perinatal outcomes in omani women with iugr who delivered at the sultan qaboos university hospital (squh), muscat, oman. methods: this retrospective cohort study included all omani women with iugr who delivered at the squh between 24–40 gestational weeks from april 2012 to march 2014. results: of the 531 babies affected by iugr, 87.4% had asymmetrical iugr and 12.6% had symmetrical iugr. perinatal outcomes included neonatal jaundice (41.1%), respiratory distress syndrome (9.4%), hypoglycaemia (8.7%), haematological disorders (11.7%) and sepsis (7.5%). a statistically significant association between low birth weight and neonatal morbidity was found (p = 0.003). the perinatal mortality rate was 22.5 per 1,000 babies. conclusions: babies with iugr have a significantly increased risk of neonatal morbidity and mortality. this is the first study on this issue from oman and provides valuable information for counselling women with iugr. heart rate variability spectral analysis for normal and pre-eclamptic pregnancies in oman *abdulnasir hossen,1 alaa barhoum,2 deepali jaju,3 vaidyanathan gowri,4 khamis al-hashmi,5 mohammed hassan,3 lamya al-kharusi4 departments of 1electrical & computer engineering and 2petroleum & chemical engineering, college of engineering, sultan qaboos university; departments of 2physiology and 3obstetrics & gynaecology, sultan qaboos university hospital; 3department of physiology, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: abhossen@squ.edu.om objectives: heart rate variability (hrv) spectral analysis has been widely used to identify pre-eclamptic pregnancies. the main objective of this study was to compare simple and non-invasive methods for identifying pre-eclampsia. methods: the fast fourier transform (fft) and the soft-decision wavelet-based techniques were used to estimate the approximate hrv spectral representation of 40 pregnant women recruited from the sultan qaboos university hospital, muscat, oman. results: the fft and soft-decision wavelet methods allowed pre-eclamptic pregnancies to be identified with efficiency rates of 80% and 85%, respectively. conclusion: women with preeclampsia show less high-frequency hrv and greater low-frequency variability when compared to women with normal pregnancies. e390 | squ medical journal, august 2016, volume 16, issue 3 2nd international conference on advances in obstetrics and gynaecology part i poster presentations maternal and perinatal outcomes in gestational diabetes mellitus diagnosed using the international association of diabetes in pregnancy study group criteria: experience at buraimi hospital, oman *kaukab naheed, usha varghese, hina s. hingora, sadia sajid, mehar fatima department of obstetrics & gynaecology, buraimi hospital, buraimi, oman. *corresponding author e-mail: naheedkaukab@yahoo.com objectives: this study aimed to evaluate the 2010 international association of diabetes in pregnancy study group (iadpsg) criteria for diagnosing gestational diabetes mellitus (gdm). methods: a retrospective study of 165 women was conducted at the buraimi hospital, buraimi, oman. in january 2013, women at 22–24 gestational weeks were given a 50 g oral glucose load, followed by a one-hour plasma glucose level test. those with a result of ≥7.8 mmol/l then received a two-hour oral glucose tolerance test (ogtt); fasting blood sugar (fbs) levels of ≥5.5 mmol/l or postprandial glucose (ppg) levels of ≥7.8 mmol/l indicated gdm. between january and october 2015, the iadpsg criteria were used with either fbs levels of ≥5.1 mmol/l or ppg levels of ≥8.5 mmol/l indicating gdm. results: diagnosis of gdm increased from 5.15% to 12.99% using the iadpsg criteria. with the iadpsg criteria, more women under 35 years of age (69.30% versus 56.93%) who were nulliparous (25.74% versus 20.00%) were diagnosed. furthermore, rates of induced labour (19.80% versus 35.38%) and caesarean sections (22.72% versus 24.62%) decreased. rates of diagnosed fetal macrosomia (4.90% versus 3.03%) and large for gestational age (lga) neonates increased. conclusion: the iadpsg criteria were associated with increased gdm diagnoses and were more predictive of fetal macrosomia and lga among neonates. comparison of the outcomes of severely pre-eclamptic omani women with and without management with magnesium sulphate hamna al-musalhi,1 *maryam al-shukri,2 asma al-jahwari,1 vaidyanathan gowri2 1medical student, college of medicine & health sciences, sultan qaboos university; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: mnalshukri@gmail.com objectives: severely pre-eclamptic women are admitted to hospital if they have uncontrolled blood pressure or symptoms suggesting end-organ involvement. magnesium sulphate (mgso4) is used to prevent and treat eclamptic seizures. this study aimed to compare the effect of mgso4 on symptomatology, maternal and fetal complications and the admission-to-delivery interval among severely preeclamptic women. methods: a retrospective review was undertaken of all omani women with severe pre-eclampsia admitted to a high-dependency unit at the sultan qaboos university hospital, muscat, oman over a three-year period. results: no difference was observed between those who received mgso4 and those who did not with regards to admission-to-delivery interval. in the mgso4 and control groups, 19.0% and 6.3% versus 8.1% and 2.7% developed hellp (haemolysis, elevated liver enzyme levels and low platelet levels) syndrome and pulmonary oedema, respectively. higher rates of pre-term delivery were observed in the mgso4 group; however, these neonates did not have low birth weight or low apgar scores. conclusion: while the mgso4 group showed more severe symptoms of pre-eclampsia, they had similar admission-to-delivery intervals when compared to those of the control group. congenital diaphragmatic hernia: prenatal detection, postnatal surgical interventions and long-term outcomes einas al-yaqoubi,1 *lovina machado,2 tamima al-dughaishi,2 mohamed abdellatif,3 zainab al-balushi,4 nihal al-riyami2 1obstetrics and gynecology residency program, oman medical specialty board, muscat, oman; departments of 2obstetrics & gynaecology, 3child health and 4surgery, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: lovina1857@gmail.com objectives: this study aimed to compare antenatal diagnosis and neonatal findings among babies with congenital diaphragmatic hernia (cdh) in order to assess prognostic indicators of neonatal morbidity and mortality. methods: a retrospective cohort study took place of all babies with cdh treated at the sultan qaboos university hospital (squh), muscat, oman from january 2009 to december 2014. results: a total of 23 cases of cdh were identified. of these, 14 babies were delivered at squh, while the remainder were referred from other hospitals. most babies (n = 22; 95.7%) were delivered at term. left-sided cdh was observed in 78.3% of cases. associated congenital anomalies were noted in 13.0% of cases. surgical intervention with a good outcome took place in 82.6% of cases. antenatal diagnosis and the presence of congenital anomalies significantly influenced surgical outcomes, whereas mode of delivery, site of lesion and gestational age at delivery did not affect prognosis. conclusion: the overall mortality of babies with cdh was inversely related to increased antenatal detection of the condition. surgical interventions performed soon after birth resulted in better outcomes. the survival rate was higher in cases of isolated hernia rather than hernias with associated anomalies. demographic characteristics, clinical profile and outcomes of severe preeclampsia among omani women at a tertiary care centre asma al-jahwari,1 *maryam al-shukri,2 hamna al-musalhi,1 vaidyanathan gowri2 1medical student, college of medicine & health sciences, sultan qaboos university; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: mnalshukri@gmail.com objectives: severe pre-eclampsia is a major cause of maternal and neonatal morbidity and mortality. this study aimed to evaluate the clinical profile and maternal and fetal outcomes of omani women with severe pre-eclampsia who delivered at the sultan qaboos university hospital (squh), muscat, oman. methods: a retrospective review was conducted of all omani women admitted to a high-dependency unit (hdu) at squh with severe pre-eclampsia over a three-year period. results: severe pre-eclampsia occurred in approximately 1% of all women who delivered during the study period. of these severely pre-eclamptic women, 41% were 25–29 years old and 52% were obese. indications for admission to the hdu included symptoms in 58% of the subjects and abnormal biochemical results in 51% of the women. almost three-quarters of the subjects required a caesarean section delivery. two-thirds of neonates had a low birth weight and 60% were admitted for neonatal intensive care. conclusion: severe pre-eclampsia occurs among omani women at a similar frequency to other populations. maternal and neonatal outcomes are also similar. abstracts | e391 sultan qaboos university, 22–24 january 2016 outcomes of external cephalic version procedures at sultan qaboos university hospital, muscat, oman, between 2004–2014 nawal al-maamari,1 *rahma al-hadabi,2 tamima al-dughashi2 1obstetrics and gynaecology residency program, oman medical specialty board, muscat, oman; 2department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: rahmahamed@hotmail.com objectives: this study aimed to investigate the success rate and feto-maternal complications of external cephalic version (ecv) procedures among term pregnancies. methods: a retrospective cross-sectional study was conducted on 59 women who underwent ecv procedures for breech presentation at term and who attended the sultan qaboos university hospital, muscat, oman between january 2004 and june 2014. results: the ecv procedure was successful in 44% of cases. the majority of patients who underwent successful ecv procedures had a vaginal delivery (80.8%). the rate of caesarean section deliveries was 49%. the most common indication for a caesarean section delivery was a failed ecv procedure. no adverse fetal outcomes or major maternal complications occurred following ecv procedures. conclusion: in general, ecv procedures had a good success rate and were relatively safe. this procedure helped prevent a significant number of caesarean section operations. as such, well-equipped obstetrics units should routinely offer this procedure in relevant cases. patient preferences regarding the management of first trimester pregnancy loss in a tertiary care centre in oman: medical termination with misoprostol or surgical termination? *tamima al-dughaishi,1 mussab al-jabri,2 amjad al-haddabi,2 maryam al-shukri,1 suhaila al-wahaibi,3 wadha al-ghafri,1 vaidyanathan gowri1 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3obstetrics and gynaecology residency program, oman medical specialty board, muscat, oman. *corresponding author e-mail: aldughaishit@hotmail.com objectives: this study aimed to discover patient preferences regarding the management of pregnancy loss at the sultan qaboos university hospital (squh), muscat, oman. specifically, this study sought to ascertain whether patient preferences for termination using either misoprostol or dilation and curettage (d/c) was influenced by parameters such as age, parity and termination history. methods: a retrospective chart review was conducted on 441 patients admitted to squh for first-trimester miscarriages between either january and december 2010 or january and december 2014. data were collected from an electronic healthcare information system. results: a greater number of patients preferred misoprostol (79.30%) compared to d/c (69.57%). in the 2014 cohort, there was a slight increase in preference for d/c. age and termination history had no significant impact on patient preferences (p >0.005), although older patients and patients with a history of terminations showed a slight preference for d/c. conclusion: patient preferences regarding termination choices may be linked to the number of days of admission to hospital required or the side-effects of each procedure. previous experience with a specific procedure may also have an impact on preference. outcome of misoprostol use for the medical termination of pregnancies at a tertiary care centre in oman *tamima al-dughaishi,1 amjad al-haddabi,2 mussab al-jabri,2 maryam al-shukri,1 suhaila al-wahaibi,3 wadha al-ghafri,1 vaidyanathan gowri1 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3obstetrics and gynaecology residency program, oman medical specialty board, muscat, oman. *corresponding author e-mail: aldughaishit@hotmail.com objectives: the aim of this study was to determine the success rate of misoprostol for the medical termination of pregnancies at the sultan qaboos university hospital (squh), muscat, oman, in relation to various parameters. methods: a retrospective chart review study was conducted on all patients admitted to squh for the medical termination of pregnancies between either january and december 2010 or january and december 2014. two time periods were chosen to evaluate the effectiveness of the new departmental protocol implemented in 2014. results: the success rate of misoprostol in 2010 was 62.14% compared to 53.8% in 2014. there was little difference in the success rate of misoprostol between age groups in either year. in both 2010 and 2014, misoprostol had a higher success rate when used on primigravidae women than on patients with previous pregnancies. conclusion: misoprostol was more effective at inducing complete evacuation in 2010 than 2014, following the implementation of departmental protocol. the role of nurses in infertility management: holistic approach divya raghavan department of maternal & child health, college of nursing, sultan qaboos university, muscat, oman. e-mail: divyam@squ.edu.om infertility can be a major crisis and the inability to conceive can have serious consequences for a couple and their family. infertility management and treatment has significantly improved with advancements in care and new technologies. however, the role of the nurse remains undervalued. this poster presents various possibilities utilising a holistic approach for extending the role of nurses in managing infertility. the holistic management of infertility includes three main components: mind, body and spirit. it requires a deep understanding of the interaction between these components within a couple and their family in order to deal with infertilityrelated challenges. nurses take on many roles in providing care and support to an infertile couple, including as communicators, patient advocates and counsellors. nurses must balance multiple components—including assisted reproduction technologies and their client’s emotional and personal experiences—in order to integrate psychological and spiritual care with existing medical treatments. e392 | squ medical journal, august 2016, volume 16, issue 3 2nd international conference on advances in obstetrics and gynaecology part i poster presentations conservative management of a cervical pregnancy in a female with a history of multiple caesarean sections seema zulfikar,1 *vaidyanathan gowri,1 anupam kakaria,2 marwa al-riyami,3 athebele manjunath,1 mariam mathew1 departments of 1obstetrics & gynaecology, 2radiology & molecular imaging and 3pathology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: gowrie61@hotmail.com cervical pregnancies (cps) are the rarest form of ectopic pregnancies, with an incidence of one in between 1,000 and 18,000 individuals. we report a gravida 4 para 3 woman who presented to the sultan qaboos university hospital, muscat, oman, at 10 gestational weeks with abdominal pain and vaginal bleeding. the patient had had three previous caesarean sections. a speculum examination showed a closed ballooned cervix and heavy vaginal bleeding. a transvaginal scan suggested a cervical pregnancy. evacuation and curettage was performed after the placement of uterine artery balloon catheters. a foley catheter was inserted in the cervix for haemostasis. estimated blood loss was 1.5 l and two units of packed red blood cells were transfused. products of conception from the cervix and decidua from the endometrium were confirmed via histopathology. although cps are associated with life-threatening haemorrhage, timely intervention and uterine artery embolisation allowed a hysterectomy to be avoided in this case. ruptured cornual pregnancy masquerading as a heterotopic pregnancy durdana khan, ayesha salahudin, *mariam mathew department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: mariamm1762@gmail.com cornual ectopic or interstitial pregnancies make up 2–4% of all tubal pregnancies and have a mortality rate of 2–2.5%. we report a 33-year-old gravida 4 para 3 woman who presented to the sultan qaboos university hospital, muscat, oman, with shock and haemoglobin levels of 3.5 g/dl. at admission, a scan revealed a single live intrauterine fetus of 11 gestational weeks as well as massive haemoperitoneum. the patient was diagnosed with a heterotopic pregnancy and underwent an immediate laparotomy which revealed 3.5 l of haemoperitoneum and a ruptured right cornual ectopic pregnancy with a protruding fetus. cornual resection and a right salpingectomy were performed. an intraoperative scan showed an empty uterus. the patient received six units each of packed red blood cells and fresh frozen plasma. histopathology confirmed a cornual pregnancy. a ruptured cornual pregnancy can be life-threatening. laparoscopic surgery and medical management with methotrexate are safe options in early unruptured cases. iatrogenic injuries encountered in two minimally invasive surgeries *vandana pandit, arif jahan, joseph malliakal, sheikha al-jabri department of obstetrics & gynecology, new sohar hospital, sohar, oman. *corresponding author e-mail: vandsu@hotmail.com we report two cases of iatrogenic injuries encountered after minimally invasive surgeries (mis) involving diathermy and trocar use performed at the new sohar hospital, sohar, oman. the first patient was a 31-year-old female who underwent a hysteroscopic myomectomy for submucosal fibroids. she presented four days later after having suffered abdominal pain, nausea and dysuria for two days. on exploration, a 6 x 2 cm uterine perforation along the anterior wall and an incidental 2 x 3 cm bladder perforation were noted. the second patient was a 23-year-old female who underwent a diagnostic laparoscopy for infertility. she presented two days later with abdominal pain and dysuria. a through-and-through 0.5 cm perforation of the anterior and posterior bladder walls was found at suprapubic trocar entry points, with leakage of clear urine at the intraand extraperitoneal planes. medical practitioners should have a high index of suspicion of mis as a potential cause of bladder and other viscus organ injuries. sclerosing ovarian tumour in pregnancy: clinicohistopathological features of a rare case *sarva saiseema, forough radfar, zahra g. al-abri, mina george, hunaina al-kindi, sultana khan department of obstetrics & gynaecology, khoula hospital, muscat, oman. *corresponding author e-mail: saiseema@yahoo.com sclerosing stromal tumours are an extremely rare benign subtype of ovarian sex cord stromal neoplasms, with a prevalence of 1.5–6%. approximately 100 cases have previously been described in the literature. we report a 27-year-old pregnant female diagnosed antenatally with an ovarian tumour following magnetic resonance imaging. the patient underwent an emergency caesarean section delivery at term at the khoula hospital, muscat, oman. during the procedure, the left ovarian tumour was easily dissectible from the healthy ovarian tissue and was excised. histopathological examination revealed pseudolobulation, sclerotic stroma and prominent vascular spaces, confirming the diagnosis of a sclerosing stromal ovarian tumour. to date, no recurrence has been observed. this case report highlights an extremely rare ovarian tumour with unique clinical and histopathological features. due to the benign nature of the tumour and the generally young age of occurrence, recommended treatments include excision of the ovarian tumour or a unilateral oophorectomy. massive secondary postpartum haemorrhage: successful management of a rare case *shahila sheik,1 mariam mathew,1 asha nair,1 aisha al-hamdani,2 sinan al-azzawi,3 nihal al-riyami1 departments of 1obstetrics & gynaecology, 2pathology and 3radiology & molecular imaging, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: drshahila@hotmail.com placental polyps are placental tissue retained following parturition which may present later as massive secondary postpartum haemorrhage (pph). we report a para 2 woman who presented to the sultan qaboos university hospital, muscat, oman, three weeks after a caesarean section with a massive haemorrhage. she was haemodynamically unstable and required resuscitation. a scan raised suspicions of a fibroid polyp. the patient underwent uterine artery embolisation (uae) to control the bleeding. after two days, her β-human chorionic gonadotropin levels increased and magnetic resonance imaging suggested the possibility of a choriocarcinoma. a polypoidal growth was resected during a hysteroscopy and was confirmed via histopathology to be a placental polyp. retained placental tissue is usually treated with blind curettage. however, this carries risks of infection, perforation and haemorrhage, potentially resulting in a hysterectomy. in cases of severe secondary pph, uae is strongly recommended to control haemorrhage before surgical intervention is considered. evacuation of the uterus following uae can avoid unnecessary hysterectomies. abstracts | e393 sultan qaboos university, 22–24 january 2016 umbilical cord hypercoiling: rare cause of intrauterine fetal death *mariam mathew,1 majeda al-bash,1 asem shalaby,2 vaidyanathan gowri1 1department of obstetrics & gynaecology, sultan qaboos university hospital; 2department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: mariamm1762@gmail.com abnormal coiling of the umbilical cord can lead to miscarriage, fetal growth restriction, fetal heart deceleration and intrauterine fetal death (iufd). we report a 35-year-old gravida 6 para 4 woman with iufd who was referred to the sultan qaboos university hospital, muscat, oman, at 30 gestational weeks. the patient had had four previous caesarean sections, all resulting in healthy babies. the results of a previous anomaly scan had been normal. a lower-segment caesarean section was performed, during which an extremely low birth weight stillborn female baby weighing 930 g was delivered. the placenta weighed 285 g with marginal insertion of the umbilical cord which was hypercoiled with stricture at the fetal end. placental histopathology showed a three-vessel cord with no abnormalities. levels of umbilical cord coiling can be measured using the umbilical coiling index (uci) which defines hypercoiling as ≥0.30 coils/cm. determining the uci may reduce unexplained iufd rates. large pelvic abscess following oocyte retrieval and embryo transfer in an in vitro fertilisation cycle *lovina machado, asha nair, mariam mathew, lamya al-kharusi department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: lovina1857@gmail.com pelvic inflammatory disease (pid) is a rare complication of in vitro fertilisation, oocyte retrieval and embryo transfers which occurs in <1% of patients. we report a 29-year-old female with primary infertility who underwent these procedures with antibiotic prophylaxis at the sultan qaboos university hospital, muscat, oman. two weeks later, she developed symptoms of pid and was prescribed intravenous broad-spectrum antibiotics. she had previously developed a pelvic infection following a hysterosalpingography two years earlier. a laparotomy revealed pelvic adhesions. the right ovary was 9 x 10 cm in size with multiple haemorrhagic, endometriotic and simple cysts. a large pelvic abscess related to the left ovary and extending to the left lateral pelvic wall was drained. her postoperative recovery was uneventful. bacteriological tests revealed multidrug-resistant escherichia coli. in this case, the direct inoculation of vaginal micro-organisms was deemed to be the cause of pid. the risk of infection is higher for patients with endometriomas or a previous history of pid. isolated fetal umbilical vein varix with spontaneous complete postnatal resolution *lovina machado,1 sumaiya al-shukaili,2 sara abuzaid,1 fatma al-wahaibi,2 nihal al-riyami1 1department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman; 2obstetrics and gynaecology residency program, oman medical specialty board, muscat, oman. *corresponding author e-mail: lovina1857@gmail.com a fetal intra-abdominal umbilical vein varix (fiuvv) occurs when the subhepatic segment of the umbilical vein is ≥50% wider than the non-dilated intrahepatic portion or is dilated >9 mm. varix rupture, thrombosis and fetal death are major concerns. we report a 26-year-old gravida 3 abortus 2 woman who presented to the sultan qaboos university hospital, muscat, oman, at 33 gestational weeks. ultrasonography revealed an appropriately grown fetus with a round vascular cystic structure of 1.3 cm in the anterior diameter situated to the left of the fetal urinary bladder and communicating with the umbilical cord via an intra-abdominal dilated segment. an isolated umbilical vein varix was diagnosed. labour was induced at 38 gestational weeks and a normal vaginal delivery followed. the varix spontaneously resolved the next day. overall, fiuvvs comprise 4% of umbilical cord malformations and may be isolated, as with the current patient, or associated with other abnormalities. isolated cases generally have a good prognosis. a pregnant female with a ruptured appendix at 37 gestational weeks nusiba taufik department of obstetrics & gynaecology, liverpool women’s hospital, liverpool, uk. e-mail: ntaufik@doctors.org.uk although rare, appendicitis is the most common non-obstetrical surgical problem in pregnancy and causes significant maternal and infant morbidity and mortality. appendiceal ruptures are more likely in pregnancy, especially in the third trimester; however, physicians should maintain a high index of suspicion as symptoms can mirror those of other conditions. we report a 37-week pregnant female who was admitted to the liverpool women’s hospital, liverpool, uk, for a 48-hour period with appendicitis. this later developed into a rupture due to a lack of early clinical suspicion. this presentation offers insights into the diagnostic difficulties of appendicitis and provides a comprehensive review of the literature. a ruptured appendix during pregnancy leads to fetal loss in 35% of cases; awareness of this risk among medical practitioners is therefore essential. a multidisciplinary team should be involved in cases of appendicitis during pregnancy and a number of factors should be taken into account when considering surgical versus medical management. torted ovarian fibroma mimicking a uterine fibroid in the second trimester of pregnancy: diagnostic challenge hazel gonasalves,1 a. al-hadhrami,2 m. al-riyami,2 *vaidyanathan gowri1 1department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman; 2obstetrics and gynaecology residency program, oman medical specialty board, muscat, oman. *corresponding author e-mail: gowrie61@hotmail.com ovarian fibromas are generally asymptomatic and are usually detected incidentally during routine imaging. we report a 32-yearold gravida 3 para 1 abortus 1 pregnant woman who was admitted to the sultan qaboos university hospital, muscat, oman, at 20 gestational weeks with abdominal pain, vomiting and a fever of five days’ duration. three days earlier, she had been diagnosed with red degeneration of uterine fibroids at another institution. on physical examination, the patient was pale with normal vital signs. the uterus was relaxed, although there was tenderness in the right iliac fossa. abdominal ultrasonography revealed a live fetus and an adnexal mass of 8 cm. doppler ultrasonography indicated no blood flow. a gangrenous torted right adnexa was removed during an emergency laparotomy and a right salpingo-oophorectomy. histological examinations revealed an ovarian fibroma. on ultrasonography, an ovarian fibroma is typically hypoechoic with sound attenuation. it is important that radiologists differentiate between ovarian fibromas and uterine fibroids to avoid misdiagnosis. e394 | squ medical journal, august 2016, volume 16, issue 3 2nd international conference on advances in obstetrics and gynaecology part i poster presentations non-ovarian pelvic cyst in early pregnancy: challenging diagnosis hazel gonsalves,1 sarya m. a. bella,1 noreen ishrat,1 asem shalaby,2 sreedharan velupurath,3 *mariam mathew1 departments of 1obstetrics & gynaecology and 3surgery, sultan qaboos university hospital; 2department of pathology, college of medicine & health sciences, sultan qaboos university, oman. *corresponding author e-mail: mariamm1762@gmail.com a cystic non-ovarian pelvic mass arising in early pregnancy can be a challenging diagnosis. we report a 23-year-old primigravida women with a six-week history of amenorrhoea who presented to the sultan qaboos university hospital, muscat, oman, with acute abdominal pain. her β-human chorionic gonadotropin (β-hcg) levels were 600 iu. on physical examination, the patient’s abdomen was tense and tender, with noticeable guarding. ultrasonography revealed a huge cystic mass around the ovaries, with good flow. the uterus was empty, with minimal free pelvic fluid. the mass persisted after urinary catheterisation, raising the suspicion of bladder diverticulum. computed tomography revealed a unilocular intra-abdomino-pelvic cyst of 20 x 13 cm, separate from the bladder and ovaries. the patient’s β-hcg levels dropped, indicating a miscarriage. a 20 x 10 cm uniloculated cyst attached to the mesocolon was excised via laparoscopy. histopathology confirmed an omental cyst. although rare, omental/mesenteric cysts should be considered in the differential diagnosis for pelvic cysts of non-ovarian origin. placenta membranacea: rare placental abnormality seema zulfikar, maryam al-shukri, hana al-sayed, asha nair, *lovina machado department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: lovina1857@gmail.com placenta membranacea is a rare placental abnormality (one in 20,000–40,000 pregnancies) whereby the fetal membranes are completely or partially covered by chorionic villi. perinatal outcomes can include stillbirth, preterm delivery and neonatal death. we report a gravida 2 para 1 female who presented at the sultan qaboos university hospital, muscat, oman, at 18 gestational weeks with a threatened miscarriage. she had previously undergone a caesarean section. ultrasonography confirmed placenta membranacea and the patient was managed conservatively. however, episodes of antepartum haemorrhage continued. she underwent an emergency caesarean section at 25 gestational weeks due to heavy vaginal bleeding. intraoperatively, the placenta was observed to cover the internal orifice of the cervix uteri and the entire uterine wall. postpartum haemorrhaging from the placental bed was managed with multiple haemostatic sutures. the patient was transfused with four units of packed red blood cells. although her recovery was uneventful, her baby died two days after delivery due to extreme prematurity. unilateral live right tubal twin ectopic pregnancy nawal al-maamari,1 *anita zutshi,2 seerat minocha2 1obstetrics and gynecology residency program, oman medical specialty board, muscat, oman; 2department of obstetrics & gynecology, royal hospital, muscat, oman. *corresponding author e-mail: anitazutshi@gmail.com unilateral live twin ectopic pregnancies occur at a frequency of one in 125,000 pregnancies. factors which increase the risk of ectopic pregnancy include pelvic inflammatory disease, congenital anomalies, tumours and adhesions resulting in anatomically distorted fallopian tubes. we report a 31-year-old female who presented to the sultan qaboos university hospital, muscat, oman, with vaginal bleeding, following an eight-week history of amenorrhea. she had conceived after treatment with clomiphene citrate. a serum pregnancy test was positive. transvaginal ultrasonography revealed one gestational sac, with two live discordant embryos in a right adnexal mass. a laparoscopic salpingectomy was performed. the diagnosis was confirmed by histopathological examination. a live discordant monochorionic twin ectopic pregnancy in the right fallopian tube is extremely rare. physicians should consider this condition when examining ultrasound scans, especially in patients undergoing assisted reproduction, as twin ectopic pregnancies carry high risks of morbidity and mortality. swyer syndrome: rare case report of a female phenotype with 46,xy karyotype and gonadoblastoma *muna m. al-badi, nishat fatema, fatma m. al-abri department of gynaecology & obstetrics, ibri hospital, ibri, oman. *corresponding author e-mail: mmralbadi@yahoo.com swyer syndrome is a rare disorder with an incidence rate of 1:80,000 in which the testes fail to develop due to a mutation of the sex determining region y (sry) gene. the incidence of sry mutations is thought to be 10–15%. we report a 17-year-old patient of female phenotype who presented to the ibri hospital, ibri, oman, with primary amenorrhoea and tanner stage iv breast and pubic hair development. she had complete gonadal dysgenesis, a 46,xy karyotype, a hypoplastic uterus and streak gonads. upon diagnosis of swyer syndrome, a prophylactic laparoscopic bilateral gonadectomy was performed. histopathological examination revealed a gonadoblastoma without evidence of malignant transformation. the patient subsequently underwent hormone therapy which improved her secondary sexual characteristics. early diagnosis of a gonadoblastoma is crucial to avoid malignant transformation. the recommended treatment for this condition is a gonadectomy. catamenial haemopneumothorax: atypical presentation of endometriosis *shahila sheik,1 ashok sharma,2 noreen ishrat,1 seema zulfikar,1 moza al-kalbani1 departments of 1obstetrics & gynaecology and 2surgery, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: drshahila@hotmail.com catamenial haemopneumothorax is a variant of thoracic endometriosis syndrome. this rare disorder is characterised by the presence of functioning endometrial tissue in the pleura, lung parenchyma, airways and/or diaphragm. we report a 31-year-old nulliparous female with known pelvic endometriosis who presented to the sultan qaboos university hospital, muscat, oman, with sudden-onset shortness of breath. a chest x-ray revealed hydropneumothorax. dark-coloured blood was aspirated through an intercostal drain using intensive chest physiotherapy and continuous low-voltage suction. as no clinical improvement was observed, a right posterolateral thoracotomy was conducted, with a biopsy of the diaphragmatic deposits, closure of diaphragmatic fenestration and parietal pleurectomy. histological examination of the parietal pleura, diaphragm and diaphragmatic deposits confirmed endometriosis. the patient was prescribed a combined oral contraceptive. a multidisciplinary team approach, involving both thoracic and gynaecological surgeons, maximises the likelihood of accurate diagnosis and treatment for women with this rare condition. abstracts | e395 sultan qaboos university, 22–24 january 2016 ovarian ectopic pregnancy: rare variant of ectopic pregnancy *shahila sheik, noreen ishrat, hana al-sayed, sunita kumari, lovina machado department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: drshahila@hotmail.com ovarian pregnancies are a rare form of ectopic pregnancy that pose a significant diagnostic challenge. we report a 34-year-old primigravida woman who presented to the sultan qaboos university hospital, muscat, oman, at 6 gestational weeks with lower abdominal pain and vaginal bleeding. although her initial serum β-human chorionic gonadotrophin (β-hcg) test showed the expected doubling and ultrasonography indicated no extrauterine gestation, her third β-hcg value failed to show doubling, suggesting an ectopic pregnancy. a suspicious mass was noted via scan. the patient opted for medical management and was treated with a methotrexate injection. four days later, the patient experienced severe abdominal pain and a scan indicated a cyst in the left ovary and some free fluid. an emergency laparoscopy revealed normal fallopian tubes, with trophoblast-like tissue over the left ovary. a histopathological examination of the tissue confirmed an ectopic pregnancy. preoperative diagnosis of this condition is challenging as ectopic tissue often resembles a corpus luteum cyst. polypoid adenomyoma in a postmenopausal female: rare case aneeta bai,1 jai kumari,1 hana al-sayed,1 anna saparamadu,2 mariam mathew1 departments of 1obstetrics & gynaecology and 2pathology, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: aneeta@squ.edu.om atypical polypoid adenomyomas (apams) are rare polypoid tumours that occur in women of reproductive age who have abnormal uterine bleeding. we report a 59-year-old para 12 postmenopausal woman who presented to the sultan qaboos university hospital, muscat, oman. she was asymptomatic and known to be diabetic. ultrasonography revealed a thick endometrium of 19 mm and hydrosonography showed a mass of 3.4 x 2.9 cm in the uterine cavity. hysteroscopy, polypectomy and endometrial curettage were performed. a polypoid lesion of 3 x 2 cm was excised under hysteroscopic guidance. histopathological examination revealed a polypoid adenomyoma without atypia or evidence of malignancy. threeand six-month follow-up examinations were unremarkable. pathologically, apams are classified as benign lesions and typically have favourable outcomes. however, patients with an apam have a high risk of residual lesions, recurrence and the concomitant development of endometrial adenocarcinomas. care should therefore be taken during diagnosis, treatment and follow-up. departments of 1anaesthesia & intensive care unit and 2behavioural medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: aravindn@squ.edu.om بروتوكالت التخدير العام للمرضى الذين خيضعون للعالج باجللسات الكهربائية حتليل اسرتجاعي لـ 504 جلسة خالل مدة مخس سنوات يف مستشفى رعاية ثالثية يف عمان ارفيند ناريان, �ضندر الل, حمد ال�ضناوي abstract: objectives: this study aimed to review general anaesthesia protocols for patients undergoing electroconvulsive therapy (ect) at a tertiary care hospital in oman, particularly with regards to clinical profile, potential drug interactions and patient outcomes. methods: this retrospective study took place at the sultan qaboos university hospital (squh), muscat, oman. the electronic medical records of patients undergoing ect at squh between january 2010 and december 2014 were reviewed for demographic characteristics and therapy details. results: a total of 504 modified ect sessions were performed on 57 patients during the study period. all of the patients underwent a uniform general anaesthetic regimen consisting of propofol and succinylcholine; however, they received different doses between sessions, as determined by the treating anaesthesiologist. variations in drug doses between sessions in the same patient could not be attributed to any particular factor. self-limiting tachycardia and hypertension were periprocedural complications noted among all patients. one patient developed aspiration pneumonitis (1.8%). conclusion: all patients undergoing ect received a general anaesthetic regimen including propofol and succinylcholine. however, the interplay of anaesthetic drugs with ect efficacy could not be established due to a lack of comprehensive data, particularly with respect to seizure duration. in addition, the impact of concurrent antipsychotic therapy on anaesthetic dose and subsequent complications could not be determined. keywords: general anesthesia; propofol; succinylcholine; electroconvulsive therapy; drug interactions; oman. امللخ�ص: الهدف: تهدف هذه الدرا�ضة ملراجعة بروت�ك�الت التخدير للمر�ضى الذين يخ�ضع�ن للعالج باجلل�ضات الكهربائية يف م�ضت�ضفى رعاية ثالثة مرجعي ب�ضلطنة عمان, مع مراعاة التاريخ املر�ضي وال�رسيري للمر�ضى والنتائج املحتملة لتفاعالت االدوية. الطريقة: اأخذت الدرا�ضة من امللفات االلكرتونية لل�ضجل الطبي للمر�ضى الذين يتلق�ن العالج باجلل�ضات الكهربائية يف م�ضت�ضفى جامعة ال�ضلطان قاب��ص بعمان مع اأخذ التفا�ضيل الدمي�غرافية للمر�ضى والتاريخ املر�ضي خالل الفرتة بني يناير 2010م اإىل دي�ضمرب 2014م. النتائج: اأجريت 504 جل�ضة كهربائية لـ 57 مري�ص خالل فرتة الدرا�ضة خ�ضع فيها املر�ضى لنظام م�حد للجل�ضات الكهربائية مع تخدير عام م�حد مك�ن طبيب حتديد ح�ضب على واملتتابعة املختلفة اجلل�ضات بني االأدوية لهذه خمتلفة جرعات تلقيهم مع وال�ضك�ضينيل الربب�ف�ل اأدوية من الدم و�ضغط املت�ضارعة القلب دقات وكانت حمدد. لعامل تعزى ال�احد للمري�ص اجلل�ضات بني املختلفة اجلرعات تلك تكن مل التخدير. املرتفع وا�ضحة كاأحد امل�ضاعفات التي حتدث قبل اإجراء العالج باجلل�ضات الكهربائية بني املر�ضى. تعر�ص اأحد املر�ضى للتهاب رئ�ي )%1.8(. اخلال�صة: ح�ضل جميع املر�ضى الذين تعر�ض�ا للعالج باجلل�ضات الكهربائية على نظام م�حد للتخدير العام مك�ن من الربوب�ف�ل وال�ضك�ضينيل. مع هذا ال ميكن احلكم على تاثري اأدوية التخدير وفاعلية العالج باجلل�ضات الكهربائية لعدم وج�د معل�مات كافية اأو معرفة لتاأثريها على مدة الذهان احلا�ضلة خالل فرتة تلقي العالج. باال�ضافة اإىل اأنه مل تت�ضح الروؤية لتاثري اأدوية عالج الذهان التي يتلقاها املري�ص مع جرعات التخدير و امل�ضاعفات احلا�ضلة. الكلمات املفتاحية: التخدير العام؛ الربب�ف�ل؛ ال�ضكي�ضنيل؛ العالج باجلل�ضات الكهربائية؛ تفاعل االدوية؛ عمان. general anaesthesia protocols for patients undergoing electroconvulsive therapy retrospective analysis of 504 sessions over a five-year period at a tertiary care hospital in oman *aravind narayanan,1 chandar lal,1 hamed al-sinawi2 clinical & basic research sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e43–49, epub. 30 mar 17 submitted 26 jun 16 revisions req. 1 aug & 27 sep 16; revisions recd. 25 aug & 5 oct 16 accepted 13 oct 16 doi: 10.18295/squmj.2016.17.01.009 advances in knowledge to the best of the authors’ knowledge, this study is the first to evaluate anaesthesia protocols among patients undergoing modified electroconvulsive therapy (ect) in oman. application to patient care correlating antipsychotic and anaesthetic drug protocols with the quality and duration of ect-induced seizures may help caregivers choose more suitable pharmaceutical agents. the findings of the current study may help in creating standard protocols for the safe administration of anaesthetic agents during ect treatment. general anaesthesia protocols for patients undergoing electroconvulsive therapy retrospective analysis of 504 sessions over a five-year period at a tertiary care hospital in oman e44 | squ medical journal, february 2017, volume 17, issue 1 in clinical practice, the concept ofinducing convulsions was first introduced in 1934 when camphor oil was used to induce convulsions in a patient with catatonic schizophrenia; electricallyinduced seizures were subsequently reported in 1938.1–6 in 1951, the use of general anaesthesia with muscle relaxants during electroconvulsive therapy (ect) was proposed to alleviate the adverse effects and injuries resulting from seizure-induced motor activity, such as tongue biting and long bone fractures.7 currently, performing ect on a patient without anaesthesia is considered unethical.8 during ect sessions, anaesthesiologists provide diligent cardiorespiratory monitoring services, life support expertise and the pharmacological reduction of actual seizures while allowing unimpeded electrical activity.9 globally, anaesthesia protocols during ect procedures are not standardised, primarily due to the varying availability of drugs and the preferences of individual anaesthetic care providers.10 however, the increasing number of psychopharmaceutical drugs available necessitates greater vigilance with regards to possible interactions with anaesthetic agents so as to avoid the development of cardiovascular complications.11 moreover, the expanding geriatric population worldwide and the increasing burden of chronic diseases like diabetes, hypertension and ischaemic heart disease are also added risk factors for the increased incidence of adverse effects and drug interactions due to anaesthesia and ect. a thorough understanding of pre-existing medical conditions is needed when determining the selection of suitable anaesthetic drugs, monitoring options and management of complications arising from anaesthesia and induced seizures.12 anaesthetic drugs alone should not cause added complications or attenuate the efficacy of the seizure therapy.13 it is imperative for anaesthesia care providers to refine management strategies and treatment regimens for patients undergoing ect sessions, thus ensuring the safety and comfort of the patient and enhancing overall acceptance of ect. this study aimed to analyse the anaesthesia protocols used during modified ect sessions at a tertiary care hospital in oman over a five year period and determine patient outcomes, periprocedural complications and potential correlations with demographic, clinical, pharmacological and therapeutic factors. by identifying potential deficits in existing anaesthesia protocols, more objective anaesthetic and psychopharmaceutical treatment plans can be determined, which could then be extended into a region-based standard of care. methods this retrospective study was conducted at the sultan qaboos university hospital (squh), muscat, oman. the electronic medical records of all patients receiving ect at squh between january 2010 and december 2014 were analysed. information was collected regarding demographic characteristics, psychiatric diagnosis, the presence of any comorbidities at the time of ect treatment, physical status as per american society of anaesthesiologists (asa) classifications, overall number of ect sessions performed and type of anaesthetic drugs used during the ect session.14 patients with critical illnesses or with asa grades of ≥iii were deemed unfit for ect and excluded from the study. all of the patients were assessed the day before the ect session by a trained anaesthesiologist. any use of antipsychotic drugs for primary behavioural disorders was documented, especially with regards to concomitant use immediately preceding the ect session. additional sedative premedication was not prescribed by the anaesthesiologist for any patient. the ect procedures were conducted in the operation theatre recovery room by a behavioural medicine specialist, an anaesthesiologist and an anaesthesia nurse. a complete set of resuscitation equipment and drugs along with a piped oxygen supply and central suction unit were available on-hand. before induction of the anaesthesia, intravenous (iv) access was ensured and monitoring equipment was connected. bitemporal electrical shocks were delivered using a thymatron® system iv integrated ect instrument (somatics llc, lake bluff, illinois, usa). after the ect procedure, the patients were monitored until they were transferred to a general ward. data were tabulated using an excel spreadsheet, version 2013 (microsoft inc., redmond, washington, usa) and analysed statistically using the statistical package for the social sciences (spss), version 23 (ibm corp., chicago, illinois, usa). as some inpatients were admitted more than once, each admission period was considered an episode. for those patients receiving several sessions of maintenance ect as outpatients, these were recorded as sessions but not episodes. drug dosing was interpreted according to kg of body weight for comparative purposes. ethical approval for this study was granted by the medical ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #911). patient confidentiality was maintained by coding the medical records to conceal patient identity. aravind narayanan, chandar lal and hamed al-sinawi clinical and basic research | e45 results during the study period, a total of 504 ect sessions were performed on 57 patients, including 20 male and 37 female patients. among these patients, a total of 71 episodes (admission periods) were noted, with 10 inpatients having two episodes and four inpatients having three episodes or more. male and female patients were statistically comparable in terms of age, weight and body mass index; however, men were significantly taller than women (p = 0.002). the mean number of ect sessions per patient was 8.8 (range: 2–23 sessions). the mean hospital stay duration was 35.8 days prior to the completion of ect treatment and 4.2 days after the final ect session [table 1]. among the patients who underwent ect during the study period, 34 patients (59.6%) were diagnosed with major depression, 10 (17.5%) with schizophrenia and seven (12.3%) with bipolar disorder. the remaining six patients (10.5%) had postpartum behavioural and/ or obsessive-compulsive disorders. the majority of the patients had no comorbid illnesses and were classified as asa grade i (n = 45; 78.9%). there were 12 patients (21.1%) classified as asa grade ii or iii in terms of physical status. six patients had a single systemic disease, while the remaining six had two or more illnesses, with the most common being diabetes, hypertension and controlled ischaemic heart disease [table 2]. table 1: demographic and clinical variables of patients undergoing electroconvulsive therapy sessions at the sultan qaboos university hospital, muscat, oman, according to gender (n = 57) variable mean ± sd inter-gender comparison females (n = 37) males (n = 20) t value* mannwhitney u p value age in years 42.7 ± 18.9 45.1 ± 17.7 -0.470 0.640 height in m 1.54 ± 0.06 1.61 ± 0.09 -3.299 0.002† weight in kg 64.9 ± 16.6 70.3 ± 19.4 1.102 0.275 bmi in kg/m2 27.2 ± 6.4 26.9 ± 6.6 0.131 0.896 ect sessions (range) 8.9 ± 19 (4–23) 8.6 ± 21 (2–23) 0.208 0.836 hospital stay in days (range) 34.5 ± 99 (8–107) 37.1 ± 58 (7–65) 0.427 0.671 post-ect hospital stay in days (range) 4.0 (0–36) 4.3 (0–17) 0.196 0.845 asa status, n (%) grade 1 28 (49.1) 17 (29.8) 331 0.341 grade 2 5 (8.8) 3 (5.3) grade 3 4 (7.0) 0 (0.0) propofol dose in mg/kg minimum 1.36 ± 0.38 1.38 ± 0.29 404 0.567 maximum 1.94 ± 0.45 1.94 ± 0.52 366.5 0.953 succinylcholine dose in mg/kg minimum 0.64 ± 0.17 0.64 ± 0.15 369 0.986 maximum 0.84 ± 0.23 0.87 ± 0.26 379 0.879 bmi = body mass index; ect = electroconvulsive therapy; asa = american society of anaesthesiologists. *using t(55). †statistically significant. table 2: prevalence of comorbid diseases among patients undergoing electroconvulsive therapy at the sultan qaboos university hospital, muscat, oman (n = 57) comorbid illness n (%)* hypertension 5 (8.8) diabetes 4 (7.0) ischaemic heart disease 3 (5.3) liver cirrhosis 1 (1.8) obesity-related sleep apnoea 1 (1.8) gastric ulcer 1 (1.8) chronic nephritis 1 (1.8) breast carcinoma 1 (1.8) hypothyroidism 1 (1.8) *patients with more than one comorbid illness have been included in several categories. general anaesthesia protocols for patients undergoing electroconvulsive therapy retrospective analysis of 504 sessions over a five-year period at a tertiary care hospital in oman e46 | squ medical journal, february 2017, volume 17, issue 1 every patient received between one and five sedative drugs before each ect session as part of their psychiatric medical therapy. as numerous adjustments were made to the doses due to changes in the clinical condition of each patient, definitive premedication doses were not recorded. atropine was not used as routine premedication for any of the patients. during the ect sessions, all of the patients were attended by a trained staff anaesthesiologist and intravenously received propofol as an anaesthetic agent and succinylcholine as a muscle relaxant. propofol doses ranged from 1.36–1.94 mg/kg with individual doses titrated to clinical loss of consciousness by the attending anaesthesiologist. variations in dosing were noted between different ect sessions for the same patient in subsequent episodes; however, these variations could not be attributed to any particular factor. mean doses of succinylcholine ranged between 0.64–0.87 mg/kg. subsequent doses of succinylcholine during later ect sessions for the same patient were tailored according to the clinical observations of the attending anaesthesiologist and the behavioural medicine team. electrocardiography (ecg) monitoring took place throughout all ect sessions. in addition, pulse, heart rate, blood oxygen saturation and automated non-invasive blood pressure were monitored at regular intervals during the session. during the ect procedure, transient tachycardia and hypertension were observed in all patients, initially after the succinylcholine administration and then during the clonic phase of the seizures, following the initial parasympathetic activity of the tonic phase. intravenous lidocaine was administered prophylactically to one patient (1.8%) with a history of frequent premature ventricular contractions, which did not lead to haemodynamic instability. table 3 presents a summary of the periand postprocedural complications which required additional medication or management. beta-blocker therapy was required for five patients (8.8%), although not during all ect sessions for each patient. transient bradycardia and hypersalivation were documented in two (3.5%) and four patients (7.0%), respectively; the development of these complications were not related to asa grade severity. after the ect procedure, glycopyrrolate was administered to four patients (7.0%) to reduce profuse oral secretions and atropine was administered to one patient (1.8%) due to persistent bradycardia. another patient with a pre-existing atrial fibrillation was diagnosed with bradycardia after the ect procedure but did not require atropine therapy. sustained seizure activity was documented in one patient (1.8%) classified as asa grade i who needed an additional propofol dose and a higher succinylcholine dose in subsequent ect sessions. one ect session (0.2%) was aborted after the administration of anaesthetic drugs as the ect energy delivery unit malfunctioned. delayed recovery was documented in one patient (1.8%) classified as asa grade i. one patient (1.8%) went into respiratory distress and oxygen desaturation after his third ect session which presented within an hour of being moved from the recovery room. the initial diagnosis of a pulmonary embolism was ruled out by chest imaging and a subsequent diagnosis of aspiration pneumonitis was made, likely due to diabetes-related gastroparesis. the patient was given supplemental oxygen and noninvasive ventilatory support in a high-dependency ward and was prescribed a five-day course of antibiotics. he was subsequently discharged from the hospital after a complete recovery. anaesthetic regimens could not be correlated with patient outcomes. unfortunately, information table 3: complications*, management and patient outcomes of electroconvulsive therapy sessions at the sultan qaboos university hospital, muscat, oman (n = 504) complication n (%) management (dose) patient outcome facial flush 1 (0.2) continuous monitoring self-limiting tachycardia 2 (0.4) esmolol (50 mg) control of symptom bradycardia 2 (0.4) atropine (0.5 mg) control of symptom hypersalivation 4 (0.8) glycopyrrolate (0.4 mg) control of symptom hypertension 2 (0.4) labetalol (10 mg) control of symptom hypotension 1 (0.2) ephedrine (5 mg) control of symptom delayed recovery 1 (0.2) continuous monitoring complete recovery hyperglycaemia 1 (0.2) iv insulin (10 units) with blood glucose monitoring control of blood glucose to <10 mmol sustained seizures 1 (0.2) propofol (20 mg) control of seizures aspiration pneumonitis 1 (0.2) non-invasive ventilation and antibiotics patient recovered and was discharged from hospital machine failure 1 (0.2) ect was not delivered patient recovered from anaesthesia iv = intravenous; ect = electroconvulsive therapy. *including only those complications which required additional medication or management. aravind narayanan, chandar lal and hamed al-sinawi clinical and basic research | e47 regarding the energy level of shocks delivered and seizure duration was unavailable for any of the patients, presumably due to equipment constraints. as such, the effect of the anaesthetic drugs on the efficacy of ect could not be established. the effect of concurrent antipsychotic therapy on anaesthetic drug dose and subsequent complications could also not be determined. discussion in spite of its mechanism of action, ect is one of the safest therapeutic procedures for the treatment of mental illness, with reported post-treatment mortality rates of 1:25,000–50,000.3 nevertheless, care providers should remain vigilant as induced seizures affect the cardiorespiratory and autonomic systems; although transient, these physiological effects pose a serious hazard, particularly to elderly patients or those with multiple comorbidities.15 according to previous research, ect is currently available in 23 asian countries; however, the use of this type of therapy in the asian region is considered critically suboptimal in terms of conduct, monitoring and training.16 in the middle east, objective studies of mental illness—and, more specifically, the use of ect and associated anaesthetic regimens—have not yet been conducted.17 a 10-year audit of ect treatment at a university hospital in saudi arabia is currently the largest body of work on this topic in the arab region.18 as such, to the best of the authors’ knowledge, this is the first study to evaluate the use of anaesthesia among patients undergoing ect in oman. the use of anaesthetic agents during ect, primarily central nervous system (cns) depressors which attenuate the intensity/duration of seizures, has been widely researched.19 in general, most anaesthetic agents depress the cns, thus ironically countering the objective of ect, which is to excite the cns and induce seizures.20 although methohexital and sodium thiopental were previously the most frequently used anaesthetic agents for ect, these drugs have now been largely replaced by propofol due to its wider availability, faster recovery profile and favourable effect on haemodynamic stability, despite its effect in reducing seizure production.19,21 other inhalational anaesthetic agents have been compared favourably with propofol.22 ketamine and etomidate do not have anticonvulsant properties and seem to provide a higher quality and duration of seizures.23,24 however, associated side-effects such as hallucinations, symp athetic activation of the nervous system and hypothalamic depression have excluded their routine use during ect treatment.25 numerous adjuncts to induction agents have been suggested so as to reduce the required dose of propofol and provide good sedation depth and seizure quality; remifentanil, a novel ultra-short-acting opioid, has a favourable profile in this respect.26 the current study sought to correlate concomitant use of antipsychotic medications with anaesthesia dosages during ect sessions in order to determine a pattern which might allow the clinical utilisation of a narrower dosage range. this would eliminate dose variations between anaesthesiologists and be more objective and safe for general patient use. concomitant antipsychotic drugs (e.g. benzodiazepines) have been implicated in raising the seizure threshold, thus reducing the overall efficacy of ect; in such patients, cognitive function should be monitored on an on-going basis or at least after each ect course, as recommended in the national institute of clinical excellence guidelines.27 unfortunately, the varied drug regimens and dosages and differing clinical conditions of the patients in the current study made it difficult to determine a statistical or clinical correlation with either anaesthetic drug dose or ect efficacy. in addition, the short-acting muscle relaxant succinylcholine minimises physical musculoskeletal manifestations of induced seizures, while allowing seizure activity to proceed in the brain tissue.28 this complete attenuation of the clinical signs of a seizure means that the only way to record seizure duration is by electroencephalography (eeg). in the current study, seizure duration could not established either via clinical observation or eeg recordings, due to a lack of proper equipment and the absence of a specific clinical directive. this precluded any correlation between anaesthetic drug doses and attenuation of seizure intensity or duration. finally, the dose of electrical energy delivered during ect sessions in the current study was not recorded in the patients’ medical records. analysis of the energy dose, in correlation with the seizure duration and the anaesthetic drug dose, would have provided a good measure of the efficacy and robustness of the anaesthetic regimen used for ect.9 succinylcholine is the gold standard for modified ect sessions.28 as mentioned earlier, it is recommended that the lowest possible dose of muscle relaxants be used so as to maintain minimal muscle fasciculation and obtain visual evidence of seizures.29 the goal is to prevent massive tonic-clonic seizures resulting in movements that could lead to soft tissue/ bony injury, rhabdomyolysis or hyperkalemia. in situations where a depolarising muscle relaxant is contraindicated, such as with paraplegia, stroke, hyperkalemic syndromes and major trauma/burns, general anaesthesia protocols for patients undergoing electroconvulsive therapy retrospective analysis of 504 sessions over a five-year period at a tertiary care hospital in oman e48 | squ medical journal, february 2017, volume 17, issue 1 rocuronium has been administered with rapid reversal of its neuromuscular blockade using the novel cyclodextrin agent sugammadex.30 low-dose atropine has been advocated to counter transient parasympathetic-mediated dysrhythmia and increased exocrine secretions after ect.31 however, given the arid environment and high ambient temperatures of the middle east, the potential thermogenic action of parasympatholytic agents precludes their routine use as a premedication.32 additionally, patients undergoing ect are usually also prescribed various antipsychotic agents known to trigger the serotonin-mediated hypothalamic resetting of body temperature-control mechanisms.33 beta-blockers such as esmolol or labetalol are the mainstay of therapy for the management of hypertension and tachyarrhythmia, which are usually persistent after ect is administered.34 however, esmolol has a doserelated effect of shortening the duration of a seizure, with minimal impact on eeg measurements. in comparison, the novel alpha agonist dexmedetomidine has been shown to more favourably reduce the hyperdynamic circulatory response after ect.35 during short anaesthesia sessions for ect, patients undergo ventilation with a face mask or positive pressure ventilation with a bag-mask device, without definitive airway protection devices; this is because the procedure is always performed on an elective basis and with an adequate fasting period, obviating the need for such interventions. however, due to seizure-induced relaxation of the oesophageal sphincter, patients with oesophageal reflux disease or gastric dysmotility/gastroparesis due to diabetic or autonomic neuropathy are likely candidates for aspiration while unconscious. hence, it is necessary to monitor oxygen saturation throughout the procedure so as to detect possible life-threatening episodes of desaturation.36 sudden cardiac death has also been reported following ect, likely due to proarrhythmogenic interactions between antipsychotic medications and the application of electrical energy; hence, there is a need for diligent pre-anaesthetic and periprocedural 12-lead ecg monitoring.37 using bispectral index monitoring to determine sedation depth and titrate anaesthetic agents is a promising new technology in ensuring patient safety during ect sessions.38 novel shorter-acting adjunctive pharmacologic agents also need to be explored, particularly for patients undergoing ect who present at an older age or with comorbidities.18 a major limitation of the present study was the lack of documentation regarding the energy level, number and duration of the electric shocks delivered during ect sessions, particularly with regards to the lack of eeg data. moreover, the use of differing primary antipsychotic drug regimens in patients, many with additional anti-seizure activities, confounded attempts to identify optimum anaesthetic drug doses for seizure quality and duration and precluded more objective correlations with the anaesthetic drug doses used. in order to determine safer and more objective anaesthesia protocols, prospective studies are recommended to correlate energy levels of electric shocks delivered during ect, seizure duration, concomitant antipsychotic agents and overall patient outcomes. conclusion all ect sessions in the current study were conducted using a uniform anaesthesia protocol consisting of propofol and succinylcholine. wide dosage variations were observed among patients and between different sessions for the same patient. no specific factor could explain these variations, nor could the anaesthetic regimen be correlated with eventual patient outcomes. increased oral secretions and transient tachycardia, bradycardia and hypertension were the most common periprocedural complications, which did not necessitate any major change in the anaesthetic regimen. due to a lack of data with regards to the energy level, number and duration of the electric shocks delivered during ect sessions, correlations between anaesthetic drugs and ect efficacy could not be established. furthermore, the impact of concurrent antipsychotic therapy on anaesthetic regimen and patient outcomes could not be determined. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. faedda gl, becker i, baroni a, tondo l, asplund e, koukopoulos a. the origins of electroconvulsive therapy: prof. bini’s first report on ect. j affect disord 2010; 120:12–15. doi: 10.1016/j.jad.2009.01.023. 2. mayo c, kaye ad, conrad e, baluch a, frost e. update on anaesthesia considerations for electroconvulsive therapy. middle east j anaesthesiol 2010; 20:493–8. 3. baghai tc, möller hj. electroconvulsive therapy and its different indications. dialogues clin neurosci 2008; 10:105–17. 4. spodniaková b, halmo m, nosáľová p. electroconvulsive therapy in pregnancy: a review. j obstet gynaecol 2015; 35:659–62. doi: 10.3109/01443615.2014.990427. https://doi.org/10.1016/j.jad.2009.01.023 https://doi.org/10.3109/01443615.2014.990427 aravind narayanan, chandar lal and hamed al-sinawi clinical and basic research | e49 5. bolwig tg. how does electroconvulsive therapy work? theories on its mechanism. can j psychiatry 2011; 56:13–18. doi: 10.1177/070674371105600104. 6. lesage a, lemasson m, medina k, tsopmo j, sebti n, potvin s, et al. the prevalence of electroconvulsive therapy use since 1973: a meta-analysis. j ect 2016; 32:236–42. doi: 10.1097/yct.0000000000000320. 7. wagner kj, möllenberg o, rentrop m, werner c, kochs ef. guide to anaesthetic selection for electroconvulsive therapy. cns drugs 2005; 19:745–58. doi: 10.2165/00023210-2005 19090-00002. 8. andrade c, shah n, tharyan p, reddy ms, thirunavukarasu m, kallivayalil ra, et al. position statement and guidelines on unmodified electroconvulsive therapy. indian j psychiatry 2012; 54:119–33. doi: 10.4103/0019-5545.99530. 9. peterchev av, rosa ma, deng zd, prudic j, lisanby sh. electroconvulsive therapy stimulus parameters: rethinking dosage. j ect 2010; 26:159–74. doi: 10.1097/yct.0b013e 3181e48165. 10. leiknes ka, jarosh-von schweder l, høie b. contemporary use and practice of electroconvulsive therapy worldwide. brain behav 2012; 2:283–344. doi: 10.1002/brb3.37. 11. attri jp, bala n, chatrath v. psychiatric patient and anaesthesia. indian j anaesth 2012; 56:8–13. doi: 10.4103/0019-5049.93337. 12. sundsted kk, burton mc, shah r, lapid mi. preanesthesia medical evaluation for electroconvulsive therapy: a review of the literature. j ect 2014; 30:35–42. doi: 10.1097/yct.0b0 13e3182a3546f. 13. saito s. anesthesia management for electroconvulsive therapy: hemodynamic and respiratory management. j anesth 2005; 19:142–9. doi: 10.1007/s00540-004-0288-7. 14. daabiss m. american society of anaesthesiologists physical status classification. indian j anaesth 2011; 55:111–15. doi: 10. 4103/0019-5049.79879. 15. cristancho ma, alici y, augoustides jg, o’reardon jp. uncommon but serious complications associated with electroconvulsive therapy: recognition and management for the clinician. curr psychiatry rep 2008; 10:474–80. doi: 10.1007/s11920-008-0076-4. 16. chanpattana w, kramer ba, kunigiri g, gangadhar bn, kitphati r, andrade c. a survey of the practice of electroconvulsive therapy in asia. j ect 2010; 26:5–10. doi: 10.1097/yct.0b013e3181a74368. 17. al-adawi s, dorvlo as, al-ismaily ss, al-ghafry da, alnoobi bz, al-salmi a, et al. perception of and attitude towards mental illness in oman. int j soc psychiatry 2002; 48:305–17. doi: 10.1177/002076402128783334. 18. alhamad am, al-haidar f. a retrospective audit of electroconvulsive therapy at king khalid university hospital, saudi arabia. east mediterr health j 1999; 5:255–61. 19. lihua p, su m, ke w, ziemann-gimmel p. different regimens of intravenous sedatives or hypnotics for electroconvulsive therapy (ect) in adult patients with depression. cochrane database syst rev 2014; cd009763. doi: 10.1002/14651858. cd009763.pub2. 20. canbek o, ipekcıoglu d, menges oo, atagun mi, karamustafalıoglu n, cetinkaya oz, et al. comparison of propofol, etomidate, and thiopental in anesthesia for electroconvulsive therapy: a randomized, double-blind clinical trial. j ect 2015; 31:91–7. doi: 10.1097/yct.00000 00000000190. 21. jarineshin h, kashani s, fekrat f, vatankhah m, golmirzaei j, alimolaee e, et al. seizure duration and hemodynamic state during electroconvulsive therapy: sodium thiopental versus propofol. glob j health sci 2015; 8:126–31. doi: 10.5539/gjhs. v8n2p126. 22. wang x, chen y, zhou x, liu f, zhang t, zhang c. effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. j ect 2012; 28:128–32. doi: 10.1097/yct.0b013e31824d1d02. 23. rybakowski jk, bodnar a, krzywotulski m, chlopockawozniak m, michalak m, rosada-kurasinska j, et al. ketamine anesthesia, efficacy of electroconvulsive therapy, and cognitive functions in treatment-resistant depression. j ect 2016; 32:164–8. doi: 10.1097/yct.0000000000000317. 24. ayhan y, akbulut bb, karahan s, gecmez g, öz g, gurel sc, et al. etomidate is associated with longer seizure duration, lower stimulus intensity, and lower number of failed trials in electroconvulsive therapy compared with thiopental. j ect 2015; 31:26–30. doi: 10.1097/yct.0000000000000149. 25. hoyer c, kranaster l, janke c, sartorius a. impact of the anesthetic agents ketamine, etomidate, thiopental, and propofol on seizure parameters and seizure quality in electroconvulsive therapy: a retrospective study. eur arch psychiatry clin neurosci 2014; 264:255–61. doi: 10.1007/s00406-013-0420-5. 26. macpherson r, marroquin-harris m, gálvez v, tor p, loo c. the effect of adjuvant remifentanil with propofol or thiopentone on seizure quality during electroconvulsive therapy. anaesth intensive care 2016; 44:278–80. 27. shah a. the impact of the national institute of clinical excellence guidance on the use of electroconvulsive therapy in england. int psychogeriatr 2010; 22:164–6. doi: 10.1017/ s1041610209990809. 28. zolezzi m. medication management during electroconvulsant therapy. neuropsychiatr dis treat 2016; 12:931–9. doi: 10.2147/ ndt.s100908. 29. mirzakhani h, guchelaar hj, welch ca, cusin c, doran me, macdonald to, et al. minimum effective doses of succinylcholine and rocuronium during electroconvulsive therapy: a prospective, randomized, crossover trial. anesth analg 2016; 123:587–96. doi: 10.1213/ane.0000000000001218. 30. chow tk. titration of electroconvulsive therapy: the use of rocuronium and sugammadex with adjunctive laryngeal mask. br j anaesth 2012; 108:882–3. doi: 10.1093/bja/aes115. 31. anastasian zh, khan n, heyer ej, berman mf, ornstein e, prudic j, et al. effect of atropine dose on heart rate during electroconvulsive therapy. j ect 2014; 30:298–302. doi: 10.10 97/yct.0000000000000123. 32. sessler di. temperature monitoring and perioperative thermoregulation. anesthesiology 2008; 109:318–38. doi: 10.10 97/aln.0b013e31817f6d76. 33. cheng yc, liang cm, liu hc. serotonin syndrome after electroconvulsive therapy in a patient on trazodone, bupropion, and quetiapine: a case report. clin neuropharmacol 2015; 38:112–13. doi: 10.1097/wnf.0000000000000076. 34. boere e, birkenhäger tk, groenland th, van den broek ww. beta-blocking agents during electroconvulsive therapy: a review. br j anaesth 2014; 113:43–51. doi: 10.1093/bja/aeu153. 35. aydogan ms, yücel a, begec z, colak yz, durmus m. the hemodynamic effects of dexmedetomidine and esmolol in electroconvulsive therapy: a retrospective comparison. j ect 2013; 29:308–11. doi: 10.1097/yct.0b013e3182972bec. 36. surve r, bansal s, sriganesh k, subbakrishna dk, thirthalli j, umamaheswara rao gs. incidence and risk factors for oxygen desaturation during recovery from modified electroconvulsive therapy: a prospective observational study. j anaesthesiol clin pharmacol 2015; 31:99–103. doi: 10.4103/0970-9185.150555. 37. wang z, wang j. sudden cardiac death after modified electroconvulsive therapy. shanghai arch psychiatry 2015; 27:315–18. doi: 10.11919/j.issn.1002-0829.214169. 38. kranaster l, hoyer c, janke c, sartorius a. bispectral index monitoring and seizure quality optimization in electroconvulsive therapy. pharmacopsychiatry 2013; 46:147–50. doi: 10.1055/s-0032-1331748. https://doi.org/10.1177/070674371105600104 https://doi.org/10.1097/yct.0000000000000320 https://doi.org/10.2165/00023210-200519090-00002 https://doi.org/10.2165/00023210-200519090-00002 https://doi.org/10.4103/0019-5545.99530 https://doi.org/10.1097/yct.0b013e3181e48165 https://doi.org/10.1097/yct.0b013e3181e48165 https://doi.org/10.1002/brb3.37 https://doi.org/10.4103/0019-5049.93337 https://doi.org/10.1097/yct.0b013e3182a3546f https://doi.org/10.1097/yct.0b013e3182a3546f https://doi.org/10.1007/s00540-004-0288-7 https://doi.org/10.4103/0019-5049.79879 https://doi.org/10.4103/0019-5049.79879 https://doi.org/10.1007/s11920-008-0076-4 https://doi.org/10.1097/yct.0b013e3181a74368 https://doi.org/10.1177/002076402128783334 https://doi.org/10.1002/14651858.cd009763.pub2 https://doi.org/10.1002/14651858.cd009763.pub2 https://doi.org/10.1097/yct.0000000000000190 https://doi.org/10.1097/yct.0000000000000190 https://doi.org/10.5539/gjhs.v8n2p126 https://doi.org/10.5539/gjhs.v8n2p126 https://doi.org/10.1097/yct.0b013e31824d1d02 https://doi.org/10.1097/yct.0000000000000317 https://doi.org/10.1097/yct.0000000000000149 https://doi.org/10.1007/s00406-013-0420-5 https://doi.org/10.1017/s1041610209990809 https://doi.org/10.1017/s1041610209990809 https://doi.org/10.2147/ndt.s100908 https://doi.org/10.2147/ndt.s100908 https://doi.org/10.1213/ane.0000000000001218 https://doi.org/10.1093/bja/aes115 https://doi.org/10.1097/yct.0000000000000123 https://doi.org/10.1097/yct.0000000000000123 https://doi.org/10.1097/aln.0b013e31817f6d76 https://doi.org/10.1097/aln.0b013e31817f6d76 https://doi.org/10.1097/wnf.0000000000000076 https://doi.org/10.1093/bja/aeu153 https://doi.org/10.1097/yct.0b013e3182972bec https://doi.org/10.4103/0970-9185.150555 https://doi.org/10.11919/j.issn.1002-0829.214169 https://doi.org/10.1055/s-0032-1331748 sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp.121-126 , epub. 27th feb 13 submitted 14th may 12 revision req. 13th jun 12, revision recd. 8th oct 12 accepted 18th oct 12 department of internal medicine & cardiology, school of medicine, united arab emirates university, al ain, united arab emirates e-mail: a.shehab@uaeu.ac.ae آراء أساتذة التدريب السريري حول التعليم السريري عبداهلل �صهاب امللخ�ص: الهدف: تبني يف السنوات األخرية وجود اخنفاض يف الوقت املخصص للتعليم السريري. هتدف هذه الدراسة إىل تقييم مدى إدراك أساتذة التدريب السريري وممارستهم وطرق أساليبهم للتعليم السريري. الطريقة: أجريت هذه الدراسة يف مستشفى ناينويلز جبامعة دندي يف اململكة املتحدة. حيث مت استحداث استبيان ذايت وجتريبه على أساتذة التدريب السريري باجلامعة العاملني بدوام كامل، تضمن االستبيان على 36 سؤاال يتعلق باخلربة يف جمال التدريس ومدى إملام أعضاء اهليئة التدريسية ب 12 منهجاً للنتائج التعليمية يف كلية دندي الطبية وخربهتم وممارستهم لقواعد وآداب التعليم السريري. كما أجريت مقارنة لكل بند بني األطباء االستشاريني واالختصاصيني. النتائج: شارك يف الدراسة 54 )%70( أستاذ سريري من أصل 64، من بينهم 26 استشاري )%57(، و19 اختصاصي )%42.3(. أوضحت النتائج أن جمموع 17 استشاري)%65( مت تدريبهم لتعليم طلبة الطب يف املستشفى، بينما خضع 9 اختصاصيني فقط )%47( لتدريب مماثل. 13 استشاري )%50( كانوا على دراية تامة ب12 منهجاً للنتائج التعليمية بكلية دندي الطبية يف حني كان 7 )%36( من االختصاصيني فقط على نفس الدراية باملناهج التعليمية. العوائق اليت مت ذكرها من قبل االستشاريني واالختصاصيني كانت جمموعات ألكثر من 6 طالب) %65 باملقابل، %61 على التوايل(، عدد املرضى احملدود الذين يعانون من األعراض السريرية اجليدة )%67 باملقابل، %63 على التوايل(، قصر مدة اإلقامة باملستشفى )%73 باملقابل، %68 على التوايل(، االفتقار إىل اخلصوصية يف العنابر املزدمحة )%76 باملقابل، %73 على التوايل(، اإلزعاج الناتج عن اهلاتف والزوار )%57 باملقابل، %64 على التوايل(. اخلال�صة: فعالية برامج التأهيل والتدريب اليت يلقاها أساتذة التدريب السريري وقدرهتم على فهم مناهج التدريس بدقة تساهم بشكل كبري يف جناح التعليم السريري. كما أن حتديد العقبات اليت تؤثر سلبا على التعليم السريري سيساهم أيضا يف احلصول على برامج أكثر فعالية وكفاءة. مفتاح الكلمات: �رسيري، تعليم، طبي، املنهج، ا�صت�صاريني، اخت�صا�صيني، اململكة املتحدة. abstract: objectives: in recent years, there has been a decline in estimated time spent on bedside teaching. the aim of this study was to evaluate clinical teachers’ perceptions and practice of, and approaches to, bedside teaching. methods: the study site was ninewells hospital in dundee, uk. a self-administered questionnaire was developed and piloted on full-time clinical academic university staff. responses were solicited to 36 questions relating to teaching experience, familiarity with the 12 learning outcomes of dundee medical school's curriculum, and perception and practice of basic bedside etiquette. for each of these items, a comparison between consultants and specialist registrars (sprs) was carried out. results: out of the 64 clinical teachers approached, 45 (70%) participated in the study: 26 of them (57.7%) were consultants and 19 (42.3%) sprs. a total of 17 (65%) of the consultants had been trained to teach medical students at the bedside, while only 9 sprs (47%) had had similar training. in addition, 13 consultants (50%) reported being familiar with dundee medical school's 12 learning outcomes, while only 7 (36%) sprs were familiar with it. obstacles reported by consultants and sprs were groups of over 6 students (65% versus 61%, respectively), a limited number of patients with good clinical signs (67% versus 63%, respectively), a shorter length of stay in hospital (73% versus 68%, respectively), lack of privacy in crowded wards (76% versus 73%, respectively), and interruptions from telephones and visitors (57% versus 64%, respectively). conclusion: effective clinical teacher training and a thorough understanding of curriculum outcomes are crucial to successful bedside clinical teaching. identifying obstacles to bedside clinical teaching will contribute to a more effective and efficient programme. keywords: bedside; teaching; clinical; curriculum; consultants; registrars; uk. clinical teachers’ opinions about bedside-based clinical teaching abdullah shehab clinical & basic research advances in knowledge this study shows the importance of ward-based bedside teaching practice particularly in teaching hospitals despite the decline in this form of teaching in recent years. the current study shed more light on bedside teaching as a pivotal element in the training of medical students and interns in particular as regards the teaching and reinforcing of history-taking and physical examination skills. the study describes some of the important aspects to be considered during the bedside teaching by evaluating current practice in a teaching hospital setting. it also demonstrates the significant difference in perceptions of bedside teaching practice principles between consultants and specialist registrars. clinical teachers’ opinions about bedside-based clinical teaching 122 | squ medical journal, february 2013, volume 13, issue 1 bedside teaching is the only medical learning situation where history-taking, physical examination, empathy, and a caring attitude can all be learnt simultaneously and by example. it brings together a learning triad of patients, students, and tutors and involves an interaction between all three.1 the method acts as an important tool for the acquisition of knowledge and clinical skills that are difficult to teach through other methods, as well as to evaluate trainee competencies in a diversity of areas (e.g. physical examination, procedural, and communication skills). in bedside teaching, the teacher is able to model the interpersonal skills and humanistic aspects of patient care, which are essential to a strong doctor-patient relationship. in order to teach clinical skills effectively, a teacher must involve patients in the educational process, and there is strong evidence that patients favour the method; additionally, they report a better understanding of their illnesses when they are active participants in bedside teaching sessions.1–3 several authors have identified barriers to the full utilisation of the potential benefits of ward rounds. these barriers include time constraints, faculty attitude, knowledge and skills, lack of respect for patients, and over-reliance on technology.4 according to one study, the most important detractors to the success of rounds include a disrespectful attitude, and rounds that are too long or too short.5 time constraints have also been shown to be a powerful detractor, arising from the pressure to see more and more patients during the course of what are becoming severely shortened hospital stays.6 additionally, increased demands for documentation has decreased the time that was previously spent in bedside teaching.6,7 unfortunately, while time spent learning at the bedside decreases, other studies suggest that it is primarily through ward rounds that learners acquire the skills of observation, communication, examination, and professionalism, and learn to perform diagnostic and treatment procedures.6 william osler emphasised this interaction, stating medicine should be taught at the bedside.7–13 however, in spite of the recognised importance of bedside education, in the usa the estimated time allotted to it as a component of medical training declined from 75% in 1960 to 16% in 1978.12,14,15 one study revealed lack of time as the most frequent obstacle to this method and, as a result, bedside teaching was allotted only ~17% of instructional time in hospitals.1 this decline may be related to increasing reliance on computer technologies and imaging and laboratory testing, along with the increasing administrative and research duties of senior doctors. these variables impinge on the time set aside for bedside teaching. consequently, doctors’ skills in history-taking and physical examination have declined, making both trainees and attending physicians less willing to be tested at the bedside. additionally, medical educators sometimes work under the misunderstanding that their job is to teach the curriculum rather than the student.15,16 the main aim of our study was to investigate the challenges inherent to bedside teaching and propose recommendations to enhance both the effectiveness and efficiency of such teaching. the main objectives were to assess participants’ perceptions relevant to bedside teaching, detail the factors considered relevant during bedside teaching, and observe participants’ approaches to bedside teaching. we compared the perceptions, practices, and approaches of consultants and specialist registrars (sprs) to bedside teaching. by conducting this study, we aimed to assess if bedside teaching is still a preferred method of medical education among clinical teachers. methods an ethically approved study was conducted among clinical teachers at ninewells hospital, which is the main teaching hospital of the university of dundee in dundee, uk, in june 2001. the programme for application to patient care this study highlights the finding that bedside is the premier location for teaching and reinforcing history-taking and physical examination skills. bedside teaching also provides an excellent opportunity to enhance the learner's observational skills. this study emphasises how to communicate better with patients. abdullah shehab clinical and basic research | 123 bedside teaching was provided by the medical faculty, which has an innovative, systematically integrated, problem-based undergraduate medical curriculum. all clinical teachers of dundee medical school (n = 87) were invited to participate in the study. they were then emailed a questionnaire and a reminder was sent to non-respondents four weeks later. a total of 64 clinical tutors and staff agreed to participate in the study. the majority had honorary appointments with the university, and held degrees in medical education. the self-administered questionnaire was developed in consultation with local expertise in medical teaching and was piloted and posted to a sample representing the study population of fulltime clinical academic university staff (n = 20). the questionnaire contained 3 main sections. the first section included questions about the respondent's clinical and teaching experience, and included age, gender, specialty, clinical teaching background, whether clinical staff undertook teaching courses, level of clinical staff seniority, access to an expert in clinical education, and level of familiarity with the learning outcomes of dundee’s undergraduate and postgraduate curricula which are emphasised during bedside teaching.17 this section also included queries about the participant's response to teaching different specialties (for example, a surgeon teaching the cardiovascular system), the medical speciality system covered in bedside teaching, and whether the participant was in favour of continuing bedside teaching. finally, in this section, participants were asked to list the three most essential elements in preparation for bedside teaching. the second section asked the participant to rate factors that were considered important during bedside teaching, such as the learning outcomes of dundee’s undergraduate and postgraduate curricula.17 this included the respondent rating the importance of displaying good bedside manners on a 4-point scale: vitally important; considerably important; of little importance, and not at all important. the third section asked about the participant's practice and approach to bedside teaching as per the learning outcomes of dundee’s undergraduate and postgraduate curricula.17 participants were asked to indicate how often they performed different activities in bedside teaching by grading such statements as “i model good teaching behaviour by showing enthusiasm” using the 4-point scale always, sometimes, rarely, and never. two open-ended questions for further comments about hindrances and any other comments were included. the data were analysed anonymously. for each item, a comparison between consultants and specialist registrars was carried out. microsoft excel, version 7 (microsoft, redmond, washington, usa) and the statistical package for social sciences (spss), version 12 (ibm, inc., chicago, illinois, usa) were used to enter and analyse data. the results were expressed as mean ± standard deviation (sd). quantitative data were compared by means of a two-tailed student’s t-test and qualitative data was analysed by a chi-square test. a p value of ≤0.05 was considered statistically significant. results out of the 64 clinical teachers approached, 45 (70%) participated in the study. there were 26 consultants (57.7%) and 19 sprs (42.3%). the distribution of the participants according to age, gender, and clinical specialties is presented in table 1. table 2 demonstrates that 17 consultants (65%) had been trained on how to teach medical students at the bedside, while only 9 sprs (47%) had had similar training. in addition, 13 consultants (50%) reported table 1: professional profiles of study participants characteristics consultants (n = 26) (%) *sprs (n = 19) (%) age (mean ± sd) in years 42 ± 1.3 30 ± 1.1 male 20 (62.5) 12 (37.5) medicine 9 (34.6) 7 (36.8) anaesthesia 4 (15.4) 3 (15.8) surgery 5 (19.3) 2 (10.5) ent 3 (11.6) 1 (5.3) neurology 2 (7.7) 1 (5.3) ophthalmology 1 (3.8) 2 (10.5) orthopaedics 1 (3.8) 2 (10.5) obstetrics and gynaecology 1 (3.8) 1 (5.3) total number (%) 26 (57.7) 19 (42.3) sd = standard deviation; *sprs = specialist registrars; ent = ear, nose, and throat. clinical teachers’ opinions about bedside-based clinical teaching 124 | squ medical journal, february 2013, volume 13, issue 1 being familiar with dundee medical school's 12 outcomes curriculum, while only 7 sprs (36%) reported this. similarly, more consultants (n = 24) favoured bedside teaching (92%) while only 12 sprs did so (63%). also, 10 sprs (52%) compared with 9 consultants (34%) supported the idea of teaching a different specialty (e.g. surgeons teach the cardiovascular system) [table 2]. overall, 93% of participants agreed that displaying good bedside manners was of vital importance. while 100% of consultants agreed with this item as compared to 84% of sprs, this factor was not statistically significant (15.8%, 95% confidence interval [ci] 1.6– 32.0%, p = 0.07). the majority of consultants considered demonstrating enthusiasm during bedside teaching of vital importance. compared to consultants, more sprs considered the demonstration of technique when teaching procedures was of vital importance [table 3]. there was a significant difference between consultants and sprs in rating a statement regarding the importance of motivating learners to learn aspects of specialty medicine (p = 0.036). compared to consultants, more sprs indicated that time constraints affected their bedside clinical teaching (42.7%, 95% ci 1.5%, 83.0%; p = 0.04) and (39%, 95% ci 6.6%, 73.0%; p = 0.02), respectively. there were no significant differences between the two groups’ responses to other items such as “i’m effective in teaching learners something new about the specialty at the end of the session” (p = 0.09) [table 3]. the participants had close similarities regarding practice, approach to bedside clinical teaching, and response to essential common bedside factors such as briefing and debriefing [tables 3]. the obstacles to bedside clinical teaching reported by consultants and sprs were group sizes of over 6 students (65% versus 61%), a limited number of patients with good clinical signs (67% versus 63%), shorter length of patients’ stay in hospital (73% versus 68%), lack of privacy in crowded wards (76% versus 73%), and interruptions from telephones and visitors (57% versus 64%), respectively. adequate warning to patients about bedside clinical teaching, emphasis on feedback, discussing the history in the presence of the patient, polishing communication skills, and reducing work demands were reported as solutions to improve and facilitate bedside clinical teaching. table 2: comparison between consultants and sprs in teaching related items items consultants *n = 26 (%) †sprs *n = 19 (%) p value in favour of bedside teaching 24 (92) 12 (63) 0.02 training in teaching or access to educational experts 17 (65) 9 (47) 0.04 supporting idea of teaching different specialties 9 (34) 10 (52) 0.04 familiarity with 12 learning outcomes of dundee medical school’s curriculum 13 (50) 7 (36) 0.03 sprs = specialist registrars. table 3: factors considered relevant during bedside teaching bedside factors consultants *n = 26 (%) sprs *n = 19 (%) p value demonstrating enthusiasm during bedside teaching 17 (65.4) 10 (52.6) 0.04 motivation (mean ± sd) 3.1 ± 0.6 2.7 ± 0.6 0.04 demonstrating technique when teaching procedures 13 (50) 13 (68.4) 0.02 time constraints (mean ± sd) 2.9 ± 0.6 3.3 ± 0.4 0.02 displaying good bedside manner 22 (84.6) 16 (84.2) <0.087 admitting “i don’t know” 13 (50) 07 (36.8) < 0.034 teaching new things about an area of specialty 22 (84.6) 12 (63.2) < 0.012 preparing students for the session and debriefing 08 (30.8) 11 (57.9) < 0.015 sd = standard deviation; sprs = specialist registrars. *percentages were derived from n = total number for each of the clinical teacher groups. abdullah shehab clinical and basic research | 125 discussion in this survey of clinical teachers, light was shed on the practicalities of bedside teaching and clinical tutors’ understanding of effective styles. the study highlighted issues that have been reported previously, such as the importance of the bedside as the premier location for clinical teaching. it was also seen as the most logical location for medical instructors to reinforce history-taking and physical examination skills, and enhance observational skills.7 the participants identified several elements for effective bedside clinical teaching. they emphasised their need to learn how to be gentle with students and house staff, better communicate with patients, and maintain appropriate ethics and professionalism with the patient. this finding confirmed similar results of other studies.16,18-22 a high percentage of consultants demonstrated enthusiasm during bedside clinical teaching. this was attributed to the fact that the majority of consultants, as compared to sprs, had had training in teaching or had been trained on how to teach medical students. they were also more familiar with dundee medical school’s learning outcomes and were in favor of bedside clinical teaching. the majority of sprs considered demonstrating techniques when teaching procedures of vital importance. this may be related to the proactive involvement of sprs in the physical and procedural aspects of bedside clinical teaching. the obstacles to bedside clinical teaching reported here can be categorised as teacher-related (e.g. teacher had not been appropriately trained in bedside teaching, or the teacher’s discipline was mainly technology-oriented), climate-related (e.g. busy, noisy, or poorly equipped), system-related (e.g. a specialty with no bedside component), patientrelated (e.g. patient very sick or not interested in participating), or other miscellaneous factors (e.g. teaching time occurs during visiting hours or during the business ward round). clinical education that integrates substantial bedside teaching is an effective approach to satisfying the public need to train intelligent, skilled, and compassionate clinicians. collaborating with learners, developing faculty skills, including the patient, and promoting a supportive institutional culture can rectify a variety of barriers to bedside clinical teaching.5,23–24 there is a need to include new innovations and approaches in bedside teaching such as level-specific teaching and miniclinical evaluation exercise (cex) examinations as an evaluation tool.25 despite the fact that few studies exist regarding the effectiveness of bedside clinical teaching, our results support the findings reported in many studies that surveyed clinical educators and advocate bedside clinical teaching’s value in training physicians.5,26 conclusion bedside teaching will continue to play an important role in the training of medical students as it is perceived as best practice and is favoured by the majority of surveyed clinical teachers and medical tutors. however, effective clinical teacher training and a thorough understanding of curriculum outcomes are crucial to successful bedside clinical teaching. identifying obstacles to bedside clinical teaching will contribute to a more effective and efficient programme. references 1. nair br, coughlan jl, hensley mj. student and patient perspectives on bedside teaching. med educ 1997; 31:341–6. 2. linfors ew, neelon fa. the case for bedside rounds. n engl j med 1980; 303:1230–3 3. lehamann ls, brancati fl, chen m, roter d, dobs as. the effect of bedside case presentations on patients' perceptions of their medical care. n engl j med 1997; 336:1150–5. 4. castiglioni a, shewchuk rm, willett ll, heudebert gr, centor rm. a pilot study using nominal group technique to assess residents' perceptions of successful attending rounds. j gen intern med 2008; 23:1060–5. 5. williams kn, ramani s, fraser b, orlander jd. improving bedside teaching: findings from a focus group study of learners. acad med 2008; 83:257–64. 6. kroenke k, omori dm, landry fj, lucey cr. bedside teaching. south med j 1997; 90:1069–74. 7. nair br, coughlan jl, hensley mj. impediments to bedside teaching. med educ 1998; 32:159–62. 8. osler w. books and men. in: aequanimitas with other addresses. philadelphia: p. blakiston’s son & company, 1932. pp. 209–13. 9. fitzgerald ft. bedside teaching. west j med 1993; clinical teachers’ opinions about bedside-based clinical teaching 126 | squ medical journal, february 2013, volume 13, issue 1 158:418–20. 10. langlois jp, thach s. teaching at the bedside. fam med 2000; 32:528–30. 11. kelliher gj, sachdeva ak, fleetwood j. preserving the best of the art of teaching. acad med 1996; 71:248–50. 12. lacombe ma. on bedside teaching. ann intern med 1997; 126:217–20. 13. crumlish, cm, yialamas ma, mcmahon gt. quantification of bedside teaching by an academic hospitalist group. j hosp med 2009; 4:304–7. 14. lazar a. shame and humiliation in the medical encounter. arch intern med 1987; 147:1653–8. 15. medio fj, wilkerson l, maxwell ja, cohen rm. improving teaching rounds: action research in medical education. proc res med educ 1984; 23:283–8. 16. simons rj, bailey rg, zwillich cw. the physiological and psychological effects of the bedside presentation. n eng j med 1989; 321:1273–5. 17. school of medicine, ninewells hospital and medical school, dundee, uk. from: http://www.dundee. ac.uk/medicalschool/. accessed: apr 2012. 18. kroenke k, simmons jo, copley jb. attending rounds: a survey of physicians’ attitudes. j gen intern med 1990; 5:229–33. 19. farnsworth we. training physicians to be doctorsteachers and healers, problem-solvers and decisionmakers. j am osteopath assoc 1991; 91:1005–18. 20. kroenke k. attending rounds: guidelines for teaching on the wards. j gen intern med 1992; 7:68– 75. 21. general medical council, uk. tomorrow’s doctors. london: general medical council, 1993. 22. luciano gl, carter bl, garb jl, rothberg mb. residents-as-teachers: implementing a toolkit in morning report to redefine resident roles. teach learn med 2011; 23:316–23. 23. ramani s, orlander jd, strunin l, barber tw. whither bedside teaching? a focus group study of clinical teachers. acad med 2003; 78:384–90. 24. alexandraki i, mooradian ad. academic advancement of clinician educators: why is it so difficult? int j clin pract 2011; 65:1118–25. 25. norcini jj. workplace-based assessment in clinical training. in: swanwick t, ed. understanding medical education series. edinburgh: association for the study of medical education, 2007. pp. 195–6. 26. el-bagir m,ahmed k. what is happening to bedside clinical teaching? med educ 2002; 36:1185–8. 1department of dental health, faculty of applied medical sciences, al baha university, al baha, saudi arabia; 2department of oral & maxillofacial surgery, sudan medical specialization board, khartoum, sudan; 3epidemiology department, federal ministry of health, khartoum, sudan *corresponding author e-mail: dr.hamdi.hakimi@gmail.com معرفة العامة من الناس عن سرطان الفم و صياغة العوامل الدميوغرافية املؤثرة على هذه املعرفة يف والية اخلرطوم، السودان حمدي عبدالوهاب احلكيمي، عبدالقاهر اإ�صماعيل عثمان، اأميمة جاداهلل حممد، عبدالعال �صعيد، وليد اأمني اأحمد abstract: objectives: knowledge of oral cancer affects early detection and diagnosis of this disease. this study aimed to assess the current level of public knowledge of oral cancer in khartoum state, sudan, and examine how demographic background factors affect this knowledge. methods: this cross-sectional study involved 501 participants recruited by systematic random sampling from the outpatient records of three major hospitals in khartoum state between november 2012 and february 2013. a pretested structured questionnaire was designed to measure knowledge levels. a logistic regression model was utilised with demographic background variables as independent variables and knowledge of oral cancer as the dependent variable. a path analysis was conducted to build a structural model. results: of the 501 participants, 42.5% had no knowledge of oral cancer, while 5.4%, 39.9% and 12.2% had low, moderate and high knowledge levels, respectively. logistic regression modelling showed that age, place of residence and education levels were significantly associated with knowledge levels (p = 0.009, 0.017 and <0.001, respectively). according to the structural model, age and place of residence had a prominent direct effect on knowledge, while age and residence also had a prominent indirect effect mediated through education levels. conclusion: education levels had the most prominent positive effect on knowledge of oral cancer among outpatients at major hospitals in khartoum state. moreover, education levels were found to mediate the effect of other background variables. keywords: oral cancer; knowledge; logistic regression; statistical model; patient-specific modeling; sudan. امللخ�ص: اأهداف: املعرفة عن �رضطان الفم توؤثر على االإكت�صاف و الت�صخي�ض املبكر لهذا املر�ض، تهدف هذه الدرا�صة اإىل تقييم م�صتوى املعرفة. منهجية: هذه على الدميوغرافية العوامل تاأثري مدى و بال�صودان اخلرطوم والية يف الفم �رضطان عن النا�ض من العامة معرفة للثالث اخلارجية العيادة �صجالت من الع�صوائية النظامية العينة بوا�صطة اإختيارهم مت م�صرتكًا 501 امل�صحية الدرا�صة هذه ا�صتهدفت جتربته( )�صبق حمكم اإ�صتبيان ت�صميم مت 2013م، فرباير اإىل 2012م نوفمرب من الفرتة خالل اخلرطوم والية يف الكربى امل�صت�صفيات لقيا�ض م�صتوى معرفة العامة، ومت اإ�صتخدام االإنحدار اللوج�صتي بحيث كانت العوامل الدميوغرافية هي متغريات م�صتقلة و م�صتوى املعرفة عن �رضطان الفم هو املتغري التابع، مت اإ�صتخدام حتليل امل�صار لبناء منوذج هيكلي. نتائج: من بني 501 م�صرتكًا اأظهر %42.5 جهال ً تامًا عن �رضطان الفم بينما كان هناك %5.4، %39.9 و %12.2 لديهم م�صتوى منخف�ض و متو�صط وعايل على التوايل من املعرفة عن �رضطان الفم، اأو�صحت نتائج االإنحدار اللوج�صتي اأن العمر و مكان االإقامة و م�صتوى التعليم لديهم تاأثري ذو داللٍة معنويٍة على م�صتوى املعرفة عن �رضطان الفم )0.001< و p = 0.009, 0.017(. بينما اأظهر النموذج الهيكلي اأن العمر و مكان االإقامة لهما تاأثرٌي مبا�رٌض على م�صتوى املعرفة و كذلك تاأثري غري مبا�رض من خالل تاأثريهم على م�صتوى التعليم و الذي بدوره يوؤثر على م�صتوى املعرفة، خامتة: كان مل�صتوى التعليم االأثر االأكرب على م�صتوى املعرفة عن �رضطان الفم �صمن مرتادي العيادات اخلارجية يف امل�صت�صفيات الرئي�صية بوالية اخلرطوم، كما اأثر م�صتوى التعليم بطريقة غري مبا�رضة على املعرفة من خالل تاأثريه على العوامل الدميوغرافية االأخرى. كلمات مفتاحية: �رضطان الفم؛ معارف؛ االإنحدار اللوج�صتي؛ النموذج االإح�صائي؛ النمذجة اخلا�صة باملري�ض؛ ال�صودان. public knowledge of oral cancer and modelling of demographic background factors affecting this knowledge in khartoum state, sudan *hamdi a. al-hakimi,1 abdulqaher e. othman,2 omima g. mohamed,3 abdulaal m. saied,2 waled a. ahmed1 clinical & basic research sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e335–340, epub. 19 aug 16 submitted 27 jan 16 revision req. 20 mar 16; revision recd. 17 apr 16 accepted 16 may 16 doi: 10.18295/squmj.2016.16.03.012 advances in knowledge few studies have used advanced statistical techniques to examine the effects of different variables on public knowledge of oral cancer. to the best of the authors’ knowledge, this is the first study to use path analysis to build an explanatory model to examine the effect of demographic background factors on public knowledge of oral cancer. in the current study, education level was found to prominently affect knowledge of oral cancer in a structural model. this model could potentially be used as a basis for models of other diseases. application to patient care the results of this study may help public health practitioners in sudan to identify which population groups should be targeted for oral cancer prevention and control programmes. public knowledge of oral cancer and modelling of demographic background factors affecting this knowledge in khartoum state, sudan e336 | squ medical journal, august 2016, volume 16, issue 3 there is wide geographical variation in the incidence of oral cancer (oc).1 it is a common cancer in developing countries, particularly brazil and countries in southeast asia.2 there is a good chance of survival with early diagnosis and among those who receive necessary treatment.3 despite this, public awareness of oc is low, which contributes to delays in diagnosis.4–6 in sudan, oc was one of the 10 most common cancers from 1967–1984; however, in recent years it has begun to occur less frequently.7 unfortunately, the majority of patients only seek healthcare during advanced stages of oc, leading to a relatively low five-year survival rate.7 enhanced public knowledge of oc can improve the early detection and self-identification of precancerous lesions.6,8 certain countries, such as india, have conducted mass media campaigns as a prevention strategy, aiming to increase public knowledge of oc.9 in a prospective study conducted in india, gupta et al. observed decreased tobacco use and a lower incidence of leukoplakia among participants of educational programmes regarding risk factors for oc.10 however, assessment of the baseline level of public knowledge of oc is essential for evaluating the effectiveness of such campaigns. in addition, understanding how factors such as age, gender, place of residence and education levels affect knowledge of oc may help improve public health programmes. this study aimed to assess the current level of public knowledge of oc in khartoum state, sudan, and examine how demographic background factors affect this knowledge. methods this cross-sectional study involved participants recruited from the outpatient clinics of three major hospitals in khartoum state between november 2012 and february 2013. an appropriate sample size was calculated according to the following equation: where p represents the percentage of those who are aware of oc, set at 50% since no data were available from sudan and to yield the largest possible sample size. as a result, the minimum sample size was calculated to be 384 participants. this was increased to 500 because modelling usually requires a large sample size, with 50 subjects necessary for each variable. accordingly, a total of 501 participants were included. participants were selected by systematic random sampling from the outpatient records of the khartoum teaching hospital (n = 300), omdurman general hospital (n = 100) and bahri general hospital (n = 101). khartoum teaching hospital is the largest hospital in sudan and usually receives triple the number of patients of the other two hospitals; therefore, the number of study subjects selected from this hospital was three times higher than that of the other hospitals. an arabic-language 23-item pre-tested structured questionnaire was designed to assess the participants’ knowledge of oc. during face-to-face interviews, questions were explained to the study participants and answers recorded. the first five items of the questionnaire focused on demographic background variables, while item 6 determined whether patients had heard of oc. subsequently, items 7–14 determined awareness of risk factors, items 15–18 awareness of the symptoms of oc and items 19–23 knowledge of treatments for and outcomes of oc. for all items except items 1–6 and 22, a score of 1 was given for correct answers, 0.5 when participants indicated that they did not know the answer and zero for incorrect responses, allowing for a maximum score of 16.11 for item 22, scores ranged from 1–3, as this question was multiple choice with three possible correct answers. therefore, a total of 17 questions evaluated knowledge of oc among those who indicated that they had heard of oc. scores were added to obtain a total knowledge score for each participant ranging from 0–19. scores of <9.5 (below the median) were considered to indicate a low level of knowledge, scores of 9.5–14.5 to indicate a moderate level of knowledge (representing the third quartile of data) and scores >14.5 to indicate a high level of knowledge (representing the upper quartile). the internal consistency of the questionnaire was assessed using cronbach’s alpha test. subsequently, certain items of the questionnaire were modified in order to obtain a cronbach’s alpha score of ≥71%. data were analysed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa) to provide descriptive statistics and conduct the logistic regression modelling. for the latter analysis, participants were divided into two groups—those with no or low knowledge versus those with moderate or high knowledge. demographic background variables (e.g. gender, age, education level and place of residence) were introduced into the logistic regression model as independent variables, with knowledge level as the dependent variable. logistic regression assesses the association between an independent variable and the dependent variable while adjusting for the confounding effect of other independent variables. however, this can be a disadvantage if some independent variables have a mediating effect on other variables.12 using regression analysis to adjust for the effect of a mediating variable can yield incorrect estimations n = z2pq d2 hamdi a. al-hakimi, abdulqaher e. othman, omima g. mohamed, abdulaal m. saied and waled a. ahmed clinical and basic research | e337 for a studied association.12 path analysis is the logical extension of multiple regression models as it can correctly estimate the shape and strength of relations between independent variables, mediators and dependent variables.13 therefore, path analysis using lisrel software, version 8.51 (scientific software international inc., skokie, illinois, usa) was subsequently performed to analyse and estimate the relationships between background variables and knowledge of oc. specification of the structural model was undertaken by assuming that the independent variables could have a direct effect on knowledge as a dependent variable or an indirect effect mediated by another variable. the identification step was conducted by satisfying the necessary condition where the number of free estimated parameters should be equal to or less than the number of distinct values. the number of free parameters was obtained from the following equation: where ρ is the number of variables. as the number of variables was five, the number of free parameters was 15. in the structural model, the number of estimated free parameters was 12. thus, the necessary condition showed that the model was over-identified, which is acceptable.14 the estimates were standardised to allow for comparisons among variables of different scales. ethical approval for this study was granted by the sudan medical specialization board in khartoum. written consent from literate subjects and witnessed verbal consent from illiterate subjects was obtained after the objectives of the study were explained and confidentiality assured. results the demographic characteristic of the participants are shown in table 1. a total of 288 participants (57.5%; confidence interval [ci]: 53–61%) had previously heard of oc. overall, 42.5% had no knowledge of oc, 5.4% had a low level of knowledge, 39.9% had a moderate level of knowledge and 12.2% had a high level of knowledge [table 2]. there were apparent background similarities between those who had no or low knowledge and those who had moderate or high knowledge. table 3 presents the knowledge levels of table 1: demographic background variables of outpatients at three major hospitals in khartoum state, sudan (n = 501) variable n (%) gender male 257 (51) female 244 (49) place of residence urban 327 (65) rural 174 (35) age in years 18–30 247 (49.3) 31–40 106 (21.2) 41–50 80 (16.0) 51–60 41 (8.2) >60 27 (5.4) education level illiterate 115 (23.0) primary 141(28.1) secondary 112 (22.4) university 133 (26.5) employment status student 104 (21.0) housewife 143 (29.0) unskilled worker 154 (31.0) private or public sector employee 67 (13.0) farmer 21 (4.0) unemployed 12 (2.0) table 2: levels of oral cancer knowledge among outpatients at three major hospitals in khartoum state, sudan (n = 501) level of knowledge n (%) none 213 (42.5) low 27 (5.4) moderate 200 (39.9) high 61 (12.2) ρ x ρ + 1 2 table 3: levels of knowledge of risk factors, symptoms, treatment options and outcomes of oral cancer among outpatients* at three major hospitals in khartoum state, sudan (n = 288) level of knowledge n (%) risk factors symptoms treatment options and outcomes low 79 (27.4) 88 (30.6) 103 (35.8) moderate 170 (59.0) 85 (29.5) 155 (53.8) high 39 (13.5) 115 (39.9) 30 (10.4) *including only those individuals who had previously heard of oral cancer. public knowledge of oral cancer and modelling of demographic background factors affecting this knowledge in khartoum state, sudan e338 | squ medical journal, august 2016, volume 16, issue 3 that education levels would mediate the effect of other background variables on knowledge levels. according to the structural model, age and place of residence had a prominent direct effect on knowledge, while age and residence also had a prominent indirect effect mediated through education level. education level had the largest positive effect on oc knowledge (r = 0.36) followed by age, which had a slightly weaker positive effect (r = 0.12). on the other hand, age had a moderately negative effect on education level (r = -0.41) while urban residence had a weak positive effect on oc knowledge (r = 0.09). in addition, urban residence had a weak positive effect on education level (r = 0.10). measures testing the fitness of the model are presented in table 5. the structural model was an almost perfect fit according to a chi-squared goodnessof-fit test (χ2 = 0.52; p = 0.915), where a non-significant value means that the model fits the data. the model did not need any modification, thereby indicating good specification of variables and relationships. discussion this study aimed to assess current levels of public knowledge of oc in khartoum state and examine how demographic background factors affected knowledge levels. in terms of background variables, the study sample was quite similar to that of the general population living in khartoum state.15 furthermore, there were apparent background similarities between those who had no or low knowledge and those who had moderate or high knowledge; this supports the grouping of these participants together during the logistic regression analysis. in the current study, knowledge of oc was significantly affected by age, residence and, in particular, education levels. this latter association has been observed in many studies.9,11,16,17 the present oc risk factors, symptoms, treatment options and outcomes among those who had previously heard of oc. table 4 shows the results of logistic regression modelling. age, urban residence and education level were significantly associated with knowledge levels (p = 0.009, 0.017 and <0.001, respectively). as gender did not significantly contribute to the logistic regression model, it was excluded. a best-fit model was selected to show the effect of background variables on knowledge levels. the effect of education levels on knowledge of oc was significant. when the education level increased from illiterate to primary school, knowledge levels increased fourfold; when education level increased from illiterate to secondary school, knowledge levels increased nine-fold; and when education levels increased from illiterate to university level, knowledge levels increased fourteen-fold. additionally, levels of knowledge increased slightly with age. finally, living in an urban area resulted in a one-and-a-half-fold increase in knowledge levels in comparison to living in a rural area. the path analysis structural model is shown in figure 1. in the path analysis, it was assumed logically figure 1: path analysis structural model of the effect of background variables on knowledge of oral cancer among outpatients at three major hospitals in khartoum state, sudan (n = 501). df = degrees of freedom; rms = root-mean-square. table 4: logistic regression modelling of demographic background variables with knowledge of oral cancer among outpatients at three major hospitals in khartoum state, sudan (n = 501) variable or (ci) p value age 1.02 (1.01–1.04) 0.009 urban residence* 1.64 (1.10–2.46) 0.017 primary education† 4.30 (2.40–7.71) <0.001 secondary education† 9.26 (4.84–17.71) <0.001 university education† 14.24 (7.30–27.76) <0.001 or = odds ratio; ci = confidence interval. *reference group include those living in a rural residence. †reference group include those who were illiterate. table 5: fitness measures of a path analysis structural model for demographic background variables and knowledge of oral cancer among outpatients at three major hospitals in khartoum state, sudan (n = 501) measure acceptable level current model chi-squared test non-significant p value p = 0.915 gf index 0 (no fit) to 1 (perfect fit) 1 adjusted gf index 0 (no fit) to 1 (perfect fit) 0.998 rms residual researcher-defined 0.0026 rms error of approximation <0.080 0.000 nf index 0 (no fit) to 1 (perfect fit) 0.997 gf = goodness-of-fit; agfi = adjusted gf index; rms = root-meansquare; nf = normed fit. hamdi a. al-hakimi, abdulqaher e. othman, omima g. mohamed, abdulaal m. saied and waled a. ahmed clinical and basic research | e339 study included participants with wide variability in educational backgrounds and found that education level prominently affected oc knowledge; in contrast, research focusing on homogenous populations might fail to detect this association. for example, comunian et al. found that the association between education and oc knowledge levels was not statistically significant; however, the study investigated a population with a high base level of education—professors, students and administrative staff at a university.18 knowledge of oc was also affected by place of residence in the current study, with urban participants found to be more knowledgeable than their rural counterparts. agrawal et al. have reported similar findings.17 however, amarasinghe et al. found that residents of rural villages in sri lanka had higher levels of oc knowledge than residents of urban tea estates.19 socioeconomic status can affect access to information, so this finding could be due to the lower socioeconomic status of the estate residents in comparison to the villagers. moreover, the majority of villagers reported receiving information regarding oc from the mass media, whereas estate residents reported receiving information from family members.19 information received from the media generally could be considered more accurate than information gathered from family members in less socioeconomically developed communities. additionally, knowledge of oc was affected by age in the current study, which is a similar finding to those reported by previous studies.9,16,17,20,21 generally, studies from different countries have shown a nonlinear association between age and knowledge of oc, where knowledge of oc increases with age until patients are 60–65 years old, at which point knowledge of oc begins to decline.16,20,21 some studies from india have shown higher knowledge of oc in younger age groups.9,17 increased awareness among individuals of younger age groups in india can be attributed to wide media exposure of oc and various anti-tobacco campaigns conducted in recent years.9,17 on the other hand, other research has indicated that knowledge of oc is unaffected by age.4,19 this variation in findings may be due to methodological flaws, which can decrease the statistical power of a study to detect a significant effect. rogers et al. found that age had no effect on knowledge of oc in general, but significantly affected certain important oc risk factors, like smoking.4 in the study conducted by amarasinghe et al., although a robust methodology was used, the researchers included only participants aged over 30 years old, which may have reduced detection of the effect of age on knowledge of oc.19 finally, the current study found that knowledge of oc was unaffected by gender, which is similar to findings from the international literature.9,16–19,21–23 nevertheless, a few studies have found a significant association between gender and knowledge of oc.20,24 however, oh et al. reported that the effect of gender on knowledge levels was minor, as they found that males were only slightly more knowledgeable than females (odds ratio = 1.2).20 rogers et al. and al-rawi et al. conducted surveys with convenience samples and found that females had statistically significant greater knowledge than males using a chi-squared test.4,24 however, the use of statistical tests is questionable in surveys with convenience or non-random samples, as differences could be the result of sampling bias. the path analysis structural model from the current study demonstrated excellent specification and goodness-of-fit, as shown by fitness measures. the model showed that age and place of residence had a prominent direct effect on knowledge of oc and a prominent indirect effect mediated through education level. the purpose of path analysis in the present study was to avoid the incorrect estimation of associations during regression analysis; in this structural model, estimates were produced using the full information method where all other associations were taken into consideration during calculation. education level was found to have the largest positive effect on oc knowledge, followed by age. however, age had a moderately negative effect on education level. the latter finding is to be expected as, in sudan, individuals of younger age groups are more educated than their elders.15 this direct and indirect effect of age on oc knowledge may explain why certain studies from india have found a negative effect of age on oc knowledge;9,17 while the direct positive effect of age on oc knowledge might be low, the indirect negative effect mediated by education level might be much higher. urban residence was also found to increase oc knowledge in the current study; however, it had a weak positive effect. in addition, education levels were weakly positively affected by urban residence; this makes sense as urban residents are more educated than their rural counterparts in sudan.15 gender was found to affect knowledge of oc indirectly; this may be because of its effect on education level, as males have greater access to education than females in many developing countries.25 based on the findings from this study, public health programmes in khartoum state which aim to improve knowledge of oc should focus on non-educated persons and those from rural areas. educational strategies should be designed to benefit these individuals, since current strategies seem to target educated people and those living in urban areas. education plays a fundamental role in any long-term strategy aiming to improve public knowledge and awareness of oc. the structural model designed in public knowledge of oral cancer and modelling of demographic background factors affecting this knowledge in khartoum state, sudan e340 | squ medical journal, august 2016, volume 16, issue 3 the current study may potentially be used in other developing countries which have populations with a similar demographic structure and background variables. however, this study is limited by its cross sectional design, as generally a longitudinal design is more appropriate for model development. additionally, this study did not utilise a standardised questionnaire with predetermined reliability and validity to determine oc knowledge; however, cronbach’s alpha test was used to ensure internal consistency. conclusion approximately half of the sudanese outpatients in the current study had never heard of oc. furthermore, among those who had heard of oc, the majority only had a moderate level of knowledge of the disease. education level was found to have the most prominent positive effect on knowledge of oc. moreover, education level was found to mediate the effect of other background variables. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors wish to thank the authorities of the khartoum teaching hospital, omdurman general hospital and bahri general hospital for their cooperation during the data collection process. references 1. warnakulasuriya s. global epidemiology of oral and oropharyngeal cancer. oral oncol 2009; 45:309–16. doi: 10.1016/j.oraloncology.2008.06.002. 2. scully c, porter s. abc of oral health: oral cancer. bmj 2000; 321:97–100. doi: 10.1136/bmj.321.7253.97. 3. sankaranarayanan r, ramadas k, thomas g, muwonge r, thara s, mathew b, et al. effect of screening on oral cancer mortality in kerala, india: a cluster-randomised controlled trial. lancet 2005; 365:1927–33. doi: 10.1016/s0140-6736 (05)66658-5. 4. rogers s, pabla r, mcsorley a, lowe d, brown js, vaughan ed. an assessment of deprivation as a factor in the delays in presentation, diagnosis and treatment in patients with oral and oropharyngeal squamous cell carcinoma. oral oncol 2007; 43:648–55. doi: 10.1016/j.oraloncology.2006.08.001. 5. zakrzewska jm. fortnightly review: oral cancer. bmj 1999; 318:1051–4. doi: 10.1136/bmj.318.7190.1051. 6. seoane-romero jm, vázquez-mahía i, seoane j, varelacentelles p, tomás i, lópez-cedrún jl. factors related to late stage diagnosis of oral squamous cell carcinoma. med oral patol oral cir bucal 2012; 17:e35–40. doi: 10.4317/medoral.17399. 7. hamad hm. cancer initiatives in sudan. ann oncol 2006; 17:viii32–viii36. doi: 10.1093/annonc/mdl985. 8. van der waal i. are we able to reduce the mortality and morbidity of oral cancer: some considerations. med oral patol oral cir bucal 2013; 18:e33–7. doi: 10.4317/medoral.18486. 9. devadiga a, prasad kv. knowledge about oral cancer in adults attending a dental hospital in india. asian pac j cancer prev 2010; 11:1609–13. 10. gupta pc, mehta fs, pindborg jj, bhonsle rb, murti pr, daftary dk, et al. primary prevention trial of oral cancer in india: a 10-year follow-up study. j oral pathol med 1992; 21:433–9. doi: 10.1111/j.1600-0714.1992.tb00970.x. 11. shirzaiy m, dalirsani z, pakfetrat a. oral cancer awareness of people attending the oral medicine center of zahedan dental school. aust j basic appl sci 2011; 5:984–9. 12. amorim ld, fiaccone rl, santos ca, santos tn, moraes lt, oliveira nf, et al. structural equation modeling in epidemiology. cad saude publica 2010; 26:2251–62. doi: 10.1590/ s0102-311x2010001200004. 13. baker sr, gibson bg. social oral epidemi(olog)(2) y where next: one small step or one giant leap? community dent oral epidemiol 2014; 42:481–94. doi: 10.1111/cdoe.12118. 14. schumacker re, lomax rg. a beginner’s guide to structural equation modelling, 3rd ed. mahwah, new jersey, usa: routledge, 2010. p. 214. 15. sudan central bureau of statistics. sudan national baseline household survey 2009: north sudan tabulation report. from: http://ecastats.uneca.org/aicmd/portals/1/publications/ others/poverty%202009.pdf accessed: apr 2016. 16. tomar sl, logan hl. florida adults’ oral cancer knowledge and examination experiences. j public health dent 2005; 65:221–30. doi: 10.1111/j.1752-7325.2005.tb03022.x. 17. agrawal m, pandey s, jain s, maitin s. oral cancer awareness of the general public in gorakhpur city, india. asian pac j cancer prev 2012; 13:5195–9. doi: 10.7314/apjcp.2012.13.10.5195. 18. comunian cr, abdo en, mendonça ll, naves md. basic knowledge on oral cancer among a specific brazilian population. odontol clín cient 2011; 10:351–6. 19. amarasinghe hk, usgodaarachchi us, johnson nw, lalloo r, warnakulasuriya s. public awareness of oral cancer, of oral potentially malignant disorders and of their risk factors in some rural populations in sri lanka. community dent oral epidemiol 2010; 38:540–8. doi: 10.1111/j.1600-0528.2010.00566.x. 20. oh j, kumar j, cruz g. racial and ethnic disparity in oral cancer awareness and examination: 2003 new york state brfss. j public health dent 2008; 68:30–8. doi: 10.1111/j.17527325.2007.00075.x. 21. patton ll, agans r, elter jr, southerland jh, strauss rp, kalsbeek wd. oral cancer knowledge and examination experiences among north carolina adults. j public health dent 2004; 64:173-80. doi: 10.1111/j.1752-7325.2004.tb02748.x. 22. ariyawardana a, vithanaarachchi n. awareness of oral cancer and precancer among patients attending a hospital in sri lanka. asian pac j cancer prev 2005; 6:58–61. 23. monteiro ls, salazar f, pacheco j, warnakulasuriya s. oral cancer awareness and knowledge in the city of valongo, portugal. int j dent 2012; 2012:376838. doi: 10.1155/2012/376838. 24. al-rawi nh, al-kawas s, imad o. public awareness and attitude toward oral cancer screening in the united arab emirates. j int dent med res 2012; 5:149–54. 25. king em, hill ma. women’s education in developing countries: barriers, benefits, and policies. washington d.c., usa: world bank publications, 1997. pp. 7–10. http://dx.doi.org/10.1016/j.oraloncology.2008.06.002 http://dx.doi.org/10.1016/j.oraloncology.2008.06.002 http://dx.doi.org/10.1136/bmj.321.7253.97 http://dx.doi.org/10.1016/s0140-6736%2805%2966658-5 http://dx.doi.org/10.1016/s0140-6736%2805%2966658-5 http://dx.doi.org/10.1016/j.oraloncology.2006.08.001 http://dx.doi.org/10.1136/bmj.318.7190.1051 http://dx.doi.org/10.4317/medoral.17399 http://dx.doi.org/10.1093/annonc/mdl985 http://dx.doi.org/10.4317/medoral.18486 http://dx.doi.org/10.1111/j.1600-0714.1992.tb00970.x http://dx.doi.org/10.1590/s0102-311x2010001200004 http://dx.doi.org/10.1590/s0102-311x2010001200004 http://dx.doi.org/10.1111/cdoe.12118 http://dx.doi.org/10.1111/j.1752-7325.2005.tb03022.x http://dx.doi.org/10.7314/apjcp.2012.13.10.5195 http://dx.doi.org/10.1111/j.1600-0528.2010.00566.x http://dx.doi.org/10.1111/j.1752-7325.2007.00075.x http://dx.doi.org/10.1111/j.1752-7325.2007.00075.x http://dx.doi.org/10.1111/j.1752-7325.2004.tb02748.x http://dx.doi.org/10.1155/2012/376838 case report | 453 sultan qaboos university med j, august 2013, vol. 13, iss. 3, pp. 460-462, epub. 25th jun 13 submitted 4th sep 12 revision req. 20th nov 12, revision recd. 22nd dec 12 accepted 21st jan 13 departments of 1surgery, 3radiology & molecular imaging, 4medicine, and 5pathology, sultan qaboos university hospital; 2department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, oman note: all authors are members of the breast unit, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: varna@squ.edu.om ورم الكلية قد يكون مؤشرا النتشار سرطان الثدي احلويصلي عادل اجلراح، فارنا ترانيكانتي، �شوكبال �شوين، حممد فروخ، حممد احلو�شني، انا �شوبرامادو، �شاندو دي �شلفا امللخ�ص: من املعروف اأن �رشطان الثدي قد ينت�رش يف اأع�شاء خمتلفة من اجل�شم. ويف حالت نادرة جدا قد يكون اكت�شافه نتيجة لأمل �شديد نا�شئ عن ورم ثانوي يف اإحدى الكليتني. و قد ر�شدنا حالة ملري�شة تبلغ من العمر 58 عاما ح�رشت اإىل العيادة ت�شتكي من اأمل يف اجلانب الأي�رش من املنطقة ال�شفلى من الظهر؛ ومع الفحو�شات مت اكت�شاف اأنها تعاين من ورم �رشطاين حوي�شلي م�شدره الثدي. هذا الك�شف ظهر يف الأ�شعة املقطعية عندما كانت املري�شة تخ�شع لفح�ص ورم يف اإحدى كليتيها حيث افرت�شنا باأنها تعاين من �رشطان الكلية. و لكن بعد ذلك مت اكت�شاف ورم يف الثدي والذي مت ت�شخي�شة الدقيق بوا�شطة الفح�ص املناعي الكيميائي . يف هذه الورقة �شوف نناق�ص اأهمية عمل فحو�شات املناعة الكيميائية يف حتديد الت�شخي�ص و مراحل منو الأورام. مفتاح الكلمات: الثدي، احلوي�شلي، انت�شار ال�رسطان، الكلية، الفح�س املناعي الكيميائي. abstract: breast cancer is known to metastasise to different organs in the body, but an initial presentation of breast cancer with loin pain secondary to a metastatic renal mass is extremely rare. we report a 58-year-old woman who presented with recurrent left loin pain due to a metastatic deposit of invasive lobular carcinoma of the breast. the detection of a renal mass on computed tomography led to the assumption of a renal pelvic malignancy. the diagnostic dilemma posed by the detection of a breast mass during staging and the usefulness of immunohistochemistry in the confirmation of diagnosis are discussed. keywords: breast; lobular carcinoma; metastasis; renal; immunohistochemistry; case report; oman. metastatic invasive lobular carcinoma of the breast masquerading as a primary renal malignancy adil al-jarrah,1 *varna taranikanti,2 sukhpal sawhney,3 muhammad furrukh,4 mohammad al-hosni,1 p. a. m. saparamadu,5 m. v. c. de silva5 case report breast cancer is the commonest cancer among women in oman, with an incidence of 15.6:100,000.1 due to a lack of awareness, strong cultural barriers and late access to specialised clinics, most patients in oman present with a breast lump at an advanced stage of the disease.2 the most common presentation of breast cancer is a painless lump in the breast, and only 5% of breast tumours present with dissemination to different organs, such as the bones, lungs, brain or liver. however, such metastases have been reported either during the follow-up of treated breast cancer patients or at autopsy.3 initial presentation of breast cancer with symptoms pertaining to an isolated metastatic deposit in the kidney is very uncommon.4 we report the occurrence of an isolated metastatic renal deposit of an invasive lobular carcinoma (ilc) of the breast in a 58-year-old woman who presented with recurrent left loin pain. case report a 58-year-old woman presented with recurrent left loin pain of 4 months’ duration. there were no other genitourinary or bowel symptoms. a contrast-enhanced coronal computed tomography (ct) scan of the abdomen showed an enhanced soft tissue mass along the inferior pole calyces of the left kidney, extending to the renal pelvis, ureter and left lateral wall of the urinary bladder, suggesting early infiltration. there was also perirenal and periureteric stranding with perinephric lymphadenopathy [figure 1]. metastatic invasive lobular carcinoma of the breast masquerading as a primary renal malignancy 454 | squ medical journal, august 2013, volume 13, issue 3 a provisional diagnosis of transitional cell carcinoma was considered. a ct scan of the chest done for staging purposes showed a left breast lesion with significantly enlarged left axillary lymph nodes. examination of the breasts at this stage revealed a 1.5 x 1.5 cm mobile lump in the outer upper quadrant of the left breast, and palpable, mobile, discrete, left axillary lymph nodes. a breast ultrasound and mammography were suggestive of malignancy. a bone scan did not show any deposits. the results of the ct-guided biopsies obtained from the renal and breast masses showed tumours with identical histological appearances. they were comprised of poorly cohesive sheets of round to polygonal cells with mildly pleomorphic nuclei. some cells contained intracytoplasmic vacuoles. signet ring-like cells and scattered mitotic figures were present [figure 2]. the tumour cells stained positive for epithelial membrane antigen (ema) and oestrogen receptor (er). the staining was focally positive for cytokeratin (ck) 7 antibodies. progesterone receptor (pr), human epidermal growth factor receptor 2 (her2/neu), epithelial cadherin (e-cadherin) and cd10 and ck20 tests were negative. ki-67 staining showed proliferative activity in 40–50% of cells. the pathological diagnosis was ilc of the breast with a renal metastatic deposit. discussion ilc of the breast represents approximately 10–15% of mammary malignancies compared to infiltrating duct carcinomas (idc), which accounts for 80% of breast malignancies.5 ilcs are usually bilateral and are difficult to detect clinically since they fail to form a discrete circumscribed palpable mass. mammographic detection of ilc can also be very challenging since the typical features of microcalcification and cytoarchitectural distortion of the breast tissue may not be seen. the atypical clinical and radiological appearance may be attributed to the histopathological features of ilc, which is characterised by small, round tumour cells which are non-cohesive in nature and infiltrate the tissues insidiously without destroying the anatomic architecture.6 in this case, the non-cohesive nature was confirmed by immunohistochemistry, which was negative for e-cadherin and thus suggestive of ilc. furthermore, the metastatic patterns of both idc and ilc are different. distant metastases in the retroperitoneum, gastrointestinal tracts, leptomeninges, orbit and genitourinary tract have been reported more frequently in ilc.7 most cases of breast cancer metastasising to the urinary tract are detected as a part of disseminated disease either during follow-up or at autopsy. a review of autopsies in 181 cases of metastatic breast cancer showed ureteral involvement in 8.3% of cases.8 most patients who present with ureterorenal colic, hydronephrosis, acute renal failure, or urinary incontinence due to ureteric and bladder metastases also present with symptoms pertaining to common sites of involvement such as the bone, lungs, liver and brain.9 presentation with urinary symptoms secondary to isolated urinary tract involvement is very rare.10 guiliano et al. reported figure 1: contrast-enhanced coronal computed tomography scan of the abdomen. white arrows indicate an enhancing soft tissue mass extending along the left kidney, ureter and bladder. figure 2: microscopic appearance of the tumor showing poorly-cohesive sheets of cells with intra cytoplasmic vacuoles, signet ring like cells and scattered mitotic figures. adil al-jarrah, varna taranikanti, sukhpal sawhney, muhammad furrukh, mohammad al-hosni, p. a. m. saparamadu and m. v. c. de silva case report | 455 one such patient who presented with renal colic due to ureteral obstruction and, after investigation, this was diagnosed as a solitary renal metastasis from the breast.11 hudolin et al. described a 59-year-old woman presenting with right flank pain and fever secondary to stenosis of the ureter caused by a tumour which stained positively for ck, er and pr.12 no primary cancer or additional metastases could be detected at that time. however, 11 months later the patient developed right breast cancer with metastasis to the left supraclavicular region. as our patient presented with loin pain, the detection of a left renal mass upon ct led to the assumption of a renal pelvic malignancy. the detection of the breast mass after admission to hospital led to the diagnostic dilemma of whether the patient had separate primary cancers in the breast and the kidney or metastatic cancer from either site. the possibility of a primary renal tumour was excluded when the tumour tissue stained positive for ck7 and negative for ck20 by immunohistochemistry. the diagnosis of metastatic ilc of the breast was possible only after immunohistochemistry, which showed an absence of e-cadherin expression. this case is one of the very rare reported cases of breast cancer metastasis to the kidneys and ureters. however, in the presence of a renal mass, a secondary or metastatic tumour should be suspected and a more comprehensive physical examination and additional ancillary studies are warranted to rule out malignancy as the underlying aetiology. conclusion this case highlights the importance of considering the possibility of metastatic deposits when an isolated renal mass shows histological features which are not typical of known variants of renal cell carcinoma. it also emphasises the need for comprehensive physical examination, the importance of mammography screening for women older than 40 years in order to achieve early diagnoses, and the institution of proper therapy. references 1. kumar s, burney ia, al ajmi a, al-moundhri ms. changing trends of breast cancer survival in sultanate of oman. j oncol 2011; 2011:316243. 2. al-moundhri a, al-bahrani b, pervez i, ganguly ss, nirmala v, al-madhani a, et al. the outcome of treatment of breast cancer in a developing country— oman. breast 2004; 13:139–145. 3. patanaphan v, salazar om, risco r. breast cancer: metastatic patterns and their prognosis. south med j 1988; 81:1109–12. 4. shah kg, modi pr, rizvi j. breast carcinoma metastasizing to the urinary bladder and retroperitoneum presenting as acute renal failure. indian j urol 2011; 27:135–6. 5. borst mj, ingold ja. metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. surgery 1993; 114:637–41. 6. ferlicot s, vincent-salomon a, medioni j, genin p, rosty c, sigal-zafrani b, freneaux p. wide metastatic spreading in infiltrating lobular carcinoma of the breast. eur j cancer 2004; 40:336–41. 7. yousef gm, gabril my, al-haddad s, mulligan am, honey rj. invasive lobular carcinoma of the breast presenting as retroperitoneal fibrosis: a case report. j med case rep 2010; 4:175. 8. geller sa, lin c. ureteral obstruction from metastatic breast carcinoma. arch pathol 1975; 99:476–8. 9. elia g, stewart s, makhuli zn, krenzer be, mathur s, simon hm, et al. metastatic breast cancer diagnosed during a work-up for urinary incontinence: a case report. int urogynecol j pelvic floor dysfunct 1999; 10:39–42. 10. joo js, im cm, lee js, oh kj, kang tw, kwon dd. solitary metastatic renal tumor from breast cancer. korean j urol 2006; 47:670–3. 11. giuliano ae, sparks fc, morton dl. breast cancer presenting as renal colic. am j surg 1978; 135:842–5. 12. hudolin t, nola i, nola n, milas m, juretic a. ureteral metastasis of occult breast cancer. breast 2004; 13:530–2. كيس ليمفاوي سرطاين يف القصبة اهلوائية واحلنجرة الورم الذي أوشك علي خطف أنفاسها tracheolaryngeal adenoid cystic carcinoma the tumour that almost took her breath away dear sir, a 40-year-old female patient presented to the southern command hospital, pune, india, in august 2015 with a six-month history of breathlessness. she was experiencing three to four episodes of dyspnoea per week with each episode lasting a few minutes. the breathlessness was aggravated on exertion and relieved with rest. she had no known comorbidities and had previously been treated symptomatically for asthma with no significant improvement. an indirect laryngoscopy revealed a proliferative growth inferior to the postcricoid area which was partially filling the trachea without affecting the glottic closure [figure 1a]. contrast-enhanced computed tomography of the neck revealed a well-defined soft tissue lesion (2.5 x 2.2 x 2.2 cm) in the infraglottic cavity and upper trachea with no significant enhancement [figure 1b]. an emergency tracheostomy was performed and a biopsy revealed tumour cells arranged in cribriform structures, tubules and clusters amidst a fibrous stroma [figure 1c]; the cells had minimal eosinophilic cytoplasm, indistinct cell borders, oval hyperchromatic nuclei and inconspicuous nucleoli. on subsequent elective excision, all of the surgical margins were positive with the tumour abutting the tracheal cartilage [figure 1d] and involving the inferior and posterior margins of the left lobe of the thyroid. the tumour showed similar histomorphology with foci of perineural invasion. a diagnosis of an adenoid cystic carcinoma (adcc) was made at stage t4n0m0, indicating no regional lymph node or distant metastasis. as all of the surgical margins and the thyroid gland were seen to be involved during a frozen section procedure, the surgeons opted for palliative surgery with minimal local resection of the cricoid cartilage and first tracheal ring in addition to a total thyroidectomy. the defect was closed by end-to-end anastomosis with no attempt made at reconstruction. the patient subsequently received palliative radiotherapy (70 gy) for four weeks. due to the possibility of mucosal erosion and tracheal restenosis, the tracheostomy was continued for 12 weeks and the incision was closed at the end of the 14th week. the patient was stable with no clinical evidence of recurrence at a four-month follow-up. adccs are malignant neoplasms of the laryngeal salivary glands characterised by a protracted and aggressive clinical course.1 these carcinomas form less than 1% of all tracheolaryngeal malignancies and are known to reach large sizes; they usually occur among patients in their fifth and sixth decades of life and no gender predilection has been observed.2 as with the current case, adcc can present with symptoms of obstruction, such as breathlessness.3 the differential diagnosis for adcc includes polymorphous low-grade adenocarcinomas, basal cell adenomas, mixed tumours and basaloid squamous cell carcinomas.4 a cribriform pattern of tumour cells is typical of adcc; however, this pattern is rarely seen in basal cell adenomas, basaloid squamous cell carci nomas and mixed tumours. while distinc tion between polymorphous low-grade adenocarcinomas and adccs can be challenging, the ki-67 index is 10 times higher for the latter.4 in addition, smooth letter to the editor sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 261–262, epub. 15 may 16 submitted 13 jan 16 revision req. 3 feb 16; revision recd. 8 feb 16 accepted 25 feb 16 doi: 10.18295/squmj.2016.16.02.024 figure 1a‒d: a: fibre-optic bronchoscopy image of a 40-year-old female with a tracheolaryngeal adenoid cystic carcinoma showing a proliferative growth (arrow) inferior to the postcricoid area, partially filling the trachea without hampering the glottic closure. b: contrastenhanced computed tomography of the neck revealing a well-defined soft tissue lesion (arrow) in the infraglottic area and upper trachea with no significant enhancement. c: haematoxylin and eosin stain at x400 magnification showing tumour cells arranged in cribriform structures, tubules and clusters amidst a fibrous stroma. d: haematoxylin and eosin stain at x400 magnification showing the tumour abutting the tracheal cartilage. tracheolaryngeal adenoid cystic carcinoma the tumour that almost took her breath away e262 | squ medical journal, may 2016, volume 16, issue 2 muscle markers of myoepithelial differentiation are positive in cases of adcc but negative for polymorphous low-grade adenocarcinomas. pseudocysts are usually positive with periodic acid-schiff and alcian blue stains and contain basement membrane components.4 the epithelial cells are usually positive for carcinoembryonic and epithelial membrane antigens while duct-lining cells are positive for cluster of differentiation 117 and tumour protein 63. alterations in chromosomes 6q, 9p and 17p12‒13 are the most frequent cytogenetic alterations reported.4 although the histologic appearance of adcc is well-described with certain features that may predict prognosis, surgical removal is often difficult given the infiltrative nature of these neoplasms with their propensity to invade into the adjacent tissues and extend along nerve segments.5 this is further compounded by the deceptively circumscribed macroscopic appearance of the tumours.3 these factors are challenging for surgeons attempting to remove the tumour with negative margins. due to inadequate surgical excision, recurrence rates are high, ranging from 75‒90%.6 radical surgery has not been shown to improve survival rates or decrease local recurrence when compared with a conservative surgical approach and postoperative radiation.3 optimal treatment therefore remains wide local excision with or without postoperative radiation. rajat bajaj,1 *manoj m. gopal,1 sunil mathews2 departments of 1pathology and 2otorhinolaryngology, armed forces medical college, pune, india *corresponding author e-mail: manoj.gopal@gmail.com references 1. cason ra, binnie wh, speight pm, barrett aw, wright jm. lucas’s pathology of tumors of the oral tissues. 5th ed. london, uk: churchill livingstone, 1998. pp. 330–5. 2. jaso j, malhotra r. adenoid cystic carcinoma. arch pathol lab med 2011; 135:511–15. doi: 10.1043/2009-0527-rs.1. 3. wang h, xu l, li f. subglottic adenoid cystic carcinoma mistaken for asthma. j zhejiang univ sci b 2009; 10:707–10. doi: 10.1631/jzus. b0920071. 4. chundru nsv, amudala r, thankappan p, nagaraju cd. adenoid cystic carcinoma of palate: a case report and review of literature. dent res j india: 2013 feb;10(2):274–8. 5. matsuba hm, spector gj, thawley se, simpson jr, mauney m, pikul fj. adenoid cystic salivary gland carcinoma: a histomorphologic review of treatment failure patterns. cancer 1986; 57:519–24. doi: 10.1002/1097-0142(19860201)57:3<519::aid-cncr2820570319>3.0.co;2-v 5. kokemueller h, eckardt a, brachvogel p, hausamen je. adenoid cystic carcinoma of the head and neck: a 20 years experience. int j oral maxillofac surg 2004; 33:25–31. doi: 10.1054/ijom.2003.0448. 6. wenig bm. atlas of head and neck pathology. 3rd ed. new york, usa: elsevier, 2015. p. 176. http://dx.doi.org/10.1043/2009-0527-rs.1 http://dx.doi.org/10.1631/jzus.b0920071 http://dx.doi.org/10.1631/jzus.b0920071 http://dx.doi.org/10.1002/1097-0142%2819860201%2957:3%3c519::aid-cncr2820570319%3e3.0.co%3b2-v http://dx.doi.org/10.1054/ijom.2003.0448 squ med j, february 2012, vol. 12, iss. 1, pp. 97-102, epub. 7th feb 12. submitted 29th jun 11 revision req. 7th sep 11, revision recd. 1st nov 11 accepted 16th nov 11 departments of 1child health and 2behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; departments of 3child health and 4behavioural medicine, sultan qaboos university hopsital, muscat, oman; corresponding author e-mail: munasa@squ.edu.om إساءة معاملة األطفال أنواعه ونتائجه: تقرير ست حاالت من مستشفى جامعي يف ُعمان منى ال�سعدون، مروان ال�رصبتي، ابت�سام النور، ب�سمة اآل �سعيد امللخ�ص: اإ�ساءة معاملة الأطفال وا�سعة النت�سار يف العامل، وتكون على عدة اأنواع، وقد تهدد حياة الأطفال )خا�سة �سغار ال�سن( ونوعية حياتهم اإىل حد كبري، مما يوؤدي اإىل نتائج كارثية بعيدة املدى على م�ستوى الطفل والعائلة واملجتمع. ندرج هنا تقريرا ل�ست حالت لأطفال تعّر�سوا لإ�ساءة معاملة مّت ت�سخي�سها من قبل فريق حماية الطفل بق�سم طب الأطفال وق�سم الطب ال�سلوكي يف م�ست�سفى جامعة ال�سلطان قابو�س. الهدف من هذا التقرير هو زيادة الوعي اجتاه اإ�ساءة معاملة الأطفال عند العاملني يف القطاع الطبي، واإلقاء ال�سوء على �سعوبات الت�سخي�س وتوفري العالج املنا�سب لالأطفال امُل�ساء معاملتهم. ولو اأّن نظام الرعاية الطبية يف ُعمان ُيقّدم العالج، لكن من الوا�سح اأّن هناك فجوات يف النظام احلايل توؤّثر على جودة اخلدمات التي ُتَقّدم حلماية الأطفال وتوفري الرعاية لهم ولعائالتهم. مفتاح الكلمات: اإ�ساءة معاملة، اأطفال، مراهقون/يافعون، حوادث مق�سودة، اإهمال، تقرير حالة، ُعمان. abstract: child maltreatment (cm) is common worldwide, and can take many forms. it may even endanger the child’s life, especially when younger children are the victims. cm affects the child’s quality of life and consequently leads to long term issues to be dealt with by the child, family and community. this case series discusses six children who have been subjected to cm, and diagnosed by the child protection team of the departments of child health and behavioural medicine at sultan qaboos university hospital (squh), oman. the aim of this case series is to increase the level of awareness of cm among oman’s medical professionals and to highlight the difficulties encountered in diagnosing and providing optimal care for these children. although treatment is provided in oman’s health care system, it is clear that there are gaps in the existing system which affect the quality of child protection services provided to the children and their families. keywords: maltreatment; abuse; child; adolescent; non accidental injuries, negligence; case report; oman. child maltreatment types and effects: series of six cases from a university hospital in oman *muna al-saadoon1 marwan al-sharbati,2 ibtisam el nour,3 basma al-said2 case report child abuse or maltreatment constitutes all forms of physical and/or emotional ill-treatment, sexual abuse, neglect or negligent treatment or commercial or other exploitation, resulting in actual or potential harm to the child’s health, survival, development or dignity in the context of a relationship of responsibility, trust or power.1 article 19 of the convention on the right of the child (crc) clearly states the need of all countries to put into place legislative and administrative measures to protect children from violence and abuse.2 data concerning child maltreatment (cm) is scarce in arab countries, but in recent years medical professionals of the arabian peninsula have recognised that cm exists, as is evident due to the increase in publications about cm in medical journals.3–8 a study from bahrain reported 150 cases of maltreated children, in which the mean age was 7±4 years. the majority of the children were males (53%). in that study, physical abuse constituted 33% of the instances of maltreatment, while sexual abuse was found in 58%, and combined physical and sexual abuse in 7%.3 a school-based study from yemen noted that 80% of mothers in rural areas were using physical discipline compared to 59% of mothers living in urban areas. boys were significantly more likely to be spanked than girls.4 the outcome of cm may be very serious, leading to death in extreme instances. to whatever extent child maltreatment types and effects: series of six cases from a university hospital in oman 98 | squ medical journal, february 2012, volume 12, issue 1 cm is committed, it negatively and significantly affects quality of life. in the usa in 2007, among 3.2 million referrals for cm, 794,000 cases were determined to be victims of cm (out of 5.8 millions cases of alleged maltreatment).9,10 younger children are more often subjected to maltreatment and are more susceptible to its disastrous effects. for example, the infant rate of victimisation during 2007 was 21.9 per 1,000 children, with a slight predominance of females (52% females versus 48% males). an estimated 1,760 children died during the same year because of cm, with an overall rate of 2.35 deaths per 100,000. of these children, 75% were under four years old.10 the long term consequences of cm, if the child survives the abuse, depend on many factors, including the intelligence and the resilience of the child/adolescent; the severity, duration, frequency, and type of maltreatment; the presence of family and social support, and, finally, the relationship between the victim and the abuser. according to different theories of personality development, the importance of positive experiences during childhood and adolescence is clearly highlighted for the proper “crystallisation” of a balanced, normal personality. conversely, the negative experiences will be responsible for defects in personality. for example, according to maslow’s humanistic theory of the hierarchy of needs, individuals cannot become fully actualised, neither living nor working to their full potential, without all their basic needs having been met.11 cm disrupts the satisfaction of all of an individual’s needs, whether they are physiological needs, or the need for safety, love and belonging, and self-esteem. another example of a possible effect of cm is illustrated through the psychoanalytic approach of personality development described by erick erickson. during a person’s lifetime, he or she must pass through eight stages of psychosocial development in order to develop healthily. erickson stresses the importance of trustful relationships between the child and his carer during early stages of development (trust versus mistrust stage). if a child fails to experience trust and is constantly frustrated because his or her needs are not being met, the child may end up with a deep-seated feeling of worthlessness and a mistrust of the world in general. this results in difficult relationships in the future. 12 it is not surprising that victims of cm will exhibit a long series of abnormal behaviours and emotions, and distorted thoughts. these may include poor self-image, an inability to trust or love others, aggressive and antisocial behavior, anger spells and rage, social withdrawal, selfmutilation, suicidal thoughts, and passivity. also, the maltreated child may exhibit fear of engaging in new relationships or activities, anxiety, poor school performance, depression, flashbacks, sleep problems, and possibly drug and alcohol abuse. treatment for cm is multidisciplinary, and should be conducted in a team setting which involves parents, teachers, psychologists, social workers, psychiatrists, paediatricians, family doctors, police, and lawyers. treatment should be offered to the child, family and the abuser. different therapeutic approaches should be implemented, including cognitive behavioural therapy, psychotherapy, art therapy, social support and medications when required.13,14 thus, early recognition of the abuse and prompt intervention will reduce the possibility of long-term negative effects. children in the arab peninsula are subjected to all forms of cm, but it is either ignored or tolerated, and physical discipline is accepted in child rearing practice in the cultural context; hence, maltreated children continue to suffer and most abusers go free.7 failure to identify these cases is another major issue that delays diagnosis. therefore, strong collaboration among different parties (medical professionals, religious persons, teachers, mass media, lawyers, and politicians, etc.) is essential to protect children’s health, safety and rights, and let them live a life which enables healthy development. our literature review identified three articles which describe cases of cm originating in oman. the first describes 5 children who were treated for epilepsy, but diagnosed after treatment as victims of münchausen syndrome by proxy.5 a second paper reported factitious hypoglycaemia and a third raised the question concerning vehicle entrapment as child neglect.6,8 in this paper, we report six cases of cm from squh, with the aim of highlighting the existence of the problem. in order to increase the level of awareness of this potentially devastating problem, methods of diagnosis are discussed as are the challenges faced by the child protection team in case management. muna al-saadoon, marwan al-sharbati, ibtisam el nour, basma al-said case report | 99 to-mouth resuscitation and chest compressions at home. on arrival at the emergency room she was conscious but drowsy, with a weak cry petechial rash on the face and neck, and bruises around the neck. the child was admitted and treated as an inpatient and fortunately survived. at the time of discharge, no neurological deficit was detected, but the girl will need long term follow-up for neurological sequelae. case 4 a 12-year-old girl was referred to squh for an evaluation of chronic abdominal pain, bloody stool, perianal abscess and progressive weight loss over the previous year. she had been seen previously by many paediatricians, but her mother repeatedly refused to consent to any invasive diagnostic investigations. upper and lower gastrointestinal tract endoscopies were done at squh and the diagnosis of inflammatory bowel disease was established. the child was started on both immunosuppressive and supportive therapies for crohn’s disease. later on, poor compliance with treatment was suspected based on uncontrolled symptoms and a non-reduction in inflammatory indices. a subsequent colonoscopy showed persistent lesions and the mother admitted to not giving the child her medications. the child subsequently developed a urinary tract infection and the mother refused admission for intravenous antibiotics. the child was then discharged against medical advice. case 5 a 3 year-old boy was brought to the clinic by his mother, who had observed remarkable changes in his behaviour. the boy had become aggressive and had begun expressing sexualised behaviors. the parents were separated and in the process of divorce. the boy’s mother suspected recurrent sexual abuse of the child by three teenaged male relatives during the weekly visits to the father’s family home. accordingly, the child was seen once in the local health centre and reported to have bruises around the anus. the child was referred to a paediatric psychologist for analysis and therapy. the huge efforts of the mother and the child protection team resulted in a stop to the abuse. the child and mother are currently receiving psychotherapy. it is important to mention here that all of the cases were diagnosed based on the clinical and social information gathered by the child protection team in the departments of child health and behavioural medicine at squh. the electronic medical records of all suspected cases of cm between the years 2007–2010 were reviewed. six cases which represent different types and severity of cm were selected for this case series. case 1 a newborn boy, the result of an unwanted pregnancy, was transferred from the post-natal ward to the neonatology unit at the age of two days for treatment of neonatal sepsis. the mother had abandoned the baby after admission. she was brought back after a few days by the police. the case was referred to the ministry of social development for social evaluation and support. the child was discharged with his mother after a few days following completion of the treatment, even though the squh child protection team advised against discharge. at the age of 1 month, the baby was brought by his father and stepmother to the emergency room in a state of cardio-respiratory arrest, with bleeding from the nose and mouth. resuscitation was performed, but efforts were not successful and it was not possible to revive him. case 2 a 12 year-old girl was admitted to the paediatric intensive care unit with fulminant hepatic and multi-organ failure. all investigations as to possible causes of the above were negative, but the girl had high mercury levels. parents admitted to applying mercury as a traditional treatment for hair lice. the girl, who had been completely normal prior to the lice treatment, unfortunately died of acute mercury poisoning. case 3 a 22 month-old girl was admitted to the hospital following apparent strangulation. she had been playing unattended in a swing in her house when the child’s mother had found her hanging from the neck by the swing’s rope. the child was unresponsive, floppy, and not breathing, and required mouthchild maltreatment types and effects: series of six cases from a university hospital in oman 100 | squ medical journal, february 2012, volume 12, issue 1 case 6 a 7 month-old boy with recurrent episodes of limb fractures was referred from a peripheral hospital. the boy’s medical history had been unremarkable apart from of a cystic hygroma in the right side of the neck which was surgically removed at the age of two months. a few days after being discharged after the cystic hygroma removal surgery, the mother noticed reduced movements of the boy’s right upper arm. evaluation at the local hospital revealed a fracture of the lower end of the right humerus. at the age of four months, a second fracture of the lower end of the left femur was diagnosed after the mother observed reduced movements of the left leg. investigations for bone diseases were negative at that stage. a third new fracture of the left humerus was diagnosed at the age of six months. the patient was then referred to squh for the possibility of physical maltreatment. the parents denied any history of trauma preceding any of the above mentioned fractures. it is important to note that the mother suffers from hypothyroidism and she is on medication. the parents informed us that they sent an expatriate housemaid back to her country ten days after the first event without revealing the reasons for termination of her contract. the mother claimed that she sees a female jinn (spirit of evil) that watches her and her son. her husband confirmed that the jinn is hurting their baby. the parents were extensively counselled concerning the apparent non-accidental injury. the child has been under close follow-up for the last three years and no fractures or major injuries have been noted. discussion cm, also known as child abuse and neglect, is common worldwide. the exact incidence and rates of prevalence of cm are not well known as only a minority of the children who are countable as abused or neglected would be reported to, and investigated in, centres and institutions dealing with child protection.15 there are many definitions of cm; however, the keeping children and families safe act of 2003 defines child/adolescent abuse and neglect as: “any recent act or failure to act on the part of a parent or caretaker which results in death, serious physical or emotional harm, sexual abuse or exploitation”.16 cm is divided into four classifications: neglect, physical, sexual, and psychological (emotional) maltreatment. child neglect is the most common type observed, which includes various categories: physical, medical, emotional, and educational neglect, or, inadequate supervision which leads to accidental poisoning and injury.17,18 a child may be subjected to one or more forms of cm at the same time. it is widely accepted that it is difficult to define neglect, as it is difficult to know whether neglect should include actual harm or potential harm. additionally, one must recognise and address contributory factors when defining cases.19 in this paper, we have reported cases of children subjected to different types of cm. the first baby in case 1 was unwanted, as evidenced by the mother trying to abandon the child. in the end, the mother was forced to take the child as according to the rules of the orphanage only children of unknown parentage could be accommodated. this illustrates the need for cultural flexibility in dealing with children in potentially abusive situations. case 2 reflects the harmful effect of a traditional medication which had been prescribed by a local healer and given with good intentions by the parents. this case has exposed the need for community health education regarding harmful consequences of heavy metals which are elemental to some traditional treatments. case 3 illustrates the need for quality supervision of toddlers. according to the history obtained from the mother, the child had been unattended while playing on the swing. the child protection committee raised questions regarding the height of the swing and the possibility that a 2 year-old child could have independently become entangled in the rope. was the incident a result of an intentional act by an adult or was it an unintentional act by other children? lack of a proper investigative system left the questions unanswered. case 4 is one of the most common ethical problems faced by paediatricians in oman: refusal of investigations and medical treatments by a caregiver. as of the publication of this article, there is no law by which a physician can stop parents from removing a child from hospital against medical advice, regardless of the child’s medical status. refusal of the mother to consent to investigations and therapy delayed the diagnosis of crohn’s disease in this child, and interfered with the control of the muna al-saadoon, marwan al-sharbati, ibtisam el nour, basma al-said case report | 101 part of the problem, especially when it is widely known that, in oman, there is no legislation to foster such children in special homes. as there is no foster care support system for children subjected to violence, all surviving children must be sent home to the same environment from which they have come and followed closely by their paediatricians. conclusion cm exists in oman as elsewhere. these 6 cases represent different forms of cm faced by the paediatricians of squh in oman. this article exposes the need for community education regarding children’s rights, the need for judicious support to protect these children, the deficiency of supportive multi-disciplinary teams, the lack of experienced investigators, proper social support and the unavailability of a place of safety for those unfortunate victims of cm. we are shedding light on child abuse and neglect in oman while waiting for the different governmental authorities to develop an efficient and effective system for child protection. d i s c l o s u r e this case series was presented during the 20102011 academic year under the title i deserve more care. it was presented as part of scraps (surgery, clinical disciplines, radiology, anatomy, psychiatry & laboratory sciences), the weekly clinico-pathological presentations in the college of medicine & health sciences at sultan qaboos university hospital. it was awarded third prize in the annual scraps prize giving. references 1. world health organization. report on the consultation on child abuse prevention. geneva, 29–31 march, 1999. geneva: who, 1999. 2. office of the united nations high commissioner for human rights. convention on the rights of the child. from: http://www2.ohchr.org/english/law/ crc.htm. accessed: oct 2011. 3. al-mahroos f, abdulla f, kamalb s, al-ansari a. child abuse: bahrain’s experience. child abuse & neglect 2005; 187–93. 4. alyahri a. mental health, education and corporal punishment in yemeni school-aged children. london: king’s college, institute of psychiatry, 2004. child’s symptoms. case 5 is an example of the consequences of family disharmony and parental separation when there is inadequate supervision during a child’s visit to the non-custodial parent. the child indirectly disclosed the abuse, which had taken place during visits to the father’s family home, during consultations with the paediatric psychologist. in case 6, the baby presented with 3 bone fractures between the ages of 2 and 6 months; none were preceded by trauma. considering the developmental motor capabilities of the baby, the diagnosis of non-accidental physical maltreatment was discussed with the parents. sending the housemaid home after the first incident may reflect acceptance of the parents that the baby was subjected to an intentional trauma. parents blamed the last two events on an evil spirit. no further events were noted on follow up. all six of the cases were assessed by one or more members of the child protection team, which is composed of 2 paediatricians, a paediatric ophthalmologist, a child psychiatrist, a psychologist, and a nurse. it is evident from the reported cases that the investigation of all cases, with regard to social circumstances, and the financial and psychological status of the care providers and the children were incomplete or absent. the management lacks the protective and supportive aspect of care necessary for such cases. researchers have shown that cm may lead to the development of many negative behaviours and emotions that affect the quality of life of such unfortunate children.20 negligence, the incidence of which approaches 60% of identified cases, is the most common type of maltreatment and is associated with, and predisposes children and adolescents to, other types of maltreatment, including physical and sexual abuse. on the other hand, psychological maltreatment is implicitly associated with other types of maltreatment.18 management of such cases is critical and urgent and should be performed quickly and effectively to protect the lives of the victims. the policy adopted at squh is to educate the parents, and to involve them in order to protect the children from further abuse. parents are also encouraged to design solutions to the problem of abuse of their children. squh’s policy is to avoid blaming the parents. the idea is to make them part of the solution and not child maltreatment types and effects: series of six cases from a university hospital in oman 102 | squ medical journal, february 2012, volume 12, issue 1 14. malchiodi ca. breaking the silence: art therapy with children from violent home. 2nd ed. florence, usa: brunner mazel, 1997. 15. sedlak aj. a history of the national incidence study of child abuse and neglect, 2001. from: http:// www.nis4.org/nis_history.pdf . accessed: jan 2011. 16. keeping children and families safe act of 2003. public law 108–36—june 25, 2003. from: http:// w w w.ac f.hhs .gov/pro g rams/cb/laws_p olic ie s/ policy/im/2003/im0304a.pdf. accessed: jan 2010. 17. al-sharbati m, elburghthy s, sudani o. accidental poisoning in children. saudi med j 1998; 19:423–8. 18. depanfilis d. child neglect: a guide for prevention, assessment and intervention. children’s bureau, office on child abuse and neglect. us department of health & human services: administration for children and families, 2006. from: http://www. c h i l d w el f a re . g o v / p u b s / u s e r m a nu a l s / n e g l e c t / chaptertwo.cfm#fnb1. accessed: feb 2011. 19. dubowitz h, pitts sc, litrownik aj, cox ce, runyan d, black mm. defining child neglect based on child protective services data. child abuse negl 2005; 29:493–511. 20. tonmy l, williams g, hovdestad we, draca j. anxiety and/or depression in 10-15 year-olds investigated by child welfare in canada. j adolesc health 2011; 48:493–8. 5. koul rl, chacko a, al-lamki z, al-amri am, alkhusaiby s. munchausen syndrome by proxy. saudi med j 2000; 21:482–6. 6. bappal b, george m, nair r, khusaiby sa, de silva v. factitious hypoglycemia: a tale from the arab world. pediatrics 2001; 107:180–1. 7. al-mahroos f. child abuse and neglect in the arab peninsula. saudi med j 2007; 28:241–8. 8. roshan k, al futaisi a, al-sadoon m, el nour i, chacko a, hira m, et al . vehicular entrapment and heat stroke in three children: is it a form of child neglect? oman med j. 2010; 25:222–4. 9. al-sharbati m. child maltreatment. arab psy net e-j (3 n°10-11) 2006; 93-108 (in arabic). from: http:// www.arabpsynet.com/archives/op/opj10-11.alsharbati.pdf. accessed: dec 2010. 10. u.s. department of health & human services: administration for children and families. from: http://www.acf.hhs.gov/programs/cb/pubs/cm07/ summary.htm. accessed: dec 2010. 11. maslow’s hierarchy of needs. from: http:// en.wikipedia .org/wiki/maslow ’s_hierarchy_of_ needs. accessed: dec 2011. 12. harder af. the developmental stages of erik erikson, 2009. from: http://www.learningplaceonline.com/ stages/organize/erikson.htm. accessed: jun 2011. 13. cohen, ja, mannarino ap, murray lk, igelman r. psychosocial interventions for maltreated and violence-exposed children. j social iss 2006; 62:737– 66. sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e85–90, epub. 21 jan 15 submitted 20 mar 14 revisions req. 6 may & 3 jul 14; revisions recd. 21 may & 5 jul 14 accepted 8 jul 14 1department of child health, sultan qaboos university hospital; 2department of paediatric haemato-oncology, royal hospital, muscat, oman *corresponding author e-mail: fatmarabah@gmail.com أورام الكبد اجلنينيه يف عمان قصة جناح فاطمه رباح، جنوى البنا، ديباىل بويان، ، ابراهيم الغيثي، حممد الهنائي، امل ال�ضباحية، نوال امل�ضايخية، ا�ضماعيل ب�ضلوي abstract: objectives: primary malignant liver tumours account for more than 1% of all paediatric malignancies, with the most common form being hepatoblastomas (hb). such malignancies among arab populations have rarely been addressed in the literature. using data from oman’s sole national referral centre for childhood solid malignancies, this study aimed to present the nationwide omani experience with hb over the past 21 years. methods: this retrospective study reviewed the medical records of all children with hb who were managed in the royal hospital, muscat, oman, between january 1991 and april 2012. clinical, radiological and laboratory characteristics were examined as well as treatments and outcomes. results: during the study period, 15 patients with hb were treated. of these, 10 have survived to date. nine of the survivors were no longer receiving treatment and one patient still had the disease but was in a stable condition. of the remaining five patients, three did not survive and two were lost to follow-up. the survival rate among patients who completed therapy was 91%. conclusion: hb has an excellent prognosis in oman. the main obstacle to improving outcomes among omani patients is non-compliance with therapy. keywords: hepatoblastoma; neoadjuvant therapy; hepatic cancer; oman. امللخ�ص: الهدف: متثل اأورام الكبد اخلبيثة االأولية اأكرث من %1 من جميع االأورام اخلبيثة عند االأطفال واكرثها �ضيوعا الورم اجلنيني. نادرا ماو�ضفت تلك االأورام بني ال�ضكان العرب يف االأدبيات املن�ضورة. با�ضتخدام بيانات مركز عمان الوحيد الوطني للأورام اخلبيثة ال�ضلبة يف االأطفال، فاإن هدف هذه الدرا�ضة هو تقدمي التجربة العمانية الوطنية مع اأورام الكبد اجلنينية منذ 21 �ضنة. الطريقة: ا�ضتعر�ضت هذه الدرا�ضة الفرتة يف عمان، �ضلطنة م�ضقط، يف ال�ضلطاين امل�ضت�ضفى يف وعوجلو املر�س لديهم الذين االأطفال جلميع الطبية ال�ضجلت رجعي باأثر احلاالت. لكل والنتائج العلجات وكذلك واملخربية االإ�ضعاعية واخل�ضائ�س ال�رضيري، الفح�س كذلك مت .2012 واأبريل ،1991 يناير من النتائج: خلل فرته الدرا�ضة عولج 15 طفال لديهم ورم الكبد اجلنيني. ع�رضة اأطفال اأمتوا العلج ووتعافوا حتى االآن. ت�ضعة من الناجني مل يعودوا يتلقوا العلج وطفل واحد ال زال عنده املر�س ولكنه يف حالة م�ضتقرة. وبالن�ضبة للخم�ضة الباقني فثلثة منهم توفوا واثنني فقدوا عند املتابعة. كان معدل البقاء على قيد احلياة لدى املر�ضى الذين اأنهوا العلج %91. اخلال�صة: علج اأورام الكبد اجلنينية فى سلطنةعمان حقق جناحا عاليا. العقبة الرئي�ضة اأمام حت�ضني النتائج بني املر�ضى العمانيني هو عدم االلتزام بالعلج. مفتاح الكلمات: اأورام الكبد اجلنينية؛ العلج املبدئي؛ �رضطان الكبد؛ عمان. hepatoblastomas in oman unveiling success *fatma rabah,1 nagwa el-banna,2 dipali bhuyan,2 ibrahim al-ghaithi,2 mohamed al-hinai,2 amal al-sabahi,2 nawal al-mashaikhi,2 ismail beshlawi1 advances in knowledge this is the first study from oman measuring the outcomes of childhood hepatoblastoma (hb) in terms of overall survival. there are very few studies of this kind in the gulf cooperative council (gcc) region. application to patient care the results of this study will raise awareness among primary care physicians in the gcc region regarding the favourable outcomes for hb patients receiving treatment in oman. an improved awareness of such positive outcomes would help improve patient counselling for chemotherapy and surgery. raising awareness of these positive outcomes would also help reduce patient non-compliance with treatment as well as reduce the number of patients who choose to opt for treatment abroad. approximately two-thirds of child-hood liver tumours are malignant, with hepatoblastomas (hb) representing the most common type.1–3 other paediatric liver malignancies include sarcomas, hepatocellular carcinomas and germ cell and rhabdoid tumours.1,4 hb accounts for 60–85% of all hepatic tumours in children, with an incidence of 0.5–1.5 per million.2,3 hb is more frequent in males than females, with a median age at diagnosis of 18 months. only 5% of patients present beyond clinical & basic research hepatoblastomas in oman unveiling success e86 | squ medical journal, february 2015, volume 15, issue 1 the age of four years. the right lobe of the liver is most commonly affected.1 histologically, hb is divided into either epithelial or mixed epithelial/mesenchymal tissue types, with the majority classified as epithelial and consisting of a mixture of embryonal and fetal cells.3 approximately 5% of hb cases are classified as small cell undifferentiated hb; this subtype is associated with a worse prognosis compared to other subtypes.5–7 the standard treatment for hb includes preoperative neoadjuvant chemotherapy, surgical resection and postoperative chemotherapy. the main determinants of clinical outcomes for patients with hb include the presence or absence of any metastatic disease and whether the tumour is resectable.1–3 in addition, unique histological variants of hb, such as the small cell subtype, have been shown to adversely affect survival rates.5–7 conventional radical treatment (complete resection, neoadjuvant and adjuvant therapy and chemotherapy) is achievable in approximately 90% of patients, with 75–85% reportedly achieving long-term survival.1–3 a liver transplant is the only remaining option for those patients with tumours that are rendered unresectable after a predetermined course of chemotherapy.8 paediatric liver malignancies have been previously reported among the omani population.9 the current study aimed to present the nationwide omani experience with paediatric hb over the past 21 years and to demonstrate the outcomes of standard treatment for hb in oman. methods this retrospective observational cohort study was undertaken at the royal hospital in muscat, oman. this large tertiary-level hospital is the only referral centre for paediatric solid tumours in the country. a retrospective review of the medical records of all children diagnosed with hb by pathological examination and managed at the hospital between january 1991 and april 2012 was undertaken. data were collected from the records regarding patient demographics, clinical presentation, abdominal computed tomography (ct), magnetic resonance imaging (mri), chest cts (for pulmonary lesions), surgeries and pathology reports of biopsies. alpha-fetoprotein (afp) levels for each patient were recorded at diagnosis, before and after each chemotherapy course (neoadjuvant and postoperative), immediately after any operations and at the end of the therapy. patients with other primary or secondary liver tumours were excluded from the study. all patients diagnosed with hb before 2005 were classified according to the staging system of the north american cooperative group on hb.10 four stages were identified: stage i (complete resection with no microscopic residual disease); stage ii (microscopic residual disease); stage iii (macroscopic residual disease), and stage iv (distant metastases).10 all patients diagnosed after 2005 were classified according to the pretreatment extent of disease (pretext) staging system.11,12 except for those classified as pretext i, all patients were initially started on a neoadjuvant chemotherapy course to ensure safe and complete resection [figure 1]. this chemotherapy course was repeated 3–4 times a week. after approximately 3–4 courses, patients were reassessed for tumour resectability. once a tumour was deemed resectable, a standard anatomical resection with clear margins was attempted. following this, postoperative chemotherapy was commenced. upon completion of a determined number of chemotherapy courses and the normalisation of the patient’s afp levels, a ct was performed to confirm the response of the tumour and to inform decisions to end the therapy. this study was approved by the royal hospital ethical committee. results a total of 15 patients were diagnosed with hb during the study period. the mean age at diagnosis was 20.5 months (range: 5–68 months) with a male predominance of 3:2. a palpable mass in the abdomen was the main presenting symptom in 12 patients figure 1: flowchart identifying the process of paediatric hepatoblastoma management at the royal hospital in muscat, oman. ct = computed tomography; pretext = pretreatment extent of disease staging system; na = neoadjuvant; po = postoperative; afp = alpha-fetoprotein. fatma rabah, nagwa el-banna, dipali bhuyan, ibrahim al-ghaithi, mohamed al-hinai, amal al-sabahi, nawal al-mashaikhi and ismail beshlawi clinical and basic research | e87 (80%). of the remaining three patients, one presented with constipation, fever, irritability and excessive crying, the second had had a fever of unknown origin of one month’s duration and the third patient presented with acute abdomen pain due to a ruptured tumour. one ex-preterm child with a congenital heart defect (tetralogy of fallot) died before treatment could be administered. afp levels were elevated in all but one of the patients. with the exception of two patients who were diagnosed by excisional biopsy, all cases of hb were diagnosed by a percutaneous needle biopsy of the liver. with regards to ct findings, the tumour was observed to occupy the entire liver in seven patients, the right lobe only in four patients and the left lobe only in the remaining four patients. pulmonary metastasis, in the form of multiple metastases in the left lung, was present in one patient at the time of diagnosis. after a preliminary work-up was completed, 12 patients received preoperative chemotherapy for 3–4 cycles starting within 7–10 days of the diagnosis. upon parental request, one patient received a fifth cycle as a bridge therapy until surgery could be performed abroad. postoperative chemotherapy was given in 2–5 cycles for 11 patients. patients underwent the following surgical procedures. one patient classified as pretext i underwent a right hepatectomy which was not preceded by chemotherapy while another patient had an immediate surgical excision due to a ruptured tumour. four patients had no surgical excisions, three were lost to follow-up and one was deemed unfit for surgery. one patient (pretext iv) received chemotherapy followed by a liver transplant for bilateral multifocal hb; this procedure was performed overseas as such services are not currently offered in oman. for the remaining nine patients, neoadjuvant chemotherapy rendered the tumours resectable [figures 2a–d]. for follow-up surveillance after the patients were discharged, afp levels were monitored monthly during the first year and then every three months for the following three years. abdominal imaging using ct and ultrasound scans was done every three months for the first three years and on a yearly basis thereafter. recurrence was detected by imaging results and the serial increment of afp levels. of the 15 patients examined, 10 have survived to date following the completion of therapy. the median follow-up period was 74 months (range: 1–288 months). the kaplan-meier probability of survival estimate is shown in figure 3. event-free survival ranged from 1–20 years in nine of the patients, while one patient still had the disease but was in a stable condition at the time of writing. among the five remaining patients, there were three fatalities. as mentioned earlier, one patient died from a cardiac comorbidity (tetralogy of fallot) prior to treatment. another patient defaulted twice on their treatment and later died of advanced figure 2a–d: computed tomography (ct) scans of (a) a hepatoblastoma tumour arising from segment 4b of the liver as a heterogeneous mass with hypodense areas of central necrosis and (b) the same tumour post-contrast. subsequent ct scans showed (c) a marked decrease in the size of the tumour after five courses of neoadjuvant chemotherapy and (d) the successful treatment of the tumour with a left lobectomy. the tumour was thus rendered resectable after neoadjuvant chemotherapy. hepatoblastomas in oman unveiling success e88 | squ medical journal, february 2015, volume 15, issue 1 refractory disease and the third patient died after multiple recurrences despite receiving therapy within the recommended timeframe. the remaining two patients were non-compliant with treatment and their outcome was unknown as contact was lost during the follow-up period. of the 11 patients who completed therapy, there was a single mortality, resulting in a survival rate of 91%. discussion this study presented the nationwide omani experience with paediatric hb over a 21-year period. the results of this study mirror previous research on cancer treatment in oman, where the outcomes of patients with early stages and fewer adverse prognostic factors are comparable to those reported in the international literature.13 however, it is important to note that the management of hb in oman has some unique characteristics. in some cases, patient treatment may be delayed for a number of reasons, for example if families wish to seek a second opinion or prefer treatment with traditional medicine (herbs and cautery). choices such as these could be the result of social pressure from extended family. moreover, one parent may request that either the other parent and/or the child being treated are not informed of the diagnosis and its implications. patient non-compliance during hb treatment was a striking feature observed during this study; this type of behavior may have many negative repercussions. parents may be reluctant to allow their child to continue chemotherapy or proceed with surgical resection after their child is in remission. this reluctance may be due to a fear of chemotherapy, which could potentially be aggravated when parents of children with the same condition socialise amongst themselves. as a result, one patient’s morbidity or mortality might negatively affect treatment decisions for another when these parents share their experiences. the incidence and survival rate of hb among arab populations has rarely been discussed in the literature. one report from the united arab emirates (uae) detailed 11 hb cases with a mortality rate of 45% following the death of five patients.14 the current study noted a survival rate of 91% in oman, a comparison which is favourable against that of the uae. this rate is consistent with previously reported studies among other countries.1,5,8 however, it is remarkable that this rate was achieved despite the fact that bilateral lobar involvement of the liver was most prevalent among the current study’s patient population. this is in contrast to other research which indicates that right lobar involvement is most common.1,2,8,7 a study performed in el salvador found that the severity of neutropaenic fever episodes in paediatric patients was associated with a low socioeconomic status or residence in rural areas.15 gavidia et al. reported significant relationships between maternal illiteracy, low household income and anticipated travel time to the hospital on the outcomes of febrile neutropaenia.15 similarly, the number and severity of febrile neutropenia episodes in the current study population were influenced by parental education, socioeconomic status and travel time. although hb is rare, it has gained attention in recent decades due to its incidence, which has increased by 5% annually.8 as can be seen by the minimal number of hb patients observed in the present study despite the lengthy study period, the incidence of hb in oman is low. however, the real incidence of this disease in oman may be underestimated. some patients may have died before diagnosis, while others may have been treated overseas. nevertheless, considering a population of approximately three million,16 the incidence of hb in oman is almost identical to reported annual incidence rates of 0.5–1.5 cases per million.2,3,8 however, the findings of the current study did not match those of other researchers regarding average patient age at presentation (20.5 versus 18 months in other studies).1–3,5 it is likely that this difference is attributable to a delay among families seeking medical advice for their child. there is mounting evidence suggesting an association between hb and prematurity.1,17,18 the present study provides further evidence to support this association as one of the studied patients was an ex-preterm infant. interestingly, several studies have observed that ex-preterm infants do not present with tumours at a younger age than term infants.17,18 it has been theorised that observed increases in hb incidence could partly be due to increasing survival figure 3: kaplan-meier probability of survival estimate curve for the paediatric hepatoblastoma cases identified over a 21-year period (n = 15). fatma rabah, nagwa el-banna, dipali bhuyan, ibrahim al-ghaithi, mohamed al-hinai, amal al-sabahi, nawal al-mashaikhi and ismail beshlawi clinical and basic research | e89 rates among extremely premature infants.1 moreover, increases in hb incidence could also be a result of the adverse effects of neonatal intensive care.17,18 regarding the laboratory findings at diagnosis, only one case in the present study had low afp levels at presentation with histopathology indicating small undifferentiated cell hb. it has been found that this pathological subtype constitutes 5% of hb cases and has a poor prognosis, especially when coupled with low afp levels at diagnosis.5,6,19,20 chemotherapy played a pivotal role in inducing tumour resectability in the current study. a total of 10 patients had tumours that were initially inoperable. however, preoperative neoadjuvant chemotherapy enabled the tumours to be resected in nine of these patients. surgical resection is the mainstay of hb therapy.1,6 approximately 10–20% of all hb cases involve the entire liver, are extensively multifocal or exhibit macrovascular invasion. such cases require a liver transplant to achieve long-term survival, which ranges from 55–100% as reported in several single centre series.8,21 although the hb survival rate in oman was determined to be 91%, this good prognosis is not well known among primary care physicians. thus, some families of hb patients may opt for overseas treatment or default on therapy without realising the significant impact this may have on the patient’s chances of survival. a greater awareness of the success rate for hb therapy in oman is required among treating physicians and their patients. the families of survivors should be encouraged to share their experiences with successful hb treatment in oman. conclusion patients diagnosed with hb in oman have an excellent prognosis, with the results of this 21-year study demonstrating a 91% survival rate. however, there is a need for greater awareness of this positive prognosis among primary care physicians in oman in order to overcome patient non-compliance. prevention of patient non-compliance could have a significant impact on the disease outcome and may be accomplished in collaboration with the families of survivors. a c k n o w l e d g e m e n t s the authors are grateful to all the physicians, nurses and staff who participated in the care of the patients in this study, with special thanks to dr. anil pathare. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. mueller bu, lopez-terrada d, finegold mj. liver tumors. in: pizzo pa, poplack dg, eds. principles and practice of pediatric oncology, 5th ed. houston, texas, usa: lippincott williams & wilkins, 2006. pp. 887–904. 2. stringer md. liver tumors. semin pediatr surg 2000; 9:196– 208. doi: 10.1053/spsu.2000.18844. 3. litten jb, tomlinson ge. liver tumors in children. oncologist 2008; 13:812–20. doi: 10.1634/theoncologist.2008-0011. 4. allan bj, wang b, davis js, parikh pp, perez ea, neville hl, et al. a review of 218 pediatric cases of hepatocellular carcinoma. j pediatr surg 2014; 49:166–71. doi: 10.1016/j. jpedsurg.2013.09.050. 5. haas je, feusner jh, finegold mj. small cell undifferentiated histology in hepatoblastoma may be unfavorable. cancer 2001; 92:3130–4. doi: 10.1002/1097-0142(20011215)92:12<3130::aidcncr10115>3.0.co;2-#. 6. trobaugh-lotrario ad, tomlinson ge, finegold mj, gore l, feusner jh. small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. pediatr blood cancer 2009; 52:328–34. doi: 10.1002/pbc.21834. 7. perilongo g, shafford e, maibach r, aronson d, brugières l, brock p, et al. risk-adapted treatment for childhood hepatoblastoma: final report of the second study of the international society of paediatric oncology siopel 2. eur j cancer 2004; 40:411–21. doi: 10.1016/j.ejca.2003.06.003. 8. emre s, umman v, rodriguez-davalos m. current concepts in pediatric liver tumors. pediatr transplant 2012; 16:549–63. doi: 10.1111/j.1399-3046.2012.01704.x. 9. ministry of health oman. cancer incidence in oman: report of 2010. muscat, oman: ministry of health. pp. 86. 10. malogolowkin mh, katzenstein hm, krailo m, meyers rl. treatment of hepatoblastoma: the north american cooperative group experience. front biosci (elite ed) 2012; 4:1717–23. doi: 10.2741/492. 11. brown j, perilongo g, shafford e, keeling j, pritchard j, brock p, et al. pretreatment prognostic factors for children with hepatoblastoma: results from the international society of paediatric oncology (siop) study siopel 1. eur j cancer 2000; 36:1418–25. doi: 10.1016/s0959-8049(00)00074-5. 12. czauderna p, otte jb, aronson dc, gauthier f, mackinlay g, roebuck d, et al. guidelines for surgical treatment of hepatoblastoma in the modern era: recommendations from the childhood liver tumour strategy group of the international society of paediatric oncology (siopel). eur j cancer 2005; 41:1031–6. doi: 10.1016/j.ejca.2005.02.004. 13. burney ia, al moundhri ms, rizvi aj, ganguly ss, al abri r, ashrafi ra. outcome as a measure of quality of care in oncology: experience at sultan qaboos university hospital, oman. sultan qaboos univ med j 2008; 8:27–36. 14. nawaz a, matta h, jacobsz a, mpofu c, al-salem a. unresectable hepatoblastoma: the role of preoperative chemotherapy. ann saudi med 1999; 19:553–6. 15. gavidia r, fuentes sl, vasquez r, bonilla m, ethier mc, diorio c, et al. low socioeconomic status is associated with prolonged times to assessment and treatment, sepsis and infectious death in pediatric fever in el salvador. plos one 2012; 7:e43639. doi: 10.1371/journal.pone.0043639. 16. sultanate of oman. demographics. from: www.omansultanate. com/demographics.htm accessed: jul 2014. 17. reynolds p, urayama ky, von behren j, feusner j. birth characteristics and hepatoblastoma risk in young children. cancer 2004; 100:1070–6. doi: 10.1002/cncr.20061. 18. spector lg, feusner jh, ross ja. hepatoblastoma and low birth weight. pediatr blood cancer 2004; 43:706. doi: 10.1002/ pbc.20122. hepatoblastomas in oman unveiling success e90 | squ medical journal, february 2015, volume 15, issue 1 19. de ioris m, brugieres l, zimmermann a, keeling j, brock p, maibach r, et al. hepatoblastoma with a low serum alphafetoprotein level at diagnosis: the siopel group experience. eur j cancer 2008; 44:545–50. doi: 10.1016/j.ejca.2007.11.022. 20. jassem n, jones cm, briscoe t, horner jh. the hook effect: a need for constant vigilance. ann clin biochem 2006; 43:314– 17. doi: 10.1258/000456306777695726. 21. hishiki t, matsunaga t, sasaki f, yano m, ida k, horie h, et al. outcome of hepatoblastomas treated using the japanese study group for pediatric liver tumor (jplt) protocol-2: report from the jplt. pediatr surg int 2011; 27:1–8. doi: 10.1007/ s00383-010-2708-0. الوقاية من الندب اجللدية وعالجها نظرة عامة على العالجات املستخدمة حاليا �شلط�نالشقيص و تيمور البلو�شي abstract: cutaneous scarring is common after trauma, surgery and infection and occurs when normal skin tissue is replaced by fibroblastic tissue during the healing process. the pathophysiology of scar formation is not yet fully understood, although the degree of tension across the wound edges and the speed of cell growth are believed to play central roles. prevention of scars is essential and can be achieved by attention to surgical techniques and the use of measures to reduce cell growth. grading and classifying scars is important to determine available treatment strategies. this article presents an overview of the current therapies available for the prevention and treatment of scars. it is intended to be a practical guide for surgeons and other health professionals involved with and interested in scar management. keywords: scarring; hypertrophy; keloids; silicone; steroids; surgery. امللخ�ص: ت�شيع الندب اجللدية بعد ح�الت الر�شح اأواجلراحة اأو العدوى. وحتدث عندم� ت�شتبدل اأن�شجة اجل�شم الطبيعية ب�أن�شجة اأرومية ليفية اأثن�ء عملية االلتئ�م. واإىل االآن ال تزال الفيزيلوجي� املر�شية لعملية تكوين الندب غري مفهومة ب�شورة ت�مة. اإال اأنه من املعروف اأن لدرجة التوتر عرب اأطراف اجلرح، و�رضعة منو اخلالي� دورا مهم� يف هذه العملية. من ال�رضوري الوق�ية من الندب، ويتم هذا ب�النتب�ه اإىل الطرق اجلراحية امل�شتخدمة، وب��شتخدام الو�ش�ئل املن��شبة للتقليل من منو اخلالي�. ومن املهم معرفة الندب بح�شب درجته� و�شنفه� كي حتدد له� اال�شرتاتيجي�ت العالجية املتوفرة. نقدم يف هذا املق�ل نظرة ع�مة للعالج�ت املتوفرة ح�لي� للوق�ية والعالج من الندب، ال�شتخدامه كدليل عملي للجراحني واملهنيني االآخرين يف جم�ل ال�شحة من الع�ملني يف الوق�ية من الندب وعالجه�، اأو من الراغبني يف معرفة املزيد يف هذا املو�شوع. مفتاح الكلمات: تكوين الندب؛ ت�شخم؛ جدرات؛ �شي�يكون؛ ا�شتريويدات؛ جراحة. cutaneous scar prevention and management overview of current therapies *sultan al-shaqsi and taimoor al-bulushi review sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e3–8, epub. 2 feb 16 submitted 20 apr 15 revisions req. 24 may & 13 jul 15; revisions recd. 21 jun & 21 jul 15 accepted 30 jul 15 doi: 10.18295/squmj.2016.16.01.002 every physical injury to the human skin leaves a footprint in the form of a scar which can range in appearance from hardly visible to extensively disfiguring. cutaneous scars commonly form after surgical operations, trauma, burns and infections. it is estimated that approximately 100 million people develop scars after trauma and elective surgery in middle-income countries every year.1,2 furthermore, 15% of this population will require surgical intervention for their scars due to aesthetic considerations or functional impairment.2 scars can have disturbing physical, aesthetic, functional, psychological and social connotations.3 physical symptoms frequently reported by sufferers of excessive scarring include uncontrollable pruritus, stiffness, scar contracture and pain while the psychological consequences include diminished selfesteem and confidence and increased stigmatisation and mental suffering (e.g. anxiety and depression). several societies use unique scars as a permanent marker for low social status.1 for example, in ancient arab cultures, scars around the tip of the nose of a man indicated that he had been defeated in war.4 studies have shown that the physical appearance of a surgical scar following elective surgery is strongly associated with patient satisfaction; one study found that 95% of patients who underwent elective surgery described their overall healthcare experience based on the physical appearance of their surgical scar.5,6 therefore, a good understanding of scar prevention and management is relevant to many areas of medical practice. this review provides a practical flowchart for scar prevention and discusses management guidelines based on recent international recommendations published by the international advisory panel of scar management (iapsm).1,2,7 along with recommendations for scar prevention and management, this article highlights emerging and future strategies in the treatment of scars. department of plastic & reconstructive surgery, khoula hospital, muscat, oman *corresponding author e-mail: drsultanalshaqsi@gmail.com cutaneous scar prevention and management overview of current therapies e4 | squ medical journal, february 2016, volume 16, issue 1 scar formation a scar is the fibroblastic replacement of normal skin tissue that has healed by resolution rather than regeneration. the degree of scarring is determined by the extent of the initial wound and the time interval between the injury and complete healing. several factors contribute to the formation of scars, including infections, retention of foreign bodies and prolonged healing beyond 2–3 weeks.1–4 normal skin has a matrix of collagen sheets, while scars have organised unidirectional collagen bundles. this leads to prominent or raised tissue in comparison to normal skin. t y p e s o f s c a r s clinically significant scars are divided into two categories: hypertrophic or keloid [figure 1]. hypertrophic scars are defined as excessive tissue production at the site of a physical injury to the skin which remains within the boundaries of the initial lesion.1 these can be subdivided into linear or widespread hypertrophic scars. linear scars usually result from surgery or localised trauma while widespread hypertrophic scars can be a consequence of extensive burns or soft tissue infections.1 unlike hypertrophic scars, keloids involve excessive scarring that extends beyond the boundaries of the initial lesion. they have a low chance of regression and a high chance of recurrence after treatment.1 keloids are described as minor if the scar extends less than 0.5 cm beyond the border of the initial lesion or major if the scar extends more than 0.5 cm beyond the border.1 there are several histological differences between hypertrophic and keloid scars on a cellular level. for instance, hypertrophic scars contain well organised type iii collagen fibres while keloids contain a disarray of type i and iii collagen bundles.5 scar prevention prevention of scars is critical as it is much easier to prevent formation than to rely on management once figure 1 a–f: photographs of a (a) mature scar, (b) immature scar, (c) linear hypertrophic scar, (d) widespread hypertrophic scar, (e) minor keloid and (f) major keloid. figures reproduced with permission from the department of plastic & reconstructive surgery, khoula hospital, muscat, oman. figure 2: flowchart depicting the recommended strategy for prevention of scarring. sultan al-shaqsi and taimoor al-bulushi review | e5 the scars have formed [figure 2]. the first step in scar prevention is meticulous attention to presurgical details, operative procedures and postoperative wound care. certain surgical techniques—such as making incisions along tension-free lines, approximating skin edges with minimal tension and maintaining haemostasis—are examples of factors to be considered when aiming to lower the risk of wound scarring.2 furthermore, identifying patients at high risk of developing scars is essential. these include patients with a previous history of scarring and those undergoing surgeries in high-risk scarring regions of the body, such as the neck and thorax.2–4 several measures have been shown to prevent scar formation.1 silicone-based products (i.e. gels, sheets and tapes) are the preferred preventative measure.8‒10 such products should be applied after epithelisation is established and used for at least a month to maximise results. silicone sheets are commonly available and should be applied for at least 12 hours per day. silicone gels, creams and ointments are acceptable alternatives for face and neck scars as well as for patients in hot or humid climates.9–11 intralesional corticosteroid injections are considered second-line approaches in scar prevention.12,13 however, silicone and intralesional steroid injections should be used synergistically in high-risk patients. exposure to sunlight during wound healing has been associated with scar pigmentation; therefore, it is recommended that patients minimise sun exposure during wound healing.6–8 scar management the management of scarring is both complex and challenging due to several factors. the exact pathophysiology of scar formation has yet to be completely elucidated, although several factors are believed to play a role, including the degree of tension across the edges of the wound and the speed of cell growth.9,10 variable systems exist to quantify changes in scar appearance and there is also a lack of theoretical models available to evaluate current therapies. this has led to a limited amount of useful data derived from prospective randomised studies. nevertheless, there are several measures which can be utilised for the prevention and treatment of scars. g r a d i n g a n d c l a s s i f i c at i o n in order to tackle the issue of scar management, a grading system must be used as a common framework as this is critical in determining treatment for affected patients. cutaneous scars can be graded based on pigmentation, vascularity, pliability, thickness, height and depression, as well as patient factors such as comfort and acceptability.4 several scales have been reported in the literature such as the vancouver scar scale and the patient and observer scar assessment scale.14,15 these tools have good consistency and acceptability but are heavily subjective and have limited sensitivity with regards to detecting changes in the appearance of a scar.4,6 there is currently no gold-standard system to classify or grade scars. nevertheless, regardless of the scale initially chosen by the clinician, the same scale should be used throughout the course of treatment for that particular patient. the iapsm suggests that any assessment of a scar should consider the size and thickness of the scar tissue, the severity of the symptoms and any concerns the patient may have.2 the iapsm classification of scars can be found in table 1.2,7 r e c o m m e n d at i o n s measures used to treat scars are largely determined by the type of scar and symptomology. below is a table 1: international advisory panel of scar management classification of different types of scars2,7 scar type appearance characteristics mature •light-coloured •flat immature •red •slightly pruritic and painful •can develop into a linear hypertrophic scar linear hypertrophic •rope-like appearance •red •raised •confined to the border of the original injury •develops weeks after initial insult •may slowly grow widespread hypertrophic •widespread •red •raised •confined to the border of the original injury •burns are the main cause minor keloid •raised •extends <0.5 cm beyond the border of the original injury •develops months to years after the event •does not regress •high recurrence rate major keloid •large •raised •extends >0.5 cm beyond the border of the original injury •slightly pruritic and painful •continues to grow •does not regress •very high recurrence rate cutaneous scar prevention and management overview of current therapies e6 | squ medical journal, february 2016, volume 16, issue 1 detailed description of current recommendations on scar management based on scar type. it is essential to address symptoms using adequate analgaesics, systemic antihistamines, moisturisers, topical corticosteroids, antidepressants, massage or hydrotherapy. immature scars immature scars are scars which are still in the process of maturing and remodelling.2,7 these types of scars can potentially develop into linear hypertrophic scars and are considered as such if symptoms persist beyond one month. therefore, a preventative strategy is recommended. monthly pulsed dye laser therapy sessions for 2–3 months have been shown to provide some benefit for immature scars.16,17 if the scar shows minimal improvement to pulsed dye laser therapy, then fractional laser therapy may be attempted.1 linear hypertrophic scars based on randomised controlled trials, silicone sheets and gels are the recommended first-line treatment strategy for linear hypertrophic scars.8,18,19 success rates are improved if the sheets or gels are applied for at least 12 hours every day for a minimum of two months.9,19 if the patient has severe scarring, then augmentation of therapy using intralesional corticosteroid injections or 5-fluorouracil (5-fu) is indicated.12,13,20,21 it is important to note that hyperpigmentation and skin irritation at the injection site are well-known sideeffects of 5-fu therapy.20 second-line strategies for linear hypertrophic scars should be instituted if first-line measures fail. pulsed dye or fractional laser therapies have been shown to help scar regression in persistent linear hypertrophic scars if used in combination with silicone products and/or intralesional injections.16,17 studies have shown that surgical intervention is required if 12 months of augmented treatment fails to treat a scar.2 in such cases, tension of the wound edges is almost always evident.2 surgeons should aim to reduce this tension during the procedure. immediate first-line measures should be instituted post-surgery. several surgical techniques have been reported to reduce scar tension in linear hypertrophic scars, including zand w-plasty. both of these wellknown techniques have similar recurrence rates.22 new research shows that small-wave or s-plasty is equivalent in effectiveness to the z-plasty approach.6,7 skin grafts and local flaps are reserved as a last resort if all other strategies fail to treat linear hypertrophic scars.1–4 adjunctive biological therapy such as dermal scaffolds, matrices and epithelial cell suspensions have been reported to enhance wound healing, but evidence in favour of the routine use of these therapies is currently lacking.23 post-surgical use of silicone products and intralesional combined corticosteroid and 5-fu injections are essential in reducing the rate of scar recurrence. widespread hypertrophic scars burns are the main cause of widespread hypertrophic scarring; as such, patients with widespread hypertrophic scars should ideally be treated in a specialised burn unit. clinical evidence supports the early use of silicone sheets, gels and pressure therapy as firstline strategies for treating widespread hypertrophic scars.10–12 if these fail to improve regression of the scar, then fractional ablative laser therapy should be added as a second-line adjunct.12,17 such scars are usually complex and require a combination of therapies, including silicone products, pressure therapy and surgical procedures such as skin grafts, contracture release and flaps.24 furthermore, burn scars can cause significant pruritus and pain; therefore, neoadjuvant therapies such as analgaesics and systemic antihistamines are essential before embarking on significant surgical reconstructive procedures.1,7 minor keloids for minor keloids, silicone sheets or gels in combination with monthly intralesional corticosteroid injections is considered the first line of therapy.1,7 several studies have also shown potential benefits from contact or intralesional cryotherapy in arresting the expansion of minor keloid scars.25,26 cryotherapy generally provokes intense pain when applied; as a result, it is critical to provide adequate oral analgaesia and pre-therapy local anaesthesia. if the above treatment does not result in scar improvement after 8–12 weeks, then intralesional 5-fu, laser therapy or surgical resection is warranted.1 it is important to counsel patients with keloids and inform them that the post-surgery recurrence rate is very high in order to ensure that their expectations are realistic.1 partial surgical excision is the therapy of choice if a full excision would damage underlying important structures. local and free flaps are surgical options in some refractory keloid cases.3–6 in order to reduce the recurrence rate of keloids after surgery, adjunct therapies such as silicone sheets and intralesional corticosteroid injections should be applied promptly. post-surgery radiotherapy at the keloid site has shown benefits.7 available evidence supports the use of 5-fu following a keloid resection.2–5 the use of other chemotherapeutic agents, such as bleomycin, mitomycin c and 5% imiquimod cream, have been shown to slow cell growth, thereby reducing the recurrence rate of keloids post-surgical sultan al-shaqsi and taimoor al-bulushi review | e7 resection.27–30 however, skin irritation and erythema are common side-effects from such therapies.25–28 major keloids major keloids are a surgical challenge, particularly as the post-treatment recurrence rate is very high.1 current evidence recommends the use of monthly corticosteroid injections and cryotherapy as a firstline therapy.2–4 unfortunately, most major keloids are refractory to this therapy and intralesional 5-fu and surgical intervention is usually required. it is important to transfer patients with major keloids to a specialised plastic surgery unit to ensure improved functional outcomes. post-surgical prophylactic therapy is even more important in keloids than in other scars.2–4 emerging therapies understanding the physiology of wound healing is critical in emerging future therapies for abnormal scar formation. several experimental therapies reported in the literature may soon become standard practice. gassner et al. found that injections of botulinum toxin a (bta) enhanced wound healing and reduced the rate of scar formation in comparison to a placebo.31 although the biological basis of this scar treatment is plausible—bta paralyses the local muscles around the edges of a wound, thereby reducing tension— conclusive evidence is still lacking. most of the published literature are case reports or retrospective studies.32–34 as such, there is a lack of randomised controlled trials to assess bta therapy in scar prevention and treatment. other therapies used to prevent or treat scars include calcineurin inhibitors, retinoic acid, tamoxifen, verapamil and interferon alfa-2b.3,30 however, such therapies have not yet been supported by randomised controlled trials and there is currently no evidence to support their routine use in clinical practice. conclusion scars continue to represent a significant medical burden. wound healing processes and the pathophysiology of scar formation are evolving areas of research and treatment modalities will continue to change accordingly. current prevention methods strongly supported by the literature include meticulous surgical techniques and the utilisation of silicone products. scar classification and grading systems are essential in determining the appropriate choice of therapy. silicone products are the first-line strategy in most cases. adjunct therapies such as intralesional corticosteroids, chemotherapy, cryotherapy, radiotherapy and pressure therapy are useful synergistic modalities if first-line therapy fails. surgical interventions are usually required for extensive major keloids. references 1. arno ai, gauglitz gg, barret jp, jeschke mg. up-todate approach to manage keloids and hypertrophic scars: a useful guide. burns 2014; 40:1255–66. doi: 10.1016/j. burns.2014.02.011. 2. gold mh, berman b, clementoni mt, gauglitz gg, nahai f, murcia c. updated international clinical recommendations on scar management: part 1 evaluating the evidence. dermatol surg 2014; 40:817–24. doi: 10.1111/dsu.0000000000000049. 3. tziotzios c, profyris c, sterling j. cutaneous scarring: pathophysiology, molecular mechanisms, and scar reduction therapeutics part ii: strategies to reduce scar formation after dermatologic procedures. j am acad dermatol 2012; 66:13–24. doi: 10.1016/j.jaad.2011.08.035. 4. durani p, mcgrouther da, ferguson mw. current scales for assessing human scarring: a review. j plast reconstr aesthet surg 2009; 62:713–20. doi: 10.1016/j.bjps.2009.01.080. 5. leventhal d, furr m, reiter d. treatment of keloids and hypertrophic scars: a meta-analysis and review of the literature. arch facial plast surg 2006; 8:362–8. doi: 10.1001/ archfaci.8.6.362. 6. fearmonti r, bond j, erdmann d, levinson h. a review of scar scales and scar measuring devices. eplasty 2010; 10:e43. 7. gold mh, mcguire m, mustoe ta, pusic a, sachdev m, waibel j, et al. updated international clinical recommendations on scar management: part 2 algorithms for scar prevention and treatment. dermatol surg 2014;40:825‒31. doi: 10.1111/ dsu.0000000000000050. 8. chan ky, lau cl, adeeb sm, somasundaram s, nasirzahari m. a randomized, placebo-controlled, double-blind, prospective clinical trial of silicone gel in prevention of hypertrophic scar development in median sternotomy wound. plast reconstr surg 2005; 116:1013–20. doi: 10.1097/01. prs.0000178397.05852.ce. 9. momeni m, hafezi f, rahbar h, karimi h. effects of silicone gel on burn scars. burns 2009; 35:70–4. doi: 10.1016/j. burns.2008.04.011. 10. mustoe ta. evolution of silicone therapy and mechanism of action in scar management. aesthetic plast surg 2008; 32:82–92. doi: 10.1007/s00266-007-9030-9. 11. signorini m, clementoni mt. clinical evaluation of a new self-drying silicone gel in the treatment of scars: a preliminary report. aesthetic plast surg 2007; 31:183–7. doi: 10.1007/ s00266-005-0122-0. 12. manuskiatti w, fitzpatrick re. treatment response of keloidal and hypertrophic sternotomy scars: comparison among intralesional corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulsed-dye laser treatments. arch dermatol 2002; 138:1149–55. doi: 10.1001/archderm.138.9.1149. 13. hayashi t, furukawa h, oyama a, funayama e, saito a, murao n, et al. a new uniform protocol of combined corticosteroid injections and ointment application reduces recurrence rates after surgical keloid/hypertrophic scar excision. dermatol surg 2012; 38:893–7. doi: 10.1111/j.15244725.2012.02345.x. 14. baryza mj, baryza ga. the vancouver scar scale: an administration tool and its interrater reliability. j burn care rehabil 1995; 16:535–8. doi: 10.1097/00004630-19950900000013. http://dx.doi.org/10.1016/j.burns.2014.02.011 http://dx.doi.org/10.1016/j.burns.2014.02.011 http://dx.doi.org/10.1111/dsu.0000000000000049 http://dx.doi.org/10.1016/j.jaad.2011.08.035 http://dx.doi.org/10.1016/j.bjps.2009.01.080 http://dx.doi.org/10.1001/archfaci.8.6.362 http://dx.doi.org/10.1001/archfaci.8.6.362 http://dx.doi.org/10.1111/dsu.0000000000000050 http://dx.doi.org/10.1111/dsu.0000000000000050 http://dx.doi.org/10.1097/01.prs.0000178397.05852.ce http://dx.doi.org/10.1097/01.prs.0000178397.05852.ce http://dx.doi.org/10.1016/j.burns.2008.04.011 http://dx.doi.org/10.1016/j.burns.2008.04.011 http://dx.doi.org/10.1007/s00266-007-9030-9 http://dx.doi.org/10.1007/s00266-005-0122-0 http://dx.doi.org/10.1007/s00266-005-0122-0 http://dx.doi.org/10.1001/archderm.138.9.1149 http://dx.doi.org/10.1111/j.1524-4725.2012.02345.x http://dx.doi.org/10.1111/j.1524-4725.2012.02345.x http://dx.doi.org/10.1097/00004630-199509000-00013 http://dx.doi.org/10.1097/00004630-199509000-00013 cutaneous scar prevention and management overview of current therapies e8 | squ medical journal, february 2016, volume 16, issue 1 15. draaijers lj, tempelman fr, botman ya, tuinebreijer we, middelkoop e, kreis rw, et al. the patient and observer scar assessment scale: a reliable and feasible tool for scar evaluation. plast reconstr surg 2004; 113:1960–5. doi: 10.1097/ 01.prs.0000122207.28773.56. 16. tanzi e, alster ts. laser treatment of scars. skin therapy lett 2004; 9:4–7. 17. vrijman c, van drooge am, limpens j, bos jd, van der veen jp, spuls pi, et al. laser and intense pulsed light therapy for the treatment of hypertrophic scars: a systematic review. br j dermatol 2011; 165:934–42. doi: 10.1111/j.13652133.2011.10492.x. 18. karagoz h, yuksel f, ulkur e, evinc r. comparison of efficacy of silicone gel, silicone gel sheeting, and topical onion extract including heparin and allantoin for the treatment of postburn hypertrophic scars. burns 2009; 35:1097–103. doi: 10.1016/j. burns.2009.06.206. 19. o’brien l, pandit a. silicon gel sheeting for preventing and treating hypertrophic and keloid scars. cochrane database syst rev 2006; 1:cd003826. doi: 10.1002/14651858.cd003826.pub2. 20. apikian m, goodman g. intralesional 5 fluorouracil in the treatment of keloid scars. australas j dermatol 2004; 45:140–3. doi: 10.1111/j.1440-0960.2004.00072.x. 21. darougheh a, asilian a, shariati f. intralesional triamcinolone alone or in combination with 5-fluorouracil for the treatment of keloid and hypertrophic scars. clin exp dermatol 2009; 34:219–23. doi: 10.1111/j.1365-2230.2007.02631.x. 22. darzi ma, chowdri na, kaul sk, khan m. evaluation of various methods of treating keloids and hypertrophic scars: a 10-year follow-up study. br j plast surg 1992; 45:374–9. doi: 10.1016/0007-1226(92)90008-l. 23. janis j, harrison b. wound healing: part ii clinical applications. plast reconstr surg 2014; 133:383e–92e. doi: 10.1097/prs.0000000000000077. 24. van den kerckhove e, stappaerts k, fieuws s, laperre j, massage p, flour m, et al. the assessment of erythema and thickness on burn related scars during pressure garment therapy as a preventive measure for hypertrophic scarring. burns 2005; 31:696–702. doi: 10.1016/j.burns.2005.04.014. 25. rusciani l, rossi g, bono r. use of cryotherapy in the treatment of keloids. j dermatol surg oncol 1993; 19:529–34. doi: 10.1111/j.1524-4725.1993.tb00386.x. 26. har-shai y, amar m, sabo e. intralesional cryotherapy for enhancing the involution of hypertrophic scars and keloids. plast reconstr surg 2003; 111:1841–52. doi: 10.1097/01. prs.0000056868.42679.05. 27. berman b, kaufman j. pilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids. j am acad dermatol 2002; 47:s209–11. doi: 10.1067/ mjd.2002.126585. 28. gupta m, narang t. role of mitomycin c in reducing keloid recurrence: patient series and literature review. j laryngol otol 2011; 125:297–300. doi: 10.1017/s0022215110002045. 29. naeini ff, najafian j, ahmadpour k. bleomycin tattooing as a promising therapeutic modality in large keloids and hypertrophic scars. dermatol surg 2006; 32:1023–9. doi: 10.1111/ j.1524-4725.2006.32225.x. 30. profyris c, tziotzios c, do vale i. cutaneous scarring: pathophysiology, molecular mechanisms, and scar reduction therapeutics part i: the molecular basis of scar formation. j am acad dermatol 2012; 66:1–10. doi: 10.1016/j.jaad.2011.05.055. 31. gassner hg, brissett ae, otley cc, boahene dk, boggust aj, weaver al, et al. botulinum toxin to improve facial wound healing: a prospective, blinded, placebo-controlled study. mayo clin proc 2006; 81:1023–8. doi: 10.4065/81.8.1023. 32. sherris da, gassner hg. botulinum toxin to minimize facial scarring. facial plast surg 2002; 18:35–9. doi: 10.1055/s-200219825. 33. wilson am. use of botulinum toxin type a to prevent widening of facial scars. plastic reconstr surg 2006; 117:1758–66. doi: 10.1097/01.prs.0000209944.45949.d1. 34. xiao z, zhang f, cui z. treatment of hypertrophic scars with intralesional botulinum toxin type a injections: a preliminary report. aesthet plast surg 2009; 33:409–12. doi: 10.1007/ s00266-009-9334-z. http://dx.doi.org/10.1097/01.prs.0000122207.28773.56 http://dx.doi.org/10.1097/01.prs.0000122207.28773.56 http://dx.doi.org/10.1111/j.1365-2133.2011.10492.x http://dx.doi.org/10.1111/j.1365-2133.2011.10492.x http://dx.doi.org/10.1016/j.burns.2009.06.206 http://dx.doi.org/10.1016/j.burns.2009.06.206 http://dx.doi.org/10.1002/14651858.cd003826.pub2 http://dx.doi.org/10.1111/j.1440-0960.2004.00072.x http://dx.doi.org/10.1111/j.1365-2230.2007.02631.x http://dx.doi.org/10.1016/0007-1226%2892%2990008-l http://dx.doi.org/10.1097/prs.0000000000000077 http://dx.doi.org/10.1016/j.burns.2005.04.014 http://dx.doi.org/10.1111/j.1524-4725.1993.tb00386.x http://dx.doi.org/10.1097/01.prs.0000056868.42679.05 http://dx.doi.org/10.1097/01.prs.0000056868.42679.05 http://dx.doi.org/10.1067/mjd.2002.126585 http://dx.doi.org/10.1067/mjd.2002.126585 http://dx.doi.org/10.1017/s0022215110002045 http://dx.doi.org/10.1111/%0aj.1524-4725.2006.32225.x http://dx.doi.org/10.1111/%0aj.1524-4725.2006.32225.x http://dx.doi.org/10.1016/j.jaad.2011.05.055 http://dx.doi.org/10.4065/81.8.1023 http://dx.doi.org/10.1055/s-2002-19825 http://dx.doi.org/10.1055/s-2002-19825 http://dx.doi.org/10.1097/01.prs.0000209944.45949.d1 http://dx.doi.org/10.1007/s00266-009-9334-z http://dx.doi.org/10.1007/s00266-009-9334-z departments of 1dermatology & venereology and 2pathology, virgen de las nieves hospital, granada, spain *corresponding author e-mail: gonzaloblascomorente@gmail.com مرض فوكس فورديس جونزالو بال�شكو-مورينتى، م�ري� خو�شيه ن�رانخو-دي�ز، اإ�رضائيل برييز-لوبيز، اأنطونيو م�رتينيز-لوبيز، ريك�ردو رويز-فيالفريد، خو�شي اأنريو�ص-فرن�نديز fox-fordyce disease *gonzalo blasco-morente,1 maría j. naranjo-díaz,1 israel pérez-lópez,1 antonio martínez-lópez,1 ricardo ruiz-villaverde,1 josé aneiros-fernández2 a 42-year-old woman presented to the department of dermatology & venereology, virgen de las nieves hospital, granada, spain, in may 2015 with a severe pruritic rash and hair loss in both axillary regions. physical examination showed skin coloured papules and alopecia [figure 1a], which showed no fluorescence under a wood’s lamp. dermoscopy revealed hair follicle-centred papules, figure 1a–d: a 42-year-old woman with fox-fordyce disease with (a) skin coloured papules of 1–2 mm and moderate alopecia in the right axilla and (b) folliculocentric papules with a few traumatised terminal hairs and blackheads. haematoxylin and eosin stains showed (c) inflammatory infiltrate of lymphocytes affecting the follicle at x10 magnification and (d) eccrine and apocrine sweat glands showing dilatation at x4 magnification. interesting medical image sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e119–120, epub. 2 feb 16 submitted 14 jul 15 revision req. 7 sep 15; revision recd. 30 sep 15 accepted 25 oct 15 doi: 10.18295/squmj.2016.16.01.025 fox-fordyce disease e120 | squ medical journal, february 2016, volume 16, issue 1 features include dilatation of the follicular infundibula with hyperkeratosis, acanthosis and spongiosis of the infundibular epithelium and perifollicular infiltration of lymphocytes and foamy histiocytes, leading to hair loss.3–5 differential diagnoses which can be considered include graham-little-piccardi-lasseur syndrome and trichostasis spinulosa; however, patients with ff disease would not have cicatricial alopecia or lesions elsewhere on the body or the mucosa.5 various treatments for ff disease have been suggested with limited improvement, including the administration of oral contraceptives; topical, intralesional or systemic corticosteroids; topical clindamycin; pimecrolimus; phototherapy; surgical treatments like electrocoagulation and curettage with liposuction; and topical and oral retinoids, as prescribed in the current case.1–5 references 1. kassuga le, medrado mm, chevrand ns, salles sde a, vilar eg. fox-fordyce disease: response to adapalene 0.1%. an bras dermatol 2012; 87:329–31. doi: 10.1590/s0365-059620 12000200029. 2. kao ph, hsu ck, lee jy. clinicopathological study of foxfordyce disease. j dermatol 2009; 36:485–90. doi: 10.1111/ j.1346-8138.2009.00689.x. 3. yost j, robinson m, meehan sa. fox-fordyce disease. dermatol online j 2012; 18:28. 4. milcic d, nikolic m. clinical effects of topical pimecrolimus in a patient with fox-fordyce disease. australas j dermatol 2012; 53:e34–5. doi: 10.1111/j.1440-0960.2010.00711.x. 5. george a, bhatia a, thomas e. fox-fordyce disease: a report of 2 cases responding to topical clindamycin. indian j dermatol venereol leprol 2015; 81:87–8. doi: 10.4103/0378-6323.148597. traumatised terminal hairs and blackheads [figure 1b]. the histology of the skin biopsy indicated an inflammatory infiltrate of lymphocytes affecting the follicle [figure 1c] and the obstruction of the eccrine and apocrine sweat glands [figure 1d]. the patient was diagnosed with fox-fordyce (ff) disease. following treatment with tretinoin (0.05%), she demonstrated moderate symptomatic improvement. comment ff disease is a rare and chronic condition usually seen in adolescent women which affects the apocrine gland-bearing areas. the underlying aetiology of ff remains unclear, although a history of trauma caused by laser hair removal or hormonal factors may be triggers.1–4 the pathophysiology consists of the obstruction of the apocrine gland duct due to the insertion of a keratin plug in the hair follicle wall. this causes secretion retention with consequent rupture of the glandular structure and secondary inflammation of the dermis.2,3 the extravasation of the glandular content can be the cause of the pruritus.3 clinically, the lesions are uniform, firm, folliculocentric papules, which can range in colour from normal skin colour to slightly brownish.3–5 the axillae are the most common areas involved, as in the present case, although ff also can involve the anogenital and periareolar areas, lips, umbilicus, sternum, perineum and upper medial aspects of the thighs.3,4 the diagnosis of ff disease is based on characteristic clinical features, as well as non-specific histopathological features.1–5 the histopathological http://dx.doi.org/10.1590/s0365-05962012000200029 http://dx.doi.org/10.1590/s0365-05962012000200029 http://dx.doi.org/10.1111/j.1346-8138.2009.00689.x http://dx.doi.org/10.1111/j.1346-8138.2009.00689.x http://dx.doi.org/10.1111/j.1440-0960.2010.00711.x http://dx.doi.org/10.4103/0378-6323.148597 squ med j, august 2011, vol. 11, iss. 3, pp. 369-377, epub. 15th aug 11 submitted 10th jan 11 revision req. 11th apr 11, revision recd. 4th jun 11 accepted 12th jun 11 department of otolaryngology, king saud university and king abdulaziz university hospital, riyadh, saudi arabia. corresponding author email: dhagr90@yahoo.com <ìèiáí÷]<ÿ√à÷]<ïåöê<ìèfí√÷]<ìe^rjâ¯÷<ç√e<‡¬<å^èœ÷] kfnπ^e<ÿ^}å˝]<ìèflœi<›]ç~jâ^e<l^è◊€√÷]<ÿ}]å ìèe]üi_<ìèœ^fjâ]<ìâ]öå<v<ì√œáœ÷]<å^€¬<ìœfi^√⁄ê<      30    16 30 11 354 14    :مفتاح الكلمات abstract: objectives: the development of cochlear implant (ci) electrode arrays has focused on the use of a minimally invasive technique involving a modiolus-hugging placement of the electrode. the aim of this study was to evaluate the “advance-in-stylet” (ais) technique compared to the advance-off-stylet (aos) technique recommended for the current cochlear nucleus® device. in the ais technique, the stylet is not removed. we evaluated the electrical auditory thresholds measured when the stylet was removed (modiolus-hugging) compared to measurements taken with the stylet in place (lateral wall cochlea electrode placement). methods: in this prospective cohort study, 30 consecutive patients received unilateral nucleus freedom® cis using ais insertion. measurement of the acoustic reflex (ar) and neural response telemetry (nrt) were performed with the stylet in place (lateral wall placement of the electrodes) and then removed (perimodiolar placement), and the results compared. the responses were measured in the basal, middle and apical turns in both groups—with and without stylet. results: the ais surgery was completed without complication in 30 patients (16 males and 14 females, age range 3-54 years [mean 11]). based on neural response telemetry, only apical electrodes showed statistically significant differences in thresholds, but the ar was not significantly different before or after stylet removal in any of the electrode groups tested. conclusions: the effects of modiolus-hugging do not seem to result in a large difference in electrical stimulation thresholds so, in difficult cases, the stylet may be left in place without significantly changing the thresholds, except perhaps at the apical turn. keywords: cochlear implant; telemetry intra-operative neural response telemetry and acoustic reflex assessment using an advance-in-stylet technique and modiolus-hugging a prospective cohort study abdulrahman hagr clinical & basic research advances in knowledge 1. the effects of modiolus-hugging do not seem to result in a large difference in electrical performance in cochlear implant. intra-operative neural response telemetry and acoustic reflex assessment using an advance-in-stylet technique and modiolus-hugging a prospective cohort study 370 | squ medical journal, august 2011, volume 11, issue 3 the cochlear implant (ci) is a device that electrically stimulates the auditory nerve via an intracochlear electrode array placed in the scala tympani, bypassing the inner ear in subjects with severe to profound hearing loss. ci technology has improved considerably over the past decade as researchers and manufacturers have attempted to maximise speech perception. although many advances have already been made, there are still several unresolved issues with regard to ci surgery, one of which is the utility of the advance-offstylet (aos) technique, with its resulting modiolar hugging array morphology. the classic straight ci electrode array slides along the lateral wall of the scala tympani during insertion, and it remains in this location. newer designs from some companies have featured implants with a preformed shape memory, which causes the implant to spiral inwards towards the modiolus. different manufacturers have achieved modiolus-hugging in different ways, but in this study we used the implementation developed by cochlear corporation (sydney, australia), which employs a stylet to stent a preformed coiled array into a straight shape. the recommendation is to insert this electrode to a predefined distance, and then advance the electrode off the stylet. this has two effects: first, the soft, flexible tip leads and, because the stylet has been withdrawn from the tip, the distal electrode is no longer stiff, avoiding penetration of the basilar membrane or spiral ligament; second, it allows the electrode to take up its pre-coiled shape and hug the modiolus. this is called the advance-off-stylet (aos) technique. this can be a difficult surgical manoeuvre to perform because the whole array may be withdrawn instead of advanced when the surgeon attempts to slide it off the stylet, which is held steady. this can result in intraoperative extrusion of the array, and, if it curls with the stylet withdrawn, the stylet is not designed to be re-introduced. this could potentially waste an expensive ci because it is very difficult to insert the array once it is coiled. perimodiolar ci electrodes place the electrode contacts in closer proximity to the excitable neural elements. theoretically, this offers better resolution and improved transfer of the electrical stimuli to the neural structures of the viiith nerve endings, where it results in more specific frequency stimulation, reduced electric current spread, increased dynamic range and reduced energy consumption.1 these combined features result in performance gains for the listener and reduced electrical power consumption, thereby prolonging battery life. behavioural response studies have found significant decreases in average threshold and comfort (t&c) levels across electrodes with perimodiolar placement when compared to lateral wall cochlea arrays,2,3and this placement may also potentially improve speech perception.4 additionally, facial nerve stimulation may be reduced by placing the electrode further away from the outer wall of the scala tympani.5 most of the early studies showing lowered thresholds and a wider dynamic range with perimodiolar arrays using electrically evoked auditory brainstem responses (eabr) in animals.6,7 however, some newer studies have shown that these supposed benefits are variable.8,9,10 histological studies to assess the cochlear damage resulting from insertion of different types of perimodiolar electrodes were performed on cadaver temporal bones of normal-hearing individuals;11,12 however, these studies did not take into account that, with time, fibrosis, scarring, and ossification resulting from insertion trauma could theoretically alter the amount of current necessary for stimulation. these factors are independent of the distance of the electrode from the modiolus and the remaining spiral ganglion cells. therefore, the impact of localised damage to the spiral ligament during implantation in humans is uncertain.12,13 in addition, many other studies have shown no improvement in ci performance in relation to hearing conservation or in the dynamic range. 3,14-16 perimodiolar aos electrode surgery is relatively atraumatic due to the flexible tip, though it may result in lower lateral wall stress and forces. it may preserve the integrity of the spiral lamina and basilar membrane, further preventing the subsequent neuronal losses that have been reported using conventional straight electrode arrays.11,17as mentioned above, the impact of localised damage to the spiral ligament during implantation is uncertain and may take time to become evident.13 as noted above, many studies have shown that application to the patient care 1. the stylet in cochlear implant may be left during electrodes insertion without significantly changes in the threshholds. abdulrahman hagr clinical and basic research | 371 stimulation in the perimodiolar location using eabr results in less power consumption.18-21 neural response telemetry (nrt) is a system that measures electrically evoked compound action potential (ecap) thresholds from the auditory nerve using the ci. the system applies an electrical pulse to a given intracochlear electrode, and the evoked neural response is recorded at a neighbouring electrode. the measured potentials are telemetered back to the system’s interface for clinical analysis. the response is probably from the proximal auditory nerve, and this method has several advantages over eabr. one is that nrt requires a shorter collection time which is important for intraoperative use. second, there is little need for patient cooperation or sedation, which is required to apply the eabrs’ surface electrodes, because nrt uses the ci as both the stimulating and recording electrodes. additionally, using nrt, postoperative data can be compared to intraoperative data. moreover, nrt can be used to predict the behavioural threshold (t levels) and maximum comfort levels (c levels) to build stimulation maps for the ci patient and facilitate the postsurgical rehabilitation process. nrt provides information that reflects the activity of a smaller number of auditory neurons, thus effectively negating the influence of neural response from higher levels in the brain. eabr requires a larger number of sweeps and a longer acquisition time, it is more difficult to elicit, and it is often associated with artefacts.22,23 the acoustic reflex (ar) is the contraction of the stapedius muscle, traditionally in response to sound stimulation. the ipsilateral pathway for the stapedius reflex travels via the viiith nerve synapses in the ipsilateral cochlear nucleus, and then travels to the superior olivary nucleus and the facial nerve nucleus, which supplies the stapedius muscle by way of the facial nerve. the ar also helps to verify implant position and integrity in addition to validating the functioning of the auditory and facial nerves. to our knowledge, there has been no study to date evaluating the effects of perimodiolar positioning (by removing the stylet) compared to lateral wall placement of the array (by non-removal of the stylet) measured using the acoustic reflex threshold (art) and neural response telemetry (nrt) performed intraoperatively for the nucleus® (cochlear corporation, sydney, australia) electrode array. the purpose of this study was to determine this effect, within the same cochlea and using the same array. we will refer to the procedure in which the stylet is left in place as the advancein-stylet (ais) technique for the nucleus freedom® electrode array. methods thirty patients who received the nucleus freedom® device between april 2009 and january 2010 were studied. inclusion criteria for this study were age greater than 2 years, no inner ear malformation, and compliance with our ci candidacy criteria. exclusion criteria were failure of full insertion, inability to remove the stylet, the presence of a cerebrospinal fluid (csf) gusher and intra-operative measures performed by audiologists other than our investigating audiologist. this prospective study was performed at the king abdulaziz university hospital in riyadh, saudi arabia. a total of 30 consecutive ci patients of a single surgeon and a single audiologist were recruited and evaluated with intra-operative ci testing (art and nrt) after full insertion with stylet in place (ais). then, these test results were compared with the results of procedures performed with the stylet explanted (with perimodiolar hugging) in the same patient in a repeated measures fashion. the freedom® ci developed by cochlear corporation was used in all of our patients. our institution research board (irb) approved this study (project no. e-10-198). in our study, nrt responses were recorded at table 1: characteristics of the sample variable statistic age minimum maximum mean median mode standard deviation 3 54 11.47 5.00 5.00 13.68 sex male female 16 (53.3%) 14 (46.7%) site right left 14 (46.7%) 16 (53.3%) intra-operative neural response telemetry and acoustic reflex assessment using an advance-in-stylet technique and modiolus-hugging a prospective cohort study 372 | squ medical journal, august 2011, volume 11, issue 3 apical, basal, and middle electrodes in each patient. the stimulated electrodes ranged from 1 to 7 at the basal end, 8 to 15 in the middle, and 16 to 22 at the apex. the ar thresholds were observed by the same surgeon before and after stylet removal without knowing which electrodes were being stimulated. in all cases, facial nerve monitoring was used, and then the mastoidectomy and transfacial recess were done. the middle ear was normal in all cases, and a cochleostomy was performed anteriorinferiorly to the round window. the electrode was inserted gently and slowly into the scala tympani without using the aos technique, i.e. insertion with the stylet-in-place (ais technique). this renders the array similar to a conventional straight electrode array, which will lie against the lateral cochlear wall. the cochleostomy site was sealed by muscle after full insertion of the electrodes. the art were evaluated by the surgeon, and the lowest stimulation level at which visible stapedial contractions could be seen was recorded. the ar thresholds were measured at the electrodes numbered 1, 6, 11, 16 and 22. then the nrt was measured at the electrodes numbered 1, 3, 6, 9, 11, 13, 16 17, 21 and 22. the stylet was then removed, allowing the electrode array to coil closer to the modiolus. the stimulation threshold measurements were then repeated. all the patients’ intra-operative evaluations were done by the same audiologist. therefore, identical stimulation and recording procedures were used for the measurements before and after stylet removal within and across subjects. the next day, an x-ray was taken for all patients to confirm intracochlear electrode insertion. all statistical analyses were done using sas (sas institute, inc., cary, nc, usa.). the results of t-tests having an alpha p value of 0.05 or less were considered statistically significant. results the patient population consisted of 16 males and 14 females ranging in age from 3 to 54 years (mean 11). for 14 patients, the ci was placed on the right and for 16 placed on the left [table 1]. all patients had full ci insertion. all quantitative variables (except age) were proven to follow the normal distribution. the kolmogrov test was used to test normality of data so the parametric paired t-test was used for comparison of data. the effects of changing electrode placement method from the stylet-in procedure (lateral wall table 2: comparison of the 30 subjects’ means and standard deviations of nrt with and without stylet mean difference 95% confidence interval lower upper pair 1 nrt3 with 9.59nrt3 without 0.40 -8.79 pair 2 nrt9 with 7.20nrt9 without 2.10 -3.00 pair 3 nrt13 with 8.71nrt13 without 4.87 1.02 pair 4 nrt17 with 10.83nrt17 without 5.00 -0.83 pair 5 nrt21 with 10.34nrt21 without 5.87 1.39 pair 6 nrt1 with 8.96nrt1 without 1.17 -6.63 pair 7 nrt6 with 9.71nrt6 without 3.07 -3.57 pair 8 nrt11 with 4.22nrt11 without 2.87 -9.95 pair 9 nrt16 with 6.50nrt16 without 3.27 0.04 pair 10 nrt22 with 9.02nrt22 without 5.20 1.38 pair 11 mean apical with 9.08 mean apical without 5.66 2.23 pair 12 mean middle with 4.84mean middle without 1.37 -2.10 pair 13 mean basal with 8.26 mean basal without 1.54 -5.17 abdulrahman hagr clinical and basic research | 373 cochlea) to the stylet-out procedure (medial wall cochlea) were characterised by comparing ar responses and nrts between the positions. table 2 shows the comparison of the 30 subjects’ means and standard deviations of nrt with and without stylet, while table 3 shows the threshold measures from nrt averaged across subjects for the lateral (with stylet) and medial (without stylet) placements for the apical, middle, and basal electrodes. standard deviations and p values are indicated for each electrode using t-tests. statistically significant differences were found in thresholds with medial placement for some electrodes (13, 16, 21, 22) using nrt, as indicated with asterisks [table 3]. however, when all subgroups are collapsed into apical, middle and basal categories, only the apical electrodes showed statistically significant differences in thresholds, as indicated with asterisks. the effect of perimodiolar electrode placement on neural responses was analysed across stimulation levels by cross tabulation of the ar responses for electrodes 1, 6, 11, 16 and 22, as shown in tables 4 to 8, respectively. this cross tabulation was performed for each electrode’s ar with and without the stylet. based on a t-test, there was no statistical difference between the ar results with or without the stylet across all tested electrodes. ar comparison (separately for electrode 1, 6, 11, 16 and 22) was carried out with 2 x 2 table and is presented showing odds ratio with 95% confidence in table 9. discussion in the current study, we used an efficient method to test the impact of modiolus-hugging on electrically evoked auditory thresholds in an acute intra-operative setting. this method combines intraoperative ar and nrt before and after stylet removal. the patient group studied in this analysis is very typical of the patient population at our large ci centre. because we do not yet have a neonatal screening programme for deafness, our patients usually present late. in this study, we used a single device (nucleus freedom®), which is the most common type of device used in our centre and worldwide. we expect other devices to be similar in their performance using modiolar hugging or lateral wall placement comparisons with the same stimulation parameters. there is no reported statistically significant difference among the three major manufacturers of electrodes (cochlear corporation, medel table 3: comparison of neural response telemetry (nrt) for each electrode with and without the stylet in place using p value mean standard deviation p value pair 1 nrt3 with 184.07 29.56 .930 nrt3 without 183.67 17.51 pair 2 nrt9 with 192.97 16.02 .407 nrt9 without 190.87 12.38 pair 3 nrt13 with 191.57 16.01 .015* nrt13 without 186.70 12.26 pair 4 nrt17 with 185.73 17.03 .090 nrt17 without 180.73 15.34 pair 5 nrt21 with 183.20 18.12 .012* nrt21 without 177.33 16.41 pair 6 nrt1 with 186.80 29.87 .762 nrt1 without 185.63 22.23 pair 7 nrt6 with 188.30 26.35 .353 nrt6 without 185.23 18.56 pair 8 nrt11 with 187.00 20.62 .415 nrt11 without 189.87 13.92 pair 9 nrt16 with 185.00 16.58 .048* nrt16 without 181.73 15.66 pair 10 nrt22 with 179.67 16.76 .009* nrt22 without 174.47 17.47 pair 11 mean apical with 184.23 15.59 .002* mean apical without 178.57 13.84 pair 12 mean middle with 190.51 14.48 .427 mean middle without 189.14 11.38 pair 13 mean basal with 186.39 25.55 .642mean basal without 184.84 17.69 note: *significant. table 4: acoustic reflex (ar) in electrode 1 with and without the stylet: cross tabulation ar1 with total no yes ar1 without no count 17 3 20 % of total 56.7 10.0 66.7 yes count 2 8 10 % of total 6.7 26.7 33.3 total count 19 11 30 % of total 63.3 36.7 100.0 note: p >0.05. intra-operative neural response telemetry and acoustic reflex assessment using an advance-in-stylet technique and modiolus-hugging a prospective cohort study 374 | squ medical journal, august 2011, volume 11, issue 3 table 5: acoustic reflex (ar) in electrode 6 with and without the stylet: cross tabulation ar6 with total no yes ar6 without no count 10 2 12 % of total 33.3 6.7 40.0 yes count 3 15 18 % of total 10.0 50.0 60.0 total count 13 17 30 % of total 43.3 56.7 100.0 note: p >0.05 and advanced bionics) with respect to inner ear trauma,12 modiolar wall contact,24,25 or facial nerve stimulation rates.26 our study did not show a major disadvantage of the ais technique. this procedure is actually easier to perform than removal of the stylet in the aos technique. we did not observe any complications in our patients as a result of leaving the stylet on during insertion of the electrode. this may lower the learning and implementation curves for this increasingly used surgery and aid in teaching trainees in ci insertion. moreover, the ais technique may be suitable for some difficult cases, such as cochlear fracture, re-insertion, and fibrosis of the inner ear, where the presence of the stylet may give extra rigidity to the implant and prevent early coiling of the tip. in addition, not removing the stylet allows preservation of the uncoiled implant for a second trial if there is difficulty or malplacement of the electrode. the nrt results only showed significant differences between the medial position (modiolar hugging) and the lateral position at the apical electrodes, which is consistent with other studies.18,27 this difference may be due to the larger diameter of the apical neurons,28 the greater density of surviving neural fibres in the cochlear apex, or both.29 removal of the stylet also results in a deeper insertion of the electrodes because the inner circle path around the modiolus is shorter than the outer circle path around the lateral wall, so the same electrode length is able to reach further. theoretically, this would lead to stimulation of a larger neural population along the apical electrodes. in this study, there was no significant difference between the ar thresholds in medial (modiolar hugging) and lateral positions at all location. however, mens et al.10 reported lower stapedius reflex thresholds in a modiolar hugging configuration. one point worth mentioning is that we usually turn the facial nerve monitor off after we finish the facial recess; therefore, stapedial reflexes secondary to direct facial nerve stimulation cannot be excluded completely. a limitation of this study is its inability to ensure that the implant was inserted completely into the scala tympani and that removal of the stylet table 6: acoustic reflex (ar) in electrode 11 with and without the stylet: cross tabulation ar11 with total no yes ar11 without no count 7 0 7 % of total 23.3 .0 23.3 yes count 3 20 23 % of total 10.0 66.7 76.7 total count 10 20 30 % of total 33.3 66.7 100.0 note: p >0.05 table 7: acoustic reflex in electrode 16 with and without the stylet: cross tabulation ar16 with total no yes ar16 without no count 10 0 10 % of total 33.3 .0 33.3 yes count 1 19 20 % of total 3.3 63.3 66.7 total count 11 19 30 % of total 36.7 63.3 100.0 note: p >0.05. table 8: acoustic reflex in electrode 22 with and without the stylet: cross tabulation ar22 with total no yes ar22 without no count 11 0 11 % of total 36.7 .0 36.7 yes count 2 17 19 % of total 6.7 56.7 63.3 total count 13 17 30 % of total 43.3 56.7 100.0 note: p >0.05. abdulrahman hagr clinical and basic research | 375 actually resulted in perimodiolar hugging because an electrode array that may penetrate the basilar membrane could become tethered by the osseous spiral lamina, preventing full coiling or close perimodiolar proximity. one legitimate concern is that it is possible that sequential stimulation between the two conditions may affect the recordings, as there may be fatigue of the ar or evoked compound potentials after repeated stimulation. this is more likely to be an issue with the ar than with the evoked potentials because, in our experience, intraoperative ar and nrt recordings are usually very stable. although this study only shows a significant difference in thresholds at apical regions with stylus removal, the psychoacoustic and perceptual consequences of this warrant further study, and our results need to be confirmed with longer term follow-up in cases where the stylet was or was not removed to assess the effects of scarring or damage to structures such as the basilar membrane and spiral ligament. conclusion according to the result of this study, removal of the stylet with the nucleus freedom® only results in a significant stimulation difference in the apical electrodes. we suggest this alternative technique in difficult cases and for new ci surgeons. a c k n o w l e d g m e n t s this research was financially supported by grants from the prince sultan research chair for hearing disability. the author thanks professor manohar bance for helpful comments on the manuscript. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. seidman md, vivek p, dickinson w. neural response telemetry results with the nucleus 24 contour in a perimodiolar position. otol neurotol 2005; 26:620– 3. 2. parkinson aj, arcaroli j, staller sj, arndt pl, cosgriff a, ebinger k. the nucleus 24 contour ci system: adult clinical trial results. ear hear 2002; 23:41–8. 3. saunders e, cohen l, aschendorff a, shapiro w, knight m, stecker m, et al. threshold, comfortable level and impedance changes as a function of electrode-modiolar distance. ear hear 2002; 23:28– 40. 4. blamey pj, pyman bc, gordon m, clark gm, brown am, dowell rc, et al. factors predicting postoperative sentence scores in postlinguistically deaf adult ci patients. ann otol rhinol laryngol 1992; 101:342–8. 5. battmer r, pesch j, stover t, lesinski-schiedat a, lenarz m, lenarz t. elimination of facial nerve stimulation by reimplantation in ci subjects. otol neurotol 2006; 27:918–22. 6. shepherd rk, hatsushika s, clark gm. electrical stimulation of the auditory nerve: the effect of electrode position on neural excitation. hear res 1993; 66:108–20. table 9: comparison of acoustic reflex in different electrodes electrode stylet yes no odds ratio 95% confidence interval lower upper 1 with 11 19 0.15 0.04 0.56 without 10 20 6 with 17 13 0.26 0.10 0.72 without 18 12 11 with 20 10 0.30 0.12 0.77 without 23 7 16 with 19 11 0.09 0.01 0.59 without 20 10 22 with 17 13 0.15 0.04 0.55 without 19 11 intra-operative neural response telemetry and acoustic reflex assessment using an advance-in-stylet technique and modiolus-hugging a prospective cohort study 376 | squ medical journal, august 2011, volume 11, issue 3 7. marsh rr, yamane h, potsic wp. effect of site of stimulation on the guinea pig’s electrically evoked brain stem response. otolaryngol head neck surg 1981; 89:125–30. 8. frijns jh, briaire jj, grote jj. the importance of human cochlear anatomy for the results of modiolushugging multichannel cochlear implants. otol neurotol 2001; 22:340–9. 9. eisen md, franck kh. electrically evoked compound action potential amplitude growth functions and hiresolution programming levels in pediatric cii implant subjects. ear hear 2004; 25:528–38. 10. mens lh, boyle pj, mulder jj. the clarion electrode positioner: approximation to the medial wall and current focussing? audiol neurootol 2003; 8:166–75. 11. shepherd rk, clark gm, pyman bc, webb rl. banded intracochlear electrode array: evaluation of insertion trauma in human temporal bones. ann otol rhinol laryngol 1985; 94:55–9. 12. eshraghi aa, yang nw, balkany tj. comparative study of cochlear damage with three perimodiolar electrode designs. laryngoscope 2003; 113:415–19. 13. linthicum fh, jr, galey fr. histologic evaluation of temporal bones with cochlear implants. ann otol rhinol laryngol 1983; 92:610–13. 14. marrinan ms, roland jt jr, reitzen sd, waltzman sb, cohen lt, cohen nl. degree of modiolar coiling, electrical thresholds, and speech perception after cochlear implantation. otol neurotol 2004; 25:290–4. 15. balkany tj, connell ss, hodges av, payne sl, telischi ff, eshraghi aa, et al. conservation of residual acoustic hearing after cochlear implantation. otol neurotol 2006; 27:1083–8. 16. hodges av, schloffman j, balkany t. conservation of residual hearing with cochlear implantation. am j otol 1997; 18:179–83. 17. fayad j, linthicum fh jr, otto sr, galey fr, house wf. cochlear implants: histopathologic findings related to performance in 16 human temporal bones. ann otol rhinol laryngol 1991; 100:807–11. 18. wackym pa, firszt jb, gaggl w, runge-samuelson cl, reeder rm, raulie jc. electrophysiologic effects of placing ci electrodes in a perimodiolar position in young children. laryngoscope 2004; 1141:71–6. 19. firszt jb, wackym pa, gaggl w, burg ls, reeder rm. electrically evoked auditory brain stem responses for lateral and medial placement of the clarion hifocus electrode. ear hear 2003; 24:184–90. 20. runge-samuelson c, firszt jb, gaggl w, wackym pa. electrically evoked auditory brainstem responses in adults and children: effects of lateral to medial placement of the nucleus 24 contour electrode array. otol neurotol 2009. 30:464–70. 21. pasanisi e, vincenti v, bacciu a, guida m, bacciu s. the nucleus contour electrode array: an electrophysiological study. laryngoscope 2002; 112:1653–6. 22. brown cj, hughes ml, luk b, abbas pj, wolaver a, gervais j. the relationship between eap and eabr thresholds and levels used to program the nucleus 24 speech processor: data from adults. ear hear 2000; 21:151–63. 23. abbas pj, brown cj, shallop jk, firszt jb, hughes ml, hong sh, et al. summary of results using the nucleus ci24m implant to record the electrically evoked compound action potential. ear hear 1999; 20:45–59. 24. balkany tj, eshraghi aa, yang n. modiolar proximity of three perimodiolar cochlear implant electrodes. acta otolaryngol 2002; 122:363–9. 25. gstoettner wk, adunka o, franz p, hamzavi j jr, plenk h jr, susani m, et al. perimodiolar electrodes in cochlear implant surgery. acta otolaryngol 2001; 121:216–19. 26. smullen jl, polak m, hodges av, payne sb, king je, iii, telischi ff, et al. facial nerve stimulation after cochlear implantation. laryngoscope 2005; 115:977–82. 27. tsuji rk, goffi-gomez mv, peralta co, guedes mc, magalhaes at, neto rb, et al. neural response thresholds in the nucleus contour cochlear implant before and after stylet removal. acta otolaryngol 2009; 129:1330–6. 28. tavartkiladze ga, potalova la, kruglov av, belov a. effect of stimulation parameters on electrically evoked auditory brainstem responses. acta otolaryngol 2000; 120:214–17. 29. shallop jk, beiter al, goin dw, mischke re. electrically evoked auditory brain stem responses (eabr) and middle latency responses (emlr) obtained from patients with the nucleus multichannel cochlear implant. ear hear 1990; 11:5–15. departments of 1pediatrics and 3pathology, chacha nehru bal chikitsalya, new delhi, india; 2department of pediatrics, sitaram bhartia institute of science and research, new delhi, india *corresponding author e-mail: dramit_amy@yahoo.co.in اإلستجابة املتأخرة للعالج يف طفل حديث الوالدة مصاب مبرض الجنرهانز هيستيوسيتوزيس تقرير حالة ومراجعة الألدبيات اأميتاب �سينغ، اأنريبان ماندال، الفلني �سينغ، �ساتاروبا مي�رشا، اأنكيتا باتيل abstract: langerhans cell histiocytosis (lch) is a rare proliferative disorder of the langerhans cells, which are part of the mononuclear phagocytic system. the disorder varies in terms of the extent of the disease, its natural course and patient outcomes. while skin rashes are a common presentation of neonatal lch, other systems or organs may also be involved. delays in the diagnosis of neonatal lch may occur due to its non-specific presentation and a lack of awareness of the condition among doctors. we report a two-month-old male neonate who presented to the chacha nehru bal chikitsalya hospital, new delhi, india, in 2016 after the onset of pulmonary symptoms. he had been noted to have a generalised rash which had progressively worsened from 15 days of age. following a skin biopsy and chest imaging, he was diagnosed with multisystem lch with risk organ involvement. there was a delayed response to combined chemotherapy with no major side-effects. keywords: langerhans cell histiocytosis; seborrheic dermatitis; tachypnea; anemia; infant; case report; india. وحيدات البلعمة نظام من جزء هي والتي الجنرهانز، خلاليا نادر تكاثري ا�سطراب هو هي�ستيو�سيتوزي�س الجنرهانز مر�س امللخ�ص: النوى. ويختلف املر�س من حيث مدى انت�ساره، وتدرجه الطبيعي ونتائج املر�سى. و يف حني اأن الطفح اجللدي هو عر�س �سائع للمر�س يف حديثي الوالدة، ميكن اأي�سا اأن ت�سمل اأعرا�س املر�س اأع�ساء اأو اأجهزة اأخرى. قد يحدث تاأخرييف ت�سخي�س املر�س يف حديثي الوالدة ب�سبب بدايته باأعرا�س غري حمددة واأي�سا عدم وجود الوعي الكايف باملر�س واأعرا�سه بني االأطباء. هذا تقرير حالة لذكرحديث الوالدة يبلغ �سهرين من العمر قدم اإىل م�ست�سفى ت�سات�سا نهرو بال �سيكيت�سااليا، نيودلهي، الهند، يف عام 2016 بعد ظهور االأعرا�س الرئوية عليه. وقد لوحظ عليه اأي�سا طفح جلدي عام، تفاقم تدريجيا من 15 يوما من العمر. وقد مت اأحذ خزعة من اجللد والت�سوير ال�سدري، مت ت�سخي�سه الكيميائي للعالج متاأخرة ا�ستجابة هناك كانت املختلفة. اجل�سم اأع�ساء ا�سابة خطر وجود مع هي�ستيو�سيتوزي�س الجنرهانز مبر�س املركب مع عدم حدوث اأي اآثار جانبية كبرية. الكلمات املفتاحية: مر�س الجنرهانز هي�ستيو�سيتوزي�س؛ التهاب اجللد الدهني؛ ت�سارع النف�س؛ فقر الدم؛ ر�سيع؛ تقريرحالة؛ الهند. delayed treatment response in a neonate with multisystem langerhans cell histiocytosis case report and review of literature *amitabh singh,1 anirban mandal,2 lavleen singh,3 sataroopa mishra,1 ankita patel1 sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e225–228, epub. 20 jun 17 submitted 16 jan 17 revision req. 7 feb 17; revision recd. 13 feb 17 accepted 2 mar 17 case report doi: 10.18295/squmj.2016.17.02.016 langerhans cell histiocytosis (lch) is a very rare disease resulting from the clonal proliferation of langerhans cells in the mononuclear phagocytic system.1 the disorder can occur at any age and may be either completely benign and self-resolving or fatal and refractory. clinically, the presentation varies depending on whether the patient has single-system (i.e. involvement of only one organ or system) or multisystem (i.e. involvement of two or more organs or systems) lch.1 the involvement of the liver, spleen, bone marrow or lungs is classified as risk organ (ro) involvement, as this may adversely affect patient outcomes.2 neonatal lch is believed to be under-reported with an incidence of slightly over 1 per million newborns.3 nearly all cases present within the first four weeks of life, most commonly with singlesystem lch with spontaneous remission (also known as hashimoto-pritzker disease or congenital selfhealing lch).4 however, a thorough investigation of most single-system neonatal lch cases will show involvement other sites; moreover, multisystem lch in neonates has a less favourable prognosis compared to those of other age groups.3 similarly to older children, the optimal treatment option for infants with lch is combination chemotherapy as per the 2009 histiocyte society guidelines for lch evaluation and treatment.2 this report describes a case of neonatal multisystem lch with ro involvement treated successfully with combined chemotherapy as per the 2009 histiocyte society guidelines.2 delayed treatment response in a neonate with multisystem langerhans cell histiocytosis case report and review of literature e226 | squ medical journal, may 2017, volume 17, issue 2 case report a two-month old male neonate presented to the chacha nehru bal chikitsalya hospital, new delhi, india, in 2016 with tachypnoea over the past seven days and a progressive generalised rash of one and a half months’ duration. the baby was the first child of nonconsanguineous healthy parents. the antenatal course had been uneventful and he was born at term via normal vaginal delivery. at birth, he weighed 3.4 kg with no adverse perinatal events. the neonate was breastfed exclusively. shortly after birth, the mother noted a rash on the infant’s scalp which rapidly spread over the whole body over the next 15 days. initially, the baby was treated for cradle cap after consultation with a paediatrician; however, as the skin lesions increased, he was referred to a dermatologist who diagnosed him with extensive seborrhoeic dermatitis. topical medications were prescribed but were ineffective. there was no medical history of fever, coughing, lethargy, poor feeding, cyanosis, jaundice, abdominal distention, vomiting, loose stools, seizures or bleeding. however, there was a history of ear discharge and increased urine output. at presentation, the child had tachypnoea and mild chest retractions but maintained normal oxygenation in room air. there were extensive papulonodular lesions with crusting over his whole body, although the mucosal surfaces were unaffected [figure 1a]. there was no evidence of pallor, icterus or lymphadenopathy. a systemic examination revealed hepatomegaly and fine crepitations in both sides of the chest. blood test results revealed mild microcytic hypochromic anaemia and hepatitis [table 1]. a peripheral smear showed microcytic hypochromic red blood cells with anisopoikilocytosis and no abnormal cells. bilateral diffuse lung parenchymal opacities with cysts were observed on a chest x-ray, with computed tomography (ct) confirming the presence of diffuse cystic lesions in both lungs [figure 2]. an ultrasound of the liver indicated a heterogeneous echotexture with peri-portal echogenicity. a skin biopsy revealed figure 1: photographs of a two-month-old male neonate (a) at presentation, with extensive papulonodular lesions and crusting over the whole body and a seborrhoea-like rash over the scalp, (b) after six weeks of chemotherapy, with limited resolution of the lesions and hypopigmented macules, and (c) after six months of therapy, with very few remaining hyperpigmented lesions and fine scaling. table 1: blood investigation results of a two-monthold male neonate with pulmonary symptoms and a generalised whole-body rash investigation result hb in gm/dl 10.5 wbc per mm3 10,600 neutrophils in % 76 lymphocytes in % 19 monocytes in % 4 eosinophils in % 1 platelet count per mm3 301 x 103 total bilirubin in g/dl 0.9 conjugated bilirubin in g/dl 0.4 ast in u/l 115 alt in u/l 213 total protein in g/dl 5.9 albumin in g/dl 3.5 alp in u/l 81 ggt in u/l 115 urea in mg/dl 28 creatinine in mg/dl 0.3 hb = haemoglobin; wbc = total leukocyte count; ast = aspartate transaminase; alt = alanine transaminase; alp = alkaline phosphatase; ggt = gamma glutamyl transferase. amitabh singh, anirban mandal, lavleen singh, sataroopa mishra and ankita patel online case report | e227 discussion the differential diagnosis of a neonatal skin rash includes congenital infections (e.g. cytomegalovirus, rubella, toxoplasma, herpes simplex virus or syphilis infections), seborrhoeic dermatitis, lch, disseminated candidiasis, neonatal varicella, neonatal pustular melanosis and mastocytosis.1,5 this report describes a case of neonatal multisystem lch with ro involvement which was initially misdiagnosed as seborrhoeic dermatitis and only accurately diagnosed following the onset of pulmonary symptoms. although the presentation in this case was similar to other cases described in the literature, there was a delay of approximately one and a half months before the correct diagnosis was established.3,4 according to data from a european lch study group, only 32.7% of neonatal lch cases were diagnosed during the neonatal period.3 in an american cohort, the mean age at diagnosis was three and a half months for neonatal lch cases, with initial misdiagnoses often including psoriasis and chronic dermatitis.6 as the type and characteristics of skin lesions in neonatal lch are not predictive of the extent of disease involvement, a thorough multiorgan evaluation is indicated for all patients.6,7 data from a european lch study group indicated that most neonatal lch cases had multisystem involvement (59%), with skin lesions being the most common initial presentation; in addition, 5.5% of multisystem cases had dyspnoea.3 as such, dyspnoea secondary to lung involvement could indicate an advanced disease state, as seen in the present case. park et al. reported that skin lesions were also the most common initial presentation among six neonatal lch cases in korea (83.3%).7 in a case series of 19 neonatal lch patients with dermatological presentations in the usa, stein et al. noted that 68% were male and 63% had multisystem involvement.6 the most common skin lesions observed were erythematous vesicopustules infiltration by langerhans cells with cluster of differentiation (cd) 1a positivity, confirming the diagnosis of lch [figure 3]. a skeletal survey, bone marrow examination and brain magnetic resonance imaging ruled out any skeletal, bone marrow or central nervous system involvement. following the diagnosis, the neonate was treated with daily prednisolone and weekly vinblastine at modified doses as per the 2009 histiocyte society guidelines.2 however, although the lesions began to atrophy and depigment after six weeks, new lesions began to appear, some of which were deeply ulcerated [figure 1b]. due to worsening dyspnoea, the child was admitted to hospital as an inpatient for monitoring. as he had demonstrated an incomplete response to the initial treatment, prednisolone and vinblastine were continued for another six weeks. following this, positron emission tomography/computed tomography indicated that the disease was non-active [figure 4]; as such, continuation therapy was initiated. at the time of writing, after a total of six months of therapy, the child was asymptomatic and appeared to be thriving. the pneumatoceles had disappeared completely, with only a few hyperpigmented skin lesions remaining [figure 1c]. as per the 2009 histiocyte society guidelines, another 12 months of treatment were subsequently planned.2 figure 3: a: haematoxylin and eosin (h&e) stain of a punch biopsy at x200 magnification showing diffuse replacement of the superficial dermis by enlarged mononuclear cells (arrow). b: h&e stain at x400 magnification showing mononuclear cells with abundant eosinophilic cytoplasm and kidney-shaped grooved folded nuclei (arrow) and fine vesicular chromatin and inconspicuous nucleoli. c: immunohistochemistry stain at x400 magnification showing neoplastic langerhans cells immunopositive for cluster of differentiation 1a (arrow). figure 2: a: chest x-ray of a two-month-old male neonate with pulmonary symptoms and a generalised whole-body rash showing bilateral diffuse lung parenchymal opacities with cysts. b: computed tomography in the chest axial view showing cysts of variable sizes involving both lungs. delayed treatment response in a neonate with multisystem langerhans cell histiocytosis case report and review of literature e228 | squ medical journal, may 2017, volume 17, issue 2 (53%), often with crusting, followed by eczematous scaling lesions in a seborrhoea-like distribution (37%) and oral mucosal lesions (20%).6 in contrast, the present patient had a seborrhoea-like skin rash without any mucosal involvement. an accurate diagnosis of lch requires either a histopathological examination of the involved tissue to demonstrate the presence of pathognomonic cd1aand/or cd207-positive langerhans cells or an electron microscopy study to identify birbeck granules.1 however, a recent case report by kumar et al. suggests that fine-needle aspiration cytology may also be effective in diagnosing lch, alleviating the need for an invasive biopsy.8 lung involvement in lch has a variable appearance on chest ct scans, ranging from small peribronchiolar nodular opacities to multiple irregularly-shaped cysts.1 in the current case, the ct findings were pathognomonic, showing cysts of variable size in both lungs. while a few cases of multisystem lch have been reported to resolve spontaneously, this is very rare; only 8% of multisystem lch cases reported by the european lch study group, all without ro involvement, experienced complete resolution without systemic therapy and the five-year survival rate for multisystem lch cases was 57%.3 among the six korean neonatal lch cases, the probability of survival at 12 years was 50%.7 in an american cohort, survival was 16% with a variable follow-up period.6 combination chemotherapy is the first line of treatment for lch cases.2 the reactivation rate falls from 54% to 37% after treatment is prolonged from six to 12 months.9 however, patients frequently develop various diseaseand treatment-related complications, including diabetes insipidus, hearing impairments and liver fibrosis; as such, it is recommended that all patients be monitored for at least five years after the end of therapy for related complications and disease recurrence.1 conclusion this report describes a case of neonatal multisystem lch with ro involvement. in order to avoid a delayed diagnosis of neonatal lch, paediatricians should become more familiar with this rare disorder. in addition, a thorough multiorgan evaluation is warranted in all cases of neonatal lch with cutaneous presentations in order to rule out ro involvement. use of the 2009 histiocyte society guidelines is recommended for the successful management of infants with lch. references 1. haupt r, minkov m, astigarraga i, schäfer e, nanduri v, jubran r, et al. langerhans cell histiocytosis (lch): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. pediatr blood cancer 2013; 60:175–84. doi: 10.1002/pbc.24367. 2. histiocyte society. histiocyte society evaluation and treatment guidelines: april 2009. from: www.histiocytesociety.org/docu ment.doc?id=290 accessed: feb 2017. 3. minkov m, prosch h, steiner m, grois n, pötschger u, kaatsch p, et al. langerhans cell histiocytosis in neonates. pediatr blood cancer 2005; 45:802–7. doi: 10.1002/pbc.20362. 4. aggarwal v, seth a, jain m, krishnamurthy s, chandra v, aneja s. congenital langerhans cell histiocytosis with skin and lung involvement: spontaneous regression. indian j pediatr 2010; 77:811–12. doi: 10.1007/s12098-010-0104-3. 5. nunley ks, crone k, bayliss sj, vachharajani a. newborn who has a diffuse rash. neoreviews 2007; 8:e448–51. doi: 10.1542/ neo.8-10-e448. 6. stein sl, paller as, haut pr, mancini aj. langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series. arch pediatr adolesc med 2001; 155:778–83. doi: 10.1001/archpedi.155.7.778. 7. park yr, yeo ms, kim sy, kim hj, koh kn, im hj, et al. langerhans cell histiocytosis diagnosed at the neonatal period. clin pediatr hematol oncol 2011; 18:92–6. 8. kumar n, sayed s, vinayak s. diagnosis of langerhans cell histiocytosis on fine needle aspiration cytology: a case report and review of the cytology literature. patholog res int 2011; 2011:439518. doi: 10.4061/2011/439518. 9. gadner h, minkov m, grois n, pötschger u, thiem e, aricò m, et al. therapy prolongation improves outcome in multisystem langerhans cell histiocytosis. blood 2013; 121:5006–14. doi: 10.1182/blood-2012-09-455774. figure 4: positron emission tomography/computed tomography showing no metabolically active disease in a twomonth-old male neonate presenting with pulmonary symptoms and a generalised whole-body rash following 12 weeks of treatment for multisystem langerhans cell histiocytosis. https://doi.org/10.1002/pbc.24367 https://doi.org/10.1002/pbc.20362 https://doi.org/10.1007/s12098-010-0104-3 https://doi.org/10.1542/neo.8-10-e448 https://doi.org/10.1542/neo.8-10-e448 https://doi.org/10.1001/archpedi.155.7.778 https://doi.org/10.4061/2011/439518 https://doi.org/10.1182/blood-2012-09-455774 cystinosis is a lysosomal storage disease that is inherited in an autosomal recessive manner. cystinosis, which is a lysosomal transport molecule needed to carry cystine out of the cells, is defective in this disease. this leads to the intracellular accumulation of the amino acid cystine in different organ tissues leading to multiple organ damage with subsequent failure. infantile cystinosis is the most severe form. infants appear normal at birth, but soon they fail to thrive and develop renal fanconi syndrome, due to accumulation of cystine in the proximal tubules. cystinosis is the most common cause of inherited fanconi syndrome amongst caucasians. this condition is frequently reported in the caucasian population, but has never been reported in oman. in this report, we describe the first case of infantile nephropathic cystinosis in oman. here, we will describe the clinical features, mainly renal and ophthalmological, and include a literature review of cystinosis in the middle east. case report a 21 month-old omani girl was referred to sultan qaboos university hospital for evaluation of severe failure to thrive. this was the second child born to first degree consanguineous parents at full term by spontaneous vaginal delivery. her birth weight was 2.8 kg. according to the parents she was doing well until the age of 7 months, when she was noted by the primary care physician to be below the 3rd centile for both weight and height. at that point, it was felt that the failure to thrive was nutritional, since her mother gave history of exclusive breast feeding until the age of 7 months. despite the nutritional advice and nutritional support for several months, the child did not gain weight and was referred to the department of child health at sultan qaboos university hospital at the age of 21 months with a weight of 5.36 kgs. the mother gave a history of polyuria, which was suggested by the fact that she had 10 wet diapers per day, polydipsia and squ med j, november 2011, vol. 1, iss. 4, pp. 503-506, epub. 25th oct 11 submitted 1st apr 11 revision req. 11th jun 11, revision recd. 11th jul & 26th sep 11 accepted 28th sep 11 departments of 1child health and 2opthalmology, sultan qaboos university hospital, muscat, oman. *corresponding author email: mnaggari@squ.edu.om يْستينيُِّ الكلوي الدَّاُء السيِ تسجيل احلالة األوىل يف ُعمان دانا النبهاين، حممد النجاري، رنا ال�ضناوي، الك�ضندر ت�ضاكو، اأنورادها غاني�س، ابت�ضام النور تتميز التي احَلالَّة اجُل�َضيرَْمات يف ِتزاِن الخرْ داُء وهو املتنحية، اجل�ضدية ال�ضبغية ال�ضطرابات من الكلوي ال�ضي�ضتيني الداء ُيعد امللخ�ص: برتاكم احلم�س الأميني )�ضي�ضتني( يف خمتلف الأجهزة والأن�ضجة. وميكن اأن يظهر الداء على �ضكل اأعرا�س كلوية اأوغريها. هناك ثلثة اأنواع من الداء ال�ضي�ضتيني ويكون الداء ال�ضي�ضتيني الكلوي الوليدي هو ال�ضكل الأكرث �ضدة. نقدم يف هذا التقرير امللمح ال�رسيرية املعهودة من الداء ال�ضي�ضتيني الكلوي يف طفل ُعماين. ُتَعّد هذه احلالة نادرة جدا يف منطقة ال�رسق الأو�ضط، وهي احلالة الوىل التي مت و�ضفها يف ُعمان. ِتزاِن يف اجُل�َضيرَْمات احلاّلة، �ضي�ضتيامن، بلورات، تقرير حالة، ُعمان. مفتاح الكلمات: الداء ال�ضي�ضتيني، متلزمة فانكوين، داُء الخرْ abstract: cystinosis is an autosomal recessive, lysosomal storage disease characterised by the accumulation of the amino acid cystine in different organs and tissues. it is a multisystemic disease that can present with renal and extra renal manifestations. there are three types of cystinosis, infantile nephropathic cystinosis being the most severe form. in this report we present the classic clinical features of nephropathic cystinosis in an omani child. this condition remains quite rare in the middle east and is the first reported case of nephropathic cystinosis in the omani population. keywords: cystinosis; fanconi syndrome; lysosomal storage disease; cysteamine; crystals; case report; oman. nephropathic cystinosis first reported case in oman dana al-nabhani,1 *mohammed el-naggari,1 rana al-sinawi,1 alexander p. chacko,1 anuradha ganesh,2 ibtisam el nour1 case report nephropathic cystinosis first reported case in oman 504 | squ medical journal, november 2011, volume 11, issue 4 constipation since the age of 18 months. she had a voracious appetite. developmentally, she was able to sit without support; however, she needed support for standing and walking. she had appropriate social development for her age. the family history was negative for similar conditions and for any renal or metabolic diseases. also there was no history of miscarriages. on physical examination, the child was dark skinned, identical to her parents’ skin complexion. her growth parameters were as follows: height 66 cm, weight 5.36 kg, which are both below the 5th percentile; the head circumference was 45.5 cm which was normal for her age. she did not have any dysmorphic features. she had frontal bossing and sparse, thin hair. she also had wide wrists, rachitic rosary, double malleoli and genu valgum. the abdomen was protuberant without organomegaly. the cardiovascular and respiratory examinations were normal. the initial blood investigations are summarised in table 1. urinalysis was positive for glucose (+2) and protein (+1) .the urine ph was 5, the specific gravity was 1.010 and the urine anion gap was positive. urine reducing substances were negative. urinary amino acid tests were done and showed significant elevation of all measured amino acids with the exception of aspartic acid, methionine, 1-methylhistidine, and turine. an indirect clue of this was the significantly elevated protein to creatinine ratio 106 mg/mmol (normal <50 mg/mmol) with mild proteinuria in the dipstick. the tubular reabsorption of phosphate was 55% (normal > 85%). a wrist x-ray was obtained in view of the physical findings. this showed reduced bone density, widened metaphysis of the ulna and radius with cupping and fraying. no carpal bones were noted and the bone age was delayed [figure 1]. an abdominal ultrasound was also obtained and this showed normal intra-abdominal organs including two normal kidneys. she also underwent an ophthalmic examination that revealed normal visual acuity in both eyes. no strabismus, nystagmus or ocular motility disturbance was noted. however, slit lamp examination of the anterior segment of both eyes revealed fine, shiny crystal-like deposits diffusely distributed in the corneal epithelium and stroma. the surface of the epithelium was intact and the rest of the examination was unremarkable. the fundus examination showed no abnormal morphology of the disc, macula and vessels and a normal retinal background. with the presence of failure to thrive in a child with renal tubular acidosis and features of fanconi syndrome, the ophthalmic findings of crystals in the cornea led to the diagnosis of cystinosis [figure 2]. retinopathy is usually a late finding of this condition and not seen in early childhood; it is preceded by corneal crystals. the child was started on supportive treatment table 1: results of the initial blood investigations test patient result reference range sodium 132 mmol/l 135–145 mmol/l potassium 3.1 mmol/l 3.5–6.1 mmol/l chloride 105 mmol/l 98–107 mmol/l bicarbonate 17 mmol/l 22–29 mmol/l creatinine 16 umol/l 15–31 umol/l urea 1.6 mmol/l 2.1–7.1 mmol/l anion gap 10 mmol/l 5–13 mmol/l total calcium 2.42 mmol/l 2.17–2.55 mmol/l corrected calcium 0.64 mmol/l 2.1–2.55 mmol/l phosphate 0.58 mmol/l 1.16–2.10 mmol/l alkaline phosphatase 841 units/l 0–281 units/l albumin 46 g/l 38–54 g/l parathyroid hormone 2.1 pmol/l 1.6–9.3 pmol/l 25-oh vitamin d 55 nmol/l 22.5– 93.8 nmol/l 1,25 vitamin d 45 pmol/l 40–140 pmol/l figure 1: patient’s wrist x-ray showing reduced bone density, widened metaphysis of the ulna and radius with cupping and fraying. dana al-nabhani, mohammed el-naggari, rana al-sinawi, alexander p. chacko, anuradha ganesh and ibtisam el nour case report | 505 which included potassium citrate to correct the metabolic acidosis and hypokalemia, calcium sandoz, phosphate sandoz and alfacaclidol. calcium was given for the severe hypocalcaemia. also phosphate supplements were indicated due to severe hypophosphatemia. to avoid the risk of precipitation, a gap of at least four hours was left between each dose of the supplements. with this supportive treatment her weight increased to 7.2 kg and she was able to progress on her motor development milestones. cysteamine, which is a cystine depleting agent and the mainstay treatment for this disease, had to be ordered since it had never been used before in oman. she was started on cysteamine 50 mg orally every 6 hrs (30 mg/kg/day) as soon as the medication was available. the aim was to increase the dose slowly to reach 50 mg/kg/ day over 4-6 weeks. discussion there are different types of cystinosis: the nephropathic and non-nephropathic. the nephropathic type has renal and extra renal manifestations. this can present in an infantile or late onset form. the infantile form is the most severe and, if left untreated, can lead to end stage renal disease by late childhood. the nonnephropathic type presents with photophobia and only corneal cystine crystals without renal or systemic involvement. this type is also called ocular cystinosis. children with the infantile form appear normal at birth. the clinical picture becomes apparent between 3 and 6 months of age. the most common renal manifestation is the renal fanconi syndrome due to renal proximal tubular dysfunction. this classically presents with failure to thrive, polyuria up to 2-3 litres/day, polydipsia, constipation, dehydration, weakness and hypophosphatemic rickets. patients will also have glucosuria, proteinuria, phosphaturia, aminoaciduria and metabolic acidosis. our patient presented at the age of 7 months with failure to thrive and had the classic features of renal fanconi syndrome such as polyuria, polydipsia and constipation. she also had signs of rickets clinically, biochemically and radiologically. the laboratory investigations were also classic for renal fanconi syndrome: normal anion gap, metabolic acidosis with hypokalemia and hypophosphatemia. she also had evidence of renal wasting of glucose which was suggested by normal serum glucose and a positive dipstick for glucose. the protein to creatinine ratio was quite elevated despite normal albumin and minimal proteinuria on dipstick. this suggests that the proteins lost are low molecular weight amino acids rather than the albumin which is a large molecular weight protein. she also had evidence of renal phosphate wasting suggested by hypophosphatemia and low tubular reabsorption of phosphate which was 55% (less than 85% indicates renal wasting). the other manifestations of nephropathic cystinosis are extrarenal and present later on. these include myopathy and dysphagia due to accumulation of cystine in the muscles, endocrine involvement such as hypothyroidism and diabetes mellitus, hepatomegaly, hypersplenism and photophobia from the corneal accumulation of cystine in the cornea. fundoscopy may show depigmentaion of the retina. retinal changes may appear before the corneal features. the corneal crystals require slit lamp examination. these crystals are not present at birth; they appear between 16 and 20 months of age,1,2 the corneal crystals are virtually pathognomonic. however, their absence does not exclude the diagnosis of cystinosis. our patient had the typical crystal deposits in the cornea as seen in figure 2. nephropathic cystinosis is the most common cause of renal fanconi syndrome in the caucasian population. this disease is quite rare in the middle east. only three middle eastern countries, egypt, figure 2: photo of patient’s eye showing crystal deposits in the cornea typical of cystinosis. nephropathic cystinosis first reported case in oman 506 | squ medical journal, november 2011, volume 11, issue 4 saudi arabia and iran, have reported this disease in their populations.3-5 these studies have provided a lot of important information on nephropathic cystinosis in the region. soliman et al., in the egyptian study, were able to identify 16 patients with nephropathic cystinosis out of 33 who presented with fanconi syndrome to a single centre.3 the saudi study, by aldahmesh et al., identified 8 mutations, 4 of which were novel, in 21 patients with nephropathic cystinosis of arab origin.5 the iranian study by mirdehghan et al. described the clinical features of patients with nephropathic cystinosis presenting over a five year period to a single centre.4 the diagnosis of nephropathic cystinosis in this case was based on the presence of corneal cystine crystals in an infant with fanconi syndrome. traditionally, white blood cell cystine assay was the test of choice to confirm the diagnosis. this test is not available in oman and it is costly and technically difficult to perform; there are only a few laboratories worldwide that can perform it. currently, genetic testing by mutation analysis of the ctns gene is a better alternative to confirm the diagnosis. it is necessary to consider sending samples to a specialised laboratory in case the diagnosis of nephropathic cystinosis is suspected in an infant younger than 20 months where the cystine crystals might not be present. early treatment with cysteamine which is a cystine depleting agent can delay the progression to end stage renal disease. conclusion given the high consanguinity rate in the omani population, nephropathic cystinosis should be considered in any child presenting with fanconi syndrome. immediate referral to a tertiary hospital with nephrology and ophthalmology services is important to avoid delay in treatment. references 1. gahl wa, thoene jg, schneider ja. cystinosis. n engl j med 2002; 347:111–21. 2. nesterova g, gahl w. nephropathic cystinosis: late complications of a multisystemic disease. pediatr nephrol 2008; 23:863–78. 3. soliman na, el baroudy r, rizk a, bazaraa h, younan a. nephropathic cystinosis in children: an overlooked disease. saudi j kidney dis transpl 2009; 20:436–42. 4. mirdehghan m, ahmadzadeh a, bana-behbahani m, motlagh i, chomali b. infantil cystinosis. indian pediatr 2003; 40:21–4. 5. aldahmesh ma, humeidan a, almojalli ha, khan ao, rajab m, al-abbad aa, et al. characterization of ctns mutations in arab patients with cystinosis. ophthalmic genet 2009; 30:185–9. sultan qaboos university med j, february 2014, vol. 14, iss. 1, pp. e37-41, epub. 27th jan 14 submitted 27th oct 13 peer-reviewed accepted 18th nov 13 how did a country physician in 19th century europe emerge as an icon in the world of medicine for all times to come? what inspires and motivates a discoverer to achieve what many observed and debated before him but were unable to achieve? what sweat and toil culminate in irrefutable evidence that peers accept and generations follow, expand and investigate? is a landmark discovery, invention or innovation merely an idea whose time has come? the succeeding paragraphs illustrate how one man’s life and times provide an answer to these complex questions and forever relegate the pre-koch era of tuberculosis (tb) to antiquity.3 born heinrich hermann robert koch, in 1843, this prussian physician’s abbreviated name ‘robert koch’ became a byword in infectious diseases practice, for having identified the bacillary aetiology of tb, the 19th century scourge.4 the enormous public health impact of this discovery on a disease that, at the time, claimed the lives of humans in epidemic proportions, overshadowed his first contribution to the field of bacteriology: the identification of the bacillus anthracis. the juggernaut of bacterial discoveries continued with the identification of the staphylococcus species (wound infections) and the vibrio cholerae bacterium (cholera).5 the pied piper of bacteriology the date of friday 24th march 1882 became a milestone in medical microbiology when koch’s brilliant exposition of his findings on tb was witnessed, in the reading room of the library of the institute of physiology at 7pm, by the dazzled fraternity of the berlin physiological society.4 he explained and illustrated all the scientific evidence, which his laboratory and animal experiments had yielded for the identification and isolation of the tubercle bacillus and demonstrated its transmissible nature and how it caused tb in man. four seminal papers followed that stamped his mark on his discovery.6 this new concept of an exogenous agent initiating disease challenged and department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ritu@squ.edu.om إرث روبرت كوخ تكّهن، إحبث، أثبت ريتو لكتاكيا medical history the legacy of robert koch surmise, search, substantiate ritu lakhtakia seldom has an investigator been able to comprehend in advance with such clear-sightedness a new, unbroken field of investigation, and seldom has someone succeeded in working on it with the brilliance and success with which robert koch has done. seldom have so many discoveries of such decisive significance to humanity stemmed from the activity of a single man, as is the case with him.1 nobel prize for medicine or physiology, presentation speech, professor the count k.a.h. mörner, rector of the royal caroline institute (karolinska institute), stockholm, sweden, 10th december 1905.2 robert koch (1843–1910)1 the legacy of robert koch surmise, search, substantiate e38 | squ medical journal, february 2014, volume 14, issue 1 decimated the prevailing concept (spearheaded by luminaries like virchow) that all diseases were endogenous in origin.7 koch’s labour of love, that unveiled the anthrax and tubercle bacilli, was to spawn a generation of ‘microbe hunters’ who rapidly identified and linked specific bacteria to the diseases they caused. in 1884, koch’s assistant, loeffler, and his pupil, kaffky, identified the diphtheria and typhoid bacillus, respectively.8 in a span of thirty years, beginning from 1876, at least 20 bacterial pathogens were identified for a host of diseases including gonorrhoea, tetanus, pneumonia and the plague—all killers of those times.5 ehrlich modified koch’s staining techniques and gram, ziehl and neelsen found their names embedded in laboratory manuals through the stains they developed which we still use today. it deserves mention that koch, a prolific explorer and intrepid traveller, dabbled in the investigation of a variety of tropical illnesses, like the plague, dysentery, trachoma, typhus and a host of veterinary infections. the pied piper’s tune (translated here as koch’s ‘style’ of research) was thus not a call to doom but heralded the light of knowledge and life for humankind. the blueprint for identifying infectious pathogens had been developed and treatment was just a few steps away. to see what everyone has seen; to think what no one has thought the foundation of koch’s principles lay in the scientific legacy koch inherited from his teachers henle, meissner, wohler and krause at the university of göttingen.9,10 pasteur’s contribution to wound sepsis and lister’s disinfection techniques had already made inroads in the warfare against germs. villemin, cohnheim and others had encouraged acceptance of the communicability of infection.11 early in his pursuit for recognition of the anthrax germ, koch sought the technical patronage of cohn, a botanist. cohn’s encouragement enabled publication of their joint drawings of the anthrax bacillus when koch was only 32 years old.12 koch however, built upon their achievements and stole a march on his mentors and collaborators by his elegant animal experiments and ingenious culture techniques that were verifiable and reproducible. they resulted in the eponymous henle-koch’s postulates that stipulated that an organism could be considered the cause of an infectious disease if: (1) it occurred in every case of the disease; (2) it did not occur in other diseases or non-pathogenic conditions, and (3) after isolation and growth in culture, it could produce the same disease when inoculated into a healthy animal.13 a technologist par excellence in vivo and in vitro innoculations in the cornea and aqueous humour; establishing superiority of solidover liquid-based media for obtaining pure cultures; microscopy and illumination methods; the fixation of bacterial smears on slides, and a host of stains that made it easy to identify bacteria (the alkaline methylene blue solution stained tubercular bacteria that contrasted with the background tissue stained with the vesuvin brown dye) are some of the significant ‘bench’ methods which koch toiled to produce [figure 1].7 these became the bedrock methods of modern bacteriological laboratories. it is noteworthy that his co-workers, hesse and petri, were responsible for the establishment of agar as a vital base for solid media and the shallow ‘petri’ dish, respectively.5 koch’s comprehensive approach to the scientific method is illustrated by his integration of these exacting techniques with animal innoculations and, in the case of cholera, with autopsies.14 koch is also credited with replacing pencil drawings by microphotography as an established tool for scientific documentation and figure 1: original drawing by koch of tubercle bacilli within infected tissue which accompanied his groundbreaking report on the aetiology of tuberculosis.7 figure reproduced with permission. ritu lakhtakia editorial | e39 robert koch institute in his honour. the million marks provided by the banker bleichroeder to transform the erstwhile government house into this institute is a telling comment on the relevance of financial patronage for science and research.4 the nobel prize for medicine and physiology, bestowed on him in 1905, recognised both his discovery of the tubercular bacillus and its monumental impact on public hygiene measures, as well as the pioneering impact of his postulates on the broader understanding of infectious diseases as a whole.2 at the same time, the nobel prize presentation speech, with equal clarity, offered a critique on the controversy surrounding his ongoing experimentation with tuberculin as a form of therapy. since 1982, 24th february has been designated ‘world tuberculosis day’ by the world health organization (who) to honour the day koch first presented his findings on the aetiology of tb. frustrations, dissent and disappointment the history of discoveries is replete with human emotions of exultation and despair. convinced of his proposed ‘germ theory’ koch went to great lengths to see, and show his sceptical colleagues, the germs that circulated in the blood in septicaemia. this, as we can well imagine, was no easy task but he developed the simple potato medium that would make the organisms multiply. complemented with staining techniques, the organisms were revealed in all their glory. the koch-pasteur squabbles based on the physician versus chemist approach to disease created political boundaries that prevented the use of koch’s culture techniques and pasteur’s immunisation schedules in france and germany, respectively.16 elated by his triumphal march on tb he attempted to prove that tuberculin (a glycerine extract of the tubercle bacilli) would provide a cure for the disease. while tuberculin proved useful in diagnosis, it met with disappointment and failure in therapy.7 after the revolutionary highpoints of his early career, this setback was particularly difficult to accept. at the fourth world congress on tb, he vehemently opposed the notion that bovine tb could spread to humans, declaring, “i therefore consider it unnecessary to take any measures against this form of tb. the fight against tb clearly has to the representation of bacteria.4 personal attributes: passion, patience, persistence a child prodigy, koch had astonished his parents when, at the age of five, they learnt that he had taught himself to read through newspapers; it was no surprise that he went on to graduate maxima cum laude in his m.d. in 1866.15 the motto nunquam otiosus (latin: never idle) was the driving force behind the prodigious contributions of this man who was passionate in equal measure about biological sciences, nature and travel. this drove him from the temples of learning in france, berlin, london and hannover to exotic locations like alexandria and calcutta. the hallmarks of his life’s mission were technological excellence and indisputable scientific logic. these stood him in good stead in convincing—where others had failed—his hard-nosed scientific peers of the veracity of the hotly-debated ‘germ theory’. the economics of animal husbandry has often spearheaded ground-breaking research in human disease. others before koch had recognised the anthrax bacilli in the blood of infected animals, but failed to establish its transmissibility. koch persisted and was able to establish growth of the bacilli in culture and observe the formation of spores: “after anthrax bacilli develop for a short time, shiny egg-shaped bodies form in the filaments. shortly thereafter, the filaments decompose… if they are placed in a nourishing medium, they germinate and grow into rods and then into long filaments”.16 this sound scientific observation succeeded in explaining the time-lag in the transmission of the disease between animals. it predated the deluge of attention showered on him after the identification of the tubercle bacillus. accolades and patronage koch’s success earned him the order of the crown, 100,000 marks and appointments such as privy imperial councillor by emperor wilhelm i, professor of hygiene at the university of berlin and director of the hygiene institute.4,15 he then went on to head the newly established institute of infectious diseases which, after his death, was renamed the the legacy of robert koch surmise, search, substantiate e40 | squ medical journal, february 2014, volume 14, issue 1 concentrate on the human bacillus”.17 fortunately, his opponents won the day and milk pasteurisation became the norm.18 and the story continued... the indefatigable war against tb continued in the wake of koch’s discoveries and extended to other medical domains. roentgen’s discovery of x-rays in 1896 was a giant leap forward in medical diagnostic tools.19 in addition to public health measures, the french bacteriologists calmette and guérin’s bovine tubercular strain created the bacillus calmette–guérin (bcg) vaccine that turned the tide from a therapy-only approach to tb to one of active prevention.20 in 1944, for the first time, streptomycin showed a light at the end of the tunnel—although monotherapy left many with hearing loss for the rest of their lives. soon, other drugs (rifampicin, pyrazinamide, para-amino salicylic acid, ethambutol, etc.) joined the fray and the philosophy of treatment rested on combinations in adequate doses for long periods of time. since 1993, the adoption of the directly observed treatment, short-course (dots) strategy by the who, as part of its stop tb strategy, is credited with having made a significant impact on the global tb burden.21 like many bacteria, the tubercular bacterium adopted wily ways of acquiring multi-drug resistance and the battle between it and newer drugs continues. since the turn of the last century, the hiv-aids epidemic has rendered a mortal blow to attempts to control tb, especially in sub-saharan africa. industrialisation, urban slums and poverty are no longer the only determinants of disease prevalence. it is certain that as newer epidemics emerge, ‘old’ infections like the ‘white plague’ will seize the advantage and challenge generations of scientists to fight back through gruelling research efforts and newer weaponry. lessons from koch’s life and times henle’s influence and cohn’s support in koch’s early experiments show us that pupils often surpass their gurus and surprise their peers by trailblazing their way into eternity. in today’s world of subspecialisation, it is pertinent to recall that a wellrounded knowledge of pathology and bacteriology integrated with a physician’s knowledge of human disease, combined with technology, microscopy, animal experiments and autopsies have been the mantra for the deluge of successful discoveries in the last two centuries. the discovery of the spore stage of bacterial dormancy in anthrax demonstrates that a hands-on approach to the laboratory bench can yield unexpected and astonishing results. koch’s investigative forays as a district medical officer into anthrax were inspired by the affliction of country cattle in his rural backyard and his experiments were first performed in a makeshift laboratory in his own house on mice caught in his barn! his wife’s resilience and support needs no better endorsement. research rests first and foremost on the ‘spirit’ of enquiry. funding, state-of-art laboratories and fame are not necessary pre-requisites. koch’s insistence on use of tuberculin for therapy, despite the incontrovertible evidence to the contrary, illustrates the fact that spectacular discoveries may be followed by offbeat theories that are anticlimactic. fame and acclaim can impose an unreasonable burden of expectations for a single man’s lifetime. references 1. koch r. zur aetiologie des milzbrandes. mitteilungen aus dem kaiserliche gesundheitsamte 1881; 1:174–206. 2. nobel prize laureates 1905. from: http://www.nobelprize. org/nobel_prizes/medicine/laureates/1905/press.html accessed oct 2013. 3. lakhtakia r. of animalcula, phthisis and scrofula – historical insights into tuberculosis in the pre-koch era. sultan qaboos university med j 2013; 13:486–90. 4. munch r. review. on the shoulders of giants. robert koch. microbes infect 2003; 5:69–74. 5. blevins sm, bronze ms. robert koch and the ‘golden age’ of bacteriology. int j infect dis 2010; 14:e744–51. 6. gradmann c. robert koch and the pressures of scientific research: tuberculosis and tuberculin. med hist 2001;45:1– 32. 7. kaufmann she, schaible ue. 100th anniversary of robert koch’s nobel prize for the discovery of the tubercle bacillus. trends in microbiol 2005;13:469–75. 8. sakula a. robert koch (1843-1910): founder of the science of bacteriology and discoverer of the tubercle bacillus. br j dis chest 1979;73:389–94. 9. schwentker fn. robert koch (1843–1910). invest urol 1964; 2:300–1. 10. lakhani sr. early clinical pathologists: robert koch (1843– 1910). j clin pathol 1993; 46:596–8. ritu lakhtakia editorial | e41 17. kaufmann she. a short history of robert koch’s fight against tuberculosis: those who do not remember the past are condemned to repeat it. tuberculosis (edinb) 2003; 83:86–90. 18. smith ae. report on the international congress on tuberculosis. ill med j 1909;15:303–10. 19. roentgen wc. über eine neue art von strahlen (vorläufige mitteilung). in: sitzungsberichte der physikalischmedizinischen gesellschaft in würzburg, 1895; 137:132141. in: weber al. history of head and neck radiology: past, present, and future. radiology 2001; 218:15–24. 20. luca s, mihaescu t. history of bcg vaccine. maedica (buchar) 2013; 8:53–8. 21. bayer r, wilkinson d. directly observed therapy for tuberculosis: history of an idea. lancet 1995; 345:1545–8. 11. carter kc, ed. essays of robert koch. westport: greenwood press,1987. p. 83. 12. koch r. die aetiologie der milzbrand-krankheit, begründet auf die entwicklungsgeschichte des bacillus anthracis. beiträge zur biologie der pflanzen. vol. 1, 1876. pp. 277–308. 13. carter kc, ed. essays of robert koch. westport: greenwood press,1987. pp. 9–25. 14. koch r. lecture at the first conference for discussion of the cholera question (1884). in: carter kc, ed. essays of robert koch. westport: greenwood press,1987. pp. 151–70. 15. ligon bl. robert koch: nobel laureate and controversial figure in tuberculin research. semin pediatr infect dis 2002; 13:289–99. 16. baxter ag. louis pasteur’s beer of revenge. nature rev immunol 2001; 1:229–32. clinical & basic research sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e375-381, epub. 24th jul 14 submitted 30th sep 13 revisions req. 19th dec 13 & 4th feb 14; revisions recd. 17th jan 14 & 17th feb 14 accepted 23rd mar 14 faculty of nursing, islamic university of gaza, gaza, palestine *corresponding author e-mail: aajedi19772@hotmail.com االلتزام بالربوتوكول الوطين الفلسطيين ملنع ومكافحة العدوى يف مستشفيات األطفال احلكومية يف حمافظات غزة اأ�رسف اجلدي، �رسيف الدلو abstract: objectives: nosocomial infections are a significant burden for both patients and the healthcare system. for this reason, infection prevention and control (ipc) practices are extremely important. the palestinian ministry of health adopted the national ipc protocol in 2004. this study aimed to assess the compliance of healthcare providers (hcps) with the protocol in three governmental paediatric hospitals in gaza governorates. methods: this descriptive cross-sectional study was conducted from february to november 2010. data were collected from a sample of doctors, nurses and physiotherapists (n = 334) using a self-administered questionnaire and observation checklists to record hcp practices and assess the hospital environment. results: the response rate was 92%. the most important reasons for non-compliance with the ipc protocol were the absence of an education programme (61.5%), lack of knowledge (52.4%) and the scarcity of required supplies (46.9%). only 2.3% of respondents had a copy of the ipc protocol, while 65.8% did not know of its existence. only 16.9% had participated in training sessions regarding general ipc practices. the observation checklist regarding hcp practices revealed low levels of compliance in hand washing (45.9%), wearing gloves (40.7%) and using antiseptics/disinfectants (49.16%). the health facilities checklist indicated that there was a lack of certain essential equipment and materials, such as covered waste containers and heavy-duty gloves. conclusion: due to the lack of hpc knowledge, the authors recommend that the ipc protocol be made available in all hospitals. in addition, a qualified team should implement intensive ipc education and training programmes and facilities should provide the required equipment and materials. keywords: cross infection; infection, prevention and control; protocol compliance; palestine. امللخ�ص: الهدف: ت�سكل عدوى امل�ست�سفيات عبئا كبريا على املري�س وعلى نظام الرعاية ال�سحية. لهذا ال�سبب تعترب ممار�سات منع ومكافحة العدوى ذات اأهمية كربى. وقد تبنت وزارة ال�سحة الفل�سطينية بروتوكول منع ومكافحة العدوى عام 2004. تهدف هذه الدرا�سة اإىل تقييم مدى التزام مقدمي اخلدمات ال�سحية بالربوتوكول الفل�سطيني ملنع ومكافحة العدوى يف م�ست�سفيات الأطفال احلكومية الثالثة املوجودة بقطاع غزة. الطريقة: اأجريت هذه الدرا�سة الو�سفية امل�ستعر�سة خالل الفرتة من فرباير اإىل نوفمرب 2010. وقد مت جمع البيانات با�ستخدام ا�ستبانة لعينة من الأطباء واملمر�سني واأخ�سائيي العالج الطبيعي بعدد اإجمايل )334(، وا�ستمارة مالحظة اأداء مقدمي اخلدمات ال�سحية مقدمي التزام لعدم الرئي�سي ال�سبب اأن الدرا�سة اأظهرت وقد .92% اإىل ال�ستجابة ن�سبة و�سلت النتائج: العمل. بيئة تقييم وا�ستمارة اخلدمات ال�سحية بربوتوكول منع ومكافحة العدوى هو عدم وجود برامج تعليم اأو تدريب )%61.5(، وقلة املعرفة )%52.4(، ونق�س الأدوات واملواد الالزمة للعمل وفق الربوتوكول )%46.9(. وقد اأظهرت الدرا�سة اأنه يوجد ن�سخة من بروتوكول منع ومكافحة العدوى فقط مع %2.3 من عينة البحث، بينما %65.8 من امل�ستطلعة اآراوؤهم ل يعرفون بوجود بروتوكول فل�سطيني كما اأن %16.9 فقط �ساركوا مبحا�رسة اأو تدريب يف منع ومكافحة العدوى. وقد عك�ست ا�ستمارة مالحظة الأداء م�ستويات متدنية من اللتزام بغ�سيل الأيدي )45.9%(، وبارتداء القفازات )%40.7(، وبا�ستخدام املطهرات)%49.16(. واأظهر تقييم بيئة العمل وجود نق�س يف التجهيزات والأدوات الالزمة لتطبيق بروتوكول منع ومكافحة العدوى مثل عدم وجود قفازات ثقيلة، وعدم وجود حاويات مغطاة. اخلال�صة: ب�سبب نق�س املعلومات لدى مقدمي اخلدمات ال�سحية يف هذه الدرا�سة نو�سى بتوفري ن�سخ من بروتوكول منع ومكافحة العدوى يف كل م�ست�سفى، وتنفيذ برامج تعليم وتدريب مكثفة يف منع ومكافحة العدوى، مع �رسورة توفري الأدوات واملعدات الالزمة. مفتاح الكلمات: انتقال العدوى؛ العدوى؛ منع ومكافحة العدوى؛ اللتزام بالربوتوكول؛ فل�سطني. compliance with the national palestinian infection prevention and control protocol at governmental paediatric hospitals in gaza governorates *ashraf eljedi and shareef dalo advances in knowledge the results of this study will increase the recognition of the factors contributing to healthcare providers’ non-compliance with the infection prevention and control (ipc) guidelines of the palestinian ministry of health (moh). in addition, this study expands the body of knowledge regarding appropriate methods to minimise nosocomial infections in paediatric hospitals in gaza governorates. compliance with the national palestinian infection prevention and control protocol at governmental paediatric hospitals in gaza governorates e376 | squ medical journal, august 2014, volume 14, issue 3 children are more liable to contract infections than any other age group. many paediatric morbidities are due to infections and infectious diseases.1 according to a 2006 world health organization (who) report, birth asphyxia and infections are the two main causes of death among infants.2 the gaza strip is located in the south of palestine on the coast of the mediterranean sea. it is considered an overcrowded area, with approximately 1.8 million people living in 365 km2 of land and an estimated population density of 4,000 people per km2. the gaza strip is characterised by its youthful population with 49% of the populace under 15 years of age.1 gaza has three paediatric hospitals and there are also paediatric departments in most of the other nonspecialty hospitals. nosocomial infections are a heavy burden for both the patients and healthcare providers (hcps) of hospitals in the gaza governorates. about 10% of paediatric hospitalisations are related to a nosocomial infection; in addition, about 16.4% of deaths in individuals between 1 and 4 years old are related to meningitis, pneumonia and other infectious diseases (1.3%, 10.9% and 4.2%, respectively).3 it is therefore important that infection prevention and control (ipc) practices are implemented and adhered to within paediatric hospitals. the palestinian ministry of health (moh) adopted the national ipc protocol in 2004, aiming to combat infections among hcps, clients and within the community. each health institution is supposed to adopt and implement specific ipc activities or protocol. employees working in paediatric hospitals are supposed to take precautions to protect their patients and staff from exposure to potentially infectious materials. a fundamental component of standard infection prevention measures are a system of barrier precautions to be used by all personnel while in contact with patients, regardless of a patient’s specific diagnosis.4 however, compliance with the national palestinian ipc protocol has not yet been assessed in paediatric hospitals in the gaza strip. the aim of this study was to assess the compliance of hcps with the national ipc protocol in three governmental paediatric hospitals in gaza governorates thus helping to improve the infection control practices in this region and decrease the rates of childhood morbidity and mortality. methods this descriptive cross-sectional study was conducted in three paediatric hospitals in the gaza governorates between february and november 2010. the three hospitals are directed and owned by the palestinian moh: al-nasser pediatric hospital, al-durrah children’s hospital and ranteesy specialized pediatric hospital. of the total participants (n = 363), all doctors (n = 112), nurses (n = 240) and physiotherapists (n = 11) working at the three paediatric hospitals at the time of this study had more than six months’ experience. however, 18 subjects were excluded from the study as they were on an extended holiday, working under a temporary contract or working voluntarily. the final sample therefore included 334 hcps, with 106 doctors, 220 nurses and 8 physiotherapists. three instruments were used to collect the data: a self-administered questionnaire, an observation checklist for the hcps and an observation checklist of the three hospitals’ physical environment. the self-administered questionnaire consisted of five sections and took approximately 15 minutes to complete. the first part covered personal and professional information. the second part assessed each hcp’s knowledge about the national ipc protocol and included questions designed to assess the hospital’s actions to improve infection control practices. the third part explored barriers that decreased a hcp’s compliance with the ipc protocol. the fourth part assessed each hcp’s perception and attitude towards the ipc protocol and its recommended practices. the last part explored whether the hcp’s practices were congruent with the national ipc protocol’s recommendations. a total of 334 questionnaires were distributed and 307 were returned, resulting in a response rate of 92%. the researchers distributed the questionnaires to hcps and stayed in the hospital to receive the the study highlights the importance of ipc guidelines in the prevention of nosocomial infections and the barriers that can arise during the application of these protocols and guidelines. application to patient care decreasing the prevalence of nosocomial infections will directly improve patient outcomes. specifically, the data from this study may help to minimise morbidity and mortality rates in governmental paediatric hospitals in the gaza governorates. based on the results of this study, it is recommended that the palestinian moh organise a highly qualified team to set up intensive education and training programmes promoting the application of the national ipc protocol among healthcare providers. ensuring the provision of the necessary equipment and facilities is crucial to establishing effective ipc practices. ashraf eljedi and shareef dalo clinical and basic research | e377 completed questionnaires during the same shift, repeating this process three to four times in different shifts each week for 10 successive weeks. an observation checklist was used by the researchers to assess hcp compliance with the six main practices recommended in the national protocol: wearing a uniform; hand washing; using gloves; using antiseptics/disinfectants; proper use of disposable medical equipment, and following the correct disposal practices for sharp implements/objects. a second observation checklist was used by the researchers to assess each hospital’s physical environment and compliance with the national ipc protocol. it also assessed the availability of equipment and supplies in each department of the three paediatric hospitals. the researchers completed the observation checklists while waiting to receive completed questionnaires. as the researchers had worked with the hpcs previously, the researchers were familiar to most of the participants; thus, they behaved normally in the presence of the investigators as they were unaware of being under observation. this allowed the researchers to observe the hcps’ levels of compliance with the ipc protocol. the data were processed and analysed using the statistical package for the social sciences (spss), version 18 (ibm corp., chicago, illinois, usa). frequencies, cross tabulation, pearson’s chi-square test and analysis of variances (anova) were used to analyse the data. a p value of ≤0.05 was considered statistically significant. ethical approval for the study was obtained from the moh and the study was conducted according to the declaration of helsinki. each participant was given an explanatory letter about the purpose of the study, ensuring the confidentiality of the information and the right to refuse participation or withdraw at any time. consent was received from each participant. results regarding the participant’s knowledge and perceptions of infection control, the study found that 59.3% of the participants believed that they knew universal standard infection control precautions and that 34.2% knew of the existence of a set of national ipc guidelines for palestine; however, only 2.3% of the study population actually had a copy of the palestinian ipc protocol in their departments. of the participants, 62.9% stated that their hospitals conducted continuous surveillance programmes for nosocomial infections. a total of 21.5% of the study population had participated in a hospital education or training session about general table 1: comparison between actual and perceived infection prevention and control practices among healthcare providers in three paediatric hospitals in the gaza governorates practice perceived practices n = 307 n (%) observed practices n = 1,008 n (%) p value hand washing immediately upon arrival at the unit 208 (67.6) 47 (4.7) 0.001* hand washing before touching patients 245 (79.8) 76 (7.5) 0.001* hand washing after working with patients 245 (79.8) 775 (76.9) 0.286 hand washing before leaving the unit 255 (83.1) 493 (48.9) 0.001* hand washing after touching blood or body fluids 298 (97.1) 982 (97.4) 0.848 removal of any jewelry, watches and/or rings while hand washing 217 (70.7) 319 (31.6) 0.001* hand washing for 15–30 seconds with soap and running water 244 (79.5) 564 (56.0) 0.001* wearing gloves when in contact with blood or other body fluids 271 (88.2) 854 (84.7) 0.127 using clean gloves when handling contaminated instruments 276 (89.9) 839 (83.2) 0.003* disinfection of each patient unit/room after patient discharge 235 (76.5) 578 (57.3) 0.001* removal of used needles from syringes before disposal 223 (72.6) 277 (27.5) 0.001* bending or breaking used needles prior to disposal 226 (73.6) 770 (76.4) 0.295 recapping used needles 192 (62.5) 414 (41.1) 0.001* disposal of all sharp items in punctureresistant containers 270 (88.0) 705 (69.9) 0.001* *p values were significant at <0.05. compliance with the national palestinian infection prevention and control protocol at governmental paediatric hospitals in gaza governorates e378 | squ medical journal, august 2014, volume 14, issue 3 ipc procedures, but only 16.9% felt that they had received sufficient information during that session. in terms of the promotion of general ipc practices within the hospital setting, only 25% thought that no effort had been made to promote ipc practices. although 84.7% of hcps had received vaccinations for hepatitis b, only 63.2% had received all three of the doses recommended for protection. of the participants, 66% had been injured by needles or sharp medical instruments. concerning perception of the importance of the practices described in the national ipc protocol, almost all of the participants indicated high levels of understanding and recognition of the importance of most of the national ipc protocol practices. all of the study participants demonstrated a high level of agreement with the importance of general ipc practices. the respondents strongly agreed with the following statements: ipc is important in paediatric units; hand washing is important in preventing infections; physical barriers decrease the rate of cross-infection; the proper handling of contaminated instruments inhibits the transmission of infections; the routine cleaning and disinfection of a patient’s unit is important, and safe work practices and proper waste disposal management decrease infection hazards. regarding the perceptions of hcps toward their own general ipc practices, 79.7% declared that they were compliant with all the hand washing guidelines. it was found that 84.7% of hcps reported wearing gloves when in contact with blood or other body fluids, while 89.9% stated that they wore gloves when handling contaminated instruments. about 20% believed that they were sometimes committed to keeping instruments sterile. an average of 68.05% of the hcps reported that they recapped, broked or bent used needles before disposal, while 72.6% reported that they discarded the used syringe after removing the needle [table 1]. the researchers filled in the observation checklist of hcps’ practices so as to reflect the actual practices table 2: differences between years of experience and infection prevention and control practices among healthcare providers in three paediatric hospitals in the gaza governorates (n = 307) practice years of experience p value 1–5 (n = 137) 6–15 (n = 107) 16–36 (n = 63) n (%) n (%) n (%) wearing a uniform 125 (91.2) 97 (90.7) 52 (82.5) 0.002* hand washing 110 (80.2) 86 (80.4) 49 (77.8) 0.359 wearing gloves 121 (88.3) 97 (90.7) 54 (85.7) 0.103 using antiseptics 108 (78.8) 86 (80.4) 50 (79.4) 0.637 proper use of disposable medical equipment 110 (80.2) 89 (83.2) 50 (79.4) 0.356 safe handling of sharp medical instruments 107 (78.1) 86 (80.4) 52 (82.5) 0.250 *p values were significant at <0.05. table 3: relationship between healthcare profession and compliance with selected infection prevention and control practices among healthcare providers in three paediatric hospitals in the gaza governorates (n = 307) practice specialist doctors (n = 48) general physicians (n = 47) bsn nurses (n = 124) prn nurses (n = 80) physiotherapists (n = 8) p value n (%) wearing a uniform 39 (81.3) 40 (85.1) 114 (91.9) 74 (92.5) 8 (100) 0.000* hand washing 38 (79.2) 36 (76.6) 98 (79.0) 65 (81.3) 6 (75.0) 0.430 wearing gloves 43 (89.6) 42 (89.4) 109 (87.9) 70 (87.5) 7 (87.5) 0.921 using antiseptics 37 (77.1) 36 (76.6) 101 (81.5) 62 (77.5) 6 (75.0) 0.534 proper use of disposable medical equipment 39 (81.3) 37 (78.7) 102 (82.3) 64 (80.0) 5 (62.5) 0.197 safe handling of sharp medical instruments 40 (83.3) 40 (85.1) 95 (76.6) 62 (77.5) 5 (62.5) 0.004* bsn = registered nurse with a bachelor of science in nursing (four-year programme); prn = licensed practical nurse (two-year associate degree programme). *p values were significant at <0.05. ashraf eljedi and shareef dalo clinical and basic research | e379 of all hcps in relation to the national ipc protocol. most of the observed actual practices differed from the perception of the hcps regarding their practices (p <0.0001) [table 1]. under observation, less than half of the study population (48.9%) washed their hands before leaving the unit, while only a third of them (34.2%) washed their hands before performing an invasive or septic procedure. approximately 28% of the study population did not remove the needles from used syringes before disposal and 41% did not recap used needles before disposal. the observed results of hand washing practices reflected that only 45.9% of the participants washed their hands properly compared with the 79.7% who had indicated otherwise in their questionnaire responses. only 3.8% of the sample used an antiseptic solution during hand washing prior to a septic or invasive procedure and only 8% used sterile gowns, masks and gloves when making patient contact within a sterile field. the researchers assessed the physical environment of the three hospitals in terms of their ability to support the national ipc protocol. these observations indicated that copies of the ipc protocol were not available in any department. in addition, no heavy-duty gloves were provided for the hpcs in any department (0%); these should be used by hpcs when dealing with medical waste disposal and contaminated instruments. there was good compliance with maintaining clean nursing rooms, suction tubes and bottles (81.2%); the availability of antiseptic and disinfectant solutions (85.5%) and other supplies for hand washing (87%) was satisfactory. however, puncture-resistant containers were only available in 26% of the departments. the results also indicated that the more experienced the personnel were, the less compliant they were with ipc practices; however, the difference was significant only regarding the wearing of uniforms (f = 6.366, p <0.002) [table 2]. regarding the compliance according to profession, the results showed that there was a statistically significant difference for only two of the six ipc protocol practices: wearing a uniform (f = 6.305, p <0.001) and using safe work practices (f = 3.880, p <0.004) [table 3]. scheffé’s test revealed that the nurses were more committed to wearing uniforms, hand washing, using antiseptics and proper use of disposable medical equipment than doctors. discussion this study found significant differences between actual hcp practices as observed by the researchers and perceived practices recorded in the hcps’ selfassessments. the greatest differences were observed in hand washing practices, both immediately on arrival and before touching patients, and in dealing with sharp objects. compliance with hand washing protocol is still a major challenge for achieving a good level of infection control in the gaza strip and strategies are needed to improve compliance among hcps. this is consistent with the findings of many studies. mahfouz et al., ataei et al. and abdella et al. indicated that hand hygiene compliance among hcps was found to be low, especially among doctors.5–7 the problem exists even in intensive care units; for example, panhotra et al. assessed hand washing compliance among healthcare workers in an intensive care unit (icu) in saudi arabia.8 compliance was observed in 72.8% of all categories of staff. the highest compliance level (97.5%) was recorded among nurses. the compliance level among technicians was 47.7%, while the lowest level of compliance (37.6%) was observed among doctors (relative risk [rr]: 2.591, p <0.0001).8 the disappointing level of hand washing compliance among doctors visiting and working in icus, despite their improved understanding of hospital-acquired infections, remains a cause for concern.8 another study evaluated adherence to hand washing and glove wearing practices among hcps in five medical and five surgical wards of a 1,250-bed hospital in riyadh, saudi arabia.9 the overall frequency of hand washing was 6.7% before patient contact and 23.7% after patient contact. adherence to hand washing was 18.8% among nurses, 12.5% among residents and 9.1% among consultants. the duration of hand washing was suboptimal for all hcps (an average of 4.7 seconds).9 this is consistent with a review by pittet, who found that compliance with hand hygiene recommendations varied between hospital wards, among professional categories of healthcare workers and according to working conditions.10 the estimated frequency of hand washing was <50%.10 the present study also indicated that most participants lacked knowledge of infection control strategies and that most of them did not know of the existence of the palestinian ipc protocol. researcher observations indicated that there were no copies of the ipc protocol in any department; this is a major obstacle to the application of the protocol in the gaza strip hospitals. this supported the findings of awad’s study, which was conducted in the icus of hospitals in the gaza strip. only 27% of hcps in that study recognised the existence of the palestinian ipc protocol; of these, only 47% knew about the contents of the protocol.11 only 16.9% of this study’s participants had received sufficient information about general ipc procedures. this is very low compared with the results obtained by struelens et al. in a study of compliance with the national palestinian infection prevention and control protocol at governmental paediatric hospitals in gaza governorates e380 | squ medical journal, august 2014, volume 14, issue 3 169 acute care hospitals in 32 european countries assessing the organisation, components and human resources of infection control programmes.12 they found that educational sessions for healthcare workers concerning infection control practices existed in 77% of centres.12 this finding reflects the real need for continuous training and education to enhance hcps’ knowledge, skills and practice of standard infection control precautions as recommended by the palestinian ipc protocol. this is consistent with the results of other studies demonstrating the importance of conducting educational programmes as an effective strategy to increase staff compliance with standard ipc practices.13–15 there is a need to develop a system of continuous education for all categories of staff.13 the present study revealed that nurses were more committed to the most of ipc practices than all other groups. askarian et al.’s study, of hcp compliance with personal hygiene and safety guidelines and its effect on nosocomial infections in shiraz, iran, reflected that compliance varied among healthcare workers; physicians (10%) and nurses (32.2%) were less compliant than cleaners (56.7%) in adhering to the personal hygiene and safety practices.16 studies by gershon et al., panhotra et al., basurrah et al. and askarian et al. when examining compliance with universal precautions among hcps found different levels of compliance. compliance was highest among nurses, moderate among technicians and lowest among doctors.8,9,17,18 in the present study, only 63.2% of the hcps had received all three of the recommended doses of the hepatitis b vaccination; however, these results are much better than those from studies of the gharbia governorate in egypt and dental clinics in jordan, where the percentage of hcps who had received a full vaccination course against hepatitis was 11.3%19 and 36%,20 respectively. the frequency of injuries received from used needles or sharp medical instruments in the present study was very high (66%) in comparison to the results of a study conducted in a university hospital in germany, which indicated that only 31.4% of all healthcare workers had received needle stick injuries.21 however, the frequency noted in this study was superior to that found in a study of health centres in assiut city, egypt, by hassan et al., which found that 97.2% of hcps had been injured by used needles.22 the main barriers to ipc found in this study are congruent with the results of research performed in neonatal icus in gaza.11 the researcher found that the main obstacles to compliance with infection control regulations were the absence of training programmes, updates and feedback of performance from the administration; a lack of knowledge and education; a heavy workload; insufficient supplies, and no accountability.11 this is similar to the findings of madani et al. in their study of the effect of audit on compliance; their findings indicated that the proper handling of clean and soiled linens improved to 60–70% after specific interventions.23 this rate of improvement could be achieved in other hospitals by implementing recurrent audits and offering a sufficient quantity of disposable medical equipment. in order to improve infection control practices, it is important to encourage public awareness of this issue and to increase motivation within the hospital community. it is also necessary for the hospital to provide special containers for the safe disposal of syringe needles, arrange the necessary facilities for hand washing and administer hepatitis b vaccines to their staff.24 conclusion this study is the first of its kind in the gaza strip evaluating the compliance of hcps with the palestinian ipc protocol and assessing ways in which the implementation of the protocol could be facilitated. the findings revealed that the most important reasons for non-compliance with the ipc protocol were the absence of education or training programmes (61.5%), lack of knowledge (52.4%) and the scarcity of the required supplies (46.9%). only 2.3% of respondents had a copy of the national ipc protocol, while 65.8% did not know of its existence. only 16.9% of respondents had participated in training sessions about general ipc procedures while 66.1% had been exposed to an injury from used needles. the observation checklist revealed a lower level of compliance in all infection control practices than was perceived by the hcps in self-administered questionnaires. nurses were more compliant to the most of ipc practices than other groups of hcps. observations of the health facility environment indicated a lack of certain essential equipment and materials, such as covered waste containers and heavy-duty gloves. from the results of this study, it is recommended that the palestinian ipc protocol be made available in all departments of the gaza hospitals. in addition, it is recommended that these hospitals be provided with the much-needed equipment and facilities required by the national protocol guidelines. a highly qualified team should be assembled to intensify education and training programmes to promote the application of the precautions noted in the national ipc protocol. moreover, it is recommended that each hospital create an infection control committee responsible and accountable for standardising and developing ashraf eljedi and shareef dalo clinical and basic research | e381 infection control policies. these committees should be observed and regulated by a macro-committee based in the moh. moreover, the results of regular hospital infection control audits and hospital surveillance programme should be reported on a regular basis, ideally leading to a significant improvement of infection control practices in the region. a c k n o w l e d g e m e n t s the researchers acknowledge the considerable role of the palestinian moh in facilitating data collection and providing the required permissions to conduct the study. special thanks are extended to the staff of the three paediatric hospitals in the gaza governorates for their cooperation during the study. references 1. state of palestine ministry of health. annual report 2006. from: www.moh.ps/?lang=1&page=4&id=142 accessed: may 2014. 2. world health organization. neonatal and prenatal mortality: country, regional and global estimates. from: www.whqlibdoc.who.int/publications/2006/9241563206_eng. pdf accessed: sep 2010. 3. state of palestine ministry of health. annual report 2007: mortality file. from: www.moh.ps/attach/149.pdf accessed: may 2014. 4. highton l, bandak a. infection prevention and control: palestinian health sector reform and development flagship project short-term technical assistance report. from: www. pdf.usaid.gov/pdf_docs/pnadw214.pdf accessed: may 2014. 5. mahfouz aa, el gamal mn, al-azraqi ta. hand hygiene non-compliance among intensive care unit health care workers in aseer central hospital, south-western saudi arabia. int j infect dis 2013; 17:e729–32. doi: 10.1016/j.ijid.2013.02.025. 6. ataei b, zahraei sm, pezeshki z, babak a, nokhodian z, mobasherizadeh s, et al. baseline evaluation of hand hygiene compliance in three major hospitals, isfahan, iran. j hosp infect 2013; 85:69–72. doi: 10.1016/j.jhin.2013.07.001. 7. abdella nm, tefera ma, eredie ae, landers tf, malefia yd, alene ka. hand hygiene compliance and associated factors among health care providers in gondar university hospital, gondar, north west ethiopia. bmc public health 2014; 14:96. doi: 10.1186/1471-2458-14-96. 8. panhotra br, saxena ak, al-arabi amag. the effect of a continuous educational program on handwashing compliance among healthcare workers in an intensive care unit. j infect prev 2004; 5:15–8. doi: 10.1177/14690446040050030401. 9. basurrah mm, madani ta. handwashing and gloving practice among health care workers in medical and surgical wards in a tertiary care centre in riyadh, saudi arabia. scand j infect dis 2006; 38:620–4. doi: 10.1080/00365540600617025. 10. pittet d. improving adherence to hand hygiene practice: a multidisciplinary approach. emerg infect dis 2001; 7:234–40. 11. awad n. adherence to infection prevention and control protocols in the neonatal intensive care units in the ministry of health hospitals in gaza governorates. unpublished master’s degree thesis, 2009. al-quds university, jerusalem, palestine. 12. struelens mj, wagner d, bruce j, mackenzie fm, cookson bd, voss a, et al. status of infection control policies and organisation in european hospitals, 2001: the arpac study. clin microbol infect 2006; 12:729–37. doi: 10.1111/j.14690691.2006.01462.x. 13. suchitra jb, lakshmi devi n. impact of education on knowledge, attitudes and practices among various categories of health care workers on nosocomial infections. indian j med microbiol 2007; 25:181–7. doi: 10.4103/0255-0857.34757. 14. al-rawajfah om. infection control practices among intensive care unit registered nurses: a jordanian national study. nurs crit care 2014. epub ahead of print. doi: 10.1111/nicc.12078. 15. tada a, watanabe m, senpuku h. factors influencing compliance with infection control practice in japanese dentists. int j occup environ med 2014; 5:24–31. 16. askarian m, khalooee a, emroodi nn. personal hygiene and safety of governmental hospital staff in shiraz, islamic republic of iran. east mediterr health j 2006; 12:768–74. 17. gershon rr, vlahov d, felknor sa, vesley d, johnson pc, delclos gl, et al. compliance with universal precautions among health care workers at three regional hospitals. am j infect control 1995; 4:225–36. doi: 10.1016/0196-6553(95)90067-5. 18. askarian m, hajiabadi mj, kashkooli ya, yousofi m, fathi h, kouchack f, et al. improving infection prevention methods in hemodialysis units: a multicenter survey. am j infect control 2014; 42:193–4. doi: 10.1016/j.ajic.2013.09.024. 19. ismail na, aboul ftouh am, el-shoubary wh, mahaba h. safe injection practice among health-care workers in gharbia governorate, egypt. east mediterr health j 2007; 13:893–906. 20. al-omari ma, al-dwairi zn. compliance with infection control programs in private dental clinics in jordan. j dent educ 2005; 69;693–8. 21. wicker s, jung j, allwinn r, gottschalk r, rabenau hf. prevalence and prevention of needle stick injuries among health care workers in a german university hospital. int arch occup environ health 2008; 81:347–54. doi: 10.1007/s00420007-0219-7. 22. hassan ak, moftah fm, alaa el-din sm, bayomi ss. assessment of an educational training program for nurses working in maternal and child health (mch) centers in assiut city regarding infection control. ass univ bull environ res j 2004; 7;91–105. 23. madani ta, albarrak am, alhazmi ma, alazraqi ta, althaqafi ao, ishaq ah. steady improvement of infection control services in six community hospitals in makah following annual audits during hajj for four consecutive years. bmc infect dis 2006; 6:135. doi: 10.1186/1471-2334-6-135. 24. el ayyat aa, sayed ha, abou had am. a kap study among staff and student nurses about infection control in theodor bilharz hospital. j egypt soc parasitol 2000; 30:511–22. department of physiotherapy, swami vivekanand national institute of rehabilitation training & research, cuttack, odisha, india *corresponding author e-mail: shankarpt@rediffmail.com النشاط البدين وجودة احلياة بني البالغني املصابني بالشلل السفلي يف أوديشا باهلند �ش�نكر ج�ني�ص و �شيت�راجن�ن مي�رضا abstract: objectives: the complete rehabilitation of patients with spinal cord injuries (sci) comprises both physical and psychosocial factors. this study therefore aimed to assess physical activity and quality of life (qol) among paraplegic patients with sci in odisha, india. methods: this cross-sectional prospective study was conducted between march 2010 and december 2013. all paraplegic patients treated at the swami vivekanand national institute of rehabilitation training & research in odisha, india, during the study period who met the inclusion criteria were invited to participate in the study (n = 364). structured face-to-face interviews were held with participants and qol and physical activity were assessed using the abbreviated world health organization qol instrument and the physical activity scale for individuals with physical disabilities, respectively. results: a total of 84 people participated in the study (response rate: 23.1%). the mean age was 32.54 ± 10.75 years and 90.5% of the participants were male. participants had a low mean metabolic equivalent score (18.18 ± 10.68 hours/day). additionally, low mean scores were noted for the physical health, psychological well-being, social relationships and environment qol domains (49.76 ± 18.74, 48.57 ± 17.04, 57.88 ± 17.04 and 49.85 ± 17.77, respectively). there was a strong positive association between levels of physical activity and all qol domains (p <0.050). physical activity and employment status were significant predictors of all qol domains (p <0.001). conclusion: low physical activity levels and qol were noted among the paraplegic subjects. interventions promoting physical activity and employment may help to improve qol among this patient group. keywords: paraplegia; spinal cord injuries; quality of life; physical activity; rehabilitation; india. تقييم اإىل الدرا�شة هذه تهدف ونف�شية. بدنية عوامل من تت�ألف ال�شوكي احلبل اإ�ش�ب�ت ملر�ص الك�ملة الت�أهيل اإع�دة امللخ�ص: الهدف: املقطعية الدرا�شة هذه اأجريت الطريقة: ب�لهند. اأودي�ش� يف امل�شلولني ال�شوكي احلبل اإ�ش�ب�ت مر�شى بني احلي�ة وجودة البدين الن�ش�ط االإ�شتب�قية بني م�ر�ص 2010 ودي�شمرب 2013. �شملت الدرا�شة جميع املر�شى امل�شلولني الذين مت عالجهم يف مركز �شوامي فيفيكن�ند الوطني لت�أهيل التدريب واالأبح�ث ب�لهند والذين تنطبق عليهم مع�يري االأ�شتم�ل )عدد 364(. مت اإجراء مق�بالت منظمة وجه� لوجة مع امل�ش�ركني ومت تقييم الن�ش�ط البدين وجودة احلي�ة عن طريق اأدوات جودة احلي�ة املخت�رضة ملنظمة ال�شحة الع�ملية ومقي��ص الن�ش�ط البدين لالأفراد امل�ش�بني ب�الإع�ق�ت اجل�شدية على التوايل. النتائج: �ش�رك جمموع 84 �شخ�ش� يف هذه الدرا�شة )معدل االأ�شتج�بة:%23.1(. متو�شط العمر ك�ن10.75 ± 32.54 �شنوات وك�ن %90.5 من امل�ش�ركني ذكورا. ح�شل امل�ش�ركون على نتيجة منخف�شة ملتو�شط مع�دل االأي�ص )10.68 ± 18.18 �ش�عة/يوم(. مت مالحظة وجود متو�شط منخف�ص للنت�ئج يف جم�الت ال�شحة البدنية والنف�شية و العالق�ت االأجتم�عية وبيئة جودة احلي�ة )18.74 ± 49.76، 17.04 ± 48.57، 17.04 ± 57.88 و 17.77 ± 49.85، على التوايل(. ك�نت هن�ك عالقة اإيج�بية قوية بني م�شتوي�ت جم�ل الن�ش�ط البدين وجودة احلي�ة )p >0.050(. ك�ن الن�ش�ط البدين والو�شع الوظيفي متنبئ كبري جلميع جم�الت جودة احلي�ة )0.001< p(. اخلال�صة: مت مالحظة اأنخف��ص معدالت الن�ش�ط البدين وجودة احلي�ة بني االأ�شخ��ص امل�شلولني. كم� اأن التدخالت التى تعزز الن�ش�ط البدين والتوظيفي قد ت�ش�عد يف حت�شني جودة احلي�ة بني هذه الفئة من املر�شى. مفتاح الكلمات: ال�شللالسفيل؛ اإ�ش�ب�ت احلبل ال�شوكي؛ جودة احلي�ة؛ الن�ش�ط البدين؛ اإع�دة الت�أهيل؛ الهند. physical activity and quality of life among adults with paraplegia in odisha, india *shankar ganesh and chittaranjan mishra advances in knowledge low physical activity levels and quality of life (qol) were noted among the studied individuals with spinal cord injuries (sci) in odisha, india. the study found a strong positive association between physical activity and all domains of qol. furthermore, physical activity and employment status were significant predictors of all qol domains. application to patient care the identification of variables affecting qol is necessary to inform rehabilitation protocols for patients with sci. rehabilitation measures should address emotional, social and cognitive factors as well as physical rehabilitation in order to achieve better qol for these patients. as the qol of patients with sci in the current study was found to be influenced by physical activity and employment status, initiatives to promote physically active lifestyles and re-employment among the sci population should be encouraged. clinical & basic research sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e54–61, epub. 2 feb 16 submitted 17 jun 15 revision req. 7 sep 15; revision recd. 5 oct 15 accepted 25 oct 15 doi: 10.18295/squmj.2016.16.01.010 shankar ganesh and chittaranjan mishra clinical and basic research | e55 advances in the medical management of spinal cord injuries (sci) have reduced the severity of this disability and increased patient longevity.1 following the completion of inpatient rehabilitation, most patients with sci are discharged and are expected to resume their lives and find ways of coping with their disability.2 however, health and wellbeing are best understood in terms of a combination of biological, psychological and social factors. as certain disabilities are permanent, including those associated with sci, there is a need to identify factors affecting well-being which can be influenced by the rehabilitation team. traditional health indicators provide a measure of the impact of disease but do not assess quality of life (qol) in the context of an individual’s culture, value systems, goals, expectations, standards and concerns.3 wilson et al. stated that qol should be routinely assessed among individuals with sci along with neurological and functional outcomes.4 subjective qol is considered by some researchers to be the only relevant measure of qol among individuals with sci as it reflects their own perception of their well-being.5 the inclusion of qol assessments in healthcare will promote a holistic treatment approach and encourage healthcare professionals to account for the personal perceptions and values of their patients. hence, the evaluation of qol is a crucial issue for future national health planning. very few studies have evaluated the qol of sci patients in india, where the estimated sci prevalence is 236 per million.6 gupta et al. found that patients with neurological illnesses, including sci, reported impaired qol in all domains of life; moreover, the social relationships domain of qol was noted to adversely affect functional abilities.7 singh et al. reported that gender, employment, mobility, autonomy, partner relations and social adjustment were associated with fair-to-good qol scores among individuals with sci in northern india.8 tasiemski et al. compared life satisfaction and life values among sci-affected individuals living in india, vietnam and sri lanka; no significant relationships were observed between these variables.9 in an international cross-sectional study, geyh et al. examined the qol of sci patients across six countries using five satisfaction items from the world health organization qol (whoqol) assessment.10 the results indicated inter-country qol differences that could not be explained by differences in demographic or lesion-related characteristics; future research in this area was hence recommended.10 as little is known about the subjective differences in qol among sci patients with different backgrounds, this study aimed to determine physical activity levels and qol among sci patients in odisha, india, and identify relationships between demographic/clinical data, physical activity levels and qol. methods this cross-sectional study was conducted between march 2010 and december 2013 at the swami vivekanand national institute of rehabilitation training & research in odisha. during this period, a total of 364 paraplegic inor outpatients with sci of at least one year’s duration were invited to participate in the study. as physical function, independence and physical well-being is known to affect the qol of quadriplegic patients to a greater extent than paraplegic patients, the study was limited to patients with paraplegia.11 patients with thoracic and lumbar injuries and without mental health problems or medication usage that might affect their decisionmaking skills were included. the exclusion criteria included patients with traumatic brain injuryassociated sci, brachial plexus injuries and/or fractures of the extremities and systemic medical diseases that would restrict physical activity. individuals who met these criteria were invited to participate in the study. data were collected using surveys in combination with interviews to ensure uniformity in the research process. each subject participated in a structured faceto-face interview which lasted an average of 45 minutes. the interviews were conducted in oriya, the regional dialect spoken in odisha. all questions were translated from english to oriya by two translators using back-translation methods. interviews were conducted by one researcher while another monitored the proceedings. demographic data and information on qol and physical activity was collected during the interviews using questionnaires. the questionnaires were filled out by the researcher who conducted the interviews due to the lack of reading literacy amongst some of the participants. at the end of each interview, the interviewee was given the opportunity to clarify any doubts or ask questions. a custom-made oriya-language survey with closeended questions was used to collect demographic data from participants, including age, gender, time since injury, marital status, level of education and employment status. for the purpose of the study, participants were categorised into age groups of fiveyear intervals. education level was recorded on a scale from 1–4 (1 = no education, 2 = primary education, 3 = secondary education and 4 = university-level edu cation). the employment and marital statuses of the participants before and after their injury were also noted. for statistical analysis, only post-injury physical activity and quality of life among adults with paraplegia in odisha, india e56 | squ medical journal, february 2016, volume 16, issue 1 values were considered. paraplegia was classified as either complete (categories a and b) or incomplete (categories c and d) according to the american spinal injury association impairment scale (ais).12 physical activity levels were measured using the physical activity scale for individuals with physical disabilities (pasipd), which assesses the long-term effects of sci on the health, functional ability and independence of persons with sci.13 this scale has been found to have good test-retest reliability and criterion validity.14 participants’ qol was assessed using the abbreviated version of the whoqol assessment (whoqol-bref).3 this international crossculturally comparable instrument measures qol across four domains: physical health (pain/discomfort, energy/fatigue and sleep/rest), psychological wellbeing (body image/appearance, negative feelings, positive feelings, self-esteem and thinking/learning/ memory/concentration), social relationships (personal relationships, social support and sexual activity) and environment (financial resources, freedom/physical safety/security, accessibility/quality of health/social care, home environment, opportunities for acquiring new information/skills, participation in/opportunities for recreation/leisure activities, physical environment e.g. pollution/noise/traffic/climate and transport).3 the whoqol-bref assessment is currently the most accepted and established instrument to assess qol among individuals with sci.15 the instrument has shown good differentiation, content validity and testretest reliability.3 based on an individual’s responses to the questionnaire, qol is scored between zero (poor qol) and 100 (high qol). in addition, domain scores correlate at approximately 0.9 with those of the full version of the whoqol instrument.3 data were analysed using the statistical package for the social sciences (spss), version 16 (ibm corp., chicago, illinois, usa). a pearson product-moment correlation coefficient analysis was used to identify relationships between qol and physical activity, time since injury, age, gender, marital status, employment status, paraplegia severity and educational level. a multiple linear regression analysis with backward elimination was used to determine the significance of eight predictors (age, gender, education level, paraplegia severity, time since injury, employment status, physical activity and marital status) of qol. for all analyses, a p value of <0.050 was considered significant. ethical approval for this study was granted from the ethics committee of the swami vivekanand national institute of rehabilitation training & research. participation in the study was voluntary and informed consent was obtained from each participant. due to the sensitive nature of the study, all participants were provided with the telephone number of the institute’s clinical psychologist for counselling services. results a total of 84 individuals with sci participated in the study (response rate: 23.1%). of these, there were 76 men (90.5%) and eight women (9.5%). the mean age was 32.54 ± 10.75 years (range: 15–60 years old). all of the participants used mechanical wheelchairs daily, were independent and needed no nursing. the post-injury employment rate of the participants was 7.1% and the average time since the onset of their injuries was 26.73 ± 23.94 months. the descriptive characteristics of the participants are reported in table 1. participants reported a mean metabolic equivalent score of 18.18 ± 10.68 hours/day out of a possible table 1: demographic characteristics of individuals with spinal cord injuries in odisha, india (n = 84) characteristic n (%) gender male 76 (90.5) female 8 (9.5) mean age in years (range) 32.54 ± 10.75 (15‒60) marital status unmarried 40 (47.6) married 44 (52.4) education level no education 12 (14.3) primary 10 (11.9) secondary 28 (33.3) university-level 34 (40.5) employment status employed 6 (7.1) unemployed 78 (92.9) paraplegia severity* a 40 (47.6) b 16 (19.0) c 16 (19.0) d 12 (14.3) mean time since injury in months (range) 26.73 ± 2.39 (12‒84) *paraplegia was classified as either complete (categories a and b) or incomplete (categories c and d) according to the american spinal injury association impairment scale.12 shankar ganesh and chittaranjan mishra clinical and basic research | e57 199.5 hours/day, suggesting that patients were physically active for a few hours during the day and a few days during the week. in the physical health, psychological well-being, social relationships and environment qol domains, participants had mean scores of 49.76 ± 18.74, 48.57 ± 17.04, 57.88 ± 17.04 and 49.85 ± 17.77, respectively. there was a strong association between levels of physical activity and the physical health (r = 0.819; p <0.050), psychological well-being (r = 0.776; p <0.050), social relationships (r = 0.706; p <0.050) and environment (r = 0.627; p <0.050) domains of qol [figure 1]. a weak correlation was found between employment status and the physical health (r = 0.262; p <0.050), psychological well-being (r = 0.277; p <0.050) and environment (r = 0.332; p <0.050) domains of qol. no correlation was found between employment status and the social relationship domain (r = 0.144; p >0.050). there were moderate and weak associations between the time since injury and the physical health (r = 0.456; p <0.050) and psychological well-being (r = 0.277; p <0.050) domains of qol, respectively. however, there was no significant relationship between the time since injury and the social relationships and environment domains. paraplegia severity according to ais scores was significantly related to all domains of qol (r = 0.300; p <0.050). no association was found between qol and age, gender, marital status or educational level [table 2]. according to the multiple regression analysis, none of the predictors of qol exceeded bonferroniadjusted critical values [table 3]. time since injury table 2: correlations between quality of life* and demographic characteristics and physical activity† among individuals with spinal cord injuries in odisha, india (n = 84) qol domain age gender time since injury paraplegia severity‡ employment status marital status education level physical activity physical health 0.109 -0.157 0.456§ 0.561§ 0.267 0.164 0.033 0.819¶ psychological well-being 0.142 -0.019 0.277¶ 0.358§ 0.277 0.156 0.019 0.776§ social relationships 0.032 -0.500 0.195 0.466§ 0.144 0.007 0.138 0.706§ environment 0.073 -0.048 0.198 0.330¶ 0.332 0.022 0.098 0.627§ qol = quality of life. *qol was assessed using the abbreviated version of the world health organization qol measure.3 †physical activity was assessed using the physical activity scale for individuals with physical disabilities.13 ‡paraplegia was classified as either complete (categories a and b) or incomplete (categories c and d) according to the american spinal injury association impairment scale.12 §p <0.001. ¶p <0.050. figure 1a‒d: scatter plots showing the relationship between physical activity* and (a) physical health, (b) psychological well-being, (c) social relationships and (d) environment domains of quality of life† among individuals with spinal cord injuries in odisha, india (n = 84). *physical activity was assessed using the physical activity scale for individuals with physical disabilities.13 †quality of life (qol) was assessed using the abbreviated version of the world health organization qol measure.3 physical activity and quality of life among adults with paraplegia in odisha, india e58 | squ medical journal, february 2016, volume 16, issue 1 (t = 3.274; p <0.001), employment status (t = 2.383; p <0.001) and physical activity (t = 12.550; p <0.001) were strong predictors for the physical health domain components of qol. paraplegia severity (t = 2.215; p <0.050), employment status (t = 3.458; p <0.001) and physical activity (t = 7.778; p <0.001) were strong predictors of the psychological well-being domain components of qol. marital status (t = -2.482; p <0.001), employment status (t = 1.927; p <0.001) and physical activity (t = 9.340; p <0.001) significantly predicted the social relationships domain of qol. employment status (t = 3.480; p <0.001) and physical activity (t = 7.563; p <0.001) were the two predictors found to influence the environment domain of qol. discussion among the studied individuals with sci, very low mean qol scores were reported in comparison to normal mean scores for the physical health (49.76 ± 18.74 versus 73.50 ± 18.10), psychological well-being (48.57 ± 17.04 versus 70.60 ± 14.00), social relationships (57.88 ± 17.04 versus 71.50 ± 18.20) and environment (49.85 ± 17.77 versus 75.10 ± 13.00) domains.16 the results of the current study are therefore consistent with previous research reporting poor qol in patients with sci. de frança et al. evaluated qol among 47 sci patients (mean age: 42.95 years) using the whoqol-bref and obtained mean scores of 58.59, 63.82, 68.79 and 55.20 for the physical health, psychological well-being, social relationships and environment domains, respectively.17 a statistically significant and strong positive association between physical activity and all domains table 3: multiple regression analysis of variables predicting quality of life domains* among individuals with spinal cord injuries in odisha, india (n = 84) variable b se b b p value physical health <0.050 constant 11.833 10.747 age -0.214 0.882 -0.024 gender -2.954 4.839 -0.042 paraplegia severity 2.640 3.081 0.071 time since injury 0.139 0.053 0.182 marital status 0.183 4.086 0.005 employment status 11.399 5.283 0.161 physical activity† 1.242 0.162 0.679 education level -0.739 1.242 -0.042 psychological well-being <0.050 constant -17.585 11.844 age -0.261 0.972 -0.029 gender 6.552 5.333 0.094 paraplegia severity 8.780 3.395 0.239 time since injury -0.040 0.059 -0.053 marital status 1.347 4.503 0.037 employment status 14.770 5.822 0.211 physical activity† 1.107 0.179 0.611 education level 0.269 1.368 0.015 social relationships <0.050 constant 28.532 12.371 age -0.143 1.015 -0.018 gender -1.698 5.570 -0.027 paraplegia severity 4.873 3.546 0.148 time since injury -0.032 0.061 -0.048 marital status -3.421 4.703 -0.104 employment status 6.387 6.081 0.102 physical activity† 0.899 0.187 0.554 education level -2.798 1.429 -0.179 environment <0.050 constant -9.140 12.371 age -0.487 1.075 -0.057 gender -4.849 5.898 -0.072 paraplegia severity 2.079 3.755 0.059 time since injury -0.031 0.065 -0.043 marital status 2.956 4.981 0.085 employment status 9.582 6.440 0.143 physical activity† 0.759 0.198 0.438 education level 1.527 1.514 0.092 se = standard error. *quality of life (qol) was assessed using the abbreviated version of the world health organization qol measure.3 †physical activity was assessed using the physical activity scale for individuals with physical disabilities.13 shankar ganesh and chittaranjan mishra clinical and basic research | e59 of qol was observed among the studied sample of sci patients. the mean metabolic equivalent score of the participants was suggestive of a low level of physical activity among sci patients in odisha, indicating that patients were physically active for fewer hours per day and fewer days per week than highly-active individuals with physical disabilities (36.34 ± 15.28).18 another study found that higher pasipd scores (22.5 ± 14.8) were reported by individuals with physical disabilities who rated their level of physical activity as active/extremely active.13 stevens et al. also demonstrated reduced physical activity among individuals with sci.19 low physical activity has been found to correlate strongly with qol in patients with sci.20 previous studies have found that people with disabilities are less likely to engage in physically active lifestyles than those without disabilities.21,22 reasons for the low levels of physical activity among participants in the current study were beyond the scope of this study. however, architectural barriers (i.e. a lack of transportation facilities or wheelchairaccessible environments), societal attitudes, climate, logistical issues (i.e. problems with wheelchairs), loss of motor function and a lack of knowledge about how to engage in physical activity may play decisive roles, along with psychological factors. employment status was found to be a strong predictor of all domains of qol in the current study. critically, participants had a very low postinjury employment rate. unemployment and low income may result in financial difficulties, which is an important factor affecting the qol of those with sci.23 financial hardships may also be associated with emotional problems.24 harrison et al. found that only 8% of 222 sci patients were employed following their injuries.25 another study showed a considerable drop in employment rates after sci.26 these studies indicated that unemployment rates were 10-fold higher among sci patients compared with the general population.25,26 access to place of work, employer attitudes and patients’ beliefs in their own abilities may influence the decision to resume employment following sci.26 singh et al. found that employment status was associated with a higher qol among those with sci living in india.8 chapin et al. reported that sci patients who had been successfully rehabilitated and were employed had a significantly higher qol in all four domains.27 in the current study, physical activity and employment status were found to strongly predict scores in the physical health domain of qol. reduced physical activity among individuals with sci may be related to changes in metabolism.28 among paraplegic individuals, 25% have a maximum oxygen consumption of 15 ml/kg/minute; the normal range is 34–61 ml/kg/minute for males and 30–42 ml/kg/ minute for females.29 this reduced maximum oxygen consumption is inadequate to meet the requirements of independent living.29 furthermore, the total caloric intake per day for individuals with sci is lower than that of the general population.28 these factors may result in increased fatigue during work-related or daily living activities. several studies have shown no relationship between the time since injury and qol among individuals with sci.30,31 in contrast, the current study identified a strong predictive relationship between the time since injury and the physical health domain of qol. this could be attributed to a gradual reduction in pain and improvement in function over time. in a cross sectional study, saadat et al. compared the healthrelated qol of veterans and non-veterans with sci in iran and noted that better health-related qol was associated with a longer period of time since the injury.32 hu et al. found a significant difference between patients with complete and incomplete paraplegia with regards to the environment domain of qol.33 however, the results of the current study indicated that the severity of paraplegia significantly predicted and was associated with the psychological wellbeing domain of qol. the researchers hypothesise that this finding is a result of low self-esteem and negative feelings related to a lack of control over the environment due to the severity of the disability. selfefficacy and self-esteem have been found to correlate highly with participation and contribute to a better understanding of functioning, disability and health in those with sci.34 access to the environment has been shown to be related to neurological status, with the environment more accessible to individuals with mild impairment than to those with severe impairment.35 in the current study, marital status was a significant predictor of the social relationships domain of qol. married subjects may have been less satisfied with their lives, more anxious about their sex lives and felt pressured by their inability to function normally in the household. reasons for not wanting or not having the courage to be sexually intimate may be related to physical problems, low sexual desire, low self-esteem and feelings of being unattractive.36 the findings of this study indicate that rehabilitation should aim to improve qol among individuals with sci. this may be done by facilitating shared clinical decision-making to help individuals with sci to achieve their preferences, adjust to their disability, improve their interpersonal relationships and reintegrate within the community. the development of interventions and programmes to increase levels of physical activity and quality of life among adults with paraplegia in odisha, india e60 | squ medical journal, february 2016, volume 16, issue 1 physical activity may also be effective in improving qol among this population. marital counselling, vocational rehabilitation training and creating job opportunities for those affected by sci are important components of comprehensive rehabilitation programmes. there are several potential limitations to this study. the percentage of female participants was low, which may have adversely influenced the effect of gender on qol. in addition, the study was restricted to participants who had undergone rehabilitation after sci of at least one year’s duration. this may have affected the results; a longitudinal multicentre study found that individuals with sci reported changes in the physical health domain of qol during the first two years post-injury.37 in the current study, secondary complications of sci (including pain, urinary tract infections, chronic illness and changes in bowel and bladder function) were not considered. furthermore, the qol instrument considers the level of function only at the time of assessment. despite these limitations, the present study fulfilled its objectives in identifying key predictors of qol among paraplegic individuals in a developing country. conclusion rehabilitation for individuals with sci should focus on aspects of all qol domains, including physical health, psychological well-being, social relationships and environment. a strong positive correlation between physical activity and employment status with all domains of qol was found among the studied group of individuals with sci from odisha. in light of these findings, programmes to increase physical activity and employment status among sci patients are recommended. a c k n o w l e d g e m e n t s a poster presentation of this study was displayed at the 53rd international spinal cord society scientific meeting in maastricht, the netherlands, in september 2014. an abstract of the poster was published in the abstracts booklet for this meeting. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. trieschmann rb. spinal cord injuries: psychological, social, and vocational rehabilitation. 2nd ed. new york, usa: demos publications, 1998. pp. 1–24. 2. forchheimer m, tate dg. enhancing community re-integration following spinal cord injury. neurorehabilitation 2004; 19:103–13. 3. the world health organization quality of life group. development of the world health organization whoqolbref quality of life assessment. psychol med 1998; 28:551–8. doi: 10.1017/s0033291798006667. 4. wilson jr, hashimoto re, dettori jr, fehlings mg. spinal cord injury and quality of life: a systematic review of outcome measures. evid based spine care j 2011; 2:37–44. doi: 10.1055/ s-0030-1267085. 5. dijkers m. quality of life after spinal cord injury: a meta analysis of the effects of disablement components. spinal cord 1997; 35:829–40. doi: 10.1038/sj.sc.3100571. 6. hagen em, rekand t, gilhus ne, grønning m. traumatic spinal cord injuries: incidence, mechanisms and course. tidsskr nor laegeforen 2012; 132:831–7. doi: 10.4045/tidsskr.10.0859. 7. gupta a, deepika s, taly ab, srivastava a, surender v, thyloth m. quality of life and psychological problems in patients undergoing neurological rehabilitation. ann indian acad neurol 2008; 11:225–30. doi: 10.4103/0972-2327.44557. 8. singh r, dhankar ss, rohilla r. quality of life of people with spinal cord injury in northern india. int j rehabil res 2008; 31:247–51. doi: 10.1097/mrr.0b013e3282fb7d25. 9. tasiemski t, priebe mm, wilski m. life satisfaction and life values in people with spinal cord injury living in three asian countries: a multicultural study. j spinal cord med 2013; 36:118–26. doi: 10.1179/2045772312y.0000000074. 10. geyh s, ballert c, sinnott a, charlifue s, catz a, d’andrea greve jm, et al. quality of life after spinal cord injury: a comparison across six countries. spinal cord 2013; 51:322–6. doi: 10.1038/sc.2012.128. 11. manns pj, chad ke. components of quality of life for persons with a quadriplegic and paraplegic spinal cord injury. qual health res 2001; 11:795–811. doi: 10.1177/10497320112911 9541. 12. spinal cord injury research evidence project. american spinal injury association impairment scale (ais): international standards for neurological classification of spinal cord injury. from: www.scireproject.com/outcome-measures-new/americ a n s p i n a l i n j u r y a s s o c i a t i o n i m p a i r m e n ts c a l e a i s international-standards accessed: oct 2015. 13. washburn ra, zhu w, mcauley e, frogley m, figoni sf. the physical activity scale for individuals with physical disabilities: development and evaluation. arch phys med rehabil 2002; 83:193–200. 14. van der ploeg hp, streppel kr, van der beek aj, van der woude lh, vollenbroek-hutten m, van mechelen w. the physical activity scale for individuals with physical disabilities: test-retest reliability and comparison with an accelerometer. j phys act health 2007; 4:96–100. 15. hill mr, noonan vk, sakakibara bm, miller wc; scire research team. quality of life instruments and definitions in individuals with spinal cord injury: a systematic review. spinal cord 2010; 48:438–50. doi: 10.1038/sc.2009.164. 16. hawthorne g, herrman h, murphy b. interpreting the whoqol-brèf: preliminary population norms and effect sizes. soc indic res 2006; 77:37–59. doi: 10.1007/s11205-0055552-1. 17. de frança is, coura as, de frança eg, basílio nn, souto rq. [quality of life adults with spinal cord injury: a study using the whoqol-bref.] rev esc enferm usp 2011; 45:1346–71. doi: 10.1590/s0080-62342011000600013. 18. giacobbi pr jr, stancil m, hardin b, bryant l. physical activity and quality of life experienced by highly active individuals with physical disabilities. adapt phys activ q 2008; 25:189–207. http://dx.doi.org/10.1017/s0033291798006667 http://dx.doi.org/10.1055/s-0030-1267085 http://dx.doi.org/10.1055/s-0030-1267085 http://dx.doi.org/10.1038/sj.sc.3100571 http://dx.doi.org/10.4045/tidsskr.10.0859 http://dx.doi.org/10.4103/0972-2327.44557 http://dx.doi.org/10.1097/mrr.0b013e3282fb7d25 http://dx.doi.org/10.1179/2045772312y.0000000074 http://dx.doi.org/10.1038/sc.2012.128 http://dx.doi.org/10.1177/104973201129119541 http://dx.doi.org/10.1177/104973201129119541 http://www.scireproject.com/outcome-measures-new/american-spinal-injury-association-impairment-scale-ais-international-standards http://www.scireproject.com/outcome-measures-new/american-spinal-injury-association-impairment-scale-ais-international-standards http://www.scireproject.com/outcome-measures-new/american-spinal-injury-association-impairment-scale-ais-international-standards http://dx.doi.org/10.1038/sc.2009.164 http://dx.doi.org/10.1007/s11205-005-5552-1 http://dx.doi.org/10.1007/s11205-005-5552-1 http://dx.doi.org/10.1590/s0080-62342011000600013 shankar ganesh and chittaranjan mishra clinical and basic research | e61 19. stevens sl, caputo jl, fuller dk, morgan dw. physical activity and quality of life in adults with spinal cord injury. j spinal cord med 2008; 31:373–8. 20. dijkers mp. correlates of life satisfaction among persons with spinal cord injury. arch phys med rehabil 1999; 80:867–76. doi: 10.1016/s0003-9993(99)90076-x. 21. rimmer jh. health promotion for people with disabilities: the emerging paradigm shift from disability prevention to prevention of secondary conditions. phys ther 1999; 79:495–502. 22. rimmer jh. health promotion for individuals with disabilities: the need for a transitional model in service delivery. dis manag health outcomes 2002; 10:337–43. doi: 10.2165/00115677200210060-00002. 23. tasiemski t, nielsen s, wilski m. quality of life in people with spinal cord injury: earthquake survivors from sichuan province in china. asia pac disabil rehabil j 2010; 21:28–36. 24. migliorini ce, new pw, tonge bj. comparison of depression, anxiety and stress in persons with traumatic and non-traumatic post-acute spinal cord injury. spinal cord 2009; 47:783–8. doi: 10.1038/sc.2009.43. 25. harrison c, kuric j. community reintegration of sci persons: problems and perceptions. sci nurs 1989; 6:44–7. 26. ottomanelli l, lind l. review of critical factors related to employment after spinal cord injury: implications for research and vocational services. j spinal cord med 2009; 32:503–31. 27. chapin mh, holbert d. employment at closure is associated with enhanced quality of life and subjective well-being for persons with spinal cord injuries. rehabil couns bull 2010; 54:6–14. doi: 10.1177/0034355210367685. 28. groah sl, nash ms, ljungberg ih, libin a, hamm lf, ward e, et al. nutrient intake and body habitus after spinal cord injury: an analysis by sex and level of injury. j spinal cord med 2009; 32:25–33. 29. noreau l, shephard rj. spinal cord injury, exercise and quality of life. sports med 1995; 20:226–50. doi: 10.2165/00007256199520040-00003. 30. barker rn, kendall md, amsters di, pershouse kj, haines tp, kuipers p. the relationship between quality of life and disability across the lifespan for people with spinal cord injury. spinal cord 2009; 47:149–55. doi: 10.1038/sc.2008.82. 31. ebrahimzadeh mh, soltani-moghaddas sh, birjandinejad a, omidi-kashani f, bozorgnia s. quality of life among veterans with chronic spinal cord injury and related variables. arch trauma res 2014; 3:e17917. doi: 10.5812/atr.17917. 32. saadat s, javadi m, divshali bs, tavakoli ah, ghodsi sm, montazeri a, et al. health-related quality of life among individuals with long-standing spinal cord injury: a comparative study of veterans and non-veterans. bmc public health 2010; 10:6. doi: 10.1186/1471-2458-10-6. 33. hu y, mak jn, wong yw, leong jc, luk kd. quality of life of traumatic spinal cord injured patients in hong kong. j rehabil med 2008; 40:126–31. doi: 10.2340/16501977-0150. 34. geyh s, nick e, stirnimann d, ehrat s, michel f, peter c, et al. self-efficacy and self-esteem as predictors of participation in spinal cord injury: an icf-based study. spinal cord 2012; 50:699–706. doi: 10.1038/sc.2012.18. 35. richards js, bombardier ch, tate d, dijkers m, gordon w, shewchuk r, et al. access to the environment and life satisfaction after spinal cord injury. arch phys med rehabil 1999; 80:1501–6. doi: 10.1016/s0003-9993(99)90264-2. 36. kreuter m, siösteen a, erkholm b, byström u, brown dj. health and quality of life of persons with spinal cord lesion in australia and sweden. spinal cord 2005; 43:123–9. doi: 10.1038/sj.sc.3101692. 37. lude p, kennedy p, elfström ml, ballert cs. quality of life in and after spinal cord injury rehabilitation: a longitudinal multicenter study. top spinal cord inj rehabil 2014; 20:197–207. doi: 10.1310/sci2003-197. http://dx.doi.org/10.1016/s0003-9993%2899%2990076-x http://dx.doi.org/10.2165/00115677-200210060-00002 http://dx.doi.org/10.2165/00115677-200210060-00002 http://dx.doi.org/10.1038/sc.2009.43 http://dx.doi.org/10.1177/0034355210367685 http://dx.doi.org/10.2165/00007256-199520040-00003 http://dx.doi.org/10.2165/00007256-199520040-00003 http://dx.doi.org/10.1038/sc.2008.82 http://dx.doi.org/10.5812/atr.17917 http://dx.doi.org/10.1186/1471-2458-10-6 http://dx.doi.org/10.2340/16501977-0150 http://dx.doi.org/10.1038/sc.2012.18 http://dx.doi.org/10.1016/s0003-9993%2899%2990264-2 http://dx.doi.org/10.1038/sj.sc.3101692 http://dx.doi.org/10.1310/sci2003-197 department of pharmacology, gujarat medical education & research society medical college, gotri, vadodara, gujurat, india *corresponding author e-mail: dr.tkp2006@yahoo.co.in إدراك استخدام املخطط التفصيلي للتقييم النظري التشكيلي يف تدريس علم األدوية تيج��س ب�تيل, م�نوج كوم�ر �شورب�ه, براف�تي ب�تيل abstract: objectives: this study aimed to assess perceptions of the use of a blueprint in a pharmacology formative theory assessment. methods: this study took place from october 2015 to february 2016 at a medical college in gujurat, india. faculty from the department of pharmacology used an internal syllabus to prepare an assessment blueprint. a total of 12 faculty members prepared learning objectives and categorised cognitive domain levels by consensus. learning objectives were scored according to clinical importance and marks were distributed according to proportional weighting. a three-dimensional test specification table of syllabus content, assessment tools and cognitive domains was prepared. based on this table, a theory paper was created and administered to 126 pharmacology students. feedback was then collected from the faculty members and students using a 5-point likert scale. results: the majority of faculty members agreed that using a blueprint ensured proper weighting of marks for important topics (90.00%), aligned questions with learning objectives (80.00%), distributed questions according to clinical importance (100.00%) and minimised inter-examiner variations in selecting questions (90.00%). few faculty members believed that use of the blueprint created too many easy questions (10.00%) or too many difficult questions (10.00%). most students felt that the paper had a uniform distribution of questions from the syllabus (90.24%), that important topics were appropriately weighted (77.23%), was well organised (79.67%) and tested indepth subject knowledge (74.80%). conclusion: these findings indicate that blueprinting should be an integral part of written assessments in pharmacology education. keywords: medical education; educational measurement; perceptions; students; faculty; reliability and validity. الأدوية. علم يف الت�شكيلي النظري للتقييم التف�شيلي املخطط ا�شتخدام اإدراك تقييم اإىل الدرا�شة هذة تهدف الهدف: امللخ�ص: الطريقة: اأجريت هذة الدرا�شة من اأكتوبر 2015 اإىل فرباير 2016 يف كلية الطب بجوجرات, الهند. ق�م اأع�ش�ء هيئة التدري�س بق�شم علم الأدوية ب��شتخدام املنهج الداخلي لتح�شري التقييم للمخطط التف�شيلي. اأعد 12 من اأع�ش�ء هيئة التدري�س اأهداف التعليم ومت ت�شنيف م�شتوي�ت جم�لت املعرفة ب�لإجم�ع. مت ت�شجيل اأهداف التعليم وفق� لأهميته� ال�رسيرية و كذلك مت توزيع الدرج�ت ح�شب الرتجيح الن�شبي. مت اأعداد اأختب�ر ثالثي الأبع�د بن�ءا على ق�ئمة حمتوي�ت املنهج, اأدوات التقييم, واملج�لت املعرفية. بن�ءا على هذة الق�ئمة, مت اأنت�ج ورقة نظرية و تقدميه� لعدد 126 ط�لب� يف علم الأدوية. مت جمع ردود الأفع�ل من هيئة التدري�س و الطلبة ب��شتخدام مقي��س ليكرت ذو اخلم�س نق�ط. النتائج: الغ�لبية العظمى من اأع�ش�ء هيئة التدري�س اأتفقوا على اأن اأ�شتخدام املخطط التف�شيلي يكفل التوازن ال�شحيح للدرج�ت ب�لن�شبة للموا�شيع اله�مة )%90.00(, مت��شي الأ�شئلة مع اأهداف التعليم )%80.00(, توزيع الأ�شئلة ح�شب الأهمية ال�رسيرية )%100.00( و التقليل من الأختالف�ت بني املمتحنني يف اإختي�ر الأ�شئلة )%90.00(. اأعتقد القليل من اأع�ش�ء هيئة التدري�س اأن ا�شتخدام املخطط التف�شيلي خلق العديد من الأ�شئلة ال�شهلة )%10.00( اأو الكثري من الأ�شئلة ال�شعبة )%10.00(. �شعر معظم الطلبة اأن الورقة �شملت توزيع متم�ثل لالأ�شئلة من املنهج )%90.24(, املوا�شيع املهمة ك�نت ذات توازن جيد )%77.23(, وك�نت منظمة )%79.67( و اأختربت املعرفة املتعمقة للموا�شيع )%74.80(. اخلال�صة: ت�شري هذة النت�ئج اإىل �رسورة اأن يكون املخطط التف�شيلي جزءا ل يتجزاأ من التقييم الكت�بي يف تدري�س علم الأدوية. الكلمات املفتاحية: التعليم الطبي؛ قي��س التعليم؛ الإدراك؛ الطلبة؛ هيئة التدري�س؛ املوثوقية و امل�شداقية. perceptions of the use of blueprinting in a formative theory assessment in pharmacology education *tejas patel, manoj k. saurabh, parvati patel clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e475–481, epub. 30 nov 16 submitted 25 apr 16 revisions req. 12 jun & 31 jul 16; revisions recd. 9 jul & 6 aug 16 accepted 11 aug 16 doi: 10.18295/squmj.2016.16.04.012 advances in knowledge this study prepared a blueprint for a formative theory assessment in pharmacology. a blueprint aligns an assessment with learning objectives and distributes questions according to weighting based on clinical importance and the core learning objectives of the syllabus. the findings of this study indicated that the majority of the faculty members and students had positive perceptions of the use of blueprinting in the formation of the assessment. application to patient care a blueprint is an important approach to stimulating deep learning among medical students, thus indirectly influencing future patient care and clinical practice. positive attitudes towards scientific research among undergraduate medical students is likely to enhance the quality of future patient care. perceptions of the use of blueprinting in a formative theory assessment in pharmacology education e476 | squ medical journal, november 2016, volume 16, issue 4 written examinations are the most commonly employed method to assess knowledge in medical education and are used to test recall abilities as well as higher-order cognitive functions, such as the interpretation of data and problem-solving skills.1,2 valid assessment methods are necessary to determine whether students have learned the required information.3 content validity gauges the extent to which an assessment covers a representative sample of the material which should be assessed; for example, if examination questions cover the learning objectives of the syllabus, the examination is considered to have content validity.4 in contrast, construct validity covers all aspects of subject knowledge such as application, data gathering and interpretation as a collection of interrelated components, which together allow for the assessment to make sense.5 construct under-representation and construct irrelevance variance are two important challenges to construct validity. if an examiner creates a test with overly easy or difficult questions, asks well-known questions or uses unnecessarily complex language, it would mean that there is construct irrelevance variance, which can lead to the inflation or deflation of test scores.6,7 content under-representation in a paper can occur due to the inadequate weighting of marks for clinically relevant topics, unequal distribution of course content across the assessment or examiner bias, such as a tendency to focus on popular topics.7 moreover, the teachers who deliver lectures are usually not the ones who create the assessments; this can reduce the content and construct validity of an assessment, which in turn can lead to a mistrust in the assessment system on the part of the students.7,8 content imbalance may also result in students focusing less on key areas of learning during revision.7 for an assessment paper to be valid, it should match course content, have proportional weighting of content according to clinical importance, consist of questions which are neither overly difficult nor easy and have multiple tools to determine various types of information.7 blueprinting can be defined as the creation of a template to determine the content of a test; it lists the number and type of questions across the course content, with learning objectives and relative weight ing given to each topic.7,8 a blueprint provides a systematic multi-step approach to an assessment, defining the purpose (e.g. formative/summative and written/practical) and scope (e.g. for undergraduate or postgraduate students) of the test in order to subsequently determine content and method of assessment. based on the content, learning object ives and their domains are identified and different assessment tools are chosen, such as short answer questions (saqs), essay questions (eqs) or multiple choice questions.7,8 the content of the assessment is then proportionally weighted as per clinical importance, learning domains and methods of assessment. the total weighting of the number of items to be included in the assessment is decided and a three-dimensional (3d) table of test specifications is prepared to align content, learning domains and assessment tools, as well as prepare individual questions.7,8 blueprinting is increasingly used in the field of medical education worldwide.9,10 in the uk, assessments created using a blueprint are considered essential to enable future doctors to meet mandatory standards; the assessments are prepared in such a way that students who have not met important learning outcomes are not able to graduate.10 previous research indicates that blueprinting optimises student assessment, making a positive impact and helping them to focus on key areas in an examination, thereby improving performance.11–13 this approach can reduce inter-individual variability by providing guidance to examiners; moreover, set question papers are usually more valid and reliable than those created without a blueprint.7 however, studies conducted on the use of blueprinting in india are scarce. at the gujarat medical education & research society (gmers) medical college in gotri, vadodara, gujurat, india, a five-year undergraduate medical education programme results in a bachelor of medicine and bachelor of surgery (mbbs). pharmacology education is mainly taught to second-year mbbs students for a total of three semesters of six months’ duration each. the assessment system consists of one summative and two formative examinations, with two written papers in the summative examination and one written paper in one of the formative examinations. each paper is scored out of 58 marks, although students now receive up to 40 marks due to optional questions. the papers include constructed-response open-ended questions including eqs (4 marks each), short eqs (3 marks each) and saqs (2 marks each); the maximum number of marks for eqs, short eqs and saqs are 20, 24 and 14, respectively. in order to pass, a student must get at least 50% on the examination. traditionally, the assessment content is determined by a paper setter who selects the questions according to the syllabus and question format. this study aimed to prepare a blueprint for a written theory paper and to analyse subsequent feedback on its use in a formative examination by pharmacology faculty members and students. tejas patel, manoj k. saurabh and parvati patel clinical and basic research | e477 methods this study was conducted between october 2015 and february 2016 at the department of pharmacology of gmers medical college. in order to familiarise departmental faculty members with the concept of preparing a theory paper via blueprinting, a pilot test consisting of 16 saqs worth two marks each was administered to 12 members of the faculty. a halfday interactive session was then conducted in three sessions: the first focused on assessment methods and tools, the second on validity and reliability in assessments and the third on the purpose and implementation of blueprinting, including the weighting of topics and assessment methods and how to prepare tables of test specifications. faculty members were then re-tested using the same saqs in order to determine the learning outcomes of the interactive session. the syllabus of the first formative theory examination for second-year mbbs students was used to prepare a blueprint for the written paper, consisting of seven topics: general pharmacology; the autonomic nervous system; the peripheral nervous system; the respiratory system; the gastrointestinal tract; autacoid-related drugs; and drugs affecting blood and blood formation. a literature review of the undergraduate regulations, vision documents, essential drug lists and national health programmes of the medical council of india as well as pharmacology textbooks and previous test papers was undertaken to determine learning objectives for each topic.14–20 each learning objective was categorised into either recall or reasoning domain categories as per miller’s pyramid of competence.21 learning objectives and cognitive domain categorisations were then discussed by the same 12 faculty members who had participated in the pilot test. each faculty member scored learning objectives individually according to clinical importance, with a score of 3 indicating high importance, a score of 2 indicating moderate importance and a score of 1 reflecting little/no clinical importance.7 mean scores for each learning objective were calculated using a microsoft excel spreadsheet, version 2010 (microsoft corp., redmond, washington, usa). differences were resolved via consensus. based on the learning objective scores, total scores were calculated for each topic as well as the overall syllabus. proportional weighting was calculated for each topic by dividing the topic score with the total syllabus score.3,7 table 1 shows the learning objectives, total scores, proportional weighting and mark distribution calculations. based on the literature review and faculty consensus, a total of 292 learning objectives were identified. the total syllabus score was 663 and the maximum number of marks on the theory test paper was 58, with marks in each topic weighted proportionally. in the next phase, a 3d table of test specifications for the distribution of marks was prepared by aligning content, assessment tools and cognitive domain categories. table 2 shows the 3d table of test specifications, representing the mark distribution for each topic according to assessment tool (e.g. eq, short eq or saq) and cognitive domain category (i.e. recall or reasoning). in terms of assessment tools, eqs were used only to assess reasoning abilities (20 marks; 100.00%). short eqs were more often used to assess reasoning (15 marks; 62.50%) rather than table 1: learning objectives, mean total scores, proportional weighting and distribution of marks per syllabus topic syllabus topic learning objectives mean total score* proportional weighting† distribution of marks‡ general pharmacology 87 201 0.30 17.40 (17) autonomic nervous system 70 163 0.25 14.50 (15) peripheral nervous system 24 45 0.07 4.06 (4) gastrointestinal tract 21 44 0.07 4.06 (4) respiratory tract 17 43 0.06 3.48 (4) autacoid-related drugs 31 71 0.11 6.38 (6) drugs affecting blood and blood formation 42 96 0.14 8.12 (8) total 292 663 1.00 58.00 (58) *learning objectives were scored by faculty members according to clinical importance, with a score of 3 indicating high importance, a score of 2 indicating moderate importance and a score of 1 reflecting little/no clinical importance. †proportional weighting was calculated by dividing the mean total score per topic by the total syllabus score. ‡distribution of marks was determined by multiplying the proportional weighting by the total number of marks overall. the numbers within the brackets show the actual marks allotted per topic in the test paper. perceptions of the use of blueprinting in a formative theory assessment in pharmacology education e478 | squ medical journal, november 2016, volume 16, issue 4 recall (9 marks; 37.50%). in comparison, saqs were more frequently used to test recall (8 marks; 57.14%) rather than reasoning (6 marks; 42.86%). overall, the distribution of recall (17 marks; 29.31%) to reasoning (41 marks; 70.69%) marks was approximately 30:70. based on the blueprint, a paper setter prepared individual test questions following good practices.7 the questions were framed using directive verbs from the revised bloom’s taxonomy of learning domains to assess the appropriate cognitive domain according to the blueprint and to give students clear directions for their responses.22 the verb “remember” was used to frame recall questions, while the verbs “understand”, “apply” and “analyse” were used for reasoning questions.22 the verbs “evaluate” and “create” were not used. the paper setter selected questions of high, moderate and no/little clinical importance in a ratio of 60:30:10. the paper was then administered to a total of 126 second year pharmacology students. the 12 faculty members were requested to provide feedback regarding their perceptions of the quality and use of the theory assessment paper designed using blueprinting. they were provided with two previous assessment papers for comparison. feedback was collected using closedand open-ended questionnaires. for the former, participants were given 14 statements and asked to respond on a 5-point likert scale using the following responses: strongly disagree, disagree, neutral, agree and strongly agree. in the open-ended questionnaire, they were asked to describe benefits and difficulties in the preparation and implementation of the blueprint as well as the feasibility of this approach for future implementation in formative assessments. the perceptions of the students regarding the paper were determined one week after the assessment. a questionnaire consisting of nine statements was distributed and the students were asked to respond on the previously described 5-point likert scale. for the pilot test, the saq scores of the faculty members were presented as means and standard deviations and compared using a paired t-test. results from the feedback questionnaires were presented as percentages. strongly disagree and disagree responses were merged, as were the agree and strongly agree responses. statistical analysis was performed using graphpad prism, version 6.0 (graphpad software inc., la jolla, california, usa). a p value of <0.050 was considered statistically significant. this study received ethical approval from the institutional human ethics committee of gmers medical college, gotri (ihec #101/2015/ pharmacology-16). informed consent was obtained from the faculty and undergraduate medical students before data collection. results among the 12 faculty members, the mean test scores before and after the interactive session were 7.72 ± 4.19 and 19.29 ± 5.29, respectively, out of a maximum score of 32 (paired t-test t-value: 10.23; degree of freedom: 11; p <0.001). in total, 10 out of 12 faculty members gave their opinions of the blueprint (response rate: 83.33%). the two remaining faculty members were transferred before the formative assessment was conducted. all of the faculty members agreed that the blueprint ensured a uniform distribution of questions across the syllabus topics, helped to maintain a balance between questions in the recall and reasoning domains and assured the distribution of questions according to clinical importance. in addition, the majority agreed table 2: table of test specifications showing the distribution of marks for each topic according to assessment tool and cognitive domain category syllabus topic marks allotted (questions) eqs short eqs saqs total reasoning recall reasoning recall reasoning general pharmacology 8 (2) 3 (1) 3 (1) 2 (1) 2 (1) 18 (6) autonomic nervous system 4 (1) 3 (1) 3 (1) 2 (1) 2 (1) 14 (5) peripheral nervous system 3 (1) 3 (1) gastro-intestinal tract 3 (1) 2 (1) 5 (2) respiratory system 4 (1) 4 (1) autacoid-related drugs 4 (1) 2 (1) 6 (2) drugs affecting blood and blood formation 3 (1) 3 (1) 2 (1) 8 (3) total 20 (5) 9 (3) 15 (5) 8 (4) 6 (3) 58 (20) eqs = essay questions; saqs = short answer questions. tejas patel, manoj k. saurabh and parvati patel clinical and basic research | e479 that the blueprint resulted in the adequate weighting of important topics (90.00%), aligned questions with learning objectives (80.00%), ensured well-organised theory test papers (70.00%), tested in-depth subject knowledge (60.00%) and minimised inter-examiner variations in selecting questions (90.00%). few faculty members believed that the blueprint created too many easy questions (10.00%) or too many difficult questions (10.00%) [figure 1]. the majority of faculty members (90.00%) believed that a blueprint should be incorporated into the design of future examinations and all of them agreed that the blueprint should be an integral part of theory paper framing. moreover, the majority of faculty members thought that blueprints should be prepared for the entire syllabus (90.00%) and that there was a need to change teaching schedules as per the blueprint (90.00%) [figure 2]. table 3 summarises faculty responses to open-ended questions about their perceptions of the blueprint and assessment paper. a total of 123 out of 126 students provided feed back regarding the formative assessment paper (response rate: 97.62%). the majority of students believed that the distribution of questions was uniform and covered each topic (90.24%) and allowed for proper weighting of clinically important topics (77.23%). in addition, the paper was generally perceived to be well organised (79.67%). most of the students believed that all of the questions were from the defined syllabus (90.24%) and that the paper tested in-depth knowledge of the subject (74.80%). overall, few students believed that there were too many easy questions (12.20%) or too many difficult questions (9.75%); indeed, only a minority of the students felt that the paper was exhausting/lengthy (26.83%) or stressful (17.08%) [figure 3]. discussion an assessment drives, directs and influences learning and is a tool for educational improvement.7,23 students successfully learn when a relationship exists between teaching, assessment and results. in an assessment, every question format (e.g. eqs, short eqs and saqs) has advantages and disadvantages; using a variety of formats helps to counter the possible bias associated with one individual format.1 a blueprint helps to figure 1: perceptions of faculty members regarding the use of a blueprint in the formation of a pharmacology theory assessment paper (n = 10). *one faculty member did not respond to these statements. figure 2: perceptions of faculty members regarding the feasibility of future implementation of a blueprint in pharmacology education (n = 10). table 3: summary of faculty responses to open-ended questions regarding the use of a blueprint in the formation of a pharmacology theory assessment paper (n = 10) open-ended responses what are the advantages of using a blueprint? •it makes the assessment more objective •there is less chance of subjectivity, bias and prejudice •it makes the theory test examination fairer •students are tested on different cognitive domains •it is easy for the examiner to prepare question papers •it creates a well-organised paper and syllabus what are the disadvantages of using a blueprint? •it is time-consuming to score learning objectives by clinical importance •it takes time to adjust marks according to recall and reasoning domains •it is sometimes difficult to reach a consensus between faculty members •it will require periodic revisions in future •the choice of questions is restricted •there is a chance that questions in the paper will be more predictable what were the differences between the paper created with a blueprint and previous years’ papers? •the questions in the blueprint-created paper were more specific •the distribution of marks and questions followed the recommendations of the blueprint •there was greater clarity in student assessment •the blueprint-created paper allowed for more questions in a higher-function cognitive domain •the paper devised with a blueprint was well structured perceptions of the use of blueprinting in a formative theory assessment in pharmacology education e480 | squ medical journal, november 2016, volume 16, issue 4 ensure the balance between different format questions by specifying the content, learning domains across the syllabus and assessment tools of an examination in a rational manner.7,8 in the current study, a blueprint was used to create a written assessment paper for pharmacology students; learning objectives were identified and syllabus topics were marked using a proportional weighting system based on clinical importance to ensure content validity. moreover, the paper assessed not only knowledge recall, but also understanding, application and critical analysis abilities using the interrelated cognitive domain of reasoning, thus ensuring construct validity.5 in the current study, the majority of faculty members and students agreed that the use of a blueprint in the formation of a pharmacology forma tive assessment paper resulted in a uniform distribution of questions and adequate weighting of clinically important topics and testing of in-depth subject knowledge. faculty members also agreed that the test paper struck an appropriate balance between questions in the recall and reasoning domains and that the questions were aligned with the learning objectives of the syllabus. these findings suggest that the test paper created through the blueprint was able to avoid construct under-representation. previous research has also indicated that the use of a blueprint in assessment ensures coverage of all aspects of the curriculum, learning objectives and educational domains.5,24,25 very few faculty members and students in the current study believed that the assessment contained questions which were too easy or too difficult; this suggests that the use of a blueprint resulted in a rational paper and avoided construct irrelevance variance. moreover, the blueprint seemed to make the assessment more ‘fair’ in the eyes of both faculty members and students. the experience of an authentic assessment seems to be a motivating factor; among medical students, a fair assessment has been reported to stimulate a deep approach to learning when tailored to curricular objectives.26 this may subsequently affect clinical practice and patient care once the students have graduated. earlier reports in the literature have provided evidence that blueprints make it easier for an examiner to select questions, set papers according to accepted norms and standards, test higher-order cognitive domains and create well-organised theory papers.7,24 these findings were also reflected in the current study during faculty responses to open-ended questions concerning the benefits of blueprinting. however, certain challenges to the use of blueprinting were also identified; many faculty members stated that the preparation of a blueprint was time-consuming and that it was occasionally difficult to reach a consensus. nevertheless, despite these barriers, the majority of faculty members found blueprinting to be a promising approach for preparing assessment papers and indicated that they would use this approach in future examinations and change their teaching patterns accordingly. overall, the use of a blueprint in a formative assessment paper had a positive impact on faculty perceptions; it is therefore realistic to recommend the inclusion of this approach as a valid tool to frame theory papers for summative assessment. nevertheless, the data from this study would be more valuable if they were combined with evidence of increased academic achievement due to the blueprint; unfortunately, the study was limited in this regard as the students’ performance could not be compared to students in previous years due to the differences in syllabus. conclusion according to the perceptions of both pharmacology faculty members and students, the use of blueprinting in the formation of a written formative assessment paper was found to result in high content and construct validity. as this approach helps to align the content, cognitive domains and assessment tools of a paper in a rational way, it should be implemented as an integral part of the framing of theory assessments in future. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. figure 3: perceptions of students regarding the use of a blueprint in the formation of a pharmacology theory assessment paper (n = 123). tejas patel, manoj k. saurabh and parvati patel clinical and basic research | e481 a c k n o w l e d g e m e n t s the authors wish to thank all of the faculty members and students who participated in this study. in addition, they are grateful to dr. neena doshi of the gmers medical college, gotri, for critically reviewing the manuscript before publication. references 1. al-wardy nm. assessment methods in undergraduate medical education. sultan qaboos univ med j 2010; 10:203–9. 2. ghosh a, mandal a, das n, tripathi sk, biswas a, bera t. students’ performance in written and viva-voce components of final summative pharmacology examination in mbbs curriculum: a critical insight. indian j pharmacol 2012; 44:274–75. doi: 10.4103/0253-7613.93870. 3. tabish sa. assessment methods in medical education. int j health sci (qassim) 2008; 2:3–7. 4. alias m. assessment of learning outcomes: validity and reliability of classroom tests. world trans eng technol edu 2005; 4:235–8. 5. adkoli bv. attributes of a good question paper. in: sood r, ed. assessment in medical education: trends and tools, 1st ed. new delhi, india: kl wig centre for medical education & technology, 1995. pp. 65–82. 6. downing sm. threats to the validity of locally developed multiple-choice tests in medical education: constructirrelevant variance and construct underrepresentation. adv health sci educ theory pract 2002; 7:235–41. doi: 10.1023/ a:1021112514626. 7. adkoli bv, deepak kk. blueprinting in assessment. in: singh t, anshu, eds. principles of assessment in medical education, 1st ed. new delhi, india: jaypee brothers medical publishers ltd., 2012. pp. 205–13. doi: 10.5005/jp/books/11647_19. 8. patil sy, gosavi m, bannur hb, ratnakar a. blueprinting in assessment: a tool to increase the validity of undergraduate written examinations in pathology. int j appl basic med res 2015; 5:s76–9. doi: 10.4103/2229-516x.162286. 9. ten cate o. medical education in the netherlands. med teach 2007; 29:752–7. doi: 10.1080/01421590701724741. 10. general medical council. assessment in undergraduate medical education. from: www.gmc-uk.org/assessment_in_ undergraduate_me dical_e ducation___guidance_under_ review_0815.pdf_56439668.pdf accessed: aug 2016. 11. mookherjee s, chang a, boscardin ck, hauer ke. how to develop a competency-based examination blueprint for longitudinal standardized patient clinical skills assessments. med teach 2013; 35:883–90. doi: 10.3109/0142159x.2013.809408. 12. ahmad rg, hamed oa. impact of adopting a newly developed blueprinting method and relating it to item analysis on students’ performance. med teach 2014; 36:s55–61. doi: 10.31 09/0142159x.2014.886014. 13. mclaughlin k, coderre s, woloschuk w, mandin h. does blueprint publication affect students’ perception of validity of the evaluation process? adv health sci educ theory pract 2005; 10:15–22. doi: 10.1007/s10459-004-8740-x. 14. medical council of india. regulations on graduate medical education, 1997. from: www.mciindia.org/rules-and-regu lation/gme_regulations.pdf accessed: aug 2016. 15. medical council of india. vision 2015. from: www.mciindia. org/tools/announcement/mci_booklet.pdf accessed: aug 2016. 16. central drugs standard control organization. report of the core-committee for revision of national list of essential medicines: november 2015. from: cdsco.nic.in/ wr i t e r e a d d a t a / n l e m 2 0 1 5 / r e c o m m e n d a t i o n s . p d f accessed: aug 2016. 17. katzung bg, masters sb, trevor aj. basic and clinical pharmacology, 12th ed. new york, usa: mcgraw-hill medical, 2012. pp. 1–1170. 18. tripathi kd. essentials of medical pharmacology, 7th ed. new delhi, india: jaypee brothers medical publishers ltd., 2013. pp. 1–973. 19. satoskar rs, rege nn, bhandarkar sd. pharmacology and pharmacotherapeutics, 24th ed. guragon, india: elsevier health inr, 2015. pp. 1–1127. 20. sharma hl, sharma kk. principles of pharmacology, 2nd ed. hyderabad, india: paras publications, 2012. pp. 1–928. 21. miller ge. the assessment of clinical skills/competence/ performance. acad med 1990; 65:s63–7. doi: 10.1097/00001888199009000-00045. 22. adams ne. bloom’s taxonomy of cognitive learning objectives. j med libr assoc 2015; 103:152–3. doi: 10.3163/1536-5050. 103.3.010. 23. astin aw, banta tw, cross kp, el-khawas e, ewell pt, hutchings p, et al. american association for higher education (aahe) principles of good practice for assessing student learning. from: www.algonquincollege.com/profres/ files/2013/10/9-principles-of-good-practice-for-assessingstudent-learning.pdf accessed: aug 2016. 24. patil sy, hashilkar nk, hungund br. blueprinting in assessment: how much is imprinted in our practice? j educ res med teach 2014; 2:4–6. 25. coderre s, woloschuk w, mclaughlin k. twelve tips for blueprinting. med teach 2009; 31:322–4. doi: 10.1080/ 01421590802225770. 26. al kadri hm, al-moamary ms, magzoub me, roberts c, van der vleuten c. students’ perceptions of the impact of assessment on approaches to learning: a comparison between two medical schools with similar curricula. int j med educ 2011; 2:44–52. doi: 10.5116/ijme.4ddb.fc11. وبائية داء السكري يف سلطنة عمان نتائج عقدين من البحوث جواد اللوالتي، برا�سانت بندغرا، هالة ال�سيخ، جمدي مر�سي، نبيل حم�سن، راجيف خانديكار، حوراء اللواتية، ريا�ض بيومي abstract: objectives: this study aimed to describe the epidemiology of diabetes mellitus over the past two decades in oman, particularly in terms of its prevalence and incidence. in addition, the study sought to estimate the future incidence of diabetes in oman. methods: three national and three regional surveys conducted between 1991 and 2010 were analysed to obtain the age-adjusted prevalence and undiagnosed proportion of type 2 diabetes mellitus (t2dm) among omani subjects aged ≥20 years. diabetes mellitus registers and published studies were used to determine incidence rates of both type 1 diabetes mellitus (t1dm) and t2dm in oman. linear regression was used to determine trends and projections for diabetes in 2050. results: the age-adjusted prevalence of t2dm in oman varied from 10.4% to 21.1%, while the highest prevalence of impaired fasting glucose was found in males (35.1%). in comparison to men, higher incidence rates of t2dm were found in women (2.7 cases compared to 2.3 cases per 1,000 person-years, respectively). no significant trends were observed for the prevalence or incidence of t2dm in both genders. undiagnosed t2dm was more common in men (range: 33–68%) than women (range: 27–53%). the results of this study show that by 2050, there will be an estimated 350,000 people with t2dm living in oman (a 174% increase compared to estimates for 2015). conclusion: health authorities need to prioritise diabetes prevention and control in order to prevent or delay long-term complications and avert a potential epidemic of diabetes in oman. keywords: diabetes mellitus; epidemiology; incidence; prevalence; trends; oman. انت�ساره حيث من وخا�سة عمان، يف املا�سيني العقدين مدى على ال�سكري وبائيات و�سف اإىل الدرا�سة هذه تهدف الهدف: امللخ�ص: ووقوعه. كما �سعت الدرا�سة لتقدير معدالت وقوع ال�سكري يف امل�ستقبل يف �سلطنة عمان. الطريقة: جرى حتليل ثالثة م�سوح وطنية وثالثة م�سوح اإقليمية اأجريت بني عامي 1991م و 2010م للح�سول على معدل االنت�سار املعدل بح�سب العمر ون�سبة االأفراد غري امل�سخ�سني بالنوع الثاين من ال�سكري بني االأفراد الذين ترتاوح اأعمارهم 20 �سنة فاأكرث. وا�ستخدمت �سجالت ال�سكري والدرا�سات املن�سورة لتحديد معدالت االإ�سابة بالنوعني االأول والثاين. كما مت ا�ستخدام االنحدار اخلطي لتحديد االجتاهات والتوقعات لداء ال�سكري لعام 2050. النتائج: تراوح معدل االنت�سار املعدل بح�سب العمر للنوع الثاين من ال�سكري يف عمان من %10.4 اإىل %21.1، يف حني بلغت اأعلى ن�سبة انت�سار الختالل ال�سكر على الريق يف الذكور )%35.1(. وباملقارنة مع الرجال، وجد اأعلى معدل ارتفاع ملعدالت الوقوع للنوع الثاين من الداء ال�سكري يف الن�ساء )2.7 حالة مقارنة مع 2.3 حالة لكل 1,000 �سخ�ض-�سنة، على التوايل(. ومل ُيالحظ وجود اأي اجتاه معتد لالنت�سار اأو االإ�سابة للنوع الثاين من ال�سكري يف كال اجلن�سني. كانت ن�سبة النوع الثاين من ال�سكري غري امل�سخ�ض اأكرث �سيوعا يف الرجال )املجال: %68-33( منه يف الن�ساء )املجال: %53-27(. نتائج هذه الدرا�سة تظهر اأنه بحلول عام 2050، �سيكون هناك ما يقدر بنحو 350,000 �سخ�ض م�سابون بالنوع الثاين من ال�سكري يف عمان )زيادة بن�سبة %174 باملقارنة مع التقديرات لعام 2015(. اخلال�صة: حتتاج ال�سلطات ال�سحية و�سع خطط الوقاية من ال�سكري وال�سيطرة عليه كاأولوية من اأجل منع اأو تاأخري م�ساعفاته على املدى الطويل وجتنب انت�سار وباء حمتمل لل�سكري يف �سلطنة عمان. مفتاح الكلمات: ال�سكري؛ علم االأوبئة؛ معدل الوقوع؛ معدل االنت�سار؛ االجتاهات؛ عمان. epidemiology of diabetes mellitus in oman results from two decades of research *jawad a. al-lawati,1 prashanth panduranga,2 hala a. al-shaikh,3 magdi morsi,4 nabil mohsin,5 rajiv b. khandekar,6 hawra j. al-lawati,7 riad a. bayoumi5 sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e226–233, epub. 28 may 15 submitted 4 sep 14 revision req. 23 oct 14; revision recd. 25 nov 14 accepted 24 dec 14 departments of 1non-communicable disease control and 4research, ministry of health, muscat, oman; 2department of cardiology, royal hospital, muscat, oman; 3department of paediatric endocrinology, muscat private hospital, muscat, oman; 5department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; 6department of research, king khalid eye specialist hospital, riyadh, saudi arabia; 7weill cornell medical college, doha, qatar *corresponding author e-mail: jallawati@gmail.com advances in knowledge the epidemiology of diabetes mellitus (dm) and related conditions in oman over the past 20 years is described, utilising data from six surveys conducted between 1991 and 2010. the prevalence, incidence, proportion of undiagnosed cases and projections of the number of diabetes cases expected in oman by the year 2050 using current trends are estimated for the first time. application to patient care with the recognition of the high prevalence and incidence of dm and associated risk factors in oman, governmental and public health authorities are recommended to prioritise the control and prevention of this condition. clinical & basic research jawad a. al-lawati, prashanth panduranga, hala a. al-shaikh, magdi morsi, nabil mohsin, rajiv b. khandekar, hawra j. al-lawati and riad a. bayoumi clinical and basic research | e227 the global prevalence of diabetesmellitus is on the rise and is projected to increase by 55% between 2013 and 2035.1 currently, four out of five people with diabetes live in lowor middle-income countries where resources are scarce.1 the prevalence of diabetes is projected to double in the middle eastern and north african (mena) region; three countries in the mena region are already ranked amongst the global top 10 in terms of diabetes prevalence.1 between 1990 and 2010, diabetes mellitus was also recorded as the fifth leading cause of death among arab states of the mena region.2 oman is classified as a high-income country and the total population is estimated to reach 3.6 million inhabitants, of which 58% are nationals.3,4 nearly 14% of the population are under five years of age, 34% are under 15 years and only 6% are aged 60 years or over.5 the world health organization (who) classifies oman as a country with low child and adult mortality rates (crude death rate: 3.2 per 1,000).6 in terms of diabetes mellitus prevalence, oman is ranked eighth among the top 10 countries of the mena region.7 in 2010, diabetes mellitus was the fourth leading cause of premature mortality in the country and the third leading cause of disability-adjusted life years lost.8 in the early 1990s, the omani ministry of health believed that non-communicable diseases, particularly type 2 diabetes mellitus (t2dm) and cardiovascular diseases (cvd), constituted a major and increasing workload for clinicians in omani hospitals. a who ad hoc consultation found that 9% of all adult hospital admissions, 12% of all hospital bed occupancy and 20– 30% of all outpatient attendance in regional hospitals were associated with diabetes mellitus.9 to the best of the authors’ knowledge, although several epidemiological studies of diabetes have been published in oman, none have collated data over the past two decades in a comprehensive single study as of yet. the aim of this study was therefore to provide a summary and up-to-date data on the epidemiology of diabetes mellitus in oman from the early 1990s to 2010, as well as to estimate the future incidence of diabetes in oman based on current trends. methods data from the following three national and three regional population-based surveys were analysed. the national diabetes survey was conducted in 1991 to ascertain and validate the findings of the previous who ad hoc consultation.10 thereafter, the national health survey in 2000 and the oman world health survey in 2008 were conducted to monitor various health indicators, including changes in the prevalence of diabetes.11,12 in addition, the city of nizwa (located 150 km south of the capital city, muscat) conducted two regional surveys, known as the nizwa healthy lifestyle project surveys, in 2001 and 2010 to monitor cvd risk factors.13,14 a third regional survey, the healthy lifestyle study, was conducted in 2006 in the city of sur (located 200 km east of muscat).15 each national survey was designed to include a nationally representative sample and included all 11 governorates of oman. the regional surveys also followed a similar sampling method. the response rate for these surveys ranged from 75–93%. the two national surveys (2000 and 2008) and two of the regional surveys (2006 and 2010) obtained blood samples to measure fasting plasma glucose (fpg) from subjects after they had fasted overnight for at least eight hours. in the 1991 and 2001 surveys, an oral glucose tolerance test (ogtt) was used to measure plasma glucose two hours post 75 g oral glucose load, as recommended by the who.16 further methodological details of each survey are published elsewhere.10–15 data analysis was limited to omani nationals aged ≥20 years with complete data regarding the following variables: nationality; age; gender; fasting blood glucose levels; plasma glucose levels two hours post 75 g oral glucose load; an existing diabetes diagnosis from a physician, or a newly diagnosed case of diabetes. patients were determined to have undiagnosed diabetes (ud) if they had stated that they were not diabetic but had a fasting blood glucose (fbg) level of ≥7 mmol/l. proportions of ud cases were calculated by dividing the number of ud cases by the total number of subjects with a fpg level of ≥7 mmol/l. subjects who reported a diagnosis of diabetes from a health professional or who were taking anti-diabetic medications were classified to have t2dm regardless of their measured glucose levels. glucose metabolism abnormalities, including diabetes mellitus, impaired glucose tolerance (igt) and/ or impaired fasting glycaemia (ifg), were classified according to diagnostic criteria from both the who and the american diabetes association (ada).16,17 annual incidence rates for t2dm were calculated by dividing the number of all new cases diagnosed and documented in the national diabetes register in a calendar year by the estimated mid-year population at risk of that year to obtain cases per person-years (p-y). the average incidence rate for the period 2003– 2013 was calculated by dividing the mean number of cases in this period by the mean p-y at risk in the same period. as gender distribution of diabetes cases for the years 2003–2007 was not available, the mean gender distribution in subsequent years (2008–2012) was calculated and applied to that period. the mean epidemiology of diabetes mellitus in oman results from two decades of research e228 | squ medical journal, may 2015, volume 15, issue 2 age at diagnosis for incidence cases was calculated from aggregated age groups by multiplying the midinterval of the age group by the frequency in that group. population data and projections were obtained from the annual health reports and the directorate general of planning of the omani ministry of health.5 trends over time were determined by gender for prevalence rates of t2dm and ifg using linear regression, with prevalence as a dependent variable and study year as an independent variable. a p value of <0.05 for the regression slope was considered to be significant. age-standardised prevalence rates of t2dm were calculated using the world standard population determined by segi.18 linear regression was used to evaluate the gender-specific increase in t2dm prevalence per year. projections of expected cases of t2dm between 2015 and 2050 were calculated by multiplying the gender-specific expected prevalence by the population. statistical analysis was performed using stata® data analysis and statistical software, version 11 (statacorp lp, college station, texas, usa). results among subjects aged ≥20 years, the 1991 survey, which was the first epidemiological survey to map t2dm in oman, found the crude prevalence of t2dm to be 10.7% and the prevalence of igt to be 10.3% [table 1]. in the 2000 and 2008 surveys, the t2dm prevalence was 11.1% and 9.6%, respectively. a similar prevalence rate was found in the 2001 survey carried out in nizwa (9.9%). the highest crude prevalence of t2dm was recorded in sur in 2006 (13.9%), with 13.5% for males and 14.1% for females. age-adjustment inflated all prevalence rates, particularly in the 2006 survey in sur, where the highest t2dm rates were observed in females (21.1%). the prevalence of ifg varied drastically depending on the diagnostic criteria used. with who criteria, most ifg prevalence rates were between 5–7%, while age-adjusted rates were between 7–10% [table 1]. on the other hand, using ada criteria led to much higher prevalence rates of ifg (three to four times higher than the crude rates). the combined proportion of omanis affected by either diabetes or ifg/igt exceeded 30% in two of the regional studies in nizwa and sur (2001 and 2006) [figure 1]. neither of the diagnostic criteria showed a statistically significant trend in crude or age-adjusted prevalence rates of t2dm and ifg for both genders [figure 2]. the mean age of subjects with prevalent diabetes during successive surveys increased from 47.4 years in 1991 to 51.4 years in 2008 and 52.5 years in 2010. it was found that there were approximately 4,900 new cases of t2dm diagnosed in oman each year among patients aged ≥20 years. the mean age of incident cases was 48 years, with males at 48.1 years and females at 47.8 years (p = 0.001; male to female ratio = 100:113). the incidence rate of t2dm in females was higher than males (2.7 compared to 2.3 cases per 1,000 p-y, respectively; p = 0.789). the agespecific incidence rate increased in both genders from 0.7 cases per 1,000 p-y in the second decade, peaking in the fifth decade for both men and women (14 and 16 cases per 1,000 p-y, respectively) and declining thereafter. no significant temporal trend in incidence rate over two decades was observed for men or women (ptrend = 0.42 and 0.43, respectively). table 2 shows that the proportion of subjects with ud decreased in nizwa from 60.3% in 2001 to 30.7% in 2010. overall, men had a significantly higher proportion of ud (51.5%) compared to women (42.8%; p = 0.009). table 3 forecasts the total number of t2dm cases expected in oman between 2015 and 2050 by gender, using mean prevalence rates of the national surveys and the predicted increase rate using linear regression models. on average, more than 350,000 people with t2dm are estimated to be living in oman in 2050. this is an increase of approximately 174% compared to 2015. discussion a persistently high prevalence of t2dm among sub jects aged ≥20 years in oman over the past two decades was found after analysing data from six surveys, reaching as high as 21% in the region of sur. similar rates have been reported in egypt (15.2%), saudi arabia (16.2%), qatar (16.7%) and iran (9.3%).19 a similar proportion of the omani population suffer from igt and/or ifg. despite the statistically nonsignificant increase in the trend of t2dm prevalence and incidence over the past two decades, the absolute number of people living with t2dm in oman is expected to increase by 174% by the year 2050, when compared to current estimates. there are several indications of an impending epidemic of t2dm and cvd in oman. first, high prevalences of obesity, physical inactivity and sedentary lifestyles have been reported in oman.20 data regarding obesity from the three national surveys used in this study show an increasing proportion of males with a body mass index (bmi) of ≥30 kg/ jawad a. al-lawati, prashanth panduranga, hala a. al-shaikh, magdi morsi, nabil mohsin, rajiv b. khandekar, hawra j. al-lawati and riad a. bayoumi clinical and basic research | e229 m2 (10.5%, 16.7% and 22.0% in 1991, 2000, and 2008 surveys, respectively).10–12 while the prevalence of obesity among women remained stable between the 1991 and 2000 surveys (25.1% and 23.8%, respectively), it increased in the 2008 survey to 26.0%.10–12 despite this increase in the prevalence of obesity, the rate of diabetes has remained stable in oman with no significant increase in trend among either gender. a similar analysis of data from the usa has shown doubling of both the incidence and prevalence of diabetes mellitus between 1990 to 2008; this increase subsequently plateaued between 2008 and 2012.21 the levelling off of both of these parameters is thought to be linked to the stabilisation of obesity rates in the table 1: crude and age-adjusted prevalence of diabetes mellitus, impaired glucose tolerance and fasting glycaemia among omani adults aged ≥20 years between 1991–2010 according to diagnostic criteria survey type, location and year test sample size crude prevalence in % age-adjusted prevalence in % m f m f total m f total dm by who criteria16 ptrend 0.53 0.81 0.69 0.32 0.62 0.51 national (1991)10 two hour post-ogtt 2,097 2,938 10.7 10.8 10.7 12.5 14.4 13.5 national (1991)10 fpg 2,097 2,938 10.2 8.8 9.4 11.6 11.5 11.5 national (2000)11 fpg 2,887 2,922 11.3 11.0 11.1 13.2 13.3 13.2 national (2008)12 fpg 1,259 1,479 10.6 8.8 9.6 13.0 11.5 12.2 regional (nizwa, 2001)13 two hour post-ogtt 694 790 10.4 9.5 9.9 12.3 14.2 13.0 regional (nizwa, 2001)13 fpg 694 790 8.7 7.1 7.8 10.6 10.8 10.4 regional (nizwa, 2010)14 fpg 827 1,024 10.9 8.3 9.5 13.9 12.3 12.9 regional (sur, 2006)15 fpg 599 772 13.5 14.1 13.9 17.9 21.1 19.5 impaired glucose tolerance and impaired fasting glycaemia by who criteria16 ptrend 0.87 0.53 0.68 0.79 0.71 0.73 national (1991)10 two hour post-ogtt 2,097 2,938 7.3* 12.5* 10.3* 8.2* 14.3* 11.6* national (1991)10 fpg 2,097 2,938 5.3 5.1 5.2 5.9 6.4 6.2 national (2000)11 fpg 2,887 2,922 7.2 5.2 6.2 7.9 5.8 6.8 national (2008)12 fpg 1,259 1,479 4.8 4.4 4.6 5.5 4.8 5.1 regional (nizwa, 2001)13 two hour post-ogtt 694 790 14.7* 16.0* 15.4* 15.4* 18.1* 16.7* regional (nizwa, 2001)13 fpg 694 790 10.1 5.8 7.8 10.9 7.4 9.0 regional (nizwa, 2010)14 fpg 827 1,024 6.4 6.5 6.5 7.5 7.4 7.5 regional (sur, 2006)15 fpg 599 772 9.5 8.6 9.1 10.4 11.7 10.8 impaired fasting glycaemia by ada criteria17 ptrend 0.68 0.52 0.58 0.66 0.59 0.61 national (1991)10 fpg 2,097 2,938 15.9 14.2 14.9 16.8 16.5 16.6 national (2000)11 fpg 2,887 2,922 18.3 14.0 16.1 19.5 15.0 17.3 national (2008)12 fpg 1,259 1,479 16.2 11.6 13.7 16.8 13.1 14.7 regional (nizwa, 2001)13 fpg 694 790 34.0 20.5 26.8 35.1 23.6 29.1 regional (nizwa, 2010)14 fpg 827 1,024 21.6 20.7 21.1 23.4 22.2 22.9 regional (sur, 2006)15 fpg 599 772 31.8 29.3 30.3 33.1 32.4 32.5 m = males; f = females; t = total; dm = diabetes mellitus; who = world health organization; ogtt = oral glucose tolerance test; fpg = fasting plasma glucose; ada = american diabetes association. *values for impaired glucose tolerance. epidemiology of diabetes mellitus in oman results from two decades of research e230 | squ medical journal, may 2015, volume 15, issue 2 usa.21 second, increasing urbanisation will lead to a future increase in diabetes; 75% of the current omani population live in urban areas as compared to 47% in 1980.22 higher frequencies of t2dm and igt were found in urban areas of oman, such as muscat (12% and 5.6%, respectively), compared to rural areas like the musandam peninsula, which is over 400 km from muscat (7.8% and 2.2%, respectively).23 the third indicator of an impending epidemic of t2dm and cvd in oman is the proportion of the population aged 65 years and over. this proportion is expected to increase 10 times by the year 2035 (from 2.5% to 21%); this will also contribute to higher rates of diabetes.22 finally, a high prevalence of ifg combined with a conversion rate of 5.6% per annum to diabetes and a high familial predisposition to diabetes is likely to aggravate the already high prevalence rates of this condition.24,25 in the present study, the incidence rate of t2dm among omanis aged ≥20 years was 2.5 cases per 1,000 p-y. high incidence rates of t2dm have been reported from south korea and taiwan (7.6 and 7.7 per 1,000 p-y respectively),26,27 compared to sweden (3.5 cases per 1,000 p-y).28 changes in the diagnostic criteria for diabetes usually have an impact on diabetes incidence and prevalence depending on the cut-off values adopted. in 1997, the ada adopted new diagnostic criteria for diabetes, followed by similar changes by the who in 1999.16,17 however, such changes did not affect the current study as original data collected from the field were analysed based on both who and ada diagnostic criteria. the only study documenting the incidence of childhood t1dm in children aged 0–14 years in oman was conducted by soliman et al. over two years.29 the reported incidence rate was 2.45 and 2.62 per 100,000 p-y in 1993 and 1994, respectively. the gender-specific incidence rates among boys and girls were 3.23 and 1.99 per 100,000 p-y in 1993 and 2.91 and 1.95 per 100,000 p-y in 1994, respectively. the age-specific incidence rates during these two years were higher figure 1: total age-adjusted prevalence of diabetes mellitus and impaired glucose tolerance/impaired fasting glucose among omanis aged ≥20 years between 1991–2010 using data from six population-based national and regional surveys.10–15 the world health organization diagnostic criteria for diabetes was used.16 igt = impaired glucose tolerance; ifg = impaired fasting glycaemia; ogtt = oral glucose tolerance test; fpg = fasting plasma glucose. figure 2: trend in age-adjusted prevalence of diabetes mellitus among omani adults aged ≥20 years between 1991–2010 using data from six population-based national and regional surveys.10–15 trends are presented according to gender, survey and method of test used. ogtt = oral glucose tolerance test; fpg = fasting plasma glucose. jawad a. al-lawati, prashanth panduranga, hala a. al-shaikh, magdi morsi, nabil mohsin, rajiv b. khandekar, hawra j. al-lawati and riad a. bayoumi clinical and basic research | e231 in the 10–14-year-old age group (3.69 and 4.22 per 100,000 p-y in 1993 and 1994, respectively) compared to those aged 5–9-year-old (2.32 and 2.79 per 100,000 p-y) and those aged 0–4-year-old (1.54 and 0.97 per 100,000 p-y). the same study also reported that the number of new cases was markedly higher in the relatively cooler months of the year (september to march).29 however, the reported incidence rate of t1dm in omani children by soliman et al. was lower than that reported in other arabian gulf states, such as saudi arabia and kuwait (27.5 and 15.4 per 100,000 p-y, respectively).30,31 the present study observed that approximately 30–60% of t2dm cases were undiagnosed in oman. similar or higher proportions have been reported from other arab countries (75%, 48% and 62% in tunisia, saudi arabia and egypt, respectively).32 studies from developed nations such as france, portugal and finland have reported the prevalence of ud to be 50%, 44% and 61%, respectively.32 in an effort to detect ud cases earlier and to reduce the burden of diabetes and other non-communicable diseases in oman, the ministry of health initiated a national screening programme in 2006 inviting subjects aged ≥40 years to be screened for diabetes and other risk factors by attending their local primary healthcare centre after fasting overnight.33 those who attended had their arterial blood pressure and weight measured and venous blood and urine samples collected. results of the screening programme are shown in table 4.33 in 2007, al-lawati et al. developed a simple diabetes risk score to screen for t2dm among adults aged ≥20 years.34 the tool contained specified scores for questions on age, waist circumference, bmi, family history of diabetes and current hypertension status. the sensitivity of the score was reported to be 78.6% and its specificity was 73.4%.34 the impact of both the screening programme and risk score have not yet been evaluated. current data from omani ministry of health institutions indicate that 5% of all pregnant women are diagnosed with gestational diabetes mellitus (gdm).5 in addition, 14.3% of fetal deaths are attributed to diabetes during pregnancy.5 dashora et al. reported testing 564 women attending an antenatal clinic at a secondary hospital for glucose intolerance using an ogtt.35 results indicated that 20.2% of women had two hour post-load glucose levels table 2: prevalence of undiagnosed diabetes mellitus among omani adults aged ≥20 years between 1991–2010* survey type, location and year prevalence of ud in % m f t national (1991)10 47.4 45.9 46.6 national (2000)11 64.0 53.4 58.7 national (2008)12 46.3 35.4 40.9 regional (nizwa, 2001)13 68.3 51.8 60.3 regional (nizwa, 2010)14 33.3 27.1 30.7 regional (sur, 2006)15 49.4 43.1 45.8 ud = undiagnosed diabetes mellitus; m = males; f = females; t = total. table 3: projected number of cases of diabetes among omanis aged ≥20 years between 2015–2050* year diabetes cases m f t 2015 69,323 60,548 128,769 2020 80,490 69,779 149,195 2030 108,339 92,522 199,918 2040 149,571 125,425 274,265 2050 192,790 159,603 352,156 total increase in % 178.1 163.6 173.5 m = males; f = females; t = total. *projections of expected cases were calculated by multiplying the gender-specific expected prevalence by the estimated population of that particular year . table 4: prevalence of risk factors among omanis aged ≥40 years screened for selected non-communicable diseases in primary healthcare centres between 2008–2009* risk factor prevalence in % m (n = 15,115) f (n = 24,861) t (n = 39,976) gender 38 62 100 bmi of ≥30 kg/m2 22 36 31 abnormal wc** 54 76 68 pre-htn† 15 13 13 htn‡ 22 19 20 pre-diabetes§ 35 35 35 diabetes¶ 10 7 8 high cholesterol 47 49 48 egfr of <90 ml/ minute 33 26 29 egfr of <60 ml/ minute 11 8 9 egfr of <30 ml/ minute 1 1 1 m = males; f = females; t = total; bmi = body mass index; wc = waist circumference; htn = hypertension; egfr = estimated glomerular filtration rate. *data from oman ministry of health. operational and management guidelines for the national non-communicable diseases screening program. muscat, oman: ministry of health, 2009.33 **defined as ≥94 cm for males and ≥80 cm for females. †defined as systolic blood pressure (sbp) of ≥130 mmhg and <140 mmhg and/or diastolic blood pressure (dbp) of ≥85 mmhg and <90 mmhg. ‡defined as sbp of ≥140 mmhg and/or dbp ≥ of 90 mmhg. §defined as fasting plasma glucose (fpg) of ≥5.6 mmol/l and <7 mmol/l. ¶defined as fpg of ≥7 mmol/l. epidemiology of diabetes mellitus in oman results from two decades of research e232 | squ medical journal, may 2015, volume 15, issue 2 of ≥7.8 mmol/l. over 87% of cases of gdm in this study were diagnosed at the first antenatal visit (≤12 gestational weeks). second (at 16–20 gestational weeks) and third ogtt (at 24–28 gestational weeks) results added additional information in only a minority of cases (10% and 2.5%, respectively).35 in another study investigating gdm, barakat et al. reported that women in oman with gdm were three times more likely to have a child with macrosomia (adjusted odds ratio [or] = 3.03) and to have a caesarean section delivery (adjusted or = 2.7).36 adjusted ors for the same conditions were 7.2 and 4.4 for women with pregestational diabetes. the prevalence of gdm depends on the type of test and the diagnostic cut-off values used. in oman, the reported prevalence of gdm (20.2%) was similar to that reported from the united arab emirates (20.6%) and qatar (19.0%), but higher than that reported from bahrain (13.5%) and saudi arabia (12.5%).35,37 however, oman’s only study investigating gdm was based in a regional hospital.35 thus, a national study to further elucidate the epidemiology of gdm may be warranted. with oman being a high prevalence country, screening for gdm earlier than usually recommended (for example, at the first trimester rather than at 24–28 gestational weeks) may prove beneficial in the light of recent data which show that women with hyperglycaemia have an increased risk of adverse maternal, fetal and neonatal outcomes even within ranges of glycaemia previously considered normal for pregnant women.35,38 over the past four and a half decades, oman has achieved conspicuous advances in the delivery of modern and free healthcare services to its entire population, including those living in remote areas. this has led to successful control and eradication of communicable diseases. on the other hand, the burden of non-communicable diseases, including diabetes, has increased.39 despite this, information regarding how to prevent t2dm through lifestyle modifications is available.40 the public should be encouraged to adopt healthy lifestyles in order to prevent or delay t2dm and its complications. it is paramount that omani health authorities pay greater attention to healthcare services that will result in reducing the burden of this condition in order to prevent or delay its complications and avert an impending epidemic. the results of the current study highlight the current gaps in epidemiological knowledge and the need to update information regarding the incidence of t1dm. this may be done by investigating the accuracy of diabetes registers and examining ways to improve their utilisation in secondary and tertiary health institutions where the diagnosis of such cases occur. there is also a noticeable paucity of epidemiological data regarding the incidence and prevalence of t1dm in oman, with the only available study dating back to two decades ago.29 as the incidence of this chronic disease is increasing worldwide, there is an urgent need to establish a national registry and to conduct further studies to monitor the magnitude of this condition to help plan for future healthcare services. furthermore, no studies could be identified regarding the cost of diabetes in oman. thus, future work on determining the cost of diabetes to the omani national health service would be vital. the major strength of this study lies in the fact that all six surveys used for the data analysis were population-based with similar sampling methods and were thus representative and generalisable to the entire omani population. however, the study has several limitations. first, in estimating the incidence of diabetes, an assumption of a full year of patient follow-up was made. this may have overestimated the incidence rate as some patients are censored during the study period (perhaps due to death, loss to follow-up, migration, etc.). nonetheless, it is worthwhile noting that local health centre staff make enquiries regarding patients who do not follow-up their treatments and these patients are henceforth struck from the diabetes register which minimises this bias. second, incidence rates are also likely to be underestimated as nearly 50% of diabetic subjects are undiagnosed; hence the true incidence is likely to be twice that reported. third, incidence data on diabetes registers are not specifically collected to determine incidence rates. their accuracy and completeness is often undetermined, especially in the absence of any evaluation of such registers. conclusion there is a high prevalence of t2dm and, to a lesser extent, incidence of t2dm. additionally, high proportions of ud cases were recorded in oman. health authorities need to prioritise detection, control and treatment strategies for this condition so that a future overwhelming epidemic of diabetes mellitus is averted in oman. this may include encouraging the general population to adopt healthy lifestyles in order to prevent or delay t2dm and its related complications. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. international diabetes federation. idf diabetes atlas: sixth edition. from: www.idf.org/diabetesatlas/download-book accessed: nov 2014. jawad a. al-lawati, prashanth panduranga, hala a. al-shaikh, magdi morsi, nabil mohsin, rajiv b. khandekar, hawra j. al-lawati and riad a. bayoumi clinical and basic research | e233 2. mokdad ah, jaber s, aziz mi, albuhairan f, alghaithi a, alhamad nm, et al. the state of health in the arab world, 1990-2010: an analysis of the burden of diseases, injuries, and risk factors. lancet 2014; 383:309–20. doi: 10.1016/s0140-6736(13)62189-3. 3. the world bank. country and lending groups: middle east and north africa. from: data.worldbank.org/about/country-andlending-groups#mena accessed: nov 2014. 4. national center for statistics & information. population. from: www.ncsi.gov.om/ncsi_website/book/syb2014/2-population. pdf#search="population" accessed: jul 2014. 5. directorate general of planning, oman ministry of health. annual health report. muscat, oman: ministry of health, 2000–2012. 6. world health organization. the world health report 2003: shaping the future. from: www.who.int/whr/2003/en/ accessed: nov 2014. 7. majeed a, el-sayed aa, khoja t, alshamsan r, millett c, rawaf s. diabetes in the middle-east and north africa: an update. diabetes res clin pract 2014; 103:218–22. doi: 10.1016/j. diabres.2013.11.008. 8. institute for health metrics and evaluation. gbd profile: oman. from: www.healthdata.org/sites/default/files/files/country_ profiles/gbd/ihme_gbd_country_report_oman.pdf accessed: nov 2013. 9. asfour mg, samantray sk, dua a, king h. diabetes mellitus in the sultanate of oman. diabet med 1991; 8:76–80. doi: 10.1111/ j.1464-5491.1991.tb01520.x. 10. asfour mg, lambourne a, soliman a, al-behlani s, al-asfoor d, bold a, et al. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabet med 1995; 12:1122–5. doi: 10.1111/j.14645491.1995.tb00431.x. 11. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. doi: 10.1046/j.1464-5491.2002.00818.x. 12. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1 methodology, sociodemographic profile and epidemiology of non-communicable diseases in oman. oman med j 2012; 27:425–43. 13. oman ministry of health. summary report of the nizwa healthy lifestyle project survey 2001. muscat, oman: ministry of health, 2002. 14. al-siyabi h, al-anquodi z, al-hinai h, al-hinai s. nizwa healthy lifestyle project evaluation report 2010. ad dakhiliyah, oman: ministry of health, 2010. 15. al-farsi m, el-melighy m, mohammed s, ali l. healthy lifestyle study: assessment of lifestyle risk factors among sur city population. sur, oman: ministry of health, 2006. 16. alberti kg, zimmet pz. definition, diagnosis and classification of diabetes mellitus and its complications: part 1: diagnosis and classification of diabetes mellitus provisional report of a who consultation. diabet med 1998; 15:539–53. doi: 10.1002/ (sici)1096-9136(199807)15:7<539::aid-dia668>3.0.co;2-s. 17. american diabetes association. standards of medical care in diabetes: 2014. diabetes care 2014; 37:s14–80. doi: 10.2337/ dc14-s014. 18. segi m. cancer mortality for selected sites in 24 countries (1950‒57). sendai, japan: department of public health, tohuku university of medicine, 1960. 19. whiting dr, guariguata l, weil c, shaw j. idf diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. diabetes res clin pract 2011; 94:311–21. doi: 10.1016/j.diabres.2011.10.029. 20. mabry r, owen n, eakin e. a national strategy for promoting physical activity in oman: a call for action. sultan qaboos univ med j 2014; 14:e170–5. 21. geiss ls, wang j, cheng yj, thompson tj, barker l, li y, et al. prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, united states, 1980-2012. jama 2014; 312:1218–26. doi: 10.1001/jama.2014.11494. 22. united nations. world population prospects: the 2012 revision. from: esa.un.org/wpp/documentation/publications.htm accessed: nov 2014. 23. al-lawati ja, mohammed aj. diabetes in oman: comparison of 1997 american diabetes association classification of diabetes mellitus with 1985 who classification. ann saudi med 2000; 20:12–15. 24. nichols ga, hillier ta, brown jb. progression from newly acquired impaired fasting glusose to type 2 diabetes. diabetes care 2007; 30:228–33. doi: 10.2337/dc06-1392. 25. al-sinani s, al-shafaee m, al-mamari a, woodhouse n, al-shafie o, hassan m, et al. familial clustering of type 2 diabetes among omanis. oman med j 2014; 29:51–4. doi: 10.5001/omj.2014.11. 26. kim dj. the epidemiology of diabetes in korea. diabetes metab j 2011; 35:303–8. doi: 10.4093/dmj.2011.35.4.303. 27. chang ch, shau wy, jiang yd, li hy, chang tj, sheu wh, et al. type 2 diabetes prevalence and incidence among adults in taiwan during 1999‒2004: a national health insurance data set study. diabet med 2010; 27:636–43. doi: 10.1111/j.14645491.2010.03007.x. 28. andersson t, ahlbom a, magnusson c, carlsson s. prevalence and incidence of diabetes in stockholm county 1990-2010. plos one 2014; 9:e104033. doi: 10.1371/journal.pone.0104033. 29. soliman at, al-salmi is, asfour mg. epidemiology of childhood insulin-dependent diabetes mellitus in the sultanate of oman. diabet med 1996; 13:582–6. doi: 10.1002/(sici)1096-9136(199606)13:6<582::aiddia114>3.0.co;2-e. 30. abduljabbar ma, aljubeh jm, amalraj a, cherian mp. incidence trends of childhood type 1 diabetes in eastern saudi arabia. saudi med j 2010; 31:413–18. 31. shaltout aa, qabazard ma, abdella na, laporte re, al arouj m, ben nekhi a, et al. high incidence of childhood-onset iddm in kuwait: kuwait study group of diabetes in childhood. diabetes care 1995; 18:923–7. doi:10.2337/diacare.18.7.923. 32. beagley j, guariguata l, weil c, motala aa. global estimates of undiagnosed diabetes in adults. diabetes res clin pract 2014; 103:150–60. doi: 10.1016/j.diabres.2013.11.001. 33. oman ministry of health. operational and management guidelines for the national non-communicable diseases screening program. muscat, oman: ministry of health, 2009. 34. al-lawati ja, tuomilehto j. diabetes risk score in oman: a tool to identify prevalent type 2 diabetes among arabs of the middle east. diabetes res clin pract 2007; 77:438–44. doi: 10.1016/j. diabres.2007.01.013. 35. dashora u, dashora v, kennedy l. two-hour 75-g oral glucose tolerance test early in pregnancy detects most cases of gestational diabetes. diabetes care 2002; 25:803. doi: 10.2337/diacare.25.4.803. 36. barakat mn, youssef rm, al-lawati ja. pregnancy outcomes of diabetic women: charting oman’s progress towards the goals of the saint vincent declaration. ann saudi med 2010; 30:265–70. doi: 10.4103/0256-4947.65253. 37. bener a, saleh nm, al-hamaq a. prevalence of gestational diabetes and associated maternal and neonatal complications in a fast-developing community: global comparisons. int j womens health 2011; 3:367–73. doi: 10.2147/ijwh.s26094. 38. hapo study cooperative research group; metzger be, lowe lp, dyer ar, trimble er, chaovarindr u, coustan dr, et al. hyperglycemia and adverse pregnancy outcomes. n engl j med 2008; 358:1991–2002. doi: 10.1056/nejmoa0707943. 39. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 40. knowler wc, barrett-connor e, fowler se, hamman rf, lachin jm, walker ea, et al.; diabetes prevention program research group. reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. n engl j med 2002; 346:393–403. doi: 10.1056/nejmoa012512. sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e223-230, epub. 7th apr 14 submitted 21st aug 13 revision req. 13th nov; revision recd. 19th dec 13 accepted 23rd jan 14 1department of oral medicine, oral & dental diseases research center, kerman university of medical sciences, kerman, iran *corresponding author e-mail: m_s_hashemipour@yahoo.com املعرفة واستخدام علم طب األسنان القائم على األدلة من قبل أطباء األسنان اإليرانيني نادر نفابي، اأرا�س �صاهرفان، �صبيده بورموناجم، مرمي ال�صادات ها�صميبور abstract: objectives: the objective of this study was to assess the knowledge and use of evidence-based dentistry (ebd) among iranian dentists. methods: a cross-sectional survey was conducted by means of a questionnaire among dentists attending the 52nd national annual congress of the iranian dental association in tehran in april 2012. the questions covered the participants’ level of knowledge and use of ebd. results: the mean knowledge score of the 310 respondents was 3.66 ± 1.19 out of a maximum of 5. the majority of the dentists had little (56.1%) or no (20.7%) knowledge of ebd. the main reported barrier to the use of ebd was lack of time (44.1% of respondents) with 42.8% of dentists using the internet less than one hour per week. conclusion: ebd was not a familiar concept to these iranian dentists; the majority of them preferred consultation with colleagues over seeking evidence from electronic databases. keywords: evidence-based dentistry, trends; knowledge; iran. الإيرانيني. الأ�صنان اأطباء قبل من الأدلة على القائم الأ�صنان طب علم واإ�صتخدام املعرفة م�صتوى تقييم اإىل الدرا�صة هذه تهدف الهدف: امللخ�ص: الطريقة: مت اإجراء ا�صتق�صاء مقطعي عن طريق ا�صتبيان من قبل اأطباء الأ�صنان احلا�رشين للموؤمتر ال�صنوي الثاين واخلم�صون للجمعية الإيرانية لطب الأ�صنان بطهران يف مايو 2012. غطت الأ�صئلة حماور م�صتوى املعرفة للم�صارك وا�صتخدام علم طب الأ�صنان القائم على الأدلة. النتائج: متو�صط نتائج املعرفة ل310 م�صتجيب كانت 3.66 ± 1.19 من اأ�صل 5. مع�صم اأطباء الأ�صنان كان لديهم قليل )%56.1( اأو عدم وجود )%20.7( معرفة عن علم طب الأ�صنان القائم على الأدلة. اأكرث العوائق املذكورة عن عدم ا�صتخدام علم طب الأ�صنان القائم على الأدلة هو عدم توفر الوقت )%44.1 من امل�صتجيبني( مع وجود 42.8% من الأطباء ي�صتخدمون �صبكة النرتنت مبعدل اأقل من �صاعة اأ�صبوعيا. اخلال�صة: علم طب الأ�صنان القائم على الأدلة لي�س مفهوم معريف لدى اأطباء الأ�صنان الإيرانيني، مع ن�صبة كبرية منهم يف�صلون ا�صت�صارة الزملء اأكرث من طلب الدليل عن طريق قواعد البيانات الإلكرتونية. مفتاح الكلمات: طب اأ�صنان قائم على الأدلة؛ اجتاهات؛ املعرفة؛ اإيران. knowledge and use of evidence-based dentistry among iranian dentists nader navabi, arash shahravan, sepideh pourmonajem, *maryam a. hashemipour clinical & basic research advances in knowledge according to the literature review and to the best of our knowledge, no studies have been carried out in iran to evaluate iranian dental practitioners’ use and knowledge of evidence-based dentistry (ebd). based on the findings of the present study, ebd is not a familiar concept for iranian dentists. applications to patient care teaching ebd to dental students is the key to increasing the proportion of treatments based on dental evidence and thus enhancing their quality and patient outcomes. evidence-based medicine (ebm) is an accepted activity in the medical field worldwide.1,2 ebm entails the application of the best results of clinical research studies to improve the quality of decision-making during the treatment of patients and to pave the way to achieving the best treatment modalities.3 evidence-based dentistry (ebd) has attracted the attention of researchers in tandem with ebm.4 the american dental association defines ebd as “an approach to oral healthcare that requires the judicious integration of systemic assessments of clinically relevant scientific evidence, relating to the patient’s oral and medical condition and history, with the dentist’s clinical expertise and the patient’s treatment needs and preferences”.5,6 ebd is valuable and useful in many ways. it has been demonstrated that dentists who make their decisions based on evidence, rather than personal ideas and judgments, improve their clinical skills and expertise.1–6 dentists can improve knowledge and use of evidence-based dentistry among iranian dentists e224 | squ medical journal, may 2014, volume 14, issue 2 the quality and results of treatment by using ebd in accordance with clinical results; furthermore, they will be able to judge the advantages and disadvantages of potential treatment modalities after evaluating the validity of the available evidence. in addition, the awareness that treatments received are based on the best evidence available may increase patient trust in dental services. therefore, ebd is considered a necessity in the routine treatment of patients and has gained great popularity.2,4 teaching ebd to current dental students is key to increasing the proportion of treatments that are based on evidence in the future.7–9 this type of education facilitates a dentists’ understanding of basic and applied sciences and also their knowledge on how to treat difficult cases.8 as a result, dental students will be able to update their knowledge after graduation using this method; this newly gained information will affect the clinical treatments they choose thereafter.10,11 at present, ebd has opened new horizons in dental research. additionally, by applying ebd, the existing gap between dental researchers and clinicians decreases.12,13 ebd also opens up a large number of new fields for dental research, but this opportunity is in need of more extensive evaluation. it will be necessary for dental researchers to work hard in order to achieve the aims of ebd.14,15 based on these points and considering that, to the best of the authors’ knowledge, no previous studies have been carried out in iran to evaluate this practice, the present study was designed to evaluate the knowledge and use of ebd among iranian dental practitioners. methods in this cross-sectional study, a self-administered questionnaire was designed, modelled after similar studies.16–18 the researcher-designed questionnaire included three sections. the first section consisted of five statements about the process and benefits of ebd. respondents had to judge these statements according to a 3-point likert scale: “correct”, “incorrect” or “don’t know”. to calculate the total knowledge score, each correct answer received a score of 1, with a score of 0 being given for wrong answers or for “don’t know”. the second section consisted of six terms related to ebd; respondents had to state their knowledge of these terms by selecting “know well”, “little is known” or “don’t know anything”. responses were calculated as percentages for each term, with a score of 0 being given for wrong answers or for “don’t know”. the third section consisted of six questions relating to the respondents’ information sources in the case of treatment uncertainties and their use of online information sources; respondents could make multiple choices in response to these questions. the answers were recorded as percentages. the scientific reliability of the questionnaire was confirmed by two experts in the field using hamilton methods. these experts labelled the validity of the questionnaire as optimal and all of the items were deemed highly appropriate. in the next stage, the questionnaire was given to 20 dental practitioners to evaluate its internal consistency, which yielded a cronbach’s alpha coefficient of 0.71 for the section regarding knowledge of the ebd terms and a value of 0.63 for questions regarding the process and benefits of ebd.10 the necessary revisions were then made. the difference in proportions formula was used and, based on the pilot study results (α = 0.05, p = 38%, d = 70%), the sample size was calculated to be 300. the questionnaires were distributed among dentists attending the 52nd national annual congress of the iranian dental association in april 2012; they were selected by a convenience sampling procedure. the volunteers were asked to fill in the questionnaires anonymously and return them at the end of the lectures after having been given sufficient time to complete them. each participant completed a separate questionnaire sheet which included questions about age, gender and graduation year. questionnaires that were returned with more than 30% of the questions unanswered were excluded from the study and the non-response rate was determined. all responses were kept confidential. data were analysed using pearson’s chi-squared test for the comparison of frequencies and mean scores and the statistical package for the social sciences, version 16 (ibm, corp., chicago, illinois, usa). a p value of <0.05 was considered significant. this study was approved by the ethics committee of kerman university of medical sciences (no. k.91.54). results a total of 310 dental practitioners completed the questionnaire with a response rate of 100%. of the respondents, 65.6% were male, with 80.7% being general dental practitioners. a total of 64.4% of the practitioners had graduated from one of the major dental university faculties in iran (tehran, mashhad, shiraz and isfahan) and 6.8% had graduated from universities abroad. a total of 43.2% of the respondents worked in private offices and only 3.9% were involved in academic activities. the mean age of the respondents was 39.4 ± 9.1 years, with an age range of 23–70 years. nader navabi, arash shahravan, sepideh pourmonajem and maryam a. hashemipour clinical and basic research | e225 the mean number of years since graduation was 9.87 ± 8.3, with a range of 1–47 years. the majority of the participants had graduated between 1–5 years previously and 8.5% had graduated more than 20 years previously [table 1]. regarding the first part of the questionnaire, participants responded to five statements designed to test the participants’ knowledge of the process and benefits of ebd [table 2]. the highest frequency of correct answers was related to the statements that ebd is a process of making decisions based on scientifically proven evidence and that it allows dentists to improve their knowledge and clinical skills (82% for each). the most frequently incorrectly answered statement was the third one—that evidence from all published articles in scientific journals can be used in ebd (46.5%). the mean total knowledge of the respondents was 3.66 ± 1.19 out of a maximum score of 5. no significant relationship was noted between the knowledge scores and any of the demographic data (p = 0.12). the mean knowledge scores for general dental practitioners and specialists were 3.66 ± 0.75 and 3.7 ± 0.16, respectively, with no statistically significant differences (p = 0.23). for the second section of the questionnaire regarding terms related to ebd, the majority of the respondents chose “little is known” when presented with standard ebm terms such as “clinical effectiveness”, “relative risk”, “systematic review”, “critical appraisal” and the “cochrane collaboration” [table 3]. in the third section, there were six questions on the participants’ clinical information sources. in response to the first question: “if you have any uncertainties in any of the treatment procedures, which sources do you use to resolve the uncertainty and find a proper table 1: demographic profiles of the participants (n = 310) parameter n % gender male 203 65.6 female 107 34.4 university experience major university 199 64.4 minor university 89 28.8 universities abroad 22 6.8 type of activity clinic 69 22.4 dental office 151 48.8 dental faculty 90 28.8 years since graduation 1–5 82 32.9 6–10 69 27.7 11–15 42 16.9 16–20 36 14.5 >20 25 8.49 table 2: frequency of answers to selected statements eliciting knowledge of evidence-based dentistry processes and benefits (n = 310) statements male female total *p value c n (%) ic n (%) dk n (%) c n (%) ic n (%) dk n (%) c n (%) ic n (%) dk n (%) ebd is a process of making decisions based on scientifically proven evidence. 251 (81.1) 20 (6.7) 39 (12.2) 259 (83.7) 11 (3.5) 40 (12.8) 254 (82) 17 (5.6) 39 (12.4) **0.001 ebd involves a series of steps from identifying the clinical question, finding the answer/evidence, assessing the validity of the evidence, to applying it if clinically suitable. 241 (78) 18 (6.1) 51 (15.9) 104 (33.7) 128 (41.3) 78 (35) 239 (77.2) 21 (6.8) 50 (16) **0.001 evidence from all published articles in scientific journals can be used in ebd. 115 (37.2) 138 (44.5) 57 (18.3) 97 (31.4) 159 (51.2) 54 (17.4) 109 (35.2) 118 (46.8) 83 (18) 0.06 ebd benefits patients by improving quality and effectiveness of clinical treatments. 247 (79.8) 34 (11) 29 (9.2) 235 (75.9) 35 (11.6) 40 (12.8) 243 (78.3) 35 (11.2) 32 (10.4) **0.001 ebd allows dentists to improve their knowledge and clinical skills. 254 (81.7) 34 (11) 22 (7.3) 256 (82.6) 22 (7) 32 (10.5) 254 (82) 30 (9.6) 26 (8.4) **0.001 c = correct; ic = incorrect; dk = don’t know; ebd = evidence-based dentistry. *pearson’s chi-squared test; **significant. knowledge and use of evidence-based dentistry among iranian dentists e226 | squ medical journal, may 2014, volume 14, issue 2 solution?” the respondents chose the following items in descending order: “refer to reference books” (71.6%), “ask colleagues” (70.7%), “refer to electronic sources and databases” (40.3%) and “continue the procedure based on personal experience and judgment” (29.4%). no statistically significant differences were noted between the mean knowledge scores of the respondents and the use of difference information sources (p = 0.08). in response to the second question: “do you use the available research evidence in various databases to find answers to your clinical questions?”, the majority of respondents chose “sometimes” (44.5%). the other responses to this question were “always” (9.0%), “mostly”( 31.3%), “seldom”(14.2%) and “never”( 1.0%), respectively. in response to the third question “how many hours a week do you use websites to promote your knowledge in dentistry?”, most respondents (42.8%) replied that they spent less than an hour a week searching the internet. in response to the fourth question, only 0.8% of the respondents spent more than 10 hours a week using the internet as an information resource. no statistically significant relationships were noted between the mean knowledge scores of various groups in relation to the use of databases in order to find answers to clinical questions and their weekly use of the internet (p = 0.11). in response to the fifth question, “what is the most important obstacle to your routine use of ebd?”, the most frequent answer was “lack of time” (44.1%). in response to the sixth question “have you ever participated in any ebd educational programs?”, 81.6% of respondents answered that they had not participated in any ebd educational programmes to date. discussion in order to develop appropriate treatment plans, dentists should combine the treatment needs and preferences of the patient with the best available scientific evidence as well as the dentist’s own clinical expertise.19–21 ebd champions are committed to improving the quality, effectiveness and appropriateness of dental care through the application of evidence-based principles and tools.22–24 additionally, ebd leads to better oral healthcare by allowing the dentist systematically to collect and analyse scientific evidence to answer a specific clinical question.20,21,25,26 ebd requires dentists to learn new skills not traditionally taught in dental schools. a great deal of motivation is therefore required by older clinicians who are comfortable with the conventional model for clinical decision-making.27 the importance of evidence in teaching and in the support of clinical decisions is well-established in healthcare, including dentistry.28 the literature contains very little information on the knowledge and use of evidence-based practice for the dental field. three papers have investigated dental professionals, general dental practitioners and dentists in both the private and public sector.16,18,29 several studies had differing response rates. in a study carried out by iqbal et al. the response rate was 69.6%.16 mcinerney et al. had a 8.8% response rate;30 in contrast, the present study evaluated the knowledge and use of ebd by iranian dental practitioners with a 100% response rate. the variation in these response rates could be attributed to the differences in research methodologies between these studies. in some studies, the questionnaires were sent to the dental table 3: frequency of answers and percentage of participants who responded “know well”, “little is known” or “don’t know anything”, regarding selected evidence-based dentistry terms (n = 310) terms male female total *p value kw n (%) lk n (%) dk n (%) kw n (%) lk n (%) dk n (%) kw n (%) lk n (%) dk n (%) ebd 43 (14) 174 (59.3) 93 (26.7) 62 (20) 177 (57.2) 71 (22.8) 72 (23.2) 174 (56.1) 64 (20.7) **0.001 clinical effectiveness 68 (22.1) 144 (46.5) 98 (31.4) 73 (23.6) 155 (50) 82 (26.4) 76 (24.4) 161 (51.8) 73 (23.8) **0.001 relative risk 43 (14) 162 (52.3) 105 (33.7) 56 (18) 162 (52.4) 92 (29.6) 62 (20.1) 162 (52.4) 86 (27.4) **0.001 systematic review 102 (32.6) 119 (38.4) 89 (29.1) 101 (32.8) 129 (41.6) 80 (25.6) 102 (32.9) 134 (43.3) 74 (23.8) 0.07 critical appraisal 54 (17.4) 137 (44.2) 119 (38.4) 85 (27.3) 112 (36.2) 113 (36.7) 76 (24.4) 127 (40.9) 107 (34.8) 0.08 cochrane collaboration 25 (8.1) 97 (31.4) 188 (60.5) 46 (14.8) 99 (32) 165 (53.2) 57 (18.3) 102 (32.9) 151 (48.8) **0.01 kw = know well; lk = little is known; dk = don’t know anything ; ebd = evidence-based dentistry. *pearson’s chi-squared test; **significant. nader navabi, arash shahravan, sepideh pourmonajem and maryam a. hashemipour clinical and basic research | e227 practitioners in traditional hard copy format—it has been suggested that responses to electronic surveys are generally lower than those of paper surveys.16,31,32–34 however, kaplowitz et al. showed that web surveys can achieve a comparable response rate to mailed hard copy surveys.35 another factor that differed significantly in the present study was the number of years of experience of the study participants. almost one-third of respondents (32.9%) had graduated 1‒5 years before the study took place. however, in a study carried out by yusof et al., 36.8% of the participants had at least 20 years of work experience.17 in the study by iqbal et al., 62% of the respondents had worked as dental practitioners for more than 15 years.16 under half (44.8%) of mcinerney et al.’s sample were in senior positions.30 over half (53.3%) had worked at the university for 10 years or longer while only 33.3% had been practising for between 2–5 years.30 it appears that the relatively limited job experience of the dental practitioners in the present study might be attributed to the large number of dental practitioners who have recently graduated in iran. the majority of participants in the present study were familiar with the correct definition of ebd and were also aware that ebd develops clinical knowledge and expertise (82% for each). in addition, 77.2% of participants gave correct responses to the various steps constituting ebd and 78.3% confirmed the efficacy of ebd in helping patients. however, 46.8% of participants gave the wrong answer to the statement asserting that all articles published in scientific journals are suitable to be used in ebd, which was remarkable. this finding is consistent with the results of the study carried out by yusof et al.17 in iqbal et al.’s study, most respondents felt that the use of evidence-based practice and ebd is important and they showed great interest in learning more.16 another study by richards et al. found that more than two-thirds of respondents were aware of ebd, which is consistent with other research.16,30,36,37 similarly to results reported by yusof et al., the current study found no significant relationship between the knowledge scores of the participants and their demographic data, including age, gender and number of years since graduation.17 in the present study, the majority (34‒56%) of participants chose the response “little is known” for terms related to ebd. yousof et al. found that the knowledge rates of dental practitioners were 80%, 71% and 61.5% for the evidence-based practice terms “ebd”, “systematic review” and “critical appraisal”, respectively; these were higher than the rates in the present study.17 however, another study also reported that surveyed dentists had little understanding of the terminologies involved in ebd, with only about a third of the dentists able to choose the correct definitions for “ebd”, “critical appraisal” and “systematic review”.38 the concept which was defined correctly most often was “critical appraisal” (31.6%) and “evidence-based practice” (30.7%), followed by “systematic review” (21.1%).38 additionally, in the current study, many more dentists were able to correctly define “critical appraisal” (54%) as opposed to “evidence-based practice” and “systematic review”, which is similar to findings by other investigators.6,17,22,39 mccoll et al. reported that most of their respondents had some understanding of the technical terms used in evidence-based practice and a third felt capable of explaining these terms to others.39 these findings are confirmed by fritsche et al.’s finding that “self-perception of ability in ebm correlates poorly with objective assessment of knowledge and skills”.40 in addition, morris et al. found that clinicians who have not undertaken any formal education in evidencebased practice have generally been found not to have the necessary skills or knowledge to search for information.41 the cochrane collaboration is a fast-growing international organisation founded in 1992, and is an excellent source of systematic reviews in all fields of healthcare. this source is fundamental in the use of ebd, particularly as it includes the cochrane oral health review group, which addresses the prevention, treatment and rehabilitation of oral, dental and craniofacial diseases and disorders.18,42 in this study, the rate of unfamiliarity of dental practitioners with the cochrane collection was 48.8%, which is similar to findings from other studies.17,18,34,42 in a study carried out by iqbal et al., more than 73% of the respondents were unfamiliar with the term.16 adeoye similarly found that the majority of dentists were unaware of the cochrane collaboration.38 a total of 3.2% of respondents in the current study believed that the use of electronic databases was the only reliable method to achieve certainty in difficult cases. this interesting finding was similar to the rate reported by iqbal et al. (2%).16 however, the use of electronic databases along with other sources (including consultation with colleagues) comprised 40.32% of responses by the dental practitioners as a way to solve clinical problems, which was consistent with other reports.17,24,41,42 adeoye found that only two participants reported using an electronic database in cases of doubt; however, this source of information is usually the most accurate and up-to-date option.38 in the study by richards et al., the three most frequent actions chosen by the respondents when knowledge and use of evidence-based dentistry among iranian dentists e228 | squ medical journal, may 2014, volume 14, issue 2 faced with clinical uncertainties were to “ask friends and colleagues”, “refer the patient” and/or “consult textbooks.”36 slawson et al.43 found that more than half of the respondents asked friends or colleagues when uncertain about a treatment choice.34 experts and colleagues have proven to be a quick, cheap and easy-to-use source of information as well as providing dentists with guidance, support, affirmation and other psychological benefits that computerised sources cannot provide. textbooks were also consulted by some of the respondents, which could be problematic as textbooks are often already out-of-date by the time they are published. therefore, it appears that dental practitioners currently only accept the use of electronic databases concomitantly with other more conventional methods, including consultation with colleagues. the authors recommend using index medicus, pubmed, the cochrane collaboration, scopus, ovid, oxford university press, proquest, science direct, springer, the british medical journal, the journal of the american medical association and google scholar as the best online resources to consult for ebd. in response to the question “how many hours a week do you use websites to promote your knowledge in dentistry?”, most respondents (42.8%) replied that they spent less than an hour a week doing so. only 0.8% of the respondents spent more than 10 hours a week searching websites to enhance their dentistry knowledge. hadley et al. reported that only 19.9% of their research population searched the medical literature more than once a week and 24.6% searched only once every 1–2 weeks; the rest searched less frequently or not at all.28 only 38.2% of their sample reported that they read regularly every week to keep up-to-date. in this study, 43.5% reported that they spent 1–3 hours per week reading. this finding may be lower than that of jette et al. who reported that 66% of their sample read an average of two to five articles per month.44 davidoff et al. suggested that a general physician would need to read 17 articles each day to keep up with the current medical literature.45 in response, sackett et al. suggested that a journal club can be a useful forum to develop and enhance critical appraisal skills.46 the most important reported obstacle in the present study as regards the routine use of ebd was lack of sufficient time, which is consistent with the findings of yusof et al.,17 coleman et al.47 and bader.48 however, yusof et al. reported that the second most important obstacle was financial problems (40%).17 studies in medicine and dentistry have previously shown that clinicians do not have the time or inclination to appraise the evidence gathered from research themselves.18,32,39,42,49 in the study carried out by yusof et al., 22.2% of respondents reported a lack of the necessary skills to critically evaluate scientific articles as an obstacle to turning to ebd.17 however, only 5.3% of respondents in the present study reported it as an obstacle. it appears the respondents in the present study primarily focussed on their lack of time, which may have resulted in their overlooking other obstacles which might play a more important role. similar results have been reported by rabe et al. from sweden who discovered that one of the most common perceived barriers towards ebd among dental professionals was lack of time.18 barriers to the application of ebd have been highlighted in previous studies. upton et al. found that barriers to implementing evidence-based practice were similar for allied health professions and health science services, with the lack of both time and money cited as the main obstacles to implementing evidence-based practice.50 rabe et al. found that the most commonly perceived barriers to evidence-based practice were a lack of time and the poor availability of evidence.18 morris et al. obtained a 48.6% response rate to a postal survey of students who had undertaken an evidencebased practice module and reported that the greatest barriers to accessing and reviewing information were related to issues of time and lack of availability, with 48% stating that they had insufficient time to find research reports and 29% stating that reports were not available.41 jette et al. found that more physical therapists reported having access to the internet at home (89%) in comparison with work (65%) and that 46% rated insufficient time as the most important barrier to the use of evidence-based practice.44 the results of the present study and other similar studies show that ebd is not well recognised in developing countries. akadiri et al. carried out a study in dental faculties in nigeria, concluding that only six articles related to ebd had been published in nigeria. the respondents, who were members of the academic staff of these faculties, had little information about the principles of ebd, although they were aware of its exisistence.37 in the present study, 81.6% of respondents had not participated in any ebd educational courses to date; however, iqbal et al. reported a rate of 86% for this variable.16 in the study carried out by yusof et al., 81.3% of respondents had expressed interest in taking part in such courses.17 finally, the results of this study found that dentists in iran pay little attention to ebd for many reasons. the main factors were a lack of ebd education in dental schools and the fact that the respondents were nader navabi, arash shahravan, sepideh pourmonajem and maryam a. hashemipour clinical and basic research | e229 not familiar with ebd websites. moreover, there is a deficit of research studies and papers in the field of ebd. conclusion the results of the present study show that specialists and dental practitioners in iran are not sufficiently familiar with ebd, choosing instead to use more conventional methods to find answers to clinical questions, such as consultations with colleagues, rather than using the internet and other electronic resources. a lack of ebd education in dental schools and the fact that the majority of respondents in this study were not familiar with ebd websites highlights the need for ebd awareness programmes targeting dental practioners. references 1. rabb-waytowich d. you ask, we answer: evidence-based dentistry: part 1: an overview. j can dent assoc 2009; 75:27–8. 2. werb sb, matear dw. implementing evidence-based practice in undergraduate teaching clinics: a systematic review and recommendations. j dent educ 2004; 68:995–1003. 3. olatunbosun oa, edouard l, pierson ra. physicians’ attitudes toward evidence based obstetric practice: a questionnaire survey. bmj 1998; 316:365–6. 4. azarpazhooh a, mayhall jt, leake jl. introducing dental students to evidence-based decisions in dental care. j dent educ 2008;72:87–109. doi: 10.1136/bmj.316.7128.365. 5. hackshaw ak, paul ea, davenport es. evidence-based dentistry: an introduction. oxford, uk: wiley-blackwell, 2006. pp. 1–9. 6. richards d, clarkson j, matthews d, niederman r. evidencebased dentistry: managing information for better practice. london, uk: quintessence publishing co. ltd., 2008. pp. 1–14. 7. faggion cm jr, tu yk. evidence-based dentistry: a model for clinical practice. j dent educ 2007; 71:825–31. 8. meyer dm. evidence-based dentistry mapping the way from science to clinical guidance. j am dent assoc 2008; 139:1444– 6. doi: 10.14219/jada.archive.2008.0057. 9. sakaguchi r. evidence-based dentistry: achieving a balance. j am dent assoc 2010; 141:496–7. doi: 10.14219/jada. archive.2010.0204. 10. potomkova j, mihal v, zapletalova j, subova d. integration of evidence-based practice in beside teaching paediatrics supported by e-learning. biomed pap med fac univ palacky olomouc czech repub 2010; 154:83–7. doi: 10.5507/ bp.2010.014. 11. karimbux ny. evidence-based dentistry. j dent educ 2013;77:123. 12. bader j, ismali a, clarkson j. evidence-based dentistry and the dental research community. j dent res 1999; 78:1480–3. doi: 10.1177/00220345990780090101. 13. benjamin p; dpbrn collaborative group. promoting evidenced-based dentistry through “the dental practice-based research network”. j evid based dent pract 2009; 9:194–6. doi: 10.1016/j.jebdp.2009.06.014. 14. rabb-waytowich d. evidence-based dentistry: part 2: finding the research. j can dent assoc 2009; 75:191–3. 15. marinho vc, richards d, niederman r. variation, certainty, evidence, and change in dental education: employing evidencebased dentistry in dental education. j dent educ 2001; 65:449– 55. 16. iqbal a, glenny am. general dental practitioners’ knowledge of and attitudes towards evidence based practice. br dent j 2002; 193:587–91. doi: 10.1038/sj.bdj.4801634. 17. yusof zy, han lj, san pp, ramli as. evidence-based practice among a group of malaysian dental practitioners. j dent educ 2008; 72:1333–42. 18. rabe p, holmén a, sjögren p. attitudes, awareness and perceptions on evidence based dentistry and scientific publications among dental professionals in the county of holland, sweden: a questionnaire survey. swed dent j 2007; 31:113–20. 19. ismail ai, bader jd; ada council on scientific affairs and division of science; journal of the american dental association. evidence-based dentistry in clinical practice. j am dent assoc 2004; 135:78–83. doi: 10.14219/jada.archive.2004.0024. 20. frideres t, gillette j. evidence-based dentistry professional development and training for the dental office team. j evid based dent pract 2009; 9:129–34. doi: 10.1016/j.jebdp.2009.06.009. 21. gillette j. striving for excellence with evidence-based dentistry. j evid based dent pract 2009; 9:125–8. doi: 10.1016/j. jebdp.2009.06.008. 22. bader jd, frantsve-hawley j. american dental association resources supporting evidence-based dentistry. semin orthod 2013; 19:158–61. doi: 10.1053/j.sodo.2013.03.005. 23. forrest jl. introduction to the basics of evidence-based dentistry: concepts and skills. j evid based dent pract 2009; 9:108–12. doi: 10.1016/j.jebdp.2009.07.002. 24. clarkson je, bonetti d. why be an evidence-based dentistry champion? j evid based dent pract 2009; 9:145–50. doi: 10.1016/j.jebdp.2009.06.012. 25. gillette j. answering clinical questions using the principles of evidence-based dentistry. j evid based dent pract 2009; 9:1–8. doi: 10.1016/j.jebdp.2008.12.013. 26. gillette j, matthews jd, frantsve-hawley j, weyant rj. the benefits of evidence-based dentistry for the private dental office. dent clin north am 2009; 53:33–45. doi: 10.1016/j. cden.2008.09.002. 27. dodson tb. evidence based medicine: its role in the modern practice and teaching of dentistry. oral surg oral med oral pathol oral radiol endod 1997; 83:192–7. 28. hadley ja, wall d, khan ks. learning needs analysis to guide teaching evidence-based medicine: knowledge and beliefs amongst trainees from various specialties. bmc med educ 2007; 7:11. doi: 10.1186/1472-6920-7-11. 29. lalloo r. evidence-based practice: knowledge and attitudes of selected south african dental practitioners. sadj 2003; 58:358. 30. mcinerney p, suleman f. exploring knowledge, attitudes, and barriers toward the use of evidence-based practice amongst academic health care practitioners in their teaching in a south african university: a pilot study. worldviews evid based nurs 2010; 7:90–7. doi: 10.1111/j.1741-6787.2009.00180.x. 31. sheehan kb. e-mail survey response rates: a review. j comp mediat commun 2001; 6:45–52. doi: 10.1111/j.1083-6101.2001. tb00117.x. 32. madhavji a, araujo ea, kim kb, buschang ph. attitudes, awareness, and barriers towards evidence-based practice in orthodontics. am j orthod dentofacial orthop 2011; 140:309– 16. doi: 10.1016/j.ajodo.2010.05.023. 33. kiesler s, sproull ls. response effects in the electronic survey. public opin q 1986; 50:402–13. doi: 10.1086/268992. knowledge and use of evidence-based dentistry among iranian dentists e230 | squ medical journal, may 2014, volume 14, issue 2 34. bean ag, roszkowski mj. the long and short of it. j mark res 1995; 7:20–6. 35. kaplowitz md, hadlock td, levine r. a comparison of web and mail survey response rates. public opin q 2004; 68:94– 101. doi: 10.1093/poq/nfh006. 36. richards d, lawrence a. evidence based dentistry. br dent j 1995; 179:270–3. doi: 10.1038/sj.bdj.4808896. 37. akadiri ao, adeyemo wl. evidence-based dentistry in a developing economy: the nigerian example. open dent j 2010; 4:51–4. doi: 10.2174/1874210601004020051. 38. adeoye ot. knowledge and attitude of dentists towards evidence-based dentistry in lagos, nigeria: a thesis submitted in partial fulfilment of the requirements for the degree of msc in dental science, university of the western cape, 2008. from: www.etd.uwc.ac.za/usrfiles/modules/etd/ docs/etd_gen8srv25nme4_7293_1265842221.pdf accessed: feb 2014. 39. mccoll a, smith h, white p, field j. general practitioner’s perceptions of the route to evidence based medicine: a questionnaire survey. bmj 1998; 316:361–5. doi: 10.1136/ bmj.316.7128.361. 40. fritsche l, greenhalgh t, falck-ytter y, neumayer h, kunz r. do short courses in evidence based medicine improve knowledge and skills? validation of berlin questionnaire and before and after study of courses in evidence-based medicine. bmj 2002; 325:1338–41. doi: 10.1136/bmj.325.7376.1338. 41. morris j, maynard v. the value of an evidence based practice module to skill development. nurse educ today 2007; 27:534– 41. doi: 10.1016/j.nedt.2006.08.022. 42. turpin dl. consensus builds for evidence-based methods. am j orthod dentofacial orthop 2004; 125:1–2. doi: 10.1016/j. ajodo.2003.11.014. 43. slawson dc, shaughnessy af. obtaining useful information from expert based sources. bmj 1997; 314:947–9. doi: 10.1136/ bmj.314.7085.947. 44. jette du, bacon k, batty c, carlson m, ferland a, hemingway rd, et al. evidence-based practice: beliefs, attitudes, knowledge, and behaviors of physical therapists. phys ther 2003; 83:786– 805. 45. davidoff f, haynes b, sackett d, smith r. evidence based medicine. bmj 1995; 310:1085–6. doi: 10.1136/ bmj.310.6987.1085. 46. sackett dl, haynes rb, guyatt gh, tugwell p, eds. clinical epidemiology: a basic science for clinical medicine. 2nd ed. boston, usa: lippincott, williams & wilkins, 1991. pp. 398– 418. 47. coleman p, nicholl j. influence of evidence-based guidance on health policy and clinical practice in england. qual health care 2001; 10:229–37. doi: 10.1136/qhc.0100229. 48. bader jd. stumbling into the age of evidence. dent clin north am 2009; 53:15–22. doi: 10.1016/j.cden.2008.09.001. 49. o’donnell ca. attitudes and knowledge of primary care professionals towards evidence-based practice: a postal survey. j eval clin prac 2004; 10:197–205. doi: 10.1111/j.13652753.2003.00458.x. 50. upton d, upton p. knowledge and use of evidence-based practice by allied health and health science professionals in the united kingdom. j allied health 2006; 35:127–33. clinical & basic research sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 344-351, epub. 15th jul 12 submitted 30th nov 11 revision req. 30th jan 12, revision recd. 26th feb 12 accepted 17th mar 12 إستجابة الطالب على التعلم القائم على الفريق وِفَرق اختالط اجلنسني يف مساق املعلوماتية الطبية يف الدراسات اجلامعية كني ما�سرتز امللخ�ص: الهدف: يتزايد ا�ستخدام التعلم القائم على الفريق يف امل�ساقات الطبية واملرتبطة بالطب. الهدف من هذه الدرا�سة تقييم ا�ستجابات الطالب للتعلم القائم على الفريق مل�ساق املعلوماتية الطبية يف جامعة ال�سلطان قابو�ض يف ُعمان. الطريقة: بعد اإجناز 11 جل�سة مبنية على التعلم القائم على الفريق خالل ف�سل درا�سي يتكون من 14 اأ�سبوعا من امل�ساق الثاين للمعلوماتية الطبية يف جامعة ال�سلطان قابو�ض، ُقمنا باإجراء تقييم للطلبة من خالل �سبكة املعلومات العاملية يف الأ�سبوع 13 من امل�ساق. النتائج: من بني 108 طالبا ُمدرجا يف امل�ساق، فائدة على وح�سلت الفريق، على القائم التعلم ا�ستخدام ل�سالح �سّوتت الأغلبية اأن وظهر ال�ستبيان، على منهم )%88.9( 96 اأجاب كبرية من جل�سات ذلك التعلم. غري اأن التقاليد الجتماعية على ما يبدو قد انعك�ست �سلبا على جتربة الإناث يف جل�سات التعلم تلك. اخلال�صة: اأقّر الطالب بفوائد التعلم القائم على الفريق يف م�ساق املعلوماتية الطبية. ومع ذلك ويف مثل هذه البيئة، ينبغي على امل�رسفني اأن ي�سعوا يف احل�سبان على الدوام التقاليد الجتماعية. مفتاح الكلمات: املعلوماتية الطبية ، التعلم القائم على فريق، مواقف الطالب، ُعمان. abstract: objectives: team-based learning (tbl) is increasingly being used in medical and medically-related courses. the aim of this study was to evaluate student responses to a tbl-based course in medical informatics at the sultan qaboos university, oman. methods: a total of 11 tbl sessions were run during a 14-week semester of the medical informatics ii course at squ. an online student evaluation was performed in week 13 of the course. results: of the 108 students on the course, 96 (88.9%) of the students responded to the survey. for the most part, the students regarded tbl favourably, and derived great benefit from the tbl sessions. cultural norms, however, appear to have impacted negatively on the females’ experience of the tbl sessions. conclusion: tbl’s benefits in the medical informatics course were recognised by the students. in such an environment, however, facilitators will have to bear in mind and continually address cultural issues. keywords: medical informatics; team-based learning; medical students; attitude; oman. student response to team-based learning and mixed gender teams in an undergraduate medical informatics course ken masters clinical & basic research medical education unit, sultan qaboos university, muscat, oman. e-mail: itmeded@gmail.com advances in knowledge team-based learning (tbl) can be applied successfully in undergraduate medical informatics courses. the impact of cultural practices that moderate interaction between demographic groups can mostly be reduced, but course facilitators need to be keenly aware of cultural issues. applications to patient care tbl in the undergraduate years has shown itself to be valuable in the acquisition of content necessary for effective patient care during and after the clinical years. the social skill of working effectively in teams, crucial to good patient care, can begin to be inculcated in students at a very early stage of their careers, even in a social environment that may mediate against heterogeneous teamwork. ken masters clinical and basic research | 345 team-based learning (tbl) is increasingly being used in university education, and in the teaching of medical and medically-related courses, but this is not the place to give a detailed description of tbl, as other excellent descriptions exist.1–9 nevertheless, it is useful to note that a tbl session emphasises active learning and follows a process during which students receive stimulus material (e.g. readings), perform a short multiple choice question (mcq) test taken individually, followed by the same mcq test taken in teams of 5–8 students. the two tests are frequently referred to as the individual readiness assessment test (irat), and the group readiness assessment test (grat) respectively.2,4,7,10 the scores from the tests usually contribute significantly towards the final course assessment. feedback on the grat is given immediately in class, and the tbl session continues with a more in-depth question in which the information learned is applied. this is followed by further feedback and clarifications from the facilitator. apart from the pedagogical value of tbl, and its demonstrated positive impact on examinations, using tbl in medical professional training has a further advantage: medical professionals need to be able to work in diverse teams and tbl offers a fine opportunity for medical students to come to grips with the complexities of teamwork at an early stage in their training.2,11–15 these skills should be included in the students’ training, and can be learned (along with attitudes and values) through practice.2,16–22 in 2010, the college of medicine and health sciences at sultan qaboos university (squ) in oman hosted tbl workshops for staff who were interested in using tbl in their courses. in 2011, the author implemented tbl in the medical informatics ii course. this course has 4 contact hours per week, builds on the more basic medical informatics i course, runs through a 14-week semester, covers a range of theoretical and practical aspects of medical informatics, and is designed to equip the students with the foundational attitudes, knowledge, and skills in information systems required by doctors. in the first week of the medical informatics ii course, students were given an orientation to tbl, and were then able to run through the tbl process twice. as part of the course orientation, the need for teamwork in medical practice was described, with reference to common practices in oman and internationally, and the link between this teamwork and tbl was made. during the course, students were frequently reminded of this by reference back to the discussions in the orientation week; the overarching philosophy was that tbl was part of their training as members of a health care team. as part of this orientation, a small but significant change was made to the nomenclature. in much tbl writing, the words “group” and “team” appear to be used interchangeably.9 reference has already been made to the fact that the assessment taken by the team is usually referred to as a group readiness assessment test (grat).2,4,7,10 the confusion of “group” with “team” is antithetical to the concept of teamwork in general, and it was felt would undermine the team aspect of tbl. as a result, the instructor never used the word “group,” and the team assessment was always referred to as a team readiness assessment test (trat) to emphasise that it was an assessment taken by a team. the term trat is used in the rest of this paper. because the first two tbl sessions held in the first week were practice sessions, they did not contribute to the course grade (this work was examined in the final examination). during the orientation, the instructor divided the students into 14 teams of 7–8 students each. students were randomly chosen except in the case of gender: because of the high female to male student ratio on the course, there was a need to ensure that each team had at least two males. the teams of students remained fixed for the duration of the course. the objectives and readings for each tbl session were made available in the learning management system (lms) at the start of the semester.5 in preparation for each tbl session, students had to read approximately five pages of text. during the rest of the semester, a 2-hour tbl session was run every week for 11 weeks, while the other 2-hour weekly contact time of the course consisted of student presentations on advanced topics. during each session, the irats and trats consisted of 5 mcqs covering the basics of the topic. students had 8 minutes to complete the irat, and 15 minutes to complete the trat. because the attendance policy at squ allows students to be absent from some classes, only the highest nine irat and trat scores would contribute to the students’ scores. student response to team-based learning and mixed gender teams in an undergraduate medical informatics course 346 | squ medical journal, august 2012, volume 12, issue 3 the irat and trat scores each counted for 20% of the total score for the course. this proportion is in line with practices elsewhere, and is considered a substantial contribution.1,3, 4,10 because the course was a medical informatics course, classes were held in computer laboratories. as a result, the irats were taken online. the students then broke into their teams in the computer laboratory and continued with the trat. after the trat, application questions were given, and students had approximately 45 minutes to solve the problems. this was followed by feedback and wrap-up. when running tbl sessions at squ, however, one needs to be sensitive to a particular aspect of omani culture that may conflict with a central tenet of tbl. tbl expressly relies on the diversity of the teams in respect to culture, background, and gender.9 in oman, classes in public schools after 5th grade are usually single-gender (although not all students at squ are from public schools), and interaction between genders outside of one’s family is generally discouraged. in the college of medicine & health sciences, while classes are of mixed gender, the students separate themselves by gender in the classroom. the result is that the majority of the college’s undergraduate students are not used to working in mixed gender teams. it was expected that this would have an impact on the running of the tbl sessions. given the professional needs within this complex setting, this study set out to gauge the students’ reactions to tbl in their course. methods the study was conducted among the 108 medical students at squ who were taking the medical informatics ii course in the spring semester of 2011. an in-course evaluation of the tbl process, conducted three weeks into the course, indicated that there had been a general acceptance of the new teaching model amongst students, although there was also some reluctance and uncertainty. the literature indicates that this is common in the early stages of tbl introduction.7 the issues and problems raised by the students regarding the process were addressed, and the process continued. while the results of the preliminary evaluation were useful because the evaluation had been conducted early in the semester, there was the risk that results may have been influenced by the novelty of the teaching method. there was a need to determine students’ attitudes towards tbl after 11 sessions of tbl across the semester. for this study, a survey form and consent form were created. the core of the survey form was based on the 12-item survey form by wiener, plass and marz.8 students responded to statements with a lickert scale running from 1 (strongly disagree) to 6 (strongly agree). small language changes were made to some of wiener et al.’s questions to account for local interpretations, and additional questions were added to gather further information about students’ attitudes towards tbl. because of the cultural issues discussed above, a crucial question regarding the comfort of students working in mixed-gender teams was also added. finally, an open text question allowed students to add any further comments. the in-course tbl evaluation used this revised form and also served as a pilot for students’ feedback on the questionnaire. as a result of students’ feedback, some minor language alterations were made to the questions. a consent form was designed, based on a standard consent form used in previous research by the author, and approved by squ. the consent form indicated that the survey was anonymous, and students were under no obligation to participate. the language of instruction at squ is english, but many of the students do not have english as their mother tongue. as a result, the language of the consent form and the survey form needed to be easily accessible. common (albeit not absolutely perfect) scales of measuring english language levels are the flesch reading ease and the flesch-kincaid grade level.2,31 using these scales, the level of english of the consent and survey forms was determined as shown in table 1. the figures indicate that the forms would be understood by native english speakers in middle school, so the students in this study would be able to understand the forms. ethical approval for the study was granted by the squ college of medicine & health sciences medical research & table 1: flesch reading ease and flesch-kincaid grade level of the consent and survey forms scoring system item flesch reading ease fleschkincaid grade level consent form 50.6 9.9 survey 64.9 6.2 ken masters clinical and basic research | 347 ethics committee (mrec #417). the survey was conducted electronically near the end of the semester (may 2011), in week 13, by which time 11 tbl sessions had been run. the survey remained open for a week. all data were collected and stored anonymously and electronically, and were secured by means of passwords and 256-bit encryption. the data were placed into a microsoft excel 2010 spread sheet (microsoft, redmond, washington, usa), and descriptive statistical analyses were performed. wiener et al. had used the mann-whitney u-test to determine the differences in responses based on gender, so, for consistency in the comparison of the two studies, the mannwhitney u-test was also chosen for analysis of the data in this study (qi macros spc software for excel, knowware international, denver, colorado, 2012), and statistical difference was taken at p <0.05. results attendance at the tbl sessions was 96.97%, with only three students missing the maximum allowable number of two tbl sessions. a total of 96 students table 2: student responses to questions in the tbl survey (n = 96) options mean score (sc) and standard deviation (sd) numerical scale and percentage responses n = 96 total sample n = 96 female n = 52 male n = 38 questions put to students 1–2 3–4 5–6 sc. sd sc. sd sc. sd p i do the readings properly before the tbl sessions. 3 29 68 4.7 1.1 5.1 0.8 4.4 1.4 0.02 the irats are a good test of my knowledge. 6 34 59 4.6 1.2 4.8 1.1 4.6 1.3 0.86 the trats help to clarify areas that i’m unsure of. 5 19 76 5.0 1.2 5.3 1.0 4.8 1.2 0.04 the discussion after the trat clarifies areas that i’m unsure of. 3 31 66 4.8 1.1 4.9 1.0 4.9 1.3 0.81 the appl. questions are useful for applying the basic knowledge. 4 49 47 4.3 1.0 4.4 0.9 4.3 1.2 0.53 i believe the tbl sessions are more valuable than normal lectures. 5 38 57 4.6 1.2 4.6 1.2 4.7 1.3 0.56 i enjoy the tbl sessions. 7 42 51 4.5 1.3 4.3 1.3 5.1 1.1 0.00 tbl helps to assess present knowledge. 1 43 56 4.6 1.0 4.7 1.0 4.8 1.0 0.65 tbl helps to get me to a higher level of knowledge. 4 42 54 4.6 1.0 4.7 1.0 4.5 1.1 0.44 tbl reduces the amount of time needed for self-study. 10 44 46 4.2 1.2 4.4 1.2 3.9 1.3 0.09 tbl challenges me to give my best. 3 51 46 4.4 1.0 4.6 1.0 4.4 1.1 0.25 tbl has a positive impact on my learning attitudes. 1 41 58 4.6 1.0 4.5 0.9 4.7 1.0 0.47 tbl is an effective, motivating learning strategy. 4 32 65 4.7 1.1 4.7 1.2 4.9 1.0 0.39 the lecturer facilitated the learning process well. 5 26 69 4.8 1.2 5.0 0.9 5.0 1.4 0.30 the tbl course is well organized. 3 21 76 5.0 1.1 5.0 1.0 5.2 1.2 0.13 i would recommend tbl to other students. 3 29 68 4.9 1.1 4.7 1.1 5.2 1.1 0.02 tbl should be offered more frequently in the curriculum. 5 42 53 4.5 1.3 4.3 1.3 5.0 1.2 0.01 overall, i am very satisfied with this tbl approach. 14 38 59 4.6 1.1 4.5 1.1 4.9 1.1 0.13 i frequently study with colleagues. 25 34 41 3.8 1.6 3.8 1.5 4.0 1.7 0.43 i am happy working in a tbl team with males and females together. 21 25 54 4.3 1.7 3.7 1.8 5.2 1.3 0.00 legend: tbl = team-based learning ; irat = individual readiness assurance test; trat = team readiness assurance test student response to team-based learning and mixed gender teams in an undergraduate medical informatics course 348 | squ medical journal, august 2012, volume 12, issue 3 completed the survey form, giving a response rate of 88.9%. of the 96 students, 90 indicated their gender, of which 38 (42.2%) were male. there was no statistical difference between the female/male ratio of the respondents and the total class population. the students’ responses to the questions are given in table 2. for purposes of reporting, following the process given by wiener et al.8, the responses to the lickert scale were reduced to three groups (1–2; 3–4; 5–6). on the organisation and facilitation of the tbl sessions, the students were generally satisfied, and there was consistency of satisfaction across both genders. in addition, there is general acceptance of the effectiveness of the tbl process (including the discussion after the trats), and the belief that tbl is more valuable than normal lectures. overall, more than half the class enjoyed the tbl sessions, but 42% were neutral. the application questions, however, were not seen to be as valuable as the irat and trat. obvious, however, was the significant differences between a) females and males in the enjoyment of the tbl session (4.3 vs. 5.1); b) the likelihood of recommending the method to other students (4.7 vs. 5.2), and c) the interest in the college offering tbl more frequently (4.3 versus 5.0). the greatest difference between female and male scores, and possibly the root for the other differences, is that females were far less happy than males to work in mixed-gender teams (3.7 versus 5.2). superficially, one might be tempted to believe that this lower figure amongst females is simply a gravitation towards the central options (3 and 4) on the lickert scale, and that the females did not have particularly strong feelings either way. when inspecting these figures in more detail, however, we find that this is not the case. figure 1 indicates that, while there are fewer females agreeing with the statement, the central gravitation had not occurred. the reason for the low mean score was that a large number of females appeared directly opposed to the mixed-gender groups. a total of 19.2% of the females selected “strongly disagree” and 15.4% selected “disagree” in response to questions about working in mixed-gender teams, giving a combined score of 34.7%, as opposed to only 5.3% for the males [figure 1]. in the open text response question, two female students commented negatively on the mixed-gender teams. one of them wrote: “we are not happy to work as males and females together, so we prefer to separate us as groups of males and other groups of females.” in addition, during the running of the tbl sessions, almost all the teams formed themselves into sub-groups, split on gender lines. the facilitator had to tread a delicate line of encouraging greater cohesion while ensuring that cultural sensitivities were not offended. this was usually done with reference to the need for cohesion in clinical teams. students were informed that they were already doctors, but in their early stages of their training, and that the problems to be solved should be viewed as if they were those of actual patients in need of the best possible medical care. it was underlined that this could be provided only by a proper team of medical personnel. by the end of the semester, there was greater cohesion within teams, with most of the teams forming a circle around a computer or two. they were still, however, divided along lines of gender, and some teams remained in a single row, refusing to form a cohesive circle of any type. an added factor that may have led to the dissatisfaction amongst the females is that the results indicate that the males did less reading preparation than the females, and many females may have felt that they were being forced to carry the load in the trats. this paper focuses on student responses, and so does not report on student performance in any detail. nevertheless, because an important reason for emphasising teamwork is to improve on individual performance, it is appropriate to report 0% 10% 20% 30% 40% 50% 60% 70% 80% 1+2 3+4 5+6 all students males females figure 1: graph showing percentages of responses to the question “i am happy working in a tbl team with males and females together.” 1= strongly disagree; 6 = strongly agree. ken masters clinical and basic research | 349 briefly on aggregated data. for the class, the mean irat score was 87.9% (range: 60–100%) and the mean trat score was 99.7%, with most teams scoring 100%. similar scores have been found elsewhere.10 discussion for the most part, there was a positive response to the value of tbl, its ability to increase knowledge, and its benefits in comparison to the value of lectures. this positive attitude has been found by several other researchers.3,4,8,24 the increase in scores from irat to trat certainly demonstrated the value of working in teams. in addition, the students mostly enjoyed the sessions. specifically, 51% of the students enjoyed the tbl sessions, 42% were neutral, and only 7% did not enjoy the sessions. although the facilitator would have preferred a greater indication of enjoyment, these figures are encouraging, especially when viewed in the light of other research.1 (the issue of the male/female dichotomy is discussed below). there may be many factors that increase student enjoyment of tbl. the results certainly indicate that the students recognise that the course was well-organised, and this would have an impact on their perception of the course. in addition, having the tbl so early in their medical training might have helped because they had not yet come to believe that powerpoint-driven lectures are the only method of teaching at university, as has been suggested by other researchers.1 this early offering of tbl, however, may also have a great disadvantage. at this early stage, the students are not convinced of the need to work in teams, especially as so much of their other course work is individually assessed. trying to convince students that they will need to learn to work in teams for their later student years, as well as during their medical careers, may sound like trying to sell a concept rather than preparing them for that scenario. in this cultural setting, this would have been a particular problem and was possibly exaggerated by the fact that the course convenor and facilitator was a non-omani male who may have been perceived to be importing foreign and culturally-insensitive practices into the curriculum. readers familiar with tbl may have noticed that these sessions did not have peer-evaluation. a system of peer-evaluation is recommended as a crucial part of tbl, primarily because it encourages individual accountability, and has been implemented by several researchers.4,5,7,9 some of these researchers, however, have reported that the peer-evaluation system is manipulated by students and also causes great dissatisfaction amongst them.4,7 for these reasons, the facilitator decided that having both the irat and trat each counting 20% of the course grade would be enough incentive for individual accountability. as a result, at this stage, there is no plan to introduce peer-evaluation; however, the course could probably benefit from future course evaluation questions on participation in teams. this would be especially important given the apparent differences between males and females in the reading preparation described above. there is also the argument that, as tbl contributes as much as 40% of the overall grade, this could inflate the end-of-year grade. a counter argument, however, is that it makes little sense to introduce tbl, and to emphasise the need to work in teams, unless one is prepared to have it contribute significantly to the students’ final marks. allowing the students to skip 2 out of 11 sessions possibly inappropriately boosted their grades, so this allowance may be reduced to only 1 in the future. the greatest problem encountered was that of the mixed-gender teams. gender segregation exists at other public higher education institutions in the arabian gulf region.25–27 unfortunately, this segregation—and its possible impact on education—is seldom mentioned or discussed when researchers present overviews of the educational environment at institutes of higher education in the gulf region.28–30 this is a shortcoming that has been investigated in other cultural settings.31as a result, this would appear to be an area for more detailed future research. at this stage, when we compare the results of this study to wiener et al.’s results, we can see there are similar male/female trends in the response to many of the questions.8 simultaneously, however, when one looks at questions dealing with recommending tbl to other students, offering tbl more in the curriculum, and overall satisfaction with tbl, one sees that there is a reversal: females in this study were less satisfied than the males. student response to team-based learning and mixed gender teams in an undergraduate medical informatics course 350 | squ medical journal, august 2012, volume 12, issue 3 until further research is conducted, it will be prudent for the facilitator of such a course to be vigilant about the gender issue. however, as tbl becomes used more frequently in the students’ courses, the problems associated with mixedgender teams may subside. although this study covered the impact of 11 tbl sessions, it was conducted in one course in one university only. the results will benefit from repeated studies to determine the overall student response to the use of tbl in medical informatics classes. in addition, because the cultural impact had not been foreseen, there were too few questions regarding students’ backgrounds for a detailed understanding of possible reasons behind the students’ responses. a repeat study should include questions on students’ ages, ethnic background, schooling, and whether their family is from an urban or rural setting. conclusion team-based learning is being increasingly used in medical and medically-related courses. this paper has described the student response to the use of tbl in a medical informatics course in the college of medicine & health sciences at squ in oman. for the most part, the students accepted the use of tbl in the course and perceived the benefits; however, issues pertaining to omani cultural norms may have impacted negatively on the females’ perceptions of tbl. because working in mixedgender teams is crucial to the delivery of health care, facilitators working in such sensitive cultures will need to address the issue continually so that that the students’ experience of tbl is as positive as possible. a c k n o w l e d g e m e n t s i am indebted to dr. nadia al-wardy for comments on an earlier draft of the paper, to my students for participating in the tbl sessions and the survey, and to the reviewers who commented on an earlier version of this paper. d i s c l a i m e r a n d c o n f l i c t o f i n t e r e s t the author is the sole author of the paper. there are no known conflicts of interest. references 1. clark mc, nguyen ht, bray c, levine re. teambased learning in an undergraduate nursing course. j nurs. educ. 2008; 47:111–7. 2. levine re, o’boyle m, haidet p, lynn dj, stone mm, wolf dv, et al. transforming a clinical clerkship with team learning. teach learn med 2004; 16:270–5. 3. mcinerney mj, fink ld. team-based learning enhances long-term retention and critical thinking in an undergraduate microbial physiology course. jmbe 2003; 4:4–12. 4. nieder gl, parmelee dx, stolfi a, hudes pd. teambased learning in a medical gross anatomy and embryology course. clin anat 2005; 18:63. 5. parmelee dx, michaelsen lk. twelve tips for doing effective team-based learning (tbl). med teach 2010; 32:118–22. 6. touchet bk, coon ka. a pilot use of team-based learning in psychiatry resident psychodynamic psychotherapy education. acad psychiatry 2005; 29:293–6. 7. thompson b, schneider v, haidet p, levine r, mcmahon k, perkowski lc, et al. team-based learning at ten medical schools: two years later. med educ 2007; 41:250–7. 8. wiener h, plass h, marz r. team-based learning in intensive course format for first-year medical students. croat med j 2009; 50:69–76. 9. michaelsen l. getting started with team-based learning. in: michaelsen l, knight ab, fink l, eds. team-based learning: a transformative use of small groups. 1st ed. new york: praeger, 2003. pp. 27–52. 10. koles p, nelson s, stolfi a, parmelee d, destephen d. active learning in a year 2 pathology curriculum. med educ 2005; 39:1045–55. 11. koles pg, stolfi a, borges n, nelson s, parmelee dx. the impact of team-based learning on medical students’ academic performance. acad med 2010; 85:1739–2145. 12. letassy na, fugate se, medina ms, stroup js, britton ml. using team-based learning in an endocrine module taught across two campuses. am j pharm educ 2008; 72:103. 13. tan nc, kaniah n, chan yh, umapathi t, lee sh, tan k. a controlled study of team-based learning for undergraduate clinical neurology education. bmc med educ 2011; 11:91. 14. hall p, weaver l. interdisciplinary education and teamwork: a long and winding road. med educ 2001; 35:867–75. 15. hamilton cb, smith a, butters jm. interdisciplinary student health teams: combining medical education and service in a rural community-based experience. j rural health 1997; 13:320–7. ken masters clinical and basic research | 351 16. edmunds s, brown g. effective small group learning: amee guide no. 48. med teach 2010; 32:715–26. 17. fagin c. collaboration between nurses and physicians: no longer a choice. acad med 1992; 67:295–303. 18. hendricson w, payer af, rogers i, markus jf. the medical school curriculum committee revisited. acad med 1993; 68:183–9. 19. hunt dp, haidet p, coverdale jh, richards b. the effect of using team learning in an evidence-based medicine course for medical students. teach learn med 2003; 15:131–9. 20. sibley j, parmelee dx. knowledge is no longer enough: enhancing professional education with team-based learning. new direc teach learn 2008; 116:41–53. 21. stubblefield c, houston c, haire-joshu d. interactive use of models of health-related behavior to promote interdisciplinary collaboration. j allied health 1994; 23:237–43. 22. thompson b, schneider v, haidet p, levine r, mcmahon k, perkowski lc, et al. team-based learning at ten medical schools: two years later. med educ 2007; 41:250–7. 23. bernstam ev, shelton dm, walji m, mericbernstam f. instruments to assess the quality of health information on the world wide web: what can our patients actually use? int j med inf 2005; 74:13– 9. 24. clark mc. using team-based learning as a substitute for lectures in a required undergraduate nursing course. in: michaelson l, parmelee d, mcmahon k, levine r, eds. team-based learning for health professions’ education. 1st ed. sterling, virginia: stylus, 2007. pp. 151–60. 25. faculty of medicine king abdulaziz university. institutional self-study summary report. jeddah: saudi arabia. from: http://www.kau.edu.sa/getfile. aspx?id=90913&fn/finalsumrep150211revised.pdf accessed: oct 2011. 26. krause w. gender and participation in the arab gulf. kuwait: kuwait programme on development, governance and globalisation in the gulf states, 2009. 27. mazawi ae. the academic workplace in public arab gulf universities. in: altbach pg, ed. the decline of the guru: the academic profession in developing and middle-income countries. new york: palgrave macmillan, 2003. pp. 231–70. 28. bin abdulrahman ka. the current status of medical education in the gulf cooperation council countries. ann saudi med 2008; 28:83–8. 29. hamdy h, telmesani a, al-wardy n, abdel-khalek n, carruthers g, hassan f, et al. undergraduate medical education in the gulf cooperation council: a multi-countries study (part 1). med teach 2010; 32:219–24. 30. hamdy h, telmesani a, al-wardy n, abdel-khalek n, carruthers g, hassan f, et al. undergraduate medical education in the gulf cooperation council: a multi-countries study (part 2). med teach 2010; 32:290–5. 31. jackson se, joshi a, erhart nl. recent research on team and organizational diversity: swot analysis and implications. j management 2003; 29:801–30. departments of 1pharmacy and 2surgery, king hussein cancer centre, amman, jordan *corresponding author e-mail: fdaoud@khcc.jo حتسن يف االلتزام بتطبيق قواعد االستخدام الوقائي للمضادات احليوية يف العمليات اجلراحية بعد تطبيق مشروع حتسني اجلودة املتعدد التخصصات �رسوق طلفاح، ملى ناظر، منار ديراين، فايز داوود abstract: objectives: this study aimed to show the impact of a multidisciplinary quality improvement project on adherence to antimicrobial prophylaxis guidelines in oncological surgery. methods: this preand post-intervention prospective observational study was carried out at the king hussein cancer centre (khcc) in amman, jordan, between august 2009 and february 2012. the quality improvement project consisted of revising the institutional guidelines for surgical antimicrobial prophylaxis, assigning a clinical pharmacist to the surgical department, establishing an operating room satellite pharmacy and providing education regarding the appropriate utilisation of antibiotics. the medical records of adult cancer patients who underwent surgery were evaluated one month before and one month after the project was implemented to assess adherence to the guidelines with regards to antibiotics prescribed, drug doses and timing and treatment duration. results: a total of 70 patients were evaluated before and 97 patients were evaluated after the intervention, of which 57 (81.4%) and 95 (97.9%) patients received antibiotics, respectively. in comparing the preand post-intervention groups, an improvement was observed in the proportion of patients who received antibiotics at the appropriate time (n = 12 versus n = 79; 21.1% versus 83.2%; p <0.01), for the appropriate duration of time (n = 22 versus n = 94; 38.6% versus 99.0%; p <0.01) and in the appropriate dose (n = 9 versus n = 87; 56.3% versus 98.9%; p <0.01). conclusion: adherence to the antimicrobial prophylaxis guidelines at khcc improved significantly after the implementation of a quality improvement project. keywords: antibiotic prophylaxis; surgery; operative surgical procedures; quality improvement; pharmacists; education; jordan. ال�ستخدام قواعد بتطبيق اللتزام على التخ�س�سات املتعدد اجلودة حت�سني م�رسوع تاأثري و�سف اإىل الدرا�سة هذه هدفت الهدف: امللخ�ص: الوقائي للم�سادات احليوية يف العمليات اجلراحية املتعلقة بال�رسطان. الطريقة: هو بحث و�سفي ا�ستطالعي ي�ستمل على مرحلة ما قبل ومرحلة ما بعد تطبيق م�رسوع حت�سني اجلودة. مت تنفيذ البحث يف مركز احل�سني لل�رسطان بالأردن يف الفرتة ما بني �سهر اأغ�سط�ض 2009 و �سهر فرباير العمليات يف احليوية للم�سادات الوقائي بال�ستخدام اخلا�ض امل�ست�سفى دليل وتعديل :مراجعة يلي ما اجلودة حت�سني م�رسوع �سمل .2012 لغرف الأدوية بتزويد خا�سة فرعية �سيدلية اإن�ساء اجلراحة، ق�سم مر�سى مبتابعة خمت�ض كامل بدوام �رسيري �سيدلين تعيني اجلراحية، ال�سجالت مراجعة مت اجلراحية. العمليات يف الوقائية احليوية للم�سادات ال�سليم ال�ستخدام يف للم�ساعدة تثقيفية دورات وتقدمي العمليات، الطبية ملر�سى ال�رسطان البالغني الذين خ�سعوا جلراحة داخل امل�ست�سفى )ملدة �سهر قبل وبعد تطبيق الربنامج يف كل مرحلة( لتقييم اللتزام احليوي امل�ساد نوع التايل: النحو علي اجلراحية العمليات يف احليوية للم�سادات الوقائي بال�ستخدام اخلا�سة امل�ست�سفى قواعد بتطبيق املو�سوف، اجلرعة املو�سوفة، توقيت اإعطاء امل�ساد احليوي، ومدة العالج. النتائج: ا�ستمل البحث على 70 مري�سا قبل م�رسوع حت�سني اجلودة و 97 مري�سا يف مرحلة ما بعد امل�رسوع. مت اإعطاء م�سادات حيوية وقائية لـ 57 )%81.4( مري�ض يف مرحلة ما قبل م�رسوع حت�سني اجلودة و 95 )%97.9( مري�ض يف مرحلة ما بعد التح�سني. كان هنالك حت�سن ملحوظفي مرحلة ما بعد تطبيق م�رسوع اجلودة من حيث وقت اإعطاء n = 94 %38.6؛ versus 99.0% p؛ >0.01( اإعطائه ومدة )n = 12 versus n = 79 %21.1؛ versus 83.2% p؛ >0.01( احليوي امل�ساد حت�سني بعد ما مرحلة يف �سحيحــة بجرعات ال�سحيح احليوي امل�ساد لهم اأعطي الذين املر�سى عدد يف حت�سن لوحظ )n = 22 versus اللتزام حت�سن اخلال�صة: .)n = 9 versus n = 87 %56.3؛ versus 98.9% p؛ >0.01(. التح�سني قبل ما مبرحلة مقارنة اجلودة م�رسوع م�رسوع تنفيذ بعد ملحوظ ب�سكل لل�رسطان احل�سني مركز يف اجلراحية العمليات يف احليوية للم�سادات الوقائي ال�ستخدام قواعد بتطبيق حت�سني جودة. مفتاح الكلمات: الوقاية بامل�سادات احليوية؛ جراحة؛ عمليات جراحية؛ حت�سني اجلودة؛ �سيدلين؛ التعليم؛ الأردن. improvement in adherence to surgical antimicrobial prophylaxis guidelines after implementation of a multidisciplinary quality improvement project shorouq telfah,1 lama nazer,1 manar dirani,1 *faiez daoud2 clinical & basic research advances in knowledge the current study indicated that the implementation of a multidisciplinary quality improvement programme at the king hussein cancer centre in amman, jordan, significantly improved compliance with surgical antimicrobial prophylaxis guidelines. sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e523–527, epub. 23 nov 15 submitted 5 may 15 revision req. 16 jun 15; revision recd. 25 jul 15 accepted 13 aug 15 doi: 10.18295/squmj.2015.15.04.014 improvement in adherence to surgical antimicrobial prophylaxis guidelines after implementation of a multidisciplinary quality improvement project 524 | squ medical journal, november 2015, volume 15, issue 4 the programme consisted of revising institutional guidelines for surgical antimicrobial prophylaxis, assigning a clinical pharmacist to the surgical service, establishing an operating room satellite pharmacy and providing educational sessions and tools to aid in the appropriate utilisation of antibiotics. application to patient care surgical antimicrobial prophylaxis is necessary to reduce the incidence of potential surgical infections. this study demonstrated that adherence to a set of antimicrobial prophylaxis guidelines can be significantly improved with the implementation of a multi disciplinary project. surgical site infections (ssis) are con-sidered the most common type of nosocomial infections in surgical patients and are associated with high morbidity and mortality as well as increased costs.1–4 therefore, antimicrobial prophylaxis is recommended in a wide range of surgical procedures for the prevention of ssis.5 guidelines are available to provide clinicians with a standardised approach to the rational, safe and effective use of antimicrobial agents.6 however, despite the presence of evidence-based guidelines, poor adherence to guidelines has been reported internationally.7–13 the king hussein cancer centre (khcc) in amman, jordan, is a 170-bed comprehensive teaching cancer centre with a surgical service consisting of nine teams with various specialties. among these teams, an average of 25 patients are seen and five major elective surgeries are performed per day. a quality improvement initiative was planned at khcc to improve adherence to surgical prophylaxis guidelines. this study aimed to evaluate the impact of this multidisciplinary quality improvement project on adherence to surgical antimicrobial prophylaxis guidelines. methods this preand post-intervention prospective observational study was conducted between august 2009 and february 2012 in the surgical department of khcc. the pre-intervention phase was carried out in august 2009, one month prior to implementing a quality improvement project, and the post-intervention phase was carried out in february 2012, one month after the full implementation of all elements in the quality improvement project. the intervention itself consisted of four initiatives: revising the institutional guidelines for surgical antimicrobial prophylaxis; assigning a full-time clinical pharmacist to the surgical service; establishing an operating room satellite pharmacy (orsp); and offering various educational sessions and tools for the medical, nursing and pharmacy staff to aid in the appropriate utilisation of antibiotics. the quality improvement project was implemented as follows. the surgical antimicrobial prophylaxis guidelines were revised and updated based on the most recent international clinical practice guidelines available at that time.6 in the preintervention phase, the institutional guidelines were very limited and did not include recommendations for certain types of oncological surgeries, such as breast cancer or orthopaedic surgeries; as a result, the revised guidelines were made more comprehensive by including recommended antimicrobial therapy for all surgeries commonly performed at khcc. the revised khcc guidelines for surgical antimicrobial prophylaxis outlined the recommended antibiotics for each type of surgery along with the appropriate dose and duration. the most recommended antibiotic in the revised guidelines was cefazolin which treats the most common ssis caused by gram-negative and -positive pathogens (bacteria of the staphylococcus and streptococcus genera and escherichia coli).5 metronidazole was also included to treat anaerobic infections common after certain operations (e.g. gastrointestinal surgeries). an assigned clinical pharmacist was available at khcc during weekdays to review and evaluate all prescribed medications. in addition, a clinical pharmacist was available at all times via mobile phone for any pharmacotherapy-related consultations and was responsible for medication reconciliation and discharge counselling for surgery patients. prior to the implementation of the orsp at khcc, antibiotics were stored in the operating room and were dispensed and prepared by surgical nurses. this meant that the antibiotic orders were not reviewed by a pharmacist prior to administration to a patient. due to the potential risk and errors associated with such practice, the pharmacy and surgery departments agreed to create an orsp adjacent to the operating room as part of the quality improvement project. an orsp was established and was open from 8 a.m. to 5 p.m. every day. the pharmacy was staffed by a pharmacist and a pharmacy technician, who were responsible for processing all orders and preparing and dispensing the necessary medications. the pharmacist at the orsp had full access to patient electronic records to ensure that each prescription was in compliance with the guidelines. all orders from the operating room were thus reviewed by a pharmacist and prepared in the orsp using aseptic techniques. shorouq telfah, lama nazer, manar dirani and faiez daoud clinical and basic research | 525 several educational sessions were also conducted by the clinical pharmacist, the physicians and the head nurse of surgery for the medical, nursing and pharmacy staff. the aim was to increase awareness about the revised institutional guidelines and to promote evidence-based practice. in addition, e-mail reminders were sent to the staff regarding the new guidelines and one-to-one educational sessions were continuously offered to all members of staff. the study group included all eligible patients admitted to khcc during the preand postintervention phases. all cancer patients who were assigned to the surgery service and who underwent an elective surgery during their admission were included in the study. patients admitted and/or discharged on a weekend were excluded since the pharmacist conducting the profile review was not available on those days and therefore a full assessment of the condition would be difficult to conduct. in addition, those who were prescribed antibiotics for the treatment of a suspected or proven infection were excluded. the medical records of the eligible patients were reviewed to assess the type of prophylactic antibiotic prescribed, the dose administered and the timing and duration of the antibiotic administration. the appropriateness of the antibiotic prescribed and the administered dose were evaluated according to either the revised or initial antimicrobial prophylaxis guidelines, depending on the phase of the study. the timing of the antibiotic was considered appropriate if the antibiotic was administered at least 60 minutes prior to surgical incision and the duration of the antibiotic was deemed appropriate if it did not exceed 24 hours following the surgery. these details were recorded for both the preand post-intervention patient groups; the data between the two groups was then compared accordingly in order to determine any changes in the compliance to antimicrobial prophylaxis guidelines. all analyses were performed using the statistical analysis system (sas), version 9.1 (sas institute inc, cary, north carolina, usa). categorical data were reported as counts and percentages, while continuous data were reported as means with standard deviations. adherence to the guidelines in the preand postintervention phases was compared using chi-squared and fisher’s exact tests. a significance criterion of p <0.05 was used. this study received ethical approval from the institutional review board at khcc for both the preand post-intervention phases of the study (irb# 12-khcc-12). results during the study period, a total of 70 patients were evaluated in the pre-intervention phase and 97 patients were evaluated in the post-intervention phase [table 1]. in the preand post-intervention groups, 57 (81.4%) and 95 (97.9%) patients received antibiotics, respectively. the most common types of surgeries during both phases were breast surgeries (modified radical and skin-sparing mastectomies), gastrointestinal surgeries (hemicolectomies and ileostomy closures) and genitourinary surgeries (transurethral resections of bladder tumours). in the post-intervention phase, a significant improvement in adherence to the antimicrobial prophylaxis guidelines was observed. of the patients in the post-intervention group who received antibiotics, 79 (83.2%) received their antibiotic dose at the appropriate time compared to 12 patients (21.1%) in the pre-intervention group (p <0.01). furthermore, 94 patients (99.0%) in the post-intervention group were prescribed antibiotics for the appropriate duration of time, in comparison to 22 patients (38.6%) in the preintervention group (p <0.01) [figure 1]. among patients who were prescribed antibiotics, only 29 patients (50.9%) in the pre-intervention phase were found to require antibiotics according to the guidelines. in comparison, all of the patients who were prescribed antibiotics in the post-intervention phase required antibiotics according to the guidelines (n = 95; 100.0%). of the patients who received antibiotics in accordance with the guidelines, 16 table 1: patient characteristics prior to and following a multidisciplinary quality improvement project on adherence to antimicrobial prophylaxis guidelines at the king hussein cancer centre, amman, jordan characteristic n (%) p value preintervention (n = 70) postintervention (n = 97) mean age in years ± sd 50.0 ±12.6 50.0 ± 15.4 0.34 penicillin and/or cephalosporin allergies 4 (5.7) 5 (5.1) 0.91 type of surgery 0.81 breast 22 (31.4) 31 (32.0) gastrointestinal 18 (25.7) 21 (21.7) genitourinary 12 (17.1) 22 (22.7) gynaecological 8 (11.4) 6 (6.2) head and neck 5 (7.1) 7 (7.2) other 5 (7.1) 10 (10.3) sd = standard deviation. improvement in adherence to surgical antimicrobial prophylaxis guidelines after implementation of a multidisciplinary quality improvement project 526 | squ medical journal, november 2015, volume 15, issue 4 patients (55.2%) received the appropriate antibiotic in the pre-intervention phase while 88 patients (92.6%) received the appropriate antibiotic in the post-intervention group (p <0.01). furthermore, among those who were correctly prescribed antibiotics according to the guidelines, the number of patients who received appropriate doses of the appropriate antibiotic was 87 (98.9%) in the post-intervention group compared to nine (56.3%) in the pre-intervention group (p <0.01) [figure 1]. discussion this study revealed poor adherence to the surgical prophylaxis guidelines at khcc in the pre-intervention phase. this lack of adherence was attributed mainly to the absence of comprehensive institutional guidelines, easy accessibility to several antibiotics that were not included in the guidelines and a lack of awareness about the guidelines. these pre-intervention findings are consistent with those reported by other studies at both local and international hospitals.1–4,7 however, significant improvement was observed in the adherence to surgical prophylaxis guidelines after the implementation of a multidisciplinary quality improvement project in the current study, particularly with regards to the appropriateness, dosage, timing and duration of antibiotic therapy. to the best of the authors’ knowledge, this is the first study to evaluate a comprehensive approach aiming to improve adherence to antimicrobial prophylaxis guidelines. the implementation of institutional protocols and guidelines for surgical prophylaxis plays a major role in guiding surgeons to use the most appropriate anti biotic and dose based on evidence-based recommendations. these guidelines should be tailored to the needs of each institution based on the most common types of surgeries performed and the antibiotics available. in a study conducted by willemsen et al., a standardised, clear and simple protocol for perioperative antibiotic prophylaxis was associated with improvement in antibiotic dosing and timing.14 in the current study, the pre-intervention guidelines did not include recommendations for breast surgery even though it was one of the most common surgeries performed at khcc. as with any programme, education is essential to promote evidence-based practice. however, educa tional intervention alone is not sufficient to change practice, as demonstrated by ozgun et al.15 in their study, the educational intervention resulted in improvements in indications, choice and dosage of surgical antimicrobial prophylaxis but did not result in improved prophylaxis use or total compliance rate. the researchers suggested that educational interventions should be augmented with protocols and guidelines in order to improve overall adherence.15 in the current study, the authors believe that the presence of a clinical pharmacist on the surgery floor was essential in encouraging adherence to the revised antimicrobial prophylaxis guidelines. this clinical pharmacist helped with specific recommendations related to prescribed antibiotics and offered oneto-one and group educational sessions for surgical residents. unfortunately, the exact number of interventions conducted by the pharmacist during the post-intervention phase was not recorded but anecdotal evidence from surgical and pharmaceutical department staff members indicated that these were numerous. additionally, the implementation of an orsp was extremely helpful, as the close proximity of the pharmacy to the operating room ensured the timely delivery of the antibiotics and administration of the medication one hour prior to incision. in a recent study, the presence of a pharmacist in a surgical department was associated with a decrease in the number of patients receiving prophylactic antibiotics without justifiable indications, a decrease in the rate of prolonged duration of prophylaxis and an increase in the number of patients receiving correct antibiotics.16 a significant improvement in the adherence to antimicrobial prophylaxis guidelines was noted in the current study after the implementation of a quality improvement project. the provision of multidisciplinary revised guidelines and educational sessions clearly played a major role in the improved compliance figure 1: proportion of patients whose antibiotic treatment adhered to antimicrobial prophylaxis guide lines prior to (n = 57) and following (n = 97) a multidisciplinary quality improvement project at the king hussein cancer centre, amman, jordan. among the patients, 29 (50.9%) and 95 (100.0%) in the pre and post-intervention phase, respectively, were found to require antibiotics according to the guidelines. use of appropriate antibiotics and appropriate doses were subsequently assessed for the patients who received antibiotics in accordance with the guidelines. shorouq telfah, lama nazer, manar dirani and faiez daoud clinical and basic research | 527 observed in the post-intervention phase. this may have been due to the presence of clear guidelines that outlined the appropriate antibiotics for common surgeries, along with increased knowledge among physicians and surgeons regarding appropriate practices in terms of the appropriate drug, dose and duration. however, there are a few limitations to the study. these limitations include the short duration and relatively small sample size in both the preand post-intervention groups. furthermore, only the total impact of the quality improvement project was measured; the effect of each individual element of the project on the adherence to the guidelines was not determined. finally, the incidence of post-surgical infections was not evaluated. future studies are recommended to explore adherence to antimicrobial prophylaxis on the rate of post-surgical infections. conclusion a multidisciplinary quality improvement project carried out at khcc resulted in a significant improvement in adherence to antimicrobial prophylaxis guidelines among surgical staff. in the postintervention stage, a significant improvement was seen in the correct choice of antibiotic administered as well as the timing, duration and dosage of antibiotics. surgical antimicrobial prophylaxis is necessary to reduce the incidence of potential ssis. the results of this study suggest that a focused multidisciplinary intervention can enhance adherence to institutional antimicrobial prophylaxis guidelines. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. de lissovoy g, fraeman k, hutchins v, murphy d, song d, vaughn bb. surgical site infection: incidence and impact on hospital utilization and treatment costs. am j infect control 2009; 37:387–97. doi: 10.1016/j.ajic.2008.12.010. 2. weber wp, zwahlen m, reck s, feder-mengus c, misteli h, rosenthal r, et al. economic burden of surgical site infections at a european university hospital. infect control hosp epidemiol 2008; 29:623–9. doi :10.1086/589331. 3. anderson dj. surgical site infections. infect dis clin north am 2011; 25:135–53. doi: 10.1016/j.idc.2010.11.004. 4. whitehouse jd, friedman nd, kirkland kb, richardson wj, sexton dj. the impact of surgical-site infections following orthopedic surgery at a community hospital and a university hospital: adverse quality of life, excess length of stay, and extra cost. infect control hosp epidemiol 2002; 23:183–9. doi: 10.1086/502033. 5. dhar h, al-busaidi i, rathi b, nimre ea, sachdeva v, hamdi i. a study of post-caesarean section wound infections in a regional referral hospital, oman. sultan qaboos univ med j 2014; 14:e211–17. 6. american society of health-system pharmacists. ashp therapeutic guidelines on antimicrobial prophylaxis in surgery. am j health syst pharm 1999; 56:1839–88. 7. goede wj, lovely jk, thompson rl, cima rr. assessment of prophylactic antibiotic use in patients with surgical site infections. hosp pharm 2013; 48:560–7. doi: 10.1310/hpj4807560. 8. tourmousoglou ce, yiannakopoulou ec, kalapothaki v, bramis j, st papadopoulos j. adherence to guidelines for antibiotic prophylaxis in general surgery: a critical appraisal. j antimicrob chemother 2008; 61;214–18. doi: 10.1093/jac/ dkm406. 9. al-momany nh, al-bakri ag, makahleh zm, wazaify mm. adherence to international antimicrobial prophylaxis guidelines in cardiac surgery: a jordanian study demonstrates need for quality improvement. j manag care pharm 2009; 15:262–71. 10. parulekar l, soman r, singhal t, rodrigues c, dastur fd, mehta a. how good is compliance with surgical antibiotic prophylaxis guidelines in a tertiary care private hospital in india? a prospective study. indian j surg 2009; 71:15–18. doi: 10.1007/s12262-009-0004-9. 11. hosoglu s, sunbul m, erol s, altindis m, caylan r, demirdag k, et al. a national survey of surgical antibiotic prophylaxis in turkey. infect control hosp epidemiol 2003; 24:758–61. doi: 10.1086/502127. 12. al-azzam si, alzoubi kh, mhaidat nm, haddadin rd, masadeh mm, tumah hn, et al. preoperative antibiotic prophylaxis practice and guideline adherence in jordan: a multi-centre study in jordanian hospitals. j infect dev ctries 2012; 6:715–20. doi: 10.3855/jidc.1676. 13. abdel-aziz a, el-menyar a, al-thani h, zarour a, parchani a, asim m, et al. adherence of surgeons to antimicrobial prophylaxis guidelines in a tertiary general hospital in a rapidly developing country. adv pharmacol sci 2013; 2013:842593. doi: 10.1155/2013/842593. 14. willemsen i, van den broek r, bijsterveldt t, van hattum p, winters m, andriesse g, et al. a standardized protocol for perioperative antibiotic prophylaxis is associated with improvement of timing and reduction of costs. j hosp infect 2007; 67:156–60. doi: 10.1016/j.jhin.2007.07.025. 15. ozgun h, ertugrul bm, soyder a, ozturk b, aydemir m. perioperative antibiotic prophylaxis: adherence to guidelines and effects of educational intervention. int j surg 2010; 8:159–63. doi: 10.1016/j.ijsu.2009.12.005. 16. zhang hx, li x, huo hq, liang p, zhang jp, ge wh. pharmacist interventions for prophylactic antibiotic use in urological inpatients undergoing clean or clean-contaminated operations in a chinese hospital. plos one 2014; 9:e88971. doi: 10.1371/journal.pone.0088971. http://dx.doi.org/10.1016/j.ajic.2008.12.010 http://dx.doi.org/10.1086/589331 http://dx.doi.org/10.1016/j.idc.2010.11.004 http://dx.doi.org/10.1086/502033 http://dx.doi.org/10.1310/hpj4807-560 http://dx.doi.org/10.1310/hpj4807-560 http://dx.doi.org/10.1093/jac/dkm406 http://dx.doi.org/10.1093/jac/dkm406 http://dx.doi.org/10.1007/s12262-009-0004-9 http://dx.doi.org/10.1086/502127 http://dx.doi.org/10.3855/jidc.1676 http://dx.doi.org/10.1155/2013/842593 http://dx.doi.org/10.1016/j.jhin.2007.07.025 http://dx.doi.org/10.1016/j.ijsu.2009.12.005 http://dx.doi.org/10.1371/journal.pone.0088971 departments of 1child health and 2haematology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: alsineidiksk@hotmail.com أدلة على وجود اختالل مبكر يف وظيفة القلب االنبساطية باستخدام ختطيط القلب عند األطفال املصابني مبرض تكون العظم الناقص خلفان �سامل ال�سنيدي، عرفان اهلل، ها�سم جواد، مرت�سى اخلابوري، �سيف اليعربي abstract: objectives: structural and functional cardiovascular abnormalities have been reported in adults with osteogenesis imperfecta (oi); however, there is a lack of paediatric literature on this topic. this study aimed to investigate cardiovascular abnormalities in children with oi in comparison to a control group. methods: this case-control study was conducted at the sultan qaboos university hospital in muscat, oman, between may 2013 and august 2014. data from eight patients with oi and 24 healthy controls were compared using conventional and tissue doppler echocardiography (tde). results: the oi group had significantly lower peak early mitral valve flow velocity (p = 0.027), peak a-wave reversal in the pulmonary vein (p = 0.030) and peak early diastolic velocity of the mitral valve and upper septum (p = 0.001 each). the peak late diastolic velocities of the mitral valve (p = 0.002) and the upper septum (p = 0.037) were significantly higher in the oi group; however, the peak early/late diastolic velocity ratios of the mitral valve (p = 0.002) and upper septum (p = 0.001) were significantly lower. left ventricular dimensions and aortic and pulmonary artery diameters were larger in the oi group when indexed for body surface area. both groups had normal systolic cardiac function. conclusion: children with oi had normal systolic cardiac function. however, changes in myocardial tissue doppler velocities were suggestive of early diastolic cardiac dysfunction. they also had increased left ventricular dimensions and greater vessel diameters. these findings indicate the need for early and detailed structural and functional echocardiographic assessment and follow-up of young patients with oi. keywords: children; osteogenesis imperfecta; cardiovascular abnormalities; doppler echocardiography. امللخ�ص: الهدف: اأظهرت الدرا�سات العلمية وجود اختاللت تكوينية ووظيفية يف القلب والأوعية الدموية يف البالغني الذين يعانون من مر�ض تكون العظم الناق�ض )oi( اإل اأن هناك نق�ض يف الدرا�سات املتعلقة بهذا املر�ض عند الأطفال. الطريقة: هدفت هذه الدرا�سة اإىل التحقق من مدى وجود اختاللت يف القلب والأوعية الدموية لدى الأطفال امل�سابني بهذا املر�ض باملقارنة مع جمموعة املراقبة. الطريقة: اأجريت هذه الدرا�سة يف م�ست�سفى جامعة ال�سلطان قابو�ض يف م�سقط، عمان، بني مايو 2013 واأغ�سط�ض 2014 حيث متت مقارنة بيانات اأ�سعة �سدى القلب التكوينية والوظيفية بني 8 مر�سى م�سابني مبر�ض تكون العظم الناق�ض و 24 حالة من جمموعة املراقبة ال�سليمة. النتائج: بينت الدرا�سة اأن مر�سى تكون العظم الناق�ض لديهم قيا�سات اأقل بكثري من جمموعة املقارنة لذروة �رسعة التدفق املبكر لل�سمام التاجي )p = 0.027( وذروة موجة الرتاجع يف الوريد الرئوي )p = 0.030( وذروة ال�رسعة النب�ساطية املبكرة لل�سمام التاجي واحلاجز العلوي )p = 0.001 لكل منهما(. وكانت ذروة ال�رسعة النب�ساطية املتاأخرة لل�سمام التاجي )p = 0.002( واحلاجز العلوي )p = 0.037( اأعلى بكثري يف جمموعة مر�سى تكون العظم )p = 0.001( واحلاجز العلوي )p = 0.002( الناق�ض؛ ومع ذلك، فاإن ن�سبة الذروة يف ال�رسعة النب�ساطية املبكرة/املتاأخرة لل�سمام التاجي كانت اأقل من جمموعة املقارنة بكثري. اأي�سا كانت اأبعاد البطني الأي�رس واأقطار ال�رسيان الأبهر و الرئوي اأكرب يف جمموعة مر�سى تكون العظم الناق�ض عندما مت فهر�ستها مل�ساحة �سطح اجل�سم. وبينت الدرا�سة كذلك اأن وظيفة القلب النقبا�سية لكال الفريقني ذات معدل طبيعي. اخلال�صة: بينت الدرا�سة اأن وظيفة القلب النقبا�سية لدى الأطفال امل�سابني مبر�ض تكون العظم الناق�ض ذات معدل طبيعي اإل اأنه توجد تغريات ب�سيطة توحي بوجود خلل اأّويل يف وظائف القلب النب�ساطية. كما اأنها بينت عن وجود زيادة اأبعاد البطني الأي�رس وكذلك كرب حجم الأوعية الدموية الرئي�سية. هذه النتائج ت�سري اإىل احلاجة اإىل التقييم املبكر واملتابعة امل�ستمرة للمر�سى ال�سغار امل�سابني مبر�ض تكون العظم الناق�ض بتخطيط �سدى القلب الوظيفي. مفتاح الكلمات: الأطفال؛ مر�ض تكون العظم الناق�ض؛ ت�سوهات القلب والأوعية الدموية؛ دوبلر �سدى القلب. echocardiographic evidence of early diastolic dysfunction in asymptomatic children with osteogenesis imperfecta *khalfan s. al-senaidi,1 irfan ullah,1 hashim javad,1 murtadha al-khabori,2 saif al-yaarubi1 advances in knowledge this study highlights for the first time early changes in the myocardial tissue doppler velocities of a group of children with osteogenesis imperfecta (oi). these changes suggest the early development of diastolic cardiac dysfunction and preservation of systolic cardiac function in young patients with this genetic disorder. application to patient care cardiovascular assessment of children with oi provides important additional information to support management of this disease. clinical & basic research sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e456–462, epub. 23 nov 15 submitted 3 jan 15 revisions req. 9 apr & 5 may 15; revisions recd. 22 apr & 19 may 15 accepted 28 may 15 doi: 10.18295/squmj.2015.15.04.003 khalfan s. al-senaidi, irfan ullah, hashim javad, murtadha al-khabori and saif al-yaarubi clinical and basic research | e457 previously, physicians focused primarily on skeletal malformation and structural and systolic cardiac function; however, with the availability of non-invasive echocardiographic tests, this focus can be extended to diastolic function. early and newer therapeutic modalities could help treat or modify the progression of oi. this could prevent further deterioration of cardiac function. early intervention is essential considering the tendency for this group of patients to be limited in their activities and in sports when they reach adulthood. osteogenesis imperfecta (oi) is a group of autosomal disorders of the connective tissues and is commonly caused by mutations in genes encoding the α-1 and α-2 chains of type 1 collagen or proteins involved in the posttranslational modification of type 1 collagen.1 oi is characterised by various skeletal and extraskeletal manifestations.2 the disease has considerable clinical and biochemical heterogeneity between and within different patients. common clinical manifestations of this disease are well-known and include blue sclera, brittle bones, conductive hearing defects and dental abnormalities.2 tissue doppler echocardiography (tde) offers a non-invasive quantitative method of assessing longitudinal systolic and diastolic ventricular performance by measuring velocities directly from the myocardium.3–5 while a few studies have described cardiovascular involvement among adults with oi, there is very little data available for paediatric patients.6,7 to the best of the authors’ knowledge, this is the first study assessing cardiovascular abnormalities, particularly systolic and diastolic function, in paediatric patients with oi using both conventional and tde techniques. methods this case-control study was conducted at the sultan qaboos university hospital (squh) in muscat, oman, between may 2013 and august 2014. all patients diagnosed with oi and followed-up at squh during the study period were enrolled in the study. the diagnosis of oi was based on the classification developed by sillence et al.8 ageand gender-matched healthy children were included in the study as the control group. the selected controls were either healthy volunteers or had been referred to the clinic because of heart murmurs which were later found to be innocent. a detailed medical history was recorded for each subject, including any existing comorbidities. anthropometric and physical examinations were performed and heart rates were measured for all participants. routine complete blood count tests, 12-lead electrocardiography, two-dimensional doppler echocardiography and pulse tde were performed on all of the subjects during routine visits to the hospital. blood pressure was measured in the right arm with an age-appropriate cuff size. systolic and diastolic cardiac function was assessed using conventional and tde techniques. twodimensional echocardiography was performed using an ultrasound echocardiography machine (vivid e9, ge vingmed ultrasound as, horten, norway) while the subjects were at rest. motion (m)-mode, twodimensional doppler echocardiography and pulse tde data were collected by a qualified echocardiographer. the subjects were fully awake during the procedure according to the recommendations of the american society of echocardiography.9 the left ventricular end systolic (lvisd) and diastolic (lvidd) dimensions, as well as the septal (ivsd) and left ventricular posterior wall thickness in diastole (lvpwd) were assessed using m-mode from the parasternal long axis view. subsequently, the shortening fraction (sf) and ejection fraction (ef) were determined.9 using the left parasternal long axis view, the aortic annulus (aoan), sinus of valsalva (sinvals), sinotubular junction (sintubj) and ascending aorta (ascao) diameters were measured. from the parasternal high short axis view, diameter measurements of the pulmonary valve annulus (pvan), main pulmonary artery (mpa) and left (lpa) and right (rpa) pulmonary arteries were taken. the early (em) and late (am) peak velocities of the mitral valve inflow, deceleration time of the em wave (dtm) and am wave duration were measured from the four chamber view with placement of the pulse doppler sample volume at the tips of the valve leaflets. isovolumic relaxation time (ivrt) was measured by placing the continuous doppler sample volume in the left ventricular outflow tract in the three chamber view. assessment of the right upper pulmonary vein pulse doppler pattern was taken from a four chamber view to measure the systolic (spv), diastolic (dpv) and a-wave reversal peak velocity (apv) and duration (apvd). the spv/dpv ratio and the mitral valve inflow late velocity duration and a-wave duration ratio of the pulmonary veins (amd/apvd) were obtained. tde was performed by placing the sample volume at the corner of the mitral annulus, the upper part of the interventricular septum and the corner of the tricuspid valve in the four chamber view. in each region, the systolic (s’) wave, early diastolic (e’) and late diastolic (a’) velocities were recorded and the echocardiographic evidence of early diastolic dysfunction in asymptomatic children with osteogenesis imperfecta e458 | squ medical journal, november 2015, volume 15, issue 4 em/peak early diastolic velocity of the mitral valve (e’m) ratio was obtained. global systolic myocardial function was evaluated by ef and sf using m-mode in addition to the peak systolic velocities (s’) of the tde. in the early stages of diastolic dysfunction, impaired relaxation and passive filling of the left ventricle predominates, resulting in a low em and e’m, high am and peak late diastolic velocity of the mitral valve (a’m) and low em/am and e’m/a’m ratios.10 another reliable indicator of diastolic dysfunction is a high em/e’m ratio, which is an estimate of the filling pressure of the left ventricle.11 assessment of pulmonary hypertension was performed by measuring the maximum velocity of the tricuspid valve regurgitation jet, if present, as well as the pulmonary valve regurgitation peak velocity. the z score was calculated for aoan, sinvals, sintubj, pvan, mpa, rpa, lpa and left ventricular dimensions.12 all measurements reported in this study represent the average value of at least three cardiac cycles per subject. statistical analysis of the data was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa). all results were expressed as means ± standard deviation. the independent student’s t-test and mann-whitney u test were used when appropriate. a multivariate linear regression was used to find the impact of baseline differences between the two groups, including the diagnosis of oi. differences were considered statistically significant at p <0.050. this study was approved by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #672). informed written consent was obtained from the parents or caregivers of all subjects before inclusion in the study. results a total of eight oi patients with a mean age of 7.3 ± 4.3 years were diagnosed and followed-up at squh during the study period. the male-to-female ratio was 3:5. seven of these patients had oi type ш while one had oi type iv. a total of 24 controls with a mean age of 6.9 ± 2.5 years were also included. the male-to-female ratio was 11:13. both groups were proportionately similar in age and gender; however, there were significant differences in their height, weight and body surface area (bsa) [table 1]. all of the oi patients had fractures and had been receiving pamidronate infusions every three months as part of their disease management plans. there was no evidence of systemic disease and none of the patients were taking other medications. the oi subjects were asymptomatic from a cardiac point of view and none had mitral or aortic valve regurgitation. none of the oi subjects had systemic hypertension and they were all in sinus rhythm. there was no electrocardiographic evidence of wolff-parkinson-white syndrome among any of the patients. standard two-dimensional echocardiography mea surements and z scores for both groups are reported in table 2. left ventricle and left atrium dimensions, aortic and pulmonary artery diameters and left ventricular systolic function data were not statistically significant between the two groups. however, when the left ventricular dimensions, aortic and pulmonary artery diameters were corrected for bsa, there was a statistically significant difference between the two groups. none of the subjects who had mild tricuspid valve regurgitation showed evidence of pulmonary hypertension (18.6 ± 1.4 mmhg [n = 7] versus 17.4 ± 2.7 mmhg [n = 22]; p = 0.278) and the other subjects did not have echocardiographic evidence of elevated right ventricular pressure from assessment of the septal curvature and pulmonary valve regurgitation jet. corrected ivrt for heart rate was comparable between the oi and control group (88.1 ± 17.4 ms versus 79.5 ± 11.9 ms; p = 0.125). calculations of the z score revealed that there was a statistically significant difference between the oi and the control group regarding aortic and pulmonary artery diameters. regarding the left ventricular dimensions, the oi group had a larger z score for the ivsd and lvpwd, but no significant difference was observed for the lvisd and lvidd z scores. none of the control subjects had a z score of >2. other conventional and tde assessment data are summarised in table 3. there was a statistically significant decrease in the em velocity for the oi group compared to the controls (84.8 ± 23.4 cm/s versus 103.4 ± 18.4 cm/s; p = 0.027). however, the am and dtm measurements and em/am ratio were similar. a significant difference was observed in the tde measurements of the lateral mitral valve and upper septum but with a comparable em/e’m ratio and peak systolic velocity at all the measured sites. tde measurements at the lateral tricuspid valve were similar between the two groups. right upper pulmonary vein doppler velocities and duration showed no statistically significant difference between the two groups with respect to spv and dpv peak velocities. however, a significant difference was observed for the spv/dpv ratio, peak a-wave reversal and duration. in contrast, there was a comparable amd/ apvd ratio for the oi and control subjects (1.6 ± 0.5 versus 1.3 ± 0.4; p = 0.136). multiple linear regression analysis showed that bsa was a significant predictor for lvidd, lvisd, khalfan s. al-senaidi, irfan ullah, hashim javad, murtadha al-khabori and saif al-yaarubi clinical and basic research | e459 table 1: characteristics of children with osteogenesis imperfecta in comparison to an ageand gendermatched control group (n = 32) characteristic mean ± sd p value oi group (n = 8) control group (n = 24) male-to-female ratio 3:5 11:13 0.692 age in years 7.3 ± 4.3 6.9 ± 2.5 0.743 height in cm 87.3 ± 24.9 124.0 ± 14.3 0.001 weight in kg 15.0 ± 9.9 22.7 ± 7.4 0.025 bsa in m2 0.60 ± 0.28 0.89 ± 0.19 0.001 systolic bp in mmhg 100.6 ± 5.0 103.4 ± 6.8 0.324 diastolic bp in mmhg 57.1 ± 4.0 60.5 ± 5.0 0.136 heart rate in beats per minute 105.5 ± 22.0 85.9 ± 17.0 0.054 qtc in ms 422.4 ± 11.0 418.4 ± 22.0 0.623 haemoglobin in g/dl 11.9 ± 1.3 11.7 ± 0.6 0.634 median haematocrit % (iqr) 0.4 (0.34‒0.40) 0.4 (0.35‒0.38) 0.717 age started on pamidronate in months 38.9 ± 29.1 duration of pamidronate therapy in months 54.5 ± 60.8 sd = standard deviation; oi = osteogenesis imperfecta; bsa = body surface area; bp = blood pressure; qtc = qt interval corrected for heart rate; iqr = interquartile range. table 2: echocardiographic measurements and z scores of children with osteogenesis imperfecta in comparison to an ageand gender-matched control group (n = 32) measurement/z score mean ± sd p value oi group (n = 8) control group (n = 24) median lvidd in mm (iqr) 31.0 (25.5–38.0) 38.0 (33.0–41.0) 0.051 lvidd/bsa ratio 61.4 ± 13.6 44.1 ± 7.1 0.009 lvidd z score 0.7 ± 1.1 0.1 ± 0.8 0.080 lvisd in mm 20.0 ± 5.3 24.3 ± 3.6 0.065 lvisd/bsa ratio 37.4 ± 8.5 27.9 ± 3.9 0.015 lvisd z score 0.4 ± 1.1 0.2 ± 0.7 0.441 ivsd in mm 6.5 ± 1.3 5.7 ± 1.0 0.151 ivsd/bsa ratio 12.7 ± 4.3 6.7 ± 1.8 0.005 ivsd z score 1.4 ± 0.8 -0.1 ± 0.9 0.001 median lvpwd in mm (iqr) 5.0 (5.0–6.5) 5.0 (4.0–5.0) 0.160 lvpwd/bsa ratio 10.7 ± 2.8 5.7 ± 1.6 0.001 lvpwd z score 1.6 ± 0.3 -0.3 ± 0.8 0.001 ef in % 71.0 ± 4.2 66.4 ± 5.8 0.050 sf in % 39.1 ± 3.1 36.3 ± 4.6 0.068 aoan in mm 14.8 ± 2.5 15.1 ± 1.8 0.680 aoan/bsa ratio 28.5 ± 7.8 17.3 ± 2.0 0.005 aoan z score 2.9 ± 1.2 0.3 ± 0.5 0.001 sinvals in mm 18.6 ± 2.5 18.9 ± 2.7 0.793 sinvals/bsa ratio 36.6 ± 11.1 21.7 ± 2.6 0.007 sinvals z score 1.8 ± 1.6 -0.5 ± 8.0 0.001 sintubj in mm 16.9 ± 2.0 16.6 ± 2.3 0.786 sintubj/bsa ratio 33.2 ± 10.5 19.1 ± 2.6 0.007 sintubj z score 2.4 ± 1.3 0.2 ± 0.7 0.001 ascao in mm 17.3 ± 3.6 16.9 ± 2.2 0.758 ascao/bsa ratio 33.5 ± 11.6 19.4 ± 2.4 0.011 ascao z score 2.1 ± 2.3 -0.3 ± 1.0 0.001 pvan in mm 15.4 ± 2.9 16.0 ± 2.8 0.570 pvan/bsa ratio 29.4 ± 7.2 18.4 ± 2.8 0.003 pvan z score 1.6 ± 2.3 -0.7 ± 0.8 0.001 mpa in mm 16.4 ± 1.8 15.3 ± 2.1 0.189 mpa/bsa ratio 32.1 ± 9.6 17.7 ± 3.3 0.003 mpa z score 1.2 ± 1.1 -1.1 ± 0.8 0.001 lpa in mm 11.5 ± 1.9 11.5 ± 1.1 0.941 lpa/bsa ratio 22.3 ± 6.0 13.5 ± 3.2 0.004 lpa z score 2.7 ± 0.9 0.9 ± 0.8 0.001 rpa in mm 11.9 ± 3.1 11.3 ± 1.2 0.473 rpa/bsa 22.3 ± 5.0 13.2 ± 2.6 0.001 rpa z score 2.0 ± 0.7 0.0 ± 0.8 0.001 tvmax in mmhg 18.6 ± 1.4 (7)* 17.4 ± 2.7 (22)* 0.278 la/ao ratio 1.4 ± 0.2 1.5 ± 0.2 0.315 ivrt in ms 67.5 ± 14.1 67.2 ± 11.2 0.946 corrected ivrt† in ms 88.1 ± 17.4 79.5 ± 11.9 0.125 sd = standard deviation; oi = osteogenesis imperfecta; lvidd = left ventricular end diastolic dimension; iqr = interquartile range; bsa = body surface area; lvisd = left ventricular end systolic dimension; ivsd = interventricular septal dimension in diastole; lvpwd = left ventricular posterior wall dimension in diastole; ef = ejection fraction; sf = shortening fraction; aoan = aortic valve annulus; sinvals = sinus of valsalva; sintubj = sinotubular junction; ascao = ascending aorta; pvan = pulmonary valve annulus; mpa = main pulmonary artery; lpa = left pulmonary artery; rpa = right pulmonary artery; tvmax = tricuspid valve regurgitation maximum peak velocity; la/ao = left atrium aortic dimension ratio by m-mode; ivrt = isovolumic relaxation time. *number of subjects with mild tricusoid valve regurgitation and for whom tvmax could be measured. †corrected for heart rate. echocardiographic evidence of early diastolic dysfunction in asymptomatic children with osteogenesis imperfecta e460 | squ medical journal, november 2015, volume 15, issue 4 ivsd, lvpwd, aoan, ascao and sinvals diameters (p = 0.01, 0.01, 0.04, 0.03, 0.01, 0.01 and 0.03, respectively). in comparison, oi was a significant predictor for ivsd, lvpwd, aoan, sinvals and sintubj (p = 0.03, 0.01, 0.04, 0.029 and 0.01, respectively). systolic blood pressure was not a significant predictor for any of the tested independent variables [table 4]. discussion in comparison to control subjects, there was significantly decreased peak early diastolic velocity and its ratio with the peak late diastolic velocity of the lateral mitral valve and upper septum among the studied group of oi patients. in addition, peak late diastolic velocity was significantly increased at the same sites among oi patients. furthermore, the oi group had lower em and lower peak a-wave reversal velocity and duration at the pulmonary vein. these findings indicate mild early changes in myocardial diastolic function; however, these changes are not considered as severe as those indicated by the em/e’m and amd/apvd ratios, which were similar in the two groups. migliaccio et al. compared adult oi patients with controls (n = 40 each) and observed a decrease in the em velocity and em/am ratio with a significant increase in the ivrt and dtm.13 in the current study, pulmonary vein wave velocity data in oi patients compared to the control subjects showed a significant decrease in the a-wave reversal velocity and duration and an increase in the peak systolic and diastolic ratio. the likely explanation of such changes in oi patients is the greater stiffness of the myocardial tissue and decreased elasticity, leading to echocardiographic changes and altered myocardial relaxation.11 while oi is primarily a bone disease, it presents with important extraskeletal abnormalities. involvement of the heart is due to an alteration in type 1 collagen fibres.14 myocardial collagen is primarily made up of collagen type 1, which contributes significantly to the myocardial and aortic wall strength and stiffness.15 mutations in oi can directly alter the properties of collagen, either by decreasing synthesis or by altering functional and structural properties.16–18 such alterations in the collagen fibres could lead to the abnormalities seen in the myocardial and aortic wall echocardiographic parameters; this has been demonstrated in histological analyses of animal models.19–21 radunovic et al. reported increased lvidd, indexed aortic diameters for bsa and mitral and aortic regurgitation in oi adult patients compared to controls.22 the current study showed that left ventricular dimensions and wall thicknesses were similar between the two groups. however, the oi group had higher dimensions when corrected for bsa. table 3: tissue doppler echocardiographic measurements of children with osteogenesis imperfecta in comparison to an age and gender-matched control group (n = 32) measurement mean ± sd p value oi group (n = 8) control group (n = 24) mitral valve em in cm/s 84.8 ± 23.4 103.4 ± 18.4 0.027 am in cm/s 52.4 ± 20.9 50.9 ± 11.6 0.810 em/am ratio 1.8 ± 0.6 2.1 ± 0.4 0.156 amd in ms 102.1 ± 21.7 110.9 ± 24.7 0.380 dtm in ms 130.6 ± 23.3 137.3 ± 22.9 0.485 corrected dtm† in ms 169.4 ± 20.7 162.7 ± 26.3 0.519 s’m in cm/s 8.4 ± 1.9 8.8 ± 1.6 0.551 e’m in cm/s 14.4 ± 2.5 18.9 ± 2.8 0.001 a’m in cm/s 8.6 ± 2.2 6.7 ± 0.9 0.002 e’m/a’m ratio 1.8 ± 0.6 2.9 ± 0.4 0.002 em/e’m ratio 6.1 ± 2.2 5.6 ± 1.3 0.484 septum median s’s in cm/s (iqr) 7.0 (7.0‒8.5) 8.0 (7.25‒8.0) 0.204 e’s in cm/s 10.6 ± 1.7 14.9 ± 2.2 0.001 median a’s in cm/s (iqr) 6.5 (6.0‒7.0) 6.0 (5.25‒8.0) 0.037 e’s/a’s ratio 1.6 ± 0.3 2.6 ± 0.54 0.001 tricuspid valve median s’t in cm/s (iqr) 12.0 (7.5‒14.7) 12.0 (12.0‒13.0) 0.611 e’t in cm/s 14.5 ± 2.7 15.8 ± 1.8 0.141 a’t in cm/s 10.6 ± 2.9 10.1 ± 1.8 0.543 e’t/a’t ratio 1.4 ± 0.38 1.6 ± 0.45 0.217 pulmonary vein spv in cm/s 52.9 ± 4.6 49.3 ± 8.9 0.288 dpv in cm/s 51.6 ± 14.0 60.9 ± 11.9 0.080 apv in cm/s 17.4 ± 3.4 21.1 ± 5.2 0.030 apvd in ms 68.3 ± 18.4 88.7 ± 17.0 0.018 spv/dpv ratio 1.1 ± 0.3 0.8 ± 0.2 0.002 amd/apvd ratio 1.6 ± 0.5 1.3 ± 0.4 0.136 sd = standard deviation; oi = osteogenesis imperfecta; em = peak early mitral valve flow velocity; am = peak late mitral valve flow velocity; amd = am duration; dtm = deceleration time of the em wave; s’m = peak systolic velocity of the mitral valve; e’m = peak early diastolic velocity of the mitral valve; a’m = peak late diastolic velocity of the mitral valve; s’s = peak systolic velocity of the septum; iqr = interquartile range; e’s = peak early diastolic velocity of the septum; a’s = peak late diastolic velocity of the septum; s’t = peak systolic velocity of the tricuspid valve; e’t = peak early diastolic velocity of the tricuspid valve; a’t = peak late diastolic velocity of the tricuspid valve; spv = peak systolic velocity of the pulmonary vein; dpv = peak diastolic velocity of the pulmonary vein; apv = peak a-wave reversal in the pulmonary vein; apvd = peak a-wave reversal duration in the pulmonary vein. †corrected for heart rate. khalfan s. al-senaidi, irfan ullah, hashim javad, murtadha al-khabori and saif al-yaarubi clinical and basic research | e461 this has been similarly reported in both adult and paediatric oi patients.7,13 the incidence of mitral valve prolapse in oi is about 3–8%;6,7 however, none of the patients in the current study had mitral valve prolapse or aortic valve regurgitation. the studied subjects had normal systolic cardiac function and ivrt. there was no significant difference between the oi and control groups regarding the four aortic and pulmonary artery diameters. however, these diameters were significantly larger in the oi group compared to the control subjects when indexed for bsa. moreover, regression analysis revealed that the diagnosis of oi was a significant predictor for larger left ventricular wall diameters in diastole and a larger diameter of the aoan, sinvals and sintubj. karamifar et al. described aortic valve regurgitation in two out of 24 oi patients (8.3%).23 radunovic et al. reported increased right ventricular outflow tract measurements and main pulmonary artery diameters in adult oi patients when indexed for bsa, indicating involvement of both the right and left sides of the heart.22 when the significant increase in the four pulmonary artery diameters were indexed to bsa and their z scores were calculated, the findings of the current study were in line with the findings of radunovic et al.22 the patients in the current study did not have any systemic illnesses, including hypertension or anaemia to confound the above changes. moreover, none of the subjects had evidence of pulmonary hypertension. this study highlights the need for detailed assessments of cardiac function in oi patients who are limited in their physical activities. early therapeutic modalities could help to treat or modify the progression of the disease to prevent the deterioration of cardiac function. in order to draw a definitive conclusion, largescale, multicentre research is recommended to assess cardiovascular involvement in children with oi. as there are insufficient data available describing cardiovascular involvement in children with oi, patients in the current study will be followed-up and oi patients with altered diastolic parameters or great vessel dilation will be monitored. patients with progressive aortic dilation may be prescribed beta blockers and angiotensin receptor blockers as both of these approaches have been suggested to prevent the progression of aortic root dilation in marfan syndrome.24 this study was limited by its small sample size. additionally, the patients were not symptomatic from a cardiac point of view and no normal values exist for the echocardiographic parameters in this particular group of patients. for this reason, age-matched controls were used for comparative purposes. it was not possible to perform further cardiac function assessments using two-dimensional speckle tracking as only limited echocardiographic views could be obtained due to table 4: simple regression analysis of left ventricular and four aortic dimensions of children with osteogenesis imperfecta in comparison to an ageand gender-matched control group (n = 32) dimension b regression coefficient (95% ci) r2 oi* age gender sbp dbp bsa lvidd -0.51 (-2.92, 3.94) 0.69 (0.07, 1.31)† -2.70 (-5.06, -0.34)† 0.09 (-0.10, 0.27) 0.19 (-0.05, 0.43) 11.34 (3.05, 19.62)† 0.83 lvisd 0.61 (-3.91, 2.69) 0.09 (-0.51, 0.68) 0.11 (-2.16, 2.38) 0.03 (-0.16, 0.21) 0.09 ( -0.14, 0.32) 13.47 (5.50, 21.44)† 0.71 ivsd -1.49 (-2.80, -0.18)† -0.19 (-0.43, 0.05) 1.03 (0.13, 1.94)† 0.04 (-0.03, 0.11) -0.05 (-0.14, 0.05) 3.31 (0.13, 6.48)† 0.33 lvpwd -1.26 (-2.11, -0.41)† 0.03 (-0.12, 0.19) -0.44 (-1.03, 0.14) 0.01 (-0.04, 0.05) -0.07 (-0.13, -0.01)† 2.35 (0.25, 4.37)† 0.57 aoan -1.20 (-2.32, -0.08)† 0.20 (-0.01, 0.40) -0.08 (-0.85, 0.70) 0.02 (-0.04, 0.09) 0.04 (-0.04, 0.12) 5.56 (2.84, 8.28)† 0.86 sinvals -1.68 (-4.36, 1.00)† 0.15 (-0.34, 0.63) 0.71 (-1.13, 2.56) -0.01 (-0.16, 0.14) 0.03 (-0.16, 0.22) 7.12 (0.63, 13.59)† 0.72 sintubj -2.00 (-3.55, -0.45)† 0.10 (-0.18, 0.38) 1.50 (0.46, 2.59)† 0.09 (-0.01, 0.18) -0.01 ( -0.11, 0.11) 6.14 (2.4, 9.88) 0.77 ascao -2.04 (-4.15, -0.08) 0.11 (-0.28, 0.49) 1.14 (-0.31, 2.59) 0.07 (-0.05, 0.18) 0.03 (-0.12, 0.18) 7.14 (2.04, 12.25)† 0.67 ci = confidence interval; oi = osteogenesis imperfecta; sbp = systolic blood pressure; dbp = diastolic blood pressure; bsa = body surface area; lvidd = left ventricular end diastolic dimensions; lvisd = left ventricular end systolic dimensions; ivsd = interventricular septal thickness at diastole; lvpwd = left ventricular posterior wall thickness in diastole; aoan = aortic annulus; sinvals = sinus of valsalva; sintubj = sinotubular junction; ascao = ascending aorta. *in comparison to the control group. †p <0.05. echocardiographic evidence of early diastolic dysfunction in asymptomatic children with osteogenesis imperfecta e462 | squ medical journal, november 2015, volume 15, issue 4 chest deformities. additionally, the echocardiographers performing the scans were not blinded to the study subjects, which may have introduced observer bias. as the majority of the oi subjects were diagnosed with type ш oi, it was not possible to analyse the group of oi patients by disease subtype. conclusion the paediatric oi subjects in the current study had normal systolic cardiac function and early changes in myocardial tissue doppler velocities. this is suggestive of early diastolic cardiac dysfunction. since these changes may worsen with time, careful cardiological evaluation and follow-up of these patients is warranted. larger observational tde studies assessing diastolic function in children with oi are recommended. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. prockop dj, kivirikko ki. heritable diseases of collagen. n engl j med 1984; 311:376–86. doi: 10.1056/nejm198408093110606. 2. cheung ms, glorieux fh. osteogenesis imperfecta: update on presentation and management. rev endocr metab disord 2008; 9:153–60. doi: 10.1007/s11154-008-9074-4. 3. abdurrahman l, hoit bd, banerjee a, khoury pr, meyer ra. pulmonary venous flow doppler velocities in children. j am soc echocardiogr 1998; 11:132–7. doi: 10.1016/s08947317(98)70071-9. 4. eidem bw, mcmahon cj, cohen rr, wu j, finkelshteyn i, kovalchin jp, et al. impact of cardiac growth on doppler tissue imaging velocities: a study in healthy children. j am soc echocardiogr 2004; 17:212–21. doi: 10.1016/j.echo.2003.12.005. 5. o’leary pw, durongpisitkul k, cordes tm, bailey kr, hagler dj, tajik j, et al. diastolic ventricular function in children: a doppler echocardiographic study establishing normal values and predictors of increased ventricular end-diastolic pressure. mayo clin proc 1998; 73:616–28. doi: 10.1016/s0025-6196(11)64884-2. 6. hortop j, tsipouras p, hanley ja, maron bj, shapiro jr. cardiovascular involvement in osteogenesis imperfecta. circulation 1986; 73:54–61. doi: 10.1161/01.cir.73.1.54. 7. vetter u, maierhofer b, müller m, lang d, teller wm, brenner r, et al. osteogenesis imperfecta in childhood: cardiac and renal manifestations. eur j pediatr 1989; 149:184–7. doi: 10.1007/bf01958277. 8. sillence do, senn a, danks dm. genetic heterogeneity in osteogenesis imperfecta. j med genet 1979; 16:101–16. doi: 10.1136/jmg.16.2.101. 9. lopez l, colan sd, frommelt pc, ensing gj, kendal k, younoszai ak, et al. recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the pediatric measurements writing group of the american society of echocardiography pediatric and congenital heart disease council. j am soc echocardiogr 2010; 23:465–95. doi: 10.1016/j.echo.2010.03.019. 10. nishimura ra, tajik aj. evaluation of diastolic filling of left ventricle in health and disease: doppler echocardiography is the clinician’s rosetta stone. j am coll cardiol 1997; 30:8–18. doi: 10.1016/s0735-1097(97)00144-7. 11. frommelt pc. echocardiographic measures of diastolic function in pediatric heart disease. curr opin cardiol 2006; 21:194–9. doi: 10.1097/01.hco.0000221580.63996.93. 12. parameter(z). pediatric and fetal echo z-score calculators. from: www.parameterz.blogspot.com/ accessed: jan 2015. 13. migliaccio s, barbaro g, fornari r, di lorenzo g, celli m, lubrano c, et al. impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: casuality or causality? int j cardiol 2009; 131:200–3. doi: 10.1016/j.ijcard.2007.10.051. 14. caulfield jb, borg tk. the collagen network of the heart. lab invest 1979; 40:364–72. 15. ju h, dixon im. extracellular matrix and cardiovascular diseases. can j cardiol 1996; 12:1259–67. 16. byers ph, steiner rd. osteogenesis imperfecta. annu rev med 1992; 43:269–82. doi: 10.1146/annurev.me.43.020192.001413. 17. wheeler vr, cooley nr jr., blackburn wr. cardiovascular pathology in osteogenesis imperfecta type iia with a review of the literature. pediatr pathol 1988; 8:55–64. doi: 10.3109/15513818809022279. 18. mackenna da, vaplon sm, mcculloch ad. microstructural model of perimysial collagen fibers for resting myocardial mechanics during ventricular filling. am j physiol 1997; 273:1576–86. 19. soma k, abe h, takeda n, shintani y, takazawa y, kojima t, et al. myocardial involvement in patients with osteogenesis imperfecta. int heart j 2012; 53:75–7. doi: 10.1536/ihj.53.75. 20. pfeiffer bj, franklin cl, hsieh fh, bank ra, phillips cl. alpha 2(i) collagen deficient oim mice have altered biomechanical integrity, collagen content, and collagen crosslinking of their thoracic aorta. matrix biol 2005; 24:451–8. doi: 10.1016/j.matbio.2005.07.001. 21. weis sm, emery jl, becker kd, mcbride dj jr, omens jh, mcculloch ad. myocardial mechanics and collagen structure in the osteogenesis imperfecta murine (oim). circ res 2000; 87:663–9. doi: 10.1161/01.res.87.8.663. 22. radunovic z, wekre ll, steine k. right ventricular and pulmonary arterial dimensions in adults with osteogenesis imperfecta. am j cardiol 2012; 109:1807–13. doi: 10.1016/j. amjcard.2012.01.402. 23. karamifar h, ilkhanipoor h, ajami g, karamizadeh z, amirhakimi g, shakiba am. cardiovascular involvement in children with osteogenesis imperfecta. iran j pediatr 2013; 23:513‒18. 24. zanjani ks, niwa k. aortic dilatation and aortopathy in congenital heart diseases. j cardiol 2013; 61:16–21. doi: 10.1016/j.jjcc.2012.08.018. http://dx.doi.org/10.1056/nejm198408093110606 http://dx.doi.org/10.1007/s11154-008-9074-4 http://dx.doi.org/10.1016/s0894-7317%2898%2970071-9 http://dx.doi.org/10.1016/s0894-7317%2898%2970071-9 http://dx.doi.org/10.1016/j.echo.2003.12.005 http://dx.doi.org/10.1016/s0025-6196%2811%2964884-2 http://dx.doi.org/10.1161/01.cir.73.1.54 http://dx.doi.org/10.1007/bf01958277 http://dx.doi.org/10.1136/jmg.16.2.101 http://dx.doi.org/10.1016/j.echo.2010.03.019 http://dx.doi.org/10.1016/s0735-1097%2897%2900144-7 http://dx.doi.org/10.1097/01.hco.0000221580.63996.93 http://dx.doi.org/10.1016/j.ijcard.2007.10.051 http://dx.doi.org/10.1146/annurev.me.43.020192.001413 http://dx.doi.org/10.3109/15513818809022279 http://dx.doi.org/10.1536/ihj.53.75 http://dx.doi.org/10.1016/j.matbio.2005.07.001 http://dx.doi.org/10.1161/01.res.87.8.663 http://dx.doi.org/10.1016/j.amjcard.2012.01.402 http://dx.doi.org/10.1016/j.amjcard.2012.01.402 http://dx.doi.org/10.1016/j.jjcc.2012.08.018 breast cancer is the most frequently diagnosed cancer worldwide (23%) and the leading cause of cancer-related deaths among women (14%).1 in oman, the incidence of breast cancer increased from 53 cases in 1996 to 104 cases in 2008, with 100–150 new cases reported annually.2 moreover, in comparison to western women, women in oman are often diagnosed in the later stages of cancer, at an earlier age and have lower survival rates.2,3 a diagnosis of breast cancer can be devastating and can trigger distressing psychological reactions in patients, including feelings of hopelessness, anxiety, fear, loneliness, negative self-image and self-blaming as well as sexual problems.4–6 women with breast cancer have also reported suffering from social discrimination and stigma; hence, they may be less able to cope with the subsequent challenges and adjustments which come with their diagnosis.5–7 psychological interventions are a form of couns elling which can minimise the devastating effects and treatment-related symptoms of patients diagnosed with cancer.8,9 during direct face-to-face interpersonal sessions, counsellors use various techniques, such as education, coping skills training, psychotherapy and relaxation, either alone or in combination.8,9 the aim of these types of therapies is to help the patient resolve any psychological disturbances arising from their cancer diagnosis and teach them the necessary skills to cope, both during and after cancer treatment, so as to enhance their health-related quality of life (qol).10 these interventions can be used for patients of both genders with many different types of cancer.11 research has shown that psychological interventions can give a feeling of empowerment to women who are diagnosed with cancer, thus improving the qol of breast cancer sufferers and survivors.12,13 psychological and mindful therapies have also been found to positively affect psychological outcomes in women with breast cancer, such as anxiety, depression and mood disturbance; as such, it is recommended that this type of therapy be initiated as soon as a cancer diagnosis is confirmed.14 another type of therapeutic intervention is supportive-expressive group therapy which involves many cancer patients receiving treatment at once, allowing them to analyse and express their concerns more effectively.15 this form of therapy provides a platform for patients to express their emotions, improves familial and social relationships and teaches patients to cope with their cancer symptoms.16 qualified counsellors conduct these sessions in person, helping cancer patients to deal with their emotional pain and distress and encouraging them to speak openly about their health conditions.15,16 a study of omani women diagnosed with breast cancer revealed that they encountered psychological and social distress post-diagnosis which affected their personal and social lives.5 the women reported being worried about death; feeling that their future was threatened; that their families were shocked by their diagnosis; that the cancer interfered with their work and their familial responsibilities; feeling isolated from society; and reluctance to disclose their diagnosis to other people.5 another study found that omani women diagnosed with breast cancer used numerous strategies to cope with their symptoms, including denial, social withdrawal, religion and support from family members and healthcare providers.6 the authors of both of these studies recommended that healthcare professionals in oman be aware of, and respect, their patients’ coping strategies and that these women should be provided with more support to reduce the psychological symptoms, distress and 1higher medical committee, ministry of health, muscat, oman; 2department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: mhalazri@squ.edu.om احلاجة إىل خدمات تدخل ودعم نفسي للنساء العمانيات اللوايت مت تشخيص إصابتهن بسرطان الثدي ن�ش�أت �شم�س و حممد العزري editorial the need for psychological interventional supportive services for omani women diagnosed with breast cancer nishat shams1 and *mohammed al-azri2 sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e403–405, epub. 30 nov 16 submitted 14 aug 16 revision req. 18 sep 16; revision recd. 23 sep 16 accepted 25 sep 16 doi: 10.18295/squmj.2016.16.04.001 the need for psychological interventional supportive services for omani women diagnosed with breast cancer e404 | squ medical journal, november 2016, volume 16, issue 4 dilemmas related to a breast cancer diagnosis.5,6 indeed, care for cancer patients should be provided as a “continuum”, including risk assessment, primary and secondary prevention, early detection, diagnosis, treatment, follow-up and end-of-life care.17 bearing in mind the qol benefits of psychological interventions in helping women cope with a breast cancer diagnosis, several measures should be considered to integrate psychological interventions into the healthcare system in oman. a psychological intervention service to support patients and their caregivers immediately following diagnosis and during treatment should be established in the oncology units of tertiary care referral hospitals. the oncology teams in these hospitals also need to be made aware of the importance of the psychological aspects of a cancer diagnosis, so that they can anticipate and recognise patients suffering from psychological symptoms, allowing them to make timely referrals to counsellors. supportive-expressive groups should be initiated in the main government hospitals of oman, such as the national oncology center at the royal hospital and the sultan qaboos university hospital in muscat, oman. nurses as well as other healthcare professionals can be trained by mental healthcare providers to conduct psychological interventions for omani women diagnosed with breast cancer. psychological services can also be introduced at the community level through local health centres, providing mental health services and forming support groups for patients who have been discharged. policy-makers, in cooperation with health psychologists, should initiate public screening and awareness programmes to educate omani women on the benefits of the early detection of breast cancer and post-diagnosis psychological support services. although the omani government has initiated campaigns on breast cancer awareness in the past, these campaigns alone were not effective.6 nongovernmental organisations, such as the oman cancer association, could take steps to improve public awareness of the benefits of psychological interventions. there is also a need for collaboration with the media, both print and electronic, such as local newspapers and magazines as well as radio and television stations, in order to spread cancer awareness and support for breast cancer patients and the need for psychological support services. furthermore, an arabic-language interactive website for patient education and promotion of psychological interventional therapy for cancer patients is necessary. there is a definite need and role for clinical psychologists in the management of cancer patients from the outset, at the screening and genetic testing stages. however, the successful implementation of psychological support services and active interventions for omani women with breast cancer can only be brought about following the development of the necessary human resources, training, commitment, advocacy and infrastructure. the initiation of these services could be taken on by appropriate authorities at the ministry of health in oman, with support from the sultan qaboos university hospital as well as the national oncology center. these efforts could help decrease the negative attitudes and shame associated with a breast cancer diagnosis, in the hope that oman will be able to transform itself into a stigma-free nation with regards to the fight against breast cancer. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin 2011; 61:69–90. doi: 10.3322/caac.20107. 2. mehdi i, monem ea, al bahrani bj, al kharusi s, nada am, al lawati j, et al. age at diagnosis of female breast cancer in oman: issues and implications. south asian j cancer 2014; 3:101–6. doi: 10.4103/2278-330x.130442. 3. al-moundhri m, al-bahrani b, pervez i, ganguly ss, nirmala v, al-madhani a, et al. the outcome of treatment of breast cancer in a developing country: oman. breast 2004; 13:139–45. doi: 10.1016/j.breast.2003.10.001. 4. badger ta, braden cj, mishel mh, longman a. depression burden, psychological adjustment, and quality of life in women with breast cancer: patterns over time. res nurs health 2004; 27:19–28. doi: 10.1002/nur.20002. 5. al-azri m, al-awisi h, al-rasbi s, el-shafie k, al-hinai m, al-habsi h, et al. psychosocial impact of breast cancer diagnosis among omani women. oman med j 2014; 29:437–44. doi: 10.5001/omj.2014.115. 6. al-azri mh, al-awisi h, al-rasbi s, al-moundhri m. coping with a diagnosis of breast cancer amongst omani women. j health psychol 2014; 19:836–46. doi: 10.1177/135 9105313479813. 7. else-quest nm, loconte nk, schiller jh, hyde js. perceived stigma, self-blame, and adjustment among lung, breast and prostate cancer patients. psychol health 2009; 24:949–64. doi: 10.1080/08870440802074664. 8. abu-helalah m, al-hanaqta m, alshraideh h, abdulbaqi n, hijazeen j. quality of life and psychological well-being of breast cancer survivors in jordan. asian pac j cancer prev 2014; 15:5927–36. doi: 10.7314/apjcp.2014.15.14.5927. 9. hodges lj, walker j, kleiboer am, ramirez aj, richardson a, velikova g et al. what is a psychological intervention? a metareview and practical proposal. psychooncology 2011; 20:470–8. doi: 10.1002/pon.1780. 10. casellas-grau a, font a, vives j. positive psychology interventions in breast cancer: a systematic review. psychooncology 2014; 23:9–19. doi: 10.1002/pon.3353. 11. faller h, schuler m, richard m, heckl u, weis j, küffner r. effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis. j clin oncol 2013; 31:782–93. doi: 10.1200/jco.2011.40.8922. dx.doi.org/10.3322/caac.20107 dx.doi.org/10.4103/2278-330x.130442 dx.doi.org/10.1016/j.breast.2003.10.001 dx.doi.org/10.1002/nur.20002 dx.doi.org/10.5001/omj.2014.115 dx.doi.org/10.1177/1359105313479813 dx.doi.org/10.1177/1359105313479813 dx.doi.org/10.1080/08870440802074664 dx.doi.org/10.7314/apjcp.2014.15.14.5927 dx.doi.org/10.1002/pon.1780 dx.doi.org/10.1002/pon.3353 dx.doi.org/10.1200/jco.2011.40.8922 nishat shams and mohammed al-azri editorial | e405 12. hunter ms, coventry s, hamed h, fentiman i, grunfeld ea. evaluation of a group cognitive behavioural intervention for women suffering from menopausal symptoms following breast cancer treatment. psychooncology 2009; 18:560–3. doi: 10.1002/pon.1414. 13. andersen bl. biobehavioral outcomes following psychological interventions for cancer patients. j consult clin psychol 2002; 70:590–610. doi: 10.1037/0022-006x.70.3.590. 14. jassim ga, whitford dl, hickey a, carter b. psychological interventions for women with non-metastatic breast cancer. cochrane database syst rev 2015; 28:cd008729. doi: 10.1002/ 14651858.cd008729.pub2. 15. spiegel d, bloom jr, yalom i. group support for patients with metastatic cancer: a randomized outcome study. arch gen psychiatry 1981; 38:527–33. doi: 10.1001/archpsyc.1980.0178 0300039004. 16. classen c, butler ld, koopman c, miller e, dimiceli s, giese-davis j, et al. supportive-expressive group therapy and distress in patients with metastatic breast cancer: a randomized clinical intervention trial. arch gen psychiatry 2001; 58:494–501. doi: 10.1001/archpsyc.58.5.494. 17. al-moundhri m. the need for holistic cancer care framework: breast cancer care as an example. oman med j 2013; 28:300–1. doi: 10.5001/omj.2013.90. dx.doi.org/10.1002/pon.1414 dx.doi.org/10.1037/0022-006x.70.3.590 dx.doi.org/10.1002/14651858.cd008729.pub2 dx.doi.org/10.1002/14651858.cd008729.pub2 dx.doi.org/10.1001/archpsyc.1980.01780300039004 dx.doi.org/10.1001/archpsyc.1980.01780300039004 dx.doi.org/10.1001/archpsyc.58.5.494 dx.doi.org/10.5001/omj.2013.90 departments of 1surgery and 2radiology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drkhalidmunirbhatti@yahoo.com اإلصابات اجلذعية غري احلادة يف األطفال اليات اإلصابة، واألمناط والنتائج بني األطفال الذين حيتاجون إىل التنومي يف مستشفى جامعة السلطان قابوس، عمان خالد منري بهاتي، كاظم م�سطفى تقي، اأحمد زاهر �سعيد احلارثي، رانا �سعيب حامد، زينب نا�رس البلو�سي، ديليب كومار �سانكال، هاين اأحمد القا�سي abstract: objectives: trauma is the greatest cause of morbidity and mortality in paediatric/adolescent populations worldwide. this study aimed to describe trauma mechanisms, patterns and outcomes among children with blunt torso trauma admitted to the sultan qaboos university hospital (squh) in muscat, oman. methods: this retrospective single-centre study involved all children ≤12 years old with blunt torso trauma admitted for paediatric surgical care at squh between january 2009 and december 2013. medical records were analysed to collect demographic and clinical data. results: a total of 70 children were admitted with blunt torso trauma during the study period, including 39 (55.7%) male patients. the mean age was 5.19 ± 2.66 years. of the cohort, 35 children (50.0%) received their injuries after having been hit by cars as pedestrians, while 19 (27.1%) were injured by falls, 12 (17.1%) during car accidents as passengers and four (5.7%) by falling heavy objects. according to computed tomography scans, thoracic injuries were most common (65.7%), followed by abdominal injuries (42.9%). the most commonly involved solid organs were the liver (15.7%) and spleen (11.4%). the majority of the patients were managed conservatively (92.9%) with a good outcome (74.3%). the mortality rate was 7.1%. most deaths were due to multisystem involvement. conclusion: among children with blunt torso trauma admitted to squh, the main mechanism of injury was motor vehicle accidents. as a result, parental education and enforcement of infant car seat/child seat belt laws are recommended. conservative management was the most successful approach. keywords: pediatrics; trauma; blunt injury; thoracic injury; abdominal injury; oman. هذه هدفت العامل. اأنحاء جميع يف وواملراهقني الأطفال بني والوفيات االعتالل م�سببات اأكرث هي اإل�سابات تعترب اأهداف: امللخ�ص: إىل وادخلوا احلادة غري اجلذعية اإل�سابات من يعانون الذين الأطفال بني ونتائجها واأمناطها الأ�سابات، اآليات و�سف اإىل الدرا�سة م�ست�سفى جامعة ال�سلطان قابو�س )squh( يف م�سقط، عمان. منهجية: �سملت هذه الدرا�سة اال�ستعادية التي اأجريت يف مركز واحد على جميع الأطفال 12≥ عاما امل�سابني إ�سابات جذعية غري حادة و يتلقون الرعاية يف وحدة جراحة الأطفال يف م�ست�سفى جامعة ال�سلطان قابو�س، �سلطنة عمان، بني يناير 2009 ودي�سمرب 2013. مت حتليل ال�سجالت الطبية جلمع البيانات الدميوغرافية وال�رسيرية. نتائج: مت قبول جمموعه 70 طفال مع �سدمة اجلذع احلادة خالل فرتة الدرا�سة، مبا يف ذلك 39 )%55.7( من املر�سى الذكور. بلغ متو�سط العمر 2.66 ± 5.19 �سنة. من الفوج، تلقى 35 طفال )%50.0( اإ�سابات مبا�رسة من ال�سيارات أثناء ال�سري يف الطريق )م�ساه(، يف حني اأن 19 )%27.1( اأ�سيبوا لأ�سعة ووفقا الثقيلة. الأج�سام �سقوط جراء من واأربعة )5.7%( ال�سيارات حوادث خالل راكبا )17.1%( بينما أ�سيب 12 لل�سقوط، نتيجة �سيوعا الأكرث امل�سابة الأع�ساء وكانت .)42.9%( البطن اإ�سابات تليها ،)65.7%( �سيوعا الأكرث ال�سدر اإ�سابات كانت املقطعي، امل�سح هي الكبد )%15.7( ثم الطحال )%11.4(. وقد اأمكن عالج معظم املر�سى بدون تدخل جراحي )%92.9( مع نتائج جيدة يف )%74.3(. وكان معدل الوفيات %7.1. وكانت معظم الوفيات الناجمة عن اإ�سابات للعديد من اأجهزة اجل�سم. خامتة: كانت حوادث ال�سيارات هي اكرث األيات الإ�سابة �سيوعا بني الأطفال امل�سابني بإ�سابات جذعية غري حادة يف الأطفال املحتاجني اإىل التنومي يف امل�ست�سفى يف م�ست�سفى جامعة ال�سلطان قابو�س. نتيجة لذلك، ين�سح بتعليم الأباء عن اأهمية مقعد وحزام الأمان لالأطفال و الر�سع واإنفاذ القوانني التي تلزم باأ�ستخدامه. وكان التدخل التحفظي الغري جراحي هو التدخل الأكرث جناحا. كلمات مفتاحية: طب الأطفال؛ ال�سدمات؛ ال�سابات غري احلادة؛ اإ�سابات ال�سدر؛ اإ�سابات البطن؛ عمان. paediatric blunt torso trauma injury mechanisms, patterns and outcomes among children requiring hospitalisation at the sultan qaboos university hospital, oman *khalid m. bhatti,1 kadhim m. taqi,1 ahmed z. s. al-harthy,1 rana s. hamid,2 zainab n. al-balushi,1 dilip k. sankhla,2 hani a. al-qadhi1 clinical & basic research sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 210–216, epub. 15 may 16 submitted 12 dec 15 revision req. 24 jan 16; revision recd. 17 feb 16 accepted 3 mar 16 doi: 10.18295/squmj.2016.16.02.012 advances in knowledge in this study, school-aged children were most often the victims of blunt torso trauma. furthermore, trauma injuries were rarely isolated and most deaths were due to multisystem involvement. application to patient care as the findings of this study indicated that most cases of paediatric blunt trauma to the torso involved multiple systems, careful patient evaluation is of paramount importance to rule out intra-abdominal injuries. nonoperative management was the most successful approach for cases of paediatric blunt torso trauma in the current study. as such, this approach is recommended, particularly when treating children with solid organ injuries. khalid m. bhatti, kadhim m. taqi, ahmed z. s. al-harthy, rana s. hamid, zainab n. al-balushi, dilip k. sankhla and hani a. al-qadhi clinical and basic research | e211 2013. medical records were obtained for all children ≤12 years old with thoracic, abdominal or combined injuries due to trauma who were admitted to squh for paediatric surgical care during the study period. data were collected by two independent researchers using the hospital’s computerised database and records from the emergency, paediatric and surgical wards. demographic and clinical data were collected, including gender, age, mechanism of injury, associated injuries, glasgow coma scale scores and clinical condition at presentation to the emergency department (ed). diagnostic modalities used, radiol ogical findings and management approaches were also recorded. furthermore, admission to and duration of stay at the paediatric intensive care unit (picu), utilisation of inotropic support (if needed), overall duration of hospital stay, intraoperative findings, transfers to other hospitals (if needed) and patient outcomes, including rates of complications, mortality and residual morbidity at discharge, were also noted. radiological findings were validated by a senior radiologist at squh. data were analysed using the statistical package for the social sciences (spss), version 16 (ibm corp., chicago, illinois, usa). this study was approved by the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #903). results over the four-year study period, 7,417 paediatric patients were brought to the ed with a history of allcause trauma, including 15 patients who were dead on arrival (incidence: 20/10,000 individuals) and 125 patients who were subsequently admitted (incidence: 650/10,000 individuals). of those admitted, a total of 70 children (56.0%) presented with blunt torso trauma, including 39 males (55.7%) and 31 females (44.3%). these patients ranged in age from 0–12 years old, with a mean age of 5.19 ± 2.66 years. school-aged children (6–12 years old) were most commonly involved (n = 31; 44.3%). in terms of mechanism of injury, the majority were pedestrians who had been hit by cars (n = 35; 50.0%). children also received blunt trauma injuries due to falls (n = 19; 27.1%), motor vehicle accidents in which the children were passengers (n = 12; 17.1%) and from falling heavy objects (n = 4; 5.7%) [table 1]. chest and pelvic x-rays were the primary diagnostic modality; chest x-rays were normal for 53 patients (75.7%) while pelvic x-rays were normal for 70 patients (100.0%). pneumothorax was evident on the chest x-rays of 15 patients (21.4%) and lung contusions were seen on the chest x-rays of two patients. underlying trauma is the single greatest cause of morbidity and mortality in paediatric or adolescent populations and an estimated one in four children require medical care due to unintentional trauma every year.1,2 trauma can either be blunt or penetrating and different principles of management exist accordingly. blunt trauma is more prevalent and usually involves multiple systems in children due to their small size.3 isolated skeletal or head injuries are managed by the concerned specialties, while blunt trauma that involves other areas is known as blunt torso trauma. the torso is generally considered a single unit as thoracic and abdominal injuries tend to occur simultaenously.4 for this reason, children with this type of trauma require more vigilant assessment and the involvement of multidisciplinary teams in the management of their injuries. in oman, trauma is one of the most common causes of death in patients below 18 years of age.5 since 2009, children with blunt torso trauma have been referred to the sultan qaboos university hospital (squh), a tertiary care hospital in muscat and one of the main trauma referral centres in oman. although squh meets many of the standards of a level i paediatric trauma centre, it is considered a level iii paediatric trauma centre because the hospitalisation rate for children with trauma is less than 100 admissions per year.6 to the best of the authors’ knowledge, no study to date has yet documented the patterns, management practices and outcomes of paediatric blunt torso trauma cases in oman. in order to improve the care of such patients, the current study therefore aimed to provide a detailed description of trauma mechanisms, patterns and outcomes among children hospitalised for the management of blunt torso trauma at squh. methods this retrospective single-centre study was conducted at squh between january 2009 and december table 1: mechanism of trauma by age group among children with blunt torso trauma admitted to the sultan qaboos university hospital, muscat, oman (n = 70) mechanism of trauma age in years total <1 1–3 4–5 6–12 pedestrian hit by car in mcv 2 6 9 18 35 fall 2 5 7 5 19 passenger in mvc 2 2 1 7 12 fall of a heavy object 0 2 1 1 4 total 6 15 18 31 70 mvc = motor vehicle collision. paediatric blunt torso trauma injury mechanisms, patterns and outcomes among children requiring hospitalisation at the sultan qaboos university hospital, oman e212 | squ medical journal, may 2016, volume 16, issue 2 thoracic injuries in 31 patients (44.3%) were not observed on chest x-rays; however, the injuries were subsequently observed on helical chest computed tomography (ct) scans. most of the patients in the current study who were haemodynamically normal or responded to resuscitation were evaluated by intravenous contrast cts of the head, chest, abdomen and pelvis. a total of 65 patients (92.9%) underwent abdominal ct scans with intravenous contrast; these detected 34 injuries in 29 patients. all cases of rib fracture were missed on initial chest x-rays (n = 5; 10.9%). of the 37 cases with lung contusions, most were missed via x-ray (n = 35; 94.6%). similarly, none of the pelvic fractures observed via ct scans (n = 14) were picked up by the pelvis x-rays. more than 50% of the abdominal ct scans were negative for intra-abdominal injuries. according to ct scans, single system thoracic injuries (n = 10; 14.3%) or multisystem thoracic injuries (n = 36; 51.4%) were most common (n = 46; 65.7%), followed by abdominal injuries (n = 30; 42.9%). of the thoracic injuries, the most common injuries were lung contusions (n = 37; 80.4%), followed by pneumothorax (n = 18; 39.1%), haemothorax (n = 6; 13.0%) and rib fractures (n = 5; 10.9%) [table 2]. among those with abdominal trauma, 10 patients (33.3%) had single system abdominal injuries while 20 (66.7%) had multisystem injuries [figure 1]. two patients, one hit by a car causing a perforation of the small bowel with a mesenteric tear and extensive liver damage and the other patient with a duodenal blow-out due to a fall, had hollow viscous injuries which were managed by exploratory laparotomy; another two patients had multisystem involvement which developed into haemodynamic instability. intra-abdominal injuries were noted in 29 patients (44.6%) via ct scan, with one patient taken to the operating theatre without initial imaging. the most commonly involved solid organs were the liver (n = 11; 15.7%)—in isolation (n = 8; 72.7%) or in combination with other organs (n = 3; 27.3%)— and the spleen (n = 8; 11.4%). seven patients had a minimal amount of free fluid in the absence of any solid or hollow viscus injury. the majority of the children with single or multiple solid organ injuries were managed successfully through a conservative approach (88.9%) [table 3]. all of the patients were managed according to advanced trauma life support protocols. five patients (7.1%) required surgical interventions while the rest of the patients were managed conservatively (92.9%). a total of 15 patients (32.6%) with thoracic injuries required chest intubation in the ed due to x-ray evidence of pneumothorax. three additional cases of pneumothorax required chest intubation due to helical chest ct findings. in total, 62 patients (88.6%) were haemodynamically stable at presentation. of the eight patients (11.4%) who were not, seven (87.5%) responded to resuscitation while the remaining patient underwent an exploratory laparotomy without an initial abdominal ct scan; the surgical exploration revealed a splenic injury which required a splenectomy. unfortunately, the patient died five days after the operation while in the picu. four patients (6.2%) required an exploratory laparotomy after an abdominal ct scan. one patient died intra-operatively and the other three patients were moved to the picu. two of these patients died while in the picu; the remaining patient, who had an isolated small bowel injury, survived. another patient who had extensive table 2: thoracic injuries among children with blunt torso trauma admitted to the sultan qaboos university hospital, muscat, oman (n = 46) type of injury single system multisystem total lung contusions 7 16 23 lung contusions and pneumothorax 1 7 8 pneumothorax 0 4 4 haemopneumothorax 1 2 3 lung contusions and rib fractures 0 3 3 lung contusions, pneumothorax and haemothorax 1 2 3 rib fractures 0 2 2 total 10 36 46 figure 1: patterns of blunt torso trauma among children admitted to the sultan qaboos university hospital, muscat, oman (n = 70). all injuries were diagnosed via computed tomography. khalid m. bhatti, kadhim m. taqi, ahmed z. s. al-harthy, rana s. hamid, zainab n. al-balushi, dilip k. sankhla and hani a. al-qadhi clinical and basic research | e213 of the patients admitted to the picu required blood transfusions (1–13 units of 10 ml/kg of packed red blood cells) and 15 patients (44.1%) required inotropic support (range of duration: <1 hour–10 days). of the surviving patients, 52 patients (74.3%) were discharged without any residual morbidities, two patients (2.9%) were discharged with neurological complications and 11 patients (32.4%) were referred to other hospitals for further management [figure 2]. the two patients who were discharged with severe head injuries developed permanent disabilities. retroperitoneal haematoma and was on expectant management died in the picu. the mortality rate was therefore 7.1% (n = 5). most of the patients who died had multisystem injuries [table 4]. in total, 35 patients (50.0%) were managed in wards—eight (22.9%) in a high dependency unit and 27 (77.1%) in normal wards—while 34 (48.6%) required observation in the picu. of those transferred to the picu, four (11.8%) were moved post-surgery while 30 (88.2%) were transferred directly after ct evaluation. in the picu, 21 patients (61.8%) required invasive ventilation (range of duration: <24 hours–29 days). all table 3: intra-abdominal injuries among children with blunt torso trauma admitted to the sultan qaboos university hospital, muscat, oman (n = 30) type of injury total grade management 1 2 3 4 5 operative (successful) nom (successful) solid organ injuries 18 liver alone 8 5 1 2 1 (0) 7 (7) spleen alone 6 2 2 1 1 1 (0) 5 (5) liver and spleen 2 1* 2† 1‡ 2 (2) renal 2 1 1 2 (2) other iais 12 adrenal with retroperitoneal haematoma 2 1 1 2 (1) bowel 1 1 (1) liver and bowel 1 1‡ 1 (0) suspected iai 1 1 (0) free abdominal fluid without obvious solid organ injury 7 7 (7) iai = intra-abdominal injury; nom = nonoperative management. *spleen injury grade only. †spleen and liver injury grades for two different patients, respectively. ‡liver injury grade only. table 4: fatalities among children with blunt torso trauma admitted to the sultan qaboos university hospital, muscat, oman (n = 70) age in years/ gender mechanism of injury haemodynamic status at presentation type of injuries management head chest abdomen other 2/f pedestrian hit by car unstable severe liver and bowel retroperitoneal haematoma laparotomy 5/f pedestrian hit by car unstable severe haemopneumothorax and rib fracture liver laparotomy 6/m pedestrian hit by car unstable severe lung contusion, pneumothorax and haemothorax adrenal retroperitoneal haematoma and pelvic fracture expectant 6/m pedestrian hit by car unstable severe spleen retroperitoneal haematoma and pelvic fracture laparotomy and splenectomy 7/m pedestrian hit by car unstable severe suspected injury laparotomy* f = female; m = male. *negative. paediatric blunt torso trauma injury mechanisms, patterns and outcomes among children requiring hospitalisation at the sultan qaboos university hospital, oman e214 | squ medical journal, may 2016, volume 16, issue 2 discussion factors which determine the types and patterns of paediatric injury include the age and gender of the patient group and the cause of trauma. in the current study, the age group most commonly involved was 6–12-year-olds and children were most often injured as a result of being hit by a vehicle as a pedestrian. these findings could possibly be due to the fact that children of this age group are often allowed to play in the streets unattended. in contrast, toddlers (<1-yearolds) and preschool-aged children (1–3-year-olds) were collectively more likely to be injured in a fall or by having a heavy object fall upon them. as a result, parental education and strict enforcement of infant car seat and child seat belt laws are recommended as strategies to reduce the number of paediatric trauma patients in oman. regarding gender, slightly more male children presented with torso trauma than females in the current study. this is consistent with findings from other research—being male has been documented as a risk factor for trauma in many studies, with differences between males and females in involvement in trauma appearing from the first year of life.7,8 in children under 15 years of age, the mortality rate due to trauma is reportedly 24% higher in boys than girls.7,8 differences in behaviour between genders may be one reason for such findings, as well as higher activity levels, greater freedom to play alone and increased involvement in risky sports among males. most of the patients in the current study who were haemodynamically stable were evaluated by cts of the head, chest, abdomen and pelvis. although ct scans are considered the primary diagnostic modality for the evaluation of haemodynamically stable children with torso trauma, there are concerns of cost and the potential for radiation-associated malignancies.9 recently, a clinical decision rule (cdr) has been suggested to identify children who are at very low risk of intra-abdominal injuries and hence would not require abdominal cts; however, although costeffective, the validity of this cdr still requires further research.9,10 in the current study, the ct scan rate appears high; however, this may be because all children with torso trauma detected on ct scans were included in the study cohort. hence, the exact ct scan rate for children presenting with torso trauma at squh is unknown. nevertheless, ct scans were effective in the detection of additional injuries, including underlying lung injuries such as lung contusions and rib fractures. similarly, none of the pelvic fractures were picked up by the pelvis x-rays. the major concern in children with torso trauma is diagnosing potential intra-abdominal injuries. in the current study, all of the patients who underwent an abdominal ct did so with intravenous contrast. oral contrast cts are not used to screen paediatric trauma patients at squh as they are time-consuming and may be unsuccessful if the patient is scared or nauseous. delayed emptying can also increase the risk of aspiration and may mask the imaging of the liver and spleen. moreover, ellison et al. recently showed that routine use of oral contrast is unnecessary and delays performance of ct scans and angiographic studies, if indicated.11 in the current study, more than half of the abdominal ct scans were negative for intra-abdominal injuries. however, ct scans can nonetheless play an important role in the management of patients with torso trauma as they can exclude potential intra-abdominal or pelvic sources of blood loss.12 the thorax was the most commonly involved region in combination with other regions in the current study. this is consistent with the findings of peres et al., who described thoracic involvement in 50% of children with polytrauma.13 although lung contusions were the most common injury, the majority of these were figure 2: flowchart showing management approaches and treatment outcomes among children with blunt torso trauma admitted to the sultan qaboos university hospital, muscat, oman (n = 70). squh = sultan qaboos university hospital; doa = dead on arrival; nom = nonoperative management; picu = paediatric intensive care unit; hdu = high-dependency unit; incl. = including. khalid m. bhatti, kadhim m. taqi, ahmed z. s. al-harthy, rana s. hamid, zainab n. al-balushi, dilip k. sankhla and hani a. al-qadhi clinical and basic research | e215 included in the study, although most paediatric trauma series have an upper age limit of 15–19 years old; for this reason, differences in trauma patterns may exist.8,13,14,17 secondly, the current study was retrospective and focused only on hospitalised patients admitted to a single trauma centre; as such, the findings may not represent the exact ct scan rate at squh or the true number of paediatric blunt torso trauma cases occurring in oman during the study period. thirdly, the current study did not describe the precise management algorithms utilised by the ed physicians, if any. the results of this study should hence be interpreted in light of the above limitations. conclusion the main mechanism of torso trauma injury among children admitted to squh involved motor vehicle accidents. in order to reduce the number of paediatric trauma patients, parental education and strict enforcement of infant car seat and child seat belt laws is recommended. the majority of patients were managed conservatively with a good outcome. the optimal approach in treating paediatric trauma patients therefore seems to be conservative management. mortality, although low, stemmed from multisystem involvement. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. seid t, ramaiah r, grabinsky a. pre-hospital care of pediatric patients with trauma. int j crit illn inj sci 2012; 2:114–20. doi: 10.4103/2229-5151.100887. 2. danesco er, miller tr, spicer rs. incidence and costs of 19871994 childhood injuries: demographic breakdowns. pediatrics 2000; 105:e27. doi: 10.1542/peds.105.2.e27. 3. inaba as, seward pn. an approach to pediatric trauma; unique anatomic and pathophysiologic aspects of the pediatric patient. emerg med clin north am 1991; 9:523–48. 4. trunkey dd. torso trauma. curr probl surg 1987; 24:209–65. doi: 10.1016/0011-3840(87)90016-5. 5. hill ag, muyeed az, al-lawati ja (eds). the mortality and health transitions in oman: patterns and processes. from: www2.unicef.org/spanish/evaldatabase/files/2000_oman_ health_transition_rec_347399.pdf accessed: feb 2016. 6. missouri department of health & senior services. 19 csr 30-40.440: standards for pediatric trauma center designation. from: health.mo.gov/living/healthcondiseases/chronic/tcdsys tem/pdf/pediatric_trauma_designation_7-21-10.pdf accessed: feb 2016. 7. world health organization, unicef. world report on child injury prevention. from: www.unicef.org/eapro/world_report.pdf accessed: feb 2016. not observed via chest x-ray; furthermore, very few cases of associated rib fractures were found among the children in the current study. karadaş et al. reported a similarly low rib fracture incidence in children under 19 years of age (11.1%).14 these findings imply that lung parenchymal injuries can occur in the absence of associated rib fractures, perhaps due to the greater pliability of the rib cage in children; furthermore, such injuries can be missed on initial chest x-rays.14,15 an interesting finding on the ct scans of some of the patients in the current study was the presence of more than a trace amount of free fluid in the absence of solid organ injuries. the presence of this fluid indicates a mesenteric tear or hollow viscous injury, both of which require surgical intervention; however, there is a lack of consensus on the correct approach to be taken in such cases.16 hollow viscous injuries pose a significant diagnostic challenge and management options include performing another ct scan with oral contrast or a diagnostic laparoscopy.12,17,18 the reported incidence of hollow viscous injuries among children with polytrauma varies from 1–23% and may involve any part of the gastrointestinal tract.17 only two patients were found to have such injuries in the current study. hollow viscous injuries involving other organs like the stomach, large bowel or rectum were not found in the study. abdominal exploration was performed for five patients due to either hollow viscous injuries or haemodynamic instability. in the current study, all thoracic injuries were managed conservatively or by chest intubation, with the intention to intervene in case of haemodynamic instability or the development of peritonitis. ismail et al. reported that the most common intervention for children with blunt thoracic trauma was chest intubation.19 in the present study, none of the patients required thoracotomies. currently, the management of solid organ injuries in stable children with blunt trauma is primarily nonoperative.20 in the current study, the vast majority of the children with single or multiple solid organ injuries were managed successfully through a conservative approach. failed nonoperative management is concerning because it carries a higher mortality rate than operative management (~5%).21 potential reasons for the high success rate of conservative management in the present study could include the availability of support, blood and blood products received by the patients in the picu. however, another major contributor to the success rate may have been the absence of highrisk factors such as bicycle-related injuries, isolated pancreatic injuries and grade five solid organ injuries.21 the current study had a number of limitations. firstly, only children aged up to 12 years old were http://dx.doi.org/10.4103/2229-5151.100887 http://dx.doi.org/10.1542/peds.105.2.e27 http://dx.doi.org/10.1016/0011-3840%2887%2990016-5 paediatric blunt torso trauma injury mechanisms, patterns and outcomes among children requiring hospitalisation at the sultan qaboos university hospital, oman e216 | squ medical journal, may 2016, volume 16, issue 2 8. fabricant pd, robles a, downey-zayas t, do ht, marx rg, widmann rf, et al. development and validation of a pediatric sports activity rating scale: the hospital for special surgery pediatric functional activity brief scale (hss pedi-fabs). am j sports med 2013; 41:2421–9. doi: 10.1177/0363546513496548. 9. streck cj jr, jewett bm, wahlquist ah, gutierrez ps, russell ws. evaluation for intra-abdominal injury in children after blunt torso trauma: can we reduce unnecessary abdominal computed tomography by utilizing a clinical prediction model? j trauma acute care surg 2012; 73:371–6. doi: 10.1097/ta.0 b013e31825840ab. 10. nishijima dk, yang z, clark ja, kuppermann n, holmes jf, melnikow j. a cost-effectiveness analysis comparing a clinical decision rule versus usual care to risk stratify children for intraabdominal injury after blunt torso trauma. acad emerg med 2013; 20:1131–8. doi: 10.1111/acem.12251. 11. ellison am, quayle ks, bonsu b, garcia m, blumberg s, rogers a, et al. use of oral contrast for abdominal compu ted tomography in children with blunt torso trauma. ann emerg med 2015; 66:107–14. doi: 10.1016/j.annemergmed. 2015.01.014. 12. sivit cj. abdominal trauma imaging: imaging choices and appropriateness. pediatr radiol 2009; 39:s158–60. doi: 10.1007/ s00247-008-1127-z. 13. peres a, chaves m, vieira m, santos e, cruz j, feijó s et al. [polytraumatism in childhood: it can be more than it seems.] acta med port 2010; 23:511–14. 14. karadaş s, gönüllü h, çobanoğlu u, selvi f, dursun r, güner s. comparison of pediatric and adult patients with thoracic trauma in emergency department. j exp clin med 2013; 30:323–6. doi: 10.5835/jecm.omu.30.04.008. 15. tovar ja. the lung and pediatric trauma. semin pediatr surg 2008; 17:53–9. doi: 10.1053/j.sempedsurg.2007.10.008. 16. banz vm, butt mu, zimmermann h, jeger v, exadaktylos ak. free abdominal fluid without obvious solid organ injury upon ct imaging: an actual problem or simply over-diagnosing? j trauma manag outcomes 2009; 3:10. doi: 10.1186/17522897-3-10. 17. chirdan lb, uba af, chirdan oo. gastrointestinal injuries following blunt abdominal trauma in children. niger j clin pract 2008; 3:250–3. 18. adelgais km, kuppermann n, kooistra j, garcia m, monroe dj, mahajan p, et al. accuracy of the abdominal examination for identifying children with blunt intra-abdominal injuries. j pediatr 2014; 165:1230–5. doi: 10.1016/j.jpeds.2014.08.014. 19. ismail mf, al-refaie ri. chest trauma in children, single center experience. arch bronconeumol 2012; 48:362–6. doi: 10.1016/j. arbres.2012.04.016. 20. gaines ba. intra-abdominal solid organ injury in children: diagnosis and treatment. j trauma 2009; 67:s135–9. doi: 10.10 97/ta.0b013e3181adc17a. 21. holmes jh 4th, wiebe dj, tataria m, mattix kd, mooney dp, scaife er, et al. the failure of nonoperative management in pediatric solid organ injury: a multi-institutional experience. j trauma 2005; 59:1309–13. doi: 10.1097/01.ta.00001 97366.38404.79. http://dx.doi.org/10.1177/0363546513496548 http://dx.doi.org/10.1097/ta.0b013e31825840ab http://dx.doi.org/10.1097/ta.0b013e31825840ab http://dx.doi.org/10.1111/acem.12251 http://dx.doi.org/10.1016/j.annemergmed.2015.01.014 http://dx.doi.org/10.1016/j.annemergmed.2015.01.014 http://dx.doi.org/10.1007/s00247-008-1127-z http://dx.doi.org/10.1007/s00247-008-1127-z http://dx.doi.org/10.5835/jecm.omu.30.04.008 http://dx.doi.org/10.1053/j.sempedsurg.2007.10.008 http://dx.doi.org/10.1186/1752-2897-3-10 http://dx.doi.org/10.1186/1752-2897-3-10 http://dx.doi.org/10.1016/j.jpeds.2014.08.014 http://dx.doi.org/10.1016/j.arbres.2012.04.016 http://dx.doi.org/10.1016/j.arbres.2012.04.016 http://dx.doi.org/10.1097/ta.0b013e3181adc17a http://dx.doi.org/10.1097/ta.0b013e3181adc17a http://dx.doi.org/10.1097/01.ta.0000197366.38404.79 http://dx.doi.org/10.1097/01.ta.0000197366.38404.79 evaluating resilience factors in the face of traumatic events in kuwait medical sciences (2000), 2, 111−116 © 2000 sultan qaboos university 1department of sociology and social work kuwait university, safat, kuwait 13150. email: alnaser@qualitynet.net 2tri county trauma and education, 702 park way, santa cruz, ca. 95065-1326. email: :tattoo@ix.netcom.com *to whom correspondence should be addressed. 111 evaluating resilience factors in the face of traumatic events in kuwait *al-naser f1, sandman m2 األحداث مواجهة في المرونة عوامل تقييم الكويت دولة في الصدمية ساندمان مارك الناصر، فهد . سنة الكويت دولةل العراقي الجتياح ا آلثار نتيجة الحالي الكويتي المجتمع في ةللمرون الشخصية السمات على التعرف الى البحث يهدف :الهدف: ألملخص من495 من مكونة الكويت جامعة طالب من من عينة على وزع سؤاال 14 من يتكون مقياس وهو )89er (الذاتية المرونة مقياس طبق:لطريقةا1990 ،والمستوى األجتماعية والمكانة-األسرة ،ونمط التعليم للجنس،والعمر،ونوع تبعا مجموعات الى بالطال قسم ،وقد فأآثر سنة 17 أعمارهم واألناث،تبلغ الذآور المطلقة المتغيرات تجاه الثانوية للمتغيرات األحصائي التحليل وتقييم المرونة لتحديد للنقاط تبعا المتغيرات تلك تأثير لتقييم وذلك األجتماعية والحالة التعليمي، :آالتالي النتائج وجاءت الجنس مقابل في األسرة ونمط واألناث للذآور للمرونة العالية واألنماط باألساليب المقارنة مع تزامنا المجموعات تلفمخ في المستقلة على ممتدة أسر من الطالب حصل وقد األناث من أعلى نقاط على الذآور حصل وقد عالية مرونة وذو بأنهم صنفوا العينة أفراد من%) 37 (الثلث من أآثر أن اًًفروق ظهرت الدراسة أ:الخالصة. اآلداب آليات طالب من أعلى نقاط على حصلوا العلمية الكليات طالب أن آما نووية، أسر من عليه حصل ممن أعلى نقاط لبحث اساسا الدراسة تكون قد .األناث من ءللشفا أآبر امكانية الذآورعلى حصل آما واألناث الذآور الكويتيين الطالب بين نة المرو في احصائية داللة ذات .العربي الخليج منطقة في العربية الشعوب لدى المرونة ونوعية ومقدرة قوة لقياس مستقبلي abstract: objective – to identify the personality characteristics of resilience in contemporary kuwaiti society, in the aftermath of iraqi invasion of the state of kuwait during 1990. method – ego resiliency scale (er89), a 14-item self-report inventory scale with a maximum score of 56, was administered to a sample of 495 male and female students of kuwait university, aged 17 and above. students were also grouped according to gender, age, type of education, family type, social status, educational bent, and marital status to assess the effect of these variables in their resilience scores. results – over one-third (37%) of valid subjects qualified as highly resilient, with the males scoring higher than scores than the females. students from extended families scored higher than those from nuclear families. science students had higher resilience scores than arts students. conclusion – there is significant resilience and adaptability among kuwaitis, with males scoring higher than females. this study could serve as a baseline for future inquiry into strength and resilience qualities of the arab population in the arabian gulf region. key words: kuwait, personality, resilience, arab, ego, er89. ans selye, the noted international authority on stress and author of the first published scientific paper on stress in 1936 stated, ‘it is not what happens to you that matters, but how you take it’.1 in the face of traumatic events, people cope and adapt in varied ways and show varying degrees of resilience. investigation into the qualities of personality resilience form the basis of this study, which seeks to identify the personality characteristics of resilience in contemporary kuwaiti society, in the aftermath of invasion of the state of kuwait by iraqi army on august 2, 1990. the random and arbitrary violence inflicted by the invaders resulted in many kuwaitis becoming affected by post-traumatic stress disorder (ptsd). families were separated, in some cases, permanently. kuwaiti families had to draw heavily from their emotional resources of courage, stability and durability. the frustration and anxiety persisted even after the liberation. many found they lacked the motivation to work; few were able to sleep well. kuwaiti children remained fearful and anxious and parents became over-protective. a great deal of the invasion related trauma experiences for kuwaiti families appear to be connected to family separations, some of them permanent. the feelings of deep insecurity caused by these appear to have had a lasting impact on family readjustment. yet, it was the family that played a pivotal role in the process of recovery and served as a gauge of the h a l n a s e r & s a n d m a n 112 cultural durability that allowed many kuwaitis to survive the horrors of the invasion. individual differences in personality also contributed to the differences in the degree of recovery. these were the factors that the present study investigated. several western studies that focused on such qualities in human personality as strength and resilience, covering psychological, social and physiological domains, have direct bearing upon the present study. in some of these studies, ego resilience has been primarily examined within the context of coping with extreme adversity,2,3 while others have focused on specific personality domains or attributes.5 over the last decade, the term resilience has come into increasing use, most notably focusing on stress resistance.6–8 more recently, attempts have been made to understand the protective processes underlying resilience.8–9 block7 identified the role of ego control and ego resilience in the organization of behaviour and found strong connections between ego resilience and effective functioning in diverse areas of life. subsequently, many studies clearly identified ego resilience in several contexts. for example, several studies10–13 sought to define the concept of ego resilience as a particular theory dependent one, and sought to express some useful recognition achieved by psychodynamic theory as well as to generate explicit behavioural predictions. in the recent years however, the trend has been for using the term resilience without the prefix of ego, thus making it less formal, simpler, although a descriptive term. still other researchers14–17 use resilience to describe invulnerable individuals and survivors, identifying individual characteristics of successful adaptation, despite seemingly significant challenges or threats to that adaptation.18 other notable research19 endorses the encompassing possibilities of the ego resiliency scale 89 (er89).11 in general, ego resilience can be evaluated in different ways including in laboratory situations, prolonged contextual evaluations of individuals in their daily lives and by using a specifically constructed self-report questionnaire scale such as the er89. the er89 is a brief inventory scale, with a relatively high reliability. however, although several personality studies have been conducted in the arab world, we have been unable to locate any previous study that used the er89 scale to specifically identify resilience. this work then, must be viewed as a base line study for this part of the world. method the present study used the latest version of the er89 scale, which is based on several previous samples entirely different from this one. a major advantage of the er89 scale is its simplicity, which enabled an accurate and reliable translation from english to arabic and vice versa, thereby minimising the potential for cultural misunderstandings. secondly, the fact that er89 evolved over many years in various studies of non-psychiatric populations12 has given it proven reliability. the scale attempts to measure the quality of resilience by assessing the way each person manages the fluctuations in daily life and what they do about their own experiences. while those scoring higher in the scale are not necessarily free of emotional distress and impairment, emotional problems would be expected to be much more prevalent among those ranked lower. table 1 ego resiliency scale 89 [er89] # 1. i am generous with my friends. # 2. i quickly get over and recover from being startled. # 3. i enjoy dealing with new and unusual situations. # 4. i usually succeed in making a favourable impression on people. # 5. i enjoy trying new foods i have never tasted before. # 6. i am regarded as a very energetic person. # 7. i like different paths to familiar places. # 8. i am more curious than most people. # 9. most of the people i meet are likeable. # 10. i usually think carefully about something before acting. # 11. i like to do new and different things. # 12. my daily life is full of things that keep me interested. # 13. i would be willing to describe myself as a "pretty strong personality". # 14. i get over my anger at someone reasonably quick. the study randomly selected 500 students (250 male, 250 female) of ages 17 and above, enrolled in the two colleges of arts and science of kuwait university (only 495 responses were used). the 14-item self-report inventory scale (table 1), a simple and accurate way of recording the ‘pure qualities of resilience’ was administered to the students. added to the original er89 scale were questions on age, social status, education, intended to reveal social and personal characteristics. each of the 14 items in the questionnaire required response on the following 4-point scale: 1 = does not apply at all 2 = applies slightly, if at all 3 = applies somewhat 4 = applies very strongly. r e s i l i e n c e i n k u w a i t i s 113 a response of 4 represents a high ranking on the er89 scale. the maximum score is 14 × 4 = 56 and the minimum 14 × 1 = 14. the top of the scale suggests a person with energy and excitement for life, curious, secure, with ability to recover quickly from life’s stresses and one who is likable and likes others. using data from the er89 scale (table 1) the initial ‘split’ was made using the tertile deviation method instead of a mean split, shown in table 2. we aimed to evaluate the dependent variables against the independent variables in various combinations to compare the high resilience styles of male/female and gender versus family style. there were one or more missing values for those dependent variables in approximately 10% of the subjects, leaving us with 447 valid subjects of the original 495. the 447 subjects were divided equally into 3 groups 149 each. the groups were split based on a ‘frequency distribution’, and it was determined that the lowest one-third had a range of scores from 20–38 (based on the sum of all 14 dependent variables). the number in this ‘low group’ (lg) was 152, coming close to our target of 149. the high group (hg1) did not seem to come out as clean. when a range was used from 43–55, (the highest score) the number of subjects in this group was 164. when a range was used from 44–55 the number of subjects was 134 high group 2 (hg2). by choosing a scoring range that differed by 1 point 30 subjects were included or excluded. finally, in order to test for significant differences in the different permutations of grouping variables, two types of analyses were run: t-tests and analysis of variance (anova). the ttests were used to evaluate groups of two categories: gender, college type, family structure, and marital status. anova was used to evaluate groups of two or more categories. table 2 grouping using tertile deviation method statistics all groups low group (lg) high group 1 (hg1) high group 2 (hg2) count 447 152 164 134 mean 40.6 34.7 49 46.6 maximum 55 38 55 55 minimum 20 20 43 44 sum 18144 5279 7537 6247 variance 29 11.8 6.6 5.7 standard 5.4 3.4 2.6 2.4 note: a few respondents did not fit into a particular category that would have classified them within the lg, hg1 or hg2 since they fell outside the variables required to place them into one of these three groups. therefore, the total number of the lg, hg1 and hg2 on the count line do not total 447. results based on the tertile grouping method and using the hg1 results, over one-third (37%) of valid subjects (447) qualified as highly resilient. the respondents were then grouped by gender, age, type of education, family type (nuclear, extended) social status, educational bent, and marital status, to assess whether the various groups’ resilience scores differed significantly. the only groupings that produced significant results were, respectively, gender, family type, and college affiliation. gender: males (41.15%) had significantly higher resilience scores than females (39.66%) and (t = 3.10, p = 0.002) in the study. family type: extended families (41.34) exhibited higher resilience scores than nuclear families (40.04) and (t= – 2.61, p = 0.009). college affiliation: college of science students (41.06) had higher resilience scores than those students enrolled in the college of arts (39.95) (t = –2.11, p = 0.038) (tables 3 and 4). discussion as indicated earlier, higher scores (above 43) suggest above-average resilience qualities. such a person could be expected to possess a secure personality with energy, enthusiasm curiosity, ability to recover from stress, liking company of others and generous. as we expected, gender roles were important in the results; high female scores tended to indicate a person who was independent, flexible, and personally satisfied. high scoring males suggested someone who had warm relationships, who was ethical and responsible, with the ability to temper any feelings of hostility and antisocial destructive behaviours associated with low self-esteem and low self-confidence. the interpersonal achievement of control and reduced aggression is not highly associated with resilience in kuwaiti women, possessing lower levels of aggression. high scoring kuwaiti women would be expected to be independent, skilful in interpersonal relations, and not submissive. a high scoring male would be ethical, responsible in behaviour, conservative, predictable, consistent and able to accept societal limitations,18 while a high scoring female can be characterized as assertive with the ability to express feelings directly and a high regard for themselves, social poise and presence, while playful and without fear of recrimination. the resilient kuwaiti male scoring high can express his feeling directly, is cheerful and protective and has the capacity for warmth and intimacy while remaining relatively free of interpersonal hostility and mistrust. the members of nuclear families and those who have come from extended family situations are significantly notable because of the current transitions of modern kuwait society with respect to how the shifting family styles of the kuwaiti people has evolved. it is known that different type of socialization pressures experienced by girls can affect the form, style and a l n a s e r & s a n d m a n 114 knowledge as to their ability to negotiate through the world of interpersonal relations.13 kuwaiti men develop structures that help to modulate aggression, in turn helping to ensure a more successful socialization. there are sources of resilience that lie in kuwaiti society that have helped to support a survivability under duress, perhaps demonstrating an individual and cultural ability to thrive during misfortunes. a clear example of this unity and personality can be seen in the diwaniya in kuwait, which has historically played a prominent role in a society where family, tribal roots and friendship are highly valued. diwaniyas are informal gatherings of nonassociation groups, and fall into the same general category as tribes and families. they are unregulated and informal, highly fluid and somewhat hidden, although not secretive, and rely on personal interactional patterns of communication. diwaniyas are highly influential and informal meetings with friends, family members and others included, representing all socio-economic levels of society. diwaniyas function within the extended family networks, creating bonds of trust and loyalty. the socialization process in kuwait is an important part of personality resilience and is perhaps partially explained by the different roles prescribed by traditional kuwaiti society, its institutions, customs, and normative scripts. the arab culture has been considered throughout its history more as a collectivist culture, where a person’s identity is based more on the social system with greater dependence on their institutions and organizations. the influence of these organizations in turn helps provide order and security to individuals. the strength and resilience of kuwaiti personality could not be mentioned without including references to family and their personality qualities, as well. the traditional extended family has been predominantly associated with less than modern societies, especially those in which business and industry are viewed as less important than agriculture.21 historically, family life for early kuwaitis was very stable and consistent. beginning in ancient times, from which historical records are extant, to the present day, arab gulf families have appeared to remain the same, made up largely of the same personnel, structured along the same lines, fulfilling the same functions and commanding the same loyalties from its members.21 the dignity of women was guarded through veiling and seclusion. family commitment was so deep and complete that divorce was not considered to be a viable option and not an easy thing to come by. marriage was a social and economic agreement between families. early kuwaitis prized and valued the importance of the extended family, and during hard times or crisis, the extended family would come together to provide emotional and psychological support and encouragement for each other. marriages usually occurred at a very young age for women and at an older age for the men. family members were very dependent on each other for their economic survival, mainly functioning as an economic, social and psycho table 3 ttest results groups resilience sd t-value p-value gender 2.55 0.011 male (256) 41.15 5.47 5.19 female (191) 39.84 5.19 college –1.86 –0.064 arts (198) 40.02 5.41 science (201) 41.03 5.55 family structure (total) –1.8 0.072 nuclear (256) 40.22 5.53 extended (176) 41.17 5.18 family structure (male) 0.15 0.884 nuclear (130) 41.26 5.57 extended (119) 41.26 5.46 family structure (female) –2.53 0.12 nuclear (126) 39.14 5.29 extended (57) 41.19 4.6 marital status (total) –0.03 0.975 single (331) 40.58 5.31 married (113) 40.6 5.58 marital status (male) –0.55 0.584 single (178) 41.03 5.41 married (75) 41.44 5.56 marital status (female) 1.19 0.236 single (153) 40.07 5.15 married (38) 38.95 5.33 table 4 analysis of variance (anova) results groups resilience sd t-value p-value education 1.39 0.200 first year (80) 41.34 5.82 second year (137) 40.58 5.53 third year (95) 39.71 5.17 fourth year (127) 40.74 5.19 age (total) 0.75 0.474 17–20 years (149) 40.49 5.59 21–24 years (235) 40.46 5.23 25 and above (58) 41.4 5.37 age (male) 0.18 0.830 17–20 years (51) 41.39 6.16 21–24 years (146) 41.46 5.44 25 and above (56) 41.46 5.44 age (female) 0.19 0.820 17–20 years (98) 40.02 5.24 21–24 years (89) 39.56 5.04 25 and above (2) 39.53 0.54 r e s i l i e n c e i n k u w a i t i s 115 logical unit. a son could usually look forward to taking on the role of head of the family business and inheriting the family land. the family would provide the education and would regulate the marriages. of late, however, the kuwaiti society has been undergoing tremendous pressure from social changes resulting from the effects of urbanization, education and the war with iraq. the rapid pace of this change has impacted most specifically upon the family. the traditional son/daughter now grows up in a society that values patriotism and career development. emancipation of women is another powerful force directing the current course of the kuwaiti society. even though marriages are still arranged, sons and daughters are now consulted. while men follow the tradition of marrying relatively late in life, women, who once married very young, are now older when they marry. the traditional practice and preference to marry within the family has declined, and a slow, noticeable shift in where the couples choose to live after marriage has been observed. the main psychological ties that bind families together have remained alive even though enormous social changes have occurred through the years. decisionmaking is also done in a more cooperative manner involving both husband and wife. as a result, the divorce rate and the practice of polygamy have declined. kuwaiti citizens now exercise their own personal choice in selecting a marriage partner resulting from physical attraction and love.22 in short, despite traditions remaining strong, a measure of social change has occurred, with social stratification becoming less determined by family origin and tribal affiliation and more by personal achievement and other tangible forms of success. our study revealed that the added responsibilities of kuwaiti married life have created a stronger, flexible person who is accommodative of change. conclusion after a review of available historical records, we have perhaps found the origin of the contemporary resilient kuwaiti personality. because there were no scientific studies done in early kuwaiti history, we felt compelled to rely upon the use of available archival records in an attempt to construct the basic ingredients of the early kuwaiti personality. we decided the most accurate method of obtaining this information would be through the use of the socio-historical perspective. prior to the discovery of oil, kuwaitis led rugged lives, characterised by scarcity and hard work. the first guiding principles for kuwaiti life were based on the belief in simplicity, spontaneity and social cohesion. we discovered that the early kuwaiti personality consisted of included components of what we now call a resilient personality or resilience. this study helped identify some of the underlying qualities that characterize the kuwaiti resilience and adaptability. our results have yielded a reliable representation of the long-term structural nature of pure resilience in the kuwaiti population. referring to the er89 scores, 67.6% of the answers fell into the ‘applies somewhat’ and ‘applies strongly’ categories of the scale, indicating strong resilience qualities. however it is not possible at this stage to draw concrete conclusions as to how those involved in this study compare to other peoples in the arabian gulf region. we believe that this study does, however, demonstrate certain unique aspects of the kuwaiti people. therefore, the scope of this study did not include the adaptation of the subjects to the invasion experience. future studies should be directed toward personality resilience and adaptations of subjects exposed to the invasion experience of 1990. another potential area for study is ptsd among military personnel. references 1. selye ha. syndrome produced by diverse nocuous agents. nature 1936, 138, 32. 2. campas be. coping with stress during childhood and adolescence. psychol bull 1987, 101, 393–403 3. cowen el, wyman pa, work wc. and parker gr.. the rochester child resilience project: overview and summary of first year findings. dev psychopathol 1990, 5, 517–28 4. garmezy n. children in poverty: resilience despite risk. psychiatry, 1993, 56, 127–36. 5. werner e.e, smith rs. vulnerable but invincible. a study of resilient children, mcgraw-hill, new york 1982 6. garmezy n. resiliency and vulnerability to adverse developmental outcomes. associated with poverty. am behav sci 1991, 344, 416–30. 7. rutter m. protective factors in children’s responses to stress and disadvantage. in: kent mw and rolf je (eds.) primary prevention of psychopathology: social competence in children (vol 3) 1979, university press of new england hanover, nh. pp: 49–74. 8. rutter m. psychosocial resilience and protective mechanisms. am j orthopsychiatry 1987, 373, 316–29. 9. egeland b, carlson e, stroufe la. resilience as process. devel psychol 1993, 5, 517–28. 10. block j. an experimental investigation of the construct of ego control. unpublished doctoral dissertation. stanford university. 1950. 11. block jh. an experimental study of topological representation of ego structure. unpublished doctoral dissertation. stanford university. 1950. 12. block j, kremen am. iq and ego-resiliency: conceptual and empirical connections and separateness. j pers soc psychol 1996, 70, 349–61. 13. block j, block jh. the california child q-set, consulting psychologists press, palo alto, california, 1980. 14. hauser st, vieyra mab, jacobson am, wertlieb d. vulnerability and resilience in adolescence: views from the family. j early adolescence 1985, 5, 81–90 15. masten as, best km, garmezy n. resilience and dea l n a s e r & s a n d m a n 116 velopment: contributions from the study of children who overcome adversity. dev psychopathol 1990, 2, 425–44 16. milgram na, palti g. psychosocial characteristics of resilient children. j res pers 1993, 27, 207–21 17. rutter m. psychosocial resilience and protective mechanisms. in rolf j, masten a, cicchetti d, nuechterlein k, weintraub s (eds), risk and protective factors in the development of psychopathology, cambridge university press, cambridge 1990. pp: 181–214. 18. block j, kremen a. iq and ego resiliency: conceptual and empirical connections and separateness. j pers soc psychol, 1996, 70, 349–61. 19. zuckerman m, kuhlman dm, joireman j, teta p, kraft m. a comparison of three structural models for personality: the big three, the big five and the alternative five. j pers soc psychol 1993, 65, 757–68. 20. al-naser f. the social and political roles of diwaniyas in kuwait. unpublished manuscript. 1998. 21. patai r. golden river to golden road: society, culture, and change in the middle east. university of pennsylvania press, philadelphia 1962. 22. al thakeb f. the kuwaiti family: today and yesterday. unpublished doctoral dissertation, ohio state university. 1974. evaluating resilience factors in the face of �traumatic events in kuwait method table 1 table 1 table 2 table 2 results discussion ttest results table 4 analysis of variance (anova) results conclusion references psychological and physiological complications of post-burn patients in pakistan a narrative review meher b. ali and *mashal b. ali sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 8–13, epub. 28 feb 22 submitted 7 oct 20 revisions req. 1 dec 20 & 27 jan 21; revisions recd. 13 jan & 4 mar 21 accepted 9 mar 21 department of medicine, dow medical college, dow university of health sciences, karachi, pakistan *corresponding author’s e-mail: mashalali99@hotmail.com according to world health organization, burn injuries account for 180,000 deaths annually, with the majority of such injuries occurring in lowand middle-income countries.1 pakistan has a burn mortality rate of 6.5%, with a burns centre in karachi reporting an exceptionally high mortality rate of 55.9%, which may be due to the lack of adequate infrastructure needed to manage burn patients.2,3 however, it is also possible that the more severely affected patients are admitted to the burns centre causing a difference in the general burn mortality rate and the mortality rate in rehabilitation centres. females, children and people living in poverty are at particular risk for burn injuries and the most common cause of burns are accidental injuries at home or the workplace.1 although these are not usually fatal, they carry a significant morbidity risk. according to a recent study conducted at the burns center, civil hospital karachi, almost 94% of burns were accidental and 1.5% were suicidal.4 another study reported accidental burns in 83.78% of their sample while 9.88% were homicidal and 6.34% were of a suicidal nature.5 public and private sector hospitals throughout pakistan face a large influx of burn patients, which places significant burden on the healthcare system.2 despite a decrease in mortality, morbidity from burns is a significant cause of disability-adjusted life-years lost in lowand middle-income countries.1 in pakistan, there is a shortage of burn rehabilitation centres.6 civil hospital karachi is the only hospital in the sindh province that has a burns centre, catering to patients from all parts of the province.7 baluchistan province does not have a single burn rehabilitation centre. hence, burn victims have no choice but to travel to karachi for treatment. in a province such as khyber pakhtunkhwa, which also caters to patients from tribal areas, the lack of burns centres is a glaring deficiency in its health infrastructure as one of the major burn units after three years of construction remains nonfunctional.8 there are only four burn units in punjab, the most populated province of pakistan, and most have limited resources and beds.9 rehabilitative medicine is still a relatively new concept in pakistan; emphasis is only on treating acute injury rather than preventing future complications.10 in pakistan, there is generally a lack of awareness of burn victims and the challenges they have to endure.11 the long-term effects are not just limited to the physical complications of burn injuries such as scarring or contractures; they also include the, at times more severe and debilitating, psychological ones (e.g. depression and phobias). treatment, therapy and effective rehabilitation of burn patients can drastically increase if doctors of pakistan and other third-world countries become aware of these issues. physicians must start looking beyond the hospital-confined treatment given to burn patients and start developing insight and sympathy about the future of the patients after they have gone home. this concise literature review aimed to outline the important physiological and psychological after-effects of burn injuries and their risk factors that clinicians must take into account during the treatment, discharge, followup and rehabilitation of burn patients. review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.118 abstract: pakistan has a burn mortality rate of 6.5%, with a considerable percentage of survivors suffering from long-term complications due to lack of rehabilitation. this review aimed to outline the important physiological and psychological after-effects of burn injuries. google scholar, medline® and pubmed were searched for relevant articles between march and may 2020. psychological complications of burns include depression, post-traumatic stress disorder, anxiety, sleep disturbance, phobias, guilt, suicidal thoughts and personality changes. physiological complications include scarring, contractures, pain, muscle wasting and hypothermia; other complications include infections. this review revealed a scarcity of literature regarding the prevalence and impact of long-term complications in post-burn patients. a lack of rehabilitative services and high rate of post-burn complications in pakistan were found. rehabilitation of burn patients should be a continuation of active treatment and should begin from the day of admission, to reduce the morbidity and improve the quality of life of burn patients. keywords: burns; physiology; psychology; rehabilitation; quality of life; pakistan. https://creativecommons.org/licenses/by-nd/4.0/ meher b. ali and mashal b. ali review | 9 data collection a literature review on the possible complications that occur in burn patients was carried out by a compre hensive search of the databases google scholar, pubmed and medline® between march and may 2020. the search algorithms used were: ‘post-burn complications’, ‘quality of life in burn patients’, ‘psychological complic ations in burn patients’, ‘physiological complications in burn patients’, ‘rehabilitation of burn patients' and other variations. relevant publications including liter ature reviews, systematic reviews, meta-analysis studies, newspaper articles, datasheets and cross-sectional studies published between 1970 and 2020 were included. only articles written in english were included. full articles were read after screening the titles and abstracts. each article was included in the review on the consensus of the authors; finally, a total of 59 articles were included. psychological complications psychological problems manifest most visibly 1–4 years after discharge, as discussed in ter smitten et al.’s study.12 more than half of diagnosed patients fell within the category of diagnostic and statistical manual of mental disorders, 5th edition axis i psychiatric disorders (consisting of all disorders except mental retardation and personality disorders) within 2–4 years after the burn injury.12 a recent study conducted at a tertiary care burns unit in karachi reported a depression prevalence of 31.9% in burn patients.13 depression is a major factor that affects a patient’s quality of life. it was found that depression scores remained stable at one month, one year and two years post-burn.13 this may also cause reduced body functioning.14 the visibility of the burn injury leads to a higher occurrence of depression and feelings of dissatisfaction with facial disfigurement being most valuable in the estimation of psychological outcome.15–17 total body surface area (tbsa) of the burn(s) does not significantly affect depression scores according to a recent study conducted in pakistan.17 post-traumatic stress disorder (ptsd) has been found in up to 45% of burn survivors one year after the initial injury.18 talking specifically about pakistan, in a recent study, more than half of the burn population was found to be suffering from ptsd; these high statistics may be due to stigmatisation and lack of mental health care.19 in another study from pakistan, it was found that ptsd symptoms are more severe in the female population due to decreased resilience among women.20 low socioeconomic condition of the patient is a risk factor for the development of ptsd.21 according to roca et al.’s study, individual symptoms of ptsd were more common in post-burn patients than the fully expressed syndrome; however, the prevalence of the complete syndrome has a delayed onset occurring mostly within 3–4 months after discharge.22,23 the presenting symptoms include those that meet ptsd criterion c (i.e. emotional numbing and symptoms of avoidance such as an inability to recall events and estrangement from others) and ptsd criterion d (i.e. increased arousals such as heightened irritability and hypervigilance).22 ptsd is a greatly neglected sector of medicine and is underdiagnosed by doctors.24 in follow-up cases, anxiety is a common pres enting complaint; a study showed 37% of burn patients fell within the criteria of hospital anxiety and depression scale (hads).16 patients scoring 8–10 on hads were regarded as borderline and those scoring more than 11 were regarded as actual cases. increased size/intensity of burn injury increased the severity of anxiety.16 in a recent study conducted in pakistan, the entire burns patient sample was found to have anxiety, using the hamilton anxiety rating scale, with severe anxiety more prevalent in deep burn injuries.17 sleep is an important factor in the determination of the effects of a traumatic event on an individual since the quality of sleep is inevitably affected.25 sleep table 1: complications in post-burn patients post-burn complication psychological depression* post-traumatic stress disorder* anxiety* sleep disturbance phobias personality changes guilt suicidal thoughts physiological scarring* contractures* chronic inflammation muscle wasting hypothermia pain infection other *indicates common complication. psychological and physiological complications of post-burn patients in pakistan a narrative review 10 | squ medical journal, february 2022, volume 22, issue 1 disturbance in burn patients consists of lack of deep sleep, nightmares and alterations in sleep patterns and sleep onset.25 according to boeve et al.’s study, 87% of burn patients had frequent night-time awakenings.25 in lee et al.’s study, almost half the patients complained of sleep dissatisfaction 36 months after the injury.26 agoraphobias, with or without panic disorders, and social phobias may also be developed in burn patients, albeit not as much as ptsd, anxiety and depression. they may be found up to 1–2 years postburn.12 the most prevalent among the phobias are specific phobias that manifest after discharge and may increase the comorbidity in burn patients.12 personality changes appearing in burn patients are usually classified as neuropsychiatric complications and may be due to the result of direct hypoxic injury to the brain.27 in a study on neuropsychiatric complications in burn patients, it was found that severe regression, a form of personality change, occurs in approximately 20% of adult burn patients and is characterised by child-like and primitive behaviour patterns such as throwing tantrums.28 in a recent systemic review by kornhaber et al., the feeling of guilt, shame and self-blame were emphasised as important manifesting problems among burn survivors.29 one of the most extreme psychological sequelae of burn injuries is suicide.30,31 according to van loey and van son’s extensive systemic review, 18 studies showed that previous psychiatric history such as depression, anxiety or mood disorders had the most impact on post-burn mental health changes. subjective factors such as coping style, personality traits and patient’s perception have an effect on post-burn mental health changes.18 social support and family attitude also considerably affect the intensity of psychological sequelae in burn patients, especially in children.32 in a study conducted in pakistan, it was found that social support was extremely lacking in the lives of burn patients, both from family and friends, which undoubtedly hinders the healing process.33 the most common form of coping strategy used by burn patients is problemfocused coping which contributes positively to posttraumatic growth such as appreciation of life and personal strength.18,34 problem-focused coping or active coping consists of identifying the stressor, making a plan, taking an action and seeking help/ assistance for instrumental reasons, contributing to a positive change and helping the burn patient in the long-run.35 according to fong’s study, women tend to gravitate more towards emotional-coping, which involves seeking social support for moral backing, sympathy and understanding, which possibly may hinder the long-term psychological adjustment if used for too long.35,36 physiological complications scarring is found in all types of burns, except in superficial or first-degree burns, and can only be reduced by measures such as plastic surgery.37 acc ording to gangemi et al.’s study, the most commonly used method to reduce a burn scar is excision and coverage with autologous skin grafts.38 according to a recent systemic review on the incidence of hypertrophic scarring in burn patients, the prevalence of scarring varies from 32–72%.39 keloids are scars that grow and extend beyond the borders of the original burn wound, are often painful and pruritic, and never regress spontaneously; on the other hand, hypertrophic scars stay confined within the wound and ultimately regress.40 in studies devoted solely to hypertrophic and keloid scarring, it is stated that these are the greatest challenges that post-burn patients face, which significantly reduces the quality of life of the burn patient.40,41 according to goel and shrivastava’s study, post-burn scars may be mature/ immature, stable/unstable and depigmented/hyperpigmented, but regardless of the nature, they are inevitable after burn injury.37 another study concludes that pathological scars, consisting of hypertrophic scars, hypertrophic scars with contractures and pure contractures, have an overall prevalence of 77%.38 contracture development is a phenomenon in which the skin contracts over the wound to reduce its exposure site.37 in a recent study it was found that contracture severity mainly depends on the size of burn injury and length of hospital stay.42 development of this post-burn complication is a common finding among burn patients in pakistan, as is documented in saaiq et al.’s study.43 according to their study, there is a high prevalence due to inadequate initial management of burn wounds such as lack of initiation of appropriate surgery, physiotherapy and antideformity splinting, all leading to early contracture development.43 with regards to chronic inflammation and metabolic changes in post-burn patients, jeschke et al.’s study displayed the persistence of these physiological reactions as long as three years after the initial burn injury.44 cytokines, particularly interleukin (il)-6, il-8, g-csf, mcp-1 and acute-phase proteins, are considerably increased in burn patients during admission as well as after discharge.44 in another study, it was ascertained that burn patients stay in a state of chronic inflammatory response.45 meher b. ali and mashal b. ali review | 11 muscle wasting is defined as a loss of at least 5–10% of the muscle mass; it is a common physiological complication in burn patients, occurring due to hyper-metabolism and altered protein kinetics such as increased protein breakdown and decreased protein synthesis.46 managing post-burn hyper-metabolism is essential in decreasing burn-related muscle cata bolism.46 according to hart et al.’s study, a larger burn wound area, increased weight of the patient and a delay in surgery increases the risk of muscle catabolism.47 in williams et al.’s study, it was established that increased production of catecholamines in burn patients resulted in the development of severe cardiac stress consisting of elevated heart rate, stroke volume, cardiac work, rate pressure product, myocardial oxygen consumption and cardiac index; these derailed values lasted as long as two years after the burn injury.48 hypothermia is also an important physiological complication in burn patients due to loss of skin which is the body’s main temperature regulator.49 some of the factors affecting hypothermia in burn patients are the tbsa of the burn injury, anaesthesia and surgery duration.49 burn patients presenting with hypothermia have an increased risk of mortality.50 table 1 summarises the complications in post-burn patients. pain according to gauffin et al.’s study, one third of the burn patients still felt pain 2–7 years after the initial burn injury. this affected the patients’ general activity, mood, work and health related quality of life as measured by the euroqol five-dimensional instrument.51 burn pain is affected by factors such as tbsa and the location of the burn. the severity does not significantly depend on gender, age or time of injury.51 treatment procedures themselves also give rise to severe pain which affects successful rehabilitation after discharge and also increases the patients’ anxiety levels.52 infection according to two different studies, infection is a major complication in hospitalised burn patients, that is influenced by the length of hospital stay, decreased immunity, the number of catheters inserted and tbsa of burn injury.53,54 the mechanism of this phenomenon is that thermal energy in burns induces a state of immunosuppression which leads to increased susceptibility to infections.55 in öncül et al.’s study, nearly half of all burn wounds cultured positive for microorganisms such as pseudomonas aeruginosa, staphylococcus epidermidis, methicillinsensitive strains of staphylococcus, enterococcus and escherichia coli.53 in a recent study conducted in pakistan, it was found that children are most afflicted due to comparatively decreased immunity and resilience.56 post-burn infections, rather than the burn injury itself, may be a cause of mortality in burn patients.57 in another study conducted in pakistan, sepsis was the most common cause of death in burn patients.58 in pakistan, the topic of burns is under-researched and basic knowledge about complications that are bound to arise in burn patients after they have been discharged and treated is even rarer.2 countless studies on epidemiology and hospital stay management have been reported, however, little information has been compiled about the physiological and psychological complications of burns which play a major role in effective rehabilitation of patients. this literature review provides a concise framework of the main complic ations that occur in burn patients. mental health screening and early intervention in burn patients is recommended along with burn preventive sessions.59 furthermore, there is a pressing need to enhance the development of rehabilitation services. the scarcity of burn rehabilitation centres in pakistan supports the importance of this study. the already existing units should be fully functioning with international protocols. consistent follow-up in multidisciplinary burn clinics is suggested as this is a predictor of better long-term results and social adjustments. it is hoped that through this review the plight of burn patients and the importance of their rehabilitation can be highlighted. conclusion this review summarises various psychological and physiological complications in burn patients and reveals a scarcity of research on the prevalence and impact of long-term burn complications in pakistan. lack of rehabilitative services and the high rate of post-burn complications (depression, ptsd, anxiety, scarring and contractures are most prevalent) in pakistan have been highlighted. rehabilitation of burn patients should be a continuation of active treatment and should begin from the day of admission to reduce morbidity and improve the quality of life of burn patients. a u t h o r s’ c o n t r i b u t i o n meba and maba took part in designing, drafting and revising the review. meba and maba were responsible for data collection and analysis of the data. both authors approved the final version of the manuscript. psychological and physiological complications of post-burn patients in pakistan a narrative review 12 | squ medical journal, february 2022, volume 22, issue 1 references 1. world health organization. fact sheets burns 2018. from: https://www.who.int/news-room/fact-sheets/detail/burns accessed: mar 2021. 2. siddiqui e, zia n, feroze a, awan s, ali a, razzak j, et al. burn injury characteristics: findings from pakistan national emergency department surveillance study. bmc emerg med 2015; 15:s5. https://doi.org/10.1186/1471-227x-15-s2-s5. 3. afzal i, naz r, afzal mk, mughal mi. epidemiology and mortality of burns in karachi. med forum 2014; 25:36–41. 4. anwer mo, rauf mu, chishti n, anwer s. etiology and charact eristics of burn injuries in patients admitted at burns center, civil hospital karachi. indian j burns 2016; 24:36–40. https:// doi.org/10.4103/0971-653x.195535. 5. ahmed a, asad s, khan r, ibrahim m, siddique m. epidem iology of burns and its relation with morbidity and mortality in ayub teaching hospital. pak j surg 2016; 32:156–61. 6. mehsud r. in pakistan, shortage of burn centers haunts victims. from: www.newslens.pk/in-pakistan-shortage-of-burn-centers -haunts-victims accessed: mar 2021. 7. ppi. slow burn lack of burn centers leaves sindh in limbo. from: www.pakistantoday.com.pk/2015/03/17/slow-burn-lack of-burns-centres-leaves-sindh-in-limbo/ accessed: mar 2021. 8. dawn. no burns centre in kp. from: www.dawn.com/news/ 1343960 accessed: mar 2021. 9. ousat a. dearth of burn units hurting punjab. from: www. tribune.com.pk/stor y/1632480/treatment-facility-dearthburn-units-hurting-punjab accessed: mar 2021. 10. world health organization. overview of rehabilitation services in health system perspective: rehabilitation 2030: a call for action. from: who.int/disabilities/care/1130-pakistan. pdf accessed: mar 2021. 11. ali mb, ali mb. burns awareness day letter to editors. j pak med assoc 2019; 69:605. 12. ter smitten mh, de graaf r, van loey ne. prevalence and comorbidity of psychiatric disorders 1–4 years after burn. burns 2011; 37:753–61. https://doi.org/10.1016/j.burns.2010.12.018. 13. ali h, pervaiz m. depression in adults post burn injury: a descriptive study conducted in the burn centre of a tertiary care hospital in karachi. ann burns fire disasters 2019; 32:33–6. 14. ullrich pm, askay sw, patterson dr. pain, depression, and physical functioning following burn injury. rehabil psychol 2009; 54:211–16. https://doi.org/10.1037/a0015613. 15. williams ee, griffiths ta. psychological consequences of burn injury. burns 1991; 17:478–80. https://doi.org/10.1016/03054179(91)90075-r. 16. shakespeare v. effect of small burn injury on physical, social and psychological health at 3–4 months after discharge. burns 1998; 24:739–44. https://doi.org/10.1016/s0305-4179(98)00098-9. 17. jain m, khadilkar n, de sousa a. burn-related factors affecting anxiety, depression and self-esteem in burn patients: an exploratory study. ann burns fire disasters 2017; 30:30–4. 18. van loey ne, van son mj. psychopathology and psychological problems in patients with burn scars: epidemiology and manage ment. am j clin dermatol 2003; 4:245–72. https://doi.org/10.216 5/00128071-200304040-00004. 19. waqas a, raza n, zahid t, rehman a, hamid t, hanif a, et al. predictors of post-traumatic stress disorder among burn patients in pakistan: the role of reconstructive surgery in post-burn psychosocial adjustment. burns 2018; 44:620–5. https://doi. org/10.1016/j.burns.2017.09.012. 20. bibi a, kalim s, khalid ma. post-traumatic stress disorder and resilience among adult burn patients in pakistan: a cross-sectional study. burns trauma 2018; 6:8. https://doi.org/10.1186/s41038018-0110-7. 21. giannoni-pastor a, eiroa-orosa fj, fidel kinori sg, arguello jm, casas m. prevalence and predictors of posttraumatic stress symptomatology among burn survivors: a systematic review and meta-analysis. j burn care res 2016; 37:e79–89. https:// doi.org/10.1097/bcr.0000000000000226. 22. roca rp, spence rj, munster am. posttraumatic adaptation and distress among adult burn survivors. am j psychiatry 1992; 149:1234–8. https://doi.org/10.1176/ajp.149.9.1234. 23. sadeghi-bazargani h, maghsoudi h, soudmand-niri m, ranjbar f, mashadi-abdollahi h. stress disorder and ptsd after burn injuries: a prospective study of predictors of ptsd at sina burn center, iran. neuropsychiatr dis treat 2011; 7:425–9. https:// doi.org/10.2147/ndt.s23041. 24. el hamaoui y, yaalaoui s, chihabeddine k, boukind e, moussaoui d. post-traumatic stress disorder in burned patients. burns 2002; 28:647–50. https://doi.org/10.1016/s0305-4179(02)00100-6. 25. boeve sa, aaron la, martin-herz sp, peterson a, cain v, heimbach dm, et al. sleep disturbance after burn injury. j burn care rehabil 2002; 23:32–8. https://doi.org/10.1097/00004630200201000-00007. 26. lee af, ryan cm, schneider jc, kazis le, li nc, rose m, et al. quantifying risk factors for long-term sleep problems after burn injury in young adults. j burn care res 2017; 38:e510–20. https://doi.org/10.1097/bcr.0000000000000315. 27. varney nr, ju d, shepherd js, kealey gp. long-term neuropsycho logical sequelae of severe burns. arch clin neuropsychol 1998; 13:737–49. https://doi.org/10.1016/s0887-6177(98)00011-0. 28. andreasen nj. neuropsychiatric complications in burn patients. int j psychiatry med 1974; 5:161–71. https://doi.org/10.2190/ fatv-k0dw-12m7-j9bh. 29. kornhaber r, childs c, cleary m. experiences of guilt, shame and blame in those affected by burns: a qualitative systematic review. burns 2018; 44:1026–39. https://doi.org/10.1016/j. burns.2017.11.012. 30. onarheim h, vindenes ha. high risk for accidental death in previously burn-injured adults. burns 2005; 31:297–301. https://doi.org/10.1016/j.burns.2004.10.010. 31. kimmo t, jyrki v, sirpa as. health status after recovery from burn injury. burns 1998; 24:293–8. https://doi.org/10.1016/ s0305-4179(98)00007-2. 32. noronha do, faust j. identifying the variables impacting postburn psychological adjustment: a meta-analysis. j pediatr psychol 2007; 32:380–91. https://doi.org/10.1093/jpepsy/jsl014. 33. waqas a, naveed s, bhuiyan mm, usman j, inam-ul-haq a, cheema ss. social support and resilience among patients with burn injury in lahore, pakistan. cureus 2016; 8:e867. https:// doi.org/10.7759/cureus.867. 34. rosenbach c, renneberg b. positive change after severe burn injuries. j burn care res 2008; 29:638–43. https://doi. org/10.1097/bcr.0b013e31817de275. 35. carver cs, scheier mf, weintraub jk. assessing coping strategies: a theoretically based approach. j pers soc psychol 1989; 56:267–83. https://doi.org/10.1037/0022-3514.56.2.267. 36. fong j. a study of self-monitoring processes and coping behaviour in burns victims. burns 1997; 23:s8–11. https://doi. org/10.1016/s0305-4179(97)90094-2. 37. goel a, shrivastava p. post-burn scars and scar contractures. indian j plast surg 2010; 43:s63–71. https://doi.org/10.410 3/0970-0358.70724. 38. gangemi en, gregori d, berchialla p, zingarelli e, cairo m, bollero d, et al. epidemiology and risk factors for pathologic scarring after burn wounds. arch facial plast surg 2008; 10:93–102. https://doi.org/10.1001/archfaci.10.2.93. 39. lawrence jw, mason st, schomer k, klein mb. epidemiology and impact of scarring after burn injury: a systematic review of the literature. j burn care res 2012; 33:136–46. https://doi. org/10.1097/bcr.0b013e3182374452. https://doi.org/10.1186/1471-227x-15-s2-s5 https://doi.org/10.4103/0971-653x.195535 https://doi.org/10.4103/0971-653x.195535 https://doi.org/10.1016/j.burns.2010.12.018 https://doi.org/10.1037/a0015613 https://doi.org/10.1016/0305-4179(91)90075-r https://doi.org/10.1016/0305-4179(91)90075-r https://doi.org/10.1016/s0305-4179(98)00098-9 https://doi.org/10.2165/00128071-200304040-00004 https://doi.org/10.2165/00128071-200304040-00004 https://doi.org/10.1016/j.burns.2017.09.012 https://doi.org/10.1016/j.burns.2017.09.012 https://doi.org/10.1186/s41038-018-0110-7 https://doi.org/10.1186/s41038-018-0110-7 https://doi.org/10.1097/bcr.0000000000000226 https://doi.org/10.1097/bcr.0000000000000226 https://doi.org/10.1176/ajp.149.9.1234 https://doi.org/10.2147/ndt.s23041 https://doi.org/10.2147/ndt.s23041 https://doi.org/10.1016/s0305-4179(02)00100-6 https://doi.org/10.1097/00004630-200201000-00007 https://doi.org/10.1097/00004630-200201000-00007 https://doi.org/10.1097/bcr.0000000000000315 https://doi.org/10.1016/s0887-6177(98)00011-0 https://doi.org/10.2190/fatv-k0dw-12m7-j9bh https://doi.org/10.2190/fatv-k0dw-12m7-j9bh https://doi.org/10.1016/j.burns.2017.11.012 https://doi.org/10.1016/j.burns.2017.11.012 https://doi.org/10.1016/j.burns.2004.10.010 https://doi.org/10.1016/s0305-4179(98)00007-2 https://doi.org/10.1016/s0305-4179(98)00007-2 https://doi.org/10.1093/jpepsy/jsl014 https://doi.org/10.7759/cureus.867 https://doi.org/10.7759/cureus.867 https://doi.org/10.1097/bcr.0b013e31817de275 https://doi.org/10.1097/bcr.0b013e31817de275 https://doi.org/10.1037/0022-3514.56.2.267 https://doi.org/10.1016/s0305-4179(97)90094-2 https://doi.org/10.1016/s0305-4179(97)90094-2 https://doi.org/10.4103/0970-0358.70724 https://doi.org/10.4103/0970-0358.70724 https://doi.org/10.1001/archfaci.10.2.93 https://doi.org/10.1097/bcr.0b013e3182374452 https://doi.org/10.1097/bcr.0b013e3182374452 meher b. ali and mashal b. ali review | 13 40. seifert o, mrowietz u. keloid scarring: bench and bedside. arch dermatol res 2009; 301:259–72. https://doi.org/10.1007/ s00403-009-0952-8. 41. finnerty cc, jeschke mg, branski lk, barret jp, dziewulski p, herndon dn. hypertrophic scarring: the greatest unmet challenge after burn injury. lancet 2016; 388:1427–36. https:// doi.org/10.1016/s0140-6736(16)31406-4. 42. godleski m, lee af, goverman j, herndon dn, suman oe, kowalske kj, et al. quantifying contracture severity at hospital discharge in adults: a burn model system national database study. j burn care res 2018; 39:604–11. https://doi.org/10.1093/ jbcr/irx027. 43. saaiq m, zaib s, ahmad s. the menace of post-burn contractures: a developing country’s perspective. ann burns fire disasters 2012; 25:152–8. 44. jeschke mg, gauglitz gg, kulp ga, finnerty cc, williams fn, kraft r, et al. long-term persistance of the pathophysiologic response to severe burn injury. plos one 2011; 6:e21245. https://doi.org/10.1371/journal.pone.0021245. 45. greenhalgh dg, saffle jr, holmes jh 4th, gamelli rl, palmieri tl, horton jw, et al. american burn association consensus conf erence to define sepsis and infection in burns. j burn care res 2007; 28:776–90. https://doi.org/10.1097/bcr.0b013e318 1599bc9. 46. pereira c, murphy k, jeschke m, herndon dn. post burn muscle wasting and the effects of treatments. int j biochem cell biol 2005; 37:1948–61. https://doi.org/10.1016/j.biocel.2005.05.009. 47. hart dw, wolf se, chinkes dl, gore dc, mlcak rp, beauford rb, et al. determinants of skeletal muscle catabolism after severe burn. ann surg 2000; 232:455–65. https://doi.org/10.1097/000 00658-200010000-00001. 48. williams fn, herndon dn, suman oe, lee jo, norbury wb, branski lk, et al. changes in cardiac physiology after severe burn injury. j burn care res 2011; 32:269–74. https://doi. org/10.1097/bcr.0b013e31820aafcf. 49. boorom ja. heat loss in burn patients. aorn j 1973; 17:80–5. https://doi.org/10.1016/s0001-2092(07)60305-6. 50. l. trembley a, page d. are we keeping our burn patients warm enough? jems 2014. from: www.jems.com/2014/09/15/arewe-keeping-our-burn-patients-warm-en/ accessed: mar 2021. 51. gauffin e, öster c, sjöberg f, gerdin b, ekselius l. health-related quality of life (eq-5d) early after injury predicts long-term pain after burn. burns 2016; 42:1781–8. https://doi.org/10.10 16/j.burns.2016.05.016. 52. deniz s, arslan s. pain and anxiety in burn patients. int j caring sci 2017; 10:1723–7. 53. öncül o, öksüz s, acar a, ülkür e, turhan v, uygur f, et al. nosocomial infection characteristics in a burn intensive care unit: analysis of an eleven-year active surveillance. burns 2014; 40:835–41. https://doi.org/10.1016/j.burns.2013.11.003. 54. appelgren p, björnhagen v, bragderyd k, jonsson ce, ransjö u. a prospective study of infections in burn patients. burns 2002; 28:39–46. https://doi.org/10.1016/s0305-4179(01)00070-5. 55. church d, elsayed s, reid o, winston b, lindsay r. burn wound infections. clin microbiol rev 2006; 19:403–34. https:// doi.org/10.1128/cmr.19.2.403-434.2006. 56. uddin mn, jabeen b, saadat mehmood m, rizwan m. characterization of isolated bacteria from burn patients and its susceptibility against different antibiotics in district swat. pure appl biol 2018; 7:121–32. https://doi.org/10.19045/bsp ab.2018.70015. 57. krishnan p, frew q, green a, martin r, dziewulski p. cause of death and correlation with autopsy findings in burns patients. burns 2013; 39:583–8. https://doi.org/10.1016/j.burns.2012.09.017. 58. chaudhry ia. burns: frequency and mortality related to various age groups. j surg pakistan 2009; 14:67–71. 59. idrees s, gul i, faize fa, akhtar m. psychological reactions, social support, and coping styles in pakistani female burn survivors. j burn care res 2017; 38:e934–43. https://doi.org/10.1097/ bcr.0000000000000525. https://doi.org/10.1016/s0140-6736(16)31406-4 https://doi.org/10.1016/s0140-6736(16)31406-4 https://doi.org/10.1093/jbcr/irx027 https://doi.org/10.1093/jbcr/irx027 https://doi.org/10.1371/journal.pone.0021245 https://doi.org/10.1097/bcr.0b013e3181599bc9 https://doi.org/10.1097/bcr.0b013e3181599bc9 https://doi.org/10.1016/j.biocel.2005.05.009 https://doi.org/10.1097/00000658-200010000-00001 https://doi.org/10.1097/00000658-200010000-00001 https://doi.org/10.1097/bcr.0b013e31820aafcf https://doi.org/10.1097/bcr.0b013e31820aafcf https://doi.org/10.1016/s0001-2092(07)60305-6 https://doi.org/10.1016/j.burns.2016.05.016 https://doi.org/10.1016/j.burns.2016.05.016 https://doi.org/10.1016/j.burns.2013.11.003 https://doi.org/10.1016/s0305-4179(01)00070-5 https://doi.org/10.1128/cmr.19.2.403-434.2006 https://doi.org/10.1128/cmr.19.2.403-434.2006 https://doi.org/10.19045/bspab.2018.70015 https://doi.org/10.19045/bspab.2018.70015 https://doi.org/10.1016/j.burns.2012.09.017 https://doi.org/10.1097/bcr.0000000000000525 https://doi.org/10.1097/bcr.0000000000000525 department of radiology, armed forces hospital, muscat, oman *corresponding author e-mail: drphilipsgm@yahoo.com حالة نادرة لتواجد متالزمة الشريان املساريقي العلوي سويا مع ظاهرة كسارة البندق فيليب�ص جورج مايكل، طاهرة ال�سعدية، راكي�ص جاخمانديكار a rare case of coexisting superior mesenteric artery syndrome and nutcracker phenomenon *philips g. michael, tahra al-saadi, rakesh jamkhandikar a 28-year-old man was referred as an emergency case from a regimental medical clinic to the surgical unit of the armed forces hospital, muscat, oman, in 2016 with complaints of severe vomiting, epigastric pain and bloating of two days’ duration. the patient gave a history of abdominal bloating associated with early satiety, postprandial pain and occasional vomiting over the past year and a half. there was no other significant medical or surgical history. clinically, the patient was underweight and pale with a body mass index of 17 kg/m2. an abdo minal examination revealed upper abdominal tenderness and distention. the findings of initial blood tests and laboratory investigations were unremarkable. an ultrasound of the abdomen performed two days prior at the previous institution demonstrated no sonographical abnormalities. due to the patient’s long-standing symptoms and weight loss, a contrast-enhanced computed tomo graphy (ct) scan of the abdomen was performed using a philips brilliance 64-slice ct scanner (philips healthcare, cleveland, ohio, usa). this revealed a distended stomach and dilated proximal duodenum with narrowing of the third part of the duodenum between the angle of the superior mesenteric artery (sma) and the abdominal aorta, with a shortened aortomesenteric distance (amd) of 7 mm and a decreased aortomesenteric angle (aa) of 15 degrees. in addition, the left renal vein was compressed by the sma close to its origin [figures 1 and 2]. based on these imaging findings, a diagnosis of sma syndrome and nutcracker phenomenon was made. upon further questioning, the patient gave a history of intentional dieting and weight loss of approximately 15 kg over the last two years in order to meet the fitness criteria for military recruitment; subsequently, he had continued his dietary regimen even after being recruited into the army. however, he denied experiencing any interesting medical image sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e368–370, epub. 10 oct 17 submitted 17 dec 16 revision req. 16 jan 17; revision recd. 16 feb 17 accepted 2 mar 17 figure 1: axial contrast-enhanced computed tomography scans of the abdomen of a 28-year-old man showing (a) duodenal compression between the superior mesenteric artery (sma) and abdominal aorta and (b) impingement of the left renal vein by the sma. sma = superior mesenteric artery. doi: 10.18295/squmj.2017.17.03.022 philips g. michael, tahra al-saadi and rakesh jamkhandikar interesting medical image | e369 results in duodenal compression and a reduced mean amd of 2–8 mm in symptomatic patients compared to normal mean values of 10–28 mm.3 abnormally steep angulation between the sma and the aorta can cause a short amd and predispose to nutcracker syndrome.2 a significantly decreased amd of 3 mm and decreased aa of <15 degrees has been previously reported in patients with nutcracker syndrome.2–4 a decreased aa may be due to rapid weight loss resulting in reduced fat and lymphatic tissue at the origin of the sma, decreasing the ability to cushion the duodenum and protect it from compression.2,3 in the current case, the patient’s significant weight loss, particularly of intra-abdominal fat, was thought to be a contributing factor to the unusual vascular compression of the duodenum. other factors can include anatomical abnormalities such as a short ligament of treitz, pressure from external sources such as body casts and postoperative complications from procedures such as abdominal aortic aneurysm repairs, scoliosis surgeries, ileo-anal pouch anastomoses and total proctocolectomies.3,4 for most patients with sma syndrome, conservative management—including the correction of electrolyte imbalances along with appropriate enteral or parenteral nutrition—usually results in sufficient weight gain and symptomatic improvement.3 surgical procedures such as a duodenojejunostomy or the surgical release of the treitz ligament are reserved for cases which do not respond to conservative treatment.2–4 nutcracker phenomenon refers to the compression of the left renal vein between the sma and the abdominal aorta.2,3 affected patients may be asymptomatic or present with haematuria, proteinuria or left-sided flank pain or varicoceles.1–3 conservative management is often sufficient for symptomatic patients, although endovascular stenting is the treatment of choice if necessary.4 although the terms ‘nutcracker syndrome’ and ‘nutcracker phenomenon’ are sometimes used interchangeably, some symptoms may be unassociated and certain anatomical findings may represent a normal variant; hence, the term ‘nutcracker syndrome’ should be reserved for patients with characteristic clinical symptoms associated and demonstrable morphological features.2–4 besides the classic (i.e. anterior) nutcracker syndrome, other anatomical variants have been described.4,5 posterior nutcracker syndrome involves compression of the left renal vein between the abdominal aorta and vertebral spine, whereas combined nutcracker syndrome refers to a duplication of the vein causing compression of either the anterior branch between the abdominal aorta and sma or posterior branch between the abdominal aorta and haematuria and a second clinical examination did not reveal any left-sided varicoceles. the patient was managed conservatively with nutritional support to encourage weight gain via combined total parenteral and enteral nutrition. multidisciplinary treatment with input from general surgery, gastroenterology and dietetic experts was effective in reducing his epigastric abdominal pain. the patient also underwent a gastroduodenoscopy which did not reveal any intrinsic obstructions. since he had normal renal function parameters with normal blood pressure, no further intervention was deemed necessary to treat the nutcracker phenomenon. the patient was discharged and subsequently had an uneventful recovery. comment the extrinsic compression of the third part of the duo denum between the sma and the abdominal aorta as the artery crosses the duodenum anteriorly—known as sma syndrome—is a rare cause of upper gastrointestinal obstruction.1 patients may present with chronic or vague postprandial symptoms, such as upper abdominal pain, nausea, vomiting, weight loss and a feeling of early satiety or bloating, although acute presentations with symptoms of duodenal obstruction have also been described.1,2 the syndrome occurs due to an abnormally acute angle between the proximal part of the sma and the abdominal aorta which ranges from 6–16 degrees in symptomatic patients compared to 38–56 degrees in normal individuals; this figure 2: sagittal contrast-enhanced computed tomography scan of the abdomen of a 28-year-old man demonstrating the acute angle of the superior mesenteric artery at its point of origin from the abdominal aorta, with a decreased aortomesenteric distance. sma = superior mesenteric artery. a rare case of coexisting superior mesenteric artery syndrome and nutcracker phenomenon e370 | squ medical journal, august 2017, volume 17, issue 3 references 1. inal m, unal daphan b, karadeniz bilgili my. superior mesenteric artery syndrome accompanying with nutcracker syndrome: a case report. iran red crescent med j 2014; 16:e14755. doi: 10.5812/ircmj.14755. 2. barsoum mk, shepherd rf, welch tj. patient with both wilkie syndrome and nutcracker syndrome. vasc med 2008; 13:247−50. doi: 10.1177/1358863x08092272. 3. karaosmanoğlu d, karcaaltincaba m, akata d, ozmen m. unusual causes of left renal vein compression along its course: mdct findings in patients with nutcracker and pelvic congestion syndrome. surg radiol anat 2010; 32:323−7. doi: 10.1007/s00276-009-0548-1. 4. nunn r, henry j, slesser aa, fernando r, behar n. a model example: coexisting superior mesenteric artery syndrome and the nutcracker phenomenon. case rep surg 2015; 2015:649469. doi: 10.1155/2015/649469. 5. polguj m, topol m, majos a. an unusual case of left venous renal entrapment syndrome: a new type of nutcracker phenomenon? surg radiol anat 2013; 35:263−7. doi: 10.1007/ s00276-012-1027-7. spine.3,4 lateral or anterolateral nutcracker phenomenon describes venous compression as the vein passes between the sma and the right renal artery.5 clinically, nutcracker syndrome has been differentiated into the typical subtype with renal manifestations such as haematuria and proteinuria with or without flank pain and the atypical subtype involving urological manifestations such as fatigue, flank/abdominal pain, orthostatic intolerance and dysmenorrhoea and dyspareunia in women and varicoceles in men.2–5 both nutcracker phenomenon and sma syndrome are rare vascular compression entities and ct findings of a decreased aa and shortened amd are suggestive of a diagnosis for both conditions.1–5 however, clinical symptoms may not correlate with the severity of the anatomical distortion, even in extreme cases, thus making it challenging to diagnose.3–5 very few coexisting cases have been described in the existing medical literature.2–5 clinicians and radiologists should therefore be aware of and consider these conditions in cases of unexplained abdominal pain without corresponding biochemical or clinical findings. https://doi.org/10.5812/ircmj.14755 https://doi.org/10.1177/1358863x08092272 https://doi.org/10.1007/s00276-009-0548-1 https://doi.org/10.1155/2015/649469 https://doi.org/10.1007/s00276-012-1027-7 https://doi.org/10.1007/s00276-012-1027-7 جناة مريض بعد إصابة عميقة جدا اخرتقت احلجايب اجلمجمي patient survival after a very deep penetrating orbitocranial injury sir, a seven-year-old girl was referred to the emergency ward at the khatamolanbia hospital, zahedan, iran, in march 2012 after she fell face-first onto a pencil she was holding. the blunt end of the pencil had entered the orbit beneath the medial canthus. upon ophthalmological examination, the ocular globe was intact but laterally displaced and vision in the left eye had diminished to only light perception. moreover, the examination revealed a positive relative afferent pupillary defect in the left eye. further funduscopic examinations were not performed due to the patient’s condition. her vital signs were normal and she was conscious without any neurological deficits. computed tomography (ct) scans of the brain without contrast revealed a foreign body in the medial left orbit which had passed through the superior orbital fissure into the cranium near the temporal lobe and was positioned laterally to the cavernous sinus [figure 1]. the foreign body had passed next to the petrous apex, tangentially to the brainstem and had entered the cerebellum to a depth of 4 cm. a four-vessel angiography produced a normal angiogram [figure 2]. the pencil was removed slowly along the route of entry while the patient was under general anaesthesia. the pencil measured 18 cm, of which 14 cm had entered into the orbit. a surgical team remained on standby to perform an emergency craniotomy in case of sudden intracranial haemorrhage. fortunately, a postoperative ct scan showed no evidence of haematomas or vascular leaks. the wound was irrigated and sutured. the patient was prescribed prophylactic antibiotics and high-dose corticosteroids for the ophthalmic nerve injury. she recovered well with no signs of postoperative infection. at followup ophthalmological and neurological examinations 10 months later, she showed normal eye movements with 10/20 visual acuity and no neurological deficits. impalement through the eye orbit accompanied by transorbital penetration of the calvarium is rare. most cases are reported in children.1,2 stab injuries of letter to the editor sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e121–122, epub. 2 feb 16 submitted 30 mar 15 revision req. 31 may 15; revision recd. 2 jul 15 accepted 23 aug 15 doi: 10.18295/squmj.2016.16.01.026 figure 1: plain cranial computed tomography scans showing the path of the foreign object (arrows) in a seven-year-old girl with a very deep penetrating orbitocranial injury due to a pencil. figure 2: normal four-vessel angiography scan in a seven-year-old girl with a very deep penetrating orbitocranial injury due to a pencil. the red arrows indicate the path of the foreign body. inset: photograph showing the foreign body entering the left orbit beneath the medial canthus. patient survival after a very deep penetrating orbitocranial injury e122 | squ medical journal, february 2016, volume 16, issue 1 the orbit more frequently occur among young male children;1 this may be due to an increased participation in riskier forms of play. the majority of reported cases of transorbital injury in children are accidental.2 there have been some reports of intracranial complications due to transorbital brain injuries.1,2 most accidental transorbital penetrating injuries are reported to be caused by pens.3 in such cases, because of the pyramid shape and weak structure of the orbital apex, the treating physician must be aware of potential brain injuries.1 since these injuries are classified as low-velocity, the trajectory of the foreign object and the injured anatomical elements in the path determine the extent of the neurological damage.3,4 sections of the frontal, ethmoid, lacrimal, maxillary, zygomatic and greater wing of the sphenoid bones are joined together and form the pyramidal shape of the orbital cavity. the opening of the optic nerve, superior and inferior orbital fissures are positioned at the apex of this cavity. the ocular globe is adjacent to the lateral in comparison to the medial orbital wall; because of its mobile property, a penetrating object is usually directed next to the medial wall, reaching the cranial cavity through the orbital plate or superior orbital fissure.1,4 the optic nerve, cavernous sinus, suprasellar cistern, internal carotid artery, temporal lobe, pons and brainstem are all vulnerable to injury during transorbital penetration.1,2,4 depending on the site of the injury, intracranial penetration can be immediately fatal or present asymptomatically for some time.1,2,4 penetration through the orbital roof and superior orbital fissure are the most common events in transorbital penetrating injuries, resulting in a trajectory into the frontal lobe passing near the optic nerve or internal carotid artery, respectively, to the brainstem.3 turbin et al. concluded that penetrating injuries involving the superior orbital fissure may result in temporal lobe, cavernous sinus and brainstem or cerebellar injuries.1 in the case of low-velocity penetrating brain injuries, immediate complications are associated with anatomical damage and could include cranial nerve or cerebral vascular injuries and haemorrhagic complications.4 di roio et al. reported two cases of craniocerebral injury with transorbital penetration.2 the first was a four-year-old boy who fell onto a metal rod; his mother subsequently pulled the metal rod out of the entry site near the left internal canthus. on examination, the child was in a coma and developed meningeal syndrome with a cerebral abscess. in the second case, a six-year-old boy had poked a chopstick in his left eye. the child remained asymptomatic for some time before developing a cerebral abscess.2 al-otaibi et al. reported a case of transorbital brain injury without serious neurological deficits in which the bulk of the pencil was removed under general anaesthesia.5 however, this approach carries some risks as the foreign object may shred the vasculature and cranial nerves within its path. the most common cause of delayed death due to a penetrating brain injury is intracranial infection. al-otaibi et al. proposed that prophylactic antibiotics be prescribed as soon as possible after the removal of wooden foreign object fragments prone to microbial contamination.5 this recommendation is congruent with that of di roio et al.; both of the reported patients were treated with wide-spectrum antibiotics with no subsequent sign of post-surgical infection.2 the authors of this letter advocate non-invasive surgical management for transorbital penetrating brain injuries due to smooth objects, particularly for patients with normal angiograms and without haemorrhage. in the present patient, a craniotomy was not deemed necessary as the only complication was an ophthalmic nerve injury with light perception. nevertheless, surgical teams should be ready to perform an emergency craniotomy in the event of unexpected complications. hamid rezaei,1 anita alenabi,2 mostafa dahmardeh,3 zeynab nasri-nasrabadi,4 *sayed mahdi marashi5 departments of 1neurosurgery, 2pathology and 3plastic surgery, zahedan university of medical sciences, zahedan, iran; 4department of pediatrics, tehran university of medical sciences, tehran, iran; 5emergency room & division of medical toxicology, hazrat-e ali asghar hospital, shiraz university of medical sciences, shiraz, iran *corresponding author e-mail: marashi@sums.ac.ir references 1. turbin re, maxwell dn, langer pd, frohman lp, hubbi b, wolansky l, et al. patterns of transorbital intracranial injury: a review and comparison of occult and non-occult cases. surv ophthalmol 2006; 51:449–60. doi: 10.1016/j.survophthal.2006.06.008. 2. di roio c, jourdan c, mottolese c, convert j, artru f. craniocerebral injury resulting from transorbital stick penetration in children. childs nerv syst 2000; 16:503–6. doi: 10.1007/s003810000291. 3. arslan m, eseoğlu m, güdü bo, demir i. transorbital orbitocranial penetrating injury caused by a metal bar. j neurosci rural pract 2012; 3:178–81. doi: 10.4103/0976-3147.98228. 4. shkrum mj, ramsay da. forensic pathology of trauma: common problems for the pathologist. 1st ed. new jersey, usa: humana press, 2007. pp. 383–4. 5. al-otaibi f, baeesa s. occult orbitocranial penetrating pencil injury in a child. case rep surg 2012; 2012:716791. doi: 10.1155/2012/716791. http://dx.doi.org/10.1016/j.survophthal.2006.06.008 http://dx.doi.org/10.1007/s003810000291 http://dx.doi.org/10.4103/0976-3147.98228 http://dx.doi.org/10.1155/2012/716791 there have been tremendous develop-ments in the area of medical education of late, including the introduction of problembased learning (pbl) and team-based learning (tbl). undoubtedly, these new methods of teaching have significant benefits in enhancing learning skills and medical learning outcomes. however, it is still too early to conclude that these relatively recent techniques can solve problems that have persisted from following structured curricula in the past. one issue worth highlighting is the gender learning gap. for years, female students have repeatedly shown superior academic results in comparison to their male counterparts.1–3 a greater number of women gain admission into medical schools, where they outperform their male colleagues academically; they also go on to earn more graduate degrees.4,5 the widening of this gender learning gap—particularly in the medical and healthcare fields—is of growing concern. reasons for this phenomenon may include social, cultural, psychological and emotional components.4 since the 1960s, various women’s equality move ments have encouraged the development of environ ments which support education and career advancements for women. some researchers claim that the superior academic performance demonstrated by women in medical careers is due to their instinctive desire to help humankind.4,6 women have also been described as being more perceptive to emotions, enabling them to be more caring and empathetic.6 their enhanced academic performance may also be due to goal setting, commitment and discipline in following a structured curriculum, spending more time studying and developing stronger social networks; these attributes may develop as a result of social and cultural customs that encourage women to perform well academically.7 one theoretical explanation proposed by raymond et al. is the influence of family practices, such as parents encouraging gender-specific roles among their children; for example, girls are usually expected to be well-mannered, compliant and accept rules.8 these behaviours evidently promote academic achievement in traditional academic settings.9,10 conversely, male students favour less constrained learning environments and focus on achieving high grades in their final tests, developing learning skills to meet this purpose.11–15 nevertheless, researchers have expressed concern that the perceived idea of female students as “highly motivated” may encourage teachers to give them more attention and overlook equally motivated male students, further enhancing the gender learning gap.9 another theory is that increasing numbers of independent, educated and employed mothers are acting as role models for their daughters.9 furthermore, it may be that although women sense their lower status in society compared to men, they anticipate that implementing greater efforts in their education may justly reward them with a more equitable future. in 1989, mickelson proposed the ‘pollyanna principle’ to explain the tendency for individuals to remember agreeable occurrences over unpleasant ones.16 in light of this theory, many young women may remain optimistic about their future as, in their view, gender discrimination in the workplace is a problem of the past and society is moving towards gender equity. this may explain the higher academic achievements of young women who have not yet suffered occasions of gender inequality. stereotyping in medical education is a significant factor that influences women’s academic aspirations by discouraging interest in occupations usually dominated by males, such as engineering and mathematics.17,18 the authors of some studies have argued that the gender gap in medical specialties may be due to reinforcement of the idea that genetic department of biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: jumana@squ.edu.om هل الرجال من املريخ والنساء من الزهرة؟ سد الفجوة التعليمية بني اجلنسني يف التعليم الطيب جمانة �صالح editorial are men from mars and women from venus? bridging the gender learning gap in medical education jumana saleh sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e267–269, epub. 19 aug 16 submitted 14 jun 16 revision req. 29 jun 16; revision recd. 27 jul 16 accepted 31 jul 16 doi: 10.18295/squmj.2016.16.03.001 are men from mars and women from venus? bridging the gender learning gap in medical education e268 | squ medical journal, august 2016, volume 16, issue 3 factors render males more capable of performing in fields related to mathematics and physics.19–21 unfortunately, stereotyping is still apparent in certain medical specialties; in general, more women practice in so-called “feminine” specialisations, such as paediatrics and gynaecology, while more men specialise in “masculine” areas, such as orthopaedic surgery. moreover, male healthcare practitioners tend to hold positions with higher status and better pay in comparison to their equally qualified female colleagues.22,23 the differences in academic performance attributed to effort and engagement, as a result of social and cultural aspects, have been studied extensively. however, there is mounting evidence which indicates that gender disparity in academic performance is inherently associated with biological differences that influence learning behaviours in males and females. the author of the female brain highlights that males and females have brains that are biochemically and neurologically programmed to perform different tasks from an early age.15 other researchers have commented that young boys occupy more space when learning, due to their continuous movements, compared to girls.1,15 in addition, boys seem to prefer engaging and interacting in rough play, sports and building activities as well as reading action books.1 interestingly, a recent comprehensive study also showed that the neural connections in male and female brains are different; female brains were found to have more connections between the two hemispheres of the brain while males had more connections within each hemisphere.24 these findings agree with those of clements et al., who observed that males prefer to execute individual tasks and are better at performing motor activities than women.25 testosterone, the male hormone, enhances the spatial and visual acuity of the sense organs, affecting activities that require spatial skills such as geometry, physics, engineering and navigation.26–28 this may explain why more men become pilots and architects. specific areas of the male brain mature earlier than females and males have more grey matter related to intelligence, including tasks involving mathematics and problem-solving.29,30 on the other hand, increased interhemispheric neural connectivity and the largely increased white matter related to intelligence in female brains renders women more capable of coordinating analytical reasoning and intuition.24 as such, women tend to excel in multitasking which requires the use of both hemispheres; this might explain why women are traditionally tasked with handling various household activities and responding to family needs simultaneously. also, the cerebral cortex in women is highly organised in a pattern which has been linked to increased empathy and creative expression.31,32 nevertheless, it is important to keep in mind that there are more similarities than differences between male and female brains.24 in collaboration with other scientists, dr. denckla from the kennedy krieger institute found that anatomical differences in the brain—specifically, the language functioning areas of the brain—occur from an early age.33 female fetuses at 26 gestational weeks had a thicker corpus callosum, the nerve tissue connecting the right and left hemispheres of the brain, compared to males; upon listening to certain triggers, the brains of the female fetuses showed activity in both the left and right hemispheres, whereas only the left hemisphere was activated in males.33 dr. denckla also revealed that the areas of the female brain linked to language skills mature approximately six years earlier than for males, which may result in stronger language and communication skills among women.29,33 clements et al. also provided clear evidence of lateral differences between females and males when processing language versus visuospatial information.25 differences in brain function may also be explained from the perspective of human development. in a hunter-gatherer society, male hunters had to exhibit intense sensory reflexes to be able to detect their prey and kill it without feeling sympathetic.34 strong motor function skills would also have helped men to design hunting tools and weapons. conversely, greater emotional intelligence may have been a factor that drove women to respond intuitively to the needs of a crying baby without requiring verbal expression.34 the adoption of pbl and tbl techniques in medical education, while still advantageous for female students with their proficient communication skills, could be a major shift for male students who can now display their problem-solving skills in suitable academic settings that encourage and nurture their abilities and remove gender-based stereotypes. gradually, pbl and tbl may remove the academic bias in favour of females, or males in certain specialties, as a result of social, cultural, behavioural and biological factors. consequently, curricular changes towards pbl and/or tbl approaches may help bridge the gender learning gap in medicine. references 1. diprete ta, buchmann c. the rise of women: the growing gender gap in education and what it means for american schools, 1st ed. new york, usa: russell sage foundation, 2013. pp. 1–24. 2. voyer d, voyer sd. gender differences in scholastic achievement: a meta-analysis. psychol bull 2014; 140:1174–204. doi: 10.1037/a0036620. http://dx.doi.org/10.1037/a0036620 jumana saleh editorial | e269 3. stoet g, geary dc. sex differences in academic achievement are not related to political, economic, or social equality. intell 2015; 48:137–51. doi: 10.1016/j.intell.2014.11.006. 4. ecklund eh, lincoln ae, tansey c. gender segregation in elite academic science. gend soc 2012; 26:693–717. doi: 10.1177 /0891243212451904. 5. penington c. gender proves large factor in academic performance. from: www.elon.edu/e-web/pendulum/issues/ 2004/3_11/news/gender.xhtml accessed: jul 2016. 6. hojat m, gonnella js, mangione s, nasca tj, veloski jj, erdmann jb, et al. empathy in medical students as related to academic performance, clinical competence and gender. med educ 2002; 36:522–7. doi: 10.1046/j.1365-2923.2002.01234.x. 7. banks ja. encyclopedia of diversity in education, 1st ed. washington, usa: sage publications, 2012. doi: 10.4135/ 9781452218533. 8. raymond cl, benbow cp. gender differences in mathematics: a function of parental support and student sex typing? develop psychol 1986; 22:808–19. doi: 10.1037/0012-1649.22.6.808. 9. zusman m, knox d, lieberman m. gender differences in reactions to college course requirements or “why females are better students”. coll stud j 2005; 39:621–6. 10. stockard j, schmuck k, kempner p, williams s, edson k, smith ma. sex equity in education. new york, usa: academic press, 1980. 11. zhou yx, zhao zt, li l, wan cs, peng ch, yang j, et al. predictors of first-year gpa of medical students: a longitudinal study of 1285 matriculates in china. bmc med educ 2014; 14:87. doi: 10.1186/1472-6920-14-87. 12. gnaulati e. why girls tend to get better grades than boys do. from: www.theatlantic.com/education/archive/2014/09/ why-girls-get-better-grades-than-boys-do/380318/ accessed: jul 2016. 13. american psychological association. girls make higher grades than boys in all school subjects, analysis finds. from: www.apa. org/news/press/releases/2014/04/girls-grades.aspx accessed: jul 2016. 14. duckworth al, seligman mep. self-discipline gives girls the edge: gender in self-discipline, grades, and achievement test scores. j educ psychol 2006; 98:198–208. doi: 10.1037/00220663.98.1.198. 15. brizendine l. the female brain, 1st ed. new york, usa: broadway books, 2006. pp. 1–10. 16. mickelson ra. why does jane read and write so well? the anomaly of women’s achievement. sociol educ 1989; 62:47–63. doi: 10.2307/2112823. 17. correll sj. constraints into preferences: gender, status, and emerging career aspirations. am sociol rev 2004; 69:93–113. doi: 10.1177/000312240406900106. 18. rydell rj, rydell mt, boucher kl. the effect of negative performance stereotypes on learning. j pers soc psychol 2010; 99:883–96. doi: 10.1037/a0021139. 19. steele jr, ambady n. “math is hard!” the effect of gender priming on women’s attitudes. j exp soc psychol 2006; 42:428–36. doi: 10.1016/j.jesp.2005.06.003. 20. thoman db, white ph, yamawaki n, koishi h. variations of gender-math stereotype content affect women’s vulnerability to stereotype threat. sex roles 2008; 58:702–12. doi: 10.1007/ s11199-008-9390-x. 21. dweck cs. is math a gift? beliefs that put females at risk. from: http://psychology.stanford.edu/sites/all/files/cdweckmath gift_0.pdf accessed: jul 2016. 22. jagsi r, griffith ka, decastro ra, ubel p. sex, role models, and specialty choices among graduates of us medical schools in 2006-2008. j am coll surg 2014; 218:345–52. doi: 10.1016/j. jamcollsurg.2013.11.012. 23. fox m. white male doctors earn more than women and black peers, study finds. from: www.nbcnews.com/health/healthnews/white-male-doctors-earn-more-women-black-peersstudy-finds-n588146 accessed: jul 2016. 24. ingalhalikar m, smith a, parker d, satterthwaite td, elliott ma, ruparel k, et al. sex differences in the structural connectome of the human brain. proc natl acad sci u s a 2014; 111:823–8. doi: 10.1073/pnas.1316909110. 25. clements am, rimrodt sl, abel jr, blankner jg, mostofsky sh, pekar jj, et al. sex differences in cerebral laterality of language and visuospatial processing. brain lang 2006; 98:150–8. doi: 10.1016/j.bandl.2006.04.007. 26. abramov i, gordon j, feldman o, chavarga a. sex & vision i: spatio-temporal resolution. biol sex differ 2012; 3:20. doi: 10.1186/2042-6410-3-20. 27. halpern df. sex differences in intelligence: implications for education. am psychol 1997; 52:1091–102. doi: 10.1037/0003066x.52.10.1091. 28. celec p, ostatníková d, hodosy j. on the effects of testosterone on brain behavioral functions. front neurosci 2015; 9:12. doi: 10.3389/fnins.2015.00012. 29. popova m. researchers reveal sex differences in the brain’s form and function. from: http://studopedia.org/11-34801.html accessed: jul 2016. 30. zhu z. gender differences in mathematical problem solving patterns: a review of literature. int educ j 2007; 8:187–203. 31. christov-moore l, simpson ea, coudé g, grigaityte k, iacoboni m, ferrari pf. empathy: gender effects in brain and behavior. neurosci biobehav rev 2014; 46:604–27. doi: 10.1016/j.neubiorev.2014.09.001. 32. science daily. intelligence in men and women is a gray and white matter. from: www.sciencedaily.com/releases/2005/ 01/050121100142.htm accessed: jul 2016. 33. higher purpose. how male and female brains work differently? from: www.dubheannk.com/tag/male-and-female-brain/ accessed: jul 2016. 34. davidson h, cave kr, sellner d. differences in visual attention and task interference between males and females reflect differences in brain laterality. neuropsychologia 2000; 38:508–19. doi: 10.1016/s0028-3932(99)00084-6. http://dx.doi.org/10.1016/j.intell.2014.11.006 http://dx.doi.org/10.1177/0891243212451904 http://dx.doi.org/10.1177/0891243212451904 http://dx.doi.org/10.1046/j.1365-2923.2002.01234.x http://dx.doi.org/10.4135/9781452218533 http://dx.doi.org/10.4135/9781452218533 http://dx.doi.org/10.1037/0012-1649.22.6.808 http://dx.doi.org/10.1186/1472-6920-14-87 http://dx.doi.org/10.1037/0022-0663.98.1.198 http://dx.doi.org/10.1037/0022-0663.98.1.198 http://dx.doi.org/10.2307/2112823 http://dx.doi.org/10.1177/000312240406900106 http://dx.doi.org/10.1037/a0021139 http://dx.doi.org/10.1016/j.jesp.2005.06.003 http://dx.doi.org/10.1007/s11199-008-9390-x http://dx.doi.org/10.1007/s11199-008-9390-x http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.012 http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.012 http://dx.doi.org/10.1073/pnas.1316909110 http://dx.doi.org/10.1016/j.bandl.2006.04.007 http://dx.doi.org/10.1186/2042-6410-3-20 http://dx.doi.org/10.1037/0003-066x.52.10.1091 http://dx.doi.org/10.1037/0003-066x.52.10.1091 http://dx.doi.org/10.3389/fnins.2015.00012 http://dx.doi.org/10.1016/j.neubiorev.2014.09.001 http://dx.doi.org/10.1016/s0028-3932%2899%2900084-6 departments of 1obstetrics & gynecology and 5public health & community medicine, faculty of medicine, jordan university of science and technology, irbid, jordan; 2department of pediatrics, king abdullah university hospital, ramtha, jordan; 3department of maternal-fetal medicine & ultrasound, king fahad medical city, riyadh, saudi arabia; 4faculty of nursing, al-bayt university, mafraq, jordan *corresponding author e-mails: naobeidat@just.edu.jo and naobeidat@yahoo.com فعالية الربط الوقائي لعنق الرحم يف اطالة مدة احلمل لدى التوائم املتعددة نائل عبيدات، هيفا اجللبي، مها عبيدات، بهاء الدين �سلوت، �سريين حمادنة، جيهان حمادنة، يو�سف خ�رص، زهري اأمارين abstract: objectives: this study aimed to assess the value of prophylactic cervical cerclage in prolonging higherorder multiple pregnancies. methods: this retrospective study included all women with higher-order multiple pregnancies beyond 24 gestational weeks treated at the king abdullah university hospital in irbid, jordan, and king fahad medical city in riyadh, saudi arabia, between february 2014 and january 2015. selected maternal characteristics and obstetric outcomes were compared between women who received prophylactic cervical cerclage and those who did not. results: a total of 146 women with higher-order multiple pregnancies were included in the study; of these, 94 (64.4%) underwent a prophylactic cervical cerclage insertion procedure and 52 (35.6%) women did not. no significant difference was found between the two groups with regards to maternal age, parity or number of fetuses. however, the mean gestational age at delivery was significantly higher for women without compared to those with prophylactic cervical cerclage (32.9 weeks versus 31.7 weeks) according to both univariate and multivariate analyses (p = 0.013 and 0.046, respectively). additionally, 40.4% of women without and 14.9% of women with prophylactic cervical cerclage gave birth after 34 gestational weeks (p = 0.003). conclusion: overall, prophylactic cervical cerclage was not associated with prolongation of the pregnancy among women with higherorder multiple pregnancies in the current study. keywords: multiple pregnancies; preterm births; cervical cerclage; prophylactic surgical procedure; jordan; saudi arabia. درا�سة اأجريت الطريقة: املتعددة. التوائم يف احلمل مدة اإطالة يف وقائي ب�سكل الرحم عنق غرزة و�سع فائدة تقييم الهدف: امللخ�ص: االأردن، اإربد، يف اجلامعي اهلل عبد امللك م�ست�سفى يف للحمل 24 االأ�سبوع بعد متعددة توائم يحملن اللواتي الن�ساء جلميع ا�سرتجاعية ومدينة امللك فهد الطبية بالريا�ص، اململكة العربية ال�سعودية، خالل فرتة من فرباير 2014 اإىل يناير 2015. مت مقارنة خ�سائ�ص االأمهات و احل�سيلة التوليدية لدى الن�ساء اللواتي تلقني ربط وقائي لعنق الرحم مع الن�ساء اللواتي مل يتلقني ربط وقائي لعنق الرحم. النتائج: �سملت عينة البحث عدد 146 اإمراة حامل للتوائم املتعددة، تلقى منهن )%64.4( 94 ربط وقائي لعنق الرحم و )%35.6( 52 امراأة مل تتلقى ربط وقائي لعنق الرحم. مل يكن هناك فرق كبري بني هاتني املجموعتني يف عمر االأم وعدد االأجنة. وكان متو�سط عمر احلمل عند الوالدة اأعلى بكثري بالن�سبة للن�ساء اللواتي مل يكن لديهن ربط وقائي لعنق الرحم مقارنة بالن�ساء اللواتي ح�سلن على ربط وقائي لعنق الرحم )32.9 اأ�سبوع مقابل 31.7 اأ�سبوع( يف حتليل متغري ومتعدد املتغريات على التوايل)p = 0.013 و 0.046(. هذا باالأ�سافة ايل ان حوايل %40.4 من .)p = 0.003( اأجننب بعد 34 اأ�سبوعا من احلمل )الن�ساء اللواتي مت عمل ربط وقائي لهن و %14.9 من الن�ساء اللواتي مل يو�سع لهن ربط وقائي اخلال�صة: مل يكن لربط عنق الرحم الوقائي فائدة الطالة مدةاحلمل يف التوائم املتعددة. الكلمات املفتاحية: التوائم املتعددة؛ حمل التوائم؛ الوالدة املبكرة؛ غرزة عنق الرحم؛ عنق الرحم؛ االأردن؛ اململكة العربية ال�سعودية. effectiveness of prophylactic cervical cerclage in prolonging higher-order multiple pregnancies *nail obeidat,1 haifa alchalabi,1 maha obeidat,2 bahauddin sallout,3 shereen hamadneh,4 jehan hamadneh,1 yousef khader,5 zouhair amarin1 clinical & basic research sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e314–318, epub. 10 oct 17 submitted 12 apr 17 revision req. 4 jun 17; revision recd. 13 jun 17 accepted 6 jul 17 advances in knowledge preterm birth poses a great risk to the newborns of multiple pregnancies; however, reliable data are lacking concerning the effectiveness of prophylactic cervical cerclage in prolonging pregnancy. this study confirmed that prophylactic cervical cerclage had no positive impact on perinatal outcomes among women with multiple pregnancies treated at institutions in jordan and saudi arabia. application to patient care potential complications of prophylactic cervical cerclage placement include laceration, vaginal bleeding, infection, discharge, rupture of the fetal membranes and anaesthesia-related side-effects. the findings of this study do not support the use of this procedure among women with higher-order multiple pregnancies and may instead subject such patients to unnecessary and dangerous complications. doi: 10.18295/squmj.2017.17.03.009 since the early 1980s, there has been an alarming increase of over 400% in the incidence of higher-order multiple pregnancies due to the use of ovarian hyperstimulants by women after the birth of their first baby conceived via in vitro fertilisation.1–5 this increase has been associated with financial and logistical problems as well as higher perinatal morbidity and mortality rates among women nail obeidat, haifa alchalabi, maha obeidat, bahauddin sallout, shereen hamadneh, jehan hamadneh, yousef khader and zouhair amarin clinical and basic research | e315 with higher-order multiple pregnancies in comparison to their singleton counterparts.6–10 the rate of higherorder multiple pregnancies is especially high in certain countries, particularly those in the developing world where there are no legal restrictions on the number of embryos transferred at in vitro fertilisation centres. despite advances in modern obstetric practice, preterm labour remains a difficult problem to prevent, stop or even delay in higher-order pregnancies.6–10 the approximate mean gestational age at delivery is 36, 33, 29 and 28 weeks for twin, triplet, quadruplet and quintuplet pregnancies, respectively.5,8,11 while the pathophysiology of preterm birth in higher-order multiple pregnancies remains unclear, the most likely cause is overdistension of the uterus.12 although routine prophylactic cervical cerclage has been suggested as a strategy for prolonging gestation and some evidence exists suggesting that its routine use in twin pregnancies is beneficial, its role or advantage in higher-order multiple pregnancies is unclear.8,9,13 this study therefore aimed to determine the effect of prophylactic cervical cerclage in the prolongation of higher-order multiple pregnancies. methods all women with triplet or higher-order pregnancies beyond 24 gestational weeks seen between february 2014 and january 2015 at the king abdullah university hospital in irbid, jordan, or the king fahad medical city in riyadh, saudi arabia, were included in this retrospective study. a review was conducted of the electronic patient databases at each tertiary institution. for maternal characteristics, the following variables were reviewed: age, parity and body mass index (bmi); history of previous cervical insufficiency, cervical surgery, preterm labour or premature rupture of membranes (pprom); and number of fetuses and method of conception. obstetric outcome measures included the incidence of preterm labour, pprom and neonatal or intrauterine fetal death; admission to the neonatal intensive care unit (nicu); gestational age at delivery; and the mode and indications for delivery. all patients were under the direct supervision of consultant obstetricians during their care. for women who received prophylactic cervical cerclage, the suture was placed into and around the cervix at between 11–16 gestational weeks, regardless of past obstetric history or the state of the cervix. all cerclage sutures were of the mcdonald type, using 5 mm mersilene® polyester tape (ethicon inc., somerville, new jersey, usa), and were inserted under general anaesthesia with no specific instructions for suture placement. following the procedure, patients received an ultrasound to check fetal wellbeing before being discharged on the same day, with instructions to seek attention at the emergency room if they experienced any symptomatic abnormalities. patients were also advised to refrain from demanding physical activities but were not assigned complete bed rest. a follow-up visit to the antenatal clinic was arranged two weeks later to assess the state of the cervix. patients were then seen regularly until the elective removal of the suture, or earlier in the case of an emergency. most cervical cerclage sutures were removed during the 36th gestational week without sedatives or any form of anaesthesia. no antimicrobial or tocolytic medications were administered. for patients in both groups, decisions regarding the timing and mode of delivery and pain relief options offered during labour were made according to the policies and protocols for higher-order multiple pregnancies at each institution. the women were categorised into two groups for statistical analysis according to whether they had received prophylactic cervical cerclage or not. the sample size yielded a power of >80% to detect a 5% difference in outcomes between the two groups. the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa), was used to analyse the data. chi-squared and student’s t-tests were used to compare percentages and means. a general linear model was used to conduct the regression analysis to determine statistical differences in gestational age at birth. the level of statistical significance was set at p ≤0.050. this retrospective study received ethical approval from the institutional review boards at both the king abdullah university hospital and the king fahad medical city. results a total of 146 women with higher-order multiple pregnancies were seen at the two tertiary institutions during the study period. of these, 94 (64.4%) underwent a prophylactic cervical cerclage insertion procedure and 52 (35.6%) did not. the majority of the pregnancies (94.5%) were the result of assisted reproductive techniques (art), mainly intracytoplasmic sperm injection and embryo transfers; 98.9% of women with versus 86.5% of women without prophylactic cervical cerclage had used art (p = 0.002). none of the women had a history of cervical insufficiency, prior cervical surgery, preterm labour or pprom or had undergone fetal reduction. there was no statistically significant difference between the two groups in relation to maternal age (p = 0.674), parity (p = 0.177) effectiveness of prophylactic cervical cerclage in prolonging higher-order multiple pregnancies e316 | squ medical journal, august 2017, volume 17, issue 3 or number of fetuses (p = 0.563) [table 1]. in addition, no statistically significant differences were noted between the two groups with regards to bmi. all of the women delivered by caesarean section after 24 gestational weeks, with the majority of cases (92.5%) considered emergency or urgent procedures. there was no statistically significant difference between the two groups in relation to the mode of delivery (p = 0.139), the occurrence of stillbirths or neonatal deaths (p = 0.406) or admission to the nicu (p = 0.682). however, 14.9% and 40.4% of women with and without prophylactic cervical cerclage, respectively, gave birth after 34 gestational weeks (p = 0.003). moreover, the mean gestational age at delivery was significantly higher among women without compared to those with prophylactic cervical cerclage (32.9 versus 31.7 weeks; p = 0.013) [table 2]. this difference remained significant during the multivariate analysis after adjusting for art, number of fetuses, parity and maternal age (p = 0.046). among those who received prophylactic cervical cerclage, there was no statistically significant difference in studied outcomes according to the time of cerclage insertion. the mean gestational age at delivery was 31.6 and 32.0 weeks for women who underwent the cerclage procedure at 11–13 and 14–16 gestational weeks, respectively (p = 0.542). one miscarriage occurred in the prophylactic cervical cerclage group. of the women who had not initially received prophylactic cervical cerclage, none required subsequent emergency or rescue cerclage. discussion theoretically, there may be a higher pressure burden on the uterine cervix, particularly the internal opening of the cervix, in cases of higher-order multiple pregnancies in comparison to singleton pregnancies.12,13 intuitively, a routine prophylactic cervical cerclage procedure for women with higher-order multiple pregnancies should automatically decrease the chances of preterm birth by preventing undue cervical shortening and dilatation. however, the role of the cervix in the aetiology of preterm birth in multiple pregnancies is not clear. furthermore, the function of the cervix in higherorder multiple pregnancies might differ from that of singleton pregnancies.12,14 the anatomical status of the cervix and the likelihood of preterm birth can be evaluated by reviewing past obstetric history and carrying out a speculum or digital vaginal examination or reviewing abdominal and vaginal ultrasound findings in the second trimester. in comparison, the diagnosis of true cervical insufficiency is more challenging.15–17 table 1: maternal characteristics of women with higherorder multiple pregnancies treated at the king abdullah university hospital in irbid, jordan, and king fahad medical city in riyadh, saudi arabia (n = 146) characteristic n (%) p value no pcc (n = 52) pcc (n = 94) mean maternal age in years ± sd 30.6 ± 4.6 30.9 ± 5.1 0.674 nulliparity 23 (44.2) 52 (55.9) 0.177 number of fetuses 0.563 quadruplets/ quintuplets 4 (7.7) 10 (10.6) triplets 48 (92.3) 84 (89.4) use of art 0.002 no 7 (13.5) 1 (1.1) yes 45 (86.5) 93 (98.9) pcc = prophylactic cervical cerclage; sd = standard deviation; art = assisted reproductive techniques. table 2: pregnancy outcomes among women with higher-order multiple pregnancies treated at the king abdullah university hospital in irbid, jordan, and king fahad medical city in riyadh, saudi arabia (n = 146) outcome n (%) p value no pcc (n = 52) pcc (n = 94) mode/indication of delivery urgent cs due to bleeding 0 (0.0) 4 (4.3) 0.139 elective cs 6 (11.5) 5 (5.3) urgent cs due to labour 46 (88.5) 85 (90.4) neonatal deaths/stillbirths 0.406 none 46 (88.5) 87 (92.6) at least one 6 (11.5) 7 (7.4) nicu admissions 0.682 none 3 (5.8) 4 (4.3) at least one 49 (94.2) 90 (95.7) gestational age at delivery in weeks 0.003 24–31 + 6 days 19 (36.5) 50 (53.2) 32–34 12 (23.1) 30 (31.9) >34 21 (40.4) 14 (14.9) mean ± sd 32.9 ± 2.7 31.7 ± 2.9 0.013 pcc = prophylactic cervical cerclage; cs = caesarean section; nicu = neonatal intensive care unit; sd = standard deviation. nail obeidat, haifa alchalabi, maha obeidat, bahauddin sallout, shereen hamadneh, jehan hamadneh, yousef khader and zouhair amarin clinical and basic research | e317 the insertion of cervical cerclage sutures for patients with ultrasonographically-documented cerv ical shortening has been proposed so as to avoid unnecessary surgery.18 on the other hand, its effectiveness and safety in higher-order multiple pregnancy remains unclear.8,13,19 the criteria for patient and sample size selection and hospitalisation in previous research is not uniform.10,19–21 some studies have demonstrated that prophylactic cerclage is of no value in prolonging gestation in high-order multiple pregnancies.10,14,19,22 in contrast, other studies have found that prophylactic cerclage significantly increases the mean gestational age and decreases the incidence of extreme prematurity.20–22 nevertheless, routine prophylactic cervical cerclage is not recommended for every woman with a multiple pregnancy and the safety and efficacy of the procedure as a form of preterm birth prevention should be appraised on a case-by-case basis according to obstetric history and cervical assessment.12,14 in a study of current practices to prevent preterm births, baker et al. found that the majority of canadian specialists (82%) recommended routine cervical length assessment at 16–21 gestational weeks, with none supporting routine cerclage insertion; however, 71% stated that they would perform cerclage based on the patient’s history or an ultrasound.23 prophylactic cerclage procedures in the current study were performed at between 11–16 gestational weeks, irrespective of obstetric history or cervical assessment. it is likely that this gestational age is somewhat early for cerclage, even in cases of multiple pregnancies in which there may yet be further physiological shortening of the uterine cervix.23 however, the timing of the prophylactic cervical cerclage insertion in the current study did not prolong pregnancy or have a significant difference on pregnancy outcomes. limitations of the present study include its retrospective nature and the lack of randomisation in the selection of the patients. furthermore, the incidence of immediate adverse effects of prophylactic cervical cerclage, such as rupture of the membranes, infection and pregnancy loss, between the date of the cerclage insertion and the beginning of the study when the women were at ≥24 gestational weeks was not evaluated. conclusion the current study found that the routine use of prophylactic cervical cerclage to prolong gestation among women with higher-order multiple pregnancies was not effective. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. sumners je, moore es, ramsey cj, eggleston mk. transabdominal cervical cerclage in triplet pregnancies and risk of extreme prematurity and neonatal loss. j obstet gynaecol 2011; 31:111–17. doi: 10.3109/01443615.2010.542512. 2. reddy um, wapner rj, rebar rw, tasca rj. infertility, assisted reproductive technology, and adverse pregnancy outcomes: executive summary of a national institute of child health and human development workshop. obstet gynecol 2007; 109:967–77. doi: 10.1097/01.aog.0000259316.04136.30. 3. shinwell es, haklai t, eventov-friedman s. outcome of multiplets. neonatology 2009; 95:6–14. doi: 10.1159/000151750. 4. wimalasundera rc, trew g, fisk nm. reducing the incidence of twins and triplets. best pract res clin obstet gynaecol 2003; 17:309–29. doi: 10.1016/s1521-6934(02)00135-9. 5. martin ja, hamilton be, sutton pd, ventura sj, menacker f, kirmeyer s, et al. births: final data for 2005. natl vital stat rep 2007; 56:1–103. 6. imaizumi y. infant mortality rates in single, twin and triplet births, and influencing factors in japan, 1995-98. paediatr perinat epidemiol 2001; 15:346–51. doi: 10.1046/j.1365-3016. 2001.00378.x. 7. shinwell es, blickstein i, lusky a, reichman b. excess risk of mortality in very low birthweight triplets: a national, population based study. arch dis child fetal neonatal ed 2003; 88:f36–40. doi: 10.1136/fn.88.1.f36. 8. martin ja, kung hc, mathews tj, hoyert dl, strobino dm, guyer b, et al. annual summary of vital statistics: 2006. pediatrics 2008; 121:788–801. doi: 10.1542/peds.2007-3753. 9. refuerzo js, momirova v, peaceman am, sciscione a, rouse dj, caritis sn, et al. neonatal outcomes in twin pregnancies delivered moderately preterm, late preterm, and term. am j perinatol 2010; 27:537–42. doi: 10.1055/s-0030-1248940. 10. bernasko j, lee r, pagano m, kohn n. is routine prophylactic cervical cerclage associated with significant prolongation of triplet gestation? j matern fetal neonatal med 2006; 19:575–8. doi: 10.1080/14767050600825607. 11. keith l, oleszczuk jj. iatrogenic multiple birth, multiple pregnancy and assisted reproductive technologies. int j gynaecol obstet 1999; 64:11–25. doi: 10.1016/s0020-7292 (98)00230-6. 12. hodgson ej, lockwood cj. preterm birth: a complex disease. in: berghella v, ed. preterm birth: prevention and management, 1st ed. oxford, uk: wiley-blackwell, 2010. pp. 8–16. 13. rafael tj, berghella v, alfirevic z. cervical stitch (cerclage) for preventing preterm birth in multiple pregnancy. cochrane database syst rev 2014; 9:cd009166. doi: 10.1002/14651858. cd009166.pub2. 14. rebarber a, roman as, istwan n, rhea d, stanziano g. prophylactic cerclage in the management of triplet pregnancies. am j obstet gynecol 2005; 193:1193–6. doi: 10.1016/j.ajog. 2005.05.076. 15. rust oa, atlas ro, jones kj, benham bn, balducci j. a randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os. am j obstet gynecol 2000; 183:830–5. doi: 10.1067/mob.2000.109040. https://doi.org/10.3109/01443615.2010.542512 https://doi.org/10.1097/01.aog.0000259316.04136.30 https://doi.org/10.1159/000151750 https://doi.org/10.1016/s1521-6934%2802%2900135-9 https://doi.org/10.1046/j.1365-3016.2001.00378.x https://doi.org/10.1046/j.1365-3016.2001.00378.x https://doi.org/10.1136/fn.88.1.f36 https://doi.org/10.1542/peds.2007-3753 https://doi.org/10.1055/s-0030-1248940 https://doi.org/10.1080/14767050600825607 https://doi.org/10.1016/s0020-7292%2898%2900230-6 https://doi.org/10.1016/s0020-7292%2898%2900230-6 https://doi.org/10.1002/14651858.cd009166.pub2 https://doi.org/10.1002/14651858.cd009166.pub2 https://doi.org/10.1016/j.ajog.2005.05.076 https://doi.org/10.1016/j.ajog.2005.05.076 https://doi.org/10.1067/mob.2000.109040 effectiveness of prophylactic cervical cerclage in prolonging higher-order multiple pregnancies e318 | squ medical journal, august 2017, volume 17, issue 3 16. berghella v, odibo ao, tolosa je. cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial. am j obstet gynecol 2004; 191:1311–17. doi: 10.1016/j.ajog. 2004.06.054. 17. to ms, alfirevic z, heath vc, cicero s, cacho am, williamson pr, et al. cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. lancet 2004; 363:1849–53. doi: 10.1016/s0140-6736(04)16351-4. 18. mrc/rcog working party on cervical cerclage. final report of the medical research council/royal college of obstetricians and gynaecologists multicentre randomised trial of cervical cerclage. br j obstet gynaecol 1993; 100:516–23. doi: 10.1111/ j.1471-0528.1993.tb15300.x. 19. mordel n, zajicek g, benshushan a, schenker jg, laufer n, sadovsky e. elective suture of uterine cervix in triplets. am j perinatol 1993; 10:14–16. doi: 10.1055/s-2007-994691. 20. elimian a, figueroa r, nigam s, verma u, tejani n, kirshenbaum n. perinatal outcome of triplet gestation: does prophylactic cerclage make a difference? j matern fetal med 1999; 8:119–22. doi: 10.1002/(sici)1520-6661(199905/06)8:3<119::aid-mfm9 >3.0.co;2-o. 21. strauss a, heer im, janssen u, dannecker c, hillemanns p, müller-egloff s. routine cervical cerclage in higher order multiple gestation: does it prolong the pregnancy? twin res 2002; 5:67–70. doi: 10.1375/1369052022910. 22. goldman ga, dicker d, peleg d, goldman ja. is elective cerclage justified in the management of triplet and quadruplet pregnancy? aust n z j obstet gynaecol 1989; 29:9–12. doi: 10.1111/j.1479-828x.1989.tb02867.x. 23. baker e, hunter t, okun n, farine d. current practices in the prediction and prevention of preterm birth in patients with higher-order multiple gestations. am j obstet gynecol 2015; 212:671.e1–7. doi: 10.1016/j.ajog.2014.12.031. https://doi.org/10.1016/j.ajog.2004.06.054 https://doi.org/10.1016/j.ajog.2004.06.054 https://doi.org/10.1016/s0140-6736%2804%2916351-4 https://doi.org/10.1111/j.1471-0528.1993.tb15300.x https://doi.org/10.1111/j.1471-0528.1993.tb15300.x https://doi.org/10.1055/s-2007-994691 https://doi.org/10.1002/%28sici%291520-6661%28199905/06%298:3%3c119::aid-mfm9%3e3.0.co%3b2-o https://doi.org/10.1002/%28sici%291520-6661%28199905/06%298:3%3c119::aid-mfm9%3e3.0.co%3b2-o https://doi.org/10.1375/1369052022910 https://doi.org/10.1111/j.1479-828x.1989.tb02867.x https://doi.org/10.1016/j.ajog.2014.12.031 department of oral medicine, school of dentistry, kerman university of medical sciences, kerman, iran *corresponding author e-mail: m_s_hashemipour@yahoo.com التحقق من مصداقية نسخة فارسية خمتصرة الستبيان موحد لتقييم معرفة وممارسات وتوجهات أطباء األسنان جتاه سرطان الفم نادر نفابي, مرمي ال�ضادات ها�ضميب�ر, عايده روغانى abstract: objectives: oral cancer is a global health problem; however, many dentists lack the necessary skills, knowledge and capacity to diagnose oral cancers early. this study aimed to examine the validity and reliability of a persian short-form version of a standardised questionnaire to assess dentists’ knowledge, practice and attitudes towards oral cancer. methods: this cross-sectional analytical study was carried out in may 2015 in tehran, iran. an original 39-item english-language questionnaire developed by yellowitz et al. was translated into persian using forward and backward translation methods. a total of 15 dental professionals were asked to assess the questionnaire for content validity. based on their feedback, a 20-item short-form version was prepared, including six demographic, six knowledge, four attitude and four practice items. the translated short-form questionnaire was subsequently distributed to 973 general dental practitioners attending a dental conference in tehran. internal consistency and reliability were assessed with cronbach’s alpha coefficient and item-total correlation calculations. results: a total of 13 professionals and 313 general dentists participated in the study (response rates: 86.7% and 32.2%, respectively). after the elimination of six items (two knowledge, two attitude and two practice items), the validity and reliability of the questionnaire was confirmed. conclusion: the final persian 14-item version of the questionnaire had acceptable validity and internal consistency. these results indicate that researchers can use this translated short-form version to evaluate oral cancer knowledge, attitudes and practices among persian-speaking dentists; this will allow for a comparison of data between different populations. keywords: oral cancer; knowledge; attitudes; dentists; validity and reliability; translations; questionnaire design; iran. واملعرفة الالزمة املهارات اإىل يفتقرون االأ�ضنان اأطباء من العديد فاإن ذلك, ومع عاملية �ضحية م�ضكلة الفم �رسطان الهدف: امللخ�ص: والقدرة على ت�ضخي�ص �رسطان الفم يف وقت مبكر. هدفت هذه الدرا�ضة اإىل درا�ضة م�ث�قية وم�ضداقية ن�ضخة فار�ضية خمت�رسة ال�ضتبيان م�حد لتقييم معرفة وممار�ضات وت�جهات اأطباء االأ�ضنان جتاه �رسطان الفم. الطريقة: اأجريت هذه الدرا�ضة التحليلية امل�ضتعر�ضة يف ماي� 2015 يف طهران, اإيران. مت ترجمة اال�ضتبيان االأ�ضلي الذي �ضممه يل�ويتز واملك�ن من 39 بند باللغة االإجنليزية اإىل الفار�ضية با�ضتخدام ن�ضخة اإعداد مت مالحظاتهم, على بناء املحت�ى. �ضحة حيث من اال�ضتبيان تقييم اأ�ضنان طبيب 15 من طلب خمتلفة. ترجمة اأ�ضاليب خمت�رسة مك�نة من 20 بند, منها �ضتة بن�د تتعلق بالدمي� غرافية, و�ضتة باملعرفة, واأربعة بالت�جهات واأربعة باملمار�ضة الطبية. مت ت�زيع اال�ضتبيان على 973 من ممار�ضي طب االأ�ضنان ح�رسوا م�ؤمتر طب االأ�ضنان يف طهران. مت تقييم االت�ضاق الداخلي وم�ث�قية اال�ضتبيان عن طريق معامل كرونباخ األفا وح�ضابات معامل ارتباط البن�د الكلي. النتائج: �ضارك 13 من املتخ�ض�ضني و 313 من ممار�ضي طب االأ�ضنان العام يف الدرا�ضة )معدالت اال�ضتجابة: %86.7 و %32.2 على الت�ايل( بعد حذف �ضتة عنا�رس )اثنني من املعرفة, واثنني من الت�جهات مقب�لة بند على 14 املحت�ية الفار�ضية الن�ضخة كانت اال�ضتبيان. اخلال�صة: وم�ضداقية م�ث�قية اإثبات مت الطبية(, املمار�ضة من واثنني امل�ضداقية واالت�ضاق الداخلي. ت�ضري النتائج اإىل اأنه من املمكن للباحثني ا�ضتخدام هذه الن�ضخة املرتجمة واملخت�رسة لتقييم اأطباء االأ�ضنان املتكلمني بالفار�ضية من حيث املعرفة ب�رسطان الفم وت�جهاتهم و ممار�ضاتهم الطبية يف هذا ال�ضدد؛ وهذا �ض�ف ي�ضمح ملقارنة البيانات بني جمم�عات خمتلفة من اأطباء االأ�ضنان. الكلمات املفتاحية: �رسطان الفم؛ املعرفه؛ االجتاهات؛ اأطباء االأ�ضنان؛ �ضحة وم�ث�قية؛ ترجمة؛ ت�ضميم اال�ضتبيان؛ اإيران. validation of a persian short-form version of a standardised questionnaire assessing oral cancer knowledge, practice and attitudes among dentists nader navabi, *maryam a. hashemipour, aida roughani advances in knowledge the results of the current study confirmed that the final persian 14-item version of an existing oral cancer questionnaire had acceptable validity and internal consistency. this version of the questionnaire can be used in other studies to assess knowledge, attitudes and practices associated with oral cancer among persian-speaking dentists. clinical & basic research sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e80–87, epub. 30 mar 17 submitted 8 aug 16 revision req. 21 sep 16; revision recd. 23 oct 16 accepted 3 nov 16 doi: 10.18295/squmj.2016.17.01.014 nader navabi, maryam a. hashemipour and aida roughani clinical and basic research | e81 oral cavity cancers are considered a major health risk, especially for individuals in developing countries; approximately 400,000 new cases of oral and pharyngeal cancer are identified annually worldwide.1 in addition, almost 13,000 deaths occur globally per year due to squamous carcinomas of the head and neck and there has been a relative increase in the incidence of oral cancer in recent decades.2 unfortunately, many oral cancer lesions are not diagnosed until they have reached advanced stages; for example, squamous cell carcinomas in the oropharynx may be confused with pharyngitis and viral tonsillitis, consequently resulting in delays in diagnosis and treatment.3 since the majority of individuals undergo dental check-ups at least once or twice a year, dentists can carry out thorough and accurate examinations of regions at high risk for oral cancer, potentially allowing for an early diagnosis.4 however, many dentists lack the necessary skills, knowledge and capacity to diagnose oral cancers early.4–6 previous studies have emphasised the importance of promoting knowledge of oral cancer among dentists so as to ensure rapid patient screening, successful treatments and decreased mortality rates.5,6 therefore, the design and implementation of a standard validated questionnaire in this field is important; it would reduce bias in relation to the selection of questions, thereby allowing a more accurate comparison of results from different studies. yellowitz et al. introduced the first comprehensive questionnaire to determine dentists’ knowledge, attitudes and practices in relation to oral cancer.7 however, many dentists did not have the time or inclination to answer all of the questions in the original 39-item questionnaire; the incomplete questionnaires resulted in a decrease in the accuracy of responses, thereby compromising the validity of the evalua tion.7 the present study was undertaken to validate a persian short-form version of yellowitz et al.’s original english-language questionnaire on dentists’ oral cancer knowledge, attitudes and practices.7 methods this cross-sectional analytical study took place in may 2015 in kerman and tehran, iran. an original english-language questionnaire for dentists developed by yellowitz et al. on oral cancer knowledge, attitudes and practices was translated into persian.7 five items (questions 22, 25, 31, 37 and 39) in the original questionnaire were deemed to be specific to the usa and were removed at the agreement of the translators and researchers. the resulting 34-item questionnaire was first translated based on standard principles; as such, two experts in translating dental technical terms separately carried out a literal translation of the original english-language questionnaire into persian.8 if the literal translation resulted in distortion of the meaning of a question, a conceptual translation was performed. subsequently, two other individuals translated the questionnaire back into english; these individuals were experienced in translating from persian into english and had not previously read the english version of the questionnaire. the resulting translations were then compared with the original text to identify possible discrepancies. discussions were held among all of the translators until an agreement on the final text was reached. final corrections were subsequently made to the questionnaire items with discrepancies.9 the final persian translation of the 34-item questionnaire was distributed to 10 oral medicine and five oral/maxillofacial pathology specialists from kerman dental school, kerman. in order to prepare a short-form version of the questionnaire, the specialists were asked to evaluate the questionnaire and identify items that could be removed. as per the feedback obtained, only items deemed necessary by >80% of the specialists were included in the shortform version of the questionnaire.9 this resulted in the final inclusion of six demographic and 14 oral cancer items (six knowledge, four attitude and four practice items). one of the questions eliminated from the final version was related to precancerous lesions. subsequently, a total of 973 general dental practitioners participating in the 55th annual congress of the iranian dental association in tehran were recruited via a convenience sampling method to complete the persian short-form version of the questionnaire. the necessary sample size was calculated to be 300 (α = 95%; d = 0.05; p = 38%).10 completed questionnaires in which over 30% of the questions were unanswered were not included in the analysis. data from the questionnaire responses were analysed using the statistical package for the social sciences (spss), version 21 (ibm corp., chicago, application to patient care improved knowledge, attitudes and practices among dentists can help prevent oral cancers or ensure an early diagnosis, thus improving patient survival rates. validation of a persian short-form version of a standardised questionnaire assessing oral cancer knowledge, practice and attitudes among dentists e82 | squ medical journal, february 2017, volume 17, issue 1 illinois, usa). results were analysed descriptively using a student’s t-test and chi-squared test. the internal consistency and reliability of the questionnaire items were determined using cronbach’s alpha coefficients and item-total correlations.8,9 acceptable cut-off values for cronbach’s alpha coefficients and item-total correlations were set at ≥0.70 and ≥0.30, respectively. if an item resulted in an unacceptable coefficient value, the item was eliminated and the coefficient was recalculated; if the new coefficient was subsequently acceptable, the item was removed entirely from the final version of the questionnaire. for attitude items, items were scored on a five-point likert scale, with scores of 1 indicating strongly disagree and 5 indicating strongly agree. the protocol for this study was approved by the ethics committee of the kerman university of medical sciences, kerman, iran (#k.95.62). informed oral consent was obtained from all of the dentists before participating in this study. all personal and identifying information was kept confidential. results the persian short-form version of the questionnaire was completed by 323 general dentists; however, a total of 10 questionnaires were excluded from the study due to unclear responses and a lack of demographic data, resulting in a final sample size of 313 participants (response rate: 32.2%). table 1 presents the demographic characteristics of the participants. no significant differences were found between demographic characteristics and oral cancer knowledge, attitudes or practices. with regards to the six knowledge items, the second item had the highest table 1: demographic characteristics of general dental practitioners in tehran, iran (n = 313) characteristic n (%) employment status private practice 158 (50.5) clinic 83 (26.5) other 72 (23.0) year of graduation ≤1979 14 (4.5) 1980–1989 21 (6.7) 1990–1999 69 (22.0) 2000–2009 111 (35.5) 2010–2016 98 (31.3) age in years <40 187 (59.7) 40–60 107 (34.2) ≥60 19 (6.1) gender male 186 (59.4) female 127 (40.6) previous participation in oral cancer cme programmes last year 45 (14.4) 2–5 years before 69 (22.0) >5 years before 34 (10.9) never 104 (33.2) new graduate 24 (7.7) not sure 37 (11.8) interest in participating in future oral cancer cme programmes yes 257 (82.1) no 22 (7.0) not sure 34 (10.9) cme = continuing medical education. table 2: internal consistency and reliability of oral cancer knowledge items in a persian short-form version of a standardised questionnaire* completed by general dental practitioners in tehran, iran (n = 313) item frequency,† % cronbach’s alpha coefficient‡ i-t corr. 1. the most common site of oral cancer besides the lips is the tongue and oral cavity floor 26.7 0.32 0.33 2. the most common form of oral cancer is squamous cell carcinoma 66.7 0.22 0.42 3. oral cancer typically presents at 30–49 years of age 33.3 0.33 0.31 4. in oral cancer, metastatic lymph nodes are fixed and nontender, with a stony-hard consistency 48.6 0.21 0.42 5. a two-finger method is the right method for a tongue examination for oral cancer 66.3 0.37 0.05 6. tobacco and alcohol consumption are the most common risk factors for oral cancer 26.7 0.34 0.12 i-t corr = item-total correlation. *an english-language questionnaire on dentists’ oral cancer knowledge, attitudes and practices developed by yellowitz et al.7 †using correct responses only. ‡this value represents the cronbach’s alpha coefficient after elimination of the item from the questionnaire. nader navabi, maryam a. hashemipour and aida roughani clinical and basic research | e83 rate of correct responses (66.7%). the elimination of any of these six items did not result in acceptable cronbach’s alpha values; however, items five and six were eliminated due to their low item-total correlation coefficients (0.05 and 0.12, respectively) [table 2]. for the four attitude items, calculation of the item-total correlation coefficients resulted in the elimination of items one and two [table 3]. in addition, the initial overall cronbach’s alpha value for all of the attitude items was 0.32; this increased to 0.62 (close to the cut-off value of 0.70) after elimination of these two items, indicating the necessity of their removal from the final version of the questionnaire. in the practice section, elimination of none of the individual items resulted in acceptable cronbach’s alpha coefficients [table 4]. the overall cronbach’s alpha coefficient for all of the practice items was 0.11; however, following the removal of items one and two, this was recalculated to be 0.64 (close to the cut-off value of 0.70). in addition, these two items exhibited unacceptable item-total correlation coefficients (0.21 and 0.04, respectively). therefore, these two practice items were subsequently eliminated from the final version of the questionnaire. an english version of the final short-form questionnaire is shown in table 5. discussion the current study sought to validate a persian short-form version of an existing english-language questionnaire assessing dentists’ knowledge, practice and attitudes towards oral cancer.7 the original questionnaire was translated from english into persian and then back into english; however, this process can introduce errors. it is vital that the original intention of the author of a questionnaire item not be changed during translation, as the purpose of the translation process is not to rephrase or improve an existing instrument.11 fortunately, the majority of the suggestions made by the specialist evaluators in the current study referred to the style of the translation table 3: reliability of oral cancer attitude items in a persian short-form version of a standardised questionnaire* completed by general dental practitioners in tehran, iran (n = 313) item frequency,† % i-t corr. 1. i received adequate oral cancer education at my previous dental school 41.3 0.01 2. the quality of my previous education about oral cancer examinations is adequate 54.3 0.11 3. a) my knowledge of oral cancer is up-to-date b) it is necessary to perform annual oral cancer screening examinations for patients >40 years old c) it is easy to refer patients with suspicious lesions to oral cancer specialists d) the early detection of oral cancer increases five-year survival rates 26.7 82.2 92.7 87.9 0.34 0.32 0.31 0.31 4. a) i am well-trained in providing education on smoking cessation b) i am well-trained in performing oral cancer examinations c) the majority of dentists can competently perform oral cancer examinations d) the majority of physicians can competently perform oral cancer examinations 27.9 29.2 20.2 13.4 0.32 0.32 0.33 0.32 i-t corr = item-total correlation. *an english-language questionnaire on dentists’ oral cancer knowledge, attitudes and practices developed by yellowitz et al.7 †including positive attitudes only. table 4: internal consistency and reliability of oral cancer practice items in a persian short-form version of a standardised questionnaire* completed by general dental practitioners in tehran, iran (n = 313) item frequency, % cronbach’s alpha coefficient† i-t corr. 1. number of biopsies of suspicious lesions performed in the last year a) 0 b) <10 c) ≥10 64.8 30.6 4.6 0.41 0.21 2. number of patients with suspicious lesions referred to specialists in the last year a) 0 b) <10 c) ≥10 23.2 65.2 11.6 0.40 0.04 3. referral department for patients with suspicious lesions: a) oral medicine b) other 94.2 5.8 0.31 0.28 4. factors evaluated during history-taking: a) smoking b) alcohol consumption c) smoking type and frequency d) history of other cancers e) family history of cancer 87.2 76.5 76.5 75.9 75.2 0.13 0.11 0.12 0.13 0.14 0.54 0.46 0.52 0.53 0.55 i-t corr = item-total correlation. *an english-language questionnaire on dentists’ oral cancer knowledge, attitudes and practices developed by yellowitz et al.7 †this value represents the cronbach’s alpha coefficient after elimination of the item from the questionnaire. validation of a persian short-form version of a standardised questionnaire assessing oral cancer knowledge, practice and attitudes among dentists e84 | squ medical journal, february 2017, volume 17, issue 1 and no translation errors were reported. overall, the persian short-form version of the questionnaire exhibited suitable validity and reliability; this is consistent with the findings of other studies.9,12 the availability of high-quality translations is of vital importance in order to guarantee the successful implementation of existing questionnaires in other non-english-speaking populations and to assure the international comparability of the results. a key issue with existing oral cancer questionnaires is variations in the total number of questions, which can range from approximately 12–50.13–15 consequently, this results in divergent scores, making it impossible to compare total scores between studies; for example, razavi et al. reported an acceptable knowledge score to be ≥53.8% (seven or more correct responses out of 13 questions) among iranian dentists, while honarmand et al. reported poor knowledge scores to be ≤33.3% (less than four correct responses out of 12 questions) among senior dental students in iran.13,15 kujan et al. reported that 81% of saudi undergraduate dental students correctly answered all knowledge questions, although the researchers did not define what constituted acceptable knowledge scores.14 in the current study, 26.7% of the dentists correctly answered the knowledge item related to the most common location of oral cancers; this is low in comparison to previous results from the usa and iran (39% and 80.9%, respectively).16,17 furthermore, in the study conducted in iran, borhan-mojabi et al. found that only 25.7% of general medical and dental practitioners were aware that the oral cavity floor is a high-risk area for oral cancer.17 in contrast, dumitrescu et al. reported that 54.3% of romanian dental students were aware of this fact.18 overall, 66.7% of respondents in the present study correctly identified the most common form of oral cancer; this is lower than the percentage of correct responses reported by alaizari et al. (82.8%) and higher than those reported by colella et al. (50.5%) and rochabuelvas et al. (52.69%).19–21 various factors may affect differences in knowledge among dentists, such as potential differences in undergraduate dental curricula worldwide. a total of 33.3% of the dentists in the current study were aware of the predominant age range in which oral cancer presents. in comparison, vijay kumar et al. reported that 59% of indian dentists correctly responded to this question.22 lópezjornet et al. reported that short-term oral cancer knowledge scores among the general population increased following an educational intervention.23 with regards to knowledge of the metastatic lymph node characteristics of oral cancer, 48.6% of respondents in the current study provided correct responses. decuseara et al. reported that 54% of irish dentists in their study had been adequately trained to palpate lymph nodes to detect oral cancer.24 it is often difficult to determine which aspects of oral cancer are most important and should be prioritised in questionnaires assessing oral cancer knowledge. common symptoms of oral cancer and awareness of diagnostic tools, such as cytology smears, are rarely emphasised.14,16,20 a major difference between the final short-form version of the questionnaire used in the present study and those of similar studies was the lack of inclusion of questions assessing awareness of the main risk factors for oral cancer (i.e. smoking and alcohol use).19,22,25,26 one reason for removing this table 5: questionnaire items included in the final persian short-form 14-item version of a standardised questionnaire* assessing oral cancer knowledge, practice and attitudes among dentists questionnaire items† knowledge 1. the most common site of oral cancer besides the lips is the tongue and oral cavity floor 2. the most common form of oral cancer is squamous cell carcinoma 3. oral cancer typically presents at 30–49 years of age 4. in oral cancer, metastatic lymph nodes are fixed and nontender, with a stony-hard consistency attitude 5. a) my knowledge of oral cancer is up-to-date b) it is necessary to perform annual oral cancer screening examinations for patients >40 years old c) it is easy to refer patients with suspicious lesions to oral cancer specialists d) the early detection of oral cancer increases five-year survival rates 6. a) i am well-trained in providing education on smoking cessation b) i am well-trained in performing oral cancer examinations c) the majority of dentists can competently perform oral cancer examinations d) the majority of physicians can competently perform oral cancer examinations practice 7. referral department for patients with suspicious lesions: a) oral medicine b) other 8. factors evaluated during history-taking: a) smoking b) alcohol consumption c) smoking type and frequency d) history of other cancers e) family history of cancer *an english-language questionnaire on dentists’ oral cancer knowledge, attitudes and practices developed by yellowitz et al.7 †not including six demographic items included in the final questionnaire. nader navabi, maryam a. hashemipour and aida roughani clinical and basic research | e85 item from the final version of the short-form questionnaire was because it was deemed relatively easy in comparison to other knowledge-related questions. however, horowitz et al. reported low overall knowledge of risk factors and signs or symptoms of oral cancer among adults in the general population.27 the inclusion of such questions should be re-evaluated in future studies. with regards to attitudes towards oral cancer, 29.2% of iranian respondents in the current study believed that they were well-trained in the performance of oral cancer examinations; this finding is much lower than that reported by colella et al. (64.8%).20 carter et al. found that significantly more general dental practitioners than general medical practitioners routinely inspected the oral mucosa during patient examinations (95.49% versus 20.17%; p <0.001).28 in the present study, 82.1% of the iranian dentists expressed an interest in attending continuing education programmes regarding oral cancer; this is higher than that reported by shaila et al. (72%) and gajendra et al. (75%).29,30 dentists have also indicated a need for more training to detect oral cancer, for example in studies by ariyawardana et al. (70%), jaber et al. (37.6%) and alaizari et al. (86%).19,31,32 overall, few participants in the current study believed that their oral cancer knowledge was up-todate (26.7%). in a study by decuseara et al., 53% of respondents provided positive responses to a similar question.24 carter et al. also reported that significantly fewer general medical practitioners felt that they had sufficient knowledge regarding the prevention and detection of oral cancers in comparison to general dental practitioners (25.2% versus 54.1%; p <0.001); however, both general medical and dental practitioners requested further oral cancer training (71.4% and 80.4%, respectively).28 the majority of the dentists in the current study believed that annual oral cancer examinations were necessary for patients over 40 years old (82.2%). responses to questionnaire items in the practice section indicated that 94.2% of respondents in the present study referred patients with suspicious oral lesions to specialists; this was consistent with the findings of vijay kumar et al. and dumitrescu et al. (98% and 92.9%, respectively).18,22 in addition, the majority of iranian dentists in the current study questioned patients about their history of other cancers (75.9%), family history of cancer (75.2%) and smoking habits (87.2%). in a study by rochabuelvas et al., 22.8% of south colombian dentists asked their patients about a family history of cancer while tanriover et al. found that 70.1% of turkish primary care physicians asked patients about their tobacco use habits.21,33 only 27.9% of iranian dentists in the present study believed that they possessed the necessary training to instruct their patients on how to quit smoking; in contrast, kujan et al. observed this rate to be 63% among saudi dental undergraduates.14 several studies have posed this question in different formats.22,24,29,34 it should be noted that 57% of the undergraduate dental students in kujan et al.’s study believed that it was not their responsibility to encourage patients to give up smoking.14 in the final short-form version of the questionnaire designed in the present study, the questionnaire item on the number of biopsies taken was removed; moreover, no items on the number of oral cancer examinations performed were included. previously, shaila et al. reported that 29.5% of indian dentists took biopsy samples of questionable lesions.29 several previous studies have assessed the number of oral cancer examinations performed among dentists.16,22,24,35 future research should seek to determine the necessity of including such questions in this type of questionnaire. determining the awareness, attitudes and practices related to oral cancer among dentists is critical; however, homogeneous study tools are necessary to ensure that the evidence and conclusions drawn from specific research is more widely applicable and comparable between population groups. in addition, short-form questionnaires may result in larger sample sizes, as participants are more likely to complete the entire questionnaire. however, the current study was subject to certain limitations. it is likely that those who did not answer all of the questions had poorer knowledge in comparison to those who did. as such, the knowledge levels of the dentists reported in the current study may have been inaccurate, hence weakening the validity of the results. further studies are recommended to improve the potential weaknesses of this study. conclusion the findings from this study indicate that the final persian 14-item version of a standard questionnaire had acceptable validity and internal consistency. researchers can use this short-form questionnaire to evaluate persian-speaking dentists’ knowledge of, attitudes towards and practices associated with oral cancer. this would subsequently allow for greater comparison of findings between different populations. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. validation of a persian short-form version of a standardised questionnaire assessing oral cancer knowledge, practice and attitudes among dentists e86 | squ medical journal, february 2017, volume 17, issue 1 f u n d i n g this study was supported by the kerman dental & oral diseases research center and a grant from the vice chancellor for research of the kerman university of medical sciences (grant #k.95.62). references 1. international agency for research on cancer, world health organization. world cancer report 2008. from: www.iarc.fr/ en/publications/pdfs-online/wcr/2008/ accessed: oct 2016. 2. shah jp, lydiatt w. treatment of cancer of the head and neck. ca cancer j clin 1995; 45:352–68. doi: 10.3322/canjc lin.45.6.352. 3. jafari a, najafi sh, moradi f, kharazifard m, khami m. delay in the diagnosis and treatment of oral cancer. j dent (shiraz) 2013; 14:146–50. 4. monteiro ls, warnakulasuriya s, cadilhe s, sousa d, trancoso pf, antunes l, et al. oral cancer awareness and knowledge among residents in the oporto city, portugal. j investig clin dent 2016; 7:294–303. doi: 10.1111/jicd.12158. 5. maybury c, horowitz am, yan af, green km, wang mq. maryland dentists’ knowledge of oral cancer prevention and early detection. j calif dent assoc 2012; 40:341–50. 6. alami ay, el sabbagh rf, hamdan a. knowledge of oral cancer among recently graduated medical and dental professionals in amman, jordan. j dent educ 2013; 77:1356–64. 7. yellowitz ja, goodman hs. assessing physicians’ and dentists’ oral cancer knowledge, opinions and practices. j am dent assoc 1995; 126:53–60. doi: 10.14219/jada.archive.1995.0024. 8. navabi n, nakhaee n, mirzadeh a. validation of a persian version of the oral health impact profile (ohip-14). iran j public health 2010; 39:135–9. 9. slade gd. derivation and validation of a short-form oral health impact profile. community dent oral epidemiol 1997; 25:284–90. doi: 10.1111/j.1600-0528.1997.tb00941.x. 10. kadam p, bhalerao s. sample size calculation. int j ayurveda res 2010; 1:55–7. doi: 10.4103/0974-7788.59946. 11. koller m, aaronson nk, blazeby j, bottomley a, dewolf l, fayers p, et al. translation procedures for standardised quality of life questionnaires: the european organisation for research and treatment of cancer (eortc) approach. eur j cancer 2007; 43:1810–20. doi: 10.1016/j.ejca.2007.05.029. 12. yellowitz ja, horowitz am, drury tf, goodman hs. survey of u.s. dentists’ knowledge and opinions about oral phar yngeal cancer. j am dent assoc 2000; 131:653–61. doi: 10.14 219/jada.archive.2000.0239. 13. razavi sm, zolfaghari b, foroohandeh m, doost me, tahani b. dentists’ knowledge, attitude, and practice regarding oral cancer in iran. j cancer educ 2013; 28:335–41. doi: 10.1007/ s13187-013-0460-6. 14. kujan o, alzoghaibi i, azzeghaiby s, altamimi ma, tarakji b, hanouneh s, et al. knowledge and attitudes of saudi dental undergraduates on oral cancer. j cancer educ 2014; 29:735–8. doi: 10.1007/s13187-014-0647-5. 15. honarmand m, hajihosseini a, akbari f. oral cancer knowledge of senior dental students in zahedan, south-east of iran. asian pac j cancer prev 2014; 15:3017–20. doi: 10.7314/ apjcp.2014.15.7.3017. 16. applebaum e, ruhlen tn, kronenberg fr, hayes c, peters es. oral cancer knowledge, attitudes and practices: a survey of dentists and primary care physicians in massachusetts. j am dent assoc 2009; 140:461–7. doi: 10.14219/jada.arch ive.2009.0196. 17. borhan-mojabi k, moradi a, yazdabadi a. evaluating the degree of knowledge on oral cancer among general practitioners and dentists in qazvin. j eval clin pract 2012; 18:498–501. doi: 10.1111/j.1365-2753.2010.01613.x. 18. dumitrescu al, ibric s, ibric-cioranu v. assessing oral cancer knowledge in romanian undergraduate dental students. j cancer educ 2014; 29:506–13. doi: 10.1007/s13187-014-0659-1. 19. alaizari na, al-maweri sa. oral cancer: knowledge, practices and opinions of dentists in yemen. asian pac j cancer prev 2014; 15:5627–31. doi: 10.7314/apjcp.2014.15.14.5627. 20. colella g, gaeta gm, moscariello a, angelillo if. oral cancer and dentists: knowledge, attitudes, and practices in italy. oral oncol 2008; 44:393–9. doi: 10.1016/j.oraloncology.2007.05.005. 21. rocha-buelvas a, hidalgo-patiño c, collela g, angelillo i. oral cancer and dentists: knowledge, attitudes and practices in a south colombian context. acta odontol latinoam 2012; 25:155–62. 22. vijay kumar kv, suresan v. knowledge, attitude and screening practices of general dentists concerning oral cancer in bangalore city. indian j cancer 2012; 49:33–8. doi: 10.4103/0019-509x. 98915. 23. lópez-jornet p, camacho-alonso f, miñano fm, sanchezsiles m. evaluation of the different strategies to oral cancer knowledge: a randomized controlled study. psychooncology 2013; 22:1618–23. doi: 10.1002/pon.3189. 24. decuseara g, maccarthy d, menezes g. oral cancer: knowledge, practices and opinions of dentists in ireland. j ir dent assoc 2011; 57:209–14. 25. al-maweri sa, addas a, tarakji b, abbas a, al-shamiri hm, alaizari na, et al. public awareness and knowledge of oral cancer in yemen. asian pac j cancer prev 2014; 15:10861–5. doi: 10.7314/apjcp.2014.15.24.10861. 26. rahman b, hawas n, rahman mm, rabah af, al kawas s. assessing dental students’ knowledge of oral cancer in the united arab emirates. int dent j 2013; 63:80–4. doi: 10.1111/ idj.12017. 27. horowitz am, moon hs, goodman hs, yellowitz ja. maryland adults’ knowledge of oral cancer and having oral cancer examinations. j public health dent 1998; 58:281–7. doi: 10.1111/j.1752-7325.1998.tb03010.x. 28. carter lm, ogden gr. oral cancer awareness of general medical and general dental practitioners. br dent j 2007; 203:e10. doi: 10.1038/bdj.2007.630. 29. shaila m, shetty p, decruz am, pai p. the self-reported knowledge, attitude and the practices regarding the early detection of oral cancer and precancerous lesions among the practising dentists of dakshina kannada: a pilot study. j clin diagn res 2013; 7:1491–4. doi: 10.7860/jcdr/2013/5321.3171. 30. gajendra s, cruz gd, kumar jv. oral cancer prevention and early detection: knowledge, practices, and opinions of oral health care providers in new york state. j cancer educ 2006; 21:157–62. 31. ariyawardana a, ekanayake l. screening for oral cancer/precancer: knowledge and opinions of dentists employed in the public sector dental services of sri lanka. asian pac j cancer prev 2008; 9:615–18. https://doi.org/10.3322/canjclin.45.6.352 https://doi.org/10.3322/canjclin.45.6.352 https://doi.org/10.1111/jicd.12158 https://doi.org/10.14219/jada.archive.1995.0024 https://doi.org/10.1111/j.1600-0528.1997.tb00941.x https://doi.org/10.4103/0974-7788.59946 https://doi.org/10.1016/j.ejca.2007.05.029 https://doi.org/10.14219/jada.archive.2000.0239 https://doi.org/10.14219/jada.archive.2000.0239 https://doi.org/10.1007/s13187-013-0460-6 https://doi.org/10.1007/s13187-013-0460-6 https://doi.org/10.1007/s13187-014-0647-5 https://doi.org/10.7314/apjcp.2014.15.7.3017 https://doi.org/10.7314/apjcp.2014.15.7.3017 https://doi.org/10.14219/jada.archive.2009.0196 https://doi.org/10.14219/jada.archive.2009.0196 https://doi.org/10.1111/j.1365-2753.2010.01613.x https://doi.org/10.1007/s13187-014-0659-1 https://doi.org/10.7314/apjcp.2014.15.14.5627 https://doi.org/10.1016/j.oraloncology.2007.05.005 https://doi.org/10.4103/0019-509x.98915 https://doi.org/10.4103/0019-509x.98915 https://doi.org/10.1002/pon.3189 https://doi.org/10.7314/apjcp.2014.15.24.10861 https://doi.org/10.1111/idj.12017 https://doi.org/10.1111/idj.12017 https://doi.org/10.1111/j.1752-7325.1998.tb03010.x https://doi.org/10.1038/bdj.2007.630 https://doi.org/10.7860/jcdr/2013/5321.3171 nader navabi, maryam a. hashemipour and aida roughani clinical and basic research | e87 32. jaber l, shaban s, hariri d. oral cancer prevention and early detection: knowledge and practice among saudi arabian healthcare practitioners. int j health care qual assur 2012; 25:64–74. doi: 10.1108/09526861211192412. 33. tanriover o, hidiroglu s, save d, akan h, ay p, karavus m, et al. knowledge of oral cancer, preventive attitudes, and behaviors of primary care physicians in turkey. eur j cancer prev 2014; 23:464–8. doi: 10.1097/cej.0000000000000020. 34. awan kh, khang tw, yee tk, zain rb. assessing oral cancer knowledge and awareness among malaysian dental and medical students. j cancer res ther 2014; 10:903–7. doi: 10.4103/09731482.138011. 35. lehew cw, kaste lm. oral cancer prevention and early detection knowledge and practices of illinois dentists: a brief communication. j public health dent 2007; 67:89–93. doi: 10.1111/j.1752-7325.2007.00020.x. https://doi.org/10.1108/09526861211192412 https://doi.org/10.1097/cej.0000000000000020 https://doi.org/10.4103/0973-1482.138011 https://doi.org/10.4103/0973-1482.138011 https://doi.org/10.1111/j.1752-7325.2007.00020.x 1department of pulmonary medicine, kolkata medical college & hospital, kolkata, west bengal, india; 2department of pathology, murshidabad medical college & hospital, murshidabad, west bengal, india; 3department of neurology, amri hospital, kolkata, west bengal, india *corresponding author’s e-mail: dravradip@gmail.com سل قيب يف طفل ما قبل املدرسة ظاهرة غري شائعة اأفراديب �صانرتا، اأرايا �صن، اأتري �صاتارجي abstract: calvarial tuberculosis is a rare manifestation of tuberculosis, especially in children under five years of age. we report a two-and-a-half-year-old male child who presented to the nilratan sircar medical college, kolkata, india, in 2015 with frontoparietal fluctuant swelling of three months’ duration. he had also had chronic sinus discharge from the left lower eyelid over the previous six months. computed tomography of the head revealed a frontal swelling along with erosion of both the outer and inner plates of the left frontal bone. fine needle aspiration of the pus indicated the presence of acid-fast bacilli. unfortunately, no primary focus of tuberculosis could be established. the patient improved after one year of antitubercular therapy without requiring any surgical intervention and with no sign of subsequent disease recurrence. keywords: tuberculosis; skull; preschool child; antitubercular agents; case report; india. امللخ�ص: ال�صل القبي هو ظاهرة نادرة لل�صل، وبالأخ�ض يف الأطفال حتت عمر اخلم�ض �صنوات. نعر�ض هنا حالة طفل ذكر عمره �صنتان ون�صف مت عر�صه لكلية نلراتان �رشكار الطبية، كالكتا، الهند، عام 2015 وكان م�صاب بورم جبهي جداري متموج ملدة ثالثة اأ�صهر. وكان اأي�صا م�صاب بخراج جيب مزمن من اجلهة الي�رشى للجفن ال�صفلي خالل ال�صتة اأ�صهر املا�صية. الأ�صعة املقطعية للراأ�ض اأظهرت وجود ورم ع�صيات وجود للخراج اأظهرت الدقيقة ال�صافطة الأبرة اجلبهي. للعظم الي�صار جهة من والداخلي اخلارجي اللوح يف تاآكل يرافقه جبهي �صادمة للحم�ض. ل�صوء احلظ مل يتم التعرف على البوؤرة الأوىل لل�صل. حت�صن املري�ض بعد مرور �صنة على اأ�صتخدام عالج م�صادات ال�صل بدون احلاجة للتدخل اجلراحي مع عدم وجود ظواهر لعودة املر�ض. الكلمات املفتاحية: ال�صل؛ اجلمجمة؛ طفل ما قبل املدر�صة؛ م�صادات ال�صل؛ تقرير حالة؛ الهند. calvarial tuberculosis in a preschool-aged child an uncommon entity *avradip santra,1 arya sen,2 atri chatterjee3 sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e484–486, epub. 10 jan 18 submitted 10 jul 17 revision req. 12 sep 17; revision recd. 2 oct 17 accepted 26 oct 17 case report doi: 10.18295/squmj.2017.17.04.020 calvarial tuberculosis (tb) is a rare form of extrapulmonary tb arising in the calvarial bones of the skull; despite the high prevalence of tb in india, this form of tb is encountered infrequently.1 nevertheless, the incidence of calvarial tb is on the rise due to malnutrition, poor socioeconomic conditions and an increase in the prevalence of hiv/aids and other immunodeficiency conditions.2 this report describes a rare case of calvarial tb occurring in a preschool-aged child who presented with a left frontoparietal swelling. case report a two-and-a-half-year-old male child presented to the neurology outpatient department of the nilratan sircar medical college in kolkata, india, in 2015 with a gradually progressive yet painless swelling on the left side of the head of three months’ duration associated with a low-grade fever. there was no history of severe head trauma, coughing, loss of appetite or failure to thrive. six months previously, the child had experienced trivial trauma to the lateral aspect of the left eye and head; this was followed by swelling of the lateral part of the lower left eyelid. an ophthalmologist had diagnosed this as an abscess and incision and drainage of the area was performed. however, intermittent serous discharge from the eyelid continued to occur despite repeated courses of antibiotics. the child’s father had a history of tb lymphadenitis, for which he had completed six months of directly observed treatment short course (dots) antitubercular therapy (att) one year previously. all of the child’s immunisations were up-to-date, including the bacillus calmette-guerin (bcg) vaccine which he had received when he was three days old. on examination, the child appeared healthy, wellnourished and weighed 13 kg. his vital parameters were all within normal limits. a fluctuant non-tender swelling of 4 x 3 cm in size was noted over the left frontoparietal area without any evidence of overlying inflammation [figure 1]. in terms of visual acuity, the patient had a 6/6 snellen equivalent fraction as measured using a crowded acuity test (kay pictures avradip santra, arya sen and atri chatterjee case report | e485 ltd., tring, hertfordshire, uk). an ocular examination was normal, except for the small discharging sinus present over the lateral part of the lower left palpebra. a characteristic bcg scar was present on the lateral aspect of the patient’s left arm and a single small non-tender left submandibular lymph node was palpable. the rest of the physical examination was essentially normal. a complete blood count revealed mild anaemia with a haemoglobin level of 10.6 g/dl. the total leucocyte count was 11,000/mm3, with 48% neutrophils and 46% lymphocytes. the results of renal function, liver function and serum electrolyte tests were all within normal ranges. subsequently, a non-contrast computed tomo graphy (ct) scan of the brain showed a well-defined hypodense lesion of 3 x 2.5 cm over the left frontal region of the scalp, along with erosion of the underlying left frontal bone [figure 2]. fine needle aspiration (fna) of the scalp swelling yielded purulent material and a ziehl-neelsen stain indicated the presence of acid-fast bacilli (afb) [figure 3]. the fna cytology panel also indicated the presence of an epithelioid granuloma and langhans giant cells on a caseonecrotic background. a cartridge-based nucleic acid amplification test also confirmed the presence of a rifampicin-sensitive mycobacterium tuberculosis complex. however, both a chest x-ray and ultrasonography of the abdomen did not reveal any abnormalities. due to its small size, fna cytology of the left submandibular lymph node was not attempted. an afb smear of the serous discharge from the left lower eyelid sinus was negative. however, a mantoux test with two tuberculin units was positive with an induration of 14 mm. a final diagnosis of microbiologically-confirmed calvarial tb was made, although a primary focus could not be determined. category i dots att was initiated as per the revised national tuberculosis control programme (rntcp) guidelines.3 this consisted of a two-month intensive phase of treatment with the thrice weekly administration of 150 mg of rifampicin, 150 mg of isoniazid, 400 mg of ethambutol and 500 mg of pyrazinamide, followed by a 10-month continuation phase involving the thrice weekly admin istration of 150 mg of rifampicin and 150 mg of isoniazid. while the patient was receiving att, the scalp swelling and left submandibular lymphadenopathy gradually reduced in size and the lower left eyelid lesion healed completely. no surgical intervention was required. at the time of writing, the patient had been under observation for one year following the completion of att, with no sign of disease recurrence. discussion among all active tb cases, approximately 1–2% have involvement of the skeletal system of which only 0.2–1.3% constitute calvarial tb.1 due to its rarity, a high degree of clinical suspicion is essential to enable early identification of this entity as it can cause extensive bony destruction and significant neurological impairment if left untreated.4 in particular, younger figure 1: photograph of a two-and-a-half-year-old male child with a swelling in the left frontoparietal area (black arrow). a small discharging sinus can be seen in the lateral part of the left lower palpebra (white arrow). figure 2: computed tomography scans of the brain of a two-and-a-half-year-old male child from the (a) reconstructed sagittal and (b) axial views showing a hypodense lesion in the left frontal region of the scalp (white arrow). note the erosion of the underlying left frontal bone (black arrow). figure 3: ziehl-neelsen stain at x1,000 magnification confirming the presence of acid-fast bacilli (arrow) against a caseonecrotic background. calvarial tuberculosis in a preschool-aged child an uncommon entity e486 | squ medical journal, november 2017, volume 17, issue 4 central nervous system tb, consisting of a two-month intensive phase followed by a 10-month continuation phase.3 however, att may be administered for up to 24 months depending on the clinicoradiological response. surgical intervention may be required, especially in cases with large extradural collections causing neurodeficits or large scalp swellings with sinus formation, with some evidence to suggest that combined surgery and att may yield better outcomes than att alone.12 conclusion calvarial tb is an extremely rare form of skeletal tb which needs to be diagnosed early. among young patients, tb of the skull should be considered as a differential diagnosis, particularly among those presenting with a frontoparietal swelling within the first two decades of life, even if there is no evidence of active tb in other parts of the body. with or without surgical intervention, att remains the cornerstone of therapy for this condition. references 1. diyora b, kumar r, modgi r, sharma a. calvarial tuberculosis: a report of eleven patients. neurol india 2009; 57:607–12. doi: 10.4103/0028-3886.57814. 2. millet jp, moreno a, fina l, del baño l, orcau a, de olalla pg, et al. factors that influence current tuberculosis epidemiology. eur spine j 2013; 22:539–48. doi: 10.1007/s00586-012-2334-8. 3. kumar a, gupta d, nagaraja sb, singh v, sethi gr, prasad j; indian academy of pediatrics. updated national guidelines for pediatric tuberculosis in india, 2012. indian pediatr 2013; 50:301–6. 4. rajmohan bp, anto d, alappat jp. calvarial tuberculosis. neurol india 2004; 52:278–9. 5. raut aa, nagar am, muzumdar d, chawla aj, narlawar rs, fattepurkar s, et al. imaging features of calvarial tuberculosis: a study of 42 cases. ajnr am j neuroradiol 2004; 25:409–14. 6. zaki s, dadge d, shanbag p. calvarial tuberculosis. int j infect dis 2010; 14:e86–7. doi: 10.1016/j.ijid.2009.03.014. 7. shakarchi fi. ocular tuberculosis: current perspectives. clin ophthalmol 2015; 9:2223–7. doi: 10.2147/opth.s65254. 8. narsani ak, jatoi sm, dabir sa. isolated eyelid tuberculosis. j liaquat univ med health sci 2007; 6:37–9. 9. meng cm, wu yk. tuberculosis of the flat bones of the vault of the skull: a study of forty cases. j bone joint surg 1942; 24:341–53. 10. barton cj. tuberculosis of the vault of skull. br j radiol 1961; 34:286–90. doi: 10.1259/0007-1285-34-401-286. 11. awasthy n, chand k, singh a. calvarial tuberculosis: review of six cases. ann indian acad neurol 2006; 9:227–9. doi: 10. 4103/0972-2327.29205. 12. ip m, tsui e, wong kl, jones b, pung cf, ngan h. disseminated skeletal tuberculosis with skull involvement. tuber lung dis 1993; 74:211–14. doi: 10.1016/0962-8479(93)90015-p. individuals are at higher risk of developing tb of the skull; raut et al. reported 42 cases of calvarial tb over a 10-year period, with an age range of 5–48 years old and a mean age of 16 years.5 in another study, the mean age at presentation was 15.09 years among 11 patients with calvarial tb.1 however, in the current case, the patient presented at a much younger age. both previous studies also documented a male predominance.1,5 scalp swelling is the most common presenting feature of calvarial tb, followed by sinus discharge, localised pain, seizures and meningitis.1 the duration of such symptoms is usually six months or less, as noted in the current case. a similar case was reported from mumbai, india, describing a 10-yearold boy who presented with a left frontal swelling of two months’ duration.6 although ocular tb is quite common in endemic countries like india, tb of the eyelid is another extremely rare condition that often presents in the form of chronic sinus discharge.7,8 in the present case, the patient had a non-healing discharging sinus over the lower left palpebra and, although the exact origin of the tb could not be determined, the site healed completely during the course of the att. trauma has been mentioned as a predisposing factor to skeletal tb among 42.8% of patients.5 following injury, increased vascularity, decreased resistance and the discovery of a latent infection might be contributing factors, although this hypothesis has been challenged by other researchers.9,10 among common sites of skull tb, involvement of the parietal or frontal bones is most frequent, as these both have greater diploic space and more cancellous bone.1,5 it is believed that skull tb occurs as a consequence of the haematogenous seeding of bacilli to the diploë from a primary tb infection elsewhere in the body.5 however, it was impossible to establish a primary tb focus in the current patient. often, the microbiological confirmation of skull tb is not possible due to necrosis.1 in a previous case series, only one out of six patients with calvarial tb was found to have an afb-positive stain.11 an appropriate clinicoradiological presentation combined with histopathological evidence of a caseating granuloma is often sufficient for diagnosing tb, while a positive mantoux test or raised erythrocyte sedimentation rate is only an ancillary aid.1,5 a ct scan usually demonstrates soft tissue swelling with the accompanying destruction of one or both of the inner and outer tables of the calvaria while highly specific magnetic resonance imaging characteristics often allow for a conclusive diagnosis.5 under the rntcp protocol, a 12-month att course is recommended for cases of https://doi.org/10.4103/0028-3886.57814 https://doi.org/10.1007/s00586-012-2334-8 https://doi.org/10.1016/j.ijid.2009.03.014 https://doi.org/10.2147/opth.s65254 https://doi.org/10.1259/0007-1285-34-401-286 https://doi.org/10.4103/0972-2327.29205 https://doi.org/10.4103/0972-2327.29205 https://doi.org/10.1016/0962-8479%2893%2990015-p 1department of anesthesiology & pain medicine, bern university hospital inselspital, bern, switzerland; departments of 2health economics and 3surgery, marienhospital, vechta, germany *corresponding author’s e-mail: markus.luedi2@insel.ch التناقضات بني أوقات التحول الفعلية و املخطط هلا يف غرف العمليات يف مستشفى ريفي كبري يف أملانيا ريجول مورجينيغ، فرانزي�صكا هاينز، كاثارينا ويفري�ض، رالف �صيفر، فرانك �صتيرب، ماركو�ض لويدي، ديرتي�ض دول abstract: objectives: while several factors have been shown to influence operating room (or) turnaround times, few comparisons of planned and actual or turnaround times have been performed. this study aimed to compare planned and actual or turnaround times at a large rural hospital in northern germany. methods: this retrospective study examined the or turnaround data of 875 elective surgery cases scheduled at the marienhospital, vechta, germany, between july and october 2014. the frequency distributions of planned and actual or turnaround times were compared and correlations between turnaround times and various factors were established, including the time of day of the procedure, patient age and the planned duration of the surgery. results: there was a significant difference between mean planned and actual or turnaround times (0.32 versus 0.64 hours; p <0.001). in addition, significant correlations were noted between actual or turnaround times and the time of day of the surgery, patient age, actual duration of the procedure and staffing changes affecting the surgeon or the medical specialty of the surgery (p <0.001 each). the quotient of actual/planned or turnaround times ranged from 1.733–3.000. conclusion: significant discrepancies between planned and actual or turnaround times were noted during the study period. such findings may be potentially used in future studies to establish a tool to improve or planning, measure or management performance and enable benchmarking. keywords: operating room, organization and administration; patient care management; strategic planning; time management; quality control; germany. بني املقارنات عن التقارير من قليل عدد ال ليوجد العمليات، غرف يف الت�صغيل اأوقات على توؤثر عوامل عدة هناك الهدف: امللخ�ص: اأوقات التحول املخطط لها والفعلية. هدفت هذه الدرا�صة اإىل مقارنة اأوقات التحول املخطط لها والفعلية و يف م�صت�صفى ريفي كبري يف �صمال اأملانيا. الطريقة: فح�صت هذه الدرا�صة الرجعية بيانات اأو حتويالت 875 حالة جراحة اختيارية املقررة يف م�صت�صفى مارين، في�صتا، والعوامالل التحول فرتات بني العالقة واأظهرت والفعلية لها املخطط العمليات مواقيت مقارنة متت .2014 واأكتوبر يوليو بني اأملانيا، خمتلفة املوؤثرة فيه، مبا يف ذلك وقت اليوم من العملية وعمر املري�ض واملدة املقررة للجراحة. النتائج: كان هناك فرق كبري بني متو�صط املدة الزمنية املخطط لها والفعلية .)0.32 مقابل 0.64 �صاعة؛p >0.001( وبالإ�صافة اإىل ذلك، لوحظ وجود ارتباط كبري بني الزمن الفعلي يف العاملني يف والتغيريات لالإجراء الفعلية واملدة املري�ض، وعمر اجلراحية، العملية لجراء اليوم من الوقت من وكل التحول زمن اأو غرف العمليات والتي قد توؤثر على اجلراح اأو التخ�ص�ض الطبي للجراحة. p >0.001 لكل منهما وتراوحت حوا�صل الفرتة الزمنية الفعلية اأو املخطط لها من 3.000-1.733. اخلال�صة: لوحظت خالل فرتة الدرا�صة وجود اأوجه تباين كبرية بني الأوقات الفعلية للعمليات واملخطط لها. وميكن ا�صتخدام هذه النتائج يف الدرا�صات امل�صتقبلية لإن�صاء اأداة لتح�صني التخطيط و اأداء الإدارة و متكني القيا�ض الدقيق لزمن اجراء العمليات اجلراحية وا�صتخدام غرف العمليات. الكلمات املفتاحية: غرف العمليات، التنظيم والإدارة؛ اإدارة رعاية املر�صى؛ التخطيط الأ�صرتاتيجي؛ اإدارة الوقت؛ مراقبة اجلودة؛ اأملانيا. discrepancies between planned and actual operating room turnaround times at a large rural hospital in germany regula morgenegg,1 franziska heinze,2 katharina wieferich,2 ralf schiffer,2 frank stueber,1 *markus m. luedi,1 dietrich doll3 clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e418–423, epub. 10 jan 18 submitted 8 jul 17 revision req. 5 sep 17; revision recd. 27 sep 17 accepted 19 oct 17 advances in knowledge this study identified significant discrepancies between planned and actual operating room (or) turnaround times at a large rural hospital in northern germany. application to patient care the findings of the current study could potentially be used to improve or planning and management and provide a reference point for optimal or turnaround times. the correction of any discrepancies between planned and actual or turnaround times can reduce patient wait times and increase or optimisation by allowing more surgeries to be performed in a specific or. doi: 10.18295/squmj.2017.17.04.007 regula morgenegg, franziska heinze, katharina wieferich, ralf schiffer, frank stueber, markus m. luedi and dietrich doll clinical and basic research | e419 organisational decisions related to the planning of surgeries are based on a series of hierarchical priorities, including patient safety, the surgeon’s access to an available operating room (or), or efficiency and patient wait times.1 in contrast, longer-term strategic decisions focus on increasing or capacity utilisation despite potential uncertainties in future caseloads.2 the interval between the end of one surgery on a patient and the beginning of the next surgery on another patient is known as the or turnaround time; this should be distinguished from or turnover time which conventionally indicates the interval between the previous patient leaving the or and the next patient entering the room, although these terms are sometimes used interchangeably.3–6 various factors have been shown to influence or turnaround times; for example, the time of day of the surgery, the age and american society of anesthesiology physical status of the patient and the assignment of the right anaesthesiologist to a surgeon have all been associated with a reduction in or overutilisation.4,5,7,8 in contrast, a change in surgeon has been found to have no significant impact on or efficiency.9 in an in-depth analysis of or data, including causes of delays and personal accountability, overdyk et al. found that teamwork improved or efficiency.10 however, masursky et al. observed that both surgeons and, to a lesser extent, anaesthesiologists, judged or turnaround times according to mental models of factors influencing turnover; thus, the perceptions of surgeons or anaesthesiologists should not be relied upon to make or management decisions.11 a direct comparison between planned and actual or turnaround times is useful as any discrepancies between the two times can affect or efficiency. to this end, the current study aimed to compare factors influencing planned and actual or turnaround times at a large hospital in vechta, northern germany. methods this retrospective study was conducted at the marienhospital, a rural 321-bed hospital with six ors in vechta.4,5 the or data of elective surgical cases scheduled at the marienhospital between july and october 2014 were analysed. only those elective surgeries under the following medical specialties were included: general surgery; orthopaedic/trauma surgery; visceral surgery (including coloproctology related procedures); ear, nose and throat (ent) surgery; obstetrics and gynaecology surgery; dermatology surgery; and internal medicine surgery (including the surgical implantation of cardiac pacemakers). information related to the surgeries, patients and or turnaround times was retrieved from the hospital’s electronic information system (orbis krankenhaus-informationssystem, bureau van dijk, amsterdam, the netherlands). during the study period, 2,651 or procedures were recorded in the hospital’s electronic database. of these, 28 were duplicate entries and 225 cases were scheduled in an or reserved for preparatory and/or poorly documented procedures. another 550 cases were excluded because they were performed during public holidays. of the remaining cases, 426 were unplanned emergency surgeries and 207 were surgeries which were planned but not performed, resulting in 1,215 cases. however, 320 surgeries were the first cases of the day and were therefore excluded as turnaround time could not be determined. an additional 14 surgeries were excluded as they were deemed to be delayed, with turnaround times longer than 90 minutes or deviating more than 15 minutes from the median.8,12 finally, six cases were excluded because they were emergency cases which began at night but continued into the next day. accordingly, a total of 875 surgeries were included in the final analysis. the statistical analyses were performed using an excel spreadsheet, version 2010 (microsoft inc., redmond, washington, usa) and graphpad prism software, version 6.0 (graphpad software inc., la jolla, california, usa). results derived from twotailed t-tests were considered significant at the level of p <0.050. non-parametric testing was employed as the specific grouping of cases according to surgical lists and time would further decrease the sample size. a chi-squared test was used to compare frequency distributions and planned and actual or turnaround times were correlated using wilcoxon and mannwhitney u tests. the kruskal-wallis test was utilised to correlate turnaround times with the specific time of day at hourly intervals. correlations between planned and actual or turnaround times and patient age and the duration of surgery were determined according to spearman’s rank correlation. this study was approved by the ethics committee of the medical association of lower saxony, hanover, germany, as per their professional code of conduct. formal ethical approval was waived as the patients were neither psychologically nor physically affected by the study. results the mean planned or turnaround time was 0.32 hours (95% confidence interval [ci]: 0.30–0.33 hours); in contrast, the mean actual or turnaround time differed significantly at 0.64 hours (95% ci: 0.62–0.65 hours; discrepancies between planned and actual operating room turnaround times at a large rural hospital in germany e420 | squ medical journal, november 2017, volume 17, issue 4 p <0.001). actual or turnaround times exceeded planned times in 773 cases (88.3%), while they fell short of planned times in 93 cases (10.6%) and were exactly the same in nine cases (1.0%). no significant relationship was found between planned or turnaround times and the time of day of the procedure (p = 0.444). however, actual or turnaround times increased significantly as the day progressed, increasing on average from 0.37 to 0.72 hours between 8 am and 3 pm before dropping back to 0.56 hours at 4 pm (p = 0.001) [figure 1]. in addition, while no correlation was noted between planned or turnaround time and patient age (r = 0.0163; p = 0.622), there was a significant relationship between planned or turnaround time and the planned duration of the procedure (r = 0.0767; p = 0.020) [figures 2a and b]. in contrast, actual or turnaround times correlated significantly with both patient age (r = 0.2375; p <0.001) and the actual duration of the procedure (r = 0.5114; p <0.001) [figures 2c and d]. significant discrepancies between planned and actual or turnaround times were noted among all medical specialties, with discrepancies ranging from 3.4-fold for dermatology surgeries to 1.7-fold for ent surgeries [figure 3]. correlations between changes in staffing and discrepancies in planned and actual or turnaround times were assessed. the mean actual or turnaround time was 0.59 hours when there was no change in either the surgeon performing the procedure or the specialty of the surgery. no significant differences in planned or turnaround time were observed with either a change of surgeon within the same medical specialty (p = 0.140) or a change in medical specialty entirely (p = 0.752). however, the mean actual or turnaround time differed significantly with either a change in surgeon (0.67 hours versus 0.59 hours; p <0.001) or a change in medical specialty (0.87 hours versus 0.59 hours; p <0.001) [figure 4]. quotients of planned and actual or turnaround times were generated according to medical specialty, excluding 49 cases with a planned turnaround time of 0 as this is impossible in reality although obtainable in theoretical figure 1: mean (a) planned and (b) actual operating room turnaround times according to time of day* among elective surgical cases scheduled at a large rural hospital in northern germany (n = 875). or = operating room. *data at specific hours include the preceding 60 minutes. figure 2: correlations between mean (a & b) planned and (c & d) actual operating room turnaround times and patient age and duration of surgery, respectively, among elective surgical cases scheduled at a large rural hospital in northern germany (n = 875). or = operating room. regula morgenegg, franziska heinze, katharina wieferich, ralf schiffer, frank stueber, markus m. luedi and dietrich doll clinical and basic research | e421 planning. of the remaining 826 cases, median quotients ranged from 1.733 for ent surgeries to 3.000 for dermatology surgeries. none of the specialties achieved a perfect mean quotient of 1.0 [figure 5]. discussion significant discrepancies were found between planned and actual or turnaround times in the current study. these discrepancies correlated with the time of day figure 3: mean (a) planned and (b) actual operating room turnaround times according to medical specialty among elective surgical cases scheduled at a large rural hospital in northern germany (n = 875). the error bars represent 95% confidence intervals. obgyn = obstetrics and gynaecology; ent = ear, nose and throat; or = operating room. figure 5: boxplots of quotients of actual and planned operating room turnaround times according to specialty among elective surgical cases scheduled at a large rural hospital in northern germany (n = 826)*. the boxplots are presented on a log 2 scale. obgyn = obstetrics and gynaecology; ent = ear, nose and throat; or = operating room. *total data set for this variable was 826 as 49 cases were excluded. figure 4: correlations between mean (a) planned and (b) actual operating room turnaround times and staffing changes (i.e. either a change in surgeon or the medical specialty of the surgery) among elective surgical cases scheduled at a large rural hospital in northern germany (n = 875). or = operating room. discrepancies between planned and actual operating room turnaround times at a large rural hospital in germany e422 | squ medical journal, november 2017, volume 17, issue 4 of the procedure, patient age, actual duration of the procedure and staffing changes. the observed correlations between prolonged turnaround times and both time of day and patient age were in line with previously described findings.4,7 however, austin et al. determined that a change in surgeon had a negligible effect on or turnover time.9 despite evidence that these individuals hold much of the responsibility for procedural efficiency, masursky et al. previously found that surgeons were biased when it came to planning or turnaround times.11,13 correcting discrepancies between planned and actual or turnaround times can reduce patient wait times, potentially enabling more procedures to be performed in a single or, especially when numerous short surgeries are scheduled. the findings of the current study have potential managerial applications at the marienhospital in order to increase the accuracy of or planning and measure or efficiency; in addition, these results can be used as a yardstick against which future data can be benchmarked.14 further investigations are planned to develop a tool incorporating those factors found to significantly impact or turnover times in the current study. nevertheless, it remains a matter of debate as to whether statistical analyses such as those utilised in the present study will accurately assess nonmathematical factors. for example, there is evidence that financial incentive programmes, interviews with stakeholders and the assignment of an appropriate anaesthesiologist can influence turnaround times.5,15,16 moreover, psychological factors such as emotional intelligence may affect patient safety as well as perioperative performance.17,18 this study is subject to certain limitations. other variables potentially affecting or turnaround time were not included in the current analysis, such as variations in or cleaning needs, patient transportation, the individual experience of the surgeon, the availability of senior surgical team members during a procedure, the specialties of other personnel present (e.g. surgeons, anaesthesiologists and nurses) and the use of operative devices/materials requiring extra preparation time. in addition, the study was limited by its retrospective nature; as such, the correlations observed are not definitive proof of causation. it is likely that certain correlations were only marginally significant due to their small sample sizes (e.g. or turnaround times for dermatology and internal medicine surgeries were based on 14 and 15 cases, respectively). additionally, while the results of this study can be used to improve the accuracy of or planning at the marienhospital, they cannot be extrapolated to other hospitals. nevertheless, the findings of this study are supported by the fact that discrepancies between planned and actual or turnaround times were identified and correlations found with most parameters. conclusion significant discrepancies between planned and actual or turnaround times were observed in the current study. moreover, actual or turnaround times were significantly affected by the time of day of the surgery, patient age, actual duration of the procedure and staffing changes. these findings have important managerial implications and may be used by or managers to increase the accuracy of or planning, measure or performance and enable potential benchmarking. future investigations are planned to construct a tool to accommodate identified factors impacting or turnover times. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. dexter f, epstein rh, traub rd, xiao y. making management decisions on the day of surgery based on operating room efficiency and patient waiting times. anesthesiology 2004; 101:1444–53. doi: 10.1097/00000542-200412000-00027. 2. dexter f, ledolter j, wachtel re. tactical decision making for selective expansion of operating room resources incorporating financial criteria and uncertainty in subspecialties’ future workloads. anesth analg 2005; 100:1425–32. doi: 10.1213/01. ane.0000149898.45044.3d. 3. sandberg ws, daily b, egan m, stahl je, goldman jm, wiklund ra, et al. deliberate perioperative systems design improves operating room throughput. anesthesiology 2005; 103:406–18. doi: 10.1097/00000542-200508000-00025. 4. luedi mm, kauf p, mulks l, wieferich k, schiffer r, doll d. implications of patient age and asa physical status for operating room management decisions. anesth analg 2016; 122:1169–77. doi: 10.1213/ane.0000000000001187. 5. luedi mm, doll d, boggs sd, stueber f. in response. anesth analg 2017; 124:1738–9. doi: 10.1213/ane.0000000000001999. 6. association of anesthesia clinical directors. glossary of times used for scheduling and monitoring of diagnostic and therapeutic procedures. aorn j 1997; 66:601–6. doi: 10.1016/ s0001-2092(06)62913-x. 7. doll d, wieferich k, erhart t, hoenemann c. waiting for godot: an analysis of 2622 operating room turnover times. eur j anaesthesiol 2014; 31:388–9. doi: 10.1097/eja.0000000 000000059. 8. dexter f, epstein rh, marcon e, ledolter j. estimating the incidence of prolonged turnover times and delays by time of day. anesthesiology 2005; 102:1242–8. doi: 10.1097/00000542200506000-00026. https://doi.org/10.1097/00000542-200412000-00027 https://doi.org/10.1213/01.ane.0000149898.45044.3d https://doi.org/10.1213/01.ane.0000149898.45044.3d https://doi.org/10.1097/00000542-200508000-00025 https://doi.org/10.1213/ane.0000000000001187 https://doi.org/10.1213/ane.0000000000001999 https://doi.org/10.1016/s0001-2092%2806%2962913-x https://doi.org/10.1016/s0001-2092%2806%2962913-x https://doi.org/10.1097/eja.0000000000000059 https://doi.org/10.1097/eja.0000000000000059 https://doi.org/10.1097/00000542-200506000-00026 https://doi.org/10.1097/00000542-200506000-00026 regula morgenegg, franziska heinze, katharina wieferich, ralf schiffer, frank stueber, markus m. luedi and dietrich doll clinical and basic research | e423 9. austin tm, lam hv, shin ns, daily bj, dunn pf, sandberg ws. elective change of surgeon during the or day has an operationally negligible impact on turnover time. j clin anesth 2014; 26:343–9. doi: 10.1016/j.jclinane.2014.02.008. 10. overdyk fj, harvey sc, fishman rl, shippey f. successful strategies for improving operating room efficiency at academic institutions. anesth analg 1998; 86:896–906. doi: 10.1213/ 00000539-199904000-00057. 11. masursky d, dexter f, isaacson sa, nussmeier na. surgeons’ and anesthesiologists’ perceptions of turnover times. anesth analg 2011; 112:440–4. doi: 10.1213/ane.0b013e3182043049. 12. dexter f, abouleish ae, epstein rh, whitten cw, lubarsky da. use of operating room information system data to predict the impact of reducing turnover times on staffing costs. anesth analg 2003; 97:1119–26. doi: 10.1213/01.ane.000008 2520.68800.79. 13. fong aj, smith m, langerman a. efficiency improvement in the operating room. j surg res 2016; 204:371–83. doi: 10.1016/j. jss.2016.04.054. 14. helkiö p, aantaa r, virolainen p, tuominen r. productivity benchmarks for operative service units. acta anaesthesiol scand 2016; 60:450–6. doi: 10.1111/aas.12676. 15. scalea tm, carco d, reece m, fouche yl, pollak an, nagarkatti ss. effect of a novel financial incentive program on operating room efficiency. jama surg 2014; 149:920–4. doi: 10.1001/jamasurg.2014.1233. 16. pimentel mt, flanagan h, philip bk, urman rd. qualitative analysis of barriers to efficient operating room turnovers in a tertiary care academic medical center. j med pract manag 2015; 30:30–5. 17. luedi mm, boggs sd, doll d, stueber f. on patient safety, teams and psychologically disturbed pilots. eur j anaesthesiol 2016; 33:226–7. doi: 10.1097/eja.0000000000000403. 18. luedi mm, doll d, boggs sd, stueber f. successful personalities in anesthesiology and acute care medicine: are we selecting, training, and supporting the best? anesth analg 2017; 124:359–61. doi: 10.1213/ane.0000000000001714. https://doi.org/10.1016/j.jclinane.2014.02.008 https://doi.org/10.1213/00000539-199904000-00057 https://doi.org/10.1213/00000539-199904000-00057 https://doi.org/10.1213/ane.0b013e3182043049 https://doi.org/10.1213/01.ane.0000082520.68800.79 https://doi.org/10.1213/01.ane.0000082520.68800.79 https://doi.org/10.1016/j.jss.2016.04.054 https://doi.org/10.1016/j.jss.2016.04.054 https://doi.org/10.1111/aas.12676 https://doi.org/10.1001/jamasurg.2014.1233 https://doi.org/10.1097/eja.0000000000000403 https://doi.org/10.1213/ane.0000000000001714 squ med j, february 2012, vol. 12, iss. 1, pp. 103-108, epub. 7th feb 12. submitted 14th may 11 revision req. 19th jul 11, revision recd. 25th jul & 20th sep 11 accepted 21st sep 11 acquired myasthenia gravis (mg) is an eminently treatable neuromuscular disorder characterised by autoimmunity against postsynaptic antigenic epitopes such as the skeletal muscle acetyl choline receptor or musclespecific tyrosine kinase (musk).1–3 while the typical clinical manifestations include ocular and generalised (with or without bulbar paresis) forms, occasional cases might pose diagnostic challenges with atypical manifestations.4–9 a high index of clinical suspicion is required in these circumstances to avoid unnecessary delay in the diagnosis and treatment. further, failure to reconsider the other diagnoses entertained on previous medical evaluation, but not based on solid clinical evidence (for instance, lack of documentation or inability to ascertain the diagnosis from previous clinical or laboratory records), could hinder further diagnostic and therapeutic endeavours. in this report, we provide the clinical account of a young 1department of medicine, sultan qaboos university hospital, muscat, oman; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author email: rnandagopal@yahoo.com اخلطأ يف تشخيص مرض الوهن العصيب واآلثار السريرية الالحقة تقرير حالة ومراجعة األدبيات عبداهلل العا�سمي، رام�سان ديران نانذاجوبال، بي �سي جاكوب، اأرونداي جوجار يوؤدي مما الع�سبية ال�سطرابات من متنوعة جمموعة حماكاة الذاتية باملناعة املتعلق الوبيل الع�سلي الوهن ملر�س ميكن امللخ�ص: اإىل تاأخري يف الت�سخي�س والعالج. ويف بع�س الأحيان يوؤدي اخلطاأ يف ت�سخي�س املر�س اإىل تدخالت عالجية غري �رصورية ورمبا تكون �سارة. ندرج يف هذا التقرير حالة طفل يف الثانية ع�رصة من عمره م�ساب مبر�س الوهن الع�سلي الوبيل، حيث �سخ�ست حالته خطاأ على اإنها م�ساعفات ناجتة عن التهاب ال�سحايا، وبالتايل جنم عن العتالل الع�سبي/الع�سلي معاناة هذا املري�س من هذه احلالة مدة تقارب عقداً من الزمن. نتج عن الت�سخي�س ال�سحيح للحالة املر�سية والعالج الأمثل لها حت�سنًا كبرياً يف احلالة الوظيفية. و�سوف نناق�س يف هذا التقرير اأهمية اأخذ مر�س الوهن الع�سلي الوبيل يف الت�سخي�س التفريقي املحتمل للحالت املر�سية الأخرى كحالة ف�سل امل�سخة التنف�سية املتكرر، اأو اإحدى م�ساعفات ال�سلل الب�سلي، اإذ اأن هناك نق�سًا يف الإثبات الوثائقي للت�سخي�سات املذكورة اآنفًا والتي تت�سمن اإجراءات الت�سخي�س ملر�س الوهن الع�سلي الوبيل. كما ن�ستعر�س يف هذا التقرير الأدبيات الطبية املن�سورة عن خطاأ ت�سخي�س مر�س الوهن الع�سلي الوبيل، و�سرنكز على خماطر ذلك. الكلمات: مر�س الوهن الع�سلي الوبيل، ال�سلل الب�سلي، التهاب الرئة، اإلتهاب ال�سحايا، م�ساعفات مر�س معني )عقاِبْيل(، تقرير حالة، مفتاح عمان. abstract: the autoimmune disease, myasthenia gravis (mg), can mimic a variety of neurological disorders leading to a delay in diagnosis and treatment. on occasions, misdiagnosis of mg could lead to unnecessary and potentially harmful therapeutic interventions. we report on a 12 year-old boy, in whom mg was mistaken for meningitic sequelae and subsequently for critical neuropathy/myopathy resulting in considerable morbidity for nearly a decade. subsequent correct diagnosis and optimal management resulted in significant improvement in his functional status. we discuss the importance of considering mg as one of the potential differential diagnoses among cases of recurrent respiratory pump failure, or unexplained bulbar symptoms where documentary proof of the previous diagnoses including work-up for mg is lacking. we also review the literature on mg misdiagnosis and highlight the potential pitfalls in mg diagnosis. keywords: myasthenia gravis; bulbar palsy; pneumonia; meningitis, sequelae; case report; oman. misdiagnosis of myasthenia gravis and subsequent clinical implication a case report and review of literature abdullah al-asmi,1 *ramachandiran nandhagopal,1 p c jacob,2 arunodaya gujjar2 case report misdiagnosis of myasthenia gravis and subsequent clinical implication a case report and review of literature 104 | squ medical journal, february 2012, volume 12, issue 1 man with mg in whom the bulbar symptom was attributed to the sequelae of basal meningitis in childhood and subsequently to critical neuropathy/ myopathy which was followed by a prolonged delay in reaching the ultimate diagnosis. we highlight the importance of early diagnostic consideration of mg and provide a review of english language medical literature on mg misdiagnosis; for this we used search terms such as myasthenia gravis, misdiagnosis, and diagnostic errors in pubmed for the period 1988 to 2010. case report a 12 year-old boy developed hoarseness of voice and dysphagia with nasal regurgitation for liquids following a febrile illness. basal meningitis was suspected and the bulbar symptoms (dysphagia, difficulty in chewing and dysarthria) were attributed to lower cranial nerve palsies as part of meningitic sequelae. full details of this diagnostic evaluation and management could not be ascertained at a later date. at age 18, he underwent flexible laryngoscopy that was reported to have shown bowing of the left vocal cord. following that finding, augmentation and medialisation of the left vocal cord and palatapexy were performed with questionable improvement of his voice and dysphagia. at age 19, he developed lethargy, weight loss, nocturnal dyspnoea of 2 month duration and aspiration pneumonia in the left mid-zone and type ii respiratory failure. he required prolonged ventilatory assistance followed by tracheostomy despite adequate antibiotic coverage. neurologically, he demonstrated intermittent confusion, ophthalmoparesis, bifacial weakness, reduced palatal movements with hypoactive gag reflex, and mild to moderate proximal weakness in arms and legs. critical illness neuropathy/myopathy was suspected at that point in time because of a difficulty in weaning him off the ventilator. phrenic nerve conduction was within normal limits and needle electromyography (emg) did not reveal any evidence of denervation or myopathic changes. serum creatine kinase and a computed tomography (ct) scan of the brain were normal. apart from an abnormal blood gas study, suggestive of type ii respiratory failure prior to mechanical ventilation and elevated c reactive protein, his other laboratory parameters, including basic metabolic profile, were within normal limits. to prevent further episodes of aspiration, he underwent percutaneous endoscopic feeding gastrostomy. after weaning him off the ventilator and subsequent hospital discharge, he later required multiple hospitalisations for optimisation of his respiratory care and care of the permanent tracheostomy. at age 21, he required ventilatory assistance (through a miniventilator connected through the tracheostomy) and was evaluated in our institution. neurologically, he was conscious and demonstrated bilateral ophthalmoparesis (but no blepharoptosis) table 1. differential diagnosis of oculo-bulbar syndrome with limb girdle weakness neuromuscular junctional disorder autoimmune myasthenia gravis congenital myasthenia eaton lambert myasthenic syndrome botulism tick paralysis snake bite with envenomation organo-phosphorus compound poisoning myopathy oculo-pharyngeal dystrophy limb girdle muscular dystrophy inclusion body myositis critical illness myopathy radiculo-neuropathy guillain-barré syndrome (including polyneuritis cranialis) chronic inflammatory demyelinating polyradiculoneuropathy heavy metal poisoning diphtheritic neuropathy critical illness neuropathy central nervous system disorders motor neuron disease mutiple sclerosis brain stem lesion: posterior circulation stroke, glioma sequelae of basal meningitis locked-in syndrome psychiatric disorders conversion disorders abdullah al-asmi,ramachandiran nandhagopal, p c jacob, arunodaya gujjar case report | 105 table 2: literature review on misdiagnosis/masquerade of myasthenia gravis (mg) initial misdiagnosis/ masquerade (with reference no.) number of patients age (in years) at mg diagnosis gender m or f time to mg diagnosis after symptom onset comments posterior circulation stroke4,6 4 91 77 66 58 all f 1 yr 3 wks; several mos; 9 days; 3 days initial treatment included anticoagulation for the stroke mimic. mg diagnostic consideration was prompted by negative brain imaging, along with thymic lesion, when present, and subsequently confirmed by electrophysiological studies, or positive edrophonium test, or elevated serum acetyl choline receptor antibody titre. lesson: incidental brain infarcts should be interpreted with caution in elderly patients. blepharospasm8 2 74 57 both m 4 yrs, 3 mos; 7 yrs, 9 mos periocular injection with botulinum toxin for the initial treatment resulted in prolonged and complete ptosis. blinking that returned after wearing-off of the toxin effect and the subsequent fluctuating ptosis was confirmed to be due to mg by electrophysiological study. further, the ptosis improved with mg treatment. lesson: isolated blinking mimicking blepharospasm could be the initial atypical presentation of mg in occasional patients. amyotrophic lateral sclerosis9 1 38 f 4 yrs bulbar symptoms, ventilatory assistance and muscle denervation in leg muscles simulated amyotrophic lateral sclerosis. symptoms and signs were confirmed to be due to mg by electrophysiological study and improved with mg treatment. initial finding of muscle denervation was attributed to functional nerve and muscle disconnection in that the spontaneous muscle activity disappeared with mg treatment. lesson: mg may masquerade as other neuromuscular disorders. velopharyngeal incompetence9 1 17 f 3.5 yrs bulbar symptoms, especially nasal speech was misdiagnosed with velopharyngeal incompetence, though the patient lacked the associated findings of cleft (or submucosal cleft) palate. subsequent generalised weakness with fatiguability and a positive edrophonium test clinched the diagnosis of mg. lesson: a broader differential diagnosis for bulbar symptoms would avoid missing the diagnosis of mg. no diagnosis of mg9 1 18 f 2.5 yrs fatiguable ptosis, diplopia and bulbar symptoms in pregnancy were ignored and the clinical status was presumed to be normal. subsequently mg diagnosis was confirmed with a positive edrophonium test, electrophysiological study and elevated titer of serum acetyl choline receptor antibody. lesson: careful clinical evaluation, including tests for fatiguability and ordering the appropriate tests for mg would avoid diagnostic uncertainty. myofacial pain syndrome7 1 20 f 3 mos the primary symptom was facial pain and cheek swelling with worsening in the later part of the day. presence of bilateral ptosis, weakness of jaw closure and fatiguability while speaking along with a positive edrophonium test and electrophysiological study confirmed mg diagnosis. lesson: occasionally, nonspecific musculo-skeletal symptoms might override the classical mg symptoms. so, the advice is to look carefully for mg clinical signs and arrange the appropriate tests. hysteria5 1 54 m several mos initial complaint of generalized weakness was associated with over-reactivity and anxious behaviour. subsequent progressive dysphagia and limb weakness prompted diagnostic evaluation and confirmation of mg. lesson: neurotic symptoms could be present along with mg or be a reaction to mg signs and symptoms. misdiagnosis of myasthenia gravis and subsequent clinical implication a case report and review of literature 106 | squ medical journal, february 2012, volume 12, issue 1 with good pupillary reaction, bifacial weakness, bulbar palsy, neck muscle weakness and mild to moderate weakness (with subtle fatiguability of weakness) in his upper and lower limbs. there was no family history of neuromuscular disorders. in view of subtle fatiguability of limb weakness, pupilsparing ophthalmoparesis, recurrent exacerbation of cranial-motor symptoms, and well preserved cognitive function, a possibility of myasthenia gravis was considered. repetitive nerve stimulation test at 3 hertz revealed significant decremental response from the right facial nerve (recording from nasalis: a decrement of 47% between the first and fourth compound muscle action potentials at rest) and right accessory nerve (recording from trapezius: a decrement of 38%). on pharmacological testing with edrophonium, there was significant improvement of ocular mobility and limb weakness. chest imaging did not reveal thymoma. he was subsequently treated with immunoglobins (as we did not at that time have access to plasma exchange) and pyridostigmine to which the immunosuppressive medications (prednisolone and azathioprine) were added. the serum antiacetylcholine receptor antibody test later turned out to be negative. however, the anti-musk antibody titer was elevated (14.2 nmol/l; normal range <0.4 nmol/l). this result was obtained in a reference laboratory in france at a later date. the patient had improvement of his bulbar symptoms, ocular motility and limb weakness and was discharged with a home ventilator. after discharge, he could breathe spontaneously without the need to use the home ventilator and he successfully pursued college education. the prednisolone was subsequently tapered and he was maintained on azathioprine. later, he was hospitalised twice for pneumonia and at the time of his latest hospitalisation, the sputum grew pseudomonas aeruginosa that was successfully treated with antibiotics, ventilatory support, and intravenous immunoglobulins. the mg medications were further optimised. he was subsequently discharged with significant improvement in his functional status. the mg was classed as myasthenia gravis foundation of america clinical class iia and he was treated with pyridostigmine, prednisolone and azathioprine. regular follow-up in the ambulatory clinic was planned. discussion our patient had anti-musk antibody positive mg with prominent bulbar symptoms that were mistaken for meningitic sequelae and critical illness neuropathy/myopathy. this case illustrates the diagnostic challenges posed by mg and the importance of entertaining the diagnosis in the first place in the case of patients presenting with rather unexplained bulbar symptoms, aspiration pneumonia and respiratory insufficiency. such an atypical presentation, in the absence of ptosis, does not exclude mg. careful evaluation for other ocular-motor and facial weaknesses and clinical tests for fatiguability would aid in the clinical diagnosis, as well as arranging for appropriate pharmacological, electrophysiological, serological and imaging studies. further, the management pathways should include reconsideration of previous diagnoses at different times, specifically in the context of a poorly documented diagnostic entity in the past. timely diagnosis of mg is crucial and would obviate the need for needless surgical procedure(s), or potentially harmful interventions with significant morbidity and negative influence on the quality of life. table 1 shows other neurological disorders and competing diagnoses that mg could mimic. the oculopharyngeal symptoms, with or without limb weakness, could be mistaken for oculo-pharnygeal muscular dystrophy, or mitochondrial cytopathy. in the acute setting, differential diagnoses include: posterior circulation stroke;4,6 atypical guillainbarré syndrome (polyneuritis cranialis); botulism (distinguished by pupillary involvement in botulism); heavy metal poisoning; tick paralysis, and snake bite with envenomation. in the absence of ocular symptoms and signs, limb girdle myasthenia could be misdiagnosed as muscular dystrophy. rarely, the condition could be confused with central nervous system disorder such as demyelinating disorder—especially in the presence of pseudointernuclear ophthalmoplegia10 and easily elicitable deep tendon reflexes. a pubmed search revealed 11 cases of mg which were initially misdiagnosed, or had atypical presentations, leading to a delay in the ultimate diagnosis and treatment.4–9 the patients with initial misdiagnoses had bulbar symptoms that prompted consideration of posterior circulation stroke in the acute setting,4–6 or amyotrophic lateral abdullah al-asmi,ramachandiran nandhagopal, p c jacob, arunodaya gujjar case report | 107 sclerosis, or velopharyngeal incompetence9 when the bulbar and associated symptoms were of longer duration. other misdiagnoses include hysteria,5 myofascial pain syndrome7 and blepharospasm8 [table 2]. in our patient, there was a delay of nine years in reaching the diagnosis. this delay was compounded by the following issues: 1) occurrence or precipitation of symptoms after febrile illness, myasthenic symptoms being well known to be precipitated by systemic illness, especially infectious diseases; 2) failure to reconsider the initial diagnosis considered several years previously with unavailable documentary evidence. it is interesting to note from table 2 that many patients with initial misdiagnosis had bulbar symptoms that prompted consideration of posterior circulation stroke in the acute setting,4,6 or amyotrophic lateral sclerosis, or velopharyngeal incompetence9 when the bulbar and associated symptoms were of longer duration. fluctuating weakness would favour a diagnosis of myasthenia gravis over stroke, meningitic sequelae and critical illness neuropathy or myopathy. potential pitfalls in the diagnosis of mg include, first, a variable response to cholinesterase inhibitors; in fact, mg associated with anti-musk antibodies may, at times, not significantly benefit from treatment with cholinesterase inhibitors.2 however, pharmacological testing with edrophonium or neostigmine for unequivocal objective benefits is warranted in all patients with oculo-bulbar symptoms with limb weakness. more importantly, the target weak muscle for such outcome should be pre-specified. a second diagnostic pitfall is subjective improvement of symptoms with cholinesterase inhibitors in occasional patients with brainstem glioma11 or amyotrophic lateral sclerosis; this underscores the importance of considering unequivocal objective benefits while performing diagnostic testing with edrophonium or neostigmine. a third pitfall is the absence of decremental response to 3 hz repetitive nerve stimulation test in occasional patients. volitional or stimulated single fibre electromyography (sfemg) would be useful in this setting; normal findings (absence of abnormal jitters or block) in a clinically weak muscle virtually rules out the diagnosis of mg. however, sfemg is not available widely and is technically demanding requiring physician patience and patient's cooperation. a fourth diagnostic pitfall is heterogeneity in clinical progression and course. diurnal variation of symptoms may not always be apparent and the clinical tests for fatiguability may not be performed in busy clinical practice. the final pitfall is that the anti-acetyl choline receptor antibodies test, although specific for the diagnosis of autoimmune mg, is not positive in all cases of mg. these seronegative cases may harbour anti-musk antibodies, or low affinity anti-acetyl choline receptor antibodies.1 anti-musk antibody is most often present in women, with peak onset of the disease in the third to fourth decade. conclusion in conclusion, we underscore the importance of entertaining the timely diagnosis of mg in obscure cases with oculo-bulbar-limb girdle paresis to obviate the need for unnecessary or potentially harmful therapeutic procedures. previous diagnostic consideration with uncertain documentation should be reviewed with an open mind for the diagnosis of potentially treatable conditions such as mg, as the diagnosis could be otherwise delayed or missed. references 1. leite mi, jacob s, viegas s, cossins j, clover l, morgan bp, et al. igg1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. brain 2008; 131:1940-52. 2. pasnoor m, wolfe gi, nations s, trivedi j, barohn rj, herbelin l, et al. clinical findings in musk-antibody positive myasthenia gravis: a u.s. experience. muscle nerve 2010; 41:370-4. 3. selcen d, fukuda t, shen xm, engel ag. are musk antibodies the primary cause of myasthenic symptoms? neurology 2004; 62:1945-50. 4. kleiner-fisman g, kott hs. myasthenia gravis mimicking stroke in elderly patients. mayo clin proc 1998; 73:1077-8. 5. kutz i, garb r, kuritzky a. diagnosis of misdiagnosis: on some of the origins and functions of psychophysical misdiagnosis. gen hosp psychiatry 1983; 5:197-202. 6. libman r, benson r, einberg k. myasthenia mimicking vertebrobasilar stroke. j neurol 2002; 249:1512-14. 7. lloyd jm, mitchell rg. myasthenia gravis as a cause of facial pain. oral surg oral med oral pathol 1988; 66:45-6. misdiagnosis of myasthenia gravis and subsequent clinical implication a case report and review of literature 108 | squ medical journal, february 2012, volume 12, issue 1 8. roberts me, steiger mj, hart ik. presentation of myasthenia gravis mimicking blepharospasm. neurology 2002; 58:150-1. 9. wheeler sd. misdiagnosis of myasthenia gravis. j natl med assoc 1987; 79:425-9. 10. khanna s, liao k, kaminski hj, tomsak rl, joshi a, leigh rj. ocular myasthenia revisited: insights from pseudo-internuclear ophthalmoplegia. j neurol 2007; 254:1569-74. sultan qaboos university med j, august 2015, vol. 15, iss. 3 pp. e382–389, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.013. submitted 3 nov 14 revision req. 17 dec 14; revision recd. 20 jan 15 accepted 19 feb 15 1department of communicable disease surveillance & control, ministry of health, muscat, oman; 2department of communicable disease surveillance & control, directorate general of health services, ministry of health, al batinah south governorate, rustaq, oman *corresponding author e-mail: prasannaar@yahoo.com تفشى وبائي حلاالت الشِّيِغلَّة، حمافظة جنوب الباطنة، ُعمان دراسة حاالت وضوابط اإدري�س عبيدانى، برا�سانا اأبور راجو، عي�سى ال�سعيلى، خالد ال�سعدى، نا�رس ال�سق�سى، عامر اخلاطري abstract: objectives: an outbreak of acute gastroenteritis due to shigella flexneri occurred in august 2012 in the catchment area of the wadi sahtan health center in rustaq, al batinah south governorate, oman. the aim of this study was to discover possible causes of this outbreak in the villages of fassa, rogh and amk and to measure the risk of exposure among cases and controls. methods: a case-control study was conducted in september 2012 in fassa, rogh and amk. all households in the three villages were interviewed. case and control households were compared to determine possible exposure avenues, including place of residence, source of drinking water, hand hygiene levels and practices related to drinking water, food preparation and environmental sanitation. results: residing in fassa (p <0.0001; odds ratio [or] = 4.86, 95% confidence interval [ci] = 2.22–10.63) and average hand hygiene practices (p = 0.008; or = 13.97, 95% ci = 1.58–123.36) were associated with an increased risk of contracting shigellosis. no significant differences were found with regards to the other exposure avenues. conclusion: this was the first study conducted in oman regarding an outbreak of shigellosis in a community setting. the only variables that significantly impacted the risk of acute gastroenteritis were residing in fassa and average hand hygiene practices. the source of the outbreak could not be identified. however, septic tank sanitation and water and food consumption practices were not satisfactory in the studied villages. these need to be addressed to prevent similar outbreaks of acute gastroenteritis in this region in the future. keywords: case-control study; disease outbreaks; shigellosis; transmission; risk factors; oman. ة فى اإحداث تف�سى وبائي حلالت نزلة معوية حادة فى اأغ�سط�س من عام 2012 فى يِغلَّة الفِلْك�سرِنيَّ امللخ�ص: الهدف: ت�سبب ميكروب ال�سِّ املنطقة املحيطة مبركز �سحى وادى ال�سحنت بالر�ستاق يف حمافظة جنوب الباطنة، ُعمان. الطريقة: اأجريت هذه الدرا�سة لكت�ساف الأ�سباب هذه اأجريت الطريقة: وال�سوابط. احلالت بني التعر�س خطورة معدل وقيا�س عمق و الروغ ف�سح، بقرى الوبائي التف�سى لهذا اأدت التى الدرا�سة فى �سهر �سبتمرب 2012 فى القرى الثالث ف�سح، الروغ و عمق. متت مقابلة جميع الأ�رس بالقرى الثالث. ومتت املقارنة بني احلالت وال�سوابط لتحديد اأ�سباب التعر�س لعوامل اخلطورة وت�سمل ال�سكن، م�سدر مياه ال�رسب، م�ستوى نظافة الأيدى واملمار�سات اخلا�سة ب�رسب املياه، اإعداد الطعام، ال�رسف ال�سحي والتخل�س من النفايات. النتائج: الإقامة فى ف�سح )p >0.0001; ن�سبة الأرجحية 95% ,4.86 = الثقة فا�سل )or( = 13.97, 95% الأرجحية ن�سبة p = 0.008( الأيدي غ�سل وممار�سات )]ci[ = 2.22-10.63 الثقة فا�سل )or( ci( = 1.58-123.36( كانت مرتبطة بزيادة خماطر الإ�سابة. مل توجد فروق ذات دللة اإح�سائية فيما يتعلق ببقية عوامل اخلطورة التى يِغلَّة داخل املجتمع. وقد تبني اأن �سملتها الدرا�سة. اخلال�صة: تعترب هذه الدرا�سة هى الأوىل ميدانيًا فى ُعمان بخ�سو�س تف�سي وباء ال�سِّ حتديد يتم مل و املعوية النزلة حلالت الوبائي التف�سى اإحداث على املوؤثران هما الأيدي بغ�سل اخلا�سة واملمار�سات ف�سح بقرية ال�سكن م�سدر العدوى. على اأية حال كانت العوامل الأخرى مثل ت�رسيف خزانات املجاري واملمار�سات اخلا�سة ب�رسب املياه واإعداد الطعام غري كافية وفى حاجة ملزيد من الدرا�سة لو�سع حلول لها ملنع حدوث تف�سيات وبائية لنزلت معوية م�ستقبلية بهذه املنطقة. يِغيلَّيُة؛ انتقال املر�س؛ عوامل اخلطورة؛ عمان. مفتاح الكلمات: درا�سة حالت و�سوابط؛ التف�سي الوبائي لالأمرا�س؛ ال�سِّ shigellosis outbreak in al batinah south governorate, oman case-control study idris abaidani,1 *prasanna a. raju,2 issa al-shualli,1 khalid al-sa’di,2 nasser al-shaqsi,2 amer al-khatri2 advances in knowledge this is the first study conducted in oman regarding a shigellosis outbreak in a community setting and investigating sources and risks of exposure. application to patient care the findings of this study will aid the implementation of preventative measures to protect against outbreaks of shigellosis in oman and among other communities. clinical & basic research idris abaidani, prasanna a. raju, issa al-shualli, khalid al-sa’di, nasser al-shaqsi and amer al-khatri clinical and basic research | e383 shigellosis is an important public health problem and outbreaks have been reported both in developed and developing countries.1,2 person-to-person contact and contaminated food and water are the major modes of transmission.3–5 while waterborne outbreaks of shigellosis have been reported in many countries, to the best of the authors’ knowledge, there have been no published studies of shigellosis outbreaks in oman to date.2,5 the wadi sahtan health center is located nearly 45 km from rustaq hospital in the wilayat (district) of rustaq, al batinah south governorate, oman. there are 51 villages in the catchment area of the health centre, with a total population of 10,304 people, of which 9,944 are omani (96.5%).6 in august 2012, an outbreak of acute gastroenteritis due to shigella flexneri occurred in this catchment area.7 a total of 142 cases of acute gastroenteritis were reported from the villages of fassa, rogh and amk. of these cases, 26 were admitted to rustaq hospital. stool samples were collected from 21 out of the 26 admitted cases; 7 of these were positive for s. flexneri. all of the isolates had the same antibiotic sensitivity pattern (sensitive to nalidixic acid, ciprofloxacin, cefotaxime, co-trimoxazole and resistant to ampicillin, augmentin and chloramphenicol). households from the three affected villages shared a common desalinated water source—a three-tank water storage system—which contained a mixture of water originally pumped from four tube wells and water from a desalination plant in rustaq which had been transported to the villages by water tankers.7 the desalinated water had been chlorinated at a facility in barka, a city approximately 96 km away, before being transmitted via pipeline to the desalination plant in rustaq. other sources of drinking water included personal mineral and well water supplies and water supplied through tankers to individual households. field staff from the communicable disease control center of the ministry of health in al batinah south governorate collected 15 water samples in august 2012 for bacteriological examinations from either transporting tankers, mosques, other public facilities or from houses as collection was not possible from the tube wells or overhead storage tanks.8 samples were tested for escherichia coli and coliforms and determined to be either satisfactory or not suitable for human consumption. samples collected from water tankers were found to be satisfactory. three water samples collected from households, one water sample collected from a public cooler and one water sample collected from a mosque were not suitable for human consumption. faecal coliforms were found in two water samples and coliform bacilli were present in three samples.8 the epidemic curve [figure 1], clinical data and geographical distribution of cases with similar symptoms, greater number of cases in children and the isolation of s. flexneri with the same antibiotic sensitivity profile from stool samples all indicated that this was an outbreak of shigellosis with a common source. this study was conducted in order to describe the outbreak and estimate the risk of certain exposure factors in the development of shigellosis in this community setting in the wilayat of rustaq, oman. methods this case-control study was carried out in the villages of fassa, rogh and amk in september 2012 to identify figure 1: epidemic curve chart of a shigellosis outbreak in rustaq, al batinah south governorate, oman (n = 142). a total of 114 outpatients presented to the wadi sahtan health center between mid-august and the beginning of september 2012. in addition, 26 inpatients were admitted to rustaq hospital during the same 20-day period. shigellosis outbreak in al batinah south governorate, oman case-control study e384 | squ medical journal, august 2015, volume 15, issue 3 the cause of the august 2012 shigellosis outbreak. face-to-face interviews were conducted with all households in the three villages by 12 health educators and school health nurses working in six teams. interviewers had received a one-day training course from a regional epidemiologist and regional infection control specialist and were trained on interview techniques and questionnaire completion procedures in order to ensure uniformity and minimise any potential bias in the data collection. demographic details and data on possible exposures were collected, including sources of both drinking water and water for washing fruit/vegetables. other variables included the presence of houseflies and practices related to water consumption; hand hygiene; food preparation and consumption; household waste collection and disposal; and septic tank maintenance. households were considered to be case households if any member of the household had had diarrhoea ≥3 times per day (with or without vomiting, fever, abdominal pain and dehydration) between the date of the interview in september and two days before the first reported case of shigellosis in august. if no members were reported to have been affected, the household was considered a control household. during the interview, households were asked questions related to water consumption and storage practices. these questions focused on whether drinking water was boiled and cooled before consumption; the frequency of water storage tank cleaning in the previous six months; whether water purifying filters were used and, if so, the frequency of changing these filters in the previous six months and the type of filters used. with regards to hand hygiene practices, household members were asked to report whether they washed their hands with soap and water before preparing food and eating and after using the toilet and changing diapers. if all of these practices were carried out by all members of the household, then hand hygiene practices were considered good. practices were considered unsatisfactory if household members indicated that they did not wash their hands after using the toilet or changing diapers. other combinations of responses were considered to indicate average practices. household members were asked whether raw vegetables and fruits were washed before they were eaten or used in salads and, if so, the source of the water used. additionally, interviewers enquired as to whether meals were prepared fresh before consumption. if meals were not prepared immediately before consumption, interviewers asked where the food was stored and whether it was reheated before consumption. information about household waste collection was also obtained during the interview. specifically, household members were asked whether waste was disposed of in open or closed containers and the frequency with which household waste was dumped in the community bin (either on a daily basis, once every 2–3 days or every three days or longer). the frequency of collection of household waste from the community bin by the municipality was also assessed (either on a daily basis, every 2–3 days, every 4–7 days, every 8–14 days or every 14 days or longer). the presence of any houseflies in the house during the interview was noted by interviewers. full or clogged septic tanks in close proximity to water supply lines places the population at risk for acute gastroenteritis via possible contamination of the drinking water sources. households were therefore asked about the presence of septic tanks and, if present, the frequency with which the septic tanks were emptied. this was an open-ended question. additionally, interviewers observed and noted the presence of any overflowing or leaking septic tanks in the households during the interview. collected data were presented in numbers and percentages and analysed using the statistical package for the social sciences (spss), version 16 (ibm corp., chicago, illinois, usa). the chi-squared test of significance was used to compare the case and control groups. fisher’s exact test was used when there were less than five observations in a group. the odds ratio (or) and 95% confidence interval (ci) was calculated. a p value of ≤0.05 was considered statistically significant. this study was approved by the research & ethical committee of the al batinah south governorate in oman. the purpose of the study was explained to all subjects and oral consent received before the interviews were conducted. results a total of 154 households were included in the study, with 44 (28.6%) classified as cases and 110 (71.4%) as controls. the greatest number of households (48.7%) were located in fassa, followed by amk (31.2%) and rogh (20.1%). among the case households, fassa was the village most affected by acute gastroenteritis (n = 33; 75.0%) with only six (13.6%) and five (11.4%) affected households from rogh and amk, respectively. the distribution of control households was 42 (38.2%), 25 (22.7%) and 43 (39.1%) households located in fassa, rogh and amk, respectively. the case-to-control ratio was 1:1.3 in fassa, 1:4.2 in rogh and 1:8.6 in amk. descriptive data of shigellosis exposure variables idris abaidani, prasanna a. raju, issa al-shualli, khalid al-sa’di, nasser al-shaqsi and amer al-khatri clinical and basic research | e385 from all households are shown in table 1. the vast majority of households (87.1%) indicated that their drinking water originated from the common water tank which supplied all three villages. water filters were used for purification purposes in 134 households (87.0%). fruit/vegetables were washed before consumption in 98.7% of households, with 87.6% using common tank water for this purpose. only 3.2% of source of water for vegetable washing common tank filtered not filtered 9 (5.8) 126 (81.8) tanker 5 (3.2) well 6 (3.9) other 8 (5.2) fresh preparation of food before consumption yes 143 (92.9) no 11 (7.1) waste collection container open 93 (60.4) closed 61 (39.6) frequency of waste disposal daily 141 (91.6) every 2–3 days 13 (8.4) every three days or longer 0 (0.0) frequency of waste collection by municipality daily 0 (0) every 2–3 days 0 (0) every 4–7 days 10 (6.5) every 8–14 days 6 (3.9) every 14 days or longer 138 (89.4) presence of houseflies yes 65 (42.2) no 88 (57.1) not observed 1 (0.7) presence of septic tank yes 149 (96.8) no 5 (3.2) presence of septic tank overflow/leakage yes 9 (5.8) no 145 (94.2) *total number of households for these variables was 134 as 20 households did not use water filters. †total number of households for this variable was 153 due to missing data for one household. table 1: descriptive data of shigellosis exposure variables from households in rustaq, al batinah south governorate, oman (n = 154) variable n (%) place of residence fass 75 (48.7) amk 48 (31.2) rogh 31 (20.1) presence of affected household members yes 44 (28.6) no 110 (71.4) source of drinking water common tank 134 (87.1) personal mineral water 8 (5.2) tanker 5 (3.2) well 6 (3.9) other 1 (0.6) use of water filters yes 134 (87.0) no 20 (13.0) type of water filters* electrical 119 (77.3) candle 15 (9.7) frequency of changing water filters* at least once in six months 124 (92.5) not changed 10 (7.5) water boiled/cooled before drinking† yes 5 (3.2) no 148 (96.1) frequency of cleaning water tank at least once in six months 114 (74.0) not clean 36 (23.4) not answered 4 (2.6) hand hygiene practices good 148 (96.1) average 5 (3.2) unsatisfactory 1 (0.6) washing fruit/vegetables before consumption yes 152 (98.7) no 2 (1.3) shigellosis outbreak in al batinah south governorate, oman case-control study e386 | squ medical journal, august 2015, volume 15, issue 3 table 2: comparison of shigellosis exposure variables between case and control households study in rustaq, al batinah south governorate, oman (n = 154) variable n (%) p value or 95% ci case control lower upper place of residence fassa 33 (75.0) 42 (38.2) <0.0001 4.857 2.219 10.631 rogh/amk 11 (25.0) 68 (61.8) source of drinking water common tank 40 (90.9) 95 (86.4) 0.590 1.579 0.493 5.053 other 4 (9.1) 15 (13.6) use of water filters no 4 (9.1) 16 (14.5) 0.437 0.558 0.185 1.867 yes 40 (90.9) 94 (85.5) type of filters* candle 4 (10.0) 11 (11.7) >0.05 0.838 0.250 2.810 electrical 36 (90.0) 83 (2.8) frequency of changing water filters* at least once in six months 3 (7.9) 7 (7.3) >0.05 1.090 0.267 4.454 not changed 35 (92.1) 89 (92.7) water boiled/cooled before drinking† no 42 (95.5) 106 (97.2) 0.626 0.594 0.096 3.685 yes 2 (4.5) 3 (2.8) frequency of cleaning water tank not clean 14 (33.3) 22 (18.6) 0.095 1.955 0.883 4.325 at least once in six months 28 (66.7) 86 (81.4) hand hygiene practices average/unsatisfactory 5 (11.4) 1 (0.9) 0.008 13.974 1.583 123.369 good 39 (88.6) 109 (99.1) washing fruit/vegetables before consumption no 2 (4.5) 0 (0.0) 0.080 0.276 0.214 0.357 yes 42 (95.5) 110 (100.0) fresh preparation of food before consumption no 4 (9.1) 7 (6.4) 0.511 1.471 0.408 5.301 yes 40 (90.9) 103 (93.6) waste collection container open 26 (59.1) 67 (60.9) 0.835 0.927 0.455 1.891 closed 18 (40.9) 43 (39.1) presence of house flies† yes 22 (50.0) 43 (39.4) 0.232 1.535 0.759 3.106 no 22 (50.0) 66 (60.6) presence of septic tank no 0 (0.0) 5 (4.5) 0.322 0.000 0.000 0.000 yes 44 (100.0) 105 (95.5) *total number of households for these variables was 134 as 20 households did not use water filters. †total number of households for this variable was 153 due to missing data for one household. idris abaidani, prasanna a. raju, issa al-shualli, khalid al-sa’di, nasser al-shaqsi and amer al-khatri clinical and basic research | e387 households reported boiling and cooling their drinking water before consumption. the water tanks in 23.4% and water filters in 7.5% of households had not been cleaned or changed at all in the previous six months. hand hygiene practices were rated as good in 96.1% of households. waste was collected in an open container in 60.4% of households; however, household waste was disposed of on a daily basis in 91.6% of the households. the majority of the households (89.4%) reported that it took more than 14 days for waste in common bins to be collected and disposed of by the local municipality. houseflies were observed in 42.2% of households. the majority of households (96.8%) had septic tanks, although overflowing/leaking septic tanks were observed in 5.8% of residences. additionally, 112 households (72.7%) reported that they had never emptied their septic tanks. sources of exposure were compared between case and control households [table 2]. as the greatest number of acute gastroenteritis cases resided in fassa, households in fassa were compared to the households from both amk and rogh. the risk of shigellosis occurring in a household in fassa was 4.85 times higher than for the villages of amk and rogh combined (or = 4.857, 95% ci = 2.219–10.631). this was statistically significant (p <0.005). as common tank water was the suspected source of the shigellosis outbreak, drinking water sources were categorised into either common tank or other water sources. the risk of shigellosis was 1.5 times greater in households using water from the common tank water source (or = 1.579, 95% ci = 0.493–5.053) compared to those using other sources of drinking water; however, this was not statistically significant (p = 0.590). not changing water filters regularly increased the odds of being a case household but was not statistically significant (or = 1.090, 95% ci = 0.267–4.454; p >0.05). water tanks in 33.3% of case and 18.6% of control households had not been cleaned in the previous six months. while the risk of shigellosis was 1.95 times greater among these households (or = 1.955, 95% ci = 0.883–4.325) compared to those who had cleaned their water tanks at least once during that time period, this was not statistically significant (p = 0.095). when hand hygiene practices were compared, there was a statistically significant risk of acute gastroenteritis among households with average or unsatisfactory hand hygiene practices (p = 0.008). the risk was 13.97 times higher in these households than in those with good hand hygiene practices. the risk of acute gastroenteritis occurring in a household was 1.47 times higher in residences where food was not freshly prepared compared to those who habitually consumed fresh food (or = 1.471, 95% ci = 0.408–5.301; p = 0.511). the presence of houseflies increased the risk of shigellosis by 1.5 (or = 1.535, 95% ci = 0.759–3.106; p = 0.232). these were not statistically significant. discussion shigellosis is a highly infectious diarrhoeal disease that can lead to explosive, common source or prolonged propogated epidemics.9–14 studies have linked unboiled water, contaminated food and household contact with shigellosis.15–18 the current study sought to determine the cause of an outbreak of shigellosis occuring in august 2012 in al batinah south governorate, oman. waterborne outbreaks of shigellosis are relatively common. arias et al. investigated the relationship between an outbreak of s. sonnei and water supplied by the municipal network of santa maria de palautordera in catalonia, spain.19 although the causal agent was not isolated from the water samples taken, various other factors—such as the attack rate (a biostatistical measure of the speed of spread in an at-risk population) and evidence from environmental investigations which showed that the levels of free residual chlorine in the water were not sufficient to prevent the contamination of the water network— suggested that it was a waterborne outbreak.19 a casecontrol study in sichuan province, china, established that a shigellosis outbreak in a rural elementary school was associated with a contaminated well.5 the well was shallow, constructed with stones and one metre away from a pond. sewage from the school and the surrounding farms was discharged directly into the pond without treatment. the untreated well water was found to yield s. flexneri serotype 2b.5 in the 2012 outbreak in al batinah south governorate, water samples were collected from the villages affected by acute gastroenteritis and tested by disease control specialists.7 the unsatisfactory results of the water samples, which were due to the presence of coliform bacilli and e. coli, were communicated to municipality officials.7,8 measures were taken to supply an alternate source of drinking water until the common water storage and supply sources were disinfected and the water was fit for consumption again.7 the common water supply source for the three villages and evidence of faecal contamination (due to the presence of coliforms) from bacteriological examinations by the ministry of health in rustaq of drinking water samples collected from households, a publicly accessible community water cooler and a mosque indicate that this shigellosis outbreak was probably waterborne.8 unfortunately, the exact point shigellosis outbreak in al batinah south governorate, oman case-control study e388 | squ medical journal, august 2015, volume 15, issue 3 of contamination could not be identified. shigella bacteria are difficult to culture from water and isolation from water is unusual.20–22 the current case-control study investigated other exposures which could have caused this outbreak of shigellosis. no significant differences were found between case and control households with regards to exposure variables related to sources of or practices related to drinking water. only residence in fassa and average hand hygiene practices were associated with an increased risk of acute gastroenteritis and statistically significant odds of a household being a case household. it is important to note that the three water samples which were found to have coliforms were collected from fassa.8 furthermore, fassa was the nearest village to the common water source.7 all of the individuals with average hand hygiene practices also lived in fassa. therefore, some degree of personto-person infection could have occurred. a systemic review by curtis et al. demonstrated that handwashing could reduce the risk of severe intestinal infections by 48% and of shigellosis by 59%.23 health education on the importance of maintaining hand hygiene before and after food consumption and after toilet use should therefore be provided to households in the wilayat of rustaq by health educators and community support group members. critically, the current study found that drinking water was boiled and cooled in only 3.2% of households before consumption. this could have been because the majority of households used filters to purify water. infrequent cleaning of water tanks and changing of water filters as well as the use of open waste collection containers were also observed in the interviewed households. these are all factors that introduce a greater risk of acute gastroenteritis.24–26 the importance of regularly cleaning overhead tanks, changing water filters, using closed containers to collect household waste, emptying full septic tanks and maintaining general hygiene in household surroundings should be stressed in this community setting. additionally, common houseflies are mechanical vectors of shigella and, as these organisms cohabitate with humans, they can readily contaminate food and eating utensils.27 waste collected less frequently than every 14 days (the average life cycle of the common housefly) places residents at risk of contracting acute gastroenteritis. findings from the current study suggest that municipal waste collection in the wilayat of rustaq needs to be done regularly and at more frequent intervals. in a study in first nation reserves in manitoba, canada, rosenberg et al. found that a lack of piped water and inadequate sewage disposal were significantly associated with an increased incidence of shigellosis.28 when compared to communities with piped water, the rate ratio for shigellosis was 6.0 (95% ci = 3.5–9.1) in communities where trucks delivered water to water barrels, while areas in which 50% of the houses did not have sewage removal had a rate ratio of 2.0 (95% ci = 1.6–2.6) compared with other communities.28 in the current study, the majority of households in the three villages had never emptied their septic tanks. this introduces the possibility that the contents of septic tanks may be diffusing underground and causing underground contamination, since most septic tanks are not leak-proof. with this scenario, a high chance of contaminating drinking water sources exists if there is a break in the water pipeline. hence, the public should be made aware of the importance of installing leak-proof septic tanks and carrying out regular cleaning. the current study is subject to a number of limitations. as the frequency of shigellosis cases had declined by the end of august 2012 and interviews were conducted nearly a month after the initial outbreak, there could have been a recall bias. mild and asymptomatic cases and individuals who did not seek medical care may not have been identified during the interview process, resulting in the potential misclassification of case and control households. for questions related to water, food and environmental hygiene practices, interviewees could have indicated that they were following well-known ‘good’ practices, even if this was not the case. this self-reporting bias could have impacted the significance of findings between case and control households. the contribution of certain demographic characteristics like age and gender to the outbreak of shigellosis was not assessed as the study intended to compare households only and not individuals. these demographic variables could have impacted the findings. conclusion this is the first study conducted in oman on a shigellosis outbreak in a community setting. possible exposure variables behind the shigellosis outbreak in three villages in the wilayat of rustaq in oman were assessed. the only variables that were significantly associated with an increased risk of contracting acute gastroenteritis were residence in fassa and average hand hygiene practices. no significant difference between households with acute gastroenteritis cases and those without cases were noted with regards to other exposure avenues, including sources of drinking water and practices related to drinking water, food preparation and environmental sanitation. while the source of the outbreak could not be identified, idris abaidani, prasanna a. raju, issa al-shualli, khalid al-sa’di, nasser al-shaqsi and amer al-khatri clinical and basic research | e389 the study found that practices related to water tank and septic tank maintenance and the consumption of freshly cooked food were not satisfactory in these villages. these need to be addressed regularly to prevent similar outbreaks of acute gastroenteritis in this community in the future. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. sjölund karlsson m, bowen a, reporter r, folster jp, grass je, howie rl, et al. outbreak of infections caused by shigella sonnei with reduced susceptibility to azithromycin in the united states. antimicrob agents chemother 2013; 57:1559–60. doi: 10.1128/aac.02360-12. 2. saha t, murhekar m, hutin yj, ramamurthy t. an urban, water-borne outbreak of diarrhoea and shigellosis in a district town in eastern india. natl med j india 2009; 22:237–9. 3. el bushra he, bin saeed aa. intrafamilial person-to-person spread of bacillary dysentery due to shigella dysenteriae in southwestern saudi arabia. east afr med j 1999; 76:255–9. 4. guzman-herrador b, vold l, comelli h, macdonald e, heier bt, wester al, et al. outbreak of shigella sonnei infection in norway linked to consumption of fresh basil. euro surveill 2011; 16:20007. 5. he f, han k, liu lg, sun w, zhang lj, zhu b, et al. shigellosis outbreak associated with contaminated well water in a rural elememtary school: sichuan province, china, june 7-16, 2009. plos one 2012; 7:e47239. doi: 10.1371/journal.pone.0047239. 6. department of planning, al batinah south governorate, oman ministry of health. wadi sahtan catchment population 2012: estimated population based on population data from the national center for statistics and information (ncsi). al batinah south, oman: oman ministry of health, 2012. 7. vaidya sk. gastroenteritis cases in oman village on decline: ffah village in rustaq area hit by outbreak believed to be due to water supply. gulf news. from: www.m.gulfnews.com/ news/gulf/oman/gastroenteritis-cases-in-oman-village-ondecline-1.1068296 accessed: jan 2015. 8. department of laboratories, directorate general of health affairs, oman ministry of health. bacteriological examination of water samples: laboratory reports 1–7 #m-168. al batinah south, oman: oman ministry of health, 2012. 9. levine mm, dupont hl, formal sb, hornick rb, takeuchi a, gangarosa ej, et al. pathogenesis of shigella dysenteriae 1 (shiga) dysentery. j infect dis 1973; 127:261–70. doi: 10.1093/ infdis/127.3.261. 10. egoz n, shmilovitz m, kretzer b, lucian m, porat v, raz r. an outbreak of shigella sonnei infection due to contamination of a municipal water supply in northern israel. j infect 1991; 22:87–93. doi: 10.1016/0163-4453(91)91122-e. 11. centers for disease control (cdc). hospital-associated outbreak of shigella dysenteriae type 2: maryland. mmwr morb mortal wkly rep 1983; 32:250–2. 12. benny e, mesere k, pavlin bi, yakam l, ford r, yoannes m, et al. a large outbreak of shigellosis commencing in an internally displaced population, papua new guinea, 2013. western pac surveill response j 2014; 5:18–21. doi: 10.5365/ wpsar.2014.5.2.003. 13. sorvillo fj, waterman sh, vogt jk, england b. shigellosis associated with recreational water contact in los angeles county. am j trop med hyg 1988; 38:613–17. 14. mahoney fj, farley ta, moriniere bj, winsor dk, silberman rl, mcfarland lm. evaluation of an intervention program in the control of an urban outbreak of shigellosis. am j prev med 1991; 7:292–7. 15. taylor dn, bodhidatta l, brown je, echeverria p, kunanusont c, naigowit p, et al. introduction and spread of multi-resistant shigella dysenteriae i in thailand. am j trop med hyg 1989; 40:77–85. 16. swaddiwudhipong w, karintraratana s, kavinum s. a common-source outbreak of shigellosis involving a piped public water supply in northern thai communities. j trop med hyg 1995; 98:145–50. 17. hoge cw, bodhidatta l, tungtaem c, echeverria p. emergence of nalidixic acid resistant shigella dysenteriae type 1 in thailand: an outbreak associated with consumption of a coconut milk dessert. int j epidemiol 1995; 24:1228–32. doi: 10.1093/ ije/24.6.1228. 18. gaudio pa, sethabutr o, echeverria p, hoge cw. utility of a polymerase chain reaction diagnostic system in a study of the epidemiology of shigellosis among dysentery patients, family contacts, and well controls living in a shigellosis-endemic area. j infect dis 1997; 176:1013–18. doi: 10.1086/516531. 19. arias c, sala mr, domínguez a, bartolomé r, benavente a, veciana p, et al. waterborne epidemic outbreak of shigella sonnei gastroenteritis in santa maria de palautordera, catalonia, spain. epidemiol infect 2006; 134:598–604. doi: 10.1017/s0950268805005121. 20. morera ma, espejo e, coll p, simó m, uriz ms, llovet t, et al. [epidemic outbreak of shigellosis following water intake]. enferm infecc microbiol clin 1995; 13:160–5. 21. samonis g, elting l, skoulika e, maraki s, tselentis y. an outbreak of diarrhoeal disease attributed to shigella sonnei. epidemiol infect 1994; 112:235–45. doi: 10.1017/ s0950268800057642. 22. centers for disease control and prevention (cdc). shigellosis outbreak associated with an unchlorinated fill-and-drain wading pool—iowa, 2001. mmwr morb mortal wkly rep 2001; 50:797–800. 23. curtis v, cairncross s. effect of washing hands with soap on diarrhoea risk in the community: a systematic review. lancet infect dis 2003; 3:275–81. doi: 10.1016/s1473-3099(03)00606-6. 24. weissman jb, craun gf, lawrence dn, pollard ra, saslaw ms, gangarosa ej. an epidemic of gastroenteritis traced to a contaminated public water supply. am j epidemiol 1976; 103:391–8. 25. mwabi jk, mamba bb, momba mn. removal of escherichia coli and faecal coliforms from surface water and ground water by household water treatment devices/systems: a sustainable solution for improving water quality in rural communities of the southern african development community region. int j environ res public health 2012: 9:139–70. doi: 10.3390/ ijerph9010139. 26. gebru t, taha m, kassahun w. risk factors of diarrhoeal disease in under-five children among health extension model and non-model families in sheko district rural community, southwest ethiopia: comparative cross-sectional study. bmc public health 2014; 14:395. doi: 10.1186/1471-2458-14-395. 27. levine os, levine mm. houseflies (musa domestica) as mechanical vectors of shigellosis. rev infect dis 1991; 13:688–96. doi: 10.1093/clinids/13.4.688. 28. rosenberg t, kendall o, blanchard j, martel s, wakelin c, fast m. shigellosis on indian reserves in manitoba, canada: its relationship to crowded housing, lack of running water, and inadequate sewage disposal. am j public health 1997; 87: 1547–51. doi: 10.2105/ajph.87.9.1547. http://dx.doi.org/10.1128/aac.02360-12 http://dx.doi.org/10.1371/journal.pone.0047239 http://dx.doi.org/10.1093/infdis/127.3.261 http://dx.doi.org/10.1093/infdis/127.3.261 http://dx.doi.org/10.1016/0163-4453%2891%2991122-e http://dx.doi.org/10.5365/wpsar.2014.5.2.003 http://dx.doi.org/10.5365/wpsar.2014.5.2.003 http://dx.doi.org/10.1093/ije/24.6.1228 http://dx.doi.org/10.1093/ije/24.6.1228 http://dx.doi.org/10.1086/516531 http://dx.doi.org/10.1017/s0950268805005121 http://dx.doi.org/10.1017/s0950268800057642 http://dx.doi.org/10.1017/s0950268800057642 http://dx.doi.org/10.1016/s1473-3099%2803%2900606-6 http://dx.doi.org/10.3390/ijerph9010139 http://dx.doi.org/10.3390/ijerph9010139 http://dx.doi.org/10.1186/1471-2458-14-395 http://dx.doi.org/10.1093/clinids/13.4.688 http://dx.doi.org/10.2105/ajph.87.9.1547 departments of 1dermatology and 2pathology, complejo hospitalario de granada, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com ساركومة سرطانية جلدية أولية ورم جلدي يف جَتَلِّي استثنائي وريكاردو رويز-فيال فريدي و هوزي انرييو�ض فريناند�ض primary cutaneous carcinosarcoma a cutaneous neoplasm with an exceptional presentation *ricardo ruiz-villaverde1 and josé aneiros-fernández2 an 85-year-old woman with a history of hypertension and diabetes mellitus was referred to the dermatology outpatient clinic of the complejo hospitalario de granada, granada, spain, in 2016 with an excrescent tumour on her upper forehead measuring 8 mm in diameter that had been present for the past two years [figure 1]. she had been exposed to significant ultraviolet (uv) radiation and undergone excision of two basal cell carcinomas (bccs) 10 years prior. upon physical examination, the lymph nodes were not palpable and there was no evidence of hepatosplenomegaly. a blood cell count and general biochemistry tests showed no abnormalities. the tumour was removed via complete conventional surgical excision with a 1 cm margin. upon histological examination, the neoplasia consisted of double cellular components. the first comprised typical bcc cells, while the other was composed of short spindle cells with moderate pleomorphism and pronounced mitotic activity corresponding to epithelial and sarcomatous components, respectively [figure 2]. an immunohistochemical analysis revealed the bcc component to be cytokeratin (ck) ae1/ae3positive and vimentin-negative, while the sarcomatous component was ck-negative and vimentin-positive [figure 3]. at a follow-up appointment one year later, there was no evidence of recurrence of the lesion. comment visceral carcinosarcomas have been described in num erous locations, including the adrenal glands, breast tissue, colon, endometrium, lungs and urogenital tract.1 first described in 1953, cutaneous carcinosarcomas (ccss) are uncommon cutaneous neoplasms involving biphasic malignant epithelial and sarcomatous components.2 the epithelial component is represented by a bcc, squamous cell carcinoma or adnexal carcinoma of the skin such as a porocarcinoma, trichilemmal cystic carcinoma or spiradenocarcinoma, whereas the interesting medical image sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e114–115, epub. 4 apr 18 submitted 13 nov 17 revision req. 18 dec 17; revision recd. 24 dec 17 accepted 11 jan 18 figure 1: photograph of an excrescent ulcerated tumour on the upper forehead of an 85-year-old woman. doi: 10.18295/squmj.2018.18.01.022 ricardo ruiz-villaverde and josé aneiros-fernández interesting medical image | e115 in ccs cases, mohs micrographic surgery is the treatment of choice and has been reported to result in a cure rate of ≥98%; in contrast, a recurrence rate of 33% has been reported without this surgery.4 as such, close observation of the patient is required if mohs surgery is not performed. there is no evidence to support the use of adjuvant radiotherapy. the prevalence of metastasis in ccs with a basal cell epith elial component has been reported in 2% of cases.4,5 references 1. rose rf, merchant w, stables gi, lyon cl, platt a. basal cell carcinoma with a sarcomatous component (carcinosarcoma): a series of 5 cases and a review of the literature. j am acad dermatol 2008; 59:627–32. doi: 10.1016/j.jaad.2008.05.035. 2. ormea f. [carcinosarcomas and cutaneous pseudosarcomas]. minerva dermatol 1953; 28:153–9. 3. tran ta, muller s, chaudahri pj, carlson ja. cutaneous carcinosarcoma: adnexal vs. epidermal types define highand low-risk tumors results of a meta-analysis. j cutan pathol 2005; 32:2–11. doi: 10.1111/j.0303-6987.2005.00260.x. 4. müller cs, pföhler c, schiekofer c, kömer r, vogt t. primary cutaneous carcinosarcomas: a morphological histogenetic con cept revisited. am j dermatopathol 2014; 36:328–39. doi: 10.1097/dad.0b013e318297cc34. 5. clark jj, bowen ar, bowen gm, hyngstrom jr, hadley ml, duffy k, et al. cutaneous carcinosarcoma: a series of six cases and a review of the literature. j cutan pathol 2017; 44:34–44. doi: 10.1111/cup.12843. sarcomatous component is formed of an osteosarcoma, chondrosarcoma, fibrosarcoma or malignant fibrous histiocytoma.3 the diagnostic criteria for a ccs include an absence of transitional areas in the malignant components and lack of cytokeratin expression in the sarcomatous components.3 however, müller’s criteria should be additionally considered to more thoroughly confirm the diagnosis.4 according to müller et al., a ccs is a malignant entity composed of two well defined cell populations as evidenced by conventional histology (i.e. haematoxylin and eosin stains) and an adequate immunohistochemical panel. metastases from distant sites and sarcomatous changes in the stroma of the neoplasm should also be excluded.4 there are at least four aetiopathogenic theories to explain the genesis of ccs. of these, the monoc lonal theory is particularly important as it justifies the rapid growth of the lesion by implicating the metaplastic transformation of the sarcomatous com ponent.5 other theories to explain the pathogenesis of this variety of tumour are polyclonal-, collision and composition-based.4 from a clinical perspective, ccss typically occur in damaged and sun-exposed skin. in the current case, the presence of p53 mutations in the two components of the neoplasm confirms the role of uv radiation as a triggering factor.5 figure 2: haematoxylin and eosin stains at (a) x2 magnification showing the panoramic pathological view of the lesion and (b) x10 magnification showing a biphasic tumour with an epithelial component (atypical basaloid proliferation) and a sarcomatous component (pleomorphic spindle cells). no vascular or perineural invasion was detected. figure 3: immunohistochemistry stains at x20 magnification showing (a) cytokeratin ae1/ae3-positivity in the epithelial component and (b) vimentin-positivity in the sarcomatous component of the lesion. https://doi.org/10.1016/j.jaad.2008.05.035 https://doi.org/10.1111/j.0303-6987.2005.00260.x https://doi.org/10.1097/dad.0b013e318297cc34 https://doi.org/10.1111/cup.12843 squ med j, november 2011, vol. 11, iss. 4, pp. 507-510, epub. 25th oct 11 submitted 21st dec 10 revision req. 7th mar 11, revision recd. 27th apr 11 accepted 18th may 11 acute fatty liver of pregnancy (aflp), a life threatening obstetric emergency, was first described by sheehan in 1940.1 the most common presentation is malaise, nausea, vomiting and epigastric pain followed by jaundice. laboratory tests usually demonstrate high bilirubin levels, deranged liver and renal functions, coagulopathy and hypoglycaemia. at presentation, one should keep in mind other pregnancy related liver diseases that mimic aflp such as hellp syndrome: haemolysis (h), elevated liver enzymes (el) and low platelet count (lp), and intrahepatic cholestasis of pregnancy. liver biopsy is the gold standard for diagnosing aflp, but due to the presence of coagulation abnormalities diagnosis is usually made by clinical and laboratory findings. bleeding and disseminated intravascular coagulation (dic) are one of most common complications. case report a 36 year-old healthy woman, gravida 3 para 2, presented to a peripheral hospital at 34 weeks gestation with a 3-day history of malaise, nausea, vomiting and abdominal pains. her pregnancy had been uncomplicated. on admission, her vitals appeared to be stable, but her blood pressure was 150/90 mmhg with no proteinuria. the results of the complete blood count was as follows: haemoglobin 13.4 g/dl; white blood count 22 x 109/l, and platelets, 227 x 109/l. the biochemical markers were as follows: total bilirubin 122.8 µmol/l; serum aspartate aminotransferase (ast) 118.9 iu/l; serum alanine aminotransferase (alt) 129.8 iu/l, and creatinine 158.5 µmol/l. the coagulation profile was as follows: prothrombin time (pt) 13 sec; activated partial thromboplastin time (aptt) 41 sec. the patient underwent an emergency caesarean section because of a non-reassuring fetal heart tracing. the outcome was a live male baby with good apgar scores. the next day, the patient started bleeding profusely through the vagina and her haemoglobin dropped to 4.9 g/dl; the platelet count was 25 x 109/l and fibrinogen 0.5 g/l. she was assessed, but no cause of bleeding identified. she was taken to the operating room and an exploratory midline laparotomy was performed. no departments of 1obstetrics and gynaecology, 2surgery and 3haematology sultan qaboos university hospital, muscat, oman. *corresponding author email: drriyami@hotmail.com حالة ال منطية للكبد الدهن احلاد يف احلمل نهال الريامي، عبد اهلل احلارثي، فهميدا �ضياء امللخ�ص:ُيَعّد الكبد الدهني احلاد يف احلمل من احلالت الطارئة التي تهدد احلياة. ت�صمل الأعرا�ص الأكرث �صي�عا: الت�عك والغثيان والتقي�ؤ والأمل ال�رس�ص�يف يتبعها الريقان. ينبغي اإجراء الت�صخي�ص مبكرا والإ�رساع بالعالج والرعاية نظرا لرتفاع معدل وفيات الأمهات وحديثي ال�لدة. ندرج هنا و�صف حلالة ل منطية من الكبد الدهني احلاد يف احلمل ونناق�ص العالج وامل�صاعفات لهذه احلالة النادرة من ال�صطراب. مفتاح الكلمات: الكبد الدهني احلاد يف احلمل ؛ النزف بعد الولدة؛ تخرث الدم داخل الأوعية، تقرير حالة، ُعمان. abstract: acute fatty liver of pregnancy (aflp) is a life threatening obstetric emergency. the most common presentation is malaise, nausea, vomiting and epigastric pain followed by jaundice. due to high maternal and perinatal mortality, early diagnosis, prompt delivery and supportive care are required. we report an atypical case of aflp and discuss the management and complications of this rare obstetric disorder. keywords: acute fatty liver of pregnancy; postpartum haemorrhage; disseminated intravascular coagulation; case report; oman. atypical case of acute fatty liver of pregnancy nihal al riyami,1 abdullah al-harthy,2 fehmida zia3 case report atypical case of acute fatty liver of pregnancy 508 | squ medical journal, november 2011, volume 11, issue 4 source of bleeding was identified intraoperatively and the abdomen was packed, closed and an intraperitoneal drain was inserted. a hysterectomy was not performed and no other intervention was done. the patient was then transferred to the intensive care unit (icu) at sultan qaboos university, tertiary hospital, oman, after receiving a total of 10 units of packed red blood cells, 19 units of fresh frozen plasma, 7 units of cryoprecipitate and 7 units of platelets. she was ventilated and was on intravenous dopamine infusion. the patient was bleeding profusely from her intraperitoneal jackson-pratt (j-p) drain. the laboratory findings on admission at our hospital were as follows: hb 12.4 g/dl; platelets 56 x 109/l; pt 23 sec; aptt 40 sec; fibrinogen 1.5 g/l; total bilirubin 155 µmol/l; ast 123 iu/l; alt 123 iu/l, and creatinine 163.9 µmol/l. the patient required further replacement of blood products. at our hospital, she received a total of 5 units of packed red blood cells, 5 units of fresh frozen plasma, 11 units of cryoprecipitate and 10 units of platelets. two units of recombinant activated factor vii (rfviia) were given to her and the bleeding lessened thereafter. she was taken to the operating room 24 hours after admission for removal of the abdominal packs. at the time of surgery, it was noted the abdominal packs were foul smelling and adherent to the serosal layers. the abdominal wall was bruised, but no active bleeding was observed. since there was no active bleeding, a hysterectomy was not performed, the packs were removed and abdomen was irrigated well and closed in layers. during the patient’s icu stay, she was on intravenous labetalol infusion for 48 hours to control her blood pressure. she was extubated on day 4 and moved to the ward on day 8 of admission. the patient’s status improved gradually, but she remained severally jaundiced with high bilirubin levels, mainly of the conjugated type (maximum total bilirubin level of 280), raised liver enzymes remaining in the hundreds and hypoalbuminemic (15 g/dl). viral hepatitis screening was done, but was negative. the dilemma was the amount of serous fluid drainage, first from the j-p drain that was removed on day 8 of admission and then from the patient’s wound site. clinical assessment and several investigations were performed including creatinine levels of the draining fluid, intravenous pyelogram, and ultrasound and computed tomography (ct) scans of the abdomen that excluded wound dehiscence, urinoma and seroma. on the bases of her clinical presentation including her signs, symptoms, massive bleeding and laboratory findings, the diagnosis of aflp was made and supportive care continued. further investigations with liver ultrasound and ct scans did not show evidence of fatty changes of the liver and a liver biopsy was not performed. on day 18 of admission, the patient was febrile and her wound grew a pseudomonas species infection that was treated with intravenous antibiotics (meropenem). on day 21 of admission, complete wound dehiscence was found and an emergency surgery was performed. it was noted during the surgery that there were lots of adhesions, the liver was frozen with multiple adhesions, the bowel was inflamed and the rectus fascia was not healthy. after adhesiolysis and extensive washing of the abdominal cavity with normal saline, a mass closure of the abdomen was performed using tension sutures. postoperatively, the patient did well. the wound healed with the assistance of the vacuum assisted closure (vac) system. the sutures were removed after 4 weeks and she was discharged home. she was monitored closely in the outpatient clinic and on her six weeks follow-up, the liver enzymes, bilirubin and albumin levels were normal and she was off antihypertensive medications. discussion hypertensive and liver disorders of pregnancy comprise a spectrum of conditions associated with adverse fetomaternal outcomes.1 the patient’s initial presentation may vary during the antepartum, intrapartum and even the postpartum period. clear understanding of the pathophysiology and mechanism of these disorders in pregnancy is very important. although severe preeclampsia is commoner than aflp and other liver disorders related to pregnancy, our patient's presentation and laboratory test results were in favour of an aflp diagnosis. ch'ng et al. first set the swansea criteria for diagnosing aflp that have been used by many institutions.2,3 six or more of the following features are used to diagnose aflp in the absence of other explanation: vomiting; abdominal pain; polydipsia/polyuria; encephalopathy; nihal al riyami, abdullah al-harthy and fehmida zia case report | 509 elevated bilirubin >14 µmol/l; hypoglycaemia <4 mmol/l; elevated urate >340 µmol/l; leukocytosis >11x109/l; ascites or bright liver on ultrasound; elevated tramsaminases; elevated ammonia >47 µmol/l; renal impairment creatinine >150 µmol/l; coagulopathy (pt >14 sec or aptt >34 sec), or microvesicular steatosis on liver biopsy. using these criteria we anticipated the diagnosis of aflp. the patient had vomiting, abdominal pain, elevated bilirubin and transaminases, elevated creatinine and coagulopathy at presentation. a patient with severe preeclampsia/hellp will usually present with proteinuria. aflp was first described by sheehan in 1940.1 the aetiology of the disease is unknown with an incidence of 1 in 10,000 to 1 in 15,000.5 it is a life threatening obstetrical emergency that can lead to high maternal and perinatal morbidity and mortality. due to the development of more rapid diagnosis tools and early termination of pregnancy, the maternal mortality rate due to this disease has decreased from 80–85% to 7–18% and the fetal mortality rate from 50% to 9–23%.6-8 the disease usually presents in the first pregnancy and in the third trimester with a mean gestational age of 34–37 weeks.9,10 the signs and symptoms at initial presentation may vary, making the diagnosis of this disease difficult, or there might be delay in diagnosis. similarly, the differential diagnosis may be difficult in a patient with abnormal hepatic function in pregnancy since a number of pathologies such as hellp syndrome, viral hepatitis and hormoneinduced cholestasis share some of the same symptoms and signs. the diagnosis of aflp remains challenging since there is no specific non-invasive diagnostic test to identify it. ultrasound and ct scans of the liver have been used, but the specificity and sensitivity of these studies are insufficient to make a diagnosis and the likelihood of false negative results is high.11 our patient had normal liver ultrasound and ct scan results. liver biopsy is the gold standard test, but it is invasive and requires a patient with normal coagulation status.4,5,12 the clinical presentation of both aflp and hellp syndrome are very similar but nausea, vomiting, epigastric pain and jaundice are more commonly seen in aflp patients.5 although aflp is an uncommon disease, our patient’s presentation and the development of jaundice with chronic hypoalbuminemia made this diagnosis more likely. moreover, the patient developed dic requiring massive blood transfusion (total of 76 units), making the diagnosis of aflp more likely. dic is seen in about 80–100% of patients with aflp as opposed to 21% of patients with hellp syndrome.5,12-14 the dic might be a severe and potentially fatal complication of aflp. the main cause of the coagulopathy leading to dic in patients with aflp is the severe hepatic dysfunction. it is less likely to be a complication for patients with other obstetrical or medical disorders such as hellp syndrome. early identification and correction of the coagulopathy before any obstetrical procedure is very important. when the patient presented to our icu, after having two surgeries within 24 hours, it was very difficult to make the decision to take her back to the operating room to control her bleeding. we continued replacing her with blood products and decided to give her rfviia and observe if the latter would control the bleeding. fortunately, the bleeding settled and the patient stabilised after receiving two doses of rfviia. there are an increasing number of case reports in the literature describing the successful “offlabel” use of rfviia (novoseven, novo nordisk, denmark) in the treatment of massive postpartum haemorrhage (pph) refractory to conventional medical and surgical therapy.15 the rationale for the use of rfviia in this setting is based on the observation that it directly activates factor x on the surface of activated platelets at the site of injury, factors viii, and ix. this results in a “thrombin burst” with the conversion of prothrombin into large amounts of thrombin and the local formation of a stable fibrin clot that may control bleeding.16 a recent systematic review was undertaken by a group in italy looking at the effects and role of rfviia in patients with massive pph.17 nine studies met the inclusion criteria and there were 272 patients involved. the group made the following recommendations: 1) consider the use of rfviia in cases of massive pph refractory to medical therapy including replacement of other blood products and even after a conservative/invasive surgical approach such as internal iliac or uterine artery ligation fails; 2) consider a second dose of rfviia (90 mg/kg iv bollus over 3–5 min) if there is no response after 20 minutes from the first dose, and 3) if bleeding atypical case of acute fatty liver of pregnancy 510 | squ medical journal, november 2011, volume 11, issue 4 persists after 2 doses of rfviia, consider performing a hysterectomy. conclusion despite the critical condition at presentation, and the complications she went through such as dic, chronic hypoalbuminemia, infection and burst abdomen, our patient finally went home in a good condition. early diagnosis of obstetrical emergencies, prompt therapy, adequate supportive care and a multidisciplinary approach are the key elements for a good outcome. a c k n o w l e d g e m e n t i wish to thank all the staff at sultan qaboos university hospital, especially those in the blood bank, for all their support and efforts in this case. references 1. national high blood pressure education program working group. report on high blood pressure in pregnancy. am j obstet gynecol 1990; 163:1691– 712. 2. joshi d, james a, quaglia a, westbrook rh, heneghan ma. liver disease in pregnancy, lancet 2010; 375:594–605. 3. knight m, nelson-piercy c, kurinczuk jj, spark p, brocklehurst p. a prospective national study of acute fatty liver of pregnancy in the uk. gut 2008; 57:951– 6. 4. vigil-de gracia p, lavergne ja. acute fatty liver of pregnancy. int j gynaecol obstet 2001; 72:193–5. 5. vigil-de gracia p. acute fatty liver and hellp syndrome: two distinct pregnancy disorders. int j gynaecol obstet 2001; 73:215–20. 6. moldenhauer js, o'brien j m, barton jr, sibai b. acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication. am j obstet gynecol 2004; 190:502–5. 7. pereira sp, o'donohue j, wendon j, williams r. maternal and perinatal outcome in severe pregnancy-related liver disease. hepatology 1997; 26:1258–62. 8. hay je. liver disease in pregnancy. hepatology 2008; 47:1067–76. 9. fesenmeier mf, coppage kh, lambers ds, barton jr, sibai bm. acute fatty liver of pregnancy in 3 tertiary care centers. am j obstet gynecol 2005; 192:1416–19. 10. mjahed k, charra b, hamoudi d, noun m, barrou l. acute fatty liver of pregnancy. arch gynecol obstet 2006; 274:349–53. 11. usta im, barton jr, amon ea, gonzalez a, sibai bm. acute fatty liver of pregnancy: an experience in the diagnosis and management of fourteen cases. am j obstet gynecol 1994; 171:1342–7. 12. castro ma, goodwin tm, shaw kj, ouzounian jg, mcgehee wg. disseminated intravascular coagulation and antithrombin iii depression in acute fatty liver of pregnancy. am j obstet gynecol 1996; 174:211–16. 13. williams j, mozurkewich e, chilimigras j, van de ven c. critical care in obstetrics: pregnancy-specific conditions. best pract res clin obstet gynaecol 2008; 22:825–46. 14. sibai bm. imitators of severe preeclampsia. obstet gynecol 2007; 109:956–66. 15. franchini m, franchi m, bergamini v, salvagno gl, montagnana m, lippi g. a critical review on the use of recombinant factor viia in life-threatening obstetric postpartum hemorrhage. semin thromb hemost 2008; 34:104–12. 16. bomken c, mathai s, biss t, loughney a, hanley j. recombinant activated factor vii (rfviia) in the management of major obstetric haemorrhage: a case series and a proposed guideline for use. obstet gynecol int 2009; 2009:364843. 17. dat franchini m, franchi m, bergamini v, montagnana m, salvagno gl, targher g, lippi g. the use of recombinant activated fvii in postpartum hemorrhage, clin obstet gynecol 2010; 53:219–27. clinical & basic research squ med j, august 2011, vol. 11, iss. 3, pp. 377-382, epub. 15th aug 11 submitted 15th jan 11 revision req. 4th may 11, revision recd. 28th may 11 accepted 4th jun 11 <ì�◊j~π]<^ëö¯π^e<ôêç√÷]<l^à¬^ñ⁄ê<ìëüëüä÷]<ì◊“^é÷]<∞e<ìfiö^œ⁄ <ìëå^u˘]<ôêç√÷]<ÿe^œ⁄<ì�èéfl÷]<ïöáíjπ]ê<ìè◊rflπ]ïö̌áí̌ǰ� π]<i ìè◊rflπ]<ïöáíjπ^e    200810    60  51.7% 35%  16.7% 5%  46.6% 15.8%  66.6% 36.8%  28% 2%    –:مفتاح الكلمات abstract: objectives: this study aimed to compare the clinical presentations and complications in patients having mixed malaria infection of plasmodium falciparum and plasmodium vivax with those of patients with malaria due to a p. falciparum mono-infection. methods: the medical records of malaria patients admitted to kasturba medical college, manipal, india, during the years 2008–10 were analysed. inclusion criteria were patients in whom p. falciparum and p. vivax coinfection or p. falciparum mono-infection alone was confirmed on peripheral smear examination. exclusion criteria were patients in whom p. vivax infection alone was diagnosed on peripheral smear examination. the sample size was twenty patients diagnosed with mixed infection of p. falciparum and p. vivax and 60 patients diagnosed with p. falciparum mono-infection. results: 35% of mixed infections had thrombocytopenia as compared to 51.7% of p. falciparum mono-infections. a total of 5% of the mixed infections had renal failure as compared to 16.7% of the falciparum mono-infections. total bilirubin was raised in 15.8% of mixed infections and in 46.6% of falciparum mono-infections. abnormal liver enzymes were seen in 36.8% of mixed infections and in 66.6% of falciparum mono-infections. none of the mixed infections had a parasite index over 2% while it was present in 28% of the falciparum mono-infections. conclusion: patients with mixed infections were found to have a lower incidence of severe complications such as anaemia, thrombocytopenia, liver and renal dysfunction and a lower parasite index. thus mixed malaria tends to have a more benign course as compared to malaria due to p. falciparum mono-infection. keywords: malaria, falciparum; epidemiology; parasitology; vivax; host-parasite interactions; india comparison of the clinical profile and complications of mixed malarial infections of plasmodium falciparum and plasmodium vivax versus plasmodium falciparum mono-infection *vivek joseph,1 muralidhar varma,2 sudha vidhyasagar,2 alvin mathew1 clinical & basic research 1medical students and 2department of medicine, kasturba medical college, manipal, karnataka, india. *corresponding author email: vivek101@gmail.com comparison of the clinical profile andcomplications of mixed malarial infections of plasmodium falciparum and plasmodium vivax versus plasmodium falciparum mono-infection 378 | squ medical journal, august 2011, volume 11, issue 3 malaria is a tropical disease caused by the protozoan parasite plasmodium. it is one of leading causes of morbidity and mortality in the tropics affecting around 190–311 million people worldwide and killing 7–10 million people every year.1 the disease in humans is caused by the direct effects of red blood cell (rbc) invasion and destruction by the parasite and the host’s response. splenic, immunologic and filtrative clearance is augmented and the removal of both parasitised and uninfected erythrocytes is accelerated. parasitised cells escaping splenic removal are destroyed when the schizont ruptures; this in turn induces activation of macrophages and cytokines which cause fever and other pathological effects. the complications seen in malaria include severe anaemia, hypoglycaemia, coma, convulsions, renal failure, bleeding and shock.2 malaria in humans is caused by plasmodium falciparum, p. vivax, p. ovale, p. malariae and the predominantly simian parasite p. knowlesi.3 of these, falciparum and vivax are the two most common infecting species. p. falciparum causes the most severe disease and almost all the fatalities, whereas p. vivax, although usually considered to be benign, causes repeated debilitating relapses, sometimes life-threatening complications, and intrauterine growth retardation. as several plasmodium species may be present in a particular area, infections with more than one species of plasmodium transmitted by the same vector at the same time are to be expected. malaria is not unique in this regard, mixed infections with lyme disease, human granulocytic ehrlichiosis and babesiosis, transmitted by ixodes ticks occur in the northeastern usa,4 and positive associations between geohelminths are common globally.5 however, there are only sporadic reports on mixed malarial infections. this can be attributed to the fact that mixed infections are often difficult to diagnose on routine smear examination. this is due to a combination of observer error, difficulty in distinguishing between the ring forms of the various plasmodium species, the undetectable presence of p. vivax and p. ovale liver hypnozoites, and low density infection below the threshold of detection by microscopy (<1 x 108 parasites in an adult). the relevance of interactions between the different plasmodium species extends beyond mere academic curiosity.6,7 studies report variable and sometimes even contradicting results on the effect of interactions in mixed malarial infections;8‒10 therefore, we undertook this study to compare the clinical presentations and complications of mixed malarial infections of p. falciparum and p. vivax to those of malaria due to p. falciparum alone. methods this retrospective observational study included all the malaria patients who were admitted to kasturba medical college, a tertiary teaching hospital in karnataka, south india, during the period june 2008 to july 2010. malaria is an endemic disease in this part of india. there are 150–200 annual reported cases of malaria in our college. the majority of the complicated cases are due to p. falciparum infection. the patients included in the study were all over 18 years of age and presented to the hospital on their own initiative with various complaints such as fever and were subsequently admitted. only those in whom malaria was confirmed on peripheral smear examination were included in the study. on the basis of peripheral smear examination two groups were formed. patients who showed both p. falciparum and p. vivax on their peripheral smear were allocated to group 1, while those who showed only p. falciparum on peripheral smear examination were allocated to group 2. those patients who showed only p. vivax on the peripheral smear were excluded from the study. due to the small number of mixed malaria cases (n = 20) it was decided to select all the patients from group 1 (mixed infection of p. falciparum and p. vivax) for the study. patients in advances in knowledge 1. the literature on the clinical outcome on mixed malarial infections is scanty. it is intuitive to think that mixed infections will add to morbidity, but our study in fact shows an improvement in the outcome. application to patient care 1. our study throws light on the potential dangers of treatment and preventive measures that selectively suppress the less virulent plasmodium vivax infection. this can have important clinical implications. vivek joseph, muralidhar varma, sudha vidhyasagar, alvin mathew clinical and basic research | 379 group 2 (p. falciparum mono-infection) who were age and sex matched to each of the 20 cases of mixed malarial infection were taken for the study. the total number of p. falciparum mono-infections selected was 60, thus giving a ratio of 1:3 (i.e. three p. falciparum mono-infections for every mixed malarial infection). prior to the start of the study the following terms were defined. anaemia was defined as haemoglobin less than 10g/dl; thrombocytopenia as platelets less than 100,000; raised bilirubin as total bilirubin greater than 2 g/dl; raised liver enzymes as serum aspartate transferase (ast)/ serum alanine transferase (alt) greater than 4 times normal range; serum creatinine was defined as raised when serum levels were greater than 1.6 g/dl. the parasite index was defined as the number of infected rbcs seen on peripheral smear examination per 1,000 rbcs expressed in percentage. the research was undertaken in the period march to december 2010. prior approvals from the ethical committee of kasturba medical college and from the superintendent of the medical records department at kasturba medical college were taken before commencement of the study. all the relevant patient records were collected from the medical records department and analysed. the data of the two groups were compared using the chi square test for each study parameter using the statistical package for the social sciences (spss, ibm, usa, version 18). table 1: comparison of the incidence of the various study parameters among mixed malarial infection of p. falciparum and p. vivax to that of p. falciparum mono-infection along with their p values parameter mixed infections of p. falciparum and p. vivax p. falciparum mono-infection p value number percentage number percentage anaemia 3 15 17 28.3 0.233 splenomegaly 6 30 42 70 0.0015 thrombocytopenia 7 35 31 51.4 0.196 raised bilirubin 3 15.8 28 46.6 0.0118 raised liver enzymes 7 36.6 32 66.6 0.155 serum creatinine 1 5 10 16.7 0.189 parasite index >2% 0 0 16 28 0.009 0% 15% 28.30% 30% 70% 35% 36.60% 5% 28% 16.70% 0% 66.60% 15.80% 46.60% 51.40% 10% 20% 30% 40% 50% 60% 70% 80% ana em ia spl eno me galy thr om boc ytop enia rai sed bil iubi n rai sed liv er e nzy me s ser um n c rea tine par asit e in dex >2 % mixed infection p falciparum mono-infection figure 1: the incidence of complications in mixed malarial infection of p. falciparum and p. vivax compared to that of p. falcipaum mono-infection. comparison of the clinical profile andcomplications of mixed malarial infections of plasmodium falciparum and plasmodium vivax versus plasmodium falciparum mono-infection 380 | squ medical journal, august 2011, volume 11, issue 3 results the study consisted of data on 80 subjects collected over a period of 2 years. it consisted of 20 cases of mixed malarial infection of p. falciparum and p. vivax and 60 cases of p. falciparum mono-infection. the cases of mixed infections consisted of 14 males (70%) and 6 females (30%). the p. falciparum mono-infection consisted of 45 males (75%) and 15 females (25%). the mean age of both the groups was 35 years. all patients in both the groups recovered from the disease. table 1 shows a comparison of the results for each parameter along with their p values. figure 1 gives a pictorial representation comparing the incidence of complications in mixed malarial infection of p. falciparum and p. vivax to that of p. falciparum mono-infection. patients with mixed malarial infections of p. falciparum and p. vivax were found to have a lower incidence of all the study parameters as compared to p. falciparum monoinfection. for example splenomegaly was found in 30% of mixed malaria infections as compared to 70% of p. falciparum mono-infections. similarly only 35% of mixed infections had thrombocytopenia as compared to 51.7% of p. falciparum monoinfections. raised serum creatinine was seen in 5% of the mixed infections as compared to 16.7% of the falciparum mono-infections. total bilirubin was raised in only 15.8% of mixed infections while it was raised in 46.6% of falciparum mono-infections. a parasite index of more than 2% was not seen in any mixed infections but it was seen in 28% of p. falciparum mono-infections. discussion mixed-malarial (falciparum and vivax) infections very often go unrecognised, or are underestimated. in our study, only 20 patients (2.9%) with mixed malaria infection, on peripheral smear examination, were identified out of a total of 689 cases admitted to kasturba medical college as malaria cases during the study period of 2 years. this is consistent with surveys done in thailand, which report that mixed infections constitute less than 2% of all malaria cases. however, studies using sensitive polymerase chain reaction (pcr) methods in the same region as the survey put the incidence of mixed infections at around 30% of all malarial infections.11 thus mixed malarial infections are often under estimated and can have a significant impact on patient management. in our study anaemia was seen only in 15% of mixed malarial infections of p. falciparum and p. vivax as compared to 36.6% of p. falciparum monoinfections. these findings correlated with studies conducted in thailand where they found that likelihood of developing anaemia was 1.8 times less in mixed malaria as compared to falciparum malaria.12 similarly, in our study, 30% of patients with mixed malaria infections had splenomegaly as compared to 70% of patients with p. falciparum mono-infection. thus splenomegaly is significantly (p = 0.0015) more common in p. falciparum monoinfection as compared to mixed malarial infection. a study done in punjab, india, found that the presence of splenomegaly is three times more common in p. falciparum infection compared to other forms of malaria.13 thrombocytopenia, one of the severe complications of malaria is attributed to reduced platelet life span and splenic pooling.14,15 macrophage activation and hyperplasia, especially in the spleen, may also play a role. our study noted that thrombocytopenia was more common in falciparum mono-infections as compared to mixed infections of both falciparum and vivax. thrombocytopenia was seen in 51% of falciparum malaria cases as compared to 35% of mixed malarial infections; however, this finding is not statistically significant. it is interesting to notes that a study done in kuwait showed a higher prevalence of thrombocytopenia in mixed and p. vivax monoinfections infections.8 our study showed a higher incidence of renal failure in patients with falciparum mono-infection (17%) as compared to mixed malarial infections (5%). studies have shown that there is a lower incidence and better prognosis for renal failure in patients with vivax malaria;16 however, no similar studies on renal failure in patients with mixed malarial infection have been seen. the precise mechanism of renal failure in malaria is not clearly known. cytoadherence of p. falciparum infected red blood cells to the vascular endothelial cells of different host organs along with rosette formation is considered as the most important mechanism of severe malaria.16,17 another complication of malaria is liver dysfunction which, when accompanied by other vital organ dysfunction (often renal vivek joseph, muralidhar varma, sudha vidhyasagar, alvin mathew clinical and basic research | 381 impairment), often carries a poor prognosis. hepatic dysfunction contributes to the severe complications of malaria such as hypoglycaemia, lactic acidosis, and impaired drug metabolism.2 in our study, it was seen that the signs of liver failure such as raised bilirubin levels and deranged liver enzymes were seen more commonly in p. falciparum mono-infection as compared to mixed infections of p. falciparum and p. vivax. the p value for the association of raised bilirubin with mixed and falciparum mono-infections was found to be significant (p = 0.0118) while the p value for raised liver function tests was not found to be significant (p = 0.155). mixed infections of p. falciparum and p. vivax were associated a with statistically significant (p = 0.009) lower parasite index as compared to p. falciparum mono-infection. none of the mixed infections had a parasite index of more than 2%, while 28% of cases in falciparum mono-infection had a parasite index of more than 2%. similar studies done in tanzania arrived at the same findings.18 immunity to malaria in humans is poorly understood, but it is thought to be both species and genotype specific. our study suggests that a coinfection of p. vivax protects against the severe complications of p. falciparum; however, this protective phenomenon of mixed malaria has proved to be controversial, as some workers have suggested that mixed infections are beneficial, whereas others have suggested that they are detrimental to the host. for example, in the 1930s, the classical clinical studies of human malariotherapy for neurosyphilis demonstrated that p. falciparum suppressed p. vivax parasitaemia when both species were inoculated simultaneously.19 in another more recent study done in thailand, it was seen that naturally acquired mixed infections with other less severe malaria species appear to attenuate the severity of p. falciparum infection.20 on the thaiburmese border, pregnant women whose first attack of malaria during pregnancy was caused by p. vivax had a significantly lower risk of developing p. falciparum later in the pregnancy.9 however, there are also several conflicting reports in the literature; for example, gopinathan and subramanian’s study in 1986 found that mixed infections with p. falciparum and p. vivax were associated with an increased incidence of complications like cerebral malaria.10 a major limiting factor in our study was the very small sample size of only 20 mixed malarial infections of p. falciparum and p. vivax over a period of 2 years. however, as mentioned earlier, we believe that mixed malarial infections are very often underestimated and only by using newer, more sensitive investigations such as pcr can we determine the true extent of mixed malarial infections. if further studies confirm our hypothesis that p. vivax co-infection indeed has a beneficial disease-modifying effect on the more severe p. falciparum infection, it would then be legitimate to speculate whether therapeutic suppression of the more benign p. vivax species in the population would cause p. falciparum malaria to become an even more serious public health problem. this scenario may explain why there is an increase in mortality resulting from the continued use of chloroquine as a first line treatment in africa in the face of mounting resistance to this drug by p. falciparum, but not by the other parasite species.6,7 thus we believe that we have to ask ourselves whether two mosquito bites are better than one. conclusion in this study, it was seen that patients with mixed malarial infections of p. falciparum and p. vivax were found to have a lower incidence of severe complications such as anaemia, thrombocytopenia, liver failure and renal failure that are often associated with p. falciparum mono-infections. it was also seen that mixed malarial infections had a lower parasite index as compared to p. falciparum mono-infections. from the above findings, we conclude that the p. vivax infection has a beneficial disease modifying effect on the more severe p. falciparum malaria. we believe that further studies are required to fully address this complex, but often understudied aspect of malaria. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. world health organization. world malaria report 2009. from: www.who.int/malaria/world_malaria_ report_2009/index.html. accessed: may 2011. 2. fauci as, brownwald e, kasper dl, hauser sl, longo dl, jameson jl et al. harrison’s principle of comparison of the clinical profile andcomplications of mixed malarial infections of plasmodium falciparum and plasmodium vivax versus plasmodium falciparum mono-infection 382 | squ medical journal, august 2011, volume 11, issue 3 internal medicine. 16th ed. new york: mcgraw hill, 2005. 3. singh jc, davis tme, lee ks, shamsul ssg, matusop a, ratnam s. et al. plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. clin infect dis 2008; 46:165–71. 4. thompson c, spielman a, krause pj. coinfecting deer-associated zoonoses: lyme disease, babesiosis, and ehrlichiosis. clin infect dis 2001; 33:676–85. 5. howard sc, donnelly ca, chan ms. methods for estimation of association between multiple species parasite infections. parasitol 2001; 122:233–51. 6. trape jf, pison g, preziosi mp, enel c, dulou ad, delaunay v, et al. impact of chloroquine resistance on malaria mortality. c r acad sci gen 1998; 321:689–97. 7. snow rw, trape jf, marsh k. the past, present and future of childhood malaria mortality in africa. trends parasitol 2001; 17:593–7. 8. taha k, el-dein sz, idrees m, makboul g, baidas g. hematological changes in malaria: relation to plasmodium species. kuwait med j 2007; 39:262–7. 9. nosten f, mcgready r, simpson ja, thwai kl, s balkan s, cho t, et al. effects of plasmodium vivax malaria in pregnancy. lancet 1999; 354:546–9. 10. gopinathan vp, subranmania ar. vivax and falciparum malaria seen at an indian service hospital. j trop med hyg 1986; 89:51–5. 11. mayxay m, pukrittayakamee s, newton pn, white nj. mixed-species malaria infections in humans. trends parasitol 2004; 5:233–40. 12. price rn, simpson ja, nosten f, luxemburger c, hkirjaroen l, kuile f, et al. factors contributing to anemia after uncomplicated falciparum malaria. am j trop med hyg 2001; 65:614–22. 13. strickland gt, fox e, hadi h. malaria and splenomegaly in the punjab. trans r soc trop med hyg 1988; 65:667–70. 14. horstmann rd, dietrich m. malaria-induced thrombocytopenia. ann hematol 1981; 42:157–64. 15. essien em, ebhota mi. platelet hypersensitivity in acute malaria (plasmodium falciparum) infection in man. j thromb haemost 1981; 46:547–9. 16. barsoum rs. malaria in acute renal failure. j am soc nephrol 2000; 11:2147–54. 17. eiam-ong s, sitprija v. falciparum malaria and the kidney: a model of inflammation. am j kidney dis 1998; 32:361–75. 18. alifrangis m, lemnge m, moon r, theisen m, bygbjerg i, ridley rg, et al. igg reactivities against recombinant rhoptry-associated protein-1 (rrap-1) are associated with mixed plasmodium infections and protection against disease in tanzanian children. parasitol 1999; 119:337–42. 19. boyd mf, kitchen sf. simultaneous inoculation with plasmodium vivax and falciparum. am j trop med 1937; 17:855–61. 20. luxemburger c, van vugt m, jonathan s, mcgready r, looareesuwan s, white nj. treatment of vivax malaria on the western border of thailand. trans r soc trop med hyg 1999; 93:433–8. clinical & basic research sultan qaboos university med j, february 2013, vol. 13, iss. 1, pp. 43-50, epub. 27th feb 13 submitted 24th apr 12 revision req. 31st jul 12, revision recd. 1st aug 12 accepted 2nd sep 12 1department of non-communicable diseases surveillance & control, ministry of health, muscat, oman; 2department of cardiology, royal hospital, muscat, oman *corresponding author e-mail: jallawati@gmail.com وبائيات متالزمة الشريان التاجي احلادة يف سلطنة عمان نتائج دراسة عمانريس جواد اأحمد اللواتي، كاظم جعفر �صليمان، برا�صانت بندوغرا مت التي البيانات حتليل املنهجية: عمان. �صلطنة يف احلادة التاجي ال�رسيان ملتالزمة اخلطر وعوامل وبائية تقييم الهدف: امللخ�ص: جمعها من خالل درا�صة متعددة املراكز يف عدة دول، بني املر�صى اللذين اأدخلوا على التوايل اىل امل�صايف والذين ترتاوح اأعمارهم 20 والإمارات وقطر والكويت والبحرين )عمان العربي اخلليج دول من خم�ض يف احلادة التاجي ال�رسيان متالزمة بت�صخي�ض اأكرث اأو عاما العربية املتحدة(، واليمن على مدى فرتة 5 اأ�صهر. هذا التحليل يلخ�ض بيانات املر�صى العمانيني الذين اأدخلوا امل�صت�صفى بت�صخي�ض مبدئي مبتالزمة ال�رسيان التاجي احلادة. النتائج: مت تاأكيد 1,340 حالة ملتالزمة ال�رسيان التاجي احلادة منها 748 بني الرجال 592 بني الن�صاء حيث بلغ العمر الو�صيط 61 �صنة. وكان معدل الإ�صابة للمتالزمة 338.9 حالة لكل 100,000 �صخ�ض�صنة. بينما بلغت 779 و 674 حالة لكل100,000 �صخ�ض�صنة بني الرجال والن�صاء على التوايل. وكان ن�صبة الذكور اإىل الإناث اأعلى بني مر�صى اإرتفاع مقطع st )فى ر�صم قلب الإحت�صاء التجلطى )2.26، بفا�صل ثقة %95 1.63 اىل 3.15( ويليه اإحت�صاء ع�صلة القلب غري املرتبط مبقطع st و�صكلت اىل 0.99(. 0.66 ثقة 95% بفا�صل 0.79( امل�صتقرة غري ال�صدرية والذبحة ،)2.21 اىل 1.28 ثقة 95% بفا�صل ،86.1 الذبحة ال�صدرية غري امل�صتقرة %55 من احلالت، واإحت�صاء ع�صلة القلب الناجم عن ارتفاع مقطع st %26 واإحت�صاء ع�صلة القلب غري الدم �صغط ارتفاع انت�صار معدل التاجيزيادة ال�رسيان مبتالزمة خطرالأ�صابة عوامل بني من احلالت. من st 19% مبقطع املرتبط )%68( وداء ال�صكري )%36(، وارتفاع الدهون )%63( وزيادة الوزن / ال�صمنة )%65(، مع معدل منخف�ض ن�صبيا من ا�صتخدام التبغ يف الوقت احلا�رس )%11( واخلال�صة: درا�صتنا توؤكد حدوث معدلت مرتفعة ملتالزمة ال�رسيان التاجي احلادة بني العمانيني ويدعم فكرة اأن وباء مر�ض القلب والأوعية الدموية جتتاح البلدان النامية. مفتاح الكلمات: متالزمة ال�رسيان التاجي احلادة، اأمرا�ض القلب والأوعية الدموية، نق�ض تروية القلب، عوامل اخلطر، و�صلطنة عمان. abstract: objectives: this study aimed to evaluate the epidemiology and coronary risk factors of acute coronary syndrome (acs) in oman. methods: data were collected through a prospective, multinational, multicentre survey of consecutive patients, hospitalised over a 5-month period in 2007 with a diagnosis of acs, in yemen and five arabian gulf countries (oman, bahrain, kuwait, qatar, united arab emirates). here we present data of omani patients aged ≥20 years who received a provisional diagnosis of acs and were consequently admitted to 14 different hospitals. results: there where 1,340 confirmed acs episodes in 748 men and 592 women (median age 61 years). the overall crude incidence rate of acs was 338.9 per 100,000 person-years (p-y). the age-standardised rate (asr) of acs was 779 and 674 per 100,000 p-y for men and women, respectively. the asr male-to-female rate ratio was highest in the st-elevation myocardial infarction (stemi) group (2.26, 95% confidence interval ([ci], 1.63 to 3.15) followed by the non-stemi (nstemi) group (1.68, 95% ci 1.28 to 2.21) and unstable angina (0.79, 95% ci 0.66 to 0.99). unstable angina accounted for 55%, stemi for 26% and nstemi for 19% of acs cases. among the coronary risk factors, there was a high prevalence of hypertension (68%), diabetes mellitus (dm) (36%), hyperlipidaemia (63%), and overweight/obesity (65%), with a relatively low rate of current tobacco use (11%). conclusion: our study confirms a high incidence of acs in omanis and supports the notion that the cardiovascular disease epidemic is also sweeping developing countries. keywords: acute coronary syndrome; incidence; cardiovascular disease; ischemic heart disease; risk factors; oman. the epidemiology of acute coronary syndrome in oman results from the oman-race study *jawad al-lawati,1 kadhim sulaiman,2 prashanth panduranga2 advances in knowledge this paper provides nationwide population-based incidence rates of acute coronary syndrome in a large prospective cohort recruited from multiple centres in oman. a comparable methodology was used, assessing the omani population against other arab gulf states, and based upon an international comparison with other arab, asian, and european populations. the epidemiology of acute coronary syndrome in oman results from the oman-race study 44 | squ medical journal, february 2013, volume 13, issue 1 current evidence indicates that cardiovascular diseases (cvd) make the largest contribution to mortality in most developing countries.1 of all cvd, ischaemic heart disease (ihd) is the single largest cause of death in such nations.2 worldwide, ihd was the second and third leading cause of disability-adjusted life years lost in men and women in 2002, respectively.1 although rates of ihd have fallen by up to 70% in the past three decades in some industrialised countries, it is likely to remain as the undisputed leading cause of death globally until the year 2030.2,3 since the early 1990s, cvds have been the leading cause of in-patient mortality in oman.4 in 2006, ihd was oman’s leading cause of morbidity and fourth cause of mortality among patients aged 45-60 years.5 although clinical management patterns of acute coronary syndrome (acs) have been reported in oman,6 to the best of our knowledge, the epidemiology of ihd and/or acs has not been studied. through a joint collaborative effort, the gulf registry for acute coronary events (gulf race) was established in 2006 to study such events in five arabian gulf countries and yemen.7 the aim of this registry was to estimate the incidence of acs in the participating countries, the distribution of cvd risk factors among affected patients, and types and practice patterns for the management of acs.7 this study details the epidemiology and coronary risk factors of acs patients throughout oman. methods the gulf registry of acute coronary events (gulf race) study was organised as a prospective, multinational, multicentre survey of consecutive patients over 20 years-old who had been hospitalised with the final diagnosis of acute coronary syndrome (acs) in yemen and five arabian gulf countries— oman, bahrain, kuwait, qatar, and the united arab emirates (uae)—over a period of 6 months. the pilot phase lasted throughout may 2006 and is described in detail elsewhere.7 enrolment for the study itself commenced on 29 january 2007, and continued for 5 months. an attempt was made to include all admissions that had been given a provisional diagnosis of acs with no exclusion criteria. patients who were admitted for non-acs causes to general wards but later developed acs in hospital were also included in the study. of the 16 requested centres (15 secondary and one tertiary care hospital, all with facilities to manage acs patients), 14 participated in the registry and enrolled patients according to the survey’s inclusion criteria. the study thus covered at least 85% of the total population of oman. ethical approval for the study was granted by the national or institutional ethical bodies in all participating countries. during the study period, all recruiting hospitals managed their patients independently. however, patients were referred to royal hospital in muscat, the capital of oman, on an emergency basis for primary angiography and/or angioplasty. study forms initiated in the parent institution, or secondary care hospital, were sent with patients during transfer to the royal hospital to complete data collection procedures and avoid duplicate reporting. all medical services, including acs management, are provided free of charge to omani nationals throughout government institutions in the country. data collected included patient demographics, past medical history, provisional diagnosis on admission, final discharge diagnosis, clinical features at hospital presentation, electrocardiogram (ecg) findings, laboratory investigations, medications administered within 24 hours of admission and those prescribed on discharge, use of cardiac procedures and interventions, inhospital outcomes, and in-hospital mortality. all management decisions were at the discretion of the treating physician. the external auditor visited 20% of the centres where filled forms and source documents (i.e. patients’ case notes) were inspected to verify that data collected in the case report form matched source documents. no attempt was made to validate the accuracy of discharge diagnosis of application to patient care with the recognition of the high incidence of acute coronary syndrome (acs) in oman, the government and public health authorities should give higher priority to the control of the underlying cardiovascular disease risk factors which are shown to be highly prevalent in omani patients. jawad al-lawati, kadhim sulaiman and prashanth panduranga clinical and basic research | 45 the attending physician. diagnosis of the different types of acs and definitions of data variables were based on the american college of cardiology clinical data standards published in december 2001.8 these definitions are based on clinical presentations, ecg findings, and cardiac biomarkers. the biomarkers were measured locally at each hospital’s laboratory using its own assays and reference ranges. only two centres used troponin (t) as routine assays in the diagnosis of myocardial injury. body mass index (bmi) was used to characterise overweight (bmi 25–29.9 kg/m2) or obese patients (bmi ≥30 kg/m2).9 a waist circumference ≥94 cm in males and ≥80 cm in females was considered abnormal. diagnosis of diabetes mellitus (dm) was based on past diagnosis by a physician, intake of antidiabetic medications, or post-admission fasting plasma glucose (fpg) values using the 1999 diagnostic criteria recommended by the world health organization (who).10 hypertension was diagnosed if systolic and/or diastolic arterial blood pressure exceeded 130/85 mmhg, or if a patient was on anti-hypertensive medication. subjects were classified as having high total cholesterol if fasting levels exceeded 5.2 mmol/l; hypertriglyceridaemia if levels exceeded 1.69 mmol/l, and/or abnormal levels of high density lipoproteins if levels were <1.04 in males and <1.29 mmol/l in females.11 data were entered in epi info, version 6 (centers for disease control, atlanta, georgia, usa). categorical variables were presented as a number of cases and percentages and compared using the chisquare test. the k-sample equality-of-medians test was used to examine differences between groups of median age. incidence rates of coronary events were calculated from index episodes during the study period using the mid-year 2007 population estimates for oman obtained from the omani ministry of national economy.12 to facilitate comparisons with other published rates, age-standardised incidence rates (asr) were calculated by direct method within 10-year bands for ages 20 years and above, using the world standard population.13 for comparisons with world health organization monitoring trends and determinants in cardiovascular disease (who-monica), monica age weights in the 5-year age bands for ages 35–64 years were used.14,15 a 95% confidence interval (ci) for asr ratio (rr) was calculated using the standard error of the natural logarithm of the rrs.16 observed differences were expressed as p values. a value of p <0.05 was considered statistically significant. analyses were performed with intercooled stata, version 9.1 (stata corporation, texas, usa) and microsoft excel 2003 (microsoft corporation, redmond, washington, usa). completeness of data was 98% for all the analysed variables. patients with a diagnosis of left bundle branch block (n = 9) were grouped with the st-elevation myocardial infarction (stemi) patients. results the baseline characteristics of the acs patients enrolled in the study are given in table 1. over the 153-day recruitment period, 1,340 cases of acs were reported with complete core data. the median age of acs patients was 61 years (males 60 years and females 61 years; p = 0.39). among the risk factors, a high prevalence of hypertension (56%), dm (38.2%), and hyperlipidaemia (36.4%) was reported on admission. when fasting blood sugar, blood pressure, and total cholesterol were measured 24 hours post-admission, there was a significant increase in the detection of hypertension (56–69%; p <001) and hyperlipidaemia (36.4–63.3%, p <001). the prevalence of dm was around 32% using random blood sugar, and increased to 46% when using fasting plasma glucose levels in patients with stemi (p <001). one-half to two-thirds of acs patients were either overweight or obese according to who criteria.9 current tobacco use was relatively low (11.1%). of the total acs patients, 741 (55.3%) were discharged from hospitals with unstable angina, 345 (25.7%) with non-st elevation myocardial infarction (nstemi) and 254 (18.9%) with stemi [table 1]. unstable angina was also the most common diagnosis across all 10-year age strata, followed by nstemi and stemi. patients with unstable angina and nstemi were also more likely to report a medical history of percutaneous coronary intervention, dm, hypertension, and hyperlipidaemia. on the other hand, stemi patients were more likely to be current tobacco users. women were more likely to present with unstable angina compared to men (54% versus 46%, p <03) [table 2], while men were twice as likely to present with stemi and nstemi compared to the epidemiology of acute coronary syndrome in oman results from the oman-race study 46 | squ medical journal, february 2013, volume 13, issue 1 women. table 2 demonstrates the crude and asr of incidence of acs in oman in patients aged 20 years and above, and in a subgroup aged 35– 64 years. the period of case ascertainment (5 months) encompassed 395,389 person-years (p-y) of observations in 748 men and 592 women (all omanis) with episodes of acs. the overall crude incidence of acs was 338.9 per 100,000 p-y. the asr of acs was 779 and 674 per 100,000 p-y for men and women, respectively. the asr of acs were significantly higher in men than women with table 1: baseline characteristics of patients admitted with acute coronary syndrome (oman race study, 2006) characteristic stemi % (n = 254) nstemi % (n = 345) unstable angina % (n = 741) all % (n = 1,340) median age (yrs) 61 61 61 61 age groups 20–29 0.8 0.6 0.9 0.8 30–39 4.7 4.6 3.5 4.0 40–49 12.6 13.9 13.9 13.7 50–59 22.0 26.1 25.9 25.2 60–69 29.5 33.0 33.3 32.5 70+* 30.3 21.7 22.4 23.7 men* 73 65 46.0 56.0 medical history angina pectoris* 30.3 52.2 60.9 52.8 mi 16.1 22.6 19.5 19.6 pci* 3.9 9.0 9.1 8.0 cabg* 3.1 7.0 9.5 7.6 aspirin use* 31.6 54.2 60.2 53.2 current tobacco use* 23.6 12.5 6.2 11.1 diabetes* 30.3 37.4 41.3 38.2 hypertension* 39.4 55.6 61.8 56.0 hyperlipidaemia* 23.2 35.6 41.3 36.4 measurements 24 hours post-admission rbg ≥ 11.1 mmol/l 32.4 30.7 28.7 29.9 fbg ≥ 7.0 mmol/l* 46.0 41.9 30.7 36.5 hypertension* 61.0 68.0 71.8 68.8 tc >5.2mmol/l 63.3 63.4 63.3 63.3 abnormal hdl 51.6 57.3 57.7 56.4 abnormal tg 33.5 30.1 36.8 34.4 bmi 25-29.9 kg/m2 33.5 40.3 38.3 37.9 bmi ≥30 kg/m2 25.2 26.4 28.9 27.5 abnormal wc (cm)* 43.7 57.2 66.1 59.8 stemi = st-elevation myocardial infarction; nstemi = non-st elevation myocardial infarction; mi = myocardial infarction; pci = percutaneous coronary intervention; cabg = coronary artery bypass graft; rbg = random blood glucose; fbg = fasting blood glucose; tc = total cholesterol; hdl = high density lipoprotein; tg = triglycerides; bmi = body mass index; wc = waist circumference. * = p < 0.05; chi-square tests were utilised to examine the statistical significance of differences between the respective comparison groups with regards to the distribution of categorical variables. a k-sample equality-of-medians test was used to examine between group differences in median age. for cut-off points for each variable, see methods section. jawad al-lawati, kadhim sulaiman and prashanth panduranga clinical and basic research | 47 a rate ratio of 1.16 (95% ci: 1.01 to 1.32). the male to female age-standardised incident rate ratio was highest in the stemi group (2.26, 95% ci: 1.63 to 3.15) followed by the nstemi group at 1.68 (95% ci: 1.28 to 2.21) and that with unstable angina at 0.79. (95% ci: 0.66 to 0.99). when data were analysed in a subgroup aged 35–64 years for broad comparisons with the monica project cohort, there were 448 events in males and 350 events in females within 128,187 p-y.14 age-standardised acs event incident rates were higher in men than in women in this age band with a rate ratio of 1.21 (95% ci: 1.01 to 1.45). discussion we provide the first age-standardised populationbased incidence rates of acs and associated risk factors in oman. the asr of acs in omanis (men 779, women 674 per 100,000 p-y) were similar to rates reported among palestinian arabs of jerusalem (796 and 503 per 100,000 men and women p-y, respectively).17 these incidence rates are markedly higher than those reported in industrialised nations such as denmark (men 331 and women 137 per 100,000 p-y), greece (both genders 226 per 100,000 p-y), and france (men 262 and women 55 per 100,000 p-y), thus confirming the double burden of already existing communicable diseases and the present non-communicable diseases in table 2: crude and age-standardised annual incidence rates (all per 100,000 person-years) of acute coronary syndrome and its components in omani men and women aged 20 years and above (oman race study, 2006) age group all acs stemi nstemi unstable angina male (20+ years) no. of cases 748 184 224 340 p-y 198,324 198,324 198,324 198,324 crude rate (95% ci) 377.2 (350.6 to 405.1) 92.8 (79.9 to 107.2) 112.9 (98.6 to 128.8) 171.4 (153.7 to 190.6) asr (95% ci) 779.7 (723.2 to 836.2) 184.9 (164.6 to 221.5) 239.5 (200.5 to 262.3) 355.3 (723.2 to 836.2) female (20+ years) no. of cases 592 70 121 401 p-y 197,065 197,065 197,065 197,065 all crude (95% ci) 300.4 (276.7 to 325.6) 35.5 (27.7 to 44.9) 61.4 (50.9 to 73.4) 203.5 (184.1 to 224.4) all asr (95% ci) 674.3 (619.5 to 729.1) 81.7 (64.1 to 103.8) 142.2 (114.7 to 165.3) 450.4 (619.5 to 729.1) male (35-64 years) no. of cases 448 139 103 206 person-years 63,543 63,543 63,543 63,543 asr for ages 35–64 835.0 (757.3 to 912.8) 189.7 (152.6 to 226.8) 256.9 (213.7 to 300.2) 388.3 (335.0 to 441.7) females (35-64 yrs) no. of cases 350 39 241 p-y 64,644 64,644 64,644 64,644 asr for ages 35–64 691.6 (618.7 to 764.5) 81.1 (55.5 to 106.7) 138.9 (106.0 to 171.7) 471.6 (411.4 to 531.7) male:female rate ratio, 20+ years (95% ci) 1.16 (1.01 to 1.32) 2.26 (1.63 to 3.15) 1.68 (1.28 to 2.21) 0.79 (0.66 to 0.99) rate ratio, 35–64 years (95% ci) 1.21 (1.01 to 1.45) 2.34 (1.47 to 3.73) 1.85 (1.28 to 2.68) 0.82 (0.65 to 1.05) acs = acute coronary syndrome; stemi = st-elevation myocardial infarction; nstemi = non st-elevation myocardial infarction; p-y = person-years; asr = age-standardised rate; ci = confidence interval. for age-standardising, see reference no. 13. the epidemiology of acute coronary syndrome in oman results from the oman-race study 48 | squ medical journal, february 2013, volume 13, issue 1 middle and low-income developing countries.18– 21notwithstanding the differences in the definitions of coronary events between the present study and the monica populations studied between 1981 and 1995, the coronary event incidence rate in omani men aged 35–64 years (835 per 100,000 p-y) are comparable to the highest rates recorded in the monica project (907 per 100,000 p-y among finnish men).22 similarly, in the 35–64 year old cohort, the incidence rate of acs among omani women (692 per 100,000 p-y) was more than double the rate in their scottish counterparts in the uk (241 per 100,000 p-y), although, the latter was the highest rate reported among monica women.22 when compared with other arabs in the same age group of 35–64 years, the acs incidence rate among omanis surpassed the rate reported in palestinian men (799 per 100,000 p-y) while the rate in omani women was three times the rate in palestinian women (234 per 100,000 p-y).17 the high incidence of acs among omanis (and other arab ethnic groups) may stem from greater susceptibility and excess exposure to established cvd risk factors.23 in asian populations, morbidity and mortality appear to occur at lower cut-off point values for some cvd risk factors such as bmi and waist circumference than in caucasians, possibly indicating greater susceptibility at a lower threshold for adverse health outcomes.24–26 in our study, omani patients appeared to experience acs at an earlier age (mean 60.7 years; median 61 years) than their counterparts from europe, australia, the united states, and brazil (median range 63.4– 68.1) by an average of 2 to 7 years.27the difference in age can extend up to 11 years if compared with europeans with unstable angina.28 arab patients with acs from other countries were also reported to be younger (mean age: saudi arabia 57.1, kuwait 56.7, and palestine 57.9),17,29,30 the interheart study also showed arab patients to be a decade younger at presentation with acute myocardial infarction than europeans, chinese, or latin american patients.31 the earlier onset of acs in arabs has not been studied systematically. however, greater susceptibility to cvd risk factors may be implied, in a similar way suspected to occur among south asians through genetic differences or a mismatch of metabolic processes during early or middle age.23 other findings like low levels of high density lipoproteins and a lack of regular physical activity among omanis may have contributed further to their susceptibility to adverse coronary outcomes.32 our study’s main strength lies in the fact that it is the first to provide nationwide estimates of incidence and risk factors of acs in a large prospective cohort recruited from multiple centres in oman using a methodology comparable with other arab gulf states. on the other hand, the lack of a vital registration system within the country implies that sudden cardiac deaths due to acs could not be estimated and thus are not included in the current incidence estimates presented here. further, due to limited resources, out of 1,340 patients, t assays were used in less than 21% (277 patients) to diagnose myocardial injury. however, this is unlikely to have biased results towards the under diagnosis of stemi and nstemi as proportions of the later two in oman are similar (42% and 58%, respectively) to the overall gulf-race (39% and 61%, respectively) and gulf-race 2 (46% and 54%, respectively) studies after discarding results from unstable angina patients.33,34 finally, comparison data were presented with monica cohorts in spite of changes of some diagnostic criteria and temporality between the two studies, mainly due to wide use of t assays in the current survey. conclusion the incidence of acs among omanis is one of the highest in the world and flags up an impending cvd epidemic that is yet to reach its peak. the need to address root causes of established cvd risk factors could not be more urgent.35 health reforms and prevention strategies are needed to counter a cvd epidemic, with a particular focus on reducing the high number of preventable risk factors. a c k n o w l e d g e m e n t s we would like to thank all patients who consented to this study. we thank all physicians who collaborated in the data collection and data management for this study. without their collaboration this study would have not been possible. references 1. world health organization. the world health report 2003: shaping the future. geneva: world jawad al-lawati, kadhim sulaiman and prashanth panduranga clinical and basic research | 49 health organization 2003. 2. mathers cd, loncar d. projections of global mortality and burden of disease from 2002 to 2030. plos med 2006; 3:e442. 3. world health organization. preventing chronic diseases: 2005: a vital investment. geneva: world health organization 2005. 4. hill ag, muyeed az, al-lawati ja. the mortality and health transitions in oman: patterns and processes. cairo: world health organization regional office for the eastern mediterranean and unicef, 2000. 5. directorate general of planning, ministry of health, oman. annual health report, 2007. muscat: ministry of health 2007. 6. panduranga p, sulaiman k, al-zakwani i. acute coronary syndrome in oman: results from the gulf registry of acute coronary events. sultan qaboos univ med j 2011; 11:338–42. 7. zubaid m, rashed wa, al-khaja n, almahmeed w, al-lawati j, sulaiman k, et al. clinical presentation and outcomes of acute coronary syndromes in the gulf registry of acute coronary events (gulf race). saudi med j 2008; 29:251–5. 8. cannon cp, battler a, brindis rg, cox jl, ellis sg, every nr, et al. american college of cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. a report of the american college of cardiology task force on clinical data standards (acute coronary syndromes writing committee). j am coll cardiol 2001; 38:2114–30. 9. world health organization. obesity: preventing and managing the global epidemic. world health organization (who technical report series, no. 894). geneva: world health organization, 2000. 10. world health organization. definition, diagnosis and classification of diabetes mellitus and its complications. part 1: diagnosis and classification of diabetes mellitus. report of a who consultation. geneva: world health organization, 1999. who/ ncd/ncs/99.2. 11. national cholesterol education program. third report of the national cholesterol education program (ncep) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii) final report. circulation 2002; 106:3143-421. 12. directorate general of planning. annual health report. muscat: ministry of health, 2007. 13. segi m. cancer mortality for selected sites in 24 countries (1950–57). sendai, japan: tohoku university school of medicine, department of public health, 1960. 14. tunstall-pedoe h, kuulasmaa k, mahonen m, tolonen h, ruokokoski e, amouyel p. contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10year results from 37 who monica project populations. monitoring trends and determinants in cardiovascular disease. lancet 1999; 353:1547–57. 15. mahonen m, tolonen h, kuulasmaa k. monica coronary event registration data book 1980-1995, october 2000. from: http://www.ktl.fi/publications/ monica/coredb/coredb.htm accessed: oct 2009. 16. breslow ne, day ne, eds. statistical methods in cancer research. vol ii. the design and analysis of cohort studies. international agency for research on cancer. lyon, france: international agency for research on cancer, scientific publication no. 82, 1987. p. 64. 17. kark jd, fink r, adler b, goldberger n, goldman s. the incidence of coronary heart disease among palestinians and israelis in jerusalem. int j epidemiol 2006; 35:448–57. 18. nielsen km, foldspang a, larsen ml, gerdes lu, rasmussen s, faergeman o. estimating the incidence of the acute coronary syndrome: data from a danish cohort of 138,290 persons. eur j cardiovasc prev rehabil 2007; 14:608–14. 19. pitsavos c, panagiotakos db, antonoulas a, zombolos s, kogias y, mantas y, et al. epidemiology of acute coronary syndromes in a mediterranean country: aims, design and baseline characteristics of the greek study of acute coronary syndromes (greecs). bmc public health 2005; 5:23. 20. ferrieres j, cambou jp. epidemiology of acute coronary syndrome in france. ann cardiol angeiol (paris) 2007; 56:s8–15. 21. boutayeb a. the double burden of communicable and non-communicable diseases in developing countries. trans r soc trop med hyg 2006; 100:191–9. 22. tunstall-pedoe h, kuulasmaa k, amouyel p, arveiler d, rajakangas am, pajak a. myocardial infarction and coronary deaths in the world health organization monica project. registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. circulation 1994; 90:583–612. 23. bhopal r. epidemic of cardiovascular disease in south asians. bmj 2002; 324:625–6. 24. world health organization western pacific region. the asia-pacific perspective: redefining obesity and its treatment. geneva: world health organization 2000. 25. kanazawa m, yoshiike n, osaka t, numba y, zimmet p, inoue s. criteria and classification of obesity in japan and asia-oceania. asia pac j clin nutr 2002; 11:s732–7. 26. deurenberg-yap m, yian tb, kai cs, deurenberg p, staveren wa. manifestation of cardiovascular risk factors at low levels of body mass index and waistto-hip ratio in singaporean chinese. asia pac j clin nutr 1999; 8:177–83. the epidemiology of acute coronary syndrome in oman results from the oman-race study 50 | squ medical journal, february 2013, volume 13, issue 1 27. goldberg rj, currie k, white k, brieger d, steg pg, goodman sg, et al. six-month outcomes in a multinational registry of patients hospitalized with an acute coronary syndrome (the global registry of acute coronary events (grace). am j cardiol 2004; 93:288–93. 28. hasdai d, behar s, wallentin l, danchin n, gitt ak, boersma e, et al. a prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in europe and the mediterranean basin; the euro heart survey of acute coronary syndromes (euro heart survey acs). eur heart j 2002; 23:1190–201. 29. alhabib kf, hersi a, alfaleh h, kurdi m, arafah m, youssef m, et al. the saudi project for assessment of coronary events (space) registry: design and results of a phase i pilot study. can j cardiol 2009; 25:e255–8. 30. zubaid m, suresh cg, thalib l, rashed w. differential distribution of risk factors and outcome of acute coronary syndrome in kuwait: three years' experience. med princ pract 2004; 13:63–8. 31. yusuf s, hawken s, ounpuu s, dans t, avezum a, lanas f, et al. effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the interheart study): case-control study. lancet 2004; 364:937–52. 32. al-lawati ja, mohammed aj, al-hinai hq, jousilahti p. prevalence of the metabolic syndrome among omani adults. diabetes care 2003; 26:1781– 5. 33. zubaid m, rashed wa, almahmeed w, al-lawati j, sulaiman k, al-motarreb a, et al. management and outcomes of middle eastern patients admitted with acute coronary syndromes in the gulf registry of acute coronary events (gulf race). acta cardiol 2009; 64:439–46. 34. alhabib kf, sulaiman k, al-motarreb a, almahmeed w, asaad n, amin h, et al. baseline characteristics, management practices, and long-term outcomes of middle eastern patients in the second gulf registry of acute coronary events (gulf race-2). ann saudi med 2012; 32:9–18. 35. al-lamki l. acute coronary syndrome, diabetes and hypertension: oman must pay more attention to chronic non-communicable diseases. sultan qaboos unv med j 2011; 11:318–21. 1oral & dental diseases research centre and departments of 2endodontics and 3operative dentistry, school of dentistry, kerman university of medical sciences, kerman, iran *corresponding author e-mail: fr.rafie87@yahoo.com اإلجهاد املهين وسلوكيات التأقلم بني أطباء األسنان يف كرمان، إيران �صيفا بوراديلي، ارا�ض �صارافان، علي ا�صكندرزيده، فوروزان رفيع، مرمي ها�صميبور abstract: objectives: recognising causes of stress can help prevent associated adverse effects. this study aimed to investigate causes of occupational stress and coping behaviours among general dentists in iran. methods: this cross-sectional study was carried out from april to december 2014. a modified version of the occupational stress indicator questionnaire was used to assess causes of stress and coping behaviours among 142 general dentists in kerman, iran. results: a total of 93 dentists participated in the study (response rate: 65.5%). of these, 58.9% reported often being stressed. the mean general stress score was 63.33 ± 19.99. the most common causes of stress were maintaining high levels of concentration while working (65.6%), time pressures (64.5%), concern over their ability to deliver dental services in future (60.2%) and rising costs (59.1%). no significant relationships between stress and gender, age, workplace or working hours per week were noted (p >0.05). however, there was a significant correlation between general stress scores and years of job experience (p = 0.05) and number of patients treated daily (p = 0.03). the most common methods for coping with stress were resting (71.0%), sports (45.2%) and entertainment (43.0%). most dentists felt that stress management courses could help to reduce stress (89.7%). conclusion: general dentists in kerman were subject to many sources of stress in their workplaces, with significant relationships between stress scores and years of work experience and number of patients treated daily. dentists should be encouraged to participate in stress management courses to help alleviate stress. keywords: psychological stress; dentists; coping behavior; iran. امللخ�ص: اأهداف: اإن اإدراك اأ�صباب التوتر قد ي�صاعد على منع االآثار ال�صلبية املرتبطة به، وقد هدفت الدرا�صة اإىل التحقيق يف اأ�صباب االإجهاد عام دي�صمرب اإىل اإبريل من الفرتة خالل امل�صحية الدرا�صة هذه اأجريت اإيران، منهجية: يف االأ�صنان اأطباء بني التاأقلم و�صلوكيات املهني 2014م، وقد ا�صتخدمت ن�صخةمعدلة من ا�صتبيان موؤ�رضاالإجهاد املهني لتقييم اأ�صباب التوتر و�صلوكيات التاأقلم بني 142 من اأطباء االأ�صنان العموميني يف كرمان، اإيران. نتائج: لقد �صارك ما جمموعه 93 من اأطباء االأ�صنان يف الدرا�صة )معدل اال�صتجابة: %65.5(، اأكد %58.9 من هوؤالء تعر�صهم لالأجهاد املهني يف كثري من االأحيان، وبلغ متو�صط عالمات موؤ�رض االإجهاد 19.99 ± 63.33، كانت االأ�صباب االأكرث �صيوعًا لالإجهاد هي احلفاظ على م�صتويات عالية من الرتكيز اأثناء العمل )%65.6(، و�صغوط الوقت )%64.5(، والقلق اإزاء القدرة على تقدمي خدمات طب االأ�صنان يف امل�صتقبل )%60.2( اأو ارتفاع تكاليف العالج )%59.1(، ومل يالحظ وجود اأي عالقة ذات داللة اإح�صائية بني حدوث االإجهاد وكل من اجلن�ض والعمر ومكان العمل اأو عدد �صاعات العمل االأ�صبوعية )p <0.05(. ومع ذلك، كان هناك ارتباط كبري بني عالمات االإجهاد مع للتعامل �صيوعا االأكرث االأ�صاليب وكانت .)p = 0.03( يوميا املعاجلني املر�صى وعدد )p = 0.05( العمل يف اخلربة و�صنوات العامة االإجهاد هي الراحة )%71.0(، والريا�صة )%45.2(، والرتفيه )%43.0(. وراأى معظم اأطباء االأ�صنان امل�صاركني اأن دورات اإدارة االإجهاد ميكن اأن ت�صاعد على احلد من التوتر )%89.7(. خامتة: تعر�ض اأطباء االأ�صنان العموميني يف كرمان مل�صادر كثرية من االإجهاد يف اأماكن عملهم، هناك عالقة ذات داللة اإح�صائية بني عالمات االإجهاد و�صنوات اخلربة يف العمل وعدد املر�صى املعاجلني يوميًا، وينبغي ت�صجيع اأطباء االأ�صنان على امل�صاركة يف دورات اإدارة االإجهاد للم�صاعدة يف تخفيف التوتر بينهم. كلمات مفتاحية: االإجهاد النف�صي؛ اأطباء االأ�صنان؛ �صلوكيات التاأقلم؛ اإيران. occupational stress and coping behaviours among dentists in kerman, iran shiva pouradeli,1 arash shahravan,2 ali eskandarizdeh,3 *forozan rafie,1 maryam a. hashemipour1 clinical & basic research sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e341–346, epub. 19 aug 16 submitted 12 feb 16 revisions req. 22 mar & 27 apr 16; revisions recd. 5 apr & 18 may 16 accepted 9 jun 16 doi: 10.18295/squmj.2016.16.03.013 advances in knowledge previous research has shown that dentists lack awareness of stress management strategies. this is the first study from iran to evaluate sources of job-related stress and coping strategies among general dentists. application to patient care modern dentistry involves a number of occupational hazards, including high levels of stress. prolonged stress can have harmful effects, including damage to interpersonal and professional relationships; diminished health and wellbeing ; burnout and depression; lowered motivation to engage in work; and low self-esteem. successful stress reduction requires that the causes of stress be identified. the results of this study could help researchers in the fields of occupational health, dentistry and psychiatry to develop future interventions to minimise workplace stress among general dentists in iran. occupational stress and coping behaviours among dentists in kerman, iran e342 | squ medical journal, august 2016, volume 16, issue 3 long-term exposure to stress cancause physical and psychological problems such as anxiety, depression, cardiovascular diseases, digestive problems, insomnia and headaches.1–3 individuals face occupational stress when there are inconsistencies between the professional requirements of their job and their own strengths, abilities or desires.4 stress can have professional consequences which include absenteeism, reduced productivity and job dissatisfaction, leading in some cases to redundancy or early retirement.5 modern dentistry involves numerous occupational health hazards, including stress, allergic reactions, high noise levels, radiation and musculoskeletal disorders.6,7 dentists face considerable stress at work from dental school onwards.8 the development of new and complex technologies, methods and treatment techniques can be an additional source of pressure. several studies have reported high levels of stress among dentists and many researchers have classified dentistry as a stressful job.5,8,9 in a study conducted in the uk by myers et al., 60% of dentists reported being nervy, tense or depressed due to work stress.10 cooper et al. indicated that causes of stress among dentists included too little work, administrative difficulties, attempts to establish a practice and dealing with different patients.8 in a similar study, humphris et al. found that sources of occupational stress included treating a high volume of patients, dealing with nervous patients and collecting payment.11 prolonged experiences of stress among dentists can have detrimental effects on interpersonal and professional relationships, as well as on mental and physical health.8 for mental health, the consequences can include burnout, depressive disorders, decreased motivation and self-esteem; in contrast, the most commonly reported stress-related physical health issues are lower back pain, increased musculoskeletal complaints, headaches and gastrointestinal problems.12,13 dentists at a higher risk for stress exhibit poorer health and a higher rate of unhealthy behaviours than their less stressed colleagues.9 research has shown that dentists with high stress levels have low awareness of strategies to manage stress.14 before preparing policies for the prevention and management of stress among dental practitioners, it is necessary to identify job-related stressors and available coping strategies.15 recognising sources of stress is important for future prevention and intervention initiatives. although various surveys have been undertaken to assess stress among general dentists in other regions, no such studies have yet been conducted in iran. this study therefore aimed to investigate sources of occupational stress and coping strategies among general dentists in kerman, iran. methods this cross-sectional study took place between april and december 2014 among general dentists working in kerman, iran. in order for the sample size to be large enough for the results to be statistically significant, all 142 general dentists working in kerman were invited to participate in the study. general dentists with less than one year of work experience were excluded. a modified version of the occupational stress indicator questionnaire was used.8 the first section of the questionnaire collected demographic information, while the second section consisted of 33 items to assess causes of stress and coping behaviours. participants rated stressors in terms of their frequency, using the following terms: ‘never’, ‘seldom’, ‘sometimes’, ‘often’, ‘very often’ and ‘always’. general stress scores were calculated by summing the items. the original english questionnaire was translated into persian and the internal consistency of the modified and revised questionnaire was assessed using cronbach’s alpha (α = 88%). similar questionnaires have been used in different studies all over the world.9,11,16,17 the questionnaire was distributed to the participants for self assessment before being collected three days later. data were analysed using the statistical package for the social sciences (spss), version 18 (ibm corp., chicago, illinois, usa). descriptive statistics were expressed as means, standard deviations and frequencies. a student’s t-test was used to compare the effects of variables. the level of significance was defined at p <0.05. this study was approved by the research ethics committee of the kerman university of medical sciences. the aims of the study were explained to all subjects and informed consent was obtained before participation. results of the 142 general dentists invited to participate in the study, 93 responded (response rate: 65.5%). of these, 58.9% reported often being stressed. the demographic characteristics of the participants and relationships with general stress scores are presented in table 1. the mean general stress score was 63.33 ± 19.99. there was no significant relationship between general stress scores and age, gender, workplace or working hours per week. however, general stress scores showed a significant correlation with years of experience (p = 0.05) and number of patients treated per day (p = 0.03). a post hoc analysis showed that general dentists with less than 10 years of experience exhibited higher stress scores than general dentists who had shiva pouradeli, arash shahravan, ali eskandarizdeh, forozan rafie and maryam a. hashemipour clinical and basic research | e343 more than 20 years of experience; the mean difference was statistically significant (p = 0.05). in addition, general dentists who treated fewer than 12 patients per day had lower stress scores compared with general dentists who treated more than 12 patients per day (p = 0.03). dentists working in the public sector were more stressed by a lack of patient appreciation while those working in the private sector identified undesirable auxiliary help as a source of stress. the most common sources of stress were maintaining high levels of concentration during working hours (65.6%), time pressures (64.5%), concern over their ability to provide dental services in future (60.2%) and rising costs (59.1%). common stressors identified as occurring very often or always are presented in table 2. the most common coping strategies used were resting (71.0%) and playing sports (45.2%). the least common strategies were smoking (4.3%) and consumption of alcohol (1.1%) [figure 1]. a total of 89.7% of participants felt that completing stress management table 1: demographic characteristics and general stress scores* among general dentists in kerman, iran (n = 93) variable n (%) mean stress score ± sd p value gender 0.77 female 39 (41.9) 64.03 ± 21.5 male 54 (58.1) 62.83 ± 18.9 age in years 0.90 <38 49 (52.7) 65.31 ± 18.9 38–52 39 (41.9) 63.21 ± 20.8 >52 5 (5.4) 45.00 ± 17.6 place of employment 0.76 private clinic 59 (63.4) 62.7 ± 20.5 government clinic 13 (14.0) 67.1 ± 20.0 both 21 (22.6) 62.5 ± 18.9 years of experience 0.05† <10 50 (53.8) 65.98 ± 18.9 10–20 34 (36.6) 63.35 ± 21.3 > 20 9 (9.7) 48.56 ± 15.1 number of patients treated per day 0.03† <12 72 (77.4) 61.49 ± 19.5 >12 21 (22.6) 74.38 ± 18.4 working hours per week 0.87 <20 26 (28.0) 62.62 ± 19.8 20–40 59 (63.4) 61.68 ± 20.0 >40 8 (8.6) 57.83 ± 24.7 sd = standard deviation. *assessed using a modified version of the occupational stress indicator questionnaire.8 †significant at p <0.05. table 2: common stressors* among general dentists in kerman, iran (n = 93) stressor n (%) maintaining high levels of concentration during working hours 61 (65.6) time pressures 60 (64.5) concern over their ability to provide dental services in future 56 (60.2) rising costs 55 (59.1) earning enough money to meet lifestyle needs 49 (52.7) quoting fees/collecting payments 45 (48.4) supply of dentists 44 (47.3) unsatisfactory laboratory service from technicians 43 (46.2) coping with difficult patients 40 (43.0) repetitive nature of work 39 (41.9) conflict between profit and professional ethics 35 (37.6) cancellations/no-shows 33 (35.5) equipment breakdown/defective materials 33 (35.5) decisions about future career direction 31 (33.3) possible contraction of viral infections 31 (33.3) long working hours 31 (33.3) working with children 30 (32.3) finding time for family and friends 29 (31.2) causing pain 29 (31.2 ) treating extremely nervous patients 25 (26.9) lack of patient appreciation 24 (25.8) unsatisfactory auxiliary help 24 (25.8) staff-related problems 23 (24.7) inability to meet own expectations/standards 22 (23.7) seeing more patients for income-related reasons 21 (22.6) feeling isolated 20 (21.5) making mistakes 18 (19.4) medical emergencies during surgery 16 (17.2) possibility of making mistakes 15 (16.1) perceived problems with colleagues 14 (15.1) feeling underrated by patients 13 (14.0) *stressors identified as occurring ‘very often’ or ‘always’. occupational stress and coping behaviours among dentists in kerman, iran e344 | squ medical journal, august 2016, volume 16, issue 3 courses during their graduate studies would have helped them to manage and reduce their stress. discussion stress has widely documented physical and psychological consequences, such as anxiety, burn-out and the development of cardiovascular diseases.5,10,18,19 previous studies have shown that dentistry can be a stressful occupation;20,21 research on the sources of this stress may be able to assist early prevention and intervention initiatives. this study aimed to study sources of stress and strategies for managing stress among general dentists in kerman. in the current study, 58.9% of the dentists surveyed suffered from stress. similar results have been reported in studies of general dentists in the uk (68.4%), dentists in denmark (59.7%) and orthodontists in morocco (44%).10,17,20 the most common stressors among general dentists in the current study were maintaining concentration, constant time pressures, concern over their ability to provide dental services in future and rising costs. ayers et al. reported consistent findings, in which the second and third most common sources of stress among general dentists in new zealand were time-related pressure (48%) and the need to maintain high levels of concentration at work (43%); however, the most common source of stress was treating uncooperative children (52%).22 similarly, the most common sources of stress among general dentists in the uk involved treating difficult or uncooperative patients (64.8%), continuous time pressures (64.4%) and constraints imposed by the national health service (46.2%).5 kay et al. also reported that the most common stressors at work among uk dental practitioners consisted of demands made by patients (75%), problems associated with practice management and staff (56%) and fears relating to complaints and litigation (54%).12 in a study of dentists in islamabad, pakistan, finding enough time for family and friends was reported as the most common source of stress.13 cooper et al. indicated that time management problems were a common source of stress among dentists.8 in the current study, constant time pressures were also identified as a major source of stress; these pressures may lead to difficulties with time management and staying on schedule. this findings is consistent with previous research.1,5,11,14 time constraints may be a cause of stress for dentists due to the pressure to schedule as many appointments as possible or perhaps because it impinges on time with family or on other non-work-related interests. however, in contrast to the population surveyed in the present study, dentists in other studies have shown less concern about their ability to work and provide dental services in future.11,22 no significant differences were observed between males and females in the current study with regards to occupational stress. this finding mirrored a study in yemen which reported no statistical differences in stress among men and women.3 however, rogers et al. reported that female irish dentists were more stressed than males.23 in the present study, there was no statistically significant difference in stress scores between younger and older dentists. however, dentists with fewer than 10 years of experience exhibited higher stress scores than dentists with over 20 years of experience. previous studies have similarly indicated that experience is a factor in controlling and managing stress.8,23 this could be attributed to reduced practical and clinical experience, a heightened fear of making mistakes and a lack of familiarity with patients.23,24 additionally, dentists in the present study who treated fewer than 12 patients per day had lower stress scores compared to those who treated more than 12 patients per day. this could be because of the additional patient load resulting in longer working hours, the increased need for concentration, time pressures, tiredness and the repetitive nature of the work. this finding is consistent with those of ayers et al., in which time pressures had a significant impact on dentist stress levels.22 in the current study, dentists working in the public sector were more stressed by a lack of patient appreciation, while those working in the private sector identified undesirable auxiliary help as a source of stress. however, there was no significant relationship between stress scores and type of workplace, which may be due to the low ratio of public sector to private sector practitioners surveyed. in addition, general stress scores were not associated with hours worked per week. these results contrast with those reported by ayers et al.22 figure 1: strategies for coping with stress among general dentists in kerman, iran (n = 93). shiva pouradeli, arash shahravan, ali eskandarizdeh, forozan rafie and maryam a. hashemipour clinical and basic research | e345 the most common techniques for managing stress identified in the current study were resting and engaging in sport activities, while the least commonly used were smoking and alcohol consumption. these findings are consistent with those reported by dentists in new zealand, who use social interactions (77.3%), forgetting about work (58.6%) and engaging in sports (63.4%) to manage stress.22 tobacco use as a coping mechanism is similarly low in the uk, with only 8.6% of dentists reporting that they smoke to manage stress.8 similarly, smoking and drug use were not frequently reported as strategies used by dutch dentists to manage stress.9 a major cause of stress among dentists is a lack of knowledge about managing stress.14,24 in the present study, most dentists felt that participation in a stress management course during their studies would have helped them to learn to manage their stress levels. stress management and coping behaviours should therefore be included in the dental curriculum in order to avoid physical and psychological problems that may occur later as a result of occupational stress. moreover, workshops, seminars and education programmes on occupational stress for clinical dental staff should be organised periodically. to the best of the authors’ knowledge, the present study is the first to evaluate stress among dentists in iran. however, the study is limited by its crosssectional nature. in addition, the study focused on the experiences of general dentists and, as a result, it was not possible to generalise conclusions to other branches of dentistry.25 additionally, the response rate of this study was not ideal. in future studies, a larger sample size is recommended as well as the inclusion of general dentists, specialists and other physicians. psychological and personal characteristics may also have an impact on stress management.26 these were not analysed in this study and should be considered in future research. conclusion this study showed that many general dentists in kerman face several sources of stress, including time pressures, maintaining high levels of concentration during work hours and rising costs. therefore, it is recommended that workshops, seminars and education programmes on occupational stress be organised for clinical dental staff periodically. this may help general dentists to manage stress levels and improve their working conditions. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors would like to thank all of the general dentists who participated in this study. references 1. agrawal n, gupta nd, bey a, garg ak, sharma v. occupational hazards in modern dentistry: a review. int j med health res 2014; 1:1–9. 2. aloha k, havanen j. job strain, burnout, and depressive symptoms: a prospective study among dentists. j affect disord 2007; 104:103–10. doi: 10.1016/j.jad.2007.03.004. 3. al-zubair nm, al-ak’hali ms, ghandour ia. stress among dentists in yemen. saudi j dent res 2015; 6:140–5. doi: 10.10 16/j.sjdr.2014.09.003. 4. seward jp. occupational stress. in: ladou j. current occupational & environmental medicine, 3rd ed. new york, usa: mcgraw-hill medical, 2003. pp. 603–18. 5. cooper cl. dentists under pressure: a social psychological study. in: cooper cl, marshall j. white collar and professional stress. chichester, uk: john wiley & sons, 1980. pp. 3–17. 6. dalband m, nasab af. evaluation of stress-inducing factors of educational environment in hamadan dentistry school’s students. sci j hamadan univ med sci 2007; 13:48–52. 7. denton da, newton jt, bower ej. occupational burnout and work engagement: a national survey of dentists in the united kingdom. br dent j 2008; 11;205:e13. doi: 10.1038/ sj.bdj.2008.890. 8. cooper cl, watts j, kelly m. job satisfaction, mental health, and job stressors among general dental practitioners in the uk. br dent j 1987; 162:77–81. doi: 10.1038/sj.bdj.4806030. 9. gorter rc, eijkman ma, hoogstraten j. burnout and health among dutch dentists. eur j oral sci 2000; 108:261–7. doi: 10.1034/j.1600-0722.2000.108004261.x. 10. myers hl, myers lb. ‘it’s difficult being a dentist’: stress and health in the general dental practitioner. br dent j 2004; 197:89–93. doi: 10.1038/sj.bdj.4811476. 11. humphris gm, cooper cl. new stressors for gdps in the past ten years: a qualitative study. br dent j 1998; 185:404–6. doi: 10.1038/sj.bdj.4809826. 12. kay ej, lowe jc. a survey of stress levels, self-perceived health and health-related behaviours of uk dental practitioners in 2005. br dent j 2008; 204:e19. doi: 10.1038/sj.bdj.2008.490. 13. khan a, alvi h, qadeer s, khan a, khan ki, khan ns. the prevalence of stress and associated factors in dentists working at islamic international dental college hospital, islamabad. pak oral dent j 2010; 30;521–5. 14. bourassa m, baylard jf. stress situations in dental practice. j can dent assoc 1994; 60:65–7. 15. lehto tu, helenius hy, alaranta ht. musculoskeletal symptoms of dentists assessed by a multidisciplinary approach. community dent oral epidemiol 1991; 19:38–44. doi: 10.1111/ j.1600-0528.1991.tb00103.x. 16. möller at, spangenberg jj. stress and coping amongst south african dentists in private practice. j dent assoc s afr 1996; 51:347–57. 17. moore r, brødsgaard i. dentists’ perceived stress and its relation to perceptions about anxious patients. community dent oral epidemiol 2001; 29:73–80. doi: 10.1034/j.16000528.2001.00011.x. http://dx.doi.org/10.1016/j.jad.2007.03.004 http://dx.doi.org/10.1016/j.sjdr.2014.09.003 http://dx.doi.org/10.1016/j.sjdr.2014.09.003 http://dx.doi.org/10.1038/sj.bdj.2008.890 http://dx.doi.org/10.1038/sj.bdj.2008.890 http://dx.doi.org/10.1038/sj.bdj.4806030 http://dx.doi.org/10.1034/j.1600-0722.2000.108004261.x http://dx.doi.org/10.1038/sj.bdj.4811476 http://dx.doi.org/10.1038/sj.bdj.4809826 http://dx.doi.org/10.1038/sj.bdj.2008.490 http://dx.doi.org/10.1111/j.1600-0528.1991.tb00103.x http://dx.doi.org/10.1111/j.1600-0528.1991.tb00103.x http://dx.doi.org/10.1034/j.1600-0528.2001.00011.x http://dx.doi.org/10.1034/j.1600-0528.2001.00011.x occupational stress and coping behaviours among dentists in kerman, iran e346 | squ medical journal, august 2016, volume 16, issue 3 18. newbury-birch d, lowry rj, kamali f. the changing patterns of drinking, illicit drug use, stress, anxiety and depression in dental students in a uk dental school: a longitudinal study. br dent j 2002; 192:646–9. doi: 10.1038/sj.bdj.4801448. 19. newton jt, mistry k, patel a, patel p, perkins m, saeed k, et al. stress in dental specialists: a comparison of six clinical dental specialties. prim dent care 2002; 9:100–4. doi: 10.13 08/135576102322492954. 20. ousehal l, lazrak l, hassani k. evaluation of stress among 100 moroccan orthodontists. open j stomatol 2011; 1:1–6. doi: 10.4236/ojst.2011.11001. 21. rada re, johnson-leong c. stress, burnout, anxiety and depression among dentists. j am dent assoc 2004; 135:788–94. doi: 10.14219/jada.archive.2004.0279. 22. ayers km, thomson wm, newton jt, rich am. job stressors of new zealand dentists and their coping strategies. occup med (lond) 2008; 58:275–81. doi: 10.1093/occmed/kqn014. 23. rogers c, malone km. stress in irish dentists: developing effective coping strategies. j ir dent assoc 2009; 55:304–7. 24. brake ht, gorter r, hoogstraten j, eijkman m. burnout intervention among dutch dentists: long-term effects. eur j oral sci 2001; 109:380–7. doi: 10.1034/j.1600-0722.2001. 00086.x. 25. wilson rf, coward py, capewell j, laidler tl, rigby ac, shaw tj. perceived sources of occupational stress in general dental practitioners. br dent j 1998; 184:499–502. doi: 10.1038/ sj.bdj.4809674. 26. gomathi kg, ahmed s, sreedharan j. causes of stress and coping strategies adopted by undergraduate health professions students in a university in the united arab emirates. sultan qaboos univ med j 2013; 13:437–41. http://dx.doi.org/10.1038/sj.bdj.4801448 http://dx.doi.org/10.1308/135576102322492954 http://dx.doi.org/10.1308/135576102322492954 http://dx.doi.org/10.4236/ojst.2011.11001 http://dx.doi.org/10.14219/jada.archive.2004.0279 http://dx.doi.org/10.1093/occmed/kqn014 http://dx.doi.org/10.1034/j.1600-0722.2001.00086.x http://dx.doi.org/10.1034/j.1600-0722.2001.00086.x http://dx.doi.org/10.1038/sj.bdj.4809674 http://dx.doi.org/10.1038/sj.bdj.4809674 sultan qaboos university med j, may 2014, vol. 14, iss. 2, pp. e166-169, epub. 7th apr 14 submitted 26th feb 14 revision req. 9th mar 14, revision recd. 10th mar 14 accepted 10th mar 13 the female breast has always been a symbol of beauty, fertility and femininity. in disease, however, it has challenged physicians since antiquity. surgery, which ruled the roost for cancer therapy, inevitably caused disfigurement when the knife was applied to the breast. the history of breast cancer is a complex maze of attempts to understand the wily nature of this hormone-responsive cancer and the will of physicians to conquer it by physical removal (surgery), cell destruction (chemo-radiotherapy) or targeted therapy to cell receptors (biomodulation). it is also a saga of intense exploration to find the tools to enable early diagnosis. the story of the domination of surgery over two millennia and its evolution from fatalistic choices to minimal damage is told in the succeeding paragraphs. the pathobiological basis of breast cancer that changed chirurgical practice from crudity to finesse is woven through the narrative. beliefs and practices through antiquity it is not surprising that written records and illustrations of breast cancer date back to antiquity since the location of the organ permitted easy identification. the edwin smith surgical papyrus, dating back to 3,000–2,500 b.c., and possibly attributable to imhotep (the egyptian physician-architect), provides authentic accounts of breast cancer. a case was deemed incurable if the disease was “cool to touch, bulging and spread all over the breast”.1 in ancient greece, a divinity was exhorted to offer relief from breast maladies, as evidenced by votive offerings in the shape of breasts in greek temples that housed asclepius, the god of medicine.2 carcinoma (karkinoma), scirrhous (hard, greek skirros) and cacoethes (malignant disease, greek kakoethes) in the medical lexicon owe their origins to hellenistic writings. hippocrates’ theory in c. 400 b.c. of the imbalance of humours (blood, phlegm, and yellow and black bile) as a cause of disease, and his classic descriptions of the progressive stages of breast cancer, represent early hypotheses on the cause of cancer.3 leonides of alexandria, in 1st century a.d., preserving the greek traditions, boldly and skillfully detailed his approach of incision and cautery.4 his stipulation of leaving a wide margin of excision and only removing tumours of limited extent, foreshadows the oncological principles of contemporary surgical practice.5 galen, attributing breast cancer in a.d. 200 to the accumulation of black bile in the blood, concluded that it was a systemic disease.6 these ancient physicians postulated that the cessation of menstruation was somehow linked to cancer; in fact it probably had to do with the association of cancer with old age. in line with this theory, galen allowed surgical wounds to bleed freely to get rid of the black bile and frowned on the use of ligatures. the word ‘crab’ for cancer was coined by him to illustrate the dilated veins radiating from the tumour.5 surgical stagnation in the middle ages between 476 and 1,500 a.d. medical progress was inextricably intertwined with the emerging religious philosophies. early christian beliefs favoured faith healing and miracles over surgery, which was perceived as barbaric. islamic emergence revived greek medicine and, through meticulous translations, saved medical knowledge for posterity. avicenna (ibn sina, persia) and albucasis (abu al-qasim al-zahrawi, spain) in the 10th century and maimonides (spain) in the 12th century were arab physicians of renown, forming a department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: ritu@squ.edu.om تاريخ موجز لسرطان الثدي اجلزء األول: إعادة اخرتاع هيمنة اجلراحة ريتو لكتاكيا medical history a brief history of breast cancer part i: surgical domination reinvented ritu lakhtakia ritu lakhtakia medical history | e167 trio of exemplars who spread medical excellence to the boundaries of the expanding islamic conquests;2 albucasis was a strong advocate of the use of cautery in surgery.7 the use of caustic pastes to annihilate the tumour and render it operable, is reminiscent of the same logic for using chemotherapy for large breast cancers today. unique instruments to aid in the rapid removal of breast tumours were introduced into the surgical armamentarium by albucasis, henri de mondeville (‘father’ of french surgery, 13th century) and guy de chauliac (france, 14th century). renaissance: a celebration of arts and the emergence of surgery the 16th to 18th centuries not only bred artistic creativity but proved to be the golden age for the emergence of surgery. the craft of surgery was unshackled from its previous conjoint status with the barber’s trade and grew on the shoulders of a strong anatomical exploration of the human body by andreas vesalius in 16th century belgium. in 18th century england and france, respectively, cooper’s eponymous ligaments of the breast and sappey’s subareolar plexus of lymphatics ushered in an era that revisited the origins and spread of breast cancer.8,9 in the same era, john hunter (the scottish ‘father’ of investigative surgery) replaced ‘black bile’ with lymph as the cause of breast cancer. a multitude of theories ranging from inspissated milk, trauma, personality type, exposure to air and infection were fed into the cauldron of carcinogenesis. the observation of the disease within families was naturally attributed to infection. amidst this chaotic search for the truth, accounts of heroic surgeries from simple lumpectomies to radical removal of the pectoralis, enliven medical records.4 these are rendered more vivid and admirable when it is recalled that in the absence of anaesthesia, skill and speed were the sole attributes of a successful surgeon. it is also a grim reminder that surgery was the solitary modality for hope of relief with anecdotal incidences of cure. more conservative compatriots used ligatures or lead plates to strangulate the tumours, preferring them to the horrors of breast amputation. nineteenth century: the golden age of surgery the surgical discipline rapidly grew on the bedrock of a spate of discoveries that rendered it safer with a good outcome for the patient. disinfection and sterilisation and the use of sterile gloves were the first landmark events. general anaesthesia revolutionised the surgeon’s ease (and indeed the patient’s too!). although in 1818 james blundell attempted blood transfusion in postpartum haemorrhage, safe transfusions would be achieved only at the dawn of the 20th century with the discovery of blood groups by karl landsteiner. against this background, seminal contributions to cancer came from the microscopic identification of normal cells and their cancerous brethren all the way from hooke in 17th century england to müller and virchow in 19th century germany. müller dismissed the humoral theory of the origin of cancer, declaring that cancers were composed of living cells and suggesting that metastasis was due to spread of these cells.6 the demonstration that breast cancer spread along the lymphatics to the guardian axillary nodes was to form the basis of a variety of excision techniques. unique forms of spread leading to the clinical manifestations of carcinoma en cuirasse or peau d’orange and paget’s disease would demand alternative ways of approaching treatment. the middle years of the 19th century celebrated the newly acquired surgical freedom with bold and radical surgeries. the en bloc resections of charles moore in london,10 and kuster and volkmann in germany ran a parallel course.11 axillary lymph node dissections as part of the philosophy of extermination were performed in 1882 by william banks in liverpool, uk.12 while they may appear particularly mutilating today, they provided a unique opportunity to study the disease spread. breast cancer surgery at the turn of the century came to be synonymous with the name of william s. halstead, professor of surgery at johns hopkins hospital in baltimore, usa. his radical mastectomy (first reported in 1894) with its emphasis on removing tissues in one piece to prevent spread and removal of the pectoralis major to prevent recurrence, became the undisputed path that generations of surgeons trod with diligence.13 “the suspected tissue should be removed in one piece, (1) lest the wound become infected by the division of tissues invaded by the disease or of lymphatic vessels containing cancer cells, and (2) because shreds or pieces of cancerous tissue might readily be overlooked in the piecemeal extirpation.”14 these strict rules for non-violation of the tumour area precluded a preoperative biopsy to confirm whether the patient had a cancer at all: such was the strength of a skilled clinical diagnosis! another ageold practice that came to a close was to leave the excised surgical wound open to granulate. the use of ligatures now allowed better wound healing through low infection rates. a brief history of breast cancer part i: surgical domination reinvented e168 | squ medical journal, may 2014, volume 14, issue 2 manifestation of axillary lymph node dissections, to the annals of surgical history. once surgeons lead the revolution towards minimising extirpation, the first faltering steps towards restoring cosmesis were taken by verneuil, a french surgeon who transferred autologous tissue from the normal breast to the diseased one in 1887.23this released the floodgates for a variety of innovative autologous and synthetic materials offering a restored shape that could even outdo nature’s original creation. muscle, myocutaneous flaps, lipomas and omentum were natural choices. the transverse rectus abdominis myocutaneous flap (tram) introduced in 1979 by holmstrom has stood the test of time, undergoing several modifications in its evolution.24 prosthetic and synthetic options brought industry and commerce into the fray: petroleum jelly, glass balls, ivory, rubber, polyvinyl alcohol sponge and silicone— the list is ever growing! surgical domination over the treatment of breast cancer held sway for the millennia, ever since the first recorded medical literature. the hope for a cure by the radical removal of a diseased organ was always counterbalanced by fascinating and fearsome accounts of surgery sans anaesthesia as a physically and psychologically mutilating therapeutic option. while nowhere near its nadir, surgery remains at the heart of management in a multimodality setting. instead of annihilation it now provides succour to the breast cancer survivor thus balancing cure and cosmesis. lessons from the history of surgery in breast cancer there are three lessons to be gained from the history of surgery in breast cancer. first, to delve into history is to rediscover buried insights: galen’s perceptive assessment that breast cancer is a systemic disease was echoed two millennia later in fisher’s 20th century observations. second, the evolution of therapeutic weaponry raises the fortunes of medical disciplines (as antisepsis and anaesthesia did for surgery) or minimises their supremacy as stand-alone choices for panacea or cure (as chemoradiotherapy did for surgery). third, stooping to conquer is the mark of survival in contemporary medical practice. surgery has won the day by adapting and playing a complementary role in modern cancer management as a stylised, scientific and patient-friendly craft. twentieth century: surgery reinvents itself the hormone dependency of breast cancer was initially hypothetical, through the observation that the disease was aggressive in younger women. beatson ignited the era of endocrine surgery in 190615—long before the discovery of estrogen receptors by jensen in 196716 and oopherectomy and adrenalectomy (to achieve castration) came in vogue. these rather drastic methods were gradually overtaken by estrogen receptor modulators, luteinising hormone-releasing agonists and aromatase inhibitors. halstead’s legacy was, for a while, preserved by margottini and veronesi in milan who additionally removed internal mammary nodes and others who extended the scope of ‘radicality’ to supraclavicular and mediastinal nodes. however, the late 19th and early 20th centuries gradually heralded the demise of the adage: big surgeons make big incisions (and hence perform big surgeries). patey and handley from london and auchincloss jr. of new york ushered in a movement that ‘modified’ the radical mastectomy and preserved the pectoralis major.17 rapid advances in medical radiation as a means of killing cancer cells and new forms of chemotherapy that did the same, but also achieved medical castration or targeted mutated tumour receptors, forced a rethink of cancer management strategies. these were coupled with the burgeoning knowledge of the biological behaviour of breast cancer and the less-than-guaranteed success of surgery alone. early cancer detection of smaller lesions by mammography added a new dimension to surgical management. the clarion call to reorient to limited surgery came from the surgery fraternity. bernard fisher, professor of surgery at the university of pittsburgh, revived galen’s ancient belief that breast cancer was a systemic disease. large randomised controlled clinical trials like the national surgical adjuvant breast and bowel project (nsabp), published in 1989, provided scientific support.18 it is ironic that the disbandment of the radical halstedian approach, the institution of trials and the acceptance of neoadjuvant therapy were the brainchildren of a surgeon! veronesi from italy and many others supported the notion of limited surgery complemented by adjuvants.19 surgery reinvented itself to join hands with the other modalities. since the close of the 20th century breast conservation and breast reconstruction—combined, where necessary, with sentinel node dissection—have held sway.20–22 the removal of only selected ‘sentinel’ nodes (those to which the tumour had spread) would relegate the swollen lymphoedematous arm, a distressing ritu lakhtakia medical history | e169 references 1. breasted jh, ed. the edwin smith surgical papyrus. chicago, illinois: the university chicago press, 1930; special edition, 1984. 2. lyons as, petrucelli rj. medicine an illustrated history. new york: harry n. abrams publishers, 1978. pp. 294–317. 3. homer. iliad. [translated by whd rouse]. new york: a signet classic. new american library, 1966. p. 36. 4. ariel im. breast cancer, a historic review: is the past prologue? in: ariel im, cleary jb, eds. breast cancer diagnosis and treatment. new york: mcgraw-hill, 1987. pp. 3–26. 5. lewison ef. the surgical treatment of breast cancer; an historical and collective review. surgery 1953; 34:904–53. 6. de moulin d. a short history of breast cancer. boston: martinus nijhoff; 1983. pp. 1–107. 7. cooper wa. the history of radical mastectomy. ann med hist 1941; 36–54. 8. cooper ap. the anatomy and diseases of the breast. philadelphia: lea and blanchard, 1845. 9. sappey mpc. anatomie, physiologie, pathologie des vaisseaux lymphatiques considérés chez l’homme et les vertébrés. paris: a delahaye and e lecrosnier, 1874. 10. moore c. on the influence of inadequate operations on the theory of cancer. royal medical and chirurgical society. london. med chir trans 1867; 32:245–80. 11. ekmektzoglou ka, xanthos t, german v, zografos gc. breast cancer: from the earliest times through to the end of the 20th century. eur j obstet gynecol reprod biol 2009; 145:3–8. doi: 10.1016/j.ejogrb.2009.03.017. 12. banks wm. free removal of mammary cancer with extirpation of the axillary glands as a necessary accompaniment. paper read before the british medical association at worcester, 1882. 13. halsted ws. the results of operations for the cure of cancer of the breast performed at the johns hopkins hospital from june 1889 to january 1894. johns hopkins hospital reports, baltimore, 1894–95; 4:297–350. 14. sakorafas gh, safioleas m. breast cancer surgery: an historical narrative. part ii. 18th and 19th centuries. eur j cancer care 2010; 19:6–29. doi: 10.1111/j.1365-2354.2008.01060.x. 15. horsley js iii, horsley gw. twenty years’ experience with prophylactic bilateral oophorectomy in the treatment of carcinoma of the breast. ann surg 1962; 155:935–9. 16. jensen ev, desomber er, jungblut pw. estrogen receptors in hormone responsive tissues and tumors. in: wissler rw, dao tl, wood s jr., eds. international symposium on endogenous factors influencing host-tumor balance. chicago and london: university of chicago press, 1967. 17. special report: treatment of primary breast cancer. n engl j med 1979; 301:340. 18. fisher b, redmond c, poisson r, margolese r, wolmark n, wickerham l, et al. eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. n engl j med 1989; 320:822–8. doi: 10.1056/nejm198903303201302. 19. veronesi u, volterrani f, luini a, saccozzi r, del vecchio m, zucali r, et al. quadrantectomy versus lumpectomy for small size breast cancer. eur j cancer 1990; 26:671–3. 20. sakorafas gh, safioleas m. breast cancer surgery: an historical narrative. part iii. from the sunset of the 19th to the dawn of the 21st century. eur j cancer care 2010; 19:145–66. doi: 10.1111/j.1365-2354.2008.01061.x. 21. guilliano ae, jones rc, brennan m, statman r. sentinel lymphadenectomy in breast cancer. j clin oncol 1997; 15:2345–50. 22. krag dn, weaver dl, alex jc, fairbank jt. surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. surg oncol 1993; 2:335–40. 23. rozen wm, rajkomar aks, anavekar ns, ashton mw. postmastectomy breast reconstruction: a history in evolution. clinical breast cancer 2009; 9:145–54. doi: 10.3816/ cbc.2009.n.024. 24. holmstrom h. the free abdominoplasty flap and its use in breast reconstruction. scand j plast reconstr surg 1979; 13:423–7. sultan qaboos university med j, august 2012, vol. 12, iss. 3, pp. 352-356, epub. 15th jul 12 submitted: 6th dec 11 revision: req. 30th jan 12, revision recd. 7th feb 12 accepted: 17th mar 12 department of surgery, sultan qaboos university hospital, muscat, oman. *corresponding author e-mail: rajeevkariyattil@gmail.com انفتاق الدماغ الَرْضِحي احلاد من خالل األذن يف طفل كسر مركب خمفي راجيف كارياتل، اأونيكري�سنان موثوكوتيبارامبل امللخ�ص: فتاة يف ال�سابعة من عمرها تعر�ست حلادث �سيارة، اأ�سيبت على اأثره بان�سباب ال�سائل النخاعي من الأذن اليمنى، وبعد اأ�سبوع ال�سمعية بالقناة املو�سل ال�سقيف يف ك�رس وجود للدماغ املحو�سب املقطعي الت�سوير م�سح اأظهر اليمنى. الأذن خالل من الدماغ انبثق اخلارجية. مل يكن هناك اأي �سعف يف ال�سمع اأو الع�سب الوجهي، واأظهر الفح�ض مبنظار الأذن �سالمة غ�ساء الطبلة. خ�سعت الطفلة لإ�سالح عرب اجلمجمة من قاعدة احلفرة القحفية الو�سطى، ك�سف ذلك عن وجود خلل �سحائي وعظمي وا�سع يف ال�سقيف مع فتق يف الف�ض ال�سدغي. اأ�سلح اخللل داخل اجلافية بن�سيج ا�سطناعي. وتناق�ض ندرة هذا النوع من العر�ض من ك�سور العظام ال�سدغية وكيفية عالجها. مفتاح الكلمات: طب الأطفال، ك�رس يف اجلمجمة، قاعدة القحف، قيَلٌة ِدماِغيٌَّة َلكي�ِسيَّة، تقرير حالة؛ ُعمان. abstract: a seven-year-old girl presented to sultan qaboos university hospital, oman, with a history of having been hit by a motor vehicle. after this, she had right-sided cerebrospinal fluid otorrhoea, and a week later, brain matter extruded through the right ear. a computed tomography scan of the brain demonstrated a tegmen fracture communicating with the external auditory canal. there was no hearing or facial nerve impairment and an otoscopic examination showed an intact tympanic membrane. she underwent a transcranial repair of the middle cranial fossa base, which revealed a wide dural and bony defect of the tegmen with herniation of the temporal lobe. repair was made with an intradural patch of artificial dura. the rarity of this type of presentation of temporal bone fracture and its management are discussed. keywords: pediatric; skull fracture, basilar; encephalocele; case report; oman. traumatic acute brain herniation through the ear in a child concealed compound fracture *rajeev kariyattil and unnikrishnan muthukuttiparambil case report skull-base fractures are rare in childhood, with reported frequencies being 5–14% of head injuries but, when they do occur, they are most often located in the temporal bone. of the temporal bone fractures, only about 8% cause cerebrospinal fluid (csf) otorrhoea, and most of these cease spontaneously.1 endaural brain herniation, though uncommonly seen following mastoid surgery, is a very rare complication following trauma and, when it occurs, has a delayed presentation.2,8 acute herniation of brain matter through the ear following trauma has not been previously reported. we report a child presenting with acute herniation of brain matter through the ear following trauma, and the successful management of the herniation. case report a seven-year-old girl who was brought to the emergency room after being hit by a car while out walking. her glasgow coma scale (gcs) score on arrival was 11, with evidence of bleeding from nasal and oral cavities, and the right ear. her pupils were equal in reaction to light, and she was able to move her limbs equally. there was a scalp swelling in the right temporal region. as she was restless and irritable, she was intubated and taken for an emergency computed tomography (ct) scan. the ct scan showed a comminuted fracture of rajeev kariyattil, unnikrishnan muthukuttiparambil case report | 353 the right squamous temporal bone extending to the occipital bone, and an oblique fracture of the right petrous temporal bone sparing the otic capsule with wide separation of the margins [figures 1a and 1b]. in addition, there was fracture of the basisphenoid with blood in the sphenoid and ethmoid sinuses and evidence of pneumocephalus in the frontal region and basal cisterns. after mechanical ventilation overnight, the level of consciousness improved. a repeat scan showed no new changes and she was extubated. there was no facial nerve palsy. the otorrhoea persisted and examination of the right ear showed blood clots, which were cleaned. csf otorrhoea and clots continued to be seen over the next week when it was noticed that there was a whitish substance coming out of the right ear, especially when the child coughed or strained. closer examination revealed this substance to be brain matter. an otoscopic examination after clearing the canal, revealed an intact tympanum. no discernible defect in the canal could be seen. the child underwent transcranial surgical repair of the skull base defect. after a right temporal craniotomy, subtemporal exploration extradurally revealed a wide fracture defect in the tegmen with figure 1: (a) axial computed tomography scan showing an oblique fracture of the right petrous temporal bone sparing the otic capsule (arrow). (b) coronal reconstruction of computed tomography scan showing the fracture involving the squamous and petrous temporal bone with wide separation of the fragments and involvement of the external auditory canal (arrow). (c) 3d-reconstruction computed tomography scan showing the fracture line isolating the squamous and mastoid parts of the temporal bone as a single unit. traumatic acute brain herniation through the ear in a child concealed compound fracture 354 | squ medical journal, august 2012, volume 12, issue 3 the dura adherent to the margins. the dura was then opened, revealing brain matter herniating into the bony defect. the herniating brain was transected and an intradural repair was carried out using a patch of artificial dura (durepair®, medtronic neurosurgery, minneapolis, usa). after wound closure, the external canal was again examined and cleaned, but there was no active csf leak. a lumbar intrathecal drain was placed at the end of the procedure, which was removed after 3 days. there was no further csf otorrhoea. on the 5th postoperative day, however, she developed fever along with meningeal signs. lumbar csf was turbid and grew acinetobacter baumannii, which was treated with intravenous antibiotics for 2 weeks. she was then discharged with no further sequelae. a follow-up after 2 months revealed no neurological deficit. a ct scan after 4 months showed a barely discernible fracture line in the petrous bone with no brain herniation [figures 2a and 2b]. discussion about 4% of patients treated for head trauma have skull fractures, of which around 14–22% figure 2: (a) post operative axial computed tomography (ct) scan after 4 months showing an almost completely healed fracture line (arrow). (b) post operative coronal reconstruction ct scan after 4 months showing the tegmen defect with no brain herniation into the external auditory canal (arrow). rajeev kariyattil, unnikrishnan muthukuttiparambil case report | 355 have temporal bone fractures.3 paediatric skull base fractures are relatively uncommon, with reported incidences between 5 and 14%, of which temporal bone fractures were the most common at about 63.5%.1 cadaveric studies have shown that a significant force of lateral impact of up to 1,875 pounds (c. 850 kg) is required to fracture the temporal bone and hence is often associated with other significant intracranial injuries.3 temporal bone fractures have traditionally been divided into transverse and longitudinal, based on the orientation of the fracture line to the axis of the petrous ridge. however, in practice, fractures often tend to be more random, comminuted and difficult to describe in just two axes alone, and hence the terms oblique and mixed have also been used. another classification system is based on whether the otic capsule is spared as this directly influences neurological function. otic capsule involvement has been associated with a higher rate of csf leak, facial nerve injury, and hearing deficts.3,9 this patient had a comminuted fracture involving the temporal squama and an oblique fracture line passing through the petrous bone anterolateral to the otic capsule, through the tegmen tympani, external auditory canal, middle ear, and the mastoid. the whole segment of the squamous temporal bone along with the lateral part of the petrous bone had become an isolated fragment minimally displaced downwards [figure 1c]. in spite of the severity of the injury, there was no significant neurological deficit, including of the facial or vestibulocochlear nerves, probably because the fracture spared the otic capsule. facial injuries have also been reported to be less common in the paediatric age group irrespective of the otic capsule’s involvement.5 csf otorrhoea occurs in about 11–45% of temporal bone fractures, with petrous fractures being 10 time more likely to cause a csf leak.10 of these, the otic sparing types are less likely to have a leak.3,9 the majority of the leaks subside spontaneously—78% within 7 days and 95% within 14 days.3 traumatic endaural brain herniation is a rare occurrence. for brain herniation to occur, three pre-requisites have been described: there needs to be a bony defect, a dural defect, and increased intracranial pressure.8 most of the cases described in the literature have been due to a congenital defect, chronic otitis, or surgery. of the few post-traumatic cases described, all have presented in the form of a delayed recurrence of csf leak or meningitis.2,4–8 temporal fractures usually occur along points of weakness like the skull base foramina, tegmen tympani, and a well-pneumatised mastoid.3 the dura over the skull base is densely adherent to the bone, especially in the paediatric age group.1 in the event of a fracture with wide separation, as in this patient, it can result in a large dural tear with the margins adherent to this wide bony defect. a significant trauma like this with extensive bone fractures involving the frontal and temporal skull base can also cause associated parenchymal laceration of the basal temporal lobe and cerebral oedema. the fracture line passing through the external auditory canal could have also given rise to a concealed laceration of the roof of the canal. the combination of cortical injury, the wide dural and bony defect, and raised intracranial tension would have contributed to the brain herniation through this laceration like a concealed compound fracture. the management of acute brain herniation mandates urgent surgical repair to avoid serious infective complications. repair of csf otorrhoea and endaural herniation has been done by a transcranial, transmastoid, or combined surgical approach. in neurosurgical literature, where the leak is usually post-traumatic, a middle fossa approach has been favoured.7 in the otorhinolaryngological literature, where most herniations follow mastoid surgeries, either a purely transmastoid route, or a combined middle fossa-transmastoid approach, has been advocated, depending on the size of the defect.5,6,8 the primary goal of surgery is to disconnect the encephalocele and perform dural repair. dural repair is preferably done intradurally as the encephalocele is better handled under direct vision and the weight of the temporal lobe would support the graft better.6 extradural repair would also entail more dural elevation and risk additional tears. various materials have been used for the dural repair including fascia lata, vascularised pericranium, temporalis fascia, lyophilised dura, or a biosorbable polyglycolic acid sheet.5–8 repair of the bony defect with bone or cartilage has also been described.5 however, this is perhaps not always required as removal of the herniated brain and stoppage of csf flow will in itself enable the fracture edges to heal in a bony or fibrous union [figures 2a and 2b] and thereby prevent recurrence. traumatic acute brain herniation through the ear in a child concealed compound fracture 356 | squ medical journal, august 2012, volume 12, issue 3 conclusion temporal bone fractures, though less common in childhood, can result in csf otorrhoea and, rarely, acute brain herniation. wide fracture lines should alert us to this possibility as the herniation could be occult. urgent repair is indicated to avoid serious infective complications. a transcranial, intradural repair is the most appropriate procedure, with a wide choice of possible repair materials available. a c k n o w l e d g e m e n t the authors wish to thank dr. faisal al-azri, consultant neuroradiologist, sultan qaboos university hospital, oman, for reviewing and selecting the images. references 1. perheentupa u, kinnunen i, grénman r, aitasalo k, mäkitie aa. management and outcome of pediatric skull base fractures. int j pediatr otorhinolaryngol 2010; 74:1245–50. 2. bowes ak, wiet rj, monsell em, hahn ys, o’connor ca. brain herniation and space-occupying lesions eroding the tegmen tympani. laryngoscope 1987; 97:1172–5. 3. brodie ha, thompson tc. management of complications from 820 temporal bone fractures. am j otol 1997; 18:188–97. 4. dedo hh, sooy fa. endaural brain hernia (encephalocele): diagnosis and treatment. laryngoscope 1970; 80:1090–9. 5. feenstra l, sanna m, zini c, gamoletti r, delogu p. surgical treatment of brain herniation into the middle ear and mastoid. am j otol 1985; 6:311–5. 6. jackson cg, pappas dg jr, manolidis s, glasscock me iii, von doersten pg, hampf cr, et al. brain herniation into the middle ear and mastoid: concepts in diagnosis and surgical management. am j otol 1997; 18:198–206. 7. nishiike s, miyao y, gouda s, shimada n, nagai m, nakagawa a, et al. brain herniation into the middle ear following temporal bone fracture. acta otolaryngol 2005; 125:902–5. 8. ramsden rt, latif a, lye rh, dutton jem. endaural cerebral hernia. j laryngol otol 1985; 99:643–51. 9. rafferty ma, mc conn walsh r, walsh ma. a comparison of temporal bone fracture classification systems. clin otolaryngol 2006; 31:287–91. 10. saraiya pv, aygun n. temporal bone fractures. emerg radiol 2009; 16:255–65. إستخدام تنظري البطن يف عالج املرضى املصابني بصدمات مراجعة موجزة يحيى البندارى اأحمد البندارى، جهينة اآل العدوية، ه�ين الق��شي abstract: laparoscopy is one of the most effective intervention modalities, resulting in improved outcomes for major surgeries. in the past decade, the laparoscopic approach in trauma patients has shown better diagnostic outcomes than traditional laparotomies. furthermore, this approach is cost-effective, significantly reduces the length of hospital stay and contributes to reduced complication rates. however, the use of laparoscopies in trauma cases is generally restricted to patients with normal haemodynamic parameters and is contraindicated for individuals with head injuries. with advances in knowledge and improved training, laparoscopies can also be used in the treatment of other conditions, such as diaphragmatic injuries and organ lacerations. this article briefly reviews the extent of laparoscopy use and its significance in the management of trauma patients. keywords: laparoscopy; laparotomy; trauma; abdominal injuries; diaphragm; penetrating wounds; acute abdomen. العقد يف كربى. جراحية عملي�ت لتح�شري النت�ئج حت�شني اإىل يوؤدي و فع�لية الطبي التدخل طرق اأكرث من البطن تنظري امللخ�ص: امل��شي، اأظهر ا�شتخدام املنظ�ر يف املر�شى امل�ش�بني ب�شدم�ت، نت�ئج ت�شخي�ص اأف�شل من اجلراح�ت التقليدية. كام إن هذه الطريقة غري مكلفة، وتقلل اإىل حد كبري من طول االإق�مة يف امل�شت�شفى وتسهم كذلك يف تقليل امل�ش�عف�ت. ومع ذلك، ف�إن ا�شتخدام املنظ�ر يف ح�الت املر�شى امل�ش�بني ب�ل�شدمة تقت�رض على املر�شى الذين لديهم دين�ميك� دم طبيعية، ومتنع لالأفراد الذين يع�نون من اإ�ش�ب�ت الراأ�ص. مع تقدم املعرفة وحت�شن التدريب، ميكن ا�شتخدام التنظري يف عالج ح�الت اأخرى، مثل اإ�ش�ب�ت احلج�ب احل�جز وتهتك االأجهزة. ي�شتعر�ص هذا املق�ل ب�إيج�ز مدى ا�شتخدام تنظري البطن واأهميته يف عالج املر�شى امل�ش�بني ب�شدم�ت. مفتاح الكلمات: تنظري البطن؛ فتح البطن؛ �شدمة؛ اإ�ش�ب�ت البطن؛ احلج�ب احل�جز؛ اجلروح املخرتقة؛ البطن احل�د. the use of laparoscopy in the management of trauma patients brief review *yehia b. a. el-bendary, juhaina al-adawi, hani al-qadhi review sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e9–14, epub. 2 feb 16 submitted 28 apr 15 revisions req. 6 jul & 27 aug 15; revisions recd. 4 aug & 27 sep 15 accepted 14 oct 15 doi: 10.18295/squmj.2016.16.01.003 trauma—whether from a blunt or penetrating injury, an explosion or a fall—is one of the leading causes of mortality in young patients worldwide. multiple guidelines and management modalities have been suggested to provide optimal care and prognostic outcomes for these patients with minimal morbidity. one continuously evolving method that allows medical personnel to meet the specifications outlined in these guidelines is the laparoscopy. laparoscopic interventions have positively affected patient outcomes for both trauma and surgical cases, including cholecystectomy, appendectomy, visceral perforation and hernia repair cases.1 the main goal of a laparoscopy is to use the least invasive method to identify or exclude organ and visceral injuries and, if possible, reach a diagnosis. therefore, with evolving techniques and improved practice, laparoscopy may potentially be a therapeutic option for patients with selected traumatic injuries. in the management of trauma patients, laparoscopies have proven to be safer and more cost-effective than laparotomies in terms of hospital stay and the prevention of subsequent unnecessary laparotomies.2–6 unfortunately, most of the published literature on this subject are case reports or retrospective analyses; few prospective randomised trials have been undertaken to compare the benefits of laparoscopies versus laparotomies in trauma cases. the present article aims to assess the indications for and outcomes of laparoscopy in trauma patients in comparison to traditional laparotomy methods and to outline the risks and benefits of each procedure. history the first laparoscopic intervention was performed by stone et al. in 1942 to diagnose internal bleeding in a patient with traumatic injuries.7 in 1970, department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: yb.elbendary@gmail.com the use of laparoscopy in the management of trauma patients brief review e10 | squ medical journal, february 2016, volume 16, issue 1 heselson advocated the use of the laparoscopy to detect penetrating injuries and injuries to internal abdominal organs.7 since then, there has been a major improvement in laparoscopic technology and instruments with a corresponding improvement in outcomes.1 ahmed et al. revealed that the laparoscopic technique was both safe and accurate in the management of penetrating abdominal injuries.8 the use of laparoscopy has since spread rapidly throughout trauma centres worldwide and is slowly replacing the need for exploratory laparotomies.9 indications for laparoscopy the role of the laparoscopy in screening, diagnosis and therapy has been studied extensively throughout the past few decades. many studies have confirmed that laparoscopies can be safely performed for patients with a normal haemodynamic status and equivocal abdominal/pelvic computed tomography (ct) or ultrasonography (us).1,10,11 the european association of endoscopic surgeons has published evidence-based guidelines for the use of laparoscopies in patients with blunt or penetrating abdominal trauma.12 this minimally invasive procedure may potentially prevent non-therapeutic laparotomies; in a study of 819 patients with small bowel injuries, sitnikov et al. found that video-assisted laparoscopies were associated with postoperative complication and mortality rates of 11.8% and 2.3%, respectively.13 d i a g n o s t i c u s e among patients with abdominal trauma, the main concern is a possible injury to the liver or spleen which is not identified during the initial assessment, especially for patients with normal haemodynamic parameters. the use of a laparoscopy in such cases would help to rule out any associated organ injuries or haemorrhage, particularly of the bowel, that were not visible on imaging. while intra-abdominal fluid can usually be seen on ct or us scans, this may either be associated with abdominal trauma or be secondary to resuscitative measures. it is difficult to identify the type of fluid based on diagnostic imaging alone; therefore, a laparoscopy can be utilised in these circumstances to identify the fluid and obtain samples for analysis. nonetheless, the diagnostic utility of a laparoscopy depends primarily on the skills of the operating surgeon. in a recent study from taiwan, two groups of trauma patients underwent either a laparotomy or a laparoscopy carried out by surgeons who had previously performed at least 10 acute care laparoscopies per month.5 laparoscopies were found to have a 100% sensitivity in detecting injuries;5 this suggests that better patient outcomes are associated with increased laparoscopic experience in acute care settings. in the usa, 4,755 out of 2.5 million trauma patients in 467 trauma centres underwent diagnostic laparoscopies between 2007–2010; among these, there was a 0.5% rate of missed injuries requiring a delayed laparotomy and therapeutic intervention.6 this could potentially be due to a reduced level of expertise in the use of minimal invasive surgery in trauma patients. nevertheless, results from both studies indicated better outcomes for laparoscopic patients in terms of reduced hospital stay and fewer complications.5,6 p e n e t r at i n g i n j u r i e s penetrating abdominal trauma, including stabbing and gunshot-related wounds, is one of the most common causes of mortality in trauma patients.9 this form of trauma does not have to penetrate the peritoneal cavity itself—some injuries can be tangential without violating the peritoneum. in one study, it was estimated that 45% of patients with normal haemodynamic parameters who sustained a penetrating abdominal wound had a tangential path of injury.14 therefore, there is a need to develop an accurate and sensitive diagnostic modality to identify patients with true penetration of the peritoneum. laparoscopies have shown superior specificity and sensitivity in identifying peritoneal penetration when compared to ct and focused assessment with sonography for trauma (fast).15,16 in a study conducted to analyse 10 years of laparoscopy experience in a level-one trauma centre, 83% of the 131 patients who underwent laparoscopic interventions had a penetrating abdominal injury.1 the indications for a laparoscopy in these patients included a gunshot wound involving the flanks, an anterior abdominal stab wound with fascia penetration, evidence of peritonitis on fast scans and uncertainty regarding the tangential path of injury. had any of these patients experienced a decline in vital signs, a laparotomy would have been the modality of choice.1 d i a p h r a g m at i c i n j u r i e s one of the most common injuries associated with penetrating trauma is a diaphragmatic tear or rupture. thoracoabdominal trauma is any injury within the region bounded by the posterior nipple line superiorly to the costal margin inferiorly. diaphragmatic injuries should always be suspected in such conditions, as they can be easily missed during the initial diagnosis. powell et al. found that 20% of patients who sustained penetration to the thoracoabdominal area developed a diaphragmatic injury.11 a study estimating mortality yehia b. a. el-bendary, juhaina al-adawi and hani al-qadhi review | e11 and morbidity due to complicated diaphragmatic injuries reported rates of 20% and 30%, respectively.17 the most common complication of a diaphragmatic injury is the herniation of abdominal content into the thorax which, if untreated, can cause complications that can lead to death.17,18 accordingly, ruling out violations or breaches of the diaphragm is crucial. unfortunately, non-invasive imaging modalities (ct and us) have been associated with high false-negative rates in the diagnosis of diaphragmatic injuries.19,20 in addition, mihos et al. reported that 74% of traumatic diaphragmatic injuries in their study were diagnosed intra-operatively after being missed initially on noninvasive imaging.21 a laparoscopy enables visual examination of the left lobe of the diaphragm and, to a lesser extent, the right lobe, which would otherwise be obscured by the liver on imaging. direct laparoscopic visualisation of the diaphragm has been shown to be the best diagnostic modality to identify diaphragmatic tears and ruptures.11 however, ct scans remain the standard imaging modality in patients involved in trauma. b l u n t a b d o m i n a l t r a u m a non-invasive radiological imaging has shown good sensitivity and specificity in detecting intra-abdominal injuries following blunt abdominal trauma (97% and 98%, respectively).22 however, there is still a degree of ambiguity involved with certain splenic lacerations and pancreatic or gastrointestinal tract injuries. the indications for the use of a laparoscopy in blunt trauma cases include evidence of a hollow viscous injury on ct scans or peritonitis on physical examination.5 additionally, physical examinations may be unreliable due to a patient’s altered mental status. however, as mentioned previously, haemodynamic stability is mandatory in the choice of a laparoscopic intervention over a traditional laparotomy.10 diaphragmatic injuries have also been associated with blunt trauma, manifesting as larger ruptures and tears in comparison to penetrating trauma. these injuries account for 2.1% of patients with blunt trauma injuries.23 laparoscopic examinations can confirm the presence of blunt trauma injuries but a laparotomy is still essential in cases of large tears.23 t h e r a p e u t i c u s e the use of a laparoscopy is not limited to screening and diagnostics. multiple centres worldwide have implemented therapeutic laparoscopies for the management of specific injuries.10 patients with normal haemodynamic parameters and no associated head or chest injuries are ideal candidates for a therapeutic laparoscopic intervention.10 in a recent systematic review on the use of laparoscopies in trauma, 20 research papers on therapeutic laparoscopies were identified.9 of the 1,263 patients involved in these studies, 143 therapeutic laparoscopy procedures were performed. the most common injuries repaired were diaphragmatic injuries (54%), followed by liver and mesenteric injuries (13% each).9 in liver injuries, laparoscopies have been utilised to provide haemostasis by the application of fibrin glue to minimally bleeding lacerations.24 laparoscopies have also been used to wash accumulated blood from the peritoneal cavity as a sequel to intra-abdominal bleeding. this ensures a reduction in associated complications, including peritonitis, ileus and inflam mation.25 carrillo et al. reported the use of laparoscopies in suction drainage to evacuate residual fluids and prevent further fluid accumulation.25 contraindications for laparoscopy a b n o r m a l h a e m o d y n a m i c s patients with abnormal haemodynamic parameters are not considered appropriate candidates for laparoscopic interventions.10 suspected major bleeding or an injury which might cause the patient’s condition to deteriorate usually calls for urgent surgery. rapid identification of the bleeding source or critical injury is important in trauma patients; this cannot be carried out efficiently via a laparoscopy. m u lt i p l e o r g a n i n v o lv e m e n t no advantage has been found in the use of a laparoscopy over a laparotomy among patients with injuries involving multiple organs.10 in fact, the time required to perform a laparoscopy increases in cases of complicated multiple injuries. thus, a laparotomy is preferred in such situations as it allows full exploration of the intraperitoneal and retroperitoneal structures and provides more efficient damage control and repair of injuries.10 h e a d i n j u r i e s few studies in the literature cover the effect of pneumoperitoneum on intracranial pressure. one report relayed a rise in intracranial pressure among trauma patients managed laparoscopically.26 this is thought to be due to an increase in the partial pressure of carbon dioxide, as it is used to provide the pneumoperitoneum required for a laparoscopy.26 therefore, it is advisable to proceed directly with a traditional laparotomy for patients with suspected head injuries. the use of laparoscopy in the management of trauma patients brief review e12 | squ medical journal, february 2016, volume 16, issue 1 benefits of laparoscopy one of the greatest advantages of laparoscopies in trauma cases is the reduction in the rate of negative or non-therapeutic laparotomies performed; this in turn reduces hospitalisation, laparotomy-associated morbidity and overall costs and improves outcomes.4,5 one study found that 50% of patients who sustained blunt trauma with equivocal findings and underwent a laparoscopy avoided the necessity for a laparotomy.27 in other centres, the use of laparoscopic procedures resulted in a 70–80% reduction in the number of nontherapeutic laparotomies.11,28 this reduction may be due to the tremendous improvement in laparoscopic techniques and tools over the past few decades.29 laparoscopy-associated complications and morbidity are significantly lower than in cases of traditional laparotomy.2‒4 recent research on the complications associated with diagnostic laparoscopy versus negative laparotomy showed reduced complication rates (3% versus 22%) and decreased hospital stay (1.4 versus 5.1 days).2 other studies have found that laparoscopies can significantly reduce hospitalisationand complicationrelated costs when compared to the traditional laparotomy, with an estimated total reduction of 1.78–2 times.3,4 kaban et al. reported that the laparoscopy had sensitivity and specificity rates of 92% and 100%, respectively, in detecting injuries.30 another study confirmed the superiority of laparoscopy over diagnostic peritoneal lavage with regards to sensitivity and specificity; additionally, no significant bleeding or trauma was observed during a subsequent laparotomy for 8% of those in the laparoscopy group compared to 27% of those in the peritoneal lavage group.31 direct visualisation using laparoscopy has been shown to be more accurate than ct and us in detecting diaphragmatic tears or ruptures and other solid organ injuries.32 however, it has been found to have a low sensitivity (20%) in the identification of hollow viscous injuries.32 in a recent systematic review on laparoscopic interventions in trauma cases, only 24.6% of the research papers had therapeutic applications, the majority of which focused on the laparoscopic repair of diaphragmatic injuries.9 the low prevalence of laparoscopy use was thought to be due to a lack of expertise in using laparoscopy in a trauma setting.9 nevertheless, the rate of therapeutic laparoscopy is expected to rise with continuous advancements in the development of new techniques and training programmes. in a randomised control trial, 20 haemodynamically stable patients with no signs of peritonitis underwent an exploratory laparotomy and 23 underwent a diagnostic laparoscopy; there were no statistically significant differences between the two groups, apart from length of hospital stay, which was lower among those who underwent diagnostic laparoscopies.33 in the same study, patients with equivocal peritoneal violations underwent either a diagnostic laparoscopy (n = 28) or expectant nonoperative management (n = 31). diagnostic laparoscopies were performed more often for minor organ injuries; however, there were no statistical differences in therapeutic operation rates, morbidity or hospital costs.33 complications of laparoscopy as with any other invasive procedure, the laparoscopy carries a risk of complications; however, it has been estimated that only 1–11% of patients undergoing a diagnostic laparoscopy will develop complications related to the procedure.34 m i s s e d i n j u r i e s previously, high rates (up to 77%) for missed bowel injuries have been reported while using laparoscopies as a screening or diagnostic modality.9 however, kawahara et al. reported that a systemic approach for laparoscopic abdominal examinations resulted in the complete absence of missed bowel injuries and high avoidance of unnecessary laparotomies (73.33%).35 nevertheless, patients with suspected retroperitoneal involvement and those with deteriorating haemodynamic parameters should undergo an open laparotomy to prevent complications secondary to a missed injury. t e n s i o n p n e u m o t h o r a x pneumothorax occurs with the insufflation of air during the laparoscopic procedure when an underlying diaphragmatic injury allows communication between the abdominal and thoracic cavities. if undetected or left untreated, this serious condition can lead to death. tension pneumothorax is one of the most common laparoscopy-associated complications in trauma patients.29,36 it is mandatory to insert a thoracotomy tube in such a situation to prevent further deterioration of the patient’s condition.29,36 conclusion laparoscopic interventions in trauma patients with normal haemodynamic parameters are an excellent modality to identify diaphragmatic injuries and peritoneal penetration. in comparison with yehia b. a. el-bendary, juhaina al-adawi and hani al-qadhi review | e13 traditional laparotomies, laparoscopies are more efficient and cost-effective and associated with fewer complications. however, clear guidelines to support and indicate the use of laparoscopy in trauma patients are still lacking. additionally, there is a need for prospective randomised controlled trials to provide stronger evidence for the use of the laparoscopic approach in the management of trauma patients. references 1. johnson jj, garwe t, raines ar, thurman jb, carter s, bender js, et al. the use of laparoscopy in the diagnosis and treatment of blunt and penetrating abdominal injuries: 10-year experience at a level 1 trauma center. am j surg 2013; 205:317–21. doi: 10.1016/j.amjsurg.2012.10.021. 2. sosa jl, baker m, puente i, sims d, sleeman d, ginzburg e, et al. negative laparotomy in abdominal gunshot wounds: potential impact of laparoscopy. j trauma 1995; 38:194–7. doi: 10.1097/00005373-199502000-00007. 3. taner as, topgul k, kucukel f, demir a, sari s. diagnostic laparoscopy decreases the rate of unnecessary laparotomies and reduces hospital costs in trauma patients. j laparoendosc adv surg tech 2001; 11:207–11. doi: 10.1089/109264201750539718. 4. demaria ej, dalton jm, gore dc, kellum jm, sugerman hj. complementary roles of laparoscopic abdominal exploration and diagnostic peritoneal lavage for evaluating abdominal stab wounds: a prospective study. j laparoendosc adv surg tech a 2000; 10:131–6. doi: 10.1089/lap.2000.10.131. 5. lin hf, chen yd, lin kl, wu mc, wu cy, chen sc. laparoscopy decreases the laparotomy rate for hemodynamically stable patients with blunt hollow viscus and mesenteric injuries. am j surg 2015; 210:326–33. doi: 10.1016/j.amjsurg.2014.11.009. 6. zafer sn, onwugbufor mt, hughes k, greene wr, cornwell ee 3rd, fullum tm, et al. laparoscopic surgery for trauma: the realm of therapeutic management. am j surg 2015; 209: 627–32. doi: 10.1016/j.amjsurg.2014.12.011. 7. heselson j. peritoneoscopy in abdominal trauma. s afr j surg 1970; 8:53–61. 8. ahmed n, whelan j, brownlee j, chari v, chung r. the contribution of laparoscopy in evaluation of penetrating abdominal wounds. j am coll surg 2005; 201:213–16. doi: 10.1016/j.jamcollsurg.2005.04.021. 9. o’malley e, boyle e, o’callaghan a, coffey jc, walsh sr. role of laparoscopy in penetrating abdominal trauma: a systemic review. world j surg 2013; 37:113–22. doi: 10.1007/s00268012-1790-y. 10. goettler ce, bard mr, toschlog ea. laparoscopy in trauma. curr surg 2004; 61:554–9. doi: 10.1016/j.cursur.2004.06.017. 11. powell bs, magnotti lj, schroeppel tj, finnell cw, savage sa, fischer pe, et al. diagnostic laparoscopy for the evaluation of occult diaphragmatic injury following penetrating thoracoabdominal trauma. injury 2008; 39:530–4. doi: 10.1016/j.injury.2007.10.020. 12. sauerland s, agresta f, bergamaschi r, borzellino g, budzynski a, champault g, et al. laparoscopy for abdominal emergencies: evidence-based guidelines of the european association for endoscopic surgery. surg endosc 2006; 20: 14–29. doi: 10.1007/s00464-005-0564-0. 13. sitnikov v, yakubu a, sarkisyan v, turbin m. the role of video-assisted laparoscopy in management of patients with small bowel injuries in abdominal trauma. surg endosc 2009; 23:125–9. doi: 10.1007/s00464-008-9910-3. 14. ivatury rr, simon fj, stahl wm. a critical evaluation of laparoscopy in penetrating abdominal trauma. j trauma 1993; 34:822–7. doi: 10.1097/00005373-199207000-00054. 15. guth aa, pachter hl. laparoscopy for penetrating thoracoabdominal trauma: pitfalls and promises. jsls 1998; 2:123–7. 16. ivatury rr, simon rj, weksler b, bayard v, stahl wm. laparoscopy in the evaluation of intrathoracic abdomen after penetrating injury. j trauma 1992; 33:101–8. doi: 10. 1097/00005373-199207000-00019. 17. hallfeldt kk, trupka aw, erhard j, waldner h, schweiberer l. emergency laparoscopy for abdominal stab wounds. surg endosc 1998; 12:907–10. doi: 10.1007/s004649900743. 18. madden mr, paull de, finkelstein jl, goodwin cw, marzulli v, yurt rw, et al. occult diaphragmatic injury from stab wounds to the lower chest and abdomen. j trauma 1989; 29:292–8. doi: 10.1097/00005373-198903000-00003. 19. friese rs, coln ce, gentilello lm. laparoscopy is sufficient to exclude occult diaphragm injury after penetrating abdominal trauma. j trauma 2005; 58:789–92. doi: 10.1097/01.ta.000015 8243.78299.b5. 20. mahajna a, mitkal s, bahuth h, krausz mm. diagnostic laparoscopy for penetrating injuries in the thoracoabdominal region. surg endosc 2004; 18:1485–7. doi: 10.1007/s00464-0039296-1. 21. mihos p, potaris k, gakidis j, paraskevopoulos j, varvatsoulis p, gougoutas b, et al. traumatic rupture of the diaphragm: experience with 65 patients. injury 2003; 34:169–72. doi: 10.1016/s0020-1383(02)00369-8. 22. shanmuganathan k, mirvis se, chiu wc, killeen kl, hogan gj, scalea tm. penetrating torso trauma: triplecontrast helical ct in peritoneal violation and organ injury a prospective study in 200 patients. radiology 2004; 231:775–84. doi: 10.1148/radiol.2313030126. 23. rubikas r. diaphragmatic injuries. eur j cardiothorac surg 2001; 20:53–7. doi: 10.1016/s1010-7940(01)00753-9. 24. chen rj, fang jf, lin bc, hsu yb, kao jl, kao yc, et al. selective application of laparoscopy and fibrin glue in the failure of nonoperative management of blunt hepatic trauma. j trauma 1998; 44:691–5. doi: 10.1097/00005373-19980400000024. 25. carrillo eh, reed dn jr, gordon l, spain da, richardson jd. delayed laparoscopy facilitates the management of biliary peritonitis in patients with complex liver injuries. surg endosc 2001; 15:319–22. doi: 10.1007/s004640000300. 26. mobbs rj, yang mo. the dangers of diagnostic laparoscopy in the head injured patient. j clin neurosci 2002; 9:592–3. doi: 10.1054/jocn.2001.1070. 27. biffl wl, kaups kl, cothren cc, brasel kj, dicker ra, bullard mk, et al. management of patients with anterior abdominal stab wounds: a western trauma association multicenter trial. j trauma 2009; 66:1294–301. doi: 10.1097/ ta.0b013e31819dc688. 28. saribeyoglu k, pekmezci s, baca b, zengin k, karatas a, erenler kilic i, et al. laparoscopy offers diagnosis and treatment in abdominal stab injuries. surg laparosc endosc percutan tech 2007; 17:396–401. doi: 10.1097/sle.0b013e3181378e79. 29. villaviencio rt, aucar ja. analysis of laparoscopy in trauma. j am coll surg 1999; 189:11–20. doi: 10.1016/s1072-7515(99) 00052-6. 30. kaban gk, novitsky yw, perugini ra, haveran l, czerniach d, kelly jj, et al. use of laparoscopy in evaluation and treatment of penetrating and blunt abdominal injuries. surg innov 2008; 15:26–31. doi: 10.1177/1553350608314664. http://dx.doi.org/10.1016/j.amjsurg.2012.10.021 http://dx.doi.org/10.1097/00005373-199502000-00007 http://dx.doi.org/10.1089/109264201750539718 http://dx.doi.org/10.1089/lap.2000.10.131 http://dx.doi.org/10.1016/j.amjsurg.2014.11.009 http://dx.doi.org/10.1016/j.amjsurg.2014.12.011 http://dx.doi.org/10.1016/j.jamcollsurg.2005.04.021 http://dx.doi.org/10.1007/s00268-012-1790-y http://dx.doi.org/10.1007/s00268-012-1790-y http://dx.doi.org/10.1016/j.cursur.2004.06.017 http://dx.doi.org/10.1016/j.injury.2007.10.020 http://dx.doi.org/10.1007/s00464-005-0564-0 http://dx.doi.org/10.1007/s00464-008-9910-3 http://dx.doi.org/10.1097/00005373-199207000-00054 http://dx.doi.org/10.1097/00005373-199207000-00019 http://dx.doi.org/10.1097/00005373-199207000-00019 http://dx.doi.org/10.1007/s004649900743 http://dx.doi.org/10.1097/00005373-198903000-00003 http://dx.doi.org/10.1097/01.ta.0000158243.78299.b5 http://dx.doi.org/10.1097/01.ta.0000158243.78299.b5 http://dx.doi.org/10.1007/s00464-003-9296-1 http://dx.doi.org/10.1007/s00464-003-9296-1 http://dx.doi.org/10.1016/s0020-1383%2802%2900369-8 http://dx.doi.org/10.1148/radiol.2313030126 http://dx.doi.org/10.1016/s1010-7940%2801%2900753-9 http://dx.doi.org/10.1097/00005373-199804000-00024 http://dx.doi.org/10.1097/00005373-199804000-00024 http://dx.doi.org/10.1007/s004640000300 http://dx.doi.org/10.1054/jocn.2001.1070 http://dx.doi.org/10.1097/ta.0b013e31819dc688 http://dx.doi.org/10.1097/ta.0b013e31819dc688 http://dx.doi.org/10.1097/sle.0b013e3181378e79 http://dx.doi.org/10.1016/s1072-7515%2899%2900052-6 http://dx.doi.org/10.1016/s1072-7515%2899%2900052-6 http://dx.doi.org/10.1177/1553350608314664 the use of laparoscopy in the management of trauma patients brief review e14 | squ medical journal, february 2016, volume 16, issue 1 31. cuschieri a, hennessy tp, stephens rb, berci g. diagnosis of significant abdominal trauma after road traffic accidents: preliminary results of a multicenter clinical trial comparing minilaparoscopy with peritoneal lavage. ann r coll surg engl 1988; 70:153–5. 32. ivatury rr, simon rj, stahl wm. selective celiotomy for missile wounds of the abdomen based on laparoscopy. surg endosc 1994; 8:366–9. doi: 10.1007/bf00642432. 33. leppäniemi a, haapiainen r. diagnostic laparoscopy in abdominal stab wounds: a prospective, randomized study. j trauma 2003; 55:636–45. doi: 10.1097/01.ta.0000063000. 05274.a4. 34. society of american gastrointestinal and endoscopic surgeons. guidelines for diagnostic laparoscopy. from: www.sages.org/ publications/guidelines/guidelines-for-diagnostic-laparoscopy/ accessed: sep 2015. 35. kawahara nt, alster c, fujimura i, poggetti rs, birolini d. standard examination system for laparoscopy in penetrating abdominal trauma. j trauma 2009; 67:589–95. doi: 10.1097/ ta.0b013e3181a60593. 36. leppäniemi ak, elliott dc. the role of laparoscopy in blunt abdominal trauma. ann med 1996; 28:483–9. doi: 10.3109/07853899608999112. http://dx.doi.org/10.1007/bf00642432 http://dx.doi.org/10.1097/01.ta.0000063000.05274.a4 http://dx.doi.org/10.1097/01.ta.0000063000.05274.a4 http://dx.doi.org/10.1097/ta.0b013e3181a60593 http://dx.doi.org/10.1097/ta.0b013e3181a60593 http://dx.doi.org/10.3109/07853899608999112 4department of haematology, 1college of medicine & health sciences, sultan qaboos university; departments of 2medicine and 3nursing, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: khabori@squ.edu.om معرفة وسلوك املرضى جتاه املشاركة يف التجارب السريرية يف عمان دراسة مقطعية ح�سني علي اللواتي، خالد البيماين، مهرة الزدجايل، ن�رصة العبيداين، زيانة الكيومي، مرت�سى خمي�ض اخلابوري abstract: objectives: clinical trials are prospective studies on human subjects designed to answer various clinical questions. however, only a limited number of clinical trials have been conducted in oman. this study aimed to assess the knowledge and attitudes of omani patients and their relatives towards participating in clinical trials. methods: this cross-sectional study was conducted between october 2015 and march 2016 among 174 patients and relatives attending the haematology and oncology outpatient clinics and day care unit of the sultan qaboos university hospital, muscat, oman. a self-administered questionnaire was designed to elicit participants’ knowledge of and attitudes towards participation in clinical trials. results: a total of 100 patients and relatives agreed to take part in the study (response rate: 57.5%). the male-to-female ratio was 1:1.2. only 31.3% of the studied population knew what clinical trials were and only 6.5% had themselves previously participated in a clinical trial. the majority agreed or strongly agreed that they would participate in clinical trials related to their own condition (59.2%). overall, 89.7% expected to be informed about potential clinical trials by their treating physicians. conclusion: omanis had a low level of knowledge of clinical trials and a very low rate of previous participation in such trials, despite a moderate level of interest. patients should therefore be educated and informed of ongoing clinical trials in order to improve participation rates for clinical trials conducted in oman. keywords: attitudes; knowledge; clinical trials as topic; patient participation; oman. امللخ�ص: الهدف: التجارب ال�رصيرية هي درا�سات مرتقبة م�ستقبلية على الب�رص م�سممة لالإجابة على اأ�سئلة خمتلفة تخ�ض الطب ال�رصيري، بالرغم من ذلك، هناك ندرة يف التجارب ال�رصيرية التي اأجريت يف عمان. هدفت هذه الدرا�سة اإىل تقييم معرفة و�سلوك املر�سى العمانيني واأقاربهم جتاه امل�ساركة يف التجارب ال�رصيرية. الطريقة: اأجريت هذه الدرا�سة املقطعية بني اأكتوبر 2015 و مار�ض 2016 من بني 174 من املر�سى واأقاربهم الذين ح�رصوا عيادات اأمرا�ض الدم واالأورام ووحدة الرعاية النهارية مب�ست�سفى جامعة ال�سلطان قابو�ض يف م�سقط ال�رصيرية. التجارب يف امل�ساركة جتاه وموقفهم امل�ساركني معرفة مب�ستوى تتعلق بيانات ال�ستخال�ض ا�ستبيان ت�سميم مت عمان، يف النتائج: وافق ما جمموعه 100 مري�ض اأواأقارب مر�سى على امل�ساركة يف الدرا�سة )معدل اال�ستجابة: %57.5(. وكانت ن�سبة الذكور اإىل االإناث 1:1.2. اأظهرت النتائج باأن %31.3 من امل�ساركني لديهم معرفة م�سبقة عن التجارب ال�رصيرية و %6.5 فقط كانوا قد �ساركوا �سابقًا يف جتربة �رصيرية. وافق االأغلبية على اأنهم �سي�ساركون يف التجارب ال�رصيرية املتعلقة بحالتهم اخلا�سة )%59.2(، و %89.7 توقعوا باأن املعرفة من منخف�ض م�ستوى العمانيني لدى كان اخلال�صة: املعاجلني. االأطباء قبل من حمتملة �رصيرية جتربة باأي علم على يكونوا االإهتمام. من معتدل م�ستوى وجود من بالرغم التجارب، هذه مثل يف ال�سابقة امل�ساركة من جداً منخف�ض ومعدل ال�رصيرية بالتجارب لذلك ينبغي تثقيف املر�سى واطالعهم على التجارب ال�رصيرية اجلارية من اأجل حت�سني معدالت امل�ساركة للتجارب ال�رصيرية يف عمان. الكلمات املفتاحية: �سلوك؛ املعرفة؛ التجارب ال�رصيرية كمو�سوع؛ م�ساركة املر�سى؛ عمان. knowledge and attitudes towards clinical trial participation in oman a cross-sectional study hussain al-lawati,1 khalid al-baimani,2 mahra al-zadjali,3 nasra al-obaidani,3 ziyana al-kiyumi,3 *murtadha k. al-khabori4 clinical & basic research sultan qaboos university med j, february 208, vol. 18, iss. 1, pp. e54–60, epub. 4 apr 18 submitted 17 aug 17 revision req. 7 nov 17; revision recd. 29 nov 17 accepted 14 dec 17 advances in knowledge omani patients and their relatives were found to have low levels of knowledge of clinical trials; however, there was a moderate level of interest in participating. application to patient care making patients aware of clinical trials is likely to improve their knowledge of and participation in such trials. based on the findings of this study, physicians in oman should be encouraged to discuss the option of participating in clinical trials with patients when suitable. moreover, information about ongoing clinical trials should be made accessible to patients at different hospitals. doi: 10.18295/squmj.2018.18.01.009 a clinical trial is a prospective study of human subjects in which the effect of one or more interventions is compared with a control group in order to answer important clinical questions.1 it is a major type of investigative research methodology that assesses new interventions in order hussain al-lawati, khalid al-baimani, mahra al-zadjali, nasra al-obaidani, ziyana al-kiyumi and murtadha k. al-khabori clinical and basic research | e55 to provide non-biased insight into their effectiveness, as well as their potential adverse events and complications. the results of clinical trials are considered to constitute high-quality evidence in clinical medicine and have contributed to vast improvements in the quality of healthcare provision in various fields.2–4 however, according to the clinical trial registry of the national library of medicine (bethesda, maryland, usa), only 20 registered clinical trials to date have involved oman, most of which were sponsored by various pharmaceutical companies.5 while patients’ attitudes towards participating in clinical trials have been analysed in other areas of the world, they have not yet been studied in oman; as such, the reasons underlying low clinical trial participation among the local population remain unclear.6–8 various personal, sociocultural or religious factors may cause patients to be reluctant to participate in clinical trials. in addition, inadequate knowledge about clinical trials among patients, relatives and physicians, a lack of local expertise or previous experience in running clinical trials and limited funding, support and infrastructure may all act as barriers to participation.1 accordingly, in order to improve the status of clinical trials in oman, it is important to understand patients’ attitudes towards participation in such trials so as to identify areas for improvement. this study therefore aimed to assess the knowledge and attitudes of omani patients and their relatives towards participating in clinical trials. methods this cross-sectional study was conducted at the sultan qaboos university hospital (squh), muscat, oman, between october 2015 and march 2016. a total of 174 adult patients and their relatives visiting the squh haematology and oncology outpatient clinics and the day care unit were invited to participate in the study. patients were excluded from the study if they refused to participate or were too sick to fill out the questionnaire. based on assumptions of 10% accuracy and using a 95% confidence interval with a convenient sampling strategy, a minimum sample of 97 participants was deemed necessary.9 however, given the potential for missing data, the target sample size was increased to 100 participants. a 48-item questionnaire to determine knowledge of and attitudes towards participating in clinical trials was designed based on an extensive literature review of questionnaires covering similar topics. new items were added and existing items were modified in order to conform to the local culture in oman. the final version of the questionnaire included three domains. the first 11-item domain served to elicit sociodemographic information about the subjects, including age, gender and disease characteristics. the second 14-item domain assessed participants’ knowledge of clinical trials, with participants answering either “yes”, “no” or “not applicable” to each question. the third 23-item domain consisted of a number of statements with which the participants were asked to rate their level of agreement. this domain covered various topics which might impact a participant’s willingness to participate in a clinical trial, such as the blinded nature of a clinical trial, the random allocation of participants to intervention and control groups during the clinical trial, potential side-effects of the treatment used in the clinical trial and other factors influencing the decision-making process for clinical trial participation. each item was scored on a fivepoint likert scale using the responses “strongly agree”, “agree”, “neutral”, “disagree” or “strongly disagree”. all responses to the questionnaire were self-assessed by the participants, without the aid of physicians or nurses. during the design of the questionnaire, an exten sive literature review was performed to ensure that all areas related to the topic of clinical trial participation were included. subsequently, an expert assessed the face validity of the content and design of the questionnaire. the items included in the survey were found to reasonably cover all important areas of assessment. the questionnaire was translated into arabic and back-translated to english to ensure the semantic equivalence of the arabic version.10 in order to remove any ambiguous items, the questionnaire was pilot-tested on 10 medical students and five of the participants of the full study. the reliability of all items in the second and third domains of the questionnaire was assessed using cronbach’s alpha (0.944). data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp, armonk, new york, usa). continuous variables were presented as means and standard deviations or medians and ranges, as appropriate. categorical variables were presented as frequencies and percentages. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #1178). results a total of 100 subjects agreed to participate in the study, with the remaining 74 declining due to time limitations or an inability to read and write (response rate: 57.5%). the mean age of the participants was 36 years (range: 17–71 years old) and the male-tofemale ratio was approximately equal (1:1.2). most of knowledge and attitudes towards clinical trial participation in oman a cross-sectional study e56 | squ medical journal, february 2018, volume 18, issue 1 the participants were patients (70%) and resided in muscat or ad dakhiliyah (27% and 20%, respectively). their travel time varied, with 38% travelling less than one hour and 35% travelling more than two hours to arrive at squh. the majority of patients had been educated to a high school level or higher (81%). approximately half of the participants had a monthly income of less than 1,000 omani riyals per month (51%). the majority of the participants suffered from a chronic condition (54%), most of which were related to the medical subspecialties of oncology (51%) or haematology (34%) [table 1]. in terms of their knowledge regarding clinical trials, only 31.3% and 31.6% of the participants knew what clinical trials were and why they were conducted. very few of the participants had previously participated in clinical trials (6.5%). just under a third of the patients knew that clinical trials were experiments on human subjects (32.6%). few of the participants thought that there was risk involved in clinical trial participation (16.3%). of the participants, 66.3% knew that clinical trials were ethical, 70.5% were aware that clinical trials were beneficial to society and 71.4% knew that clinical trials were critical for the advancement of medical care and knowledge. most of the participants (66.7%) thought that the omani government should allow pharmaceutical companies to conduct clinical trials, with 62.3% aware that such companies would require governmental approval prior to conducting a trial. many participants (33.7%) had found out about clinical trials from their medical care professionals, whereas 32.9% had read about them on the internet. mass media and other patients were the least frequent sources of information about clinical trials (31% and 14.9% of participants, respectively) [table 2]. with regards to their attitudes towards and willingness to participate in clinical trials, 59.2% of the participants either agreed or strongly agreed that they would participate in clinical trials related to their table 1: sociodemographic characteristics of patients and relatives visiting the sultan qaboos university hospital, muscat, oman (n = 100) characteristic percentage* gender male 46 female 54 type of participant patient 70 patient’s relative 28 non-relative escort 1 travel time in hours <1 38 1–2 26 >2 35 place of residence muscat 27 al batinah north 17 al batinah south 11 al sharqiya 8 ad dakhiliyah 20 dhofar 6 al wusta 1 al dhahirah 9 education level elementary school 6 secondary school 9 high school 35 diploma 23 bachelor’s degree 21 master’s degree 2 marital status single 28 married 62 widowed /divorced 8 monthly income in omr <1,000 51 1,000–2,000 21 >2,000 7 nature of illness acute 21 chronic 54 none 18 main medical specialty involved none 6 cardiology 1 dermatology 2 gastrointestinal 1 internal medicine 2 haematology 34 ent 1 psychiatry 1 oncology 51 omr = omani riyals; ent = ear, nose and throat. *percentages do not add up to 100% due to missing data. hussain al-lawati, khalid al-baimani, mahra al-zadjali, nasra al-obaidani, ziyana al-kiyumi and murtadha k. al-khabori clinical and basic research | e57 condition. most patients either agreed or strongly agreed that they would not mind being contacted regarding clinical trials by phone (57.3%) or e-mail (42.7%). of the participants, 38.5% either agreed or strongly agreed that they did not mind the randomised nature of allocation to a study group in a clinical trial, while 33.4% of the cohort either agreed or strongly agreed that they did not mind participating in a blinded trial. however, 32.1% were unsure if they would participate in a clinical trial if the treatment involved had potential side-effects. nevertheless, the majority of the participants either agreed or strongly agreed that they would want to be informed of the results of the clinical trial in which they had participated (84.6%). the vast majority of participants either agreed or strongly agreed that they expected to be informed by their doctors about ongoing clinical trials related to their medical condition (89.7%). moreover, most participants agreed or strongly agreed that clinical trials conducted at squh would likely follow both safety (86.1%) and privacy (79.5%) precautions. however, 47.7% of participants either agreed or strongly agreed that clinical trials sponsored by pharmaceutical compa nies were likely to result in a conflict of interest. more than half of participants either agreed or strongly agreed that most current treatments in medicine were based on evidence from clinical trials (53.5%). just over half of the participants indicated that they would involve a family member in their decision as to whether to participate in a clinical trial (50.6%). factors which positively influenced willingness to participate in a clinical trial included recommendations by a treating physician (61.2%) and the ineffectiveness of current therapy (59.3%). just under half of the participants indicated that a negative perception of clinical trials would not alter their decision to participate in a trial (49.4%). similarly, 44.1% either agreed or strongly agreed that the unconfirmed nature of treatment in a clinical trial would not affect their decision to participate. lastly, 14% strongly agreed and 45.3% agreed that they would be more likely to participate in clinical trials focusing on complementary or alternative medicine [table 3]. discussion the results of the current study revealed that most omani patients and their relatives had a low level of knowledge about clinical trials. this finding was to be expected, given the generally low number of clinical trials conducted in oman.5 other countries in the region have reported a low level of knowledge and awareness concerning clinical trials in similar populations.11 a study from india also reported that only 40.2% of participants knew what clinical trials were.12 local awareness of clinical trials and the rationale for such research can be improved, potentially leading to higher rates of participation. to this end, patients in oman should be kept informed of ongoing clinical trials, perhaps via posted advertisements in local hospitals and on social media platforms. in the current study, a very low proportion of the surveyed patients and relatives had previously been enrolled in clinical trials. nair et al. observed that only 0.5% of all clinical trials conducted worldwide included participants from the middle east and north africa.13 this finding is discouraging and may reflect various barriers to clinical trial participation in the region, such as poor infrastructure, low expertise, lack of funding and patient reluctance. nevertheless, the majority of participants in the present study believed that clinical trials were beneficial to society; this is consistent with findings from balasubramanian et al.’s study, in table 2: knowledge of clinical trials among patients and relatives visiting the sultan qaboos university hospital, muscat, oman (n = 100) questionnaire item percentage yes no do you know what clinical trials are? 31.3 68.7 do you know why clinical trials are conducted? 31.6 68.4 have you participated in clinical trials before? 6.5 93.5 is a clinical trial an experiment on humans? 32.6 67.4 do you think that clinical trials benefit society? 70.5 29.5 are clinical trials ethical to conduct? 66.3 33.7 is there risk involved in participating in a clinical trial? 16.3 83.7 is it necessary for a company to get approval from the government to conduct a clinical trial? 62.3 37.7 are clinical trials critical to advance medicine and improve therapy effectiveness? 71.4 28.6 should pharmaceutical companies be allowed to conduct clinical trials in oman? 66.7 33.3 did you find out about clinical trials from physicians or medical professionals? 33.7 66.3 did you find out about clinical trials from mass media? 31 69 did you find out about clinical trials from the internet? 32.9 67.1 did you find out about clinical trials from other patients? 14.9 85.1 knowledge and attitudes towards clinical trial participation in oman a cross-sectional study e58 | squ medical journal, february 2018, volume 18, issue 1 table 3: attitude towards clinical trials among patients and relatives visiting the sultan qaboos university hospital, muscat, oman (n = 100) item percentage strongly agree agree neutral disagree strongly disagree i would be interested in participating in clinical trials related to my medical condition 18.1 41.1 32.5 7.2 1.2 i find it appropriate for an investigator to contact me by phone to inform me of a research project 6.1 51.2 14.6 26.8 1.2 i find it appropriate for an investigator to contact me by e-mail to inform me of a research project 4.9 37.8 24.4 28 4.9 i find it acceptable to be allocated in a random fashion to receive either treatment or a placebo during a clinical trial 9.6 28.9 21.7 26.5 13.3 i find it acceptable to participate in a blinded clinical trial, knowing that both the participants and physicians often have no knowledge of which treatment arm the patient will be allocated to 2.5 30.9 29.6 25.9 11.1 even if i was told that the treatment prescribed to me in a clinical trial had potential side-effects, i would still be interested in participating 8.3 27.4 32.1 22.6 9.5 it is important for me to be informed by the investigator about the results of the clinical trial in which i participated 31 53.6 11.9 2.4 1.2 i expect my treating physician to inform me about current clinical trials involving medical conditions related to me 41.4 48.3 5.7 3.4 1.1 all reasonable precautions to ensure my safety are likely to be taken in clinical trials conducted at squh 32.6 53.5 10.5 2.3 1.2 all reasonable precautions to protect my privacy are likely to be taken in clinical trials conducted at squh 36.1 43.4 15.7 3.6 1.2 clinical trials sponsored by pharmaceutical companies are likely to have conflicts of interest 16.7 31 42.9 4.8 4.8 most current medical treatments are based on evidence from clinical trials 7 46.5 36 8.1 2.3 i would not involve anyone else in my decision to participate in a clinical trial 4.8 27.7 30.1 27.7 9.6 i would ask my children/spouse/parents before i participated in a clinical trial 9.6 41 22.9 18.1 8.4 the availability of a new medical treatment not available outside of a clinical trial would influence my decision to participate in the trial 12.5 32.5 36.3 15 3.8 the idea of contributing to medical knowledge would influence my decision to participate in a clinical trial 8.4 37.3 32.5 18.1 3.6 i would participate in a clinical trial if my doctor recommended it to me 18.8 42.4 24.7 12.9 1.2 i would be more likely to participate in clinical trials if i was not benefitting from my current treatment 15.1 44.2 23.3 14 3.5 a negative perception of clinical trials would not influence my decision to participate in a trial 9.2 40.2 33.3 14.9 2.3 the unconfirmed nature of treatment would not influence my decision to participate in a clinical trial 4.8 39.3 32.1 20.2 3.6 the thought of having to come to hospital frequently would not influence my decision to participate in a clinical trial 8.2 37.6 30.6 18.8 4.7 preferring standard treatment would not influence my decision to participate in a clinical trial 10.6 38.8 37.6 11.8 1.2 i would be more likely to participate in clinical trials if they focused on complementary/alternative medicine 14 45.3 25.6 12.8 2.3 squh = sultan qaboos university hospital. hussain al-lawati, khalid al-baimani, mahra al-zadjali, nasra al-obaidani, ziyana al-kiyumi and murtadha k. al-khabori clinical and basic research | e59 which the same sentiment was echoed by 54.5% of indian patients.12 not unexpectedly, most participants agreed that clinical trials were ethical and that clinical trials conducted at squh (i.e. in a university hospital setting) would conform to necessary safety and privacy standards. a recent study from saudi arabia found that 48.7% of respondents believed clinical trials were conducted in an ethical manner.11 a low percentage of participants in the current study believed that there was risk involved in participating in clinical trials. in comparison, 48.71% of indian participants in balasubramanian et al.’s study considered clinical trial participation to be risky.12 the reason for this difference in results is unclear, especially as the level of knowledge of clinical trials in both cohorts was poor. despite the potential risk of adverse events or side-effects, over one-third of the omani participants in the present study reported that they would still be inclined to participate in a clinical trial. this finding could potentially be explained by expectations that clinical trial protocols would undergo rigorous review by various regulatory committees in order to ensure the participants’ safety. for the majority of patients worldwide, their main point of reference regarding medical treatments is their treating or family physician. in the present study, most participants were made aware of clinical trials by their treating physicians; moreover, the vast majority expected to be informed of relevant ongoing clinical trials by their physician and to be updated regarding the results of any clinical trials in which they had participated. a korean study reported that 52% of oncology patients were informed of available clinical trials by their treating physicians and that 26.8% were willing to participate in clinical trials if such participation was recommended by their treating physician.14 in a study from the mayo clinic in the usa, most participants indicated that they expected their treating physician to inform them about ongoing clinical trials as a treatment option and that they would not be willing to participate in future clinical trials if the results of previous trials had not been disclosed to them.6 as is to be expected given the local culture, approximately half of the omani participants in the present study were in favour of involving their family members when making decisions regarding their participation in clinical trials. in contrast, lee et al. reported that only 24.1% of korean participants would involve their family members before agreeing to enrol in a clinical trial.14 in the current study, the availability of a new treatment not available outside of a clinical trial was a strong influencing factor when it came to choosing to enrol in a clinical trial. this is generally considered to be one of the major benefits of clinical trial enrolment. as reported by madsen et al., access to a new drug or diagnostic tool and a desire for enhanced monitoring are major influencing factors for clinical trial participation.7 this study had a number of strengths. to the best of the authors’ knowledge, this is the first survey detailing the knowledge of and attitudes towards clinical trials among a cohort of omani patients and relatives. moreover, although the sample was small, the findings of this study could be used as a basis to further develop the questionnaire and to carry out more extensive surveys on this topic. finally, as the study sample included participants from both haematology and oncology outpatient departments, the responses are likely homogeneous. nevertheless, the results of this study should be interpreted in the light of certain limitations. according to previous research, only 6% of eligible participants choose to enrol in clinical trials.15 in the researchers’ personal experience, the majority of omani patients who are invited to enrol in an actual clinical trial refuse to participate. as such, the favourable responses observed in the current study are likely attributable to response bias due to the social desirability of a positive response, especially considering that the survey instrument was distributed by members of the patients’ treating team. moreover, the items included in the questionnaire could have been further tailored to the participants as, for example, knowledge of terms like randomisation and study blinding may not have been clearly understood. conclusion the current study found that omani patients and their relatives had low level of knowledge of clinical trials. however, there was a moderate level of interest in participating in such trials, especially when partic ipation was suggested by a treating physician. these findings should therefore be considered when developing initiatives to encourage clinical trial enrolment in oman. further research on omani patients’ and relatives’ attitudes towards clinical trial participation is recommended. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. knowledge and attitudes towards clinical trial participation in oman a cross-sectional study e60 | squ medical journal, february 2018, volume 18, issue 1 references 1. friedman lm, furberg cd, demets d. fundamentals of clinical trials, 3rd ed. new york, usa: springer, 1998. pp. 1–15. 2. srivastava a, serban m, werner s, schwartz ba, kessler cm; wonders study investigators. efficacy and safety of a vwf/ fviii concentrate (wilate®) in inherited von willebrand disease patients undergoing surgical procedures. haemophilia 2017; 23:264–72. doi: 10.1111/hae.13106. 3. motaweih ak, usova e, hussain w, dello z, schmidt b, petri t. effectiveness of combination therapy with nifedipine gits: a prospective, 12-week observational study (adadose). bmc cardiovasc disord 2015; 15:35. doi: 10.1186/s12872-015-0037-x. 4. takeda m, yamanaka t, seto t, hayashi h, azuma k, okada m, et al. bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (west japan oncology group 5910l): an open-label, randomized, phase 2 trial. cancer 2016; 122:1050–9. doi: 10.1002/cncr.29893. 5. u.s. national library of medicine. clinical trials search results: oman. from: clinicaltrials.gov/ct2/results?cond=&te rm=&cntr y1=me%3aom&state1=&re crs=%-%tabletop accessed: nov 2017. 6. sood a, prasad k, chhatwani l, shinozaki e, cha ss, loehrer ll, et al. patients’ attitudes and preferences about participation and recruitment strategies in clinical trials. mayo clin proc 2009; 84:243–7. doi: 10.1016/s0025-6196(11) 61141-5. 7. madsen sm, mirza mr, holm s, hilsted kl, kampmann k, riis p. attitudes towards clinical research amongst participants and nonparticipants. j intern med 2002; 251:156–68. doi: 10.10 46/j.1365-2796.2002.00949.x. 8. bevan eg, chee lc, mcghee sm, mcinnes gt. patients’ attitudes to participation in clinical trials. brit j clin pharmacol 1993; 35:204–7. doi: 10.1111/j.1365-2125.1993.tb05687.x. 9. dean ag, sullivan km, soe mm. openepi: open source epidemiologic statistics for public health. from: www.openepi. com/menu/oe_menu.htm accessed: nov 2017. 10. tsang s, royse cf, terkawi as. guidelines for developing, translating, and validating a questionnaire in perioperative and pain medicine. saudi j anaesth 2017; 11:s80–9. doi: 10.4103/ sja.sja_203_17. 11. al-tannir ma, el-bakri n, abu-shaheen ak. knowledge, atti tudes and perceptions of saudis towards participating in clinical trials. plos one 2016; 11:e0143893. doi: 10.1371/journal. pone.0143893. 12. balasubramanian j, rukmani a, kumar rr, purushothaman k. a questionnaire based survey on awareness of clinical trials among general population. int j allied med sci clin res 2013; 1:8–17. 13. nair sc, ibrahim h, celentano dd. clinical trials in the middle east and north africa (mena) region: grandstanding or grandeur? contemp clin trials 2013; 36:704–10. doi: 10.1016/j. cct.2013.05.009. 14. lee sj, park lc, lee j, kim s, choi mk, hong jy, et al. unique perception of clinical trials by korean cancer patients. bmc cancer 2012; 12:594. doi: 10.1186/1471-2407-12-594. 15. bansal n. the opportunities and challenges in conducting clinical trials globally. clin res regul aff 2012; 29:9–14. doi: 10.31 09/10601333.2011.647034. https://doi.org/10.1111/hae.13106 https://doi.org/10.1186/s12872-015-0037-x https://doi.org/10.1002/cncr.29893 https://doi.org/10.1016/s0025-6196%2811%2961141-5 https://doi.org/10.1016/s0025-6196%2811%2961141-5 https://doi.org/10.1046/j.1365-2796.2002.00949.x https://doi.org/10.1046/j.1365-2796.2002.00949.x https://doi.org/10.1111/j.1365-2125.1993.tb05687.x https://doi.org/10.4103/sja.sja_203_17 https://doi.org/10.4103/sja.sja_203_17 https://doi.org/10.1371/journal.pone.0143893 https://doi.org/10.1371/journal.pone.0143893 https://doi.org/10.1016/j.cct.2013.05.009 https://doi.org/10.1016/j.cct.2013.05.009 https://doi.org/10.1186/1471-2407-12-594 https://doi.org/10.3109/10601333.2011.647034 https://doi.org/10.3109/10601333.2011.647034 1departmemt of family medicine & public health, sultan qaboos university hospital, muscat, oman; 2department of dermatology & skin science, university of british columbia, vancouver, british columbia, canada; 3division of dermatology, faculty of medicine, mcgill university, montreal, quebec, canada *corresponding author e-mails: a.alkhalili@hotmail.com and alkhalili2014@gmail.com انتباذ بطاين رمحي سري عايدة عبد اهلل اخلليلية و روبن بيليك umbilical endometriosis *ayida a. al-khalili1,2 and robin billick3 a 43-year-old nulliparous woman presentedto a dermatology clinic in montreal, quebec, canada, in 2015 with swelling and pain in the umbilical area which worsened and occasionally bled during menstruation. the onset of these symptoms coincided with the discontinuation of oral contraceptive pills, which she had been taking for the last seven years. the patient complained of dysmenorrhoea and had no history of abdominal or pelvic surgeries. upon clinical examination, multiple ill-defined bluish erythematous papules were noted in and surrounding the umbilicus [figure 1]. a skin biopsy showed glandular proliferation with hemosiderin deposition and myometrial stroma, consistent with a diagnosis of endometriosis [figure 2]. a gynaecological evaluation revealed an ovarian cyst. she was treated with progestin which relieved the dysmenorrhoea and resulted in the regression of both the ovarian cyst and her umbilical symptoms. as most of the remaining umbilical nodules were small and remained asymptomatic, the patient did not wish to have them surgically removed. comment endometriosis refers to the presence of endometrial tissue outside of the uterine cavity. extrapelvic or extragenital endometriosis has been described in several anatomical locations, including the skin, brain, lungs, gastrointestinal tract, urinary system and musculature.1 while umbilical endometriosis—also known as villar’s nodule—is a rare site for endometriosis, it is the most common form of cutaneous endometriosis.2 there are many theories to explain the pathophysiology of umbilical endometriosis, including migration via the vascular or lymphatic vessels, metaplastic transformation and iatrogenic implants.2 umbilical endometriosis is classified as primary if it occurs spontaneously or secondary if it results from iatrogenically-seeded endometrial implants following various surgical procedures, with the latter being more common.2,3 umbilical endometriosis constitutes 3.2–40% of all extragenital endometrioses.2 symptoms include umbilical masses with swelling and pain interesting medical image sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e371–372, epub. 10 oct 17 submitted 19 mar 17 revision req. 23 apr 17; revision recd. 27 apr 17 accepted 25 may 17 figure 1: multiple erythematous papules on the lower umbilical area of a 43-year-old nulliparous woman. doi: 10.18295/squmj.2017.17.03.023 umbilical endometriosis e372 | squ medical journal, august 2017, volume 17, issue 3 to each patient and will depend on the severity of symptoms and the coexistence of pelvic endometriosis.4 suggested therapeutic options include various surgical procedures and treatment with hormonal therapy or danazol.2,4,5 references 1. davis ac, goldberg jm. extrapelvic endometriosis. semin reprod med 2017; 35:98–101. doi: 10.1055/s-0036-1597122. 2. victory r, diamond mp, johns da. villar’s nodule: a case report and systematic literature review of endometriosis externa of the umbilicus. j minim invasive gynecol 2007; 14:23–32. doi: 10.1016/j.jmig.2006.07.014. 3. calagna g, perino a, chianetta d, vinti d, triolo mm, rimi c, et al. primary umbilical endometrioma: analyzing the pathogenesis of endometriosis from an unusual localization. taiwan j obstet gynecol 2015; 54:306–12. doi: 10.1016/j. tjog.2014.03.011. 4. mechsner s, bartley j, infanger m, loddenkemper c, herbel j, ebert ad. clinical management and immunohistochemical analysis of umbilical endometriosis. arch gynecol obstet 2009; 280:235–42. doi: 10.1007/s00404-008-0900-4. 5. fancellu a, pinna a, manca a, capobianco g, porcu a. primary umbilical endometriosis: case report and discussion on management options. int j surg case rep 2013; 4:1145–8. doi: 10.1016/j.ijscr.2013.11.001. during menstruation and, to a lesser extent, bleeding.2 the differential diagnosis of the condition includes both benign and malignant tumours, such as primary and metastatic neoplasms, polyps, granulomas and keloids.1 however, the risk of malignant transformation is minimal.3 currently, there is as yet no consensus on the optimal management strategy for umbilical endometriosis; therefore, treatment should be personalised figure 2: haematoxylin and eosin stain at x40 magnification showing glandular proliferation (black arrows) with hemosiderin deposition (white arrow) and myometrial stroma (arrowhead). these features were deemed indicative of umbilical endometriosis. https://doi.org/10.1055/s-0036-1597122 https://doi.org/10.1016/j.jmig.2006.07.014 https://doi.org/10.1016/j.tjog.2014.03.011 https://doi.org/10.1016/j.tjog.2014.03.011 https://doi.org/10.1007/s00404-008-0900-4 https://doi.org/10.1016/j.ijscr.2013.11.001 s truma ovarii are mature ovarian teratomas derived from one type of germ cell; these monodermal variants account for >5% of mature teratomas and 0.3–1% of ovarian tumours.1 these types of tumours predominantly consist of thyroid tissue (>50% of the overall ovarian mass) and the usual age of presentation is during the fifth and sixth decades of life.1 the reported rate of malignant transformation is 5–37%, in which the struma ovarii transforms into a thyroid-type carcinoma.2 the usual presentation of struma ovarii is as an abdomino pelvic mass, although it may present with hyperthyroidism in approximately 5% of cases.3 radio logically, a benign ovarian mass presenting with ascites and raised cancer antigen (ca)-125 levels can be misdiagnosed as a malignant ovarian tumour.2,4,5 in such cases, a correct intraoperative diagnosis can prevent extensive surgery. case report a 55-year-old female presented to the lok nayak jai prakash narayan hospital, new delhi, india, in 2016 with progressively increasing abdominal discomfort, 1department of pathology, maulana azad medical college, new delhi, india; 2department of obstetrics & gynecology, lok nayak jai prakash narayan hospital, new delhi, delhi, india *corresponding author e–mail: surekha134@yahoo.com سرتوما أوفاري مع متالزمة شبيهة-ميغس املصحوبة بأرتفاع مستوى مستضد السرطان 125-يف املشابه لسرطان املبيض تقرير حالة ومراجعة األدبيات �سوريخا ياداف، رينا تومار، نيدهي فريما، نيتا خورانا، ريوا تريباثي abstract: the monodermal teratoma struma ovarii is a rare ovarian tumour; however, struma ovarii presenting with pseudo-meigs’ syndrome and raised cancer antigen (ca)-125 levels is even rarer. in elderly patients, this presentation can potentially lead to a misdiagnosis of a malignant ovarian carcinoma, resulting in unnecessary extensive surgery. we report a 55-year-old female who presented to the lok nayak jai prakash narayan hospital, new delhi, india, in 2016 with progressive abdominal discomfort, fatigue and abdominal distention. clinical and radiological features were indicative of a malignant ovarian tumour and ascites. serum ca-125 levels were elevated at 258 u/ml. a left-sided salpingo-oophorectomy was performed, after which the serum ca-125 levels normalised. there was no evidence of recurrence at a six-month follow-up. a frozen section procedure confirmed the diagnosis of a struma ovarii. this rare condition should be considered as a differential diagnosis in patients presenting with ovarian masses, ascites and raised ca-125 levels. keywords: ovarian cancers; struma ovarii; meigs’ syndrome; carcinoma; ascites; frozen section; case report; india. ب�سيودو-ميغ�س متالزمة مع وجوده ولكن النادرة املبي�س اأورام من اأوفاري �سرتوما الطبقة اأحادي امل�سخي الورم يعترب امللخ�ص: اإىل العر�س هذا يوؤدي اأن املمكن من امل�سنني، املر�سى يف ندرة. اكرث امل�سل 125-يف ال�رشطان م�ست�سد م�ستوى باأرتفاع امل�سحوبة ت�سخي�س خاطئ ل�رشطان املبي�س اخلبيث مما قد يوؤدى اإىل جراحة وا�سعة ال لزوم لها. هذا تقرير حالة عن اأنثى تبلغ من العمر 55 عاما قدمت اإىل م�ست�سفى لوك ناياق جاي براكا�س نارايان، نيودلهي، الهند، يف عام 2016 باأعرا�س عدم الراحة واالأمل التدريجي يف البطن، وارتفاع اال�ست�سقاء، مع املبي�س يف خبيث ورم وجود على دالئل واالإ�سعاعية ال�رشيرية اخل�سائ�س واأظهرت البطن. وانتفاخ واالأرهاق م�ستويات امل�ست�سد كا 125-يف امل�سل اإىل u/ml 258 مل. مت اإجراء عملية ا�ستئ�سال للمبي�س واأنابيب فالوب على اجلانب االأي�رش، وبعد ذلك عادت م�ستويات كا 125-يف امل�سل اإىل قيمها الطبيعية. وبعد �ستة اأ�سهر من املتابعة مل يوجد هناك دليل على اأرتداد اأو عودة املر�س. واأكد فح�س العينة املجمدة ت�سخي�س �سرتوما اأوفاري. ينبغي اأن توؤخذ هذه احلالة النادرة يف االأعتبار يف الت�سخي�س التفريقي يف املر�سى الذين يعانون من اأورام املبي�س واال�ست�سقاء واأرتفاع م�ستويات امل�ست�سد كا 125-يف امل�سل. الكلمات املفتاحية: �رشطان املبي�س؛ �سرتوما اأوفاري؛ متالزمة ميغ�س؛ �رشطان؛ ا�ست�سقاء؛ العينة املجمدة؛ تقريرحالة؛ الهند. struma ovarii with pseudo-meigs’ syndrome and raised cancer antigen-125 levels masquerading as an ovarian carcinoma case report and literature review surekha yadav,1 reena tomar,1 *nidhi verma,1 nita khurana,1 rewa triathi2 case report sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e229–233, epub. 20 jun 17 submitted 26 oct 16 revision req. 1 dec 16; revision recd. 21 jan 17 accepted 16 feb 17 doi: 10.18295/squmj.2016.17.02.017 struma ovarii with pseudo-meigs’ syndrome and raised cancer antigen-125 levels masquerading as an ovarian carcinoma case report and literature review e230 | squ medical journal, may 2017, volume 17, issue 2 fatigue and abdominal distention for the preceding five months. she had been postmenopausal for the last five years. she had three children, with her last childbirth having taken place 28 years previously. her medical, surgical and family history was normal. a pelvic examination revealed a left-sided pelvic mass of 6 x 5 x 5 cm in which the uterus moved with the mass. her ca-125 level was 258 u/ml (normal value: <35 u/ml). all haematological investigation results were within normal range. a chest x-ray was unremarkable, with no indications of pleural effusion. ultrasonography revealed a left-sided solid cystic adnexal mass measuring 6 x 5 x 3.5 cm. the right-sided adnexa, uterus and cervix appeared normal. there was 680 ml of free fluid in the recto-uterine pouch. computed tomography of the pelvis revealed a left-sided heterogeneously enhancing solid-cystic pelvic mass measuring 6.2 x 5 x 4 cm [figure 1]. the left ovary was not visualised separately. there was no evidence of organomegaly or lymphadenopathy. overall, the radiological findings were suggestive of a malignant mass. a total of 500 ml of peritoneal serous fluid was removed via abdominal paracentesis. cytological examination of this fluid indicated only reactive mesothelial cells with a few leukocytes, with no malignant cells identified. an exploratory laparotomy was performed. the left-sided adnexal mass measured 6 x 5 x 4.5 cm and was solid-cystic, with a smooth external surface. the uterus and cervix were normal and there was no evidence of intraperitoneal spread to the omentum, liver or appendix. the patient subsequently underwent a left-sided salpingo-oophorectomy and the excised specimen was sent for frozen analysis to rule out malignancy. during the postoperative period, the results of a thyroid function test were normal. the patient recovered well after surgery and there was no evidence of any re-accumulation of ascitic fluid. by the eighth postoperative day, her postoperative ca-125 levels had normalised. at a six-month follow-up, there were no signs of recurrence of the ovarian mass. on gross examination, the excised ovarian mass measured 6 x 5 x 4 cm and there was no evidence of haemorrhage, bone, cartilage or hair. the external surface was smooth and glistening white. the cut surface revealed a solid-cystic mass which had replaced the entire ovarian parenchyma [figure 2]. an omental biopsy and peritoneal washing was performed on the excised specimen, with benign results. the scrape smears showed cuboidal cells forming thyroid follicles and monolayered sheets in a thin colloid background [figure 3a]. the frozen section revealed that the specimen was composed figure 1: abdominal computed tomography of a 55-year-old female with progressive abdominal discomfort and abdominal distention showing a left adnexal mass (arrow). figure 3: a: toluidine blue scrape smear at x20 magnification showing thyroid follicles with colloid in the background. b: haematoxylin and eosin (h&e) stained frozen section at x40 magnification showing variable-sized colloid-filled thyroid follicles. c: h&e stained frozen section at x20 magnification showing various thyroid follicles. figure 2: photograph showing an encapsulated left ovarian solid-cystic mass (arrow), which had replaced the entire normal ovarian parenchyma. surekha yadav, reena tomar, nidhi verma, nita khurana and rewa triathi case report | e231 specificity in the diagnosis of epithelial ovarian cancers since it is also raised in other malignancies, a few benign conditions and certain physiological states.8 the mechanism behind raised ca-125 levels in cases of meigs’ and pseudo-meigs’ syndromes is still not understood, although mui et al. have postulated that it is the result of free fluid irritation leading to inflammation of the pleural and peritoneal surfaces.9 in the current case, features of a complex solid-cystic pelvic mass with ascites and raised serum ca-125 levels in a middle-aged woman were initially suggestive of a pelvic malignancy. however, the ca-125 levels normalised on the eighth postoperative day without any adjuvant therapy. postoperatively, a thyroid hormone profile was also normal. unfortunately, a preoperative thyroid hormone profile was not performed as the patient was asymptomatic and a struma ovarii was not considered during the differential diagnosis. in an extensive search of the literature, obeidat et al. presented 26 struma ovarii cases associated with ascites and raised ca-125 levels.10 all of these patients were initially thought to have malignant tumours; in addition, in all cases, the ascites disappeared completely and ca-125 levels returned to normal after the removal of the tumour. most of the diagnosed patients were in their fifth decade or older, with the exception of one patient who was 31 years old.11 the tumour sizes ranged between 4–23 cm in the greatest dimension, with an average size of 12 cm.10 in all cases, the volume of ascitic fluid was over 1 l, except for five cases.5,12–15 the most common presenting symptom was abdominal distension.2–4,9,10,12,13,15–22 pleural effusion was noted in 15 cases.10 in one case, the struma ovarii was an incidental finding.14 no relationship was reported between pleural effusion and the volume of ascites.10 the mean follow-up period was approximately 8 months, ranging from 1–36 months.4,5,9–11,15,17,18,20,22–25 most cases were treated via total abdominal hysterectomy and bilateral of colloid-filled follicles of various sizes, resembling thyroid follicles [figures 3b and c]. based on analysis of the scrape smears and frozen section, a provisional diagnosis of struma ovarii was made. the remaining specimen underwent routine histopathological examination. microscopically, the tumour was lobular and composed of central normal thyroid parenchymal tissue with peripherally compressed normal ovarian tissue [figure 4]. the tumour cells were cuboidal to the low columnar cells with eosinophilic cytoplasm and minimal cytological atypia. the intervening stroma was oedematous. there was no evidence of papillary carcinoma or mitotic figures. these histological features confirmed the diagnosis of a struma ovarii. discussion meigs’ syndrome is a rare disorder involving the co-occurrence of a fibroma or fibroma-like tumour with ascites and hydrothorax, in which the ascites and hydrothorax resolve following removal of the tumour; in contrast, pseudo-meigs’ syndrome consists of ascites, pleural effusion with serous or serosanguinous fluid and tumours other than fibromas.6,7 in their report of a case of pseudo-meigs’ syndrome due to a uterine leiomyoma, amant et al. suggested various mechanisms which might cause ascites in such cases, including lymphatic obstruction by the tumour, irritation of the peritoneum by the tumour, the release of toxins and inflammatory products, hypoalbuminemia and decreased venous and lymphatic drainage.7 in addition, the use of a dye test was advocated to determine the exact cause of pleural effusion. in their case, amant et al. noted that the pleural effusion originated from the mechanical transfer of ascitic fluid through a diaphragmatic opening.7 however, the aetiology of ascites and pleural effusion in patients with struma ovarii is still unclear. although it is usually a serum tumour marker of great diagnostic importance, ca-125 has poor figure 4: a: haematoxylin and eosin (h&e) stained paraffin section at x10 magnification showing colloid-filled thyroid follicles (white arrow) and compressed normal thyroid parenchyma at the periphery (black arrow). b: h&e stained paraffin section at x40 magnification showing normal ovarian parenchyma at the periphery (arrow) with central thyroid parenchyma. struma ovarii with pseudo-meigs’ syndrome and raised cancer antigen-125 levels masquerading as an ovarian carcinoma case report and literature review e232 | squ medical journal, may 2017, volume 17, issue 2 salpingo-oophorectomy.2–5,9,11,12,15,17–22,24,25 only three patients underwent conservative surgery.13,14,23 in the present case, the patient underwent conservative surgery in the form of a salpingo-oophorectomy, as there was no evidence of malignancy according to the frozen section analysis. all other organs were healthy-looking with no adhesions or evidence of organomegaly or lymphadenopathy. scrape smears and frozen sections are of great importance in accurately diagnosing ovarian neoplasms and planning surgical management. according to various studies, the accuracy of an intraoperative frozen section varies from 80% to >90%.26 a scrape smear of a struma ovarii shows benign follicular epithelial cells forming follicles of various sizes and a monolayered sheet in a colloidfilled background.27 a frozen section also shows the classical pattern of variable-sized follicles filled with colloid. malignant transformation in struma ovarii usually results in a thyroid-type carcinoma (i.e. a papillary and follicular carcinoma), which is ruled out via histological examination.15 the criteria for malignancy in struma ovarii are the same as those of a thyroid carcinoma.27 nuclear features such as nuclear grooves are more clearly visible on scrape smears and their absence rules out a papillary carcinoma. in addition, follicular carcinomas have capsular breaches and vascular invasion.27 conclusion intraoperative frozen section and scrape cytology analyses are of critical importance in cases of ovarian masses wherein the clinical, biochemical and radiological features indicate a malignant aetiology. in the present case, a correct diagnosis due to an intraoperative frozen section analysis prevented radical surgery in a patient with struma ovarii, pseudomeigs’ syndrome and raised ca-125 levels. this rare presentation of a struma ovarii should therefore be considered during the differential diagnosis of a patient with a suspected ovarian carcinoma. references 1. md nor nb, kusumoto t, inoue s, nakamura k, seki n, hongo a, et al. three cases of struma ovarii underwent laparoscopic surgery with definite preoperative diagnosis. acta med okayama 2013; 67:191–5. 2. loizzi v, cappuccini f, berman ml. an unusual presentation of struma ovarii mimicking a malignant process. obstet gynecol 2002; 100:1111–12. doi: 10.1097/00006250-200211001-00022. 3. guida m, mandato vd, di spiezio sardo a, di carlo c, giordano e, nappi c. coexistence of graves’ disease and benign struma ovarii in a patient with marked ascites and elevated ca-125 levels. j endocrinol invest 2005; 28:827–30. doi: 10.1007/bf03347575. 4. rim sy, kim sm, choi hs. struma ovarii showing clinical characteristics of ovarian malignancy. int j gynecol cancer 2005; 15:1156–9. doi: 10.1111/j.1525-1438.2005.00328.x. 5. leung yc, hammond ig. limitations of ca125 in the preoperative evaluation of a pelvic mass: struma ovarii and ascites. aust n z j obstet gynaecol 1993; 33:216–17. doi: 10.1111/j.1479-828x.1993.tb02400.x. 6. macciò a, madeddu c, kotsonis p, pietrangeli m, paoletti am. large twisted ovarian fibroma associated with meigs’ syndrome, abdominal pain and severe anemia treated by laparoscopic surgery. bmc surg 2014; 14:38. doi: 10.1186/1471-2482-14-38. 7. amant f, gabriel c, timmerman d and vergote i: pseudomeigs’ syndrome caused by a hydropic degenerating uterine leiomyoma with elevated ca 125. gynecol oncol 2001; 83:153–7. doi: 10.1006/gyno.2001.6251. 8. jacobs i, bast rc jr. the ca 125 tumour-associated antigen: a review of the literature. hum reprod 1989; 4:1–12. doi: 10.1093/oxfordjournals.humrep.a136832. 9. mui mp, tam kf, tam fk, ngan hy. coexistence of struma ovarii with marked ascites and elevated ca-125 levels: case report and literature review. arch gynecol obstet 2009; 279:753–7. doi: 10.1007/s00404-008-0794-1. 10. obeidat r, perren tj, saidi sa. struma ovarii associated with pseudo-meigs’ syndrome and elevated serum ca 125: a case report and literature review. gynecol obstet 2012; 2:129. doi: 10.4172/2161-0932.1000129. 11. huh jj, montz fj, bristow re. struma ovarii associated with pseudo-meigs’ syndrome and elevated serum ca 125. gynecol oncol 2002; 86:231–4. doi: 10.1006/gyno.2002.6741. 12. bokhari a, rosenfeld gs, cracchiolo b, heller ds. cystic struma ovarii presenting with ascites and an elevated ca-125 level: a case report. j reprod med 2003; 48:52–6. 13. hurlow ra, greening wp, krantz e. ascites and hydrothorax in association with struma ovarii. br j surg 1976; 63:110–12. doi: 10.1002/bjs.1800630205. 14. mancuso a, triolo o, leonardi i, de vivo a. struma ovarii: a rare benign pathology which may erroneously suggest malignancy. acta obstet gynecol scand 2001; 80:1075–6. doi: 10.1034/j.1600-0412.2001.801121.x. 15. rana v, srinivas v, bandyopadhyay s, ghosh sk, singh y. bilateral benign non functional struma ovarii with pseudomeigs’ syndrome. indian j pathol microbiol 2009; 52:94–6. doi: 10.4103/0377-4929.44978. 16. lenehan pm, colgan t, vernon cp. struma ovarii presenting with ascites: a difficult diagnostic problem. eur j gynaecol oncol 1985; 6:89–91. 17. amr ss, hassan aa. struma ovarii with pseudo-meigs’ syndrome: report of a case and review of the literature. eur j obstet gynecol reprod biol 1994; 55:205–8. doi: 10.1016/00282243(94)90039-6. 18. bethune m, quinn m, rome r. struma ovarii presenting as acute pseudo-meigs syndrome with an elevated ca 125 level. aust n z j obstet gynaecol 1996; 36:372–3. doi: 10.1111/j.1479828x.1996.tb02734.x. 19. jotkowitz mw, gee dc. unique case of massive ascites, extreme elevation of serum ca 125 tumour marker. aust n z j obstet gynaecol 1993; 33:453–4. doi: 10.1111/j.1479828x.1993.tb02139.x. https://doi.org/10.1097/00006250-200211001-00022 https://doi.org/10.1007/bf03347575 https://doi.org/10.1111/j.1525-1438.2005.00328.x https://doi.org/10.1111/j.1479-828x.1993.tb02400.x https://doi.org/10.1186/1471-2482-14-38 https://doi.org/10.1006/gyno.2001.6251 https://doi.org/10.1093/oxfordjournals.humrep.a136832 https://doi.org/10.1007/s00404-008-0794-1 https://doi.org/10.4172/2161-0932.1000129 https://doi.org/10.1006/gyno.2002.6741 https://doi.org/10.1002/bjs.1800630205 https://doi.org/10.1034/j.1600-0412.2001.801121.x https://doi.org/10.4103/0377-4929.44978 https://doi.org/10.1016/0028-2243%2894%2990039-6 https://doi.org/10.1016/0028-2243%2894%2990039-6 https://doi.org/10.1111/j.1479-828x.1996.tb02734.x https://doi.org/10.1111/j.1479-828x.1996.tb02734.x https://doi.org/10.1111/j.1479-828x.1993.tb02139.x https://doi.org/10.1111/j.1479-828x.1993.tb02139.x surekha yadav, reena tomar, nidhi verma, nita khurana and rewa triathi case report | e233 24. mitrou s, manek s, kehoe s. cystic struma ovarii presenting as pseudo-meigs’ syndrome with elevated ca125 levels: a case report and review of the literature. int j gynecol cancer 2008; 18:372–5. doi: 10.1111/j.1525-1438.2007.00998.x. 25. obeidat br, amarin zo. struma ovarii with pseudo-meigs’ syndrome and elevated ca125 levels. j obstet gynaecol 2007; 27:97–8. doi: 10.1080/01443610601076267. 26. geomini p, bremer g, kruitwagen r, mol bw. diagnostic accuracy of frozen section diagnosis of the adnexal mass: a metaanalysis. gynecol oncol 2005; 96:1–9. doi: 10.1016/j. ygyno.2004.09.042. 27. nogales f, talerman a, kubik-huch ra, tavassoli fa, devouassoux-shisheboran m. germ cell tumours. in: tavassoli fa, devilee p, eds. pathology and genetics: tumours of the breast and female genital organs. lyon, france: international agency for research on cancer press, 2003. pp. 163–75. 20. long cy, chen yh, chen sc, lee jn, su jh, hsu sc. pseudomeigs syndrome and elevated levels of tumor markers associated with benign ovarian tumors: two case reports. kaohsiung j med sci 2001; 17:582–5. 21. mantouvalos c, metallinos c, gouskos a. struma ovarii with meigs’ syndrome. aust n z j obstet gynaecol 1982; 22:101–2. doi: 10.1111/j.1479-828x.1982.tb01414.x. 22. jiang w, lu x, zhu zl, liu xs, xu cj. struma ovarii associated with pseudo-meigs’ syndrome and elevated serum ca 125: a case report and review of the literature. j ovarian res 2010; 3:18. doi: 10.1186/1757-2215-3-18. 23. loizzi v, cormio g, resta l, fattizzi n, vicino m, selvaggi l. pseudo-meigs syndrome and elevated ca125 associated with struma ovarii. gynecol oncol 2005; 97:282–4. doi: 10.1016/j. ygyno.2004.12.040. https://doi.org/10.1111/j.1525-1438.2007.00998.x https://doi.org/10.1080/01443610601076267 https://doi.org/10.1016/j.ygyno.2004.09.042 https://doi.org/10.1016/j.ygyno.2004.09.042 https://doi.org/10.1111/j.1479-828x.1982.tb01414.x https://doi.org/10.1186/1757-2215-3-18 https://doi.org/10.1016/j.ygyno.2004.12.040 https://doi.org/10.1016/j.ygyno.2004.12.040 newer, longer acting local anesthetics the future of postoperative pain management looks bright sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 157–158, epub. 22 submitted 8 feb 21 accepted 11 may 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.119 letter to the editor dear editor, multimodal analgesia after major surgery comprises opioids, non-steroidal anti-inflammatory drugs, various adjuvants such as gabapentinoids, alpha-2 agonists, magnesium sulphate and lidocaine infusion and regional anaesthesia (ra) techniques such as a central neuraxial block (e.g. continuous epidural analgesia, a peripheral nerve block or the fascial plane blocks). although single-shot ra techniques work well for a certain period of time, a continuous infusion provides opioid-sparing analgesia, facilitates early rehabilitation and prevents the incidence of chronic postoperative pain syndrome. continuous infusion is facilitated by placing catheters in the epidural space, around the targeted peripheral nerves or in the desired fascial plane for continuous local anesthetic (la) infusion. the continuous la infusion is delivered via syringe pumps or elastomeric pumps filled with the desired volume of la. this led to the development of liposomal bupivacaine marketed as exparel® (pacira pharmaceuticals inc., parsippany, new jersey, usa) which was approved by the usfood and drug administration (fda) as wound infiltration for providing postoperative analgesia. exparel® (pacira pharmaceuticals inc.) is available for injection in the form of vesicles of bupivacaine loaded in the aqueous chambers using depofoam® technology (pacira pharmaceuticals inc., san diego, california, usa). each particle in the preparation is composed of a honeycomblike structure with numerous internal aqueous chambers which contains encapsulated bupivacaine. kaye et al. comprehensively reviewed the existing literature in which liposomal bupivacaine was used as a component of multimodal analgesia and concluded that when used there was prolonged analgesia, opioid-sparing effect and was better than placebo or conventional bupivacaine infiltration.1 the success of liposomal bupivacaine encouraged the researchers to develop better liposomal products which can be used in clinical practice. this led to the development of saber®-bupivacaine (durect corp., cupertino, california, usa) and htx-011 (heron therapeutics inc., san diego, california, usa). saber®-bupivacaine (durect corp.) is sucrose acetate isobutyrate extended-release bupivacaine. the biodegradable sucrose acetate isobutyrate biolayer stores bupivacaine and thus acts as a depot. upon injecting at the incision site, there is a slow and sustained release of la at the infiltrated site.2 in a double-blinded, randomised controlled trial, hadj et al. infiltrated 5 ml of saber®-bupivacaine (durect corp.) into patients undergoing open inguinal hernia repair.3 they found that there was good pain relief, lesser analgesic consumption postoperatively and the infiltration did not interfere with wound healing. till date, this is the only randomised controlled study investigating saber®-bupivacaine (durect corp.). this drug has not been approved by the us-fda. htx-011 (heron therapeutics inc.) is an extended-release, fixed-ratio agent which consists of bupivacaine along with low-dose meloxicam, which is a cyclooxygenase-2 inhibitor, to enhance the effectiveness of infiltrated bupivacaine. this preparation is integrated into a bioerodible polymer (biochronomer). htx-011 (heron therapeutics inc.) has been approved by the us-fda in 2021.4 after injection at the wound site, there is controlled hydrolysis of the polymer leading to sustained release of both bupivacaine and meloxicam for the next 72 hours. it was earlier demonstrated that in acidic ph environments, which is present at the incision site due to inflammation, the efficacy of infiltrated bupivacaine is reduced. meloxicam thus plays a dual role in this preparation. meloxicam helps in normalising the ph at the site of injection and thus retains the efficacy of polymerised bupivacaine. in a phase ii clinical study in patients undergoing bunionectomy, ottoboni et al. recruited 237 patients to investigate htx-011 (heron therapeutics inc.).5 they found that those who received htx-011 (heron therapeutics inc.) infiltration after undergoing bunionectomy had significantly lower pain scores over the first 24, 48 and 72 hours compared to patients who received htx-002 (bupivacaine alone), htx-009 (meloxicam alone) and placebo (saline). singla et al. divided patients undergoing herniorrhaphy into two sequential cohorts. patients in both cohorts received htx-011 (heron therapeutics inc.) prior to wound closure. patients in cohort two received intraoperative dose of ketorolac in addition to htx-011 (heron therapeutics inc.) infiltration. during analysis, the authors found that more than 90% of patients did not receive any opioids as rescue analgesia for 72 hours and that the addition of ketorolac did not confer any additional benefit. all patients who received htx-011 (heron therapeutics inc.) tolerated wound infiltration well.6 https://creativecommons.org/licenses/by-nd/4.0/ newer, longer acting local anesthetics the future of postoperative pain management looks bright 158 | squ medical journal, february 20212 volume 22, issue 1 apart from htx-011, these novel formulations are still not approved by the us-fda for clinical use and are thus not marketed yet. however, on reviewing their unique mechanism of action, sustained-release properties, safety and opioid-sparing effects, once available, these products could be a game-changer in managing postoperative pain. pain physicians and perioperative physicians would be eager to add these to their armament of multimodal analgesia depending on its availability and cost-effectiveness. a u t h o r s’ c o n t r i b u t i o n both authors contributed equally to the drafting of this manuscript. both authors approved the final version of the manuscript. *abhijit nair1 and suresh seelam2 1department of anesthesiology, ibra hospital, ibra, oman; 2department of anesthesiology and intensive care, royal hospital, muscat, oman *corresponding author’s e-mail: abhijitnair95@outlook.com references 1. kaye ad, armstead-williams c, hyatali f, cox ks, kaye rj, eng lk et al. exparel for postoperative pain management: a comprehensive review. curr pain headache rep. 2020; 24:73. https://doi.org/10.1007/s11916-020-00905-4. 2. gabriel ra, swisher mw, sztain jf, furnish tj, ilfeld bm, said et. state of the art opioid-sparing strategies for post-operative pain in adult surgical patients. expert opin pharmacother 2019; 20:949–61. https://doi.org/10.1080/14656566.2019.1583743. 3. hadj a, hadj a, hadj a, rosenfeldt f, nicholson d, moodie j, et al. safety and efficacy of extended-release bupivacaine local anaesthetic in open hernia repair: a randomized controlled trial. anz j surg 2012; 82:251–7. https://doi.org/10.1111/j.1445-2197.2011.05754.x. 4. nair a, mantha ssp, suvvari p, anne p. htx-011: another game changer multimodal analgesic or an ephemeral, experimental drug! saudi j anaesth 2020; 14:419–20. https://doi.org/10.4103/sja.sja_227_20. 5. ottoboni t, quart b, pawasauskas j, dasta jf, pollak ra, viscusi er. mechanism of action of htx-011: a novel, extended-release, dualacting local anesthetic formulation for postoperative pain. reg anesth pain med. 2020; 45:117–23. https://doi.org/10.1136/rapm-2019100714. 6. singla n, winkle p, bertoch t, hu j, beaton a, redan j. opioid-free recovery after herniorrhaphy with htx-011 as the foundation of a multimodal analgesic regimen. surgery 2020; 168:915–20. https://doi.org/10.1016/j.surg.2020.06.036. https://doi.org/10.1007/s11916-020-00905-4 https://doi.org/10.1080/14656566.2019.1583743 https://doi.org/10.1111/j.1445-2197.2011.05754.x https://doi.org/10.4103/sja.sja_227_20 https://doi.org/10.1136/rapm-2019-100714. https://doi.org/10.1136/rapm-2019-100714. https://doi.org/10.1016/j.surg.2020.06.036 clinical & basic research sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e537−545, epub. 14th oct 14 submitted 28th jan 14 revisions req. 10th mar & 30th apr 14; revisions recd. 8th apr & 11th may 14 accepted 25th jun 14 املمارسة املبنية على األدلة املعرفة، التوجهات، املمارسات و العوائق اليت حتول دون املمارسة لدى املمرضني و املمرضات يف سلطنة عمان علي أمحد العموري، أمحد حسن أبو رداحة، برييت ديسوزا، رينو جيثاكريشنان، جودث أجنيلتا نورهنا، أروى عاطف عبيدات، لينا شقمان abstract: objectives: the aim of this study was to describe nurses’ practices, attitudes, knowledge/skills and perceived barriers in relation to evidence-based practice (ebp) in oman. methods: this descriptive cross-sectional study was conducted between february and november 2012. a self-reported 24-item questionnaire was used to measure ebp practices, attitudes and knowledge/skills among a convenience sample of 600 nurses working in four governmental hospitals in muscat, oman. responses were scored on a one to seven rating scale. barriers to ebp were measured on a five-point likert scale using two subscales. descriptive statistics and general linear regression were used to analyse the data. results: a total of 414 nurses were included in the study. the greatest barriers to developing ebp among nurses were insufficient time for research (3.51 ± 0.97) and insufficient resources to change practices (3.64 ± 0.99). nurses with more years of experience reported increased use of ebp (p <0.01), more positive attitudes towards ebp (p <0.001) and fewer barriers to research (p <0.01). significant positive correlations were found between years of experience and practice (r = 0.16) and attitudes (r = 0.20). nurses with a baccalaureate degree reported fewer barriers to research than those qualified at a diploma level (p <0.001). nurses who perceived more barriers to research reported less use of ebp (p <0.001), less positive attitudes towards ebp (p <0.001) and limited ebp knowledge/skills (p <0.001). conclusion: these findings provide a basis for enhancing nursing practices, knowledge and skills. continuing education for nurses and minimising barriers is crucial to increasing the use of ebp in oman. keywords: evidence-based practice; nurses; attitudes; knowledge; oman. امللخ�ص: الهدف: هدفت هذه الدرا�ضة اإىل و�ضف املمار�ضات و التوجهات و املعرفة و املهارات وعوائق التنفيذ عند املمر�ضني واملمر�ضات ونوفمرب فرباير بني ما الو�ضفية املقطعية الدرا�ضة هذه اأجريت عمان.الطريقة: �ضلطنة يف الأدلة على املبنية باملمار�ضة يتعلق فيما عام2012. مت ا�ضتخدام ا�ضتبيان ذاتي مكون من 24 بند و مق�َضم اإىل ثالثة اأق�ضام لقيا�س املمار�ضات و التوجهات و املعرفة واملهارات للممار�ضة املبنية على الأدلة. �ضجلت الإجابات على مقيا�س م�ضنف من واحد اإىل �ضبعة. ومت قيا�س العوائق للممار�ضة املبنية على الأدلة با�ضتخدام مقيا�س ليكرت من خم�س نقاط. اأجريت الدرا�ضة علي عينة من 600 ممر�س و ممر�ضة يعملون يف اأربعة م�ضت�ضفيات حكومية ما ت�ضمني مت النتائج: البيانات. لتحليل العام اخلطي والنحدار الو�ضفي الإح�ضاء ا�ضتخدام مت عمان. �ضلطنة م�ضقط، العا�ضمة يف جمموعه414ممر�س وممر�ضة يف الدرا�ضة. اأظهرت نتائج الدرا�ضة اأن اأكرب العوائق التي حتول دون تطوير املمار�ضات املبنية على الأدلة بني املمر�ضني و املمر�ضات هي عدم كفاية الوقت للبحث العلمي )0.97 ± 3.51(، وعدم كفاية املوارد لتغيري املمار�ضة التمري�ضية على القائمة املمار�ضة جتاه اإيجابية واأكرث ،)p <0.01( ممار�ضة اأكرث خربة الأكرث املمر�ضات و املمر�ضني كان .)3.64 ± 0.99( الأدلة )p <0.001(، وكانت لديهم اأقل العوائق جتاه البحث العلمي )p <0.01(. مت العثور على ارتباطات اإيجابية ذات دللة اإح�ضائية بني عدد �ضنوات اخلربة واملمار�ضة )r = 0.16(والتوجهات )r = 0.20(. املمر�ضني و املمر�ضات من حاملي �ضهادة البكالوريو�س يف التمري�س كانت لديهم عوائق اأقل جتاه البحث العلمي من نظائرهم حاملي �ضهادة الدبلوم )p <0.001(. املمر�ضني و املمر�ضات الذين معرفة p(واأقل <0.001( اإيجابية واأقل ،)p <0.001( ممار�ضة اأقل كانوا العلمي البحث جتاه العوائق من كثري هنالك اأن يعتقدون ومهارة )p <0.001( للممار�ضة املبنية على الأدلة. اخلال�صة: توفر نتائج هذه الدرا�ضة اأ�ض�س تعزيز املعرفة، واملهارات، و املمار�ضات التمري�ضية. التعليم امل�ضتمر للممر�ضني واملمر�ضات مع تقليل العوائق اأمر حا�ضم لزيادة املمار�ضة املبنية على الأدلة يف �ضلطنة عمان. مفتاح الكلمات: املمار�ضة املبنية على الأدلة؛ املمر�ضات؛ التوجهات؛ املعرفة؛ املمار�ضة؛ عمان. evidence-based practice knowledge, attitudes, practice and perceived barriers among nurses in oman *ali a. ammouri,1 ahmad a. raddaha,2 preethy dsouza,3 renu geethakrishnan,4 judith a. noronha,4 arwa a. obeidat,2 lina shakman4 advances in knowledge the results of this study show that nurses in oman view evidence-based practice (ebp) positively. however, their greatest perceived barriers to engaging in ebp were insufficient time and resources. omani nurses with more years of experience reported greater engagement in ebp, more positive attitudes towards ebp and fewer barriers to finding and reviewing research. the nurses with baccalaureate degrees reported fewer barriers to finding and reviewing research than nurses with diploma qualifications. departments of 1adult health & critical care and 4maternal & child health, 2college of nursing, sultan qaboos university, muscat, oman; 3college of nursing, manipal university, manipal, india *corresponding author e-mail: aliammouri@yahoo.com evidence-based practice knowledge, attitudes, practice and perceived barriers among nurses in oman e538 | squ medical journal, november 2014, volume 14, issue 4 evidence-based practice (ebp) has become a major focus for healthcare policymakers, practitioners and researchers.1 it has gained momentum as an approach that can influence knowledge and practice within the nursing profession.2 ebp is defined as a systematic adoption of the most current evidence to answer a clinical question, along with consideration of the practitioner’s own clinical experience and the patient’s values and preferences.3 recently, greater emphasis has been placed on ebp and it is now considered critical for promoting excellence in healthcare.4 melnyk et al. found that patient outcomes were improved by 28% when clinical care was based on evidence rather than traditional practices.3 a 2003 report from the institute of medicine in the usa emphasised that ebp is an important aspect in maintaining the quality of healthcare.5 in the last 20 years, there has been progress in implementing ebp in patient care; however, a study of nurses working at rural hospitals in the usa found that the use of ebp as a routine and integral part of patient care was inconsistent.6 a review of the literature indicates that ebp results in a more efficient use of resources, improved patient care, decreased costs and length of hospital stay, increased patient satisfaction and the elimination of unnecessary or ineffective practices.3,5,7 in contrast, previous research has shown that nursing methods are not consistently based on evidence. common drivers of nursing care and practices have traditionally included rituals, precedent (e.g. the way a certain practice has always been done) and personal opinions, at times with a lack of concern for patient values. pravikoff et al. used a descriptive, exploratory method to study 3,000 nurses’ readiness for ebp in the usa.8 the results showed that only 46% of respondents were familiar with the term ebp, while 67% obtained information from other nurses to guide their own practices. encouraging findings were recorded with regards to the nurses’ computer skills, as 83% reported that they were somewhat successful in searching the internet. however, adequate search skills using the medline or cumulative index to nursing and allied health literature (cinahl) databases were identified among only 36% and 19% of the nurses, respectively. additionally, only 36% of the respondents reported that they had access to electronic databases at their facility and 46% classified the available online resources as inadequate. similarly, roberts et al. reported that, although nurses agree with evidence-based findings, many continue to practice by tradition.9 koehn et al. studied nurses’ perceptions, attitudes and knowledge associated with ebp. their findings indicated that participants had lower scores on knowledge and skills, and moderate scores on practice and attitudes.10 the available scientific literature on nurses and ebp describes several barriers to the implementation of nursing research. in a study of 500 nurses, melnyk et al. found that while the participants realised the importance of ebp, there was a lack of knowledge regarding research information.3 paramonczyk revealed that inadequate time and knowledge were the top barriers to the implementation of research among nursing professionals in canada.11 in a study of 340 nurses and midwives (response rate: 51%), the study population stated that the complexity of statistics and a lack of time were the major barriers to research utilisation.12 however, a number of the participants reported some knowledge on the topic. other studies have indicated the role of the institution and administration as a barrier to ebp. happell et al. reported that workplace culture had a significant influence on their participants’ perception of research importance.13 in addition, valente described the lack of role models to support staff in research as the major barrier.14 in summary, although research has indicated that nursing care is not consistently based on evidence, nurses worldwide continue to have positive attitudes towards the utilisation of ebp. in general, lack of time and knowledge of research information are the major barriers to implementing ebp. strategies to promote ebp among nurses should be based on evidence and address current ebp knowledge/skills and practice of ebp as well as barriers to the adoption of ebp in general nursing practice.15 therefore, in hospitals where nurses are underutilising ebp, it is prudent to consider their characteristics and perceptions prior to developing an ebp implementation plan. in oman, several initiatives have been implemented to train health personnel working application to patient care the results of this study highlight the need for continuing education activities for nurses, including statistical analysis, research application and utilisation of the internet. this may encourage nurses to further engage in ebp in order to promote excellence in clinical practice. in addition, inexperienced nurses should be supported and led by senior nurses. through encouragement and the provision of necessary resources, newer nurses can better engage in ebp. ali a. ammouri, ahmad a. raddaha, preethy dsouza, renu geethakrishnan, judith a. noronha, arwa a. obeidat and lina shakman clinical and basic research | e539 at the ministry of health (moh) and sultan qaboos university (squ) in the use of ebp. conferences and workshops have been conducted by experts from the usa, uk and australia to train medical and nursing staff on the concepts and application of ebp. despite the rising emphasis on this form of practice, as yet nothing is known about the existing knowledge/skills and practice of ebp among nurses in oman and the barriers faced in its application within general practice. the purpose of this study, therefore, was to examine and describe the practices, attitudes, and knowledge/ skills associated with ebp, as well as the perceived barriers to ebp implementation, reported by nurses in oman. methods this descriptive, correlational, cross-sectional study was conducted between february and november 2012. self-reported questionnaires were designed to fulfill the following research objectives: (1) to determine perceptions of ebp practice, attitudes, knowledge and skills among nurses in oman; (2) to discover perceived barriers to the implementation of ebp; (3) to investigate associations between selected demographic variables (age, gender, nationality, academic qualifications, years of experience and year of last academic degree) and perceived ebp practice, attitudes, knowledge/skills and barriers, and (4) to detect associations between perceived barriers to ebp and perceived ebp practice, attitudes, and knowledge/ skills. the study was conducted in four major governmental referral hospitals in muscat, oman, including a university teaching and referral hospital (557 beds and 1,240 nurses), a referral hospital (630 beds and 1,298 nurses), a tertiary national referral hospital providing specialised services (517 beds and approximately 903 nurses) and an armed forces referral hospital providing specialised services (350 beds and approximately 400 nurses). the four hospitals were selected for this study because they provide both intensive care and coronary care (with accessible cardiac laboratories) as well as outpatient and inpatient care in the areas of clinical, medical, surgical, orthopaedic, emergency and open heart surgical medicine. in addition, the four hospitals all provide specialised healthcare for patients referred from other hospitals within oman. all four hospitals are also designated teaching hospitals, using electronic patient information systems and with internetconnected computers in the clinical units. due to the utilisation of electronic computer-based patient record systems in all hospitals, all of the nurses were considered to be familiar with and able to use computers. as these hospitals are adequately staffed and offer specialised nursing care, they provided the most appropriate setting from which to recruit an adequate number of nurses to participate in this study. the majority of nurses employed in these hospitals have a baccalaureate or diploma in nursing with specialised experience. all registered nurses working in the hospitals were invited to participate in the study. a total of 600 questionnaires were distributed to nurses in the four hospitals during the study period. to avoid a selection bias, a convenience sample of approximately 150 nurses were invited from each hospital. nurses working on all three shifts in the participating hospitals were invited to participate. the researchers provided potential participants with detailed verbal information, including a brief description of the study’s purpose and instructions on how to complete the questionnaire. a total of 414 participants responded, resulting in a response rate of 69%. a power analysis based on cohen’s power table using regression analysis with six independent variables was conducted. this analysis calculated that a sample size of 97 was required, based on a medium effect size (ƒ2 = 0.15), a 0.05 significance level and a power of 0.80.16 therefore, it was determined that the sample size of 414 was adequate for the planned statistical analysis. the english version of the 24-item self-reported evidence-based practice questionnaire (ebpq) developed by upton et al. was used to measure ebp practices, attitudes, knowledge and skills.17 this 24item questionnaire is categorised under three distinct subscales: practice of ebp, attitudes towards ebp and knowledge of/skills associated with ebp.17 items were scored on a visual rating scale ranging from one to seven, with a higher score representing a more positive attitude towards ebp and greater use and knowledge of ebp. in the attitudes subscale, each item had two pairs of opposing statements, with a negative statement and a corresponding positive statement. the respondents were asked to rank their attitudes towards ebp using these statements. responses were considered positive if scores were greater than four. previous studies have assessed the internal consistency of the ebpq and found a cronbach’s alpha coefficient of 0.87 for the entire questionnaire: 0.85 for the practice subscale, 0.79 for the attitudes subscale and 0.91 for the knowledge/ skills subscale.17 the construct validity was assessed by using an independent measure of ebp awareness, with the results yielding a positive relationship between the scales.17 in this study, the cronbach’s alpha coefficient evidence-based practice knowledge, attitudes, practice and perceived barriers among nurses in oman e540 | squ medical journal, november 2014, volume 14, issue 4 was 0.91 for the entire questionnaire, 0.84 for the practice subscale, 0.74 for the attitudes subscale and 0.94 for the knowledge/skills subscale. barriers to ebp were measured using two subscales of the english version of the developing evidencebased practice questionnaire (debpq).18 the first 10-item subscale focused on barriers to finding and reviewing evidence; the second five-item subscale addressed barriers to changing practice. a five-point likert scale ranging from 1 (strongly disagree) to 5 (strongly agree) was used to measure items. the mean scores for each item and for subscales were calculated; higher scores indicated a greater perception of ebp barriers. the percentage of ‘agree’ or ‘strongly agree’ responses for each item was calculated. construct validity was assessed by the identification of 10 factors that showed interpretable structure and measurable approaches to ebp.1 in this study, cronbach’s alpha coefficient for internal consistency was 0.84 for the barriers to finding and reviewing evidence subscale and 0.78 for the barriers to changing practice subscale. the demographic variables of the participants were measured using a six-item data collection instrument designed for the purpose of the study. the demographic data included age, gender, nationality, academic qualifications, years of experience and the year that each nurse had completed their last academic degree. the data analysis was performed using the statistical package for the social sciences (spss), version 19 (ibm corp., chicago, illinois, usa). categorical data were reported as frequencies and percentages. continuous data were used to report measures of central tendency. prior to testing, methods of assessing statistical assumptions, collinearity and the adequacy of the regression were employed. based on the test for collinearity, one variable (age) was excluded from the regression analysis because it had a high correlation with another variable (years of experience). all data were analysed at an alpha level of 0.05. descriptive statistics were used to answer the first two research objectives outlined earlier. to fulfil the third objective, a multiple regression analysis was used to assess the associations between demographic variables and perceived ebp practice, attitudes and knowledge/skills and barriers to ebp implementation. for the fourth objective, a multiple regression analysis was used to assess the associations between perceived barriers to ebp and perceived ebp practice, attitudes, knowledge and skills. the survey and protocol used in this study were reviewed and approved by the research & ethics committee of the college of nursing at sultan qaboos university (crc#2012/20.1.2012). written consent was obtained from the nurses prior to the administration of the questionnaires. participation was voluntary and data were kept confidential. every participant was given an identification number used throughout the study to ensure anonymity. results the sample was comprised of 414 respondents. the mean age of the participants was 35 ± 8.25 years and the mean number of years of experience was 12.6 ± 8.03 years. the majority of the participants (89.6%) were female. of the participants, 47% were indian, 31.4% were omani, 13.3% were filipino and 8.3% were of another nationality. the highest level of professional education for 267 (65.4%) of the participants was a nursing diploma, while 141 (34.6%) held a baccalaureate degree in nursing. just over half of the participants (52.1%) had gained their last academic degree before 2004 while the rest reported completing their last academic qualification after 2005. in terms of the nurses’ perceptions of practice, attitude towards and knowledge/skills regarding ebp, the ebpq results found that the attitudes subscale had the highest mean score (6.63 ± 1.18) followed by the knowledge/skills subscale (4.97 ± 0.86) and then the practice subscale (4.92 ± 1.25) [table 1]. for each subscale, the respondents’ overall mean scores were rank-ordered to determine the priority of each item as a top learning need. for the practice subscale, the two most frequently reported practices were sharing information with colleagues (5.68 ± 1.46) and evaluating the outcomes of their practice (5.45 ± 1.52). on the attitudes subscale, the top two attitudes among the nurses were that ebp was fundamental to professional practice (6.14 ± 1.37) and that nurses welcomed questions on their practice (5.82 ± 1.46). the top two items among the nurses for the knowledge/skills subscale were the sharing of ideas and information to colleagues (5.68 ± 1.08) and the ability to review their own practice (5.44 ± 1.10) [table 1]. the nurses also reported the barriers faced in implementing ebp. the results from the debpq subscales indicated that the greatest barriers to ebp were the difficulty in finding research reports (3.85 ± 0.92) and insufficient time to find research reports (3.51 ± 0.97). the lowest scored barriers were not knowing how to find and difficulty in finding organisational information, e.g. guidelines of protocols (3.13 ± 1.07 and 3.15 ± 1.02, respectively). insufficient resources to change practice (3.64 ± 0.99) and insufficient time at work to implement changes in practice (3.53 ± 0.97) ali a. ammouri, ahmad a. raddaha, preethy dsouza, renu geethakrishnan, judith a. noronha, arwa a. obeidat and lina shakman clinical and basic research | e541 were identified as the two greatest barriers to changing practice. the least significant barrier to changing practice was a lack of confidence about beginning to change practices (3.07 ± 0.85) [table 2]. correlations between the demographic variables and the ebp subscales are shown in table 3. there were significant positive correlations between the nurses’ years of experience and the practice (r = 0.16) and attitude (r = 0.20) subscales. participants with more years of experience had better practice and attitude scores compared to the newer nurses. further, the nurses with more years of experience perceived fewer barriers to finding research (r = -0.17) or changing their practice (r = -0.12). moreover, academic qualifications were significantly associated with perceived barriers to finding research. nurses who had a bachelor’s degree in nursing tended to perceive fewer barriers to finding research compared to nurses with a diploma only (r = 0.18). table 1: nurses’ questionnaire scores by education level regarding their perceived knowledge, skills, attitude and practice of evidence-based practice (n = 414) item scores total % of positive responses (mean ± sd) education level mean ± sd baccalaureate degree n = 141 diploma n = 267 practice 74.6 (4.92 ± 1.25) 4.87 ± 1.28 5.01 ± 1.17 sharing information with colleagues 90.2 (5.68 ± 1.46) 5.69 ± 1.45 5.63 ± 1.49 evaluating the outcomes of own practice 88.3 (5.45 ± 1.52) 5.44 ± 1.51 5.49 ± 1.51 formulating clear questions 83.4 (4.79 ± 1.71) 4.76 ± 1.79 4.81 ± 1.52 integrating evidence with expertise 83.4 (4.79 ± 1.73 4.70 ± 1.78 4.96 ± 1.57 finding relevant evidence 57.0 (4.71 ± 1.73) 4.63 ± 1.81 4.83 ± 1.53 critically appraising literature 56.8 (4.12 ± 1.87) 4.03 ± 1.91 4.31 ± 1.75 attitudes 75.4 (5.63 ± 1.18) 5.67 ± 1.17 5.53 ± 1.18 ebp is fundamental to professional practice 84.8 (6.14 ± 1.37) 6.12 ± 1.39 6.16 ± 1.34 welcoming questions on own practice 79.0 (5.82 ± 1.46) 5.86 ± 1.46 5.72 ± 1.44 changing practice due to evidence found 77.8 (5.68 ± 1.54) 5.76 ± 1.46 5.49 ± 1.66 making time in a work schedule for research 60.1 (4.89 ± 1.90) 4.93 ± 1.94 4.78 ± 1.80 knowledge/ skills 63.3 (4.97 ± 0.86) 4.93 ± 0.86 5.04 ± 0.79 sharing ideas and information with colleagues 86.5 (5.68 ± 1.08) 5.64 ± 1.09 5.76 ± 1.01 reviewing own practices 81.4 (5.44 ± 1.10) 5.42 ± 1.14 5.48 ± 0.98 disseminating new ideas about care to colleagues 76.8 (5.38 ± 1.16) 5.35 ± 1.15 5.44 ± 1.16 applying information to individual cases 74.4 (5.25 ± 1.10) 5.24 ± 1.12 5.26 ± 1.04 determining how useful (clinically applicable) material is 72.7 (5.13 ± 1.09) 5.09 ± 1.10 5.19 ± 1.01 identifying gaps in professional practice 69.8 (5.06 ± 1.12) 5.06 ± 1.11 5.07 ± 1.12 monitoring and reviewing practice 69.3 (5.05 ± 1.10 5.04 ± 1.10 5.04 ± 1.08 determining the validity (close to the truth) of material 64.3 (4.89 ± 1.15) 4.91 ± 1.13 4.85 ± 1.13 retrieving evidence 63.3 (4.88 ± 1.21) 4.84 ± 1.20 4.94 ± 1.17 critically analysing evidence against set standards 61.4 (4.80 ± 1.17) 4.75 ± 1.18 4.89 ± 1.08 awareness of major information types/sources 61.4 (4.79 ± 1.17) 4.75 ± 1.14 4.89 ± 1.17 it skills 59.9 (4.75 ± 1.18) 4.67 ± 1.18 4.88 ± 1.53 converting information needs into a research question 44.9 (4.31 ± 1.23) 4.21 ± 1.18 4.51 ± 1.23 research skills 39.1 (4.16 ± 1.24) 4.04 ± 1.25 4.40 ± 1.13 sd = standard deviation; ebp = evidence-based practice; it = information technology. evidence-based practice knowledge, attitudes, practice and perceived barriers among nurses in oman e542 | squ medical journal, november 2014, volume 14, issue 4 three demographic variables (years of experience, academic qualifications and year of last academic achievement) had significant associations with the ebp subscales [table 4]. nurses who had more years of experience reported more frequent use of ebp (β = 0.170; p <0.01), more positive attitudes towards ebp (β = 0.197; p <0.001) and fewer barriers to finding and reviewing research (β = −0.162; p <0.01). meanwhile, nurses with baccalaureate degrees in nursing reported fewer barriers to finding and reviewing research than nurses with diplomas only (β = −0.198; p <0.001). nurses who had gained their last academic qualification after 2005 reported less knowledge and fewer skills associated with ebp (β = −0.109; p <0.05) as well as more barriers to changing their practice (β = 0.123; p <0.05) in comparison to nurses whose last academic degree was gained on or before 2004 [table 4]. in terms of perceived barriers to implementing ebp, and the practice, attitudes and knowledge/skills associated with ebp, the study’s results indicated that nurses who perceived more barriers to finding and reviewing research described reduced use of ebp (β = −0.242; p <0.001). they also reported less positive attitudes towards ebp (β = −0.280; p <0.001) and reduced ebp knowledge/skills (β = −0.306; p <0.001). meanwhile, there was no significant association between barriers to changing practice and ebpassociated practice, attitudes and knowledge/skills. discussion the results of this study indicate that the nurses viewed ebp positively and their attitudes towards ebp tended to be more positive than their knowledge/skills and use of ebp. these results were consistent with previous studies describing attitudes, practices and knowledge/ skills associated with ebp.10,15,19 therefore, it appears that nurses’ ebp attitudes commonly differ from their ability to implement ebp and that this is not unique to nurses in oman. insufficient time and resources were identified as the main barriers to using ebp among nurses in oman. similar responses have been observed in other table 2: nurses’ questionnaire scores by education level regarding their perceived barriers to evidencebased practice (n = 414) item scores total % of positive responses (mean ± sd) education level mean ± sd baccalaureate degree n = 141 diploma n = 267 barriers to finding and reviewing research 51.6 (3.40 ± 0.67) 3.32 ± 0.65 3.49 ±.64 research reports are not easy to find 77.1 (3.85 ± 0.92) 3.77 ± 0.94 3.96 ± 0.81 insufficient time to find research reports 60.4 (3.51 ± 0.97) 3.46 ± 0.95 3.59 ± 0.98 lack of confidence in judging the quality of research reports 60.1 (3.47 ± 0.96) 3.44 ± 0.96 3.51 ± 0.91 difficulty identifying the implications of research findings for own practice 55.8 (3.44 ± 0.83) 3.37 ± 0.81 3.54 ± 0.80 difficulty understanding research reports 50.9 (3.40 ± 0.99) 3.30 ± 1.01 3.54 ± 0.92 not knowing how to find appropriate research reports 46.1 (3.37 ± 0.89) 3.29 ± 0.89 3.48 ± 0.83 difficulty identifying the implications of organisational information (guidelines/ protocols etc.) for own practice 45.6 (3.30 ± 0.91) 3.19 ± 0.91 3.47 ± 0.87 insufficient time to find organisational information 43.7 (3.28 ± 0.91) 3.19 ± 0.91 3.40 ± 0.87 organisational information is not easy to find 43.3 (3.15 ± 1.02) 3.15 ± 1.01 3.14 ± 1.01 not knowing how to find organisational information 37.5 (3.13 ± 1.07) 2.99 ± 1.03 3.34 ± 1.06 barriers to changing practice 64.6 (3.30 ± 0.65) 3.27 ± 0.65 3.31 ± 0.64 insufficient resources (e.g. equipment) to change own practice 70.6 (3.64 ± 0.99) 3.61 ± 0.82 3.66 ± 0.86 insufficient time at work to implement changes in own practice 62.2 (3.53 ± 0.97) 3.57 ± 0.87 3.44 ± 0.89 team culture is not receptive to changing practice 43.2 (3.12 ± 0.90) 3.08 ± 0.98 3.19 ± 0.94 lacking the authority to change practice 42.2 (3.12 ± 1.06) 3.14 ± 1.06 3.06 ± 1.02 lack of confidence about beginning to change own practice 40.3 (3.07 ± 0.85) 2.99 ± 1.00 3.22 ± 0.96 sd = standard deviation. ali a. ammouri, ahmad a. raddaha, preethy dsouza, renu geethakrishnan, judith a. noronha, arwa a. obeidat and lina shakman clinical and basic research | e543 studies.8,15,19 in their study of turkish nurses’ use of research evidence in clinical practice, ozdemir et al. were of the opinion that the perceived lack of time by nurses was a justification adopted in order to guard themselves from unfamiliar ideas that might require changing their practices.20 it appears that a better understanding of the practice environment is crucial to the understanding and development of interventions to advance ebp in the nursing community.21 in this light, hospital management should consider making adjustments to nurses’ work schedules so that nurses have additional time to attend classes on conducting ebp, reviewing relevant literature and planning practice changes. the results of this study also indicated that nurses with more years of experience reported greater use of ebp, more positive attitudes towards ebp and fewer barriers to finding and reviewing research. these results are consistent with those reported in a previous study which found that nurses with more years of experience in nursing were more confident in implementing ebp because they had had more exposure to evidenced-based information as part of their continuing education.22 in a similar study, ferguson et al. concluded that new nurses were less confident in using ebp due to their limited practical knowledge and experience.23 on the other hand, majid et al. found that the relationship between years of experience and the implementation of ebp was weak.24 the current study, and another study with similar findings, seem to suggest that, in order to effectively implement ebp, less experienced nurses should be supported by senior nurses and nursing leaders with encouragement and the provision of necessary resources.25 such support could be provided by increasing the opportunities for nurses to attend ebp training, as this is likely to improve their confidence in and utilisation of ebp.24 nurses with baccalaureate degrees reported fewer barriers to finding and reviewing research than nurses with diplomas. the reason could be that baccalaureate education programmes prepare their graduates to read and understand research findings, as compared to diploma programmes, which usually do not. majid table 3: correlations between the nurses’ demographic variables and their scores on the evidence-based practice questionnaire by subscale (n = 414) variable questionnaire subscale practice attitudes knowledge/skills barriers to finding research barriers to changing practice gender −0.18 −0.021 −0.070 0.014 −0.045 nationality −0.051 0.049 −0.031 −0.063 −0.033 years of experience 0.160‡ 0.202‡ 0.062 −0.014† −0.123† academic qualification 0.067 −0.039 0.076* −0.179‡ −0.049 year of last academic qualification −0.076 −0.091* −0.101* 0.073 0.152† *p <0.05; †p <0.01; ‡p <0.001. table 4: multiple regression analysis of the evidence-based practice questionnaire subscales on selected demographic variables (n = 414) variable questionnaire subscale practicea attitudesb knowledge/skillsc barriers to finding researchd barriers to changing practicee β t value β t value β t value β t value β t value gender −0.048 −0.96 −0.024 −0.47 −0.095 −1.87 0.033 0.660 −0.010 −0.189 nationality −0.011 −0.114 0.044 0.451 −0.083 −0.915 −0.020 −0.223 −0.062 −0.671 years of experience 0.170 3.18† 0.197 3.71‡ 0.049 0.91 −0.162 −0.308† −0.082 −1.53 academic qualification 0.084 1.72 −0.017 −0.340 0.080 1.63 −0.198 −4.08‡ −0.060 1.39 year of last academic qualification −0.027 −0.507 −0.019 −0.360 −0.109 −2.03* 0.031 0.590 0.123 2.31* af (4, 409) = 3.79, p <0.01, r2 = 0.036; bf (4, 409) = 4.45, p <0 .01, r2 = 0.042; cf (4, 409) = 2.82, p <0.05, r2 = 0 .017; df (4, 409) = 2.87, p <0 .001, r2 = 0.061; ef (4, 409) = 1.42, p <0.01, r2 = 0.033; *p <0 .05, †p <0.01; †p <0.001. evidence-based practice knowledge, attitudes, practice and perceived barriers among nurses in oman e544 | squ medical journal, november 2014, volume 14, issue 4 et al. found that nurses with higher qualifications were better able to benefit from ebp activities.24 youngblut et al. indicated that nurses who had graduated from baccalaureate programmes had knowledge of the research process, which facilitated their interpretation of scientific evidence.26 additionally, majid et al. concluded that the creation of an environment that provides opportunities for nurses to share knowledge and information should be a key priority for hospital management.24 this suggests that nurses who have not received any research or ebp training need additional education—perhaps enabled by providing additional tuition assistance for those who wish to complete a nursing baccalaureate qualification. most higher education systems prepare nurses to generate different types of evidence, accumulate evidence in a mental repository for subsequent application in clinical practice, synthesise different forms of evidence and translate this information by evaluating, interpreting and disseminating data through formal and informal means. the importance of education was emphasised in a study conducted in the uk by grant et al.27 they found that nurses with a master’s degree often promoted ebp among their clinical nursing colleagues.27 although baccalaureate degree-holding nurses are educated in research techniques, unless these skills are maintained and supported within their place of employment, they may quickly be forgotten. additionally, if nurses do not have access to the appropriate technology to conduct comprehensive searches of the literature (for example, using databases such as cinahl or medline), then such issues become major barriers to practicing ebp. future research is recommended targeting nurses with a diploma-level qualification to determine their ebp skills and practices. the current study’s results indicated that nurses who perceived more barriers to finding and reviewing research reported less frequent use of ebp, fewer positive attitudes towards ebp and less knowledge/ skills associated with ebp. several studies have also shown that nurses do not readily integrate research into their clinical setting, reporting inadequate organisational support, lack of knowledge about research studies/utilisation, lack of time and difficulty in understanding statistical analyses as the major barriers of implementation.1,28,29 nurses should receive sufficient education in informational technology to be able to implement ebp. continuing education should include training in statistical analysis, research application and the utilisation of the internet so as to encourage nurses to use ebp in clinical practice. the results for this study were congruent with the wider research literature on this topic. the results of this study should be viewed cautiously, taking into account some limitations. the cross-sectional nature of this study hindered the ability to infer causal relationships between the study variables. furthermore, this study was based on self-reported data which may represent an inherent bias. additionally, the recruitment method relied on convenience sampling and may not be truly representative of the nursing population in oman. conclusion the findings of this study provide a basis from which omani organisations can begin educational initiatives to increase the utilisation and implemention of ebp among nurses. this study found that nurses’ attitudes towards ebp were more positive than their knowledge/skills and practices of ebp. the greatest barriers to developing ebp among nurses in oman were insufficient time to find and read research and insufficient resources to change their practice. more years of nursing experience and a baccalaureatelevel education were positively associated with ebp attitudes, practice and knowledge/skills, and were negatively associated with barriers to ebp. additionally, barriers to finding and reviewing research were negatively associated with ebp practice, attitudes and knowledge/skills. these findings suggest that continuing education regarding ebp for nurses is crucial in order to enhance nurses’ clinical practice, knowledge and skills, and that hospital management should take steps to minimise the barriers to ebp implementation. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. gerrish k, ashworth p, lacey a, bailey j. developing evidencebased practice: experiences of senior and junior clinical nurses. j adv nurs 2008; 62:62–73. doi: 10.1111/j.1365-2648.2007.04579.x. 2. sherriff kl, wallis m, chaboyer w. nurses’ attitudes to and perceptions of knowledge and skills regarding evidence-based practice. int j nurs pract 2007; 13:363–9. doi: 10.1111/j.1440172x.2007.00651.x. 3. melnyk bm, fineout-overholt e. evidence-based practice in nursing & healthcare: a guide to best practice. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2005. pp. 3–39. 4. coopey m, nix mp, clancy cm. translating research into evidencebased nursing practice and evaluating effectiveness. j nurs care qual 2006; 21:195–202. 5. institute of medicine of the national academies. health professions education: a bridge to quality. washington, d.c., usa: national academies press, 2003. 6. olade ra. evidence-based practice and research utilization activities among rural nurses. j nurs scholarsh 2004; 36:220–5. doi: 10.1111/j.1547-5069.2004.04041.x. ali a. ammouri, ahmad a. raddaha, preethy dsouza, renu geethakrishnan, judith a. noronha, arwa a. obeidat and lina shakman clinical and basic research | e545 7. titler mg. the evidence for evidence-based practice implementation. in: hughes rg, ed. patient safety and quality: an evidence-based handbook for nurses. vol. 1. rockville, maryland, usa: agency for healthcare research and quality, 2008. pp. 113– 61. 8. pravikoff ds, tanner ab, pierce st. readiness of u.s. nurses for evidence-based practice. am j nurs 2005; 105:40–51. 9. roberts k, belcher d, jacobson j. the evidence trip: a researcher helps nurses ‘practice by evidence, not tradition’. am j nurs 2004; 104:102–3. 10. koehn ml, lehman k. nurses’ perceptions of evidence-based nursing practice. j adv nurs 2008; 62:209–15. doi: 10.1111/j.13652648.2007.04589.x. 11. paramonczyk a. barriers to implementing research in clinical practice. can nurse 2005; 101:12–5. 12. veeramah v. utilization of research findings by graduate nurses and midwives. j adv nurs 2004; 47:183–91. doi: 10.1111/j.13652648.2004.03077.x. 13. happell b, johnston l, hill c. implementing research findings into mental health nursing practice: exploring the clinical research fellowship approach. int j ment health nurs 2003; 12:251–8. doi: 10.1046/j.1447-0349.2003.t01-3-.x. 14. valente sm. research dissemination and utilization improving care at the bedside. j nurs care qual 2003; 18:114–21. 15. brown ce, wickline ma, ecoff l, glaser d. nursing practice, knowledge, attitudes and perceived barriers to evidence-based practice at an academic medical center. j adv nurs 2009; 65:371–81. doi: 10.1111/j.1365-2648.2008.04878.x. 16. cohen j. a power primer. psychol bull 1992; 112:155–9. doi: 10.1037/0033-2909.112.1.155. 17. upton d, upton p. development of an evidence-based practice questionnaire for nurses. j adv nurs 2006; 53:454–8. doi: 10.1111/j.1365-2648.2006.03739.x. 18. gerrish k, ashworth p, lacey a, bailey j, cooke j, kendall s, et al. factors influencing the development of evidence-based practice: a research tool. j adv nurs 2007; 57:328–38. doi: 10.1111/j.13652648.2006.04112.x. 19. yadav bl, fealy gm. irish psychiatric nurses’ self-reported barriers, facilitators and skills for developing evidence-based practice. j psychiatr ment health nurs 2012; 19:116–22. doi: 10.1111/j.13652850.2011.01763.x. 20. ozdemir l, akdemir n. turkish nurses’ utilization of research evidence in clinical practice and influencing factors. int nurs rev 2009; 56:319–25. doi: 10.1111/j.1466-7657.2009.00707.x. 21. cummings gg, estabrooks ca, midodzi wk, wallin l, hayduk l. influence of organizational characteristics and context on research utilization. nurs res 2007; 56:s24–39. doi: 10.1097/01. nnr.0000280629.63654.95. 22. griffiths jm, bryar rm, closs sj, cooke j, hostick t, kelly s, et al. barriers to research implementation by community nurses. br j community nurs 2001; 6:501–10. doi: 10.12968/ bjcn.2001.6.10.9466. 23. ferguson lm, day ra. challenges for new nurses in evidencebased practice. j nurs manag 2007; 15:107–13. doi: 10.1111/j.13652934.2006.00638.x. 24. majid s, foo s, luyt b, zhang x, theng yl, chang yk, et al. adopting evidence-based practice in clinical decision making: nurses’ perceptions, knowledge, and barriers. j med libr assoc 2011; 99:229–36. doi: 10.3163/1536-5050.99.3.010. 25. stichler jf, fields w, kim sc, brown ce. faculty knowledge, attitudes, and perceived barriers to teaching evidence-based nursing. j prof nurs 2011; 27:92–100. doi: 10.1016/j.profnurs.2010.09.012. 26. youngblut jm, brooten d. evidence-based nursing practice: why is it important? aacn clin issues 2001; 12:468–76. doi: 10.1097/00044067-200111000-00003. 27. grant hs, stuhlmacher a, bonte-eley s. overcoming barriers to research utilization and evidence-based practice among staff nurses. j nurses staff dev 2012; 28:163–5. doi: 10.1097/ nnd.0b013e31825dfaff. 28. gerrish k, guillaume l, kirshbaum m, mcdonnell a, tod a, nolan m. factors influencing the contribution of advanced practice nurses to promoting evidence-based practice among front-line nurses: findings from a cross-sectional survey. j adv nurs 2011; 67:1079– 90. doi: 10.1111/j.1365-2648.2010.05560.x. 29. gerrish k, mcdonnell a, nolan m, guillaume l, kirshbaum m, tod a. the role of advanced practice nurses in knowledge brokering as a means of promoting evidence-based practice among clinical nurses. j adv nurs 2011; 67:2004–14. doi: 10.1111/j.13652648.2011.05642.x. رد: مستوى معدن الزنك يف مصل دماء األطفال املصابني بإسهال دموي أو مائي حاد re: serum zinc concentrations in children with acute bloody and watery diarrhoea sir, i have two comments regarding the interesting study by mahyar et al. published in the squmj november 2015 issue.1 firstly, apart from the two limitations addressed by the authors—failure to estimate serum zinc concentrations after patients had completed their course of treatment and the small sample size—i believe that there is another important limitation to this study. giardiasis is highly prevalent in developing countries.2 it is commonly linked to chronic diarrhoea and malabsorption; available data indicate that giardiasis is the aetiological agent in 7.0% of childhood cases of acute diarrhoea.3 in iran, paediatric giardiasis still represents a substantial health threat, with an estimated prevalence of 10.6%.4 moreover, giardiasis has been shown to be markedly associated with hypozincaemia in the iranian population.5 in mahyar et al.’s study, stool cultures were used to determine the causative pathogens in their studied population.1 no growth was seen in 32 (53.3%) patients while 28 (46.7%) patients were found to have bacterial diarrhoea caused by pathogenic escherichia coli (n = 15), shigella (n = 10) and salmonella (n = 3).1 general stool examinations were not carried out prior to the cultures; this could have resulted in the exclusion of a significant number of patients with giardiasis-associated acute diarrhoea.1 accordingly, this might affect the accuracy of mahyar et al.’s results. secondly, mahyar et al. studied the correlation between serum zinc levels and various inflammatory and non-inflammatory variables.1 the study showed a non-significant correlation between these variables and serum zinc levels; thus, these variables could not be considered predictors of zinc deficiency in iranian children with acute diarrhoea.1 this is an interesting observation as it contrasts with previously reported observations; strand et al. studied the association between plasma zinc concentration and several clinical and biochemical variables in a cohort of nepalese children with acute diarrhoea.6 the study revealed an association between axillary temperature and plasma zinc concentrations. as such, a reduction was seen in the mean plasma zinc concentration per degree of increased axillary temperature (0.59 µmol/l per ºc). reduced plasma zinc levels were also associated with elevated levels of c-reactive protein, dysentery and decreased plasma albumin levels. the study also found that there were increased levels of plasma zinc in children who were dehydrated compared to those who were not.6 mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, baghdad university, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. mahyar a, ayazi p, chegini v, sahmani m, oveisi s, esmaeily s. serum zinc concentrations in children with acute bloody and watery diarrhoea. sultan qaboos univ med j 2015; 15:e512–16. doi: 10.18295/squmj.2015.15.04.012. 2. world health organization. the treatment of diarrhoea: a manual for physicians and other senior health workers. from: www.who.int/ maternal_child_adolescent/documents/9241593180/en/ accessed: dec 2015. 3. el-mohammady h, mansour a, shaheen hi, henien nh, motawea ms, raafat i, et al. increase in the detection rate of viral and parasitic enteric pathogens among egyptian children with acute diarrhea. j infect dev ctries 2012; 6:774–81. doi: 10.3855/jidc.2349. 4. daryani a, sharif m, nasrolahei m, khalilian a, mohammadi a, barzegar g. epidemiological survey of the prevalence of intestinal parasites among schoolchildren in sari, northern iran. trans r soc trop med hyg 2012; 106:455–9. doi: 10.1016/j.trstmh.2012.05.010. 5. zarebavani m, dargahi d, einollahi n, dashti n, mohebali m, rezaeian m. serum levels of zinc, copper, vitamin b12, folate and immunoglobulins in individuals with giardiasis. iran j public health 2012; 41:47–53. 6. strand ta, adhikari rk, chandyo rk, sharma pr, sommerfelt h. predictors of plasma zinc concentrations in children with acute diarrhea. am j clin nutr 2004; 79:451–6. letter to the editor sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e123–124, epub. 2 feb 16 submitted 3 dec 15 accepted 20 dec 15 doi: 10.18295/squmj.2016.16.01.027 http://dx.doi.org/10.18295/squmj.2015.15.04.012 http://dx.doi.org/10.3855/jidc.2349 http://dx.doi.org/10.1016/j.trstmh.2012.05.010 re: serum zinc concentrations in children with acute bloody and watery diarrhoea e124 | squ medical journal, february 2016, volume 16, issue 1 response from the authors sir, we thank you for your comments on our recently published article.1 as mentioned in our article, the main objectives of our study were to compare serum zinc levels in children with acute diarrhoea and in healthy control subjects, as well as to compare serum zinc concentration in children with acute watery versus bloody diarrhoea, regardless of the identification of aetiological factors such as rotavirus infection or giardiasis. the diagnosis of acute diarrhoea, acute watery diarrhoea and dysentery was based on the definitions of the world health organization.2 in general, our goal was to prove that patients with acute diarrhoea, particularly acute bloody diarrhoea, have low concentrations of serum zinc. we aimed to suggest that zinc should be prescribed to all patients with acute diarrhoea regardless of their aetiologic factors. in developing countries, certain diagnostic facilities (including cultures, rapid diagnostic or polymerase chain reaction tests) for the diagnosis of aetiological agents are unavailable. giardiasis can present as acute diarrhoea and the diagnosis is traditionally established by microscopic evidence of trophozoites or cysts in stool specimens. however, stool enzyme immunoassay or direct fluorescent antibody tests for giardia antigens are the tests of choice for giardiasis. under certain conditions, it may be necessary to use other diagnostic methods such as aspiration or biopsy of the duodenum or upper jejunum.3 *abolfazl mahyar,1 parviz ayazi,1 victoria chegini,1 mehdi sahmani,2 sonia oveisi,3 shiva esmaeily4 departments of 1pediatrics and 4statistics and centres for 2cellular & molecular research and 3metabolic diseases research, qazvin university of medical sciences, qazvin, iran *corresponding author e-mail: abolfazl473@yahoo.com references 1. mahyar a, ayazi p, chegini v, sahmani m, oveisi s, esmaeily s. serum zinc concentrations in children with acute bloody and watery diarrhoea. sultan qaboos univ med j 2015; 15:e512–6. doi: 10.18295/squmj.2015.15.04.012. 2. world health organization. the treatment of diarrhoea: a manual for physicians and other senior health workers. from: www.who.int/ maternal_child_adolescent/documents/9241593180/en/ accessed: dec 2015. 3. john cc. giardiasis and balantidiasis. in: kliegman rm, stanton b, st. geme j, schor nf, eds. nelson textbook of pediatrics, 20th ed. philadelphia, pennsylvania, usa: elsevier, 2015. pp. 1692–94. http://dx.doi/org/10.18295/squmj.2015.15.04.012 1department of dermatology, complejo hospitalario universitario de granada, granada, spain; 2department of gynecology & obstetrics, hospital universitario virgen de las nieves, granada, spain; 3department of clinical management dermatology, hospital general universitario virgen de las nieves, granada, spain *corresponding author’s e-mail: paula872190@gmail.com مرض باجيت يف الثدي مقلد خطري إللتهاب اجللد التحسسي بول اأغويو-كاريرا�ض، لورا بونيال-غار�صيا، اإ�رشائيل برييز-لوبيز، كارلو�ض كن�صا-بارالي�ض، جي�صو�ض تر�صيدور-�صان�صيز paget’s disease of the breast a dangerous imitator of eczema *paula aguayo-carreras,1 laura bonilla-garcía,2 israel pérez-lópez,1 carlos cuenca-barrales,1 jesús tercedor-sánchez3 a 46-year-old woman with no personal or family history of cancer presented to the department of dermatology at the complejo hospitalario universitario de granada, granada, spain, in 2017 with an eczematous plaque in the areola of the left breast. the plaque had developed over the course of the past four years and was associated with stinging, itching and occasional suppuration. she had been previously treated with topical corticosteroids and antibiotics without improvement. a mammogram performed the previous year showed a small benign nodule of 8 x 5 mm in diameter and a simple cyst of 5 mm in diameter in the right breast. there was no evidence of ductal ectasia or alterations at the left retroareolar level l. a physical examination revealed an erythematous-squamous plaque of 4 x 5 cm in diameter on the left breast without infiltration and with effacement of the areola-nipple complex [figure 1]. no local lymph nodes were palpated. a cutaneous ultrasound showed hyperkeratosis of the epidermis with a hypoechoic area in the dermis with increased vascularisation. a large incisional biopsy confirmed a diagnosis of paget’s disease of the nipple with ductal carcinoma in situ. a quadrantectomy and selective sentinel node biopsy were performed, the latter of which was negative. the patient was subsequently monitored for the next three years without evidence of clinical recurrence. comment paget’s disease of the breast is characterised by the intraepidermal infiltration of malignant glandular interesting medical image sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e487–488, epub. 10 jan 18 submitted 28 aug 17 revision req. 16 oct 17; revision recd. 29 oct 17 accepted 16 nov 17 figure 1: photograph of an uninfiltrated erythematous plaque on the left breast of a 46-year-old woman with effacement of the areola-nipple complex. doi: 10.18295/squmj.2017.17.04.021 paget’s disease of the breast a dangerous imitator of eczema e488 | squ medical journal, november 2017, volume 17, issue 4 usually bilateral, without accompanying induration and responds quickly to the application of topical corticosteroids.1 treatment for paget’s disease is based on surgery, radiation therapy and chemotherapy, either alone or in combination.3 the incidence of axillary lymph node involvement and metastasis in paget’s disease is higher in patients with a palpable mass than in patients without a palpable mass. patients with areolar changes only in the nipple and without a palpable mass usually have negative mammograms and less invasive carcinomas.3 physicians should maintain a high level of suspicion of nipple-areola complex abnormalities since a superficial lesion reminiscent of paget’s disease may be the only sign of a more serious underlying neoplasm.5 therefore, paget’s disease should be considered in cases of eczematous breast lesions that persist for more than three weeks despite topical treatment. references 1. casals-felip r, martin-ezquerra g, esgueva pallares r, corominas torres jm. [paget disease of the breast]. med clin (barc) 2007; 129:440. doi: 10.1157/13110469. 2. martín pérez a, rodríguez nevado im, chaves álvarez aj, salguero bodes i. [paget’s disease of the breast]. semergen 2008; 34:470–1. doi: 10.1016/s1138-3593(08)75210-9. 3. muttarak m, siriya b, kongmebhol p, chaiwun b, sukhamwang n. paget’s disease of the breast: clinical, imaging and pathologic findings a review of 16 patients. biomed imaging interv j 2011; 7:e16. doi: 10.2349/biij.7.2.e16. 4. bijker n, rutgers ej, duchateau l, peterse jl, julien jp, cataliotti l. breast-conserving therapy for paget disease of the nipple: a prospective european organization for research and treatment of cancer study of 61 patients. cancer 2001; 91:472−7. doi: 10.1002/1097-0142(20010201)91:3<472::aidcncr1024>3.0.co;2-q. 5. lin ch, lee hs, yu jc. melanoma of the nipple mimicking paget’s disease. dermatol online j 2007; 13:18. epithelial cells which usually unilaterally affects the nipple or areola and clinically simulates chronic eczematous dermatitis.1 generally, the onset of the disease is insidious, occurring over several months or years; moreover, many cases are asymptomatic with palpable mass lesions present in 14–44% of patients.1 in symptomatic cases, the mass may be associated with pruritus, pain and a burning sensation and may be accompanied by exudate, haemorrhage, ulceration and invagination of the nipple.2 upon exploration, lesions usually range in size from 3–15 cm and their appearance varies from small flaps to welldelimited erythematous and desquamative plaques with irregular borders.3 patients with paget’s disease have a high incidence of associated mammary intraductal carcinomas; as such, mammography should be performed.3 a definitive diagnosis of paget’s disease is made via a large wedge biopsy that includes the nipple and areola.4 at the outset, this will reveal an in situ carcinoma of the galactophorous ducts that later extends until the epidermis where it causes diffuse modifications or nest-like clusters of cells, before subsequently breaking the wall of the conduits and invading the periglandular connective tissue. paget cells can be seen in the galactophorous ducts and later in the epidermis while a chronic inflammatory infiltrate, vasodilatation and oedema is observed in the superficial dermis.2 the differential diagnosis of paget’s disease includes eczema, psoriasis, bowen’s disease, cutaneous melanomas, nodular localised cutaneous amyloidosis, benign intraductal papillomas, hyperkeratosis, erosive adenomatosis, impetigo, pityriasis versicolor, cutaneous squamous cell carcinoma in situ and benign familial pemphigus.1 eczematous dermatitis of the nipple—with which paget’s disease can easily be confused—is https://doi.org/10.1157/13110469 https://doi.org/10.1016/s1138-3593%2808%2975210-9 https://doi.org/10.2349/biij.7.2.e16 https://doi.org/10.1002/1097-0142%2820010201%2991:3%3c472::aid-cncr1024%3e3.0.co%3b2-q https://doi.org/10.1002/1097-0142%2820010201%2991:3%3c472::aid-cncr1024%3e3.0.co%3b2-q التلقني مقابل التعلم الذايت يف السياق العريب ‘spoon-fed’ versus self-directed learning in an arab context dear editor, during my many years of teaching, planning and research at both undergraduate and postgraduate medical education institutions in saudi arabia, i have witnessed the establishment of new learning environments following the adaptation of different curricula and application of new teaching and learning strategies, such as problem-based learning (pbl).1 however, it is debatable whether such environments are conducive for learning in saudi arabia and whether they will produce independent self-directed and lifelong learners. while people in various parts of the world have different lifestyles, they also think in distinctly different ways.2 countries with predominantly arab cultures, especially in the middle east, have their own traditions that reflect varying elements of achievement, hierarchy and uncertainty. this may therefore complicate attempts to simply transfer existing skill-based systems from western to arab countries.2 in secondary schools with teacher-centred educational systems, students are generally less independent within the learning process; one might claim that such students are ‘spoon-fed’ the requisite knowledge by their teachers.3,4 furthermore, the examination process encourages students to focus solely on their grades, inhibiting them from learning information outside of the set curricula. unfortunately, the expectation of being ‘spoon-fed’ is often carried on from secondary school to medical school. this deters self-directed learning (sdl), which incorporates highly useful skills, particularly when subsequently entering a demanding and challenging learning environment such as a medical school.5 graduating from a secondary school to a medical school presents a transitional challenge for many students due to the lack of academic rigour, self-motivation and dedication to lifelong learning necessary to become a competent physician. in general, many students favour a ‘spoon-feeding’ learning approach because it provides easy access to the right answers. however, such methods give students the incorrect impression that such knowledge is known to or accessible only via their teachers.3 as a result, it is common for students who have been ‘spoon-fed’ to only be capable of regurgitating information they have been told.6 in situations wherein students lack sdl skills, exposing first-year medical students to an independent learning environment without guidance may cause difficulties. consequently, students may feel forced to turn to tutors, follow predetermined learning objectives or partake in rote learning in order to maintain their grade point average.6,7 this results in students who either attempt to apply rote learning during examinations or are not able to answer examination questions at all. overall, pbl involves a constructivist approach whereby students build new knowledge upon prior knowledge.1 however, the acquirement of new knowledge requires time. therefore, instead of expecting arab students to take part in a fully independent sdl approach, such students should be guided towards directed self-learning.8,9 this approach provides initial guidance and a support system for students, thereby offering more time to acquire new knowledge and develop sdl skills. in addition, medical educators should create a grassroots strategy for the development of self-regulation skills in order to enable these future physicians to become selfdirected lifelong learners.10 abdul s. khan department of family & community medicine, king faisal university, hafuf, saudi arabia e-mails: yardockhan.ask@gmail.com and amkhan@kfu.edu.sa letter to the editor sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e247–248, epub. 9 sep 18 submitted 7 dec 17 revisions req. 8 jan & 14 feb 18; revisions recd. 23 jan & 14 feb 18 accepted 1 mar 18 doi: 10.18295/squmj.2018.18.02.025 ‘spoon-fed’ versus self-directed learning in an arab context e248 | squ medical journal, may 2018, volume 18, issue 2 references 1. bielenberg b, gillway m. adapting problem-based learning to meet the life-long learning needs of developmental students. learn teach high educ gulf perspect 2007; 4:1–13. 2. hofstede g. culture’s consequences: comparing values, behaviors, institutions, and organizations across nations, 2nd ed. thousand oaks, california, usa: sage publications inc., 2003. pp. 1–40. 3. dehler ge, welsh ma. against spoon-feeding: for learning reflections on students’ claims to knowledge. j manag educ 2014; 38:875–93. doi: 10.1177/1052562913511436. 4. smith h. spoon-feeding: or how i learned to stop worrying and love the mess. teach high educ 2008; 13:715–18. doi: 10.1080/13 562510802452616. 5. frambach jm, driessen ew, chan lc, van der vleuten cp. rethinking the globalization of problem-based learning: how culture challenges self-directed learning. med educ 2012; 46:738–47. doi: 10.1111/j.1365-2923.2012.04290.x. 6. mckay j, kember d. spoon feeding leads to regurgitation: a better diet can result in more digestible learning outcomes. high educ res dev 1997; 16:55–67. doi: 10.1080/0729436970160105. 7. loyens sm, magda j, rikers rm. self-directed learning in problem-based learning and its relationships with self-regulated learning. educ psychol rev 2008; 20:411–27. doi: 10.1007/s10648-008-9082-7. 8. miflin bm, campbell cb, price da. a lesson from the introduction of a problem-based, graduate entry course: the effects of different views of self-direction. med educ 1999; 33:801–7. doi: 10.1046/j.1365-2923.1999.00399.x. 9. brydges r, dubrowski a, regehr g. a new concept of unsupervised learning: directed self-guided learning in the health professions. acad med 2010; 85:s49–55. doi: 10.1097/acm.0b013e3181ed4c96. 10. lens w, vansteenkiste m. promoting self-regulated learning: a motivational analysis. in: schunk dh, zimmerman bj (eds). motivation and self-regulated learning: theory, research, and applications. abingdon, uk: routledge, 2007. pp. 141–68. https://doi.org/10.1177/1052562913511436 https://doi.org/10.1080/13562510802452616 https://doi.org/10.1080/13562510802452616 https://doi.org/10.1111/j.1365-2923.2012.04290.x https://doi.org/10.1080/0729436970160105 https://doi.org/10.1007/s10648-008-9082-7 https://doi.org/10.1046/j.1365-2923.1999.00399.x https://doi.org/10.1097/acm.0b013e3181ed4c96 óïüπ]<ì⁄¯ä÷<ÿê˘]<í÷êç÷]<ü≥ˆπ] åáe^œ<·^�◊ä÷]<ì√⁄^q<óàéjä⁄ 2 –31 abstracts first international conference on patient safety sultan qaboos university hospital 31st jan 2nd feb 2011 squ med j, august 2011, vol. 11, iss. 3, pp. 428-435, epub. 15th aug 11 s e l e c t e d a b s t r a c t s educating future leaders in patient safety: world health organisation patient safety curriculum guide dr. agnes leotsakos patient safety technical officer, who, geneva, switzerland. email: leotsakos@who.int. patient safety education of future health care staff has the potential to improve the safety of patients worldwide by creating a basis for students to build on in professional life. the world health organisation (who) embarked on this project to assist the development of patient safety education in health care and contribute towards safer care by developing and disseminating globally the who patient safety curriculum guide. the guide, published by in 2009, is a comprehensive guide for implementation of patient safety education in medical schools worldwide. it contains information for all levels of staff and lays the foundation for capacity building in essential patient safety principles and concepts. it has been tested in 12 sites (medical schools/universities) in 9 countries worldwide. the evaluation study indicated that the who guide is highly valued and has a clear structure and excellent content. it also showed that 1) faculty are very open to incorporating patient safety topics into the existing curricula; 2) learners' perceptions of their knowledge of patient safety issues significantly increased, and 3) significant improvements in the 'know how' of the before and after cohorts were observed. the requirement of health professionals’ education to develop and integrate patient safety learning into the curricula of the different professions is a challenge for many institutions because of the limited education and training of faculty staff in patient safety concepts. it is for this reason that who began, in early 2010, to develop a multi-professional guide to facilitate the education and training in patient safety of dentists, doctors, nurses, midwives, pharmacists through the introduction of safety topics in curricula. an expert working group comprised of experts from around the world was called to contribute towards the development of the multi-professional edition. the testing and evaluation of the multi-professional edition of the who guide is being planned for 2011 in 12 sites representing dental, midwifery, nursing and pharmacy schools around the world. who is focusing on raising awareness about patient safety education; it plans to disseminate the multi-professional edition of the curriculum guide worldwide and lead global efforts to mobilise resources and increase commitment to patient safety education. addressing global patient safety issues: an advocacy toolkit for patients organizations hussain jafri international alliance of patients’ organizations (iapo). email: hussain1@hotmail.com. when we receive health care we expect, as a basic right, that it will be safe and of good quality; however, this is not always the case with patient safety incidents affecting patients all over the world, regardless of the status of national health care systems. in november 2008, the international alliance of patients organizations (iapo) launched an advocacy toolkit with the aims to equip patient advocates with a basic understanding of a range of important patient safety issues and provide a range of basic information and tools. iapo has a core value of providing capacity building resources for patients’ organisations and involving patients and patients’ organisations in debate and policy-making at the international, regional, national and local levels. the toolkit, “addressing global patient safety issues: an advocacy toolkit for patients’ organizations”, is the first multi-issue resource for patient groups, providing the means for patients and patients’ organisations to engage in the provision of health care and contribute to a quality and safe health care system, and a reduction in harm to patients. iapo’s toolkit presents information so patients’ organisations can develop their understanding of the issues and enable them to get involved in information provision to patients and participate in policy debates in a meaningful way to improve patient safety. the toolkit focuses on a number of specific patient safety issues for example: counterfeit medicines, risk benefit choice, reuse of single use medical devices, medical errors etc. each section of the toolkit has an introduction explaining the issue and guiding the reader through the different materials available. iapo is involved in a number of patient safety initiatives and these initiatives are highlighted in the toolkit (iapo is on the steering group for patients for patient safety, the patient involvement strand of the world abstracts | 429 31st jan 2nd feb 2011 health organization’s world alliance for patient safety and a member of the world health organization initiated international medical products anti-counterfeiting taskforce). patient’s safety challenges in oman: need for collaborative thinking ahmed al-mandhari director general, sultan qaboos university hospital, muscat, oman. email: manar96@yahoo.com. health care services in oman have witnessed tremendous improvements during the last few years. that was reflected in the number of health care facilities available and the number and type of specialised and sub-specialised health care services introduced recently. this improvement is coupled with assurance of good quality and safe health care service provision. however, such a noble target is faced with challenges that require in-depth analysis and then appropriate actions to avoid any dents in the successes already achieved by the health care system in oman. one challenge is the changing trend of diseases from acute illnesses requirng few visits to health care facilities to chronic diseases, such as diabetes, that need frequent visits and the use of poly-therapy. this carries its own risk to patients and staff alike. other challenges are the pushing and pulling factors that have affected the stable supply of skilled and competent health care professionals. this ultimately affects the quality and safe provision of services. such a challenge is linked to the increasing cost of health care services, given the introduction of new modalities of treatment and equipment. the mass media present another challenge as issues they bring to public notice may impact the trust and the health care seeking behaviour of the community, thus affecting the quality and safe provision of services. patient empowerment, on the other hand, is further challenge; if used appropriately it will help health care providers to make the patients and the community active players in any quality and safety assurance system. finally, legislative rules and regulations play a major role in strengthening and sustaining the relationship between health care systems and patients, thus helping to build up a good rapport. the media and legislative rules and regulations on the delivery of good quality and safe health care services can use words that could widen the gap between health care providers and patients thus negatively affecting trust levels. in summary, the success of a health care system in delivering good quality and safe services is guaranteed if such challenges are faced and analysed, and then acted upon accordingly. what does patient centered care look like? triona fortune director of programmes, international society for quality in health care, dublin, ireland. email: tfortune@isqua.org. patients are the most powerful drivers of quality improvement and patient safety. it is now an accepted fact that achieving high levels of patient satisfaction is fundamental to the clinical success of health care organisations; however patients still feel marginalised rather than empowered and involved in their care. while it is vital to ensure patients are treated with dignity and respect, research has also shown that patient centred organisations have achieved higher compliance with patient safety initiatives. examples of this include: decreased rates of hospital acquired infections, decreased surgical complication, decreased mortality rates, improved clinical outcomes, greater compliance with medication safety and higher levels of staff satisfaction and retention. yet despite the above, evidence suggests that while clinicians think it is important to ask patients about their expectations they are failing to perform this step. this presentation will examine international trends and the reasons why focusing on the patient is so important. different frameworks for involving patients in their own care and in influencing service design and quality improvement projects will be explored. these will range from international programmes such as the kings fund point of care project in the uk and planetrees designated hospital programmes in the us. international accreditation programmes will be assessed from the service users’ point of view. strategies for acquiring and using patient feedback will be examined. the trend of measuring patient satisfaction has now shifted towards patient experience tools. patient satisfaction questionnaires are viewed as an entry point, but due to their subjective nature should be supported by other measures such as focus groups and open interviews. learning from adverse events and patient complaints is another source of rich data that can be used to improve services. finally, some results of key surveys and the importance of using results of measures to create change will be addressed. influence of media on health norms mohammed kamal head of quality, directorate general health services north batinah region, ministry of health, oman. email: kamal7112004@yahoo.com. mass media are an integral part of the social environment in which people, especially young people grow up. television, radio, movies and music videos can contribute to setting social norms. socio-environmental models of health and well-being have considered mass media as an important and overwhelming force of social influence and socialisation for individuals and families. media play a very important role in formulating the community culture so combined efforts by decision makers, health authorities and media experts could become a positive force in developing a positive health culture thus beneficially impacting both individuals and the community as a whole. media can have both positive and negative effects. a number of issues and themes may be relevant to designing and implementing media programmes for young people such as the fact that– adolescents experience frequent strong emotions. adolescents could be taught about the ways in which emotions can affect their thinking and therefore their behaviour and how to control them to make better decisions. over self-confidence makes people feel they know something (whether they actually do or not) and means they will be unlikely to seek the additional information needed for good decision making. teenagers need a variety of messages as no single message will be effective. they must be believable, and concrete and focus on social, health and legal risks. exaggerating the prevalence of negative behaviors may encourage some youngsters to try risky behaviours because they perceive that everyone is doing it. the consequences of avoiding risky behaviors as well as the consequences of engaging in such behaviours should be stressed. young people may fear the social consequences more than they fear the long-range health risks. adolescents distinguish between experimental risky behavior and regular risky behavior, but may make decisions about engaging in a behaviour as if it were a one-time occurrence. 430 | squ medical journal, august 2011, volume 11, issue 3 first international conference on patient safety sultan qaboos university hospital subtracting insult from injury disclosure of medical errors krishnan sankaranarayana patient safety officer, tawam hospital, al ain, united arab emirates. email: ksankara@tawamhospital.ae. patients are often in vulnerable physical or psychological states, even with routine procedures. therefore, when harm from an unexpected event occurs, especially from someone they trust, reactions can be severe and traumatic. a common human response to something going wrong is to ask: ‘what happened?’ a health care provider goes through the same issues after an error and equally powerful emotions are felt, such as shame, humiliation, fear, panic, guilt, anger and self-doubt. in response to this stress, physicians employ several coping mechanisms, including denial and distancing. “physicians felt upset and guilty about harming the patient, disappointed about failing to practice medicine to their own high standards, fearful about a possible lawsuit, and anxious about the error’s repercussions regarding their reputation” (gallagher, waterman & ebers, 2003, p. 1005). this is compounded by fear of litigation, which causes physicians to feel guarded in their dealings with patients following an error. health care professionals who are at the socalled “sharp end” of medical error are called the “second victim.” a common perception among physicians is that good doctors do not make mistakes. because of this, physicians learn to keep mistakes to themselves rather than risk the judgment of their peers. in fact, the pressure to be perfect is so great that doctors admit they would lie to colleagues or patients to cover up a mistake. out of concern for liability exposure, some doctors have given up their practices, limited the kinds of procedures they perform, or restricted the types of patients they see. some patients resort to threatening lawsuits to solve a medical problem. growing evidence indicates that apologies reduce litigation and offer great, though unquantifiable, emotional benefits for patients, families, and health care providers. a trusting relationship between provider and patient is the bedrock of medical care. following an adverse medical event, patient and provider relationships face their greatest test. the key to success is open patient– provider communication and a true sense of caring. an apology helps to maintain a patient–provider relationship which should be followed by personal, repeated attention to the needs of the patient and family. safety in health care partnership jolanta bilinska patient safety foundation, iapo board member, poland. email: j.bilinska@nfz-lodz.pl. in 2004, the world health organization (who) launched the world alliance for patient safety. the main goals were: coordination and acceleration of international improvements in patient safety, ensuring the perspective and viewpoint of patients, families and health care consumers in developed and developing countries, and work in such areas as research, reporting and learning, designing and implementing solutions, classification for patient safety and a global patient safety challenge. twenty-one participants were selected through an international call for applications from 19 countries from all who six geographical regions. this helped to create the global patient voice, statement of purpose – london declaration. the most important issue here is to encourage patients to be actively involved in their treatment. leaders in patient safety should teach patients to initiate conversations about their condition and diagnosis, how to ask about the results of their treatment and the medicine dosage, and how to read leaflets about their care. it is important to ask caregivers how particular patient populations can be better reached and to promote staff collaboration at all levels and as well as strive for open communication. protocol for prevention of wrong site surgery vasudev aithal department of orthopedics, nizwa hospital, nizwa, oman. email: vasuaith@yahoo.com. wrong site, wrong side, wrong person and wrong procedure are disastrous to the patient and to the surgeon involved, hence they must be prevented. despite all the universal precautionary measures, wrong site surgery is still more common than surgeons are willing to accept. this results either from misinformation or misperception. a simple, practical protocol for prevention of wrong surgical event is presented with multiple checks incorporated into the system: involving many personnel and several stations. these include the outpatient department (opd), ward, operating theatre reception area and finally the operating room. the checks are done at every stage in an easy, clear-cut manner as the patient is handled: initially by the clinician at the clinic, the anaesthetist at the preanaesthesia assessment, nurses in the opd, in the ward or short-stay, and nurses in the premed room, and finally the operating surgeon, anaesthetist, circulating and scrub nurses in the operating room during the “time-out”. this paper focuses on the role of various health care personnel, the consent techniques, the pre-op marking of the surgical site and the role of “time out” in the ot. the various problems that can be encountered include patientand clinician-related factors. the protocol implements a system which prevents caregivers from committing errors and enables them to catch errors before they cause harm. the key to preventing wrong site surgery is multiple independent checks of critical information. integrating patient safety indicators with quality performance measures yasmeen al-hatmi deputy director of quality & development, sultan qaboos university hospital, muscat, oman. email: yaz4me2@yahoo.ca. in health care it is well-known that what you cannot measure, you can not improve. as health care professionals we seek continual improvement of the health care service we provide; therefore, the use of reliable indicators to measure service performance is a necessity in order efficiently to identify potential problems and make corrective actions. furthermore, through trend analysis over a period of time, across communities or regions and over a population, we are able to establish preventive measures and mechanisms to avoid reoccurrence. when the 2001 institute of medicine study entitled “to err is human” was brought to the public’s attention, it became abstracts | 431 31st jan 2nd feb 2011 clear that such measures in fact extend beyond the acute care and needs of the patient, to multiple dimensions of care and coping with the needs and expectations of the patient, family and community. in modern and specialised hospitals and health care institutions, quality performance measures are being used for applications beyond quality improvement, building on performance demonstration projects for excellence. they respond to the multi-processes, disciplines and specialities of health care delivery and quality care. measures include audit, peer review, key performance indicators and continuous quality initiatives. seeking continual improvement with concern for the safety of the patient and the environment raises the need for patient safety awareness and the implementation of indicators which integrate with the established quality performance measures, ultimately resulting in multiple dimensional indicators. in response to this need of multiple dimensional, accessible quality and safety indicators in a hospital environment, this presentation aims to identify and emphasis the importance of developing and implementing a family of measures. these can be used by health care providers, policy makers, statisticians and researchers with their own inpatient data to identify variations in the quality of inpatient and outpatient care and to move towards excellence in quality health care provision and safety for all. nurses perceptions of safety culture at hamad medical corporation (hmc) in the state of qatar moza al ishaq assistant executive director risk management, hamad medical corporation, doha, qatar.email: mabdulla@hmc.org.qa. the safety culture in any health care organisation depends on the improvement of the safety measures delivered to increase patient care and learn from lessons, and the proactive strategies in place to prevent future errors. we evaluated registered nurses’ perceptions of safety culture in the units where they provide nursing care at hamad medical corporation (hmc). the agency for health care research and quality’s (ahrq) patient safety culture instrument (hospital survey of patient culture) was modified and used for the purpose of this study. a total of 800 questionnaires were distributed to randomly selected nurses from 8 targeted clinical services with a response rate of 57%. the results of this study were compared with those from american hospitals using the original ahrq survey. ranking of subscales for this study in terms of strengths and areas needing improvement were almost identical to the ranking us hospitals results, with teamwork within units ranking highest and indicating a strength; and the subscale non-punitive response to errors the lowest, and indicating an area for improvement. positive response rates in terms of safety culture for this study were generally lower on most subscales compared to the us results and may reflect the intensity of patient safety improvement activity in the us over the last eight years. this was done in response to the institute of medicine’s report on medical errors in 1999. results from this study are presented with a baseline measurement for safety culture at hmc and suggestions as to how the instrument that can be adapted for use in other middle eastern health care organisations. improving quality and safety in health care through connected technology a chief executive officer’s perspective professor stan capp regional director, intersystems corporation, sydney, australia. email: stan.capp@intersystems.com. the role of health service boards of governance now is far greater than simply ensuring that financial and corporate matters are appropriately managed. the emergence over the past 10 years of the principle of clinical governance now requires boards and chief executive officers (ceos) to be accountable for the quality and safety of all those who enter their facilities whether they be patients, staff or visitors. while modern patient administration and clinical information systems provide sophisticated functionality to support quality of care objectives, recent developments enabling health care organisations to harness the data collected in these systems in realtime is empowering these organisations to make smarter, faster, more informed decisions than ever. connected systems with embedded business intelligence capabilities enable ceos to track key performance indicators in a single view, triggering alerts to enable early intervention. at a higher level, boards can receive reports that signal areas of concern while ensuring that clinicians and managers are more accountable for the activities that occur throughout their hospitals. improving patient safety using quality tools and techniques asila al-ghuniani head of quality, ibra hospital, ibra, oman. email: aremass@hotmail.com. patient safety is a discipline in the health care sector that applies safety science methods toward the goal of achieving a trustworthy system of health care delivery. patient safety is also an attribute of health care systems; it minimises the incidence and impact of adverse events and maximises recovery from them. the focus is on how to improve patient safety in health care. by using different tools and techniques, two of the tools represented will include: failure mode and effect analysis (fmea) and root cause analysis (rca). these tools were used to avoid events and improve or maintain the quality of care. fmea was used prospectively to identify potential areas of failure where experimental characterisation of the process at the desired speed of change could be assessed. retrospectively rca was used to characterise the safety of a process by identifying potential areas of failure and learning about the process from the staff ’s point of view. using a flow chart of the process, before beginning the analysis, got the team to focus and work from the same document. information learned from the fmea was used to provide data for prioritising improvement strategies, serve as a benchmark for improvement efforts, educate and provide a rationale for diffusion of these practice changes to other settings, and increase the ability of the team to facilitate change across all services and departments within the hospital. using fmea facilitated systematic error management which was important to good clinical care in complex processes and settings. it depended on a multidisciplinary approach, integrated incident and error reporting, decision support, standardisation of terminology, and education of caregivers. 432 | squ medical journal, august 2011, volume 11, issue 3 first international conference on patient safety sultan qaboos university hospital patient safety at sultan qaboos university hospital salem al-tamemi department of child health, sultan qaboos university hospital, muscat, oman. email: tamemi@squ.edu.om. sultan qaboos university hospital (squh), opened in 1990, is the leading teaching hospital for medical students, medical and surgical residents and nursing students in oman. in addition to teaching and conducting medical scientific research it provides excellent clinical services and the health care quality standards are in compliance with international norms. patient safety is one area of quality practised at squh. the international patient safety goals recognised by the world health organization have been adopted by many health care institutions in order to provide safe care for their patients. these goals address the following crucial patient safety subjects: improving the accuracy of patient identification; making communication more effective; improving the safety of using high-alert medications; ensuring correct-site, correct-procedure, correct-patient surgery; reducing the risk of health care associated infections, and reducing the risk of patient harm resulting from falls. currently patient identification is addressed by using both verbal and visual verification techniques and patient id bands contain the full name of the patient and medical record number; they are matched during investigations and procedures and prior to administering medications. electronic labels are used for blood samples and medications. newborns receive two id bands in the delivery suite and another one is placed on mothers’ wrist. identifications of both caller and receiver are used when communicating critical laboratory values. the values are read out with the unit and the receiver must read back the report; both documented medical records and numerical digits pronounced separately. there are restrictions for verbal medication orders. high alert medications are handled with extra care. preoperative checklists and the ‘time out’ technique are practiced to ensure correct site procedures and correct patient surgery. various measures exist to reduce health care related infections: use of antiseptics and sterilisation procedures together with the implementation of hand hygiene and surveillance of nosocomial infections. finally, measures are in place to reduce risks of patient falls by giving instructions to the patient, as well as the use of bed bars. medical error(s) disclosure and its impact on malpractice litigation abdullah al-asmi department of medicine (neurology), sultan qaboos university hospital, muscat, oman; chair higher medical committee, muscat, oman. email: aalasmi@gmail.com. regardless of all attempts made to minimise medical errors, they still nonetheless occur and place significant financial burdens on health services as well as having a negative impact on health professionals. the debate continues on the advantages and disadvantages of disclosing medical errors to patients or their relatives. there are still a number of barriers related to medical error disclosure, due to issues related to the health system, patients, and law. however, emerging evidence from hospitals where medical error disclosure to patients/relatives is systemically employed shows that disclosure has reduced litigation liabilities considerably. it is therefore imperative that efforts be made to train health workers in medical error disclosure as this will consequently have a positive impact on patient safety and may reduce endless litigations against physicians and the health system. a study to analyze the use of internet as a tool in increasing safety of medical devices abdullah al-hashmi madhan g, biomedical engineering department, sultan qaboos university hospital, muscat, oman. email: amhashmi@squ.edu.om. high quality, well designed medical devices are required to provide safe and effective clinical care for patients as well as ensuring the health and safety of health care practitioners and users. the internet is a very important source of information for health care providers providing immediate access to updated information in health care technology. factors limiting practitioner access to the internet have been identified and the literature shows that access to the internet varies across and within health professions. there has, however,been no identified empirical research investigating practitioner access to or use of the internet in medical device technology assessment. this study sought to establish the professional use of internet-based tools by sultan qaboos university hospital (squh) practitioners in increasing the safety of medical device use. in this study, both qualitative and quantitative approaches were used, including interviews with 30 practitioners from nurses, technologists, doctors, to consultants and biomedical engineers. in addition, a one page survey questionnaire was distributed 75 randomly selected 75 practitioners. they were asked different questions related to their use of the internet as a tool to increase patient safety. also preventive maintenance (pm) records of 400 equipment items were analysed for device recalls or alerts. in conclusion, the internet as a vital source of information was widely used by squh practitioners; however, there was no indication that they used it to obtain safety updates on medical devices. nonetheless, more than 70% of the practitioners were willing to be part of a systematic approach to using the internet as a tool to increase medical devices safety. this study provides baseline data to establish an internet based approach in increasing the safe use of medical devices. a safe patient journey through patient flow management samira al-rasbi nursing services, sultan qaboos university hospital, muscat, oman. patient flow management plays a key role in the hospital; it helps health care organisations achieve safe and advanced outcomes of patient care, through improving patient access to acute care services and their safe and effective flow through the hospital towards discharge. however, it also allows real-time information about their patients without multiple calls to various departments and staff. it should be a collaborative process that assesses, plans, implements, monitors, and evaluates the options and services required to meet an individual’s health needs, using communication and available resources to promote quality outcomes. an effective patient flow abstracts | 433 31st jan 2nd feb 2011 management system actively manages patient care from admission through the entire continuum of care. each hospital should have a core patient flow management team with operational responsibility for bed management and discharge planning. the main three goals for the patient flow manager are: improve accident & emergency performance; facilitate reductions in the length of stay, and improve the patient experience. the flow of patients through an acute hospital depends upon a complex set of relationships between many departments, services and people. conquering developments in the way patients move through such a complex system requires a synchronised approach to admission, treatment and discharge of patients based on core principles of system efforts. it requires hospitals to unpick the complexity of their existing processes so they can understand where the key bottlenecks exist within their clinical units. it also requires a fundamental commitment to providing safe, effective, efficient and timely care whereby services are designed first and foremost according to patient needs. successfully improving flow across an organisation requires an extraordinary level of commitment to a complex and exhaustive change process. it also requires acknowledgement that there may, at times, be a requirement to tackle issues that have previously been ‘taboo’ within the organisation. improve the accuracy of patient identification asila al-busaidi and kauthar al-kiyumi nursing services, sultan qaboos university hospital, muscat, oman. email: asila69@yahoo.com. sultan qaboos university hospital (squh) is committed to provide a safe environment for all of its patients. the vision of the squh nursing directorate vision is to strive for safe practice for their in and outpatients. one of the main goals for the joint commission of national patient safety in usa is to promote patient safety in the practice of the organisations (jci, 2010). the national patient safety goals make an effort to improve the health care before patient errors occurs. squh has adopted six patient safety goals. one of the goals is patient identification. it is internationally recognised as a goal which is adopted by major patient safety agencies like the world health organization, jci, center for patient safety and other agencies who deal with patient safety and aim to reduce errors and improve patient identification. there are many causes of patient identification errors during admission, discharge and transfer. the failure to identify, or the misidentification of a patient, can lead to medication errors, transfusion errors, wrong-site of surgery and wrong diagnosis. a randomised audit with closed-ended questions was distributed to the nursing staff. data from unannounced audits of patient identification were plotted and shared with the nursing directorate and staff nurses. the results of the audit bring significant improvement and awareness among the staff about patient identification with clear expectations to immediately stop the line if a patient identification error is identified. patient identification accuracy is an essential procedure in patient safety and, in many hospitals, correct patient identification and wearing of an identification band are essential procedures to meet accreditation standards. policies in patient identification vary from hospital to hospital to comply with standard practices of patient identification. safe care is the soul of your care fatima al-amri sultan qaboos hospital, salalah, oman. email: cattyom3@gmail.com. yearly hundreds of thousands of patients worldwide either die or end up with disabilities because of errors committed by health care providers. such statistical reports shocked the international community and prompted the world health organization and other organisations to take strong action. they have made efforts had taken place to identify the sources of these errors; astonishingly, the causes were negligence and ignorance of the basic rules and regulations that had been set in place to ensure patient safety. the poster shows three areas that affect patient safety. caricature illustrations have been used to show four situations which are then described below. ‘to err is human’ is not only statement but an undeniable fact as has been proven by many studies. in 2009, the world health organization (who) announced that their study conducted in 2004 found that of 187–281 millions surgeries performed, 5–10% resulted in death due to complications and that half of these were preventable. when patient identification rules are followed before surgery, the risk of errors and their negative or even fatal consequences decreases. some of the studies have rated medication error as the highest cause for morbidity and mortality related medical injuries. they found that most of these errors occur during medication administration. therefore, joint commission international or jci (an internationally recognised body for accreditation of health care institutions) has set medication safety as one of the highest priority goals for patient safety. the internet and psychiatry, effect on suicidal behaviours samah al-araimi nursing department, royal hospital, muscat, oman. email: omahmed2008@windowslive.com. the internet is increasingly used to access health data and information. this explosive growth brings threats as well as opportunities. the internet has a remarkable effect on medicines and psychiatry. it can promote the idea of several harmful behaviours, such as suicidal attempts. it is extremely easy to access information about suicide from the internet. recent articles have described use of the internet by individuals to obtain instructions on how to complete a suicide. editorials and discussions have focused on the existence of these sites and the information they provide. a large number of websites and discussion groups provide information identifying methods of self-harm. one site described using guns, overdosing, slashing one’s wrists, and hanging as the "best methods to commit suicide." the researchers used popular search engines to find pages using simple terms like "painless suicide" and "how to kill yourself " and were disturbed to find that only a fifth of the resultant sites offered support or prevention. vulnerable individuals have been sharing information about suicide. there are examples of interactive notes followed by a suicide fatality. many studies have reported a significant degree of clustering of suicides following media coverage of a suicidal event or personal contact with a suicide victim. the internet can potentially influence people’s thoughts and behaviours when it comes to suicide; however, it can be utilised to prevent such events. comprehensive studies should be conducted to support internet use for suicide prevention. 434 | squ medical journal, august 2011, volume 11, issue 3 first international conference on patient safety sultan qaboos university hospital together we shine media, patient safety and nurses shreedevi balachandran college of nursing, sultan qaboos university, muscat, omanز email: shreedev@squ.edu.om. the role of media in promoting patient safety around the world has been well established. it is fast becoming one of the most effective ways to monitor patient safety and provide real time commentary. movement toward these media networks is evident as the health care industry recognises the importance and benefits of spread using media. the news media have been an important force in prompting patient safety improvement efforts around the world. it was the news media's history of skepticism about the medical profession that ultimately changed the attitude of health care industry towards patient safety. however, allowing media to be a part of the patient safety initiative has also proven to be effective in not only reducing errors, but also empowering patients and families as partners of health care. the media is influential at the level of individual patient, his/her family and society at large. the media can promote patient safety in the following ways: disturb, stir up, encourage debate; set agendas “tell people what to think about”; legitimise “if the newspapers are talking about safety, it must be important”; reporting cases to the world the world is interested; reporting data; explaining error: why does it happen? what can be done? and generating political commitment for improvement. what we need currently is a cultural and a political change in the health care industry towards consciousness of patient safety issues. the willingness on part of the health care industry to accept the errors and remedy them will emerge only through a cultural shift. nurses have always been advocates of patient safety. changes in attitudes and culture will not occur if efforts are not united. a joint effort of the nurses with the media will ensure that appropriate attention is given to patient safety issues. the formulation of a joint committee with members from the local media at every hospital will be the first step in this endeavour. patient safety goals nada farah sultan qaboos hospital, salalah, oman. patient safety has become a serious global issue in recent years. this was the result of many reports and studies initiated for patient safety. in 1999, a report by the institute of medicine estimated that as many as 44,000 to 98,000 people die in u.s. hospitals each year as the result of lapses in patient safety measures. one study found that there is one chance in 1,000,000 of travellers being harmed in aircraft; in comparison there is a one in 300 chance of a patient being harmed during health care. another study showed that at any given time 1.4 million people worldwide suffer from infections acquired in hospitals. another study estimated that in developed countries as many as one in 10 patients is harmed while receiving hospital care; this could be caused by a whole range of errors or adverse events as stated by world health organization (who) in 2010. therefore, countries have increasingly recognised the importance of improving patient safety. in 2002, who member states agreed upon a world health assembly resolution on patient safety. the joint commission international (established in 2002 to help accredit health organisations) set the national patient safety goals (npsgs) which address specific areas of concern in regards to patient safety. npsgs underwent an extensive review process in 2009 resulting in revised 2010 npsgs. to highlight the importance of this global movement, we use informative and eye-catching posters throughout our hospital to communicate and reinforce the awareness and importance of psgs to health care workers. psg posters are based on the 2008 national patient safety goals of the who and the joint commission. medication market in patient safety salima balushi and buthaina al-harthy nursing department, ministry of health, muscat, oman. emails: womens_wisdom@lire.com, salma.albalushi@villanova.edu. patient safety and medical error have become major issue socially and legally worldwide. technology can play a role in preventing the possibly fatal consequences of such errors. the electronic medication administration record (emar) bar code is an important way to improve medication safety. emar is a combination of technologies that ensures that the correct medication is administered in the correct dose at the correct time to the correct patient. when nurses use this combination of technologies, medication orders appear electronically in a patient's chart after pharmacist approval. alerts are sent to nurses electronically if a patient's medication is overdue. before administering medication, nurses are required to scan the bar codes on the patient's wristband and then on the medication. if the two do not match the approved medication order, or it is not time for the patient's next dose, the system issues a warning. moreover, several studies have shown that the emar system reduces the rate of error not only in medication administration, but even in the order transcription, and as well as reducing potential adverse drug events. furthermore, it plays a role in educating the nurses, doctors and pharmacists. for instance, bar code scanning requires the nurse to check heart rate prior to administration of diagoxin. in conclusion, bar codes can be beneficial only if health care providers use them properly so training is vital to assure the success of emar. parental knowledge and compliance with neutropenia care guidelines in children admitted with leukaemia at squh, oman nancy reyes, preethy dsouza, renu g, norah ngcamu, mamatha p. nursing services, sultan qaboos university hospital, muscat, oman. email: b2-nrs@squ.edu.om. leukaemia, cancer of the blood forming tissues, is the most common form of childhood cancer (american cancer society, 2007). acute leukaemia is the most common malignancy in children in oman. it accounts for over one-third of all childhood cancers, 75% of them being acute lymphoblastic leukaemia (all). the paediatric hemato-oncology unit at sultan qaboos university hospital (squh) is the national referral centre for childhood leukaemia in oman. despite advancements in the management of childhood leukaemia, the complexity and challenge of caring for children continues. chemotherapy is the mainstream treatment for child hood leukaemia. aggressive chemotherapy protocols result in neutropenia in approximately half of all patients receiving chemotherapy (ozer et al., abstracts | 435 31st jan 2nd feb 2011 2000). thus, neutropenia continues to be a significant and potentially life-threatening side effect of treatment. in a paediatric setting, the families of children are actively involved in the management and care of leukaemia. hence, it is necessary to ensure that they provide a safe therapeutic environment for children in the neutropenia stage in the hospital and at home. the study examined parental knowledge and compliance with neutropenia care guidelines in children admitted with leukaemia at squh. the objectives of the study include assessing the knowledge and compliance of parents regarding neutropenia in children admitted with leukaemia; identifying the information needs of parents of children with neutropenia; exploring the factors affecting compliance in the home care of children with neutropenia, and to examine compliance of parents with neutropenia care guidelines and selected factors. patient safety a shared responsibility for ensuring quality care noronha ja, seshan v, raman s, ramasubramaniam s, madavan g, muliira rs, akintola a, shellah e. college of nursing, sultan qaboos university, muscat, oman. email: juval12@squ.edu.om. patient safety is one of the nation’s most pressing health care challenges. statistical reports suggest that 1 in 10 patients globally are adversely affected by health care errors. worldwide 1.4 million people suffer from hospital acquired infection (world health organization, 2009). patient safety is defined by the institute of medicine as “the prevention of harm to patients”. the current emphasis is on the health care system focussing on preventing error, learning from the errors that have taken place in other health care set ups else, and building a culture of safety that involves health care professionals, organisations and patients. patient safety, as a vital component of quality nursing care, requires that safe care is delivered in an appropriate, timely, efficient, equally to all individuals seeking health care. this paper highlights the role of health team members in providing safe care by ensuring the necessary communication, leadership, and mutual support with constant situation monitoring. it is the responsibility of the health care team to give their best performance, to increase their level of knowledge and to have a positive attitude towards safer health care. teamwork and shared responsibility will ensure better health care, minimise errors and thus promote better health care outcomes role of the media in patient empowerment sana jubran and manal al-bulushi nursing services, sultan qaboos hospital, salalah, oman. the mass media have become an integral part of our daily life; we spend most of our time in front of the tv, on the internet or reading newspapers. mass media have long been an attractive method for implementing and discharging institutional responsibility for the promotion of good health practices as well as the prevention of various social and health problems. the huge amounts of information available has affected peoples’ attitudes to health related issues including outcomes. an issue of great importance for public health today is how to develop programmes that change behaviour in order to improve the health of our population. over time people’s knowledge about health related issues has increased in terms of their ability to make their own decisions regarding their health management. it is no longer just the word of the health care provider that ensures better health outcomes for the patient; the responsibility is now shared by the health care provider and the patient. mass media indeed could be used effectively in providing the proper information so that clients can cooperate with the health care provider to improve their life style and health outcomes; however, this study shows that mass media can also transfer poor information to people. it also illustrates how mass media contributes to people’s knowledge of their rights to participate in their health care plan; how people interact and deal with the media; whether they believe in the information broadcasted by the media, and whether they apply that information in their life. nurses’ role in patient empowerment and autonomy for safe care: speak up melba dsouza and ramesh venkatesaperumal college of nursing, sultan qaboos university, muscat, oman. the words “empowerment and autonomy” have been broadly defined as an enabling process through which individuals or communities take control of their lives and their environment. in this millennium, patients are no longer just the receivers but also the partners of care. as such, patients have the right and power to change the way the health care system functions. in order to do this, they need to be empowered with the necessary information. nursing places patient empowerment and autonomy as a central remit of nurses; however, achieving genuine patient empowerment is not easy and requires individuals and organisations to alter their beliefs, values and behaviours. the word empowerment builds upon the latin root potis, from which we derive both the words power and freedom. patient empowerment or autonomy in the health care context means to promote autonomous self-regulation so that the individual’s potential for health and wellness is maximised. empowerment requires an individual to have the autonomy to take care of him or herself and make choices about care from among the options identified by the doctor. patient empowerment begins with information and education and includes seeking out information about one’s own illness or condition, and actively participating in treatment decisions. autonomy means that patients actively participate in their treatment and are empowered to be assertive and communicate their concerns. this paper describes how a nurse-led campaign, ‘speak up” can empower patients for safe care through education and autonomy. speak up if you have questions or concerns; pay attention to the care you are receiving; educate yourself about your condition; ask a trusted friend to be your advocate; know your medications (what and why); use a health provider that measures safety; participate in all decisions about your care. 1dermatology service, hospital universitario reina sof ía, instituto maimónides de investigación biomédica, córdoba, spain; 2department of dermatology, complejo hospitalario de granada, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com ورم عصيب متحدد ومنعزل قرائن فحص اجللد لتسهيل التشخيص بابلو فريدينانز-كريهوت و ريكاردو رويز-فيال فريدي solitary circumscribed neuroma dermoscopic clues to facilitate diagnosis pablo fernández-crehuet1 and *ricardo ruiz-villaverde2 a 66-year-old woman presented to the dermatology outpatient clinic of the hosp-ital universitario reina sof ía, córdoba, spain in 2017 with a 10-year history of a painful slowgrowing erythematous lesion on her chin. a clinical examination revealed a pink, translucent, firm, nonulcerated papule of 6 mm [figure 1]. no similar cutaneous or mucosal lesions were noted anywhere else on the body. polarised non-contact dermoscopy of the papule (dermlite dl3n®, 3gen inc., san juan capistrano, california, usa) indicated arborising vessels on a pinkish-reddish background, a central white spot and peripheral pigmentation [figure 2]. following complete surgical excision of the lesion, a histopathological examination revealed a well-cir cumscribed partially-encapsulated dermal proliferation comprised of spindle cells with scanty pale cyto plasm and elongated wavy nuclei. the nuclei were grouped in distinct fascicles set in fibrillar, collagenous and occasionally myxoid stroma [figure 3]. the patient was subsequently diagnosed with a solitary circumscribed neuroma (scn). she recovered successfully following the surgery, with no recurrence observed after 10 months of follow-up. comment also known as palisaded encapsulated neuromas, scns usually present in adulthood as asymptomatic small nodules of between 2–6 mm, mainly located on the face. however, cases have been described in other locations, including the shoulder, hands, arms, feet and mucosal areas.1,2 mucosal neuromas have been linked with multiple endocrine neoplasia 2b syndrome and phosphatase and tensin homolog deleted on chromosome 10 hamartoma tumour syndromes, including cowden syndrome, proteus syndrome and bannayanriley-ruvalcaba syndrome.3,4 histologically, the examination of an scn reveals a well-circumscribed partiallyencapsulated intradermal nodule comprised of spindle cells grouped in distinct fascicles with a lack of nuclear interesting medical image sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e116–117, epub. 4 apr 18 submitted 4 nov 17 revision req. 31 dec 17; revision recd. 2 jan 18 accepted 11 jan 18 figure 1: photograph of a pink, translucent, firm, dome-shaped papule on the left side of the chin of a 66-year-old woman. doi: 10.18295/squmj.2018.18.01.023 pablo fernández-crehuet and ricardo ruiz-villaverde interesting medical image | e117 ovoid nests, globules, dots or blotches and browngrey leaf-like small erosions or ‘wheel-spoke’ areas—is not sufficient to warrant avoiding excision of the lesion. clinicians should be aware of the characteristic arborising vascular patterns of scn which appear dermoscopically as white patches on a pink-white background.4,5 references 1. reed rj, fine rm, meltzer hd. palisaded, encapsulated neuromas of the skin. arch dermatol 1972; 106:865–70. doi: 10.1001/ archderm.1972.01620150051016. 2. magnusson b. palisaded encapsulated neuroma (solitary circumscribed fibroma) of the oral mucosa. oral surg oral med oral pathol oral radiol endod 1996; 82:302–4. doi: 10.1016/ s1079-2104(96)80356-8. 3. megahed m. palisaded encapsulated neuroma (solitary circ umscribed neuroma): a clinicopathologic and immunohistochemical study. am j dermatopathol 1994; 16:120–5. doi: 10.10 97/00000372-199404000-00002. 4. fernández-crehuet p, fernández-crehuet jl, ruiz-villaverde r, sanz-trelles a. solitary circumscribed neuroma: a clinical and dermoscopic mimicker of basal cell carcinoma. int j dermatol 2015; 54:e275–7. doi: 10.1111/ijd.12828. 5. moyano eg, blanca ma, pilar lm, martos ao, fernandez ballesteros md, trelles as. homogeneous white patch in dermoscopy of solitary circumscribed neuroma. j am acad dermatol 2017; 76:s84–5. doi: 10.1016/j.jaad.2015.11.020. pleomorphism and mitosis.4 immunohistochemical studies of scn cases have demonstrated positive cell staining for s100 proteins, collagen type iv and vimentin.2–4 in cases where the diagnosis is not clear, glial fibrillary acid protein and epithelial membrane antigen staining may also be necessary.3 from a physiopathological point of view, it has been suggested that scns are caused by the inexplicable hamartomatous growth of schwann cells over axons.4 the clinical and dermoscopical differential diagnosis should include basal cell carcinomas (bccs), adnexal tumours, neurothekeomas, vascular tumours and intradermal melanocytic naevi.4 in addition, scns may have similar histological findings to those of neurofibromas and schwannomas; however, while neurofibromas lack a capsule and contain a mucopolysaccharide ground substance, schwannomas are generally subcutaneous and contain antoni types a and b tissue patterns and verocay bodies with no axons present.3 immunostaining with human melanoma black-45, melan-a, tyrosinase and cluster of differentiation (cd)34 can be useful to differentiate these entities. dermoscopy is a useful noninvasive tool that helps to identify tumours that mimic bccs.4 however, the absence of bcc features—including blue-grey figure 2: dermoscopic image showing a symmetrical non-pigmented lesion with an arborising vascular pattern and surrounded by a peripheral dark-yellowish halo. figure 3: haematoxylin and eosin stain at x10 magnification showing a well-circumscribed dermal nodular tumour comprised of small spindle cells (asterisk) without atypia or mitotic evidence of malignancy. the cells are grouped in small fascicles separated by grooves embedded in an eosinophilic fibrillar matrix (arrow). https://doi.org/10.1001/archderm.1972.01620150051016 https://doi.org/10.1001/archderm.1972.01620150051016 https://doi.org/10.1016/s1079-2104%2896%2980356-8 https://doi.org/10.1016/s1079-2104%2896%2980356-8 https://doi.org/10.1097/00000372-199404000-00002 https://doi.org/10.1097/00000372-199404000-00002 https://doi.org/10.1111/ijd.12828 https://doi.org/10.1016/j.jaad.2015.11.020 1department of community medicine, hawler medical university, erbil, iraq; 2department of preventive health, public health institute, erbil, iraq *corresponding author e-mail: awringmaroof62@yahoo.com قياس مستوى التعاطف لدى طالب الطب الكرد يف مدينة أربيل يف العراق دراسة مقطعية اأورينك معروف روؤوف و بريف�ن عدن�ن ي��شني abstract: objectives: empathy is a crucial attribute within the physician-patient relationship. this study aimed to evaluate the empathy levels of students in the college of medicine at hawler medical university (hmu) in erbil city, iraq. methods: this cross-sectional study took place between january and may 2015 and included all medical undergraduates enrolled at hmu (n = 989). the validated self-administered english language version of the jefferson scale of physician empathy-student version (jspe-sv) was used to measure empathy levels. students reported their conformity to each statement of the 20-item questionnaire on a 7-point likert scale. levels of empathy were considered directly relative to their final score. results: a total of 927 students completed the questionnaire (response rate: 93.7%). the male-to-female ratio was 0.72:1 and the mean age was 21.3 ± 1.4 years. the mean empathy score was 101.9 ± 19.2. female students had significantly higher empathy (p = 0.023) and more frequently chose people-oriented specialties (p = 0.001) than males. first-year students reported the highest mean score (112.9 ± 20.1) while fourth-year students had the lowest (92.7 ± 16.0). there was a significant decline in mean scores between firstand second-year male students (p = 0.020) and firstand fourth-year male students (p = 0.050). students who chose people-oriented specialties had significantly higher scores than those who chose technologyoriented specialties (p = 0.002). conclusion: the studied cohort of hmu students demonstrated low empathy levels. as such, the inclusion of empathy instruction in medical school curricula is recommended to promote professionalism and patient welfare. keywords: empathy; attitudes; medical students; physician-patient relations; medical education; iraq. امللخ�ص: الهدف: يعد التقم�ص الع�طفي �شفة مهمه يف عالقة الطبيب مع املري�ص. ك�ن الهدف من هذه الدرا�شة تقييم م�شتوى التع�طف لدى طالب كلية الطب يف ج�معة هولري الطبية )hmu( مبدينة اأربيل يف العراق. الطريقة: اأجريت هذه الدرا�شة املقطعية يف كلية الطب يف مدينة اأربيل بني �شهر ك�نون jefferson scale ا�شتبي�ن الطالب اإعط�ء مت .)n = 989( hmu يف للدرا�شة امل�شجلني الطالب جميع وت�شمنت ،2015 ع�م من م�يو �شهر و الث�ين املوثق ذاتي االإكم�ل ب�للغة االإنكليزية لقي��ص م�شتوى التع�طف. ت�شمن االإ�شتبي�ن ع�رضين �شوؤاال على مقي��ص ليكرت ذوي النق�ت ال�شبعة. ومت قي��ص درجة .)93.7% )ن�شبةاال�شتج�بة: ط�لب� 927 قبل من االإ�شتبي�ن اإكم�ل مت الط�لبة. النتائج: اأو الط�لب �شجله� النه�ئيةالتي النق�ط عدد اإىل من�شوب� التع�طف ك�نت ن�شبة الذكور اإىل االإن�ث 0.72:1. وك�ن معدل اأعم�رهم 1.4 ± 21.3 �شنة. ك�ن معدل التع�طف للطالب 19.2 ± 101.9 وك�نت درجة تع�طف االإن�ث .)p = 0.001( اإح�ش�ئية داللة مع الذكور اأكربمن ال�رضيرية للفروع االإن�ث اختي�ر ن�شبة وك�نت )p = 0.023( اإح�ش�ئية بداللة اأكرب الذكور اإىل ن�شبة ك�نت اأعلى الدرج�ت لطالب ال�شنة االأوىل )20.1 ± 112.9( بينم� درج�ت طالب ال�شنة الرابعة ك�نت االأقل )16.0 ± 92.7( ك�ن هن�ك نق�ش�ن يف معدل الدرج�ت لطالب ال�شنة الث�نية مق�رنة مع طالب ال�شنة االأوىل ذا داللة اإح�ش�ئية )p = 0.002( و�شجل طالب الفروع ال�رضيرية معدل اأعلى من طالب الفروع التكنولوجية. اخلال�صة: ك�ن معدل التع�طف متدني� يف املجموعة املدرو�شة من hmu. تو�شي هذه الدرا�شة ب�إعط�ء االأهمية للتوجيه املعنوي يف املن�هج الدرا�شية للكلية لتعزيز االأداء املهني ورع�ية املر�شى. مفتاح الكلمات: التع�طف؛ ال�شلوكية؛ طالب الطب؛ عالقة الطبيب مع املري�ص؛ التعليم الطبي؛ العراق. measuring empathy levels among kurdish medical students in erbil city, iraq cross-sectional study *awring m. raof1 and bervian a. yassin2 advances in knowledge low empathy levels were reported among a group of medical undergraduate students in erbil city, iraq. female students had significantly higher empathy levels than male students among the studied group and a significant decline in empathy scores was observed among male students according to academic year. the results of this study suggest that students with higher empathy levels may select people-oriented over technology-oriented specialties. application to patient care while the results of this study cannot be generalised to all medical students in iraq, the low levels of empathy reported among the studied medical students have alarming implications for future patient care. the inclusion of empathy education in medical school curricula is therefore of vital importance due to the significant impact of this attribute on physician-patient relationships. clinical & basic research sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e62–67, epub. 2 feb 16 submitted 14 jun 15 revision req. 26 jul 15; revision recd. 24 aug 15 accepted 2 sep 15 doi: 10.18295/squmj.2016.16.01.011 awring m. raof and bervian a. yassin clinical and basic research | e63 in order to be effective, physicians need to form sympathetic and beneficial relationships with their patients.1 one of the most important skills needed to form and maintain a relationship is empathy.2 although there are several different definitions of empathy, it is generally defined as the capacity to “see the world as others see it, be nonjudgmental, understand another’s feelings, and communicate the understanding”.3 communications between patients and caregivers rely upon the empathetic nature of the medical doctor.4 hojat et al. verified that physician compassion is strongly related to enhanced patient outcomes, compliance and contentment and a decline in medicolegal problems.5 previous studies have determined various factors that affect levels of empathy, including gender, academic performance and an individual’s relationship with their mother.6,7 a study from the usa observed significant differences in empathy levels between genders and between physicians in people-oriented versus technology-oriented specialties, suggesting that certain aspects of empathy may be related to gender and choice of medical specialty.8,9 the hawler medical university (hmu) is a public university in erbil city, iraq. the recently revised sixyear undergraduate medical curriculum in the hmu college of medicine includes a series of courses on medical ethics and communication skills with the aim of strengthening future patient-physician relationships. this training is intended to guarantee that medical graduates will have the necessary clinical skills to competently and empathetically consider patients’ feelings and experiences, thus improving care by reducing patient suffering and helping them to feel more relaxed. this study therefore sought to measure empathy levels among a sample of medical students at hmu. specifically, differences in empathy levels were assessed according to gender, academic year and choice of specialty. to the best of the authors’ knowledge, no such study has yet been conducted among kurdish medical students and this is the first time that the jefferson scale of physician empathystudent version (jspe-sv) has been used in erbil city. methods this cross-sectional study was carried out between january and may 2015 and included all undergraduate students enrolled in the 2014–2015 academic year at the college of medicine at hmu (n = 989; male-to-female ratio: 0.74:1). empathy levels were determined using the jspe-sv. this self-administered english language 20-item questionnaire was originally developed in 2001 to measure medical students’ attitudes towards physician empathy in a patient-care situation.8 it has been validated in the usa, mexico and japan.8,10,11 the measurement of internal consistency (cronbach’s alpha) is 0.76.12 the english language version of the jspe-sv questionnaire was distributed to all students at the end of each class.8 the questionnaire was completed anonymously in approximately 30 minutes and returned to the researchers. respondents reported their degree of agreement with each item on a 7-point likert scale; however, 10 of the items were negative statements and were marked in reverse order.9 the final score ranged between 20–140 and a participant’s level of empathy was considered directly relative to their score. a non-responder was defined as a student who failed to return the survey. surveys with less than 16 completed items were excluded from the results. demographic information such as age, gender and choice of specialty was also collected. missing gender values for respondents who did not provide their gender was determined using a discriminate function test. males and females were categorised using forms in which the gender was identified as the endpoint. this procedure was then applied to data from those in the unknown gender group. choice of speciality was categorised as either technologyor people-oriented. technology-oriented specialties included surgery and related subspecialties; oncology; preventative and social medicine; pathology; radiology; and anaesthesiology.6 people-oriented specialties included family medicine; neurology; paediatrics; psychiatry; emergency medicine; obstetrics and gynaecology; ophthalmology; dermatology; and internal and rehabilitation medicine.6 students were asked to determine their choice of speciality by rating their future likelihood of entering each specialty mentioned above on a 4-point likert scale ranging from 1 (very unlikely) to 4 (very likely).8 each student was then classified as choosing either technologyor peopleoriented specialties after comparing their overall scores for each group. data were analysed using the statistical package for the social sciences (spss), version 21 (ibm corp., chicago, illinois, usa). measures of central tendencies and distributions were determined. the one-way analysis of variance (anova), bonferroni post hoc test and student’s t-test were used to assess statistical significance. pearson’s chi-squared test was used for group frequency comparisons. statistical significance was set at p ≤0.050. this study was granted ethical approval by the research ethics committee at the college of medicine of hmu (meeting #1 paper #5). all students were informed that participation in the study was voluntary and anonymity was guaranteed. all forms were coded to avoid respondent identification. measuring empathy levels among kurdish medical students in erbil city, iraq cross-sectional study e64 | squ medical journal, february 2016, volume 16, issue 1 results of the 989 students included in the study, a total of 927 completed the survey (response rate: 93.7%) [table 1]. there were 391 male respondents (42.2%) and 536 female respondents (57.8%) with a male-to-female ratio of 0.72:1. the mean age of the respondents was 21.3 ± 1.4 years (range: 17‒25 years old). overall, the mean empathy score of the students was 101.9 ± 19.2. table 2 displays the mean empathy scores of male and female students, respectively (98.6 ± 16.2 versus 102.5 ± 19.9). this difference was statistically significant (p = 0.023). mean empathy scores decreased as academic years increased; first-year medical students reported the highest mean empathy score (112.9 ± 20.1) while the lowest mean score was observed among the fourthyear medical students (92.7 ± 16.0) [table 3]. when adjusted for age, gender and choice of future specialty, the difference in empathy scores between firstand fourth-year students was 16.1. a significant decline in mean empathy scores was noted between male students in their first versus second academic year (bonferroni test = 8.7; p = 0.020) and between male students in their first versus fourth academic year (bonferroni test = 10.1; p = 0.005) [table 4]. there was a statistically significant difference between genders with regards to choice of specialty. females more frequently chose people-oriented specialties in comparison to males (62.3% versus 25.8%; p = 0.001) [table 5]. furthermore, students who chose people-oriented specialties had higher mean empathy scores, whereas those who selected technology-oriented specialties had lower scores (109.9 ± 20.2 versus 99.8 ± 16.1; p = 0.002) [table 6]. table 1: questionnaire distribution by academic year among students at hawler medical university in erbil city, iraq (n = 989) academic year total 1st year 2nd year 3rd year 4th year 5th year 6th year students per class 172 161 170 153 161 172 989 questionnaires distributed 172 160 169 152 159 170 982 respondents per questionnaires (response rate, %) 165 (95.9) 159 (99.4) 167 (98.8) 150 (98.7) 155 (97.5) 131 (77.1) 927 (94.4) response rate of class, % 95.9 98.8 98.2 98.0 96.3 76.2 93.7 table 2: distribution by mean empathy score* and gender of the studied sample of students at hawler medical university in erbil city, iraq (n = 927) gender n (%) mean empathy score ± sd p value male 391 (42.2) 98.6 ± 16.2 0.023 female 536 (57.8) 102.5 ± 19.9 total 927 (100.0) 101.9 ± 19.2 sd = standard deviation. *empathy was self-assessed by respondents using the english version of the 20-item jefferson scale of physician empathy-student version.8 table 3: distribution by academic year and mean empathy score* of the studied sample of students at hawler medical university in erbil city, iraq (n = 927) academic year n (%) empathy score mean ± sd 95% ci lowest score highest score 1st year 165 (17.8) 112.9 ± 20.1 112.4–121.3 35.0 139.0 2nd year 159 (17.2) 110.5 ± 20.0 94.3–114.7 44.0 134.0 3rd year 167 (18.0) 101.8 ± 20.0 97.1–106.5 33.0 137.0 4th year 150 (16.2) 92.7 ± 16.0 91.1–101.4 53.0 130.0 5th year 155 (16.7) 94.7 ± 17.0 90.8–106.5 56.0 134.0 6th year 131 (14.1) 93.7 ± 17.0 91.8–106.5 45.0 131.0 total 927 (100.0) 101.9 ± 19.2 99.2–104.6 33.0 139.0 sd = standard deviation; ci = confidence interval. *empathy was self-assessed by respondents using the english version of the 20-item jefferson scale of physician empathy-student version.8 awring m. raof and bervian a. yassin clinical and basic research | e65 discussion the current study sought to measure self-assessed empathy levels among a sample of medical students at a public university in erbil city. the response rate to the questionnaire was much higher than those reported from similar studies in the usa, iran, portugal, japan, kuwait and the uk.10,11,13–16 the overall mean empathy score among the studied sample in the current study (101.9) was close to scores from studies conducted in japan (104.3) and iran (104.1), but lower than those reported from western countries.11–14 however, the mean empathy score for first-year medical students in the current study (112.9) was similar to that reported in iran (110.3) and the usa (115.5).13,14 additionally, the higher level of empathy among female students noted in the current study was consistent with previous research.9,17,18 in the current study, the mean empathy score reported by first-year students was highest, with mean empathy scores declining in the second and subsequent academic years—second-year students displayed higher empathy scores than fourth-year students and final year students displayed lower empathy scores than students in their first academic year. this finding was consistent with other studies, which suggests that levels of empathy decline during clinical training.10,13,14 after empathy scores were adjusted for age, gender and choice of future specialty, the difference in mean scores between firstand fourthyear students in the current study (16.1) was higher than that of an american study (11.9).13 another study conducted among dental students reported a decline in empathy levels after the introduction of clinical tasks.19 in a longitudinal study of undergraduate nursing students conducted to evaluate changes in empathy levels, ward et al. found that students showed a decline in empathy over the course of one year.20 there are a number of possible factors which may influence the reduction in empathy levels among students as education progresses. low levels of empathy may be reflective of the prevalent teaching methods at a particular academic institution. the education and training of medical students may be stressful and include extensive work hours and a lack of sleep. bedside communication may also become reduced due to time constraints, leading to a decrease in empathy.21 the increasingly emotionally demanding and harsh conditions of their academic career could negatively affect feelings of compassion among medical students.22–24 furthermore certain table 4: mean difference* in empathy scores† between male students according to academic year‡ among the studied sample at hawler medical university in erbil city, iraq (n = 927) academic year mean difference i j p value 95% ci i j 1st year 2nd year 8.7 0.020 0.9–18.5 1st year 4th year 10.1 0.005 2.2–20.0 2nd year 1st year -8.7 0.020 -18.5–-0.9 4th year 1st year -10.1 0.005 -20.0–-2.2 ci = confidence interval. *calculated using the bonferroni post hoc test to assess dependent variable scores with multiple comparisons. †empathy was self-assessed by respondents using the english version of the 20-item jefferson scale of physician empathy-student version.8 ‡there were no significant differences between empathy scores among female students according to academic year and between empathy scores among male students in other academic years. table 5: distribution by gender and choice of specialty* of the studied sample of students at hawler medical university in erbil city, iraq (n = 927) specialty n (%) male female people-oriented 101 (25.8) 334 (62.3)† technology-oriented 290 (74.2) 202 (37.7) total 391 (100.0) 536 (100.0) *students rated their future likelihood of entering various specialties categorised as either peopleor technology-oriented on a 4-point likert scale ranging from 1 (very unlikely) to 4 (very likely).8 each student was then classified according to their overall scores for each group. †statistically significant at p = 0.001. table 6: mean empathy scores* by academic year and choice of specialty† among the studied sample of students at hawler medical university in erbil city, iraq (n = 927) academic year mean score ± sd people-oriented specialty technologyoriented specialty 1st year 120.1 ± 21.2 106.8 ± 17.2 2nd year 111.4 ± 21.2 99.0 ± 16.1 3rd year 110.8 ± 20.2 99.1 ± 16.1 4th year 110.8 ± 20.2 96.3 ± 15.1 5th year 104.2 ± 20.1 98.7 ± 16.2 6th year 102.2 ± 20.0 98.7 ± 16.1 total 109.9 ± 20.2 99.8 ± 16.1 anova 4.940 p value 0.002 anova = one-way analysis of variance. *empathy was self-assessed by respondents using the english version of the 20-item jefferson scale of physician empathy-student version.8 †students rated their future likelihood of entering various specialties categorised as either peopleor technology-oriented on a 4-point likert scale ranging from 1 (very unlikely) to 4 (very likely).8 each student was then classified according to their overall scores for each group. measuring empathy levels among kurdish medical students in erbil city, iraq cross-sectional study e66 | squ medical journal, february 2016, volume 16, issue 1 humanities topics are not included in most medical curricula; these subjects may help improve students’ empathetic abilities.25 another possible explanation for the observed decrease in empathy among medical students is the sense of privilege that grows throughout a doctor’s medical training; being part of an advantaged group has been suggested to contribute to changes in an individual’s capacity for empathy.26 in the current study, students who chose a peopleoriented specialty reported significantly higher empathy level scores than those who selected technology-oriented specialties. these findings are similar to another study which found that students who chose internal medicine, family medicine, psychiatry, paediatrics or obstetrics and gynaecology as specialties had higher empathy scores.27 these specialties require more patient contact; students may therefore have scored higher on the empathy scale because of increased patient interaction. the authors of the current study believe that students with higher empathy levels may gravitate towards people-oriented careers. this construct does not imply that future career preference calibrates empathy but rather that students with greater empathy may naturally prefer specialties that require higher levels of patient contact. nevertheless, it is important to note that the mean differences in empathy levels between the peopleoriented and technology-oriented specialty groups were low. this may be because many students were not yet definite in their future speciality career decisions; additionally, many of them may change preferences during the course of their undergraduate studies. future research should seek to determine whether the promotion of empathy skills impacts students’ career preferences. one of the limitations of this study was that the measurement of empathy was self-reported, focusing on the students’ perceptions of empathy rather than their performance. a second limitation was the use of a cross-sectional study design, which did not allow for demonstration of causal relationships. lack of significant clinical exposure may also have affected how the students answered the questions on the survey as the first three years of medical school include only partial clinical exposure; this may have influenced empathy. furthermore, participation in the survey and understanding of the questionnaire items may have been biased by events during data collection. finally, as this study was limited to the college of medicine at hmu in erbil city, the results cannot be generalised to other medical colleges in iraq. nevertheless, the results of this study are still worthy of consideration. the development of empathy is vital to the advancement of a student’s professionalism during their undergraduate education.28 in order to increase levels of empathy among medical students, programmes teaching empathetic skills are recommended for incorporation into medical syllabi. these programmes should involve small group teaching and include training in practical skills that can be maintained and reinforced throughout a student’s medical training, such as effective patient interviewing and interpersonal communication techniques. further research on empathy among medical students should focus on factors that contribute to the development of high empathy levels and methods for augmenting these factors in both medical education and practice. conclusion low empathy levels were reported among the studied group of medical students at hmu, which may be a reason for concern. specifically, males demonstrated significantly lower overall mean empathy levels in comparison to females. mean empathy scores were also found to decline with academic progression. programmes highlighting empathy are therefore recommended for incorporation into medical curricula in order to encourage the development of empathetic skills among medical students. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. jani bd, blane dn, mercer sw. the role of empathy in therapy and the physician-patient relationship. forsch komplementmed 2012; 19:252–7. doi: 10.1159/000342998. 2. charon r. the patient-physician relationship: narrative medicine a model for empathy, reflection, profession, and trust. jama 2001; 286:1897–902. doi: 10.1001/jama.286.15. 1897. 3. kaplan sh, greenfield s, ware je jr. assessing the effects of physician-patient interactions on the outcomes of chronic disease. med care 1989; 27:s110–27. 4. larson eb, yao x. clinical empathy as emotional labor in the patient-physician relationship. jama 2005; 293:1100–6. doi: 10.1001/jama.293.9.1100. 5. hojat m, zuckerman m, magee m, mangione s, nasca t, vergare m, et al. empathy in medical students as related to specialty interest, personality, and perceptions of mother and father. pers individ dif 2005; 39:1205–15. doi: 10.1016/j. paid.2005.04.007. 6. hojat m, gonnella js, nasca tj, mangione s, veloksi jj, magee m. the jefferson scale of physician empathy: further psychometric data and differences by gender and specialty at item level. acad med 2002; 77:s58–60. doi: 10.1097/00001888200210001-00019. 7. roh ms, hahm bj, lee dh, suh dh. evaluation of empathy among korean medical students: a cross-sectional study using the korean version of the jefferson scale of physician empathy. teach learn med 2010; 22:167–71. doi: 10.1080/ 10401334.2010.488191. http://dx.doi.org/10.1159/000342998 http://dx.doi.org/10.1001/jama.286.15.1897 http://dx.doi.org/10.1001/jama.286.15.1897 http://dx.doi.org/10.1001/jama.293.9.1100 http://dx.doi.org/10.1016/j.paid.2005.04.007 http://dx.doi.org/10.1016/j.paid.2005.04.007 http://dx.doi.org/10.1097/00001888-200210001-00019 http://dx.doi.org/10.1097/00001888-200210001-00019 http://dx.doi.org/10.1080/10401334.2010.488191 http://dx.doi.org/10.1080/10401334.2010.488191 awring m. raof and bervian a. yassin clinical and basic research | e67 8. hojat m, mangione s, nasca tj, cohen mjm, gonnella j, erdmann jb, et al. the jefferson scale of physician empathy: development and preliminary psychometric data. educ psychol meas 2001; 61:349–65. doi: 10.1177/00131640121971158. 9. hojat m, gonella js, nasca tj, mangione s, vergare m, magee m. physician empathy: definition, components, measurement, and relationship to gender and specialty. am j psychiatry 2002; 159:1563–9. doi: 10.1176/appi.ajp.159.9.1563. 10. hojat m, mangione s, nasca tj, rattner s, erdmann jb, gonnella js, et al. an empirical study of decline in empathy in medical school. med educ 2004; 38:934–41. doi: 10.1111/j.13652929.2004.01911.x. 11. kataoka hu, koide n, ochi k, hojat m, gonnella js. measurement of empathy among japanese medical students: psychometrics and score differences by gender and level of medical education. acad med 2009; 89:1192–7. doi: 10.1097/ acm.0b013e3181b180d4. 12. tavakol s, dennick r, tavakol m. psychometric properties and confirmatory factor analysis of the jefferson scale of physician empathy. bmc med educ 2011; 11:54. doi: 10.1186/1472-692011-54. 13. chen d, lew r, hershman w, orlander j. a cross-sectional measurement of medical student empathy. j gen intern med 2007; 22:1434–8. doi: 10.1007/s11606-007-0298-x. 14. rahimi-madiseh m, tavakol m, dennick r, nasiri j. empathy in iranian medical students: a preliminary psychometric analysis and differences by gender and year of medical school. med teach 2010; 32:e471–8. doi: 10.3109/0142159x.2010.509419. 15. magalhães e, salgueira ap, costa p, costa mj. empathy in senior year and first year medical students: a cross-sectional study. bmc med educ 2011; 11:52. doi: 10.1186/1472-6920-1152. 16. hasan s, al-sharqawi n, dashti f, abdulaziz m, abdullah a, shukkur m, et al. level of empathy among medical students in kuwait university, kuwait. med princ pract 2013; 22:385–9. doi: 10.1159/000348300. 17. austin ej, evans p, goldwater r, potter v. a preliminary study of emotional intelligence, empathy and exam performance in first year medical students. pers individ dif 2005; 39:1395–1405. doi: 10.1016/j.paid.2005.04.014. 18. tavakol s, dennick r, tavakol m. empathy in uk medical students: differences by gender, medical year and specialty interest. educ prim care 2011; 22:297–303. doi: 10.1080/14739879.2011.11494022. 19. sherman jj, cramer a. measurement of changes in empathy during dental school. j dent educ 2005; 69:338–45. 20. ward j, cody j, schaal m, hojat m. the empathy enigma: an empirical study of decline in empathy among undergraduate nursing students. j prof nurs 2012; 28:34–40. doi: 10.1016/j. profnurs.2011.10.007. 21. benbassat j, baumal r. what is empathy, and how can it be promoted during clinical clerkships? acad med 2004; 79:832–9. doi: 10.1097/00001888-200409000-00004. 22. branch w, pels rj, lawrence rs, arky r. becoming a doctor: critical-incident reports from third-year medical students. n engl j med 1993; 329:1130–2. doi: 10.1056/ nejm199310073291518. 23. rakel d, barrett b, zhang z, hoeft t, chewning b, marchand l, et al. perception of empathy in the therapeutic encounter: effects on the common cold. patient educ couns 2011; 85:390–7. doi: 10.1016/j.pec.2011.01.009. 24. hojat m, louis dz, markham fw, wender r, rabinowitz c, gonnella js. physicians’ empathy and clinical outcomes for diabetic patients. acad med 2011; 86:359–64. doi: 10.1097/ acm.0b013e3182086fe1. 25. winefield hr, chur-hansen a. evaluating the outcome of communication skill teaching for entry-level medical students: does knowledge of empathy increase? med educ 2000; 34:90–4. doi: 10.1046/j.1365-2923.2000.00463.x. 26. brazeau cm, schroeder r, rovi s, boyd l. relationships between medical student burnout, empathy, and professionalism climate. acad med 2010; 85:s33–6. doi: 10.1097/ acm.0b013e3181ed4c47. 27. newton bw, savidge ma, barber l, cleveland e, clardy j, beeman g, et al. differences in medical students’ empathy. acad med 2000; 75:1215. doi: 10.1097/00001888-20001200000020. 28. shapiro j, morrison e, boker j. teaching empathy to first year medical students: evaluation of an elective literature and medicine course. educ health (abingdon) 2004; 17:73–84. doi: 10.1080/13576280310001656196. http://dx.doi.org/10.1177/00131640121971158 http://dx.doi.org/10.1176/appi.ajp.159.9.1563 http://dx.doi.org/10.1111/j.1365-2929.2004.01911.x http://dx.doi.org/10.1111/j.1365-2929.2004.01911.x http://dx.doi.org/10.1097/acm.0b013e3181b180d4 http://dx.doi.org/10.1097/acm.0b013e3181b180d4 http://dx.doi.org/10.1186/1472-6920-11-54 http://dx.doi.org/10.1186/1472-6920-11-54 http://dx.doi.org/10.1007/s11606-007-0298-x http://dx.doi.org/10.3109/0142159x.2010.509419 http://dx.doi.org/10.1186/1472-6920-11-52 http://dx.doi.org/10.1186/1472-6920-11-52 http://dx.doi.org/10.1159/000348300 http://dx.doi.org/10.1016/j.paid.2005.04.014 http://dx.doi.org/10.1080/14739879.2011.11494022 http://dx.doi.org/10.1016/j.profnurs.2011.10.007 http://dx.doi.org/10.1016/j.profnurs.2011.10.007 http://dx.doi.org/10.1097/00001888-200409000-00004 http://dx.doi.org/10.1056/nejm199310073291518 http://dx.doi.org/10.1056/nejm199310073291518 http://dx.doi.org/10.1016/j.pec.2011.01.009 http://dx.doi.org/10.1097/acm.0b013e3182086fe1 http://dx.doi.org/10.1097/acm.0b013e3182086fe1 http://dx.doi.org/10.1046/j.1365-2923.2000.00463.x http://dx.doi.org/10.1097/acm.0b013e3181ed4c47 http://dx.doi.org/10.1097/acm.0b013e3181ed4c47 http://dx.doi.org/10.1097/00001888-200012000-00020 http://dx.doi.org/10.1097/00001888-200012000-00020 http://dx.doi.org/10.1080/13576280310001656196 departments of 1allied health sciences, 2haematology and 4genetics, college of medicine & health sciences, sultan qaboos university; 3department of haematology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: boulassel@squ.edu.om الدقة يف عد الصفيحات بواسطة طرق بصرية ومعاوقية عند مرضى مصابني بقلة الصفيحات وصغر الكريات احلمراء حممد-ر�سيد بولع�سل، ريا الفار�سي، �سليمان الها�سمي، حمد الريامي، حمد خان، �سالم الكندي abstract: objectives: obtaining accurate platelet counts in microcytic blood samples is challenging, even with the most reliable automated haematology analysers. the cell-dyn™ sapphire (abbott laboratories, chicago, illinois, usa) analyser uses both optical density and electronic impedance methods for platelet counting. this study aimed to evaluate the accuracy of optical density and electrical impedance methods in determining true platelet counts in thrombocytopaenic samples with microcytosis as defined by low mean corpuscular volume (mcv) of red blood cells. additionally, the impact of microcytosis on platelet count accuracy was evaluated. methods: this study was carried out between february and december 2014 at the haematology laboratory of the sultan qaboos university hospital in muscat, oman. blood samples were collected and analysed from 189 patients with thrombocytopaenia and mcv values of <76 femtolitres. platelet counts were tested using both optical and impedance methods. stained peripheral blood films for each sample were then reviewed as a reference method to confirm platelet counts. results: the platelet counts estimated by the impedance method were on average 30% higher than those estimated by the optical method (p <0.001). the estimated intraclass correlation coefficient was 0.52 (95% confidence interval: 0.41–0.62), indicating moderate reliability between the methods. the degree of agreement between methods ranged from -85.5 to 24.3 with an estimated bias of -30, suggesting that these methods generate different platelet results. conclusion: the impedance method significantly overestimated platelet counts in microcytic and thrombocytopaenic blood samples. further attention is therefore needed to improve the accuracy of platelet counts, particularly for patients with conditions associated with microcytosis. keywords: electrical impedance; optical devices; platelet counts; thrombocytopenia; anemia; mean corpuscular volume. امللخ�ص: الهدف: ميثل احل�سول على تعداد دقيق لل�سفيحات يف عينات دم امل�سابني ب�سغر الكريات احلمراء حتديا كبريا حتى عند ا�ستخدام الينوي-الوليات ب�سيكاغو-ولية اأبوت معامل )من cell-dyn™ داين �سيل جهاز ويقوم وثوقية. الأتوماتيكية التحليل اأجهزة اأكرث املتحدة( با�ستخدام الكثافة الب�رسية واملعاوقية الكهربائية لعد ال�سفيحات. ويهدف هذا البحث لتقومي دقة الطرق الب�رسية واملعاوقية الكهربائية لتحديد اأعداد ال�سفيحات بدقة يف عينات دماء املر�سى امل�سابني بقلة ال�سفيحات و�سغر الكريات احلمراء، واملعرفة ب�سغر حجم الكرية الو�سطى )mcv(. ومت كذلك بحث تاأثري �سغر الكريات احلمراء على دقة عد ال�سفيحات. الطريقة: اأجريت الدرا�سة بني فرباير ودي�سمرب 2014م. مبخترب علم الدم مب�ست�سفى جامعة ال�سلطان قابو�ض مب�سقط يف عمان. وجمع عينات دم من 189 من املر�سى امل�سابني بقلة ال�سفيحات وقيم mcv اأقل من 76< فيمتوليرت. ومت عد ال�سفيحات عن طريق ا�ستخدام الكثافة الب�رسية واملعاوقية الكهربائية. ومت فح�ض �رسائح دم حميطي من كل عينة دم كمرجعية لعد ال�سفيحات. النتائج: كانت نتائج عد ال�سفيحات بوا�سطة الطريقة املعاوقية تفوق تلك املتح�سل عليها من بالطريقة الب�رسية بنحو %30 يف املتو�سط )p >0.001( وكان معامل الرتباط هو 0.52 )%95 فا�سل املوثوقية: 0.62–0.41( مما يوؤ�رس اإىل اعتمادية متو�سطة عند الطريقتني. وتراوحت درجة التوافق بني الطريقتني بني 85.5و 24.3، مع حتيز )خطاأ منهجي( يبلغ 30-. مما يدل على اأن الطريقتني تخرجان بنتائج خمتلفة لعدد ال�سفيحات. اخلال�صة: النتائج املتح�سل عليها من الطريقة املعاوقية هي اأكرب من غريها عند ا�ستخدامها يف دماء مر�سى م�سابني بقلة ال�سفيحات و�سغر الكريات احلمراء. لذا ينبغي الهتمام اأكرث بتح�سني الدقة، خا�سة عند املر�سى امل�سابني ب�سغر الكريات احلمراء. مفتاح الكلمات: الطريقة املعاوقية الكهربائية؛ الأجهزة الب�رسية؛ عد ال�سفيحات؛ قلة ال�سفيحات؛ الأنيميا؛ حجم الكرية الو�سطى. accuracy of platelet counting by optical and impedance methods in patients with thrombocytopaenia and microcytosis *mohamed-rachid boulassel,1,2 raya al-farsi,3 sulaiman al-hashmi,4 hamad al-riyami,4 hammad khan,3 salam al-kindi2 clinical & basic research advances in knowledge the findings of this study indicate that the impedance method overestimates the platelet count in thrombocytopaenic samples with low mean corpuscular volume (mcv) of red blood cells in comparison to the optical method. the optical method is therefore more reliable for platelet counting in samples with a low mcv value and thrombocytopaenia. sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e463–468, epub. 23 nov 15 submitted 16 mar 15 revisions req. 4 may & 28 jun 15; revisions recd. 28 may & 9 jul 15 accepted 13 aug 15 doi: 10.18295/squmj.2015.15.04.004 accuracy of platelet counting by optical and impedance methods in patients with thrombocytopaenia and microcytosis 464 | squ medical journal, november 2015, volume 15, issue 4 application to patient care physicians and laboratory scientists should keep in mind that the impedance method may overestimate the platelet count in samples with microcytosis and thrombocytopaenia, thereby potentially affecting transfusion decisions for patients at risk of bleeding. the results of the study indicate that more attention needs to be directed towards improving the accuracy of platelet counts, particularly for patients with conditions associated with microcytosis and thrombocytopaenia. in most clinical laboratories, platelet counts are routinely and reliably performed by modern automated blood cell analysers. however, the lack of accuracy of automated analysers when enumerating low platelet counts continues to pose problems.1 recent studies have shown significant inaccuracies occurring among current automated haematology analysers when counting platelets at low levels; these may subsequently lead to the provision of overor under-transfusions of platelet concentrates to patients at risk of bleeding.2–4 these findings are concerning because transfusion decisions based on inaccurate platelet counts may either result in serious bleeding complications or waste valuable blood products. furthermore, patients may be unnecessarily exposed to blood products and their associated complications. finding a reliable method to enumerate low platelet counts therefore remains a challenge. currently, two basic methods—optical density and electrical impedance—are employed by automated haematology analysers to count platelets.1 an optical platelet count is generally obtained through a twodimensional analysis that estimates the complexity and density of platelets represented as a cytogram of the light intensity at 7° and 90° angles. the impedance platelet count uses hydrodynamic focusing and singledimensional histogram analysis to count the platelets based on their size. while most automated analysers use either method separately, newer equipment can now use both optical and impedance techniques simultaneously, for example the cell-dyn™ sapphire (abbott laboratories, chicago, illinois, usa) and the xe-2100™ (sysmex corp., kobe, japan) analysers. however, both methods have been associated with limitations that may affect the accuracy of the platelet count. these limitations are mainly related to the inability of automated analysers to discriminate between platelet and nonplatelet particles, such as microcytic or fragmented red blood cells, cell debris, white cell fragments and giant platelets.1 to overcome these limitations, immunological methods using flow cytometry technology have been developed that use conjugated monoclonal antibodies directed against specific platelet antigens such as cluster of differentiation (cd) 41 and cd61.1,5 although immunological methods are highly accurate for counting platelets even in severely thrombocytopaenic samples, they are not available in all laboratories and the total cost per platelet count is expensive compared to the optical or impedance methods.1 limited information is available on the accuracy of optical and impedance methods for platelet counting in cases of thrombocytopaenia with microcytosis, as defined by the mean corpuscular volume (mcv) of red blood cells. as microcytosis can lead to inaccurate platelet counting by automated analysers, determining true platelet counts is necessary to minimise counting errors, especially in areas where causes of microcytosis are common, such as thalassaemia and iron deficiency anaemia, as both of these conditions are associated with low mcv.6 reliably determining the true platelet count in these conditions may help not only the physicians in charge of care, but also health providers and laboratory scientists to optimise workflow and meet the demands of increasing workloads. to date, the accuracy of platelet counts by either the impedance or optical method is questionable, particularly in thrombocytopaenic samples due to chemotherapy, bone marrow transplantation or marrow diseases associated with myeloid aplasia or myelodysplasia. indeed, the accuracy of both methods is further influenced by some conditions affecting the size of red blood cells that result in low mcv, thereby leading to false platelet counts. therefore, this study aimed to evaluate the optical and impedance methods for platelet counting in thrombocytopaenic samples with microcytosis from hospitalised adult patients in oman. platelet counts produced by the two methods were compared with those obtained from a microscopic examination of blood smears as a reference method. additionally, the study aimed to assess the impact of microcytosis on platelet count accuracy. methods this study was carried out between february and december 2014 at the haematology laboratory of the sultan qaboos university hospital in muscat, oman. blood specimens were collected from the morning batch of samples received at the laboratory for complete blood counts. samples selected for inclusion in the study were those with a platelet count of <100 x 109/l (normal range: 150–450 x 109/l), indicating mohamed-rachid boulassel, raya al-farsi, sulaiman al-hashmi, hamad al-riyami, hammad khan and salam al-kindi clinical and basic research | 465 thrombocytopaenia, and those with a mcv of ≤76 femtolitres (fl) (normal range: 78–95 fl), indicating microcytosis. samples with mcv values of 61–70 fl constituted group one while samples with values of 71–76 fl constituted group two. the patients’ specific diseases or conditions were not considered in the inclusion or exclusion criteria. all blood samples were collected in ethylenediaminetetraacetic acid tubes and were tested four to six hours after the phlebotomy. the cell-dyn™ sapphire (abbott laboratories) analyser was used to enumerate platelet counts by both optical and impedance methods. calibration, quality control and maintenance procedures were performed daily according to the manufacturer’s instructions. floating thresholds were used to discriminate between platelets and non-platelet particles. optical and impedance platelet counts were measured independently on each blood sample. stained peripheral blood smears were also evaluated by microscopy to obtain a reference platelet count against which to evaluate the accuracy of the optical and impedance methods. furthermore, blood smears were evaluated to determine the presence of factors that could interfere with platelet counts (including platelet aggregates, thrombocyte abnormalities, cell debris and white and red blood cell fragments). analyses were performed using graphpad prism, version 5 (graphpad software, inc., san diego, california, usa). descriptive statistics for platelet counts were produced for each method. the paired student’s t-test and pearson’s correlation coefficient were used to evaluate the difference in mean platelet counts and to measure the linear regression between the methods, respectively. the bland-altman method was used to assess agreement between measurements. the reliability of the platelet measurements was evaluated by the intraclass correlation coefficient (icc). the patients were divided into two groups according to mcv values and the mean value of the overall data in each group was used to examine the influence of mcv on platelet counts for each method. all tests were two-tailed with an alpha level of 0.05. this study was approved by the medical research & ethics committee at the college of medicine & health sciences of sultan qaboos university, muscat, oman (mrec #680). results a total of 189 thrombocytopaenic and microcytic blood specimens were included in the study. the examined study population were between 17 and 85 years old with a mean age of 39 ± 18 years. of the patients who contributed these samples, 88 (47%) were male. according to the optical method, platelet counts ranged from 3–100 x 109/l with a mean count of 73 ± 19 x 109/l. the mean mcv of red blood cells was 70 ± 4 fl (range: 61–76 fl) [figure 1a]. the mean red cell distribution width was 18 ± 4% (range: 12–34%). figure 1a–c: distribution of mean corpuscular volume (mcv) of red blood cells and platelet counts in thrombocytopaenic blood specimens with microcytosis (n = 189). a: frequency of mcv distribution in the study population. b: comparison of platelet counts among the optical method, impedance method and microscopic examination of blood smears. the minimum, maximum, median and p values for each boxplot are shown. c: comparisons of platelet counts between the optical and impedance methods according to mcv values. the minimum, maximum, median and p values for each boxplot are shown. the open and filled boxes represent the optical and impedance methods, respectively. accuracy of platelet counting by optical and impedance methods in patients with thrombocytopaenia and microcytosis 466 | squ medical journal, november 2015, volume 15, issue 4 the impedance method failed to provide counts for two samples that had low platelet counts (<10 x 109/l) according to the optical method. the impedance method yielded significantly higher platelet counts when compared to the optical method or the microscopy examination of blood smears (p <0.001) [figure 1b]. estimated platelet values from the impedance method were on average 30% higher than those of the optical method. however, in five samples, the impedance method measured a platelet count that was two-fold lower than that observed by the optical method. microscopic examination of the peripheral blood smears revealed no platelet clumps, giant platelets or white or red blood cell fragments in the majority of cases (92%). additionally, microcytosis was evident on all blood films, supporting the mcv values obtained by the complete blood count. the samples were divided into two groups according to mean mcv values. the impedance method showed significantly higher platelet counts in both groups compared to the optical method [figure 1c]. interestingly, no significant difference was found between the groups for platelet counts assessed by the optical method (74 ± 16 x 109/l versus 72 ± 20 x 109/l; p = 0.070). in contrast, a significant difference was observed between the two groups for platelet counts assessed by the impedance method (107 ± 4 x 109/l versus 102 ± 3 x 109/l; p = 0.008). linear regression analysis revealed a moderately positive correlation between optical and impedance methods (r = 0.65; p <0.001) [figure 2a]. interestingly, this correlation, although statistically significant, was weaker (n = 73; r = 0.45; p <0.001) in samples with lower mcv values [figure 2b] and stronger (n = 116; r = 0.74; p <0.001) in samples with higher mcv values [figure 2c]. the estimated icc was 0.52 (95% confidence interval: 0.41–0.62), indicating moderate figure 2a–c: linear regression analyses of platelet counts between optical and impedance methods in thrombocytopaenic blood specimens with microcytosis (n = 189). the dotted lines show the 95% confidence band of the best-fit line. the correlation coefficient and p values are shown. a: correlation analysis of platelet counts using the entire data set. b: correlation analysis of platelet counts using samples with mean corpuscular volume (mcv) values of 60–70 femtolitres (fl). c: correlation analysis of platelet counts using samples with mcv values of 71–76 fl. figure 3: bland-altman plot depicting the degree of agreement between optical and impedance methods in platelet counts among thrombocytopaenic blood specimens with microcytosis (n = 189). the solid line represents zero difference between the two methods. the dotted lines represent the upper and lower limits of agreement between the two methods as measured by the mean ± two standard deviations. table 1: reliability analysis for platelet counts by optical and impedance methods in thrombocytopaenic blood specimens with microcytosis (n = 189) intraclass correlation coefficient 95% confidence interval p value lower bound upper bound single measure 0.52 0.41 0.62 <0.001 average measure 0.68 0.58 0.76 <0.001 mohamed-rachid boulassel, raya al-farsi, sulaiman al-hashmi, hamad al-riyami, hammad khan and salam al-kindi clinical and basic research | 467 to fair reliability between the two methods [table 1]. the degree of agreement between the two methods was also in line with these findings [figure 3]. the estimated bias was -30 with a reasonably wide limit of agreement ranging from -85.5 to 24.3. discussion there remains some debate regarding which method is most accurate for platelet counting in thrombocytopaenic samples with microcytosis. while some studies report that the optical method is more accurate in assessing samples with low platelet levels, others have shown that the impedance method gives the best platelet count in chemotherapy samples.1,7,8 so far, few studies have investigated the accuracy of platelet counting in thrombocytopaenic samples with microcytosis, particularly in regions with a high prevalence of thalassaemia carriers, such as oman, where the α-thalassaemia gene is seen in 48% of the local population.6,9 the current study found that the impedance method yielded a higher platelet count compared to the optical method and the reference method (microscopic examination of blood smears). these results were in agreement with those reported by pińkowski, who also found that the optical method yielded a more reliable platelet count in microcytic samples than the impedance method.10 however, the two studies differed in many aspects. firstly, in pińkowski’s study, 90% of the 30 microcytic blood samples showed a normal platelet count of above 150 x 109/l by the optical method,10 while all 189 samples in the present study had thrombocytopaenia with platelet counts below 100 x 109/l. secondly, the mean mcv value in pińkowski’s study was 73 ± 5.9 fl (range: 57–80 fl) and 43% of the samples had mcv values >76 fl.10 in comparison, all samples in the present study had mcv values <76 fl. lastly, different instruments were used between the studies, with the cell-dyn™ 4000 (abbott laboratories) automated analyser being used in pińkowski’s study,10 in comparison to the cell-dyn™ sapphire (abbott laboratories) analyser utilised in the present study. nevertheless, it should be noted that both blood cell analysers rely on the same optical and impedance principles for platelet counting. interestingly, the impedance method further overestimated platelet counts in samples with mcv values <70 fl in the current study. in addition, it showed a weak but significant correlation with the optical method. these findings suggest that the impedance method will not provide the most accurate platelet counts at low mcv values and may instead yield a false-high count, potentially affecting platelet transfusion decisions for patients. these results are in line with those from a study by ninama et al., who reported that the impedance method was not always reliable for assessing platelet counts in cases of severe microcytosis after comparing platelet counts obtained by the impedance method on the cell-dyn™ 3700 (abbott laboratories) analyser with those obtained from a manual technique with ammonium oxalate.11 similarly, pan et al. showed that the impedance method overestimated platelet counts in microcytic samples using the xe 2100™ automated analyser (sysmex corp.).12 collectively, these findings suggest that the optical method is more accurate for estimating platelet counts in samples with low mcv values, especially in those with severe microcytosis. however, it should be noted that five samples assessed by the impedance method in the current study showed a platelet count that was two-fold lower than that indicated by the optical method. in these samples, a review of the peripheral blood films showed that the true platelet count was close to the values yielded by the optical method. it is of concern that the true platelet counts in these five cases did not correspond with the general trend of overestimation seen with the impedance method. although the comparison of the two methods in the current study demonstrated a moderately positive correlation, this does not necessarily mean that the techniques are interchangeable. the same association was not observed with the icc value, which determines the reliability of the impedance method to yield the same or compatible platelet counts in comparison to the optical method. the icc is calculated using variance estimates, which are obtained from the analysis of platelet measurement variance, and is measured on a scale from 0 to 1, where the closer the value is to 1, the higher the reliability. excellent reliability is usually determined by an icc value of ≥0.75, which was not obtained in the current study.13 additionally, the bland-atman limits of agreement, which assume that differences are constant throughout the range of platelet measurements, further indicate that the impedance method produced different platelet counts with a high level of bias in comparison to the optical method. the current study had a number of limitations. first, selected blood samples were tested within four to six hours following the phlebotomy. it is possible that this may have caused the platelets to swell when measured by the impedance method or the internal intensity of platelets to decrease when using the optical method. second, blood samples with normal mcv values and platelet counts were not included as a control group. finally, immunological-based methods of counting platelets were not used. conclusion the results of the current study provide evidence that the optical method is superior to the impedance method in estimating platelet counts in samples with low mcv values. as a result, physicians and laboratory scientists should keep in mind that the impedance method may significantly overestimate the platelet count in microcytic samples with thrombocytopaenia, which may potentially affect transfusion decisions. more attention needs to be directed towards improving the accuracy of platelet counts, particularly for patients with conditions associated with microcytosis. a c k n o w l e d g e m e n t s the authors are deeply grateful to all of the haematology laboratory staff, especially the main section, for their technical assistance. this work was supported in part by grants from the research council, oman (#org/hss/13/002) and the sultan qaboos university (#ig/med/haem/14/01). c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. briggs c, harrison p, machin sj. continuing developments with the automated platelet count. int j lab hematol 2007; 29:77–91. doi: 10.1111/j.1751-553x.2007.00909.x. 2. de la salle bj, mctaggart pn, briggs c, harrison p, doré cj, longair i, et al. the accuracy of platelet counting in thrombocytopenic blood samples distributed by the uk national external quality assessment scheme for general haematology. am j clin pathol 2012; 137:65–74. doi: 10.1309/ ajcp86jmbfucfcxa. 3. lozano m, mahon a, van der meer pf, stanworth s, cid j, devine d, et al. counting platelets at transfusion threshold levels: impact on the decision to transfuse a best collaborative-uk neqas(h) international exercise. vox sang 2014; 106:330–6. doi: 10.1111/vox.12110. 4. cid j, nascimento jd, vicent a, aguinaco r, escoda l, ugarriza a, et al. evaluation of low platelet counts by optical, impedance, and cd61-immunoplatelet methods: estimation of possible inappropriate platelet transfusion. transfusion 2010; 50:795–800. doi: 10.1111/j.1537-2995.2009.02504.x. 5. harrison p, horton a, grant d, briggs c, machin s. immunoplatelet counting: a proposed new reference procedure. br j haematol 2000; 108:228–35. doi: 10.1046/j.13652141.2000.01846.x. 6. alkindi s, al zadjali s, al madhani a, daar s, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. doi: 10.3109/03630261003677213. 7. segal hc, briggs c, kunka s, casbard a, harrison p, machin sj, et al. accuracy of platelet counting haematology analysers in severe thrombocytopenia and potential impact on platelet transfusion. br j haematol 2005; 128:520–5. doi: 10.1111/j.1365-2141.2004.05352.x. 8. sandhaus lm, osei es, agrawal nn, dillman ca, meyerson hj. platelet counting by the coulter lh 750, sysmex xe 2100, and advia 120: a comparative analysis using the rbc/platelet ratio reference method. am j clin pathol 2002; 118:235–41. 9. al-riyami aa, suleiman aj, afifi m, al-lamki zm, daar s. a community-based study of common hereditary blood disorders in oman. east mediterr health j 2001; 7:1004–11. 10. pińkowski r. difference between impedance and optical platelet count methods in patients with microcytosis of red blood cells. lab hematol 1999; 5:22–7. 11. ninama nj, shah nk. impedance platelet count in severe microcytosis: study of 161 patients. nhl j med sci 2014; 3:32–6. 12. pan ll, chen cm, huang wt, sun ck. enhanced accuracy of optical platelet counts in microcytic anemia. lab med 2014; 45:32–6. doi: 10.1309/lm7qpuldm5ihbo3l. 13. rafdzah z, bulgiba a, ismail n. method comparison studies in medicine. j health transl med 2013: 16:1–7. http://dx.doi.org/10.1111/j.1751-553x.2007.00909.x http://dx.doi.org/10.1309/ajcp86jmbfucfcxa http://dx.doi.org/10.1309/ajcp86jmbfucfcxa http://dx.doi.org/10.1111/vox.12110 http://dx.doi.org/10.1111/j.1537-2995.2009.02504.x http://dx.doi.org/10.1046/j.1365-2141.2000.01846.x http://dx.doi.org/10.1046/j.1365-2141.2000.01846.x http://dx.doi.org/10.3109/03630261003677213 http://dx.doi.org/10.1111/j.1365-2141.2004.05352.x http://dx.doi.org/10.1309/lm7qpuldm5ihbo3l 1department of child health, sultan qaboos university hospital; 2department of psychology, college of education, sultan qaboos university, muscat, oman *corresponding author e-mail: watfa.almamari@gmail.com التالزم بني اضطرابات التعلم واضطراب نقص االنتباه املصاحب باحلركة الزائدة يف عينة من تالميذ املدارس يف سلطنة عمان وطفة املعمرية، حممود حممد اإمام، اأمنة الفطي�سية، علي مهدي كاظم abstract: objectives: the estimated worldwide prevalence of learning disorders (lds) is approximately 2‒10% among school-aged children. lds have variable clinical features and are often associated with other disorders. this study aimed to examine the comorbidity of lds and attention deficit hyperactivity disorder (adhd) among a sample of schoolchildren in oman. methods: this study was conducted between january 2014 and january 2015 at the sultan qaboos university, muscat, oman. the learning disabilities diagnostic inventory (lddi) and the 28item version of the conners’ teacher rating scale was completed by classroom teachers to determine the existence of ld and adhd symptoms in 321 children in grades 1‒4 who had been referred to a learning support unit for lds from elementary schools in muscat. results: the mean age of the students was 8.5 years. among the cohort, 30% were reported to have symptoms of adhd, including conduct problems (24%), hyperactivity (24%) and inattentivepassive behaviours (41%). male students reportedly exhibited greater conduct problems and hyperactivity than females. however, there were no gender differences noted between lddi scores. conclusion: this study suggests that omani schoolchildren with lds are likely to exhibit signs of adhd. the early identification of this disorder is essential considering the chronic nature of adhd. for interventional purposes, multidisciplinary teams are recommended, including general and special educators, clinical psychologists, school counsellors, developmental or experienced general paediatricians and child psychiatrists. keywords: learning disorders; attention deficit hyperactivity disorder; comorbidity; children; oman. امللخ�ص: الهدف: تقدر معدلت اإنت�سار ا�سطرابات التعلم يف خمتلف اأنحاء العامل بحوايل %10–2 لدى تالميذ املدار�ض. وتت�سم اإ�سطرابات التعلم ب�سمات �رسيرية متباينة كما ترتبط با�سطرابات اأخرى. وقد هدفت الدرا�سة احلالية اإىل فح�ض التالزم املوجود بني اإ�سطرابات التعلم وا�سطراب نق�ض الإنتباه امل�ساحب لفرط الن�ساط لدى عينة من تالميذ املدار�ض ب�سلطنة عمان. الطريقة: مت اإجراء الدرا�سة بني �سهر يناير من عام 2014 و�سهر يناير عام 2015 يف جامعة ال�سلطان قابو�ض مبدينة م�سقط ب�سلطنة عمان. وقد ا�ستملت اأدوات الدرا�سة على قائمة ت�سخي�ض �سعوبات التعلم ومقيا�ض كونرز لتقدير املعلمني )الن�سخة املكونة من 28 نقطة(. وقد قام املعلمون مبلىء املقيا�سني لتقييم عينة الدار�سة من اأجل فح�ض �سمات ا�سطرابات التعلم وا�سطراب نق�ض الإنتباه امل�ساحب لفرط الن�ساط يف عينة قوامها 321 يف ال�سفوف من 4–1 والذين متت اإحالتهم اإىل وحدات �سعوبات التعلم باملدار�ض الإبتدائية يف م�سقط. ، وقد كان متو�سط عمر العينة حوايل 8.5�سنوات. النتائج: اأظهرت النتائج اأن حوايل %30 من التالميذ اأظهروا اأعرا�ض ا�سطراب نق�ض الإنتباه امل�ساحب لفرط الن�ساط م�ستماًل على )24%( م�سكالت �سلوكية، )%24( حركة زائدة، )%41( �سلوكيات عدم النتباه ال�سلبية. وقد اأظهر الذكور �سمات اأعلى من الإناث يف بعدي امل�سكالت ال�سلوكية و فرط الن�ساط. ومل توجد اأية فروق ذات دللة اإح�سائية بني الذكور والإناث يف املقايي�ض الفرعية لقائمة ت�سخي�ض �سعوبات التعلم. اخلال�صة: خل�ست هذه الدرا�سة اإىل اأن تالميذ املدار�ض الإبتدائية املحالني لوحدات �سعوبات التعلم يف م�سقط ب�سلطنة عمان يظهروا �سمات ا�سطراب نق�ض الإنتباه امل�ساحب لفرط الن�ساط. كما اأكدت الدرا�سة على �رسورة التعرف املبكر على هذا ال�سطراب وخا�سة مع من يتكون التخ�س�سات متعدد فريق قيام ينبغي كما الن�ساط. لفرط امل�ساحب الإنتباه نق�ض ا�سطراب مع تداخله الإعتبار يف الو�سع املدر�سني العامني ومدر�سي الرتبية اخلا�سة واخ�سائي علم النف�ض ال�رسيري ومر�سد املدر�سة واأخ�سائي طب الأطفال التطوري واخ�سائي الطب النف�سي لالأطفال القيام بعمليات الت�سخي�ض من اأجل البدء يف تقدمي خدمات التدخل العالجي. مفتاح الكلمات: اإ�سطرابات التعلم؛ اإ�سطراب نق�ض النتباه امل�ساحب لفرط الن�ساط؛ التالزم؛ الأطفال؛ عمان. comorbidity of learning disorders and attention deficit hyperactivity disorder in a sample of omani schoolchildren *watfa s. al-mamari,1 mahmoud m. emam,2 amna m. al-futaisi,1 ali m. kazem2 advances in knowledge the co-occurrence of learning disorders (ld) and attention deficit hyperactivity disorder (adhd) is well known. however, data on this topic are still lacking in oman. to the best of the authors’ knowledge, this is the first study that reports the coexistence of adhd in a group of omani schoolchildren with lds. the current study provides evidence that approximately one-third of omani children referred to a learning support unit for lds exhibited adhd symptomatology as rated by their teachers. clinical & basic research sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e528–533, epub. 23 nov 15 submitted 29 apr 15 revision req. 9 jun 15; revision recd. 17 jun 15 accepted 25 jun 15 doi: 10.18295/squmj.2015.15.04.015 watfa s. al-mamari, mahmoud m. emam, amna m. al-futaisi and ali m. kazem clinical and basic research | e529 application to patient care the identification and management of adhd in children with ld may have a positive outcome on their academic performance. the findings of this study encourage the use of multidisciplinary teams to manage and support children with adhd in oman. learning disorders (lds) are neuro-developmental conditions that affect approxi-mately 2‒10% of school-aged children world wide.1 children with lds frequently exhibit comorbidities with other disorders, including attention deficit hyperactivity disorder (adhd). the high comorbidity of lds and adhd has been well delineated in the literature while the overall estimate of lds in children with adhd ranges from 7‒92%.2,3 research has shown that the prevalence of adhd in schoolchildren with lds ranges from 18‒60%, which is seven times higher than that of the general population.4 multiple factors contribute to this wide range, including differences in methodologies, definitions of lds and adhd and population samples. most epidemiological information is gathered from clinically referred samples compared to school-based samples; it is well known that clinically referred students usually have multiple comorbidities.2 there is a lack of data from middle eastern countries with regards to the prevalence of adhd among children with lds. in oman, a cross-sectional study carried out in 2008 screened 1,502 omani schoolboys for adhd using the short version of the conners’ teacher rating scale (ctrs).2 the findings showed that 7.8% of the sample exhibited hyperactivity, which was strongly associated with conduct disorder, poor academic performance and behavioural problems.2 other research noted that the observed rate of adhd among omani schoolgirls was 5.1%.3 this rate is lower than those reported in similar studies of other populations (11.0‒19.8%).5‒7 the high variability of adhd prevalence rates between omani and other populations has been attributed to sociocultural, ecological and/or methodological factors.2 in oman, schoolchildren with lds receive their education in regular classroom settings alongside their non-affected peers. however, they are sometimes removed from the classroom to receive instruction from specialist teachers within a specialised learning support unit. these units were established in every elementary school in oman in order to cater for the needs of children with lds.8,9 students with lds are also eligible for additional drop-in support if needed. a referral to a learning support unit is based on a teacher’s nomination due to the student’s non-responsiveness to instruction as shown by their monthly reading and mathematics grades. within the learning support unit, students typically receive approximately eight hours of support per week from a specialised ld teacher, including assistance with reading, writing and mathematical activities and problem-solving. the omani ministry of education initiated the inclusion and support programme for children with lds in 2007 in omani elementary schools.8,9 in most cases, ld teachers have a specialised diploma. some hold a master’s degree and/or have received specialised inhouse training. children with adhd can exhibit academic, educational and neurobehavioural problems such as anxiety, depression, disruptive behaviours and tics. these associations often result in higher rates of school suspension, grade retention and the use of special education or ancillary services.7 it is therefore important to recognise adhd symptoms in order to effectively plan for and manage affected children.10 as such, the present study was designed to examine the relationship between lds and adhd among an omani school-based sample referred to a learning support unit for lds. methods this study was conducted between january 2014 and january 2015 at the sultan qaboos university, muscat, oman. students between grades 1‒4 from elementary public schools across muscat, oman, who had been referred for lds to a learning support unit from elementary schools in oman were recruited for inclusion in the study. the sample was drawn from a large pool of students referred for learning support in elementary schools across oman. general classroom teachers were requested to complete two questionnaires rating the existence of ld and adhd symptoms in a particular child based on their personal views and experiences teaching the child. the learning disabilities diagnostic inventory (lddi) is a rating scale designed to examine the presence of lds in students between the ages of 0‒8 and 11‒17 years and consists of six independent 15-item subscales (listening, speaking, reading, writing, mathematics and reasoning).11 each item is rated on a 9-point likert scale. the normalisation sample of the inventory includes 2,152 students with lds from the usa.11 teachers were requested to complete an adapted arabic version of the lddi following two rounds of consecutive translation and one round of back-translation.11 the back-translation comorbidity of learning disorders and attention deficit hyperactivity disorder in a sample of omani schoolchildren e530 | squ medical journal, november 2015, volume 15, issue 4 complete an adapted arabic version of the ctrs-28 following forwardand back-translation.14 the backtranslation was conducted by an external translator with a background in educational psychology and without the original questionnaire. an empirical study validated the ctrs-28 on a large egyptian sample and found moderate internal consistency (α = 0.76).15 test-retest reliability of the validated arabic version of the four subscales was as follows: hyper activity = 0.48; conduct problems = 0.46; inattentivepassive behaviours = 0.59; and hyperactivity index = 0.52. internal consistency estimates for the hyperactivity, conduct problems, inattentive-passive behaviours and hyperactivity index subscales were α = 0.80, 0.85, 0.82 and 0.85, respectively. data were collected, coded and analysed using the statistical package for the social sciences (spss), version 21.0 (ibm corp., chicago, illinois, usa). the association between ld and adhd was measured using the correlation coefficient of the lddi and ctrs-28 scores. gender differences among ld and adhd symptoms were estimated using an independent two-sample t-test after calculating the mean scores and standard deviation. this study was approved by the research ethical committee board of the sultan qaboos university (#sr/edu/psyc/12/01). consent was obtained from the administration of the involved elementary schools was conducted by a translator with a background in a related discipline and without access to the original questionnaire. a number of items from the original inventory were modified in order to fit the structure, morphology and phonology of the arabic language.12 the questionnaire items originally included english examples which were replaced by arabic examples. examples were provided to the teachers in order to help them understand statements before rating the pupil. these examples increased the face validity of the arabic version of the lddi. additionally, cronbach’s alpha for the validated arabic versions of the subscales used were as follows: α = 0.95 (listening); α = 0.96 (speaking, writing and mathematics); α = 0.97 (reading and reasoning). scores were reported in percentiles or scaled on a 9-point standard scale with a mean of five and a standard deviation of two. the ctrs is a widely used measure to assess the presence of adhd in children and adolescents. the 28-item version of the ctrs (ctrs-28) assesses behaviour on four subscales (hyperactivity, conduct problems, inattentive-passive behaviours and hyper activity index) as defined in the psychiatric nomenclature.13 the items on the hyperactivity index subscale are drawn from the other three subscales and provide a sensitive indicator of adhd symptoms in children. each item is rated on 3-point likert scale.13 general classroom teachers were requested to table 1: correlation matrix between learning disorders* and attention deficit hyperactivity disorder† among omani schoolchildren referred for learning disorders (n = 321) correlation matrix‡ lddi subscale ctrs-28 subscale conduct problems hyperactivity inattentive-passive behaviours hyperactivity index total listening speaking reading writing mathematics reasoning 0.243 0.259 0.278 0.297 0.205 0.294 0.193 0.206 0.218 0.229 0.172 0.246 0.367 0.421 0.461 0.457 0.347 0.503 0.260 0.291 0.325 0.339 0.242 0.366 male (n = 203) listening speaking reading writing mathematics reasoning 0.215 0.250 0.260 0.255 0.236 0.286 0.138§ 0.183 0.156§ 0.146§ 0.163§ 0.227 0.290 0.376 0.385 0.370 0.303 0.448 0.201 0.260 0.263 0.253 0.248 0.330 female (n = 118) listening speaking reading writing mathematics reasoning 0.328 0.288 0.344 0.394 0.227§ 0.324 0.305 0.248 0.336 0.365 0.248 0.281 0.487 0.494 0.578 0.586 0.421 0.594 0.382 0.351 0.451 0.487 0.295 0.441 lddi = learning disabilities diagnostic inventory; ctrs-28 = 28-item version of the conners’ teacher rating scale. *learning disorders were scored by teachers using an arabic version of the lddi.11 †attention deficit hyperactivity disorder was scored by teachers using an arabic version of the ctrs-28.13,14 ‡all values except those otherwise marked were significant at the 0.01 level using an independent twosample t-test. §significant at the 0.05 level using an independent two-sample t-test. watfa s. al-mamari, mahmoud m. emam, amna m. al-futaisi and ali m. kazem clinical and basic research | e531 and from all parents of the participating children before data collection began. results among the cohort, there were 118 female students (36.8%) and 203 male students (63.2%). the mean age of the children was 8.53 ± 0.76 years. the subjects were predominantly arabic-speaking and of omani nationality. according to their teachers, 30.0% of pupils referred to the learning support unit for suspected lds exhibited significant adhd symptomatology. these included conduct problems (24.0%), hyperactivity (24.0%) and inattentive-passive behaviours (41.0%). the correlation matrix for the lddi and ctrs-28 subscales is shown in table 1. there were positive correlation coefficients between all of the subscales for the total sample as well as by gender. gender differences between ld and adhd symptoms are shown in table 2. there were no gender differences observed in lddi scores. however, there were gender differences observed in three of the ctrs-28 subscales, with males displaying greater conduct problems, hyperactivity and hyperactivity indexes according to their teachers. there were no reported gender differences with regards to the inattentivepassive behaviours subscale. discussion in the current study, the majority of the referred children with lds were boys. this is consistent with a previous study on lds carried out in oman.2 however, no significant gender differences were observed among the current cohort regarding teachers’ ratings of ld symptoms as expressed within the lddi. previous research has suggested that boys are more likely to be referred for lds associated with difficulties in reading, comprehension and mathematics.15 however, gender differences in lds are still controversial and have yet not been confirmed by recent epidemiological studies.16 it is likely that behavioural problems which result in a referral among girls are seen as more extreme. interestingly, gender differences in the mani festation of adhd were also observed in the current study. boys were reported to exhibit greater conduct problems, hyperactivity and hyperactivity indexes than girls. additionally, more boys met the diagnostic criteria for both lds and adhd. however, the reported male-to-female ratio for adhd varies widely.17 the findings of the present study suggest that adhd has a significant correlation with lds among schoolchildren. although a number of studies have examined the coexistence of lds and adhd, only a few have studied the prevalence of adhd in a cohort of school-aged children diagnosed with lds.4 positive correlation coefficients were noted in the current study between all of the subscales for the total sample as well as according to gender. this finding suggests that there are common symptoms identified by both the lddi and ctrs-28 questionnaires. nevertheless, it is not surprising that adhd and lds were interconnected in the current study. the overall effect of psychological and educational difficulties has been previously confirmed in children from the general population. research has provided substantial evidence that children with internalised and externalised psychological problems are poor learners.18 additionally, educational difficulties are likely to affect academic performance as well as selfesteem. however, researchers have yet to agree on implications for children at risk of developing lds.18 a detailed examination of such associations in previous studies has indicated that literacy difficulties are predicted by both hyperactivity and conduct problems.19 another study also postulated that the link between conduct problems and literacy difficulties is mediated by adhd, of which hyperactivity is table 2: gender differences between learning disorders* and attention deficit hyperactivity disorder† among omani schoolchildren referred for learning disorders (n = 321) mean ± sd t p value male (n = 203) female (n = 118) lddi subscale listening 5.11 ± 1.58 5.10 ± 1.74 0.04 0.970 speaking 5.42 ± 1.58 5.32 ± 1.68 0.50 0.617 reading 5.83 ± 1.65 5.79 ± 1.86 0.21 0.833 writing 6.04 ± 1.50 5.89 ± 1.78 0.81 0.422 mathematics 5.90 ± 1.56 6.20 ± 1.63 1.64 0.103 reasoning 6.12 ± 1.55 6.02 ± 1.63 0.54 0.592 ctrs-28 subscale conduct problems 0.81 ± 0.55 0.59 ± 0.41 3.80 0.001 hyperactivity 0.82 ± 0.61 0.60 ± 0.53 3.32 0.001 inattentivepassive behaviours 1.21 ± 0.58 1.23 ± 0.59 0.27 0.790 hyperactivity index 0.97 ± 0.54 0.77 ± 0.47 3.23 0.001 sd = standard deviation; lddi = learning disabilities diagnostic inventory; ctrs-28 = 28-item version of the conners’ teacher rating scale. *learning disorders were scored on a 9-point likert scale by teachers using an arabic version of the lddi.11,12 †attention deficit hyperactivity disorder was scored on a 3-point likert scale by teachers using an arabic version of the ctrs-28.13,14 comorbidity of learning disorders and attention deficit hyperactivity disorder in a sample of omani schoolchildren e532 | squ medical journal, november 2015, volume 15, issue 4 noted between lddi scores. these findings suggest that omani children referred for lds are likely to exhibit adhd symptomatology. as adhd can have serious implications for paediatric development, it is vital that these children are assessed and treated by a multidisciplinary team including experts in the fields of education and child psychology. a c k n o w l e d g e m e n t s the data reported in this study were part of a larger dataset of a strategic project aiming to identify key stage one pupils with lds in omani schools. this project was funded by a grant from the his majesty’s research trust fund (hmrtf) at sultan qaboos university (#sr/edu/psyc/12/01). the authors therefore wish to thank the hmrtf organisers for their technical and financial support. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. polanczyk g, de lima ms, horta bl, biederman j, rohde la. the worldwide prevalence of adhd: a systematic review and metaregression analysis. am j psychiatry 2007; 164:942–8. doi: 10.1176/ajp.2007.164.6.942. 2. al-sharbati m, al-adawi s, ganguly s, al-lawatiya s, almshefri f. hyperactivity in a sample of omani schoolboys. j atten disord 2008; 12:264–9. doi: 10.1177/1087054708315136. 3. farah lg, fayyad ja, eapen v, cassir y, salamoun mm, tabet cc, et al. adhd in the arab world: a review of epidemiologic studies. j atten disord 2009; 13:211–22. doi: 10.1177/1087054708325976. 4. dupaul gj, stoner g. adhd in the schools: assessment and intervention strategies. 2nd ed. new york, usa: the guilford press, 2004. pp. 22–23. 5. bussing r, fernandez m, harwood m, wei hou, garvan cw, eyberg sm, et al. parent and teacher snap-iv ratings of attention deficit hyperactivity disorder symptoms: psychometric properties and normative ratings from a school district sample. assessment 2008; 15:317–28. doi: 10.1177/1073191107313888. 6. lefever gb, dawson kv, morrow al. the extent of drug therapy for attention deficit-hyperactivity disorder among children in public schools. am j public health 1999; 89:1359–64. doi: 10.2105/ajph.89.9.1359. 7. rowland as, umbach dm, stallone l, naftel aj, bohlig em, sandler dp. prevalence of medication treatment for attention deficit-hyperactivity disorder among elementary school children in johnson county, north carolina. am j public health 2002; 92:231–4. doi: 10.2105/ajph.92.2.231. 8. gaad e. inclusive education in the middle east. 1st ed. new york, usa: routledge, 2010. pp. 16–67. 9. al-said sk, emam mm. working towards inclusive education in oman: reflections from teachers of students with learning disabilities in elementary schools. in: o’rouke s, martins ap, gumpel tp, santos ac, pereira ap, et al., eds. proceedings of braga 2014 embracing inclusive approaches for children and youth with special education needs conference. braga, portugal: university of minho research center on education, 2014. pp. 137–41. a marker.16 alternatively, several researchers have argued that the association between adhd and literacy difficulties has a genetic basis and that one disorder cannot be entirely explained as a consequence of the other.20,21 the comorbid association between ld and adhd symptoms highlights the need for caution in assigning the ld label to children during the referral process.18 several limitations should be considered with regards to the findings of the current study. the results were obtained from a sample of children referred to a learning support unit based on teacher nominations. potential teacher bias and subjectivity in rating adhd symptoms should therefore be kept in mind. an independent non-ld school-aged sample should be used to test whether the findings of the current study can be generalised to all children in oman. furthermore, only one measure of adhd was used; the generally accepted practice involves using multiple measures (such as parental ratings or expert evaluation) to reach a definitive adhd diagnosis.22 in addition, the presence of adhd was assessed in a general ld group with subjects not classified according to the specific type of ld.10 it is therefore recommended that future studies examine the association between different ld subtypes and adhd symptoms. regardless of the aforementioned limitations, the findings of adhd symptoms in students with possible lds have several implications for physicians and educators in oman. within their meta-analysis of behavioural treatments for adhd, fabiano et al. found that students with low academic performance tend to exhibit adhd symptoms; the poor academic performance usually increases as the behavioural manifestations of the adhd become more severe.23 considering the chronic nature of adhd, its varied forms and impact on multiple areas of functioning, it is critical that it is identified early in affected children. moreover, different treatment modalities are needed and should be provided by various members of a multidisciplinary team, including general/special educators, clinical psychologists/psychoeducators, school counsellors, developmental or experienced general paediatricians and child psychiatrists. conclusion among the studied sample of schoolchildren in oman referred for lds, 30.0% were reported to have symptoms of adhd by their teachers, including conduct problems, hyperactivity and inattentivepassive behaviours. male students were reported to show greater conduct problems and hyperactivity than the females. however, there were no gender differences http://dx.doi.org/10.1176/ajp.2007.164.6.942 http://dx.doi.org/10.1177/1087054708315136 http://dx.doi.org/10.1177/1087054708325976 http://dx.doi.org/10.1177/1073191107313888 http://dx.doi.org/10.2105/ajph.89.9.1359 http://dx.doi.org/10.2105/ajph.92.2.231 watfa s. al-mamari, mahmoud m. emam, amna m. al-futaisi and ali m. kazem clinical and basic research | e533 10. faraone sv, biederman j, monuteaux mc, doyle ae, seidman lj. a psychometric measure of learning disability predicts educational failure four years later in boys with attention-deficit/hyperactivity disorder. j atten disord 2001; 4:220–30. doi: 10.1177/108705470100400404. 11. hammill dd, bryant br. lddi: the learning disabilities diagnostic inventory. austin, texas, usa: pro-ed inc., 1998. pp. 10–11. 12. hambleton rk. issues, designs, and technical guidelines for adapting tests into multiple languages and cultures. in: hambleton rk, merenda pf, spielberger cd, eds. adapting educational and psychological tests for cross-cultural assessment. hillsdale, new jersey, usa: lawrence erlbaum associates inc., 2005. pp. 34–35. 13. conners ck. conners’ rating scales manual: instruments for use with children and adolescents. new york, usa: multihealth systems, 1989. pp. 17–19. 14. elbheary ah. the connor’s teacher rating scale-28 (ctrs-28) manual: an instrument for use with children in schools. cairo, egypt: anglo-egyptian library, 2011. pp. 31–32. 15. emam mm. associations between social potential and emotional and behavioural difficulties in egyptian children. emot behav diffic 2012; 17:83–96. doi: 10.1080/13632752.2012.652429. 16. willcutt eg, pennington bf, boada r, ogline js, tunick ra, chhabildas na, et al. a comparison of the cognitive deficits in reading disability and attention-deficit/hyperactivity disorder. j abnorm psychol 2001; 110:157‒72. doi: 10.1037/0021-843x .110.1.157. 17. rappley md. clinical practice: attention deficit hyperactivity disorder. n engl j med 2005; 352:165–73. doi: 10.1056/nejm cp032387. 18. fletcher jm, lyon gr, fuchs ls, barnes ma. learning disabilities: from identification to intervention. new york, usa: the guilford press, 2006. pp. 25–27. 19. mcgee r, brodeur d, symons d, andrade b, fahie c. time perception: does it distinguish adhd and rd children in a clinical sample? j abnorm child psychol 2004; 32:481–90. doi: 10.1023/b:jacp.0000037778.61929.1b. 20. im-bolter n, johnson j, pascual-leone j. processing limitations in children with specific language impairment: the role of executive function. child dev 2006; 77:1822–41. doi: 10.1111/j.1467-8624.2006.00976.x. 21. scourfield j, john b, martin n, mcguffin p. the development of prosocial behaviour in children and adolescents: a twin study. j child psychol psychiatry 2004; 45:927–35. doi: 10.1111/j.14697610.2004.t01-1-00286.x. 22. massetti gm, lahey bb, pelham we, loney j, ehrhardt a, lee ss, et al. academic achievement over 8 years among children who met modified criteria for attention-deficit/ hyperactivity disorder at 4-6 years of age. j abnorm child psychol 2008; 36:399–410. doi: 10.1007/s10802-007-9186-4. 23. fabiano ga, pelham we jr, coles ek, gnagy em, chronistuscano a, o’connor bc. a meta-analysis of behavioral treatments for attention-deficit/hyperactivity disorder. clin psychol rev 2009; 29:129–40. doi: 10.1016/j.cpr.2008.11.001. http://dx.doi.org/10.1177/108705470100400404 http://dx.doi.org/10.1080/13632752.2012.652429 http://dx.doi.org/10.1037/0021-843x.110.1.157 http://dx.doi.org/10.1037/0021-843x.110.1.157 http://dx.doi.org/10.1056/nejmcp032387 http://dx.doi.org/10.1056/nejmcp032387 http://dx.doi.org/10.1023/b:jacp.0000037778.61929.1b http://dx.doi.org/10.1111/j.1467-8624.2006.00976.x http://dx.doi.org/10.1111/j.1469-7610.2004.t01-1-00286.x http://dx.doi.org/10.1111/j.1469-7610.2004.t01-1-00286.x http://dx.doi.org/10.1007/s10802-007-9186-4 http://dx.doi.org/10.1016/j.cpr.2008.11.001 departments of 1surgery and 2anaesthesia & intensive care, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: drkhalidmunirbhatti@yahoo.com إستئصال الطحال باملنظار ملرض فقر الدم املنجلي تقرير عن مخسون حالة يف األطفال زينب ن��رس البلو�شية, خ�لد منري به�تي, حممد اإح�ش�ن توفيق, يو�شف ال�شق�شي, نوال عبداهلل را�شد ال�رسجية, ح�مت علي م��شي, حممود ح�مت �رسيف abstract: objectives: in oman, the most frequent indication for a splenectomy in children is sickle cell disease (scd), which is one of the most common haematological disorders in the gulf region. this study aimed to describe paediatric laparoscopic splenectomies alone for scd at a tertiary hospital in oman. methods: this study was conducted between february 2010 and october 2015 at the sultan qaboos university hospital, muscat, oman. the medical records of all children aged ≤15 years old undergoing splenectomies during the study period were reviewed. results: a total of 71 children underwent laparoscopic splenectomies during the study period; of these, 50 children (28 male and 22 female) underwent laparoscopic splenectomies alone for scd. the children’s weight ranged between 11–43 kg. the most common indication for a splenectomy was a recurrent splenic sequestration crisis (92%). surgically removed spleens weighed between 155–1,200 g and measured between 9–22 cm. operative times ranged between 66–204 minutes and intraoperative blood loss ranged between 10–800 ml. one patient required conversion to an open splenectomy. postoperative complications were noted in only four patients. the median hospital stay duration was three days. conclusion: among this cohort, the mean operating time was comparable to that reported in the international literature. in addition, rates of conversion and postoperative complications were very low. these findings indicate that a laparoscopic splenectomy alone in paediatric patients with scd is a feasible option. keywords: laparoscopy; splenectomy; pediatrics; sickle cell disease; oman. امللخ�ص: الهدف: اإن ال�شبب الأكرث �شيوع� ل�شتئ�ش�ل الطح�ل يف الأطف�ل يف عم�ن هو مر�س فقر الدم املنجلي, والذي يعد من اإ�شطراب�ت الدم الأكرث �شيوع� يف منطقة اخلليج. هدفت هذه الدرا�شة لو�شف ح�لت ا�شتئ�ش�ل الطح�ل ب�ملنظ�ر عند الأطف�ل امل�ش�بني مبر�س فقر الدم املنجلي يف م�شت�شفى ث�لثي يف عم�ن. الطريقة: اأجريت هذه الدرا�شة بني فرباير 2010 واأكتوبر 2015 يف م�شت�شفى ج�معة ال�شلط�ن طفال 71 النتائج: الدرا�شة. فرتة خالل ع�م� ≤15 اأعم�رهم الذين الأطف�ل جلميع الطبية ال�شجالت ا�شتعرا�س مت عم�ن. م�شقط, ق�بو�س, خ�شع لعملية ا�شتئ�ش�ل الطح�ل ب�ملنظ�ر خالل فرتة الدرا�شة. من هوؤلء, مت ا�شتئ�ش�ل الطح�ل ب�ملنظ�ر حل�لت مر�س فقر الدم املنجلي خلم�شني طفال )28 من الذكور و 22 من الإن�ث(. وتراوح اأوزان الأطف�ل م� بني 43-11 كجم. اإن اأكرث الأ�شب�ب �شيوع� ل�شتئ�ش�ل الطح�ل بني 9-22 م� وقي��شه غرام بني 155-1,200 م� جراحي� ازالته مت الذي الطح�ل وزن تراوح املتكرر )92%(. الطح�ل احتج�ز اأزمة ك�ن �شم. وتراوحت اأوق�ت اجلراحة بني 204-66 دقيقة وتراوح فقدان الدم اأثن�ء العملية بني 800-10 مل. مت حتويل مري�س واحد اإىل العملية امل�شت�شفى يف الإق�مة مدة متو�شط ك�ن فقط. املر�شى من اأربعة يف اجلراحة بعد م� م�ش�عف�ت وجدت الطح�ل. ل�شتئ�ش�ل املفتوحة ثالثة اأي�م. اخلال�صة: يف جمموعة الدرا�شة هذه, ك�ن وقت العملية مم�ثل لتلك التي �شجلت يف الأدبي�ت الع�ملية. ب�لإ�ش�فة اإىل ذلك, ك�نت معدلت التحويل وم�ش�عف�ت م� بعد العملية اجلراحية منخف�شة جدا. وت�شري هذه النت�ئج اإىل اأن ا�شتئ�ش�ل الطح�ل ب�ملنظ�ر حل�لت مر�س فقر الدم املنجلي يف الأطف�ل هو خي�ر مت�ح. الكلمات املفتاحية: تنظري البطن؛ ا�شتئ�ش�ل الطح�ل؛ طب الأطف�ل؛ مر�س فقر الدم املنجلي؛ عم�ن. laparoscopic splenectomy alone for sickle cell disease account of 50 paediatric cases zainab n. al-balushi,1 *khalid m. bhatti,1 muhammad t. ehsan,1 yousuf al-shaqsi,1 nawal a. r. al-sharji,1 hatem a. a. mady,2 mahmoud h. sherif1 advances in knowledge this study describes the results of laparoscopic splenectomies alone in a cohort of omani children with sickle cell disease (scd). to the best of the authors’ knowledge, this study is the first of its kind in the region and the only one to exclude splenectomies performed for other haematological indications or combined with other procedures. application to patient care the findings of the current study indicate that a laparoscopic splenectomy alone for paediatric patients with scd is a safe and acceptable procedure. clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e482–486, epub. 30 nov 16 submitted 7 dec 15 revisions req. 26 jan, 15 mar & 9 may 16; revisions recd. 20 feb, 4 apr & 10 jul 16 accepted 14 jul 16 doi: 10.18295/squmj.2016.16.04.013 zainab n. al-balushi, khalid m. bhatti, muhammad t. ehsan, yousuf al-shaqsi, nawal a. r. al-sharji, hatem a. a. mady and mahmoud h. sherif clinical and basic research | e483 haematological indications for a splenectomy vary globally. in the western world, the most common indications for a splenectomy in children are hereditary spherocytosis and idiopathic thrombocytopaenic purpura.1–4 in oman, the most common indication for a splenectomy in children is sickle cell disease (scd).5 this haematological disorder is one of the most prevalent in the gulf region, with an incidence of one in 323 live births and a prevalence of 5.8%.6–8 the management of paediatric patients with scd can be challenging, as surgical procedures may precipitate a sickling crisis.9 paediatric scd patients may require a splenectomy for various indications, such as recurrent splenic sequestration or splenic dysfunction.10 the effectiveness of splenectomies in improving haematological outcomes is well-established.11,12 however, most studies in the medical liter ature combine the results of laparo-scopic splenec tomies carried out for various indications such as hereditary spherocytosis, idiopathic thrombocytopaenic purpura or chronic myelomonocytic leukaemia, with only a small number focusing solely on laparoscopic splenectomies among patients with scd.1,3,4 moreover, some researchers include chil dren who undergo a combined laparoscopic cholecystectomy and splenectomy.3 hence, there is a lack of research describing the results of laparoscopic splenectomies alone among children with scd. this study aimed to describe the results of laparoscopic splenectomies alone among a cohort of children with scd. to the best of the authors’ knowledge, this is the first study of its kind to analyse laparoscopic splenectomies due to scd alone, excluding splenectomies performed as a result of other haematological disorders or combined with other surgical procedures. methods this retrospective study was conducted at the sultan qaboos university hospital (squh), muscat, oman. a review of all patients ≤15 years old undergoing a laparoscopic splenectomy alone for scd between february 2010 and october 2015 was undertaken. patients who were operated upon for other haematological diseases or who underwent splenectomies combined with other procedures (e.g. a cholecystectomy) were excluded. the study was retrospective for the first three years of data collection but was then maintained prospectively. the medical records of the patients were reviewed for the following information: demographic characteristics; indications for the splenectomy; operative time; preoperative and postoperative transfusion requirements; intraoperative complications or blood loss; the need for conversion to open surgery; postoperative complications (including acute chest syndrome [acs], vaso-occlusive crises and general/ wound infections); administration of narcotic analgaesia; and length of hospital stay. acs was diagnosed according to previously described criteria.9 indications for splenectomies alone in children with scd included either hypersplenism or acute splenic sequestration. hypersplenism was defined as splenic enlargement with one of the following conditions: anaemia (requiring a transfusion of packed red blood cells exceeding 250 ml/kg per year); thrombocytopaenia (indicated by a platelet count of ≤100,000/mm3); and neutropaenia (indicated by a white blood cell count of ≤4,000/mm3).13 children were considered to have acute splenic sequestration if they suffered from at least one major or two minor attacks. major attacks were characterised by a combination of splenic enlargement, a 2–3 g/dl drop in haemoglobin (hb) levels and associated hypovolemia while minor attacks constituted splenic enlargement and a drop in hb levels only, without hypovolemia.12 laparoscopic splenectomies were performed according to the following procedure. preoperatively, all patients received a pneumococcal polyvalent vaccine at least two weeks before the surgery. in addition, ultrasonography scans were performed to determine the size of the spleen and to rule out the presence of concomitant gall stones. patients were transfused preoperatively if their hb levels were <10 g/dl. in the operating theatre, patients were placed in a semi-decubitus position with their left side elevated.3,5,14 a total of 25 mg/kg of cefuroxime was administered as an induction dose. the positioning of the ports during the splenectomy is shown in figure 1. maryland forceps figure 1: photograph showing the positioning of ports during a laparoscopic splenectomy alone for sickle cell disease. the child is lying in a semi-decubitus position with the arrow pointing towards the head. note the placement of the camera port (c), retraction port (r) in the epigastrium and right hand working port (rhwp) in the left iliac fossa. laparoscopic splenectomy alone for sickle cell disease account of 50 paediatric cases e484 | squ medical journal, november 2016, volume 16, issue 4 to 12 patients (24%). there were seven cases of postoperative complications occurring in four patients, including acs (n = 4; 8%), general infections (n = 2; 4%) and acute pancreatitis (n = 1; 2%). [table 2]. the patient with acute pancreatitis had received an injury to the tail of the pancreas and was diagnosed on the 10th postoperative day when high amylase levels were noted in the drained fluid. the same patient also developed acs and remained in the hospital for 55 days. septic episodes were noted in two patients (4%) and the blood culture of one patient tested positive for salmonella. these patients required intravenous antibiotics (90 mg/kg of intravenous piperacillin/ tazobactam every 8 hours) for an average of 12 days. (olympus medical systems, tokyo, japan) were used to isolate the splenic vessels where needed while a harmonic scalpel (harmonic® shears, ethicon endo-surgery inc., blue ash, ohio, usa) was used to control the hilar vessels and divide the ligaments supporting the spleen. all patients underwent total splenectomies as there is currently a lack of evidence regarding the benefits of partial splenectomies in improving scd haematological parameters; moreover, partial splenectomies are associated with greater intraoperative blood loss and higher rates of conversion to open surgery.14,15 postoperatively, patients were managed by a physician specialising in paediatric haematology. one month after discharge, the patients were followed-up in the paediatric surgery outpatient department. ethical approval for this study was received from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #396). results a total of 71 children underwent laparoscopic splenectomies during the study period. of these, 18 patients were excluded because they underwent laparoscopic cholecystectomies combined with splenectomies and three patients were excluded because they had haematological disorders other than scd. as such, a total of 50 paediatric patients (28 male and 22 female) underwent splenectomies alone for scd. the most common reason splenectomies were performed was due to a recurrent splenic sequestration crisis (92%). most of the children were ≤5 years old (60%). the mean age of the patients was 6.00 ± 2.76 years (range: 2–15 years old) and their mean weight was 18.66 ± 6.84 kg (range: 11.2–43.0 kg). the mean operative time was 119.66 ± 30.39 minutes (range: 66–204 minutes). the mean intraoperative blood loss was 94.80 ± 148.64 ml (range: 10–800 ml). the median hospital stay duration was three days. the mean weight of removed spleens was 457.76 ± 178.88 g (range: 155–1,200 g) while the mean size of the spleens was 13.62 ± 3.39 cm (range: 9–22 cm) [table 1]. the mean size of the spleen in patients ≤5 years old was lower than that of patients >5 years old (12.56 ± 2.66 cm versus 15.22 ± 3.79 cm; p = 0.026). however, mean weight did not vary significantly between patients ≤5 years old and those >5 years old (450.00 g versus 469.00 g, respectively; p = 0.820). five patients required intraoperative blood trans fusions while five patients were transfused postoperatively. narcotic analgaesia was administered table 1: descriptive characteristics of paediatric laparoscopic splenectomies alone for sickle cell disease conducted at the sultan qaboos university hospital, muscat, oman (n = 50) characteristic range median mean ±sd patient age in years 2–15 5 6.00 ± 2.76 patient weight in kg 11.2–43.0 16.7 18.66 ± 6.84 size of spleen in cm 9.0–22.0 12.4 13.62 ± 3.39 weight of spleen in g 155–1,200 485 457.76 ± 178.88 operating time in minutes 66–204 120 119.66 ± 30.39 operative blood loss in ml 10–800 50 94.80 ± 148.64 hospital stay in days 1–55 3 4.38 ± 7.57 sd = standard deviation. table 2: frequency of intraoperative and postoperative variables of paediatric laparoscopic splenectomies alone for sickle cell disease conducted at the sultan qaboos university hospital, muscat, oman (n = 50) variable n (%) blood transfusions 10 (20) intraoperative 5 (10) postoperative 5 (10) conversion to open surgery 1 (2) narcotic analgaesia administration 12 (24) picu admissions 2 (4) postoperative complications 7 (14) acute pancreatitis 1 (2) acute chest syndrome 4 (8) general infections 2 (4) wound infections 0 (0) vaso-occlusive crisis 0 (0) mortality 0 (0) picu = paediatric intensive care unit. zainab n. al-balushi, khalid m. bhatti, muhammad t. ehsan, yousuf al-shaqsi, nawal a. r. al-sharji, hatem a. a. mady and mahmoud h. sherif clinical and basic research | e485 only one patient required conversion to open surgery due to intractable intraoperative bleeding requiring both intraand postoperative transfusions. this patient was kept under observation in the paediatric intensive care unit for 48 hours. in two other patients, a small incision was made in the lower quadrant to remove the spleen. the mean duration of follow-up with paediatric haematologists was 27.00 ± 21.20 months (range: 1–69 months; median: 18 months). discussion to the best of the authors’ knowledge, this singlecentre study is the first of its kind in the region describing the results of laparoscopic splenectomies in paediatric patients with scd. in the current study, the most common indication for a splenectomy was an acute splenic sequestration crisis; the percentage of children requiring a splenectomy for this indication (92%) is higher than that reported in any other study in the literature to date.2,13,16,17 this may be due to early diagnosis or increased acceptance of a laparoscopic approach among family members or caregivers. however, 60% of the children who underwent laparoscopic splenectomies in the present study were under five years old, which is the most common age for an acute splenic sequestration crisis.10 as sequestration is rare beyond this age, it seems likely that some patients required a splenectomy for some other reason. splenectomies can be performed either using an open or laparoscopic technique.11,12 many researchers have reported that a laparoscopic procedure is the superior choice.1,12,14 reported advantages include minimal trauma during access, enhanced cosmetic results, reduced pain and a shorter hospital stay.1–3 moreover, there is a reduced incidence of acs following a laparoscopic splenectomy compared to the open procedure; this can be attributed to several factors, including the decreased risk of pulmonary fat embolisms and wound infection and a lower incidence of hypoventilation due to reduced postoperative pain.11 nevertheless, conversion to an open splenectomy may be needed during a laparoscopic splenectomy due to intractable bleeding, adhesion of the spleen, anatomical variations and difficulties in removing the spleen.3 in the current study, the conversion rate was very low (2%); conversion rates in the literature vary from 0–18%.3 the dissection of the hilar vessels is an important aspect of a laparoscopic splenectomy; to this end, various dissections tools are available, including linear staplers and clipping and harmonic devices.1,3,4,14 although it shortens the operative time, en bloc stapling of the hilum can increase the risk of the patient developing arteriovenous fistulae, injuries to the pancreatic tail and splenic or portal vein thrombosis.4 in a small study of 17 patients, vargün et al. established a one-year follow-up as a safe period of time for evaluation following en bloc stapling; however, this procedure has not yet been adopted at squh.4,5 in the current study, the splenic hila were handled with maryland forceps (olympus medical systems) for isolation and an ultrasonic harmonic scalpel was used to seal and divide the vessels. the efficacy of ultrasonic shear coagulation has been previously documented by schaarschmidt et al.18 during splenectomies, the length of operative time depends on many factors, including the choice of instrument for hilar dissection and the experience of the surgeon.4,5,19–21 in the current study, the mean operative time was 119 minutes. this is comparable to times reported in the international literature which record a mean operative time of 107 minutes for en bloc stapling, 130 minutes using the ligasure™ vessel sealing system (medtronic, minneapolis, minnesota, usa) and 150 minutes for individual ligation.4,19,20 however, it is important to note that the mean operative time decreases over the years as surgeons become more experienced.5,21 among postoperative complications, acs is the most disease-specific in that the complication is caused by the underlying scd rather than the procedure. in a recent retrospective study, bonnard et al. reported the incidence of acs following a laparoscopic splenectomy to be 23%.9 in the present study, the incidence of acs was much lower (8%). other serious postoperative complications include pancreatitis due to an injury to the tail of the pancreas during a laparoscopic splenectomy, with a reported incidence of up to 15%.4 in the current study, only one patient (2%) received an injury to the tail of the pancreas. moreover, none of the patients developed wound infections, overwhelming post-splenectomy infections (opsis), portal or splenic vein thrombosis or visceral injuries. these findings indicate that a laparoscopic splenectomy alone in paediatric patients with scd is a safe and feasible surgical approach. the current study had several limitations. this was a descriptive study and lacked a comparison of laparoscopic and open splenectomy techniques. however, the superiority of a laparoscopic approach over an open technique has been previously wellestablished.1–3,12,14 nevertheless, this study presents only the results of laparoscopic surgeries for patients with a single haematological condition; hence, the results should be interpreted carefully. studies documenting the quality of life of scd patients and laparoscopic splenectomy alone for sickle cell disease account of 50 paediatric cases e486 | squ medical journal, november 2016, volume 16, issue 4 almasrouri sm. current status of pediatric minimal access surgery at sultan qaboos university hospital: a 3-year experience. ann pediatr surg 2013; 9:140–3. doi: 10.1097/01. xps.0000434487.93877.be. 6. el-hazmi ma, al-hazmi am, warsy as. sickle cell disease in middle east arab countries. indian j med res 2011; 134:597–610. doi: 10.4103/0971-5916.90984. 7. al-riyami aa, suleiman aj, afifi m, al-lamki zm, daar s. a community-based study of common hereditary blood disorders in oman. east mediterr health j 2001; 7:1004–11. 8. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 9. bonnard a, masmoudi m, boimond b, capito c, holvoet l, skhiri a, et al. acute chest syndrome after laparoscopic splenectomy in children with sickle cell disease: operative time dependent? pediatr surg int 2014; 30:1117–20. doi: 10.1007/ s00383-014-3600-0. 10. brousse v, buffet p, rees d. the spleen and sickle cell disease: the sick(led) spleen. br j haematol 2014; 166:165–76. doi: 10.1111/bjh.12950. 11. machado no, grant cs, alkindi s, daar s, al-kindy n, al lamki z, et al. splenectomy for haematological disorders: a single center study in 150 patients from oman. int j surg 2009; 7:476–81. doi: 10.1016/j.ijsu.2009.08.004. 12. rice he, crary se, langer jc, kemper ar; splenectomy in congenital hemolytic anemia consortium. comparative effectiveness of different types of splenectomy for children with congenital hemolytic anemias. j pediatr 2012; 160:684–9. doi: 10.1016/j.jpeds.2011.09.030. 13. al-salem ah. indications and complications of splenectomy for children with sickle cell disease. j pediatr surg 2006; 41:1909–15. doi: 10.1016/j.jpedsurg.2006.06.020. 14. englum br, rothman j, leonard s, reiter a, thornburg c, brindle m, et al. hematologic outcomes after total splenectomy and partial splenectomy for congenital hemolytic anemia. j pediatr surg 2016; 51:122–7. doi: 10.1016/j.jped surg.2015.10.028. 15. esposito c, corcione f, garipoli v, ascione g. pediatric laparoscopic splenectomy: are there real advantages in comparison with the traditional open approach? pediatr surg int 1997; 12:509–10. doi: 10.1007/bf01258713. 16. al-salem ah. splenic complications of sickle cell anemia and the role of splenectomy. isrn hematol 2011; 2011:864257. doi: 10.5402/2011/864257. 17. meshikhes aw, mubarek ma, abu-alrahi ai, al-saif oh. the pattern of indications and complications of splenectomy in eastern saudi arabia. saudi med j 2004; 25:1892–5. 18. schaarschmidt k, kolberg-schwerdt a, lempe m, saxena a. ultrasonic shear coagulation of main hilar vessels: a 4-year experience of 23 pediatric laparoscopic splenectomies without staples. j pediatr surg 2002; 37:614–16. doi: 10.1053/ jpsu.2002.31620. 19. de lagausie p, bonnard a, benkerrou m, rorlich p, de ribier a, aigrain y. pediatric laparoscopic splenectomy: benefits of the anterior approach. surg endosc 2004; 18:80–2. doi: 10.1007/ s00464-003-9048-2. 20. romano f, caprotti r, franciosi c, de fina s, colombo g, sartori p, et al. the use of ligasure during pediatric laparoscopic splenectomy: a preliminary report. pediatr surg int 2003; 19:721–4. doi: 10.1007/s00383-003-1037-y. 21. cusick ra, waldhausen jh. the learning curve associated with pediatric laparoscopic splenectomy. am j surg 2001; 181:393–7. doi: 10.1016/s0002-9610(01)00609-2. their long-term outcomes should be conducted in order to determine the efficacy of a laparoscopic splenectomy in improving blood counts and reducing the risk of acute splenic sequestration, blood transfusion requirements and the incidence of acs and opsis. moreover, children with scd from the gulf region have been reported to have persistent splenomegaly later in life (≥18 years old), possibly due to high fetal hb levels.16 in the current study, fetal hb levels were not recorded; however, it was noted that spleens were larger among older patients >5 years old. future qualitative studies should therefore explore this issue in greater detail. conclusion among the studied children with scd, the most common indication for a laparoscopic splenectomy was recurrent splenic sequestration. a low conversion rate to open surgery was noted and very few patients suffered from postoperative complications. these findings indicate that a laparoscopic splenectomy alone is a safe and feasible approach for paediatric patients with scd. a c k n o w l e d g e m e n t s the authors would like to thank the department of haematology at squh, who played a vital role in pre and postoperative patient management, diagnosis and establishing indications for splenectomies. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. curran tj, foley mi, swanstrom ll, campbell tj. laparoscopy improves outcomes for pediatric splenectomy. j pediatr surg 1998; 33:1498–500. doi: 10.1016/s0022-3468(98)90484-5. 2. sandoval c, stringel g, ozkaynak mf, tugal o, jayabose s. laparoscopic splenectomy in pediatric patients with hematologic diseases. jsls 2000; 4:117–20. 3. murawski m, patkowski d, korlacki w, czauderna p, sroka m, makarewicz w, et al. laparoscopic splenectomy in children: a multicenter experience. j pediatr surg 2008; 43:951–4. doi: 10.1016/j.jpedsurg.2007.11.040. 4. vargün r, göllü g, fitöz s, yagmurlu a. en-bloc stapling of the splenic hilum in laparoscopic splenectomy. minim invasive ther allied technol 2007; 16:360–2. doi: 10.1080/ 13645700701699414. 5. bhatti km, alsibai sm, albalushi zn, alisaee as, أمناط وصفات األدوية اليت يصفها األطباء النفسانيون يف العيادات اخلارجية اخلاصة يف حمافظة كرمان بإيران عبدالر�سا �سباحي، غالم ر�سا �سبيهري، مطهره حم�سن بيكي، اإح�سان �سبيهري abstract: objectives: the aim of this study was to assess the pattern and utilisation of psychotropic drug prescriptions by psychiatrists in kerman province, iran. methods: the prescriptions of 27 psychiatrists were randomly selected from two iranian public insurance organisations and were analysed for the mean number of drugs/prescriptions, drug category and the most frequently prescribed drug in each category as well as overall. results: a total of 6,414 prescriptions were analysed. the mean number of drugs per prescription was 2.9. antidepressants (61.0%) were the most frequently prescribed category of psychotropic medications, followed by antipsychotics (29.5%), sedative/hypnotics or anti-anxiety drugs (27.5%) and mood stabilisers (18.5%). the combination of antidepressants with antipsychotics was the most commonly prescribed combination (18.8%). fluoxetine (16.5%) and trifluoperazine (13.5%) were among the most frequently prescribed antidepressants and antipsychotics, respectively. clonazepam (10.5%) was the most commonly prescribed benzodiazepine agent, followed by alprazolam (8.5%). in terms of total drug utilisation, sertraline (12.4%) was the most commonly used psychotropic medication followed by fluoxetine (9.7%), trifluoperazine (6.6%), propranolol (4.5%) and clonazepam (3.7%). conclusion: a high proportion of psychotropic prescriptions in kerman province were for antidepressants, followed by antipsychotics and the benzodiazepines. further research is needed to determine the underlying correlation between prescription practice and the diagnosis and patient characteristics, as well as to investigate the use of different psychotropic medications. keywords: prescriptions, trends; prescriptions, utilization; psychotropic drugs; psychiatrists; iran. امللخ�ص: الهدف: تهدف هذه الدرا�سة لتقييم اأمناط و�سفات الأدوية التي ي�سفها الأطباء النف�سانيون يف عيادات الطب النف�سي اخلارجية اإيرانيتني منظمتني من كرميان حمافظة يف نف�سيا طبيبا 27 و�سفات ع�سوائيا اأختريت الطرق: باإيران. كرميان حمافظة يف اخلا�سة للتاأمني العام، ومت حتليلها للح�سول على متو�سط عدد الأدوية وت�سنيف الأدوية املو�سوفة، واأكرث الأدوية التي مت و�سفها يف كل �سنف. املو�سوفة الأدوية مناذج درا�سة من ووجد دواء. هو 2.9 و�سفة كل يف الأدوية عدد متو�سط وكان و�سفة، حتليل 6,414 مت النتائج: اأن %61.0 من تلك الأدوية كانت من م�سادات الكتئاب، تلتها م�سادات الذهان )بن�سبة %29.5( ثم املهدئات/املنومات/م�سادات القلق )بن�سبة %27.5( ثم مثبتات املزاج )%18.5(. وكانت اأكرث الأدوية التي اأعطيت معا هي م�سادات الكتئاب مع م�سادات القلق .)13.5% )بن�سبة بريازين فلو تراي الذهان م�ساد مع )16.5% )بن�سبة فلوك�سوتني الإكتئاب م�ساد اأعطي حيث ،)18.8% )بن�سبة وكان اأكرث الأدوية التي و�سفت يف جمموعة البنزودايزبني هو كلونازبيام )بن�سبة %10.5(، تليه الربازولم )بن�سبة %8.5(. وبالن�سبة اإىل كل اأ�سناف الأدوية كان �سريتالين هو اأكرث دواء مت و�سفه )بن�سبة %12.4( وتاله فلوك�ستني )بن�سبة %9.7( ثم برارانالول )بن�سبة يف النف�سية الأدوية و�سفات ن�سب اأعلى كانت )بن�سبة %6.6(. اخلال�صة: بريازين فلو تراي ثم )بن�سبة 3.7%( وكلونازيبام )4.5% حمافظة كرمان باإيران هي مل�سادات الكتئاب وتالها م�سادات الذهان وجمموعة بينزي دايزبني. ويجب يف الدرا�سات القادمة حتديد العالقة الكامنة بني ممار�سة كتابات الو�سفات الطبية والت�سخي�س وخ�سائ�س املري�س، ودرا�سة ا�ستخدام خمتلف الأدوية امل�ستخدمة يف الطب النف�سي. مفتاح الكلمات: و�سفات طبية؛ توجهات؛ ا�ستخدام الأدوية؛ الأدوية النف�سية؛ الأطباء النف�سانيون؛ اإيران. patterns of psychotropic medication prescriptions by psychiatrists for private clinic outpatients in kerman province, iran abdolreza sabahi,1 *gholamreza sepehri,1 mottahareh mohsenbeigi,2 ehsan sepehri3 clinical & basic research sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e382-387, epub. 24th jul 14 submitted 1st feb 14 revision req. 24th mar 14; revision recd. 26th mar 14 accepted 17th apr 14 1neuroscience research center, kerman university of medical sciences, kerman, iran; 2kerman social security organization, kerman, iran; 3tehran university of medical sciences, tehran, iran *corresponding author e-mail: gsepehri@yahoo.com advances in knowledge antidepressant drugs are the group of psychotropic drugs most frequently prescribed by psychiatrists in kerman province, iran, followed by antipsychotics and sedative/hypnotics. fluoxetine, sertraline, propranolol and clonazepam are among the most frequently prescribed psychotropic drugs by this group of psychiatrists. abdolreza sabahi, gholamreza sepehri, mottahareh mohsenbeigi and ehsan sepehri clinical and basic research | e383 an increasing trend in the prescription of psychotropic medications by physicians has been noted in recent years and the increase in psychotropic prescriptions by psychiatrists and general practitioners (gps) has been reported in both developing and developed countries.1–4 psychotropic medications are often prescribed for non-psychotic disorders, such as eating disorders in children, adolescents and adults.5 there is also an increased prevalence of antipsychotic drug use among children and adolescents, as well as an increasing trend in the abuse of central nervous system (cns) stimulants among young adolescents, including amphetamines, methylphenidate and ecstasy. this has been observed in many countries, including iran.6–9 there is a significant difference in the rate of prescription and consumption of sedative/hypnotic drugs and antidepressants between developed and developing countries. antianxiety drugs were the most frequently prescribed psychotropic drugs in various psychiatric disorders followed by antipsychotic drugs and antidepressant drugs in outpatients (opd) of a psychiatry department in india;10 however, stimulants and antidepressants consistently ranked first and second in psychotropic medication treatment for youths in usa.11 only a few studies have examined prescribing practices among physicians in kerman province, iran. one study reported prescription practices among gps, reported that sedative/hypnotic drugs were prescribed for 19.56% of patients visited by gps.12 another study among residents living in bam, a city in iran, observed that drugs affecting the cns were the most frequently prescribed, representing 52.7% of all prescribed drugs.13 to date there has been no reliable information on the prescribing habits of psychiatrists in iran; thus, this study aimed to assess the pattern of drug prescription and utilisation of psychotropic medications in outpatients visited by psychiatrists at private clinics in kerman province, iran. methods this retrospective cross-sectional study was conducted over a one-year period between 1st may 2012 and 1st may 2013. the prescriptions of 27 psychiatrists were randomly selected from two iranian public insurance organisations in kerman province. the iranian social security organization (sso) provides legally compulsory insurance coverage to workers and employees in the private sector. selfemployed individuals can also elect to belong to the sso (n = 4,391). the iranian medical services insurance organization (msio) covers a wide range of individuals in the community, including government employees and individuals of various socioeconomic levels who are not eligible to be covered by other insurance organisations (n = 2,023). a total of 6,414 prescriptions were randomly selected from these two public insurance companies and analysed, with at least 100 prescriptions per psychiatrist. prescriptions that had been issued to patients of all ages and both genders and which contained at least one psychotropic medication were included in the study. drug-related information (including the drug names, dose, dosage form and route of administration) were recorded on a customised data collection sheet. anaesthetics, antiepileptic medications and drugs used in the management of parkinsonism were excluded from the study. the data were also analysed using three world health organization (who) indicators to determine drug use in a health facility: the average number of drugs per encounter, the percentage of drugs prescribed under a generic name and the percentage of injections prescribed per encounter.14 the drug categories and the most frequently prescribed drugs table 1: drug use indicators for psychiatrist-prescribed psychotropic prescriptions for outpatients in kerman province, iran* indicators n % average number of drugs per prescription 2.9 number of drugs prescribed by generic name 5,452 85 prescriptions with complete documentation† 6,029 94 number of drug injections prescribed 257 4 *using the world health organization indicators to determine drug use in a health facility.14 †including complete drug name, dose, dosage form and route of administration. application to patient care the high rate of antidepressant prescriptions found in this study is of special importance. further research should be carried out to determine whether these drugs are prescribed for outpatients with depression or if they are used to treat patients with diagnoses other than depressive disorders. in addition, it is recommended that health organisations investigate the reasons for the high rate of psychotropic prescriptions in kerman province and implement interventional programmes to improve the rational prescription of these medications through standardised treatment guidelines. e384 | squ medical journal, august 2014, volume 14, issue 3 patterns of psychotropic medication prescriptions by psychiatrists for private clinic outpatients in kerman province, iran in each category were also recorded. drug utilisation was measured by taking the total defined daily doses for each drug or drug category and dividing this by the total defined daily doses of all psychotropic medications. the psychotropic drugs were classified into six therapeutic drug classes: antipsychotics, antidepressants; sedative/hypnotics (anti-anxiety); cns stimulants; mood stabilisers (lithium, sodium valproate or carbamazepine) and others (beta blockers, antihistamines, anticholinergic agents, etc.). the data were processed and presented using the statistical package for the social sciences (spss), version 13 (ibm, corp., chicago, illinois, usa). the mann-whitney u nonparametric test was used to compare the differences between the utilisation of each drug group. approval to use the data was granted by both the sso and the msio. results a total of 6,414 psychiatric outpatient prescriptions were analysed using the who indicators to determine drug use in a health facility.14 overall, the mean number of drugs per prescription was 2.9 (range: 1–12). the majority of prescriptions (94%) had complete documentation regarding the drug information. most of the drugs (85%) were prescribed by a generic name. injectable drugs were prescribed in 4% of the prescriptions (range: 1–15%) [table 1]. a total of 52 different drugs were prescribed to outpatients of which 32 drugs were from the psychotropic category. the most frequently prescribed psychotropic medications were antidepressants (61.0%), followed by antipsychotics (29.5%), sedative/ hypnotic/anti-anxiety drugs (27.5%) and mood stabilisers (18.5%) [table 2]. in the antidepressant drug category, fluoxetine (16.5%) was the most commonly prescribed antidepressant, followed by sertraline (15.0%). trifluoperazine (13.5%) was the preferred drug within the antipsychotics group, followed by quetiapine (4.5%). clonazepam (10.5%) was the most commonly prescribed benzodiazepine agent among the sedative/ hypnotics category, followed by alprazolam (8.5%). among the mood stabilisers, lithium (12.3%) was preferred over sodium valproate (4.8%) and table 3: utilisation patterns of the most common psychiatrist-prescribed psychotropic drugs for outpatients in kerman province, iran drug (dosage form) prescription rate % total drug utilisation % dose in mg fluoxetine (c) 16.5 9.7 10 sertraline (t) 15.0 12.4 50 trifluoperazine (sct) 13.5 3.6 1 propranolol (fct) 11.5 4.5 10 clonazepam (st) 10.5 3.7 2 alprazolam (st) 8.5 1.4 0.5 citalopram (t) 6.5 3.1 30 quetiapine (t) 4.5 1.3 100 chlordiazepoxide (st) 3.5 0.9 5 olanzapine (t) 3.0 0.6 5 c = capsule; t = tablet; sct= sugar-coated tablet; fct= film-coated tablet; st = scored tablet. table 2: prescription patterns of the most common psychiatrist-prescribed psychotropic drugs by selected drug categories for outpatients in kerman province, iran drug category prescription rate n (%)* total drug utilisation % antidepressants 3,912 (61.0) 38.2 fluoxetine 1,058 (16.5) 9.7 sertraline 962 (15.0) 12.4 citalopram 417 (6.5) 3.2 others 1,475 (23.0) 12.9 antipsychotics 1,892 (29.5) 17.5 trifluoperazine 866 (13.5) 6.6 quetiapine 289 (4.5) 2.4 olanzapine 192 (3.0) 1.6 others 545 (8.5) 6.9 sedative/hypnotics 1,764 (27.5) 17.5 clonazepam 674 (10.5) 3.7 alprazolam 545 (8.5) 3.2 chlordiazepoxide 224 (3.5) 2.8 others 321 (5.0) 7.8 mood stabilisers 1,187 (18.5) 8.6 lithium 789 (12.3) 6.0 sodium valproate 308 (4.8) 2.1 carbamazepine 90 (1.4) 0.5 stimulants 481 (7.5) 4.8 methylphenidate 481 (7.5) 4.8 other cns drugs 923 (14.4) 11.4 cns = central nervous system. *more than one drug may have been prescribed per patient. abdolreza sabahi, gholamreza sepehri, mottahareh mohsenbeigi and ehsan sepehri clinical and basic research | e385 carbamazepine (1.4%). methylphenidate was the most commonly prescribed stimulant (7.5%) [table 2]. utilisation patterns of the most commonly prescribed drugs were measured by taking the total defined daily doses for each drug or drug category and dividing this by the total defined daily doses of all psychotropic medications. in terms of total drug utilisation, antidepressants were the most commonly prescribed psychotropic medications (38.2%), followed by antipsychotics (17.5%) and sedative/hypnotics (17.5%). in all drug categories, sertraline (12.4%) was the most commonly used psychotropic medication followed by fluoxetine (9.7%), propranolol (4.5%) and clonazepam (3.7%) [table 3]. the results of the current study showed that drug utilisation patterns in kerman province are in accordance with the prescription pattern. table 4 shows the types of psychotropic drug combinations prescribed to outpatients by the psychiatrists. antidepressants and antipsychotics were the most commonly prescribed combination (18.8%), followed by the triple combination of antidepressants, antipsychotics and sedative/hypnotics (12.6%). discussion since the prescription pattern of iranian psychiatrists has not been reported previously, to the best of the authors’ knowledge, this study is a preliminary report for psychotropic medications in iran. on average, a mean of 2.9 drugs were prescribed to outpatients per prescription. this is significantly higher than reported in similar studies in both developing and developed countries, such as thailand and the usa, respectively.3,15 however, the findings of this study are comparable with a similar report from india.16 the majority of drugs were prescribed by their generic names. the rate of prescriptions that were accompanied by complete documentation and the percentage of injectable drugs prescribed were comparable to a similar study by udomratn et al.17 the results of this study showed that psychiatrists prescribed antidepressants most frequently. the psychiatrists’ antidepressant prescription rate was significantly higher than the reported values for a similar study (23.1–48.6%).18 antidepressants paired with antipsychotics were the most commonly prescribed combination (18.8%), which is comparable to findings from the study by udomratn et al.17 in the usa, goodwin et al. reported that stimulants were the most commonly prescribed drug category, followed by antidepressants, anxiolytics, antipsychotics and mood stabilisers.19 psychotropic medication consumption patterns in a study of the general population in the uk was dominated by hypnotics, antidepressants and anxiolytics.20 the reasons behind this high rate of antidepressant prescription are of special importance; the diagnosis by which antidepressant drugs are prescribed should be clarified. specifically, it is important to know whether antidepressant drugs are prescribed for depression or for patients with diagnoses other than depressive disorders, such as anxiety disorders, eating disorders, enuresis, urinary stress incontinence or personality disorders.10,21 the high rate of antidepressant prescriptions found in the current study suggests a need for continued investigation and a systematic analysis of the specific disorders that are being treated with antidepressants. an increase in psychotropic and antidepressant prescriptions and their utilisation has been reported from other parts of the world as well.11,22 von soest et al. reported a relationship between socioeconomic status and antidepressant prescriptions.23 the results of the present study showed that the most frequently prescribed antidepressants in kerman province were fluoxetine and sertraline, which accounted for 57% of all prescriptions; this finding is comparable to some previous studies in which selective serotonin reuptake inhibitors (ssris) were the preferred prescribed antidepressant class of drugs.24,25 fluoxetine, paroxetine and sertraline were the most frequently prescribed antidepressants in a spanish study, accounting for 58% of all prescriptions in depressed patients.24 the tolerability and efficacy of ssris in comparison with tricyclic antidepressants (tcas) is controversial; however, some investigators have reported that ssris show an advantage in terms of tolerability in contrast to most tcas.25,26 the current study’s results showed that antipsychotics were the second most frequently prescribed drug category by psychiatrists, which is not comparable to the results of similar studies in other parts of the world.19,20 goodwin et al. reported table 4: psychiatrist-prescribed psychotropic drug category combinations for outpatients in kerman province, iran drug category combination prescription rate n (%) antidepressants and antipsychotics 1,206 (18.8) antidepressants, antipsychotics and sedative/hypnotics 808 (12.6) antidepressants, antipsychotics, sedative/hypnotics and mood stabilisers 353 (5.5) other combinations 1,379 (21.5) e386 | squ medical journal, august 2014, volume 14, issue 3 patterns of psychotropic medication prescriptions by psychiatrists for private clinic outpatients in kerman province, iran that stimulants were the most commonly prescribed psychotropic medications to youths in office-based practice in the usa followed by antidepressants, anxiolytics, antipsychotics and mood stabilisers;19 however, hypnotics were the most commonly prescribed psychotropic medications in the uk general population followed by antidepressants and anxiolytics.20 in an indian outpatient setting, antipsychotics were the second most commonly prescribed psychotropic drugs.10 a marked variation in antipsychotic and sedative/hypnotic prescriptions by psychiatrists and an increase in typical and atypical antipsychotic drug use has been reported in both developed and developing countries.7,27 these variations could be due to economic and social factors, drug availability, knowledge of adverse drug reactions and differences in morbidity.22 in the present study, trifluoperazine was the preferred antipsychotic followed by quetiapine and olanzapine. the results were comparable to those of xiang et al., who found that quetiapine and olanzapine, second-generation antipsychotics, were the drugs most commonly prescribed to treat older schizophrenic patients in asia between 2001–2009.28 the results of the present study showed that 27.5% of patients were prescribed a benzodiazepine agent, which is higher than rates reported in some developing and developed countries.29,30 however, a higher benzodiazepine prescription rate (82.83%) by psychiatrists was reported in a study of outpatients in india.16 benzodiazepines are efficacious for a wide range of conditions such as anxiety, insomnia, tonicclonic seizures and muscular spasms; however, their rational use requires an understanding of the variable differences in potency, efficacy and duration of action between different benzodiazepines.31 in the current study, lithium was the preferred mood stabiliser and was prescribed over sodium valproate and carbamazepine—this finding is in harmony with another study from asia.32 however, other researchers have reported that sodium valproate was the most frequently prescribed drug for manic-depressive patients.33 the appropriateness of prescribing psychotropic medications as mood stabilisers needs further research. methylphenidate was the only psychiatristprescribed stimulant for the treatment of attention deficit disorder in children, which is comparable to the reports of other investigators.34,35 however, the rate of methylphenidate misuse or abuse was not determined in the current study and requires further investigation. fluoxetine, sertraline, trifluoperazine and clonazepam were among the most commonly prescribed psychotropic medications, which is in agreement with a previous report.24 however, propranolol was also among the most frequently prescribed drugs, which is one of the noteworthy findings of this study. propranolol is mainly prescribed by psychiatrists to relieve the somatic manifestations of general and performance anxiety. the reasons underlying the overall high rate of psychotropic medication prescription found in this study should be investigated. it is hoped that this type of research may provide a greater understanding of the prescribing patterns observed in the current study. the study has several limitations which should be clarified. this survey is the result of the prescription patterns of 27 psychiatrists in kerman province in iran; this population does not represent all psychiatrists throughout iran (approximately 400). in addition, the information recorded on the prescriptions analysed did not include the patient’s age, main diagnosis or socioeconomic status; these are significant factors affecting prescription patterns.23 a larger survey is recommended to evaluate iranian psychiatrists’ psychotropic medication prescription patterns with an emphasis on the relationship between prescription pattern and patient diagnosis. conclusion in summary, this is the first study to investigate prescription practices among psychiatrists in iran. the results showed that the most common prescriptions were for antidepressants, followed by antipsychotics and benzodiazepines (sedative/hypnotics). the high rate of antidepressant prescriptions is of special importance. future studies are recommended to investigate whether antipressant drugs are prescribed solely for depressive disorders or if they are used to treat patients with other diagnoses. further research is also needed to investigate a possible link between prescription practices, diagnoses, patient characteristics and the prescription of different antidepressants. a c k n o w l e d g e m e n t s this study was supported by a grant from the neuroscience research center, kerman university of medical sciences, kerman, iran references 1. aparasu rr, bhatara v, gupta s. us national trends in the use of antipsychotics during office visits, 1998-2002. ann clin psychiatry 2005; 17:147–52. 2. olfson m, marcus sc. national patterns in antidepressant medication treatment. arch gen psychiatry 2009; 66:848–56. doi: 10.1001/archgenpsychiatry.2009.81. abdolreza sabahi, gholamreza sepehri, mottahareh mohsenbeigi and ehsan sepehri clinical and basic research | e387 3. thomas cp, conrad p, casler r, goodman e. trends in the use of psychotropic medications among adolescents, 1994 to 2001. psychiatr serv 2006; 57:63–9. doi: 10.1176/appi.ps.57.1.63. 4. olfson m, blanco c, liu sm, wang s, correll cu. national trends in the office-based treatment of children, adolescents, and adults with antipsychotics. arch gen psychiatry 2012; 69:1247–56. doi: 10.1001/archgenpsychiatry.2012.647. 5. katzung bg, masters sb, trevor aj, eds. basic and clinical pharmacology. 12th ed. new york, usa: mcgraw-hill medical, 2011. pp. 532–3. 6. cooper wo, arbogast pg, ding h, hickson gb, fuchs dc, ray wa. trends in prescribing of antipsychotic medications for us children. ambul pediatr 2006; 6:79–83. doi: 10.1016/j. ambp.2005.11.002. 7. patel nc, crismon ml, hoagwood k, johnsrud mt, rascati kl, wilson jp, et al. trends in the use of typical and atypical antipsychotics in children and adolescents. j am acad child adolesc psychiatry 2005; 44:548–56. doi: 10.1097/01. chi.0000157543.74509.c8. 8. brière fn, fallu js, janosz m, pagani ls. prospective associations between meth/amphetamine (speed) and mdma (ecstasy) use and depressive symptoms in secondary school students. j epidemiol community health 2012; 66:990–4. doi: 10.1136/jech-2011-200706. 9. shamshiri milani h, abadi ar, helmzadeh z, abachizadeh k. prevalence of ecstasy use and predisposing factors among iranian female high school students. j pak med assoc 2011; 61:566–71. 10. piparva kg, parmar dm, singh ap, gajera, mv, trivedi hr. drug utilization study of psychotropic drugs in outdoor patients in a teaching hospital. indian j psychol med 2011; 33:54. doi: 10.4103/0253-7176.85396. 11. zito jm, safer dj, dosreis s, gardner jf, magder l, soeken k, et al. psychotropic practice patterns for youth: a 10-year perspective. arch pediatr adolesc med 2003; 157:17–25. doi: 10.1001/archpedi.157.1.17. 12. gholamreza s, meimandi ms. the quality of prescribing in general practice in kerman, iran. int j health care qual assur inc leadersh health serv 2005; 18:353–60. doi: 10.1108/09526860510612207. 13. sepehri g, haj-akbari n, sepehri e, mohsen-beigi m. the quality of prescription drug utilization 5 years after the 2003 bam earthquake. int j health care qual assur 2012; 25:582–91. doi: 10.1108/09526861211261181. 14. world health organization. how to investigate drug use in health facilities: selected drug use indicators. from: www. apps.who.int/medicinedocs/en/d/js2289e/ accessed: may 2104. 15. mojtabai r, olfson m. national trends in psychotropic medication polypharmacy in office-based psychiatry. arch gen psychiatry 2010; 67:26–36. doi: 10.1001/ archgenpsychiatry.2009.175. 16. piparva kg, parmar dm, singh ap, gajera mv, trivedi hr. drug utilization study of psychotropic drugs in outdoor patients in a teaching hospital. ind j psychol med 2011; 33:54– 8. doi: 10.4103/0253-7176.85396. 17. udomratn p, vasiknanonte s. pattern of prescribing antipsychotic drugs in thailand. asean j psych assoc 2009; 10:75–82. 18. olfson m, marcus sc, pincus ha, zito jm, thompson jw, zarin da. antidepressant prescribing practices of outpatient psychiatrists. arch gen psychiatry 1998; 55:310–16. doi: 10.1001/archpsyc.55.4.310.. 19. goodwin r, gould ms, blanco c, olfson m. prescription of psychotropic medications to youths in office-based practice. psychiatr serv 2001; 52:1081–7. doi: 10.1176/appi.ps.52.8.1081. 20. ohayon mm, caulet m, priest rg, guilleminault c. psychotropic medication consumption patterns in the uk general population. j clin epidemiol 1998; 51:273–83. doi: 10.1016/s0895-4356(97)00238-2. 21. uchida n, chong my, tan ch, nagai h, tanaka m, lee ms, et al. international study on antidepressant prescription pattern at 20 teaching hospitals and major psychiatric institutions in east asia: analysis of 1898 cases from china, japan, korea, singapore and taiwan. psychiatry clin neurosci 2007; 61:522– 8. doi: 10.1111/j.1440-1819.2007.01702.x. 22. tan ch, shinfuku n, sim k. psychotropic prescription practices in east asia: looking back and peering ahead. curr opin psychiatry 2008; 21:645–50. doi: 10.1097/ yco.0b013e32830e6dc4. 23. von soest t, bramness jg, pedersen w, wichstrøm l. the relationship between socio-economic status and antidepressant prescription: a longitudinal survey and register study of young adults. epidemiol psychiatr sci 2012; 21:87–95. doi: dx.doi. org/10.1017/s2045796011000722. 24. de las cuevas c, sanz ej, de la fuente ja. variations in antidepressant prescribing practice: clinical need or market influences? pharmacoepidemiol drug saf 2002; 11:515–22. doi: 10.1002/pds.715. 25. anderson im. selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. j affect disord 2000; 58:19–36. doi: 10.1016/s01650327(99)00092-0. 26. macgillivray s, arroll b, hatcher s, ogston s, reid i, sullivan f, et al. efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. bmj 2003; 326:1014. doi: 10.1136/bmj.326.7397.1014. 27. mond j, morice r, owen c, korten a. use of antipsychotic medications in australia between july 1995 and december 2001. aust n z j psychiatry 2003; 37:55–61. doi: 10.1046/j.14401614.2003.01110.x. 28. xiang yt, kreyenbuhl j, dickerson fb, ungvari gs, wang cy, si tm, et al. use of firstand second-generation antipsychotic medications in older patients with schizophrenia in asia (2001-2009). aust n z j psychiatry 2012; 46:1159–64. doi: 10.1177/0004867412453625. 29. khawaja mr, majeed a, malik f, merchant ka, maqsood m, malik r, et al. prescription pattern of benzodiazepines for inpatients at a tertiary care university hospital in pakistan. j pak med assoc 2005; 55:259–63. 30. rankin k, brakoulias v. patterns of hypnotic medication use for sleep disturbance amongst hospital inpatients. australas psychiatry 2012; 20:301–4. doi: 10.1177/1039856212448102. 31. ashton h. guidelines for the rational use of benzodiazepines: when and what to use. drugs 1994; 48:25–40. doi: 10.2165/00003495-199448010-00004. 32. sim k, yong kh, chan yh, tor pc, xiang yt, wang cy, et al. adjunctive mood stabilizer treatment for hospitalized schizophrenia patients: asia psychotropic prescription study (2001-2008). int j neuropsychopharmacol 2011; 14:1157–64. doi: 10.1017/s1461145711000563. 33. walpoth-niederwanger m, kemmler g, grunze h, wei u, hortnagl c, strau r, et al. treatment patterns in inpatients with bipolar disorder at a psychiatric university hospital over a 9-year period: focus on mood stabilizers. int clin psychopharmacol 2012; 27:256–66. doi: 10.1097/yic.0b013e328356ac92. 34. contini v, rovaris dl, victor mm, grevet eh, rohde la, bau ch. pharmacogenetics of response to methylphenidate in adult patients with attention-deficit/hyperactivity disorder (adhd): a systematic review. eur neuropsychopharmacol 2013; 22:555–60. doi: 10.1016/j.euroneuro.2012.05.006. 35. hodgkins p, shaw m, coghill d, hechtman l. amfetamine and methylphenidate medications for attention-deficit/ hyperactivity disorder: complementary treatment options. eur child adolesc psychiatry 2012; 21:477–92. doi: 10.1007/ s00787-012-0286-5. ischaemic heart disease (ihd) is one of theleading causes of mortality and morbidity worldwide; in 2012, ihd resulted in approximately 7.4 million deaths, accounting for 13% of all deaths worldwide.1,2 in the middle east, the prevalence of ihd appears to be increasing, while that of other cardiovascular conditions such as rheumatic heart disease appears to be decreasing.3 the risk factors involved in the pathogenesis of ihd are classified as either modifiable (e.g. diabetes, hypertension or obesity) or not modifiable (e.g. age, gender or genetic factors). from a public health perspective, modifiable risk factors are very important since changes or alterations to reduce these risk factors can benefit ihd patients.4 certain lifestyle changes—such as the adoption of a mediterranean-type diet, regular exercise, cessation of smoking and decreased consumption of alcohol—are beneficial in the prevention of ihd.5 however, knowledge and motivation on the part of the patient are key to successfully implementing and maintaining necessary lifestyle modifications.6 in oman, previous research has focused on lifestyle changes, knowledge and attitudes regarding primary ihd prevention and has indicated that overall knowledge about disease risk factors is low, partic ularly among elderly ihd patients.7 it is therefore department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: sunilnadar@gmail.com املعرفة بأمناط احلياة للوقاية الثانوية لدى املصابني مبرض الشريان التاجي يف عمان دراسة استطالعية متيم را�ضد التميمي, حفيظ الهادي باعمر, سونيل نادر abstract: objectives: secondary prevention of ischaemic heart disease (ihd) is very important. this study aimed to assess knowledge of necessary lifestyle changes among omani patients diagnosed with ihd. methods: this cross-sectional pilot study took place between october 2015 and february 2016 at the sultan qaboos university hospital (squh), muscat, oman. a total of 30 random patients with ihd from the cardiology outpatient clinic of squh were included. a 30-item survey was used to determine patients’ knowledge of necessary lifestyle practices following their ihd diagnosis, with scores of <70% indicating poor knowledge. results: overall, 21 patients (70.0%) had low knowledge levels. scores ranged from 38.9−94.4% (mean: 60.7% ± 14.1%). no demographic factors were found to predict low scores, although there were some differences in individual questions. conclusion: low knowledge levels regarding lifestyle changes were observed among ihd patients in oman. more efforts should be made to educate these patients for the secondary prevention of ihd. keywords: secondary prevention; ischemic heart disease; myocardial infarction; healthy lifestyle; oman. وممار�ضات معرفة تقييم اإىل الدرا�ضة هذه هدفت التاجي. ال�رسيان مر�ص من الثان�ية لل�قاية �ضديدة اأهمية هناك الهدف: امللخ�ص: االأ�ضاليب ال�قائية لدى املر�ضى الذين مت ت�ضخي�ضهم مبر�ص ال�رسيان التاجي. الطريقة: اأجريت هذه الدرا�ضة امل�ضحية يف الفرتة ما بني اأكت�بر 2015 م وفرباير 2016 م يف م�ضت�ضفى جامعة ال�ضلطان قاب��ص, يف م�ضقط, عمان. متت خالل البحث مقابلة 30 من مر�ضى ال�رسيان منط تغيري الأ�ضاليب وممار�ضتهم معرفتهم مدى لتحديد �ض�ؤاال من 30 مك�نة ا�ضتبانة اإعطائهم ومت بامل�ضت�ضفى, القلب عيادة يف التاجي احلياة ال�قائية للحد من االأ�ضابة مرة اأخرى مبر�ص ال�رسيان التاجي بعد ت�ضخي�ضهم بهذا املر�ص. مت اعتبار جمم�ع اأقل من %70< داال على نق�ص يف املعرفة. النتائج: ح�ضل 21 )%70.0( مري�ضا على نتائج تدل على نق�ص يف املعرفة ب�ضكل عام. تراوحت نتائج املر�ضى بني %94.4 38.9 )املت��ضط: %14.1 ± %60.7(. مل تكن هناك اأي عالقة بني الع�امل ال�ضخ�ضية ونق�ص املعرفة, بالرغم من وج�د اختالفات يف بع�ص االأ�ضئلة منفردة. اخلال�ضة: ت�ضري هذه النتائج اإىل وج�د نق�ص يف معرفة امل�ضابني مبر�ص ال�رسيان التاجي يف عمان, ولذلك نحتاج اإىل بذل املزيد من اجله�د يف تعليم املر�ضى وعمل برامج ت�ع�ية لل�قاية واحلد من مر�ص ال�رسيان التاجي ومن تط�ره. الكلمات املفتاحية: ال�قاية الثان�ية؛ مر�ص ال�رسيان التاجي؛ احت�ضاء ع�ضلة القلب؛ النمط احلياتي ال�ضحي؛ عمان. knowledge regarding secondary prevention lifestyle practices among patients with ischaemic heart disease in oman pilot study tamim r. al-tamimi, hafidh a. ba-omar, *sunil nadar brief communication sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e88–92, epub. 30 mar 17 submitted 7 aug 16 revision req. 27 sep 16; revision recd. 19 oct 16 accepted 25 oct 16 doi: 10.18295/squmj.2016.17.01.015 tamim r. al-tamimi, hafidh a. ba-omar and sunil nadar brief communication | e89 unclear whether patients in oman adopt healthier lifestyles after being diagnosed with a myocardial infarction (mi) or ihd. moreover, few studies have examined ihd patients’ knowledge of lifestyle changes with regards to secondary ihd (i.e. disease recurrence after a previous mi or ihd diagnosis) prevention. this study therefore aimed to investigate knowledge regarding necessary lifestyle modifications linked to ihd risk reduction among omani patients with a previous diagnosis of mi or ihd. in addition, the study sought to identify factors affecting levels of knowledge of these lifestyle practices. the findings of this study may help in formulating future secondary prevention strategies for ihd in oman. methods this cross-sectional pilot study was conducted at the cardiology outpatient clinic of the sultan qaboos university hospital, muscat, oman, from october 2015 to february 2016. a randomly chosen sample of 30 patients with ihd seen at the clinic during the study period was included. the inclusion criteria were >18-year-old patients with stable ihd and a history of either stable angina or a mi occurring more than six months beforehand. patients were excluded if they had had a mi in the previous six months or if they had unstable symptoms. in addition, those with terminal illnesses or disabling diseases prohibiting normal exercise were excluded. for the purposes of the study, a 30-item survey was designed which included 10 demographic questions, 10 multiple choice questions regarding dietary habits and 10 multiple choice questions regarding exercise habits. existing questionnaires on lifestyle factors were not utilised for this study as it was felt that these previously published questionnaires did not align with the customs and practices of the local omani population. the survey was initially designed in english and then translated into arabic, as most people in oman are arabic-speaking. however, an english version was made available to the patients at their request. the questionnaire was pre-tested for validity and clarity by non-medical volunteers recruited from patients’ relatives and staff of the sultan qaboos university. according to the feedback obtained, the survey was then modified before being used in the main pilot study. the survey took a maximum of 10 minutes to complete. for patients who were unable to read, the investigators read the questions and potential responses aloud and gave the participants sufficient time to answer without any prompting, either on the part of relatives or investigators. a score of ≥70% was defined as adequate knowledge of necessary lifestyle changes. data were analysed using the statistical package for the social sciences (spss), version 21 (ibm corp., chicago, illinois, usa). subsequently, the data were categorised as necessary for calculating associations. a chi-squared test was used to determine associations between sociodemographic factors and knowledge levels. a p value of <0.050 was considered statistically significant. the medical ethics committee of the college of medicine & health sciences at the sultan qaboos university gave ethical approval for this study (mrec #1121). all patients gave informed consent before participating in the study. table 1: demographic characteristics of patients with ischaemic heart disease at the sultan qaboos university hospital, muscat, oman (n = 30) characteristic n (%) age in years 18−30 1 (3.3) 31−45 3 (10.0) 46−60 12 (40.0) >60 14 (46.7) gender male 21 (70.0) female 9 (30.0) education level illiterate 11 (36.7) reading/writing 4 (13.3) high school 10 (33.3) higher education 5 (16.7) employment status employed 7 (23.3) unemployed/retired 23 (76.7) presence of diabetes yes 7 (23.3) no 23 (76.7) presence of hypertension yes 17 (56.7) no 13 (43.3) presence of hypercholesterolaemia yes 17 (56.7) no 13 (43.3) knowledge regarding secondary prevention lifestyle practices among patients with ischaemic heart disease in oman pilot study e90 | squ medical journal, february 2017, volume 17, issue 1 table 2: prevalence of self-reported secondary prevention lifestyle changes among patients with ischaemic heart disease at the sultan qaboos university hospital, muscat, oman (n = 30) questionnaire item n (%) how many meals a day do you eat? 1−2 0 (0.0) 3−4 23 (76.7) >5 1 (3.3) no response 6 (20.0) do you feel your lifestyle has improved since you were diagnosed with ihd? yes 18 (60.0) no 12 (40.0) how much of your daily diet is composed of carbohydrates? <25% 20 (66.7) 25−50% 10 (33.3) >50% 0 (0.0) how much of your daily diet is composed of fat? <25% 21 (70.0) 25−50% 9 (30.0) >50% 0 (0.0) how much of your daily diet is composed of protein? <25% 17 (56.7) 25−50% 13 (43.3) >50% 0 (0.0) how much of your daily diet is composed of fruit/vegetables? <25% 8 (26.7) 25−50% 20 (66.7) >50% 2 (6.7) do you mostly eat homemade food? yes 26 (86.7) no 4 (13.3) what type of meat do you eat most often? fish 12 (40.0) chicken 2 (6.7) goat or beef 1 (3.3) all 15 (50.0) do you smoke? yes 0 (0.0) no 30 (100.0) do you drink alcohol? yes 0 (0.0) no 30 (100.0) if you were offered the following food items, which one would you choose? fried chips 2 (6.7) an apple 28 (93.3) pizza 0 (0.0) do you feel you take more care with your diet since your ihd diagnosis? yes 21 (70.0) no 9 (30.0) in your opinion, how do you compare to other people of the same age with regards to physical activity? more active 6 (20.0) less active 10 (33.3) as active 14 (46.7) how many times per week do you exercise? <2 times 9 (30.0) 2−3 times 3 (10.0) 4−5 times 4 (13.3) >5 times 14 (46.7) what type of exercise do you do? team sports 2 (6.7) running 0 (0.0) walking 26 (86.7) strength training 0 (0.0) cycling 2 (6.7) would you walk or drive for a distance of 500 m? drive 11 (36.7) walk 19 (63.3) would you use an elevator if it were available? yes 17 (56.7) no 13 (43.3) how much time do you spend walking daily? <1 hour 20 (66.7) 1−2 hours 10 (33.3) >2 hours 0 (0.0) how many hours do you sleep at night? <5 hours 3 (10.0) 5−8 hours 25 (83.3) >8 hours 2 (6.7) have you exercised more since you were diagnosed with ihd? no 18 (60.0) yes 12 (40.0) ihd = ischaemic heart disease. tamim r. al-tamimi, hafidh a. ba-omar and sunil nadar brief communication | e91 results all 30 patients included in the study were omani nationals. the majority of the participants were under 60 years old (53.3%), male (70.0%), literate (63.3%) and unemployed/retired (76.7%). the majority were not diabetic (76.7%), but did have hypertension and hypercholesterolemia (56.7% each) [table 1]. overall, 21 participants (70.0%) scored <70%, indicating low levels of knowledge of secondary prevention lifestyle changes. the maximum and minimum scores were 94.4% and 38.9%, respectively. the mean score was 60.7% ± 14.1%. with regards to their survey responses, the majority of the patients had made changes to their lifestyle following their ihd diagnosis (60.0%). in addition, the majority of the patients reported adequately controlling the fat content of their daily diets (70.0%). however, less than half of the participants exercised more following their diagnosis of ihd (40.0%). a few participants perceived themselves to be more active than other individuals of the same age (20.0%). most participants reported exercising four or more times per week (60.0%). in general, the type of exercise most preferred was walking (86.7%). while most participants would choose to walk for a distance of 500 m instead of using a car (63.3%), less than half would take the stairs rather than an elevator if one were available (43.3%). approximately a third of the participants walked for at least one hour daily (33.3%) and the majority slept for between 5–8 hours per night (83.3%) [table 2]. no significant associations were identified between knowledge scores and sociodemographic factors, including education level or employment status. however, there was a significant association between consumption of fish and education level, with participants who had a high school education eating more fish than those with a lower level of education (p = 0.025). in addition, unemployed participants appeared to walk significantly more than those who were employed (p = 0.031). discussion this pilot study was conducted to evaluate knowledge of secondary prevention lifestyle factors among patients diagnosed with ihd in oman. in general, knowledge of healthy lifestyle practices among the participants was low. while the majority of patients said they were more aware of their diet and exercise habits after their ihd diagnosis, this awareness does not appear to have been translated into practice. one of the reasons for this could be due to misconceptions about the disease and the benefits of exercise following a mi or ihd diagnosis. accordingly, after taking the survey, some of the patients explained that they felt that they should not exercise and put more stress on their hearts. therefore, it is necessary for health professionals in oman to emphasise the need to undertake controlled exercise to prevent disease recurrence among patients with ihd. in the current study, no specific demographic factor was found to be associated with poor levels of knowledge regarding lifestyle changes. this may be due in part to the small sample size, in which statistically significant differences could not be determined. while minor differences in responses between specific questions were observed, this could have been related to the activity itself; for example, unemployed/retired patients may have been found to walk significantly more than employed participants because they had more free time to walk rather than because they had greater knowledge of lifestyle changes. unfortunately, the patients were not asked to explain why they responded as they did to individual questions and thus the reason for these associations could not be clarified. secondary prevention and cardiac rehabilitation are an important part of the management of patients with ihd.8 however, most patients are only given a limited amount of verbal information on necessary lifestyle modifications upon discharge from hospital following an acute coronary syndrome diagnosis. in busy outpatient clinics, there is often insufficient time to provide patients with necessary information regarding the disease and the lifestyle changes required to prevent recurrence. in addition, most public health campaigns target the primary prevention of ihd, but often tend to ignore secondary prevention, which is equally important.8 therefore, more emphasis should be placed on the secondary prevention of ihd in oman, with more health education to be given to ihd patients and the development and implementation of national cardiac rehabilitation facilities. the current study was subject to some limitations, including the small sample size and the high male-tofemale ratio. in addition, as a cross-sectional study, the findings may not be reliable. the qualitative and self-reported nature of the majority of the questions in the newly created survey tool may also have led to inaccuracies. in general, questionnaire-based studies are subject to response bias, with respondents potentially modifying their responses by overreporting positive behaviours and under-reporting negative behaviours based on what they think is the correct answer, rather than reporting behaviours accurately.9 despite these limitations, the findings of this pilot study are important as they highlight a lack knowledge regarding secondary prevention lifestyle practices among patients with ischaemic heart disease in oman pilot study e92 | squ medical journal, february 2017, volume 17, issue 1 of knowledge with regards to lifestyle modifications in a high-risk patient group in oman. further studies are recommended with a larger sample size and perhaps based within the general community rather than a busy outpatient clinic in order to better identify patients who would benefit from more intensive health education regarding necessary lifestyle changes. conclusion according to the results of this pilot study, patients with ihd in oman have inadequate knowledge of the necessary lifestyle changes required for secondary prevention. as a result, cardiac rehabilitation facilities should be made available to patients with ihd and health professionals should highlight the need for lifestyle modifications to prevent disease recurrence. however, further research on this topic is recommended. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this pilot study. references 1. writing group members, mozaffarian d, benjamin ej, go as, arnett dk, blaha mj, et al. heart disease and stroke statistics: 2016 update a report from the american heart association. circulation 2016; 133:e38−60. doi: 10.1161/cir. 0000000000000350. 2. world health organisation. cardiovascular diseases (cvds). from: www.who.int/mediacentre/factsheets/fs317/en/ accessed: oct 2016. 3. celermajer ds, chow ck, marijon e, anstey nm, woo ks. cardiovascular disease in the developing world: prevalences, patterns, and the potential of early disease detection. j am coll cardiol 2012; 60:1207−16. doi: 10.1016/j.jacc.2012.03.074. 4. achari v, thakur ak. association of major modifiable risk factors among patients with coronary artery disease: a retrospective analysis. j assoc physicians india 2004; 52:103−8. 5. jhamnani s, patel d, heimlich l, king f, walitt b, lindsay j. meta-analysis of the effects of lifestyle modifications on coronary and carotid atherosclerotic burden. am j cardiol 2015; 115:268−75. doi: 10.1016/j.amjcard.2014.10.035. 6. alm-roijer c, stagmo m, udén g, erhardt l. better knowledge improves adherence to lifestyle changes and medication in patients with coronary heart disease. eur j cardiovasc nurs 2004; 3:321−30. doi: 10.1016/j.ejcnurse.2004.05.002. 7. ammouri aa, tailakh a, isac c, kamaniyre jk, muliira j, balachandran s. knowledge of coronary heart disease risk factors among a community sample in oman: pilot study. sultan qaboos university med j 2016; 16:e189−96. doi: 10.18295/squmj.2016.16.02.009. 8. smith sc jr, benjamin ej, bonow ro, braun lt, creager ma, franklin ba, et al. aha/accf secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update a guideline from the american heart association and american college of cardiology foundation. circulation 2011; 124:2458−73. doi: 10.1161/cir.0b013e318235eb4d. 9. goodman r. the strengths and difficulties questionnaire: a research note. j child psychol psychiatry 1997; 38:581−6. doi: 10.1111/j.1469-7610.1997.tb01545.x. https://doi.org/10.1161/cir.0000000000000350 https://doi.org/10.1161/cir.0000000000000350 https://doi.org/10.1016/j.jacc.2012.03.074 https://doi.org/10.1016/j.amjcard.2014.10.035 https://doi.org/10.1016/j.ejcnurse.2004.05.002 https://doi.org/10.18295/squmj.2016.16.02.009 https://doi.org/10.1161/cir.0b013e318235eb4d https://doi.org/10.1111/j.1469-7610.1997.tb01545.x 1department of anatomic & molecular pathology, lagos university teaching hospital, yaba, lagos, nigeria; 2nucleus diagnostic center, iganmu, lagos, nigeria; departments of 3anatomic & molecular pathology and 4surgery, college of medicine, university of lagos, yaba, lagos, nigeria *corresponding author e-mail: dozieanunobi@yahoo.com التقارير املختصرة واملبوَّبة يف مقابل التقارير السردية عن نتائج خزعات الربوستاتة يف مؤسسة رعاية صحية ثالثية التحديات والنجاحات والتوقعات ننامدي ابومنمي اأواره، �سارل�ص انابوبي، ريفي�ص ويل اوجولو abstract: objectives: cancer pathology reports are expected to contain all information required for patient management and disease surveillance. moreover, reports for patients with prostate cancer have become increasingly complex with the addition of more pathological details. this study aimed to compare narrative and synoptic prostate cancer reports for core needle biopsies received at a tertiary hospital in nigeria in order to determine which form was most complete according to international standards. methods: this study was conducted from january 2010 to december 2015 at the lagos university teaching hospital, lagos, nigeria. all malignant prostate cancer histopathology reports received during this period were analysed for the presence of important clinicopathological parameters, including the numbers of cores taken and those involved by the tumour, percentage of tumour involvement, gleason score and the presence of high-grade prostatic intraepithelial neoplasms (hgpins) and perineural and lymphovascular invasion. results: a total of 83 reports were reviewed, of which 27 were in narrative and 56 in synoptic format. the documentation of clinicopathological characteristics in narrative reports was significantly incomplete compared to synoptic reports in recording the number of cores (33.3% versus 96.4%), number of cores involved by the tumour (11.1% versus 94.6%), percentage of cores involved by the tumour (3.7% versus 100.0%) and the presence of hgpins (7.4% versus 100.0%) and perineural (59.3% versus 98.2%) and lymphovascular (48.1% versus 100.0%) invasion (p <0.001 each). conclusion: synoptic reports of malignant prostate cancer biopsies received at the lagos university teaching hospital were found to contain more complete information than narrative reports. keywords: pathology; biopsy; prostate cancer; prostatic intraepithelial neoplasia; nigeria. امللخ�ص: الهدف: يتوقع اأن ت�ستمل تقارير باثولوجيا ال�رصطان على كل املعلومات املطلوبة لعالج املري�ص وتر�سد املر�ص. وباالإ�سافة لذلك غدت التقارير التي تكتب عن مر�سى �رصطان الربو�ستاتة اأكرث تعقيدا ب�سبب اإ�سافة املزيد من التفا�سيل الباثولوجية فيها. وتهدف هذه بة يف مقابل التقارير ال�رصدية عن نتائج خزعات اللب باالإبرة، والتي وردت مل�ست�سفى ثالثي يف الدرا�سة ملقارنة التقارير املخت�رصة واملبَوّ نيجرييا، وذلك لتحديد اأي نوع من تلك التقارير اأقرب للكمال بح�سب املعايري الدولية. الطريقة: اأجريت الدرا�سة بني يناير 2010 ودي�سمرب 2015م يف م�ست�سفى جامعة الجو�ص التعليمي بنيجرييا. ومت حتليل كل التقارير الهي�ستوباثلوجية التي كتبت عن عينات �رصطان الربو�ستاتة اخلبيث يف تلك الفرتة، وتقييم احتوائها على املتثابتات الباثولوجية–ال�رصيرية، والتي ت�سمل اأعداد االألباب التي اأخذت، واأعداد تلك التي لها عالقة بال�رصطان، والن�سبة املئوية لتلك العالقة، وا�ستخدم حرز جلي�سون، ووجود اأورام بدرجة عالية يف داخل ظهارة الربو�ستاتة، ووجود غزو ملفاوي وعائي وغزو حميط بالع�سب. النتائج: مت حتليل 83 تقريرا، كان 27 منها تقريرا �رصديا، و56 تقريرا خمت�رصا مبوبا. وكان بة فيما يتعلق توثيق اخلوا�ص الباثولوجية–ال�رصيرية يف التقارير ال�رصدية اأقل كماال ب�سورة معنوية مقارنة مع التقارير املخت�رصة واملبَوّ عدد االألباب )%33.3 يف مقابل%96.4(، وكان عدد االألباب التي لها عالقة بال�رصطان )%11.1 يف مقابل%94.6( وكانت الن�سبة املئوية لعدد االألباب التي لها عالقة بال�رصطان )%3.7 يف مقابل %100.0( ووجود اأورام بدرجة عالية يف داخل ظهارة الربو�ستاتة )%7.4 يف p >0.001( )100.0% مقابل %100.0(، ووجود غزو حميط بالع�سب )%59.3 يف مقابل %98.2( وغزو ملفاوي وعائي )%48.1 يف مقابل تلقاها التي خبيث ب�رصطان امل�سابة الربو�ستاتة خزعات نتائج عن بة واملبَوّ املخت�رصة التقارير اأن وجدنا اخلال�صة: حالة(. كل يف م�ست�سفى الجو�ص التعليمي حتتوي على معلومات اأكرث �سموال من تلك التي وردت يف التقارير ال�رصدية. الكلمات املفتاحية: الباثولوجيا؛ خزعة؛ �رصطان الربو�ستاتة؛ اأورام بداخل ظهارة الربو�ستاتة؛ نيجرييا. synoptic versus narrative reporting of prostate biopsies at a tertiary healthcare institution challenges, successes and expectations nnamdi o. orah,1,2 *charles c. anunobi,3 rufus w. ojewola4 clinical & basic research sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e319–323, epub. 10 oct 17 submitted 11 mar 17 revisions req. 24 apr & 20 jun 17; revisions recd. 31 may & 24 jun 17 accepted 6 jul 17 doi: 10.18295/squmj.2017.17.03.010 advances in knowledge the findings of this study confirm the significant advantage of synoptic over narrative report formats in ensuring the completeness of histopathology reports for prostate cancer biopsies. recommendations are suggested to facilitate the adoption of the synoptic reporting template at other healthcare institutions. synoptic versus narrative reporting of prostate biopsies at a tertiary healthcare institution challenges, successes and expectations e320 | squ medical journal, august 2017, volume 17, issue 3 application to patient care complete prostate cancer biopsy reports should document the various clinicopathological parameters required for prognostication purposes. as such, the usefulness of certain reporting styles over others in highlighting significant parameters may contribute to management decisions, thereby improving the quality of patient care. in nigeria, prostate cancer is the most common form of male cancer and the highest cause of cancer-related deaths among men.1 prostate cancer management requires a multidisciplinary approach which brings together both clinicians and pathologists. currently, histological assessments remain the gold standard for making a diagnosis of prostate cancer.2 therefore, the precise and thorough documentation of histological findings is important to ensure an accurate diagnosis, determine patient prognosis and inform patient management decisions.3 the need for increased details and standardisation in histology reports has led to the development of various checklists; accordingly, both the college of american pathologists (cap) and the royal college of pathologists (rcpath) have developed specific formats and protocols for histopathology reporting.3,4 for prostate cancer, the necessary information in a pathology report includes the presence and type of cancer, gleason score, neural involvement, lymphovascular invasion, periprostatic fat and seminal vesicle involvement (where applicable) and the presence of high-grade prostatic intraepithelial neoplasms (hgpins). in addition, the rcpath documentation also includes a microscopic count of the number of cores and the percentage of cores involved by the tumour.4 however, these details depend on whether the biopsy sample was taken via core needle or radical prostatectomy. at the lagos university teaching hospital, a tertiary healthcare centre in lagos, nigeria, the synoptic form of reporting prostate cancer specimens was adopted in 2015, with a gradual transition from the former narrative style between 2015 and 2016. this study aimed to compare narrative versus synoptic forms of prostate cancer histopathology reports received at the lagos university teaching hospital according to established international standards. in addition, the benefits of synoptic reporting are discussed as well as solutions to offset possible challenges that may arise during the transition to a synoptic style of reporting. methods this study was conducted from january 2010 to december 2015 at the lagos university teaching hospital. all reports of malignant core needle prostate cancer biopsy specimens received during this period were reviewed. as per the cap and rcpath protocols for reporting prostate cancer, inclusion of the following parameters in the reports was noted: microscopic count of the number of cores, nature of the tumour, number of cores involved, total percentage of cores involved by the tumour, gleason score and the presence of high-grade prostatic intraepithelial neoplasms (hgpins) and lymphovascular and neural invasion.3,4 data were analysed using descriptive statistics. statistical significance was determined using fisher’s exact test with the level of significance set at p <0.005. ethical approval for the study was granted by the health research and ethics committee of the lagos university teaching hospital. the names of the patients were blinded and only biopsy numbers were used for the purposes of identification. results a total of 83 malignant prostate biopsies were received during the study period. of these, 27 (32.5%) were reported narratively and 56 (67.5%) were reported synoptically. synoptic reports documented the number of cores in 96.4% of cases, while narrative reports contained this information in only 33.3% of cases. the number of cores involved by the tumour and percentage of core involvement was described in 94.6% and 100.0% of synoptic reports, respectively, and 11.1% and 3.7% of narrative reports, figure 1: comparison of parameters documented in synoptic versus narrative reports of malignant prostate cancer biopsies received at the lagos university teaching hospital, lagos, nigeria (n = 83). hgpin = high-grade prostatic intraepithelial neoplasia. nnamdi o. orah, charles c. anunobi and rufus w. ojewola clinical and basic research | e321 respectively. gleason scores were recorded in all reports, regardless of format. only 7.4% of narrative reports noted the presence of hgpins as compared to 100.0% of synoptic reports. finally, perineural and lymphovascular invasion was documented in 98.2% and 100.0% of synoptic reports, respectively, and 59.3% and 48.1% of narrative reports, respectively [figure 1]. apart from gleason score, documentation of all clinicopathological parameters was significantly greater in synoptic compared to narrative reports (p <0.001 each) [table 1]. discussion in prostate cancer biopsy reports, recording the number of cores is important as this count is subsequently correlated with the number of biopsies taken, processed and present on the histology slide; this approach serves as an internal quality control measure to ensure that all tissues submitted for biopsy are duly processed. moreover, the number of cores involved by the tumour and the total percentage of cores involved are major determinants of prognosis as they are both indicative of the overall size of the tumour.5–7 as per the cap protocols, it is imperative that the number of positive cores out of the total number of cores are invariably reported for needle core biopsy specimens, except in cases where a precise count is impossible due to fragmentation.5 freedland et al. reported that the percentage of the area of biopsy tissue with cancer was the strongest predictor of biochemical recurrence, seminal vesicle invasion and non-organconfined disease.6 in addition, brimo et al. reported that the portion of cores involved by the tumour, total percentage of tumour involvement and both the total and greatest tumour lengths in millimetres were the variables most closely linked with pathological stage and treatment failure.7 critically, there was a vast difference between the documentation of these parameters in the synoptic and narrative reports reviewed in the current study. another remarkable discrepancy between synoptic and narrative reports in the present study was in the documentation of hgpins. according to the cap, the documentation of hgpins in a prostate cancer specimen is optional.5 however, this factor may be important in benign cases in which widespread hgpins could signify the potential development of an adenocarcinoma and therefore warrant close follow-up; for example, netto et al. found that 40 out of 41 patients with widespread hgpins developed prostate cancer within two years of diagnosis.8 the presence of perineural invasion is similarly important in determining treatment strategy. after a two-year follow up of patients treated with external beam radiotherapy, yu et al. demonstrated that perineural invasion was more prevalent in higher-risk groups and was associated with an increased risk of biochemical recurrence.9 however, this factor did not result in significantly different long-term psa recurrence rates in a study by o’malley et al., nor was there any significant difference in final gleason scores or pathological staging among cohorts.10 in contrast, vargas et al. found that perineural invasion was a likely predictor of extraprostatic extension in prostatectomy samples.11 in the current study, gleason score was the only factor which was emphasised in both synoptic and narrative reports. this finding might be connected with longstanding and irrefutable evidence indicating that gleason table 1: parameters documented in narrative versus synoptic reports of malignant prostate cancer biopsies received at the lagos university teaching hospital, lagos, nigeria (n = 83) parameter n (%) p value* narrative reports (n = 27) synoptic reports (n = 56) documented not documented documented not documented number of cores† 9 (33.3) 18 (66.7) 54 (96.4) 2 (3.6) <0.001 number of cores involved by tumour 3 (11.1) 24 (88.9) 53 (94.6) 3 (5.4) <0.001 percentage of cores involved 1 (3.7) 26 (96.3) 56 (100.0) 0 (0.0) <0.001 gleason score 27 (100) 0 (0.0) 56 (100.0) 0 (0.0) >0.999 presence of high-grade pin 2 (7.4) 25 (92.6) 56 (100.0) 0 (0.0) <0.001 perineural invasion 16 (59.3) 11 (40.7) 55 (98.2) 1 (1.8) <0.001 lymphovascular invasion 13 (48.1) 14 (51.9) 56 (100.0) 0 (0.0) <0.001 pin = prostatic intraepithelial neoplasia. *using fisher’s exact test. †as observed microscopically. synoptic versus narrative reporting of prostate biopsies at a tertiary healthcare institution challenges, successes and expectations e322 | squ medical journal, august 2017, volume 17, issue 3 score is a major determinant of prognosis in prostate cancer.12 in general, there are numerous benefits to synoptic in comparison to narrative biopsy reporting. with narrative reports, clinicians must comb through a large amount of macroscopic, microscopic, diagnostic and other information in order to unearth the essential knowledge required for clinical decision-making.3 in contrast, the uniform template of synoptic reports facilitates research and decisionmaking by highlighting significant diagnostic and prognostic findings; this also lessens the likelihood of misinterpreting results or making clinical errors.13 moreover, the reporting of results in a synoptic format is useful for tumour registries, government agencies, health planners and researchers by ensuring the uniformity of documentation received from various sources.13 previous studies evaluating various formats for reporting head and neck, colorectal and breast cancer specimens have concluded that synoptic reporting is associated with significantly higher rates of information completeness.14–16 overall, the implementation of standard synoptic reporting criteria will lead to the production of uniform highquality prostate cancer biopsy reports. nevertheless, the transition from narrative to synoptic reporting standards can be challenging. at the lagos university teaching hospital, ultrasoundguided prostate biopsies are not routinely received and sometimes all biopsies taken from one patient are transported in a single container due to financial constraints. such practices make synoptic reports less valuable as the cores involved cannot be traced to one particular zone of the prostate. suggestions that may be helpful to ensure compliance with cap standards include financial incentives to participating institutions for producing a complete pathology report and grading the performance of an individual centre with regards to their adoption of the cap checklist.13 in particular, a constructive feedback loop should be established between surgeons and pathologists, of which the latter should be encouraged to comply with synoptic reporting methods and train resident doctors in their use. the involvement of surgeons during the transition to a synoptic checklist is one factor that cannot be overemphasised, particularly as they are the final recipient of the biopsy report in most cases.13 these strategies were implemented at the lagos university teaching hospital and, although constraints still exist in terms of surgical equipment and patient costs, the institution has witnessed a gradual adoption of the synoptic style of reporting. conclusion synoptic reporting of malignant prostate cancer biopsies received at the lagos university teaching hospital produced significantly more complete reports than those documented in a narrative format. the adoption of synoptic reporting standards is highly recommended to ensure the production of complete and uniform biopsy reports. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. jedy-agba e, curado mp, ogunbiyi o, oga e, fabowale t, igbinoba f, et al. cancer incidence in nigeria: a report from population-based cancer registries. cancer epidemiol 2012; 36:e271–8. doi: 10.1016/j.canep.2012.04.007. 2. barry mj. clinical practice: prostate-specific antigen testing for early diagnosis of prostate cancer. n engl j med 2001; 344:1373–7. doi: 10.1056/nejm200105033441806. 3. srigley jr, humphrey pa, amin mb, chang ss, egevad l, epstein ji, et al.; members of the cancer committee, college of american pathologists. protocol for the examination of specimens from patients with carcinoma of the prostate gland. arch pathol lab med 2009; 133:1568–76. doi: 10.1043/15432165-133.10.1568. 4. oxley j, varma m, berney d; the royal college of pathologists. standards and datasets for reporting cancers: dataset for histopathology reports for prostatic carcinoma – june 2016. from: www.rcpath.org/asset/8cc88604-2c8d-4df4-a99542 df41c102af/ accessed: jul 2017. 5. srigley jr, humphrey pa, amin mb, chang ss, egevad l, epstein ji, et al.; college of american pathologists. protocol for the examination of specimens from patients with carcinoma of the prostate gland; protocol applies to invasive carcinomas of the prostate gland. from: https://pdfs.semanticscholar. org/1401/51e2a1852013f7e61085709425b27f b04dd8.pdf accessed: jul 2017. 6. freedland s, csathy g, dorey f, aronson w. percent prostate needle biopsy tissue with cancer is more predictive of biochemical failure or adverse pathology after radical prostatectomy than prostate specific antigen or gleason score. j urol 2002; 167:516–20. doi: 10.1016/s0022-5347(01)69076-1. 7. brimo f, vollmer rt, corcos j, kotar k, bégin lr, humphrey pa, et al. prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue. histopathology 2008; 53:177–83. doi: 10.1111/j.1365-2559.2008.03087.x. 8. netto gj, epstein ji. widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma. am j surg pathol 2006; 30:1184–8. doi: 10.1097/01. pas.0000213324.97294.54. 9. yu hh, song dy, tsai yy, thompson t, frassica da, deweese tl. perineural invasion affects biochemical recurrence-free survival in patients with prostate cancer treated with definitive external beam radiotherapy. urology 2007; 70:111–16. doi: 10.1016/j.urology.2007.03.020. https://doi.org/10.1016/j.canep.2012.04.007 https://doi.org/10.1056/nejm200105033441806 https://doi.org/10.1043/1543-2165-133.10.1568 https://doi.org/10.1043/1543-2165-133.10.1568 https://doi.org/10.1016/s0022-5347%2801%2969076-1 https://doi.org/10.1111/j.1365-2559.2008.03087.x https://doi.org/10.1097/01.pas.0000213324.97294.54 https://doi.org/10.1097/01.pas.0000213324.97294.54 https://doi.org/10.1016/j.urology.2007.03.020 nnamdi o. orah, charles c. anunobi and rufus w. ojewola clinical and basic research | e323 10. o’malley kj, pound cr, walsh pc, epstein ji, partin aw. influence of biopsy perineural invasion on long-term biochemical disease-free survival after radical prostatectomy. urology 2002; 59:85–90. doi: 10.1016/s0090-4295(01)01486-8. 11. vargas so, jiroutek m, welch mr, nucci mr, d’amico av, renshaw aa. perineural invasion in prostate needle biopsy specimens: correlation with extraprostatic extension at resection. am j clin pathol 1999; 111:223–8. doi: 10.1093/ ajcp/111.2.223. 12. bostwick dg, grignon dj, hammond me, amin mb, cohen m, crawford d, et al. prognostic factors in prostate cancer: college of american pathologists consensus statement 1999. arch pathol lab med 2000; 124:995–1000. doi: 10.1043/0003-9985(2000)124<0995:pfipc>2.0.co;2. 13. srigley jr, mcgowan t, maclean a, raby m, ross j, kramer s, et al. standardized synoptic cancer pathology reporting: a population-based approach. j surg oncol 2009; 99:517–24. doi: 10.1002/jso.21282. 14. zarbo rj. interinsititutional assessment of colorectal carcinoma surgical pathology report adequacy: a college of american pathologists q-probes study of practice patterns from 532 laboratories and 15,940 reports. arch pathol lab med 1992; 116:1113–19. 15. hammond eh, flinner rl. clinically relevant breast cancer reporting: using process measures to improve anatomic pathology reporting. arch pathol lab med 1997; 121:1171–5. 16. yunker wk, matthews tw, dort jc. making the most of your pathology: standardized histopathology reporting in head and neck cancer. j otolaryngol head neck surg 2008; 37:48–55. https://doi.org/10.1016/s0090-4295%2801%2901486-8 https://doi.org/10.1093/ajcp/111.2.223 https://doi.org/10.1093/ajcp/111.2.223 https://doi.org/10.1043/0003-9985%282000%29124%3c0995:pfipc%3e2.0.co%3b2 https://doi.org/10.1002/jso.21282 squ med j, february 2012, vol. 12, iss. 1, pp. 5-18, epub. 7th feb 12 submitted 6th jul 11 revision req. 25th oct 11, revision recd. 13th nov 11 accepted 7th dec 11 diabetes is widely recognised as one of the leading causes of death and disability worldwide.1 the prevalence of diabetes will rise from 6% to over 10% in the next decade.2 in 2000, the world health organization (who) recorded a total of 171 million people for all age groups worldwide (2.8% of the global population) who have diabetes, and the numbers are expected to rise to 366 million (4.4% of the global population) by 2030.3 1programme of biomedical science, school of diagnostic & applied health sciences, faculty of health sciences, universiti kebangsaan malaysia, kuala lumpur, malaysia; 2department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: fatmahmatough@yahoo.com دور اإلجهاد التأكسدي واملواد املضادة لألكسدة يف مضاعفات مرض السكري فاطمة علي، �ستي بلقي�س بودين، زاريانتي عبداحلميد، ن�رص الوهيبي، جمال الدين حممد امللخ�ص: ُيَعد مر�س ال�سكري اأحد الأمرا�س املزمنة ال�سائعة يف العامل. هناك اهتمام علمي وعام متزايد حول ربط الإجهاد التاأك�سدي مع خمتلف احلالت املر�سية مبا فيها مر�س ال�سكري، وكذلك الأمرا�س الأخرى التي ت�سيب الإن�سان. ذكرت الدرا�سات التجريبية وال�رصيرية ال�سابقة بـاأن الإجهاد التاأك�سدي يلعب دورا رئي�سيا كُم�سّبب مر�سي ويف تطور م�ساعفات كال النوعني من مر�س ال�سكري. من جهة اأخرى اإىل بحاجة وتبقى ناق�سة ال�سكري مر�س م�ساعفات تطور �رصعة يف التاأك�سدي الإجهاد بها ي�ساهم التي الدقيقة الآلية معرفة فاإن تو�سيح اأكرب.من جهة اأخرى، ُيعترب ارتفاع م�ستوى ال�سكر يف الدم اأحد العوامل التي حتث علي اإنتاج اجلذور احلرة، ومن ناحية اأخرى فاإنه يوؤدي اإىل �سعف النظام الدفاعي مل�سادات الأك�سدة الداخلي. ت�سمل اآليات دفاع م�سادات الأك�سدة الداخلية كال من امل�سارات الأنزميية م�سادات ت�سمل لالأك�سجني. التفاعلية امل�ستقات ل�ُسّمية كم�سادات دورها هي الإن�سان خاليا يف وظائفها اأهم ومن الأنزميية، وغري الأك�سدة الداخلية: الفيتامينات اأ، ج، اإي، جلوتاثيون، والأنزميات، ومنها اأنزمي �سوبراأك�سيد دي�سميوتيز، كاتاليز، جلوتاثيون بريوك�سيديز، وجلوتاثيون ريداكتيز. هذه املراجعة ت�سف اأهمية النظام الدفاعي مل�سادات الأك�سدة الداخلية وعالقتها مبختلف العمليات الف�سيولوجية املر�سية واآثارها العالجية املمكنة يف اجل�سم احلي. والأوعية القلب اأمرا�س احلرة، اجلذور ال�سكري، مر�س الأك�سدة، م�سادات التفاعلية، الأك�سجني م�ستقات تاأك�سدي، الكلمات:اإجهاد مفتاح الدموية، م�ساعفات مر�س ال�سكري، بريوك�سيد الدهون. abstract: diabetes is considered to be one of the most common chronic diseases worldwide. there is a growing scientific and public interest in connecting oxidative stress with a variety of pathological conditions including diabetes mellitus (dm) as well as other human diseases. previous experimental and clinical studies report that oxidative stress plays a major role in the pathogenesis and development of complications of both types of dm. however, the exact mechanism by which oxidative stress could contribute to and accelerate the development of complications in diabetic mellitus is only partly known and remains to be clarified. on the one hand, hyperglycemia induces free radicals; on the other hand, it impairs the endogenous antioxidant defense system in patients with diabetes. endogenous antioxidant defense mechanisms include both enzymatic and non-enzymatic pathways. their functions in human cells are to counterbalance toxic reactive oxygen species (ros). common antioxidants include the vitamins a, c, and e, glutathione (gsh), and the enzymes superoxide dismutase (sod), catalase (cat), glutathione peroxidase (gpx), and glutathione reductase (grx). this review describes the importance of endogenous antioxidant defense systems, their relationship to several pathophysiological processes and their possible therapeutic implications in vivo. keywords: oxidative stress; reactive oxygen species; antioxidants; diabetic mellitus; free radicals; cardiovascular diseases; diabetic complications; lipid peroxidation. review the role of oxidative stress and antioxidants in diabetic complications *fatmah a matough,1 siti b budin,1 zariyantey a hamid,1 nasar alwahaibi,2 jamaludin mohamed1 the role of oxidative stress and antioxidants in diabetic complications 6 | squ medical journal, february 2012, volume 12, issue 1 diabetes is a group of metabolic diseases characterised by high levels of blood sugar (hyperglycemia). it results from defects in insulin production and/or insulin action, and impaired function in the metabolism of carbohydrates, lipids and proteins which leads to long term health complications.4,5 in diabetic patients, longterm damage, dysfunction, and failure of different organs, especially the eyes (diabetic retinopathy), kidneys (diabetic nephropathy), nerves (diabetic neuropathy), heart (myocardial infarction), and blood vessels (atherosclerosis) are related to uncontrolled hyperglycemia.5–7 however, diabetic patients vary in their predisposition to the development of complications.8 the genetic hypothesis suggests that complications from diabetes are genetically predetermined as part of the diabetic syndrome, whereas the metabolic hypothesis suggests that complications such as cellular and vascular damage are the effects of longterm hyperglycemia.9 the diabetes control and complications trial (dcct) convincingly showed that complications from diabetes can be delayed and reduced by maintaining tight glycemic control.9 role of oxidative stress in diabetic complications the balance between the rate of free radical generation and elimination is important. excess cellular radical generation can be harmful;10 however, if there is a significant increase in radical generation, or a decrease in radical elimination from the cell, oxidative cellular stress ensues.11 there is convincing experimental and clinical evidence that the generation of reactive oxygen species (ros) increases in both types of diabetes and that the onset of diabetes is closely associated with oxidative stress.2,12 oxidative stress results from increased ros and/or reactive nitrogen species (rns).13 examples of ros include charged species such as superoxide and the hydroxyl radical, and uncharged species such as hydrogen peroxide and singlet oxygen.2 the possible sources of oxidative stress in diabetes might include auto-oxidation of glucose, shifts in redox balances, decreased tissue concentrations of low molecular weight antioxidants, such as reduced glutathione (gsh) and vitamin e, and impaired activities of antioxidant defence enzymes such as superoxide dismutase (sod) and catalase (cat).14 ros generated by high glucose is causally linked to elevated glucose and other metabolic abnormalities important to the development of diabetic complications. however, the exact mechanism by which oxidative stress may contribute to the development of diabetic complications is undetermined.15 in the past few decades, increasing evidence has connected oxidative stress to a variety of pathological conditions, including cancer, cardiovascular diseases (cvds), chronic inflammatory disease, post-ischaemic organ injury, diabetes mellitus, xenobiotic/drug toxicity, and rheumatoid arthritis.16,17 over time, convincing evidence has established the role of free radicals and oxidative stress in the pathogenesis and development of complications from dm,9,18 including retinopathy, nephropathy, neuropathy, and accelerated coronary artery disease.19 several studies have shown that elevated extraand intra-cellular glucose concentrations result in oxidative stress20,21 which was reported both in experimental diabetes in animals and in diabetic patients.21–23 the source of oxidative stress is a cascade of ros leaking from the mitochondria. this process has been associated with the onset of type 1 diabetes (t1dm) via the apoptosis of pancreatic beta-cells, and the onset of type 2 diabetes (t2dm) via insulin resistance.21 the underlying mechanisms in the onset of diabetes are complex because hyperglycemia could also be due to the cause-effect relationship of increased oxidative stress.21 biomarkers of increased oxidative stress, as measured by indices of lipid peroxidation and protein oxidation, increase in both t1dm, and t2dm.24 the aetiology of oxidative stress in diabetes arises from a variety of mechanisms such as excessive oxygen radical production from auto-oxidation of glucose,25 glycated proteins, and glycation of antioxidative enzymes, which limit their capacity to detoxify oxygen radicals.20 in addition to these mechanisms, two others have been suggested as being responsible for the generation of oxygen radicals in diabetes. first, jain demonstrated that high glucose levels could stimulate cytochrome p450-like activity by excessive nicotinamide adenine dinucleotide phosphate-oxidase (nadph) produced by glucose metabolism.26 second, ketosis, a hallmark of t1dm in particular, could increase fatmah a matough, siti b budin, zariyantey a hamid, nasar alwahaibi, jamaludin mohamed review | 7 mrna expression of transforming growth factor beta 1 (tgf-β1) and fibronectin, which are the genes implicated in diabetic glomerular injury, and 4) inhibition of oxidative stress ameliorates all the manifestations associated with diabetic nephropathy.36 preview studies demonstrated that there is a close relationship between endothelial dysfunction and the development and progression of renal and cardiovascular pathology in patients with t1dm.37 the combined development of renal and cardiovascular complications is referred to as cardiorenal syndrome. the causes of the development of cardiorenal syndrome in t1dm are poorly understood. previous studies suggest that endothelial dysfunction and the concomitant atherosclerotic process may lead to simultaneous development and progression of renal and cardiac pathology, since endothelial dysfunction is already present at the early stages of t1dm.38 reactive oxygen species although molecular oxygen is required to sustain life, it can be toxic through the formation of ros.39 indeed, the unusual triplet state of the oxygen molecule, due to the presence of two unpaired electrons, confers a remarkable chemical stability, based on the pauli exclusion principle, which forbids reactions between a singlet and a triplet molecule. due to electron spin constraints, the oxygen molecule cannot readily react with organic substrates.40 approximately 1–3% of oxygen consumed by the body is converted into ros.41 activation of oxygen can occur through two different mechanisms. the first mechanism of activation is absorption of sufficient energy to reverse the spin on one of the unpaired electrons, called a monovalent reduction. the biradical form of oxygen is in a triplet ground state because the electrons have parallel spins. if triplet oxygen absorbs sufficient energy to reverse the spin of one of its unpaired electrons, it will become singlet oxygen, in which the two electrons have opposite spins [figure 1]. this activation overcomes the spin restriction and singlet oxygen can consequently participate in reactions involving the simultaneous transfer of two electrons (divalent reduction). the second mechanism of activation is by the stepwise monovalent reduction of oxygen to form superoxide oxygen radical production in diabetic patients.27 nowadays, diabetic microand macroangiopathy are considered to be poly aetiological multifactorial diseases. a number of studies have evaluated the role of oxidative stress in the aetiology of microvascular and macrovascular complications of diabetes in the fasting state.28 furthermore, there is growing evidence suggesting the role of hyperglycemia, hyperinsulinemia and dyslipidaemia in diabetic patients, all of which have been implicated in the development of macroangiopathies, which possibly act upon their ability to induce oxidative stress, leading to endothelial dysfunction and atherosclerosis.20 many studies have suggested that oxidative stress is a common pathogenic factor for the dysfunction of beta and endothelial cells.29,30 beta cell dysfunction results from prolonged exposure to high glucose, elevated free fatty acid (ffa) levels, or a combination of both.30 beta cells are particularly sensitive to ros because they are low in free-radical quenching (antioxidant) enzymes such as catalase (cat), glutathione peroxidase (gpx) and superoxide dismutase (sod).31 therefore, the ability of oxidative stress to damage mitochondria and markedly blunt insulin secretion is not surprising.32,33 for example, it has been demonstrated that oxidative stress generated by short exposure of beta cell preparations to hydrogen peroxide (h2o2) increases the production of protein cyclin-dependent kinase inhibitor 1 (p21) and decreases insulin messenger ribonucleic acid (mrna), cytosolic adenosine triphosphate (atp), and calcium flux in cytosol and mitochondria.34 in other studies, much experimental evidence has been accumulated to show that various types of vascular cells are able to produce ros under hyperglycemic conditions.20 the pathogenesis of diabetic nephropathy remains far from clear. an important role of oxidative stress for the development of nephropathy and neurological complications is suggested by experimental and clinical studies.35 these studies establish a causal relationship between oxidative stress and diabetic nephropathy by observations that 1) lipid peroxides and 8-hydroxydeoxyguanosine, indices of oxidative tissue injury, increase in the kidneys of diabetic rats with albuminuria; 2) high glucose directly increases oxidative stress in glomerular mesangial cells and target cells of diabetic nephropathy; 3) oxidative stress induces the role of oxidative stress and antioxidants in diabetic complications 8 | squ medical journal, february 2012, volume 12, issue 1 (o2), h2o2, hydroxyl radical (oh) and finally water according to the scheme shown in figure 2. the first step in the reduction of oxygen forming superoxide is endothermic, but subsequent reductions are exothermic.42 humans are exposed to many carcinogens, but the most significant may be the reactive species derived from the metabolism of oxygen and nitrogen known as ros and rns. on the one hand, the formation of ros and rns in the human body can cause oxidative damage to biological macromolecules, especially the plasma membrane,43 which may contribute to the development of cancer, cvd, diabetes and other oxidative stress-mediated dysfunctions.44 on the other hand, ros are known mediators of intracellular signalling cascades.45 even though ros are generated under physiological conditions and are involved to some extent as signalling molecules and defence mechanisms as seen in phagocytosis, neutrophil function, macrophages and other cells of immune system,46 ros are a heterogeneous group of molecules that are generated by mature myeloid cells during innate immune responses, and are also implicated in normal intracellular signalling. when phagocytes are activated, they produce ros in amounts high enough to kill intruding bacteria.47 also, shear-stress induced vasorelaxation and excess production of ros may, on the other hand, lead to oxidative stress, loss of cell function, and ultimately to apoptosis or necrosis.46 ros are produced by oxidative phosphorylation, nadph, xanthine oxidase, the uncoupling of lipoxygenases, cytochrome p450 monooxygenases, and glucose autoxidation.18 once formed, ros deplete antioxidant defenses, rendering the affected cells and tissues more susceptible to oxidative damage by reacting with lipids in cellular membranes, nucleotides in dna,48 sulphydryl groups in proteins, and cross linking fragmentation of ribonucleoproteins,49 leading to changes in cellular structure and function.19 levels of ros are under tight control by the protective actions of antioxidant enzymes and nonenzymatic antioxidants in normal and healthy cells. however, in diabetes, excessive cellular levels of ros are induced by hyperglycemia causing a major complication of dm.50 furthermore, in the case of diabetes or insulin resistance, a higher oxidative glucose metabolism itself increases mitochondrial production of o2 ● which will then be converted to oh● and h2o2. 51 beyond glucose, ros formation is also increased by ffas, through its direct effect on mitochondria.52 it has been proposed that overexpression and activity of mitochondrial inner membrane uncoupling proteins (ucps) contribute to an increase in superoxide formation under diabetic conditions.53 the ros52,54 listed in table 1 include free radicals such as superoxide (o2 ●) hydroxyl (oh●), and rns52,54 include free radicals like nitric oxide (no●). of these reactive molecules, o2 ●, no●and onoo are the most widely studied species and play important roles in diabetic cardiovascular complications.12 in diabetes, nadph oxidase is a major source of the generation of ros. nadph oxidase is located in the plasma membrane of various renal cell types, including mesangial and proximal tubular cells, vascular smooth muscle cells, endothelial cells, and fibroblasts. nadph oxidase-dependent figure 1: nomenclature of the various forms of oxygen.42 figure 2: the activation states of oxygen.42 fatmah a matough, siti b budin, zariyantey a hamid, nasar alwahaibi, jamaludin mohamed review | 9 structures alter the relative susceptibility of certain amino acids.42 experimental studies show that the decrease in the total protein concentration in the serum of diabetes-induced rats may be ascribed to: 1) decreased amino acids uptake;55 2) a greatly decreased concentration of a variety of essential amino acids;56 3) an increased conversion rate of glycogenic amino acids to co2 and h2o, and 4) a reduction in protein synthesis secondary to a decreased amount and availability of mrna.57 in vitro studies show that myeloperoxidase, a heme protein secreted by neutrophils and monocytes, catalyses a very specific reaction, leading to the conversion of l-tyrosine to 3-3-dityrosine.58 in addition, the oxidative formation of dityrosine in proteins may serve as a crosslink between adjacent polypeptide chains of the same or different proteins. dityrosine is a very unusual molecule linked not by a peptide, but by a covalent bond resistant to protolytic degradation and acid hydrolysis.59 this property of dityrosine makes it a convenient marker for protein oxidation. oxidatively induced crosslinking of proteins with this modified amino acid was suggested to be a signal for rapid and selective in vivo degradation by intracellular protease.60 however, accumulation of oxidatively modified proteins with age was thought to be a result of their increased resistance to degradation.61 b. l i p i d s in recent years, much attention has been focused on the role of oxidation stress, and it has been reported that the imbalance between oxidative stress measures and antioxidant levels in diabetes is present because of the generation of ros during glycation, and glucose and lipid oxidation.62,25 lipid hydroperoxides (lhp), produced from a variety of long-chain polyunsaturated fatty acid precursors via intermediate radical reactions, involve oxygen and metal cations (iron and copper). the net result of these combined reactions is the generation of highly reactive and cytotoxic lipid radicals, which generate new lhp because of their close proximity in biomembranes to other lipids.63 in addition, diabetes produces disturbances of lipid profiles, especially an increased susceptibility to lipid peroxidation,64 which is responsible for an increased incidence of atherosclerosis,65 a major complication of dm.66 lipid peroxidation is a critical biomarker of free radical-mediated oxidative overproduction of ros plays a key role in promoting hyperglycemia-induced oxidative stress. the nadph oxidase increase oxidative stress and finally this increases results in the development of diabetic nephropathy in rats.47 oxidative stress-induced cellular damage the targets of ros damage include all major groups of biomolecules and can be described as follows: a. p r o t e i n s since ros can target almost all cellular compounds, several studies report that ros can react with several amino acid residues in vitro, generating anything from modified and less active enzymes to denatured, non-functioning proteins.55 fragmentation of the peptide chain and aggregation of cross-linked reaction products result in an altered electrical charge and increased susceptibility to proteolysis.42 the amino acids in a peptide differ in their susceptibility to attack, and the various forms of activated oxygen differ in their potential reactivity. primary, secondary, and tertiary protein table 1: overview of different types of free reactive species2 reactive oxygen species radicals non radicals superoxide, o2 ● hydroxyl, oh● peroxyl, roo● alkoxyl, ro● hydroperoxyl, ho2 hydrogen peroxide, h2o2 hypochlorous acid, hocl ozone, o3 singlet oxygen,1o2 peroxynitrite, onoo reactive nitrogen species nitric oxide, (nitrogen mono) no● nitrogen dioxide, no2 ● peroxynitrite, onoo alkyl peroxynitrites, roono dinitrogen trioxide, n2o3 dinitrogen tetroxide, n2o4 nitrous acid, hno2 nitronium anion, no2+ nitroxyl anion, nonitrosyl cation, no+ nitryl chloride, no2cl reactive chlorine species atomic chlorine, cl hypochlorous acid, hocl chlorine, cl2 nitronium (nitryl ) chloride, no2cl the role of oxidative stress and antioxidants in diabetic complications 10 | squ medical journal, february 2012, volume 12, issue 1 stress, and it is probably the most explored area of research when it comes to ros.67 it is also an important pathological indicator in many diseases.56 consequently, mechanisms in the formation of lipid hydroperoxides and biologically active metabolites, together with their effect on cellular structure and function, are of increasing importance to the study of diabetogenesis.68 there is much evidence from experimental studies that polyunsaturated fatty acids (pufa) in the plasma membrane, because of their multiple double bonds, are extremely susceptible to attack by free radicals.69 hydroxyl radicals initiate a free radical chain reaction and remove a hydrogen atom from one of the carbon atoms in the pufa and lipoproteins, causing lipid peroxidation characterised by membrane protein damage through subsequent free radical attacks.70 one major hypothesis as to why this occurs is that oxidised lipoprotein (oxldl) contributes to the cardiovascular complications of diabetes. lowdensity lipoprotein (ldl) is the major cholesterol carrier in plasma, and elevated levels of circulating ldl are associated with increased risk for atherosclerosis; notably, increased levels of oxldl have been associated with hypertension in men.71 several studies have demonstrated increased ldl oxidation in diabetic patients when compared to their corresponding controls.72 oxidised lipids can affect cell function by accumulating in the cell membrane causing leakage of the plasma lemma and interfering with the function of membranebound receptors.73 in addition, the by-products of lipid peroxidation, such as unsaturated aldehydes and other metabolites, have cytotoxic and mutagenic properties, and oxldl itself has a specific role in the pathogenesis of atherosclerosis.74 the effects of oxldl on the vessel walls themselves include stimulation of cytokine and growth factor production and generation of endothelial dysfunction, including inhibition of endothelial cell vasodilator function, all of which contribute to atherosclerosis.41 lipid peroxidation-mediated membrane defects have also been implicated in the decreased reactivity of thiol group membrane proteins.75 as a consequence, enriching the membranes with pufa could restore oxidative membrane damage and subsequently normalise decreased membrane fluidity and function. antioxidants (i.e., dietary supplements) compensating for loss of pufa may enhance the activity of transmembrane enzymes, membraneembedded receptors and membrane transport systems.52 role of antioxidant defense system and protection mechanism in the late 19th and early 20th centuries, chemists studied antioxidants, a loosely defined group of compounds characterised by their ability to be oxidised in place of other compounds present. at first, their uses ranged from food storage to the vulcanisation of rubber, but it was only later that biologists realised the importance of antioxidants in health with the 1960s publications of vitamins and flavanoids.39 in the 1970s, cameron and pauling, followed by later research, found that ascorbic acid (vitamin c) is a potential human cancer protective agent.76 with many well-known scientists actively researching antioxidants as protecting agents,77 explanations for the effects of antioxidants on cancer susceptibility and overall health expanded rapidly in subsequent decades with research into mechanisms, molecular targets, and molecular interactions.78 in recent years, many conferences and reviews testify to the increasing interest in the roles of the body's antioxidants system working together in human cells against toxic reactive oxygen species, their relationship with several pathophysiologic processes and their possible therapeutic implications.79 antioxidant defense mechanisms involve both enzymatic and nonenzymatic strategies. common non-enzymatic antioxidants include the vitamins a, c, and e, glutathione, α-lipoic acid, mixed carotenoids, coenzyme q10 (coq10), several bioflavonoids, antioxidant minerals (copper, zinc, manganese and selenium), and cofactors like folic acid, uric acid, albumin, and vitamins b1, b2, b6, and b12. enzymatic antioxidants include superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase.80 through normal physiological processes, antioxidants affect signal transduction and regulation of proliferation and the immune response. while ros have been linked to cancer, diabetic complications and cvd, antioxidants have shown promise as a possible therapy for the prevention and treatment of these diseases, especially given the tantalising links fatmah a matough, siti b budin, zariyantey a hamid, nasar alwahaibi, jamaludin mohamed review | 11 a significantly improved lipid composition, and maintenance of membrane fluidity in the brains of the rats.84 coleman suggested that triple antioxidant therapy (vitamin e, lipoic acid [la] and vitamin c) in diabetic volunteers attenuates the experimental oxidative stress of methemoglobin formation in vitro and reduces haemoglobin glycation in vivo.85 panjwani suggested that vitamin c administered alone or in combination with vitamin e reduced the fall in ulnar nerve conduction velocity.86 sivan and reece investigated whether dietary supplementation with vitamin e would reduce the incidence of diabetic embryopathy in an in vivo rat model.87 fifty pregnant rats were designated as the control group and received a normal diet while the diabetic group received vitamin e supplements (400 mg/day). this experimental study found that supplementation with vitamin e reduces the incidence of neural tube defects by more than 75%.87 these findings suggest that vitamin e reduces this oxidative load, confers a protective effect against diabetic embryopathy, and thus may potentially serve as a dietary prophylaxis in the future. these results are in line with the reports from chang and others which showed that diabetic embryopathy of rat or mouse embryos is prevented by vitamin c, vitamin e, sod, n-acetyl-cysteine, or glutathione ethyl ester.88 another study by otero et al. showed the effects of supplementation with vitamin e to diabetic mice. the beneficial effect of vitamin e observed in this model was shown to retard coronary atherosclerosis accelerated by dm, and was demonstrated to be due to a reduction in oxidative stress, and not secondary to a decrease in plasma glucose or cholesterol since their respective plasma concentrations remained unchanged in the diabetic mice supplemented with vitamin e.89 furthermore, it has been recently reported that macrophages from diabetic mice are under excess oxidative stress, and that the antioxidant vitamin e can attenuate macrophage oxidative stress which exists in dm and leads to accelerated atherosclerosis development.90 in addition, there have been other experimental studies assessing the prophylactic effects of vitamin e against heart failure in type 1 diabetic cardiomyopathy. these studies have found that supplementation of streptozotocin-induced (stz)-diabetic rats with 2000 iu of vitamin e/ kg of feed beginning immediately after induction of dm and continuing for 8 weeks provided a observed between diets high in fruits and vegetables (and presumably antioxidants) and decreased risks of cancer.41 evidence from experimental, epidemiological and clinical studies have proven the utility of antioxidants which might therefore be helpful for treating diabetes and its complication. evidence from experimental studies worldwide, several animal studies on antioxidants as protective agents have been conducted. the most important studies have been performed utilising antioxidants in experimental diabetic models. the effects of antioxidants on oxidative stress are measured through certain observable biomarkers. these markers include the enzymatic activities of cat, sod, gsh-px, and glutathione reductase (gsh-rx), as well as thiobarbituric acid reacting substances (tbars) levels, an indirect measurement of free radical production that has been shown to be consistently elevated in diabetes.12 kunisaki investigated the effects of treatments with classical antioxidants such as vitamin e, vitamin c and lipoic acid. specifically, vitamin e normalises retinal blood flow and protein kinase c (pkc) activity in the vascular tissue of diabetic rats.81 one short-term experimental study showed that high doses of vitamin c can improve some aspects of endothelial dysfunction in diabetes.82 another experimental study has demonstrated that intraperitoneal administration of α-lipoic acid to streptozotocin (stz) diabetic wistar rats normalises tbars levels in plasma, and the retina, liver, and pancreas.83 furthermore, it has been reported that α-lipoic acid leads to a decrease in the severity of diabetic neuropathy by maintaining gsh levels and/or by its direct antioxidant properties.83 however, lipoic acid administration improved endothelial function in subjects with metabolic syndrome. in another study to determine the effects of vitamin e on oxidative stress and cell membrane fluidity in the brains of diabetes-induced experimental rats, hong et al. reported that vitamin e was found to be effective for strengthening the antioxidant defense system. they noted a reduction of the accumulation of ros such as superoxide radicals, a decrease in the generation of oxidative damaging substances such as the carbonyl value, the role of oxidative stress and antioxidants in diabetic complications 12 | squ medical journal, february 2012, volume 12, issue 1 significant protection against cardiac dysfunction induced by t1dm. this cardioprotective effect was simultaneously associated with the ability of vitamin e to blunt diabetes-induced amplification of myocardial infarction.91 these findings suggest the usefulness of vitamin e supplementation during the early phases of t1dm for the prophylaxis of cardiomyopathy and subsequent heart failure. ozkan et al. examined the protective effects of a triple antioxidant combination (vitamins e and c plus α-lipoic acid) on the total lipid and cholesterol levels and the fatty acid composition of brain tissues in experimental diabetic and nondiabetic rats. vitamin e and α-lipoic acid were injected intraperitoneally (50 mg/kg) four times per week and vitamin c was provided as a supplement dissolved in the rats’ drinking water (50 mg/kg). the result of this study confirms that treatment with a triple combination of antioxidants protects the arachidonic acid level in the brains of diabetic and non-diabetic rats. in addition, both antioxidants and insulin treatment have beneficial effects on the d-6 desaturase system and unsaturated fatty acid levels. antioxidants may also have protective effects on unsaturated fatty acids, and reduce oxidative stress, thus impairing the progression to ldl oxidation, cell membrane lipid peroxidation and decreased endoneurial blood flow, thereby reducing peripheral nerve and vascular dysfunction.92 evidence from clinical studies early interest in the use of vitamin e supplementation in patients with chd came from the enthusiastic reports of a canadian physician, evan shute, who recommended vitamin e for all his patients with coronary heart disease (chd) and presented a case series showing its significant benefit in reducing symptoms of angina pectoris.93 in a clinical trial study conducted by bursell, et al., they evaluated 36 patients with t1dm. in their crossover trial, individuals were divided into two groups; one group received a placebo while the other group received high dose vitamin e supplementation (1,800 iu/ day). the major aim of this study was to determine the effectiveness of vitamin e in normalising retinal blood flow and renal function in patients with t1dm. they found that oral vitamin e treatment appears to be effective in normalising retinal haemodynamic abnormalities and improving renal function in patients with t1dm, especially those with short disease duration, without inducing a significant change in glycemic control. this suggests that vitamin e supplementation may provide an additional benefit in reducing the risks for developing diabetic retinopathy or nephropathy.94 in terms of vitamin e supplementation in diabetes, ross and others have demonstrated beneficial effects on cataract genesis in diabetic rats.95 furthermore, in a study done over a four month period, paolisso, et al. evaluated the efficacy of oral supplementation of vitamin e (900 mg\day) in t2dm patients. they found that supplementation of vitamin e decreased lowered insulin resistance and improved glucose uptake as shown by euglycemic glucose clamp assays performed both before and after the supplementation period.96 in addition, they also concluded that vitamin e may be a useful adjunct in reducing oxidative stress in t2dm. these findings confirmed an earlier study by ceriello et al. in which glycosylated haemoglobin and other proteins were significantly decreased after two months’ treatment with either 600 or 1200 mg/day of vitamin e.97 the potential for vitamin e in pharmacological doses to be used as a means to delay or prevent secondary complications of diabetes seems well established. vitamin c supplementation is effective in reducing sorbitol accumulation in the red blood cells of diabetics. these findings have been confirmed by a clinical study carried out by cunningham, et al., who investigated the effect of two different doses of vitamin c supplements (100 and 600 mg) during a 58 day trial on young adults with t1dm. the results of this study showed that within 30 days, vitamin c supplementation at either dose normalised sorbitol levels in those with diabetes. furthermore, vitamin c also helps to reduce capillary fragility which also contributes to complications from dm. moreover, several studies suggest that chronic vitamin c administration has beneficial effects on glucose and lipid metabolism in t2dm patients.98 in addition, vitamin c supplementation improved glycemic control, fasting blood glucose levels, cholesterol and triglycerides.99 in a placebo-controlled, randomised trial of diabetic patients, reaven investigated the effect of 1600 iu of rrr-α-tocopherol supplementation daily for 10 weeks on hyperglycemia-induced ldl fatmah a matough, siti b budin, zariyantey a hamid, nasar alwahaibi, jamaludin mohamed review | 13 effect of rrr-α-tocopherol supplementation on the hyperglycemia-induced ldl modifications in t1dm and t2dm diabetic patients.100 based on nutrition recommendations and interventions for diabetes, there is no clear evidence of benefits that can be derived from vitamin or mineral supplementation in people with diabetes. routine supplementation with antioxidants, such as vitamins e and c and carotene, is not advised because of lack of evidence of efficacy, and concern related to long term safety, and therefore cannot be recommended.102 the majority of studies included in this review support a possible role of antioxidant supplementation in reducing the risk of cvd and diabetic complications. however, the results of the majority of the prospective randomised controlled modifications. the result of the study pointed to a reduction of approximately 60% of plasma ldl oxidation in diabetic patients, which was statistically significant when compared to healthy controls.100 these results are supported and confirmed by other similar clinical data. salonen, et al. found that doses equal to or higher than 450 iu are sufficient to significantly ameliorate the susceptibility of ldl to oxidation, indicating that relatively high doses of rrr-α-tocopherol for supplementation are needed.101 furthermore, bellomo and others have shown that the effects of rrr-α-tocopherol supplementation on ldl oxidation are accompanied by a concomitant reduction in autoantibody levels against hyperglycemia-induced ldl modifications. moreover, clinical studies have shown an inhibitory table 2: selected controlled clinical trials of antioxidant supplements’ effect on preventing diabetic complications study name with type of supplementation number sex age dose duration in years (y) or months (m) study outcome dietary supplementation (gissi). 1999106 vitamin e 11,324 m, f no age limits 300 mg 3.5 y no effect on mi + cvd death + stroke yusuf, et al. 2000107 vitamin e 9541 m, f ≥55 400 iu 4.5 y no effect on mi, cvd death, or stroke pruthi, et al. 2001108 vitamin e 39,910 m no age limits 100 iu/day 2 y 37% lower risk of chd kritharides, et al. 2002109 vitamins a and c, folic acid, niacin,β-carotene, selenium, zinc 87,000 m, f no age limits not available 10 y significantly lower risk of cvd, mortality deepak, et al. 2003105 vitamins e and c, and β-carotene 20,500 m, f 40–80 ve 600 mg, vc 250 mg, β-carotene 20 mg 5 y no significant difference in cardiovascular mortality and incidence of vascular events between vitamin and placebo groups lee, et al. 2005110 vitamin e 40000 f ≥45 600 iu 10 y no effect on cardiovascular events costacou, et al. 2006111 vitamin supplementation with multivitamin pills m, f <17 multivitamin pills 10 y significant decreased risk of cad incidence in t1dm milman, et al. 2008112 vitamin e 1434 m, f ≥55 400 u/day 18 m reduced cardiovascular events in individuals with dm hodis, et al. 2009113 folic acid, vitamin b12, and b6 506 m, f 40–89 folic acid 5 mg,vb12 0.4 mg, vb6 50 mg 3.1y significantly reduced progression of earlystage subclinical atherosclerosis and low risk for cvd shargorodsky, et al. 2010114 combined antioxidant (vitamins e and c, coenzyme q10) 70 m, f no age limits ve (400 iu/day),vc (1000 mg/d), q10 (120mg\ day) 6 m positive effects on cardiovascular risk factors the role of oxidative stress and antioxidants in diabetic complications 14 | squ medical journal, february 2012, volume 12, issue 1 antioxidant clinical trials have failed to demonstrate a significant benefit in antioxidant supplementation in the prevention of atherosclerotic events, as shown in table 2. as also supported by more recent metaanalysis studies of antioxidant-intervention trials in humans, doses of vitamin e supplements (400 or 800 iu) given in many clinical trials are associated with adverse effects,103 or are associated with an increased risk of death.104 furthermore, the results of the majority of the prospective randomised controlled antioxidant clinical trials have failed to demonstrate a significant benefit of antioxidant supplementation (vitamins c, e and β-carotene) in primary patients (i.e. those without clinical evidence of cvd) or secondary patients (i.e. those with clinical evidence of cvd) in the prevention of cardiovascular events.105 moreover, in clinical trials the supplementation of vitamins c and e, and/or β-carotene was associated with an increased risk for all-cause mortality, a finding also supported by a recent meta-analysis.104 conclusion in conclusion, there is considerable evidence that induction of oxidative stress is a key process in the onset of diabetic complications. the precise mechanisms by which oxidative stress may accelerate the development of complications in diabetes are only partly known. evidence for the protective effect of antioxidants has been presented in experimental, clinical, and epidemiological studies, which have demonstrated that antioxidants might be helpful in treating diabetes and its complications. in contrast, the results of the majority of the prospective randomised controlled antioxidant clinical trials have failed to demonstrate a significant benefit, in the prevention of cardiovascular events, of antioxidant supplementation (vitamins c, e and β-carotene) in primary patients without clinical evidence of cvd, or in secondary patients with clinical evidence of cvd. references 1. american diabetes association. diagnosis and classification of diabetes mellitus. j diabetes care 2010; 33:s62-9. 2. rosen p, nawroth pp, king g, moller w, tritschler hj, packer l. the role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a congress series sponsored by unesco mcbn, the american diabetes association and the german diabetes society. diabetes metab res rev 2001; 17:189-912. 3. wild sh, roglic g, green a, sicree r, king h. global prevalence of diabetes: estimates for the year 2000 and projections for 2030. diabetes care 2004; 27:1047-53. 4. oktayoglu gs, basaraner h, yanardag r, bolkent s. the effects of combined treatment of antioxidants on the liver injury in stz diabetic rats. diges dis sci 2009; 54:538-46. 5. american diabetes association. diagnosis and classification of diabetes mellitus. diabetes care 2010; 33:s62. 6. tesfaye s, gill g. chronic diabetic complications in africa. afr j diabetes med. 2011; 19:4-8. 7. chintan ap, nimish lp, nayana b, bhavna m, mahendra g, hardik t. cardiovascular complication of diabetes mellitus. j appl pharm sci 2011; 4:1-6. 8. jain sk. the mechanism(s) of complications and benefits of vitamin e supplementation in diabetic patients. from: www.diabetologia.html. accessed: jul 2000. 9. dcct. the diabetes control and complications trial research group. the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. n engl j med 1993; 329:977-86. 10. rice ec, miller n, paganaga g. antioxidant properties of phenolic compounds. tre pla sci 1997; 2:152-9. 11. valko m, leibfritz d, moncol j, cronin mtd, mazur m, telser j. free radicals and antioxidants in normal physiological functions and human disease. int j biochem cell biol 2007; 39:44-84. 12. johansen js, harris ak, rychly dj, ergul a. oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. cardiovasc diabet 2005; 4:5. 13. joseph le, ira dg, betty am, gerold mg. are oxidative stress activated signaling pathways mediators of insulin resistance and cell dysfunction? diabetes 2003; 52:1-8. 14. haskins k, bradley b, powers k. oxidative stress in type 1 diabetes. ann n y acad sci 2003; 1005:43–54. 15. kowluru ra, chan ps. oxidative stress and diabetic retinopathy. exp diabetes res 2007; 4:43603. 16. el faramawy sm, rizk ra. spectrophotometric studies on antioxidants-doped liposomes. j am sci 2011; 7:363-9. 17. samanthi rpm, rolf ea, jelena aj, maria a, paresh cd. novel conjugates of 1,3-diacylglycerol and lipoic acid: synthesis, dpph assay, and rp-lc-ms-apci analysis. j lipids 2011; 10:1-10. fatmah a matough, siti b budin, zariyantey a hamid, nasar alwahaibi, jamaludin mohamed review | 15 triggered signaling pathways. toxicol lett 2011; 20:15–26. 33. gisela d, peter kd, martina d. oxidative stress and beta-cell dysfunction. eur j physiol 2010; 460:70318. 34. maechler p, jornot l, wolheim cb. hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. j biol chem 1999; 274:27905–13. 35. sharma p, joel s, shuping s, betty l, ruc t. diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. j am soc nephrol 2007; 18:2945–52. 36. ha h, kim kh. pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase c. diabetes res clin pract 1999; 45:147-51. 37. shestakova mv, jarek ir, ivanishina ns, kuharenko ss, yadrihinskaya mn, aleksandrov aa, et al. role of endothelial dysfunction in the development of cardiorenal syndrome in patients with type 1 diabetes mellitus. diabetes res clin pract 2005; 68:s65-72. 38. rossing p, huggard p, borch-johnsen k, parving hh. predictors of mortality in iddm: 10 year observational follow-up study. bmj 1996; 313:779– 84. 39. rowe l. dna damage-induced reactive oxygen species: a genotoxic stress response. phd thesis, 2009, emory university, georgia, usa. 40. miinea cp. antioxidant protection mechanisms and arachidonic acid metabolism in diabetic rat nerve and schwann cells cultured in elevated glucose, phd thesis, 2002. university of houston, texas, usa. 41. seifried he, anderson de, fisher ei, milner ja. a review of the interaction among dietary antioxidants and reactive oxygen species. j nutr biochem 2007; 18:567–79. 42. oxidative stress. from: http://www.plantstress.com/ articles. accessed: dec 1996. 43. vaughan m. oxidative damage to macromolecules mini review series. j biol chem 1997; 272:18513. 44. sies h. oxidative stress: oxidants and antioxidants. exp physiol 1997; 82:291-5. 45. nordberg j, arnér esj. reactive oxygen species, antioxidants, and the mammalian thioredoxin system. free radic biol & medic 2001; 31:1287-312. 46. halliwell b, cross ce, gutteridge jmc. antioxidants in human health and disease. annu rev nutr 1996; 16:33–50. 47. hole ps, darley rl, tonks a. do reactive oxygen species play a role in myeloid leukemia? blood 2011; 117:5816–26. 48. ahsan h, ali a, ali r. oxygen free radicals and systemic autoimmunity. clin exp immunol 2003; 31:398-404. 49. waris g, alam k. attenuated antigenicity of 18. niedowicz d, daleke d. the role of oxidative stress in diabetic complications. cell biochem biophys 2005; 43:289-330. 19. phillips m, cataneo rn, cheema t, greenberg j. increased breath biomarkers of oxidative stress in diabetes mellitus. clin chim acta 2004; 344:189-94. 20. giugliano d, ceriello a, paolisso g. diabetes mellitus, hypertension and cardiovascular diseases: which role for oxidative stress? metabolism 1995; 44:363–8. 21. west ic. radicals and oxidative stress in diabetes. diabetes med 2000; 17:171–80. 22. sayed mr, iman mm, dawlat as. biochemical changes in experimental diabetes before and after treatment with mangifera indica and psidium guava extracts. int j pharm biomed sci 2011; 2:29-41. 23. agnieszka p, dorota r, iren a, maciej j, stefan a. high glucose concentration affects the oxidantantioxidant balance in cultured mouse podocytes. j cell biochem 2011; 112:1661-72. 24. cederberg j, basu s, eriksson uj. increased rate of lipid peroxidation and protein carbonylation in experimental diabetic pregnancy. diabetologia 2001; 44:766-74. 25. wolff sp. diabetes mellitus and free radicals: free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. br med bull 1993; 49:642. 26. jain sk. hyperglycemia can cause membrane lipid peroxidation and osmotic fragility in human red blood cells. j biol chem 1989; 264:21340-5. 27. jain sk, kannan k, lim g. ketosis (acetoacetate) can generate oxygen radicals and cause increased lipid peroxidation and growth inhibition in human endothelial cells. free radic biol med 1998; 25:10838. 28. zagar a, wani ai, masoodi sr, laway ba, bashir mi. mortality in diabetes mellitus data from a developing region of the world. diabetes res clin pract 1999; 43:67-74. 29. zourek m, kyselova p, mudra j, krcma m, jankoveci z, lacigova s, et al. the relationship between glycemia, insulin and oxidative stress in hereditary hypertriglyceridemic rats. physiol 2008; 57:531-8. 30. evans j, goldfine id, maddux ba, grodsky gm. are oxidative stress activated signaling pathways mediators of insulin resistance and beta cell dysfunction? diabetes 2003; 52-8. 31. tiedge m, lortz s, drinkgern j, lenzen s. relation between antioxidant enzyme gene expression and antioxidative defense status of insulin producing cells. diabetes 1997; 46:1733–42. 32. lu ht, chin s, ya wc, ching yy, chin cw, dong zh, et al. arsenic induces pancreatic cell apoptosis via the oxidative stress-regulated mitochondriadependent and endoplasmic reticulum stressthe role of oxidative stress and antioxidants in diabetic complications 16 | squ medical journal, february 2012, volume 12, issue 1 ribonucleoproteins modified by reactive oxygen species. biochem molec biol int 1998; 45:33-45. 50. lim j. effects of low-level light therapy on 2,3,7,8-tetrachlorodibenzo-p-dioxin and diabetesinduced oxidative damage in chicken and rat kidneys. phd thesis, 2009, indiana university, usa. 51. nishikawa t, edelstein dd, yamagishi s, matsumura t, kaneda y, yorek ma, et al. normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. nature 2000; 404:787-90. 52. evans jl, goldfine id, maddux ba, grodsky gm. oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. endocr rev 2002; 23:599-22. 53. rolo ap, palmeira cm. diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. toxicol appl pharmacol 2006; 212:167-78. 54. turko iv, marcondes s, murad f. diabetesassociated nitration of tyrosine and inactivation of succinyl-coa:3-oxoacid coa transferase. am j physiol heart circ physiol 2001; 281:h2289-94. 55. butterfield da, howard b, subramaniam r, hall n, hensley k, yatin s, et al. structural and functional changes in proteins induced by free radicalmediated oxidative stress and protective action of the antioxidants n-tert-butyl-alpha-phenylnitrone and vitamin e. ann n y acad sci 1998; 854:448–62. 56. brosnan jt, man kc, hall he, clobourne sa, brosnan me. inter organ metabolism of amino acids in streptozotocin-diabetic rats. am j physiol 1984; 244:e151-8. 57. peavy de, taylor jm, jefferson ls. time course of changes in albumin synthesis and mrna in diabetic and insulin treated diabetic rats. am j physiol 1985; 248:e656-63. 58. leeuwen c, rasmussen je, hsu ff, mueller dm, pennathur s, heinecke jw. mass spectrometric quantification of markers for protein oxidation by tyrocyle radicals, copper, and hydrocyle radicals in ldl isolated from human athersosclerotic plaques. j biol chem 1997; 227:3520-6. 59. lipinski b. pathophysiology of oxidative stress in diabetes mellitus. j diabetes complications 2001; 15:203-10. 60. davies kj. protein damage and degredation by oxygen radicals: iv. degredation of denatured protein. j biol chem 1987; 262:9914-20. 61. berlett bs, stadtman er. protein oxidation in aging, disease and oxidative stress. j biol chem 1997; 272:20313-16. 62. rosen p, du xl, tschope d. role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by a-tocopherol? molec cell biochem 1998; 188:103–11. 63. nishigaki i, hagishara m, tsumakawa h, maseki m, yagi k. lipid peroxide levels of serum lipoprotein fractions of diabetic patients. biochem med 1981; 25:373-8. 64. lyons tj. oxidized low density lipoproteins: a role in the pathogenesis of atherosclerosis in diabetes? diabet med 1991; 8:411–19. 65. giugliano d, ceriollo a, paolisso g. oxidative stress and diabetic vascular complications. diabetes care 1996; 19:257-67. 66. steiner g. atherosclerosis, the major complication of diabetes. adv exp med biol 1985; 189:277–97. 67. yla hs. oxidized ldl and atherogenesis. ann n y acad sci 1999; 874:134–7. 68. crabb m. diabetic complications: scientific and clinical aspects. new york: churchill livingston, inc., 1987. 69. esterbauer h, schaur rj, zollner h. chemistry and biochemistry of 4-hydroxynonenal malonaldehyde and related aldehydes. free radic biol med 1991; 11:81-128. 70. halliwell b. oxidation of low-density lipoproteins: questions of initiation, propagation, and the effect of antioxidants. j clin nutr 1995; 61:670-7s. 71. frostegard j, wu r, lemne c, thulin t, witztum jl, faire u. circulating oxidized low-density lipoprotein is increased in hypertension. clin sci (lond) 2003; 105:615–20. 72. rabini ra, fumelli p, galassi r. increased susceptibility to lipid oxidation of low-density lipoproteins and erythrocyte membranes from diabetic patients. metab clin exp 1994; 43:1470–4. 73. cai h, harrison dg. endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. circ res 2000; 87:840–4. 74. goldstein jl, ho yk, basu sk, brown m. binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. proc natl acad sci 1979; 76:333–7. 75. ohyashiki t, sakata n, matsui k. changes in sh reactivity of the protein in porcine intestinal brush-border membranes associated with lipid peroxidation. j biochem 1994; 115:224–9. 76. cameron e, pauling l. supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. proc natl acad sci 1976; 73:3685–9. 77. willett wc, macmahon b. diet and cancer an overview. n engl j med 1984; 310:633–8. 78. world cancer research fund / american institute for cancer research. food, nutrition, physical activity, and the prevention of cancer: a global perspective. washington, dc: aicr, 1997. 79. mats j, pérez g, cristina d, castro j. antioxidant enzymes and human diseases. clin biochem 1999; 32:595–603. 80. maritim ac, sanders ra, watkins jb. diabetes, fatmah a matough, siti b budin, zariyantey a hamid, nasar alwahaibi, jamaludin mohamed review | 17 93. shute ev. proposed study of vitamin e therapy. cmaj 1972; 106:1057. 94. bursell se, clermont ac, aiello lp, aiello lm, schlossman dk, feener ep, et al. high-dose vitamin e supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. diabetes care 1999; 22:1245. 95. ross wm, creighton mo, trevithick jr, stewartdehaan pj, sanwal m. modelling cortical cataractogenesis: vi. induction by glucose in vitro or in diabetic rats: prevention and reversal by glutathione. exp eye res 1983; 37:559–73. 96. paolisso g, amore a, giugliano d, ceriello a, varricchio m, onofrio f. pharmacologic doses of vitamin e improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. am j clin nutr 1993; 57:650. 97. ceriello a, giugliano d, quatraro a, russo pd, lefebvre pj. metabolic control may influence the increased superoxide generation in diabetic serum. diabet med 1991; 8:540–2. 98. cunningham jj, mearkle pl, brown rg. vitamin c: an aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus. j am coll nutr 1994; 13:344. 99. eriksson j, kohvakka a. magnesium and ascorbic acid supplementation in diabetes mellitus. ann nutr metab 1995; 39:217–23. 100. reaven pd, herold da, barnett j, edelman s. effects of vitamin e on susceptibility of low-density lipoprotein and low-density lipoprotein subfractions to oxidation and on protein glycation in niddm. diabetes care 1995; 18:807. 101. salonen jt, korpela h, salonen r, nyyssonen k, yli-kerttula s, yamamoto r, et al. autoantibody against oxidised ldl and progression of carotid atherosclerosis. lancet 1997; 339:883–7. 102. american diabetes association. nutrition recommendations and interventions for diabetes. diabetes care 2008; 31:s61–78. 103. maret g, traber ab, jan f, stevens ac. vitamins c and e: beneficial effects from a mechanistic perspective. free radic biol med 2011; 51:1000–13. 104. bjelakovic g, nikolova d, gluud ll, simonetti rg, gluud c. mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. jama 2007; 297:842–57. 105. deepak p vivekananthan dp, penn ms, sapp sk, hsu a, topol ej. use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. lancet 2003; 361:2017–23 106. gruppo italiano per lo studio della sopravvivenza nell’infarto miocardico (gissi). dietary supplementation with n-3 polyunsaturated fatty acids and vitamin e after myocardial infarction: results of the gissi-prevenzione trial. lancet 1999; 354:447–55. 107. yusuf s, dagenais g, pogue j, bosch j, sleight p. vitamin e supplementation and cardiovascular oxidative stress, and antioxidants: a review. j biochem molec toxicol 2003; 17:24–38. 81. kunisaki mse, bursell ac, clermont h, ishii lm, ballas mr, jirousek f, et al. vitamin e prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase c pathway. am j physiol endocrinol metab 1995; 269:239–46. 82. mohora m, greabu m, muscurel c, duţă c, totan a. the sources and the targets of oxidative stress in the etiology of diabetic complications. romanian j biophys 2007; 17:63–84. 83. obrosova ifl, greene d. early changes in lipid peroxidation and antioxidative defense in rat retina. eur j pharm 2000; 398:139–46. 84. hong jh, kim mj, park mr, kwang aj, lee is, byun bh, et al. effects of vitamin e on oxidative stress and membrane fluidity in brain of streptozotocininduced diabetic rats. clinic chimic acta 2004; 340:107–15. 85. coleman md, fernandes s, khanderia l. a preliminary evaluation of a novel method to monitor a triple antioxidant combination (vitamins e, c and [alpha]-lipoic acid) in diabetic volunteers using in vitro methaemoglobin formation. j environ toxicol pharmacol 2003; 14:69–75. 86. panjwani u, yadav dk, kumar a, singh sb, selvamurthy w. effect of vitamin c and e supplementation in modulating the peripheral nerve conduction following cold exposure in humans. int j biometeorol 2003; 48:103–7. 87. sivan e, reece ea, wu yk, homko cj, polansky m. dietary vitamin e prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. am j obstet gynecol 1996; 175:793–9. 88. chang tm, horal m, jain s, wang f, patel r, loeken mr. oxidant regulation of gene expression and neural tube development: insights gained from diabetic pregnancy on molecular causes of neural tube defects. diabetologia 2003; 46:538–45. 89. otero p, bonet b, herrera e, rabano a. development of atherosclerosis in the diabetic balb/c mice prevention with vitamin e administration. atheroscler 2005; 182:259–65. 90. hayek t, kaplan m, kerry r, aviram m. macrophage nadph oxidase activation, impaired cholesterol fluxes, and increased cholesterol biosynthesis in diabetic mice: a stimulatory role for d-glucose. atheroscler 2007; 195:277–86. 91. hamblin m, smith hm, hill mf. dietary supplementation with vitamin e ameliorates cardiac failure in type 1 diabetic cardiomyopathy by suppressing myocardial generation of 8-isoprostaglandin f2 [alpha] and oxidized glutathione. j card fail 2007; 13:884–92. 92. ozkan y, yilmaz ok, ihsan ao, yasemin e. effects of triple antioxidant combination (vitamin e, vitamin c and a-lipoic acid) with insulin on lipid and cholesterol levels and fatty acid composition of brain tissue in experimental diabetic and non-diabetic rats. cell biol int 2005; 29:754–60. the role of oxidative stress and antioxidants in diabetic complications 18 | squ medical journal, february 2012, volume 12, issue 1 events in high-risk patients. the heart outcomes prevention evaluation study investigators. n engl j med 2000; 342:154–60. 108. pruthi s, allison tg, hensrud dd. vitamin e supplementation in the prevention of coronary heart disease. mayo clin proc 2001; 76:1131-6. 109. kritharides l, stocker r. the use of antioxidant supplements in coronary heart disease. atheroscler 2002; 164:211–9. 110. lee im, cook n r, gaziano jm, gordon d, ridker pm, manson je, et al. vitamin e in the primary prevention of cardiovascular disease and cancer: the women’s health study: a randomized controlled trial. jama 2005; 294:56–65. 111. costacou t, zgibor jc, evans rw, tyurina yy, kagan ve, orchard tj. antioxidants and coronary artery disease among individuals with type 1 diabetes: findings from the pittsburgh epidemiology of diabetes complications study. j diabet complications 2006; 20:387–94. 112. milman u, blum s, shapira c, aronson d, miller-lotan r, anbinder y, et al. vitamin e supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial. arterioscler thromb vasc biol 2008; 28:341–7. 113. hodis hh, mack wj, dustin l, mahrer pr, azen sp, detrano r, et al. high-dose b vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial stroke 2009; 40:730–6. 114. shargorodsky m, debby o, matas z, zimlichman r. effect of long-term treatment with antioxidants (vitamin c, vitamin e, coenzyme q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors. nutr metab (lond) 2010; 7:55. 1department of dermatology, complejo hospitalario de granada, jaén, granada, spain; 2department of internal medicine, hospital santa ana, motril, granada, spain *corresponding author e-mail: ismenios@hotmail.com ضمور اجللد حبسب بازيين وبرييين ريكاردو رويز-فيالفريدي، دانيل �سان�سيز-كانو، لوي�ص �سلفادور-رودريقي�ص، كارلو�ص �سيونكا-باريلز atrophoderma of pasini and pierini *ricardo ruiz-villaverde,1 daniel sánchez-cano,2 luis salvador-rodriguez,1 carlos cuenca-barrales1 a 25-year-old man with no personal or family history of interest attended the out-patient clinic of the complejo hospitalario de granada, granada, spain, in 2017 with multiple, non-pruritic, atrophic, mildly indurated, brownish, erythematous patches on his back of one year’s duration [figure 1]. he denied any regular medication use or having had any previous conditions. there was no history of trauma preceding the appearance of the skin lesions. routine laboratory tests were within normal limits, including a complete blood cell count, urinalysis, thyroid profile, protein electrophoresis and general biochemistry, antinuclear/extractable nuclear antibody and rheumatoid factor tests. immunoglobulin m and g tests for borrelia burgdorferi were negative. a histopathological examination showed a normal epidermis with a slight mononuclear perivascular infiltrate in the papillary dermis and focal sclerosis with hyalinisation of the reticular dermis [figure 2]. narrowband ultraviolet b phototherapy was proposed as the first line of treatment; however, the patient refused to consent to the therapy. comment idiopathic atrophoderma of pasini and pierini (iapp) is a rare, exclusively cutaneous condition which occurs most frequently in female patients, with a peak incidence in the second and third decades of life.1 overall, fewer than 100 cases have been reported interesting medical image sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e373–374, epub. 10 oct 17 submitted 5 apr 17 revision req. 21 may 17; revision recd. 21 may 17 accepted 8 jun 17 doi: 10.18295/squmj.2017.17.03.024 figure 1: photograph of multiple round, pink-coloured, atrophic plaques on the back of a 25-year-old male patient. atrophoderma of pasini and pierini e374 | squ medical journal, august 2017, volume 17, issue 3 in the literature.2 the pathophysiology of this entity remains unknown and the role of borrelia burgdorferi infections remains controversial.2 some researchers believe that iapp should be included as a manifestation of the spectrum of localised scleroderma.3 some cases of familial iapp have been described; however, a genetic link has not yet been confirmed.2 from a clinical point of view, iapp lesions may present in various patterns (i.e. rounded, oval or circular) and may be single or multiple.3 the edges of the patches are usually well defined and multiple lesions, such as in the present case, have been described as having a ‘swiss cheese’ or ‘footprints in the snow’ appearance. the sites predominantly affected are the lower and upper extremities or the trunk and it is not unusual for the lesions to follow a zosteriform or blaschkoid pattern.3 the condition can cause pain, pruritus or even paresthesia. the pathological findings of iapp are variable. in many cases, no alterations can be observed in the epidermis or dermis.2,3 the most common finding is a thinning of the affected dermis and no quantitative or qualitative alterations have yet been reported on the appendages.3 collagen changes can include atrophy, sclerosis, fragmentation and hyalinisation.2 elastic fibre changes may be variable and reduction and fragmentation similar to that of anetoderma cases have been reported.4 the therapeutical approach to iapp includes the use of different medications such as antibiotics (i.e. penicillin and tetracyclines) and hydroxychloroquine (with good response in cases with associated lupus) as well as topical treatments such as calcineurin inhibitors (although with variable responses).5–7 treatment with a q-switched alexandrite laser has also been reported to result in the clinical improvement of hyperpigmented lesions.8 references 1. batista cm, lemos mo, franceschi le, basilio cb, reis cm. case for diagnosis. an bras dermatol 2014; 89:671–3. doi: 10.1590/abd1806-4841.20142977. 2. gonzález-morán a, martín-lópez r, ramos ml, román c, gonzález-asensio mp. [idiopathic atrophoderma of pasini and pierini: study of 4 cases]. actas dermosifiliogr 2005; 96:303–6. doi: 10.1016/s0001-7310(05)75059-6. 3. arif t, adil m, amin ss, ahmed m. atrophoderma of pasini and pierini in a blaschkoid pattern. j dtsch dermatol ges 2017; 15:663–4. doi: 10.1111/ddg.13198. 4. saleh z, abbas o, dahdah mj, kibbi ag, zaynoun s, ghosn s. atrophoderma of pasini and pierini: a clinical and histopathological study. j cutan pathol 2008; 35:1108–14. doi: 10.1111/j.1600-0560.2008.00986.x. 5. lohrer r, barran l, kellnar s, belohradsky bh. [pasini and pierini idiopathic and progressive atrophoderma in childhood]. monatsschr kinderheilkd 1986; 134:878–80. 6. carter jd, valeriano j, vasey fb. hydroxychloroquine as a treatment for atrophoderma of pasini and pierini. int j dermatol 2006; 45:1255–6. doi: 10.1111/j.1365-4632.2006.03021.x. 7. pope e, laxer rm. diagnosis and management of morphea and lichen sclerosus and atrophicus in children. pediatr clin north am 2014; 61:309–19. doi: 10.1016/j.pcl.2013.11.006. 8. arpey cj, patel ds, stone ms, qiang-shao j, moore kc. treatment of atrophoderma of pasini and pierini-associated hyperpigmentation with the q-switched alexandrite laser: a clinical, histologic, and ultrastructural appraisal. lasers surg med 2000; 27:206–12. doi: 10.1002/1096-9101(2000)27:3<206::aidlsm2>3.0.co;2-1. figure 2: haematoxylin and eosin stain at x4 magnification showing a normal epidermis with discrete thinning of the upper dermis (arrow) and mild hyalinisation and sclerosis on the reticular dermis (arrowhead). https://doi.org/10.1590/abd1806-4841.20142977 https://doi.org/10.1016/s0001-7310%2805%2975059-6 https://doi.org/10.1111/ddg.13198 https://doi.org/10.1111/j.1600-0560.2008.00986.x https://doi.org/10.1111/j.1365-4632.2006.03021.x https://doi.org/10.1016/j.pcl.2013.11.006 https://doi.org/10.1002/1096-9101%282000%2927:3%3c206::aid-lsm2%3e3.0.co%3b2-1 https://doi.org/10.1002/1096-9101%282000%2927:3%3c206::aid-lsm2%3e3.0.co%3b2-1 cannabis is the most widely used illicit drug in many developed societies. it is estimated in the usa that the population incidence rates of marijuana use from late childhood to adolescence increase from 1.30% to 16.29% from age 11 to 16 years, and then appear to plateau. a sharp increase is noted during ages 13–15 years.1 there is a paucity of statistics about the prevalence of cannabis use in oman; however, the government has recently established a new 50 bed psychiatric hospital specialised in the treatment of addiction. absolute numbers from 1994 indicate that 150 people were addicted to cannabis (hashish) and, in 2009, 19 people died of drug abuse.2 according to botanical classification, cannabis comes from family of cannabaceae and species of stiva, indica and ruleralis.3 the common names for cannabis are: marijuana, marihuana, potweed, grass and mary jane.3 there are multiple risks from using cannabis, e.g. decreased ability to concentrate, decreased motivation, balance problems, increased heart rate and blood pressure, damage to fertility and increased risk of serious psychiatric illness.4 behavioural problems were associated with early marijuana use specifically in those who started to use cannabis prior to 15 years of age.5 recent cannabinoid research discovered an endocannabinoid system with specific genes coding for cannabinoid receptors (cbrs).6 the availability of these endocannabinoids in breast milk can affect the development of the newborn baby.6 substance abuse includes the abuse of legal drugs as well as the use of illegal drugs. a caregiver's self-use and abuse of alcohol, cannabis (marijuana), squ med j, november 2011, vol. 1, iss. 4, pp. 511-514, epub. 25th oct 11 submitted 21st mar 11 revision req. 13th jun 11, revision recd. 2nd jul 11 accepted 14th sep 11 1oman medical specialty board, muscat, oman, and academic fellowship program, university of toronto, canada; 2leslie dan facul ty of pharmacy, university of toronto, canada. *corresponding author email: shidhanitutu@gmail.com تعرض طفلة ُعمانية للحشيش )القّنب( تقرير ألول حالة من ُعمان ثريا ال�ضيداين وفينيتا اأرورا امللخ�ص: هذا تقرير حلالة م�ؤكدة تبني تعر�ص طفلة ُعمانية للح�صي�ص، وهي تعاين اأي�صا من تاأخر يف النم�. ميكن اأن ي�ؤدي تعر�ص الأطفال للح�صي�ص اإىل الكثري من التداعيات، على �صبيل املثال، ال�صتخدام املزمن ميكن اأن ي�ؤدي اإىل تاأخر يف النم�، وال�صل�ك ال�صاذ، وفرط الن�صاط، يف حني اأن هناك خماطر من ح�ص�ل غيب�بة يف حالة التعر�ص احلاد. من املهم بالن�صبة لالأطباء النظر يف تعاطي املخدرات ب��صفها الت�صخي�ص التفريقي لعرو�ص مماثلة عند الأطفال املر�صى، حيث املالحظ اأن يك�ن الأطفال عر�صة خلطر التعر�ص للح�صي�ص اإذا كان ال�الدان/مقدم� الرعاية يعان�ن من الإدمان عليه. مفتاح الكلمات: تعاطي احل�ضي�س، اإ�ضاءة معاملة الطفل، منو الطفل، ا�ضطرابات تاأخر النمو، تقرير حالة، ُعمان. abstract: we report a confirmed case of cannabis exposure in an omani female child with developmental delay. cannabis exposure in children can lead to many consequences; for example, chronic use can result in developmental delay, abnormal behaviour, and hyperactivity while there is a risk of coma with acute exposure. it is important for clinicians to consider substance abuse as a differential diagnosis for similar presentations in paediatric patients, noting that children are at risk of cannabis exposure if their parents/caregivers are cannabis users. keywords: cannabis abuse; child abuse; child development; developmental delay disorders; case report; oman. cannabis exposure in an omani child first case report from oman *thuraya a. al-shidhani1 and vinita arora2 case report cannabis exposure in an omani child first case report from oman 512 | squ medical journal, november 2011, volume 11, issue 4 heroin, cocaine, methamphetamine, and other drugs expose children to risk in multiple ways. members of the medical community need to understand these risks, and be aware of the consequences on children in the care of adult abusers. the misuse of drug substances by children may have far-reaching consequences, and may impact family unit functions. many substance abusers are polysubstance users leading to a compounded negative effect which may be difficult to measure. often, other interrelated social factors, such as untreated mental illness, alcoholism, trauma history and domestic violence also affect these families.7 there are several paediatric case reports found in the literature regarding cannabis abuse/exposure leading to effects on cognitive function/behavior and coma, but none specifically on cannabis exposure in children in oman.8,9 this case report describes illicit cannabis exposure in an omani female child with developmental delay. case report an omani female child, aged 2 years and 10 months, was brought by her parents to the accident and emergency department of sultan qaboos university hospital, muscat, oman. the patient presented with drowsiness, abnormal eye movements, was lethargic and had been unable to sit or stand for the previous 4 hours. the history was reluctantly provided, so the physician on call documented the unconfirmed information given by the parents, noting that it was somewhat inconsistent in nature. the father made little eye contact with medical personnel, and seemed uncomfortable. his verbal and non-verbal expressions and cues to his wife indicated that she was not to offer any information. apparently, the patient had ingested an unknown blackish substance mixed with sand, followed by vomiting, further lethargy and drowsiness, with nystagmus. the parents sought medical assistance approximately 4 hours after the onset of symptoms. of note, the child’s chart indicated that she had been a full term baby. however, there had been a delay in gross motor skill and language development noted to have begun at approximately 2 years of age. the parents indicated that the patient was a hyperactive child who occasionally ate her own hair. the physician noted that the family as a unit presented with psychosocial and alcoholism/substance issues, and loss of income. it was noted that two older siblings were “normal” as indicated by the mother of the patient. on initial examination, the following parameters were significant: lethargy, drowsiness, glasgow coma scale of 12/15, tachycardia, nystagmus, and pupils dilated (4 mm), but reactive to light. a gastric lavage was performed, producing gastric aspirate mixed with food particles. during this procedure, the child vomited a blackish sticky substance, with subsequent clinical improvement over the ensuing hours. the samples were sent for analysis, and she was hydrated intravenously. investigations revealed microcytic hypochromic anaemia while all other investigations were normal. the patient rested through the night, and continued to improve. the subsequent plan was to involve social work and perform an hiv test, but the patient’s father discharged her against medical advice. an incident report indicating suspected child abuse was filed. five days later, tetracannabinoid substance was confirmed in the child’s vomit. discussion children exposed to maternal addiction have increased rates of cognitive, socio-emotional, and behavioural problems.10 this case report illustrates an omani female child who was exposed to cannabis. the child was noted to have developmental delay and hyperactivity to which prenatal/chronic cannabis exposure may have been a contributing factor. a prospective investigation showed that there is a significant association between substance use disorder in parents and cannabis use disorder and behavioural disinhibition in their sons.11 the generation r study showed that multiple demographic, emotional and social characteristics were associated with maternal cannabis use. these characteristics should be considered when investigating offspring exposed to cannabis in utero as they may be important in mother-child interaction and child development.12 there is indirect evidence of post-pregnancy resumption of substance use. pregnant and parenting women, regardless of race or ethnicity, benefit from prevention efforts focusing on cessation rather than temporary abstinence from substance use.13 thuraya a. al-shidhani and vinita arora case report | 513 this patient demonstrated speech delays and hyperactivity, which were also found in one case report in which a californian teacher of a 7 year-old boy, who had been exposed prenatal to cannabis, noted that he demonstrated frequent fidgety behaviour, hyperactivity, and trouble focusing on learning tasks. noted by family to be a "sweet and happy" child at home, his parents still expressed concern about his repetitive behaviours, fear of leaving the house, and insistence on a certain order of his toys. he also displayed "meltdowns" and tantrums at non-compliance with his wishes. a receptive and expressive language disorder had previously been diagnosed at 4 years of age, and been followed by speech therapy and a social skills language group programme.14 survival analysis in another study revealed that aggressive, co-morbid, and inattentive/hyperactive schoolchildren had a significantly earlier onset of drinking, drunkenness, marijuana and overall illicit drug use compared to healthy schoolchildren.15 the conclusions of this study were as follows: three levels of behavioural risk of substance abuse exist: 1) the highest level has trajectories of increased aggressive and inattentive/hyperactive problems throughout childhood; 2) the next level involves only an increased inattentive/hyperactive behavioural trajectory, and 3) the lowest level involves those with neither type of problem.15 children with both inattention/hyperactivity and aggression have the greatest need for childhood intervention to prevent substance abuse in adolescence.11 emerging evidence from human studies and animal research demonstrates that an early onset of cannabis consumption might have lasting consequences on cognition; may increase the risk of neuropsychiatric disorders, promote further illegal drug use, and increase the likelihood of cannabis dependence. these findings suggest that young people represent a highly vulnerable cannabis consumer group, carrying a higher risk than adult consumers of suffering adverse consequences from cannabinoid exposure.16 there are four independent factors in early or middle childhood that predict early initiation of use of substances and subsequent substance use disorders by early adulthood: 1) disrupted families or drug-using parents 2) problem behaviours; 3) poor parental monitoring, and 4) poor parental supervision.17 the father of this patient had no consistent employment, possibly partly due to cannabis abuse. high levels of cannabis abuse are related to poorer educational outcomes, lower income, greater welfare dependence and unemployment, and lower relationship and life satisfaction.18 conclusion it is important for clinicians to consider substance abuse as a differential diagnosis for presentations similar to this case in other paediatric patients. emergency medicine clinicians should be able to detect suspicious behaviour as described above, supported by inconsistent information/history given by family members in order to provide appropriate immediate treatment, and also initiate follow-up care for the patient and possibly also for the family. a c k n o w l e d g e m e n t s the authors gratefully acknowledge the great support and motivation to publish this case of the following physicians: dr. hashim javad and dr. alexander p chacko of the department of child health, sultan qaboos university hospital, muscat, oman, and dr kamlesh bhargava of the department of family medicine and public health, sultan qaboos university hospital and program director for family medicine at the oman medical specialty board references 1. tang z, orwin rg. marijuana initiation among american youth and its risks as dynamic processes: prospective findings from a national longitudinal study. subst use misuse 2009; 44:195–211. 2. oman drug addiction. narcinon international. from: www.narconon.org/drug-information/omandrug-addiction.html. accessed: jun 2011. 3. the vaults of erowid. cannabis. from: www.erowid. org/plants/cannabis/cannabis.shtml accessed sep 2011. 4. bbc health. what is cannabis? from: www. bbc.co.uk/health/emotional_health/addictions/ cannabis.shtml accessed: sep 2011. 5. falls bj, wish ed, garnier lm, caldeira km, o'grady ke, vincent kb, et al. the association between early conduct problems and early marijuana use in college students. j child adolesc subst abuse 2011; 20:221–36. cannabis exposure in an omani child first case report from oman 514 | squ medical journal, november 2011, volume 11, issue 4 6. onaivi es. commentary: functional neuronal cb2 cannabinoid receptors in the cns. curr neuropharmacol 2011; 9:205–8. 7. wells k. substance abuse and child maltreatment. pediatr clin north am 2009; 56:345–62. 8. bonkowsky jl, sarco d, pomeroy sl. ataxia and shaking in a 2-year-old girl: acute marijuana intoxication presenting as seizure. pediatr emerg care 2005; 21:527–8. 9. shukla pc, moore ub. marijuana-induced transient global amnesia. south med j 2004; 97:782–4. 10. simmons la, havens jr, whiting jb, holz jl, bada h. illicit drug use among women with children in the united states: 2002-2003. ann epidemiol 2009; 19:187–93. 11. ridenour ta, tarter re, reynolds m, mezzich a, kirisci l, vanyukov m. neurobehavior disinhibition, parental substance use disorder, neighborhood quality and development of cannabis use disorder in boys. drug alcohol depend 2009; 102:71–7. 12. el marroun h, tiemeier h, jaddoe vw, hofman a, mackenbach jp, steegers ea, et al. demographic, emotional and social determinants of cannabis use in early pregnancy: the generation r study. drug alcohol depend 2008; 98:218–26. 13. muhuri pk, gfroerer jc. substance use among women: associations with pregnancy, parenting, and race/ethnicity. matern child health j 2009; 13:376– 85. 14. stein mt, drahota a, chavira da. ian: a 7-year old with prenatal drug exposure and early exposure to family violence. j dev behav pediatr 2008; 29:512–5. 15. jester jm, nigg jt, buu a, puttler li, glass jm, heitzeg mm, et al. trajectories of childhood aggression and inattention/hyperactivity: differential effects on substance abuse in adolescence. j am acad child adolesc psychiatry 2008; 47:1158–65. 16. schneider m. puberty as a highly vulnerable developmental period for the consequences of cannabis exposure. addict biol 2008; 13:253–63. 17. hayatbakhsh mr, mamun aa, najman jm, o'callaghan mj, bor w, alati r. early childhood predictors of early substance use and substance use disorders: prospective study. aust n z j psychiatry 2008; 42:720–31. 18. fergusson dm, boden jm. cannabis use and later life outcomes. in: addiction, wiley online library. from:www.onlinelibrary.wiley.com/doi/10.1111/ j . 1 3 6 0 0 4 4 3 . 2 0 0 8 . 0 2 2 2 1 . x / ab s t r a c t . acce s s e d : mar 2011. squ med j, february 2012, vol. 12, iss. 1, pp. 109-112, epub. 7th feb 12. submitted 8th jun 11 revision req. 30th oct 11, revision recd. 4th dec 11 accepted 14th dec 11 department of medicine royal hospital, muscat, oman corresponding author e-mail: enhsa@hotmail.com َتّجر وَتَصّلب القصبة الرُّغاَمية تقرير حالة ومراجعة أدبيات نا�رص البو�سعيدي، دوللي دوليا، ذو الفقار حبيب اهلل ّلب الق�سبة الرُّغاَمية من احلالت النادرة احلميدة التي ُت�سيب الق�سبة الّرغامية، وتتميز بوجود ُعَقيدات عظمية امللخ�ص: ُيعّد حَتّجر وَت�سَ غ�رصوفية حتت الغ�ساء املخاطي للق�سبة الّرغامّية، دون اجلدار اخللفي للق�سبة الرغامية. ُنَقّدم هنا اأول حالة ُمَوّثقة يف ُعمان ل�ساب ُعماين عمره 25 �سنة، كان ي�سكو من �ُسعال متكّرر م�سحوبا بالبلغم طوال العامني ال�سابقني. مَتّ ت�سخي�س احلالة عن طريق الَتْفري�َسٌة امَلْقَطِعيٌَّة ٌة امُلَحو�َسَبة، ونتائج تنظري الق�سبات وفح�س مر�سيات الأن�سجة. امِلْحَوِريَّ مفتاح الكلمات: َت�سّيق الق�سبة الرغامية ، حتّجر وت�سّلب الق�سبة الرغامية، َت�سّيق الرُّغاَمى، َتَعّظم، الق�سبة الرغامية، تقرير حالة، ُعمان. abstract: tracheobronchopathia osteochondroplastica (tpo) is a rare, benign condition involving the trachea. tpo is characterised by osteocartilaginous nodules developing within the submuscosa of the trachea, sparing the posterior wall. we present the first documented case of tpo in oman in a 25 year-old omani male who presented with a recurrent, productive cough from which he had suffered throughout the previous two years. diagnosis was made by characteristic computed tomography scan, bronchoscopic findings, and a histopathological examination. keywords: tracheobronchopathia; tracheobronchopathia osteoplastica; tracheal stenosis; tracheal disease, ossification; tracheobronchial; case report; oman. tracheobronchopathia osteochondroplastica case report and literature review *nasser al-busaidi, dolly dhuliya, zulfikar habibullah case report tr a c h e o b r o n c h o p a t h i a osteochondroplastica (tpo) is a rare, benign condition involving the trachea, and possibly major bronchi. tpo was first described in detail by wilks in 1857.1 since then, cases have been reported sporadically throughout the world. the disease is characterised by diffuse nodularities, or polyps, consisting of cartilaginous and/or osseous metaplastic tissue involving the anterior and lateral walls of the tracheobronchial tree and sparing the pars membranacea. the nodules are 1 to 3 mm in diameter and may cause narrowing and rigidity of the trachea and bronchi if the nodules larger in diameters which rarely hapen.2 the majority of people with tpo remain asymptomatic throughout their lives unless severe airway stenosis develops, in which case patients may experience symptoms such as dyspnoea, hoarseness, persistent and often productive cough, haemoptysis, and recurrent or slowly resolving pneumonia.3,4 hence, this condition is usually discovered incidentally during bronchoscopy, or at autopsy or during difficult intubation,2,5 it seldom requires any treatment. here we report possibly the first case of tpo in oman. case report a 25 year-old omani male who presented with a recurrent productive cough of two years duration was examined and further investigated for the underlying cause of unexplained recurrent chest infections. other than fever during acute episodes of chest infection, he did not have haemoptysis, dyspnoea or weight loss. he was not known to have any chronic illness and had never been admitted to hospital. the patient had no history of smoking, recent travel or usage of illicit drugs. he is a tracheobronchopathia osteochondroplastica case report and literature review 110 | squ medical journal, february 2012, volume 12, issue 1 radiographer by profession and his family history was unremarkable. on clinical examination, his general condition was good, with no clubbing or lymphadenopathy, and a systemic examination was unremarkable. all routine blood tests were normal. sputum microscopy and culture were negative for acid fast bacilli on three consecutive visits and the reaction to a tuberculin test was 10mm. a chest radiograph was normal; however, a plain computed tomography (ct) scan of the chest showed diffuse irregular thickenings of the tracheal wall, with the proximal bronchi, and the infraglottic part of the larynx as indicated by arrows in figures 1a to 1c. three subsequent ct scans showed no new changes and the nodularities persisted. upon simultaneous bronchoscopy multiple whitish nodular lesions were seen in the tracheobronchial tree. a biopsy sample was taken from the right main bronchus and a histopathological examination revealed squamous metaplasia with hyperkeratosis as indicated by the arrows in figure 2. hence, after excluding malignancy, interstitial lung disease, and infection as the cause of the lesions, a presumptive diagnosis of endobronchial sarcoidosis was made and the patient was treated with prednisolone. a year later, another bronchoscopy was required due to recurrent chest infection with klebsiella and pseudomonas bacterial infections. at this second bronchoscopy, the lesions were still present; however, they had become softer and more fragile compared to the period before the start of systemic steroid treatment. hence, in addition to prednisolone, gentamicin and ciprofloxacin were added to treat the pneumonia. at a repeat bronchoscopy a few months later, the lesions were still present, with widespread non-uniform thickening of the whole anterolateral tracheal wall along with the proximal bronchi and infraglottic area, sparing the posterior wall. in addition, small calcified papillary projections had also arisen from the lesions, which appeared to be submucosal in origin. a biopsy was taken and a histopathological examination showed cartilaginous tissue, squamous metaplasia, and hyperkeratosis, all features consistent with tpo. therefore, prednisolone treatment was stopped and no further treatment offered. figure 1: sagittal section of trachea with arrows showing thickening and calcified lesions in the anterior wall of the trachea. figures 1b & 1c: axial sections of the chest with arrows showing thickening and calcified lesions in the anterior wall of the trachea. nasser al-busaidi, dolly dhuliya, zulfikar habibullah case report | 111 discussion tpo is an uncommon abnormality of the cartilaginous tracheal wall.6 many cases of tpo have been reported since wilks first identified it in 1857. in a study of 8,760 patients above 6 years of age who underwent bronchoscopy, jabbardarjani et al. encountered 10 cases of tpo with a median age at diagnosis of 51 years, with a male predominance.7 tpo is characterised by osteocartilaginous nodules developing within the submucosa of the trachea and/or bronchi, sparing the posterior wall, and having a similar presentation to amyloidosis. its aetiology is unknown, although, theories suggest chronic infection, congenital anomaly, chemical or mechanical irritation, degenerative or metabolic abnormalities, and genetic predisposition as possible factors contributing to a person developing tpo.8 the majority of patients remain asymptomatic unless they develop severe airway obstruction. in a retrospective review of 18 cases, patients had mainly experienced symptoms such as persistent and often productive cough, haemoptysis, dyspnoea and wheezing.9 chest x-rays are usually normal, or may show signs of chest infections. pulmonary function tests may also be normal or trace an obstructive type of flow-volume loop.3 thus, diagnosis is mainly based on a ct scan showing irregular thickening and/or calcified nodularities protruding into the tracheobronchial lumen, and bronchoscopic findings of the same described as having a ‘rock garden’ or ‘cobblestone’ appearance.8 further confirmation of the diagnosis is done by histopathologic examination of the biopsied tissue of the tracheal or bronchial walls at the site of the nodules. the tissue usually shows an osteocartilageous change, composed of a normal epithelium, but cartilage and bone tissue with intervening bone marrow.8 a magnetic resonance imaging (mri) examination of the chest may show diffuse thickening of the trachea and bronchi with intermediate signal intensity, and punctiform low signal intensity suggesting calcifications and no enhancement.10 differential diagnosis of these nodularities includes endobronchial sarcoidosis, amyloidosis, papilomatosis, tuberculosis, bronchial carcinoma, and tracheobronchial calcinosis. it is important to be aware of this condition as a differential diagnosis of neoplasms to avoid unnecessary chemotherapy or surgery.11 treatment is seldom required except in patients with severe airway obstruction presenting with debilitating symptoms. in this case, bronchoscopic resectioning of the mass is the treatment of choice.12 other treatment modalities include endobronchial nd:yag laser photoevaporation (lpe), coring of the lesions with the tip of a rigid bronchoscope, and endobronchial stent placement.7 conclusion tpo is a rare, benign condition characterised by diffuse nodularities consisting of cartilaginous or osseous metaplastic tissue which involves the trachea with or without the major bronchi. the condition is often asymptomatic unless the nodules are large enough to obstruct the airway. diagnosis is usually based on a ct scan and bronchoscopic biopsy reports. treatment is usually symptomatic except in the case of severe obstructions, when a surgical approach proves beneficial. a diagnosis of tpo should be considered in patients who have an irregular thickening and/ or calcified nodularities protruding into the tracheobronchial lumen, or who have similar bronchoscopic findings. a histopathological examination should always be carried out in order to distinguish tpo from other diseases that present figure 2: histopatholgy of tracheal biopsy with arrows showing the squamous metaplasia with hyperkeratosis. tracheobronchopathia osteochondroplastica case report and literature review 112 | squ medical journal, february 2012, volume 12, issue 1 similar types of radiological or bronchoscopic examination results. a c k n o w l e d g e m e n t s we acknowledge with gratitude the help of dr. atheel kamona, senior consultant radiologist, and dr. sosama thomas, senior consultant histologist, of the royal hospital, for their contribution in the ct report and histology report, respectively. references 1. wilks s. ossific deposit on the larynx, trachea and bronchi. trans pathol soc lond 1857; 8:88. 2. williams sm, jones et. general case of the day. radiographics 1997; 17:797–9. 3. bergeron d, cormier y, desmeules m. tracheobronchopathia osteochondroplastica. j am rev respir dis 1976; 114:803–6. 4. zack jr. tracheobronchopathia osteochondroplastica: report of three cases j comput assist tomogr; 2002; 26:33–6. 5. tadjeddein a, khorgami z, akhlaghi h. tracheobronchopathia osteoplastica: cause of difficult tracheal intubation. j ann thorac surg; 2006; 81:1480–2. 6. restrepo s, pandit m, villamil ma, rojas ic, perez jm gascue a. tracheobronchopathia osteochondroplastica: helical ct findings in 4 cases. j thoracic imaging, 2004; 19:112. 7. jabbardarjani hr, radpey b, kharabian s, masjedi mr. tracheobronchopathia osteochondroplastica: presentation of ten cases and review of the literature. lung 2008; 186:293–7. 8. doshi h, thankachen r, philip ma, kurien s, shukla v, korula rj. tracheobronchopathia osteochondroplastica presenting as an isolated nodule in the right upper lobe bronchus with upper lobe collapse. j thorac cardiovasc surg; 2005; 130:901–2. 9. vilkman s, keistinen t. tracheobronchopathia osteochondroplastica. report of a young man with severe disease and retrospective review of 18 cases. j respiration; 1995; 62:151–4. 10. hantous-zannad s, sebaï l, zidi a, ben khelil j, mestiri i, besbes m, et al. tracheobronchopathia osteochondroplastica presenting as a respiratory insufficiency: diagnosis by bronchoscopy and mri. eur j radiol 2003; 45:113–6. 11. meyer cn. tracheobronchopathia osteochondroplastica; j respir med; 1997; 91:499–502. 12. van nierop ma, wagenaar ss, van den bosch jm, westermann cj. tracheobronchopathia osteochondroplastica. report of four cases. eur j respir dis; 1983; 64:129–33. department of 1epidemiology & biostatistics, college of public health & health informatics and 4college of nursing, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia; 2king abdullah international medical research center, riyadh, saudi arabia; 3college of medicine, king saud university, riyadh, saudi arabia; 5college of medicine, university of hail, hail, saudi arabia *corresponding author e-mail: ahmeda5@vcu.edu االكتئاب والقلق والتوتر بني مرضى األمراض اجللدية السعوديني دراسة مستعرضة اأنور اأحمد، عبدالعزيز حممد الدهم�س، قمراء البقمي، يزيد فار�س التبيناوي abstract: objectives: this study aimed to determine the prevalence of depression, anxiety and stress among saudi arabian dermatology patients and to assess associations with sociodemographic and clinical characteristics. methods: this cross-sectional study was conducted among 300 consecutive dermatology patients visiting king abdulaziz medical city in riyadh, saudi arabia, in august 2015. the arabic version of the depression, anxiety and stress scale was used to screen for symptoms of depression, anxiety and stress. quality of life (qol) was assessed using the dermatology life quality index. results: a total of 254 dermatology patients participated in the study (response rate: 84.7%). the prevalence of depression, anxiety and stress was 12.6%, 22.1% and 7.5%, respectively. the presence of at least one of these negative emotional states was noted among 24.4% of the cohort (95% confidence interval: 19.3–30.2%). depression was significantly higher among subjects who lacked family support (26.5% versus 10.7%; p = 0.006) while anxiety was less common among patients who engaged in physical exercise (14.5% versus 29.4%; p = 0.005). according to the multivariate logistic regression analysis, poor qol and a lack of family support were significant predictors of a negative emotional state. conclusion: almost a quarter of the studied saudi arabian dermatology patients were found to suffer from at least one negative emotional state. a lack of family support and poor qol were the primary factors associated with a negative emotional state. interventional studies are needed to examine the effects of social and family support on psychological conditions among saudi arabian dermatology patients. keywords: depression; anxiety; psychological stress; quality of life; social support; dermatology; saudi arabia. امللخ�ص: اأهداف: هدفت هذه الدرا�سة اإىل حتديد مدى انت�سار الكتئاب والقلق والتوتر لدى مر�سى الأمرا�س اجللدية ال�سعوديني، وتقييم بالأمرا�س م�ساب 300 على امل�ستعر�سة الدرا�سة هذه اأجريت : منهجية وال�رسيرية. والدميوغرافية الجتماعية باخل�سائ�س عالقتها اجللدية على التوايل ملدينة امللك عبد العزيز الطبية يف الريا�س، اململكة العربية ال�سعودية، يف �سهر اأغ�سط�س 2015. وقد ا�ستخدمت الن�سخة با�ستخدام )qol( احلياة نوعية تقييم مت والتوتر. والقلق الكتئاب اأعرا�س عن للك�سف والإجهاد والقلق الكتئاب مقيا�س من العربية موؤ�رس جودة احلياة لالأمرا�س اجللدية. نتائج: �سارك يف الدرا�سة ما جمموعه 254 مري�سا بالأمرا�س اجللدية )معدل ال�ستجابة: 84.7%(. بلغت ن�سبة انت�سار الكتئاب والقلق والتوتر يف العينة %12.6، %22.1 و %7.5 على التوايل. ولوحظ وجود واحد على الأقل منها بني 24.4% من العينة قيد الدرا�سة )فا�سل الثقة %95: املدى %30.2–19.3(. وجد اأن معدل انت�سار الكتئاب اأعلى بكثري بني األ�سخا�س الذين يفتقرون اإىل الدعم الأ�رسي )%26.5 مقابل %10.7؛ p = 0.006( بينما كان القلق اأقل �سيوعا يف املر�سى الذين �ساركوا يف ممار�سة الريا�سة البدنية )%14.5 مقابل p = 0.005 ،29.4%(. وفقا لتحليل النحدار اللوج�ستي متعدد املتغريات، كان �سوء نوعية احلياة )qol( وعدم وجود الدعم الأ�رسي هي اأقوي العوامل التتي تتنباأ بوجود حالة عاطفية �سلبية. خامتة: عانى ما يقرب من ربع مر�سى الأمرا�س اجللدية ال�سعوديني قيد الدرا�سة من حالة عاطفية �سلبية واحدة على الأقل. كان عدم وجود دعم الأ�رسة و �سوء نوعية احلياة )qol( هي اكرث العوامل الأ�سا�سية املرتبطة بوجود حالة عاطفية �سلبية. هناك حاجة لدرا�سات تدخلية لدرا�سة اآثار الدعم الجتماعي والأ�رسي على حت�سني الظروف النف�سية لدى مر�سى الأمرا�س اجللدية ال�سعوديني. كلمات مفتاحية: الكاآبة؛ القلق؛ الإجهاد النف�سي؛ جودة احلياة؛ الدعم الأجتماعي؛ الأمرا�س اجللدية؛ العربية ال�سعودية. depression, anxiety and stress among saudi arabian dermatology patients cross-sectional study *anwar e. ahmed,1,2 abdulaziz m. al-dahmash,3 qamra t. al-boqami,4 yazeed f. al-tebainawi5 clinical & basic research advances in knowledge little is known regarding the prevalence of depression, anxiety and stress among saudi arabian dermatology patients. the findings of this study indicated that 24.4% of saudi arabian dermatology patients had at least one of these negative emotional states. in this study, the primary factors associated with a negative emotional state were a lack of family support and poor quality of life (qol). application to patient care as almost a quarter of the studied saudi arabian dermatology patients were found to suffer from at least one negative emotional state, dermatology patients should be routinely screened for psychological symptoms, a lack of social/family support and poor qol. appropriate psychiatric counselling should then be provided as part of the dermatological treatment. sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 217–223, epub. 15 may 16 submitted 19 oct 15 revision req. 17 dec 15; revision recd. 20 dec 15 accepted 7 jan 16 doi: 10.18295/squmj.2016.16.02.013 depression, anxiety and stress among saudi arabian dermatology patients cross-sectional study e218 | squ medical journal, may 2016, volume 16, issue 2 psychiatric or psychological factors play a role in approximately 30% of dermato-logy disorders; stress, for example, can affect or exacerbate chronic skin diseases.1–3 an international multicentre cross-sectional study across 13 european countries found that 10.1% and 17.2% of dermatology patients suffered from depression and anxiety, respect ively.4 when compared to healthy controls or the general population, dermatology patients are more likely to suffer from anxiety and depression; in a norwegian study, 13% versus 3.7% and 5.8% versus 0.9% of dermatology patients versus controls suffered from anxiety and depression, respectively.5 another study found the overall prevalence of depression and anxiety in patients with atopic dermatitis to be 15% and 12%, respectively; in terms of gender, these negative emotional states were more prevalent in females.6 another study explored the factors associated with psychiatric morbidity among 1,389 dermatological outpatients; the overall prevalence of psychiatric morbidity was 20.6%, although female subjects with lesions on the face or hands had a greater prevalence over males.7 other psychiatric disorders, such as suici dal ideation, also appear to be more common in dermatology patients in comparison to the general public.8,9 anxiety levels and quality of life (qol) have likewise been shown to be affected by dermatological disorders, with atopic dermatitis patients suffering from increased anxiety and a poorer qol when compared to healthy individuals.10,11 although psychological symptoms are common among dermatology patients, few relevant studies on this subject have been conducted among arab populations. at the khartoum hospital in sudan, mufaddel et al. found that rates of depression and anxiety were higher among dermatology outpatients with acne, vitiligo, eczema and psoriasis compared with healthy controls.12 at the king khalid university hospital in riyadh, saudi arabia, 29% and 14% of dermatology patients had anxiety and depression, respectively.13 another study examined arab vitiligo patients’ beliefs and perceptions of their condition; 54% and 57% of the subjects reported feeling depressed or anxious, respectively.14 in the qassim region of saudi arabia, 54.5% of vitiligo patients were found to suffer from depression.15 as there has been little research conducted on this topic among arab dermatology patients, this study aimed to assess depression, anxiety and stress among a sample of saudi arabian dermatology patients and to investigate associations with sociodemographic and clinical characteristics. methods this cross-sectional survey was conducted among 300 consecutive outpatients visiting the dermatology outpatient clinic at king abdulaziz medical city (kamc) in riyadh, saudi arabia, in august 2015. only teenagers (14–17 years old) and adults (≥18 years old) were included in the study. patients who could not read or write arabic were excluded. based on the literature, the estimated prevalence of psychiatric morbidities among dermatology outpatients was set at 20.6%.7 in order to determine the prevalence among the study cohort with a precision of 5% and a 95% confidence interval (ci), the required sample size was 252 subjects. consequently, 300 kamc dermatological patients were included in the study. demographic and clinical data (including age, gender, marital status, education level, employment status, income, physical activity level, smoker status, family support and the presence of specific dermatological conditions, obesity or hypertension) were collected from all participants. depression, anxiety and stress were self-assessed by participants using an arabic version of the 21-item depression, anxiety and stress scale (dass-21).16,17 each item had four possible responses (never, sometimes, often and almost always) represented by scores of 0, 1, 2 and 3, respectively.16,17 participants were considered to have a negative emotional state if they suffered from at least one symptom of depression, anxiety or stress according to their questionnaire responses. quality of life (qol) was assessed using the validated arabic version of the 10-item dermatology life quality index (dlqi).18,19 the dlqi is a self-administered tool which evaluates the impact of dermatological diseases on qol.18,19 items were scored on a four-point scale (range: 0–3); a score of <1 was considered to indicate an adequate qol.18,19 data were analysed using the statistical package for the social sciences (spss), version 22 (ibm corp., chicago, illinois, usa). demographic and clinical characteristics were reported descriptively. prevalence rates of depression, anxiety and stress, as well as the prevalence rate of at least one of these negative emotional states, were reported with 95% cis. a chi-squared test was used to analyse associations between categorical variables and negative emotional states. a p value of ≤0.050 was considered statistically significant and indicated an association through a bivariate analysis. a multivariate logistic regression model was used to study the associations between clinical or sociodemographic variables and negative anwar e. ahmed, abdulaziz m. al-dahmash, qamra t. al-boqami and yazeed f. al-tebainawi clinical and basic research | e219 emotional states. adjusted odds ratios (aors) were used to measure the strength of the associations between risk factors and negative emotional states. this study was approved by the institutional review board at the king abdullah international medical research center (#rss15/047). results a total of 254 subjects participated in the study (response rate: 84.7%). of these, 59.8% were female, 43.4% were employed and 40.0% were married. only 17.7% of the subjects were teenagers while 82.3% were adults. approximately half of the subjects did not engage in regular physical activity (50.2%), 22.5% were obese, 11.7% were hypertensive and 8.5% were smokers. more than half of the subjects (51.3%) had a university degree. a total of 23.6% reported a lack of family support. the majority of the subjects had acne vulgaris (29.5%), followed by atopic dermatitis (22.3%), vitiligo (20.7%) and psoriasis (6.4%); the remainder had other diseases such as alopecia areata, lichen planus or warts. prevalence rates of depression, anxiety and stress were 12.6% (95% ci: 8.8–17.3%), 22.1% (95% ci: 17.1–27.7%) and 7.5% (95% ci: 4.6–11.4%), respectively. the prevalence of at least one of these negative emotional states was 24.4% (95% ci: 19.3–30.2%). table 1 presents rates of depression, anxiety, stress or at least one of these negative emotional states in relation to demographic and clinical data. depression was significantly more common among subjects who reported a lack of family support in comparison to those reporting sufficient family support (26.5% versus 10.7%; p = 0.006). those with poor qol were also significantly more likely to be depressed compared to those with adequate qol (15.6% versus 1.9%; p = 0.007). anxiety was significantly less common among subjects who engaged in regular physical exercise compared to those who did not (14.4% versus 29.4%; p = 0.005) and among non-obese compared to obese subjects (18.7% versus 33.3%; p = 0.037). participants with sufficient family support were significantly less likely to be stressed than those without family support (6.3% versus 16.3%; p = 0.041), while those with poor qol were significantly more likely to be stressed than those with adequate qol (9.6% versus 0.0%; p = 0.016). subjects engaging in regular physical activity compared to those who did not regularly exercise (16.8% versus 31.8%; p = 0.006) and those with family support compared to those without (22.6% versus 38.8%; p = 0.025) were significantly less likely to have at least one negative emotional state. no significant associations were found between negative emotional states and other demographic or clinical characteristics. after controlling for clinical and sociodemographic variables, the multivariate logistic regression model revealed that only poor qol was significantly associated with the presence of at least one negative emotional state. the odds of suffering from at least one negative emotional state were 3.5 times higher in subjects with poor qol compared to those with an adequate qol (aor: 3.5, 95% ci: 1.1–11.5; p = 0.039). sufficient family support was negatively associated with the risk of at least one negative emotional state (aor: 0.3, 95% ci: 0.1–0.8; p = 0.013). although the effect of gender was not significant, the presence of at least one negative emotional state occurred 2.9 times more frequently in females than in males (aor: 2.9, 95% ci: 1.0–8.4; p = 0.057) [table 2]. discussion prevalence rates of depression, anxiety and stress among saudi arabian dermatological patients in the current study were similar to a previous study investigating psychological disorders among dermatology patients.1 however, other local studies have reported much higher rates of depression and anxiety in dermatology patients.13–15 one possible reason for this discrepancy in prevalence rates may be the use of different assessment tools. for example, the study conducted in the qassim region used the beck depression scale, while the current study used the dass-21.15 mina et al. reported differences in levels of anxiety and depression between males and females.6 although gender differences were not significant in the current study, negative emotional states nevertheless occurred 2.9 times more frequently among females. certain studies have indicated a link between the type of dermatological disorder and the presence of depression, anxiety or stress. an international multicentre observational cross-sectional study found that patients with psoriasis, atopic dermatitis, hand eczema and leg ulcers had the highest prevalence of depression and anxiety among dermatology patients.4 another study also found a relationship between negative emotional states and types of skin disease; patients suffering from hair loss had the highest combined scores of anxiety and depression while those with psoriasis had the highest depression scores.13 sharma et al. found evidence of depression in 23.3% of psoriasis patients and 10% in vitiligo patients.20 a recent review of the literature reported the prevalence of depression in psoriasis patients depression, anxiety and stress among saudi arabian dermatology patients cross-sectional study e220 | squ medical journal, may 2016, volume 16, issue 2 table 1: prevalence of depression, anxiety and stress* according to sociodemographic and clinical characteristics among saudi arabian dermatology patients (n = 254) characteristic† overall, n (%) negative emotional state depression (n = 32) anxiety (n = 56) stress (n = 19) at least one (n = 62) n (%) p value n (%) p value n (%) p value n (%) p value gender 0.272 0.166 0.770 0.131 male 102 (40.2) 10 (9.8) 18 (17.7) 7 (6.9) 19 (18.6) female 152 (59.8) 22 (14.5) 38 (25.0) 12 (7.9) 43 (28.3) age 0.188 0.249 0.999 0.256 teenager 44 (17.7) 3 (6.8) 7 (15.9) 3 (6.8) 8 (18.2) adult 205 (82.3) 29 (14.2) 49 (23.9) 16 (7.8) 54 (26.3) marital status 0.757 0.421 0.845 0.952 unmarried 150 (60.0) 20 (13.3) 31 (20.7) 11 (7.3) 37 (24.7) married 100 (40.0) 12 (12.0) 25 (25.0) 8 (8.0) 25 (25.0) education level 0.324 0.326 0.405 0.706 high school or less 116 (48.7) 13 (11.2) 30 (25.9) 11 (9.5) 31 (26.7) university 122 (51.3) 19 (15.6) 25 (20.5) 8 (6.6) 30 (24.6) employment status 0.938 0.163 0.729 0.340 employed 106 (43.4) 13 (12.3) 28 (26.4) 9 (8.5) 30 (28.3) unemployed 64 (26.2) 9 (14.0) 16 (25.0) 5 (7.8) 17 (26.6) student 74 (30.3) 10 (13.5) 11 (14.9) 4 (5.4) 14 (18.9) income in sr 0.384 0.364 0.802 0.379 none 83 (35.6) 10 (12.1) 16 (19.3) 6 (7.2) 18 (21.7) <10,000 114 (48.9) 19 (16.7) 31 (27.2) 10 (8.8) 34 (29.8) ≥10,000 36 (15.5) 3 (8.3) 7 (19.4) 2 (5.6) 8 (22.2) regular physical activity 0.362 0.005‡ 0.840 0.006‡ yes 125 (49.8) 13 (10.4) 18 (14.4) 9 (7.2) 21 (16.8) no 126 (50.2) 18 (14.3) 37 (29.4) 10 (7.9) 40 (31.8) smoker 0.999 0.425 0.999 0.236 yes 21 (8.5) 2 (9.5) 3 (14.3) 1 (4.8) 3 (14.3) no 227 (91.5) 30 (13.2) 53 (23.4) 18 (7.9) 59 (26.0) obese 0.526 0.037† 0.768 0.143 yes 45 (22.5) 5 (11.1) 15 (33.3) 3 (6.7) 15 (33.3) no 155 (77.5) 23 (14.8) 29 (18.7) 14 (9.0) 35 (22.6) hypertensive 0.392 0.484 0.999 0.722 yes 29 (11.7) 2 (6.9) 8 (27.6) 2 (6.9) 8 (27.6) no 220 (88.4) 30 (13.6) 48 (21.8) 17 (7.7) 54 (24.6) family support 0.006‡ 0.086 0.041‡ 0.025‡ yes 159 (76.4) 17 (10.7) 33 (20.8) 10 (6.3) 36 (22.6) no 49 (23.6) 13 (26.5) 16 (32.7) 8 (16.3) 19 (38.8) anwar e. ahmed, abdulaziz m. al-dahmash, qamra t. al-boqami and yazeed f. al-tebainawi clinical and basic research | e221 type of skin disease 0.516 0.124 0.189 psoriasis 16 (6.4) 3 (18.8) 3 (18.8) 1 (6.3) 3 (18.8) vitiligo 52 (20.7) 5 (9.6) 7 (13.5) 4 (7.7) 8 (15.4) atopic dermatitis 56 (22.3) 6 (10.7) 12 (21.4) 4 (7.1) 14 (25.0) acne vulgaris 74 (29.5) 13 (17.6) 24 (32.4) 9 (12.2) 25 (33.8) other 53 (21.1) 5 (9.4) 10 (18.9) 1 (1.9) 12 (22.6) qol§ 0.007‡ 0.067 0.016‡ 0.062 poor 199 (78.7) 31 (15.6) 49 (24.6) 19 (9.6) 54 (27.1) adequate 54 (21.3) 1 (1.9) 7 (13.0) 0 (0.0) 8 (14.8) sr = saudi arabian riyal; qol = quality of life. *depression, anxiety and stress were self-assessed by participants using the arabic version of the depression, anxiety and stress scale.16,17 †some data missing from certain variables as the participants did not respond to all questionnaire items. ‡significant at α = 0.05 using chi-squared or fisher’s exact tests. §qol was self-assessed by participants using the arabic version of the dermatology life quality index.18,19 table 2: sociodemographic and clinical factors influencing negative emotional states* among saudi arabian dermatology patients (n = 254) factor reference b se wald p value aor 95% ci lower upper female male 1.0 0.5 3.6 0.057 2.9 1.0 8.4 adult teenager 0.6 1.0 0.4 0.526 1.9 0.3 13.7 married unmarried -0.4 0.5 0.5 0.470 0.7 0.3 1.9 university-educated high school education or less -0.8 0.6 1.9 0.169 0.4 0.1 1.4 employed student 0.6 0.7 1.0 0.326 1.9 0.5 7.0 unemployed student -0.3 0.8 0.2 0.688 0.7 0.2 3.3 income <10,000 sr no income 0.3 0.6 0.3 0.585 1.4 0.4 4.5 income ≥10,000 sr no income 0.3 0.9 0.1 0.770 1.3 0.2 7.5 physical activity no physical activity -0.3 0.4 0.4 0.526 0.8 0.3 1.7 smoker non-smoker 0.2 0.9 0.1 0.820 1.2 0.2 6.9 obese not obese 0.4 0.5 0.7 0.398 1.6 0.6 4.3 hypertensive not hypertensive -0.7 0.8 0.8 0.369 0.5 0.1 2.2 family support no family support -1.2 0.5 6.1 0.013† 0.3 0.1 0.8 vitiligo psoriasis -0.6 1.0 0.4 0.505 0.5 0.1 3.4 atopic dermatitis psoriasis -1.1 1.0 1.2 0.270 0.3 0.1 2.3 acne vulgaris psoriasis -0.2 0.9 0.0 0.863 0.9 0.2 5.0 other skin disease psoriasis -0.8 1.0 0.7 0.406 0.5 0.1 3.0 poor qol‡ adequate qol‡ 1.3 0.6 4.3 0.039† 3.5 1.1 11.5 constant -1.6 1.3 1.4 0.229 0.2 se = standard error; aor = adjusted odds ratio; ci = confidence interval; sr = saudi arabian riyal; qol = quality of life. *depression, anxiety and stress were self-assessed by participants using the arabic version of the depression, anxiety and stress scale.16,17 †significant as a risk factor for a negative emotional state at α = 0.05. ‡qol was self-assessed by participants using the arabic version of the dermatology life quality index.18,19 depression, anxiety and stress among saudi arabian dermatology patients cross-sectional study e222 | squ medical journal, may 2016, volume 16, issue 2 to be 10–62%.21 in another study, depression (67% versus 12%) and anxiety (45% versus 18%) rates were higher in psoriasis patients than a control group.11 kurd et al. noted that the risk of being diagnosed with depression, anxiety or suicidal ideation was 39% higher in patients with psoriasis compared to healthy controls.22 however, no relationship was seen in the current study between negative emotional states and the type of dermatological disease. the current study also assessed whether saudi arabian dermatology patients received sufficient family support. lower levels of depression and stress were found among subjects with family support compared to those who had none. another factor which contributed significantly to depression and stress among the studied saudi arabian dermatological patients was poor qol. considering these findings, the researchers recommend screening dermatology patients for psychological morbidities and including appropriate psychiatric counselling and qol evaluations as part of standardised dermatological treatment and management. in addition, future intervention studies are necessary to examine the effects of social and family support on the frequency of depression, anxiety and stress among saudi arabian dermatology patients. there are several limitations to the current study. first, the findings are based on a cross-sectional assessment in which associations do not indicate causation. second, the study relies on self-reported responses to the dass-21 questionnaire and not on clinical diagnoses. third, a healthy control group was not included in this study to determine the overall rate of negative emotional states in the general saudi arabian population. conclusion almost a quarter of the studied saudi arabian dermatology patients were found to suffer from at least one negative emotional state, including depression, anxiety or stress. a lack of family support and poor qol were significantly associated with a negative emotional state among the subjects. as such, further research is needed to investigate the effects of qol and social and family support on psychological morbidities among saudi arabian dermatology patients. screening for psychological symptoms should be carried out among all dermatology patients and appropriate psychiatric counselling should be provided as required. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. gupta ma, gupta ak. psychiatric and psychological comorbidity in patients with dermatologic disorders: epidemiology and management. am j clin dermatol 2003; 4:833–42. doi: 10.2165/00128071-200304120-00003. 2. jafferany m. psychodermatology: a guide to understanding common psychocutaneous disorders. prim care companion j clin psychiatry 2007; 9:203–13. doi: 10.4088/pcc.v09n0306. 3. osman ot, mufaddel a, almugaddam f, augusterfer ef. the psychiatric aspects of skin disorders. expert rev dermatol 2011; 6:195–209. doi: 10.1586/edm.11.10. 4. dalgard fj, gieler u, tomas-aragones l, lien l, poot f, jemec gb, et al. the psychological burden of skin diseases: a crosssectional multicenter study among dermatological out-patients in 13 european countries. j invest dermatol 2015; 135:984–91. doi: 10.1038/jid.2014.530. 5. balieva f, lien l, kupfer j, halvorsen ja, dalgard f. are common skin diseases among norwegian dermatological outpatients associated with psychological problems compared with controls? an observational study. acta derm venereol 2016; 96:227–31. doi: 10.2340/00015555-2200. 6. mina s, jabeen m, singh s, verma r. gender differences in depression and anxiety among atopic dermatitis patients. indian j dermatol 2015; 60:211. doi: 10.4103/0019-5154.152564. 7. picardi a, abeni d, renzi c, braga m, puddu p, pasquini p. increased psychiatric morbidity in female outpatients with skin lesions on visible parts of the body. acta derm venereol 2001; 81:410–4. doi: 10.1080/000155501317208345. 8. hughes je, barraclough bm, hamblin lg, white je. psychiatric symptoms in dermatology patients. br j psychiatry 1983; 143:51–4. doi: 10.1192/bjp.143.1.51. 9. dieris-hirche j, gieler u, kupfer jp, milch we. [suicidal ideation, anxiety and depression in adult patients with atopic dermatitis]. hautarzt 2009; 60:641–6. doi: 10.1007/s00105-0091744-y. 10. linnet j, jemec gb. an assessment of anxiety and dermatology life quality in patients with atopic dermatitis. br j dermatol 1999; 140:268–72. doi: 10.1046/j.1365-2133.1999.02661.x. 11. golpour m, hosseini sh, khademloo m, ghasemi m, ebadi a, koohkan f, et al. depression and anxiety disorders among patients with psoriasis: a hospital-based casecontrol study. dermatol res pract 2012; 2012:381905. doi: 10. 1155/2012/381905. 12. mufaddel a, abdelgani ae. psychiatric comorbidity in patients with psoriasis, vitiligo, acne, eczema and group of patients with miscellaneous dermatological diagnoses. open j psychiatr 2014; 4:168–75. doi: 10.4236/ojpsych.2014.43022. 13. alshahwan ma. the prevalence of anxiety and depression in arab dermatology patients. j cutan med surg 2015; 19:297–303. doi: 10.2310/7750.2014.14110. 14. alghamdi km. beliefs and perceptions of arab vitiligo patients regarding their condition. int j dermatol 2010; 49:1141–5. doi: 10.1111/j.1365-4632.2010.04514.x. 15. al-harbi m. prevalence of depression in vitiligo patients. skinmed 2013; 11:327–30. 16. antony mm, bieling pj, cox bj, enns mw, swinson rp. psychometric properties of the 42-item and 21-item versions of the depression anxiety stress scales in clinical groups and a community sample. psychol assess 1998; 10:176–81. doi: 10.1037/1040-3590.10.2.176. 17. taouk m, lovibond pf, laube r. psychometric properties of an arabic version of the depression anxiety stress scales (dass). from: www2.psy.unsw.edu.au/dass/arabic/arabic%20 dass%20report.doc accessed: dec 2015. http://dx.doi.org/10.2165/00128071-200304120-00003 http://dx.doi.org/10.4088/pcc.v09n0306 http://dx.doi.org/10.1586/edm.11.10 http://dx.doi.org/10.1038/jid.2014.530 http://dx.doi.org/10.2340/00015555-2200 http://dx.doi.org/10.4103/0019-5154.152564 http://dx.doi.org/10.1080/000155501317208345 http://dx.doi.org/10.1192/bjp.143.1.51 http://dx.doi.org/10.1007/s00105-009-1744-y http://dx.doi.org/10.1007/s00105-009-1744-y http://dx.doi.org/10.1046/j.1365-2133.1999.02661.x http://dx.doi.org/10.1155/2012/381905 http://dx.doi.org/10.1155/2012/381905 http://dx.doi.org/10.4236/ojpsych.2014.43022 http://dx.doi.org/10.2310/7750.2014.14110 http://dx.doi.org/10.1111/j.1365-4632.2010.04514.x http://dx.doi.org/10.1037/1040-3590.10.2.176 anwar e. ahmed, abdulaziz m. al-dahmash, qamra t. al-boqami and yazeed f. al-tebainawi clinical and basic research | e223 18. finlay ay, khan gk. dermatology life quality index (dlqi): a simple practical measure for routine clinical use. clin exp dermatol 1994; 19:210–16. doi: 10.1111/j.1365-2230.1994. tb01167.x. 19. khoudri i, lamchahab fz, ismaili n, senouci k, hassam b, abouqal r. measuring quality of life in patients with psoriasis using the arabic version for morocco of the dermatology life quality index. int j dermatol 2013; 52:795–802. doi: 10.1111/j.1365-4632.2011.05450.x. 20. sharma n, koranne rv, singh rk. psychiatric morbidity in psoriasis and vitiligo: a comparative study. j dermatol 2001; 28:419–23. doi: 10.1111/j.1346-8138.2001.tb00003.x. 21. chamoun a, goudetsidis l, poot f, bourdeaud’hui f, titeca g. [psoriasis and depression]. rev med brux 2015; 36:23–8. 22. kurd sk, troxel ab, crits-christoph p, gelfand jm. the risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. arch dermatol 2010; 146:891–5. doi: 10.1001/archdermatol.2010.186. http://dx.doi.org/10.1111/j.1365-2230.1994.tb01167.x http://dx.doi.org/10.1111/j.1365-2230.1994.tb01167.x http://dx.doi.org/10.1111/j.1365-4632.2011.05450.x http://dx.doi.org/10.1111/j.1346-8138.2001.tb00003.x http://dx.doi.org/10.1001/archdermatol.2010.186 department of radiology, royal hospital, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com نوع جديد من ازدواجية الشريان التاجي النازل االمامي النوع احلادي عشر را�شد العمريي، فايزة الكندية، �شقر الطائي abstract: a dual left anterior descending (lad) artery is a rare congenital anomaly which is classified into different types based on the origin, course and termination of the short and long lad arteries. to date, 10 variants of dual lad artery anomalies have been described. we report a 44-year-old woman who was referred to the department of radiology, royal hospital, muscat, oman, in 2017. coronary computed tomography angiography revealed a dual lad artery anomaly in which the short and long lad arteries shared a common ostium with the right coronary artery from the right coronary sinus. to the best of the authors’ knowledge, this type of variant has not been prev iously reported in the literature. keywords: coronary angiography; congenital abnormality; coronary vessel anomalies; case report; oman. امللخ�ص: تعترب ازدواجية ال�رسيان التاحي النازل المامي من احلالت الوراثية النادرة والتي ت�شنف ا اىل عدة انواع اعتمادا على اأ�شل وم�شار ونهاية كل من ال�رسيان التاجي النازل المامي الق�شري وال�رسيان التاجي النازل المامي الطويل. حتى الن توجد هناك ع�رسة اأنواع خمتلفة من ازدواجية ال�رسيان التاجي النازل المامي. نعر�ص هنا حالة امراأة تبلغ من العمر 44 عاما مت حتويلها اىل ق�شم ال�شعة وجود عن ك�شفت والتي املقطعية الأ�شعة با�شتخدام التاجية ال�رسايني لت�شوير 2017 عام يف عمان، م�شقط، ال�شلطاين، امل�شت�شفى يف النازل التاجي وال�رسيان الق�شري المامي النازل التاجي ال�رسيان من كل بكون متيز والذي المامي النازل التاجي ال�رسيان ازدواجية المامي الطويل ي�شرتكان يف املن�شاأ من اجليب التاجي الأمين. هذا النوع من ازدواجية ال�رسيان التاجي النازل المامي مل ي�شبق وان مت ت�شنيفه من قبل. الكلمات املفتاحية: ت�شوير الوعية التاجية؛ ت�شوهات خلقية؛ ت�شوهات ال�رسيان التاجية؛ تقرير عن حالة؛ عمان. a new variant of dual left anterior descending artery anomaly type xi *rashid s. al-umairi, faiza a. al-kindi, saqar a. al-tai online case report sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e386–388, epub. 19 dec 18 submitted 24 jan 18 revision req. 5 mar 18; revision recd. 19 mar 18 accepted 5 apr 18 doi: 10.18295/squmj.2018.18.03.021 a dual left anterior descending (lad) artery is a rare coronary anomaly with an estimated incidence of 0.03–0.2% among patients undergoing routine coronary catheterisation.1 it is def ined as the presence of both short and long lad arteries.2 awareness of the different types of dual lad artery anomalies is critical when planning percutaneous and surgical reperfusion strategies.2–4 this report describes a unique case which, to the best of the authors’ knowledge, does not fall into any of the 10 categories of dual lad artery anomalies currently reported in the literature.5,6 case report a 44-year-old woman was referred to the department of radiology, royal hospital, muscat, oman, in 2017 for coronary computed tomography angiography (ccta). she had a history of chest pain, shortness of breath upon exertion and palpitations. however, a physical examination, electrocardiogram and cardiac enzyme testing were normal. therefore, 384-slice ccta was performed at 2 × 192 kw. this revealed a dual lad artery anomaly in which the short and long lad arteries shared a common ostium with the right coronary artery from the right cor onary sinus [figure 1a]. the short lad artery followed a course caudal to the pulmonary artery and through the interventricular septum to the left, before emerging within the proximal anterior interventricular groove where it terminated as the first diagonal branch. the long lad artery coursed anterior to the pulmonary artery to the left and then entered the distal interventricular groove [figure 1b]. the left circumflex artery originated from the right coronary sinus then followed a retroaortic course before reaching the left atrioventricular groove [figures 1c and d]. there was no evidence of coronary artery atherosclerotic disease and no other congenital anomalies were detected. as there were no signs of any stenosis of signif icant haemodynamic severity, the decision was made to keep the patient under regular observation and follow-up. rashid s. al-umairi, faiza a. al-kindi and saqar a. al-tai online case report | e387 discussion normally, the lad artery originates from the left main coronary artery and then courses within the anterior interventricular groove towards the apex where it gives rise to diagonal and septal branches. in contrast, a dual lad artery is a rare congenital anomaly characterised by the presence of short and long lad arteries.1,2 it is traditionally classified into four different types based on the origin, course and termination of the short and long lad arteries.2,5,7 however, ccta has since enabled the recognition of other variants. to date, 10 dual lad artery variants have been described [table 1].5,6 the short lad artery typically originates from the main stem of the lad artery and terminates in the proximal interventricular groove. the long lad artery takes a more variable course around the short segment, returning to the interventricular groove distally.2,6,8,9 in previously described cases of dual lad artery anomalies, the short lad artery originates from either figure 1: coronary computed tomography angiography (ccta) sequence of a 44-year-old woman with a dual left anterior descending (lad) artery anomaly. a: axial max imum-intensity projected ccta image showing the anom alous origin of the long and short lad arteries from the right coronary sinus with a prepulmonic course for the long lad artery and transeptal course for the short lad artery. b: three-dimensional volume-rendered ccta image showing the course of the long lad artery anterior to the right ventricular outflow track and entering the distal anterior interventricular groove. c & d: three dimensional volume-rendered ccta images showing the common origin of the long lad artery, short lad artery, right coronary artery and left circumflex artery from the right coronary sinus. lad = left anterior descending artery; rca = right coronary artery; lcx = left circumflex artery. table 1: types of dual left anterior descending artery variants5,6 type short lad artery long lad artery origin course origin course i lmca proximal aivg proximal lad artery epicardial course on the lv side of the proximal aivg and then re-enters the distal aivg ii lmca proximal aivg proximal lad artery epicardial course on the rv side of the proximal aivg and then re-enters the distal aivg iii lmca proximal aivg proximal lad artery intramyocardial course in the proximal septum followed by an epicardial course in the distal aivg iv lmca proximal aivg rca epicardial course anterior to the rvot and then enters the distal aivg v lcs proximal aivg rcs intramyocardial course within the septal crest and then emerges in the distal aivg vi lmca proximal aivg rca course between the rvot and aortic root and then enters the mid or distal aivg vii lad artery proximal aivg lad artery epicardial course on the lv side of the proximal aivg and then re-enters the distal aivg* new variant of type vii lmca proximal aivg rcs course on the lv side of the proximal aivg and the re-enters the distal aivg* viii lmca proximal aivg mid-rca epicardial course on the inferior wall of the rv and then turns around the apex and reaches the distal aivg† ix lad mid aivg lad artery epicardial course on the lv side of the proximal aivg and then re-enters the distal aivg and terminates before reaching the apex‡ x lmca proximal aivg rcs epicardial course anterior to the rvot and then enters the distal aivg current case (xi) rcs intramyocardial course within the proximal septum and then emerges in the proximal aivg rcs epicardial course anterior to the rvot and then enters the distal aivg lad = left anterior descending ; lmca = left main coronary artery; aivg = anterior interventricular groove; lv = left ventricular; rv = right ventricular; rca = right coronary artery; rvot = right ventricle out-flow tract; lcs = left coronary sinus; rcs = right coronary sinus. *the lmca originates from the rcs and has an interarterial malignant course. †the lmca originates from the rcs and has a retroaortic course. ‡the posterior descending coronary artery extends distal to the aivg. a new variant of dual left anterior descending artery anomaly type xi e388 | squ medical journal, august 2018, volume 18, issue 3 the main stem of the lad artery or the left main coronary artery.1–10 however, the current case was unique in that the short lad originated from the right coronary sinus and then coursed within the proximal septum before emerging in the proximal interventricular groove. the long lad artery originated from the right coronary sinus and then coursed anterior to the main pulmonary artery before entering the distal interventricular groove. to the best of the authors’ knowledge, this type of lad artery anomaly has not been previously reported in the literature and may be considered a new variant (type xi). during conventional coronary angiography, the entire coronary vasculature might not be visible, partic ularly in cases wherein the coronary arteries have anom alous origins. awareness of potential dual lad artery variants is therefore crucial when interpreting cardiac imaging as well as in the planning of percut aneous and surgical reperfusion strategies. for example, among patients with variants in which the long lad artery originates from the right coronary sinus, only the short lad artery can be visualised via angiography which means it may be mistaken for a mid-lad artery occlusion.6 furthermore, among patients requiring a coronary bypass graft, a lack of awareness may result in a bypass to only one artery, thus leading to deficient revascularisation if both the short and long lad arteries are stenosed. in addition, awareness of the various dual lad artery variants can prevent vascular injuries during a median sternotomy in cases wherein the long lad artery courses anterior to the pulmonary artery behind the sternum.6,10 conclusion a dual lad artery is a rare congenital anomaly and awareness of the various types of dual lad artery variants is critical. the current case report describes a new variant of dual lad artery anomaly, provisionally designated type xi, in which the short lad artery orig inated from the right coronary sinus and then coursed within the proximal septum before emerging in the prox imal interventricular groove, while the long lad coursed anterior to the pulmonary artery to the left and then entered the distal interventricular groove. references 1. peixoto oliveira md, de melo ph, esteves filho a, kajita lj, ribeiro ee, lemos pa. type 4 dual left anterior descending artery: a very rare coronary anomaly circulation. case rep cardiol 2015; 2015:580543. doi: 10.1155/2015/580543. 2. spindola-franco h, grose r, solomon n. dual left anterior descending coronary artery: angiographic description of imp ortant variants and surgical implications. am heart j 1983; 105:445–55. doi: 10.1016/0002-8703(83)90363-0. 3. moulton km, kraushaar g, fladeland da. an unusual case of dual left anterior descending artery with coronary computed tomographic angiographic correlation. case rep radiol 2013; 2013:348624. doi: 10.1155/2013/348624. 4. manchanda a, qureshi a, brofferio a, go d, shirani j. novel variant of dual left anterior descending coronary artery. j cardio vasc comput tomogr 2010; 4:139–41. doi: 10.1016/j.jcct.2009. 12.007. 5. bozlar u, uğurel mş, sarı s, akgün v, örs f, taşar m. prevalence of dual left anterior descending artery variations in ct angiography. diagn interv radiol 2015; 21:34–41. doi: 10.5152/ dir.2014.14275. 6. celik t, bozlar u, ozturk c, balta s, verim s, demir m, et al. a new anomaly of the left anterior descending artery: type x dual lad. indian heart j 2015; 67:s14–17. doi: 10.1016/j.ihj.20 15.09.004. 7. baydar o, oktay v, coskun u, yildiz a, gurmen t. a rare case of type iv dual left anterior descending coronary artery. j clin diagn res 2016; 10:od15–16. doi: 10.7860/jcdr/2016/17489. 7424. 8. vohra a, narula h. dual left anterior descending artery with anomalous origin of long lad from pulmonary artery: rare coronary anomaly detected on computed tomography coronary angiography. indian j radiol imaging 2016; 26:201–5. doi: 10.4103/0971-3026.184423. 9. nasrin s, cader fa, haq mm, shafi mj. type iv dual left anterior descending coronary artery: a case report. bmc res notes 2017; 10:659. doi: 10.1186/s13104-017-2984-z. 10. agarwal pp, kazerooni ea. dual left anterior descending coronary artery: ct findings. ajr am j roentgenol 2008; 191:1698–701. doi: 10.2214/ajr.08.1193. https://doi.org/10.1155/2015/580543 https://doi.org/10.1016/0002-8703%2883%2990363-0 https://doi.org/10.1155/2013/348624 https://doi.org/10.1016/j.jcct.2009.12.007 https://doi.org/10.1016/j.jcct.2009.12.007 https://doi.org/10.5152/dir.2014.14275 https://doi.org/10.5152/dir.2014.14275 https://doi.org/10.1016/j.ihj.2015.09.004 https://doi.org/10.1016/j.ihj.2015.09.004 https://doi.org/10.7860/jcdr/2016/17489.7424 https://doi.org/10.7860/jcdr/2016/17489.7424 https://doi.org/10.4103/0971-3026.184423 https://doi.org/10.1186/s13104-017-2984-z https://doi.org/10.2214/ajr.08.1193 1department of orthodontics, m. s. ramaiah university of applied sciences, bangalore, india; 2department of orthodontics, military dental centre, ministry of defence, muscat, oman; 3department of orthodontics, oman dental college, muscat, oman *corresponding author’s e-mail: pacchi77@yahoo.com املعايري الطبيعية لقياس الرأس لدى السكان العمانيني العرب البالغني بار�شنثا �شيافامورتي جوفيناكويف، اإبراهيم البو�شعيدي، في�شوابورنا �شنجوتوفان abstract: objectives: this study aimed to establish cephalometric norms for an omani population of arab descent and to compare these with established cephalometric values for caucasians. methods: this cross-sectional study was conducted at the military dental centre and oman dental college in muscat, oman, between may 2014 and october 2016. a total of 150 omani patients between 20–29 years old seeking orthodontic treatment were included. all participants had a symmetrical face, class i molar and canine relationships, proper intercuspation, a normal overjet/overbite (<3 mm) and mild spacing/crowding of the teeth (≤3 mm). lateral cephalography was performed in centric occlusion with the lips relaxed and the head in a natural position. cephalometric measurements were then compared with eastman standard norms. results: the omani subjects were found to have a slightly retrusive maxilla, an increased angle between the maxillary and mandibular planes and shorter facial heights in comparison to the eastman standard norms. furthermore, incisor relations were edge-to-edge in nature and the interincisal angle was reduced, suggesting that the omani subjects had more proclined incisors. in addition, the lips were more protrusive and the nasolabial angle was more obtuse. conclusion: in the omani sample, increased proclination of the incisors was observed in comparison to eastman standard norms. as such, slightly more proclined incisors should be considered acceptable and natural among omani patients of arab descent. the cephalometric findings of this study may be helpful in the diagnosis and treatment planning of orthodontic problems among omanis of arab descent. keywords: cephalometry, standards; population characteristics; ethnic groups; arabs; orthodontics; oman. الراأ�ض قيا�شات قيم مع ومقارنتها العرب العمانيني ال�شكان لدى الراأ�ض لقيا�ض معايري و�شع اإىل الدرا�شة هذه هدفت الهدف: امللخ�ص: املعتمدة لدى القوقازيني. الطريقة: اأجريت هذه الدرا�شة املقطعية العر�شية يف مركز طب الأ�شنان الع�شكري وكلية عمان لطب الأ�شنان يف م�شقط، عمان، بني عامي 2014 و 2016. مت اختيار جمموعة من 150 مري�شا عمانيا بني �شن 29–20 عاما كانوا يبحثون عن عالج لتقومي الأ�شنان. كان لدى جميع امل�شاركني وجه متماثل، اإطباق الرحى والأنياب من الدرجة الأوىل، ت�شابك حدبات متكافئ، قيا�ض طبيعي لرتاكب الع�شة العمودي والأفقي )اأقل من 3 ملم(، وكان التباعد/الر�ش�ض ال�شني معتدل بني الأ�شنان )3≤ ملم(. مت اإجراء اأ�شعة الراأ�ض اجلانبية يف و�شع اإنطباق مركزي لالأ�شنان مع ارتخاء ال�شفاه والراأ�ض يف و�شعها الطبيعي. مت بعد ذلك مقارنة قيا�شات الراأ�ض مع معايري اإي�شتمان القيا�شية. النتائج: وجد اأن املجموعة العمانية لديها تراجع ب�شيط يف الفك العلوي، زيادة الزاوية بني م�شتوى الفك العلوي وال�شفلي وق�رض يف ارتفاعات الوجه مقارنة مبعايري اإي�شتمان القيا�شية. كما كان طابع العالقة بني القواطع من احلافة اىل احلافة، وزاوية الإنق�شام بينهم منخف�شة العالقات بني القواطع ذات طبيعة من احلافة اإىل احلافة، وانخفا�ض يف زاوية النق�شام بني القواطع، مما يوحي باأن املجموعة العمانية لديهم قواطع اأكرث اإنحراف اإىل الأمام. بالإ�شافة اإىل ذلك، كانت ال�شفتني اأكرث بروزا وكانت الزاوية الأنفية ال�شفوية اأكرث انفراجا. اعتبار ينبغي النحو، هذا على القيا�شية. ال�رضقية املعايري مع باملقارنة القواطع تداخل تزايد لوحظ العمانية، املجموعة يف اخلال�صة: القواطع املنحرفة لالأمام ب�شكل طفيف مقبولة وطبيعية بني املر�شى العمانيني العرب. قد تكون نتائج قيا�شات الراأ�ض يف هذه الدرا�شة مفيدة يف ت�شخي�ض وعالج م�شاكل تقومي الأ�شنان بني العمانيني العرب. الكلمات املفتاحية: قيا�شات الراأ�ض؛ معايري؛ خ�شائ�ض ال�شكان؛ فئات اأثنية؛ عرب؛ تقومي الأ�شنان؛ عمان. cephalometric norms in an omani adult population of arab descent *prashantha s. govinakovi,1 ibrahim al-busaidi,2 viswapurna senguttuvan3 clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e182–189, epub. 9 sep 18 submitted 12 dec 17 revision req. 21 jan 18; revision recd. 22 feb 18 accepted 15 mar 18 doi: 10.18295/squmj.2018.18.02.010 because cephalometric norms vary widely between different ethnic groups.1–3 while minor differences between an individual’s cephalometric values and those of the respective norms is routine, major differences may indicate a structural deviation. knowledge of the the diagnosis of potential orthodontic anomalies necessitates the comparison of an individual patient’s cephalometric values with those of established norms.1 however, the patient’s ethnic background needs to be taken into consideration advances in knowledge to the best of the authors’ knowledge, this study is the first to establish cephalometric norms for an omani population of arab descent. application to patient care establishing cephalometric norms for omanis of arab descent could help dentists to detect any orthodontic deviations for diagnostic or treatment purposes. prashantha s. govinakovi, ibrahim al-busaidi and viswapurna senguttuvan clinical and basic research | e183 nature of the mandible and bimaxillary dento-alveolar protrusion, with males having a steeper mn angle.2 among saudi arabian students with acceptable profiles and occlusion, a craniofacial analysis indicated the students had a slightly protrusive maxilla, with a tendency towards class ii facial patterns, high mn angles and procumbent maxillary and mandibular incisors in comparison to caucasian subjects.8 in oman, the native population has a unique culture and lineage, with a history of considerable ethnic diversity.9 although previous studies have attempted to set normative standards in the arabian gulf region, none have so far focused on omanis of arab descent.2–4,7,8 therefore, the present study aimed to establish cephalometric standards for an omani population of arab descent and compare these with eastman standard norms.10–27 methods this cross-sectional study was conducted at the military dental centre and oman dental college in muscat, oman, from may 2014 to october 2016. a sample of 150 omani patients aged 20–29 years old seeking orthodontic treatment at these two institutions were selected. all subjects were of arab descent from both parents’ side, without any history of interracial marriages occurring for at least two generations. each subject underwent a clinical examination by two orthodontists to ensure they had a symmetrical face (in which a line drawn from the forehead to the chin would yield measurements conforming to the mathematical concept of the golden ratio), class i molar and canine relations with proper intercuspation and an acceptable overjet and overbite (<3 mm), mild spacing/crowding (≤3 mm), no transverse discrepancies and no detectable lateral and sagittal way in which an individual’s cephalometric values differ from accepted norms will allow clinicians to conclude whether the anomaly is dento-alveolar or skeletal in origin and undertake corrective measures if necessary.4 in a comparison of cephalometric norms between egyptian adolescents and those of a sample in iowa, usa, bishara et al. concluded that egyptian boys tended to have bimaxillary dental protrusion and greater posterior facial heights (pfhs), whereas egyptian girls had mandibular dental protrusion and more convex skeletal profiles.5 in a jordanian population, hamdan et al. concluded that, in comparison to a british sample, jordanians had reduced lower facial heights and more proclined upper incisors (uis) and lower incisors (lis); this finding was substantiated by a reduced interincisal angle.3 al-awwad et al. compared the cephalometric norms of a sample of adult kuwaitis with those of previously published caucasian norms, reporting that the kuwaiti subjects had more proclined incisors and significantly more obtuse nasolabial angles; moreover, females had more protrusive lower lips with more proclined lis compared to males.6 another study found that adolescent kuwaitis had a steeper mandibular plane (mn) and a more convex profile, with reduced chin protrusion and more protrusive dentition compared to published norms.4 shalhoub et al. established cephalometric radiographical norms for saudi arabian adults by comparing normal facial proportions with a north american sample; the saudi subjects showed reasonably normal dental relationships, with no severe anteroposterior, vertical or transverse skeletal discrepancies.7 in western saudi arabia, previous findings have suggested that western saudis have an increased a point/ nasion/b point (anb) angle due to the retrognathic figure 1: example of a cephalogram with (a) identified anatomical landmarks and (b) automated cephalometric measurements generated using imaging software. ans = anterior nasal spine; ui = upper incisor; li = lower incisor. cephalometric norms in an omani adult population of arab descent e184 | squ medical journal, may 2018, volume 18, issue 2 shifts. medically compromised subjects and those with congenital abnormalities, facial trauma, missing/ extracted teeth or a history of orthodontic treatment, orthognathic surgery or plastic surgery were excluded from the study, as such individuals were deemed not to represent the typical facial characteristics of an arab omani population. the sample size was calculated using nmaster software, version 1.0 (department of biostatistics, christian medical college, vellore, india) based on the following formulae: where sp is the target population, z is the confidence interval (1.96), a is the α error (assumed to be 1%), b is the β error (assumed to be 10% at a power of 90%), d is the effect size (i.e. the mean difference between males and females) and sd is the standard deviation. the mean and sd of randomly selected variables, including the anb, sella/nasion (sn) line to the maxillary plane (mp) and the lower dental facial height (ldfh), defined as the distance between the li tip to the mn, was estimated based on 15 male and 35 female subjects. the minimum sample size was therefore calculated to be 35 subjects of each gender. however, in order to improve the statistical power of the results, the sample size was increased to a total of 150 subjects. all of the subjects underwent routine twodimensional (2d) lateral cephalography in centric 2sp2 [z1 − + z1 − b] 2 n = d2 a 2 sd of males + sd of females sp − pooled sd = 2 table 1: definition of various cephalometric parameters used in the current study parameter definition skeletal sna position of the maxilla in relation to the skull base (i.e. the angle between the sn and na planes) snb position of the mandible in relation to the skull base (i.e. the angle between the sn and nb planes) anb sagittal relationship between the maxilla and mandible (i.e. the angle between the na and nb planes) sn-mp vertical relationship between the maxilla and cranium (i.e. the angle between the sn and ans and pns planes) ppl-mn angle between the ppl and mn lafh distance between the me and mp (i.e. distance between the me and ans) uafh distance between the n and mp (i.e. distance between the n and ans) lafh/tafh ratio of lafh to the tafh (i.e. ratio of the n-ans to the ans-me) lpfh distance between the go and mp (i.e. distance between the go and pns) upfh distance between the s and mp (i.e. distance between the s and pns) pfh distance between the s and go wits appraisal extent to which the jaws are related to each other* dental overjet horizontal overlap of the incisors from the labial aspect of the li to the incisal edge of the ui overbite vertical overlap of the incisors from the incisal edge of the ui to the incisal edge of the li ui-mp angle between the ui axis and mp li-mp angle between the li axis and mp ui-li angle between the ui and li axes li protrusion distance between the incisal edge of the li and the line joining point a to po li-fp distance between the incisal edge of the li and the line joining n to po b-npo distance between point b and the line joining n to po ldfh distance between the tip of the li and the mp soft tissue ul-ep distance between the ul and ricketts’ e line† ll-ep distance between the ll and ricketts’ e line† nla angle between the co and sn of the ul chin thickness distance between the hard and soft tissue po sna = sella (s)/nasion (n) point a; snb = sn point b; anb = a point/n/b point; mp = maxillary plane; ans = anterior nasal spine; pns = posterior nasal spine; ppl = palatal plane; mn = mandibular plane; lafh = lower anterior facial height (afh); me = menton; uafh = upper afh; tafh = total afh; lpfh = lower posterior facial height (pfh); go = gonion; upfh = upper pfh; li = lower incisor; ui = upper incisor; po = pogonion; fp = facial plane; ldfh = lower dental facial height; ul = upper lips; ep = e plane; ll = lower lips; nla = nasolabial angle; col = columella; sn = philtrum. *measured by drawing perpendicular lines from points a and b on the maxilla and mandible, respectively, to the occlusal plane through the region of overlapping cusps of the first premolar and first molars. †measured by drawing a line from the tip of the nose to the soft tissue po. prashantha s. govinakovi, ibrahim al-busaidi and viswapurna senguttuvan clinical and basic research | e185 occlusion with the lips relaxed and a natural head position, in which the frankfort plane was parallel to the floor. the cephalograms were taken from a distance of 150 cm away using an orthophos xg 5 sd x-ray unit (dentsply sirona, york, pennsylvania, usa). although three-dimensional (3d) cephalometric analyses have recently gained popularity, recent research has indicated that 3d analysis does not ensure more accurate results than conventional 2d analysis.28 subsequently, digital versions of the lateral cephalograms were examined using dolphin imaging software, version 11.8 (dolphin imaging & management solutions, chatsworth, california, usa). a single examiner identified anatomical landmarks on the cephalogram directly on the monitor using markings on a ruler to calibrate the magnification. a dot was placed and moved around on the image until the examiner was satisfied that the position of the landmark had been accurately recorded. after all of the landmarks were clearly identified, various linear and angular measurements were automatically generated by the program [figure 1]. in order to assess if any errors were made while localising the landmarks, 10 random radiographs were retraced after three weeks to determine examiner error and confirm the reproducibility of measurements at a 95% confidence interval. there were very few measurement errors for all of the variables tested, except for pfh, measured from the sella to the gonion, which resulted in an intra-class correlation coefficient of 0.504 for the male subjects. table 1 lists the definitions used in the measurement of each cephalometric parameter. microsoft excel, version 2007, (microsoft corp., redmond, washington, usa), and the statistical package for the social sciences (spss), version 10.0 (ibm corp., armonk, new york, usa), were used for data entry and analysis. the data were tested for normalcy as per previously described methods.29 the results were presented as means ± sd for continuous variables and numbers and percentages for discrete variables. due to the large sample size and normal distribution of the results, parametric tests were applied. each of the parameters for male and female subjects were compared using an independent samples t-test. a one-sample t-test was used for comparison between published eastman standard values and those of the current study.10–27 the level of statistical significance was set at p <0.050. ethical approval to conduct this study was obtained from the research & ethical review & approval committee of the ministry of health in oman (#mh/dgp/r&s/30/2013). all of the subjects included in the study were informed of the nature and purpose of the study and the radiographic procedures involved. verbal consent was provided for the use of the radiographs for research purposes, under the condition that the subjects’ anonymity was maintained. results a total of 150 omani subjects of arab descent were included in the study, of which 91 (60.7%) were female and 59 (39.3%) were male. the mean age was 25.3 ± 0.5 years old. in terms of gender, males had significantly higher palatal-mp angles compared to females (28.22 ± 5.69 table 2: cephalometric norms according to gender in an adult omani population (n = 150) parameter mean ± sd p value males (n = 59) females (n = 91) skeletal sna in degrees 80.94 ± 4.7 81.44 ± 4.23 0.498 snb in degrees 80.00 ± 4.77 78.98 ± 3.92 0.157 anb in degrees 1.04 ± 2.84 2.46 ± 2.31 0.001 sn-mp in degrees 7.57 ± 4.04 9.22 ± 3.65 0.010 ppl-mn in degrees 28.22 ± 5.69 25.95 ± 5.15 0.012 lafh in mm 60.87 ± 10.31 58.38 ± 6.45 0.070 uafh in mm 49.59 ± 6.39 49.93 ± 3.56 0.674 lafh/tafh ratio in % 34.90 ± 27.75 38.24 ± 25.32 0.449 lpfh in mm 34.08 ± 7.09 34.21 ± 5.85 0.902 upfh in mm 41.20 ± 5.90 39.05 ± 4.26 0.011 pfh in mm 73.95 ± 9.92 71.99 ± 6.18 0.138 wits appraisal in mm -1.47 ± 3.73 -0.03 ± 2.79 0.008 dental overjet in mm 2.21 ± 1.91 2.79 ± 2.16 0.095 overbite in mm 1.12 ± 1.77 1.68 ± 1.8 0.063 ui-mp in degrees 116.61 ± 7.22 115.51 ± 8.77 0.423 li-mn in degrees 93.91 ± 8.17 96.54 ± 7.53 0.046 ui-li in degrees 121.25 ± 10.06 121.78 ± 11.59 0.773 li protrusion in mm 3.11 ± 2.89 2.54 ± 2.44 0.202 li-fp in mm 2.83 ± 3.07 3.27 ± 2.84 0.368 b-npo in mm -1.59 ± 1.82 -1.47 ± 1.19 0.632 ldfh in mm 38.23 ± 5.02 36.54 ± 3.33 0.014 soft tissue ul-ep in mm 2.76 ± 3.71 2.43 ± 2.86 0.533 ll-ep in mm -1.00 ± 2.27 -0.7 ± 1.84 0.380 nla in degrees 106.00 ± 8.82 105.31 ± 10.34 0.672 chin thickness in mm 12.17 ± 2.60 11.81 ± 2.48 0.390 sd = standard deviation; sna = sella (s)/nasion (n) point a; snb = sn point b; anb = a point/n/b point; mp = maxillary plane; ppl = pala tal plane; mn = mandibular plane; lafh = lower anterior facial height (afh); uafh = upper afh; tafh = total afh; lpfh = lower posterior facial height (pfh); upfh = upper pfh; ui = upper incisor; li = lower incisor; fp = facial plane; b-npo = point b/n/pogonion; ldfh = lower dental facial height; ul = upper lips; ep = e plane; ll = lower lips; nla = nasolabial angle. cephalometric norms in an omani adult population of arab descent e186 | squ medical journal, may 2018, volume 18, issue 2 degrees versus 25.95 ± 5.15 degrees; p = 0.012). however, females had higher anb (2.46 ± 2.31 degrees versus 1.04 ± 2.84 degrees; p = 0.001) as well as sn-mp (9.22 ± 3.65 degrees versus 7.57 ± 4.04 degrees; p = 0.010) angles. as per the wits appraisal value, jaw disharmony among males was significantly more severe compared to females (-1.47 ± 3.73 mm versus -0.03 ± 2.79 mm; p = 0.008). females had significantly higher li-mn angles (96.54 ± 7.53 degrees versus 93.91 ± 8.17 degrees; p = 0.046) and lower ldfhs (36.54 ± 3.33 mm versus 38.23 ± 5.02 mm; p = 0.014) when compared to males [table 2]. in comparison with eastman standard norms, statistically significant differences were noticed for all of the mean cephalometric values of the omani subjects, apart from sn point b (snb) and anb values. the omani subjects had a significantly smaller sn point a (sna) value (81.24 ± 4.40 degrees versus 82.01 ± 3.89 degrees; p = 0.036), suggesting a retro-positioned maxilla.12 in addition, the omani subjects had slightly more divergent basal planes, as indicated by their significantly higher palatal-mp (26.84 ± 5.46 degrees versus 25 ± 6 degrees; p <0.001) and sn-mp (8.57 ± 3.87 degrees versus 7 ± 3 degrees; p <0.001) angles.12,13 in addition, the omani subjects had significantly smaller anterior and pfhs (p <0.001 each).11,13–16 according to the wits appraisal value, the sd value of jaw disharmony of the omani population was just over 1 mm less than that of the eastman standard norms (-0.59 ± 3.25 mm versus 0.59 ± 1.84 mm; p <0.001).19 both the overjet and overbite of the omani subjects was significantly decreased in comparison to eastman standard norms (p <0.001 each), with the omani subjects having more proclined incisors.20,21 with regards to soft tissue parameters, the upper and lower lips were significantly more protrusive in the omani subjects and the nasolabial angle was significantly more obtuse (p <0.001 each) [table 3].10–27 discussion during orthodontic evaluation, a cephalometric analysis can reveal important anatomical information regarding the internal structures of the facial complex, particularly in terms of skeletal and dento-alveolar anomalies.30 while various cephalometric norms have been published in an attempt to define normal skeletal characteristics, most attempts have utilised populations of north american or european caucasians.10,11,31,32 however, it is apparent that the cephalometric norms for one ethnic group do not necessarily apply to others.5,32–41 the present study was undertaken to establish cephalometric norms for a young population of omanis of arab descent. statistically significant differences were observed in comparison to eastman standard norms for almost all of the cephalometric variables.10–27 with regards to skeletal parameters, the omani subjects had a significantly smaller sna angle in comparison to the eastman standard norms, suggesting a retro-positioned maxilla.12 in contrast, previous studies conducted to establish cephalometric norms in other arab populations have shown variations in sna and snb angles [table 4].2–5,8,38–40,42 overall, arab omanis were found to have a more retruded maxilla when compared to the eastman standard norms or egyptian, saudi, kuwaiti and emirati samples; however, they were less retruded than jordanian, moroccan and yemeni samples.3–5,8,38–40,42 nevertheless, results table 3: comparison of cephalometric norms in an adult omani population (n = 150) with eastman standard norms10–27 parameter mean ± sd p value arab omanis (n = 150) eastman standard norms skeletal sna in degrees 81.24 ± 4.40 82.01 ± 3.8912 0.036 snb in degrees 79.38 ± 4.28 79.77 ± 3.6912 0.272 anb in degrees 1.90 ± 2.61 2.04 ± 1.8112 0.517 sn-mp in degrees 8.57 ± 3.87 7 ± 313 <0.001 ppl-mn in degrees 26.84 ± 5.46 25 ± 614 <0.001 lafh in mm 59.35 ± 8.24 64.95 ± 3.5511 <0.001 uafh in mm 49.79 ± 4.85 52.35 ± 2.815,16 <0.001 lafh/tafh ratio in % 36.92 ± 26.25 5517 <0.001 lpfh in mm 43.00 ± 34.50 43.0 ± 418 <0.001 upfh in mm 39.89 ± 5.06 52.25 ± 1.9513 <0.001 pfh in mm 72.75 ± 7.89 79.0 ± 4.513 <0.001 wits appraisal in mm -0.59 ± 3.25 0.59 ± 1.8419 <0.001 dental overjet in mm 2.56 ± 2.07 3.2 ± 0.520,21 <0.001 overbite in mm 1.45 ± 1.80 3.2 ± 0.720,21 <0.001 ui-mp in degrees 115.93 ± 8.18 112 ± 613 <0.001 li-mn in degrees 95.50 ± 7.86 91.4 ± 3.7810 <0.001 ui-li in degrees 121.57 ± 10.98 135.4 ± 5.7610 <0.001 li protrusion in mm 2.76 ± 2.62 1 ± 222 <0.001 li-fp in mm 3.10 ± 2.93 1.6 ± 223 <0.001 b-npo in mm -1.52 ± 1.46 -2 ± 227 <0.001 ldfh in mm 37.20 ± 4.14 40 ± 215,16 <0.001 soft tissue ul-ep in mm 2.55 ± 3.21 -5.4 ± 222 <0.001 ll-ep in mm -0.82 ± 2.01 -2.0 ± 222 <0.001 nla in degrees 105.57 ± 9.74 102.0 ± 424 <0.001 chin thickness in mm 11.95 ± 2.52 12.65 ± 1.925,26 <0.001 sd = standard deviation; sna = sella (s)/nasion (n) point a; snb = sn point b; anb = a point/n/b point; mp = maxillary plane; ppl = palatal plane; mn = mandibular plane; lafh = lower anterior facial height (afh); uafh = upper afh; tafh = total afh; lpfh = lower posterior facial height (pfh); upfh = upper pfh; ui = upper incisor; li = lower incisor; fp = facial plane; b-npo = point b/n/pogonion; ldfh = lower dental facial height; ul = upper lips; ep = e plane; ll = lower lips; nla = nasolabial angle. prashantha s. govinakovi, ibrahim al-busaidi and viswapurna senguttuvan clinical and basic research | e187 from the present study showed no significant difference with eastman standard norms regarding the sagittal relationship between the maxilla and the mandible (i.e. the anb angle).12 previous studies in saudi arabia and jordan have reported similar findings, while other studies in kuwait, saudi arabia, morocco and yemen have reported conflicting findings.2,3,37–40 arab omanis were found to have relatively reduced anb angles compared to reports for other arab populations.2–5,8,38–40,42 on the other hand, the angle between the palatal and mn planes was significantly higher among the current sample of omani adults in comparison to eastman standard norms.14 furthermore, the sn-mp angle was significantly higher among the omani subjects by 1.57 degrees.13 it can therefore be concluded that omanis have slightly more divergent basal planes, as well as a more caudally tipped palatal plane. this is in accordance with a previous study conducted in saudi arabia, but in contrast to hamdan et al.’s findings among jordanian adolescents.2,3 in the current study, the lower and upper anterior facial heights of the omani subjects were significantly shorter than those in eastman standard norms, by 5.6 mm and 2.6 mm, respectively; moreover, the ratio of lower anterior facial height to upper anterior facial height was significantly lower (-18.1%).11,15–17 thus, it seems that omanis have considerably smaller anterior facial heights, which is in accordance with hamdan et al.’s findings.3 in addition, the upper pfh and overall pfh of the omani subjects were significantly shorter, by 12.4 mm and 6.3 mm, respectively, compared to eastman standard norms.13 however, lower pfh was similar to that of eastman standard norms.18 this is in contrast to the findings of bishara et al. and behbehani et al. among egyptian and kuwaiti adolescents, respectively.5,37 the wits appraisal value for the studied omani population was also significantly different to that of eastman standard norms.19 in terms of dental parameters, both the overjet and overbite values for the studied omani population were significantly lower than those of eastman standard norms.20,21 moreover, the angles between the ui and mp and the li and mn were increased by 3.9 and 4.1 degrees, respectively, while the interincisal angle was decreased by 13.8 degrees, suggesting that the omani subjects had more proclined incisors compared to eastman standard norms.10,13 in addition, omanis had the greatest degree of incisor proclination compared to other arab populations, apart from emiratis.2–5,8,38–40,42 protrusion of the li and the distance between the li and facial plane was also increased by 1.8 mm and 1.5 mm, respectively.22,23 this finding is in accordance with other studies of arab populations which indicated greater proclined incisor relations.2–5,8,38–40,42 finally, the ldfh of the omani subjects was shorter than those of eastman standard norms by 2.8 mm.15,16 within soft tissue parameters, both the upper and lower lips were more protrusive in the current omani sample in comparison to eastman standard norms, by 7.9 and 1.2 mm, respectively.22 behbehani et al. reported similar findings in a kuwaiti population.37 in the current study, the nasolabial angle was also significantly more obtuse by 3.6 degrees in comparison to eastman standard norms.22 regarding gender differences within the studied omani population, females had a significantly greater sagittal relationship between the maxilla and mandible, as evidenced by their anb values. this feature was further supported by the females having a more positive wits appraisal value. these findings suggest that omani females display a more retrusive mandible, which is in contrast to reported findings from other arab populations.3,5,42 in addition, females in the current table 4: comparison of selected cephalometric norms in an adult omani population (n = 150) with other arab populations2–5,8,38–40,42 author and year of study population mean ± sd sna in degrees snb in degrees anb in degrees wits appraisal in mm ui-li in degrees current study (2018) 150 omani adults 81.24 ± 4.40 79.38 ± 4.28 1.90 ± 2.61 -0.59 ± 3.25 121.57 ± 10.98 hassan (2006)2 70 saudi adults 80.8 ± 4.06 77.5 ± 4.48 3.7 ± 1.522 hamdan et al. (2001)3 65 jordanian adolescents 80.7 ± 3.67 77.7 ± 3.19 3.0 ± 1.96 127.5 ± 7.93 bishara et al. (1990)5 90 egyptian adolescents 82.7 ± 3.6 79.5 ± 3.5 3.2 ± 1.7 -0.1 ± 2.8 124.1 ± 8.4 al-jasser (2000)8 87 saudi students 83.6 ± 4.3 81.0 ± 3.7 2.5 ± 2.0 124.8 ± 6.9 al-jame et al. (2006)4 162 kuwaiti adolescents 83.04 ± 3.6 79.44 ± 3.4 3.6 ± 2.16 -0.48 ± 2.36 aldrees (2011)38 485 saudi adults 82.49 ± 4.17 79.55 ± 3.84 2.93 ± 2.31 0.13 ± 2.47 ousehal et al. (2012)39 71 moroccan adults 80.59 ± 3.8 77.68 ± 3.55 3.11 ± 1.68 daer et al. (2016)40 194 yemeni students 80.86 ± 2.54 77.89 ± 2.52 2.97 ± 1.35 126.65 ± 7.19 al zain et al. (2012)42 61 emirati adults 81.7 78.6 3.1 118.6 sd = standard deviation; sna = sella (s)/nasion (n) point a; snb = sn point b; anb = a point/n/b point; ui = upper incisor; li = lower incisor. cephalometric norms in an omani adult population of arab descent e188 | squ medical journal, may 2018, volume 18, issue 2 study had significantly more proclined lis compared to males, as expressed by the li-mn angle; this is in accordance with findings of bishara et al.5 this study is subject to certain limitations. as noted earlier, oman is a heterogenous country and is native to individuals of various ethnicities and races, with arabs representing only a portion of the total population.9 therefore, in order to determine accurate and specific cephalometric norms for the omani population, a larger sample comprising all of the different tribes existing in the country should be evaluated. conclusion in comparison to eastman standard norms, the arab omani subjects were found to have a slightly more retrusive maxilla and an increased mp-mn angle. their vertical facial heights were also significantly shorter than those of eastman standard norms. the wits appraisal value for the omani subjects was also comparatively reduced, nearing zero. in terms of dental parameters, the incisor relations of the omani subjects were edge-to-edge in nature and the interincisal angle was reduced, suggesting more proclined incisors. with regards to soft tissue parameters, the lips of the omani subjects were significantly more protrusive and the nasolabial angle more obtuse compared to the eastman standard norms. these findings suggest that certain cephalometric parameters, such as slightly more proclined incisors, should be considered acceptable and normal within the arab omani population, despite differing from eastman standard norms. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. kapila s. selected cephalometric angular norms in kikuyu children. angle orthod 1989; 59:139–44. doi: 10.1043/0003 3219(1989)059<0139:scanik>2.0.co;2. 2. hassan ah. cephalometric norms for saudi adults living in the western region of saudi arabia. angle orthod 2006; 76:109–13. doi: 10.1043/0003-3219(2006)076[0109:cnfsal]2.0.co;2. 3. hamdan am, rock wp. cephalometric norms in an arabic population. j orthod 2001; 28:297–300. doi: 10.1093/ortho/28.4.297. 4. al-jame b, artun j, al-azemi r, behbehani f, buhamra s. lateral cephalometric norms for adolescent kuwaitis: hard tissue measurements. med princ pract 2006; 15:91–7. doi: 10.11 59/000090910. 5. bishara se, abdalla em, hoppens bj. cephalometric comparison of dentofacial parameters between egyptian and north american adolescents. am j orthod dentofacial orthop 1990; 97:413–21. doi: 10.1016/0889-5406(90)70113-q. 6. al-awwad a, preston cb, al-jewair ts, al-awwad m, tabbaa s. cephalometric norms for kuwaiti adults: a preliminary study. orthod waves 2014; 73:136–45. doi: 10.1016/j.odw.2014.09.007. 7. shalhoub sy, sarhan oa, shaikh hs. adult cephalometric norms for saudi arabians with a comparison of values for saudi and north american caucasians. br j orthod 1987; 14:273–9. doi: 10.1179/bjo.14.4.273. 8. al-jasser nm. cephalometric evaluation of craniofacial variations in normal saudi population according to steiner analysis. saudi med j 2000; 21:746–50. 9. encyclopaedia britannica. oman: the early period. from: www. britannica.com/place/oman/the-early-period accessed: feb 2018. 10. downs wb. variations in facial relationships: their significance in treatment and prognosis. am j orthod 1948; 34:812–40. doi: 10.1016/0002-9416(48)90015-3. 11. mcnamara ja jr. a method of cephalometric evaluation. am j orthod 1984; 86:449–69. doi: 10.1016/s0002-9416(84)90352-x. 12. riedel ra. the relation of maxillary structures to cranium in malocclusion and in normal occlusion. angle orthod 1952; 22:142–5. 13. bell wh, proffit wr, white rl. surgical correction of dentofacial deformities. philadelphia, pennsylvania, usa: saunders, 1980. pp. 137–50. 14. lundström a, ed. introduction to orthodontics. new york, usa: mcgraw-hill, 1960. pp. 104–40. 15. burstone cj, james rb, legan h, murphy ga, norton la. cephalometrics for orthognathic surgery. j oral surg 1978; 36:269–77. 16. legan hl, burstone cj. soft tissue cephalometric analysis for orthognathic surgery. j oral surg 1980; 38:744–51. 17. worms fw, issacson rj, speidel tm. surgical orthodontic treatment planning: profile analysis and mandibular surgery. angle orthod 1976; 46:1–25. doi: 10.1043/0003-3219(1976)04 6<0001:sotppa>2.0.co;2. 18. henderson d. color atlas and textbook of orthognathic surgery: the surgery of facial skeletal deformity. maryland heights, missouri, usa: mosby, 1999. p. 212. 19. jacobson a. the “wits” appraisal of jaw disharmony. am j orthod 1975; 67:125–38. doi: 10.1016/0002-9416(75)90065-2. 20. arnett gw, bergman rt. facial keys to orthodontic diagnosis and treatment planning. part i. am j orthod dentofacial orthop 1993; 103:299–312. doi: 10.1016/0889-5406(93)70010-l. 21. arnett gw, bergman rt. facial keys to orthodontic diagnosis and treatment planning: part ii. am j orthod dentofacial orthop 1993; 103:395–411. doi: 10.1016/s0889-5406(05)81791-3. 22. ricketts rm. planning treatment on the basis of the facial pattern and an estimate of its growth. angle orthod 1957; 27:14–37. 23. park cs, park jk, kim h, han ss, jeong hg, park h. comparison of conventional lateral cephalograms with corresponding cbct radiographs. imaging sci dent 2012; 42:201–5. doi: 10.5624/isd.2012.42.4.201. 24. brown jb, mcdowell f. plastic surgery of the nose, 1st ed. maryland heights, missouri, usa: mosby, 1951. pp. 30–8. 25. holdaway ra. a soft-tissue cephalometric analysis and its use in orthodontic treatment planning: part i. am j orthod 1983; 84:1–28. doi: 10.1016/0002-9416(83)90144-6. 26. holdaway ra. a soft-tissue cephalometric analysis and its use in orthodontic treatment planning: part ii. am j orthod 1984; 85:279–93. doi: 10.1016/0002-9416(84)90185-4. https://doi.org/10.1043/0003-3219%281989%29059%3c0139:scanik%3e2.0.co%3b2 https://doi.org/10.1043/0003-3219%281989%29059%3c0139:scanik%3e2.0.co%3b2 https://doi.org/10.1043/0003-3219%282006%29076%5b0109:cnfsal%5d2.0.co%3b2 https://doi.org/10.1093/ortho/28.4.297 https://doi.org/10.1159/000090910 https://doi.org/10.1159/000090910 https://doi.org/10.1016/0889-5406%2890%2970113-q https://doi.org/10.1016/j.odw.2014.09.007 https://doi.org/10.1179/bjo.14.4.273 https://doi.org/10.1016/0002-9416%2848%2990015-3 https://doi.org/10.1016/s0002-9416%2884%2990352-x https://doi.org/10.1043/0003-3219%281976%29046%3c0001:sotppa%3e2.0.co%3b2 https://doi.org/10.1043/0003-3219%281976%29046%3c0001:sotppa%3e2.0.co%3b2 https://doi.org/10.1016/0002-9416%2875%2990065-2 https://doi.org/10.1016/0889-5406%2893%2970010-l https://doi.org/10.1016/s0889-5406%2805%2981791-3 https://doi.org/10.5624/isd.2012.42.4.201 https://doi.org/10.1016/0002-9416%2883%2990144-6 https://doi.org/10.1016/0002-9416%2884%2990185-4 prashantha s. govinakovi, ibrahim al-busaidi and viswapurna senguttuvan clinical and basic research | e189 27. al-gunaid t, yamaki m, takagi r, saito i. soft and hard tissue changes after bimaxillary surgery in japanese class iii asymmetric patients. j orthod sci 2012; 1:69–76. doi: 10.4103/ 2278-0203.103865. 28. cassetta m, altieri f, di giorgio r, silvestri a. two-dimensional and three-dimensional cephalometry using cone beam computed tomography scans. j craniofac surg 2015; 26:e311–15. doi: 10. 1097/scs.0000000000001700. 29. ghasemi a, zahediasl s. normality tests for statistical analysis: a guide for non-statisticians. int j endocrinol metab 2012; 10:486–9. doi: 10.5812/ijem.3505. 30. proffit wr, white rp jr, sarver dm. contemporary treatment of dentofacial deformity, 1st ed. st louis, missouri, usa: mosby, 2003. pp. 2–31. 31. steiner cc. the use of cephalometrics as an aid to planning and assessing orthodontic treatment: report of a case. am j orthod 1960; 46:721–35. doi: 10.1016/0002-9416(60)90145-7. 32. tweed ch. the diagnostic facial triangle in the control of treat ment objectives. am j orthod 1969; 55:651–67. doi: 10.1016/ 0002-9416(69)90041-4. 33. connor am, moshiri f. orthognathic surgery norms for american black patients. am j orthod 1985; 87:119–34. doi: 10.1016/0002-9416(85)90021-1. 34. wylie ga, fish lc, epker bn. cephalometrics: a comparison of five analyses currently used in the diagnosis of dentofacial deformities. int j adult orthodon orthognath surg 1987; 2:15–36. 35. flynn tr, ambrogio ri, zeichner sj. cephalometric norms for orthognathic surgery in black american adults. j oral maxillofac surg 1989; 47:30–9. doi: 10.1016/0278-2391(89)90120-1. 36. alcalde re, jinno t, pogrel ma, matsumura t. cephalometric norms in japanese adults. j oral maxillofac surg 1998; 56:129–34. doi: 10.1016/s0278-2391(98)90849-7. 37. behbehani f, hicks ep, beeman c, kluemper gt, rayens mk. racial variations in cephalometric analysis between whites and kuwaitis. angle orthod 2006; 76:406–11. doi: 10.1043/00 03-3219(2006)076[0406:rvicab]2.0.co;2. 38. aldrees am. lateral cephalometric norms for saudi adults: a meta-analysis. saudi dent j 2011; 23:3–7. doi: 10.1016/j.sd entj.2010.09.002. 39. ousehal l, lazrak l, chafii a. cephalometric norms for a moroccan population. int orthod 2012; 10:122–34. doi: 10. 1016/j.ortho.2011.12.001. 40. daer aa, abuaffan ah. cephalometric norms among a sample of yamani adults. orthod waves 2016; 75:35–40. doi: 10.1016/j. odw.2016.03.001. 41. al-barakati sf. the wits appraisal in a saudi population sample. saudi dent j 2002; 14:89–92. 42. al zain t, ferguson dj. cephalometric characterization of an adult emirati sample with class i malocclusion. j orthod sci 2012; 1:11–15. doi: 10.4103/2278-0203.94772. https://doi.org/10.4103/2278-0203.103865 https://doi.org/10.4103/2278-0203.103865 https://doi.org/10.1097/scs.0000000000001700 https://doi.org/10.1097/scs.0000000000001700 https://doi.org/10.5812/ijem.3505 https://doi.org/10.1016/0002-9416%2860%2990145-7 https://doi.org/10.1016/0002-9416%2869%2990041-4 https://doi.org/10.1016/0002-9416%2869%2990041-4 https://doi.org/10.1016/0002-9416%2885%2990021-1 https://doi.org/10.1016/0278-2391%2889%2990120-1 https://doi.org/10.1016/s0278-2391%2898%2990849-7 https://doi.org/10.1043/0003-3219%282006%29076%5b0406:rvicab%5d2.0.co%3b2 https://doi.org/10.1043/0003-3219%282006%29076%5b0406:rvicab%5d2.0.co%3b2 https://doi.org/10.1016/j.sdentj.2010.09.002 https://doi.org/10.1016/j.sdentj.2010.09.002 https://doi.org/10.1016/j.ortho.2011.12.001 https://doi.org/10.1016/j.ortho.2011.12.001 https://doi.org/10.1016/j.odw.2016.03.001 https://doi.org/10.1016/j.odw.2016.03.001 https://doi.org/10.4103/2278-0203.94772 1department of general surgery, faculty of medicine, alexandria university, alexandria, egypt; 2department of surgical oncology, king faisal specialist hospital & research center, riyadh, saudi arabia; 3cheeloo college of medicine, shandong university, jinan, shandong, china *corresponding author’s e-mail: aazzam70@yahoo.com سرطانة كبدية اخلاليا مهاجرة إىل األذين األمين عرب الوريد األجوف السفلي اأمين زكي عزام و كرمي اأمين عزام hepatocellular carcinoma migrating to the right atrium through the inferior vena cava *ayman z. azzam1,2 and kareem a. azzam3 an 82-year-old man presented to the emergency department of the king faisal specialist hospital & research center, riyadh, saudi arabia, in 2013 with jaundice, bilateral lower limb oedema and dyspnoea. his laboratory test results were normal, except for elevated α-fetoprotein levels (258.3 ug/l). an ultrasound showed a right hepatic lobe hepatocellular carcinoma (hcc) in segments 6 and 7 of the liver, with tumour extension into the inferior vena cava (ivc) and a right atrial mass lesion. an urgent computed tomography (ct) scan of the abdomen indicated that the hcc was located in the liver segments 6 and 7 and invading the right hepatic vein; in addition, the confluence of the ivc extended into the right atrium where a tumour thrombus was present [figure 1]. an ultrasound-guided fine needle aspiration cytology biopsy also revealed the presence of an hcc. an echocardiogram showed sinus rhythm and a large mass in the right atrium occupying most of the cavity and extending into the ivc, causing interesting medical image sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e118–119, epub. 4 apr 18 submitted 7 nov 17 revision req. 10 jan 18; revision recd. 14 jan 18 accepted 25 jan 18 figure 1: a: computed tomography (ct) scan of the abdomen and chest of an 82-year-old man in the coronal view showing a hepatocellular carcinoma migrating through the inferior vena cava to the right atrium (arrows). b: chest ct scan showing a tumour thrombus in the right atrium (arrowhead). doi: 10.18295/squmj.2018.18.01.024 figure 2: a: computed tomography scan of the abdomen and chest of an 82-year-old man in the sagittal view showing a hepatocellular carcinoma (hcc) migrating through the hepatic veins and inferior vena cava to the right atrium (arrow), with a tumour thrombus located in the right atrium (arrowhead). b: magnetic resonance imaging of the chest and abdomen in the coronal view showing the hcc migrating to the right atrium (arrow) and the tumour thrombus in the right atrium (arrowhead). ayman z. azzam and kareem a. azzam interesting medical image | e119 references 1. hanfling sm. metastatic cancer to the heart: review of the literature and report of 127 cases. circulation 1960; 22:474–83. doi: 10.1161/01.cir.22.3.474. 2. luo x, zhang b, dong s, zhang b, chen x. hepatocellular carcinoma with tumor thrombus occupying the right atrium and portal vein: a case report and literature review. medicine (baltimore) 2015; 94:e1049. doi: 10.1097/md.000000000000 1049. 3. kamal mw, farshidpour m, long aw, farooqui s, cunningham sc. hepatocellular carcinoma with intra-atrial extension responding to transarterial chemoembolization via the right hepatic and right inferior phrenic arteries. gastrointest cancer res 2014; 7:111–16. 4. barrett m, viglianti bl, hanson ca, schildhouse rj. a case of right atrial obliteration caused by intracardiac extension of hepatocellular carcinoma. case rep oncol 2017; 10:8–14. doi: 10.1159/000455092. 5. bussani r, de-giorgio f, abbate a, silvestri f. cardiac metastases. j clin pathol 2007; 60:27–34. doi: 10.1136/jcp.2005. 035105. flow obstruction. a ct scan and magnetic resonance imaging of the abdomen and chest showed the hcc migrating through the hepatic veins and the ivc to the right atrium, with a tumour thrombus in the right atrium [figure 2]. after the diagnosis was made, the patient did not respond to treatment and died due to cardiopulmonary failure during the admission period. comment the heart is affected in up to 20% of metastatic hcc cases.1 although hcc has a tendency to spread into the venous system, intracardiac involvement is extremely rare and has a very poor prognosis.2 metastasis to the heart can occur via the blood stream, the lymphatic system or direct invasion through the ivc to the right atrium, with the latter occurring in 6.5–44% of hcc patients.3,4 such patients often exhibit symptoms of heart failure due to flow obstruction or a thromboembolism.4,5 survival usually does not exceed four months, regardless of the type of treatment offered.4 a c k n o w l e d g e m e n t s the authors wish to acknowledge the involvement of dr mohamed neimatallah, department of radiology, king faisal specialist hospital & research center, in the care of the reported patient. https://doi.org/10.1161/01.cir.22.3.474 https://doi.org/10.1097/md.0000000000001049 https://doi.org/10.1097/md.0000000000001049 https://doi.org/10.1159/000455092 https://doi.org/10.1136/jcp.2005.035105 https://doi.org/10.1136/jcp.2005.035105 sultan qaboos university med j, august 2014, vol. 14, iss. 3, pp. e319-322, epub. 24th jul 14 submitted 15th apr 13 revision req. 13th may 14; revision recd. 18th may 14 accepted 18th may 14 the origins of pathology (greek, pathologia = ‘study of emotions or suffering’) could perhaps date back to ancient physicians struggling through observations and philosophy to unravel the mysteries of the human body and its afflictions. while the recordings of the egyptians (3,500–2,000 b.c.) revealed through the edwin smith papyrus, the mesopotamians (code of hammurabi, 2200 b.c.) and the greek civilisation (hippocrates 460–370 b.c.) attributed deformity and destruction to demonical, deitical or humoral influences,1,2,3 it was only during the golden islamic age from the 8th century and the renaissance period of european history that the earliest seeds of scientific pathological practice were sown. surgery, until the last century the only modality to treat breast cancer, predated the evolution of ‘surgical’ pathology by millennia narrated in part i of this article.4 technological advancement combined with insightful understanding of pathogenesis made pathology the focal point of oncological practice only in the 19th century. the science of breast cancer benefited from its emergence. physicians, anatomists and surgeons: forerunners of macroscopic pathology the philosopher-physicians hippocrates and galen, contemplating the origin of disease, were perhaps the first to attempt an understanding of ‘pathogenesis’ (the aetiology and mechanisms of disease causation). undeniably, a more vital and demonstrable direction emerged in the performance of autopsies as far back as the 12th century by arabian physicians avenzoar (1090–1162)5,6 and ibn al-nafis (1213–1288),7 followed by antonio benivieni (florence, 15th century), giovanni morgagni (italy, early 18th century) and karl von rokitansky (vienna, mid-19th century). many of these physicians had the foresight to perform and record their autopsy findings. von rokitansky is believed to have performed over 30,000 autopsies in his lifetime. this accumulation of knowledge, initially aimed at teaching and research, subsequently generated a wealth of information on which surgeons could draw when dealing with live patients.8 the practice of medicine witnessed an enviable intertwining between disciplines—demonstrated best by surgeons beginning their careers as anatomists. american surgeons in the 19th century, in turn initiated ‘surgical’ pathology and the role of the surgical pathologist. their astounding clinical and intraoperative appraisals, guiding the steps of a surgical procedure, laid the foundation for the development of pathology as an independent specialty in later years.9,10 many of them trained under 19th century physicians of repute in germany and went on to lay the foundations of medicine and pathology in their own country. the english anatomist and surgeon, sir astley paston cooper (1768–1841), brought breast disease to the forefront through his prolific publications on a host of organs including the breast (illustrations of diseases of the breast, 1829; anatomy of the breast, 1840). modern day oncoplastic breast surgery owes its principles of segmental resection to cooper’s incisive exploration of breast anatomy. he lent his name to the eponymous cooper’s ligaments (suspensory ligaments of the breast), cooper’s disease (cystic disease of the breast) and cooper’s neuralgia (neuralgia of the breast).11 john collins warren (1778–1856) of the massachusetts general hospital (mgh), boston, and joseph colt bloodgood (1867–1935) of johns hopkins hospital, baltimore, surgical pioneers of renown, drew the pathologist to the surgeon’s theatre of operations 1department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2prince aly khan hospital, mazgaon, mumbai, india *corresponding author e-mail: ritu@squ.edu.om تاريخ سرطان الثدي اجلزء الثاين تطور علم األمراض اجلراحية ريتو لكتاكيا و رو�سان �سينوي medical history a brief history of breast cancer part ii evolution of surgical pathology *ritu lakhtakia1 and roshan f. chinoy2 a brief history of breast cancer part ii evolution of surgical pathology e320 | squ medical journal, august 2014, volume 14, issue 3 with the promise that “the combination of energies which accomplishes most in surgical progress is that contained by the cooperation of the laboratory investigator with the surgeon of clinical experience”.12 championing the significance of macroscopic appearance to guide surgical options they paved the way for rapid diagnosis by the intra-operative frozen section. warren, defying contemporary practice, also advocated the pre-surgical biopsy of breast tumours. his intense preoccupation with microscopy is exemplified in the extensive illustrations of breast tumours in a book published in 1895.13 across the atlantic, sir george lenthal cheatle (1865–1951), a british surgeon, and his american colleague dr. max cutler, not only operated and studied thin slices of breast tissue, but documented their findings for posterity in 1931, in what is recognised as the first modern textbook of mammary pathology, tumors of the breast, their pathology, symptoms, diagnosis and treatment.12 their prodigious contributions to pathogenesis included postulating the origin of breast cancer from mammary epithelial cells and changing the understanding of papillary and biphasic tumours. technological renaissance and the microscopic eye the emergence of microscopy, beginning with the chiselling of lenses, was transformed into a new world of disease visualisation by the early, simple (antonie van leeuwenhoek, 1632–1723) and compound (robert hooke, 1635–1703) microscopes.14 the 19th century german pioneer johannes müller (1801–1858) laid the foundation for the understanding of the cellular character of new growths in his work on the fine structure and form of morbid tumors in 1838, leaning heavily on the clinical differences between benign and malignant tumours. schwann, henle and virchow, themselves historical figures of note, were his protégés; henle authored the handbook of rational pathology (1846–1853) used extensively by students of the time.15 the success of the collaboration between the science of optics and human biology is best exemplified in virchow’s (1821–1902) medical epic die cellularpathologie, published in 1871 nearly 150 years since the advent of microscopy. the brave new world of cellular pathology heralded by the ‘father of pathology’ was to unravel disease as never before. virchow’s now famous aphorism omnis cellula e cellula (every cell stems from another cell) in 1855 resounds through medical history right up to the modern era of stem cell technology.16 his legendary contributions to medicine could be considered the launching pad for the post-virchow era of diagnostic pathology as we know it today. from microscopic diagnosis to photomicrography (illustrating disease patterns to peers through publications or presentations) was just another short step. while microscopy offered magnification of tissues, it was the innovations in tissue processing (fixation and embedding), microtomy (section-cutting) and finally the fine art of staining that allowed the pathologist’s eye to analyse the myriad complex tissue patterns that define disease.17 breast cancer and the pathologist: biopsy and cytology take a leap forward once microscopy became a part of disease evaluation, the time was ripe for establishing departments of pathology in institutions, removed from the ‘gross’ pathology observations and recordings by surgeons. in 1854, dr. barnard jackson became the first professor of morbid anatomy at the harvard medical school (and the first in the usa). however, he was still of the old school—relying exclusively on macroscopy. the microscope was pressed into service in 1847 through the efforts of his friend and colleague oliver wendell holmes.13 j. collins warren (1842–1927),18 grandson of john collins warren (co-founder of mgh) drew on his european training in surgery and pathology and pioneered the use of needle biopsy in the diagnosis of breast cancer and the frozen section (the latter technique has also been credited to the johns hopkins gynaecologist-pathologist, thomas s. cullen).19 the procedure revolutionised decision-making at the operating table. notable luminaries in the saga of the various forms of breast neoplasia in the 20th century include new york pathologists, arthur purdy stout (1885–1967) and cushman d. haagensen (columbia university 1933– 1975) who elucidated the nature of papillary lesions and lobular neoplasia.20 at the memorial hospital, new york, fred stewart and frank foote’s lifetime explorations into breast disease were documented through their classification of tumours.21 in the latter half of the 20th century, john g. azzopardi (1929– 2013) at the university of london stood as a giant in breast pathology. his authoritative masterpiece problems in breast pathology has served as a bible of breast pathology.22 fine-needle aspiration cytology provided a simple, ritu lakhtakia and roshan f. chinoy medical history | e321 lessons from the evolution of surgical pathology in breast cancer the history of the pathological diagnosis of breast cancer is a fine example of the emergence of a discipline driven by clinical observations and curiosity and fuelled by technological advances. the breaking point in this journey came with the advent of microscopy that solidified forever the superiority of microscopic diagnosis. it is also an excellent example of the achievements possible with contributions from physics (optics), chemistry and natural sciences (stains) and engineering (microscopes, microtomes and automation). in the last half century, immunology and genetics have enabled the refinement of diagnosis, a better understanding of tumour biology and have brought in targeted therapy. genetic inputs will still need to be tempered and teased into context by the tenacity of the pathologist’s eyeballing skills, backed by the knowledge of the complexities of tumour biology. these remarkable contributions allow breast preservation and even a cure for a once incurable disease. references 1. breasted jh, ed. the edwin smith surgical papyrus. chicago, illinois: the university chicago press, 1930. special ed. 1984. the classics of surgery library. division of gryphon editions, ltd. birmingham (ab). frontispiece. 2. lyons as, petrucelli rj. medicine: an illustrated history. new york: harry n. abrams publishers, 1978. pp. 294–317. 3. homer. iliad. rouse whd, transl. new york: new american library; 1966. p. 36. 4. lakhtakia r. a brief history of breast cancer: part i: surgical domination reinvented. sultan qaboos univ med j 2014; 14:53–6. 5. encyclopaedia britannica online academic edition. ibn zuhr. from: www.britannica.com/ebchecked/topic/280879/ ibn-zuhr accessed: apr 2014. 6. abdel-halim re. contributions of ibn-zuhr (avenzoar) to the progress of surgery: a study and translations of his book altaisir. saudi med j 2005; 26:1333–9. 7. abdel-halim re. contributions of ibn al-nafis (1210-1288 ad) to the progress of medicine and urology. a study and translations from his medical works. saudi med j 2008; 29:13– 22. 8. nezelof c. european roots of pathology. path res pract 1994;190:103–14. doi: 10.1016/s0344-0338(11)80506-6. 9. fechner re. the birth and evolution of american surgical pathology. in: rosai j, ed. guiding the surgeon’s hand: the history of american surgical pathology. washington dc: american registry of pathology, 1997. pp. 7–21. 10. jacyna ls. the laboratory and the clinic: the impact of pathology on surgical diagnosis in the glasgow western infirmary, 1875– 1910. bull hist med 1988; 62. pp. 384–406. 11. singal r, singla rp, mittal a, sangwan s, gupta n. sir astley paston cooper, history, english surgeon and anatomist. indian j surg 2011; 73:82–4. doi: 10.1007/s12262-010-0177-2. relatively non-invasive tool for the rapid diagnosis of breast lumps with high reliability. early reports of its usage in the 20th century originated from the memorial hospital, new york, in the 1930s.23 however, in the usa its subsequent practice became erratic, partly due to the prevailing litigious environment in healthcare. later in the century, scandinavian workers anchored its popularity.24 its usefulness has remained steady across the world as part of the triple assessment of a breast lump; publications on its use for breast disease rank it first in frequency in developing and second in developed countries.25 new frontiers of pathobiology of breast cancer: prediction and prognosis conventionally, consensus-based morphological classifications (world health organization classification of breast tumours),26 grading systems illustrating tumour differentiation,27 and the tumournodes-metastasis (tnm) staging30 have been the bedrock for assessing tumour aggressiveness. pathobiologists started exploring cell biology to identify new pathways of tumourigenesis leading to new therapeutic options. the hormone-dependence of breast cancer, long suspected through clinical observation became a scientific fact through jensen’s identification of oestrogen and progesterone receptors (er, pr) on breast cancer cells in 1967.29 today, the immunohistochemical demonstration of er/pr and the epidermal growth factor receptor (her2/neu) on core biopsies has been standardised through wellestablished protocols.30 the modern-day pathologist is, thus, at the heart of therapeutic decision-making and shares the responsibility of rendering information on prognostication and prediction. in a seminal article in nature in 2000, perou et al. created ‘molecular portraits’ of breast cancer by analysing 65 surgical specimens using complementary dna microarrays of 8,102 genes.31 intense exploration of this information resulted in high throughput gene expression profiling technology-driven assays (oncotype dx, mammaprint) rapidly transiting from the bench to the bedside and holding promise for ‘personalised’ medicine.32 industry-driven and automated, their expanding role is being watched carefully; the future may see some of these incorporated into practice, while others will fall by the wayside. alternatively, a marriage between pathological and molecular inputs may provide a unified diagnostic tool bridging efficacy, availability and affordability for global practice.33 a brief history of breast cancer part ii evolution of surgical pathology e322 | squ medical journal, august 2014, volume 14, issue 3 12. koerner fc. a brief historical perspective on the pathology of the breast: from cheatle to azzopardi and beyond. semin diagn pathol 2004; 21:3–9. doi: 10.1053/j.semdp.2003.10.008. 13. young rh, louis dn. the warrens and other pioneering clinician pathologists of the massachusetts general hospital during its early years: an appreciation on the 200th anniversary of the hospital founding. mod pathol 2011; 24:1285–94. doi: 10.1038/modpathol.2011. 14. encyclopaedia britannica online academic edition. antonie van leeuwenhoek. from: www.britannica.com/ebchecked/ topic/334699/antonie-van-leeuwenhoek accessed: apr 2014. 15. long er. a history of pathology. london: baillière, tindall & cox. 1928. pp. 187–90. 16. schultz m. rudolf virchow. emerg infect dis 2008; 14:1480–1. doi: 10.3201/eid1409.086672. 17. gal aa. in search of the origins of modern surgical pathology. adv anat pathol 2001; 8:1–13. 18. warren jc. the surgeon and the pathologist. a plea for reciprocity as illustrated by the classification and treatment of benign tumours of the breast. jama 1905; 45:149–65. doi: 10.1038/modpathol.2011.132. 19. wright jr. william osler medal essay: the development of the frozen section technique, the evaluation of surgical biopsy and the origins of surgical pathology. bull hist med 1985; 59:295– 326. 20. haagensen cd, stout ap, phillips js. the papillary neoplasms of the breast: i. benign intraductal papilloma. ann surg 1951;133:18–36. doi:10.1001/jama.1905.52510030006002. 21. foote fw jr, stewart fw. a histological classification of carcinoma of the breast. surgery 1946; 19:74–99. 22. azzopardi jg. problems in breast pathology. in: bennington jl, ed. major problems in pathology, vol ii. london: saunders, 1979. pp. 168–74. 23. martin he, ellis eb. biopsy by needle puncture and aspirations. ann surg 1930; 92:169–81. 24. söderström n. fine needle aspiration biopsy. stockholm: almqvist & wiksell, 1966. 25. das dk. fine needle aspiration cytology: its origin, development and present status with special reference to a developing country, india. diagn cytopathol 2003; 28:345–51. 26. lakhani sr, ellis io, schnitt sj, tan ph, van de vijver mj, eds. international agency for research on cancer, world health organization. who classification of tumors of the breast. 4th ed. lyon: international agency for research on cancer, 2012. doi: 10.1002/dc.10295. 27. bloom hj, richardson ww. histological grading and prognosis in breast cancer: a study of 1,409 cases of which 359 have been followed for 15 years. br j cancer 1957; 11:359–77. doi:10.1038/ bjc.1957.43. 28. sobin lh, gospodarowicz mk, wittekind c, eds. international union against cancer (uicc). tnm classification of malignant tumors. 7th ed. oxford: wiley-blackwell, 2009. doi:10.1038/bjc.1957.43. 29. jensen ev, desombre er, jungblut pw. estrogen receptors in hormone responsive tissues and tumors. in: wissler rw, dao tl, wood s jr, eds. endogenous factors influencing host-tumor balance. chicago: university of chicago press, 1967. 30. hammond me, hayes df, dowsett m, allred dc, hagert kl, badve s, et al. american society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. j clin oncol 2010; 28:2784–95. doi: 10.1200/jco.2009.25.6529. 31. perou cm, sorlie t, eisen mb, van de rijn m, jeffrey ss, rees ca, et al. molecular portraits of human breast tumors. nature (london) 2000; 406:747–52. doi: 10.1038/35021093. 32. goldhirsch a, winer ep, coates as, gelber rd, piccartgebhart m, thürlimann b, et al. personalizing the treatment of women with early breast cancer: highlights of the st gallen international expert consensus on the primary therapy of early breast cancer 2013. ann oncol 2013; 24:2206–23. doi: 10.1093/ annonc/mdt303. 33. leong as, zhuang z. the changing role of pathology in breast cancer diagnosis and treatment. pathobiology 2011; 78:99–114. doi: 10.1159/000292644. osteomas are benign osteogenic lesionspredominantly found in the craniomaxillofacial bones which can be central, peripheral or extraskeletal, arising either from the endosteum, periosteum or soft tissues, respectively.1,2 peripheral osteomas of the jaw bones are quite rare and usually remain asymptomatic until they cause asymmetry or compression of the adjacent structures due to their progressive growth.1–3 although developmental, infect ious, traumatic and neoplastic theories have been proposed, the exact aetiology of these lesions is still unknown.4,5 osteomas have been reported to arise from bone graft sites.6 multiple maxillofacial osteomas can also occur among patients with gardner’s syndrome.5,7,8 this report presents a rare case of solitary peripheral osteoma of the hard palate, followed by a comprehensive literature review. case report a 72-year-old female patient presented to the department of oral & maxillofacial surgery, dental school of athens, athens, greece, in 2015 with complaints of swelling of the palate following extraction of her upper right second molar. eight months earlier, she had noticed a slowly growing asymptomatic mass in the palate at the site of the extraction. she had a medical history of hypothyroidism, diabetes mellitus, arterial hypertension, hypercholesterolaemia, osteopaenia and phlebitis. a clinical examination revealed a well-defined firm bony painless mass of approximately 2 cm in diameter located in the posterior right part of the hard palate. the overlying mucosa was intact with no ulcerations, associated pain or changes in colour [figure 1a]. cone-beam computed tomography (cbct) revealed a well-defined ‘mushroom’-like exophytic pedunculated radiopaque lesion originating from the palatine bone [figure 2]. a comprehensive examination for gardner’s syndrome was negative. based on the clinical and radiographical findings, a diagnosis of a peripheral osteoma was made and an excisional biopsy was performed. under local anaesthesia, a mucosal incision was made and a full thickness flap was elevated. the lesion was wellcircumscribed and attached by a pedicle to the adjacent alveolar bone of the palate. using a chisel and mallet, the lesion was removed and the surgical site debrided. the flap was closed with non-absorbable department of oral & maxillofacial surgery, dental school of athens, athens, greece *corresponding author e-mail: fboudaniotis@yahoo.gr األورام العظمية الطرفية اإلنفرادية للحنك الصلب تقرير حالة ومراجعة األدبيات فوتيو�س بونتانيوتي�س، اإيوني�س ميالكوبولو�س، فوتيو�س تزيربو�س abstract: osteomas are benign slow-growing osteogenic lesions of unknown aetiology which can be central, peripheral or extraskeletal. peripheral osteomas of the maxilla are very uncommon. we report a 72-year-old female patient who presented to the department of oral & maxillofacial surgery, dental school of athens, athens, greece, in 2015 with swelling of the palate following a tooth extraction. clinical and radiographical features were indicative of a solitary peripheral osteoma of the hard palate. an excisional biopsy and histological examination of the lesion confirmed the diagnosis. no complications occurred during the postoperative period and there was no evidence of recurrence at a one-year follow-up. keywords: bone tissue neoplasms; osteomas; maxilla; hard palate; case report; greece. امللخ�ص: االأورام العظمية من االآفات احلميدة بطيئة النمو الغري معروفة ال�سبب و ميكن اأن تكون مركزية، طرفية اأو خارج اجلهازالعظمي. االأورام العظمية الطرفية بالفك العلوي غري �سائعة. ن�سجل هنا حالة مري�سة تبلغ من العمر 72 عاما قدمت اإىل ق�سم جراحة الفم والوجه والفكني، كلية طب االأ�سنان، اأثينا، اليونان، عام 2015، مع تورم يف احلنك بعد خلع اأحد االأ�سنان. كانت اخل�سائ�س ال�رشيرية وال�سعاعية تدل على وجود ورم عظمي طريف انفرادي يف احلنك ال�سلب. واأكدت اخلزعة اال�ستئ�سالية وفح�س اله�ستولوجي هذا الت�سخي�س. مل حتدث اأي م�ساعفات خالل فرتة ما بعد اجلراحة ومل يكن هناك تكرار للحاله خالل �سنة من املتابعه. الكلمات املفتاحية: اأورام االأن�سجة العظمية؛ االأورام العظمية؛ الفك العلوي؛ احلنك ال�سلب؛ تقرير حالة؛ اليونان. solitary peripheral osteoma of the hard palate case report and literature review *fotios bountaniotis, ioannis melakopoulos, fotios tzerbos sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e234–237, epub. 20 jun 17 submitted 25 sep 16 revision req. 31 oct 16; revision recd. 15 nov 16 accepted 15 dec 16 case report doi: 10.18295/squmj.2016.17.02.018 fotios bountaniotis, ioannis melakopoulos and fotios tzerbos case report | e235 3-0 silk sutures. there were no postoperative complications. a histopathological examination revealed mature compact and cancellous bone with marrow spaces and osteocytes, confirming the diagnosis of a peripheral osteoma [figure 3]. at a one-year follow-up, the patient had healed completely and there was no evidence of recurrence [figure 1b]. discussion according to boffano et al., patients with osteomas have a mean age of 48 years and the male-to-female ratio is 0.4:1.9 in the jaws, osteomas appear either on the surface of the bones, as pedunculated and sessile masses arising from the periosteum, or in the medullary space arising from the endosteum.2,4,10 peripheral osteomas of the maxillofacial area are rare, appearing mainly in the paranasal sinuses; the most common site is the frontal sinus, followed by the ethmoidal and maxillary sinuses.8,11 solitary peripheral osteomas of the jaw bones are very uncommon and generally involve the mandible more often than the maxilla.1–3,12 clinical symptoms of an osteoma depend on the location, size and direction of tumour growth; generally, osteomas of the maxillofacial bones remain asymptomatic until they grow large enough to cause disfigurement or compression of the adjacent structures.1–3 neurological symptoms caused by nerve compression may also occur.3,13 on histology, osteomas may be either compact or cancellous masses. compact osteomas usually have a sessile base with normal-appearing dense bone, while cancellous osteomas are generally pedunculated and resemble the bone of origin.14,15 radiographically, peripheral osteomas appear as wellcircumscribed pedunculated or sessile radiopaque masses which seem to have normal bone density.16 in cases of superimposition of the lesion on imaging, cbct can be useful.17 however, it may be difficult to differentiate peripheral osteomas from other lesions using imaging techniques; the differential diagnosis includes peripheral ossifying fibromas, exostoses, sessile osteochondromas, osteoid osteomas, periosteal osteoblastomas and parosteal osteosarcomas.4,5,15 the patient’s medical history and clinical characteristics of the lesion can be helpful in distinguishing a peripheral osteoma from an exostosis, even though there are no histological differences between the two entities; an osteoma will continue to grow during adulthood, unlike exostoses, which usually stop growing after puberty.5,14,18 in addition, the osteoid subtype of figure 1: intraoral photographs of the oral cavity of a 72-year-old female patient (a) at presentation showing a welldefined firm bony painless mass (arrow) in the posterior right part of the hard palate covered by intact mucosa and (b) one year after the successful excisional biopsy of a solitary peripheral osteoma of the hard palate. figure 3: haematoxylin and eosin stain at x200 magnification showing a osteoma consisting of lamellar bone (black arrow), osteocytes (white arrow) and marrow spaces (arrowhead). figure 2: cone-beam computed tomography of a 72-year-old female patient with swelling of the palate showing a ‘mushroom’-like exophytic radiopaque mass originating from the palatine bones (arrows). solitary peripheral osteoma of the hard palate case report and literature review e236 | squ medical journal, may 2017, volume 17, issue 2 osteomas usually grows rapidly and is painful.14,19 a periosteal osteoblastoma has similar characteristics in terms of growth rate and symptoms.14,19 similar to an osteoma, a peripheral ossifying fibroma appears as a radiopaque mass; however, it does not intrude into the cortical bone.15,19 in the current case, the clinical and radiographical features were indicative of a peripheral osteoma. it is difficult to clinically and histologically differentiate an osteoma from torus palatinus; however, the latter is usually located in the midline of the hard palate.19,20 it is worth mentioning that the patient in the present case had undergone a tooth extraction in the area of the osteoma a few months previously; however, it is not clear if this trauma was related to the aetiology of the lesion. although asymptomatic osteomas are treated conservatively with regular follow-up, surgical excision is necessary if the lesion becomes symptomatic, grows too large or is indicated for cosmetic reasons.3 the surgical removal of osteomas is usually performed with a chisel and mallet, as in the present case, although rotary instruments can also be used. following the surgery, recurrence of the lesion is extremely uncommon and malignant transformation has not been reported to date.3,11 the appearance of an osteoma in the maxillofacial region should raise suspicions of gardner’s syndrome; this conditions consists of multiple peripheral and/or central osteomas in any bone—most frequently those in the craniomaxillofacial area—as well as cutaneous sebaceous cysts, desmoid tumours, multiple super numerary teeth and colorectal polyposis.5,7,8 symptoms may also include rectal bleeding, diarrhoea and abdominal pain. in patients with gardner’s syndrome, the osteomas often develop before the colorectal polyposis; therefore, an early diagnosis is of paramount importance.2,3,7 the patient in the current case underwent a thorough examination for gardner’s syndrome, which was eventually ruled out. conclusion peripheral osteomas of the jaws are relatively uncommon and dentists and maxillofacial surgeons should be aware of the differential diagnosis and clinical characteristics of these lesions. multiple osteomas can be indicative of gardner’s syndrome; as such, an early diagnosis can be very important for the patient’s prognosis. osteomas are treated conservatively in asymptomatic cases, but may require surgical excision when indicated. references 1. woldenberg y, nash m, bodner l. peripheral osteoma of the maxillofacial region: diagnosis and management a study of 14 cases. med oral patol oral cir bucal 2005; 10:e139–42. 2. shakya h. peripheral osteoma of the mandible. j clin imaging sci 2011; 1:56. doi: 10.4103/2156-7514.90483. 3. sharma d, sathe s, rawat b, agrawal d, khasgiwala a, shakya n. a study on peripheral osteomas of the maxillofacial region. j evol med dent sci 2015; 4:8545–51. doi: 10.14260/ jemds/2015/1237. 4. prabhuji ml, kishore hc, sethna g, moghe ag. peripheral osteoma of the hard palate. j indian soc periodontol 2012; 16:134–7. doi: 10.4103/0972-124x.94623. 5. gundewar s, kothari ds, mokal nj, ghalme a. osteomas of the craniofacial region: a case series and review of literature. indian j plast surg 2013; 46:479–85. doi: 10.4103/0970-0358. 121982. 6. colletti g, autelitano l, rabbiosi d, tewfik k, frigerio a, biglioli f. parosteal osteoma arising in an iliac bone graft used for mandibular reconstruction. j oral maxillofac surg 2012; 70:e477–80. doi: 10.1016/j.joms.2012.03.008. 7. boffano p, bosco gf, gerbino g. the surgical management of oral and maxillofacial manifestations of gardner syndrome. j oral maxillofac surg 2010; 68:2549–54. doi: 10.1016/j.joms. 2009.09.084. 8. lew d, dewitt a, hicks rj, cavalcanti mg. osteomas of the condyle associated with gardner’s syndrome causing limited mandibular movement. j oral maxillofac surg 1999; 57:1004–9. doi: 10.1016/s0278-2391(99)90026-5. 9. boffano p, roccia f, campisi p, gallesio c. review of 43 osteomas of the craniomaxillofacial region. j oral maxillofac surg 2012; 70:1093–5. doi: 10.1016/j.joms.2011.05.006. 10. iwai t, izumi t, baba j, maegawa j, mitsudo k, tohnai i. peripheral osteoma of the mandibular notch: report of a case. iran j radiol 2013; 10:74–6. doi: 10.5812/iranjradiol.3734. 11. hu w, thadani s, agrawal m, sharma n, tailor s. peripheral osteoma of the palate: report of a case and review of literature. j clin diagn res 2014; 8:zd29–31. doi: 10.7860/ jcdr/2014/7888.5351. 12. bulut e, acikgoz a, ozan b, gunhan o. large peripheral osteoma of the mandible: a case report. int j dent 2010; 2010:834761. doi: 10.1155/2010/834761. 13. ogbureke ku, nashed mn, ayoub af. huge peripheral osteoma of the mandible: a case report and review of the literature. pathol res pract 2007; 203:185–8. doi: 10.1016/j. prp.2007.01.004. 14. manjunatha bs, das n, sutariya r, ahmed t. peripheral osteoma of the body of mandible. bmj case rep 2013; 2013:bcr2013009857. doi: 10.1136/bcr-2013-009857. 15. johann ac, de freitas jb, de aguiar mc, de araújo ns, mesquita ra. peripheral osteoma of the mandible: case report and review of the literature. j craniomaxillofac surg 2005; 33:276–81. doi: 10.1016/j.jcms.2005.02.002. 16. durão ar, chilvarquer i, hayek je, provenzano m, kendall mr. osteoma of the zygomatic arch and mandible: report of two cases. rev port estomatol cir maxilofac 2012; 53:103–7. doi: 10.1016/j.rpemd.2012.02.006. 17. boffano p, gallesio c, roccia f, berrone s. radiographic superimposition and mandibular peripheral osteoma: the importance of clinical and ct findings. j craniofac surg 2013; 24:e141–2. doi: 10.1097/scs.0b013e31827c7e87. https://doi.org/10.4103/2156-7514.90483 https://doi.org/10.14260/jemds/2015/1237 https://doi.org/10.14260/jemds/2015/1237 https://doi.org/10.4103/0972-124x.94623 https://doi.org/10.4103/0970-0358.121982 https://doi.org/10.4103/0970-0358.121982 https://doi.org/10.1016/j.joms.2012.03.008 https://doi.org/10.1016/j.joms.2009.09.084 https://doi.org/10.1016/j.joms.2009.09.084 https://doi.org/10.1016/s0278-2391%2899%2990026-5 https://doi.org/10.1016/j.joms.2011.05.006 https://doi.org/10.5812/iranjradiol.3734 https://doi.org/10.7860/jcdr/2014/7888.5351 https://doi.org/10.7860/jcdr/2014/7888.5351 https://doi.org/10.1155/2010/834761 https://doi.org/10.1016/j.prp.2007.01.004 https://doi.org/10.1016/j.prp.2007.01.004 https://doi.org/10.1136/bcr-2013-009857 https://doi.org/10.1016/j.jcms.2005.02.002 https://doi.org/10.1016/j.rpemd.2012.02.006 https://doi.org/10.1097/scs.0b013e31827c7e87 fotios bountaniotis, ioannis melakopoulos and fotios tzerbos case report | e237 18. rodriguez y baena r, rizzo s, fiandrino g, lupi s, galioto s. mandibular traumatic peripheral osteoma: a case report. oral surg oral med oral pathol oral radiol endod 2011; 112:e44–8. doi: 10.1016/j.tripleo.2011.05.006. 19. soni s, bhargava a. revisiting peripheral osteoma of the mandible with case series and review of literature. indian j otolaryngol head neck surg 2014; 66:212–18. doi: 10.1007/ s12070-012-0583-9. 20. apinhasmit w, jainkittivong a, swasdison s. torus palatinus and torus mandibularis in a thai population. scienceasia 2002; 28:105–11. https://doi.org/10.1016/j.tripleo.2011.05.006 https://doi.org/10.1007/s12070-012-0583-9 https://doi.org/10.1007/s12070-012-0583-9 an awake craniotomy is a procedure used for the resection of brain tumours from the eloquent cortex and during surgeries for epilepsy and movement disorders.1 this technique is also used for the management of aneurysms and arteriovenous malformations near key areas of the brain, such as areas responsible for movement, language, sensation, vision, hearing, thought processing, fine motor skills and coordination. the principal advantage of this technique is that it permits lesion removal without compromising the functional integrity of the brain by damaging the eloquent cortex, therefore resulting in enhanced neurological recovery.1 growing evidence also indicates that there are greater survival benefits associated with an awake craniotomy.2 other advantages include shorter intensive care unit (icu) and overall hospital stays, a decreased incidence of postoperative complications such as nausea and vomiting and significantly reduced cost of care.3 case report a 29-year-old man presented to the khoula hospital, muscat, oman, in 2016 with a two month history of headaches and convulsions. he had initially been managed at a peripheral hospital where a computed departments of 1anaesthesia & intensive care and 2neurosurgery, khoula hospital, muscat, oman *corresponding author e-mail: nilay.chatt@gmail.com ة من مزيج من الدكسميديتوميدين )باجلرعة املستمرة( مع جرعة خمفضة ومعريَّ الفنتانيل و الربوبوفول يف عملية حج القحف واملريض يف وعيه تقرير حالة �صامار�ض دا�ض، علي املع�صني، نيالم �صوري، نرياج �صالوترا، نيلوي ت�صاترجي abstract: an awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. we report a 29-year-old male patient who presented to the khoula hospital, muscat, oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. an awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofol-fentanyl. the patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. this case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. to the best of the authors’ knowledge, this is the first awake craniotomy conducted successfully in oman. keywords: anesthesia; craniotomy; dexmedetomidine; propofol; fentanyl; case report; oman. امللخ�ص: حج القحف )�صق اجلمجمة( اأثناء الوعي هي تقنية تتطور با�صتمرار ال�صتئ�صال اأورام املخ من الق�رضة البليغة، ح�رض مري�ض يبلغ من العمر 29 عامًا اإىل م�صت�صفى خولة، م�صقط، �صلطنة عمان، يف عام 2016. وكان يعاين املري�ض من ال�صداع امل�صتمر والت�صنجات ملدة �صهرين ب�صبب ورم بالدماغ على مقربة من الق�رضة احلركية الي�رضى، ثم اأجريت عملية حج القحف واملري�ض يف حالة الوعي با�صتخدام ة من الفنتانيل و الربوبوفول، تخدير فروة الراأ�ض املو�صعي مع مزيج من الدك�صميديتوميدين )باجلرعة امل�صتمرة( و جرعة خمف�صة ومعريَّ ظل املري�ض يف حالة ارتياح وا�صتقرار من خالل ا�صتئ�صال الورم كما اأظهر ذلك ر�صم خرائط الدماغ وجميع االإختبارات النف�صية الع�صبية اأثناءالعملية. ي�صري هذا التقرير اإىل فعالية ا�صتخدام املزيج املذكور يف التخدير لعملية حج القحف واملري�ض يف وعيه مما قد ي�صاعد يف حدوث تخدير اأف�صل و اإزالة تثبيط اأقل و اإعادة ا�صتقرار �رضيع، بالن�صبة للموؤلفني تعترب عملية حج القحف واملري�ض يف وعيه االأوىل من نوعها يف �صلطنة عمان. كلمات مفتاحية: التخدير؛ حج القحف؛ الديك�صميديتوميدين؛ الربوبوفول؛ الفنتانيل؛ تقرير حالة؛ ُعمان. combination of continuous dexmedetomidine infusion with titrated ultra-low-dose propofol-fentanyl for an awake craniotomy case report samaresh das,1 ali al-mashani,2 neelam suri,1 neeraj salhotra,2 *nilay chatterjee1 sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e347–351, epub. 19 aug 16 submitted 2 mar 16 revision req. 3 apr 16; revision recd. 24 apr 16 accepted 12 may 16 case report doi: 10.18295/squmj.2016.16.03.014 combination of continuous dexmedetomidine infusion with titrated ultra-low-dose propofol-fentanyl for an awake craniotomy case report e348 | squ medical journal, august 2016, volume 16, issue 3 tomography scan of the brain revealed a left frontoparietal parafalcine lesion measuring 3.7 x 3.6 x 3.0 cm. he was prescribed antiepileptics including dexamethasone and referred to the khoula hospital, a tertiary care neurosurgical centre. before referral, the patient had multiple episodes of left-sided jerky movements in his upper limbs. magnetic resonance imaging revealed a left cortical-subcortical frontal gyrus lesion surrounded by oedema with peripheral diffusion restriction. the lesion reached the premotor cortex and was in close proximity with the motor cortex, although it did not affect the left precentral gyrus [figure 1]. considering the critical location of the lesion, an awake craniotomy was scheduled. the patient was counselled by both a neurosurgeon and neuroanaesthesiologists and given a detailed explanation of the procedure, including the benefits and associated risks and the need for intraoperative neuropsychological testing. he was reassured that any complications arising during the procedure would be addressed immediately. during the pre-anaesthetic check-up, the patient’s airway was assessed and the results of previous investigations were reviewed. anticonvulsants and dexamethasone were continued as previously prescribed and 7.5 mg of midazolam was administered orally the night before the procedure. on the day of the surgery, 4 mg of ondansetron, 40 mg of pantoprazole and 7.5 mg of midazolam were administered to the patient at 6 am. after the patient was transferred to the operating theatre, a 16g intravenous cannula and a 20g arterial cannula in the left radial artery were placed under local anaesthesia. standard monitoring as recommended by the american society of anesthesiologists was initiated.4 dexmedetomidine was infused (1 µg/kg over the first 10 minutes as a loading dose followed by 0.5 µg/kg/hour), along with propofol (50 µg/kg/minute) and fentanyl (0.01 µg/kg/minute). the patient was oxygenated through a face mask (4 l/minute) and end-tidal carbon dioxide was monitored by attaching the sampling tube to the inner surface of the mask. the propofol and dexmedetomidine infusions were adjusted to maintain a ramsay sedation scale score of between 2–3. a scalp block was applied bilaterally, targeting the nerves supplying the scalp (e.g. the supratrochlear, supraorbital, zygomaticotemporal, auriculotemporal, great auricular and greater and lesser occipital nerves). approximately 2–3 ml of 0.25% bupivacaine was used for each nerve. the head was positioned and fixed using skull pins (mayfield® skull pins, integra lifesciences corp., plainsboro, new jersey, usa) applied 15 minutes after the scalp block. surgical drapes were adjusted so as to maintain easy access to the patient’s airway. considering the patient’s cooperation and level of tolerance, it was decided that he would be kept awake throughout the craniotomy. an emergency plan was formulated to secure the patient’s airway with a laryngeal mask airway device (lma proseal™, teleflex® incorporated, wayne, pennsylvania, usa), if needed. before starting the surgery, the dura was infiltrated with 10 ml of 2% lignocaine. the dura incision was made [figure 2a] without the patient complaining of pain. upon opening the dura, increased intracranial pressure was figure 1a–f: magnetic resonance imaging (mri) of a patient with headaches and convulsions due to a space-occupying brain lesion. a: coronal t2-weighted mri showing a hyperintense left frontal intra-axial space-occupying lesion in the left superior frontal gyrus surrounded by oedema (arrow). b: coronal fluid-attenuated inversion recovery mri showing peripheral hyperintensity around the lesion (arrow). c: axial t2-weighted mri showing the lesion (arrow). d: sagittal post-contrast mri showing the non-contrast enhancing lesion in the left frontal lobe approaching the motor cortex (arrow). e: diffusion-weighted mri showing peripheral diffusion restriction of the lesion (arrow). f: mri spectroscopy showing decreased n-acetylaspartate and enhanced choline peaks, indicating a high-grade tumour. samaresh das, ali al-mashani, neelam suri, neeraj salhotra and nilay chatterjee case report | e349 figure 2a & b: photographs of an awake craniotomy performed on a patient with a space-occupying brain lesion showing the (a) opening of the dura and (b) resection of the tumour. and patient are key.3 during awake craniotomies, patients do not always remain awake throughout the course of the entire surgery. varying levels of sedation or anaesthesia are needed for certain parts of the procedure, such as during the scalp incision, craniotomy or opening of the dura.3 depending on the anaesthetist’s preference and the extent of the patient’s understanding and cooperation, either an “awake throughout” or “asleep/awake and asleep” technique is selected. in the former technique, only sedation and analgaesia are used, whereas the latter includes general anaesthesia and involves securing the airway with a laryngeal mask airway device during the initial “asleep” phase.3 however, regardless of technique, the patient must be completely awake during the brain mapping and neuropsychological tests. thereafter, the patient can either be kept awake or re-anesthetised depending on the situation. a scalp block is frequently used for pain relief in both types of awake craniotomy techniques.3 to the best of the authors’ knowledge, this case reports the first awake craniotomy conducted successfully in oman. the most commonly used anaesthetic agents for an awake craniotomy are propofol, opioids and dexmedetomidine. an infusion of propofol supplemented with an opioid is the most frequently used combination, as it improves the quality of the analgaesia and reduces hypnotic requirements.3,6–8 gignac et al. found no difference in operative conditions, electrocorticography findings and stimulation testing results when comparing various opioids.9 in another study, both intermittent fentanyl and continuous remifentanil infusions resulted in similar rates of patient satisfaction, recall and intraoperative complications.10 overall, these opioids seem to be equally efficacious for awake craniotomies.6 increasingly, the α2 agonist dexmedetomidine is used in awake craniotomies due to its unique sedative, observed; this was managed with mannitol (0.5 g/kg) and frusemide (10 mg). the propofol and fentanyl infusions were then stopped and the patient was woken completely. supplemental doses of anticonvulsants and ondansetron were administered. neuropsychological tests were carried out to check the patient’s motor functions, orientation, memory, attention, articulation, ability to name pictures and objects, read and repeat words and perform arithmetic calculations. additionally, brain mapping by direct electrical stimulation using bipolar electrodes was performed. the patient remained completely awake, cooperative and responsive. the tumour was excised [figure 2b] and cortical mapping ensued. throughout the surgery, the patient remained haemodynamically stable and was able to follow verbal commands and communicate effectively. the dexmedetomidine infusion (0.5 μg/kg/hour) was continued throughout the procedure. after completing the tumour resection, propofol and fentanyl infusions were initiated once again and the sedation was increased. following the closure of the skin incision, all infusions of sedatives were discontinued and the patient was transferred to the icu for observation. postoperatively, the patient exhibited no neurological deficits and his icu stay was uneventful. the patient was transferred to a normal ward the following morning and was discharged on the fourth postoperative day. histopathological analysis of the lesion revealed it to be an astrocytoma (world health organization grade ii).5 discussion the anaesthetic considerations required for an awake craniotomy are challenging. careful patient selection, preoperative preparation and effective communication between the neuroanaesthetist, neurosurgeon combination of continuous dexmedetomidine infusion with titrated ultra-low-dose propofol-fentanyl for an awake craniotomy case report e350 | squ medical journal, august 2016, volume 16, issue 3 analgaesic and anxiolytic properties and because of its minimal effects on ventilation.7 dexmedetomidine reduces opioid requirements by 30–50%, is not associated with disinhibition—a common problem with propofol and benzodiazepines—and has minimal effects on electrocorticography.7 however, no research is as yet available to make a direct comparison between propofol-opioids and dexmedetomidine for awake craniotomies. in the current case, a constant infusion of dexmedetomidine and an ultra-low-dose infusion of propofol-fentanyl were used to ensure optimum sedation, minimal disinhibition and a rapid recovery. the propofol-fentanyl infusions were halted after the dura was opened to allow the patient sufficient time to emerge from sedation and undergo intraoperative testing; the necessary amount of time has been reported to be approximately nine minutes with such combinations.11 the principal advantages of this combination are that the propofol-fentanyl can be titrated for the individual’s specific physiological requirements to maintain sleep and that it can be terminated before brain mapping; in addition, it can be reinitiated to deepen sedation or to induce a second sleep phase if needed.11 neuropsychological tests and cortical mapping are critical steps during an awake craniotomy.3 during this stage, the patient is awoken if asleep beforehand and is allowed to gradually adjust to the environment before clinical evaluation. emergence from sedation can cause several complications, such as pain and discomfort, agitation, nausea and vomiting.3 if any of these occur, they should be addressed immediately before they lead to poor surgical conditions. the objective of cortical stimulation or brain mapping is to localise the eloquent areas of the brain—the areas involved in speech and language comprehension— and the motor and sensory cortex through direct electrical stimulation of the cerebral cortex.8 if there are any alterations in the patient’s speech, language or motor function during electrical stimulation, the neurosurgeon is immediately notified.12 once the cortex has been mapped functionally, resection of the lesion continues. during cortical mapping, focal or generalised seizures have been reported to occur in up to 16% of patients undergoing craniotomies with conscious sedation.13 these are usually managed by irrigating the brain tissue with ice-cold saline; seizures which do not respond to ice-cold saline are treated with benzodiazepines, anti-epileptics or sedation with control of the airway.6 the anaesthetist should always have an emergency plan for airway control, keeping in mind that securing the airway in a patient whose head is fixed in place with skull pins can be extremely challenging. the proseal™ laryngeal mask airway device (teleflex® incorporated) is an optimal choice in this context.8 intolerance to the awake craniotomy procedure on the part of the patient is the most frequently encountered complication, commonly due to prolonged or improper positioning, the presence of a urinary catheter or the occurrence of intraoperative seizures.8 other known intraoperative adverse events include hypoventilation, hypoxia, hypercapnia, hypo or hypertension, bradyor tachycardia, brain swelling, anxiety, agitation or fatigue.14,15 conclusion an awake craniotomy is a well-tolerated procedure with few inherent complications. this case report describes a successful awake craniotomy using continuous dexmedetomidine combined with ultralow-dose titrated propofol-fentanyl infusions. this effective combination allows for the rapid titration of the sedative to desired levels during the initial part of the surgery and the discontinuance of the propofol-fentanyl infusion thereafter in order to allow the patient to wake up rapidly for intraoperative neuropsychological tests and cortical mapping. references 1. ghazanwy m, chakrabarti r, tewari a, sinha a. awake craniotomy: a qualitative review and future challenges. saudi j anaesth 2014; 8:529–39. doi: 10.4103/1658-354x.140890. 2. yordanova yn, moritz-gasser s, duffau h. awake surgery for who grade ii gliomas within “noneloquent” areas in the left dominant hemisphere: toward a “supratotal” resection clinical article. j neurosurg 2011; 115:232–9. doi: 10.3171/2011.3.jns101333. 3. burnard c, sebastian j. anaesthesia for awake craniotomy. contin educ anaesth crit care pain 2013; 14:6–11. doi: 10. 1093/bjaceaccp/mkt024. 4. american society of anesthesiologists. standards and guidelines. from: www.asahq.org/quality-and-practice-manage ment/standards-and-guidelines accessed: april 2016. 5. louis dn, perry a, reifenberger g, von deimling a, figarella-branger d, cavenee wk, et al. the 2016 world health organization classification of tumors of the central nervous system: a summary. acta neuropathol 2016; 131:803–20. doi: 10.1007/s00401-016-1545-1. 6. chui j. anesthesia for awake craniotomy: an update. rev colomb anestesiol 2015; 43:22–8. doi: 10.1016/j.rcae.2014. 07.003. 7. bekker a, sturaitis mk. dexmedetomidine for neurological surgery. neurosurgery 2005; 57:1–10. doi: 10.1227/01.neu.0000 163476.42034.a1. 8. brydges g, atkinson r, perry mj, hurst d, laqua t, wiemers j. awake craniotomy: a practice overview. aana j 2012; 80:61–8. 9. gignac e, manninen ph, gelb aw. comparison of fentanyl, sufentanil and alfentanil during awake craniotomy for epilepsy. can j anaesth 1993; 40:421–4. doi: 10.1007/bf03009510. http://dx.doi.org/10.4103/1658-354x.140890 http://dx.doi.org/10.3171/2011.3.jns101333 http://dx.doi.org/10.1093/bjaceaccp/mkt024 http://dx.doi.org/10.1093/bjaceaccp/mkt024 http://dx.doi.org/10.1007/s00401-016-1545-1 http://dx.doi.org/10.1016/j.rcae.2014.07.003 http://dx.doi.org/10.1016/j.rcae.2014.07.003 http://dx.doi.org/10.1227/01.neu.0000163476.42034.a1 http://dx.doi.org/10.1227/01.neu.0000163476.42034.a1 http://dx.doi.org/10.1007/bf03009510 samaresh das, ali al-mashani, neelam suri, neeraj salhotra and nilay chatterjee case report | e351 13. archer dp, mckenna jm, morin l, ravussin p. conscioussedation analgesia during craniotomy for intractable epilepsy: a review of 354 consecutive cases. can j anaesth 1988; 35:338–44. doi: 10.1007/bf03010852. 14. olsen ks. the asleep-awake technique using propofolremifentanil anaesthesia for awake craniotomy for cerebral tumours. eur j anaesthesiol 2008; 25:662–9. doi: 10.1017/ s0265021508003633. 15. lobo f, beiras a. propofol and remifentanil effect-site concentrations estimated by pharmacokinetic simulation and bispectral index monitoring during craniotomy with intraoperative awakening for brain tumor resection. j neurosurg anesthesiol 2007; 19:183–9. doi: 10.1097/ana. 0b013e31805f66ad. 10. manninen ph, balki m, lukitto k, bernstein m. patient satisfaction with awake craniotomy for tumor surgery: a comparison of remifentanil and fentanyl in conjunction with propofol. anesth analg 2006; 102:237–42. doi: 10.1213/01. ane.0000181287.86811.5c. 11. keifer jc, dentchev d, little k, warner ds, friedman ah, borel co. a retrospective analysis of a remifentanil/propofol general anesthetic for craniotomy before awake functional brain mapping. anesth analg 2005; 101:502–8. doi: 10.1213/01. ane.0000160533.51420.44. 12. pereira lc, olivira km, l’abbate gl, sugai r, ferreira ja, da motta la. outcome of fully awake craniotomy for lesions near the eloquent cortex: analysis of a prospective surgical series of 79 supratentorial primary brain tumors with long follow-up. acta neurochir (wien) 2009; 151:1215–30. doi: 10.1007/s00701-009-0363-9. http://dx.doi.org/10.1007/bf03010852 http://dx.doi.org/10.1017/s0265021508003633 http://dx.doi.org/10.1017/s0265021508003633 http://dx.doi.org/10.1097/ana.0b013e31805f66ad http://dx.doi.org/10.1097/ana.0b013e31805f66ad http://dx.doi.org/10.1213/01.ane.0000181287.86811.5c http://dx.doi.org/10.1213/01.ane.0000181287.86811.5c doi:%2010.1213/01.ane.0000160533.51420.4410.1213/01.ane.0000160533.51420.44 doi:%2010.1213/01.ane.0000160533.51420.4410.1213/01.ane.0000160533.51420.44 http://dx.doi.org/10.1007/s00701-009-0363-9 سرطان الدم الليمفاوي الناتج عن خلية-ت-الكبرية مع انتشار املرض يف اجللد t cell large granular lymphocyte leukaemia with cutaneous infiltration sir, a 63-year-old woman was referred to the department of dermatology of the complejo hospitalario de granada, granada, spain, in 2016 with painful erythematous desquamative nodules and papules of three weeks’ duration. she had a history of stage i infiltrating ductal carcinoma of the breast, unilinear myelodysplastic syndrome with granulocytic involvement, chronic neutropaenia and a diagnosis of t cell (cluster of differentiation [cd]8+) large granular lymphocyte (lgl) leukaemia. upon examination, the papules were distributed mainly on the forehead and right upper and lower limbs [figures 1a–c]. some of the lesions were fluctuating and suppurative, while the others were of a solid consistency. the examination also revealed oral aphthae which were causing dysphagia [figure 1d]. at referral, the patient was receiving treatment with 50 mg of low-dose cyclosporine on alternate days and 300 μg of granulocyte-colony stimulating factor per week, to which a partial response was noted. given the suspicion of leukaemia cutis, a biopsy of the lesions was taken. the findings were compatible with a diagnosis of folliculitis, with polymerase chain reaction and direct immunofluorescence tests negative for mycobacterium tuberculosis and immunoglobulin (ig) g, iga, igm and complement 3 deposits, respectively. consequently, treatment with 500 mg of cloxacillin every six hours and 15 mg of prednisone per day was initiated; however, there was no evidence of clinical improvement. successive biopsies indicated systemic vasculitis caused by granulomatosis with polyangiitis. eventually, nine months after the onset of the symptoms, a final biopsy revealed that the papules represented the cutaneous infiltration of lgl leukaemia [figure 2], associated with secondary interstitial granulomatous dermatitis. at the time of writing, the patient was being treated with combined cyclophosphamide, vincristine, doxorubicin and prednisone (chop) therapy which resulted in the resolution of her cutaneous symptoms [figure 3]. there was no evidence on computed tomography of any systemic progression to other organs. lgl leukaemia is a low-grade lymphoproliferative disorder characterised by monoclonal expansion in the peripheral blood and bone marrow with either an activated cytotoxic t lymphocyte (i.e. cd8 or cd57+ cells) or, less frequently, a natural killer (cd3-, cd8or cd56+ cells) phenotype.1 generally, lgls represent 10–15% of circulating mononuclear cells and are identified morphologically by their large size and rounded or dentate nuclei and abundant cytoplasm with azurophilic granules.2 clonality has been confirmed by t cell receptor gene letter to the editor sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e489–490, epub. 10 jan 18 submitted 31 may 17 peer-reviewed accepted 10 aug 17 doi: 10.18295/squmj.2017.17.04.022 figure 1: photographs of infiltrated papules and patches on the (a) forehead and right (b) upper and (c) lower limbs of a 63-year-old woman with large granular lymphocyte leukaemia. the clinical examination also revealed (d) major aphthae in the oral cavity. figure 2: immunohistochemistry panel at x20 magnification showing positive (a) cluster of differentiation (cd)2, (b) cd8, (c) cd57 and (d) t cell intracytoplasmic antigen 1 stains. t cell large granular lymphocyte leukaemia with cutaneous infiltration e490 | squ medical journal, november 2017, volume 17, issue 4 rearrangement testing.3 frequently, lgl leukaemia is related to autoimmune diseases such as felty’s syndrome and has a chronic and indolent course, with a mean survival of 10 years.4,5 occasionally, the behaviour of this form of leukaemia can be more aggressive, especially in cases with a natural killer phenotype.2 approximately one-third of patients with lgl leukaemia are clinically asymptomatic, with neutropaenia observed in up to 85% of cases.3 the disease is sometimes associated with arthritis, cytopaenia and splenomegaly, but only exceptionally with lymphadenopathy.4 cuta neous infiltration is rare and usually manifests as papules, nodules or, even less frequently, leg ulcers.4,6 other reports have described lgl leukaemia patients presenting with generalised erythema and pruritus, petechiae and disseminated granuloma annulare.6–8 the indolent course of the disease usually permits a ‘wait and see’ approach, although indications for treatment include recurrent infections, anaemia, symptomatic splenomegaly or severe b symptoms.5 immunosuppressants are the first line of treatment, such as methotrexate, cyclosporine, or cyclophosphamide; these monotherapies are effective in almost 50% of patients by correcting cytopaenia without eradicating the leukaemia cells.9 however, for those with refractory or highly aggressive forms of the disease, chop therapy or a similar chemotherapy regimen is recommended. trials with purine analogues, alemtuzumab, bortezomib, splenectomies or allogeneic bone marrow transplants have resulted in variable outcomes.1,9 *ricardo ruiz-villaverde,1 ahinoa bueno-rodriguez,1 paula aguayo-carreras,1 daniel sánchez-cano,2 norberto ortego-centeno3 1department of dermatology, complejo hospitalario de granada, granada, spain; 2department of internal medicine, hospital comarcal santa ana de motril, motril, spain; 3systemic autoimmune diseases unit, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com references 1. lamy t, loughran tp jr. how i treat lgl leukemia. blood 2011; 117:2764−74. doi: 10.1182/blood-2010-07-296962. 2. lois iglesias a, sifuentes giraldo wa, bachiller corral j, saiz gonzález a, brito brito e, zea mendoza a. large granular lymphocyte leukemia as a complication of rheumatoid arthritis. reumatol clin 2012; 8:365−7. doi: 10.1016/j.reuma.2011.12.014. 3. mohan sr, maciejewski jp. diagnosis and therapy of neutropenia in large granular lymphocyte leukemia. curr opin hematol 2009; 16:27−34. doi: 10.1097/moh.0b013e32831c8407. 4. duarte af, nogueira a, mota a, baudrier t, canelhas a, cancela j, et al. leg ulcer and thigh telangiectasia associated with natural killer cell cd56(-) large granular lymphocyte leukemia in a patient with pseudo-felty syndrome. j am acad dermatol 2010; 62:496−501. doi: 10.1016/j.jaad.2009.03.001. 5. liu x, loughran tp jr. the spectrum of large granular lymphocyte leukemia and felty’s syndrome. curr opin hematol 2011; 18:254−9. doi: 10.1097/moh.0b013e32834760fb. 6. sia pi, figueira e, kuss b, craig j, selva d. t-cell large granular lymphocyte leukemia in the lower eyelid. ophthal plast reconstr surg 2016; 32:e126−8. doi: 10.1097/iop.0000000000000297. 7. granjo e, lima m, correia t, lisboa c, magalhães c, cunha n, et al. cd8(+)/v beta 5.1(+) large granular lymphocyte leukemia associated with autoimmune cytopenias, rheumatoid arthritis and vascular mammary skin lesions: successful response to 2-deoxycoformycin. hematol oncol 2002; 20:87−93. doi: 10.1002/hon.695. 8. granjo e, lima m, lopes jm, fernandes jc, antunes i, candeias j, et al. response to cyclosporine in a patient with disseminated granuloma annulare associated with cd4+/cd8+(dim)/cd56+ large granular lymphocytic leukemia. arch dermatol 2002; 138: 274−6. doi: 10.1001/archderm.138.2.266. 9. lazaro e, caubet o, menard f, pellegrin jl, viallard jf. [large granular lymphocyte leukemia]. presse med 2007; 36:1694−700. doi: 10.1016/j.lpm.2007.06.002. figure 3: photographs of the (a) forehead and (b) upper right limb of a 63-year-old woman showing the resolution of large granular lymphocyte leukaemia-infiltrated papules and patches following chemotherapy treatment. https://doi.org/10.1182/blood-2010-07-296962 https://doi.org/10.1016/j.reuma.2011.12.014 https://doi.org/10.1097/moh.0b013e32831c8407 https://doi.org/10.1016/j.jaad.2009.03.001 https://doi.org/10.1097/moh.0b013e32834760fb https://doi.org/10.1097/iop.0000000000000297 https://doi.org/10.1002/hon.695 https://doi.org/10.1001/archderm.138.2.266 https://doi.org/10.1016/j.lpm.2007.06.002 pathophysiology of obstructive sleep apnoea syndrome: a review medical sciences (2000), 2, 117–124 © 2000 sultan qaboos university 1department of medicine, 2department of clinical physiology, college of medicine, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. e-mail: bazdawi@squ.edu.om 117 pathophysiology of obstructive sleep apnoea syndrome: a review *al riyami b1, al rawas o1, hassan mo2 االنسدادي النفس إنقطاع لمالزمة الفيزيولوجياالمرضية مراجعة: النوم أثناء بزدوي الريامي ، عمر الرواس ومحمد حسن عثمان المراضه نسبة في زيادة من تسببه لما وذلك آبيًرا صحيًا خطًرآ وتشكل الشائعة األمراض من النوم أثناء االنسدادي لنفسا إنقطاع متالزمة تعتبر :الخالصة الرغبة في ونقص االآتئاب ، العام والضعف االرهاق ، النهار أثناء المفرط النوم المتالزمة هذه من أعراض . والدماغ القلب شرايين أمراض من والوفيات . وراثية عوامل له أن آما العمر أواسط في الرجال وخاصة المفرطة السمنة أصحاب عند المرض هذا ويكثر . الصماء الغدد اضطرابات جانب الى ةالجنسي من أقل النامية لالدو في زال ما به االهتمام فإن الكبيرة الصحية المشاآل من آونه ربغال في رض مؤخرا الم ا هذ القاه الذي المتزايد االهتمام من وبالرغم أثناء االنسدادي النفس إنقطاع لمتالزمة المرضية الفيزيولوجيا لمناقشة تعرضنو النوم أثناء التنفسية باألمراض بالتعريف قومن المراجعة هذه في. المطلوب .للمؤلفين السريرية الخبرة جانب الى الحالية المعرفة ضوء في النوم abstract: sleep apnoea syndrome is a common disorder and a major health hazard that affects many body systems. it is particularly associated with increased cardiovascular and cerebrovascular morbidity and mortality. among its other manifestations include increased daytime somnolence, fatigue, depression, reduced sexual libido and endocrine dysfunction. the main risk factors are obesity, male gender, middle age and heredity. despite being a recognised major health problem in the industrialised countries, this condition has not yet received its due importance in the developing world. this review introduces breathing disorders during sleep and discusses the pathophysiological features of obstructive sleep apnoea syndrome in the light of the currently available literature and the authors’ own clinical experience. key words: sleep; apnoea; obstructive; mortality; cardiovascular; airway isordered breathing during sleep is a common condition with an estimated prevalence of up to 24% in men and 9% in women in north america.1 it is associated with excessive morbidity and increased mortality from cardiovascular and cerebrovascular events and increased risk of road traffic accidents.2 the condition can be suspected clinically in the presence of classic symptoms such as snoring, daytime hypersomnolence, obesity and male gender. the diagnosis is confirmed by polysomnography. continuous positive airway pressure (cpap) has been the mainstay of treatment although various other modalities are still being investigated. the most important among these disorders is obstructive sleep apnoea syndrome (osas), also known as sleep apnoea hypopnoea syndrome (sahs). this condition is so much linked to excessive morbidity and mortality that it is considered a public health hazard at par with smoking.3 this review details the pathophysiological mechanisms and clinical effects of this condition. pathophysiology upper airway features in patients with osas an apnoea is complete cessation of breathing, either due to the failure of the central nervous system to initiate breathing stimulus (central apnoea), or more commonly due to obstruction of the upper airways (obstructive apnoea). concurrent occurrence of central and obstructive apnoeas is called mixed apnoea. the term hypopnoea refers to 50% reduction in breathing.4 most, if not all, obstructive apnoeas are caused by a collapse of the pharyngeal airway. pharyngeal patency depends critically on the action of dilator muscles, which contract during each inspiration to prevent the upper airway from being closed by suction. muscle tone decreases d a l r i y a m i e t a l 118 throughout the body during sleep, and the upper airway dilating muscles relax. in many individuals, this results in considerable upper airway narrowing during inspiration, and causes the turbulent flow and vibration of snoring.5 these events were thought to be clinically important only if they resulted in occlusion of the airway, cessation of airflow, and apnoea.6,7 however, more recent studies have indicated that these same effects may result from episodes of hypopnoea which effect continued but reduced ventilation.8 recent investigations suggest that episodes of airway narrowing that result in increased ventilatory effort without diminution of ventilation may also produce symptoms of the so-called upper airways resistance syndrome (uars). typical findings of uars on sleep study are: (1) repetitive arousals from eeg sleep coinciding with a (2) waxing and waning of the respiratory airflow pattern and (3) increased respiratory effort as measured by oesophageal pressure monitoring.9 there may be few, if any, obvious apnoeas or hypopnoeas with desaturation, but snoring may be a very prominent finding.10 arousals usually restore upper airway dilating muscle tone and the patient gasps, takes a few deep breaths, and falls back to sleep, at which point the upper airway dilating muscles relax again and the cycle starts off once more. these episodes of upper airway narrowing, terminated by arousal, may recur many hundred times in a night. this recurrent sleep disruption accounts for the daytime symptoms and clinical features of the condition.11 the narrowest point of the upper airway in awake normal subjects is behind the soft palate especially when the person is supine. during sleep, airway narrowing occurs in normal subjects. about 50% of normal subjects display the largest increase in resistance at the level of the palate, and the other 50% in the hypopharynx.11 similarly, half the osas patients have obstruction at palatal level and half have it at hypopharyngeal level.12 it is not clear whether anatomical or physiological factors are the main determinants of the primary site of occlusion during sleep, nor is it clear why only some individuals have upper airway obstruction during sleep. the main anatomical factors that predispose to upper airway narrowing are obesity and facial structure.7 patients with osas tend to have narrower airways than normal subjects when awake, although there is considerable overlap.13 much of this narrowing may be due to fat deposition around, and particularly lateral to, the upper airways. palatal enlargement with increased fat and muscle bulk and facial structure abnormalities with retroposition of the mandible and /or maxilla, have also been found in osas.14 however, the relative importance of differences in bony structure and fat deposition between osas patients and the normal population is not known and could vary with patient type. for instance, facial structure perhaps is important in thinner patients, and the location of fat deposits more critical in the obese. around 50% of osas patients have body mass indices > 30 kg/m2.15 the physiological factors that inhibit the function of upper airway dilating muscles are sleep, alcohol16 and hypnotics.17 narrowing of the nose or nasopharynx calls for extra effort to breathe, and thus generate an increase in upper airway pressure during inspiration, and further predisposes to upper airway narrowing and collapse.14 the upper airways of osas patients are not only narrower, but also more compliant both during wakefulness and sleep.18 the reason for this increase in compliance is unclear and cannot be accounted for by differences in muscle tone or in upper airway calibre. if the upper airway dilating tone is above normal in osas patients when awake,15 then deflatory compliance of the airway would be expected to decrease rather than to increase. conversely, if narrowing of the upper airway by fat deposition or by retroposition of the jaw is the factor, expiratory compliance would be expected to decrease, but not increase in patients with osas. pharmacologic enhancement of serotonergic transmission by serotonin uptake inhibition has been suggested as one approach to improve upper airway patency, and thus nocturnal breathing in patients with osas.19 in our view, more work is required to explain the discrepancies found in such patients before firm conclusions could be drawn. \\ \\ factors predisposing to osas gender any explanation of the pathogenesis of osas has to encompass the main predisposing factors: male sex, middle age, and obesity. it is far from clear why 85% of patients presenting with osas are men.20 there seems to be no consensus in the literature regarding upper airway calibre differences between the genders.21–23 the upper airways in men seem to have different physical properties, with bigger changes in airway size with fluctuations in lung volumes,22 and on lying down.23 it is not clear if these differences are the result of anatomical factors or from differences in the upper airway dilating muscle function. in addition, the effects of gender on these factors are unclear. although androgens have been reported to induce osas, anti-androgen drugs given for one week did not significantly affect osas severity.24 it is possible that androgens’ effects on fat deposition in the neck or on upper airway muscle function were not evident within one week. men have thicker necks than women even when matched for body mass index.1 this difference could cause increased mass loading on the airway in men when they lie down, predisposing to upper airway narrowing during sleep. another gender-related puzzle is that, although 85% of individuals presenting to sleep clinics with osas are male, recent epidemiological studies have consistently found that men are only twice as likely o b s t r u c t i v e s l e e p a p n o e a 119 as women to have abnormal breathing during sleep.1,25 clarification is required as to whether this discrepancy results from referral bias or from differences between the sexes in the severity of symptoms resulting from a given degree of irregular breathing during sleep. age osas affects all age groups, but there is no obvious reason for it to be commonest in middle age.26 although upper airway resistance has been reported to increase with age in men,27 a recent study indicates that the pharyngeal lumen in awake men becomes greater as they get older.28 this study also showed that the electromyographic response of the tongue to negative upper airway pressure was greater in subjects aged 60–79 years than in either 20–39 or 40–59-year-olds.28 thus, there is no convincing evidence of either structural narrowing or functional impairment of upper airway dilating muscles in middle age. nevertheless, a common observation in clinical practice is that a young snorer is likely to become a middle-aged patient with osas.29 obesity the association with obesity is easier to explain. indirect evidence of increased fat deposition in the neck comes from the observation that patients with osas tend to have large necks.27 magnetic resonance imaging (mri) studies have shown that patients with osas have increased fat deposition adjacent to the pharyngeal airway,23 especially posterolateral to the airway at the level of the soft palate, so that there is squashing of the lateral aspects of the upper airway.15 mri studies have also shown fat deposition in the soft palate itself.16 morphological studies have shown increased fat deposition in the soft palates and uvulae of osas patients.28 deposition of fat could narrow the upper airways and predispose to critical airway narrowing during sleep. inheritance there were early case-reports that osas cluster among family members.30 however, this might have been due to familial occurrence of obesity alone. studies in families of non-obese patients with osas have shown definite family clustering of osas, with evidence of abnormal facial structure, narrowed upper airways, and enlarged uvulae compared with weight, height, and sex matched controls.31 it remains to be determined if these abnormalities are causal and inherited or whether they are consequences of the abnormal breathing during sleep. clinical effects of osas the severity of daytime sleepiness relates poorly to the frequency of either respiratory events or electroencephalographic (eeg) arousal during the night.32,33 the fragmented sleep invariably causes daytime somnolence which may be associated with impaired cognitive function, fatigability and morning headaches.33 what constitutes a clinically significant arousal from sleep or even whether any cortical eeg change is needed for an event to contribute to subsequent daytime sleepiness is not well understood.14 the degree of effort to breathe seems to act as the stimulus for arousal to terminate an apnoea. but does the threshold to arousal vary between subjects, or are there qualitative differences in arousals between subjects that could account for the disparity between respiratory event frequency and sleepiness? unlike sleepiness, impaired daytime cognitive function does relate to the severity of sleep disruption and particularly to the frequency of brief cortical eeg arousals. the large individual variation calls for better quantification of sleep fragmentation. untreated patients with osas are at increased risk of cardiovascular and cerebrovascular events. there is conflicting evidence on whether osas patients have higher daytime blood pressure than do normal subjects matched for age, sex, weight, and alcohol consumption.34 however, each apnoea or hypopnoea is associated with a transient rise in systemic blood pressure which occurs at the time of the arousal. this rise may occur even when there are no obvious eeg changes.35 it is tempting to speculate that the excess of cardiovascular and cerebrovascular disease among osas patients probably results from hundreds of these blood pressure rises occurring every night for years or even decades although the natural history of these consequences are ill understood. apart from its effects on the systemic circulation, osas results in raised pulmonary arterial pressure in about 25% of patients,36 and this might predispose to cor pulmonale, especially in patients with co-existing lung disease. effects of osas on the cardiovascular system 1. systemic hypertension systemic blood pressure normally decreases by 5– 14% in non-rapid eye movement (non-rem) sleep compared with awake resting values.37 blood pressure fluctuates considerably during rem sleep and is on average 5% higher than the preceding non-rem sleep. in patients with sleep disordered breathing there are brief phasic changes in blood pressure superimposed on a cyclical pattern which coincide with the upper airways obstruction. the brief phasic changes in blood pressure are secondary to the large changes in intrathoracic pressure during obstructed respiration. systemic blood pressure may increase by up to 20% during osas and is maximal immediately after termination of apnoea.38 the mechanism of the cyclical pattern in blood pressure during osas is probably multifactorial in origin. hypoxaemia, a l r i y a m i e t a l 120 hypercapnic acidosis, increased respiratory effort and the increased sympathetic activity associated with awakening have all been proposed.39 hypoxaemia does not appear to be a major causative factor as blood pressure remains unchanged in patients with osa during supplemental oxygen therapy.40 both sympathetic nervous output and catecholamine production increase during osas.41,42 catecholamine secretion decreases following effective treatment with either tracheostomy43, 44 or nasal cpap therapy.45 systemic hypertension occurs in 40–60% patients with osas,46 and its severity is related to apnoea severity.38 the association between sleep disordered breathing and systemic hypertension appears to be mainly due to similar risk factors for both conditions. it is important to consider the diagnosis of sleep disordered breathing in patients with systemic hypertension, especially those resistant to therapy, but further diagnostic studies are not indicated in the absence of other features of sleep disordered breathing. 2. cardiac function there is a variation in cardiac output during episodes of apnoeas/hypopnoeas. it drops during bradycardia and increases with the rebound tachycardia and it has been hypothesised that this would result in left ventricular hypertrophy or dysfunction.47 there are several reports of echocardiography in patients with osas. hedner and associates48 excluded patients with systemic hypertension and found a larger left ventricular mass in patients with osas compared with control subjects. however, results of controlled study showed no difference in left ventricular size or function between snorers and osa patients.49 in our own observation, normotensive patients osas failed to dip their blood pressure during sleep and had increased lv mass.50 cardiovascular variability is altered in patients with osas. this alteration is evident even in the absence of hypertension, heart failure, or other disease states, and may be linked to the severity of osas. abnormalities in cardiovascular variability may be implicated in the subsequent development of overt cardiovascular disease in patients with osas.51 3. ischaemic heart disease osas has been shown to be a significant risk factor in the development of ischaemic heart disease.52 the combined effects of systemic hypertension, hypoxaemia and increased sympathetic activity during sleep are thought to promote the development of atherosclerosis.53 st depression is relatively common in patients with osas during overnight ecg monitoring, and the duration of this is reduced by nasal cpap therapy.54 this st depression may reflect myocardial ischaemia or nonspecific changes associated with osas. myocardial ischaemia is reported to have occurred during polysomnography in five of 20 patients with combined ischaemic heart disease and osas.55 new evidence suggesting a role for vascular endothelium in the development of vascular disease in osas is now emerging.56 4. cardiac arrthythmias cardiac rate normally decreases by 5–10% during non-rem sleep, with a slight increase during rem sleep.47 in patients with sleep disordered breathing the vagal stimulation caused by inspiring against the upper airway obstruction results in sinus bradycardia during the apnoea followed by a reflex tachycardia at apnoea termination.57 the degree of bradycardia is related to the severity of the associated arterial oxygen desaturation.58 cardiac arrhythmias during sleep occur in up to 50% of patients with osas.59 these arrhythmias are more frequent when osas is associated with arterial oxygen desaturation, and resolve following effective treatment of the osas. the cyclical changes in heart rate seen in patients with sleep disordered breathing can be confused with sick sinus syndrome, and could result in inappropriate treatment such as cardiac pacing.60 5. cerebrovascular disease patients with osas have increased cerebrovascular mortality and morbidity.61 one report described 53% of male patients with a cerebrovascular accident (cva) to be chronic snorers.62 of these, 35% had cva during sleep and snoring was the only factor which correlated with the diurnal variation in the time of cva. a case controlled study of patients admitted to hospital with a cva showed that snoring was an important risk factor for the development of a cva and adversely affected the prognosis.60,61 6. pulmonary hypertension/right heart failure pulmonary artery pressures usually remain relatively unchanged during sleep in normal subjects. in contrast, pulmonary artery pressure increases by up to 100% during rem sleep in patients with osas.63 the cyclical changes in pulmonary artery pressure parallel the changes in systemic blood pressure. these changes are due to the effects of obstructed inspiratory efforts on pulmonary and cardiac dynamics, and hypoxic pulmonary vasconstriction. pulmonary pressor response to hypoxia was augmented (> 10 mm hg) by hypercapnia in patients with osas but not in normal subjects.64 pulmonary hypertension occurs in a substantial proportion of patients with sleep disordered breathing. the prevalence of pulmonary hypertension in patients with osas has been reported to be between 10% and 20%, but may be as high as 55% in moderate to severe disease.65 the presence of pulmonary hypertension and o b s t r u c t i v e s l e e p a p n o e a 121 associated right heart failure in patients with sleep disordered breathing is invariably indicative of severe disease which requires prompt diagnosis and treatment. it is important to consider the diagnosis of sleep disordered breathing in patients with unexplained pulmonary hypertension. however, further diagnostic studies are not indicated in the absence of other features of sleep disordered breathing. 7. psychological / psychiatric consequences intellectual deterioration, personality and behavioural changes are well recognized features of sleep disordered breathing. interpersonal relationships at work and at home are affected. psychological testing in patients with sleep disordered breathing show significant impairments in thinking, perception, memory and the ability to learn.66 dysfunction of cognitive behaviour is related to the severity of the sleep hypoxaemia67 and sleep fragmentation.68 treatment of osas may improve psychological status and result in reduced anxiety and depression.69 sleepiness, as assessed by the epworth sleepiness scale, has an important impact on general health and functional status, specifically influencing self-perceptions regarding energy and fatigue.70–72 8. endocrine decreased libido and impotence are frequently associated with sleep disordered breathing.46 of 50 patients with severe osa, 44% were reported to have either diminished sexual interest or performance.46 this sexual dysfunction is probably related in part to the daytime sleepiness or depression associated with sleep disordered breathing. there are however, two reports that suggest that sleep disordered breathing causes hypothalamic pituitary dysfunction, which is reversible following effective treatment.73 this reversible neuroendocrine dysfunction might contribute to the decrease in libido and impotence in osas.74 in postmenopausal women, the incidence of osas increases and changes in reproductive hormones might have a role in this condition.75 treatment with testosterone has been reported to cause osas in men.76 some patients with acromegaly may develop osas which may be related to changes in facial features. interestingly osas responds to growth hormone lowering drugs.77 osas and hypothyroidism overlap in symptoms and signs. the sleep-disordered breathing that accompanies hypothyroidism could lead to significant risk of misdiagnosis of sleep apnoea among patients referred to sleep clinics who have undiagnosed hypothyroidism.78 nevertheless routine thyroid testing in osas is not recommended except in clinically relevant cases.79 similarly routine sleep studies in all hypothyroid patients.80 good clinical judgement alone is the important in diagnosing and managing both conditions in a cost effective way. melatonin has a strong circadian rhythm with high values during the night-time and low values in the afternoon and it was hypothesized that sleep disordered breathing may change the circadian rhythm of melatonin which may have diagnostic implications.81 even though exogenous melatonin has proven to have clear phaseshifting effects,82 and can influence sleep and circadian parameters, low endogenous melatonin is not related to sleep disturbances, nor does it predict response to melatonin therapy. 9. renal atrial natriuretic peptide concentrations are increased during sleep in patients with sleep disordered breathing and decrease with nasal cpap therapy.82,83 patients with sleep disordered breathing commonly complain of nocturia which could improve with effective treatment.84 the frequent nocturia in patients with sleep disordered breathing is probably related to diuresis and natriuresis caused by the recurrent hypoxaemia. patients with sleep disordered breathing are also more prone to have proteinuria85 which improves with effective treatment. the mechanism of this proteinuria is unclear.87 10. mortality there are limited retrospective data on the mortality associated with osas, but most studies suggest a decreased long term survival.88 guilleminault and colleagues89 reported decreased five year survival in patients with untreated osa compared with both patients treated by tracheostomy and cpap. the us age adjusted survival curve was the same. there is a decreased survival in patients with untreated osas with an apnoea index of >20/hour.90 this difference was most evident in patients below 50 years of age.91 the major cause of increased mortality in sleep-disordered breathing appears to be cardiovascular in nature.92 there is no difference in the long term survival of patients with osa treated with either corrective upper airway surgery or nasal cpap.93 conclusion obstructive sleep apnoea syndrome is a multi system disorder and a major health hazard, which has gained its due recognition in the developed world. unfortunately this recognition is still largely lacking in developing countries. although treatment is effective and relatively simple, the fundamental abnormality which initiates the cascade of events described above remains to be identified. references 1. young t, palta m, dempsey j, skatrud j, webber s, bader s. occurrence of sleep-disordered breathing among middle-aged adults. n engl j med 1993, 328, 1230–35. a l r i y a m i e t a l 122 2. findley lf, unverzagt me, suratt pm. automobile accidents involving patients with obstructive sleep apnea. am rev respir dis 1988, 138, 337–40. 3. phillipson ea. sleep apnoea—a major public health problem. n engl j med 1993, 328, 1271–73. 4. tsai wh, flemons ww, whitelaw wa, remmers je. a comparison of apnea-hypopnea indices derived from different definitions of hypopnea. am j respir crit care med 1999, 159, 43–8. 5. rodenstein do, dooms g, thomas y, liistro g, stanescu dc, culee c et al. pharyngeal shape and dimensions in healthy subjects, snorers, and patients with obstructive sleep apnoea. thorax 1990; 45, 722–27. 6. reisch s, schneider m, timmer j, geiger k, guttmann j. evaluation of forced oscillation technique for early detection of airway obstruction in sleep apnoea: a model study. technol health care 1998, 6, 245–57. 7. bijaoui e, tuck sa, remmers je, bates jht. estimating respiratory mechanics in the presence of flow limitation. j appl physiol 1999, 86, 418–26 8. stradling jr. obstructive sleep apnoea: definitions, epidemiology and natural history. thorax 1995, 50, 683– 689. 9. hasan n, fletcher ec. upper airway resistance syndrome. j ky med assoc 1998, 96, 261–3. 10. exar en, collop na. the upper airway resistance syndrome. chest 1999, 115, 1127–39. 11. ferguson ka, fleetham ja. consequences of sleep disordered breathing. thorax 1995, 50, 998–1004. 12. hudgel dw, hendricks c. palate and hypopharynxsites of inspiratory narrowing of the upper airway during sleep. am rev respir dis 1988, 138, 1542–47. 13. bradley td, brown ig, grossman rf, zamel n, martinez d, phillpson ea et al. pharyngeal size in snorers, nonsnorers and patients with obstructive sleep apnea. n engl j med 1986, 315, 1327–31. 14. shelton ke, woodson h, kay s, suratt pm. pharyngeal fat in obstructive sleep apnoea. am rev respir dis 1993, 148, 462–66. 15. horner rl, mohiaddin rh, lowell dg, shea sa, burman ed, longmore db, et al. sites and sizes of fat deposits around the pharynx in obese patients with obstructive sleep apnoea and weight matched controls. eur respir j 1989, 2, 613–22. 16. aldrich ms, brower kj, hall jm. sleep-disordered breathing in alcoholics. alcohol clin exp res 1999, 23, 134–40. 17. hanly p, powles p. hypnotics should never be used in patients with sleep apnoea. j psychosom res 1993, 37, 59– 65. 18. suratt pm, mctier rf, wilhoit sc. upper airway muscle activation is augmented in patients with obstructive sleep apnoea compared with that in normal subjects. am rev respir dis 1988, 137, 889–94. 19. kraiczi h, hedner j, dahlof p, ejnell, h, carlson j. effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnoea. sleep 1999, 22, 61–7. 20. gislason t, almqvist m, eriksson g, taube a, boman g. prevalence of sleep apnoea syndrome among swedish men—an epidemiological study. j clin epidemiol 1988, 41, 571–6. 21. gleadhill ic, schwartz ar, schubert n, wise ra, perimutt s, smith pl. upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea. am rev respir dis 1991, 143, 1300–03. 22. smith pl, wise ra, permutt s. upper airway pressure-flow relationships in patients with obstructive sleep apnoea. j appl physiol 1988, 64, 789–95. 23. white dp, lombard rm, cadieux rj, zwillich cw. pharyngeal resistance in normal humans: influence of gender, age, and obesity. j appl physiol 1985, 58, 365– 71. 24. stewart da, grunstein rr, berthon-jones m, handelsman dj, sullivan ce. androgen blockade does not affect sleep disordered breathing or chemosensitivity in men with obstructive sleep apnoea. am rev respir dis 1992, 146,1389–93. 25. jennum p, sjol a. epidemiology of snoring and obstructive sleep apnoea in a danish population aged 30– 60. j sleep res 1992, 1, 240–44. 26. stradling jr, crosby jh. predictors and prevalence of obstructive sleep apnoea and snoring in 1001 middle aged men. thorax 1991, 46, 85–90. 27. martin se, mathur r, douglas nj. the effect of age, sex and posture on upper airway calibre in normal subjects. am j resp crit care med 1994, 149, al47. 28. davies rjo, stradling jr. the relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. eur respir j 1990, 3, 509–14. 29. cirignotta f, d'alessandro r, partinen m, zucconi m, cristina e, gerardi r, et al. prevalence of every night snoring and obstructive sleep apnoeas among 30– 69 years old men in bologna, italy. acta neurol scand 1989, 79, 366–72. 30. redline s, tosteson t, tishler pv, carskadon ma, millman rp. studies in the genetics of obstructive sleep apnoea. familial aggregation of symptoms associated with sleep-related breathing disturbances. am rev respir dis 1992, 145, 440–4. 31. mathur r, douglas nj. a prospective case controlled study of the inheritance of the sleep apnoea/ hypopnoea syndrome. am rev respir dis 1993, 147, a233. 32. zucconi m, oldani a, ferini-strambi l, calori g, castronovo c, smirne s. eeg arousal pattern in habitual snorers with and without obstructive sleep apnoea. j sleep res 1995, 4, 107–112. 33. sforza e, krieger j, petiau c. arousal threshold to respiratory stimuli in osa patients: evidence for a sleepdependent temporal rhythm. sleep 1999, 22, 69–75. 34. davies rjo, belt pj, roberts sj, ali nj, stradling jr. arterial blood pressure responses to graded transient arousal from sleep in normal humans. j appl physiol 1993, 74, 1123–30. 35. calverley pm, rees k. systemic arterial blood pressure during obstructive sleep apnoea. j sleep res 1995, 4, 93–96. 36. laks l, krieger j, podszus t. pulmonary hypertension in obstructive sleep apnoea: multicenter study. am o b s t r u c t i v e s l e e p a p n o e a 123 rev respir dis 1992, 145, a865. 37. khatri im, freis ed. hemodynamic changes during sleep. j appl physiol 1967, 22, 867–73. 38. lavie p, yoffe n, berger i, peled r. the relationship between the severity of sleep apnoea syndrome and 24h blood pressure values in patients with obstructive sleep apnoea. chest 1993, 103, 717–21. 39. hedner ja, wilcox i, laks l, grunstein rr, sullivan ce. a specific and potent pressor effect of hypoxia in patients with sleep apnea. am rev respir dis 1992, 146,1240–5. 40. ringler j, basner rc, shannon r, schwartxstein r, manning h, weinberger se, et al. hypoxemia alone does not explain blood pressure elevations after obstructive apnoeas. j appl physiol 1990, 69, 2143–8. 41. marrone o, riccobono l, salvaggio a, mirabella a, bonanno a, bonsignore mr. catecholamines and blood pressure in obstructive sleep apnoea syndrome. chest 1993, 103, 722–7. 42. fletcher ec. sympathetic activity and blood pressure in the sleep apnoea syndrome. respiration 1997, 64 suppl 1, 22–8. 43. fletcher ec, liller j, schaaf jw, fletcher jg. urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnoea and hypertension. sleep 1987, 10, 35–44. 44. loredo js, ziegler mg, ancoli-israel s, clausen jl, dimsdale je. relationship of arousals from sleep to sympathetic nervous system activity and bp in obstructive sleep apnoea. chest 1999, 116, 655–9. 45. jennum p, wildschiodtz g, christensen nj, schwartz t. blood pressure, catecholamines and pancreatic polypeptide in obstructive sleep apnea with and without nasal continuous positive airway pressure (ncpap) treatment. am j hypertens 1989, 2, 847–52. 46. guilleminault c, tilkian a, dement wc. the sleep apnoea syndromes. am rev med 1976, 27, 465–84. 47. guilleminault c, connolly s, winkle r, melvin k, tilkian a. cyclical variation of the heart rate in sleep apnoea syndrome. lancet 1984, 126–31. 48. hedner j, ejneil h, caidahl k. left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea. j hypertens 1990, 8, 941–6. 49. hanly p, sasson z, zuberri n, alderson m. ventricular function is snorers and patients with obstructive sleep apnoea. chest 1992, 102, 100–5. 50. al-riyami b, hussain s, al-khatim, hassan mo. non-dipping blood pressure in normotensive patients with obstructive sleep apnoea. squ j sci res: med sci. 1999, 1, 5–8. 51. narkiewicz k, montano n, cogliati c, van de borne pj, dyken me, somers vk. altered cardiovascular variability in obstructive sleep apnoea. circulation 1998, 11, 1071–7. 52. kosenvuo m, kaprio j, telakivi t, partinen m, heikkila k, sarna s. snoring as a risk factor for ischaemic heart disease and stroke in men. bmj 1987, 294, 16–9. 53. hung j, whitford eg, parsons re, hillman dr. association of sleep apnoea with myocardial infarction in men. lancet 1990, 336, 261–4. 54. hanly p, sasson z, zuberi n, lunn k. st-segment depression during sleep in obstructive sleep apnea. am j cardiol 1993, 71, 1341–5. 55. koehler u, dubler h, glaremin t, junkermann h, lubbers c, ploch t, et al. nocturnal myocardial ischemia and cardiac arrhythmia in patients with sleep apnoea with and without coronary heart disease. klin wochenschr 1991, 69, 474–82. 56. hedner j. vascular function in osa. sleep 1996, 10, 213–7. 57. hanly pj, george cf, millar tw, kryger mh. heart rate response to breath-hold, valsalva and mueller maneuvers in obstructive sleep apnoea. chest 1989, 95, 735–9. 58. zwillich d, devlin t, white d, douglas n, weil j, martin r. bradycardia during sleep apnoea. j clin invest 1982, 69, 1286–92. 59. guilleminault c, connolly sj, winkle ra. cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. am j cardiol 1983, 52, 4. 60. smirne s, palazzi m, juvela s, kaste m. snoring as a risk factor for acute vascular disease. eur respir j 1993, 6, 1357–61. 61. spriggs da, french jm, murdy jm, curless rh, bates d, james of. snoring increases the risk of stroke and adversely affects prognosis. q j med 1992, 303, 555–62. 62. palomalid h, partinen m, juvela s, kaste m. snoring as a risk factor for sleep-related brain infarction. stroke 1989, 20, 1310–5. 63. coccagna g, mantovani m, brignani f, parchi c, lugaresi e. continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. bull eur physiopathol respir 1972, 8, 1159–72. 64. laks l, lehrhaft b, grunstein rr, sullivan ce. pulmonary artery pressure response to hypoxia in sleep apnea. am j respir crit care med 1997, 155, 193–8. 65. weitzenblum e, krieger j, apprill m, vallee e, ehrhart m, ratomaharo j, et al. daytime pulmonary hypertension in patients with obstructive sleep apnea. am rev respir dis 1988, 138, 345–9. 66. kales a, caldwell ab, cadieux rj, vela-bueno a, ruch lg, mayes sd. severe obstructive sleep apnoea: associated psychopathology and psychosocial consequences. j chron dis 1985, 38, 427–34. 67. findley lj, barth jt, powers dc, wilhoit sc, boyd dg, suratt pm. cognitive impairment in patients with obstructive sleep apnoea and associated hypoxemia. chest 1986, 90, 686–90. 68. cheshire k, engleman h, deary i, shapiro c, douglas nj. factors impairing daytime performance in patients with sleep apnoea/hypopnoea syndrome. arch intern med 1992, 152, 538–41. 69. klonoff h, fleetham j, taylor dr, clark c. treatment outcome of obstructive sleep apnoea – physiological and neuro-psychological concomitants. j nerv ment dis 1987, 175, 208–12. a l r i y a m i e t a l 124 70. briones b, adams n, strauss m, rosenberg c, whalen c, carskadon m et al. relationship between sleepiness and general health. sleep 1996, 19, 583–8. 71. furuta h, kaneda r, kosaka k, arai h, sano j, koshino y. epworth sleepiness scale and sleep studies in patients with obstructive sleep apnoea syndrome. psychiatry clin neurosci 1999, 53, 301–2. 72. lugaresi e, coccagna g, mantovani m, lebrun r. some periodic phenomena arising during drowsiness and sleep in man. electroencephalogr clin neurophysiol 1972, 32, 701–5. 73. santamaria jd, prior jc, fleetham ja. reversible reproductive dysfunction in men with obstructive sleep apnoea. clin endocrinol 1988, 28, 461–70. 74. grunstein rr, handelsman dj, lawrence sj, blackwell c, caterson id, sullivan ce. neuroendocrine dysfunction in sleep apnoea: reversal by continuous positive airways pressure therapy. j clin endocrinol metab 1989, 68, 352–8. 75. dexter dd, dovre ej. obstructive sleep apnoea due to endogenous testosterone production in woman. mayo clin proc 1998, 73, 246–8. 76. cistulli pa, grunstein rr, sullivan ce. effect of testosterone administration on upper airway collapsibility during sleep. am j respir crit med 1994, 149, 530–2. 77. ziemer dc, dunlap db. relief of sleep apnea in acromegaly by bromomcriptine. am j med sci 1988, 295, 49–51. 78. skjodt nm, atkar r, easton pa. screening for hypothyroidism in sleep apnea. am j respir crit care med 1999, 160, 732–5. 79. kapur vk, koepsell td, demaine j, hert r, sandblom re, psaty bm. association of hypothyroidism and obstructive sleep apnea. am j respir crit care med 1998, 158, 1379–83. 80. lin cc, tsan kw, chen pj. the relationship between sleep apnoea syndrome and hypothyroidism. chest 1992, 102, 1663–7. 81. ulfberg j, micic s, strom j. afternoon serummelatonin in sleep-disorded breathing. j intern. med 1998, 244, 163–8. 82. arendt j, deacon s, english j, hampton s, morgan l. melatonin and adjustment to phase shift. j sleep res 1995, 4, 74–79. 83. kunz d, schmitz s, mahlberg r, mohr a, stoter c, wolf kj et al. a new concept for melatonin deficit: on pineal calcification and melatonin excretion. neuropsychopharmacol 1999, 21, 765–72. 84. baruzzi a, riva r, cirignotta f, zucconi m, cappelli m, lugaresi e. atrial natriuretic peptide and catecholamines in obstructive sleep apnoea syndrome. sleep 1991, 14, 83–6. 85. kreiger j, imbs jl, schmidt m, kurtz d. renal function in patients with sleep apnoea. effects of nasal continuous positive airways pressure. arch intern med 1988, 48, 1337–40. 86. bliwise d, bliwise n, partinen m, pursley a, dement w. sleep apnea and mortality in an aged cohort. am j public health 1988, 78, 544–7. 87. partinen m, jamieson a, guilleminault cg. longterm outcome for obstructive sleep apnoea syndrome patients mortality. chest 1988, 94, 1200–4. 88. partinen m, guilleminault c. daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnoea patients. chest 1990, 97, 2700–4. 89. guilleminault c, simmons fb, motta j, cummiskey j, rosekind m, schroeder js, et al. obstructive sleep apnea syndrome and tracheostomy – longterm follow up experience. arch intern med 1981, 141, 985–8. 90. keyger mh, zorick fj, conway w, roth t. mortality and apnoea index in obstructive sleep apnoea – experience in 385 male patients. chest 1988, 94, 9–14. 91. keenan sp, burt h, ryan cf, fleetham ja. longterm survival of patients with obstructive sleep apnoea treated by uvulopalatopharyngoplasty or nasal cpap. chest 1994, 105, 155–9. 92. chaudhary ba, sklar ah, chaudhary tk, kolbeck rc, speir wa jr. sleep apnoea, proteinuria and nephrotic syndrome. sleep 1998, 11, 69–74. 93. chaudhary ba, rehman ou, brown tm. proteinuria in patients with sleep apnoea. j fam pract 1995, 40, 139–41. pathophysiology of �obstructive sleep apnoea syndrome: a review pathophysiology upper airway features in patients with osas factors predisposing to osas gender age obesity inheritance clinical effects of osas effects of osas on the cardiovascular system 1. systemic hypertension 2. cardiac function 3. ischaemic heart disease 4. cardiac arrthythmias 5. cerebrovascular disease 6. pulmonary hypertension/right heart failure 7. psychological / psychiatric consequences 8. endocrine 9. renal 10. mortality conclusion references learning disabilities (lds) refer to a group of heterogeneous disorders which may affect the acquisition, organisation, retention, understanding or use of verbal or nonverbal information.1 the fifth edition of the diagnostic and statistical manual of mental disorders introduced a new term, specific learning disorder, as a single diagnosis to describe all of these conditions.2 a specific learning disorder is defined as a neurodevelopmental disorder of biological origin which manifests in learning difficulties and problems in acquiring ageappropriate academic skills during the early school years.2 learning difficulties can manifest in any of the following essential skills: reading, written expression or mathematical calculations. the difficulties should last for at least six months and should not be attribut able to any of the following causes: intellectual disabilities, a lack of visual or auditory acuity and other mental or neurological problems.2 additionally, these learning problems should not be the result of psychological adversity, lack of proficiency in the language of academic instruction or inadequate educational instruction.2 the learning difficulties should cause significant interference with academic/occupational performance or with activities of daily living.2 despite what the term might suggest, individuals with lds have only specific learning difficulties but maintain an average or above average intelligence quotient.3 the main causative factor for lds is presumed to be neurobiological in origin, due to an as-yetunidentified brain pathology.3,4 additionally, both hereditary and environmental factors have been implicated.3,5 it is possible that these aetiological factors intertwine to trigger the development of lds. generally, lds affect approximately 5% of school-aged children globally.6 however, some researchers have argued that that the true prevalence could be as high as 15–20%.3,7 reportedly, 4.9% of canadian children aged 6–15 years were found to have an ld; this prevalence varied across the age spectrum, from 1.6% among 6-year-olds to 7.2% among 10-year-olds.8 data from public schools in the usa showed an estimated ld prevalence of 5% among school-aged children, with 2.4 million students found to have lds.9 dyslexia, which affects a complex range of abilities related to reading and language, represents the most common ld, as 80% of people with lds are dyslexic.5,10,11 other common types of lds include dysgraphia, which affects writing abilities, dyscalculia, which affects the application of mathematical operations, and visualspatial organisation problems.3,11 nonverbal lds are another type of learning difficulty whereby individuals demonstrate adequate verbal expression, vocabulary or reading skills, but have difficulties with certain nonverbal activities, such as problem-solving, visualspatial tasks and reading body language or recognising social cues.3 the effects of lds can persist during adulthood, as reading, writing and mathematical skills are usually essential to perform routine daily activities. affected individuals may also face limited opportunities for employment. furthermore, the frequent co-existence of two or more lds within the same individual makes the picture even more complex; in the usa, 30% of students with a primary ld were also found to have a secondary disability, while 7% had two or three additional disabilities, such as speech/language impairments or emotional disturbance.9 furthermore, other research has also shown that lds are usually associated with other comorbidities including attention deficit hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder, anxiety and depression.12 an ld diagnosis should be confirmed by individually administered standardised achievement measures and comprehensive clinical assessment. in departments of 1family medicine & public health and 2child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: abdulaziz@squ.edu.om صعوبات التعلم الفرص والتحديات يف عمان عبد العزيز املحرزي، اآمنة الفطي�سية، وطفة املعمرية editorial learning disabilities opportunities and challenges in oman *abdulaziz al-mahrezi,1 amna al-futaisi,2 watfa al-mamari2 sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 129–131, epub. 15 may 16 submitted 4 oct 15 revision req. 11 jan 16; revision recd. 8 feb 16 accepted 22 feb 16 doi: 10.18295/squmj.2016.16.02.001 learning disabilities opportunities and challenges in oman e130 | squ medical journal, may 2016, volume 16, issue 2 view of the difficulties in diagnosing children with lds, a three-level diagnostic approach has been advocated.13 the first level is the behavioural level, at which the main players are the parents and the school teachers of an affected child; this is the most important step, because it is here that an appropriate intervention can be initiated and followed-up. the second level is the neuro-behavioural level, whereby learning problems are analysed using appropriate neurocognitive tests and an attempt can be made at a diagnosis. the third level refers to the neurobiological basis of lds; specific questions about the exact cause of the ld can be addressed by performing sophisticated investigations such as genetic marker analyses, neurophysiological tests and neuroimaging.13 searching for the neurobiological underpinning of a particular ld may potentially rule out other diagnoses or comorbidities. the mainstay of ld treatment is remedial intervention—that is, utilising behavioural and medical techniques to improve the functioning of ld-affected individuals. remediation is usually performed by educators specialising in dealing with children with special needs or talents. the aim of remediation is to address a specific ld by providing intensive and individualised instruction and allowing the student extra time to practice certain skills. there have been calls to implement intensive empiricallybased interventions and make them easily available to all children in general education.4 an integral part of remediation is the early identification of at-risk children so that timely interventions can follow suit. the role of the family physician comes to the forefront with regards to this issue—every interaction with school-aged children and their families should be exploited to determine the child’s educational progress and any early signs of an ld. teachers are another potential avenue for early identification. in the usa, yearly reading assessments for kindergarten children have resulted in the earlier detection of lds.4 several longitudinal studies have shown that preschool diagnosis and early interventions have the net outcome of reducing the severity of lds; indeed, early interventions have been shown to have a durable and lasting effect on the school performance of ld-affected children.4,14 conversely, shaywitz et al. observed that ‘late’ interventions bore no beneficial effects for children with persistent reading disabilities.15 oman has witnessed a drastic improvement in its educational system during the last four decades.16 the number of schools rose from three in 1970 to 1,052 in 2008; the number of teachers similarly increased from 30 in 1970 to 41,988 in 2008.16,17 in 1998, comprehensive educational reforms were carried out to keep up with new trends in education.17 at that time, a new curriculum was implemented, focusing on practical education, real-life experiences and the acquisition of essential life-long skills. in addition, teaching methods became more student-centred and new assessment methods were introduced.17 unfortunately, very little research has yet been published regarding ld prevalence rates in oman or other arab countries.18 nevertheless, specialised education for students with lds has received attention; the ministry of education (moe) established a special education section in 1974 which later became a department within the moe.17 furthermore, the moe adopted the concept of inclusive education to provide opportunities for all learners, regardless of differences in their learning abilities in mainstream schools.17 in 2001, the moe initiated a pilot project to provide support to students with lds.16 the project has since been very successful; from the first two schools in 2001, it had expanded to include 1,471 schools in 2015.17 as part of this project, a special education teacher is assigned to each participating school to identify students with lds in grades 1‒4. subsequently, the teacher will work with these students both in the general classrooms and in individualised classes to help them overcome their learning difficulties, primarily with regards to their reading and mathematical skills.16 although the establishment of these initiatives in oman seems promising, there are several challenges which need to be addressed.19 there is a dearth of qualified special education teachers catering to the needs of children with special needs and talents. training teachers in this field has been difficult; however, the availability of local postgraduate training since 2006 will hopefully provide more opportunities for training. similarly, there are few qualified clinical psychologists and developmental paediatricians and no tertiary care centres which are adequately equipped to manage children with lds. there are also few validated arabic assessment and screening tools which can be used for children with suspected lds.18 there is a need to establish an appropriate system for monitoring and evaluating current strategies to identify areas for improvement. integration of care by different service providers, such as ministries and non-governmental agencies, is also required. finally, efforts should be continued to increase the level of awareness of the community and to educate parents about lds and the available services in oman. in view of the recent progress made in the fields of genetics and neuroimaging, there is great hope that improved treatment strategies, interventions and the remedial services for individuals with lds will be found in the near future.20,21 moreover, prevention of lds may be abdulaziz al-mahrezi, amna al-futaisi and watfa al-mamari editorial | e131 possible with a better understanding of aetiological factors at the neurobiological and social levels. this will hopefully allow us to identify children at risk of lds prior to their manifestation. learning disabilities are not a prescription for failure. with the right kinds of instruction, guidance and support, there are no limits to what individuals with ld can achieve. sheldon h. horowitz, director of learning disability resources, national center for learning disabilities.9 references 1. putting a canadian face on learning disabilities (pacfold), learning disabilities association of canada. what are learning disabilities? from: www.pacfold.ca/about/index.shtml accessed: feb 2016. 2. american psychiatric association. diagnostic and statistical manual of mental disorders, 5th edition. arlington, virginia, usa: american psychiatric association publishing, 2013. 3. handler sm, fierson wm, section on ophthalmology, council on children with disabilities, american academy of ophthalmology; american association for pediatric ophthalmology and strabismus; american association of certified orthoptists. learning disabilities, dyslexia, and vision. pediatrics 2011; 127:e818–56. doi: 10.1542/peds.2010-3670. 4. lyon gr. learning disabilities. future child 1996; 6:54–76. doi: 10.2307/1602494. 5. shaywitz se. dyslexia. n engl j med 1998; 338:307–12. doi: 10.1056/nejm199801293380507. 6. lagae l. learning disabilities: definitions, epidemiology, diagnosis, and intervention strategies. pediatr clin north am 2008; 5:1259–68. doi: 10.1016/j.pcl.2008.08.001. 7. shaywitz se, escobar md, shaywitz ba, fletcher jm, makuch r. evidence that dyslexia may represent the lower tail of a normal distribution of reading ability. n engl j med 1992; 326:145–50. doi: 10.1056/nejm199201163260301. 8. putting a canadian face on learning disabilities (pacfold), learning disabilities association of canada. what does it mean to have learning disabilities in canada? from: pacfold.ca/ download/nationalprofiles/en/6-15.pdf accessed: feb 2016. 9. national center for learning disabilities. the state of learning disabilities: third edition, 2014. from: www.ncld.org/ wp-content/uploads/2014/11/2014-state-of-ld.pdf accessed: feb 2016. 10. shaywitz se, shaywitz ba. the science of reading and dyslexia. j aapos 2003; 7:158–66. doi: 10.1016/s1091-8531(03)00002-8. 11. berninger vw, may mo. evidence-based diagnosis and treatment for specific learning disabilities involving impairments in written and/or oral language. j learn disabil 2011; 44:167–83. doi: 10.1177/0022219410391189. 12. willcutt eg, pennington bf. psychiatric comorbidity in children and adolescents with reading disability. j child psychol psychiatry 2000; 41:1039–48. doi: 10.1111/1469-7610.00691. 13. frith u. what framework should we use for understanding developmental disorders? dev neuropsychol 2001; 20:555–63. doi: 10.1207/s15326942dn2002_6. 14. torgesen jk. catch them before they fail: identification and assessment to prevent reading failure in young children. from: www.aft.org/pdfs/americaneducator/springsummer1998/ torgesen.pdf accessed: feb 2016. 15. shaywitz se, fletcher jm, holahan jm, shneider ae, marchione ke, stuebing kk, et al. persistence of dyslexia: the connecticut longitudinal study at adolescence. pediatrics 1999; 104:1351–9. doi: 10.1542/peds.104.6.1351. 16. oman ministry of education. inclusive education in the sultanate of oman: national report of the sultanate of oman, 2008. from: www.ibe.unesco.org/national_reports/ice_2008/ oman_nr08.pdf accessed: feb 2016. 17. alfawair a, al tobi a. special needs education in sultanate of oman: past, present and future. schol j arts hum soc sci 2015; 3:415–22. 18. al-mamari ws, emam mm, al-futaisi am, kazem am. comorbidity of learning disorders and attention deficit hyperactivity disorder in a sample of omani schoolchildren. sultan qaboos univ med j 2015; 15:e528–33. doi: 10.18295/ squmj.2015.15.04.015. 19. al-lamki l. dyslexia: its impact on the individual, parents and society. sultan qaboos univ med j 2012; 12:269–72. 20. norton es, beach sd, gabrieli jd. neurobiology of dyslexia. curr opin neurobiol 2015; 30:73–8. doi: 10.1016/j.conb. 2014.09.007. 21. foster a, titheradge h, morton j. genetics of learning disability. paediatr child health 2015; 25:450–57. doi: 10.1016/j. paed.2015.06.005. http://dx.doi.org/10.1542/peds.2010-3670 http://dx.doi.org/10.2307/1602494 http://dx.doi.org/10.1056/nejm199801293380507 http://dx.doi.org/10.1016/j.pcl.2008.08.001 http://dx.doi.org/10.1056/nejm199201163260301 http://dx.doi.org/10.1016/s1091-8531%2803%2900002-8 http://dx.doi.org/10.1177/0022219410391189 http://dx.doi.org/10.1111/1469-7610.00691 http://dx.doi.org/10.1207/s15326942dn2002_6 http://dx.doi.org/10.1542/peds.104.6.1351 http://dx.doi.org/10.18295/squmj.2015.15.04.015 http://dx.doi.org/10.18295/squmj.2015.15.04.015 http://dx.doi.org/10.1016/j.conb.2014.09.007 http://dx.doi.org/10.1016/j.conb.2014.09.007 http://dx.doi.org/10.1016/j.paed.2015.06.005 http://dx.doi.org/10.1016/j.paed.2015.06.005 رد: جدل يف األورام سنية املنشأ مراجعة re: controversies in odontogenic tumours review dear editor, we read with great interest the recent review article by siwach et al. published in the august 2017 issue of squmj.1 we congratulate the authors on their elaborative narrative review of the controversies regarding various tumours of odontogenic origin. we would like to further contribute by adding an interesting odontogenic tumour to the debate—adenoid ameloblastomas with dentinoid. first reported by slabbert et al., this tumour shows histopathological features of both an ameloblastoma and an adenomatoid odontogenic tumour (aot), along with hard tissue formation (i.e. dentin or dentinoid-like material).2 while ameloblastic elements such as epithelial whorls, duct-like structures and occasional signs of induction cover a major portion of the tumour, aot-like areas are also visually evident, indicating a composite odontogenic tumour.2 initially known as dentinoameloblastomas, the suggestion that these tumours were the result of the hybridisation of an ameloblastoma and aot with fibrous separation resulted in significant controversy, as numerous cases revealed duct-like structures with bordering cells displaying subnuclear vacuoles.2,3 subsequently, loyola et al. described a similar neoplasm with the potential for recurrence and suggested the term ‘adenoid ameloblastoma with dentinoid’ for such lesions.3 to date, adenoid ameloblastomas have not yet been included by the world health organization (who) in the histological classification of odontogenic tumours.4 the exclusion of this entity is interesting as other tumours with comparatively fewer documented cases, such as sclerosing odontogenic carcinomas, have nevertheless been incorporated in the latest who classification of odontogenic tumours.4 while the nature of the hard tissue in these tumours is unknown, ectomesenchymal cells showing odontoblastic differentiation can be completely absent.5 according to sonone et al., the formation of dysplastic dentin in these tumours may be the result of a metaplastic process rather than the currently accepted theory of epithelial-ectomesenchymal interaction.5 this new hypothesis is further supported by the expression of certain genes by ameloblastic epithelial cells usually present in ectomesenchymal cells, thereby resulting in the conversion and co-expression of a mesenchymal phenotype.6 further studies with more detailed molecular profiling are needed to determine whether the hard tissue in adenoid ameloblastoma is the result of a metaplastic process or a true inductive phenomenon. the co-occurrence of multiple phenotypes of ameloblastoma within the same lesion is not uncommon.4 in general, the diverse histological hybridisation of subtypes of solid and multicystic ameloblastoma does not impact the clinical behaviour of the lesion. however, substantial evidence indicates that adenoid ameloblastomas are locally aggressive.3 adenoid ameloblastomas can present with hypercellularity and atypia, thus posing a challenge in distinguishing these lesions from ameloblastic carcinomas. nevertheless, features of loss of ameloblastic differentiation, basilar hyperplasia, necrosis and vascular/perineural invasion can assist in differentiating a true ameloblastic carcinoma from an adenoid ameloblastoma.3 *divya gopinath1 and rohit k. menon2 1department of oral rehabilitation, faculty of dentistry, university of hong kong, hong kong; 2department of prosthodontics, international medical university, kuala lumpur, malaysia *corresponding author’s e-mail: drdivyakmenon@gmail.com letter to the editor sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e249–251, epub. 9 sep 18 submitted 4 mar 18 revision req. 5 apr 18; revision recd. 9 apr 18 accepted 3 may 18 doi: 10.18295/squmj.2018.18.02.026 re: controversies in odontogenic tumours review e250 | squ medical journal, may 2018, volume 18, issue 2 references 1. siwach p, joy t, tupkari j, thakur a. controversies in odontogenic tumours: review. sultan qaboos univ med j 2017; 17:e268–76. doi: 10.18295/squmj.2017.17.03.003. 2. slabbert h, altini m, crooks j, uys p. ameloblastoma with dentinoid induction: dentinoameloblastoma. j oral pathol med 1992; 21:46–8. doi: 10.1111/j.1600-0714.1992.tb00969.x. 3. loyola am, cardoso sv, de faria pr, servato jp, eisenberg al, dias fl, et al. adenoid ameloblastoma: clinicopathologic description of five cases and systematic review of the current knowledge. oral surg oral med oral pathol oral radiol 2015; 120:368–77. doi: 10.1016/j. oooo.2015.05.011. 4. el-naggar ak, chan jk, grandis jr, takata t, slootweg pj, eds. who classification of head and neck tumours, 4th ed. lyon, france: iarc press, 2017. 5. sonone a, hande a, chaudhary m, bonde r, sheorain a, agni n. adenoid ameloblastoma with dentinoid and ghost cells: a composite odontogenic tumour a rare case report and review of the literature. oral surg 2011; 4:77–81. doi: 10.1111/j.1752-248x.2010.01109.x. 6. papagerakis p, peuchmaur m, hotton d, ferkdadji l, delmas p, sasaki s, et al. aberrant gene expression in epithelial cells of mixed odontogenic tumors. j dent res 1999; 78:20–30. doi: 10.1177/00220345990780010201. response from the authors dear reader, thank you very much for reading our article and for your suggestion to include adenoid ameloblastomas with dentinoid to the current debate regarding odontogenic tumours. we did not include this entity in our review article because it was not incorporated in the 2017 world health organization classification of odontogenic tumours.1,2 considerable variations in the histopathological presentation of epithelial odontogenic tumours can sometimes be confusing and increase the chance of misdiagnosis.3 an adenoid ameloblastoma with dentinoid is considered a hybrid tumour of the odontogenic apparatus in that it demonstrates the histopathological characteristics of two or more previously recognised odontogenic tumours and/or cysts.4 the exact cause for this is not known. odontogenic tumours originate from the odontogenic epithelium, which has the potential for diverse differentiation and complex inductive interactions. therefore, it is possible that the pluripotent odontogenic epithelium can induce the formation of different histopathological patterns within the same tumour.5 only a few cases have been reported of tumours with histopathological features of both an ameloblastoma and an adenomatoid odontogenic tumour (aot), along with hard tissue formation.6 of these, almost half of the cases were initially diagnosed as ameloblastomas and treated via resection, while the others were believed to be aots and were consequently undertreated, leading to the recurrence of the lesion. in such cases, the aot-like areas predominated, overshadowing the ameloblastomatous areas and leading to a benign diagnosis and conservative treatment.6 therefore, a thorough examination of the biopsy sample is mandatory to rule out the existence of another lesion; moreover, it is better that such hybrid lesions be treated with the more aggressive lesion in mind. similarly, ide et al. reported a lesion initially diagnosed as a globulomaxillary cyst, subsequently identified as an aot upon histopathological analysis and retrospectively confirmed to be consistent with an adenoid ameloblastoma with dentinoid after the lesion had recurred four times over an 11-year period.3 according to the authors, most lesions reported in the literature as recurrent aots are almost certainly adenoid ameloblastomas with dentinoid.3 whether hybrid tumours should be considered to be new entities, subtypes of two separate odontogenic lesions or solely histopathological variations of established entities is yet to be concluded.4,5 however, while such hybrid histopathological appearances illustrate the differentiation potential of the odontogenic epithelium and ectomesenchyme along with their complex inductive interactions, a detailed subdivision is meaningless in clinical practice.4 furthermore, considering these hybrid lesions to be new entities may further complicate the already long list of odontogenic tumours and cause confusion with regards to widely accepted terminology.2 nevertheless, it is important that oral pathologists bear knowledge of such hybrid lesions in mind so that they can aid the operating surgeon when decided on the best treatment plan for affected patients. *pooja siwach, tabita joy, jagdish tupkari, arush thakur department of oral pathology & microbiology, government dental college & hospital, mumbai, maharashtra, india *corresponding author’s e-mail: poojasiwach127@gmail.com https://doi.org/10.18295/squmj.2017.17.03.003 https://doi.org/10.1111/j.1600-0714.1992.tb00969.x https://doi.org/10.1016/j.oooo.2015.05.011 https://doi.org/10.1016/j.oooo.2015.05.011 https://doi.org/10.1111/j.1752-248x.2010.01109.x https://doi.org/10.1177/00220345990780010201 divya gopinath and rohit k. menon letter to the editor | e251 references 1. siwach p, joy t, tupkari j, thakur a. controversies in odontogenic tumours: review. sultan qaboos univ med j 2017; 17:e268–76. doi: 10.18295/squmj.2017.17.03.003. 2. el-naggar ak, chan jk, grandis jr, takata t, slootweg pj, eds. who classification of head and neck tumours, 4th ed. lyon, france: iarc press, 2017. 3. ide f, mishima k, saito i, kusama k. diagnostically challenging epithelial odontogenic tumors: a selective review of 7 jawbone lesions. head neck pathol 2009; 3:18–26. doi: 10.1007/s12105-009-0107-4. 4. ide f, horie n, shimoyama t, sakashita h, kusama k. so-called hybrid odontogenic tumors: do they really exist? oral med pathol 2001; 6:13–21. doi: 10.3353/omp.6.13. 5. choudhari sk, gadbail ar. hybrid odontogenic tumors: a controversy. pathol oncol res 2015; 21:501–2. doi: 10.1007/s12253-014-9844-0. 6. saxena k, jose m, chatra lk, sequiera j. adenoid ameloblastoma with dentinoid. j oral maxillofac pathol 2012; 16:272–6. doi: 10.4103/0973029x.99088. https://doi.org/10.18295/squmj.2017.17.03.003 https://doi.org/10.1007/s12105-009-0107-4 https://doi.org/10.3353/omp.6.13 https://doi.org/10.1007/s12253-014-9844-0 https://doi.org/10.4103/0973-029x.99088 https://doi.org/10.4103/0973-029x.99088 رعاية املرضى الذين يعانون من مرض قدم السكري يف عمان اإبراهيم �صالح البو�صعيدي، نادية نور عبد الهادي، كري�صنت كوبيل abstract: diabetes mellitus is a major public health challenge and causes substantial morbidity and mortality worldwide. diabetic foot disease is one of the most debilitating and costly complications of diabetes. while simple preventative foot care measures can reduce the risk of lower limb ulcerations and subsequent amputations by up to 85%, they are not always implemented. in oman, foot care for patients with diabetes is mainly provided in primary and secondary care settings. among all lower limb amputations performed in public hospitals in oman between 2002–2013, 47.3% were performed on patients with diabetes. the quality of foot care among patients with diabetes in oman has not been evaluated and unidentified gaps in care may exist. this article highlights challenges in the provision of adequate foot care to omani patients with diabetes. it concludes with suggested strategies for an integrated national diabetic foot care programme in oman. keywords: diabetes mellitus, complications; diabetic foot; amputations; ulcers; preventive health services; epidemiology; oman. امللخ�ص: ي�صكل داء ال�صكري حتديا كبريا على ال�صحة العامة كونه يوؤدي اإىل الوفاة واعتالل حاد يف ال�صحة، ويعترب مر�ض قدم ال�صكري خماطر من للحد الب�صيطة الوقائية التدابري بع�ض اأتخاذ املمكن من و باملر�ض. للم�صابني واملكلفة املنهكة امل�صاعفات اأكرث من التقرحات وبرت االأطراف ال�صفلى بن�صبة ت�صل اإىل %85 ولكنها ال تطبق ب�صكل دائم. تقدم رعاية م�صاعفات قدم ال�صكري يف مراكز الرعاية االأولية والثانوية يف �صلطنة ُعمان. خالل الفرتة من 2013-2002 اأجريت %47.3 من كل عمليات برت االأطراف ال�صفلية يف مر�صى داء ال�صكري يف عمان. مل جترى بحوث علي جودة الرعاية ال�صحية املقدمة ملر�صى قدم ال�صكري يف عمان، وبالتايل فاأنه من املتوقع وجود الكثري من الثغرات يف العناية بهوؤالء املر�صـى. نناق�ض يف هذه املقالة حتديات الرعاية ال�صحية املقدمة ملر�صى القدم ال�صكري يف عمان. يختتم املقال بعر�ض بع�ض املقرتحات لتنفيذ برنامج متكامل لرعاية مر�صى قدم ال�صكري على م�صتوى ال�صلطنة. كلمات مفتاحية: مر�ض ال�صكري، م�صاعفات؛ مر�ض قدم ال�صكري؛ َبرْت؛ تقْرحات؛ اخلدمات ال�صحية الوقاِئية؛ الَوباِئيَّات؛ ُعمان. care of patients with diabetic foot disease in oman *ibrahim s. al-busaidi,1 nadia n. abdulhadi,2 kirsten j. coppell1 review sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e270–276, epub. 19 aug 16 submitted 18 jul 15 revisions req. 5 oct 15 & 18 feb 16; revisions recd. 24 jan 16 & 3 mar 16 accepted 13 mar 16 doi: 10.18295/squmj.2016.16.03.002 diabetes mellitus is a chronic diseaseof worldwide significance.1 on a global scale, the prevalence of diabetes has continued to increase steadily, reaching 8.8% among adults aged 20–79 years old in 2015.2 diabetes is associated with long-term microvascular and macrovascular complications, including diabetic foot disease (dfd) —a group of heterogeneous foot conditions in which peripheral neuropathy and vascular disease, sometimes complicated by infection, may result in foot ulceration and lower limb amputation.3,4 due to its substantial morbidity and mortality, dfd is regarded as a global public health challenge and is considered to be one of the most debilitating complications of diabetes, with severe personal, societal and economic costs.1,3 nevertheless, dfd continues to be inadequately managed by healthcare services in many countries.1 globally, the prevalence of diabetic foot ulcers ranges from 1–12%, with national rates generally higher among arab countries, from 5% in jordan to 12% in algeria.5,6 approximately half of all lower limb amputations are due to diabetes, and of these lower limb amputations, active foot ulceration has been found to be a precursor in more than 85% of cases.3,7 in 2015, the reported age-adjusted prevalence of diabetes in oman was 14.8%.2 in response to the rise in diabetes prevalence over the past two decades, diabetes care is currently a priority in the national health programme coordinated by the omani ministry of health (moh).8,9 while advances have been made in the delivery of diabetes care, the prevalence of long-term complications of diabetes, including foot ulceration and lower limb amputation, is expected to rise.9,10 a structured well-resourced national programme is therefore vital to prevent and effectively manage dfd in oman.11 the aim of this article was to review diabetesrelated amputations and describe the current status of foot care services among patients with diabetes in 1edgar diabetes & obesity research centre, dunedin school of medicine, university of otago, dunedin, new zealand; 2department of research & studies, directorate general of planning & research, ministry of health, muscat, oman *corresponding author e-mail: ibra.3sk@gmail.com ibrahim s. al-busaidi, nadia n. abdulhadi and kirsten j. coppell review | e271 oman. challenges in the provision of adequate foot care to omani patients with diabetes are discussed and recommendations drawn from international guide lines are presented in order to improve diabetic foot care in primary and secondary care settings in oman. both relevant published and grey literature was reviewed. diabetes-related lower limb amputations despite the burden of diabetes-related lower limb amputations, there is a paucity of research regarding the epidemiology of dfd in oman, including a lack of published studies exploring the national prevalence of diabetic foot ulcerations and/or lower limb amputations.3,9,11 currently, the only available data on diabetes-related lower limb amputations in oman are from the moh.12–24 the reported annual incidence rate of diabetes-related lower limb amputations ranges between 20–36 per 10,000 patients with diabetes.12 yearly trends in diabetesand non-diabetes-related lower limb amputations performed in moh institutions in oman are shown in figure 1.13–24 between 2002–2013, a total of 3,675 lower limb amputations were performed, including 1,739 (47.3%) diabetesrelated amputations. additionally, over two-thirds (69.1%) of the patients with diabetes were male.13–24 in general, the number of lower limb amputations performed on male patients was consistently higher than for females; this finding is consistent with previous studies.25,26 however, the overall annual number of diabetes-related amputations was similar throughout the 12-year period;13–24 this observation is inconsistent with recent studies from other countries, which demonstrate an overall decrease in diabetesrelated lower limb amputation rates.25,27,28 the generally static annual number of lower limb amputations in oman may reflect suboptimal foot care among patients with diabetes.13–24 however, these data may underestimate the true number of diabetesrelated amputations for several reasons. first, the reported data represent amputations performed in public hospitals only and do not include amputation data from tertiary institutions not managed by the moh.13–24 indeed, the number of private hospitals providing surgical services is increasing in oman.29 second, inaccurate and under-reporting of diabetesrelated data is commonplace in diabetes care.30 third, the number of omanis seeking medical treatment abroad is increasing.31 these factors therefore complicate estimations of the true rate of diabetes-related amputations in oman. figure 1a & b: trends in (a) overall diabetesand non-diabetes-related lower limb amputations and (b) diabetes-related lower-limb amputations by gender performed in ministry of health institutions in oman between 2002–2013.13–24 care of patients with diabetic foot disease in oman e272 | squ medical journal, august 2016, volume 16, issue 3 diabetic foot disease management it is widely acknowledged that the implementation of evidence-based preventative and therapeutic foot care strategies can reduce lower limb ulceration rates and subsequent amputations by 45–85% in patients with diabetes.5,25,27,28 such strategies include optimised glycaemic control, regular foot selfcare, screening/identification of at-risk feet, risk reduction through podiatry, appropriate footwear/ orthotic devices, patient/staff education and multidisciplinary management of dfd cases.5,11,32 surgical interventions—including both prophylactic and revascularisation surgeries—play a role in preventing foot ulceration, improving wound healing and reducing the incidence and site of lower limb amputations.32 a successful foot care programme requires a coordinated healthcare system with a multidisciplinary approach.11,32 international guidelines recommend that all countries adopt a three-level model of foot care management which should be resourced to provide appropriate foot care services for patients with different levels of risk [table 1].11 in 1990, the national diabetes prevention and control programme was established in oman to tackle the growing burden of diabetes as well as to reduce the rate of long-term diabetes-related complications.9 in 2006, the national programme for screening of non-communicable diseases was implemented to provide screening services for five chronic conditions (diabetes, hypertension, obesity, hypercholesterolaemia and chronic renal impairment) to all omanis aged ≥40 years old attending primary health care centres (phccs).33 however, this latter programme does not screen for diabetes-related complications and there is currently no specific national goal to reduce the burden of dfd in oman. p r i m a r y c a r e in oman, routine foot care is provided mainly in primary care settings at phccs as part of overall diabetes care. the diabetes care team consists of a primary care physician or family physician, a diabetes practice nurse and a dietitian.34 local diabetes guidelines mandate primary care professionals perform at least one annual foot examination on all patients with diabetes, including an assessment of skin abnormalities, structural deformities, protective sensation, circulation and footwear.9,12 patients with foot ulcers are frequently managed by nurses, most of whom are not trained in diabetic foot care.35 to date, no detailed national guidelines for the prevention and management of dfd have been published or implemented. however, the moh launched several nurse-led clinics in selected catchment areas throughout oman in 2004 so that patients with diabetic foot ulcers could be initially managed by nurses trained in wound and diabetic foot care.35 situated in phccs, the clinics are equipped with basic wound care materials including scalpels, forceps and cotton gauze for basic wound dressing. by december 2013, 25 nurse-led diabetic foot clinics had been established in oman; however, more are required.35 s e c o n d a r y c a r e patients with more severe or complicated cases of dfd are referred from phccs to secondary care facilities known as polyclinics.34 within these polyclinics, highrisk diabetes clinics and foot care clinics are situated next to each other and operate simultaneously on specific days of the week. in most cases, a multidisciplinary team manages dfd cases, including a diabetologist, dietitian and nurse with training in diabetes and sometimes a podiatrist or wound care nurse in certain cases. foot care clinics are equipped with some of the equipment and materials required for the diagnosis and management of peripheral vascular disease, peripheral neuropathy and foot ulcers (e.g. semmes-weinstein monofilament, 128 hertz tuning forks, hand-held 5–10 megahertz doppler probes and advanced wound care products such as charcoal, hydrogels and calcium alginate dressings). however, it is important to note that secondary care diabetic foot care clinics are not available in all areas of oman due to a lack of local resources, staffing and infrastructure. furthermore, there is a shortage of other diagnostic and therapeutic resources, such as vibration perception threshold devices, insoles, orthotic and off-loading devices, casting techniques and radiological studies. podiatric services the role and value of podiatrists in the primary and secondary prevention of dfd is recognised internationally.36 regular access to podiatry services can decrease the prevalence and size of foot callosities, improve foot care knowledge and self-care table 1: levels of foot care required at the national level in the management of diabetic foot disease level of care description level 1 general practitioner, podiatrist, and diabetic nurse level 2 diabetologist, surgeon (general and/or vascular and/or orthopaedic), podiatrist, and diabetic nurse level 3 specialized foot centre with multiple disciplines specialized in diabetic foot care reproduced with permission from bakker k, apelqvist j, schaper nc; international working group on diabetic foot editorial board. practical guidelines on the management and prevention of the diabetic foot 2011.11 ibrahim s. al-busaidi, nadia n. abdulhadi and kirsten j. coppell review | e273 and significantly reduce the risk of foot ulceration recurrence in patients with diabetes.36,37 in oman, podiatrists mainly work as part of multidisciplinary teams in secondary care settings. unfortunately, there is a severe shortage in the podiatry workforce of oman; this is common for many countries worldwide, particularly developing countries.24,38 currently, there are 16 podiatrists in the public health system in oman, of which 13 are based in the capital city of muscat and the other three are located in the ad dakhilyah, ash sharqiyah north and al-batinah north governorates.35 this equates to approximately one podiatrist per 5,000 patients with diabetes in oman.24 due to this workforce shortage, diabetes podiatry services are essentially limited to the care and management of high-risk patients. fortunately, the existing shortage of podiatrists in oman has been recognised by decision-makers—in coordination with the ministry of higher education, the moh currently provides scholarships for students to complete their podiatry studies at overseas universities. as of december 2015, there were 10 students (eight undergraduate and two postgraduate) from oman undergoing podiatry training abroad.35 t e r t i a r y c a r e patients who require more specialised diabetic foot management are referred to regional or national centres in oman where tertiary care is provided. in addition to advanced non-surgical services, tertiary care centres provide surgical interventions for the management of dfd, including wound debridement, revascularisation surgeries and lower limb amputations.35 further details and discussion of the surgical management of dfd cases in oman is outside the scope of this review. diabetic foot care education patient and carer education about dfd risk factors and foot self-care is instrumental in preventing foot ulcers and subsequent amputations.11,32 during routine follow-up consultations, diabetes care providers are mandated by local guidelines to provide foot care education.9 although phccs in oman are staffed with qualified professionals, opportunities for patient education are somewhat limited. currently, no established programmes focus on the delivery of diabetic foot care education. a recent pilot study evaluated the provision of foot care education to 310 omani diabetic patients attending phccs and found that less than 50% of patients reported receiving education on recommended foot self-care practices and protective footwear.39 a number of factors could contribute to suboptimal diabetic foot care education in oman. first, healthcare professionals are faced with a number of organisational and system-related barriers to effective diabetes care education. these include heavy workloads, language/communication barriers, a perceived lack of teamwork and a shortage in the number of diabetes service providers.40 second, a large proportion of omani patients with diabetes, especially patients over the age of 50 years, have minimal or no formal education, as access to education was limited prior to the 1970s.41 finally, health literacy is poor among people with diabetes in oman, which is a factor associated with poor diabetes outcomes.42 diabetic foot care training diabetic foot education and wound care training directed at diabetes healthcare providers is equally vital in the prevention and management of dfd.11,32 in oman, few educational facilities provide on-going diabetic foot care training. however, the establishment of the national diabetic foot training centre in 2012 was the first step in providing nursing staff with the necessary training to manage patients with diabetic foot ulcers. the centre is based in the diabetic foot clinic in bausher specialized polyclinic in muscat and is staffed with a podiatrist, a wound care nurse specialist and wound management nurses. in addition to being a referral centre for patients with dfd, it provides nurses from all over the country with short training courses in foot examination, basic and advanced wound management and diabetic foot care. however, advances in training healthcare professionals are limited as the centre accommodates only 2–3 trainees per month. as of february 2016, 100 nurses had received training in diabetic foot care, of which 61 work in muscat.35 recommendations to improve diabetic foot care in oman given that diabetes-related foot amputations are largely preventable, there is room for improvement in the delivery of diabetic foot care in oman.3,5,11,32 the increasing national prevalence of diabetes highlights the importance of providing sufficient high-quality health services for those with the condition. the following recommendations are suggested to improve diabetic foot care services in oman. i m p l e m e n tat i o n o f a n at i o n a l p r o g r a m m e alongside current programmes to manage and prevent diabetes, a national diabetic foot care care of patients with diabetic foot disease in oman e274 | squ medical journal, august 2016, volume 16, issue 3 programme needs to be designed and implemented to address system-wide changes required for the prevention and management of dfd.9,34 successful programmes of this kind have been implemented in both poorand well-resourced countries.43–45 the primary goal of this programme should be to reduce diabetes-related lower limb amputations. the save the diabetic foot project in brazil is a commendable example of how the implementation of simple and low-cost preventative measures can result in a large reduction in amputation rates among patients with diabetes (77.8% over nine years).45 taking into account shortages in diabetic foot care services and human resources in oman, the establishment of a national diabetic foot care programme should occur in phases and be based on time-limited, attainable targets.11 coordination between diabetes care providers and health policymakers is pivotal to facilitate the implementation of such a programme.46 in addition, the impact of foot care improvement strategies as part of the programme should be evaluated continuously through a set of process and outcome indicators, such as the completion and outcomes of foot examinations and amputation rates. this type of monitoring will enhance understanding of the epidemiology and burden of dfd in oman. pat i e n t e d u c at i o n education programmes for patients with diabetes and their families should be provided to enhance community awareness of dfd and emphasise the importance of optimal diabetes control to prevent complications in general and regular foot self-care practices to prevent foot ulcers in particular. this education needs to be tailored to oman, as a number of sociocultural factors may put patients with diabetes in oman at particularly high risk for dfd—for example, many individuals may find it uncomfortable to wear closed shoes and socks due to the characteristically hot and dry weather in oman; patients with diabetes therefore often continue to wear traditional sandals, which do not offer protection from external trauma.7 given the limited literacy and education among many individuals with diabetes in oman, the mode of delivery and the content of educational initiatives needs to be simple, repetitive, clearly presented and targeted for education/literacy level and sociocultural practices.41,42 ideally, foot care education, as part of self-management education for patients with diabetes, should be delivered by health educators, nurses or doctors to patients in groups rather than individuals; furthermore, attractive written materials with pictorial diagrams should be used.40–42 h e a lt h p r o f e s s i o n a l e d u c at i o n a n d t r a i n i n g the national diabetic foot training centre in muscat should be expanded to provide high-quality diabetic foot care training to a larger number of health professionals. this could be accomplished by increasing training capacity to include primary care physicians, podiatrists and diabetes nurses. furthermore, regional diabetic foot training centres should be established in each governorate in oman to equip diabetes care providers with continuous training in the management of patients with dfd. an alternative would be to hold annual workshops on foot examination, identification of at-risk feet and management of foot ulcers for hospital-based and primary care health professionals involved in diabetes care. moreover, the training should be supported by the development and regular updating of diabetes foot care guidelines. d i a b e t i c f o o t c a r e r e s o u r c e s a n d fa c i l i t i e s given the shortage of human resources and health infrastructure in oman, the set-up of multidisciplinary diabetic foot care teams in primary and secondary care should be done in stages, with various specialist team members introduced gradually.11,24 in phccs, healthcare teams should consist of a primary care physician, diabetes nurse, health educator and podiatrist. secondary care-based teams should include a diabetologist, surgeon, podiatrist, diabetes nurse and orthotist. continuous coordination between policymakers at the moh and ministry of higher education in oman is necessary to increase the numbers of skilled professionals in the labour pool. moreover, diabetic foot care clinics should be set up throughout the country and equipped with the necessary resources for the management of diabetic foot ulcers, including diagnostic devices, customised footwear and orthotics, offloading devices, casting techniques and imaging studies. r e s e a r c h diabetic foot care and dfd research in oman is still in its infancy which undoubtedly leaves knowledge gaps in understanding the national burden of dfd. future research should focus primarily on understanding the burden and extent of dfd. population-based studies are urgently needed to better describe and understand the epidemiology of diabetic foot ulcers and lower limb amputations in oman. the contribution and effectiveness of current diabetic foot services should also be evaluated regularly. ibrahim s. al-busaidi, nadia n. abdulhadi and kirsten j. coppell review | e275 conclusion this review highlights existing gaps in the provision of diabetic foot care in oman. while initiatives to improve the quality of diabetes care have been implemented in recent years, the increase in the prevalence of diabetes in oman indicates an urgent need for a national diabetes foot care programme with trained staff that integrates all levels of healthcare within the country. the ultimate target should be to significantly reduce the rate of diabetes-related lower limb amputations. this programme should be coupled with an organised monitoring system to enable examination of the epidemiology and impact of dfd in oman. a c k n o w l e d g e m e n t s the authors would like to thank the staff of the department of non-communicable diseases surveillance & control, directorate general of health affairs, moh, oman, for providing some of the information and statistics used in this article. references 1. putting feet first in diabetes. lancet 2005; 366:1674. doi: 10.10 16/s0140-6736(05)67672-6. 2. international diabetes federation. idf diabetes atlas, 7th ed. watermael-boitsfort, belgium: international diabetes federation, 2015. pp. 50–120. 3. boulton aj. the diabetic foot: grand overview, epidemiology and pathogenesis. diabetes metab res rev 2008; 24:s3–6. doi: 10.1002/dmrr.833. 4. krans hmj. diabetes care and research in europe: the st vincent declaration action programme implementation document, 2nd ed. copenhagen, denmark: who regional office for europe, 1995. p. 8. 5. boulton aj, vileikyte l, ragnarson-tennvall g, apelqvist j. the global burden of diabetic foot disease. lancet 2005; 366:1719–24. doi: 10.1016/s0140-6736(05)67698-2. 6. ahmed aa, elsharief e, alsharief a. the diabetic foot in the arab world. j diabet foot complications 2011; 3:55–61. 7. apelqvist j, larsson j. what is the most effective way to reduce incidence of amputation in the diabetic foot? diabetes metab res rev 2000; 16:s75–83. doi: 10.1002/1520 7560(200009/10)16:1+<::aid-dmrr139>3.0.co;2-8. 8. al-lawati ja, panduranga p, al-shaikh ha, morsi m, mohsin n, khandekar rb, et al. epidemiology of diabetes mellitus in oman: results from two decades of research. sultan qaboos univ med j 2015; 15:e226–33. 9. oman ministry of health. diabetes mellitus management guidelines for primary health care, 2nd ed. muscat, oman: ministry of health, 2003. 10. world health organization regional office for the eastern mediterranean. country cooperation strategy for who and oman: 2010-2015. from: www.who.int/countryfocus/ cooperation_strategy/ccs_omn_en.pdf accessed: mar 2016. 11. bakker k, apelqvist j, schaper nc; international working group on diabetic foot editorial board. practical guidelines on the management and prevention of the diabetic foot 2011. diabetes metab res rev 2012; 28:225–31. doi: 10.1002/ dmrr.2253. 12. oman ministry of health. diabetes foot clinical examination: physical signs interpretation. muscat, oman: ministry of health, 2009. 13. oman ministry of health. annual health report 2002. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 14. oman ministry of health. annual health report 2003. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 15. oman ministry of health. annual health report 2004. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 16. oman ministry of health. annual health report 2005. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 17. oman ministry of health. annual health report 2006. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 18. oman ministry of health. annual health report 2007. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 19. oman ministry of health. annual health report 2008. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 20. oman ministry of health. annual health report 2009. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 21. oman ministry of health. annual health report 2010. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 22. oman ministry of health. annual health report 2011. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 23. oman ministry of health. annual health report 2012. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 24. oman ministry of health. annual health report 2013. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2016. 25. van houtum wh, rauwerda ja, ruwaard d, schaper nc, bakker k. reduction in diabetes-related lower-extremity amputations in the netherlands: 1991-2000. diabetes care 2004; 27:1042–6. doi: 10.2337/diacare.27.5.1042. 26. peek me. gender differences in diabetes-related lower extremity amputations. clin orthop relat res 2011; 469:1951–5. doi: 10.1007/s11999-010-1735-4. 27. larsson j, eneroth m, apelqvist j, stenström a. sustained reduction in major amputations in diabetic patients: 628 amputations in 461 patients in a defined population over a 20-year period. acta orthop 2008; 79:665–73. doi: 10.10 80/17453670810016696. 28. canavan rj, unwin nc, kelly wf, connolly vm. diabetes and nondiabetes-related lower extremity amputation incidence before and after the introduction of better organized diabetes foot care: continuous longitudinal monitoring using a standard method. diabetes care 2008; 31:459–63. doi: 10.2337/dc071159. 29. alshishtawy mm. four decades of progress: evolution of the health system in oman. sultan qaboos univ med j 2010; 10:12–22. 30. anwar h, fischbacher cm, leese gp, lindsay rs, mcknight ja, wild sh, et al. assessment of the under-reporting of diabetes in hospital admission data: a study from the scottish diabetes research network epidemiology group. diabet med 2011; 28:1514–19. doi: 10.1111/j.1464-5491.2011.03432.x. http://dx.doi.org/10.1016/s0140-6736%2805%2967672-6 http://dx.doi.org/10.1016/s0140-6736%2805%2967672-6 http://dx.doi.org/10.1002/dmrr.833 http://dx.doi.org/10.1016/s0140-6736%2805%2967698-2 http://dx.doi.org/10.1002/1520-7560%28200009/10%2916:1%2b%3c::aid-dmrr139%3e3.0.co%3b2-8 http://dx.doi.org/10.1002/1520-7560%28200009/10%2916:1%2b%3c::aid-dmrr139%3e3.0.co%3b2-8 http://dx.doi.org/10.1002/dmrr.2253 http://dx.doi.org/10.1002/dmrr.2253 http://dx.doi.org/10.2337/diacare.27.5.1042 http://dx.doi.org/10.1007/s11999-010-1735-4 http://dx.doi.org/10.1080/17453670810016696 http://dx.doi.org/10.1080/17453670810016696 http://dx.doi.org/10.2337/dc07-1159 http://dx.doi.org/10.2337/dc07-1159 http://dx.doi.org/10.1111/j.1464-5491.2011.03432.x care of patients with diabetic foot disease in oman e276 | squ medical journal, august 2016, volume 16, issue 3 31. al-hinai ss, al-busaidi as, al-busaidi ih. medical tourism abroad: a new challenge to oman’s health system al dakhilya region experience. sultan qaboos univ med j 2011; 11:477–84. 32. singh n, armstrong dg, lipsky ba. preventing foot ulcers in patients with diabetes. jama 2005; 293:217–28. doi: 10.1001/ jama.293.2.217. 33. oman ministry of health. operational and management guidelines for the national non-communicable diseases screening program. muscat, oman: ministry of health, 2009. 34. oman ministry of health. policy on quality improvement of diabetes care. muscat, oman: ministry of health, 2009. 35. oman ministry of health representatives. personal communications, 2015. 36. plank j, haas w, rakovac i, görzer e, sommer r, siebenhofer a, et al. evaluation of the impact of chiropodist care in the secondary prevention of foot ulcerations in diabetic subjects. diabetes care 2003; 26:1691–5. doi: 10.2337/diacare.26.6.1691. 37. hämäläinen h, rönnemaa t, toikka t, liukkonen i. long-term effects of one year of intensified podiatric activities on foot-care knowledge and self-care habits in patients with diabetes. diabetes educ 1998; 24:734–40. doi: 10.1177/014572179802400609. 38. unwin n. the diabetic foot in the developing world. diabetes metab res rev 2008; 24:s31–3. doi: 10.1002/dmrr.857. 39. al-busaidi is, coppell kj, abdulhadi n. the quality of foot care amongst omani diabetic patients attending primary health care facilities in muscat, oman: a pilot study. paper presented at the 5th annual conference of the otago international health research network, dunedin, new zealand, 7–8 nov 2012. 40. elliott ja, abdulhadi nn, al-maniri aa, al-shafaee ma, wahlström r. diabetes self-management and education of people living with diabetes: a survey in primary health care in muscat oman. plos one 2013; 8:e57400. doi: 10.1371/journal. pone.0057400. 41. al shafaee ma, al-shukaili s, rizvi sg, al farsi y, khan ma, ganguly ss, et al. knowledge and perceptions of diabetes in a semi-urban omani population. bmc public health 2008; 8:249. doi: 10.1186/1471-2458-8-249. 42. noor abdulhadi nm, al-shafaee ma, wahlström r, hjelm k. doctors’ and nurses’ views on patient care for type 2 diabetes: an interview study in primary health care in oman. prim health care res dev 2013; 14:258–69. doi: 10.1017/ s146342361200062x. 43. ramachandran a. specific problems of the diabetic foot in developing countries. diabetes metab res rev 2004; 20:s19–22. doi: 10.1002/dmrr.440. 44. thomson fj, veves a, ashe h, knowles ea, gem j, walker mg, et al. a team approach to diabetic foot care: the manchester experience. the foot 1991; 2:75–82. doi: 10.1016/09582592(91)90034-9. 45. pedrosa hc, leme la, novaes c, saigg m, sena f, gomes eb, et al. the diabetic foot in south america: progress with the brazilian save the diabetic foot project. int diabetes monit 2004; 16:10–17. 46. van houtum wh. barriers to the delivery of diabetic foot care. lancet 2005; 366:1678–9. doi: 10.1016/s0140-6736(05)67675-1. http://dx.doi.org/10.1001/jama.293.2.217 http://dx.doi.org/10.1001/jama.293.2.217 http://dx.doi.org/10.2337/diacare.26.6.1691 http://dx.doi.org/10.1177/014572179802400609 http://dx.doi.org/10.1002/dmrr.857 http://dx.doi.org/10.1371/journal.pone.0057400 http://dx.doi.org/10.1371/journal.pone.0057400 http://dx.doi.org/10.1186/1471-2458-8-249 http://dx.doi.org/10.1017/s146342361200062x http://dx.doi.org/10.1017/s146342361200062x http://dx.doi.org/10.1002/dmrr.440 http://dx.doi.org/10.1016/0958-2592%2891%2990034-9 http://dx.doi.org/10.1016/0958-2592%2891%2990034-9 http://dx.doi.org/10.1016/s0140-6736%2805%2967675-1 e568 | notice of author affiliation correction تصحيح لعنوان كاتب مقال نقطة الرعاية للمسلك اهلوائي بتخطيط الصدى قبل عملية بضع الغشاء احللقي الدرقي الطارئة تقرير حالة erratum notice erratum notice of author affiliation correction point-of-care airway ultrasonography prior to an emergency cricothyroidotomy case report the editors of sultan qaboos university medical journal (squmj) have been informed that the authors of an article by iqhbal et al. in the may 2018 issue of squmj wish to make a correction to the affiliation details of the authors of the above article.1 the first and corresponding author, mohamad iqhbal, contacted squmj in january 2019 notifying the editors of a mistake in the spelling of the institution in the authors’ affiliation details: department of emergency medicine, faculty of medicine, mara university of technology, selangor, malaysia. however, this correction could not be made as the article had already been published several months previously.1 for the reasons stated herein, the editors of squmj wish to notify readers that the affiliation details of the authors for the above article are changed to the following: department of emergency medicine, faculty of medicine, universiti teknologi mara, selangor, malaysia. the corresponding author takes sole responsibility for this notice and would like to apologise to the readers, reviewers and editors of squmj for this correction made after publication. references 1. iqhbal m, noor jm, karim na, ismail i, sanib h, mokhtar ma, et al. point-of-care airway ultrasonography prior to an emergency cricothyroidotomy: case report. sultan qaboos univ med j 2018; 18:e219–22. https://doi.org/10.18295/squmj.2018.18.02.017. notice of erratum for: iqhbal et al. point-of-care airway ultrasonography prior to an emergency cricothyroidotomy: case report. sultan qaboos univ med j 2018; 18:e219–22. https://doi.org/10.18295/squmj.2018.18.02.017. sultan qaboos university med j, november 2018, vol. 18, iss. 4, p. e568, epub. 28 mar 19 doi: 10.18295/squmj.2018.18.04.028 1cancer research center, tehran university of medical sciences & health services, tehran, iran; departments of 2internal medicine and 3community medicine, shahid sadoughi university of medical sciences, yazd province, iran *corresponding author’s e-mail: drmmirzadeh@gmail.com معدل الوفيات وعدد السنوات الضائعة بسبب سرطان الربوستاتة يف حمافظة يزد بإيران دراسة ملدة عشر سنوات جمتبى مريزائى، حمبوبه ال�صادات مريزاده، حم�صن مريزائى abstract: objectives: prostate cancer is a leading cause of cancer-related deaths. the number of deaths and years of life lost (yll) due to a disease can be used to monitor health status, assess healthcare needs and determine the prioritisation and allocation of health resources within a population; in addition, the latter calculation can serve as a baseline indicator of premature mortality. this study aimed to measure prostate cancer-related mortality and yll in yazd province, iran. methods: this study included all prostate cancer-related deaths in yazd province reported between march 2001 and march 2010. mortality data were obtained from a provincial death registration system which integrates data from different sources. yll was calculated based on an individual’s age at death and their life expectancy according to age group. results: during the study period, prostate cancer was the fourth most common fatal cancer among men, resulting in 324 deaths or 10.0% of all cancer-related deaths. the crude mortality rate per 100,000 individuals increased from 4.7 in 2001 to 8.8 in 2010. premature deaths caused 1,358.7 yll and the yll caused by prostate cancer deaths more than doubled from 94.7 in 2001 to 196.5 in 2010. conclusion: due to changes in population structure, it is likely that the burden of prostate cancer will continue to increase in yazd province. as such, it is necessary that the national health system implements screening programmes and improves public awareness of prostate cancer-associated risk factors. keywords: prostate cancer; years of potential life lost; mortality; health status indicators; iran. التي وال�صنوات به، املتوفني اأعداد ا�صتخدام وميكن ال�رشطان. اآثار من الوفاة اأ�صباب اأهم من الربو�صتاتة �رشطان يعد الهدف: امللخ�ص: وتخ�صي�ض الأولويات، وحتديد ال�صحية، الرعاية احتياجات وتقييم ال�صحية، احلالة ر�صد يف املر�ض ذلك ب�صبب اأعمارهم من �صاعت للقيمة كموؤ�رش املر�صى عمر من �صاعت التي ال�صنوات ح�صابات ت�صتخدم اأن ميكن لذلك وبال�صافة معينة. منطقة يف لل�صكان املوارد يف الربو�صتاتة �رشطان ب�صبب ال�صائعة ال�صنوات وعدد الوفيات معدل لقيا�ض الدرا�صة هذه وهدفت املبت�رشة. الوفيات ملعدل القاعدية وحت�صلنا .2010 ومار�ض 2001 مار�ض بني يزد مبحافظة الربو�صتاتة �رشطان مر�صى كل الدرا�صة �صملت باإيران. الطريقة: يزد حمافظة على اأعداد املتوفني باملر�ض من �صجالت املوتى مبحافظة يزد، والتي جتمع من م�صادر خمتلفة. ومت ح�صاب عدد ال�صنوات ال�صائعة ب�صبب املر�ض بناءا على عمر املري�ض عند الوفاة، وماأمول احلياة بح�صب املجموعة العمرية التي يقع فيها. النتائج: كان �رشطان الربو�صتاتة يف غ�صون �صنوات البحث هو الرابع بني اأنواع ال�رشطانات القاتلة، فقد ت�صبب يف وفاة 324 مري�صا، اأي %10.0 من كل الوفيات ب�صبب اأنواع املبت�رش املوت وت�صبب .2010 عام يف 8.8 اإىل 2001 عام يف �صخ�ض 100,000 لكل 4.7 من الوفيات معدل وزاد املختلفة. ال�رشطانات يف �صياع 1,358.7 �صنة. اأما �رشطان الربو�صتاتة فقد �صبب �صياع �صنوات من اأعمار املر�صى بلغت 94.7 يف عام 2001، وت�صاعفت يف عام 2010 اإىل 196.5. اخلال�صة: يتوقع زيادة عبء �رشطان الربو�صتاتة يف حمافظة يزد ب�صبب التغيريات يف تركيبة ال�صكان. ولهذا من ال�رشوري اأن يطبق النظام ال�صحي القومي برامج مل�صح وحتري املر�ض بني ال�صكان، واأن يح�صن من وعيهم بعوامل الختطار املرتبطة ب�رشطان الربو�صتاتة. الكلمات املفتاحية: �رشطان الربو�صتاتة؛ �صنوات احلياة املحتملة املفقودة؛ الوفيات؛ موؤ�رشات احلالة ال�صحية؛ اإيران. mortality rate and years of life lost due to prostate cancer in yazd province, iran a 10-year study mojtaba mirzaei,1 *mahboobehsadat mirzadeh,2 mohsen mirzaei3 clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e424–429, epub. 10 jan 18 submitted 3 may 17 revisions req. 29 may & 17 jul 17; revisions recd. 29 jun & 31 jul 17 accepted 3 aug 17 doi: 10.18295/squmj.2017.17.04.008 advances in knowledge this study found that both the prostate cancer-related mortality rate and years of life lost due to prostate cancer increased over a 10-year period in yazd province, iran. application to patient care the findings of this study have implications for modifying on-going cancer screening programmes, prioritising health interven tion programmes and integrating prostate cancer screening within the national health system in iran. mojtaba mirzaei, mahboobehsadat mirzadeh and mohsen mirzaei clinical and basic research | e425 cancer is a leading cause of mortality and years of life lost (yll) worldwide; by 2050, the incidence of cancer in developing countries is forecast to increase by 45%.1 due to the high fatality rate of most cancers, yll account for 90% of the burden of the disease and can therefore help policy-makers to prioritise health problems and design health interventions.2–4 the calculation of trends in cause-specific mortality can also help to indicate the effectiveness of healthcare programmes and the role of environmental risk factors in disease incidence and management.5 in 2012, approximately 1.1 million men worldwide were diagnosed with prostate cancer, making it the second most common cancer among men, equivalent to 15% of all male cancers.6 the incidence of this disease varies widely by geographical region, from 4.5 and 10.5 cases per 100,000 individuals in south central and eastern asia, respectively, to 111.6 cases per 100,000 individuals in new zealand and australia.6 of all new cases of prostate cancer in 2012, approximately 70% were reported from developed countries.6,7 apart from the role of screening, this variation may be due to lifestyle, dietary, environmental and genetic differences.8 nevertheless, while prostate cancer mort ality in western countries has reduced due to early diagnosis and treatment, the burden of prostate cancer is still growing in many developing countries, including iran.9–14 in iran, cancer is the third leading cause of mortality after cardiovascular disease and accidents, while prostate cancer is the third most common cancer and the eighth leading cause of mortality.13 however, trends in prostate cancer-related mortality have not been reliably measured in different regions within the country. therefore, this study aimed to determine the burden and trends of prostate cancer-related mortality over a 10-year period in yazd province, a region at the geographic centre of iran. in addition, the impact of premature deaths due to prostate cancer was quantified by calculating yll due to the disease. methods this study included all deaths due to malignant neoplasms of the prostate reported in yazd province between march 2001 and march 2010. mortality data were obtained from the national death registration system in iran which consists of information reported by physicians, healthcare institutions and cemeteries. trained physicians at various institutions in iran first report and code causes of death according to national protocols and the international classification of diseases; thereafter, hospitals, local health centres and cemeteries report these data monthly to a death registry committee.15 these reports are then matched and compared with data from the national organization for civil registration and the forensic medicine department. for the purposes of the study, duplicate death reports as determined based on similarities in the names of fathers, times of death and national identification numbers were excluded. when a garbage code or incomplete report was found, the researchers tried to retrieve the correct information via telephone interview with the responsible physician. this protocol was similarly used to obtain data for other causes of death. total population estimates in yazd province were calculated using information from health centre databases and national census data from 1996–2011 for which annual population growth was estimated exponentially.16 as such, the population of yazd province was set at 900,964 in 2001 and 1,056,638 in 2010, with the proportion of elderly individuals increasing from 8.3% to 9.1%, respectively. estimated demographic data for each year were used to calculate the indices for that specific year. subsequently, the mortality rate from prostate cancer per 100,000 individuals, percentage of prostate cancer deaths out of all cancer deaths and yll due to prostate cancer were calculated. the formula used to calculate yll was determined as follows:17,18 where n is the number of deaths within a certain age group and gender, l is the standard life expectancy of the deceased according to age group and gender, r is a discount rate of 0.03, β is an age weight of 0.04, c is an age weight correction factor of 0.165, a is the age at death and e is euler’s constant which is approximately equal to 2.71828. the average yll (ayll), which indi cates how many more years a person would have lived had they not died prematurely, was calculated by dividing the total yll by the total number of prostate cancer deaths annually. analysis of the data was performed using a yll template developed by the world health organization in an excel spreadsheet, version 2007 (microsoft corp., redmond, washington, usa).17 a chi-squared test was used to compare annual mortality rates. a p value of <0.05 was considered statistically significant. the protocol of this study was reviewed and approved by the ethics committee of the shahid sadoughi university of medical sciences, yazd province. all aspects of the study were conducted in accordance with the ethical codes of the university and only anonymous secondary data were utilised for the analysis. yll = n ce(ra)/(β + r)2 [e-(β + r) (l + a)[(β + r) (l + a) -1] e-(β + r) a [(β + r) a-1]] mortality rate and years of life lost due to prostate cancer in yazd province, iran a 10-year study e426 | squ medical journal, november 2017, volume 17, issue 4 results according to mortality data, a total of 324 deaths due to prostate cancer were reported in yazd province between 2001 and 2010. prostate cancer was the fourth leading fatal cancer among men [figure 1], accounting for 10.0% of all male cancer-related deaths. the total number of annual deaths due to prostate cancer increased significantly over the 10-year study period (p <0.05) [figure 2]. the mean age of the victims was 78 years (95% confidence interval: 77–79 years) and mean age did not differ significantly according to year (p >0.05). the majority of deaths occurred among men aged 70 years or older (87.7%) [table 1], although the youngest victim was only 33 years old. the mortality rate per 100,000 individuals increased from 4.7 in 2001 to 8.8 in 2010. the total yll was 1,358.7 years and the overall ayll was 4.2 years over the study period. the annual yll more than doubled during the study period from 94.7 years in 2001 to 196.5 years in 2010 [table 2]. discussion in the current study, the prostate cancer-related mortality rate per 100,000 individuals in yazd province increased from 4.7 in 2001 to 8.8 in 2010. a similar increasing trend has been reported in another study from iran, although the annual mortality rates were comparatively lower (0.63 in 1995 to 5.49 in 2004).19 this difference highlights the likelihood of regional differences within the country with regards to the incidence and mortality of this type of cancer.13,19–21 research conducted in other iranian provinces has also shown wide variation in the incidence of prostate cancer, ranging from 3.2 to 16.0 cases per 100,000 individuals.22 furthermore, the incidence of prostate cancer directly correlates with age and is rarely diagnosed among men under 50 years old; as such, the rate of mortality due to prostate cancer increases correspondingly with age.23 as a higher percentage of the population in yazd province is elderly in comparison to the rest of iran, this may also explain the higher incidence and mortality rates observed in the current study.24 in general, yll due to prostate cancer are lower on average compared to other cancers; however, within elderly populations, prostate cancer significantly contributes to total yll.4 currently, the incidence of prostate cancer remains higher in developed rather than developing countries.14 nevertheless, although prostate cancerrelated mortality varies widely throughout the world, there is an increasing trend in prostate cancer-related mortality in less developed countries in contrast to western countries.14 in 2012, prostate cancer-related mortality rates in asian countries ranged from 0.7 and 1.2 per 100,000 individuals in bhutan and nepal to 17.1 and 22.8 per 100,000 individuals in turkey and lebanon, respectively.7 in iran, the prostate cancer-related mortality rate has been reported to be 6 per 100,000 individuals.13 differences in mortality between various countries, specifically in comparison to incidence, may be due to variations in the implementation of screening programmes and the availability of better diagnostic resources and treatment facilities.25 in addition, the effect of ethnic and genetic figure 1: the ten leading causes of male cancer-related deaths between 2001–2010 in yazd province, iran (n = 2,669). cns = central nervous system. figure 2: trend in the number of prostate cancer-related deaths among deaths reported between 2001–2010 in yazd province, iran (n = 324). table 1: prostate cancer-related mortality by age group among deaths reported between 2001–2010 in yazd province, iran (n = 324) age group in years number of deaths mortality rate per 100,000 individuals percentage* 30–49 2 0.2 0.5 50–59 12 3.7 3.2 60–69 26 12.4 4.6 70–79 133 87.0 13.6 ≥80 151 249.5 21.8 *percentage of prostate cancer deaths out of all cancer deaths. mojtaba mirzaei, mahboobehsadat mirzadeh and mohsen mirzaei clinical and basic research | e427 variations on the incidence of prostate cancer has not yet been well determined.26,27 these variations may explain differences in the rate of deaths reported in yazd province as compared to other regions in iran. in the current study, the majority of deaths from prostate cancer occurred among those aged 70 years or older, which is consistent with the findings of other studies worldwide, indicating that age is one of the most important risk factors for prostate cancer.28,29 after the age of 50 years old, the lifetime risk of developing evidence of histological prostate cancer-related changes is estimated to be 42%.28 moreover, according to research performed on autopsy samples, the prevalence of prostate cancer doubles approximately every 14 years.29 the combined effect of increased life expectancy and a growing elderly population underscores the importance of management strategies for prevalent diseases such as prostate cancer. therefore, the increasing rate of prostate cancer-related mortality in iran can be prevented through the development of additional screening programmes targeting the elderly in order to provide early diagnosis and care, specifically in provinces with a higher percentage of elderly and middle-aged people. nevertheless, it is possible that a greater number of younger people may be diagnosed with prostate cancer if they are provided with easier access to screening and diagnostic tests. both lifestyle and dietary habits play a role in the pathogenesis of prostate cancer.30 a diet rich in red meat and smoking are risk factors for prostate cancer, whereas the consumption of tomatoes and participating in physical activity are potential preventative factors.31,32 a previous study found that 75.7% of elderly men in yazd province consumed red meat twice or more per week and 28.2% engaged only in low levels of physical activity; this may therefore explain the higher than average rates of prostate cancer in yazd province.33 however, establishing a definitive correlation between these factors would require further and more specific research. the reported incidence and prevalence of prostate cancer is directly correlated with diagnostic measures; as such, the number of undiagnosed and non-reported cases should be considered when comparing prostate cancer incidence, prevalence and mortality rates. for example, many elderly individuals may die from other causes before showing signs of prostate cancer.34 moreover, in addition to the introduction of the prostate-specific antigen (psa) test, other changes in diagnostic and therapeutic methods may play a role in observed variations in prostate cancer incidence. accordingly, rises in the diagnosis of prostate cancer have been linked to greater use of transurethral resections for benign prostate hyperplasia (bph), as the surgery involves sampling and pathological assessment of the prostate. on the other hand, the use of α-blockers and 5-α-reductase for bph treatment decreases the frequency of tissue sampling and may subsequently cause a reduction in reported incidence rates.35 researchers disagree about the effectiveness of psa screening in reducing prostate cancer-related mortality rates; while some studies propose this test as a noninvasive, easy-to-use, early screening tool in the general population, other studies have recommended psa testing only for those at a high risk for the disease.36–38 an algorithm has been suggested to identify high-risk patients based on their family history, digital rectal examination results and ethnicity.39 in the current study, while the overall mortality trend was found to have increased over the study period, there was a reduction in certain years, perhaps due to inconsistencies in the data collection. temporarily rising trends may be due to the improved reporting and registration of deaths. unfortunately, the specific diagnostic and treatment modalities offered to the patients involved in the current study prior to their deaths were not investigated. therefore, further studies are required to determine whether the increased mortality was treatment-related or due to a lack of comprehensive screening. the current study table 2: mortality and years of life lost due to prostate cancer among deaths reported between 2001–2010 in yazd province, iran (n = 324) 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 number of deaths 22 19 24 36 25 38 39 31 42 48 mortality rate per 100,000 individuals 4.7 4.0 4.9 7.3 5.0 7.3 7.5 5.9 7.8 8.8 yll 94.7 68 102.6 159.1 115.1 172.8 133.6 133.4 182.9 196.5 percentage* 9.6 7.6 8.7 11.4 7.7 11.5 9.8 8.6 10.8 13.0 yll = years of life lost. *percentage of prostate cancer deaths out of all cancer deaths. mortality rate and years of life lost due to prostate cancer in yazd province, iran a 10-year study e428 | squ medical journal, november 2017, volume 17, issue 4 was also subject to other limitations. first, the data obtained originated from a death registry based on death records, so the effect of spatial and temporal variations in diagnostic approaches on the incidence of prostate cancer was not evaluated. second, telephone interviews with responsible physicians were undertaken only in cases of missing data or garbage codes. thus, the researchers were unable to determine potential mistakes in diagnosis or reporting. finally, postmortem examinations to confirm prostate cancer diagnoses were performed only in certain cases based on the decision of the primary physician. conclusion overall, there was an increasing trend in mortality rate and yll due to prostate cancer in yazd province between 2001–2010. moreover, the incidence of prostate cancer is expected to rise further in the near future due to increasing life expectancy. as such, the national healthcare system in iran should develop specifically targeted plans for the prevention and management of various diseases, particularly those more prevalent among the elderly, such as prostate cancer. early prostate cancer screening programmes should be developed and healthy diet and lifestyle choices should be promoted among the general population. however, in order to implement these measures successfully, further studies are needed to investigate the effectiveness of various methods for reversing the rising trend of prostate cancer. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. pakzad r, rafiemanesh h, ghoncheh m, sarmad a, salehiniya h, hosseini s, et al. prostate cancer in iran: trends in incidence and morphological and epidemiological characteristics. asian pac j cancer prev 2016; 17:839–43. doi: 10.7314/apjcp.2016. 17.2.839. 2. burnet ng, jefferies sj, benson rj, hunt dp, treasure fp. years of life lost (yll) from cancer is an important measure of population burden—and should be considered when allocating research funds. br j cancer 2005; 92:241–5. doi: 10.1038/sj. bjc.6602321. 3. aragón tj, lichtensztajn dy, katcher bs, reiter r, katz mh. calculating expected years of life lost for assessing local ethnic disparities in causes of premature death. bmc public health 2008; 8:116. doi: 10.1186/1471-2458-8-116. 4. naghavi m, abolhassani f, pourmalek f, lakeh m, jafari n, vaseghi s, et al. the burden of disease and injury in iran 2003. popul health metr 2009; 7:9. doi: 10.1186/1478-7954-7-9. 5. carter aj, nguyen cn. a comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding. bmc public health 2012; 12:526. doi: 10.1186/1471-2458-12-526. 6. international agency for research on cancer, world health organization. prostate cancer estimated incidence, mortality and prevalence worldwide in 2012. from: http://globocan. iarc.fr/old/factsheets/cancers/prostate-new.asp accessed: jul 2017. 7. center mm, jemal a, lortet-tieulent j, ward e, ferlay j, brawley o, et al. international variation in prostate cancer incidence and mortality rates. eur urol 2012; 61:1079–92. doi: 10.1016/j.eururo.2012.02.054. 8. zahir st, nazemian mr, zand s, zare s. survival of patients with prostate cancer in yazd, iran. asian pac j cancer prev 2014; 15:883–6. doi: 10.7314/apjcp.2014.15.2.883. 9. rafiemanesh h, rajaei-behbahani n, khani y, hosseini s, pournamdar z, mohammadian-hafshejani a, et al. incidence trend and epidemiology of common cancers in the center of iran. glob j health sci 2016; 8:146–55. doi: 10.5539/gjhs. v8n3p146. 10. sadjadi a, nooraie m, ghorbani a, alimohammadian m, zahedi mj, darvish-moghadam s, et al. the incidence of prostate cancer in iran: results of a population-based cancer registry. arch iran med 2007; 10:481–5. doi: 07104/aim.0011. 11. conceição mb, boing af, peres kg. time trends in prostate cancer mortality according to major geographic regions of brazil: an analysis of three decades. cad saude publica 2014; 30:559–66. doi: 10.1590/0102-311x00005813. 12. jerez-roig j, souza dl, medeiros pf, barbosa ir, curado mp, costa ic, et al. future burden of prostate cancer mortality in brazil: a population-based study. cad saude publica 2014; 30:2451–8. doi: 10.1590/0102-311x00007314. 13. iran ministry of health and medical education mortality profile in iran (29 provinces) over the years 2006 to 2010. tehran, iran: ministry of health and medical education, 2013. 14. torre la, bray f, siegel rl, ferlay j, lortet-tieulent j, jemal a. global cancer statistics, 2012. ca cancer j clin 2015; 65:87–108. doi: 10.3322/caac.21262. 15. jafari n, kabir mj, motlagh me. death registration system in i.r.iran. iran j public health 2009; 38:127–9. 16. statistical center of iran. population and housing censues: census 2011. from: www.amar.org.ir/english/census-2011 accessed: jul 2017. 17. world health organization; mathers cd, bernard c, iburg km, inoue m, fat dm, shibuya k, et al. global burden of disease in 2002: data sources, methods and results. from: www.who.int/ healthinfo/paper54.pdf acccessed: jul 2017. 18. ayatollahi sm, hassanzadeh j, ramezani aa. the burden of traffic accidents in south khorasan province, iran in 2005. iran j epidemiol 2009; 4:51–7. 19. fazeli z, pourhoseingholi ma, vahedi m, abadi a, gholiizadeh s, zali mr. mortality rate of prostate cancer in iranian men. int j anal pharm biomed sci 2015; 4:70–5. 20. rafiemanesh h, enayatrad m, salehiniya h. epidemiology and trends of mortality from prostate cancer in iran. j isfahan med sch 2015; 33:515–21. 21. esmaeimzadeh n, salahi-moghaddam a, khoshdel ar. geographic distribution of important cancers in iran. hormozgan med j 2015; 19:73–82. 22. mousavi sm. toward prostate cancer early detection in iran. asian pac j cancer prev 2009; 10:413–18. 23. almasi a, shamsi m, eshrati b, javaheri j, alast ss, ghasemi z, et al. epidemiology of prostate cancer in markazi province in 2005-2010. j neyshabur univ med sci 2014; 2:1–8. https://doi.org/10.7314/apjcp.2016.17.2.839 https://doi.org/10.7314/apjcp.2016.17.2.839 https://doi.org/10.1038/sj.bjc.6602321 https://doi.org/10.1038/sj.bjc.6602321 https://doi.org/10.1186/1471-2458-8-116 https://doi.org/10.1186/1478-7954-7-9 https://doi.org/10.1186/1471-2458-12-526 https://doi.org/10.1016/j.eururo.2012.02.054 https://doi.org/10.7314/apjcp.2014.15.2.883 https://doi.org/10.5539/gjhs.v8n3p146 https://doi.org/10.5539/gjhs.v8n3p146 https://doi.org/07104/aim.0011 https://doi.org/10.1590/0102-311x00005813 https://doi.org/10.1590/0102-311x00007314 https://doi.org/10.3322/caac.21262 mojtaba mirzaei, mahboobehsadat mirzadeh and mohsen mirzaei clinical and basic research | e429 24. khosravi a, alizadeh m, torkashvand m, aghaei n. population ageing in ir iran. from: http://catalog.ihsn.org/index.php/ citations/56631 accessed: jul 2017. 25. stattin p, carlsson s, holmström b, vickers a, hugosson j, lilja h, et al. prostate cancer mortality in areas with high and low prostate cancer incidence. j natl cancer inst 2014; 106:dju007. doi: 10.1093/jnci/dju007. 26. dechello lm, gregorio di, samociuk h. race-specific geography of prostate cancer incidence. int j health geogr 2006; 5:59. doi: 10.1186/1476-072x-5-59. 27. cook mb, rosenberg ps, mccarty fa, wu m, king j, eheman c, et al. racial disparities in prostate cancer incidence rates by census division in the united states, 1999-2008. prostate 2015; 75:758–63. doi: 10.1002/pros.22958. 28. stangelberger a, waldert m, djavan b. prostate cancer in elderly men. rev urol 2008; 10:111–19. 29. bell kj, del mar c, wright g, dickinson j, glasziou p. prevalence of incidental prostate cancer: a systematic review of autopsy studies. int j cancer 2015; 137:1749–57. doi: 10.1002/ ijc.29538. 30. roshandel g, boreiri m, sadjadi a, malekzadeh r. a diversity of cancer incidence and mortality in west asian populations. ann glob health 2014; 80:346–57. doi: 10.1016/j.aogh.2014.09.012. 31. wolk a. diet, lifestyle and risk of prostate cancer. acta oncol 2005; 44:277–81. doi: 10.1080/02841860510029572. 32. huncharek m, haddock ks, reid r, kupelnick b. smoking as a risk factor for prostate cancer: a meta-analysis of 24 prospective cohort studies. am j public health 2010; 100:693–701. doi: 10.2105/ajph.2008.150508. 33. bahrami d, mirzaei m, salehi-abargouei a. dietary behaviors of elderly people residing in central iran: a preliminary report of yazd health study. elderly health j 2016; 2:6–13. 34. haas gp, delongchamps n, brawley ow, wang cy, de la roza g. the worldwide epidemiology of prostate cancer: perspectives from autopsy studies. can j urol 2008; 15:3866–71. 35. dickinson j, shane a, tonelli m, connor gorber s, joffres m, singh h, et al. trends in prostate cancer incidence and mortality in canada during the era of prostate-specific antigen screening. cmaj open 2016; 4:e73–9. doi: 10.9778/cmajo.20140079. 36. schröder fh, hugosson j, roobol mj, tammela tl, ciatto s, nelen v, et al. screening and prostate-cancer mortality in a randomized european study. n engl j med 2009; 360:1320–8. doi: 10.1056/nejmoa0810084. 37. andriole gl, crawford ed, grubb rl 3rd, buys ss, chia d, church tr, et al. mortality results from a randomized prostatecancer screening trial. n engl j med 2009; 360:1310–19. doi: 10.1056/nejmoa0810696. 38. busato wf jr, almeida gl. prostate cancer screening in brazil: should it be done or not? int braz j urol 2016; 42:1069–80. doi: 10.1590/s1677-5538.ibju.2015.0709. 39. carroll pr, parsons jk, andriole g, bahnson rr, castle ep, catalona wj, et al. nccn guidelines insights: prostate cancer early detection, version 2.2016. j natl compr canc netw 2016; 14:509–19. doi: 10.6004/jnccn.2016.0060. https://doi.org/10.1093/jnci/dju007 https://doi.org/10.1186/1476-072x-5-59 https://doi.org/10.1002/pros.22958 https://doi.org/10.1002/ijc.29538 https://doi.org/10.1002/ijc.29538 https://doi.org/10.1016/j.aogh.2014.09.012 https://doi.org/10.1080/02841860510029572 https://doi.org/10.2105/ajph.2008.150508 https://doi.org/10.9778/cmajo.20140079 https://doi.org/10.1056/nejmoa0810084 https://doi.org/10.1056/nejmoa0810696 https://doi.org/10.1590/s1677-5538.ibju.2015.0709 https://doi.org/10.6004/jnccn.2016.0060 sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e15–19, epub. 2 feb 16 submitted 26 mar 15 revision req. 1 jul 15; revision recd. 24 jul 15 accepted 11 aug 15 the united nations office for disaster risk reduction defines a disaster as a “serious disruption of the functioning of a community or society involving widespread human, material, economic or environmental losses and impacts which exceeds the ability of the affected community and society to cope using its own resources”.1 disasters can be natural or man-made and range from localised events to large-scale public health emergencies. the occurrence of a disaster is unpredictable and may result in chaos, mass casualties and destruction of property with devastating long-term social, physical, psychological, environmental and economic consequences that affect the health of a population and strain the capacity of the healthcare system.1 globally, there has been a steady increase in the magnitude and frequency of disasters and public health emergencies in recent years. in the last decade, there has been an estimated 60% increase in disasters worldwide in which an estimated two million people lost their lives, 4.2 million were injured, 33 million were left homeless and three billion were otherwise affected.2,3 climate change is thought to play a role in the larger number and greater impact of natural disasters; as a result, countries worldwide are encouraged to prepare accordingly.4 disasters have increasingly become a global concern as an event in one region can have a great impact on another; as such, no nation, region or community is immune. for instance, the recent ebola outbreak in west africa put major cities across the globe on alert.5,6 disasters demand concrete plans for management. the international council of nurses (icn) disaster management continuum model has four main components: mitigation, preparedness, response and recovery.7 the aim of the model is to reduce the impact on lives and infrastructure, enhance recovery and build community resilience to disasters.7 the hyogo framework for action, which has been endorsed by the united nations general assembly, highlights department of adult health & critical care, college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mail: susana@squ.edu.om التأهب جملاهبة الكوارث ضرورة إدخاله يف منهج التمريض التعليمي للدراسات اجلامعية �شوزان اأكورا و جوي كب��شيندي ك�م�ن�ير abstract: with the increasing global frequency of disasters, the call for disaster preparedness training needs to be reinforced. nurses form the largest group of the healthcare workforce and are often on the frontline in disaster management. therefore, nurses should be adequately equipped with the knowledge and skills to respond to disasters, starting from their pre-service training to their in-service professional training. however, the inclusion of disaster preparedness education in undergraduate nursing curricula is minimal in most countries. the purpose of this article is to highlight the current state of nursing education and training in disaster management, both generally and in oman. the significance of disaster preparedness training and recommendations for its inclusion in nursing practice and education are also discussed. keywords: disasters; disaster planning; nursing education; students; health personnel; oman. امللخ�ص: مع تزايد وقوع احلوادث يف اأرج�ء الع�مل املختلفة، يجب ت�أكيد الدعوة للتدريب على الت�أهب ملج�بهة الكوارث. ي�شكل املمر�شون واملمر�ش�ت اأكرب جمموعة من القوى الع�ملة يف املج�ل الطبي وال�شحي، وغ�لب� م� يكونون يف مقدمة ال�شفوف عند جم�بهة الكوارث. لذا يجب اأن تن�ل هذه الفئة التدريب والتعليم املالئم لزي�دة مع�رفهم ومه�راتهم لال�شتج�بة للكوارث يف مرحلة مبكرة من مراحل درا�شتهم، قبل بدء دخولهم جم�ل اخلدمة املهنية ويف اأثن�ئه� كذلك. غري اأن التثقيف يف جم�ل الت�أهب ملواجهة الكوارث يف من�هج كلي�ت التمري�ص على م�شتوى الدرا�ش�ت اجل�معية قليل جدا يف غ�لب الدول. والغر�ص من هذا املق�ل هو اإبراز الو�شع احل�يل للتعليم يف جم�ل التمري�ص اال�شتعداد على التدريب اأهمية اأي�ش� املق�ل وين�ق�ص خ��شة. �شورة عم�ن ويف ع�مة، ب�شورة الع�مل يف الكوارث، ملواجهة والتدريب ملواجهة الكوارث، ويقدم بع�ص التو�شي�ت الإدخ�له يف مم�ر�شة التمري�ص وتعليمه. مفتاح الكلمات: الكوارث؛ تخطيط الكوارث؛ تعليم التمري�ص؛ الطالب؛ الع�ملني ب�ل�شحة؛ عم�ن. sounding board disaster preparedness need for inclusion in undergraduate nursing education *susan achora and joy k. kamanyire doi: 10.18295/squmj.2016.16.01.004 disaster preparedness need for inclusion in undergraduate nursing education e16 | squ medical journal, february 2016, volume 16, issue 1 strengthening disaster preparedness at all levels as a priority for effective disaster management.8 disaster preparedness involves planning and preparation to effectively respond to any disaster situation. this includes implementing capacity development, coordinating the participation of responsible organisations, individuals and volunteers and ensuring that all personnel are equipped for response.8 role of the nurse in disasters when disasters occur, members of the healthcare professions are often among the first individuals to respond to the situation. as such, the disaster preparedness training of all healthcare professionals is essential to maintaining an efficient healthcare system in the midst of a disaster, particularly in view of the potentially widespread nature and complex environment of this type of incident.9 however, disaster preparedness training in most countries is based in specialised hospitals, public health schools or medical schools.9 surveys of recent global disasters have noted persistent gaps in the education, training and abilities of healthcare professionals in emergency situations.7,10 in response to these deficiencies, several organisations and groups based mainly in developed countries have begun to develop competency-based education and training for members of the healthcare workforce and other responders.7 due to the recent global increase in disasters, the world health organization (who) recommends that all countries, no matter how frequently they experience disasters, consider training their healthcare professionals to respond to disasters as a national and local priority.11 as nurses make up the majority of healthcare providers, they represent an indispensable workforce during disasters. the fundamental attributes of the nursing practice are to provide care to the injured or ill, assist individuals and families to deal with physical and emotional issues and work to improve health and well-being within the community. these attributes require competent nurses who are ready to respond in all situations, including in the event of a disaster. nurses must be able to adapt their skills from focusing on individuals to large numbers of patients, both in their delivery of lifesaving and emergency care and in the maintenance of public health.7,9 therefore, disaster training for nurses is vital. nurses must be involved in all phases of disaster planning in order to increase their understanding of their role and expected contributions in response to a disaster. disasters and disaster management in oman oman has a history of frequent tropical storms which can have devastating effects on lives and infrastructure, the most recent of which was cyclone gonu in 2007.12 in addition, oman is at risk of emerging public health emergencies such as the influenza a virus subtype haemagglutinine-1 neuraaminidase-1 (swine flu) and coronavirus (middle east respiratory syndrome), among others. the national disaster management committee coordinated by the oman national committee for civil defence has standards for health emergency plans which involve prevention, mitigation, preparedness and response measures to both natural and man-made disasters.13 nevertheless, emergency management in oman is still lacking and large gaps in disaster management have been reported following major disasters; according to interviews with health personnel, they were often confused, disoriented or left to work without prior guidelines during cyclone gonu.12 in addition, infrequent training and unclear staff training modalities were found to exist in healthcare disaster plans designed and implemented by the ministry of health (moh) in oman.14 role of nursing undergraduate curricula in disaster preparedness higher education institutions are capable of making great contributions to all phases of disaster management. first, these institutions can inculcate a culture of disaster preparedness and mitigation by developing training curricula, promoting educational opportunities and raising awareness of institutional disaster management plans. second, academic institutions can conduct relevant research and develop capacity-building programmes for healthcare workers and those involved in humanitarian work.15 these measures would create a wealth of resources that could be utilised in national preparedness and response systems through academicpublic health partnerships.16 disaster preparedness is a critical component of undergraduate education for health professionals. students must be adequately educated to successfully carry out their roles in disasters as a professional requirement.9 as such, core competencies must be established and function effectively. in 2009, the who and the icn developed the framework of disaster nursing competencies; all nurses susan achora and joy k. kamanyire sounding board | e17 worldwide are expected to be able to demonstrate the outlined competencies, thus providing an avenue to adequately prepare nurses for their future roles in disaster management.5 however, many health academic institutions around the world lack disaster preparedness curricula and have no developed competencies for students in health professions.7,17,18 global trends in disaster preparedness education in the usa, education on preparing for disasters was introduced within nursing curricula in the early 1970s but was then gradually removed.7 it wasn’t until the late 1990s that the increasing involvement of nurses in disaster response situations strengthened the need to once again include disaster nursing education in the curriculum.7 in 2003, the national student nurses’ association in the usa passed resolutions to include disaster preparedness content in the nursing curricula of all nursing schools.19 a few other nursing programmes worldwide have adopted the american curriculum.20 in the uk, as one of the requirements for nursing education pre-registration, nurses joining adult health specialties are mandated to recognise their role in disaster management, major incidents and public health emergencies and to respond appropriately according to their level of competence.21 disaster nursing education for undergraduate students was recently introduced in 44 nursing schools in china.22 in contrast, less than half of the nursing education programmes in japan included disaster nursing courses in 2009.7 universities in hong kong and australia did not include disaster content in their undergraduate nursing curricula in 2013.17,18 there is little information available on disaster training in nursing curricula among universities in africa or the middle eastern region, apart from certain universities in iran, turkey and jordan.23−25 disaster preparedness education in oman currently, there is no information on the availability of disaster nursing content in the undergraduate curriculum for nursing students in oman. diplomalevel training of nurses in oman began in the early 1970s and the first baccalaureate nursing programme commenced in 2002.26 currently, two universities in oman provide degree programmes and the moh plans to encourage nursing institutions offering diploma programmes to upgrade their curricula to the baccalaureate level.26,27 however, there is no documented evidence that disaster preparedness is or will be included within the core competencies of either diploma or undergraduate nurses in oman. it can therefore be assumed that disaster training for nursing students in oman is suboptimal; critically, this may translate into a generation of future nurses who are ill-equipped to handle disasters. barriers to implementing disaster preparedness education several barriers exist to the implementation of disaster training for student nurses. for a long time, disaster preparedness training was reserved only for nurses practicing in emergency departments or was offered only as a specialised post-basic course.28 additionally, existing nursing curricula in many countries are already at maximum capacity without the addition of further modules on disaster preparedness.29 to cope with this, there is a need to review nursing curricula to identify areas where disaster concepts can be integrated into current courses within nursing programmes.20 furthermore, teaching faculty may lack the knowledge and confidence to teach disaster content. in the usa, the national league for nurses reported that 75% of faculty teaching 348 nursing programmes were poorly prepared to teach disaster preparedness content.29 significance of disaster preparedness training for undergraduate students in general, the number of undergraduate programmes preparing student nurses for disaster management is still limited in many countries, resulting in professional nurses with limited competencies to participate effectively during a disaster.7,20 various international regulatory bodies have called for the inclusion of disaster content in nursing education at all levels.7 introducing disaster nursing content at the undergraduate level will not only increase the capacity of the health workforce to respond but will provide graduates entering the workforce with a foundation which can be developed further through in-service training and continuing professional development (cpd) programmes, thus saving resources.20 effective prior training also ensures the safety and health of healthcare workers and responders during a disaster.9 additionally, it may also improve the willingness of students to help during a disaster; undergraduate nursing students may be called upon during large-scale disasters to boost the capacity of practicing nurses disaster preparedness need for inclusion in undergraduate nursing education e18 | squ medical journal, february 2016, volume 16, issue 1 and these students must therefore possess the basic knowledge and skills of disaster nursing.17,18 student nurses trained in disaster management could also assist in community education programmes as part of a community disaster preparedness health initiative.29 recommendations for improving disaster preparedness education in preparation for disasters, nurses must be able to assess their own limitations, knowledge and skills. integrating disaster management courses into nursing curricula and offering cpd courses in disaster management would prepare nurses for emergency situations.2 the development of the teaching faculty through partnerships with agents involved in training personnel for disaster management is a step in the right direction to ensure proficiency in the undergraduate teaching of disaster preparedness.20 the who and icn framework of disaster nursing competencies could be adopted by universities to underpin undergraduate nursing curriculum content.7 currently, there is no evidence in the literature of a national action to prepare nurses for disasters in oman. academic institutions and the moh should work together to develop a national framework for disaster training in oman. this will provide a more consistent approach and standardisation of nursing education programmes in order to ensure that subsequent generations of nurses have been reliably and consistently trained in disaster management. the regulatory authority of professional nurses in oman needs to ensure that all nursing graduates meet the who/icn disaster competencies by including disaster nursing as a mandatory component in nursing curricula.7 the oman medical specialty board, as a body responsible for cpd in oman, should include evidence-based disaster preparedness as a mandatory course for all health professionals in the country. national disaster plans are needed, with clearly specified steps to be undertaken and transparent guidelines to be followed in the event of an emergency. furthermore, educational institutions should implement simulated disaster drills to encourage practicing nurses to maintain competence in this area. conclusion given the increasing global frequency of disasters, it is critical that nurses are able to effectively respond to disaster situations. however, many health professionals still lack the necessary knowledge and skills. there is therefore an urgent need to include disaster preparedness content in undergraduate nursing curricula, both globally and within oman. the who and icn framework of disaster nursing competencies is recommended for inclusion within nursing education. as part of their cpd process, practicing nurses in oman should also undergo regular evidence-based simulated training and skill updates. references 1. the united nations office for disaster risk reduction. terminology. from: www.unisdr.org/eng/library/lib-terminology -eng%20home.htm accessed: jul 2015. 2. international federation of red cross and red crescent societies. world disasters report 2007: focus on discrimination. from: www.ifrc.org/pagefiles/99876/wdr2007-english.pdf accessed: jul 2015. 3. centre for research on the epidemiology of disasters. the international disaster database: disasters trends index. from: www.emdat.be/disaster_trends/index.html accessed: jul 2015. 4. quaile i. more natural disasters due to climate change? from: www.dw.com/en/more-natural-disasters-due-to-climatechange/a-4598063 accessed: jul 2015. 5. matua ga, van der wal dm, locsin rc. ebolavirus and haemorrhagic syndrome. sultan qaboos univ med j 2015; 15:e171–6. 6. european centre for disease prevention and control. ebola outbreak in west africa. from: www.ecdc.europa.eu/en/ healthtopics/ebola_marburg_fevers/pages/ebola-outbreakwest-africa.aspx accessed: jul 2015. 7. international council of nurses and world health organization western pacific region. icn framework of disaster nursing competencies. from: www.wpro.who.int/hrh/documents/icn_ framework.pdf accessed: jul 2015. 8. the united nations office for disaster risk reduction. hyogo framework for action 2005-2015: building the resilience of nations and communities to disasters. from: www.unisdr.org/ we/inform/publications/1037 accessed: jul 2015. 9. chapman k, arbon p. are nurses ready? disaster preparedness in the acute setting. australas emerg nurs j 2008; 1:135–44. doi: 10.1016/j.aenj.2008.04.002. 10. arbon p, bobrowski c, zeitz k, hooper c, williams j, thitchener j. australian nurses volunteering for the sumatraandaman earthquake and tsunami of 2004: a review of experience and analysis of data collected by the tsunami volunteer hotline. australas emerg nurs j 2006; 9:171–8. doi: 10.1016/j.aenj.2006.05.003. 11. world health organization. emergency and disaster risk management for health. from: www.who.int/hac/techguidance/ preparedness/en/ accessed: jul 2015. 12. al-shaqsi s. care or cry: three years from cyclone gonu what have we learnt? oman med j 2010; 25:162–7. doi: 10.5001/omj.2010.50. 13. al-shaqsi sz. emergency management in the arabian peninsula: a case study from the sultanate of oman. from: www.training. fema .gov/hie du/dow nloads/comp emmgmtb o okproje ct/ comparative%20em%20book%20-%20em%20in%20oman.doc accessed: jul 2015. 14. al-shaqsi s, gauld r, mcbride d, al-kashmiri a, al-harthy a. the state of healthcare disaster plans in new zealand and the sultanate of oman: an international comparative analysis. adv emerg med 2014; 2014:758728. doi: 10.1155/2014/758728. www.unisdr.org/eng/library/lib-terminology%0a-eng%2520home.htm www.unisdr.org/eng/library/lib-terminology%0a-eng%2520home.htm www.ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/pages/ebola-outbreak-west-africa.aspx www.ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/pages/ebola-outbreak-west-africa.aspx www.ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/pages/ebola-outbreak-west-africa.aspx www.wpro.who.int/hrh/documents/icn_%0aframework.pdf www.wpro.who.int/hrh/documents/icn_%0aframework.pdf www.unisdr.org/we/inform/publications/1037 www.unisdr.org/we/inform/publications/1037 http://dx.doi.org/10.1016/j.aenj.2008.04.002 http://dx.doi.org/10.1016/j.aenj.2006.05.003 www.who.int/hac/techguidance/preparedness/en/ www.who.int/hac/techguidance/preparedness/en/ http://dx.doi.org/10.5001/omj.2010.50 www.training.fema.gov/hiedu/downloads/compemmgmtbookproject/comparative%2520em%2520book%2520-%2520em%2520in%2520oman.doc www.training.fema.gov/hiedu/downloads/compemmgmtbookproject/comparative%2520em%2520book%2520-%2520em%2520in%2520oman.doc www.training.fema.gov/hiedu/downloads/compemmgmtbookproject/comparative%2520em%2520book%2520-%2520em%2520in%2520oman.doc http://dx.doi.org/10.1155/2014/758728 susan achora and joy k. kamanyire sounding board | e19 15. dunlop al, logue km, isakov ap. the engagement of academic institutions in community disaster response: a comparative analysis. public health rep 2014; 129:87–95. 16. galliara m, prabhawalkar a. disaster management and role of academic institutions. soc work chron 2012; 1:1–29. 17. cusack l, arbon p, ranse j. what is the role of nursing students and schools of nursing during disaster? a discussion paper. collegian 2010; 17:193–7. doi: 10.1016/j.colegn.2010.09.006. 18. usher k, mayner l. disaster nursing: a descriptive survey of australian undergraduate nursing curricula. australas emerg nurs j 2011; 14:75–80. doi: 10.1016/j.aenj.2011.02.005. 19. national student nurses’ association. resolutions 2003. from: www.nsna.org/portals/0/skins/nsna/pdf/resolution2003.pdf accessed: dec 2015. 20. halstead ja. when disaster strikes: are you and your nursing students prepared? nurs educ perspect 2013; 34:213. doi: 10.5480/1536-5026-34.4.213. 21. nursing & midwifery council. standards for pre-registration nursing education. from: www.nmc.org.uk/globalassets/site documents/standards/nmc-standards-for-pre-registrationnursing-education.pdf accessed: jul 2015. 22. chan ss, chan ws, cheng y, fung ow, lai tk, leung aw, et al. development and evaluation of an undergraduate training course for developing international council of nurses disaster nursing competencies in china. j nurs scholarsh 2010; 42: 405–13. doi: 10.1111/j.1547-5069.2010.01363.x. 23. al khalaileh ma, bond e, alasad ja. jordanian nurses’ perceptions of their preparedness for disaster management. int emerg nurs 2012; 20:14–23. doi: 10.1016/j.ienj.2011.01.001. 24. zarea k, beiranvand s, sheini-jaberi p, nikbakht-nasrabadi a. disaster nursing in iran: challenges and opportunities. australas emerg nurs j 2014; 17:190–6. doi: 10.1016/j. aenj.2014.05.006. 25. öztekin sd, larson ee, yüksel s, altun uğraş g. undergraduate nursing students’ perceptions about disaster preparedness and response in istanbul, turkey, and miyazaki, japan: a crosssectional study. jpn j nurs sci 2015; 12:145–53. doi: 10.1111/ jjns.12058. 26. minority nurse. professional nursing in oman. from: www. minoritynurse.com/professional-nursing-in-oman/ accessed: jul 2015. 27. ghosh b. health workforce development planning in the sultanate of oman: a case study. hum resour health 2009; 7:47. doi: 10.1186/1478-4491-7-47. 28. nyamathi am, king m, casillas a, gresham ls, mutere m. nurses’ perceptions of content and delivery style of bioterrorism education. j nurses staff dev 2007; 23:251–9. doi: 10.1097/01. nnd.0000300843.97222.dc. 29. weiner e, irwin m, trangenstein p, gordon j. emergency preparedness curriculum in nursing schools in the united states. nurs educ perspect 2005; 26:334–9. doi: 10.1043 /1536-5026(2005)026[0334:epcins]2.0.co;2. http://dx.doi.org/10.1016/j.colegn.2010.09.006 http://dx.doi.org/10.1016/j.aenj.2011.02.005 http://dx.doi.org/10.5480/1536-5026-34.4.213 http://www.nmc.org.uk/globalassets/site%0adocuments/standards/nmc-standards-for-pre-registration-nursing-education.pdf http://www.nmc.org.uk/globalassets/site%0adocuments/standards/nmc-standards-for-pre-registration-nursing-education.pdf http://www.nmc.org.uk/globalassets/site%0adocuments/standards/nmc-standards-for-pre-registration-nursing-education.pdf http://dx.doi.org/10.1111/j.1547-5069.2010.01363.x http://dx.doi.org/10.1016/j.ienj.2011.01.001 http://dx.doi.org/10.1016/j.aenj.2014.05.006 http://dx.doi.org/10.1016/j.aenj.2014.05.006 http://dx.doi.org/10.1111/jjns.12058 http://dx.doi.org/10.1111/jjns.12058 http://dx.doi.org/10.1186/1478-4491-7-47 http://dx.doi.org/10.1097/01.nnd.0000300843.97222.dc http://dx.doi.org/10.1097/01.nnd.0000300843.97222.dc http://dx.doi.org/10.1043%0a/1536-5026%282005%29026%5b0334:epcins%5d2.0.co%3b2 http://dx.doi.org/10.1043%0a/1536-5026%282005%29026%5b0334:epcins%5d2.0.co%3b2 clinical & basic research squ med j, august 2011, vol. 11, iss. 3, pp. 383-390, epub. 15th aug 11 submitted 24th apr 11 revision req. 24th may 11 revision recd. 1st jun 11 accepted 8th jun 11 department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: ibrahim1@squ.edu.om <‹èèœj÷<∞jœëüõ<‡⁄< �g�÷]<h¯õ<ãœ]á⁄ê<l^¬^f�fi] �îüéf÷]<xëüéj÷]<ïå^π< �í◊€√÷]<gfi^r◊÷<ì�è€◊√÷]<‹„j ü√⁄              :مفتاح الكلمات abstract: objectives: traditionally, summative practical examination in anatomy takes the form of ‘spotters’ consisting of a stream of prosections, radiological images and dissections with pins indicating specific structures. recently, we have started to administer similar examinations online using the quiz facility in moodle™ (a free, open-source web application for producing modular internet-based courses) in addition to the traditional format. this paper reports on an investigation into students’ perceptions of each assessment environment. methods: over a 3-year period, practical assessment in anatomy was conducted either in traditional format or online via learning management software called moodle™. all students exposed to the two examination formats at the college of medicine & health sciences, sultan qaboos university, oman, were divided into two categories: junior (year 3) and senior (year 4). an evaluation of their perception of both examination formats was conducted using a selfadministered questionnaire consisting of restricted and free response items. results: more than half of all students expressed a clear preference for the online environment and believed it was more exam-friendly. this preference was higher amongst senior students. compared to females, male students preferred the online environment. senior students were less likely to study on cadavers when the examination was conducted online. specimen quality, ability to manage time, and seating arrangements were major advantages identified by students who preferred the online format. conclusion: computer-based practical examinations in anatomy appeared to be generally popular with our students. the students adopted a different approach to study when the exam was conducted online as compared to the traditional ‘steeplechase’ format. keywords: anatomy; attitude to computers; medical education perceptions and attitudes of medical students towards two methods of assessing practical anatomy knowledge *ibrahim m inuwa, varna taranikanti, maimouna al-rawahy, omar habbal clinical & basic research advances in knowledge 1. this study reports on an online method of organising anatomy “spotter” examinations. 2. it provides insight into student perceptions of assessment methods in medical education. 3. over 44% of the students surveyed preferred the online examination method. perceptions and attitudes of medical students towards two methods of assessing practical anatomy knowledge 384 | squ medical journal, august 2011, volume 11, issue 3 during the last 20 to 25 years, digital technology has emerged rapidly from a novelty to being ubiquitous in medical education.1 the advances in computer technology and software available for medical education purposes have concurrently brought technological and software advances for the development and administration of computer-based examinations for medical students.2 several advantages of computer-based examination over traditional methods have been suggested. these include an increase in the efficiency and reliability of the assessment process,3 immediate scoring and feedback for the student and the instructor,4 the opportunity for item banking and the collection of item statistics, and the ability to incorporate multimedia into examinations, as well as a wide range of new items and new testing formats.1 concurrent with studies reporting advantages, others attempted to examine student attitudes toward computer-based testing and its impact on students' study habits. one such previous study found that paediatric residents' attitudes were strongly positive toward the process and that the majority of residents preferred computer-based test administration over written examinations.5 later, rattan et al.6 also reported that medical students preferred a computer test over a paper and pencil test. miller et al.7 in a study on computerbased examination in anatomic pathology similarly reported that medical students valued such a method and supported its use. in addition to the many practical advantages alluded to, computer-based testing could also facilitate the development of more valid assessment strategies. this is because one of the most important goals of a good examination design is to minimise influences that interfere with the unambiguous expression of an examinee’s ability. examinations should therefore be designed so that all examinees have an opportunity to perform their best in relation to the constructs being measured. the medium through which such examination is administered (on paper or online) should not act as a hindrance to the students’ performance and not just reflect their ability to adapt to a technology or to an examination format.1 the medical curriculum at sultan qaboos university extends over seven academic years. the first phase lasts for four years following which the degree of b.sc. health sciences is awarded whilst the remaining three years comprise a clinical programme leading to the md degree. an academic year consists of two semesters, each of 15 weeks duration. anatomy teaching is provided mainly during the b.sc. health sciences programme, first as an introductory course and later integrated with other disciplines in organ-system courses.8 the teaching approach involves didactic tutor-led sessions, student-centered tutorials, based on patient scenarios that illustrate relevant anatomy, and practical classes in the dissection room. the anatomy practical uses prosected cadavers, plastinated organs, plastic models and radiological images. although students learn on cadavers, these are mainly tutor-led demonstrations in small groups on already dissected specimens. for cultural reasons, there is no established body donation programme in the country; therefore, all cadavers have to be imported from abroad. over the last decade it had become increasingly difficult to obtain cadavers due to restrictions placed on export by the countries of origin; this is partly because such countries do not seem to have enough cadavers to satisfy the need of their own medical schools.9 assessment in anatomy is conducted in the form of written examinations such as multiple choice or short answer questions. in addition, students’ ability to identify anatomical structures or correlate morphology with function is traditionally assessed through practical examinations. these consist of a circular stream of prosections, radiological images and dissections with pins pointing to specific structures (popularly referred to as ‘spotters’). specific questions are then asked about where the pin is placed so as to identify a structure, its source of blood supply or function. with the increasing difficulty in obtaining a constant supply of cadaveric material, the wear and tear of the existing ones became a real problem to the extent that the normal anatomy has become increasingly unrecognisable. in such a situation, innovation is needed both in teaching and assessment so as to use the available cadaveric material optimally. this led to the idea of developing an online summative assessment system using digitised images of the same material used in teaching. our goal has been to create digital resources for conducting examinations similar ibrahim m inuwa, varna taranikanti, maimouna al-rawahy, omar habbal clinical and basic research | 385 to the traditional anatomy practical examination (spotter). computer-based assessment is not just an alternative method of delivering examinations, it represents an important qualitative shift from traditional methods such as paper based tests.10 consequently, when examinations migrate from paper-and-pencil format to computer delivery, a wide range of issues could arise such as test fairness, students’ preparation habits and their perception of the examination format. in this study, we investigated our students’ perceptions of both online and traditional methods of practical assessment in anatomy. in particular, we were interested in investigating whether students adopt similar or different learning and test-taking strategies depending on the examination method. methods ethical approval for this project was obtained from the research and ethics committee of the college of medicine & health sciences at sultan qaboos university. data collection was carried out during the six fall and spring semesters from 2007 to 2009 (inclusive) when organ-system courses were delivered. teaching of anatomy in a 7-year medical curriculum is delivered over three academic years (years 2 to 4) within integrated organ-system courses. practical examinations are administered at the end of each course. typically, the number of questions ranges from 40–50 items for each organsystem course. the practical examination in the online environment utilised digitised ‘assessment objects’ from materials used for teaching. these included figure 1: two examples of online spotter questions. perceptions and attitudes of medical students towards two methods of assessing practical anatomy knowledge 386 | squ medical journal, august 2011, volume 11, issue 3 dissected cadavers, surface anatomy and radiological images and microscopic slides [figure 1]. in addition, short video clips of 30 seconds duration demonstrating muscle action were also used. these ‘objects’ were optimised for online viewing and then uploaded onto the learning management software, moodle™ (a free, open-source web application for producing modular internet-based courses).11 this software has been used for online learning experiences in a variety of courses for the health professions.12-16 using the quiz tool in the software, a bank of questions was created and linked to the assessment objects. access to the software and the questions is through the password-protected secure university server. with regards to the examination in the traditional format, the actual specimens were laid out in a circular stream in the dissecting room. lettered tags were then attached with pins to specific spots on the specimens and questions were asked regarding those tagged spots. the number of questions was similar to that of the online environment. the questions were reviewed by a team of two faculty members to ensure accuracy and concordance with course objectives before the start of the examination. the perception of medical students towards anatomy practical examination was studied among those in years 3 and 4 (comprising about 120 students in each cohort) for three consecutive years, and anatomy practical examinations in organ-system courses were conducted both in traditional and online formats for all students. students are informed by the course director about the format of practical examination at the beginning of each course. our policy specifies that only course directors familiar with moodle are permitted to administer online examinations. others not yet trained, or not favourably inclined towards virtual learning philosophy, administer the practical examinations in the usual traditional format within the dissecting room. immediately after each examination, and before results were announced, a paper-based or electronic student survey was carried out requesting voluntary feedback on their experience. students had the right to decline taking part in the survey and were informed that the data would be published. the responses were categorised into those from senior students (year 4) and junior students (year 3). a chisquare test for independence between gender and seniority was computed using graphpad prism, version 5.00 for windows (graphpad software, san diego, california, usa, www.graphpad.com). a p value of 0.05 or lower was considered significant. results a total of 515 completed responses were returned (71.5 % response rate). this comprised 165 (32%) senior and 350 (68%) junior students. there was an equal gender distribution amongst both junior and senior respondents (male: female = 1: 1.01). the actual distribution of students that preferred one of the examination formats, or had no preference, is presented in table 1a. overall, 229 (44.5%) of all respondents preferred the online environment whilst 190 (36.9%) preferred the traditional format and 96 (18.6%) had no particular preference [table 1a]. a significant proportion (82%) of students who preferred the traditional format were junior students (p <0.001). similarly, there was a slight but significant gender difference with females and junior students expressing more preference for table 1a: distribution of students that preferred either examination format or had no preference gender seniority online examination traditional format no preference totals male female male female male female junior 60 45 70 87 40 48 350 senior 70 54 8 25 2 6 165 total 130 99 78 112 42 54 515 table 1b: chi-square statistics on preference of examination format by medical students gender seniority chi-square 5.9 245.2 degree of freedom (df ) 1 1 significance <0.05 <0.001 ibrahim m inuwa, varna taranikanti, maimouna al-rawahy, omar habbal clinical and basic research | 387 traditional examination format (p <0.05) [table 1b]. interestingly, amongst those respondents expressing no preference, 91% were junior students with no significant gender difference [table 1a]. amongst all students who responded, the major reasons given for prefering the online examination format (n = 229) included better specimen quality (151), ability to manage the total time for the examination rather than being forced to spend an equal time on each question (160), and not having to keep moving throughout the examination, but remaining seated in one place (123) [figure 2a]. on the other hand, slow internet connectivity and fear of computer software/hardware failure were some of the major concerns expressed by students who preferred the traditional format [figure 2b]. when asked about the influence of the type of examination format (online or traditional) on their mode of preparation and study habits, 129 (78%) of senior students indicated being significantly influenced by the examination format while, only 27 (8%) of junior students agreed that the examination format had influenced their study habits and mode of preparation [figure 3]. in addition, 119 (72%) of senior students and 116 (33%) of junior students said that they did not study on cadaveric specimens when the examination was conducted in the online format [figure 4]. 0 10 20 30 40 50 60 70 good specimen quality what important reasons made you prefer the online examination format? (n = 229) seating during exam time management mcq format % o f s tu de nt s figure 2a: distribution of the most important reasons for student preference of online examination format. 0 10 20 30 40 50 60 70 80 slow internet connection what important reasons made you prefer the traditional examination format? (n = 190) computer glitch technophobia eye strain % o f s tu de nt s figure 2b: distribution of the most important reasons for student preference of traditional examination format. perceptions and attitudes of medical students towards two methods of assessing practical anatomy knowledge 388 | squ medical journal, august 2011, volume 11, issue 3 discussion the computer-based examination setting has been in use for over four decades.17 such a setting is attractive because it makes automated marking possible, and the students receive instant feedback. recently, apart from formative assessment, computer-based examinations are increasingly being used for end point, summative examinations (such as the us medical licensing examination). its acceptability as a means of assessment in high stakes examinations is now well established. several surveys have shown that computer-based tests were more popular than traditional tests. the preference for online assessment found in our results is similar to that reported earlier in the literature regarding computer-based tests.5,7 based on the results [table 1a and figure 2a], the main reasons for this preference were higher quality specimens and easier time management whereby students could scan through the questions at their own pace. this is in contrast to the traditional format where they 0 25 50 75 100 significantly n = 156 not significantly n = 227 less likely n = 132 when the spotter is online does it influence the way you prepare for the examination? (n = 515) junior students senior students % o f s tu de nt s figure 3: distribution of student responses and their mode of preparation and study habits when asked if the examination format (online or traditional steeplechase) significantly influenced the way they prepare for the examination. 0 10 20 30 40 50 60 70 80 significantly n = 156 not significantly n = 227 less likely n = 235 what is the likelihood of you studying on cadaveric specimen in the dissecting room when the spotter will be conducted online? junior students senior students % o f s tu de nt s figure 4: distribution of student responses when asked about the likelihood of them studying on cadaveric specimen when the examination format is conducted online. ibrahim m inuwa, varna taranikanti, maimouna al-rawahy, omar habbal clinical and basic research | 389 are restricted to the same length of time for each question regardless of difficulty. being seated for online format examinations as opposed to moving about constantly during the examination could potentially be beneficial in reducing the level of anxiety. this could be an added explanation for student preference of the online format. the impact of gender on computer related attitudes, abilities, and usage has been actively documented.19,20 many findings in the literature indicated that males had more positive attitudes, higher ability, and used computers more.21 other studies, however, suggest that the differences between males and females may be on the decline, although male dominance is still prevalent with respect to attitude, ability, and use of computers.19,20 in this study, we found a clear overall gender difference in the preference for examination format with female students more likely to prefer the traditional than the online format. amongst a single cohort of students senior or junior, however, the proportion of males and females who preferred the online format was similar. this suggests that the gender ‘digital divide’ within the same group of students in our setting is not as wide as has been reported elsewhere.22 when asked about the influence of the examination format on their study habits and preparation, the majority of students indicated that they usually study as normal before an examination. however, a great majority of senior students indicated that their study habits and preparation for the practical examination later became influenced by the format of examination. we observed a growing tendency amongst the majority of students to prepare for examination using image atlases rather than dissected specimens. this is not surprising considering the fact that assessment is well known to be a major determinant of how students learn.23 a likely explanation for this occurrence could be due to the difference in specimen quality in both examination formats. because of the extreme wear and tear on some of our specimens, the traditional format has been associated with examination difficulty since exact identification in some situations became problematic. the senior students became aware of this reality and thereby modified their preparation according to the examination formats. this was in sharp contrast with junior students, possibly due to their lack of both experience and exposure to the two examination formats. the results in this study have a number of implications for anatomy teaching in settings similar to ours. first, medical students are in general favourably disposed to and comfortable with the use of computer-based technology for the assessment of learning. this attitude should help to reassure faculty members intending to include such tools in their teaching. another equally important implication is to what extent should one rely on anatomy learning on cadavers if the assessment of such learning will be conducted differently? in a situation where the physical condition of cadaveric specimens is not appropriate for learning, or the specimens are in short supply, should the use of technology be given more emphasis for teaching? a more crucial implication of this study is related to the quality of students certified through computerbased assessment; will they be any better or worse than students who are assessed in the traditional format? are both formats equally valid? clearly, further research is indicated to address some of the questions raised above. conclusion in conclusion, computer-based practical examinations in anatomy appear to be generally popular with medical students in our setting. however, we found a clear split in this popularity, with students in senior classes more favourably disposed to computer-based practical examination. the majority of students adopted a different approach to study when informed that the practical examination would be conducted online as compared to the traditional format. we suggest further investigation to determine whether there is a significant difference in student performance between the two examination formats. a c k n o w l e d g e m e n t s we wish to thank the research council (trc), oman, for funding this project and mr. alexander george of the anatomy department for helping with the compilation of student questionnaire responses. perceptions and attitudes of medical students towards two methods of assessing practical anatomy knowledge 390 | squ medical journal, august 2011, volume 11, issue 3 c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. peterson mw, gordon j, elliott s, kreiter c. computer-based testing: initial report of extensive use in a medical school curriculum. teach learn med 2004; 16:51–9. 2. ogilvie rw, trusk tc, blue av. students' attitudes towards computer testing in a basic science course. med educ 1999; 33:828–31. 3. kreiter cd, ferguson k, gruppen ld. evaluating the usefulness of computerized adaptive testing for medical in-course assessment. acad med 1999; 74:1125–8. 4. ferguson kj, kreiter cd, peterson mw, rowat ja, elliott st. is that your final answer? relationship of changed answers to overall performance on a computer-based medical school course examination. teach learn med 2002; 14:20–3. 5. butzin dw, friedman cp, brownlee rc. a pilot study of microcomputer testing in paediatrics. med educ 1984; 18:339–42. 6. rattan a, mittal s, gupta a. role of computers in learning application in formative assessment. indian j pediatr 1994; 61:139–44. 7. miller ap, haden p, schwartz pl, loten eg. pilot studies of in-course assessment for a revised medical curriculum. ii. computer-based. acad med 1997; 72:13–15. 8. abu hijleh mf, habbal oa, moqatash s, harris pf. clinical anatomy and anatomical skills: an innovative course. med teach 1995; 17:283–8. 9. gunderman rb. giving ourselves: the ethics of anatomical donation. anat sci educ 2008; 1:217–19. 10. cantillon p, irish b, sales d. using computers for assessment in medicine. bmj 2004; 329:606–9. 11. inuwa im, alrawahy m, taranikanti v, habbal o. anatomy "steeplechase" online: necessity sometimes is the catalyst for innovation. anat sci educ 2010; 4:115–18. 12. kukolja-taradi s, dogas z, dabic m, drenjancevic pi. scaling-up undergraduate medical education: enabling virtual mobility by online elective courses. croat med j 2008; 49:344–51. 13. shah im, walters mr, mckillop jh. acute medicine teaching in an undergraduate medical curriculum: a blended learning approach. emerg med j 2008; 25:354–7. 14. carley s, kway-jones k. developing a virtual learning course in emergency medicine for f2 doctors. emerg med j 2007; 24:525–8. 15. carbonaro m, king s, taylor e, satzinger f, snart f, drummond j. integration of e-learning technologies in an interprofessional health science course. med teach 2008; 30:25–33. 16. romanov k, nevgi a. do medical students watch video clips in elearning and do these facilitate learning? med teach 2007; 29:484–8. 17. swets ja, feurzeig w. computer-aided instruction. science 1965; 150:572–6. 18. neuderth s, jabs b, schmidtke a. strategies for reducing test anxiety and optimizing exam preparation in german university students: a prevention-oriented pilot project of the university of wurzburg. j neural transm 2009; 116:785–90. 19. adrianson l. gender and computer-mediated communication: group processes in problem solving. comput human behaviour 2001; 17:71–94. 20. atan h, sulaiman f, rahman z, idrus rm. gender differences in availability, internet access and rate of usage of computers among distance education learners. educ media internat 2002; 39:205–10. 21. kay robin. addressing gender differences in computer ability, attitudes and use: the laptop effect. j educ computing res 2006; 34:187–211. 22. brosnan m, lee w. a cross-cultural comparison of gender differences in computer attitudes and anxieties: the united kingdom and hong kong. comput human behav 1998; 14:559–77. 23. duffield ke, spencer ja. a survey of medical students' views about the purposes and fairness of assessment. med educ 2002; 36:879–86. ífi^n÷]<;õá÷]<oëçvj÷] ‡⁄àπ]<îáòü÷]<å]çäfi˜]<öü⁄<ª åáe^œ<·^�◊ä÷]<ì√⁄^qê<ìèäàflj÷]<ö]ü⁄˙÷<ìèfi^€√÷]<ìè√€¢] 201014 abstracts second national update on chronic obstructive pulmonary disease (copd) oman respiratory society and sultan qaboos university 14th october 2010 squ med j, august 2011, vol. 11, iss. 3, pp. 436-438, epub. 15th aug 11 introduction the oman respiratory society, in collaboration with college of medicine & health sciences, sultan qaboos university, held its 2nd national chronic obstructive pulmonary disease (copd) symposium on 14th october 2010, which was celebrated as world spirometry day by the european respiratory society and the european lung foundation. the oman respiratory society supported this event by conducting a workshop on spirometry in the afternoon. primary care physicians and the other health care workers got hands-on experience in performing and interpreting spirometry. a workshop on non-invasive ventilation was also organised on the same day. the symposium was held under the auspices of his excellency dr. abdullah al-futaisi, executive president of the oman medical specialty board. s e l e c t e d a b s t r a c t s copd: definition and pathophysiology issa al-jahdhami department of medicine, armed forces hospital, muscat, oman. email: essajah111@yahoo.co.uk. chronic obstructive pulmonary disease (copd) is a preventable and treatable disease characterised by irreversible airway obstruction. it is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. though common, copd often remains under diagnosed. the exact prevalence worldwide is unknown, but varies from 7–19% in different studies. the prevalence increases with age and is variable between different countries. in the united states more than 12.7 million patients were diagnosed with copd in 2005. the exact incidence in oman is unknown. in women, copd is most commonly misdiagnosed as asthma. smoking is the main risk factor for copd. in healthy non-smokers, lung function normally declines by around 20 ml per year. this decline is accelerated in smokers. other risk factors include exposure to smoke from biomass fuels used for cooking in rural areas, organic dust in crops and animal farming and also to chemicals in the plastics and textile industries. outdoor air pollution, long standing asthma and bronchiectasis can also lead to irreversible airway obstruction. exposure to smoke and various noxious agents starts a cascade of inflammatory processes that lead to small airway remodelling and loss of alveolar attachments with decrease of elastic recoil. this inflammation is mainly driven by neutrophils with the release of various cytokines. copd leads to disabling symptoms and substantial mortality. functional assessment in copd omar al-rawas department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: orawas@squ.edu.om. functional assessment, a major component of copd management, helps in the differential diagnosis, the classification of copd and in treatment decisions. assessment consists of several components and steps including history taking, clinical examination and investigations. the focus of this presentation is on the objective physiological investigations such as spirometry, extended lung function testing, cardiopulmonary exercise testing, and respiratory muscle strength estimation. spirometry is the main investigation and should be done in all patients suspected of having copd. this has to be made available at all the levels of health care facility providing care for copd patients. in the global initiative for chronic obstructive lung disease (gold) guidelines, spirometric values are used for the definition and classification of copd severity. the presence of airway obstruction is confirmed by a post bronchodilator forced expiratory volume 1 (fev1)/forced vital capacity (fvc) value of less than 70% and is then further classified based on fev1 values (stage 14th october 2010 abstracts | 437 i: mild fev1 ≥80%; stage ii: moderate fev1 -50 to <80%; stage iii: severe fev1 -30 to <50%, and stage iv: very severe fev1 <30% predicted). spirometry before and after bronchodilator administration identifies reversibility of airway obstruction and helps to distinguish copd from asthma. lung volume measurements identify air trapping and hyperinflation which are characteristics of emphysema. this is considered when there is an uncertainty about the diagnosis and should be available in all secondary care hospitals. the pulmonary diffusing capacity (lung transfer factor), a non-invasive index of gas exchange, is reduced in emphysema, but remains normal in pure chronic bronchitis and asthma. cardiopulmonary exercise testing helps in the differential diagnosis of patients with exertional dyspnoea and objectively quantifies the severity of exercise limitation. the other useful functional tests include arterial blood gases, respiratory muscle strength testing and the six-minute walk test. management of chronic stable copd jayakrishnan b department of medicine, sultan qaboos university hospital , muscat, oman. email: drjayakrish@hotmail.com. the goals of treatment in copd are to relieve, improve and reduce symptoms and also to reduce the frequency and severity of exacerbations. a stepwise, comprehensive approach combining pharmacotherapy and non-pharmacotherapeutic interventions is needed to achieve this. annual influenza vaccination reduces the mortality, morbidity and also the frequency of hospitalisations. periodic pneumococcal vaccination is recommended in patients over 65 years, or in patients with a forced expiratory volume 1 (fev1) of <40%. education about the chronic nature of the disease, the purpose and dosing of medications and the inhaler technique is needed. bronchodilators form the mainstay of pharmacological therapy for copd. they decrease airway smooth muscle tone, improve the expiratory flow rates and reduce hyperinflation. short acting bronchodilators, both β2-agonists (salbutamol, terbutaline) and anticholinergics (ipratropium bromide) improve pulmonary function, dyspnoea and exercise performance. long-acting β2-agonists (laba) produce sustained improvements in pulmonary function and dyspnoea, but the effects of laba on exercise performance have been inconsistent. long acting anticholinergics (laac) provide sustained improvement and also improves exercise endurance. there is evidence that the combination of laac (tiotropium bromide) and laba (salmeterol, formoterol) produce additive improvement in pulmonary function. patients with mild copd should be provided with a short acting bronchodilator, to be taken on an ‘as and when needed’ basis. short-acting β2-agonists and anticholinergics can be used alone or in combination. if the disease severity increases from mild to moderate, it is quite logical to add a long acting bronchodilator, either laba or laac. theophylline clearly has a bronchodilatory effect, but given the risk of side effects it should not be considered as a first line drug. in patients with stage ii-iv copd whose symptoms are not well controlled with a single long-acting bronchodilator, the combination of both an anticholinergic and a β2agonist long-acting bronchodilator may provide better symptom relief. for repeated exacerbations, or for patients with stage iii disease, long-term inhaled corticosteroids (ics) are indicated. inhaled steroids decrease exacerbations and modestly slow the progression of respiratory symptoms, but have little impact on lung function and mortality. regular treatment with ics is advised for symptomatic copd patients with an fev1 <50% predicted and repeated exacerbations. in patients with severe disease triple therapy with laba, ics and laac are often preferred. thick tenacious secretions could cause a major problem, but there is no evidence that thinning or increasing the clearance of secretions can bring about clinical improvement. supplemental therapies, such as oxygen, pulmonary rehabilitation, and smoking cessation also play an important role in treatment. in patients not responding to treatment, comorbid conditions like continued smoking, coronary heart disease, heart failure, pulmonary hypertension and thromboembolic disease should be considered. new therapeutic options include phosphodiesterase-4 inhibitors (roflumilast) and indacaterol, a novel once daily ultra long-acting β2-agonist. management of acute exacerbation of copd nabil m al-lawati department of medicine, royal hospital, muscat, oman. email: nabil.allawati@gmail.com. an acute exacerbation of copd (aecopd) is defined as an acute change in patient’s dyspnoea, cough and/or sputum volume or purulence. aecopd is the most frequent cause of medical visits, hospital admissions and death among patients with copd. these events are an important determinant of quality of life and each attack further accelerates lung function decline. short-term mortality from aecopd in patients with mild to moderate copd can be as high as 24% for those needing intensive care. infections, both viral and bacterial, account for 60% of the precipitating factors. risk factors include advanced age, chronic mucous hypersecretion, admission with an exacerbation in the previous year and the presence of comorbidities such as diabetes or heart failure. general indicators for hospital admission include acute respiratory acidosis, worsening hypoxemia, marked dyspnoea, altered sensorium and inability to care for oneself. the immediate measure is to give controlled oxygen therapy to alleviate hypoxaemia and improve tissue oxygenation. venturi masks are the preferred interface for such therapy. short acting bronchodilators namely salbutamol and ipratropium bromide given via a nebuliser work synergistically to improve airflow. systemic corticosteroids are indicated for moderate to severe attacks and in particular if the forced expiratory volume 1 (fev1) is less than 50% predicted. corticosteroids have been shown to shorten recovery time, improve lung function in terms of fev1 and arterial oxygenation and reduce the risk of early relapse. unlike asthma, antibiotics have a major role in management of moderate to severe aecopd. they can reduce the short term mortality by 77%. aminophylline is not recommended routinely in the acute setting as they lack efficacy and can contribute to the development of serious side effects. one of the major recent advances in management of an acute exacerbation is the use of non-invasive positive pressure ventilation (niv). this should be started for every patient with a respiratory rate of more than 25, arterial ph of < 7.35 and a paco2 of >45mmhg without any delay. niv reduces the work of breathing by 60%; moreover, it obviates the need for mechanical ventilation, decreases treatment failure and short-term mortality by as much as 50%. finally mechanical ventilation may be needed in very sick and unstable patients, or in those who either fail or are thought to be unsuitable candidates for niv. second national update on chronic obstructive pulmonary disease (copd) oman respiratory society and sultan qaboos university 438 | squ medical journal, august 2011, volume 11, issue 3 systemic effects and mortality in copd yacoub al-mahrooqui department of medicine, royal hospital, muscat, oman. email: yaqpal@yahoo.com. copd is a systemic disease. in addition to causing pulmonary abnormalities, copd is associated with systemic consequences outside the lungs. the comorbidities associated with this disease include skeletal muscle dysfunction, cardiovascular disease, osteoporosis, anaemia, metabolic abnormalities, depression and gastrointestinal diseases. higher rates of hospitalisation are common among copd patients who have comorbidities. because these consequences can seriously affect quality of life and worsen prognosis, preventing and treating the systemic effects is important in copd management. persistent local and systemic inflammation and oxidative stress may contribute to these changes. several studies had shown the elevation of various inflammatory markers in copd like c reactive protein, tumor necrosis factor alpha, fibrinogen, leucocytes and vascular endothelial growth factor. fat free mass is often low in copd. risk of developing ischaemic heart disease or stroke is higher among copd patients. they are also at risk of developing osteoporosis. the prevalence of diabetes and metabolic syndromes is also higher among copd patients. respiratory failure is the leading cause of mortality followed by cardiovascular disease and lung cancer. validated indices are often used to classify the severity of disease and predict the outcome or mortality. when, forced expiratory volume 1 (fev1), the widely used prognostic indicator, is low it is associated with an increased risk of all-cause mortality. in summary, in copd one should look for comorbidities, and in smokers with the above problems look for copd as well. non-pharmacological management of copd dimitrije ponomarev department of medicine, royal hospital, muscat, oman. email: dponomarevster@gmail.com. the components of non-pharmacological management of copd are: 1) rehabilitation; 2) oxygen therapy; 3) ventilatory support, and 4) surgical management. the goals of rehabilitation include the reduction of symptoms, improvement of quality of life, increasing physical and emotional participation in everyday activities and reducing health care costs by stabilising or reversing the systemic manifestations of the disease. non-pulmonary problems that cannot be treated by medicines are de-conditioning, relative social isolation, depression, muscle wasting, and weight loss. rehabilitation programs can contribute to the improvement of exercise capacity, reduction of the perceived intensity of breathlessness, reduction of anxiety and depression, improvement of health-related quality of life, and reduction in the number of hospital admissions and length of hospital stay. comprehensive pulmonary rehabilitation should involve a team of various medical specialists involved in exercise training, nutrition counselling, education and psychological support. the primary goal of oxygen therapy is to increase the baseline oxygen level to at least 8 kpa (60 mmhg) or to produce a spo2 of at least 90% in the waking state. in the long term this brings a beneficial effect to haemodynamics, haematological characteristics, exercise capacity, lung mechanics and mental state. the benefits of non-invasive ventilatory support include the improvement of inspiratory flow rate, correction of hypoventilation, rest to respiratory muscles and resetting central respiratory drive. non-invasive nocturnal positive pressure ventilation is indicated in hypercapnic patients with copd who have recurrent oxygen desaturation during sleep despite the use of supplemental oxygen; moreover, it is useful in patients recovering from an acute exacerbation that required the use of mechanical ventilation. surgical management of copd includes bullectomy and lung volume reduction surgery. bullectomy is indicated if the bulla occupies ≥50% of the hemithorax and produces definite displacement of the adjacent lung. lung volume reduction is a recent surgical technique where parts of the lung are removed to reduce hyperinflation which in turn improves the mechanical efficiency of respiratory muscles leading to an improvement in the overall gas exchange. lung transplantation can be considered in selected patients when forced expiratory volume 1 (fev1) is less than 25% of the predicted value with features of respiratory failure smoking cessation zahir a. m. al-anqoudi control of non-communicable diseases section, directorate general of health services dakhilyah region, nizwa, oman. email: alanqoudi@gmail.com. statistics indicate that it will not be possible to reduce tobacco-related deaths over the next 50 years, unless adult smokers are encouraged to quit. the world health organization (who) emphasises the need to have a multiple approach strategy including taxation, legislation, a ban on pro-tobacco advocacy and encouraging tobacco cessation rogrammes. the addiction starts with nicotine use for pleasure, enhanced performance and mood regulation and slowly tolerance and physical dependence develop. the process of addiction has three main aspects: physiological, due to nicotine; behavioural, where it is linked to different day-to-day behaviours and psychological, which is seen mostly in patients with depression or anxiety. unfortunately, although a good percentage of smokers are considering cessation, the medical team somehow fails to reach them. physicians, especially the primary care providers, have a role in all aspects of care. the “5a” intervention approach serves as a guide: ask about tobacco use on every visit—this could easily be practised by including this questions in the vital signs chart; advice patients to quit; assess willingness to make a quit attempt; assist by helping the patient formulate a quit plan, and arrange follow-up contact to prevent relapses. the main step at the level of primary care team is the (ask) screening. the management of tobacco cessation is a behavioural approach for those with a low fagerström addiction score and the use of pharmacological therapy in selected cases. the “5r’s” in the behavioural approach are: relevance, motivational information being more effective if it is relevant to a patient's circumstances; risks, emphasising the acute and long-term risks of smoking; rewards, identifying potential benefits of smoking cessation; roadblocks, detection of the barriers, and repetition, repeating the motivational interventions at each visit. drug therapy doubles the chance of long term cessation. this includes several forms of nicotine replacement therapy and bupropion. the selective serotonin re-uptake inhibitors, nortriptyline and naltrexone, are not that effective. the nizwa healthy lifestyle project, a community based initiative with technical support from the ministry of health and the who, is running a tobacco cessation clinic staffed by family physicians, nurses, dietitians and dentists. behavioural and motivational approaches, drug therapy and follow-up telephone calls are the tools employed. the preliminary data on a 5-month abstinence is encouraging, reaching an impressive 62%. we recommend extending our local experience so that tobacco cessation clinics are established throughout oman with an initial focus on regions of high prevalence. األثار اجلانبية املرتبطة بالعضالت ألدوية الستاتني حتديث لألطباء السريرين مه� املحي�شن, م�رث� اجن�شف�شكي, يريي فرولك, اأندرو اجن�شف�شكي abstract: statins are potent medications which reduce low-density lipoprotein cholesterol (ldl-c) levels. their efficacy in cardiovascular risk reduction is well established and indications for their use are expanding. while statins are generally well tolerated and safe, adverse events are relatively common, particularly statinassociated muscle adverse events (samaes), which are the most frequently encountered type of adverse event. recent guidelines and guideline updates on samaes and statin intolerance have included revised definitions of samaes, incorporating new evidence on their pathogenesis and management. as samaes emerge as a therapeutic challenge, it is important for physicians to be aware of updates on management strategies to ensure better patient outcomes. the majority of patients who are considered statin-intolerant can nevertheless tolerate some forms of statin therapy and successfully achieve optimal ldl-c levels. this review article discusses the recent classification of samaes with emphasis on pathogenesis and management strategies. keywords: hydroxymethylglutaryl-coa reductase inhibitors; hyperlipidemias; hypercholesterolemia; myopathies; adverse effects. امللخ�ص: العق�قري املخف�شة للكولي�شرتول من فئة ال�شت�تني هي اأدوية فع�لة يف التقليل من م�شتوي�ت الربوتني الدهني منخف�س الكث�فة يف ا�شتخدامه� ودواعي جيد ب�شكل الدموية والأوعية القلب اأمرا�س خم�طر من احلد يف الأدوية هذة فع�لية من الت�أكد مت .)ldl-c( ن�شبي�, �ش�ئعة تعترب عنه� الن�جتة اجل�نبية الت�أثريات ان اإل واآمنة, م�شت�ش�غة , ع�مة ب�شفة ال�شت�تني, عق�قري اأن حني ويف ازدي�د. وبخ��شة الت�أثريات اجل�نبية املرتبطة ب�لع�شالت والتي تعد الأكرث �شيوع� بني الت�أثريات اجل�نبية املرتبطة ب�ل�شت�تني. �شملت املب�دئ التوجيهية الأخرية اخل��شة ب�لت�أثريات اجل�نبية لل�شت�تني املرتبطة ب�لع�شالت وحتديث�ته�, تع�ريف منقحة للت�أثريات اجل�نبية املرتبطة ب�لع�شالت و تت�شمن اأدلة علمية جديدة عن طرق الإمرا�س و املع�جلة. ومب� اأن الت�أثريات اجل�نبية لل�شت�تني املرتبطة ب�لع�شالت تظهر كتحد عالجي, ف�نه من املهم لالأطب�ء اأن يكونوا على بينة بو�ش�ئل املع�جلة احلديثة ل�شم�ن حتقيق نت�ئج اأف�شل للمر�شى. ان غ�لبية للربوتني مثلى م�شتوي�ت وحتقيق ب�ل�شت�تني العالج اأ�شك�ل بع�س يتحملوا اأن ميكن لل�شت�تني متحملني غري يعتربون الذين املر�شى املرتبطة لل�شت�تني اجل�نبية للت�أثريات الأخري الت�شنيف مراجعة املق�لة هذه تتن�ول بنج�ح. ldl-c الكث�فة منخف�س الدهني ب�لع�شالت مع الرتكيز على اإ�شرتاتيجي�ت الإمرا�س وو�ش�ئل املع�جله. الكلمات املفتاحية: مثبط�ت انزمي ات�س ام جي-كو اي املختزلة؛ فرط �شحمي�ت الدم؛ فرط كولي�شتريوِل الدم؛ العتالل الع�شلي؛ اآث�ر �شلبية. statin-associated muscle adverse events update for clinicians *maha a. al-mohaissen,1 martha j. ignaszewski,2 jiri frohlich,3 andrew p. ignaszewski4 review sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e406–415, epub. 30 nov 16 submitted 9 apr 16 revisions req. 9 may & 21 jun 16; revisions recd. 6 jun & 24 jun 16 accepted 30 jun 16 doi: 10.18295/squmj.2016.16.04.002 statins are a group of potent low-density lipoprotein cholesterol (ldl-c)-lower-ing drugs.1 their efficacy in improving cardiovascular morbidity and mortality is supported by a large body of evidence.2 although statins are generally well-tolerated and safe, side-effects are relatively common, with muscular complaints occurring most frequently.3,4 in the majority of patients, these are mild and reversible; however, in rare cases, patients may develop more severe adverse effects.3 in clinical practice, the management of patients with statin-associated muscle adverse events (samaes) has emerged as a therapeutic challenge among physicians seeking evidence-based ldl-c-lowering therapies. recently, positive results from an international trial supported the use of non-statin drugs for the management of statin-intolerant dyslipidaemic patients and confirmed the “lower is better” ldl-c hypothesis.5 in addition, the introduction of proprotein convertase subtilisin/ kexin type 9 (pcsk9) inhibitors, although parenteral, offers a potentially strong alternative.6 in view of these data, the american college of cardiology (acc) expert consensus decision pathway was created to incorporate recent evidence on ldl-c-lowering agents in patient management to reduce the risk of atherosclerotic cardiovascular disease (ascvd).7 besides these advances in therapy, new guidelines and guideline updates have been issued on statinassociated adverse events in recent years. in 2015, the national lipid association (nla) updated their 1department of clinical sciences, college of medicine, princess nourah bint abdulrahman university, riyadh, saudi arabia; 2department of psychiatry, baystate medical center, tufts university school of medicine, springfield, massachusetts, usa; departments of 3pathology & laboratory medicine and 4cardiology, faculty of medicine, university of british columbia, vancouver, british columbia, canada *corresponding author e-mail: mahaabdulrahman@hotmail.com maha a. al-mohaissen, martha j. ignaszewski, jiri frohlich and andrew p. ignaszewski review | e407 2006 guidelines, redefining samaes and providing recommendations on management.4 the original consensus statement of the canadian consensus working group (ccwg) for the diagnosis, prevention and management of statin-associated adverse effects and intolerance was updated in 2013 and 2016; these outlined the adverse effects of statins and reviewed recent evidence on the management of statinintolerant patients.8–10 the european atherosclerosis society (eas) consensus panel issued a statement that focused specifically on the diagnosis and management of statin-associated muscle symptoms.11 it is important for clinicians to be aware of these recommendations and current management options based on recent trial results. statin intolerance and adverse effects several definitions have been proposed for statin intolerance.3,9 the nla defines statin intolerance as the inability to tolerate at least two statins, with one of them administered at the lowest starting daily dose and the other at any dose.3 this intolerance may manifest as symptoms, signs or laboratory abnormalities which negatively affect an individual’s quality of life and lead to a decrease in dosage or discontinuation of the statin. these abnormalities must be temporally associated with statin therapy, resolve upon statin discontinuation and be reproducible by rechallenge.3 there is some ambiguity regarding the concept of the lowest dose for each statin drug. in the most recent ccwg consensus statement, mancini et al. referred to the approved statin drug doses in their definition of statin intolerance.10 intolerance to statins can be complete (intolerance to all statins at any dose) or partial (intolerance to certain statins at specific doses). the exclusion of other established predisposing factors to observed side-effects—including drug drug interactions, untreated hypothyroidism and febrile illness—is a prerequisite for a diagnosis of statin intolerance.9 samaes are reported by 5–29% of treated patients.11,12 data from the arabian gulf on the prevalence and management of samaes are currently lacking. results from the dyslipidemia international study-middle east indicated that patients from the united arab emirates, saudi arabia, lebanon and jordan were most commonly prescribed statin doses at a potency equivalent to 40 mg/day and 80 mg/day of simvastatin.13 this observation, along with the expanding indications for statins, are expected to lead to increases in the prevalence of statin-intolerant patients from the arabian gulf.14 studies investigating this important issue are therefore warranted. definitions and diagnosis the nla no longer uses the term ‘statin-associated myopathy’; this was replaced by ‘samaes’ in 2014.4 the new definitions utilise neuromuscular terminology for descriptions of myalgia and myopathy and require objective evidence of muscle inflammation (e.g. a skeletal muscle biopsy and/or magnetic resonance imaging) for a diagnosis of myositis.4 the guidelines also account for differences in age, gender and muscle mass when defining normal creatine kinase (ck) thresholds, with preferential use of the patient’s own pre-statin ck levels, when available. moreover, the guidelines acknowledge that clinical entities may overlap in clinical presentation.4 the eas consensus panel, on the other hand, retains the general term ‘statin-associated myopathy’ and classifies the spectrum based on the presence or absence of statinassociated muscle symptoms, which cover a broader range of clinical presentations and ck levels.11 the ccwg introduced the concept of goal-inhibiting statin intolerance to emphasise the negative impact of these symptoms on achieving treatment goals.10 statin therapy-associated myalgia is usually identified as a result of clinical characteristics, resolution with statin discontinuation and recurrence with rechallenge within an expected time limit; however, this is not true in all cases and concerns exist regarding reliable diagnosis of this disorder.12 recent evidence from several clinical trials suggests that many patients who were previously considered to be statin intolerant based on clinical characteristics, were not actually intolerant.12,15,16 although clinical myalgia scales exist, they have not yet been validated for diagnosis.4 in clinical practice, myalgia and/or mild ck elevations may persist for a lengthy period following statin discontinuation, although the mechanisms behind this delay are not clear.17 several algorithms for diagnosing patients presenting with samaes have been proposed.4,10 classification the classification and spectrum of samaes is summarised in table 1.1,4,12,18–25 based on pathogenesis, samaes are classified into two major categories: toxic (i.e. nonautoimmune and self-limited) and autoimmune.26 the clinical manifestations of toxic samaes range from muscle pain to severe muscle damage leading to rhabdomyolysis. the statin-associated muscle adverse events update for clinicians e408 | squ medical journal, november 2016, volume 16, issue 4 muscle adverse events in patients with toxic samaes stabilise and show marked improvement within 2–3 months following statin cessation.18 until recently, samaes referred to the nonautoimmune form.26 autoimmune inflammatory myositis and/or necrotising myopathy, on the other hand, starts or persists even after drug discontinuation.27 this entity is very rare and is characterised clinically by myalgia, symmetrical proximal muscle weakness, universally persistently elevated creatine phosphokinase (cpk) levels in individuals with active disease (cpk >2,000 iu/l or >10 times the upper limit of the normal range in nearly 90% of cases) and the presence of autoantibodies to 3-hydroxy-3-methylglutarylcoenzyme a reductase (hmgcr), the pharmacological target of statins.20,24 the presence of muscle weakness is a characteristic feature.24 an algorithm for the evaluation of potential cases of statin-associated autoimmune myopathy has been proposed.24 in statin-associated autoimmune myositis or myopathy, skeletal muscle involvement is not associated with cutaneous or pulmonary involvement, as observed with other inflammatory myopathies.17 spontaneous improvement has been reported in a few very mild samae cases following discontinuation of the statin therapy.24 however, immunosuppressive medications are necessary in the majority of patients.24 immunosuppression may attenuate the myopathy, allowing muscle regeneration to outpace muscle table 1: classification and spectrum of statin-associated muscle adverse events1,4,12,18–25 type clinical presentation incidence/ prevalence long-term outcome myalgia unexplained muscle discomfort without ck elevation, including muscle aches, soreness, stiffness, tenderness and exercise-related cramps.4 the pain is dull, aching, widespread and involves the trunk and proximal muscles. calf and forearm pain is less common and is usually bilateral. 1–5% in controlled trials and 11–29% in observational studies4 myalgias are generally tolerable but can become debilitating, requiring statin withdrawal. the long-term outcome is favourable. symptoms improve or full recovery occurs in the majority of patients on cessation of statin therapy; however, the condition can continue beyond 14 months.22 myopathy muscle weakness (not due to pain and/or ck elevation). a diagnosis is made by the detection of proximal weakness of grade ≤4/5 and standardised muscle testing with confirmation by electromyography and/or muscle biopsy.4 other causes of muscle weakness should be excluded. ≈3%25 an annual assessment of muscle strength is indicated in patients with minimal symptoms without >3 x uln ck elevations who elect to remain on statin therapy. serial assessment in asymptomatic patients is unnecessary.4 among patients with persistent symptoms after statin withdrawal, 10% have underlying neuromuscular disease.23 myositis muscle inflammation (determined by skeletal muscle biopsy and/ or magnetic resonance imaging), commonly associated with muscle pain and tenderness.4 unknown as it is no longer diagnosed by clinical and cpk criteria can be toxic or autoimmune. the former improves with statin discontinuation, whereas in the latter only a few patients improve with drug discontinuation; for the remaining patients, the disease is persistent or progressive despite statin discontinuation.21,23,24 the autoimmune type is associated with anti-hmgcr antibodies and requires immunosuppressive therapy (steroids and/or intravenous immunoglobulin).20 myonecrosis elevated muscle enzymes or consistently increased serum ck levels. muscle injury is graded as mild (>3 x baseline untreated ck levels or age-, raceand gender-adjusted uln), moderate (≥10 x baseline untreated ck levels or age-, raceand gender-adjusted uln) or severe (≥50-fold above baseline ck levels or age-, raceand gender-adjusted uln; consistent with an absolute ck concentration of 10,000 iu/l).4 incidence is not well defined as ck levels are not routinely measured no data available for this pathological entity in its full spectrum. clinical rhabdomyolysis severe myonecrosis, with myoglobinuria and/or acute renal failure*.4 rare (0.1–8.4/100,000 patients/year)21 carries a 7.6% risk of death with 19.8% of patients developing acute renal failure and 17% developing renal dysfunction. there is a 5.2% risk of dialysis in affected patients.19 ck = creatine kinase; uln = upper limit of normal; cpk = creatine phosphokinase; hmgcr = 3-hydroxy-3-methylglutaryl-coenzyme a reductase. *increased serum creatinine levels of >0.5 mg/dl.4 maha a. al-mohaissen, martha j. ignaszewski, jiri frohlich and andrew p. ignaszewski review | e409 destruction, although it may not completely abolish the underlying pathophysiological processes in all cases.20,24 during follow-up, antibody titres are useful for assessing treatment response in affected patients.26 diagnostic role of anti-3hydroxy-3-methylglutarylcoenzyme a reductase autoantibodies in patients with samaes, autoantibodies to hmgcr are highly specific for autoimmune myositis or myopathy and have not been detected to date in asymptomatic patients or patients with selflimited samaes, including myalgia, weakness, mild asymptomatic ck elevations or severe self-limited myopathy or rhabdomyolysis.28,29 a positive test for anti-hmgcr autoantibodies strongly supports the presence of an autoimmune process, while an alternative diagnosis should be considered if the test is negative.24 however, anti-hmgcr antibodies are not pathognomonic for statin-related autoimmune myositis or myopathy; in the largest cohort studied to date, one-third of patients who were positive for antihmgcr had autoimmune myositis or myopathy due to various causes.24 in general, the risk of antibody development is higher among individuals with prior statin exposure and those positive for human leukocyte antigen d-related (hla-dr) 11; limaye et al. found that 42% of statin-naive hla-dr 11 subjects had detectable antibodies, which increased to 90% following statin exposure.27 several laboratory techniques have been developed to detect anti-hmcgr autoantibodies, including the enzyme-linked immunosorbent assay (elisa), addressable laser bead immunoassay and immunoblotting.17 screening for anti-hmgcr auto antibodies via elisa has achieved a sensitivity and specificity of 94.4% and 99.3%, respectively.28 false-positive results on commercial elisas (0.7%) are commonly due to the anti-cortactin antibody, another recently described myositis-associated antibody.17,24 confirmation of positive elisa samples by immunoprecipitation or immunoblotting is mandatory.17,30 the negative predictive value of elisa in an unselected population was greater than 0.999; in a specialised myositis clinic, it was estimated at 0.996.28 therefore, a negative hmgcr elisa result, regardless of clinical setting, means that it is very unlikely that a patient has an anti-hmgcr autoimmune myopathy requiring immunosuppressive therapy.28 to avoid erroneous diagnoses, only patients with markedly elevated muscle enzyme levels should be tested for these autoantibodies.24 muscle biopsy findings muscle biopsy findings vary among patients with samaes. in one study, vacuolation of the t-tubular system with intact sarcolemmas was noted in the lesions of 56.8% of symptomatic patients with myalgia, weakness and cramps.31 this pathology may occur without ck elevations as the muscle fibre damage is largely restricted to the intracellular space while the table 2: risk factors for statin-induced myopathy8,21,33,34 patient-related factors drug interactionrelated factors advanced age (especially >80 years old) gemfibrozil (contraindicated with statins) female red yeast rice (contraindicated with statins) low bmi niacin (limit to 1 g/day) asian ethnicity macrolide antibiotics presence of renal disease azole antifungals presence of hepatic disease protease inhibitors untreated hypothyroidism large quantities of grapefruit juice low vitamin d levels nefazodone (discontinued antidepressant) hypertension cyclosporine (avoid simvastatin, lovastatin and atorvastatin) diabetes mellitus verapamil/diltiazem biliary tract obstruction warfarin personal or family history of samaes digoxin family history of myopathy amiodarone genetic polymorphisms of the cyp isozymes ticagrelor (avoid simvastatin) inflammatory or inherited metabolic muscle disease (e.g. mcardle’s disease or carnitine palmitoyltransferase ii deficiency) colchicine strenuous exercise fusidic acid surgery with severe metabolic demands antipsychotics alcohol abuse (independently predisposes to myopathy) drug abuse (e.g. cocaine, amphetamines or heroin) high statin dose bmi = body mass index; samaes = statin-associated muscle adverse events; cyp = cytochrome p450. statin-associated muscle adverse events update for clinicians e410 | squ medical journal, november 2016, volume 16, issue 4 intact lateral sarcolemma prevents ck leakage. similar biopsy findings have been observed in asymptomatic patients as well.32 in cases of toxic necrotising myo pathy, muscle fibre necrosis with prominent phagocytosis and small basophilic regenerating fibres have been observed in patients with elevated serum ck levels and weakness or myalgia; these patients did not have detectable hmgcr antibodies.18 in anti-hmgcr clinical syndrome, autoimmune inflammatory myositis and/or necrotising myopathy is observed.17 necrotising myopathy is a characteristic pathological pattern consisting of scattered muscle fibre necrosis and regeneration, macrophage infil trates, a few endomysial inflammatory cells (including cluster of differentiation [cd] 4+ and cd8+ t cells and plasmacytoid dendritic cells) and sarcolemmal complement deposition on the surface of non-necrotic muscle fibres.17 some patients have predominantly autoimmune necrotising myopathy, which is characterised by necrotic muscle fibre infiltrating macrophages without inflammation, while the myositis subtype exhibits greater inflammatory cell infiltration.25 the two conditions likely represent one pathophysiological spectrum rather than separate entities and transformation has been reported on consecutive histological biopsies.25 it is important to emphasise that this entity is very rare; however, while general practitioners may not come across such cases in practice, they must remain vigilant regarding the basic principles and features of the syndrome. risk factors risk factors for samaes are shown in table 2.8,21,33,34 attention to these factors may be the best way to minimise the risk of muscle injuries, which are reported with all marketed statins.33 the highest risk of developing an samae is with 80 mg of simvastatin (18.2%); therefore, this dose is better avoided.8,35 atorvastatin, pravastatin and fluvastatin (80 mg) have lower samae risks (14.9%, 10.9% and 5.1%, respectively) and are better tolerated.35,36 drug interactions vary with statin type and dose; specific statin-drug interactions and contraindications have been previously reviewed in more detail.34 management of dyslipidaemia in the management of dyslipidaemia among patients with samaes, ldl-c reduction using evidence-based therapies to nationally-supported guideline-based targets is the optimal goal.7,10 the nla/acc/american heart association guidelines advise clinicians to reinforce the importance of adherence to statins and lifestyle changes; however, high-risk patients who are completely statin-intolerant or tolerant only at a lower-than-recommended statin intensity may be considered for non-statin cholesterol-lowering (nscl) therapy.3,7 drugs that have demonstrated ascvd risk reduction benefits outweighing the potential for adverse events and drug-drug interactions are recommended, while addressing patient risks and preferences.36 it is important to exclude risk factors for samaes and non-side-effect-related causes for discontinuation, such as insurance-related or financial causes and patient misconceptions regarding duration of therapy and the benefit-to-adverse effects ratio.3,37 in mild cases, the decision to continue treatment with statins belongs to the patient, aided by effective communication from the clinician.3 s t e p 1: s tat i n r e c h a l l e n g e among patients with samaes, 92.2% can tolerate a second statin upon rechallenge, approximately 50% can tolerate the original statin—occasionally with increases in dose—and up to 72.5% can successfully tolerate a third statin.37,38 tolerance is improved when doses of a lower potency are prescribed.4 stein et al. reported that 97% of patients with a history of samaes tolerated switching to 80 mg of daily fluvastatin, which reduced ldl-c levels by 32.8%.39 figure 1 outlines recommended steps to approaching statin rechallenge among patients with samaes. non-daily regimens include every other day, twice weekly and weekly dosing.40 rosuvastatin and atorvastatin have long half-lives which makes them suitable for non-daily dosing.4 rosuvastatin every other day has been reported to lower ldl-c levels by 40.9% at a dose of 20 mg, by 39% at 10 mg and by 34% at a mean dose of 5.6 mg (range: 2.5–10 mg).40,41 additionally, atorvastatin every other day decreases ldl-c levels by 23% in comparison to 39% with daily dosing. with 20 mg of lovastatin every other day, ldl-c levels were reduced by 21% and the drug was tolerated by 98% of the studied subjects.40 a total of 5–10 mg of rosuvastatin twice weekly significantly decreased ldl-c levels by 26%, whereas changing doses of simvastatin from 10–20 mg daily to 40–80 mg twice weekly was not effective in reducing ldl-c levels. weekly doses of 5–20 mg of rosuvastatin decreased ldl-c levels by 6–62% in a small series.40 overall, non-daily regimens are better tolerated compared to daily dosing, but result in lower ldl-c reductions.40 nonetheless, even modest ldl-c reductions are thought to be useful in improving long-term outcomes; therefore, aiming for the highest maha a. al-mohaissen, martha j. ignaszewski, jiri frohlich and andrew p. ignaszewski review | e411 tolerated dose is a reasonable endpoint.4 it is important to note, however, that while non-daily regimens are better tolerated, their use does not eliminate the possibility of on-going muscle pathology existing in the absence of clinical symptoms.30 s t e p 2: a d d i t i o n/s u b s t i t u t i o n o f n o n-s tat i n c h o l e s t e r o ll o w e r i n g d r u g s while nscl monotherapy has been found to improve major cardiovascular endpoints, the evidence for its combination with statins has been consistently inadequate, except with ezetimibe.5 in addition, nscld monotherapy has been found to result in lower ldl-c reductions and is not without adverse effects.42 ezetimibe is well tolerated but may cause nausea and bloating.43 when added to simvastatin therapy, it has resulted in incremental ldl-c lowering and an absolute risk reduction of 2% in the rate of cardiovascular mortality, myocardial infarction or stroke over a seven-year follow-up.5 combined ezetimibe/atorvastatin, on the other hand, has resulted in lower ldl-c levels and greater coronary plaque regression than atorvastatin alone.44 bile acid sequestrants (e.g. cholestyramine, colestipol and colesevelam) have been found to decrease ldl-c levels by approximately 15%.7 a combination of ezetimibe/ colesevelam has reduced ldl-c levels by 42% with no reports of discontinuation due to adverse events.45 in the lipid research clinics trial, cholestyramine decreased cardiovascular disease events by 25%.43 figure 1: flowchart outlining the first step (statin rechallenge) of recommended cholesterol-lowering therapy for patients with statin-associated muscle adverse events. samaes = statin-associated muscle adverse events. niacin monotherapy reduced nonfatal myocardial infarctions by 27% and cerebrovascular events by 26% at a six-year follow-up as well as resulted in an 11% relative reduction in all-cause mortality at 15 years compared to a placebo in one study.46 moreover, niacin in combination with clofibrate significantly reduced overall mortality and ischaemic heart diseaserelated mortality in comparison to a placebo.46 a statin/niacin combination, on the other hand, did not result in incremental clinical benefits in patients with atherosclerotic disease despite ldl-c reduction and an increase in high-density lipoprotein cholesterol (hdl-c) levels.47,48 there is currently a lack of data on the safety, efficacy or tolerability of niacin in statinintolerant individuals.10 fibrates decrease triglyceride levels and raise hdl-c levels.49 however, cardiovascular disease out comes with fibrate monotherapy have been mixed. post hoc subgroup analyses in monotherapy studies have suggested the beneficial effects of fibrate therapy in subjects with high triglyceride levels, with or without low hdl-c levels.49 there is also evidence for a reduction in cardiovascular disease risk with fibrates, particularly among patients with diabetes and metabolic syndrome.8,43 however, doubling the statin dose yields a greater ldl-c reduction compared to the addition of fibrate therapy.50 moreover, statin/ fibrate combinations do not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarctions or nonfatal strokes compared with simvastatin monotherapy; however, there is a trend of cardiovascular disease event reduction (p = 0.057) with a statin/fibrate combination in patients with high triglyceride and low hdl-c levels.51 the interaction between gemfibrozil and statins is known to increase statin toxicity due to the inhibition of cytochrome p4502c8 and organic anion-transporting polypeptide 1b1 by gemfibrozil and its glucuronide, leading to increased plasma statin concentrations.52 on the other hand, the coadministration of statin with fenofibrate among patients with combined hyperlipidaemia is safe, although attention to factors predisposing to statin toxicity is always warranted when statins are used as either a monotherapy or in combination with other drugs.10,53 monoclonal antibodies against pcsk9 have shown good efficacy and tolerability in patients with statin intolerance. at 12 weeks, evolocumab was found to reduce ldl-c levels by 53–56% compared to 15–18% with ezetimibe.6 alirocumab resulted in an absolute ldl-c reduction of 84 mg/dl and had the lowest muscle-related adverse event rate of 33% versus 41% with ezetimibe (p = 0.10) and 46% with atorvastatin statin-associated muscle adverse events update for clinicians e412 | squ medical journal, november 2016, volume 16, issue 4 (p = 0.04).6 preliminary evidence on the efficacy of pcsk9 inhibitors combined with statins shows reduced cardiovascular outcomes.49 however, the safety and tolerability profile of pcsk9 inhibitors remains to be proven; this is the aim of large trials of cardiovascular outcomes currently underway.6 if the benefits of pcsk9 inhibitors follow a similar trend to statins, major vascular events could be reduced by up to 40–50% in high-risk patients.6 the use of pcsk9 inhibitors has been approved in europe and north america as adjuncts to diet and maximally-tolerated statin therapy in adult patients with heterozygous or homozygous familial hypercholesterolaemia and patients with clinical ascvd who require additional lowering of ldl-c levels.49,54,55 lomitapide and mipomersen have been recently approved in the usa for the treatment of familial hypercholesterolaemia; these drugs substantially reduce ldl-c levels via distinct low-density lipoprotein receptor-independent mechanisms.49 other potential therapeutic options include plant sterol esters or stanol esters (found in margarines), viscous fibre (found in oat bran, legumes and psyllium) and the dietary substitution of monoor polyunsaturated fats for trans-unsaturated or -saturated fats.3 following statin rechallenge, the choice of nscl drug in patients deemed to have partial or complete intolerance to statins is governed by the degree of ldl-c reduction required to achieve a prespecified goal. figure 2 presents the recommended steps in prescribing non-statins to patients with samaes and details possible non-statin drug choices. priority should be given to agents with proven cardiovascular outcomes, particularly ezetimibe, bile acid sequestrants or both.4,7,8,33,36,43,54,55 it has been suggested that if the patient is within 20% of their clinical ldl-c goal, then ezetimibe is preferred; in contrast, for patients who need a >20% reduction in their ldl-c levels, the choice is between multiple standard agents added sequentially (e.g. ezetimibe, a bile acid sequestrant and niacin), pcsk9 inhibitors, lomitapide or mipomersen (for patients with homozygous familial figure 2: flowchart outlining the second step (addition or substitution of non-statins) of recommended cholesterollowering therapy in patients with statin-associated muscle adverse events. bas = bile acid sequestrants; pcsk9 = proprotein convertase subtilisin/kexin type 9; sc = subcutaneously; tg = triglycerides; urti = upper respiratory tract infection; alt = alanine aminotransferase; uln = upper limit of normal; egfr = estimated glomerular filtration rate. *approved for use as an adjunct to diet and maximally-tolerated statin therapy in adult patients with heterozygous or homozygous familial hypercholesterolaemia and patients with clinical atherosclerotic cardiovascular disease who require additional lowering of their low-density lipoprotein cholesterol levels. †three evolucumab injections consecutively within 30 minutes. maha a. al-mohaissen, martha j. ignaszewski, jiri frohlich and andrew p. ignaszewski review | e413 hypercholesterolaemia), apheresis (if available) or complex polypharmacy.10 it is important to keep in mind that non-daily statin doses and the combination of statin plus non-statin therapy may provide treatment alternatives and result in ldl-c reductions similar to those seen with high-dose statin regimens.4 p o ly p h a r m a c y c h a l l e n g e s patients with clinical ascvd who have lower ldl-c goals and those with significant baseline ldl-c elev ations (i.e. familial hyperlipidaemia) may pose a treatment challenge and require polypharmacy to achieve their prespecified ldl-c goals. while ezetimibe is well tolerated, the addition of a resin or niacin may not be tolerated in all patients. since the maximal ldl-c reduction which can be achieved with ezetimibe is approximately 20%, other safe and effective lipid-lowering agents for patients who require greater ldl-c reductions are necessary.7 the use of pcsk9 inhibitors is governed by cost and local policies.56 it is important to emphasise that pcsk9 inhibitors are approved only as adjuncts to statins unless the patient is completely intolerant.48,53,54 conclusion cardiovascular benefits are strongly linked to reductions in ldl-c levels, as long as proven and safe ldlc-lowering agents are used. while most samaes are mild and reversible, a subgroup of patients treated with statins may develop autoimmune inflammatory myositis or necrotising myopathy which does not resolve with statin discontinuation and requires immunosuppressive therapy. statin rechallenge is successful in the majority of cases and is the first choice of therapy; in these instances, the maximal tolerated dose should be used and continued—even if outcomes are modest—in order to meet nationally-supported guideline-based ldl-c goals and reduce the patient’s cardiovascular risk. nevertheless, evidence regarding the effectiveness of nscl therapy is accumulating and ezetimibe, bile acid sequestrants and pcsk9 inhibitors are currently the most effective statin alternatives. references 1. antonopoulos as, margaritis m, lee r, channon k, antoniades c. statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. curr pharm des 2012; 18:1519–30. doi: 10.2174/ 138161212799504803. 2. cholesterol treatment trialists’ (ctt) collaboration; baigent c, blackwell l, emberson j, holland le, reith c, et al. efficacy and safety of more intensive lowering of ldl cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. lancet 2010; 376:1670–81. doi: 10.1016/ s0140-6736(10)61350-5. 3. guyton jr, bays he, grundy sm, jacobson ta; the national lipid association statin intolerance panel. an assessment by the statin intolerance panel: 2014 update. j clin lipidol 2014; 8:s72–81. doi: 10.1016/j.jacl.2014.03.002. 4. rosenson rs, baker sk, jacobson ta, kopecky sl, parker ba; the national lipid association’s muscle safety expert panel. an assessment by the statin muscle safety task force: 2014 update. j clin lipidol 2014; 8:s58–71. doi: 10.1016/j. jacl.2014.03.004. 5. cannon cp, blazing ma, giugliano rp, mccagg a, white ja, theroux p, et al. ezetimibe added to statin therapy after acute coronary syndromes. n engl j med 2015; 372:2387–97. doi: 10.1056/nejmoa1410489. 6. giugliano rp, sabatine ms. are pcsk9 inhibitors the next breakthrough in the cardiovascular field? j am coll cardiol 2015; 65:2638–51. doi: 10.1016/j.jacc.2015.05.001. 7. writing committee; lloyd-jones dm, morris pb, ballantyne cm, birtcher kk, daly dd jr, et al. 2016 acc expert consensus decision pathway on the role of non-statin therapies for ldlcholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the american college of cardiology task force on clinical expert consensus documents. j am coll cardiol 2016; 68:92–125. doi: 10.1016/j. jacc.2016.03.519. 8. mancini gb, baker s, bergeron j, fitchett d, frohlich j, genest j, et al. diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a canadian working group consensus conference. can j cardiol 2011; 27:635–62. doi: 10.1016/j.cjca.2011.05.007. 9. mancini gb, tashakkor ay, baker s, bergeron j, fitchett d, frohlich j, et al. diagnosis, prevention, and management of statin adverse effects and intolerance: canadian working group consensus update. can j cardiol 2013; 29:1553–68. doi: 10.1016/j.cjca.2013.09.023. 10. mancini gb, baker s, bergeron j, fitchett d, frohlich j, genest j, et al. diagnosis, prevention, and management of statin adverse effects and intolerance: canadian consensus working group update (2016). can j cardiol 2016; 32:s35–65. doi: 10.1016/j. cjca.2016.01.003. 11. stroes es, thompson pd, corsini a, vladutiu gd, raal fj, ray kk, et al. statin-associated muscle symptoms: impact on statin therapy european atherosclerosis society consensus panel statement on assessment, aetiology and management. eur heart j 2015; 36:1012–22. doi: 10.1093/eurheartj/ehv043. 12. nissen se, stroes e, dent-acosta re, rosenson rs, lehman sj, sattar n, et al. efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the gauss-3 randomized clinical trial. jama 2016; 315:1580–90. doi: 10.1001/jama.2016.3608. 13. al sifri sn, almahmeed w, azar s, okkeh o, bramlage p, jünger c, et al. results of the dyslipidemia international study (dysis)-middle east: clinical perspective on the prevalence and characteristics of lipid abnormalities in the setting of chronic statin treatment. plos one 2014; 9:e84350. doi: 10.1371/ journal.pone.0084350. 14. mahmood d, jahan k, habibullah k. primary prevention with statins in cardiovascular diseases: a saudi arabian perspective. j saudi heart assoc 2015; 27:179–91. doi: 10.1016/j. jsha.2014.09.004. dx.doi.org/10.2174/138161212799504803 dx.doi.org/10.2174/138161212799504803 dx.doi.org/10.1016/s0140-6736%2810%2961350-5 dx.doi.org/10.1016/s0140-6736%2810%2961350-5 dx.doi.org/10.1016/j.jacl.2014.03.002 dx.doi.org/10.1016/j.jacl.2014.03.004 dx.doi.org/10.1016/j.jacl.2014.03.004 dx.doi.org/10.1056/nejmoa1410489 dx.doi.org/10.1016/j.jacc.2015.05.001 dx.doi.org/10.1016/j.jacc.2016.03.519 dx.doi.org/10.1016/j.jacc.2016.03.519 dx.doi.org/10.1016/j.cjca.2011.05.007 dx.doi.org/10.1016/j.cjca.2013.09.023 dx.doi.org/10.1016/j.cjca.2016.01.003 dx.doi.org/10.1016/j.cjca.2016.01.003 dx.doi.org/10.1093/eurheartj/ehv043 dx.doi.org/10.1001/jama.2016.3608 dx.doi.org/10.1371/journal.pone.0084350 dx.doi.org/10.1371/journal.pone.0084350 dx.doi.org/10.1016/j.jsha.2014.09.004 dx.doi.org/10.1016/j.jsha.2014.09.004 statin-associated muscle adverse events update for clinicians e414 | squ medical journal, november 2016, volume 16, issue 4 15. joy tr, monjed a, zou gy, hegele ra, mcdonald cg, mahon jl. n-of-1 (single-patient) trials for statin-related myalgia. ann intern med 2014; 160:301–10. doi: 10.7326/m13-1921. 16. moriarty pm, thompson pd, cannon cp, guyton jr, bergeron j, zieve fj, et al. efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the odyssey alternative randomized trial. j clin lipidol 2015; 9:758–69. doi: 10.1016/j.jacl.2015.08.006. 17. selva-o’callaghan a, alvarado-cardenas m, marin a, pinalfernandez i. statins and myositis: the role of anti-hmgcr antibodies. expert rev clin immunol 2015; 11:1277–9. doi: 10.1586/1744666x.2015.1102632. 18. pasnoor m, barohn rj, dimachkie mm. toxic myopathies. neurol clin 2014; 32:647–70. doi: 10.1016/j.ncl.2014.04.009. 19. holbrook a, wright m, sung m, ribic c, baker s. statinassociated rhabdomyolysis: is there a dose-response relationship? can j cardiol 2011; 27:146–51. doi: 10.1016/j. cjca.2010.12.024. 20. mammen al, tiniakou e. intravenous immune globulin for statin-triggered autoimmune myopathy. n engl j med 2015; 373:1680–2. doi: 10.1056/nejmc1506163. 21. alfirevic a, neely d, armitage j, chinoy h, cooper rg, laaksonen r, et al. phenotype standardization for statininduced myotoxicity. clin pharmacol ther 2014; 96:470–6. doi: 10.1038/clpt.2014.121. 22. armour r, zhou l. outcomes of statin myopathy after statin withdrawal. j clin neuromuscul dis 2013; 14:103–9. doi: 10.1097/cnd.0b013e3182852558. 23. echaniz-laguna a, mohr m, tranchant c. neuromuscular symptoms and elevated creatine kinase after statin withdrawal. n engl j med 2010; 362:564–5. doi: 10.1056/nejmc0908215. 24. mammen al. statin-associated autoimmune myopathy. n engl j med 2016; 374:664–9. doi: 10.1056/nejmra1515161. 25. wu y, lach b, provias jp, tarnopolsky ma, baker sk. statinassociated autoimmune myopathies: a pathophysiologic spectrum. can j neurol sci 2014; 41:638–47. doi: 10.1017/ cjn.2014.22. 26. babu s, li y. statin induced necrotizing autoimmune myopathy. j neurol sci 2015; 351:13–17. doi: 10.1016/j.jns.2015.02.042. 27. limaye v, bundell c, hollingsworth p, rojana-udomsart a, mastaglia f, blumbergs p, et al. clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy. muscle nerve 2015; 52:196–203. doi: 10.1002/mus.24541. 28. mammen al, pak k, williams ek, brisson d, coresh j, selvin e, et al. rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme-a reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. arthritis care res (hoboken) 2012; 64:269–72. doi: 10.1002/acr.20662. 29. floyd js, brody ja, tiniakou e, psaty bm, mammen a. absence of anti-hmg-coa reductase autoantibodies in severe selflimited statin-related myopathy. muscle nerve 2016; 54:142–4. doi: 10.1002/mus.25127. 30. mammen al, chung t, christopher-stine l, rosen p, rosen a, doering kr, et al. autoantibodies against 3-hydroxy3-methylglutaryl-coenzyme a reductase in patients with statinassociated autoimmune myopathy. arthritis rheum 2011; 63:713–21. doi: 10.1002/art.30156. 31. mohaupt mg, karas rh, babiychuk eb, sanchez-freire v, monastyrskaya k, iyer l, et al. association between statinassociated myopathy and skeletal muscle damage. cmaj 2009; 181:e11–18. doi: 10.1503/cmaj.081785. 32. draeger a, monastyrskaya k, mohaupt m, hoppeler h, savolainen h, allemann c, et al. statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. j pathol 2006; 210:94–102. doi: 10.1002/path.2018. 33. rallidis ls, fountoulaki k, anastasiou-nana m. managing the underestimated risk of statin-associated myopathy. int j cardiol 2012; 159:169–76. doi: 10.1016/j.ijcard.2011.07.048. 34. kellick ka, bottorff m, toth pp; the national lipid association’s safety task force. a clinician’s guide to statin drug-drug interactions. j clin lipidol 2014; 8:s30–46. doi: 10.1016/j.jacl.2014.02.010. 35. bruckert e, hayem g, dejager s, yau c, bégaud b. mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients: the primo study. cardiovasc drugs ther 2005; 19:403–14. doi: 10.1007/s10557-005-5686-z. 36. stone nj, robinson jg, lichtenstein ah, bairey merz cn, blum cb, eckel rh, et al. 2013 acc/aha guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the american college of cardiology/american heart association task force on practice guidelines. circulation 2014; 129:s1–45. doi: 10.1161/01.cir.0000437738.63853.7a. 37. zhang h, plutzky j, skentzos s, morrison, f, mar p, shubina m, et al. discontinuation of statins in routine care settings: a cohort study. ann intern med 2013; 158:526–34. doi: 10.7326/00034819-158-7-201304020-00004. 38. neal rc, ferdinand kc, ycas j, miller e. relationship of ethnic origin, gender, and age to blood creatine kinase levels. am j med 2009; 122:73–8. doi: 10.1016/j.amjmed.2008.08.033. 39. stein ea, ballantyne cm, windler e, sirnes pa, sussekov a, yigit z, et al. efficacy and tolerability of fluvastatin xl 80 mg alone, ezetimibe alone, and the combination of fluvastatin xl 80 mg with ezetimibe in patients with a history of musclerelated side effects with other statins. am j cardiol 2008; 101:490–6. doi: 10.1016/j.amjcard.2007.09.099. 40. elis a, lishner m. non-every day statin administration: a literature review. eur j intern med 2012; 23:474–8. doi: 10.1016/j.ejim.2012.02.006. 41. dulay d, lahaye sa, lahey ka, day ag. efficacy of alternate day versus daily dosing of rosuvastatin. can j cardiol 2009; 25:e28–31. doi: 10.1016/s0828-282x(09)70480-5. 42. mampuya wm, frid d, rocco m, huang j, brennan dm, hazen sl, et al. treatment strategies in patients with statin intolerance: the cleveland clinic experience. am heart j 2013; 166:597–603. doi: 10.1016/j.ahj.2013.06.004. 43. ewang-emukowhate m, wierzbicki as. lipid-lowering agents. j cardiovasc pharmacol ther 2013; 18:401–11. doi: 10.1177/1074248413492906. 44. tsujita k, sugiyama s, sumida h, shimomura h, yamashita t, yamanaga k, et al. impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled precise-ivus trial. j am coll cardiol 2015; 66:495–507. doi: 10.1016/j.jacc.2015.05.065. 45. zema mj. colesevelam hcl and ezetimibe combination therapy provides effective lipid-lowering in difficult-to-treat patients with hypercholesterolemia. am j ther 2005; 12:306–10. 46. al-mohaissen ma, pun sc, frohlich jj. niacin: from mechanisms of action to therapeutic uses. mini rev med chem 2010; 10:204–17. doi: 10.2174/138955710791185046. 47. aim-high investigators; boden we, probstfield jl, anderson t, chaitman br, desvignes-nickens p, et al. niacin in patients with low hdl cholesterol levels receiving intensive statin therapy. n engl j med 2011; 365:2255–67. doi: 10.1056/ nejmoa1107579. 48. hps2-thrive collaborative group; landray mj, haynes r, hopewell jc, parish s, aung t, et al. effects of extended-release niacin with laropiprant in high-risk patients. n engl j med 2014; 371:203–12. doi: 10.1056/nejmoa1300955. dx.doi.org/10.7326/m13-1921 dx.doi.org/10.1016/j.jacl.2015.08.006 dx.doi.org/10.1586/1744666x.2015.1102632 dx.doi.org/10.1016/j.ncl.2014.04.009 dx.doi.org/10.1016/j.cjca.2010.12.024 dx.doi.org/10.1016/j.cjca.2010.12.024 dx.doi.org/10.1056/nejmc1506163 dx.doi.org/10.1038/clpt.2014.121 dx.doi.org/10.1097/cnd.0b013e3182852558 dx.doi.org/10.1056/nejmc0908215 dx.doi.org/10.1056/nejmra1515161 dx.doi.org/10.1017/cjn.2014.22 dx.doi.org/10.1017/cjn.2014.22 dx.doi.org/10.1016/j.jns.2015.02.042 dx.doi.org/10.1002/mus.24541 dx.doi.org/10.1002/acr.20662 dx.doi.org/10.1002/mus.25127 dx.doi.org/10.1002/art.30156 dx.doi.org/10.1503/cmaj.081785 dx.doi.org/10.1002/path.2018 dx.doi.org/10.1016/j.ijcard.2011.07.048 dx.doi.org/10.1016/j.jacl.2014.02.010 dx.doi.org/10.1007/s10557-005-5686-z dx.doi.org/10.1161/01.cir.0000437738.63853.7a dx.doi.org/10.7326/0003-4819-158-7-201304020-00004 dx.doi.org/10.7326/0003-4819-158-7-201304020-00004 dx.doi.org/10.1016/j.amjmed.2008.08.033 dx.doi.org/10.1016/j.amjcard.2007.09.099 dx.doi.org/10.1016/j.ejim.2012.02.006 dx.doi.org/10.1016/s0828-282x%2809%2970480-5 dx.doi.org/10.1016/j.ahj.2013.06.004 dx.doi.org/10.1177/1074248413492906 dx.doi.org/10.1016/j.jacc.2015.05.065 dx.doi.org/10.2174/138955710791185046 dx.doi.org/10.1056/nejmoa1107579 dx.doi.org/10.1056/nejmoa1107579 dx.doi.org/10.1056/nejmoa1300955 maha a. al-mohaissen, martha j. ignaszewski, jiri frohlich and andrew p. ignaszewski review | e415 49. hegele ra, gidding ss, ginsberg hn, mcpherson r, raal fj, rader dj, et al. nonstatin low-density lipoprotein-lowering therapy and cardiovascular risk reduction: statement from atvb council. arterioscler thromb vasc biol 2015; 35:2269–80. doi: 10.1161/atvbaha.115.306442. 50. ouwens mj, nauta j, ansquer jc, driessen s. systematic literature review and meta-analysis of dual therapy with fenofibrate or fenofibric acid and a statin versus a double or equivalent dose of statin monotheraphy. curr med res opin 2015; 31:2273–85. doi: 10.1185/03007995.2015.1098597. 51. accord study group; ginsberg hn, elam mb, lovato lc, crouse jr 3rd, leiter la, et al. effects of combination lipid therapy in type 2 diabetes mellitus. n engl j med 2010; 362:1563–74. doi: 10.1056/nejmoa1001282. 52. neuvonen pj, niemi m, backman jt. drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. clin pharmacol ther 2006; 80:565–81. doi: 10.1016/j.clpt. 2006.09.003. 53. guo j, meng f, ma n, li c, ding z, wang h, et al. meta-analysis of safety of the coadministration of statin with fenofibrate in patients with combined hyperlipidemia. am j cardiol 2012; 110:1296–301. doi: 10.1016/j.amjcard.2012.06.050. 54. sanofi-aventis canada inc. product monograph including patient medication information: prpraluent™. from: www. products.sanofi.ca/en/praluent.pdf accessed: jun 2016. 55. u.s. food and drug administration. highlights of prescribing information: repatha™. from: www.accessdata.fda.gov/ drugsatfda_docs/label/2015/125522s000lbl.pdf accessed: jun 2016. 56. bergeron n, phan ba, ding y, fong a, krauss rm. proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. circulation 2015; 132:1648–66. doi: 10.1161/ circulationaha.115.016080. dx.doi.org/10.1161/atvbaha.115.306442 dx.doi.org/10.1185/03007995.2015.1098597 dx.doi.org/10.1056/nejmoa1001282 dx.doi.org/10.1016/j.clpt.2006.09.003 dx.doi.org/10.1016/j.clpt.2006.09.003 dx.doi.org/10.1016/j.amjcard.2012.06.050 dx.doi.org/10.1161/circulationaha.115.016080 dx.doi.org/10.1161/circulationaha.115.016080 1department of nursing, faculty of nursing & midwifery, urmia university of medical sciences, urmia, iran; 2school of health, nursing & midwifery, university of the west of scotland, paisley, uk *corresponding author’s e-mail: milan.z.nu93@gmail.com نتائج التعليم مبساعدة األقران والفيديو واجلمع بني التعليم باألقران والفيديو على القلق لدى املرضى اخلاضعني لتصوير األوعية التاجية دراسة سريرية منضبطة ح�سني حبيب زاده، زهرة داالي ميالن، موالود رادفر، ليلى عليلو، اأردري كوند abstract: objectives: coronary angiography can be stressful for patients and anxiety-caused physiological responses during the procedure increase the risk of dysrhythmia, coronary artery spasms and rupture. this study therefore aimed to investigate the effects of peer, video and combined peer-and-video training on anxiety among patients undergoing coronary angiography. methods: this single-blinded randomised controlled clinical trial was conducted at two large educational hospitals in iran between april and july 2016. a total of 120 adult patients undergoing coronary angiography were recruited. using a block randomisation method, participants were assigned to one of four groups, with those in the control group receiving no training and those in the three intervention groups receiving either peer-facilitated training, video-based training or a combination of both. a persian-language validated version of the state-trait anxiety inventory was used to measure preand post-intervention anxiety. results: there were no statistically significant differences in mean pre-intervention anxiety scores between the four groups (f = 0.31; p = 0.81). in contrast, there was a significant reduction in post-intervention anxiety among all three intervention groups compared to the control group (f = 27.71; p <0.01); however, there was no significant difference in anxiety level in terms of the type of intervention used. conclusion: peer, video and combined peer-and-video education were equally effective in reducing angiography-related patient anxiety. such techniques are recommended to reduce anxiety amongst patients undergoing coronary angiography in hospitals in iran. keywords: cardiac imaging techniques; coronary angiography; anxiety; patient education; iran. امللخ�ص: الهدف: ت�سوير االأوعية التاجية ميكن اأن يكون مقلقا للمر�سى وردود القلق الف�سيولوجية اأثناء التدخل قد يزيد من خطورة عدم واجلمع والفيديو االأقران تثقيف نتائج من التحقق اإىل الدرا�سة هذة تهدف والتمزق. التاجي ال�رصيان وت�سنجات القلب �رصبات انتظام بينهما على القلق عند املر�سى الذين �سيخ�سعون لت�سوير االأوعية التاجية. الطريقة: مت اإجراء هذة الدرا�سة الطبية املن�سبطة يف م�ست�سفيني تعلمني كبريين يف اإيران من اأبريل اإىل اأغ�سط�ض 2016. مت جتنيد جمموع 120 مري�سا �سيخ�سعون لعملية ت�سوير االأوعية التاجية. باأ�ستخدام طريقة الكتلة الع�سوائية، مت تعيني امل�ساركني اإىل اأحد االأربع جمموعات، بحيث اأن امل�ساركني يف جمموعة التحكم مل يتلقوا اأي تدريب و من الفار�سية باللغة حمققة ن�سخة اأ�ستخدام الحقا مت كليهما. اأو الفيديو اأو االأقران م�ساعدة اإما تلقت التداخلية جمموعات الثالثة بقية القلق نتائج متو�سط يف معتد اإح�سائي فارق اأي هناك يكن مل التدخل. النتائج: وبعد قبل القلق م�ستوى لقيا�ض القلق �سمة قائمة حالة جميع بني التدخل بعد القلق يف كبري انخفا�ض هناك كان املقابل، يف .)f = 0.31; p = 0.81( جمموعات االأربع بني التدخل قبل ما جمموعات التدخل الثالثة مقارنة مع جمموعة التحكم )f = 27.71; p >0.01(؛ اإال اأنه مل يوجد فارق معتد مل�ستوى القلق من حيث نوعية التدخل امل�ستخدم. اخلال�صة: اأ�ستخدام و�سائل التدري�ض باالأقران والفيديو واجلمع بينهما تعترب و�سائل فعالة يف خف�ض م�ستوىات القلق املرتبطة بت�سوير االأوعية التاجية. هذة الو�سائل يو�سى بها لتخفي�ض م�ستوى القلق للمر�سى الذين يخ�سعون لت�سوير االأوعية التاجية يف امل�ست�سفيات االإيرانية. الكلمات املفتاحية: طرق الت�سوير القلبي؛ ت�سوير االأوعية التاجية؛ القلق؛ تثقيف املري�ض؛ اإيران. effects of peer-facilitated, video-based and combined peer-and-video education on anxiety among patients undergoing coronary angiography randomised controlled trial hosein habibzadeh,1 *zahra d. milan,1 moloud radfar,1 leyla alilu,1 audrey cund2 clinical & basic research sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e61–67, epub. 4 apr 18 submitted 11 jul 17 revisions req. 14 sep & 6 nov 17; revisions recd. 19 oct & 20 nov 17 accepted 23 nov 17 doi: 10.18295/squmj.2018.18.01.010 advances in knowledge the findings of this study indicate that either peer-facilitated training, video-based training or a combination of both may reduce the anxiety levels of patients undergoing coronary angiography. application to patient care peer-facilitated, video-based or peer-and-video training is recommended to reduce anxiety among patients undergoing coronary angiography in iranian hospitals. effects of peer-facilitated, video-based and combined peer-and-video education on anxiety among patients undergoing coronary angiography randomised controlled trial e62 | squ medical journal, february 2018, volume 18, issue 1 anxiety is an emotional state whereby an individual experiences feelings of uneasi-ness or apprehension in response to a perceived or actual threat. the subsequent activation of the autonomic nervous system can trigger various physical symptoms, including palpitations, tachycardia and chest pain.1 moreover, intense anxiety is associated with decreased immune response and changes in cardiovascular function, such as impaired heart rate, endothelial dysfunction and vascular inflammation, which may lead to a deterioration in a patient’s coronary condition.2 previous research has shown that patients undergoing clinical or surgical procedures such as coronary angiography often experience high levels of anxiety.3,4 as such, methods to improve clinical outcomes and identify appropriate interventions to reduce patient anxiety are necessary. for patients undergoing coronary angiography or similar procedures, a lack of knowledge regarding the procedure may be directly related to their anxiety levels; accordingly, the provision of necessary, detailed and accurate procedure-related information as well as a breakdown of the actions that must be taken before, during and after the procedure can help reduce stress and anxiety.4–7 several studies have confirmed the effect iveness of providing information about the angiography process in reducing patient anxiety.8,9 however, further research is required to identify the most effective approach and time to prepare a patient and their family for the procedure.10 the use of an appropriate educational technique—such as educational leaflets or peer-facilitated or video-based training—may be effect ive in reducing patient anxiety.11 peer-facilitated train ing is based on the social learning theory that people learn from each other via observation, imitation and modelling; patients can therefore benefit from their peers’ experiences in terms of learning to cope with their illness or the planned investigation.12 video-based train ing may also reduce anxiety, stress and depression while a combination of both visual and auditory information is an effective tool to facilitate knowledge acquisition and retention, reduce anxiety, improve coping skills and increase self-care behaviours.13,14 however, while the use of peer-facilitated and video-based patient education is well established world wide, there is a lack of research on this topic in iran. moreover, although medical technologies have progressed rapidly, strategies focusing on health education, promotion and self-management are not yet widely implemented in iranian hospitals. this study therefore sought to investigate the effects of peer-facilitated, video-based and combined peer-and-video training on anxiety among patients undergoing coronary angiography at two hospitals in iran. methods this randomised controlled trial was conducted among 120 patients undergoing coronary angiography at two large educational hospitals in iran between april and july 2016. patients were recruited from the ayatollah taleghani hospital and seyed-al-shohada hospital in urmia. only patients aged 18–80 years old with no prior history of angiography and no cognitive disorders or physical disabilities were included in the study. patients were excluded if they underwent emergency angiography, were employed as a staff member at the hospital, were receiving intensive care or had been admitted to the cardiac care unit. the necessary sample size was calculated as a minimum of 23 participants per group at a confidence level and test power of 95%.15 accounting for potential participant loss, 30 patients per group were subsequently recruited for a total of 120 patients [figure 1]. figure 1: diagram showing the clinical trial design used in the current study. once randomly assigned to each group, none of the patients were lost to follow-up or excluded from the final analysis. hosein habibzadeh, zahra d. milan, moloud radfar, leyla alilu and audrey cund clinical and basic research | e63 a single-blind clinical trial design was adopted with four parallel arms to examine the effects of peerfacilitated, video-based and combined peer-and-video training as an intervention to reduce anxiety levels in patients undergoing coronary angiography. participants were randomly assigned to each group on a weekly basis to avoid interference between the groups. in the first week, the first group received peer-facilitated training, while the second group received video based training the following week and the third group received combined peer-and-video training the week after that. in the fourth week, the control group received routine care. recruitment continued until the required sample size was achieved. to avoid data contamination arising from patients discussing their experiences with each other and to minimise researcher bias, the recruitment and sampling process for each subsequent group occurred once all previous patients from the previous week had been discharged. patients were randomly allocated to a group by a person uninvolved in the sampling and data collection process. each intervention took place in a quiet room with sufficient lighting and suitable seating on the evening before the angiography procedure. the first intervention group took part in a 30-minute peer-facilitated training session. under the supervision of the researcher, two patients who had recently undergone angiography were asked to talk to between four and six of the participants about their feelings and experiences before, during and after the procedure. in the video-based intervention group, the participants watched a fiveminute movie about what they should expect before, during, and after angiography and another 15-minute movie filmed within the actual operating room where the procedure would take place. both movies were broadcast under the researcher’s supervision during a 20-minute period. at the end of the intervention, the effectiveness of the film was evaluated during a brief question-answer session. in the combined peer-and-video intervention group, all of the training steps described for the afore mentioned groups were performed. as before, a 20 minute video-based training session took place; then, after a 15-minute break, a 30-minute peer-facilitated group session was carried out under the supervision of the researcher. verbal feedback was again used to evaluate effectiveness of the training. for those in the control group, each participant received routine care which involved no education or preparation for the procedure from a health professional. regardless of group, each patient was admitted to the hospital in advance of the procedure for surveillance purposes, including the monitoring of their vital signs, laboratory tests and an electrocardiogram. all participants remained under the supervision of the researcher between the end of the intervention and the beginning of the procedure. the state-trait anxiety inventory (stai) is a 20-item questionnaire tool designed to assess an individual’s feelings at the time of assessment.16 a persian-language version of the stai questionnaire was used to measure patient anxiety both the day before the coronary angiography prior to the delivery of any training as well as 30 minutes before the patient was transferred to the operating room. responses to the stai questionnaire were self-assessed by participants and scored on a four-point likert scale, with one indicating “not at all anxious”, two indicating “sometimes anxious”, three indicating “often anxious” and four indicating “frequently anxious.” total anxiety scores from 20–80 were calculated for each patient, with scores of 20–29, 30–49, 50–69 and 70–80 indicating mild, relatively mild, relatively severe and severe anxiety, respectively. the questionnaire had been previously validated in iran with a cronbach’s alpha of 0.91.17 demographic and clinical characteristics of the participants were also recorded, including age, gender, duration of disease, marital status, history of hospitalisation, education level and economic status. economic status was classified as unfavourable (monthly income of <$250 usd), partly favourable (monthly income of $250–500 usd) or favourable (monthly income of >$500 usd). data were analysed using the statistical package for the social sciences (spss), version 19.0 (ibm corp., armonk, new york, usa). the normality of the quan titative data was confirmed using a kolmogorovsmirnov test. a chi-squared test and one-way analysis of variance was used to compare the sociodemographic and clinical characteristics of the groups, as appropriate. a tukey’s post-hoc test was employed for the pairwise comparison of post-intervention differences in anxiety scores between the groups. a p value of ≤0.05 was considered statistically significant. ethical approval for this study was obtained from the committee of ethics of the urmia university of medical sciences, urmia, iran (#ir.umsu.rec.1395,21). this study was registered under the iranian registry of clinical trials (#2016072429052n1). written informed consent was obtained from all participants prior to their inclusion in the study. results table 1 shows the sociodemographic characteristics of the participants according to group. there were no significant differences between the groups in terms of age, gender, marital status, duration of disease, history of effects of peer-facilitated, video-based and combined peer-and-video education on anxiety among patients undergoing coronary angiography randomised controlled trial e64 | squ medical journal, february 2018, volume 18, issue 1 hospitalisation, presence of chronic disease and income or education levels; accordingly, all four groups were considered homogenous. mean pre-intervention anxiety scores were 41.40 ± 9.90, 41.80 ± 8.76, 39.96 ± 8.28 and 40.00 ± 9.98 for the peer education, video education, combined peer-and-video education and control groups, respect ively, with no statistically significant difference between the groups (p = 0.81). however, mean post-intervention anxiety scores were 34.30 ± 7.21, 36.23 ± 7.29, 30.73 ± 5.56 and 42.86 ± 11.64, respectively, with a statistically significant difference between the intervention groups and the control group (p <0.01). the mean difference between preand post-intervention anxiety scores was -6.70 ± 4.39, -5.53 ± 2.19 and -7.56 ± 6.45 for the peer education, video education and combined peer-andvideo education groups, respectively, in contrast to the control group (5.85 ± 2.86; p <0.01) [table 2]. a pairwise comparison showed a statistically signi ficant mean difference between preand post-intervention anxiety scores of participants undergoing peer facilitated training group, video-based training or com bined peer-and-video training in comparison to the control group; however, there was no significant difference in terms of the type of intervention used [table 3]. table 1: sociodemographic and clinical characteristics of adult patients undergoing coronary angiography at two large hospitals in iran (n = 120) characteristic n (%) p value peer intervention group video intervention group combined intervention group control group age in years 35–50 5 (17) 9 (30) 8 (27) 12 (40) 0.51†51–65 18 (60) 17 (57) 15 (50) 14 (47) 66–80 7 (23) 4 (13) 7 (23) 4 (13) mean ± sd 58.80 ± 8.57 56.07 ± 8.89 57.27 ± 9.32 54.30 ± 9.79 0.28* gender male 16 (53) 16 (53) 15 (50) 17 (57) 0.96† female 14 (47) 14 (47) 15 (50) 13 (43) marital status married 26 (87) 23 (77) 29 (97) 28 (93) 0.11† unmarried 4 (13) 7 (23) 1 (3) 2 (7) medical history presence of chronic disease 17 (57) 17 (57) 13 (43) 13 (43) 0.77† mean duration of disease in years ± sd 3.12 ± 2.47 3.21 ± 2.60 1.70 ± 1.67 2.60 ± 1.97 0.51* history of hospitalisation 19 (63) 0 (0) 15 (50) 15 (50) 0.65† mean number of hospital admissions ± sd 1.46 ± 1.17 2.45 ± 1.60 1.06 ± 0.90 0.99 ± 0.80 0.22* years of education 9–11 24 (80) 24 (80) 20 (67) 22 (74) 0.39†12 6 (20) 6 (20) 10 (33) 7 (23) >13 0 (0) 0 (0) 0 (0) 1 (3) economic status unfavourable 17 (57) 20 (67) 17 (57) 18 (60) 0.98†partly favourable 9 (30) 7 (23) 10 (33) 9 (30) favourable 4 (13) 3 (10) 3 (10) 3 (10) sd = standard deviation. *calculated using a one-way analysis of variance. †calculated using a chi-squared test. hosein habibzadeh, zahra d. milan, moloud radfar, leyla alilu and audrey cund clinical and basic research | e65 discussion in the current study, peer-facilitated training, videobased training and combined peer-and-video training were all found to significantly reduce anxiety levels among patients undergoing coronary angiography in comparison to a control group. lundén et al. similarly found that it was necessary to provide patients with comprehensive and accurate information reflecting the actual conditions of the angioplasty unit in order for patients to remain calm during and after an angioplasty procedure.18 tame et al. also confirmed that written and verbal education was an effective approach to reduc ing preoperative anxiety.19 however, in another randomised controlled trial, goodman et al. found that prov iding information alone had no significant effect on levels of anxiety among patients scheduled for a coronary artery bypass surgery.20 in the present study, one of the interventions involved patients watching video footage taken in the surgical environment and an explanation of the actions taken before, during and after the procedure. tou et al. also found a reduction in patients’ anxiety levels follow ing a video-based intervention.21 previous studies have concluded that peer-facilitated training is similarly effective in reducing anxiety among patients who are candidates for coronary surgery or who have multiple sclerosis.9,22 eslami et al. noted reduced mean stress scores among patients undergoing coronary angiography who participated in peer-facilitated education in comparison to a control group.23 one explanation for the efficacy of this educational technique may be that patients trust and respect the views and experiences of individuals with similar conditions or undergoing similar medical procedures. the use of a combined peer-and-video training has also been previously found to be effective in reducing patient anxiety; moumeni et al. observed that supplementing video training sessions with an educational booklet led to reduced preoperative as well as postintervention anxiety among patients undergoing coronary artery bypass grafting.24 a similar study found that a combined education programme reduced anxiety among orthopaedic surgery candidates.25 in addition, mosavi et al. showed that anxiety and depression among open heart surgery patients were significantly reduced using face-to-face training combined with an educational booklet.26 overall, the results of the current study found no significant difference in post-intervention anxiety reduction between the three different interventions; in other words, peer-facilitated, video-based and combined peer-and-video training were all equally effective in reducing anxiety among patients undergoing angiography. this finding is consistent with the results of previous research.27–29 najafi et al. reported no significant difference in terms of state and trait anxiety levels among echocardiography patients undergoing various table 3: comparison of anxiety scores* between intervention groups among adult patients undergoing coronary angiography at two large hospitals in iran (n = 120) group b group a peer intervention group video intervention group combined intervention group difference† p value‡ difference† p value‡ difference† p value‡ video intervention group -1.93 0.80 combined intervention group 3.56 0.35 5.50 0.05 control group -8.56 <0.01 -6.63 0.01 -12.13 <0.01 *anxiety levels were assessed using a validated version of the 20-item state-trait anxiety inventory.16,17 †mean difference in anxiety score in group a versus b for post-intervention comparisons. ‡calculated using tukey’s post hoc test. table 2: anxiety scores* according to intervention group among adult patients undergoing coronary angiography at two large hospitals in iran (n = 120) mean anxiety score ± sd p value† peer intervention group video intervention group combined intervention group control group pre-intervention 41.40 ± 9.90 41.80 ± 8.76 39.96 ± 8.28 40.00 ± 9.98 0.81 post-intervention 34.30 ± 7.21 36.23 ± 7.29 30.73 ± 5.56 42.86 ± 11.64 <0.01 mean difference -6.70 ± 4.39 -5.53 ± 2.19 -7.56 ± 6.45 5.85 ± 2.86 <0.01 sd = standard deviation. *anxiety levels were assessed using a validated version of the 20-item state-trait anxiety inventory.16,17 †calculated using a one-way analysis of variance. effects of peer-facilitated, video-based and combined peer-and-video education on anxiety among patients undergoing coronary angiography randomised controlled trial e66 | squ medical journal, february 2018, volume 18, issue 1 forms of training (booklets and face-to-face training).27 face-to-face, pamphlet and electronic training among patients with acute myocardial infarctions have similarly resulted in no statistically significant differences in anxiety levels according to the type of training received.28,29 the current study is subject to certain limitations. as patients were hospitalised one day before the angiography procedure, the amount of time available for patients to take part in training or review information about the procedure was minimal. hence, patients undergoing emergency angiography and those hospital ised on the day of the procedure were excluded as there was insufficient time to perform the pre-procedure training; furthermore, inconsistencies in the length of time between the training and the procedure might affect the generalisability of the findings. however, the anxiety levels of such patients should be determined and further studies should include these patients in the analysis. furthermore, in order to avoid data contamination and researcher bias, patients in the current study were recruited in staggered phases, with new participants recruited only after all those involved in the previous intervention had been discharged. however, physiological variations among patients were not investigated; thus, it is recommended that future studies include appropriate measurements to rule out the impact of clinical and haemodynamic parameters on anxiety. moreover, prior knowledge of a coronary angiography procedure—for example, gleaned from the internet or based on the experiences of friends or family members—may have influenced feelings of anxiety among the participants, regardless of intervention type. future research should seek to determine baseline levels of knowledge of the procedure prior to ascertaining anxiety levels. conclusion this study found that peer-facilitated, video-based and combined peer-and-video training were equally effective in reducing anxiety among patients undergoing coronary angiography in comparison to a control group. such methods are therefore recommended and may be incorporated as part of routine pre-angiography clinical care in iranian hospitals in order to reduce patient anxiety. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g this study was funded with the aid of a grant from the urmia university of medical sciences (grant #ir. umsu.rec.1395.21). references 1. nekouei zk, yousefy a, manshaee g, nikneshan s. comparing anxiety in cardiac patient candidate for angiography with normal population. arya atherosclerosis 2011; 7:93–6. 2. munk ps, isaksen k, brønnick k, kurz mw, butt n, larsen ai. symptoms of anxiety and depression after percutaneous coronary intervention are associated with decreased heart rate variability, impaired endothelial function and increased inflammation. int j cardiol 2012; 28:173–6. doi: 10.1016/j.ijcard.2012.04.085. 3. homeyra t, soghra h, homeyra a, hadi d. trait anxiety and state anxiety before coronary angiography. j health breeze fam health 2012; 1:41–6. 4. buzatto ll, zanei ss. patients’ anxiety before cardiac catheterization. einstein (sao paulo) 2010; 8:483–7. doi: 10.1590/s167945082010rw1517. 5. abollahzadeh f, moghaddasian s, rahmani a, shahmar m. effect of video education in native language on the anxiety level of patients undergoing coronary angiography. qom univ med sci j 2015; 8:53–60. 6. varaei s, shamsizadeh m, cheraghi ma, talebi m, dehghani a, abbasi a. effects of a peer education on cardiac self-efficacy and readmissions in patients undergoing coronary artery bypass graft surgery: a randomized-controlled trial. nursing crit care 2014; 1:19–28. doi: 10.1111/nicc.12118. 7. jamshidi n, abbaszadeh a, kalyani mn. comparison of video & verbal education on satisfaction and post operative complications of patients undergoing coronary angiography. j fasa univ med sci 2012; 1:233–7. 8. doğan mv, şenturan l. the effect of music therapy on the level of anxiety in the patients undergoing coronary angiography. open j nurs 2012; 2:165–9. doi: 10.4236/ojn.2012.23025. 9. varaei sh, cheraghi ma, seyedfatemi n, talebi m, bahrani n, dehghani a, et al. effect of peer education on anxiety in patients candidated for coronary artery bypass graft surgery: a randomized control trial. j nurs educ 2013; 2:28–37. 10. corones k, coyer fm, theobald ka. exploring the information needs of patients who have undergone pci. br j card nurs 2009; 4:123–30. doi: 10.12968/bjca.2009.4.3.40047. 11. fortinash km, holoday worret pa. psychiatric mental health nursing, 5th ed. maryland heights, missouri, usa: mosby, 2011. pp. 59–86. 12. price n, knibbs s. how effective is peer education in addressing young people’s sexual and reproductive health needs in developing countries? child soc 2009; 23:291–302. doi: 10.1111/j.1099-0860. 2008.00175.x. 13. jamshidi n, abbaszadeh a, kalyani mn. effects of video inform ation on anxiety, stress and depression of patients undergoing coronary angiography. pak j med sci 2009; 25:901–5. 14. ruffinengo c, versino e, renga g. effectiveness of an informative video on reducing anxiety levels in patients undergoing elective coronarography: an rct. eur j cardiovasc nurs 2009; 8:57–61. doi: 10.1016/j.ejcnurse.2008.04.002. 15. spielberger cd, gorsuch rl, lushene r, vagg pr, jacobs ga. manual for the state-trait anxiety inventory. palo alto, california, usa: consulting psychologists press, 1983. https://doi.org/10.1016/j.ijcard.2012.04.085 https://doi.org/10.1590/s1679-45082010rw1517 https://doi.org/10.1590/s1679-45082010rw1517 https://doi.org/10.1111/nicc.12118 https://doi.org/10.4236/ojn.2012.23025 https://doi.org/10.12968/bjca.2009.4.3.40047 https://doi.org/10.1111/j.1099-0860.2008.00175.x https://doi.org/10.1111/j.1099-0860.2008.00175.x https://doi.org/10.1016/j.ejcnurse.2008.04.002 hosein habibzadeh, zahra d. milan, moloud radfar, leyla alilu and audrey cund clinical and basic research | e67 16. moradi t, adib-hajbaghery m. the effect of a multi-modal preparation package on anxiety in patients undergoing coronary angiography. int cardiovasc res j 2015; 9:10–16. 17. mahram b. [validation of spielberger anxiety test in mashhad]. phd thesis, 1994, tehran university of education, tehran, iran. 18. lundén m, lundgren sm, persson l, lepp m. patients’ feelings and experiences during and after peripheral percutaneous trans luminal angioplasty. radiography (lond) 2015; 21:e9–15. doi: 10.10 16/j.radi.2014.06.006. 19. tame ae, sadeghi r, safari m, esmaeili-douki z. effect of verbal and audio methods of training on pre-surgery anxiety of patients. j qazvin univ med sci 2011; 15:21–5. 20. goodman h, parsons a, davison j, preedy m, peters e, shuldham c, et al. a randomised controlled trial to evaluate a nurse-led programme of support and lifestyle management for patients awaiting cardiac surgery: ‘fit for surgery: fit for life’ study. eur j cardiovasc nurs 2008; 7:189–95. doi: 10.1016/j. ejcnurse.2007.11.001. 21. tou s, tou w, mah d, karatassas a, hewett p. effect of pre operative two-dimensional animation information on perioperative anxiety and knowledge retention in patients undergoing bowel surgery: a randomized pilot study. colorectal dis 2013; 15:e256–65. doi: 10.1111/codi.12152. 22. dehghani a, kermanshahi sm, memarian r, baharlou r. the effect of peer group education on anxiety of patients with multiple sclerosis. iran j med educ 2012; 12:249–57. 23. eslami r, sajadi sa, farsi z. comparing the effect of peer education and orientation tour on the stress of patients candidate for coronary angiography in selected hospital of aja university of medical sciences. j urmia nurs midwifery fac 2015; 12:1119–27. 24. moumeni l, yarandi na, hamid h. comparative study of the effects of education using vcd and booklet in two different times on pre-operative anxiety. iran j nurs 2009; 21:81–93. 25. tol a, shahri pm, shahmirzadi es, mohebbi b, javadinia sa. effect of blended education program on anxiety among orthopedic patients surgery. j nurs educ 2013; 2:1–8. 26. mosavi s, sabzevari s, abbaszadeh a, nakhaee fh. the effect of preparatory face to face education to reduce depression and anxiety in open heart surgery adult patient in shafa hospital in kerman, 2008. iran j nurs res 2011; 6:29–38. 27. najafi m, ahmadi mr, kheiri s, mirzaei zh, erfan a. effect of face-to-face training and pamphlets in reducing anxiety in 7–25 years old clients referred to echocardiography. iran j med educ 2011; 10:1251–6. 28. saki a, bahabadi ah, noghabi aa, mehran a. comparison of face-to-face and electronic education methods on anxiety in patients with acute myocardial infarction. j hayat 2014; 20:6–14. 29. khah ym, abedini a, akbari h, nezhad zm. comparison of different methods of education on reducing the anxiety of patients with myocardial infarction. iran j nurs 2012; 24:36–44. https://doi.org/10.1016/j.radi.2014.06.006 https://doi.org/10.1016/j.radi.2014.06.006 https://doi.org/10.1016/j.ejcnurse.2007.11.001 https://doi.org/10.1016/j.ejcnurse.2007.11.001 https://doi.org/10.1111/codi.12152 the rising cost of healthcare around the world is a source of increasing concern for many governments.1,2 although there are many factors driving this trend at both the national and international levels, every doctor has a responsibility to justify ordering investigations and prescription medications. patient demand and a consumerist approach to healthcare puts pressure on doctors to investigate and prescribe more; however, this may not always be in a patient’s best interests and can lead to overdiagnosis and the development of iatrogenic disease.3,4 the national health service (nhs) in the uk has struggled with these problems for years and doctors working within the nhs—especially in primary care—have become increasingly aware of the predictive value of investigations and the cost-effectiveness of medical treatments.5 in oman, doctors often want to offer, and patients increasingly expect to receive, the latest treatments and investigations. although these are often more expensive, they are not always more effective; to this end, the world health organization (who) runs a programme promoting the rational use of medicines in countries where polypharmacy is a major problem.6 it is important that doctors in training have an appreciation of these financial issues in order to carry forward best medical practices. the uk and omani governments both provide socialised comprehensive national health services to all citizens, free at the point of delivery.7,8 additionally, in both countries, primary care physicians are the gateway to secondary care services and have easy access to blood tests, medical imaging and clinical physiology tests. trainees in department of family medicine & public health, sultan qaboos university hospital, muscat, oman e-mails: robinguthriedavidson@gmail.com and robin@squ.edu.om وصف األدوية والفحوصات عند أطباء الرعاية الصحية األولية يف عمان و اململكة املتحدة روبن ديفيد�شون abstract: objectives: this audit aimed to investigate the use of prescription drugs and investigations by trainee doctors in primary care settings in oman and the uk. methods: this audit took place between february and april 2015. the medical records of consecutive patients seen by five family medicine trainee doctors at a primary care setting in oman were retrospectively reviewed. these data were compared to those gathered from two trainees at a general practice clinic in the uk as well as an experienced general practitioner (gp) who had practiced in both countries. results: the average number of items prescribed per patient was 1.19, 0.43 and 0.24 and the rate of investigations was 20%, 21% and 11% for omani trainees, uk trainees and the gp, respectively. conclusion: this audit suggests that family medicine trainees in oman prescribe almost three times as many drugs as trainees in the uk. the findings also point towards an over-investigation of the relatively young omani patient population. keywords: prescriptions; health resources; primary health care; oman; united kingdom. امللخ�ص: الهدف: يهدف هذا البحث التدقيقي للتحقق من و�شف الأدوية والفحو�ش�ت عند املتدربني من اأطب�ء الرع�ية ال�شحية الأولية يف �شلطنة عم�ن واململكة املتحدة. الطريقة: اأجرى هذا البحث التدقيقي بني فرباير واأبريل من ع�م 2015م, حني مت فح�س ال�شجالت الطبية هذه وقورنت عم�ن. يف الأولية ال�شحية الرع�ية عي�دات يف الأ�رسة طب تخ�ش�س من متدربني اأطب�ء خم�شة ع�جلهم الذين للمر�شى يف املهنة م�ر�س متمر�س طبيب ومن املتحدة, اململكة يف ع�مة طبية بعي�دة اثنني متدربني و�شف�ت من جمعت التي بتلك املعلوم�ت الدولتني. النت�ئج: ك�ن متو�شط عدد الو�شف�ت التي اأعط�ه� الأطب�ء املتدربون يف عم�ن, ويف بريط�ني�, والطبيب املتمر�س لكل مري�س يف عم�ن هي 0.24 و 0.43, 1.19, وك�ن معدل طلب الفحو�ش�ت عند هوؤلء هو %11 و %21, %20, على التوايل. اخلال�شة: اأ�ش�ر هذا البحث التدقيقي اأن متدربي طب الأ�رسة يف عم�ن ي�شفون عددا من الأدوية اأكرث من نظرائهم يف بريط�ني� بنحو ثالث مرات. وي�شري البحث اأي�ش� اإىل الفراط يف طلب فحو�ش�ت للمر�شى العم�نيني ال�شغ�ر ال�شن ن�شبي�. الكلمات املفتاحية: الو�شف�ت الطبية؛ املوارد الطبية؛ الرع�ية ال�شحية الأولية؛ عم�ن؛ اململكة املتحدة. use of prescription drugs and investigations by doctors in primary care settings in oman and the uk robin davidson brief communication sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e487–490, epub. 30 nov 16 submitted 24 may 16 revisions req. 26 jun & 11 aug 16; revisions recd. 22 jul & 15 aug 16 accepted 18 aug 16 doi: 10.18295/squmj.2016.16.04.014 use of prescription drugs and investigations by doctors in primary care settings in oman and the uk e488 | squ medical journal, november 2016, volume 16, issue 4 both countries face similar challenges as they move from the disease-centred and systematic approach of hospital practice to a more patient-centred and focused approach in family medicine. this audit therefore aimed to compare the use of resources (i.e. prescription drugs and investigations) by trainee doctors in primary care settings in oman and the uk. methods this audit was carried out between february and april 2015. a retrospective review was conducted of the medical records of consecutively attending patients in february and march 2015 seen by five final year trainees at the family & community medicine clinic of sultan qaboos university hospital in muscat, oman. as there is no international benchmark for rates of prescription and investigations, these data were compared with those of two trainees from st augustine’s medical practice, bristol, uk, and an experienced general practitioner (gp) who had practised medicine in both oman and the uk. the data from the uk trainees were collected in the same way and during the same time period as that of the omani trainees. for the experienced gp, only data on patients seen in the uk in april 2015 were used in the analysis. the audit examined the number of items prescribed per patient and the percentage of patients who underwent investigations for all three groups. the number and category of drugs prescribed was also analysed. only patients presenting with medical conditions requiring same day consultations were included. data for the three groups were compared using means and 95% confidence intervals (cis). results overall, the records of 347 patients were reviewed, including 102 patients (29%) seen by trainees in oman, 190 patients (55%) seen by trainees in the uk and 55 patients (16%) seen by the experienced gp. the average age of patients seen by the omani trainees was 26.1 years compared to 46.9 years for patients seen by the uk trainees and 47.2 years for patients seen in the uk by the experienced gp. the omani trainees prescribed a mean of 1.19 items per patient (95% ci: 1.02–1.36) compared to 0.43 items per patient (95% ci: 0.34–0.51) prescribed by trainees in the uk and 0.24 items per patient (95% ci: 0.12–0.35) prescribed by the experienced gp [figure 1]. investigations were carried out on 20% of patients (95% ci: 12–27%) seen by trainees in oman compared with 21% of patients (95% ci: 15–27%) seen by trainees in the uk and 11% of patients (95% ci: 2–20%) seen by the experienced gp [figure 2]. figure 3 shows the percentage of drugs prescribed according to drug category for all three groups. figure 1: mean number of items prescribed per patient by five trainee doctors in oman, two trainee doctors in the uk and an experienced general practitioner. the error bars indicate 95% confidence intervals. gp = general practitioner. figure 3: drugs prescribed by category by five trainee doctors in oman, two trainee doctors in the uk and an experienced general practitioner. gp = general practitioner; nsaids = non-steroidal anti-inflammatory drugs; rx = prescriptions; ors = oral rehydration solutions. figure 2: rate of investigations by five trainee doctors in oman, two trainee doctors in the uk and an experienced general practitioner. gp = general practitioner. robin davidson brief communication | e489 discussion as might be expected, the current audit showed that the experienced gp had lower rates of prescriptions and investigations than either group of trainees. there was no significant difference in the rates of investigation between the two groups of trainees in the current audit, although the average age of patients in oman was much lower, which might point to overinvestigation. omani trainees prescribed almost three times as many drugs as uk trainees in the present audit. however, this finding needs to be interpreted with caution; although there are many similarities between primary care settings in oman and the uk, it is important to recognise that prescription charges apply for certain patients or specific drugs in the uk.7 although these fees apply to only approximately 10% of prescriptions, it has led to an expectation that many symptomatic treatments can be purchased over-thecounter by the patient from pharmacies, decreasing the pressure on the physician to prescribe such medications.9 indeed, in the current audit, the majority of items prescribed in oman were symptomatic treatments and most likely prescribed for self-limiting illnesses, while the rates of antibiotic prescribing were similar among all three groups. prescribing rates are collected and reported by the who; however, this includes long-term drugs used in the treatment of chronic diseases and thus cannot be used as an international standard.6 in 1989, hogerzeil et al. reported that the number of drugs prescribed per patient ranged from 1.4–3.8 in developing countries and 1.3–2.2 in developed countries.10 in 2000, kinnersley et al. measured the prescription and investigation practices of gps from 10 nhs practices; the findings indicated that the gps prescribed an average of 0.61 items per patient and carried out investigations for approximately 10% of patients.11 although not the primary objective of this research, this is the only study in the literature that can be regarded as a benchmark to compare with the findings of the current audit [table 1].11 within the arab region, research from iran in 2010 indicated a rate of 3.34 items prescribed per patient, while a study from yemen in the same year reported a rate of 2.65 items prescribed per patient.12,13 however, these data should be only regarded as indicative of possible trends as it is not entirely clear whether these studies were conducted in similar primary care populations.12,13 this audit suggests the overuse of some prescription drugs by omani trainees; moreover, the average age of the patients seen in oman was much lower than that of the uk trainees or the experienced gp, indicating the existence of a younger patient population. further formal comparative studies with larger sample sizes are required to explore the underlying reasons for the apparent over-prescription of certain drugs by trainees in oman. nevertheless, it is important to note that, although the health services available in oman and the uk are similar, there are profound differences in lifestyle and culture. patients’ understanding of health issues and their expectations of treatment are also very different; as such, there may be considerable pressure on young doctors in oman to prescribe and investigate, sometimes inappropriately. there were several limitations to this audit. first, the number of trainees involved was small, as was the number of patients; this is especially true for the number of patients seen by the experienced gp, as senior doctors tend to have fewer same day consultations. second, the data were gathered by individual doctors who manually reviewed the patients they had seen each day; therefore, the data may have been subject to errors and omissions. automatic and electronic data collection systems would be likely to yield more reliable results. table 1: comparison of prescription and investigation practices of trainee doctors in oman and the uk and an experienced general practitioner with an international benchmark number of trainees/gps number of patients seen average age of patient in years mean number of items prescribed per patient rate of investigations uk trainees 2 190 46.9 0.43 21% omani trainees 5 102 26.1 1.19 20% experienced gp* 1 55 47.2 0.24 11% kinnersley et al.11 2000 10 nhs practices 711 30.0 0.61 10% gp = general practitioner; nhs = national health services. *with experience in both oman and the uk. use of prescription drugs and investigations by doctors in primary care settings in oman and the uk e490 | squ medical journal, november 2016, volume 16, issue 4 conclusion this simple audit suggests that family medicine trainees in oman prescribe almost three times more drugs than gp trainees in the uk. additionally, the findings seem to point towards the over-investigation of a much younger patient population in oman. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this audit. a c k n o w l e d g e m e n t s the author is grateful to his colleagues at st augustine’s medical practice for collecting the data on the uk trainees. the author would also like to acknowledge that the experienced gp in the current study is himself. references 1. organisation for economic co-operation and development. focus on health spending: oecd health statistics 2015. from: www.oecd.org/health/health-systems/focus-health-spend ing-2015.pdf accessed: aug 2016. 2. berwick dm, hackbarth ad. eliminating waste in us health care. jama 2012; 307:1513–16. doi: 10.1001/jama.2012.362. 3. fang h, miller n, rizzo j, zeckhauser r. demanding customers: consumerist patients and quality of care. from: www.nber.org/ papers/w14350.pdf accessed: aug 2016. 4. grady d, redberg rf. less is more: how less health care can result in better health. arch intern med 2010; 170:749–50. doi: 10.1001/archinternmed.2010.90. 5. nuffield trust. nhs in numbers. from: www.nuffieldtrust.org. uk/nhs-numbers-0 accessed: aug 2016. 6. world health organization. the pursuit of responsible use of medicines: sharing and learning from country experiences. from: apps.who.int/iris/bitstream/10665/75828/1/who_em p_mar_2012.3_eng.pdf accessed: aug 2016. 7. boyle s. health systems in transition: united kingdom (england) health system review 2011. from: www.euro.who. int/__data/assets/pdf_file/0004/135148/e94836.pdf accessed: aug 2016. 8. world health organization regional health systems observatory. health system profile: oman. from: apps.who. int/medicinedocs/documents/s17304e/s17304e.pdf accessed: aug 2016. 9. health and social care information centre. prescriptions dispensed in the community: england 2004-14. from: www. hscic.gov.uk/catalogue/pub17644/pres-disp-com-eng-200414-rep.pdf accessed: aug 2016. 10. hogerzeil hv, walker gj, sallami ao, fernando g. impact of an essential drugs programme on availability and rational use of drugs. lancet 1989; 1:141–2. doi: 10.1016/s0140-6736 (89)91152-5. 11. kinnersley p, anderson e, parry k, clement j, archard l, turton p, et al. randomised controlled trial of nurse practitioner versus general practitioner care for patients requesting “same day” consultations in primary care. bmj 2000; 320:1043–8. doi: 10.1136/bmj.320.7241.1043. 12. safaeian l, mahdanian a, hashemi-fesharaki m, salami s, kebriaee-zadeh j, sadeghian gh. general physicians and prescribing pattern in isfahan, iran. oman med j 2011; 26:205–6. doi: 10.5001/omj.2011.50. 13. bashrahil ka. indicators of rational drug use and health services in hadramout, yemen. east mediterr health j 2010; 16:151–5. 1department of dermatology, complejo hospitalario de granada, jaén, granada, spain; 2department of internal medicine, hospital santa ana, motril, granada, spain *corresponding author e-mail: ismenios@hotmail.com أورم ليفية جلدية عنقودية متعددة عقب عالج الصدفية الشائعة بدواء يوستكنيوماب ريكاردو رويز-فيالفريدي، مقويل اأنطونيو دياز-مارتنيز، دانيل �سان�سيز-كانو multiple clustered dermatofibromas following ustekinumab treatment for psoriasis vulgaris *ricardo ruiz-villaverde,1 miguel a. díaz-martinez,1 daniel sánchez-cano2 a 24-year-old man with a six-year history of psoriasis vulgaris was referred to the dermatological outpatient clinic of the complejo hospitalario de granada, granada, spain, in 2016 with multiple brownish cutaneous lesions of different sizes in the right gluteal region. no previous injuries, comorbid conditions or use of concomitant medications were reported. the patient had been undergoing treatment for psoriasis vulgaris with 45 mg of ustekinumab every three months over the previous eight months after other methods of treatment had failed, including methotrexate, cyclosporine and narrowband ultraviolet b phototherapy. the ustekinumab treatment had since resulted in good control of the psoriasis vulgaris (psoriasis area and severity index score: 0.8; body surface area: 1; physician global assessment score: 1). however, the gluteal lesions had begun to appear one month after ustekinumab treatment was initiated. a physical examination revealed a total of 17 hyperpigmented nodules and plaques grouped within the right gluteal area ranging from 0.3–2.4 cm in size [figure 1]. a polarised dermoscopy using the dermlite iii dermascope (3gen llc, san juan capistrano, california, usa) revealed a peripheral delicate pigment network and white scar-like patch [figure 2]. a histological examination of a punch biopsy of one of the lesions showed acanthosis and hyperpigmentation of the basal keratinocytes on the epidermis with fibroblastic proliferation without atypia on the reticular dermis [figure 3a]. an immunohistochemical study indicated positivity to vimentin and factor xiiia and negativity to s100 and cluster of differentiation (cd)34 [figures 3b and c]. these findings excluded a diagnosis of dermatofibrosarcoma protuberans and confirmed a diagnosis of multiple dermatofibromas. routine laboratory investigations, including a complete blood count and general biochemistry, hiv, hepatitis b, hepatitis c, autoimmune and thyroid tests, were within normal limits. serological tests were negative for rheumatoid factor and antinuclear antibodies. a purified protein derivative test and interesting medical image sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e375–377, epub. 10 oct 17 submitted 16 may 17 revision req. 1 jun 17; revision recd. 3 jun 17 accepted 15 jun 17 figure 1: photograph of multiple clustered purple-brown plaques in the right gluteal region of a 24-year-old man with psoriasis vulgaris. doi: 10.18295/squmj.2017.17.03.025 multiple clustered dermatofibromas following ustekinumab treatment for psoriasis vulgaris e376 | squ medical journal, august 2017, volume 17, issue 3 case has been reported, the age of onset for most patients with multiple clustered dermatofibromas is between the first and third decade of life.6,7 no reports of metastasis or malignancy have been described so far, even with follow-up periods of up to 20 years.7 in the present case, with regards to the role of ustekinumab, causation cannot be proven; however, a similar case has been described with the biological drug efalizumab.8 moreover, the development of multiple eruptive dermatofibromas in immunomodulated situations could be explained by the inhibition of downregulatory t cells.8–10 systemic lupus erythematosus is the most common underlying disease associated with multiple eruptive dermatofibromas.9 however, it is important to note that the degree of immunosuppression does not seem to correlate with the number of dermatofibromas.11 histologically, the differential diagnosis for multiple clustered dermatofibromas includes dermatofibrosarcomas protuberans, dermatomyofibromas, leiomyomas and, in paediatric cases, plaque-like myofibroblastic tumours. immunostaining with cd34 may be helpful in confirming the diagnosis.12 clinically, the lesions may mimic atypical fibroxanthomas, nodular fasciitis and dermatofibrosis lenticularis disseminata.13 from a therapeutic point of view, a conservative approach is advisable. techniques used with varying success include cryotherapy, intralesional steroids, surgery and phototherapy.13,14 references 1. baraf cs, shapiro l. multiple histiocytomas: report of a case. arch dermatol 1970; 101:588–90. doi: 10.1001/arch derm.1970.04000050092013. 2. dupré a, christol b, martinez d. [multiple clustered histiocytofibroma]. ann dermatol venereol 1984; 111:163–4. 3. gershtenson pc, krunic al, chen hm. multiple clustered dermatofibroma: case report and review of the literature. j cutan pathol 2010; 37:e42–5. doi: 10.1111/j.1600-0560.2009. 01325.x. radiography of the thorax also indicated no anomalies. with the patient’s consent, the decision was made to continue ustekinumab treatment. as the patient refused any surgical or medical treatment, the lesions persisted. comment multiple dermatofibromas are defined as the appearance of at least 15 dermatofibromas in less than a year or 5–8 dermatofibromas within four months.1 dupré et al. first used the term ‘clustered’ in 1984 to refer to the grouping of these lesions in a segmental distribution.2 to date, very few cases of multiple clustered dermatofibromas have been reported in the literature.3 the individual lesions of multiple dermatofibromas are not clinically, histologically or phenotypically different from that of a solitary dermatofibroma.3 multiple clustered dermatofibromas have not been found to be associated with any underlying malignancies, immunosupression, previous trauma or other comorbidities.4 viseux et al. reported a kidney transplant patient who had developed multiple clustered dermatofibromas over the pathway of thrombosed superficial veins.5 although a congenital figure 2: dermoscopy image at x10 magnification showing a peripheral delicate pigment network (arrow) and white scarlike patch (asterisk). figure 3: a: haematoxylin and eosin stain of a punch biopsy at x2 magnification showing a proliferation of spindle cells (arrow) in the dermis and subcutaneous tissue. b: immunohistochemistry stain at x4 magnification showing cells negative for cluster of differentiation (cd)34 (arrow). c: immunohistochemistry stain at x10 magnification showing cells positive for factor xiii (arrow). https://doi.org/10.1001/archderm.1970.04000050092013 https://doi.org/10.1001/archderm.1970.04000050092013 https://doi.org/10.1111/j.1600-0560.2009.01325.x https://doi.org/10.1111/j.1600-0560.2009.01325.x ricardo ruiz-villaverde, miguel a. díaz-martinez and daniel sánchez-cano interesting medical image | e377 4. bhabha fk, magee j, ng sy, grills ce, su j, orchard d. multiple clustered dermatofibroma presenting in a segmental distribution. australas j dermatol 2016; 57:e20–2. doi: 10.1111/ ajd.12257. 5. viseux v, chaby g, agbalika f, luong ms, chatelain d, westeel pf, et al. multiple clustered dermatofibromas on a superficial venous thrombosis in a kidney-transplanted patient. dermatology 2004; 209:156–7. doi: 10.1159/000079603. 6. de unamuno p, carames y, fernandez-lopez e, hernandezmartin a, peña c. congenital multiple clustered dermatofibroma. br j dermatol 2000; 142:1040–3. doi: 10.1046/j.13652133.2000.03494.x. 7. castellanos-gonzález m, rodríguez-peralto jl, zarco c, ortízromero p. [multiple clustered dermatofibromas: an atypical presentation of a common disease]. actas dermosifiliogr 2011; 102:467–8. doi: 10.1016/j.ad.2010.12.003. 8. santos-juanes j, coto-segura p, mallo s, galache c, soto j. multiple eruptive dermatofibromas in a patient receiving efalizumab. dermatology 2008; 216:363. doi: 10.1159/000 117708. 9. caldarola g, bisceglia m, pellicano r. multiple eruptive plaque-like dermatofibromas during anti-tnfα treatment. int j dermatol 2013; 52:638–41. doi: 10.1111/j.1365-4632.20 11.05047.x. 10. zaccaria e, rebora a, rongioletti f. multiple eruptive dermatofibromas and immunosuppression: report of two cases and review of the literature. int j dermatol 2008; 47:723–7. doi: 10.1111/j.1365-4632.2008.03575.x. 11. goldbach h, wanat k, rosenbach m. multiple eruptive dermatofibromas in a patient with sarcoidosis. cutis 2016; 98:e15–19. 12. reynolds h, perry a, satter ek. multiple clustered and focally atrophic dermatofibromas (df). dermatol online j 2014; 20:22612. 13. shaheen b, saldanha g, calonje e, johnston ga. multiple clustered dermatofibromas (fibrous histiocytomas): an atypical clinical variant of dermatofibroma. clin exp dermatol 2014; 39:88–90. doi: 10.1111/ced.12200. 14. soloeta r, yanguas i, saracíbar n, goday jj. [multiple clustered histiocytofibroma: apropos of a case with immunohistochemical study]. ann dermatol venereol 1994; 121:482–4. https://doi.org/10.1111/ajd.12257 https://doi.org/10.1111/ajd.12257 https://doi.org/10.1159/000079603 https://doi.org/10.1046/j.1365-2133.2000.03494.x https://doi.org/10.1046/j.1365-2133.2000.03494.x https://doi.org/10.1016/j.ad.2010.12.003 https://doi.org/10.1159/000117708 https://doi.org/10.1159/000117708 https://doi.org/10.1111/j.1365-4632.2011.05047.x https://doi.org/10.1111/j.1365-4632.2011.05047.x https://doi.org/10.1111/j.1365-4632.2008.03575.x https://doi.org/10.1111/ced.12200 department of neurology, college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia *corresponding author’s e-mail: snmohammadali@iau.edu.sa العالقة بني مستوى السكر الرتاكمي يف الدم ومرض تصلب الشريان السبايت بني املرضى الذين يعانون من السكتة الدماغية احلادة صامية نازي�ص، اأزرا زعفر، ر�شوانة �شهيد، عائ�شة البكر، فهد اأحمد اخلمي�ص، دانة اجلعفري، ماجد العبديل، عبد اهلل ال�شليمان، في�شل عبد العزيز املال abstract: objectives: this study aimed to determine the relationship between glycaemic control and carotid atherosclerotic disease among patients with acute ischaemic stroke (ais). methods: this retrospective crosssectional study took place in the neurology department of king fahad hospital of university, khobar, saudi arabia, from april to october 2017. data were collected from the medical records of 244 patients with a diagnosis of ais confirmed by computed tomography. doppler ultrasounds of the carotid artery were performed to determine the presence of increased carotid intima media thickness (cimt) and plaques. results: significantly higher mean glycated haemoglobin (hba1c) levels were noted in cases with high cimt values (p = 0.002), but not in cases with carotid plaques (p = 0.360). in addition, there was a significant association between diabetes mellitus (dm) and high cimt (p = 0.045), but not with carotid plaques (p = 0.075). finally, while dyslipidaemia and age were independently correlated with high cimt values (p = 0.034 and <0.001, respectively) and carotid plaques (p <0.001 each), no independent relationships were noted in terms of gender and other risk factors like dm, hypertension and smoking (p >0.050 each). conclusion: high hba1c levels were associated with high cimt values, but not with carotid plaques. therefore, hba1c levels may be useful as an indirect marker of the initial stages of carotid artery atherosclerosis. keywords: glycated hemoglobin a1c; diabetes mellitus; carotid intima-media thickness; atherosclerotic plaque; stroke. بني ال�شباتي ال�رسايني ت�شلب ومر�ص الدم يف ال�شكر ن�شبة على ال�شيطرة بني العالقة حتديد ايل الدرا�شة هذه هدفت الهدف: امللخ�ص: الع�شبية الأمرا�ص ق�شم يف رجعي باأثر امل�شتعر�شة الدرا�شة هذه اأجريت الطريقة: احلادة. الدماغية ال�شكتة من يعانون الذين املر�شى يف م�شت�شفى امللك فهد التابع جلامعة الإمام عبد الرحمن بن في�شل، اخلرب، اململكة العربية ال�شعودية، يف الفرتة مابني اأبريل اإىل اأكتوبر مت املقطعية. الأ�شعة بوا�شطة والثابتة احلادة الدماغية بال�شكتة م�شابني مري�شا 244 ل الطبية ال�شجالت من البيانات جمع مت .2017 النتائج: والرت�شبات. ال�شباتي ال�رسيان بطانة �شماكة زيادة وجود لتحديد ال�شباتي ال�رسيان من دوبلر ال�شوتية فوق املوجات اإجراء ،)p= 0.002( لوحظ ارتفاع م�شتوى ال�شكر الرتاكمي يف الدم ب�شكل ملحوظ يف احلالت ذات قيم �شماكة بطانة ال�رسيان ال�شباتي العالية ولكن لي�ص يف احلالت مع تر�شبات ال�رسيان ال�شباتي )p = 0.360(. بالإ�شافة اإىل ذلك، كان هناك ارتباط كبري بني داء ال�شكري وارتفاع �شماكة بطانة ال�رسيان ال�شباتي )p = 0.045(، ولكن لي�ص مع تر�شبات ال�رسيان ال�شباتي )p = 0.075(. واأخريا، يف حني اأن ع�رس �شحميات والرت�شبات التوايل( على ،>0.001 و p = 0.034( العالية ال�شباتي ال�رسيان بطانة �شماكة قيم مع م�شتقل ب�شكل مرتبطان والعمر الدم ال�شباتية )p >0.001 لكل منهما(، مل تالحظ اأي عالقات م�شتقلة من حيث اجلن�ص وعوامل اخلطر الأخرى مثل داء ال�شكري، ارتفاع �شغط الدم والتدخني )p <0.050 لكل منهما(. اخلال�صة: ارتبطت م�شتويات م�شتوى ال�شكر الرتاكمي العالية مع ارتفاع قيم �شماكة بطانة ال�رسيان ال�شباتي، ولكن لي�ص مع تر�شبات ال�رسيان ال�شباتي. لذلك، قد تكون م�شتويات ال�شكر الرتاكمي مفيدة كعالمة غري مبا�رسة للمراحل الأولية من ت�شلب ال�رسايني ال�شباتية. الكلمات املفتاحية: م�شتوى ال�شكر الرتاكمي؛ داءال�شكرى؛ �شماكة بطانة ال�رسيان ال�شباتي؛ تر�شبات ال�رسيان؛ ال�شكتة الدماغية. relationship between glycated haemoglobin and carotid atherosclerotic disease among patients with acute ischaemic stroke *saima nazish, azra zafar, rizwana shahid, aishah albakr, fahd a. alkhamis, danah aljaafari, majed alabdali, abdullah alsulaiman, faisal a. al-mulla clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e311–317, epub. 19 dec 18 submitted 19 nov 17 revisions req. 26 nov 17, 9 jan & 22 feb 18; revisions recd. 3 dec 17, 30 jan & 8 mar 18 accepted 25 mar 18 advances in knowledge the association between glycated haemoglobin (hba1c) and carotid intima-media thickness (cimt) has been studied in different populations. this study demonstrated a relationship between hba1c and cimt in patients with ischaemic stroke. application to patient care the findings of this study may help in the early recognition of carotid artery atherosclerotic disease as well as in the formulation of strategies and guidelines for stroke prevention. however, further clinical research regarding different stroke risk factors would be beneficial. doi: 10.18295/squmj.2018.18.03.008 relationship between glycated haemoglobin and carotid atherosclerotic disease among patients with acute ischaemic stroke e312 | squ medical journal, august 2018, volume 18, issue 3 extracranial carotid artery atherosclerotic disease is an important thromboembolic cause of stroke and a key target in stroke prev ention.1 in addition, growing evidence suggests that carotid atherosclerotic disease is a risk factor for neurocognitive dysfunction.2 approximately 30% of ischaemic strokes are caused by carotid occlusive disease.3 the sensitivity and specificity of a carotid doppler ultrasound—which measures the reduction in carotid dia meter as well as the carotid intima media thick ness (cimt)—is 90–95%, making it highly sensitive for the detection of atherosclerotic plaques.4 according to previous research, cimt increases in patients with diab etes mellitus (dm).5 moreover, raised glycated haemo globin (hba1c) levels are related to the risk of carotid atherosclerotic plaques as well as their subsequent thickening and hardening. such plaque changes are an independent risk factor for stroke, with the risk abruptly increasing at an hba1c level of >7% regardless of a diag nosis of dm.6–8 in addition to predicting overall stroke risk, poor glycaemic control also influences functional outcomes following an ischaemic stroke. recovery largely depends on the intrinsic rewiring and remapping of damaged structures, along with surviving regions. the damage induced by chronically altered glycaemic levels is not limited to the extracranial large vessels but also involves the vascular and neural pathways in the brain.9 the effect of chronic hyperglycaemia-induced metabolic dys function on the structure and function of the cerebrovascular system leads to impaired blood supply to the salvageable penumbra zone through the collateral vessels and increases susceptibility to reperfusion injuries. thus, chronic exposure to abnormally high glycaemic levels may significantly impair reparative neovascularisation and reduce neural circuit functional plasticity.9 the association between hba1c and cimt has been studied in various populations.10,11 in addition, previous studies have analysed the frequency of carotid artery stenosis among patients with stroke as well as those with severe triple vessel coronary artery disease and dm.12,13 choi et al. studied the association between hba1c levels and arterial stiffness and peripheral arterial disease among korean patients with type 2 dm.14 however, there is a lack of local data from saudi arabia analysing the relationship between glycaemic control and carotid atherosclerotic disease. this study therefore aimed to investigate the relationship between elevated hba1c levels and cimt and carotid plaques in ischaemic stroke patients in saudi arabia. this popul ation is susceptible to multiple vascular risk factors as well as a rising prevalence of neurocognitive disorders and stroke, with evidence of both small vessel disease and large vessel occlusion.15,16 methods this retrospective cross-sectional study was carried out in the department of neurology, king fahad hospital of university, khobar, saudi arabia, between april and october 2017. retrospective data were collected from the medical records of 400 adult patients with acute ischaemic stroke (ais) seen at an affiliated hospital between february 2010 and september 2016. as per the guidelines of the world health organization, ais was defined as “rapidly developed clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than of vascular origin”.17 all ais diagnoses were confirmed by cranial computed tomography. patients with isolated transient ischaemic attacks, strokes of card ioembolic aetiology or due to vasculitis syndromes and those with coagulation disorders were excluded. therefore, a final sample of 244 patients with ais were included in the study. high-resolution b-mode carotid doppler ultrasono graphy of each patient was performed by a radiologist using a mylab™ class c® 7 mhz linear transducer (esaote group, genoa, italy), as per international guide lines.18 the cimt was calculated as the mean maximal intima media thickness of each carotid artery measured at both the bifurcation and the internal carotid arteries. a cimt value of >0.8 mm was considered high, as this cut-off value has been found to correlate with vascular risk factors.19,20 a plaque was defined as a localised pro trusion of the internal part of the vessel wall into the lumen with a thickness of >1.5 mm between the intimalumen and media-adventitia interfaces.21 hba1c levels were measured using high-performance liquid chroma tography with a g8 hplc analyser® (tosoh bioscience inc., san francisco, california, usa) as per the national glycohemoglobin standardization program guidelines.22 according to the american diabetes association criteria, dm was defined as either a fasting glucose level of ≥126 mg/dl or an hba1c level of ≥6.5%.23 other risk factors for stroke and carotid artery disease were also noted, such as hypertension (htn), dyslipidaemia and smoking. htn was defined as a systolic or diastolic blood pressure (bp) of >140 mmhg or 90 mmhg, respect ively. dyslipidaemia was defined as a fasting serum cholesterol level of >200 mg/dl, triglyceride level of >150 mg/dl, low-density lipoprotein level of >120 mg/dl and a high-density lipoprotein level of 35–60 mg/dl.24 however, a higher hdl cut-off point (<40mg/dl) was used when assessing cardiac risk in female patients, given the observed incidence of coronary disease in women with comparatively higher hdl-c levels than men.25 saima nazish, azra zafar, rizwana shahid, aishah albakr, fahd a. alkhamis, danah aljaafari, majed alabdali, abdullah alsulaiman and faisal a. al-mulla clinical and basic research | e313 data were analysed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). the results were presented as frequencies and percentages for age, gender, dm, htn, smoking, dyslipidaemia, stroke subtype, high/normal cimt and the presence/absence of carotid plaques and means and standard deviations for age and hba1c level. an independent t-test was used to compare means and a chi-squared test was used to compare categorical variables. a p value of <0.050 was deemed statistically significant. a logistic regression analysis was performed to ascertain the effects of age, gender, htn, dyslipidaemia, smoking and hba1c level on the likelihood of high cimt values and carotid plaques. ethical approval for this study was received from the institutional review board of imam abdulrahman bin faisal university (#irb-2017-01026). table 2: relationship between glycated haemoglobin and carotid intima media thickness and carotid plaques in acute ischaemic stroke patients (n = 244) variable n (%) mean hba1c level in % ± sd p value* cimt in mm >0.8 140 (57.4) 7.8 ± 2.4 0.002 <0.8 104 (42.6) 6.9 ± 1.8 presence of carotid plaques yes 117 (48) 7.5 ± 2.3 0.360 no 127 (52) 7.3 ± 2.2 hba1c = glycated haemoglobin; sd = standard deviation; cimt = car otid intima media thickness. *using an independent sample t-test. table 3: association between carotid intima media thick ness and carotid plaques presence in acute ischaemic stroke patients according to diabetes status (n = 244) variable n (%) p value* diabetic patients (n = 140) non-diabetic patients (n = 104) cimt in mm >0.8 88 (62.9) 52 (50) 0.045 <0.8 52 (37.1) 52 (50) presence of carotid plaques yes 74 (52.9) 43 (41.3) 0.075 no 66 (47.1) 61 (58.7) cimt = carotid intima media thickness. *using a chi-squared test. table 1: demographic and clinical characteristics of acute ischaemic stroke patients according to diabetes status (n = 244) characteristic n (%) total diabetic patients (n = 140) nondiabetic patients (n = 104) gender male 160 (65.6) 93 (66.4) 67 (64.4) female 84 (34.4) 47 (33.6) 37 (35.6) age in years ≤50 74 (30.3) 41 (29.3) 33 (31.7) 51–60 26 (10.7) 19 (13.6) 7 (6.7) 61–70 54 (22.1) 32 (22.9) 22 (21.2) >70 90 (36.9) 48 (34.3) 42 (40.4) mean ± sd 64.3 ± 14.5 64.4 ± 13.5 64.2 ± 15.9 range 26–120 34–98 26–120 risk factors* htn 193 (79.1) 118 (84.3) 75 (72.1) dyslipidaemia 185 (75.8) 118 (84.3) 67 (64.4) smoking 49 (20.1) 32 (22.9) 17 (16.3) htn and dyslipidaemia 144 (59) 93 (66.4) 51 (49) htn and smoking 35 (14.3) 26 (18.6) 9 (8.7) dyslipidaemia and smoking 40 (16.3) 29 (20.7) 11 (10.6) htn, dyslipidaemia and smoking 31 (12.7) 24 (17.1) 7 (6.7) type of stroke laa 113 (46.3) 66 (47.1) 47 (45.2) svd 131 (53.7) 74 (52.9) 57 (54.8) cimt in mm >0.8 140 (57.4) 88 (62.9) 52 (50) <0.8 104 (42.6) 52 (37.1) 52 (50) presence of carotid plaques yes 117 (48) 74 (52.9) 43 (41.3) no 127 (52) 66 (47.1) 61 (58.7) hba1c level in % mean ± sd 7.4 ± 2.2 8.6 ± 2.2 5.7 ± 0.8 range 3.8–14.0 5.0–14.0 3.8–10.0 sd = standard deviation; htn = hypertension; laa = large artery atherosclerosis; svd = small vessel disease; cimt = carotid intima media thickness; hba1c = glycated haemoglobin. *percentages do not add up to 100% as some patients may have had several risk factors. relationship between glycated haemoglobin and carotid atherosclerotic disease among patients with acute ischaemic stroke e314 | squ medical journal, august 2018, volume 18, issue 3 results overall, 244 patients with ais were included in the study. of these, 65.6% were male and the mean age was 64.3 ± 14.5 years. most patients were ≥61 years old (59%). a total of 193 patients were hypertensive (79.1%), 185 had dyslipidaemia (75.8%), 140 were diabetic (57.4%) and 49 were smokers (20.1%). among the diabetics, the prev alence of htn, dyslipidaemia and smoking was 84.3%, 84.3% and 22.9%, respectively. there were 93 patients (66.4%) with both htn and dyslipidaemia, 26 smokers with htn (18.6%) and 29 smokers with dyslipidaemia (20.7%). in 24 cases, all four risk factors were present (17.1%). more than half of the patients (53.7%) had small vessel disease, while 46.3% had large artery atherosclerosis. high cimt values were observed in 140 cases (57.4%), while carotid plaques were present in 117 (48%). mean hba1c levels were higher among diabetic patients comp ared to non-diabetic patients (8.6 ± 2.2% versus 5.7 ± 0.8%) 7.4 ± 2.2% [table 1]. this difference was statistically significant (p <0.001). in addition, mean hba1c levels were significantly higher in patients with high cimt values compared to those with normal cimt values (7.8 ± 2.4% versus 6.9 ± 1.8%; p = 0.002). however, there was no significant difference in the mean hba1c levels of patients with carotid plaques compared to those without (7.5 ± 2.3% versus 7.3 ± 2.2%; p = 0.360) [table 2]. finally, a significant association was observed between the frequency of high cimt values and the presence of dm (62.9% versus 50%; p = 0.045). however, no significant association was found between the frequency of carotid plaques and the presence of dm (52.9% versus 41.3%; p = 0.075) [table 3]. according to the logistic regression analysis, dyslipidaemia (odds ratio [or]: 2.06, confidence interval [ci]: 1.05–4.04; p = 0.034), hba1c levels (or: 0.81, ci: 0.68–0.96; p = 0.019) and age (or: 1.95, ci: 0.87–2.17; p <0.001) were independent predictors of high cimt values. similarly, dyslipidaemia (or: 2.88, ci: 1.30–6.37; p <0.001) and age (or: 1.87, ci: 0.85–2.05; p <0.001) were independently correlated with carotid plaques. however, gender (or: 0.82, ci: 0.44–1.15; p = 0.532), dm (or: 0.78, ci: 0.38–1.60; p = 0.519), htn (or: 1.56, ci: 0.78–3.10; p = 0.205) and smoking (or: 1.92, ci: 0.88–4.15; p = 0.097) were not independently correlated with cimt. similarly, gender (or: 0.72, ci: 0.36–1.45; p = 0.367), hba1c levels (or: 0.97, ci: 0.82–1.16; p = 0.811), dm (or: 1.41, ci: 0.63–3.15; p = 0.401), htn (or: 2.10, ci: 0.92–4.78; p = 0.070) and smoking (or: 1.79, ci: 0.77–4.15; p = 0.170) were not independently correlated with carotid plaques [table 4]. discussion assessing hba1c levels is a useful method of determ ining glucose control. such testing is now recommended not only for diagnosing dm and pre-dm, but also for predicting cardiovascular risk.26 it has been suggested that glucose variability strongly correlates with hba1c levels among elderly male patients with type 2 dm.27 fluctuations in glucose levels can harm the arterial wall due to oxidative stress and endothelial dysfunction.28 furthermore, glycaemic status is strongly associated with all grades of carotid artery disease.29 the risk of major adverse cardiovascular events is significantly higher among type 2 dm patients who have had the disease for a long time and who have advanced carotid artery stenosis.30 b-mode ultrasonography is a noninvasive method of measuring intimal thickness, plaque formation and stenosis in the peripheral arteries. an increase in cimt is an early manifestation of carotid artery atherosclerosis; this is subsequently followed by plaque formation table 4: predictors of carotid intima media thickness and carotid plaques in acute ischaemic stroke patients (n = 244) risk factor high cimt* carotid plaques adjusted or (95% ci) p value adjusted or (95% ci) p value age 1.95 (0.87–2.17) <0.001 1.87 (0.85–2.05) <0.001 gender 0.82 (0.44–1.15) 0.532 0.72 (0.36–1.45) 0.367 dm 0.78 (0.38–1.60) 0.519 1.41 (0.63–3.15) 0.401 htn 1.56 (0.78–3.10) 0.205 2.10 (0.92–4.78) 0.070 dyslipidaemia 2.06 (1.05–4.04) 0.034 2.88 (1.30–6.37) <0.001 smoking 1.92 (0.88–4.15) 0.097 1.79 (0.77–4.15) 0.170 hba1c 0.81 (0.68–0.96) 0.019 0.97 (0.82–1.16) 0.811 hosmer-lemeshow goodness-of-fit 0.08 0.45 cimt = carotid intima-media thickness; or = odds ratio; ci = confidence interval; dm = diabetes mellitus; htn = hypertension; hba1c = glycated haemoglobin. *a cimt value of >0.8 mm. saima nazish, azra zafar, rizwana shahid, aishah albakr, fahd a. alkhamis, danah aljaafari, majed alabdali, abdullah alsulaiman and faisal a. al-mulla clinical and basic research | e315 and then carotid stenosis due to the narrowing of the lumen.29,31 several studies have shown that doppler ultrasonography of the carotid artery can help to predict subsequent major adverse cardiovascular events.31,32 the demographic characteristics of the sample included in the present study were similar to those of previous research concerning ischaemic stroke patients. in accordance with other studies conducted in the gulf region, the majority of patients were male.16,33 critically, 30.3% of cases were under 50 years of age, indicating a relatively young age of stroke onset. dyslipidaemia was the second most frequent risk factor; however, this finding requires further verification with populationbased prospective studies. the prevalence of dm in the current study was slightly lower than reported in a previous study of ais patients in khobar (57.4% versus 62.7%).16 the mean hba1c level was comparable to that reported by singh et al. among stroke patients in india (7.4 ± 2.2% versus 7.51 ± 1.75%).20 in the current study, high cimt values and carotid artery plaques were present in 57.4% and 48% of cases, respectively. the relation between hba1c levels and cimt and carotid plaques has been addressed in several studies. saha et al. found that the prevalence of high cimt in stroke patients was ≈71%.34 singh et al. noted high hba1c concentrations in ischaemic stroke patients with high cimt values and carotid plaque while lee et al. noted an increase in cimt and plaque formation among ischaemic stroke patients with dm.20,35 the present study similarly found that hba1c level—as a reflection of poor glycaemic control—was significantly higher among ais patients with high cimt values. in contrast, hba1c level was not significantly associated with carotid plaques. this might be due to the high freq uency of htn and dyslipidaemia in the sample which may have confounded the results. according to a logistic regression analysis, dyslip idaemia was an independent risk factor for both high cimt and plaque formation in the current study. carotid plaque formation is thought to be multifactorial. cardoso et al. reported that type 2 dm, advanced age, being male, smoking and ambulatory bp (particularly night-time pulse pressure) were the main independent predictors of atherosclerosis.36 in another study, kowall et al. concluded that cimt is highly dependent on traditional cardiovascular risk factors; however, the association between blood glucose levels and cimt disappears after risk factor adjustment.37 the present study was subject to certain limitations. first, as the study was retrospective, the exact duration of dm and increased hba1c levels could not be establ ished. second, some of the patients had multiple risk factors which can confound associations. performing a risk factor adjustment would therefore have strengthened the results. third, data regarding bp variability—which affects stroke outcomes in carotid artery occlusion and is an important predictor of carotid artery disease—were lacking.38,39 finally, although doppler ultrasonography has high sensitivity, there is nevertheless a risk of operatordependent variability. conclusion among the studied sample of ais patients, high hba1c levels were significantly associated with high cimt values, but not with carotid plaques. accordingly, hba1c may be beneficial as an indirect marker of the initial stages of carotid artery atherosclerosis. further clinical studies adjusting for risk factors are recommended to determine the true relationship between glycaemic control and carotid artery disease. a c k n o w l e d g e m e n t s this study made use of the computational resources and technical services of the scientific & high performance computing center at imam abdulrahman bin faisal university. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. eliasziw m, kennedy j, hill md, buchan am, barnett hj; north american symptomatic carotid endarterectomy trial group. early risk of stroke after a transient ischemic attack in patients with internal carotid artery disease. cmaj 2004; 170:1105–9. doi: 10.1503/cmaj.1030460. 2. lattanzi s, carbonari l, pagliariccio g, bartolini m, cagnetti c, viticchi g, et al. neurocognitive functioning and cerebrovascular reactivity after carotid endarterectomy. neurology 2018; 90:e307–15. doi: 10.1212/wnl.0000000000004862. 3. strickman ne, loyalka p. carotid artery stenosis: an endovascular specialist’s perspective. tex heart inst j 2005; 32:318–22. 4. jahromi as, cinà cs, liu y, clase cm. sensitivity and spec ificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and meta-analysis. j vasc surg 2005; 41:962–72. doi: 10.1016/j.jvs.20 05.02.044. 5. cheng ks, mikhailidis dp, hamilton g, seifalian am. a review of the carotid and femoral intima-media thickness as an indic ator of the presence of peripheral vascular disease and cardiovascular risk factors. cardiovasc res 2002; 54:528–38. doi: 10.10 16/s0008-6363(01)00551-x. 6. jørgensen l, jenssen t, joakimsen o, heuch i, ingebretsen oc, jacobson bk. glycated hemoglobin level is strongly related to the prevalence of carotid artery plaques with high echogenicity in nondiabetic individuals: the tromsø study. circulation 2004; 110:466–70. doi: 10.1161/01.cir.0000136809.55141.3b. https://doi.org/10.1503/cmaj.1030460 https://doi.org/10.1212/wnl.0000000000004862 https://doi.org/10.1016/j.jvs.2005.02.044 https://doi.org/10.1016/j.jvs.2005.02.044 https://doi.org/10.1016/s0008-6363%2801%2900551-x https://doi.org/10.1016/s0008-6363%2801%2900551-x https://doi.org/10.1161/01.cir.0000136809.55141.3b relationship between glycated haemoglobin and carotid atherosclerotic disease among patients with acute ischaemic stroke e316 | squ medical journal, august 2018, volume 18, issue 3 7. syed ia, khan wa. glycated haemoglobin: a marker and predictor of cardiovascular disease. j pak med assoc 2011; 61:690–5. 8. myint pk, sinha s, wareham nj, bingham sa, luben rn, welch aa, et al. glycated hemoglobin and risk of stroke in peo ple without known diabetes in the european prospective investigation into cancer (epic)-norfolk prospective population study: a threshold relationship? stroke 2007; 38:271–5. doi: 10.11 61/01.str.0000254549.75763.5f. 9. lattanzi s, bartolini m, provinciali l, silvestrini m. glycosylated hemoglobin and functional outcome after acute ischemic stroke. j stroke cerebrovasc dis 2016; 25:1786–91. doi: 10.1016/j. jstrokecerebrovasdis.2016.03.018. 10. hung cs, lee pc, li hy, ma wy, lin ms, wei jn, et al. haemoglobin a1c is associated with carotid intima-media thickness in a chinese population. clin endocrinol (oxf ) 2011; 75:780–5. doi: 10.1111/j.1365-2265.2011.04129.x. 11. saba l, ikeda n, deidda m, araki t, molinari f, meiburger km, et al. association of automated carotid imt measurement and hba1c in japanese patients with coronary artery disease. diabetes res clin pract 2013; 100:348–53. doi: 10.1016/j.diabres.2013.03.032. 12. shaikh na, bhatty s, irfan m, khatri g, vaswani as, jakhrani n. requency, characteristics and risk factors of carotid artery stenosis in ischaemic stroke patients at civil hospital karachi. j pak med assoc 2010; 60:8–12. 13. gill bu, saleemi s, abbas t, qureshi ba, bukhari ni. frequency of severe carotid artery stenosis in diabetic patients having triple vessel coronary artery disease. pak heart j 2013; 46:133–8. 14. choi sw, shin mh, yun wj, kim hy, lee yh, kweon ss, et al. association between hemoglobin a1c, carotid atherosclerosis, arterial stiffness, and peripheral arterial disease in korean type 2 diabetic patients. j diabetes complications 2011; 25:7–13. doi: 10.1016/j.jdiacomp.2009.12.001. 15. alkhunizan, m, alkhenizan a, basudan l. prevalence of mild cognitive impairment and dementia in saudi arabia: a community-based study. dement geriatr cogn dis extra 2018; 8:98–103. doi: 10.1159/000487231. 16. zafar a, al-khamis fa, al-bakr ai, alsulaiman aa, msmar ah. risk factors and subtypes of acute ischemic stroke. a study at king fahd hospital of the university. neurosciences (riyadh) 2016; 21:246–51. doi: 10.17712/nsj.2016.3.20150731. 17. aho k, harmsen p, hatano s, marquardsen j, smirnov ve, strasser t. cerebrovascular disease in the community: results of a who collaborative study. bull world health organ 1980; 58:113–30. 18. touboul pj, hennerici mg, meairs s, adams h, amarenco p, bornstein n, et al. mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011): an update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th european stroke conferences, mannheim, germany, 2004, brussels, belgium, 2006, and hamburg, germany, 2011. cerebrovasc dis 2012; 34:290–6. doi: 10.1159/000343145. 19. hansa g, bhargava k, bansal m, tandon s, kasliwal rr. carotid intima-media thickness and coronary artery disease: an indian perspective. asian cardiovasc thorac ann 2003; 11:217–21. doi: 10.11 77/021849230301100308. 20. singh as, atam v, chaudhary sc, sawlani kk, patel ml, saraf s, et al. relation of glycated hemoglobin with carotid atherosclerosis in ischemic stroke patients: an observational study in indian population. ann indian acad neurol 2013; 16:185–9. doi: 10.4103/0972-2327.112462. 21. stein jh, korcarz ce, hurst rt, lonn e, kendall cb, mohler er, et al. use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the american society of echocardiography car otid intima-media thickness task force endorsed by the society for vascular medicine. j am soc echocardiogr 2008; 21:93–111. doi: 10.1016/j.echo.2007.11.011. 22. national glycohemoglobin standardization program. list of ngsp certified methods. from: www.ngsp.org/docs/methods. pdf accessed: mar 2018. 23. american diabetes association. classification and diagnosis of diabetes. diabetes care 2016; 39:s13–22. doi: 10.2337/dc16-s005. 24. expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. executive summary of the third report of the national cholesterol education program (ncep) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel iii). jama 2001; 285:2486–97. doi: 10.1001/jama.285.19.2486. 25. eapen dj, kalra gl, rifai l, eapen ca, merchant n, khan bv. raising hdl cholesterol in women. int j womens health 2010; 1:181–91. doi: 10.2147/ijwh.s5110. 26. di pino a, scicali r, calanna s, urbano f, mantegna c, rabuazzo am, et al. cardiovascular risk profile in subjects with prediabetes and new-onset type 2 diabetes identified by hba (1c) according to american diabetes association criteria. diab etes care 2014; 37:1447–53. doi: 10.2337/dc13-2357. 27. fang fs, li zb, li cl, tian h, li j, cheng xl. influence of glycemic variability on the hba1c level in elderly male patients with type 2 diabetes. intern med 2012; 51:3109–13. doi: 10.2169/ internalmedicine.51.8077. 28. ceriello a, esposito k, piconi l, ihnat ma, thorpe je, testa r, et al. oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. diabetes 2008; 57:1349–54. doi: 10.23 37/db08-0063. 29. mostaza jm, lahoz c, salinero-fort ma, de burgos-lunar c, laguna f, estirado e, et al. carotid atherosclerosis severity in relation to glycemic status: a cross-sectional population study. atherosclerosis 2015; 242:377–82. doi: 10.1016/j.atherosclero sis.2015.07.028. 30. noh m, kwon h, jung ch, kwon su, kim ms, lee wj, et al. impact of diabetes duration and degree of carotid artery stenosis on major adverse cardiovascular events: a single center, retrospective, observational cohort study. cardiovasc diabetol 2017; 16:74. doi: 10.1186/s12933-017-0556-0. 31. meschia jf, bushnell c, boden-albala b, braun lt, bravata dm, chaturvedi s, et al. guidelines for the primary prevention of stroke: a statement for healthcare professionals from the amer ican heart association/american stroke association. stroke 2014; 45:3754–832. doi: 10.1161/str.0000000000000046. 32. o’leary dh, polak jf, kronmal ra, manolio ta, burke gl, wolfson sk jr. carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: cardiovascular health study collaborative research group. n engl j med 1999; 340:14–22. doi: 10.1056/nejm1999010734 00103. 33. deleu d, inshasi j, akhtar n, ali j, vurgese t, ali s, et al. risk factors, management and outcome of subtypes of ischemic stroke: a stroke registry from the arabian gulf. j neurol sci 2011; 300:142–7. doi: 10.1016/j.jns.2010.08.023. 34. saha a, sinha pk, paul r, bandyopadhyay r, biswas k, banerjee ak. study of carotid intima media thickness and its correlation with novel risk factors in ischemic stroke. neurol asia 2011; 16:25–31. 35. lee ej, kim hj, bae jm, kim jc, han hj, park cs, et al. relevance of common carotid intima-media thickness and carotid plaque as risk factors for ischemic stroke in patients with type 2 diabetes mellitus. ajnr am j neuroradiol 2007; 28:916–19. 36. cardoso cr, marques ce, leite nc, salles gf. factors associated with carotid intima-media thickness and carotid plaques in type 2 diabetic patients. j hypertens 2012; 30:940–7. doi: 10.10 97/hjh.0b013e328352aba6. 37. kowall b, ebert n, then c, thiery j, koenig w, meisinger c, et al. associations between blood glucose and carotid intimamedia thickness disappear after adjustment for shared risk fac tors: the kora f4 study. plos one 2012; 7:e52590. doi: 10.13 71/journal.pone.0052590. https://doi.org/10.1161/01.str.0000254549.75763.5f https://doi.org/10.1161/01.str.0000254549.75763.5f https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.018 https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.018 https://doi.org/10.1111/j.1365-2265.2011.04129.x https://doi.org/10.1016/j.diabres.2013.03.032 https://doi.org/10.1016/j.jdiacomp.2009.12.001 https://doi.org/10.1159/000487231 https://doi.org/10.17712/nsj.2016.3.20150731 https://doi.org/10.1159/000343145 https://doi.org/10.1177/021849230301100308 https://doi.org/10.1177/021849230301100308 https://doi.org/10.4103/0972-2327.112462 https://doi.org/10.1016/j.echo.2007.11.011 https://doi.org/10.2337/dc16-s005 https://doi.org/10.1001/jama.285.19.2486 https://doi.org/10.2147/ijwh.s5110 https://doi.org/10.2337/dc13-2357 https://doi.org/10.2169/internalmedicine.51.8077 https://doi.org/10.2169/internalmedicine.51.8077 https://doi.org/10.2337/db08-0063 https://doi.org/10.2337/db08-0063 https://doi.org/10.1016/j.atherosclerosis.2015.07.028 https://doi.org/10.1016/j.atherosclerosis.2015.07.028 https://doi.org/10.1186/s12933-017-0556-0 https://doi.org/10.1161/str.0000000000000046 https://doi.org/10.1056/nejm199901073400103 https://doi.org/10.1056/nejm199901073400103 https://doi.org/10.1016/j.jns.2010.08.023 https://doi.org/10.1097/hjh.0b013e328352aba6 https://doi.org/10.1097/hjh.0b013e328352aba6 https://doi.org/10.1371/journal.pone.0052590 https://doi.org/10.1371/journal.pone.0052590 saima nazish, azra zafar, rizwana shahid, aishah albakr, fahd a. alkhamis, danah aljaafari, majed alabdali, abdullah alsulaiman and faisal a. al-mulla clinical and basic research | e317 38. buratti l, cagnetti c, balucani c, viticchi g, falsetti l, luzzi s, et al. blood pressure variability and stroke outcome in patients with internal carotid artery occlusion. j neurol sci 2014; 339:164–8. doi: 10.1016/j.jns.2014.02.007. 39. manning ls, rothwell pm, potter jf, robinson tg. prognostic significance of short-term blood pressure variability in acute stroke: systematic review. stroke 2015; 46:2482–90. doi: 10.1161/ strokeaha.115.010075. https://doi.org/10.1016/j.jns.2014.02.007 https://doi.org/10.1161/strokeaha.115.010075 https://doi.org/10.1161/strokeaha.115.010075 1rehabilitation research center, department of orthotics & prosthetics, school of rehabilitation sciences, iran university of medical sciences, tehran, iran; 2department of mechanical engineering, sharif university of technology, tehran, iran; 3department of biomechanics, djavad mowafaghian research centre of intelligent neuro-rehabilitation technologies, tehran, iran *corresponding author’s e-mail: saeedi.h@iums.ac.ir تصميم وتنفيذ واختبار منوذج جديد ملفصل اصطناعي للركبة مع درجيت حرية حركة يف مريض مصاب بالتهاب مفصل الركبة �شيامك اآقاجاين ف�شاركي، فرزام فرهمند، ح�شن �شعيدي، اإح�شان عبدالهي abstract: knee braces are a conservative treatment option for patients with knee osteoarthritis (koa). however, no commercially available orthotic knee joint currently reflects natural knee movements. a prototype orthotic knee joint with two degrees of freedom (dof) in the sagittal and transverse planes was developed to more closely simulate the natural motion of the knee joint. the prototype was tested on a male subject with medial koa during a sit-to-stand task. the efficacy of the transverse plane dof was assessed by comparing the limb-orthosis interaction force when the transverse plane was locked to mimic a one-dof setting versus when it was unlocked. unlocking the transverse plane eliminated the 45-newton shearing force produced with the one-dof setting at wide angles of flexion. the two-dof orthotic knee joint prototype demonstrated greater conformity to natural knee movements, allowing the wearer to better tolerate bracing-related difficulties. keywords: knee joint; knee osteoarthritis; orthotic devices; braces; rotation; movement; materials testing. امللخ�ص: دعامة الركبة هي خيار عالجي حمافظ للمر�شى الذين يعانون من التهاب مف�شل الركبة. ومع ذلك، ل يوجد اأي جهاز تقوميي ملف�شل ركبة متوفر جتاريا يف الوقت احلايل يوفر حركات الركبة الطبيعية. مت تطوير منوذج جديد لداعم تقوميي للركبة مع درجتي حرية حركة يف امل�شتوىين ال�شهمّي و العر�شي من اأجل حماكاة احلركة الطبيعية ملف�شل الركبة ب�شكل اأكرث قرًبا. مت اختبار النموذج الأويل على ذكر مري�س م�شاب بالتهاب مف�شل الركبة الأن�شي خالل احلركة الطبيعية للوقوف من و�شع اجللو�س. مت تقييم فعالية احلركة يف امل�شتوى العر�شي من خالل مقارنة قوة تفاعل اأطراف الأطراف عندما مت قفل امل�شتوى العر�شي لتقليد احلركة الطبيعية ملف�شل الركبة عند الفتح واإلأغالق. فتح امل�شتوى العر�شي األغى قوة الق�س 45 نيوتن املنتجة باإعداد جمال حركي واحد يف زوايا انثناء وا�شعة. اأظهر النموذج ثنائي احلركة للداعم التقوميي للركبة قدًرا اأكرب من التوافق مع حركات الركبة الطبيعية، مما اأتاح ملرتديه اأن يتحملوا ب�شكل اأف�شل ال�شعوبات املتعلقة باحلركة. الكلمات املفتاحية: مف�شل الركبة؛ التهاب مف�شل الركبة؛ اأجهزة تقومي العظام؛ اأجهزة داعمة؛ داعمدوران؛ حركة؛ اختبار املواد. design, implementation and testing of a novel prototype orthotic knee joint with two degrees of freedom in a patient with medial knee osteoarthritis siamak aghajani-fesharaki,1 farzam farahmand,2 *hassan saeedi,1 ehsan abdollahy3 technical note sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e524–528, epub. 28 mar 19 submitted 28 apr 18 revision req. 12 jun 18; revision recd. 11 jul 18 accepted 2 aug 18 doi: 10.18295/squmj.2018.18.04.016 knee braces are a conservative treat-ment option for patients with medial knee osteoarthritis (koa).1–3 nevertheless, despite the positive effects of various types of knee braces, they limit the motion of the joint in all directions.4,5 this is partly due to the structural design of these orthotic devices, which generally follow simpler kinematic path ways than those of the natural anatomic knee joint. this mismatch can result in the pistoning of the brace components over the lower limb, constraining the wearer’s normal range of motion with the subsequent distal move ment and potentially leading to misalignment of the brace and uncomfortable pressure on the skin.6 furthermore, axial misalignment causes unnecessary reaction forces at skin and joint attachment points, resulting in discom fort and even outright injury.7 currently available orthotic knee joints, including both single-axis or polycentric devices, have one degree of freedom (dof) in the sagittal plane and therefore can only mimic the range of flexion and extension of the anatomic knee, thus restricting the joint’s natural move ment.8,9 as such, the incorporation of an additional dof in the transverse plane would allow the brace to more closely imitate the natural motion of the knee by allowing internal and external rotation. to the best of the authors’ knowledge, no commercially available orthotic knee joint with more than one dof is currently available.8,9 as such, a prototype orth siamak aghajani-fesharaki, farzam farahmand, hassan saeedi and ehsan abdollahy technical note | e525 otic knee joint was developed with two dof in both the sagittal (i.e. flexion/extension) and transverse (i.e. internal/external rotation) planes. the prototype was tested to determine its efficacy in more closely simulating the natural motion of the knee joint by assessing the limb-orthosis interaction force when the transverse plane dof was locked versus when it was unlocked. methods the first step in developing the two-dof orthotic knee joint prototype involved sketching potential designs in order to choose a realistic option for bracing the knee joint. secondly, currently available polycentric knee joints were examined, modified and tested following the addition of a rotary component. a computer-aided design was then created digitally using solidworks®, version 5 (dassault systèmes, paris, france) and catia™ software, version 5 (dassault systèmes). this allowed for more detailed conceptual input and to assess whether the orthotic knee joint could be manufactured. the design and construction of the prototype was performed concurrently in the djavad mowafaghian research center of intelligent neuro-rehabilitation technologies and the department of orthotics & prosthetics of the iran university of medical sciences, tehran, iran. the final design of the prototype consisted of a polycentric hinge with a hyperextension stop to allow flexion/extension and a drawer joint above the polycentric hinge for transverse rotation [figures 1a and b]. the transverse plane motion of the drawer joint could be locked by a screw and plate, hindering the joint’s movement in the transverse plane and mimicking one dof products currently available in the market.8,9 when unscrewed and detached, the joint was released and the device returned to its original two-dof configuration [figure 1c]. overall, the range of motion of the prototype in the sagittal and transverse planes was 140 and 20 degrees, respectively [table 1]. the drawer joint measured 60 × 47 × 15 mm, weighed 300 g and was made from stainless steel. the aluminium sidebars (20 × 5 mm) attached proximally to the drawer joint as femoral components and distally to the polycentric hinge as tibial components. the hinge was mediolaterally attached to a knee brace consisting of white copolymer polypropylene and 4-mm-thick anterior thigh and tibial shells lined with a 5-mmthick ethylene vinyl acetate (eva) copolymer closed cell foam for comfort. four 5-mm-wide nylon straps with hook and loop closures were attached around the outside of the device to allow the wearer to adjust the fit. each strap had a protective pad made from a 5-mmthick eva copolymerclosed cell foam positioned to protect the posterior leg skin [figures 1d–f]. subsequently, the testing phase was initiated to assess the performance of the prototype. a 45-year-old male subject with grade ii medial koa according to kellgren and lawrence classifications was recruited to perform a sit-to-stand task.10 briefly, the subject was asked to rise from sitting in a chair and, after a short pause, sit down again without support at a self-selected speed. the chair had no arms and was adjusted to the subject’s height to ensure that the thighs lay parallel figure 1: computer-aided designs (cads) and photographs of a novel prototype orthotic knee joint with two degrees of freedom. a: cad showing the polycentric hinge (red arrow) and drawer joint (yellow arrow) in a neutral position. b: cad showing the joint components in a flexed and rotated position in the sagittal and transverse planes, respectively. c: cad showing the position of the upper (red arrow) and lower (yellow arrow) joint components and miniature tension load cell (arrowhead). the transverse plane motion of the drawer joint could be locked and unlocked using a screw and plate (asterisk). d–f: photographs of the (d) anterior, (e) medial and (f) posterior views of the prototype. design, implementation and testing of a novel prototype orthotic knee joint with two degrees of freedom in a patient with medial knee osteoarthritis e526 | squ medical journal, november 2018, volume 18, issue 4 to the seat when the subject was in a sitting position. the feet were kept parallel to one another on the ground while the arms were placed against the chest. a mini ature tension load cell (umma® 100 kg-force model, dacell co. ltd., nami-myeon, cheongwon-gun, south korea) was used to measure the interactive shearing force between the limb and orthosis in the shell area during knee joint motions. the load cell was embedded between the posterior aspect of the orthotic joint in the medial side and the detachable aluminium plate [figure 1c]. in order to measure the angle of knee flexion at the moment of lowest and highest interactive shearing force between the limb and orthosis, an incremental rotary encoder (e30s series, autonics co. ltd., busan, south korea) allowing 1,000 pulses/ revolution was installed co-axially at the centre of the orthotic joint on the lateral side. after three practice sit-to-stand trials, the mean values were calculated for the final analysis. the output signal of the miniature tension load cell was filtered through a low pass filter and amplified 1,000 times using a dn-am100® dynamic load cell amplifier (dacell co. ltd.). the amplified voltage was then digitised using a 3.3-v 84-mhz arduino du e® arm core data acquisition board (arduino, turin, italy). the microcontroller in the data acquisition board was programmed with custom software and the recorded data were uploaded to a computer from a secure digital card. the results were input into an excel spreadsheet, version 2013 (microsoft corp., redmond, washington, usa) and presented in the form of a line chart. all procedures and components involved in the design, implementation and testing of the prototype were approved by the ethics committee of the iran university of medical sciences (#92-11-50-3209). voluntary informed consent was provided by the subject prior to the testing of the prototype. results when the transverse plane of the orthotic knee joint was locked (i.e. providing only one dof), the orthotic joint only partially mimicked the path of the anatomic knee during the sit-to-stand task, allowing only flexion and extension movement. furthermore, the miniature tension load cell mounted behind the joint detected a mean shearing force load of 45 newtons (n) between the limb and orthosis in the shell area when the subject sat down and flexed his knee to approximately 90 degrees. the amount of force increased as the flexion angle exceeded 40 degrees, with the maximum amount of force occurring in the final phase of the sitting movetable 1: manufacturing characteristics of a novel prototype orthotic knee joint with two degrees of freedom characteristic measurement aluminium polycentric hinge weight in g 100 height in mm 50 width in mm 33 thickness in mm 18 range of motion in degrees 140 stainless steel drawer joint weight in g 300 height in mm 47 width in mm 60 thickness in mm 15 range of motion in degrees 20 aluminium sidebars thickness in mm 5 width in mm 20 figure 2: line graph showing the interactive shearing force load between the limb and orthosis in the shell area during a sit-to-stand task using a novel prototype orthotic knee joint with two degrees of freedom (dof) compared to one dof alone. n = newtons; dof = degrees of freedom. siamak aghajani-fesharaki, farzam farahmand, hassan saeedi and ehsan abdollahy technical note | e527 ment, when the knees were flexed at approximately 90 degrees. this interactive shearing force was transmitted through the sidebars into the orthotic joint. however, when the task was repeated with the transverse plane unlocked (i.e. providing two dof), the orthotic joint was able to more closely mimic natural knee joint movements. in addition, the miniature tension load cell detected almost no load when the subject sat down and flexed his knee to approximately 90 degrees [figure 2]. the subject also declared that he was more comfortable while seated when the transverse plane was unlocked. the maximum displacement of the rotary part of the orthotic joint in the transverse plane (i.e. the drawer joint) between the two sliding components was 15 mm. this occurred just after the subject had begun to sit down from a standing position [figure 3]. discussion patients often report discomfort, poor fit and skin irrit ation as reasons for poor compliance with or discontinuation of the use of knee braces.11,12 furthermore, previous research indicates that koa patients wear their braces for less than four hours a day.13,14 there is therefore a need to redesign knee orthotic devices in order to increase wear time, more closely mimic natural movement and reduce patient discomfort.12 accordingly, a novel prototype orthotic knee joint with two dof in both the sagittal and transverse planes was designed and tested on a subject with medial koa. when the transverse plane of the two-dof proto type was locked into a one-dof setting, the mounted load cell behind the joint detected a mean shearing force load of 45 n. this could be due to mismatch between the movement of the orthotic and anatomic joints as the orthosis attempted to force the knee to follow a simplified movement pattern, thereby preventing natural rotary motion. as a result, unwanted constraint force (i.e. interactive shear force) was generated between the orthosis and the limb in contact areas. as the flexion angle exceeded 40 degrees, the amount of force increased. the maximum amount of force was recorded in the very last phase of movement into a seated position, when the subject flexed his knees to approximately 90 degrees. this is understandable consid ering that the limb volume increases as the knee joint moves into deep flexion.15 in other words, as the motion of the orthotic joint does not accurately reflect natural knee kinematics, the tightly fitting interface magnifies the pistoning constraint, leading to a high load. however, when the transverse plane of the prototype was unlocked to allow two dof, there were fewer limitations in the path of the anatomic knee joint. as such, the subject was able to both flex and rotate his knee, allowing for a much freer range of motion. the internal and external rotation decreased the extra shearing force between the limb and orthosis, resulting in increased comfort for the wearer when sitting and standing, which are movements which require deep flexion and among the most routinely practiced activities in daily living.16 conclusion a novel prototype orthotic knee joint with two dof was designed to more accurately reflect natural knee movements by allowing motion in both the sagittal and transverse planes. when compared with the one-dof setting, the two-dof mechanism allowed the subject to move his knee more freely and complete the range of motion with a lower constraint force when sitting and standing. such devices are recommended to mitigate the inconvenience and discomfort associated with traditional one-dof knee braces, thereby improving the quality of life of patients with koa. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this research. references 1. gaasbeek rd, groen be, hampsink b, van heerwaarden rj, duysens j. valgus bracing in patients with medial compartment osteoarthritis of the knee: a gait analysis study of a new brace. gait posture 2007; 26:3–10. https://doi.org/10.1016/j.gaitpost. 2006.07.007. figure 3: photographs showing the displacement of the upper and lower components of the drawer joint of a novel prototype orthotic knee joint with two degrees of freedom. during a sit-to-stand test, these two components were displaced by 15 mm when the subjects flexed his knees from (a) full extension to (b) approximately 90 degrees, representing movement in the transverse plane. design, implementation and testing of a novel prototype orthotic knee joint with two degrees of freedom in a patient with medial knee osteoarthritis e528 | squ medical journal, november 2018, volume 18, issue 4 2. komistek rd, dennis da, northcut ej, wood a, parker aw, traina sm. an in vivo analysis of the effectiveness of the osteoarthritic knee brace during heel-strike of gait. j arthroplasty 1999; 14:738–42. https://doi.org/10.1016/s0883-5403(99) 90230-9. 3. richards jd, sanchez-ballester j, jones rk, darke n, livingstone bn. a comparison of knee braces during walking for the treatment of osteoarthritis of the medial compartment of the knee. j bone joint surg br 2005; 87:937–9. https://doi.org/10.1302/0301620x.87b7.16005. 4. branch tp, hunter re. functional analysis of anterior cruciate ligament braces. clin sports med 1990; 9:771–97. 5. cawley pw, france ep, paulos le. comparison of rehabilitative knee braces: a biomechanical investigation. am j sports med 1989; 17:141–6. https://doi.org/10.1177/036354658901700201. 6. lewis jl, lew wd, patrnchak cm, shybut gt. a new concept in orthotics joint design: the northwestern university knee orthosis system. orthot prosthet 1983; 37:15–23. 7. choi b, lee y, kim j, lee m, lee j, roh sg, et al. a self-aligning knee joint for walking assistance devices. conf proc ieee eng med biol soc 2016; 2016:2222–7. https://doi.org/10.1109/ embc.2016.7591171. 8. regalbuto ma, rovick js, walker ps. the forces in a knee brace as a function of hinge design and placement. am j sports med 1989; 17:535–43. https://doi.org/10.1177/036354658901700415. 9. walker ps, rovick js, robertson dd. the effects of knee brace hinge design and placement on joint mechanics. j biomech 1988; 21:965–74. https://doi.org/10.1016/0021-9290(88)90135-2. 10. kellgren jh, lawrence js. radiological assessment of osteoarthrosis. ann rheum dis 1957; 16:494–502. https://doi.org/ 10.1136/ard.16.4.494. 11. squyer e, stamper dl, hamilton dt, sabin ja, leopold ss. unloader knee braces for osteoarthritis: do patients actually wear them? clin orthop relat res 2013; 471:1982–91. https://doi.org/10.1007/s11999-013-2814-0. 12. arazpour m, hutchins sw, bani ma, curran s, aksenov a. the influence of a bespoke unloader knee brace on gait in medial compartment osteoarthritis: a pilot study. prosthet orthot int 2014; 38:379–86. https://doi.org/10.1177/0309364613504780. 13. jones rk, nester cj, richards jd, kim wy, johnson ds, jari s, et al. a comparison of the biomechanical effects of valgus knee braces and lateral wedged insoles in patients with knee osteo arthritis. gait posture 2013; 37:368–72. https://doi.org/10.1016/j. gaitpost.2012.08.002. 14. zhang w, moskowitz rw, nuki g, abramson s, altman rd, arden n, et al. oarsi recommendations for the management of hip and knee osteoarthritis: part ii oarsi evidence-based, expert consensus guidelines. osteoarthritis cartilage 2008; 16:137–62. https://doi.org/10.1016/j.joca.2007.12.013. 15. neumann da. kinesiology of the musculoskeletal system: foundations for rehabilitation, 2nd ed. st. louis, missouri, usa: mosby, 2009. pp. 463–681. 16. frykberg ge, häger ck. movement analysis of sit-to-stand: research informing clinical practice. phys ther rev 2015; 20:156–67. https://doi.org/10.1179/1743288x15y.0000000005. رد: سل قيب يف طفل بسن ما قبل املدرسة ظاهرة غري شائعة re: calvarial tuberculosis in a preschool-aged child an uncommon entity sir, i read with interest the case report by santra et al. published in the november 2017 issue of squmj in which the clinical presentation and management plan of a two-and-a-half-year-old indian child with calvarial tuberculosis (tb) was described.1 it is possible that an hiv infection could have contributed to such a rare case of paediatric calvarial tb. as a result of the development of more potent antitubercular drugs and improved socioeconomic standards, there has been a remarkable reduction in the number of tb cases worldwide; however, atypical and extrapulmonary tb cases among hiv/aids patients nevertheless represent a major proportion of new tb cases.2 in particular, hiv and tb remain distressing health hazards in india, with a substantial prevalence of co-infection (12.3%); moreover, 56% of tb lesions among co-infected indian patients are extrapulmonary.3 it has been recommended that all tb patients in india should be evaluated for hiv risk factors and counselled to undergo hiv testing, while all hiv-positive cases should be screened for tb.3 although there are no recent data on the exact seroprevalence of paediatric hiv in india, the available literature indicates that the hiv seroprevalence rate among pregnant indian women is 1.03%.4 according to santra et al., the hiv status of the mother of the studied child was not determined; therefore, i presume that some sort of vertical hiv transmission could have occurred.1 a cluster of differentiation (cd)4 count and viral overload estimation should hence be undertaken. if this diagnostic battery of tests were to reveal an hiv infection, the case in question could be considered the second case of hiv-associated calvarial tb in india, following the first case reported by tripathi et al. a decade ago.5 regardless, the case is still novel in that it documents the youngest patient with calvarial tb reported in the literature to date.1 mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq author’s e-mail: mdalmendalawi@yahoo.com references 1. santra a, sen a, chatterjee a. calvarial tuberculosis in a preschool-aged child: an uncommon entity. sultan qaboos univ med j 2017; 17:e484–6. doi: 10.18295/squmj.2017.17.04.020. 2. saleeb pg, buchwald uk. [update on the epidemiology, diagnosis and therapy of tuberculosis in hiv-infected patients]. pneumologie 2014; 68:666–75. doi: 10.1055/s-0034-1377514. 3. manjareeka m, nanda s. prevalence of hiv infection among tuberculosis patients in eastern india. j infect public health 2013; 6:358–62. doi: 10.1016/j.jiph.2013.04.004. 4. sibia p, mohi mk, kumar a. seroprevalence of human immunodeficiency virus among antenatal women in one of the institute of northern india. j clin diagn res 2016; 10:qc08–9. doi: 10.7860/jcdr/2016/20615.8421. 5. tripathi ak, gupta n, khanna m, ahmad r, tripathi p. tuberculosis presenting as osteolytic soft tissue swellings of skull in hiv positive patient: a case report. indian j tuberc 2007; 54:193–5. letter to the editor sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e120–121, epub. 4 apr 18 submitted 15 jan 18 accepted 23 jan 18 doi: 10.18295/squmj.2018.18.01.025 https://doi.org/10.18295/squmj.2017.17.04.020 https://doi.org/10.1055/s-0034-1377514 https://doi.org/10.1016/j.jiph.2013.04.004 https://doi.org/10.7860/jcdr/2016/20615.8421 mahmood d. al-mendalawi letter to the editor | e121 response from the authors sir, thank you very much for your useful comments regarding our recently published case report.1 as you quite rightly mentioned, hiv and tuberculosis (tb) are serious concerns in india; in our experience, we very often come across cases of hiv-tb co-infections. as such, every tb patient should be screened for hiv as per the guidelines of the revised national tuberculosis control programme.2 the child in question was in fact tested for hiv and found to be negative; therefore, hiv was not considered to be a contributory factor to the development of tb in this case.1 in fact, this is why the child’s mother was not tested for hiv. unfortunately, we did not provide this important piece of information in the published case report.1 we are thankful to you for aptly pointing this out. additionally, to the best of our knowledge, our case report documents the second youngest patient with calvarial tb. in a previous case series, diyora et al. reported a one-year-old male child who presented with calvarial tb and was cured via surgical excision and a 12-month course of antitubercular therapy.3 *avradip santra,1 arya sen,2 atri chatterjee3 1department of pulmonary medicine, kolkata medical college & hospital, kolkata, west bengal, india; 2department of pathology, murshidabad medical college & hospital, murshidabad, west bengal, india; 3department of neurology, amri hospital, kolkata, west bengal, india *corresponding author’s e-mail: dravradip@gmail.com references 1. santra a, sen a, chatterjee a. calvarial tuberculosis in a preschool-aged child: an uncommon entity. sultan qaboos univ med j 2017; 17:e484–6. doi: 10.18295/squmj.2017.17.04.020. 2. kumar a, gupta d, nagaraja sb, singh v, sethi gr, prasad j; indian academy of pediatrics. updated national guidelines for pediatric tuberculosis in india, 2012. indian pediatr 2013; 50:301–6. doi: 10.1007/s13312-013-0085-1. 3. diyora b, kumar r, modgi r, sharma a. calvarial tuberculosis: a report of eleven patients. neurol india 2009; 57:607–12. doi: 10.4103/00283886.57814. https://doi.org/10.18295/squmj.2017.17.04.020 https://doi.org/10.1007/s13312-013-0085-1 https://doi.org/10.4103/0028-3886.57814 https://doi.org/10.4103/0028-3886.57814 research centers for 1immunodeficiencies, children’s medical center, 3hematology, oncology & stem cell transplantation and 6radiation oncology, cancer institute and departments of 2medical genetics, school of medicine and 5epidemiology & biostatistics, school of public health, tehran university of medical sciences, tehran, iran; 4non-communicable diseases research center, alborz university of medical sciences, karaj, iran. †these authors contributed equally to this work. *corresponding author’s e-mail: mz_dizaji@yahoo.com التقييم الفردي للحساسية اإلشعاعية لعائالت مرض اختالج احلركة الناشئ عن متدد الشعريات الدموية بواسطة إلغاء نقاط تفتيش ج2 اأ�شغر اآقاحممدي، �شيد حممد اكرمي، مرجان يغمايي، نيما ر�شايي، غالم ر�شا عزيزي، مهدي يا�رصي، ح�شن ن�رصتي، جميد ذكي ديزجي abstract: objectives: ataxia-telangiectasia (a-t) is an autosomal recessive multisystem disorder characterised by cerebellar degeneration, telangiectasia, radiation sensitivity, immunodeficiency, oxidative stress and cancer suscept ibility. epidemiological research has shown that carriers of the heterozygous ataxia-telangiectasia mutated (atm) gene mutation are radiosensitive to ionising irradiation and have a higher risk of cancers, type 2 diabetes and athero sclerosis. however, there is currently no fast and reliable laboratory-based method to detect heterozygous atm carriers for family screening and planning purposes. this study therefore aimed to evaluate the ability of a modified g2-assay to identify heterozygous atm carriers in the families of a-t patients. methods: this study took place at the tehran university of medical sciences, tehran, iran, between february and december 2017 and included 16 a-t patients, their parents (obligate heterozygotes) and 30 healthy controls. all of the subjects underwent individual radiosensitivity (irs) assessment using a modified caffeine-treated g2-assay with g2-checkpoint abrogation. results: the mean irs of the obligate atm heterozygotes was significantly higher than the healthy controls (55.13% ± 5.84% versus 39.03% ± 6.95%; p <0.001), but significantly lower than the a-t patients (55.13% ± 5.84% versus 87.39% ± 8.29%; p = 0.001). a receiver operating characteristic (roc) curve analysis of the g2-assay values indicated high sensitivity and specificity, with an area under the roc curve of 0.97 (95% confidence interval: 0.95–1.00). conclusion: the modified g2-assay demonstrated adequate precision and relatively high sensitivity and specificity in detecting heterozygous atm carriers. keywords: ataxia-telangiectasia; chromosome breakage; genetic carrier screening; heterozygote; radiation sensitivity; sensitivity and specificity. بتدهور يتميز متنحي الوجوه متعدد ج�شدي ا�شطراب هو الدموية ال�شعريات متدد عن النا�شئ احلركة اختالج مر�س الهدف: امللخ�ص: اأظهرت ال�رصطان. حدوث وقابلية التاأك�شدي الإجهاد املناعة، نق�س الإ�شعاع، ح�شا�شية الدموية، ال�شعريات متدد املخيخ، وظائف ال�رصطان، حلدوث اأعلى وقابلية املوؤين لالإ�شعاع ح�شا�شية لديهم املر�س لهذا املتغايرة اجلينية الطفرات حاملي اأن الأبحاث لأكت�شاف بها وموثوق �رصيعة خمتربية طريقة حاليا يوجد ل ذلك، ومع ال�رصايني. ت�شلب ومر�س النوعالثاين من ال�شكري وداء قدرة تقييم اإىل الدرا�شة هذه تهدف الأ�رصي. التخطيط بغر�س الأ�رصة اأفراد لفح�س املر�س لهذا املتغايرة اجلينية الطفرات حاملي احلركة. اختالج مر�شى عائالت يف املر�س لهذا املتغايرة اجلينية الطفرات حاملي حتديد على املعدلة ج2 تفتي�س نقاط اختبار من ا مري�شً 16 و�شملت 2017 ودي�شمرب فرباير بني اإيران، طهران، الطبية، للعلوم طهران جامعة يف الدرا�شة هذه اأجريت الطريقة: كمجموعة �شحيحا �شخ�شا 30 و اجلربيني( املر�س )حاملي اأمورهم واأولياء الدموية، ال�شعريات متدد عن النا�شئ احلركة اختالج نقاط اإلغاء مع املعدل ج2 الكافيني مقيا�س اختبار با�شتخدام الفردية لالأفراد احل�شا�شية لتقييم امل�شاركني جميع خ�شع ظابطة. بكثري اأعلى املر�س لهذا املتغايرة اجلينية الطفرات حلاملي املجازية لالأفراد احل�شا�شية تقييم متو�شطات كانت النتائج: ج2. التفتي�س احلركة اختالج مر�شى من بكثري اأقل ولكنها ،)p >0.001 %39.03؛ ± 6.95% مقابل 55.13% ± 5.84%( ال�شابطة املجموعة من عالية ح�شا�شية اإىل ج2 اختبار لقيم املتميز الت�شغيل منحنى حتليل اأ�شار .)p = 0.001 %87.39؛ ± 8.29% مقابل 55.13% ± 5.84%( وخ�شو�شية، مع وجود منطقة حتت املنحنى تبلغ 0.97 )%95 فا�شل الثقة: 1.00-0.95(. اخلال�صة: اأظهر اختبار ج2 املعدل دقة كافية وح�شا�شية عالية ن�شبيا يف الك�شف عن حاملي الطفرات اجلينية املتغايرة لهذا املر�س. الكلمات املفتاحية: اختالج احلركة النا�شئ عن متدد ال�شعريات الدموية؛ تك�رص الكرومو�شومات؛ فح�س حاملي املر�س؛ الطفرات اجلينية املتغايرة؛احل�شا�شية لالأ�شعاع؛ احل�شا�شية و اخل�شو�شية. individual radiosensitivity assessment of the families of ataxia-telangiectasia patients by g2-checkpoint abrogation asghar aghamohammadi,1† seyed m. akrami,2† marjan yaghmaie,3 nima rezaei,1 gholamreza azizi,4 mehdi yaseri,5 hassan nosrati,6 *majid zaki-dizaji1 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e440–446, epub. 28 mar 19 submitted 30 apr 18 revisions req. 31 may & 8 jul 18; revisions recd. 17 jun & 22 jul 18 accepted 2 aug 18 doi: 10.18295/squmj.2018.18.04.003 asghar aghamohammadi, seyed m. akrami, marjan yaghmaie, nima rezaei, gholamreza azizi, mehdi yaseri, hassan nosrati and majid zaki-dizaji clinical and basic research | e441 ataxia-telangiectasia (a-t) is a rare auto-somal recessive pleiotropic syndrome charact-erised by cerebellar ataxia, oculocutaneous tel angiectasia, chromosomal instability, radiosensitivity, variable immunodeficiency, oxidative stress and a high risk of malignancy.1,2 worldwide, only one in 40,000–100,000 neonates is homozygous for the a-t mutated (atm) gene mutation; however, 0.5–2% of the general population are heterozygous carriers.1 although heterozygous atm carriers are commonly asymptomatic, they have a higher sensitivity to ionising radiation (ir) and a higher risk of type 2 diabetes mellitus, cardiovascular diseases and cancers.2,3 however, the exact mechanism and the resp onsible mutations for this increased susceptibility to certain cancers are not yet understood. the atm gene codes for a ubiquitous serine/ threonine protein kinase that has been implicated in the maintenance of genomic stability.1 over 480 different mutations—which occur across the full-length transcript without any hotspots—have been described in a-t patients.3 in addition, the atm gene has many polymor phisms/missense dna changes that must be disting uished from deleterious mutations.1 early identification of the syndrome is useful for establishing prognosis and initiating genetic counselling for the family members of affected patients.4 however, the diagnosis can be problem atic and is usually based on clinical symptoms as well as high levels of serum α-fetoprotein (afp), acquired translocations between chromosomes 7 and 14 in the blood karyotype and reduced cell sensitivity to ir or the absence of the atm protein.5 despite advancement in functional and sequencing based assays, no reliable low-cost test is yet available for identifying a-t patients and heterozygous atm carriers.6 however, certain techniques developed to evaluate radio sensitivity in a-t patients may constitute methods of differentiating heterozygous atm carriers, such as g2 chromosomal radiosensitivity assays, comet assays, fluor escence in situ hybridisation, messenger ribonucleic acid (rna)/microrna expression profiling of the atm gene and gamma-h2ax and psmc1 gene assays.6–16 however, these findings need to be confirmed among additional individuals carrying different atm gene mutations. the g2-checkpoint eases chromosome damage repair, probably by inhibiting the deleterious progression of cells through the cell cycle.17 caffeine has been reported to increase radiosensitivity and abrogate radiationinduced cell cycle inhibition/delays by inhibiting the g2/m checkpoint, either with or without inactivating the atm and a-t rad3-related genes.18 terzoudi et al. reported that caffeine treatment increased g2-assay sensitivity and reduced interlaboratory and intra-experi mental variations.19 similarly, pantelias et al. proposed a standardised caffeine-treated g2-assay for predicting individual radiosensitivity (irs).20 this study aimed to evaluate the ability of a modified caffeine-treated g2 breakage assay to identify heterozygous atm carriers in the families of a-t patients. methods this study was conducted at the tehran university of medical sciences, tehran, iran, from february to december 2017. a total of 78 individuals were included in the study, comprising 16 a-t patients, their 32 parents (obligate heterozygotes) and 30 healthy controls. the a-t patients were recruited from previously diagnosed cases or from those who were being followed-up at the children’s medical center hospital in tehran. in all cases, the a-t diagnosis was based on evidence of disabling mutations on both alleles of the atm gene and either increased radiation-induced chromosomal breakage in cultured cells or progressive cerebellar ataxia.5 additional supportive tests, including specific serum afp and immunoglobulin measurements, were also carried out. the control subjects were recruited from members of staff at the children’s medical center hospital and the department of medical genetics, tehran university of medical sciences. only individuals who were unrelated to a-t patients and had no family history of malignancy, atherosclerosis or type 2 diabetes were included as controls. the controls were approximately matched for age and gender with the heterozygous atm carriers. a total of 2 ml of peripheral blood was collected from each subject. a modified g2 breakage assay was performed based on previously published protocols.20 briefly, 1 ml of whole blood was added to 10 ml of gibco™ roswell park memorial institute 1640 medium (thermo fisher scientific, waltham, massachusetts, usa) and supplemented with 15% fetal bovine serum, 2% phytohaemagglutinin, 1% l-glutamine and 1% penic advances in knowledge this study demonstrates the relatively high sensitivity and specificity of a modified caffeine-treated g2-assay in the detection of heterozygous carriers of the ataxia-telangiectasia mutated (atm) gene mutation. application to patient care a modified caffeine-treated g2-assay is proposed as an alternative method for identifying heterozygous atm carriers within the families of patients with ataxia-telangiectasia for family screening and planning purposes. individual radiosensitivity assessment of the families of ataxia-telangiectasia patients by g2-checkpoint abrogation e442 | squ medical journal, november 2018, volume 18, issue 4 figure 1: diagrams showing chromatid breaks and gaps (arrows) in a peripheral blood lymphocyte at metaphase stage from a heterozygous carrier of the ataxia-telangiectasia mutated gene mutation after 0.9 grays per minute of gamma irradiation using (a) conventional and (b) modified g2-assays. figure 2: box plot of the individual radiosensitivity percentages of healthy controls, heterozygous ataxia-telangiectasia (a-t) mutated gene carriers and a-t patients after 0.9 grays per minute of gamma irradiation (n = 78). irs = individual radiosensitivity; atm = ataxia-telangiectasia (a-t) mutated. table 1: demographic and clinical data of ataxia-telangiectasia patients (n = 16) patient presence of consanguinity age in years/ gender age at ataxia onset in years age at telangiectasia onset in years afp level in mg/dl igg level in mg/dl iga level in mg/dl igm level in mg/dl ige level in iu/ml 1 yes 14/m 5 6 103 960 0 195 40 2 yes 9/m 2 3 161 670 7 225 7 3 yes 7/m 1 1 380 809 173 111 10 4 yes 4/f 2 3 90 982 16 100 1 5 yes 16/f 1 2 75 <5 4 284 14 6 no 11/m 2 5 406 1,200 145 200 na 7 no 11/f 2 8 104 5 1 208 <1 8 no 9/m 1 5 150 613 <5 60 <1 9 yes 10/f 7 9 319 687 595 149 5 10 no 4/m 1 1 30 468 7 89 <1 11 no 10/f 2 4 520 na na na na 12 yes 22/m na na 666 1,185 249 112 na 13 yes 10/m 3 2 619 826 108 43 <1 14 yes 10/f 1 1 155 <1 <1 430 <1 15 yes 7/f 2 7 87 143 9 2,257 <1 16 yes 8/f 1 8 157 643 1 71 <1 afp = α-fetoprotein; ig = immunoglobulin; m = male; f = female; na = not available. asghar aghamohammadi, seyed m. akrami, marjan yaghmaie, nima rezaei, gholamreza azizi, mehdi yaseri, hassan nosrati and majid zaki-dizaji clinical and basic research | e443 illin/streptomycin. the mixture was then incubated for 72 hours at 37 °c in a humidified incubator with 5% carbon dioxide. each sample was cultured in two flasks to assess spontaneous breakage and radiation-induced breakage. after 72 hours, gamma irradiation was performed using a theratron® 780e teletherapy machine (mds nordion inc., ottawa, ontario, canada) at a dose rate of 0.9 grays (gy) per minute for 1.12 minutes at room temperature. after irradiation, each culture was divided into two flasks, of which one was treated with 4 mm of caffeine, before being incubated for 20 minutes at 37 °c. the cultures were then treated with demecolcine for 75 minutes. after incubation, the cells were harvested, prepared on slides and stained with giemsa according to conventional cytogenetic techniques.21 stained slides were coded and underwent blinded analysis by two separate researchers. only well-spread metaphases with 44–47 chromosomes each were eval uated. for each sample, a total of 50 metaphases were examined for chromatid aberrations (i.e. breaks and gaps). moreover, the level of spontaneous chromatid anomalies was evaluated in non-irradiated lymphocyte cultures and the resultant number was subtracted from the radiation-induced g2 yield of chromatid breaks. a chromatid gap was defined as an interruption in the staining of a chromatid greater than the width of the chromatid, without displacement of the segment distal to the lesion.22 a lesion was considered to be a chromatid break if there was distinct dislocation and misalignment of the broken segment [figure 1]. for each individual, two different yields of chrom atid aberrations were calculated. the first yield was similar to that of a conventional g2-assay and the second was the maximum yield of chromatid breaks achieved when the g2-checkpoint was abolished by caffeine. the i r s was calculated as below [equation 1]: where g2caf is the yield when the g2-checkpoint is abolished by caffeine and g2 is the conventional g2-assay yield. for samples which deviated by more or less than 5% from formerly published cut-off values, an additional 50 metaphases were analysed.20 the freq uency of exchanges and rings was not included in the calculation of aberration yields. the inter-day precision of the g2-assay was determined by analysing six samples of peripheral blood mononuclear cells from one healthy donor on six different days. the precision of the test was assessed only at between-run levels. data were analysed using graphpad prism software, version 6 (graphpad software, san diego, california, usa). statistical differences between groups were deter mined using kruskal-wallis and dunn’s multiple comp arison post-hoc tests. receiver operating characteristic (roc) curves were calculated to assess the relevant sensitivity and specificity of the g2-assay values. a sign ificance level of p ≤0.050 was used throughout the experi ments. the inter-day precision was presented as a coeff icient of variation. this study was approved by the research ethics committee of the tehran university of medical sciences (#26489-154-02-93). all subjects gave informed consent prior to their inclusion in the study. results the male-to-female ratios of the a-t patients and controls were 0.9 and 1.4, respectively. the mean ages of the a-t patients, heterozygous atm carriers and healthy controls were 10, 37 and 32 years old, respectively (ranges: 4–22, 26–55 and 19–46 years, respectively). the clinical and demographic data of the a-t patients are presented in table 1. there was a significant increase in irs across all three groups (p <0.001). the mean frequency of induced chromatid aberrations in cells from heterozygous atm carriers were significantly higher than in those from healthy controls (55.13% ± 5.84% versus 39.03% ± 6.95%; p <0.001) and significantly lower than in a-t patients (55.13% ± 5.84% versus 87.39% ± 8.29%; p = 0.001) [figure 2]. an roc curve analysis of g2-assay values demonstrated high sensitivity and specificity for the identification of heterozygous atm figure 3: receiver operating characteristic curve analysis of g2-assay data for (a) healthy controls versus heterozygous ataxia-telangiectasia mutated (atm) gene carriers, (b) healthy controls versus ataxia-telangiectasia (a-t) patients and (c) heterozygous atm carriers versus a-t patients (n = 78). (1 [equation 1]irs = × 100)g2g2 g2-caf caf individual radiosensitivity assessment of the families of ataxia-telangiectasia patients by g2-checkpoint abrogation e444 | squ medical journal, november 2018, volume 18, issue 4 carriers versus controls, with an area under the curve of 0.97 (95% confidence interval: 0.95–1.00) [figure 3 and table 2]. the overall inter-day coefficient of variation of the assay was 4.28% (mean: 45.84% ± 1.96%). overall, the g2-checkpoint efficiency was easily discriminated in a-t patients; however, there was an overlap of chromatid aberration frequencies observed between controls and heterozygous atm carriers. aberrations in non-irradiated lymphocytes were not noticeable in any of the three groups. discussion along with chromosomal instability, cells with atm gene mutations display extreme radiosensitivity both in vivo and in vitro.3 these phenotypes suggest that the atm gene plays a critical role in the dna repair system. furthermore, as serine/threonine kinase acts as a sensor of oxidative stress in normal cells, the loss of this protein in individuals with atm mutations disturbs the redox balance and increases levels of reactive oxygen species and oxidative stress, contributing to increased radiosensitivity.23,24 however, the exact role of the atm gene in these systems and the tissue specificity of such defects remains unknown. the atm gene coordinates cell cycle checkpoint signalling via the phosphorylation of different substrates, including p53, checkpoint kinase 2, structural maintenance of chromo somes 1 (smc1), activating transcription factor 2 and nibrin.1 a lack of serine/threonine kinase leads to the loss of these checkpoints and, therefore, the potentially deleterious progression of cells through the cell cycle. the screening and identification of heterozygous carriers of atm-related haploinsufficiencies and allelic variants is an important public health goal due to their high frequency in the population and increased suscept ibility to cancer, diabetes and atherosclerosis.1,2 the current study evaluated the irs of a-t patients, hetero zygous atm carriers and healthy controls by assessing the frequency of radiation-induced chromatid aberrations during the g2/m transition stage in stimulated blood lymphocytes using a modified caffeine-treated g2-assay with g2-checkpoint abrogation. a significantly higher frequency of chromatid breaks and gaps was observed in the cells of a-t patients compared to those of the heterozygous atm carriers. similarly, there was a significantly higher frequency of chromatid breaks and gaps among the cells of heterozygous atm carriers compared to those of the healthy controls. unfortunately, the range of these aberrations overlapped to some extent between the latter two groups, thus precluding the absolute detection of heterozygous atm carriers. never theless, this method—which required only 2 ml of peripheral blood from the subjects—showed acceptable inter-day variation and relatively high sensitivity and specificity for the identification of heterozygous atm carriers. several previous studies have attempted to dist inguish heterozygous atm carriers from normal controls using g2-assays.7,8,25 tchirkov et al. detected 13 hetero zygous atm carriers without any overlap of results with those of normal donors.10 however, these findings were not consistent with those of other studies.22,26–28 this may be due to variations in the number of subjects, type of cells under consideration, nature of the atm mutation, technical procedures, treatment dose and dose rate, number of analysed metaphases, time interval between irradiation and fixation and the type of analysed aberration. leonard et al. distinguished obligate heterozygotes from controls utilising lympho blast cell lines which had been treated with camptothecin; however, this method requires further study using peripheral blood samples from a larger cohort.11 likewise, terzoudi et al. introduced a new approach to g2/m cell cycle checkpoint abrogation for assessing irs using caffeine treatment; this method demonstrated better discrimination and minimal intra-individual and inter-laboratory variations compared to the conventional g2-assay.19,20 claes et al. reported the use of a modified s-g2 micronucleus assay in which caffeine treatment formed a complementary assay for the identification of atypical a-t patients and heterozygous atm carriers.29 prodosmo et al. proposed a new, fast and cost-effective test to deter mine atm zygosity based on p53 centrosomal local isation visualised by immunofluorescence staining.30 porcedda et al. identified heterozygotes using a twotier analysis of histone h2ax phosphorylation, h2ax phosphorylation levels and residual gamma-h2ax table 2: diagnostic potential of a modified g2-assay in the differentiation of healthy controls, heterozygous ataxia telangiectasia mutated gene carriers and ataxia-telangiectasia patients (n = 78) healthy controls versus heterozygous atm gene carriers healthy controls versus a-t patients heterozygous atm gene carriers versus a-t patients auc (95% ci) 0.97 (0.95–1.00) 1.00 (1.00–1.00) 1.00 (1.00–1.00) sensitivity, % (95% ci) 100 (89–100) 100 (80–100) 100 (79–100) specificity, % (95% ci) 90 (73–98) 100 (88–100) 100 (89–100) cut-off value, % 45 60 70 a-t = ataxia-telangiectasia; atm = a-t mutated; auc = area under the curve; ci = confidence interval. asghar aghamohammadi, seyed m. akrami, marjan yaghmaie, nima rezaei, gholamreza azizi, mehdi yaseri, hassan nosrati and majid zaki-dizaji clinical and basic research | e445 foci.16 in addition, a-t patients and heterozygous atm carriers have been identified by evaluating serine/threo nine kinase-dependent phosphorylation of smc1 foll owing dna damage; however, this assay could not discriminate between carriers and controls via enzyme linked immunosorbent assay.31 a more recent, quick, labour-intensive cell division assay using flow cytometry reported similar results to that of a colony-survival assay (csa).32 a csa is the gold-standard method of evaluating radiosensitivity as it resolves the technical difficulties involved in standardisation and optimisation which interfere with predictive accuracy.5 this study was subject to certain limitations. some of the healthy controls may have been dna repairdeficient or radiosensitive.20,22 on the other hand, some of the obligate heterozygotes may have had a range of atm mutations; consequently, these individuals may, like a-t patients, have exhibited various degrees of radiosensitivity both in vitro and clinically.7–11,19,25,28,29 furthermore, technical issues in different laboratories can intensify such variations.22 finally, the assay was not specific for atm mutations and may therefore have identified mutations in other genes which modify dna repair system efficiency. for these reasons, it is recommended that this assay be used only for the screening of families of confirmed a-t patients, as hypersensitivity in such cases is more likely to truly reflect heterozygosity of the atm gene.33,34 further investigation is recommended to confirm the practicality of using this assay. the results of experiments like those conducted in the current study are preliminary and need to be further confirmed in additional subjects carrying different atm mutations. conclusion the results of this study indicate that a modified caffeine treated g2-assay is a potential method of identifying heterozygous atm carriers within the families of a-t patients. acknowledgements the preliminary version of this study was submitted as a thesis to the tehran university of medical sciences in 2015. conflict of interest the authors declare no conflicts of interest. funding this study was funded with the aid of a grant from the research center for immunodeficiency, tehran university of medical sciences (grant #26489-154-02-93). references 1. zaki-dizaji m, akrami sm, abolhassani h, rezaei n, aghamohammadi a. ataxia telangiectasia syndrome: moonlighting atm. expert rev clin immunol 2017; 13:1155–72. https://doi.org/10.1080/1744666x.2017.1392856. 2. zaki-dizaji m, akrami sm, azizi g, abolhassani h, aghamohammadi a. inflammation, a significant player of ataxia telangiectasia pathogenesis? inflamm res 2018; 67:559–70. https://doi.org/10.1007/s00011-018-1142-y. 3. chun hh, gatti ra. ataxia-telangiectasia, an evolving phenotype. dna repair (amst) 2004; 3:1187–96. https://doi.org/10.1016/j. dnarep.2004.04.010. 4. abolhassani h, rezaei n, mohammadinejad p, mirminachi b, hammarstrom l, aghamohammadi a. important differences in the diagnostic spectrum of primary immunodeficiency in adults versus children. expert rev clin immunol 2015; 11:289–302. https://doi.org/10.1586/1744666x.2015.990440. 5. pietrucha b, heropolitańska-pliszka e, gatti ra, bernatowska e. ataxia-telangiectasia: guidelines for diagnosis and comprehensive care. cent eur j immunol 2007; 32:234–8. 6. dizaji mz, rezaei n, yaghmaie m, yaseri m, sayedi sj, azizi g, et al. phospho-smc1 in-cell elisa-based detection of ataxia telangiectasia. int j pediatr 2016; 4:3957–67. https://doi.org/10.2 2038/ijp.2016.7751. 7. chen p, farrell a, hobson k, girjes a, lavin m. comparative study of radiation-induced g2 phase delay and chromatid damage in families with ataxia-telangiectasia. cancer genet cytogenet 1994; 76:43–6. https://doi.org/10.1016/0165-4608(94)90069-8. 8. sanford kk, parshad r, price fm, jones gm, tarone re, eierman l, et al. enhanced chromatid damage in blood lymphocytes after g2 phase x irradiation, a marker of the ataxia-telangiectasia gene. j natl cancer inst 1990; 82:1050–4. https://doi.org/10.10 93/jnci/82.12.1050. 9. shiloh y, parshad r, sanford kk, jones gm. carrier detection in ataxia-telangiectasia. lancet 1986; 1:689–90. https://doi.org/ 10.1016/s0140-6736(86)91773-3. 10. tchirkov a, bay jo, pernin d, bignon yj, rio p, grancho m, et al. detection of heterozygous carriers of the ataxia-telangiectasia (atm) gene by g2 phase chromosomal radiosensitivity of peripheral blood lymphocytes. hum genet 1997; 101:312–16. https://doi.org/10.1007/s004390050634. 11. leonard jc, mullinger am, schmidt j, cordell hj, johnson rt. genome instability in ataxia telangiectasia (a-t) families: camp tothecin-induced damage to replicating dna discriminates bet ween obligate a-t heterozygotes, a-t homozygotes and controls. biosci rep 2004; 24:617–29. https://doi.org/10.1007/s10540005-2796-6. 12. djuzenova cs, schindler d, stopper h, hoehn h, flentje m, oppitz u. identification of ataxia telangiectasia heterozygotes, a cancer-prone population, using the single-cell gel electrophoresis (comet) assay. lab invest 1999; 79:699–705. 13. distel lv, neubauer s. chromosomal instability in ataxia telangiectasia. in: ahmad si, ed. molecular mechanisms of ataxia telangiectasia. boca raton, florida, usa: crc press, 2009. pp. 52–62. 14. zhang l, simpson da, innes cl, chou j, bushel pr, paules rs, et al. gene expression signatures but not cell cycle checkpoint functions distinguish at carriers from normal individuals. physiol genomics 2013; 45:907–16. https://doi.org/10.1152/physiolge nomics.00064.2013. 15. watts ja, morley m, burdick jt, fiori jl, ewens wj, spielman rs, et al. gene expression phenotype in heterozygous carriers of ataxia telangiectasia. am j hum genet 2002; 71:791–800. https://doi.org/10.1086/342974. individual radiosensitivity assessment of the families of ataxia-telangiectasia patients by g2-checkpoint abrogation e446 | squ medical journal, november 2018, volume 18, issue 4 16. porcedda p, turinetto v, orlando l, lantelme e, brusco a, de marchi m, et al. two-tier analysis of histone h2ax phosphorylation allows the identification of ataxia telangiectasia heter ozygotes. radiother oncol 2009; 92:133–7. https://doi.org/10.10 16/j.radonc.2008.12.010. 17. stark gr, taylor wr. analyzing the g2/m checkpoint. methods mol biol 2004; 280:51–82. https://doi.org/10.1385/1-59259-7882:051. 18. cortez d. caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (atm) and atmand rad3related (atr) protein kinases. j biol chem 2003; 278:37139–45. https://doi.org/10.1074/jbc.m307088200. 19. terzoudi gi, hatzi vi, barszczewska k, manola kn, stavropoulou c, angelakis p, et al. g2-checkpoint abrogation in irradiated lymphocytes: a new cytogenetic approach to assess individual radiosensitivity and predisposition to cancer. int j oncol 2009; 35:1223–30. https://doi.org/10.3892/ijo_00000439. 20. pantelias ge, terzoudi gi. a standardized g2-assay for the prediction of individual radiosensitivity. radiother oncol 2011; 101:28–34. https://doi.org/10.1016/j.radonc.2011.09.021. 21. bryant pe, gray l, riches ac, steel c, finnon p, howe o, et al. the g2 chromosomal radiosensitivity assay. int j radiat biol 2002; 78:863–6. https://doi.org/10.1080/09553000210144484. 22. scott d, spreadborough ar, jones la, roberts sa, moore cj. chromosomal radiosensitivity in g2-phase lymphocytes as an indicator of cancer predisposition. radiat res 1996; 145:3–16. https://doi.org/10.2307/3579189. 23. yeo aj, fantino e, czovek d, wainwright ce, sly pd, lavin mf. loss of atm in airway epithelial cells is associated with susceptibility to oxidative stress. am j respir crit care med 2017; 196:391–3. https://doi.org/10.1164/rccm.201611-2210le. 24. maciejczyk m, mikoluc b, pietrucha b, heropolitanska-pliszka e, pac m, motkowski r, et al. oxidative stress, mitochondrial abnormalities and antioxidant defense in ataxia-telangiectasia, bloom syndrome and nijmegen breakage syndrome. redox biol 2017; 11:375–83. https://doi.org/10.1016/j.redox.2016.12.030. 25. humphreys mw, nevin nc, wooldridge ma. cytogenetic investigations in a family with ataxia telangiectasia. hum genet 1989; 83:79–82. https://doi.org/10.1007/bf00274154. 26. waghray m, gascon gg, al-sedairy s, hannan ma. cytogenetic investigations in three cell types of a saudi family with ataxia telangiectasia. hum genet 1991; 87:285–9. https://doi.org/10.1 007/bf00200905. 27. wiencke jk, wara dw, little jb, kelsey kt. heterogeneity in the clastogenic response to x-rays in lymphocytes from ataxiatelangiectasia heterozygotes and controls. cancer causes control 1992; 3:237–45. https://doi.org/10.1007/bf00124257. 28. pandita tk, hittelman wn. increased initial levels of chromosome damage and heterogeneous chromosome repair in ataxia telangiectasia heterozygote cells. mutat res 1994; 310:1–13. https://doi.org/10.1016/0027-5107(94)90004-3. 29. claes k, depuydt j, taylor am, last ji, baert a, schietecatte p, et al. variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and rel atives. neuromolecular med 2013; 15:447–57. https://doi.org/10.1 007/s12017-013-8231-4. 30. prodosmo a, de amicis a, nisticò c, gabriele m, di rocco g, monteonofrio l, et al. p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes. j clin invest 2013; 123:1335–42. https://doi.org/10.1172/jci67289. 31. dizaji mz, rezaei n, yaghmaie m, yaseri m, sayedi sj, azizi g, et al. phospho-smc1 in-cell elisa based detection of ataxia telangiectasia. int j pediatrics 2016; 4:3957–67. https://doi.org/ 10.22038/ijp.2016.7751. 32. mathew st, johansson p, gao y, fasth a, ek t, hammarsten o. a flow cytometry assay that measures cellular sensitivity to dna-damaging agents, customized for clinical routine labor atories. clin biochem 2016; 49:566–72. https://doi.org/10.1016/ j.clinbiochem.2016.01.009. 33. aghamohammadi a, moin m, kouhi a, mohagheghi ma, shirazi a, rezaei n, et al. chromosomal radiosensitivity in patients with common variable immunodeficiency. immuno biology 2008; 213:447–54. https://doi.org/10.1016/j.imbio.200 7.10.018. 34. nahas sa, gatti ra. dna double strand break repair defects, primary immunodeficiency disorders, and ‘radiosensitivity’. curr opin allergy clin immunol 2009; 9:510–16. https://doi.org/10. 1097/aci.0b013e328332be17. رد: أحباث طب األعصاب يف اململكة العربية السعودية دعوة عاجلة للعمل re: neurology research in saudi arabia urgent call for action sir, i read with great interest the study by algahtani et al. published in the august 2017 issue of squmj in which a bibliometric analysis was performed of neurology-related articles published from saudi arabia over the past two decades.1 the findings from this study indicated substantial growth in the number of neurology-related publications from this country, particularly over the last four years.1 this is an encouraging trend that may perhaps reflect a high degree of research activity conducted in saudi arabia. the quality and quantity of research produced in the arabian gulf has recently been the subject of scholarly attention.2,3 similar to the findings reported in algahtani et al.’s study, rising trends in biomedical research productivity have been reported in saudi arabia and other arabian gulf countries.1–4 however, such trends deserve further discussion. algahtani et al. examined the quality of saudi-based neurology publications using measures of research design and journal impact factor (if); firstly, they found that the observed growth in neurology-related publications was mainly accounted for by a growing body of case reports/observational studies and, secondly, that more than half of the identified articles (55%) were published in journals with low ifs.1 the validity of using the if as a measure of quality in scholarly research has been extensively debated.5 while publication in prestigious high-impact journals may reflect high-quality research, it does not necessarily represent the value of that research within a local context. furthermore, as most biomedical journals with high ifs are published in high-income western countries (i.e. north america and europe), they often focus on topics and health problems of interest to that region of the world. for these reasons, researchers working on projects of interest to the arabian gulf region often face challenges publishing their findings in top-tier international journals.6 in addition, some researchers may deem publication in local journals more appropriate than in highly-ranked international journals. in light of this, using a journal’s if as the sole indicator of research quality—especially for studies conducted in low-income countries and those with emerging economies, such as those in the arabian gulf region—should be avoided. another proxy measure of research quality is the prevalence of scientific collaboration with other local (i.e. gulf-based) and international research institutions.4 collaboration between different research bodies within a country and/or with external institutions may reflect the complexity of the research and mirror an increasing trend in multicentre studies. overall, in order to better examine the quality of neurology literature produced in saudi arabia, further research is required to evaluate patterns in authorship (i.e. the number of authors per publication over time) and local/international collaboration. ibrahim s. al-busaidi department of general medicine, christchurch hospital, canterbury district health board, christchurch, new zealand; edgar diabetes & obesity research centre, dunedin school of medicine, university of otago, dunedin, new zealand e-mail: ibrahim.al-busaidi@cdhb.health.nz references 1. algahtani h, shirah b, boker f, algamdi a, alkahtani a. neurology research in saudi arabia: urgent call for action. sultan qaboos univ med j 2017; 17:e324–8. doi: 10.18295/squmj.2017.17.03.011. 2. al-bishri j. evaluation of biomedical research in saudi arabia. saudi med j 2013; 34:954–9. 3. al-maawali a, al busadi a, al-adawi s. biomedical publications profile and trends in gulf cooperation council countries. sultan qaboos univ med j 2012; 12:41–7. doi: 10.12816/0003086. letter to the editor sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e491–492, epub. 10 jan 18 submitted 29 oct 17 accepted 9 nov 17 doi: 10.18295/squmj.2017.17.04.023 https://doi.org/10.18295/squmj.2017.17.03.011 https://doi.org/10.12816/0003086 re: neurology research in saudi arabia urgent call for action e492 | squ medical journal, november 2017, volume 17, issue 4 4. moed hf. iran’s scientific dominance and the emergence of south-east asian countries as scientific collaborators in the persian gulf region. scientometrics 2016; 108:305–14. doi: 10.1007/s11192-016-1946-x. 5. neuberger j, counsell c. impact factors: uses and abuses. eur j gastroenterol hepatol 2002; 14:209–11. doi: 10.1097/00042737-20020300000001. 6. habibzadeh f. scientific research in the middle east. lancet 2014; 383:e1–2. https://doi.org/10.1007/s11192-016-1946-x https://doi.org/10.1097/00042737-200203000-00001 https://doi.org/10.1097/00042737-200203000-00001 1department of medicine, 3king abdullah international medical research center, king saud bin abdulaziz university for health sciences, jeddah, saudi arabia; 2king abdulaziz medical city, riyadh, saudi arabia; 4department of medicine, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia *corresponding author e-mail: halgahtani@hotmail.com أحباث طب األعصاب يف اململكة العربية السعودية دعوة عاجلة للعمل ح�سني القحطاين، بدر �سريه، في�سل بوكر، الرباء الغامدي، عبداهلل القحطاين abstract: objectives: research activities in saudi arabia are promoted at the governmental and institutional levels. however, the output and quality of research conducted in the field of neurology has not yet been measured quantitatively. this study therefore aimed to analyse neurology-related publications from saudi arabia. methods: this study was conducted in january 2016. a systematic search using the pubmed® search engine (national library of medicine, bethesda, maryland, usa) was conducted to identify all neurology-related articles published from saudi arabia between january 1996 and december 2015. results: a total of 1,292 neurologyrelated publications were identified. neurology research increased linearly with time, with most publications originating from riyadh (67%) and the university sector (≈47%). however, most neurology-related articles were published in journals which had an impact factor of <1 (55%). conclusion: neurology research in saudi arabia has increased substantially over the last 20 years. however, as most articles were published in low-impact journals, the quality of research remains inadequate and should be improved. it is important that an official research culture be established in both governmental and private universities as well as colleges and health institutions in saudi arabia. the formation of clinical academic departments staffed by research experts is recommended to ensure the quality of neurology research output. keywords: neurology; research; publications; journal impact factor; saudi arabia. امللخ�ص: الهدف: اإن االأن�سطة البحثية يف اململكة العربية ال�سعودية عادة ما تكون مدعومة من قبل املوؤ�س�سات احلكومية ب�ستى اأنواعها. ومع ذلك، حتى االآن مل يتم قيا�ص كمية ونوعية االأبحاث التي اأجريت يف جمال طب االأع�ساب. لذلك تهدف هذه الدرا�سة اإىل حتليل االأبحاث املن�سورة يف جمال طب االأع�ساب من اململكة العربية ال�سعودية. الطريقة: مت اإجراء هذا البحث يف يناير 2016. مت اإجراء بحث منهجي �سامل با�ستخدام حمرك البحث بومبد )املكتبة الوطنية للطب، بيثي�سدا، ماريالند، الواليات املتحدة االأمريكية( لتحديد جميع املقاالت املتعلقة مبجال طب االأع�ساب التي ن�رصت من اململكة العربية ال�سعودية بني يناير 1996 ودي�سمرب 2015. النتائج: مت حتديد ما جمموعه 1,292 االأبحاث معظم اأن لوحظ كما الوقت، مع ت�ساعديا االأع�ساب طب اأبحاث ازدياد لوحظ لقد االأع�ساب. طب مبجال يتعلق من�سورا بحثا طب مبجال املتعلقة املقاالت معظم ن�رص مت ذلك، ومع .)≈47%( اجلامعات وقطاع )67%( الريا�ص مدينة من �سادرة كانت املن�سورة االأع�ساب يف جمالت كان لها عامل تاأثري 1< )%55(. اخلال�صة: لقد زادت االأبحاث يف جمال طب االأع�ساب يف اململكة العربية ال�سعودية فاإن التاأثري، منخف�سة جمالت يف ن�رصت قد املقاالت معظم اأن ومبا ذلك، ومع املا�سية. الع�رصين ال�سنوات مدى على ملحوظ ب�سكل جودة االأبحاث ال تزال غري كافية وينبغي حت�سينها. من املهم اإن�ساء ثقافة بحثية ر�سمية يف اجلامعات العامة واخلا�سة، وكذلك الكليات واملوؤ�س�سات ال�سحية يف اململكة العربية ال�سعودية. يو�سى بت�سكيل اإدارات واأق�سام اأكادميية بحثية تدار من قبل خرباء يف جمال االأبحاث الطبية ل�سمان جودة االأبحاث يف جمال طب االأع�ساب. الكلمات املفتاحية: طب االأع�ساب؛ بحث؛ املن�سورات؛ عامل تاأثري املجلة؛ اململكة العربية ال�سعودية. neurology research in saudi arabia urgent call for action *hussein algahtani,1,2 bader shirah,3 faisal boker,1 albaraa algamdi,1 abdulah alkahtani4 clinical & basic research sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e324–328, epub. 10 oct 17 submitted 22 jan 17 revision req. 15 mar 17; revision recd. 27 mar 17 accepted 12 apr 17 advances in knowledge this study analyses neurology-related articles published from saudi arabia between january 1996 and december 2015, highlighting the status of past and current neurology research in the country. the findings of this study indicate that research culture urgently needs to be promoted in saudi arabia, perhaps by establishing clinical academic departments staffed by research experts. application to patient care the results of this study may encourage institutions in saudi arabia to promote research and research methodology education. the subsequent increase in high-quality neurology-related publications would support medical practice and patient care by improving understanding of disease trends and risk factors as well as informing management guidelines for diseases and conditions specific to saudi arabia. doi: 10.18295/squmj.2017.17.03.011 hussein algahtani, bader shirah, faisal boker, albaraa algamdi and abdulah alkahtani clinical and basic research | e325 publishing a paper is the most common way of communicating the results of research to other researchers, health professionals and members of the scientific community, with publications in international peer-reviewed journals usually seen as an indicator of proper scientific research.1 in saudi arabia, research activities are promoted at the governmental and institutional levels.2 nevertheless, clinical neuroscience research productivity in saudi arabia still lags behind that of other countries.3 to the best of the authors’ knowledge, the quantity and quality of research conducted in the field of neurology in saudi arabia has not yet been measured quantitatively. therefore, this study was conducted to analyse neurology-related publications from saudi arabia between january 1996 and december 2015. methods this study was conducted in january 2016. a search of all neuroscience-related articles from saudi arabia published between january 1996 and december 2015 was performed using the pubmed® search engine (national library of medicine, bethesda, maryland, usa). this search engine was selected due to its specialisation in medical literature, the feasibility of use of its boolean operator search function and medical subject headings (mesh) classifications and the increased likelihood of compiling the largest number of eligible publications due to the huge number of records available from publisher-supplied citations and the medline® (national library of medicine) database. the search strategy involved 206 terms deemed relevant and specific to the field of neuroscience which were combined using the boolean operators “and” and “or”, with saudi arabia designated as the country of affiliation. the national library of medicine mesh terms were used to ensure that the search was comprehensive. the inclusion criteria consisted of publications conducted in saudi arabia with the primary author affiliated with a saudi arabian institution and the study sample or population consisting of saudi nationals or residents. in addition, only original articles, reviews, case reports or case series were included while abstracts of meetings, news items, book reviews, communications, letters, editorials and supplementary articles were excluded. duplicate articles and false-positive neuroscience publications were also excluded. overall, the literature search revealed 5,626 neuroscience-related publications affiliated with saudi arabia. subsequently, two consultant neurologists independently screened the titles and abstracts of these publications for suitability. in total, 3,251 falsepositive articles and 142 duplicate publications were excluded. another 210 and 156 publications were excluded due to article type and because they did not meet the inclusion criteria, respectively. the 2,009 remaining publications were categorised based on their subspecialty, which revealed 1,292 articles in neurology, 299 in neurosurgery, 155 in psychiatry and 263 in basic sciences subspecialties [figure 1]. for all neurology-related articles, information was collected related to study design, institution affiliations, authors, year of publication, city of origin, journal and journal impact factor (if). results a total of 1,292 neurology-related articles from saudi arabia were identified. neurology research production showed a clearly increasing linear trend over time, with the greatest number of articles published in 2014 figure 1: diagram illustrating the search strategy used to identify neurology-related articles published from saudi arabia between january 1996 and december 2015. neurology research in saudi arabia urgent call for action e326 | squ medical journal, august 2017, volume 17, issue 3 and 2015 (138 and 125 articles, respectively) [figure 2]. most neurology publications were from riyadh (67%), the capital of saudi arabia, followed by jeddah (15%). other cities with contributions to neurology research output included al-khobar (4%), dammam (3%), abha (2%), medina (1%), mecca (1%), dhahran (1%) and hofuf (1%). the remaining cities had few or no neurology-related publications [figure 3]. approximately 47% of all neurology-related publications were affiliated with the university sector. the king faisal specialist hospital and research centre was the most prolific institution, accounting for 23% of all publications. among universities, the king saud university and king abdulaziz university published 21% and 9% of publications, respectively [figure 4]. overall, 55% of articles were published in journals with an if of <1 and 1% were published in journals without an if. only 2% of papers were published in journals with an if of ≥7 [figure 5]. among all of the articles analysed, the publishing journal with the highest if was the lancet, which had an if of 44.002 in 2015.4 in terms of research design, randomised controlled trials (rcts) constituted only 4% of all publications; the remaining articles were case reports (40%), retrospective cohort studies (18%), reviews (15%), prospective cohort studies (14%), cross-sectional studies (5%) or case series (4%) [figure 6]. the most common neurology research subspecialties were infectious diseases (15%), paediatrics (13%), epilepsy (12%), genetics (10%) and stroke research (10%). surprisingly, very few articles were published on cognitive and behavioural neurology and neuroimmunology (i.e. multiple sclerosis and neurorehabilitation). discussion this study highlights the status of neurology research and types of neurology-related articles published in saudi arabia between january 1996 and december 2015. these findings indicate where saudi arabia stands in terms of past and present figure 3: percentage of neurology-related publications from saudi arabia between january 1996 and december 2015 by city (n = 1,292). figure 4: number of neurology-related publications from saudi arabia between january 1996 and december 2015 by institution (n = 1,292). kfshrc = king faisal specialist hospital and research center; mngha = ministry of national guard health affairs; ksauhs = king saud bin abdulaziz university for health sciences; kkesh = king khaled eye specialist hospital. figure 5: percentage of neurology-related publications from saudi arabia between january 1996 and december 2015 by journal impact factor (n = 1,292). figure 2: number of neurology-related publications from saudi arabia between january 1996 and december 2015 per year (n = 1,292). hussein algahtani, bader shirah, faisal boker, albaraa algamdi and abdulah alkahtani clinical and basic research | e327 research production and should be considered an urgent call for action. neurology research showed a clear linear increase over the past two decades; this may be attributable to realisation on the part of the saudi arabian government and its universities and medical institutes of the importance of such research in improving quality-of-life and long-term sustainable development. in addition, the growth in the number of published scientific papers in the field of neurology may also be due to the recent increase in the number of tertiary care centres and universities, the return of highly educated saudi neurologists from abroad and the establishment of scientific journals based in saudi arabia. according to the ministry of education, saudi arabia is currently recognised as a regional leader in science, including medicine; in addition, it is forecast to become an asian power by 2020 and a knowledgebased advanced industrial nation by 2025.5 however, the research designs of most neurologyrelated publications identified in the current study were found to be of low quality and importance, with an absence of well-designed rcts and most articles consisting of case reports, retrospective cohort studies, reviews and prospective cohort studies. moreover, more than half of the identified articles were published in journals with an if of <1 and only 2.3% were published in journals with an if of ≥7. these findings suggest that there is a lack of support for research in saudi arabia and that further action is required to promote the publication of saudi arabian research in high-impact medical journals. as such, one recommendation would be to establish clinical academic departments in institutions so as to ensure and monitor the quality of research output. in the current study, most neurology-related publications originated from the two largest cities in saudi arabia—riyadh and jeddah—with very little contribution from other cities. tadmouri et al. similarly observed that the vast majority of biomedical research from saudi arabia between 1982–2000 originated from riyadh, with all other cities together accounting for only 30% of the total research output.6 despite the recent establishment of new universities, colleges, hospitals and research centres in other saudi arabian cities, their contribution to research remains minimal. moreover, the relative contribution of different sectors indicated that most neurology research was conducted by universities, with the saudi arabian ministry of health and private hospitals producing very few papers. in addition, newer universities were found to produce fewer neurology-related publications, with most originating from the more established king saud university and king abdulaziz university. it could be argued that the newer institutions were created principally to educate medical students and provide health services to the local population rather than to conduct research; however, the authors of the current study believe that all medical colleges should actively engage in research and that medical education should be provided hand-in-hand with research training. furthermore, the promotion of academic staff at universities often depends upon the publication of a certain number of articles in scientific journals. close monitoring and strict regulations for academic promotions at saudi arabian institutions should therefore be implemented to encourage the publication of high-quality research. to the best of the authors’ knowledge, this study is the first to analyse neurology research productivity in saudi arabia. in order to avoid inaccuracies, each article was screened manually to exclude false-positive results and articles with duplicated content in multiple journals. however, the quantitative analysis was limited to neurology-related publications only and primarily addressed frequency of publication; the quality of the research or its benefits to the medical field or general public were not analysed. further studies are therefore recommended to analyse these aspects of neurology research productivity in saudi arabia. conclusion while neurology research in saudi arabia was found to have increased over the last 20 years, most articles were published in journals with low ifs. thus, the quality of research publications must be improved. it was also noted that most research was conducted by government-run institutions, with few contributions from private institutions. it is therefore vital that the importance of establishing a research culture in governmental and private universities, colleges and figure 6: percentage of neurology-related publications from saudi arabia between january 1996 and december 2015 by research design (n = 1,292). rcts = randomised controlled trials. neurology research in saudi arabia urgent call for action e328 | squ medical journal, august 2017, volume 17, issue 3 health institutions be promoted so as to increase research productivity in the country. to this end, the authors recommend the establishment of clinical academic departments at higher education institutions to promote and monitor research output. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. macilwain c. science economics: what science is really worth. nature 2010; 465:682–4. doi: 10.1038/465682a. 2. meo sa, hassan a, usmani am. research progress and prospects of saudi arabia in global medical sciences. eur rev med pharmacol sci 2013; 17:3265–71. 3. jamjoom ab. state of clinical neuroscience research in saudi arabia: where do we rank in the world? neurosciences (riyadh) 2016; 21:268–70. doi: 10.17712/nsj.2016.3.20160001. 4. science citation index. lancet impact factor. from: www.scijournal. org/impact-factor-of-lancet.shtml accessed: mar 2017. 5. latif r. medical and biomedical research productivity from the kingdom of saudi arabia (2008-2012). j family community med 2015; 22:25–30. doi: 10.4103/2230-8229.149583. 6. tadmouri go, tadmouri nb. biomedical research in the kingdom of saudi arabia (1982-2000). saudi med j 2002; 23:20–4. https://doi.org/10.1038/465682a https://doi.org/10.17712/nsj.2016.3.20160001 https://doi.org/10.4103/2230-8229.149583 taurine levels in human aqueous humour medical sciences (2000), 2, 125–126 © 2000 sultan qaboos university department of surgery, college of medicine, sultan qaboos university, p o box 35 al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. 125 laparoscopic deroofing of hepatic cyst *al kindy n m, grant c s, daar a s أزالة سقف آيس آبدي بواسطة المنظار داعر عبداهللا غرانت، توفرآريس الكندي، نائل وعندها أعراض الى األآياس هذه تؤدي ما نادراو عالج الى تحتاج وال جانبية أعراض بدون المعزولة الالطفيلية الكبدية األآياس تكون ما عادة: الملخص الكيس سقف بإزالة بالمنظار عالجناها حالةنعرض . لجد موضع اليزال لألعراض المسببة األآياس لهذه جراحي عالج وأفضل. جراحيا أستئصالها يفضل .ومؤثرة سليمة الطريقة جدليا وهذه abstract: solitary non-parasitic cysts of the liver are commonly asymptomatic and do not require treatment. rarely, the cysts become symptomatic and are then best treated surgically. the optimal surgical treatment is debatable. we report a case treated by laparoscopic deroofing which is arguably a safe and effective approach. key words: solitary non-parasitic liver cysts; laparoscopic deroofing ost non-parasitic solitary liver cysts are asymptomatic and need no treatment. symptoms result from either an increase in the size of the cyst or the development of complications.1 symptomatic or large solitary non-parasitic hepatic cysts are best treated surgically, though this in the past meant open surgery with its attendant morbidity and long hospital stay. the minimally invasive laparoscopic approach is of late being reported to be a safe and effective alternative.2–5 we report the case of a symptomatic large solitary non-parasitic hepatic cyst treated by laparoscopic deroofing of the external part of the cyst wall. patient and method a 46-year-old omani woman presented with an 8month history of progressive right hypochondrial pain. the liver edge was palpable 10 cm below the costal margin. abdominal ultrasound and ct scan showed a large, solitary smooth-walled unilocular cyst, 17 cm in diameter, located in the right lobe of the liver (figure 1). the cyst had been aspirated once in another local hospital 6 months prior to her presentation, and cytology of the fluid had been reported as negative. serological tests for hydatid liver disease were negative and an upper gastrointestinal endoscopy was normal. under general anaesthesia and carbon dioxide pneumoperitoneum, a 30-degree laparoscope was introduced through a 10-mm cannula inserted through a subumbilical incision. the cyst was clearly seen. a second 10-mm cannula was inserted in the epigastrium to the right of the midline and a further 5-mm cannula was inserted in the right subcostal region just lateral to the midclavicular line. laparoscopy-guided percutaneous needle aspiration was carried out to decompress the cyst and to avoid leakage of the cystic fluid into the abdominal cavity. a total of 1,200 ml of clear serous fluid was aspirated. urgent cytology of the cystic fluid showed no malignant cells or scolices. the cyst wall was next widely deroofed using diathermy scissors and hook, excising all of the nonparenchymal cyst wall. bleeding from the cut edge was minimal and easily controlled with diathermy. the excised cyst wall (6.5 x 9 cm) was then removed through the epigastric port. a small suction drain was inserted through the right subcostal 5-mm cannula, and placed within the cavity of the cyst, after which the pneumoperitoneum was deflated. the instruments were then removed and the wounds closed. total operating time was 90 minutes. the patient's recovery was rapid and uneventful; the drain was removed on the second postoperative day, and the patient discharged home on the third postoperative day. twelve months after the operation, she remains asymptomatic with no recurrence. histology of the cyst wall showed only a dense fibrovascular tissue, lined with cuboidal cells, confirming the benign nature. discussion non-parasitic solitary hepatic cysts are considered to be retention cysts, which result from inflammatory hyperplasia and obstruction of congenital aberrant bile ducts.1 most are small and remain asymptomatic, though a few cysts occasionally increase in size and eventually cause symptoms. in the absence of complications, symptoms m a l k i n d y e t a l 126 from solitary non-parasitic liver cysts are almost always the result of a space-occupying effect of the cyst either on the liver itself or on adjacent viscera.1 figure 1. computed tomographic scan showing a large 17 cm diameter solitary unilocular cyst in the right lobe of the liver. non-surgical treatment in the form of percutaneous ultrasound-guided aspiration of the cyst, followed by injection of a sclerosing agent, is associated with an unacceptably high recurrence rate.6 current surgical management relies on fenestration or deroofing of the cyst as described by lin in 1968,7 with or without placement of an omental flap into the residual cyst cavity to prevent the edges from co-apting. recently, the laparoscopic approach to this technique has been shown to be feasible and safe.3–5 precise preoperative assessment of the location of the cyst with ct scans is necessary as cysts located posteriorly in segments vi and vii of the liver are difficult to approach laparoscopically.5 intra-operative localization of the cyst is also crucial as the laparoscopic approach can be limited by the lack of manual palpation. superficial cysts are obvious or easily localized by aspiration at laparoscopy as in our case. intra-operative ultrasound should be used to confirm the anatomy, especially where the cyst is not obvious on surface laparoscopy. laparoscopic ultrasound provides accurate anatomical localization of lesions and identifies adjacent vascular pedicles.8 the wide deroofing of superficial cysts can be achieved by using diathermy which is satisfactory for both dissection and haemostasis3,4 but the ultrasonic coagulating shears may be considered ideal because they provide excellent haemostasis in a relatively smoke-free environment.8 with careful selection of cases, laparoscopic deroofing of symptomatic solitary hepatic cysts is safe and effective, and offers all the advantages of minimally invasive surgery.9,10 patients with symptomatic polycystic liver disease characterised by a limited number of large cysts mainly located on the liver surface have also been reported to benefit from the laparoscopic technique.2,3 references 1. jones wl, mountain jc, warren kw. symptomatic non-parasitic cysts of the liver. br j surg 1978, 61, 118–23. 2. paterson-brown s, garden oj. laser-assisted laparoscopic excision of liver cyst. br j surg 1991, 78, 1047. 3. morino m, degiuli m, festa v, garrone c. laparoscopic management of symptomatic nonparasitic cysts of the liver. ann surg 1994, 219, 157– 64. 4. ker cg, chen js, lee kt, sheen pc. laparoscopic fenestration for a giant liver cyst. endoscopy 1994, 26, 754. 5. krahenbuhl l, baer hu, renzulli p, zgraggen k, frei e, buchler mw. laparoscopic management of nonparasitic symptom-producing solitary hepatic cysts. j am coll surg 1996, 183, 493–8. 6. saini s, mueller pr, ferrucci jt jr, simeone jf, wittenberg j, butch rj. percutaneous aspiration of hepatic cysts does not provide definitive therapy. am j roentgenol 1983, 141, 559–60. 7. lin ty, chen cc, wang sm. treatment of nonparasitic cystic disease of the liver: a new approach to therapy with polycystic liver. ann surg 1968, 921–7. 8. martin i, garden oj. laparoscopic radical deroofing of hepatic cysts using the ultrasonic scalpel. aust nz j surg 1999, 69, 743–4. 9. klinger pj, gadenstatter m, schmid t, bodner e, schwelberger hg. treatment of hepatic cysts in the era of laparoscopic surgery. br j surg 1997, 84, 438–44. 10. martin ij, mckinley aj, currie ej, holmes ph, garden oj. tailoring the management of non-parasitic liver cysts. ann surg 1998, 228, 167–72. laparoscopic deroofing of hepatic cyst patient and method discussion figure 1. computed tomographic scan showing a large 17 cm diameter solitary unilocular cyst in the right lobe of the liver. references رد: سرطان اخلاليا الصغرية يف الغدد الصم العصبية من عنق الرحم تشابه ورم عنق الرحم الليفي تقرير حالة نادرة re: small-cell neuroendocrine carcinoma of the cervix masquerading as a cervical fibroid report of a rare entity dear editor, i read with interest the recent case report by pujani et al. published in the february 2018 issue of squmj in which the authors describe a case of small-cell neuroendocrine carcinoma (snec) of the cervix in a 44-year-old indian woman.1 i presume, given the rarity of this condition and the highly aggressive nature of the tumour, the authors have considered that the reported patient may have had an altered immune status.1 in india, hiv infection is a sizable health problem, with available data indicating a heightened seroprevalence of 0.26% compared to the global average of 0.2%.2 among those with altered immune states, hiv status is of the utmost importance. my presumption is based on the fact that hiv-infected patients are more vulnerable to various types of tumours compared to immunocompetent individuals. this increased vulnerability has been attributed to various factors, including suppressed immunity, associated infection with oncogenic viruses and prolonged life expectancy due to antiretroviral treatment.3 high rates of cervical cancer have been reported among hiv-infected patients.4 furthermore, genital cancers are found to occur in a substantial proportion of hiv-infected women in india.5 hence, a diagnostic blood workup, cluster of differentiation (cd)4 count and viral overload measurements should have been conducted in order to determine the hiv status of the reported patient.1 if the patient was subsequently found to have an hiv infection, the case in question would surely be considered novel as, to the best of my knowledge, hiv-associated snec of the cervix has not been reported in the literature to date. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. pujani m, singh k, chauhan v, chawla r, ahuja r. small-cell neuroendocrine carcinoma of the cervix masquerading as a cervical fibroid: report of a rare entity. sultan qaboos univ med j 2018; 18:e100–3. doi: 10.18295/squmj.2018.18.01.017. 2. paranjape rs, challacombe sj. hiv/aids in india: an overview of the indian epidemic. oral dis 2016; 22:10–4. doi: 10.1111/odi.12457. 3. valencia ortega me. malignancies and infection due to the human immunodeficiency virus: are these emerging diseases? rev clin esp 2018; 218:149–55. doi: 10.1016/j.rce.2017.07.011. 4. kohler re, tang j, gopal s, chinula l, hosseinipour mc, liomba ng, et al. high rates of cervical cancer among hiv-infected women at a referral hospital in malawi. int j std aids 2016; 27:753–60. doi: 10.1177/0956462415592999. 5. sharma sk, soneja m, ranjan s. malignancies in human immunodeficiency virus infected patients in india: initial experience in the haart era. indian j med res 2015; 142:563–7. doi: 10.4103/0971-5916.171283. letter to the editor sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e252–253, epub. 9 sep 18 submitted 12 apr 18 accepted 21 may 18 doi: 10.18295/squmj.2018.18.02.027 https://doi.org/10.18295/squmj.2018.18.01.017 https://doi.org/10.1111/odi.12457 https://doi.org/10.1016/j.rce.2017.07.011 https://doi.org/10.1177/0956462415592999 https://doi.org/10.4103/0971-5916.171283 mahmood d. al-mendalawi letter to editor | e253 response from a subject editor dear reader, i would like to respond to the above letter to the editor with regards to the aforementioned article by pujani et al.1 small-cell neuroendocrine carcinoma (nec) of the cervix is uncommon and accounts for less than 2% of all cervical cancers.2 although the diagnostic work-up for squamous cell carcinomas (sccs) or adenocarcinomas of the cervix is very well described, the management plan for a cervical nec is essentially extrapolated from that of cervical ssc and/or nec of the lung. up to 85% of cervical nec cases may be caused by the human papilloma virus (hpv), especially strains 16 and 18, with very few case reports implicating hiv in the aetiopathogenesis of this tumour.3,4 overall, nec is an aggressive cancer in which over 50% of patients present at an advanced stage; additionally, patients have a poorer prognosis and a higher chance of recurrence compared to those with sccs or adenocarcinomas of the cervix.5 various factors—including the age of the patient, clinical stage and extent of the disease (i.e. tumour size, parametrial involvement, depth of stromal invasion and lymph node metastasis) and type of treatment (either a radical hysterectomy in the early stages or chemotherapy for advanced disease)—predict survival after treatment.6 in their recent study of the molecular characteristics of cervical nec, xing et al. suggest that the tumour has an aggressive course.7 whereas high-risk hpv is involved at an early stage of oncogenesis, alterations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, k-ras and tumour suppressor p53/breast cancer pathways have been suggested to facilitate the progression of the disease. other mutations include erb-b2 receptor tyrosine kinase 2, c-myc, notch-1, b-cell lymphoma-6 or nuclear receptor coactivator-3.7 in summary, although snec of the cervix is an uncommon cancer, recent research suggests that it follows an aggressive course, regardless of the patient’s immune status.6,7 surveillance for hiv is therefore not routinely recommended and should be considered only in cases wherein the patient’s clinical features or results of routine serological investigations raise suspicion of the disease. ikram a. burney department of medicine, sultan qaboos university hospital, muscat, oman e-mail: ikramburney@hotmail.com references 1. pujani m, singh k, chauhan v, chawla r, ahuja r. small-cell neuroendocrine carcinoma of the cervix masquerading as a cervical fibroid: report of a rare entity. sultan qaboos univ med j 2018; 18: e100–3. doi: 10.18295/squmj.2018.18.01.017. 2. gardner gj, reidy-lagunes d, gehrig pa. neuroendocrine tumors of the gynecologic tract: a society of gynecologic oncology (sgo) clinical document. gynecol oncol 2011; 122:190–8. doi: 10.1016/j.ygyno.2011.04.011. 3. castle pe, pierz a, stoler mh. a systematic review and meta-analysis on the attribution of human papillomavirus (hpv) in neuroendocrine cancers of the cervix. gynecol oncol 2018; 148:422–9. doi: 10.1016/j.ygyno.2017.12.001. 4. balega j, ulbright tm, look ky. coexistence of metastatic neuroendocrine carcinoma of the uterine cervix with human immunodeficiency virus infection. int j gynecol cancer 2001; 11:334–7. doi: 10.1046/j.1525-1438.2001.011004334.x. 5. hou wh, schultheiss te, wong jy, wakabayashi mt, chen yj. surgery versus radiation treatment for high-grade neuroendocrine cancer of uterine cervix: a surveillance epidemiology and end results database analysis. int j gynecol cancer 2018; 28:188–93. doi: 10.1097/ igc.0000000000001143. 6. zhang q, xiong y, ye j, zhang l, li l. influence of clinicopathological characteristics and comprehensive treatment models on the prognosis of small cell carcinoma of the cervix: a systematic review and meta-analysis. plos one 2018; 13:e0192784. doi: 10.1371/journal. pone.0192784. 7. xing d, zheng g, schoolmeester jk, li z, pallavajjala a, haley l, et al. next-generation sequencing reveals recurrent somatic mutations in small cell neuroendocrine carcinoma of the uterine cervix. am j surg pathol 2018; 42:750–60. doi: 10.1097/pas.0000000000001042. https://doi.org/10.18295/squmj.2018.18.01.017 https://doi.org/10.1016/j.ygyno.2011.04.011 https://doi.org/10.1016/j.ygyno.2017.12.001 https://doi.org/10.1046/j.1525-1438.2001.011004334.x https://doi.org/10.1097/igc.0000000000001143 https://doi.org/10.1097/igc.0000000000001143 https://doi.org/10.1371/journal.pone.0192784 https://doi.org/10.1371/journal.pone.0192784 https://doi.org/10.1097/pas.0000000000001042 squ med j, november 2011, vol. 11, iss. 4, pp. 515-518, epub. 25th oct 11 submitted 15th jan 11 revision req. 6th mar 11, revisions recd. 1st may & 2nd sep 11 accepted 2nd oct 11 prior to the advent of laparoscopy, laparotomy and open repair of intraperitoneal bladder injuries was thought to be necessary in all cases. laparoscopic surgery offered new possibilities in treating traumatic intraperitoneal bladder ruptures. laparoscopy as a diagnostic modality in trauma has been reported; however, therapeutic laparoscopy for trauma remains a controversial subject. the reason for the controversy is that laparoscopy might not identify occult small bowel perforation unless it is done by an experienced laparoscopic surgeon who can examine the bowel laparoscopically. the most common cause of bladder rupture is blunt trauma to the lower abdomen associated with pelvic fractures. traumatic intraperitoneal bladder rupture is a true surgical emergency managed conventionally by open laparotomy with single layer or double layer repair. 1 case report a 37 year-old driver, who was wearing a seat belt, was involved in a motor vehicle collision and brought by the emergency medical services to the emergency department of sultan qaboos university hospital. he had no history of loss of consciousness or vomiting. he complained of severe left hip pain. on physical examination, he was confused with glasgow coma scale 14, but no neurological deficit. he had normal vital signs with blood pressure of 105/60 mmhg, a pulse rate of 63 beats per min and normal oxygen saturation. he had a left periorbital haematoma, multiple abrasions in his face and small lacerated wounds on the left forehead and cheek. his abdomen was distended and tense with multiple small abrasions, but there was no tenderness. he had multiple bruising and abrasions on his lower limbs. his left hip was flexed and medially rotated. an x-ray of the departments of 1surgery, 2emergency medicine, sultan qaboos university hospital, muscat, oman. *corresponding author email: hani_qadhi@hotmail.com العالج عن طريق اجلراحة باملنظار لتمزق املثانة داخل الصفاق �ضعاد الأغربي، عبداهلل احلارثي، م�ضطفى اأحمد، عبداهلل الري�ضي، خليفة الوهيبي، هاين القا�ضي امللخ�ص: متزق املثانة داخل ال�ضفاق حدث غري �ضائع وينتج عادة عن ك�ضور احلو�س، وُيَعّد من حالت الطوارئ اجلراحية التي تعالج على نحو تقليدي بعملية فتح البطن مع اإ�ضلح طبقة واحدة اأو مزدوجة. هذا و�ضف لعملية ناجحة باملنظار حلالة متزق مثانة داخل ال�ضفاق نتيجة �ضدمة كليلة يف منطقة البطن وك�رس يف احلو�س لرجل عمره 37 �ضنة. وقد اأجريت له عملية ناجحة باملنظار با�ضتخدام طبقة اإ�ضلح واحدة. مفتاح الكلمات: داخل ال�ضفاق، مثانة، متزق، اإ�ضلح باملنظار، تقرير حالة، ُعمان. abstract: intraperitoneal rupture of the bladder is an uncommon condition that is usually caused by pelvic fractures. this is a true surgical emergency managed conventionally by open laparotomy with single or double layer repair. we present a case of successful laparoscopic repair of an intraperitoneal bladder rupture secondary to blunt abdominal trauma and pelvic fracture in a 37 year-old man. the repair was done using single layer repair, with successful results. keywords: intraperitoneal; urinary bladder; rupture; laparoscopic repair; case report; oman. laparoscopic repair of traumatic intraperitoneal bladder rupture suad al-aghbari,1 abdullah al-harthy,1 moustafa ahmed,2 abdullah al-reesi,2 khalifa al-wahaibi,1 *hani al-qadhi1 case report laparoscopic repair of traumatic intraperitoneal bladder rupture 516 | squ medical journal, november 2011, volume 11, issue 4 pelvis showed left hip dislocation with a fractured acetabulum [figure 1]. a foley catheter was inserted as there were no signs of urethral injury, and there was gross haematuria. a contrast abdominal computed tomography (ct) scan revealed a moderate amount of free fluid in the abdomen and pelvis with a laceration of the anterior pole of the spleen and a 3 cm liver laceration. the kidneys and ureters were normal. the abdominal ct was followed by a ct cystogram which revealed intraperitoneal extravasation of contrast seen from the bladder [figure 2]. the posterior dislocation of the left hip and the fracture of the posterior margin of the acetabulum were also identified [figure 1]. a ct scan of the head showed fractures of the left mandible and zygoma bones, and damage to the pterygoid muscle, and the lateral wall of the left maxillary sinus. the trauma team then planned for an emergency laparoscopic repair of the bladder rupture. during the operation, a three port-technique and a 30-degree angle 10 mm camera were used and the findings were minimal blood collection in the pelvis about 15 ml with a 4 cm bladder rupture at the dome [figure 3]. the laceration was sutured with a continuous single layer of absorbable suture 2/0 vicryl. then the repair was tested by injecting 500 ml of normal saline into the bladder through the foley catheter; no leak was noticed from the suture line. a drain was then placed in the perivesical space to monitor postoperatively for possible urine extravasation. the bladder repair was combined with an orthopaedic procedure, where a closed reduction of the left hip dislocation and skeletal traction, using a pin to the proximal tibia, were performed. postoperatively, the patient was admitted to the surgical high dependency area. he had a threeway foley catheter with continuous irrigation until his urine became clear. daily monitoring of his complete blood count, liver function test, urea and electrolytes revealed normal results. a broadspectrum antibiotic and low molecular weight heparin, as prophylaxis for deep vein thrombosis, were administered. he was managed in conjunction with the ophthalmologist, and otolaryngological, maxillofacial and orthopaedic surgeons for the associated injuries and treated accordingly. on the 7th postoperative day, a cystogram revealed no leakage, so the foley catheter and the intraperitoneal drain were removed and he had an uneventful recovery. discussion bladder catheterisation for extratroperitoneal perforation and cystorrhaphy for intraperitoneal perforations are well established treatment recommendations for bladder rupture.2 traumatic intraperitoneal bladder rupture always requires surgical exploration and suturing. this type of damage is usually repaired by laparotomy, often because of accompanying figure 1: coronal non-contrast computed tomography scan shows a fractured and dislocated left hip joint. figure 2: axial computed tomography cystogram scan showing free intra-peritoneal extravasation of contrast from the anterior left lateral wall of the urinary bladder. suad al-aghbari,abdullah al-harthy, moustafa ahmed, abdullah al-reesi, khalifa al-wahaibi and hani al-qadhi case report | 517 damage to other organs and pelvic bone fractures. in addition, this type of injury does not heal with prolonged catheterisation alone.3 the first case of successful laparoscopic repair of iatrogenic intraperitoneal bladder rupture was reported in 1990. subsequently, a number of cases using the laparoscopic approach have been reported for the treatment of traumatic, spontaneous and iatrogenic bladder rupture.4 the first case of laparoscopic repair of traumatic intraperitoneal bladder rupture was reported in 1996,5 and the first case of laparoscopic repair of idiopathic intraperitoneal bladder rupture was reported in 1997.6 a literature review supports the fact that laparoscopy can be used safely and effectively instead of open laparotomy for the diagnosis and treatment of traumatic abdominal injuries.7 figueiredo et al. found in their case of a 20 year-old female, who suffered ventral collision and a 5 cm bladder rupture in the dome after a fall from the second floor, that in stable patients the laparoscopic approach is a less traumatic treatment allowing visualisation of the entire peritoneal cavity to exclude other lesions and offers the shortest recovery time.8 mikulskajovanovic et al. concluded in their report on a 34 year-old male, who suffered blunt lower abdomen injury, that laparoscopy is an effective and timely way to treat this type of injury, gives a favourable cosmetic effect, shortens the time of hospitalisation, and reduces the risk of wound infection after the operation.9 this conclusion was corroborated by kim et al. in their report.3 matsui et al. reported a case of extraperitoneal and intraperitoneal traumatic bladder injury successfully managed with combined endoscopic and laparoscopic procedures.10 laparoscopy can avoid laparotomy in 63% of the cases, decreasing its associated morbidity.11 as was shown in several studies, there was no difference in outcome between single layer repair3,8,9 and double layer repair.12-14 in haemodynamically stable patients without diffuse peritonitis, diagnostic laparoscopy is an effective intervention in stab wounds, gunshot wounds with questionable peritoneal penetration and in blunt trauma with free peritoneal fluid or equivocal physical examination.8 conclusion laparoscopy can be a safe, feasible and effective procedure for the evaluation and treatment of haemodynamically stable patients with abdominal trauma. it can reduce the number of nontherapeutic laparotomies performed. laparoscopic repair of traumatic intraperitoneal rupture of urinary bladder is an effective and timely way to treat this type of injury. it has the advantage of being less traumatic, enables exclusion of other peritoneal injuries, is cosmetically acceptable, and reduces both length of hospital stay and infection risk. references 1. bhanot a, bhanot a. laparoscopic repair in intraperitoneal rupture of urinary bladder in blunt trauma abdomen. surg laparosc endosc percutan tech 2007; 17:58–9. 2. gunnarsson u, heuman r. intraperitoneal rupture of the urinary bladder: the value of diagnostic laparoscopy and repair. surg laparosc endosc 1997; 7:53–5. 3. kim fj, chammas mf jr, gewehr ev, campagna a, moore ee. laparoscopic management of intraperitoneal bladder rupture secondary to blunt abdominal trauma using intracorporeal single layer suturing technique. j trauma 2008; 65:234–6. 4. reich h, mcglynn f. laparoscopic repair of bladder injury. obstet gynecol 1990; 76:909–10. 5. iselin ce, rohner s, tuchschmid y, schmidlin f, graber p. laparoscopic repair of traumatic intraperitoneal bladder rupture: urol int 1996; 57:119–21. 6. gunnarsson u, heuman r. intraperitoneal rupture of the urinary bladder: the value of diagnostic laparoscopy and repair. surg laparosc endosc 1997; 7:53–5. figure 3: laparoscopic view of the abdomen showing 4 cm bladder rupture in the dome. laparoscopic repair of traumatic intraperitoneal bladder rupture 518 | squ medical journal, november 2011, volume 11, issue 4 7. yun tk, seo si, kim jc, park yh, hwang tk. laparoscopic repair of traumatic intraperitoneal urinary bladder rupture. korean j urol 2003; 44:372– 4. 8. figueiredo aa, tostes jgt, jacob mvm. laparoscopic treatment of traumatic intraperitoneal bladder rupture. international braz j urol 2007; 33:380–2. 9. mikulska-jovanovic m, kraśnicki k, wolski z, dąbrowiecki s, gniłka w laparoscopic treatment of traumatic bladder rupture. centr europ j urol 2009; 62:2. 10. matsui y, ohara h, ichioka a, terada n, yoshimura k, terai a. traumatic bladder rupture managed successfully by laparoscopic surgery. int j urol 2003; 10:278–80. 11. gorecki pj, cottam d, angus ld, shaftan gw. diagnostic and therapeutic laparoscopy of trauma: a technique of safe and systematic exploration. surg laparosc endosc percutan tech 2002; 12:195–8. 12. cottam d, gorecki pj, curvelo m, shaftan gw. laparoscopic repair of traumatic perforation of the urinary bladder. surg endosc 2001; 15:1488–9. 13. yee ds, kalisvaart jf, borin jf. preoperative cystoscopy is beneficial in selection of patients for laparoscopic repair of intraperitoneal bladder rupture. j endourol 2007; 21:1145–8. 14. burkner a, neuhaus v, shob o. ascites and hematuria after falling in an alcoholic patient. praxis (bern 1994) 2010; 99:191–3. department of obstetrics & gynaecology, royal hospital, muscat, oman *corresponding author e-mail: nooralqabas@hotmail.com دراسة فاعلية ميسوبروستول كعالج غري جراحي حلاالت اإلجهاض يف الثلث األول من احلمل خربة املستشفى السلطاين، عمان قمرية اأمبو�سعيدية و اأنيتا زت�سي abstract: objectives: non-invasive methods of inducing a miscarriage are now considered an effective alternative to surgical evacuation (dilatation and curettage). this study aimed to evaluate the effectiveness of misoprostol in the termination of first-trimester miscarriages. methods: this prospective study was conducted between october 2009 and september 2010 and assessed all patients admitted to the royal hospital in muscat, oman, for the termination of first-trimester miscarriages during the study period. all patients received misoprostol and the rates of successful termination were measured. patient satisfaction was assessed using a short questionnaire. results: a total of 290 women were included in the study. termination with misoprostol was successful in 61.38% of the subjects. of the remaining subjects requiring additional surgical evacuation (n = 112), 58.93% required evacuation due to failed termination with misoprostol and 65.18% underwent early evacuation (≤24 hours since their last misoprostol dose). the majority of patients experienced no side-effects due to misoprostol (89.66%). pain was controlled with simple analgesics in 70.00% of the subjects. a high satisfaction rate (94.83%) with the misoprostol treatment was reported. conclusion: misoprostol was a well-tolerated drug which reduced the rate of surgical evacuation among the study subjects. this medication can therefore be used safely in the management of incomplete miscarriages. keywords: misoprostol; first trimester pregnancy; miscarriage; incomplete abortion; dilation and curettage; oman. امللخ�ص: الهدف: تعترب العالجات غري اجلراحية حلث الإجها�ض˗يف الوقت احلايل˗فعالة و بدائل ماأمونة للتفريغ اجلراحي. هدفت هذه ا�ستطالعية )م�ستقبلية( درا�سة احلمل. الطريقة: من الأول الثلث يف احلمل˗الإجها�ض لإنهاء املي�سوبرو�ستول فاعليةعقار لتقييم الدرا�سة يف الفرتة ما بني اأكتوبر 2009 و �سبتمرب 2010. �سمت الدرا�سة جميع املري�سات اللواتي مت قبولهن يف ق�سم اأمرا�ض الن�ساء يف امل�ست�سفى ال�سلطاين˗م�سقط، �سلطنة عمان˗لإنهاء الإجها�ض يف الثلث الأول من احلمل با�ستخدام اأقرا�ض املي�سوبرو�ستول. مت قيا�ض فاعلية العالج املي�سوبرو�ستول عقار جنح الدرا�سة. يف مري�سة 290 �ساركت النتائج: ق�سري. با�ستبيان للعالج املري�سات قبول م�ستوى تقييم مت كما ب�سبب منهن 58.93% اجلراحي، التفريغ لعملية حالة 112 خ�سعت الدرا�سة. يف امل�ساركات من 61.38% يف الإجها�ض اإحداث يف كان ف�سل املي�سوبرو�ستول. وقد لوحظ اأن التفريغ اجلراحي قد مت خالل فرتة اأق�رس من 24 �ساعة من اأخذ اأقرا�ض املي�سوبرو�ستول يف 65.18% من احلالت. مل تكن هناك اأي م�ساعفات يف %89.66 من احلالت. مت ت�سكني الأمل ل %70.00 من احلالت مب�سكنات ب�سيطة. تقبلت معظم املري�سات العالج ب�سكل جيد. اخلال�صة: املي�سوبرو�ستول هو دواء جيد وي�ساعد على تقليل معدل عمليات التفريغ اجلراحي و ميكن ا�ستخدامه باأمان لعالج حالت الإجها�ض غري املكتمل. مفتاح الكلمات: املي�سوبرو�ستول؛ الثلث الأول من احلمل؛ اإجهَا�ض؛ اإجها�ض غري مكتمل؛ تفريغ جراحي للرحم؛ عمان. effectiveness of misoprostol for induction of first-trimester miscarriages experience at a single tertiary care centre in oman *qamariya ambusaidi and anita zutshi advances in knowledge this study is the first in oman to investigate the effectiveness of misoprostol in inducing first-trimester miscarriages. results from this study showed that the medication had minimal side-effects among the studied group of women. application to patient care surgical evacuations can result in complications that affect future obstetric outcomes, including cervical incompetence, uterine perforation, intrauterine adhesions and morbidly adherent placenta. misoprostol is a non-invasive alternative to induce miscarriage and avoid these potential complications. misoprostol is currently not available in all hospitals in oman. the results of this study may help to encourage wider utilisation of this medication in inducing miscarriages. clinical & basic research sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e534–538, epub. 23 nov 15 submitted 4 feb 15 revision req. 10 may 15; revision recd. 17 may 15 accepted 18 jun 15 doi: 10.18295/squmj.2015.15.04.016 qamariya ambusaidi and anita zutshi clinical and basic research | e535 miscarriage is defined as a pregnancy that ends spontaneously before the fetus is viable. the most common complication of early pregnancy is miscarriage; robledo et al. estimated that approximately 8–20% of clinically recognised pregnancies under 20 gestational weeks end in miscarriage, with 80% occurring in the first 12 gestational weeks.1 three options exist for managing a miscarriage in a patient: expectant management, surgical evacuation or medical/pharmaceutical management. while surgical evacuation is a fast and effective procedure when performed by a well-trained physician, it is nevertheless a blind and invasive procedure that carries a risk of injury, bleeding and infection, in addition to possible complications from the anaesthesia. medical methods for the induction of miscarriage are now considered an effective alternative to surgical evacuation. prostaglandin analogues, of which misoprostol is the most common, are widely utilised in several countries. in 2009, 40%, 72% and 76% of abortions were induced via medication in the uk, sweden and finland, respectively.2 misoprostol is a synthetic prostaglandin e1 analogue which causes uterine contractions and softening and dilation of the cervix. it has been used offlabel in the management of miscarriage, postpartum haemorrhage, induction of labour and ripening of the cervix.3 although misoprostol is not yet licensed by the food and drug administration in the usa for the above indications, pregnancy was removed from the list of absolute contraindications to misoprostol use in 2002.4 the advantages of misoprostol include its low cost, long shelf life, lack of need for refrigeration and worldwide availability.3 the aim of this study was to evaluate the success of misoprostol as an agent for medical termination in first-trimester miscarriages at the royal hospital, muscat, oman. methods this prospective study was conducted between october 2009 and september 2010 and included all patients admitted for the termination of a firsttrimester miscarriage to the gynaecology ward at the royal hospital during the study period. the exclusion criteria were termination of a viable pregnancy and absolute contraindications for misoprostol, including patients with a suspected or confirmed ectopic pregnancy, gestational trophoblastic diseases, a high risk of uterine rupture, an intrauterine device in situ, an allergy to prostaglandins or haemodynamic instability. women who underwent a medical termi nation of pregnancy for maternal or fetal indications were excluded from the study and only those with a diagnosis of an incomplete or missed/silent miscarriage were included. all subjects underwent a thorough physical examination. baseline characteristics, inclu ding age, parity, gestational age and type of miscarriage, were obtained. a complete blood count was performed to assess pre-treatment haemoglobin levels in all candidates, in addition to blood grouping. rhesus typing and antibody screening tests were also performed. all of the subjects were given misoprostol according to hospital protocol. patients with incomplete miscarriages received a single oral dose of 600 µg of misoprostol. those with missed miscarriages received vaginal misoprostol with a maximum of three doses of 800 µg every 24 hours. vaginal misoprostol was avoided for patients with vaginal bleeding or leaking and for those with a high white blood cell count. in such cases, the same dose was given orally. for patients with previous uterine scarring, a half dose of misoprostol was given. all of the subjects were admitted as inpatients to monitor bleeding and the development of any side-effects. patients’ analgaesia requirements were also recorded. all patients with rhesus-negative blood were given an anti-d immunoglobulin injection before discharge. the complete miscarriage rate was determined to assess the efficacy of misoprostol. complete miscarriages were defined as successful cases that did not require surgical evacuation after the administration of misoprostol. ultrasonography was performed on each patient to confirm that no products of conception remained. diagnosis of a complete miscarriage was based on the clinical judgment of the attending obstetrician. however, an endometrial thickness of 14 mm was considered to be the cut-off value for a complete miscarriage. retained products of conception indicated the need for a surgical evacuation. the time interval between the last dose of misoprostol and surgical evacuation was also assessed. following the completion of their treatment with misoprostol, patient satisfaction was determined using a short questionnaire. responses to the following two questions were recorded: “are you satisfied with the treatment?” and “if you have a similar problem in the future, are you going to use misoprostol again?”. data were analysed using the statistical package for the social sciences (spss), version 17.0 (ibm corp., chicago, illinois, usa). this study was approved by the medical ethics & scientific research committee of the royal hospital (mesrc #37). all patients gave informed verbal consent prior to their inclusion in the study. effectiveness of misoprostol for induction of first-trimester miscarriages experience at the royal hospital, oman e536 | squ medical journal, november 2015, volume 15, issue 4 results a total of 290 women with first-trimester miscarriages were admitted to the royal hospital during the study period. the mean age was 32.9 years and mean parity was 2.6. the majority of the subjects were admitted due to a diagnosis of incomplete miscarriage (63.45%). fetal age ranged from 5–12 gestational weeks with a mean age of 9.4 gestational weeks. the overall rate of complete termination with misoprostol was 61.38%, while 38.62% of cases required further surgical evacuation. a total of 112 patients underwent surgical evacuation. the indications for surgical evacuation are shown in figure 1. the vast majority of patients discontinued misoprostol and underwent evacuation because of failed termination with the drug (58.93%). the second most common indication was bleeding (19.64%), although seven patients only had postevacuation haemoglobin levels for comparison. four patients experienced a significant drop in haemoglobin levels (>2.0 g/dl). however, only one patient required a blood transfusion. the mean drop in haemoglobin level was 2.2 g/dl [figure 2]. surgical evacuation was carried out for 19 patients who refused to continue the misoprostol treatment. three patients underwent a surgical evacuation due to fever and one patient due to a suspected septic abortion indicated by foul smelling discharge, although a subsequent culture was negative for infection. the distribution of patients undergoing surgical evacuation by miscarriage type is shown in figure 3. early surgical evacuations (within 24 hours of the last dose of misoprostol) were performed for 65.18% of the subjects. after excluding cases with bleeding and suspected infection, 44.64% of the women who underwent a surgical evacuation due to failed termination did so within 24 hours of receiving their last dose of misoprostol. only 10.71% of the patients underwent surgical evacuation after 72 hours [figure 4]. the majority of patients experienced no side-effects from misoprostol (89.66%). the remaining women had the following side-effects: bleeding (7.59%), fever (2.41%) and chills (0.34%). all patients with significant bleeding based on the subjective assessment of the attending doctor underwent surgical evacuation. all of the febrile women had fevers which subsided figure 1: indications leading to surgical evacuation after the use of misoprostol among patients admitted for the termination of first-trimester miscarriages (n = 112). figure 3: distribution of patients undergoing suction evacuation according to their miscarriage diagnosis among patients admitted for the termination of firsttrimester miscarriages (n = 112). figure 2: haemoglobin levels preand post-treatment with misoprostol among patients admitted for the termination of first-trimester miscarriages and who underwent suction evacuation for heavy vaginal bleeding (n = 7). hb = haemoglobin. figure 4: time interval between the last dose of misoprostol and surgical evacuation among patients admitted for the termination of first-trimester miscarriages and requiring evacuation (n = 112). qamariya ambusaidi and anita zutshi clinical and basic research | e537 within 24 hours. none of the patients experienced any gastrointestinal side-effects. only one patient experienced prolonged bleeding lasting for four weeks after management with misoprostol; she underwent a surgical evacuation and subsequent histopathology showed only blood clots with no retained products of conception. analgaesics were offered to all of the patients, but the majority tolerated the pain well. pain was controlled with paracetamol and non-steroidal antiinflammatory drugs (nsaids) such as mefenamic acid, diclofenac sodium tablets or intramuscular injections in 70.00% of patients. of the remaining patients, 26.55% did not require analgesia, while 3.45% received tramadol due to nsaid allergies. in terms of patient satisfaction, 277 subjects (95.52%) said they were satisfied with misoprostol. of these, 275 indicated that they would use it again. despite their satisfaction, the remaining two patients stated that they would not undergo misoprostol treatment a second time due to the longer hospital stay required. of the 13 patients who were not satisfied with misoprostol, two nevertheless stated that they would try it again in the future in order to avoid the potential complications of a surgical evacuation [table 1]. discussion during their reproductive years, 25.00% of all women will experience at least one early pregnancy miscarriage.1 suction evacuation is the usual treatment for miscarriage, regardless of gestational age. in three small randomised controlled trials, expectant management showed a success rate of 79.00% in three days for incomplete miscarriages and only 37.00% in seven days for silent miscarriages.5 there were no differences in complication rates.5 studies have suggested that pregnancy termination efficacy may be higher among early pregnancies (six gestational weeks). faúndes et al. determined that the rate of effectiveness for misoprostol in first-trimester pregnancy terminations was 85.00%.6 davis et al. also reported a success rate of 85.00% for misoprostol.7 however, they noted that post-treatment bleeding occurred for longer periods of time with misoprostol, although none of the patients required a blood transfusion.7 the duration of post-treatment bleeding was difficult to assess in the current study as most cases were straightforward and were therefore followed-up by local general practitioners outside of the royal hospital. chen et al. reported that nearly 30.00% of deliveries in the usa were performed via caesarean section;8 it is therefore not surprising that many women who suffer from miscarriages also have a history of uterine surgery. misoprostol may be a preferable option for these patients. in the present study, there were no cases of uterine rupture or adverse outcomes. misoprostol can be administered at different doses and through different routes (vaginal, oral, sublingual or rectal). a cochrane review of 19 randomised controlled trials indicated that the vaginal route is the best option, with no significant difference in sideeffects.9 vaginal misoprostol administration results in slower absorption of the drug and longer duration of stimulation in comparison to oral administration. the sublingual route avoids the first-pass effect and is associated with more rapid absorption and higher peak levels than those obtained with other routes.9 misoprostol is usually administered vaginally in three doses of 800 µg each; this regimen has been found to yield a success rate of 90.00% in the first trimester, with 80.00% and 95.00% of patients expelling the products of conception within 24 and 48 hours of the dose, respectively.5 the same treatment plan was used in the current study but had lower success rates due to early intervention with surgical evacuation. it should be noted that the majority of patients who underwent a surgical evacuation in the current study did so within 48 hours of their last misoprostol dose. the efficacy of misoprostol is related to the dosage as a lower dose will have a weaker effect. however, the rate of side-effects does not seem to be related to the dosage. while sublingual misoprostol has a similar efficacy to vaginal misoprostol, gemzell-danielsson et al. observed that this route was associated with more frequent side-effects (e.g. diarrhoea).10 different factors may have influenced the decision for surgical evacuation in the current study. importantly, misoprostol was restricted to inpatient use only and there was pressure from both the patients and hospital administration to shorten hospital stays, increase patient turnover and reduced patient overflow and bed shortages. early interventions in first trimester miscarriages could be minimised by the initiation of misoprostol as an outpatient treatment. additionally, table 1: patient satisfaction with the use of misoprostol among patients admitted for the termination of firsttrimester miscarriages (n = 290) willingness to try treatment again in future total no yes satisfaction with treatment no 11 2 13 yes 2 275 277 total 13 277 290 effectiveness of misoprostol for induction of first-trimester miscarriages experience at the royal hospital, oman e538 | squ medical journal, november 2015, volume 15, issue 4 delaying the assessment of misoprostol efficacy until a week after the last dose is recommended. however, more studies on this topic are needed. side-effects of misoprostol are usually transient and self-limiting. the most commonly reported side-effect is vaginal bleeding, which can last for 2–6 weeks. faúndes et al. reported a mean drop in haemoglobin levels of 0.2–1.0 g/dl for patients receiving misoprostol, although blood transfusions were rarely necessary.6 in the current study, the mean drop in haemoglobin was significant, with one patient requiring a blood transfusion. there is no clear reason for this discrepancy; however, pre-existing iron deficiencies and anaemia may have contributed to the low haemoglobin levels detected. abdominal cramping beginning as early as 30 minutes after administration of the drug is another common sideeffect of misoprostol.6 for this reason, most patients in the present study were given analgesics and nsaids concurrently with misoprostol. there is no consensus regarding the use of antibiotics during treatment of miscarriage. although research has shown that the infection rate is lower after a medical/pharmaceutical induction of miscarriage, it is important to note that antibiotics are more commonly used after pharmaceutical inductions rather than surgical evacuations.6 in this study, the decision to use post-procedure antibiotics was left to the treating physician. patient satisfaction is a useful measure to determine the efficacy of any treatment and assess the quality of healthcare provision. additionally, patient satisfaction rates indicate acceptance of a treatment. in the present study, two direct close-ended questions were used to assess satisfaction among the subjects. however, general patient satisfaction was not assessed beyond the acceptance of misoprostol as an alternative to surgical evacuation. ideally, patients should be surveyed regarding a wide range of factors associated with their treatment, including inpatient care, experience with misoprostol, route of misoprostol administration, type of analgesia received and patient-provider relationship. the current study is also limited as a more precise satisfaction rate could have been determined by analysing women who had had previous surgical evacuations and comparing them with women receiving pharmaceutical treatment for a current miscarriage. conclusion misoprostol was an effective treatment for the management of first-trimester miscarriages in the studied group. the administration of misoprostol significantly reduced the surgical evacuation rate with minimal side-effects. subjects reported high rates of satisfaction and acceptance with misoprostol. therefore, misoprostol is recommended as a safe drug for use among outpatients with incomplete miscarriages as an alternative to surgical evacuation. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. robledo c, zhang j, troendle j, barnhart k, creinin md, westhoff c, et al. clinical indictors for success of misoprostol treatment after early pregnancy failure. int j gynaecol obstet 2007; 99:46–51. doi: 10.1016/j.ijgo.2007.04.031. 2. niinimäki m, suhonen s, mentula m, hemminki e, heikinheimo o, gissler m. comparison of rates of adverse events in adolescent and adult women undergoing medical abortion: population register based study. bmj 2011; 342:d2111. doi: 10.1136/bmj.d2111. 3. allen r, o’brien bm. uses of misoprostol in obstetrics and gynecology. rev obstet gynecol 2009; 2:159–68. doi: 10.3909/ riog0055. 4. american college of obstetrician and gynecologists. acog committee opinion: number 283, may 2003 new u.s. food and drug administration labeling on cytotec (misoprostol) use and pregnancy. obstet gynecol 2003; 101:1049–50. doi: 10.1016/s0029-7844(03)00396-x. 5. trinder j, brocklehurst p, porter r, read m, vyas s, smith l. management of miscarriage: expectant, medical, or surgical? results of randomised controlled trial (miscarriage treatment (mist) trial). bmj 2006; 332:1235–40. doi: 10.1136/ bmj.38828.593125.55. 6. faúndes a, fiala c, tang os, velasco a. misoprostol for the termination of pregnancy up to 12 completed weeks of pregnancy. int j gynaecol obstet 2007; 99:s172–7. doi: 10.1016/j.ijgo.2007.09.006. 7. davis ar, hendlish sk, westhoff c, frederick mm, zhang j, gilles jm, et al. bleeding patterns after misoprostol vs surgical treatment of early pregnancy failure: results from a randomized trial. am j obstet gynecol 2007; 196:e1–7. doi: 10.1016/j. ajog.2006.07.053. 8. chen ba, reeves mf, creinin md, gilles jm, barnhart k, westoff c, et al. misoprostol for treatment of early pregnancy failure in women with previous uterine surgery. am j obstet gynecol 2008; 198:e1–5. doi: 10.1016/j.ajog.2007.11.045. 9. canadian pharmacists association. compendium of pharmaceuticals and specialties: the canadian drug reference for health professionals. ottawa, canada: canadian pharmaceutical association, 2005. 10. gemzell-danielsson k, ho pc, gómez ponce de león r, weeks a, winikoff b. misoprostol to treat missed abortion in the first trimester. int j gynecol obstet 2007; 99:s182–5. doi: 10.1016/j.ijgo.2007.09.008. http://dx.doi.org/10.1016/j.ijgo.2007.04.031 http://dx.doi.org/10.1136/bmj.d2111 http://dx.doi.org/10.3909/riog0055 http://dx.doi.org/10.3909/riog0055 http://dx.doi.org/10.1016/s0029-7844%2803%2900396-x http://dx.doi.org/10.1136/bmj.38828.593125.55 http://dx.doi.org/10.1136/bmj.38828.593125.55 http://dx.doi.org/10.1016/j.ijgo.2007.09.006 http://dx.doi.org/10.1016/j.ajog.2006.07.053 http://dx.doi.org/10.1016/j.ajog.2006.07.053 http://dx.doi.org/10.1016/j.ajog.2007.11.045 http://dx.doi.org/10.1016/j.ijgo.2007.09.008 departments of 1oral medicine & radiology and 2conservative dentistry & endodontics, government dental college kozhikode, kozhikode, kerala, india; 3department of oral medicine & radiology, government dental college trivandrum, thiruvananthapuram, kerala, india *corresponding author e-mail: archana.dent@gmail.com استخدام التصوير املقطعي باملوجات املخروطية يف تشخيص وعالج تشوهات األنياب غري املعتاد اأرت�سانا غوباالكري�سنان، اأونكري�سنا ك.، اأنيتا باالن، هاري�س ب. �س. abstract: diagnosis and treatment planning are important for successful endodontic treatment. we report a 24-year old male who presented to the government dental college in kozhikode, kerala, india, in 2015 with pain in his right upper canine. a digital periapical radiograph indicated the presence of a supernumerary tooth superimposing the root of the canine. however, cone-beam computed tomography (cbct) confirmed that the supernumerary tooth was an illusion and that the canine root had a sharp invagination involving the labial and pulpal dentin surfaces, with evidence of periapical bone destruction. a blunt resection was performed at the level of the invagination and the resected end was filled with a dentin substitute. at a one-year follow-up, the patient was asymptomatic and the periapical region appeared to be healing well. this report highlights the importance of cbct in visualising abnormal canine morphology, thus allowing appropriate endodontic treatment. keywords: diagnostic imaging; cone-beam computed tomography; tooth abnormalities; case report; india. امللخ�ص: الت�سخي�س والتخطيط العالجي مهمان لعالج جذور االأ�سنان بنجاح. هذا تقريرحلالة مري�س يبلغ من العمر 24 عاما قدم اإىل كلية طب االأ�سنان احلكومية يف كوزيكود، والية كرياال، الهند، يف عام 2015 مع اأمل يف الناب العلوي االأمين. واأ�سار الت�سوير ال�سعاعي الرقمي ايل وجود �سن زائدة فوق جذر الناب. بعد ذلك، اأظهرت اأ�سعة الت�سوير املقطعي باملوجات املخروطية اأن ال�سن الزائدة كانت وهمية، واأن جذر الناب له اإلتوائة حادة على االأ�سطح ال�سفية واللبية العاجية للثة، مع وجود اأدلة على تاآكل العظام املحيطة. مت اإجراء ا�ستئ�سال على م�ستوى اإلتوائة ومت ح�سو نهاية اجلذر املقطوع. بعد املتابعة ملدة �سنة واحدة، كانت التوجد اأي اأعرا�س على املري�س، ومت االألتئام و ال�سفاء ب�سكل جيد. هذا التقرير ي�سلط ال�سوء على اأهمية الت�سوير املقطعي باملوجات املخروطية يف ت�سخي�س االأنياب غري طبيعية التكوين، مما ي�سمح بالعالج املنا�سب للجذر. الكلمات املفتاحية: الت�سخي�س الت�سويري؛ الت�سوير املقطعي باملوجات املخروطية؛ ت�سوهات االأ�سنان؛ تقرير حالة؛ الهند. use of cone-beam computed tomography in the diagnosis and treatment of an unusual canine abnormality *archana gopalakrishnan,1 unnikrishna k.,2 anita balan,3 haris p. s.1 case report sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e238–240, epub. 20 jun 17 submitted 1 dec 16 revision req. 3 jan 17; revision recd. 18 jan 17 accepted 9 feb 17 doi: 10.18295/squmj.2016.17.02.019 while dental radiology plays a vital role in visualising dental pathologies, it is important that endodontists opt for the right imaging modality to ensure a correct diagnosis and, subsequently, successful treatment. currently, the use of cone-beam computed tomography (cbct) allows visualisation of related anatomic structures in three dimensions, thus improving overall diagnostic efficacy and accuracy in many clinical situations.1,2 in addition, with the ability to obtain a small field of view in cbct imaging, high-resolution images can be obtained while minimising patient exposure to ionising radiation and reducing reconstruction time.3 among endodontists, cbct has become a popular imaging modality as it allows greater insight into root canal morphology and can aid in the early detection of apical pathosis.4 case report a 24-year old male presented to the oral medicine department of the government dental college in kozhikode, kerala, india, in 2015 with a complaint of pain in his right upper canine of four days’ duration. his medical and family history was normal. he had previously undergone an unsuccessful root canal treatment, after which he had been referred to an endodontic specialist. clinically, the crown of the canine appeared to have a normal morphology with evidence of an access opening in the palatal aspect. on palpation, the attached gingiva of the canine revealed a depression 5 mm apical to the gingival margin, very close to a bony prominence. the patient reported that the tooth was tender upon percussion. archana gopalakrishnan, unnikrishna k., anita balan and haris p. s. case report | e239 a digital periapical radiograph of the tooth showed a canine with a short blunt root and attempted root canal preparation with inadequate access to the cavity. the apical third of the root appeared to be superimposed by the crown of an impacted supernumerary tooth [figure 1a]. additional exposure with 10–15 degree changes in horizontal angulation revealed only minimal changes in the position of the supernumerary tooth. in accordance with ‘as low as reasonably achievable’ principles, cbct of the maxilla was performed at a dose of 19 µsv (cs 9300 system, carestream health inc., rochester, new york, usa). the axial, sagittal and transverse cbct reformations were inspected using 0.16 mm slice thicknesses. interestingly, this revealed that there was no supernumerary tooth; instead, the radicular portion of the canine was malformed, with a sharp invagination on the labial aspect of the middle-third of the root involving the labial and pulpal dentin surfaces, giving the appearance of a dens in dente. the entire tooth measured 27.2 mm from the cusp tip to the end of the root, with the invagination 17.1 mm from the cusp tip. in addition, there was an ill-defined radiolucency in the apical and palatal aspect of the apical third of the root, suggestive of periapical bone destruction [figure 1b]. subsequently, an access opening to the tooth was secured via the palatal aspect and the canal was negotiated up to the root tip. biomechanical preparation was performed until the measured length of the invagination and a dentin substitute (biodentine®, septodont, paris, france) was inserted. two weeks later, a labial full-thickness rectangular mucoperiosteal flap was elevated following the administration of local anaesthesia using 2% lidocaine and 1:100,000 adrenaline. there was evidence of dehiscence in the apical third of the root. the labial cortical plate coronal to the dehiscence was explored, exposing the sharp indentation on the middle third of the root. a blunt resection at 45 degrees was performed at the level of the invagination, with the resected end then filled with the dentin substitute (biodentine®, septodont). the surgical bed was rinsed with saline and the flap was secured with sutures. postoperatively, the retrograde filling was assessed using radiography. the resected end was subjected to ground sectioning and light microscopy revealed normal-looking dentin and cementum. at a one-year follow-up, the patient was asymptomatic and a periapical radiograph showed healing of the periapical region [figure 1c]. discussion radiographically, the accuracy of detection of the number and morphology of root canals greatly depends on the angulation of the incident x-ray beam and the superimposition of any adjacent structures.5 conventional radiography merely displays a twodimensional (2d) image of a three-dimensional (3d) structure; as such, intra-oral periapical radiographs only highlight features in the mesiodistal plane and it is often difficult to visualise the buccolingual dimension of the tooth.6 however, with the advent of volumetric computerised tomography or cbct, visualisation of a tooth in all dimensions is possible. these newer imaging modalities provide faster results and greater image resolution, making diagnosis and treatment planning easier.1–3 the current case described a patient who presented with pain in the right upper canine. on periapical radiography, the root of the canine appeared extremely short and blunt, with the apical third seemingly superimposed by the crown of an impacted figure 1: a: digital periapical radiograph of a 24-year old male with right upper canine pain showing a supernumerary tooth superimposing the apical third of the canine (arrow). b: cone-beam computed tomography of the canine in the sagittal aspect revealing altered root morphology with a sharp indentation in the labial aspect (arrow) and an ill-defined radiolucency (arrowhead) in the palatal and apical aspect of the apical third of the root. c: radiograph of the periapical region one year following treatment showing satisfactory healing. use of cone-beam computed tomography in the diagnosis and treatment of an unusual canine abnormality e240 | squ medical journal, may 2017, volume 17, issue 2 conclusion conventional intra-oral radiography reveals an image of a tooth in two dimensions, with limited information regarding its spatial relationships with other anatomical structures in the third dimension. this may potentially result in inaccurate diagnoses and unnecessary or inappropriate treatments. for endodontic patients, treatment planning should be based on a comprehensive evaluation using all diagnostic modalities available, including newer 3d imaging techniques, particularly in cases where conventional imaging is inconclusive. references 1. nair mk, nair up. digital and advanced imaging in endodontics: a review. j endod 2007; 33:1–6. doi: 10.1016/j. joen.2006.08.013. 2. patel s, durack c, abella f, shemesh h, roig m, lemberg k. cone beam computed tomography in endodontics: a review. int endod j 2015; 48:3–15. doi: 10.1111/iej.12270. 3. scarfe wc, levin md, gane d, farman ag. use of cone beam computed tomography in endodontics. int j dent 2009; 2009:634567. doi: 10.1155/2009/634567. 4. leonardi dutra k, haas l, porporatti al, flores-mir c, nascimento santos j, mezzomo la, et al. diagnostic accuracy of cone-beam computed tomography and conventional radiography on apical periodontitis: a systematic review and meta-analysis. j endod 2016; 42:356–64. doi: 10.1016/j. joen.2015.12.015. 5. patel s, dawood a, whaites e, pitt ford t. new dimensions in endodontic imaging: part 1 conventional and alternative radiographic systems. int endod j 2009; 42:447–62. doi: 10.1111 /j.1365-2591.2008.01530.x. 6. cohenca n, simon jh, roges r, morag y, malfaz jm. clinical indications for digital imaging in dento-alveolar trauma: part 1 traumatic injuries. dent traumatol 2007; 23:95–104. doi: 10.1111/j.1600-9657.2006.00509.x. 7. wang s, xu y, shen z, wang l, qiao f, zhang x, et al. the extent of the crack on artificial simulation models with cbct and periapical radiography. plos one 2017; 12:e0169150. doi: 10.1371/journal.pone.0169150. 8. patel s. new dimensions in endodontic imaging: part 2 cone beam computed tomography. int endod j 2009; 42:463–75. doi: 10.1111/j.1365-2591.2008.01531.x. 9. nakata k, naitoh m, izumi m, inamoto k, ariji e, nakamura h. effectiveness of dental computed tomography in diagnostic imaging of periradicular lesion of each root of a multirooted tooth: a case report. j endod 2006; 32:583–7. doi: 10.1016/j. joen.2005.09.004. supernumerary tooth. however, there was no evidence of any supernumerary teeth upon cbct. rather, this newer diagnostic imaging technique revealed a long canine with altered root morphology and an invagination at the middle-third of the root. this was particularly noticeable in the midsagittal aspect wherein the root canal took a slightly tortuous course at the middle-third to reach the apex. the illusion of the supernumerary tooth on the periapical radiograph was formed by the overlapping of two segments of the root of the canine along the direction of the x-ray beam [figure 2]. this case highlights the difficulty of assessing the spatial relationships of a tooth root via 2d imaging alone. reconstructed cbct scans are invaluable for assessing teeth with unusual anatomies, such as those with an unusual number of roots, dilacerated teeth and dens in dente.7 wang et al. similarly reported that cbct has a significantly higher sensitivity compared to periapical radiographs when detecting cracks in teeth in all planes.8 nakata et al. emphasised that relevant cbct views and slices are necessary for accurate planning in periapical microsurgery.9 in the present case, cbct allowed the accurate diagnosis and precise assessment of an unusual root morphology and periapical pathosis not visible on conventional diagnostic radiography, thus paving the way for an appropriate treatment plan. figure 2: diagram showing how the angulation of an incident x-ray beam in two-dimensional imaging of a canine with unusual morphology can create the illusion of a supernumerary tooth. https://doi.org/10.1016/j.joen.2006.08.013 https://doi.org/10.1016/j.joen.2006.08.013 https://doi.org/10.1111/iej.12270 https://doi.org/10.1155/2009/634567 https://doi.org/10.1016/j.joen.2015.12.015 https://doi.org/10.1016/j.joen.2015.12.015 https://doi.org/10.1111/j.1365-2591.2008.01530.x https://doi.org/10.1111/j.1365-2591.2008.01530.x https://doi.org/10.1111/j.1600-9657.2006.00509.x https://doi.org/10.1371/journal.pone.0169150 https://doi.org/10.1111/j.1365-2591.2008.01531.x https://doi.org/10.1016/j.joen.2005.09.004 https://doi.org/10.1016/j.joen.2005.09.004 1department of paediatrics, klatovy hospital, klatovy, czech republic; departments of 2paediatrics and 3otorhinolaryngology, pardubice hospital, pardubice, czech republic *corresponding author’s e-mail: kutilek@nemkt.cz سببان خمتلفان لفرط كالسيوم الدم عند األطفال ستيفان كوتليك، اإيفانا فال�شيلوفا، فيكتور �رسوبوك abstract: paediatric hypercalcaemia is a rare condition which can be easily overlooked or misdiagnosed. we report two paediatric patients who presented to the department of paediatrics, pardubice hospital, pardubice, czech republic, in 2009 and 2010, respectively. each patient was diagnosed with hypercalcaemia due to a different cause. the first case involved a seven-month-old infant who presented with failure to thrive, vomiting and psychomotor retardation. fluorescent in situ hybridisation revealed williams-beuren syndrome. the second patient was a 16-year-old girl with abdominal pain and renal colic due to hypercalcaemia-induced urolithiasis. high parathyroid hormone serum levels suggested primary hyperparathyroidism. an adenoma of the left upper parathyroid gland was diagnosed via technetium-99m-labelled methoxyisobutyl isonitrile single photon emission computed tomography and removed surgically. hypercalcaemia should be considered in the differential diagnosis of various disease states, particularly among infants who fail to thrive or children with abdominal pain. keywords: hypercalcemia; williams-beuren syndrome; hyperparathyroidism; parathyroid adenoma; case report; czech republic. امللخ�ص: يعد فرط الكال�شيوم يف دماء الأطفال حالة نادرة، ميكن اأن ُتغفل اأو ُيغلط يف ت�شخي�شها. ونعر�ص هنا حلالتي طفلني مري�شني ِجيَء بهما لق�شم الأطفال يف م�شت�شفى باردوب�ص بجمهورية الت�شيك يف عامي 2009 و 2010، على التوايل. ومت ت�شخي�ص كل من احلالتني على اأنهما فرط كال�شيوم الدم ل�شببني خمتلفني. وكانت احلالة الأوىل لر�شيع عمره �شبعة اأ�شهر توقف منوه، وكان م�شابا بقيء وتخلف حركي نف�شي. وثبت من التهجني الفلوري املو�شعي اأن هذا املري�ص م�شاب مبتالزمة ويليام-بيورين. اأما احلالة الثانية فكانت لفتاة يف ال�شاد�ص ع�رس من عمرها م�شابة باأمل بطني ومغ�ص كلوي نتيجة حت�شي احلالب الذي �شببه فرط كال�شيوم الدم. وُوجد لدى هذه املري�شة اأي�شا ارتفاع يف تركيز هرمون الدريقات يف م�شل الدم. واكت�شف عن طريق الت�شوير املقطعي بالنبعاث الفوتوين املنفرد وجود ورم غدي يف اجلزء ال�شمايل الأعلى من الدريقة، ومتت اإزالته جراحيا. ينبغي اأن يو�شع احتمال وجود فرط الكال�شيوم يف الت�شخي�ص التفريقي بني خمتلف الأمرا�ص، خا�شة عند الر�شع الذين توقف منوهم، اأو امل�شابني باأمل يف البطن. الكلمات املفتاحية: فرط كال�شيوم الدم؛ مبتالزمة ويليام-بيورين؛ ارتفاع تركيز هرمون الدريقات؛ ورم الدريقات الغدي؛ تقرير حالة؛ جمهورية الت�شيك. two different causes of paediatric hypercalcaemia *stepan kutilek,1 ivana plasilova,2 viktor chrobok3 online case report sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e389–392, epub. 19 dec 18 submitted 29 nov 17 revision req. 23 jan 18; revision recd. 21 feb 18 accepted 15 mar 18 doi: 10.18295/squmj.2018.18.03.022 hypercalcaemia is defined as serumcalcium (s-ca) levels of >2.7 mmol/l, with s-ca levels of >3.0 mmol/l requiring therapeutic intervention and those of >3.5 mmol/l considered life-threatening and requiring immediate action.1–4 treatment consists of ensuring adequate hydration and administering glucocorticoids, diuretics (i.e. furosemide) and bisphosphonates (e.g. pamidronate or zoledronate). vitamin d and calcium supplementation should be avoided, as well as exposure to sunshine.1–3 hypercalcaemia in childhood is rare and may have different origins, including vitamin d intoxication, hyper parathyroidism, hyperthyroidism, granulomatous disease, williams-beuren syndrome, calcium-sensing receptor mutations, jansen’s metaphyseal chondrodysplasia, hypo phosphatasia, subcutaneous fat necrosis and humoral or osteolytic malignancy.1–3 a complete evaluation of blood minerals together with assessments of serum alkaline phosphatase (s-alp) activity and parathyroid hormone (s-pth) levels usually helps to ensure the correct diagn osis. this case report describes two cases of paediatric hypercalcaemia arising from different causes, one case in an infant and the other in an adolescent girl. case one a seven-month-old girl was referred to the department of paediatrics, pardubice hospital, pardubice, czech republic, in 2009 due to lethargy, psychomotor retard ation, muscle hypotonia, anorexia, vomiting, constipation and failure to thrive. her family and perinatal history was normal, with a 41-week gestational period, birthweight of 3,670 g, birth length of 50 cm and apgar scores of 6–9. up until the age of five months, her rate of weekly weight gain had been normal at 150–200 g; however, between months five and six, she gained only 100 g (from 7,200 g to 7,300 g) and between months six and seven, she lost 460 g (from 7,300 g to 6,840 g). she was being two different causes of paediatric hypercalcaemia e390 | squ medical journal, august 2018, volume 18, issue 3 s-ca levels (from 3.54 to 3.02 mmol/l and 2.4 mmol/l, respectively) within 48 hours. one week after admission, the patient was discharged with a bodyweight of 7,300 g. she continued receiving a low-calcium milk-free diet (≤200 mg of calcium/day), primarily consisting of vegetable soup, poultry, mixed fruit and pastries, with no vitamin d supplementation. her s-ca levels remained between 2.25–2.6 mmol/l; however, after an isolated attempt to reintroduce milk at the age of eight months, her s-ca levels increased transiently to 3.5 mmol/l [figure 1a]. despite the normalisation in her s-ca levels, the patient’s psychomotor development remained slow and the muscle hypotonia persisted. furthermore, her weight gain rate remained inappropriately low. she had no apparent dysmorphic facial features. accordingly, at the age of 11 months, the patient underwent fluorescent in situ hybridisation (fish) which revealed a chromosome 7q11.23 deletion indicative of williamsbeuren syndrome. this was confirmed when ‘elfin’ facial features became apparent at the age of one year (i.e. a broad forehead, stellate iris pattern, flat nasal bridge, full cheeks and lips, long smooth philtrum and wide mouth). in the following years, she displayed behaviour characteristic of williams-beuren syndrome (i.e. over friendliness, empathy, generalised anxiety, specific phobias and attention deficit disorder).5–8 from the age of 10 months, her blood s-ca levels rem-ained normal. at the time of writing, the patient was nine years old and under close surveillance. although mildly to moderately developmentally delayed, her anthropometric data were within normal reference ranges for the syndrome.8 case two a 16-year old girl was admitted to the department of paediatrics, pardubice hospital, in 2010 with complaints of recurrent abdominal pain. her family and personal breastfed, administered infant formula and vegetable soup and was receiving regular antirachitic prophylaxis (oral cholecalciferol at 500 iu/day). upon admission, blood biochemistry tests revealed high levels of s-ca (3.8 mmol/l), low levels of s-alp (1.5 µkat/l), mildly elevated serum creatinine levels (52 µmol/l) and low s-pth levels (4.8 ng/l). other biochemistry results were normal [table 1]. echocardiography revealed very mild pulmonary artery stenosis (gradient of 10–15 mmhg) and nephro calcinosis was apparent on a renal ultrasound. however, a wrist x-ray was normal, without any osteolytic signs. the combination of hypercalcaemia, normophosphataemia and low s-pth and s-alp levels ruled out primary hyperparathyroidism (hpt); additionally, vitamin d intox ication was excluded by the low-to-normal 25-hydroxy vitamin d levels. accordingly, idiopathic infantile hyper calcaemia was suspected and, on the second day of admission, the patient received an intravenous infusion of 0.9% sodium chloride with 5% dextrose together with methylprednisolone and furosemide (2 mg/kg/day each). this resulted in a gradual decrease in table 1: blood biochemistry results of case one serum levels result normal range* calcium in mmol/l 3.8 2.2–2.6 sodium in mmol/l 134 135–145 potassium in mmol/l 3.7 3.5–5.0 phosphorus in mmol/l 1.13 1.1–2.2 magnesium in mmol/l 0.7 0.6–1.1 alp in µkat/l 1.5 2.2–9.3 creatinine in µmol/l 52 20–40 pth in ng/l 4.8 15–65 25-oh vitamin d in nmol/l 72 75–125 alp = alkaline phosphatase; pth = parathyroid hormone; oh = hydroxy. *age-specific reference range. figure 1: serum calcium changes over time for (a) case one and (b) case two. the dotted lines represent the upper and lower reference values. s-ca = serum calcium. stepan kutilek, ivana plasilova and viktor chrobok online case report | e391 histological evaluation confirmed the diagnosis of an adenoma. subsequently, her s-pth levels dropped to 15 ng/l and thereafter remained between 10–20 ng/l. the postoperative course was uneventful over the next three days; however, on the fourth day, the patient developed hungry bone syndrome with a drop in s-ca levels (1.9 mmol/l) [figure 1b]. accordingly, she received calcium (3,000 mg/day) and cholecalciferol (5,000–7,500 iu/day) supplementation for four months. at the time of writing, the patient was 24 years old, in a good state of health with normal s-ca levels and was being monitored by an endocrinologist. discussion hypercalcaemia should be considered in infants and children with failure to thrive, constipation, hypotonia and psychomotor retardation. in the current case report, the two presented cases of paediatric hypercalcaemia serve as an important clinical reminder of the complex differential diagnosis of mineral metabolism disorders. in the first patient, the underlying cause of hypercalcaemia was williams-beuren syndrome, while the second was caused by primary hpt due to an adenoma of the parathyroid gland. williams-beuren syndrome is caused by a 7q11.23 contiguous gene deletion of the williams-beuren syndrome critical region that encompasses the elastin gene.5 it is transmitted in an autosomal dominant manner and occurs in one in 10,000 live births, of which most cases are de novo. hypercalcaemia occurs in 15–50% of affected children, although the specific causative mechanism by which this occurs is currently unknown.5 apart from hypercalcaemia, typical manifestations include congenital heart defects (especially supravalvular aortic and periph eral pulmonary artery stenosis), hypercalciuria with nephrocalcinosis/urolithiasis, endocrine abnormalities (i.e. thyroid hypoplasia, impaired glucose tolerance and growth hormone deficiency), feeding problems, failure to thrive, hypertension, dental anomalies and distinctive facial features and behavioural characteristics, such as irritability, anxiety, overfriendliness and hypersensitivity to noise.6–8 however, not all of these are present among affected infants, with certain manifestations only becoming apparent later, usually in early childhood.6 while the prognosis is generally good, there is an incr eased risk of cardiovascular morbidities and patients require periodic monitoring by specialists (i.e. an endocr inologist, cardiologist, neurologist, psychologist, psychiatrist, stomatologist and orthopaedic surgeon).5,8 generally, primary hpt is rare in children and adolescents, constituting less than 5% of all cases.9–12 at the johns hopkins children’s center in baltimore, mary land, usa, only 16 paediatric and adolescent patients history was normal. one week prior, a urinalysis had revealed proteinuria and microscopic haematuria and she had been provisionally diagnosed with a urinary tract infection and prescribed painkillers and amoxicillin/cla vulanate by a general practitioner. this resulted in temp orary cessation of the pain. however, the abdominal pain and microscopic haematuria recurred and she was admit ted to hospital. upon admission, her blood pressure was normal (120/80 mmhg) and an abdominal x-ray and ultrasound examination failed to show any concrements, although dilation of the left renal pelvis and ureter was apparent. laboratory results revealed high s-ca levels of 3.2 mmol/l, normal phosphorus levels of 0.9 mmol/l (normal age-specific range: 0.7–1.5 mmol/l), normal s alp levels of 1.5 µkat/l (normal age-specific range: 0.7–2.5 µkat/l) and high s-pth levels of 126.0 ng/l (normal age-specific range: 15.0–65.0 ng/l). a helical computed tomography (ct) scan revealed a 3-mm urolithiasis which was voided spontaneously. multiple endocrine neoplasia (men) types i and ii and a jaw tumour were ruled out as the patient’s thy rotropin and free thyroxin levels were normal, along with magnetic resonance imaging (mri) of the brain, skull and abdomen. a diagnosis of primary hpt was established. as a technetium-99m (99tc)-labelled metho xyisobutyl isonitrile (mibi) scan showed only mild accum ulation at the upper left parathyroid gland, 99tc-mibi single photon emission ct (spect) was performed; this confirmed left upper parathyroid enlargement, most probably due to an adenoma. this was also corroborated by mri and a neck ultrasound. as measured by dual x-ray absorptiometry, her bone mineral density was within normal limits for her age. she was prescribed 20 mg/day of furosemide and her s-ca levels dropped below 3 mmol/l within one week. two months later, the patient underwent a parathy roidectomy of the left upper parathyroid gland [figure 2]. figure 2: gross photograph of a parathyroid adenoma excised from a 16-year-old girl with recurrent abdominal pain and hypercalcaemia. two different causes of paediatric hypercalcaemia e392 | squ medical journal, august 2018, volume 18, issue 3 references 1. lietman sa, germain-lee el, levine ma. hypercalcemia in children and adolescents. curr opin pediatr 2010; 22:508–15. doi: 10.1097/mop.0b013e32833b7c23. 2. davies jh. approach to the child with hypercalcaemia. endocr dev 2015; 28:101–18. doi: 10.1159/000380998. 3. mcneilly jd, boal r, shaikh mg, ahmed sf. frequency and aetiology of hypercalcaemia. arch dis child 2016;101:344–7. doi: 10.1136/archdischild-2015-309029. 4. elshafie ot, woodhouse nj. the diagnosis and management of severe hypercalcaemia: a simplified approach report of five cases. sultan qaboos univ med j 2010; 10:388–95. 5. morris ca. williams syndrome. in: adam mp, ardinger hh, pagon ra, eds. genereviews®. from: www.ncbi.nlm.nih.gov/ books/nbk1249/ accessed: feb 2018. 6. sindhar s, lugo m, levin md, danback jr, brink bd, yu e, et al. hypercalcemia in patients with williams-beuren syndr ome. j pediatr 2016; 178:254–60.e4. doi: 10.1016/j.jpeds.2016. 08.027. 7. güven a. seven cases with williams-beuren syndrome: endocrine evaluation and long-term follow-up. j pediatr endocrinol metab 2017; 30:159–65. doi: 10.1515/jpem-2016-0039. 8. committee on genetics. american academy of pediatrics: health care supervision for children with williams syndrome. pediatrics 2001; 107:1192–204. 9. hsu sc, levine ma. primary hyperparathyroidism in children and adolescents: the johns hopkins children’s center experience 1984-2001. j bone miner res 2002; 17:n44–50. 10. paunovic i, zivaljevic v, stojanic r, kalezic n, kazic m, diklic a. primary hyperparathyroidism in children and young adults: a single institution experience. acta chir belg 2013; 113:35–9. doi: 10.1080/00015458.2013.11680882. 11. libánský p, astl j, adámek s, nanka o, pafko p, spacková j, et al. surgical treatment of primary hyperparathyroidism in children: report of 10 cases. int j pediatr otorhinolaryngol 2008; 72:1177–82. doi: 10.1016/j.ijporl.2008.04.005. 12. lou i, schneider df, sippel rs, chen h, elfenbein dm. the changing pattern of diagnosing primary hyperparathyroidism in young patients. am j surg 2017; 213:146–50. doi: 10.1016/j.amj surg.2016.03.019. 13. wei wj, shen ct, song hj, qiu zl, luo qy. comparison of spet/ct, spet and planar imaging using 99mtc-mibi as independent techniques to support minimally invasive parathyroidectomy in primary hyperparathyroidism: a meta-analysis. hell j nucl med 2015; 18:127–35. doi: 10.1967/s002449910207. 14. ozkan zg, unal sn, kuyumcu s, sanli y, gecer mf, ozcinar b, et al. clinical utility of tc-99m mibi spect/ct for preoperative localization of parathyroid lesions. indian j surg 2017; 79:312–18. doi: 10.1007/s12262-016-1489-7. 15. kundel a, thompson gb, richards ml, qiu lx, cai y, schwenk fw, et al. pediatric endocrine surgery: a 20-year experience at the mayo clinic. j clin endocrinol metab 2014; 99:399–406. doi: 10.1210/jc.2013-2617. 16. ajmi s, sfar r, trimeche s, ben ali k, nouira m. scintigraphic findings in hungry bone syndrome following parathyroidectomy. rev esp med nucl 2010; 29:81–3. doi: 10.1016/j.re mn.2009.10.003. 17. witteveen je, van thiel s, romijn ja, hamdy na. hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism a systematic review of the literature. eur j endocrinol 2013; 168:r45–53. doi: 10.1530/eje-12-0528. with primary hpt (mean age: 16.3 ± 2.9 years) were reported between 1984 and 2001.9 in another study from belgrade, serbia, there were seven paediatric cases (mean age: 15.7 years) out of 522 patients with primary hpt seen between 2004 and 2010.10 libánský et al. analysed 10 primary hpt patients between 10–17 years old between 1996 and 2007.11 currently, the diagnosis of primary hpt in children and adolescents is mostly incidental.11,12 the most frequent manifestation of paed iatric primary hpt is urolithiasis in 64% of cases, with other symptoms including limb pain, fractures, hypertension, fatigue and constipation.1,9–12 in the current case report, the second patient presented with renal colic and hypercalcaemia due to a single parathyroid adenoma. among children, primary hpt is mostly due to a parathyroid adenoma; how ever, it can also occur within the context of other syndr omes, such as parathyroid hyperplasia in men types i and ii and hpt with jaw tumours.9–12 while a 99tc-mibi scan, neck ultrasound and mri scan can help to localise a parathyroid adenoma, 99tc-mibi spect is the most reliable method in this regard.13,14 in cases of paediatric parathyroid adenomas, surgical removal is the only effective treatment for primary hpt.11,15 however, hungry bone syndrome is a frequent postoperative complication and usually lasts for 3–4 months, with the duration reflecting the time span of bone remodelling.16,17 conclusion hypercalcaemia should be considered in the differential diagnosis for various disease states, especially among infants with psychomotor retardation and failure to thrive and children with abdominal pain, renal colic and urolithiasis. a c k n o w l e d g e m e n t s the authors wish to thank dr vladimir nemec, dr hana teterova-cerna, dr olga machacova, dr kristyna machata-hanulikova, dr katerina sachova, dr iva lebedova and dr petr munzar who took care of the patients during their stay in hospital as well as dr vera jüttnerova and dr jozef kubinyi who performed the fish procedure and 99tc-mibi spect scan, respectively, in the second case. a poster of the preliminary version of the first case in this case report was presented at the 7th international conference on children’s bone health from 27–30 june 2015 in salzburg, austria. an abstract of this poster presentation was subsequently published in bone abstracts in 2015 (volume 4, issue s3, p. 84). https://doi.org/10.1097/mop.0b013e32833b7c23 https://doi.org/10.1159/000380998 https://doi.org/10.1136/archdischild-2015-309029 https://doi.org/10.1016/j.jpeds.2016.08.027 https://doi.org/10.1016/j.jpeds.2016.08.027 https://doi.org/10.1515/jpem-2016-0039 https://doi.org/10.1080/00015458.2013.11680882 https://doi.org/10.1016/j.ijporl.2008.04.005 https://doi.org/10.1016/j.amjsurg.2016.03.019 https://doi.org/10.1016/j.amjsurg.2016.03.019 https://doi.org/10.1967/s002449910207 https://doi.org/10.1007/s12262-016-1489-7 https://doi.org/10.1210/jc.2013-2617 https://doi.org/10.1016/j.remn.2009.10.003 https://doi.org/10.1016/j.remn.2009.10.003 https://doi.org/10.1530/eje-12-0528 1department of medical education, college of medicine, king saud university, riyadh, saudi arabia; departments of 2ophthalmology and 3research, king khaled eye specialist hospital, riyadh, saudi arabia; 4college of medicine, alfaisal university, riyadh, saudi arabia; 5wilmer eye institute, johns hopkins hospital, baltimore, maryland, usa *corresponding author e-mail: saraalhilali@gmail.com سلوك طلبة الطب السعوديون جتاه األحباث يف اجملال الصحي �ش�رة حممد الهاليل، اإمي�ن القحط�ين، ب�ب�ر زم�ن، راجيف خ�ندك�ر، عبداهلل ال�شهري، ديب�ك اإدوارد abstract: objectives: this study aimed to evaluate attitudes, perceptions and perceived barriers towards health research among saudi arabian undergraduate medical students. methods: this cross-sectional study took place between august and october 2014 and included 520 students from five medical schools across saudi arabia. an anonymous online survey with 21 close-ended questions was designed to assess students’ attitudes towards research, contribution to research-related activities, awareness of the importance of research, perception of available resources/opportunities for research, appreciation of medical students’ research contributions and perceived barriers to research. responses were scored on a 5-point likert scale. results: a total of 401 students participated in the study (response rate: 77.1%). of these, 278 (69.3%) were female. a positive attitude towards research was reported by 43.9% of the students. no statistically significant differences were observed between genders with regards to attitudes towards and available resources for research (p = 0.500 and 0.200, respectively). clinical students had a significantly more positive attitude towards research compared to preclinical students (p = 0.007). only 26.4% of the respondents believed that they had adequate resources/opportunities for research. according to the students, perceived barriers to undertaking research included time constraints (n = 200; 49.9%), lack of research mentors (n = 95; 23.7%), lack of formal research methodology training (n = 170; 42.4%) and difficulties in conducting literature searches (n = 145; 36.2%). conclusion: less than half of the surveyed saudi arabian medical students had a positive attitude towards health research. medical education policies should aim to counteract the barriers identified in this study. keywords: research; medical students; attitudes; perceptions; medical education; saudi arabia. امللخ�ص: الهدف: هدف البحث اإىل تقييم �شلوك وت�شورات طالب الطب ال�شعوديون، والعقب�ت امللحوظة من قبلهم نحو اإجراء االأبح�ث يف من وط�لبة ط�لب� 520 و�شملت .2014 واأكتوبر اأغ�شط�ص �شهر بني م� الفرتة يف املقطعية الدرا�شة هذه اأجريت ال�شحي. الطريقة: املج�ل عرب اإر�ش�له ومت مغلق� �شوؤاال 21 على يحتوي االنرتنت على لال�شتطالع ا�شتبي�ن �شمم ال�شعودية. العربية اململكة يف طب كلي�ت خم�ص �شبكة االإنرتنت لتقييم �شلوك الطلبة جت�ه االأبح�ث، مقدار م�ش�ركتهم يف اأن�شطة متعلقة ب�الأبح�ث، مدى وعيهم ب�أهمية البحوث وم�ش�دره� وفر�ص امل�ش�همة يف االأبح�ث، ومدى تقدير م�ش�همة الطلبة يف البحوث والعقب�ت امللحوظة نحو اإجرائه�. مت ح�ش�ب االأجوبة ب��شتخدام مقي��ص ليكرت املكون من خم�ص نق�ط. النتائج: �ش�رك 401 ط�لب وط�لبة يف ا�شتكم�ل اال�شتبي�ن )معدل اال�شتج�بة = %77.1(، منهم 278 )%69.3( من االإن�ث. وجد �شلوك اإيج�بي جت�ه البحث بني %43.9 من الطلبة. مل يتم العثور على اختالف ذو قيمه اإح�ش�ئيه بني اجلن�شني فيم� يخ�ص ال�شلوك جت�ه االأبح�ث يف املج�ل ال�شحي وتوفراملوارد البحثية )p = 0.500.و p = 0.200 ب�لتوايل(. ُوجد �شلوك اإيج�بي اأكرب لدى طلبة الطب يف ال�شنوات االإكلينيكية مق�رنة بطلبة الطب يف ال�شنوات م� قبل االإكلينيكية، )p = 0.007(. ن�شبة الطلبة الذين يوؤمنون ب�أن هن�لك م�ش�در وفر�ص ك�فية الإجراء االأبح�ث يف املج�ل ال�شحي يف كلي�تهم هي %26.4. ك�نت العوائق التي يواجهه� الطالب ومتنعهم من امل�ش�ركة يف اإجراء االأبح�ث هي ك�لت�يل: �شيق الوقت )%49.9؛ n = 200(، عدم توفر م�رضف على البحث )%23.7؛ n = 95(، عدم فع�لية التدريب مبنهجية البحث )%42.4؛ n = 170( و�شعوبة اإجراء امل�شح االأدبي )%36.2؛ n = 145(. اخلال�صة: اأقل منن�شف طلبة الطب ال�شعوديني يف هذه الدرا�شة لديهم �شلوك اإيج�بي جت�ه البحث الطبي. يجب اأن تهدف خطط التثقيف الطبي للتو�شل اإىل حلول للمعوق�ت املذكورة يف هذه الدرا�شة. مفتاح الكلمات: بحث؛ طلبة الطب؛ �شلوك؛ ت�شورات؛ التعليم الطبي؛ اململكة العربية ال�شعودية. attitudes of saudi arabian undergraduate medical students towards health research *sara m. al-hilali,1 eman al-kahtani,2 babar zaman,3 rajiv khandekar,3 abdullah al-shahri,4 deepak p. edward2,5 clinical & basic research sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e68–73, epub. 2 feb 16 submitted 4 jun 15 revision req. 22 jul 15; revision recd. 10 aug 15 accepted 2 sep 15 doi: 10.18295/squmj.2016.16.01.012 advances in knowledge to the best of the authors’ knowledge, this study is the first to investigate the attitudes and perceptions of saudi arabian medical students towards health research. less than half of the surveyed medical students were found to have a positive attitude towards research. application to patient care understanding of the attitudes and barriers faced by undergraduate medical students with regards to research may help educators to identify key areas that need to be addressed in medical education. sara m. al-hilali, eman al-kahtani, babar zaman, rajiv khandekar, abdullah al-shahri and deepak p. edward clinical and basic research | e69 the number of physician-scientists in medical practice is declining; over the last two decades, the number of physician-scientists on staff at medical school faculties has decreased by nearly 25%.1–3 this suggests that the learning environment in medical schools is not conducive to clinical and basic research.2,3 while certain medical schools do include instruction in research methodologies within their curricula, it is also essential to evaluate how medical students respond to these strategies in order to further enhance their medical education. to date, most of the data regarding medical students’ attitudes and perceptions towards research have originated from industrialised countries.1–4 saudi arabia is the largest country in the middle east, with a gross domestic product of usd $24,911 per capita.5 over the last decade, there has been a significant shift in medical education in saudi arabia and surrounding countries in the gulf cooperation council (gcc) region; saudi arabia is currently moving towards a knowledge-based economy, of which research is an important component.6,7 new medical schools have been established and large numbers of medical graduates are expected over the next decade. other gcc and southeast asian countries also have greater numbers of graduating medical students and are opening new medical schools.8,9 in saudi arabia, national efforts are increasingly focused on strengthening the education and health systems; in 2014, 6.9% of government expenditures were directed towards the health sector and there were almost 1,200 medical graduates from saudi arabian schools in 2009.7,10 the government promotes evidence-based education and policy-making within the medical community.11 evidence suggests that saudi arabian medical students are increasingly participating in and contributing to health research.12 the development of a positive attitude towards scientific research is a fundamental element of modern undergraduate medical education.13 however, to the best of the authors’ knowledge, there is a paucity of data regarding undergraduate medical students’ attitudes towards research and their perceptions of available resources and opportunities for research. additionally, no studies from saudi arabia on this topic yet exist in the peer-reviewed literature. this study therefore aimed to evaluate attitudes and perceived barriers towards participating in health-based research among a cohort of saudi arabian undergraduate medical students. methods this cross-sectional study took place between august and october 2014 and included undergraduate medical students from medical schools across saudi arabia. for an estimated population of 3,900 saudi arabian medical students, a sample size of at least 407 respondents (370 + 10% to compensate for nonparticipation) was needed to achieve a 95% confidence interval and a 7% margin of error with a study design effect of two.14 to calculate the sample size, it was assumed that 57% of medical students were involved in research projects.1 at least one university from each of the central, eastern, western and northern regions of saudi arabia were contacted for permission to access their email database of medical students; of these, six universities (one private and five public universities) from the central, eastern and western regions gave their consent. five of the six medical schools were randomly selected and all 520 students of these schools were included in the study. two senior researchers and two medical students were field investigators for the study. firstand second-year students were grouped as preclinical students and students in their third, fourth and fifth years of medical school were grouped as clinical students. an anonymous self-reported online survey was developed by an information technology expert from the research department of the king khaled eye specialist hospital in riyadh, saudi arabia. the english-language survey was based on a previously validated survey and used limesurvey© (limesurvey project, hamburg, germany).1 a pilot study on 10 medical students who were excluded from the subsequent study was performed to ensure that the survey was easily accessible and that the language utilised was appropriate and clear. based on the results of the pilot study, no changes to the questionnaire were required. the survey included 21 close-ended questions to determine the students’ demographic information, past contributions to research-related activities, awareness of the importance of research, attitudes towards health-based research, perceptions of available resources/opportunities for research, appreciation of medical students’ contributions to research and perceived barriers to research. each questionnaire item was scored on a 5-point likert scale; positive responses (completely agree and agree) received scores of 2 and 1, respectively, while negative responses (completely disagree and disagree) positive attitudes towards scientific research among undergraduate medical students is likely to enhance the quality of future patient care. attitudes of saudi arabian undergraduate medical students towards health research e70 | squ medical journal, february 2016, volume 16, issue 1 received scores of -2 and -1, respectively. a score of zero was given to neutral answers (do not know). total scores for questions in each category were then summed and divided by the maximum possible score in order to calculate the percentage proportion of the score. percentages >75% were considered to be positive. data were analysed using the statistical package for the social sciences (spss), version 22 (ibm corp., chicago, illinois, usa). a univariate analysis was performed to calculate frequencies and proportions of the responses. to compare responses by gender, odds ratios and 95% confidence intervals were estimated. to review the frequency of responses by academic year, a chi-squared analysis was performed. a p value of <0.050 was considered statistically significant. the institutional research board at the king khaled eye specialist hospital granted ethical approval for this study (#1467-p). as responses were anonymous, the written consent of participants was waived; however, the online survey began with a participation agreement form. additionally, an introductory email was sent with each survey confirming the voluntary nature of participation and stating the research objectives of the study. results a total of 401 respondents participated in the survey (response rate: 77.1%), including 123 (30.7%) male and 278 (69.3%) female students. the proportion of students within each academic year was similar and the number of students per year ranged from 73–102 (18.2–25.4%). a positive attitude towards research was reported by 178 respondents (44.4%) and 106 (26.4%) believed that they had adequate resources/ opportunities for research in their medical school [table 1]. of the participants, 188 (46.9%) were aware of the usefulness of research in achieving their longterm medical career goals and 233 (58.1%) were aware of the importance of research in medical education. gender variations in attitudes towards and perceptions of available resources/opportunities for research were not statistically significant (p = 0.500 and 0.200, respectively). however, significantly more male students appreciated contributions to research compared to female students (p = 0.001) [table 2]. clinical students had a significantly more positive attitude towards research compared to their preclinical counterparts (p = 0.007). in addition, significantly more clinical students believed they had adequate resources/ opportunities for research compared to preclinical students (p = 0.007); however, the difference was not significant with regards to appreciation of research contributions (p = 0.060) [table 3]. according to the participants, there were several perceived barriers to undertaking research. these included time constraints (n = 200; 49.9%), lack of research mentors (n = 95; 23.7%), lack of formal research methodology training (n = 170; 42.4%) and lack of training/difficulties in conducting literature searches (n = 145; 36.2%). discussion half of the surveyed saudi arabian medical students in the current study reported an awareness of the table 1: participation in and perceptions of healthbased research among surveyed saudi arabian undergraduate medical students (n = 401) item n (%) 95% ci participation in research projects 278 (69.3) 64.8–73.8 participation in medical school research projects 250 (62.3) 57.6–67.1 publication of research papers as first author in peer-reviewed journals 13 (3.2) 1.5–5.0 positive attitude towards research 178 (44.4) 39.5–49.3 adequate resources/ opportunities for research 106 (26.4) 22.1–30.7 appreciation of contribution to research 161 (40.2) 35.2–44.8 ci = confidence interval. table 2: variations by gender in perceptions of health-based research among surveyed saudi arabian undergraduate medical students (n = 401) item n (%) or (95% ci) p value* male (n = 123) female (n = 278) attitude towards research 1.2 (0.8–1.8) 0.500 positive 58 (47.1) 120 (43.2) negative 65 (52.9) 158 (56.8) resources/opportunities for research 1.4 (0.9–2.2) 0.200 adequate 38 (30.9) 68 (24.5) inadequate 85 (69.1) 210 (75.5) appreciation of contribution to research 2.0 (1.3–3.1) 0.001 appreciation 64 (52.0) 97 (34.9) lack of appreciation 59 (48.0) 181 (65.1) or = odds ratio; ci = confidence interval. *p <0.050 was considered statistically significant. sara m. al-hilali, eman al-kahtani, babar zaman, rajiv khandekar, abdullah al-shahri and deepak p. edward clinical and basic research | e71 importance of undertaking research. less than half of the surveyed students had a positive attitude towards participating in research activities. no significant differences in attitudes towards or perceptions of research were noted between genders. however, appreciation for student contributions to research was greater among male students compared to females. gender equality is an important consideration worldwide, particularly with regards to education.15 although saudi arabia was ranked 130 out of 142 countries for gender equality in the global gender gap report for 2014, the educational attainment score was 0.987, suggesting that saudi females attain a very high educational level.16 due to their positive attitude towards research evidenced in the present study, educated saudi females seem to be committed to enhancing education and healthcare through research. the higher number of female participants in the current study is also notable, particularly as the average male-to-female ratio of student enrolment in undergraduate medical education in saudi arabia was nearly 3:1 in 2011.17 in the current study, clinical students were significantly more likely to have a positive attitude towards research than preclinical students, with half of the fifth-year students having a positive attitude compared to less than a third of the first-year students. an increased awareness and maturity among students in their clinical years could explain this observation; this suggests a steady increase in awareness of research throughout the course of a student’s medical education. similarly, khan et al. found that both knowledge and attitudes improved significantly the longer a medical student was enrolled in college.18 clinical students in the current study were also significantly more inclined to perceive that they had adequate resources/ opportunities for research compared to students in their preclinical years. in addition, they were more inclined to value contributions to research. again, this is likely because older students are more likely to be aware of available resources within their respective medical schools. furthermore, at this stage in their careers, research participation is considered an asset when applying for residency and postgraduate training programmes. medical students in the current study revealed four main barriers to conducting research, including time constraints, lack of mentorship and inadequate training in literature searches and research methodology. similar barriers to research were reported by medical students in canada.1 these results also concur with those of an irish study which found that lack of time was the greatest barrier to pursuing scientific research among a cohort of undergraduate medical students in the uk.19 unnikrishnan et al. observed that time constraints were the main barrier reported by undergraduate medical students in india; medical professors and mentors also confirmed that time constraints precluded supervision of student research projects.20 the second most important factor was limited training in research among undergraduate students.20 a randomised controlled trial in the uk found that insufficient instruction on the basics of scientific research in medical colleges hindered table 3: variations by academic year in perceptions of health-based research among surveyed saudi arabian undergraduate medical students (n = 401) item n (%) or (95% ci) p value* preclinical clinical first year second year total third year fourth year fifth year total attitude towards research 1.9 (1.3–3.0) 0.007 positive 22 (30.1) 29 (38.2) 51 (34.2) 41 (54.0) 35 (47.3) 51 (50.0) 127 (50.4) negative 51 (69.9) 47 (61.8) 98 (65.8) 35 (46.0) 39 (52.7) 51 (50.0) 125 (49.6) resources/opportunities for research 1.9 (1.2–3.2) 0.007 adequate 11 (15.1) 17 (22.4) 28 (18.8) 27 (35.5) 27 (36.5) 24 (23.5) 78 (31.0) inadequate 62 (84.9) 59 (77.6) 121 (81.2) 49 (64.5) 47 (63.5) 78 (76.5) 174 (69.0) appreciation of contribution to research 2.0 (1.3–3.1) 0.060 appreciation 23 (31.5) 22 (29.0) 45 (30.2) 38 (50.0) 38 (51.4) 41 (40.2) 117 (46.4) lack of appreciation 50 (68.5) 54 (71.0) 104 (69.8) 38 (50.0) 36 (48.6) 61 (59.8) 135 (53.6) or = odds ratio; ci = confidence interval. *p <0.050 was considered statistically significant. attitudes of saudi arabian undergraduate medical students towards health research e72 | squ medical journal, february 2016, volume 16, issue 1 students from participating in or leading research projects.21 similarities in results between the current study and those of international research suggest that unified solutions should be developed to overcome these obstacles to research participation. the survey used in the current study assessed the attitudes of medical students towards health research and related factors. a croatian study reported a more positive attitude towards science among students who took mandatory research courses compared to those who did not.2 another study found that students enrolled in problem-based learning courses had a healthier attitude towards research compared to those participating in lecture-based learning.22 this outcome indicates the positive impact of a problem-based curriculum on the attitude of medical students towards health research.22 medical schools should consider offering online self-paced courses to address the issues of time constraints and inadequate training as well as web-based consultancy services to guide students who are interested in conducting research studies. the saudi digital library offers unlimited access to over 310,000 articles and offers tutorials on how to search for content and navigate their website.23 saudi medical students should therefore be encouraged to use this resource. databases of available qualified research professionals within saudi arabia and the gcc region willing to provide mentorship services could also be made available to medical students. a previous study from saudi arabia reported that publications in medical sciences increased between 1996–2012.12 this resulted in saudi arabia being ranked 45th in the world in 2012 in terms of research productivity.12 more than half of the students believed that research was relevant to medical education in saudi arabia. these findings imply that, with effective policies and opportunities, current medical students will soon be willing to participate in research and further increase saudi arabia’s ranking in the near future. administrative, research and medical education departments in saudi arabia should seek to develop policies targeting students to enhance their understanding of the importance of research. telmesani et al. noted challenges in executing changes in the saudi medical education system.8 they also opined that reforms were directed more toward changing curricula rather than defining the essential skills, knowledge and standards needed for graduating physicians.8 the results of the current study indicate a need for reforms that will lead to improved perceptions of research among medical students and increased research productivity within the country. certain limitations to the current study should be noted when interpreting the results. the findings were based on responses from a self-reported web-based anonymous survey. furthermore, there are a total of 28 medical schools in saudi arabia;24 only six were targeted in this study. additionally, these schools were highly ranked and may therefore have had greater research-related resources than other universities in saudi arabia. further studies are recommended to survey the attitudes of students from all medical schools in the country. nevertheless, despite these limitations, it is important to note that participant responses to the anonymous survey used in the current study may have been more honest than those from other research utilising different methods of data collection.25 conclusion half of the surveyed saudi arabian medical students were aware of the importance of undertaking research although less than half had a positive attitude towards research. four main barriers to research participation were identified—time constraints, lack of mentorship and inadequate training in literature searches and research methodology. in order to strengthen the medical research environment in saudi arabia, policymakers should take these barriers into account. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. siemens dr, punnen s, wong j, kanji n. a survey on the attitudes towards research in medical school. bmc med educ 2010; 10:4. doi: 10.1186/1472-6920-10-4. 2. hren d, lukić ik, marusić a, vodopivec i, vujaklija a, hrabak m, et al. teaching research methodology in medical schools: students’ attitudes towards and knowledge about science. med educ 2004; 38:81–6. doi: 10.1111/j.13652923.2004.01735.x. 3. solomon ss, tom sc, pichert j, wasserman d, powers ac. impact of medical student research in the development of physician-scientists. j investig med 2003; 51:149–56. doi: 10. 1097/00042871-200305000-00017. 4. reinders jj, kropmans tj, cohen-schotanus j. extracurricular research experience of medical students and their scientific output after graduation. med educ 2005; 39:237. doi: 10.1111/ j.1365-2929.2004.02078.x. 5. kingdom of saudi arabia ministry of health. statistical book for the year 1433. from: www.moh.gov.sa/en/ministry/ statistics/book/documents/1433.pdf accessed: aug 2015. 6. king abdulaziz city for science and technology and kingdom of saudi arabia ministry of economy and planning. strategic technology program summary document. from: www.kacst. edu.sa/en/research/it/documents/ghq.pdf accessed: aug 2015. 7. althubaiti a, alkhazim m. medical colleges in saudi arabia: can we predict graduate numbers? high educ stud 2014; 4:1–8. doi: 10.5539/hes.v4n3p1. http://dx.doi.org/10.1186/1472-6920-10-4 http://dx.doi.org/10.1111/j.1365-2923.2004.01735.x http://dx.doi.org/10.1111/j.1365-2923.2004.01735.x http://dx.doi.org/10.1097/00042871-200305000-00017 http://dx.doi.org/10.1097/00042871-200305000-00017 http://dx.doi.org/10.1111/j.1365-2929.2004.02078.x http://dx.doi.org/10.1111/j.1365-2929.2004.02078.x http://dx.doi.org/10.1111/j.1365-2929.2004.02078.x. http://www.moh.gov.sa/en/ministry/statistics/book/documents/1433.pdf http://www.moh.gov.sa/en/ministry/statistics/book/documents/1433.pdf http://www.kacst.edu.sa/en/research/it/documents/ghq.pdf http://www.kacst.edu.sa/en/research/it/documents/ghq.pdf http://dx.doi.org/10.5539/hes.v4n3p1 sara m. al-hilali, eman al-kahtani, babar zaman, rajiv khandekar, abdullah al-shahri and deepak p. edward clinical and basic research | e73 8. telmesani a, zaini rg, ghazi ho. medical education in saudi arabia: a review of recent developments and future challenges. east mediterr health j 2011; 17:703–7. 9. khalid ba. the current status of medical education in the gulf cooperation council countries. ann saudi med 2008; 28:83–8. 10. world health organization. country cooperation strategy at a glance: saudi arabia. from: www.who.int/countryfocus/ cooperation_strategy/ccsbrief_sau_en.pdf accessed: aug 2015. 11. king abdulaziz city for science and technology and kingdom of saudi arabia ministry of economy and planning. kingdom of saudi arabia: strategic priorities for advanced medical and health research. from: www.kacst.edu.sa/en/research/ documents/medicalandhealth.pdf accessed: aug 2015. 12. meo sa, hassan a, usmani am. research progress and prospects of saudi arabia in global medical sciences. eur rev med pharmacol sci 2013; 17:3265–71. 13. o’mara rj, hsu si, wilson dr. should md-phd programs encourage graduate training in disciplines beyond conventional biomedical or clinical sciences? acad med 2015; 90:161–4. doi: 10.1097/acm.0000000000000540. 14. kingdom of saudi arabia ministry of higher education. the current status of higher education in the kingdom of saudi arabia: 2011. from: he.moe.gov.sa/en/ministry/general-admini stration-for-public-relations/bookslist/stat7eng.pdf accessed: aug 2015. 15. united nations. millennium developmental goals beyond 2015: goal 3 promote gender equality and empower women. from: www.un.org/millenniumgoals/gender.shtml accessed: aug 2015. 16. world economic forum. the global gender gap report 2014. from: www3.weforum.org/docs/gggr14/gggr_complete report_2014.pdf accessed aug 2015. 17. abdulghani hm, alkanhal aa, mahmoud es, ponnamperuma gg, alfaris ea. stress and its effects on medical students: a cross-sectional study at a college of medicine in saudi arabia. j health popul nutr 2011; 29:516–22. doi: 10.3329/jhpn. v29i5.8906. 18. khan h, khawaja mr, waheed a, rauf ma, fatmi z. knowledge and attitudes about health research amongst a group of pakistani medical students. bmc med educ 2006; 6:54. doi: 10.1186/1472-6920-6-54. 19. burgoyne ln, o’flynn s, boylan gb. undergraduate medical research: the student perspective. med educ online 2010; 10:15. doi: 10.3402/meo.v15i0.5212. 20. unnikrishnan b, kanchan t, holla r, kumar n, rekha t, mithra p, et al. medical students’ research: facilitators and barriers. j clin diagn res 2014; 8:xc01–4. doi: 10.7860/jcdr /2014/10223.5291. 21. parkes j, hyde c, deeks j, milne r. teaching critical appraisal skills in health care settings. cochrane database syst rev 2001; cd001270. doi: 10.1002/14651858.cd001270. 22. khan h, taqui am, khawaja mr, fatmi z. problem-based versus conventional curricula: influence on knowledge and attitudes of medical students towards health research. plos one 2007; 2:e632. doi: 10.1371/journal.pone.0000632. 23. saudi digital library. policy and user guide from: www.sdl. edu.sa/sdlportal/en/usermanual.aspx accessed: aug 2015. 24. kingdom of saudi arabia ministry of education. higher education: study in ksa. from: www.he.moe.gov.sa/en/ studyinside/pages/default.aspx accessed: aug 2015. 25. alsayed n, eldeek b, tayeb s, ayuob n, al-harbi a. research practices and publication obstacles among interns at king abdulaziz university hospital, jeddah, saudi arabia, 2011-2012. j egypt public health assoc 2012; 87:64–70. doi: 10.1097/01.epx.0000417978.44502.61. http://www.who.int/countryfocus/cooperation_strategy/ccsbrief_sau_en.pdf http://www.who.int/countryfocus/cooperation_strategy/ccsbrief_sau_en.pdf http://www.kacst.edu.sa/en/research/documents/medicalandhealth.pdf http://www.kacst.edu.sa/en/research/documents/medicalandhealth.pdf http://dx.doi.org/10.1097/acm.0000000000000540 http://he.moe.gov.sa/en/ministry/general-admini%0astration-for-public-relations/bookslist/stat7eng.pdf http://he.moe.gov.sa/en/ministry/general-admini%0astration-for-public-relations/bookslist/stat7eng.pdf http://www.un.org/millenniumgoals/gender.shtml http://www3.weforum.org/docs/gggr14/gggr_complete%0areport_2014.pdf http://www3.weforum.org/docs/gggr14/gggr_complete%0areport_2014.pdf http://dx.doi.org/10.3329/jhpn.v29i5.8906 http://dx.doi.org/10.3329/jhpn.v29i5.8906 http://dx.doi.org/10.1186/1472-6920-6-54 http://dx.doi.org/10.3402/meo.v15i0.5212 http://dx.doi.org/10.7860/jcdr/2014/10223.5291 http://dx.doi.org/10.7860/jcdr/2014/10223.5291 http://dx.doi.org/10.1002/14651858.cd001270 http://dx.doi.org/10.1371/journal.pone.0000632 http://www.sdl.edu.sa/sdlportal/en/usermanual.aspx http://www.sdl.edu.sa/sdlportal/en/usermanual.aspx http://www.he.moe.gov.sa/en/studyinside/pages/default.aspx http://www.he.moe.gov.sa/en/studyinside/pages/default.aspx http://dx.doi.org/10.1097/01.epx.0000417978.44502.61 علم التشريح جدول زمين تارخيي عمر الحبال humans have long been interestedin the form and structure of living things. the focus on anatomy in the ancient world began as a way to determine the nature of the soul.1 ancient anatomical drawings and sculptures have been found in caves in western europe, africa, asia and australia; while the exact dating of such artefacts is uncertain, some are at least 25,000 years old.2 regardless of how crude some of these illustrations are, they represent evidence that ancient artists had some knowledge of the formation of muscles and viscera. the stone age (750000–500000 bce) ancient skulls from the late palaeolithic period have shown evidence of trephining or trepanning (i.e. the process of cutting a hole in the skull).3 notably, some of these skulls demonstrate evidence of new bone formation around the holes, indicating that some of the victims of these primitive rituals survived the procedure.4,5 such practices are thought to have been carried out to release ‘evil spirits’ from people suffering from mental health disorders as well as other physical symptoms, such as cranial fractures or headaches.4,5 until recent times, similar practices were still being performed amongst certain native tribes.6 the ancient egyptians (3150–332 bce) the earliest records indicate that medicine was first recognised as a craft by the ancient egyptians; medical practitioners were highly thought of, although there is little evidence that these early ‘doctors’ had anything but a superficial knowledge of anatomy, as demonstrated by their drawings and sculptures.7 their mummification practices, which required the evisceration of human bodies, did not provide them with an exact knowledge of internal organs.8 mummification only required a small incision to remove the viscera for the sake of embalming and the priests who carried out the process were not interested in studying the extracted organs. ancient civilizations such as the sumerians and babylonians appear to have had equal or even greater ignorance of human anatomy.9 the ancient greeks (500–336 bce) the ancient greeks appear to have made the first real scientific advances in the field of anatomy.10 it is claimed that alcmaeon of croton, who lived in approximately the fifth century bce, practised human dissection; unfortunately, none of his notes on these dissections have ever been found.11 another notable greek anatomist was hippocrates, whose elementary anatomical work dates from around 400 bce. subsequently, aristotle contributed much information to the fields of comparative anatomy and embryology; he was the first of the ancient greeks to dissect animals in a systematic way. his anatomical studies led him to the conclusion that the soul was the life source of the body.1,12 with the fall of the greek empire, some outposts of civilisation survived and emerged as centres of learning. a particularly famous one was alexandria; some of the anatomists from this school—such as its founder, herophilus of chalcedon, and his disciple, erasistratus of chios—greatly contributed to existing knowledge of the nervous system, blood vessels and lymphatics.13 in particular, herophilus developed a library of anatomical knowledge which was much more informed regarding the actual structure of the department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: habbal@squ.edu.om the science of anatomy a historical timeline omar habbal sultan qaboos university med j, february 2017, vol. 17, iss. 1, pp. e18–22, epub. 30 mar 17 submitted 18 dec 16 revision req. 12 jan 17; revision recd. 22 jan 17 accepted 31 jan 17 doi: 10.18295/squmj.2016.17.01.004 medical history omar habbal medical history | e19 human body in comparison to previous works.14 additionally, herophilus was the first physician to dissect human bodies and is considered to be the founder of anatomy; he contradicted aristotle’s notion that the heart was the “seat of intelligence”, arguing instead that it was the brain.10 however, he was eventually accused by his contemporaries of dissecting live criminals. his disciple, erasistratus, believed that the animal form was determined by environmental rather than innate factors, in line with aristotle’s views. accordingly, erasistratus introduced the diametric notions of heredity and environment (e.g. nature versus nurture), both at the level of the individual and the species as a whole.15 the ancient romans (670 bce–480 ce) ancient roman physicians gained much of their anatomical knowledge of the human body by treating wounded gladiators. as the dissection of human bodies was forbidden, ancient roman anatomists had to rely primarily on animal dissections to further their knowledge.16,17 they were therefore limited in what they could learn about human anatomy. galen was an experimentalist and investigator who was born in the greek city pergamon but later travelled to rome in pursuit of knowledge, where he became a successful practicing physician.18 he is known for his anatomical observations and experimental approaches in emphasising the interrelationships between function (i.e. physiology) and form (i.e. anatomy). the majority of his anatomical knowledge was based on his dissections of animals, especially monkeys. he noted the importance of the spinal cord, motor and sensory loss following the ligation of a peripheral nerve in the area of its distribution and experimentally demonstrated the function of the recurrent laryngeal nerve.19 galen also noted that blood must pass from the right side of the heart to the left side, although he was unaware of the concept of pulmonary circulation. great credit is owed to galen for explaining many of the mysteries of the human body during that period, as his beliefs were to last for a long time.20 the islamic golden age (701–1300 ce) while europe was in the midst of the dark ages, arabia was a beacon of medical knowledge. baghdad in particular was a noted haven for scholars who had scattered after the fall of constantinople.21 during this era, many notable muslim scholars made discoveries which provided greater anatomical insight, such as the contributions of muhammad al-razi (862–930 ce) to the field of neuroanatomy, ibn al-haytham (965–1040 ce) who provided new insight into optics, avicenna or abu ibn sina (980–1037 ce) who famously wrote the canon of medicine and ibn alnafis (1210–1288 ce) who explained pulmonary circulation, paving the way for william harvey (1578–1657 ce), many centuries later.22–24 the late middle ages (1000–1300 ce) in approximately 1000 ce, an educational revival began in europe with the foundation of the medical school schola medica salernitana in salerno. this southern italian port became the main hub of medical knowledge in europe, after having imported important translations of medical knowledge from arab and muslim scholars.25 two centuries later, the university of bologna, which was initially a law school, incorporated medicine and other disciplines into its curriculum; it is believed that post-mortems were carried out here, possibly for medico-legal reasons, potentially leading to a revived interest in anatomical dissections to increase knowledge.26 at that time, thaddeus alderoti (c. 1206–1295 ce) was the most active anatomist in this field.26 the first human dissection manual ever written, the anathomia corporis humani, was produced by one of alderoti’s students, mondino de luzzi (also known as mundinus), in approximately 1316 ce.27 the renaissance period (1301–1700 ce) during the renaissance period, various anatomical sketches of the human body were made by artists like leonardo da vinci and, to a lesser extent, michelangelo di buonarroti, rembrandt van rijn, albrecht dürer and raphael da urbino [figures 1–3]. these sketches contributed to anatomical knowledge, but were later disregarded with the production of newer updated anatomical drawings.28 artists were keen to gain accurate knowledge of the inner workings of the human body, which would allow them to paint and sculpt the body in many different positions. even though it was banned by the catholic church, many artists and scientists performed dissections to better understand the human body. however, dissection required readily available bodies and the most readily available subjects for dissection in those days were executed criminals.29 during these dissection sessions, the science of anatomy a historical timeline e20 | squ medical journal, february 2017, volume 17, issue 1 a professor would read aloud from galen’s works, while a demonstrator attempted to isolate or point to the various body parts mentioned.30 in the 16th century, andreas vesalius, a student from brussels who frequently assisted at human dissections, decided to investigate the accuracy of these galenic concepts and so began to fastidiously record his dissection findings.31 in 1537 ce, he obtained his doctorate from padua university, which was the location of the first established anatomical theatre for human dissections; a day after graduating, he was made a professor of anatomy and surgery. six years later, at the age of 27 years, he completed writing de humani corporis fabrica [figure 4].32 this seminal work was a key milestone in the history of human anatomy and was the first illustrated scientific work to evoke astonishment and admiration from the scientific community. vesalius died in 1564 while on a pilgrimage to jerusalem. he is credited for raising the field of anatomy from merely a mixture of facts and fiction to an exact science, a fundamental basis of medicine.33 in 1553 ce, michael servetus proved that blood flows from the heart, through the lungs and back to the heart; he was burnt alive for this finding, which was deemed heretical by the catholic church.34 17 th–20 th century (1601–2000 ce) over time, many eminent scientists, physicians and academics have attempted to refine the existing anatomical knowledge available. their names are often used to label the anatomical structures or diseases they described, for example: antonio pacchioni (pacchioni’s granulations), antonio scarpa (scarpa’s fascia and scarpa’s fluid, among many others), alfonso giacomo gaspare corti (organ of corti), filippo pacini (pacinian corpuscles), camillo golgi (golgi apparatus), johann friedrich meckel (meckel’s diverticulum), leopold auerbach (auerbach’s plexus), georg meissner (meissner’s plexus), ludwig edinger (edinger’s tract), heinrich lissauer (tract of lissauer), johann christian reil (reil’s finger and the islands of reil, among many others), anders retzius (cave of retzius or retzius’ space), alfred wilhelm volkmann (volkmann’s canals), franciscus sylvius (sylvian fissure and sylvian aqueduct), françois magendie (foramen of magendie), pierre paul broca (broca’s area), charles-édouard brown-séquard (brownséquard syndrome), jean-martin charcot (charcot disease), vladimir betz (pyramidal cells of betz), william edwards horner (horner muscle), santiago ramón y cajal (interstitial cell of cajal), thomas willis (circle of willis), alexander monro secundus figure 2: a sketch by michelangelo di buonarroti entitled écorché (skinned) (c. unknown), detailing the muscles and anatomical structure of the torso. reproduced from the public domain. figure 3: oil painting by rembrandt van rijn entitled the anatomy lesson of dr. nicolaes tulp (c. 1632 ce), demonstrating an educational dissection session. reproduced from the public domain. figure 1: pen and ink sketches by leonardo da vinci entitled (a) a dead or moribund man in bust length (c. 1487 ce), detailing the muscles of the arm and the veins of the arm and trunk, and (b) the vitruvian man (c. 1490 ce), showing the proportions of the human body. reproduced from the public domain. omar habbal medical history | e21 (foramen of monro) and sir charles bell (bell’s palsy). these eponymous terms, which are routinely used in medical practice, remind us of the monumental efforts that these anatomists made in the advancement of medical knowledge. sadly, these names are now being discarded in modern texts and are also often considered to be a nuisance by young medical students. pioneers who devoted their lives to the science and art of medicine deserve to have their names immortalised. such great achievements were not easily attained as, more often than not, such important work was performed during times of religious or political prejudice, repression, superstition, persecution and sometimes even execution.34 after the development of the microscope by anton van leeuwenhoek (1632–1723 ce) and his assistant, marcello malpighi, new frontiers were opened up for anatomical research. van leeuwenhoek managed to magnify and display the fine details of various tissues and is regarded as the founder of microscopic anatomy (i.e. histology).35 subsequently, robert hooke (1635–1703 ce) was the first to recognise and name cells in the tissues and, two centuries later, robert brown (1773–1858 ce) recognised the presence of nuclei.35 in 1989 ce, following these discoveries, theodor schleiden and matthias schwann proposed the theory that cells are universal in all tissues, where they play a vital role.35 this theory is the basis for modern concepts of histology, embryology and pathology. in 1761, giovanni battista morgagni, an italian researcher, made several discoveries which resulted in him being regarded as the first morbid anatomist or pathologist.36 up until the recent past, there was mass hostility towards anyone who carried out dissection practices and it was very difficult to secure cadavers for this purpose.30 however, with the increasing number of medical schools came an escalating demand for bodies and ‘body-snatching’ became increasingly common. unless legislation was made to regulate the donation of bodies for medical and educational purposes, the authorities anticipated that such demands would soon implicitly encourage murder in order for doctors and medical students to obtain the bodies necessary for their research.30,37 at the turn of the twentieth century, abraham flexner wrote his famous report on medical education and the importance of the basic medical sciences.38 this highlighted anatomy as an essential science for basic medical training. however, in the years since, there has been an ongoing debate as to how much anatomy education is needed in the medical curriculum.39 while there are many methodologies for anatomy teaching, the consensus seems to be that the optimal teaching method for anatomy education is to use prosected cadaveric material with other adjunct facilities.40 this necessitates a continuous supply of cadaveric material. in certain cultures, bequeathal programmes have been founded to regulate body donations to medical schools.30,41 full bodies, body parts and specific organs are maintained using preservation techniques including plastination and advanced digital imagery, all of which aim to ensure an adequate provision of material for medical students.42 conclusion currently, teachers and students of anatomy have the necessary illustrations and information they need to conduct anatomical research. modern technology ensures that this information is readily available and of the utmost clarity. however, the past eminent scholars who discovered and developed the various tenants of today’s anatomical knowledge should be remembered for the mental, physical and social challenges they faced in the course of their research, which sometimes cost them their lives. references 1. apostle hg. aristotle’s on the soul. grinell, iowa, usa: peripatetic press, 1981. 2. valladas h. direct radiocarbon dating of prehistoric cave paintings by accelerator mass spectrometry. meas sci technol 2003; 14:1487–92. doi: 10.1088/0957-0233/14/9/301. 3. gross cg. a hole in the head. neuroscientist 1999; 5:263–9. doi: 10.1177/107385849900500415. 4. petrone p, niola m, di lorenzo p, paternoster m, graziano v, quaremba g, et al. early medical skull surgery for treatment of post-traumatic osteomyelitis 5,000 years ago. plos one 2015; 10:e0124790. doi: 10.1371/journal.pone.0124790. 5. foerschner am. the history of mental illness: from skull drills to happy pills. inquiries j 2010; 2:1–4. figure 4: an anatomical sketch by andreas vesalius from the de humani corporis fabrica (c. 1543). reproduced from the public domain. https://doi.org/10.1088/0957-0233/14/9/301 https://doi.org/10.1177/107385849900500415 https://doi.org/10.1371/journal.pone.0124790 the science of anatomy a historical timeline e22 | squ medical journal, february 2017, volume 17, issue 1 6. durand vm, barlow dh. introduction to abnormal psychology and the dsm-iv-tr. in: essentials of abnormal psychology, 4th ed. belmont university, nashville, tennessee, usa: wadsworth, 2006. pp. 1–15. 7. porter r. the greatest benefit to mankind: a medical history of humanity. new york, usa: w. w. norton & company, 1999. pp. 49–50. 8. brier b, wade rs. surgical procedures during ancient egyptian mummification. chungará (arica) 2001; 33:117–23. doi: 10.40 67/s0717-73562001000100021. 9. von soden w, schley dg (trans). sumerian and babylonian science. in: the ancient orient: an introduction to the study of the ancient near east, 1st ed. grand rapids, michigan, usa: wm. b. eerdmans publishing company, 1994. pp. 145–172. 10. lloyd ge. early greek science: thales to aristotle, 1st ed. new york, usa: w. w. norton & co., 1974. pp. 144–6. 11. codellas ps. alcamaeon of croton: his life, work, and fragments. proc r soc med 1932; 25:1041–6. 12. torello j. the hippocratic soul. j psychol clin psychiatry 2015; 4:00230. doi: 10.15406/jpcpy.2015.04.00230. 13. reverón rr. herophilus and erasistratus, pioneers of human anatomical dissection. vesalius 2014; 20:55–8. 14. bay ns, bay bh. greek anatomist herophilus: the father of anatomy. anat cell biol 2010; 43:280–3. doi: 10.5115/acb. 2010.43.4.280. 15. lloyd ge. a note on erasistratus of ceos. j hellenic stud 1975; 95:172-5. doi: 10.2307/630879. 16. ghosh sk. human cadaveric dissection: a historical account from ancient greece to the modern era. anat cell biol 2015; 48:153–69. doi: 10.5115/acb.2015.48.3.153. 17. tubbs rs, linganna s, loukas m. jacobus sylvius (1478-1555): physician, teacher, and anatomist. clin anat 2007; 20:868–70. doi: 10.1002/ca.20553. 18. peterson dw. observations on the chronology of the galenic corpus. bull hist med 1977; 51:484–95. 19. frampton m. embodiments of will: anatomical and physiological theories of voluntary animal motion from greek antiquity to the latin middle ages, 400 b.c-a.d, 1st ed. 1300. saarbrücken, germany: vdm verlag dr. müller, 2008. pp. 180–323. 20. nutton v. the chronology of galen’s early career. class q 1973; 23:158–71. doi: 10.1017/s0009838800036600. 21. herrin j. the fall of constantinople. history today 2003; 6:1–7. 22. le floch-prigent p, delaval d. the discovery of the pulmonary circulation by ibn al nafis during the 13th century: an anatomical approach. faseb j 2014; 28:543.9. 23. numan mt. ibn al nafis: his seminal contributions to cardiology. pediatr cardiol 2014; 35:1088–90. doi: 10.1007/ s00246-014-0990-7. 24. lakhtakia r. a trio of exemplars of medieval islamic medicine: al-razi, avicenna and ibn al-nafis. sultan qaboos univ med j 2014; 14:e455–9. 25. garcia-ballester g, french r, arrizabalaga j, cunningham a, eds. practical medicine from salerno to the black death. cambridge, uk: cambridge university press, 1994. pp. 353–94. 26. siraisi ng. taddeo alderotti and bartolomeo da varignana on the nature of medical learning. isis 1977; 68:27–39. doi: 10.1086/351712. 27. wilson l. william harvey’s prelectiones: the performance of the body in the renaissance theater of anatomy. representations (berkeley) 1987; 17:62–95. doi: 10.2307/3043793. 28. jose am. anatomy and leonardo da vinci. yale j biol med 2001; 74:185–95. 29. mclachlan jc, patten d. anatomy teaching: ghosts of the past, present and future. med educ 2006; 40:243–53. doi: 10.1111/j.1365-2929.2006.02401.x. 30. ghosh sk. human cadaveric dissection: a historical account from ancient greece to the modern era. anat cell biol 2015; 48:153–69. doi: 10.5115/acb.2015.48.3.153. 31. heseler b, eriksson e. andreas vesalius’ first public anatomy at bologna 1540: an eyewitness report. uppsala, sweden: almqvist & wiksells, 1959. 32. garrison dh, hast mh. the fabric of the human body: an annotated translation of the 1543 and 1555 editions of “de humani corporis fabrica libri septem”, 1st ed. basel, switzerland: karger publishers, 2013. 33. tan sy, yeow me. andreas vesalius (1514-1564): father of modern anatomy. singapore med j 2003; 44:229–30. 34. stefanadis c, karamanou m, androutsos g. michael servetus (1511-1553) and the discovery of pulmonary circulation. hellenic j cardiol 2009; 50:373–8. 35. wolpert l. the evolution of ‘the cell theory’. curr biol 1996; 6:225–8. doi: 10.1016/s0960-9822(02)00463-3. 36. adams ew. founders of modern medicine: giovanni battista morgagni (1682–1771). med library hist j 1903; 1:270–7. 37. rosner l. the anatomy murders: being the true and spectacular history of edinburgh’s notorious burke and hare and of the man of science who abetted them in the commission of their most heinous crimes. philadelphia, pennsylvania, usa: university of pennsylvania press, 2011. 38. flexner a. medical education in the united states and canada: a report to the carnegie foundation for the advancement of teaching. from: http://archive.carnegiefoundation.org/pdfs/ elibrary/carnegie_flexner_report.pdf accessed: jan 2017. 39. craig s, tait n, boers d, mcandrew d. review of anatomy education in australian and new zealand medical schools. anz j surg 2010; 80:212–16. doi: 10.1111/j.1445-2197.2010.05241.x. 40. habbal o. the state of human anatomy teaching in medical schools of gulf cooperation council countries: present and future perspectives. sultan qaboos univ med j 2009; 9:24–31. 41. riederer bm. body donations today and tomorrow: what is best practice and why? clin anat 2016; 29:11–18. doi: 10.1002/ ca.22641. 42. von hagens g, tiedemann k, kriz w. the current potential of plastination. anat embryol (berl) 1987; 175:411–21. doi: 10.1007/bf00309677. https://doi.org/10.4067/s0717-73562001000100021 https://doi.org/10.4067/s0717-73562001000100021 https://doi.org/10.15406/jpcpy.2015.04.00230 https://doi.org/10.5115/acb.2010.43.4.280 https://doi.org/10.5115/acb.2010.43.4.280 https://doi.org/10.2307/630879 https://doi.org/10.5115/acb.2015.48.3.153 https://doi.org/10.1002/ca.20553 https://doi.org/10.1017/s0009838800036600 https://doi.org/10.1007/s00246-014-0990-7 https://doi.org/10.1007/s00246-014-0990-7 https://doi.org/10.1086/351712 https://doi.org/10.2307/3043793 https://doi.org/10.1111/j.1365-2929.2006.02401.x https://doi.org/10.5115/acb.2015.48.3.153 https://doi.org/10.1016/s0960-9822%2802%2900463-3 https://doi.org/10.1111/j.1445-2197.2010.05241.x https://doi.org/10.1002/ca.22641 https://doi.org/10.1002/ca.22641 https://doi.org/10.1007/bf00309677 إشعار عن تراجع املؤلف االستخدام الوقائي ملرشحات الوريد األجوف السفلي يف حاالت اإلصابات والصدمات notice of authorship retraction notice of authorship retraction use of prophylactic inferior vena cava filters in trauma the editors of sultan qaboos university medical journal (squmj) have been informed that one of the authors of an article by naiem et al. in the february 2016 issue of squmj, alreem k. al-hinai, wishes to retract their authorship from the above article.1 al-hinai initially submitted the article to squmj in january 2015 and was intended to be the first/corresponding author. however, due to her busy schedule, she was unable to contribute significantly. in december 2015, al-hinai informed the editors of squmj that ahmed naeim was the author responsible for the majority of the work on this article and that her contribution was negligible; at her request, naeim was designated by the editors of squmj as the first and corresponding author of the article. in april 2016, al-hinai contacted the editors of squmj stating that she wished to retract her authorship of the above article as she does not fulfil the four criteria of authorship as defined by the international committee of medical journal editors.2 for the reasons stated herein, the editors of squmj wish to notify readers that the authorship of al-hinai is hereby retracted from the above article. al-hinai takes sole responsibility for this retraction notice and would like to apologise to the readers, reviewers and editors of squmj for retracting her authorship after publication. however, in the interest of scholarly ethics, she does not wish for her name to be attributed to a publication without having contributed significantly to the research in question. references 1. naiem aa, al-hinai ak, al-sukaiti r, al-qadhi h. use of prophylactic inferior vena cava filters in trauma. sultan qaboos univ med j 2016; 16:e82–5. doi: 10.18295/squmj.2016.16.01.015. 2. international committee of medical journal editors. defining the role of authors and contributors. from: www.icmje.org/recommendations/ browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html accessed: may 2016. notice of authorship retraction for: naiem et al. use of prophylactic inferior vena cava filters in trauma. sultan qaboos univ med j 2016; 16:e82–5. doi: 10.18295/squmj.2016.16.01.015. sultan qaboos university med j, august 2016, vol. 16, iss. 3, p. e396, epub. 19 aug 16 doi: 10.18295/squmj.2016.16.03.027 e396 | notice of authorship retraction http://dx.doi.org/10.18295/squmj.2016.16.01.015 aluminium phosphide (alp) is a very effective outdoor and indoor pesticide used for protecting stored grains from rodents and other pests.1 in iran, alp tablets are widely used for protecting rice against pests and so are traditionally called “rice tablets”.2 phosphine gas (ph3) is rapidly formed and released when alp comes into contact with water or dilute acids, such as those found in the stomach, and is the fatal active form of the pesticide.3 the two main routes of acute toxicity due to alp are the ingestion of alp tablets and inhalation of released ph3. although the exact mechanism of action of alp is not clearly understood, ph3 is thought to induce toxicity by blocking the cytochrome c oxidase enzyme and inhibiting oxidative phosphorylation which eventually leads to myocyte death.1,2 alp poisoning has a very high mortality rate (30–100%) and survival is unlikely if more than 1,500 mg is ingested; the lethal dose for an individual weighing 70 kg is 150–500 mg.1 exposure to alp is rarely accidental and the majority of cases of severe alp poisoning are reportedly due to the deliberate ingestion of alp tablets with suicidal intentions.2,3 although there are reports of accidental inhalation of ph3 gas, especially among workers, alp is known as a suicide poison with no effective antidote that can be easily bought.2 presenting features of alp intoxication include the rapid onset of shock, vomiting, nausea, retrosternal and epigastric pain, dyspnoea, anxiety, agitation and garlic-odour breath.3 an early sign of alp poisoning is severe metabolic acidosis and hypotension, which leads to shock and tissue perfusion failure in the first couple of hours after ingestion due to cardiogenic shock and peripheral circulatory failure.1–4 other cardiovascular complications include cardiac arrhythmias and acute myocardial infarctions.1 profound circulatory collapse 1department of medical toxicology, kerman university of medical sciences, kerman, iran; 2atherosclerosis & coronary artery research centre and 3medical toxicology & drug abuse research centre, birjand university of medical sciences, birjand, iran *corresponding author e-mail: omid.mehrpour@yahoo.com.au عالج تسمم فوسفيد األلومنيوم مبزيج من الغلوكاغون الوريدي والدجيوكسني و مواد مضادة للتأكسد زهرة اأجابيان و اأوميد مهربور abstract: aluminium phosphide (alp) is used to protect stored grains from rodents. it produces phosphine gas (ph3), a mitochondrial poison thought to cause toxicity by blocking the cytochrome c oxidase enzyme and inhibiting oxidative phosphorylation, which results in cell death. alp poisoning has a high mortality rate among humans due to the rapid onset of cardiogenic shock and metabolic acidosis, despite aggressive treatment. we report a 21-yearold male who was referred to the afzalipour hospital, kerman, iran, in 2015 after having intentionally ingested a 3 g alp tablet. he was successfully treated with crystalloid fluids, vasopressors, sodium bicarbonate, digoxin, glucagon and antioxidant agents and was discharged from the hospital six days after admission in good clinical condition. for the treatment of alp poisoning, the combination of glucagon and digoxin with antioxidant agents should be considered. however, evaluation of further cases is necessary to optimise treatment protocols. keywords: aluminum phosphide; phosphine; poisoning; digoxin; glucagon; antioxidants; case report; iran. ي�صبب اأنه يعتقد متقدري �صم وهو الف�صفني، غاز وينتج القوار�ض. من املخزنة احلبوب حلماية االألومينيوم فو�صفيد ي�صتخدم امللخ�ص: ال�صمية من خالل اإعاقة اأنزمي اأك�صيد c من ال�صيتوكروم و تثبيط الف�صفتة االأك�صيدية، التي توؤدي اإىل موت اخللية. ت�صمم فو�صفيد االألومينيوم له معدل عايل للوفاة عند الب�رض؛ نظراً ل�رضعة حدوث ال�صدمة قلبية املن�صاأ و احلما�ض االأ�صتقالبي. نعر�ض حالة لذكر عمره 21 عاما الذي مت حتويله اإىل م�صت�صفى اأفزاليبور، كرمن، اإيران عام 2015م بعد بلعه عمداً 3 غرامات من حبة فو�صفيد االألومينيوم، مت عالج احلالة بنجاح عن طريق �صوائل بلورانية وروافع التوتر الوعائي وبيكربونات ال�صوديوم والديجوك�صن و الغلوكاغون وم�صادات التاأك�صد، و مت اإخراجه من امل�صت�صفى بعد �صتة اأيام و هو يف و�صٍع �صحٍي جيد، لذا ينبغي اأن يوؤخذ بعني االإعتبار هذا املزيج من الغلوكاغون وديجوك�صني مع م�صادات التاأك�صد لعالج ت�صمم فو�صفيد االألومينيوم، كم اأنه البد من تقييم حاالت اأخرى لتح�صني �صيا�صات العالج يف مثل هذه احلاالت. كلمات مفتاحية: فو�صفيد االألومينيوم؛ الف�صفني؛ ت�صمم؛ ديجوك�صني؛ غلوكاغون؛ م�صادات التاأك�صد؛ تقرير حالة؛ اإيران. treatment of aluminium phosphide poisoning with a combination of intravenous glucagon, digoxin and antioxidant agents zohreh oghabian1 and *omid mehrpour2,3 sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e352–355, epub. 19 aug 16 submitted 8 feb 16 revision req. 13 mar 16; revision recd. 6 apr 16 accepted 24 apr 16 case report doi: 10.18295/squmj.2016.16.03.015 zohreh oghabian and omid mehrpour case report | e353 is commonly associated with alp poisoning; this is believed to be due to the direct effect of ph3 on the heart cells.5 cardiogenic shock is one of the main causes of death.5,6 there is currently no known antidote for this poison and most treatment modalities are not successful; however, the effective treatment of alp poisoning using an intra-aortic balloon pump (iabp) and digoxin has previously been reported.5,6 in addition, other researchers have reported that glucagon, digoxin or antioxidants administered individually to poisoned patients have had a beneficial effect.3,5 this report is the first to present the combined administration of glucagon, digoxin and antioxidants in the management of a patient with alp poisoning. case report a 21-year-old man was referred to the afzalipour hospital, kerman, iran, in 2015 after the intentional ingestion of a 3 g rice tablet containing alp. the patient had swallowed the tablet whole with one glass of water, without crushing the alp tablet into a powder. he had vomited approximately 45 minutes after ingesting the tablet and was admitted to a local hospital four hours later. at this point, he was completely awake and complained of abdominal and retrosternal pain and severe thirst. he had previously had a ventricular septal defect which had been repaired five years earlier. at presentation to the local hospital, the patient’s initial vital signs were as follows: blood pressure of 90/60 mmhg; pulse rate of 140 beats/minute; respiratory rate of 18 breaths/minute; axillary temperature of 36.4 °c; and oxygen saturation of 95% in ambient air. approximately 10 hours after ingestion of the tablet, the patient was referred to the afzalipour hospital, the main referral toxicology centre in kerman province.7 he was confused and his vital signs were as follows: blood pressure of 85/40 mmhg; pulse rate of 130 beats/minute; respiratory rate of 16 breaths/minute; axillary temperature of 36.7 °c; and oxygen saturation of 93% in ambient air. arterial blood gas analysis indicated that his ph, partial pressure of carbon dioxide, bicarbonate (hco3) and table 1: clinical and laboratory findings of a patient with aluminium phosphide poisoning finding post-admission time in hours 0 2 12 24 48 144* blood pressure in mmhg 85/40 90/60 98/70 100/40 120/85 110/70 pulse rate in beats/minute 130 120 112 115 98 85 respiratory rate in breaths/minute 16 17 18 12 14 16 temperature in °c 36.7 36.0 37.1 37.2 36.8 37.3 o2 saturation in % 93 92 90 95 97 96 paco2 in mmhg 28.5 26.8 33.6 30.2 41.7 47.6 ph 7.18 7.20 7.43 7.37 7.45 7.43 hco3 in mmol/l 11.7 11.1 22.7 17.6 29.7 32.5 be in mmol/l -17.6 -16.7 -0.2 -5.6 5.8 8.1 na in meq/l 135 137 135 140 k in meq/l 4.6 3.8 3.7 3.8 wbc 14,300 9,200 hct 45.3 34.5 pt 17 16 inr 1.6 1.1 blood glucose in mg/dl 133 141 123 bun in mg/dl 20 40 24 creatinine in mg/dl 1.7 1.4 1.1 *at discharge. o 2 = oxygen; paco2 = partial pressure of carbon dioxide; hco3 = bicarbonate; be = base excess; na = sodium; meq = milliequivalent; k = potassium; wbc = white blood cell count; hct = haematocrit; pt = prothrombin time; inr = international normalised ratio; bun = blood urea nitrogen. treatment of aluminium phosphide poisoning with a combination of intravenous glucagon, digoxin and antioxidant agents e354 | squ medical journal, august 2016, volume 16, issue 3 been suggested to be the inhibition of cytochrome c oxidase, secondary toxic myocarditis and alp-induced oxidative stress that lead to pump failure and cardiac arrest.1 there is currently no specific antidote for alp poisoning and supportive therapy is the mainstay of treatment for poisoned patients.3,5 antioxidant therapy using vitamins e and c and nac may theoretically have a therapeutic role in acute alp poisoning, as one of the main mechanisms of alpinduced toxicity is oxidative stress. some researchers have suggested the use of these agents—especially nac—to treat alp poisoning.9 in the current case, the patient was treated successfully with vitamins e and c and nac. the treatment of cardiogenic shock caused by alp poisoning with digoxin and an iabp has been suggested for mechanical support of the heart in toxic myocarditis and refractory shock; this approach has also had positive responses.5,6 tehrani et al. found that hospital stay duration and rates of intubation, ventilation and mortality were significantly lower among alp-poisoned patients who received nac in comparison to controls.9 in addition, there is some evidence suggesting that glucagon is useful for the treatment of cardiogenic shock.10,11 glucagon is an antidote for β-blocker poisoning but is also used to treat cardiogenic shock due to verapamil and, sometimes, imipramine.10 it has been postulated that glucagon activates adenylate cyclase at a different site to β-adrenergic agents, resulting in an increase in cyclic adenosine monophosphate; this increases the calcium pool available for release during depolarisation and contractility.11,12 glucagon can also increase heart rate but has no effect on arterial pressure; thus, it has been reportedly useful in increasing mean blood pressure and heart rate in amitriptyline toxicity, although it is still unclear whether glucagon increases blood pressure.13 glucagon receptors in the ventricular myocardium cause its inotropic effects.14 thus, glucagon is a probable antidote for alp poisoning by potentially increasing blood pressure and heart rate. moreover, treating cardiogenic shock with glucagon may result in enhanced tissue perfusion.11 a previous case report described the successful treatment of a woman with alp poisoning in kerman, iran, and concluded that the early administration of glucagon to alp-poisoned patients in refractory shock may be beneficial.15 in addition to routine supportive treatments, managing the two main hazards of toxicity—oxidative stress and cardiogenic shock leading to circulatory collapse and lactic acidosis—is essential for the successful treatment of alp poisoning. for this reason, agents with antioxidant properties such as vitamins e and c and nac were administered to the patient in the base excess were 7.18, 28.5 mmhg, 11.7 mmol/l and -17.6 mmol/l, respectively. electrocardiography revealed that the patient had sinus tachycardia. using bedside echocardiography, the left ventricular ejection fraction was 35%. serial vital signs and laboratory findings over time are presented in table 1. the patient was prescribed 44 milliequivalents of sodium bicarbonate every 15 minutes until the metabolic acidosis was corrected. he was also given an intravenous infusion of normal saline and vaso pressors; additionally, 1 mg of glucagon was administered intravenously every 5–10 minutes until his blood pressure normalised after a total of 4 mg of glucagon. this was followed by a 4 mg/hour slow intravenous infusion of glucagon. subsequently, digoxin (0.5 mg initially followed by 0.25 mg every six hours for 24 hours and 0.25 mg daily thereafter), magnesium sulphate (1 g initially followed by 1 g every six hours), 10% calcium gluconate (1 g initially followed by 1 g every six hours), hydrocortisone (200 mg initially followed by 200 mg every six hours), vitamin c (1,000 mg every 12 hours via slow intravenous infusion), vitamin e (400 units intramuscularly) and n-acetylcysteine (nac; 140 mg/kg orally as a loading dose followed by 70 mg/kg orally every 4 hours for up to 17 doses) were administered. with the improvement of the metabolic acidosis and stabilisation of the patient’s vital signs, all medications were gradually tapered off. the patient was discharged from the hospital six days after admission in good clinical condition and completely symptom-free. he did not require tracheal intubation at any point during admission. repeat echocardiography at discharge revealed that the left ventricle ejection fraction was 50%. discussion alp induces oxidative stress and boosts the extramitochondrial release of free oxygen radicals that lead to lipid peroxidation and protein denaturation of the cell membrane in various organs.1 ph3 inhibits mitochondrial cytochrome c oxidase and catalase, induces superoxide dismutase and reduces the concentration of glutathione in alp-poisoned patients, which leads to the generation of superoxide radicals and cellular peroxides.1,2 cellular injury subsequently occurs via lipid peroxidation and other oxidant mechanisms, such as protein denaturation of the cell membrane and hypoxic cell damage.8 the major lethal consequences of alp ingestion (i.e. profound circulatory collapse) are reportedly secondary to the toxins generated which directly affect cardiac myocytes and cause fluid loss and adrenal gland damage.1,3,4 the main causes of cardiogenic shock in alp poisoning have zohreh oghabian and omid mehrpour case report | e355 current case as well as glucagon and digoxin to allow for better tissue perfusion. since the sites of entrance and accumulation of calcium ions within the cell are different, glucagon and digitalis have synergistic inotropic effects.14 coadministration of glucagon and digoxin is more effective than utilising each alone.16 due to the short duration of action, prolonged continuous infusion of glucagon is necessary.12 although alter native therapies such as angiotensin-converting enzyme inhibitors, intravenous diuretics and other intravenous inotropes are usually safer and more effective in cases of acutely decompensated heart failure, these treatments are less effective for patients with alp poisoning.5 successful treatment in the current case with glucagon and digoxin suggests that the concurrent use of high doses of these two agents may be useful in the treatment of alp poisoning; however, this finding needs to be confirmed by further studies. the patient in the present case suffered from late vomiting; louriz et al. observed that vomiting is a common symptom of alp poisoning and that a lack of vomiting is a poor prognostic factor.17 in the present case, levels of paraoxonase 1 as well as the total antioxidant and total oxidant statuses and oxidative stress index were not evaluated. these are important to determine the patient’s oxidant and antioxidant status. previous studies have demonstrated that iabps are another excellent treatment modality in cases of alp poisoning;1,6 the addition of an iabp to the treatment protocol used in the present case is recommended, especially in severe cases of alp poisoning. however, it is important to bear in mind that iabps are not available at all poisoning centres. the authors of this report recommend that other strong antioxidants such as superoxide dismutase and intracellular antioxidants like tempol should be used when treating cases of alp poisoning. conclusion a combination of glucagon and digoxin with antioxidant agents was used to successfully treat a patient with alp poisoning. however, the clinical significance of this approach requires further consideration and evaluation in order to optimise management protocols for alp poisoning. references 1. mehrpour o, jafarzadeh m, abdollahi m. a systematic review of aluminium phosphide poisoning. arh hig rada toksikol 2012; 63:61–73. doi: 10.2478/10004-1254-63-2012-2182. 2. mehrpour o, singh s. rice tablet poisoning: a major concern in iranian population. hum exp toxicol 2010; 29:701–2. doi: 10.1177/0960327109359643. 3. gurjar m, baronia ak, azim a, sharma k. managing aluminum phosphide poisonings. j emerg trauma shock 2011; 4:378–84. doi: 10.4103/0974-2700.83868. 4. mehrpour o, keyler d, shadnia s. comment on aluminum and zinc phosphide poisoning. clin toxicol (phila) 2009; 47:838–9. doi: 10.1080/15563650903203684. 5. mehrpour o, farzaneh e, abdollahi m. successful treatment of aluminum phosphide with digoxin: a case report and review of literature. int j pharmacol 2011; 7:761–4. doi: 10.3923/ ijp.2011.761.764. 6. mehrpour o, amouzeshi a, dadpour b, oghabian z, zamani n, amini s, et al. successful treatment of cardiogenic shock with an intraaortic balloon pump following aluminium phosphide poisoning. arh hig rada toksikol 2014; 65:121–6. doi: 10.2478/10004-1254-65-2014-2393. 7. mehrpour o, abdollahi m. poison treatment centers in iran. hum exp toxicol 2012; 31:303–4. doi: 10.1177/096032711 0392086. 8. mehrpour o, abdollahi m, sharifi md. oxidative stress and hyperglycemia in aluminum phosphide poisoning. j res med sci 2014; 19:196. 9. tehrani h, halvaie z, shadnia s, soltaninejad k, abdollahi m. protective effects of n-acetylcysteine on aluminum phosphideinduced oxidative stress in acute human poisoning. clin toxicol (phila) 2013; 51:23–8. doi: 10.3109/15563650.2012.743029. 10. white cm. a review of potential cardiovascular uses of intravenous glucagon administration. j clin pharmacol 1999; 39:442–7. doi: 10.1177/009127009903900502. 11. arefi m, tabrizchi n. could glucagon be a therapeutic option in the management of acute aluminium phosphide toxicity? endocrinol metab syndr 2012; 1:5. doi: 10.4172/2161-1017. 1000109. 12. pollack cv jr. utility of glucagon in the emergency department. j emerg med 1993; 11:195–205. doi: 10.1016/0736-4679(93) 90519-d. 13. love jn, howell jm. glucagon therapy in the treatment of symptomatic bradycardia. ann emerg med 1997; 29:181–3. doi: 10.1016/s0196-0644(97)70327-5. 14. gonzalez-muñoz c, nieto-cerón s, cabezas-herrera j, hernández-cascales j. glucagon increases contractility in ventricle but not in atrium of the rat heart. eur j pharmacol 2008; 587:243–7. doi: 10.1016/j.ejphar.2008.04.001. 15. torabi m. successful treatment of aluminium phosphide poisoning: a case report. iran j pharmacol ther 2013; 12:77–9. 16. lvoff r, wilcken de. glucagon in heart failure and in cardiogenic shock: experience in 50 patients. circulation 1972; 45:534–42. doi: 10.1161/01.cir.45.3.534. 17. louriz m, dendane t, abidi k, madani n, abouqal r, zeggwagh aa. prognostic factors of acute aluminum phosphide poisoning. indian j med sci 2009; 63:227–34. doi: 10.4103/0019-5359.53386. http://dx.doi.org/10.2478/10004-1254-63-2012-2182 http://dx.doi.org/10.1177/0960327109359643 http://dx.doi.org/10.4103/0974-2700.83868 http://dx.doi.org/10.1080/15563650903203684 http://dx.doi.org/10.3923/ijp.2011.761.764 http://dx.doi.org/10.3923/ijp.2011.761.764 http://dx.doi.org/10.2478/10004-1254-65-2014-2393 http://dx.doi.org/10.1177/0960327110392086 http://dx.doi.org/10.1177/0960327110392086 http://dx.doi.org/10.3109/15563650.2012.743029 http://dx.doi.org/10.1177/009127009903900502 http://dx.doi.org/10.4172/2161-1017.1000109 http://dx.doi.org/10.4172/2161-1017.1000109 http://dx.doi.org/10.1016/0736-4679%2893%2990519-d http://dx.doi.org/10.1016/0736-4679%2893%2990519-d http://dx.doi.org/10.1016/s0196-0644%2897%2970327-5 http://dx.doi.org/10.1016/j.ejphar.2008.04.001 http://dx.doi.org/10.1161/01.cir.45.3.534 http://dx.doi.org/10.4103/0019-5359.53386 sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century squ med j, february 2012, vol. 12, iss. 1, pp. 19-24, epub. 7th feb 12 submitted 26th jun 11 revision req. 7th sep 11, revision recd. 21st sep 11 accepted 30th oct 11 the last two decades of medical education have been marked by a push towards curricular reform, and anatomy as a discipline, the unshakable foundation of medical teaching for hundreds of years, has been at the centre of this development. disagreements and controversies surround teaching styles, content, and the time dedicated to the discipline within the greater medical school curriculum.1 with traditional teaching marginalised, many anatomists department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: ibrahim1@squ.edu.om "بني املطرقة والسندان" تفاوت وجهات النظر بني أساتذة الطب عن حمتويات مناهج مادة التشريح البشري خالل الدراسة اجلامعية اإبراهيم اإنوا، فارنا تارانيكانتي، ميمونة الرواحي، �سادانا رويت�ساودري، عمر احلّبال يف كذلك الب�رصي الت�رصيح مادة كانت وبالطبع الإ�سالح. نحو م�سطرد بدفع املا�سيني العقدين خالل الطبي التعليم متّيز امللخ�ص: خ�سّم هذا التغيري والتطوير، كونها وملئات ال�سنني علم اأ�سا�سي يف املناهج الطبية، يف خ�سم هذا التغيري والتطوير. فمن املّتفق عليه اأّن الأطباء اجليدين على معرفة كافية بعلم الت�رصيح، ولكن هناك من يقل اتفاقًا على مدى الَكّم لهذه املعرفة ومن هو الطرف الذي يحدد هذا الَكّم. فالعديد من الأطّباء املمار�سني يعتقدون باأّن طلبة الطب لي�سوا على م�ستوى كاف من املعرفة لهذا العلم الأ�سا�سي قبل انتقالهم اىل املراحل ال�رصيرية لتدريبهم. وُت�سّجع جمال�س العتماد املهني على احلّد من كّمية املعلومات التي ُتدّر�س يف م�ساقات التعليم اجلامعي خ�سّم يف يقع وبالنتيجة الأ�سا�سية. املادة هذه لتدري�س املخ�س�س الوقت تقلي�س ا�ستمرار من الت�رصيح مادة مدر�سو وي�سكو الأدنى. تقوم اأن اأول، هو، الأمام اإىل والطريق اآمنًا. ِمهنيًا لُي�سِبَح منه مطلوب هو ما حول والرتباك باحلرية الّت�رصيح علم طالُب اجَلَدل هذا وار بني الّطلبة واأ�ساتذة علم الت�رصيح والأطباء املمار�سني لتحقيق هذه الروؤى املتباينة وو�سعها كليات الطب بت�سهيل اجلو املنا�سب حِلِ على طريق متنا�سق ومتزن. وثانيًا، اإّن اأ�ساتذة علم الت�رصيح يحتاجون اإىل اإعادة النظر باأنف�سهم يف اأمرين اثنني من الهيكلية الرئي�سية، الأول: اإىل تدري�س هذا العلم يف ال�سياق الذي �سيتم ا�ستخدامه عمليًا من قبل الطالب، والثاين: توظيف تقنيات تعليمية حديثة معا�رصة يف تدري�سهم وتقييمهم لهذه املادة. مفتاح الكلمات: الت�رصيح ، املنهاج ، اجلامعي ، التعليم الطبي. abstract: the last two decades of medical education have been marked by a persistent push towards curricular reform. anatomy as a discipline, the unshakable foundation of medical teaching for hundreds of years, has been at the centre of this development. although it is widely agreed that for doctors to be competent, they need an adequate knowledge of anatomy underpinning medicine, there is much less agreement over the quantity required, and who should decide and define it. many clinicians feel medical students are being under-trained in this basic medical science before reaching the clinical stages. professional accreditation boards advocate the reduction of factual information in undergraduate medical courses. anatomists complain of a progressive erosion of the time allocated to the subject. caught in the midst of this controversy is the student of anatomy who is left bewildered and confused about what is required from him to become a safe and competent health professional. the way forward might, first, be for medical schools to facilitate discussions between students, anatomy professors, and clinicians to bring these divergent perspectives into alignment. second, the anatomists need to re-invent themselves in two principal frameworks: first, to present the subject in the context within which it will be utilised by the student, and second to employ the overwhelming learning tool of today, i.e. technology, in their teaching and assessment of the subject. keywords: anatomy; curriculum; undergraduate; medical education. special contribution “between a rock and a hard place” the discordant views among medical teachers about anatomy content in the undergraduate medical curriculum *ibrahim m inuwa, varna taranikanti, maimouna al-rawahy, sadhana roychoudhry, omar habbal “between a rock and a hard place” the discordant views among medical teachers about anatomy content in the undergraduate medical curriculum 20 | squ medical journal, february 2012, volume 12, issue 1 defend territory within the medical curriculum. they complain of progressive erosion of the time allocated to teaching the subject within the undergraduate programme. caught in the midst of this three-way controversy, in other words, "between a rock and a hard place", are the medical students who are understandably concerned as to whether the clinicians’ fears are justified, or whether detailed anatomy content is in fact simply not necessary at their stage in the continuum of medical education. the aim of this article is therefore to encourage discussion between various interest groups in our medical school setting, and others similar to ours, regarding this pivotal discipline. in an attempt to tackle the various related areas of this controversy, the basic question that needs to be addressed might be: how much anatomy is enough for the undergraduate medical programme? how much anatomy is enough? ‘‘so, they only give you 6 weeks of anatomy, then send you out onto our surgical service chock-full of ignorance, huh? there are some basic things i need you to come in knowing, and you can’t possibly have learned them in 6 weeks of ‘anatomy lite’.14 the rapid rise of integrated curricula and approaches that are a departure from traditional didactic methods have given rise to concern about the level of knowledge attained by students graduating from innovative programmes, for basic medical sciences in general, and for anatomy in particular. however, the concerns of teachers and clinicians are mostly anecdotal and expressed informally. anatomists (and surgeons involved in the higher surgical examinations) have commented on the decline of students’ knowledge and their lack of understanding of anatomy in discussions, anatomical meetings, and other fora.15 waterston and stewart, for instance, surveyed the opinions of clinicians on this subject. their results indicated that the majority believed that anatomy is not adequately taught, and as a result, students’ knowledge is below the minimum necessary for safe medical practice.11 ‘‘we can’t remember all of it by the time we start clinicals…. the teaching was too intense... we ended up cramming rather than learning aspects useful for clinicals” (intern).16 as illustrated by this comment, and clinicians judge anatomy to be in a state of crisis.2,3 others, especially those anatomists with awareness of technology and education principles who have adopted a more ‘‘modernist’’ approach, are embracing new teaching methods and the use of technology.4 proponents of traditional teaching insist that the dissection of human cadavers be the mainstay of rigorous basic medical science training as it underpins subsequent clinical learning.5,6 those who support newer teaching modalities (e.g. computer-assisted learning) argue not only about the difficulty in obtaining human material in some settings, but also about the ethical, moral, and legal aspects related to the use of human materials in teaching.7,8 on one side of the controversy, are the clinicians who remain increasingly worried that medical students are under-trained in basic medical sciences before reaching the clinical years.9 for example, in 2003, mckeown, et al. found that students in their school’s new systems-based curriculum scored poorly in anatomy assessments compared to students from previous years.10 data collected by waterston and stewart, published in 2005, led them to conclude that ‘‘the majority of clinicians feel that the current anatomical education of medical students is inadequate, and below the minimum necessary for safe medical practice.”11 on the other side of this controversy are the educationalists in medical schools and professional accreditation boards who are saying very loudly, ‘more reasoning and less memorising is better’. for example, in the united kingdom, the move to re-examine how much anatomy (and, indeed, how much of all basic medical sciences) is taught was partly motivated by the uk general medical council’s (gmc) report ‘tomorrow’s doctors’.12 this report stated that undergraduate training is only the first step in a continuum of medical education and recommended that factual information in undergraduate medical courses be kept to the essential minimum. similarly, in the usa, the general professional education of the physician (gpep) report,13 and subsequent publications, recommended a reduction in lecture hours, increased problem solving, more conceptualisation, and decreased passive memorisation in medical programmes.14 a third angle in this controversy comes from professional academic anatomists who are increasingly concerned about how to stake out and ibrahim m inuwa, varna taranikanti, maimouna al-rawahy, sadhana roychoudhry, omar habbal special contribution | 21 may help to generate more realistic learning objectives.19 this type of bottom-up approach is more efficacious because the process recognises that successful curriculum implementation relies on its acceptance by teachers and students.20 indeed, a wider collaborative processes involving a number of stakeholders, such as senior clinicians, students, foundation doctors, local decision makers, educational experts, who determine what is to be learnt, have been reported to promote ownership of the content.21,22 this is because all stakeholders are likely to sign-up to the content and get involved in its delivery because they were consulted during its formulation. how should anatomy be learnt and evaluated? a solid foundation in anatomy is still perceived by many students and anatomists to be the best preparation for safe basic clinical procedures.23 in recent years, anatomy curricula in many institutions have undergone change concomitant with a significant reduction in the time allocated to anatomy teaching.24,25 few institutions, even within a single country, have the same curriculum.26,27 anatomists have been forced to curtail their curricula because of the introduction of additional subjects and different teaching modes to the medical course and, in some cases, the belief that the subject should be content-driven and not skillsbased.28 in many medical schools, most teaching is still done through dissection sessions, which could last for months whilst others rely only on prosections, medical imaging and learning on living subjects (actors) and videos. there are strongly held opinions even amongst anatomists for and against dissection as the primary method of teaching and learning in anatomy.29-32 this dichotomy is most unhelpful to the teaching of the subject because, in some settings, there are, for various reasons, no available cadavers33 and hence learning by dissection is not an option. the underlying consideration of how the subject should be taught ought to focus on the clinical scenario that anatomy is seen most often by the general practitioner. this is mostly in the form of surface anatomy of the human body, radiological images, endoscopic procedures,34 and when performing basic clinical procedures such as intravascular administration of drugs. in the counter argument is that there is ‘too much anatomy in the undergraduate curriculum’ and that ‘not every medical student will become a surgeon’ and so it unnecessary for him or her to have such a detailed knowledge of human structure. in a survey of graduating students about to commence internship, fitzgerald et al. reported a common perception that the amount of anatomy in the curriculum was too great to allow for meaningful reflection of its application.16 what these conflicting tendencies reveal is the lack of agreement on how much anatomical knowledge is enough for the undergraduate phase of medical education. this makes it imperative that very careful consideration be given to two issues: the quantity of anatomy knowledge medical students need to gain, and the stage of the curriculum at which such knowledge should be acquired. the basic principle that should guide this discourse ought to be a definition of the minimum working knowledge of human anatomy that allows an independent practitioner to practice safely and communicate effectively with patients and other medical professionals. this however, raises two equally vital questions: first, who decides how much anatomy to teach? and second, how to evaluate this learning? who decides how much anatomy to teach? who should decide how much anatomy to teach? should this decision be left to the discipline experts, the specialist clinicians, or the general practitioner? the two main approaches commonly reported in the literature, are the top-down approach, where groups of experts determine the educational objectives and disseminate them to teachers, and the bottom-up approach, where teachers, students and other stakeholders determine the learning outcomes.17 whilst specialist clinicians and professional anatomists have excellent knowledge of the discipline and can ensure that relevant areas of practice do not go unnoticed,18 they tend to propose learning outcomes that are too ambitious19 and the net effect can be a factually overloaded anatomy curriculum. conversely, asking a group of experts representing different disciplines within the undergraduate curriculum to reach consensus “between a rock and a hard place” the discordant views among medical teachers about anatomy content in the undergraduate medical curriculum 22 | squ medical journal, february 2012, volume 12, issue 1 the second phase was the major revision of the entire medical curriculum between 2002 and 2007 which culminated in the introduction of the new undergraduate medical curriculum in 2008. this revision was partially in response to a period when some subjects were claiming a greater share of curriculum time, especially those whose research has advanced most rapidly, particularly molecular biology and biochemistry. therefore, the emphasis during the revision process was on reducing ‘content overload’ to ensure that only ‘core’ material was presented, and on establishing not only horizontal integration with other basic medical sciences, but also some vertical integration with clinicians taking part in teaching during the early years of the curriculum. the way forward arguably, the discipline of anatomy has a very central role in the process of training doctors and supporting modern medical practice. the current controversy therefore, has a number of implications for the discipline and its position within the medical curriculum of the future. historically, most anatomy content has been taught predominantly in the first undergraduate year with very limited exposure to the subject in subsequent clinical training. this is educationally faulty, as, at the preclinical stage, the material is likely to appear irrelevant thereby encouraging superficial learning. a solution would be to integrate anatomy vertically into medical education so that students are exposed to anatomy teaching throughout undergraduate professional training.40 revisiting the subject throughout the continuum of undergraduate studies, most especially during clinical training so as to emphasise relevance, would appear to be the rational step to take. indeed, in 2005, waterston and stewart reported widespread support among clinicians for more vertical integration of anatomy teaching throughout the undergraduate curriculum.11 it is unrealistic to expect detailed proficiency in anatomical knowledge at the undergraduate level of medical education. there is a need for wide consultation with a broad stakeholder group to identify core anatomical content that is indispensable for safe medical practice at the point of graduation. regardless of whether a top-down this manner, the teaching method could then be organised to provide maximum opportunities for learning using those clinical scenarios. it is believed assessment is a major determining factor that drives student learning.35 therefore, closely linked to the process of deciding what parts of anatomy to learn, is the issue of evaluation of such learning. inappropriate assessment is not only detrimental to learning, but also has the potential to result in learning that is not transferred to the workplace.36 medical students generally look to assessments (examinations) for guidance on what material is worth studying. for example, creating examination items that require students merely to recall isolated facts without testing them on the application of those facts is likely to result in pure memorisation of structures without an understanding of the relationships between the components. clearly, in order to encourage learning for understanding, assessments need to test more than a recall of isolated facts. instead, assessments should focus on the application of basic medical science knowledge, often to clinical situations, and on integration of knowledge across topics and courses to achieve a coordinated, cross-disciplinary understanding of those situations.37 implications for the undergraduate curriculum over the last 25 years, the entire anatomy curriculum at our medical school has seen two major phases. the first was the development of the medical programme itself. this still extends over seven academic years:38 the first four years are preclinical and lead to the award of the b.sc. health sciences degree; the remaining three years are a clinical programme leading to the md (doctor of medicine) degree. in phase one, anatomy teaching took place mainly during the b.sc. health sciences programme. the bulk of the subject was presented by integrating not only the components of the subject among themselves, but also by integrating them with the other basic medical sciences in body-system courses.39 the content was taught by basic medical scientists who had little or no interaction with their clinical colleagues, either when determining the content, or in the process of teaching it to medical students. ibrahim m inuwa, varna taranikanti, maimouna al-rawahy, sadhana roychoudhry, omar habbal special contribution | 23 anatomists complain of a progressive erosion of the time allocated to the subject within the medical curriculum. in the interest of transparency, the way forward might be, first, for medical schools to facilitate discussions between students, anatomy professors, and clinicians to bring these divergent perspectives into alignment. second, the anatomists need to re-invent themselves. foremost in their mind should be the question as to how doctors encounter anatomy in clinical practice. emphasis on these issues should dominate the debate regarding anatomy teaching for medical students. finally, it goes without saying, that if student learning of anatomy is to change then assessment methods must also change. a future article on this issue would address the question of the nature and content of this new anatomy for undergraduate education, particularly in developing countries such as ours. it will also offer some practical suggestions on the way this knowledge should be assessed. references 1. patel k, moxham b. attitudes of professional anatomists to curricular change. clin anat 2006; 19:132–41. 2. raftery a. anatomy teaching in the uk. surgery 2006; 25:1–2. 3. older j. anatomy: a must for teaching the next generation. surgeon 2004; 2:79–90. 4. mclachlan j. new path for teaching anatomy: living anatomy and medical imaging vs. dissection. anat rec b new anat 2004; 281:4–5. 5. aziz m, mckenzie j, wilson j, cowie r, ayeni s, dunn b. the human cadaver in the age of biomedical informatics. anat rec b new anat 2002; 269:20–32. 6. newell rl. follow the royal road: the case for dissection. clin anat 1995; 8:124–7. 7. lempp hk. perceptions of dissection by students in one medical school: beyond learning about anatomy. a qualitative study. med educ 2005; 39:318–25. 8. mclachlan jc, bligh j, bradley p, searle j. teaching anatomy without cadavers. med educ 2004; 38:418– 24. 9. fasel j, morel p, gailloud p. a survival strategy for anatomy. lancet 2005; 365:754. 10. mckeown pp, heylings dj, stevenson m, mckelvey kj, nixon jr, mccluskey dr. the impact of curricular change on medical students' knowledge of anatomy. med educ 2003; 37:954–61. 11. waterston sw, stewart ij. survey of clinicians' attitudes to the anatomical teaching and knowledge or bottom-up approach is adopted to identify this core content, medical schools should facilitate discussions between students, basic medical science professors, and clinicians in order to bring their various perspectives into alignment.41 once this core content is identified, any other extra content may be regarded as elective and could be studied by students requiring an indepth exploration for their chosen specialty. in the process of identifying this ‘core anatomy’, the clinicians, the majority of whom were trained under the traditional lecture-based, dissectionbased anatomy curricula, need to realise that the aim of the undergraduate curriculum is not to produce specialists. as such they should resist the temptation to insist that undergraduate students have detailed anatomy knowledge related to their specialty. it could as well be argued that dogmatic support amongst some professional anatomists for detailed anatomy courses at the undergraduate level may have been detrimental to the evolution of anatomy as a subject. probably, the discipline of anatomy needs to reinvent itself as a subject. it should evolve to address the requirements of the subject in a medical curriculum in the 21st century.40 in the interest of promoting knowledge retention, contextual learning and clinical application of the discipline, anatomy professors need to become more innovative. this innovation should include the adoption of sound pedagogy as well as the use of technology in teaching and assessing the subject.33,42 an example of how anatomists need to innovate, especially in the middle east, relates to the lack of human material (cadavers) for teaching. this challenge ought be turned into an advantage by the enhanced usage of radiological, surface and living anatomy. conclusion although it is widely agreed that for doctors to be competent, they need an adequate knowledge of anatomy underpinning medicine, there is much less agreement over the quantity required, and who should decide and define it. many clinicians feel medical students are being under-trained in this basic medical science before reaching the clinical stages; professional accreditation boards advocate the reduction of factual information in undergraduate medical courses such as anatomy. “between a rock and a hard place” the discordant views among medical teachers about anatomy content in the undergraduate medical curriculum 24 | squ medical journal, february 2012, volume 12, issue 1 28. patel km, moxham bj. attitudes of professional anatomists to curricular change. clin anat 2006; 19:132–41. 29. granger n. dissection laboratory is vital to medical gross anatomy education. anat rec b new anat 2004; 281b:6–8. 30. mclachlan j. new path for teaching anatomy: living anatomy and medical imaging vs. dissection. anat rec b new anat 2004; 281b:4–5. 31. pawlina w, lachman n. dissection in learning and teaching gross anatomy: rebuttal to mclachlan. anat rec b new anat 2004; 281b:9–11. 32. topp k. prosection vs. dissection, the debate continues: rebuttal to granger. anat rec b new anat 2004; 281b:12–14. 33. inuwa im, al rawahy m, taranikanti v, habbal o. anatomy "steeplechase" online: necessity sometimes is the catalyst for innovation. anat sci educ 2011; 4:115–18. 34. kumar pa, norrish m, heming t. laparoscopic surgery recording as an adjunct to conventional modalities of teaching gross anatomy. sultan qaboos univ med j 2011; 11:497–502. 35. newble di, jaeger k. the effect of assessments and examinations on the learning of medical students. med educ 1983; 17:165–71. 36. louw g, eizenberg n, carmichael sw. the place of anatomy in medical education: amee guide no 41. med teach 2009; 31:373–86. 37. swanson d, case s. assessment in basic science instruction: directions for practice and research. adv health sci educ theory pract 1997; 2:71–84. 38. hassan m, gumaa k, harper a, heseltine g. contribution of english language to the learning of basic medical sciences in sultan qaboos university. med teach 1995; 17:277–82. 39. abu hijleh mf, habbal oa, moqatash s, harris pf. clinical anatomy and anatomical skills: an innovative course. med teach 1995; 17:283–8. 40. turney b. anatomy in a modern medical curriculum. ann r coll surg engl 2007; 89:104–7. 41. habbal o. the state of human anatomy teaching in the medical schools of gulf cooperation council countries: present and future perspectives. sultan qaboos univ med j 2009; 9:24–31. 42. inuwa im, taranikanti v, al-rawahy m, habbal o. perceptions and attitudes of medical students towards two methods of assessing practical anatomy knowledge. sultan qaboos univ med j 2011; 11:383– 90. of medical students. clin anat 2005; 18:380–4. 12. general medical council. tomorrow's doctors. london: the general medical council, 1993. 13. muller s. physicians for the twenty-first century: report of the project panel on the general professional education of the physician and college preparation for medicine. washington, dc: association of american medical colleges, 1984. 14. joslin s. perceptions of anatomy educationa student's view. anat sci educ 2008; 1:133–4. 15. heylings dj. anatomy 1999-2000: the curriculum, who teaches it and how? med educ 2002; 36:702–10. 16. fitzgerald je, white mj, tang sw, maxwellarmstrong ca, james dk. are we teaching sufficient anatomy at medical school? the opinions of newly qualified doctors. clin anat 2008; 21:718–24. 17. bull s, mattick k. what biomedical science should be included in undergraduate medical courses and how is this decided? med teach 2010; 32:360–7. 18. wilson s, eagles jm, platt je, mckenzie h. core undergraduate psychiatry: what do non-specialists need to know? med educ 2007; 41:698–702. 19. leinster s. education and practice: curriculum planning. lancet 2003; 362:750. 20. moercke am, eika b. what are the clinical skills levels of newly graduated physicians? self-assessment study of an intended curriculum identified by a delphi process. med educ 2002; 36:472–8. 21. morcke am, wichmann-hansen g, nielsen dg, eika b. complex perspectives on learning objectives: stakeholders' beliefs about core objectives based on focus group interviews. med educ 2006; 40:675–81. 22. newble d, stark p, bax n, lawson m. developing an outcome-focused core curriculum. med educ 2005; 39:680–7. 23. moxham bj, plaisant o. perception of medical students towards the clinical relevance of anatomy. clin anat 2007; 20:560–4. 24. dangerfield p, bradley p, gibbs t. learning gross anatomy in a clinical skills course. clin anat 2000; 13:444–7. 25. verhoeven bh, verwijnen gm, scherpbier aj, van der vleuten cp. growth of medical knowledge. med educ 2002; 36:711–17. 26. cottam ww. adequacy of medical school gross anatomy education as perceived by certain postgraduate residency programs and anatomy course directors. clin anat 1999; 12:55–65. 27. gartner lp. anatomical sciences in the allopathic medical school curriculum in the united states between 1967-2001. clin anat 2003; 16:434–9. department of medicine, college of medicine, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia *corresponding author e-mail: alanezi@hotmail.com تصوُّراُت املرضى جتاه مشاركة طالَّب الطب يف العناية هبم د الغامدي، عالء عرب، نورا عالمي، تركي الدري�س، ميعاد رحيم د الغبني، حممَّ حممَّ abstract: objectives: patient interaction is a vital part of healthcare training. this study aimed to investigate patients’ perceptions of the participation of medical students in their care. methods: this descriptive cross-sectional study was conducted between october 2014 and march 2015 among 430 patients admitted to the medical and surgical wards at the king abdulaziz medical city, riyadh, saudi arabia. an arabic questionnaire was designed to assess the demographic characteristics of the patients and their perceptions of students’ participation in their medical care. results: a total of 416 patients completed the survey (response rate: 97%). overall, 407 patients (98%) acknowledged the educational benefit of involving medical students in their care. a total of 368 patients (88%) had no objection to a medical student being involved in their care. of these, 98% were willing to be asked about their medical history by medical students, 89% would permit physical examinations by medical students and 39% preferred that the gender of the medical student match their own. education level (p <0.003), a positive prior experience with a medical student (p <0.001) and perception of the medical students’ attitudes (p <0.001) had a significant effect on patients’ acceptance of medical students participating in their care. conclusion: in general, the patients had a positive perception of medical students, with most patients acknowledging the educational benefit of student participation in patient care. as patients’ perceptions of students’ professionalism, confidence and respect for privacy were significantly related to acceptance of care, education on these aspects should be a priority in medical curricula. keywords: patients; perceptions; attitudes; medical students; medical education; saudi arabia. رات املر�سى ية. لذلك، هدفت هذه الدرا�سُة اإىل التعرُّف على ت�سوُّ امللخ�ص: اأهداف: يعّد التفاعل مع املري�س ُجْزءاً حيويًا من التدريب على الرعاية ال�سحِّ مني حوَل م�ساركة طالَّب الطب يف رعايتهم. منهجية: اأُجرَيت هذه الدرا�سُة الو�سفيَّة املقطعيَّة بني اأكتوبر 2014 ومار�س 2015 على 430 من املر�سى املنوَّ يف الأق�سام الطبِّية واجلراحية مبدينة امللك عبد العزيز الطبِّية، الريا�س، اململكة العربية ال�سعودية. وقد مت ت�سميُم ا�ستبيان باللغة العربية لَتْقييم اخل�سائ�س وب�سفه .)97% ال�ستجابة: )معدَّل ال�ستبيان مري�سًا 416 اأكمل نتائج: الطبِّية. رعايتهم يف الطالَّب م�ساركة حوَل راتهم وَت�سوُّ للمر�سى الدِّميوغرافية عامة، كان 407 من املر�سى )%98( ُمدِركني للَجْدوى التعليمية من اإ�رساك طالب الطبِّ يف رعايتهم؛ ومل ُيْبِد 368 مري�سًا )%88( اأيَّ اعرتا�س على م�ساهمة طاّلب الطبِّ يف رعايتهم. ومن بني هوؤلء، كانت %98 على ا�ستعداد لالإجابة عن �سوؤال طاّلب الطب حوَل التاريخ الطبي لهم، كما �سمح %89 منهم بفح�سهم )p >0.003( الحتمال )ن�سبة التعليم مل�ستويات كان لهم. مواِفق الطالب جُن�س يكوَن اأن امل�ساركني املر�سى من 39% وف�سل الطالَّب. ِقَبل من طبِّيًا ابقة مع طاّلب الطّب )ن�سبة الحتمال )p >0.001( وطبيعة مواقف هوؤلء الطاّلب )p >0.001( تاأثرٌي كبري يف َتقبُّل املر�سى للطالَّب والتجربة الإيجابية ال�سَّ م معظم املر�سى امل�ساركني للجدوى التعليمية مل�ساركة ٌر اإيجابي جتاه طالَّب الطب، مع تفهُّ امل�ساركني يف رعايتهم. خامتة: ب�سكٍل عام، كان للمر�سى ت�سوُّ راُت ايجابية للمر�سى مع تقبُّل الرعاية اجتاه مهنية الطالَّب والثقة واحرتام اخل�سو�سيَّة ولذلك الطالَّب يف رعايتهم. كما كان هناك ارتباطًا مهمًا و ت�سوَّ لبدَّ اأن يكوَن لتعليُم هذه اجلوانب اأولويًة يف املناهج الطبِّية كلمات مفتاحية: املر�سى؛ ت�سور؛ موقف؛ طالب الطب؛ التعليم الطبي؛ اململكة العربية ال�سعودية. patients’ perceptions towards the participation of medical students in their care *mohammed al ghobain, abdullah alghamdi, ala arab, nora alaem, turki aldress, mead ruhyiem advances in knowledge the majority of the patient cohort of this study demonstrated positive attitudes towards the involvement of medical students in their care. among those with no objection to medical student participation, most patients permitted students to take their medical histories and perform physical examinations. patient education levels were significantly associated with positive attitudes towards medical student participation. moreover, positive prior experiences with a medical student and perceptions of the students’ attitudes had a significant effect on patient acceptance of student involvement in their care. application to patient care research indicates that student-patient interactions are necessary to improve medical students’ competencies. the findings of this study indicate that physicians should not hesitate to involve medical students in patient care, including historytaking and physical examinations. however, the majority of patients preferred that physicians remain present during interactions with medical students, particularly during physical examinations. this would serve to increase patient safety and minimise the rejection of medical students’ involvement in patient care. clinical & basic research sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 224–229, epub. 15 may 16 submitted 11 nov 15 revision req. 30 dec 15; revision recd. 18 jan 16 accepted 14 feb 16 doi: 10.18295/squmj.2016.16.02.014 mohammed al ghobain, abdullah alghamdi, ala arab, nora alaem, turki aldress and mead ruhyiem clinical and basic research | e225 it is vital that medical students are able to interact with patients from an early stage in their medical education.1,2 in order to accomplish this, medical schools have employed a variety of methods including practice scenarios with simulations or mannequins.3,4 nevertheless, previous studies have found that allowing medical students contact with real patients is fundamental to enhancing their clinical skills prior to graduation.5,6 several studies have evaluated patients’ perceptions of medical students in a range of medical specialties and have indicated that patients have a generally accepting attitude towards the participation of medical students in their care.3,7 however, certain factors or characteristics may affect patient attitudes towards medical students, such as previous experiences with medical students, education level, nature of the medical issue and the students’ genders and attitudes.2,3,7–9 to the best of the authors’ knowledge, only two cross-sectional studies regarding patients’ attitudes towards the participation of medical students in their care have yet been conducted in saudi arabia.3,10 abdulghani et al. found that 64% and 90.1% of 492 patients were accepting of medical students attending physical examinations and of students taking their medical histories, respectively, while bukhari et al. observed that 80% of 102 outpatient respondents were willing to let medical students participate in their treatment.3,10 the king abdulaziz medical city (kamc) is a tertiary healthcare centre in riyadh, saudi arabia, with a patient capacity of over 800 beds. in 2004, kamc founded the college of medicine which later became the king saud bin abdulaziz university for health sciences; the university currently utilises kamc as an educational institution for clinical practice. the current study was designed primarily to evaluate patients’ perceptions of medical students’ participation in their medical care at kamc. in addition, patients’ prior experiences with medical students, preferences regarding student gender and their willingness to be involved in medical education were assessed. methods this descriptive cross-sectional study was conducted at kamc between october 2014 and march 2015. a total of 430 arabic-speaking adult inpatients of both genders admitted to the medical and surgical wards at kamc during the study period were included. patients who were below 18 years old, mentally or critically ill, clinically unstable or who required emergency and/ or ambulatory care were not eligible for inclusion. in addition, long-term and geriatric patients were excluded as students are not usually exposed to these types of patients. the required sample size was determined using a sample size calculator (raosoft inc., seattle, washington, usa). the recommended sample size was 377 with a 95% confidence interval, 5% margin of error and 50% response distribution; a sample size of 430 patients was chosen in order to mitigate the effect of possible incomplete data. weekly lists of admitted patients in the medical and surgical wards were provided by the admissions office at kamc. systemic sampling began via a randomised start-point and by selecting every fifth patient on the list. using this method, selected patients who met the inclusion criteria were subsequently invited to participate in the study. an arabic language questionnaire was designed to assess the patients’ perceptions of medical student participation in their care. the first section elicited the demographic data of the participants, including age, gender, marital status, educational level and current medical problem. the second section involved 12 items regarding the patient’s opinion of students’ participation in their medical care, their preference for the attending medical students’ gender and their perceptions of the students’ attitudes. these items were scored using a five-point likert scale. the final section included two questions to determine the patients’ prior experiences with medical students; answers were recorded on a yes/no basis. the questionnaires were distributed among the selected patients by fourth and fifth-year medical students. patients completed the questionnaire on their own or, if they were incapable of doing so, with the help of the medical students. the medical students then collected the completed questionnaires. collected data were entered into an excel spreadsheet, version 2010 (microsoft inc., redmond, washington, usa). the statistical package for the social sciences (spss), version 21.0 (ibm corp., chicago, illinois, usa) was used to calculate descriptive and comparative statistics. pearson’s chi-squared test was used to determine associations between categorical variables. this study was granted ethical approval by the research committee at the king abdullah international medical research center in riyadh (#rc12/71). all of the subjects gave informed consent for their inclusion in the study. confidentiality was ensured in all of the study processes. results a total of 416 patients participated in the study (response rate: 97%). the participants ranged in age patients’ perceptions towards the participation of medical students in their care e226 | squ medical journal, may 2016, volume 16, issue 2 from 18–107 years old with a mean age of 52.7 ± 18.9 years. males accounted for 55% of the participants while 84% were married. education levels varied, with 27% of the cohort having had no education at all. overall, 49% of the participants were in medical wards while the remainder were in surgical wards [table 1]. the educational benefit of involving a medical student in their treatment was acknowledged by 407 patients (98%; p <0.001). a total of 368 patients (88%) stated that they would allow medical students to participate in their medical care (p <0.001). of the patients who would allow medical students to aid in their care, 362 (98%) reported that they had no problem being asked about their medical history by medical students (p <0.001). however, only 314 (85%) of those agreeable to medical student participation would disclose sensitive or personal information related to their health (such as a history of sexually transmitted diseases, substance abuse and genetic diseases) when giving their history to a medical student (p <0.001). of those allowing medical students to participate in their medical care, 351 patients (95%) reported that they would not object to a medical student being present during a doctor-administered examination (p <0.001), while 326 patients (89%) would agree to be examined by a medical student (p <0.001). the presence of a doctor during history-taking or a physical examination by a medical student was preferred by 357 patients (97%) among those who would allow medical students to aid in their care (p <0.001). with regards to the gender of the medical student, 143 patients (39%) reported that they would prefer the medical student to be of the same gender as themselves [table 2]. patients’ education levels were strongly correlated with patient acceptance (p <0.003). no other demographic characteristics were significantly associated with patient acceptance [table 3]. in total, 165 patients (40%) indicated that they had had a prior experience with medical students; of these, 157 patients (95%) rated their previous experiences as positive. a total of 143 patients (87%) perceived the behaviour of medical students to be professional and 144 (87%) reported that medical students had displayed confidence while treating them. however, five patients (3%) felt that medical students had not respected their privacy [table 4]. a positive prior experience with a medical student was significantly associated with patient acceptance of a medical student administering their care (p <0.001). six of the eight patients (75%) who had had a negative prior experience with a medical student stated that they would not allow a table 1: demographic characteristics of inpatients at the king abdulaziz medical city, riyadh, saudi arabia (n = 416) characteristic n (%) mean age in years ± sd 52.7 ± 18.9 gender male 229 (55) female 187 (45) marital status married 350 (84) unmarried 66 (16) education level none 114 (27) primary and secondary 199 (48) university 103 (25) type of care medical 205 (49) surgical 211 (51) sd = standard deviation. table 2: self-reported perceptions regarding medical students’ participation in their healthcare among inpatients at the king abdulaziz medical city, riyadh, saudi arabia (n = 416) questionnaire item n (%) p value agree disagree i accept the participation of medical students in my healthcare 368 (88) 48 (12) <0.001 i believe that the participation of medical students in my healthcare is important in medical education 407 (98) 9 (2) <0.001 i agree to be asked by a medical student about my medical history* 362 (98) 6 (2) <0.001 i agree to disclose personal information related to my health to a medical student* 314 (85) 54 (15) <0.001 i agree to have a medical student present when the doctor is examining me* 351 (95) 17 (5) <0.001 i agree to be clinically examined by a medical student* 326 (89) 42 (11) <0.001 i prefer to have the doctor present when a medical student is taking my medical history or performing a clinical examination* 357 (97) 11 (3) <0.001 i prefer to have a medical student of my gender* 143 (39) 225 (61) <0.001 *responses include only those patients who accepted the participation of medical students in their care. mohammed al ghobain, abdullah alghamdi, ala arab, nora alaem, turki aldress and mead ruhyiem clinical and basic research | e227 student to care for them. medical students’ perceived attitudes in terms of professionalism, respect for patient privacy and confidence were significantly related to the patients’ acceptance of medical student participation (p <0.001). discussion contact with patients is vital to improving medical students’ education and expanding their knowledge of various medical specialties.1,2 however, patients’ perceptions of care can potentially be affected by the presence or involvement of medical students; this may, in turn, influence the students’ educational experience.11 ellett et al. found that 88% of patients attending a student-run clinic were aware that the clinic was run by medical students and 98% were satisfied with their treatment.12 a study conducted at a dermatology clinic in the usa showed a high rate of patient acceptance for medical students regardless of gender and willingness to share private information with students.13 the majority of patients in the current study had a positive perception of medical students and would allow medical students to take part in their care; of these, most were willing to share their medical histories with medical students. however, patients were more accepting of a medical student being present during a doctor-performed physical examination than of a medical student performing the examination themselves and most patients preferred that a doctor be present during a student-led historytaking or physical examination session. however, almost two-thirds of the patients indicated that the gender of the medical student was not an issue. the results of the current study are comparable to those of previous studies conducted in saudi arabia.3,10 abdulghani et al. reported lower rates of patient acceptance with regards to medical students taking patient histories and interacting with medical students of a different gender.3 however, although patients were aware of their right to refuse medical student participation in their care, most recognised the benefits of accepting student involvement and were agreeable to participating in the students’ medical education.3 additionally, patients perceived the role of medical students to be either treating physicians, physician helpers or observers, highlighting the impor tance of patient awareness regarding the purpose of student participation.3 bukhari et al. noted that 32.4% of patients preferred to be physically examined by a physician alone; furthermore, 58.5% of the respondents either agreed or strongly agreed that they would prefer having a medical student of the same gender as themselves.10 table 3: associations between demographic characteristics and acceptance of medical students’ participation in their healthcare among inpatients at the king abdulaziz medical city, riyadh, saudi arabia (n = 416) characteristic n (%) p value acceptance of medical student participation (n = 368) refusal of medical student participation (n = 48) age in years 0.101 18–44 128 (92) 11 (8) 45–64 90 (83) 18 (17) >65 150 (89) 19 (11) gender 0.172 male 207 (90) 22 (10) female 161 (86) 26 (14) marital status married 308 (88) 42 (12) 0.497 unmarried 60 (91) 6 (9) type of care 0.182 medical 177 (86) 28 (14) surgical 191 (91) 20 (9) education level <0.003 none 91 (80) 23 (20) primary and secondary 184 (92) 15 (8) university 93 (90) 10 (10) table 4: self-reported perceptions of medical students among inpatients with previous experiences of medical students at the king abdulaziz medical city, riyadh, saudi arabia (n = 165) questionnaire item n (%) p value agree neutral disagree i felt comfortable when the medical student took my medical history or performed a clinical examination 129 (78) 32 (19) 4 (2) <0.001 the medical student dealt with me in a professional and attentive manner 143 (87) 21 (13) 1 (1) <0.001 the medical student respected my privacy 151 (92) 9 (6) 5 (3) <0.001 the medical student treated me with confidence 144 (87) 17 (10) 4 (2) <0.001 patients’ perceptions towards the participation of medical students in their care e228 | squ medical journal, may 2016, volume 16, issue 2 monnickendam et al. confirmed that 59.7% and 34% of israeli patients, respectively, would allow a student to take their medical history and examine them, as long as the students were supervised by a tutor.14 this is in line with the findings of the current study; while most patients in the current study had few reservations in giving their medical histories to students, some felt uncertain in allowing medical students to perform a physical examination. in these situations, practice of patient care using simulated patients and/or mannequins is a valuable method to fill in these skill gaps.3,4 moreover, as the current study found that medical students’ perceived attitudes in terms of professionalism, respect for patient privacy and confidence were significantly related to the patients’ acceptance of their care, medical schools should incorporate modules on professionalism and patient-doctor relations within the medical curricula, prior to allowing student-patient interactions. in terms of gender preference, several studies have indicated that male patients are reportedly less comfortable with a female student undertaking history-taking and physical examinations and vice versa.2–4,15 in general, the primacy factors cited by patients for refusing medical student care include concerns about confidentiality or privacy, longer visit durations, unease regarding potential mistakes made during treatment and negative previous experiences with medical students.2,7,9 furthermore, medical students may be barred from working with certain patients due to different religious and cultural backgrounds or gender preferences.5,8 the results of a study by onotai et al. support the notion that patients’ perceptions are affected by previous negative experiences with medical students.8 the present study also showed that previous experience had an effect on patients’ acceptance of medical students. previous positive experiences make it more likely that patients will comfortably accept medical students’ involvement in their care.7,16 such experiences have been found to contribute to lowering patients’ sensitivity towards the gender of participating medical students.5 comparable to the results of malhotra et al., the majority of the patients in the current study acknowledged the educational advantages of medical student involvement in their care.1 other research has also supported this theory; most patients, whether accepting of medical students’ involvement in their care or not, appreciate the educational benefit of student participation in care as a means of improving practice as well as in encouraging students to become better doctors.8,17 indeed, research has indicated that patients who are appreciative of the importance and benefit of patient-student interactions willingly choose to take part in students’ medical education.2,3,18 despite the low rate of previous experience with medical students, the patients in the current study tended nevertheless to be accepting of medical students’ participation in their care. a previous study showed that 77% of patients felt that they received an improved standard and duration of care when students were involved.15 further studies in medical education are vital to the development of this field; in particular, patients’ perceptions of their interactions with medical students require more detailed evaluation. the results of the present study may be beneficial to medical schools in evaluating their own patient-student interactions. points of investigation unique to this study included the random sampling of adult patients across both genders and various medical specialties as well as the inclusion of forms of student-patient interaction that were not explored in previous local studies, such as medical students’ professionalism, respect for patient privacy and confidence. however, this study has several limitations. due to its nature as a crosssectional study, there was possible bias in reporting results. moreover, potential bias may have been introduced when medical students completed forms on behalf of the patients. the study was also limited to surgical and medical patients and did not include patients from other specialities. conclusion the majority of the surveyed patients had a positive perception of medical students. most patients were accepting of medical students’ participation in their care and had no objection to giving students their medical history nor to having a student perform their medical examination. however, the vast majority of patients preferred that the doctor remain present with the student when performing these interactions. most patients who had had a previous experience with medical students rated their experience as positive. as the medical students’ perceived professionalism, respect for patient privacy and confidence were significantly related to patients’ acceptance of student participation in their care, these social competencies should be a priority in medical curricula. this may, in turn, encourage patients to be more accepting of the participation of medical students in their care. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. mohammed al ghobain, abdullah alghamdi, ala arab, nora alaem, turki aldress and mead ruhyiem clinical and basic research | e229 references 1. malhotra rk, hosdurga g. patients’ attitudes towards the involvement of medical students during induction of regional anesthesia. local reg anesth 2010; 3:73–6. doi: 10.2147/lra. s13098. 2. shah-khan m, chowdhry s, brand mi, saclarides tj. patient attitudes toward medical students in an outpatient colorectal surgery clinic. dis colon rectum 2007; 50:1255–8. doi: 10.1007 /s10350-007-0274-x. 3. abdulghani hm, al-rukban mo, ahmad ss. patient attitudes towards medical students in riyadh, saudi arabia. educ health (abingdon) 2008; 21:69. 4. rizk de, al-shebah a, el-zubeir ma, thomas lb, hassan my, ezimokhai m. women’s perceptions of and experiences with medical student involvement in outpatient obstetric and gynecologic care in the united arab emirates. am j obstet gynecol 2002; 187:1091–100. doi: 10.1067/mob.2002.126284. 5. racz jm, srikanthan a, hahn pm, reid rl. gender preference for a female physician diminishes as women have increased experience with intimate examinations. j obstet gynaecol can 2008; 30:910–17. doi: 10.1016/s1701-2163(16)32972-3. 6. o’flynn n, rymer j. women’s attitudes to the sex of medical students in a gynaecology clinic: cross sectional survey. bmj 2002; 325:683–4. doi: 10.1136/bmj.325.7366.683. 7. simons rj, imboden e, martel jk. patient attitudes toward medical student participation in a general internal medicine clinic. j gen intern med 1995; 10:251–4. doi: 10.1007/bf0259 9880. 8. onotai lo, asuquo eo, amadi e, amadi-oparelli a, ali du. patients’ perception and attitude towards medical students’ involvement in patients care at a nigerian university teaching hospital. educ res 2012; 3:732–43. 9. howe a, anderson j. involving patients in medical education. bmj 2003; 327:326–8. doi: 10.1136/bmj.327.7410.326. 10. bukhari i, alakloby o, al saeed w. patients’ attitude towards medical students rotating in the dermatology clinic. indian j dermatol 2008; 53:12–14. doi: 10.4103/0019-5154.39734. 11. simon sr, peters as, christiansen cl, fletcher rh. the effect of medical student teaching on patient satisfaction in a managed care setting. j gen intern med 2000; 15:457–61. doi: 10.1046/j.1525-1497.2000.06409.x. 12. ellett jd, campbell ja, gonsalves wc. patient satisfaction in a student-run free medical clinic. fam med 2010; 42:16–18. 13. townsend b, marks jg, mauger dt, miller jj. patients’ attitudes toward medical student participation in a dermatology clinic. j am acad dermatol 2003; 49:709–11. doi: 10.1067/s01909622(03)00915-0. 14. monnickendam sm, vinker s, zalewski s, cohen o, kitai e. patients’ attitudes towards the presence of medical students in family practice consultations. isr med assoc j 2001; 3:903–6. 15. prislin md, morrison e, giglio m, truong p, radecki s. patients’ perceptions of medical students in a longitudinal family medicine clerkship. fam med 2001; 33:187–91. 16. ryder n, ivens d, sabin c. the attitude of patients towards medical students in a sexual health clinic. sex transm infect 2005; 81:437–9. doi: 10.1136/sti.2004.014332. 17. sadıkoglu g. family medical centre patients’ attitudes toward senior medical students’ participation in the examinations. middle east j fam med 2007; 5:38–41. 18. lucas b, pearson d. patient perceptions of their role in undergraduate medical education within a primary care teaching practice. educ prim care 2012; 23:277–85. doi: 10.10 80/14739879.2012.11494121. http://dx.doi.org/10.2147/lra.s13098 http://dx.doi.org/10.2147/lra.s13098 http://dx.doi.org/10.1007/s10350-007-0274-x http://dx.doi.org/10.1007/s10350-007-0274-x http://dx.doi.org/10.1067/mob.2002.126284 http://dx.doi.org/10.1016/s1701-2163%2816%2932972-3 http://dx.doi.org/10.1136/bmj.325.7366.683 http://dx.doi.org/10.1007/bf02599880 http://dx.doi.org/10.1007/bf02599880 http://dx.doi.org/10.1136/bmj.327.7410.326 http://dx.doi.org/10.4103/0019-5154.39734 http://dx.doi.org/10.1046/j.1525-1497.2000.06409.x http://dx.doi.org/10.1067/s0190-9622%2803%2900915-0 http://dx.doi.org/10.1067/s0190-9622%2803%2900915-0 http://dx.doi.org/10.1136/sti.2004.014332 http://dx.doi.org/10.1080/14739879.2012.11494121 http://dx.doi.org/10.1080/14739879.2012.11494121 covid-19 and pregnancy a narrative review of maternal and perinatal outcomes *nihal al riyami1 and shahila sheik2 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 167–178, epub. 26 may 22 submitted 18 may 21 revisions req. 7 jun 21 & 30 jun 21; revisions recd. 18 jun & 11 aug 21 accepted 19 aug 21 1department of obstetrics & gynecology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of obstetrics & gynecology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drriyami@hotmail.com covid-19 is a severe respiratory illness caused by a novel strain of single-stranded rna betacoronavirus—known as severe acute respiratory syndrome (sars) coronavirus 2 (cov-2).1 the disease was first reported in december 2019 in wuhan, china, and has since spread rapidly worldwide, resulting in 206,273,369 cases and more than 4,347,832 deaths in august 2021.2 the main route of transmission is direct transmission from close contact (i.e. within 2 m) with an infected person through aerosol/droplet spread.3 the average incubation period is five days (range: 2–14 days), and the illness varies in severity from very mild, with flulike symptoms, to severe respiratory illness and death. the word health organization (who)–china joint mission comprising 25 national and international experts, headed by the who, reported the following common symptoms in 75,465 covid-19 patients: fever (87.9%), dry cough (67.7%), fatigue (38.1%), sputum production (33.4%), shortness of breath (18.6%) and myalgia (14.8%).4 however, some patients were asymptomatic.5,6 to date, limited data are available regarding the effect of covid-19 on pregnancy.4 it can be postulated that the anatomical and physiological changes inherent to pregnancy—such as diaphragmatic elevation by the gravid uterus leading to reduced functional residual capacity, increased oxygen consumption and airway oedema—might increase susceptibility to severe respiratory infections and decrease tolerance to hypoxia, as was found by a study conducted in hong kong on patients with sars-cov-1.7 the effects of other coronaviruses such as sars-cov-1 and middle east respiratory syndrome (mers) on pregnant women might also provide insight into the possible impact of covid-19 on this population.1 in the largest series of pregnancy outcomes in sars-cov-1 cases, wong et al. reported 12 pregnancies resulting in a 25% fatality rate.7 maternal complications included acute respiratory distress syndrome (ards; 33.3%), renal failure (25%), disseminated intravascular coagulopathy (dic; 25%), sepsis (16.7%) and secondary bacterial pneumonia (16.7%). four out of seven women (57.1%) experienced spontaneous miscarriages in the first trimester, and four out of five (80%) had preterm deliveries at 24–32 gestational weeks.7 a total of 13 case reports on pregnancy outcomes in mers revealed a 23% fatality rate, including three deaths due to ards.8–13 in addition, there were two cases of intrauterine fetal death and two preterm births.10,11,13 however, no evidence of vertical transmission has been reported in either sars-cov-1 or mers patients in 2016 and 2014, respectively. this review aimed to evaluate available evidence from the beginning of the covid-19 pandemic in january 2020 to february 2021 regarding maternal and perinatal outcomes in pregnant women infected with sars-cov-2. methods this narrative review was conducted in march 2021 to identify articles reporting maternal and review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.120 abstract: as of august 11, 2021, approximately 206 million people worldwide had been infected with sars-cov-2. however, limited data are available regarding the effects of covid-19 infection on pregnancy and maternal and perinatal outcomes. this review aimed to resolve this gap in literature. the medline®, scopus and cumulative index to nursing and allied health literature databases were searched to identify relevant english-language articles published between january 2020 and february 2021. a total of 17 articles describing the outcomes of 762 pregnancies were identified. there were 613 babies born, including 16 sets of twins. within the cases studied, 12 (1.6%) maternal deaths and eight (1.3%) stillbirths were reported. a small proportion of mothers (3.9%) required admission to the intensive care unit, usually due to associated comorbidities. rates of caesarean and preterm delivery ranged from 27–100% and 4–50%, respectively. further research is necessary to determine the effect of covid-19 infection on early pregnancy. keywords: covid-19; pregnancy; maternal death; perinatal death; pregnancy outcome; stillbirth; preterm birth; review. https://creativecommons.org/licenses/by-nd/4.0/ covid-19 and pregnancy a narrative review of maternal and perinatal outcomes 168 | squ medical journal, may 2022, volume 22, issue 2 perinatal outcomes in pregnant women diagnosed with covid-19. the medline® (national library of medicine, bethesda, maryland, usa), scopus (elsevier, amsterdam, netherlands) and cumulative index to nursing and allied health literature (ebsco information services, ipswich, massachusetts, usa) databases were searched electronically utilising appro priate medical terminology related to the topic. the following search terms were used both individually and in combination: ‘covid-19 infection’, ‘coronavirus’ and ‘pregnancy’. the search was restricted to english-language articles published between january 2020 and february 2021. all full-text articles investigating pregnancy and perinatal outcomes in women with covid-19, such as case reports, case series and original studies, were included. review articles were excluded due to the possibility of duplication of data. articles related to other types of coronavirus infections such as mers and sars-cov-1 were excluded. the initial search revealed 24 articles, of which seven were excluded due to duplication of data already incorporated in other articles. subsequently, a total of 17 articles (case series and case reports) were included in the final analysis. each article was reviewed to determine the maternal and perinatal outcomes. the pregnancy or maternal outcomes of interest in this review included maternal age, maternal comorbidity, major presenting symptom, relevant investigation, miscarriage, preterm delivery (defined as birth before 37 gestational weeks), fetal growth restriction (fgr), mode of delivery, complication related to covid-19 infection, intensive care unit (icu) admission and death. perinatal outcomes included gestational age at delivery, neonatal admission to the icu, perinatal asphyxia, stillbirth, neonatal death and any evidence of vertical transmission. in addition, data related to investigations and treatment modalities used in the included articles were extracted and tabulated. results a total of 24 articles were documented, but only 17 articles related to pregnancy and covid-19 were included in the analysis as they fit the inclusion criteria.14–30 in terms of article type, six case reports and 11 case series were identified. in total, the articles described the outcomes of 762 pregnancies and 613 babies, including 16 sets of twins.14–30 the maternal age ranged from 20–49 years. pregnant women most commonly presented in the third trimester with symptoms of fever.14,16–22,25–26,28 common laboratory findings included leukopaenia, lymphopaenia, elevated c-reactive protein levels and chest x-ray changes suggestive of viral pneumonia.14–22,24,25,29 although maternal comorbidities were not specified in many articles, the most commonly reported was obesity (n = 131, 17.2%).15,16,18 a total of 30 (3.9%) women required icu admission and mechanical ventilation for respiratory support due to ards.14–18,24,26 in the cases studied, 12 (1.6%) maternal deaths occurred, of which seven were reported in a case series of nine women with severe disease in iran.18 the rate of caesarean section delivery was high in the studied cohort, ranging from 27–100%, due to the mother and physician’s preferences.14–30 however, other indications included fetal distress, preterm premature rupture of the membranes, placenta previa, failure to progress and covid-19 pneumonia [table 1].16 out of the 17 articles, only six reported preeclampsia investigations.14,15,17,20,23,25 eight articles mentioned the use of anti-viral medications, but only two articles specified remdesivir use.15,23 four articles did not mention the use of corticosteroids, and in the remaining articles, the use of corticosteroids ranged from 12.5–100%.14,16,18,22 maternal thromboprophylaxis was given in only three instances,14,18,24 and was not given in eight series.17,21,22,25,27,28–30 moreover, data about thromboprophylaxis were not available in the remaining five articles [table 2].15,16,19,20,23,26 there was no evidence that covid-19 infection increased the risk of miscarriage, early pregnancy loss, teratogenicity or fgr. however, 10 out of the 17 articles reported preterm delivery (83 babies) occurring in 24– 37 gestational weeks (4–50%).15–20,22,23,25,28 in addition, eight (1.3%) intrauterine fetal deaths or stillbirths and four (0.7%) neonatal deaths were reported.15,17,18,22,24,28 of the 524 neonates who were tested for sars-cov-2, seven babies tested positive.23,28 six of these neonates were reported from the series published by adhikari et al. wherein four neonates were positive at 24 hours and two at 48 hours.23 only one of these (preterm birth at 34 weeks with prelabour rupture of membranes) was suspected to be intra-uterine transmission, as electron microscopy of the placental tissue revealed sars-cov-2 viral particles. no specific route of sars-cov-2 transmission could be determined in the remaining cases. no samples were obtained from the amniotic fluid. although one (0.2%) case of neonatal infection with covid-19 was confirmed at 36 hours after birth via pharyngeal swab, there was no evidence of vertical transmission as samples from the placenta, cord blood and breast milk tested negative [table 3].21 discussion there is limited information regarding the effect of covid-19 infection on pregnancy and childbirth due to the short time-frame since the start of the nihal al riyami and shahila sheik review | 169 table 1: maternal outcomes of pregnant women infected with sars-cov-2 no. author and year of publication [type of study] number of pregnant women/ pregnancies purpose of study age range or mean in years n (%) symptom comorbidities/laboratory findings icu admission cs maternal death 1 federici et al.14 (2020) [case report] 1 woman to study the continuation of pregnancy in spite of icu admission and mechanical ventilation 33 fever: 39.2 ºc dyspnoea co-morbidity: 0 cxr/ct viral changes: yes lymphocytopaenia thrombocytopaenia ↑hepatic transaminases yes no 0 2 lokken et al.15 (2021) [case series] 240 women (85 undelivered) 24 hospitalised 1 postpartum to describe disease severity and outcomes of sars-cov-2 infections during pregnancy across washington state including pregnancy complications and outcomes, hospitalisation and case fatality 20–39 symptomatic: 185 (77.1) details of symptoms including cough, fever and dyspnoea were not provided severe: 18 (7.5) critical: 4 (1.7) obesity: 102 (49.5) (bmi ≥30+ ≥40) asthma: 20 (8.3) dm: 13 (5.4) htn: 11 (4.6) lymphopaenia: 10/23 (43.5) ↑crp: 8/15 (53.3) ↑hepatic transaminases: 17/22 (77.3) 8 (3.3) 55/155 (35.5) 3 (1.3) 3 breslin et al.16 (2020) [case series] 43 women (25 undelivered) to determine the clinical characteristics of sars-cov-2 infection in 29 symptomatic pregnant women (26 with mild disease and 3 severe) 20–39 fever: 14 (48.3) cough: 19 (65.6) myalgia: 11 (37.9) dyspnoea: 7 (24.1) obesity: 26 (60.5) asthma: 8 (18.6) dm: 3 (7) htn: 3 (7) cxr/ct viral changes: 3/3 (100) with severe disease 2 (4.7) 8/18 (44.4) 0 4 yan et al.17 (2020) [case series] 116 women (17 undelivered) to report the maternal and neonatal outcomes of covid-19 patients 24–41 fever: 59 (50.9) cough: 33 (28.4) myalgia: 6 (5.2) dyspnoea: 3 (2.6) lymphopaenia: 51 (44) ↑crp: 51 (44) cxr/ct viral changes: 104 (96.3) gdm: 9 (7.8) htn: 5 (4.3) preeclampsia: 4 (3.4) 8 (6.9) 85/99 (85.9) 0 5 hantoushzadeh et al.18 (2020) [case series] 9 women to describe maternal and perinatal outcomes and death in a case series of pregnant women with covid-19 disease 25–49 fever: 9 (100) cough: 9 (100) dyspnoea: 6 (66.7) myalgia: 4 (44.4) obesity: 3 (33) age: >40yrs (22) lymphopaenia: 100% ↑crp: 100% cxr/ct viral changes: 100% 9 (100) 1 with renal failure 6 (67) 7 (78) 6 zheng et al.19 (2020) [2 case reports] 2 women maternal and neonatal outcomes 29–33 fever: 1 (50) dyspnoea: 1 (50) lymphopaenia: 100% ↑crp: 50% cxr/ct viral changes: 100% n/a 100% 0 7 wu et al.20 (2020) [case series] 13 women (8 undelivered) to assess if vaginal secretions and breast milk of women with covid-19 contain sars-cov-2 26–40 fever: 8 (61.5) cough: 5 (38.5) dyspnoea: 1 (7.6) myalgia: 1 (7.6) lymphopaenia: 2 (15.4) ↑crp: 5 (38.5) ↑hepatic transaminases: 2 (15.4%) ct chest changes: 8 (61.5) 0 4/5 (80) 0 8 wang et al.21 (2020) [case report] 1 woman to report the first case of neonatal sars-cov-2 infection in china where the mother was diagnosed with covid-19 34 fever: 100% cxr/ct viral changes: 100% 0 100% 0 9 zhu et al.22 (2020) [case series] 9 women (1 set of twins) to report the clinical features and outcomes of 10 neonates (including 2 twins) born to 9 mothers with confirmed 2019-ncov infection in 5 hospitals that were retrospectively analysed -25–35 fever: 9 (88.9) cough: 4 (44.5) cxr/ct viral changes: 100% 0 7 (78) 0 icu = intensive care unit; cxr = chest x-ray; ct = computed tomography; bmi = body mass index; dm = diabetes mellitus; htn = hypertension; crp = c-reactive protein; gdm = gesta tional diabetes mellitus; n/a = not available; hep = hepatitis; sob = shortness of breath; b/l =bilateral. covid-19 and pregnancy a narrative review of maternal and perinatal outcomes 170 | squ medical journal, may 2022, volume 22, issue 2 table 1 (cont’d.): maternal outcomes of pregnant women infected with sars-cov-2 no. author and year of publication [type of study] number of pregnant women/ pregnancies purpose of study age range or mean in years n (%) symptom comorbidities/laboratory findings icu admission cs maternal death 10 adhikari et al.23 (2020) [case series] 252 women (245 delivered, 7 aborted) to evaluate adverse outcomes associated with severe sarscov-2 infection in pregnancy and to describe clinical management, disease progression, hospital admission, placental abnormalities and neonatal outcomes 27 details not available dm (gdm + dm): 15 (6%) htn: 12 (5%) bmi mean: 30.5 (7.2%) investigation details not available 0 65/245 (27) 0 11 rawat et al.24 (2021) [case reports] 4 women to report maternal death in sagar city of central india 25–31 fever (n = 2), cough (n = 2), sore throat (n = 1), loss of smell and taste (n = 1) no symptoms (1) vomiting and breathless (n = 1) co-morbidity: 0 crp high in 1 (25) cxr: prominent bronchovascular marking in 1 woman, but recovered patchy ground glass changes in 1 (25) woman 1 1/3 (33) 1 12 qiancheng et al.25 (2020) [case series] 28 women (2 undelivered, 4 medical abortion) to compare clinical course and outcomes between pregnant (28) and non-pregnant (54) women with covid-19 and assess the vertical transmission 30 (26.75–32) fever: 5 (17.9) malaise: 1 (3.6) cough: 7 (25) dyspnoea: 2 (7.1) abdominal pain: 5 (17.9) htn: 1 (3.6) diabetes: 2 (7.1) chronic hep b infection: 2 (7.1) hypothyroidism: 1 (3.6) lymphopaenia: 8 (28.6) thrombocytopaenia: 2 (7.1) radiological findings of pneumonia: 26 (92.9) 0 17 (60.7) 0 13 chaudhary et al.26 (2020) [case series] 26 women (12 undelivered) to examine the disease course in covid19-affected pregnant women 27 (19–35) 16 symptomatic fever: 14 (87.5) cough: 11 (68.8) body ache: 3 (18.8) sob: 2 (12.5) co-morbidity: 0 lymphocytopaenia: 1 (3.8) crp raised: 5 (19.2) cxr: b/l peripheral opacities: 5 (19.2) 1 11/14 (78.5) 1 14 elkafrawi et al.27 (2020) [case report] 1 woman to present first case report of sars-cov-2 in pregnancy in the usa 34 myalgia, fatigue and nonproductive cough co-morbidity: type ii diabetes, chronic hep b 0 yes 0 15 birindwa et al.28 (2021) [case report] 1 woman to study the possibility of vertical transmission to the neonate 25 fever 0 0 yes (previous 2 cs) 0 16 gheysarzadeh et al.29 (2020) [case series] 4 women (2 undelivered) to describe the outcomes of 4 pregnant women with covid-19 27–42 fever: 4 (100) sob: 2 (50) cough: 1 (25) abdominal pain: 1 (25) co-morbidity: 0 crp raised: 2 (50%) 0 1 (50) 0 17 doria et al.30 (2020) [case series] 12 women (10 delivered, 1 set of twins) to study the outcome of covid-19-infected pregnant women in one region of portugal 22–41 headache: 1 (8.3) co-morbidity: ulcerative colitis and psoriasis, severe scoliosis, behcet’s disease, severe myopia, asthma and raynaud syndrome, chronic htn (in different women) 7 women with no co-morbidities 0 6 (60) 0 icu = intensive care unit; cxr = chest x-ray; ct = computed tomography; bmi = body mass index; dm = diabetes mellitus; htn = hypertension; crp = c-reactive protein; gdm = gesta tional diabetes mellitus; n/a = not available; hep = hepatitis; sob = shortness of breath; b/l =bilateral. nihal al riyami and shahila sheik review | 171 table 2: maternal treatment modalities of pregnant women infected with sars-cov-2 no. author and year of publication [type of study] n (%) maternal treatment preeclampsia investigations 1 federici et al.14 (2020) [case report] corticosteroids: no hydroxychloroquine: no thromboprophylaxis: yes antibiotics: yes antiviral: no convalescent plasma: no mechanical ventilation: yes minimal haemolysis, thrombocytopaenia: 86 × 109/l proteinuria (creatininuria): 0.14 g/mmol liver enzymes: raised (alt & ast) sflt-1 to plgf ratio: low (neg) 2 lokken et al.15 (2021) [case series; 24 hospitalised patients] corticosteroids: 3 (12.5) hydroxychloroquine: 2 (8.3) thromboprophylaxis: n/a antibiotics: n/a antiviral (remdesivir): 9 (37.5) convalescent plasma: 2 (8.3) mechanical ventilation: 4 (16.7) ↑liver transaminases: 17 (77.3) rest n/a 3 breslin et al.16 (2020) [case series; 4 symptomatic patients requiring admission] corticosteroids: no hydroxychloroquine: 2 (50) thromboprophylaxis: n/a antibiotics: 2 (50) antiviral: no convalescent plasma: no mechanical ventilation: no data not available 4 yan et al.17 (2020) [case series] corticosteroids: 37 (31.9) hydroxychloroquine: no thromboprophylaxis: no antibiotics: 104 (94) antiviral: 63 (54.3) convalescent plasma: no mechanical ventilation: 2 (1.7) ecmo: 1 (0.9) 4 (3.4) with preeclampsia but the related investigations were not provided—including platelet count, liver enzymes and urine protein creatinine ratio 5 hantoushzadeh et al.18 (2020) [case series; 9 cases] corticosteroids: no hydroxychloroquine: 5 (55.6) thromboprophylaxis: 9 (100) antibiotics: 9 (100) antiviral (not remdesivir): 9 (100) convalescent plasma: 1 (11.1) mechanical ventilation: 7 (77.8) 0 6 zheng et al.19 (2020) [2 case reports] corticosteroids: 2 (100) hydroxychloroquine: 2 (100) thromboprophylaxis: n/a antibiotics: 2 (100) antiviral: 2 (100) convalescent plasma: no mechanical ventilation: no 0 7 wu et al.20 (2020) [case series] corticosteroids: 32 (23.1) hydroxychloroquine: no thromboprophylaxis: n/a antibiotics: 8 (61.5) antiviral: 8 (61.5) convalescent plasma: no mechanical ventilation: no ↑liver transaminases: 5 (38.5) 8 wang et al.21 (2020) [case report] corticosteroids: yes hydroxychloroquine: no thromboprophylaxis: no antibiotics: yes antiviral: yes convalescent plasma: no mechanical ventilation: no n/a 9 zhu et al.22 (2020) [case series] corticosteroids: no hydroxychloroquine: no thromboprophylaxis: no antibiotics: no antiviral: 5 (55.56) convalescent plasma: no mechanical ventilation: no n/a 10 adhikari et al.23 (2020) [case series; 13 women with severe/critical disease] corticosteroids: 5 (38) hydroxychloroquine: no thromboprophylaxis: no antibiotics: 3 (23) antiviral (remdesivir): 5 (38) convalescent plasma: 2 (15) mechanical ventilation: 2 (15) 26 (11) not significantly higher than in pregnant women negative for sars-cov-2 alt = alanine transaminase; ast = aspartate aminotransferase; sflt = soluble fms-like tyrosine kinase; plgf = placental growth factor; ecmo = extra corporeal membrane oxygenation; n/a = not applicable; ldh = lactate dehydrogenase. covid-19 and pregnancy a narrative review of maternal and perinatal outcomes 172 | squ medical journal, may 2022, volume 22, issue 2 table 2 (cont’d.): maternal treatment modalities of pregnant women infected with sars-cov-2 no. author and year of publication [type of study] n (%) maternal treatment preeclampsia investigations 10 adhikari et al.23 (2020) [case series; 13 women with severe/critical disease] corticosteroids: 5 (38) hydroxychloroquine: no thromboprophylaxis: no antibiotics: 3 (23) antiviral (remdesivir): 5 (38) convalescent plasma: 2 (15) mechanical ventilation: 2 (15) 26 (11) not significantly higher than in pregnant women negative for sars-cov-2 11 rawat et al.24 (2021) [case reports; 1 patient sick] corticosteroids: yes hydroxychloroquine: n/a thromboprophylaxis: yes antibiotics: n/a antiviral (remdesivir): no convalescent plasma: n/a mechanical ventilation: yes not mentioned 12 qiancheng et al.25 (2020) [case series; 7 hospitalised] corticosteroids: 4 (14.3) hydroxychloroquine: no thromboprophylaxis: no antibiotics: 24 (85.7) antivirals (not remdesivir): 21 (75) convalescent plasma: no mechanical ventilation: no low platelets (<100): 2 ↑ldh: 4 13 chaudhary et al.26 (2020) [case series] corticosteroids: n/a hydroxychloroquine: n/a thromboprophylaxis: n/a antibiotics: n/a antiviral (remdesivir): n/a convalescent plasma: n/amechanical ventilation: 1 14 elkafrawi et al.27 (2020) [case report] corticosteroids: no hydroxychloroquine: no thromboprophylaxis: no antibiotics: no antiviral (remdesivir): no convalescent plasma: no mechanical ventilation: no n/a 15 birindwa et al.28 (2021) [case report] corticosteroids: yes hydroxychloroquine: no thromboprophylaxis: no antibiotics: yes antiviral (remdesivir): no convalescent plasma: no mechanical ventilation: no n/a 16 gheysarzadeh et al.29 (2020) [case series] corticosteroids: n/a hydroxychloroquine: no thromboprophylaxis: no antibiotics: n/a antiviral (remdesivir): n/a convalescent plasma: no mechanical ventilation: no n/a 17 doria et al.30 (2020) [case series] not described mechanical ventilation: no n/a alt = alanine transaminase; ast = aspartate aminotransferase; sflt = soluble fms-like tyrosine kinase; plgf = placental growth factor; ecmo = extra corporeal membrane oxygenation; n/a = not applicable; ldh = lactate dehydrogenase. table 3: perinatal outcomes of women infected with sars-cov-2 no. author and year of publication [type of study] number of babies n (%) prematurity <37 weeks nicu admission neonatal death stillbirth/ iufd vertical transmission comments 1 federici et al.14 (2020) [case report] 1 0 2 lokken et al.15 (2021) [case series] 158 (3 set of twins) 15 (9.7) 11 (7.1) 0 2 (1.3) 0 tested 3 breslin et al.16 (2020) [case series] 18 1 (6) 3 0 0 0 nicu = neonatal intensive care unit; iufd = intrauterine fetal demise; dcda = dichorionic diamniotic; cpap = continuous positive airway pressure; lbw = low birth weight; rt = reverse transcriptase; pcr = polymerase chain reaction; rrt = real-time reverse-transcriptase; fgr = fetal growth restriction; pprom = preterm premature rupture of membranes; gdm = gest ational diabetes mellitus; htn = hypertension. nihal al riyami and shahila sheik review | 173 table 3 (cont’d.): perinatal outcomes of women infected with sars-cov-2 no. author and year of publication [type of study] number of babies n (%) prematurity <37 weeks nicu admission neonatal death stillbirth/ iufd vertical transmission comments 4 yan et al.17 (2020) [case series] 100 (1 pair of twins) 21 (21) 47 (47) 1 0 0 5 hantoushzadeh et al.18 (2020) [case series] 12 (3 sets of twins) 24–28 weeks: 3 (25); all dcda twins) <32 weeks: 3 (25) <37 weeks: 2 (17) 4 (1 set of twins at 28 weeks) 2 (set of twins on day 3 of life) 4 0 2 pregnancies with dcda twins undelivered -maternal death 6 zheng et al.19 (2020) [2 case reports] 2 1 (50) 2 (100) 0 0 0 7 wu et al.20 (2020) [case series] 5 2 (40) 2 (40) 0 0 0 8 wang et al.21 (2020) [case report] 1 0 1 0 0 pharyngeal swab +ve at 36 hours but the umbilical cord and placenta reported negative confirming that it was not a vertical transmission postpartum neonatal infection possibly acquired through an infected contact as the neonate was not isolated in the neonatal unit 9 zhu et al.22 (2020) [case series] 10 (1 set of twins) <32 weeks: 2 (20); set of twins) 34–36 weeks: 4 (40) 6 1 0 0 10 adhikari et al.23 (2020) [case series] 248 outcomes assessed total: 251 (6 set of twins) (3 major malformations) total: 27 (11) < 34 weeks: 9 (4) < 37 weeks: 18 (7) 9 (3.6) 1 with cord ph <7 8 requiring cpap support 0 0 6 (3) only 188 neonates were tested 4 were positive at 24 hours and 2 at 48 hours. only one suspected intra-uterine infection 11 rawat et al.24 (2021) [case reports] 3 0 0 0 1 0 iufd in a dead mother 12 qiancheng et al.25 (2020) [case series] 23 (1 set of twins) 35 weeks: 1 (4.4) 0 0 0 0 (2 sars-cov-2 infection rt-pcr tests 24–48 hours apart were negative for all neonates) 1 lbw for the set of twin = 2,350 g 13 chaudhary et al.26 (2020) [case series] 14 0 0 0 0 0 (nasopharyngeal covid-19 rt-pcr negative for all neonates who delivered during mother’s hospital stay; n = 9) 9 women delivered during their hospital stay 14 elkafrawi et al.27 (2020) [case report] 1 0 0 0 0 0 nasopharyngeal swab tested rrt-pcr negative at delivery 15 birindwa et al.28 (2021) [case report] 1 34 weeks 0 0 yes, from sepsis yes sars-cov-2 oropharyngeal swab positive on day 3 (neonate was doing well until day 3) thrombotic vasculopathy in the placenta and umbilical cord vessels on histopathology 16 gheysarzadeh et al.29 (2020) [case series] 2 0 0 0 0 0 17 doria et al.30 (2020) [case series] 11 (1 set of twins) 0 0 0 0 0 (all tested negative for sars-cov-2 rt-pcr) fgr: 8 (72.7) with 1 discordant growth pprom: 1 (9.1) gdm: 1 (9.1) gestestional htn: 1 (9.1) nicu = neonatal intensive care unit; iufd = intrauterine fetal demise; dcda = dichorionic diamniotic; cpap = continuous positive airway pressure; lbw = low birth weight; rt = reverse transcriptase; pcr = polymerase chain reaction; rrt = real-time reverse-transcriptase; fgr = fetal growth restriction; pprom = preterm premature rupture of membranes; gdm = gest ational diabetes mellitus; htn = hypertension. covid-19 and pregnancy a narrative review of maternal and perinatal outcomes 174 | squ medical journal, may 2022, volume 22, issue 2 pandemic.4 pregnant women do not appear to be more likely to contract the sars-cov-2 infection than the general population. however, pregnancy itself alters the body’s immune system and response to viral infections, in addition to various anatomical and physiological changes, which can result in women experiencing more severe symptoms such as respiratory distress, especially towards the end of their term.3,31 as such, it is crucial that healthcare workers understand how the sars-cov-2 virus affects pregnancy so that they can better tailor antenatal, intrapartum and postpartum care in order to optimise maternal and fetal outcomes. this review article provides an overview of the available evidence regarding the maternal and perinatal outcomes of pregnant women diagnosed with covid-19. the most important finding was that pregnancy did not appear to aggravate symptoms or imaging features of covid-19-associated pneumonia.14–30 the majority of pregnant women infected with sars-cov-2 presented in the third trimester with mild to moderate covid-19 symptoms in the form of fever, cough and myalgia.14,16–22,25–28 these rates are similar to those described in non-pregnant adults with covid-19 infections in various reviews and case series.31–33 in a case series of 43 pregnant women, breslin et al. found that 32.6% were asymptomatic and were diagnosed only due to the development of symptoms after admission or as a result of the implementation of universal covid-19 screening in their unit.16 there is growing evidence that severe covid-19 infection during pregnancy leads to a preeclampsialike syndrome or atypical haemolysis, elevated liver enzymes and low platelets syndrome.34,35 however, in the current review, no overwhelming evidence of such an association was found, but this could be explained by the fact that not many of the case series and reports have addressed the specific investigations that look for preeclampsia in pregnancies diagnosed with covid-19. apart from the case report by federici et al., preeclampsia has been mentioned in the case series by yan et al. and adhikari et al. at the rate of 3.4% and 11%, respectively.14,17,23 these rates are not significantly higher than the incidence of the condition in pregnant women without infection with sars-cov-2.36 in this review, there were 12 maternal deaths, seven of which were reported in a single case series of nine women from iran.18 the most common comorbidity reported was obesity.15,16,18 in the general (non-pregnant) population, obesity similarly appears to increase the need for intubation and ventilatory support.37,38 however, it should be acknowledged that the pandemic is still ongoing and a number of cases are yet to be reported. according to the current review, the average rate of preterm delivery in covid-19 pregnancies was approximately 27%, with most cases representing late preterm births (i.e. at 34–37 gestational weeks).15–20,22,23,25,28 a systematic review and metaanalysis of all coronavirus spectrum infections, including 19 studies from 79 hospitalised women and 41 (51.9%) pregnancies affected by covid-19, 12 (15.2%) by mers and 26 (32.9%) by sars-cov-1, reported a 24.3% preterm delivery rate, which is similar to this review.39 in contrast, the global rate of preterm delivery at <37 gestational weeks was 10.6%.40 similarly, the frequency of caesarean section in covid-19 pregnancies in this cohort was high compared to international rates (4–50% versus 10–15%, respectively).31,32,39–41 however, this rate is comparable to sars-cov-1, where it was reported as 84%.40 although many researchers did not report indications for the caesarean section procedure, the most common were fetal distress and the mother and physician’s preferences.16,17 nevertheless, the high rate of caesarean deliveries in the current review may be due to the fact that most of the cohorts were based in china. in 2014, feng et al. expressed increasing concern about the rapidly rising rate of caesarean deliveries in china (~40%), most of which were performed due to nonclinical factors.42 covid-19 has not shown significant effect on fetal growth.14–30 in contrast, the rate of fgr in sarscov-1 cases was found to be 13.3%.39 however, it is too early to conclude definitively that covid-19 does not impact fetal growth as the outcomes of early pregnancies during this pandemic are yet to be reported. further confirmation of this finding may require assessment in the future once a greater number of women who contracted covid-19 in their first or second trimester reach full term and deliver. moreover, rates of stillbirth and neonatal death were low, with these adverse outcomes mainly related to the severity of the mother’s condition.15,17,18,22,24,28 overall, the perinatal mortality rate was 2%, further decreasing to 0.7% if the iranian case series were to be excluded as an outlier, as compared to a rate of 33.2% with mers.39 no case of perinatal death was reported with sarscov-1. the highest preterm delivery rate was reported as 50%, but this was in a report of two cases.19 the largest case series by adhikari et al. reported the perinatal outcomes of 248 babies with a preterm rate of 21.8%.23 among nine pregnant chinese patients with sars-cov-2 infections, zhu et al. found that six nihal al riyami and shahila sheik review | 175 (60%) births occurred at 31–34 gestational weeks.22 neonatal morbidities were more marked in this series, probably due to greater prematurity. in particular, there were two cases of disseminated intravascular coagulation, of which one born at 34 gestational weeks subsequently developed multi-organ failure and died on day nine of life.22 panigada et al. suggested that covid-19 infection might increase the risk of micro and macrothrombi.43 given that the placenta is an organ fundamentally affected by hypercoagulable states, as reported by greer et al., it can be extrapolated that covid-19 carries possible increased risks for embryonic or fetal death due to its placental effects.44 in addition, the presence of high fever in the first trimester could lead to a higher incidence of miscarriage, as seen with sars-cov-1 cases.7 however, more research is needed to confirm this hypothesis. until then, greater attention should be given to ensuring adequate thromboprophylaxis in pregnant women contracting covid-19 as pregnancy is a known hypercoagulable state, which increases risk of venous thrombosis.44 in their latest guideline, the royal college of obstetricians and gynaecology, uk, recommends thromboprophylaxis for all pregnant women diagnosed with sars-cov-2 infection while they are selfisolating or hospitalised due to the disease and for 10 days following discharge from the hospital.3 however, this review revealed that maternal thromboprophylaxis was given in only three instances.14,18,24 this dearth could be explained by the fact that the association of pro-thrombotic state with sars-cov-2 infection was realised late into the progression of the pandemic. treatment guidelines for sars-cov-2 infection have been evolving over time and might continue to change. at the time of writing, chloroquine or hydroxychloroquine with or without azithromycin are not recommended for the treatment of covid-19.45 at present, remdesivir is the only food and drug administration-approved broad spectrum anti-viral drug approved for the treatment of covid-19. it is recommended for use in hospitalised patients who require supplemental oxygen, invasive mechanical ventilation or extracorporeal membrane oxygenation.46 in addition, bamlanivimab and etesevimab were approved to treat people with elevated risk for severe disease, including adults over 65 years and those with relevant comorbidities.47,48 remdesivir was the only drug recommended for pregnant women during the study period, though it is not recommended by the who anymore. in this review, eight articles mentioned the use of anti-viral medications, but only two articles specified remdesivir use.15,23 there is a case report of a pregnant woman with covid-19 who required icu care in the third trimester and received remdesivir. her pregnancy continued after discharge from the icu and she delivered at term without any complications.49 another case series reported 86 pregnant and postpartum women who received remdesivir for severe covid-19 with an oxygen saturation of less than 94% on room air and had high recovery rates with low rate of adverse effects.50 corticosteroids, specifically dexamethasone, have been found to reduce mortality in hospitalised patients who require supplemental oxygen; the greatest effect was observed in patients requiring mechanical ventilation. in pregnant women with covid-19, dexamethasone is recommended for fetal lung maturity if preterm delivery is anticipated. once the course of four doses of 6 mg over 48 hours is completed, if the patient still requires steroids due to severe covid-19 disease, the course is recommended to be changed to prednisolone 40 mg once daily if oral intake is possible or hydrocortisone 80 mg intravenous twice daily. prednisolone and hydrocortisone are extensively metabolised in the placenta and do not cross over to the fetus, thus reducing any concerns about detrimental effects of prolonged steroid exposure on the fetus.3 in this review, four articles did not mention the use of corticosteroids, and in the remaining articles, the use of corticosteroids ranged from 12.5–100%.14,16,18,22 this variation could be because the pregnant women did not require hospitalisation, supplemental oxygen or mechanical ventilation, which are indications for steroid use. antibiotics use in the treatment of sarscov-2 infection has not been proven to be beneficial, although it is being widely used empirically to prevent secondary bacterial infection. this raises the concerns of antibiotic resistance in the long term and whether its use is justifiable.51 in this review, eight articles documented the use of antibiotics. antibiotics were not used in the case series by zhu et al. and data were not available in the case series by lokken et al.15,22 convalescent plasma use is not recommended anymore in the treatment of sars-cov-2 infection and it was used minimally in the studied case series. the use of plasma was reported in two (8%) cases by lokken et al., in one (11%) case in the series by hantoushzadeh et al. and in two (15%) cases in the series by adhikari et al.15,18,23 to date, there is low incidence of vertical transmission of the sars-cov-2 virus. a review of the literature indicated that of the approximately 55 neonatal samples taken from the amniotic fluid, umbilical cord, breast milk and throat immediately after birth, all were found to be negative.16,22,24,30,52,53 covid-19 and pregnancy a narrative review of maternal and perinatal outcomes 176 | squ medical journal, may 2022, volume 22, issue 2 dong et al. reported a neonate born to a mother with covid-19 who was found to have raised serum levels of immunoglobulin (ig)m antibodies to sars-cov-2 at birth.54 since igm does not cross the placenta, this could be due to a neonatal immune response to an intrauterine infection. the current review is subject to certain limitations. as the literature search was conducted using specific databases, it is possible that some relevant studies and articles were missed from the analysis, leading to potential bias. finally, it is important to recognise that these findings are preliminary and may change as the number of cases reported increases. conclusion as of august 2021, covid-19 pregnancies resulted in 12 maternal deaths and eight stillbirths as reported in the literature. although limited data are available regarding the effect of the disease in early pregnancy, rates of preterm birth and caesarean delivery appear to be high. healthcare practitioners in conjunction with infectious disease specialists should develop and review protocols for the management of covid-19 in pregnancy. despite promising reports regarding the outcomes of covid-19 infections during pregnancy, it would be prudent to remain vigilant. as such, the authors recommend close monitoring of all pregnant women. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n both authors reviewed and analysed the data and drafted and edited the manuscript. both authors approved the final version of the manuscript. references 1. rasmussen sa, smulian jc, lednicky ja, wen ts, jamieson dj. coronavirus disease 2019 (covid-19) and pregnancy: what obstetricians need to know. am j obstet gynecol 2020; 222:415–26. https://doi.org/10.1016/j.ajog.2020.02.017. 2. worldometer. coronavirus worldwide graphs. from: https:// w w w . w o r l d o m e t e r s . i n f o / c o r o n a v i r u s / w o r l d w i d e graphs/#total-cases accessed: aug 2021. 3. royal college of obstetricians and gynaecologists. coronavirus (covid-19) infection in pregnancy: information for healthcare professionals. version 13. from: www.rcog.org.uk/globalassets/ documents/guidelines/2020-04-17-coronavirus-covid-19infection-in-pregnancy-v13.pdf accessed: aug 2021. 4. world health organization. report of the who-china joint mission on coronavirus disease 2019 (covid-19). from: www. who.int/publications/i/item/report-of-the-who-china-jointmission-on-coronavirus-disease-2019-(covid-19) accessed: aug 2021. 5. zhu n, zhang d, wang w, li z, yang b, song j, et al. a novel coronavirus from patients with pneumonia in china, 2019. n engl j med 2020; 382:727–33. https://doi.org/10.1056/ nejmoa2001017. 6. huang c, wang y, li x, ren l, zhao j, hu y, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet 2020; 395:497–506. https://doi.org/10.1016/s0140-673 6(20)30183-5. 7. wong sf, chow km, leung tn, ng wf, ng tk, shek cc, et al. pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. am j obstet gynecol 2004; 191:292–7. https://doi.org/10.1016/j.ajog.2003.11.019. 8. alserehi h, wali g, alshukairi a, alraddadi b. impact of middle east respiratory syndrome coronavirus (mers-cov) on pregnancy and perinatal outcome. bmc infect dis 2016; 16:105. https://doi.org/10.1186/s12879-016-1437-y. 9. jeong sy, sung si, sung jh, ahn sy, kang es, chang ys, et al. mers-cov infection in a pregnant woman in korea. j korean med sci 2017; 32:1717–20. https://doi.org/10.3346/ jkms.2017.32.10.1717. 10. assiri a, abedi gr, al masri m, bin saeed a, gerber si, watson jt. middle east respiratory syndrome coronavirus infection during pregnancy: a report of 5 cases from saudi arabia. clin infect dis 2016; 63:951–3. https://doi.org/10.1093/ cid/ciw412. 11. park mh, kim hr, choi dh, sung jh, kim jh. emergency cesarean section in an epidemic of the middle east respiratory syndrome: a case report. korean j anesthesiol 2016; 69:287–91. https://doi.org/10.4097/kjae.2016.69.3.287. 12. malik a, el masry km, ravi m, sayed f. middle east respiratory syndrome coronavirus during pregnancy, abu dhabi, united arab emirates, 2013. emerg infect dis 2016; 22:515–17. https://doi.org/10.3201/eid2203.151049. 13. payne dc, iblan i, alqasrawi s, al nsour m, rha b, tohme ra, et al. stillbirth during infection with middle east respiratory syndrome coronavirus. j infect dis 2014; 209:1870–2. https:// doi.org/10.1093/infdis/jiu068. 14. federici l, picone o, dreyfuss d, sibiude j. successful contin uation of pregnancy in a patient with covid-19-related ards. bmj case rep 2020; 13:e237511. https://doi.org/10.1136/bcr2020-237511. 15. lokken em, huebner em, taylor gg, hendrickson s, vander hoeven j, kachikis a, et.al. disease, pregnancy outcomes, and maternal deaths among pregnant patients with severe acute respiratory syndrome coronavirus 2 infection in washington state. am j obstet gynecol 2021; 225:77.e1–14. https://doi. org/10.1016/j.ajog.2020.12.1221. 16. breslin n, baptiste c, gyamfi-bannerman c, miller r, martinez r, bernstein k, et al. coronavirus disease 2019 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of new york city hospitals. am j obstet gynecol mfm 2020; 2:100118. https://doi.org/10.1016/j.ajogmf.2020.100118. 17. yan j, guo j, fan c, juan j, yu x, li j, et al. coronavirus disease 2019 in pregnant women: a report based on 116 cases. am j obstet gynecol 2020; 223:111.e1–14. https://doi.org/10.1016/j. ajog.2020.04.014. 18. hantoushzadeh s, shamshirsaz aa, aleyasin a, seferovic md, aski sk, arian se, et al. maternal death due to covid-19. am j obstet gynecol 2020; 223:109.e1–16. https://doi.org/10.1016/j. ajog.2020.04.030. https://doi.org/10.1016/j.ajog.2020.02.017 https://doi.org/10.1056/nejmoa2001017 https://doi.org/10.1056/nejmoa2001017 https://doi.org/10.1016/s0140-6736(20)30183-5 https://doi.org/10.1016/s0140-6736(20)30183-5 https://doi.org/10.1016/j.ajog.2003.11.019 https://doi.org/10.1186/s12879-016-1437-y https://doi.org/10.3346/jkms.2017.32.10.1717 https://doi.org/10.3346/jkms.2017.32.10.1717 https://doi.org/10.1093/cid/ciw412 https://doi.org/10.1093/cid/ciw412 https://doi.org/10.4097/kjae.2016.69.3.287 https://doi.org/10.3201/eid2203.151049 https://doi.org/10.1093/infdis/jiu068 https://doi.org/10.1093/infdis/jiu068 https://doi.org/10.1136/bcr-2020-237511 https://doi.org/10.1136/bcr-2020-237511 https://doi.org/10.1016/j.ajog.2020.12.1221 https://doi.org/10.1016/j.ajog.2020.12.1221 https://doi.org/10.1016/j.ajogmf.2020.100118 https://doi.org/10.1016/j.ajog.2020.04.014 https://doi.org/10.1016/j.ajog.2020.04.014 https://doi.org/10.1016/j.ajog.2020.04.030 https://doi.org/10.1016/j.ajog.2020.04.030 nihal al riyami and shahila sheik review | 177 19. zheng t, guo j, he w, wang w, yu h, ye h. coronavirus disease 2019 (covid-19) in pregnancy: 2 case reports on maternal and neonatal outcomes in yichang city, hubei province, china. medicine (baltimore) 2020; 99:e21334. https://doi.org/10.1097/ md.0000000000021334. 20. wu y, liu c, dong l, zhang c, chen y, liu j, et al. coronavirus disease 2019 among pregnant chinese women: case series data on the safety of vaginal birth and breastfeeding. bjog 2020; 127:1109–15. https://doi.org/10.1111/1471-0528.16276. 21. wang s, guo l, chen l, liu w, cao y, zhang j, et al. a case report of neonatal 2019 coronavirus disease in china. clin infect dis 2020; 71:853–7. https://doi.org/10.1093/cid/ciaa225. 22. zhu h, wang l, fang c, peng s, zhang l, chang g, et al. clin ical analysis of 10 neonates born to mothers with 2019-ncov pneumonia. transl pediatr 2020; 9:51–60. https://doi.org/10.21 037/tp.2020.02.06. 23. adhikari eh, moreno w, zofkie ac, macdonald l, mclntire dd, collins rrj, et al. pregnancy outcomes among women with and without severe acute respiratory syndrome coronavirus 2 infec tion. jama netw open 2020; 3:e2029256. https://doi.org/10.10 01/jamanetworkopen.2020.29256. 24. rawat sk, saad t, jindal a, vyas ak. coronavirus disease 2019 in pregnancy: case report on maternal death in sagar city of central india. j obstet gynaecol res 2021; 47:1579–82. https:// doi.org/10.1111/jog.14696. 25. qiancheng x, jian s, lingling p, lei h, xiaogan j, weihua l, et al. coronavirus disease 2019 in pregnancy. int j infect dis 2020; 95:376–83. https://doi.org/10.1016/j.ijid.2020.04.065. 26. chaudhary s, humayun s, akhter h, malik n, humayun s, nazir s. covid-19 in pregnant women: a case series. ann king edw med univ 2020; 26:336–40. 27. elkafrawi d, joseph j, schiattarella a, rodriguez b, sisti g. intrauterine transmission of covid-19 in pregnancy: case report and review of literature. acta biomed 2020; 91:e2020041. https://doi.org/10.23750/abm.v91i3.9795. 28. birindwa ek, mulumeoderhwa gm, nyakio o, mateso mbale gq, mushamuka sz, materanya jm, et al. a case study of the first pregnant woman with covid-19 in bukavu, eastern democratic republic of the congo. matern health neonatol perinatol 2021; 7:6. https://doi.org/10.1186/s40748-021-00127-5. 29. gheysarzadeh a, sadeghifard n, safari m, rashidian t, mohammadyari e, tavan h. case series of four pregnant women with covid-19 in ilam, iran. new microbes new infect 2020; 38:100783. https://doi.org/10.1016/j.nmni.2020.100783. 30. dória m, peixinho c, laranjo m, mesquita varejão a, silva pt. covid-19 during pregnancy: a case series from an universally tested population from the north of portugal. eur j obstet gynecol reprod biol 2020; 250:261–2. https://doi.org/10.1016/j.ejogr b.2020.05.029. 31. wu z, mcgoogan jm. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention. jama 2020; 323:1239–42. https://doi.org/10.1001/jama.2020.2648. 32. mullins e, evans d, viner rm, o’brien p, morris e. coronavirus in pregnancy and delivery: rapid review. ultrasound obstet gynecol 2020; 55:586–92. https://doi.org/10.1002/uog.22014. 33. liu d, li l, wu x, zheng d, wang j, yang l, et al. pregnancy and perinatal outcomes of women with coronavirus disease (covid-19) pneumonia: a preliminary analysis. ajr am j roentgenol 2020; 215:127–32. https://doi.org/10.2214/ajr.20.2 3072. 34. ronnje l, länsberg jk, vikhareva o, hansson sr, herbst a, zaigham m. complicated covid-19 in pregnancy: a case report with severe liver and coagulation dysfunction promptly improved by delivery. bmc pregnancy childbirth 2020; 20:511. https://doi.org/10.1186/s12884-020-03172-8. 35. mendoza m, garcia-ruiz i, maiz n, rodo c, garcia-manau p, serrano b, et al. pre-eclampsia-like syndrome induced by severe covid-19: a prospective observational study. bjog 2020; 127:1374–80. https://doi.org/10.1111/1471-0528.16339. 36. say l, chou d, gemmill a, tuncalp o, moller ab, daniel j, et al. global causes of maternal death: a who systematic analysis. lancet glob health 2014; 2:e323–33. https://doi.org/10.1016/ s2214-109x(14)70227-x. 37. intensive care national audit & research centre. icnarc report on covid-19 in critical care. from: www.icnarc.org/ our-audit/audits/cmp/reports accessed: aug 2021. 38. breslin n, baptiste c, miller r, fuchs k, goffman d, gyamfibannerman c, et al. coronavirus disease 2019 in pregnancy: early lessons. am j obstet gynecol mfm 2020; 2:100111. https://doi.org/10.1016/j.ajogmf.2020.100111. 39. di mascio d, khalil a, saccone g, rizzo g, buca d, liberati m, et al. outcome of coronavirus spectrum infections (sars, mers, covid-19) during pregnancy: a systematic review and metaanalysis. am j obstet gynecol mfm 2020; 2:100107. https:// doi.org/10.1016/j.ajogmf.2020.100107. 40. chawanpaiboon s, vogel jp, moller ab, lumbiganon p, petzold m, hogan d, et al. global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. lancet glob health 2019; 7:e37–46. https://doi.org/10.10 16/s2214-109x(18)30451-0. 41. world health organization. who statement on caesarean section rates. from: www.who.int/reproductivehealth/publications/mat ernal_perinatal_health/cs-statement/en/ accessed: aug 2021. 42. feng xl, wang w, an l, ronsmans c. cesarean section in the people’s republic of china: current perspectives. int j womens health 2014; 6:59–74. https://doi.org/10.2147/ijwh.s41410. 43. panigada m, bottino n, tagliabue p, grasselli g, novembrino c, chantarangkul v, et al. hypercoagulability of covid-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. j thromb haemost 2020; 18:1738–42. https://doi.org/10.1111/jth.14850. 44. greer ia, aharon a, brenner b, gris jc. coagulation and placenta-mediated complications. rambam maimonides med j 2014; 5:e0034. https://doi.org/10.5041/rmmj.10168. 45. covid-19 treatment guidelines panel. coronavirus disease 2019 (covid-19) treatment guidelines. national institutes of health. from: https://www.covid19treatmentguidelines.nih. gov/ accessed: aug 2021. 46. u.s. food & drug administration. coronavirus (covid-19) update: fda authorizes drug combination for treatment of covid-19. from: h t t p s : / / w w w . f d a . g o v / n e w s e v e n t s / p r e s s a n n o u n cements/coronavirus-covid-19-update-fda-authorizes-drugcombination-treatment-covid-19 accessed: aug 2021. 47. webmd. fda grants emergency use to two new covid treatments. from: https://www.webmd.com/lung/ ne ws/20210210/fda-grants-emergenc y-use-to-two-ne wcovid-treatments accessed: aug 2021. 48. rasmussen sa, jamieson dj, bresee js. pandemic influenza and pregnant women. emerg infect dis 2008; 14:95–100. https:// doi.org/10.3201/eid1401.070667. 49. maldarelli ga, savage m, mazur s, oxford-horrey c, salvatore m, marks km. remdesivir treatment for severe covid-19 in third-trimester pregnancy: case report and management dis cussion. open forum infect dis 2020; 7:ofaa345. https://doi. org/10.1093/ofid/ofaa345. 50. burwick rm, yawetz s, stephenson ke, collier ar, sen p, blackburn bg, et al. compassionate use of remdesivir in preg nant women with severe coronavirus disease 2019. clin infect dis 2020; 73:e3996–4004. https://doi.org/10.1093/cid/ciaa1466. https://doi.org/10.1097/md.0000000000021334 https://doi.org/10.1097/md.0000000000021334 https://doi.org/10.1111/1471-0528.16276 https://doi.org/10.1093/cid/ciaa225 https://doi.org/10.21037/tp.2020.02.06 https://doi.org/10.21037/tp.2020.02.06 https://doi.org/10.1001/jamanetworkopen.2020.29256 https://doi.org/10.1001/jamanetworkopen.2020.29256 https://doi.org/10.1111/jog.14696 https://doi.org/10.1111/jog.14696 https://doi.org/10.1016/j.ijid.2020.04.065 https://doi.org/10.23750/abm.v91i3.9795 https://doi.org/10.1186/s40748-021-00127-5 https://doi.org/10.1016/j.nmni.2020.100783 https://doi.org/10.1016/j.ejogrb.2020.05.029 https://doi.org/10.1016/j.ejogrb.2020.05.029 https://doi.org/10.1001/jama.2020.2648 https://doi.org/10.1002/uog.22014 https://doi.org/10.2214/ajr.20.23072 https://doi.org/10.2214/ajr.20.23072 https://doi.org/10.1186/s12884-020-03172-8 https://doi.org/10.1111/1471-0528.16339 https://doi.org/10.1016/s2214-109x(14)70227-x https://doi.org/10.1016/s2214-109x(14)70227-x https://doi.org/10.1016/j.ajogmf.2020.100111 https://doi.org/10.1016/j.ajogmf.2020.100107 https://doi.org/10.1016/j.ajogmf.2020.100107 https://doi.org/10.10 16/s2214-109x(18)30451-0 https://doi.org/10.10 16/s2214-109x(18)30451-0 https://doi.org/10.2147/ijwh.s41410 https://doi.org/10.1111/jth.14850 https://doi.org/10.5041/rmmj.10168 https://doi.org/10.3201/eid1401.070667 https://doi.org/10.3201/eid1401.070667 https://doi.org/10.1093/ofid/ofaa345 https://doi.org/10.1093/ofid/ofaa345 https://doi.org/10.1093/cid/ciaa1466 covid-19 and pregnancy a narrative review of maternal and perinatal outcomes 178 | squ medical journal, may 2022, volume 22, issue 2 51. chedid m, waked r, haddad e, chetata n, saliba g, choucair j. antibiotics in treatment of covid-19 complications: a review of frequency, indications, and efficacy. j infect public health 2021; 14:570–6. https://doi.org/10.1016/j.jiph.2021.02.001. 52. chen h, guo j, wang c, luo f, yu x, zhang w, et al. clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records. lancet 2020; 395:809–15. https:// doi.org/10.1016/s0140-6736(20)30360-3. 53. schwartz da. an analysis of 38 pregnant women with covid-19, their newborn infants, and maternal-fetal transmission of sars-cov-2: maternal coronavirus infections and pregnancy outcomes. arch pathol lab med 2020; 144:799–805. https:// doi.org/10.5858/arpa.2020-0901-sa. 54. dong l, tian j, he s, zhu c, wang j, liu c, et al. possible vert ical transmission of sars-cov-2 from an infected mother to her newborn. jama 2020; 323:1846–8. https://doi.org/10.1001/ jama.2020.4621. https://doi.org/10.1016/j.jiph.2021.02.001 https://doi.org/10.1016/s0140-6736(20)30360-3 https://doi.org/10.1016/s0140-6736(20)30360-3 https://doi.org/10.5858/arpa.2020-0901-sa https://doi.org/10.5858/arpa.2020-0901-sa https://doi.org/10.1001/jama.2020.4621 https://doi.org/10.1001/jama.2020.4621 erratum notice | e493 إشعار بتصحيح التنسيق اإلضافة للسيستني يعيد تنشيط أنزمي کولينسرتاز البشري اليت يثبطها مبيد احلشرات العضوية الفوسفاتية الديكلوروفوس erratum notice erratum notice of formatting correction in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases the editors of sultan qaboos university medical journal (squmj) have been informed of formatting errors in an article by mohammadi et al. in the august 2017 issue of squmj.1 the corresponding author, seyed v. shetab-boushehri, contacted squmj in october 2017 to inform the editors of errors in the formatting of units of measurement throughout the article. the units of measurement had been erroneously formatted as “mg/kg-1”, “μmol.l-1”, “μg.ml-1”, “μmol.l-1”, “mg.ml-1”, “mmol.l-1”, “mol.l-1”, “l.μmol-1.cm-1” and “u.l-1” instead of “mg.kg-1”, “μmol.l-1”, “μg.ml-1”, “μmol.l-1”, “mg.ml-1”, “mmol.l-1”, “mol.l-1”, “l.μmol-1.cm-1” and “u.l-1”, respectively. however, these corrections could not be made as the article had already been published the week previously. for the reasons stated herein, the editors of squmj wish to notify readers that the formatting of the aforementioned units of measurement should therefore be interpreted as the following: “mg.kg-1”, “μmol.l-1”, “μg.ml-1”, “μmol.l-1”, “mg.ml-1”, “mmol.l-1”, “mol.l-1”, “l.μmol-1.cm-1” and “u.l-1”.1 the editors of squmj take sole responsibility for this notice and would like to apologise to the authors and readers for this correction made after publication. references 1. mohammadi h, jalilian j, karimi my, shetab-boushehri sv. in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases. sultan qaboos univ med j 2017; 17:e293–300. doi: 10.18295/squmj.2017.17.03.006. notice of erratum for: mohammadi et al. in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases. sultan qaboos univ med j 2017; 17:e293–300. doi: 10.18295/squmj.2017.17.03.006. sultan qaboos university med j, november 2017, vol. 17, iss. 4, p. e493, epub. 10 jan 18 doi: 10.18295/squmj.2017.17.04.024 https://doi.org/10.18295/squmj.2017.17.03.006 1department of medicine, university of khartoum, khartoum, sudan; 2department of medicine, khartoum north hospital, khartoum, sudan; 3department of pharmacy, king hussein cancer center, amman, jordan *corresponding author’s e-mail: hagirrayan@gmail.com خصائص املرضى املصابني حباالت حرجة مبستشفيات الرعاية الثالثية يف السودان هاجر �شليمان، وائل املهدي، مهند عو�شالكرمي، ملى الناظر abstract: objectives: knowledge of intensive care unit (icu) admission patterns and characteristics is necessary for the development of critical care services, particularly in low-resource settings. this study aimed to describe the characteristics of critically-ill patients admitted to icus in sudan. methods: this prospective observational study was conducted between february and may 2017 in the icus of two government tertiary care hospitals in khartoum, sudan. a total of 100 consecutive adult patients admitted to the icus were included in the study. the patients’ demographic and clinical characteristics and acute physiologic assessment and chronic health evaluation (apache ii) scores upon admission were recorded, as well as the reason for admission, presence of any underlying comorbidities, interventional requirements like mechanical ventilation or haemodialysis, length of stay in the icu and patient outcome. results: of the sample, 58% were female and 42% were male. the mean age was 47.4 ± 18.3 years old. upon admission, the mean apache ii score was 14.2 ± 9.6. in total, 54% of the patients had no known underlying comorbidities. the most common reasons for icu admission were neurological diseases (27%), sepsis or infectious diseases (19%) and postoperative management (12%). mechanical ventilation and haemodialysis were required by 35% and 11% of the patients, respectively. the average length of stay was 10.0 ± 7.2 days and the mortality rate was 24%. conclusion: most of the patients admitted to the icus were middle-aged females with no known underlying comorbidities. larger studies are necessary to provide a comprehensive understanding of the critical care needs of sudanese hospitals. keywords: intensive care units; patient admission, trends; critical care outcomes; developing countries; sudan. يف �شيما ل احلرجة، الرعاية خدمات لتطوير )icu( املركزة العناية لوحدة الدخول وخ�شائ�ض اأمناط معرفة ال�رضوري من امللخ�ص: البيئات منخف�شة املوارد. هدفت هذه الدرا�شة اإىل و�شف خ�شائ�ض املر�شى ذوي احلالت احلرجة املنومة يف وحدات العناية املركزة يف ال�شودان. الطريقة: جريت هذه الدرا�شة الر�شدية امل�شتقبلية بني فرباير ومايو 2017 يف وحدات العناية املركزة يف م�شت�شفيني حكوميني العناية وحدات يف التوايل على املقبولني البالغني املر�شى من 100 جمموعه ما ت�شمني مت ال�شودان. اخلرطوم، يف الثالثة الدرجة من املركزة يف الدرا�شة. مت ت�شجيل اخل�شائ�ض الدميوغرافية وال�رضيرية للمر�شى واأي�شا ر�شد مقيا�ض )apache ii( والذي ي�شمل التقييمات الفي�شيولوجية احلادة وتقييم ال�شحة املزمنة عند القبول، وكذلك �شبب القبول، وجود اأي اأمرا�ض م�شاحبة كامنة، متطلبات التدخل مثل التنف�ض ال�شناعي اأو غ�شيل الكلى، مدة الإقامة يف وحدة العناية املركزة وناجت عالج املري�ض. النتائج: من العينة وجد اأن، %58 من الإناث و %42 ذكور. كان متو�شط العمر 18.3 ± 47.4 �شنة. عند القبول، كان متو�شط درجة مقيا�ض apache ii هو 9.6 ± 14.2. يف املجموع كان، %54 من املر�شى لي�ض لديهم اأمرا�ض م�شاحبة كامنة معروفة. الأ�شباب الأكرث �شيوعا لدخول وحدة العناية املركزة هي الأمرا�ض الع�شبية )%27(، الإنتان اأو الأمرا�ض املعدية )%19( و اإدارة ما بعد اجلراحة )%12(. كان %35 و %11 من املر�شى على جهاز التنف�ض .24% الوفيات معدل وكان اأيام، 10.0 ± 7.2 الإقامة مدة متو�شط كان التوايل. على بالوحدة، القبول عند الكلوي اأوالغ�شيل ال�شناعي اأمرا�ض اأي لديهم لي�ض ممن العمر منت�شف يف الإناث من املركزة العناية وحدات اإىل اإدخالهم مت الذين املر�شى معظم كان اخلال�صة: م�شاحبة كامنة. نو�شي بعمل درا�شات اكرب لتوفري فهم �شامل لحتياجات الرعاية احلرجة للم�شت�شفيات ال�شودانية. الكلمات املفتاحية: وحدات العناية املركزة قبول املر�شى؛ قبول املر�شى، الجتاهات؛ نتائج الرعاية احلرجة؛ الدول النامية؛ ال�شودان. characteristics of critically-ill patients at two tertiary care hospitals in sudan *hagir sulieman,1 wael el-mahdi,2 mohannad awadelkareem,2 lama nazer3 clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e190–195, epub. 9 sep 18 submitted 25 oct 17 revisions req. 13 dec 17, 1 feb & 11 mar 18; revisions recd. 14 jan, 15 feb & 19 mar 18 accepted 25 mar 18 advances in knowledge to the best of the authors’ knowledge, this study is the first to describe the characteristics and outcomes of critically-ill patients in sudan. most patients admitted to the intensive care units (icus) of two major tertiary government hospitals in sudan were middle-aged females. the most frequent reasons for icu admission were neurological disorders and sepsis or infectious diseases. the average length of stay was relatively high and the mortality rate was 24%. application to patient care characterising patients who require critical care is essential to identify areas that need improvement. the findings of this study provide a general understanding of the type of patients managed in two icus in sudan and highlights areas that may need to be addressed. doi: 10.18295/squmj.2018.18.02.011 intensive care units (icus) were first introduced over half a century ago; since then, critical care medicine has progressed significantly worldwide, particularly in industrialised developed countries, resulting in significant improvements in the quality of care and outcomes of critically-ill patients.1–3 hagir sulieman, wael el-mahdi, mohannad awadelkareem and lama nazer clinical and basic research | e191 however, in developing countries such as those in subsaharan africa, critical care medicine has evolved at a considerably slower pace.4,5 moreover, hospitals in these countries often cannot fully implement wellestablished standards of care in icus due to limited financial resources and lack of equipment, medications and trained clinical staff.4–6 proposed strategies to improve critical care services in developing countries include incorporating a structured critical care training programme, increasing the nursing workforce and collecting data regarding patient outcomes.6 sudan has a population of approximately 40 mill ion people, of which nine million reside in the capital of khartoum.7 all four tertiary care hospitals in khartoum have government-funded critical care units which serve the entire country; however, these 74-bed icus are almost fully occupied year-round. the facilities and services available at the icus of all four government tertiary hospitals in khartoum are listed in table 1. while a few government-operated icus outside of khartoum have been developed recently, these icus generally have limited bed capacity, equip ment and critical care specialists. although nongovernmental critical care units are available at teaching and private institutions, these also have a limited number of beds. at the khartoum north hospital and ibrahim malik hospital, two of the four tertiary care hospitals in khartoum, approximately 700 adult patients are admitted each month; the former serves northern khartoum and the surrounding area, while the latter receives patients from all over the country. most neurological cases from outside khartoum are also referred to the ibrahim malik hospital for both critical and non-critical care. at the 17-bed icu of the khartoum north hospital, there are approximately 25–35 admissions per month. the icu operates on an open admission policy, so that any physician at khartoum north hospital may admit a patient to the unit and thereafter manage the patient during their icu stay. while the icu itself does not have a haemodialysis machine, patients who require dialysis can be referred elsewhere within the hospital. in addition, although the hospital does not have arterial blood gas analysis facilities, blood samples from icu patients are transported to a nearby laboratory for immediate analysis. at the 7-bed icu of the ibrahim malik hospital, there are approximately 15–20 admissions per month. a semi-closed system is used, in which an intensive care consultant is responsible for icu patients, conducts daily rounds and discusses patient management with the primary team. despite the expansion of critical care services in sudan over the past decade, the characteristics and outcomes of critically-ill patients at governmental tertiary care hospitals have not yet been studied. this information is essential for guiding admission and discharge policies and estimating the resources necessary for managing these patients.6 this study therefore aimed to describe the characteristics of critically-ill adults admitted to the icus of the khartoum north hospital and ibrahim malik hospital. methods this prospective observational study was conducted between february and may 2017 at the khartoum north hospital and ibrahim malik hospital. the sample consisted of consecutive ≥16-year-old patients admitted to the icus of these hospitals during the table 1: characteristics of intensive care units at governmental tertiary care hospitals in khartoum, sudan characteristic afh oth knh imh capacity number of hospital beds 550 500 400 287 number of icu beds 40 10 17 7 icu admission system semiclosed semiclosed open semiclosed equipment number of mechanical ventilators 40 10 7 7 number of arterial blood gas machines 1 1 0 1 number of dialysis machines 1 1 0 1 number of portable x-ray machines 1 1 0 1 number of bedside ultrasound machines 1 1 1 1 staffing nurse-to-bed ratio 1:1 1:1 1:2 1:1 number of icu consultants 5 3 0 1 number of icu clinical pharmacists 1 3 1 1 number of icu respiratory therapists 3 0 0 0 number of icu medical residents per day 6–8 2 3 2 afh = armed forces hospital; oth = omdurman teaching hospital; knh = khartoum north hospital; imh = ibrahim malik hospital; icu = intensive care unit. characteristics of critically-ill patients at two tertiary care hospitals in sudan e192 | squ medical journal, may 2018, volume 18, issue 2 study period until a total of 100 patients had been included. patients were enrolled in the study by two medical officers who worked 24 hours per week in the icu of the hospitals. patients admitted consecutively on the days on which the medical officers were on duty were included, while patients admitted on days that neither medical officer was available were excluded. the demographic and clinical characteristics of the patients were recorded by the two medical officers upon admission to the icu. in addition, the reason for admission, admitting department, presence of any underlying comorbidities, need for interventions (i.e. mechanical ventilation and haemodialysis), length of stay in the icu and mortality rate were also noted. in each case, the acute physiologic assessment and chronic health evaluation (apache ii) score was determined using the worst/most severe measurements of various physiological and laboratory parameters recorded during the first 24 hours of admission.8 data were analysed using the statistical analysis system program, version 9.4 (sas institute, cary, north carolina, usa). descriptive data were presented as counts and percentages for categorical data and means and standard deviations or medians and interquartile ranges for continuous data. either a chi-squared test or fisher’s exact test was used to compare categorical variables, as appropriate, while the kruskal-wallis test was used for continuous variables. a p value of ≤0.05 was deemed statistically significant. the institutional review boards of both the khartoum north hospital and the ibrahim malik hospital approved the protocols of this study. the need for informed patient consent was waived as all data included in the analysis were deidentified. results table 2 outlines the demographic and clinical characteristics of the study cohort. most of the patients admitted to the icus of the khartoum north hospital and ibrahim malik hospital were female (58%) and table 2: characteristics of patients admitted to the intensive care units of the khartoum north hospital and ibrahim malik hospital in khartoum, sudan (n = 100) characteristic n (%) gender female 58 (58) male 42 (42) mean age in years ± sd 47.4 ± 18.3 place of residence khartoum 75 (75) elsewhere 25 (25) mean apache ii score ± sd 14.2 ± 9.6 presence of comorbidities yes 46 (46) no 54 (54) type of comorbidity* diabetes 28 (60.9) hypertension 24 (52.2) cad 3 (6.5) asthma/copd 6 (13) renal disease 7 (15.2) other 3 (6.5) location prior to icu admission emergency department 50 (50) hospital ward 24 (24) operating theatre 8 (8) other hospital 18 (18) reason for admission neurological disorders 27 (27) sepsis/infectious diseases 19 (19) postoperative management 12 (12) cardiac disorders 8 (8) respiratory failure 8 (8) renal failure 8 (8) dka 7 (7) other 11 (11) intervention requirements mechanical ventilation 35 (35) tracheostomy 9 (9) haemodialysis 11† (11) medications prescribed during icu stay* antibiotics 100 (100) pain medications 42 (42) antihypertensives 25 (25) vasopressors 19 (19) sedatives 30 (30) muscle relaxants 2 (2) thrombolytics 1 (1) h2 blockers/ppis 100 (100) length of icu stay in days mean ± sd 10.0 ± 7.2 median (iqr) 8 (6–13) sd = standard deviation; apache ii = acute physiologic assessment and chronic health evaluation; cad = coronary artery disease; copd = chronic obstructive pulmonary disease; icu = intensive care unit; dka = diabetic ketoacidosis; ppi = proton pump inhibitor; iqr = interquartile range. *percentages do not add up to 100% as some patients may have been included in more than one category. †of these patients, four required dialysis due to acute renal failure and seven due to chronic renal failure. hagir sulieman, wael el-mahdi, mohannad awadelkareem and lama nazer clinical and basic research | e193 residents of khartoum (75%). the mean age was 47.4 ± 18.3 years old and the mean apache ii score was 14.2 ± 9.6. the majority of patients (54%) had no identifiable comorbidities prior to icu admission. of those with comorbidities, the most common were diabetes (60.9%) and hypertension (52.2%). although none of the patients had a history of cancer, two patients were diagnosed with cancer during their icu stay. half of the patients were admitted from the emergency department; of these, 16% had neurological disorders, 16% had sepsis and 10% had respiratory illnesses. overall, the most common reason for icu admission was a neurological disorder (27%), with haemorrhagic and ischaemic strokes diagnosed in five (18.5%) and eight (29.6%) of these patients, respectively. following this, 19% were admitted due to sepsis or infectious diseases and 12% for post-surgical management. all of the patients were prescribed antibiotics and h2 blockers at some point during their icu stay. about one-third of the patients (35%) required mechanical ventilation at the time of admission. all of these patients received continuous infusions of analgaesics and sedatives during intubation, with two patients (5.7%) requiring a muscle relaxant as well. furthermore, 11% of the patients required dialysis during their stay; of these, four patients (36.4%) were diagnosed with acute renal failure during their icu stay, while seven (63.6%) had chronic renal failure and were on dialysis prior to icu admission. the mean length of stay in the icu was 10.0 ± 7.2 days. table 3: comparison of characteristics affecting survival among patients admitted to the intensive care units of the khartoum north hospital and ibrahim malik hosp ital in khartoum, sudan (n = 100) characteristic n (%) p value survivors (n = 76) nonsurvivors (n = 24) gender female 44 (57.9) 14 (58.3) 0.99 male 32 (42.1) 10 (41.7) mean age in years ± sd 45.6 ± 17.8 47.9 ± 18.5 0.57 place of residence khartoum 69 (90.8) 6 (25) <0.01 elsewhere 7 (9.2) 18 (75) mean apache ii score ± sd 12.5 ± 8.8 18.6 ± 9.7 0.02 presence of comorbidities yes 35 (46.1) 11 (45.8) 0.99 no 41 (53.9) 13 (54.2) type of comorbidity* diabetes 21 (60) 7 (63.6) 0.88 hypertension 19 (54.3) 5 (45.5) 0.99 cad 3 (8.6) 0 (0) 0.32 asthma/copd 4 (11.4) 2 (18.2) 0.66 renal disease 6 (17.1) 1 (9.1) 0.53 other 1 (2.9) 2 (18.2) location prior to icu admission emergency department 36 (47.4) 14 (58.3) 0.39† hospital ward 21 (27.6) 3 (12.5) operating theatre 5 (6.6) 3 (12.5) other hospital 14 (18.4) 4 (16.7) reason for admission neurological disorders 21 (27.6) 6 (25) 0.13 sepsis/infectious diseases 11 (14.5) 8 (33.3) postoperative management 11 (14.5) 1 (4.2) cardiac disorders 4 (5.3) 4 (16.7) respiratory failure 7 (9.2) 1 (4.2) renal failure 8 (10.5) 0 (0) dka 6 (7.9) 1 (4.2) other 8 (10.5) 3 (12.5) intervention requirements mechanical ventilation 21 (27.6) 14 (58.3) <0.01 tracheostomy 7 (9.2) 2 (8.3) 0.94 haemodialysis 10‡ (13.2) 1§ (4.2) 0.11 medications prescribed during icu stay*¶ antibiotics 76 (100) 24 (100) pain medications 24 (31.6) 18 (75) antihypertensives 20 (26.3) 5 (20.8) vasopressors 7 (9.2) 12 (50) sedatives 17 (22.4) 13 (54.2) muscle relaxants 0 (0) 2 (8.3) thrombolytics 0 (0) 1 (4.2) h2 blockers/ppis 76 (100) 24 (100) length of icu stay in days mean ± sd 11.8 ± 11.2 10.5 ± 12.6 0.07 median (iqr) 8 (7–14) 6 (4–10) sd = standard deviation; apache ii = acute physiologic assessment and chronic health evaluation; cad = coronary artery disease; copd = chronic obstructive pulmonary disease; icu = intensive care unit; dka = diabetic ketoacidosis; ppi = proton pump inhibitor; iqr = interquartile range. *percentages do not add up to 100% as some patients may have been included in more than one category. †each variable was statistically compared with the other variables combined. ‡of these patients, three had acute renal failure and seven had chronic renal failure. §this patient had acute renal failure. ¶a statistical comparison was not possible for this variable as patients received multiple combinations of medications throughout their icu stay. characteristics of critically-ill patients at two tertiary care hospitals in sudan e194 | squ medical journal, may 2018, volume 18, issue 2 the overall mortality rate of the study cohort was 24%. table 3 compares the characteristics of the survivors and non-survivors. the non-survivors had significantly higher apache ii scores upon icu admission compared to the survivors (18.6 ± 9.7 versus 12.5 ± 8.8; p = 0.02). moreover, significantly more of the non-survivors required mechanical ventil ation compared to the survivors (58.3% versus 27.6%; p <0.01). in addition, among the non-survivors, significantly more patients resided outside khartoum comp ared to the survivors (75% versus 9.2%; p <0.01). discussion to the best of the authors’ knowledge, this study is the first to evaluate the characteristics and outcomes of critically-ill patients admitted to icus in sudan. previous research published on the patterns and outcomes of patients admitted to icus in other subsaharan countries, including benin, nigeria, tanzania and uganda, indicated wide variations in disease characteristics and mortality rates.9–14 moreover, it is to be expected that the characteristics and outcomes of patients admitted to icus in developing countries will differ from those in industrialised countries due to vast differences in diseases patterns and the available healthcare infrastructure and resources. dünser et al. reported significant differences in patient characteristics, icu practices and patient outcomes at the icus of a 400-bed tertiary care university hospital in mongolia and a 429-bed hospital in austria.15 specifically, patients admitted to the icu in mongolia had fewer chronic diseases, more frequently presented with tuberculosis and did not receive medical care prior to icu admission. moreover, the overall mortality rate was significantly higher (19.7% versus 6.2%; p <0.001).15 in the present study, the most common reason for icu admission was neurological disorders, such as a stroke, followed by sepsis/infectious diseases and postoperative management. in an earlier study of obstetric and gynaecological admissions to the icu at khartoum hospital, the most common reasons for icu admission were eclampsia (44.8%) and postpartum haemorrhage (31.3%) among obstetric cases and infections (59.3%) and ovarian or cervical cancer (18.7%) among gynaecological cases.16 in their review of critical care services in the least developed countries worldwide, dünser et al. found the commonest reasons for admission to the icu to be post-surgical treatment, infectious diseases, trauma and peripartum maternal or neonatal complications.5 the higher incidence of neurological-related disorders in the current study may partly be due to the fact that the emergency room of the ibrahim malik hospital is also shared by the national center for neuroscience in sudan; thus, neurological patients referred to this centre and requiring critical care would be admitted to the hospital’s icu. almost one-fourth of the patients in the current study died during their icu stay. although this mortality rate was lower than that reported for other populations of critically-ill patients in sub-saharan countries (range: 27–64%), it was nevertheless higher than the predicted mortality rate based on the mean apache ii score upon icu admission (≈15%).8–14,17 although the exact reason for this higher mortality rate is unclear, several factors may have contributed to this outcome. first, it is possible that there was a delay in providing therapy for some patients. second, no comorbidities were recorded for over half of the cohort; certain patients may hence have had unidentified underlying diseases that went untreated prior to admission. finally, despite having been admitted to the icu with less severe conditions and therefore lower apache ii scores, some patients may have developed complications during their stay, worsening their condition. the latter possibility is supported by the relatively long mean icu stay, which is generally reflective of patients with ongoing critical conditions requiring continued icu services. in the current study, factors which were found to significantly affect mortality included higher apache ii scores upon icu admission, the need for mechanical ventilation and residing outside khartoum. in particular, the latter finding is concerning and raises questions regarding the potentially less-than-timely management of critically-ill patients in more rural parts of sudan, as well as the necessity of ensuring the availability of icu equipment and critical care personnel. future research is recommended to identify other factors related to mortality rates in icus in sudan so as to improve patient outcomes. medical care for patients presenting to government hospitals in sudan is cheaper than for private hospitals and medical fees are usually waived for patients who are unable to pay; thus, the ability to pay is not a factor in determining icu admission patterns or mortality rates. this study was limited by its relatively small sample size and the inclusion of only two out of the four government tertiary hospitals in khartoum. unfortunately, due to logistical issues with the data collection process, it was not possible to include the other two government hospitals, the armed forces hospital and omdurman teaching hospital. therefore, the study was conducted solely in the hospitals at which two of the authors worked. nevertheless, as hagir sulieman, wael el-mahdi, mohannad awadelkareem and lama nazer clinical and basic research | e195 all four hospitals serve the entire country, critically-ill patients admitted to the khartoum north hospital and ibrahim malik hospital may be considered nationally representative of this patient population. conclusion this study provides insight into the characteristics and outcomes of icu admissions at two government hospitals in khartoum. more than half of the patients were middle-aged females, with the majority having no known underlying comorbidities. the overall mortality rate was 24%. large multicentre studies are necessary to form a comprehensive understanding of the critical care needs in sudan; these findings would help guide the national healthcare system in formulating policies to improve and increase the capacity of current critical care services. a c k n o w l e d g m e n t s the authors are grateful to the members of the critical care research academy for their valuable mentorship while conducting this research project, with special thanks to dr. abdulrazaq al-jazairi and dr. elisabeth heseltine for their help in reviewing and editing the manuscript. the authors also wish to thank dr. a. al-muhaimen, dr. mohammed al-amin and dr. omima shihabeldin for helping with the data analysis. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. berthelsen pg, cronqvist m. the first intensive care unit in the world: copenhagen 1953. acta anaesthesiol scand 2003; 47:1190–5. doi: 10.1046/j.1399-6576.2003.00256.x. 2. vincent jl, creteur j. paradigm shifts in critical care medicine: the progress we have made. crit care 2015; 19:s10. doi: 10.11 86/cc14728. 3. grenvik a, pinsky mr. evolution of the intensive care unit as a clinical center and critical care medicine as a discipline. crit care clin 2009; 25:239–50. doi: 10.1016/j.ccc.2008.11.001. 4. baelani i, jochberger s, laimer t, otieno d, kabutu j, wilson i, et al. availability of critical care resources to treat patients with severe sepsis or septic shock in africa: a self-reported, continent-wide survey of anaesthesia providers. crit care 2011; 15:r10. doi: 10.1186/cc9410. 5. dünser mw, baelani i, ganbold l. a review and analysis of intensive care medicine in the least developed countries. crit care med 2006; 34:1234–42. doi: 10.1097/01.ccm.0000 208360.70835.87. 6. haniffa r, pubudu de silva a, de azevedo l, baranage d, rashan a, baelani i, et al. improving icu services in resourcelimited settings: perceptions of icu workers from low-middle-, and high-income countries. j crit care 2018; 44:352–6. doi: 10.1016/j.jcrc.2017.12.007. 7. world bank. sudan. from: https://data.worldbank.org/country/ sudan accessed: mar 2018. 8. knaus wa, draper ea, wagner dp, zimmerman je. apache ii: a severity of disease classification system. crit care med 1985; 13:818–29. 9. adudu op, adudu og. working practices and patient outcome in the intensive care unit of the university of benin teaching hospital. j med biomed res 2004; 3:67–72. doi: 10.4314/jmbr. v4i1.10668. 10. isamade es, yiltok sj, uba af, isamade ei, daru ph. intensive care unit admissions in the jos university teaching hospital. niger j clin pract 2007; 10:156–61. 11. merah na, okeke ci, olatosi jo. an audit of surgical admissions to the intensive care unit of the lagos university teaching hospital (1997 2002). niger postgrad med j 2006; 13:153–6. 12. sawe hr, mfinanga ja, lidenge sj, mpondo bc, msangi s, lugazia e, et al. disease patterns and clinical outcomes of patients admitted in intensive care units of tertiary referral hospitals of tanzania. bmc int health hum rights 2014; 14:26. doi: 10.1186/1472-698x-14-26. 13. kwizera a, dünser m, nakibuuka j. national intensive care unit bed capacity and icu patient characteristics in a low income country. bmc res notes 2012; 5:475. doi: 10.1186/1756-05005-475. 14. dünser mw, towey rm, amito j, mer m. intensive care medicine in rural sub-saharan africa. anaesthesia 2017; 72:181–9. doi: 10.1111/anae.13710. 15. dünser mw, bataar o, tsenddorj g, lundeg g, torgersen c, romand ja, et al. differences in critical care practice between an industrialized and a developing country. wien klin wochenschr 2008; 120:600–7. doi: 10.1007/s00508-008-1064-8. 16. ibrahim ia, rayis da, alsammani ma, adam i. obstetric and gynecologic admissions to the intensive care unit at khartoum hospital, sudan. int j gynaecol obstet 2015; 129:84. doi: 10.1016/j.ijgo.2014.10.019. 17. ouédraogo n, niakara a, simpore a, barro s, ouédraogo h, sanou j. [intensive care in africa: a report of the first two years of activity of the intensive care unit of ouagadougou national hospital (burkina faso)]. sante 2002; 12:375–82. https://doi.org/10.1046/j.1399-6576.2003.00256.x https://doi.org/10.1186/cc14728 https://doi.org/10.1186/cc14728 https://doi.org/10.1016/j.ccc.2008.11.001 https://doi.org/10.1186/cc9410 https://doi.org/10.1097/01.ccm.0000208360.70835.87 https://doi.org/10.1097/01.ccm.0000208360.70835.87 https://doi.org/10.1016/j.jcrc.2017.12.007 https://doi.org/10.4314/jmbr.v4i1.10668 https://doi.org/10.4314/jmbr.v4i1.10668 https://doi.org/10.1186/1472-698x-14-26 https://doi.org/10.1186/1756-0500-5-475 https://doi.org/10.1186/1756-0500-5-475 https://doi.org/10.1111/anae.13710 https://doi.org/10.1007/s00508-008-1064-8 https://doi.org/10.1016/j.ijgo.2014.10.019 department of biology, college of science, sultan qaboos university, muscat, oman *corresponding author e-mail: eatayeb@squ.edu.om توصيف النيكوتني واأليونات السالبة احملفزة للسرطان يف التبغ عدمي الدخان "أفضل" الشائع االستعمال يف عمان نوال املخينية، طاهر باعمر، ال�سادق الطيب، عائ�سة ال�سحية abstract: objectives: afzal is a common smokeless tobacco product (stp) available illegally in oman. this study aimed to assess ph and moisture levels and determine cancer-enhancing factors in a randomly selected sample of afzal. methods: this study was carried out at the sultan qaboos university in muscat, oman, between april and december 2013. a package of afzal was purchased from a single provider and divided into samples. the ph and moisture content of the samples were measured according to the protocols of the centers for disease control and prevention. gas chromatography-mass spectrometry was used to analyse nicotine levels and ionexchange chromatography (ic) was used to determine concentrations of nitrate, nitrite, chloride, fluoride, bromide, sulphate and phosphate anions. results: the samples had an alkaline ph of 10.46 with high levels of total (48,770.00 µg per g of stp [µg/g]) and unionised (48,590.00 µg/g) nicotine. the concentration of nitrate (8,792.20 µg/g) was alarmingly high. the chloride concentration (33,170.80 µg/g) showed a surge on ic chromatography. the moisture content percentage was 52.00%. conclusion: the moisture content percentage and chloride concentration of afzal was consistent with those of other stps. in contrast, nitrite, sulphate and phosphate concentrations were below reported levels of other stps. all anion concentrations were below the maximum daily limit set by international health organisations. however, the high concentrations of nitrite, nitrate and nicotine and the elevated alkaline ph observed in the analysed afzal samples suggest that stp users will face health risks as a result of their use. keywords: smokeless tobaccos; gas chromatography-mass spectrometry; ion-exchange chromatography; carcinogens; nicotine; anions; oman. لتعيني الدرا�سة هذه هدفت عمان. �سلطنة يف قانوين غري ب�سكل انت�ساراَ الأكرث ويعترب الدخان عدمي تبغ هو اأف�سل الهدف: امللخ�ص: م�ستويات درجة احلمو�سة والرطوبة وكذلك العوامل املحفزة لل�رسطان يف عينة ع�سوائية من تبغ اأف�سل. الطريقة: نفذت هذه الدرا�سة يف جامعة ال�سلطان قابو�ض يف م�سقط، �سلطنة عمان، يف الفرتة من اإبريل اإىل دي�سمرب 2013. مت �رساء كمية من تبغ اأف�سل من م�سدر فردي ومت تق�سيمها لعدة عينات. مت قيا�ض حمتوى درجة احلمو�سة والرطوبة للعينات طبقَا لنظام مركز ال�سيطرة على الأمرا�ض والوقاية منها وا�ستخدام النيكوتني م�ستويات لتحليل للكتلة طيفي ومبقيا�ض اللوين بالتخطيط الغاز تقنية ا�ستخدام مت الأمريكية. املتحدة بالوليات تقنية التخطيط اللوين لالأيونات لتحديد تراكيز كل من الأيونات ال�سالبة للنرتات، والنيرتايت، والكلوريد، والفلوريد، والربوميد، والكربيتات والفو�سفات. النتائج: اأظهرت العينات درجة حمو�سة قلوية تعادل 10.46 وم�ستويات عالية من النيكوتني الكلي )48,770.00 ميكروجرام/ جم( ملادة التبغ عدمي الدخان والنيكوتني غري املوؤين )48,590.00 ميكروجرام جم(. كان تركيز النرتات )8,792.20 ميكروجرام/جم( عاليَا ب�سكل حتذيري. كما اظهر تركيز الكلوريد )33,170.80 ميكروجرام/جم( موجة عالية بالتخطيط اللوين لالأيونات. بلغت ن�سبة الرطوبة لتبغ الدخان عدمي التبغ ملنتجات �سواه ما مع متنا�سقة اأف�سل لتبغ الكلورايد وتركيز الرطوبة ن�سبة كانت اخلال�صة: .52.00% ن�سبة اأف�سل كل كانت الأخرى. الدخان عدمي التبغ مبنتجات مثيالتها عن اأقل والفو�سفات والكربيتات النيرتايت تركيزات كانت وباملثل الأخرى. تركيزات الأيونات ال�سالبة اأقل عن امل�ستويات الق�سوى اليومية املو�سى بها من قبل منظمات ال�سحة العاملية. ومع ذلك فاإن الرتاكيز العالية لكل من النيرتايت والنرتات والنيكوتني وم�ستوى احلمو�سة القلوي املرتفع املالحظ بعينات تبغ اأف�سل املحللة يفيد باأن م�ستخدمي التبغ عدمي الدخان �سيواجهون خماطر �سحية نتيجة لذلك ال�ستخدام. اللوين التخطيط للكتلة؛ طيفي ومبقيا�ض اللوين بالتخطيط الغازات كروماتوغرام جهاز الدخان؛ عدمي التبغ منتجات الكلمات: مفتاح لالأيونات؛ مواد م�رسطنة؛ نيكوتني؛ الأيونات ال�سالبة؛ عمان. characterisation of nicotine and cancer-enhancing anions in the common smokeless tobacco afzal in oman nawal m. al-mukhaini, taher a. ba-omar, *elsadig a. eltayeb, aisha h. al-shehi clinical & basic research advances in knowledge this study shows that afzal, an illegal smokeless tobacco product (stp) commonly available in oman, contains high levels of nitrites, nitrates and nicotine and an elevated alkaline ph. sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e469–476, epub. 23 nov 15 submitted 1 apr 15 revisions req. 18 may & 22 jul 15; revisions recd. 30 jun & 4 aug 15 accepted 27 aug 15 doi: 10.18295/squmj.2015.15.04.005 characterisation of nicotine and cancer-enhancing anions in the common smokeless tobacco afzal in oman e470 | squ medical journal, november 2015, volume 15, issue 4 according to the international agency for research on cancer, smokeless tobacco products (stps) are carcinogenic.1 understanding the chemical composition of these products is therefore the first step in assessing their potential toxicity.2 the majority of stps contain compounds that are potentially detrimental to health, including tobacco-specific nitrosamines (tsnas); nitrosodimethylamine; polycyclic aromatic hydrocarbons (e.g. benzo(a)pyrene); and heavy metals.3 additionally, they generally have elevated alkaline ph and moisture levels and contain nicotinic secondary metabolites and anions such as nitrite (no2 -) and chloride (cl-), which may enhance cancer formation.4 the most harmful carcinogens in stps are tsnas, which normally form during the preservation, fermentation, maturation and storage stages of the tobacco process.3,5 the presence of certain agents in tobacco—including nicotine, elevated moisture levels, a high ph level and no2 and nitrate (no3 -) concentrations—usually facilitates the accumulation of high concentrations of tsnas.6 as such, stps must be analysed and their compounds quantified in order to estimate their potential health risk. the nicotine content of a specific stp is the primary determinant of both its appeal and cause of addiction among users.7 the absorption of nicotine is strongly associated with the ph and moisture content of the product.8 the naturally occurring form of nicotine is the unprotonated form, which is easily absorbed by the oral mucus membranes into the blood stream and delivered directly to the brain.2 within stps, an alkaline ph value helps make more of the total nicotine absorbable.9 furthermore, the moisture content of an stp enhances microbial activity, resulting in an elevated formation of tsnas.10,11 microflora in the buccal cavity cause the reduction of no3 to no2 -, which is more toxic to humans.12 in turn, no2 forms the nitrosating agent of the alkaloids in the tobacco (mainly nicotine and its secondary metabolites), which leads to the formation of carcinogenic nitrosamines.4 afzal is a commonly used stp available illegally in oman. in order to educate consumers, public health officials and regulatory policy-makers regarding the levels of toxicants in afzal, analyses of the contents of this stp are needed. previous research has determined the composition of heavy metals in afzal.13 the aim of this study was therefore to measure ph and moisture levels and assess cancer-causing agents in a random sample of afzal. methods this study was carried out at the sultan qaboos university (squ) in muscat, oman, between april and december 2013. a single package of 4.00 kg of afzal was purchased from a single source in order to maintain uniformity. the ph levels and moisture content of the sample were tested on the day of purchase according to the methods described below. the product was subsequently labelled with the date of purchase as well as the original ph level and moisture content so that any changes that occurred after storage could be noted. the sample was then kept refrigerated at 4 ºc in plastic bags until analysis. in order to assess ph levels, the package of afzal was divided into three samples of 2.00 g each. each sample was then mixed with 20 ml of deionised water. the ph levels were measured using a ph meter (benchtop ph meter, mettler-toledo international inc., columbus, ohio, usa) with two-point calibration to an accuracy of two decimal places using standard ph buffers (4.00 and 7.00). the ph was measured with continuous stirring at the first five, 15 and 30 minutes to ensure no variation in the results. the mean ph value was obtained in accordance with standard protocols from the centers for disease control and prevention (cdc).14 three samples of 5.00 g each of afzal were dried to determine their moisture content. this was measured by obtaining the difference in weight of the samples before and after they had been dried in an oven for three hours at 99 ± 1 ºc. the mean moisture value was reported as a percentage of the original weight and compared to cdc protocols.14 ion-exchange chromatography (ic) analysis was performed for no2 -, no3 -, cl-, fluoride (f-), bromide (br-), phosphate (po4 2-) and sulphate (so4 2-) ions. dried afzal samples were ground into a homogenous powder and three samples of 1.00 g each were transferred into three 50 ml centrifuge tubes. subsequently, 20 ml of milli-q® water (merck kgaa, darmstadt, germany) was added to each tube. samples were sonicated for 30 minutes followed by centrifugation at 3,000 revolutions per minute (rpm) for 30 minutes. finally, the samples were filtered through a 0.45 μm cellulose acetate application to patient care this study may encourage health officials and relevant government departments to continue increasing awareness among young afzal users about the potential health risks associated with this stp. health practitioners should be aware of afzal use among patients and the medical complications that could arise as a result. nawal m. al-mukhaini, taher a. ba-omar, elsadig a. eltayeb and aisha h. al-shehi clinical and basic research | e471 polytetrafluoroethylene membrane nylon syringe filter (whatman®, sigma-aldrich corp., st. louis, missouri, usa) to remove solids before the solution was injected into the 881 compact ic pro anion system with an 858 professional sample processor (metrohm ag, ionenstrasse, switzerland). in order to ensure the accuracy of the readings, each sample was injected into the ic instrument twice. each sample was diluted five-fold before ic analysis. the ic method used was validated and applied by the environmental engineering laboratory of the college of engineering at squ. the conditions of the analysis were as follows: column size of 250.00 x 4.00 mm; flow rate of 0.7 ml/ minute; suppressed conductivity detector; ambient temperature of 21–23 ºc; pressure of 13.7 megapascals; and a sample size of 20 µl. the eluent was prepared by dissolving 678,400.00 µg (3.2 mm/l) of 98% pure sodium carbonate (vwr international ltd., lutterworth, leicestershire, uk) and 168,000.00 µg (1.0 mm/l) of sodium bicarbonate with 99% purity (vwr international ltd.) in 2 l of deionised ultrapure water. the suppressor regenerating solution used was 50 mm of analytical-grade sulphuric acid (honeywell specialty chemicals seelze gmbh, seelze, germany). in order to form a five-point calibration curve, 1,000 parts per million of each anion was concentrated using six anion standard concentrations (fluka® analytical, sigma-aldrich corp.). the no2 standard was laboratory-prepared from 98% pure sodium no2 (merck kgaa). deionised water at a purity of 18 megohms (ultrapure private limited, singapore) was used throughout the analysis. the mean total nicotine value of afzal samples was obtained from gas chromatography-mass spectrometry (gc-ms) analysis. the nicotine analysis procedure was performed as previously described.15,16 a total of 5 ml of a 2 m solution of sodium hydroxide and 50 ml of extraction solution (methyl tert-butyl ether) with quinoline as an internal standard was added to a 1.00 g sample of afzal. sample vials were shaken on an orbital shaker at 160 rpm for two hours. the resulting extract was transferred to a 2 ml autosampler vial. the analysis was performed by injecting 1 ml from each vial into a clarus® 600 gas chromatograph (perkinelmer inc., waltham, massachusetts, usa) fitted with an rtx®-5ms capillary column (restek corp., bellefonte, pennsylvania, usa) of 30.00 m x 0.25 mm x 0.25 μm film thickness at a maximum temperature of 350 ºc and coupled to a clarus® 600c mass spectrometer (perkinelmer inc.). ultra-high-purity helium (>99.9%) was used as a carrier gas at a constant flow of 1.0 ml/ minute. the injection, transfer line and ion source temperatures were 290, 280 and 280 ºc, respectively. the ionising energy was 70 electron volts. the injected volume for each sample was 1 μl with a split ratio of 80:1. the oven temperature was initially 80 ºc for five minutes and then accelerated at a rate of 10 ºc per minute to 280 ºc for 30 minutes. unknown compounds were identified by comparing the spectra obtained with national institute of standards and technology (nist) software, version 11 (united states department of commerce, gaithersburg, maryland, usa) and nist mass spectral library, version 14 (united states department of commerce). all chemicals used for gc-ms analysis were of analytical grade (sigma-aldrich corp.). for method validation purposes, blank samples of deionised water were run 10 times to calculate the limits of detection (lod) and limits of quantitation (loq) of the tested analytes. blank reagent samples of the tested anions were also used to subtract the results of all tested anion standards and samples. the lod was calculated using the following equation: where sdblank is the standard deviation for the signal recorded on the blank for the corresponding element studied and concnsample is the concentration in μg/l of the respective sample aspired. the inet value was calculated as below: where isample and iblank are the signal intensities recorded for the sample and blank, respectively. the loq was approximately 10 times the lod for all studied anions. each analysed standard and sample was injected three times. this reflected high precision as it was automatically calculated using the relative standard deviation for each analyte. six-point calibration standards curves were plotted at 50, 100, 150, 200, 250 and 300 parts per billion for each analyte. the percentage of unprotonated nicotine was calculated using the ph and the pka value of the pyrolic nitrogen of nicotine (pka = 8.02), which was substituted into the henderson-hasselbalch equation.14 the total amount of unprotonated nicotine was then calculated by multiplying the percentage of unprotonated nicotine by the total nicotine as follows:14 where wistd is the weight of the internal standard (6,250.00 µg), wsample is the weight of the afzal sample (1.00 g), anicotine is the area of nicotine from the chromatogram and aistd is the area of the internal standard. unprotonated nicotine was calculated lod = 3 x sdblank x concnsample/inet inet = isample iblank total nicotine = (wistd/wsample) x (anicotine/aistd) characterisation of nicotine and cancer-enhancing anions in the common smokeless tobacco afzal in oman e472 | squ medical journal, november 2015, volume 15, issue 4 according to the following henderson-hasselbalch equation:17 where b is the amount of unprotonated nicotine, bh+ is the amount of ionised nicotine, pka is 8.02 and ph is 10.46. the percentage of unprotonated nicotine was calculated according to the following formula: this was then used to calculate the total free nicotine as per the below formula: excel spreadsheet software, version 2010 (microsoft corp., redmond, washington, usa) was used for the statistical analysis. for each afzal sample, the mean ph value, moisture content and nicotine concentrations were calculated. this study did not require ethical approval as it involved a chemical analysis of afzal. results the minimum detection limit values of the samples revealed satisfactory sensitivity of the ic method. the calibration of the linearity (r value) of the tested anion standards ranged between 0.996–0.999. the chromatograms from both the gc-ms and ic analyses validated the methods, as evidenced by the consistency figure 1a–c: gas chromatography-mass spectrometry graphs of the nicotine in the (a) first, (b) second and (c) third afzal samples. the long peak represents nicotine while the short one represents quinoline (the internal standard). the numbers on the peaks represent the retention time. the spectra mass value is represented in the area under the peak. total free nicotine = total nicotine x % unprotonated nicotine/100 ph = pka + log (b/bh+) % unprotonated nicotine = (b/bh+)/([b/bh+] + 1) x 100 nawal m. al-mukhaini, taher a. ba-omar, elsadig a. eltayeb and aisha h. al-shehi clinical and basic research | e473 and repeatability of the results [figures 1 and 2]. the afzal samples had a mean ph of 10.46 and moisture content of 2.60 g. the calculated moisture content percentage was 52.00%. with regards to nicotine, the mean total nicotine and unprotonated nicotine levels were 48,770.00 µg per g of stp (µg/g) and 48,590.00 µg/g, respectively. the percentage of unprotonated nicotine was 99.64%. the chromatograms of the afzal nicotine analysis showed two peaks—a long peak representing nicotine and a shorter one representing the internal standard [figure 1]. the ion-exchange chromatograms also showed a long peak for cl[figure 2]. table 1 shows the anion concentrations within the afzal samples. clconcentrations were highest at 33,170.00 µg/g while no2 was the lowest at 6.22 µg/g. the nitrate concentration (8,792.20 µg/g) was alarmingly high. the order of the ion concentrations from highest to lowest was as follows: cl-, no3 -, so4 2-, f-, br-, po4 2 and no2 -. discussion in the current study, samples of afzal were found to have an alkaline ph; this is known to encourage the formation of tsnas, which are potent carcinogens.6 an alkaline ph environment also plays an important role in causing nicotine to become more absorbable, thus increasing its addictiveness.8 the elevated alkaline ph of afzal noted in the current study may therefore figure 2a–c: ion-exchange chromatograms of the anions in the (a) first, (b) second and (c) third afzal samples. each sample was injected twice into the instrument. there was a high chloride peak in all samples. numbers on top of each anion peak represent the retention time. µs/cm = microsiemens/cm. characterisation of nicotine and cancer-enhancing anions in the common smokeless tobacco afzal in oman e474 | squ medical journal, november 2015, volume 15, issue 4 increase health risks for users, including the possibility of heightened addiction rates and carcinogenicity. substances such as slaked lime are often added to the tobacco blend during the curing process, thereby increasing the alkaline ph.7 the afzal samples in this study had a higher ph value (ph 10.46) than the value described in the quality standards used by gothiatek® (swedish match, stockholm, sweden) for snus (ph 8.50), a moist powder tobacco which is highly regulated and monitored by the swedish national food act.10 it has been shown that the ph value of snus is affected by its storage temperature.10 similarly, a ph range of 9.2–10.0 has been reported for other stps including khaini and gul from india, toombak from sudan and snuff products from south africa.15 however, traditional alaskan iq’mik appears to have the highest alkalinity (ph 11.00).18 bearing in mind the pka of nicotine, any increase in ph levels would favour transformation of the nicotine to its unprotonated form. moisture content is another major factor enhancing the permeability of both nicotine and tsnas into the mucosal membrane of the mouth, since both are watersoluble.7,19 higher nicotine levels are found in moist snuff in comparison to the dry form.1 additionally, it has been found that american moist snuff contains higher levels of no2 and clthan the dry type.2 thus, the observed moisture content of afzal in the current study (52.00%), which was similar to that of the american moist snuff (51.00%), can be expected to contain similarly elevated nicotine, no2 and cllevels. the moisture content of the afzal samples in the current study was also higher than that reported for the indian tobacco bidi (10.26%), but within the range of snus (45.00–60.00%).2,10,20 nicotine content in stps is considered low at ≤7,500.00 µg/g, moderate between 10,300.00– 11,400.00 µg/g and high at >11,400.00 µg/g.21 this is worth noting since, besides addiction, nicotine may cause other physiological effects such as an increase in pulse rate, blood pressure and plasma free fatty acids and the mobilisation of blood sugar and catecholamines in the blood.22,23 a high nicotine content has been found in toombak (40,600.00 µg/g) and iq’mik (42,700.00 µg/g).18,24 however, the nicotine content of afzal in the current study exceeded these values (48,770.00 µg/g); as evidenced by henningfield et al., nearly all of its nicotine content would have been in the unprotonated form because of its high ph level.21 as is the case with snus, stps with higher unprotonated nicotine content hold the highest market share.25 all of the anions analysed in this study were below the recommended daily intake limits determined by international health organisations (f= 33.30 µg/kg/ day; cl= 9,000.00 µg/kg/day; no2 = 60.00 µg/kg/ day; br= 400.00 µg/kg/day; no3 = 370.00 µg/kg/ day; po4 2= 13,330.00 µg/kg/day; and so4 2= 8,330.00 µg/kg/day).26–32 although anions are vital to the human body, they can be toxic at excessive levels. sodium chloride is often added to tobacco blends to improve the flavour of the product and act as a preservative.2,10 however, high quantities of this compound may contribute to several disease mechanisms, including chronic inflammation, tumour promotion and cocarcinogenesis (mutations in the gastric epithelium).33 although the clcontent of afzal in the current study showed a high peak compared to other anions, it was below the recommended daily uptake.27 in the usa, stps were found to contain higher cllevels table 1: anion concentrations in afzal samples determined by ion-exchange chromatography afzal sample* anion levels in µg/g fluoride chloride nitrite bromide nitrate phosphate sulphate 1a 16.73 1,639.21 0.29 4.49 432.49 1.98 73.23 1b 16.67 1,639.71 nd nd 432.91 1.92 74.59 2a 17.11 1,677.85 0.36 4.30 447.34 1.77 75.06 2b 17.05 1,678.62 0.32 4.30 446.46 nd 76.59 3a 17.05 1,656.96 0.30 1.91 438.56 nd 76.05 3b 17.06 1,658.87 0.30 1.90 439.90 nd 75.12 mean concentration ± sd 16.95 ± 0.19 1,658.54 ± 17.36 0.31 ± 0.03 3.38 ± 1.35 439.61 ± 6.38 1.89 ± 0.11 75.11 ± 1.17 concentration 339.00 33,170.80 6.22 67.60 8,792.20 37.80 1,502.20 instrument detection limit in ppm 0.02 0.02 0.03 0.02 0.02 0.03 0.03 nd = not detected; sd = standard deviation; ppm = parts per million. *three afzal samples were tested, of which each was injected twice into the ion-exchange chromatography instrument (a and b). nawal m. al-mukhaini, taher a. ba-omar, elsadig a. eltayeb and aisha h. al-shehi clinical and basic research | e475 in the moist form (95,000.00 µg/g) than the dry form (23,100.00 µg/g); this finding was similar to the levels in moist snus sold in the usa at the same time.2 the reported clcontent in unused snus (35,300.00 µg/g) was close to that of afzal as observed in the current study (33,170.80 µg/g).19 quantities of swedish snus are well monitored as they are typically sold in 1.00 g tea bag-sized sachets;19 in contrast, afzal users usually self-determine doses (typically a pinch-sized amount per single dose ranging from 1.00–2.00 g) which are then repeated as desired.13 as a result, clconsumption will increase due to repeated afzal use during the day.16 few studies have investigated the other anions tested in this study (including f-, br-, so4 2and po4 2-). stepanov et al. analysed so4 2(4,560.00–12,300.00 µg/g) and po4 2(309.00–1,300.00 µg/g) levels in american stps; their findings were higher than anion levels indicated in the current study (1,502.20 µg/g and 37.80 µg/g, respectively).4 no3 is an endogenous component of tobacco which originates from the presence of inorganic fertilisers in the soil.34 in saliva, it is converted to no2 (the more toxic form) by the oral microflora and no3 reductase, leading to various toxic products such as methaemoglobin, which reduces oxygen transport and can lead to cyanosis.35,36 in addition, the formed no2 promotes the conversion into nitrosating agents which in turn facilitate the formation of endogenous tsnas from tobacco alkaloids and dietary amines.4 besides the oral reduction of no3 to no2 -, there is a natural endogenous formation of no3 processes in other areas of the gastrointestinal tract.12 the no3 content reported in unused snus (1,220.00 µg/g) was much lower than that of the afzal samples in the current study (8,792.20 µg/g).19 borgerding et al. reported that the no2 value of american stps was >20.00 μg/g, although hoffmann et al. have reported that values range much higher in moist snuff.2,37 stepanov et al. reported that newer stps generally contain <10 μg/g of no2 -.4 however, the no2 content of afzal found in the current study (6.22 µg/g) was below all of these levels, including the gothiatek® limits for snus (7.00 µg/g).38 nevertheless, afzal use is potentially harmful due its elevated no3 content which can be reduced in the body to no2 and subsequently to carcinogens (in the form of tsnas). critically, elevated no3 levels have been found to result in an increased risk of gastric cancer.39 many tobacco manufacturing companies are now attempting to produce stps with low no3 and no2 levels in order to reduce their toxicity and limit tsna formation during tobacco processing.4 conclusion afzal was analysed chemically for toxicants that enhance cancer formation. there was a surge in both nicotine and clcontent, with alarmingly elevated no3 levels. the levels of certain factors, including ph value, nicotine content and no3 -, were above those reported for other international stps, while the levels of cland moisture content were consistent and the levels of no2 -, so4 2and po4 2were below those found in other stps. all tested anions were below the maximum recommended daily intake advised by international organisations. however, the frequent use of afzal poses a health risk to users which may potentially manifest as cancer. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. world health organization international agency for research on cancer. iarc monographs on the evaluation of carcinogenic risks to humans: volume 89 smokeless tobacco and some tobacco-specific n-nitrosamines. from: www.monographs.iarc. fr/eng/monographs/vol89/mono89.pdf accessed: aug 2015. 2. borgerding mf, bodnar ja, curtin gm, swauger je. the chemical composition of smokeless tobacco: a survey of products sold in the united states in 2006 and 2007. regul toxicol pharmacol 2012; 64:367–87. doi: 10.1016/j. yrtph.2012.09.003. 3. national cancer institute. smoking and tobacco control monographs: monograph 2 smokeless tobacco or health: an international perspective. from: www.cancercontrol.cancer. gov/brp/tcrb/monographs/2/index.html accessed: aug 2015. 4. stepanov i, jensen j, hatsukami d, hecht ss. new and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. nicotine tob res 2008; 10:1773–82. doi: 10.1080/14622200802443544. 5. rickert ws, joza pj, trivedi ah, momin ra, wagstaff wg, lauterbach jh. chemical and toxicological characterization of commercial smokeless tobacco products available on the canadian market. regul toxicol pharmacol 2009; 53:121–33. doi: 10.1016/j.yrtph.2008.12.004. 6. zakiullah ms, saeed m, muhammad n, khan sa, gul f, khuda f, et al. assessment of potential toxicity of a smokeless tobacco product (naswar) available on the pakistani market. tob control 2012; 21:396–401. doi: 10.1136/tc.2010.042630. 7. prabhakar v, jayakrishnan g, nair sv, ranganathan b. determination of trace metals, moisture, ph and assessment of potential toxicity of selected smokeless tobacco products. indian j pharm sci 2013; 75:262–9. doi: 10.4103/0250474x.117398. 8. lauterbach jh, bao m, joza pj, rickert ws. free-base nicotine in tobacco products: part ii determination of free-base nicotine in the aqueous extracts of smokeless tobacco products and the relevance of these findings to product design parameters. regul toxicol pharm 2011; 59:8–18. doi: 10.1016/j. yrtph.2010.09.002. http://dx.doi.org/10.1016/j.yrtph.2012.09.003 http://dx.doi.org/10.1016/j.yrtph.2012.09.003 http://dx.doi.org/10.1080/14622200802443544 http://dx.doi.org/10.1016/j.yrtph.2008.12.004 http://dx.doi.org/10.1136/tc.2010.042630 http://dx.doi.org/10.4103/0250-474x.117398 http://dx.doi.org/10.4103/0250-474x.117398 http://dx.doi.org/10.1016/j.yrtph.2010.09.002 http://dx.doi.org/10.1016/j.yrtph.2010.09.002 9. tomar sl, henningfield je. review of the evidence that ph is a determinant of nicotine dosage from oral use of smokeless tobacco. tob control 1997; 6:219–25. doi: 10.1136/tc.6.3.219. 10. rutqvist le, curvall m, hassler t, ringberger t, wahlberg i. swedish snus and the gothiatek® standard. harm reduct j 2011; 8:11. doi: 10.1186/1477-7517-8-11. 11. ammigan n, nagabhushan m, nair uj, amonkar aj, bhide sv. effect of nutritional status on mutagenicity of urine excreted by rats treated with standard/experimental carcinogens. indian j exp biol 1990; 28:711–13. 12. hsu j, arcot j, lee na. nitrate and nitrite quantification from cured meat and vegetables and their estimated dietary intake in australians. food chem 2009; 115:334–9. doi: 10.1016/j. foodchem.2008.11.081. 13. al-mukhaini n, ba-omar t, eltayeb e, al-shehi a. determination of heavy metals in the common smokeless tobacco afzal in oman. sultan qaboos univ med j 2014; 14:e349–55. 14. centers for disease control and prevention. notice regarding requirement for annual submission of the quantity of nicotine contained in the smokeless tobacco products manufactured, imported, or packaged in the united states. fed regist 1999; 64:14086–96. 15. stanfill sb, connolly gn, zhang l, jia lt, henningfield je, richter p, et al. global surveillance of oral tobacco products: total nicotine, unionised nicotine and tobacco-specific n-nitrosamines. tob control 2011; 20:e2. doi: 10.1136/ tc.2010.037465. 16. lawler ts, stanfill sb, zhang l, ashley dl, watson ch. chemical characterization of domestic oral tobacco products: total nicotine, ph, unprotonated nicotine and tobaccospecific n-nitrosamines. food chem toxicol 2013: 57:380–6. doi: 10.1016/j.fct.2013.03.011. 17. centers for disease control and prevention. laboratory protocol to measure the quantity of nicotine contained in smokeless tobacco products manufactured, imported, or packaged in the united states. federal register 2009; 62:24116–19. 18. hearn ba, renner cc, ding ys, vaughan-watson c, stanfill sb, zhang l, et al. chemical analysis of alaskan iq’mik smokeless tobacco. nicotine tob res 2013; 15:1283–8. doi: 10.1093/ntr/nts270. 19. digard h, gale n, errington g, peters n, mcadam k. multianalyte approach for determining the extraction of tobacco constituents from pouched snus by consumers during use. chem cent j 2013; 7:55. doi: 10.1186/1752-153x-7-55. 20. bhisey ra. chemistry and toxicology of smokeless tobacco. indian j cancer 2012; 49: 364–72. doi: 10.4103/0019-509x. 107735. 21. henningfield je, radzius a, cone ej. estimation of available nicotine content of six smokeless tobacco products. tob control 1995; 4:57–61. doi: 10.1136/tc.4.1.57. 22. dani ja, heinemann s. molecular and cellular aspects of nicotine abuse. neuron 1996; 16:905–8. doi: 10.1016/s08966273(00)80112-9. 23. benowitz nl. nicotine and smokeless tobacco. ca cancer j clin 1988; 38:244–7. doi: 10.3322/canjclin.38.4.244. 24. idris am, ibrahim so, vasstrand en, johannessen ac, lillehaug jr, magnusson b, et al. the swedish snus and the sudanese toombak: are they different? oral oncol 1998; 34:558–66. doi: 10.1016/s1368-8375(98)00047-5. 25. wallström m. harm and harm reduction in smokeless tobacco users. an in vitro and clinical study. from: gupea.ub.gu.se/ handle/2077/23719 accessed: aug 2015. 26. world health organization. environmental health criteria 36: fluorine and fluorides. from: www.inchem.org/documents/ ehc/ehc/ehc36.htm accessed: aug 2015. 27. world health organization. chloride in drinking-water: background document for development of who guidelines for drinking-water quality. from: www.who.int/water_sanitation_ health/dwq/chloride.pdf accessed: aug 2015. 28. european commission. reports of the scientific committee for food (thirty-eighth series): opinions of the scientific committee for food on nitrates and nitrite. from: ec.europa. eu/food/safety/docs/labelling_nutrition-special_groups_foodchildren-scf_reports_38_en.pdf accessed: aug 2015. 29. reinik m, tamme t, roasto m, juhkam k, jurtsenko s, tenńo t, et al. nitrites, nitrates and n-nitrosoamines in estonian cured meat products: intake by estonian children and adolescents. food addit contam 2005; 22:1098–105. doi: 10.1080/02652030500241827. 30. food and agriculture organization of the united nations and world health organization. bromide ion. from: www. i n c h e m . o r g / d o c u m e n t s / j m p r / j m p m o n o / v 8 8 p r 0 3 . h t m accessed: aug 2015. 31. national research council. recommended dietary allowances. 10th ed. washington, usa: national academy press, 1989. pp. 186. 32. world health organization. sulfate in drinking water: background document for development of who guidelines for drinking-water quality. from: www.who.int/water_sanitation_ health/dwq/chemicals/sulfate.pdf accessed: aug 2015. 33. takahashi m, nishikawa a, furukawa f, enami t, hasegawa t, hayashi y. dose-dependent promoting effects of sodium chloride (naci) on rat glandular stomach carcinogenesis initiated with n-methyl-n’-nitro-n-nitrosoguanidine. carcinogenesis 1994; 15:1429–32. doi: 10.1093/carcin/15.7.1429. 34. world health organization. nitrate and nitrite in drinking water: background document for development of who guidelines for drinking-water wuality. from: www.who.int/water_ sanitation_health/dwq/chemicals/nitratenitrite2ndadd.pdf accessed: aug 2015. 35. gangolli sd, van den brandt p, feron vj, janzowsky c, koeman jh, speijers gj, et al. nitrate, nitrite and n-nitroso compounds. eur j pharmacol 1994; 292:1–38. doi: 10.1016/0926-6917(94)90022-1. 36. jaffé er. methaemoglobinaemia in the differential diagnosis of cyanosis. hosp pract (off ed) 1985; 20:92–6. 37. hoffmann d, djordjevic mv, fan j, zang e, glynn t, connolly gn. five leading u.s. commercial brands of moist snuff in 1994: assessment of carcinogenic n-nitrosamines. j natl cancer inst 1995; 87:1862–9. doi: 10.1093/jnci/87.24.1862. 38. swedish match. gothiatek® standard: gothiatek® limits for undesired components. from: www.swedishmatch.com/ en/snus-and-health/gothiatek/gothiatek-standard/ accessed: aug 2015. 39. joossens jv, hill mj, elliott p, stamler r, lesaffre e, dyer a, et al. dietary salt, nitrate and stomach cancer mortality in 24 countries: euopean cancer prevention (ecp) and the intersalt cooperative research group. int j epidemiol 1996; 25:494–504. doi: 10.1093/ije/25.3.494. http://dx.doi.org/10.1136/tc.6.3.219 http://dx.doi.org/10.1186/1477-7517-8-11 http://dx.doi.org/10.1016/j.foodchem.2008.11.081 http://dx.doi.org/10.1016/j.foodchem.2008.11.081 http://dx.doi.org/10.1136/tc.2010.037465 http://dx.doi.org/10.1136/tc.2010.037465 http://dx.doi.org/10.1016/j.fct.2013.03.011 http://dx.doi.org/10.1093/ntr/nts270 http://dx.doi.org/10.1186/1752-153x-7-55 http://dx.doi.org/10.4103/0019-509x.107735 http://dx.doi.org/10.4103/0019-509x.107735 http://dx.doi.org/10.1136/tc.4.1.57 http://dx.doi.org/10.1016/s0896-6273%2800%2980112-9 http://dx.doi.org/10.1016/s0896-6273%2800%2980112-9 http://dx.doi.org/10.3322/canjclin.38.4.244 http://dx.doi.org/10.1016/s1368-8375%2898%2900047-5 http://dx.doi.org/10.1080/02652030500241827 http://dx.doi.org/10.1093/carcin/15.7.1429 http://dx.doi.org/10.1016/0926-6917%2894%2990022-1 http://dx.doi.org/10.1016/0926-6917%2894%2990022-1 http://dx.doi.org/10.1093/jnci/87.24.1862 http://dx.doi.org/10.1093/ije/25.3.494 sultan qaboos university med j, november 2014, vol. 14, iss. 4, pp. e455−459, epub. 14th oct 14 submitted 3rd jul 14 revision req. 18th aug 14; revision recd. 20th aug 14 accepted 28th aug 14 between the earliest recorded greek and roman philosophical theories of medicine and the dynamic spurt in medical discoveries in western civilizations from the 17th century onwards lies an era of relative obscurity in medical advancements, running parallel with the islamic conquest of europe; an era which deserves due recognition. from the 8th to 16th centuries a.d., islamic physician-philosophers revived the hippocratic philosophy that based disease causation on bodily ‘humors’. political patronage promoted these efforts: one excellent example is that of chosroes i (also known as khusraw) in the 6th century, who sent the persian zoroastrian doctor, perzhoe, to distant lands like india to learn both philosophy and medicine so as to enrich the lives of the people in his empire.2 the preeminence of medical men was recorded by persian littérateurs who held three types of respected society members to be at par: the physician, the ruler (amir) and the scholar.3 lost in the shroud of history is the less acknowledged establishment of the first ‘bimaristans’ (persian = hospitals for the diseased), noteworthy for being the first formal centres dedicated to the practice of academic medicine. one institution founded at jundi-shapur (persian = “beautiful garden”; once located in south-west persia and now in ruins) has secured its place in history due to the belief that harith bin kalada, the prophet mohammed’s physician, was trained there.4 the arab model of hospitals (remarkably organised into both fixed and mobile units) became the forerunner for european hospitals in later centuries. as the lingua franca of the medieval islamic period, the arabic language anchored the translations of greek and roman medical texts which would otherwise have been doomed to obscurity.5 from alandalusia (modern day southern spain) this fount of knowledge found its way back into european medicine in the second millennium. the history of islamic traditional medicine during the golden period of islamic civilisation lists a compendium of prominent scholars, including al-razi, avicenna (also known as ibn-sina), ibn al-nafis, al-taberi, al-magusi, al-baitar, al-zahrawi, ibn-haitam, ibn-zuhr and ibn-rushd.6,7 this article revisits the extraordinary contributions of the first three of these eminent physicians of islamic medicine. these ‘chosen’ few not only feature prominently in recorded accounts of the period but share the common legacy of being prolific medical writers, free thinkers and achievers in multiple fields, including philosophy, medicine, astrology, maths and poetry. succeeding one another over three centuries, al-razi laid the foundations of islamic medical thought, avicenna’s medical writings were undisputed for centuries and ibn al-nafis established unique concepts of cardiopulmonary circulation. they represent a rich academic heritage whose impressive credentials are shared by many of their peers who will earn their place in subsequent writings on the subject. al-razi (rhazes): the father of islamic medicine 8 mohammed ibn zakariya al-razi (latin = rhazes), was a persian physician-philosopher (865–925 a.d.),8 well-versed in such diverse disciplines as music and alchemy.9 he was also a devout muslim who distinguished his medical practice by placing an emphasis on reasoning as opposed to blindly department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman corresponding author e-mail: ritu@squ.edu.om ثالثة من مناذج الطب اإلسالمي يف القرون الوسطى الرازي، ابن سينا، وابن النفيس ريتو لكتاكيا medical history a trio of exemplars of medieval islamic medicine al-razi, avicenna and ibn al-nafis ritu lakhtakia it is a muslim history that had been more intellectually accomplished than christian europe of the day, and a muslim past where christians, jews, hindus and buddhists had flourished and worked together.1 a trio of exemplars of medieval islamic medicine al-razi, avicenna and ibn al-nafis e456 | squ medical journal, november 2014, volume 14, issue 4 following scripture.9 this free-thinking spirit coloured his medical practice and writings. long before geographical boundaries separated modern day iraq and iran, al-razi was sought after as a physician both in his birthplace rayy (near tehran, iran) and baghdad (iraq). a seminal feature of his genius was his acknowledgement of the wisdom of the greeks and romans balanced by relevant critique and correction when this wisdom was proved otherwise by his own observations and considerable experience, as expressed in his book shukuk ala alinusor (persian = “doubts about galen”).9 a prolific writer, a host of al-razi’s voluminous recordings provide insight into his thought and operational techniques. in akhlaq-al-tabib (persian = “medical ethics”), he stressed the triumvirate of ethical responsibility—the physician to his patient, the patient to his physician and the physician to himself.8 al-razi and his peer al-ruhawi, who authored adab al tabib, are credited with laying the foundations of medical ethics;10 assimilating hellenistic knowledge with unique insights from islamic teachings a millennium before modern western ethical medical principles were recorded. in a series of essays, al-razi explored the tenuous trust between physician and patients; one interesting title among his essays reads the reasons for people’s preference of inferior physicians.9 a pioneer in medical education, he taught his pupils the art of imparting knowledge: “when you find that conscientious individual who enjoys your confidence, who is not easily moved by whim, and accepts the truth satisfactorily and honestly, he will ask you for its contents, gradually cognisant of the sequence from the precedent”.11 his paradigm of an ethical physician, which was based on characteristics such as appearance, voice modulation, virtuosity, behaviour as a role model and a life-long desire to update their knowledge, resonate with our current 21st century ideas of professionalism. confidentiality, empathy and psychological counselling were to him essential ingredients for healing and ethical practice. it is remarkable that he made special mention of the social nuances of medical ethics by exhorting physicians to treat rich and poor alike and to treat women with respect.10 the kitab al-hawi fi al-tibb (persian = “the comprehensive book of medicine”), also known as continens liber (latin) and the virtuous life (english), conveyed its encyclopaedic knowledge in over 23 volumes covering the causes and manifestations of diseases in different systems.12 this book would sustain generations of medical students over the following centuries. the oldest recorded copy of part of this treatise covers gastrointestinal diseases and is preserved in the united states national library of medicine.13 political patronage, an important incentive for scientific productivity, ensured the contribution of the samanid prince abu salih al-mansur ibn ishaq (10th century) to his 10-volume epic al-mansuri, complementing the kitab al-hawi fi al-tibb as a reference in medical teaching. his appreciation of the role of overconsumption by the affluent class (with its accompanying ills and dietary remedies) is well chronicled in the kitab al-hawi fi al-tibb. al-razi was apparently the first to attribute hay fever to the smell of roses at springtime in his manual on coryza (rhinitis).13 stones of the kidney and bladder, small pox and measles were some of the specific diseases on which he wrote extensively.9 he also described the valves of the heart.14,15 avicenna (ibn sina): the arab galen 11,16 abu ali al hussein ibn abdulla ibn sina (980–1037 a.d.), a persian scholar, was born in afshaneh, bokhara (part of the persian empire then and now in present-day uzbeikistan) [figure 1].17 referred to in western records as avicenna, this pioneer of islamic medicine (who was also a poet, politician, philosopher and mathematician) has his name etched in the annals figure 1: portrait of avicenna.17 figure reproduced with permission from wellcome images. ritu lakhtakia medical history | e457 inclusivity, expounding on a wide range of subjects from structure-function relationships and causes of disease to therapy and lifestyle choices. a good example is volume three which gives detailed accounts of neuroanatomy, neurological and neuropsychiatric disorders, history, signs and symptoms.21,22 this inclusivity and level of detail explains the influence this opus has had for centuries. the depth of observation and logic are illustrated within this volume in the section detailing an impressive 15 types of headaches and simple remedies to alleviate them. this labour of love constructed over twelve years (1012–1024) lays the foundation of the scientific method, which was unusual for the times. it is the opinion of the author that avicenna’s pronouncements on the psychological and organic causation of ulcers and the curability of superficial versus deep cancers are validated in contemporary medical knowledge. a teacher par excellence, he distilled the essence of his medical knowledge in a poem called al-urjuzah fi al-tibb (arabic = “the medical poem”) which is a fine illustration of inspiring pupils of medicine through the humanities. readers are exhorted to refer to an eloquent appraisal of this poem in a recent review.23 avicenna’s legacy is alive today through the establishment of an award by the united nations educational, scientific and cultural organization in 2002, titled the avicenna prize for ethics in science.22 it is noteworthy that the second recipient of this award was dr. abdallah daar, an omani academic associated with the sultan qaboos university in muscat, oman.24 avicenna’s name finds mention in the avicenna directory of medical schools maintained by the world federation for medical education and the foundation for advancement of international medical education and research in collaboration with the university of copenhagen and the world health organization. in 2014, this directory was merged with the international medical education directory to create the world directory of medical schools. the avicenna journal of medicine and the avicenna journal of medical biotechnology honour his timeless contributions. this ‘prince of physicians’ lives on in the 21st century through his inspirational heritage. ibn al-nafis: the second avicenna 15 a 13th century syrian physician, alauddin ibn al-nafis (1210–1288 a.d.) trained at one of the scholarly centres of medicine, the al-nasiri hospital in damascus.25 at a youthful 29 years of age, he authored the commentary on anatomy in avicenna’s canon, questioning galen’s view that blood flow was directed from the right to the of medical history. a child prodigy, he received timely patronage to pursue his studies when he treated a prince of the samanid dynasty. in a twist of fortunes, he later suffered imprisonment for his political stance. western writings refer to him as ‘the aristotle of islam’.18 a prolific writer, whose repertoire spanned philosophy, religion, medicine, astronomy and natural sciences, avicenna made seminal contributions to medicine with al shifa (arabic = “the book of healing for the soul”) and the qanun fil tibb (arabic = “the canon of medicine for the body”) [figure 2],19 among the 300 or so books he is known to have authored.16,20 his dedication to science without boundaries is reflected in his painstaking preservation for posterity of the knowledge accrued from aristotle and ptolemy in the first, and of galen in the second of the two aforementioned books. to this heritage he applied his own appreciation of science derived through islamic culture and practices. it is interesting to note that under the shadow of turbulent times the canon was written in arabic and not in persian. the canon was translated into latin by gerardo de cremona in the 13th century and dominated medical curriculum in european universities until the 17th century,20 earning the accolade of ‘the most famous medical textbook ever written’ by sir william osler.21 the expansive five volumes are remarkable in their figure 2: the title page of the canon of medicine.19 figure reproduced with permission from the royal college of physicians of edinburgh. a trio of exemplars of medieval islamic medicine al-razi, avicenna and ibn al-nafis e458 | squ medical journal, november 2014, volume 14, issue 4 left ventricle through the septum, pithily remarking that “the septum between the two ventricles is of thicker substance than other parts”.25 he proposed instead that the right ventricular blood travelled through the pulmonary circulatory system before reaching the left side of the heart. this revolutionary idea was reiterated by michael servetus (1511– 1533), who was burnt at the stake for this and other pronouncements that were declared as heresies by the church, and predated william harvey’s supposed ‘discovery’ of the circulation system by seven centuries. ibn al-nafis went on to coin the term manafidh (arabic = pores) for the communications between the pulmonary venous and arterial circulations (which we recognise today as the pulmonary capillary bed). he is, appropriately, recognised by many to be the ‘father of circulatory physiology’.25,26 ibn al-nafis also described the coronary circulatory system, stipulating that the heart could not draw its perfusion directly from the blood in its chambers.15 among several other compositions, his kitab al-mujaz fi al-tibb was a valuable handbook for medical students.27 his authoritative observations of anatomy and physiology are unlikely to have been founded on human dissections, as his grounding in shari’a law would have dictated otherwise.28 other authors refute this conclusion, citing the prevalent practice of using the corpses of criminals to study disease as well as the strong belief among muslims that anyone who undertook dissection was also increasing their faith in god, as underscored by the muslim philosopher-physician averroes (1149– 1209).29 however there is ample evidence that the strong traditions of evidence-based medicine supported by experimentation, initiated by al-razi, are echoed time and time again in the works of avicenna and ibn al-nafis. these included the rational recording and analysis of case histories, case-controlled testing of therapeutic procedures, drug potency trials and even animal experimentation.30 lessons from the exemplars of islamic medicine al-razi, avicenna and ibn al-nafis’ lives enriched the medical fraternity and their patients through their philosophical insights, excellence in medical practice and the arduous scholarly preservation and assimilation of medical knowledge in their writings. individually, they are remembered best for their ground-breaking contribution to ethics (al-razi), medical teaching (avicenna) and experimental research (ibn al-nafis). the richness of islamic civilisation nourished and promoted medical advancement. political endowments nurtured scientific effort; political antagonism could diminish productivity or inhibit free thought. the enormous impact of the triumvirate who dominate this article originated in their willingness to draw from the wisdom of others—hellenic, roman and indian medical lore—and then to review and critique this wisdom, aided by their own experimentation and observations. in turn, their prodigious written records and later translations laid the foundations on which medicine was to thrive in the renaissance period. today, when the globalisation of medicine brings with it the virtue of enhanced access to knowledge and the contrasting vices of patents and secrecy, al-razi and his contemporaries remind us of the necessity of freely sharing knowledge for the benefit of humanity. their vital principles of scientific thought and ethics were ideas well before their time. these luminaries of the islamic golden age were distinguished polymaths, integrating the sciences and humanities, and providing a vision of health and life beyond the narrow field of medical practice. references 1. morgan mh. lost history: the enduring legacy of muslim scientists, thinkers, and artists. washington d.c., usa: national geographic society, 2007. pp. xx111–iv. 2. meletis j, konstantopoulos k. the beliefs, myths, and reality surrounding the word hema (blood) from homer to the present. anemia 2010; 2010:857657. doi: 10.1155/2010/857657. 3. kolahdouzan a, vahabi f. medicinal behavior in persian literature by emphasis on ibn-sina popular literature. mat sociomed 2013; 25:70–1. doi: 10.5455/msm.2013.25.70-71. 4. miller ac. jundi-shapur, bimaristans, and the rise of academic medical centres. j r soc med 2006; 99:615–17. 5. batirel hf. early islamic physicians and thorax. ann thorac surg 1999; 67:578–80. doi: 10.1016/s0003-4975(98)01295-8. 6. masić i, konjhodzić f. [great arab physician-practitioners]. med arh 1994; 48:79–84. 7. kelishadi r, hatami h. avicenna as the forerunner of preventive medicine: on the occasion of 1032nd birth anniversary of avicenna (22 august 980). int j prev med 2012; 3:517–19. 8. karaman h. abu bakr al-razi (rhazes) and medical ethics. ondokuz mayis univ rev faculty divinity 2011; 30:77–87. 9. islamic philosophy online inc., philosophia islamica. al-razi (rhazes). from: www.muslimphilosophy.com/ei2/razi.htm accessed: jun 2014. 10. chamsi-pasha h, albar ma. islamic medical ethics a thousand years ago. saudi med j 2013; 34:673–5. 11. sa’di lm. glimpses into the history of arabic medicine. bull med libr assoc 1958; 46:206–18. 12. world digital library. the comprehensive book on medicine. from: www.wdl.org/en/item/7458/ accessed: jun 2014. 13. united states national library of medicine. islamic culture and the medical arts: al-razi, the clinician. from: www.nlm. nih.gov/exhibition/islamic_medical/islamic_06.html accessed: jun 2014. ritu lakhtakia medical history | e459 23. abdel-halim rel-s. the role of ibn sina (avicenna)’s medical poem in the transmission of medical knowledge to medieval europe. urol ann 2014; 6:1–12. doi: 10.4103/0974-7796.127010. 24. united nations educational, scientific and cultural organization.avicenna prize for ethics in science. from: www. unesco.org/new/en/social-and-human-sciences/events/prizesand-celebrations/unesco-prizes/avicenna-prize/ accessed: aug 2014. 25. west jb. ibn al-nafis, the pulmonary circulation, and the islamic golden age. j appl physiol (1985) 2008; 105:1877–80. doi: 10.1152/japplphysiol.91171.2008. 26. hehmeyer i, khan a. islam’s forgotten contributions to medical science. cmaj 2007; 176:1467–8. doi: 10.1503/cmaj.061464. 27. abdel-halim re. contributions of ibn al-nafis (1210-1288 ad) to the progress of medicine and urology: a study and translations from his medical works. saudi med j 2008; 29:13– 22. 28. savage-smith e. attitudes toward dissection in medieval islam. j hist med allied sci 1995; 50:67–110. doi: 10.1093/ jhmas/50.1.67. 29. shoja mm, tubbs rs. the history of anatomy in persia. j anat 2007; 210:359–78. doi: 10.1111/j.1469-7580.2007.00711.x. 30. abdel-halim re. experimental medicine 1000 years ago. urol ann 2011; 3:55–61. doi: 10.4103/0974-7796.82168. 14. azizi mh, nayernouri t, azizi f. a brief history of the discovery of the circulation of blood in the human body. arch iran med 2008; 11:345–50. doi: 08113/aim.0022. 15. masic i, dilic m, solakovic e, rustempasic n, ridjanovic z. why historians of medicine called ibn al-nafis second avicenna? med arh 2008; 62:244–9. 16. aburawi eh. the great professor ibnosina (avicenna). libyan j med 2007; 2:116–17. doi: 10.4176/070515. 17. james lind library. ibn sīnā (c.1012 ce; c.402 ah) portraits. from: www.jameslindlibrary.org/illustrating/records/kitab-alqanun-fi-al-tibb-avicennas-the-canon-of-medicine/portraits accessed: aug 2014. 18. golzari se, khan zh, ghabili k, hosseinzadeh h, soleimanpour h, azarfarin r, et al. contributions of medieval islamic physicians to the history of tracheostomy. anesth analg 2013; 116:1123–32. doi: 10.1213/ane.0b013e3182884313. 19. james lind library. ibn sīnā (c.1012 ce; c.402 ah) title page(s). from: www.jameslindlibrary.org/illustrating/records/ kitab-al-qanun-fi-al-tibb-avicennas-the-canon-of-medicine/ title_pages accessed: aug 2014. 20. masic i. thousand-year anniversary of the historical book: “kitab al-qanun fit-tibb” the canon of medicine, written by abdullah ibn sina. j res med sci 2012; 17:993–1000. 21. mannan aa, kahvic m. ibn sina: a tribute. gulf j oncolog 2010; 7:60–3. 22. zargaran a, mehdizadeh a, zarshenas mm, mohagheghzadeh a. avicenna (980-1037 ad). j neurol 2012; 259:389–90. doi: 10.1007/s00415-011-6219-2. e254 | retraction notice إشعار عن تراجع املعارف املتعلقة بالسكري واملمارسات الوقائية بني املوظفني احلكوميني املصابني بالسكري يف الكويت retraction notice retraction notice diabetes-related knowledge and preventative practices among government employees with diabetes in kuwait the editors of sultan qaboos university medical journal (squmj), in association with the authors, have retracted the above article by abdulsalam et al. which appeared in the november 2017 issue of squmj.1 the article was retracted because the editors were informed by the first and corresponding author that the authors did not have the necessary ethical approval to conduct the study. in the article published in the november 2017 issue of squmj, the ethical approval statement affirmed that “this study was approved by the kuwait ministry of health and the ethical committee of the kuwait institute for scientific research”. however, in may 2018, the editors were informed by the first and corresponding author that, upon retrospective investigation, the appropriate ethical approval procedures had not been undertaken and ethical permission had not been granted by the kuwait ministry of health or the kuwait institute for scientific research. in accordance with the recommendations and guidelines of the international committee of medical journal editors and the committee on publication ethics, this constitutes grounds for retraction of the published article.2,3 for the reasons stated herein, the editors of squmj wish to notify readers that the above article is retracted.1 the authors have agreed to the publication of this notice and apologise sincerely to both the editors and readers of squmj for any inconvenience caused. the authors take joint responsibility for this notice as well as for the publication of research lacking ethical approval. references 1. abdulsalam aj, al-daihani ae, francis k. diabetes-related knowledge and preventative practices among government employees with diabetes in kuwait. sultan qaboos univ med j 2017; 17:e444–51. doi: 10.18295/squmj.2017.17.04.011. 2. international committee of medical journal editors. scientific misconduct, expressions of concern, and retraction. from: www.icmje.org/ recommendations/browse/publishing-and-editorial-issues/scientific-misconduct-expressions-of-concern-and-retraction.html accessed: may 2018. 3. committee on publication ethics. guidelines for retracting articles. from: https://publicationethics.org/files/retraction%20guidelines_0.pdf accessed: may 2018. notice of retraction for: abdulsalam et al. diabetes-related knowledge and preventative practices among government employees with diabetes in kuwait. sultan qaboos univ med j 2017; 17:e444–51. doi: 10.18295/squmj.2017.17.04.011. sultan qaboos university med j, may 2018, vol. 18, iss. 2, p. e254, epub. 9 sep 18 doi: 10.18295/squmj.2018.18.02.028 https://doi.org/10.18295/squmj.2017.17.04.011 1general surgery residency programme, oman medical specialty board, muscat, oman; 2college of medicine & health sciences, sultan qaboos university; 3department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: kadhim.lawati@gmail.com توزيع مرافق الرعاية الصحية للمصابني يف عمان فيما يتعلق مبواقع إصابات حوادث املرور املرتفعة دراسة جتريبية �صارة الكندية، اأحمد اأ�رشف نعيم، كاظم م�صطفى تقي، جنالء الغيثية، اختيار التوبية، ن�رشة قا�صم البو�صعيدية، اأحمد زاهر احلارثي، عالء م�صطفى تقي، �رشيف باعلوي، هاين اأحمد القا�صي abstract: objectives: road traffic injuries (rtis) are considered a major public health problem worldwide. in oman, high numbers of rtis and rti-related deaths are frequently registered. this study aimed to evaluate the distribution of trauma care facilities in oman with regards to their proximity to rti-prevalent areas. methods: this descriptive pilot study analysed rti data recorded in the national royal oman police registry from january to december 2014. the distribution of trauma care facilities was analysed by calculating distances between areas of peak rti incidence and the closest trauma centre using google earth and google maps software (google inc., googleplex, mountain view, california, usa). results: a total of 32 trauma care facilities were identified. four facilities (12.5%) were categorised as class v trauma centres. of the facilities in muscat, 42.9% were ranked as class iv or v. there were no class iv or v facilities in musandam, al-wusta or al-buraimi. general surgery, orthopaedic surgery and neurosurgery services were available in 68.8%, 59.3% and 12.5% of the centres, respectively. emergency services were available in 75.0% of the facilities. intensive care units were available in 11 facilities, with four located in muscat. the mean distance between a rti hotspot and the nearest trauma care facility was 34.7 km; however, the mean distance to the nearest class iv or v facility was 83.3 km. conclusion: the distribution and quality of trauma care facilities in oman needs modification. it is recommended that certain centres upgrade their levels of trauma care in order to reduce rti-associated morbidity and mortality in oman. keywords: traffic accidents; motor vehicles; trauma centers; public health; emergency medical services; oman. امللخ�ص: الهدف: تعترب الإ�صابات الناجمة عن حوادث الطرق اأحد امل�صاكل ال�صحية الرئي�صية يف جميع اأنحاء العامل. يتم ت�صجيل العديد من حالت الإ�صابة و الوفيات الناجمة عن حوادث الطرق يف عمان. هدفت هذه الدرا�صة اإىل تقييم توزيع مرافق الرعاية ال�صحية مل�صابي الدرا�صة هذه ت�صمل الطرق. الطريقة: حوادث اإ�صابات من عالية ن�صب بها التي املناطق من بقربها يتعلق فيما عمان يف الطرق حوادث كانون من الفرتة يف ال�صلطانية عمان ل�رشطة الوطني ال�صجل يف امل�صجلة املرور حوادث اإ�صابات بيانات حتليل الو�صفية التجريبية الثاين/يناير اإىل كانون الأول/دي�صمرب من العام 2014. وقد مت حتليل توزيع مرافق الرعاية ال�صحية مل�صابي احلوادث عن طريق ح�صاب امل�صافات بني مناطق الذروة يف اإ�صابات حوادث الطرق واأقرب مرفق �صحي لرعاية امل�صابني با�صتخدام برنامج جوجل اإيرث وبرنامج ما على الدرا�صة ا�صتملت النتائج: الأمريكية(. املتحدة الوليات كاليفورنيا، فيو، ماونتني جوجلبليك�ض، جوجل، )�رشكة ماب�ض. جوجل م�صابي لرعاية اخلام�صة الدرجة من كمرافق )12.5%( مرافق اأربعة ت�صنيف مت احلوادث. م�صابي لرعاية �صحيًا مرفقًا 32 جمموعه احلوادث. مت ت�صنيف )%42.9( من املرافق املوجودة يف حمافظة م�صقط �صمن الدرجة الرابعة واخلام�صة. مل تكن هناك اأي مرافق من الدرجة الرابعة اأو اخلام�صة يف حمافظات م�صندم والو�صطى والربميي. توفرت اأق�صام اجلراحة العامة وجراحة العظام وجراحة املخ والأع�صاب يف ما ن�صبته %68.8، %59.3 و %12.5 من املرافق ال�صحية على التوايل. ويف املقابل توفرت خدمات الطوارئ يف ما ن�صبته %75.0 منها. اأما بالن�صبة خلدمة العناية املركزة فتوفرت فقط يف 11 مرفقًا �صحيًا، اأربعة من هذه املرافق تقع يف حمافظة م�صقط. متو�صط امل�صافة بني نقاط الذروة يف اإ�صابات حوادث الطرق واأقرب مرفق �صحي لرعاية امل�صابني كانت 34.7 كيلومرتاً، غري اأن متو�صط امل�صافة اإىل اأقرب مرفق �صحي لرعاية م�صابي احلوادث من الدرجتني الرابعة واخلام�صة كان 83.3 كيلومرتاَ. اخلال�صة: حتتاج مرافق الرعاية ال�صحية مل�صابي احلوادث يف عمان اإىل تعديالت من ناحية التوزيع اجلغرايف وتوافر نوعية اخلدمات ال�صحية. ومن هذا املنطلق نو�صي برفع م�صتويات بع�ض مرافق الرعاية ال�صحية مل�صابي احلوادث من اأجل احلد من الإ�صابات الناجمة عن حوادث الطرق والوفيات املرتبطة بها يف عمان. الكلمات املفتاحية: حوادث الطرق؛ ال�صيارات؛ مرافق الرعاية ال�صحية مل�صابي احلوادث؛ ال�صحة العامة؛ خدمة الإ�صعاف الطبي؛ عمان. distribution of trauma care facilities in oman in relation to high-incidence road traffic injury sites pilot study sara m. al-kindi,1 ahmed a. naiem,1 *kadhim m. taqi,1 najla m. al-gheiti,1 ikhtiyar s. al-toobi,1 nasra q. al-busaidi,1 ahmed z. al-harthy,1 alaa m. taqi,2 sharif a. ba-alawi,2 hani a. al-qadhi3 clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e430–435, epub. 10 jan 18 submitted 15 mar 17 revisions req. 24 apr & 14 jun 17; revisions recd. 23 may & 17 jun 17 accepted 13 jul 17 doi: 10.18295/squmj.2017.17.04.009 sara m. al-kindi, ahmed a. naiem, kadhim m. taqi, najla m. al-gheiti, ikhtiyar s. al-toobi, nasra q. al-busaidi, ahmed z. al-harthy, alaa m. taqi, sharif a. ba-alawi and hani a. al-qadhi clinical and basic research | e431 trauma represents a major yet preventable health burden worldwide; in particular, the world health organization (who) identifies road traffic injuries (rti) to be a major public health problem, with over a million people killed due to rtis annually.1 by 2020, this number is expected to increase by 65% and 80% in higherand lower-income countries, respectively.1,2 a major factor in preventing rti-related deaths is the rapid transfer of victims to a trauma care centre within 60 minutes of the incident, also known as the “golden hour”.3–5 therefore, ensuring the regional availability of trauma care facilities can be tremendously beneficial. many methods have been suggested to identify shortcomings in national trauma care systems and their structure in order to improve survival for trauma victims, including estimating the distance between high-incidence rti sites and trauma care centres, which can help in the planning of future trauma centres and when improving the existing infrastructure.4,6 in oman, rtis account for high mortality and morbidity; in 2013, the ministry of health (moh) reported 646 rti-related deaths on arrival (doas) to hospitals or prior to admission.7 in addition, 68.4% of inpatient deaths at moh-affiliated hospitals were attributed to rtis in 2013, with more than twothirds of the deaths occurring among individuals aged 15–44 years old.7 geographically, oman is divided into 11 administrative governorates extending over an area of 309,500 km2, with each governorate subdivided into smaller wilayats [figure 1]. the governorate with the highest population density is muscat, the capital city; however, only 7.3% of rti-related doas in 2013 were reported to have occurred in this region.7,8 in contrast, al-batinah north and al-dakhiliyah accounted for the highest number of doas (18.7% each); these governorates have estimated populations of 772,590 and 336,651 individuals, respectively. the lowest number of doas was reported in musandam (0.2%), which has an estimated population of 31,425 individuals.7,8 according to the who, oman is considered a high-income country with good death registration data.1 in 2010, the who reported 820 rti-related deaths in oman, with estimates of permanent disability set at 1.4%.1 to the best of the authors’ knowledge, no study has yet evaluated the accessibility and quality of trauma care facilities in oman with regards to known sites of rtis. therefore, the purpose of this pilot study was to evaluate the distribution of trauma centres in oman and their proximity to rti-prevalent areas in order to lay the groundwork for future analyses. methods this descriptive pilot study was performed between january and december 2014. existing healthcare facilities in oman which provided care to trauma victims during this period as well as the number of victims presenting to different healthcare facilities by governorate were identified from multiple sources at the moh.7,9 identified trauma centres were broadly advances in knowledge the current study found that the mean distance between a road traffic injury (rti) hotspot and the nearest trauma care facility in oman was 34.7 km; moreover, rti hotspots were a mean distance of 83.3 km away from the nearest class iv or v facility. the majority of class iv and v trauma care facilities in oman were found to be located in muscat, with such facilities entirely lacking in certain other governorates. application to patient care the findings of the current study suggest that the distribution and quality of trauma care facilities in oman is inadequate. upgrading existing trauma care facilities in certain locations and building new trauma centres closer to known rti hotspots may help to decrease morbidity and mortality associated with rtis. figure 1: geographical map of oman showing the administrative division of governorates. map created using scribble maps software (52 stairs studio inc., windsor, ontario, canada). distribution of trauma care facilities in oman in relation to high-incidence road traffic injury sites pilot study e432 | squ medical journal, november 2017, volume 17, issue 4 categorised based on the classifications of the american college of surgeons committee on trauma (acscot), which classifies trauma care facilities based on their capacity to treat trauma patients, the volume of cases they can accommodate and their educational and research commitments in the field of trauma.10 unfortunately, it was not possible to utilise the exact acscot classifications as certain prerequisites were not applicable to trauma care facilities in oman. instead, the trauma care facilities were similarly divided into five classes based on the provision of various surgical and medical services, with class v indicating the highest level of care offered and class i the lowest [table 1]. subsequently, data on all rtis occurring in oman during the study period were obtained from the royal oman police registry, which keeps track of the geographical locations where rtis occur and the overall number of rtis which occur at certain rtiprevalent locations known as hotspots, where rtis are known to have resulted in death or serious injury. google earth and google maps software interfaces (google inc., googleplex, mountain view, california, usa) were then used to obtain the coordinates of rti sites and the closest trauma care facilities and to calculate distances between the two locations. the results were displayed on maps created using scribble maps software (52 stairs studio inc., windsor, ontario, canada). data were analysed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). administrative approval was obtained from all of the concerned authorities for use of the secondary data utilised in this study. table 1: classification of trauma care facilities based on service availability class available services general surgery ct icu orthopaedic surgery neuro surgery i no no no no no ii yes no no no no iii yes yes yes no no iv yes yes yes yes* yes* v yes yes yes yes yes ct = computed tomography; icu = intensive care unit. *one or the other, but not both. table 2: distribution of trauma care facilities in oman according to governorate, class and distance to road traffic injury hotspots (n = 32) governorate population density in people/km2 number of facilities per class mean distance from rti hotspot to nearest facility in km mean distance from rti hotspot to nearest class iv or v facility in km muscat 300.8 class v 2 class iv 1 class iii 1 class i 3 4.1 22.4 al-batinah south 80.5 class iv 1 class i 1 35.9 35.9 al-batinah north 83.0 class v 1 30.0 30.0 musandam 21.4 class iii 1 class ii 1 4.7 304.0 al-sharqiyah south 22.2 class iv 1 class ii 2 class i 1 5.7 5.7 al-sharqiyah north 10.0 class iv 1 class iii 1 class i 4 4.8 4.8 al-buraimi 12.4 class iii 1 39.6 85 al-dhahirah 5.2 class iv 1 9.0 9.0 al-dakhiliyah 12.6 class iv 1 class ii 3 class i 1 3.0 3.0 al-wusta 0.5 class i 1 3.5 374.0 dhofar 3.8 class v 1 class iii 1 3.7 14.9 rti = road traffic injuries. sara m. al-kindi, ahmed a. naiem, kadhim m. taqi, najla m. al-gheiti, ikhtiyar s. al-toobi, nasra q. al-busaidi, ahmed z. al-harthy, alaa m. taqi, sharif a. ba-alawi and hani a. al-qadhi clinical and basic research | e433 results a total of 32 trauma care facilities were identified, of which 11 (34.4%) were class i centres. only four centres (12.5%) were categorised as class v facilities; these were located in muscat, al-batinah north and dhofar. muscat had the largest overall number of trauma care facilities, with 42.9% of its facilities ranked as class iv or v. in contrast, musandam, al-wusta and al-buraimi lacked class iv or v facilities entirely. the overall mean distance between rti hotspots and the nearest trauma care facility was 34.7 km, while the mean distance to a class iv or v trauma facility was 83.3 km. the governorate with the shortest mean distance between rti hotspots and class iv or v centres was al-dakhiliyah (3.0 km), whereas al-wusta (374.0 km) and musandam (304.0 km) had the greatest mean distances [table 2]. mapping the distribution of rti hotspots and available trauma care facilities showed a dense clustering of trauma centres around muscat in comparison to other governorates [figure 2]. a total of 22 (68.8%) and 24 (75.0%) of the trauma facilities had general surgery and emergency services, respectively. neurosurgery and orthopaedic surgery services were available in four (12.5%) and 18 (59.3%) centres, respectively. ventilation support was only available in 15 facilities (46.9%). general surgery services were available in all governorates apart from al-wusta, which had no special services available at all; however, neurosurgery services were only available in three governorates (muscat, al-batinah north and dhofar). in total, only 11 centres (68.8%) had an intensive care unit (icu), of which four were located in muscat (12.5%), while al-sharqiyah south and al-wusta completely lacked any type of icu services [figure 3]. discussion in this pilot study, the application of non-acscot classifications to omani trauma care facilities enabled the identification of centres which lacked definitive trauma services but nevertheless contributed to trauma management by allowing the early stabilisation and transfer of the patient to other centres. in oman, although major trauma centres have both surgeons and emergency physicians who can provide resuscitation and management procedures, certain strict requirements for certification as a trauma centre by the american college of surgeons are not met (e.g. the admission of ≥1,200 trauma cases annually).10 as such, a broader classification was devised based on the availability of those specialty services most commonly required when managing trauma cases. figure 2: distribution map of available trauma care facilities in oman in relation to road traffic injury hotspots (n = 32). map created using scribble maps software (52 stairs studio inc., windsor, ontario, canada) and google maps software interface (google inc., googleplex, mountain view, california, usa). figure 3: availability of various services in trauma care facilities in oman according to governorate (n = 32). icu = intensive care unit; ct = computed tomography. distribution of trauma care facilities in oman in relation to high-incidence road traffic injury sites pilot study e434 | squ medical journal, november 2017, volume 17, issue 4 trauma usually involves multiple systems, particularly the nervous and musculoskeletal systems. traumatic brain injuries are the most common cause of death in trauma cases, highlighting the necessity of providing neurosurgery services.11 musculoskeletal injuries are also frequent and most trauma causes therefore require consultation with an orthopaedic surgeon.2 additionally, a dedicated icu facility is integral in reducing preventable deaths.12 according to the american college of surgeons, computed tomography imaging modalities are also deemed mandatory for large trauma centres; moreover, a general surgeon—either as a leader or member of the trauma team—should represent the cornerstone of a trauma system.10 finally, the emergency department is usually the site of the initial encounter between the trauma team and victim; thus, the involvement of emergency physicians is vital.10,13 according to the findings of the current pilot study, the distribution of high-class trauma care facilities in oman seems to correspond with population density. muscat appears to be the best-equipped governorate in oman for the management of trauma cases, particularly those that might require specialised services like general surgery, orthopaedic surgery or neurosurgery; this is fitting in view of its position as the most densely-populated governorate in oman.8 on average, rti victims in muscat were only 4.1 km away from the closest trauma facility where initial resuscitation and preparation for transfer could take place; moreover, definite management at a iv or v trauma care facility, of which 27.3% were based in muscat, was also highly accessible at a mean distance of 22.4 km away. other relatively densely-populated governorates such as al-batinah north and al-batinah south also had facilities where initial trauma care could be delivered; in addition, definitive care at a vi or v trauma centre was usually available within 36 km. this is particularly important as al-batinah north has one of the highest numbers of rti-related doas in the country.7 al-dakhiliyah, which has a similarly high level of rti-related doas, has a lower population density but was found to have both initial management facilities and transfer capabilities to a high-level facility within 3.0 km of rti hotspots.7,8 although this was the shortest mean hotspot-to-facility distance recorded in the current study, the governorate nevertheless lacked specialised neurosurgery services, which therefore necessitates the transfer of trauma cases involving head injuries to other governorates. as the least densely populated governorate, al-wusta was correspondingly found in the present study to lack any kind of high-level trauma facilities.8 although initial management and resuscitation was on average accessible within 3.5 km of an rti hotspot, definitive trauma care was over 370 km away, in the separate governorate of al-dakhiliyah. as with al-wusta, trauma cases in musandam had to be transported an average of 304 km away to north al-batinah for definitive care. it is therefore clear that both air and land transportation infrastructure constitute an important part of the trauma system in oman due to the potentially lengthy distances between known rti hotspots and definitive trauma care facilities. as such, certain regions in oman need to upgrade their available trauma care facilities and potentially build entirely new trauma facilities so as to reduce rti-associated morbidity and mortality in the country. to the best of the author’s knowledge, this pilot study is the first of its kind to evaluate the accessibility of trauma care health facilities in oman in relation to known rti-prevalent sites, with most existing studies targeting preventative aspects or focusing purely on the management of trauma cases. however, this study is not without its limitations and could not fully address the relationship between rti sites and trauma care facilities. given that oman has no nationwide trauma registry, multiple variables could not be included, including modifiable factors associated with morbidity and mortality and data related to preand in-hospital management. conclusion the findings of this pilot study indicate that certain areas in oman need to upgrade available trauma care facilities or build entirely new trauma centres. this may help to improve identified gaps in the existing trauma care infrastructure and reduce rti-associated morbidity and mortality in the country. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. global status report on road safety 2013: supporting a decade of action. from: www.who. int/violence_injury_prevention/road_safety_status/2013/en/ accessed: jun 2017. 2. world health organization. world report on road traffic injury prevention. from: whqlibdoc.who.int/publications/ 2004/9241562609.pdf accessed: jun 2017. sara m. al-kindi, ahmed a. naiem, kadhim m. taqi, najla m. al-gheiti, ikhtiyar s. al-toobi, nasra q. al-busaidi, ahmed z. al-harthy, alaa m. taqi, sharif a. ba-alawi and hani a. al-qadhi clinical and basic research | e435 3. sampalis js, lavoie a, williams ji, mulder ds, kalina m. impact of on-site care, prehospital time, and level of in-hospital care on survival in severely injured patients. j trauma 1993; 34:252–61. 4. sampalis js, denis r, lavoie a, fréchette p, boukas s, nikolis a, et al. trauma care regionalization: a process-outcome evaluation. j trauma 1999; 46:565–81. 5. blackwell th, kaufman js. response time effectiveness: comparison of response time and survival in an urban emergency medical services system. acad emerg med 2002; 9:288–95. doi: 10.1197/aemj.9.4.288. 6. mohan hm, mullan d, mcdermott f, whelan rj, o’donnell c, winter dc. saving lives, limbs and livelihoods: considerations in restructuring a national trauma service. ir j med sci 2015; 184:659–66. doi: 10.1007/s11845-014-1234-9. 7. oman ministry of health. annual health report 2013. from: w w w.moh.gov.om/en_us/web/statistics/annual-reports accessed: jun 2017. 8. oman national centre for statistics and information. population. from: https://data.gov.om/search?query=popul ation&scope=datasets accessed: jun 2017. 9. oman ministry of health. health vision 2050: health atlas. from: www.moh.gov.om/documents/16506/120542/health+atlas /4a611e16-cdb9-4596-9e67-3bd9e2c0126d accessed: jun 2017. 10. american college of surgeons. resources for optimal care of the injured patient 2014. from: www.facs.org/quality-programs /trauma/vrc/resources accessed: jun 2017. 11. pfeifer r, tarkin is, rocos b, pape hc. patterns of mortality and causes of death in polytrauma patients: has anything changed? injury 2009; 40:907–11. doi: 10.1016/j.injury.2009.05.006. 12. nathens ab, rivara fp, mackenzie ej, maier rv, wang j, egleston b, et al. the impact of an intensivist-model icu on trauma-related mortality. ann surg 2006; 244:545–54. doi: 10. 1097/01.sla.0000239005.26353.49. 13. gerardo cj, glickman sw, vaslef sn, chandra a, pietrobon r, cairns cb. the rapid impact on mortality rates of a dedicated care team including trauma and emergency physicians at an academic medical center. j emerg med 2011; 40:586–91. doi: 10.1016/j.jemermed.2009.08.056. https://doi.org/10.1197/aemj.9.4.288 https://doi.org/10.1007/s11845-014-1234-9 https://doi.org/10.1016/j.injury.2009.05.006 https://doi.org/10.1097/01.sla.0000239005.26353.49 https://doi.org/10.1097/01.sla.0000239005.26353.49 https://doi.org/10.1016/j.jemermed.2009.08.056 in the ventrolateral region of the neck, the muscles are arranged in three strata: the subcutaneous, superficial and deep brachiocephalic layers. these three layers are derived through the stratification of a single primitive muscle sheet, which can still be found in some lower vertebrates, and retains direct continuity with the abdominal part of the ventral muscle.1 the sternothyroid (st) muscle is a part of the deep brachiocephalic layer and lies deep to as well as medial to the sternohyoid muscle; it originates from the posterior surface of the manubrium sterni and the posterior margin of the first costal cartilage, passing into the oblique line of the thyroid cartilage.2 the st muscle may be in two layers or many fascicles; among them, the lateral layer may end in the fascia colli.3,4 a levator glandulae thyroideae (lgt) fibrous or fibromuscular band may descend from the inferior margin of the hyoid bone to the lobes, isthmus or pyramidal lobe of the thyroid gland.4 a lgt muscle may be present alongside variations of the infrahyoid muscles.5 case report a regular anatomy dissection session of a 65-yearold male cadaver was performed at the sri manakula vinayagar medical college, madagadipet, pondicherry, india, in 2015. during this dissection, an anomalous right st muscle was found. the muscle originated from the posterior surface of the manubrium sterni at the medial end of the costal cartilage of the first rib. it divided into a medial and a lateral slip approximately 2.7 cm distal to its origin. the medial slip was inserted superiorly to the oblique line of the thyroid cartilage; however, the lateral slip ascended and some of its fibres were attached to the fascial sheath of the great vessels of the neck, also known as the carotid sheath [figure 1]. the muscle terminated between the internal jugular (ij) vein and internal carotid (ic) artery as well as the emerging glossopharyngeal and hypoglossal nerves [figure 2]. it was attached to the lower sharp edge of the tympanic plate of the temporal bone and also to the bony ridge 1department of anatomy, sri manakula vinayagar medical college & hospital, madagadipet, pondicherry, india; 2department of anatomy, sri lakshminarayana institute of medical sciences, villianur commune, pondicherry, india *corresponding author e-mail: senthilanatomy@gmail.com األمهية السريرية حلالة اختالف خلقي غري مألوف بطن إضافية شاذة للعضلة القصية الدرقية سنثل مرجان٬ سودا٬ راجييش هبراجافان abstract: the infrahyoid muscles are involved in vocalisation and swallowing; among these, the sternothyroid muscle is derived from the common primitive sheet. the improper differentiation of this muscle may therefore result in morphological variations. we report an unusual variation found during the dissection of a 65-year-old male cadaver at the sri manakula vinayagar medical college, madagadipet, pondicherry, india, in 2015. an anomalous belly of the right sternothyroid muscle was observed between the internal jugular (ij) vein and the internal carotid artery with an additional insertion into the tympanic plate and petrous part of the temporal bone and the presence of a levator glandulae thyroideae muscle. the anomalous muscle may compress the ij vein if it is related to the neurovascular structures of neck; hence, knowledge of variations of the infrahyoid muscles can aid in the evaluation of ij vein compression among patients with idiopathic symptoms resulting from venous congestion. keywords: neck muscles; thyroid gland; cervical plexus; jugular veins; case report; india. الدرقية, الق�شية الع�شلة الع�شالت تلك ومن والبلع. )الت�شويت( الأ�شوات اإ�شدار عمليتي يف الالمي حتت الع�شالت ت�ش�رك امللخ�ص: وهي م�شتقة من ال�شحيفة البدائية. ويوؤدي التم�يز اخل�طيء لهذه الع�شلة اإىل حدوث ح�لت اختالف�ت مورفوجلية. وهن� نقوم بت�شجيل ح�لة �ش�ذة �ش�دفن�ه� يف ع�م 2015م اأثن�ء ت�رسيح جثة رجل عمره 65 ع�م� يف كلية �رسي م�ن�كول فينق�ر الطبية مبدينة م�داقيب�شت, بوندا�شريي ب�لهند. متت مالحظة وجود بطن اإ�ش�فية �ش�ذة للع�شلة الق�شية الدرقية اليمنى بني الوريد الوداجي الداخلي وال�رسي�ن ال�شب�تي هذه ت�شغط وقد رافعة. درقية غدية ع�شلة ووجود ال�شدغي, العظم من ال�شخري واجلزء الطبلية ال�شفيحة يف غرز اإ�ش�يف مع الداخلي, الع�شلة )ال�ش�ذة( على الوريد الوداجي الداخلي اإن ك�ن له� عالقة ب�لبني�ت الع�شبية الوع�ئية يف العنق. لذا ف�إن معرفة الختالف�ت يف الع�شالت حتت الالمي مهمة للم�ش�عدة يف تقومي ح�لت ان�شغ�ط الوريد الوداجي عند املر�شى امل�ش�بني ب�أعرا�س جمهولة ال�شبب ن�جتة عن احتق�ن وريدُي. الكلمات املفتاحية: ع�شالت العنق؛ الغدة الدرقية؛ ال�شفرية الرقبية؛ الأوردة الوداجية؛ ت�شجيل ح�لة؛ الهند. clinical significance of an unusual variation anomalous additional belly of the sternothyroid muscle *senthil murugan m.,1 sudha r.,1 rajesh bhargavan2 sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e491–494, epub. 30 nov 16 submitted 30 mar 16 revision req. 22 may 16; revision recd. 14 jun 16 accepted 30 jun 16 case report doi: 10.18295/squmj.2016.16.04.015 clinical significance of an unusual variation anomalous additional belly of the sternothyroid muscle e492 | squ medical journal, november 2016, volume 16, issue 4 of the petrous part of the temporal bone between the carotid canal and jugular fossa. the medial bundle was supplied by a branch of the ansa cervicalis nerves, whereas the lateral bundle was supplied by branches of the ansa cervicalis (c2 and c3) nerves as well as the hypoglossal nerve (c1) before it formed the descendens hypoglossi. an lgt muscle was also found on the same side, arising from the hyoid bone and passing into the false capsule on the anterior margin of the right lobe of the thyroid gland. since the anomalous lateral belly of the st muscle was between the great vessels of the neck, this could have caused compression of the ij vein and potentially resulted in venous stasis of its formative tributary, the sigmoid sinus. the cranial cavity was therefore opened to examine the variation in the size of the sigmoid sulcus on the right side. an osseous bridge was observed over the right sigmoid sulcus in the posterior cranial fossa connecting the angulation of the anterior lip with the posterior lip. the sigmoid sulcus of the sinus was significantly larger and deeper on the right side of the posterior cranial fossa [figure 3]. discussion pre-muscle tissue (approximately 7 mm in length) appears in the cervical region of very young embryos as a result of mesenchymal condensation and with the contribution of myoblasts of the cervical hypomere (e.g. the hypaxial mesoderm).6 the tbx1 gene regulates the myogenic differentiation and cellular fate within the mesoderm.7 this gene codes for the t-box protein and is found on the q arm of chromosome 22 at position 11.21. inactivation or deletion of this gene can lead to serious alterations in the morphology of neck muscles.7,8 mesenchymal condensation later develops into a distinct band of infrahyoid pre-muscle tissue extending to either side, from the base of the tongue caudolaterally towards the tip of the first rib. cleavage of this tissue thus forms the most ventral muscles of the neck which are supplied by the ramus of the descendens hypoglossi.6 initially, the infrahyoid pre-muscle band divides into deep and superficial layers, after which the superficial sheath then divides into inner and outer muscles; the inner muscle eventually forms the sternohyoid muscle and the figure 1: photograph of a deep dissection of the right side of the neck of a 65-year-old male cadaver showing the sternothyroid muscle divided into two slips. the medial slip passed above the oblique line on the lamina of the thyroid cartilage. the lateral slip passed into the tympanic plate of temporal bone and to the bony ridge of the petrous part of the temporal bone between the carotid canal and jugular fossa. a nerve twig from c1 supplied the lateral slip (yellow arrow). note the location of the hypoglossal nerve (white arrow) and levator glandulae thyroideae muscle (black arrow). tt = tympanic plate of temporal bone; l = lateral slip; h = hypoglossal nerve; ic = internal carotid artery; th = thyrohyoid muscle; tc = thyroid cartilage; t = thyroid gland; m = medial slip; lgt = levator glandulae thyroideae muscle; st = sternothyroid muscle. figure 2: photograph of a deep dissection of the right side of the neck of a 65-year-old male cadaver showing an anomalous lateral belly of the right sternothyroid muscle. the terminal part of the belly was located between the internal jugular vein and the internal carotid artery and ascended between the hypoglossal and glossopharyngeal (white arrow) nerves. note the location of the lateral slip (yellow arrow), ansa cervicalis (blue arrow) and levator glandulae thyroideae muscle (black arrow). tt = tympanic plate of temporal bone; ic = internal carotid artery; ij = internal jugular vein; gp = glossopharyngeal nerve; h = hypoglossal nerve; ec = external carotid artery; sm = submandibular salivary gland; l = lateral slip; cc = common carotid artery; ac = ansa cervicalis; th = thyrohyoid muscle; tc = thyroid cartilage; lgt = levator glandulae thyroideae muscle; t = thyroid gland; m = medial slip; st = sternothyroid muscle; s = sternum. senthil murugan m., sudha r. and rajesh bhargavan case report | e493 lower part of the outer muscle forms the omohyoid muscle.9 the deep stratum of the undifferentiated muscle mass becomes the st and thyrohyoid muscles. since the pre-muscle mass extends from the base of the tongue to the tip of first rib, improper cleavage and differentiation may lead to variations of the derivative muscles. to the best of the authors’ knowledge, the variation of the st muscle observed in the present case is unique and has not been previously reported. among 36 cadavers with muscular variations reported in previous research, one had a duplicate st muscle with the additional slip arising from the first costal cartilage and the costoclavicular ligament, joining the normal one halfway up the neck.10 in an earlier similar observation by the same author, the abnormal slip (known as the costo-fascialis cervicalis) terminated in the cervical fascia under the sternocleidomastoid muscle.10 humphry reported that the st muscle can be double, either wholly, partially or divided into two lateral portions running parallel with one another.1 however, in the present case, the lateral belly was attached to the carotid sheath as well as to the bony ridge between the jugular fossa and the lower opening of the carotid canal. in the present case, the cranial half of the anomalous lateral belly of the st muscle passed between the ij vein and the ic artery for a short distance before its insertion. these neurovascular links are of great clinical value; other reports have indicated that variations of the omohyoid muscle resulted in compression of the ij vein, which could in turn hinder venous return from the head and neck.11−13 in addition, the ij vein can be compressed by other abnormal neck muscles, including variations of the figure 3: photograph of the posterior cranial fossa of a 65-year-old male cadaver. the right sigmoid sulcus (rss) was larger and deeper compared to the left sigmoid sulcus. an osseous bridge connected the anterior and posterior lips of the rss (arrowhead). c = clivus; fm = foramen magnum; lss = left sigmoid sulcus; rss = right sigmoid sulcus. sternocleidomastoid and digastric muscles.11,12,14−16 compression of the ij vein may lead to ij vein thrombosis and cause an embolism in the pulmonary artery.17 in the current case, the anomalous lateral belly of the st muscle may have compressed the ij vein and caused thrombosis; however, this cannot be known for sure. in addition, the anomalous belly of the st muscle lay between the glossopharyngeal and hypoglossal nerves near its termination. this may have compressed the nerves related to this region, potentially resulting in unilateral palsy. as such, it is possible that the cadaver suffered from collet-sicard syndrome; this condition involves the ix to xii cranial nerves and can be caused by idiopathic ij vein thrombosis.18 sigmoid sinus enlargement can cause pulsatile tinnitus.19 in the current case, the sulcus of the right sigmoid sinus was significantly enlarged, perhaps due to the compression of the ij vein by the anomalous lateral belly on the right side. the usual course of the sigmoid sulcus is vertical on the mastoid section of the temporal bone, followed by anteromedial in the jugular process of the occipital bone and terminating at the jugular foramen.20 the anterior margin of the sulcus is more prominent than the posterior margin. moreover, the anterior lip has three parts: lateral, junctional (with angulation) and medial; the first section is formed by the mastoid part of the temporal bone, whereas the other two are formed by the jugular process of the occipital bone.20 in the present case, an osseous bridge over the right sigmoid sulcus in the posterior cranial fossa connected the angulation of the anterior lip with the posterior lip of the sigmoid sulcus. the presence of an osseous bridge over the terminal part of the right sigmoid sinus may be due to the ossification of a thickened dura mater at the angulation.20 in the authors’ opinion, this bridge could compress the sigmoid sinus and cause fatal thrombosis of the sigmoid sinus or ij vein. thrombosis of the sigmoid sinus or sigmoid jugular complex would block the drainage of the cerebral veins into the ij vein; this could raise the intracranial pressure, which might subsequently cause epileptic seizures.21 thus, in cases of epileptic seizures of unknown aetiology, ij vein compression by an additional belly of the st muscle should be considered. the presence of a lgt muscle along with a variation of the st muscle might be due to the improper stratification of the embryological primordial muscle sheet. since the lgt muscle and other infrahyoid muscles are derived from a common source, any variation in the infrahyoid muscle group may accompany the occurrence of the lgt muscle. kim et al. reported a rare finding of a duplicated omohyoid muscle with the occurrence of a lgt clinical significance of an unusual variation anomalous additional belly of the sternothyroid muscle e494 | squ medical journal, november 2016, volume 16, issue 4 muscle; the lgt muscle rose from the hyoid bone and inserted into the sheath on the anterior margin of the right lobe of the thyroid gland.5 according to mori’s classification system, this is categorised as a hyoglandularis muscle.22 this variation should be considered during surgeries to avoid iatrogenic injuries to the neurovascular structures supplying the lgt muscle. the embryological origin of a lgt muscle is under debate. lehr opined that this muscle might be a derivative of the cricothyroid muscle.23 eisler et al. also theorised that this muscle might be derived from the cricothyroid, thyrohyoid and inferior constrictor muscles of the pharynx.24 kim et al. suggested that the development of a lgt muscle is genetic and may be similar to the development of the omohyoid muscle.5 conclusion a unique variation was noted in a cadaver involving the insertion of an anomalous lateral belly of the st muscle which passed between the ij vein and ic artery for a short distance before insertion and lay between the glossopharyngeal and hypoglossal nerves near its termination. infrahyoid muscles may show variations due to the improper stratification of the primordial muscle sheet; this theory is supported by the presence of a lgt muscle along with an anomalous lateral belly, as seen in this case. knowledge of possible variations of the infrahyoid muscles is necessary in order to avoid iatrogenic trauma during surgery as well as to evaluate compression of the ij vein in cases of idiopathic seizures. references 1. humphry gm. lectures on the varieties in the muscles of man: delivered at the royal college of surgeons of england. br med j 1873; 2:51–4. doi: 10.1136/bmj.2.655.51. 2. standring s. gray’s anatomy: the anatomical basis of clinical practice, 40th ed. atlanta georgia, usa: churchill livingstone, 2008. p. 442. 3. bergman ra, afifi ak, miyauchi r. omohyoideus, sternohyoideus, thyrohyoideus, sternothyroideus, (infrahyoid muscles). from: www.anatomyatlases.org/anatomicvariants/muscular system/text/o/14omohyoideus.shtml accessed: jun 2016. 4. nayak sr, rai r, krishnamurthy a, prabhu lv, potu bk. an anomalous belly of sternothyroid muscle and its significance. rom j morphol embryol 2009; 50:307–8. 5. kim di, kim hj, park jy, lee ks. variation of the infrahyoid muscle: duplicated omohyoid and appearance of the levator glandulae thyroideae muscles. yonsei med j 2010; 51:984–6. doi: 10.3349/ymj.2010.51.6.984. 6. keibel f, mall fp. manual of human embryology 12: the ventrolateral muscles of the neck. from: embryology.med. unsw.edu.au/embr yology/index.php/book_-_manual_of_ human_embryology_12#the_ventrolateral_muscles_of_the_ neck accessed: jun 2016. 7. dastjerdi a, robson l, walker r, hadley j, zhang z, rodriguez-niedenführ m, et al. tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm. dev dyn 2007; 236:353–63. doi: 10.1002/dvdy.21010. 8. zhang z, huynh t, baldini a. mesodermal expression of tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. development 2006; 133:3587–95. doi: 10.1242/dev.02539. 9. tripathy pr, preetam c. unilateral absence of the sternohyoid muscle with contralateral tendinous belly of superior belly of omohyoid muscle: a very rare form of infrahyoid muscle variation. int j anat res 2015; 3:1302–5. doi: 10.16965/ ijar.2015.216. 10. wood j. variations in human myology observed during the winter session of 1865-66 at king’s college, london. proc r soc lond 1867; 15:229–44. doi: 10.1098/rspl.1866.0054. 11. thakur a, a b, parmar sk. multiple variation in neck musculature and their surgical implications. int j anat var 2011; 4:171–3. 12. simka m, majewski e, fortuna m, zaniewski m. internal jugular vein entrapment in a multiple sclerosis patient. case rep surg 2012; 2012:293568. doi: 10.1155/2012/293568. 13. patra p, gunness tk, robert r, rogez jm, heloury y, le hur pa, et al. physiologic variations of the internal jugular vein surface, role of the omohyoid muscle, a preliminary echographic study. surg radiol anat 1988; 10:107–12. doi: 10.1007/bf02307818. 14. jayaraman mv, boxerman jl, davis lm, haas ra, rogg jm. incidence of extrinsic compression of the internal jugular vein in unselected patients undergoing ct angiography. anjr am j neuroradiol 2012; 33:1247–50. doi: 10.3174/ajnr.a2953. 15. mehta v, gupta v, arora j, yadav y, suri rk, rath g. bilateral bipartite origin of the posterior belly of digastric muscle: a clinico-anatomical appraisal. anat 2011; 5:44–7. doi: 10.2399/ ana.09.042. 16. zaniewski m, simka m. biophysics of venous return from the brain from the perspective of the pathophysiology of chronic cerebrospinal venous insufficiency. rev recent clin trials 2012; 7:88–92. doi: 10.2174/157488712800100288. 17. ball e, morris-stiff g, coxon m, lewis mh. internal jugular vein thrombosis in a warfarinised patient: a case report. j med case rep 2007; 1:184. doi: 10.1186/1752-1947-1-184. 18. handley tp, miah ms, majumdar s, hussain ss. collet-sicard syndrome from thrombosis of the sigmoid-jugular complex: a case report and review of the literature. int j otolaryngol 2010; 2010:203587. doi:10.1155/2010/203587. 19. hofmann e, behr r, neumann-haefelin tn, schwager k. pulsatile tinnitus: imaging and differential diagnosis. dtsch arztebl int 2013; 110:451−8. doi: 10.3238/arztebl.2013.0451. 20. singh p, tuli a, choudhry r, dhall u, makwane uk. morphology and imaging of bony projections on sigmoid sulcus with clinical implication. surg radiol anat 2004; 26:46−50. doi: 10.1007/s00276-003-0173-3. 21. alvis-miranda hr, milena castellar-leones s, alcala-cerra g, rafael moscote-salazar l. cerebral sinus venous thrombosis. j neurosci rural pract 2013; 4:427–38. doi: 10.4103/0976-31 47.120236. 22. mori m. statistics on the musculature of the japanese. okajimas folia anat jpn 1964; 40:195–300. doi: 10.2535/ ofaj1936.40.3_195. 23. lehr rp jr. musculus levator glandulae thyroideae: an observation. anat anz 1979; 146:494–6. 24. eisler p, der m. levator glandulae thyroideae und verwandte praelaryngeale muskelbildungen. anat anz 1900; 17:183–9. إشعار عن تغيري يف تسلسل املؤلفني التوافق يف مرض السكري عند النساء املتزوجات املراجعات للمؤسسات الصحية يف عجمان، اإلمارات العربية املتحدة erratum notice erratum notice of author sequence change spousal concordance of diabetes mellitus among women in ajman, united arab emirates the editors of sultan qaboos university medical journal (squmj) have been informed that the authors of an article by al-sharbatti et al. in the may 2016 issue of squmj wish to change the sequence of authors in the above article.1 the first/corresponding author, shatha s. al-sharbatti, contacted squmj in may 2016 requesting a change in the author sequence. al-sharbati informed the editors of squmj that the second author, yasmeen i. abed, should instead be designated as the first author. however, this correction could not made as the article had already been published several days previously. for the reasons stated herein, the editors of squmj wish to notify readers that the sequence of authors for the above article is changed to the following: yasmeen i. abed, shatha s. al-sharbatti, lujain m. al-heety, shaikh a. basha.2 the corresponding author, al-sharbati, takes sole responsibility for this notice and would like to apologise to the readers, reviewers and editors of squmj for this correction made after publication. references 1. al-sharbatti ss, abed yi, al-heety lm, basha sa. spousal concordance of diabetes mellitus among women in ajman, united arab emirates. sultan qaboos univ med j 2016; 16:e197–202. doi: 10.18295/squmj.2016.16.02.010. 2. abed yi, al-sharbatti ss, al-heety lm, basha sa. spousal concordance of diabetes mellitus among women in ajman, united arab emirates. sultan qaboos univ med j 2016; 16:e197–202. doi: 10.18295/squmj.2016.16.02.010. notice of erratum for: al-sharbatti et al. spousal concordance of diabetes mellitus among women in ajman, united arab emirates. sultan qaboos univ med j 2016; 16:e197–202. doi: 10.18295/squmj.2016.16.02.010. sultan qaboos university med j, august 2016, vol. 16, iss. 3, p. e397, epub. 19 aug 16 doi: 10.18295/squmj.2016.16.03.028 erratum notice | e397 http://dx.doi.org/10.18295/squmj.2016.16.02.010 http://dx.doi.org/10.18295/squmj.2016.16.02.010 although the exact number of hours spent sleeping may across our lifespan, adults require on average between six to eight hours of sleep per day.1 while the true purpose of sleep is not yet fully understood, it appears to serve many important functions, including energy restoration, revitalisation, self-repair and growth; furthermore, research suggests that sleep plays a role in brain plasticity by promoting synapse formation and maintenance.2 sleep deprivation occurs when sleep cannot support adequate alertness, performance and health, either as a result of sleep of insufficient quantity (i.e. duration) and/or quality (i.e. depth). poor sleep hygiene—which refers to habits and practices that are unconducive to sleeping well on a regular basis—is usually the cause of insufficient sleep duration, while sleeping disorders such as sleep-disordered breathing (sdb) and obstructive sleep apnoea (osa) can result in poor-quality sleep.3 identifying patients with chronic sleep deprivation can be challenging, especially those suffering from partial sleep deficit over longer periods of time.4 one manifestation of sleep deprivation is excessive daytime sleepiness (eds), defined as an inability to stay awake and alert during the major waking hours of the day, with sleep occurring unintentionally or at inappropriate times almost daily for at least three months.5 in addition, patients may experience brief involuntary episodes of ‘microsleep’, in which there is a temporary lapse in consciousness that can last up to 30 seconds, during which the individual is unable to respond to sensory stimuli. in fact, most individuals are unaware of a microsleep episode and believe they have been awake continuously.6,7 sleep deprivation can lead to numerous adverse health consequences. in a recent large prospective study by deng et al., short sleep duration was associated with the development of several cardiometabolic conditions—including central obesity, elevated fasting glucose hypertension, lowand high-density lipoprotein cholesterol levels, hypertriglyceridaemia and meta bolic syndrome—among over 160,000 healthy nonobese adults over an 18-year period.8 similarly, baldwin et al. found that the health scores of subjects with severe sdb (in terms of difficulty initiating and maintaining sleep) and eds were comparable to those of patients with hypertension, type 2 diabetes mellitus and clinical depression.9 apart from physical manifestations, sleep deprivation can impair a number of important cognitive funct ions such as judgment, attention, executive function, cognitive processing speed, memory, reaction time and muscular coordination, all of which are critical when driving.10 in a survey conducted by the foun dation for traffic safety in the usa, 41% of participants reported having nodded off or fallen asleep at the wheel at least once in their lifetime; of these, 11% admitted to having done so within the past year and 3.9% within the past month.11 unfortunately, sleep deprivation and associated daytime sleepiness increases the risk of being involved in a motor vehicle crash, which can be up to 2.5–7-fold higher compared to non-sleepy drivers.12–14 moreover, sleepy driving accounts for approximately one in six fatal crashes and one in eight crashes leading to the hospitalisation of the driver or passengers.11 in the usa, an average of 83,000 crashes per year are due to sleepy driving, causing 886 deaths and 37,000 injuries.15 sleepiness and fatigue can affect a driver to a similar extent to that of alcohol impairment.16 powell et al. noted that the reaction times of subjects who had stayed awake for extended periods of time were comparable to those of drivers with blood alcohol levels of 0.08%, with frequent lane deviations and simulated crashes.17 similar effects have been documented in patients with chronic sleep disruption due to untreated department of medicine, royal hospital, muscat, oman e-mail: nabil.allawati@gmail.com نعاس السائقني حان الوقت للعمل نبيل اللواتي editorial sleepy drivers high time for action nabil m. al-lawati sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e127–129, epub. 9 sep 18 submitted 29 apr 18 revision req. 3 may 18; revision recd. 14 may 18 accepted 24 may 18 doi: 10.18295/squmj.2018.18.02.001 sleepy drivers high time for action e128 | squ medical journal, may 2018, volume 18, issue 2 sleep disorders, such as osa.12,17,18 sassani et al. reported that 1,400 lives are lost annually due to osa-related collisions, costing an estimated usd $15.9 billion dollars; in comparison, encouraging early osa treatment would save 980 lives and an estimated usd $11.1 billion in collision costs.12 patients with osa are also more likely to acquire injuries when involved in a motor vehicle crash. mulgrew et al. compared objective crash data from the insurance records of patients with suspected osa, a mean apnoea-hypopnoea index of 22 events per hour and a mean epworth sleepiness scale (ess) score of 10 with those of ageand gender-matched controls.18 the results indicated that the rate of crashes causing injury was 3.0–4.8-fold higher for patients with osa, with the rate of crashes increasing correspondingly with apnoea severity.18 although there is a paucity of data about sleepy driving-related deaths in oman, the annual number of deaths due to road traffic crashes was estimated to have increased from 23 to 30 per 100,000 individuals between 1995 and 2009.19 overall, this was a 50% inc rease in mortality, from 479 to 953 deaths per year, with half of the casualties being between 26–59 years old; this is alarming considering the fact that the majority of the population is below 50 years of age.19 extrapolating results from the usa, the rate of sleepy drivingrelated deaths in oman would be five deaths per 100,000 individuals, or approximately 17% of the total death toll; these estimates are very similar to data reported from the uk.11,20 in this issue of squmj, al-abri et al. present novel and important findings regarding the prevalence of daytime sleepiness while driving and osa in muscat, oman.21 the authors observed that sleepiness while driving was common among omani private motor vehicle drivers, with just over one-quarter of the drivers experiencing sleepiness while driving at least once per month. unhealthy sleep habits appeared to be the major culprit, as almost two-thirds of the population sampled reported sleeping less than six hours per night, with evidence of a significant association between an inadequate night’s sleep and feeling sleepy while driving.21 another alarming finding was the high rate of excessive daytime sleepiness, with 37.8% of the participants scoring greater than 10 on the ess. the paper also reported an osa prevalence of 10.6%, with a significant association between osa and sleepiness while driving.21 it is important to note that these data were subjectively collected using self-reported tools; it is therefore likely that the obtained results underestimate the true magnitude of the problem. in conclusion, there is a need for similar studies confirming the actual magnitude of the problem of sleepy driving in oman using objective tools. the medical community should initiate nationwide campaigns advocating healthy sleep habits and raising public awareness of the numerous risks associated with sleep deprivation, both at the individual as well as societal levels. it is high time that sleep medicine professionals join hands with law enforcement authorities and non governmental organisations in oman to create a common platform and work on preventing and dealing with the critical health-related and socioeconomic consequences of sleep deprivation, especially on the roads. references 1. ohayon mm, carskadon ma, guilleminault c, vitiello mv. meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan. sleep 2004; 27:1255–73. doi: 10.1093/sleep/27.7.1255. 2. yang g, lai cs, cichon j, ma l, li w, gan wb. sleep promotes branch-specific formation of dendritic spines after learning. science 2014; 344:1173–8. doi: 10.1126/science.1249098. 3. porkka-heiskanen t, zitting km, wigren hk. sleep, its regulation and possible mechanisms of sleep disturbances. acta physiol (oxf ) 2013; 208:311–28. doi: 10.1111/apha.12134. 4. carskadon ma, dement wc. cumulative effects of sleep restriction on daytime sleepiness. psychophysiology 1981; 18:107–13. doi: 10.1111/j.1469-8986.1981.tb02921.x. 5. sateia mj. international classification of sleep disorders: third edition highlights and modifications. chest 2014; 146:1387–94. doi: 10.1378/chest.14-0970. 6. torsvall l, akerstedt t. sleepiness on the job: continuously measured eeg changes in train drivers. electroencephalogr clin neurophysiol 1987; 66:502–11. doi: 10.1016/0013-4694(87) 90096-4. 7. durmer js, dinges df. neurocognitive consequences of sleep deprivation. semin neurol 2005; 25:117–29. doi: 10.1055/s-20 05-867080. 8. deng hb, tam t, zee bc, chung ry, su x, jin l, et al. short sleep duration increases metabolic impact in healthy adults: a population-based cohort study. sleep 2017; 40:zsx130. doi: 10. 1093/sleep/zsx130. 9. baldwin cm, griffith ka, nieto fj, o’connor gt, walsleben ja, redline s. the association of sleep-disordered breathing and sleep symptoms with quality of life in the sleep heart health study. sleep 2001; 24:96–105. doi: 10.1093/sleep/24.1.96. 10. lim j, dinges df. a meta-analysis of the impact of short-term sleep deprivation on cognitive variables. psychol bull 2010; 136:375–89. doi: 10.1037/a0018883. 11. foundation for traffic safety. asleep at the wheel: the prev alence and impact of drowsy driving. from: www.greylit.org/ site s/def ault/file s/colle cte d_file s/2012-12/2010drows y drivingreport_1.pdf accessed: may 2018. 12. sassani a, findley lj, kryger m, goldlust e, george c, davidson tm. reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. sleep 2004; 27:453–8. doi: 10.1093/sleep/27.3.453. 13. lyznicki jm, doege tc, davis rm, williams ma. sleepiness, driving, and motor vehicle crashes: council on scientific affairs, american medical association. jama 1998; 279:1908–13. doi: 10.1001/jama.279.23.1908. https://doi.org/10.1093/sleep/27.7.1255 https://doi.org/10.1126/science.1249098 https://doi.org/10.1111/apha.12134 https://doi.org/10.1111/j.1469-8986.1981.tb02921.x https://doi.org/10.1378/chest.14-0970 https://doi.org/10.1016/0013-4694%2887%2990096-4 https://doi.org/10.1016/0013-4694%2887%2990096-4 https://doi.org/10.1055/s-2005-867080 https://doi.org/10.1055/s-2005-867080 https://doi.org/10.1093/sleep/zsx130 https://doi.org/10.1093/sleep/zsx130 https://doi.org/10.1093/sleep/24.1.96 https://doi.org/10.1037/a0018883 https://doi.org/10.1093/sleep/27.3.453 https://doi.org/10.1001/jama.279.23.1908 nabil m. al-lawati editorial | e129 14. bioulac s, franchi jm, arnaud m, sagaspe p, moore n, salvo f, et al. risk of motor vehicle accidents related to sleep-iness at the wheel: a systematic review and meta-analysis. sleep 2017; 40:zsx134. doi: 10.1093/sleep/zsx134. 15. u.s. department of transportation. traffic safety facts: crash stats drowsy driving. from: https://crashstats.nhtsa.dot.gov/ api/public/viewpublication/811449 accessed: may 2018. 16. williamson am, feyer am. moderate sleep deprivation produces impairments in cognitive and motor performance equivalent to legally prescribed levels of alcohol intoxication. occup environ med 2000; 57:649–55. doi: 10.1136/oem.57.10.649. 17. powell nb, riley rw, schechtman kb, blumen mb, dinges df, guilleminault c. a comparative model: reaction time perfor mance in sleep-disordered breathing versus alcohol-impaired controls. laryngoscope 1999; 109:1648–54. doi: 10.1097/00005 537-199910000-00019. 18. mulgrew at, nasvadi g, butt a, cheema r, fox n, fleetham ja, et al. risk and severity of motor vehicle crashes in patients with obstructive sleep apnoea/hypopnoea. thorax 2008; 63:536–4. doi: 10.1136/thx.2007.085464. 19. al-maniri aa, al-reesi h, al-zakwani i, nasrullah m. road traffic fatalities in oman from 1995 to 2009: evidence from police reports. int j prev med 2013; 4:656–63. 20. horne j, reyner l. vehicle accidents related to sleep: a review. occup environ med 1999; 56:289–94. 21. al-abri ma, al-adawi s, al-abri i, al-abri f, dorvlo a, wesonga r, et al. daytime sleepiness among young adult omani car drivers. sultan qaboos univ med j 2018; 18:e143–8. doi: 10.18295/squmj.2018.18.02.004. https://doi.org/10.1093/sleep/zsx134 https://doi.org/10.1136/oem.57.10.649 https://doi.org/10.1097/00005537-199910000-00019 https://doi.org/10.1097/00005537-199910000-00019 https://doi.org/10.1136/thx.2007.085464 https://doi.org/10.18295/squmj.2018.18.02.004 املرارة اخلزفية الكشف عن احلقيقة اخلبيثة نورم�ن اونيل م��ش�دو abstract: gallbladder calcification, also referred to as porcelain gallbladder, has received significant attention in the medical literature due to its perceived role in increasing the risk of developing a gallbladder carcinoma. however, recent reports raise questions challenging this purported high risk. while previous studies reported a concomitant incidence of gallbladder cancer in porcelain gallbladder ranging from 7–60%, more recent analyses indicate the incidence to be much lower (6%). based on evidence in the current literature, a prophylactic cholecystectomy is not routinely recommended for all patients with porcelain gallbladder and should be restricted to those with conventional indications, such as young patients. however, it is important to note that a nonoperative approach may require prolonged follow-up. a laparoscopic cholecystectomy is a feasible therapeutic option for patients with porcelain gallbladder, although some researchers have indicated a higher incidence of complications and conversion due to technical difficulties. keywords: gallbladder diseases; carcinomas; cholecystectomy; physiological calcification. امللخ�ص: جذب تكل�س املرارة الذي يعرف اأي�ش� ب�ملرارة اخلزفية اهتم�م� كبريا من الب�حثني يف الأدبي�ت الطبية ن�شبة اإىل الدور الذي الرتابط هذا يف �شككت التي احلديثة الأبح�ث بع�س هن�لك اأن غري املرارة. ل�رسط�ن حتوله� من الختط�ر زي�دة يف يلعبه اأنه يعتقد املفرت�س. لقد اأثبتت درا�ش�ت �ش�بقة وجود ع�ر�س م�ش�حب للمرارة اخلزفية و �رسط�ن املرارة يرتاوح بني %60-7. غري اأن الدرا�ش�ت التحليلية الأحدث اأو�شحت اأن الع�ر�س بني املرارة اخلزفية و �رسط�ن املرارة اأقل بكثري من ذلك )%6(. وبن�ء على البي�ن�ت احل�لية, ف�إنه ل ين�شح ب�إجراء عملية ا�شتئ�ش�ل املرارة من ب�ب الوق�ية ب�شورة روتينية لكل امل�ش�بني بتكل�س املرارة. وينبغي ق�رس اإجراء هذه العملية على من يظهرون ا�شتطب�ب�ت تقليدية, مثل م� عند �شغ�ر املر�شى. اإل اأنه يجب اأن نذكر اأي�ش� ب�أن عدم اإجراء عملية اإ�شتئ�ش�ل املرارة عند هوؤلء املر�شي يتطلب مت�بعة مطولة. وهن�لك خي�ر اآخر مت�ح ملر�شى تكل�س املرارة وهو اإجراء عملية اإ�شتئ�ش�ل املرارة عن طريق منظ�ر البطن. غري اأن بع�س الب�حثني اأ�ش�روا اإىل حدوث ع�ر�س اأعلى من امل�ش�عف�ت والتحويل ب�شبب م�ش�كل تقنية. الكلمات املفتاحية: اأمرا�س املرارة؛ �رسط�ن�ت؛ ا�شتئ�ش�ل املرارة؛ التكل�س الفيزيلوجي. porcelain gallbladder decoding the malignant truth norman o. machado review sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e416–421, epub. 30 nov 16 submitted 29 jun 16 revision req. 25 aug 16; revision recd. 28 aug 16 accepted 22 sep 16 doi: 10.18295/squmj.2016.16.04.003 the term porcelain gallbladder (pgb) is often used to describe calcification of the gallbladder wall.1–3 when infiltrated by extensive calcium deposits, the gallbladder wall can become fragile, brittle and bluish in appearance, resulting in a ‘porcelain’ appearance.2–6 there are two distinct types of gallbladder calcification: selective mucosal calcification and diffuse intramural calcification. the latter type is often associated with the traditional description of pgb.1,2 the reported overall five-year survival and one-year mortality rates of pgb are 5% and 88%, respectively.1 historically, pgb was reported to be associated with carcinoma of the gallbladder (cagb), with the incidence sometimes exceeding 60%.6 since then, a cholecystectomy has become the norm for treating current and preventing future malignancy in patients with pgb.1,2 modern techniques for investigating gallbladder pathology have led to the earlier detection of pgb in comparison to plain x-rays.7,8 this change has led to a distortion of the evidence base and a considerable decrease in the rate of detection of cagb among patients with pgb.1,2,9,10 several recent reports have indicated a much lower incidence of cagb, thus raising questions regarding the age-old practice of performing a routine cholecystectomy on patients with pgb.2,9,10 moreover, complications following a cholecystectomy are reportedly higher in patients with pgb.10 based on the present evidence in the literature, this review discusses the incidence of pgb, its association with cagb and the need for a cholecystectomy in patients with pgb. risk factors among 44 patients with pgb, stephen et al. noted that nonspecific symptoms of a calcified gallbladder included abdominal pain alone (47%), abdominal pain, department of surgery, sultan qaboos university hospital, muscat, oman e-mail: oneilnorman@gmail.com norman o. machado review | e417 nausea and vomiting (16%), abdominal pain and fever (9%), abdominal pain and jaundice (5%) and anorexia, nausea and vomiting (5%); however, 18% of patients were asymptomatic.1 the development of cagb in addition to pgb is associated with other risk factors, including gallstones of >3.0 cm in size, cholecystoenteric fistulae, an anomalous pancreaticobiliary junction, gallbladder adenomas or polyps, choledochal cysts, occupational exposure to carcinogens and chronic salmonella typhi infections.1,11 gallbladder cancer is notoriously aggressive, often diagnosed late and has a poor prognosis; hence, there is a need for aggressive treatment for individuals with pgb and a perceived risk of cagb.1,12,13 a late diagnosis of cagb is often due to its nonspecific and variable presentation in the initial stages and the close anatomical relationship of the gallbladder with the liver, which facilitates its spread.1,2 historical perspective the association between gallbladder cancer and calcium deposition on the gallbladder wall was first proposed in 1797.5 since then, several reports have emerged.1–6,9–12,14–18 in one study of 4,271 cholecystectomy specimens collected between 1922–1956, adenocarcinomas were noted in two out of 16 calcified gallbladders (12.5%).5 in another report from argentina, cagb was detected in 16 out of 26 calcified gallbladder specimens (61.5%).6 in their analysis of 25,900 gallbladder specimens collected between 1962–1999, stephen et al. found the incidence of gallbladder cancer and calcium deposition to be 7%.1 interestingly, the incidence and association was related to the type of calcification; gallbladder cancer was restricted to those with selective mucosal calcification (odds ratio [or]: 13.89; p = 0.01) and no cancer was found in gallbladders with diffuse intramural calcification.1 however, a recent literature review suggests that the overall incidence of pgb and gallbladder cancer is 0.2% and 0.8%, respectively—with a 15% concomitant incidence—while another report notes the incidence of gallbladder malignancy in patients with gallbladder wall calcification to be 6%.2,9 calcification and risk of malignancy c a l c i f i c at i o n pat t e r n s the extent of calcification in gallbladders can range from small focal plaques restricted to the mucosal layer and its glandular spaces to the involvement of the full thickness of the gallbladder wall, replacing the muscularis layer with calcified fibrosis and leading to the subsequent denuding of the mucosa.1,2 the absence of mucosa in these cases reduces the risk of malignancy.1,4 the radiographical appearance of a calcified gallbladder varies based on the extent, degree and location of the calcification. less intense calcification of the mucosa is unlikely to be identified on a plain x-ray, while more diffuse intramural calcification will appear as a curvilinear or rounded opacity in the right upper quadrant [figure 1a].1 recently, the increased use of ultrasonography (us) as part of the investigation process for patients with abdominal discomfort has resulted in the earlier and improved detection of pgb.14 unfortunately, due to its rarity, the natural history and progression of a calcified gallbladder is unknown and could vary based on different patterns of calcification.1,2 a definitive diagnosis of pgb can usually be established with an abdominal us or plain noncontrast computed tomography (ct) scan demonstrating the characteristic calcification of the gallbladder wall [figure 1b].19 in general, us findings are reported as complete or incomplete and have been classified into three types based on the extent and nature of calcification: type i is characterised by a hyperechoic semilunar structure with posterior acoustic shadowing; type ii displays a curvilinear echogenic structure with acoustic shadowing; and type iii is characterised by irregular clumps of echoes with posterior acoustic shadowing.7,8,13,20 while type i corresponds to complete intramural calcification of the gallbladder, types ii and iii reflect the variations of selective mucosal calcification.8,20 in some cases, flecks of mucosal calcification may not be detected during radiological examinations but are found only on pathology.1 khan et al. noted complete transmural and mucosal calcification in 69% and 23% of 13 patients with pgb, respectively.9 r i s k o f m a l i g n a n c y although the aetiology of gallbladder wall calcification is poorly understood, it is believed to be a consequence of a chronic inflammatory process.4,9 dystrophic calcification and errors in calcium metabolism have been implicated in the formation of pgb and inflammation and ischaemia may progress to transmural calcification.9 there is a well-documented association between pgb and the development of cagb.1,3–6,9,12,14,15 chemicals within stagnant bile or degeneration and regeneration processes within the gallbladder epithelium, leading to mucosal dysplasia, may act as a carcinogenic stimulus.9 most carcinomas associated with pgb are diffusely infiltrating adenocarcinomas.21 porcelain gallbladder decoding the malignant truth e418 | squ medical journal, november 2016, volume 16, issue 4 a recent systematic review by schnelldorfer studied the association of pgb with gallbladder cancer; of 111 articles detailing 340 patients with gallbladder wall calcification, the incidence of gallbladder malignancy was 21%.2 while the author noted that patients with calcified gallbladders were indeed statistically at risk of developing gallbladder malignancy, on careful analysis of the data, the actual risk of malignancy was significantly less. moreover, schnelldorfer indicated certain limitations which could have resulted in an overestimation in the reported incidence of gallbladder cancer among patients with pgb, including: (1) publication bias, in that publishers might prefer to publish rare or ‘curious’ cases only; (2) selection bias, whereby researchers selected subjects from a population of gallbladder cancer patients rather than from the general population or because most reported patients were published in case series and thus did not include a systematic selection of patients; and (3) sampling bias, as most studies represented institutional experiences of patients with gallbladderrelated symptoms seeking medical advice.2 these factors are further compounded by the fact that most gallbladder wall calcifications are asymptomatic, and hence undiagnosed, resulting in an underreporting of benign cases.1,2 in a subgroup analysis of 13 studies without obvious selection bias, the rate of gallbladder malignancy was noted to be only 6% (0–33%) in patients with gallbladder calcification compared to 1% (0–4%) in a matched cohort of patients without gallbladder calcification (p = 0.036; relative risk: 8.0; 95% confidence interval [ci]: 1.0–63.0).2 there has been a recent decline in the reported incidence of cagb among patients with pgb [table 1].1,3,5,6,9,10,16–18,22 a number of potential reasons for this decreasing incidence have been proposed, ranging from possible changes in the natural history of the disease as a consequence of diet or environment to the early detection of calcification due to modern methods for investigating abdominal pain such as us and ct scans.9 these factors, along with the increased incidence of laparoscopic cholecystectomies due to the willingness of patients to undergo this less invasive table 1: literature review of case series showing the incidence of porcelain gallbladder with concomitant gallbladder carcinoma1,3,5,6,9,10,16–18,22 author and year of case series samples n (%) pgb cases concomitant pgb and cagb cases kapoor et al.16 2016 116 1 0 (0.0) chen et al.10 2015 192 0 (0.0)* khan et al.9 2011 1,200 13 (1.1) 0 (0.0) kim et al.22 2009 3,159 9 (0.3) 0 (0.0) puia et al.18 2005 12,000 4 (0.0) 0 (0.0) kwon et al.17 2004 1,608 13 (0.8) 1 (7.7) stephen et al.1 2001 25,900 44 (0.2) 2 (4.5) towfigh et al.3 2001 10,741 15 (0.1) 0 (0.0) etala6 1962 1,786 26 (1.5) 16 (61.5) cornell et al.5 1959 4,271 16 (0.4) 2 (12.5) total 60,781 333 (0.5) 21 (6.3) pgb = porcelain gallbladder; cagb = carcinoma in the gallbladder. *among the 192 cases of pgb, 102 underwent a cholecystectomy while 90 were observed only; no malignancy was found in either group. figure 1: a: plain x-ray revealing a diffuse intramural calcification (arrow) in a patient with a porcelain gallbladder. b: computed tomography of the abdomen showing rim calcification of the gallbladder wall (arrow) in a patient with a porcelain gallbladder. reproduced with permission from sen kk, upadhyaya a, pimpalwar y, d’souza j. cancer in porcelain gallbladder: rare imaging trait.19 norman o. machado review | e419 surgery, may result in the removal of pgbs well before their progression to malignancy.23 moreover, geographical variation in the incidence of cagb has been suggested, as the number of cases of concomitant cagb and pcb appears to be lower in reports from the usa in comparison to the rest of the world.3,6,7,10,17 the incidence of gallbladder cancer in incomplete gallbladder calcification has been reported to range from 7–42%.1,24 however, additional investigations may be required to detect malignancy if a ct scan does not provide conclusive results. diffusionweighted magnetic resonance imaging (mri) has been reported to show hypercellular tumour regions, distinguishing benign and malignant gallbladder lesions; in a recent study, solak et al. utilised diffusionweighted mri to reveal cagb arising from a pgb, identified by linear hyperintense lines due to the hypercellularity of the tumour.7 diffuse malignancies may not be distinguishable from cholecystitis on us and ct scans; moreover, malignant lesions and inflammation can both capture intravenous contrast on a routine mri scan.7 however, diffusion-weighted mri imaging with fat suppression can delineate the hypercellular tumour regions from cholecystitis.7 potential predictors of malignancy most reports suggest that the association between cagb and pgb can be found in patients with focal mucosal calcification rather than those with extensive calcification and mucosal sloughing.1,8,20 however a recent systematic review did not support the view that the depth of calcification is a predictor of malignancy; hence, this factor should not be used as an indicator of the risk of developing malignancy in the future.2 patient age, calcifications limited to a focal area of the gallbladder wall and the absence of stones or microcrystals within the gall bladder lumen were also not found to be a significant risk factors for gallbladder malignancy in pgb.2 in terms of clinical presentation, typical symptoms of gallbladder cancer (including painless jaundice, courvoisier’s sign and unexplained weight loss) and a gallbladder mass were the only statistical significant independent predictors of the presence of malignancy (or: 83.6, 95% ci: 2.3–2,979.1; p = 0.015 and or: 3226.6, 95% ci: 17.2–603,884.8; p = 0.003, respectively).2 unfortunately, both typical gallbladder cancer symptoms and gallbladder masses are indicative of advanced malignancy; hence, these indicators are of little use in detecting early malignancy when a curative resection is still feasible.2 the clinician’s role clinicians are often concerned of the risk of malignancy among pgb patients. when these patients are symptomatic, even in the absence of malignancy, a cholecystectomy is a prudent approach.1,2,9 however, a dilemma arises when dealing with patients who are asymptomatic, have been diagnosed incidentally and have no features to suggest malignancy. unfortunately, current evidence from the literature does not indicate predictors for the development of malignancy in the future.1,2,9 with an overall risk of malignancy of 0.8–6% among patients with pgb, the role of a prophylactic cholecystectomy is debatable.2,12,22,25 moreover, the risk of major complications following a laparoscopic chole cystectomy favours a nonoperative approach.1,3,9,22 proponents of a prophylactic cholecystectomy emphasise the benefit of removing the gallbladder and thus eliminating any early undetected malignancies at a potentially curative stage.23,26 such an approach could achieve both a better long-term outcome and avoid the potential legal issues associated with delayed management. therefore, for patients who are relatively young and fit, a prophylactic cholecystectomy is a reasonable option; however, for those whose perceived risk of perioperative morbidity or mortality is greater than the 6% risk of developing malignancy, a nonoperative approach is advisable.2 nevertheless, it is important to note that patients who are managed conservatively may require close follow-up with frequent radiological imaging to detect malignancy. in addition, the failure to eject bile due to a calcified gallbladder might lead to gallstone formation.2,9 the role of a hepatobiliary scan in assessing the ejection fraction of the gallbladder in such patients is not clear.8 during a prophylactic cholecystectomy on patients with pgb, the cholecystectomy specimen should be subjected to frozen section/histopathological examination. if this reveals a malignancy, then a conversion to an extended/radical cholecystectomy should be carried out by wedge resection of liver tissue and the gallbladder bed, followed by a lymphadenectomy.16 in a recent report, kapoor et al. recommended an anticipatory extended cholecystectomy in patients whose gallbladder wall thickness was >3 mm on radiological imaging and in whom the possibility of malignancy could not be ruled out.16 this procedure involves the removal of a 2 cm wedge of segments ivb and v of the adjoining liver and a subsequent lymphadenectomy if the frozen section confirms malignancy. using this approach, the cholecystohepatic plane is not breached and it is possible to perform an porcelain gallbladder decoding the malignant truth e420 | squ medical journal, november 2016, volume 16, issue 4 en masse removal of the malignant lesion; resection of the adjoining liver en masse prevents the possible microscopic infiltration of gallbladder cancer into the liver.16 l a pa r o s c o p i c c h o l e c y s t e c t o m i e s patients with pgb are generally not considered ideal patients for a laparoscopic cholecystectomy because of the brittle nature of the calcified gallbladder and the difficulty in grasping and dissecting it.1 however, in the absence of evidence of malignancy, successful laparoscopic cholecystectomies (including single-port procedures) have been reported, with a conversion rate to open surgery of 5–25%.9,10,21 in their case series, khan et al. indicated that the main cause of conversion was an inability to obtain an adequate critical view of the cystic duct and artery.9 in most patients, the risk of cholecystectomyrelated complications is relatively low, with major complications occurring in 3–4% of cases, including perioperative mortality and common bile duct injuries (0.5% each).2,27 however, the risk may be significantly higher in patients with adverse gallbladder conditions, such as recurrent inflammation or cirrhosis, or in individuals with significant comorbidities, particularly those of a cardiac or respiratory nature.27,28 in a recent report, perioperative complications following a cholecystectomy in patients with pgb varied based on the presence of symptoms prior to the surgery; the rate of complications was 10.7% among those who were asymptomatic and 16.7% among those who were symptomatic.15 moreover, complications led to eight endoscopic or percutaneous interventions and five additional surgeries.15 conclusion in summary, recent evidence has shown that that the potential risk of developing malignancies among patients with pgb is much lower than previously believed. however, there are as yet no clinical indicators to suggest which patients might develop malignancies in the future. typical symptoms which are suggestive of gallbladder cancer are of little clinical benefit as they tend to indicate advanced malignancy with a poor prognosis. the optimal management for symptomatic patients with pgb or individuals who are young and fit is a prophylactic cholecystectomy. for those with a perioperative risk of complications or mortality greater than the risk of developing malignancy, a prophylactic cholecystectomy is not recommended. however, a nonoperative approach may subsequently require close follow-up. references 1. stephen ae, berger dl. carcinoma in the porcelain gallbladder: a relationship revisited. surgery 2001; 129:699–703. doi: 10.10 67/msy.2001.113888. 2. schnelldorfer t. porcelain gallbladder: a benign process or concern for malignancy? j gastrointest surg 2013; 17:1161–8. doi: 10.1007/s11605-013-2170-0. 3. towfigh s, mcfadden dw, cortina gr, thompson je jr, tompkins rk, chandler c, et al. porcelain gallbladder is not associated with gallbladder carcinoma. am surg 2001; 67:7–10. 4. polk hc jr. carcinoma and the calcified gall bladder. gastroenterology 1966; 50:582–5. doi: 10.1016/s0016-5085 (66)80037-9. 5. cornell cm, clarke r. vicarious calcification involving the gallbladder. ann surg 1959; 149:267–72. doi: 10.1097/00000658195902000-00013. 6. corsetti rl, wanebo hj. gallbladder cancer. in: cameron jl, ed. current surgical therapy, 5th edition. st. louis, missouri, usa: mosby, 1998. pp. 462–8. 7. solak a, solak i, genç b, sahin n. the role of diffusion-weighted examination in non-polyploid gallbladder malignancies: a preliminary study. turk j gastroenterol 2013; 24:148–53. doi: 10.4318/tjg.2013.0659. 8. kane ra, jacobs r, katz j, costello p. porcelain gallbladder: ultrasound and ct appearance. radiology 1984; 152:137–41. doi: 10.1148/radiology.152.1.6729103. 9. khan zs, livingston eh, huerta s. reassessing the need for prophylactic surgery in patients with porcelain gallbladder: case series and systematic review of the literature. arch surg 2011; 146:1143–7. doi: 10.1001/archsurg.2011.257. 10. chen gl, akmal y, difronzo al, vuong b, o’connor v. porcelain gallbladder: no longer an indication for prophylactic cholecystectomy. am surg 2015; 81:936–40. 11. nagorney dm, mcpherson ga. carcinoma of the gallbladder and extrahepatic bile ducts. semin oncol 1988; 15:106–15. 12. rana ss, bhasin dk. porcelain gall bladder on endoscopic ultrasound. endosc ultrasound 2013; 2:112–13. doi: 10.4103/ 2303-9027.117702. 13. rakić m, patrlj l, kopljar m, kliček r, kolovrat m, loncar b, et al. gallbladder cancer. hepatobiliary surg nutr 2014; 3:221–6. doi: 10.3978/j.issn.2304-3881.2014.09.03. 14. gómez-lópez jr, de andrés-asenjo b, ortega-loubon c. a porcelain gall bladder and a rapid tumor dissemination. ann med surg (lond) 2014; 3:119–22. doi: 10.1016/j.amsu. 2014.09.002. 15. ansari s. porcelain gallbladder. indian j gastroenterol 2014; 33:399. doi: 10.1007/s12664-013-0362-x. 16. kapoor vk, singh r, behari a, sharma s, kumar a, prakash a, et al. anticipatory extended cholecystectomy: the ‘lucknow’ approach for thick walled gall bladder with low suspicion of cancer. chin clin oncol 2016; 5:8. doi: 10.3978/j.issn.23043865.2016.02.07. 17. kwon ah, inui h, matsui y, uchida y, hukui j, kamiyama y. laparoscopic cholecystectomy in patients with porcelain gallbladder based on the preoperative ultrasound findings. hepatogastroenterology 2004; 51:950–3. 18. puia ic, vlad l, iancu c, al-hajjar n, pop f, bălă o, et al. [laparoscopic cholecystectomy for porcelain gallbladder]. chirurgia (bucur) 2005; 100:187–9. 19. sen kk, upadhyaya a, pimpalwar y, d’souza j. cancer in porcelain gallbladder: rare imaging trait. indian j cancer 2011; 48:132–4. doi: 10.4103/0019-509x.76646. norman o. machado review | e421 20. shimizu m, miura j, tanaka t, itoh h, saitoh y. porcelain gallbladder: relation between its type by ultrasound and incidence of cancer. j clin gastroenterol 1989; 11:471–6. doi: 10.1097/00004836-198908000-00027. 21. shivanna puttasubbappa p, pallavi p. porcelain gall bladder mimicking carcinoma gallbladder: a case report and review of literature. indian j surg 2013; 75:208–9. doi: 10.1007/s12262012-0545-1. 22. kim jh, kim wh, yoo bm, kim jh, kim mw. should we perform surgical management in all patients with suspected porcelain gallbladder? hepatogastroenterology 2009; 56:943–5. 23. cavallaro a, piccolo g, panebianco v, lo menzo e, berretta m, zanghì a, et al. incidental gallbladder cancer during laparoscopic cholecystectomy: managing an unexpected finding. world j gastroenterol 2012; 18:4019–27. doi: 10.3748/ wjg.v18.i30.4019. 24. sheth s, bedford a, chopra s. primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. am j gastroenterol 2000; 95:1402–10. doi: 10.1111/j.1572-0241.2000.02070.x. 25. igami t, usui h, ebata t, yokoyama y, sugawara g, takahashi y, et al. single-incision laparoscopic cholecystectomy for porcelain gallbladder: a case report. asian j endosc surg 2013; 6:52–4. doi: 10.1111/ases.12008. 26. gollan jl, bulkley gb, diehl am. national institutes of health consensus conference: gallstones and laparoscopic cholecystectomy. jama 1993; 269:1018–24. doi: 10.1001/ jama.1993.03500080066034. 27. machado no. biliary complications postlaparoscopic cholecystectomy: mechanism, preventive measures, and approach to management: a review. diagn ther endosc 2011; 2011:967017. doi: 10.1155/2011/967017. 28. machado no. laparoscopic cholecystectomy in cirrhotics. jsls 2012; 16:392–400. doi: 10.4293/108680812x13462882736493. university of the twentyfirst century m arch 2001 saw an important conference being held in muscat, heralding signifi cant changes in higher education in oman and in the arabian gulf region in general. with the theme the university of the 21st century, the conference outlined strategies for modern teaching and learning methods, globalisation, information technology and funds generation. the initiative was evident in the patron’s address by the minister for higher education,1 which outlined plans for higher education in the country, to match the vision of oman for the year 2020, by which time, as a post-oil economy, the country’s most reliable asset would be its manpower. globalisation, skills in information technology, the shift from teaching to learning, a lifelong learning culture and the need to involve private sector in higher education were recurring themes in the various learned papers presented in the conference. the conference has struck the right note at the right time for the arab world, where higher education – especially professional education – lies fettered by examination-oriented courses that are rigid, pattern-bound and overcrowded. many students fail to acquire professional skills, self-learning ability and the right ethical attitudes. this is particularly true of medical education, where many new graduates are unable to perform adequately in clinical settings. the skills of the products of such an educational system may not be competitive in the future world of telemedicine, where national barriers are irrelevant. as pointed out by lord dearing2 in his keynote address of the conference, ultimately, anyone with access to a networked computer , anywhere in the world, will have at his or her fi ngertips the entire gamut of human knowledge.1 future physicians will work in settings that will require co-ordination of clinical data, utilization of consultants and physician extenders, literature retrieval and health care delivery. in an age where knowledge doubles every fi ve years, and where the shelf life of knowledge rapidly decreases, medical schools cannot rely on the traditional system of imparting knowledge any more. medical informatics should be be the medium for the new curriculum, right from the fi rst preclinical year, so that it remains an integral part of students’ routine patient management needs. it is not enough to teach it as a separate course. the curriculum must be problem based and taskoriented, giving the students the skills to effectively use the fl ood of information they encounter online. information technology (it) specialists in oman are rising to the occasion, judging by the blueprints revealed by the director of centre for information technology, sultan qaboos university (squ). among the plans is an e-learning initiative for oman, including a national academic network. however, it is the educators who should be responsible for curriculum design and development, course materials, instructional design and directly addressing the students. here comes the daunting task of educating the educator. the others – infrastructure building, communication, software acquisition, installation, running and maintenance – would be tame compared with it. college of medicine, squ is starting a medical education department, which, it is hoped, would be equal to the task. the emerging universities and medical schools are even better placed to introduce problem based and informatics oriented curricula as they are starting from the scratch. student motivation is the single most crucial element for the success of problem based and student centred learning methods. for the past two decades i have been fi nding that if we trust students to learn for themselves, motivation will automatically come—and raise their levels of aspiration. professional students are young adults who squ journal for scientific research: medical sciences 2001, 1, 1–2 ©sultan qaboos university university of the twentyfi rst century: opportunities and challenges for medical education ala’aldin al-hussaini department of behavioural medicine, college of medicine, sultan qaboos university, p.o. box: 38 al-khod 123, muscat, sultanate of oman. e-mail: aladdin@squ.edu.om e d i t o r i a l a l h u s s a i n i2 thrive in a learning environment that has mutual trust, respect, freedom of expression, where individual differences are accepted and where the learning process relates to and uses the learners’ own experiences. our own experience in the department of behavioural medicine, college of medicine, squ is a case in point. since 1996, the department has adopted studentcentred, interactive learning methods that emphasised on critical reading and thinking that was relevant to the culture of the students. after a period of initial adjustment problems, we found that there was more value in the balance between a discovery approach to learning and the covering-of-material approach to teaching. the students’ interest and involvement were overwhelming. they tapped all available sources, ranging from libraries and the internet to conducting surveys and preparing mini research papers, and discovered hitherto unknown resources in themselves. such interactive courses challenge students to acquire skills for their future lifelong education, where immense motivation and self-directed learning skills will be required, especially considering that much of future education is going to be distance learning. already many reputed universities have adopted distance learning, thus making lowcost higher education easily accessible. each of the arab universities has the potential to become a similar centre of distance learning. we could cater to students around the world, not only from the arab world. all these possibilities have arisen because distance learning is increasingly relying on electronic learning (e-learning), which is wider in scope. it is not essential that the e-learner signs up for a course. provided the student has clear goals (possible if he or she is trained in a problem based way), a substantial amount can be learnt from the web alone. the major research journals, scientifi c databases and professional discussion groups are already online, many of them free. the arab universities must contribute to this globalisation by actively doing research and making results available online. we ourselves have added our own humble stream to the ocean of interactive information: squ journal for scientific research: medical sciences is available on the internet at http://www.squ.edu.om/med/mj. a simple internet search brings up the journal, and we keep receiving feedbck from far-fl ung regions of the world. this would not have happened, had we been content with the print version . professor l. schrum of university of georgia3 suggested that globalisation would cause universities to become increasingly interlinked. i would go further and predict the university of the future to be a network of links, more residing in digital media than in campuses. already, from the comfort of one’s desktop, one can closely interact with alien cultures and concepts. however, we need not fear a global monoculture. as professor hans ginkel of the united nations university, tokyo4 rightly observed, the reverse is likely to happen, leading to a pluricultural and multipolar world. however, the danger of cultural dilution and distortion exists, which we must combat by inculcating the right ethical attitudes in students. aware of this, the college of medicine, squ, is conducting mandatory interdisciplinary activity weeks and is planning a compulsory course on medical ethics. a very important note struck in the conference was that of privatisation of higher education. the pace of change and obsolescence of knowledge will soon render higher education too expensive for the state alone to manage. privatisation is a proven way to tackle this problem. many respected centres of learning in europe, australia and america are privately owned and operated. therefore the move to privatise higher and technical education in oman – with quality control standards – is to be welcomed. to sum up, based on the insights from the conference and my own two decades’ experience as an educationist, i suggest the following action plan for the arab medical colleges: (i) evolve a curriculum based on student centred and problem based learning, (ii) emphasise hands-on skills by giving students early exposure to clinical settings, (iii) ensure that the faculty becomes adept at medical informatics to be able to guide the students, (iv) nurture in students the appropriate ethical attitudes, human values and cultural roots, (v) start a strong faculty development with the above objectives, especially in the newly opening medical schools and universities, and (vi) privatise, albeit with caution, maintaining strict quality control. in this age of fast shifting economic trends, a society has to secure itself in something that is durable and fl exible. investment in education is the best option for oman since twenty years hence, as a post-oil economy, a highly educated and trained manpower will most probably be the only reliable economic resource. the initiatives in the conference indicate the planners’ sensitivity to the needs of the times. let us allow the winds of information and globalisation blow freely through our universities, while refusing any to blow us off our feet. r e f e r e n c e s 1. h.e. al-manthari ym. status and prospects of higher education in the sultanate of oman. international conference on university of the 21st century, muscat 2001. 2. lord dearing. university of the 21st century. ibid. 3. schrum l. creating electronic educational environments: a challenge for educators and learners. ibid. 4. ginkel h. globalisation of culture and the role of the university. ibid. squ med j, november 2011, vol. 11, iss. 4, pp. 519-521, epub. 25th oct 11 submitted 14th april 11 revision req. 12th jun 11, revision recd. 10th jul 11 accepted 7th sep 11 1department of anaesthesia & icu, sultan qaboos university hospital, muscat, oman; 2department of anaesthesiology, brookdale university hospital medical centre, new york, usa. *corresponding author email: jyotiburad@yahoo.com مضاعفات القسطرة الوريدية املركزية كسر سلك الدليل – كارثة ميكن جتنبها قتيبة توفيق، براديبتا بهاكتا، جيوتي ُبراد، براجيانديبتا مي�رسا، راجيني كو�ضاليا امللخ�ص: ق�ضطرة الوريد املركزي طريقة �رسيرية غازية وا�ضعة النت�ضار يف املمار�ضة الطبية. وعلى الرغم من اأنها اإجراء اآمن عندما تتم عرب توجيه املوجات فوق ال�ضوتية، اإل اأنه حتدث ال�ضعوبات وامل�ضاعفات حتى يف اأيدي ذوي اخلربة. ن�ضف هنا ال�ضعوبات التي واجهناها عندما انك�رس �ضلك الدليل اأثناء اإدخال الق�ضطرة الوريدية املركزية يف مري�س يعاين من مر�س فقر الدم املنجلي. مفتاح الكلمات: ق�ضطرة، وريدية مركزية، فقر الدم املنجلي، حادث موؤ�ضف، �ضلك الدليل، تقرير حالة، ُعمان. abstract: central venous catheterisation (cvc) is a common bedside invasive procedure done in medical practice. even though it is a safe procedure when done with ultrasound guidance, difficulties and complications do occur even in experienced hands. here, we describe the difficulties encountered in the form of the breakage of the guidewire while inserting a cvc in a patient with sickle cell disease. keywords: catheterisation, central venous; sickle cell disease; mishap, guidewire; case report; oman. complications of central venous catheterisation breakage of guidewire-a disaster averted qutaiba a. tawfic,1 pradipta bhakta,1 *jyoti burad,1 pragyandipta mishra,2 rajini kausalya1 case report patients with sickle cell disease (scd) often experience degradation of their peripheral veins due to frequent hospital admissions for management of crises and the need for multiple central venous catheter insertion in the later part of their life. the standard seldinger’s technique for central venous catheter insertion is quick, simple and safe. more than 5 million central venous catheter insertions are performed yearly in the usa alone by physicians and nurses with different levels of experience yet the mechanical complication rate is below 10%.1 seldinger’s technique uses a j-tip guidewire for insertion of the central venous catheter; the rare mechanical complications are looping, entrapment or disengagement of venous devices, breakage, embolism, cardiac perforation, tamponade and death.2-4 we report such a mechanical complication in a scd patient with special mention of the anticipated difficulties of central venous catheter insertion in patients who need multiple central venous cannulation. case report a thirty-one year-old female patient with scd was admitted to the intensive care unit at sultan qaboos university hospital, oman, with acute chest syndrome, shock and respiratory distress requiring a mechanical ventilation. she was prepared for central venous catheter insertion following failures to obtain good peripheral access. there were several marks and scar tissue on both sides of her neck and upper chest indicating multiple previous central venous catheter insertions. the pre-procedure ultrasound revealed a good calibre right internal jugular vein in the upper neck, which became slight narrower when traced to the lower angle of sedillot's triangle; it had an irregular outline with multiple collaterals. the picture was almost same on left side. the right internal jugular vein was selected for insertions of a 7.0 french triple-lumen central venous catheter using seldinger’s technique. after obtaining a good backcomplications of central venous catheterisation breakage of guidewire-a disaster averted 520 | squ medical journal, november 2011, volume 11, issue 4 flow of blood from an 18-gauge introducer needle, a j-tip guidewire was advanced. the guidewire encountered mild resistance during insertion, which was overcome by manipulating and redirecting it. the introducer needle was removed and the skin dilator was passed over the guidewire after a small skin nick. there was significant resistance to the advancement of the dilator in the subcutaneous tissue. the skin incision was deepened and the tract was re-dilated with continuous firm pressure on the dilator. after successful dilatation, the central venous catheter was threaded over the guidewire with some resistance; a backflow of blood could be seen in the proximal two lumens confirming the correct position. while withdrawing the guidewire through the distal lumen, some resistance was encountered. gentle traction was of no avail; therefore, we advanced the guidewire for a few centimetres to release it from the central venous catheter. the guidewire was rotated by 90 degrees before its withdrawal was again attempted.5 this time, the guidewire could be retracted few centimetres more. again, some resistance was encountered; then, there was a sudden loss of resistance after which the guidewire came out. after removal, we noticed that the j-tip portion was missing. since we could not trace the j-tip, we removed the entire catheter. fortunately, the j-tip was inside the catheter half protruding from the tip. examination of the rest of the guidewire did not reveal any defect other than a sharp bend in the middle [figure 1]. later, chest fluoroscopy ruled out the possibility that any broken part of the guidewire had been left inside the patient. discussion repeated central venous catheter insertion in patients with scd or those undergoing chemotherapy may have many undesirable consequences. they are at higher risk of thrombosis due to the primary disease and multiple venipuncture attempts, which may later lead to central vein stenosis.6 stenosis of a vein at higher level in the neck can be diagnosed easily by pre-procedure ultrasound, but lower level stenosis may falsely dilate the internal jugular vein (ijv) in the neck luring the physicians to attempt forceful central venous catheter insertion. it will be difficult or impossible to insert the guidewire/central venous catheter depending on the degree of stenosis. even after successful central venous catheter insertion, the risk of further stenosis and complete occlusion remains high. there is also a theoretical risk of cannulating the dilated azygos and hemiazygos veins if the stenosis is below their union with superior vena cava. this is difficult to diagnose in a chest radiograph unless a lateral view is done where it is seen as acute posterior angulation of central venous catheter tip.7 scars due to central venous catheter and mediport insertion may cause extensive fibrosis of the skin and subcutaneous tissue and may distort the vascular anatomy. it may pose significant problems when advancing the introducer needle, dilating the guidewire tract and also threading the central venous catheter over the guidewire.7 ultrasound can be of great help in making a differential diagnosis in this type of patient with multiple previous attempts and anatomical abnormalities. also ultrasound helps during the procedure in guiding the introducer needle for venous puncture as well as inserting the guidewire in such problematic patients. even cine-ultrasound can be used to monitor the whole procedure in case a c-arm is not available. without ultrasound guidance, carotid artery puncture is very common in these patients due to their distorted anatomy.9 it is difficult to judge how much force is optimum when dilating the tract and excessive force may kink or weaken the guidewire and potentially may puncture or shear the posterior wall of the vein. therefore, even a good calibre vein seen in preprocedure ultrasound does not guarantee an easy and successful cannulation in these patients. most physicians use the standard j-tip guidewire for central venous catheter insertion. this consists of a stainless steel core wound by a spring. increased flexibility of the j-tip is obtained at the expense of potential weakness at the junction of the j-tip.4 there are incidental reports of breaking of the j-tip of guidewire during forcible extraction.3,7 shimamoto and arai described this as follows: “the guidewire was acutely bent between the first rib and clavicle as a plastic catheter over a needle was used to access the subclavian vein and the guidewire was introduced through the plastic catheter after removing the metal needle”.9 lack of experience, improper technique and manufacturing defects have also been cited as the other causes of qutaiba a. tawfic,pradipta bhakta, jyoti burad, pragyandipta mishra and rajini kausalya case report | 521 breakage.3,9 an improved guidewire design has even been recommended by few proponents in order to prevent such a complication.3 an experienced resident performed the central venous catheter insertion in our case and no manufacturing defect was found in the guidewire. we believe that difficult anatomy and improper technique were the main factors for the complication in our patient. stenosis in the vein might have caused an acute angulation of the guidewire. fibrotic tissue in the neck required excessive force for dilation that kinked and damaged the angulated guidewire. it became lodged in the central venous catheter during removal and broke off at the damaged point in spite of the application of only gentle force. thus it is always advisable to use some sort of imaging guidance like ultrasound or fluoroscopy during the whole procedure in problematic cases like this. even ultrasound can be placed along the long axis of vein and dilator in case of difficult scarred tissue dilatation, as in our case, in order to keep the dilator and the lumen of the vein in view. also, fluoroscopy should be used in conjunction with this to re-confirm the safety. if the guidewire gets lodged or damaged, the cvc and the guidewire should be removed completely and checked for integrity, but this technique entails re-puncturing the vein. to prevent this, the guidewire should be pushed a few centimetres to dislodge it from the sharp bevel of the introducer needle and then rotated by 90 to 180 degrees. this will straighten the j-tip against the tempered side of introducer needle without damaging it. with this manoeuvre, the guidewire can be withdrawn without disturbing the position of the introducer needle thus preventing re-puncturing the vein. conclusion this case reminds of possible anatomical and iatrogenic venous deformities in patients requiring multiple central venous cannulations, such as patients with scd or on chemotherapy. these can result in disastrous complications during cvc insertion if there is forcible dilatation of the scarred subcutaneous tissue. routine use of ultrasound and fluoroscope guidance throughout the procedure can be of great help in avoiding such complications. references 1. mcgee dc, gould mk. preventing complications of central venous catheterization. n engl j med 2003; 348:1123–33. 2. kusminsky re. complications of central venous catheterization. j am coll surg 2007; 204:681–96. 3. suzuki t, ito k, nishiyama j, hasegawa k, kanazawa m, fukuyama h. development of a safe guidewire. j anesth 2006; 20:64–7. 4. monaca e, trojan s, lynch j, doehn m, wappler f. broken guide wire--a fault of design? can j anaesth 2005; 52:801–4. 5. arya vk, kumar a. technique for retrieval of j-tip guide wire without withdrawing introducer needle during central venous cannulation by seldinger technique. anesth analg 2004; 98:553–4. 6. farrell j, gellens m. ultrasound-guided cannulation versus the landmark-guided technique for acute haemodialysis access. nephrol dial transplant1997; 12:1234–7. 7. asudani d, wretzel s, patel r, stayman a. a judgment call. cleve clin j med 2008; 75:690–1, 695. 8. palepu gb, deven j, subramanyam m, mohan s. impact of ultrasonography on central venous catheter insertion in intensive care. indian j radiol imaging 2009; 19:191–8. 9. shimamoto t, arai t. breakage of a seldinger spring guide wire during percutaneous catheterization of a subclavian vein. masui 1997; 46:376–8. figure 1: broken guidewire with a sharp kink in the middle and unravelled external spring at the proximal end of broken j-tip. squ med j, august 2011, vol. 11, iss. 3, pp. 391-398, epub. 15th aug 11 submitted 3rd feb 11 revision req. 11th apr 11, revision recd. 18th apr 11 accepted 18th may 11 1department of haematology, sultan qaboos university hospital, muscat, oman; 2department of haematology, the adelaide & meath hospital, incorporating the national children’s hospital, tallaght, dublin, ireland. *corresponding author email: sskindi@squ.edu.om <l^vèàí÷]<ìœfi<t¯¬<ª<ì◊ëçf÷]<ün~j÷]<l]å^ñ⁄<›]ç~jâ]<|^® vün~j÷]<l^à¬^ñ⁄<ƒ⁄<‡ëö^fè7]<ÿ^€√jâ]<‡¬<si^fl÷] l^èeå_<ì√q]ü⁄<ƒ⁄<l˜^u<ã∏<üëüœi<    35%   1%      1282 x 10938.4 x 109 7 – 1410.2         6 14 4     :مفتاح الكلمات abstract: heparin is one of the most frequently used anticoagulants. it is easy to use, but can be associated with life-threatening side effects. one of these is heparin-induced thrombocytopenia syndrome (hits), which develops in about 3–5% of patients exposed to heparin and is associated with thrombosis in 1% of cases. we report here the successful treatment of five patients with hits who were treated with alternative anticoagulants namely danaparoid or hirudin. the median time between their exposure to heparin and onset of symptoms and or signs was 10.2 days (range 7–14 days). platelet counts decreased to a mean of 38.4 x 109 /l (12–82 x 109/l). all five patients had evidence of thrombosis; four patients had clinical and radiological evidence of pulmonary emboli, one patient had confirmed deep vein thrombosis (dvt) and one patient had extensive skin necrosis of the thighs and abdomen. platelet aggregation test were positive in two patients, inconclusive in one patient and negative in two patients. two patients were anticoagulated with danaparoid and three with hirudin until their platelet counts returned to normal between 4 and 14 days (average 6 days) following the recognition of the syndrome. our patients had significant morbidity, but no mortality. immediate withdrawal of heparin is of paramount importance and introduction of alternative anticoagulant is necessary in the presence of thrombosis. keywords: unfractionated heparin; low-molecular weight heparin; heparin-induced thrombocytopenia; hirudin; danaparoid; case report; oman successful use of alternative anticoagulants in the management of heparin-induced thrombocytopenia with thrombotic complications report of 5 cases and review of literature *salam alkindi,1 owen p smith,2 helen enright2 case report successful use of alternative anticoagulants in the management of heparin-induced thrombocytopenia with thrombotic complications report of 5 cases and review of literature 392 | squ medical journal, august 2011, volume 11, issue 3 heparin is one of the most useful drugs in the prevention and treatment of arterial and venous thromboembolic diseases. it is generally very well tolerated, but it can be associated with a number of serious side effects, heparin-induced thrombocytopenia syndrome (hits) being one of them.1 there are two types of hits. type 1 hits is mild, transient, non-immune-mediated thrombocytopenia and occurs commonly following the institution of heparin. it is believed to be due to platelet aggregation and removal by the reticuloendothelial system. it is not associated with thrombosis, and no treatment is required; heparin withdrawal also may not be necessary. type ii, or immune-mediated hits, on the other hand is a more serious condition. it is thought to be due to immunoglobulin (usually immunoglobulin g (igg), but also igm and iga).1 it usually develops 5–14 days following exposure to all types of heparin, including low molecular weight heparin (lmwh), or immediately following the second exposure to heparin.2 heparin dependent antibodies are frequently encountered, however thrombocytopenia/ thrombosis is seen only in about 3–5% of patients exposed to heparin, with thrombosis seen in about 1%. usually this occurs 5–10 days after the initiation of heparin therapy.3,4,5 the incidence of thrombocytopenia was thought to be lower in lmwh as compared to unfractionated heparin (ufh); however, recent data suggest it is not as low as was initially thought.6 this may be due to the lesser interaction between lmwh and platelet pf4, which is crucial for the development of hits.3‒5 we report here five cases of type ii hits developed following exposure to heparin sodium salts including lmwh. our aim is to highlight the need for vigilance in monitoring patients with recent exposure to heparin preparations, allowing early recognition of the syndrome and commencement of prompt and appropriate therapy. methods the medical records of our patients who were diagnosed as having hits over a one year period were retrospectively evaluated. once the diagnosis of hits is suspected, samples are taken for aggregation studies. platelet aggregation is performed by combining platelet-poor patient serum to donor platelets, and adding heparin, or a control solution of normal saline. platelet aggregations are then measured for 15 minutes using a platelets aggregometer, and the test is considered positive when light transmission changes ≥20%. case one a 55 year-old man was admitted for total hip replacement and received lmwh (enoxaparin) prophylaxis. a week later he became breathless, weak, and fainted with sudden onset of apnoea; the electrocardiogram (ecg) monitor showed slow atrial fibrillation. cardiopulmonary resuscitation was performed, after which emergency angiography showed bilateral pulmonary emboli. preoperative table 1: summary of important demographic and haematological parameters of all five cases case # 1 2 3 4 5 age (years) 55 68 42 51 74 sex m f f m m platelets at admission x 109/l 201 182 225 182 139 white blood count at admissions x 109/l 7.1 12.9 7.2 6.1 7.8 type of heparin used enoxaparin enoxaparin minihep minihep minihep duration of heparin therapy (days) 9 14 11 14 7 nadir platelets counts x 109/l 78 48 12 25 35 therapy used danaparoid danaparoid hirudin hirudin hirudin day 10 platelet count x 109/l 240 287 261 210 156 time to normal counts (days) 9 7 4 6 9 salam alkindi, owen p smith, helen enright case report | 393 counts showed hb 14.1 g/dl, white blood cells (wbc) 7.1 x 109/l, platelets 201 x 109/l. at the onset of the pulmonary embolism, the blood counts showed hb 10g/dl, wbc 20 x 109/l and platelets 82 x 109/l. his platelet count dropped further to 78 x 109/l. further investigation showed prothrombin time (pt) 10.6 seconds, activated partial thromboplastin time (aptt) 26.1 seconds, fibrinogen 2.36 g/l, d-dimers > 6.4 < 12.8. testing for hit by aggregation studies was negative. treatment was commenced with danaparoid infusion, while the tissue plasminogen activator (t-pa) and lmwh were discontinued. he developed transient acute renal failure requiring dialysis due to transient hypotension. the platelet count returned to normal on day nine following the episode, when danaparoid was discontinued and he was commenced on warfarin. case two a 68 year-old diabetic woman with ischaemic heart disease and peripheral vascular disease was admitted with bilateral gangrenous toes [figure 1]. she was treated with heparin followed by aortoiliac stenting. postoperatively she received clexane (enoxaparin) subcutaneous injections. two weeks later, she became acutely dyspnoeic with tachycardia, melena, and multiple necrotic skin lesions developed at the site of heparin injections on her thighs and abdomen [figure 1]. investigations showed hb 6.3 g/dl, wbc 12.9 x 109/l, platelets 48 x 109/l. hit testing by platelet aggregometry was equivocal. the lmwh was discontinued. she was treated with red cell and platelet transfusion, and her anticoagulant treatment was changed to danaparoid (organon) 750 iu twice a day (bd) subcutaneously (sc) until her platelet count returned to normal; this occurred 7 days following the initiation of danaparoid. case three a 42 year-old woman with menorrhagia underwent a total abdominal hysterectomy. prophylaxis with “minihep” (low dose unfractionated sodiumheparin: 5000 iu bd sc) was commenced the day before surgery. on admission the complete blood count (cbc) was as follows: hb 10.9 g/dl, wbc 7.2 x 109/l and platelets 225 x 109/l. she was on minihep post-operatively until she was discharged. three days after the discharge, she presented with vaginal bleeding and right calf pain and tenderness. a doppler scan confirmed deep vein thrombosis. full blood counts showed hb 10.8 g/dl wbc 5.3 x 109/l, platelets 12 x 109/l; the coagulation screen was normal apart from elevated d-dimers. she was transfused with platelets. hit testing by platelet aggregometer was negative. she was treated with hirudin until her platelet count returned to normal (on the fourth day of hirudin infusion), and was subsequently anticoagulated with warfarin for 6 months. case four a 51 year-old man underwent anterior resection at another hospital for a colon carcinoma. he received unfractionated heparin (ufh, minihep) prophylaxis preand postoperatively. his cbc prior to surgery showed hb 10.7 g/dl, wbc 6.1 x 109/l, platelets 182 x 109/l. three weeks later, he was admitted to our hospital with a 3-day history of gradual onset of dyspnoea and haemoptysis with swelling of table 2: therapeutic agents used to treat heparin-induced thrombocytopenia (hit) agent dose grade of recommendation advantages disadvantages danaparoid sodium 2000–3000 loading done 150–200/hr maintenance dose 1b can be used in severe renal failure. used in hit prophylaxis in high risk patients. monitoring only by anti-xa 5–10% cross reactivity with heparin hirudin (lepirudin) 0.4 mg/kg bolus 0.15 mg/kg/hr continuous infusion 1c easily monitored by activated partial thromboplastin time (aptt) contraindicated in renal failure, allergic reactions fondaparinux 2.5–5 mg 2c effect could be reversed by activated factor vii requires anti-xa for monitoring, clinically-defined maturity onset diabetes of the young in omanis absence of the common caucasian gene mutations 394 | squ medical journal, august 2011, volume 11, issue 3 both calves. the ventilation perfusion scan was indicative of pulmonary emboli. his blood count now showed hb 11.2 g/dl, wbc 6.1 x 109, platelets 49 x 109/l. the platelets decreased further to 25 x 109/l during the next few hours. the coagulation screen was normal apart from elevated d-dimers. hit testing using aggregation studies was positive. he was commenced on hirudin and his platelet count returned to normal on the sixth day when hirudin was stopped. he was anticoagulated with warfarin for a further 6 months. case five a 74 year-old man was admitted for repair of an abdominal aortic aneurysm. his past medical history included hypertension, polycythaemia rubra vera and reflux oesophagitis. his counts prior to operation showed hb 16.1 g/dl, wbc 7.8 x 109/l, and platelets 139 x 109/l. he received ufh (minihep) prophylaxis preand postoperatively. one week postoperatively he became breathless and wheezy. a repeat blood count showed hb 12.4 g/dl, wbc 8.1 x 109/l, platelets 74 x 109/l, partial pressure of oxygen (po2) 10.3, partial pressure of carbon dioxide (pco2) 5.0, and phosphate buffered saline (ph) 7.43. oxygen saturation was 92%. pt 12.4 seconds, aptt 27.9 seconds, d-dimers >1.0 <2.0. during the next 24 hours, his platelet count decreased further to 35 x 109/l and hit testing was positive. a ventilation perfusion scan was indicative of multiple pulmonary emboli. he was anticoagulated with hirudin until his platelet count recovered to normal nine days later. he was then anticoagulated with warfarin. discussion hit is an antibody mediated reaction caused by exposure to heparin leading to devastating thrombotic complications.7,8 following the administration of heparin, it binds to platelet factor 4 (pf4) triggering a humoral response and the formation of anti-platelet antibodies; these are generally igg, although igm and iga antibodies have been reported.2,3,9 evidence for the pathogenic role of platelet antibodies is strengthened by the typical onset of the syndrome after 5–15 days of heparin treatment. in vitro, the addition of serum from patients with hits leads to platelet aggregation and platelet secretory response. this is the basis for the enzyme-linked immunosorbent assay (elisa) test used in the diagnosis of hits. pf4 released by the (α granules) of the platelets appears to be crucial in heparin induced platelet activation and binding to igg.10,11 t h r o m b o s i s & h e pa r i n heparin–pf4 complex binding to igg leads to platelet aggregation and thrombocytopenia. the thrombosis, however, is thought to be due to platelet microparticles. negatively charged heparin binds tightly to the positively charged protein tetramer pf4 leading to platelet activation and release of microparticles that are highly procoagulants, setting off the coagulation cascade figure 1: case two (a) multiple necrotic thigh lesions at site of heparin injection; (b f) bilateral gangreneous toes. salam alkindi, owen p smith, helen enright case report | 395 with further platelet activation/release.11,12 this leads to activation of thrombin and generation of a hypercoagulable state. acute inflammatory endothelial injury (seen in some surgical patients in particular), in connection with heparin associated igg, may increase the generation of tissue factor leading to the activation of an intrinsic coagulation pathway. these two processes lead to thrombin activation/generation.12-16 incidentally, our five patients had a recent surgical intervention prior to the development of this syndrome although medical patients can also develop this complication. this has led authorities in the field to suggest a double “hit” is needed with simultaneous antigen exposure and proinflammatory signal in order to trigger a strong immune response.17 c l i n i c a l f e at u r e s hits should be suspected when the platelet count drops by 50% or more from the initial count prior to heparin therapy, although the absolute count may not drop below 150 x 109/l. however, the development of thrombosis, which can be either arterial or venous, cannot be predicted from the level of the platelet count.14,15 thrombosis can occur at any site, but lower limbs, cardiac and central nervous systems are the most common sites resulting in limb gangrene, myocardial infarction or stroke. other manifestations include skin necrosis in particular at the site of a subcutaneous heparin injection as seen in one of our patients. haemorrhage and disseminated intravascular coagulations are rare, but recognised clinical features. significantly all our patients showed evidence of thrombosis including dvt and pulmonary emboli; in one of them it was significant enough to cause a haemodynamic instability that could have resulted in death. two of our patients showed evidence of bleeding and one of them developed skin necrosis [figure 1]. it is interesting to note that one of our cases also had background of polycythaemia, a condition that is known to predispose to thrombosis. there have been similar previous reports of hits with polycythaemia.18 d i a g n o s i s o f t h e c o n d i t i o n when hits is suspected, measures should be taken to confirm the diagnosis before major complications develop and to exclude other causes of thrombocytopenia. the most important aspect of the diagnosis is the clinical suspicion and demonstration of a drop of >50% in platelet level prior to the episode, even if the platelet level is still within the normal range. warkentin has suggested the warkentin’s “4ts” pretest clinical scoring system which helps stratify patients into low, moderate and high pretest probability of hit. it is based on the level of thrombocytopenia, timing of thrombocytopenia in relation to heparin exposure, thrombosis and presence of another diagnosis to explain the thrombocytopenia.19 there are two major diagnostic pathways: activation assays which measure platelet activation and include the platelets aggregation test (pat), and serotonin release test (srt). pat is the most widely used laboratory screening test. it is based on the demonstration of platelet aggregation upon mixing patient serum with normal donor platelets in the presence of heparin. although the test is specific, its sensitivity is only about 50%. the sensitivity could be improved by a) using the same sample of heparin which was used to treat the patient; b) using normal washed platelets, and c) screening the controls for arginine13,1 expressions as opposed to histidine which result in altered affinity in platelets fc gamma riia.11,20 the srt, on the other hand, is based on exposure of normal donor platelets to radioactive14 c-serotonin and mixing it with recently heat inactivated patient serum and heparin. platelet activation leads to increased release of serotonin and radioactivity. the limitation of this test is the need to use a radioactive substance, which a lot of laboratories try to avoid. also, it requires time and the result may not be available quickly enough for a clinical decision; however, it has a sensitivity of 90% and a specificity approaching 100%. flow cytometry is a promising alternative which avoids radioactivity, but it has not yet been widely adopted or evaluated for routine clinical testing.21-23 the antigen detection assay or elisa based assay is used to assess the presence of antibodies against heparin/pf4 complex. this test is gaining popularity, though it is associated with about 3–20% false positive results in the absence of thrombocytopenia or thrombosis. false negative results can occur particularly when antibodies against other than heparin/pf4 complex do exist;24 however, in general, it has an excellent negative predictive value. successful use of alternative anticoagulants in the management of heparin-induced thrombocytopenia with thrombotic complications report of 5 cases and review of literature 396 | squ medical journal, august 2011, volume 11, issue 3 m a n a g a m e n t the mainstay of the management of hits is that all forms of heparin, including lmwh should be stopped. efforts should be made to establish the diagnosis and/or to exclude other causes of thrombocytopenia. treatment is required for the original thrombotic process for which heparin was given, and for the treatment of the complications that follow the onset of hits. there may be a case for prophylactic anticoagulation as over 50% of patients with isolated hits subsequently develop thrombosis. a lt e r n at i v e a n t i c o a g u l a n t s there are two alternative anticoagulants danaparoid and hirudin. danaparoid is composed of low molecular weight heparanoid comprising heparin sulphate (84%), dermatan sulphate (12%) and chondroitin sulphate (4%). it is different from heparin and lmwh in the degree of sulphation and molecular weight.4,20, 21,25 it is useful in thrombosis associated with heparin (both in arterial and venous types) and in coronary heart disease and haemodialysis. however, it is associated with a number of disadvantages particularly, 5–10% cross reactivity with heparin, bleeding with no available antidote, long half-life and it has no effect on thrombin. it also requires anti-xa assay for its monitoring. the dose is not well established, however 2000 iu intravenous or sc as a bolus dose followed by 2000 iu twice daily is recommended for patients of average build. it is available in europe, but not in the usa. hirudin is a leech-derived direct thrombin inhibitor peptide achieving an effective anticoagulation in hits and without crossreactivity with heparin. hirudin and other antithrombins such as hiruko and argatroban have the advantage of easy monitoring of anticoagulant effects using aptt. it is given at a dose of 0.4 mg/ kg bolus followed by 0.15 mg/kg/hour continuous infusion and adjusted according to the desired aptt. it is metabolised by the kidneys thus it is not recommended in patients with renal failure, or in patients undergoing haemodialysis. ancord is a potent defibrinogenating agent derived from the malayan pit viper. it converts fibrinogen into abnormal non-crosslinked fibrin polymers that are cleaved rapidly and removed from the circulation. it is used in pulmonary thromboembolic disease, deep vein thrombosis and thrombosis complicating hits. it is administered at a dose of 1 u/kg by intravenous route and monitored using fibrinogen levels; however, it lacks any activity against thrombin which is increased in many patients with hits. it also has an unpredictable effect on fibrinogen and does not achieve its anticoagulants effect rapidly.26 fondaparinux (arixtra) is composed of a modified pentasaccharide similar to heparin. its selectively inhibits xa and it was shown to be effective in hit. fondaparinux does not bind to pf4 and as such does not seem to cause hit itself, although there have been some recent reports of hit antibodies present without causing platelets depletion or thrombosis. its effects could be theoretically reversed by recombinant activated factor vii.27 warfarin is a useful oral agent, particularly when further anticoagulation is required; however, warfarin is not recommended until 5 days have elapsed from the onset of hits, or the platelet counts have returned to normal. the use of warfarin early on in the acute phase can cause a precipitant drop in protein c levels causing further thrombosis; however, if the patient is already anticoagulated with warfarin, it may be continued.26 other alternative treatments, including antiplatelet agents such as aspirin, dipyridamole and dextran, have being used particularly to inhibit platelet aggregation and further platelet activation; however, they have no role in inhibiting thrombin activity and as such they are not routinely recommended. plasmapheresis has also been suggested to remove the circulating abnormal igg. plateletpheresis has also been employed particularly to stop platelet destruction in a cardiopulmonary bypass situation. intravenous immunoglobulin has also been used to treat hits with some anecdotal success. prophylactic platelet transfusions should be restricted to patients with active bleeding as giving platelets in this condition may worsen thrombosis. conclusion heparin, although commonly used for management of thromboembolic disease, can be associated with very serious side effects including thrombocytopenia and thrombosis. hits is frequently unrecognised until the development salam alkindi, owen p smith, helen enright case report | 397 of a serious life or limb threatening thrombotic episode so platelets counts should be monitored regularly in patients receiving heparin. these cases demonstrate that hits can occur with the use of all forms of heparin including prophylactic, low dose ufh and lmwh. our data suggest that hits is also seen with sodium heparin salts as opposed to calcium salts as reported previously. the use of an aggregation test is useful guide, but it is associated with a number of false negative results and the diagnosis has to remain a clinical one. serological based testing is gaining momentum and its one of the most useful tests available. prompt withdrawal of all forms of heparin including heparin flushes, or heparin impregnated intravascular catheters, is crucial to avoid further complications. early introduction of alternative anticoagulation therapy is recommended when thrombosis is present, or the risk of developing thrombosis is high. prompt recognition of this syndrome, discontinuation of all forms of heparin and institution of alternative anticoagulant therapy are the cornerstones of the successful management of this condition. references 1. cancio lc, cohen dj. heparin-induced thrombocytopenia and thrombosis. j am coll surg 1998; 186:76–91. 2. warkentin te, kelton jg. temporal aspects of heparin induced thrombocytopenia. n eng j med 2001; 344:1286–92. 3. db brieger, mak kh, marchant kk, topol ej. heparin induced thrombocytopenia. j am coll cardiol 1998; 31:1449–59. 4. warkentin te, change bh, greinacher a. heparininduced thrombocytopenia: toward consensus. thromb haemost 1998; 79:1–7. 5. gittoes njl, wilde jt, sheppard mc, ferner re heparin-induced thrombosis. postgrad med j 1997; 73:684–5. 6. prandoni p, siragusa s, girolami b, fabris f. the incidence of heparin induced thrombocytopenia in medical patients treated with low molecular weight heparin. blood 2005; 106:3049–54. 7. szokol jw. heparin-induced thrombocytopenia. semin cardiotho vasc anesth 2010; 14:73–4 8. battistelli s, genovese a, gori t. heparin-induced thrombocytopenia in surgical patients. am j surg 2010; 199:43–51. 9. wu kk, phillip m, d’souza d, hellums jd. platelet activation and arterial thrombosis. lancet 1994; 344:991–5. 10. pouplard c, may am, lochmann s, amiral j, vissac am, marchand m, et al. antibodies to platelet factor 4 heparin after cardiopulmonary bypass patients anticoagulated with unfractionated heparin or low molecular-weight heparin. clinical implications for heparin induced thrombocytopenia. circulation 1999; 99:2530–6. 11. arepally g, mckenzie se, jiang xm, poncz m, clines db. fcγriia h/h131 polymorphism, a subclass-specific igg anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin induced thrombocytopenia and thrombosis. blood 1997; 89:370–5. 12. matsuo t, tomaru t, kario k, hirokawa t. incidence of heparin–pf4 complex antibody formation and heparin–induced thrombocytopenia in acute coronary syndrome. thromb res 2005; 115:475–81. 13. visentin g, ford se, scott jp, aster rh. antibodies from patients with heparin induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. j clin invest 1994; 93:81–8. 14. warkentin te, elavathil lj, hayward cp, johnston ma, russett ji, kelton jg. the pathogenesis of venous limb gangrene associated with heparin induced thrombocytopenia. ann intern med 1997; 127:804–12. 15. kelton jg, warkentin te. heparin induced thrombocytopenia, diagnosis, natural history and treatment options. postgrad med 1998; 103:169–79. 16. lobenow n, hinz p, thomaschewski s, lietz t, volger m, ladwig a, et al. the severity of trauma determines the immune response to pf4/heparin and the frequency of heparin induced thrombocytopenia. blood 2010; 115:1797–803. 17. warkentin te. hit: more than just heparin. blood 2010; 115:1664–5. 18. hayashi t, suyama y, kaneko m, okamura j, nakao y, nonakar y, nomura t. heparin-induced thrombocytopenia and thrombosis in a patient with polycythaemia. vera inter med 2004; 43:587–9. 19. lo gk, juhl d, warkentin te, sigouin cs, greinacher a. evaluation of pretest clinical score (4ts) for the diagnosis of heparin-induced thrombocytopenia in two clinical setting. j thromb haemost 2006; 4:759– 65. 20. buerger th, tautenhahn j, meyer f, lippert h. heparin-induced vascular occlusion in vasculosurgical patients. j cardiovasc surg 1999; 40:237–42. 21. walenga jm, bick rl. heparin induced thrombocytopenia paradoxical thromboembolism and other side effects of heparin therapy. med clin n am 1998; 82:635–58. 22. gobbi g, mirandola p, tazzari pl, talarico e, caimi l, martini g, et al. new laboratory test in flow successful use of alternative anticoagulants in the management of heparin-induced thrombocytopenia with thrombotic complications report of 5 cases and review of literature 398 | squ medical journal, august 2011, volume 11, issue 3 cytometry for the combined analysis of serologic and cellular parameters in the diagnosis of heparininduced thrombocytopenia. cytometry part b (clinical cytometry) 2004; 588:32–8. 23. tomer a, masalunga c, abshire tc. determination of heparin-induced thrombocytopenia: a rapid flow cytometric assay for direct demonstration of antibody-mediated platelets activation. am j hematol 1999; 61:53–61. 24. vitale m, tazzari p, ricci f, mazza ma, zauli g, martini g, et al. comparison between different laboratory tests for the detection and prevention of heparin-induced thrombocytopenia. cytometry 2001; 46:290–5. 25. nicholson cd, meuleman dg, magnani hn, egberts jfm, leibowitz da, spinler sa, et al. danaparoid is not a low molecular weight heparin. am j hosp pharm 1994; 51:2049–50. 26. lubenow n, warkentin te, greinacher a, wessel a, sloane da, krahn el, et al. results of a systemic evaluation of treatment outcomes for heparininduced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s. thromb res 2006; 117:507–15. 27. amiral j, lormeau jc, marfaing-koka a, vissac am, wolf m, boyer-neumann c, et al. absence of cross reactivity of sr90107/a/org31540 pentasaccharide with antibodies to heparin-pf4 complexes developed in heparin-induced thrombocytopenia. blood coagul fibrinolysis 1997; 8:114–7. 28. savi p, chong bh, greinacher a, gruel y, kelton jg, warkentin te, et al. effects of fondaprinux on platelets activations in the presence of heparin dependent antibodies. a blinded comparative multicentre study with unfractionated heparin. blood 2005; 105:139–44. non-medical strategies to improve pregnancy outcomes of women with gestational diabetes mellitus a literature review *iman al hashmi,1 karabi nandy,2 vidya seshan1 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e4–10, epub. 30 may 19 submitted 12 sep 18 revisions req. 25 oct & 19 dec 18; revisions recd. 25 nov & 26 dec 18 accepted 27 dec 18 1college of nursing, sultan qaboos university, muscat, oman; 2department of biostatistics & epidemiology, university of north texas health science center, fort worth, usa *corresponding author’s e-mails: reemal-sharqia@hotmail.com and eiman@squ.edu.om gestational diabetes mellitus (gdm) is defined as any degree of glucose intolerance with onset or first recognition during preg nancy.1 gdm complicates about 2.7–27% of all preg nancies, varying according to a population’s composition and the diagnostic criteria used.2,3 gdm has a profound association with maternal and neonatal complications. in the short term, pregnant women with gdm are at higher risk of developing pregnancy-induced hypertension and requiring a caesarean section (cs). moreover, women with gdm are at an increased risk of gdm in future pregnancies and also at a higher risk of developing type 2 diabetes mellitus (t2dm) in the future.4,5 gdm has also been associated with neonatal complications such as macrosomia, shoulder dystocia, birth trauma, hypo glycaemia, respiratory distress syndrome, polycythaemia and jaundice.3 furthermore, gdm in pregnant women increases the risk of obesity and glucose intolerance in their children.6 gdm is therefore an important public health issue that has major repercussions for both mother review اإلسرتاتيجيات غري الطبية لتحسني نتائج احلمل يف النساء املصابات بسكري احلمل مراجعة األدبيات اإميان الها�سمية، كرابي ناندي، فيديا �سي�سان abstract: this review aimed to examine the literature related to non-medical strategies used to improve pregnancy outcomes of women with gestational diabetes mellitus (gdm) and to determine the risk of bias of the selected studies. treatment for gdm is changing due to the increased prevalence of gdm-related maternal and neonatal complications. a growing body of evidence suggests that early detection, aggressive monitoring and management of gdm using non-medical strategies can greatly improve outcomes for pregnant women and their babies. pubmed® (national library of medicine, bethesda, maryland, usa), cumulative index to nursing and allied health literature® (ebsco information services, ipswich, massachusetts, usa), scopus® (elsevier, amsterdam, netherlands) and other electronic databases were searched for relevant literature published between 2005–2015. a total of 15 studies on women with gdm that met the inclusion criteria were included in this review and assessment of risk of bias was performed for each study. the results of the studies were consistent with findings of significant improvement in maternal and neonatal outcomes when diet was combined with moderate exercise, self-monitoring of blood glucose and individualised health education. future intervention studies in this area should be focussed on ident ifying and implementing factors that enhance and encourage adherence to the healthy behaviours mentioned above. keywords: pregnancy outcomes; maternal health; neonatal health; health behaviors; gestational diabetes mellitus. امللخ�ص: يهدف هذا الإ�ستعرا�ض اإىل درا�سة الأدبيات املتعلقة بالإ�سرتاتيجيات غري الطبية امل�ستخدمة لتح�سني نتائج احلمل بني الن�ساء ب�سبب وذلك م�ستمر تغري يف احلمل �سكري عالج اأن املعروف من املختارة. للدرا�سات التحيز خطر وحتديد احلمل ب�سكري امل�سابات زيادة اإنت�سار امل�ساعفات املتعلقة ب�سكري احلمل يف الأمهات واملواليد. وت�سري جمموعة متزايدة من الأدلة اإىل اأن الك�سف املبكر والإدارة الفعالة ل�سكري احلمل باإ�ستخدام اإ�سرتاتيجيات غري طبية ميكن اأن يح�سن كثريا من النتائج بالن�سبة للحوامل واأطفالهن. مت البحث يف قواعد البيانات عن الأدبيات ذات ال�سلة واملن�سورة بني 2005-2015 يف امل�سادر الأكرتونية ®pubmed )املكتبة الوطنية للطب، بيثادا، مرييالند، الوليات المريكيه(، والفهر�ض الرتاكمي للتمري�ض والأدب ال�سحي املتحالفة ®ebsco )خدمات املعلومات، ايب�سويت�ض، ما�سات�سو�ست�ض(، ®scopus )�سكوب�ض، ال�سيفري، اأم�سرتدام، هولندا( وم�سادر اإلكرتونيه اأخرى. و قد مت يف هذا الإ�ستعرا�ض اإدراج جمموع 15 درا�سة م�ستوفية ملعايري ال�سمول ومت تقييم خماطر التحيز لكل درا�سة. وكانت نتائج الدرا�سات مت�سقة مع نتائج التح�سن الكبري يف النتائج بالن�سبة لالأمهات لالأمهات احلوامل واأطفالهن عندما مت اجلمع بني النظام الغذائي مع ممار�سة ن�ساط ج�سماين معتدل، والر�سد الذاتي لل�سكر يف الدم والتعليم ال�سحي الفردي. لذلك ينبغي اأن تركز درا�سات التدخل املقبلة يف هذا املجال على حتديد وتنفيذ العوامل التي تعزز وت�سجع التقيد بال�سلوكيات ال�سحية املذكورة اأعاله خالل فرتة احلمل. الكلمات املفتاحية: نتائج احلمل؛ �سحة الأم؛ �سحة حديثى الولدة؛ ال�سلوكيات ال�سحية؛ �سكري احلمل. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.002 https://creativecommons.org/licenses/by-nd/4.0/ iman al hashmi, karabi nandy and vidya seshan review | e5 and offspring. gdm is preventable and, even after onset, if detected early can be reversible. therefore, early det ection of gdm provides a window of opportunity to intervene and reduce adverse perinatal outcomes.7 the treatment of choice for gdm includes medical and non-medical interventions. medical interventions include oral hypoglycaemic agents and insulin therapy. although insulin therapy traditionally has been the first line treatment, it is not without its challenges.8 nonmedical interventions are recommended as first-line treatments and involve self-care through lifestyle modif ications (typically diet and exercise) and self-monitoring of blood glucose levels (smbg).9 therefore, the purpose of this literature review was to investigate non-medical strategies used to treat gdm in order to improve preg nancy outcomes. literature review a literature search was performed using pubmed® (nat ional library of medicine, bethesda, maryland, usa), cumulative index to nursing and allied health litera ture® (ebsco information services, ipswich, massa chusetts, usa) and scopus® (elsevier, amsterdam, netherlands) to retrieve all peer-reviewed articles publ ished between 2005–2015. abstracts were screened by at least two investigators using the following inclusion criteria: the article had to be published in a peer-reviewed journal between 2005–2015; written in english; involved human female subjects in the reproductive age group; and have the primary aim of assessing different strat egies or interventions in decreasing the incidence of at least one gdm-related complication among women with gdm. keywords used included “educational non-medical strategies”, “improved pregnancy outcomes”, “treatment”, “pregnancy”, “gdm”, “gestational diabetes”, “life-style”, “diet”, “exercise”, “maternal outcomes” and “neonatal outcomes”. the literature search identified 15 studies that met the review’s inclusion criteria [table 1]. in the reviewed articles, the intervention group received a combination of strategies or a single strategy that was compared to a control group. seven studies reported effects of particular dietary advice, one trial described the impact of regular exercise and five studies evaluated a combination of diff erent lifestyle modifications involving both diet and exercise.10–22 moreover, one study examined vitamin d supplementation and one evaluated probiotics supple mentation.23,24 insulin treatment was considered in most studies if the glycaemic target was not achieved after using other strategies. assessment of risk of bias was performed for each study by considering eight domains: 1) randomisation of participants; 2) whether the study was double-blinded; 3) sample size power; 4) the use of appropriate statistical analyses; 5) an adequate intervention period; 6) managed violations in assumptions of statist ical tests; 7) whether the study was controlled for con founding factors; and 8) controlled for co-intervention. each domain was assigned one point, where a total score ≥5 indicated low-to-moderate risk of bias and a total score of <5 indicated a moderate-to-high risk of bias. effectiveness of dietary strategies seven experimental studies evaluated the effectiveness of various dietary strategies—included a low-sodium diet, a low-to-moderate carbohydrate diet, a low-gly caemic index (lgi) diet and a high-fibre (hf) diet—for improving maternal and neonatal outcomes in women with gdm.10–16 five studies implementing dietary strat egies demonstrated statistically significant reductions in the incidence of at least one gdm-related complication.10,12,13,15,16 a detailed investigation of these studies revealed various outcomes. asemi et al.’s 2014 randomised contr olled trial (rct) revealed that consuming a low-sodium diet (2,400 mg/day) for four weeks was associated with significantly lower cs risks and macrosomia rates and less need for insulin treatment.11 the low-sodium diet included fruits, vegetables, whole grains, low-fat dairy products and reduced amounts of saturated fats. similarly, landon et al. conducted a single-blinded rct and found that a combination of dietary counselling, nutrition therapy and smbg were significantly associated with reduced rates of pre-eclampsia, cs, macrosomia and the likelihood of babies being large for gestational age (lga). furthermore, the intervention group experienced significantly lower weight gain compared to the control group (p <0.001).14 unfortunately, specific dietary recommendations were not reported in this study. a study with a quasi-experimental design cond ucted by perichart-perera et al. found that the risk of having a baby with low birth weight (<2,500 g) was sig nificantly lower among women with gdm who had received medical nutrition intervention versus those in the control group (p = 0.041).16 medical nutrition therapy consisted of moderate carbohydrate intake (40–45%), smbg and individual nutrition counselling. compliance rates were acceptable and 73.1% of the intervention participants were adherent to the recomm ended dietary advice.16 a double-blinded rct conducted by crowther et al. reported that women with gdm who received individualised dietary advice and instruc tions about smbg had a significant reduction in the incidence of serious perinatal adverse effects—including neonatal death, shoulder dystocia, bone fracture and nerve palsy—compared to women who received routine non-medical strategies to improve pregnancy outcomes of women with gestational diabetes mellitus a literature review e6 | squ medical journal, february 2019, volume 19, issue 1 table 1: summary of selected studies evaluating the non-medical strategies used to improve pregnancy outcomes of women with gestational diabetes mellitus. author and year of study summary of results odar et al.10 (2004) • no significant difference between intervention and control groups for requiring insulin therapy, average apgar scoreat five minutes, rate of induction of labour, rate of cs, rate of macrosomia, rate of neonatal admission to nicu, rate of pre-eclampsia or pregnancy induced hypertension and rate of lga (p ≥0.10). asemi et al.11 (2014) • the dash group had a significant reduction in cs rate, macrosomia rate and need for insulin therapy compared to the control group (p ≤0.01). • no significant difference was found for newborn length,apgar score at five minutes, incidence of polyhydramnios and mean gestational age (p ≥0.31). morenocastilla et al.12 (2013) • maternal weight gain was significantly higher in the control group (2.1 kg) than the low-cho group (1.1 kg; p = 0.017). • no significant difference was found for average gestational age at delivery, incidence of ketonuria or rates of cs, macrosomia, newborn hypoglycaemia or insulin treatment (p ≥0.2). crowther et al.13 (2005) • the intervention group had a significantly higher rate of nicu admission and induction of labour compared to the control group (p ≤0.01). • no significant difference was found for neonatal death, stillbirth, neonatal bone fracture, nerve palsy, neonatal jaundice requiring phototherapy and the need for either elective or emergency cs (p ≥0.11). landon et al.14 (2009) • no significant difference was found between the intervention and control groups for the average gestational age at birth, rate of neonatal jaundice, neonatal hypoglycaemia, birth trauma, preterm delivery, respiratory distress syndrome or neonatal admission to nicu (p ≥0.12). • a significant difference was found for reduced birth weight, macrosomia rate, lga, reduced risk for pre-eclampsia rate, reduced risk for cs, average bmi at delivery and average weight gain (p ≤0.02). louie et al.15 (2011) • the lgi group had a significantly lower glycaemic load than the hf group (p ≤0.001). • no significant difference was detected for average birth weight, rate of macrosomia, rate of lga, average maternal weight gain, rate of insulin treatment and rate of emergency cs (p ≥0.2). perichartperera et al.16 (2009) • a significant difference was found between control and mnt groups for rate of pre-eclampsia, first maternal hosp italisation rate and neonatal admission rate at intermediate care unit (p ≤0.001). • women in the control group were at a significantly higher risk of having babies with low birth weight (p = 0.041). sugiyama et al.17 (2014) • no significant difference was found between the intervention and control groups for pregnancy-induced hyper tension, cs or the frequency of lga and macrosomia (p >0.05). • no significant difference was found in neonatal complications (including rds, hypoglycaemia and jaundice; p >0.05). barakat et al.18 (2013) • no significant difference was found between the exercise and control groups for requirement of cs, average neonatal birth weight, average apgar score at one minute and the average gestational age in days (p ≥0.2). • rate of macrosomic babies was significantly higher in the control group than the exercise group (p = 0.002). artal et al.19 (2007) • 38.6% of dr group subjects were prescribed insulin, while only 35.1% of edr group subjects needed insulin to maintain normal blood glucose levels. • there was no significant difference for the mean infant birth weight (p = 0.24). • the incidence of cs was similar in the edr and dr groups (50.0% versus 44.7%). • subjects in both groups who experienced weight gain were at higher risk for having macrosomic babies compared to those who had weight loss or no weight change (p = 0.12). bo et al.20 (2014) • the dr group showed the highest maternal complications (12%). • neonatal complications were highest among the dr group (10%). • exercise groups (er and bder) had the lowest cs rates (17.7% and 16%, respectively). • er group had the lowest rate of lga (9.8%). cao et al.21 (2012) • the intervention group had a significant reduction in rates of premature delivery, admission to nicu and average birth weight compared to the control group (p ≤0.05). • although not significant, yet subjects who received intensive treatment had a lower macrosomic rate (p = 0.143). • risk for cs was higher in the intervention group, while the risk of pre-eclampsia was higher in the control group. • percentage receiving insulin treatment was higher in the intervention group (33.9% versus 26.4%). yang et al.22 (2014) • the control group had a significantly higher rate of macrosomia and lga than the intervention group (p ≤0.01). • pre-eclampsia was significantly higher in the intervention group than the control group (p = 0.031). • apgar score <7 was significantly higher in the control group compared to the intervention group (p = 0.02). asemi et al.23 (2015) • women receiving vitamin d supplementation had a significant improvement in relation to the incidence of poly hydramnios, neonatal jaundice and newborn admission compared to the control group (p ≤0.04). • no significant difference was found for pre-eclampsia, preterm delivery, macrosomia, need for cs, insulin treatment, babies’ gestational age at delivery, apgar scores at one and five minutes and newborn hypoglycaemia (p ≥0.13). lindsay et al.24 (2015) • probiotic supplementation had no significant effect on improving the maternal metabolic values or improving the pregnancy outcomes of women with gdm. cs = caesarean section; nicu = neonatal intensive care unit; lga = large for gestational age; dash = dietary approaches to stop hypertension; cho = carbohydrate; bmi = body mass index; lgi = low-glycaemic index; hf = high-fibre; mnt = medical nutrition therapy; rds = respiratory distress syndrome; dr = dietary recommendations only; edr = exercise and dietary recommendations; er = exercise recommendations only; bder = behavioural dietary and exercise recommendations; gdm = gestational diabetes mellitus. iman al hashmi, karabi nandy and vidya seshan review | e7 prenatal care (p ≤ 0.01).13 finally, sugiyama et al. found a significantly lower rate of lga and lower maternal weight gain when comparing diet therapy alone or in combination with smbg and insulin (if needed) with the control group that received routine antenatal care.17 they found that both pre-pregnancy body mass index (bmi) and weight gain during pregnancy were indep endently correlated with the incidence of lga. two dietary-based studies were unsuccessful in improving any maternal or neonatal outcomes of women with gdm.12,15 moreno-castilla et al. conducted a study in spain that failed to find a significant difference between the low-carbohydrate group and the control diet group in terms of the maternal and neonatal outcomes.12 similarly, louie et al. reported no significant difference between the lgi diet group and the hf diet group in relation to the incidence of macrosomia, cs, high blood glucose levels, glycated haemoglobin (hba1c) and the need for insulin therapy.15 due to the fact that the reviewed studies imple mented different dietary strategies, reported incons istent results, had diverse population compositions and heterogeneous inclusion criteria, a definitive conclusion with regard to implementation of dietary strategies could not be reached. additionally, the inclusion of pregnant women with various degrees of hyperglycaemia and the inconsistency in diagnostic criteria employed for gdm diagnosis across these studies further contributes to an inability to make informed recommendations on appro priate diets for women with gdm. for example, studies used criteria from the american diabetes association, the 2006 national diabetes and pregnancy clinical guide lines, world health organization, the australian diabetes in pregnancy society and the society of obstetrics and gynecology and one study did not clearly state which diagnostic criteria was used for gdm diagnosis.10–12,14,15 adherence to suggested dietary advice may have a considerable impact on the effectiveness of specific dietary behaviours. only one study reported that compl iance to the recommended dietary strategy resulted in improved findings.15 perichart-perera et al. studied a mixed population of women with gdm and women with t2dm; however, compliance with the dietary advice among the group of women with gdm was not reported, making it difficult to evaluate adherence.16 furthermore, women’s interest in the specific dietary advice that they received and their readiness to change their dietary behaviours were not measured in two unsuccessful studies, which may have played a role in the outcomes.12,15 changing dietary behaviours may be challenging, especially during the relatively short period of time that is pregnancy. therefore, it is essential to support and encourage women with gdm to enhance dietary adherence during the new intervention. the quality of the evidence and the risk of bias varied across the reviewed studies. two of the five clinical trials that reported a significant effect on impr oving pregnancy outcomes had a low-to-moderate risk of bias and three had a moderate-to-high risk.10,11,13,14,16 in relation to the studies that were unsuccessful in improving pregnancy outcomes in women with gdm, one had a low-to-moderate risk of bias and the other had a moderate-to-high risk.12,15 numerous factors may have contributed to an increased risk of bias among these studies, such as the study design, length of the study and the statistical analyses used. two studies were not double-blinded and lacked random assignment of subjects to treatment; these findings limit the validity of the final outcomes.16,17 all five clinical trials that reported improved preg nancy outcomes had short intervention periods which may have underestimated the true impact of the inter ventions.10,11,13,14,16 of these, four studies included women who were receiving insulin treatment.11,13,14,16 as insulin has a hypoglycaemic effect, this may have enhanced the effect of the intervention, therefore leading to an over estimation of positive findings. however, both clinical trials that reported the intervention group as having negative associations with improving pregnancy outcomes included women on insulin treatment which minimises the risk of insulin as a confounding factor.12,15 furthermore, none of the studies, except crowther et al.’s study, controlled for the subjects’ demographic charact eristics in their statistical analyses, which may have had confounding effects on the outcome and potentially increased bias.13 finally, only two studies clearly stated that assumptions related to normality of distribution had been checked and both reported significant impr ovements in pregnancy outcomes.10,13 effectiveness of exercise strategy one double-blinded rct’s objective was to evaluate the effectiveness of regular exercise in reducing the risk of gdm-related complications.17 the study found that moderate-intensity resistance and aerobic exercise (three days/week, 25–30 min/session) had a significant impact on reducing macrosomia rates, decreasing the percentage of cs and restricting weight gain. more than 95% of the subjects were adherent to the training sessions, which justifies the significant results. however, this study had a moderate-to-high risk of bias. one of the potential biases was that the group’s allocation was not blinded to the project staff, thus increasing the likeli hood of information bias. moreover, no mention was made of whether statistical assumptions were checked and whether potential violations to those assumptions non-medical strategies to improve pregnancy outcomes of women with gestational diabetes mellitus a literature review e8 | squ medical journal, february 2019, volume 19, issue 1 were corrected during analyses. uncorrected violations may have led to incorrect interpretations of the final results. effectiveness of dietary and exercise strategies five rcts examined the efficacy of mixed strategies, such as diet in combination with exercise and smbg, on improving maternal and neonatal outcomes in women with gdm and their offspring.18–21 generally, these four studies showed a beneficial effect on limiting the incidence of at least one gdm-related complication. in a non-double-blinded rct study, bo et al. found that an exercise intervention applied either alone or in combination with a behavioural intervention was associated with a significant reduction in the incidence of cs, hba1c, postprandial glucose and lga in comparison to a diet and behavioural intervention alone.20 behavioural strategies included oral and written cues to encourage the participant to make healthy dietary choices. cao et al. demonstrated that an intensive treatment regimen resulted in a significantly reduced incidence of premature delivery, neonatal admission to the neonatal intensive care unit and an average birth weight.21 comp arably, yang et al. found that lifestyle interventions significantly reduced macrosomia rates, lga and infant apgar scores less than seven at one minute.22 never theless, yang et al.’s study showed that lifestyle interventions were significantly associated with increased risk for pre eclampsia. women who received lifestyle modifications (diet and exercise) in this study had a significantly higher rate of achieving target physical activity in the previous month (30 minutes/time, ≥7 times/week) than the diet group alone; however, this finding brings to attention the risk involved in overdoing physical activities during pregnancy. artal et al.’s study showed that an exercise inter vention limited weight gain among obese gdm women but there was no significant difference in gestational age at delivery, the need for cs and birth weight.19 one possible explanation is that artal et al. considered subjects’ preference in assignment to the exercise group, possibly justifying the limited weight gain within this group. on the other hand, several factors could have contributed to the non-significant findings in artal et al.’s study. missing data for the infant birth weight, gestational age at delivery and delivery method in both groups may have resulted in biased findings. however, it was found that subjects who experienced weight gain were at higher risk for having macrosomic babies in comparison to those who had weight loss or no weight change.18 it is important to note that these findings are based on limited data generated from rcts with a moderateto-high risk of bias and caution should be taken when interpreting their results. the above studies varied in their population composition and diagnostic criteria used for gdm diagnosis.10–24 in addition, due to the nature of the pregnancies, none of these studies had an adequate intervention period, which may have led to underestimation of study findings. four studies had a risk of bias from insulin treatment administered parallel to the study interventions, thereby affecting the validity of the results.13,14,16,17 three studies shared the risk of information bias for not blinding outcome assessors, thereby potentially increasing the risk of inflated study findings.19,20,22 furthermore, only bo et al.’s study contr olled for subjects’ ages, baseline metabolic activity and pre-pregnancy bmi in their data analysis, which increases confidence in their findings.20 in light of the above limitations, the data appear to be consistent in reporting low macrosomia rates, low lga and cs rates among women with gdm who received lifestyle modifications compared to women who received only routine antenatal care.20–22 the evid ence supports the efficacy of dietary strategies combined with moderate exercise and smbg in decreasing the incidence of gdm-related complications. effectiveness of dietary supplements strategies studies that examined dietary supplements have demon strated an impact in recommended areas of gdm out comes. asemi et al.’s double-blinded rct showed that consumption of vitamin d supplements was significantly associated with a reduction in the incidence of polyhy dramnios, neonatal jaundice and neonatal admission to the neonatal intensive care unit among women with gdm compared to patients receiving a placebo supplement.23 this study was in response to accumulating evidence towards an association between abnormal glucose levels and vitamin d deficiency. in general, this study had a low to-moderate risk of bias. a potential source of bias was the risk for confounding factors since women in the control group may have received vitamin d from other sources, such as sun exposure and fortified foods. how ever, no significant difference was found between the vitamin d and placebo groups in relation to vitamin d intake. the serum 25-hydroxyvitamin d level was signif icantly higher among the vitamin d group, indicating a low risk of confounding factors. overall, it appears that supplementing the diets of women with gdm with vitamin d is promising in reducing gdm-related adverse effects. iman al hashmi, karabi nandy and vidya seshan review | e9 the metabolic effects of probiotic supplementation has recently been investigated by lindsay et al. in a double blinded, placebo-controlled rct.24 this rct revealed that probiotic supplementation did not have a significant effect on improving maternal metabolic values or impr oving the pregnancy outcomes for women with gdm. this could be due to the high drop-out rate (18%) of the rct after starting the treatment. discussion gdm is a worldwide metabolic problem that has negative maternal and neonatal effects with long-term conseq uences. in light of the reviewed literature, various inter ventions have been offered to improve maternal and neo natal outcomes among women with gdm. although the majority of the reviewed articles were rcts with powered sample sizes and appropriate statistical analyses, most of these studies had method ological issues, such as risk for confounding factors and a risk for information bias and contamination. in add ition, samples lacked diversity, with the majority of these studies targeting women who are caucasian. as the studies in this review do not provide enough evidence to guide clinical practice and health policy; well designed double-blinded rcts are needed to identify the best strategies to improve gdm outcomes. further clinical trials should explore the type, intensity and duration of exercise that would improve pregnancy outcomes. in addition, the effectiveness of probiotics and vitamin d supplementation on pregnancy outcomes in women with gdm needs to be further studied. conclusion although the literature is growing in the field of gdm management, the incidence rate of gdm-related compl ications continues to rise, most likely due to unhealthy lifestyle behaviours. in general, insufficient focus has been directed towards the prevention of gdmrelated compl ications. furthermore, there is a lack of evidence about the strategies that enhance adherence to healthy lifestyle behaviours. the focus of upcoming research should be on identifying the factors that enhance and encourage adherence to healthy behaviours, such as increased self efficacy towards healthy behaviours. a c k n o w l e d g e m e n t the authors would like to thank everyone who supported the work in this paper. references 1. world health organization. diagnostic criteria and classific ation of hyperglycaemia first detected in pregnancy. geneva: world health organization. who/nmh/nd/13.2. pp. 1–62. 2. nayak pk, mitra s, sahoo jp, daniel m, mathew a, padma a. feto-maternal outcomes in women with and without gestational diabetes mellitus according to the international association of diabetes and pregnancy study groups (iadpsg) diagnostic criteria. diabetes metab syndr 2013; 7:206–9. https://doi.org/10. 1016/j.dsx.2013.10.017. 3. gasim t. gestational diabetes mellitus: maternal and perinatal outcomes in 220 saudi women. oman med j 2012; 27:140–4. https://doi.org/10.5001/omj.2012.29. 4. barakat mn, youssef rm, al-lawati ja. pregnancy outcomes of diabetic women: charting oman’s progress towards the goals of the saint vincent declaration. ann saudi med 2010; 30:265–70. https://doi.org/10.4103/0256-4947.65253. 5. mpondo bc, ernest a, dee he. gestational diabetes mellitus: challenges in diagnosis and management. j diabetes metab disord 2015; 14:42. https://doi.org/10.1186/s40200-015-0169-7. 6. shriraam v, rani ma, sathiyasekaran bw, mahadevan s. aware ness of gestational diabetes mellitus among antenatal women in a primary health center in south india. indian j endocrinol metab 2013; 17:146–8. https://doi.org/10.4103/2230-8210.107861. 7. mithal a, bansal b, kalra s. gestational diabetes in india: science and society. indian j endocrinol metab 2015; 19:701–4. https://doi.org/10.4103/2230-8210.164031. 8. nicholson w, bolen s, witkop ct, neale d, wilson l, bass e. benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review. obstet gynecol 2009; 113:193–205. https://doi.org/10.1097/aog.0b0 13e318190a459. 9. de holanda vr, de souza ma, dos santos rodrigues mcp, pinheiro akb, damasceno mmc. knowledge of pregnant women about gestational diabetes mellitus. j nurs ufpe online 2012; 6:1648–54. 10. odar e, wandabwa j, kiondo p. maternal and fetal outcome of gestational diabetes mellitus in mulago hospital, uganda. afr health sci 2004; 4:9–14. 11. asemi z, samimi m, tabassi z, esmaillzadeh a. the effect of dash diet on pregnancy outcomes in gestational diabetes: a randomized controlled clinical trial. eur j clin nutr 2014; 68:490–5. https://doi.org/10.1038/ejcn.2013.296. 12. moreno-castilla c, hernandez m, bergua m, alvarez mc, arce ma, rodriguez k, et al. low-carbohydrate diet for the treatment of gestational diabetes mellitus: a randomized cont rolled trial. diabetes care 2013; 36:2233–8. https://doi.org/10.23 37/dc12-2714. 13. crowther ca, hiller je, moss jr, mcphee aj, jeffries ws, robinson js, et al. effect of treatment of gestational diabetes mellitus on pregnancy outcomes. n engl j med 2005; 352:2477–86. https://doi.org/10.1056/nejmoa042973. 14. landon mb, spong cy, thom e, carpenter mw, ramin sm, casey b, et al. a multicenter, randomized trial of treatment for mild gestational diabetes. n engl j med 2009; 361:1339–48. https://doi.org/10.1056/nejmoa0902430. 15. louie jc, markovic tp, perera n, foote d, petocz p, ross gp, et al. a randomized controlled trial investigating the effects of a low-glycemic index diet on pregnancy outcomes in gestational diabetes mellitus. diabetes care 2011; 34:2341–6. https://doi.org/10. 2337/dc11-0985. 16. perichart-perera o, balas-nakash m, parra-covarrubias a, rodriguez-cano a, ramirez-torres a, ortega-gonzález c, et al. a medical nutrition therapy program improves perinatal out comes in mexican pregnant women with gestational diabetes and type 2 diabetes mellitus. diabetes educ 2009; 35:1004–13. https://doi.org/10.1177/0145721709343125. https://doi.org/10.1016/j.dsx.2013.10.017 https://doi.org/10.1016/j.dsx.2013.10.017 https://doi.org/10.5001/omj.2012.29 https://doi.org/10.4103/0256-4947.65253 https://doi.org/10.1186/s40200-015-0169-7 https://doi.org/10.4103/2230-8210.107861 https://doi.org/10.4103/2230-8210.164031 https://doi.org/10.1097/aog.0b013e318190a459 https://doi.org/10.1097/aog.0b013e318190a459 https://doi.org/10.1038/ejcn.2013.296 https://doi.org/10.2337/dc12-2714 https://doi.org/10.2337/dc12-2714 https://doi.org/10.1056/nejmoa042973 https://doi.org/10.1056/nejmoa0902430 https://doi.org/10.2337/dc11-0985 https://doi.org/10.2337/dc11-0985 https://doi.org/10.1177/0145721709343125 non-medical strategies to improve pregnancy outcomes of women with gestational diabetes mellitus a literature review e10 | squ medical journal, february 2019, volume 19, issue 1 17. sugiyama t, metoki h, hamada h, nishigori h, saito m, yaegashi n, et al. a retrospective multi-institutional study of treatment for mild gestational diabetes in japan. diabetes res clin pract 2014; 103:412–18. https://doi.org/10.1016/j.diabres. 2013.12.017. 18. barakat r, pelaez m, lopez c, lucia a, ruiz jr. exercise during pregnancy and gestational diabetes-related adverse effects: a randomised controlled trial. br j sports med 2013; 47:630–6. https://doi.org/10.1136/bjsports-2012-091788. 19. artal r, catanzaro rb, gavard ja, mostello dj, friganza jc. a lifestyle intervention of weight-gain restriction: diet and exercise in obese women with gestational diabetes mellitus. appl physiol nutr metab 2007; 32:596–601. https://doi.org/10.1139/h07-024. 20. bo s, rosato r, ciccone g, canil s, gambino r, poala cb, et al. simple lifestyle recommendations and the outcomes of gestational diabetes. a 2 × 2 factorial randomized trial. diabetes obes metab 2014; 16:1032–5. https://doi.org/10.1111/dom.12289. 21. cao x, wang z, yang c, mo x, xiu l, li y, et al. comprehensive intensive therapy for chinese gestational diabetes benefits both newborns and mothers. diabetes technol ther 2012; 14:1002–7. https://doi.org/10.1089/dia.2012.0142. 22. yang x, tian h, zhang f, zhang c, li y, leng j, et al. a rando mized translational trial of lifestyle intervention using a 3-tier shared care approach on pregnancy outcomes in chinese women with gestational diabetes mellitus but without diabetes. j transl med 2014; 12:290. https://doi.org/10.1186/s12967-014-0290-2. 23. asemi z, karamali m, esmaillzadeh a. favorable effects of vita min d supplementation on pregnancy outcomes in gestational diabetes: a double blind randomized controlled clinical trial. horm metab res 2015; 47:565–70. https://doi.org/10.1055/s-00 34-1394414. 24. lindsay kl, brennan l, kennelly ma, maguire oc, smith t, curran s, et al. impact of probiotics in women with gestational diabetes mellitus on metabolic health: a randomized controlled trial. am j obstet gynecol 2015; 212:496.e1–11. https://doi.org/10. 1016/j.ajog.2015.02.008. https://doi.org/10.1016/j.diabres.2013.12.017 https://doi.org/10.1016/j.diabres.2013.12.017 https://doi.org/10.1136/bjsports-2012-091788 https://doi.org/10.1139/h07-024 https://doi.org/10.1111/dom.12289 https://doi.org/10.1089/dia.2012.0142 https://doi.org/10.1186/s12967-014-0290-2 https://doi.org/10.1055/s-0034-1394414 https://doi.org/10.1055/s-0034-1394414 https://doi.org/10.1016/j.ajog.2015.02.008 https://doi.org/10.1016/j.ajog.2015.02.008 squ med j, november 2011, vol. 11, iss. 4, pp.448-454, epub. 25th oct 11 submitted 29th jan 11 revision req. 5th mar 11, revision recd. 23rd may 11 accepted 8th jun 11 trauma caused by motor vehicle collisions (mvcs) is currently the third most common cause of death globally, with 90% of these deaths occurring in developing countries including oman. in fact, oman has one of the highest rates of deaths from mvcs in the world, with a mortality rate of 20–30 per 100,000.1 some injuries may be evident at the time of admission, while another class of injuries may remain occult for some time and then become evident when it may be too late for any intervention. blunt cerebrovascular injuries (bcvis) are one of the occult injuries caused by blunt trauma. they are considered to be relatively uncommon; however, they carry a high rate of mortality and morbidity if they remain undetected. bcvis may or may not initially present with symptoms or signs that warrant suspicion of such injuries and therefore the provision of adequate diagnostic investigations and management is crucial. the realisation of this fact led to increased awareness of the amplitude of such injuries and the need to establish adequate screening criteria and cost-effective screening modalities. if symptoms do present, however, they are usually attributable to focal neurological deficits department of surgery, sultan qaboos university hospital, muscat, oman. *corresponding author email: hani_qadhi@hotmail.com اإلصابات الَكليَلة لألوعية الدموية يف الرأس والرقبة مراجعة األدبيات عبد اهلل احلارثي، الرمي الهنائي، خليفة الوهيبي، هاين القا�ضي الكمية من ذلك ويت�ضح عامليًا، الباحثني من العديد اهتمام والرقبة الراأ�س يف الدموية للأوعية الَكليَلة الإ�ضابات نالت لقد امللخ�ص: النتائج خطورة اإىل ُيعزى قد الإ�ضابات هذه به حظيت الذي الهتمام اإن املعروفة. البحث حمركات يف املتوافرة للأدبيات الهائلة املرتبطة بها من ناحية معدلت الوفيات واملرا�ضة التي ت�ضيب الذين يتعر�ضون لها، خا�ضة مع اإمكانية ت�ضخي�ضها وجتنب م�ضاعفاتها با�ضتخدام اأجهزة الأ�ضعة املتطورة. اإن اخلطوة الأهم يف عملية جتنب عواقب هذه الإ�ضابات هو ت�ضخي�ضها املبكر بوا�ضطة فحو�ضات يتم اإجراوؤها اعتماداً على اآلية الإ�ضابة الأكرث ارتباطًا بالإ�ضابات الكليلة للأوعية الدموية يف الراأ�س والرقبة. نعر�س هنا مراجعة �ضاملة فيما يتعلق باآلية الإ�ضابة والت�ضوير ال�ضعاعي والعلج يف حالت الإ�ضابات الكليلة، ومت حتديد املقالت من خلل البحث يف ال�ضبكة الفقري، ال�ضباتي، وعائية، كليلة، الآتية: الرئي�ضية الكلمات با�ضتخدام ال�ضواهد ذات للتجارب املركزي كوكرين و�ضجل الطبية العاملية ال�ضدمة، ال�ضكتة الدماغية، تدابري علجية، وق�ضطرة جراحية. مفتاح الكلمات: وعائي، �ضباتي، فقري، اإ�ضابة، �ضكتة دماغية، علج، ق�ضطرة جراحية. abstract: blunt cerebrovascular injuries (bcvi) have been a topic of interest to many researchers worldwide as evidenced by the vast amount of available literature. the interest in these rare injuries is probably due to the significant possibility of mortality and morbidity amongst patients who sustain them, when the employment of radiological screening methods could prevent such an outcome. recognition of these injuries is the most important step towards prevention of adverse outcomes. we present a comprehensive review of the literature regarding the mechanism of injury, imaging, management, and complications of bcvi. articles were identified through a search of medline and the cochrane central register of controlled trials using the keywords blunt; vascular; carotid; vertebral; trauma; stroke; management, and endovascular. the search was limited to humans and articles in english. keywords: vascular; carotid; vertebral; trauma; stroke; management; endovascular. review blunt cerebrovascular injuries a review of the literature abdullah al-harthy, alreem al-hinai, khalifa al-wahaibi, *hani al-qadhi abdullah al-harthy, alreem al-hinai, khalifa al-wahaibi, hani al-qadhi review | 449 caused by ischaemia of the carotid or vertebral artery territories, or are due to a traumatic carotidcavernous fistula manifesting as orbital pain, proptosis, hyperaemia, cerebral swelling, or seizure.2 incidence of bcvis the general incidence of bcvis amongst all trauma admissions has been reported in the literature as <1%. the incidence of blunt carotid artery injuries (bcis) reported in the literature ranges from 0.08–0.27% while the incidence of blunt vertebral artery injuries (bvis) ranges from 0.20% to 0.77%.3,4 although these patients are a small fraction of all trauma patients, they carry risks of stroke and mortality that are as high as 58% and 59% respectively.5,6,7 mechanism of injury the three basic mechanisms of injury to the cerebrovascular vessels are: 1) severe hyperextension and rotation; 2) direct blow to the vessel, and 3) vessel laceration by adjacent bone fractures.2 injuries to the extracranial carotid artery are most commonly due to hyperextension of the vessel over the lateral articular processes of c 1–3 at the base of the skull. direct blows to the vessels in seat-belt injuries and hanging attempts are also possible causes. injuries to the intracranial segment of the carotid artery are mostly due to basal skull fractures.2 vertebral artery injuries occur most commonly in fractures involving the course of the vessel through the transverse foramina of c 2–6.8 pathogenesis with any of the mechanisms of injury mentioned above, the pathological changes in the vessels are that of intimal disruption, dissection, pseudoaneurysm formation, carotid-cavernous fistula, thrombosis and complete transection of the artery.2,3 the resultant ischaemia caused by these injuries is thought to be due to the following: 1) dissection of the artery causing haemodynamic instability, and 2) intimal disruption exposing subendothelial collagen fibres and promoting platelet aggregation, subsequent thrombosis and thromboembolism.3 is screening necessary? given the possible catastrophic implications of these injuries, the very high stroke rate in this population, and the increased awareness amongst health care professionals, the following question has been raised among investigators: “is it necessary to implement screening protocols for patients at high risk of these injuries?” the argument proposed by some investigators, who disagree with the implementation of screening protocols, is that screening this population of patients is not very cost-effective, nor does it really affect the outcome. in addition, after exposing the patient to aggressive screening and the risks of invasive digital subtraction angiography, a decision on treatment with anticoagulation therapy, interventional angiography or surgery is not always feasible. this would be because of the other morbidities from which patients of blunt trauma usually suffer, such as head injuries.9 however, other investigators attempted to prove that aggressive screening and early intervention is indeed justified and cost-effective. in a prospective analysis, between january 1996 and june 2004, cothren et al., screened 727 patients with blunt trauma who had injuries highly suspicious of an underlying bcvi, (according to comprehensive screening criteria) and underwent a 4-vessel cerebrovascular angiogram. of these patients, 244 were identified as having bcvis. antithrombotic therapy was immediately started in the 187 asymptomatic patients who had no contraindications. using the estimated stroke risk stratification according to the degree of carotid artery injury found on angiography [table 1],10 table 1: blunt cerebrovascular injuries grading scale injury grade angiographic findings i luminal irregularity or a dissection/ intramural haematoma with <25% luminal narrowing ii dissection or intramural haematoma of 25% of the lumen iii pseudoaneurysm iv vessel occlusion v vessel transection source: cothren, et al.10 blunt cerebrovascular injuries a review of literature 450 | squ medical journal, november 2011, volume 11, issue 4 bcvis among all blunt trauma patients identified in their institution.6 using the memphis criteria, 3.5% of patients were screened with bcvis identified in 29% of them. the overall incidence of bcvis in this study was found to be 1.03%.11 modalities of screening screening criteria are based on recognising types of injury mechanisms that have been shown to be highly associated with bcvis. the advent of multislice computed tomography (ct) scanners has enabled eligible patients to undergo screening with a sensitivity and specificity that is comparable to angiography, the gold standard screening tool. the treatment of most injuries is anticoagulation and in some instances, wherever indicated, endovascular therapy might be the best choice. d i g i ta l s u b t r a c t i o n a n g i o g r a p h y (d s a) digital subtraction angiography (dsa) is considered to be the gold-standard diagnostic modality to detect bcvis12,13 yet it carries a risk of serious complications given that it is an invasive modality. the risks attributable to dsa are similar to those of stroke and haemorrhage. the latter limitations and the fact that dsa is expensive and technically demanding limit its effectiveness as a screening modality for bcvis.1,14 m u lt i d e t e c t o r c o m p u t e d t o m o g r a p h i c a n g i o g r a p h y (m d c ta) multidetector computed tomographic angiography (mdcta) has emerged as a very convenient and effective screening tool for bcvi,15–19 especially after the advent of multidetector computed tomography (mdct), with some studies reporting a sensitivity and specificity approaching that of dsa. in multitrauma patients, mdct is routinely utilised to screen for injuries of the head, neck, spine, chest, abdomen and pelvic injuries. a mdcta protocol to screen for bcvis in high-risk patients is conveniently performed at the same time. it is also less expensive and non-invasive compared to dsa.14 in the literature, there only two prospective studies comparing single-slice computed tomographic angiography (cta) and magnetic resonance antithrombotic therapy was able to avert ischaemic neurological events in 32 patients. the authors concluded that the ability of screening protocols to detect these patients who are at risk of stroke, and subsequently preventing it by antithrombotic therapy, decreases the long-term morbidity associated with strokes.10 screening criteria so far, two well-established screening criteria for bcvis exist, the modified denver criteria and the memphis criteria [table 2].2 the denver criteria was the first screening protocol to be established at the denver health medical centre and was later modified by its authors. using this screening method, the percentage of patients who underwent screening during the time span of their study is 4.8%, and bcvis were identified in 18% of these patients, with an overall incidence of 0.86% of table 2: screening criteria for blunt cerebrovascular injuries denver criteria memphis criteria signs/symptoms arterial haemorrhage or expanding haematoma cervical spine fracture cervical bruit neurological exam not explained by brain imaging focal neurological deficit horner’s syndrome neurological exam inconsistent with head computed tomography (ct) findings le forte ii or iii fracture pattern stroke on follow-up head ct basilar skull fracture with involvement of the carotid canal neck soft tissue injury (seatbelt sign or hanging or haematoma) risk factors le forte ii or iii fracture pattern cervical spine fracture basilar skull fracture with involvement of the carotid canal diffuse axonal injury with glasgow coma scale <6 near hanging with anoxic brain injury source: arthurs, et al.2 abdullah al-harthy, alreem al-hinai, khalifa al-wahaibi, hani al-qadhi review | 451 angiography (mra) to dsa which were done by the denver and memphis groups. in their studies, cta had a sensitivity of 47–68% and a specificity of 67–99%. cta missed 55% of grade i, 14% of grade ii, and 13% of grade iii injuries.11,12 the authors concluded in this study that cta should only be used to diagnose bcvis when dsa is not available. however, it is important to note that the cta scanners used at that time were single slice ctas, which along with other limitations such as timing contrast injection, image acquisition protocols, post-image processing delays (reformatting process), and inexperience with interpretation, might have accounted for the disappointing results in these two studies.14 in 2003, 16-slice mdcts were widely available across the usa and so trauma surgeons found resistance to using dsa.2 in a study by berne et al. in 2004, 486 patients, identified to be at risk of bcvis, underwent cta. patients who had a negative study received no further cerebrovascular imaging and were monitored for cerebral ischaemic complications. patients who had a positive cta underwent dsa to confirm the findings. the results showed that cta had a sensitivity of 100% and a specificity of 94.0% and none of the patients who had a negative cta subsequently developed any ischaemic neurological events.20 these results were questioned because the patients who had a negative cta were not confirmed to be true negatives by dsa. in the same year, bub et al. published a retrospective analysis that included 32 patients who were suspected to have bcvis and underwent both mdcta and dsa. results showed that 17 bcvis were identified in 15 of the 32 patients. mdcta done by three different radiologists had a sensitivity of 83–92% and specificity of 88–98% for detecting bcis. however, the sensitivity for vertebral artery injuries ranged from 40–60%, and the specificity ranged from 90–97%.21 in 2006, three studies, published by three different institutes, produced very similar results with regard to the use of 16-slice mdct to scan for bcvis in high risk patients. all three groups found mdct to be as accurate as dsa in detecting bcvis,15,18,19 with the exception of one patient in the study done by eastman et al., where a grade 1 injury was missed by mdct and was detected by dsa.19 in all three studies, none of the patients who was initially found to have a negative cta later developed complications attributable to an undetected bcvi. although many of the studies discussed above do prove that the accuracy of cta approaches that of dsa, the lack of prospective data comparing 16-slice cta to dsa and the small number of patients included in each study limit the reliability of the results and the validity of the conclusion that cta is equivalent to dsa. it is recommended that patients who are at high risk for bcvis should be considered for dsa regardless of their cta findings, until a large, multicentre prospective trial proves the case.2,14 m a g n e t i c r e s o n a n c e a n g i o g r a p h y (m r a) the advantage of mra over mdct is the fact that it does not carry the risk of ionising radiation or the use of contrast, but in a multi-trauma setting mra is not really a feasible or practical option. the time needed for the patient to be taken to the mr suite, for the test to be performed and the number of personnel required to perform the study are all limitations to its accessibility in a multi-trauma setting. however, in two prospective analyses by the denver and memphis groups, which compared cta and mra to dsa in patients suspected to have bcvis, mra had a sensitivity of 50–75% and specificity of 67–100%.11,12 s o n o g r a p h y duplex ultrasound is a portable and inexpensive tool that is well established in monitoring and diagnosing non-traumatic cerebrovascular pathology. however, the fact that it is operator dependant, has a limited ability to visualise cerebral vasculature at the base of the skull and also to visualise minimal injuries and dissections that are not associated with disrupted flow, has limited its role in detecting bcvi.2,14 in the few studies performed to evaluate the accuracy of duplex ultrasound to detect bcvis, results were disappointing, showing that duplex has a low sensitivity and specificity compared to dsa and that it missed injuries in patients who later on developed ischaemic complications attributable to these injuries.22,23 blunt cerebrovascular injuries a review of literature 452 | squ medical journal, november 2011, volume 11, issue 4 for patients treated initially with anticoagulation for their bcvi in order to detect any subsequent development of pseudoaneurysms requiring surgical or endovascular interventions.24–34 a n t i p l at e l e t s t h e r a p y aspirin (and in few other reports, clopidogrel) has been used as an alternative to heparin in the treatment of patients with bcvi. it has been shown to have similar efficacy to heparin in preventing neurological events. in fact, aspirin has been proven to have a better safety profile with less risk of bleeding compared to heparin, especially in the population of trauma patients.11,26–28a combination therapy of anticoagulation and antiplatelets has been practised, but any advantage has not been proven; it definitely requires further prospective trials to elicit any added benefit to the single therapy. o p e n s u r g i c a l r e pa i r direct surgical repair is advocated for discrete lesions at the carotid bifurcation or lesions below the base of the skull making it amenable for proximal and distal control. most of the time, open surgical repair is rarely considered for patients with bcvi for the reasons mentioned above.3,7 management of pseudoaneurysms is less controversial and most authors recommend surgical repair whenever it is technically feasible.24,29,33 small or inaccessible pseudoaneurysms have been managed by anticoagulation with or without proximal ligation, or by the rarely used extracranial-intracranial bypass.7,35 e n d o va s c u l a r t h e r a p y with the development of the less invasive endovascular techniques, most carotid pseudoaneurysms and dissection flaps that result from bcvi have been managed successfully with angioplasty and endoluminal stenting.36–38 endovascular therapy is an alternative to open surgical repair and of great value in the distal carotid lesions which are not amenable for open surgical repair. this therapy is recommended in cases where there is a contraindication for anticoagulation. bare or covered stents, either balloon expandable or self-expanding, have been used extensively with good outcome and no further neurological events reported.36,39,40 as compared to data on peripheral stenting, antiplatelets management the early detection and treatment of bcvis has been shown to reduce the morbidity and mortality related to these injuries. both symptomatic and asymptomatic patients with bcvi should be managed and closely monitored for any neurological deterioration. the optimal treatment of patients with bcvi is not yet well established. the appropriate management of bcvi depends on the specific injury and its anatomic site.3,7,24–28 controversies do exist in the management of dissection, thrombosis and pseudoaneurysm formations. older studies prefer surgical over non-surgical management of dissection and thrombosis.29 however, most of these lesions extend beyond the skull base, and are therefore not amenable to open surgical repair. in addition, most neurologic sequelae of these injuries are related to acute thrombosis, thrombus propagation and distal embolisation, making surgical reconstruction irrelevant. there is therefore growing support for nonsurgical management of dissections and thromboses.13,29–32 prospective trials comparing surgery with anticoagulation are not feasible. a n t i c o a g u l at i o n t h e r a p y although its efficacy has not been proven, anticoagulation therapy has been considered the treatment of choice in patients with bcvi, especially for those with high located intimal flaps, extensive dissections and small inaccessible pseudoaneurysms. anticoagulation is documented to prevent cerebral embolisation and to avoid permanent occlusions of injured vessels.3,7,25 li 29 and parikh33 have suggested improvement of outcomes with anticoagulation alone. initial systemic heparin therapy is safe and should be considered if no contraindications are present, or if the anticipated benefit outweighs the risk of bleeding in high risk patients. this should be followed by oral anticoagulation therapy with warfarin (coumadin) for three to six months.3,7,25,28 reported complications of anticoagulation include intracranial haemorrhage, gastrointestinal bleeding, retroperitoneal haemorrhage, bleeding at the site of blunt solid organ injury and re-bleeding from surgical wounds. these complications are reported to occur in 25–54% of trauma patients.6 most authors agree on the need for follow-up abdullah al-harthy, alreem al-hinai, khalifa al-wahaibi, hani al-qadhi review | 453 therapy (aspirin and clopidogrel) is advised after endoluminal stent therapy to prevent stent thrombosis and embolic ischaemic events.41 balloon occlusion techniques are a well established mode of treatment for carotid-cavernous sinus fistulae, and the results are fair to good.13,29–32 outcome the prognosis of bcvi is generally poor. all reported cases of complete arterial disruption have been fatal. other injuries of dissection, thrombosis and pseudoaneurysm formation carry variable outcomes depending on the site of the injury as well as the time of detection of these injuries. mortality rates after bcvi have been reported to be 5–40% and reasonable neurologic recovery in only 20–60% of all survivors.13,29–32 although there is some evidence to show improved outcomes with anticoagulation and antiplatelets therapy and in selected cases of surgical and endovascular interventions, the outcome of bcvi depends more on the speed of diagnosis.12,32,33 a high index of suspicion and the maintenance of aggressive evaluation protocols for patients with possible bcvi will definitely avoid diagnostic delay and may improve the overall outcome. conclusion blunt cerebrovascular injury (bcvi) may be overtly present in more than 1% of patients with blunt trauma. aggressive screening strategies uncover injuries in up to 44% of those screened. if not appropriately diagnosed and treated in a timely manner, many such injuries are responsible for significant morbidity and mortality. aggressive screening protocols are now feasible using newer generation, multidetector helical scanners capable of detecting small intimal defects in a relatively non-invasive manner. treatment has focused on reducing the atheroembolic tendency of the disrupted vessel wall. anticoagulation with heparin and antiplatelet agents has been used; however, in a multitrauma patient, the risks of bleeding and the need for immediate surgery must be taken into account. certain injuries to cervical vessels may be amenable to endovascular therapy. therefore a multi-disciplinary team consisting of the emergency physician, trauma surgeon, vascular surgeon, interventional radiologist and intensivist is recommended for immediate and follow-up care. a high index of suspicion and maintaining aggressive evaluation protocols for patients with possible bcvi will definitely avoid diagnostic delay and may improve the overall outcome after bcvi. further research into optimal treatment strategies is warranted. references 1. crash statistics oman. from: www.salimandsalima. org accessed: oct 2010. 2. arthurs zm, starnes bw. blunt carotid and vertebral artery injuries. injury 2008; 39:1232–41. 3. singh rr, barry mc, ireland a, bouchier hayes d. current diagnosis and management of blunt internal carotid injuries. eur j vasc endovasc surg 2004; 27:577–84. 4. inamasu j, guiot bh. vertebral artery injury after blunt cervical trauma: an update. surg neurol 2006; 65:238–45. 5. berne jd, norwood sh, mcauley ce, vallina vl, creath rg, mclarty j. the high morbidity of blunt cerebrovascular injury in an unscreened population: more evidence of the need for mandatory screening protocols. j am coll surg 2001; 192:314–21. 6. biffl wl, moore ee, ryu rk, offner pj, novak z, coldwell dm, et al. the unrecognized epidemic of blunt carotid arterial injuries: early diagnosis improves neurologic outcome. ann surg 1998; 228:462–70. 7. fabian tc, patton jh jr, croce ma, minard g, kudsk ka, pritchard fe. blunt carotid injury. importance of early diagnosis and anticoagulant therapy. ann surg 1996; 223:513–22. 8. cothren cc, moore ee, biffl wl, ciesla dj, ray ce jr, johnson jl, et al. cervical spine fracture patterns predictive of blunt vertebral artery injury. j trauma 2003; 55:811–3. 9. mayberry jc, brown cv, mullins rj, velmahos gc. blunt carotid artery injury: the futility of aggressive screening and diagnosis. arch surg 2004; 139:609– 13. 10. cothren cc, moore ee, ray ce jr, ciesla dj, johnson jl, moore jb, et al. screening for blunt cerebro-vascular injuries is cost-effective. am j surg 2005; 190:845–9. 11. miller pr, fabian tc, croce ma, cagiannos c, williams js, vang m, et al. prospective screening for blunt cerebrovascular injuries: analysis of diagnostic modalities and outcomes. ann surg 2002; 236:386– 93. 12. biffl wl, ray ce jr, moore ee, mestek m, johnson jl, burch jm. noninvasive diagnosis of blunt blunt cerebrovascular injuries a review of literature 454 | squ medical journal, november 2011, volume 11, issue 4 27. miller pr, fabian tc, bee tk, timmons s, chamsuddin a, finkle r, et al. blunt cerebrovascular injuries: diagnosis and treatment. j trauma 2001; 51:279–85. (discussion 285–6). 28. wahl wl, brandt mm, thompson bg, taheri pa, greenfield lj. antiplatelet therapy: an alternative to heparin for blunt carotid injury. j trauma 2002; 52:896–901. 29. li ms, smith bm, espinosa j, brown ra, richardson p, ford r. nonpenetrating trauma to the carotid artery: seven cases and literature review. j trauma 1994; 36:265–272. 30. biffl wl, moore ee, offner pj, burch jm. blunt carotid and vertebral arterial injuries. world j surg 2001; 25:1036–43. 31. mckevitt ec, kirkpatrick aw, vertesi l, granger r, simons rk. blunt vascular neck injuries: diagnosis and outcomes of extracranial vessel injury. j trauma 2002; 52:472–6. 32. biffl wl, ray ce jr, moore ee, franciose rj, aly s, heyrosa mg, et al. treatment-related outcomes from blunt cerebrovascular injuries: importance of routine follow-up arteriography. ann surg 2002; 235:699–707. 33. parikh aa, luchette fa, valente jf, johnson rc, anderson gl, blebea j, et al. blunt carotid artery injuries. j am coll surg 1997; 185:80–6. 34. srinivasan j, newell dw, sturzenegger m, mayberg mr, winn hr, transcranial doppler in the evaluation of internal carotid artery dissection. stroke 1996; 27:1226–30. 35. ballard jl, bunt tj, fitzpatrick b, malone jm. bilateral traumatic internal carotid artery dissections: case report. j vasc surg 1992; 15:431–5. 36. bejjani gk, monsein lh, laird jr, satler lf, starnes bw, aulisi ef. treatment of symptomatic cervical carotid dissections with endovascular stents. neurosurgery 1999; 44:755–60. (discussion 760–1). 37. coldwell dm, novak z, ryu rk, brega ke, biffl wl, offner pj, et al. treatment of posttraumatic internal carotid arterial pseudoaneurysms with endovascular stents. j trauma 2000; 48:470–3. 38. kerby jd, may ak, gomez cr, rue lw. treatment of bilateral blunt carotid injury using percutaneous angioplasty and stenting: case report and review of the literature. j trauma 2000; 49:784–7. 39. liu ay, paulsen rd, marcellus ml, steinberg gk, marks mp. long-term outcomes after carotid stent placement treatment of carotid artery dissection. neurosurgery 1999; 45:1368–73. (discussion 1373– 4). 40. cohen je, ben-hur t, rajz g, umansky f, gomori jm. endovascular stent-assisted angioplasty in the management of traumatic internal carotid artery dissections. stroke 2005; 36:45–7. 41. bhatt dl, kapadia sr, bajzer ct, chew dp, ziada km, mukherjee d, et al. dual antiplatelet therapy with clopidogrel and aspirin after carotid artery stenting. j invasive cardiol 2001; 13:767–71. cerebrovascular injuries: a preliminary report. j trauma 2002; 53:850–6. 13. kerwin aj, bynoe rp, murray j, hudson er, close tp, gifford rr, et al. liberalized screening for blunt carotid and vertebral artery injuries is justified. j trauma 2001; 51:308–14. 14. sliker cw, mirvis se. imaging of blunt cerebrovascular injuries. eur radiol 2007; 64:3–14. 15. berne jd, reuland ks, villarreal dh, mcgovern tm, rowe sa, norwood sh, et al. sixteen-slice multi-detector computed tomographic angiography improves the accuracy of screening for blunt cerebrovascular injury. j trauma 2006; 60:1204–9. 16. schneidereit np, simons r, nicolaou s, graeb d, brown dr, kirkpatrick a, et al. utility of screening for blunt vascular neck injuries with computed tomographic angiography. j trauma 2006; 60:209– 15. 17. utter gh, hollingworthw, hallam kd, jarvik jg, jurkovich gj. sixteen-slice ct angiography in patients with suspected blunt carotid and vertebral artery injuries. j am coll surg 2006; 203:838–48. 18. biffl wl, egglin t, benedetto b, gibbs f, cioffi wg. sixteen-slice computed tomographic angiography is a reliable noninvasive screening test for clinically significant blunt cerebrovascular injuries. j trauma 2006; 60:745–51. 19. eastman al, chason dp, perez cl, mcanulty al, minei jp. computed tomographic angiography for the diagnosis of blunt cervical vascular injury: is it ready for primetime? j trauma 2006; 60:925–9. 20. berne jd, norwood sh, mcauley ce, villareal dh. helical computed tomographic angiography: an excellent screening test for blunt cerebrovascular injury. j trauma 2004; 57:11–7. (discussion 17–19). 21. bub ld, hollingworth w, jarvik jg, hallam dk. screening for blunt cerebrovascular injury: evaluating the accuracy of multidetector computed tomographic angiography. j trauma 2005; 59:691–7. 22. mutze s, rademacher g, matthes g, hosten n, stengel d. blunt cerebrovascular injury in patients with blunt multiple trauma: diagnostic accuracy of duplex doppler us and early ct angiography. radiology 2005; 237:884–92. 23. coqbill th, moore ee, meissner m, fischer rp, hoyt db, morris ja, the spectrum of blunt injury to the carotid artery: a multicenter perspective. j trauma 1994; 7:473–9. 24. byrne mp, welling re: penetrating and blunt extracranial carotid artery injuries. in: ernst cb, stanley jc, eds. current therapy in vascular surgery. st. louis: mosby, 1995. pp. 598–603. 25. cothren cc, moore ee, biffl wl, ciesla dj, ray ce jr, johnson jl, et al. anticoagulation is the gold standard therapy for blunt carotid injuries to reduce stroke rate. arch surg 2004; 139:540–6. 26. biffl wl, moore ee, elliott jp, ray c, offner pj, franciose rj, et al. the devastating potential of blunt vertebral arterial injuries. ann surg 2000; 23:672–81. departments of 1pediatric infectious diseases, 2cardiothoracic surgery and 3pediatric cardiology, royal hospital, muscat, oman *corresponding author e-mail: bwaili@yahoo.com التهاب غشاء التامور بامليكروب العقدي النوع أ يف طفل عمره 4 أشهر تقرير حالة بدرية را�سد الوائلي، �سني زكريا�س، عماد اأ�سلم abstract: purulent pericarditis is uncommon among paediatric patients and cases caused by group a streptococcus (gas) are even rarer. we report a four-month-old female infant who was referred to the royal hospital, muscat, oman, in 2015 with pericardial effusion and cardiac tamponade. she had initially presented to a secondary hospital with a two-week history of fever, a runny nose and shortness of breath. blood and pericardial fluid cultures confirmed gas isolates. the infant was treated with a two-week course of antibiotics and made a complete recovery with no echocardiographical evidence of pericardial effusion at a two-month follow-up. to the best of the authors’ knowledge, this case constitutes the youngest infant to present with gas pericarditis. as invasive gas infections can present in infancy, early recognition and treatment is required. keywords: infant; pericarditis; pericardial effusion; streptococcus group a; case report; oman. امللخ�ص: يعترب التهاب التامور القيحي غري �سائع بني االأطفال املر�سى واحلاالت تنتج عن االأ�سابة بامليكروب العقدي النوع اأ. هذا تقرير حالة عن ر�سيع يبلغ من العمر اأربعة اأ�سهر مت اإحالته اإىل امل�ست�سفى ال�سلطاين، م�سقط، عمان، يف عام 2015 مع اأرت�ساح �سديد بالتامور. وكانت قد قدمت يف البداية اإىل م�ست�سفى ثانوي مع تاريخ من احلمى ملدة اأ�سبوعني، مع �سيالن االأنف و�سيق يف التنف�س. وقد اأثبتت مزرعة الدم و�سائل التامور وجود امليكروب العقدي النوع اأ. مت عالج الر�سيع بامل�سادات احليوية ملدة اأ�سبوعني ومت ال�سفاء الكامل مع عدم وجود اأي دليل باملوجات فوق ال�سوتية علي القلب علي ارت�ساح غ�ساء التامور ملدة ا�سبوعني من املتابعة. وعلى حد علم املوؤلفني، هذه احلالة ت�سكل اأ�سغر طفل م�ساب بالتهاب غ�ساء التامور بامليكروب العقدي النوع اأ. والأن هذه العدوى من املمكن ان حتدث يف الر�سع فيجب تنبيه االأطباء ايل �رشورة التعرف املبكر عليها وعالجها. الكلمات املفتاحية: الر�سع؛ التهاب التامور؛ ارت�ساح التامور؛ امليكروب العقدي النوع اأ؛ تقرير حالة؛ عمان. group a streptococcal pericarditis in a four-month-old infant case report *badria r. al-waili,1 sunny k. zacharias,2 emad aslem3 case report sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e241–243, epub. 20 jun 17 submitted 16 nov 16 revisions req. 14 dec 16 & 12 feb 17; revisions recd. 16 jan & 8 mar 17 accepted 20 mar 17 doi: 10.18295/squmj.2016.17.02.020 also known as group a streptococcus (gas), streptococcus pyogenes is a genus of βhaemolytic bacteria belonging to serogroup a according to the lancefield grouping classifications.1 it is an extremely common human pathogen which can cause a variety of clinical diseases ranging from superficial to invasive and including toxin-mediated infections as well as post-infection sequelae.2,3 invasive gas disease is defined as an infection in which gas is isolated from a sterile site of the body.2 approximately 90% of all pericarditis infections are either viral or idiopathic in origin.3 purulent pericarditis is defined as an infection of the pericardium that produces pus often found via gross examination of the pericardial sac or tissue microscopy; it commonly develops secondarily to a primary bacterial infection at an alternate location, such as pneumonia.3 the pericardium is subsequently infected by septic emboli, or a direct spread of infection from the lungs.4,5 most of the identified bacterial isolates in cases of paediatric pericarditis are staphylococcus aureus or streptococcus pneumoniae.5,6 in contrast, gas is a rare cause of purulent pericarditis, with only nine paediatric cases reported to date.7–13 case report a four-month-old female infant was referred to the royal hospital, muscat, oman, in 2015. she had initially presented to a secondary hospital in muscat with a two-week history of fever, a runny nose and shortness of breath. she had no history of medical problems and had had a normal birth. upon initial presentation, she was afebrile and in marked respiratory distress with subcostal and intercostal muscle recession as well as desaturation. her respiratory rate was 40 breaths/ minute and her heart rate was 100 beats/minute. oxygen saturation was 98% with 2 l of oxygen. group a streptococcal pericarditis in a four-month-old infant case report e242 | squ medical journal, may 2017, volume 17, issue 2 a chest examination showed good air entry with no abnormal sounds. normal heart sounds were heard during a cardiovascular examination. an abdominal examination revealed hepatomegaly with the liver located 7 cm below the costal margin. a chest x-ray showed evidence of cardiomegaly, although the lungs appeared normal [figure 1]. echocardiography performed by a paediatrician at the secondary hospital revealed pericardial effusion with cardiac tamponade. a total of 30 ml of pus was drained via needle aspiration and sent for microscopy and cultures. ceftriaxone and vancomycin were prescribed for 48 hours before the infant was transferred to the royal hospital, a tertiary hospital, for evaluation by a cardiologist. upon referral, repeated echocardiography revealed pericardial effusion with 14 mm of fibrotic tissue on the right side of the left ventricle and 7 mm of fibrotic tissue at the apex, with diastolic compression of the right atrium. a pericardial drain was inserted to remove 100 ml of serous fluid. fibrous material was present in the pericardial cavity but was washed out before the drain was inserted. blood investigations revealed a haemoglobin level of 8.5 g/dl, white cell count of 49 x 109, platelet count of 773, neutrophil count of 29.9 x 109, lymphocyte count of 7.9 x 109, lactate dehydrogenase level of 561 u/mg and thyroxine stimulating hormone level of 4 iu/l. a respiratory viral panel was positive for rhinovirus. fluid protein and glucose levels were 52 g/l and <0.3 mmol/l, respectively. microscopic tests of the pericardial pus indicated no evidence of organisms with moderate polymorphs. however, her fluid and blood cultures were positive for gas. the patient was prescribed a two-week course of penicillin and made a complete recovery. at six months old, follow-up echocardiography revealed no pericardial effusion with normal cardiac structure and no valve regurgitation. discussion among paediatric patients, the most common bacteria causing purulent pericarditis are s. aureus, s. pneumonia and haemophilus influenza.5,6,9 in contrast, purulent paediatric pericarditis originating from a gas infection is rare; a review of the literature identified only nine cases, with patients ranging in age from 10 months to 14 years old.7–13 accordingly, to the best of the authors’ knowledge, the current case constitutes the youngest infant reported so far to present with gas pericarditis. of the previously reported cases in which gender was identified, five patients were male and four were female.5–7,14 for four patients, the source of the gas was identified as both pharyngitis and cellulitis, pharyngitis alone, pneumonia alone and both pharyngitis and bacteraemia.6,8 schwartz et al. reported a 10-month-old infant whose father had been diagnosed with gas pharyngitis; the infant presented with prolonged fever and purulent pericarditis with no identifiable primary focus.7 in contrast, the patient in the current case was a four-month-old infant who presented with a rhinovirus infection, which may potentially have been the source of a secondary bacterial infection and bacteraemia. she presented with a history of fever and the initial delay in prescribing antibiotics could have led to the development gas bacteraemia and purulent pericarditis. acute respiratory distress is a common presentation in paediatric emergencies and is usually caused by acute bronchiolitis.8 however, in the present case, a chest x-ray revealed cardiomegaly, consequently raising concerns of the possibility of pericarditis or myocarditis. although acute pericarditis is predominantly viral in origin, gas was not suspected as it is not a common pathogen in this age group.3,6 nevertheless, blood and pericardial fluid cultures confirmed the diagnosis of gas pericarditis. systemic antibiotics and pericardial drainage are required to treat purulent pericarditis.5 while there is as yet no agreed upon duration for courses of antibiotics for the treatment of purulent pericarditis, most cases with successful outcomes are treated for 2–4 weeks.6,9 in the current case, the patient received two weeks of antibiotics with adequate pericardial drainage, which resulted in a complete recovery. unfortunately, the mortality rate for children with bacterial pericarditis ranges from 5–12%, even with treatment.6,7,9,14 figure 1: chest x-ray of a four-month-old female infant with pericardial effusion and cardiac tamponade showing cardiomegaly and a normal lung field. badria r. al-waili, sunny k. zacharias and emad aslem case report | e243 conclusion to the best of the authors’ knowledge, this case describes the youngest infant to present with gas pericarditis to date. as it is possible for gas pericarditis to present in early infancy, physicians should be aware of this rare yet treatable condition in order to prevent poor or potentially fatal outcomes. references 1. lancefield rc. a serological differentiation of human and other groups of hemolytic streptococci. j exp med 1933; 57:571–95. doi: 10.1084/jem.57.4.571. 2. curtis n. invasive group a streptococcal infection. curr opin infect dis 1996; 9:191–202. doi: 10.1097/00001432-19960600000012. 3. shiber jr. purulent pericarditis: acute infections and chronic complications. hosp physician 2008; 45:9–17. 4. lange ra, hillis ld. clinical practice: acute pericarditis. n eng j med 2004; 351:2195–202. doi: 10.1056/nejmcp041997. 5. gersony wm, mccracken gh jr. purulent pericarditis in infancy. pediatrics 1967; 40:224–32. 6. roodpeyma s, sadeghian n. acute pericarditis in childhood: a 10-year experience. pediatr cardiol 2000; 21:363–7. doi: 10.1007/s002460010081. 7. schwartz mc, gillespie mj, stephens p jr, fisher b. cardiac tamponade due to group a streptococcal pericarditis in a 10-month-old boy and a review of the literature. open j pediatr 2011; 1:87–9. doi: 10.4236/ojped.2011.14020. 8. angoulvant f, bellanger h, magnier s, bidet p, saizou c, dauger s. acute purulent pericarditis in childhood: don’t forget β-haemolytic group-a streptococcus. intensive care med 2011; 37:1709–10. doi: 10.1007/s00134-011-2259-4. 9. bhaduri-mcintosh s, prasad m, moltedo j, vázquez m. purulent pericarditis caused by group a streptococcus. tex heart inst j 2006; 33:519–22. 10. gersony wm, mccracken gh jr. purulent pericarditis in infancy. pediatrics 1967; 40:224–32. 11. pruitt jl. group a streptococcal pericarditis in a previously well child. pediatr infect dis j 1989; 8:338. 12. thébaud b, sidi d, kachaner j. [purulent pericarditis in children: a 15 year-experience]. arch pediatr 1996; 3:1084–90. doi: 10.1016/s0929-693x(96)89513-3. 13. vigneswaran wt, hardie r, ferguson jc, faichney a. cardiac tamponade due to lancefield group a beta haemolytic streptococcal pericarditis. thorax 1985; 40:549–50. doi: 10.11 36/thx.40.7.549. 14. cakir o, gurkan f, balci ae, eren n, dikici b. purulent pericarditis in childhood: ten years of experience. j pediatr surg 2002; 37:1404–8. doi: 10.1053/jpsu.2002.35401. https://doi.org/10.1084/jem.57.4.571 https://doi.org/10.1097/00001432-199606000-00012 https://doi.org/10.1097/00001432-199606000-00012 https://doi.org/10.1056/nejmcp041997 https://doi.org/10.1007/s002460010081 https://doi.org/10.4236/ojped.2011.14020 https://doi.org/10.1007/s00134-011-2259-4 https://doi.org/10.1016/s0929-693x%2896%2989513-3 https://doi.org/10.1136/thx.40.7.549 https://doi.org/10.1136/thx.40.7.549 https://doi.org/10.1053/jpsu.2002.35401 departments of 1neurology and 2medical toxicology and drug abuse research center, birjand university of medical sciences, birjand, iran; 3rocky mountain poison and drug center, denver health medical center, denver, colorado, usa; 4department of clinical toxicology, loghman hakim hospital, tehran, iran *corresponding author’s e-mail: omid.mehrpour@yahoo.com.au التسمم بالرصاص نتيجة البتالع أفيون ملوث بالرصاص عند مريض أظهر اعتالال عصبيا حركيا وخزل بالطرف العلوي تقرير حالة مو�شوي حممد �شيد، اأكربي اأيوب، ماهبور اأومد، زمانين�شيم abstract: opium users may present with central or peripheral nervous system-related symptoms, gastrointestinal complications and anaemia; in such cases, lead poisoning should be suspected and chelation therapy initiated as soon as possible. we report a 64-year-old male patient with a 20-year history of opium addiction who was referred to the imam reza hospital, birjand, iran, in 2017 with severe motor neuropathy and paresis in both upper limbs. his primary symptoms were generalised weakness, abdominal and bone pain, constipation and lower limb paraesthesia that had started several months prior. in addition, he reported severe progressive bilateral paresis of the upper limbs of one month’s duration. a diagnosis of lead poisoning was confirmed by a blood lead level of 140 µg/dl. the patient underwent chelation therapy after which he improved significantly. at a one-year follow-up visit, he was neurologically intact and symptom-free. keywords: opium dependence; lead poisoning; lead-induced nervous system diseases; paresthesia; case report; iran. امللخ�ص: يظهر م�شتخدمو الأفيون اأعرا�شا مرتبطة باجلهازين الع�شبي املركزي والطريف وم�شاعفات معدية معوية وفقر دم؛ ويف هذه احلالت ينبغي ال�شتباه يف الت�شمم بالر�شا�س، والبدء يف العالج بالحتاد املخلبي باأ�رصع ما ميكن. ون�شجل هنا حالة رجل عمره 64 عاما ظل ي�شتخدم الأفيون ملدة 20 �شنة و�شار مدمنا له ومت حتويله عام 2017م اإىل م�شت�شفى الإمام ر�شا ببريجند يف اإيران، وهو م�شاب باعتالل ع�شبي مفرط وَخَزل بالطرفني العلويني. وكانت الأعر�س الرئي�شة عنده هي وهن عام، واآلم يف البطن والعظام، واإم�شاك، وَمَذل يف الطرفني ال�شفليني، وهي اأعرا�س بداأت عند هذا املري�س قبل عدة �شهور قبل حتويله للم�شت�شفى. كذلك حدث للمري�س َخَزل بالطرفني العلويني قبل نحو �شهر. واأثبت فح�س للدم وجود ت�شمم بالر�شا�س، اإذ اأن تركيزه بلغ 140 ميكروجرام/100 مل من الدم. ومت اإجراء عالج خملبي للمري�س اأدي لتح�شن حالة املري�س ب�شورة ملحوظة. وعند مراجعة املري�س للم�شت�شفى بعد عام على ذلك العالج وجد اأنه �شليم ع�شبيا ولي�شت لديه اأي اأعرا�س. الكلمات املفتاحية: اإدمان الأفيون؛ الت�شمم بالر�شا�س؛ اأمرا�س اجلهاز الع�شبي التي ي�شببها الر�شا�س؛ َمَذل؛ تقرير حالة؛ اإيران. lead toxicity due to ingestion of lead-contaminated opium in a patient presenting with motor neuropathy and upper limb paresis a case report seyed m. m. mirzaei,1 ayob akbari,2 *omid mehrpour,3 nasim zamani4 case report sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e529–532, epub. 28 mar 19 submitted 2 may 18 revision req. 27 may 18; revision recd. 22 jun 18 accepted 19 jul 18 doi: 10.18295/squmj.2018.18.04.017 in recent years, lead poisoning due to the ingestion of lead-contaminated opium has become a major health concern in iran.4–9 according to ghane et al., more than 4,000 patients with lead poisoning due to opium ingestion were referred in under one year to clinical centres in iran with abdominal pain and constipation.10 moreover, the researchers estimated that over 260,000 out of >700,000 opium users remained untreated and at risk of lead poisoning.10 this case report describes a patient who presented to imam reza hospital, the main referral centre for poisoning cases in the south khorasan province of iran, with severe lead-induced motor neuropathy due to the ingestion of lead-contam inated opium. exposure to certain toxic agents results in neurotoxicity which may lead to cognitive and memory disabilities, mood changes and even predispose the affected patient to psychiatric problems such as depression, anxiety and irritability.1 in factories producing glazed tiles, canned food, paint and cosmetics, workers may be affected by the presence of inorganic lead; in addition, drinking water and dust may be contaminated from industrial sources and motor vehicles.2,3 another source of potential exposure is the presence of organic lead in opium.4,5 lead may be intent ionally added to the drug to increase its weight for profit related reasons or it may be introduced accidentally during the production process.4–7 subsequently, the lead is ingested by opium users either orally or via inhalation.6,8 lead toxicity due to ingestion of lead-contaminated opium in a patient presenting with motor neuropathy and upper limb paresis a case report e530 | squ medical journal, november 2018, volume 18, issue 4 case report a 64-year-old male patient was referred to the imam reza hospital, birjand, in 2017 with generalised weak ness, abdominal and bone pain, constipation and lower limb paraesthesia that had first started several months prior. the patient had then developed severe paresis in both upper limbs 30 days previously. he reported a 20-year history of oral opium use consisting of approximately 5 g daily. a urine drug analysis was positive for opium. upon examination, the cranial nerves were normal, as were lower limb deep tendon reflexes; however, deep tendon reflexes in the upper limbs, biceps and triceps were absent. no sensory impairment was detected. the muscular power in the upper limbs was 2/5 and 1/5 in the proximal and distal areas, respectively, while the lower limbs were normal. the median and ulnar nerves were moderately affected, while the radial nerve was severely affected; the patient also had bilateral wrist drop. imaging studies yielded normal results, including brain and cervical magnetic resonance imaging (mri), computed tomography (ct), a chest x-ray and abdominal ultrasonography. brain ct and mri scans revealed no evidence of a mass, haemorrhage, hydrocephalus or abnormalities in the basal ganglia and posterior fossa structures. no established infarct and intraor extra-axial collections were detected in the major vessel vascular territory. the basal cisterns and foramen magnum were patent. the chest x-ray showed an increase in bilateral bronchovascular markings with no other abnormalities. whole body bone scintigraphy was performed to rule out malignancy; this showed only minor tracer uptake throughout the skeleton. an endoscopy and colonoscopy revealed a 7-mm polypoid lesion in the d1-d2 junction of the duodenum and internal haemorrhoids in the anus. electromyography confirmed chronic motor sensory polyneuropathy with axonal features which were more severe in the upper limbs. critically, the patient’s blood lead level was 140 µg/dl (normal range: <10 µg/dl). table 1 shows the results of various other laboratory tests. nerve conduction and f-wave parameters are shown in tables 2–4. based on his blood lead level, the patient was diagn osed with lead poisoning and admitted to hospital. he was initially treated with 4 mg/kg of dimercaprol via deep intramuscular injection every four hours, followed by 1,300 mg/day of intravenous calcium disodium (cana 2) edetate four hours after the first dose of dimercaprol. after five days of parenteral treatment, his blood lead level was 60 µg/dl. he was discharged and prescribed 10 mg/kg of oral succimer, initially every eight hours for five days followed by every 12 hours for 14 days. after 21 days of treatment, his clinical symptoms began to improve, particularly the abdominal pain, generalised table 1: laboratory test results of a 64-year-old male opium addict with severe lead-induced motor neuropathy variable result normal range white blood cell count in ×103/mm3 8.1 4–10 haemoglobin in g/dl 9.6 14–18 haematocrit in % 30.5 males: 45–52 females: 37–48 mcv in femtolitres 83.6 80–96 mch count in pg 27.1 27–33 mchc in % 32.5 32–36 platelet count in ×103/mm3 206 150–450 vitamin b12 in pg/ml 1,178 160–950 folic acid in ng/ml 6 2–20 serum iron in µg/dl 36.8 65–176 tibc in µg/dl 176 240–450 ferritin in ng/ml 338.9 12–300 serum vitamin d in ng/ml 9.55 20–50 t3 in pg/ml 4 2.3–4.2 t4 in ng/dl 9.9 4.5–11.5 tsh in µiu/ml 0.5 0.5–4.7 t3ru in % 36.7 24–37 ast in u/l 50 <37 alt in u/l 55 <41 alkaline phosphatase in u/l 188 80–306 total bilirubin in mg/dl 1.2 <1.1 direct bilirubin in mg/dl 0.4 <0.6 creatinine in mg/dl 1 0.5–1.4 prothrombin time in seconds 13 10–13.5 partial thromboplastin time in seconds 28 25–35 inr 1 <1.1 wright agglutination test negative negative 2me negative negative anas negative negative rheumatoid factor negative negative anti-ds-dna in iu/ml 2.37 <10 serum albumin in g/dl 3.6 3.5–5 α-globulin in g/dl 0.2 0.1–0.3 α-2-globulin in g/dl 0.8 0.6–1 β-globulin in g/dl 0.7 0.7–1.2 γ-globulin in g/dl 1.1 0.7–1.6 mcv = mean corpuscular volume; mch = mean cell haemoglobin; mchc = mean corpuscular haemoglobin concentration; tibc = total iron-binding capacity; t3 = triiodothyronine; t4 = thyroxine; tsh = thyroid-stimulating hormone; t3ru = t3 resin uptake; ast = aspartate aminotransferase; alt = alanine aminotransferase; inr = international normalised ratio; 2me = 2-mercaptoethanol; anas = antinuclear antibodies; ds = double-stranded. seyed m. m. mirzaei, ayob akbari, omid mehrpour and nasim zamani case report | e531 weakness and weakness in the upper limbs. however, at a three-month follow-up appointment, the patient reported that the upper limb weakness still persisted; moreover, his blood lead level was 44 µg/dl. due to a shortage of succimer, d-penicillamine treatment was initiated at a dose of 250 mg every eight hours for 10 days. after this, a neurological examination was normal, including examination of the power in the upper limbs, although the patient still complained of some upper limb weakness. he was referred to a rehabilitation clinic to undergo methadone maintenance therapy. one year later, his blood lead level was 20 μg/dl and the upper limb weakness had completely resolved. discussion symptoms of acute lead poisoning include nausea, head aches, cognitive problems and emotional impairment, while chronic lead exposure may cause fatigue, a decline in brain and cognitive function, motor impairment, psychiatric problems and, in some cases, a decline in nerve conduction velocity.11,12 critically, initial symptoms of irritability, headache, fatigue, memory loss and tremors may progress to weakness, limb paralysis, seizures, deli rium and hallucinations, coma and, eventually, death.13 as such, the early detection and immediate treatment of lead poisoning is imperative. neuropathy due to the ingestion of lead-contam inated opium is uncommon, with most patients presenting with anaemia and gastrointestinal symptoms.14,15 a comb table 2: motor nerve conduction parameters of a 64-year old male opium addict with severe lead-induced motor neuropathy nerve and site/segment latency in ms amplitude in mv distance in mm velocity in m/s right median apb wrist 3.6 1.4 wrist-elbow 8.9 1.3 240 44.5 left median apb wrist 3.3 1.0 wrist-elbow 8.2 0.959 240 39.3 right ulnar adm wrist 2.7 2.2 wrist-below elbow 7.0 1.9 260 40.8 left ulnar adm wrist 2.4 1.7 wrist-below elbow 7.1 1.5 260 39.4 right radial eip forearm absent absent elbow absent absent below spiral groove absent absent left radial eip forearm absent absent elbow absent absent below spiral groove absent absent right dpn edb ankle 3.5 1.8 ankle below fh 9.1 1.7 below fh-pf 9.8 1.8 350 41.3 left dpn edb ankle 5.1 1.8 ankle below fh 12.1 1.9 below fh-pf 12.8 1.8 340 38.4 right tibial ahb medial ankle 6.3 3.1 medial anklepf 14.3 2.9 380 37.7 left tibial ahb medial ankle 5.1 3.9 medial anklepf 13.6 4.3 380 44.3 apb = abductor pollicis brevis; adm = abductor digiti minimi; eip = extensor indicis proprius; dpn = deep peroneal nerve; edb = extensor digitorum brevis; fh = fibula head; pf = popliteal fossa; ahb = abductor hallucis brevis. table 3: sensory nerve conduction parameters of a 64-year-old male opium addict with severe lead-induced motor neuropathy nerve latency in ms amplitude in uv distance in mm velocity in m/s right median 4.0 14.6 130 43.1 left median 3.6 9.64 130 47.2 right ulnar 3.8 16.9 110 51.4 left ulnar 3.5 14.3 110 50.4 right radial 3.3 13.1 90 56.4 left radial 3.1 15.3 90 60.5 right sural 3.1 3.55 left sural 2.7 3.0 table 4: f-wave parameters of a 64-year-old male opium addict with severe lead-induced motor neuropathy nerve latency in ms f/m amplitude in uvms f % m f-m f min f max right median apb 4.3 24.2 28.6 31.1 0.11 50 left median apb 3.7 22.0 25.7 32.1 0.14 60 right ulnar adm 0.1 28.2 28.3 33.0 0.07 100 right tibial ahb 6.4 48.3 54.7 62.3 0.05 75 left tibial ahb 0.1 54.1 54.2 54.7 0.03 66 min = minimum; max = maximum; apb = abductor pollicis brevis; adm = abductor digiti minimi; hb = abductor hallucis brevis. lead toxicity due to ingestion of lead-contaminated opium in a patient presenting with motor neuropathy and upper limb paresis a case report e532 | squ medical journal, november 2018, volume 18, issue 4 ination of motor and sensory nervous system impairment, as seen in the current case, is even less common. lead-induced neuropathy commonly affects the radial and peroneal nerves and extensor muscles, resulting in wrist and foot drop, while sensory processing disorders are less frequent.2,16 beigmohammadi et al. reported a 40-year-old male oral opium addict who presented with weakness of the limbs due to severe lead poisoning (blood lead level: 200 µg/dl).17 the patient had digestive symptoms (including stomach aches and constipation) and severe weakness of the upper and lower limbs, although sensation was normal. despite treatment with cana2 edetate, dimercaprol and oral succimer, the patient remained quadriplegic, although both his blood lead levels and gastrointestinal symptoms improved.17 toxic-metabolic polyneuropathy may be induced by extrinsic or intrinsic metabolites which are toxic to the peripheral nerves, resulting in damage to the axial cylinders of the axons. the severity of this damage is dependent on the level of toxicity, duration of exposure and genetic characteristics of nervous tissue metabolism.18 clinically, the damage manifests as both sensory impair ment and muscle weakness, although muscle wasting and severe trophic disorders may also occur. in these cases, electroneuromyography would show a decrease in the amplitude of peripheral nerve sensory potentials and muscle action potential.18 in patients with axonal-type polyneuropathy, there is often sufficient retention of motor function—in the absence of severe paresis—while sensory and trophic impairments are disabling. axonal nerve damage develops slowly and gradually, although it is potentially reversible with appropriate treatment.18 in the current case, the patient developed both motor and sensory neuropathy due to long-term exposure to high levels of lead. however, all neurological symptoms completely resolved after treatment with chelating agents. most patients with sensory complications are resistant to treatment and a full recovery is not expected, even after chelation therapy.16 this case emphasises the importance of the timely diagnosis and treatment of cases of lead toxicity in order to reverse central and peripheral nervous system-related symptoms. conclusion opium addicts are predisposed to developing lead toxicity resulting from the ingestion of lead-contaminated opium. this may result in the development of serious symptoms such as cognitive, sensory and motor impairment, with delays in diagnosis and treatment potentially resulting in irreversible neurological damage. as such, lead poisoning should be suspected among opium users with central or peripheral nervous system-related symptoms, gastro intestinal complications and anaemia. chelation therapy should be initiated as soon as possible in such cases. references 1. mason lh, mathews mj, han dy. neuropsychiatric symptom assessments in toxic exposure. psychiatr clin north am 2013; 36:201–8. https://doi.org/10.1016/j.psc.2013.02.001. 2. gidlow da. lead toxicity. occup med (lond) 2004; 54:76–81. https://doi.org/10.1093/occmed/kqh019. 3. massadeh am, el-khateeb my, ibrahim sm. evaluation of cd, cr, cu, ni, and pb in selected cosmetic products from jordanian, sudanese, and syrian markets. public health 2017; 149:130–7. https://doi.org/10.1016/j.puhe.2017.03.015. 4. ghaemi k, ghoreishi a, rabiee n, alinejad s, farzaneh e, amirabadi zadeh a, et al. blood lead levels in asymptomatic opium addict patients: a case control study. emerg (tehran) 2017; 5:e69. https://doi.org/10.22037/emergency.v5i1.16636. 5. hayatbakhsh mm, oghabian z, conlon e, nakhaee s, amirabadizadeh ar, zahedi mj, et al. lead poisoning among opium users in iran: an emerging health hazard. subst abuse treat prev policy 2017; 12:43. https://doi.org/10.1186/s13 011-017-0127-0. 6. mehrpour o, karrari p, abdollahi m. chronic lead poisoning in iran: a silent disease. daru 2012; 20:8. https://doi.org/1 0.1186/2008-2231-20-8. 7. alinejad s, aaseth j, abdollahi m, hassanian-moghaddam h, mehrpour o. clinical aspects of opium adulterated with lead in iran: a review. basic clin pharmacol toxicol 2018; 122:56–64. https://doi.org/10.1111/bcpt.12855. 8. karrari p, mehrpour o, abdollahi m. a systematic review on status of lead pollution and toxicity in iran: guidance for prev entive measures. daru 2012; 20:2. https://doi.org/10.1186/1 560-8115-20-2. 9. dadpour b, mehrpour o, etemad l, moshiri m. lead poisoning induced hypertensive crisis managed by prazosin: a case report. iran red crescent med j 2013; 15:526–8. https://doi.org/10.5812/ ircmj.4557. 10. ghane t, zamani n, hassanian-moghaddam h, beyrami a, noroozi a. lead poisoning outbreak among opium users in the islamic republic of iran, 2016-2017. bull world health organ 2018; 96:165–72. https://doi.org/10.2471/blt.17.196287. 11. dobbs mr, ed. clinical neurotoxicology: syndromes, substances, environments, 1st ed. philadelphia, pennsylvania, usa: saunders, 2009. pp. 259–72. 12. davis jm, svendsgaard dj. nerve conduction velocity and lead: a critical review and meta-analysis. in: johnson bl, ed. advances in neurobehavioral toxicology: applications in environmental and occupational health, 1st ed. chelsea, miami, usa: crc press, 1990. pp. 353–76. 13. mason lh, harp jp, han dy. pb neurotoxicity: neuropsychological effects of lead toxicity. biomed res int 2014; 2014:840547. https://doi.org/10.1155/2014/840547. 14. zamani n, hassanian-moghaddam h. notes from the field: lead contamination of opium iran, 2016. mmwr morb mortal wkly rep 2018; 66:1408–9. https://doi.org/10.15585/mmwr. mm665152a4. 15. white ld, cory-slechta da, gilbert me, tiffany-castiglioni e, zawia nh, virgolini m, et al. new and evolving concepts in the neurotoxicology of lead. toxicol appl pharmacol 2007; 225:1–27. https://doi.org/10.1016/j.taap.2007.08.001. 16. moyer m. metals in medicine and the environment: peripheral neuropathy and metals. from: http://faculty.virginia.edu/metals/ cases/moyer2.html accessed: jun 2018. 17. beigmohammadi mt, aghdashi m, najafi a, mojtahedzadeh m, karvandian k. quadriplegia due to lead-contaminated opium: case report. middle east j anaesthesiol 2008; 19:1411–16. 18. kovrazhkina ea. [axonal polyneuropathies: pathogenesis and treatment]. zh nevrol psikhiatr im s s korsakova 2013; 113:22–5. departments of 1adult health & critical care and 4maternal & child health, college of nursing, sultan qaboos university, muscat, oman; 2department of adult health, school of nursing, university of north carolina, chapel hill, north carolina, usa; 3associate dean of academic affairs, school of nursing, virginia commonwealth university, richmond, virginia, usa *corresponding author e-mail: hudasn@squ.edu.om العالقة بني االلتزام باألدوية واملعتقدات بني املرضى الذين يعانون من ارتفاع ضغط الدم يف عمان دراسة ارتيادية هدى النعمانية، جيا رونغ وو، ديربا بارك�سديل، اإ�رصاء اخل�ساونة، جورج كنافل، جوين �سريوود abstract: objectives: the prevalence of hypertension (htn) in oman is alarmingly high and patient adherence to antihypertensive medications is inadequate. this study aimed to assess the relationship between medication adherence and health beliefs among omani patients with htn. methods: this descriptive cross-sectional pilot study was conducted in december 2015 and included 45 patients with htn recruited from four primary health centres in al dakhiliyah and muscat governorates, oman. medication adherence and health beliefs were assessed using the morisky medication adherence scale (mmas), beliefs about medicines questionnaire, brief illness perception questionnaire and the revised medication adherence self-efficacy scale. results: the mean mmas score was 5.3 ± 2.0, with 48.9% of patients reporting high adherence. higher self-efficacy and stronger beliefs regarding medication necessity were significantly related to adherence (p = 0.012 and 0.028, respectively). conclusion: the findings of this pilot study emphasise the role of health beliefs with regards to omani patients’ adherence to antihypertensive medications. keywords: hypertension; health behavior; medication adherence; self efficacy; oman. امللخ�ص: الهدف: يعترب معدل انت�سار ارتفاع �سغط الدم يف عمان مرتفعا ب�سكل مثري للجزع والتزام املري�ص باالأدوية اخلاف�سة لل�سغط بارتفاع امل�سابني العمانيني املر�سى لدى ال�سحية واملعتقدات باالأدوية االلتزام بني العالقة تقييم اإىل الدرا�سة هذه تهدف كاف. غري اأربعة من اختيارهم مت مري�سا 45 و�سملت ،2015 دي�سمرب يف املقطعية الو�سفية االرتيادية الدرا�سة هذه اأجريت الطريقة: الدم. �سغط مراكز �سحية اأولية يف حمافظتي الداخلية وم�سقط، يف عمان. مت تقييم االلتزام باالأدوية واملعتقدات ال�سحية با�ستخدام مقيا�ص موري�سكي باالأدوية. لاللتزام الذاتية الكفاءة وا�ستبيان وجيزة لفرتة ت�سوراملر�ص ا�ستبيان االأدوية، حول املعتقدات ا�ستبيان باالأدوية، لاللتزام النتائج: كان متو�سط درجة مقيا�ص موري�سكي 2.0 ± 5.3، مع %48.9 من املر�سى اأبلغوا عن درجة التزام عالية. كما اأن ارتفاع الكفاءة على ،0.028 و p = 0.012( باالأدوية بااللتزام كبريا ارتباطا ترتبط االأدوية باأهمية ال�سحية املعتقدات وقوة باالأدوية لاللتزام الذاتية التوايل(. اخلال�صة: توؤكد نتائج هذه الدرا�سة على دور املعتقدات ال�سحية فيما يتعلق بالتزام املر�سى العمانيني باالأدوية اخلاف�سة لل�سغط. الكلمات املفتاحية: ارتفاع �سغط الدم؛ ال�سلوك ال�سحي؛ االلتزام باالأدوية؛ الكفاءة الذاتية؛ عمان. relationship between medication adherence and health beliefs among patients with hypertension in oman pilot study *huda al-noumani,1 jia-rong wu,2 debra barksdale,3 esra alkhasawneh,4 george knafl,2 gwen sherwood2 brief communication sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e329–333, epub. 10 oct 17 submitted 8 mar 17 revisions req. 16 apr & 1 jun 17; revisions recd. 15 may & 11 jun 17 accepted 15 jun 17 doi: 10.18295/squmj.2017.17.03.012 the global prevalence of hypertension (htn) is projected to increase markedly by 2025.1 poor htn management increases healthcare expenditure and complication, mortality and morbidity rates; as such, medication adherence is key.1 however, patient adherence to antihypertensive medications is inadequate globally.1 patient beliefs about health and illness are significant predictors of medication adherence.2 moreover, beliefs regarding the severity of a disease, self-efficacy and the benefits of medication may explain patients’ attitudes towards medication adherence, as described in the health beliefs model.3 in oman, the prevalence of htn is high, with up to 40% of the population affected.4 among those with htn, 5% have severe htn (i.e. systolic blood pressure of ≥180 mmhg or diastolic blood pressure of ≥110 mmhg).4 while several studies in oman have focused on understanding htn-related risk factors, none to date have examined the relationship between patients’ health beliefs and their adherence to antihypertensive medications.5,6 greater knowledge of the health beliefs and medication habits of omani patients with htn may help clinicians and researchers develop strategies to foster medication adherence and enhance htn management. this pilot study therefore aimed to relationship between medication adherence and health beliefs among patients with hypertension in oman pilot study e330 | squ medical journal, august 2017, volume 17, issue 3 describe medication adherence, self-efficacy and health beliefs among omani patients with htn and subsequently examine the relationship between health beliefs and medication adherence. methods this descriptive cross-sectional pilot study was conducted in december 2015. adult patients with htn aged ≥21 years old were recruited from four primary health centres in the al dakhiliyah and muscat governorates in oman. all participants had been diagnosed with htn by their primary physician at least one year prior to the study and had been prescribed at least one antihypertensive medication. patients were screened for eligibility according to their medical records; those with comorbidities such as diabetes, heart disease or asthma were subsequently excluded from the study. the sample size was set at 45 with 80% power in order to identify an r2 of ≥15.4% for the bivariate regression analyses and ≥23% for the multiple regression analysis based on four predictors. consequently, the regression analyses were only powered to identify relatively large effect sizes. all participants were asked to complete a demographic form and four questionnaires, including arabic versions of the 8-item morisky medication adherence scale (mmas) to measure adherence and three different health beliefs questionnaires reflecting the basic premises of the health beliefs model (i.e. perceived self-efficacy, severity of the disease and the necessity of and concerns regarding the mediciation).3,7–12 for the mmas, scores ranged from 0–8 with a cut-off value for adequate adherence set at ≥6 for the purposes of the current study.7 beliefs about medication necessity and concerns were measured using two subscales of a validated arabic version of the beliefs about medicines questionnaire (bmq) obtained from the main developer of the original 11-item questionnaire, similarly scored on a fivepoint likert scale.10,12 beliefs about htn severity were measured using the 8-item brief illness perception questionnaire (bipq), in which each item was rated on a scale of 0–10, with the overall score ranging from 0–80.9 self-efficacy for medication adherence was measured using the 13-item revised medication adherence self-efficacy scale (mases-r), with each item rated using a four-point likert scale.8 for all questionnaires, higher scores reflect greater adherence, stronger beliefs and greater self-efficacy, respectively; in addition, previous research has confirmed the validity and reliability of these tools.7–11 permission to use these questionnaires was obtained from the relevant developers, including permission to use the arabic versions of the tools. only the bipq and mases-r questionnaires were translated to arabic by the researchers themselves; this was done using previously described translation methods.13 descriptive statistics including means, standard deviations, frequencies and percentages were computed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). relationships between demographic characteristics, health beliefs and medication adherence were assessed using a bivariate pearson’s correlation analysis for continuous variables and a oneway analysis of variance test for categorical variables. multiple linear regression analysis was conducted to examine the independent influence of beliefs on medication adherence. variables were input into the regression analysis model using the enter method. a p value of ≤0.050 was considered statistically significant. ethical approval for this pilot study was obtained from both the university of north carolina at chapel hill, chapel hill, north carolina, usa (irb #15-0684), and the research and ethical review and approval committee of the ministry of health in muscat. all of the participants provided informed written consent prior to their inclusion in the pilot study. results a total of 45 patietns were included in this pilot study. table 1 illustrates the demographic characteristics of the participants. the mean mmas score was 5.3 ± 2.0 and 48.9% of the subjects were classified as high adherers. in total, 95.6% reported that they had not missed a medication dose over the previous two weeks, 66.7% claimed that they were never annoyed about complying with their medication requirements, 64.4% reported never cutting back or stopping their medications without informing their doctor and 64.4% stated that they continued to take their medications when travelling. moreover, 50.0% of the subjects reported they had no difficulty remembering to take their medications. the mean score for the necessity subscale of the bmq was 3.8 ± 0.8. most subjects agreed to the following: that their current (88.9%) and future (55.5%) health depended on the medication; that medications protected their health from becoming worse (84.4%); and that, without the medication, they would become very ill (57.8%). however, 33.3% of the subjects were uncertain as to whether their future health depended on the medications and whether their lives would be impossible without the medicine. the mean score for the concerns subscale of the bmq was 2.7 ± 0.7. huda al-noumani, jia-rong wu, debra barksdale, esra alkhasawneh, george knafl and gwen sherwood brief communication | e331 more than half of the subjects disagreed or strongly disagreed with the following statements: that the antihypertensive medicine disrupted their life (68.2%); that having to take the medication worried them (57.8%); and that the medicine had unpleasant side-effects (51.1%). however, some of the subjects reported concerns about becoming too dependent on the medication (44.4%) and that the medication was a mystery to them (35.5%). the mean bipq score was 27.0 ± 12.2. a total of 70.0% of the subjects reported that htn had minimal or no effect on their lives; 100.0% believed that they had control over their htn; 66.7% believed that they had few or no symptoms of htn; and 72.7% reported having minimal or no concern regarding their htn diagnosis. the mean mases-r score was 3.2 ± 0.7. most subjects were confident in their ability to take their medication between meals (70.5%) or more than once a day (59.1%). in addition, the majority reported that they would continue to take the medication even when they were worried about having to take it for the rest of their lives (54.5%) or when they did not have any symptoms (54.5%) or felt well (52.3%). the cronbach’s alpha values of the mmas, the necessity and concerns subscales of the bmq, bipq and mases-r tools were 0.72, 0.78, 0.70, 0.68 and 0.90, respectively. no significant correlations were observed between medication adherence and the demographic characteristics of the sample. however, there was a significant negative correlation between health beliefs table 1: demographic characteristics and medication adherence and health belief scores* of omani patients with hypertension at four primary health centres in oman (n = 45) variable n (%) mean age in years (range) 52.1 ± 14.6 (23–84) gender men 16 (35.6) women 29 (64.4) mean number of years with htn (range) 7.3 ± 6.9 (1–30) mean number of antihypertensive medications prescribed (range) 1.9 ± 1.1 (1–5) mean frequency of daily dose (range) 1.6 ± 0.80 (1–4) residence al dakhiliyah 32 (71.1) muscat 13 (28.9) marital status single 4 (8.9) married 28 (62.2) widowed 13 (28.9) monthly income in omr† none 15 (33.3) <150 8 (17.8) 150–499 9 (20.0) 500–999 2 (4.4) >1,000 9 (20.0) education level illiterate 19 (42.2) ability to read and write only 4 (8.9) primary or preparatory 4 (8.9) high school 12 (26.7) university or higher 6 (13.3) employment status‡ government sector 7 (15.6) private sector 4 (8.9) self-employed 4 (8.9) unemployed 26 (57.8) retired 3 (6.7) smoking status nonsmoker 43 (95.6) smoker 2 (4.4) alcohol consumption no 44 (97.8) yes 1 (2.2) mean adherence and health belief scores (range) mmas 5.3 ± 2.0 (0.75–8.0) bmq-c 2.7 ± 0.7 (1.2–4.7) bmq-n 3.8 ± 0.8 (2.0–5.0) bipq 27.0 ± 12.2 (1.0–56.0) mases-r 3.2 ± 0.7 (1.6–4.0) htn = hypertension; omr = omani rials; mmas = morisky medication adherence scale; bmq-c = beliefs about medicine questionnaire concerns subscale; bmq-n = beliefs about medicine questionnaire necessity subscale; bipq = brief illness perception questionnaire; mases-r = revised medication adherence selfefficacy scale. *medication adherence was assessed using an arabic version of the 8-item morisky medication adherence scale while health beliefs were assessed using arabic versions of the 11-item beliefs about medicine questionnaire, 8-item brief illness perception questionnaire and 13-item revised medication adherence self-efficacy scale.7–10,12 †total dataset for this variable was 43 as information for two subjects was unavailable. ‡total dataset for this variable was 44 as information for one subject was unavailable. relationship between medication adherence and health beliefs among patients with hypertension in oman pilot study e332 | squ medical journal, august 2017, volume 17, issue 3 regarding perceived htn severity and medication adherence (r = −0.32; p = 0.030) and a significant positive correlation between perceived self-efficacy and medication adherence (r = 0.44; p = 0.003). no significant correlation was found between medication adherence and beliefs about medication necessity (r = 0.25; p = 0.100) or medication concerns (r = -0.28; p = 0.060). the regression model was significant (f(4,39) = 4.89; p = 0.003) and explained 33.0% of the variation in medication adherence. self-efficacy (b = 1.067; p = 0.012) and beliefs about medication necessity (b = 0.777; p = 0.028) were positively associated with medication adherence [table 2]. self-efficacy and necessity together explained 26.0% of the variation in medication adherence. discussion in the current study, the overall adherence rate was less than 50%, which is consistent with reports from the world health organization and indicative of the need for collaborative efforts to improve medication adherence in oman.1 high self-efficacy was significantly associated with medication adherence among omani patients with htn, a finding which is consistent with that reported in the literature, regardless of differences in measures, study designs or culture.8,14 self-efficacy is a critical factor in creating and sustaining health behaviours because it empowers individuals, giving them confidence in maintaining positive health behaviours (e.g. medication adherence).15 such findings highlight the fact that self-efficacy needs to be a central component in ensuring medication adherence across cultures and populations. the current study also found that stronger beliefs about the necessity of antihypertensive medications were related to higher medication adherence; other studies, including those involving arab populations, have reported similar results.2,14 no relationship was found between concerns about antihypertensive medications and medication adherence in the present study; this is inconsistent with the findings of previous research.2,14 in the current study, subjects seemed more anxious about becoming overly dependent on their medications. it is likely that the low adherence level noted among patients with more concerns about their medications could be improved by addressing these fears when developing a plan of care, particularly with major concerns related to the longterm consequences or side-effects of the medication or fears of dependency. when planning programmes that target health behaviour, the contextual meaning of health to an individual, including their health beliefs, is significant.3 furthermore, it is crucial to incorporate health beliefs and self-efficacy as key components of health education or counselling programmes designed for members of the general public in oman. this pilot study was subject to certain limitations. as a cross-sectional correlational study design was used, causal relationships and long-term adherence rates could not be inferred. additionally, the small sample size, use of convenience sampling to recruit the subjects and sole inclusion of patients with htn limited the generalisability of the findings to the larger omani population and increased the likelihood of selection bias. furthermore, the use of a self-reported measure to examine medication adherence could have caused recall bias and an overestimation of actual adherence rates. therefore, additional studies with objective measures of medication adherence are needed. future studies using a longitudinal design with a larger and randomised sample from different regions of oman are recommended to improve the generalisability of these findings and examine medication adherence over time. table 2: linear regression analysis* of health belief variables predicting medication adherence† among omani patients with hypertension at four primary health centres in oman (n = 45) variable unstandardised β coefficient ± se standardised β coefficient t p value 95% ci bipq -0.034 ± -0.024 -0.211 -1.389 0.173 -0.83–0.15 mases-r 1.067 ± 0.405 0.363 2.363 0.012 0.25–1.89 bmq-c -0.303 ± -0.402 -0.112 -0.755 0.455 -1.12–0.51 bmq-n 0.777 ± 0.339 0.303 2.289 0.028 0.09–1.46 se = standard error; ci = confidence interval; bipq = brief illness perception questionnaire; mases-r = revised medication adherence selfefficacy scale; bmq-c = beliefs about medicine questionnaire concerns subscale; bmq-n = beliefs about medicine questionnaire necessity subscale. *r2 = 0.33. †health beliefs were assessed using arabic versions of the 11-item beliefs about medicine questionnaire, 8-item brief illness perception questionnaire and 13-item revised medication adherence self-efficacy scale while medication adherence was assessed using an arabic version of the 8-item morisky medication adherence scale.7–10,12 huda al-noumani, jia-rong wu, debra barksdale, esra alkhasawneh, george knafl and gwen sherwood brief communication | e333 conclusion this pilot study was conducted to examine the relationship between omani patients’ health beliefs and their antihypertensive medication adherence. overall, health beliefs regarding the necessity of the medication and perceived self-efficacy were significantly associated with medication adherence. these findings could be used to develop health education programmes on htn management based on health beliefs to help improve overall adherence to htn medications in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this pilot study. references 1. world health organization. a global brief on hypertension: silent killer, global public health crisis. from: www.who. int/c ardiov a scular_dise a ses/public ations/global_br ief_ hypertension/en/ accessed: jun 2017. 2. rajpura jr, nayak r. role of illness perceptions and medication beliefs on medication compliance of elderly hypertensive cohorts. j pharm pract 2014; 27:19–24. doi: 10.1177/0897190013493806. 3. rosenstock im, strecher vj, becker mh. social learning theory and the health belief model. heal educ q 1988; 15:175–83. 4. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1 – methodology, sociodemographic profile and epidemiology of non-communicable diseases in oman. oman med j 2012; 27:425–43. 5. abd el-aty ma, meky fa, morsi mm, al-lawati ja, el sayed mk. hypertension in the adult omani population: predictors for unawareness and uncontrolled hypertension. j egypt public health assoc 2015; 90:125–32. doi: 10.1097/01. epx.0000470547.32952.cf. 6. al-maqbali aa, temple-smith m, ferler j, blackberry i. prevalence and determinants of pre-hypertension among omani adults attending non-communicable disease screening program in primary care setting in sohar city. oman med j 2013; 28:316–23. doi: 10.5001/omj.2013.94. 7. morisky de, ang a, krousel-wood m, ward hj. predictive validity of a medication adherence measure in an outpatient setting. j clin hypertens (greenwich) 2008; 10:348–54. doi: 10.1111/j.1751-7176.2008.07572.x. 8. fernandez s, chaplin w, schoenthaler am, ogedegbe g. revision and validation of the medication adherence selfefficacy scale (mases) in hypertensive african americans. j behav med 2008; 31:453–62. doi: 10.1007/s10865-008-9170-7. 9. broadbent e, petrie kj, main j, weinman j. the brief illness perception questionnaire. j psychosom res 2006; 60:631–7. doi: 10.1016/j.jpsychores.2005.10.020. 10. horne r, weinman j, hankins m. the beliefs about medicines questionnaire: the development and evaluation of a new method for assessing the cognitive representation of medication. psychol health 1999; 14:1–24. doi: 10.1080/ 08870449908407311. 11. zyoud sh, al-jabi sw, sweileh wm, morisky de. relationship of treatment satisfaction to medication adherence: findings from a cross-sectional survey among hypertensive patients in palestine. health qual life outcomes 2013; 11:191. doi: 10.1186/1477-7525-11-191. 12. jamous rm, sweileh wm, el-deen abu taha as, zyoud sh. beliefs about medicines and self-reported adherence among patients with chronic illness: a study in palestine. j family med prim care 2014; 3:224–9. doi: 10.4103/2249-4863.141615. 13. world health organization. management of substance abuse: process of translation and adaptation of instruments. from: www.who.int/substance_abuse/research_tools/translation/en/ accessed: jun 2017. 14. kamran a, sadeghieh ahari s, biria m, malepour a, heydari h. determinants of patient’s adherence to hypertension medications: application of health belief model among rural patients. ann med health sci res 2015; 4:922–7. doi: 10.4103/2141-9248.144914. 15. lorig k, laurent dd, plant k, krishnan e, ritter pl. the components of action planning and their associations with behavior and health outcomes. chronic illn 2014; 10:50–9. doi: 10.1177/1742395313495572. https://doi.org/10.1177/0897190013493806 https://doi.org/10.1097/01.epx.0000470547.32952.cf https://doi.org/10.1097/01.epx.0000470547.32952.cf https://doi.org/10.5001/omj.2013.94 https://doi.org/10.1111/j.1751-7176.2008.07572.x https://doi.org/10.1007/s10865-008-9170-7 https://doi.org/10.1016/j.jpsychores.2005.10.020 https://doi.org/10.1080/08870449908407311 https://doi.org/10.1080/08870449908407311 https://doi.org/10.1186/1477-7525-11-191 https://doi.org/10.4103/2249-4863.141615 https://doi.org/10.4103/2141-9248.144914 https://doi.org/10.1177/1742395313495572 األدوات واسرتاتيجيات التدريس البيين للتعليم املهين املتاحو حاليًا لطالب املهن الصحية مراجعة األدبيات نيلوفر �صامي خان، �صيد اإليا�ض �صاهناز، كاديام جوماثي abstract: interprofessional education (ipe) is designed to provide students from different health sectors with opportunities to work together to enhance future collaboration. the implementation of ipe activities is a current trend in various countries. this review exclusively targets ipe issues involving undergraduate health profession students and highlights various approaches in different regions. a total of 28 articles published in peer-reviewed journals between january 2012 and july 2015 were assessed to determine recent trends in ipe implementation. nine main strategies were identified: simulation-based education programmes; rotations in rural and community settings; interprofessional training wards; patient-centred case studies; theme-centred workshops; student seminars; student-delivered lectures; health promotion activities; and interactive lectures in a common setting. many of these institutions had not restricted themselves to a single strategy and supplemented these activities with additional teaching or learning methods. recommendations gathered from these diverse approaches may assist the development of sustainable strategies for implementing ipe in undergraduate medical curricula. keywords: interprofessional relations; interdisciplinary communication; undergraduate medical education; health professions. امل�صتقبل. يف التعاون لتعزيز معا للعمل بفر�ض املختلفة ال�صحية القطاعات طالب تزويد اإىل البيني املهني التعليم يهدف امللخ�ص: يعترب تنفيذ اأن�صطة التعليم املهني البيني هو االجتاه املتبع حاليًا يف العديد من البلدان، وت�صتهدف هذه املراجعة على وجه اخل�صو�ض ق�صايا التعليم املهني البيني عند طالب املهن الطبية للمرحلة اجلامعية االأوىل وت�صلط ال�صوء على املناهج املختلفة يف عدة مناطق. مة بني يناير 2012 و يوليو 2015 لتحديد االجتاهات احلديثة يف تنفيذ التعليم مت تقييم ما جمموعه 28 مقاال من�صورا يف جمالت حمكَّ املهني البيني. مت حتديد ت�صعة ا�صرتاتيجيات رئي�صية: برامج تعليمية قائمة على املحاكاة؛ مناوبات يف مناطق ريفية وجمتمعية؛ اأجنحة للتدريب املهنى البيني؛ درا�صات حلاالت حمورها املر�صى؛ ور�ض عمل مركزة؛ ندوات للطالب؛ حما�رضات موجهه للطلبة؛ االأن�صطة املهنية ال�صحية؛ واملحا�رضات التفاعلية يف مواقع عامة. الكثري من هذه املوؤ�ص�صات مل تقيد نف�صها ال�صرتاتيجية واحدة واإ�صافًة اإىل هذه االأن�صطة طرق تدري�ض و تعليم اإ�صافية. التو�صيات التى مت جمعها من هذه االأ�صاليب املختلفة قد ت�صاعد على تطوير ا�صرتاتيجيات م�صتدامة لتنفيذ مناهج التعليم الطبي املهني البيني للمرحلة اجلامعية االأوىل. كلمات مفتاحية: العالقات املهنية البينية؛ االت�صال متعدد االخت�صا�صات؛ التعليم الطبي للمرحلة اجلامعية االأوىل؛ املهن ال�صحية. currently available tools and teaching strategies for the interprofessional education of students in health professions literature review *nelofar s. khan,1 syed i. shahnaz,2 kadayam g. gomathi1 review sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e277–285, epub. 19 aug 16 submitted 6 mar 16 revision req. 14 apr 16; revision recd. 12 may 16 accepted 9 jun 16 doi: 10.18295/squmj.2016.16.03.003 an increased life expectancy and incidence of chronic health conditions requiring prolonged follow-up and multiple therapies or treatment approaches characterise the present day patient population. numerous options for treatment and management, evolving healthcare policies and healthcare organisational structures demanding superior results with limited resources represent existing challenges for healthcare delivery.1,2 hierarchical teams with insufficient experience of interdisciplinary collaboration and a lack of effective communication among healthcare professionals have been reported as possible reasons for the poor quality of care sometimes provided to patients.3 hence, it is expected that a more cooperative team approach in the form of interprofessional collaborative practices may overcome these challenges to provide a higher quality of patient care.1,2 in most parts of the world, healthcare professionals are trained predominantly in intraprofessional sett ings, in which educational activities occur only among students within the same profession without interdepartments of 1biochemistry and 2pharmacology, gulf medical university, ajman, united arab emirates *corresponding author e-mail: nelofer99@hotmail.com currently available tools and teaching strategies for the interprofessional education of students in health professions literature review e278 | squ medical journal, august 2016, volume 16, issue 3 action with students from other fields; each profession thus organises its own teaching and is unaware of what is taught or learnt in other professions.1,4 generally, students graduating from traditional training programmes do not possess interprofessional expertise, have unclear role definitions and lack the crucial communication skills needed to collaborate competently with other members of a healthcare team.3,5 unfortunately, this can result in problems in healthcare delivery, the inefficient utilisation of available resources, suboptimal patient care and workplace conflicts.6 interprofessional education (ipe) provided during training can overcome these problems by producing a practice-ready workforce.7 briefly, ipe trains graduates to be efficient and successful team members with the requisite skills and attitudes needed for problemsolving and good communication and collaboration between various healthcare professionals.8 in ipe, each profession looks at a topic, problem or case from its own perspective as well as that of other professions.1,4 it involves students from two or more related disciplines learning about, from and with each other during their professional training. the aim of ipe is to develop effective collaboration and team behaviours in order to achieve improved health outcomes for patients.9 thus, ipe educators and students jointly create a collaborative learning atmosphere both in academicand work-based settings and before and after qualification.10 as the responsibility for teaching teamwork and collaboration falls primarily to educators, ipe must be an intentional collaborative effort with the willing participation of faculty members and students from multiple disciplines.11,12 in 2006, the world health organization (who) created the ipe study group with the aim of developing a universal plan for ensuring the execution of ipe and collaborative practices globally.13 the who subsequently issued the framework for action on interprofessional education and collaborative practice in 2010.2 a report from the interprofessional education collaborative in 2011 concluded that, in a continuously evolving healthcare system, future healthcare professionals should be educated and trained in a collaborative manner.5 subsequently, accrediting bodies involved in health professional education and training recognised the need for ipe and initiated the process of developing accreditation standards for incorporating ipe in all healthcare-related education programmes such as medicine, nursing, pharmacy, physiotherapy, occupational therapy and social work.5 organisations such as the accreditation of interprofessional health education, the accreditation council for graduate medical education, the institute of medicine, the accreditation council for pharmacy education, the center for the advancement of pharmacy education, the american dental education association, the american association of colleges of nursing and the national league for nursing issued joint guidelines outlining the necessary competencies required for graduates of accredited programmes to function as members of an interprofessional team.5 with increased recognition of the value of ipe for interprofessional collaborative practice, the development and implementation of effective ipe practices have become a priority.12 in the usa, the aforementioned competencies have been outlined to assist with the delivery of ipe within medical education curricula.5 in australia, government and independent reports were released which emphasised the inclusion of ipe in health profession training programmes.14 furthermore, the governments of canada and the usa have awarded funding to universities to introduce ipe training for health professional students early in their curricula.15,16 although ipe has attained extensive support—including reinforcement through various government and accreditation bodies—the extent of commitment to ipe principles remains variable. although ipe is a part of medical school curricula in many countries, including canada, the usa, the uk and australia, there is little documentation of ipe initiatives in many developing countries, including those in the middle east.1,17,18 the main objective of this review was to discuss the various innovative approaches adopted and models developed and/ or pilot-tested to deliver ipe in different parts of the world, exclusively targeting ipe issues involving undergraduate health profession trainees. methods the medline, proquest, cumulative index to nursing and allied health literature, psycinfo and education resources information center databases were searched for publications linked to ipe. in addition, the following journals were also searched: medical teacher, journal of interprofessional care, teaching and learning in medicine, medical education, academic medicine and advances in health sciences education. the following search terms were used in various combinations: “interprofessional education”, “under graduate students”, “guidelines”, “models”, “implementation” and “challenges and barriers”. only publications in which the participants were undergraduate students in health professions (e.g. nursing, medicine, social work, nutrition/dietetics, pharmaceutical sciences, dentistry, occupational therapy and physiotherapy) nelofar s. khan, syed i. shahnaz and kadayam g. gomathi review | e279 were included. articles involving postgraduates, residents, physicians, community pharmacists, nurses or physiotherapists were excluded. in addition, the inclusion criteria required that the article include an educational intervention focusing on the delivery of ipe and an assessment of the effectiveness of this intervention. full-text original research articles, reviews and editorials were assessed for eligibility. articles published between january 2012 and july 2015 involving qualitative, quantitative or blended research were included to fill in the gap of existing knowledge. articles in english and english abstracts of articles published in other languages were focused upon. the following details were extracted from each article using a data abstraction form: location, innovative approaches developed and utilised for imparting ipe and challenges and guidelines for the implementation of ipe. the abstraction form was pilot-tested and refined through an iterative process before use. data were extracted by all three researchers and differences, if any, were resolved by consensus. a total of 1,053 articles were identified, of which 978 were excluded due to duplication or irrelevance to the topic and 39 were excluded as the participants were not undergraduate students in health professions. the literature search and article identification procedure is shown in figure 1. information available from the who, the centre for the advancement of interprofessional education in the uk, accreditation guidelines for different health professions and government policy documents were also included. results among the 36 selected articles published between january 2012 and july 2015, 28 focused on innovative strategies for imparting ipe to undergrad uate health professional students [table 1].6,11,17,19–43 a total of 15 articles originated from the usa, indicating a high interest in ipe programmes in this country.11,20–22,24–26,28,32,35,36,38–40,42 for the rest, three studies each were conducted in the uk and canada, two in australia and one each in sweden, malaysia, the philippines, china and switzerland.6,17,19,23,27,29–31,33,34,37,41,43 nine main strategies were identified for executing ipe activities: simulation-based education programmes; rotations in rural and community settings; interprofessional training wards; patient-centred case studies; theme-centred workshops; student seminars; student-delivered lectures; health promotion activities; and interactive lectures in a common setting.6,11,17,19–43 many of the institutions implementing ipe had not restricted themselves to one strategy and instead supplemented the aforementioned activities with additional teaching/ learning methods.6,24,26,42 figure 1: flowchart of the process used to identify articles for inclusion in the literature review. cinahl = cumulative index to nursing and allied health literature; eric = education resources information center; ipe = interprofessional education. currently available tools and teaching strategies for the interprofessional education of students in health professions literature review e280 | squ medical journal, august 2016, volume 16, issue 3 table 1: summary of a literature review of recent interprofessional education strategies for undergraduate health professional students author and year of article location professions represented main strategy description gum et al.6 2013 australia nutrition and dietetics, speech pathology, paramedics rotations in rural settings a programme designed to promote interprofessional learning in rural settings (immerse) vyas et al.11 2012 usa medicine, pharmacy, nursing and others simulationbased education programme patient simulation was used for semi-urgent case scenarios opina-tan17 2013 philippines allied medical professions, medicine, nursing and nutrition rotation in a community setting fcm involving interprofessional teams during community rotation wang et al.19 2015 china nursing and medicine simulationbased education programme interprofessional simulation-based educational programme about operating room nursing cappiello et al.20 2015 usa nursing, physician assistants and medicine rotation in a community setting experience in a community health centre to introduce students to ipc in underserved areas mcbride et al.21 2015 usa physician assistants and medicine student-delivered lectures clinical anatomy course where physician assistant students were taught by medical students diwan et al.22 2016* usa students across multiple programmes health promotion activities community health promotion providing information to older adults in an ipc setting (swfs) herrmann et al.23 2015 switzerland medicine and nursing interactive lectures in a common setting pilot project in which nursing topics and anatomy lectures were combined arndell et al.24 2014 usa pharmacy and medicine rotation in a community setting student teams and community partners provided healthcare in local homeless shelter facilities, conducted health education sessions and participated in street outreach bolesta et al.25 2014 usa pharmacy and nursing simulationbased education programme patient-care scenarios using a high-fidelity patient simulator shrader et al.26 2014 usa medicine, nursing and physician assistants simulationbased education programme and theme-centred workshops nine separate ipe activities embedded into a required clinical assessment course over a semester using various active-learning strategies morphet et al.27 2014 australia nursing, medicine, social work, nutrition/ dietetics, pharmacy and occupational therapy interprofessional training ward real-life clinical training in ipe training wards in hospitals under professional supervision von der lancken et al.28 2014 usa nursing and physical therapy simulationbased education programme and theme-centred workshops physical therapy students taught safe patient-handling skills in a simulated setting to undergraduate nursing students tan et al.29 2014 malaysia medicine and pharmacy rotations in a community setting visits to patients’ homes and to related community-based organisations (chc) netherwood et al.30 2014 uk nursing, midwifery, homeopathy and complementary therapies theme-centred workshops ipe workshops and focus-group discussions hardisty et al.31 2014 uk medicine, pharmacy and nursing theme-centred workshops and student seminars ipe seminars and workshops on medication safety and therapeutics heflin et al.32 2014 usa six professions interactive lectures in a common setting innovative prelicensure interprofessional course designed to focus on improving transitions of care for older adults through interactive teaching sessions nelofar s. khan, syed i. shahnaz and kadayam g. gomathi review | e281 simulation-based education programmes were a major strategy employed in seven studies.11,19,25,26,28,34,39 this important educational approach offers students the opportunity to apply learned theories and skills in a secure and monitored instructional atmosphere. this technique was imparted through virtual computer programmes, standardised patients, human/patient simulations during home health visits and simulation using manikins in clinical laboratories. in these studies, realistic patient-based scenarios were developed that could be managed only through interprofessional collaboration (ipc).11,19,25,26,28,34,39 students were assigned to small interprofessional groups and assumed the role of their respective professions in simulated clinical environments. six studies pilot-tested the use of ipe modules in elective courses addressing the healthcare needs of underserved and general communities.6,17,20,24,29,42 not only did this strategy give students the opportunity to work collaboratively, but it also increased their confidence in caring for vulnerable populations and provided insight into the community’s resources. in these studies, faculty from multiple disciplines collaborated with various community partners to develop and implement the elective course. rural communities were found to be an ideal setting for students to experience interprofessional clinical practice and understand its importance. in some vanier et al.33 2013 canada students from 10 health sciences and psychosocial sciences training programmes patient-centred case studies patient representatives were involved in course planning and patients were trained to become patients-as-trainers and cofacilitate interprofessional discussion workshops holland et al.34 2013 uk medicine, nursing and physiotherapy simulationbased education programme an ipe practice-based undergraduate module using acute simulation-based teaching stebbins et al.35 2013 usa pharmacy, medicine and nursing student-delivered lectures trained pharmacy students delivered 60–90-minute standardised case-based lectures about drug cost-containment strategies to health professional students and prescribers vanderwielen et al.36 2013 usa medicine, nursing, dentistry, pharmacy, social work, allied health and dietetics health promotion activities a student-led organisation provided health outreach events for underserved populations in the local community fortugno et al.37 2013 canada nutrition, nursing, early childhood education and child and youth care health promotion activities students collaborated to develop and deliver four healthy-living modules to secondary school students zhao et al.38 2013 usa undergraduate health and pre-health students health promotion activities students formed an interprofessional and collaborative team for dissemination of nutrition/exercise knowledge smithburger et al.39 2013 usa medicine, pharmacy, nursing, physician assistants and social work simulationbased education programme complex clinical scenarios using simulation in small interprofessional teams macdonell et al.40 2012 usa medicine, nursing and pharmacy theme-centred workshops workshop with an interdisciplinary team in a small-group setting pinto et al.41 2012 canada dietetics, nuclear medicine, nursing, occupational therapy, physical therapy, pharmacy, radiation therapy, radiological technology, speech and language pathology, social work and therapeutic recreation patient-centred case studies and student seminars introductory tutorial, patient-themed tutorials and an interprofessional student presentation hasnain et al.42 2012 usa medicine and pharmacy rotation in a community setting community rotation to introduce students to critical health issues affecting hiv/aids patients leisnert et al.43 2012 sweden dental sciences and dental hygiene student-delivered lectures and student seminars dental students acted as supervisors for dental hygiene students immerse = integrated multidisciplinary model of education in rural settings; fcm = family case management; ipc = interprofessional collaboration; swfs = senior wellness fairs; ipe = interprofessional education; chc = comprehensive healthcare; hiv = human immunodeficiency virus; aids = acquired immune deficiency syndrome. *published online in january 2015 before print publication in 2016. currently available tools and teaching strategies for the interprofessional education of students in health professions literature review e282 | squ medical journal, august 2016, volume 16, issue 3 studies, the faculty and students constructed and conducted ipe activities which addressed the needs of underserved populations such as the elderly, those with human immunodeficiency/acquired immune deficiency syndrome and the homeless.6,20,24,29,36,42 these ipe activities were reported to result in long term modifications in practices through the development of attitudes, values and competencies necessary to meet the health needs of vulnerable populations.24 another ipe strategy utilised was reallife clinical training in an interprofessional training ward in which senior healthcare students from a variety of disciplines worked in supervised teams to manage patients.27 structured ipe consisting of patient-centred case studies for student discussion was also practiced in several institutions.33,41 small groups were formed, including a representative from a real work setting so as to maximise potential gain for the students from these interactions. debates on different approaches to patient care not only highlighted the importance of ipc but also enriched the learning experience.33,41 theme-centred workshops conducted by students working in small interprofessional groups were also reported.26,28,30,31,40 these interactive teaching sessions promote critical thinking and effective communication as the students taught each other about various aspects of cases in small-group settings. additional methods for imparting ipe included interprofessional student seminars, roleplaying and lectures from invited speakers.31,41,43 lectures delivered by healthcare students to audiences composed of trainees from different disciplines were also utilised for ipe; these were reported to increase their confidence and awareness of future collaborative opportunities.21,35,43 students also formed interprofessional and collaborative teams in order to take part in community health promotion activities.22,36–38 combined interactive lectures for students from various health professions also provided opportunities for student interaction and reflection.23,32 discussion the provision of ipe activities during training is crucial to the development of an efficient and effective workforce. it is considered to be an important approach for improving the quality of overall patient care as it encourages interprofessional team-based collaboration among future healthcare professionals.5,44 within a healthcare setting, ipe is recognised as a means of challenging the usual intraprofessional training in order to find new responses to healthcare issues, which include the increasing complexity of care needs and the fragmentation of care provided by different specialties.45 in this literature review, nine main strategies were identified for executing ipe activities.6,11,17,19–43 these diverse educational approa ches, when implemented in combination, have the potential to provide a strong base for the interprofessional training of undergraduate healthcare professionals. l e v e l s o f i n t e r a c t i o n ipe activities provide an opportunity to train health care students in a safe environment through observation, hands-on training, team interaction and critical feedback.27 it is also apparent that ipe modifies the attitudes of prospective healthcare professionals by exposing them to three levels of interaction— communication, mutual respect/trust and teamwork, thus facilitating the adoption of ipc in health care settings.46 communication ipe provides opportunities to develop and demonstrate the verbal and nonverbal communication skills necessary for appropriate, confident and effective interactions with colleagues and patients and their relatives or carers.25 mutual respect and trust for the learner, participation in ipe activities clarifies their responsibilities while still continuing their education.47 this approach provides the opportunity for individuals in healthcare disciplines to share their skills and knowledge, thus fostering shared values and a better understanding of their own roles and abilities. ipe increases student awareness of the roles, functions, expertise and services provided by other healthcare professionals.48 thus, ipe builds mutual trust and respect between different healthcare specialties, provides students with a better understanding of the roles and limitations of various professions and facilitates team-building. a key strength of ipe is building interprofessional trust between healthcare workers who will work together in the future.20,30,36 teamwork ipe is reported as a means to enhance flexibility and adaptability, which are important for team-building and maintaining positive working relationships.17 students get the opportunity to undertake various roles—including both leader and follower—and contribute effectively as part of a multidisciplinary team, thus producing a practice-ready graduate possessing the appropriate teamwork skills.47 the ultimate aim in all ipe activities is to learn with and from members of other professions so as to improve both professional attitudes and patient care delivery. nelofar s. khan, syed i. shahnaz and kadayam g. gomathi review | e283 therefore, ipe is regarded as a crucial step in training collaborative practice-ready personnel.2 ipe activities have been reported to enhance students’ thinking and communication regarding collaborative practice, which will eventually improve patient care.24 i m p l e m e n tat i o n i n t h e c u r r i c u l u m key concepts for the implementation of ipe in medical undergraduate curriculum include early intro duction, utilisation of a variety of settings and scenarios, a variety of different instructional methods and incorporation of ipe into existing courses instead of as an additional separate course.26 with this in mind, the authors suggest a longitudinal curriculum design including a variety of interprofessional events embedded in practical learning experiences which provide exposure to simple and more complex collaboration activities over time. an ipe curriculum must advocate delivering high-quality patient care using active learning strategies.11 stand-alone schools are advised to collaborate with local health institutions and neighbouring universities in conjunction with additional allied health programmes in order to incorporate students from multiple disciplines into their ipe curriculum.25 another vital fact to consider while designing ipe activities is that they should be structured with specific learning outcomes in which the interactions between healthcare profession students are purposefully organised and facilitated.41 for students, reviewing available literature and online resources prior to the ipe session should be encouraged as it could facilitate preparation for what might be expected of them during the session.25 facilitated team-based learning sessions and reflection of the students’ experiences could also help in identifying profession-related and generic responsibilities, thus assisting students’ learning experiences.49 other recommendations include the importance of training students to investigate failures in group dynamics through a team-based approach, ensuring reflection of perceived team interactions and designing probing sessions around concepts of successful interprofessional teamwork to direct students towards enhanced understanding of the complexities of collaborative care.47 assessing impact the impact of various ipe activities on competencies and perceptions/opinions regarding ipc have been assessed in many studies by administering a survey instrument before and after the course and/or an interprofessional objective-structured clinical examination.12,26 however, as standardised methods for the assessment of interprofessional competencies are not well established, research and the development of instruments to assess meaningful outcomes of ipe should be encouraged.41 subsequent to each ipe experience, the students should also receive formative feedback and reflect on ipc. during the course of the curriculum, multiple experiences of the cyclical process of ipe exercises followed by feedback and reflection would improve and strengthen ipe concepts.26 regular feedback could also be used to improve ipe activities.17 several studies have revealed that students who participate in ipe experiences demonstrate positive changes in their opinions regarding the advantages of ipc and have enhanced professional self-confidence and a stronger sense of clinical competence.35,42 these positive changes have also been identified as being responsible for improved team dynamics and hindering the development of negative stereotypes in health professionals.41 challenges to implementation despite formal recommendations supporting ipe, the successful design and implementation of ipe programmes in health profession curricula is limited. the various intricacies involved in conducting ipe exercises may be one of the main reasons for the minimal incorporation of ipe in health professional education at many universities.6 there is also a need for agreement about crucial learning outcomes for ipe worldwide. more models of best practice are required, as reliable methods to design and deliver ipe in a curriculum do not exist.26,27 a lack of standardised assessment instruments are also a barrier as they are needed to facilitate the implementation of ipe.12 health profession schools have encountered several difficulties while implementing ipe, such as a lack of facilities, trained personnel, adequate clinical training sites and the necessary ipe resources, as well as space constraints and limited access to other healthcare disciplines.47 additionally, institutions can face difficulties in scheduling as students of different professions must be taught in the same setting in order to learn together.47 vanderwielen et al. also noted resistance to ipe among faculty members due to the increased workload and a lack of time for the development and implementation of ipe activities within the curriculum.47 as any successful curricular innovation requires support from all stakeholders, education and training of the ipe facilitators through faculty development programmes will improve the quality of ipe sessions, in addition to reinforcing collective ownership of ipe activities.26 in addition, the support of senior management is essential for currently available tools and teaching strategies for the interprofessional education of students in health professions literature review e284 | squ medical journal, august 2016, volume 16, issue 3 the smooth and widespread incorporation of such activities in health profession education.50 analysis of the studies in this review gave inconclusive evidence on the effectiveness of ipe on outcomes, mainly due to the difficulty in measuring these reliably.6 most studies only analysed immediate changes in attitudes, knowledge and skills following the intervention and did not provide long-term data on which to base assessments of the efficacy of the interventions and their transferability to clinical practice.40 furthermore, the existing literature on ipe was found to be inadequate, with poorly defined outcome validity and/or reliability measures and many studies lacking a control group. this indicates the need for the development and implementation of standard ipe programmes, along with high-quality research to assess the long-term effects of ipe activities.41 although ipe initiatives can improve the quality of healthcare personnel, maximum benefits can only be attained with the simultaneous development of interprofessional culture in healthcare settings. however, this appears to be a challenging task as it requires multiple levels of collaborative effort from health professionals and healthcare organisations.50 the current review has a few limitations. although the data abstraction form was developed and refined, external experts were not consulted. furthermore, another limitation was the lack of strict quality assessment for the included articles. conclusion this descriptive qualitative literature review focused on ipe issues involving undergraduate healthcare students and the current approaches and models used to impart ipe worldwide. nine main strategies were identified for executing ipe activities. the benefits of including ipe within the undergraduate health profession curriculum include enhanced knowledge about the benefits of collaboration, appreciation of the roles of other health professionals and improvement in individual competencies. however, there is an on-going need to evaluate the effectiveness of ipe activities on learning outcomes. although many challenges exist, recommendations synthesised from diverse approaches are expected to assist in developing sustainable strategies for implementing ipe longitudinally in various healthcare curricula. a c k n o w l e d g e m e n t s the gulf medical university, ajman, united arab emirates, provided a research assistant for data collection. references 1. reeves s, zwarenstein m, goldman j, barr h, freeth d, hammick m, et al. interprofessional education: effects on professional practice and health care outcomes. cochrane database syst rev 2008; 1:cd002213. doi: 10.1002/14651858.cd002213.pub2. 2. world health organization. health workforce: framework for action on interprofessional education and collaborative practice. from: www.who.int/hrh/resources/framework_action /en/index.html accessed: may 2016. 3. committee on quality of healthcare in america, institute of medicine. crossing the quality chasm: a new health system for the 21st century, 1st ed. washington dc, usa: national academies press, 2001. 4. barr h, koppel i, reeves s, hammick m, freeth ds. effective interprofessional education: argument, assumption and evidence, 1st ed. oxford, uk: wiley-blackwell, 2005. doi: 10.1002/9780470776445. 5. interprofessional education collaborative. core competencies for interprofessional collaborative practice: report of an expert panel, may 2011. from: www.aacn.nche.edu/educationresources/ipecreport.pdf accessed: may 2016. 6. gum lf, richards jn, walters l, forgan j, lopriore m, nobes c. immersing undergraduates into an interprofessional longitudinal rural placement. rural remote health 2013; 13:2271. 7. sargeant j, loney e, murphy g. effective interprofessional teams: “contact is not enough” to build a team. j contin educ health prof 2008; 28:228–34. doi: 10.1002/chp.189. 8. zwarenstein m, goldman j, reeves s. interprofessional collaboration: effects of practice-based interventions on professional practice and healthcare outcomes. cochrane database syst rev 2009; 3:cd000072. doi: 10.1002/14651858. cd000072.pub2. 9. world health organization. learning together to work together for health: report of a who study group on multiprofessional education for health personnel the team approach. world health organ tech rep ser 1988; 769:1–72. 10. centre for the advancement of interprofessional education. principles of interprofessional education. from: www.caipe. org.uk/resources/principles-of-interprofessional-education/ accessed: may 2016. 11. vyas d, mcculloh r, dyer c, gregory g, higbee d. an interprofessional course using human patient simulation to teach patient safety and teamwork skills. am j pharm educ 2012; 76:71. doi: 10.5688/ajpe76471. 12. jones km, blumenthal dk, burke jm, condren m, hansen r, holiday-goodman m, et al. interprofessional education in introductory pharmacy practice experiences at us colleges and schools of pharmacy. am j pharm educ 2012; 76:80. doi: 10.5688/ajpe76580. 13. yan j, gilbert jh, hoffman sj. world health organization study group on interprofessional education and collaborative practice. j interprof care 2007; 21:588–9. doi: 10.1080/ 13561820701775830. 14. garling p. final report of the special commission of inquiry: acute care services in nsw public hospitals overview. from: www. dpc.nsw.gov.au/__data/assets/pdf_file/0003/34194/overview_-_ special_commission_of_inquiry_into_acute_care_services_ in_new_south_wales_public_hospitals.pdf accessed: may 2016. 15. mann kv, mcfetridge-durdle j, martin-misener r, clovis j, rowe r, beanlands h, et al. interprofessional education for students of the health professions: the “seamless care” model. j interprof care 2009; 23:224–33. doi: 10.1080/135 61820802697735. 16. iroku-malize t, matson c, freeman j, mcgrew m, david a; adfm education transformation committee. interprofessional education. ann fam med 2013; 11:188–9. doi: 10.1370/afm.1523. http://dx.doi.org/10.1002/14651858.cd002213.pub2 http://dx.doi.org/10.1002/9780470776445 http://dx.doi.org/10.1002/chp.189 http://dx.doi.org/10.1002/14651858.cd000072.pub2 http://dx.doi.org/10.1002/14651858.cd000072.pub2 http://dx.doi.org/10.5688/ajpe76471 http://dx.doi.org/10.5688/ajpe76580 http://dx.doi.org/10.1080/13561820701775830 http://dx.doi.org/10.1080/13561820701775830 http://dx.doi.org/10.1080/13561820802697735 http://dx.doi.org/10.1080/13561820802697735 http://dx.doi.org/10.1370/afm.1523 nelofar s. khan, syed i. shahnaz and kadayam g. gomathi review | e285 17. opina-tan la. a pilot implementation of interprofessional education in a community-academe partnership in the philippines. educ health (abingdon) 2013; 26:164–71. doi: 10.41 03/1357-6283.125992. 18. inuwa im. interprofessional education (ipe) activity amongst health sciences students at sultan qaboos university: the time is now! sultan qaboos univ med j 2012; 12:435–41. doi: 10.12 816/0003168. 19. wang r, shi n, bai j, zheng y, zhao y. implementation and evaluation of an interprofessional simulation-based education program for undergraduate nursing students in operating room nursing education: a randomized controlled trial. bmc med educ 2015; 15:115. doi: 10.1186/s12909-015-0400-8. 20. cappiello jd, joy j, smith p, orgren ra. the search project: acquainting students in the health professions with interprofessional care. j allied health 2015; 44:91–5. 21. mcbride jm, drake rl. student perceptions of an interprofessional educational experience: the importance of goal articulation. anat sci educ 2015; 8:381–5. doi: 10.1002/ase.1547. 22. diwan s, perdue m, lee se, grossman br. health promotion practice and interprofessional education in aging: senior wellness fairs. gerontol geriatr educ 2016; 37:145–66. doi: 10.1080/02701960.2015.1005290. 23. herrmann g, woermann u, schlegel c. interprofessional education in anatomy: learning together in medical and nursing training. anat sci educ 2015; 8:324–30. doi: 10.1002/ase.1506. 24. arndell c, proffitt b, disco m, clithero a. street outreach and shelter care elective for senior health professional students: an interprofessional educational model for addressing the needs of vulnerable populations. educ health (abingdon) 2014; 27:99–102. doi: 10.4103/1357-6283.134361. 25. bolesta s, chmil jv. interprofessional education among student health professionals using human patient simulation. am j pharm educ 2014; 78:94. doi: 10.5688/ajpe78594. 26. shrader s, griggs c. multiple interprofessional education activities delivered longitudinally within a required clinical assessment course. am j pharm educ 2014; 78:14. doi: 10.5688/ ajpe78114. 27. morphet j, hood k, cant r, baulch j, gilbee a, sandry k. teaching teamwork: an evaluation of an interprofessional training ward placement for health care students. adv med educ pract 2014; 5:197–204. doi: 10.2147/amep.s61189. 28. von der lancken s, levenhagen k. interprofessional teaching project with nursing and physical therapy students to promote caregiver and patient safety. j nurs educ 2014; 53:704–9. doi: 10.3928/01484834-20141118-14. 29. tan ce, jaffar a, tong sf, hamzah ms, mohamad n. comprehensive healthcare module: medical and pharmacy students’ shared learning experiences. med educ online 2014; 19:25605. doi: 10.3402/meo.v19.25605. 30. netherwood m, derham r. interprofessional education: merging nursing, midwifery and cam. br j nurs 2014; 23:740–3. doi: 10.12968/bjon.2014.23.13.740. 31. hardisty j, scott l, chandler s, pearson p, powell s. interprofessional learning for medication safety. clin teach 2014; 11:290–6. doi: 10.1111/tct.12148. 32. heflin mt, pinheiro so, konrad tr, egerton eo, thornlow dk, white hk, et al. design and evaluation of a prelicensure interprofessional course on improving care transitions. gerontol geriatr educ 2014; 35:41–63. doi: 10.10 80/02701960.2013.831349. 33. vanier mc, therriault py, lebel p, nolin f, lefebvre h, brault i, et al. innovating in teaching collaborative practice with a large student cohort at université de montréal. j allied health 2013; 42:e97–106. 34. holland c, bench s, brown k, bradley c, johnson l, frisby j. interprofessional working in acute care. clin teach 2013; 10:107–12. doi: 10.1111/tct.12002. 35. stebbins mr, frear me, cutler tw, lightwood jm, fingado ar, lai cj, et al. pharmacy students teaching prescribers strategies to lower prescription drug costs for underserved patients. j manag care pharm 2013; 19:534–41. doi: 10.18553/jmcp.2013.19.7.534. 36. vanderwielen lm, enurah as, osburn if, lacoe kn, vanderbilt aa. the development of student-led interprofessional education and collaboration. j interprof care 2013; 27:422–3. doi: 10.3109/13561820.2013.790882. 37. fortugno m, chandra s, espin s, gucciardi e. fostering successful interprofessional teamwork through an undergraduate student placement in a secondary school. j interprof care 2013; 27:326–32. doi: 10.3109/13561820.2012.759912. 38. zhao sr, cao s, lin ps, yenor j, lam r, chang e, et al. interprofessional and interdisciplinary approach from undergraduate health and pre-medical students in children’s health educational initiative. j community med health educ 2013; 4:1000266. doi: 10.4172/2161-0711.1000266. 39. smithburger pl, kane-gill sl, kloet ma, lohr b, seybert al. advancing interprofessional education through the use of high fidelity human patient simulators. pharm pract (granada) 2013; 11:61–5. 40. macdonnell cp, rege sv, misto k, dollase r, george p. an introductory interprofessional exercise for healthcare students. am j pharm educ 2012; 76:154. doi: 10.5688/ajpe768154. 41. pinto a, lee s, lombardo s, salama m, ellis s, kay t, et al. the impact of structured inter-professional education on health care professional students’ perceptions of collaboration in a clinical setting. physiother can 2012; 64:145–56. doi: 10.3138/ptc.2010-52. 42. hasnain m, koronkowski mj, kondratowicz dm, goliak kl. training future health providers to care for the underserved: a pilot interprofessional experience. educ health (abingdon) 2012; 25:204–7. doi: 10.4103/1357-6283.109790. 43. leisnert l, karlsson m, franklin i, lindh l, wretlind k. improving teamwork between students from two professional programmes in dental education. eur j dental educ 2012; 16:17–26. doi: 10.1111/j.1600-0579.2011.00702.x. 44. oandasan i, reeves s. key elements of interprofessional education: part 2 factors, processes and outcomes. j interprof care 2005; 19:39–48. doi: 10.1080/13561820500081703. 45. peduzzi m, norman ij, germani ac, da silva ja, de souza gc. [interprofessional education: training for healthcare professionals for teamwork focusing on users]. rev esc enfem usp 2013; 47:977–83. doi: 10.1590/s0080-623420130000400029. 46. guitard p, dubouloz cj, savard j, metthé l, brasset-latulippe a. assessing interprofessional learning during a student placement in an interprofessional rehabilitation university clinic in primary healthcare in a canadian francophone minority context. j res interprof pract educ 2010; 1:231–46. 47. vanderwielen lm, vanderbilt aa, dumke ek, do ek, isringhausen kt, wright ms, et al. improving public health through student-led interprofessional extracurricular education and collaboration: a conceptual framework. j multidiscip healthc 2014; 7:105–10. doi: 10.2147/jmdh.s52019. 48. klasser gd, gremillion ha. past, present, and future of predoctoral dental education in orofacial pain and tmds: a call for interprofessional education. j dent educ 2013; 77:395–400. 49. gilligan c, outram s, levett-jones t. recommendations from recent graduates in medicine, nursing and pharmacy on improving interprofessional education in university programs: a qualitative study. bmc med educ 2014; 14:52. doi: 10.1186/14726920-14-52. 50. oeseburg b, hilberts r, luten ta, van etten av, slaets jp, roodbol pf. interprofessional education in primary care for the elderly: a pilot study. bmc med educ 2013; 13:161. doi: 10.1186/1472-6920-13-161. http://dx.doi.org/10.4103/1357-6283.125992 http://dx.doi.org/10.4103/1357-6283.125992 http://dx.doi.org/10.12816/0003168 http://dx.doi.org/10.12816/0003168 http://dx.doi.org/10.1186/s12909-015-0400-8 http://dx.doi.org/10.1002/ase.1547 http://dx.doi.org/10.1080/02701960.2015.1005290 http://dx.doi.org/10.1002/ase.1506 http://dx.doi.org/10.4103/1357-6283.134361 http://dx.doi.org/10.5688/ajpe78594 http://dx.doi.org/10.5688/ajpe78114 http://dx.doi.org/10.5688/ajpe78114 http://dx.doi.org/10.2147/amep.s61189 http://dx.doi.org/10.3928/01484834-20141118-14 http://dx.doi.org/10.3402/meo.v19.25605 http://dx.doi.org/10.12968/bjon.2014.23.13.740 http://dx.doi.org/10.1111/tct.12148 http://dx.doi.org/10.1080/02701960.2013.831349 http://dx.doi.org/10.1080/02701960.2013.831349 http://dx.doi.org/10.1111/tct.12002 http://dx.doi.org/10.18553/jmcp.2013.19.7.534 http://dx.doi.org/10.3109/13561820.2013.790882 http://dx.doi.org/10.3109/13561820.2012.759912 http://dx.doi.org/10.4172/2161-0711.1000266 http://dx.doi.org/10.5688/ajpe768154 http://dx.doi.org/10.3138/ptc.2010-52 http://dx.doi.org/10.4103/1357-6283.109790 http://dx.doi.org/10.1111/j.1600-0579.2011.00702.x http://dx.doi.org/10.1080/13561820500081703 http://dx.doi.org/10.1590/s0080-623420130000400029 http://dx.doi.org/10.2147/jmdh.s52019 http://dx.doi.org/10.1186/1472-6920-14-52 http://dx.doi.org/10.1186/1472-6920-14-52 http://dx.doi.org/10.1186/1472-6920-13-161 http://dx.doi.org/10.1186/1472-6920-13-161 department of biology, college of science, sultan qaboos university, muscat, oman *corresponding author e-mails: taher@squ.edu.om and tbaomar@hotmail.com حتليل نيرتوزامينات التبغ وباألخص التبغ غري املدخن "أفضل" األكثر شيوعاَ يف عمان نوال املخينية، ط�هر ب�عمر، ال�ش�دق الطيب، ع�ئ�شة ال�شحية abstract: objectives: there is a lack of awareness regarding the carcinogenicity of afzal, an illegal smokeless tobacco product (stp) widely used among the omani youth. previous research has shown that certain types of tobacco-specific nitrosamines (tsnas) are associated with oral and lung cancers. this study therefore aimed to assess levels of four common tsnas in a randomly selected sample of afzal. methods: this study was carried out at sultan qaboos university in muscat, oman, between april and september 2013. a random sample of afzal was analysed for four types of tsnas using high-performance liquid chromatography-tandem mass spectrometry. the four types of tsnas analysed were 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (nnk), n-nitrosonornicotine (nnn), n-nitrosoanatabine (nat) and n-nitrosoanabasine (nab). as a reference product, a sample of laboratory-manufactured american moist snuff (centers for disease control and prevention, atlanta, georgia, usa) was also used to confirm the accuracy and precision of the analysis. results: the analysis revealed total tsna levels of 3.573 μg/g in the afzal sample. mean levels of nnn, nnk, nat and nab were 1.205, 1.015, 0.809 and 0.545 μg/g, respectively. conclusion: levels of the two most abundant tsnas (nnn and nnk) found in the afzal sample exceeded international regulatory limits. afzal users therefore need to be educated regarding the potential health risks associated with their stp use. stricter implementation of current legislation is recommended to reduce the availability and usage of afzal in oman. keywords: smokeless tobaccos; carcinogenesis; nitrosamines; tandem mass spectrometry; liquid chromatography; oman. امللخ�ص: الهدف: هن�ك ح�جة اإىل ن�رض الوعي مب�ش�ر التبغ غري املدخن" اأف�شل" وم� يحتويه من مواد م�رضطنة. يعترب "اف�شل" اأحد انواع التبغ غري املدخن املنت�رض بني ال�شب�ب واملراهقني يف �شلطنة عم�ن. وقد ذكرت بحوث �ش�بقة اإرتب�ط بع�ص اأنواع النيرتوزامين�ت ب�رضط�ن الفم والرئة. هدفت هذه الدرا�شة اإىل تقييم اإمك�نية تواجد 4 اأنواع من النيرتوزامين�ت من خالل عينة ع�شوائية من تبغ اف�شل. الطريقة: نفذت هذه الدرا�شة يف ج�معة ال�شلط�ن ق�بو�ص يف م�شقط، �شلطنة عم�ن، يف الفرتة من اإبريل اإىل �شبتمرب 2013م. مت حتليل اأربعة من�ذج �ش�ئعة من النتريوزامين�ت املخت�شة ب�لتبغ يف العينة الع�شوائية من م�دة اأف�شل عن طريق تقنية االأداء الع�يل للتخطيط اللوين ال�ش�ئل ب�ملقي��ص 1-butanone-)3-pyridyl(-1-)n-nitrosomethylamino(-4 هي: ب�لتبغ املخت�شة النيرتوزامين�ت وهذه للكتلة. الطيفي الرتاديف التحليل دقة ولت�أكيد .)nab( n-nitrosoanabasine و ،)nat( n-nitrosoanatabine ،)nnn( n-nitrosonornicotine ،)nnk( مت اال�شتع�نة بعينة معي�رية من مركز ال�شيطرة على االأمرا�ص والوق�ية منه� يف اتالنت�، جورجي�، الوالي�ت املتحدة االأمريكية. النتائج: اأظهرت النت�ئج وجود النيرتوزامين�ت املخت�شة ب�لتبغ بكمية كلية تع�دل 3.573 ميكروجرام/ جرام والرتتيب ح�شب الوفرة هو: )1.205 = nab = 0.545( ،)nat = 0.809( ،)nnk = 1.015( ،)nnn(. اخلال�صة: اإن م�شتوى النيرتوزامين�ت )nnn و nnk( يف التبغ اف�شل قد تتعدى امل�شتوي�ت املعي�رية الع�ملية. ولذا ف�إن م�شتخدمي م�دة االأف�شل بح�جة للتثقيف عن املخ�طر ال�شحية احلرجة وكمي�ت املواد امل�رضطنة يف هذا املنتج جنب� اإىل جنب مع الدعم احلكومي و�شن قوانني اأكرث �رضامة ملنع بيع م�دة "االأف�شل" يف �شلطنة عم�ن. مفتاح الكلمات: منتج�ت التبغ غري املدخن؛ اأف�شل؛ تكون ال�رضط�ن؛ النيرتوزامين�ت؛ االأداء الع�يل للتخطيط اللوين ال�ش�ئل ب�ملقي��ص الرتاديف الطيفي للكتلة؛ عم�ن. analysis of tobacco-specific nitrosamines in the common smokeless tobacco afzal in oman nawal al-mukhaini, *taher ba-omar, elsadig a. eltayeb, aisha a. al-shehi clinical & basic research advances in knowledge this study analysed the composition of a random sample of the common omani smokeless tobacco product afzal. it revealed high levels of certain tobacco-specific nitrosamines, including 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1-butanone and n-nitrosonornicotine. application to patient care the results of this study may be utilised by healthcare policy-makers in oman to help raise awareness among afzal users about the potential dangers of this smokeless tobacco product. sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e20–26, epub. 2 feb 16 submitted 14 jun 15 revisions req. 30 aug & 22 oct 15; revisions recd. 5 oct & 26 oct 15 accepted 29 oct 15 doi: 10.18295/squmj.2016.16.01.005 nawal al-mukhaini, taher ba-omar, elsadig a. eltayeb and aisha a. al-shehi clinical and basic research | e21 smokeless tobacco products (stps) rep-resent a significant health risk and have been associated with oral and pancreatic cancers, oral lesions, coronary artery and peripheral vascular disease and adverse pregnancy outcomes.1 approximately 28 carcinogens have been identified in stps so far.2 tobacco-specific nitrosamines (tsnas) are considered a potent class of carcinogens in stps.2 during the stp curing process, tsnas form in the leaves and increase if the tobacco is subsequently fermented.3 levels of tsnas are also dependent on other factors, such as the basic ph level and the nitrite/ nitrate content of the product.4 the moisture content of the product and the related increase in microbial action are other causes of increased tsna content in stps.3 there are four primary alkaloids in tobacco—nicotine, nornicotine, anatabine and anabasine—each of which can be nitrosated by nitrite to form the following tsnas: 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1 butanone (nnk), n-nitrosonornicotine (nnn), n-nitrosoanatabine (nat) and n-nitrosoanabasine (nab), respectively.4 the international agency for research on cancer classifies nnn and nnk as group one carcinogens.5 in contrast, levels of nat and nab are lower in tobacco and their carcinogenicity is thought to be much weaker than nnn or nnk.4 although nab has been classified as a weak oesophageal carcinogen in rats, both nab and nat are classified as group three carcinogens, indicating that they are not classifiable as a human carcinogen.5,6 however, the food and drug administration in the usa considers nitrosamines as carcinogens which are not safe at any level.7 different types of stps have shown wide variations in their components and are therefore not equal in their delivery of carcinogenic tsnas into the human body.8 the world health organization (who) reports that swedish snus has the lowest level of nitrosamine— the most dangerous carcinogen—among stps available on the global market.9 in contrast, the highest levels of tsnas have been detected in sudanese toombak.10 in the usa, the three most popular brands of snuff were found to have high concentrations of tsnas.11 afzal is a stp widely used by youth and teenagers in oman.12,13 this may be perhaps due to its ease of use during manual work compared to smoked tobacco, its low cost and the limited public awareness of its harmful effects.3 high levels of certain heavy metals and cancer-enhancing anions in afzal have previously been reported.12,13 this study aimed to analyse the levels of tsnas in a random sample of afzal in order to provide further evidence of the potential carcinogenic risk of this product. methods this study was carried out at the sultan qaboos university (squ) in muscat, oman, between april and september 2013. a single package of 4.00 kg of afzal was purchased by the researchers from one source in order to maintain uniformity throughout the study. the afzal sample was labelled, ph and moisture levels were tested and the sample was refrigerated as previously described.12,13 the analysis was undertaken within six months of manufacture of the product. in order to enhance the quality of the data and to confirm the accuracy and precision of the analysis, a sample of american moist snuff was utilised as a reference. the certified reference product-2 (crp-2) is purposely manufactured for laboratory analysis by the tobacco and volatiles branch of the division of laboratory sciences at the centers for disease control and prevention ([cdc] atlanta, georgia, usa) and is not commercially available. this manufactured product is useful for comparing reference values obtained from different international analytical laboratories.14,15 samples of crp-2 were thus prepared and analysed using the same methods as the afzal samples [figure 1]. simultaneously, the crp-2 samples were dealt with in the analysis as a different stp sample matrix in order to prove the validity of the method used for other stps. afzal and crp-2 samples were dried separately in accordance with standard protocols from the cdc to determine moisture content in stps.16 approximately 15.00 g each of afzal and crp-2 were weighed separately in pre-weighed moisture dishes and placed uncovered in an oven at 99 ± 1 ºc for three hours. the samples were then removed from the oven, covered and cooled in a desiccator at room temperature for figure 1: photograph of the reference product* (left) and the common smokeless tobacco afzal (right) samples. these samples were analysed via high-performance liquid chromatography-tandem mass spectrometry to determine tobacco-specific nitrosamine levels. *american moist snuff product purposely manufactured for laboratory analysis by the tobacco and volatiles branch of the division of laboratory sciences at the centers for disease control and prevention (atlanta, georgia, usa). analysis of tobacco-specific nitrosamines in the common smokeless tobacco afzal in oman e22 | squ medical journal, february 2016, volume 16, issue 1 approximately 30 minutes to avoid drawing moisture from the air. after drying, the samples were ground separately to form a homogenised powder. the tsna analysis was performed according to methods described by lawler et al. with minor modifications.8 three afzal samples and a single crp-2 sample of 0.50 g each were transferred to 50 ml volumetric flasks and extracted using 10 ml of 100 mm aqueous ammonium acetate buffer. the samples were then shaken using an incubator shaker (ks 4000 i control shaker, ika® werke gmbh & co, staufen im breisgau, germany) at 250 revolutions per minute (rpm) for one hour. each extract was air-filtered twice with filter paper (whatman® grade 42 filtration paper, sigma-aldrich corp., st. louis, missouri, usa) followed by a 0.22 µm pore-sized nylon syringe filter (whatman® gd/x syringe filter, sigmaaldrich corp.). analytical standards of nnn, nnk, nat and nab were purchased (sigma-aldrich corp.) methanol dilution was used to prepare five different concentrations of each analyte (10, 30, 50, 70 and 100 parts per billion [ppb]). standard calibration curves were plotted for each of the tsnas. for accuracy and precision, the relative standard deviation (rsd), limit of detection (lod), limit of quantification (loq) and r-value of 10 replicate injections of 10 ppb each of the standards were calculated. analytical separation of the afzal and the crp-2 samples was performed using a high-performance liquid chromatography (hplc) system (1290 infinity lc system, agilent technologies, santa clara, california, usa) with a zorbax sb c18 1.8 µm, 2.1 x 50 mm stationary phase column (agilent technologies). eluent a (aqueous phase) was a five mm ammonium acetate solution, whereas eluent b (organic phase) was comprised of acetonitrile and water at a ratio of 70:30, along with 5 mm of ammonium acetate. the column temperature was kept at 40 ºc and the flow rate was constant at 0.4 ml/minute. the eluents were run in a gradient manner with a running time of five minutes. the detector used was a 6460 triple quadrupole lc/ ms (agilent technologies). all chromatographic data were processed using masshunter workstation software b.06.00 (agilent technologies). all chemicals used in the analysis were from sigma-aldrich corp. and were of analytical grade. deionised water from a milli-q® integral water purification system (emd millipore corp., bedford, massachusetts, usa) was used throughout the analysis. machine detection limits were calculated for each of the analysed tsnas. table 1: accuracy, precision, reliability and linearity values for each type of tobacco-specific nitrosamine analysed in the afzal samples value nab nat nnk nnn average in µg/g 10.480 83.400 23.270 89.690 sd 1.110 0.650 0.280 0.970 rsd in % 10.550 0.780 1.220 1.080 accuracy in % 104.840 92.670 93.090 99.660 r-value 0.986 0.986 0.971 0.994 lod in ppb 3.320 1.960 0.850 2.910 loq in ppb 11.060 6.530 2.850 9.710 nab = n-nitrosoanabasine; nat = n-nitrosoanatabine; nnk = 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1-butanone; nnn = n-nitrosonornicotine; sd = standard deviation; rsd = relative standard deviation; lod = limit of detection; ppb = parts per billion; loq = limit of quantification. table 2: concentrations of tobacco-specific nitrosamine levels in three afzal samples and one reference product* sample as determined by high-performance liquid chromatography-tandem mass spectrometry sample tsna levels in µg/g nnk nnn nab nat total afzal 1 1.018 1.178 0.624 0.807 3.627 afzal 2 1.017 1.221 0.524 0.818 3.580 afzal 3 1.009 1.216 0.486 0.802 3.513 mean afzal ± sd 1.015 ± 0.004 1.205 ± 0.019 0.545 ± 0.058 0.809 ± 0.007 3.573 ± 0.047 mean crp-2 ± sd 0.465 ± 0.280 1.793 ± 0.970 0.209 ± 1.110 1.668 ± 0.650 4.135 ± 0.752 tsna = tobacco-specific nitrosamine; nnk = 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1-butanone; nnn = n-nitrosonornicotine; nab = n-nitrosoanabasine; nat = n-nitrosoanatabine; sd = standard deviation; crp-2 = certified reference product-2. *american moist snuff product purposely manufactured for laboratory analysis by the tobacco and volatiles branch of the division of laboratory sciences at the centers for disease control and prevention (atlanta, georgia, usa). table 3: comparison of certified reference tobaccospecific nitrosamine levels15 with levels determined in the present study in one reference product* sample tsna levels in µg/g reference levels present study nat 1.460–2.230 1.668 nnk 0.370–0.580 0.465 nnn 1.440–2.120 1.793 nab 0.120–0.210 0.209 total 3.380–5.000 4.135 tsna = tobacco-specific nitrosamine; nat = n-nitrosoanatabine; nnk = 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1-butanone; nnn = n-nitrosonornicotine; nab = n-nitrosoanabasine. *american moist snuff product purposely manufactured for laboratory analysis by the tobacco and volatiles branch of the division of laboratory sciences at the centers for disease control and prevention (atlanta, georgia, usa). nawal al-mukhaini, taher ba-omar, elsadig a. eltayeb and aisha a. al-shehi clinical and basic research | e23 statistical analysis was performed using excel spreadsheet software, version 2010 (microsoft corp., redmond, washington, usa). as this study was a chemical analysis of two forms of stps, it did not require ethical approval. results the method used for the analysis of the afzal samples showed high sensitivity and reliable validity, as indicated by the lod, loq, rsd and other accuracy and linearity values of the calibration curves for all four tsna types [table 1]. concentrations of all four tsnas were detected in both the afzal and the crp-2 samples [table 2]. tsna levels for each of the three afzal samples were very similar, reflecting the precision of the analysis. in the afzal samples, mean analyte levels of nnn, nnk, nat and nab were 1.205 ± 0.019 µg/g, 1.015 ± 0.004 µg/g, 0.809 ± 0.007 µg/g and 0.545 ± 0.047 µg/g, respectively. for the crp-2 figure 2a–d: high-performance liquid chromatography-tandem mass spectrometry chromatograms of (a) n-nitrosoanabasine, (b) n-nitrosoanatabine, (c) 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1-butanone and (d) n-nitrosonornicotine in each of the three afzal samples. figure 3a–d: high-performance liquid chromatography-tandem mass spectrometry chromatograms of (a) n-nitrosoanabasine, (b) n-nitrosoanatabine, (c) 4-(n-nitrosomethylamino)-1-(3-pyridyl)-1-butanone and (d) n-nitrosonornicotine in one reference product* sample. *american moist snuff product purposely manufactured for laboratory analysis by the tobacco and volatiles branch of the division of laboratory sciences at the centers for disease control and prevention (atlanta, georgia, usa). analysis of tobacco-specific nitrosamines in the common smokeless tobacco afzal in oman e24 | squ medical journal, february 2016, volume 16, issue 1 sample, mean levels of the same tsnas were 1.793 ± 0.970 µg/g, 0.465 ± 0.280 µg/g, 1.668 ± 0.650 µg/g and 0.209 ± 1.110 µg/g, respectively. levels of nnn were highest while nab levels were lowest for both the afzal and the crp-2 samples. overall, the crp2 sample contained higher mean total tsna levels (4.135 µg/g) than the afzal sample (3.573 µg/g). the observed tsna values for the crp-2 sample were in line with certified reference values provided by the cdc,15 validating the results of the analysis [table 3]. chromatograms of the analysed tsnas in all three afzal samples were very similar, confirming the presence of the same analytes in each sample [figure 2]. chromatograms of tsnas in the crp-2 sample were comparable to those of afzal samples, although there were slight differences between each analyte [figure 3]. these chromatograms of tsnas in crp-2 showed comparable results, reflecting the effectiveness of the method used for the new stp sample matrix. discussion nitrosamines have been strongly associated with several human and animal cancers.4 while nitrosamines are present in many foods and items which come into contact with food in amounts ranging from 1–10 ng/g, the highest exposure to humans comes from tobacco use.17 these chemical compounds have been detected in the saliva of tobacco chewers and are believed to form in the digestive system.17 all stps demonstrate a wide diversity in their chemical compositions which result from variations in geographical location, additives used and manufacturing methods.4 in order to avoid potentially diverse chemical compositions, one random sample of afzal was chosen to conduct several chemical and toxicological tests. the presence of tsnas in the afzal samples was confirmed using a modified version of lawler et al.’s method.8 levels of nitrosamines in green tobacco leaves are negligible; however, several factors may foster the formation of tsnas in stps, including the damping, curing and fermentation processes, storage temperatures, high nitrate/nitrite content, alkaline ph and high moisture levels.18,19 most of these factors are present in afzal. as reported previously, samples of afzal were observed to have an alkaline ph (10.460), high moisture levels (52%) and a high nitrate concentration (8,792.200 μg/g).12 in general, afzal is stored illicitly in local stp shops or retail outlets where there is likely to be poor hygiene, a lack of air circulation and high temperatures which dramatically increase in the summer. shi et al. confirmed that stp storage temperatures of above 30 °c increased tsna formation significantly, as did high levels of nitrate.20 a study by the who revealed that storage at room temperature increases tsna concentrations in stps due to microbial action.9 different manufacturing processes also play a role in tsna level variations. high tsna levels in american moist snuff and low tsna levels in swedish snus have been reported to be due to the fermentation process in the former and heat treatment or a pasteurisation-like process in the latter.9 heat treatment gives rise to more sterile products by killing the bacteria implicated in the formation of nitrosamines, while fermentation leads to a high concentration of nitrites.21 afzal is manufactured using a fermentation process; this may therefore facilitate the formation of tsnas. the high tsna content in toombak has been attributed to its high nitrate content, alkaline ph and its manufacture via fermentation.10 in the current study, high levels of two specific forms of tsnas—nnn and nnk—were noted. measurements of nnk and nnn show significant variation from one country to another. levels of nnn and nnk levels in afzal noted in the current study were lower than those found in traditional american stps (135.000 μg/g and 17.800 μg/g, respectively) or dry weight toombak (3,085 μg/g and 7,870 μg/g, respectively);4 however, these levels may nevertheless increase in afzal blends due to the effect of the aforementioned factors that contribute to tsna formation. stepanov et al. reported that nnn and nnk levels in indian khaini and zarda range between 1.740–76.900 µg/g and 0.080–28.400 µg/g, respectively, while lower ranges are reported for gutkha (0.090–1.090 µg/g and 0.040–0.430 µg/g, respectively).22 in the current study, levels of nnn in afzal were much higher than those observed in gutkha, but were lower than those found in khaini and zarda. in terms of nnk levels, the results of the current study were within the same range as those found in khaini and zarda, but were higher than that of gutkha.21 the nnk and nnn levels in toombak (516.000 μg/g and 368.000 μg/g, respectively) were markedly higher than dry weight levels of bangladeshi zarda (3.840 μg/g and 28.600 μg/g, respectively).22 low levels of nnn were also noted in indian tobacco products (18.600 μg/g).23 concentrations of nnn and nnk in american moist snuff have been reported to be 42.600 μg/g and 9.950 μg/g, respectively.23 hearn et al. found that alaskan iq’mik had nnn and nnk dry weight levels of 2.700 µg/g and 0.340 µg/g, respectively.24 handmade pakistani gutkha has a lower total tsna content compared with handmade gutkha.23 new stps in the usa have decreased mean total dry weight tsna levels (2.610 µg/g) in comparison to traditional stps nawal al-mukhaini, taher ba-omar, elsadig a. eltayeb and aisha a. al-shehi clinical and basic research | e25 (7.420 µg/g); the same is true for specific nnn and nnk levels (2.050 versus 4.410 µg/g and 0.231 versus 1.200 µg/g, respectively).25 nevertheless, these nnn and nnk levels are still 100–1,000 times higher than nitrosamine levels reported in food and beer.26 both nnn and nnk are thought to be potent carcinogens.5 balbo et al. reported a significant association between nnn in drinking water and the development of oesophageal and oral cancers in rats.27 in addition, nnk has been found to increase the risk of lung cancer.28 the nnn and nnk compounds are also known to form haemoglobin adducts in humans as well as in experimental animals.29,30 the use of toombak, which has high nnn and nnk levels as mentioned above, has been associated with cancers of the oral cavity.31,32 many factors may influence the uptake or absorption of tsnas in the oral cavity. tsnas are highly water-soluble; therefore, as the moisture content of a stp increases, the levels of soluble tsnas may also rise, resulting in enhanced absorption by the oral mucosa.33 the authors of the current study strongly believe that tsnas are not safe at any level. as a result, it is strongly recommended that existing legislation in oman regarding the illegal sale of afzal be more strictly enforced. furthermore, there is a need for national public health awareness programmes regarding the potential carcinogenic effects of afzal. for swedish snus, maximum permissible levels of carcinogenic substances are laid out by the gothiatek® standard (swedish match, stockholm, sweden).34 according to this, the maximum permissible combined nnn and nnk level is 1.000 µg/g.34 between 1983 and 2004, manufacturers of swedish snus gradually decreased total tsna levels to approximately 2.000 µg/g.21 a recent study revealed that the total tsna level in an unused 1.000 g pouch of snus was approximately 0.830 µg/g, with quantifiable levels of nat, nnk, nnn and nab (0.268 µg/g, 0.191 µg/g, 0.344 µg/g and 0.025 µg/g, respectively).33 therefore, total tsna levels in the afzal sample analysed in the current study were fivefold higher than the recommended gothiatek® limits. specific tsna levels in afzal were six-fold, 2.4fold, 5.2-fold and 8.4-fold higher than the nat, nnk, nnn and nab levels, respectively, in snus. as such, tsna levels in afzal can be considered alarmingly high. the who recommends regulatory limits on the concentrations of selected carcinogens in tobacco products, including tsnas.9 their recommendations permit <2.00 µg/g of combined nnn and nnk levels on a dry weight basis.9 combined levels of these two tsnas in the studied afzal sample (2.22 μg/g) exceeded this limit. this may have a negative effect on the health of afzal users with frequent unmonitored use. moreover, afzal users may be exposed to higher levels of tsnas as a result of varying self-determined pinch sizes; pinch sizes of afzal are usually greater than the portions provided in packets of the more monitored and controlled swedish snus.12,13,33,34 it is important to bear in mind that the results obtained by the current study and previous research on afzal were derived from a single package of afzal blend.12,13 the findings of future studies may therefore differ due to variations in the additives and manufacturing processes used. conclusion this study revealed the presence of carcinogenic tsnas in a single random sample of afzal. despite being present at relatively low levels in afzal as compared to other stps, two of the most potent carcinogenic tsnas—nnn and nnk—still exceeded the regulatory limits proposed by the who. total tsna levels were five-fold higher than the limits recommended by the gothiatek® standard. these findings indicate that afzal consumption may pose serious health risks for users. consequently, existing legislation on the sale and availability of this stp should be enforced more rigorously. increased public health education regarding the potential carcinogenic effects of afzal is recommended. a c k n o w l e d g e m e n t s the authors are grateful to mr. stephen b. stanfill from cdc, usa, for his assistance in obtaining the crp2 sample for analysis. the authors would also like to acknowledge the help of mr. singaravadivel and mrs. muna al-hosni from the central analytical & applied research unit in the college of science at squ for their technical support and cooperation in one hplc tandem mass spectrometry analysis. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. united states department of health and human services. the health consequences of using smokeless tobacco: a report of the advisory committee to the surgeon general. from: www. profiles.nlm.nih.gov/ps/access/nnbbfc.pdf accessed: oct 2015. 2. brunnemann kd, hoffmann d. chemical composition of smokeless tobacco products. in: national cancer institute. smoking and tobacco control monograph 2: smokeless tobacco or health an international perspective. from: www. cancercontrol.cancer.gov/brp/tcrb/monographs/2/m2_3.pdf accessed: oct 2015. analysis of tobacco-specific nitrosamines in the common smokeless tobacco afzal in oman e26 | squ medical journal, february 2016, volume 16, issue 1 3. rutqvist le, curvall m, hassler t, ringberger t, wahlberg i. swedish snus and the gothiatek® standard. harm reduct j 2011; 8:11. doi: 10.1186/1477-7517-8-11. 4. international agency for research on cancer. iarc monograph 89: smokeless tobacco and some tobacco specific n-nitrosamines. from: www.monographs.iarc.fr/eng/ monographs/vol89/ accessed: oct 2015. 5. international agency for research on cancer. iarc monographs volume 37: tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamines. from: www. monographs.iarc.fr/eng/monographs/vol1-42/mono37.pdf accessed: oct 2015. 6. clayton pm, cunningham a, van heemst jd. quantification of four tobacco-specific nitrosamines in cigarette filter tips using liquid chromatography-tandem mass spectrometry. anal methods 2010; 2:1085–94. doi: 10.1039/b9ay00306a. 7. pauli g. history of the u.s. food and drug administration. from: www.fda.gov/downloads/aboutfda/whatwedo/history/oral histories/selectedoralhistor ytranscripts/ucm390423.pdf/ accessed: oct 2015. 8. lawler ts, stanfill sb, zhang l, ashley dl, watson ch. chemical characterization of domestic oral tobacco products: total nicotine, ph, unprotonated nicotine and tobaccospecific n-nitrosamines. food chem toxicol 2013; 57:380–6. doi: 10.1016/j.fct.2013.03.011. 9. world health organization. who study group on tobacco product regulation: report on the scientific basis of tobacco product regulation. from: www.who.int/tobacco/global_inter action/tobreg/publications/tsr_955/en/ accessed oct 2015. 10. idris am, nair j, ohshima h, friesen m, brouet i, faustman em, et al. unusually high levels of carcinogenic tobacco-specific nitrosamines in sudan snuff (toombak). carcinogenesis 1991; 12:1115–18. doi: 10.1093/carcin/12.6.1115. 11. hoffmann d, djordjevic mv, fan j, zang e, glynn t, connolly gn. five leading u.s. commercial brands of moist snuff in 1994: assessment of carcinogenic n-nitrosamines. j natl canc inst 1995; 87:1862–9. doi: 10.1093/jnci/87.24.1862. 12. al-mukhaini nm, ba-omar t, eltayeb e, al-shehi a. characterisation of nicotine and cancer-enhancing anions in the common smokeless tobacco afzal in oman. sultan qaboos univ med j 2015; 15:e469–76. doi: 10.18295/ squmj.2015.15.04.005. 13. al-mukhaini n, ba-omar t, eltayeb e, al-shehi a. determination of heavy metals in the common smokeless tobacco afzal in oman. sultan qaboos univ med j 2014; 14:e349–55. 14. borgerding mf, bodnar ja, curtin gm, swauger je. the chemical composition of smokeless tobacco: a survey of products sold in the united states in 2006 and 2007. regul toxicol pharmacol 2012; 64:367–87. doi: 10.1016/j. yrtph.2012.09.003. 15. smokeless tobacco sub-group technical report. coresta reference products 2010 analysis, february 2014. from: www.coresta.org/reports/sts-ctr_2010-4crp-analysis.pdf accessed: oct 2015. 16. centers for disease control and prevention. notice regarding requirement for annual submission of the quantity of nicotine contained in the smokeless tobacco products manufactured, imported, or packaged in the united states. fed regist 1999; 64:14086–96. 17. nair j, ohshima h, friesen m, croisy a, bhide sv, bartsch h. tobacco-specific and betel nut-specific n-nitroso compounds: occurrence in saliva and urine of betel quid chewers and formation in vitro by nitrosation of betel quid. carcinogenesis 1985; 6:295–303. doi: 10.1093/carcin/6.2.295. 18. andersen ra, burton hr, fleming pd, hamilton-kemp tr. effect of storage conditions on nitrosated, acylated, and oxidized pyridine alkaloid derivatives in smokeless tobacco products. canc res 1989; 49:5895–900. 19. chamberlain wj, chortyk ot. effects of curing and fertilization on nitrosamine formation in bright and burley tobacco. beiträge zur tabakforschung 1992; 15:87–92. doi: 10.2478/cttr2013-0625. 20. shi h, wang r, bush lp, zhou j, yang h, fannin n, et al. changes in tsna contents during tobacco storage and the effect of temperature and nitrate level on tsna formation. j agric food chem 2013; 61:11588–94. doi: 10.1021/jf404813m. 21. osterdahl b, jansson c, paccou a. decreased levels of tobaccospecific n-nitrosamines in moist snuff on the swedish market. j agric food chem 2004; 52:5085–8. doi: 10.1021/jf049931a. 22. stepanov i, hecht ss, ramakrishnan s, gupta pc. tobaccospecific nitrosamines in smokeless tobacco products marketed in india. int j cancer 2005; 116:16–19. doi: 10.1002/ijc.20966. 23. stanfill sb, connolly gn, zhang l, jia tl, henningfield j, richter p, et al. global surveillance of oral tobacco products: total nicotine, unionised nicotine and tobacco-specific n-nitrosamines. tob control 2011; 20:e2. doi: 10.1136/ tc.2010.037465. 24. hearn ba, renner cc, ding ys, vaughan-watson c, stanfill sb, zhang l, et al. chemical analysis of alaskan iq’mik smokeless tobacco. nicotine tob res 2013; 15:1283–8. doi: 10.1093/ntr/nts270. 25. stepanov i, jensen j, hatsukami d, hecht ss. new and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. nicotine tob res 2008; 10:1773–82. doi: 10.1080/14622200802443544. 26. bartsch h, spiegelhalder b. environmental exposure to n-nitroso compounds (nnoc) and precursors: an overview. eur j cancer prev 1996; 5:11–17. 27. balbo s, james-yi s, johnson cs, o’sullivan mg, stepanov i, wang m, et al. (s)-n'-nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats. carcinogenesis 2013; 34:2178–83. doi: 10.1093/carcin/bgt162. 28. yuan jm, gao yt, murphy se, carmella sg, wang r, zhong y, et al. urinary levels of cigarette smoke constituent metabolites are prospectively associated with lung cancer development in smokers. cancer res 2011; 71:6749–57. doi: 10.1158/00085472.can-11-0209. 29. murphy se, carmella sg, idris am, hoffmann d. uptake and metabolism of carcinogenic levels of tobacco-specific nitrosamines by sudanese snuff dippers. cancer epidemiol biomarkers prev 1994; 3:423–8. 30. hecht ss, carmella sg, murphy se. hemoglobin adducts as biomarkers of exposure to and metabolic activation of carcinogenic tobacco-specific nitrosamines. biomed environ sci 1991; 4:93–103. 31. idris am, prokopczyk b, hoffmann d. toombak: a major risk factor for cancer of the oral cavity in sudan. prev med 1994; 23:832–9. doi: 10.1006/pmed.1994.1141. 32. ahmed hg, mahgoob rm. impact of toombak dipping in the etiology of oral cancer: gender-exclusive hazard in the sudan. j canc res ther 2007; 3:127–30. doi: 10.4103/0973-1482.34696. 33. digard h, gale n, errington g, peters n, mcadam k. multianalyte approach for determining the extraction of tobacco constituents from pouched snus by consumers during use. chem cent j 2013; 7:55. doi: 10.1186/1752-153x-7-55. 34. swedish match. gothiatek® standard: gothiatek® limits for undesired components. from: www.swedishmatch. com/en/snus -and-he alth/g othi ate k/g othi ate kstandard/ accessed: oct 2015. http://dx.doi.org/10.1186/1477-7517-8-11 http://www.monographs.iarc.fr/eng/monographs/vol89/ http://www.monographs.iarc.fr/eng/monographs/vol89/ http://dx.doi.org/10.1039/b9ay00306a http://www.fda.gov/downloads/aboutfda/whatwedo/history/oralhistories/selectedoralhistorytranscripts/ucm390423.pdf/%20 http://www.fda.gov/downloads/aboutfda/whatwedo/history/oralhistories/selectedoralhistorytranscripts/ucm390423.pdf/%20 http://dx.doi.org/10.1016/j.fct.2013.03.011 http://www.who.int/tobacco/global_interaction/tobreg/publications/tsr_955/en/ http://www.who.int/tobacco/global_interaction/tobreg/publications/tsr_955/en/ http://dx.doi.org/10.1093/carcin/12.6.1115 http://dx.doi.org/10.1093/jnci/87.24.1862 http://dx.doi.org/10.18295/squmj.2015.15.04.005 http://dx.doi.org/10.18295/squmj.2015.15.04.005 http://dx.doi.org/10.1016/j.yrtph.2012.09.003 http://dx.doi.org/10.1016/j.yrtph.2012.09.003 http://dx.doi.org/10.1093/carcin/6.2.295 http://dx.doi.org/10.2478/cttr-2013-0625 http://dx.doi.org/10.2478/cttr-2013-0625 http://dx.doi.org/10.1021/jf404813m http://dx.doi.org/10.1021/jf049931a http://dx.doi.org/10.1002/ijc.20966 http://dx.doi.org/10.1136/tc.2010.037465 http://dx.doi.org/10.1136/tc.2010.037465 http://dx.doi.org/10.1093/ntr/nts270 http://dx.doi.org/10.1080/14622200802443544 http://dx.doi.org/10.1093/carcin/bgt162 http://dx.doi.org/10.1158/0008-5472.can-11-0209 http://dx.doi.org/10.1158/0008-5472.can-11-0209 http://dx.doi.org/10.1006/pmed.1994.1141 http://dx.doi.org/10.4103/0973-1482.34696 http://dx.doi.org/10.1186/1752-153x-7-55 the abdominal aorta divides into the right and left common iliac arteries which are anterolateral to the left side of the fourth lumbar vertebral body. both of these arteries divide into the external and internal iliac arteries at the level of the sacroiliac joints. the external iliac artery mainly supplies blood to the lower limbs, whereas the internal iliac artery delivers the principal blood supply to the walls and viscera of the pelvis, perineum and gluteal region.1 the obturator artery is a mediumsized muscular artery which usually arises from the anterior trunk of the internal iliac artery. it then runs anterolaterally on the lateral pelvic wall and is crossed by the ureter at its medial aspect, before entering into the adductor compartment of the thigh after passing through the obturator canal.1 the obturator artery has a variable origin—sometimes it originates as a direct branch of the internal iliac artery and at other times from one of the other branches of the internal iliac artery, namely the superior gluteal, inferior epigastric and inferior gluteal arteries.2 the obturator artery provides the iliac branches to the iliac fossa and iliacus muscle. occasionally, the obturator artery is replaced by an enlarged pubic branch of the inferior epigastric artery—an accessory obturator artery—which descends almost vertically to the obturator foramen.1 the obturator vein begins in the proximal adductor compartment and enters the pelvic cavity via the obturator foramen. it runs in a posterosuperior direction, below the obturator artery and between the ureter and internal iliac artery, before finally draining into the internal iliac vein.1 anatomical knowledge of the pelvic viscera and the vasculature of the retropubic pelvic region is vital for endoscopic inguinal hernioplasties, laparoscopic herniorrhaphies and during bilateral internal iliac artery ligation, a life-saving procedure to control haemorrhage following complications in gynaecological and obstetric procedures.3,4 case report a routine educational gross anatomy dissection of a female cadaver of approximately 55 years of age was conducted at the all india institute of medical sciences, new delhi, india, in 2016. the cadaver had no pathological or traumatic lesions and there were no signs of any previous surgical procedures in the pelvic and perineal region. both of the internal iliac arteries were divided at the level of the sacroiliac joints in front department of anatomy, all india institute of medical sciences, new delhi, india *corresponding author e-mail: seemahkg@gmail.com تباين األوعية الدموية لعضالت املسد خالل عملية تشريح جثة روتيين في�صواجت دي�صموخ، �صيما �صينغ، نريجا �صريوحي، ديفيا باروحي abstract: the obturator artery normally originates from the internal iliac artery while the obturator vein drains into the internal iliac vein. during a routine gross anatomy dissection class for undergraduate students at the all india institute of medical sciences, new delhi, india, in 2016, a rare unilateral variation in the obturator vasculature was found in a female cadaver of approximately 55 years of age. in this case, the left obturator artery originated from the superior gluteal artery and the left obturator vein drained into the external iliac vein. knowledge of such variations is necessary during hernia procedures, ligation of the internal iliac artery and muscle graft surgeries. keywords: iliac artery; anatomic variation; dissection; case report; india. ح�صة خالل الداخلي، احلرقفي الوريد يف امل�صد وريد ي�صب عندما الداخلي احلرقفي ال�رضيان يف عادة ال�رضيان ان�صداد ين�صاأ امللخ�ص: ت�رضيح روتينية لطالب املرحلة اجلامعية يف معهد عموم الهند للعلوم الطبية، نيودلهي، الهند، يف عام 2016م مت العثور على اختالف نادر من جانب واحد يف االأوعية الدموية لع�صلة امل�صد يف جثة الأنثى يقارب عمرها 55 عاما. يف هذه احلالة املعرو�صة، ال�رضيان االأي�رض امل�صد ن�صاأ من ال�رضيان االألوي العلوي ووريد امل�صد ي�صب يف الوريد احلرقفي اخلارجي، ويعد معرفة هذه االختالفات اأمراً �رضوريًا خالل عمليات الفتق وربط ال�رضيان احلرقفي الداخلي وعمليات ترقيع الع�صالت. كلمات مفتاحية: ال�رضيان احلرقفي؛ االإختالفات الت�رضيحية؛ ت�رضيح؛ تقرير حالة؛ الهند. variation in the obturator vasculature during routine anatomy dissection of a cadaver vishwajit deshmukh, *seema singh, neerja sirohi, divya baruhee case report sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e356–358, epub. 19 aug 16 submitted 22 feb 16 revision req. 27 mar 16; revision recd. 27 apr 16 accepted 19 may 16 doi: 10.18295/squmj.2016.16.03.016 vishwajit deshmukh, seema singh, neerja sirohi and divya baruhee case report | e357 canal.1 however, the origin of the obturator artery is highly variable.5 in a study of 50 cadavers, rajive et al. found obturator arteries arising from various locations, including the common trunk of the internal iliac artery (4%), anterior trunk of the internal iliac arteries (54%), inferior epigastric artery (22%), superior gluteal artery (2%), internal pudendal trunk (2%), inferior gluteal artery (2%) and the external iliac artery (4%).6 bilgiç et al. reported a female newborn with a common arterial trunk arising from the medial side of the external iliac artery which subsequently divided into the obturator and inferior epigastric arteries.7 in more than one-third of cases, the anastomotic connection between the pubic branch of the inferior epigastric and obturator arteries can become enlarged; this is known as an “abnormal” obturator artery.8 jusoh et al. reported that the origin of the obturator artery was the posterior division of the internal iliac artery in approximately 5.8% of cases and that this anomalous artery divided into an inferior vesical branch leading to the prostate.9 in the present case, the obturator artery originated from the superior gluteal artery on the left side and traversed the lateral pelvic wall along with the obturator nerve to enter the obturator canal. an abnormal origin of the obturator artery from the superior gluteal artery may have important surgical implications, particularly for female patients undergoing superior gluteal artery perforator flap surgery for breast augmentation/construction or to treat sacral pressure sores.10 usually, veins in the pelvis and in the lower limbs follow the same course as the arteries; nagabhooshana et al. reported a case wherein the obturator artery arose from the external iliac artery and the obturator vein drained into the external iliac vein, implying that the arteries were followed by the veins.11 however, in the present case, the artery arose from the superior gluteal artery while the left obturator vein drained into the external iliac vein and crossed the pelvic brim before termination. this type of vasculature may affect laparoscopic surgeries or open pelvic brim surgeries.3 the embryological basis for such variations in the vasculature of the limbs depends on the selection of the channels from the primary capillary plexus; the most appropriate channels will enlarge while others will retract and gradually disappear, thus establishing the final vascular pattern.12,13 another explanation for abnormal vasculature could be angiogenesis as a result of hypoxia.14 low oxygen saturation leads to the stabilisation of hypoxia-inducible factor 1-α which upregulates vascular endothelial growth factor a and nitric oxide synthase expression. subsequently, the production of nitric oxide causes dilatation of the existing vessels and extravasation of plasma proteins, of the anterior margin of the greater sciatic notch and proceeded into the anterior and posterior trunk. the anterior trunk continued into the pelvis and supplied blood to the pelvic viscera through its branches. the posterior trunk divided into the iliolumbar, lateral sacral and superior gluteal arteries. the superior gluteal artery passed along the upper margin of the piriformis through the greater sciatic foramen. the left obturator artery originated from the superior gluteal artery in the pelvic cavity and passed along the lateral pelvic wall to enter the obturator canal, below the obturator nerve. the left obturator vein, instead of draining normally into the internal iliac vein, drained into an external iliac vein and crossed the pelvic brim [figure 1]. the right-sided anatomy of the obturator vasculature was normal, as were relations between the vasculature and obturator nerve in the obturator foramen and canal. no variations were observed in any of the other arteries, nerves or muscles. discussion anatomical knowledge of the obturator vasculature is important in surgeries related to the pelvic brim and the gluteal and adductor compartments of the thigh.3,4 the obturator artery chiefly supplies blood to the adductor compartment of the thigh as well as the smaller pelvic branches. generally, the obturator artery originates from the anterior trunk of the internal iliac artery and follows the normal route along the lateral pelvic wall, to enter the thigh through the obturator figure 1: photograph showing the abnormal origin and drainage pattern of obturator vessels on the left side of the pelvic wall of a female adult cadaver. im = iliacus muscle; fn = femoral nerve; cia = common iliac artery; eia = external iliac artery; eiv = external iliac vein; iia = internal iliac artery; ov = obturator vein; on = obturator nerve; pt = posterior trunk; sga = superior gluteal artery; lst = lumbosacral trunk; oa = obturator artery; at = anterior trunk; sp = sacral promontory. variation in the obturator vasculature during routine anatomy dissection of a cadaver e358 | squ medical journal, august 2016, volume 16, issue 3 leading to protease and matrix metalloproteinase expression.14 these plasma proteins then play an important role in the proliferation and angiogenesis of endothelial cells which leads to the formation of abnormal vasculature.14 the obturator artery is formed relatively late during development, joining with an axial artery of the lower limb that accompanies the sciatic nerve.15 the origin of the obturator artery from the superior gluteal artery is due to the remains of the vascular channels related to the posterior trunk of the internal iliac arteries in circumstances where the vascular channels related to the anterior division predestined for the obturator artery may have degenerated.16 the obturator artery is an important source of collateral circulation for patients with aortoiliac and femoral arterial occlusive diseases.16 femoral head ischaemia can sometimes occur due to decreased blood flow through the obturator artery due to trauma, a tumour or tuberculosis because of decreased blood flow through the branch of the obturator artery, which supplies blood to the femoral head via the ligamentum teres of the femur.16 during graft surgeries, additional advantage can be obtained in cases where the left obturator artery is longer than the right obturator artery, as with the present case.16 conclusion during a routine dissection of a female adult cadaver, a rare unilateral variation in the obturator vasculature was observed. the variation was found to lie in the origin of the obturator artery and termination of the obturator vein. knowledge regarding potential variations in the obturator vasculature is important during pelvis and pelvic brim surgeries, particularly hernia surgeries. furthermore, anatomical information regarding the obturator vasculature is also important when performing superior gluteal muscle grafts during breast augmentation surgeries in female patients. documenting such variations is crucial and will help surgeons when considering various surg ical approaches. references 1. borley nr. true pelvis, pelvic floor and perineum. in: standring s. gray’s anatomy: the anatomical basis of clinical practice, 40th ed. london, uk: churchill livingstone, 2008. pp. 1083–98. 2. pai mm, krishnamurthy a, prabhu lv, pai mv, kumar sa, hadimani ga. variability in the origin of the obturator artery. clinics (sao paulo) 2009; 64:897–901. doi: 10.1590/s180759322009000900011. 3. lau h, lee f. a prospective endoscopic study of retropubic vascular anatomy in 121 patients undergoing endoscopic extraperitoneal inguinal hernioplasty. surg endosc 2003; 17:1376–9. doi: 10.1007/s00464-003-8800-y. 4. havaldar pp, taz s, angadi av, saheb sh. morphological study of obturator artery. int j anat res, 2014; 2:354–7. 5. pick jw, anson bj, ashley fl. the origin of the obturator artery: a study of 640 body-halves. am j anat 1942; 70:317–43. doi: 10.1002/aja.1000700206. 6. rajive av, pillay m. a study of variations in the origin of obturator artery and its clinical significance. j clin diagn res 2015; 9:ac12–15. doi: 10.7860/jcdr/2015/14453.6387. 7. bilgiç s, sahin b. rare arterial variation: a common trunk from the external iliac artery for the obturator, inferior epigastric and profunda femoris arteries. surg radiol anat 1997; 19:45–7. doi: 10.1007/bf01627734. 8. basmajian jv. grant’s method of anatomy: by regions, descriptive and deductive, 8th ed. philadelphia, pennsylvania, usa: williams & wilkins co., 1971. pp. 306–7. 9. jusoh ar, abd rahman n, abd latiff a, othman f, das s, abd ghafar n, et al. the anomalous origin and branches of the obturator artery with its clinical implications. rom j morphol embryol 2010; 51:163–6. 10. mu lh, yan yp, luan j, fan f, li sk. [anatomy study of superior and inferior gluteal artery perforator flap.] zhonghua zheng xing wai ke za zhi 2005; 21:278–80. 11. nagabhooshana s, vollala vr, rodrigues v, bhat s, pamidi n, lobo sw. anatomical variation of obturator vessels and its practical risk: a case report from an anatomic study. j vasc bras 2008; 7:275–7. doi: 10.1590/s1677-54492008000300015. 12. arey lb. the development of peripheral blood vessels. in: smith jl, orbison de, eds. the peripheral blood vessels. baltimore, maryland, usa: williams & wilkins co., 1963. pp. 1–16. 13. fitzgerald mj. human embryology: a regional approach, 1st ed. new york, usa: harpercollins college div., 1978. pp. 38–56. 14. schoenwolf gc, bleyl sb, brauer pr, francis-west ph. larsen’s human embryology, 4th ed. london, uk: churchill livingstone, 2008. pp. 396–7. 15. sañudo jr, roig m, rodriguez a, ferreira b, domenech jm. rare origin of the obturator, inferior epigastric and medial circumflex femoral arteries from a common trunk. j anat 1993; 183:161–3. 16. kumar d, rath g. anomalous origin of obturator artery from the internal iliac artery. int j morphol 2007; 25:639–41. doi: 10.4067/s0717-95022007000300028. http://dx.doi.org/10.1590/s1807-59322009000900011 http://dx.doi.org/10.1590/s1807-59322009000900011 http://dx.doi.org/10.1007/s00464-003-8800-y http://dx.doi.org/10.1002/aja.1000700206 http://dx.doi.org/10.7860/jcdr/2015/14453.6387 http://dx.doi.org/10.1007/bf01627734 http://dx.doi.org/10.1590/s1677-54492008000300015 http://dx.doi.org/10.4067/s0717-95022007000300028 departments of 1radiology, 2histopathology and 3family medicine, royal hospital, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com حالة داء النشوائي العقيدي الرئوي مشاهبا للعقيدات الرئوية السرطانية تقرير حالة و استعراض األدبيات العلمية را�شد العمريي، فاطمة اللواتية، ف�شيلة حممد البو�شعيدية abstract: amyloidosis is a disorder characterised by the extracellular deposition of amyloid, a fibrillary protein, in various organs such as the lungs. pulmonary nodular amyloidosis can mimic other lung conditions that present with pulmonary nodules, such as metastasis, sarcoidosis and hyalinising granuloma. we report a 60-year-old man who presented to the royal hospital, muscat, oman, in 2017 with a history of shortness of breath upon exertion, orthopnoea and bilateral lower limb swelling. a chest x-ray showed bilateral nodular opacities. enhanced chest computed tomography revealed bilateral pulmonary nodules with a predominantly perilymphatic and subpleural distribution, giving the impression of a neoplastic nodule. a histopathological examination of biopsied lung tissue confirmed a diagnosis of nodular pulmonary amyloidosis. keywords: multiple pulmonary nodules; amyloidosis; computed tomography; case report; oman. يف اخللية ج�شم خارج ليفي( بروتني )الأميلويد، الن�شا �شبيهة مادة برت�شب تت�شف مر�شية حالة هو )الأميلويد( الن�شواين داء امللخ�ص: اأع�شاء خمتلفة من ج�شم الأن�شان مبا يف ذلك الرئتني، داء الن�شواين العقيدي الرئوي قد ي�شابه اأمرا�شًا وحالت رئوية اأخرى تت�شف بظهور عقيدات رئوية، ومن هذه احلالت العقيدات ال�رسطانية اخلبيثة املنتقلة من ع�شو اآخر، وت�شخم ال�شاركويد والورم احلبيبي ال�شفاف، نعر�ص هنا حالة لرجل يبلغ من العمر 60 عامًا مت معاينته يف امل�شت�شفى ال�شلطاين يف م�شقط ب�شلطنة عمان يف عام 2017، وكان يعاين من �شيق يف التنف�ص عند بذل جمهود وعند ال�شطجاع وكذلك من انتفاخ يف القدمني، وقد اأظهرت ال�شعة ال�شينية لل�شدر وجود عقيدات يف كلتا الرئتني، ملعرفة املزيد عن طبيعة هذه العقيدات الرئوية مت اإجراء اإ�شعة مقطعية مع ا�شتخدام �شبغة عن طريق الوريد والتي او�شحت وجود عقيدات رئوية تتوزع ب�شكل ملحوظ يف حميط الأوعية اللمفاوية وحتت اجلنبة، اأعطت هذه العقيدات ا�شتباهًا باأنها متثل اأورامًا �رسطانية، اإل اأن الفح�ص املجهري الن�شيجي لعينة اأخذت من الرئة اأكدت ت�شخي�ص داء الن�شواين )الأميلويد( الرئوي العقيدي. الكلمات املفتاحية: عقيدات رئوية متعددة؛ داء الن�شواين )الأميلويد(؛ اأ�شعة مقطعية؛ تقرير حالة؛ عمان. nodular pulmonary amyloidosis mimicking metastatic pulmonary nodules a case report and review of the literature *rashid s. al-umairi,1 fatma al-lawati,2 fadhila m. al-busaidi3 sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e393–396, epub. 19 dec 18 submitted 3 feb 18 revisions req. 11 feb & 27 mar 18; revisions recd. 19 feb & 14 apr 18 accepted 26 apr 18 online case report doi: 10.18295/squmj.2018.18.03.023 amyloidosis is a disorder resulting from the abnormal extracellular accumulation of amy-loid in various tissues and organs.1 amyloidosis can be primary (i.e. idiopathic) or, more commonly, sec ondary to a variety of pathological conditions, including neoplastic, infectious and inflammatory aetiologies.2–4 pulmonary amyloidosis may be part of a systemic process or confined only to the lung, at which point it is classified as tracheobronchial, parenchymal nodular or diffuse alveolar septal pulmonary amyloidosis.5,6 although rare, nodular pulmonary amyloidosis can mimic other, more common, pulmonary disorders that manifest as multiple pulmonary masses or nodules, such as neoplastic and granulomatous conditions.2,7,8 therefore, pulmonary amyloidosis should be included in the differential diagnosis of single or multiple pulmonary nodules. case report a 60-year-old man presented to the emergency depart ment of the royal hospital, muscat, oman, in 2017 with a recent history of shortness of breath upon exertion, orthopnoea and bilateral lower limb swelling. he was an ex-smoker, diabetic and was currently taking insulin. there was no history of fever or chest pain, although he had dilated cardiomyopathy with a left ventricle ejection fraction of 35%. upon physical examination, there were bilateral chest crepitations and bilateral lower limb oedema. all vital signs and other systemic examinations were unremarkable. a complete blood count, erythrocyte sedimentation rate, c-reactive protein level and renal and liver function tests were within normal limits. nodular pulmonary amyloidosis mimicking metastatic pulmonary nodules a case report and review of the literature e394 | squ medical journal, august 2018, volume 18, issue 3 the patient subsequently underwent a chest x-ray which showed bilateral nodular opacities [figure 1]. further evaluation using enhanced computed tomography (ct) revealed bilateral pulmonary nodules with a predominantly perilymphatic and subpleural distrib ution. the largest nodule arose in the right upper lobe, abutting the fissure, and measured 2.3 × 2.9 cm. there was no evidence of pleural effusion or enlargement of the lymph nodes, although some of the nodules showed central calcification [figure 2]. the preliminary diagnosis was of a neoplastic nodule that required further invest igation. accordingly, ct scans of the abdomen and pelvis were performed; however, the findings were unremarkable. a tissue biopsy from the lung nodules was obtained under ct guidance. a microscopic examination of the tissue sample showed cores of hyalinised tissue with foci of haemorrhage. a haematoxylin and eosin stain showed deposits of eosinophilic amorphous material [figure 3]. a special stain with congo red and thioflavin t dyes revealed deposition of amyloid fibrils, consistent with a histological diagnosis of amyloidosis. as the patient was asymptomatic and there were no features suggestive of systemic amyloidosis, the decision was made to keep the patient under regular follow-up and observation. discussion amyloidosis has an estimated global incidence of approx imately 10 cases per million patients each year.9 to the best of the authors’ knowledge, the present case is the first to be reported from oman. according to the site of deposition, amyloidosis can be categorised as systemic or localised. the four subtypes of systemic amyloidosis are primary light-chain amyloidosis, secondary amyloid a amyloidosis, familial amyloidosis and β2-microglobulin-related amyloidosis.10 the most common is secondary amyloid a amyloidosis, resulting from deposited amyloid p component. it mainly occurs in patients with chronic infections and those with rheum atic or autoimmune diseases.1,2 in contrast, primary light chain amyloidosis is due to deposited kappa and lambda light chains and can be associated with multiple myeloma, waldenström’s macroglobulinaemia and asymptomatic monoclonal gammopathy.1 isolated pulmonary amyloidosis is rare and can be categorised into tracheobronchial, parenchymal nodular and diffuse alveolar septal amyloidosis.5,6 hui et al. rep orted 48 patients with localised respiratory amyloidosis, of which 14 had tracheobronchial amyloidosis, 28 showed either solitary or multiple pulmonary nodules and six had a diffuse interstitial parenchymal pattern.11 most of the figure 1: chest x-ray of a 60-year-old man with shortness of breath upon exertion, orthopnoea and bilateral lower limb oedema showing several nodular opacities (arrows), predominantly in the right lung. figure 3: haematoxylin and eosin stain at x10 magnification showing eosinophilic and amorphous material deposits (arrows). figure 2: high-resolution chest computed tomography scans in the (a & b) axial and (c & d) coronal views of a 60-year-old man with shortness of breath upon exertion, orthopnoea and bilateral lower limb oedema showing bilateral pulmonary nodules (arrows) with central calcif ication of the right upper nodule (arrowhead). rashid s. al-umairi, fatma al-lawati and fadhila m. al-busaidi online case report | e395 red staining, the amyloid proteins display green birefringence under polarised light.2,3,9,12 due to the rarity of the condition, no randomised controlled trials have yet been conducted regarding nodular pulmonary amyloidosis management. however, the general consensus is that treatment depends on the severity of the symptoms. for example, for asympt omatic patients, regular follow-up and careful monitoring may be sufficient.2 in contrast, different treatment options may be necessary for symptomatic patients, including conservative excision, carbon dioxide laser ablation and low-dose external beam radiation.9,18 conclusion nodular pulmonary amyloidosis is a rare and usually localised disease that can mimic other nodular pulmonary disorders, such as neoplastic and granulomatous processes. as such, this condition should be included in the differential diagnosis of pulmonary nodules or masses. references 1. baker kr, rice l. the amyloidoses: clinical features, diagnosis and treatment. methodist debakey cardiovasc j 2012; 8:3–7. 2. lee sh, ko yc, jeong jp, park cw, seo sh, kim jt, et al. single nodular pulmonary amyloidosis: case report. tuberc respir dis (seoul) 2015; 78:385–9. doi: 10.4046/trd.2015.78.4.385. 3. sipe jd, benson md, buxbaum jn, ikeda s, merlini g, saraiva mj, et al. amyloid fibril protein nomenclature: 2012 recommendations from the nomenclature committee of the international society of amyloidosis. amyloid 2012; 19:167–70. doi: 10.3109/13506 129.2012.734345. 4. gernay c, médart l. multiple calcified nodules in pulmonary amyloidosis. jbr-btr 2014; 97:370. doi: 10.5334/jbr-btr.133. 5. czeyda-pommersheim f, hwang m, chen ss, strollo d, fuhrman c, bhalla s. amyloidosis: modern cross-sectional imaging. radiographics 2015; 35:1381–92. doi: 10.1148/rg.201 5140179. 6. utz jp, swensen sj, gertz ma. pulmonary amyloidosis. the mayo clinic experience from 1980 to 1993. ann intern med 1996; 124:407–13. doi: 10.7326/0003-4819-124-4-19960215000004. 7. gaurav k, panda m. an uncommon cause of bilateral pulmonary nodules in a long-term smoker. j gen intern med. 2007; 22:1617–20. doi: 10.1007/s11606-007-0324-z. 8. morisaki k, shoji f, kawano d, yano t, maehara y. [primary nodular pulmonary amyloidosis]. kyobu geka 2009; 62:1006–9. 9. milani p, basset m, russo f, foli a, palladini g, merlini g. the lung in amyloidosis. eur resp rev 2017; 26:1740046. doi: 10.1183/16000617.0046-2017. 10. real de asúa d, costa r, galván jm, filigheddu mt, trujillo d, cadiñanos j. systemic aa amyloidosis: epidemiology, diagnosis, and management. clin epidemiol 2014; 6:369–77. doi: 10.2147/ clep.s39981. 11. hui an, koss mn, hochholzer l, wehunt wd. amyloidosis presenting in the lower respiratory tract: clinicopathologic, radiologic, immunohistochemical, and histochemical studies on 48 cases. arch pathol lab med 1986; 110:212–18. patients with nodular amyloidosis were asymptomatic, while those with tracheobronchial or diffuse interstitial amyloidosis had respiratory symptoms.11 in a 13-year study of 55 patients with biopsy-proven pulmonary amyloidosis, utz et al. reported that 35 had primary systemic amyloidosis, 17 had amyloidosis localised to the respiratory system and three had secondary or familial amyloidosis.6 of the patients with localised amyloidosis, seven had nodular amyloidosis and four had tracheobronchial amyloidosis. nodular amyloidosis was not associated with systemic amyloidosis and had a predominantly benign prognosis.6 tracheobronchial amyloidosis usually presents with symptoms related to airway obstruction such as dysp noea, coughing, recurrent pneumonia and haemoptysis.7,9 the classic radiological features of tracheobronchial amyloidosis are tracheal lumen irregularities, bronchial wall thickening and calcified amyloid deposition, which can be mural or endobronchial, resulting in subseg mental collapse.5,7,12 diffuse interstitial parenchymal amyloidosis is the rarest type of pulmonary amyloidosis and usually occurs among patients with systemic amyloidosis.9 the deposited amyloid results in alveolar wall and capillary damage, leading to impaired gas exchange. as with tracheobronchial amyloidosis, patients usually present with a cough, dyspnoea and haemoptysis, or a combination of these symptoms. classic radiol ogical findings include non-specific interstitial and alveolar opacities, predominantly basal and peripheral, well defined nodules and confluent subpleural opacities.5,13 nodular amyloidosis is usually localised to the respiratory system.6 affected patients are generally asymptomatic and the amyloid nodules detected incid entally.14 on ct imaging, nodular amyloidosis can present as multiple lesions or, less commonly, as a single lesion with lower lobe and subpleural predominance.14–16 the amyloid nodules are usually welldefined with lobulated contours; they can vary in size from 0.5–15 cm and may gradually grow over time without regression. approximately half of all amyloid nodules calcify, although they rarely cavitate.14,15 in the current case, the patient had localised amyloidosis with no evidence of systemic involvement. a chest ct scan showed bilateral pulmonary nodules with a perilymphatic and subpleural predilection and occasional central calcification. nodular pulmonary amyloidosis can mimic other nodular pulmonary disorders, such as neoplastic and granulomatous processes.7,8,17 therefore, a biopsy is required for diagnosis and to differentiate it from other nodular pulmonary disorders. immunohistochemistry remains the gold standard for the detection of amyloid material which appears inert, proteinaceous, homogeneous, acellular and eosinophilic; with congo https://doi.org/10.4046/trd.2015.78.4.385 https://doi.org/10.3109/13506129.2012.734345 https://doi.org/10.3109/13506129.2012.734345 https://doi.org/10.5334/jbr-btr.133 https://doi.org/10.1148/rg.2015140179 https://doi.org/10.1148/rg.2015140179 https://doi.org/10.7326/0003-4819-124-4-199602150-00004 https://doi.org/10.7326/0003-4819-124-4-199602150-00004 https://doi.org/10.1007/s11606-007-0324-z https://doi.org/10.1183/16000617.0046-2017 https://doi.org/10.2147/clep.s39981 https://doi.org/10.2147/clep.s39981 nodular pulmonary amyloidosis mimicking metastatic pulmonary nodules a case report and review of the literature e396 | squ medical journal, august 2018, volume 18, issue 3 12. chatkin g, pipkin m, pinto ja, silva vd, chatkin jm. [primary tracheobronchial amyloidosis]. j bras pneumol 2008; 34:528–31. doi: 10.1590/s1806-37132008000700013. 13. graham cm, stern ej, finkbeiner we, webb wr. high-reso lution ct appearance of diffuse alveolar septal amyloidosis. ajr am j roentgenol 1992; 158:265–7. doi: 10.2214/ajr.158.2. 1729778. 14. suzuki h, matsui k, hirashima t, kobayashi m, sasada s, okamato n, et al. three cases of the nodular pulmonary amyloidosis with a longterm observation. intern med 2006; 45:283–6. doi: 10.2169/internalmedicine.45.1487. 15. vieira ig, marchiori e, zanetti g, cabral rf, takayassu tc, spilberg g, et al. pulmonary amyloidosis with calcified nodules and masses: a six-year computed tomography follow-up a case report. cases j 2009; 2:6540. doi: 10.4076/1757-1626-26540. 16. feng j, li j, ling c, liu q. a rare case of multinodular pul monary amyloidosis. clin respir j 2016; 10:389–92. doi: 10.11 11/crj.12220. 17. shin b, ko j, lee ss, lim ks, han jh, chung mp, et al. [a case of pulmonary amyloidosis mimicking lymphangitic lung carcinomatosis]. korean j med 2014; 86:339–42. doi: 10.3904/ kjm.2014.86.3.339. 18. nugent am, elliott h, mcguigan ja, varghese g. pulmonary amyloidosis: treatment with laser therapy and systemic steroids. respir med 1996; 90:433–5. doi: 10.1016/s0954-6111 (96)90119-5. https://doi.org/10.1590/s1806-37132008000700013 https://doi.org/10.2214/ajr.158.2.1729778 https://doi.org/10.2214/ajr.158.2.1729778 https://doi.org/10.2169/internalmedicine.45.1487 https://doi.org/10.4076/1757-1626-2-6540 https://doi.org/10.4076/1757-1626-2-6540 https://doi.org/10.1111/crj.12220 https://doi.org/10.1111/crj.12220 https://doi.org/10.3904/kjm.2014.86.3.339 https://doi.org/10.3904/kjm.2014.86.3.339 https://doi.org/10.1016/s0954-6111%2896%2990119-5 https://doi.org/10.1016/s0954-6111%2896%2990119-5 1department of public health dentistry, kothiwal dental college & research centre, moradabad, uttar pradesh, india; departments of 2biochemistry and 3periodontology, aligarh muslim university, aligarh, uttar pradesh, india *corresponding author’s e-mail: aliamaan29@gmail.com نازعة هيدروجني الالكتات وبيتا غلوكورونيداز كوامسات لعاب حيوية كيميائية يف التهاب دواعم السن عند املدخنني وغري املدخنني �شيد اأمان علي، رايف لينجي�شا تيلجي، اأميت تريث، عرفان قادر تنرتي، عبدالعليم abstract: objectives: this study aimed to establish lactate dehydrogenase (ldh) and β-glucuronidase as salivary biomarkers of periodontitis among smokers and non-smokers. methods: this cross-sectional case-control study was conducted at the aligarh muslim university, aligarh, india, between january and june 2017. a total of 200 participants were divided into four groups based on their periodontal and smoking statuses. unstimulated mixed saliva samples were collected to estimate ldh and β-glucuronidase levels. in addition, total protein was estimated using lowry’s method. results: there was a significant increase in enzyme activity in the periodontitis groups compared to the nonperiodontitis groups (p <0.001). however, significantly lower enzyme activity was observed among smokers, irrespective of periodontal status (p <0.001). nevertheless, a receiver operating characteristic curve analysis indicated the diagnostic potential of both enzymes to be fair-to-excellent. conclusion: although smoking was found to significantly alter enzyme activity, ldh and β-glucuronidase were reliable salivary biomarkers of periodontitis among both smokers and nonsmokers. keywords: periodontitis; biomarkers; saliva; lactate dehydrogenase; beta-glucuronidase; smoking; tobacco use; india. كيميائية حيوية لعاب كوا�شمات غلوكورونيداز وبيتا الالكتات هيدروجني نازعة من التثبت اإىل الدرا�شة هذه تهدف الهدف: امللخ�ص: األيجاره جامعة يف املقطعية ال�شواهد حلالت الدرا�شة هذه اأجريت الطريقة: املدخنني. وغري املدخنني عند ال�شن دواعم التهاب يف الإ�شالمية، األيجاره، الهند، يف الفرتة ما بني يناير ويونيو 2017. مت تق�شيم ما جمموعه 200 م�شارك اإىل اأربع جمموعات على اأ�شا�ص حالة اللثة والتدخني. مت جمع عينات اللعاب املختلط وغري املحفز لتقدير م�شتويات نازعة هيدروجني الالكتات وبيتا غلوكورونيداز. بالإ�شافة اإىل ذلك، مت تقدير الربوتني الكلي با�شتخدام طريقة لأوري. النتائج: كان هناك زيادة معنوية يف ن�شاط الإنزمي يف جمموعات التهاب اللثة باملقارنة مبجموعات بدون التهاب اللثة )p >0.001(. ومع ذلك، لوحظ وجود ن�شاط اأنزمي اأقل ب�شكل ملحوظ بني املدخنني، بغ�ص النظر عن حالة اللثة )p >0.001(. ومع ذلك، اأ�شار حتليل منحنى خ�شائ�ص الت�شغيل املتلقي اإىل اإمكانات الت�شخي�ص لكل الإنزميات لتكون عادلة اإىل ممتازة. اخلال�صة: على الرغم من اأن التدخني يغري ن�شاط الإنزمي ب�شكل كبري، كانت نازعة هيدروجني الالكتات وبيتا غلوكورونيداز موؤ�رسات حيوية لعابية موثوقة للتهاب اللثة بني املدخنني وغري املدخنني على حد �شواء. ا�شتخدام تدخني؛ غلوكورونيداز؛ بيتا الالكتات؛ هيدروجني نازعة لعاب؛ بيولوجية؛ وا�شمات ال�شن؛ دواعم التهاب املفتاحية: الكلمات التبغ؛ الهند. lactate dehydrogenase and β-glucuronidase as salivary biochemical markers of periodontitis among smokers and non-smokers *syed a. ali,1 ravi l. telgi,1 amit tirth,1 irfan q. tantry,2 abdul aleem3 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e318–323, epub. 19 dec 18 submitted 8 feb 18 revision req. 28 feb 18; revision recd. 27 mar 18 accepted 12 apr 18 advances in knowledge this study rules out the effect of tobacco smoke on the diagnostic ability of two salivary enzymes—lactate dehydrogenase (ldh) and β-glucuronidase—in risk profiling for periodontal disease. application to patient care the current findings support the use of these salivary enzymes as biomarkers for periodontal disease. doi: 10.18295/squmj.2018.18.03.009 periodontal disease is a common inflamm-atory disease caused by the interaction between certain gram-negative bacterial species and components of the host immune response.1 chronic periodontal infections trigger the release of a myriad of metabolic byproducts, destructive cellular enzymes and other mediators of tissue destruction at the interface between the tooth and the periodontal pocket.2 as a result, the normal histological architecture of the periodontium is disturbed, with persistent inflammation associated with the irreversible loss of mineralised and non-mineralised tissues.1 syed a. ali, ravi l. telgi, amit tirth, irfan q. tantry and abdul aleem clinical and basic research | e319 chronic periodontitis may advance without causing severe oral discomfort; as such, subjects often seek professional care only after the periodontal tissue is considerably damaged.3 thus, there is an urgent need to diagnose this disease in its initial stages so as to initiate early intervention. ideally, a diagnostic marker should be highly specific and sensitive and should indicate the presence of a disease process prior to the occurrence of extensive clinical damage.4 at present, a diagnosis of periodontitis is usually made via imaging and clinical assessment of probing pocket depth, bleeding upon probing and clinical attachment level.5 however, the utility of such measurements is limited because these findings may display evidence of previous rather than current disease activity.6 the saliva contains a wide and unique variety of proteins and enzymes with important oral biological functions. the pathogenesis of periodontitis has been linked to alterations in various salivary enzymes, incl uding lactate dehydrogenase (ldh), alkaline phosphatase, matrix metalloproteinases 8 and 1, aminotransferases, amylase, β-glucuronidases, arginase, chitinases and dip eptidyl peptidase.7 metabolic ldh plays a key role in anaerobic glycolysis and its extracellular presence is always related to cell necrosis and tissue breakdown.8 in contrast, β-glucuronidase is a neutrophil-derived lyso somal acid hydrolase stored in the azurophilic granules. it is active in the degradation of proteoglycans and the ground substance and is considered a marker for azu rophilic granule release by polymorphonuclear leukocyte lysosomes.9 under these considerations, salivary ldh and β-glucuronidase may play a potential role as salivary biomarkers of periodontal disease.7 unfortunately, the diagnostic use of these enzymes in periodontitis cases has been hampered as current understanding of the biomolecules present in saliva and their relevance to disease aetiology is still limited. in addition, various factors may cause enzymatic alterations, such as temperature, ph, and enzyme and substrate concentrations of inhibitors or activators.10 for example, tobacco smoke compounds have been found to impair salivary enzyme activities at the molecular level.11 therefore, this study aimed to attempt to establish ldh and β-glucuronidase as salivary biochemical markers for periodontitis and to assess their diagnostic potential among both smokers and non-smokers. methods this cross-sectional case-control study was conducted at the department of periodontology of the aligarh muslim university, aligarh, uttar pradesh, india, between january and june 2017. the required sample size was calculated using g*power software, version 3.0.10 (heinrich-heine universität düsseldorf, düsseldorf, germany), based on a calculated effect size of 0.565 as per the results of a pilot study involving 20 subjects, with a 5% level of precision, 95% confidence interval and 80% statistical power. the minimum sample size was calculated to be 200 subjects. patients who had received antiseptic, professional hygiene or periodontal therapies or treat ment with anti-inflammatory drugs, immunosuppressants or corticosteroids in the preceding six months were excluded from the study. in addition, individuals under going orthodontic treatment or other dental procedures, subjects with acute oral mucosal lesions and/or suspected oral malignancies, those with adverse behavioural habits such as tobacco/paan chewing or alcohol abuse, subjects suffering from any systemic diseases and pregnant, lactating or post-menopausal women were also excluded. a total of 1,306 patients aged 30–50 years old pres enting to the department of periodontology, dr. ziauddin ahmad dental college & hospital, aligarh, uttar pradesh, were screened. a simple random sampling method was used to select 200 of these individuals for inclusion in the study. the participants were divided into four groups of 50 subjects each, including non-smokers with no/mild gingivitis, non-smokers with no/mild gingivitis, smokers with chronic generalised periodontitis and smokers with chronic generalised periodontitis [figure 1]. unfortunately, it was logistically difficult to find sufficient cases with no gingival inflammation; as such, cases with no/mild gingivitis were considered to constitute the control groups in the study design. mild gingivitis was diagnosed based on the silness-löe gingival index.12 chronic generalised periodontitis was defined as a probing pocket depth of ≥5 mm, clinical attachment loss of ≥3 mm and moderate, severe or generalised disease progression involving >30% of the mouth. patients were categorised as smokers or non-smokers based on the updated definition of the centers for disease control and prevention.13 all smokers reported currently smoking at least five times per day and had a history of smoking of at least five years. former smokers were not included in the study. a sample of approximately 5 ml of unstimulated mixed saliva was aseptically collected via aspiration from each participant while seated in an upright position. the collection was performed by a single trained expert between 9 and 11 am, five minutes after the mouth was rinsed with 15 ml of water to wash out any exfoliated cells. eating, drinking and smoking were restricted for at least two hours prior to collection. the saliva was collected in sterile test tubes capped with sterile tinfoil. the samples were transferred to a refrigerated container at 4 °c and then centrifuged for 10 minutes at 1,500 revolutions per minute. subsequently, estimations of ldh and β-glucuronidase activity were carried out lactate dehydrogenase and β-glucuronidase as salivary biochemical markers of periodontitis among smokers and non-smokers e320 | squ medical journal, august 2018, volume 18, issue 3 immediately by a single trained biochemist who was blinded to the study design. the biochemical analysis of ldh was performed following strict protocols for salivary enzyme estimation.14 ldh was assayed following the conversion of reduced nicotinamide adenine dinucleotide (nadh) to oxidised nadh at 340 nm in the presence of sodium pyruvate. briefly, 100 μl of saliva was added to a 2.8 ml reaction mixture consisting of 0.05 m tris buffer at a ph of 7.4, 3.33 mm of magnesium chloride and 1.6 mm of sodium pyruvate. then, 100 μl of nadh (at a final concentrate of 0.08 mm) was added just before the change in absorbance observed after 3 minutes using a u-2910 spectrophotometer (hitachi hightechnologies corp., tokyo, japan).14 the results were expressed in iu/l. for the analysis of salivary β-glucuronidase, 50 μl of 0.9% saline solution (as the control), 50 µl of standard 4-methylumbelliferone (sigma-aldrich corp., st. louis, missouri, usa) and 50 µl of the salivary samples were separated in designated tubes. in each tube, 100 μl of methylumbelliferyl β-d-glucuronide containing 0.001% bovine serum albumin (bsa) was added and the contents were mixed and incubated at 37 °c for 15 minutes. the reaction was stopped with 2 ml of 0.2 m glycine buffer at a ph of 11.7 and containing 0.2% sodium dodecyl sulphate. after the solution was mixed for 60 minutes, the fluorescence was measured at an excitation wavelength of 360 nm and an emission wavelength of 459 nm. for the standard, the fluorescence of 0.008 mm and 0.016 mm of 4-methylumbelliferone was measured using an rf-5301 spectrofluorophotometer (shimadzu corp., kyoto, japan), as the fluorescence of 0.008 mm of 4-methylumbelliferone is equivalent to 1 iu of β-glucur onidase.15 the total protein in the saliva was estimated by means of lowry’s method using bsa to derive standard and specific enzyme activity.16 data were analysed using the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). parametric tests (i.e. an unpaired t-test) and a one-way analysis of variance were used to compare the mean enzyme activities of the four independent groups using an f distribution, followed by a post-hoc tukey’s analysis. a receiver operating char acteristic (roc) curve was used to determine the diagn ostic ability of the enzymes as their discrimination thresholds varied. binomial logistic regression was then conducted to estimate the frequency of periodontitis among the patients. a p value of <0.050 was considered statistically significant. this study was reviewed and approved by the institutional ethical committee of the kothiwal dental college & research centre (#kdcrc/ierb/11/2015/34). written informed consent from the participants was obtained using a pre-designed proforma. all participation in the study was voluntary in nature. results the patients ranged in age between 30–35 years old (mean: 32.5 years). there were very few female smokers (20.5%). the standard and specific enzyme activity of ldh and β-glucuronidase in each group is presented in table 1. there was a significant increase in ldh and β-glucuronidase enzyme activity among participants with periodontitis compared to those without periodontitis (p <0.001) [table 2]. however, significantly lower enzyme activity was noted among the smokers, irrespective of periodontal status (p <0.001) [table 3]. overall, there was a 23.8% and 25% reduction in ldh figure 1: diagram showing the protocol and design used in the current study. syed a. ali, ravi l. telgi, amit tirth, irfan q. tantry and abdul aleem clinical and basic research | e321 enzyme activity among smokers with periodontitis and smokers with no/mild gingivitis, respectively. similarly, there was a 6.8% and 18.1% reduction in β-glucuronidase activity, respectively. nevertheless, logistic modelling highlighted a strong linear association between ldh and β-glucuronidase activity and periodontitis, regardless of smoking status (p = 0.046 and 0.010, respectively) [table 4]. furthermore, the sensitivity and specificity of the enzymes were established at the 25th, 50th and 75th quartiles. according to the roc curve analysis, the diagnostic potential of ldh at the 25th and 75th quartiles indicated that this biomarker had fair-to-good potential in predicting perio dontitis, with the 50th quartile showing excellent potential. table 1: enzyme activity of salivary lactate dehydrogenase and β-glucuronidase according to smoking and periodontal status (n = 200) group mean ldh activity ± sd mean β-glucuronidase activity ± sd standard activity in iu/l specific activity in nmol/min/ mg of total protein standard activity in iu/l specific activity in nmol/min/mg of total protein non-smokers with no/mild gingivitis 285.34 ± 35.76 237.78 ± 32.46 30.29 ± 9.43 25.24 ± 6.32 smokers with no/mild gingivitis 213.92 ± 34.70 178.26 ± 32.34 24.81 ± 7.19 20.67 ± 6.56 non-smokers with chronic generalised periodontitis 1,075.88 ± 253.76 896.56 ± 264.14 91.76 ± 12.05 76.46 ± 10.43 smokers with chronic generalised periodontitis 819.10 ± 315.59 682.58 ± 274.12 85.53 ± 13.21 71.27 ± 12.71 ldh = lactate dehydrogenase; sd = standard deviation; min = minute. table 2: comparison of specific enzyme activity of lactate dehydrogenase and β-glucuronidase according to periodontal status (n = 200) enzyme mean specific activity in nmol/min/mg of total protein ± sd p value* no/mild gingivitis chronic generalised periodontitis ldh 208.02 ± 22.95 789.57 ± 73.87 <0.001 β-glucuronidase 32.4 ± 6.44 269.13 ± 11.57 <0.001 min = minute; sd = standard deviation; ldh = lactate dehydrogenase. *using an independent t-test. table 3: comparison of specific enzyme activity of lactase dehydrogenase and β-glucuronidase according to smoking and periodontal status (n = 200) enzyme mean specific activity in nmol/min/mg of total protein ± sd p value* post hoc tukey valuenon-smokers with no/mild gingivitis smokers with no/mild gingivitis non-smokers with chronic generalised periodontitis smokers with chronic generalised periodontitis ldh 237.78 ± 32.46 178.26 ± 32.34 896.56 ± 264.14 682.58 ± 274.12 <0.001 4>3>1>2 β-glucuronidase 25.24 ± 6.23 20.67 ± 6.56 76.46 ± 10.43 71.27 ± 12.71 <0.001 4>3>1>2 min = minute; sd = standard deviation; ldh = lactate dehydrogenase. *using a one-way analysis of variance. table 4: logistic regression model of lactate dehydrogenase and β-glucuronidase as possible predictors of periodontitis among smokers and non-smokers (n = 200) predictor b se wald or (95% ci) p value ldh 0.007 0.005 2.109 1.007 (0.998– 1.016 0.046 β-glucur onidase 0.394 0.153 6.617 1.482 (1.098– 2.001) 0.010 constant −19.35 6.746 8.227 0.004 se = standard error; or = odds ratio; ci = confidence interval; ldh = lactate dehydrogenase. lactate dehydrogenase and β-glucuronidase as salivary biochemical markers of periodontitis among smokers and non-smokers e322 | squ medical journal, august 2018, volume 18, issue 3 for β-glucuronidase, the 25th and 50th percentiles indic ated excellent predictive potential, while the 75th percentile indicated fair potential [table 5]. discussion the pathogenesis of tissue destruction in periodontitis is due to host-bacteria interactions which cause the host cells (mainly polymorphonuclear leukocyte lysosomes) to release granular enzymes which are capable of invading extracellular matrix components.17 thus, the extracellular presence of certain enzymes seems to play an important role in connective tissue damage. the quant ification of enzyme activity in saliva, such as ldh and β-glucuronidase, can therefore provide important information and contribute to the timely diagnosis of periodontal disease.18 combining these two markers into a risk profile for periodontal disease may offer improved accuracy in identifying susceptible patients. in the current study, significantly higher ldh and β-glucuronidase activity was noted in the periodontitis groups compared to the non-periodontitis groups. how ever, lamster et al. observed variations in β-glucuron idase enzyme activity among subjects with periodontitis.19 this accentuates the fact that identical clinical conditions may reflect different host responses. therefore, while increased extracellular enzyme activity may have a positive correlation with disease activity, other factors could be involved in the aetiopathology of periodontitis.19 such factors may also influence treatment planning. in the current study, relatively low enzyme activity was noted among smokers, including both those with no/mild gingival inflammation as well as those with chronic generalised periodontitis. such findings are likely related to salivary changes resulting from exposure to inhaled cigarette smoke. cigarette smoke contains over 4,000 chemicals as well as oxygen free radicals and volatile aldehydes that can cause damage to biomolecules.20 nagler et al. examined the effect of the in vitro exposure of saliva to the gas phase of cigarette smoke; exposing saliva to cigarette smoke for three hours caused a 41% reduction in ldh activity.21 furthermore, avezov et al. reported a 34% reduction in ldh activity when salivary samples were exposed to different levels of cigarette smoke.22 nevertheless, although tobacco smoke significantly altered enzyme activity in the current study, these changes did not invalidate the predictive value of salivary ldh and β-glucuronidase as diagnostic biomarkers. therefore, enzyme-based salivary diagnosis can be deemed an effective option in periodontitis cases, as influence of smoking on the biomarker status of ldh and β-glucuron idase can be ruled out. with further studies, changes in enzyme activity may eventually form the basis of a convenient point-of-care diagnostic tool in routine oral health monitoring. this study was subject to certain limitations. first, the analysis focused on the estimation of ldh and β-glucuronidase in the saliva rather than the gingival crevicular fluid, which would better reflect enzyme activity. second, the methodology did not analyse the utility of these enzymes as markers of disease severity or response to treatment and, ultimately, disease progn osis. further studies are necessary to evaluate the reliab ility of these parameters in this regard. third, gender matching was not possible due to the unequal distribution of the sample. however, previous research has confirmed that gender does not significantly affect ldh levels, either among patients with periodontal disease or those with normal periodontia.23 finally, the current study was designed with strict inclusion criteria; thus, the exclusion of potential subjects may have hampered the generalisability of the results. conclusion the current study found that salivary ldh and β-glucu ronidase enzyme activity significantly increased among patients with periodontal disease in comparison to those with no/mild gingival inflammation. while smoking significantly influenced enzyme activity, these changes were within acceptable limits and did not rule out the use of these enzymes as diagnostic biomarkers of perio dontitis. however, further research is needed to identify other variables which may influence ldh and β-glucur onidase enzyme activity. table 5: sensitivity, specificity and area under receiver operating characteristic curve of salivary lactate dehydrogenase and β-glucuronidase alterations among periodontitis patients (n = 200) quartile percentile value sensitivity in % specificity in % area under roc curve* ldh 25th 206.75 63.3 90 0.774 50th 298.50 90 90 0.948 75th 841.50 100 66.7 0.819 β-glucuronidase 25th 21.95 98 98 0.980 50th 43.52 98 98 0.980 75th 72.35 100 66.7 0.750 roc = receiver operating characteristic; ldh = lactate dehydrogenase. *the diagnostic accuracy of the enzymes was interpreted as follows: 1.0–0.91 = excellent; 0.90–0.81 = good; 0.80–0.71 = fair; 0.70–0.61 = poor; 0.60–0.51 = failure. syed a. ali, ravi l. telgi, amit tirth, irfan q. tantry and abdul aleem clinical and basic research | e323 c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. guthmiller jm, novak kf. periodontal diseases. in: brogden ka, guthmiller jm, eds. polymicrobial diseases. from: www.ncbi. nlm.nih.gov/books/nbk2496/ accessed: mar 2018. 2. giannobile wv. salivary diagnostics for periodontal diseases. j am dent assoc 2012; 143:6s–11s. doi: 10.14219/jada.archive. 2012.0341. 3. ji s, choi y. point-of-care diagnosis of periodontitis using saliva: technically feasible but still a challenge. front cell infect micro biol 2015; 5:65. doi: 10.3389/fcimb.2015.00065. 4. barros sp, williams r, offenbacher s, morelli t. gingival crev icular fluid as a source of biomarkers for periodontitis. periodontol 2000 2016; 70:53–64. doi: 10.1111/prd.12107. 5. gursoy uk, könönen e. editorial: use of saliva in diagnosis of periodontitis cumulative use of bacterial and host-derived bio markers. front cell infect microbiol 2016; 6:196. doi: 10.3389/ fcimb.2016.00196. 6. srivastava n, nayak pa, rana s. point of care: a novel approach to periodontal diagnosis a review. j clin diagn res 2017; 11:ze01–6. doi: 10.7860/jcdr/2017/26626.10411. 7. khiste sv, ranganath v, nichani as, rajani v. critical analysis of biomarkers in the current periodontal practice. j indian soc periodontol 2011; 15:104–10. doi: 10.4103/0972-124x.84376. 8. almoharib hs, almubarak a, alrowis r, geevarghese a, preethanath rs, anil s. oral fluid based biomarkers in periodontal disease: part 1 saliva. j int oral health 2014; 6:95–103. 9. prabhahar cs, niazi kt, prakash r, yuvaraj a, goud s, ravishekar p. estimation of salivary β-glucuronidase activity as a marker of periodontal disease: a case control study. j int soc prev community dent 2014; 4:s193–8. doi: 10.4103/2231-0762.149039. 10. bisswanger h. enzyme assays. perspect sci (neth) 2014; 1:41–55. doi: 10.1016/j.pisc.2014.02.005. 11. zappacosta b, persichilli s, mordente a, minucci a, lazzaro d, meucci e, et al. inhibition of salivary enzymes by cigarette smoke and the protective role of glutathione. hum exp toxicol 2002; 21:7–11. doi: 10.1191/0960327102ht202oa. 12. löe h. the gingival index, the plaque index and the retention index systems. j periodontol 1967; 38:610–16. doi: 10.1902/jop. 1967.38.6.610. 13. schoenborg ca, adams pe. health behaviors of adults: united states, 2005-2007. vital health stat 10 2010; 245:1–132. 14. alonso de la peña v, diz dios p, lojo rocamonde s, tojo sierra r, rodríguez-segade s. a standardised protocol for the quantification of lactate dehydrogenase activity in saliva. arch oral biol 2004; 49:23–7. doi: 10.1016/s0003-9969(03)00196-1. 15. lamster ib, kaufman e, grbic jt, winston lj, singer re. beta glucuronidase activity in saliva: relationship to clinical periodontal parameters. j periodontol 2003; 74:353–9. doi: 10.1902/ jop.2003.74.3.353. 16. lowry oh, rosebrough nj, farr al, randall rj. protein measure ment with the folin phenol reagent. j biol chem 1951; 193:265–75. 17. pöllänen mt, laine ma, ihalin r, uitto vj. host-bacteria crosstalk at the dentogingival junction. int j dent 2012; 2012:821383. doi: 10.1155/2012/821383. 18. dabra s, china k, kaushik a. salivary enzymes as diagnostic markers for detection of gingival/periodontal disease and their correlation with the severity of the disease. j indian soc periodontol 2012; 16:358–64. doi: 10.4103/0972-124x.100911. 19. lamster ib, holmes lg, gross kb, oshrain rl, cohen dw, rose lf, et al. the relationship of beta-glucuronidase activity in crevicular fluid to clinical parameters of periodontal disease: findings from a multicenter study. j clin periodontol 1994; 21:118–27. doi: 10.1111/j.1600-051x.1994.tb00289.x. 20. yeh cc, barr rg, powell ca, mesia-vela s, wang y, hamade nk, et al. no effect of cigarette smoking dose on oxidized plasma proteins. environ res 2008; 106:219–25. doi: 10.1016/j.envres. 2007.09.008. 21. nagler rm, lischinsky s, diamond e, klein i, reznick az. new insights into salivary lactate dehydrogenase of human subjects. j lab clin med 2001; 137:363–9. doi: 10.1067/mlc.2001.114710. 22. avezov k, reznick az, aizenbud d. ldh enzyme activity in human saliva: the effect of exposure to cigarette smoke and its different components. arch oral biol 2014; 59:142–8. doi: 10.10 16/j.archoralbio.2013.11.003. 23. haghgoo jm, soheilifar s, bidgoli m, rastegarfard n, saremi m, kafilzade s. comparison of whole salivary lactate dehydrogenase level in patients with and without periodontal disease. avicenna j dent res 2016; 8:e29026. doi: 10.17795/ajdr-29026. https://doi.org/10.14219/jada.archive.2012.0341 https://doi.org/10.14219/jada.archive.2012.0341 https://doi.org/10.3389/fcimb.2015.00065 https://doi.org/10.1111/prd.12107 https://doi.org/10.3389/fcimb.2016.00196 https://doi.org/10.3389/fcimb.2016.00196 https://doi.org/10.7860/jcdr/2017/26626.10411 https://doi.org/10.4103/0972-124x.84376 https://doi.org/10.4103/2231-0762.149039 https://doi.org/10.1016/j.pisc.2014.02.005 https://doi.org/10.1191/0960327102ht202oa https://doi.org/10.1902/jop.1967.38.6.610 https://doi.org/10.1902/jop.1967.38.6.610 https://doi.org/10.1016/s0003-9969%2803%2900196-1 https://doi.org/10.1902/jop.2003.74.3.353 https://doi.org/10.1902/jop.2003.74.3.353 https://doi.org/10.1155/2012/821383 https://doi.org/10.4103/0972-124x.100911 https://doi.org/10.1111/j.1600-051x.1994.tb00289.x https://doi.org/10.1016/j.envres.2007.09.008 https://doi.org/10.1016/j.envres.2007.09.008 https://doi.org/10.1067/mlc.2001.114710 https://doi.org/10.1016/j.archoralbio.2013.11.003 https://doi.org/10.1016/j.archoralbio.2013.11.003 https://doi.org/10.17795/ajdr-29026 epstein-barr virus (ebv)-associated t/natural killer (nk) cell lymphoproliferative disease is a systemic illness characterised by the clonal proliferation of ebv-infected t or nk cells.1–4 different clinical entities include chronic active ebv (caebv) infections, ebv-associated haemophagocytic lymphohistiocytosis, severe mosquito bite allergies and hydroa vacciniforme. although ebvassociated t/nk cell lymphoproliferative disorders are primarily found among paediatric patients, several reports of adult cases have been published.1,5,6 there is a strong racial predisposition for caebv infections; most cases are described in japan and korea with predominance of the t/nk cell type, while some have been reported in native populations from mexico, peru and central america.5–8 in contrast, caebv infections are rare among caucasians and africanamericans.2 however, ab cell type caebv has been mainly observed in western countries while the prevalence in other racial groups is unknown.2,5–8 originally, caebv of the t/nk type was referred to as chronic or recurrent infectious mononucleosislike syndrome.9 clinical manifestations observed among patients with the severe form of the disease are variable and appear to be more aggressive in adult patients compared to those with childhooddepartments of 1haematology and 2pathology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: kfarsi10@yahoo.com مسار بطيء التنامي غري معتاد لالضطراب التكاثري اللمفي املزمن للخاليا الفاتكة الطبيعية املرتبطة بفريوس ابيشتاين–بار اأروى الريامي، خليل الفار�سي، مرت�سى اخلابوري، حممد احلنيني، اإبراهيم الهدابي abstract: natural killer (nk) cell lymphoproliferative disorders are uncommon and the epstein-barr virus (ebv) plays an important aetiological role in their pathogenesis. we report a 20-year-old male with a chronic active ebv infection associated with a nk cell lymphoproliferative disorder which had an unusual indolent course. he presented to the sultan qaboos university hospital in muscat, oman, in december 2011 with a history of intermittent fever and coughing. examinations revealed generalised lymphadenopathy, hepatosplenomegaly, leukocytosis, transaminitis, diffuse bilateral lung infiltrates and bone marrow lymphocyte involvement. a polymerase chain reaction (pcr) test revealed a high ebv viral load in the peripheral blood cells. the patient received a course of piperacillin-tazobactam for klebsiella pneumoniae, but no active treatment for the lymphoproliferative disorder. however, his lymphocyte count, serum lactate dehydrogenase and liver enzymes dropped spontaneously. in addition, ebv pcr copies fluctuated and then decreased significantly. he remained clinically asymptomatic over the following four years. keywords: epstein-barr virus infections; natural killer cell; lymphoproliferative disorders; spontaneous remission; case report; oman. امللخ�ص: تعد ال�سطرابات التكاثرية اللمفية املزمنة للخاليا الفاتكة الطبيعية قليلة ال�سيوع، ويلعب فريو�س ابي�ستاين–بار دورا مهما يف اإحداثها. نتناول هنا حالة �ساب يف الع�رسين من عمره م�ساب بعدوى مزمنة ن�سطة لفريو�س ابي�ستاين–بار ومرتبطة با�سطراب تكاثري ب�سلطنة م�سقط يف قابو�س ال�سلطان جامعة مل�ست�سفى املري�س ح�رس معتاد. غري التنامي بطيء م�سار وذا الفاتكة، للخاليا مزمن ملفي عمان يف دي�سمرب من عام 2011م. وبح�سب تاريخه املر�سي فقد كان يعاين من حمى متقطعة و�سعال. واأظهر الفح�س اعتالل معمما للغدد اللمفاوية، و�سخامة الكبد والطحال، وزيادة الكريات البي�ساء، وارتفاع م�ستوى انزميات ناقالت الأمني، ور�سيحة الرئة املنت�رسة ثنائية اجلانب، مع اكتناف ملفاويات نقي العظام. واظهر اختبار تفاعل البويل مرييز الت�سل�سلي حمال كبريا لفريو�س ابي�ستاين–بار يف خاليا الدم الطرفية. ومت اإعطاء املري�س جرعات مقررة من امل�ساد احليوي بيربا�سيلني–تازوباكتم لعالج بكرتيا كل�سيال نيموين، ولكنه مل يعط اأي عالج ن�سط لال�سطراب التكاثري اللمفي. اإل اأن عدد خالياه اللمفية ون�ساط انزمي نازعة هيدروجني الالكتات، وانزميات الكبد انخف�ست تلقائيا. وبالإ�سافة اإىل ذلك فقد متوجت ن�سخ اختبار تفاعل البويل مرييز الت�سل�سلي فريو�س ابي�ستاين–بار يف ثم انخف�ست ب�سورة معنوية. وظل املري�س غري مظهر لأي اأعرا�س ملدة اأربعة اأعوام تالية. كلمات مفتاحية: حمى عدوى فريو�س ابي�ستاين-بار؛ اخللية الفاتكة الطبيعية؛ ال�سطرابات التكاثرية اللمفية؛ التعايف التلقائي؛ عر�س حالة؛ عمان. unusual indolent course of a chronic active epstein-barr virus-associated natural killer cell lymphoproliferative disorder arwa z. al-riyami,1 *khalil al-farsi,1 murtadha al-khabori,1 mohammed al-huneini,1 ibrahim al-hadabbi2 sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 230–233, epub. 15 may 16 submitted 6 oct 15 revision req. 25 nov 15; revision recd. 24 dec 15 accepted 21 jan 16 doi: 10.18295/squmj.2016.16.02.015 case report arwa z. al-riyami, khalil al-farsi, murtadha al-khabori, mohammed al-huneini and ibrahim al-hadabbi case report | e231 onset disease.6 clinical features include fever, liver dysfunction, splenomegaly, lymphadenopathies and cytopaenia, with these being seen more commonly in t cell cases.1 this report describes a patient with ebvassociated nk cell lymphoproliferative disease from oman with an unusual indolent chronic course that did not require any therapeutic intervention; to the best of the authors’ knowledge, this is the first case of this kind reported from the middle east. case report a 20-year-old previously healthy male presented to the sultan qaboos university hospital, muscat, oman, in december 2011 with a six-month history of intermittent fever and a recent history of coughing. he had not lost any weight, did not suffer from night sweats and his family history was unremarkable. he had no symptoms suggestive of an underlying autoimmune disorder or a connective tissue disease. physical examination revealed bilateral non-bulky submandibular lymph nodes without skin lesions. the rest of the examination was unremarkable. abdominal ultrasonography showed mild hepatosplenomegaly with normal echogenicity and no focal lesions. a complete blood count revealed leukocytosis (total white cell count: 46.2 x 109/l; normal range [nr]: 2.2–10.0 x 109/l) and lymphocytosis (lymphocyte count: 37.3 x 109/l; nr: 1.2–4.0 x 109/l). the patient had normal haemoglobin levels (12.2 g/dl; nr: 11.5–15.5 g/dl) and a normal platelet count (351.0 x 109/l; nr: 140.0–400.0 x 109/l). a blood smear showed lymphocytosis with monomorphic large granular lymphocytes. flow cytometry revealed 82% lymphocytes, of which 90% were nk cells. these were positive for cluster of differentiation (cd) 16, partial cd56, cd2, cd7, human leukocyte antigen-d related and cd38 cells and negative for surface cd3 and cd5 cells and t cell receptors α/β and γ/δ. approximately 25–30% of the cd56-positive cells were homogenously positive for cd8dim. a bone marrow aspirate showed 33% granular lymphocytes and flow cytometry findings similar to those of the peripheral blood cells. moreover, the bone marrow biopsy showed interstitial infiltrate of cd8 and granzyme b-positive small lymphocytes. an ebv polymerase chain reaction (pcr) test revealed a high viral load (116,750 copies/ml). a trephine biopsy was positive for ebv by in situ hybridisation. consequently, the diagnosis of an ebv-associated nk cell lymphoproliferative disorder was made. laboratory investigations revealed high lactate dehydrogenase (ldh; 406 u/l; nr: 135–225 u/l), aspartate aminotransferase (74 iu/l; nr: 0–38 iu/l), alanine transaminase (91 iu/l; nr: 0–41 iu/l), alkaline phosphatase (225 iu/l; nr: 40–129 iu/l), indirect hyperbilirubinemia (total bilirubin: 25 µmol/l; nr: 0–17 µmol/l) and c-reactive protein (22 mg/l; nr: 0–8 mg/l) levels. serum calcium, uric acid, potassium, phosphate and creatinine levels were normal. serology for hepatitis b and c and human immunodeficiency virus was negative. karyotype testing showed normal results. a chest x-ray showed bilateral prominent reticulonodular changes and left hilar prominence. contrast-enhanced computed tomography (ct) of the neck, chest and abdomen revealed small subcentimetre-sized lymph nodes in the bilateral jugulodigastric, pretracheal, axillary and mesenteric areas, as well as slightly enlarged hilar lymph nodes. in addition, bilateral small ill-defined nodular pulmonary densities were observed. sputum cultures grew klebsiella pneumoniae; however, bronchoalveolar lavage was negative for microorganisms including mycobacterium tuberculosis, fungi and pneumocystis carinii. a transbronchial biopsy revealed an interalveolar infiltrate of granzyme band ebv-positive lymphocytes. no reactive follicles or granulomata were present. while a course of piperacillin/tazobactam was prescribed to treat the bacterial pneumonia, the patient declined any active therapy for his underlying lymphoproliferative disorder. he was closely monitored and a spontaneous gradual drop was observed in his lymphocyte count, serum ldh levels and liver enzymes over the following 12 months. additionally, ebv pcr copies fluctuated and then decreased significantly [figure 1]. the patient’s symptoms resolved over a period of two months and he remained clinically asymptomatic with a gradually decreasing lymphocyte count (4.0 x 109/l) with large granular lymphocyte morphology. his serum ldh levels remained normal and a repeat ct scan showed stable subcentimetre lymphadenopathy in the cervical, pretracheal and hilar areas, along with mild hepatosplenomegaly. the patient remained clinically well over the four years following his initial diagnosis. discussion in general, patients with ebv-associated nk cell lymphoproliferative disease exhibit large granular lymphocytosis, hypersensitivity to mosquito bites, skin rashes, defective nk cell activity and high immunoglobulin e levels.3,7 the diagnostic criteria for this disease entity was first proposed by okano et al. in the absence of apparent features of a known unusual indolent course of a chronic active epstein-barr virus-associated natural killer cell lymphoproliferative disorder e232 | squ medical journal, may 2016, volume 16, issue 2 ulceration/proliferation, coronary artery aneurysms, central nervous system involvement, myocarditis and interstitial pneumonia.11 in addition, these patients respond poorly to chemotherapy and have a high risk of eventual progression to overt leukaemia and lymphomas in the form of extranodal nk/t cell lymphomas of nasal type (enkls), aggressive nk cell leukaemia (ankl) and peripheral t cell leukaemia or lymphomas.1,11,12 some researchers recommend an early bone marrow transplant while the patient is in good general health, despite the associated transplant-related mortality.1 further research is required to assess the actual prevalence of ebvassociated t/nk lymphoproliferative disorders and improve patient outcomes. poor prognostic features which indicate early intervention include advanced age at onset (over eight underlying disease at the time of diagnosis.10 the patient in the current case displayed morphology similar to patients with the t cell subtype and an immunophenotype of the nk variant. he did not undergo testing for nk cell killing activity; however, he fulfilled the criteria proposed by okano et al., including persistent infectious mononucleosis-like symptoms, unusual patterns of anti-ebv antibodies, increased ebv genome in affected tissues (including peripheral blood cells) and chronic illness unexplained by other known disease processes.10 the clinical outcome for patients with caebv infections is reportedly poor and appears to be worse for cd4+ t cell cases than nk cell cases.1 caebv often results in life-threatening complications such as haemophagocytic syndrome, disseminated intravascular coagulopathy, hepatic failure, digestive tract figure 1a‒c: graphs showing the significant drop over time in (a) total white cell count, (b) liver enzyme levels and (c) epstein-barr viral load in a 20-year-old male with an unusual indolent course of chronic active epstein-barr virusassociated natural killer cell lymphoproliferative disorder. the patient declined to undergo any active therapy for the disorder and seemed to exhibit a spontaneous recovery. wbc = white blood cell count; anc = absolute neutrophil count; lymphs = lymphocyte count; ldh = lactate dehydrogenase h; ast = aspartate aminotransferase; alt = alanine transaminase; alp = alkaline phosphatase. arwa z. al-riyami, khalil al-farsi, murtadha al-khabori, mohammed al-huneini and ibrahim al-hadabbi case report | e233 years old), the presence of thrombocytopaenia (platelet count: <120,000/l) and t cell (rather than nk cell) associated disease.13 the overall outcome of nk cellassociated disease is variable. there are reports of some patients who eventually developed enkl and ankl while other cases seem to have indolent courses.1 two indolent cases reportedly achieved complete remission with oral acyclovir therapy and weekly intravenous cytarabine administration; however, the role of these agents in achieving complete remission is not clear.1 in the current case, the patient appeared to exhibit an indolent course despite persistent lymphocytosis, generalised lymphadenopathy, initial multi-organ involvement (including lung involvement) and poor prognostic indicators. conclusion ebv-associated t/nk lymphoproliferative disorders are uncommonly seen outside of japan, korea and taiwan and are often aggressive. to the best of the authors’ knowledge, the patient in this report represents the first case from the middle east with an unusual indolent course which resolved spontaneously without therapeutic intervention. references 1. kimura h, ito y, kawabe s, gotoh k, takahashi y, kojima s, et al. ebv-associated t/nk-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. blood 2012; 119:673–86. doi: 10.1182/blood-2011 10-381921. 2. cohen ji, kimura h, nakamura s, ko yh, jaffe es. epsteinbarr virus-associated lymphoproliferative disease in nonimmunocompromised hosts: a status report and summary of an international meeting, 8-9 september 2008. ann oncol 2009; 20:1472–82. doi: 10.1093/annonc/mdp064. 3. kikuta h, taguchi y, tomizawa k, kojima k, kawamura n, ishizaka a, et al. epstein-barr virus genome-positive t lymphocytes in a boy with chronic active ebv infection associated with kawasaki-like disease. nature 1988; 333:455–7. doi: 10.1038/333455a0. 4. kawa-ha k, ishihara s, ninomiya t, yumura-yagi k, hara j, murayama f, et al. cd3negative lymphoproliferative disease of granular lymphocytes containing epstein-barr viral dna. j clin invest 1989; 84:51–5. doi: 10.1172/jci114168. 5. isobe y, aritaka n, setoguchi y, ito y, kimura h, hamano y, et al. t/nk cell type chronic active epstein-barr virus disease in adults: an underlying condition for epstein-barr virusassociated t/nk-cell lymphoma. j clin pathol 2012; 65:278–82. doi: 10.1136/jclinpath-2011-200523. 6. arai a, imadome k, watanabe y, yoshimori m, koyama t, kawaguchi t, et al. clinical features of adult-onset chronic active epstein-barr virus infection: a retrospective analysis. int j hematol 2011; 93:602–9. doi: 10.1007/s12185-011-0831-x. 7. cohen ji, jaffe es, dale jk, pittaluga s, heslop he, rooney cm, et al. characterization and treatment of chronic active epsteinbarr virus disease: a 28-year experience in the united states. blood 2011; 117:5835–49. doi: 10.1182/blood-2010-11-316745. 8. kimura h, hoshino y, kanegane h, tsuge i, okamura t, kawa k, et al. clinical and virologic characteristics of chronic active epstein-barr virus infection. blood 2001; 98:280–6. doi: 10.1182/blood.v98.2.280. 9. straus se. the chronic mononucleosis syndrome. j infect dis 1988; 157:405–12. doi: 10.1093/infdis/157.3.405. 10. okano m, kawa k, kimura h, yachie a, wakiguchi h, maeda a, et al. proposed guidelines for diagnosing chronic active epsteinbarr virus infection. am j hematol 2005; 80:64–9. doi: 10.1002/ ajh.20398. 11. kimura h. pathogenesis of chronic active epstein-barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency? rev med virol 2006; 16:251–61. doi: 10.1002/rmv.505. 12. imashuku s, teramura t, tauchi h, ishida y, otoh y, sawada m, et al. longitudinal follow-up of patients with epstein-barr virusassociated hemophagocytic lymphohistiocytosis. haemato logica 2004; 89:183–8. 13. kimura h, morishima t, kanegane h, ohga s, hoshino y, maeda a, et al. prognostic factors for chronic active epsteinbarr virus infection. j infect dis 2003; 187:527–33. doi: 10.1086 /367988. http://dx.doi.org/10.1182/blood-2011-10-381921 http://dx.doi.org/10.1182/blood-2011-10-381921 http://dx.doi.org/10.1093/annonc/mdp064 http://dx.doi.org/10.1038/333455a0 http://dx.doi.org/10.1172/jci114168 http://dx.doi.org/10.1136/jclinpath-2011-200523 http://dx.doi.org/10.1007/s12185-011-0831-x http://dx.doi.org/10.1182/blood-2010-11-316745 http://dx.doi.org/10.1182/blood.v98.2.280 http://dx.doi.org/10.1093/infdis/157.3.405 http://dx.doi.org/10.1002/ajh.20398 http://dx.doi.org/10.1002/ajh.20398 http://dx.doi.org/10.1002/rmv.505 http://dx.doi.org/10.1086/367988 http://dx.doi.org/10.1086/367988 peer le arning is a t ype of le arning process whereby non-professional teachers of similar backgrounds and education levels learn from each other.1 peer-assisted learning has been demonstrated to be effective in many disciplines, including among university and elementary school students.2,3 in terms of patient care, peer-led support groups allow patients or their caregivers to meet and discuss various problems and issues. such support groups are often very popular, with participants reporting them to be extremely useful as they provide the opportunity to meet people with similar conditions and learn from each other’s experiences.4 in addition, peer learning is increasingly being used as a tool for patient education.5 it has been shown to improve learning outcomes, with positive implications for clinical practice.6 peer education programmes for patients with diseases or those undergoing certain procedures aim to improve awareness and knowledge regarding management of the disease or details of the scheduled procedure, while also providing the patients with much needed social support.4–7 such programmes have been shown to have a positive impact by reducing overuse of health services and increasing patients’ trust in the primary and hospital care system, as reflected by a reduction in the number of health centre visits and admissions.8,9 in this issue of squmj, habibzadeh et al. studied the effects of peer-facilitated, video-based and combined peer-and-video education interventions on anxiety among patients undergoing coronary angiography.10 indeed, as coronary angiography is an invasive procedure involving catheterisation of the heart, most patients are understandably anxious; unfortunately, this anxiety can translate into poor outcomes.11 habibzadeh et al. found that any form of intervention significantly reduced anxiety, with no statistical difference between the various approaches used.10 these results could be due to the relatively small sample size in the study, especially as all three counselling methods are well-established. in addition, it can also be argued that both the video and peer education interventions involved similar methods, as educational videos explaining certain procedures are sometimes filmed with the aid of non-medical professionals. despite the fact that there was no advantage to one educational approach over the others, the study nonetheless emphasises the role of peer-led education groups.10 in general, patients appear to relate better to others who have undergone the procedure themselves and may feel more comfortable asking them certain questions that they would otherwise feel embarrassed to ask a medical professional.7 however, it should be noted that peer-led education interventions should be supervised by a medical professional. previous research among students has indicated that the presence of a senior person in authority was preferred by participants in case their peers did not know the answers and in order to ensure that the correct information was imparted.12 despite this, peer-facilitated groups still have a useful role in supplementing the work done by often overstretched medical and nursing teams.5 debussche et al. have published some useful suggestions for creating a successful peer-led educational experience.9 the content of such activities should be carefully created by medical personnel and use simple language written by peers without overly complicated medical jargon. the amount of information imparted should be adequate without being overwhelming.9 in addition, the programme should contain elements or examples derived from the peers’ own previous experiences, as this can help patients who are new to the procedure or disease to relate to the information on a more personal level.9 department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com تعليم املرضى امليسر من قبل األقران مورد غري مستغل حممد �سيخ و �سونيل نادار editorial peer-facilitated patient education an underutilised resource mohammed m. shaikh and *sunil k. nadar sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e1–2 , epub. 4 apr 18 submitted 23 feb 18 revision req. 7 mar 18; revision recd. 8 mar 18 accepted 11 mar 18 doi: 10.18295/squmj.2018.18.01.001 peer-facilitated patient education an underutilised resource e2 | squ medical journal, february 2018, volume 18, issue 1 in their study, habibzadeh et al. also demonstrated the importance of visual aids in patient education, for example in the form of a video explanation of the upcoming procedure.10 this has been previously shown to be useful for other procedures such as colonoscopies and colposcopies.13,14 as with peerfacilitated educational activities, such videos or visual aids should be made with the involvement of patients, so that the language remains simple and the content refers to real-life and relatable experiences. in effect, these videos can act as a form of peer-supported learning in their own right. despite evidence that peer-led patient education is helpful, this approach is still not optimally used.15 there may be many reasons for this, including a lack of time and initiative among busy medical personnel to train patient educators. in addition, the patient educators themselves need to be motivated enough to attend peer-led events without financial incentive, as such activities are usually coordinated on a voluntary basis, although some institutions do provide some form of payment.15 furthermore, certain patients may feel reluctant to share their experiences or knowledge with other patients as they feel they are not adequately qualified to take on this role. others may question the medicolegal issues involved with allowing individuals without medical qualifications to provide information about various diseases and procedures.14 there is also concern that patients may discuss material that they have retrieved from the internet from inaccurate sources. however, most of these issues can be resolved by educating medical personnel on the benefits of peer education and making sure that the contents of peerled activities are checked by medical personnel prior to delivery.7 in conclusion, peer-led patient education has an important role in healthcare delivery. it creates an important bridge between patients and medical professionals and provides social support for the former by helping to alleviate procedureor diseaserelated anxiety. one could argue that, despite continuous advancements in technology and medical care and the increasing availability of information online, there is still no replacement for traditional human contact. references 1. topping kj. the effectiveness of peer tutoring in further and higher education: a typology and review of the literature. higher education 1996; 32:321–45. doi: 10.1007/bf00138870. 2. field m, burke jm, mcallister d, lloyd dm. peer-assisted learning: a novel approach to clinical skills learning for medical students. med educ 2007; 41:411–18. doi: 10.1111/j.13652929.2007.02713.x. 3. rohrbeck ca, ginsburg block md, fantuzzo jw, miller tr. peer-assisted learning interventions with elementary school students: a meta-analytic review. j educ psychol 2003; 95:2405. 2003. doi: 10.1037/0022-0663.95.2.240. 4. dennis cl. the effect of peer support on postpartum depression: a pilot randomized controlled trial. can j psychiatry 2003; 48:115–24. doi: 10.1177/070674370304800209. 5. dennis cl. peer support within a health care context: a concept analysis. int j nurs stud 2003; 40:321–32. doi: 10.1016/ s0020-7489(02)00092-5. 6. kronish im, goldfinger jz, negron r, fei k, tuhrim s, arniella g, et al. effect of peer education on stroke prevention: the prevent recurrence of all inner-city strokes through education randomized controlled trial. stroke 2014; 45:3330–6. doi: 10.11 61/strokeaha.114.006623. 7. matthias ms, kukla m, mcguire ab, bair mj. how do patients with chronic pain benefit from a peer-supported pain selfmanagement intervention? a qualitative investigation. pain med 2016; 17:2247–55. doi: 10.1093/pm/pnw138. 8. danet a, rodríguez má, peña fg, doblas ml, martín nl, cerdà jc. chronicity and use of health services: peer education of the school of patients. rev esc enferm usp 2017; 51:e03280. doi: 10.1590/s1980-220x2017004203280. 9. debussche x, besançon s, balcou-debussche m, ferdynus c, delisle h, huiart l, et al. structured peer-led diabetes selfmanagement and support in a low-income country: the st2ep randomised controlled trial in mali. plos one 2018; 13:e0191262. doi: 10.1371/journal.pone.0191262. 10. habibzadeh h, milan zd, radfar m, alilu l, cund a. effects of peer-facilitated, video-based and combined peer-and-video education on anxiety among patients undergoing coronary angiography: randomised controlled trial. sultan qaboos univ med j 2018; 18:e61–7. doi: 10.18295/squmj.2018.18.01.010. 11. delewi r, vlastra w, rohling wj, wagenaar tc, zwemstra m, meesterman mg, et al. anxiety levels of patients undergoing coronary procedures in the catheterization laboratory. int j cardiol 2017; 228:926–30. doi: 10.1016/j.ijcard.2016.11.043. 12. dehghani mr, amini m, kojuri j, nabeiei p. evaluation of the efficacy of peer-learning method in nutrition students of shiraz university of medical sciences. j adv med educ prof 2014; 2:71–6. 13. hayat u, lee pj, lopez r, vargo jj, rizk mk. online educational video improves bowel preparation and reduces the need for repeat colonoscopy within three years. am j med 2016; 129:1219.e1–9. doi: 10.1016/j.amjmed.2016.06.011. 14. ketelaars pj, buskes mh, bosgraaf rp, van hamont d, prins jb, massuger lf, et al. the effect of video information on anxiety levels in women attending colposcopy: a randomized controlled trial. acta oncol 2017; 56:1728–33. doi: 10.1080/ 0284186x.2017.1355108. 15. matthias ms, kukla m, mcguire ab, damush tm, gill n, bair mj. facilitators and barriers to participation in a peer support intervention for veterans with chronic pain. clin j pain 2016; 32:534–40. doi: 10.1097/ajp.0000000000000297. https://doi.org/10.1007/bf00138870 https://doi.org/10.1111/j.1365-2929.2007.02713.x https://doi.org/10.1111/j.1365-2929.2007.02713.x https://doi.org/10.1037/0022-0663.95.2.240 https://doi.org/10.1177/070674370304800209 https://doi.org/10.1016/s0020-7489%2802%2900092-5 https://doi.org/10.1016/s0020-7489%2802%2900092-5 https://doi.org/10.1161/strokeaha.114.006623 https://doi.org/10.1161/strokeaha.114.006623 https://doi.org/10.1093/pm/pnw138 https://doi.org/10.1590/s1980-220x2017004203280 https://doi.org/10.1371/journal.pone.0191262 https://doi.org/10.1016/j.ijcard.2016.11.043 https://doi.org/10.1016/j.amjmed.2016.06.011 https://doi.org/10.1080/0284186x.2017.1355108 https://doi.org/10.1080/0284186x.2017.1355108 https://doi.org/10.1097/ajp.0000000000000297 إشعار عن تغيري يف تسلسل املؤلفني التوافق يف مرض السكري عند النساء املتزوجات املراجعات للمؤسسات الصحية يف عجمان، اإلمارات العربية املتحدة erratum notice erratum notice of author sequence change spousal concordance of diabetes mellitus among women in ajman, united arab emirates the editors of sultan qaboos university medical journal (squmj) have been informed that the authors of an article by al-sharbatti et al. in the may 2016 issue of squmj wish to change the sequence of authors in the above article.1 the first/corresponding author, shatha s. al-sharbatti, contacted squmj in may 2016 requesting a change in the author sequence. al-sharbati informed the editors of squmj that the second author, yasmeen i. abed, should instead be designated as the first author. however, this correction could not made as the article had already been published several days previously. for the reasons stated herein, the editors of squmj wish to notify readers that the sequence of authors for the above article is changed to the following: yasmeen i. abed, shatha s. al-sharbatti, lujain m. al-heety, shaikh a. basha.2 the corresponding author, al-sharbati, takes sole responsibility for this notice and would like to apologise to the readers, reviewers and editors of squmj for this correction made after publication. references 1. al-sharbatti ss, abed yi, al-heety lm, basha sa. spousal concordance of diabetes mellitus among women in ajman, united arab emirates. sultan qaboos univ med j 2016; 16:e197–202. doi: 10.18295/squmj.2016.16.02.010. 2. abed yi, al-sharbatti ss, al-heety lm, basha sa. spousal concordance of diabetes mellitus among women in ajman, united arab emirates. sultan qaboos univ med j 2016; 16:e197–202. doi: 10.18295/squmj.2016.16.02.010. notice of erratum for: al-sharbatti et al. spousal concordance of diabetes mellitus among women in ajman, united arab emirates. sultan qaboos univ med j 2016; 16:e197–202. doi: 10.18295/squmj.2016.16.02.010. sultan qaboos university med j, august 2016, vol. 16, iss. 3, p. e397, epub. 19 aug 16 doi: 10.18295/squmj.2016.16.03.028 erratum notice | e397 http://dx.doi.org/10.18295/squmj.2016.16.02.010 http://dx.doi.org/10.18295/squmj.2016.16.02.010 departments of 1paediatrics, 2family & community medicine and 3physiology, arabian gulf university, manama, bahrain *corresponding author’s e-mail: fuadama@agu.edu.bh حتليل مفردات أسئلة االختيار من متعدد يف قسم األطفال جبامعة اخلليج العريب، املنامة، البحرين دينا خيامي، اأحمد جردات، طارق ال�سيباين، فوؤاد عبداهلل علي abstract: objectives: the current study aimed to carry out a post-validation item analysis of multiple choice questions (mcqs) in medical examinations in order to evaluate correlations between item difficulty, item discrimination and distraction effectiveness so as to determine whether questions should be included, modified or discarded. in addition, the optimal number of options per mcq was analysed. methods: this cross-sectional study was performed in the department of paediatrics, arabian gulf university, manama, bahrain. a total of 800 mcqs and 4,000 distractors were analysed between november 2013 and june 2016. results: the mean diff iculty index ranged from 36.70–73.14%. the mean discrimination index ranged from 0.20–0.34. the mean distractor efficiency ranged from 66.50–90.00%. of the items, 48.4%, 35.3%, 11.4%, 3.9% and 1.1% had zero, one, two, three and four nonfunctional distractors (nfds), respectively. using three or four rather than five options in each mcq resulted in 95% or 83.6% of items having zero nfds, respectively. the distractor efficiency was 91.87%, 85.83% and 64.13% for difficult, acceptable and easy items, respectively (p <0.005). distractor efficiency was 83.33%, 83.24% and 77.56% for items with excellent, acceptable and poor discrimination, respectively (p <0.005). the average kuderrichardson formula 20 reliability coefficient was 0.76. conclusion: a considerable number of the mcq items were within acceptable ranges. however, some items needed to be discarded or revised. using three or four rather than five options in mcqs is recommended to reduce the number of nfds and improve the overall quality of the examination. keywords: medical education; educational measurement; academic performance; psychometrics; examination questions; discriminant analysis; bahrain. ال�سعوبة، موؤ�رص بني العالقة ودرا�سة متعدد من االختيار اأ�سئلة مفردات حتليل اإجراء اإىل احلالية الدرا�سة هدفت الهدف: امللخ�ص: موؤ�رصالتمييز وفعالية امل�ستتات من اأجل االإحتفاظ باالأ�سئلة اأو تعديل اأو اإلغاء كل �سوؤال. باالإ�سافة اإىل ذلك مت حتليل اأف�سل عدد من البدائل يف كل �سوؤال. الطريقة: هذه درا�سة م�ستعر�سة اأجريت يف ق�سم طب االأطفال بجامعة اخلليج العربي، املنامة، البحرين. مت حتليل 800 �سوؤال اإختيار من متعدد و عدد 4,000 من امل�ستتات يف الفرتة من نوفمرب 2013 اىل يونيو 2016. النتائج: تراوح متو�سط موؤ�رص ال�سعوبة بني %73.14-36.70 و تراوح موؤ�رص التمييز من 0.34-0.20 و تراوحت فعالية امل�ستتات من %90.00-66.50 على التوايل. بلغت ن�سبة الفقرات التي حتتوي على �سفر، واحد، اثنان، ثالثة واأربعة م�ستتات غري فاعلة: %48.4، %35.3، %11.4، %3.9 و %1.1 على التوايل. با�ستخدام ثالثة اأو اأربعة بدال من خم�سة بدائل وبالتايل اإزالة واحد اأو اثنني من امل�ستتات الغري فاعلة من �ساأنه اأن تكون %95 اأو %83.6 من اال�سئلة حتوي على �سفر من امل�ستتات الغري فاعلة على التوايل. بلغت فعالية امل�ستتات %91.87، %85.83 و %64.13 بالن�سبة لالأ�سئلة ذات موؤ�رص ال�سعوبة يف املعدالت ال�سعبة واجليدة وال�سهلة على التوايل )p >0.005(. وبلغت فعالية امل�ستتات %83.33، %83.24 و %77.56 بالن�سبة لالأ�سئلة ذات موؤ�رص التمييز يف املعدالت املمتازة واجليدة وال�سعيفة على التوايل )p >0.005(. كان متو�سط اختبار املوثوقية 20 ب كودر ريت�سار�سون هو 0.76. اخلال�صة: كانت ن�سبة جيدة من مفردات اأ�سئلة االختيار من متعدد �سمن املعدالت املقبولة. ومع ذلك، يلزم اإ�ستبعاد بع�ض الفقرات اأو تنقيحها. نو�سي باإ�ستخدام ثالثة اأو اأربعة بدال من خم�سة بدائل للحد من امل�ستتات الغري فاعلة ولتح�سني جودة اأ�سئلة االختيار من متعدد. الكلمات املفتاحية: التعليم الطبي؛ القيا�ض الرتبوي؛ االأداء االأكادميي؛ ال�سيكومرتية؛ اأ�سئلة االأمتحانات؛ حتليل التمييز؛ البحرين. item analysis of multiple choice questions at the department of paediatrics, arabian gulf university, manama, bahrain deena kheyami,1 ahmed jaradat,2 tareq al-shibani,3 *fuad a. ali1 clinical & basic research sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e68–74, epub. 4 apr 18 submitted 30 aug 17 revisions req. 22 oct & 12 dec 17; revisions recd. 12 nov & 25 dec 17 accepted 7 jan 18 doi: 10.18295/squmj.2018.18.01.011 advances in knowledge designing adequate multiple choice questions (mcqs) is essential to assess learning among medical students. item analysis is an important scientific tool that provides information about the reliability and validity of mcq items. however, item analysis studies are limited, particularly in medical schools in arabian gulf countries. the findings of the current study will hopefully increase awareness of this measurement tool among medical education providers in the region. application to patient care designing appropriate mcqs improves the assessment and learning output of medical students. high-quality medical education in the arabian gulf region will encourage the provision of enhanced healthcare services to local populations. deena kheyami, ahmed jaradat, tareq al-shibani and fuad a. ali clinical and basic research | e69 while assessment is an essential part of student learning, assessment tools need to be valid, reliable and objective and reflect various achievement levels. multiple choice questions (mcqs) should not only aim to assess knowledge recollection, but also measure other teaching objectives within bloom’s taxonomy of learning, such as comprehension, application, analysis, synthesis and evaluation.1 constructing a high-quality mcq examination can be difficult and time-consuming; however, this approach is usually preferential to other types of assessment tools because it is objective and leaves little room for human bias, as answers to mcq questions can be easily and reliably scored.2,3 in recent years, the most common type of mcqs employed in examinations are type a mcqs, which consist of a stem followed by four or five options or distractors.4,5 an item analysis assesses the reliability and validity of an examination by examining student performance with regards to each mcq and applying statistical analyses to determine whether the item should be kept, reviewed or discarded from the test. common item analysis parameters include the difficulty index (difi), which reflects the percentage of correct answers to total responses; the discrimination index (di), also known as the point biserial correlation, which identifies discrimination between students with different levels of achievement; and distractor efficiency (de), which indicates whether the distractors in the item are well-chosen or have failed to distract students from selecting the correct answer. an ideal item should have a difi of between 30–70%, a di of >0.2 and a de of 100%.6,7 at the end of their 10-week clinical rotation in the department of paediatrics of the arabian gulf university (agu), manama, bahrain, paediatric clerkship students undergo mcq examinations in addition to objective standard clinical examinations, shortanswer question tests and continuous performance assessments. each mcq consists of a stem followed by five distractors. students do not receive negative marks for wrong answers and the tests are criterionreferenced, with passing standards expressed in absolute terms and a passing score of 60%. for each examination, approximately 50% of the mcqs are newly constructed while the remaining questions are taken from a question bank after revising and modifying question items according to item analysis outcomes. however, the examinations are not assessed for equivalent difficulty across the years. the current study aimed to carry out a postvalidation item analysis of mcqs used in end-of-rota tion examinations between 2013–2016 at the agu department of paediatrics. based on the item analysis outcomes, recommendations were made as to whether the questions should be retained, modified or discarded from the agu question bank. in addition, correlations between the difficulty, item discrimination and distraction effectiveness of each item were calculated and the optimal number of options in each mcq was determined. methods this cross-sectional study was performed in the department of paediatrics at agu and included all mcq items of paediatric clerkship summative examination papers from november 2013 to june 2016. there were 50 mcqs per paper and four examinations per year, resulting in a total of 800 mcqs and 4,000 distractors. in total, 608 students had taken the examtable 1: mean difficulty index, discrimination index and distractor efficiency of end-of-rotation paediatric examinations at the arabian gulf university, manama, bahrain (n = 16) year exam. mean ± sd difi % di de % 2013 1 65.81 ± 24.00 0.34 ± 0.22 70.00 ± 28.12 2 73.14 ± 20.39 0.30 ± 0.16 68.00 ± 29.47 3 70.70 ± 19.34 0.30 ± 0.20 66.50 ± 28.84 4 58.72 ± 23.19 0.23 ± 0.19 79.00 ± 21.64 total 67.09 ± 22.34 0.29 ± 0.20 70.88 ± 27.43 2014 5 56.06 ± 23.38 0.28 ± 0.17 83.50 ± 19.31 6 52.40 ± 18.74 0.28 ± 0.27 75.00 ± 23.15 7 51.70 ± 24.21 0.20 ± 0.27 83.00 ± 17.81 8 52.88 ± 21.20 0.29 ± 0.20 85.00 ± 16.75 total 53.26 ± 21.88 0.26 ± 0.23 81.62 ± 19.65 2015 9 39.54 ± 21.25 0.28 ± 0.19 90.00 ± 15.15 10 44.78 ± 23.63 0.23 ± 0.18 88.50 ± 20.34 11 43.59 ± 22.46 0.27 ± 0.19 86.50 ± 16.91 12 44.73 ± 25.25 0.23 ± 0.18 81.00 ± 21.17 total 43.16 ± 23.12 0.25 ± 0.18 86.50 ± 18.73 2016 13 41.84 ± 22.07 0.27 ± 0.15 85.50 ± 18.96 14 36.70 ± 23.26 0.22 ± 0.18 89.00 ± 16.87 15 54.68 ± 18.94 0.31 ± 0.14 84.00 ± 20.05 16 47.14 ± 22.84 0.24 ± 0.15 89.00 ± 15.29 total 45.09 ± 22.68 0.26 ± 0.18 86.88 ± 17.89 average 52.15 ± 24.37 0.27 ± 0.20 81.47 ± 22.19 exam. = examination; sd = standard deviation; difi = difficulty index; di = discrimination index; de = distractor efficiency. item analysis of multiple choice questions at the department of paediatrics, arabian gulf university, manama, bahrain e70 | squ medical journal, february 2018, volume 18, issue 1 table 2: non-functioning distractors per individual multiple choice question items in the end-of-rotation paediatric examinations at the arabian gulf university, manama, bahrain (n = 800) year parameter number of nfds per item total 0 1 2 3 4 2013 n (%) 64 (32) 73 (36.5) 37 (18.5) 18 (9) 8 (4) 200 (100) mean difi % 51.62 66.60 75.62 91.96 100.00 67.09 mean di 0.33 0.32 0.29 0.18 0.00 0.29 2014 n (%) 88 (44) 84 (42) 21 (10.5) 7 (3.5) 0 (0) 200 (100) mean difi % 45.54 56.27 65.01 78.81 53.26 mean di 0.26 0.28 0.28 0.07 0.26 2015 n (%) 116 (58) 66 (33) 13 (6.5) 4 (2) 1 (0.5) 200 (100) mean difi % 39.19 43.29 60.24 86.38 100.00 43.16 mean di 0.24 0.27 0.27 0.19 0.00 0.25 2016 n (%) 119 (59.5) 59 (29.5) 20 (10) 2 (1) 0 (0) 200 (100) mean difi % 38.98 48.89 65.02 97.37 45.09 mean di 0.27 0.25 0.27 0.16 0.26 total n (%) 387 (48.4) 282 (35.3) 91 (11.4) 31 (3.9) 9 (1.1) 800 (100) mean difi % 42.62 54.36 68.65 88.62 100.00 52.15 mean di 0.27 0.28 0.28 0.15 0.00 0.27 nfds = non-functioning distractors; di = discrimination index. inations during the study period, with an average of 38 students sitting each examination. items were only used for summative assessment and were not reviewed with the students at any time. the content and construct validity of the examinations were verified by the paediatric examination committee, which consisted of five content experts and paediatric consultants. each examination was designed according to a predetermined examination blueprint, ensuring that all essential knowledge and skills were covered based on learning objectives. the post-validation item analysis was performed using the oracle database, version 10g (oracle corp., redwood city, california, usa). the committee discarded existing mcqs based on the item analysis results, flaws in mcq construction and how frequently an item was used in previous years. the question bank was secured in the assessment office to which only authorised individuals were allowed access via a digital security system. examinees entered their answers in pencil on a scantron® optical answer sheet (scantron corp., tustin, california, usa). the item analysis parameters used in the current study included the difi, di and de. the difi ranged from 0% (i.e. none of the students answered the item correctly) to 100% (i.e. all of the students answered the item correctly). in general, items with a difi of <30% were considered difficult, those between 30–70% were considered acceptable and those >70% were considered easy. kelley’s method was used to calculate the di based on the difference between the scores of highachievers, classified as the top 27% of test-takers, and low-achievers, classified as the bottom 27% of test takers.8 the larger the difference between the highand low-achieving groups, the higher the di of an item. the dis of items ranged from -1 (all and only low achievers answered correctly) to +1 (all and only high achievers answered correctly). items with a di of ≥0.35 were considered excellent, those between 0.2–0.34 were considered acceptable and those <0.2 were considered poor. the de was calculated based on the number of nonfunctional distractors (nfds) per item. an nfd was defined as an incorrect mcq option selected by less than 5% of students.7 the de was deemed to be either 0%, 25%, 50%, 75% or 100% if an item had four, three, two, one or zero nfds, respectively.9 the reliability of the examination was measured using the kuder-richardson formula 20 coefficient (kr20); this value usually ranges from 0–1, with higher kr20 values (i.e. closer to 1) indicating greater reliability. a kr20 value of <0.3 is considered poor and a value of ≥0.7 is considered acceptable. items with difis of >70% or <30% usually yield a low kr20 value, as do items with a di of <0.2.2,10,11 data analysis was performed using the statistical package for the social sciences (spss), version 23.0 deena kheyami, ahmed jaradat, tareq al-shibani and fuad a. ali clinical and basic research | e71 (ibm corp., armonk, new york, usa). variables were presented as means ± standard deviations. the linear relationship between difi and di was measured using pearson’s correlation test. a two-way analysis of variance was used to examine the differences in de (dependent variable), difi (independent variable one) and di (independent variable two). a p value of <0.050 was considered statistically significant. the vice dean for academic affairs at agu approved this study and allowed access to the examination data. the identities of the students taking the examination were kept anonymous and confidential. no human participants were involved in this study. results the mean difi of the examinations ranged from 36.70% in 2016 to 73.14% in 2013, with the overall mean difi considered acceptable (52.15%). the overall mean di and de ranged between 0.20–0.34 and 66.50–90.00%, respectively [table 1]. of the total number of items, 48.4%, 35.3%, 11.4%, 3.9% and 1.1% had zero, one, two, three and four nfds, respectively [table 2]. it was calculated that using four rather than five options in each mcq by removing one nfd would result in 83.6% of items having zero nfds. using three options and removing two nfds resulted in 95% of items having zero nfds. the overall difi increased as the number of nfds increased, with difis of 42.62%, 54.36%, 68.65%, 88.62% and 100% for items with zero, one, two, three and four nfds, respectively. this finding was observed in the mean difi for each year as well. the overall mean difi was almost the same for items with zero, one and two nfds (0.27%, 0.28% and 0.28%), while they were 0.15% and 0% for items with three and four nfds, respectively. similar results were observed for the mean di of each year as well. more than 40% of the mcqs had an acceptable difi throughout the study period. the lowest percentage of difficult mcqs was observed in 2013 (7.5%). the highest percentage of difficult mcqs was 31.5%, noted in 2015. there were more easy mcqs in 2013 than in 2015 [figure 1a]. item dis were relatively constant across the study period [figure 1b]. approximately half of the items had an acceptable difi (53.4%), while the other half were either difficult (20.8%) or easy (25.9%). the de was directly related to the difi, with des of 91.87%, 85.83% and 64.13% for difficult, acceptable and easy items, respectively (p <0.005). items were nearly equally distributed between poor, acceptable and excellent dis. the de was 83.24% and 83.33% for items with excellent and acceptable dis, respectively, compared to 77.56% for items with poor discrimination (p <0.005) [table 3]. there was a significant dome-shaped correlation between difi and di (r = 0.162; p = 0.010), with the highest dis occurring in the acceptable difi range and decreasing for difis in the difficult range [figure 2]. the average kr 20 coefficient value was 0.76. figure 1: distribution according to (a) difficulty index and (b) discrimination index of multiple choice questions in endof-rotation paediatric examinations at the arabian gulf university, manama, bahrain (n = 800). table 3: correlation between difficulty index and discrimination index with distractor efficiency and action proposed of multiple choice questions in end-of-rotation paed iatric examinations at the arabian gulf university, manama, bahrain (n = 800) index n (%) de % p value proposed action difi difficult 166 (20.8) 91.87 <0.005* review acceptable 427 (53.4) 85.83 store and review easy 207 (25.9) 64.13 discard di poor 254 (31.8) 77.56 <0.005† discard acceptable 267 (33.4) 83.33 store and review excellent 279 (34.9) 83.24 store de = distractor efficiency; difi = difficulty index; di = discrimination index. *the de was significantly different for difficult, acceptable and easy items. †poor dis had a significantly lower de than both acceptable and excellent dis. item analysis of multiple choice questions at the department of paediatrics, arabian gulf university, manama, bahrain e72 | squ medical journal, february 2018, volume 18, issue 1 discussion in the current study, out of 16 summative examinations and 800 items, the mean difi of individual tests was acceptable. items with a high difi mostly occurred in examination papers from 2015 and 2016, while items with a low difi mostly occurred in 2013 examination papers. it is likely that this finding reflects recent improvements in mcq construction by the agu examination committee. the difi results of the current study were comparable to those of other institutions, although relative incentives and test conditions are unlikely to have been the same. mitra et al. reported mean difis ranging from 64–89% among 12 summative assessments in their foundation programme conducted between 2003 and 2006.12 other studies have reported mean difis of 39.4 ± 21.4% and 63.06 ± 18.95%, respectively.9,13 keralia et al. reported mean difis between 47.17–58.08% in mcq items from 10 summative papers.14 sharif et al. reported a mean difi of 49 ± 31% in 2,445 mcqs.15 in the basic medical sciences component of a nursing licensure examination, lin et al. found the difi to range from 10–93%, with a mean of 48%.16 karelia et al. reported that 61 ± 8.43%, 24 ± 4.08% and 15 ± 7.07% of items in pharmacology summative tests were acceptable, very easy and very difficult, respectively.14 in the current study, 53.4%, 25.9% and 20.8% of items fell within these same categories. the authors recommend selecting mcqs with lower difis for fundamental topics that students will probably know; moreover, starting the examination with such questions will raise the students’ confidence. similarly, mcqs with a high difi should be located nearer the end of the paper in order to discriminate between highand low-achievers. with regards to di, a nearly equivalent percentage of items in the current study were in the poor, acceptable and excellent ranges (31.8%, 33.4% and 34.9%, respectively). lin et al. reported that 28.8% of mcq items in the basic medical sciences section had a di of <0.2.16 other studies have reported mean dis of 0.14 ± 0.19, 0.356 ± 0.17, 0.19 ± 0.30 and 0.33 ± 0.18.6,9,13,15 items with poor dis usually result in low scores due to the use of incorrect answer keys, confusing stems or areas of controversy.17,18 such items should be removed from the question bank as they fail to discriminate between strong and weak academic performances. constructing plausible distractors and decreasing nfds is essential to improve the quality of mcqs.19 therefore, items may need to be modified if students constantly avoid choosing certain distractors. in the current study, most questions had less than two nfds, with a mean de of 66.5–90.00%. other studies have reported a mean de of 88.6 ± 18.6% and 63.97 ± 33.56%.9,13 over the study period, there was a gradual improvement in mean de from 2013 (70.88%) to 2016 (86.88%); this was likely due to the continuous improvement activities of the agu examination committee. this improvement is also reflected in the annual number of nfds. items with zero nfds increased from 32% in 2013 to 44%, 58% and 59.5% in 2014, 2015 and 2016, respectively, while items with three nfds decreased from 9% in 2013 to 3.5%, 2% and 1% in 2014, 2015 and 2016, respectively. items with four nfds decreased from 4% in 2013 to 0%, 0.5% and 0% in 2014, 2015 and 2016, respectively. items with high nfds reduce both the de and di, but increase the difi; thus, the item will be easy for the students and act as a poor discriminator of academic performance. in the current study, the de was significantly higher among difficult items compared to accep table and easy items as well as significantly higher among items with excellent and acceptable dis over poor ones. difficult items with excellent de values need to be reviewed for possible language confusion, suffic ient subject coverage or inappropriately chosen material according to the student’s level of learning. in contrast, easy items with low de values should be discarded, while items with acceptable difi and de values can be stored and reviewed for improvement. it is often necessary to revise items in which the distractor is selected more often than the correct answer.20 the number of nfds also affects di, in that items with lower nfds are associated with acceptable or excellent dis. the current study found that items with excellent and acceptable dis had a significantly higher de than items with a poor di. the authors recommend discarding items with poor dis and low des, while retaining items with acceptable or excellent dis and high des. in the current study, items with nfds of zero, one and two had acceptable difis and dis, while items with nfds of three and four had higher difis and poorer dis. mukherjee et al. reported a similar figure 2: scatter plot showing the relationship between difficulty index and discrimination index among multiple choice question items in end-of-rotation paediatric examinations at the arabian gulf university, manama, bahrain (n = 800). deena kheyami, ahmed jaradat, tareq al-shibani and fuad a. ali clinical and basic research | e73 association, with difis of 32.5%, 51.36%, 71.11% and 87.08% for items with zero, one, two and three nfds, respectively, in a community medicine assessment; only items with nfds of one and two had accept able dis (0.396 and 0.404, respectively), while items with nfds of zero and three had poor dis (0.023 and 0.195, respectively).21 items which reflect fundamental knowledge should be retained each year to determine whether all students continue to answer them correctly. while some may argue that the inclusion of more options in an mcq reduces the ‘guessing effect’, others have demonstrated that additional options beyond three do not make much difference; in fact, reducing the list of available responses to three options can actually improve psychometric features.22,23 furthermore, it is easier to develop three rather than four or five mcq options and more effective to have fewer options with a greater number of functional distractors in comparison to increased options and more nfds. tarrent et al. suggested including three instead of four options, as such questions require less time to be constructed and the performance for both is equal.24 a meta-analysis of 80 years of research concluded that three options are optimal for mcq items, resulting in a reduction in the amount of time required to prepare each mcq and allowing more questions to be set per examination.19 in addition, this will increase subject exposure and improve the reliability and validity of the test due to the inclusion of more high-quality items. according to the domeshaped correlation between difi and di in the current study, items with difis falling in the difficult or easy categories had significantly poorer dis. sim et al. similarly reported that maximum di values were seen with difis between 40–74%.25 the reliability coefficient in the current study was 0.76, which is less than excellent but still within the desirable range.2,10,11 constructing high-quality mcqs is essential to accurately assess student performance. overall, for students who know the material covered by the examination, nfds add little to the performance of a test item; in contrast, increasing the number of distractors decreases the likelihood of students accidentally choosing the correct answer by guesswork. an item analysis of questions is recommended for all examinations in order to continuously update the question bank by keeping items with acceptable indices and revising or discarding others. in the authors’ experience, it is usually better to construct an examination with the input of an examination committee in order to improve the quality of the questions. special training programmes or workshops should be offered to the members of such committees in order to hone their skills in preparing effective mcqs. further research at agu is recommended to determine any future improvements in mcq preparation. conducting similar studies for examinations in other disciplines at agu would also be useful. conclusion item analyses can be valuable to strengthen an mcq bank in order to ensure the items have an acceptable difi, acceptable or excellent di and high de. the item analysis of paediatric end-of-rotation examinations at agu indicated that a considerable percentage of test items had acceptable mean difis and dis. however, some items needed to be discarded or revised. using three or four rather than five options in an mcq is recommended. a c k n o w l e d g e m e n t s the researchers would like to thank the assessment office at agu for providing the mcq database and helping with the item analysis. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. case sm, swanson db. extended-matching items: a practical alternative to free-response questions. tech learn med 1993; 5:107–15. doi: 10.1080/10401339309539601. 2. cronbach lj, shavelson rj. my current thoughts on coefficient alpha and successor procedures. educ psycol meas 2004; 64:391–418. doi: 10.1177/0013164404266386. 3. bloom bs, hastings jt, madaus gf. handbook on formative and summative evaluation of student learning. new york, usa: mcgraw-hill, 1971. p. 103. 4. skakun en, nanson em, kling s, taylor wc. a preliminary investigation of three types of multiple choice questions. med educ 1979; 13:91–6. doi: 10.1111/j.1365-2923.1979.tb00928.x. 5. skakun en, nanson em, taylor wc, kling s. an investigation of three types of multiple choice questions. annu conf res med educ 1977; 16:111–16. 6. hingorjo mr, jaleel f. analysis of one-best mcqs: the difficulty index, discrimination index and distractor efficiency. j pak med assoc 2012; 62:142–7. 7. tarrant m, ware j, mohammed am. an assessment of functioning and non-functioning distractors in multiple-choice questions: a descriptive analysis. bmc med educ 2009; 9:40. doi: 10.1186/1472-6920-9-40. 8. kelley tl. the selection of upper and lower groups for validation of test items. j educ psychol 1939; 30:17–24. doi: 10.1037/ h0057123. 9. mehta g, mokhasi v. item analysis of multiple choice questions: an assessment of the assessment tool. int j health sci res 2014; 4:197–202. https://doi.org/10.1080/10401339309539601 https://doi.org/10.1177/0013164404266386 https://doi.org/10.1111/j.1365-2923.1979.tb00928.x https://doi.org/10.1186/1472-6920-9-40 https://doi.org/10.1037/h0057123 https://doi.org/10.1037/h0057123 item analysis of multiple choice questions at the department of paediatrics, arabian gulf university, manama, bahrain e74 | squ medical journal, february 2018, volume 18, issue 1 10. bland jm, altman dg. cronbach’s alpha. bmj 1997; 314:572. doi: 10.1136/bmj.314.7080.572. 11. nunnally jc, bernstein ih. psychometric theory, 3rd ed. new york, usa: mcgraw-hill, 1994. 12. mitra nk, nagaraja hs, ponnudurai g, judson jp. the levels of difficulty and discrimination indices in type a multiple choice questions of pre-clinical semester 1 multidisciplinary summative tests. int ej sci med educ 2009; 3:2–7. 13. gajjar s, sharma r, kumar p, rana m. item and test analysis to identify quality multiple choice questions (mcqs) from an assessment of medical students of ahemdabad, gujarat. indian j community med 2014; 39:17–20. doi: 10.4103/09700218.126347. 14. karelia bn, pillai a, vegada bn. the levels of difficulty and discrimination indices and relationship between them in fourresponse type multiple choice questions of pharmacology summative tests of year ii m.b.b.s students. int ej sci med educ 2013; 7:41–6. 15. sharif m, rahimi sm, rajabi m, sayyah m. computer software application in item analysis of exams in a college of medicine. arpn j sci tech 2014; 4:565–9. 16. lin lc, tseng hm, wu sc. item analysis of the registered nurse license exam by nursing candidates from vocational nursing high schools in taiwan. proc natl sci counc repub china d 1999; 9:24–31. 17. kaur m, singla s, mahajan r. item analysis of in use multiple choice questions in pharmacology. int j appl basic med res 2016; 6:170–3. doi: 10.4103/2229-516x.186965. 18. mackenzie j. vague and ambiguous questions on multiplechoice exercises: the case for. educ philos theory 1994; 26:23–33. doi: 10.1111/j.1469-5812.1994.tb00198.x. 19. rodriguez mc. three options are optimal for multiple-choice items: a meta-analysis of 80 years of research. educ meas issues pract 2005; 24:3–13. doi: 10.1111/j.1745-3992.2005.00006.x. 20. tomak l, bek y. item analysis and evaluation in the examinations in the faculty of medicine at ondokuz mayis university. niger j clin pract 2015; 18:387–94. doi: 10.4103/1119-3077. 151720. 21. mukherjee p, lahiri sk. analysis of multiple choice questions (mcqs): item and test statistics from an assessment in a medical college of kolkata, west bengal. iosr j dent med sci 2015; 14:47–52. doi: 10.9790/0853-141264752. 22. nwadinigwe pi, naibi l. the number of options in a multiplechoice test item and the psychometric characteristics. j educ pract 2013; 4:189–96. 23. vegada b, shukla a, khilnani a, charan j, desai c. comparison between three option, four option and five option multiple choice question tests for quality parameters: a randomized study. indian j pharmacol 2016; 48:571–5. doi: 10.4103/02537613.190757. 24. tarrant m, ware j. a comparison of the psychometric properties of threeand four-option multiple-choice questions in nursing assessments. nurse educ today 2010; 30:539–43. doi: 10.1016/j.nedt.2009.11.002. 25. sim sm, rasiah ri. relationship between item difficulty and discrimination indices in true/false-type multiple choice questions of a para-clinical multidisciplinary paper. ann acad med singapore 2006; 35:67–71. https://doi.org/10.1136/bmj.314.7080.572 https://doi.org/10.4103/0970-0218.126347 https://doi.org/10.4103/0970-0218.126347 https://doi.org/10.4103/2229-516x.186965 https://doi.org/10.1111/j.1469-5812.1994.tb00198.x https://doi.org/10.1111/j.1745-3992.2005.00006.x https://doi.org/10.4103/1119-3077.151720 https://doi.org/10.4103/1119-3077.151720 https://doi.org/10.9790/0853-141264752 https://doi.org/10.4103/0253-7613.190757 https://doi.org/10.4103/0253-7613.190757 https://doi.org/10.1016/j.nedt.2009.11.002 leaving against medical advice (lama) is a term that describes the discharge of a patient from a hospital without the agreement of the treating doctor, usually at their own request or that of their caregivers in the case of paediatric patients. lama has been documented in numerous healthcare settings and accounts for 1–26% of the discharges of general medical patients worldwide.1–4 when patients choose to leave the hospital before the recommendation of a treating physician, the consequences can involve risks associated with inadequately treated medical conditions, the need for readmission and sometimes loss of life.4–7 in many lama cases, a patient is not medically fit to be discharged; however, the treating team are not able to oppose the wishes of a patient or their caregiver. feeling better or personal/financial obligations are some of the reasons for lama reported in the literature.8 generally, once a patient or their family insists on lama, a form is completed which must be signed by both the patient/ caregiver and the responsible physician. the reason for the discharge is usually then recorded in the hospital’s electronic system by the physician. the signed lama form exists to protect the treating team and their medical institution from legal liability; good clinical practice and thorough documentation remain the best legal protection in cases of lama.9 in oman, hospital staff can obtain an order from the general prosecutor to refuse to discharge children from hospital before the completion of treatment.10 for children, the problem of lama has been addressed in many studies around the world but rarely in countries in the middle eastern region.1–3 the intensive care unit, royal hospital, muscat, oman *corresponding author e-mail: mhghafri@hotmail.com مدى انتشار واألسباب اليت تؤدي إىل مغادرة املرضى ألجنحة طب األطفال ضد املشورة الطبية يف عمان حممد الغ�فري، عبداهلل البلو�شي، اأحمد الق��شمي abstract: the objective of this study was to determine the prevalence of and reasons for patients leaving against medical advice (lama) in a paediatric setting in oman. this retrospective study was carried out between january 2007 and december 2009 and assessed patients who left the paediatric wards at the royal hospital, muscat, oman, against medical advice. of 11,482 regular discharges, there were 183 cases of lama (prevalence: 1.6%). dissatisfaction with treatment and a desire to seek a second opinion were collectively the most cited reasons for lama according to data from the hospital’s electronic system (27.9%) and telephone conversations with patients’ parents (55.0%). no reasons for lama were documented in the hospital’s electronic system for 109 patients (59.6%). the low observed prevalence of lama suggests good medical practice at the royal hospital. this study indicates the need for thorough documentation of all lama cases to ensure the availability of high-quality data for healthcare workers involved in preventing lama. keywords: children; patient discharge; documentation; oman. من )lama( الطبية امل�شورة �شد املر�شى مغ�درة وراء الك�منة واالأ�شب�ب االإنت�ش�ر مدى حتديد هو الدرا�شة هذه من الهدف امللخ�ص: اأجنحة طب االأطف�ل يف �شلطنة عم�ن. هذه درا�شة ا�شتع�دية اأجريت بني ين�ير 2007 ودي�شمرب 2009 بتقييم املر�شى الذين غ�دروا اأق�ش�م االأطف�ل يف امل�شت�شفى ال�شلط�ين، م�شقط، عم�ن �شد امل�شورة الطبية. من 11،482 ح�لة مغ�درة ع�دية، ك�نت هن�ك 183 ح�لة lama )مدى االنت�ش�ر: %1.6(. عدم الر�ش� عن العالج والرغبة يف طلب راأي ث�ن جمتمعني ك�ن� اأكرث االأ�شب�ب lama ح�شب بي�ن�ت نظ�م امل�شت�شفى االلكرتوين امل�شت�شفى نظ�م يف lama اأ�شب�ب اأي توثيق يتم مل .)55.0%( املر�شى اآب�ء مع اله�تفية واملح�دث�ت )27.9%( االلكرتوين هذه وت�شري ال�شلط�ين. امل�شت�شفى يف اجليدة الطبية املم�ر�شة على تدل lamaل املالحظ االنت�ش�ر اإنخف��ص .)59.6%( مري�ش� ل109 الدرا�شة اإىل احل�جة اإىل توثيقوايف جلميع ح�الت الlama ل�شم�ن توافر البي�ن�ت ذات اجلودة الع�لية للم�ش�ركني يف الرع�ية ال�شحية .lama ال�ش�عني ملنع مفتاح الكلمات: االأطف�ل؛ تخريج املري�ص؛ التوثيق؛ عم�ن. prevalence of and reasons for patients leaving against medical advice from paediatric wards in oman *mohamed al-ghafri, abdullah al-bulushi, ahmed al-qasmi brief communication sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e74–77, epub. 2 feb 16 submitted 28 apr 15 revisions req. 10 jun, 30 jul & 3 sep 15; revisions recd. 6 jul, 3 aug & 7 sep 15 accepted 1 oct 15 doi: 10.18295/squmj.2016.16.01.013 mohamed al-ghafri, abdullah al-bulushi and ahmed al-qasmi brief communication | e75 objectives of this study were to determine the prevalence of lama among children from the paediatric wards at the royal hospital in muscat, oman, and to examine the characteristics of these patients and the reasons for their discharge against medical advice. the royal hospital is a tertiary teaching hospital which admits patients from all regions of oman; it has three general paediatric and subspecialty wards. methods this retrospective study was conducted from january 2007 to december 2009. clinical and patient data were collected from the electronic hospital information system. manually-filed lama forms were also reviewed in order to obtain additional information. the age of the patients, time of lama (either during official working hours from 07:30 to 14:30 or during on-call hours from 14:30 to 07:30 the next day, weekdays or at the weekend), length of hospital stay and presence of documented discussion with caregivers regarding lama were reviewed. data on the designated counselling physician (i.e. consultant, registrar, resident or intern), the presence or absence of a follow-up appointment and the reasons for lama if mentioned in the discharge notes or the lama form were also collected. reasons for lama were categorised as dissatisfaction with treatment, the desire to seek a second opinion and social and/or financial reasons. the social reasons included unavailability of a caregiver for other children at home or other personal issues that were not disclosed by the patients’ parents. the patients’ diagnoses on discharge were also recorded and their diagnoses were categorised into purely acute conditions versus conditions attributed to pre-existing comorbidities (chronic conditions). in cases where the reason for lama was missing, the families were contacted by telephone in order to ascertain the reason they discharged their child against medical advice. data processing and analysis were carried out using the statistical package for the social sciences (spss), version 18 (ibm corp., chicago, illinois, usa). in addition to descriptive statistics, hypothesis testing was carried out using the student’s t-test to make comparisons and pearson’s chi-squared analysis to test for independence. pearson’s correlation coefficient was utilised to examine the relationships between relevant variables. the probability of a type two error was set at 5%. ethical approval for this study was obtained from the medical ethics & scientific research committee of the royal hospital (mesrc #6). results of the 11,482 discharges from the hospital’s paediatric wards during the study period, 183 children left the hospital against medical advice, resulting in a lama prevalence of 1.6%. a total of 74 patients (40.4%) were <1 year old, 75 patients (41.0%) were 1–5 years old and 34 patients (18.6%) were >5 years old. the length of stay ranged from 1–34 days with a mean of four days; 58 patients (31.7%) stayed in the hospital for one day, 73 (39.9%) stayed 2–5 days and 52 patients (28.4%) stayed for >5 days. in terms of diagnosis at discharge, 81 patients (44.3%) had only acute conditions, while 102 patients (55.7%) had chronic conditions. there was no statistically significant difference in the frequency of lama between these groups. counselling on lama was undertaken by physicians for the families of 172 patients (94.0%); the counselling designation was missing in 11 cases (6.0%). of those who underwent counselling, 29 families (16.9%) being counselled by consultants, 98 (57.0%) by registrars, 27 (15.7%) by residents and 18 (10.5%) by interns. a total of 160 patients (87.4%) were discharged during official working hours while the remaining 23 patients (12.6%) were discharged during. only 39 table 1: reasons for leaving against medical advice among paediatric patients in the royal hospital, muscat, oman, according to hospital electronic records (n = 183) reason for lama n (%) dissatisfaction with treatment/care 24 (13.1) social issues 20 (10.9) seeking a second opinion 27 (14.8) financial issues 3 (1.6) no documentation 109 (59.6) lama = leaving against medical advice. table 2: reasons for leaving against medical advice among paediatric patients in the royal hospital, muscat, oman, according to follow-up telephone interviews (n = 109) reasons for lama n (%) dissatisfaction with treatment/care 17 (15.6) social issues 36 (33.0) seeking a second opinion 43 (39.4) financial issues 3 (2.8) no reply 10 (9.2) lama = leaving against medical advice. prevalence of and reasons for patients leaving against medical advice from paediatric wards in oman e76 | squ medical journal, february 2016, volume 16, issue 1 patients (21.3%) were discharged in the morning while 144 (78.7%) were discharged during evening hours. follow-up appointments were made for 153 patients (83.6%) while no appointments were made for the remaining 30 patients (16.4%). according to the hospital’s electronic system, a desire to seek a second opinion and dissatisfaction with treatment/care were the most cited reasons for lama (14.8% and 13.1%, respectively) [table 1]. a total of 109 patients (59.6%) had no electronic documentation regarding their reasons for lama. the parents of these patients were contacted 1–4 years after lama. table 2 shows that seeking a second opinion followed by social issues were the most cited reasons for lama among these 109 patients (39.4% and 33.0%, respectively). discussion in this study, the lama prevalence was found to conform to reported rates in the literature; okoromah et al. and hong et al. reported a lama prevalence of 1.2% and 2% in nigeria and singapore, respectively.1,11 in contrast, al-sadoon et al. and abdulateef et al. reported a lama prevalence of only 0.32% and 0.11% in oman and qatar, respectively.12,13 the setting of the latter study was different from other studies as it was conducted in a paediatric emergency centre within the ideal observation period of 48 hours.13 al-turkistani reported a lama prevalence of 1.6% in a neonatal intensive care unit at a university hospital in saudi arabia.14 abd el malek et al. noted a surprisingly high prevalence of lama (8.49%) in a recent study carried out in kuwait.15 in the current study, lama was more common for infants under one year of age; a similar finding was reported by al-sadoon et al. (n = 24; 63.2%).12 comparable findings were also reported in other studies which could be partly attributed to the large number of cases admitted from this age group.11,16 in addition, subtle clinical presentations among infants can put them at a higher risk of being admitted for further care. the mean length of hospital stay in the present study was slightly longer compared to that reported by a previous study (3.1 days).4 moreover, almost a third of patients in the current study stayed for only one day. al-sadoon et al. reported a similar finding in their study (n = 15; 39.5%).12 this finding might be attributed to non-critical reasons for admission, including diagnostic uncertainty. in addition, a short observation time in the emergency room along with the unavailability of a short-stay ward may have contributed to the lama cases that occurred during the first 24 hours after admission. interestingly, the majority of patients were discharged during weekdays. on the other hand, abd el malek et al. reported a higher number of lama cases during the weekend; this was attributed to overcrowding and staff shortages during weekends.15 the majority of cases reviewed in the current study had poor documentation with regards to lama data, which conforms to reports from other studies.12,17 al-sadoon et al. reported poor documentation in 57.9% of lama cases.12 this finding illustrates the need for thorough recordkeeping in all lama cases to ensure that physicians, researchers, decision-makers and healthcare planners have the information they require in order to reduce the prevalence of lama. according to the hospital electronic records assessed in the current study, dissatisfaction with treatment and the desire to seek a second opinion were the most cited reasons for lama; these findings are similar to those of several other studies on lama.18,19 dissatisfaction with treatment might be attributed to a parent’s unwillingness for their child’s case to be studied for teaching purposes or due to frequent blood sampling or prolonged hospitalisation. these reasons were also the most commonly cited during telephone interviews with the parents in cases without electronic documentation. social reasons for lama were reported by a third of the parents, which could indicate a lack of willingness by the families to fully disclose their reasons for lama during the telephone interviews. these reasons might include a lack of care for other children at home or work commitments. since medical services are free for omani citizens, financial reasons represented a very small proportion of lama cases. as such, financial reasons were only reported by expatriate patients without medical insurance. although it was not statistically significant, a greater proportion of the study population with chronic medical problems were discharged against medical advice than those with non-chronic conditions. the higher frequency of lama among this group could be attributed to parents of children with chronic conditions being accustomed to caring for them at home with oral medications. the majority of lama cases in the current study occurred during on-call hours. this was expected since, in oman, fathers are anecdotally the ones to decide whether to discharge their children against medical advice, and the majority of fathers arrive at the hospital in the evening after official working hours. another reason for this result could be the absence of in-house consultants after normal daytime working hours who could potentially counsel patients’ parents in order to minimise lama cases. interestingly, few of the parents who chose to mohamed al-ghafri, abdullah al-bulushi and ahmed al-qasmi brief communication | e77 discharge their children in the current study were counselled by consultants. this strongly suggests the importance of proper communication between physicians and parents.20 limitations in the current study include a lack of a control group to compare illnesses between patients who were discharged with the recommendation of the physician and those who left against medical advice; a lack of follow-up of the discharged children; unavailability of documentation in many cases; the interval between the telephone interviews and the lama case which may have adversely affected the results; and a relatively small sample size leading to an inability to generalise the results. further studies on cases of paediatric lama are needed, particularly multi-centre studies that include a comparison of outcomes between lama cases and those with usual discharge decisions. conclusion this study sought to identify the reasons for lama among paediatric patients at the royal hospital. the results indicate that more effective communication between the treating team and families, along with early interventions, are needed in order to minimise lama. there is a need for thorough documentation of all lama cases to ensure the availability of highquality data for physicians, researchers, decisionmakers and healthcare planners. further studies are recommended to assess the outcomes for children who leave paediatric wards before the completion of their treatment. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. okoromah cn, egri-qkwaji mt. profile of and control measures for paediatric discharges against medical advice. niger postgrad med j 2004; 11:21–5. 2. ibrahim sa, kwoh ck, krishnan e. factors associated with patients who leave acute-care hospitals against medical advice. am j public health 2007; 97:2204–8. doi: 10.2105/ ajph.2006.100164. 3. mohseni saravi b, reza zadeh e, siamian h, yahghoobian m. discharge against medical advice in the pediatric wards in boo-ali sina hospital, sari, iran 2010. acta inform med 2013; 21:253–6. doi: 10.5455/aim.2013.21.253-256. 4. onyiriuka an. discharge of hospitalized under-fives against medical advice in benin city, nigeria. niger j clin pract 2007; 10:200–4. 5. weingart sn, davis rb, phillips rs. patients discharged against medical advice from a general medicine service. j gen intern med 1998; 13:568–71. doi: 10.1046/j.1525-1497.1998.00169.x. 6. hwang sw, li j, gupta r, chien v, martin re. what happens to patients who leave hospital against medical advice? cmaj 2003; 168:417–20. 7. aliyu zy. discharge against medical advice: sociodemographic, clinical and financial perspectives. int j clin pract 2002; 56:325–7. 8. roodpeyma s, hoseyni sae. discharge of children from hospital against medical advice. world j pediatr 2010; 6:353–6. doi: 10.1007/s12519-010-0202-3. 9. devitt pj, devitt ac, dewan m. an examination of whether discharging patients against medical advice protects physicians from malpractice charges. psychiatr serv 2000; 51:899–902. doi: 10.1176/appi.ps.51.7.899. 10. oman ministry of legal affairs. royal decree no. 22/2014 issuing the children's act. from: www.mola.gov.om/ officalgazette.aspx?page=4 accessed: sep 2015. 11. hong le, ling fc. discharges of children from hospital against medical advice. j singapore paediatr soc 1992; 34:34–8. 12. al-sadoon m, al-shamousi k. discharge against medical advice among children in oman: a university hospital experience. sultan qaboos univ med j 2013; 13:534–8. doi: 10.12816/0003312. 13. abdulateef h, al amri m, sayyed rf, al ansari k, lariego g, al hammadi z. discharge against medical advice in a pediatric emergency center in the state of qatar. j emerg med trauma acute care 2012; 2012:4. doi: 10.5339/jemtac.2012.4. 14. al-turkistani hk. discharge against medical advice from neonatal intensive care unit: 10 years’ experience at a university hospital. j fam comm med 2013; 20:113–15. doi: 10.4103/22308229.114774. 15. abd el malek v, alexander s, al anezi f. discharge against medical advice among children admitted into pediatric wards at al-jahra hospital, kuwait. kuwait med j 2014; 46:28–31. 16. nathoo kj, bannerman ch, pirie dj. pattern of admission to the paediatric medical wards (1995 to 1996) at harare hospital, zimbabwe. cent afr j med 1999; 45:258–63. 17. reinke da, walker m, boslaugh s, hodge d 3rd. predictors of pediatric emergency patients discharged against medical advice. clin pediatr (phila) 2009; 48:263–70. doi: 10.1177 /0009922808323109. 18. onukwugha e, saunders e, mullins cd, pradel fg, zuckerman m, weir mr. reasons for discharges against medical advice: a qualitative study. qual saf health care 2010; 19:420–4. doi: 10.1136/bmjopen-2012-000902. 19. macrohon bc. pediatrician’s perspectives on discharge against medical advice (dama) among pediatric patients: a qualitative study. bmc pediatr 2012; 12:75. doi: 10.1186/1471-2431-12-75. 20. targum sd, capodanno ae, hoffman ha, foudraine c. an intervention to reduce the rate of hospital discharges against medical advice. am j psychiatry 1982; 139:657–9. doi: 10.1176/ ajp.139.5.657. http://dx.doi.org/10.2105/ajph.2006.100164 http://dx.doi.org/10.2105/ajph.2006.100164 http://dx.doi.org/10.5455/aim.2013.21.253-256 http://dx.doi.org/10.1046/j.1525-1497.1998.00169.x http://dx.doi.org/10.1007/s12519-010-0202-3 http://dx.doi.org/10.1176/appi.ps.51.7.899 http://dx.doi.org/10.12816/0003312 http://dx.doi.org/10.5339/jemtac.2012.4 http://dx.doi.org/10.4103/2230-8229.114774 http://dx.doi.org/10.4103/2230-8229.114774 http://dx.doi.org/10.1177/0009922808323109 http://dx.doi.org/10.1177/0009922808323109 http://dx.doi.org/10.1136/bmjopen-2012-000902 http://dx.doi.org/10.1186/1471-2431-12-75 http://dx.doi.org/10.1176/ajp.139.5.657 http://dx.doi.org/10.1176/ajp.139.5.657 اليات تلف الكبد اليت يسببها مرض السكري دور األكسدة وااللتهابات �ستي بلقي�س بودين، نفي�سة نظرة، جمال الدين حممد، زرينطي عبد احلليم abstract: diabetes mellitus is a non-communicable disease that occurs in both developed and developing countries. this metabolic disease affects all systems in the body, including the liver. hyperglycaemia, mainly caused by insulin resistance, affects the metabolism of lipids, carbohydrates and proteins and can lead to nonalcoholic fatty liver disease, which can further progress to non-alcoholic steatohepatitis, cirrhosis and, finally, hepatocellular carcinomas. the underlying mechanism of diabetes that contributes to liver damage is the combination of increased oxidative stress and an aberrant inflammatory response; this activates the transcription of pro-apoptotic genes and damages hepatocytes. significant involvement of pro-inflammatory cytokines— including interleukin (il)-1β, il-6 and tumour necrosis factor-α—exacerbates the accumulation of oxidative damage products in the liver, such as malondialdehyde, fluorescent pigments and conjugated dienes. this review summarises the biochemical, histological and macromolecular changes that contribute to oxidative liver damage among diabetic individuals. keywords: diabetes mellitus; liver diseases; inflammation; oxidative stress. اأجهزة جميع على الأي�سي املر�س هذا يوؤثر والنامية. املتقدمة البلدان من كل يف يحدث معدي غري مر�س هو ال�سكري داء امللخ�ص: واأع�ساء اجل�سم، مبا يف ذلك الكبد. يوؤثر ارتفاع ال�سكر يف الدم، الناجم اأ�سا�سا عن مقاومة الأن�سولني، على عملية التمثيل الغذائي للدهون والكربوهيدرات والربوتينات وميكن اأن يوؤدي اإىل اأمرا�س الكبد الدهنية غري الكحولية، والتي ميكن أن تتطور للتهاب الكبد الدهني غري الكحوليو تليف الكبد و �رسطان اخلاليا الكبدية. إن الآلية الكامنة وراء مر�س ال�سكري الذي ي�ساهم يف تلف الكبد هي مزيج من الإجهاد التاأك�سدي وال�ستجابة اللتهابية ال�ساذة، مما ين�سط الن�سخ من اجلينات املوالية ملوت اخلاليا املربمج وتدمريخاليا الكبد. ويوؤدي وجود كميات من ال�سيتوكينات، مبا يف ذلك انرتلوكني il -1β ،il-6 وعامل نخر الورم α-إيل تراكم املنتجات املوؤك�سدة ال�ساره يف الكبد، واجلزيئية الن�سيجية البيوكيميائية، التغريات ال�ستعرا�س هذا يلخ�س املرتافقة. والداينات الفلور�سنت واأ�سباغ مالونديالدهايد، مثل التي ت�ساهم يف اأك�سدة وتلف الكبد بني مر�سى ال�سكري. كلمات مفتاحية: داء ال�سكري؛ اأمرا�س الكبد؛ اإللتهاب؛ الإجهاد التاأك�سدي. mechanisms of diabetes-induced liver damage the role of oxidative stress and inflammation jamaludin mohamed, *nazratun nafizah a. h., zariyantey a. h., budin s. b. review sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 132–141, epub. 15 may 16 submitted 28 sep 15 revisions req. 18 nov 15 & 24 jan 16; revisions recd. 18 dec 15 & 16 feb 16 accepted 25 feb 16 doi: 10.18295/squmj.2016.16.02.002 diabetes mellitus (dm) is a majorglobal public health problem with an escalating incidence and prevalence, particularly in developing and newly industrialised countries.1 concern regarding this chronic disease is focused on serious dm-related complications which can affect multiple vital organ systems, thereby leading to more severe and irreversible pathological conditions such as nephropathy, retinopathy, vasculopathy, neuropathy and cardiovascular diseases, as well as hepatopathy.2 research indicates that dm is associated with a number of liver abnormalities, such as abnormal glycogen deposition, non-alcoholic fatty liver disease (nafld), fibrosis, cirrhosis, hepatocellular carcinomas (hccs), abnormal elevated hepatic enzymes, acute liver disease and viral hepatitis.3,4 additionally, an excessive accumulation of fat in the liver may worsen insulin resistance and lead to severe metabolic dysfunction. a fatty liver and hyperglycaemia can destroy the hepatocytes and contribute to increased morbidity and mortality among diabetic patients.3 however, this subject requires further exploration and elucidation from various perspectives in order to promote understanding of the entire process involved. this review therefore analyses the various dm mechanisms which induce liver damage through the formation of a fatty liver. in addition, pathways of the histopathological and macromolecular changes that result in this complication are discussed. progression of liver damage in diabetes mellitus several critical pathways have been identified as causing liver damage in diabetic patients. insulin resistance, the main cause of hyperglycaemia and department of biomedical sciences, faculty of health sciences, university kebangsaan malaysia, kuala lumpur, malaysia *corresponding author e-mail: nazratunnafizah@gmail.com jamaludin mohamed, nazratun nafizah a. h., zariyantey a. h. and budin s. b. review | e133 compensatory hyperinsulinaemia, is the predominant causative factor.5–7 as a collection of insulin-sensitive tissues, the liver is among the primary organs susceptible to the effects of hyperglycaemia-induced oxidative stress, which may lead to liver tissue injury.7–9 this is followed by derangement of protein, carbohydrate and lipid metabolism, thereby leading to increased oxidative stress and further triggering the inflammatory cascade.6,8,9 both oxidative stress and inflammatory responses act as damaging agents in aggravating the pathological condition of dm.4,10 in some cases, dm causes excessive accumulation of fat cells in the liver resulting in a fatty liver and, consequently, nafld. subsequently, 2–3% of nafld patients experience hepatic inflammation, necrosis and fibrosis, which are symptoms of a condition known as non-alcoholic steatohepatitis (nash).2,10 injured or fibrotic livers will then become cirrhotic, form hccs and, eventually, go into liver failure [figure 1].10–12 diagnosis of liver damage h i s t o l o g i c a l a n d u lt r a s t r u c tu r a l c h a n g e s studies have revealed the prominent histopathological changes in the livers of patients with dm.2,13 during the initiation of steatosis, the accumulation of fat in the vesicles displaces the cytoplasm of the liver. this condition is known as microvesicular steatosis, which then progresses to macrovesicular steatosis when excess lipids distort the nucleus. besides glycogenated nuclei, other prominent features of steatosis include mild lymphocytic, neutrophilic and other inflammatory infiltrates. steatosis usually takes place in acinar zone iii.2,3 these features progress and worsen with steatohepatitis.3,7,14,15 steatohepatitis and nash can be diagnosed by the presence of hepatocellular steatosis, lobular inflammation and varying degrees of pericellular, perisinusoidal and periportal fibrosis, figure 1: progression of liver damage. in diabetes mellitus, insulin resistance and hyperinsulinaemia cause non-alcoholic fatty liver disease and progress to non-alcoholic steatohepatitis (nash) which manifests as inflammation and necrosis. prolonged nash will lead to liver fibrosis, known as cirrhosis, and finally hepatocellular carcinomas and end-stage liver disease. nash = non-alcoholic steatohepatitis; pt = portal triad; cv = central vein. reproduced with permission from cohen jc, horton jd, hobbs hh. human fatty liver disease: old questions and new insights.12 mechanisms of diabetes-induced liver damage the role of oxidative stress and inflammation e134 | squ medical journal, may 2016, volume 16, issue 2 including cirrhosis.2,4 other dominant features of steatohepatitis besides glycogenated nuclei are hepatocyte ballooning, varying degrees of hepatocyte necrosis and the presence of small, sparse and inconspicuous mallory bodies. degenerative changes are characterised by the vacuolation of hepatocytes in the centrizonal area of the cell and a discrepancy in the size of the nuclear and dilated sinusoidal spaces.2,4 cirrhosis has three major histological features: (1) the formation of macroand/or micronodular hepatocytes; (2) bridging of the fibrous septa; and (3) the disruption of the entire liver architecture. under these conditions, steatosis and necroinflammatory mechanisms are difficult to observe.15–18 ultrastructurally, the rough endoplasmic reticulum is significantly reduced in diabetic patients in comparison with the smooth endoplasmic reticulum.9 moreover, dm causes a marked increase in mitochondrial volume fraction with highly diminished densities of mitochondrial cristae, pyknotic nuclei with damaged nuclear membranes and the extension of the perinuclear area [figure 2].16–19 in addition, increased lipid accumulation and decreased glycogen content are also seen in the liver cells.16–19 b i o c h e m i c a l c h a n g e s the spectrum of biochemical changes that typically occur in dm resemble those of liver diseases, from the secretion of abnormal liver enzymes to the development of hccs or even end-stage liver failure.17,20 the initial and most important indicators in assessing liver injury are levels of plasma alanine transaminase (alt), aspartate transaminase (ast), alkaline phosphatase (alp) and γ-glutamyl transpeptidase (ggt).13,21,22 research has shown an increase of ast and alt in 50–80% of nafld patients; alt levels were higher than ast levels for nafld patients, while patients with alcoholic fatty livers had higher ast than alt levels.2 an increment in alt levels may indicate fatty changes in the liver regardless of the presence of dm. furthermore, serum alt concentrations have been found to correlate with hepatic insulin resistance and later decline in hepatic insulin sensitivity compared with ast and ggt levels, which showed no connection with hepatic insulin.22 however, while alp and ggt levels may be elevated, serum albumin and bilirubin levels are not.2,18,21 hepatocytes work exclusively to synthesise serum albumin, but are not a good indicator of acute or mild hepatic dysfunction.13 increased plasma triglyceride and low-density lipoprotein levels and decreased high-density lipo protein levels are common characteristics of dyslipidaemia and can be observed in diabetic and steatosis patients.13,15 this is due to insulin resistance-related lipolysis which increases the circulating fatty acids taken up by the liver as an energy source. the accumulation of fatty acids disturbs the β-oxidation system in the hepatic mitochondria and leads to further infiltration of fats in the liver. the strong association between insulin resistance and steatosis makes dm an independent predictor for cirrhosis and hccs among steatosis patients.13,15,17 o t h e r c h a n g e s the medical history and physical examination of a patient can reveal other laboratory abnormalities associated with liver damage, including hypoalbuminemia, prolonged prothrombin times and high levels of ferritin.13,23 in addition, a radiological assessment may identify fats through increased echogenicity on ultrasonography, hypodense fat on non-contrast computed tomography and fat content on magnetic resonance imaging.23 mechanisms of damage the liver plays a vital role in regulating glucose levels in physiological and pathological states such as dm. in type 2 dm, insulin resistance in the liver will cause hyperglycaemia and further distortion of glucose metabolism. even under severe hyperglycaemic conditions, the liver does not detect the availability of glucose and produces more via the combined action of a few enzymes such as glucose-6-phosphate dehydrogenase, fructose-1,6-diphosphate, hexokinase and glucokinase.2,13 the liver also regulates glucose homeostasis by modulating the expression of various figure 2a&b: electron micrographs of a (a) healthy and (b) diabetic liver. note the difference in appearance between the hepatocyte nuclei (nu), organelles, mitochondria (m) and disse’s space (arrows). in the diabetic liver, there is accumulation of homogenous substances in the nuclear chromatin (*), reduction in the number of organelles, loss of mitochondrial cristae (▲) and granular degeneration (►) in the hepatocytes. reproduced with permission from lucchesi, an, cassettari ln, spadella ct. alloxan-induced diabetes causes morphological and ultrastructural changes in rat liver that resemble the natural history of chronic fatty liver disease in humans.19 jamaludin mohamed, nazratun nafizah a. h., zariyantey a. h. and budin s. b. review | e135 kinds of genes encoding secretory proteins (i.e. hepatokines).24,25 different types of hepatokines via different pathways activate either positive or negative feedback mechanisms to control the metabolism process.24 three dominant hepatokines exist: fetuin-a, betatrophin/angiopoietin-like protein 8 (angptl8) and fibroblast growth factor 21 (fgf21). fetuin-a results in increased inflammation and insulin resistance by inhibiting the insulin receptor tyrosine kinase in skeletal muscle tissue and hepatocytes.24 in contrast, angptl8 is known for its proliferation action on the beta cells of the pancreas while fgf21 is recognised as an insulin-sensitising hormone.25 these hepatokines significantly exacerbate the diabetic condition, especially in type 2 dm, by regulating subclinical inflammation.24 according to certain studies, the aberrant signal which promotes glucose production in the liver during dm supposedly also enhances fatty acid oxidation due to a lack of fuel demand.2,13 however, other research has found that the liver stops oxidising fatty acids and uses them instead to synthesise triglycerides which then accumulate abnormally in the liver.2,13,21 in type 1 dm, insulin deficiency upregulates hormone-sensitive lipase in the adipose tissues, subsequently leading to increased lipolysis and the circulation of free fatty acids, which subsequently accumulate in the liver. these processes enhance the hepatic uptake of very-lowdensity lipoproteins and synthesis of triglycerides.2,13,14 concurrently, elevated glucagon levels inhibit hepatic triglyceride output. therefore, accumulation of fat in the liver may be due to an imbalance in the uptake, synthesis, export and oxidation of free fatty acids in the liver.12,14,15 aside from abnormalities in lipoprotein metabolism, an accumulation of hepatic fat in dm may be due to either hyperglycaemia-induced activation of the transcription factor carbohydrate-responsive element-binding protein and sterol regulatory elementbinding protein 1c, the upregulation of the glucose transporter 2 protein with subsequent intrahepatic fat synthesis or a combination of these mechanisms.12 it is worth noting that an accumulation of adipocytes in the liver will cause hepatic insulin resistance.7 environmental conditions and genetic traits also contribute to the phenotypic expression of insulin resistance; these factors act in combination with hyperinsulinaemia to increase fat mass and lipolysis and elevate the level of free fatty acids. at the same time, insulin signalling is reduced in a dosedependent manner, eventually increasing hepatic glucose and lipotoxicity.7 however, modifications of adipocytokine secretion in hyperinsulinaemia occur by triggering gene expression of pro-inflammatory cytokines, such as leptin and tumour necrosis factor-α (tnf-α); these modifications are not only involved in the development of insulin resistance but also interfere with insulin signalling, thereby worsening dm.15 an increase in adipocytokines may contribute to mitochondrial oxidative stress and trigger the formation of free radicals and peroxisome.26 an increase in mitochondrial oxidative stress will also cause dna mutation damage and trigger a series of deleterious effects on the mitochondrial respiratory chain by producing reactive oxygen species (ros). this vicious cycle will escalate exponentially to an incompatible level, which will be countered by normal physiological feedback and thereby lead to liver damage.26,27 hyperinsulinaemia may downregulate adiponectin, leading to hepatic lipogenesis and further decreasing free fatty acid oxidation.15 thus, hyperinsulinaemia may act as a major contributor to the progression of liver damage.7 inflamed and necrotic hepatocytes and adipocytokines will release several types of chemical mediators which will activate the stellate cells to produce connective tissue growth factor and collagen and cause an accumufigure 3: diagram showing the mechanism of liver damage in diabetes mellitus. insulin resistance causes peripheral adipocytes to undergo lipolysis. free fatty acids are then released to the bloodstream and eventually accumulate in the liver. at the same time, adipocytokines release tumour necrosis factor-α and leptin, worsening the hepatocyte damage by increasing oxidative stress in the mitochondria. the combined action of mitochondrial oxidative stress, hyperinsulinaemia and hyperglycaemia produce free radicals which in turn induce inflammation and cellular necrosis. tissue inflammation stimulates the hepatic stellate cells to produce collagen, leading to fibrosis, cirrhosis and, finally, hepatocellular carcinomas. dm = diabetes mellitus; ffa = free fatty acids; tnf = tumour necrosis factor; dnl = de novo lipogenesis; vldl = very-lowdensity lipoprotein. mechanisms of diabetes-induced liver damage the role of oxidative stress and inflammation e136 | squ medical journal, may 2016, volume 16, issue 2 lation in the extracellular matrix, thereby favouring fibrosis [figure 3].26 in addition to the aforementioned factors, the expression of certain genes also influences the progression and severity of dm. for example, the most important cytochrome p450 member—cytochrome p450 family 2 subfamily e polypeptide 1 (cyp2e1)—is expressed at a higher concentration in the liver than in other organs. indeed, the activity and expression of this protein increases in obese individuals and for those with nafld or nash.28 under these conditions, excessive metabolism of polyunsaturated fatty acids by cyp2e1 may yield cytotoxic products harmful to the liver. furthermore, cyp2e1 is also involved in mitochondrial respiratory chain-induced ros generation, which contributes to the increase in oxidative stress, thereby favouring the progression of nafld to nash.28 oxidative stress-mediated damage oxidative stress is defined as an imbalance in the oxidant-to-antioxidant ratio, causing the generation of free radicals.9 the liver is the main detoxification organ of the body and plays an important role in controlling normal glucose homeostasis.6 the production of oxidants such as ros-like superoxide anions, hydrogen peroxide and hydroxyl radicals by activated kupffer cells has been identified as central to hepatic injuries.29 kupffer cells, also known as hepatic macrophages, are one type of nonparenchymal cell that help maintain the integrity of liver cells. however, these phagocytic cells are also susceptible to the effects of oxidative stress produced by the surrounding cells and its own immune reactions.2,13 excessive ros production results in several deleterious events, including an irreversible oxidative modification of lipids, proteins and carbohydrates.28,30 in addition, it will induce apoptosis in hepatocytes and the release of inflammatory cytokines, thereby increasing the expression of adhesion molecules and the infiltration of leukocytes. a combination of all of these processes causes massive tissue destruction in the liver.16,29 however, the liver is equipped with potent antioxidants—such as superoxide dismutase (sod), catalase (cat) and the glutathione (gsh) enzyme family, including glutathione-s-transferases (gsts) and glutathione peroxidases (gpxs)—so as not only to neutralise free radicals but also to protect the liver cells from oxidative damage.30,31 previous research has proven that a decrease in sod and cat activities within a hyperglycaemic state leads to an increase in ros, which eventually contributes to oxidationinduced liver damage.8,30,31 the liver also plays a pivotal role in the homeostasis of the gsh enzyme family. different cell components such as the endoplasmic reticulum, mitochondria and nucleus consist of separate pools of gsh. among these, mitochondrial gsh is more essential than cytoplasmic gsh in maintaining cell viability.31 acting as the first line of defence as an endogenous antioxidant, the oxidation process takes place in the thiol group of gsh.31 reduced levels of gsh in diabetic rat livers have been associated with depletion of decreased gst, gpx and glutathione reductase activity and with the accumulation of oxidative stress products, such as advanced glycation end-products (ages), protein oxidation products (pops) and lipid peroxidation (lpo).32–34 however, measuring certain redox couples in cells—such as oxidised nicotinamide adenine dinucleotide (nad)/reduced nad and oxidised nad phosphate (nadp)/reduced nadp—is difficult; as a result, the gsh-to-glutathione disulphide ratio in the liver is considered representative of a redox state.31 o x i d at i o n p r o d u c t s carbohydrates ages are complex heterogeneous molecules characterised by fluorescence, a brown colour and crosslinking reactions.33–35 several distinct compounds exist such as pyrraline, pentosidine, imidazolone, n-carboxymethyllysine and methylglyoxal. the latter can yield irreversible ages which impair insulin signalling by forming a complex with insulin receptor substrate, thereby leading to conformational changes that affect the tyrosine phosphorylation and the docking function of these proteins.32 the formation of ages is closely related to the degree and duration of hyperglycaemia, the half-life of the protein and the permeability of the tissue to free glucose.32,34 haemoglobin a1c is a product of glycosylated haemoglobin and has been widely used as an indicator of long-term elevated plasma glucose levels.33–35 zuwała-jagiełło et al. proved that the liver plays a major role in the clearance of plasma ages, which accumulate heavily in conditions of chronic liver damage.36 moreover, age levels have been found to correlate positively with the severity of liver damage and decrease markedly after liver transplantation.36,37 however, hepatic stellate cells and myofibroblasts responsible for fibrogenesis in chronic liver disease will express the receptor for age (rage). the binding of age with rage will injure the structure of the extracellular matrix and induce a toxic effect by activating nuclear factor-kappa b (nf-κb) to stimulate jamaludin mohamed, nazratun nafizah a. h., zariyantey a. h. and budin s. b. review | e137 the transcription of genes for cytokines and growth factors, further increasing expression of adhesive molecules and vascular permeability.9,32,34,35,38 hence, age can be used as a clinical marker to evaluate liver function and diabetes severity.34–37 proteins protein oxidation has been defined as “the covalent modification of a protein induced either directly by ros or indirectly by reaction with secondary byproducts of oxidative stress”.38 this means that a massive production of free radicals may also give rise to the formation of protein-protein and protein-lipid cross-links, which in turn change the structure and function of the proteins by causing protein fragmentation and obstruction of the amino acid side chains.34,35,38 these changes lead to deleterious consequences such as inhibition of enzymatic and binding activities, increased susceptibility to aggregation, resistance to proteolysis, increased or decreased uptake by cells and altered immunogenicity.32,34,35,38 the same mechanism occurs when proteins are exposed to reactive nitrogen species (rns). protein nitration may disturb normal signalling pathways (e.g. the insulin signalling pathway), to detrimental effect; nitrated proteins also mediate hepatic injury by promoting the release of cytokines and chemokines through stimulation of kupffer cells, thereby resulting in neutrophil infiltration and causing inflammatory tissue injury.39 cysteine and methionine are among the most susceptible amino acids and can be modified by almost all oxidising species.36,38,40 coincidently, cysteine is an important residue in many metabolic enzymes, kinases, phosphatases and transcription factors; oxidative modification of cysteine may therefore alter the functional properties and activity of proteins.36,38 much like ages, research has shown that pop serum concentrations increase with the progression of chronic diseases and are exacerbated in the presence of dm.37,40,41 therefore, pops are distinct biomarkers for oxidative stress. previous studies have reported that the liver plays an important role in the elimination of pops.42,43 zuwała-jagiełło et al. demonstrated a significant increase of pops in a group of cirrhotic patients; pop levels were proportional to the severity of the disease.36 lipids lpo occurs when polyunsaturated fatty acids interact with oxygen and is often used as a marker of tissue oxidative stress.44 various aldehydes derived from lipid hydroperoxides can be measured to quantify lpo as they reflect the extent of damage associated with oxidative stress at the tissue and cellular levels. these aldehydes have longer half-lives than reactive free radicals and can diffuse from their site of origin, circulate freely in the blood vessels or incorporate with lipoproteins, thereby reaching and attacking target sites.44 notably, lpo causes a prominent increase in malondialdehyde and thiobarbituric acid-reactive substances in the livers of people with dm.3 the formation of these products alters the transbilayer fluidity gradient of plasma membranes and damages the membrane components. it also affects membranebound enzymes and receptor activity and leads to inflammation and cell necrosis.31,37 in nafld patients, lpo triggers the release of inflammatory mediators such as tnf-α via the activation of adipocytokine and other pathways.44–46 this vicious cycle activates hepatic stellate cells and further leads to the proliferation and synthesis of collagenous substances, which favours the formation of fibrosis; this is an essential step in all types of chronic liver damage processes.45 inflammation-mediated damage inflammation plays a vital role in host defence by releasing pro-inflammatory cytokines to protect the host from injury, including tnf-α, interleukin (il)-1β and il-6. chronic inflammatory conditions cause tissue damage, fibrosis and loss of cellular function. growing evidence links a low-grade chronic inflammatory state to dm complications, particularly liver-related complications.43 these conditions are further exacerbated by the combined action of a complex regulatory network of cells and mediators designed to resolve inflammatory responses, mainly macrophages. the resulting increase in circulatory cytokines will then aggravate insulin resistance; however, anti-inflammatory drugs reverse these complex reactions.14,47,48 thus, inflammation might constitute a major causal factor for non-communicable diseases such as dm, rather than an associated risk factor. for example, il-1β together with tnf-α is responsible for the development of dm types 1 and 2 via inhibition of glucose-induced insulin secretion and impairment of β-cell function, thereby decreasing the biosynthesis of insulin and inducing apoptotic cell death.48 in addition, il-1β may also stimulate proliferation of t and b cells and induce the release of adhesion molecules, in addition to triggering the production of other cytokines and pro-inflammatory mediators, thereby having a detrimental effect on the liver.29,49,50 the biological response to il-1β is mostly shown through the activation of the c-jun n-terminal kinase (jnk) pathway and the nuclear translocation of nf-κb.49 mechanisms of diabetes-induced liver damage the role of oxidative stress and inflammation e138 | squ medical journal, may 2016, volume 16, issue 2 signalling mechanisms contributing to damage n u c l e a r fa c t o r-k a p pa b first described as a nuclear factor specific to b cells bound to the b site of the κ-light chain gene enhancer, nf-κb was then found to be expressed in other cell types, including the liver epithelium, where it regulates the proliferation and survival of hepatocytes during regeneration and development.31,51 this protein com plex may be activated by the release of proinflammatory molecules such as il-1β, il-6, tnf-α and c-reactive protein.8,50 other non-inflammatory states and mediators may also trigger nf-κb activation, such as free fatty acids, hyperglycaemia, obesity, protein kinase c and oxidative stress.8,50,52 the activation of nf-κb may trigger different types of responses depending on stimuli received, such as pro-apoptotic gene activation or cell regeneration. hence, the activation of nf-κb in dm may initiate a series of deleterious events via the further elevation of pro-inflammatory cytokines.31,50,51 moreover, nf-κb may also directly and indirectly promote the production of ros and rns and increase lpo, ages and pops, thereby increasing liver tissue damage.14 these products are thought to be generated through the phosphorylation-induced ubiquitination and subsequent proteolysis of inhibitor of nf-κb kinase subunit-α and through tnf-αor lymphotoxin-βmediated pathways.51,52 it has been postulated that inappropriate activation of nf-κb increases the likelihood of hepatic steatosis progression to cirrhosis, thereby causing further liver damage.51 therefore, nfκb is not only an appropriate target for dm treatment but also for the treatment of hepatocellular injuries.9 mitogen-activated protein kinase mitogen-activated protein kinases (mapks) are signalling transducers which transmit external stimuli to the nucleus by dual phosphorylation of the thr183 and tyr185 antibodies. the mapk families consist of three different signalling cascades converging on extracellular signal-regulated kinases, jnks and p38 mapks, which exert different types of reactions upon stimulation.52 activated by cytokines and growth factors, extracellular signal-regulated kinases play a central role in regulating cell growth and differentiation. meanwhile, jnk and p38 mapks, also known as stress-activated mapks, are triggered by pro-inflammatory cytokines such as tnf-α and il-1β as well as environmental and genotoxic stressors.52 stimulation of stress-activated mapks will exert various cellular functions, such as apoptosis, necrosis, survival, proliferation, migration and inflammation.10 in dm, mapk cascades are activated by osmotic perturbation caused by hyperglycaemia, oxidative stress and ages.8 studies have shown that prolonged exposure to oxidative stress because of high levels of liver tnf-α will activate the pro-apoptotic function of jnks; detrimentally affecting the hepatocytes.52 thus, jnks are a promising therapeutic target for individuals with liver injuries. table 1: comparative analysis of previous studies investigating the effectiveness of antioxidant supplements in preventing diabetes-induced liver damage author and year of study study design antioxidant source dose duration protective effect welt et al.16 2004 in vivo ginkgo biloba extract 100 mg/kg/day 4 months antioxidative palsamy et al.9 2010 in vivo resveratrol 5 mg/kg/day 30 days anti-inflammatory, antiglycative and antioxidative parveen et al.30 2010 in vivo pinus pinaster bark 10 mg/kg/day 4 weeks anti-diabetic and antioxidative hamden et al.18 2008 in vivo 17β-estradiol 1 μg/kg/day 4 weeks anti-apoptotic, anti-diabetic and antioxidative manna et al.8 2010 in vitro and in vivo arjunolic acid 20 mg/kg/day 4 weeks anti-inflammatory, anti-apoptotic, antidiabetic, antiglycative and antioxidative kim et al.55 2009 in vivo kangen-karyu extract 50, 100 and 200 mg/kg/day 20 days anti-inflammatory, anti-diabetic, antiglycative and antioxidative maritim et al.56 2003 in vivo α-lipoic acid 10 mg/kg/day 14 days antioxidative jain et al.57 2009 in vivo l-cysteine 1 mg/kg/day 8 weeks anti-inflammatory, anti-diabetic, antiglycative and antioxidative guven et al.4 2006 in vivo melatonin 200 μg/kg/day 9 weeks antioxidative jamaludin mohamed, nazratun nafizah a. h., zariyantey a. h. and budin s. b. review | e139 clinical implications, management and treatment the treatment of dm remains a challenging issue. researchers are exploring safe and effective medications to overcome the detrimental effects of insulin resistance-related metabolic derangement, including hyperglycaemia, hyperinsulinaemia, hyper lipidaemia, oxidative stress, inflammation, atherosclerosis and other complications.53 for patients with nafld and nash, no specific treatments yet exist apart from diet and lifestyle modifications to reduce body weight and prevent further injury.23,54 however, combined pharmacological therapy is recommended to improve insulin sensitivity in the liver (metformin and pioglitazone) and its periphery (thiazolidinediones), together with other drugs such as betaine, atorvastatin, losartan and orlistate.7,13,53 however, the clinical value of these treatments are very subjective. patients taking these drugs should be closely monitored due to possible contraindications with dm medications and the vulnerable condition of the liver during the drug detoxification process.54 antioxidant therapy is a potential future therapeutic strategy; increasing antioxidant levels in patients with dm-induced liver damage may hopefully counter the effects of oxidative stress and inflammation, thereby reducing the severity of diabetic complications. a few plant-based products and vitamins have been investigated as ways of protecting against and possibly reversing liver damage believed to be caused by oxidative stress and inflammation.48 vitamin e and betaine are just a few of the antioxidants which have shown good clinical implications in the reduction of liver disease severity and the protection of the liver from dm-induced damage [table 1].4,8,9,16,18,30,55–57 conclusion liver damage is a serious complication among patients with dm. insulin resistance, which is aggravated by oxidative stress and aberrant inflammatory signals, has become one of the main factors contributing to liver damage. insulin resistance subsequently leads to more chronic and potentially fatal conditions such as cirrhosis and end-stage liver failure. antioxidants from plant-based and natural products with strong anti-diabetic, anti-inflammatory and antiglycative properties are emerging as a future therapy. as opposed to conventional medications, antioxidants may be an alternative and beneficial way to prevent and treat this life-threatening disease. references 1. danaei g, finucane mm, lu y, singh gm, cowan mj, paciorek cj, et al. national, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. lancet 2011; 378:31–40. doi: 10.1016/s0140-6736(11)60679-x. 2. reid ae. non-alcoholic fatty liver disease. in: feldman m, friedman ls, brandt lj, eds. sleisenger and fordtran’s gastrointestinal and liver disease: pathophysiology/diagnosis/ management, 8th ed. st. louis, missouri, usa: saunders, 2006. pp. 1772–99. 3. levinthal gn, tavill as. liver disease and diabetes mellitus. clin diabetes 1999; 17:73. 4. guven a, yavuz o, cam m, ercan f, bukan n, comunoglu c, et al. effects of melatonin on streptozotocin-induced diabetic liver injury in rats. acta histochem 2006; 108:85–93. doi: 10.1016/j.acthis.2006.03.005. 5. larter cz, farrell gc. insulin resistance, adiponectin, cytokines in nash: which is the best target to treat? j hepatol 2006; 44:253–61. doi: 10.1016/j.jhep.2005.11.030. 6. leclercq ia, da silva morais a, schroyen b, van hul n, geerts a. insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. j hepatol 2007; 47:142–56. doi: 10.1016/j.jhep.2007.04.002. 7. bugianesi e, mccullough aj, marchesini g. insulin resistance: a metabolic pathway to chronic liver disease. hepatology 2005; 42:987–1000. doi: 10.1002/hep.20920. 8. manna p, das j, ghosh j, sil pc. contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of nos, parp, ikappabalpha/nf-kappab, mapks, and mitochondria-dependent pathways: prophylactic role of arjunolic acid. free radic biol med 2010; 48:1465–84. doi: 10.1016/j.freeradbiomed.2010.02.025. 9. palsamy p, sivakumar s, subramanian s. resveratrol attenuates hyperglycemia-mediated oxidative stress, proinflammatory cytokines and protects hepatocytes ultrastructure in streptozotocin-nicotinamide-induced experimental diabetic rats. chem biol interact 2010; 186:200–10. doi: 10.1016/j. cbi.2010.03.028. 10. romagnoli m, gomez-cabrera mc, perrelli mg, biasi f, pallardó fv, sastre j, et al. xanthine oxidase-induced oxidative stress causes activation of nf-kappab and inflammation in the liver of type i diabetic rats. free radic biol med 2010; 49:171–7. doi: 10.1016/j.freeradbiomed.2010.03.024. 11. porepa l, ray jg, sanchez-romeu p, booth gl. newly diagnosed diabetes mellitus as a risk factor for serious liver disease. cmaj 2010; 182:e526–31. doi: 10.1503/cmaj.092144. 12. cohen jc, horton jd, hobbs hh. human fatty liver disease: old questions and new insights. science 2011; 332:1519–23. doi: 10.1126/science.1204265. 13. crawford jm, iacobuzio-donahue c. liver and biliary tract. in: kumar v, abbas ak, fausto n, aster jc, eds. robbins and cotran pathologic basis of disease. 8th ed. philadelphia, pennsylvania, usa: saunders, 2009. pp. 833–90. 14. al-hussaini aa, sulaiman nm, alzahrani md, alenizi as, khan m. prevalence of hepatopathy in type 1 diabetic children. bmc pediatr 2012; 12:160. doi: 10.1186/1471-2431-12-160. 15. regnell se, lernmark å. hepatic steatosis in type 1 diabetes. rev diabet stud 2011; 8:454–67. doi: 10.1900/rds.2011.8.454. 16. welt k, weiss j, martin r, dettmer d, hermsdorf t, asayama k, et al. ultrastructural, immunohistochemical and biochemical investigations of the rat liver exposed to experimental diabetes and acute hypoxia with and without application of ginkgo extract. exp toxicol pathol 2004; 55:331–45. doi: 10.1078/09402993-00337. http://dx.doi.org/10.1016/s0140-6736%2811%2960679-x http://dx.doi.org/10.1016/j.acthis.2006.03.005 http://dx.doi.org/10.1016/j.jhep.2005.11.030 http://dx.doi.org/10.1016/j.jhep.2007.04.002 http://dx.doi.org/10.1002/hep.20920 http://dx.doi.org/10.1016/j.freeradbiomed.2010.02.025 http://dx.doi.org/10.1016/j.cbi.2010.03.028 http://dx.doi.org/10.1016/j.cbi.2010.03.028 http://dx.doi.org/10.1016/j.freeradbiomed.2010.03.024 http://dx.doi.org/10.1503/cmaj.092144 http://dx.doi.org/10.1126/science.1204265 http://dx.doi.org/10.1186/1471-2431-12-160 http://dx.doi.org/10.1900/rds.2011.8.454 http://dx.doi.org/10.1078/0940-2993-00337 http://dx.doi.org/10.1078/0940-2993-00337 mechanisms of diabetes-induced liver damage the role of oxidative stress and inflammation e140 | squ medical journal, may 2016, volume 16, issue 2 17. moscatiello s, manini r, marchesini g. diabetes and liver disease: an ominous association. nutr metab cardiovasc dis 2007; 17:63–70. doi: 10.1016/j.numecd.2006.08.004. 18. hamden k, carreau s, boujbiha ma, lajmi s, aloulou d, kchaou d, et al. hyperglycaemia, stress oxidant, liver dysfunction and histological changes in diabetic male rat pancreas and liver: protective effect of 17 beta-estradiol. steroids 2008; 73:495–501. doi: 10.1016/j.steroids.2007.12.026. 19. lucchesi an, cassettari ln, spadella ct. alloxan-induced diabetes causes morphological and ultrastructural changes in rat liver that resemble the natural history of chronic fatty liver disease in humans. j diabetes res 2015; 2015:494578. doi: 10.1155/2015/494578. 20. mavrogiannaki an, migdalis in. nonalcoholic fatty liver disease, diabetes mellitus and cardiovascular disease: newer data. int j endocrinol 2013; 2013:450639. doi: 10.11 55/2013/450639. 21. longo dl, fauci as, kasper dl, hauser sl, jameson jl, loscalzo j. harrison’s principles of internal medicine. volume 2, 18th ed. new york, usa: mcgraw-hill, 2011. 22. nannipieri m, gonzales c, baldi s, posadas r, williams k, haffner sm, et al. liver enzymes, the metabolic syndrome, and incident diabetes: the mexico city diabetes study. diabetes care 2005; 28:1757–62. doi: 10.2337/diacare.28.7.1757. 23. elsheikh e, henry ll, younossi zm. current management of patients with nonalcoholic fatty liver disease. expert rev endocrinol metab 2013; 8:549–58. doi: 10.1586/17446651. 2013.846212. 24. stefan n, sun q, fritsche a, machann j, schick f, gerst f, et al. impact of the adipokine adiponectin and the hepatokine fetuin-a on the development of type 2 diabetes: prospective cohortand cross-sectional phenotyping studies. plos one 2014; 9:e92238. doi: 10.1371/journal.pone.0092238. 25. iroz a, couty jp, postic c. hepatokines: unlocking the multiorgan network in metabolic diseases. diabetologia 2015; 58:1699–1703. doi: 10.1007/s00125-015-3634-4. 26. garcia-compean d, jaquez-quintana jo, gonzalez-gonzalez ja, maldonado-garza h. liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. world j gastroenterol 2009; 15:280–8. doi: 10.3748/wjg.15.280. 27. shokolenko i, venediktova n, bochkareva a, wilson gl, alexeyev mf. oxidative stress induces degradation of mitochondrial dna. nucleic acids res 2009; 37:2539–48. doi: 10.1093/nar/gkp100. 28. leung tm, nieto n. cyp2e1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. j hepatol 2013; 58:395–8. doi: 10.1016/j.jhep.2012.08.018. 29. wei y, chen p, de bruyn md, zhang w, bremer e, helfrich w. carbon monoxide-releasing molecule-2 (corm-2) attenuates acute hepatic ischemia reperfusion injury in rats. bmc gastroenterol 2010; 10:42. doi: 10.1186/1471-230x-10-42. 30. parveen k, khan mr, mujeeb m, siddigui wa. protective effects of pycnogenol on hyperglycemia-induced oxidative damage in the liver of type 2 diabetic rats. chem biol interact 2010; 186:219–27. doi: 10.1016/j.cbi.2010.04.023. 31. han d, hanawa n, saberi b, kaplowitz n. mechanisms of liver injury: iii role of glutathione redox status in liver injury. am j physiol gastrointest liver physiol 2006; 291:g1–7. doi: 10.1152/ajpgi.00001.2006. 32. ahmed n. advanced glycation endproducts: role in pathology of diabetic complications. diabetes res clin pract 2005; 67:3–21. doi: 10.1016/j.diabres.2004.09.004. 33. horiuchi s. the liver is the main site for metabolism of circulating advanced glycation end products. j hepatol 2002; 36:123–5. doi: 10.1016/s0168-8278(01)00293-8. 34. yagmur e, tacke f, weiss c, lahme b, manns mp, keifer p, et al. elevation of nepsilon-(carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis. clin biochem 2006; 39:39–45. doi: 10.1016/j.clinbiochem.2005.07.016. 35. ahmed n, thornalley pj, lüthen r, häussinger d, sebekova k, schinzel r, et al. processing of protein glycation, oxidation and nitrosation adducts in the liver and the effect of cirrhosis. j hepatol 2004; 41:913–19. doi: 10.1016/j.jhep.2004.08.007. 36. zuwała-jagiełło j, pazgan-simon m, simon k, warwas m. elevated advanced oxidation protein products levels in patients with liver cirrhosis. acta biochim pol 2009; 56:679–85. 37. sebeková k, kupcová v, schinzel r, heidland a. markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis: amelioration by liver transplantation. j hepatol 2002; 36:66–71. doi: 10.1016/s01688278(01)00232-x. 38. shacter e. quantification and significance of protein oxidation in biological samples. drug metab rev 2000; 32:307–26. doi: 10.1081/dmr-100102336. 39. abdelmegeed ma, song bj. functional roles of protein nitration in acute and chronic liver diseases. oxid med cell longev 2014; 2014:149627. doi: 10.1155/2014/149627. 40. witko-sarsat v, friendlander m, nguyen khoa t, capeillèreblandin c, nguyen at, canteloup s, et al. advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. j immunol 1998; 161:2524–32. 41. nazratun n, mahmood aa, kuppusamy ur, ahmad ts, tan sy. diabetes mellitus exacerbates advanced glycation end product accumulation in the veins of end-stage renal failure patients. vasc med 2006; 11:245–50. doi: 10.1177/1358863x06072202. 42. iwao y, anraku m, hiraike m, kawai k, nakajou k, kai t, et al. the structural and pharmacokinetic properties of oxidized human serum albumin, advanced oxidation protein products (aopp). drug metab pharmacokinet 2006; 21:140–6. doi: 10.2133/dmpk.21.140. 43. svistounov d, smedsrød b. hepatic clearance of advanced glycation end products (ages): myth or truth? j hepatol 2004; 41:1038–40. doi: 10.1016/j.jhep.2004.10.004. 44. mcnuff ma, omoruyi fo, morrison ey, asemota hn. hepatic function enzymes and lipid peroxidation in streptozotocininduced diabetic rats fed bitter yam (dioscorea polygonoides) steroidal sapogenin extract. diabetol croat 2003; 32:17–23. 45. moreira rk. hepatic stellate cells and liver fibrosis. arch pathol lab med 2007; 131:1728–34. 46. mahmoud am, ashour mb, abdel-moneim a, ahmed om. hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. j diabetes complications 2012; 26:483–90. doi: 10.1016/j.jdiacomp. 2012.06.001. 47. ugochukwu nh, figgers cl. dietary caloric restriction modifies inflammatory responses in the livers of streptozotocininduced diabetic rats. nutr res 2006; 26:221–6. doi: 10.1016/j. nutres.2006.05.003. 48. seven a, guzel s, seymen o, civelek s, bolayirli m, uncu m, et al. effects of vitamin e supplementation on oxidative stress in streptozotocin induced diabetic rats: investigation of liver and plasma. yonsei med j 2004; 45:703–10. doi: 10.3349/ ymj.2004.45.4.703. 49. banerjee m, saxena m. interleukin-1 (il-1) family of cytokines: role in type 2 diabetes. clin chim acta 2012; 413:1163–70. doi: 10.1016/j.cca.2012.03.021. http://dx.doi.org/10.1016/j.numecd.2006.08.004 http://dx.doi.org/10.1016/j.steroids.2007.12.026 http://dx.doi.org/10.1155/2015/494578 http://dx.doi.org/10.1155/2013/450639 http://dx.doi.org/10.1155/2013/450639 http://dx.doi.org/10.2337/diacare.28.7.1757 http://dx.doi.org/10.1586/17446651.2013.846212 http://dx.doi.org/10.1586/17446651.2013.846212 http://dx.doi.org/10.1371/journal.pone.0092238 http://dx.doi.org/10.1007/s00125-015-3634-4 http://dx.doi.org/10.3748/wjg.15.280 http://dx.doi.org/10.1093/nar/gkp100 http://dx.doi.org/10.1016/j.jhep.2012.08.018 http://dx.doi.org/10.1186/1471-230x-10-42 http://dx.doi.org/10.1016/j.cbi.2010.04.023 http://dx.doi.org/10.1152/ajpgi.00001.2006 http://dx.doi.org/10.1016/j.diabres.2004.09.004 http://dx.doi.org/10.1016/s0168-8278%2801%2900293-8 http://dx.doi.org/10.1016/j.clinbiochem.2005.07.016 http://dx.doi.org/10.1016/j.jhep.2004.08.007 http://dx.doi.org/10.1016/s0168-8278%2801%2900232-x http://dx.doi.org/10.1016/s0168-8278%2801%2900232-x http://dx.doi.org/10.1081/dmr-100102336 http://dx.doi.org/10.1155/2014/149627 http://dx.doi.org/10.1177/1358863x06072202 http://dx.doi.org/10.2133/dmpk.21.140 http://dx.doi.org/10.1016/j.jhep.2004.10.004 http://dx.doi.org/10.1016/j.jdiacomp.2012.06.001 http://dx.doi.org/10.1016/j.jdiacomp.2012.06.001 http://dx.doi.org/10.1016/j.nutres.2006.05.003 http://dx.doi.org/10.1016/j.nutres.2006.05.003 http://dx.doi.org/10.3349/ymj.2004.45.4.703 http://dx.doi.org/10.3349/ymj.2004.45.4.703 http://dx.doi.org/10.1016/j.cca.2012.03.021 jamaludin mohamed, nazratun nafizah a. h., zariyantey a. h. and budin s. b. review | e141 50. martínez-flórez s, gutiérrez-fernández b, sánchez-campos s, gonzález-gallego j, tuñón mj. quercetin attenuates nuclear factor-kappab activation and nitric oxide production in interleukin-1beta-activated rat hepatocytes. j nutr 2005; 135:1359–65. 51. arsura m, cavin lg. nuclear factor-kappab and liver carcinogenesis. cancer lett 2005; 229:157–69. doi: 10.1016/j. canlet.2005.07.008. 52. nakagawa h, maeda s. molecular mechanisms of liver injury and hepatocarcinogenesis: focusing on the role of stress-activated mapk. patholog res int 2012; 2012:172894. doi: 10.1155/2012/172894. 53. defronzo ra, eldor r, abdul-ghani m. pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. diabetes care 2013; 36:s127–38. doi: 10.2337/dcs132011. 54. adams la, angulo p. treatment of non-alcoholic fatty liver disease. postgrad med j 2006; 82:315–22. doi: 10.1136/ pgmj.2005.042200. 55. kim hy, okamoto t, yokozawa t. beneficial effects of chinese prescription kangen-karyu on diabetes associated with hyperlipidemia, advanced glycation endproducts, and oxidative stress in streptozotocin-induced diabetic rats. j ethnopharmacol 2009; 124:263–9. doi: 10.1016/j.jep.2009.04.032. 56. maritim ac, sanders ra, watkins jb 3rd. diabetes, oxidative stress, and antioxidants: a review. j biochem mol toxicol 2003; 17:24–38. doi: 10.1002/jbt.10058. 57. jain sk, velusamy t, croad jl, bull r. l-cysteine supplementation lowers blood glucose, glycated hemoglobin, crp, mcp-1, oxidative stress and inhibits nfkappab activation in the livers of zucker diabetic rats. free radic biol med 2009; 46:1633–38. doi: 10.1016/j.freeradbiomed.2009.03.014. http://dx.doi.org/10.1016/j.canlet.2005.07.008 http://dx.doi.org/10.1016/j.canlet.2005.07.008 http://dx.doi.org/10.1155/2012/172894 http://dx.doi.org/10.2337/dcs13-2011 http://dx.doi.org/10.2337/dcs13-2011 http://dx.doi.org/10.1136/pgmj.2005.042200 http://dx.doi.org/10.1136/pgmj.2005.042200 http://dx.doi.org/10.1016/j.jep.2009.04.032 http://dx.doi.org/10.1002/jbt.10058 http://dx.doi.org/10.1016/j.freeradbiomed.2009.03.014 caesarean scar pregnancy (csp) is arare and potentially dangerous type of ectopic pregnancy resulting from the implantation of an embryo within the area of a previous caesarean section scar.1 it is a complication which can be attributed to the recent worldwide increase in caesarean births.2 the early and accurate diagnosis of such cases is essential, as a csp can be easily confused with an undetected/silent miscarriage, an incomplete miscarriage during the expulsion process or a cervical ectopic pregnancy.3 due to the lack of reported data regarding csps, the true incidence of this complication is difficult to determine; studies have reported an incidence of one in 1,800 to one in 2,216 pregnancies.4–6 csp has been found to represent 6.1% of all ectopic pregnancies where there is a history of at least one caesarean section.6 csp was first reported in the english medical literature in 1978.7 only 19 cases were reported between 1966 and 2002; however, this number rose to 268 in the following eight years.1,8 the increase in reported csp cases may have been influenced by the rise of caesarean sections, along with the more widespread availability and well-defined criteria of the transvaginal scan which aids in the earlier detection of such pregnancies. notwithstanding this recent development, current knowledge regarding the management of this potentially life-threatening condition continues to be based mainly on individual case reports and a small number of case series. suction evacuation or primary curettage are often reported as the least favoured treatment options due to their associated complications.9,10 this case series presents six patients with csps department of obstetrics & gynaecology, royal hospital, muscat, oman *corresponding author e-mail: singhsumita@hotmail.co.uk الشفط مع استخدام ميثوتريكسيت كطريقة عالج ناجحة للحمل يف الندبة القيصرية سلسلة حاالت �سوميتا داتا و �سيرتا جه abstract: pregnancy resulting from the implantation of an embryo within a scar of a previous caesarean section is extremely rare. the diagnosis and treatment of caesarean scar pregnancies (csps) are challenging and the optimal course of treatment is still to be determined. we report a case series of six patients with csps who presented to the royal hospital in muscat, oman, between october 2012 and april 2014. all of the patients were successfully treated with systemic methotrexate and five patients underwent suction evacuation either before or after the methotrexate administration. the patients were followed up for a period of 6–9 weeks after treatment and recovered completely without any significant complications. suction evacuation with methotrexate can therefore be considered an effective treatment option with good maternal outcomes. keywords: ectopic pregnancy; caesarean section; scar; suction curettage; methotrexate; case series; oman. امللخ�ص: احلمل الناجت عن غر�ض اجلنني داخل ندبة لعملية قي�رسية �سابقة حالة نادرة للغاية. ت�سخي�ض وعالج حالت احلمل يف الندبة القي�رسية �سعبة وال�سبيل الأمثل للعالج مل يتعني بعد. نعر�ض هنا �سل�سلة حالت ل�ستة ن�ساء يعانون من احلمل يف الندبة القي�رسية قدمن اإىل امل�ست�سفى امللكي يف م�سقط، عمان، بني اأكتوبر 2012 واأبريل 2014. مت عالج جميع املري�سات بنجاح با�ستخدام امليثوتريك�سيت العام بعد اأ�سابيع ملدة 6-9 املري�سات متابعة متت بامليثوتريك�سيت. العالج بعد قبل اأو �سواء الهوائي لل�سفط املري�سات من خم�سة وخ�سعت العالج وال�سفاء التام دون اأي م�ساعفات خطرية. وبالتايل، ميكن اعتبار ال�سفط الهوائي مع امليثوتريك�سيت خيار عالجي فعال مع نتائج جيدة. مفتاح الكلمات: احلمل خارج الرحم؛ عمليه قي�رسية؛ ندبة؛ �سفط كحت؛ امليثوتريك�سيت؛ �سل�سلة حالت؛ عمان. suction evacuation with methotrexate as a successful treatment modality for caesarean scar pregnancies case series *sumita datta and chitra jha case series sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e539–545, epub. 23 nov 15 submitted 10 may 15 revision req. 21 jun 15; revision recd. 27 jul 15 accepted 13 aug 15 doi: 10.18295/squmj.2015.15.04.017 suction evacuation with methotrexate as a successful treatment modality for caesarean scar pregnancies case series e540 | squ medical journal, november 2015, volume 15, issue 4 treated successfully with a combination of systemic methotrexate and suction evacuation at the royal hospital in muscat, oman, between october 2012 and april 2014. all patients consented to the publication of their anonymised data. case 1 a 33-year–old woman was referred to the royal hospital in october 2012 at seven gestational weeks into her seventh pregnancy. she had had one lower segment caesarean section five years previously, followed by a vaginal birth. at presentation, the patient had a three-day history of vaginal bleeding with clots and her β-human chorionic gonadotropin (β-hcg) level was 9,400 iu/l. a csp was suspected [figure 1] and she was referred to the royal hospital after receiving one intramuscular dose of 80 mg/m2 of methotrexate the previous day. after undergoing counselling regarding her available treatment options—repeated administration of methotrexate or surgical evacuation—the patient opted for the latter modality. during the procedure, the patient lost 200 ml of blood and a foley catheter was inserted into the uterine cavity. the patient had an uneventful postoperative course; her β-hcg level dropped to 3,336 iu/l after four days and she was discharged and followed up as an outpatient. after eight weeks, the patient’s β-hcg level was negative. the small haematoma in the scar site resolved after 12 weeks. case 2 a 30-year-old woman presented to royal hospital in november 2013 at five gestational weeks into her third pregnancy with abdominal pain and mild vaginal bleeding. she had had two lower segment caesarean sections in the past and a laparoscopic left ovarian cystectomy for a dermoid cyst 11 days previously. at presentation, her β-hcg level was 4,980 iu/l; however, this rose to 10,907 iu/l after 48 hours. an ultrasound scan suggested a csp and this was later confirmed by magnetic resonance imaging (mri). the patient received one dose of 50 mg/m2 of methotrexate when her β-hcg level reached 38,452 iu/l. she underwent a suction evacuation two days later during which she lost 700 ml of blood. the postoperative course was uneventful; her β-hcg level dropped to 3,867 iu/l after four days and she was discharged and followed up as an outpatient. her β-hcg level was negative after eight weeks. the patient had an intrauterine pregnancy the following year which unfortunately resulted in early fetal death. she subsequently underwent another successful suction evacuation. case 3 a 35-year-old woman presented to the royal hospital in october 2013 at 11 gestational weeks into her fifth pregnancy with mild vaginal bleeding and pain. she had had a lower segment caesarean section four years previously due to grade 3 anterior placenta praevia partially covering the internal opening of the cervix. a transvaginal scan showed a collapsed intrauterine gestational sac in the lower uterine segment with fetal pole and no fetal cardiac activity [figure 2]. the patient’s β-hcg level was 12,971 iu/l. a diagnosis of a silent miscarriage was made and she received two doses of 800 µg of misoprostol. the patient underwent a suction evacuation two days later as she did not respond to the treatment. although the patient lost 500 ml of blood during the procedure and her haemoglobin dropped by 2 g%, she did not require a blood transfusion. the patient was discharged two days after the surgery but was readmitted 10 days later with heavy figure 1: vaginal ultrasound showing a pregnancy in the caesarean scar site (white arrow) growing towards the endometrial cavity (arrowhead). the bladder can also be observed (red arrow). figure 2: vaginal ultrasound of an empty endometrial cavity (blue arrow) and cervix (white arrow) with a pregnancy at the caesarean scar site (black arrow). sumita datta and chitra jha case series | e541 case 5 a 32-year-old woman with a history of three lower segment caesarean sections was referred to the royal hospital in march 2014 at nine gestational weeks into her fourth pregnancy. she was referred due to a suspected silent miscarriage and molar pregnancy. she underwent a transvaginal scan which raised the suspicion of a csp; this was later confirmed by mri [figure 4]. her β-hcg level was 25,261 iu/l and she received one dose of 50 mg/m2 of methotrexate. at a follow-up appointment one week later, her β-hcg level was 5,389 iu/l and she received a second dose of 50 mg/m2 of methotrexate. she then developed vaginal bleeding and underwent an emergency evacuation of the uterus, during which she lost 1,000 ml of blood. an intrauterine foley catheter was inserted and uterine artery embolisation (uae) was performed. four days after surgery, her β-hcg level decreased significantly to 1,049 iu/l; it became negative after five weeks and the patient recovered well. case 6 a 39-year-old woman was referred to the royal hospital in april 2014 at 11 gestational weeks into her fifth pregnancy with a suspected silent miscarriage. she had a history of four previous lower segment caesarean sections. she received three 800 µg doses of misoprostol but failed to respond to the treatment. a csp was suspected and was confirmed by transvaginal scan. a combined transvaginal and transabdominal scan of the patient with a full bladder was performed. the patient received one dose of 50 mg/m2 of methotrexate. the subsequent follow-up period showed a decline in her β-hcg level to <1 iu/l bleeding. a csp was suspected following an ultrasound and confirmed by mri; a morbidly adherent placenta and haematoma formation in the anterior wall was also observed. her β-hcg level was 1,741 iu/l and she was given one dose of 50 mg/m2 of methotrexate. she was followed up as an outpatient. her β-hcg level was negative after 10 weeks; however, the haematoma persisted for four months. the patient was advised to undergo an early elective lower segment caesarean section at 37–38 gestational weeks during her next pregnancy. case 4 a 40-year-old woman was referred to the royal hospital in december 2013 at 16 gestational weeks into her sixth pregnancy with a diagnosis of a silent miscarriage. she had had three previous caesarean sections, the last one occurring during the previous year. she received three doses of 800 µg of misoprostol and then opted for surgical evacuation. she bled 2,500 ml during the evacuation and required tamponade by a foley catheter in the uterine cavity. the patient received two units of blood with six units of fresh frozen plasma. the uterine foley catheter was removed after 24 hours and the patient was subsequently discharged. the patient was readmitted one week later with heavy vaginal bleeding. a csp was suspected and then confirmed by mri [figure 3]. her β-hcg level was 15 iu/l and she was given one dose of 50 mg/m2 of methotrexate. after four weeks, during a subsequent outpatient follow-up appointment, it was noted that her β-hcg level had returned to negative and the residual pregnancy mass in the anterior uterine wall had resolved. figure 3: magnetic resonance image of the pelvis showing a caesarean scar pregnancy (white arrow) with an empty but dilated endometrial cavity (arrowhead). the bladder can also be observed (red arrow). figure 4: magnetic resonance image of the pelvis showing a scar pregnancy (white arrow) with an empty endometrial canal and cervix (arrowhead). suction evacuation with methotrexate as a successful treatment modality for caesarean scar pregnancies case series e542 | squ medical journal, november 2015, volume 15, issue 4 after five weeks. the pregnancy mass had resolved after four weeks. clinical and treatment details for each patient are presented in table 1. overall findings for the case series are presented in table 2. histopathology results for all patients showed products of conception. outpatient follow-up included weekly checks of serum β-hcg levels until the values had returned to normal. weekly ultrasound scans were performed until the csp had resolved completely. all of the women recovered completely with no methotrexate-related side-effects and no additional medical or surgical interventions. those who were planning further pregnancies were advised regarding the optimal timeframe for their next pregnancy and were encouraged to have early vaginal scans during their next pregnancy to confirm the intrauterine location of the embryo. discussion there has been a rise in the reported incidence of csp in the medical literature in recent years.2 although a series of 18 and eight csp cases were reported by jurkovic et al. and maymon et al., respectively, the majority of data on csp are found in individual case reports or small case series.4,11 to the best of the authors’ knowledge, this is the first case series to exclusively present suction evacuation and methotrexate as a treatment modality; this will hopefully aid in the acceptance of this approach as an effective treatment option for csp. vial et al. proposed two different types of csp; the first occurs due to the implantation of the gestational sac on the scar with progression towards either the cervicoisthmic space or uterine cavity and the second as a result of a deep implantation into a post-caesarean section defect with growth towards the bladder.12 table 1: clinical, radiological and interventional characteristics of each of the six presented patients with caesarean scar pregnancies age in years obstetric history years since last lscs symptoms gestational weeks + days β-hcg in iu/l imaging modality treatment follow-up period in weeks blood loss 33 •g 7, p 6 •four previous births via svd •one previous birth via lscs •one previous birth via vbac 5.0 vaginal bleeding 7 + 0 9,400 •tv scan •methotrexate •evacuation 9 •minimal 30 •g 3, p 2 •two previous births via lscs •laparoscopic cystectomy performed 11 days before presentation 1.5 abdominal pain and mild vaginal bleeding 4 + 5 38,452 •tv scan •mri •methotrexate •evacuation 8 •700 ml •one unit of blood transfused 35 •g 5, p 4 •one previous birth via lscs due to grade 3 anterior placenta praevia 4.0 heavy bleeding after evacuation for suspected silent miscarriage 11 + 4 1,741 •tv scan •mri •evacuation •methotrexate 8 •500 ml 40 •g 7, p 6 •three previous births via lscs 1.5 heavy bleeding after evacuation for suspected silent miscarriage 16 + 0 15 •tv scan •mri •evacuation •methotrexate 6 •2,500 ml •two units of blood transfused •six units of ffp transfused 32 •g 4, p 3 •three previous births via lscs 2.5 asymptomatic 9 + 2 25,261 •tv scan •mri •methotrexate (two doses) •evacuation •uae 7 •1,000 ml •one unit of blood transfused 39 •g 5, p 4 •four previous births via lscs 5.0 asymptomatic 11 + 3 1,013 •tv scan •tv/ta scan •methotrexate 8 •minimal lscs = lower segment caesarean section; β-hcg = β-human chorionic gonadotropin; g = gravida; p = para; tv = transvaginal; svd = spontaneous vaginal delivery; vbac = vaginal birth after caesarean section; mri = magnetic resonance imaging ; ffp = fresh frozen plasma; uae = uterine artery embolisation; ta = transabdominal. sumita datta and chitra jha case series | e543 potential difficulties in achieving an accurate diagnosis at presentation. early diagnosis is paramount in csp to increase the number of available treatment options and to avoid serious complications like haemorrhage and uterine rupture. many undiagnosed csp patients present with heavy bleeding, shock and haemoperitoneum after the termination of an early pregnancy or dilatation following a silent miscarriage, as was the case in two of the patients in the current series. transvaginal ultrasonography has been reported as a first-line diagnostic tool, with a sensitivity rate of 86.4%.5 sonographic criteria for diagnosing csp include an empty uterus without contact with the gestational sac; a visibly empty cervical canal; the presence of the gestational sac with or without a fetal pole and with or without fetal cardiac activity (depending on the gestational age) in the anterior segment of the uterine isthmus; and the absence of or a defect in the myometrial tissue between the bladder and the gestational sac.1,7 all cases of csp in the current series fulfilled these criteria. with transvaginal ultrasonography, a diagnosis of csp can be confidentially made using a sagittal view along the long axis of the uterus through the gestational sac.7 maymon et al. recommended a dual approach, combining transvaginal and transabdominal scans of the patient with a full bladder; the latter provides a ‘panoramic’ view of the uterus and an accurate measurement of the distance between the gestational sac and the bladder.11 this technique was used to diagnose csp in one patient in the current case series, as the patient’s uterus was pulled up due to her four previous caesarean surgeries. another diagnostic method proposed by jurkovic et al. is the negative sliding organ sign, defined as the inability to displace the gestational sac from its position at the level of the internal cervical opening using gentle pressure applied with a transabdominal probe.4 as yet, there is no proven relationship between the number of previous caesarean sections, or the time interval between caesarean sections, and the subsequent development of csp. jurkovic et al. found that 72.0% of their patients had previously had two or more caesarean sections;4 a similar percentage was observed in the current case series, with 66.7% of the patients having previously had two or more caesarean sections. previous caesarean section scars should be examined routinely during early pregnancy to help reduce the misdiagnosis of csps as silent miscarriages and to improve maternal morbidity and mortality. in the absence of a standard treatment protocol for csp, a number of treatment options exist, either singly or in combination, with varied success rates. important factors influencing choice of treatment while the first type of pregnancy may result in a viable birth, it has an increased risk of life-threatening bleeding from the implantation site.7,13 the second generally leads to a rupture and bleeding during the first trimester.12 the clinical presentation of patients in the current case series reflects the wide range of symptoms associated with this rare kind of ectopic pregnancy. symptoms varied from slight vaginal bleeding and pain to profuse vaginal bleeding and, ultimately, silent miscarriages. these cases therefore highlight the table 2: summary of the clinical characteristics, imaging modality, interventions and recovery of the six presented patients with caesarean scar pregnancies n (%) characteristics mean maternal age in years (range) 35 (30–40) gravidity (range) 5 (3–7) mean gestational age at diagnosis in weeks (range) 11 (5–16) spontaneous conception 6 (100.0) history of lscs 5 (83.3) imaging modality transvaginal ultrasonography 6 (100.0) transabdominal ultrasonography 1 (16.7) magnetic resonance imaging 4 (66.7) interventions blood transfusion 3 (50.0) •one unit 2 (33.4) •two units 1 (16.7) systemic methotrexate 6 (100.0) •first-line followed by suction evacuation 3 (50.0) •first-line with no subsequent intervention required 1 (16.7) •following evacuation 2 (33.4)* suction evacuation 5 (83.3) uae following suction evaluation 1 (16.7) recovery mean follow-up in weeks (range) 8 (6–9) full recovery 6 (100.0) methotrexate-related side-effects 0 (0.0) additional interventions 0 (0.0) lsc = lower segment caesarean section; uae = uterine artery embolisation. *these two patients underwent a suction evacuation for a missed/silent miscarriage before the correct diagnosis of csp was made at readmission. suction evacuation with methotrexate as a successful treatment modality for caesarean scar pregnancies case series e544 | squ medical journal, november 2015, volume 15, issue 4 include the clinical stability of the patient, gestational age, size of the ectopic pregnancy mass, β-hcg levels and any known contraindication to methotrexate therapy. all treatment regimens aim to resolve the csp prior to rupture and preserve future fertility, if desired. in the literature, almost all of the women whose pregnancies were managed expectantly developed placenta accreta or increta, resulting in either a hysterotomy or hysterectomy with severe haemorrhage.7 the pathophysiology of scar implantation has been suggested as a precursor of placenta accreta.14 therefore, most diagnosed cases are treated by either surgical or medical means or a combination of both. suggested medical treatments involve the administration of local intragestational methotrexate; systemic methotrexate; potassium chloride; hyperosmolar glucose; or a combined approach with varying regimens.15–17 fadhlaoui et al. reported the combination of medical modalities, either systemic or local and as a single agent or a combined regimen, with aspiration of the gestational sac.18 this approach can preserve fertility and avoid an unnecessary laparotomy; however, it requires close monitoring and follow-up of the patient as the normalisation of β-hcg levels may take up to 4–16 weeks.15,16,19 in their analysis of published case reports, jurkovic et al. found that medical treatment with methotrexate was successful in 71.0–80.0% of cases, with 6.0% of women requiring a hysterectomy.4 to date, 17 cases of csp involving uterine curettage as the primary therapy have been reported in the medical literature.9,10,20 arslan et al. reported unsuccessful or complicated uterine curettage in eight out of nine women,9 whereas wang et al. reported a failure rate of 70.0% after curettage.20 this could be attributed to an inability to evacuate all of the ectopic tissue and the increased risk of uterine rupture and severe haemorrhage.20 however, some reports have suggested that dilatation and curettage should be considered in cases with early presentation (<7 gestational weeks) and in those with sufficient myometrial tissue between the gestational sac and the bladder (>3.5 mm).9,18,20 additional adjunct and haemostatic measures—such as vasopressin, intrauterine balloon tamponade with a foley catheter, bilateral uae and bilateral uterine artery ligation—have been used for the prevention and control of profuse bleeding in a variety of treatment settings.4,21–23 minimally invasive treatment modalities are usually determined by the type of csp, with a laparoscopic approach being suitable for deeply implanted pregnancies growing towards the abdominal cavity, while a hysteroscopic approach may be considered in those growing towards the uterine cavity. hysteroscopic evacuations have been reported by wang et al. and chao et al. after failed curettage and methotrexate treatment.24,25 laparoscopic removal of the csp and laparoscopically-assisted operative hysteroscopy have also been reported as treatment options in cases where the patient is stable and appropriate facilities with a trained surgeon are available.26,27 surgical treatment, either a laparotomy with wedge resection or a hysterectomy, should be considered in haemodynamically unstable patients with late presentation of the csp, those presenting with uterine rupture, in the event of failed medical/surgical treatment or for cases where operative endoscopy is not feasible. a laparotomy has the advantage of completely removing the csp mass and repairing the scar at the same time, followed by the normalisation of β-hcg levels within 1‒2 weeks.1,11 long-term complications following treatment of a csp include fertility issues and recurrence. a follow-up study of 29 women who were successfully treated for csp reported favourable reproductive outcomes and a low recurrence rate.28 out of 24 women attempting to become pregnant, 21 conceived spontaneously (20 intrauterine pregnancies and one recurrent csp); of the intrauterine pregnancies, 13 were normal (nine of which were delivered by caesarean section) while seven ended in spontaneous miscarriages.28 using sonohysterography, the integrity of the uterine wall post-caesarean section can be determined even in non-pregnant patients.2,29 caesarean scar defects, defined by the presence of fluid within the incision site, or any filling defects at the presumed scar site might indicate uterine scar complications in a subsequent pregnancy.4,29 counselling and treatment options for these patients should therefore be tailored accordingly. conclusion csp is a potentially life-threatening complication following a previous caesarean birth and an exponential rise in the incidence of this type of pregnancy has recently been recorded. bleeding and pain in early pregnancy are the most common presenting symptoms. examining the appearance of a previous caesarean section scar should be a routine procedure in every early pregnancy to help reduce misdiagnosis and maternal morbidity and mortality. there is no general consensus on the most effective treatment modality for csp; however, this case series shows that suction evacuation combined with methotrexate is a successful treatment option with good maternal outcome. references sumita datta and chitra jha case series | e545 doi: 10.1111/j.1471-0528.1997.tb11547.x. 17. roberts h, kohlenber c, lanzarone v, murray h. ectopic pregnancy in lower segment uterine scar. aust n z j obstet gynaecol 1998; 38:114–16. doi: 10.1111/j.1479-828x.1998. tb02976.x. 18. fadhlaoui a, khrouf m, khémiri k, nouira k, chaker a, zhioua f. successful conservative treatment of cesarean scar pregnancy with systemically administered methotrexate and subsequent dilatation and curettage: a case report. case rep obstet gynecol 2012; 2012:248564. doi: 10.1155/2012/248564. 19. haimov-kochman r, sciaky-tamir y, yanai n, yagel s. conservative management of two ectopic pregnancies in previous uterine scars. ultrasound obstet gynecol 2002; 19:616–19. doi: 10.1046/j.1469-0705.2002.00719.x. 20. wang cb, tseng cj. primary evacuation therapy for cesarean scar pregnancy: three new cases and review. ultrasound obstet gynecol 2006; 27:222–6. doi: 10.1002/uog.2644. 21. chuang j, seow km, cheng wc, tsai yl, hwang jl. conservative treatment of ectopic pregnancy in a caesarean section scar. bjog 2003; 110:869–70. doi: 10.1111/j.14710528.2003.02117.x. 22. yang mj, jeng mh. combination of transarterial embolization of uterine arteries and conservative surgical treatment for pregnancy in a cesarean section scar: a report of 3 cases. j reprod med 2003; 48:213–16. 23. kung ft, huang tl, chen cw, cheng yf. image in reproductive medicine: cesarean scar ectopic pregnancy. fertil steril 2006; 85:1508–9. doi: 10.1016/j.fertnstert.2005.12.016. 24. wang cj, yuen lt, chao as, lee cl, yen cf, soong yk. caesarean scar pregnancy successfully treated by operative hysteroscopy and suction curettage. bjog 2005; 112:839–40. doi: 10.1111/j.1471-0528.2005.00532.x. 25. chao a, wang th, wang cj, lee cl, chao as. hysteroscopic management of cesarean scar pregnancy after unsuccessful methotrexate treatment. j minim invasive gynecol 2005; 12:374–6. doi: 10.1016/j.jmig.2005.05.004. 26. lee cl, wang cj, chao a, yen cf, soong yk. laparoscopic management of an ectopic pregnancy in a previous caesarean section scar. hum reprod 1999; 14:1234–6. doi: 10.1093/ humrep/14.5.1234. 27. robinson jk, dayal mb, gindoff p, frankfurter d. a novel surgical treatment for cesarean scar pregnancy: laparoscopically assisted operative hysteroscopy. fertil steril 2009; 92:1497.e13–16. doi: 10.1016/j.fertnstert.2009.07.996. 28. ben nagi j, helmy s, ofili-yebovi d, yazbek j, sawyer e, jurkovic d. reproductive outcomes of women with a previous history of caesarean scar ectopic pregnancies. hum reprod 2007; 22:2012–15. doi: 10.1093/humrep/dem078. 29. armstrong v, hansen wf, van voorhis bj, syrop ch. detection of cesarean scars by transvaginal ultrasound. obstet gynecol 2003; 101:61–5. doi: 10.1016/s0029-7844(02)02450-x. 1. fylstra dl. ectopic pregnancy within a cesarean scar: a review. obstet gynecol surv 2002; 57:537–43. doi: 10.1097/00006254200208000-00024. 2. rizk b, abuzeid m, rizk c, owens s, lafleur j, simaika y. ectopic pregnancy. in: rizk b, ed. ultrasound in reproductive medicine and infertility. cambridge, uk: cambridge university press, 2010. pp. 259–70. doi: 10.1017/cbo9780511776854.033. 3. rizk b, holliday cp, owens s, abuzeid m. cervical and cesarean scar ectopic pregnancies: diagnosis and management. middle east fertil soc j 2013; 18:67–73. doi: 10.1016/j.mefs. 2013.01.011. 4. jurkovic d, hillaby k, woelfer b, lawrence a, salim r, elson cj. first-trimester diagnosis and management of pregnancies implanted into the lower uterine segment cesarean section scar. ultrasound obstet gynecol 2003; 21:220–7. doi: 10.1002/uog.56. 5. rotas ma, haberman s, levgur m. cesarean scar ectopic pregnancies: etiology, diagnosis, and management. obstet gynecol 2006; 107:1373–81. doi: 10.1097/01.aog.00002186 90.24494.ce. 6. seow km, huang lw, lin yh, lin my, tsai yl, hwang jl. cesarean scar pregnancy: issues in management. ultrasound obstet gynecol 2004; 23:247–53. doi: 10.1002/uog.974. 7. ash a, smith a, maxwell d. caesarean scar pregnancy. bjog 2007; 114:253–63. doi: 10.1111/j.1471-0528.2006.01237.x. 8. sadeghi h, rutherford t, rackow bw, campbell kh, duzyj cm, guess mk, et al. cesarean scar ectopic pregnancy: case series and review of the literature. am j perinatol 2010; 27:111–20. doi: 10.1055/s-0029-1224874. 9. arslan m, pata o, dilek tu, aktas a, aban m, dilek s. treatment of viable cesarean scar ectopic pregnancy with suction curettage. int j gynaecol obstet 2005; 89:163–6. doi: 10.1016/j.ijgo.2004.12.038. 10. wang yl, su th, chen hs. operative laparoscopy for unruptured ectopic pregnancy in a caesarean scar. bjog 2006; 113:1035–8. doi: 10.1111/j.1471-0528.2006.01031.x. 11. maymon r, halperin r, mendlovic s, schneider d, vaknin z, herman a, et al. ectopic pregnancies in caesarean scars: the 8 year experience of one medical centre. hum reprod 2004; 19:278–84. doi: 10.1093/humrep/deh060. 12. vial y, petignat p, hohlfeld p. pregnancy in a cesarean scar. ultrasound obstet gynecol 2000; 16:592–3. doi: 10.1046/j.1469-0705.2000.00300-2.x. 13. maymon r, halperin r, mendlovic s, schneider d, herman a. ectopic pregnancies in a caesarean scar: review of the medical approach to an iatrogenic complication. hum reprod update 2004; 10:515–23. doi: 10.1093/humupd/dmh042. 14. jurkovic d. caesarean section scar ectopic pregnancy: a new problem or new name for an old one? australas j ultrasound med 12:22–23. 15. godin pa, bassil s, donnez j. an ectopic pregnancy developing in a previous caesarean section scar. fertil steril 1997; 67:398–400. doi: 10.1016/s0015-0282(97)81930-9. 16. ravhon a, ben-chetrit a, rabinowitz r, neuman m, beller u. successful methotrexate treatment of a viable pregnancy within a thin uterine scar. br j obstet gynaecol 1997; 104:628–9. http://dx.doi.org/10.1111/j.1471-0528.1997.tb11547.x http://dx.doi.org/10.1111/j.1479-828x.1998.tb02976.x http://dx.doi.org/10.1111/j.1479-828x.1998.tb02976.x http://dx.doi.org/10.1155/2012/248564 http://dx.doi.org/10.1046/j.1469-0705.2002.00719.x http://dx.doi.org/10.1002/uog.2644 http://dx.doi.org/10.1111/j.1471-0528.2003.02117.x http://dx.doi.org/10.1111/j.1471-0528.2003.02117.x http://dx.doi.org/10.1016/j.fertnstert.2005.12.016 http://dx.doi.org/10.1111/j.1471-0528.2005.00532.x http://dx.doi.org/10.1016/j.jmig.2005.05.004 http://dx.doi.org/10.1093/humrep/14.5.1234 http://dx.doi.org/10.1093/humrep/14.5.1234 http://dx.doi.org/10.1016/j.fertnstert.2009.07.996 http://dx.doi.org/10.1093/humrep/dem078 http://dx.doi.org/10.1016/s0029-7844%2802%2902450-x http://dx.doi.org/10.1097/00006254-200208000-00024 http://dx.doi.org/10.1097/00006254-200208000-00024 http://dx.doi.org/10.1017/cbo9780511776854.033 http://dx.doi.org/10.1016/j.mefs.2013.01.011 http://dx.doi.org/10.1016/j.mefs.2013.01.011 http://dx.doi.org/10.1002/uog.56 http://dx.doi.org/10.1097/01.aog.0000218690.24494.ce http://dx.doi.org/10.1097/01.aog.0000218690.24494.ce http://dx.doi.org/10.1002/uog.974 http://dx.doi.org/10.1111/j.1471-0528.2006.01237.x http://dx.doi.org/10.1055/s-0029-1224874 http://dx.doi.org/10.1016/j.ijgo.2004.12.038 http://dx.doi.org/10.1111/j.1471-0528.2006.01031.x http://dx.doi.org/10.1093/humrep/deh060 http://dx.doi.org/10.1046/j.1469-0705.2000.00300-2.x http://dx.doi.org/10.1093/humupd/dmh042 http://dx.doi.org/10.1016/s0015-0282%2897%2981930-9 1department of behavioural medicine, sultan qaboos university hospital, muscat, oman; 2department of child & adolescent psychiatry, king’s college london, london, uk; 3department of psychiatry, oman medical specialty board, muscat, oman *corresponding author’s e-mail: hsmirza@mail.com اهلذيان الناجم عن عقار الباليربيدون باملتيت عند مراهق مصاب بالفصام تقرير حالة ح�شن مريزا، دنكن هاردينج، ن�رض البلو�شي abstract: schizophrenia is a serious long-term mental disorder which usually presents in adolescence or early adulthood. however, poor adherence to oral antipsychotics can lead to relapse and rehospitalisation. we report an adolescent male with schizophrenia who was referred to the south london & maudsley national health service foundation trust, london, uk, in 2015 due to worsening psychotic symptoms. following poor compliance with oral medications, a four-week regimen of paliperidone palmitate long-acting injections was initiated, with an initial positive response. however, 10 days after the second dose, the patient developed severe acute-onset delirium with fluctuating levels of consciousness. paliperidone palmitate was discontinued and the patient instead underwent a course of zuclopenthixol decanoate long-acting injections with a favourable outcome. keywords: adolescent psychiatry; schizophrenia; antipsychotic agents; delirium; paliperidone palmitate; zuclopenthixol; case report; united kingdom. امللخ�ص: مر�ض الف�شام هو ا�شطراب نف�شي خطري على املدى الطويل وعادة ما يظهر املر�ض خالل فرتة املراهقة اأو مرحلة البلوغ املبكر. ويعترب �شعف اللتزام يف تناول الأدوية عن طريق الفم من اأ�شباب اأنتكا�شة املري�ض و�شببا لإعادة تنومي املر�شى. نعر�ض هنا تقرير حلالة مراهق ذكر م�شاب بالف�شام مت حتويلة اإىل موؤ�ش�شة جنوب لندن ومود�شلي للخدما ت ال�شحية الوطنية، لندن، اململكة املتحدة عام 2015 ب�شبب تفاقم اأعرا�ض ذهانية نتيجة �شوء اللتزام يف تناول الدوية عن طريق الفم، بداأت خطة الأربع اأ�شابيع با�شتخدام حقن الباليربيدون باملتيت طويلة املفعول مع ا�شتجابة اإيجابية اأولية. ومع ذلك، بعد 10 اأيام من اجلرعة الثانية اأ�شيب املري�ض باأعرا�ض حادة و�شديدة من املفعول طويل الزكلوبينثك�شول عقار بحقن وا�شتبداله باملتيت الباليربيدون اأ�شتخدام اإيقاف مت الوعي. م�شتوى يف تقلبات مع الهذيان والتي ترتبت علية نتائج اإيجابية. تقرير الزكلوبينثك�شول؛ عقار باملتيت؛ الباليربيدون عقار الهذيان؛ الذهان؛ م�شادات الف�شام؛ للمراهقني؛ النف�شي الطب املفتاحية: الكلمات حالة؛ اململكة املتحدة. paliperidone palmitate-induced delirium in an adolescent with schizophrenia case report *hassan mirza,1 duncan harding,2 naser al-balushi3 case report sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e208–210, epub. 9 sep 18 submitted 13 oct 17 revisions req. 24 oct & 11 dec 17; revisions recd. 2 nov 17 & 8 jan 18 accepted 25 jan 18 doi: 10.18295/squmj.2018.18.02.014 schizophrenia is a serious mental disorder characterised by the distortion of thought, perc-eption and affect.1 overall, the disease has a massive global burden, with a lifetime prevalence of four cases per 1,000 individuals.2,3 in younger patients, extra care needs to be taken when prescribing antipsychotic medications, since such individuals are at higher risk of developing side-effects.4 in general, second-generation antipsychotics (sgas) are the first line of treatment for children and adolescents, whereas first-generation antipsychotics (fgas) should be avoided due to the high risk of extrapyramidal sideeffects.5 nevertheless, adherence to oral antipsychotic medications remains an ongoing challenge among patients with schizophrenia; the administration of medication in the form of a long-acting injection (lai) can help overcome this issue, thus reducing the chance of relapse and rehospitalisation.6 case report a 16-year-old caucasian male patient was referred by his general practitioner to the child & adolescent mental health services of the south london & maudsley national health service foundation trust, london, uk, in 2015, following the worsening of existing psychotic symptoms. the patient had a oneyear history of low mood, anxiety, paranoia and social isolation. these symptoms initially presented solely in the context of cannabis use; however, the patient had stopped smoking cannabis when he noticed that this worsened his distress. psychiatrically, he exhibited all the hallmarks of paranoid ideation. he believed that his room was being monitored and described auditory command hallucinations in which voices would tell him to get dressed in the middle of the night and go outside to walk in the park, as well as hassan mirza, duncan harding and naser al-balushi case report | e209 after the second dose, the patient developed acuteonset altered sensorium and was admitted to the accident & emergency department. prior to this, the patient had been unable to sleep and reported unusual perceptual experiences such as hearing thunder and storms and smelling an unpleasant odour like burning tyres. he also suffered from fluctuating levels of consciousness, disordered speech with ‘snort’-like breathing and flailing movements of the extremities. neurological impairment was minor, with a glasgow coma scale score of 13–15. there were no frank convulsions and the patient was afebrile and did not report any headaches. he did not show any evidence of autonomic system imbalance and there was no rigidity or other features indicative of neuroleptic malignant syndrome. his c-reactive protein and serum creatine kinase levels were normal and a computed tomography scan of the brain, comprehensive metabolic panel, liver function tests, urinalysis and urine toxicology screening were unremarkable. a full blood count initially showed mildly raised leukocytes; however, when repeated the next day, all parameters were within normal ranges, with no signs indicative of a focal or systemic infection. by the evening of the next day, the patient had regained consciousness and was found to be fully alert and awake. he could not recall any of the events of the previous day. he was subsequently discharged against medical advice and returned home to the care of his mother. since the patient continued to experience both positive and negative schizophrenic symptoms, zuclopenthixol decanoate injections were prescribed at an initial test dose of 100 mg, before eventually being titrated to 200 mg monthly. after three months of treatment, there was a significant improvement in psychotic symptoms. at the time of the writing, the patient had not reported any serious side-effects and his activities of daily living had reverted to their premorbid status. discussion the present case report describes an adolescent with schizophrenia who developed postinjection delirium/ sedation syndrome (pdss) following a regimen of paliperidone palmitate lai. to the best of the authors’ knowledge, few similar cases have been reported in the literature. kokalj et al. reported a female schizophrenic patient who became delirious following an olanzapine lai and a higher dose of paliperidone palmitate; as with the current case, the patient had a history of cannabis use.8 paliperidone palmitate injections differ from other antipsychotic depot injections in that two loading making derogatory remarks about him. the command hallucinations overpowered his usual distress of leaving his house, but did not tell him to harm himself or others. he also described elements of thought interference—i.e. thoughts being taken from and put into his head—and worried that his thoughts were being broadcast to others. the patient had a strong family history of mental disorders, with a history of depression in his mother and two half-siblings who suffered from psychotic illness. regarding his personal history, he had achieved normal developmental milestones and attended primary school; however, he had been excluded from secondary school following repeated altercations with his teachers. he had no friends and led a reclusive lifestyle. his social functioning had deteriorated significantly over the last year and even more drastically in the weeks prior to his referral. he reported feelings of low mood, anxiety, anhedonia and difficulty falling asleep. upon referral, the patient was initially prescribed oral olanzapine at a dosage of 10 mg once daily, which was titrated up to 20 mg per day. however, due to poor compliance with oral medications and the persistence of his psychotic symptoms, a regimen of olanzapine lais at a dose of 300 mg every two weeks was initiated. although he demonstrated a reasonable response to the depot injections, these had to be discontinued due to the unavailability of a post-injection observation service and the lack of transport provision. subsequently, the patient was prescribed oral risperidone for approximately two months, after which risperidone lai was commenced. the dose of the depot injection was titrated to 50 mg every two weeks. the patient showed a moderate response to the treatment, although he was only partially compliant, often refusing injections and not attending his appointments every two weeks. as a result, the lai treatment was also discontinued and the patient was again prescribed oral risperidone. this oral regimen was continued for approximately one month. the option of a monthly lai formulation was then discussed with the patient and his caretaker. eventually, a regimen of paliperidone palmitate lais every four weeks was agreed upon. based on his body mass index and medium build, the patient was prescribed off-label paliperidone palmitate lais, as per the manufacturer’s instructions and the recommendations of the british national formulary for adult patients, at an initial loading dose of 150 mg, followed by 100 mg on the 8th day.7 both the patient and his mother reported an initial positive response to the medication, with a marked reduction in distressing psychotic symptoms. however, 10 days paliperidone palmitate-induced delirium in an adolescent with schizophrenia case report e210 | squ medical journal, may 2018, volume 18, issue 2 3. saha s, chant d, welham j, mcgrath j. a systematic review of the prevalence of schizophrenia. plos med 2005; 2:e141. doi: 10.1371/journal.pmed.0020141. 4. correll cu. addressing adverse effects of antipsychotic treatment in young patients with schizophrenia. j clin psychiatry 2011; 72:e01. doi: 10.4088/jcp.9101tx6c. 5. taylor d, paton c, kapur s. children and adolescents. in: the maudsley prescribing guidelines in psychiatry, 12th ed. hoboken, new jersey, usa: wiley-blackwell, 2015. pp. 353−408. 6. chue p. long-acting risperidone injection: efficacy, safety, and cost-effectiveness of the first long-acting atypical antipsychotic. neuropsychiatr dis treat 2007; 3:13−39. doi: 10.2147/nedt.2007. 3.1.13. 7. british national formulary. bnf 70: september 2015 march 2016. from: https://pharm.reviews/images/statyi/british-national-for mulary-2015.pdf accessed: jan 2018. 8. kokalj a, rijavec n, tavčar r. delirium with anticholinergic symptoms after a combination of paliperidone and olanzapine pamoate in a patient known to smoke cannabis: an unfortunate coincidence. bmj case rep 2016; 2016:bcr2016214806. doi: 10. 1136/bcr-2016-214806. 9. mcclellan j, stock s; american academy of child and adolescent psychiatry (aacap) committee on quality issues (cqi). practice parameter for the assessment and treatment of children and adolescents with schizophrenia. j am acad child adolesc psychiatry 2013; 52:976−90. doi: 10.1016/j.jaac.2013.02.008. 10. fàbrega m, sugranyes g, baeza i. two cases of long-acting paliperidone in adolescence. ther adv psychopharmacol 2015; 5:304−6. doi: 10.1177/2045125315600141. 11. alphs l, gopal s, karcher k, kent j, sliwa jk, kushner s, et al. are the long-acting intramuscular formulations of risperidone or paliperidone palmitate associated with post-injection delirium/ sedation syndrome? an assessment of safety databases. curr drug saf 2011; 6:43−5. doi: 10.2174/157488611794480070. 12. european medicines agency. xeplion. from: www.medicines. org.uk/emc/files/pil.7652.pdf accessed: jan 2018. 13. jones pb, barnes tr, davies l, dunn g, lloyd h, hayhurst kp, et al. randomized controlled trial of the effect on quality of life of secondvs first-generation antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic drugs in schizophrenia study (cutlass 1). arch gen psychiatry 2006; 63:1079−87. doi: 10.1001/archpsyc.63.10.1079. 14. crossley na, constante m, mcguire p, power p. efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: meta-analysis. br j psychiatry 2010; 196:434−9. doi: 10.1192/bjp.bp.109.066217. 15. pope s, zaraa sg. efficacy of long-acting injectable antipsychotics in adolescents. j child adolesc psychopharmacol 2016; 26:391−4. doi: 10.1089/cap.2015.0091. 16. lytle s, mcvoy m, sajatovic m. long-acting injectable antipsychotics in children and adolescents. j child adolesc psychopharmacol 2017; 27:2−9. doi: 10.1089/cap.2016.0055. doses are required at the start of treatment, consisting of 150 mg on day one and 100 mg on day eight; these are then adjusted at monthly intervals according to the patient’s response, with a recommended maintenance dose of 75 mg per month (range: 25–150 mg).7 although no long-acting antipsychotic injections are yet officially recommended for individuals under the age of 18 years, their use is not uncommon in patients with a history of poor medication adherence.9 paliperidone palmitate is deemed an effective and acceptably tolerated antipsychotic in adolescents with psychotic spectrum disorders.10 in a review of clinical trial databases, alphs et al. found no cases of pdss reported in completed trials of risperidone lai, with only one pdss case reported in a paliperidone palmitate lai trial; however, the patient in this instance had been randomly allocated to the placebo treatment.11 nevertheless, manufacturers of paliperidone palmitate lai have acknowledged that a confusional state is a possible, albeit rare, adverse reaction to the drug.12 although sgas have been increasingly used as the first line of treatment for schizophrenia over the past decade, several studies have suggested there is limited or no advantage between the two classes of antipsychotics in terms of efficacy, with the only difference being the drug side-effect profile.13,14 similarly, despite their limited use, fgas remain an option in the management of psychotic disorders among adolescents, as in the current case wherein the patient showed a good response and tolerability to zuclopenthixol decanoate.15,16 conclusion schizophrenic patients and their caretakers should be made aware that pdss is an uncommon sideeffect of sgas such as paliperidone palmitate. this case illustrates the importance of patient and family education regarding the potential side-effects of antipsychotic lais. references 1. world health organisation. the icd-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines tenth revision of the international statistical classification of diseases and related health problems. from: http://apps.who.int/iris/handle/10665/37958 accessed: jan 2018. 2. bhugra d. the global prevalence of schizophrenia. plos med 2005; 2:e151. doi: 10.1371/journal.pmed.0020151. https://doi.org/10.1371/journal.pmed.0020141 https://doi.org/10.4088/jcp.9101tx6c https://doi.org/10.2147/nedt.2007.3.1.13 https://doi.org/10.2147/nedt.2007.3.1.13 https://doi.org/10.1136/bcr-2016-214806 https://doi.org/10.1136/bcr-2016-214806 https://doi.org/10.1016/j.jaac.2013.02.008 https://doi.org/10.1177/2045125315600141 https://doi.org/10.2174/157488611794480070 https://doi.org/10.1001/archpsyc.63.10.1079 https://doi.org/10.1192/bjp.bp.109.066217 https://doi.org/10.1089/cap.2015.0091 https://doi.org/10.1089/cap.2016.0055 https://doi.org/10.1371/journal.pmed.0020151 a 62 year-old woman, diagnosed with and on treatment for hypertension, was referred to the haematology department at the royal hospital, oman, with an accidental finding of increased white blood cells (wbc) in her full blood count, a total of 76 x 109/l. there was history of giddiness, fever and easy fatigability prior to presentation. a repeat blood work-up showed a haemoglobin level of 10.8 g/dl, with normal mean corpuscular volume (mcv) and mean corpuscular haemoglobin) (mch), a platelet count of 55 x 109/l and a wbc count of 103 x 109/l. all other blood investigations including renal function tests, liver function tests and bone profile, were normal. viral studies, blood and urine cultures were negative. the blood film showed >90% large sized blasts with abundant cytoplasm and prominent nucleoli [figure 1a]. the bone marrow aspirate (bma) [figure 1b] and flow cytometry findings were consistent with acute myeloid leukaemia (aml-m1) according to the french-americanbritish [fab] classification. later, cytogenetic investigation revealed a positive flt-3 mutation. on the second day of admission, she was found to have a neck swelling and developed shortness of breath. an emergency neck computed tomography (ct) scan was done [figure 1c] which showed a soft tissue thickening (mass) of the nasopharynx and oropharynx encroaching on the airway and almost occluding it. the patient was started on standard induction chemotherapy, (cytarabine once daily for seven days and daunorubicin twice daily for three days intravenously), as well as prophylaxis with antiviral and antifungal medications. the patient remained stable and afebrile. she was discharged 22 days after the induction of chemotherapy with a haemoglobin level of 9.6 g/dl and platelet count of 44 x 109/l. a week later she was seen in the day care unit, had a squ med j, november 2011, vol. 11, iss. 4, pp. 522-523, epub. 25th oct 11 submitted 8th feb 11 revision req. 12th apr 11, revision recd. 25th may 11 accepted 24th aug 11 department of haematology & transfusion medicine, royal hospital, muscat, oman. *corresponding author email: msay99@hotmail.com ابيضاض خناعي حاد حديث التشخيص مع تورم يف الرقبة مها اليحـــيائي، �ُضليمى اللمكي، ُمهنا امل�ضلحي newly diagnosed acute myeloid leukemia with neck swelling *maha al-yahyai, sulayma al-lamki, muhanna al-musalhi interesting medical image figure 1: results of tests showing patient in leukaemic state. a: blood film showing circulating blasts; b: bone marrow aspirate showing loss of normal cells and infiltration of the marrow by blasts, and c: computed tomography scan of neck showing the swelling (arrow), nearly occluding the nasopharyngeal region. maha al-yahyai, sulayma al-lamki and muhanna al-musalhi interesting medical image | 523 repeat blood film and bma done which was consistent with morphologic remission [figure 2 a & b]. a repeat neck ct scan showed that the previously noted soft tissue thickening in the nasopharynx and oropharynx had disappeared as well [figure 2c]. a biopsy of the mass was not done earlier due to the location and the high risk of bleeding in this case. however, it disappeared after treatment and this would indicate that it was a leukaemic tissue mass. she received two consolidation chemotherapies followed by allogenic bone marrow transplantation. however, she relapsed after three months and died. the main presentations in patients with aml include peripheral blood and bone marrow involvement. extramedullary presentations, such as head and neck swellings, have been reported. in our literature search, we found only a few cases with some resemblance to ours. de fonseca reported a child with a neck swelling who sought medical attention from a dentist where no odontogenic problem was found; however, he was subsequently diagnosed to have aml.1 hayashida et al. described a nasopharyngeal mass in a patient diagnosed with acute monocytic leukemia.2 udayakumar and sundareshan reported a girl with neck swelling who was diagnosed with aml-m6.3 amin et al. mentioned that aml subtypes m4 and m5 have a higher incidence of oral infiltrations and reported one case of aml-m0 which presented with palatal swelling.4 an aml case, occurring in the tonsillar fossa as an ulcerating lesion with a neck mass, has also been described.5 a patient who achieved remission following the diagnosis of an aml-m0, presented with a mass in the left retropharyngeal and perivertebral regions, a mass in the left vallecula, and a mass infiltrating the right preepiglottic tissue. he was later diagnosed to have granulocytic sarcoma.6 finally, another study was conducted to summarise the clinical and radiologic presentations including pertinent imaging features of granulocytic sarcoma. the lesions were mainly found in the central nervous system, subcutaneous tissues, and genitourinary system.7 no articles were found in the literature mentioning an aml-m1 case with neck swelling or nasopharynx involvement. references 1. da fonseca ma. head and neck extramedullary disease as the initial presentation of acute myelogenous leukemia in a child. j dent child (chic) 2007; 74:241–4. 2. hayashida t, araki y, kawano k, kamata t, kawai y, takeuchi k, et al. extramedullary diseases as presenting features of a leukemic acute monocytic leukemia. rinsho ketsueki 1992; 33:1679–84. 3. udayakumar am, sundareshan ts. tetrasomy 21 as a sole abnormality in erythroleukemia. cancer genet cytogenet 1995; 85:85–7. 4. amin ks, ehsan a, mcguff hs, albright sc. minimally differentiated acute myelogenous leukemia (aml-m0) granulocytic sarcoma presenting in the oral cavity. oral oncol 2002; 38:516–19. 5. zapf b, carpenter rj 3rd, snyder gg 3rd. ulcerating tumor of tonsil and neck mass as occurrence of acute myelocytic leukemia. otolaryngol head neck surg 1981; 89:560–3. 6. ozcelik t, ali r, ozkalemkaş f, ozkocaman v, coşkun h, erişen l, et al. a case of granulocytic sarcoma during complete remission of acute myeloid leukemia with multiple masses involving the larynx and nasopharynx. kulak burun bogaz ihtis derg 2003; 11:183–8. 7. ooi gc, chim cs, khong pl, au wy, lie ak, tsang kw, kwong yl, et al. radiologic manifestations of granulocytic sarcoma in adult leukaemia. ajr am j roentgenol 2001; 176:1427–31. figure 2: patient’s post-treatment state. a: blood films showing normal blood cells; b: bone marrow aspirate showing normal cell lines with different stages of maturation, and c: neck ct scan showing resolution of the swelling (arrow). department of radiology, armed forces hospital, muscat, oman *corresponding author e-mail: drphilipsgm@yahoo.com مرض مندور حالة نادرة لورم مؤمل يف الثدي عد امرأة متوسطة العمر فيليب�س جورج مايكل، طاهرة ال�سعدي، راك�س جاخماندركار mondor’s disease rare case of a painful breast lump in a middle-aged woman *philips g. michael, tahra al-saadi, rakesh jamkhandikar a 52-year-old postmenopausal female presented to the surgical outpatient depart-ment of the armed forces hospital, muscat, oman, in 2015 with a mildly tender lump in the left breast of two weeks’ duration. she had no associated fever or nipple discharge. the patient had six children whom she had breastfed normally. she was not lactating at the time of presentation and did not have a history of previous breast-related surgeries or trauma. a physical examination revealed a cord-like lump in the lower inner quadrant of the left breast that was mildly tender along with mild erythematic skin changes. the axillary lymph nodes were not palpable. mammography and ultrasonography of both breasts was performed. the mammography images showed superficial diffuse cord-like tubular structures in both breasts, although these were more noticeable in the left breast [figure 1]. in addition, there was evidence of some skin thickening in the areola-nipple complex on the left side. ultrasonography indicated that the structures were markedly dilated superficial veins. some of these veins demonstrated flow on a colour doppler ultrasound, while a few of the others demonst rated intraluminal thrombosis with no flow [figure 2]. based on the imaging findings, a diagnosis of bilateral mondor’s disease was made. the patient was treated symptomatically with anti-inflammatory and analgaesic medications. she responded well to treatment and became clinically asymptomatic six weeks later. at this time, a follow-up scan demonstrated resolution of the superficial venous thrombosis. comment with an incidence of approximately 0.5–0.8%, mondor’s disease is a very rare benign condition characterised by thrombophlebitis of the subcutaneous veins of the chest wall.1,2 the disease is named after henri mondor, a french surgeon, who first reported it in 1939.3 in most cases, the condition is idiopathic; however, it can be associated with a previous history of breast-related trauma, surgical procedures, biopsies interesting medical image sultan qaboos university med j, may 2017, vol. 17 iss. 2, pp. e244–245, epub. 20 jun 17 submitted 27 nov 16 revision req. 8 jan 17; revision recd. 14 feb 17 accepted 2 mar 17 figure 1: mammography of both breasts of a 52-year-old postmenopausal female from the (a) craniocaudal and (b) mediolateral oblique aspects showing superficial diffuse cord-like tubular structures (arrows) in the left breast. r = right breast; l = left breast; cc = craniocaudal; mlo = mediolateral oblique. doi: 10.18295/squmj.2016.17.02.021 philips g. michael, tahra al-saadi and rakesh jamkhandikar interesting medical image | e245 narrowed areas, giving them a beaded appearance, most commonly located in the upper outer aspect of the breast, unlike dilated ducts.1 moreover, a thrombosed vein at a periareolar location does not terminate at the areola and bilaterality is rare in mondor’s disease.1 in their evaluation of imaging findings in mondor’s disease, yanik et al. concluded that colour doppler ultrasonography can help in establishing a correct diagnosis as well as monitoring resolution after treatment.5 similar findings were also noted by adeniji-sofoluwe et al.6 a clot may be seen as an intraluminal filling defect within the dilated superficial veins with no flow on colour or spectral doppler studies.1,5,6 after a diagnosis of mondor’s disease has been made from initial mammographic and sonographic findings, a short-interval imaging follow-up is recommended within six months to monitor resolution of the condition.1,5 since mondor’s disease is benign and selflimiting, conservative management is recommended. this may include the local application of heat, use of systemic or topical anti-inflammatory and analgaesic medications and support for the affected breast by wearing a well-fitting brassière.1 antibiotics are not required unless there is evidence of infection. in the acute phase of the disease, topical anticoagulants/ antithrombotics can be applied along with oral lowmolecular-weight heparin, which can help to relieve associated symptoms of swelling, pain and redness by decreasing the size of the thrombus.2,4 references 1. shetty mk, watson ab. mondor’s disease of the breast: sonographic and mammographic findings. ajr am j roentgenol 2001; 177:893–6. doi: 10.2214/ajr.177.4.1770893. 2. pasta v, d’orazi v, sottile d, del vecchio l, panunzi a, urciuoli p. breast mondor’s disease: diagnosis and management of six new cases of this underestimated pathology. phlebology 2015; 30:564–8. doi: 10.1177/0268355514553494. 3. mondor h. [subcutaneous subacute phlebitis of the anterolateral thoracic wall.] mem acad chir (paris) 1939; 65:1271–8. 4. paniagua ct, negron zd. mondor’s disease: a case study. j am acad nurse pract 2010; 22:312–15. doi: 10.1111/j.17457599.2010.00513.x. 5. yanik b, conkbayir i, oner o, hekimoğlu b. imaging findings in mondor’s disease. j clin ultrasound 2003; 31:103–7. doi: 10.1002/jcu.10134. 6. adeniji-sofoluwe a, afolabi o. mondor’s disease: classical imaging findings in the breast. bmj case rep 2011; 2011: bcr0720114521. doi: 10.1136/bcr.07.2011.4521. or central venous catheter insertion.4 a few cases have reported an association with breast cancer, although as yet no direct relationship has been established.1,4 in cases where the underlying aetiology is not obvious, patients with mondor’s disease should be investigated to determine the cause of the disease, if possible, and to exclude breast cancer, lymphatic spread from a carcinoma, a hypercoagulable state or connective tissue disease.2,4 recognition and differentiation of this rare condition from a breast abscess or malignancy is also essential.4 on mammography, thrombosed veins observed in cases of mondor’s disease are superficial, tubular and beaded cord-like densities which correspond to the clinically palpable and tender cord-like breast lumps.1,2 however, it is important to avoid mistaking superficial thrombosed veins for dilated ducts during imaging.1 in contrast, the thrombosed veins appear on ultrasonography as superficially located long tubular anechoic non-compressible structures interrupted by figure 2: colour doppler ultrasonography of both breasts of a 52-year-old postmenopausal female showing flow in some of the superficial veins (arrow) and intraluminal thrombosis with no flow in a few of the others (arrowheads). sag = sagittal; s = superficial; tr= transverse. https://doi.org/10.2214/ajr.177.4.1770893 https://doi.org/10.1177/0268355514553494 https://doi.org/10.1111/j.1745-7599.2010.00513.x https://doi.org/10.1111/j.1745-7599.2010.00513.x https://doi.org/10.1002/jcu.10134 https://doi.org/10.1136/bcr.07.2011.4521 1physiology research center, institute of neuropharmacology and 2department of laboratory sciences, school of para-medicine, kerman university of medical sciences, kerman, iran; 3department of immunology, school of medicine, zahedan university of medical sciences, zahedan, iran; 4molecular medicine research center and 5department of immunology, school of medicine, rafsanjan university of medical sciences, rafsanjan, iran *corresponding author e-mail: jafarzadeh14@yahoo.com فقدان التوازن يف عوامل النسخ للخلية التائية يف مرضى التهاب الدرقية املنسوب هلاشيموتو فاهد �سفدري، اإبراهيم علي جاين، مرمي نعمتي، عبداهلل جعفر زاده abstract: objectives: imbalances in effector t cell functioning have been associated with a number of autoimmune diseases, including hashimoto’s thyroiditis (ht). differentiation of effector t helper (th) 1, th2, th17 and regulatory t cell (treg) lymphocytes is regulated by transcription factors, including th1-specific t box (t-bet), gata binding protein-3 (gata3), retinoid-related orphan receptor (ror)-α and forkhead box p3 (foxp3). this study aimed to investigate th1/th2, th1/treg, th2/treg and th17/treg balances at the level of these transcription factors. methods: this study took place between october 2015 and august 2016. peripheral blood mononuclear cells were collected from a control group of 40 healthy women recruited from the zahedan university of medical sciences, zahedan, iran, and a patient group of 40 women with ht referred to the hazrat ali asghar hospital, zahedan. total ribonucleic acid extraction was performed and the gene expression of transcription factors was quantitated using a real-time polymerase chain reaction technique. results: expression of t-bet and gata3 was significantly elevated, while foxp3 expression was significantly diminished among ht patients in comparison with the controls (p = 0.03, 0.01 and 0.05, respectively). expression of rorα was higher among ht patients, although this difference was not significant (p = 0.15). expression of t-bet/foxp3, gata3/foxp3 and rorα/foxp3 ratios were increased among ht patients in comparison with the controls (p <0.02, <0.01 and <0.01, respectively). conclusion: these results indicate that ht patients have imbalances in th1/treg, th2/treg and th17/treg lymphocytes at the level of the transcription factors, deviating towards th1, th2 and th17 cells. correction of these imbalances may therefore be therapeutic. keywords: hashimoto thyroiditis; transcription factors; lymphocytes; th1 cells; th2 cells; th17 cells; regulatory t cells. امللخ�ص: الهدف: فقدان التوازن يف فعالة اخللية امل�ستفعلة التائية قد اأرتبطت بعدد من اأمرا�س املناعة الذاتية مبا فيها التهاب الدرقية املن�سوب لها�سيموتو. التفريق بني م�ستفعالت اخللية التائية امل�ساعدة 1، 2، 17، واخللية اللمفاوية التائية املنظمة ينظم عن طريق عوامل الن�سخ مبا فيها حمدد �سندوق التائية امل�ساعدة 1، الربوتني الرابط gata3، وغريها. تهدف هذة الدرا�سة اإىل التحقق من توازن اخلاليا التائية امل�ساعدة 1، 2، 17، وامل�ستفعلة على م�ستوى عوامل الن�سخ. الطريقة: اإجريت هذة الدرا�سة بني اأكتوبر 2015 و اأغ�سط�س 2016. مت جمع خاليا اأحادية النواة من الدم املحيطي ملجموعة التحكم املكونة من 40 إمراأة �سليمة �سحيا ومت اأختيارهن من جامعة زهدان للعلوم الطبية، زهدان، اإيران، وجمموعة املر�سى املكونة من 40 امراأة م�سابات بالتهاب الدرقية املن�سوب لها�سيموتو واملحوالت من م�ست�سفى زهرة علي اأ�سغر، زهدان. مت اإجراء ا�ستخال�س حام�س الريبونيوكلييك وتقديرالتعبري اجليني لعوامل الن�سخ باإ�ستخدام تقنية الوقت احلايل لبوليمرياز التفاعل الت�سل�سلي. النتائج: كان تعبري حمدد �سندوق التائية امل�ساعدة والربوتني الرابط gata3 مرتفع ب�سكل ملحوظ، بينما كان تعبري foxp3 منخف�س ب�سكل ملحوظ يف مر�سى التهاب الدرقية املن�سوب لها�سيموتو مقارنة مبجموعة التحكم ) على التوايل 0.05 .)p = 0.15( كان مرتفعا عند مر�سى التهاب الدرقية املن�سوب لها�سيموتو لكن الفارق مل يكن معتدا rorα تعبري .)p <0.03, <0.01 و ن�سبة التعبري كانت مرتفعة يف rorα /foxp3 و t-bet/foxp3 ،gata3/foxp3 يف مر�سى التهاب الدرقية املن�سوب لها�سيموتو مقارنة مبجموعة التحكم )على التوايل 0.01> و p <0.02, <0.01(. اخلال�صة: ت�سري هذة النتائج اإىل اأن مر�سى التهاب الدرقية املن�سوب لها�سيموتو لديهم فقدان التوازن يف اخلاليا اللمفاوية التائية امل�ساعدة 1، 2، 17، والتائية املنظمة عند م�ستوى عوامل الن�سخ والتحول جلهة هذة اخلاليا. ت�سحيح هذا التوازن قد يكون له دور عالجي. الكلمات املفتاحية: التهاب الدرقية املن�سوب لها�سيموتو؛ عوامل الن�سخ؛ اللمفاويات؛ خاليا تائية م�ساعدة 1؛ خاليا تائية م�ساعدة 2؛ خاليا تائية م�ساعدة 17؛ خاليا تائية منظمة. imbalances in t cell-related transcription factors among patients with hashimoto’s thyroiditis vahid safdari,1,2 ebrahim alijani,3 maryam nemati,2 *abdollah jafarzadeh4,5 clinical & basic research sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e174–180, epub. 20 jun 17 submitted 4 dec 16 revision req. 5 jan 17;revision recd. 23 jan 17 accepted 9 feb 17 advances in knowledge the results of the current study indicate that patients with hashimoto’s thyroiditis (ht) have t helper (th) 1/regulatory t cell (treg ), th2/treg and th17/treg cell imbalances at the level of the transcription factors, with a deviation towards th1, th2 and th17 cells. doi: 10.18295/squmj.2016.17.02.007 vahid safdari, ebrahim alijani, maryam nemati and abdollah jafarzadeh clinical and basic research | e175 hashimoto’s thyroiditis (ht) is one ofthe most prevalent organ-specific and t cellmediated disorders worldwide and predom inantly affects women, with approximately 4–10 women developing the disease for every one man.1 pathologically, ht is characterised by the homing of a number of leukocytes—such as cluster of differentiation (cd) 4+ t cells, cytotoxic t lymphocytes, b cells and natural killer cells—to the thyroid gland.2 these leukocytes then proceed to kill thyroid follicular cells via antibody-dependent cytotoxicity and/or apoptosis.2 serologically, anti-thyroid antibodies, especially anti-thyroglobulin (tg) and anti-thyroperoxidase (tpo), have been positively associated with more severe thyroid inflammation and the development of hypothyroidism.3 many immunological abnormalities have been reported in patients with hypothyroidism.4 autoreactive cd4+ t helper (th) lymphocytes play a major role in the pathogenesis of ht.3 the antigenic determinants of thyroglobulin are present on the surface of antigen-presenting cells and are recognised by specific cd4+ t cells.5 following antigenic stimulation, different effector cd4+ t cells are differentiated from naïve t cells, including th1, th2, th17 or regulatory t cell (treg) lymphocytes, which produce different cytokines.5,6 among patients with ht, th1 lymphocytes are the predominant cells in thyroid tissue.3 th1 cells mainly produce interferon (ifn)-γ, which triggers cellmediated immunity.7 the master transcription factor of th1 cells is th1-specific t box (t-bet).6 th2 cells produce interleukin (il)-4, il-5, il-6 and il-13, which are involved in the induction of humoral immune responses.7,8 for th2 cells, the master transcription factor is gata binding protein-3 (gata3). 6 th2 lymphocytes may contribute to thyroiditis through the stimulation of b cells, which produce antibodies against thyroid antigens.3 th17 cells secrete a number of cytokines, particularly il-17 (also known as il-17a), il-17f, il-21, il-22, tumour necrosis factor-α and granulocyte macrophage colony-stimulating factor.9,10 th17 cells are involved in the induction of inflammatory responses.11,12 retinoid-related orphan receptor (ror)-γt and rorα serve as the transcription factors of th17 cells.12,13 elevated numbers of th17 cells have been indicated in patients with ht.3 treg cells play a major role in the establishment of immune tolerance through the secretion of immunoregulatory cytokines such as transforming growth factor (tgf)-β, il-10 and il-35.14 treg cell functions depend on the expression of forkhead box p3 (foxp3).14,15 treg cells play a protective role against thyroid autoimmune diseases, with treg cell depletion shown to promote experimental autoimmune thyroiditis in mice.16,17 a balanced ratio of th1/th2, th1/treg, th2/treg and th17/treg cells is required for normal immune function; as such, imbalances in effector t cell functioning have been associated with a number of autoimmune diseases.12,13,18 functionally, th1 and th2 cells inhibit each other at the level of the transcription factors, with th17 and treg cells similarly inhibiting one another.19,20 although a few studies have investigated transcription factors among ht patients, few have measured th1/th2, th1/treg, th2/treg and th17/ treg cell balances at the level of these transcription factors.21,22 this study therefore aimed to determine the balance of effector t cells—specifically, th1, th2, th17 and treg cells—at the level of transcription factors by measuring the expression of their master transcription factors—t-bet, gata3, rorα/rorγt and foxp3, respectively—and determining their ratios in the peripheral blood mononuclear cells (pbmcs) of ht patients in comparison to healthy individuals. methods this study was conducted from october 2015 to august 2016 and included both ht patients and healthy individuals. the patient group consisted of 40 women with ht referred to the hazrat ali asghar hospital, zahedan, iran. a diagnosis of ht was made by expert endocrinologists based on commonly accepted clinical and laboratory criteria, including positive results for anti-tg and/or antitpo antibodies at high titres and evidence of thyroid dysfunction on a sonogram.23 at the time of the study, none of the patients were receiving antithyroid drugs, thyroid hormone replacement therapy or any according to these findings, a combination of th1, th2 and th17 cell-related immune responses may synergistically contribute to the pathogenesis of ht. application to patient care as ht patients in the current study were found to have th1/treg, th2/treg and th17/treg imbalances, correction of these imbalances may provide immunotherapeutic benefits for these patients. since th1-specific t box (t-bet), retinoid-related orphan receptor (ror)-α and forkhead box p3 (foxp3) are the specific transcription factors for th1, th17 and treg cells, respectively, the expression of t-bet/foxp3, gata binding protein-3/foxp3 and rorα/foxp3 messenger ribonucleic acid ratios may be a useful surrogate parameter to determine th1/treg, th2/treg and th17/treg cell status among ht patients. imbalances in t cell-related transcription factors among patients with hashimoto’s thyroiditis e176 | squ medical journal, may 2017, volume 17, issue 2 immunomodulatory or anti-inflammatory treatments. the control group comprised 40 healthy women who were recruited from members of staff at the zahedan university of medical sciences, zahedan. none of the healthy controls had thyroiditis or other relevant diseases or were currently suffering from any acute or chronic illnesses. a total of 10 ml of peripheral blood was taken from each subject and stored at -20 °c. thyroid hormones and autoantibodies were measured by assessing serum concentrations of triiodothyronine (t3), thyroxine (t4) and thyroid-stimulating hormone (tsh) using a commercial radioimmunoassay kit (kavoshyar iran co., tehran, iran). normal ranges were considered to be 80.0–190.0 ng/dl, 4.5–12.0 μg/dl and 0.3–4.0 μu/ml for t3, t4 and tsh, respectively.24 anti-tg and antitpo antibodies were measured using a rapid enzymelinked immunosorbent assay (genesis diagnostics ltd., ely, uk). positive anti-tg and anti-tpo concentrations were defined as >100.0 iu/ml and >75.0 iu/ml, respectively.24 the peripheral blood samples were then heparinised and loaded into a lymphocyte separation media (lymphosep®, biosera, labtech international ltd., uckfield, uk). subsequently, the pbmcs were separated by gradient centrifugation and the total ribonucleic acid (rna) extracted using a reagent (trizol®, thermofisher scientific inc., waltham, massachusetts, usa), according to the manufacturer’s guidelines. electrophoresis in ethidium bromide pretreated agarose gel was used to determine the quality of the extracted rna; purity was determined by measuring absorption using a spectrophotometer to achieve a ratio of 260:280. in order to prepare the extracted rna for quantification using a real-time polymerase chain reaction (pcr) technique, it was first converted to a complementary dna template using a synthesis kit (bioneer corp., daejeon, south korea) containing both oligo-deoxythymidine and random hexamer primers. the reverse transcription protocol involved 10 minutes at 70 °c, then one minute at 20 °c to cool, followed by the addition of the reverse transcription enzyme, incubation at 42 °c for 60 minutes and finally incubation at 95 °c for 10 minutes to halt activation of the reverse transcription enzyme. real-time pcr was carried out three times with a thermal cycler (corbett rotor-gene 6000, thermofisher scientific inc.) using a pcr master mix (sybr green i, bioneer corp.) that was mixed with 200 ng of complementary dna and 2 µl of each primer (5 pmol/µl) [table 1]. the thermal cycling conditions entailed 15 minutes at 95 °c as an initial denaturing step, 40 cycles for 30 seconds at 95 °c as a secondary denaturing step, 40 cycles for 30 seconds at 60 °c for annealing and extension and finally 40 cycles for 30 seconds at 72 °c. a housekeeping gene (β-actin) was applied to normalise the data. the quantity of expression of the transcription factors was calculated using the 2-δδct formula and expressed as units relative to the amount of the β-actin gene expression. the dissociation process, melting curves and data table 1: primers for gene expressions gene primer forward reverse t-bet 5-gatgtttgtggacgtggtcttg-3 5-ctttccacactgcacccactt-3 gata3 5-agccaggagagcagggacg-3 5-ctgttaatattgtgaagcttgtagtagag-3 rorα 5-gtgcgacttcattttcctccat-3 5-gcttaggtgataacatttacccatca-3 foxp3 5-gaacgccatccgccacaacctga-3 5-ccctgcccccaccacctctgc-3 β-actin 5-gccgggacctgactgactac-3 5-ttctccttaatgtcacgcacgat-3 t-bet = th1-specific t box; gata 3 = gata binding protein-3; rorα = retinoid-related orphan receptor-α; foxp3 = forkhead box p3. table 2: messenger ribonucleic acid expression of effector t cell-specific transcription factors using the peripheral blood mononuclear cells of female healthy controls and patients with hashimoto’s thyroiditis from zahedan, iran (n = 80) transcription factor mean mrna expression ± se p value healthy controls (n = 40) ht patients (n = 40) t-bet 1.06 ± 0.18 2.08 ± 0.43 0.03 gata3 1.02 ± 0.15 1.94 ± 0.32 0.01 rorα 1.00 ± 0.16 1.39 ± 0.24 0.15 foxp3 1.00 ± 0.38 0.35 ± 0.09 0.05 t-bet/gata3 1.58 ± 0.27 1.26 ± 0.22 0.36 gata3/foxp3 6.48 ± 2.90 13.30 ± 2.42 0.01 t-bet/foxp3 10.59 ± 5.26 29.37 ± 12.87 0.02 rorα/foxp3 6.36 ± 2.15 12.46 ± 3.06 0.01 mrna = messenger ribonucleic acid; se = standard error; ht = hashimoto’s thyroiditis; t-bet = th1-specific t box; gata 3 = gata binding protein-3; rorα = retinoid-related orphan receptor-α; foxp3 = forkhead box p3. vahid safdari, ebrahim alijani, maryam nemati and abdollah jafarzadeh clinical and basic research | e177 quantitation were carried out using the thermal cycler software (corbett rotor-gene 6000, thermofisher scientific inc.). gene expression amounts were presented as means ± standard error. the data were analysed statistically using a t-test. a p value of <0.05 was considered statistically significant. the ethical committee of the kerman university of medical sciences, kerman, iran, approved this study (#k93-418). moreover, informed written consent was obtained from all subjects prior to their participation. results the mean ages of the ht patients and healthy controls were 38.6 ± 10.6 years and 36.1 ± 11.2 years, respectively (p = 0.32). mean serum concentrations of t3, t4 and tsh were 25.7 ± 5.6 ng/dl, 2.8 ± 0.7 μg/dl and 7.2 ± 1.2 μu/ml, respectively, among ht patients and 105.0 ± 23.0 ng/dl, 8.2 ± 1.9 μg/dl and 1.8 ± 1.1 μu/ml, respectively, among healthy controls (p <0.01 each). all of the ht patients had hypothyroidism. the mean serum levels of anti-tg and anti-tpo were 543.1 ± 212.6 iu/ml and 283.6 ± 194.4 iu/ml, respectively, among ht patients and 16.7 ± 6.5 iu/ ml and 12.8 ± 4.5 iu/ml, respectively, among healthy controls (p <0.01 each). fold changes in the expression of the t-bet, gata3, rorα and foxp3 transcription factors and their ratios are shown in table 2. expression of t-bet and gata3 was significantly higher among patients with ht in comparison to the control group (p = 0.03 and 0.01, respectively). although rorα expression was increased in the patient group, the difference between figure 1: charts showing the mean messenger ribonucleic acid (mrna) expression of the (a) th1-specific t box (t-bet)/ gata binding protein-3 (gata3) and (b) t-bet/forkhead box p3 (foxp3) ratios using the peripheral blood mononuclear cells of female healthy controls and patients with hashimoto’s thyroiditis (ht) from zahedan, iran (n = 80). the mrna expression of the t-bet/gata3 ratio was lower among the ht patients than the healthy controls; however, this difference was not significant (p = 0.36). in comparison, the mrna expression of the t-bet/foxp3 ratio was significantly higher among ht patients than the healthy controls (p <0.02). t-bet = th1-specific t box; gata3 = gata binding protein-3; mrna = messenger ribonucleic acid; ht = hashimoto’s thyroiditis; foxp3 = forkhead box p3. figure 2: charts showing the mean messenger ribonucleic acid (mrna) expression of the (a) gata binding protein-3 (gata3)/forkhead box p3 (foxp3) and (b) retinoid-related orphan receptor (ror)-α/foxp3 ratios using the peripheral blood mononuclear cells of female healthy controls and patients with hashimoto’s thyroiditis (ht) from zahedan, iran (n = 80). the mrna expression of both the gata3/foxp3 and rorα/foxp3 ratios was significantly higher among ht patients than the healthy controls (p <0.01 each). gata3 = gata binding protein-3; foxp3 = forkhead box p3; mrna = messenger ribonucleic acid; ht = hashimoto’s thyroiditis; rorα = retinoid-related orphan receptor-α. imbalances in t cell-related transcription factors among patients with hashimoto’s thyroiditis e178 | squ medical journal, may 2017, volume 17, issue 2 ht patients and the healthy control group was not significant (p = 0.15). expression of foxp3 among ht patients was significantly downregulated as compared with the control group (p = 0.05). no significant difference was observed between ht patients and the control group regarding the mean messenger rna (mrna) expression of the t-bet/gata3 ratio [figure 1a]. however, mean mrna expression of the t-bet/ foxp3, gata3/foxp3 and rorα/foxp3 ratios was significantly higher among patients with ht in comparison with the healthy control group (p <0.02, <0.01 and <0.01, respectively) [figures 1b and 2]. discussion a number of studies have demonstrated alterations in the frequency and/or function of effector cd4+ t cells among ht patients.3,25,26 however, the molecular mechanisms of these changes remain unclear. the results of the current study show that expression of t-bet, the th1 transcription factor, was significantly higher among ht patients than in the healthy control group. th1 cells are induced in response to ifn-γ and il-12, which are secreted primarily by dendritic and natural killer cells, respectively.6 ifn-γand il-12related signal pathways are mediated through signal transducer and activator of transcription (stat) 1 and stat4, which cause t-bet expression; t-bet then induces ifn-γ production, strengthening th1 polarisation and forming a positive feedback loop.6 higher levels of ifn-γ and il-12 have been reported among patients with ht, which may account for the increased expression of t-bet in these patients.27,28 it seems that ht is a th1-dependent process in that the ifn-γ-secreting th1 cells activate cytotoxic t lymphocytes and macrophages, killing thyroid follicular cells.28 the current study also demonstrated that expression of gata3, the th2 transcription factor, was significantly increased among ht patients as compared to the healthy controls. differentiation of th2 cells is induced by il-4, which is secreted primarily by mast cells and basophils.8 the il-4related signal pathway is mediated through stat6, which causes gata3 expression, thus inducing the production of th2-type cytokines and self-activation in a self-reinforcing cycle.6 the elevated expression of il-4 has been previously reported among patients with ht, which may explain the increased expression of gata3 among these patients. 29 however, no significant difference was noted between ht patients and the control group in the current study regarding expression of the t-bet/gata3 ratio; this suggests that both th1 and th2 cell-related immune responses may contribute to the pathogenesis of ht. qin et al. demonstrated increased expression of th1-related cytokines in both the thyroid gland and pbmcs of ht patients.30 moreover, increased expression of th1related cytokines has been associated with elevated titres of anti-tpo antibodies, the destruction of thyroxisomes and the induction of apoptosis in thyroid follicular cells.31–33 however, the importance of the role of th2 cells in the pathogenesis of ht is still debatable. expression of foxp3, the treg cell transcription factor, was significantly reduced among patients with ht in comparison with the healthy control group in the current study. treg cells are divided into two subgroups—natural treg and inducible treg cells.14,15 the former are generated from precursor cells in the thymus, whereas antigenic stimulation in the presence of tgf-β and il-2 causes differentiation of naïve cd4+ t cells into the latter cells in the peripheral lymphoid organs.14,15 indeed, lower levels of tgf-β have been reported among patients with ht, potentially accounting for their decreased foxp3 expression.34 the findings of the present study suggest that the downregulation of treg cell-related functions may contribute to ht pathogenesis. moreover, diminished numbers of treg cells and low gene expression of foxp3 in pbmcs has previously been reported among ht patients.35,36 certain treg cellrelated cytokines (tgf-β, il-10 and il-35) have been associated with low-grade thyroid inflammation and an improvement in ht symptoms.26 however, another study demonstrated foxp3 upregulation in the t cells of peripheral blood samples from patients with ht.21 this discrepancy is perhaps attributable to differing inclusion criteria used in these studies.21,35,36 in the current study, expression of the t-bet/ foxp3, gata3/foxp3 and rorα/foxp3 ratios was significantly increased among patients with ht in comparison with the healthy control group; however, while the expression of t-bet, gata3 and rorα alone was increased, foxp3 expression alone was reduced among ht patients. therefore, it is logical that expression of the t-bet/foxp3, gata3/foxp3 and rorα/foxp3 ratios was significantly increased among the ht patients. xue et al. reported that the treg/th17 ratio among ht patients was significantly decreased when compared with a euthyroid control group.35 these findings indicate that imbalances in th1/treg, th2/treg and th17/treg cells at the level of transcription factors may contribute to the pathogenesis of ht, with a tendency towards th1, th2 and th17 cells. as such, the correction of these imbalances may be of immunotherapeutic benefit for vahid safdari, ebrahim alijani, maryam nemati and abdollah jafarzadeh clinical and basic research | e179 affected patients. as stat5 and stat3 regulate the differentiation of treg and th17 cells, respectively, the suppression of stat3 by small interfering rna molecules has been found to significantly reduce th17 cells and increase treg cells in the cd4+ t cells of patients with rheumatoid arthritis.13 similar immunotherapeutic strategies may be considered for the treatment of ht. additionally, t-bet/foxp, gata3/foxp3 and rorα/foxp3 ratios may be useful surrogate parameters to determine the status of th1/treg, th2/treg and th17/treg cells in affected patients. increased il-6 expression has been reported among patients with ht.37 in the presence of il-6 and tgf-β, the antigenic induction of naïve cd4+ t cells results in expression of rorγt and rorα (transcription factors of th17 cells) via stat3.11,13 pyzik et al. also observed increased numbers of th17 cells and elevated th17-related cytokines among patients with ht, highlighting the role of th17 in ht pathogenesis.3 in the present study, there was no significant difference between ht patients and the healthy group regarding rorα expression, although expression was higher among ht patients. no study has yet investigated expression of rorα in patients with ht; however, shi et al. reported increased rorγt among ht patients.22 it is possible that rorα plays a less important role than rorγt in the development of th17 cells. noack et al. demonstrated that knocking out the rorα and rorγt genes disturbed differentiation of naïve cd4+ t cells to th17 lymphocytes; however, knocking out the rorγt gene exhibited more powerful consequences, suggesting that the rorγt gene plays a more important role in this process.13 initially, ht was believed to be a th1-mediated disease; however, recent data suggest that th17 cells may play a more prominent role in ht pathogenesis.3,25 the results of the current study suggest that a combination of th1, th2 and th17 cell-related immune responses may synergistically contribute to the pathogenesis of ht. however, further research is needed to determine which th subset plays a more important role in the development of ht. recently, increased expression of foxp3 and t-bet was demonstrated among ht patients who were severely affected but not euthyroid.21 thus, it seems that different immunopathological mechanisms may be involved in the various expressions of the spectrum of ht-associated diseases. moreover, thyroid function may also influence the expression of t cell-related transcription factors in ht patients.21 conclusion the results of the current study indicate that ht patients have imbalances in th1/treg, th2/treg and th17/treg cells at the level of transcription factors, with a deviation towards th1, th2 and th17 cells. since t-bet, rorα and foxp3 are specific transcription factors for th1, th17 and treg cells, respectively, the expression of t-bet/foxp, gata3/foxp3 and rorα/foxp3 mrna ratios may be considered useful surrogate parameters to determine the status of th1/ treg, th2/treg and th17/treg cells in such patients. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the kerman university of medical sciences (grant #93-321). references 1. antonelli a, ferrari sm, corrado a, di domenicantonio a, fallahi p. autoimmune thyroid disorders. autoimmun rev 2015; 14:174–80. doi: 10.1016/j.autrev.2014.10.016. 2. ajjan ra, weetman ap. the pathogenesis of hashimoto’s thyroiditis: further developments in our understanding. horm metab res 2015; 47:702–10. doi: 10.1055/s-0035-1548832. 3. pyzik a, grywalska e, matyjaszek-matuszek b, roliński j. immune disorders in hashimoto’s thyroiditis: what do we know so far? j immunol res 2015; 2015:979167. doi: 10.1155/ 2015/979167. 4. jafarzadeh a, poorgholami m, izadi n, nemati m, rezayati m. immunological and hematological changes in patients with hyperthyroidism or hypothyroidism. clin invest med 2010; 33:e271–9. doi: 10.25011/cim.v33i5.14352. 5. cogni g, chiovato l. an overview of the pathogenesis of thyroid autoimmunity. hormones (athens) 2013; 12:19–29. 6. zhang y, zhang y, gu w, sun b. th1/th2 cell differentiation and molecular signals. adv exp med biol 2014; 841:15–44. doi: 10.1007/978-94-017-9487-9_2. 7. zhang y, zhang y, gu w, he l, sun b. th1/th2 cell’s function in immune system. adv exp med biol 2014; 841:45–65. doi: 10.1007/978-94-017-9487-9_3. 8. na h, cho m, chung y. regulation of th2 cell immunity by dendritic cells. immune netw 2016; 16:1–12. doi: 10.4110/in.20 16.16.1.1. 9. basu r, hatton rd, weaver ct. the th17 family: flexibility follows function. immunol rev 2013; 252:89–103. doi: 10.1111/ imr.12035. 10. rathore js, wang y. protective role of th17 cells in pulmonary infection. vaccine 2016; 34:1504–14. doi: 10.1016/j.vaccine. 2016.02.021. 11. volpe e, battistini l, borsellino g. advances in t helper 17 cell biology: pathogenic role and potential therapy in multiple sclerosis. mediators inflamm 2015; 2015:475158. doi: 10.1155/2015/475158. https://doi.org/10.1016/j.autrev.2014.10.016 https://doi.org/10.1055/s-0035-1548832 https://doi.org/10.1155/2015/979167 https://doi.org/10.1155/2015/979167 https://doi.org/10.25011/cim.v33i5.14352 https://doi.org/10.1007/978-94-017-9487-9_2 https://doi.org/10.1007/978-94-017-9487-9_3 https://doi.org/10.4110/in.2016.16.1.1 https://doi.org/10.4110/in.2016.16.1.1 https://doi.org/10.1111/imr.12035 https://doi.org/10.1111/imr.12035 https://doi.org/10.1016/j.vaccine.2016.02.021 https://doi.org/10.1016/j.vaccine.2016.02.021 https://doi.org/10.1155/2015/475158 imbalances in t cell-related transcription factors among patients with hashimoto’s thyroiditis e180 | squ medical journal, may 2017, volume 17, issue 2 12. etesam z, nemati m, ebrahimizadeh ma, ebrahimi ha, hajghani h, khalili t, et al. altered expression of specific transcription factors of th17 (rorγt, rorα) and treg lymphocytes (foxp3) by peripheral blood mononuclear cells from patients with multiple sclerosis. j mol neurosci 2016; 60:94–101. doi: 10.1007/s12031-016-0789-5. 13. noack m, miossec p. th17 and regulatory t cell balance in autoimmune and inflammatory diseases. autoimmun rev 2014; 13:668–77. doi: 10.1016/j.autrev.2013.12.004. 14. jafarzadeh a, jamali m, mahdavi r, ebrahimi ha, hajghani h, khosravimashizi a, et al. circulating levels of interleukin-35 in patients with multiple sclerosis: evaluation of the influences of foxp3 gene polymorphism and treatment program. j mol neurosci 2015; 55:891–7. doi: 10.1007/s12031-014-0443-z. 15. nie j, li yy, zheng sg, tsun a, li b. foxp3(+) treg cells and gender bias in autoimmune diseases. front immunol 2015; 6:493. doi: 10.3389/fimmu.2015.00493. 16. gonzález-amaro r, marazuela m. t regulatory (treg) and t helper 17 (th17) lymphocytes in thyroid autoimmunity. endocrine 2016; 52:30–8. doi: 10.1007/s12020-015-0759-7. 17. horie i, abiru n, sakamoto h, iwakura y, nagayama y. induction of autoimmune thyroiditis by depletion of cd4+cd25+ regulatory t cells in thyroiditis-resistant il-17, but not interferon-gamma receptor, knockout nonobese diabetic-h2h4 mice. endocrinology 2011; 152:4448–54. doi: 10.1210/en.2011-1356. 18. jafarzadeh a, shokri f. th1 and th2 responses are influenced by hla antigens in healthy neonates vaccinated with recombinant hepatitis b vaccine. iran j allergy asthma immunol 2012; 11:308–15. 19. evans cm, jenner rg. transcription factor interplay in t helper cell differentiation. brief funct genomics 2013; 12:499–511. doi: 10.1093/bfgp/elt025. 20. ichiyama k, yoshida h, wakabayashi y, chinen t, saeki k, nakaya m, et al. foxp3 inhibits rorgammat-mediated il-17a mrna transcription through direct interaction with rorgammat. j biol chem 2008; 283:17003–8. doi: 10.1074/jbc. m801286200. 21. tokić s, štefanić m, glavaš-obrovac l, jaman s, novosadová e, petrkova j, et al. the expression of t cell foxp3 and t-bet is upregulated in severe but not euthyroid hashimoto’s thyroiditis. mediators inflamm 2016; 2016:3687420. doi: 10.11 55/2016/3687420. 22. shi y, wang h, su z, chen j, xue y, wang s, et al. differentiation imbalance of th1/th17 in peripheral blood mononuclear cells might contribute to pathogenesis of hashimoto’s thyroiditis. scand j immunol 2010; 72:250–5. doi: 10.1111/j.1365-3083.20 10.02425.x. 23. caturegli p, de remigis a, rose nr. hashimoto thyroiditis: clinical and diagnostic criteria. autoimmun rev 2014; 13:391–7. doi: 10.1016/j.autrev.2014.01.007. 24. aminorroaya a, amini m, hovsepian s. prevalence of goitre in isfahan, iran, fifteen years after initiation of universal salt iodization. j health popul nutr 2010; 28:351–8. 25. konca degertekin c, aktas yilmaz b, balos toruner f, kalkanci a, turhan iyidir o, fidan i, et al. circulating th17 cytokine levels are altered in hashimoto’s thyroiditis. cytokine 2016; 80:13–17. doi: 10.1016/j.cyto.2016.02.011. 26. yilmaz h, cakmak m, ceydilek b, demir c, aktas a. role of interlekin-35 as a biomarker in patients with newly diagnosed hashimoto’s thyroiditis. endocr regul 2016; 50:55–61. doi: 10.1515/enr-2016-0009. 27. phenekos c, vryonidou a, gritzapis ad, baxevanis cn, goula m, papamichail m. th1 and th2 serum cytokine profiles characterize patients with hashimoto’s thyroiditis (th1) and graves’ disease (th2). neuroimmunomodulation 2004; 11:209–13. doi: 10.1159/000078438. 28. khan fa, al-jameil n, khan mf, al-rashid m, tabassum h. thyroid dysfunction: an autoimmune aspect. int j clin exp med 2015; 8:6677–81. 29. bossowski a, harasymczuk j, moniuszko a, bossowska a, hilczer m, ratomski k. cytometric evaluation of intracellular ifn-γ and il-4 levels in thyroid follicular cells from patients with autoimmune thyroid diseases. thyroid res 2011; 4:13. doi: 10.1186/1756-6614-4-13. 30. qin q, liu p, liu l, wang r, yan n, yang j, et al. the increased but non-predominant expression of th17and th1-specific cytokines in hashimoto’s thyroiditis but not in graves’ disease. braz j med biol res 2012; 45:1202–8. doi: 10.1590/s0100-879x 2012007500168. 31. karanikas g, schuetz m, wahl k, paul m, kontur s, pietschmann p, et al. relation of anti-tpo autoantibody titre and t-lymphocyte cytokine production patterns in hashimoto’s thyroiditis. clin endocrinol (oxf ) 2005; 63:191–6. doi: 10.1111/j.1365-2265.2005.02324.x. 32. marique l, van regemorter v, gérard ac, craps j, senou m, marbaix e, et al. the expression of dual oxidase, thyroid peroxidase, and caveolin-1 differs according to the type of immune response (th1/th2) involved in thyroid autoimmune disorders. j clin endocrinol metab 2014; 99:1722–32. doi: 10.1210/jc.2013-3469. 33. wang sh, bretz jd, phelps e, mezosi e, arscott pl, utsugi s, et al. a unique combination of inflammatory cytokines enhances apoptosis of thyroid follicular cells and transforms nondestructive to destructive thyroiditis in experimental autoimmune thyroiditis. j immunol 2002; 168:2470–4. doi: 10. 4049/jimmunol.168.5.2470. 34. manolova i, gerenova j, ivanova m. serum levels of transforming growth factor-β1 (tgf-β1) in patients with systemic lupus erythematosus and hashimoto’s thyroiditis. eur cytokine netw 2013; 24:69–74. doi: 10.1684/ecn.2013.0331. 35. xue h, yu x, ma l, song s, li y, zhang l, et al. the possible role of cd4+cd25(high)foxp3+/cd4+il-17a+ cell imbalance in the autoimmunity of patients with hashimoto thyroiditis. endocrine 2015; 50:665–73. doi: 10.1007/s12020-015-0569-y. 36. liu y, tang x, tian j, zhu c, peng h, rui k, et al. th17/treg cells imbalance and gitrl profile in patients with hashimoto’s thyroiditis. int j mol sci 2014; 15:21674–86. doi: 10.3390/ ijms151221674. 37. liu y, you r, yu n, gong y, qu c, zhang y, et al. increased proportions of tc17 cells and nk cells may be risk factors for disease progression in hashimoto’s thyroiditis. int immunopharmacol 2016; 40:332–8. doi: 10.1016/j.intimp. 2016.09.016. https://doi.org/10.1007/s12031-016-0789-5 https://doi.org/10.1016/j.autrev.2013.12.004 https://doi.org/10.1007/s12031-014-0443-z https://doi.org/10.3389/fimmu.2015.00493 https://doi.org/10.1007/s12020-015-0759-7 https://doi.org/10.1210/en.2011-1356 https://doi.org/10.1093/bfgp/elt025 https://doi.org/10.1074/jbc.m801286200 https://doi.org/10.1074/jbc.m801286200 https://doi.org/10.1155/2016/3687420 https://doi.org/10.1155/2016/3687420 https://doi.org/10.1111/j.1365-3083.2010.02425.x https://doi.org/10.1111/j.1365-3083.2010.02425.x https://doi.org/10.1016/j.autrev.2014.01.007 https://doi.org/10.1016/j.cyto.2016.02.011 https://doi.org/10.1515/enr-2016-0009 https://doi.org/10.1159/000078438 https://doi.org/10.1186/1756-6614-4-13 https://doi.org/10.1590/s0100-879x2012007500168 https://doi.org/10.1590/s0100-879x2012007500168 https://doi.org/10.1111/j.1365-2265.2005.02324.x https://doi.org/10.1210/jc.2013-3469 https://doi.org/10.4049/jimmunol.168.5.2470 https://doi.org/10.4049/jimmunol.168.5.2470 https://doi.org/10.1684/ecn.2013.0331 https://doi.org/10.1007/s12020-015-0569-y https://doi.org/10.3390/ijms151221674 https://doi.org/10.3390/ijms151221674 https://doi.org/10.1016/j.intimp.2016.09.016 https://doi.org/10.1016/j.intimp.2016.09.016 هبوط سكر الدم بني مرضى السكر الذين يتلقون عالجاً باإلنسولني جمموعة اإلمارات العربية املتحدة لدراسة أداة تقييم هبوط سكر الدم يف العمليات الدولية �شالح اأبو�شنانة، �شامل ب�شيه، نوال املطوع، رميا طحان، ماهر جلو، رايف اأرورا، حازم علي، �شاجار �شنغال abstract: objectives: this study aimed to evaluate the incidence of hypoglycaemia among insulin-treated patients with type 1 diabetes mellitus (t1dm) or type 2 diabetes mellitus (t2dm) from the united arab emirates (uae) cohort of the non-interventional international operations-hypoglycaemia assessment tool study. methods: this cross-sectional observational study took place at 25 patient care centres in the uae from october 2014 to may 2015. all adult patients with t1dm or t2dm who had been treated with insulin for >12 months were included. self-assessment questionnaires and patient diaries were used to determine the incidence of documented hypoglycaemia both prospectively (four weeks after baseline) and retrospectively (six months and four weeks before baseline for severe and non-severe hypoglycaemic events, respectively). results: a total of 325 patients were enrolled in the study, of which 82 (25.2%) had t1dm and 243 (74.8%) had t2dm. among patients with t1dm, 71.4% reported hypoglycaemic events retrospectively, with an incidence rate (ir) of 102.8 events per patient-year (py), while 95% reported hypoglycaemic events prospectively, with an ir of 63.1 events per py. additionally, 56.3% of patients with t2dm reported hypoglycaemic events retrospectively, with an ir of 42.2 events per py, while 91.9% reported hypoglycaemic events prospectively, with an ir of 33.3 events per py. conclusion: the prevalence and incidence of hypoglycaemia were high among insulin-treated patients with t1dm and t2dm in the uae. individualised glycaemic goals, patient education and blood glucose monitoring may help to reduce the incidence of hypoglycaemia in this population. keywords: hypoglycemia; insulin; type 1 diabetes mellitus; type 2 diabetes mellitus; united arab emirates. من ال�شكر مر�شى اأو بالإن�شولني عالجًا يتلقون الذين الأول النوع من ال�شكر مر�شى يف الدم �شكر هبوط حدوث تقييم الهدف: امللخ�ص: النوع الثاين يف درا�شة الأداة غريالتداخلية لتقييم هبوط �شكر الدم يف العمليات الدولية. الطريقة: اأجريت هذه الدرا�شة املقطعية الر�شدية يف 25 مركزا للرعاية الطبية يف الإمارات العربية املتحدة من اأكتوبر 2014 اىل مايو 2015. جميع مر�شى ال�شكر من النوع الأول اأو مر�شى ال�شكر من النوع الثاين الذين يتلقون عالجًا بالإن�شولني منذ 12> �شهراً �شاركو يف الدرا�شة. اأكمل امل�شاركون يف الدرا�شة ا�شتبيان التقييم الذاتي املكون من جزئني ويوميات املر�شى الذين �شجلوا انخفا�شًا يف �شكر الدم باأثر م�شتقبلي )4 اأ�شابيع بعد نقطة البداية( وباأثر رجعي )6 اأ�شهر/4 اأ�شابيع قبل نقطة البداية(. النتائج: مت ت�شجيل اإجمايل 325 مري�شا �شاركو يف هذه الدرا�شة منهمً 82 )%25.2( لديهم �شكري من النوع الأول و 243 )%74.8( لدمي �شكري من النوع الثاين. يف مر�شى ال�شكر من النوع الأول، ظهرت حالت هبوط �شكر الدم يف %71.4 من املر�شى مبعدل حدوث: 102.8 حالة كل عام يف التقييم باأثر رجعي بينما ظهرت حالت هبوط �شكر الدم بن�شبة %95 يف املر�شى مبعدل حدوث: 63.1 حالة كل عام يف التقييم ال�شتباقي. يف مر�شى ال�شكر من النوع الثاين، ظهرت حالت هبوط �شكر الدم يف %56.3 من املر�شى مبعدل حدوث: 42.2 حالة كل عام يف التقييم باأثر رجعي بينما ظهرت حالت نق�س �شكر الدم بن�شبة %91.9 يف املر�شى مبعدل حدوث: 33.3 حالة كل عام يف التقييم ال�شتباقي. اخلال�صة: كان انت�شار وحدوث هبوط يف �شكر الدم مرتفعًا بني مر�شى ال�شكر من النوع الأول ومر�شى ال�شكر من النوع الثاين الذين يعاجلون بالإن�شولني يف الإمارات العربية املتحدة مما ي�شبب زيادة يف ا�شتخدام الرعاية ال�شحية، و قد ي�شاعد و�شع اأهداف فردية لن�شبة ال�شكر يف الدم، وتعليم املر�شى، ومراقبة ن�شبة اجللوكوز يف الدم يف احلد من حدوث هبوط يف �شكر الدم. الكلمات املفتاحية: هبوط �شكر الدم؛ اإن�شولني؛ مر�س ال�شكر من النوع الأول؛ مر�س ال�شكر من النوع الثاين؛ الإمارات العربية املتحدة. hypoglycaemia among insulin-treated patients with diabetes evaluation of the united arab emirates cohort of the international operations-hypoglycaemia assessment tool study salah abusnana,1 *salem a. beshyah,2,3 nawal al-mutawa,4 rima tahhan,5 mahir jallo,6 ravi arora,7 hazem aly,8 sagar singhal8 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e447–454, epub. 28 mar 19 submitted 23 apr 18 revision req. 12 jun 18; revision recd. 6 jul 18 accepted 26 jul 18 advances in knowledge to the best of the authors’ knowledge, this study is the first patient-reported dataset regarding the incidence of hypoglycaemia in the united arab emirates (uae) cohort of the international operations-hypoglycaemia assessment tool study. application to patient care knowledge regarding the real-world incidence rate of hypoglycaemic events may help patients and healthcare providers to effectively manage the disease, reducing its clinical and economic burden and improving healthcare resource utilisation. doi: 10.18295/squmj.2018.18.04.004 1department of diabetes & endocrinology, university hospital sharjah, united arab emirates; 2department of medicine, sheikh khalifa medical city, abu dhabi, united arab emirates; 3department of medicine, dubai medical college, dubai, united arab emirates; 4department of diabetes & endocrinology, al qassimi hospital, sharjah, united arab emirates; 5department of internal medicine, al zahraa hospital, dubai, united arab emirates; 6department of clinical sciences, college of medicine, gulf medical university, ajman, united arab emirates; 7department of internal medicine, nmc specialty hospital, abu dhabi, united arab emirates; 8novo nordisk pharmaceutical company, dubai, united arab emirates *corresponding author’s e-mail: beshyah@yahoo.com hypoglycaemia among insulin-treated patients with diabetes evaluation of the united arab emirates cohort of the international operations-hypoglycaemia assessment tool study e448 | squ medical journal, november 2018, volume 18, issue 4 hypoglycaemia is a condition in whichblood glucose (bg) levels drop below normal levels (3.9–7.1 mmol/l).1 approximately 90% of all patients treated with insulin experience hypoglycaemic episodes/events.2 complex regimes and glycaemic restrictions have been shown to increase the risk of hypoglycaemia, with severe hypoglycaemic events asso ciated with increased mortality and morbidity.3 hypogly caemia also carries an economic burden, impacting patient productivity and disease management and utilising valu able healthcare resources.4 according to a recent meta-analysis, hypoglycaemia is prevalent among patients with type 2 diabetes mellitus (t2dm), thus necessitating an individualised approach to treatment and patient education.5 the canadian hypo glycaemia assessment tool program revealed high rates of hypoglycaemia among insulin-treated patients; the researchers advocated for the identification of high-risk insulin-treated patients in order to reduce the incidence of hypoglycaemia in this patient group.6 in germany, a patient-reported study revealed high rates of nonsevere hypoglycaemic events among those with type 1 diabetes mellitus (t1dm) or insulin-treated t2dm.7 unfortunately, it can be difficult to establish the actual rate of hypoglycaemic events as the majority of publ ished data are based on the results of randomised controlled clinical trials (rcts), which usually investigate the clinical efficacy and safety of certain drugs.8,9 moreover, patients at higher risk of hypoglycaemia are often excluded from rcts.10 in 2017, the international operations-hypoglycaemia assessment tool (io-hat) study was conducted to determine the prevalence and incidence rates (irs) of hypoglycaemic events among 7,289 insulin-treated patients with t1dm and t2dm in bangladesh, colombia, egypt, indonesia, the philippines, singapore, south africa, turkey and the united arab emirates (uae).11 the io-hat study was itself based on data gathered as part of a larger investigation of 27,585 adult patients from 24 countries.12 the current study aimed to determine the incidence of hypoglycaemia among the uae cohort of the io-hat study.11 in addition, the patients’ knowledge of and attitudes towards hypoglycaemia were assessed, as well as the relationship bet ween the incidence of hypoglycaemia and insulin regimens and glycaemic control, as determined by baseline glycated haemoglobin (hba1c) measurements. methods this cross-sectional non-interventional study was cond ucted at 25 patient care centres in the uae between october 2014 and may 2015. all patients with t1dm or t2dm who were ≥18 years old at baseline and who had been treated with an insulin regimen for >12 months were included. patients were enrolled in the study according to a consecutive sampling method during routine clinical consultation with their healthcare providers. as per the guidelines of the american diabetes association, severe hypoglycaemia was defined as an event of confirmed hypoglycaemia requiring the assistance of another individual to actively administer carbohydrate or glucagon interventions or take resusc itative action.13 non-severe events were defined as sympt omatic events not requiring biological confirmation and managed by the patient alone. nocturnal hypoglycaemia was defined as an event occurring between midnight and 6 am.13 self-reported events of hypoglycaemia were docu mented by participants using a two-part self-assessment questionnaire and patient diaries. the primary endpoint of the study was the percentage of patients experiencing at least one hypoglycaemic event during a four-week prospective period; events were recorded in patient diaries completed over a four week period from base line. the secondary endpoints included the irs of hypo glycaemia prospectively (four weeks after baseline) and retrospectively (six months and four weeks before baseline for severe and non-severe events, respectively); these were determined according to a two-part selfassessment questionnaire, with the first part completed by the participants at baseline and the second part completed four weeks later [figure 1]. the two-part self-assessment questionnaire and patient diaries were translated into local languages and all acquired data were subsequently translated back into english for analytical purposes. other secondary endpoints included the patients’ knowledge, awareness and fear of and attitudes towards hypoglycaemia and the relationship between the inc idence of hypoglycaemia and insulin regimens and gly figure 1: diagram illustrating the design of the study. sh = severe hypoglycaemia; nsh = non-severe hypoglycaemia; saq = self-assessment questionnaire. figure adapted with permission from: emral r, pathan f, cortés ca, el-hefnawy mh, goh sy, gómez am, et al. self-reported hypoglycemia in insulin-treated patients with diabetes: results from an international survey on 7289 patients from nine countries.11 salah abusnana, salem a. beshyah, nawal al-mutawa, rima tahhan, mahir jallo, ravi arora, hazem aly and sagar singhal clinical and basic research | e449 caemic control. awareness of hypoglycaemia was eval uated according to the patients’ responses to the question ‘do you have symptoms when you have low sugar levels?’, in which the response ‘usually’ denoted impaired aware ness and ‘occasionally’ or ‘never’ denoted severely imp aired awareness. fear of hypoglycaemia was self-assessed by patients on a scale of 0–10, where 0 denoted ‘not afraid at all’ and 10 was ‘absolutely terrified’. glycaemic control was determined by baseline hba1c measurements, with percentages of >9%, 7–9% and <7% indicating poor, suboptimal and good glycaemic control, respectively. comprehensive details of the design of the io-hat study and the procedures used for the assessment of hypo glycaemia have been previously reported by emral et al.11 the percentages of patients experiencing at least one hypoglycaemic event during the four-week prosp ective period were calculated along with 95% confidence intervals (cis). rates of hypoglycaemia were deemed equivalent in the retrospective and prospective periods according to two-sided statistical tests with the level of statistical significance set at p ≤0.050. the irs of hypoglycaemia were calculated as the total number of events per patient-year (py) divided by the total follow-up time in pys along with 95% cis. the difference in the reported incidence of hypoglycaemia was calculated using a negative binomial regression model, including a single binary covariate for two periods (four weeks before baseline and four weeks after baseline), specifying a logged exposure time as the offset term and using robust standard error to adjust for repeated measurements and the potential dependence between patients sharing the same site (site-level clustering). this study was approved by the local ethics committee at each patient care centre, including the al qassimi hospital research & ethics committee, sharjah (#154/2014-09-21), the dubai scientific research ethics committee, dubai (#dsrec-12/2014-03), the institutional review board/research ethics committee of sheikh khalifa medical city, abu dhabi (#rec-0 5.02.2015 rs-352) and the gulf medical university ethics committee, ajman (#novonordisk/1/30032015). all study procedures were conducted in accordance with the guidelines of the international society for pharmacoepidemiology and the ethical standards of the revised declaration of helsinki.14 all patients provided informed consent prior to their participation in the study. results a total of 325 patients were enrolled in the study at baseline, of which 82 (25.2%) had t1dm and 243 (74.8%) had t2dm. overall, the mean age of patients with t2dm was higher than those with t1dm (52.4 ± 10.4 years versus 31.5 ± 11.6 years). in addition, the mean duration table 1: characteristics of insulin-treated patients with type 1 and type 2 diabetes mellitus in the united arab emirates (n = 325) variable n (%) t1dm patients (n = 82) t2dm patients (n = 243) mean age in years ± sd 31.5 ± 11.6 52.4 ± 10.4 male gender 43 (52.4) 144 (59.3) mean diabetes duration in years ± sd 13.5 ± 8.7 14.5 ± 7.5 mean insulin duration in years ±sd 12.6 ± 8.6 6.8 ± 6.0 mean hba1c % ± sd 8.6 ± 1.9 8.6 ± 1.6 mean fbg in mmol/l ± sd 7.7 ± 3.7 7.7 ± 2.4 mean ppg in mmol/l ± sd 9.6 ± 3.5 11.1 ± 3.9 mean bmi in kg/m2 ± sd 25.5 ± 4.5 31.4 ± 6.2 previous illnesses, %* neuropathy 15.9 44 retinopathy 19.5 32.1 nephropathy 9.8 21 pvd 4.9 10.7 angina 1.2 16.5 myocardial infarction 0 11.9 none 63.4 39.1 oral antidiabetic medications α-glucosidase inhibitors 1 (1.2) 7 (2.9) metformin 9 (11) 169 (69.5) dpp-4 inhibitors 5 (6.1) 115 (47.3) glp-1 analogues 1 (1.2) 18 (7.4) metiglinides/glinides 0 (0) 3 (1.2) sglt2 inhibitors 1 (1.2) 23 (9.5) sulfonylureas 2 (2.4) 68 (28) thiazolidinediones 0 (0) 8 (3.3) other 1 (1.2) 12 (4.9) none 68 (82.9) 30 (12.3) insulin regimen† sa 2 (4) 7 (2.2) la 0 (0) 77 (24.1) premixed 6 (7.3) 73 (30) both sa and la 62 (75.6) 92 (37.9) both sa and premixed 2 (2.4) 7 (2.9) both la and premixed 1 (1.2) 4 (1.6) ability to self-assess bg levels† yes 72 (87.8) 221 (90.9) no 3 (3.7) 18 (7.4) unsure 6 (7.3) 4 (1.6) t1dm = type 1 diabetes mellitus; t2dm = type 2 diabetes mellitus; sd = standard deviation; hba1c = glycated haemoglobin; fbg = fasting blood glucose; ppg = post-prandial glucose; bmi = body mass index; pvd = peripheral vascular disease; dpp = dipeptidyl peptidase; glp = glucagon-like peptide; sglt2 = sodium-glucose cotransporter-2; sa = short-acting; la = long-acting. *percentages do not add up to 100% as some patients may have had more than one illness. †percentages are based on the number of patients with available data. hypoglycaemia among insulin-treated patients with diabetes evaluation of the united arab emirates cohort of the international operations-hypoglycaemia assessment tool study e450 | squ medical journal, november 2018, volume 18, issue 4 of insulin use was shorter among patients with t2dm compared to those with t1dm (6.8 ± 6.0 years versus 12.6 ± 8.6 years). however, mean baseline hba1c perc entages were similar in both groups (8.6 ± 1.6% versus 8.6 ± 1.9%) [table 1]. a total of 262 patients completed the second part of the questionnaire after the prospective period had elapsed. of these, 60 (22.9%) had t1dm and 202 (77.1%) had t2dm. nearly all patients with t1dm (95%; 95% ci: 86.1–99.0%) and t2dm (91.9%; 95% ci: 87.1–95.3%) reported at least one hypoglycaemic event during the prospective period. in contrast, 71.4% (95% ci: 60.0–81.2%) of patients with t1dm and 56.3% (95% ci: 49.7–62.7%) of patients with t2dm experienced hypoglycaemic events in the retrospective period. nocturnal hypoglycaemic events were reported in 56.7% (95% ci: 44.0–68.8%) and 35.6% (95% ci: 29.3–42.3%) of patients with t1dm and t2dm, respectively, in the retrospective period. during the prospective period, 43.6% (95% ci: 30.3–57.7%) of patients with t1dm and 33.5% (95% ci: 26.8–40.7%) of patients with t2dm reported nocturnal hypoglycaemic events. severe hypo glycaemic events were experienced by 39.5% (95% ci: 28.4–51.4%) and 44% (95% ci: 37.6–50.6%) of patients with t1dm and t2dm, respectively, in the retrospective period. in the prospective period, 61.7% (95% ci: 54.4–68.5%) of t2dm patients and 36.7% (95% ci: 24.6–50.1%) of t1dm patients reported severe hypoglycaemic events. among patients with t1dm, the ir of any hypoglycaemic event was higher in the retrospective period than the prospective period, although this difference was not significant (102.8 events per py, 95% ci: 94.8–11.3 events per py versus 63.1 events per py, 95% ci: 56.0–70.7 events per py; p = 0.093). the ir of nocturnal hypoglycaemia among patients with t1dm was significantly higher in the retrospective period compared to the prospective period (59.2 events per py, 95% ci: 52.7–66.2 events per py versus 12.6 events per py, 95% ci: 9.4–16.4 events per py; p <0.001). however, figure 2: incidence rates of hypoglycaemia among insulin-treated patients with (a) type 1 and (b) type 2 diabetes mellitus in the united arab emirates (n = 325). hypoglycaemic events were assessed retrospectively over a four-week and six-month period (for nocturnal/ non-severe and severe hypoglycaemia, respectively) and prospectively over a four-week period. py = patient-year; rr = risk ratio. figure 3: incidence rates of (a) any, (b) nocturnal and (c) severe hypoglycaemia according to insulin regimen among patients with type 2 diabetes mellitus in the united arab emirates (n = 243). hypoglycaemic events were assessed retrospectively over a four-week and sixmonth period (for nocturnal/non-severe and severe hypoglycaemia, respectively) and prospectively over a four-week period. py = patient-year; sa = short-acting ; la = long-acting. salah abusnana, salem a. beshyah, nawal al-mutawa, rima tahhan, mahir jallo, ravi arora, hazem aly and sagar singhal clinical and basic research | e451 the ir of severe hypoglycaemia in this group showed a non-significant increase in the prospective period compared to the retrospective period (9.4 events per py, 95% ci: 6.8–12.6 events per py versus 3.2 events per py, 95% ci: 2.6–3.8 events per py; p = 0.682) [figure 2a]. similarly, the ir of any hypoglycaemic events among patients with t2dm was slightly higher in the retrospective period compared to the prospective period (42.2 events per py, 95% ci: 39.2–45.2 events per py versus 33.3 events per py, 95% ci: 30.4–36.3 events per py). in contrast, the ir of severe hypoglycaemia was higher in the prospective period compared to the retrospective period (10.6 events per py, 95% ci: 9.0–12.4 events per py versus 2.6 events per py, 95% ci: 2.3–2.9 events per py); nevertheless, both of these differences were non-significant (p = 0.253 and 0.142, respectively). as with the t1dm patients, the ir of nocturnal hypoglycaemia among patients with t2dm was significantly higher in the retrospective period compared to the prospective period (14.5 events per py, 95% ci: 12.7–16.4 events per py versus 7.2 events per py, 95% ci: 5.9–8.7 events per py; p <0.001) [figure 2b]. the irs of any, nocturnal and severe hypoglycaemic events were calculated according to insulin regimens. for t1dm patients, the greatest ir of any hypoglycaemic events was observed with the use of a premixed insulin regimen in the prospective period (208.7 events per py). the greatest ir of nocturnal hypoglycaemic events occurred among patients using a combination of shortand long-acting insulin regimens in the retro spective period (72.1 events per py). for severe hypoglycaemic events, the greatest ir was observed among patients undertaking a long-acting insulin regimen in the prospective period (58.7 events ppy). the irs for all types of hypoglycaemic events by insulin regimen for patients with t2dm in both the retrospective and prospective periods is presented in figure 3. no correlation was found between the percentage of patients experiencing hypoglycaemic events and glyc aemic control in the prospective and retrospective periods. among patients with t1dm, the majority (73.7%) of any hypoglycaemic events in the four-week retrospective period was experienced by patients with suboptimal glycaemic control; however, the proportion of patients experiencing any hypoglycaemic events was higher in those with poor glycaemic control compared to those with good glycaemic control (63.6% versus 61.5%). among patients with t2dm, 64.8% of patients with poor glycaemic control, 54.5% with good glycaemic control and 53% with suboptimal glycaemic control experienced any hypoglycaemic events. in terms of their perceptions of how hypoglycaemic events impacted the medical system, 5.2% versus 13.6% of t1dm patients and 0.5% versus 4.3% of t2dm patients reported that the event required hospital admission in the prospective period compared to the retrospective period. in addition, t1dm patients more frequently reported that the event resulted in additional telephone contacts retrospectively (16.7% versus 8.6%), while more t2dm patients reported this prospectively (20.1% versus 16.1%). furthermore, more patients with t1dm undertook increased bg monitoring following the event compared to patients with t2dm in both the retrospective (54.9% versus 36.2%) and prospective (51.7% versus 31.7%) periods. in the retrospective period, fewer patients with t2dm compared to those table 2: actions and perceptions following hypoglycaemic events among insulin-treated patients with type 1 and type 2 diabetes mellitus in the united arab emirates (n = 325) n (%)* t1dm patients (n = 82) t2dm patients (n = 243) rt pt rt pt action following event n = 82 n = 60 n = 243 n = 202 consulted their doctor/nurse 46 (56.1) 27 (45) 141 (58) 93 (46) required medical assistance 46 (56.1) 27 (45) 146 (60.1) 94 (46.5) increased caloric intake 21 (25.6) 15 (25) 63 (25.9) 55 (27.2) avoided physical exercise 11 (13.4) 5 (8.3) 48 (19.8) 44 (21.8) reduced insulin dose 22 (26.8) 24 (40) 62 (25.5) 65 (32.2) skipped insulin injections 15 (18.3) 10 (16.7) 54 (22.2) 38 (18.8) increased bg monitoring 45 (54.9) 31 (51.7) 88 (36.2) 64 (31.7) perceived impact of event on the medical system n = 82 n = 60 n = 243 n = 202 required hospital admission 9 (13.6) 3 (5.2) 8 (4.3) 1 (0.5) added telephone contacts 11 (16.7) 5 (8.6) 30 (16.1) 39 (20.1) perceived impact of event on work/studies† n = 63 n = 46 n = 143 n = 126 took leave 17 (27) 5 (10.9) 16 (11.2) 8 (6.3) arrived late 11 (17.5) 6 (13) 13 (9.1) 7 (5.6) left early 10 (15.9) 4 (8.7) 9 (6.3) 6 (4.8) rt = retrospective; pt = prospective; t1dm = type 1 diabetes mellitus; t2dm = type 2 diabetes mellitus; bg = blood glucose. *percentages are based on the number of patients with evaluable data. †only applicable to patients who worked/studied. hypoglycaemia among insulin-treated patients with diabetes evaluation of the united arab emirates cohort of the international operations-hypoglycaemia assessment tool study e452 | squ medical journal, november 2018, volume 18, issue 4 with t1dm reported that hypoglycaemic events resulted in their absence (11.2% versus 27%), late arrival (9.1% versus 17.5%) or early departure (6.3% versus 15.9%) from work or studies [table 2]. many patients with t1dm (84.2%) and t2dm (79.4%) had baseline knowledge of hypoglycaemia before being provided with the definition in the first part of the questionnaire. the number of patients defining hypo glycaemic events based on symptoms alone or in conjunction with bg measurements was comparable in both the t1dm and t2dm groups (47.6% versus 49% and 24.4% versus 29.2%, respectively). however, a small pro portion of both t1dm and t2dm patients used only bg measurements to define hypoglycaemia (6.1% versus 2.9%). fewer patients with t1dm had severely impaired awareness of hypoglycaemia compared to t2dm patients (1.2% versus 5.8%). the mean fear of hypoglycaemia score was comparable between the two groups (4.7 ± 3.6 versus 4.8 ± 3.7) [table 3]. discussion according to the international diabetes federation, 425 million people had diabetes mellitus (dm) in 2017 and this number is expected to reach 629 million by 2045.15 the uae has one of the world’s highest prevalence rates of dm (15.4%), with 40% of those over the age of 60 years suffering from the condition and 2.7 new cases of t1dm diagnosed per 100,000 children and adolescents annually.16–19 by 2045, it is predicted that 23.4% of the population between 20–79 years old in the uae will have dm.17,18 therefore, identifying the incidence of hypoglycaemic events is paramount in order to determine disease burden. however, recent studies have detected higher rates of hypoglycaemia in real-world settings when compared with the results of clinical trials.5,8,20 this may be a result of the stringent methodological and design constraints of rcts, as well as the restricted selection of patients, uniform treatment approach and insufficient bg monitoring which limits the generalisability of such findings to routine clinical practice.9–12 as part of the larger io-hat study, the current study analysed self-reported rates of hypoglycaemic events among a cohort of insulin-treated dm patients from patient care centres in the uae.11 although higher rates of any or nocturnal hypoglycaemic events were reported in the current study during the retrospective period compared to the prospective period for both t1dm and t2dm patients, higher rates of severe hypoglycaemic events were reported prospectively in both periods; this may indicate that severe hypo glycaemic events were underreported by participants during the retrospective period. gubitosi-klug et al. similarly reported a higher incidence of severe hypoglycaemia in the prospective period among patients with t1dm.21 in the current study, the level of knowledge of the definition and symptoms of hypoglycaemia was similar to previously reported findings among diabetic individuals.19,22 this may be because such patients have individualised bg targets, greater experience with bg monitoring or have received patient education on this topic.23 fear of hypoglycaemia can have major clinical repercussions for dm management. however, in the current study, low fear of hypoglycaemia was reported among both t1dm and t2dm patients, possibly due to adequate hypoglycaemia awareness and glycaemic control.24 nevertheless, patients stated that hypoglycaemic events often negatively impacted their work or studies, with t1dm patients in particular more frequently reporting that such events resulted in absences, arriving late or leaving early compared to t1dm patients. previous research also supports the notion that hypoglycaemia restricts social or functional activities, increases absenteeism, impairs punctuality and reduces productivity.25,26 previous studies have shown that all forms of hypoglycaemia are independent of levels of glycaemic control.27,28 increased hypoglycaemic events in patients table 3: knowledge, awareness and fear of hypoglycaemia among insulin-treated patients with type 1 and type 2 diabetes mellitus in the united arab emirates (n = 325) n (%) t1dm patients (n = 82) t2dm patients (n = 243) knowledge of hypo glycaemia at baseline* 69 (84.2) 193 (79.4) definition of a hypoglycaemic event symptoms 39 (47.6) 119 (49) bg measurements 5 (6.1) 7 (2.9) either symptoms or bg measurements 15 (18.3) 26 (10.7) both symptoms and bg measurements 20 (24.4) 71 (29.2) awareness of hypoglycaemia† normal 49 (59.8) 133 (54.7) impaired 32 (39) 87 (35.8) severely impaired 1 (1.2) 14 (5.8) mean fear of hypoglycaemia ± sd‡ 4.7 ± 3.6 4.8 ± 3.7 t1dm = type 1 diabetes mellitus; t2dm = type 2 diabetes mellitus; bg = blood glucose; sd = standard deviation. *prior to the first self-assessment questionnaire being administered. †excluding nine patients with t2dm for whom data for this category were unavailable. ‡scored on a scale of 0–10, where 0 denoted ‘not afraid at all’ and 10 was ‘absolutely terrified’. salah abusnana, salem a. beshyah, nawal al-mutawa, rima tahhan, mahir jallo, ravi arora, hazem aly and sagar singhal clinical and basic research | e453 with higher hba1c levels may reflect poor self-care behaviours as well as aggressive efforts to improve their glycaemic control. lash et al. advocate for increasing hypoglycaemia awareness, patient education and shared decision-making and the adoption of risk assessment and clinical decision-making support tools to support management of the condition.29 the current study is subject to certain limitations. during the enrolment of eligible patients, the possibility of volunteer bias could not be excluded. in addition, due to the retrospective design of the study, self-reported rates of hypoglycaemia may have been affected by recall bias; for example, patients may have underor overreported severe hypoglycaemic events based on the def inition alone, regardless of the severity of their symptoms or bg measurements.3 in addition, there may have been an overestimation in reported events while adjusting for recall bias, as reported rates of hypoglycaemic events were higher in patient diaries compared to their responses to the second part of the self-assessment questionnaire. nevertheless, precautions were taken to ensure that rates of hypoglycaemia were not overreported by following the guidelines of the international society for pharmacoepidemiology.14 conclusion to the best of the authors’ knowledge, this is the first patient-reported dataset of hypoglycaemic events among the uae cohort of the io-hat study. these findings highlight the high prevalence and incidence of hypoglycaemia among insulin-treated patients with dm and the potential impact of the condition on productivity, health and healthcare resource utilisation. patient education and personalised glycaemic goals may help to lower the incidence of all forms of hypoglycaemia in this population, thus reducing associated costs to the healthcare system. a c k n o w l e d g e m e n t s the statistical analysis of the data was performed by parexel international (waltham, massachusetts, usa). medical writing and submission support was provided by cognizant technology solutions pvt. ltd. (pune, maharashtra, india). novo nordisk a/s pharmaceutical company (bagsværd, denmark) was involved in the study conception and design, data collection, statistical analysis and interpretation and provided the materials, patients and resources. the decision to submit the article for publication was made by novo nordisk a/s pharmaceutical company. c o n f l i c t o f i n t e r e s t professor salah abusnana and dr salem a. beshyah received research grants and financial support for the submitted work from novo nordisk a/s pharmaceutical company. professor salah abusnana, dr salem a. beshyah, dr mahir jallo, dr rima tahhan and dr ravi arora received payments for lectures and continuing medical education events as speakers. dr salem a. beshyah, dr mahir jallo and dr ravi arora received reimbursements for travel and accommodation expenses for national and international conferences. dr hazem aly and dr sagar singhal are currently employed as medical advisors by the uae branch of novo nordisk a/s pharma ceutical company. f u n d i n g this study was funded by novo nordisk a/s pharmaceutical company, bagsværd, denmark (hat-io #ins-4177). references 1. american diabetes association. american diabetes association issues hypoglycemia position statement: levels to be reported during clinical trials defined, based upon recommendations by international hypoglycemia study group. from: www.diabetes. org/newsroom/press-releases/2016/ada-issues-hypoglycemiaposition-statement.html accessed: jul 2018. 2. shafiee g, mohajeri-tehrani m, pajouhi m, larijani b. the importance of hypoglycemia in diabetic patients. j diabetes metab disord 2012; 11:17. https://doi.org/10.1186/2251-658111-17. 3. kalra s, mukherjee jj, venkataraman s, bantwal g, shaikh s, saboo b, et al. hypoglycemia: the neglected complication. indian j endocrinol metab 2013; 17:819–34. https://doi.org/10.4103/2 230-8210.117219. 4. meng j, casciano r, lee yc, stern l, gultyaev d, tong l, et al. effect of diabetes treatment-related attributes on costs to type 2 diabetes patients in a real-world population. j manag care spec pharm 2017; 23:446–52. https://doi.org/10.18553/ jmcp.2017.23.4.446. 5. edridge cl, dunkley aj, bodicoat dh, rose tc, gray lj, davies mj, et al. prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: a systematic review and meta-analysis of populationbased studies. plos one 2015; 10:e0126427. https://doi.org/1 0.1371/journal.pone.0126427. 6. aronson r, goldenberg r, boras d, skovgaard r, bajaj h. the canadian hypoglycemia assessment tool program: insights into rates and implications of hypoglycemia from an observational study. can j diabetes 2018; 42:11–17. https://doi.org/1 0.1016/j.jcjd.2017.01.007. 7. kulzer b, seitz l, kern w. real-world patient-reported rates of non-severe hypoglycaemic events in germany. exp clin endocrinol diabetes 2014; 122:167–72. https://doi.org/10.105 5/s-0033-1363688. 8. elliott l, fidler c, ditchfield a, stissing t. hypoglycemia event rates: a comparison between real-world data and randomized controlled trial populations in insulin-treated diabetes. diabetes ther 2016; 7:45–60. https://doi.org/10.1007/s13300-0160157-z. hypoglycaemia among insulin-treated patients with diabetes evaluation of the united arab emirates cohort of the international operations-hypoglycaemia assessment tool study e454 | squ medical journal, november 2018, volume 18, issue 4 9. uk hypoglycaemia study group. risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. diabetologia 2007; 50:1140–7. https://doi.org/10.100 7/s00125-007-0599-y. 10. nathan dm; dcct/edic research group. the diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. diabetes care 2014; 37:9–16. https://doi.org/10.2337/dc13-2112. 11. emral r, pathan f, cortés ca, el-hefnawy mh, goh sy, gómez am, et al. self-reported hypoglycemia in insulin-treated patients with diabetes: results from an international survey on 7289 patients from nine countries. diabetes res clin pract 2017; 134:17–28. https://doi.org/10.1016/j.diabres.2017.07.031. 12. khunti k, alsifri s, aronson r, cigrovski berković m, enters-weijnen c, forsén t, et al. rates and predictors of hypo glycaemia in 27 585 people from 24 countries with insulintreated type 1 and type 2 diabetes: the global hat study. diabetes obes metab 2016; 18:907–15. https://doi.org/10.1111/ dom.12689. 13. workgroup on hypoglycemia, american diabetes association. defining and reporting hypoglycemia in diabetes: a report from the american diabetes association workgroup on hypo glycemia. diabetes care 2005; 28:1245–9. https://doi.org/10.2 337/diacare.28.5.1245. 14. international society for pharmacoepidemiology. guidelines for good pharmacoepidemiology practices (gpp). pharmacoepidemiol drug saf 2008; 17:200–8. https://doi.org/10.1002/ pds.1471. 15. international diabetes federation. idf diabetes atlas: fifth edition. from: diabetesatlas.org/resources/previous-editions.html accessed: jul 2018. 16. international diabetes federation. idf diabetes atlas 8th edition 2017: regional fact sheets middle east and north africa. from: diabetesatlas.org/resources/2017-atlas.html accessed: jul 2018. 17. united health group. diabetes in the united arab emirates: crisis or opportunity? from: www.unitedhealthgroup.com/~/ media/uhg/pdf/2010/unh_workingpaperdiabetesuae. ashx?la=en accessed: jul 2018. 18. razzak ha, harbi a, shelpai w, qawas a. epidemiology of diabetes mellitus in the united arab emirates. curr diabetes rev 2018; 14:542–9. https://doi.org/10.2174/157339981366617 0920152913. 19. hamoudi nm, al ayoubi id, al sharbatti s, shirwaikar aa. awareness of diabetes mellitus among uae non-diabetic population in ajman and ras alkhaimah. j appl pharm sci 2012; 2:50–3. https://doi.org/10.7324/japs.2012.2410. 20. cariou b, fontaine p, eschwege e, lièvre m, gouet d, huet d, et al. frequency and predictors of confirmed hypoglycaemia in type 1 and insulin-treated type 2 diabetes mellitus patients in a real-life setting: results from the dialog study. diabetes metab 2015; 41:116–25. https://doi.org/10.1016/j.diabet.2 014.10.007. 21. gubitosi-klug ra, braffett bh, white nh, sherwin rs, service fj, lachin jm, et al. risk of severe hypoglycemia in type 1 diabetes over 30 years of follow-up in the dcct/edic study. diabetes care 2017; 40:1010–16. https://doi.org/10.2337/dc162723. 22. shriraam v, mahadevan s, anitharani m, jagadeesh ns, kurup sb, vidya ta, et al. knowledge of hypoglycemia and its associated factors among type 2 diabetes mellitus patients in a tertiary care hospital in south india. indian j endocrinol metab 2015; 19:378–82. https://doi.org/10.4103/2230-8210.152779. 23. martín-timón i, del cañizo-gómez fj. mechanisms of hypoglycemia unawareness and implications in diabetic patients. world j diabetes 2015; 6:912–26. https://doi.org/10.4239/wjd. v6.i7.912. 24. wild d, von maltzahn r, brohan e, christensen t, clauson p, gonder-frederick l. a critical review of the literature on fear of hypoglycemia in diabetes: implications for diabetes management and patient education. patient educ couns 2007; 68:10–15. https://doi.org/10.1016/j.pec.2007.05.003. 25. hassoun aa, abdella n, arouj ma, awadi fa, futaisi aa, lamki ma, et al. driving and diabetes mellitus in the gulf cooperation council countries: call for action. diabetes res clin pract 2015; 110:91–4. https://doi.org/10.1016/j.diabres.20 15.08.002. 26. lopez jm, annunziata k, bailey ra, rupnow mf, morisky de. impact of hypoglycemia on patients with type 2 diabetes mellitus and their quality of life, work productivity, and medication adherence. patient prefer adherence 2014; 8:683–92. https:// doi.org/10.2147/ppa.s58813. 27. cox dj, gonder-frederick l, ritterband l, clarke w, kovatchev bp. prediction of severe hypoglycemia. diabetes care 2007; 30:1370–3. https://doi.org/10.2337/dc06-1386. 28. murata gh, hoffman rm, shah jh, wendel cs, duckworth wc. a probabilistic model for predicting hypoglycemia in type 2 diabetes mellitus: the diabetes outcomes in veterans study (doves). arch intern med 2004; 164:1445–50. https://doi. org/10.1001/archinte.164.13.1445. 29. lash rw, lucas do, illes j. preventing hypoglycemia in type 2 diabetes. j clin endocrinol metab 2018; 103:1265–8. https:// doi.org/10.1210/jc.2017-02804. squ med j, august 2011, vol. 11, iss. 3, pp. 399-402, epub. submitted 19th jan 11 revision req. 11th apr 11, revision recd. 29th apr & 24th may 11 accepted 1st jun 11 cornual pregnancy accounts for 2–4% of ectopic pregnancies and can be associated with a mortality rate in the range of 2.0–2.5%.1 cornual pregnancy constitutes a medical emergency and its diagnosis and management is challenging. we present a rare case of an ectopic pregnancy located just under a cornual fibroid, at the site of right fallopian tube insertion, which did not respond to intensive medical management thus necessitating surgical intervention. case report a 25 year-old primigravida presented with a history of mild vaginal bleeding, abdominal pain and 7 weeks of amenorrhoea. she gave history of bleeding per vagina at home during the last four days. there were no identifiable risk factors for an ectopic pregnancy. on physical assessment, the patient was haemodynamically stable and not in distress. abdominal palpation revealed a 16-week size mobile non-tender mass in the midline. bimanual examination confirmed an enlarged uterus corresponding to 16 weeks with a single closed cervix and minimal cervical motion tenderness. abdominal ultrasound showed an 8 cm right cornual fibroid and transvaginal ultrasound (us) confirmed an empty endometrial cavity (endometrial thickness of 19 mm) despite high beta human chorionic gonadotropin (β-hcg) levels of 6,600 units, normal adnexa and no free fluid departments of 1obstetrics & gynaecology and 3radiology & molecular imaging, sultan qaboos university hospital, muscat, oman; 2department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat,oman. *corresponding author email: gowrie61@hotmail.com íõ^ß<k†<í∑ö<ã�è◊i<ª<ífiüœ<ÿ∑̌ <9�÷]<t¯√÷]<ÿé <ç√e<íu]üq<t¯¬           abstract: cornual pregnancy constitutes an emergency while its diagnosis and management remain a challenge. anatomical abnormalities in the uterus, such as fibroids in the cornual region, make the management even more difficult. a nulliparous patient presented with an ectopic pregnancy at the right cornua under a huge fibroid. despite multiple doses of methotrexate for a cornual ectopic gestation, the serum beta human chorionic gonadotropin (β-hcg) levels doubled on the fifth day and a viable fetus was demonstrated on imaging. thus surgical intervention in the form of laparoscopy followed by laparotomy, myomectomy of a large cornual fibroid and cornuostomy was performed. the serum beta human chorionic gonadotropin result was negative three weeks later. surgical intervention in the form of myomectomy and cornuostomy was necessary to preserve fertility in this unusual presentation of cornual ectopic pregnancy. keywords: diagnosis; ectopic pregnancy; fibroid; leiomyoma; methotrexate; surgery; case report; oman submyomatous cornual pregnancy managed surgically after failed medical management lamya al-kharusi,1 *vaidyanathan gowri,2 rashid al-sukaiti,2 wadha al-ghafri,1 kuntal rao1 case report submyomatous cornual pregnancy managed surgically after failed medical management 400 | squ medical journal, august 2011, volume 11, issue 3 in the pelvis. a complete blood count revealed haemoglobin of 10.7 g/dl, total white cell count of 4.2 x 109/l and platelets of 402 x 109/l. liver function tests revealed alanine aminotransferase (alt) 11 iu/l; aspartate aminotranferase (ast) 18 u/l; bilirubin 4 µmol/l, and alkaline phosphatase 51 u/l (all within normal limits). a right cornual ectopic was suspected in view of the location of a sac-like structure and increased doppler flow [figure 1]. after counselling, she opted for conservative management with a multidose methotrexate (ebewe pharma, austria) regimen as an inpatient. this was given on days 1, 3 and 5 intramuscularly (50 mg/m2 body surface area) with rescue doses of folinic acid (ebewe pharma, austria) to reduce bone marrow toxicity on day 2, 4 and 6. on day 3 (after receiving a second dose of methotrexate) she passed some tissue vaginally and it was sent for histopathological examination. on day 5, after the third dose of methotrexate, the repeated β-hcg test result was 12,220 units. she started having increasing lower abdominal pain. a transvaginal us was repeated and revealed a 1.5cm gestational sac located very close to a cornual fibroid which was now demonstrating fetal heart beat activity [figure 2] and some free fluid in the peritoneum. at this time, histopathology was reported as a decidual reaction with no chorionic villi present in the tissue that was passed a few days before. in view of increasing abdominal pain, a viable fetus and elevated β-hcg, the concern for rupture was high. she consented to surgical intervention. laparoscopy revealed an 8 cm subserous fibroid at the right cornua and visible pulsations just under it (on the posterior aspect) suggesting the location of the ectopic pregnancy. the adnexa were normal. it was not technically feasible to complete her management laparoscopically. hence a 7cm pfannenstiel incision was made and the laparoscopy findings were confirmed [figure 3]. needle aspiration of the cornual end was attempted blindly (as us guided aspiration was not possible in the operating room) to locate the ectopic gestation. since even that did not show any evidence of the exact location of the pregnancy, a myomectomy was performed. the fibroid appeared to have undergone some degeneration as it was soft. the ectopic pregnancy was identified as a circular mass with a tiny black dot, likely representing the embryo, at the base of the myoma bed and this was evacuated. during the procedure, the endometrial cavity was not entered. a classical wedge resection was not carried out. the myoma bed was closed in layers with interrupted vicryl no. 1 sutures (polyglactin 910, ethicon, johnson & johnson) and 2/0 vicryl to the serosa. the uterus was reconstituted and looked normal at the end of the procedure. the intraoperative blood loss was 300 ml. the serum β-hcg test results were as follows: on admission 2,035 miu; 48 hours later 6,684 miu; on day 5 (after the third dose of methotrexate) 12,647 miu; one day after cornuostomy 2200 miu. the postoperative period remained uneventful and the β-hcg was monitored weekly. it became negative after three weeks. she was advised to have early evaluation at the next pregnancy to rule out a recurrent ectopic. in addition, she was advised to have an elective cesarean section during her next pregnancy. she resumed normal periods in about 4 weeks and remains well at the time of writing. figure 1: transvaginal ultrasound scan of right adnexal region demonstrating a gestational sac and yolk sac (arrow). figure 2: transvaginal ultrasound scan of right adnexal region demonstrating a positive fetal heart activity in m-mode (arrow). lamya al-kharusi, vaidyanathan gowri, rashid al-sukaiti, wadha al-ghafri, kuntal rao case report | 401 discussion despite recent advances, cornual pregnancy remains a diagnostic and therapeutic challenge. the three criteria defined by timor et al. have increased the rate of diagnosis.2 fortunately, diagnosis was made early in our nulliparous patient and conservative measures were taken initially. systemic treatment with multiple doses of methotrexate was given in this patient as she was haemodynamically stable, willing for follow-up and there were no absolute contraindications. in a prospective observational study at st george’s hospital medical school, london, 17 out of 20 women with cornual pregnancy were treated with single-dose intramuscular methotrexate, which was administered on day 0. a second dose of methotrexate was given if the β-hcg levels had not fallen by 15%.3 all women with cornual pregnancy presenting with initial hcg values of <5000 miu were treated successfully with single-dose methotrexate, but almost all women with an initial hcg of >5000 miu required two doses according to the royal college of obstetricians and gynecologists, uk.4 medical treatment is not free of complications; it can be associated with uterine rupture and catastrophic haemorrhage. a large ectopic pregnancy and the presence of a heartbeat are relative contraindications to medical treatment.1 multiple dose methotrexate is recommended by many authors for interstitial/ cornual pregnancy despite the lack of strong evidence for or against a multidose methotrexate regimen.5 figure 3: intraoperative photograph of the uterus with the myoma (arrow) in the right cornual region. a us guided local injection of methotrexate/ potassium chloride is described by monteagudo et al. with immediate cessation of fetal heart activity.6 there was no time difference in the resolution of the ectopic whether they used potassium chloride or methotrexate and they reported a 100% success rate. many studies have reported the use of laparoscopy for local methotrexate injection into a cornual pregnancy.7 in this case, local injection of methotrexate was not feasible either by us or laparoscopy due to the position of the ectopic under the myoma. cornual excision, salpingostomy and repair are other approaches reported by many authors for cornual gestation.8 successful cornuostomy has been reported by some other authors;9,10 however, a laparoscopic cornual excision and salpingostomy was not possible as an 8 cm myoma was sitting on the ectopic pregnancy; even visualising the pregnancy completely was impossible in this case. hence a laparotomy and myomectomy, followed by a cornuostomy, were performed. conclusion this is a rare case of cornual pregnancy situated under a cornual subserous fibroid. it was successfully managed by myomectomy and cornuostomy thus preserving the future fertility of the patient. references 1. faraj r, steel m. review management of cornual (interstitial) pregnancy. obstet & gynecol 2007; 9:249–55. 2. timor-tritsch ie, monteagudo a, matera c, veit cr. sonographic evolution of cornual pregnancies treated without surgery. obstet gynecol 1992; 79:1044–9. 3. jermy k, thomas j, doo a, bourne t. the conservative management of interstitial pregnancy. bjog 2004; 111:1283–8. 4. royal college of obstetricians and gynaecologists. the management of tubal pregnancy. green top guideline no. 21. london: rcog, may 2004. from: www.rcog.org.uk/index.asp?pageid=537. accessed: jan 2011. 5. tulandi t, al-jaroudi d. interstitial pregnancy: results generated from the society of reproductive surgeons registry. obstet gynecol 2004; 103:47–50. 6. monteagudo a, minior vk, stephenson c, monda s, timor-tritsch ie. nonsurgical management of submyomatous cornual pregnancy managed surgically after failed medical management 402 | squ medical journal, august 2011, volume 11, issue 3 live ectopic pregnancy with ultrasound-guided local injection: a case series. ultrasound obstet gynecol 2005; 25:282–8. 7. benifla jl, fernandez h, sebban e, darai e, frydman r, madelenat p. alternative to surgery of treatment of unruptured interstitial pregnancy: 15 cases of medical treatment. eur j obstet gynecol reprod biol 1996; 70:151–6. 8. reich h, johns da, decaprio j, mcglynn f, reich el. laparoscopic treatment of one hundred and nine consecutive ectopic pregnancies. j reprod med 1988; 33:885–90. 9. chan ly, yuen pm. successful treatment of ruptured interstitial pregnancy with laparoscopic surgery. a report of 2 cases. j reprod med 2003; 48:569–71. 10. matsuzaki s, fukaya t, murakami t, yajima a. laparoscopic cornuostomy for interstitial pregnancy. a case report. j reprod med 1999; 44:981–2. department of community medicine, college of medicine, hawler medical university, erbil, iraq e-mail: kamaran742003@yahoo.com تصّورات االنتحال بني طالب الطب والتمريض يف أربيل، العراق كامران ح�شن اإ�شماعيل abstract: objectives: the rapidly rising incidence of plagiarism among students at universities throughout the world requires attention. this study aimed to determine the extent to which medical and nursing students in erbil, iraq, plagiarise, their knowledge, understanding and perceptions of plagiarism and the underlying factors that may lead them to plagiarise. methods: this cross-sectional study was carried out between january and june 2017 among a sample of 400 undergraduate medical and nursing students at hawler medical university in erbil. plagiarism-related data were collected through a specially designed self-administered questionnaire. results: in total, 280 (70%) medical students and 120 (30%) nursing students were included in the study. the reported prevalence of plagiarism was 54.3%, with a slightly higher prevalence among male students compared to female students (54.9% versus 53.8%; p = 0.820) and medical students compared to nursing students (58.9% versus 43.3%; (p = 0.004). alarmingly, 34.8% of the students did not know what plagiarism was, and only 28% were aware of the legal consequences of plagiarism. reported reasons for plagiarising included laziness and the ease with which others’ work could be plagiarised, confusion, cultural reasons and pressure to meet deadlines. conclusion: there was a lack of understanding of plagiarism and its legal ramifications among undergraduate medical and nursing students in erbil. the findings of this study indicate that there is an urgent need to increase students’ understanding of plagiarism and its consequences so as to reduce the incidence of this type of academic misconduct. keywords: undergraduate medical education; plagiarism; medical students; nursing students; perceptions; iraq. امللخ�ص: الهدف: التزايد ال�رضيع لالنتحال بني طالب اجلامعات حول العامل يتطلب الإهتمام. تهدف هذه الدرا�شة اإىل معرفة مدى مزاولة النتحال من قبل طالب الطب والتمري�ض يف اأربيل، العراق، ومدى معرفتهم وتفهمهم وت�شوراتهم لالنتحال والعوامل امل�شاعدة التي قد توؤدي بهم اإىل النتحال. الطريقة: اجريت هذه الدرا�شة املقطعية العر�شية بني يناير ويونيو 2017 على عينة من 400 طالبا من كلية الطب والتمري�ض يف جامعة هولري الطبية يف اأربيل، العراق. مت جمع البيانات املتعلقة بالنتحال عن طريق ا�شتمارة ال�شتبيان الذاتي امل�شممة لهذا الغر�ض. النتائج: ب�شكل عام، �شملت هذه الدرا�شة على 280 )%70( طالب طب و 120 )%30( طالب متري�ض. معدل انت�شارالنتحال كان %54.3، مع انت�شار اأعلى قليال بني الذكور مقارنة بالإناث )%54.9 مقابل %53.8؛ p = 0.820( وطالب الطب مقارنة مع طالب التمري�ض )%58.9 مقابل %43.3؛ p = 0.004(. ب�شكل ملفت للنظر، مل يكن لدى %34.8 من الطالب معرفة م�شبقة بالنتحال، واأن %28 فقط كانوا على دراية بالعواقب القانونية لالنتحال. الأ�شباب التي ذكرت ملمار�شة عمل النتحال كانت التكا�شل و�شهولة انتحال ما لغريهم، عدم الدراية الكافية، ا�شباب اجتماعية وال�شغوطات املتعلقة باأقرتاب املهلة املحددة لالإجناز. اخلال�صة: كان هناك قلة تفهم لالنتحال وما يرتتب عليه من عواقب قانونية بني طالب الطب والتمري�ض يف اأربيل. وت�شري نتائج هذه الدرا�شة اإىل وجود حاجة ملحة لزيادة فهم الطالب ملو�شوع النتحال وعواقبه للتقليل من انت�شار هذا النوع من �شوء ال�شلوك الأكادميي غري املقبول. الكلمات املفتاحية: التعليم الطبي اجلامعي الأويل؛ النتحال؛ طالب الطب؛ طالب التمري�ض؛ الإدراك؛ العراق. perceptions of plagiarism among medical and nursing students in erbil, iraq kameran h. ismail clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e196–201, epub. 9 sep 18 submitted 17 dec 17 revisions req. 6 feb & 1 mar 18; revisions recd. 22 feb & 6 mar 18 accepted 8 mar 18 doi: 10.18295/squmj.2018.18.02.012 advances in knowledge plagiarism was found to occur frequently among undergraduate medical and nursing students in erbil, iraq, with a significantly greater prevalence among medical rather than nursing students. unfortunately, very few of the students in this study were aware of the legal consequences of plagiarism. application to patient care determining reasons for plagiarism among medical students is important to guide academic policies and ensure the medical education system remains fair and rigorous. this will indirectly affect patient care once the students graduate and begin to work in clinical practice. professional behaviours and attitudes are increasingly important in medical education. unprofessional behaviours in doctors can potentially jeopardise patient safety, compromise working relationships and cause disruption and distress.1 plagiarism constitutes the use and misrepresentation of another person’s thoughts, words or ideas, without clear attribution to their original source.2 medical students who plagiarise may graduate and become doctors, despite not necessarily having the kameran h. ismail clinical and basic research | e197 requisite knowledge to competently practice medicine.3,4 the rapidly-growing prevalence of plagiarism at universities throughout the world requires attention from faculties, particularly as a lack of attention to this issue increases the risk of students plagiarising other people’s work.2,5 while plagiarism is a well-known problem, its occurrence is likely overestimated by both teachers and students alike.6,7 owunwanne et al. reported that 56% of freshmen at a business school in the usa had plagiarised some of their material.8 a recent literature review found that most studies report that 50–65%—and, in some cases, more than 70%—of students have confessed to some form of cheating.9 critically, some students do not even consider plagiarism to be cheating, seeing these as two distinct actions.10 rennie et al. reported that 56% of medical students consulted at a scottish university admitted that they would copy material directly from another source without using quotation marks.11 unfortunately, plagiarism has become easier and more prevalent in recent years due to the widespread use of computers and easy access to multiple information resources via the internet.3 in erbil, iraq, there is a lack of published data regarding the incidence of plagiarism among medical students or how such students perceive issues related to plagiarism. therefore, this study was conducted to establish the self-reported prevalence, reasons for and perceptions of plagiarism among medical and nursing students at hawler medical university in erbil. it is important to determine students’ beliefs concerning the frequency and nature of plagiarism as such knowledge may impact how courses are designed and how cases of potential plagiarism are dealt with by academic institutions. methods this cross-sectional study was carried out between january and june 2017 among a sample of 400 undergraduate students from the college of medicine and the college of nursing at hawler medical university. data were collected using a specially-designed selfadministered questionnaire after conducting a pilot study. each student completed the questionnaire which collected various data variables, including the students’ personal information (i.e. age, gender and field of study), knowledge about plagiarism (i.e. their awareness of what plagiarism is and its consequences), attitudes towards plagiarism (i.e. how serious the students consider plagiarism to be and whether plagiarism is a professional or ethical practice), prevalence of plagiarism (i.e. how frequently various forms of plagiarism are practised), reasons for plagiarism (i.e. why the students might wish to plagiarise) and the perceived attitude towards plagiarism on the part of their academic institution. data were analysed using the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). a chi-squared test was used to compare associations between variations. the level of statistical significance was set at p ≤0.050. all protocols for this study were approved by the ethical committee of the college of medicine at hawler medical university. the relevant authorities at the college of medicine and the college of nursing gave permission for this study to be carried out. verbal informed consent was obtained from all participants prior to data collection and all participation was entirely voluntary in nature. results a total of 280 (70%) medical students and 120 (30%) nursing students were included in the study. the mean age of the sample was 21.48 ± 0.95 years old (range: 9–25 years), with the mean age of the medical students being 21.33 ± 0.85 years old (range: 19–24 years) and the mean age of the nursing students being 21.85 ± 1.08 years old (range: 20–25 years). male students constituted 40.5% of the total sample, 46.4% of the medical students and 26.7% of the nursing students. the male-to-female ratio of the total sample was 1:1.5. in total, 54.3% of the students reported that they practised plagiarism. there was a slightly higher although non-significant difference in the frequency of plagiarism among male students compared to female students (54.9% versus 53.8%; p = 0.820) [table 1]. however, there was a significant difference in the prevalence of plagiarism among medical students compared to nursing students (58.9% versus 43.3%; p = 0.004). most of the students reported that they plagiarised by copying and pasting (81.1%); this practice was significantly more frequent among nursing rather than medical students (92.3% versus 77.6%; p = 0.018). table 1: prevalence of plagiarism according to gender among medical and nursing students at hawler medical university, erbil, iraq (n = 400) n (%) p value male students (n = 162) female students (n = 238) total practised 89 (54.9) 128 (53.8) 217 (54.3) 0.820 not practised 73 (45.1) 110 (46.2) 183 (45.8) perceptions of plagiarism among medical and nursing students in erbil, iraq e198 | squ medical journal, may 2018, volume 18, issue 2 ease and laziness were the most common reason for practising plagiarism among 46.5% of the sample, while the least common reason was confusion (15%) [table 2]. nearly two-thirds (65.3%) of the sample knew what plagiarism was. while medical students more frequently knew what plagiarism was in comparison to nursing students, this difference was not statistically significant (67.5% versus 60%; p = 0.149). however, only 28% of the students were aware of the legal penalties for practising plagiarism. plagiarism was considered unprofessional and unethical by the majority of students (79.5%), with no statistically significant difference according to field of study (p = 0.517) [table 3]. of the 261 students who knew the definition of plagiarism, 59.4% practised plagiarism, with a statistically significant association between plagiarising and knowledge of plagiarism (p = 0.005). of the 112 students who were aware of the legal consequences of plagiarism, 57.1% plagiarised; however, there was no statistically significant association between plagiarising and awareness of the legal consequences of plagiarism (p = 0.469). a total of 61.3% of students believed that their academic institutions were not successful at detecting plagiarism. this rate was significantly higher among medical students compared to nursing students (69.6% versus 41.7%; p <0.001). medical students most frequently reported that teachers ignored plagiarism table 3: knowledge of plagiarism among medical and nursing students at hawler medical university, erbil, iraq (n = 400) n (%) p value medical students (n = 280) nursing students (n = 120) total do you know what plagiarism is? yes 189 (67.5) 72 (60) 261 (65.3) 0.149 no 91 (32.5) 48 (40) 139 (34.8) are you aware of the legal consequences of plagiarism? yes 76 (27.1) 36 (30) 112 (28) 0.560 no 204 (72.9) 84 (70) 288 (72) do you consider plagiarism to be unprofessional or unethical? yes 225 (80.4) 93 (77.5) 318 (79.5) 0.517 no 55 (19.6) 27 (22.5) 82 (20.5) table 4: perceived academic detection of and response to plagiarism among medical and nursing students at hawler medical university, erbil, iraq (n = 400) academic institution n (%) p value medical students (n = 280) nursing students (n = 120) total successful detection of plagiarism yes 85 (30.4) 70 (58.3) 155 (38.8) <0.001 no 195 (69.6) 50 (41.7) 245 (61.3) response to plagiarism report to higher authorities 24 (8.6) 37 (30.8) 61 (15.3) <0.001 lower grades 91 (32.5) 25 (20.8) 116 (29) warn 72 (25.7) 32 (26.7) 104 (26) ignore 93 (33.2) 26 (21.7) 119 (29.8) table 2: prevalence, types and reasons for plagiarism among medical and nursing students at hawler medical university, erbil, iraq (n = 400) n (%) p value medical students (n = 280) nursing students (n = 120) total prevalence of plagiarism practised 165 (58.9) 52 (43.3) 217 (54.3) 0.004 not practised 115 (41.1) 68 (56.7) 183 (45.8) type of plagiarism practised* copy and paste 128 (77.6) 48 (92.3) 176 (81.1) 0.018 copy from peers 37 (22.4) 4 (7.7) 41 (18.9) reasons for plagiarism ease of plagiarising/ laziness 142 (50.7) 44 (36.7) 186 (46.5) 0.069 pressure to meet deadlines 59 (21.1) 30 (25) 89 (22.3) confusion 39 (13.9) 21 (17.5) 60 (15) cultural reasons 40 (14.3) 25 (20.8) 65 (16.3) *among those students who admitted to having practised plagiarism. kameran h. ismail clinical and basic research | e199 (33.2%), while the most frequent reaction according to nursing students was to have the incident reported to the higher authorities (30.8%). there was a statistically significant association between medical and nursing students with regards to the perceived response to plagiarism on the part of the academic institutions (p <0.001) [table 4]. discussion after their graduation, medical and nursing students become actively involved in patient care. unfortunately, participating in acts of plagiarism as a medical student may negatively affect their medical knowledge and clinical skills, resulting in potentially unskilled physicians entering the workforce.12,13 moreover, the incidence of plagiarism among nursing students has become more frequent in recent years, which is alarming in light of the need for integrity in this profession.14–16 the current study aimed to evaluate the frequency and perceptions of plagiarism among a sample of medical and nursing students and identify factors that may lead such students to plagiarise. to the best of the author’s knowledge, this is the first such study to take place in erbil. in the current study, more than half of the students were found to have practised plagiarism. the average percentage of plagiarised text in essays written by medical students in croatia was found to be 19%.17 another study revealed that the proportion of american undergraduate students who had cheated during written assignments ranged from 3–38%.18 in a review of literature, kusnoor et al. found that the frequency of various cheating behaviours among medical students in the usa was 4.7–87.6%.12 in a uk-based study, 61.9% of undergraduate students admitted to having plagiarised from online sources.19 in the current study, 54.3% of students reported to having practised plagiarism. this high percentage may be due to several factors, including a failure to detect plagiarism on the part of the academic institution or a lack of awareness of the legal consequences of plagiarism on the part of the students. additionally, non-native english-speakers may plagiarise material due to their lack of proficiency in the english language.20 other reasons for variations in reported rates of plagiarism may be due to differences in study methodologies, the criteria for plagiarism and the specific rules and regulations of academic institutions. despite the slightly higher incidence of plagiarism among male students in the current study, no significant association was noted between plagiarism and gender. this finding is in agreement with those of a previous study conducted in croatia.17 other research has indicated that male students who plagiarise have a significantly more positive attitude towards plagiarism than female students.21 most students in the present study stated that copying and pasting was the most common method of plagiarism; similar findings were reported in saudi arabia, with 42% of students admittedly copying material from electronic sources without appropriate citations.22 these findings are likely due to the fact that this method of plagiarism does not require much effort. critically, about one-third of the students in the present study did not know what plagiarism was; moreover, the vast majority were not aware of the legal penalties for practising plagiarism. in a study conducted in pakistan, 94% of participants were not aware of the penalties for plagiarism in place at their academic institutions.23 a newspaper article revealed that 81% and 67% of nigerian students attending two universities in the uk and 40% of students attending nigerian universities demonstrated a lack of awareness regarding plagiarism.24 this variation is likely due to differences in the curriculum whereby some students are taught about plagiarism much sooner than others. in the current study, students reported the main reason for plagiarism to be laziness and the ease of plagiarising other’s work, followed by the pressure to meet deadlines, cultural reasons and confusion about the topic or how to do research. students may not know how to integrate the ideas of others and document the sources of those ideas appropriately in their texts or how to take careful and through notes during research activities. in addition, plagiarism among university students might be due to the effects of a shared cultural framework which values social impressions more than academic honesty.25 in such cases, students may plagiarise because they fear failing or are reluctant to risk submitting their own work. in addition, insufficient time between deadlines and social or family demands may result in students not having enough time to finish their assignments, thereby encouraging them to resort to plagiarism.26 in a study conducted in south africa, laziness and poor time management were identified together to be the most common reason for plagiarism, followed by a desire for better grades, lack of understanding of the perceptions of plagiarism among medical and nursing students in erbil, iraq e200 | squ medical journal, may 2018, volume 18, issue 2 assignment, a lack of understanding of plagiarism and poor writing and referencing skills.27 the implications of these findings should be taken into consideration in association with social norms.26,28,29 ultimately, believing that others plagiarise may make students more likely to practise plagiarism themselves. if students estimate the incidence of plagiarism among their peers to be relatively high, they may consider plagiarising to be the norm and therefore less serious an offence. thus it is important for students to be given accurate information about the incidence, nature and consequences of plagiarism, including the definition and different types of plagiarism, how to prevent plagiarism and the penalties for plagiarising. such information can be imparted through lectures, seminars and workshops. moreover, educational institutions should create an environment where ethical behaviour is clearly valued, which will consequently make students less likely to plagiarise. in the current study, most participants reported that the response of their academic institution in most cases of plagiarism was to either ignore the issue completely or lower the transgressor’s grade; in contrast, reporting the act of plagiarism to the higher authorities was the least common response. higher education institutions should clearly state the procedures to be followed in cases of academic dishonesty, such as plagiarism. for example, the minimum penalty for plagiarism at certain universities in the usa and uk is a lower grade for the assignment, although the student may also fail the entire course or even be expelled, depending on the severity of the case.30,31 at hawler medical university, the majority of students in the current study reported that they believed most cases of plagiarism went undetected by the institution. as such, more accurate methods are needed to detect plagiarised material. computerised plagiarism detection software such as turnitin® (iparadigms llc, oakland, california, usa) and ithenticate® (iparadigms llc) can be used to highlight plagiarised portions of student work and thus prevent or reduce the overall incidence of plagiarism. academic institutions should make an effort to obtain licenses for such text-matching software and also provide guidelines for teachers so that these tools can be utilised appropriately. in conjunction, students should receive necessary training and support regarding how to conduct appropriate research, search for and cite high-quality sources, prevent plagiarism and improve their writing techniques.32 overall, reducing plagiarism and creating an ethical educational environ ment will result in the students developing better learning, research and writing skills. these findings may potentially help guide academic policies at hawler medical university and hopefully serve to lower the incidence of academic dishonesty. this study was subject to certain limitations. due to the lack of previous studies conducted on this topic in erbil, the author was unable to compare the findings of the current study with that of similar research in this region. similarly, the author was unable to benefit from other researchers’ experiences when designing the questionnaire. in addition, the current study included only undergraduate students. future research should seek to determine the frequency and perceptions of plagiarism among postgraduate students and lecturers as well as evaluate the effectiveness of anti-plagiarism interventions and prevention strategies. conclusion this study found that undergraduate medical and nursing students in erbil lacked understanding of plagiarism and its legal consequences. there is a need for effective policies and procedures to be imple mented to increase students’ awareness of plagiarism, thereby reducing the incidence of this form of academic dishonesty. this may necessitate the installation of specific text-matching software or a review of the academic penalties to be enforced in cases of plagiarism. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. yates j. “concerns” about medical students’ adverse behaviour and attitude: an audit of practice at nottingham, with mapping to gmc guidance. bmc med educ 2014; 14:196. doi: 10.1186/ 1472-6920-14-196. 2. mason pr. plagiarism in scientific publications. j infect dev ctries 2009; 3:1–4. doi: 10.3855/jidc.98. 3. devoss d, rosati ac. “it wasn’t me, was it?” plagiarism and the web. comput compos 2002; 19:191–203. doi: 10.1016/s87554615(02)00112-3. 4. cole af. plagiarism in graduate medical education. fam med 2007; 39:436–8 5. amiri f, razmjoo sa. on iranian efl undergraduate students’ perceptions of plagiarism. j acad ethics 2016; 14:115-31. doi: 10.1007/s10805-015-9245-3. 6. hard sf, conway jm, moran ac. faculty and college student beliefs about the frequency of student academic misconduct. j high educ 2006; 77:1058–80. doi: 10.1080/00 221546.2006.11778956. 7. engler jn, landau jd, epstein m. keeping up with the joneses: students’ perceptions of academically dishonest behaviour. teach psychol 2008; 35:99–102. doi: 10.1080/00986280801978418. https://doi.org/10.1186/1472-6920-14-196 https://doi.org/10.1186/1472-6920-14-196 https://doi.org/10.3855/jidc.98 https://doi.org/10.1016/s8755-4615%2802%2900112-3 https://doi.org/10.1016/s8755-4615%2802%2900112-3 https://doi.org/10.1007/s10805-015-9245-3 https://doi.org/10.1080/00221546.2006.11778956 https://doi.org/10.1080/00221546.2006.11778956 https://doi.org/10.1080/00986280801978418 kameran h. ismail clinical and basic research | e201 8. owunwanne d, rustagi n, dada r. students’ perceptions of cheating and plagiarism in higher institutions. j coll teach learn 2010; 7:59–68. doi: 10.19030/tlc.v7i11.253. 9. lambert eg, hogan nl, barton sm. collegiate academic dishonesty revisited: what have they done, how often have they done it, who does it, and why did they do it? electron j sociol 2003; 7:1–27. 10. bruwelheide jh. plagiarism: trends, thoughts, suggestions. techtrends 2010; 54:22–4. doi: 10.1007/s11528-010-0433-0. 11. rennie sc, crosby jr. are “tomorrow’s doctors” honest? ques tionnaire study exploring medical students’ attitudes and reported behaviour on academic misconduct. bmj 2001; 322:274–5. doi: 10.1136/bmj.322.7281.274. 12. kusnoor av, falik r. cheating in medical school: the unacknowledged ailment. south med j 2013; 106:479–83. doi: 10.10 97/smj.0b013e3182a14388. 13. mortaz hejri s, zendehdel k, asghari f, fotouhi a, rashidian a. academic disintegrity among medical students: a randomised response technique study. med educ 2013; 47:144–53. doi: 10. 1111/medu.12085. 14. johnson ja. does academic dishonesty result in unethical professional practice? j nurses prof dev 2013; 29:271–3. doi: 10.1097/01.nnd.0000433151.26007.f9. 15. krueger l. academic dishonesty among nursing students. j nurs educ 2014; 53:77–87. doi: 10.3928/01484834-20140122-06. 16. macale l, ghezzi v, rocco g, fida r, vellone e, alvaro r. academic dishonesty among italian nursing students: a long itudinal study. nurse educ today 2017; 50:57–61. doi: 10.1016/j. nedt.2016.12.013. 17. bilić-zulle l, frković v, turk t, azman j, petrovecki m. prevalence of plagiarism among medical students. croat med j 2005; 46:126–31. 18. mccabe dl. cheating among college and university students: a north american perspective. int j educ integr 2005; 1:1–11. doi: 10.21913/ijei.v1i1.14. 19. selwyn n. ‘not necessarily a bad thing…’: a study of online plagiarism amongst undergraduate students. assess eval high educ 2008; 33:465–79. doi: 10.1080/02602930701563104. 20. sri kantha s. nobel prize winners for literature as palliative for scientific english. croat med j 2003; 44:20–3. 21. jereb e, urh m, jerebic j, šprajc p. gender differences and the awareness of plagiarism in higher education. soc psychol educ 2018; 21:409–26. doi: 10.1007/s11218-017-9421-y. 22. razek n. academic integrity: a saudi student perspective. acad educ leadersh j 2014; 143–54. 23. murtaza g, zafar s, bashir i, hussain i. evaluation of student’s perception and behavior towards plagiarism in pakistani universities. acta bioeth 2013; 19:125–30. doi: 10.4067/s1726-569x 2013000100013. 24. orim sm. student plagiarism: do we care? available at: www.universityworldnews.com/article.php?story=2015060 9151735677 accessed: mar 2018. 25. wowra sa. moral identities, social anxiety, and academic dishonesty among american college students. ethics behav 2007; 17:303–21. doi: 10.1080/10508420701519312. 26. park c. in other (people’s) words: plagiarism by university students literature and lessons. assess eval high educ 2003; 28:471–88. doi: 10.1080/02602930301677. 27. sentleng mp, king l. plagiarism among undergraduate students in the faculty of applied science at a south african higher education institution. s afr j libr inf sci 2012; 78:57–67. doi: 10. 7553/78-1-47. 28. mccabe dl, trevino lk, butterfield kd. cheating in academic institutions: a decade of research. ethics behav 2001; 11:219–32. doi: 10.1207/s15327019eb1103_2. 29. rettinger da, kramer y. situational and personal causes of student cheating. res high educ 2009; 50:293–313. doi: 10.10 07/s11162-008-9116-5. 30. colorado state university. penalties for plagiarism and your legal rights. available at: https://writing.colostate.edu/guides/ page.cfm?pageid=317&guideid=17 accessed: mar 2018. 31. university of bradford. penalties for plagiarism. available at: www.brad.ac.uk/library/help/plagiarism/penalties-for-plagia rism/ accessed: mar 2018. 32. smedley a, crawford t, cloete l. an intervention aimed at reducing plagiarism in undergraduate nursing students. nurse educ pract 2015; 15:168–73. doi: 10.1016/j.nepr.2014.12.003. https://doi.org/10.19030/tlc.v7i11.253 https://doi.org/10.1007/s11528-010-0433-0 https://doi.org/10.1136/bmj.322.7281.274 https://doi.org/10.1097/smj.0b013e3182a14388 https://doi.org/10.1097/smj.0b013e3182a14388 https://doi.org/10.1111/medu.12085 https://doi.org/10.1111/medu.12085 https://doi.org/10.1097/01.nnd.0000433151.26007.f9 https://doi.org/10.3928/01484834-20140122-06 https://doi.org/10.1016/j.nedt.2016.12.013 https://doi.org/10.1016/j.nedt.2016.12.013 https://doi.org/10.21913/ijei.v1i1.14 https://doi.org/10.1080/02602930701563104 https://doi.org/10.1007/s11218-017-9421-y https://doi.org/10.4067/s1726-569x2013000100013 https://doi.org/10.4067/s1726-569x2013000100013 https://doi.org/10.1080/10508420701519312 https://doi.org/10.1080/02602930301677 https://doi.org/10.7553/78-1-47 https://doi.org/10.7553/78-1-47 https://doi.org/10.1207/s15327019eb1103_2 https://doi.org/10.1007/s11162-008-9116-5 https://doi.org/10.1007/s11162-008-9116-5 https://doi.org/10.1016/j.nepr.2014.12.003 sultan qaboos university med j, february 2015, vol. 15, iss. 1, pp. e34–38, epub. 21 jan 15 submitted 21 oct 14 revision req. 4 nov 14; revision recd. 12 nov 14 accepted 12 nov 14 this article is the last of a three-part series narrating a brief history of breast cancer that has traced the attempts by physicians to understand and conquer this disease since antiquity.2,3 the series chronicles the millennia during which crude and desperate surgery-only measures gave way to an understanding of the pathobiology of this hormone-responsive cancer. tolling the knell on halstedian heroic extirpations (1894) was the advent of chemotherapy and radiotherapy.4,5 on a historical timescale, the arrival of these new therapeutic modalities would be recorded as part of modern history. remarkable insights into tumour biology in the last century have been the catalyst to the meteoric rise of medical oncology. the dividing cell can be killed it is ironic that the birth of cancer chemotherapy occurred in the lap of chemical war weaponry; the fact that nitrogen mustard gas caused profound bone marrow depression was instrumental in the subsequent notion that it could also annihilate cancer cells. following clinical trials, it received approval from the usa food and drug administration for the treatment of patients with hodgkin lymphoma. sidney farber’s first pioneering triumph in achieving partial remission in a case of paediatric leukaemia in 1947 by administering aminopterin,6 as well as the establishment of the national cancer institute clinical trials cooperative group program in 1955,7 set in motion a wave of research that would strengthen as it gave rise to a new specialty. the principles of oncological management changed forever and resignation to certain impending death was no longer the fate of a patient diagnosed with cancer.6 nascent medical oncologists would face struggles with incredulity and disbelief before the field would establish itself through clinical trials and scientific merit. the term ‘chemotherapy’ acquired an entirely new connotation in the pharmacological lexicon as a generic synonym for anti-neoplastic drugs, far removed from its 19th century ehrlichian usage for “chemicals against infections”. it was subsequently prefixed by the adjective ‘adjuvant’ that promised greater success at inducing remission after the tumour burden had been reduced by surgical extirpation. the first beneficiaries were patients with osteosarcomas (treated with methotrexate)8 and colon cancer (treated with 5-fluorouracil).9 the landmark trials of bernard fisher, chair of the national surgical adjuvant breast and bowel project (nsabp) in the usa, and of gianni bonadonna, working in the istituto nazionale dei tumori in milan, italy, proved that a combination of drugs with different mechanisms of action (commonly cyclophosphamide, methotrexate and 5-fluorouracil) significantly extended survival after the complete 1department of pathology, college of medicine & health sciences, sultan qaboos university; 2department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ritu@squ.edu.om تاريخ موجز لسرطان الثدي بيولوجيا األورام يضع األساس لعلم األورام الطبية ريتو لكتاكيا و اإكرام بريين medical history a brief history of breast cancer part iii tumour biology lays the foundation for medical oncology *ritu lakhtakia1 and ikram burney2 to a tissue that’s trying to grow we hope these experiments show with steroids phenolic don’t get metabolic: just grab on, and never let go! limerick on the action of oestrogen on the oestrogen receptor.1 ritu lakhtakia and ikram burney medical history | e35 surgical resection of breast tumours—particularly in more advanced cancers.5,10,11 women presenting with locally advanced breast cancer inspired a re-evaluation in the ways chemotherapy could be utilised. could chemotherapy shrink an otherwise inoperable tumour, rendering it amenable to the knife with clear post-surgical margins? this assumption initiated the advent of neoadjuvant chemotherapy—another unique first for oncology— and breast cancer spearheaded its later application to other cancers. the ‘downsizing’ of a tumour had therefore moved from concept to standard practice. today, a wide choice of refined options exist for medical oncologists who are now long past the days of nitrogen mustard gas, notorious for its toxicity. among the seminal drugs whose place in the antibreast cancer armamentarium is secure, a few deserve mention. in the early 1970s, doxorubicin derived from a strain of streptomyces formed the corner-stone of chemotherapy, acting by the intercalation of dna and interruption of replication.12 paclitaxel, originally sourced from the bark of the pacific yew tree in 1962, was found to disrupt microtubule assembly.13 thirty years after its discovery, it generated excitement as a success story in treating ovarian cancer. however, it was soon tapped in 1994 for its effectiveness in treating the most common cancer in females—that of the breast.13 capecitabine, introduced in 1998, acted by blocking dna synthesis and transcription. it became one of the options for advanced or metastatic cancer after anthracycline and taxanes and had the added benefit of oral administration.6 these are just a few of the drugs which are now used to treat breast cancer and the list continues to grow! cell signalling: enabling a multipronged attack the hormone responsiveness of breast cancer was a concept proposed long before elwood jensen’s discovery of hormone receptors on breast cancer cells in 1967.1,14 circumstantial evidence existed as indicators of this, for instance in the fact that young women generally had a more aggressive form of the disease and because the removal of sources of oestrogen (e.g. via an oopherectomy or adrenalectomy) increased survival. hormone receptor-positive tumours, either oestrogen receptors (er) or progesterone receptors (pr), were found to be predictive of recurrence in several publications in 1977.15 this triggered the invention of receptor assays and, later on, direct demonstration of the receptors on the tumour cells. an arena was opened for targeted therapy, which was itself a new pharmacological approach that would be emulated in the subsequent treatment of other cancers. tamoxifen, a selective er modifier (serm), held promise for increased survival in receptor-positive tumours and was approved as an adjuvant therapy for post-menopausal women in 1986.16,17 the resultant dramatic changes in cancer recurrence and survival established its place in breast cancer therapy. subsequently, a gonadotropinreleasing hormone analogue (goserelin) and aromatase inhibitors (anastrozole, letrozole and exemestane) have been shown to improve progression-free survival in an adjuvant setting.18 the saga of the her2 gene (now known as her2/neu)—identified between 1982 and 1984 by the collaborative effort of a group of american scientists from the robert a. weinberg group at the massachusetts institute of technology, rocke feller university and harvard university—categorised breast cancers as her2-positive or -negative.19 multiple copies of the gene transcribe excess her2 receptor proteins which causes tumour cells to be more responsive to growth signals, thus making the tumour more aggressive. the trajectory of medical oncology was to see the marriage of four disciplines—genetics, immunology, pathology and pharmacology—a success story of modern day interdisciplinary integration. a therapeutic monoclonal antibody became a viable option when research in the 1990s culminated in the emergence of targeted therapy in 1998 with the production of trastuzumab (an anti-her2 molecule) by genentech inc. (roche group, san francisco, california, usa).20 tumour biology had provided yet another impetus to cancer therapy. a subset of breast cancers which are particularly difficult to treat are triple-negative tumours (i.e. expressing neither er, pr or her2). these are effectively tumours without a target! however, a silver lining was found in the application of poly-adenosine diphosphate-ribose polymerase (parp)-inhibitors that prevent cancer cells from repairing defective dna and thus makes them chemo-sensitive. the last few years have witnessed the emergence of newer drugs with diverse claims: these may find their place in future historical reviews! the genie of hereditary breast cancer genes identified in 1994–1995, the tumour suppressor genes brca1 and brca2 provided scientific support for the notion of hereditary breast cancer.21,22 their significance lay in the possibility that identification could result in closer surveillance for high-risk family members and give them the option of a bilateral salpingo-oophorectomy or prophylactic bilateral a brief history of breast cancer part iii tumour biology lays the foundation for medical oncology e36 | squ medical journal, february 2015, volume 15, issue 1 earlier examples of evidence-based medicine in this context.27 the concepts which vincent t. devita and bonadonna had postulated in the 1970s were verified by the highest levels of evidence in 1992. the role of adjuvant chemotherapy and hormone therapy was now established beyond a doubt; outcomes would improve for women with early and locally advanced breast cancer and their outlook would change forever. further refinements by these and other groups, including the breast cancer international research group (bcirg), established the role of anthracyclines as obligatory in all groups of patients as well as that of taxanes in high-risk groups.28 today, the concurrent or sequential use of anthracyclines and taxanes forms the backbone of adjuvant and neoadjuvant treatment in breast cancer. similarly, following the seminal meta-analysis by the ebctcg in 1992, adjuvant hormone therapy became the standard of care for all women with hormone receptor-positive disease, which affects approximately 50% of pre-menopausal and 70% of post-menopausal women.27 additional progress by the nsabp, ebctcg and other groups, such as the breast international group, includes the use of aromatase inhibitors in post-menopausal women, either as switch therapy or for extended use beyond tamoxifen.29 both strategies have led to an improvement in progression-free survival compared to tamoxifen, with different but acceptable side-effects. the use of the monoclonal antibody trastuzumab, which targets her2/neu oncogene amplification in a metastatic setting, became the standard of care in the late 1990s. in 2005, four groups working independently (including the nsabp, bcirg and herceptin adjuvant group) showed an unprecedented improvement in survival in the adjuvant setting with the addition of trastuzumab as the backbone of combination chemotherapy.30,31 the challenge had been transformed into an opportunity. expression of her2/neu protein on cancer cells was no longer fraught with apprehension, but rather with determination to improve survival with the use of targeted therapy. history had been made and the last decade has seen efforts to further improve outcomes by optimising the duration of trastuzumab treatment, adding another monoclonal antibody or receptor tyrosine kinase inhibitor and using antibody-drug conjugates. the role of radiotherapy after mastectomy and breast-conserving surgery has also been indisputably established as a result of large cooperative group trials and meta-analyses. postoperative radiotherapy after mastectomy has been shown to reduce local recurrence and improve overall survival even when systemic treatment is administered.32 after breastmastectomy and the possibility of chemoprevention. in 1998, more than a decade after its approval to treat hormone receptor-positive cancers, tamoxifen provided another opportunity for use—this time in a risk-reduction role for such individuals.6 personalised medicine in the century of genetics the first year of the 21st century opened with a ‘tumour-on-a-chip’ mood among breast oncologists and geneticists. multigene arrays have raised the possibility of basing tumour prognostication and treatment on the genomic fingerprints of breast cancer.23 furthermore, breast cancer classifications based on molecular subtypes hold promise for personalising medicine.24 breast cancer is no longer considered one disease, but rather a mixture of at least four diseases: hormone receptor-positive and her2-negative cancer; hormone receptor-positive and her2-positive cancer; hormone receptor-negative and her2-positive cancer, and triple-negative cancer. the targets are based on the response of the tumour and therapeutic decisions are made accordingly. the oncotype dx® test (genomic health inc., redwood city, california, usa) and other similar commercial kits based on multigene assays have since opened a market for the new predictive and personalised practice of oncology. these tests allow for risk-stratification which obviates the need for cytotoxic chemotherapy among a low-risk subset of women with breast cancer. clinical trials and evidencebased medicine: the backbone of oncology with the dubious distinction of being the globally leading cancer in women, breast cancer has had a unique primacy in the 20th century in terms of clinical trials in oncology. efforts to improve breast cancer outcomes launched the process by which large cooperative groups used evidence-based medicine to establish new standards of care, refining treatments in the adjuvant, neoadjuvant and metastatic settings. a series of large-scale phase iii trials by the nsabp and meta-analyses published by the early breast cancer trialists’ collaborative group (ebctcg) are only two examples of how breast cancer physicians, surgeons, radiotherapists and statisticians have come together and paved the way for healthcare professionals dealing with other cancers.25,26 a meta-analysis consisting of 133 studies and a total cohort of 75,000 women was one of the ritu lakhtakia and ikram burney medical history | e37 conserving surgery, treatment with radiotherapy reduces disease recurrence by half and breast cancerrelated mortality by a sixth.33 renaissance in the battle against breast cancer: surgical mutilation tempered at the beginning of the 20th century, attempts were already underway to reduce disfigurement and morbidity at the hands of the school of surgery promoting bold radical mastectomies. a notable first step was the move from radical to total mastectomies in 1971.6 in 1975–1976, the use of adjuvant chemotherapy provided the adjunct that would drive survival rates to heights that surgery alone could never achieve. only six years later, a push to breast conservation created a movement for lumpectomies, with the added choice of ‘mopping up’ any residual tumor cells with radiotherapy. in italy, veronesi et al. were one of several groups around the world espousing the use of limited surgery in combination with radiotherapy.34 the change from axillary dissection, with its attendant morbidity caused by lymphoedema of the ipsilateral arm, to sentinel node biopsy in selected groups has been referred to previously.2 b e t t e r t o g e t h e r multidisciplinary efforts in the management of breast cancer became the norm through insights into the growth kinetics and biomodulation of tumours. pathological predictive and prognostic factors, especially er, pr and her2 expression, became invaluable in determining therapeutic options.3 despite its relatively short lifetime, medical oncology has achieved its rightful place at the heart of multidisciplinary breast cancer treatment, dispelling dogma and enabling collaboration. it has demonstrated the range of its applications to patient care, from prevention to rehabilitation, by remaining grounded in evidence, accepting and discarding therapies through global trials and combining its own tools with the best of those from the disciplines of surgery and radiotherapy. e a r ly d e t e c t i o n a n d p r e v e n t i o n g a lva n i s e t h e ‘c u r e’ m o v e m e n t in the last decades of the 20th century, the advent of mammographies ran parallel with attempts to catch the disease early and ensure a cure. this involved monitoring a subsection of women whose strong family history demanded surveillance. the adage that ‘prevention is better than cure’ was adopted in both letter and spirit by breast physicians and surgeons. preventative strategic options include chemoprophylaxis, bilateral salpingo-oophorectomies and prophylactic mastectomies in brca-positive women, making headlines when espoused by iconic celebrities.35 in addition, the decreasing use of hormone replacement therapy has had a role in the overall decline of breast cancer. a host of chemoprevention options utilising serms also exist.36 lessons from the foundation of tumour biology for medical oncology in breast cancer from the mere decimation of tumour cells using single agent or combination chemotherapy to endocrine manipulation and targeted therapies, advances in breast cancer therapy have successfully anchored medical oncology in the terra firma of cancer therapy. the rise of this new discipline has been anchored by parallel, rapid and translational research in tumour biology. this has allowed the emergence of generations of drugs, either targeting the global cell cycle or specific receptors. as critical information regarding breast cancer genes and their interplay emerge, we bear witness today to the history of personalised medicine in the making. life comes with many challenges. the ones that should not scare us are the ones we can take on and take control of. angelina jolie.35 references 1. greene gl. in memoriam: elwood jensen (1920-2012). endocr rev 2013; 154:3489–91. doi: 10.1210/er.2013-7031. 2. lakhtakia r. a brief history of breast cancer: part i surgical domination reinvented. sultan qaboos univ med j 2014; 14:166–9. 3. lakhtakia r, chinoy rf. a brief history of breast cancer: part ii: evolution of surgical pathology. sultan qaboos univ med j 2014; 14:319–22. 4. halsted ws. i: the results of operations for the cure of cancer of the breast performed at the johns hopkins hospital from june, 1889, to january. ann surg 1894; 20:497–555. 5. fisher b, redmond c, poisson r, margolese r, wolmark n, wickerham l, et al. eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. n engl j med 1989; 320:822–28. doi: 10.1056/nejm198903303201302. 6. american society of clinical oncology. major cancer milestones. from: www.cancerprogress.net/sites/cancerprogr ess.net/files/category-downloads/major_cancer_milestones_ timeline_2.pdf accessed: oct 2014. 7. schilsky rl, mcintyre or, holland jf, frei e 3rd. a concise history of the cancer and leukemia group b. clin cancer res 2006; 12:3553s–5s. doi: 10.1158/1078-0432.ccr-06-9000. a brief history of breast cancer part iii tumour biology lays the foundation for medical oncology e38 | squ medical journal, february 2015, volume 15, issue 1 25. mamounas ep. nsabp breast cancer clinical trials: recent results and future directions. clin med res 2003; 1:309–26. doi: 10.3121/cmr.1.4.309. 26. early breast cancer trialists’ collaborative group. systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. lancet 1992; 339:1–15. doi: 10.1016/0140-6736(92)90139-t. 27. early breast cancer trialists’ collaborative group. systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. lancet 1992; 339:71–85. doi: 10.1016/0140-6736(92)90997-h. 28. mackey jr, martin m, pienkowski t, rolski j, guastalla jp, sami a, et al.; trio/bcirg 001 investigators. adjuvant docetaxel, doxorubicin, and cyclophosphamide in nodepositive breast cancer: 10-year follow-up of the phase 3 randomised bcirg 001 trial. lancet oncol 2013; 14:72–80. doi: 10.1016/s1470-2045(12)70525-9. 29. breast international group (big) 1-98 collaborative group; thürlimann b, keshaviah a, coates as, mouridsen h, mauriac l, forbes jf, et al. a comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. n engl j med 2005; 353:2747–57. doi: 10.1056/nejmoa052258. 30. viani ga, afonso sl, stefano ej, de fendi li, soares fv. adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. bmc cancer 2007; 7:153. doi: 10.1186/1471-2407-7-153. 31. dahabreh ij, linardou h, siannis f, fountzilas g, murray s. trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. oncologist 2008; 13:620–30. doi: 10.1634/ theoncologist.2008-0001. 32. ebctcg (early breast cancer trialists’ collaborative group); mcgale p, taylor c, correa c, cutter d, duane f, ewertz m, et al. effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. lancet 2014; 383:2127–35. doi: 10.1016/ s0140-6736(14)60488-8. 33. early breast cancer trialists’ collaborative group (ebctcg); darby s, mcgale p, correa c, taylor c, arriagada r, clarke m, et al. effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: metaanalysis of individual patient data for 10,801 women in 17 randomised trials. lancet 2011; 378:1707–16. doi: 10.1016/ s0140-6736(11)61629-2. 34. veronesi u, saccozzi r, del vecchio m, banfi a, clemente c, de lena m, et al. comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. n engl j med 1981; 305:6–11. doi: 10.1056/nejm198107023050102. 35. jolie a. the new york times: my medical choice. from: www. nytimes.com/2013/05/14/opinion/my-medical-choice.html?_ r=1& accessed: oct 2014. 36. advani p, moreno-aspitia a. current strategies for the prevention of breast cancer. breast cancer (dove med press) 2014; 6:59-71. doi: 10.2147/bctt.s39114. 8. jaffe n. historical perspective on the introduction and use of chemotherapy for the treatment of osteosarcoma. adv exp med biol 2014; 804:1–30. doi: 10.1007/978-3-319-04843-7_1. 9. bertino jr. chemotherapy of colorectal cancer: history and new themes. semin oncol 1997; 24:s183–7. 10. fisher b, carbone p, economou sg, frelick r, glass a, lerner h, et al. l-phenylalanine mustard (l-pam) in the management of primary breast cancer: a report of early findings. n engl j med 1975; 292:117–22. doi: 10.1056/nejm197501162920301. 11. ribatti d. the contribution of gianni bonadonna to the history of chemotherapy. cancer chemother pharmacol 2007; 60:309– 12. doi: 10.1007/s00280-006-0410-7. 12. code mp, todd id, wilkinson pm. a preliminary trial of doxorubicin in advanced breast cancer and other malignant disease. br j cancer 1974; 29:114–16. doi: 10.1038/bjc.1974.47. 13. national cancer institute: success story: taxol® (nsc 125973). from: www.dtp.nci.nih.gov/timeline/flash/success_stories/s2_ taxol.htm accessed: oct 2014. 14. beatson gt. on the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. lancet 1896; 148: 162–5. doi: 10.1016/ s0140-6736(01)72384-7. 15. knight wa, livingston rb, gregory ej, mcguire wl. estrogen receptor as an independent prognostic factor for early recurrence in breast cancer. cancer res 1977; 37:4669–71. 16. fisher b, redmond c, brown a, wolmark n, wittliff j, fisher er, et al. treatment of primary breast cancer with chemotherapy and tamoxifen. n engl j med 1981; 305:1–6. doi: 10.1056/nejm198107023050101. 17. early breast cancer trialists’ collaborative group. tamoxifen for early breast cancer: an overview of the randomised trials. lancet 1998; 351:1451–67. doi: 10.1016/s0140-6736(97)11423-4. 18. chumsri s, howes t, bao t, sabnis g, brodie a. aromatase, aromatase inhibitors, and breast cancer. j steroid biochem mol biol 2011; 125:13–22. doi: 10.1016/j.jsbmb.2011.02.001. 19. kumar gl, badve ss. milestones in the discovery of her2 proto-oncogene and trastuzumab (herceptin™). from: www.dako.com/index/knowledgecenter/kc_publications/ kc_publications_connection/kc_publications_connection12. htm/28827_2008_conn12_milestones_discovery_her2_protooncogene_and_trastuzumab_kumar_and_badve.pdf accessed: oct 2014. 20. ross js, fletcher ja, linette gp, stec j, clark e, ayers m, et al. the her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. oncologist 2003; 8:307–25. doi: 10.1634/theoncologist.8-4-307. 21. miki y, swensen j, shattuck-eidens d, futreal pa, harshman k, tavtigian s, et al. a strong candidate for the breast and ovarian cancer susceptibility gene brca1. science 1994; 266:66–71. doi: 10.1126/science.7545954. 22. wooster r, bignell g, lancaster j, swift s, seal s, mangion j, et al. identification of the breast cancer susceptibility gene brca2. nature 1995; 378:789–92. doi: 10.1038/378789a0. 23. perou cm, sørlie t, eisen mb, van de rijn m, jeffrey ss, rees ca, et al. molecular portraits of human breast tumors. nature 2000; 406:747–52. doi: 10.1038/35021093. 24. rouzier r, perou cm, symmans wf, ibrahim n, cristofanilli m, anderson k, et al. breast cancer molecular subtypes respond differently to preoperative chemotherapy. clin cancer res 2005; 11:5678–85. doi: 10.1158/1078-0432.ccr-04-2421. squ med j, february 2012, vol. 12, iss. 1, pp. 25-32, epub. 7th feb 12. submitted 19th jun 11 revision req. 6th sep 11, revision recd. 7th oct 11 accepted 2nd nov 11 1department of behavioural medicine, sultan qaboos university hospital, sultan qaboos university, muscat, oman; 2atlantis health care, chiswick park, london w4 5ya, uk; 3department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author e-mail: zenam@squ.edu.om اخلصائص االجتماعية والسريرية ملستخدمي العالج النفسي يف إحدى مستشفيات الرعاية الثالثية يف ُعمان زينة ال�رصبتي، كلري هال�س، هزار الزدجايل، مروان ال�رصبتي امللخ�ص: الهدف: اأثبت عدد كبري من الدرا�سات اأّن للعالج النف�سي دور فّعال يف معاجلة الأمرا�س النف�سّية ال�رّصيرّية يف املحور الأول، لكن البحث هذا من الهدف الُعماين. حّية ال�سّ الّرعاية نظام يف موؤّخرا اإل اإن�ساوؤها يتم مل النف�سي العالج خدمات فاإّن ذلك، من الرغم وعلى الرعاية م�ست�سفيات اإحدى يف النف�سي العالج خدمات من امل�ستفيدين للمر�سى والدميغرافية والجتماعية ال�رصيرية ال�سفات درا�سة هو الثالثية. الطريقة: مّت حتليل 133 من احلالت اجلديدة املحّولة للعالج النف�سي يف م�ست�سفى جامعة ال�سلطان قابو�س املرجعي. النتائج: �سّكلت الإناث معظم احلالت املحّولة )%59(،و تراوحت اأعمار املر�سى بني 18-34 عاما، وكان )%38( من احلالت من املوظفني. فكان الت�سخي�س، ناحية من اأما .)54%( املتزوجني غري ومن اأقل، اأو الثانوية ال�سهادة على احلا�سلني من )51%( املر�سى غالبية يعاين من ا�سطرابات القلق )%43(، ومن ا�سطراب الكتئاب )%22( من العينة. وكان اأكرثية املر�سى املحولني للعالج النف�سي )65%( اإطار خالل من م�ستخدميها وخ�سائ�س النف�سي العالج خدمات من ال�ستفادة مدى البحث هذا يف نناق�س النف�سّية. بالأدوية يعاجلون املجتمع العماين املتنوع ثقافيا والذي ي�سمل على معتقدات ثقافية معينة مثل الإميان بالقوى اخلارقة للطبيعة )اجلن(، والعني واحَل�َسد من لال�ستفادة ال�سخ�سية القرارات على تاأثريها لها الوقت نف�س ويف النف�سي، املر�س ُم�َسّببات ل�رصح ت�ستخدم ما عادة والتي وال�ّسحر، العالج الطبي و النف�سي. اخلال�صة: على الرغم من انخفا�س عدد احلالت املحولة للعالج النف�سي يف الفرتة املحددة يف الدرا�سة، اإل اأّن هذا التطور ُيعترب اإيجابيا و ُمرّحبا به مع زيادة الأمرا�س النف�سية يف ُعمان. مفتاح الكلمات: العالج النف�سي، القلق، الكتئاب، احل�سارة، ُعمان. abstract: objectives: there is significant evidence that psychotherapy is a pivotal treatment for persons diagnosed with axis i clinical psychiatric conditions; however, a psychotherapy service has only recently been established in the omani health care system. this study aimed to investigate the sociodemographic and clinical characteristics of attendees at a psychotherapy clinic at a tertiary care hospital. methods: an analysis was carried out of 133 new referrals to the psychotherapy service at sultan qaboos university hospital, a tertiary care hospital. results: the majority of referrals were females (59%), aged 18–34 years, employed (38%), had ≤12 years of formal education (51%), and were single (54%). a total of 43% were treated for anxiety disorders (including obsessive compulsive disorder), while 22% were treated for depression. a total of 65% were prescribed psychotropic medications. the utilisation of the psychotherapy service and its user characteristics are discussed within the context of a culturally diverse omani community which has unique personal belief systems such as in supernatural powers (jinn), contemptuous envy (hassad), evil eye (ain) and sorcery (sihr) which are often used to explain the aetiology of mental illness and influence personal decisions on utilising medical and psychological treatments. conclusion: despite the low number of referrals to the psychotherapy service, there is reason to believe that psychotherapy would be an essential tool to come to grips with the increasing number of mental disorders in oman. keywords: psychotherapy; anxiety; depression; culture; oman. sociodemographic and clinical characteristics of patients attending psychotherapy in a tertiary care hospital in oman *zena al-sharbati,1 claire hallas,2 hazar al-zadjali,1 marwan al-sharbati3 clinical & basic research advances in knowledge this paper contributes to understanding the sociodemographic and clinical characteristics of patients attending psychotherapy in a tertiary care university hospital in oman, where such services were only recently introduced. application to patient care with the recognition of the increasing number of psychological disorders in oman, alternative approaches to pharmacotherapy are needed. psychological techniques that are rooted in empirical evidence ought to be integrated into the health care system in oman. sociodemographic and clinical characteristics of patients attending psychotherapy in a tertiary care hospital in oman 26 | squ medical journal, february 2012, volume 12, issue 1 studies have been conducted (mainly within euro-american populations) to explore factors associated with the utilisation of psychotherapy services as they are increasingly being prescribed, in addition to medical treatments, to mitigate emotional and cognitive disorders.1-8 in recent years, the proportion of persons seeking outpatient treatment for depression has increased, in addition to the prescription of antidepressant medications.8 in contrast, over a ten year period the number of persons seeking psychotherapy had decreased which may suggest an increase in the trend to seek biological interventions.8 others have suggested that the decline in the utilisation of psychotherapy may be due to the growth of ‘self-help’ materials, the increasing popularity of complementary and alternative medicines, and the increased accessibility of over-the counter medications.9-13 therefore, exploring trends in the utilisation of psychotherapy is important to shed light on the patterns of health care utilisation. recent studies have explored the demographic, gender, ethnic and cultural characteristics of psychotherapy users and found that females are more likely to participate in psychotherapy than males, and that there is a preponderance towards caucasian populations utilising psychotherapy.7,14,15 the cultural context of psychotherapy utilisation is therefore significant. psychotherapy, rather than medical treatments, is favoured more generally by euro-american populations who have greater access to wider health care information and treatment choices. until relatively recently, within non-western societies, culturally˗driven healing practices were traditionally used to manage mental health problems. however, the rapid urbanisation and globalisation of non-western societies has now led to an increased interest in the application of western psychotherapy.16 this indicates increased awareness about the benefits of psychotherapy and its outcomes,17 but there is a dearth of information about the development and utilisation of psychotherapy in non-western societies.18 evidence suggests that socio-cultural patterning through the generations has had a significant influence on the assumptions of health care authorities about the therapeutic and economic value of developing psychotherapy services. this may be due to the inherent self-exploration component of psychotherapy which is discouraged within non-western societies in favour of a collectivist approach to well-being. in addition, it may be that non-western societies value traditional social support systems and thus perceive modern “talking therapies” as similar to these, thereby reducing the perceived value of speaking with a professionally qualified practitioner.14 generally, within arab countries, there is limited access to and availability of mental health services. therefore, even without considering the sub-specialty of psychotherapy, there is a paucity of studies investigating the demographic and clinical characteristics of mental health service users; this includes sources and reasons for referral, diagnosis of the client, psychotropic medication use, and the need for inpatient care. in oman, general mental health services have developed slowly with recent reports indicating that there are approximately 39 qualified registered mental health professionals in the country.19 considering that oman has a population of approximately three million people distributed over 300,000 square kilometers, this indicates that the mental health needs of the population will be largely unmet.19 furthermore there is scarcity of professionally qualified arabic speaking psychotherapists.17 investigating these trends in the sociocultural context of oman is of special interest as oman is economically a developing country experiencing rapid modernisation, urbanisation, and acculturation. oman has its own unique cultural and religious teachings in comparison with other arab populations and these are transmitted by older generations to younger cohorts.33 as a result, the development and expression of a unique individualistic self may be compromised by collectivist beliefs.20 omani culture also has unique beliefs about seeking professional mental health consultation. data from within oman has shown that, contrary to expectations, traditional omani persons do not hold stigmatising views about people diagnosed with mental illness.21 however, some cultural beliefs regarding the attribution of mental illness may be associated with supernatural powers (jinn), contemptuous envy (hassad), the evil eye (ain) and sorcery (sihr),20 which are held by both younger and older generations. these beliefs may impact the utilisation of psychotherapy services. therefore, our study objective was to investigate zena al-sharbati, claire hallas, hazar al-zadjali, marwan al-sharbati clinical and basic research | 27 the clinical and demographic characteristics of a psychiatric population utilising a newly developed (and to our knowledge the only), psychotherapy service within the omani public health care system. methods all consenting patients who were referred to the psychotherapy service within the department of behavioural medicine at sultan qaboos university tertiary care hospital (squh) were included in this study. data were collected for both inpatients and outpatients (n = 133) during the period september 2009 to march 2010. the progress notes of patients, kept in the squh elextronic system, were reviewed to obtain the socio-demographic and clinical information of patients for the study. referrals were taken through an internal system within the department of behavioural medicine (psychiatry) and from other hospital medical departments. referral forms collected information on patient demographics, psychiatric diagnosis, reason/s and level of urgency for the referral and other relevant medical information such as medical diagnosis, medications use, and comorbidities. external referrals from private hospitals, ministry of health hospitals, and primary care health centres were made directly to the psychotherapy service and were included in the sample. the study design is a retrospective one with a non-probability convenient sampling of patients. the psychotherapy service was a newly established team within the department of behavioural medicine and comprised three staff members. there were two postgraduate qualified psychologists (ph.d. health psychology and an m.a. in clinical psychology) and one assistant psychologist (b.sc. psychology). all staff provided psychotherapy after training in western academic educational institutions in the uk, the usa and canada. all staff members received regular individual and group peer supervision. individual supervision was conducted once a week (2 hours) for each staff member by the senior member of the team (phd) and the senior psychologist received regular individual supervision from an overseas clinical supervisor through telephone and video sessions. peer group supervision was conducted once a month with all staff to discuss challenging cases. psychotherapy sessions mainly utilised cognitive behavioural therapy (cbt) as a mode of treatment due to the wealth of data on the efficacy of cbt to treat axis i disorders (these include all clinical psychiatric disorders—major mental disorders, learning disorders and substance use disorders).22 therapy commenced with a first assessment consultation and then with follow-up psychology consultation sessions. psychotherapy sessions lasted 90 minutes for the first assessment, with a consultation follow-up session lasting 50 minutes. information about patients' diagnoses was collected at the time of the referral from the referring physician. patients were diagnosed by consultant psychiatrists and physicians based on the international classification of diseases, 10th edition (icd-10) diagnostic criteria.23 patients who were referred to the psychotherapy service were grouped into ten icd-10 diagnostic categories: schizophrenia; bipolar disorder; depression; phobias; other anxiety disorders; obsessive compulsive disorder; reactive stress and adjustment disorders; dissociative and somatoform disorders; non-organic sleep disorders, personality disorders; and emotional disorders of childhood. information concerning psychotropic medication use was collated from the electronic medical record at the time of their first psychotherapy session and classified according to british formulary system therapeutic classes,24 e.g., antipsychotics, benzodiazepines, mood stabilizers, antidepressants and lithium. results the total number of referrals to the psychotherapy service was 133 patients. females were more prevalent in the referral sample (59%) compared to males (41%). the age range was from 13 to over 65 years. a total of 38% of the referred patients were employed, 25% were unemployed and approximately a third of the sample was students. as to education levels, 34% of patients had less than 12 years of formal education, 46% had a diploma or bachelor’s degree (13–16 years of education), while about 3% had graduate education. as for marital status, 42% were married, 54% single and 7% separated/divorced or widowed. a total of 91% of the referrals came internally sociodemographic and clinical characteristics of patients attending psychotherapy in a tertiary care hospital in oman 28 | squ medical journal, february 2012, volume 12, issue 1 from the department of behavioural medicine (psychiatry), with most patients being referred for the treatment of a primary mental health disorder [table 1]. the remainder of the referrals was from other squh medical departments/wards, and the request was to treat psychological adjustment difficulties associated with medical conditions such as migraines, musculoskeletal and neurological conditions. only 4% of referrals came from external regional hospitals, primary care health clinics from the capital city (muscat), or from rural areas. the majority of referrals (28%) were for the treatment of anxiety disorders with 14% for phobias (primarily social phobia), 22% for clinical depression and 15% for obsessive compulsive disorder (ocd); the latter, with other comorbid conditions, constituted 10% of all referrals for mental health reasons. approximately 65% of the sample was prescribed psychotropic medications and the majority of these were on antidepressants (84%). only 12% of referrals were hospitalised either at the start of psychotherapy (i.e. referred as inpatients), or were admitted to the hospital psychiatric ward during the course of psychotherapy (see table 1 for a summary of referral data). discussion a significant proportion of the referrals in our population was young adults between 18 and 44 years old. in addition, there was a preponderance of females in our sample which also corroborates with other studies.6,7 this may suggest that female gender is more likely to be associated with greater utilisation of mental health services in a clinical setting, and not only in a community setting as previously reported.20 two hypotheses for this difference might be suggested. first, women from non-western societies experience more socio-cultural stressors (e.g. financial, familial, marriage) compared with males and are therefore more vulnerable to mental distress and seek greater support from health care services. however, this gender specific finding has not been generally observed in the region.26 second, it is possible that "masculine" identity (e.g. strength, dominance, authority) within a predominantly male -orientated culture as in oman may prevent males from seeking psychological support. it has been speculated that ‘expressing one’s feelings' may be seen as sign of wounded masculinity.27 previous studies have been inconsistent regarding the utilisation of psychotherapy and users' educational level. previous studies have found that persons with little formal education are less likely to seek psychotherapy services compared to their more table 1: clinical characteristics of psychotherapy users between the period september 2009 and march 2010 characteristic percentage hospitalisation hospitalised 12.69 never hospitalised 87.30 referral source external 3.82 internal (within hospital) 5.34 departmental (within psychiatry) 90.84 reason for visit non-mental health condition 15.1 mental conditions schizophrenia 1.5 bipolar disorder 0.98 depression 21.8 phobias 13.53 other anxiety disorders 13.53 obsessive compulsive disorder 5.0 obsessive compulsive disorder and other comorbid conditions 10.05 reactive stress and adjustment disorders 6.01 dissociative and somatoform disorders 6.77 non-organic sleep disorders 0.75 personality disorders 3.0 emotional disorders of childhood (e.g. nonorganic separation anxiety disorder). enuresis, conduct disorders, 2.0 psychotropic medication use any 64.8 antipsychotic 1.25 benzodiazepam 5 mood stabilizers 1.25 antidepressant 83.75 antidepressant and antipsychotic 6.25 antidepressant and benzodiazepam 1.25 lithium and antidepressants 1.25 zena al-sharbati, claire hallas, hazar al-zadjali, marwan al-sharbati clinical and basic research | 29 educated counterparts,6,7,28 whereas a more recent study has shown that psychotherapy is no longer the province of intelligent and successful individuals.29 our results indicated that patients with a low level of formal education were the predominant users of the psychotherapy service. this may be explained by the fact that oman has a universal free health care system for all of its nationals which allows them to utilise a wide variety of services across the country.30 also, the department of behavioural medicine serves patients from all levels of education, but it so happened that those referred were those with lower education as they are unable to access more expensive private treatment. it may have been concluded from previous data that educated persons are more likely to have higher socio-economic status and therefore are more able to afford expensive psychotherapy treatments which are not always freely available in western cultures, or prioritised only for severely unwell patients. the trend shown in this study is welcome given that persons with little formal education have been found to have a greater prevalence of mental health disorders.31 some studies have shown that there is an inconsistent relationship between rates of psychotherapy utilisation, employment status and income level.6,7 however, recent trends have shown that there is a significant increase in the rate of psychotherapy for unemployed adults which are consistent with the findings of our study.7 previous studies have found that separated/ divorced persons are more likely to utilise psychotherapy compared to married persons;6,7 however, our results found that separated and divorced patients constituted only a small proportion of the referrals. this may be explained by the stigma placed on divorcees in the arab/islamic societies32 although it may be possible that emotional distress was reduced in this population due to the support of a communal society with close family networks. in contrast, in our study, married persons and never married (single) persons constituted the majority of attendees to psychotherapy sessions. the larger number of single and married persons may reflect the cultural and religious emphasis on importance of marriage at a relatively young age. this cultural emphasis stems from the socio-cultural teaching that that marriage is a strong institution for the wellbeing of the society.33 as a result, single young adults were experiencing a cognitive conflict of cultures that required them to engage in new traditions of higher education and work whilst adhering to older traditions of marriage and family. our study showed that a third of psychotherapy referrals were for anxiety disorders which is consistent with recent data emerging from other arab countries which have shown that anxiety levels were higher in four arab countries when compared table 2: outpatient and inpatient psychotherapy use in the period september 2009 to march 2010 at sultan qaboos univesity tertiary hospital, oman, by sociodemographic characteristic characteristic age (years) percentage female male >13 2.70 11.3 13–17 8.1 9.43 18–24 28.38 26.4 25–34 31.1 25 35–44 19 17 45–54 9.46 7.55 55–64 0 3.77 >65 1.35 0 characteristic percentage sex female 59.4 male 40.4 education (years) <12 33.96 12 16.98 13–16 46.23 more than 17 2.83 marital status married 41.67 divorced/separated 2.4 widowed 3.0 never married 53.01 employment employed 38.84 unemployed 25.62 student 33.88 retired 1.65 sociodemographic and clinical characteristics of patients attending psychotherapy in a tertiary care hospital in oman 30 | squ medical journal, february 2012, volume 12, issue 1 to four western countries. the authors conclude that rapid societal transition within these cultures from a collectivist world view to an individualistic orientated attitude has brought additional stressors, responsibilities and negative experiences which have heightened general anxiety within the population.34 furthermore, the rate of depressed patients within the referrals may also reflect the changes within omani society in the last 25 years which has undergone significant socio-cultural modernisation and urbanisation. these changes may be associated with increasingly high depression rates.30,35 the very small proportion of referrals for persons diagnosed with other disorders such as dissociative and somatoform disorders, schizophrenia, bipolar disorder and personality disorders may reflect a bias by referring psychiatrists who may be less inclined to refer persons who may require more frequent long-term therapy and who they may believe would have a less beneficial outcome from psychotherapy. the service was predominantly utilised by young adults; however, as the older population were under-represented in the sample, this number may actually be an underestimation of those in need of professional mental health services.20 one broad hypothesis may provide a suggestion about the gap between service utilisation and the older generation which could be related to the beliefs about the value of psychiatric/mental health services and social/cultural teachings in treating mental health disorders. this is evidenced by the equal number of persons utilising allopathic and non-allopathic care services, with approximately 60% of arabic patients visiting a traditional healer before seeking help from a psychiatrist.20,36 the perceived value of traditional healers who adopt a culturally-sensitive therapeutic framework may play a role in the desire of traditional (and older) omani persons to seek treatment through traditional means. from a cultural perspective, traditional healers help distressed people to relieve their stress through spiritual means, given that distress is attributed to external forces such as ain (evil or envious eye) and jinn (supernatural powers). a recent study conducted in oman described the attitudes of women towards help-seeking behaviour for emotional distress and the views of their general physician. the data showed that both professionals and patients believed in external forces such as ain and jinn and in fate or god’s will as a rationale for coping with mental health problems. both professionals and patients prioritised traditional and faith practices, such as praying and reading the qu’ran, as an initial treatment method to relieve emotional distress rather than seeking medical consultation.37 conclusion this study has revealed trends in the referral process to a newly developed psychotherapy service in oman. such trends are relevant to the emerging changes in omani society. data suggest that the prevalence of anxiety, particularly social phobia and depression, within the sample may indicate that rapid socio-cultural changes and urbanisation are impacting the population’s mental health. recent affluence in the country through the discovery of oil fields and rapid modernisation has eroded traditional values and the simple outlook on life which was prevalent only 25 years ago. these changes will have repercussions for the adjustment of the older population in particular. however with a predominantly younger generation now being exposed to a wider global view it is possible that we are seeing a trend developing in their need for selfexpression which can be seen through the utilisation of psychotherapy. this study serves as the basis for future research on psychotherapy utilisation in oman. it is important for health care planners in oman to start to prioritise the specialist education and training of mental health practitioners and to explore the psychotherapy service requirements for a nation of people who are tentatively beginning to value and embrace its concepts, methods and outcomes. this study has several limitations. the psychotherapy service study sample was from a tertiary care university teaching hospital in the capital city of oman, where referrals were mainly made by hospital psychiatrists after seeking patients' consent to be referred for psychotherapy. our study population may have had more severe psychiatric problems compared to patients being seen within the primary care health care sector (e.g. private health clinics), or in provincial hospitals in oman. however, our patients may also be more stable than treatment resistant cases that are treated within specialist mental health services within oman (ibn sina hospital). also our ability to generalise zena al-sharbati, claire hallas, hazar al-zadjali, marwan al-sharbati clinical and basic research | 31 to a wider omani population from a more rural geographic location may be limited as, for logistical reasons, the majority of our patients were from the capital city or nearby towns. finally, patients who are self-selecting and motivated to prioritise psychotherapeutic treatments over medication usage were more common in our study population which may be significant for the type of psychiatric problems identified within the service. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest and state that no funding was received for this work. references 1. briffault x, sapinho d, villamaux m. factors associated with use of psychotherapy. soc psychiatry psychiatr epidemiol 2008; 43:165–71. 2. chen j, rizzo j. racial and ethnic disparities in use of psychotherapy: evidence from u.s. national survey data. psychiatr serv 2010; 61:364–72. 3. da silva pfr, blay sl. prevalence and characteristics of outpatient psychotherapy use: a systematic review. j nerv ment dis 2010; 198:783–9. 4. hämäläinen j, isometsä e, sihvo s. treatment of major depressive disorder in the finnish general population. depress anxiety 2009; 26:1049–59. 5. mojtabai r, olfson m. national trends in psychotherapy by office-based psychiatrists. arch gen psychiatry 2008; 65:962–70. 6. olfson m, pincus ha. outpatient psychotherapy in the united states i: volume, costs, and user characteristics. am j psychiatry 1994; 151:1281–8. 7. olfson m, marcus sc, druss b, pincus ha. national trends in the use of outpatient psychotherapy. am j psychiatry 2002; 159:1914–20. 8. olfson m, marcus sc, druss b, elinson l, tanielian t, pincus ha. national trends in the outpatient treatment of depression. jama 2002; 287:203–9. 9. al-rowais n, al-faris e, mohammad ag, alrukban m, abdulghanim hm. traditional healers in riyadh region: reasons and health problems for seeking their advice. a household survey. j altern complement med 2010; 16:199–204. 10. furihata r, uchiyama m, takahashi s, konno c, susuki m, osaki k, et al. self-help behaviors for sleep and depression: a japanese nationwide general population survey. j affect disord 2010;130:75–82. 11. man dw, tsang ww, hui-chan cw. do older t’ai chi practitioners have better attention and memory function? j altern complement med 2010; 16:1259– 64. 12. philip b. analysing the politics of self-help books on depression. j sociol 2009;45:151–68. 13. van straten a, cuijpers p, smit f, spermon a, verbeek i. self-help treatment for insomnia through television and book: a randomized trial. patient educ couns 2009; 74:29–34. 14. dwairy m. culture analysis and metaphor psychotherapy with arab-muslim clients. j clin psychol 2009; 65:199–209. 15. wade j, good ge. moving toward mainstream: perspectives on enhancing therapy with men. psychotherapy 2010; 47:306–15. 16. kirmayer lj. culture and psychotherapy in a creolizing world. transcult psychiatry 2006; 43:163– 8. 17. tseng w. culture and psychotherapy: review and practical guidelines. transcult psychiatry 1999; 36:131–79. 18. abel tm, metraux r. culture and psychotherapy. new haven, ct: college & university press, 1974. 19. ministry of health, sultanate of oman: annual health report, 2009. muscat. 20. al riyami a, al adawi s, al kharusi h, morsi mm, sanjay ss. health service utilization by school going omani adolescents and youths with dsm iv mental disorders and barriers to service use. int j ment health syst 2009; 3:22. doi:10.1186/1752-4458-3-22. 21. al adawi s, dorvlo as, al ismaily ss, al ghafry da, al noobi bz, al salmi a, et al. perception of and attitude towards mental illness in oman. int j soc psychiatry 2002; :305–17. 22. driessen e, hollon sd. cognitive behavioral therapy for mood disorders: efficacy, moderators and mediators. psychiatr clin north am 2010; 33:537– 55. 23. world health organization. composite international diagnostic interview. geneva: who, 1993. 24. british national formulary, 57. london: bmj group, march 2009. 25. profante a. facing the challenges of children and youth with special abilities and needs on the fringes of omani society. child youth serv rev 2009; 31:8– 15. 26. eloul l, ambusaidi a, al adawi s. silent epidemic of depression in women in the middle east and north africa region: emerging tribulation or fallacy? sultan qaboos univ med j 2009; 9:123–30. 27. el sayed sm, maghraby mm, hafeiz hb, buckley mm. psychiatric diagnostic categories in saudi arabia. acta psychiatr scand 1986;74:553–4. 28. howard ki, corniolle ta, lyons vessey jt, lueger rj, saunders sm. patterns of mental health service utilization. arch gen psychiatry 1996; 53:696–703. 29. albani c, blaserg, geyer m, schmutzer g, goldschmit s, brahler e. who is using outpatient psychotherapy in germany? psychother psychosom sociodemographic and clinical characteristics of patients attending psychotherapy in a tertiary care hospital in oman 32 | squ medical journal, february 2012, volume 12, issue 1 med psychol 2009; 59:281–3. 30. al lawati ja, mabry r, mohammad aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 31. dohrenwend bp, itzhak l, shrout p, schwartz s, naveh g, link b, et al. socioeconomic status and psychiatric disorders: the causation–selection issue. science 1992; 255:946–52. 32. kim jy, kim h. stigma in divorcees and its deterrence effect. j socio econ 2002;31:31–44. 33. al adawi s. adolescence in oman. in: jeffrey ja, eds. international encyclopedia of adolescence: a historical and cultural survey of young people around the world (vol. 2 set). new york: routledge, 2006. 34. abdel-khalek a. anxiety levels in east and west: 18 arab countries, germany, spain, uk and usa. eur psychiatry 2007; 22: s266. 35. peen j, dekker j. is urbanicity an environmental risk-factor for psychiatric disorders? lancet 2004; 363:2012–3. 36. okasha a. focus on psychiatry in egypt. br j psychiatry 2004; 185:266–72. 37. al-busaidi zq. a qualitative study on the attitudes and beliefs towards help seeking for emotional distress in omani women and omani general practitioners: implications for post-graduate training. oman med j 2010; 25:190–8. department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drjayakrish@hotmail.com فرط كالسيوم الدم نذير للساركويد يف التليف الكيسي جاياكري�شنان بالكري�شنان ناير، �شيف م�شبح املبيح�شي، م�شعود �شامل ك�شوب، جوجي جورج abstract: the coexistence of cystic fibrosis (cf) and sarcoidosis is rare. we report a 22-year-old male cystic fibrosis patient who presented multiple times to the sultan qaboos university hospital, muscat, oman, in 2013. he was diagnosed with non-parathyroid-related hypercalcaemia and anterior uveitis, while computed tomography revealed mediastinal and abdominal lymphadenopathy and mild hepatosplenomegaly. these findings, in addition to the presence of calciuria and a high angiotensin-converting enzyme (ace) level, confirmed a clinical diagnosis of sarcoidosis. the patient responded well to treatment with oral prednisolone which, over the course of two years, resulted in the near-complete resolution of parenchymal nodular infiltrates, regression of hilar lymphadenopathy, resolution of hypercalcaemia and the normalisation of his ace levels. diagnosing pulmonary sarcoidosis in cf can be challenging as most adult patients already have extensive lung disease. physicians should be aware that hypercalcaemia may be an early manifestation of sarcoidosis in such cases. keywords: sarcoidosis; cystic fibrosis; hypercalcemia; case report; oman. من يعاين عاما 22 العمر من يبلغ مري�س حالة هنا نعر�س نادر. اأمر وال�شاركويد الكي�شي التليف ملر�شي امل�شرتك التواجد امللخ�ص: مر�س التليف الكي�شي ومتت معاينته ب�شكل متكرر يف م�شت�شفى جامعة ال�شلطان قابو�س، م�شقط، عمان، يف عام 2013. وقد مت ت�شيخ�شه العقد يف ت�شخم اأظهرت املقطعية الأ�شعة اأن كما الأمامي، العنبية والتهاب للدرقية املجاورة الغدد عن ناجت الغري الدم كال�شيوم بفرط اللمفاوية يف منطقتي املن�شف والبطن وت�شخم طفيف للكبد والطحال. هذه املعطيات مع وجود البيلة الكل�شية واإرتفاع يف الإنزمي املحول لالأجنيوتن�شني اأكدت الت�شخي�س ال�رصيري لل�شاركويد. ا�شتجاب املري�س ب�شكل جيد لعالج الربيدنيزولون عن طريق الفم على مدى �شنتني مما نتج عنه اختفاء �شبه كامل للعقد املتنية الروؤية و تراجع يف حجم العقد اللمفاوية النقريية، برء فرط كال�شيوم الدم و اإعتدال م�شتوى النزمي املحول لالجنيوتن�شني اإىل النطاق الطبيعي. ت�شخي�س ال�شاركويد الرئوي عند مر�شى التليف الكي�شي ي�شكل حتدي كون معظم مر�شى التليف الكي�شي البالغني يعانون من مرحلة متقدمة من اأمر�س الرئة. يجدر بالأطباء الإنتباه اإىل اأن فرط كال�شيوم الدم قد يكون مظهر مبكر لل�شاركويد يف مثل هذه احلالت. عمان. حالة؛ تقرير الدم؛ كال�شيوم فرط الكي�شي؛ التليف ال�شاركويد؛ املفتاحية: الكلمات hypercalcaemia a portent of sarcoidosis in cystic fibrosis *jayakrishnan b., saif m. al-mubaihsi, masoud s. kashoub, jojy george case report sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e533–536, epub. 28 mar 19 submitted 30 may 18 revision req. 8 jul 18; revision recd. 18 jul 18 accepted 2 aug 18 doi: 10.18295/squmj.2018.18.04.018 sarcoidosis is a systemic disease characterised by the formation of immune granulomas in various organs—mainly the lungs and lymphatic system—usually resulting from an exaggerated reaction to unidentified antigens in susceptible individuals.1 on the other hand, cystic fibrosis (cf) is an autosomal recessive multisystem disorder that affects several organs, including the lungs, pancreas, liver and intestine.2 the former disease has a prevalence of approximately 4.7–64 per 100,000 individuals per year worldwide, while the latter occurs in approximately one in 3,000–4,000 live births among caucasians and is even less common in other ethnicities.1,2 in oman, sarcoidosis is not uncommon, with a similar clinical picture to that reported elsewhere; in contrast, the prevalence of cf is estimated to be one in 2,738 individuals.3,4 as both conditions are quite rare, the unrelated coexistence of these diseases in a single patient is extremely unlikely. this case report describes the successful response to sarcoidosis treatment in a cf patient who presented with hypercalcaemia, uveitis and mediastinal lymphadenopathy. case report a 22-year-old deaf and mute male patient with a long history of bilateral bronchiectasis was admitted to the sultan qaboos university hospital, muscat, oman, with septic shock in 2013. upon admission, his serum calcium levels were noted to be slightly elevated (2.65 mmol/l); however, they normalised following the administration of fluids. a diagnosis of cf was confirmed based on a sweat chloride test of 86 mmol/l, faecal elastase level of <50 µg/l and genetic testing showing a homozygous p.ser549arg mutation. upon discharge, the patient was advised to manage his condition with nutritional and enzyme supplements, proper dietary habits and chest hypercalcaemia a portent of sarcoidosis in cystic fibrosis e534 | squ medical journal, november 2018, volume 18, issue 4 limits. upon examination, the patient was asymptomatic and denied any nausea, vomiting, weakness, lethargy or palpitations. his urinary and bowel movements were normal and his blood pressure was 104/60 mmhg. he was mildly dehydrated with a pulse rate of 110 beats/minute. an abdominal examination revealed that the liver was palpable 2 cm below the right costal margin. moreover, his 24-hour urinary calcium level was very high (25.47 mmol), while serum parathyroid hormone (pth) levels were low (0.01 pmol/l) and pthrelated peptide levels were normal (0.7 pmol/l).the patient was also vitamin d-deficient, with a serum 25-hydroxy (oh) cholecalciferol level of 29 nmol/l, despite an elevated 1,25-oh vitamin d level. his serum angiotensin-converting enzyme (ace) level was 116 aceu. the results of other basic laboratory tests were normal [table 1]. sputum microscopy, cultures and a polymerase chain reaction analysis for mycobacterium tuberculosis were negative. autoimmune screening was also negative for rheumatoid factor, antinuclear antibodies, cytoplasmicantineutrophil cytoplasmic antibodies (ancas) and perinuclear-ancas. computed tomography (ct) of the chest showed mediastinal lymphadenopathy, with the largest lymph node in the prevascular region measuring 2.7 × 1.0 cm, and minimal bilateral bronchiectatic changes [figure 1]. a few faint irregular nodular opacities in the distal lung were also seen. a ct scan of the abdomen showed multiple lymph nodes, with the largest located in the porta hepatis measuring 2.5 × 1.4 cm; in addition, complete replacement of the pancreatic tissue by fat was observed, along with hepatosplenomegaly. a media stinoscopy and lymph node biopsy was scheduled; however, the patient and his family refused the surgery. a bone marrow biopsy showed normal trilineage repres entation without any abnormalities. a clinical diagnosis of sarcoidosis was made based on the presence of mediastinal and abdominal lymphadenopathy, anterior uveitis, mild hepatosplenomegaly, non-parathyroid-related hypercalcaemia, calciuria and elevated 1,25-oh vitamin d and ace levels. the patient was prescribed steroids in the form of oral prednisolone. physiotherapy. three months later, he was admitted again with septic shock. at this time, he complained of blurred vision and redness of the eyes. an ultra sound scan of the abdomen showed mild hepatosplenomegaly. the patient was diagnosed with bilateral nongranulomatous anterior uveitis and topical treatment was initiated. two months later, during a routine follow-up visit, a blood work-up revealed elevated calcium (3.08 mmol/l), alkaline phosphatase (165 u/l) and creatinine (134 µmol/l) levels, while all other electrolytes were within normal table 1: laboratory test results of a 22-year-old male patient with cystic fibrosis variable result normal range* hb in g/dl 12.7 11.5–15.5 platelet count in × 109/l 253 150–450 wbc count in × 109/l 6.2 2.2–10 inr 1.14 0.88–1.10 serum alt in u/l 3.7 0–41 serum albumin in g/l 42 35–52 serum crp in mg/l 5 0–5 calcium in mmol/l 3.08 2.15–2.55 alp in u/l 165 40–129 creatinine in µmol/l 134 59–104 24-hour urinary calcium in mmol 25.47 2.5–8 pth in pmol/l <0.1 1.6–9.3 pthrp in pmol/l 0.7 <1.3 vitamin a in µmol/l 2.67 1.72–2.52 serum 25-oh cholecalciferol in nmol/l 29 75–250 1,25-oh vitamin d in pmol/l 228 48–144 serum ace in aceu 116 12–68 hb = haemoglobin; wbc = white blood cell; inr = international normalised ratio; alt = alanine transaminase; crp = c-reactive protein; alp = alkaline phosphatase; pth = parathyroid hormone; pthrp = pth-related peptide; oh = hydroxy; ace = angiotensin-converting enzyme. *age-specific reference ranges. figure 1: computed tomography scans of the chest of a 22-year-old male cystic fibrosis patient with asymptomatic hypercalcaemia showing mediastinal lymphadenopathy and bilateral bronchiectatic changes (arrows). jayakrishnan b., saif m. al-mubaihsi, masoud s. kashoub and jojy george case report | e535 his serum calcium levels normalised during the first few weeks of treatment and remained normal throughout the follow-up period; however, over the following month, he developed steroid-induced diabetes and required insulin. in addition, he was subsequently admitted twice, a year apart, primarily to optimise his cf treatment and for parenteral antibiotics. prednisolone treatment was continued for two years in tapering doses, resulting in the near-complete resolution of the patient’s parenchymal nodular infilt rates, regression of hilar lymphadenopathy, resolution of hypercalcaemia and the normalisation of his ace levels. the insulin was discontinued one month after the patient stopped taking prednisolone. discussion worldwide, there are very few reports documenting the coexistence of cf and sarcoidosis; this is possibly because the true incidence of sarcoidosis in cf is under reported, as such patients already have widespread lung involvement.2 the first published cases originated from the uk in 1987, in which cooper et al. described two children with known cf, one of whom presented with multisystem disease.5 since then, a few reports have been published detailing cf patients presenting with either pulmonary or systemic symptoms of sarcoidosis.6–11 however, to the best of the authors’ knowledge, the current case is the first in which asymptomatic hypercal caemia was an early sign of sarcoidosis in a cf patient. in view of the low prevalence of both conditions, there may be a pathogenic link between cf and sarcoidosis. this may be due to either a common genetic pred isposition or an acquired immune response defect. both sarcoidosis and cf patients demonstrate defective t cell-mediated immune function and enhanced b cell activation.5 however, cf is caused by a mutation of the cystic fibrosis transmembrane regulator (cftr) gene located on chromosome 7, while sarcoidosis susceptibility, phenotype and prognosis is associated with many gene variants, including variations in the major histocompatibility complex class ii gene subgroup.1,2 nevertheless, although previous research has suggested that there is a high frequency of cftr mutations in patients with sarcoidosis, the findings of another moderately-sized study did not support an association between cftr mutations and sarcoidosis phenotype.12,13 the altered immune response in cf secondary to chronic infection could also be responsible for the develop ment of sarcoidosis.5 antigen presentation may be potent iated by tissue damage exposing the raw bronchial mucosal surfaces; as a result, sarcoid granulomas could develop in response to immune stimulation by these antigens originating from microorganisms or from glyco proteins and polypeptides generated by monocytemacrophage hyperactivity.5–7 it is worth noting that mycobacterium, propionibacterium and various fungi, viruses and spirochetes have also been implicated in the development of sarcoidosis.1 as such, further research is necessary to confirm a link between the two conditions and to establish a causative mechanism. apart from sarcoidosis, hypervitaminosis a may be another explanation for the hypercalcaemia noted in the current case. chronic vitamin a toxicity can result from the ingestion of large amounts of vitamin a over a long period, with hypercalcaemia resulting from the direct effect of vitamin a on the bone, parathyroid glands or both.14 however, in the present case, the patient had slightly high serum calcium levels prior to his cf diagnosis and recommendations for vitamin a supplementation. at the time, his serum calcium levels would have norm alised as a result of the fluids given to manage the shock. accordingly, a clinical diagnosis of sarcoidosis was made based on the presence of mediastinal and abdominal lymphadenopathy, anterior uveitis, mild hepatospleno megaly, non-parathyroid-related hypercalcaemia, calciuria and elevated 1,25-oh vitamin d and ace levels. conclusion a pathogenic link may exist between sarcoidosis and cf in terms of a common genetic predisposition or an altered immune response; however, this supposition as yet remains hypothetical and requires further research for confirmation. regardless, a diagnosis of pulmonary sarcoidosis in cf is challenging as most adult patients already have extensive lung disease. in such cases, hypercalcaemia may be an early sign. references 1. valeyre d, prasse a, nunes h, uzunhan y, brillet py, müllerquernheim j. sarcoidosis. lancet 2014; 383:1155–67. https://doi.org/ 10.1016/s0140-6736(13)60680-7. 2. sanders db, fink ak. background and epidemiology. pediatr clin north am 2016; 63:567–84. https://doi.org/10.1016/j.pcl. 2016.04.001. 3. jayakrishnan b, al-busaidi n, al-lawati a, george j, al-rawas oa, al-mahrouqi y, et al. clinical features of sarcoidosis in oman: a report from the middle east region. sarcoidosis vasc diffuse lung dis 2016; 33:201–8. 4. al-kindy h, ouhtit a, al-salmi q, al-bimani m, al-nabhani m, gupta i. novel mutation in the cftr gene of cystic fibrosis patients in oman. j mol biomark diagn 2014; 5:168. https://doi.org/10.4172/2155-9929.1000168. 5. cooper tj, day aj, weller ph, geddes dm. sarcoidosis in two patients with cystic fibrosis: a fortuitous association? thorax 1987; 42:818–20. https://doi.org/10.1136/thx.42.10.818. 6. kamarova h, thattakkat k, mccann l. cystic fibrosis with sarcoidosis: genetics vs immunology a paradigm shift? arch dis child 2010; 95:a36. https://doi.org/10.1136/adc.2010.1863 38.82. hypercalcaemia a portent of sarcoidosis in cystic fibrosis e536 | squ medical journal, november 2018, volume 18, issue 4 12. schürmann m, albrecht m, schwinger e, stuhrmann m. cftr gene mutations in sarcoidosis. eur j hum genet 2002; 10:729–32. https://doi.org/10.1038/sj.ejhg.5200868. 13. bombieri c, luisetti m, belpinati f, zuliani e, beretta a, baccheschi j, et al. increased frequency of cftr gene mutations in sarcoidosis: a case/control association study. eur j hum genet 2000; 8:717–20. https://doi.org/10.1038/sj.ejhg.5200524. 14. safi kh, filbrun ag, nasr sz. hypervitaminosis a causing hypercalcemia in cystic fibrosis: case report and focused review. ann am thorac soc 2014; 11:1244–7. https://doi.org/10.1513/a nnalsats.201404-170bc. 7. dobbin cj, moriarty c, bye pt. granulomatous diseases in a patient with cystic fibrosis. j cyst fibros 2003; 2:35–7. https://doi. org/10.1016/s1569-1993(02)00140-6. 8. doubková m, binková i, skřičková j. [hidden cystic fibrosis in patient suffering from sarcoidosis]. vnitr lek 2012; 58:329–34. 9. burton cm, pressler t, milman n. pulmonary sarcoidosis in a child with cystic fibrosis. pediatr pulmonol 2005; 39:473–7. https://doi.org/10.1002/ppul.20208. 10. soden m, tempany e, bresnihan b. sarcoid arthropathy in cystic fibrosis. br j rheumatol 1989; 28:341–3. https://doi.org/10.109 3/rheumatology/28.4.341. 11. rettinger sd, trulock ep, mackay b, auerbach hs. sarcoidosis in an adult with cystic fibrosis. thorax 1989; 44:829–30. https://doi.org/10.1136/thx.44.10.829. epidermolysis bullosa (eb) is a group of genetic vesiculobullous disorders which are characterised by skin and mucous membrane fragility and systemic manifestations of variable severity.1,2 affected individuals usually present with continuous blister formation due to mechanical trauma or heat; in some cases, the blisters even develop spontaneously without any apparent cause.3,4 the onset of the disease usually occurs immediately after birth up until five years of age.5 four major forms of eb have been described, depending on the level of skin involvement: eb simplex (ebs), which involves the intra-epidermal layer; junctional eb (jeb), which involves the lamina lucida; dystrophic eb (deb), which involves the sublamina densa; and kindler syndrome, which involves multiple layers of the epidermis. these types are further subdivided depending on the severity of the condition, mode of inheritance and the genes involved.2 the risk of morbidity and mortality among eb patients is high.6 the prevalence of eb worldwide is variable.7 in saudi arabia, abahussein et al. reported the prevalence of ebs, jeb and deb to be 1.7%, 0% and 3.7% per million, respectively; moreover, parental consanguinity was noted among 87.5% of cases.8 there are no published studies on the exact prevalence of eb in oman; however, unpublished data from national dermatology units indicate approximately 60 registered cases. this report focuses on the dental and anaesthetic challenges encountered during the management of an omani adult patient with severe deb. case report an 18-year-old male was referred to the department of oral health at sultan qaboos university hospital, muscat, oman, in 2015 for the management of recurrent dental pain and localised dental infections. the patient had been seen by many general dental practitioners in different institutions over the previous two years. he had been managed conservatively with multiple courses of antibiotics, which were successful in temporarily controlling his symptoms. in early childhood, the patient had been diagnosed with deb and had undergone multiple surgeries under general departments of 1anaesthesia & icu and 3oral health, sultan qaboos university hospital, muscat, oman; 2oral & maxillofacial surgery residency program, oman medical specialty board, muscat, oman *corresponding author e-mail: azrioman@hotmail.com حتديات طب األسنان والتخدير ملريض مصاب باحنالل البشرة الفقاعي احلثلي علي العب�دي, �شالح الدين العزري, عبدالعزيز ب�كثري, ي�رسى الري�مية abstract: epidermolysis bullosa is a group of rare genetic disorders characterised by skin and mucous membrane fragility and systemic manifestations of variable severity. we report a case of dystrophic epidermolysis bullosa in an 18-year-old male patient who presented to the department of oral health at sultan qaboos university hospital, muscat, oman, in 2015 with recurrent dental pain and infections. due to the poor dental status of the patient and anticipated operative difficulties due to microstomia and limited mouth opening, the patient underwent full dental clearance under general anaesthesia. this article discusses the dental and anaesthetic challenges encountered during the management of this patient and provides a brief literature review. keywords: dystrophic epidermolysis bullosa; dentistry; disease management; general anesthesia; case report; oman. امللخ�ص: يعترب مر�س انحالل الب�رسة الفق�عي من ال�شطراب�ت اجلينية الن�درة والتي تتميز به�ش��شة اجللد والأغ�شية املخ�طية مع مظ�هر ع�مة اأخرى متف�وتة ال�شدة. يعر�س هذا التقرير ح�لة مري�س ذكر, يف الث�منة ع�رسة من العمر, م�ش�ب ب�نحالل الب�رسة الفق�عي احلثلي عند قدومه للعالج يف ق�شم �شحة الفم مب�شت�شفى ج�معة ال�شلط�ن ق�بو�س, يف نوفمرب 2015, حيث ك�ن يع�ين من اآلم يف الأ�شن�ن والته�ب�ت متكررة. ونظرا للح�لة ال�شيئة لالأ�شن�ن وال�شعوب�ت العالجية املتوقعة ب�شبب �شغر الفم وفتحة الفم املحدودة فقد خ�شع املري�س لإزالة جميع الأ�شن�ن حتت التخدير الع�م. ين�ق�س هذا التقرير حتدي�ت عالج الأ�شن�ن والتخدير التي متت مواجهته� خالل العن�ية بهذا املري�س مع عر�س موجز لالأدبي�ت الطبية املن�شورة يف مثل هذه احل�لت. الكلمات املفتاحية: انحالل الب�رسة الفق�عي احلثلي؛ طب الأ�شن�ن؛ عالج املر�س؛ التخدير الع�م؛ تقرير ح�لة؛ عم�ن. dental and anaesthetic challenges in a patient with dystrophic epidermolysis bullosa ali al-abadi,1 *salah a. al-azri,2 abdulaziz bakathir,3 yusra al-riyami2 case report sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e495–499, epub. 30 nov 16 submitted 23 apr 16 revision req. 2 jun 16; revision recd. 19 jun 16 accepted 23 jun 16 doi: 10.18295/squmj.2016.16.04.016 dental and anaesthetic challenges in a patient with dystrophic epidermolysis bullosa e496 | squ medical journal, november 2016, volume 16, issue 4 anaesthesia (ga) at different hospitals, including balloon dilatation of oesophageal strictures, incisional release of pseudosyndactyly and insertion and removal of a percutaneous endoscopic gastrostomy tube. he applied silver sulfadiazine ointment on the skin lesions and used artificial tears on a daily basis. he had no known allergies and his diet was limited to soft and puréed food. the parents reported that they were first cousins and that he had three other siblings, the youngest of whom was a three-year-old male also affected by deb while the other two siblings were healthy. at referral, the patient was accompanied by his parents and appeared to have normal cognitive function. he was initially anxious and uncooperative during the examination due to severe dental pain. his height was 1.44 m and his weight was below the 3rd percentile for his age (27.7 kg; body mass index: 13.4 kg/m2). his vital signs were within normal limits. most of his skin was affected by generalised body blisters, although some were in the healing stage. he also had pseudosyndactyly of the hands and feet, loss of the toenails and fingernails and extensive skin contractures and scarring. most of his upper and lower limbs were covered with protective medicated gauze and bandages [figure 1]. an oral examination was conducted with difficulty due to microstomia and limited mouth opening. the patient had ankyloglossia and a smooth tongue with obliteration of the buccal and lingual vestibules. his dental status was poor, with multiple advanced dental caries in most of his teeth; these had caused the formation of numerous dental sinuses which discharged to the oral cavity. periodontally, there was involvement of the lower anterior teeth with increased mobility and alveolar bone loss [figure 2]. due to the patient’s poor dental status and prognosis, in addition to anticipated operative difficulties due to the microstomia and limited mouth opening, a full dental clearance under ga was recommended. the appropriate written consent for the procedure was obtained after comprehensive consultation with the patient and his parents. a pre-anaesthetic evaluation revealed that airway control and the maintenance of skin integrity were two major concerns. intravenous (iv) access and endotracheal intubation procedures were anticipated to cause difficulties and potentially increase the risk of trauma to the patient. as such, preoperative blood investigations were avoided. in the operating room, a full-bed-size soft sheet was placed on the operating table to avoid skin friction and the room temperature was increased to avoid hypothermia. the patient was allowed to move himself slowly onto the operating table and all pressure points were supported with padding and bandages. a clip-on pulse oximetry probe was attached to the right ear lobe to monitor capillary oxygen saturation [figure 3a]. defibrillator pads were used to attach the electrocardiography (ecg) electrodes to the chest and a non-invasive blood pressure cuff was applied after wrapping the arm with cotton pads [figure 3b]. all airway equipment was generously lubricated before touching the mucosa. the anaesthesia was induced using sevoflurane and a 50% oxygen to 50% nitrous oxide mixture. the iv figure 1: limb deformity, scarring with contractures and pseudosyndactyly of the (a) upper and (b) lower limbs of an 18-year-old male patient with dystrophic epidermolysis bullosa. note the intravenous cannula on the right thigh secured with non-adhesive paper tape and bandages to prevent tearing and blistering. figure 2: an orthopantomogram of an 18-year-old male patient with dystrophic epidermolysis bullosa showing multiple grossly carious teeth with severe bone loss in the lower anterior teeth. ali al-abadi, salah a. al-azri, abdulaziz bakathir and yusra al-riyami case report | e497 kept to a minimum to avoid soft tissue trauma and postoperative bleeding. at the end of the surgery, the patient was extubated uneventfully with no major anaesthetic complications. despite the frequent intraoperative use of hydrocortisone lubrication on the lips and perioral tissues, sloughing of the skin of the forehead [figure 3c] as well as the oral and lip mucosa [figure 3d] was observed. following the procedure, the patient recovered well and was prescribed augmentin and paracetamol. during the postoperative period, regular lip lubrication, antiseptic chlorhexidine mouth-rinsing and an adequate soft diet was maintained. the blood investigations revealed iron deficiency anaemia and the patient was subsequently prescribed iron supplements. all of the other blood investigation results were within normal limits. the patient was discharged on the third postoperative day. at a four week follow-up, the soft tissues and extraction sockets had healed satisfactorily with minimal scarring [figure 4]. at the time of writing, the patient was currently in the process of undergoing prosthetic dental rehabilitation. discussion genetic mutations can result in the production of defective or absent proteins important to the integrity of the skin and mucosa.9 the phenotypic presentation of deb varies from mild, seen mostly in the dominant type of deb, to the generalised severe scarring form, seen mostly in the recessive type.10 the patient in the present case showed clinical features of deb arising due to a mutation in the collagen type vii alpha 1 gene, which leads to reduced epidermal adherence.9 as both parents were unaffected first cousins and the patient had one affected and two healthy siblings, it is likely that he had autosomal recessive deb. oral manifestations of deb include recurrent oral blisters and erosions, which heal with scarring and eventually lead to microstomia, ankyloglossia, smooth tongue and vestibular obliteration, as observed in the present case.3,11 many published reports have highlighted that deb patients are at high risk of developing rampant caries due to enamel defects, inadequate oral hygiene caused by recurrent painful oral blisters and loss of manual dexterity and a highcalorie cariogenic diet designed to compensate for their high metabolic state.1,12,13 in the current case, these features led to the extensive destruction of the dentition and recurrent episodes of severe dental pain and infections. oral and dental features of deb present a challenge when providing dental treatment. treatment conducted under local anaesthesia is not widely practised due to microstomia and limited access was secured in the right great saphenous vein and blood was collected and sent for investigations. subsequently, the anaesthesia was supplemented with fentanyl, propofol and rocuronium. a c-mac® video assisted laryngoscope (c-mac electromag, ronse, belgium) was used to reduce the number of attempts at intubation and the vocal cords were visualised without too much opening or manipulation of the mouth. an atraumatic nasal endotracheal intubation was performed with a small 5.5 mm non-cuffed endotracheal tube after being softened with a warm saline solution and adequate lubrication. non-adhesive paper tape was used to secure the endotracheal tube and iv catheter. the eyes were lubricated with ophthalmic ointment and covered lightly with soft gauze and paper tape. the anaesthesia was maintained with sevoflurane and the analgaesia was supplemented intravenously with paracetamol. the patient was kept warm with a bair hugger™ intraoperative warming blanket (3m company, maplewood, minnesota, usa) and his temperature was monitored using an axillary probe. reasonable oral access was achieved via nasal intubation but was limited by the microstomia. intraoperatively, local anaesthesia was avoided to prevent mucosal injury and the dental extractions were done as atraumatically as possible in order to minimise injury to the oral tissues. the sockets were packed with haemostatic gauze (surgicel®, ethicon inc., somerville, new jersey, usa) and suturing was figure 3: intraoperative photographs of an 18-yearold male patient with dystrophic epidermolysis bullosa showing (a) a clip-on oxygen saturation probe attached to the ear lobe and (b) a blood pressure cuff applied over a protective cotton pad to avoid skin damage during a full dental clearance under general anaesthesia. however, after completion of the surgery, there was evidence of (c) forehead skin sloughing due to the use of a face mask during intubation and (d) mucosa and skin sloughing of the lips and perioral tissues. dental and anaesthetic challenges in a patient with dystrophic epidermolysis bullosa e498 | squ medical journal, november 2016, volume 16, issue 4 mouth opening, in addition to the risk of blister formation and soft tissue injury following administration of the anaesthetic.1,14 conducting treatments under ga is justifiable and widely reported in the literature, especially if extensive dental treatment is required.1,13−16 in the present case, the dental clearance was performed under ga due to the relatively extensive nature of the disease as well as to minimise potential trauma to the oral tissues and reduce associated stress and anxiety on the part of the patient. systemic manifestations of deb can also complicate the administration of ga and pose anaesthetic challenges in terms of iv access, monitoring of vital signs and intubation.15,16 extensive skin blistering and scarring with limb contractures can conceal venous access and the central venous route may be necessary as a last resort.17 placing adhesive dressings for iv lines and ecg pads directly onto the skin can lead to tearing and blistering.13,14 in the present case, non-adhesive defibrillator pads were attached to adhesive ecg pads. extensive skin deformities and pseudosyndactyly can also present a challenge when monitoring oxygen saturation; as in the current case, a clip-on probe can be attached to the ear lobe to circumvent this.14 as the pseudostratified nasal epithelium is ciliated and has mucus-secreting goblet cells, it is less vulnerable to blistering compared to the stratified squamous keratinised and non-keratinised epithelium of the oral mucosa; as such, nasal intubation is preferable.13−15 moreover, in comparison to an oral tube, a nasal tube is more easily secured without tape and provides a more spacious surgical field for dental treatment.13−15 oesophageal strictures and dysphagia are common in patients with deb and tend to increase the risk of gastro-oesophageal reflux, potentially affecting ga administration;18 however, this problem was not encountered in the current case. conclusion deb is a rare genetic disorder characterised by blistering and increased fragility of the skin and mucosal membranes following minor trauma. this report details the successful full dental clearance under ga of an adult with deb which resulted in satisfactory healing and minimal scarring. the dental and anaesthetic care of deb-affected individuals presents a challenge as they require special considerations and management to prevent complications. references 1. krämer sm. oral care and dental management for patients with epidermolysis bullosa. dermatol clin 2010; 28:303−9. doi: 10.1016/j.det.2010.02.021. 2. fine jd, eady ra, bauer ea, bauer jw, bruckner-tuderman l, heagerty a, et al. the classification of inherited epidermolysis bullosa (eb): report of the third international consensus meeting on diagnosis and classification of eb. j am acad dermatol 2008; 58:931−50. doi: 10.1016/j.jaad.2008.02.004. 3. fortuna g, lozada-nur f, pollio a, aria m, cepeda-valdes r, marinkovich mp, et al. patterns of oral mucosa lesions in patients with epidermolysis bullosa: comparison and agreement between oral medicine and dermatology. j oral pathol med 2013; 42:733−40. doi: 10.1111/jop.12094. 4. wright jt, fine jd, johnson lb. oral soft tissues in hereditary epidermolysis bullosa. oral surg oral med oral pathol 1991; 71:440−6. doi: 10.1016/0030-4220(91)90426-d. 5. horn hm, tidman mj. the clinical spectrum of dystrophic epidermolysis bullosa. br j dermatol 2002; 146:267−74. doi: 10.1046/j.1365-2133.2002.04607.x. 6. uitto j, mcgrath ja, rodeck u, bruckner-tuderman l, robinson ec. progress in epidermolysis bullosa research: toward treatment and cure. j invest dermatol 2010; 130:1778−84. doi: 10.1038/jid.2010.90. 7. pillay e. epidermolysis bullosa. part 1: causes, presentation and complications. br j nurs 2008; 17:292−6. doi: 10.12968/ bjon.2008.17.5.28824. 8. abahussein aa, al-zayir a, mostafa w, okoro an. epidermolysis bullosa in the eastern province of saudi arabia. int j dermatol 1993; 32:579−81. doi: 10.1111/j.1365-4362.1993. tb05029.x. 9. bruckner-tuderman l. dystrophic epidermolysis bullosa: pathogenesis and clinical features. dermatol clin 2010; 28:107−14. doi: 10.1016/j.det.2009.10.020. 10. intong lr, murrell df. inherited epidermolysis bullosa: new diagnostic criteria and classification. clin dermatol 2012; 30:70−7. doi: 10.1016/j.clindermatol.2011.03.012. 11. fortuna g, aria m, cepeda-valdes r, pollio a, morenotrevino mg, salas-alanís jc. clinical features of gingival lesions in patients with dystrophic epidermolysis bullosa: a cross-sectional study. aust dent j 2015; 60:18−23. doi: 10.1111/ adj.12264. 12. wright jt, johnson lb, fine jd. development defects of enamel in humans with hereditary epidermolysis bullosa. arch oral biol 1993; 38:945−55. doi: 10.1016/0003-9969(93)90107-w. 13. lindemeyer r, wadenya r, maxwell l. dental and anaesthetic management of children with dystrophic epidermolysis bullosa. int j paediatr dent 2009; 19:127−34. doi: 10.1111/j.1365263x.2008.00940.x. figure 4: postoperative photograph of an 18-year-old male patient with dystrophic epidermolysis bullosa four weeks after a full dental clearance showing satisfactory healing of the oral tissues and dental sockets, with minimal scarring. ali al-abadi, salah a. al-azri, abdulaziz bakathir and yusra al-riyami case report | e499 17. azrak b, kaevel k, hofmann l, gleissner c, willershausen b. dystrophic epidermolysis bullosa: oral findings and problems. spec care dentist 2006; 26:111−15. 18. fine jd, mellerio je. extracutaneous manifestations and complications of inherited epidermolysis bullosa: part i epithelial associated tissues. j am acad dermatol 2009; 61:367−84. doi: 10.1016/j.jaad.2009.03.052. 14. esfahanizade k, mahdavi ar, ansari g, fallahinejad ghajari m, esfahanizadeh a. epidermolysis bullosa, dental and anesthetic management: a case report. j dent (shiraz) 2014; 15:147−52. 15. wright jt. comprehensive dental care and general anesthetic management of hereditary epidermolysis bullosa: a review of fourteen cases. oral surg oral med oral pathol 1990; 70:573−8. doi: 10.1016/0030-4220(90)90401-d. 16. toda y, yokoyama m, morimatsu h, nakatsuka h, takeuchi m, katayama h, et al. general anesthesia in a patient with dystrophic epidermolysis bullosa. j anesth 2006; 20:138−40. doi: 10.1007/s00540-006-0388-7. a pcr-rflp test to detect the common mutation (35delg) in the connexin-26 gene 9 abstract. objective : to develop a polymerase chain reaction (pcr) based test for the detection of a common frame-shift mutation (35delg) in the connexin-26 (gjb2) gene, and to investigate the status of this mutation in oman. method: a pcr test, based on sitedirected mutagenesis, was developed for the 35delg mutation. a mutagenesis primer generated an econ i site in a short (87 bp) dna fragment amplifi ed from the connexin-26 gene. the econ i site is generated only if the 35delg mutation is present. thus, a restriction fragment length polymorphism (rflp) analysis of the amplifi ed dna fragment with econ i allowed us to detect the 35delg mutation in the connexin 26 gene. result : after validating the test using quality control dna samples, which contained the 35delg mutation in either homozygous or heterozygous form, 120 healthy subjects and 35 unrelated omani patients with nosyndromic autosomal recessive deafness (nard), were screened for 35delg mutation. the mutation was not present in any individual tested. conclusion: we have been able to develop a new pcr-rflp test for detecting the 35delg common mutation in the connexin 26 gene. our preliminary results from application of this test on a limited number of omani patients indicate that the 35delg mutation may not be associated with nard in oman. key words : pcr-rflp, connexin-26 gene, 35delg mutation c ongenital deafness occurs approximately 1 in 1000 live births, of which 50% are hereditary.1 recently, some of the mutations described in the connexin 26 gene (gjb2 ) were shown to be among the causes of non-syndromic autosomal recessive deafness (nar d ).2 a frame shift mutation, 35delg, was particularly reported to be responsible for more than 50 percent of all cases of childhood non-syndromic hearing loss in some populations.3–5 because of the high prevalence and clinical impact, early detection of congenital hearing impairment has become a public health problem. so far, only limited methods have been available for the detection of the 35delg mutation. rabionet and estivil described an allele-specifi c oligonucleotide (aso ) hybridisation method, but it required the use of radiophosphorous (32p) probes.6 recently, wilcox et al described a pcr test based on site-directed mutagenesis and restriction fragment length poly morphism (r flp) analysis.7 in most studies, however, a direct sequencing of pcr amplifi ed dna was used, because the whole protein-coding sequence of the gj b2 gene is located in one exon, which makes it relatively easy to screen for mutations in this gene.2,4,5 considering squ journal for scientific research: medical sciences 2001, 1, 9 –12 ©2001 sultan qaboos university a polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) test to detect the common mutation (35delg) in the connexin-26 gene *mehmet simsek1, nadia al-wardy1 , mazin al-khabor y 1department of biochemistry, college of medicine sultan qaboos university, p.o. box 35, al khod 123 muscat, sultanate of oman. 2department of otolaryngology and head and neck surgery al-nahda hospital, p.o. box 937, muscat-112 sultanate of oman *to whom correspondence should be addressed. e-mail: mssimsek@omantel.net.om s i m s e k e t a l10 that dna sequencing facilities may not be available in all centres, we present a new polymerase chain reaction restriction fragment length polymorphism (pcr-r flp) method for analysing the 35delg mutation. the method is based on the amplifi cation of a short (87 bp) dna fragment of the gj b2 gene using a semi-nested pcr . if the 35delg mutation is present, an econ i site is generated in the amplifi ed dna . hence, a subsequent r flp analysis with econ i easily distinguishes different genotypes at the 35delg mutation site of the gj b2 gene. m e t h o d genomic dna was extracted from whole blood of patients and healthy subjects using a kit (nucleon ii, scotlab inc). two quality control genomic dna samples containing the 35delg mutation were kindly provided by dr wilcox of murdoch institute, melbourne, australia. oligonucleotide primers were synthesized on a pharmacia dna synthesizer and used in a semi-nested pcr using two rounds of dna amplifi cations. a 285 bp dna fragment was amplifi ed in the fi rst round using the primer pair (167f and 452r) and the pcr conditions described by kelsell et al.5 in the second round, an 87 bp dna fragment was amplifi ed using a new mutagenesis primer (35dg : 5'– ctg gtg gag tgt ttg ttc c c t c –), where the lower case letters represent the two nucleotides that would produce mismatches with the template dna . the reaction mixture (50 µl) in the semi-nested pcr contained: 50 mm tris.cl ph 8.3, 2 mm magnesium chloride (mgcl 2 ), 200 µm each d ntp, 1 µm each of the primers (35dg and 167f), 0.01% gelatin, and 2µl of the previously amplifi ed 285 bp pcr product, but diluted 1000-fold before use. the pcr cycling conditions were: 95°c for 1 min, 56°c for 1 min, and 72°c for 1 min, for 35 cycles in a thermal cycler (perkin elmers 480). there was a 5 min pre-incubation at 95°c before starting the cycles, and 5 min at 72°c after the completion of the cycles. a small aliquot (10 µl) of the reaction mixture was treated with 3 units of econ i (biolabs) at 37°c for 12 hours, and subsequently analysed on a 10% polyacrylamide gel. r e s u l t s using the above method, we were able to develop a new pcr-r flp test for the detection of 35delg mutation in the connexin 26 gene. our strategy was to amplify a short (87 bp) fragment using a mutagenesis primer that generated an econ i site if the 35delg mutation was present. figure 1 shows the partial sequence of the connexin 26 gene around the mutation site, and the nature of two mismatches introduced into the mutagenesis primer (35dg ) at its (–1) and (–3) positions. these mismatches (t/t and t/c) with the template dna were essential to generate an econ i site (5'– cct n5agg ) in the amplifi ed dna. first, we amplifi ed a 285 bp product using the primer pair (167f and 452r) described previously.5 the amplifi ed dna fragment was used as a template, after serial dilutions, 167f 452r 285 bp 87 bp 35dg 5' – c c t g g g g g g t g t g a a – – 3 ' c t c c c t t – – 5 35dg primer ' 5 – c c t n 5 a g g – econ i site ♠ (generated due to two mismatches if the g deletion is present) normal sequence [g6 ] mutant sequence [g5] 5' – c c t g g g g g t g t g a a – – 3 c t c t t – 5 ' 35dg primer c c – figure 1. principles of the semi-nested pcr to amplify 285 and 87 bp dna fragments from connexin 26 gene. figure shows the position of three primers used with respect to the 35 delg mutation, and the partial sequence of the mutagenesis primer (35dg), which anneals to the sense strand of the connexin 26 gene around the mutation site. the primer pair (167f and 452r) were as described by kelsell et al.5 the mutagenesis primer (35dg) had two mismatches (t/t and t/c) at its 3'– end with the template dna. an econ i recognition site is generated if the 35delg mutation is present in the connexin 26 gene. figure 2. amplifi cation and electrophoretic pattern of 285 and 87 bp dna fragments on a 4 % agarose gel lane 1 shows the amplifi cation of a 285 bp dna fragment using the primer pair 167f and 452r; lane 2: trial amplifi cation of 87 bp with the 167f and 35dg mutagenesis primers; lane 3: negative pcr control without any added template dna; lanes 4 to 10 : semi-nested pcr for 87 bp using serially diluted 285 bp dna as template (100, 101, 102, 103, 104, 105, and 106 fold dilutions, respectively). m indicates 50 bp ladder (pharmacia ) as dna size markers. n e w p c r r f l p f o r 3 5 d e l g m u t a t i o n 11 in a subsequent semi-nested pcr [figure 2, lanes 4 to 10]. the desired 87 bp product was amplifi ed in good yield even after a 105-fold dilution of the template dna . figure 3 shows the results obtained upon treatment of the 87 bp dna fragment with econ i, followed by electrophoresis on a 10% polyacrylamide gel. for normal dna samples, there was no cleavage of the 87 bp dna fragment as expected [figure 3, lanes 1 & 2]. two shorter fragments (62 and 25 bp) were produced from a homozygous mutant dna [figure 3, lane 5], but the short (25 bp) fragment was too small to be seen in the gel. two heterozygous dna samples [figure 3, lanes 3 & 4] yielded three fragments (87, 62, and 25 bp respectively). visualization of the 25 bp fragment was not necessary since the identifi cation of the 35delg mutation was easily demonstrated by the inspection of the two larger fragments (62 and 87 bp) in different samples. d i s c u s s i o n the 35delg mutation in the connexin 26 gene does not create or destroy a restriction endonuclease site, and hence a direct pcr-r flp method cannot be used for its detection. in a recent paper it was argued that due to sequence complexity around the 35delg mutation site, a muta genesis primer could not be used to create a restriction site for the detection of this mutation.6 we designed a mutagenesis primer (35dg ) by introducing two mismatches at its 3’-end, but the amplifi cation of the desired 87 bp product was too weak when the mismatched primer was used directly in a pcr amplifi cation [figure 2, lane 2]. in addition, there were some non-specifi c pcr products of higher molecular weight. we tried various pcr conditions including different magnesium ion (mg2+) concentrations (1.0 to 3.0 mm) and annealing temperatures in the range from 50 to 65°c but all failed to produce the desired 87 bp fragment in good yield (data not shown). this problem was circumvented by using a semi-nested pcr , which resulted in better amplifi cation of the desired 87 bp product. subsequent treatment of this fragment with econ i allowed us to detect the 35delg mutation either in the homozygous or in the heterozygous state [figure 3]. the principles involved in our pcr-r flp test is very similar to the methods described by wilcox,7 and storm10 except for the use of a semi-nested pcr . a problem usually encountered in pcr-based tests is the absence or low yield amplifi cation of target dna in some samples. this makes the subsequent r flp analysis extremely diffi cult. the use of a semi-nested pcr was advantageous here since the target dna fragment (87 bp) was produced in good yield in all the samples tested, even after a dilution of the template dna up to 100,000 fold [figure 2]. another advantage of the semi-nested pcr used in our procedure is that it allows simultaneous detection of the 35delg mutation together with another frame-shift mutation, known as 167delt in the connexin 26 gene. the t deletion was observed mainly in the askhenazi jewish population,11 while in others, its prevalence was lower than the 35delg mutation. the 167delt mutation destroys an existing pst i site in the 285 bp dna fragment, which was obtained in the fi rst round of semi-nested pcr [figure 2, lane 1]. thus, a pst i treatment of this fragment followed by r flp analysis would be suffi cient for detecting the 167delt mutation. we tested the validity of our method using quality control genomic dna s [figure 3], previously characterized by sequencing. thereafter, we screened 120 healthy subjects and 35 unrelated omani patients with hereditary sensory deafness. surprisingly, none of these samples contained the 35delg mutation in the homozygous or heterozygous form, considering that it has been detected at a fairly high frequency (28 to 60%) in most populations studied.3,4,8 however, recently abe12 reported the absence of the 35delg mutation in japanese patients with prelingual hereditary deafness, a fi nding that parallels our results. c o n c l u s i o n the detection of the 35delg mutation by a robust procedure, such as the pcr-r flp method described in this figure 3. identifi cation of 35delg mutation in the connexin 26 gene by rflp analysis with econ i. an 87 bp fragment fl anking the mutation site was produced using a semi-nested pcr as in figure 2, and treated with econ i restriction endonuclease. the resulting fragments were separated on a 10 % polyacrylamide gel by electrophoresis at 100 volts for 80 minutes. control genomic dnas that contained the 35delg mutation were provided by dr wilcox. lanes 1 and 2: normal genomic dna; lanes 3 and 4: heterozygous mutant dnas; lane 5: homozygous mutant dna. lanes m indicate the 50 bp ladder as dna size markers. s i m s e k e t a l12 paper, would be a valuable complement to the clinical audiometric screens in identifying neonates with heritable hearing impairment. early diagnosis of such infants becomes particularly important for treatment and management, because some of them may be candidates for a cochlear implantation, more successful when performed by 18–24 months of age.9 dna-based detection of the 35delg mutation in the gj b2 gene would also be useful to determine the prevalence of carriers in the general population to provide a better genetic counselling in future. our preliminary studies in oman with a limited number of patients indicate that the prevalence of 35delg may be extremely low or absent in the omani deafness patients. studies with a larger group of patients should reveal the exact status of the 35delg mutation in oman. a c k n ow l e d g e m e n t s the authors wish to thank to dr wilcox at the murdoch institute for research into birth defects, melbourne, australia, for kindly providing us with characterized dna samples, which contained the 35delg mutation in either homozygous or heterozygous form. we also thank ms hameeda al-barwani for her help in the preparation of the illustrations. r e f e r e n c e s 1. morton ne. genetic epidemiology of hearing impairment. ann n y acad sci 1991, 630, 16–31. 2. estivill x, fortina p, surrey s, rabionet r, melchionda s, d’agruma l et al. connexin-26 mutations in sporadic and inherited sensorineural deafness. lancet 1998, 351, 394–8. 3. gasparini p, rabionet r, barbujani g, melchionda s, petersen m, brondum-nielsen k et al. high carrier frequency of the 35delg deafness mutation in european populations. genetic analysis consortium of gjb2 35delg. eur j hum genet 2000 8, 19–23. 4. denoyelle f, weil d, maw ma, wilcox sa, lench nj, allen-powell dr et al. prelingual deafness: high prevalence of a 30delg mutation in the connexin-26 gene. hum mol genet 1997, 6, 2173–7. 5. kelsell dp, dunlop j, stevens hp, lench nj, liang jn, parry g et al. connexin 26 mutations in hereditary non-syndromic sensorineural deafness. nature 1997, 387, 80–3. 6. rabionet r estivill x. allele specifi c oligonucleotide analysis of the common deafness mutation 35delg in the connexin 26 gene (gjb2). j med genet 1999, 36, 260–1. 7. wilcox sa, osborn ah, dahl hh. a simple pcr test to detect the common 35delg mutation in the connexin 26 gene. mol diagn 2000 5, 75–78. 8. green ge, scott da, mcdonald jm, woodworth gg, sheffi eld vc, smith rj. carrier rates in the midwestern united states for gjb2 mutations causing inherited deafness. jama 1999, 281, 2211–6. 9. cohn es, kelley pm, fowler tw, gorga mp, lefkowitz dm, kuehn hj et al. clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (gjb2/dfnb1). pediatrics 1999, 103, 546–50. 10. storm k, willocx s, flothmann k, van camp g. determination of the carrier frequency of the common gjb2 (connexin-26) 35delg mutation in the belgian population using an easy and reliable screening method. hum mutat 1999, 14, 263–6. 11. morell rj, kim hj, hood lj, goforth l, friderici k, fisher r et al. mutations in the connexin 26 gene (gjb2) among ashkenazi jews with nonsyndromic recessive deafness. n engl j med 1998 339, 1500–5. 12. abe s, usami s, shinkawa h, kelley pm, kimberling wj. prevalent connexin 26 gene (gjb2) mutations in japanese. j med genet 2000, 37, 41–43. departments of 1pediatrics and 2psychiatry & behavioral science, 3college of medicine and health sciences, national university of science and technology, sohar, oman *corresponding author’s e-mail: chhaix@gmail.com body image perceptions and body image dissatisfaction among medical students in oman *chhaya a. divecha,1 miriam a. simon,2 alhasan a. asaad,3 hassan tayyab3 clinical & basic research sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 218–224, epub. 26 may 22 submitted 31 oct 20 revision req. 4 feb 21; revision recd. 7 mar 21 accepted 23 mar 21 https://doi.org/10.18295/squmj.8.2021.121 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to examine body image perceptions and body image dissatisfaction and their relationship with body mass index (bmi) among medical students in oman. methods: this cross-sectional study was conducted among students of the college of medicine and health sciences, national university of science and technology, sohar, oman, between september and december 2019. the data (including self-reported weight and height) were collected through a questionnaire-based survey. body image perception and satisfaction were assessed using the stunkard figure rating scale. results: a total of 351 medical students (response rate: 70.2%) participated in the study with a mean age of 21.6 ± 2.2 years and a mean bmi of 22.7 ± 4.3 kg/m2. most students were within normal ranges of bmi (63%), 12% were underweight and 25% overweight/obese. approximately, 66% of students perceived their body image correctly; students at both bmi extremes were more accurate about their body image perceptions. body image dissatisfaction was high (80%) among the respondents with 73.5% of those dissatisfied desiring to be thinner. the association between self-reported bmi with perceived bmi and body image dissatisfaction was significant (p <0.001). only 18.2% of students felt ‘attractive’. the association between body image perception and body image dissatisfaction was statistically significant (p <0.05). conclusion: a high degree of body image dissatisfaction and incorrect body image perceptions exists among medical students. there is an increased desire to be thinner and the majority of this study’s participants feel unattractive. there is a need to foster healthy body image perceptions among students of health sciences as they are the future in healthcare and can influence the health beliefs in our society. keywords: body image; body image dissatisfaction; body mass index; medical students; oman. advances in knowledge a high prevalence of body image dissatisfaction exists among medical students in sohar, oman. only two-thirds of the students evaluated in the present study had correct body image perceptions. students at both extremes of the body mass index (underweight and obesity) had better perception of their image. dissatisfaction was more likely in students with obesity and those who were overweight; most of the dissatisfied students desired to be thinner. very few students felt attractive. application to patient care there is a need to review professional medical training as a starting point for developing healthy body awareness and satisfaction. medical students should be targeted for health education programmes related to an awareness of appropriate body image, healthy lifestyle and appropriate eating and exercise behaviour. early adoption of healthy behaviours by medical students will enable a lifelong commitment towards positive body awareness for patients’ health and practices as well. medical students can influence peers on a large scale, through health awareness campaigns in schools, colleges and professional institutions. body image refers to “a person’s perceptions, thoughts and feelings about his or her body”. the discrepancy between one’s perceived and ideal body image has been defined as body image dissatisfaction (bid).1 this dissatisfaction may vary in intensity among individuals and its influence on an individual’s life may range from benign to severe social concerns—such as depression, poor self-esteem and eating disorders—with pervasive consequences on the quality of life.2 due to the growing emphasis on physical attractiveness and preoccupation with one’s body image and an increase in techniques to counteract dissatisfaction such as cosmetic surgery, use of anabolic steroids, diet pills, botox, etc., research on body image has become increasingly valuable.1 with modernisation, westernisation and increased media exposure, adolescents and youth are increasingly susceptible to bid. this has been observed in a metaanalysis and systematic review of bid in adults, as well as studies in children and adolescents.2,3 adolescents are especially vulnerable due to significant physical and psychological changes associated with puberty.1 though body image is not studied extensively in medical students, studies from india, pakistan, brazil and https://creativecommons.org/licenses/by-nd/4.0/ chhaya a. divecha, miriam a. simon, alhasan a. asaad and hassan tayyab clinical and basic research | 219 (9). they had to choose their perceived body image (i.e. how they saw themselves), their ideal body image (i.e. how they wanted to look) and which image they thought their opposite gender peers found attractive (attractiveness image). bmi was calculated from self-reported body weight and height values of each student.4,17,18 bmi was further classified using the world health organization criteria into four weight status categories: (1) underweight with bmi <18.5 kg/m2; (2) normal weight with bmi 18.5–24.9 kg/m2; (3) overweight with bmi 25–29.9 kg/m2; (4) obese iran have revealed high prevalence of incorrect body size/body image perceptions (bip) and bid among their medical and health science students (33–65%).4–9 obesity has reached epidemic proportions throughout the globe and has also impacted people in arabic-speaking countries. the prevalence of obesity in children and adolescents in these higher-income, oilproducing countries ranges from 5% to 14% in males and from 3% to 18% in females.10 body dissatisfaction has been reported to be higher in individuals with obesity.2 thus, bid is not only a disorder of western culture but has also been observed in middle eastern arab countries. the increase in body weight concerns and dissatisfaction among adolescents and university students has been noted in egypt, united arab emirates, bahrain, jordan, oman and syria.11–13 oman is a developing, rapidly acculturating country with both traditional and western values. the overall incidence of obesity among children and adolescents has been found to be 13%, with increased risk of developing bid.14 studies focusing on bips and its relation to body weight, especially in medical students are lacking in oman and other middle eastern countries. to bridge this gap, the authors planned to study the magnitude of bid among medical students, note their bip and study its relationship with actual body mass index (bmi) values. methods this cross-sectional study was conducted in the college of medicine and health sciences, national university of science and technology, sohar, oman, between september and december 2019. undergraduate medical students from year 1 to year 6 were enrolled for the study. students were further grouped based on their medical and clinical exposure as pre-medical (years 1 and 2), pre-clinical (years 3 and 4) and clinical (years 5 and 6). all students who gave consent to participate were eligible and were enrolled based on convenience sampling. the survey was conducted using an english-language questionnaire that was administered to the students during breaks between classes. oral instructions and clarifications for the questionnaire and its contents were provided by medical students trained to facilitate the research study. bip was measured using the figure rating scale (frs), adapted from stunkard et al.15 frs has good overall validity and test-retest reliability based on previous research.15,16 participants had to choose a male or female silhouette that matched their body, depending upon their gender; there were nine silhouettes ranging from very skinny (1) to very obese table 1: characteristics of the medical students partic ipating in this study (n = 351) study variable n (%) mean age in years + sd 21.6 + 2.2 gender female 308 (88) male 43 (12) year of study pre-medical (years 1–2) 129 (27) pre-clinical (years 3–4) 112 (32) clinical (years 5–6) 110 (31) bmi (who classification) in kg/m2 underweight 42 (12) normal 221 (63) overweight 63 (17.9) obese 25 (7.1) perceived bmi classification underweight 66 (18.8) normal 182 (51.9) overweight 52 (14.8) obese 51 (14.5) ideal/desired bmi classification underweight 69 (19.6) normal 272 (77.5) overweight 8 (2.3) obese 2 (0.6) attractiveness image underweight 32 (9.1) normal 273 (77.8) overweight 43 (12.3) obese 3 (0.8) sd = standard deviation; bmi = body mass index; who = world health organization. body image perceptions and body image dissatisfaction among medical students in oman 220 | squ medical journal, may 2022, volume 22, issue 2 (including extremely obese) with bmi >30 kg/m2.19 the silhouettes were grouped into the same categories with: (1) underweight = figures 1 and 2; (2) normal weight = figures 3 and 4; (3) overweight = figure 5; (4) obese (including extremely obese) = figures 6, 7, 8 and 9. thus, the corresponding perceived bmi and ideal bmi were obtained from the figure scale.17 table 2: distribution of perceived bmi in relation to self-reported bmi among the medical students participating in this study (n = 351) self-reported bmi classification perceived bmi classification students who correctly perceived bmi in percent significance* underweight normal overweight obese underweight 33 9 0 0 78.6 p <0.001 normal 33 152 25 11 68.8 x2 = 293.9 overweight 0 19 26 18 41.3 df = 9 obese 0 2 1 22 88 total 66 182 52 51 66.4 bmi = body mass index; df = degrees of freedom. *pearson chi-squared test with significance (two-sided). table 3: distribution of body image dissatisfaction (perceived image ideal image) in relation to self-reported bmi among the medical students participating in this study (n = 351) self-reported bmi classification bid (i.e. perceived image ideal image) significance* -3 -2 -1 0 1 2 3 4 5 6 dissatisfied students in % underweight 1 13 21 5 1 1 0 0 0 0 88.1 p <0.001 normal 1 7 31 61 86 23 7 3 0 2 72.4 x2 = 251.7 overweight 0 0 0 2 21 28 9 3 0 0 96.8 df = 27 obese 0 0 0 0 3 10 6 4 1 1 100 total in n (%) 2 (0.6) 20 (5.7) 52 (14.8) 68 (19.4) 111 (31.6) 62 (17.7) 22 (6.3) 10 (2.8) 1 (0.3) 3 (0.8) 283 (80.6) bmi = body mass index; bid = body image dissatisfaction; df = degrees of freedom. *pearson chi-squared test with significance (two-sided). table 4: distribution of attractiveness index (perceived image attractiveness image) among medical students partic ipating in this study (n = 351) attractiveness index (perceived image attractiveness image) -4 -3 -2 -1 0 1 2 3 4 5 6 7 n (%) 1 (0.3) 9 (2.6) 47 (13.4) 72 (20.5) 64 (18.2) 81 (23.1) 44 (12.5) 20 (5.7) 7 (2) 3 (0.8) 2 (0.6) 1 (0.3) table 5: association between body image perception and body image dissatisfaction among medical students partic ipating in this study (n = 351) bid n (%) significance* body image perception underestimate correct estimate overestimate total satisfied 13 (19.1) 50 (73.5) 5 (7.4) 68 (19.4) p = 0.038 dissatisfied 42 (14.8) 183 (64.7) 58 (20.5) 283 (80.6) x2 = 6.5 total 55 (15.7) 233 (66.4) 63 (17.9) 351 df = 2 bid = body image dissatisfaction; df = degrees of freedom. *pearson chi-squared test with significance (two-sided). chhaya a. divecha, miriam a. simon, alhasan a. asaad and hassan tayyab clinical and basic research | 221 the self-reported bmi (or ‘actual bmi’) and ‘perceived bmi’ (inferred from the silhouettes) were compared to obtain bip. the ‘perceived’ and ‘ideal’ choices were compared; those who chose the same silhouette were satisfied while those who chose different silhouettes were dissatisfied.20 the data were analysed using the statistical package for social sciences (spss), version 22 (ibm corp., chicago, illinois, usa). descriptive analysis was used to analyse demographic data and students’ bip and bid. inferential statistical procedures (chisquared test) were employed to test hypotheses exploring associations among variables. this study was conducted after institutional ethics committee approval (register no. cmhs/ rec/020/18/c). results a total of 500 students were potentially eligible and administered the questionnaires, of which 351 (response rate: 70.2%) students gave consent and participated in the study. there was almost equal representation from the pre-medical (n = 129, 36.8%), pre-clinical (n = 112, 31.9%) and clinical groups (n = 110, 31.3%). the mean age of the students was 21.6 ± 2.2 years and the majority were female (88%). the mean self-reported bmi of participants was 22.7 ± 4.3 kg/m2. approximately 50% of students perceived their body image as normal, while 29.3% felt that they were overweight or obese [table 1]. students perceiving themselves as obese (14.5%), were twice the actual ‘obese’ students (7.1%). based on ideal body image, 77.5% aspired to have a normal bmi, while 19.6% wished to be underweight. on enquiring about their impression of attractiveness (by opposite gender), the majority (77.8%) chose images corresponding to normal bmi, while 13% felt appearing heavier (overweight/obese) would make them attractive [table 1]. bip is how accurately one identifies their body image in relation to their actual bmi. approximately 66.4% of students perceived their bmi category correctly [table 2]. there was a significant association between perceived bmi and self-reported bmi (p <0.001); students at bmi extremes (underweight and obese) were more likely to correctly perceive their body size. a total of 19.4% of students chose similar silhouettes for perceived and ideal image (zero discrepancy) and were thus ‘satisfied’; the remaining (80.6%) chose different silhouettes and were thus ‘dissatisfied’. of the satisfied students, 89.7% had normal bmi. students choosing a ‘smaller’ ideal image as compared to perceived image (59.5%) were approximately three times those desiring a ‘larger’ ideal silhouette (21.1%). of those with normal bmi, 72.4% were ‘dissatisfied’. the relation between actual bmi and body satisfaction was statistically significant (p <0.001). obese students were four times more likely than underweight students to develop bid (odds ratio = 4.122, 95% confidence interval = 0.76–22.33; p <0.05). only 18.2% chose similar silhouettes for both perceived self-image and image perceived as attractive by the opposite gender and thus felt ‘attractive’ [table 4]. while 45% of students chose a ‘leaner’ image (as compared to self-image) to be attractive to the opposite gender, 37% chose a ‘heavier’ image. there was no association of the attractiveness index with gender. on applying pearson’s correlation between actual bmi, perceived bmi and ideal bmi (correlation is significant at the 0.01 level [two-tailed]), positive correlation was seen between actual and perceived bmi (0.699) at a significance of <0.0001. ideal bmi did not correlate with the actual bmi, but correlated with perceived bmi (weak positive correlation of 0.168). differences between both genders were found to be insignificant on analysing all parameters. the association between bip and bid was statistically significant (p = 0.038) [table 5]; those who were ‘satisfied’ were more likely to correctly estimate their body image. discussion this study showed a high prevalence of bid among medical students in oman. only 66% of the students had correct bip. students at bmi extremes (underweight and obesity) had better perception of their image. students with obesity and those who were overweight were prone to bid. most of the ‘dissatisfied’ students (73.8%) desired to be ‘thinner’. only 18.2% of respondents felt ‘attractive’. there was a dual burden of overweight/obese (25%) and underweight (12%) among the medical students in this study. incorrect bip was seen in 33.6%, which was on the lower end of the body size/body weight imperceptions observed in medical and health science students in india, pakistan and iran (33– 65%).4–6 the curriculum at the college of medicine and health sciences, national university of science and technology, includes psychology and behavioural sciences, which introduces the students to eating disorders and related body image issues. with this kind of knowledge exposure, the authors expected the body image perceptions and body image dissatisfaction among medical students in oman 222 | squ medical journal, may 2022, volume 22, issue 2 medical students in the current study to have healthier and correct bip; however, only two-thirds estimated their image correctly. studies have shown that females and students in private universities are prone to body image misperceptions, as noticed in the present study.16 in a study of polish pharmacy students, females tended to overestimate their body weight, whereas male students were more inclined to underestimate.21,17 however, due to disparities in the proportion of males and females in the present study, significances with relation to gender were not observed. there was a significant association between perceived and self-reported bmi (p <0.001); students at the outer ranges of bmi (78% of those who were underweight and 88% of those with obesity) perceived their image accurately. this could be due to the reduced ambiguity at extremes regarding classification of their weight/size group. priya et al. and vijayalakshmi et al. also observed a significant association between bmi and body weight perception among indian medical students (p <0.001).4,7 vijayalakshmi et al. noted that most of their overweight participants perceived their weight status correctly; similar to observations by jaworowska and bazylak in polish pharmacy students.21 while proper bip motivates corrective behaviours, incorrect perceptions lead to unhealthy excesses. overestimation increases the risk of eating disorders such as anorexia nervosa, especially in those with normal bmi and underweight, whereas underest imation, especially in overweight people, decreases the likelihood of appropriate weight control.22,23 students with correct perceptions are also likelier to engage in healthy nutritional behaviours, exercise and healthy sleeping patterns.5 thus, appropriate bip is essential for accurate self-appraisal and is more decisive in generating changes in eating behaviours than actual bmi.22 eighty percent of students chose different images for perceived and ideal choices and were thus ‘dissatisfied’ with their body image. studies have shown bid in medical and health sciences students ranging from 33% to 80%.4,5,7,8,24 this wide disparity could be due to variations in gender recruitment, differences in scales, instruments or questionnaires used to measure satisfaction or different methodologies.4,5,7 moreover, some studies focused on concepts such as body dysmorphic disorder.8 it was noted that females were 13.5 times likelier than males to be ‘dissatisfied’, which could also explain the high proportion of dissatisfaction in the present study’s predominantly female student population (88%).24 in the current study, bid was noted to be significantly associated with bmi. obesity is known to be increasingly associated with bid.7 a higher percentage of overweight students and those with obesity were ‘dissatisfied’ compared to the normal or underweight students, which could be attributed to the social stigma associated with being ‘fat’. it was noted that students with obesity were four times more likely to develop bid compared to underweight students. this is similar to a study by latiff et al., who also observed that overweight and obese students were four times more likely to develop bid than normal and underweight students.25 bid was also seen among 72.4% of students with normal bmi. in their study on body image and weight control beliefs among female medical/ nursing students, rasheed similarly noted that though dissatisfaction was predominant amongst overweight (87.5%) and underweight (63.2%) students, it was also seen in half of the normal weight females (p <0.05).9 the number of students who chose a ‘leaner’ image were thrice that of those who chose a ‘heavier’ one. thus, there is an increased desire to be ‘thinner’. this desire to be ‘thinner’, even amongst those with normal bmi was also observed by rasheed where onethird of the students with normal bmi wished to lose weight.9 in another study by bosi et al., despite 78.7% of students being normal in bmi, 66.5% indicated a desire to lose weight.26 thus, the desire to be thin appears to be universal. many studies have also observed an increased desire to lose weight due to bid.5,21 high bid and preference for ‘thinness’ has also extended to the arab world. in his comparative study involving university students from five arab countries (bahrain, egypt, jordan, oman and syria), musaiger found that one-third of the student sample was ‘dissatisfied’, most preferring a ‘thinner’ image.13 in another iranian study, total prevalence of bid was 51.63%, while 53.5% of all students chose the thinnest image as desirable.5 bid has been linked to depression, poor selfesteem and eating disorders.2 due to statistically significant associations between bmi, desire to lose weight and abnormal signs of eating behaviour, bid may serve as a screening tool to detect the risk of eating disorders.26 in a study by neumark-sztainer et al., lower body satisfaction predicted higher levels of dieting, unhealthy weight control behaviours, binge eating, smoking, lower levels of physical activity and low fruit and vegetable intake. thus, lower body satisfaction does not encourage healthy weight management behaviours, but rather predicts the behaviours that could put adolescents at risk for weight gain and poorer overall health.27 approximately 20% of the current students considered themselves ‘attractive’, i.e. they felt the chhaya a. divecha, miriam a. simon, alhasan a. asaad and hassan tayyab clinical and basic research | 223 opposite gender would choose images similar to their perceived image; however, the majority felt ‘unattractive’. while the westernised culture focuses on a ‘thinner’ image, a cultural preference for obesity has been seen among the arab people. plumpness and heaviness were often seen as a sign of prosperity and hence there is skewing among body image preferences.28 almost one-third of the participants chose an image heavier than theirs as attractive to the opposite gender, thereby reinforcing the heavier stereotypes. musaiger also observed a preference for plump women among 5–16% of omanis.13 thus, though there is tolerance for obesity at one end, there is also a developing exaggerated concern for thinness due to urbanisation and media exposure at the other.9 such distorted images and attitudes may be detrimental to healthy behaviours. the relation between bip and bid was previously found to be statistically significant.7 people satisfied with their image perception have been noted to have better lifestyles and quality of life, while those with image distortion were at risk of unhealthy conditions such as depression, frequent dieting and extreme weight loss attempts.29,30 in another study, subjects with undistorted bip and bid had a higher rate of exercise and a higher amount of night sleeping hours.5 thus, how one perceives one’s image can guide the level of satisfaction and eventually impact health behaviour decisions.20 the current study presents a valuable perspective on the bips and concerns of medical students belonging to arab cultures and is the first of its kind in oman. the results imply a need to create health awareness regarding body image as well as identify its negative impact amongst young medical students, to guide appropriate preventive and therapeutic measures. despite validated measures and a suitably large sample size, the results of the present study must be interpreted within some limitations. the students surveyed were predominantly female and from one college and thus these findings may not be generalisable to all medical students in oman. moreover, the data was based on self-reported height and weight measurements, which could introduce bias due to overor under-reporting of values. convenience sampling was used which could bias the enrolment; those who perceived themselves at the extremes or were ‘dissatisfied’ could have refused to participate in the study. conclusion there was a high level of bid and discrepancies in bip among the medical students in the current study. these students represent the future doctors of society. a healthy awareness of body image not only affects their self-perception and satisfaction, but also has long-term bearing on their patients’ health and practices. it is worrying that if medical students are susceptible to incorrect judgements and feelings about their body image, the problem in the general community may run wider and deeper, thus necessitating research on a larger and wider scale. awareness campaigns amongst schools, colleges and professional institutions could facilitate dissemination of information regarding correct awareness of healthy body image. further research is also recommended to study the effectiveness of an intervention module in bip and satisfaction. the effectiveness of integration in the medical curriculum can also be measured. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study did not receive any funding. a u t h o r s’ c o n t r i b u t i o n cad and mas contributed to the study conception and design. aaa and ht were responsible for data collection, data entry and literature search. cad and mas conducted data analysis and statistical analysis. cad drafted the manuscript. all authors approved the final version of the manuscript. references 1. grogan s. body image: understanding body dissatisfaction in men, women and children, 3rd ed. london & new york: taylor & francis, 2017. 2. weinberger na, kersting a, riedel-heller sg, luck-sikorski c. body dissatisfaction in individuals with obesity compared to normal-weight individuals: a systematic review and meta analysis. obes facts 2016; 9:424–41. https://doi.org/10.1159/00 0454837. 3. jiménez flores p, jiménez cruz a, bacardi gascón m. [bodyimage dissatisfaction in children and adolescents: a systematic review]. nutr hosp 2017; 34:479–89. https://doi.org/10.20960/ nh.455. 4. vijayalakshmi p, thimmaiah r, gandhi s, badamath s. eating attitudes, weight control behaviors, body image satisfaction and depression level among indian medical and nursing under graduate students. community ment health j 2018; 54:1266–73. https://doi.org/10.1007/s10597-018-0333-x. 5. alipour b, farhangi ma, dehghan p, alipour m. body image perception and its association with body mass index and nutrient intakes among female college students aged 18–35 years from tabriz, iran. eat weight disord 2015; 20:465–71. https://doi. org/10.1007/s40519-015-0184-1. 6. saleem md, ahmed g, mulla j, haider ss, abbas m. weight misperception amongst youth of a developing country: pakistan a cross-sectional study. bmc public health 2013; 13:707. https://doi.org/10.1186/1471-2458-13-707. https://doi.org/10.1159/000454837 https://doi.org/10.1159/000454837 https://doi.org/10.20960/nh.455 https://doi.org/10.20960/nh.455 https://doi.org/10.1007/s10597-018-0333-x https://doi.org/10.1007/s40519-015-0184-1 https://doi.org/10.1007/s40519-015-0184-1 https://doi.org/10.1186/1471-2458-13-707 body image perceptions and body image dissatisfaction among medical students in oman 224 | squ medical journal, may 2022, volume 22, issue 2 7. priya d, prasanna ks, sucharitha s, vaz nc. body image perception and attempts to change weight among female medical students at mangalore. indian j community med 2010; 35:316–20. https://doi.org/10.4103/0970-0218.66886. 8. taqui am, shaikh m, gowani sa, shahid f, khan a, tayyeb sm, et al. body dysmorphic disorder: gender differences and prevalence in a pakistani medical student population. bmc psychiatry 2008; 8:20. https://doi.org/10.1186/1471-244x-8-20. 9. rasheed p. overweight status: body image and weight control beliefs and practices among female college students. ann saudi med 1999; 19:365–9. https://doi.org/10.5144/0256–4947.1999.365. 10. badran m, laher i. obesity in arabic-speaking countries. j obes 2011; 2011:686430. https://doi.org/10.1155/2011/686430. 11. schulte sj, thomas j. relationship between eating pathology, body dissatisfaction and depressive symptoms among male and female adolescents in the united arab emirates. eat behav 2013; 14:157–60. https://doi.org/10.1016/j.eatbeh.2013.01.015. 12. hatata h, awaad m, sheikh m. body image dissatisfaction and its relationships with psychiatric symptomatology, eating beliefs and self esteem in egyptian female adolescents. curr psychiatry 2009; 16:35–45. 13. musaiger a. body weight concern among female university students in five arab countries–a preliminary cross-cultural study. ann agric environ med 2015; 22:349–52. https://doi.org/10.5604/123 21966.1152093. 14. world health organization. non-communicable diseases country profiles 2018: oman. from: http://www.who.int/nmh/countries /2018/omn_en.pdf?ua=1 accessed: mar 2021. 15. stunkard aj, sørensen t, schulsinger f. use of the danish adoption register for the study of obesity and thinness. res publ assoc res nerv ment dis 1983; 60:115–20. 16. thompson jk, altabe mn. psychometric qualities of the figure rating scale. int j eating disorders 1991; 10:615–9. https:// doi.org/10.1002/1098-108x(199109)10:5<615::aid-eat22 60100514>3.0.co;2-k. 17. bhuiyan ar, gustat j, srinivasan sr, berenson gs. differences in body shape representations among young adults from a biracial (black-white), semirural community: the bogalusa heart study. am j epidemiol 2003; 158:792–7. https://doi. org/10.1093/aje/kwg218. 18. neighbors la, sobal j. prevalence and magnitude of body weight and shape dissatisfaction among university students. eat behav 2007; 8:429–39. https://doi.org/10.1016/j.eatbeh.2007.03.003. 19. clinical guidelines on the identification, evaluation, and treat ment of overweight and obesity in adults--the evidence report. national institutes of health. obes res 1998; 6:51s–209s. 20. gustat j, carton tw, shahien aa, andersen l. body image satisfaction among blacks. health educ behav 2017; 44:131–40. https://doi.org/10.1093/aje/kwg218. 21. jaworowska a, bazylak g. an outbreak of body weight dissat isfaction associated with self-perceived bmi and dieting among female pharmacy students. biomed pharmacother 2009; 63:679–92. https://doi.org/10.1016/j.biopha.2008.08.005. 22. desmond sm, price jh, gray n, o’connell jk. the etiology of adolescents’ perceptions of their weight. j youth adolesc 1986; 15:461–74. https://doi.org/10.1007/bf02146088. 23. strauss rs. self-reported weight status and dieting in a cross sectional sample of young adolescents: national health and nutrition examination survey iii. arch pediatr adolesc med 1999; 153:741–7. https://doi.org/10.1001/archpedi.153.7.741. 24. regis jm, ramos-cerqueira at, lima mc, torres ar. social anxiety symptoms and body image dissatisfaction in medical students: prevalence and correlates. j bras psiquiatr 2018; 67:65–73. https://doi.org/10.1590/0047-2085000000187. 25. latiff aa, muhamad j, rahman ra. body image dissatisfaction and its determinants among young primary-school adolescents. j taibah univ med sci 2017; 13:34–41. https://doi.org/10.1016/j. jtumed.2017.07.003. 26. bosi ml, nogueira ja, alencar ch, moreira ja. body image and eating behavior among medical students: eating disorders among medical students. epidemiology (sunnyvale). 2016; 6:256. https://doi.org/10.4172/2161-1165.1000256. 27. neumark-sztainer d, paxton sj, hannan pj, haines j, story m. does body satisfaction matter? five-year longitudinal associations between body satisfaction and health behaviors in adolescent females and males. j adolesc health 2006; 39:244–51. https:// doi.org/10.1016/j.jadohealth.2005.12.001. 28. musaiger ao. overweight and obesity in eastern mediterranean region: prevalence and possible causes. j obes 2011; 2011:407237. https://doi.org/10.1155/2011/407237. 29. blashill aj, wilhelm s. body image distortions, weight, and depression in adolescent boys: longitudinal trajectories into adulthood. psychol men masc 2014; 15:445–51. https://doi. org/10.1037/a0034618. 30. liechty jm. body image distortion and three types of weight loss behaviors among non over weight girls in the united states. j adolesc health 2010; 47:176–82. https://doi.org/10.1016/j. jadohealth.2010.01.004. https://doi.org/10.4103/0970-0218.66886 https://doi.org/10.1186/1471-244x-8-20 https://doi.org/10.5144/0256-4947.1999.365 https://doi.org/10.1155/2011/686430 https://doi.org/10.1016/j.eatbeh.2013.01.015 https://doi.org/10.5604/12321966.115209 https://doi.org/10.5604/12321966.115209 https://doi.org/10.1093/aje/kwg218 https://doi.org/10.1093/aje/kwg218 https://doi.org/10.1016/j.eatbeh.2007.03.003 https://doi.org/10.1093/aje/kwg218 https://doi.org/10.1016/j.biopha.2008.08.005 https://doi.org/10.1007/bf02146088 https://doi.org/10.1001/archpedi.153.7.741 https://doi.org/10.1590/0047-2085000000187 https://doi.org/10.1016/j.jtumed.2017.07.003 https://doi.org/10.1016/j.jtumed.2017.07.003 https://doi.org/10.4172/2161-1165.1000256 https://doi.org/10.1016/j.jadohealth.2005.12.001 https://doi.org/10.1016/j.jadohealth.2005.12.001 https://doi.org/10.1155/2011/407237 https://doi.org/10.1037/a0034618 https://doi.org/10.1037/a0034618 https://doi.org/10.1016/j.jadohealth.2010.01.004 https://doi.org/10.1016/j.jadohealth.2010.01.004 squ med j, november 2011, vol. 11, iss. 4, pp. 444 -447, epub. 25th oct 11 submitted 5th oct 11 accepted 10th oct 11 in this issue of the journal, dr. saleh al-hinai and colleagues have published their results on a survey studying the medical tourism patterns of patients going abroad from the al-dakhilya region of oman.1 they managed to obtain 40 responses to the 45 questionnaires they distributed. basically, most of the results they obtained from the patients in their region who had sought treatment abroad were similar to those of other studies: 10% of the respondents went for treatment plus tourism, and 2.5% were healthy. strikingly, 15% of the patients experienced complications after their treatment abroad and this is not an unusual finding in the literature. only a few of the patient’s in al-hinai’s study used the internet and the available medical tourism offices to obtain information on treatment abroad options instead the majority relied on word of mouth advice from friends. most of the patients went to thailand, and orthopaedic conditions were the most common indication for these patients to seek treatment abroad. this article is of special interest to oman and should stimulate discussion on the advantages and disadvantages of going abroad for medical services. what are its advantages and disadvantages to the patients, and to omani health services? likewise, what are the advantages and the disadvantages to the host country? medical tourism is part of health tourism and it has a long-standing history, going back to thousands of years. records show that in greece, thousands of years ago, patients came to the healing god asklepios in epidauria.2 at the same time in other countries, people used to travel to therapeutic spas and collect waters from holy shrines. much more recently, in the 18th century, health spas were a common feature of medical tourism. health tourism, which includes medical tourism, is generally defined as organised travel outside one’s local environment for the maintenance, enhancement, or restoration of an individual’s well-being in mind and body.3 medical tourism is regarded as more organised travel outside one’s natural health care jurisdiction.4 typically it is linked with engagement in leisure, businesses and other purposes.5 there are several types of medical tourism, and they are classified in many ways. one such classification includes: 1) “temporary visitors abroad” who go for either check-up or treatment; 2) “long-term residents” e.g. people who move to a location better for their health like many americans who go to florida or the caribbean; 3) “medical tourist, from 2 adjacent countries who share common borders” and have agreed upon sharing health care, and 4) “outsourced patients”— these are patients who are sent abroad by their government, as the neither necessary treatment nor the specialist is available locally. this last definition fits many omani patients. why do patients go abroad? jagyasi gave 5 major “factors” involved in decision making: affordable, accessible, available, acceptable and additional.5 affordable is probably the major reason and this is particularly true for patients from the well-off, developed countries like america and uk, where private health care is expensive, and some surgeries editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, oman. *email: mjournal@squ.edu.om السياحة الطبية هل هي مفيدة أم ضارة؟ ملك اللمكي editorial medical tourism beneficence or maleficence? lamk al-lamki lamk al-lamki editorial | 445 are not covered by their insurance. available is often because the medical treatment they need is not available in their local areas or not trusted by the patients, as is often the case with omani patients. accessible applies more particularly to patients from countries where the waiting list is long, particularly to national health service patients in the uk and in canada. in the uk, private health care may be available locally, but is expensive. acceptable applies to services, which may be affordable, available, and accessible, but they are not acceptable in the patient’s own country for religious, political reasons or other social reasons. additional refers to the availability of better care, perhaps better technology, or a better specialist, or simply better service and personalised care abroad compared to care in the home country. there are several reasons, related to above, why patients choose to become medical tourists. for the americans and europeans the attraction is value, i.e. affordability. for example the price of a coronary artery bypass graft (cabg) is $113,000 in the usa, but only $10,000 in india; heart valve replacements cost $150,000 in usa, but $9,500 in india, and knee replacements cost $48,000 in the states, but only $8,500 in india.2 most references quote the prices of surgery in india, thailand and singapore as only 5% to 10% of the prices in the usa.6 a forecast by deloitte consulting published in august 2008 projected that medical tourism originating in the us could jump by a factor of 10 over the next decade.2 however, besides the financial benefit, there are other advantages for a patient to have treatment abroad in a centre of excellence for certain conditions. many of the countries seeking to develop medical tourism invite specialists from well-known health care centres such as columbia and cleveland clinic, mayo clinic, harvard medical international, and are thus able to offer excellent medical care. many of them are encouraged and supported by their host governments, e.g. india has introduced a special m-visa category for medical tourists.7 malaysia’s ministry of health has formed a special national committee for the promotion of health tourism. this has contributed to the reversal of the geographical trend of medical tourism. in the past, patients from the east were travelling to the west to get the best medical treatment. now, patients from western developed countries, travel east to developing countries for the best medical and technologically advanced health care. eastern europe has now joined the bandwagon including hungary and poland which are popular for dental work. however, there are several problems with medical tourism as discussed by several agencies and scholars.8,9 these include poor or no followup care. after being in hospital for a short while and having a vacation, the patient comes home with, perhaps, complications of the surgery or side effects of the drugs. it is a surgical principle that every surgeon looks after his own complications and obviously that does not apply for most if not all patients who have been treated abroad. many countries have very weak malpractice laws and thus patients have limited ability to complain about poor medical care. medical tourism also affects the host countries with the problem of internal brain drain, whereby all good doctors give up serving the public sector to go into the exotic, private health centres, which serve the medical tourists. thailand’s bumrungrad hospital, which treats about more than half a million international patients a year, is a major source of internal brain drain, leading to a political discussion within thailand and a national public radio (npr, usa) special programme on the shortage of thai doctors in bangkok because of the higher pay offered by bumrungrad.10 thus, globalisation impacts world health care, both in the host and the donor countries.3 there are other risks which medical tourism poses to patients. for example, patients may not tolerate travel very well, or may not have inherent resistance to some of the diseases in the host countries.6 we therefore need to have better scientific studies on the impact of medical tourism on the health care services of the source and destination countries as well as on the patients themselves. we need more statistics on the rate of complications. the article in this issue of this journal reported a 15% complication rate;1 granted we do not know how severe those complications were, but that is what needs to be studied. a survey was carried out by the british association of plastic, reconstructive and aesthetic surgery. they received responses from 203 out of 325 members.4 a total of 37% of them had seen a patient in the national health service with complications arising from overseas cosmetic surgery. in another survey in the uk, 60% of complications were of emergency medical tourism beneficence or maleficence? 446 | squ medical journal, november 2011, volume 11, issue 4 nature requiring inpatient admission.4 americans and europeans now realise that they need to analyse the impact of medical tourism—beneficent or maleficent—on the patients and the country’s health care system. many medical tourists are satisfied, but satisfaction does not always parallel good outcome. often satisfaction can simply be a result of good service. it is of special interest to note that “outsourced patients,” those who were sent by the government are often dissatisfied with the total experience compared to the true self-financed medical tourist.4 that is why an institution has to be accredited for good medical care with a good quality assurance programme rather than just good service. now more and more of the provider institutions try for accreditation by either the joint commission international (jci) or trent or for canadian accreditation. the jci has accredited wockhardt hospital in india and several other institutions. patients going abroad need to get good advice. according to the world tourism organization’s global code of ethics for tourism, tourists should have the same rights as citizens of destination countries.11 unfortunately, that is not always the case and that is another potential source of problems. for example, personal data is stored electronically and may not be treated as confidentially as the patients have a right to expect. we have no control over that when patients go abroad. another major problem is informed consent, is it always informed? a further potential significant problem with medical tourism is that sometimes it impacts the source country’s health care system. a source country may become complacent by being able to send its citizens abroad for certain procedures and thus fail to develop the appropriate national services. the development of positron emission tomography (pet) in oman is an example of this. this has been delayed for years now as patients are simply sent abroad for pet imaging. sending patients abroad is not only costly to the government, but it also dilutes the political support and the will to develop certain essential national services. this situation often helps create a 2-tier system in the destination country whereby the local population receives second-class treatment while medical tourist gets much better treatment in the more sophisticated, well-equipped, state-of-the-art hospitals. among the disadvantages of medical tourism is the one related to health insurance companies, who may refuse to cover a patient going abroad for legitimate reasons, or may actually encourage patients to go abroad if the treatment is cheaper, but then not cover the airfare and other expenses. the other side of the coin is that there is now pressure on insurance companies to cover the cost of all overseas treatment and this may mean raising premiums—yet another negative side to medical tourism for some patients. the organisations that provide accreditation need to consult with each other and establish a uniform, or at least a fairly similar level of accreditation to ensure that the patient is the winner. they can do that only if they share experiences, ideas and methodology. one of the problems of medical tourism is that it generally raises the cost of health care in the host country. for example, india claims that they are improving the services for the local citizens by having more tourists and improving the health care in those tourist centres. but, the truth is that in most places, and certainly in almost all small towns and villages in india, they do not have even labour rooms and people suffer from severely overcrowded hospitals where patient bed space is both under as well as on the bed. this is exacerbated by the internal brain drain of hospital administrators and of doctors described above. one of the major concerns related to medical tourism is the ethical aspects of treatment.8 these should be examined and the risks discussed with the patient, but, on the other hand, it is important that patients have their own autonomy in decisionmaking. beneficence and nonmaleficence are the basis of medical ethics. thus it is our responsibility to promote patients’ welfare, treat them with justice and improve their health while we avoiding harming them. these ethical principles are not easily upheld in the delicate balance of commerce versus medical ethics. another aspect of medical ethics is the ownership of responsibility for treating the complications of the treatment given abroad. another ethical consideration is that each country may have a different standard of medical ethics. for example, what is considered experimental therapy in one country, like stem cell therapy, is routinely used in the private institutions providing care for medical tourists in other countries. likewise, the medical ethics related to organ transplantation differ from country to country. while most lamk al-lamki editorial | 447 countries do not allow the involvement of money in organ donation, it is a common practice in some countries, and donors can even be a living nonrelative. the declaration of istanbul on organ trafficking and transplantation tourism, 2008, has condemned organ transplant tourism.12 it is the responsibility of the medical profession to stop the trend of treating medicine and health care like goods and services traded in business.13,14 burney has pointed out in squmj that medical tourism may receive "uncalled for treatment".15 the quality assurance trend in health care has introduced the term “consumer” to describe patients in an effort to improve the quality of care in hospitals. unfortunately, the term “health consumer” is now misused in the business of delivery of health care. the quality and safety of medical treatment abroad has to be studied and questioned and it should be under the scrutiny of the medical profession and the ministry of health in oman. unless we have good grip on the quality of the care that our patients are receiving abroad, their safety may be at risk. we need more statistics, better studies and better reporting systems. the question of who will look after these patients when they return, has not been answered, but must be tackled. thus, there is a major lack of systematic data about health services provided abroad, not only for omanis, but, also for citizens of many other countries. more organised studies are needed and specifically outcome studies. research into the delivery of health care has not yet adequately evaluated medical tourism. the issue of lack of data must be taken very seriously. medical tourism has some benefits, but there are more problems with it and, as physicians, we have to keep in mind our basic principles of beneficence and nonmaleficence. references 1. al-hinai ss, al-busaidi as, al-busaidi ih. medical tourism abroad: a new challenge to oman’s health system the al dakhilya region experience. sultan qaboos university med j 2011; 11:477–86. 2. medical tourism. from: http://en.wikipedia.org/ wiki/medical_tourism accessed: oct 2011. 3. international trade in health sciences. oecd – directorate of employment, labour and social affairs. from: http:// w w w . o e c d . o r g / d o c u m e n t / 4 8 / 0 , 3 7 4 6 , e n _ 2649_33929_48724272_1_1_1_1,00.html accessed: oct 2011. 4. lunt n, smith r, exworthy m, green st, horsfal d, mannion r. medical tourism: treatments, markets and health system implications: a scoping review. oecd, directorate for employment, labour and social affairs. from: http://www.oecd.org/ dataoecd/51/11/48723982.pdf accessed: oct 2011. 5. jagyasi p. defining medical tourism – another approach. medical tourism magazine. from:http:// w w w. m e d i c a l t o u r i s m m a g . c o m / i s s u e d e t a i l . php?item=136&issue=6 accessed: oct 2011. 6. horowitz md, jones ca. medical tourism: globalization of the healthcare marketplace. med gen med 2007; 9:33. epub 13 nov 2007. from: http:// www.ncbi.nlm.nih.gov/pmc/articles/pmc2234298/ accessed: oct 2011. 7. chinai r, goswami r. medical visas mark growth of indian medical tourism. bull world health 2007; 85:164–5. from: http://www.who.int/bulletin/ volumes/85/3/07-010307/en/index.html accessed: oct 2011. 8. gray hh, poland sc. medical tourism crossing borders to access health care. kennedy inst ethics j 2008; 18:193–201. from: http://muse.jhu.edu/ journals/kennedy_institute_of_ethics_journal/ v018/18.2.gray.html accessed: oct 2011. 9. herrick dm. medical tourism: global competition in health care. national center for policy analysis. from: www.ncpa.org/pub/st/st304 accessed: oct 2011. 10. madden cl. medical tourism causes complications. asia times, 7 nov 2008. from: http://www.atimes. co m / at i m e s / a s i a n _ e co n o my / j k 0 7 d k 0 1 . ht m l accessed: oct 2011. 11. world tourism organization’s global code of ethics for tourism. from: www.unep.org/bpsp/tourism/ wto%20code%20of%20conduct.pdf accessed: oct 2011. 12. declaration of istanbul on organ trafficking and transplantation tourism. from: www. declarationofistanbul.org accessed: oct 2011. 13. top 5 medical tourism destinations. medical tourism can mean attractive opportunities for foreign patients and investors. from: http://www. n u w i r e i n v e s t o r. c o m / a r t i c l e s / t o p 5 m e d i c a l tourism-destinations-51502.aspx accessed: oct 2011. 14. tutton m. medical tourism: have illness, will travel by. cnn health. from: http://articles.cnn.com/200903-26/health/medical.tourism_1_medical-tourismjci-accredited-foreign-patients?_s=pm:health accessed: oct 2011. 15. burney i. the trend to seek a second opinion abroad amongst cancer patients in oman. sultan qaboos university med j 2009; 9:260–3. muscat directorate of general health services, ministry of health, muscat, oman e-mail: amel.albulushi@gmail.com املرضى اإلناث واملوافقة املستنرية اخللفية الثقافية لعمان اأمل اأحمد البلو�سية abstract: female patients in oman face a certain amount of pressure from their families when making high-stakes decisions regarding personal healthcare. in fact, some women waive their right to make decisions, typically giving that responsibility to their husbands or fathers. this article highlights the need to empower females in decision-making when it comes to their own well-being. moreover, informed consent should not be signed by anyone but the patient herself if the patient is deemed competent by a medical professional. keywords: informed consent; female; decision making; clinical competence; medical ethics; patient rights; oman. امللخ�ص: تواجه املري�سات يف ُعمان قدًرا معيًنا من ال�سغط من اأ�رسهن عند اتخاذ قرارات عالية املخاطر فيما يتعلق بالرعاية ال�سحية ال�سخ�سية. ويف الواقع تتنازل بع�ض الن�ساء عن حقوقهن يف اتخاذ القرارات، ومينحن عادة تلك امل�سوؤولية لأزواجهن اأو لآبائهن. يربز هذا املقال احلاجة اإىل متكني الإناث من �سنع القرار عندما يتعلق الأمر ب�سحتهن. اإ�سافة على ذلك، ل ينبغي اأن يوقع اأي �سخ�ض غري املري�ض على املوافقة امل�ستنرية اإذا اعترب املري�ض موؤهاًل للتوقيع من قبل مهني طبي. الكلمات املفتاحية: املوافقة امل�ستنرية؛ اأنثى؛ اتخاذ القرار؛ الكفاءة ال�رسيرية؛ الأخالقيات الطبية؛ حقوق املري�ض؛ عمان. female patients and informed consent oman’s cultural background amal a. al balushi sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e11–14, epub. 30 may 19 submitted 4 jun 18 revisions req. 12 jun, 30 jul & 10 oct 18; revisions recd. 20 jun, 16 sep & 7 nov 18 accepted 15 nov 18 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. a patient who signed an informed consent form cannot be considered informed without comprehending the medical procedure as well as its associated risks and benefits.1 patients often turn to their families for opinions and, in some cases, for decision-making. it was observed by the author, during specialised tertiary clinical care, that female patients in oman typically make medical decisions with their family’s approval and only sign an informed consent form after such a discussion. however, male patients, in general, inform their family of their decision and only seek advice or an opinion when the decision affects the family dyn amics. as research addressing female consent in oman is scarce, this article discusses the process of informed consent and addresses female empowerment in informed consent. “informed” and medical information due to the growing accessibility of the internet, a vast amount of medical information is widely available. patients can easily find information related to their cond itions as well as proposed procedures; however, they also risk receiving conflicting or even false information.2 this information overload can hinder a patient’s ability to make a decision. therefore, the role of healthcare providers is extremely important in guiding the patient. some studies have shown that written information provided to patients before obtaining consent increases understanding.3–5 while written forms and informative hand-outs are helpful, they cannot replace discussion or direct communication. a well-informed consent process starts with a good doctor patient relationship. communication is vital in this process to ascertain the patient’s worries, expectations and social ramifications that may affect the decisionmaking process and the delivery of medical care in general. although legal guidelines are important to regulate this process, maintaining good standards of care, pre serving patients’ rights and actively discussing proced ures are essential to the process of obtaining informed consent. providing a satisfactory explanation for com plete patient understanding should depend on a comm unicative doctor-patient relationship rather than obligation by the law.6 an informed consent document alone may not be sufficient to achieve an adequate level of under standing of the information related to or implications of a medical procedure. many factors affect a patient’s ability to understand the contents of an informed consent doc ument, including their health literacy, culture and level of https://doi.org/10.18295/squmj.2019.19.01.003 sounding board https://creativecommons.org/licenses/by-nd/4.0/ female patients and informed consent oman's cultural background e12 | squ medical journal, february 2019, volume 19, issue 1 education. active discussion is also important in revealing a patient’s values and priorities for the healthcare prov ider to deliver the intervention in a way that suits the patient best. moreover, a conversation between health care provider and female patients may reveal any incon sistencies between the consent and the wishes of the patient, implying that the decision was not autonomous. the availability of resources via the internet have improved medical literacy.7 some female patients, how ever, remain dependant on others for healthcare-related decisions. therefore, this dependency is due to a lack of female self-ownership rather than information availability. self-ownership should be empowered by refusing consent from any other parties if the female patient is deemed competent. currently, there are no available data in oman reg arding female patients who request others to sign their informed consent on their behalf. it is recommended that this issue be studied and followed up by amendments to policy and procedural documents of informed consent in oman.8 decision-making and female patients in oman for the purpose of this article, competence and decision making abilities will be considered synonymous. a patient must be competent and autonomous in order to provide informed consent.9 in addition, this process should be voluntary and free of coercion.10 to establish a person’s ability to make a decision, five conditions must be present according to the stanford encyclopedia of philosophy: (1) the person must understand the proposed treatment or management procedure; (2) they must appreciate the significance of the presented facts and the implic ations of a decision; (3) they should be able to reasonably weigh the risks and benefits of the procedure and its alternatives; (4) they should be able to communicate a decision or choice; and (5) in order to establish capacity, a person needs to have some values against which they can weigh the risks, benefits and have a construct of what is best.11 furthermore, the capacity for decisionmaking is not a permanent status.12 a patient can lose or acquire this capacity over time depending on the status at the time of decision-making. if a patient is deemed incompetent or lacks decision-making capacity on one occasion, it is necessary to re-assess the patient if there is a suspicion that the decision-making ability has changed. only the patient has the freedom to decide or to involve others in their decision-making process. laws, regulations and policies maintaining women’s rights are available in oman; however, such laws and policies require periodical assessment and modification, if necessary.13 physicians need to start encouraging the independency of women from their families, especially male members. oman has a collectivistic and family-oriented culture, which creates a strong social support system for patients, where family members support each other in difficult times. however, collectivism may limit the rights of the individual. patients in oman, as in other places, depend on their family for high-stakes decisions such as in cases of cancer or surgery.6 dependent women in oman tend to rely on their husbands, fathers or brothers, while elderly patients rely on their sons. many cultures have a patriarchal society.14 a study from china, also a country with a collectivistic culture, revealed that the majority (77.3%) of adult female patients preferred their family to make decisions on their behalf.15 in saudi arabia, patients preferred the involvement of their families when dealing with a diagnosis of a terminal or chronic illness.16 it was previously suggested that the dependence of female patients on their families may be attributed to their psychosocial development and that females develop a sense of autonomy at a slower rate than males due to societal influences.17 this development is probably much slower in patriarchal societies that encourage dependence, rendering females unable to develop their autonomy even later in life as adults. to maintain cultural integrity, female patients should choose if they wish to consult with their family members; however, the final decision on consent should be hers alone. while respecting the freedom patients have to con sult family when making high-stakes choices, healthcare providers should maintain a patient-centred approach. the focus should remain on the patient, and the healthcare provider should remind the family and the public that competent individuals are responsible for their own dec isions as they are the ones who will be most affected by the consequences. however, some cultural limitations in oman affect the validity of female consent. especially in cases of tubal ligations or hysterectomies, for example, the consent of both the male and female partner should be sought. education plays a role in mediating this cultural norm of female reliance on male family members.18 however, if a female child learns that her opinions do not matter, she may stop expressing them. standardising informed consent forms in oman informed consent documents are legal contracts. in oman, these forms need improvement to enforce the autonomy and decision-making ability of competent patients. the standardisation of forms and procedures should apply amal a. al balushi sounding board | e13 to both genders as this would enforce equality of care regardless of the patient’s gender. document standardi sation should be carried out nationally and across medical and surgical specialities. different specialties might be encouraged to design preset forms for common proc edures in their departments. some departments of some hospitals in oman have accomplished document stand ardisation through individual and team efforts. standard forms might include a description of the procedure, indic ations, steps, complications and post-operative care. these forms can be given to patients during the pre-operative period and preferably in the outpatient department prior to admission, which would help them make an informed decision.19 however, there should be sufficient time between the patient receiving such a form and the pro cedure itself. to ensure comprehension in complex interventions, patients might need to be informed on multiple occasions. for example, patients might be informed both at the out patient clinic visit and pre-operatively as an inpatient. complex medical terminology must not be used in the informed consent document or during discussion.19 moreover, the informed consent document should be written in the language used most commonly in the country or region. if a patient cannot read or understand the language, a translation should be provided by prof essional medical translators. the current practice in oman regarding translation is to acquire help of any willing and available person from the medical team regardless of the level of experience in translation. using inexp erienced individuals for translations might lead to gaps in information or the use of incorrect terminology which may affect the meaning of the consent form and, therefore, the patient’s understanding of the procedure. standardised forms should be accessible to the public through the ministry of health’s website as resources for patients so they have ample time to review the inform ation in the consent form, including how the procedure is performed and specific side effects. it is important to actively involve patients in preparing these standardised forms as they will be the end users. in addition, patient input and feedback should also be sought after publishing these documents to ensure their usability. these forms and their accompanying educational information could be supplemented with an animated video; flory et al. have shown that this improves patient comprehension.20 furthermore, special attention should be given to who is receiving the consent from the patient. commonly, consent is taken by junior members of the team, such as residents or interns; however, this task should not be delegated to a junior doctor and the surgeon performing the procedure should be the one to obtain consent.21 conclusion female patients should be empowered to make their own health-related decisions. paternalistic practices on the part of family and healthcare providers should be discouraged. decisions need to be made free from coercion or pressure and without any imposed limitations on the patient’s decisions by family members; this needs to be made clear to the public. while advice and guidance from family members may be sought, the final decision needs to be made by the patient. literature reporting on this issue in the middle east is scarce. in oman, investigations of informed consent and female patients should start by assessing the perceptions and practices of female patients regarding informed consent. research should be directed toward addressing the gap in the literature in the area of female consent not only in oman, but internationally. a c k n o w l e d g e m e n t s the author would like to thank dr abeer al mamari (director of patients’ services and clients at the ministry of health, oman) for her input and valuable comments and ms lesley carson for her assistance in editing the manuscript. references 1. sherlock a, brownie s. patients’ recollection and understanding of informed consent: a literature review. anz j surg 2014; 84:207–10. https://doi.org/10.1111/ans.12555. 2. berger, k. informed consent: information or knowledge? med law 2003; 22:743–50. 3. friedman m, arja w, batra r, daniel s, hoehn d, paniz am, et al. informed consent for blood transfusion: what do med icine residents tell? what do patients understand? am j clin pathol 2012; 138:559–65. https://doi.org/10.1309/ajcp2tn5 odjlygqr. 4. court el, robinson ja, hocken db. informed consent and patient understanding of blood transfusion. transfus med 2011; 21:183–9. https://doi.org/10.1111/j.1365-3148.2011.01069.x. 5. sahin n, oztürk a, ozkan y, demirhan erdemir a. what do patients recall from informed consent given before orthopedic surgery? acta orthop traumatol turc 2010; 44:469–75. https://doi.org/10. 3944/aott.2010.2396. 6. lee wh, kim is, kong bh, kim s, lee s. probing the issue of informed consent in health care in korea-concept analysis and guideline development. asian nurs res (korean soc nurs sci) 2008; 2:102–12. https://doi.org/10.1016/s1976-1317(08)60034-1. 7. egbert n, nanna km. health literacy: challenges and strategies. ojin: the online journal of issues in nursing 2009; 14:3. from: http : / / o j i n . nu r s i n g w o r l d . o rg / m a i n m e nu c at e g o r i e s / a namarketplace/anaperiodicals/ojin/tableofcontents/vol 1 4 2 0 0 9 / n o 3 s e p t 0 9 / h e a l th l i te r a c y c h a l l e n ge s . ht m l . accessed: nov 2018. 8. directorate general of quality assurance centre, ministry of health. policy & procedure of informed consent. from www. m o h . g o v. o m / d o c u m e n t s / 1 0 1 8 1 / 6 6 7 4 5 9 / p o l i c y + % 2 6+procedure+of+informed++cconse.pdf/ae580ace-5afe4035-89a0-8898569d2b01 accessed: nov 2018. https://doi.org/10.1111/ans.12555 https://doi.org/10.1309/ajcp2tn5odjlygqr https://doi.org/10.1309/ajcp2tn5odjlygqr https://doi.org/10.1111/j.1365-3148.2011.01069.x https://doi.org/10.3944/aott.2010.2396 https://doi.org/10.3944/aott.2010.2396 https://doi.org/10.1016/s1976-1317%2808%2960034-1 female patients and informed consent oman's cultural background e14 | squ medical journal, february 2019, volume 19, issue 1 9. slovenko r. informed consent--a ploy? med law 1997; 16:651–3. 10. eyal n. informed consent. from: plato.stanford.edu/archives/ fall2012/entries/informed-consent/ accessed: nov 2018. 11. charland lc. decision-making capacity. from: https://plato. stanford.edu/archives/fall2015/entries/decision-capacity/ accessed: nov 2018. 12. ganzini l, volicer l, nelson wa, fox e, derse ar. ten myths about decision-making capacity. j am med dir assoc 2004; 5:263–7. https://doi.org/10.1097/01.jam.0000129821.34622.a2. 13. women in oman. from: https://www.oman.om/wps/wcm/con nect/en/site/home/gov/gov12/gov1204/ accessed: nov 2018. 14. sherwin s. no longer patient: feminist ethics and healthcare. phil adelphia, pennsylvania, usa: temple university press, 1992. p17. 15. li x, xing y, lin q, wei l, dong m, ma x, et al. female cancer patients’ awareness and role in family-based medical decision making mode in confucian area. j clin oncol 2016; 34:237. https://doi.org/10.1200/jco.2016.34.26_suppl.237. 16. mobeireek af, al-kassimi f, al-zahrani k, al-shimemeri a, al-damegh s, al-amoudi o, et al. information disclosure and decision-making: the middle east versus the far east and the west. j med ethics 2008; 34:225–9. https://doi.org/10.1136/ jme.2006.019638. 17. tong r, williams n. feminist ethics. from: plato.stanford.edu/ archives/win2016/entries/feminism-ethics/ accessed: nov 2018. 18. mcginn kl, eunsil o. gender, social class, and women’s employment. current opinion in psychology 2017; 18:84–8. https://doi.org/10.1016/j.copsyc.2017.07.012. 19. anderson oa, wearne im. informed consent for elective surgery--what is best practice? j r soc med 100:97–100. https://doi.org/10.1258/jrsm.100.2.97. 20. flory j, emanuel e. interventions to improve research partic ipants’ understanding in informed consent for research: a syst ematic review. jama 2004; 292:1593–601. https://doi.org/10. 1001/jama.292.13.1593. 21. department of health. reference guide to consent for exam ination or treatment. from: assets.publishing.service.gov.uk/g over nment/uploads/s ystem/uploads/att achment_dat a/ file/138296/dh_103653__1_.pdf accessed: nov 2018. https://doi.org/10.1097/01.jam.0000129821.34622.a2 https://doi.org/10.1200/jco.2016.34.26_suppl.237 https://doi.org/10.1136/jme.2006.019638 https://doi.org/10.1136/jme.2006.019638 https://doi.org/10.1016/j.copsyc.2017.07.012 https://doi.org/10.1258/jrsm.100.2.97 https://doi.org/10.1001/jama.292.13.1593 https://doi.org/10.1001/jama.292.13.1593 departments of 1biochemistry and 2medicine, era’s lucknow medical college & hospital, lucknow, india *corresponding author e-mail: tasleem24@gmail.com ارتباط تعدد األشكال اجلينية ألنزمي حتويل األجنيوتنسني واجللوتاثيون س-ترانسفرييز مع مؤشر كتلة اجلسم بني اهلنود الشماليني املصابني بارتفاع ضفط الدم �سليحة ر�سوي، �سيد ت�سليم ر�سا، زيبا �سديقي، �سانيا عبا�ض، فرزانة مهدي abstract: objectives: this study aimed to examine the association of angiotensin-converting enzyme (ace) and glutathione s-transferase (gst) gene polymorphisms with body mass index (bmi) in hypertensive north indians. methods: this case-control study was carried out between may 2013 and november 2014 at the era’s lucknow medical college & hospital, lucknow, india, and included 378 subjects divided into three groups. one group constituted 253 hypertensive individuals (sustained diastolic blood pressure of >90 mmhg and systolic blood pressure of >140 mmhg) who were subcategorised according to normal (<25 kg/m2) or high (≥25 kg/m2) bmi. the third group consisted of 125 age-, genderand ethnically-matched normotensive controls with a normal bmi. gene polymorphisms were evaluated by polymerase chain reaction. the genotypic and allelic frequency distribution among both groups were analysed. results: a significant difference was found between gst theta 1-null and gst mu 1-positive genotype frequencies among the hypertensive overweight/obese individuals and controls (p = 0.014 and 0.033, respectively). however, no difference was observed in the frequency of ace polymorphisms. ace insertion/insertion genotype (p = 0.006), insertion and deletion alleles (p = 0.007 each) and gst theta 1-null and gst theta 1-positive genotypes (p = 0.006 each) were found to differ significantly between hypertensive cases and controls, regardless of bmi. conclusion: ace and gst gene polymorphisms were not associated with bmi but were significantly associated with hypertension among the studied group of north indians. keywords: angiotensin converting enzyme; glutathione transferase; genetic polymorphisms; hypertension; body mass index; obesity; india. واجللوتاثيون )ace( الأجنيوتن�سني حتويل لأنزمي اجليني الأ�سكال تعدد ارتباط درا�سة اإىل الدرا�سة هذه هدفت الهدف: امللخ�ص: �ض-تران�سفرييز )gst( مع موؤ�رس كتلة اجل�سم بني الهنود ال�سماليني ذوي مر�ض �سفط الدم املرتفع. الطريقة: اأجريت هذه الدرا�سة املقارنة بني احلالت وجمموعة التحكم بني مايو 2013 ونوفمرب 2014 يف كلية ايرا�ض لكناو الطبية وم�ست�سفى، لكناو، ولية اوتار برادي�ض، الهند، و�سملت 378 �سخ�ض مت تق�سيمهم اإىل ثالث جمموعات. ت�سكل املجموعة الأوىل 253 من الأفراد امل�سابني بارتفاع �سغط الدم )�سغط الدم النب�ساطي امل�ستمر 90> مم زئبق و�سغط الدم النقبا�سي 140> مم زئبق( الذين مت تق�سيمهم بعد ذلك ح�سب كتلة اجل�سم اىل )25< كجم/ م2( و)25≤ كجم/م2( وتاألفت املجموعة الثالثة من 125 متماثلي العمر واجلن�ض والعرق و �سغط الدم و موؤ�رس كتلة ج�سم طبيعيني. مت تقييم اجلينات متعددة الأ�سكال عن طريق تفاعل البلمرة املت�سل�سل. وقد مت حتليل توزيع الرتدد الوراثي واأليلية بني املجموعتني. النتائج: وجد فرق كبري بني وترية النمط اجليني ل gst ثيتا 1 امل�سفر و gst ميوالإيجابي بني الأفراد امل�سابني بارتفاع �سغط الدم و يعانون من .ace على التوايل(. ومع ذلك، مل يالحظ اأي اختالف يف تعدد اأ�سكال ،p = 0.033 و p = 0.014( زيادة الوزن/ال�سمنة وال�سوابط الأ�سحاء gst ثيتا 1-ا امل�سفر و gst لكل منهما( و p = 0.007( واإدراج وحذف الأليالت ،)p = 0.006( ace بالن�سبة لالإدراج/احلذف اجليني ل ثيتا 1 الإيجابي )p = 0.006 لكل منهما( وجد اأن هناك اختالف اح�سائي بني حالت ارتفاع �سغط الدم واملجموعة ال�سابطة بغ�ض النظر عن موؤ�رس كتلة اجل�سم. اخلال�صة: مل يرتبط تعدد الأ�سكال اجليني ل ace و gst مع موؤ�رس كتلة اجل�سم لكن ارتبط اإح�سائيا مع ارتفاع �سغط الدم يف جمموعة البحث من الهنود ال�سماليني. اجل�سم؛ كتلة موؤ�رس الدم؛ �سغط ارتفاع اجلينية؛ الأ�سكال تعدد تران�سفريز؛ اجللوتاثيون لالأجنيوتن�سني؛ املحول الإنزمي الكلمات: مفتاح ال�سمنة؛ الهند. association of angiotensin-converting enzyme and glutathione s-transferase gene polymorphisms with body mass index among hypertensive north indians saliha rizvi,1 *syed t. raza,1 zeba siddiqi,2 shania abbas,1 farzana mahdi1 advances in knowledge to the best of the authors’ knowledge, this is the first study to investigate the effect of single nucleotide polymorphisms in angiotensinconverting enzyme (ace) and glutathione s-transferase (gst) genes on body mass index (bmi) in hypertensive north indians. clinical & basic research sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e477–485, epub. 23 nov 15 submitted 16 jan 15 revisions req. 5 apr & 16 jun 15; revisions recd. 22 apr & 19 jun 15 accepted 2 jul 15 doi: 10.18295/squmj.2015.15.04.006 association of angiotensin-converting enzyme and glutathione s-transferase gene polymorphisms with body mass index among hypertensive north indians e478 | squ medical journal, november 2015, volume 15, issue 4 hypertension and obesity are emer-ging global health concerns.1 many epidemiological studies have shown an association between these medical conditions.2,3 hypertension predisposes individuals to future weight gain as compared to their normotensive counterparts, which means that even hypertensive individuals at a normal weight are at significantly higher risk of becoming obese.4 the body mass index (bmi) is used to classify individuals according to various weight categories. a high bmi is associated with an increased burden of diabetes, hypertension and cardiovascular diseases.1 aside from environmental and lifestyle factors, bmi is also influenced by genetic factors. research has confirmed the involvement of different genetic polymorphisms in the metabolism and appetite of predisposed individuals, thus causing them to become overweight or obese.1 more than 41 loci on the human genome have been linked with the development of obesity.1 the angiotensin-converting enzyme (ace) is part of the renin-angiotensin system, which is responsible for regulating blood pressure and the balance of fluids and salts inside the body. engeli et al. suggested that components of the renin-angiotensin system might be involved in the development of obesity and associated hypertension.5 the insertion/deletion polymorphism occurs in intron 16 of the ace gene due to the presence or absence of a 278 base pairs (bp) arthrobacter luteus repetitive sequence.6 this polymorphism has been found to drastically affect ace activity where the deletion/deletion genotype increases ace activity while the insertion/insertion genotype decreases activity.7 a study conducted in pakistan showed the association of the ace gene polymorphism with obesity, suggesting a role for the deletion allele in adipogenesis and adipocyte metabolism.8 hirata et al. confirmed the role of oxidative stress in linking obesity with hypertension.9 systemic oxidative stress levels increase obesity, which may lead to the development of obesity-related hypertension. glutathione s-transferase (gst) plays a major role in combating reactive oxygen species, thus protecting the body against its harmful effects.10 evidence also indicates the involvement of oxidative stress with the pathogenesis of hypertension.9 among humans, the gene coding for gst mu 1 (gstm1) and gst theta 1 (gstt1) are located on chromosomes 1p13.3 and 22, respectively. previous studies have demonstrated that gst polymorphisms were not associated with bmi in diabetic north indians or with weight gain in schizophrenic koreans.11,12 since there is a close link between hypertension and obesity, this study sought to investigate the association of ace and gst gene polymorphisms with bmi among a selected group of hypertensive north indians. methods this case-control study was carried out between may 2013 and november 2014 at the era’s lucknow medical college & hospital, lucknow, india. a total of 253 subjects with either a recent diagnosis or history of hypertension were recruited from the department of medicine at era’s lucknow medical college & hospital. these patients mostly resided in lucknow and adjoining areas, including hardoi and barabanki. a diagnosis of hypertension was based on sustained diastolic blood pressure of >90 mmhg and systolic blood pressure of >140 mmhg. hypertensive patients were subsequently subcategorised according to bmi into normal weight (bmi <25 kg/m2) or overweight/obese (≥25 kg/m2) groups. as a control group, 125 age-, genderand ethnically-matched normotensive individuals of normal weight (bmi <25 kg/m2) were recruited for inclusion in the study. patients who visited the outpatient clinics for minor illnesses and with no history of major clinical diseases were recruited as controls. subjects in either group with a history of smoking or evidence of cancer, organ dysfunction or metabolic disease were excluded. the sample size calculations were based on the proportion of ace genotypes among the cases and controls using the following formula: based on a 95% level of significance and 80% expected power (20% type 2 error), the minimum sample size was 103 in each group. subject to the n = (zα + zβ)2/{ln (1-e)}*[{(1-p1)/p1} + (1-p2)/p2}] while ace and gst gene polymorphisms were not found to be associated with bmi among this study population, they were significantly associated with hypertension. application to patient care the results of this study could be helpful in understanding the impact of genetic polymorphisms on bmi and on an individual’s predisposition to hypertension. additionally, these findings could contribute in the identification of novel factors leading to the development of a high bmi; this would assist in the prevention and cure of various related metabolic diseases. saliha rizvi, syed t. raza, zeba siddiqi, shania abbas and farzana mahdi clinical and basic research | e479 availability of cases, this was then increased so that the power would increase correspondingly. clinical data were collected from each subject, including gender, age, alcohol consumption, waist-tohip ratio (whr), weight, height and family history. quetelet’s equation (weight in kg/height in m2) was used to calculate the bmi of each participant. whr was calculated by dividing the waist circumference at the narrowest point above the hip by the hip circumference at its greatest gluteal protuberance. serum triglycerides were measured using the glycerol phosphate oxidase-peroxidase-amidopyrine method while serum cholesterol was measured by the cholesterol oxidase-peroxidase method. highdensity lipoprotein cholesterol was measured by the immunoinhibition method using the erba xl-300 fully automated chemistry analyser (erba diagnostics mannheim gmbh, mannheim, germany). very lowdensity lipoprotein levels were estimated by dividing measured triglycerides by 5 mg/dl units. low-density lipoprotein cholesterol levels were estimated using the friedewald formula.13 the dna extraction was performed using 3 ml of venous blood collected from all participants in 0.5 m ethylenediaminetetraacetic acid tubes. a stan dard phenol-chloroform extraction method was used to isolate genomic dna from the blood samples.14 the dna concentration was determined by a spectrophotometer and samples were stored at -20 °c. ace insertion/deletion polymorphisms (rs464994) were analysed by genomic dna amplification using polymerase chain reaction (pcr) technology.15 pcr amplification was conducted in a total volume of 20 µl using: 10 pmol each of forward primer 5’-ctggagaccactcccatcctttct-3’ and reverse primer 5’-gatgtggccatcttcgtcagat-3’; 200 ng of genomic dna; 3 mm of magnesium chloride; 50 mm of potassium chloride; 10 mm of trisaminomethane hydrochloride at a ph of 8.4; 0.5 mm each of deoxyribonucleotide triphosphate; and 2 u of thermus aquaticus (taq) polymerase (bioline reagents ltd., london, uk). the pcr amplification was performed using an initial denaturation at 94 °c for five minutes, followed by 35 cycles of denaturation at 94 °c for 45 seconds, annealing at 60 °c for one minute and 15 seconds, extension at 72 °c for two minutes and 30 seconds and final extension at 72 °c for five minutes. the amplified products were separated on a 2.0% agarose gel stained with 0.5 ug/ml of ethidium bromide and visualised using a bioimaging and gel documentation system (uvp llc, upland, california, usa). the gstm1 and gstt1 genetic polymorphisms were analysed by genomic dna amplification using the multiplex-pcr technique (mj mini™ thermal cycler, bio rad laboratories inc., hercules, california, usa).15 primers for gstm1 were 5’-aactccctgaaaagctaaagc-3’ and 5’-gtt gggctcaaatatacggtgg-3’, while primers for gstt1 were 5’-ttccttactggtcctcacatct c-3’ and 5’-tcaccggacatggccagca-3’. to avoid false-negative readings, β-globin was used as an internal control. primers for β-globin were 5’-caacttcatccacgttcacc-3’ and 5’-gaa gagccaaggacaggtac-3’. pcr amplification was conducted in a total volume of 25 μl using: 10 pmol of each primer; 100 ng of genomic dna; 2.5 mmol/l of magnesium chloride; 0.2 mmol/l each of deoxyribonucleotide triphosphate; and 1 u of taq polymerase (bioline reagents ltd). the pcr amplification was performed using an initial denaturation at 94 °c for five minutes, followed by 30 cycles at 94 °c for one minute, 64 °c for one minute, 72 °c for one minute and a final extension of 72 °c for seven minutes. amplified products were separated on a 1.5% agarose gel stained with 0.5 μg/ml of ethidium bromide and visualised using a bioimaging and gel documentation system (uvp llc). direct sequencing was carried out for approximately 10% of all samples for both polymorphisms studied and genotyping for 20% of the samples was further duplicated. the results were verified by two individual laboratory technicians to confirm genotyping results. statistical analysis was performed using the statistical package for the social sciences (spss), version 12 (ibm corp., chicago, illinois, usa). variables were tested for normality using the kolmogorov smirnov test. variables with a normal distribution were expressed as means ± standard deviation while variables with a non-normal distribution were expressed as medians and interquartile ranges and were log transformed before statistical analysis. a chi-squared test was used to compare genotyping data between cases and controls. a p value of ≤0.050 was considered significant. the odds ratio (or) and 95% confidence interval (ci) was calculated to test the relative risk for association. other variables were compared using the student’s t-test for normallydistributed variables. ethical approval for this study was granted by the institutional ethical committee of the department of medicine at era’s lucknow medical college & hospital (#elmc/e-1/3942). written informed consent was obtained from each subject prior to data collection. results a total of 378 patients were included in this study, association of angiotensin-converting enzyme and glutathione s-transferase gene polymorphisms with body mass index among hypertensive north indians e480 | squ medical journal, november 2015, volume 15, issue 4 ranging in age from 26‒60 years old. there were 103 subjects in the hypertensive normal weight group, 150 subjects in the hypertensive overweight/obese group and 125 subjects in the control group. obesity-related parameters were higher in the hypertensive groups compared to the control group [table 1]. for ace polymorphisms, a single 490 bp band represented an insertion/insertion genotype, two bands of 490 bp and 190 bp represented an insertion/deletion genotype, whereas the deletion/deletion genotype was confirmed by a single band of 190 bp [figure 1]. for gst genetic polymorphisms, the band sizes observed were 215 bp, 480 bp and 268 bp for gstm1, gstt1 and β-globin, respectively [figure 2]. negligible discrepancy in genotyping was observed. the genotype frequencies of ace insertion/ deletion, deletion/deletion and insertion/insertion genotypes among the hypertensive overweight/obese group and the hypertensive normal weight group were 53.34%, 19.33% and 27.33% and 54.37%, 16.50% and 29.13%, respectively (or = 0.96, 1.22 and 0.91; 95% ci = 0.56–1.66, 0.59–2.49 and 0.50–1.67; p = figure 1: agarose gel image showing polymerase chain reaction products for an angiotensin-converting enzyme polymorphism. lanes 1, 2 and 8 show the insertion/ insertion genotype at 490 base pairs (bp), lanes 6 and 7 show the insertion/deletion genotype at 490 bp and lanes 3 and 5 show the deletion/deletion genotype in a single band of 190 bp. lane 4 is a 100 bp ladder. figure 2: agarose gel image showing polymerase chain reaction products of glutathione s-transferase (gst) polymorphisms. the presence or absence of gst mu 1 (gstm1) and gst theta 1 (gstt1) was detected by 480 base pairs (bp) and 210 bp bands, respectively. β-globin was considered an internal control at 260 bp. lanes 1 and 7 show gstm1and gstt1-null genotypes, respectively, and lanes 2–5 show gstm1 and gstt1 wild-type genotypes. lane 4 is a 100 bp ladder. table 1: characteristics of overweight/obese* hypertensive subjects and hypertensive subjects of a normal weight† in comparison to an age-, genderand ethnically-matched control group† in north india (n = 378) characteristic mean ± sd p value‡ mean ± sd p value‡ hh group (n = 150) control group (n = 125) hn group (n = 103) control group (n = 125) male-to-female ratio 83:67 72:53 0.706 58:45 72:53 0.845 age in years 43.42 ± 13.29 40.03 ± 10.28 0.017 42.02 ± 16.65 40.03 ± 10.28 0.290 bmi in kg/m2 28.87 ± 3.78 21.92 ± 2.60 <0.001 21.68 ± 1.93 21.92 ± 2.60 0.424 sbp in mm hg 147.63 ± 21.16 110.00 ± 10.61 <0.001 146.96 ± 17.87 110.00 ± 10.61 <0.001 dbp in mm hg 97.85 ± 4.02 75.00 ± 9.20 <0.001 93.50 ± 5.67 75.00 ± 9.20 <0.001 sc in mg/dl 194.92 ± 43.27 166.73 ± 24.17 <0.001 181.11 ± 56.88 166.73 ± 24.17 0.017 median tg in mmol/l-1 (iqr) 2.12 (1.50–2.62) 1.32 (0.95–2.10) <0.001 1.94 (0.96–1.98) 1.32 (0.95–2.10) <0.001 hdl in mg/dl 41.24 ± 8.53 55.23 ± 9.59 <0.001 45.77 ± 8.79 55.23 ± 9.59 <0.001 vldl in mg/dl 34.41 ± 20.55 30.83 ± 11.64 0.070 33.53 ± 16.7 30.83 ± 11.64 0.166 ldl in mg/dl 102.82 ± 47.44 87.80 ± 19.83 <0.001 103.78 ± 31.93 87.80 ± 19.83 <0.001 whr 0.93 ± 0.02 0.86 ± 0.08 <0.001 0.86 ± 0.06 0.86 ± 0.08 0.667 sd = standard deviation; hh = hypertensive overweight/obese group; hn =hypertensive normal weight group; bmi = body mass index; sbp = systolic blood pressure; dbp = diastolic blood pressure; sc = serum cholesterol; tg = triglycerides; iqr = interquartile range; hdl = high-density lipoproteins; vldl = very low-density lipoproteins; ldl = low-density lipoproteins; whr = waist-to-hip ratio. *bmi ≥25 kg/m2. †bmi <25 kg/m2. ‡calculated using the student’s t-test. a p value of ≤0.050 was considered significant. saliha rizvi, syed t. raza, zeba siddiqi, shania abbas and farzana mahdi clinical and basic research | e481 0.889, 0.586 and 0.757). in the control group, the same ace genotype frequencies were 59.20%, 27.20% and 13.60%, respectively (or = 0.86, 0.68 and 2.37; 95% ci = 0.49–1.48, 0.35–1.31 and 1.16–4.83; p = 0.575, 0.245 and 0.015). frequencies of insertion and deletion alleles were 54.00% and 46.00% for the hypertensive overweight/obese group compared to 56.31% and 43.69% for the hypertensive normal weight group (or = 0.91 and 1.10; 95% ci = 0.61–1.34 and 0.75–1.63; p = 0.620 each) and 43.20% and 56.80% for the control subjects, respectively (or = 1.60 and 0.63; 95% ci = 1.08–2.36 and 0.42–0.92; p = 0.018 each) [tables 2 and 3]. the gstm1-null genotype frequency was 33.33% for the hypertensive overweight/obese group, while it was 36.89% and 45.60% for the hypertensive normal weight and control groups, respectively (or = 0.84 and 0.61; 95% ci = 0.47–1.50 and 0.35–1.07; p = 0.559 table 2: frequencies of angiotensin-converting enzyme and glutathione s-transferase genetic polymorphisms among overweight/obese* hypertensive subjects and hypertensive subjects of a normal weight† in north india (n = 253) polymorphism n (%) or 95% ci χ2 p value‡ power hn group (n = 103) hh group (n = 150) i/d 56 (54.37) 80 (53.34) 0.96 0.56–1.66 0.02 0.889 0.610 d/d 17 (16.50) 29 (19.33) 1.22 0.59–2.49 0.30 0.586 0.813 i/i 30 (29.13) 41 (27.33) 0.91 0.50–1.67 0.10 0.757 0.622 i 116 (56.31) 162 (54.00) 0.91 0.61–1.34 0.25 0.620 0.735 d 90 (43.69) 138 (46.00) 1.10 0.75–1.63 0.25 0.620 0.735 gstt1/gstm1-positive 49 (47.57) 80 (53.34) 1.26 0.73–2.18 0.70 0.403 0.900 gstt1-null 16 (15.53) 20 (13.33) 0.86 0.39–1.86 0.16 0.693 0.654 gstm1-positive 65 (63.12) 100 (66.67) 1.19 0.67–2.11 0.34 0.559 0.822 gstt1 -positive 87 (84.47) 130 (86.67) 1.17 0.54–2.54 0.16 0.693 0.753 gstm1-null 38 (36.89) 50 (33.33) 0.84 0.47–1.50 0.34 0.559 0.763 or = odds ratio; ci = confidence interval; hn = hypertensive normal weight group; hh = hypertensive overweight/obese group; ace = angiotensinconverting enzyme; i = insertion; d = deletion; gst = glutathione s-transferase; gstt1 = gst theta 1; gstm1 = gst mu 1. *bmi ≥25 kg/m2. †bmi <25 kg/m2. ‡calculated using the student’s t-test. a p value of ≤0.050 was considered significant. a c e g st g en ot yp e g en ot yp e a lle le a lle le table 3: frequencies of angiotensin-converting enzyme and glutathione s-transferase genetic polymorphisms among overweight/obese* hypertensive subjects in comparison to an age-, genderand ethnically-matched control group† in north india (n = 275) polymorphism n (%) or 95% ci χ2 p value power control group (n = 125) hh group (n = 150) i/d 74 (59.20) 80 (53.34) 0.86 0.49–1.48 0.31 0.575 0.812 d/d 34 (27.20) 29 (19.33) 0.68 0.35–1.31 1.35 0.245 0.922 i/i 17 (13.60) 41 (27.33) 2.37 1.16–4.83 5.86 0.015 0.908 i 108 (43.20) 162 (54.00) 1.60 1.08–2.36 5.60 0.018 0.882 d 142 (56.80) 138 (46.00) 0.63 0.42–0.92 5.60 0.018 0.882 gstt1/gstm1-positive 63 (50.40) 80 (53.34) 1.22 0.70–2.10 0.49 0.486 0.811 gstt1-null 5 (4.00) 20 (13.33) 3.89 1.23–12.27 6.09 0.014 0.900 gstm1-positive 68 (54.40) 100 (66.67) 1.84 1.05–3.24 4.54 0.033 0.900 gstt1 -positive 120 (96.00) 130 (86.67) 0.46 0.18–1.20 2.60 0.107 0.885 gstm1-null 57 (45.60) 50 (33.33) 0.61 0.35–1.07 2.94 0.086 0.879 or = odds ratio; ci = confidence interval; hh = hypertensive overweight/obese group; ace = angiotensin-converting enzyme; i = insertion; d = deletion; gst = glutathione s-transferase; gstt1 = gst theta 1; gstm1 = gst mu 1. *bmi ≥25 kg/m2. †bmi <25 kg/m2. ‡calculated using the student’s t-test. a p value of ≤0.050 was considered significant. a c e g st g en ot yp e g en ot yp e a lle le a lle le association of angiotensin-converting enzyme and glutathione s-transferase gene polymorphisms with body mass index among hypertensive north indians e482 | squ medical journal, november 2015, volume 15, issue 4 and 0.086). the frequency of the gstt1-null genotype was 13.33% among the hypertensive overweight/obese group as compared to 15.53% and 4.00% among the hypertensive normal weight and control groups, respectively (or = 0.86 and 3.89; 95% ci = 0.39–1.86 and 1.23–12.27; p = 0.693 and 0.014). the frequencies of gstm1and gstt1-positive genotypes were 66.67% and 86.67% in the hypertensive overweight/ obese group, while they were 63.12% and 84.47% for the hypertensive normal weight group (or = 1.19 and 1.17; 95% ci = 0.67–2.11 and 0.54–2.54; p = 0.559 and 0.693) and 54.40% and 96.00% in the control group, respectively (or = 1.84 and 0.46; 95% ci = 1.05–3.24 and 0.18–1.20; p = 0.033 and 0.107). the frequency of the gstt1-/gstm1-positive genotype was 53.34% in the hypertensive overweight/obese group, 47.57% for the hypertensive normal weight group and 50.40% in the control group (or = 1.26 and 1.22; 95% ci = 0.73–2.18 and 0.70–2.10; p = 0.403 and 0.486) [tables 2 and 3]. the ace insertion/insertion genotype frequency among the combined overweight/obese and normal weight hypertensive groups was 28.07% compared to 13.60% in the control group (or = 2.41; 95% ci = 1.27–4.57; p = 0.006). the deletion/deletion genotype frequency was 17.18% among hypertensives compared to 27.20% among healthy controls (or = 0.59; 95% ci = 0.34–1.04; p = 0.068). among the hypertensives, frequencies of the insertion and deletion alleles were 55.14% and 44.86%, respectively, compared with 43.20% and 56.80% in the control group, respectively (or = 1.59 and 0.63; 95% ci = 1.13–2.24 and 0.45– 0.88; p = 0.007 each). the frequencies of the gstt1 and gstm1-null genotypes in the hypertensive groups were 14.69% and 34.78%, respectively (or = 4.09 and 0.63; 95% ci = 1.40–11.96 and 0.39–1.03; p = 0.006 and 0.062). a significant difference was found between the gstt1-null (14.69% versus 4.00%) and -positive (85.37% versus 96.00%; or = 0.24; 95% ci = 0.08–0.71; p = 0.006) genotypes among the hypertensive groups in comparison to the control group. however, there was a non-significant difference between frequencies of gstm1-positive genotypes (65.22% versus 54.40%; or = 1.59; 95% ci = 0.97–2.58; p = 0.062) [table 4]. discussion hypertension and obesity may have a mutual or reciprocal relationship, where the presence of one potentially leads to the other.4 studies have shown that the prevalence of hypertension is directly related to a higher bmi.2,3 in the current study, lipid profile variables (including serum cholesterol, triglycerides, lowand very low-density lipoproteins and whr) were higher among the hypertensive individuals than the healthy controls, regardless of bmi category. various studies have demonstrated increased plasma renin activity and plasma angiotensinogen, angiotensin ii and aldosterone levels in obese individuals.16–18 cooper et al. pointed out that the ace insertion/ deletion polymorphism was linked to changes in ace levels, but was inconsistently associated with bmi.19 table 4: frequencies of angiotensin-converting enzyme and glutathione s-transferase genetic polymorphisms among hypertensive subjects in comparison to an age-, genderand ethnically-matched control group in north india (n = 378) polymorphism n (%) or 95% ci χ2 p value* power hypertensive subjects (n = 253) control group (n = 125) i/d 137 (54.15) 74 (59.20) 0.81 0.50–1.32 0.71 0.398 0.913 d/d 45 (17.18) 34 (27.20) 0.59 0.34–1.04 3.33 0.068 0.935 i/i 71 (28.07) 17 (13.60) 2.42 1.27–4.57 7.50 0.006 0.969 i 279 (55.14) 108 (43.20) 1.59 1.13–2.24 7.25 0.007 0.940 d 227 (44.86) 142 (56.80) 0.63 0.45–0.88 7.25 0.007 0.940 gstt1/gstm1-positive 128 (50.59) 63 (50.40) 1.02 0.63–1.64 0.01 0.936 n/a gstt1-null 37 (14.69) 5 (4.00) 4.09 1.40–11.96 7.61 0.006 0.969 gstm1-positive 165 (65.22) 68 (54.40) 1.59 0.97–2.58 3.47 0.062 0.880 gstt1 -positive 216 (85.37) 120 (96.00) 0.24 0.08–0.71 7.61 0.006 0.984 gstm1-null 88 (34.78) 57 (45.60) 0.63 0.39–1.03 3.47 0.062 0.910 or = odds ratio; ci = confidence interval; ace = angiotensin-converting enzyme; i = insertion; d = deletion; gst = glutathione s-transferase; gstt1 = gst theta 1; gstm1 = gst mu 1. *calculated using the student’s t-test. a p value of ≤0.050 was considered significant. a c e g st g en ot yp e g en ot yp e a lle le a lle le saliha rizvi, syed t. raza, zeba siddiqi, shania abbas and farzana mahdi clinical and basic research | e483 a study of a saudi population noted a higher frequency of the mutant deletion allele in hypertensive cases with a bmi of ≥30 kg/m2 in comparison to controls, although the difference was not significant.20 however, this result was reversed in the current study, as the frequency of the deletion allele among the hypertensive overweight/obese group was significantly lower than the control group. a similar study performed on korean women also confirmed this finding (p = 0.063).21 similarly, passaro et al. showed that subjects with different polymorphisms in the ace gene did not show significant variability in bmi.22 the frequency of the ace deletion/deletion genotype among hypertensive overweight/obese individuals in the current study (19.33%) was similar to that found among an overweight pakistani population (18.00%).8 the frequency of the ace insertion/ insertion genotype in the hypertensive overweight/ obese group of the current study (27.33%) was similar to that found among obese pakistani individuals (26.00%); however, it was lower than the frequency found among overweight pakistanis (32.00%).8 eisenmann et al. reported that children with the ace deletion/deletion genotype had a higher bmi compared to insertion/insertion carriers;23 this is consistent with the results obtained in the current study when comparing the hypertensive groups according to bmi, although this was not found to be significant. these results are contradictory to another report which demonstrated that the mutant deletion allele was associated with a low bmi.24 on further comparison of the hypertensive overweight/obese and control groups in the current study, a significant difference was found between the frequency of the insertion/insertion genotype and between the allele frequencies of insertion and deletion alleles. while no significant association was found between the ace insertion/deletion polymorphism and bmi in the hypertensives, a significant association was observed with hypertension. this suggests that the ace insertion/deletion polymorphism affects hypertension as opposed to bmi, with carriers of the insertion/ insertion genotype being more prone to hypertension. the insertion/insertion genotype frequency in the combined north indian hypertensive population of the current study (28.07%) was similar to that found in hypertensive pakistanis (29.30%) and another north indian population (28.62%).15,25 there was a significant association between the ace insertion/insertion genotype and hypertension; this contrasts with the results of a study conducted among south indians, although it is similar to that of the other study on north indians.15,26 the current study found an association between the ace deletion/deletion genotype and hypertension, although this was not significant. the frequency of this genotype among hypertensives in the current study (17.18%) was higher than that found for malaysian and bangladeshi individuals (10.76% and 11.40%, respectively); however, a chinese population had a lower frequency.27–29 the insertion and deletion alleles were significantly related to hypertension in the current study, which correlates with the findings of a similar north indian study.15 a positive correlation has been reported between various obesity variables like bmi and whr, including oxidative stress markers such as reduced erythrocyte glutathione.30 in the current study, significant variation was found between the gstt1-null genotype frequency among the hypertensive overweight/ obese and control groups. similarly, the frequency of the gstm1-positive genotype was significantly higher in the hypertensive overweight/obese subjects. however, this difference was not significant when compared with the hypertensive normal weight group. the frequencies of the gstm1and gstt1null genotypes among hypertensive overweight/obese subjects in the present study (33.33% and 13.33%, respectively) were lower than those of non-hispanics (45.30% and 81.60%, respectively), african americans (72.20% and 76.20%, respectively) and hispanics (46.70% and 81.70%, respectively) with higher bmis.31 in contrast, the frequencies of gstm1and gstt1positive genotypes were higher when compared to overweight/obese non-hispanics (54.70% and 18.40%, respectively), african americans (27.80% and 23.80%, respectively) and hispanics (53.30% and 18.30%, respectively).31 the gstm1and gstt1-positive genotype frequencies were somewhat higher among the overweight/obese hypertensives in the current study than for hypertensives of a normal weight, while the null genotype frequencies were lower among the former than the latter. however, these differences were not significant. the gstm1and gstt1-positive genotype findings were similar across all three groups; nevertheless, there was a slightly higher although nonsignificant frequency in the hypertensive overweight/ obese group than the hypertensive normal weight group. no association was found between gst polymorphisms and bmi in indian diabetic patients with null and positive gst genotypes.11,32 similarly, in korean schizophrenic patients, no association was observed between gst polymorphisms and druginduced weight gain.12 in view of these results, it can be concluded that gst polymorphisms are not associated with a higher bmi among hypertensive patients. association of angiotensin-converting enzyme and glutathione s-transferase gene polymorphisms with body mass index among hypertensive north indians e484 | squ medical journal, november 2015, volume 15, issue 4 in the present study, a significant difference was found between the gstt1-null and -positive genotypes among hypertensives in comparison to control subjects. however, frequencies of gstm1null and-positive genotypes were not significant. the frequencies of the gstt1and gstm1-null genotypes among hypertensive patients in the current study (14.69% and 34.78%, respectively) were lower in comparison to findings from arab (30.00% and 60.00%, respectively), chinese (58.10% and 60.00%, respectively) and korean (55.40% and 51.80%, respectively, and 61.20% and 62.40%, respectively) populations, but similar to findings from another north indian study (11.59% and 34.05%, respectively).15,33–36 in comparison, the gstm1-positive genotype was found in 65.22% of the hypertensives in the current study; this was higher than the results from arab (40.00%), chinese (40.00%) and korean (48.20% and 37.60%) populations, but again similar to results from a north indian study.15,33–36 conclusion among the studied north indian population, ace and gst genetic polymorphisms (particularly ace insertion/insertion and gstt1-null and -positive genotypes) were significantly associated with hypertension but not bmi. although they were not significantly associated with a higher bmi, ace and gst polymorphisms may nevertheless be related to the development of hypertension in overweight or obese individuals. c o n f l i c t o f i n t e r e s t the authors report no conflicts of interest. references 1. poirier p, giles td, bray ga, hong y, stern js, pi-sunyer fx, et al. obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. arterioscler thromb vasc biol 2006; 26:968–76. doi: 10.1161/01.atv.0000216787.85457.f3. 2. narkiewicz k. diagnosis and management of hypertension in obesity. obes rev 2006; 7:155–62. doi: 10.1111/j.1467789x.2006.00226.x. 3. shah s, anand p, maiya m, mukherjee s, munjal yp, wander gs, et al. indian hypertension guideline. in: munjal yp, ed. postgraduate medicine (recent advances in medicine). new delhi, india: ajanta offset & packagings ltd., 2007. pp. 315–25. 4. julius s, valentini m, palatini p. overweight and hypertension: a 2-way street? hypertension 2000; 35:807–13. doi: 10.1161/01. hyp.35.3.807. 5. engeli s, negrel r, sharma am. physiology and pathophysiology of the adipose tissue renin-angiotensin system. hypertension 2000; 35:1270–7. doi: 10.1161/01.hyp.35.6.1270. 6. rigat b, hubert c, corvol p, soubrier f. pcr detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (dcp1) (dipeptidylcarboxypeptidase 1). nucleic acids res. 1992; 20:1433. doi: 10.1093/nar/20.6.1433-a. 7. danser ah, schalekamp ma, bax wa, van den brink am, saxena pr, riegger ga, et al. angiotensin-converting enzyme in the human heart: effect of the deletion/insertion polymorphism. circulation 1995; 92:1387–8. doi: 10.1161/01. cir.92.6.1387. 8. javaid a, mansoor q, bilal n, bilal a, shaukat u, ismail m. ace gene dd genotype association with obesity in pakistani population. int j bioautomation 2011; 15:49–56. 9. hirata y, satonaka h. hypertension and oxidative stress. japan med assoc j 2001; 44:540–5. 10. hayes jd, flanagan ju, jowsey ir. glutathione transferases. annu rev pharmacol toxicol 2005; 45:51–88. doi: 10.1146/ annurev.pharmtox.45.120403.095857. 11. bid hk, konwar r, saxena m, chaudhari p, agrawal cg, banerjee m. association of glutathione s-transferase (gstm1, t1 and p1) gene polymorphisms with type 2 diabetes mellitus in north indian population. j postgrad med 2010; 56:176–81. doi: 10.4103/0022-3859.68633. 12. park ym, lee hj, kang sg, choi je, cho jh, kim l. lack of association between glutathione s-transferase-m1, -t1, and -p1 polymorphisms and olanzapine-induced weight gain in korean schizophrenic patients. psychiatry investig 2010; 7:147–52. doi: 10.4306/pi.2010.7.2.147. 13. warnick gr, knopp rh, fitzpatrick v, branson l. estimating low-density lipoprotein cholesterol by the friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. clin chem 1990; 36:15–19. 14. sambrook j, frisch ef, maniatis t, eds. molecular cloning: a laboratory manual, 2nd ed. new york, usa: cold sping harbor laboratory, 1989. pp. 9.14–19. 15. abbas s, raza st, chandra a, rizvi s, ahmed f, eba a, et al. association of ace, fabp2 and gst genes polymorphism with essential hypertension risk among a north indian population. ann hum biol 2015; 42:461–9. doi: 10.3109/03014460.2014.968206. 16. ruano m, silvestre v, castro r, garcía-lescún mc, rodríguez a, marco a, et al. morbid obesity, hypertensive disease and the renin-angiotensin-aldosterone axis. obes surg 2005; 15:670–6. doi: 10.1381/0960892053923734. 17. kidambi s, kotchen jm, grim ce, raff h, mao j, singh r, et al. association of adrenal steroids with hypertension and the metabolic syndrome in blacks. hypertension 2007; 49:704–11. doi: 10.1161/01.hyp.0000253258.36141.c7. 18. massiéra f, bloch-faure m, ceiler d, murakami k, fukamizu a, gasc jm, et al. adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. faseb j 2001; 15:2727–9. doi: 10.1096/fj.01-0457fje. 19. cooper r, mcfarlane-anderson n, bennett fi, wilks r, puras a, tewksbury d, et al. angiotensinogen and obesity: a potential pathway leading to hypertension. j hum hypertens 1997; 11:107–11. doi: 10.1038/sj.jhh.1000391. 20. ali a, alghasham a, ismail h, dowaidar m, settin a. ace i/d and enos e298d gene polymorphisms in saudi subjects with hypertension. j renin angiotensin aldosterone syst 2012; 14:348–53. doi: 10.1177/1470320312459976. 21. kim k. association of angiotensin-converting enzyme insertion/deletion polymorphism with obesity, cardiovascular risk factors and exercise-mediated changes in korean women. eur j appl physiol 2009; 105:879–87. doi: 10.1007/s00421-0080973-6. 22. passaro a, dalla nora e, marcello c, di vece f, morieri ml, sanz jm, et al. pparγ pro12ala and ace id polymorphisms are associated with bmi and fat distribution, but not metabolic syndrome. cardiovasc diabetol 2011; 10:112. doi: 10.1186/1475-2840-10-112. http://dx.doi.org/10.1161/01.atv.0000216787.85457.f3 http://dx.doi.org/10.1111/j.1467-789x.2006.00226.x http://dx.doi.org/10.1111/j.1467-789x.2006.00226.x http://dx.doi.org/10.1161/01.hyp.35.3.807 http://dx.doi.org/10.1161/01.hyp.35.3.807 http://dx.doi.org/10.1161/01.hyp.35.6.1270 http://dx.doi.org/10.1093/nar/20.6.1433-a http://dx.doi.org/10.1161/01.cir.92.6.1387 http://dx.doi.org/10.1161/01.cir.92.6.1387 http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095857 http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095857 http://dx.doi.org/10.4103/0022-3859.68633 http://dx.doi.org/10.4306/pi.2010.7.2.147 http://dx.doi.org/10.3109/03014460.2014.968206 http://dx.doi.org/10.1381/0960892053923734 http://dx.doi.org/10.1161/01.hyp.0000253258.36141.c7 http://dx.doi.org/10.1096/fj.01-0457fje http://dx.doi.org/10.1038/sj.jhh.1000391 http://dx.doi.org/10.1177/1470320312459976 http://dx.doi.org/10.1007/s00421-008-0973-6 http://dx.doi.org/10.1007/s00421-008-0973-6 http://dx.doi.org/10.1186/1475-2840-10-112 saliha rizvi, syed t. raza, zeba siddiqi, shania abbas and farzana mahdi clinical and basic research | e485 23. eisenmann jc, sarzynski ma, glenn k, rothschild m, heelan ka. ace i/d genotype, adiposity and blood pressure in children. cardiovasc diabetol 2009; 8:14. doi: 10.1186/14752840-8-14. 24. ludwig e, corneli ps, anderson jl, marshall hw, lalouel jm, ward rh. angiotensin-converting enzyme gene polymorphism is associated with myocardial infarction but not with development of coronary stenosis. circulation 1995; 91:2120–4. doi: 10.1161/01.cir.91.8.2120. 25. ismail m, akhtar n, nasir m, firasat s, ayub q, khaliq s. association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and essential hypertension in young pakistani patients. j biochem mol biol 2004; 37:552–5. doi: 10.5483/bmbrep.2004.37.5.552. 26. choudhury i, jothimalar r, patra ak. angiotensin converting enzyme gene polymorphism and its association with hypertension in south indian population. indian j clin biochem 2012; 27:265–9. doi: 10.1007/s12291-012-0217-8. 27. qu h, lu y, lin s. [meta-analysis on the association of ace/ id polymorphism and essential hypertension in chinese population.] zhonghua yu fang yi xue za zhi 2001; 35:408–11. 28. ramachandran v, ismail p, stanslas j, shamsudin n, moin s, mohd jas r. association of insertion/deletion polymorphism of angiotensin-converting enzyme gene with essential hypertension and type 2 diabetes mellitus in malaysian subjects. j renin angiotensin aldosterone syst 2008; 9:208‒14. doi: 10.1177/1470320308097499. 29. morshed m, khan h, akhteruzzaman s. association between angiotensin i-converting enzyme gene polymorphism and hypertension in selected individuals of the bangladeshi population. j biochem mol biol 2002; 35:251–4. doi: 10.5483/ bmbrep.2002.35.3.251. 30. eriksson jw. metabolic stress in insulin’s target cells leads to ros accumulation: a hypothetical common pathway causing insulin resistance. febs lett 2007; 581:3734–42. doi: 10.1016/j. febslet.2007.06.044. 31. duggan c, ballard-barbash r, baumgartner rn, baumgartner kb, bernstein l, mctiernan a. associations between null mutations in gstt1 and gstm1, the gstp1 ile(105)val polymorphism, and mortality in breast cancer survivors. springerplus 2013; 2:450. doi: 10.1186/2193-1801-2-450. 32. pinheiro ds, rocha filho cr, mundim ca, júnior pde m, ulhoa cj, reis aa, et al. evaluation of glutathione s-transferase gstm1 and gstt1 deletion polymorphisms on type-2 diabetes mellitus risk. plos one 2013; 8:e76262. doi: 10.1371/ journal.pone.0076262. 33. wang r, wang y, wang j, yang k. association of glutathione s-transferase t1 and m1 gene polymorphisms with ischemic stroke risk in the chinese han population. neural regen res 2012; 7:1420–7. doi: 10.3969/j.issn.1673-5374.2012.18.009. 34. kim sj, kim mg, kim ks, song js, yim sv, chung jh. impact of glutathione s-transferase m1 and t1 gene polymorphisms on the smoking-related coronary artery disease. j korean med sci 2008; 23:365–72. doi: 10.3346/jkms.2008.23.3.365. 35. hussain k, salah n, hussain s, hussain s. investigate the role of glutathione s transferase (gst) polymorphism in development of hypertension in uae population. iran red crescent med j 2012; 14:479–82. 36. lee bk, lee sj, joo js, cho ks, kim ns, kim hj. association of glutathione s-transferase genes (gstm1 and gstt1) polymorphisms with hypertension in lead-exposed workers. mol cell toxicol 2012; 8:203–8. doi: 10.1007/s13273-012-0025-5. http://dx.doi.org/10.1186/1475-2840-8-14 http://dx.doi.org/10.1186/1475-2840-8-14 http://dx.doi.org/10.1161/01.cir.91.8.2120 http://dx.doi.org/10.5483/bmbrep.2004.37.5.552 http://dx.doi.org/10.1007/s12291-012-0217-8 http://dx.doi.org/10.1177/1470320308097499 http://dx.doi.org/10.5483/bmbrep.2002.35.3.251 http://dx.doi.org/10.5483/bmbrep.2002.35.3.251 http://dx.doi.org/10.1016/j.febslet.2007.06.044 http://dx.doi.org/10.1016/j.febslet.2007.06.044 http://dx.doi.org/10.1186/2193-1801-2-450 http://dx.doi.org/10.1371/journal.pone.0076262 http://dx.doi.org/10.1371/journal.pone.0076262 http://dx.doi.org/10.3969/j.issn.1673-5374.2012.18.009 http://dx.doi.org/10.3346/jkms.2008.23.3.365 http://dx.doi.org/10.1007/s13273-012-0025-5 departments of 1medical laboratory sciences, faculty of allied health sciences and 3pathology and 4research & biostatistics unit, faculty of medicine, kuwait university, kuwait; 2cytology laboratory, mubarak al-kabeer hospital, kuwait *corresponding author’s e-mail: r.al-awadhi@hsc.edu.kw دراسة مدى انتشار العدوى امليكروبية يف مسحات عنق الرحم يف مستشفى مبارك الكبري، الكويت يف الفرتة مابني 2014–1997 رنا العو�شي، عزة ال�شاهني، اأحالم اجلوي�رس، �شارا �شرييل جورج، برم �شارما، كو�شوم كابيال abstract: objectives: this study aimed to examine gynaecological infectious agents observed in conventional and modified papanicolaou cervical smears (cs) at a tertiary care hospital in kuwait. methods: this retrospective study analysed 121,443 satisfactory cs samples collected between 1997–2014 at the mubarak al-kabeer hospital, kuwait. conventional cs samples were obtained between 1997–2005, while modified cs were obtained between 2006–2014 following the introduction of thinprep® testing (hologic corp., bedford, massachusetts, usa). all samples were initially screened by cytoscreeners before being analysed by cytopathologists to determine the presence of specific infectious agents. results: overall, 8,836 (7.28%) of the cervical samples had infectious agents; of these, 62.48% were conventional and 37.52% were modified cs samples. the most frequently observed infectious agents were candida species (76.05%), trichomonas vaginalis (9.72%), human papillomavirus (hpv; 9.3%), actinomyces-like organisms (3.23%), chlamydia trachomatis (1.27%) and the herpes simplex virus (hsv; 0.43%). there were significantly more cases of candida species, hpv-associated changes, c. trachomatis, t. vaginalis and actinomyces-like organisms detected in conventional compared to modified cs samples (p <0.050 each). however, there was no statistically significant difference in the frequency of hsv-associated changes (p = 0.938). the presence of two infectious agents in the same sample was identified in 0.87% of samples. conclusion: among cs samples collected during an 18-year period, candida species were most frequently detected, followed by t. vaginalis and hpv. the identification of potential infectious agents is a valuable additional benefit of papanicolaou smear testing. keywords: cervical smears; papanicolaou test; infection; candida; trichomonas vaginalis; human papilloma virus; cytology; kuwait. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل قيا�ص مدى انت�شار العدوى امليكروبية عند الن�شاء يف املسحات الإعتيادية لعنق الرحم مقارنة بعينات اللطخات امل�شبوغة ب�شبغة البابانيكولو واملاأخوذة بطريقة م�شتحدثة يف م�شت�شفى ثالثي املرجع يف دولة الكويت. الطريقة: مت جمع معلومات تتعلق بعينات للطاخات ماأخوذة �شابقًا يف الفرتة مابني 2014–1997، يبلغ عددها 121,443 عينة لعنق الرحم يف م�شت�شفى مبارك الكبري، الكويت، حيث اأخذت اللطاخات بالطريقة الإعتيادية من عام 1997 اإىل عام 2005 يف حني اأخذت العينات بالطريقة امل�شتحدثة يف الفرتة من 2006 اإىل 2014، وذلك بعد اإدخال اختبار اللطاخات ب�رسائح ®thinprep، مت فح�ص العينات مبدئيًا بوا�شطة فنيني خمت�شني باخلاليا ويف نهاية الأمر اأعد التقارير اأخ�شائيي علم الأمرا�ص واخلاليا للك�شف عن وجود عدوى ميكروبات حمددة يف عينات عنق الرحم امل�شببة لأمرا�ص عند الن�شاء. النتائج: ب�شكل عام، مت ك�شف وجود عوامل ميكروبية معدية يف 8,836 عينة لعنق الرحم )%7.28(، من هذه العينات كان هناك ن�شبة %62.48 من لطاخات الطريقة الإعتيادية ون�شبة %37.52 من عينات الطريق امل�شتحدثة، وكانت حالت العدوى امللحوظة والأكرث �شيوعًا هي من اأنواع فطريات امُلبي�شة )%76.05( وجرثومة امل�شعرات املهبلية )%9.72( وفريو�ص الورم احلليمي الب�رسي )%9.30( والكائن الدقيق امل�شابه جلرثومة ال�ُشعاعي )%3.23(، وجرثومة املتدثرة احلرثية )%1.27( وفريو�ص الهرب�ص الب�شيط )%0.43(. وقد لوحظ اأن هناك حالت عدوى بعوامل فطريات امُلبي�شة وفريو�ص الورم احلليمي الب�رسي وجرثومية امل�شعرات املهبلية والكائنات امل�شابهة جلرثومة ال�ُشعاعي اأكرث ب�شكل ملحوظ يف العينات امل�شتخرجة بالطرق العتيادية مقارنة بالطريقة امل�شتحدثة )p >0.050 لكل منها(، بينما ،)p = 0.938( ل يوجد فرق ملحوظ يف عدد حالت التي تظهر تغيريات تتعلق بفريو�ص الهرب�ص الب�شيط بني طريقتي ا�شتخال�ص املسحات من بني املسحات التي مت جمعها نف�ص العينة هي%0.87. اخلال�صة: ن�شبة ازدواجية نوعني من العدوية امليكروبية يف اإ�شافة لذلك فاإن خالل مدة 18 عامًا، كانت وجود فطريات امُلبي�شة هو الأكرث �شيوعًا من بني العوامل امليكروبية املعدية الأخرى، ويليها جرثومة امل�شعرات املهبلية ثم فريو�ص الورم احلليمي الب�رسي، كما اأن ك�شف هذه العوامل امليكروبية املعدية هي اأحد الإ�شافات املهمة التي ميكن اأن ت�شاف با�شتخدام مسحات ب�شبغة البابانيكولو. احلليمي الورم فريو�ص املهبلية؛ امل�شعرات جرثومة املبي�شة؛ فطر عدوى؛ البابانيكولو؛ فح�ص الرحم؛ عنق مسحات املفتاحية: الكلمات الب�رسي؛ علم اأمرا�ص اخلاليا؛ دولة الكويت. prevalence of infectious organisms observed in cervical smears between 1997–2014 at mubarak al-kabeer hospital, kuwait *rana al-awadhi,1 azza al-shaheen,2 ahlam al-juwaiser,2 sara s. george,3 prem sharma,4 kusum kapila3 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e324–328, epub. 19 dec 18 submitted 30 oct 17 revisions req. 28 dec 17, 18 feb & 18 mar 18; revisions recd. 24 jan, 21 feb & 22 mar 18 accepted 25 mar 18 doi: 10.18295/squmj.2018.18.03.010 rana al-awadhi, azza al-shaheen, ahlam al-juwaiser, sara s. george, prem sharma and kusum kapila clinical and basic research | e325 worldwide, most cervical screening programmes aim to detect cervical cancer at a pre-invasive stage. however, the bethesda system used to report gynaecological abnormalities also discloses other microscopic changes in cervical smears (cs), including inflammatory changes in epithelial cells caused by specific infectious agents.1 as such, the doc umentation of cervical organisms represents a valuable additional benefit of cervical cancer screening using papanicolaou (pap) smear tests. in kuwait, there is unfortunately no formal cervical cancer screening programme. in addition, the results of pap smears are not well studied, with most previous research originating from one centre, the mubarak alkabeer hospital, a tertiary care hospital which provides cytological diagnostic services to 15 hospitals, 27 clinics and multiple practitioners in kuwait.2–5 the purpose of this study was to determine and compare the prevalence of specific infectious agents in conventional and modified cs samples received over an 18-year period at the cytology laboratory of the mubarak al-kabeer hospital. methods this retrospective study reviewed 121,433 conventional and modified pap cs samples received between 1997–2014 at the cytology laboratory of the mubarak al-kabeer hospital. between 1997–2005, conventional cs samples were obtained, while modified cs samples were collected between 2006–2014 following the intro duction of thinprep® testing (hologic corp., bedford, massachusetts, usa). the cervical samples were obtained from women attending the outpatient obstetrics and gynaecology departments of general hospitals and clinics in kuwait with a wide spectrum of gynaecological complaints. all cs samples were screened and assessed for abnormalities according to the 2001 bethesda system guidelines.1 the cs slides were initially screened by cyto screeners before being analysed for specific infectious agents or benign or reactive cellular changes associated with inflammation by cytopathologists. specific infectious agents included the candida species, trichomonas vaginalis, actinomyces-like organisms, chlamydia trach omatis and changes associated with herpes simplex virus (hsv) and human papilloma-virus (hpv) infections. in addition, the cs samples were reported as either neg ative for intraepithelial lesions or malignancy (nilm) or positive for atypical squamous cells, atypical glandular cells, low-grade squamous intra-epithelial lesions (lsils) or high-grade squamous intra-epithelial lesions (hsils).1 the presence of normal vaginal flora (long rods or lactobacilli) or shifts in the overgrowth of mixed flora (i.e. bacterial vaginosis) were not evaluated. data were analysed using the statistical package for the social sciences (spss), version 16.0 (ibm corp., armonk, new york, usa). chi-squared or fisher’s exact tests were used to compare the proportions of infectious agents observed in the cs samples. a p value of <0.050 was considered statistically significant. ethical approval for this study was provided by the health science center of mubarak al-kabeer hospital (#vdr/ec/2310). all study procedures were performed in compliance with the ethical standards of the revised declaration of helsinki of 2008. results a total of 121,443 satisfactory cs samples were received during the study period. of these, 65,338 (53.8%) samples were conventional cs samples collected between 1997–2005 and 56,105 (46.2%) were modified thinprep® cs samples (hologic corp.) collected between 2006–2014. specific infectious agents were detected in 5,521 (8.45%) conventional and 3,315 (5.91%) modified cs samples, resulting in a total of 8,836 (7.28%) cs samples with infectious agents, of which 62.48% were conventional and 37.52% were modified cs samples. overall, fewer infectious agents were detected in modified cs samples compared to conventional cs samples [figure 1]. the most frequently identified infect ious organisms were candida species (76.05%), t. vaginalis (9.72%), hpv (9.3%), actinomyces-like organisms (3.23%), c. trachomatis (1.27%) and hsv (0.43%). in addition, 88.16% of cs samples with infectious agents were reported to be nilm. significantly more candida species, hpv-associated morphological changes, c. trachomatis, t. vaginalis and actinomyces-like organisms advances in knowledge this study identified potential infectious agents in papanicolaou cervical smear samples obtained using two different preparatory techniques. identifying potential infectious agents represents a valuable additional benefit of cervical smear testing. very few similar studies have been conducted in the gulf cooperative council (gcc) region, despite the relatively high incidence of low cervical neoplasia and human papillomavirus infections. application to patient care the results of this study may impact future gynaecological care in kuwait and other gcc countries, particularly in view of the relatively low rate of gynaecological examinations. prevalence of infectious organisms observed in cervical smears between 1997–2014 at mubarak al-kabeer hospital, kuwait e326 | squ medical journal, august 2018, volume 18, issue 3 table 1: gynaecological infectious agents observed in conventional and modified cervical smears received from 1997–2014 at the mubarak al-kabeer hospital, kuwait (n = 8,836) cytology diagnosis infectious organism, n (%) total candida species hpv chlamydia trachomatis trichomonas vaginalis actinomyces-like organisms hsv nilm 7,790 (88.16) 6,536 (97.26) 0 (0) 107 (95.54) 829 (96.51) 282 (98.95) 36 (94.74) conventional cs 4,915 (63.09) 4,041 (61.83) 0 (0) 87 (81.31) 565 (68.15) 200 (70.92) 22 (61.11) modified cs 2,875 (36.91) 2,495 (38.26) 0 (0) 20 (18.69) 264 (31.85) 82 (29.08) 14 (38.89) p value <0.001 <0.001 <0.001 0.002 0.007 0.944 agcs 19 (0.22) 15 (0.22) 0 (0) 0 (0) 3 (0.35) 1 (0.35) 0 (0) conventional cs 13 (68.42) 10 (66.67) 0 (0) 0 (0) 2 (66.67) 1 (100) 0 (0) modified cs 6 (31.58) 5 (33.33) 0 (0) 0 (0) 1 (33.33) 0 (0) 0 (0) p value 0.379 >0.999 0.585 ascs 139 (1.57) 117 (1.74) 0 (0) 3 (2.68) 18 (2.10) 1 (0.35) 0 (0) conventional cs 88 (63.31) 71 (60.68) 0 (0) 3 (100) 13 (72.22) 1 (100) 0 (0) modified cs 51 (36.69) 46 (39.32) 0 (0) 0 (0) 5 (27.78) 0 (0) 0 (0) p value 0.007 0.267 0.546 lsils 832 (9.42) 50 (0.74) 773 (94.04) 0 (0) 7 (0.81) 0 (0) 2 (5.26) conventional cs 467 (56.13) 34 (68) 428 (55.37) 0 (0) 4 (57.14) 0 (0) 1 (50) modified cs 365 (43.87) 16 (32) 345 (44.63) 0 (0) 3 (42.86) 0 (0) 1 (50) p value 0.686 0.101 0.196 0.755 0.584 hsils 56 (0.63) 2 (0.03) 49 (5.96) 2 (1.79) 2 (0.23) 1 (0.35) 0 (0) conventional cs 38 (67.86) 2 (100) 33 (67.35) 2 (100) 1 (50) 0 (0) 0 (0) modified cs 18 (32.14) 0 (0) 16 (32.65) 0 (0) 1 (50) 1 (100) 0 (0) p value 0.014 0.669 0.812 total 8,836 (100) 6,720 (76.05) 822 (9.3) 112 (1.27) 859 (9.72) 285 (3.23) 38 (0.43) conventional cs 5,521 (62.48) 4,158 (61.88) 461 (56.08) 92 (82.14) 585 (68.10) 202 (70.88) 23 (0.03) modified cs 3,315 (37.52) 2,562 (38.13) 361 (43.92) 20 (17.86) 274 (31.90) 83 (29.12) 15 (0.02) p value <0.001 0.046 <0.001 <0.001 <0.001 0.003 0.938 hpv = human papillomavirus; hsv = herpes simplex virus; nilm = negative for intraepithelial lesions and malignancy; cs = cervical smears; agcs = atypical glandular cells; ascs = atypical squamous cells; lsils = low-grade squamous intraepithelial lesions; hsils = high-grade squamous intraepithelial lesions. figure 1: prevalence of infectious agents observed in conventional and modified cervical smears received from 1997–2014 at the mubarak al-kabeer hospital, kuwait (n = 8,836). cs = cervical smear. rana al-awadhi, azza al-shaheen, ahlam al-juwaiser, sara s. george, prem sharma and kusum kapila clinical and basic research | e327 were detected in conventional compared to modified cs samples (p <0.050). no statistically significant difference was found between the two types of cs samples in relation to hsv (p = 0.938). a greater number of cases with hpv-associated morphological changes were detected in lsil samples than hsil samples (94.04% versus 5.96%); however, this difference was not significant (p = 0.196 and 0.669, respectively). nevertheless, when the number of cases with hpv-associated morphological changes in the lsil and hsil categories were comb ined, there was a significant difference between modified and conventional cs samples (p <0.001) [table 1]. a combination of two infectious agents was observed in 77 cases (0.87%), of which 67.53% were conventional and 32.47% were modified cs samples. among the conv entional cs samples, 84.62% involved a combination of candida species and another organism. overall, two infectious agents were most frequently detected in either nilm (49.35%) or lsil (48.05%) samples [table 2]. discussion in this study, common gynaecological infectious agents were encountered in 7.28% of cs samples collected between 1997–2014 at the mubarak al-kabeer hospital. in comparison, a previous study at the same hospital identified specific infectious agents in 15.2% of satisfactory cs samples collected between 2002–2007.4 these findings therefore indicate a 52.11% decrease in the number of specific organisms detected. this may be due to the implementation of the thinprep® technique (hologic corp.), which was only fully achieved in the last nine years of the study period. this assumption is supported by the results of the current study which indicated a drop in the number of specific infectious agents detected in modified compared to conventional cs samples (37.52% versus 62.48%). previous research has indicated that the incidence of infectious organisms in kuwait is 4.4% for samples that show cervical cancer or precancerous changes.5 this rate is similar to that of the low invasive cervical carcinoma risk estimate (4/100,000 cases annually) for kuwait and elsewhere in asia.6 additionally, malkawi et al. reported specific inflammation in only 4.8% of cs samples in jordan.7 in the current study, the most commonly identified infectious agents were candida species, followed by t. vaginalis, hpv, actinomyces-like organisms, c. trachomatis and hsv. a similar pattern was noted in other studies, wherein fungal agents were most prevalent, followed by trichomonas species.8–12 as mentioned earlier, the number of specific infectious agents detected was lower in modified compared to conventional cs samples; this reduction was noted in almost all infectious agents, except hsv. this finding has been supported by other researchers.8,13 at the mubarak al-kabeer hospital, the cytology laboratory employs in-house trained primary screeners whose work is monitored by senior checkers and a chief technician and all slides are signed off by medical practitioners, regardless of abnormalities. as such, differ ences in the detection rate of infectious agents in the present study were probably not due to the experience table 2: samples with a combination of two infectious agents observed in conventional and modified cervical smears received from 1997–2014 at the mubarak al-kabeer hospital, kuwait (n = 77) cytology diagnosis combination of infectious organisms, n (%) total conventional cs (n = 52) modified cs (n = 25) nilm 38 (49.35) 26 (50) 12 (48) candida species and trichomonas vaginalis 13 (34.21) 9 (34.62) 4 (33.33) candida species and actinomyceslike organisms 13 (34.21) 8 (30.77) 5 (41.67) candida species and chlamydia trachomatis 4 (10.53) 4 (15.38) 0 (0) candida species and hsv 4 (10.53) 3 (11.54) 1 (8.33) trichomonas vaginalis and actinomyces like organisms 3 (7.89) 2 (7.69) 1 (8.33) trichomonas vaginalis and hsv 1 (2.63) 0 (0) 1 (8.33) ascs 1 (1.30) 1 (1.92) 0 (0) candida species and trichomonas vaginalis 1 (100) 1 (100) 0 (0) lsils 37 (48.05) 24 (46.15) 13 (52) hpv and candida species 31 (83.78) 20 (83.33) 11 (84.62) hpv and trichomonas vaginalis 4 (10.81) 2 (8.33) 2 (15.38) hpv and actinomyces-like organisms 1 (2.7) 1 (4.17) 0 (0) hpv and hsv 1 (2.7) 1 (4.17) 0 (0) hsils 1 (1.3) 1 (1.92) 0 (0) hpv and trichomonas vaginalis 1 (100) 1 (100) 0 (0) cs = cervical smears; nilm = negative for intraepithelial lesions and malignancy; hsv = herpes simplex virus; ascs = atypical squamous cells; lsils = low -grade squamous intraepithelial lesions; hpv = human papillomavirus; hsils = high-grade squamous intraepithelial lesions. prevalence of infectious organisms observed in cervical smears between 1997–2014 at mubarak al-kabeer hospital, kuwait e328 | squ medical journal, august 2018, volume 18, issue 3 of the screeners. in addition, the cost of preparation was unlikely to have influenced the results as both convent ional and modified samples were collected and examined free of charge. furthermore, the number of hospitals and clinics providing conventional or modified cs services has remained the same for over 20 years, with all centres utilising both techniques. nevertheless, the difference in the number of infectious agents detected in convent ional and modified cs samples could be due to technical aspects related to the fixative used or the preparation of the modified samples, which may have caused the screener to overlook infectious agents. the fixative could cause shrinkage and therefore the inaccurate identification of organisms in the sample. in addition, filtration could result in a cleaner background and a reduction in inflammatory cell features.13 few studies have focused on hpv distribution in middle eastern countries. in the current study, most hpv infections were detected in lsil samples. in a prev ious study of modified cs samples collected from women with abnormal cervical cytology in kuwait, 89% and 67% of samples diagnosed as lsil and hsil, respectively, were infected with hpv type 16, the most common high risk genotype.14 another study in kuwait also showed high-risk hpv dna in women with squamous intra epithelial lesions, indicating that the viral load was directly related to the severity of the cervical lesions.15 conclusion this study described the prevalence of specific infectious agents identified in conventional and modified cs samples collected over an 18-year period at the mubarak al-kabeer hospital. the identification of potential infectious agents represents a valuable additional benefit of cervical sampling using pap smear tests; however, it cannot substitute other definitive diagnostic methods. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. solomon d, davey d, kurman r, moriarty a, o’connor d, prey m, et al. the 2001 bethesda system: terminology for reporting results of cervical cytology. jama 2002; 287:2114–19. doi: 10.1001/ jama.287.16.2114. 2. luthra uk, chishti m, dey p, jolly sv, abdulla m, das dk, et al. performance of monolayered cervical smears in a gynecology outpatient setting in kuwait. acta cytol 2002; 46:303–10. doi: 10.11 59/000326726. 3. kapila k, george ss, al-shaheen a, al-ottibi ms, pathan sk, sheikh za, et al. changing spectrum of squamous cell abnormalities observed on papanicolaou smears in mubarak al-kabeer hospital, kuwait, over a 13-year period. med princ pract 2006; 15:253–9. doi: 10.1159/000092986. 4. al-awadhi r, al-ramadan ba, george ss, sharma pn, kapila k. gynecologic infections seen in cervical smears in kuwait. acta cytol 2010; 54:50–4. doi: 10.1159/000324966. 5. kapila k, sharma pn, george ss, al-shaheen a, al-juwaiser a, al-awadhi r. trends in epithelial cell abnormalities observed on cervical smears over a 21-year period in a tertiary care hospital in kuwait. sultan qaboos univ med j 2015; 15:e112–15. 6. curado mp, edwards b, shin hr, storm h, ferlay j, heanue m, et al. cancer incidence in five continents: volume ix. iarc sci publ 2008; 160:1–837. 7. malkawi sr, abu hazeem rm, hajjat bm, hajjiri fk. evaluation of cervical smears at king hussein medical centre, jordan, over three and a half years. east mediterr health j 2004; 10:676–9. 8. othman n, othman nh. adequacy of cellular material in splitsampling of cervical scrapings for routine cancer screening: an analysis of 702 smears. malays j pathol 2012; 34:115–21. 9. zhou h, jia y, shen j, wang s, li x, yang r, et al. gynecologic infections seen in thinprep cytological test in wuhan, china. front med 2014; 8:236–40. doi: 10.1007/s11684-014-0322-6. 10. haltas h, bayrak r, yenidunya s. to determine of the prevalence of bacterial vaginosis, candida sp, mixed infections (bacterial vaginosis + candida sp), trichomonas vaginalis, actinomyces sp in turkish women from ankara, turkey. ginekol pol 2012; 83:744–8. 11. salih mm, alhag ft, khalifa ma, el nabi ah. cervical cytopathological changes among women with vaginal discharge attending teaching hospital. j cytol 2017; 34:90–4. doi: 10.4103/ joc.joc_214_15. 12. vieira-baptista p, grinceviciene s, bellen g, sousa c, saldanha c, broeck dv, et al. genital tract infections in an isolated community: 100 women of the príncipe island. infect dis obstet gynecol 2017; 2017:3058569. doi: 10.1155/2017/3058569. 13. henderson s, stevens m, walker t. rapid review of liquid-based smears as a quality control measure. diagn cytopathol 2004; 31:141–6. doi: 10.1002/dc.20091. 14. al-awadhi r, chehadeh w, jaragh m, al-shaheen a, sharma p, kapila k. distribution of human papillomavirus among women with abnormal cervical cytology in kuwait. diagn cytopathol 2013; 41:107–14. doi: 10.1002/dc.21778. 15. george ss, luthra uk, chishti m, shaheen aa, george j. distribution of human papillomaviruses in women. med princ pract 2000; 9:106–12. doi: 10.1159/000026126. https://doi.org/10.1001/jama.287.16.2114 https://doi.org/10.1001/jama.287.16.2114 https://doi.org/10.1159/000326726 https://doi.org/10.1159/000326726 https://doi.org/10.1159/000092986 https://doi.org/10.1159/000324966 https://doi.org/10.1007/s11684-014-0322-6 https://doi.org/10.4103/joc.joc_214_15 https://doi.org/10.4103/joc.joc_214_15 https://doi.org/10.1155/2017/3058569 https://doi.org/10.1002/dc.20091 https://doi.org/10.1002/dc.21778 https://doi.org/10.1159/000026126 although patients admitted to emerg-ency departments often suffer from chest pain, the actual incidence of acute myocardial infarction is relatively low (approximately 2–3%).1,2 the rupture of a papillary muscle is a rare but generally fatal mechanical complication; it is found in 0.5–5% of patients with acute myocardial infarctions.3,4 diagnosing an acute myocardial infarction becomes even more difficult if there is no evidence of acute ischaemia on an electrocardiogram and if echocardiography indicates no regional wall motion abnormalities. one of the current major challenges in emergency medicine is the rapid identification of these patients so as to treat them promptly with appropriate cardiac interventions. this report describes a rare case of severe ischaemic papillary muscle rupture diagnosed via transoesophageal echocardiography. case report a 67-year-old male was admitted to the emergency department of the university hospital bern in switzerland in november 2013 with dyspnoea at rest and a one-hour history of chest pains radiating down both arms. when the ambulance arrived, his oxygen saturation in room air was 84%. during transport to the hospital, the patient became hypotensive (blood pressure: 70/50 mmhg). the patient’s only known cardiovascular risk factor was a history of smoking cigarettes and he reported that he was not currently taking any regular medications. on arrival to the emergency department, the patient’s blood pressure had reduced to 60/40 mmhg. he had a pulse of 110 beats per minute, a respiratory rate of 20 breaths per minute and his oxygen saturation was 96% after the emergency department, university hospital bern, switzerland *corresponding author e-mail: christian.braun@insel.ch تشخيص عسري لتمزق إفقاري يف العضلة احلليمية تقرير حالة من قسم حضري لطب الطوارئ كري�ستيان براون، مرييت ريكلني، اري�ستومين�س اك�ساداكوتلو�س abstract: we present a rare case of severe ischaemic papillary muscle rupture in a 67-year-old male patient who was admitted to the emergency department of the university hospital bern, switzerland, in november 2013 with acute chest pain. on admission, the patient’s blood pressure was 60/40 mm/hg, his pulse was 110 beats per minute and his respiratory rate was 20 breaths per minute. an electrocardiogram was normal and focused assessment with sonography in trauma was negative. transthoracic echocardiography showed possible thickening of the mitral valve leaflet with no indications of severe mitral insufficiency or wall motion abnormalities. triple-ruleout computed tomography angiography revealed no pulmonary emboli or aortic dissection, although coronary atherosclerosis was present. finally, severe insufficiency of the mitral valve with rupture of the papillary muscle, likely due to ischaemia, was observed via transoesophageal echocardiography. the patient underwent a successful surgical intervention and was discharged 10 days later in stable condition. keywords: emergency medicine; shock; myocardial infarction; papillary muscles; heart rupture; echocardiography; case report; switzerland. يف الطوارئ طب لق�سم اأدخل عاما 67 عمره مري�س عند الإقفارية احلليمية الع�سلة لتمزق وحادة نادرة حالة هنا نعر�س امللخ�ص: امل�ست�سفى اجلامعي مبدينة برين يف �سوي�رسا يف نوفمرب 2013م ب�سبب اأمل حاد يف �سدره. وكان �سغط دمه عند اإدخاله للم�ست�سفى 60/40 التخطيط وتقييم طبيعيا، لديه القلب ر�سم وكان الدقيقة. يف مرة 20 تنف�سه ومعدل الدقيقة، يف �رسبة 110 نب�سه ومعدل زئبق، ملم الت�سواتي �سلبيا. واأو�سح تخطيط �سدى القلب عرب ال�سدر اإمكانية حدوث ثخن يف وريقة ال�سمام املرتايل من غري وجود اإ�سارات اإىل حدوث ق�سور مرتايل وخيم، اأو اعتاللت يف حركة اجلدار. واأو�سح ت�سوير الأوعية بوا�سطة الت�سوير املقطعي املحو�سب اأنه ل توجد ان�سمامات رئوية اأو ت�سلخ اأبهري، رغم وجود ت�سلب يف ال�رسايني التاجية. واأخريا مت اكت�ساف وجود ق�سور وخيم يف ال�سمام املرتايل مع متزق اإقفاري يف الع�سلة احلليمية، غالبا ما تكون قد حدثت ب�سبب الإفقار )نق�س الرتوية(، وذلك بوا�سطة تخطيط �سدى القلب عرب املريء. ومت اجراء تدخل جراحي ناجح للمري�س، ومت تخريجه من امل�ست�سفى عقب ا�ستقرار حالته بعد ع�رسة اأيام من اجراء تلك العملية. كلمات مفتاحية: طب الطوارئ؛ ال�سدمة؛ احت�ساء ع�سلة القلب؛ الع�سالت احلليمية؛ متزق القلب؛ تخطيط �سدى القلب؛ تقرير حالة؛ �سوي�رسا. the difficult diagnosis of ischaemic papillary muscle rupture case report from an urban emergency department *christian t. braun, meret e. ricklin, aristomenis k. exadaktylos case report sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 234–237, epub. 15 may 16 submitted 21 jul 15 revisions req. 23 aug & 1 sep 15; revisions recd. 24 aug & 10 sep 15 accepted 8 oct 15 doi: 10.18295/squmj.2016.16.02.016 christian t. braun, meret e. ricklin and aristomenis k. exadaktylos case report | e235 administration of 2 l of oxygen. his temperature was 36.8 °c and consciousness was measured at level 14 of the glasgow coma scale. a physical examination of the patient on arrival indicated regular heart sounds with a systolic murmur; the heart sounds were heard most clearly above erb’s point. auscultation of the lung, examination of the abdomen and a preliminary neurological examination were all normal. an electrocardiogram was normal with no evidence of acute ischaemia. focused assessment with sonography in trauma was negative. transthoracic echocardiography performed by cardiologists revealed a thickened mitral valve leaflet with mild mitral insufficiency and, most importantly, no wall motion abnormalities or pericardial effusion [figure 1]. the left ventricular ejection fraction was estimated to be 65%. creatine kinase (1,319 u/l; normal value: <190 u/l), creatine phosphokinase-mb (119.2 µg/l; normal value: <4.9 µg/l) and high-sensitivity cardiac troponin t (2.150 µg/l; normal value: <0.014 µg/l) levels were all substantially elevated. although the patient was becoming increasingly haemodynamically unstable, the diagnosis remained unclear. consequently, triplerule-out computed tomography was performed. no evidence of pulmonary emboli or aortic dissection was noted, although there were signs of general coronary atherosclerosis with plaques and without any luminal occlusion. the scan also revealed an infiltrate in the left upper lobe, perhaps due to aspiration pneumonia, with a small amount of left pleural effusion. after diagnostic and laboratory testing, the patient was prescribed vasopressin before being intubated and receiving analgaesics. he was in a progressively unstable state and was re-evaluated by an interdisciplinary team, including intensive care physicians, cardiologists and emergency physicians. although there were marked increases in heart enzymes, due to the lack of segmental wall motion abnormalities on transthoracic echocardiography, a coronary angiogram was not immediately performed. the patient was transferred to the intensive care ward for further monitoring. while there, he rapidly developed cardiogenic shock and it was not possible to stabilise him. as a result, transoesophageal echocardiography was performed. this demonstrated severe mitral valve insufficiency with rupture of the papillary muscle, dilatation of the left atrium and severe secondary pulmonary hypertension. the left ventricular ejection fraction remained the same (65%) and there were still no signs of any regional wall motion abnormalities [table 1]. a coronary angiograph was subsequently carried out which showed that the papillary muscle rupture was caused by a distally occluded right coronary artery (rca). as the patient remained unstable, cardiac surgery was performed. the mitral valve was replaced with a biological prosthesis and a coronary artery bypass graft was undertaken. the postoperative course was uneventful and the patient was discharged in a stable condition 10 days later. discussion this report presents an unusual case of ischaemic papillary muscle rupture. firstly, it is rare for cardiogenic shock to develop only a few hours after the onset of symptoms; the highest risk of shock is normally two to seven days after the myocardial infarction, when healing has begun.5 in this particular table 1: comparison of transthoracic and transoesophageal echocardiographic findings for a 67-year-old male patient with ischaemic papillary muscle rupture finding tte toe left ventricular ef normal normal regional wall motion abnormalities none none pericardial effusion none none papillary muscle rupture thickened mitral valve leaflet thickened mitral valve leaflet and rupture of the papillary muscle mitral valve regurgitation* mild insufficiency† severe insufficiency‡ left atrium no dilatation dilatation and severe secondary pulmonary hypertension tte = transthoracic echocardiography; toe = transoesophageal echocardiography; ef = ejection fraction. *using colour doppler imaging. †small jet of mitral regurgitation. ‡large eccentric jet of mitral regurgitation. figure 1: transthoracic echocardiography showing a thickened posterolateral mitral leaflet (arrow) in a 67-year-old male patient with ischaemic papillary muscle rupture. note the lack of wall motion abnormalities or pericardial effusion. the difficult diagnosis of ischaemic papillary muscle rupture case report from an urban emergency department e236 | squ medical journal, may 2016, volume 16, issue 2 patients.10 however, monin et al. found that only 5% of patients required transoesophageal echocardiography to adequately quantify the severity of mitral insufficiency.11 transthoracic echocardiography is therefore an appropriate first-line imaging modality and transoesophageal echocardiography should be reserved for patients with poor-quality transthoracic images or those with continued deterioration and an unclear diagnosis. conclusion corresponding with previous findings in the literature, the current case report supports the view that transoesophageal echocardiography is a valuable tool to confirm the diagnosis of ischaemic papillary muscle rupture. in these cases, several diagnostic measures may often be needed. as such, the utilisation of transoesophageal, rather than transthoracic, echocardiography may lead to a life-saving diagnosis for patients who are cardiovascularly unstable. references 1. cherian ps, clarke aj, burstow dj. unusual case of acute posteromedial papillary muscle rupture after acute anterior myocardial infarction. heart lung circ 2014; 23:e16–19. doi: 10.1016/j.hlc.2013.07.005. 2. bayley md, schwartz js, shofer fs, weiner m, sites fd, traber kb, et al. the financial burden of emergency department congestion and hospital crowding for chest pain patients awaiting admission. ann emerg med 2005; 45:110–17. doi: 10.1016/j. annemergmed.2004.09.010. 3. christ g, siostrzonek p, maurer g, baumgartner h. partial papillary muscle rupture complicating acute myocardial infarction: diagnosis by multiplane transoesophageal echocardiography. eur heart j 1995; 16:1736–8. 4. wei jy, hutchins gm, bulkley bh. papillary muscle rupture in fatal acute myocardial infarction: a potentially treatable form of cardiogenic shock. ann intern med 1979; 90:149–52. doi: 10.7326/0003-4819-90-2-149. 5. thompson cr, buller ce, sleeper la, antonelli ta, webb jg, jaber wa, et al. cardiogenic shock due to acute severe mitral regurgitation complicating acute myocardial infarction: a report from the shock trial registry should we use emergently revascularize occluded coronaries in cardiogenic shock? j am coll cardiol 2000; 36:1104–9. 6. czarnecki a, thakrar a, fang t, lytwyn m, ahmadie r, pascoe e, et al. acute severe mitral regurgitation: consideration of papillary muscle architecture. cardiovasc ultrasound 2008; 18:6:5. doi: 10.1186/1476-7120-6-5. 7. schroeter t, lehmann s, misfeld m, borger m, subramanian s, mohr fw, et al. clinical outcome after mitral valve surgery due to ischemic papillary muscle rupture. ann thorac surg 2013; 95:820–4. doi: 10.1016/j.athoracsur.2012.10.050. 8. bouma w, wijdh-den hamer ij, koene bm, kuijpers m, natour e, erasmus me, et al. predictors of in-hospital mortality after mitral valve surgery for post-myocardial infarction papillary muscle rupture. j cardiothorac surg 2014; 9:171 doi: 10.1186/ s13019-014-0171-z. case, the short interval of time could potentially be explained by a silent ischaemic event occurring one or two days previously. alternatively, the papillary muscle may have already been affected for some unrelated reason.6 secondly, the lack of regional wall motion abnormalities is an uncommon finding, particularly in a hypotensive patient; the only possible explanation for this would be an acute papillary muscle rupture with severe acute mitral regurgitation. as in this case, the posteromedial papillary muscle is often affected during a myocardial infarction in the area perfused by the rca; in comparison, the anterolateral papillary muscle has a dual blood supply and therefore very rarely exhibits ischaemic complications.1 thirdly, it is rare for cases of papillary muscle rupture with severe mitral regurgitation to have an uncomplicated postoperative course, as observed with the current patient. this condition usually carries a high mortality rate; schroeter et al. determined a 30-day postoperative mortality rate of 39.3%, while another study reported rates of 4.2% and 25.0% for intraoperative and in-hospital mortality, respectively.7,8 echocardiography is the imaging modality of choice for the non-invasive assessment of mechanical cardiac complications such as acute mitral regurgitation in the setting of a myocardial infarction.6 in these cases, the appearance of mitral regurgitation, often in relation to papillary muscle rupture, is an important sign of poor prognosis.9 consequently, echocardiography plays an essential role in the early diagnosis, estimation of severity and determination of the pathomechanisms of ischaemic mitral regurgitation in patients with acute myocardial infarctions.9 transoesphageal echocardiography has been well established as the initial diagnostic tool for identifying papillary muscle rupture, with a diagnostic sensitivity of 65–85%.6 due to the close proximity of the ultrasound transducer to the mitral apparatus, transoesophageal echocardiography is often used to improve reliability when diagnosing the cause of mitral regurgitation; it has been found to increase the diagnostic yield to approximately 95–100%.10 christ et al. described a case of partial papillary muscle rupture diagnosed solely by transoesophageal echocardiography; previous transthoracic echocardiographs had shown no pathologies or only posterior mitral leaflet prolapse.3 similar experiences have been reported for patients with acute septal ruptures in the acute stage of a myocardial infarction. maillier et al. found that only eight out of 15 septal ruptures could be visualised directly by conventional transthoracic echocardiography; in contrast, transoesophageal echocardiography successfully diagnosed 14 of the same http://dx.doi.org/10.1016/j.hlc.2013.07.005 http://dx.doi.org/10.1016/j.annemergmed.2004.09.010 http://dx.doi.org/10.1016/j.annemergmed.2004.09.010 http://dx.doi.org/10.7326/0003-4819-90-2-149 http://dx.doi.org/10.1186/1476-7120-6-5 http://dx.doi.org/10.1016/j.athoracsur.2012.10.050 http://dx.doi.org/10.1186/s13019-014-0171-z http://dx.doi.org/10.1186/s13019-014-0171-z christian t. braun, meret e. ricklin and aristomenis k. exadaktylos case report | e237 9. petris ao, iliescu d, alexandrescu dm, costache ii. ischemic mitral regurgitation in patients with acute myocardial infarction. rev med chir soc med nat iasi 2014; 118:618–23. 10. maillier b, metz d, nazeyrollas p, maes d, chapoutot l, jennesseaux c, et al. [value of transesophageal echocardiography in post-infarction septal ruptures.] arch mal coeur vaiss 1996; 89:695–702. 11. monin jl, dehant p, roiron c, monchi m, tabet jy, clerc p, et al. functional assessment of mitral regurgitation by transthoracic echocardiography using standardized imaging planes: diagnostic accuracy and outcome implications. j am coll cardiol 2005; 46:302–9. doi: 10.1016/j.jacc.2005.03.064. http://dx.doi.org/10.1016/j.jacc.2005.03.064 sir, in 1992, the usa food and drug administration (fda) issued a warning in the scoline® (suxamethonium chloride, glaxosmithkline, usa) package insert after receiving reports of intractable cardiac arrests.1 it stated: “since there may be no signs or symptoms to alert the practitioner as to which patients are at risk, it is recommended that the use of succinylcholine in children should be reserved for emergency intubation or instances where immediate securing of the airway is necessary, e.g. laryngospasm, difficult airway, full stomach or intramuscular (im) use when a suitable vein is inaccessible.” scoline® has been used for rapid sequence tracheal intubation since its introduction into clinical practice in europe in 1951 and in the usa in 1952.2 it gained popularity for its quick onset (less than 60 seconds) and ultrashort duration of action. scoline® came to rule the practice of anaesthesia and continues to do so even today. it is the gold standard against which the other muscle relaxants are compared;3 however, a number of clinical case reports have shown clearly that the use of scoline has been associated with a number of serious adverse effects4,5 and its use has declined since 1992. in our hospital, there have been cases (unpublished reports) of prolonged apnoea and trismus following scoline use. since it is not possible to predict at the outset which patient will have prolonged apnoea unless a family history is available, is it prudent to use scoline in cases of anticipated difficult intubation? cardiac arrests after scoline® use have been reported in japan in pregnant patients who had been immobilised due to concern about preterm labour.6 a couple of reports even mention that the use of scoline® led to a ‘can’t ventilate and can’t intubate’ situation due to severe trismus in an emergency,7,8 and even following attempts at routine intubation.9 are these adverse effects acceptable in current day practice of medicine and anaesthesia? for the quick onset of relaxation of vocal cords, rocuronium bromide, a non-depolarising muscle relaxant, is available (esmeron® n.v. organon, oss, netherlands). it was introduced in clinical practice in 1994 and has been used in many countries for the last 17 years. it belongs to the aminosteroid group and studies show that it achieves rapid onset of good intubating conditions within 60 seconds if a dose of 1.2 mg /kg is given intravenously.10-13 in patients for whom intravenous access is not available it can even be administered intramuscularly.14 it has been safely administered in the paediatric age group from 1–24 months of age.15 when comparing the intubating conditions between rocuronium and scoline®, the cochrane database meta-analysis found that rocuronium is less effective than succinylcholine for creating excellent intubation conditions and recommended that rocuronium should therefore only be used as an alternative to succinylcholine when it is known that succinylcholine should not be used.16 however, in an emergency situation it is not known and cannot be predicted which patient will have an adverse reaction to scoline®.6-8 on reviewing and comparing the overall safety and efficacy profile, rocuronium has not shown any of the serious adverse reactions seen with scoline. it is even used safely in asthmatic patients.17 the only adverse reaction is hypersensitivity, but the overall incidence is not more than scoline®, or other non-depolarising muscle relaxants. the main concern with rocuronium has been the long duration of action.18 the possibility of awakening the patients in case of an inability to ventilate was the main reason preventing the use of this drug for rapid sequence intubation. with the availability of sugammadex sodium (bridion®, schering-plough merck, usa) this should no longer be a barrier to using rocuronium. it has been recommended to the cardiac anaesthesiologist for clinical use for high risk patients at appropriate doses.21 sugammadex is a cyclodextrin derivative which seems to squ med j, november 2011, vol. 11, iss. 4, pp. 524-526, epub. 25th oct 11 submitted 26th apr 11 accepted 7th sep 11 أما آن األوان لوقف استخدام السكولني يف التنبيب السريع؟ is it not the time to stop the use of scoline® (suxamethonium chloride) for rapid sequence intubation? letter to editor sangeet narang letter to editor | 525 provide a faster onset-offset profile than that seen with 1.0 mg/kg succinylcholine.20 this drug has even been used as an antidote to the muscle relaxant in case of a hypersensitivity reaction.19 it was approved for clinical use by the european medicines agency in 2008.22 it awaits fda approval in the usa due to concerns about its hypersensitivity, but there is no concern about its efficacy.21 nowadays, we have intubating laryngeal mask airway (ilma), proseal airway and gum elastic bougie for securing the airway in case intubation is difficult. we would not like any patient to develop severe trismus and make the possibility of ventilating difficult or even impossible in an emergency situation. therefore the time has now come to reconsider the recommendations and indeed to discontinue the use of scoline® for rapid sequence intubation. c o n f l i c t o f i n t e r e s t the author has declared no conflict of interest and is in no way influenced by the manufacturers of any drug mentioned in this letter. sangeet narang department of anesthesia & icu, nizwa hospital, nizwa, oman. email: sangeet@omantel.net.om references 1. rosenberg h, gronet ga. intractable cardiac arrests in children given scoline. anesthesiology 1992; 77:1054–6. 2. foldes ff, mcnall pg, borrego-hinojosa jm. succinylcholine: a new approach to muscular relaxation in anesthesiology. new engl j med 1952; 247:596–600. 3. savarese jj, caldwell je. pharamacology of muscle relaxants and their antagonists. in: miller rd, cuccharia rf, miller ed, geral reves j, roizen mf, savarese jj, eds. 5th ed. philadelphia, pa: churchill livingstone-elsevier, 2000. vol. 1, pp. 419–26. 4. wang jm, stanley th. duchenne muscular dystrophy and malignant hyperthermia: two case reports. can anesth soc j 1986; 33:492–7. 5. wu cc, tseng cs, shen ch, yang tc, chi kp, ho wm. succinylcholine induced cardiac arrest in children with unsuspected beck muscular dystrophy: a case report. acta anaesthesiolog sin 1998; 36:165–8. 6. sato k, nishiwaki k, kuno n, kumagai k, kitamura h, yano k, et al. unanticipated hyperkalemia following succinylcholine administration in prolonged immobilized parturients treated with magnesium and ritodrine. anesthesiology 2000; 93:1539–41. 7. bauer sj, orio k, adams bd. succinylcholine induced masseter spasm during rsqi may require a surgical airway. emerg med j 2005; 22:456–8. 8. gill m, graeme k, guenterberg k. masseter spasm after succinylcholine administration. j emerg med 2005; 29:167– 71. 9. onyeka tcu. masseter muscle rigidity: atypical malignant hyperthermia presentation or isolated event? saudi j anaesth 2010; 4:205–6. 10. mccourt kc, salmela l, mirakhur rk, carrol m, miakinen mt, kansanaho m, et al. comparison of rocuronium and suxamethonium for use during rapid sequence induction of anesthesia. anaesthesia 1998; 53:867–71. 11. andrews ji, kumar n,van den brom rhg, olkkola kt, roest gj, wright pmc, et al. a large simple randomized trial of rocuronium versus succinylchoine in rapid-sequence induction of anesthesia along with propofol. acta anaesthesiol scand 1999; 43:4–8. 12. heier t, caldwell je. rapid tracheal intubation with large dose rocuronium: a probability based approach. anesth analg 2000; 90:175–9. 13. larsen pb, hansen eg, jacobsen ls, wiis j, holst p, rottensten h, et al. intubation conditions after rocuronium or succinylcholine for rapid sequence induction with alfentanil and propofol in the emergency patient. eur j anesthesiol 2005; 22:748–53. 14. reynolds lm, lau m, brown r, luks a, fisher dm. intramuscular rocuronium in infants and children: dose ranging and tracheal intubating conditions. anesthesiology 1996; 85:231. is it not the time to stop the use of scoline® (suxamethonium chloride) for rapid sequence intubation? 526 | squ medical journal, november 2011, volume 11, issue 4 15. devys jm, mourissoux g, donnette fx, platt r, schauvliège f, le bigot p, et al. intubating conditions and adverse events during sevoflurane induction in children. br j anaesthes 2011; 106:225–9. 16. perry jj, lee js, sillberg vah, wells ga. rocuronium versus succinylcholine for rapid sequence induction intubation. cochrane database syst rev 2008; 2:cd002788. doi: 10.1002/14651858.cd002788 .pub2. 17. burburan sm, xisto dg, rocco prm. anaesthetic management in asthma. minerva anestesiol 2007; 73:357–65. 18. claudius c, karacan h, viby-mogensen j. prolonged residual paralysis after a single intubating dose of rocuronium. br j anaesth 2007; 99:514–7. 19. mcdonnell nj, pavy tjg, green lk, platt pr. sugammadex in the management of rocuronium-induced anaphylaxis. br janaesthes 2011; 106:199–201. 20. lee c, jahr js, candiotti k, warriner b, zorrow mh. reversal of profound nmb with sugammadex is faster than recovery from succinylcholine. anesthesiology 2007; 107:a988. 21. hemmerling tm, zaouter c, geldner g, nauheimer d. sugammadex a short review and clinical recommendations for the cardiac anesthesiologist. ann card anaesth 2010; 13:206–16. 22. bridion r. sugammadex injection first and only selective relaxant binding agent approved in european union. schering-plough press release: 2008-07-29. from: http://www.schering-plough.com/schering_plough/news/release. jsp?releaseid=1180933. accessed: aug 2008. paediatric intensive care unit, royal hospital, muscat, oman *corresponding author e-mail: abushatha50@hotmail.com الشلل احلجايب ثنائي اجلانب عقب جراحة قلبية يف األطفال جتربة أربع حاالت يف املستشفى السلطاين، مسقط، عمان �سعيد علي م�سعود احلن�سي و حممد حمد را�سد الغافري abstract: bilateral diaphragmatic paralysis (bdp) is a rare complication of paediatric cardiac surgery. we report four children who developed bdp following cardiac surgery who were managed at the royal hospital, muscat, oman, between 2009 and 2014. all four children suffered severe respiratory distress soon after extubation and required re-intubation within two hours. in addition, all of the children underwent a tracheostomy as an interim method for ventilation. the four children were successfully weaned from positive pressure ventilation following the functional recovery of at least one side of the diaphragm. keywords: diaphragmatic paralysis; heart disease; cardiac surgical procedures; paediatrics; case series; oman. امللخ�ص: يعد ال�سلل احلجابي ثنائي اجلانب من امل�ساعفات النادرة يف جراحة القلب عند االأطفال. ون�ستعر�ص هنا اأربع حاالت الأطفال 2009 عامي بني عمان يف مب�سقط ال�سلطاين امل�ست�سفى يف عالجهم مت القلب، يف جراحة بعد اجلانب ثنائي احلجابي بال�سلل اأ�سيبوا �ساعتني. خالل التنبيب اإعادة من مطلوبا كان وما االأنبوب، نزع مبجرد �سديدة تنف�سية �سائقة من االأربعة االأطفال عانى 2014م. و وباالإ�سافة اإىل ذلك اأجريت لهوؤالء االأطفال عملية فغر الرغامي كطريقة موؤقتة للتهوية. ومت فطم االأطفال االأربعة بنجاح من تهوية ال�سغط االإيجابي بعد اأن ا�ستعيدت وظيفة جانب واحد من احلجاب احلاجز على االأقل. الكلمات املفتاحية: ال�سلل احلجابي؛ مر�ص القلب؛ عمليات اجلراحة القلبية؛ طب االأطفال؛ �سل�سلة حاالت؛ عمان. bilateral diaphragmatic paralysis following paediatric cardiac surgery experience of four cases at the royal hospital, muscat, oman *said a. m. al-hanshi and mohammed h. r. al-ghafri case series sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e334–338, epub. 10 oct 17 submitted 1 dec 16 revisions req. 19 jan & 26 mar 17; revisions recd. 2 mar & 5 apr 17 accepted 17 apr 17 doi: 10.18295/squmj.2017.17.03.013 bilateral diaphragmatic paralysis (bdp) is a rare condition that can occur after cardiac surgery in children; nevertheless, it constitutes significant morbidity and causes more severe respiratory symptoms than unilateral paralysis.1,2 arterial hypoxaemia can result from ventilation-perfusion mismatch at the base of the lungs, while hypercapnia is due to decreased tidal volume and minute ventilation.3 cardiovascular surgery is the most common cause of acquired diaphragmatic paralysis, accounting for approximately 64% of phrenic nerve injuries.4 the management of bdp involves supporting the respiratory system until the diaphragm recovers enough to ameliorate respiratory distress. as such, bdp almost always requires prompt ventilation using an endotracheal tube, tracheostomy or noninvasive mechanical ventilation (mv).5 this case series describes the management of four paediatric patients with bdp, emphasising the importance of conservative management until the diaphragm recovers, expected recovery time and the safety of an interventional tracheostomy in such cases. case one a one-year-old male child was admitted to the royal hospital, muscat, oman, in 2009 with transposition of the great arteries (tga), a ventricular septal defect (vsd), mild subpulmonic stenosis and dextrocardia. he had been born at term via normal vaginal delivery and underwent an uneventful pulmonary artery banding procedure at the age of one month. following admission, a bidirectional glenn shunt was inserted with no intraoperative complications. however, during the postoperative period, the child developed low cardiac output syndrome secondary to junctional ectopic tachycardia. he also had malignant hyperthermia and ventilator-associated pneumonia due to an acinetobacter infection. initially, the child failed to wean from mv; whenever weaning was attempted, he desaturated and developed tachypnoea and right upper lobe collapse. a bronchoscopy revealed mild right bronchomalacia, which was confirmed by computed tomography angiography. he also began to display withdrawal said a. m. al-hanshi and mohammed h. r. al-ghafri case series | e335 symptoms due to prolonged sedation, although magnetic resonance imaging of the brain was normal. the patient was extubated on the 19th day postsurgery; however, in less than two hours he developed severe respiratory distress and carbon dioxide (co2) retention, with a partial pressure of co2 (paco2) level of 77 mmhg. following re-intubation, he required minimal mv. extubation to nasopharyngeal continuous positive airway pressure (cpap) was re-attempted four days later, after his withdrawal symptoms had been controlled. although a chest x-ray was normal, this second attempt at extubation also failed. on day 24 following the surgery, fluoroscopy showed bdp, for which he underwent bilateral plication. however, a third extubation attempt to nasopharyngeal cpap one day later also failed. another trial of gradual weaning from mv using different modes was also unsuccessful. a tracheostomy tube insertion procedure was therefore performed 43 days after the initial cardiac surgery. following insertion of the tracheostomy tube, the patient was gradually weaned from mv; by the 105th postoperative day, he was no longer on mv, there was no evidence of respiratory distress and he was maintaining normal oxygen saturation with an oxygen delivery rate of 1 l/minute. he was decannulated 130 days after the initial cardiac surgery, with no significant complications arising due to the tracheostomy. the patient was transferred from the paediatric intensive care unit (picu) to a normal ward on the 133rd day and was discharged from the hospital two days later. case two a 10-day-old full-term female infant presented to the royal hospital in 2010 with tga and an intact ventricular septum. she underwent a successful atrial septostomy on the same day, followed by an uncomplicated arterial switch surgery at 16 days of age. the infant was extubated two days later but soon developed severe respiratory distress, desaturation and respiratory acidosis with a paco2 level of 67 mmhg; she was consequently re-intubated. the next day, fluoroscopy revealed bdp. unfortunately, 12 days after the cardiac surgery, the patient was accidentally extubated during the provision of standard nursing care and became dusky, desaturated and bradycardic. she was immediately reintubated. repeated fluoroscopy and ultrasonography showed persistent bdp on the 15th postoperative day. a tracheostomy tube was therefore inserted two days later and the provision of minimal mv was continued via the tube. on the 43rd postoperative day, fluoroscopy showed recovery of the right side of the diaphragm only and an attempt at gradual mv weaning failed. two weeks later, repeated fluoroscopy again showed no evidence of recovery on the left side of the diaphragm. consequently, the patient underwent plication of the left side of diaphragm 59 days after the cardiac operation. six days later, mv was discontinued and the patient was successfully decannulated on the 69th postoperative day. case three a two-day-old full-term female newborn presented to the royal hospital in 2011 with tga and vsd. she underwent a septostomy, with a subsequent arterial switch surgery and vsd closure performed when she was 15 days old. the procedure was complicated by postoperative bleeding requiring re-exploration and haemorrhage control. she was gradually weaned from mv and extubated three days after the surgery, but developed severe respiratory distress within one hour of extubation. she could not maintain oxygen saturation and subsequently developed respiratory acidosis with a ph of 7.1 and paco2 level of 81 mmhg. no improvement was noted with noninvasive ventilation and the infant was re-intubated a few hours later. an echocardiogram showed a residual vsd for which the patient underwent surgical closure at 21 days of age. five days later, a second attempt at extubation failed, with the patient requiring re-intubation within one hour. at 12 and 19 days after the arterial switch operation, fluoroscopy confirmed the diagnosis of bdp. a tracheostomy tube was inserted on the 28 postoperative day. on the 62nd day following the arterial switch surgery, fluoroscopy indicated good movement on both sides of the diaphragm. however, the patient remained ventilator-dependent due to the following complications. while the diaphragm was recovering, the patient developed pneumonia twice, for which she received full courses of antibiotics. she also developed chylothorax which lasted for 80 days and had poor weight gain. in addition, an episode of infective endocarditis required six weeks of intravenous antibiotics. the patient was eventually transferred from the picu on the 147th postsurgical day but required a long period of weaning and rehabilitation. finally, mv was discontinued 210 days after the cardiac surgery and the patient was successfully decannulated four days later. bilateral diaphragmatic paralysis following paediatric cardiac surgery experience of four cases at the royal hospital, muscat, oman e336 | squ medical journal, august 2017, volume 17, issue 3 case four a five-day-old full-term male baby was admitted to the royal hospital in 2014 for a type b interrupted aortic arch repair, ligation of the patent ductus arteriosus and vsd closure. postoperative echocardiography indicated that the arch repair was successful, although there was a small residual vsd. he was extubated six days after the surgery but developed respiratory distress and co2 retention, with a paco2 level of 57mmhg. a chest x-ray showed right lung collapse. after a trial of nasopharyngeal cpap failed, the patient was reintubated in under 90 minutes. fluoroscopy on days eight and 14 confirmed bdp. the patient underwent a tracheostomy on the 18th postoperative day. three days later, the patient was transferred to a regional hospital in stable condition. at seven weeks of age, the patient was readmitted to the picu at the royal hospital for balloon dilatation of an aortic arch re-coarctation. repeated ultrasound scans showed no movement of the diaphragm on either side. the mv support was continued and the patient was transferred from the picu. on day 84 post-surgery, ultrasonography and fluoroscopy showed good bilateral diaphragmatic movement. by the 102nd day following the initial surgery, the patient was no longer on mv. however, attempts to decannulate the patient failed. an airway assessment by an ear, nose and throat (ent) surgeon revealed left-sided vocal cord paralysis and granulomatous tissue above the tracheostomy site. the patient was subsequently discharged on the 163rd postoperative day with a tracheostomy tube in situ. regular follow-up appointments with an ent surgeon were scheduled. a summary of the demographic and operative features of each case is shown in table 1. discussion diaphragmatic paralysis due to phrenic nerve injury is potentially life-threatening in infants.6 phrenic nerve injuries due to thoracic surgeries—mainly open-heart surgeries for congenital heart disease—are the most common cause of diaphragmatic paralysis among children.7 the estimated incidence of unilateral diaphragmatic paralysis following cardiac surgery is 1.31%;8 however, the incidence of bdp is not clear as most reports are of single cases.2,9–11 in a study of 867 patients, van onna et al. described 17 cases of postoperative diaphragmatic paralysis (1.9%), of which only one was bilateral (0.1%).12 a retrospective study by dagan et al. identified nine bdp cases among 3,214 children who had undergone cardiac surgery, resulting in an incidence of 0.28%.13 zhang et al. reported four cases of bdp out of 47 patients with diaphragmatic paralysis.14 in the current case series, a late diagnosis of bdp was made for the first patient. extubation failed twice before a diagnosis could be made; while the initial extubation failure was attributed to the development of withdrawal symptoms and mild tracheomalacia, the procedure failed again following control of the symptoms and normal chest x-ray findings. a third extubation failure occurred after bilateral diaphragmatic plication. later, plication was deemed to have been an inappropriate decision due to a lack of experience with such patients. the other three patients in this case series were diagnosed table 1: demographic and operative features of four paediatric patients with bilateral diaphragmatic paralysis following cardiac surgery parameter case 1 case 2 case 3 case 4 age 12 months 16 days 15 days 5 days gender male female female male cardiac diagnosis congenitally corrected tga and a large vsd simple tga tga and a vsd iaa and a vsd type of cardiac surgery glenn shunt arterial switch arterial switch iaa repair and vsd closure chest left open after cardiac surgery no no no yes bypass time in minutes 60 160 220 180 cross-clamp time in minutes 0 76 120 100 subsequent reoperation none none residual vsd closure balloon dilatation of residual coa intraoperative complications none none bleeding none tga = transposition of the great arteries; vsd = ventricular septal defect; iaa = interrupted aortic arch; coa = coarctation of the aorta. said a. m. al-hanshi and mohammed h. r. al-ghafri case series | e337 with bdp much earlier, between 3−12 days after the initial cardiac surgery. this timing is similar to that reported by other researchers.12,13 in cases of bdp, ultrasonography and/or fluoroscopy findings are considered diagnostic.5,9,10,15–18 all bdp diagnoses in the current series were based on one of these radiological modalities. imaging was performed following failed extubation attempts or the development of severe respiratory distress soon after extubation and was repeated before the tracheostomy to confirm the diagnosis and to make sure that no early diaphragm recovery had occurred. these imaging approaches were also used subsequently to assess diaphragm recovery and to inform the timing of decannulation and mv discontinuation. a tracheostomy reduces the risk of an obstructed endotracheal tube, allows immediate oral intake and simplifies the ventilatory weaning process.15 in the current series, other benefits included reduced sedation and the transfer and management of two patients outside of the picu. tracheostomies were performed within 2−6 weeks of the cardiac surgery for all four patients reported in this series. in certain cases, the procedure was delayed so as to allow further extubation attempts and to establish non-invasive nasopharyngeal cpap. however, subsequent efforts at extubation failed. this indicates that such patients require forms of respiratory support from which they can be weaned upon diaphragm recovery. in the present case series, conservative management allowed the spontaneous recovery of function in at least one side of the diaphragm; hence, this approach is recommended for such patients. if necessary, plication of the contralateral side can be considered, as in the second case. however, plication of both sides of the diaphragm was unsuccessful in the first patient described in this case series. to the best of the authors’ knowledge, there are currently no published reports of successful early bilateral plication. in the four patients described in the current case series, diaphragm recovery took between 6−12 weeks. while this is longer than the maximum recovery time of seven weeks reported by dagan et al. for nine bdp cases, a subgroup of four patients with complicated operative and postoperative courses were reported to require prolonged ventilation for 50–62 days.13 three of the patients in the current case series also had complicated postoperative courses, which might explain the delay in diaphragm recovery. in addition, perioperative complications prolonged mv duration, particularly in two patients with multiple postoperative complications. the second patient in the current series had an uneventful postoperative period and the fastest diaphragm recovery time, in which one side of the diaphragm recovered spontaneously and the other side was plicated. she was weaned off mv nine weeks after the cardiac surgery, with removal of the tracheostomy tube a few days later. in the study by dagan et al., all nine bdp patients underwent mv via a nasotracheal tube until at least one side of the diaphragm had recovered before the contralateral side was plicated; the researchers claimed that using this approach avoided the complications of a short-term tracheostomy.13 however, intubation and positive pressure ventilation is not without risk, as it increases the likelihood of infection and lung damage and, if heavy sedation is used, augments muscle atrophy and weakness.19 kovacikova et al. described two patients in which noninvasive positive pressure ventilation was used to manage respiratory failure resulting from bdp; the first patient was fitted with a nasopharyngeal tube and the second with an anesthaesia oronasal mask, with both patients requiring ventilation pressure control.5 although the treatment was noninvasive, complications were reported such as pressure sores over the nasal bridge and cheeks and secondary herpetic and chest infections. in addition, the oronasal mask did not fit properly and there was leakage from the nasopharyngeal tube.5 in the present case series, accidental decannulation of the tracheostomy tube without loss of airway occurred in one patient; however, there were no other major complications and all of the patients survived. four episodes of lower respiratory tract infection were observed, with three of them arising in the patient with prolonged chylothorax due to immunoglobulin loss. this patient also had episodes of sepsis, endocarditis and a central line-related infection. all four patients in the current series were discharged without needing further respiratory support. other published reports of bdp cases have similarly reported no major tracheostomy-related complications.10,11 conclusion conservative management allows for the spontaneous recovery of diaphragm function among patients with bdp following paediatric cardiac surgery. however, such patients require ongoing mv support until at least one side of the diaphragm recovers and any respiratory distress is ameliorated. a tracheostomy is recommended as a relatively safe procedure for ventilating bdp patients with no major complications, as observed in the current case series. bilateral diaphragmatic paralysis following paediatric cardiac surgery experience of four cases at the royal hospital, muscat, oman e338 | squ medical journal, august 2017, volume 17, issue 3 references 1. de leeuw m, williams jm, freedom rm, williams wg, shemie sd, mccrindle bw. impact of diaphragmatic paralysis after cardiothoracic surgery in children. j thorac cardiovasc surg 1999; 118:510–17. doi: 10.1016/s0022-5223(99)70190-x. 2. tabata y, matsui h, sakamoto t, noguchi m. bilateral diaphragm paralysis after simultaneous cardiac surgery and nuss procedure in the infant. j pediatr surg case rep 2015; 3:27–9. doi: 10.1016/j.epsc.2014.11.009. 3. petersson j, glenny rw. gas exchange and ventilation-perfusion relationships in the lung. eur respir j 2014; 44:1023–41. doi: 10.1183/09031936.00037014. 4. talwar s, agarwala s, mittal cm, choudhary sk, airan b. diaphragmatic palsy after cardiac surgical procedures in patients with congenital heart. ann pediatr cardiol 2010; 3:50–7. doi: 10.4103/0974-2069.64370. 5. kovacikova l, dobos d, zahorec m. non-invasive positive pressure ventilation for bilateral diaphragm paralysis after pediatric cardiac surgery. interact cardiovasc thorac surg 2009; 8:171–2. doi: 10.1510/icvts.2008.187096. 6. akay th, ozkan s, gultekin b, uguz e, varan b, sezgin a, et al. diaphragmatic paralysis after cardiac surgery in children: incidence, prognosis and surgical management. pediatr surg int 2006; 22:341–6. doi: 10.1007/s00383-006-1663-2. 7. joho-arreola al, bauersfeld u, stauffer ug, baenziger o, bernet v. incidence and treatment of diaphragmatic paralysis after cardiac surgery in children. eur j cardiothorac surg 2005; 27:53–7. doi: 10.1016/j.ejcts.2004.10.002. 8. mehta y, vats m, singh a, trehan n. incidence and management of diaphragmatic palsy in patients after cardiac surgery. indian j crit care med 2008; 12:91–5. doi: 10.4103/0972-5229.43676. 9. hoch b, zschocke a, barth h, leonhardt a. bilateral diaphragmatic paralysis after cardiac surgery: ventilator assistance by nasal mask continuous positive airway pressure. pediatr cardiol 2001; 22:77–9. doi: 10.1007/s002460010162. 10. shamsuddin ak, biswas sk, rahman mz, biswas s, hasan na, sharifuzzaman m. a young child with bilateral diaphragmatic palsy after bilateral bidirectional glenn shunt. mymensingh med j 2014; 23:595–8. 11. tamayo e, alvarez fj, florez s, fulquet e, fernandez a. bilateral diaphragmatic paralysis after open heart surgery. j cardiovasc surg (torino) 2001; 42:785–6. 12. van onna ie, metz r, jekel l, woolley sr, van de wal hj. post cardiac surgery phrenic nerve palsy: value of plication and potential for recovery. eur j cardiothorac surg 1998; 14:179–84. doi: 10.1016/s1010-7940(98)00147-x. 13. dagan o, nimri r, katz y, birk e, vidne b. bilateral diaphragm paralysis following cardiac surgery in children: 10-years’ experience. intensive care med 2006; 32:1222–6. doi: 10.1007/ s00134-006-0207-5. 14. zhang yb, wang x, li sj, yang km, sheng xd, yan j. postoperative diaphragmatic paralysis after cardiac surgery in children: incidence, diagnosis and surgical management. chin med j (engl) 2013; 126:4083–7. 15. stewart s, alexson c, manning j. bilateral phrenic nerve paralysis after the mustard procedure: experience with four cases and recommendations for management. j thorac cardiovasc surg 1986; 1:138–41. 16. lemmer j, stiller b, heise g, hübler m, alexi-meskishvili v, weng y, et al. postoperative phrenic nerve palsy: early clinical implications and management. intensive care med 2006; 32:1227–33. doi: 10.1007/s00134-006-0208-4. 17. serraf a, planche c, lacour gayet f, bruniaux j, nottin r, binet jp. post cardiac surgery phrenic nerve palsy in pediatric patients. eur j cardiothorac surg 1990; 4:421–4. doi: 10.1016/1010-7940(90)90071-7. 18. ovroutski s, alexi-meskishvili v, stiller b, ewert p, abdul-khaliq h, lemmer j, et al. paralysis of the phrenic nerve as a risk factor for suboptimal fontan hemodynamics. eur j cardiothorac surg 2005; 27:561–5. doi: 10.1016/j. ejcts.2004.12.044. 19. ross russell ri, helms pj, elliott mj. a prospective study of phrenic nerve damage after cardiac surgery in children. intensive care med 2008; 34:728–34. doi: 10.1007/s00134-0070977-4. https://doi.org/10.1016/s0022-5223%2899%2970190-x https://doi.org/10.1016/j.epsc.2014.11.009 https://doi.org/10.1183/09031936.00037014 https://doi.org/10.4103/0974-2069.64370 https://doi.org/10.1510/icvts.2008.187096 https://doi.org/10.1007/s00383-006-1663-2 https://doi.org/10.1016/j.ejcts.2004.10.002 https://doi.org/10.4103/0972-5229.43676 https://doi.org/10.1007/s002460010162 https://doi.org/10.1016/s1010-7940%2898%2900147-x https://doi.org/10.1007/s00134-006-0207-5 https://doi.org/10.1007/s00134-006-0207-5 https://doi.org/10.1007/s00134-006-0208-4 https://doi.org/10.1016/1010-7940%2890%2990071-7 https://doi.org/10.1016/j.ejcts.2004.12.044 https://doi.org/10.1016/j.ejcts.2004.12.044 https://doi.org/10.1007/s00134-007-0977-4 https://doi.org/10.1007/s00134-007-0977-4 department of public health & community medicine, jordan university of science & technology, irbid, jordan *corresponding author’s e-mail: aokour@just.edu.jo تقييم خدمات تقدمي مشورة تنظيم األسرة يف مشال األردن عبداحلكيم حممود عكور، رامي عبداهلل �صعادة، منى زقول abstract: objectives: counselling plays a key role in enhancing reproductive services, providing contraceptionrelated information and supporting long-term family planning for women of childbearing age. this study aimed to evaluate family planning counselling sessions in selected governmental and private clinics in northern jordan. methods: this cross-sectional study was conducted between january and june 2016 in irbid, jordan. a total of 200 women attending two private clinics affiliated with the jordanian association for family planning and protection (jafpp) and six governmental clinics were invited to participate in the study. counselling sessions were attended by an independent observer and evaluated with regards to their compliance with the standard greet, ask, tell, help, explain, return (gather) framework. results: a total of 198 women participated in the study (response rate: 99.0%), including 80 women (40.4%) from jafpp clinics and 118 (59.6%) from governmental clinics. in total, 42.9% of the counselling sessions were deemed adequate, with providers applying 80% or more of the gather framework, while 26.8% of the sessions were deemed semi-adequate and 30.3% were considered inadequate. counselling services provided in the governmental clinics were significantly less adequate than those provided in jafpp clinics (p <0.001). conclusion: the quality of counselling services in governmental family planning centres in jordan needs to be improved to ensure that women receive the highest possible level of care. healthcare policymakers should therefore focus on developing and supporting effective family planning counselling services in northern jordan. keywords: family planning services; counseling; health services evaluation; community health services; reproductive health; jordan. تنظيم ودعم احلمل، مبنع املتعلقة املعلومات وتوفري الإجنابية، اخلدمات تعزيز يف رئي�صيا دورا امل�صورة توؤدي الهدف: امللخ�ص: عيادات يف الأ�رشة لتنظيم امل�صورة تقدمي جل�صات تقييم اإىل الدرا�صة هذه هدفت الإجناب. �صن يف للن�صاء الطويل املدى على الأ�رشة الأردن. اإربد، يف 2016 وحزيران الثاين كانون بني املقطعية الدرا�صة هذه اأجريت الأردن. الطريقة: �صمال يف خمتارة وخا�صة حكومية دعيت اإىل امل�صاركة يف الدرا�صة ما جمموعه 200 امراأة يف عيادتني خا�صتني تابعتني للجمعية الأردنية لتنظيم الأ�رشة وحمايتها، و�صت عيادات حكومية. ح�رش الباحث كمراقب م�صتقل جل�صات تقدمي امل�صورة لتقييمها فيما يتعلق بامتثال مزود الرعاية لإطار امل�صورة املعتمد �صاركت النتائج: للمراجعة(. التخطيط املعلومات، �رشح م�صاعدتهن، باملعلومات، تزويدهن �صوؤالهن، للن�صاء، التحية )تقدمي الدرا�صة يف 198 امراأة يف الدرا�صة )معدل ال�صتجابة: %99.0(. و�صمل ذلك 80 امراأة )%40.4( من عيادات اجلمعية الأردنية لتنظيم الأ�رشة وحمايتها بتطبيق امل�صورة مقدمي لقيام كافية امل�صورة تقدمي جل�صات من 42.9% اعترب املجموع، يف احلكومية. العيادات من )59.6%( 118 و كافية. غري اجلل�صات من 30.3% اعتربت بينما كافية �صبه اجلل�صات من 26.8% اعترب حني يف املعتمد، امل�صورة اإطار من اأكرث اأو 80% .)p >0.001( كانت خدمات تقدمي اامل�صورة املقدمة يف العيادات احلكومية اأقل كفاية بكثري من تلك املقدمة يف العيادات التابعة للجمعية اأعلى على املراأة ح�صول ل�صمان الأردن يف احلكومية الأ�رشة تنظيم مراكز يف امل�صورة تقدمي خدمات نوعية حت�صني يجب اخلال�صة: الأ�رشة لتنظيم الفاعلة امل�صورة تقدمي خدمات ودعم تطوير على ال�صحية ال�صيا�صات �صناع يركز اأن ينبغي الرعاية. من ممكن م�صتوى يف �صمال الأردن. الكلمات املفتاحية: خدمات تنظيم الأ�رشة؛ تقدمي امل�صورة؛ تقييم اخلدمات ال�صحية؛ خدمات ال�صحة املجتمعية؛ ال�صحة الإجنابية؛ الأردن. evaluation of family planning counselling in north jordan *abdulhakeem m. okour, rami a. saadeh, mona zaqoul clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e436–443, epub. 10 jan 18 submitted 18 may 17 revisions req. 18 jul & 10 sep 17; revisions recd. 14 aug & 14 sep 17 accepted 21 sep 17 advances in knowledge to the best of the authors’ knowledge, this study is the first to evaluate family planning counselling sessions in northern jordan in terms of their adherence to the standard greet, ask, tell, help, explain, return (gather) framework. this study provides information for healthcare policy-makers in jordan regarding differences in the adequacy of family planning counselling in jordan at private and governmental institutions. application to patient care the results of the current study demonstrated that family planning counselling in governmental centres in jordan was substandard and needs to be improved. doi: 10.18295/squmj.2017.17.04.010 abdulhakeem m. okour, rami a. saadeh and mona zaqoul clinical and basic research | e437 family planning counselling enhances reproductive outcomes by supporting a woman’s decision to use appropriate contraceptive methods in the manner that best fits her needs.1–3 during counselling sessions, healthcare providers can provide patients with expert clinical advice regarding contraceptive choices. however, inadequate communication between service providers and patients may impact the disclosure or understanding of salient information concerning the appropriate use and sideeffects of various contraceptives, which may in turn lead to contraceptive discontinuation.4,5 evidence indicates that structured counselling both protects women’s rights to an informed and voluntary decision regarding their reproductive choices and improves the use of modern contraception methods.5–12 ideally, counselling sessions should be acceptable to the patient, provide high-quality information and offer enough time and motivation to apply any recommendations.13 according to the world health organization (who), a successful counsellor should understand women’s beliefs, needs and concerns and be respectful, honest, highly competent and an effective communicator.14,15 in jordan, family planning services are provided by the ministry of health (moh) free of charge for those with governmental insurance and at a minimum charge for those without. in the private medical sector, such services are either partially or totally funded by insurance providers. although the fertility rate in recent years has remained essentially unchanged, with a decline from 3.5 births per woman in 2012 to 3.4 births per woman in 2015, one in three pregnancies is unintentional.11,16 in 2012, 61.2% of married jordanian women were reported to be using some method of family planning, with 42.3% using modern methods and 18.9% using traditional methods.4 in total, 44.1% of women who used modern contraceptives obtained them from a governmental source while 55.6% received them from private institutions, including pharmacies, the jordan association of family planning and protection (jafpp), the united nations refugee welfare agency and private doctors. however, 11.7% had an unmet need for family planning—whether it was to postpone their next birth or to avoid pregnancy altogether—but were not using any form of contraception.4 moreover, a high rate of contraceptive discontinuation within 12 months of use (47.8%) was reported, with only 24.2% subsequently switching to another method. the main reasons for contraceptive discontinuation included contraceptive failure (8.6%), the desire for a more effective contraceptive (10.0%), undesirable side-effects (5.2%) or wanting to become pregnant (9.9%).4 another national study in jordan has indicated that family planning services are often influenced by the personal beliefs of the providers; for example, most providers emphasised the importance of a large family and recommended short-term contraceptive methods for women with fewer children, refusing to suggest semipermanent approaches like an intrauterine device.5 religious and social beliefs also influenced family planning recommendations, with some providers expressing preference for a male child.5 according to the 2015–2019 strategic plan of the moh, the strengthening of reproductive health services is a top priority.16 however, despite the existence of moh guidelines, relatively little is known regarding the actual magnitude or quality of family planning counselling sessions in jordan. one study indicated a 20% increase in patient satisfaction with family planning services with each additional counselling protocol step.5 another study previously investigated the effect of involving men in counselling; however, the content of the sessions was not evaluated.11 finally, various other studies have analysed general family planning services rather than focusing specifically on counselling.17–21 the present study therefore aimed to evaluate family planning counselling sessions at governmental and private clinics in northern jordan in terms of their adherence to the greet, ask, tell, help, explain, return (gather) framework.22 methods this descriptive cross-sectional study was conducted in irbid, jordan, between january and june 2016. a total of 200 women attending one of eight selected family planning clinics during the study period were invited to participate in the study. of the eight clinics, six were run by the jordanian moh and two by the jafpp, which is the largest non-governmental provider of family planning services in jordan, serving roughly 20% of the population with 19 clinics nationwide.23 the target population included all women who visited the selected clinics during the data collection period, including those attending during their postpartum period, first-time users and those seeking contraceptive advice. the sample size was determined based on the following formula:24 where n is the sample size, zα is 1.96 (using a corresponding value of z from standard tables), p is the prevalence of incompetent family planning n = zα/2 p*q d2 evaluation of family planning counselling in north jordan e438 | squ medical journal, november 2017, volume 17, issue 4 counselling (15% as determined according to a pilot study), q is the difference between 100 and p (100 15 = 85%) and d is the precision of the estimate indicating an absolute error of 0.05. as such, the required sample size was calculated to be 196. in jafpp clinics, family planning services were provided during fixed-time appointments. women had to register and have their blood pressure measured before each counselling session, which was then undertaken by two social workers in a separate room designed specifically for that purpose. in contrast, family planning services at governmental facilities were provided on a ‘first-come, first-served’ basis, with registration, vital signs measurements and counselling sessions all performed in a single room with multiple personnel present, including nurses, midwifes and nurse assistants; however, midwives were the sole care givers to provide counselling services. unfortunately, as each clinic had a different daily schedule for various services and the time duration for the counselling sessions was irregular, the process of participant recruitment and data collection was not simple. in view of these factors, as well as the limited time period of the study, coordination with the facilities and the data collection process was carried out by a single person. accordingly, the observation and evaluation of counselling sessions was carried out by a single anonymous observer unrelated to the researchers. the observer remained present in the counselling room from 8 am to 1 pm during the entirety of each session. for the evaluation, a modified 20-item checklist was derived using the components of the original gather framework [table 1].22 this checklist was pretested prior to data collection in a pilot study of 15 women not subsequently included in the main study; the findings confirmed that each of the items was appropriate and understandable. subjective items were avoided and none of the items were deemed to present difficulties during evaluation or considered potentially controversial when reviewed by a panel of researchers. during each counselling session, the observer witnessed the counselling process and awarded one mark for each checklist item; the marks were subsequently added up for a total score of 20 points. scores of ≤9 (≤45%) were classified as inadequate, while scores of 10–15 (50–75%) and ≥16 (≥80%) were classified as semi-adequate and adequate, respectively. in addition, a stopwatch was used to time the duration of counselling sessions from the moment the patient stepped into the room until the provider finished the session. after each session, the participants were requested to complete a sociodemographic questionnaire to record their age, education level, employment status, age at marriage, number of children and monthly income. analysis of the data was performed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the main outcome variable of the study was the eval uation score of the counselling performed by health care providers. results were presented using descriptive statistics, including frequencies and means. the relationship between facility type and both the adequacy and duration of the counselling session was assessed as well as between the adequacy of the counselling process and the duration of the session. a p value of 0.050 was considered statistically significant. table 1: assessment checklist for the evaluation of counselling sessions according to the greet, ask, tell, help, explain, return (gather) framework22 item assessment greet greets the client in a friendly and respectful manner? ask asks about the client’s needs and concerns? asks about the client’s reproductive goals? tell informs the client of all contraceptive methods available? asks which method interests client? asks what the client already knows about the method? corrects myths/rumours/incorrect information? describes the effectiveness of the method? uses audio/visual aids during counselling? describes the benefits and risks? describes potential side-effects? answers the client’s questions clearly? help asks if anything is not understood? asks “what method do you want”? explain clearly explains instructions on successfully using the method? asks the client to repeat instructions? reminds the client of potential side-effects? reminds the client of dangerous signs/ symptoms? explains what to do if problems occur? return plans a return visit for the client? abdulhakeem m. okour, rami a. saadeh and mona zaqoul clinical and basic research | e439 this study was approved by the institutional review board of the jordan university of science & technology (#139/2015) as well as relevant authorities at the moh and jafpp. verbal consent was obtained from each of the counselling providers before the monitoring of their counselling sessions. patients provided written informed consent prior to their participation in the study and were assured of the voluntary nature of their participation and the confidentiality of any data collected. table 3: evaluation of family planning counselling sessions at selected clinics in irbid, jordan (n = 198) assessment* n (%) moh clinics (n = 118) jafpp clinics (n = 80) greet greets the client in a friendly and respectful manner? 118 (100.0) 80 (100.0) ask asks about the client’s needs and concerns? 118 (100.0) 80 (100.0) asks about the client’s reproductive goals? 118 (100.0) 80 (100.0) tell informs the client of all contraceptive methods available? 38 (32.2) 25 (31.3) asks which method interests the client? 115 (97.5) 80 (100.0) asks what the client already knows about the method? 1 (0.8) 11 (13.8) corrects myths/ rumours/incorrect information? 36 (30.5) 80 (100.0) describes the effectiveness of the method? 35 (29.7) 79 (98.8) uses audio/visual aids during counselling? 2 (1.7) 78 (97.5) describes the benefits and risks? 45 (38.1) 80 (100.0) describes the potential side-effects? 52 (44.1) 80 (100.0) answers the client’s questions clearly? 69 (58.5) 80 (100.0) help asks if anything is not understood? 3 (2.5) 80 (100.0) asks “what method do you want”? 118 (100.0) 80 (100.0) explain clearly explains instructions on successfully using the method? 42 (35.6) 80 (100.0) asks the client to repeat back instructions? 0 (0.0) 0 (0.0) reminds the client of the potential sideeffects? 51 (43.2) 80 (100.0) reminds the client of dangerous signs/ symptoms? 36 (30.5) 80 (100.0) explains what to do if problems occur? 60 (50.8) 80 (100.0) return plans a return visit for the client? 102 (86.4) 78 (97.5) moh = ministry of health; jafpp = jordan association of family planning and protection. *as per the greet, ask, tell, help, explain, return (gather) framework.22 table 2: characteristics of women attending selected family planning clinics in irbid, jordan (n = 198) characteristic n (%) age in years* ≤20 7 (3.5) 21–29 109 (55.1) 30–39 60 (30.3) 40–49 16 (18.1) ≥50 4 (2.0) age at marriage in years* ≤20 68 (34.3) 21–29 125 (63.1) 30–39 3 (1.5) monthly income in jd† ≤340 46 (23.2) 341–400 27 (13.6) >400 118 (59.6) education level basic 30 (15.2) high school 67 (33.8) university or higher 101 (51.0) employment status employed 16 (8.1) unemployed 182 (91.9) number of children none 1 (0.5) 1 32 (16.2) 2 60 (30.3) 3–4 81 (40.9) >4 24 (12.1) jd = jordanian dinar. *total dataset for this variable was 196 due to missing data for two patients. †total dataset for this variable was 191 due to missing data for seven patients. evaluation of family planning counselling in north jordan e440 | squ medical journal, november 2017, volume 17, issue 4 results a total of 198 women participated in the study (response rate: 99.0%), including 80 women (40.4%) from jafpp clinics and 118 (59.6%) from moh clinics. the mean age was 22 years (range: 17–56 years old) and 85.4% were between 21–39 years old. the age of the women at their marriage ranged between 15–35 years old. in total, 84.8% were educated to high school level or higher and 73.2% had monthly incomes of >340 jordanian dinars (usd >$480). the mean number of children per woman was three, with 53.0% of the participants having three or more children [table 2]. table 3 shows the evaluation of observed coun selling sessions according to the gather framework.22 both types of clinics consistently and adequately performed the first two steps of the gather framework (greet and ask). moreover, in the private jafpp clinics, all of the other steps of the gather framework (tell, help, explain and return) were deemed to be adequate; however, in the governmental clinics, these steps were assessed as either semiadequate or inadequate. the mean evaluation score was 12.88 (range: 5–19). of all the counselling sessions, 30.3% were considered inadequate, 26.8% were semi-adequate, and 42.9% were adequate. however, 100.0% of jafpp clinic sessions were deemed adequate in comparison to only 4.2% of governmental clinic sessions. moreover, while 88.8% of counselling sessions in jafpp clinics lasted 6–15 minutes, only 49.2% of counselling sessions in governmental clinics lasted for the same amount of time. the relationships between facility type and evaluation outcome (p <0.001) and counselling duration (p <0.001) were highly significant [table 4]. adequate counselling sessions lasted between 6–20 minutes in 95.3% of cases, while semi-adequate and inadequate sessions lasted between 2–10 minutes in 81.2% and 96.6% of cases, respectively, with a significant relationship between evaluation outcome and counselling duration (p <0.001) [table 5]. discussion the provision of high-quality family planning services encourages acceptance of contraceptive use.25 moreover, evidence from both developed and developing countries shows that high-quality care assists in reducing rates of contraceptive discontinuation and unintended fertility.25,26 to the best of the author’s knowledge, the current study is the first in jordan to evaluate family planning counselling sessions according to the gather framework.22 in the current table 5: relationship between evaluation outcomes* and duration of family planning counselling sessions at selected clinics in irbid, jordan (n = 198) session duration in minutes n (%) p value adequate sessions (n = 85) semiadequate sessions (n = 53) inadequate sessions (n = 60) total ≤5 3 (3.5) 11 (20.8) 46 (76.7) 60 (30.3) 6–10 29 (34.1) 32 (60.4) 12 (20.0) 73 (36.9) 11–15 46 (54.1) 9 (17.0) 1 (1.7) 56 (28.3) <0.001 16–20 6 (7.1) 0 (0.0) 0 (0.0) 6 (3.0) >20 1 (1.2) 1 (1.9) 1 (1.7) 3 (1.5) *as per an assessment checklist based on the greet, ask, tell, help, explain, return (gather) framework.22 table 4: relationship between facility type and evaluation outcomes and duration of family planning counselling sessions at selected clinics in irbid, jordan (n = 198) n (%) p value moh clinics (n = 118) jafpp clinics (n = 80) total evaluation outcome* adequate 5 (4.2) 80 (100.0) 85 (42.9) <0.001 semi-adequate 53 (44.9) 0 (0.0) 53 (26.8) inadequate 60 (50.8) 0 (0.0) 60 (30.3) session duration in minutes ≤5 58 (49.2) 2 (2.5) 60 (30.3) <0.001 6–10 46 (39.0) 27 (33.8) 73 (36.9) 11–15 12 (10.2) 44 (55.0) 56 (28.3) 16–20 0 (0.0) 6 (7.5) 6 (3.0) >20 2 (1.7) 1 (1.3) 3 (1.5) moh = ministry of health; jafpp = jordan association of family planning and protection. *as per the greet, ask, tell, help, explain, return (gather) framework.22 abdulhakeem m. okour, rami a. saadeh and mona zaqoul clinical and basic research | e441 study, the overall rate of adequate counselling was acceptable when considering all counselling sessions together, regardless of facility type; however, the situation was markedly different when considering the results for moh clinics alone. other countries have reported better results pertaining to the evaluation of family planning services in general, and for counselling in particular.27–29 the findings of the current study suggest that social workers working in jafpp clinics more consist ently employed the gather framework while counselling in contrast to moh midwives at govern mental clinics.22 moreover, certain aspects of the gather framework—including the use of audiovisual aids and asking what the client already knew about contraceptive methods and whether anything was not understood—were applied more consistently in jafpp clinics compared to moh clinics.22 although outside the scope of this study, it is possible that differences in the standards of services available at each type of facility may be responsible for these results. previous research has indicated that improved conditions in family health facilities and the application of appropriate counselling protocols lead to improved family planning services.26 in moh clinics, women rarely received counselling services as they were seen on a ‘walk-in’ basis, with family planning services usually restricted to the provision of contraceptives. this may be partially due to the extremely large number of women seen by moh clinics which far surpass those seen by other family planning providers in jordan. furthermore, healthcare providers at moh clinics had no incentives and few expectations placed on them with regards to family planning services and thus little motivation to offer high-quality counselling sessions.2,27 in addition, the lack of separate rooms for counselling sessions and the time demands on moh employees would not facilitate the provision of counselling services. to some extent, the lack of professional training on counselling protocols and the ‘walk-in’-based system might explain the low level of counselling competency noted at moh clinics in the current study. in contrast, counselling in jafpp clinics was performed by trained social workers in specifically designed rooms. such conditions offer a client-centred and friendly atmosphere for family planning services.17,18,27,28 moreover, the time allocation for each patient was determined by an appointmentbased system which may have helped to assure the quality of counselling. in 2009, the jordanian higher population council recommended restructuring moh protocols for the provision, evaluation and monitoring of family planning counselling services in order to reduce contraceptive failure, incorrect use and discontinuation rates.13 furthermore, compulsory training courses were recommended for all moh healthcare providers in order to facilitate more effective counselling sessions.13 training healthcare providers to be counselling specialists might also contribute to improved client services.29 previous studies have ascertained that specialised training increases providers’ knowledge of contraceptives and their willingness to prescribe appropriate methods.2,26,27,29 continuous evidence-based training is therefore a promising approach for enhancing counselling services at moh clinics in jordan. counselling services can be provided by a variety of healthcare providers, including midwifes, nurses and doctors.2,27,29 although the current study did not address the skills or qualifications of the various counselling providers, the results seem to indicate that midwives with specialised medical education and training in moh-affiliated clinics could not compete with social workers without health-related training or medical education in private clinics. an essential component in the provision of high-quality counselling is effective and efficient communication skills. it is possible that such skills could be lacking among the midwives involved in the current study. often, women or couples seeking family planning counselling services are from diverse backgrounds and can challenge the competencies of counselling providers to respect their patients’ experiences, opinions and thoughts.5 competent counselling sessions also require the allocation of adequate time to best serve the patient. in the current study, the mean duration of counselling sessions was relatively similar to other research (8.68 minutes versus 5–15 minutes).5 in the present study, longer counselling sessions had better evaluation outcomes while shorter counselling sessions had lower scores (i.e. 76.7% of inadequate sessions took ≤5 minutes). the findings of this study have various implications for research and healthcare practice. first, they contribute to the existing literature, since there is a dearth of studies evaluating family planning counselling sessions in jordan. second, they revealed several potential areas of related research that can be conducted in jordan and the wider middle eastern region. finally, they may assist policy-makers designing large-scale family planning programmes at the national level. nevertheless, this study was subject to certain limitations. it is possible that the researchers overlooked factors which contributed to the different results observed between the two types of clinics evaluated. additionally, since the data collector had more time to contact and recruit eligible women in evaluation of family planning counselling in north jordan e442 | squ medical journal, november 2017, volume 17, issue 4 governmental facilities, more women were recruited from moh clinics than from jafpp ones. as such, the total sample of women included in the study was small and not randomly selected, thus limiting generalisation of the results. in addition, a follow-up study was not carried out to examine the impact of counselling on contraceptive choice or discontinuation rates. conclusion the current study assessed the provision of family planning counselling services in selected clinics in northern jordan. overall, the results showed that counselling sessions in both moh and jafpp facilities succeeded in following the first two steps of the gather framework in terms of welcoming patients and asking about their contraceptive choices. nonetheless, counselling services at governmental clinics were otherwise deficient, particularly with regards to other interactions required by the gather framework. hopefully, these results can be utilised by healthcare policy-makers to further develop family planning services in jordan. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. halpern v, lopez lm, grimes da, stockton ll, gallo mf. strategies to improve adherence and acceptability of hormonal methods of contraception. cochrane database syst rev 2013; 10:cd004317. doi: 10.1002/14651858.cd004317.pub4. 2. saka mj, yahaya la, saka ao. counseling and client providerinteractions as related to family planning services in nigeria. j educ pract 2012; 3:16–24. 3. malawi ministry of health. preservice education family planning reference guide. from: www.intrahealth.org/sites/ihweb/files/ files/media/preservice-education-family-planning-referenceguide/mpsfprg_final_web-opt.pdf accessed: sep 2017. 4. department of statistics. jordan population and family health survey 2012. from: https://dhsprogram.com/pubs/pdf/fr282/ fr282.pdf accessed: sep 2017. 5. kamhawi s, underwood c, murad h, jabre b. client-centered counseling improves client satisfaction with family planning visits: evidence from irbid, jordan. glob health sci pract 2013; 1:180–92. doi: 10.9745/ghsp-d-12-00051. 6. bruce j. fundamental elements of the quality of care: a simple framework. stud fam plann 1990; 21:61–91. 7. khader ys, el-qaderi s, khader am. intrauterine contraceptive device discontinuation among jordanian women: rate, causes and determinants. j fam plann reprod health care 2006; 32:161–4. doi: 10.1783/147118906777888279. 8. ramarao s, mohanam r. the quality of family planning programs: concepts, measurements, interventions, and effects. stud fam plann 2003; 34:227–48. doi: 10.1111/j.1728-4465. 2003.00227.x. 9. moos mk, dunlop al, jack bw, nelson l, coonrod dv, long r, et al. healthier women, healthier reproductive outcomes: recommendations for the routine care of all women of reproductive age. am j obstet gynecol 2008; 199:s280–9. doi: 10.1016/j.ajog.2008.08.060. 10. elsinga j, de jong-potjer lc, van der pal-de bruin km, le cessie s, assendelft wj, buitendijk se. the effect of preconception counselling on lifestyle and other behaviour before and during pregnancy. womens health issues 2008; 18:s117–25. doi: 10.1016/j.whi.2008.09.003. 11. el-khoury m, thornton r, chatterji m, kamhawi s, sloane p, halassa m. counseling women and couples on family planning: a randomized study in jordan. stud fam plann 2016; 47:222–38. doi: 10.1111/sifp.69. 12. lemani c, tang jh, kopp d, phiri b, kumvula c, chikosi l, et al. contraceptive uptake after training community health workers in couples counseling: a cluster randomized trial. plos one 2017; 12:e0175879. doi: 10.1371/journal.pone.0175879. 13. united states agency for international development. reducing discontinuation of contraceptive use and unmet need for family planning: policy options. from: www.healthpolicyinitiative. com/publications/documents/1488_1_jordan_unmet_need_ brief_jan_2011.pdf accessed: sep 2017. 14. world health organization. family planning: a global handbook for providers. from: www.ippf.org/sites/default/ files/family_planning_a_global_handbook_for_providers.pdf accessed: sep 2017. 15. kim ym, davila c, tellez c, kols a. evaluation of the world health organization’s family planning decision-making tool: improving health communication in nicaragua. patient educ couns 2007; 66:235–42. doi: 10.1016/j.pec.2006.12.007. 16. jordan high health council. the national strategy for health sector in jordan: 2015-2019. from: www.hhc.gov.jo/ uploadedimages/the%20national%20strategy%20for%20 h e a l t h % 2 0 s e c t o r % 2 0 i n % 2 0 j o r d a n % 2 0 2 0 1 5 2 0 1 9 . p d f accessed: sep 2017. 17. united states agency for international development. impact of changing contraceptive method mix on jordan’s total fertility rate. from: pdf.usaid.gov/pdf_docs/pnadx849.pdf accessed: sep 2017. 18. bitar n, shahrouri m. ministry of health service providers knowledge on how to manage iuds & ocs side effects. from: bluerayjo.com/hpc/en/node/11870 accessed: sep 2017. 19. abdelnour sf. moh physicians’ kap study on hormonal methods and female sterilization. from: pdf.usaid.gov/pdf_ docs/pnadn121.pdf accessed: sep 2017. 20. mahadeen ai, khalil ao, hamdan-mansour am, sato t, imoto a. knowledge, attitudes and practices towards family planning among women in the rural southern region of jordan. east mediterr health j 2012; 18:567–72. 21. mawajdeh s. demographic profile and predictors of unmet need for family planning among jordanian women. j fam plann reprod health care 2007; 33:53–6. doi: 10.1783/ 147118907779399819. 22. rinehart w, rudy s, drennan m. gather guide to counseling. popul rep j 1998; 48:1–31. 23. united states agency for international development. jordan association for family planning and protection: needs assessment. from: www.shopsplusproject.org/sites/default/ files/resources/6%20needs%20assessment%2c%20jordan%20 a s s o c i at i o n % 2 0 f o r % 2 0 fa m i l y % 2 0 pl a n n i n g % 2 0 a n d % 2 0 protection%2c%20pspjordan%2c%20aug .%202008.pdf accessed: sep 2017. https://doi.org/10.1002/14651858.cd004317.pub4 https://doi.org/10.9745/ghsp-d-12-00051 https://doi.org/10.1783/147118906777888279 https://doi.org/10.1111/j.1728-4465.2003.00227.x https://doi.org/10.1111/j.1728-4465.2003.00227.x https://doi.org/10.1016/j.ajog.2008.08.060 https://doi.org/10.1016/j.whi.2008.09.003 https://doi.org/10.1111/sifp.69 https://doi.org/10.1371/journal.pone.0175879 https://doi.org/10.1016/j.pec.2006.12.007 https://doi.org/10.1783/147118907779399819 https://doi.org/10.1783/147118907779399819 abdulhakeem m. okour, rami a. saadeh and mona zaqoul clinical and basic research | e443 24. macinko j, almeida c, de sá pk. a rapid assessment methodology for the evaluation of primary care organization and performance in brazil. health policy plan 2007; 22:167–77. doi: 10.1093/heapol/czm008. 25. shahidzadeh-mahani a, omidvari s, baradaran hr, azin sa. factors affecting quality of care in family planning clinics: a study from iran. int j qual health care 2008; 20:284–90. doi: 10.1093/intqhc/mzn016. 26. rawal n, das g, kishen m. assessment of contraceptive services in a maternity unit of a district general hospital in the uk. j obstet gynaecol 2005; 25:179–81. doi: 10.1080/ 01443610500051478. 27. stanback j, griffey s, lynam p, ruto c, cummings s. improving adherence to family planning guidelines in kenya: an experiment. int j qual health care 2007; 19:68–73. doi: 10. 1093/intqhc/mzl072. 28. eryilmaz g. the evaluation of family planning services given in erzurum mother-child health and family planning centerin eastern turkey. eur j contracept reprod health care 2006; 11:146–50. doi: 10.1080/13625180500520141. 29. malnory me, johnson ts. the reproductive life plan as a strategy to decrease poor birth outcomes. j obstet gynecol neonatal nurs 2011; 40:109–19. doi: 10.1111/j.1552-6909. 2010.01203.x. https://doi.org/10.1093/heapol/czm008 https://doi.org/10.1093/intqhc/mzn016 https://doi.org/10.1080/01443610500051478 https://doi.org/10.1080/01443610500051478 https://doi.org/10.1093/intqhc/mzl072 https://doi.org/10.1093/intqhc/mzl072 https://doi.org/10.1080/13625180500520141 https://doi.org/10.1111/j.1552-6909.2010.01203.x https://doi.org/10.1111/j.1552-6909.2010.01203.x homozygous beta thalassaemia is an inherited blood disorder characterised by deficient synthesis of the beta globin subunits of haemoglobin. beta thalassaemia carriers comprise 1.5% of the worldwide population; an estimated 60,000 infants are born with this serious defect every year.1 it is most commonly found in people of mediterranean descent (italians and greeks), although it also affects people from other parts of the world such as africa, the middle east, the indian subcontinent and southeast asia.2 the omani population is known to have a high prevalence of alpha thalassaemia and a substantial number of the population are carriers of either haemoglobin s or beta thalassaemia.3 the genetic blood disorders survey in oman revealed a prevalence of 9.5% for clinically significant haemoglobinopathy carriers. beta thalassaemia was found to be the second most common haemoglobinopathy with a carrier rate of 2% in children under five years of age and a prevalence of 0.07% for homozygous beta thalassaemia.4 patients with thalassaemia major require life-long red blood cell transfusion for survival. senescence of transfused red cells results in iron deposition within the reticuloendothelial system with progressive deposition in the hepatic parenchyma, endocrine tissues and eventually the myocardium.5 although serum ferritin is widely used to indirectly assess iron stores, several studies have shown that it does not accurately reflect hepatic or cardiac iron levels.6,7 liver iron departments of 1child health and 2physiotherapy, sultan qaboos university hospital, muscat, oman; 3nottingham children's hospital, nottingham university hospital trust, nottingham, uk; 4department of paediatrics, faculty of medicine, university of alexandria, alexandria, egypt; departments of 5haematology and 6child health, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: tjmevada@yahoo.com حبس النفس ملرة واحدة كتقنية عالج طبيعي أداة فعالة للتصوير بالرنني املغناطيسي)*t2( يف املرضى الصغار جدا املصابني بالثالسيميا الكربى �شوريخ� ميف�دا، جنمة املحروقية، اإ�شم�عيل الب�شالوي، حممد ال�شن�وي، م�ثيو زكري�، عبد احلكيم الروا�ص، �ش�هين� دار، ي��رض وايل abstract: magnetic resonance imaging using t2* (mri t2*) is a highly sensitive and non-invasive technique for the detection of tissue iron load. although the single breath-hold multi-echo t2* technique has been available at the sultan qaboos university hospital (squh), muscat, oman, since 2006, it could not be performed on younger patients due to their inability to hold their breath after expiration. this study was carried out between may 2007 and may 2015 and assessed 50 squh thalassaemic patients aged 7‒17 years old. seven of these patients underwent baseline and one-year follow-up mri t2* scans before receiving physiotherapy training. subsequently, all patients were trained by a physiotherapist to hold their breath for approximately 15‒20 seconds at the end of expiration before undergoing baseline and one-year follow-up mri t2* scans. failure rates for the preand post-training groups were 6.0% and 42.8%, respectively. these results indicate that the training of thalassaemic patients in breathhold techniques is beneficial and increases rates of compliance for mri t2* scans. keywords: children; iron overload; breath holding; physiotherapy; thalassemia major; oman. امللخ�ص: الت�شوير ب�لرنني املغن�طي�شي ب��شتخدام *mri t2*( t2( تقنية ح�ش��شة للغ�ية غريخ�رقة لالأن�شجة للك�شف عن زي�دة احلديد يف االأن�شجة. ب�لرغم من اأن تقنية حب�ص النف�ص املتعددة ال�شدى *t2 متوفرة يف م�شت�شفى ج�معة ال�شلط�ن ق�بو�ص، م�شقط، �شلطنة عم�ن، بني الدرا�شة هذه الزفري.اأجريت بعد اأنف��شهم حب�ص على قدرتهم عدم ب�شبب ال�شغ�ر لالأطف�ل ت�شتخدم اأن ميكن ال ف�إنه ،2006 ع�م منذ م�يو 2007 وم�يو 2015 حيث مت تقييم 50 من مر�شى الثال�شيمي� ترتاوح اأعم�رهم 17-7 �شنة .خ�شع �شبعة من املر�شى للت�شوير ب�لرنني قبل من تدريبهم مت ذلك، بعد الطبيعي. العالج علي التدريب قبل �شنة ملدة ومت�بعتهم )mri t2*( ب��شتخدام االأ�ش��شي املغن�طي�شي اأخ�ش�ئي العالج الطبيعي على حب�ص اأنف��شهم ملدة 20-15 ث�نية بعد نه�ية الزفري قبل الت�شوير ب�لرنني املغن�طي�شي االأ�ش��شيومت�بعتهم ملدة �شنة ب��شتخدام *mri t2. ك�نت ن�شبة الف�شل ملجموع�ت م�قبل وم� بعد التدريب %6.0 و %42.8 ب�لتوايل. تدل نت�ئج هذه الدرا�شة املغن�طي�شي ب�لرنني للت�شوير االمتث�ل معدالت من ويزيد مفيد النف�ص حب�ص تقني�ت على ب�لثال�شيمي� املر�شى االأطف�ل تدريب اأن اإىل .)mri t2*( مفتاح الكلمات: االأطف�ل؛ احلديد الزائد؛ حب�ص النف�ص؛ العالج الطبيعي؛ الثال�شيمي� الكربى؛ عم�ن. single breath-hold physiotherapy technique effective tool for t2* magnetic resonance imaging in young patients with thalassaemia major *surekha t. mevada,1 najma al-mahruqi,2 ismail el-beshlawi,3 mohamed el-shinawy,1,4 mathew zachariah,1 abdul h. al-rawas,1 shahina daar,5 yasser wali6 technical note sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e78–81, epub. 2 feb 16 submitted 23 aug 15 revision req. 1 oct 15; revision recd. 25 oct 15 accepted 12 nov 15 doi: 10.18295/squmj.2016.16.01.014 surekha t. mevada, najma al-mahruqi, ismail el-beshlawi, mohamed el-shinawy, mathew zachariah, abdul h. al-rawas, shahina daar and yasser wali technical note | e79 concentration can be determined by a liver biopsy, but this has high sampling variability. in addition, the procedure is invasive and complications requiring hospitalisation are not uncommon.8,9 magnetic resonance imaging using t2* (mri t2*) is a highly sensitive, non-invasive and reproducible technique for the detection of tissue iron load.7,10,11 it is recommended that the first t2* cardiac magnetic resonance scan should be performed in thalassaemic patients as early as feasible without sedation to tailor the chelation treatment.12,13 in 2006, the mri t2* liver and heart technique was introduced at the sultan qaboos university hospital (squh), a tertiary care hospital in muscat, oman. initially, only patients over 10 years of age were eligible for the procedure; however, most of the patients failed to complete the procedure due to either movement or an inability to hold their breath in expiration. this prompted hospital staff to implement a training programme designed by an squh physiotherapist to enable paediatric patients to successfully complete the procedure. this study therefore aimed to evaluate the effect of this training programme. methods this study was carried out between may 2007 and may 2015 at squh. all patients between seven and 17 years old with thalassaemia major who were undergoing regular hypertransfusion at the squh paediatric thalassaemia day care center were included in the study. between may 2007 and may 2009, seven patients underwent a baseline mri t2* scan using the single breath-hold multi-echo t2* technique. between june 2009 and may 2015, all patients who fit the inclusion criteria, including the seven aforementioned patients, were individually reviewed by a physiotherapist during regular transfusion-related hospital visits (every 3‒4 weeks). all patients subsequently underwent two or more training sessions designed to teach them to hold their breath at the end of expiration for approximately 15–20 seconds. during the first training session, the required breath-hold procedure was demonstrated to each patient individually by the physiotherapist. the patients were shown how to take a deep breath and then exhale slowly, holding their breath at the end of expiration for approximately 15–20 seconds. the necessity of adequate breath-holding was emphasised as crucial for the procedure. the breath-hold at the end of expiration was timed with a stopwatch in order to achieve the required time for the procedure. each patient was asked to repeat the breath-holding exercise until they could perform it correctly. the patients were simultaneously instructed to remain still and avoid movement during breath-holding. they were also counselled to continue practicing breath-holding at home. in subsequent sessions, patients were reassessed by the physiotherapist. all patients who were able to hold their breath at the end of expiration for 15–20 seconds were scheduled for mri t2* scans. children who were still unable to hold their breath at the end of expiration were continuously reassessed at subsequent visits. most of the patients were fully trained in less than three visits. during these sessions, the doctors and nurses also interacted with the patients in order to allay their anxieties regarding the procedure and to build their confidence. all of the patients received the physiotherapy training during scheduled transfusion appointments in order to minimise hospital visits and school absenteeism. after the completion of the physiotherapy training, all patients underwent baseline cardiac mri t2* scans using the single breath-hold multi-echo t2* protocol without general anaesthesia or sedation.14,15 approximately a year later, the patients were given a follow-up mri t2* scan. failure was defined by an inability to complete the procedure either due to inadequate breath-holding or due to movement resulting in artefacts appearing on the scan. t2* values measured during the mri were calculated using cmrtools (cardiovascular imaging solutions ltd., london, uk). continuous variables were presented as means, ranges and standard deviations. categorical variables were presented as frequencies. a t-test was used to compare continuous variables in both groups. fisher’s exact test was used for 2 x 2 contingency tables. a p value of <0.050 was considered significant. this study was approved by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #980). results among the 50 patients who were included in the study, seven patients underwent mri t2* scans before physiotherapy training. these patients were aged 10‒16 years old (mean: 11.28 ± 2.13 years). of these patients, three (42.9%) failed the procedure. a total of eight follow-up mri t2* scans were performed one year later, as one patient had two follow-up mri scans. at follow-up, three patients (37.5%) failed the procedure. all 50 patients subsequently received physiotherapy training. these patients were aged 7‒17 years old (mean: 10.45 ± 2.51 years). of these patients, three single breath-hold physiotherapy technique effective tool for t2* magnetic resonance imaging in young patients with thalassaemia major e80 | squ medical journal, february 2016, volume 16, issue 1 (6.0%) failed to complete the baseline mri t2* scan. all three of these patients were nine years old. a total of 68 follow-up mri t2* scans were performed one year later, as 18 patients underwent two follow-up mri scans. of these, two patients (2.9%) aged 13 and 15 years old failed the procedure [table 1]. discussion although breath-holding for mri t2* scans is difficult for young children, the results of this study indicated that physiotherapy training among young patients with thalassaemia was effective in improving compliance to the mri t2* procedure. children as young as seven years of age were subsequently able to undergo mri t2* scans without general anaesthesia or sedation, resulting in a reduced failure rate. in the group of patients who did not receive physiotherapy training, the results were suboptimal; it was this finding that prompted the researchers to adapt a uniform approach to train all patients aged >7 years old in a physiotherapy breath-holding technique to achieve optimal results. the major limitations of cardiac mris in young children are the need to remain relatively still within the scanner and the need for breath-holding to acquire images without artefacts.16 breath-holding problems are well documented in adults and it is likely they are more of an issue in children.17 these problems include an inability to understand and follow instructions for breath-holding, an inability to maintain the breathhold for the whole scan (15‒20 seconds) and fear of the procedure.16 few studies have been reported on the use of mri t2* in children and it appears that most centres either use sedation or general anaesthesia for the procedure. some of the alternative approaches used to obtain high-quality mri scans include the use of a mock mri scanner or cinemavision (salvadorini consulting llc, lexington, north carolina, usa). a study by de bie et al. evaluated the use of a mock scanner training protocol as an alternative for sedation and for preparing young children for mri scans.18 in their cohort of 90 children aged 3.65–14.5 years old, 85 children passed the mock scanner training sessions.18 the mock scanner is a full-scale replica of an mri system without magnets and requires the services of a doctor to conduct the training sessions for several days to a maximum of three weeks before the real mri is carried out. the purpose of cinemavision (salvadorini consulting llc) is to allow patients to forget their surroundings while they watch a movie/ television or listen to music/radio. neither mock scans nor cinemavision (salvadorini consulting llc) are presently available at squh. in the current study, severe cardiac iron overload (<10 ms) was observed in a 7-year-old child as a result of the physiotherapy training and subsequent successful completion of the mri t2* scan. this had not previously been noted by serial serum ferritin monitoring or echocardiography. the patient underwent physiotherapy training prior to the initial mri t2* scan. during this scan, he was detected to have a cardiac t2* value of 9.3 ms at a serum ferritin level of 2,605 ng/ml. subsequently, he was put on chelation with desferrioxamine; however, he had sub-optimal compliance to the treatment. on follow-up, the patient was subsequently reassessed by the physiotherapist. despite extensive counselling and chelator dose optimisation, a repeat mri t2* scan performed after 18 months revealed a cardiac t2* value of 4.8 ms at a serum ferritin level of 2,796 ng/ml, indicating that the cardiac siderosis had worsened despite the fairly constant serum ferritin level. as a result, the patient was prescribed to combination chelation therapy with deferiprone and desferrioxamine. a repeat mri after a further nine months revealed an improved cardiac t2* value of 8.1 ms at a serum ferritin level of 3,197 ng/ml. in the case of this patient, the physiotherapy training enabled the successful completion of the initial and follow-up mri scans allowing the detection and subsequent treatment of the severe cardiac siderosis. the use of physiotherapy training is advantageous to prepare paediatric patients with thalassaemia for mri t2* scans using the single breath-hold, multiecho t2* technique. aside from the time-saving benefits, training also reduces the logistical issues of re-booking patients in busy hospital mri departments and avoids the risks associated with general anaesthesia or sedation. baseline and one-year follow-up mri t2* scans, together with careful monitoring of iron overload progression, offers timely intervention for table 1: age and magnetic resonance t2* failure rates among young patients with thalassaemia major before and after physiotherapy breath-hold training (n = 50) before training (n = 7) after training (n = 50) p value mean age in years ± sd (range) 11.28 ± 2.13 (10‒16) 10.45 ± 2.51 (7‒17) 0.372 baseline mri t2* failure, n (%) 3 (42.9) 3 (6.0) 0.021* follow-up mri t2* failure, n (%) 3 (37.5)† 2 (2.9)‡ 0.007* sd = standard deviation; mri = magnetic resonance imaging. *significant at p <0.050. †there were eight total scans for this group as one patient had two follow-up mri scans. ‡there were 68 total scans for this group as 18 patients had two follow-up scans. surekha t. mevada, najma al-mahruqi, ismail el-beshlawi, mohamed el-shinawy, mathew zachariah, abdul h. al-rawas, shahina daar and yasser wali technical note | e81 optimal chelation and improved quality of life among young thalassaemic patients. conclusion in this study, a high failure rate for mri t2* scans was noted in a group of young thalassaemic patients who had not received physiotherapy training. however, among those who took part in a training programme that prepared patients to hold their breath for 15‒20 seconds after expiration, the failure rate was significantly lower. this indicates that a training programme for paediatric thalassaemic patients is indeed beneficial and increases compliance. breathhold training also ensures paediatric patients avoid the complications of sedation or general anaesthesia. a c k n o w l e d g e m e n t s we thank the squh paediatric day care centre nursing staff, in particular ms. alya a. al-siyabi, as well as the squh physiotherapy team and the mri technicians for their invaluable support throughout this study. we also thank the patients and their parents for their participation and cooperation in this study. c o n f l i c t s o f i n t e r e s t the authors declare no conflicts of interest. references 1. higgs dr, engel jd, stamatoyannopoulos g. thalassaemia. lancet 2012; 379:373–83. doi: 10.1016/s0140-6736(11)60283-3. 2. qari mh, wali y, albagshi mh, alshahrani m, alzahrani a, alhijji ia, et al. regional consensus opinion for the management of beta thalassemia major in the arabian gulf area. orphanet j rare dis 2013; 8:143. doi: 10.1186/1750-1172-8-143. 3. daar s, gravell d. diagnosis of beta-thalassaemia carriers in the sultanate of oman. sultan qaboos univ med j 2006; 6:27–31. 4. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 5. nienhuis aw, nathan dg. pathophysiology and clinical manifestations of the beta thalassemias. cold spring harb perspect med 2012; 2:a011726. doi: 10.1101/cshperspect.a01 1726. 6. azarkeivan a, hashemieh m, akhlaghpoor s, shirkavand a, yaseri m, sheibani k. relation between serum ferritin and liver and heart mri t2* in beta thalassaemia major patients. east mediterr health j 2013; 19:727–32. 7. puliyel m, sposto r, berdoukas va, hofstra tc, nord a, carson s, et al. ferritin trends do not predict changes in total body iron in patients with transfusional iron overload. am j hematol 2014; 89:391‒4. doi: 10.1002/ajh.23650. 8. wood jc. use of magnetic resonance imaging to monitor iron overload. hematol oncol clin north am 2014; 28:747–64. doi: 10.1016/j.hoc.2014.04.002. 9. wood jc, zhang p, reinhoff h, abi-saab w, neufeld ej. liver mri is more precise than liver biopsy for assessing total body iron balance: a comparison of mri relaxometry with simulated liver biopsy results. magn reson imaging 2015; 33:761–7. doi: 10.1016/j.mri.2015.02.016. 10. he t. cardiovascular magnetic resonance t2* for tissue iron assessment in the heart. quant imaging med surg 2014; 4:407–12. doi: 10.3978/j.issn.2223-4292.2014.10.05. 11. daar s, hassan m, panjwani v, pathare a, al-dhuhli h, al-riyami az. utility of magnetic resonance imaging t2* in diagnosing and monitoring severe cardiac and hepatic siderosis. sultan qaboos univ med j 2015; 15:e140–e142. 12. koonrungsesomboon n, chattipakorn sc, fucharoen s, chattipakorn n. early detection of cardiac involvement in thalassemia: from bench to bedside perspective. world j cardiol 2013; 5:270–9. doi: 10.4330/wjc.v5.i8.270. 13. casale m, meloni a, filosa a, cuccia l, caruso v, palazzi g, et al. multiparametric cardiac magnetic resonance survey in children with thalassemia major: a multicenter study. circ cardiovasc imaging 2015; 8:e003230. doi: 10.1161/ circimaging.115.003230. 14. baksi aj, pennel dj. t2* imaging of the heart: methods, applications and outcomes. top magn reson imaging 2014: 23:13–20. doi: 10.1097/rmr.0000000000000011. 15. tony s, daar s, elshinawy m, al-zadjaly s, al-khabory m, wali y. t2*mri in regularly transfused children with thalasse mia intermedia: serum ferritin does not reflect liver iron stores. pediatr hematol oncol 2012; 29:579–84. doi: 10.3109 /08880018.2012.708891. 16. taylor am, dymarkowski s, de meerleer k, hamaekers p, gewillig m, mertens l, et al. validation and application of single breath-hold cine cardiac mr for ventricular function assessment in children with congenital heart disease at rest and during adenosine stress. j cardiovasc magn reson 2005; 7:743–51. doi: 10.1080/10976640500283421. 17. roujol s, basha ta, weingärtner s, akçakaya m, berg s, manning wj, et al. impact of motion correction on reproducibility and spatial variability of quantitative myocardial t2 mapping. j cardiovasc magn reson 2015; 17:46. doi: 10.1186/ s12968-015-0141-1. 18. de bie hm, boersma m, wattjes mp, adriaanse s, vermeulen rj, oostrom kj, et al. preparing children with a mock scanner training protocol results in high quality structural and functional mri scans. eur j pediatr 2010; 169:1079–85. doi: 10.1007/s00431-010-1181-z. http://dx.doi.org/10.1016/s0140-6736%2811%2960283-3 http://dx.doi.org/10.1186/1750-1172-8-143 http://dx.doi.org/10.1101/cshperspect.a011726 http://dx.doi.org/10.1101/cshperspect.a011726 http://dx.doi.org/10.1002/ajh.23650 http://dx.doi.org/10.1016/j.hoc.2014.04.002 http://dx.doi.org/10.1016/j.mri.2015.02.016 http://dx.doi.org/10.3978/j.issn.2223-4292.2014.10.05 http://dx.doi.org/10.4330/wjc.v5.i8.270 http://dx.doi.org/10.1161/circimaging.115.003230 http://dx.doi.org/10.1161/circimaging.115.003230 http://dx.doi.org/10.1097/rmr.0000000000000011 http://dx.doi.org/10.3109/08880018.2012.708891 http://dx.doi.org/10.3109/08880018.2012.708891 http://dx.doi.org/10.1080/10976640500283421 http://dx.doi.org/10.1186/s12968-015-0141-1 http://dx.doi.org/10.1186/s12968-015-0141-1 http://dx.doi.org/10.1007/s00431-010-1181-z myiasis is the infestation of the vertebrate tissues with fly larvae. most human cases of myiasis in oman are ophthalmomyiasis caused by oestrus ovis (sheep bot fly) of the oestridae family.1,2 tracheopulmonary myiasis is very rare with only a few cases reported worldwide.3–9 this case report presents a 13-year-old omani boy with an unusual case of bronchial myiasis resulting from the inhalation of mature larvae which caused a severe pulmonary reaction. a literature review of all reported cases of tracheopulmonary myiasis is also presented. myiasis due to o. ovis remains a rare cause of pulmonary disease and is a newly described cause of eosinophilic pneumonia in humans.9 case report in october 2014, a previously healthy 13-year-old boy from a mountainous area of interior oman reported inhaling a fly and experiencing a subsequent sudden coughing fit. upon inspection by a relative, all that could be seen was some white thready material at the back of his throat. he presented to the local health centre with a progressive cough and breathing difficulty. the patient was hypoxic with an oxygen (o2) saturation level of 90% when breathing room air. he was wheezy and in severe respiratory distress. he received salbutamol nebulisation without noticeable improvement. he was transferred to a regional hospital on the same day where he was adequately managed for wheezing. however, the patient remained hypoxic, requiring 3 l of o2 to maintain an o2 saturation level above 92%. as the patient was not improving, he was referred the next day to the paediatric emergency department at the royal hospital, a tertiary centre in muscat, oman, for an urgent bronchoscopy. on examination, he was found to be in severe respiratory distress, with wheezes on the right side of his upper chest and minimal air entry. he was subsequently moved to the paediatric intensive care unit (picu). in the picu, the patient was alert and conscious but still struggling to breathe; he needed 5 l of o2 department of paediatrics, royal hospital, muscat, oman *corresponding author e-mail: doctorarindomaich@yahoo.com االلتهاب الرئوي اليوزيين لدى مريض يعاين من النعف القصيب يف عمان تقرير حالة ومراجعة الألدبيات اريندوم اأي�ض، �سعاد الإ�سماعلية، فاطمة رم�سان، طالل الوردي، قا�سم ال�ساملي، هالل اله�سامي abstract: pulmonary myiasis is an unusual form of myiasis in humans and has been recently identified as a cause of eosinophilic pneumonia. we report the case of a 13-year-old omani boy who presented to the royal hospital, muscat, oman, in october 2014 with respiratory distress. bronchial aspirates revealed features of eosinophilic pneumonia. possible larvae identified in the cytology report, a high immunoglobulin e level and the patient history all indicated bronchial myiasis. the patient was treated with steroids and ventilation and has since been diseasefree with no long-term side-effects. to the best of the authors’ knowledge, this is the first case of bronchial myiasis in oman. keywords: myiasis; eosinophilic pneumonia; case report; oman. لاللتهاب الأ�سباب كاأحد موؤخرا تعريفه ومت الب�رس يف النغف داء من العتيادية غري الأ�سكال من �سكل هو الرئوي النغف داء امللخ�ص: وكان يعاين من �سيق يف التنف�ض حيث اأدخل امل�ست�سفى، وك�سفت عينات الغ�سيل الرئوي اأن الطفل يعاين من اللتهاب الرئوي اليوزيني. الرئوي اليوزيني. فقد قمنا بتحرير حالة لطفل يبلغ من العمر 13 عاما ًبعد قدومه للم�ست�سفى ال�سلطاين مب�سقط يف اأكتوبر من عام 2014 وبينت عينات الغ�سيل الرئوي، وارتفاع ن�سبة الغلوبني املناعيe والتاريخ املر�سي للم�ساب اأن املري�ض كان يعاين من داء النغف الق�سبي. عولج املري�ض با�ستخدام التنف�ض ال�سطناعي وعقار ال�سريويد وتعافى متامًا من املر�ض بدون اأي اعرا�ض �سلبية. وتعترب هذه احلالة من داء النغف الق�سبي هي الأوىل امل�سجلة يف �سلطنة عمان. مفتاح الكلمات: داء النغف؛ اللتهاب الرئوي اليوزيني؛ تقرير حالة؛ عمان. eosinophilic pneumonia in a patient with bronchial myiasis case report and literature review *arindom aich, suad al-ismaili, fatma a. ramadhan, talal h. m. al-wardi, quasem al-salmi, hilal al-hashami case report sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e546–549, epub. 23 nov 15 submitted 31 dec 14 revisions req. 22 mar & 21 may 15; revisions recd. 22 apr & 24 may 15 accepted 11 jun 15 doi: 10.18295/squmj.2015.15.04.018 arindom aich, suad al-ismaili, fatma a. ramadhan, talal h. m. al-wardi, quasem al-salmi and hilal al-hashami case report | e547 high immunoglobulin e level (897 iu/ml) and the patient history all pointed towards a parasitic cause. the eosinophilic pneumonia was treated with 14day courses of intravenous hydrocortisone and ceftriaxone, the former of which was then tapered off over the following seven days. discussion myiasis is caused by the invasion of human or animal tissues by fly larvae (maggots) and can be classified as accidental, facultative or obligate. human cases are mostly accidental. in terms of the present case, administered via a face mask and could only maintain an o2 saturation level of 90%. due to persistent hypoxia, the patient was intubated with a 6.5 size cuffed tube and mechanically ventilated for 10 days with synchronised intermittent mandatory ventilation with volume control. a direct laryngoscopy did not reveal any obvious vocal cord oedema. flexible bronchoscopy showed oedema and thick secretions in the right upper lobe and superior segment of the right lower lobe. however, no obvious foreign body was isolated. the patient developed anaphylactic shock and was treated with a 12-hour adrenaline infusion with good response. a repeat flexible bronchoscopy after two days revealed thick whitish mucous casts but no foreign body. this time, involvement of the left side was also noted. x-rays showed an initial worsening of the pneumonia followed by gradual improvement after four days of highfrequency oscillatory ventilation (hfov) [figure 1]. post-extubation, he did not require any further o2. cytology of the bronchial aspirate revealed eosinophils in scattered clusters. many neutrophils, macrophages and lymphocytes were also admixed with a thick mucus. occasional small oval structures (possibly larvae) were identified [figure 2] along with a few charcot-leyden crystals. there were no bacteria or fungi isolated in the culture and a complete blood count did not show any eosinophilia. the presence of the eosinophilic clusters and charcot-leyden crystals in the cytology report suggested a diagnosis of eosinophilic pneumonia. the presence of possible larvae in the cytology report, a figure 1a–c: portable post-intubation supine chest x-rays of a patient with pulmonary myiasis and eosinophilic pneumonia at (a) admission, (b) two days later and (c) four days after high-frequency oscillatory ventilation (hfov). note the worsening pneumonia with bilateral involvement and the improvement after hfov. figure 2: papanicolaou stain at x400 magnification showing an amphiphilic structure (large arrow) consistent with an oestrus ovis larva in a patient with pulmonary myiasis and eosinophilic pneumonia. note the inflammatory infiltrate with a predominance of eosinophils (small arrow). eosinophilic pneumonia in a patient with bronchial myiasis case report and literature review e548 | squ medical journal, november 2015, volume 15, issue 4 the responsible organism for the myiasis was likely to be o. ovis, locally known as dis’sa, because the fly is known to lay its larvae during flight and the species is very common in the patient’s home region. the eyes are usually affected in most cases of o. ovis involvement.1,2,10 many people living in the same area as the patient, including the boy’s father, had had a history of conjunctivitis and coughing. o. ovis is found worldwide and is known to cause cavitary myiasis. its hosts are sheep and goats and there is as yet no confirmation that o. ovis is able to complete its life cycle in humans. the female fly is active during the summer and early autumn, when it deposits as many as 500 already hatched first instar larvae. direct contact between the fly and its host is not necessary for infestation.10 o. ovis is the most common cause of external ophthalmomyiasis and may cause many allergic manifestations, especially when found in the throat.11,12 tracheopulmonary myiasis is a very rare form of the disease; to date, only seven cases have been reported worldwide [table 1].3‒9 the geographical distribution of cases is varied (including the usa, brazil, japan and korea) and no specific age group or gender is targeted. causative organisms range from cuterebra fontinella, megaselia spicularis, alouattamyia baeri and the lucilia and gasterophilus genera and cuterebrinae subfamily. although the likelihood of human infestation is rare, the severe medical complications and the varied worldwide distribution indicates the medical importance of this condition. as with the current patient, those suspected of having tracheopulmonary myiasis (i.e. those with severe respiratory distress and hypoxia and living in fly-prevalent regions) should be urgently treated at a tertiary care centre. eosinophilic pneumonia is a condition describing an accumulation of eosinophils in the lungs. known causes include certain medications, parasitic infections, cancer, environmental triggers and immunogenic factors. the prognosis is very good and patients usually respond well to steroid treatment. parasites can cause eosinophilic pneumonia in three different ways: either by invading the lung, living in the lung as part of their life cycle or spreading to the lung through the bloodstream. tapeworms, helminths and japanese lung flukes are the most common parasites. fly larvae infestation has recently been reported as a cause of eosinophilic pneumonia and is a very rare entity.9 a few cases of ophthalmomyiasis have been reported in oman; however, only some of these were caused by o. ovis.1,2 there have been no reported cases of bronchial myiasis in oman to date. the current case represents the first report of bronchial myiasis in oman and the middle east with eosinophilic pneumonia requiring mechanical ventilatory support, including hfov, despite treatment with steroids. conclusion bronchial myiasis can be a life-threatening infestation and should be considered in the differential diagnosis of unexplained respiratory distress and hypoxia in individuals from fly-prevalent areas. patients should be urgently referred to a tertiary centre for effective management and care. to the best of the authors’ table 1: demographic and entomological characteristics of tracheopulmonary myiasis cases in the literature author and year of report patient age in years and gender location suspected causative organism involvement confirmatory findings larvae stage ahmed et al.3 1969 n/a usa gasterophilus genus pulmonary n/a n/a scholten et al.5 1977 22 m canada cuterebra fontinella tracheal patient coughed up larvae instar 2 komori et al.7 1978 19 m japan megaselia spiracularis pulmonary larvae on lung biopsy instar 3 baird et al.4 1979 22 m usa cuterebra subgenus bronchial patient coughed up larvae instar 2 fraiha et al.6 1984 n/a brazil alouattamyia baeri n/a n/a n/a choi et al.8 2002 84 f korea lucilia genus pulmonary larvae crawled out of patient’s nose n/a cornet et al.9 2002 60 f usa cuterebra subgenus tracheal patient coughed up larvae instar 3 present case 13 m oman oestrus ovis bronchial bronchial aspirates n/a n/a = not available; m = male; f = female. arindom aich, suad al-ismaili, fatma a. ramadhan, talal h. m. al-wardi, quasem al-salmi and hilal al-hashami case report | e549 6. fraiha h, chaves lc, borges ic, de freitas rb. [human myiasis in amazonia iii: myiasis of the lung due to alouattamyia baeri (shannon & greene, 1926) (diptera, cuterebridae)]. seperata da revista da fundaҫao sesp 1984; 29:63–8. 7. komori k, hara k, smith kg, oda t, karamine d. a case of lung myiasis caused by larvae of megaselia spiracularis schmitz (diptera: phoridae). trans r soc trop med hyg 1978; 72:467–70. doi: 10.1016/0035-9203(78)90165-7. 8. choi e, lim d, na m, yang j, lee y, lee w. a case of internal myiasis of the respiratory system associated with pneumonia. tuberc respir dis 2002; 53:650–5. 9. cornet m, florent m, lefebvre a, wertheimer c, perez-eid c, bangs mj, et al. tracheopulmonary myiasis caused by a mature third-instar cuterebra larva: case report and review. j clin microbiol 2003; 41:5810–12. doi: 10.1128/jcm.41.12.58105812.2003. 10. cameron ja, shoukrey nm, al-garni aa. conjunctival ophthalmomyiasis caused by the sheep nasal botfly (oestrus ovis). am j ophthalmol 1991; 112:331–4. doi: 10.1016/s00029394(14)76736-4. 11. francesconi f, lupi o. myiasis. clin microbiol rev 2012; 25:79–105. doi: 10.1128/cmr.00010-11. 12. masoodi m, hosseini k. the respiratory and allergic manifestations of human myiasis caused by larvae of the sheep bot fly (oestrus ovis): a report of 33 pharyngeal cases from southern iran. ann trop med parasitol 2003; 97:75–81. knowledge, this is the first case of bronchial myiasis in oman. the patient presented with eosinophilic pneumonia and the causative organism was likely o. ovis. references 1. victor r, bhargva k. ophthalmomyiasis in oman: a case report and comments. wilderness environ med 1998; 9:32–5. doi: 10.1580/1080-6032(1998)009[0032:oioacr]2.3.co;2. 2. abuelhassan aa. external ophthalmomyiasis due to oestrus ovis: a case report from oman. oman med j 2010; 25. doi: 10.5001/omj.2010.94. 3. ahmed mj, miller a. pulmonary coin lesion containing a horse bot, gasterophilus; report of a case of myiasis. am j clin pathol 1969; 52:414–19. 4. baird cr, podgore jk, sabrosky cw. cuterebra myiasis in humans: six new case reports from the united states with a summary of known cases (diptera: cuterebridae). j med entomol 1982; 19:263–7. doi: 10.1093/jmedent/19.3.263. 5. scholten t, chrom vh. myiasis due to cuterebra in humans. can med assoc j 1979; 120:1392–3. http://dx.doi.org/10.1016/0035-9203%2878%2990165-7 http://dx.doi.org/10.1128/jcm.41.12.5810-5812.2003 http://dx.doi.org/10.1128/jcm.41.12.5810-5812.2003 http://dx.doi.org/10.1016/s0002-9394%2814%2976736-4 http://dx.doi.org/10.1016/s0002-9394%2814%2976736-4 http://dx.doi.org/10.1128/cmr.00010-11 http://dx.doi.org/10.1580/1080-6032%281998%29009%5b0032:oioacr%5d2.3.co%3b2 http://dx.doi.org/10.5001/omj.2010.94 http://dx.doi.org/10.1093/jmedent/19.3.263 shared treatment decision-making (tdm) is the process by which physicians and patients make treatment decisions by sharing information, expressing preferences and agreeing to implement a proposed treatment.1 among patients who are diagnosed with life-threatening diseases such as cancer, shared tdm has been associated with improved physical and psychological health outcomes, greater patient compliance with regards to oncological treatments, higher levels of patient satisfaction and reduced overall healthcare costs.2,3 indeed, it has been observed that the majority of cancer patients prefer having a role in tdm along with their physicians; however, there is controversy regarding the appropriate level of involvement of patients’ families.4,5 in an online survey of 290 middle-aged urban residents, alden et al. found that individuals who preferred to be more involved in tdm—either as shared or autonomous tdm—tended to prefer less family involvement for a variety of illnesses ranging in severity, particularly if the family member in question was young.5 interestingly, this study included samples from many eastern countries, including china, thailand, south korea, malaysia and india; this finding also held in those countries, as well as in the usa and australia.5 another study found that poor south korean patients preferred autonomous tdm for end-of-life decisions, as they were often concerned that younger relatives might more heavily weigh financial concerns versus the patient’s own preferences.6 researchers in the asian pacific region have therefore concluded that there are meaningful segments of patients across very different cultures who prefer little or no family involvement in tdm and higher levels of shared and autonomous tdm.5,6 in another study of patient-caregiver dyads in korea, most patients and caregivers valued and expected family involvement in tdm; however, there was little explicit agreement regarding which party in the dyad should take decisional leadership and which should play a supporting role.7 several studies have shown that cancer patients and their family members prefer family participation in tdm to some extent.7–9 among patients with advanced lung cancer in belgium, pardon et al. reported that patients’ family members regularly attended consultation and treatment appointments in order to provide emotional support, request further information and participate in the tdm process.10 a large, multiregional, prospective cohort study of newly diagnosed patients with lung and colorectal cancer undertaken in the usa found that most participants involved family members in treatment decisions.11 nevertheless, the study concluded that further research is required to evaluate the impact such involvement might have on patient outcomes. the authors also noted that physicians should consider determining the patients’ preferences regarding family involvement at the outset of care.11 in oman, many breast cancer patients were found to rely on their families for emotional, physical and financial support, the absence of which negatively affected the patient’s prognosis.12 it should be noted that the impact of a cancer diagnosis on family members is sometimes similar to that of the patient in terms of stress, depression, anxiety, financial constraints and interpersonal problems.13,14 in eastern countries, patients are more likely to be guided by their families during the tdm process, which is often associated with high levels of positive emotional engagement, and are therefore less likely to make key medical decisions.15 family members in such countries tend to believe that tdm should lie in the hands of the patient’s family members and that these individuals should be involved directly in the 1department of health information & statistics, al nahdha hospital, muscat, oman; departments of 2medicine and 3family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: mhalazri@squ.edu.om دور افراد عائله املرضى يف اختاذ القرارات املتعلقة بعالج السرطان تباين وجهات النظر مابني العائالت الشرقية والغربية عبد الرحيم البحري، من�صور املنذري، حممد العزري editorial the role of patients’ families in cancer treatment decision-making perspectives among eastern and western families abdulrahim al-bahri,1 mansour al-moundhri,2 *mohammed al-azri3 sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e383–385, epub. 10 jan 18 submitted 26 oct 17 revision req. 15 nov 17; revision recd. 20 nov 17 accepted 26 nov 17 doi: 10.18295/squmj.2017.17.04.001 the role of patients’ families in cancer treatment decision-making perspectives among eastern and western families e384 | squ medical journal, november 2017, volume 17, issue 4 tdm process, perhaps due to a strong sense of moral responsibility.7,16 in certain middle eastern, north african and south asian societies, the family has final authority in tdm, as often the patient is inseparably linked to the family as a whole.17 for example, the majority of cancer patients in south korea preferred shared tdm with their family members, although it was noted that there may be disagreements between family members and patients.7 in a study from pakistan, family members sometimes met the physician independently and gave consent for treatment on the patient’s behalf.18 furthermore, physicians of cancer patients in china and japan actually preferred to consult primarily with family members, giving these individuals the authority to decide whether to involve the patient in the tdm process at all.15,19 in oman, some oncologists have noted that family members play a significant role in the tdm process, sometimes to the extent that the patient loses their autonomy; this can delay treatment and even affect survival.20 another study found that, in some arabic countries, male family members held the dominant role in the tdm process, particularly if the patient was female.21 nevertheless, while most cancer patients seem to prefer family involvement in the tdm process, many physicians in western countries have raised concerns regarding the potential loss of patient autonomy when family members become involved in treatment.8 in such countries, the individual rights of cancer patients are respected and protected by physicians; therefore, family members retain only limited powers when it comes to intervening in medical care, particularly in cases wherein the patient is deemed competent enough to make their own decisions.14,16 however, physicians may sometimes encounter family members who ask them not to involve the patient in the tdm process or even, in some cases, not to inform the patient of their diagnosis at all.22 although many physicians welcome varying levels of family involvement in tdm, most families are naturally cautious of challenging the physician’s professional authority and intervening with the patient’s treatment.23 some physicians could react negatively to family members’ requests if they believe them to be in breach of the patient’s dignity and/or autonomy. indeed, medical law in many western countries states that, in the majority of circumstances, the patients themselves have the final decision with regards to tdm.17 however, the cultural background of the physicians may influence their response to involving family members in the tdm process. one study conducted in the usa showed that the majority of physicians of japanese heritage would obey a family’s request not to involve the cancer patient in tdm while very few north american physicians would consent to this request.24 in western countries, the concept of relational autonomy, which considers the individualistic perception of autonomy within a larger social framework, allows for the inclusion of family members in the tdm process.17 thus, physicians are requested to abide by their patients’ expressed wishes with regards to family involvement in tdm and to consider the family’s opinions during care, in the absence of any evidence of abuse or neglect.23 nevertheless, research conducted in the uk indicated that while the relatives of cancer patients influenced the decision-making process itself, the final decision was ultimately left to the patient.25 similarly, most australian physicians reported positive attitudes towards family involvement in tdm, but had concerns regarding a number of challenges which can arise when family members are involved in tdm, although the overall benefits of familial involvement were found to outweigh the costs.26 therefore, while family involvement in decision-making is often apprec iated, preferences for the nature and extent of their involvement may vary based on other influencing factors. as such, it may be beneficial if physicians ascertain individual patients’ preferences and remain open-minded regarding the various ways that the patient’s family can be involved. in summary, tdm in cancer cases is complex, as it involves the patient, the patient’s family members and physicians, with each stakeholder potentially having a different opinion regarding the patient’s medical needs. when it comes to the degree of acceptance of familial involvement, it seems that the most important factor is not the specific location but the cultural background of those involved. while individuals from western cultures perceive that the patient’s dignity and autonomy must be protected above all, family members of eastern cultures may not necessarily agree. further understanding of the differences between western and eastern cultures is needed. moreover, the concept of relational autonomy does not take into consideration the cultural background of the patient or allow family members any legal authority. as such, new legislation may need to be proposed, should family members wish to become more involved in the tdm process in certain countries. however, it is vital that such involvement be considered only in agreement with the patient’s wishes as evidenced by a recorded conversation with the provider present, or a legal document (i.e. a power of attorney or advanced legal directive) that specifies the conditions under which the patient desires their family be involved in the tdm process. abdulrahim al-bahri, mansour al-moundhri and mohammed al-azri editorial | e385 references 1. charles c, gafni a, whelan t. decision-making in the physician-patient encounter: revisiting the shared treatment decision-making model. soc sci med 1999; 49:651–61. doi: 10.1016/s0277-9536(99)00145-8. 2. whelan t, levine m, willan a, gafni a, sanders k, mirsky d, et al. effect of a decision aid on knowledge and treatment decision making for breast cancer surgery: a randomized trial. jama 2004; 292:435–41. doi: 10.1001/jama.292.4.435. 3. joosten ea, defuentes-merillas l, de weert gh, sensky t, van der staak cp, de jong ca. systematic review of the effects of shared decision-making on patient satisfaction, treatment adherence and health status. psychother psychosom 2008; 77:219–26. doi: 10.1159/000126073. 4. singh ja, sloan ja, atherton pj, smith t, hack tf, huschka mm, et al. preferred roles in treatment decision making among patients with cancer: a pooled analysis of studies using the control preferences scale. am j manag care 2010; 16:688–96. 5. alden dl, friend j, lee py, lee yk, trevena l, ng cj, et al. who decides: me or we? family involvement in medical decision making in eastern and western countries. med decis making 2017; 1:272989x17715628. doi: 10.1177/0272989x177 15628. 6. kim sh. preferences for autonomy in end-of-life decision making in modern korean society. nurs ethics 2015; 22:228–36. doi: 10.1177/0969733014523168. 7. shin dw, cho j, roter dl, kim sy, sohn sk, yoon ms, et al. preferences for and experiences of family involvement in cancer treatment decision-making: patient-caregiver dyads study. psychooncology 2013; 22:2624–31. doi: 10.1002/pon.3339. 8. laidsaar-powell r, butow p, bu s, charles c, gafni a, fisher a, et al. family involvement in cancer treatment decision-making: a qualitative study of patient, family, and clinician attitudes and experiences. patient educ couns 2016; 99:1146–55. doi: 10.1016/j.pec.2016.01.014. 9. burkhalter je, bromberg sr. family-oncologist communication in cancer patient care. cancer invest 2003; 21:915–23. doi: 10.1081/cnv-120025094. 10. pardon k, deschepper r, stichele rv, bernheim jl, mortier f, bossuyt n, et al. preferences of patients with advanced lung cancer regarding the involvement of family and others in medical decision-making. j palliat med 2010; 13:1199–203. doi: 10.1089/jpm.2010.0100. 11. hobbs gs, landrum mb, arora nk, ganz pa, van ryn m, weeks jc, et al. the role of families in decisions regarding cancer treatments. cancer 2015; 121:1079–87. doi: 10.1002/ cncr.29064. 12. al-azri mh, al-awisi h, al-rasbi s, al-moundhri m. coping with a diagnosis of breast cancer among omani women. j health psychol 2014; 19:836–46. doi: 10.1177/1359105313479813. 13. stenberg u, cvancarova m, ekstedt m, olsson m, ruland c. family caregivers of cancer patients: perceived burden and symptoms during the early phases of cancer treatment. soc work health care 2014; 53:289–309. doi: 10.1080/0098 1389.2013.873518. 14. cherry mj. re-thinking the role of the family in medical decision-making. j med philos 2015; 40:451–72. doi: 10.1093/ jmp/jhv011. 15. kitayama s, park h, sevincer at, karasawa m, uskul ak. a cultural task analysis of implicit independence: comparing north america, western europe, and east asia. j pers soc psychol 2009; 97:236–55. doi: 10.1037/a0015999. 16. bian l. medical individualism or medical familism? a critical analysis of china’s new guidelines for informed consent: the basic norms of the documentation of the medical record. j med philos 2015; 40:371–86. doi: 10.1093/jmp/jhv016. 17. gilbar r, miola j. one size fits all? on patient autonomy, medical decision-making, and the impact of culture. med law rev 2015; 23:375–99. doi: 10.1093/medlaw/fwu032. 18. humayun a, fatima n, naqqash s, hussain s, rasheed a, imtiaz h, et al. patients’ perception and actual practice of informed consent, privacy and confidentiality in general medical outpatient departments of two tertiary care hospitals of lahore. bmc med ethics 2008; 9:14. doi: 10.1186/14726939-9-14. 19. sekimoto m, asai a, ohnishi m, nishigaki e, fukui t, shimbo t, et al. patients’ preferences for involvement in treatment decision making in japan. bmc fam pract 2004; 5:1. doi: 10.1186/ 1471-2296-5-1. 20. burney ia. the trend to seek a second opinion abroad amongst cancer patients in oman: challenges and opportunities. sultan qaboos univ med j 2009; 9:260–3. 21. moghadam vm. patriarchy in transition: women and the changing family in the middle east. j comp fam stud 2004; 35:137–62. 22. mccabe ms, wood wa, goldberg rm. when the family requests withholding the diagnosis: who owns the truth? j oncol pract 2010; 6:94–6. doi: 10.1200/jop.091086. 23. ho a. relational autonomy or undue pressure? family’s role in medical decision-making. scand j caring sci 2008; 22:128–35. doi: 10.1111/j.1471-6712.2007.00561.x. 24. gabbay bb, matsumura s, etzioni s, asch sm, rosenfeld ke, shiojiri t, et al. negotiating end-of-life decision making: a comparison of japanese and u.s. residents’ approaches. acad med 2005; 80:617–21. 25. gilbar r. family involvement, independence, and patient autonomy in practice. med law rev 2011; 19:192–234. doi: 10.1093/medlaw/fwr008. 26. laidsaar-powell r, butow p, bu s, fisher a, juraskova i. oncologists’ and oncology nurses’ attitudes and practices towards family involvement in cancer consultations. eur j cancer care (engl) 2017; 26:e12470. doi: 10.1111/ecc.12470. https://doi.org/10.1016/s0277-9536%2899%2900145-8 https://doi.org/10.1001/jama.292.4.435 https://doi.org/10.1159/000126073 https://doi.org/10.1177/0272989x17715628 https://doi.org/10.1177/0272989x17715628 https://doi.org/10.1177/0969733014523168 https://doi.org/10.1002/pon.3339 https://doi.org/10.1016/j.pec.2016.01.014 https://doi.org/10.1081/cnv-120025094 https://doi.org/10.1089/jpm.2010.0100 https://doi.org/10.1002/cncr.29064 https://doi.org/10.1002/cncr.29064 https://doi.org/10.1177/1359105313479813 https://doi.org/10.1080/00981389.2013.873518 https://doi.org/10.1080/00981389.2013.873518 https://doi.org/10.1093/jmp/jhv011 https://doi.org/10.1093/jmp/jhv011 https://doi.org/10.1037/a0015999 https://doi.org/10.1093/jmp/jhv016 https://doi.org/10.1093/medlaw/fwu032 https://doi.org/10.1186/1472-6939-9-14 https://doi.org/10.1186/1472-6939-9-14 https://doi.org/10.1186/1471-2296-5-1 https://doi.org/10.1186/1471-2296-5-1 https://doi.org/10.1200/jop.091086 https://doi.org/10.1111/j.1471-6712.2007.00561.x https://doi.org/10.1093/medlaw/fwr008 https://doi.org/10.1111/ecc.12470 biomedical science programme, school of diagnostic science & applied health, faculty of health sciences, universiti kebangsaan malaysia, kuala lumpur, malaysia *corresponding author’s e-mail: zyantey@ukm.edu.my دور مكمالت األسيتيل سيستني على مستويات اإلجهاد التأكسدي والسمية الوراثية وقابلية عودة اإلنتساب للخاليا اجلذعية املستخلصة حيوياً خارج اجلسم يف الفئران أو اخلاليا اجلذرية زاريانتي حامد، هيو تان، پايك ت�شو، خريو هارتو، ت�شن ت�شان، جمال الدين حممد abstract: objectives: the ex vivo maintenance of haematopoietic stem/progenitor cells (hspcs) is crucial to ensure a sufficient supply of functional cells for research or therapeutic applications. however, when exposed to reactive oxygen species (ros) in a normoxic microenvironment, hspcs exhibit genomic instability which may diminish their quantity and quality. this study aimed to investigate the role of n-acetylcysteine (nac) supplementation on the oxidative stress levels, genotoxicity and lineage commitment potential of murine haematopoietic stem/progenitor cells (hspcs). methods: this study was carried out at the universiti kebangsaan malaysia, kuala lumpur, malaysia, between june 2016 and july 2017. bone marrow cells were isolated from nine mice and cultured in a growth medium. various concentrations of nac between 0.125–2 µm were added to the culture for 48 hours; these cells were then compared to non-supplemented cells harvested from the remaining three mice as the control group. a trypan blue exclusion test was performed to determine cell viability, while intracellular ros levels and genotoxicity were determined by hydroethidine staining and comet assay, respectively. the lineage commitment potential of erythroid, myeloid and pre-b-lymphoid progenitor cells was evaluated via colony-forming cell assay. results: nac supplementation at 0.25, 0.5 and 2 µm significantly increased cell viability (p <0.050), while intracellular ros levels significantly decreased at 0.25 and 0.5 µm (p <0.050). moreover, dna damage was significantly reduced at all nac concentrations (p <0.050). finally, the potential lineage commitment of the cells was not significantly affected by nac supplementation (p >0.050). conclusion: the findings of this study indicate that nac supplementation may potentially overcome the therapeutic limitations of ex vivo-maintained hspcs. keywords: hematopoietic stem cells; n-acetylcysteine; reactive oxygen species; dna damage; cell lineage. امللخ�ص: الهدف: اإن �شيانة اخلاليا اجلذعية املكونة للدم واخلاليا اجلذرية بالطريقة احليوية خارج اجل�شم يعترب �رضوريًا ل�شمان توفري ما يكفي من اخلاليا املختربية احليوية والقابلة لالإ�شتخدام لغر�ض الأبحاث اأو لالإ�شتخدامات العالجية، لكن عند تعر�ض مثل هذه اخلاليا لعنا�رضالأك�شجني التفاعلية يف بيئة متعادلة، تظهر اخلاليا الدموية اجلذعية حالة عدم ا�شتقرار جيني مما قد يقلل من عددها وجودتها، وال�شمية التاأك�شدي الإجهاد م�شتويات يف )n-acetylcysteine(-شي�شتني� الأ�شيتيل مكمالت دور معرفة اإىل الدرا�شة هذه هدفت لذلك الوراثية وقابلية عودة الإنت�شاب للخاليا اجلذعية امل�شتخل�شة خارج اجل�شم يف الفئران اأو اخلاليا اجلذرية. الطريقة: اأجريت هذه الدرا�شة يف جامعة كيباجن�شان يف كوال ملبور-ماليزيا، يف الفرتة بني يونيو 2016 ويوليو 2017، مت خاللها عزل خاليا النخاع العظمي ا�شتخرجت من عدد ت�شعة الفئران ومت تربية اخلاليا يف و�شط ا�شتنبات، متت اإ�شافة الأ�شيتيل �شي�شتني برتاكيز ترتاوح بني 2–0.125 ميكرومرت للو�شط ال�شتنباتي وملدة 48 �شاعة، ثم متت مقارنة هذه اخلاليا بخاليا مت ا�شتخال�شها من الفئران الثالثة املتبقية دون اأن يتم ا�شافة اأي مركبات لها لتقوم بدور جمموعة ال�شبط، مت اإجراء اختبار ا�شتبعاد با�شتخدام الرتيبان الأزرق لتحديد حيوية اخللية، يف حني مت حتديد م�شتويات مت كما املذنبي، املعايرة فح�ض طريق عن اجلينية وال�شميِّة هيدرواإثيدين �شبغة طريق عن اخلاليا داخل التفاعلية عنا�رضالأك�شجني خلية معايرة اختبار طريق عن نوع-ب اللمفاوي التمايز قبل ما الأ�شل اأو النخاعي الأ�شل اإىل الإنت�شابي اخلاليا التزام تقييم اإمكانية مكونة لكتلة ال�شتنبات. النتائج: مكمالت الأ�شيتيل �شي�شتني بالرتاكيز 0.25، 0.5 و 2 ميكرومرت اأدت اإىل زيادة ملحوظة يف حيوية اخللية ميكرومرت 0.5 و 0.25 الرتاكيز يف ملحوظ ب�شكل اخلاليا داخل التفاعلية عنا�رضالأك�شجني م�شتويات انخف�شت حني يف ،)p >0.050( .)p >0.050( عالوة على ذلك، لوحظ انخفا�ض معدل تلف احلم�ض النووي ب�شكل ملحوظ يف جميع تركيزات الأ�شيتيل �شي�شتني ،)p >0.050( واأخرًيا، مل يتاأثر التزام الن�شب املحتمل للخاليا بدرجة كبرية بعد ا�شافة الأ�شيتيل �شي�شتني )p >0.050(. اخلال�صة: اإن نتائج هذه الدرا�شة للدم املكونة اجلذعية للخاليا العالجي ال�شتخدام حمدودية من التقليل يف ي�شاهم قد �شي�شتني الأ�شيتيل مكمالت ا�شافة اأن اإىل ت�شري واخلاليا اجلذرية امل�شتنبتة حيويًا خارج اجل�شم. الكلمات املفتاحية: اخلاليا اجلذعية املكونة للدم؛ الأ�شيتيل �شي�شتني؛ عنا�رض الك�شجني التفاعلية؛ تلف احلم�ض النووي؛ انت�شاب اخللية. the role of n-acetylcysteine supplementation on the oxidative stress levels, genotoxicity and lineage commitment potential of ex vivo murine haematopoietic stem/progenitor cells *zariyantey a. hamid, hui y. tan, paik w. chow, khairul a. w. harto, chin yi chan, jamaludin mohamed clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e130–136, epub. 9 sep 18 submitted 3 oct 17 revisions req. 13 dec 17 & 23 jan 18; revisions recd. 14 jan & 4 feb 18 accepted 15 feb 18 doi: 10.18295/squmj.2018.18.02.002 zariyantey a. hamid, hui y. tan, paik w. chow, khairul a. w. harto, chin yi chan and jamaludin mohamed clinical and basic research | e131 haematopoietic stem/progenitor cells (hspcs) constitute a highly promising avenue for medical treatment and research; however, their potency is determined by their ability to selfrenew and differentiate into multiple lineages.1,2 prior to clinical use, stem cells often undergo ex vivo expansion—in which the cells are harvested from an intact organism and directly cultured in a laboratory setting without any biological modification—so as to ensure a sufficient number of functional cells can be harvested.3,4 in contrast, in vitro stem cells are obtained from a repository or cell lines that have been genetically transformed. physiologically, hspcs are found in the bone marrow under conditions of low oxygen tension (1–4%).5,6 this microenvironment is known as a hypoxic niche and plays a critical role in regulating hspc expan sion and cellular levels of reactive oxygen species (ros). however, the ex vivo expansion and maintenance of hspcs requires that the cells adjust to normoxic condi tions with greater oxygen tension (21%) and enhanced ros production.7 these conditions can interfere with the self-renewal capacities of hspcs and promote differentiation, leading to premature senescence and therefore fewer functional stem cells for transplantation.7,8 moreover, excessive ros production can result in genomic instability, thus compromising the quality of the stem cells and limiting their therapeutic potential.9,10 numerous efforts have been made to over come the limitations associated with the ex vivo expan sion and maintenance of hspcs, including genetic modification, co-culturing with feeder cells and the addition of a cytokine cocktail; however, these approaches have various drawbacks.11–15 recent research has indicated that the use of antioxidants may be a promising ex vivo expansion technique due to their role as excess ros scavengers.10,16,17 n-acetylcysteine (nac) is an antioxidant generated from the thiol-containing amino acid cysteine and is the precursor for glutathione.16,18 at a concentration of 0.1 µm, nac supplementation has been reported to preserve the chromosomal stability of cultured hspcs.19,20 nonetheless, while previous studies have documented the benefits of nac supplementation in maintaining haematopoiesis, few have examined their use in the ex vivo maintenance of hspcs or focused on oxidative-mediated cellular damage and lineage commitment.21,22 this study therefore aimed to determ ine the effect of nac supplementation on the survivability, dna integrity, cellular ros levels and lineage commitment potential of ex vivo hspcs. methods this study was carried out at the universiti kebangsaan malaysia, kuala lumpur, malaysia, between june 2016 and july 2017. a total of 12 imprinting control region male mice were included in the study, all of which were 10 weeks old and weighed 30–35 g. bone marrow cells from three mice were each allocated to an experimental group, while bone marrow cells from the remaining three mice constituted the control group. each experiment to determine cell viability, cellular ros production and dna integrity status was repeated in triplicate using 1 × 106 cells from a different mouse in each group, while 1 × 106 cells were used to determine the lineage commitment potential of erythroid and pre-b lymphoid progenitor cells and 1 × 105 cells were used for myeloid progenitor cells. each mouse was killed by cervical dislocation and the tibia and femur were isolated. pre-cooled gibco® dulbecco’s modified eagle’s medium (dmem; thermo fisher scientific, waltham massachusetts, usa) was flushed over the bones using a 21 gauge needle and a 10 ml syringe. harvested cells were subsequently filtered through a 40 µm cell strainer, centrifuged at 2,500 rpm for 7 minutes and resuspended in a growth medium consisting of dmem supplemented with 10% fetal bovine serum and 1% penicillinstreptomycin (thermofisher scientific). a cocktail of growth factors consisting of 100 ng/ml of stem cell factor, 10 ng/ml of interleukin (il)-6 and 5 ng/ml of il-3 was then added to the culture (miltenyi biotec, bergisch gladbach, germany). approximately 1 × 107 bone marrow cells were obtained from each mouse.10 the cells were then maintained in a 5% carbon dioxide (co2) incubator at 37 °c for 24 hours. subsequently, nac was added to cells in the experiadvances in knowledge n-acetylcysteine (nac) supplementation may potentially overcome some of the therapeutic limitations associated with the ex vivo expansion and maintenance of haematopoietic stem/progenitor cells (hspcs). specifically, nac supplementation was found to enhance the survivability of murine hspcs, while also suppressing reactive oxygen species production and dna damage and maintaining lineage commitment potential. application to patient care preservation of the quantity, quality and genomic stability of hspcs can improve the usefulness of such cells for various medical therapeutic and research applications. the role of n-acetylcysteine supplementation on the oxidative stress levels, genotoxicity and lineage commitment potential of ex vivo murine haematopoietic stem/progenitor cells e132 | squ medical journal, may 2018, volume 18, issue 2 mental groups at various concentrations (0.125, 0.25, 0.5, 1 or 2 µm) for an additional 48 hours.20 cells with out nac supplementation were used as the control group for all parameters. however, an additional positive control group was used to analyse dna damage, for which the cells received 100 µm of hydrogen peroxide for 30 minutes in a 5% co2 incubator at 37 °c. a trypan blue exclusion test was performed to quantify the number of viable cells in samples from both the experimental and control groups. the cells were seeded into 24-well plates containing hspc growth medium at a density of 1 × 106 cells/ml. the cell suspension cultures were then diluted at a ratio of 1:1 with 0.4% trypan blue solution, after which the number of viable cells were counted using a microscope. cellular ros production was determined as follows. the cells were harvested and centrifuged at 2,500 rpm for 7 minutes. approximately 1 × 106 cells were then resuspended in 1 ml of prewarmed unenriched dmem medium, stained with 10 mm of hydroethidine (he; sigma-aldrich corp., st. louis, missouri, usa) and incubated in the dark for 30 minutes in a 5% co2 incubator at 37 °c. the he-stained cells were then washed twice and centrifuged at 2,500 rpm for 5 minutes at 4 °c. the supernatant was discarded and the cell pellets resuspended in 500 μl of cold phosphate-buffered saline (pbs).10 subsequently, the intensity of he fluorescence was measured using the bd facscanto™ ii flow cytometry system (bd biosciences, san jose, california, usa), with ros production expressed as the percentage of ros-producing cells. the potentially genotoxic effect of nac supplementation was assessed via alkaline comet assay using microgel electrophoresis.23 this technique was employed due to its improved detection sensitivity in comparison to direct quantification methods which do not supply current or voltage after the unwinding and neutralisation of the dna.23,24 a total of 1 × 106/ml of cells from each group were harvested and centrifuged at 2,500 rpm for 5 minutes at 4 °c. the cells were then washed twice in a calciumand magnesium-free pbs and recentrifuged at 1,200 rpm for 5 minutes at 4 °c. the cell pellets were mixed with 70 μl of 0.6% normal melting point agarose (nmpa) gel (sigma-aldrich corp.). the mixture was loaded onto a full-frosted microscope slide, topped with a coverslip and left to cool on ice for 15 minutes. once the gel had solidified, the coverslip was gently removed and a layer of 80 μl of low melting point agarose gel (sigma-aldrich corp.) was added on top of the nmpa layer. next, the solidified slide was immersed overnight into a lysis buffer consisting of 2.5 m of sodium chloride, 100 mm of disodium ethylenediaminetetraacetic acid, 10 mm of tris(hydroxymethyl)aminomethane and 1% triton™ x-100 (sigma-aldrich corp.) at 4 °c. the slides were then equilibrated in an electrophoresis buffer at 300 ma for 20 minutes and then 25 v for 20 minutes, before being rinsed three times in a neutralisation buffer for 5 minutes each rinse. thereafter, the slides were stained with 25 μl of ethidium bromide (thermofisher scientific) at 20 μg/ml and viewed under a leica fluorescence microscope (meyers instruments, houston, texas, usa) using a 590 nm excitation filter. the amount of dna in the tail and the tail moment of 100 cells per slide was subsequently analysed using cometscore software (tritek technologies inc., annandale, virginia, usa). the lineage commitment potential of the erythroid, myeloid and lymphoid progenitor cells was determ ined via colony-forming cell assay using three types of methylcelluloses (methocult™ gf m3334, gf m3534 and m3630, stemcell™ technologies inc., vancouver, canada). these methylcelluloses were used to support the growth of colony-forming unit (cfu)erythroid, cfu-granulocytes (g), cfu-macrophages (m), cfu-gm and cfu-lymphoid (cfu-pre-b) cells. myeloid progenitor cells were classified as cfu-g, cfu-m or cfu-gm, based on a morphological analysis of the colonies derived from the assay. the plating density was optimised at 2 × 105 cells/ml for cfugm, 1 × 106 cells/ml for cfu-e and 1 × 106 cells/ml for cfu-pre-b. the cell and methylcellulose mixture was then placed into a six-well plate and incubated at 37 °c for either seven (for cfu-e and cfu-pre-b) or 14 (for cfu-gm) days. the number of colonies was then determined via light microscope observation. statistical analysis was conducted using the statist ical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the results were presented as means ± standard error and displayed graphically in the form of histograms or plot diagrams. a p value of <0.050 was considered statistically significant. a shapiro-wilk test was conducted to determine the normality of the data. where the assumption of normality was not rejected, an independent student’s t-test was employed to test the differences in studied parameters between nac-supplemented and control cell groups. all procedures involving the use of laboratory animals in this study were reviewed and approved by the animal ethics committee of the universiti kebangsaan malaysia (#fsk/2016/zariyantey/27-july/ 773-july-2016-june-2017-ar-cat2). results in terms of cell viability, there were significantly more viable cells noted among hspcs supplemented with zariyantey a. hamid, hui y. tan, paik w. chow, khairul a. w. harto, chin yi chan and jamaludin mohamed clinical and basic research | e133 0.25 μm (8.47 ± 0.29 × 105 cells/ml; p = 0.001), 0.5 μm (8.32 ± 0.72 × 105 cells/ml; p = 0.014) and 2 μm (6.37 ± 0.16 × 105 cells/ml; p = 0.011) of nac in comparison to the control group (5.18 ± 0.20 × 105 cells/ml) [figure 1]. cellular ros production was also significantly lower among cells supplemented with 0.25 µm (10.23 ± 0.47%; p = 0.011) and 0.5 µm (9.83 ± 1.43%; p = 0.040) of nac, as compared to the control group (12.20 ± 1.01%) [figure 2]. among nac-supplemented cells, dna damage was significantly suppressed, with the percentage of dna in the tail being 7.65 ± 0.40% (p = 0.048), 6.89 ± 0.08% (p = 0.022) and 5.96 ± 0.98% (p = 0.027) for concentrations of 0.25, 0.5 and 2 µm of nac, respectively, in comparison to the control group (11.08 ± 1.15%) [figure 3a]. in addition, there was also a significant reduction in the tail moment of nac-supplemented cells at concentrations of 0.25 µm (0.65 ± 0.06 arbitrary units [aus]; p = 0.002), 0.5 µm (0.71 ± 0.12 aus; p = 0.003) and 2 µm (0.34 ± 0.03 aus; p = 0.001), as compared to the control group (2.04 ± 0.10 aus) [figure 3b]. regarding the effect of nac supplementation on the lineage commitment potential of erythroid, lymphoid and myeloid progenitor cells, there was no significant difference in colony count for cfu-gm at 0.25 µm (82.67 ± 11.05 × 105 cells/ml; p = 0.075), 0.5 µm (77.00 ± 12.74 × 105 cells/ml; p = 0.063) and 2 µm (69.33 ± 18.67 × 105 cells/ml; p = 0.072) of nac supplementation, in comparison to the control group (128.67 ± 15.76 × 105 cells/ml). for cfu-g, the control group again demonstrated the highest number of colonies (61.67 ± 7.88 × 105 cells/ml); however, this difference was not significant in comparison to cells supplemented with 0.25 µm (36.00 ± 9.64 × 105 cells/ml; p = 0.108), figure 3: histograms showing the effect of 48-hour n-acetylcysteine (nac) supplementation on (a) the percentage of tail dna and (b) the tail moment of ex vivo haematopoietic stem/progenitor cells. cells treated with 100 µm of hydrogen peroxide served as a positive control group for the purposes of assay validation. all values represent means ± standard error. h2o2 = hydrogen peroxide; nac = n-acetylcysteine; aus = arbitrary units. *significant difference in comparison to the control group (p <0.050). figure 1: plot diagram showing the effect of 48-hour n-acetylcysteine (nac) supplementation on the viability of ex vivo haematopoietic stem/progenitor cells. all values represent means ± standard error. nac = n-acetylcysteine. *significant difference in comparison to the control group (p <0.050). figure 2: histogram showing the effect of 48-hour n-acetylcysteine supplementation on the level of reactive oxygen species in ex vivo haematopoietic stem/progenitor cells. all values represent means ± standard error. ros = reactive oxygen species; nac = n-acetylcysteine. *significant difference in comparison to the control group (p <0.050). the role of n-acetylcysteine supplementation on the oxidative stress levels, genotoxicity and lineage commitment potential of ex vivo murine haematopoietic stem/progenitor cells e134 | squ medical journal, may 2018, volume 18, issue 2 0.5 µm (50.33 ± 12.60 × 105 cells/ml; p = 0.393) or 2 µm (36.67 ± 6.69 × 105 cells/ml; p = 0.073) of nac. similar results were noted for cfu-m, with the highest colony count identified in the control group (37.00 ± 7.81 × 105 cells/ml), followed by cells supplemented with 0.5 µm (30.33 ± 10.41 × 105 cells/ml; p = 0.636), 0.25 μm (27.00 ± 6.56 × 105 cells/ml; p = 0.382) and 2 µm (23.33 ± 6.44 × 105 cells/ml; p = 0.248) and of nac [figure 4a]. similarly, no significant differences in cfu-e counts were noted between nac-supplemented cells at 0.25 µm (84.30 ± 2.91 × 106 cells/ml; p = 0.330), 0.5 µm (65.00 ± 14.11 × 106 cells/ml; p = 0.177) and 2 µm (68.7 ± 7.84 × 106 cells/ml; p = 0.073) and those in the control group (88.30 ± 2.19 × 106 cells/ml). the colony counts for cfu-pre-b also showed no significant difference between the control group (47.00 ± 6.08 × 106 cells/ml) and the nac-supplemented cells at concentrations of 0.25 µm (48.00 ± 4.58 × 106 cells/ml; p = 0.902), 0.5 µm (42.67 ± 11.05 × 105 cells/ml; p = 0.748) and 2 µm (34.00 ± 11.68 × 106 cells/ml; p = 0.379) [figure 4b]. discussion maintenance of ros production at optimum levels is crucial to regulate the intracellular and extracellular signalling pathways involved in the self-renewal and differentiation activities of hspcs.5,25 excessive levels of ros can trigger cells to undergo differentiation rather than self-renewal, while too few ros can inhibit prolif eration.26 the production of ros is closely related to cellular respiration among metabolically inactive hspcs in a dormant state.6–8 inversely, when hspcs are placed under stress, such as in normoxic conditions, mitochon drial activities are elevated and contribute to elevated ros production.5,27 previous studies have reported that altering the microenvironment of hspcs to normoxic conditions can lead to a reduction in the number of hspcs due to an increase in differentiation, premature ageing and apoptosis.7,28 in the current study, nac supplementation was found to enhance the survivability of hspcs at specific concentrations (0.25, 0.5 and 2 μm). moreover, hspcs which did not receive nac supplementation showed the lowest cell viability. this finding is in accordance with a previous study which reported the beneficial effects of nac in minimising cytotoxicity among irradiated rat bone marrow cells by improving the mitotic index.22 moreover, the current study found that nac supplementation at concentrations of 0.25 and 0.5 µm suppressed cellular ros levels; this finding is in agreement with those of a previous study.5 altinoz et al. also demonstrated the protective role of nac against acrylamide-induced oxidative stress in rats.29 it can therefore be postulated that optimum ros levels play a role in promoting survivability and maintenance in hspcs. increased ros production can overload the cellular antioxidant capacity, exposing macromolecules such as dna, ribonucleic acid and proteins to ros attack.30 this can lead to the accumulation of dna damage and premature cell ageing during long-term culturing.26 in the present study, nac supplementation was found to have a genoprotective function, as evidenced by the remarkably low levels of dna damage observed in nac-supplemented cells as compared to those in the control group. other studies have reported that nac has the ability to reverse dna damage in rat models with irradiated bone marrow, hepatopulmonary syndrome and acrylamide-induced genotoxicity.21,22,29 the current study also investigated the effects of nac supplementation on the lineage commitment potential of erythroid, myeloid and lymphoid progenitor cells and found that nac supplementation did not affect the lineage commitment potential of these respective progenitors. to the best of the authors’ knowledge, no previous studies have been conducted figure 4: histograms showing the effect of 48-hour n-acetylcysteine supplementation on the lineage commitment potential of ex vivo haematopoietic stem/progenitor cells. all values represent means ± standard error. cfu = colony-forming unit; m = macrophages; g = granulocytes; e = erythroid; pre-b = lymphoid; nac = n-acetylcysteine. zariyantey a. hamid, hui y. tan, paik w. chow, khairul a. w. harto, chin yi chan and jamaludin mohamed clinical and basic research | e135 to assess the lineage commitment potential among nac-supplemented ex vivo hspcs. however, a previous study reported that the administration of 100 µm of nac for four weeks in mice enhanced the repopulation of myeloid progenitors, as evidenced by increased colony counts.31 as previously discussed, hspcs are at greater risk of oxidative stress exposure following ex vivo main tenance, a factor which can impair their usefulness in terms of both quality and quantity.7–10 overall, the results of the present study indicate that nac may have a potential role as an antioxidant supplement for the optimal expansion and maintenance of hspcs, without compromising their potential for self-renewal and multilineage differentiation. however, further research is necessary to support these findings, especially considering the small sample size of the current study necessitated by financial constraints and the short study duration. nevertheless, despite these limitations, these findings may serve as a platform for future research exploring the use of antioxidants in hspc expansion and maintenance. conclusion the findings of this study support the use of nac supplementation for the ex vivo maintenance of hspcs by reducing oxidative stress and maintaining their selfrenewal and multilineage differentiation properties without genotoxic effects. however, further research with a larger sample size is needed to investigate the role of nac supplementation on the oxidative status and genomic stability of hspcs following long-term ex vivo maintenance. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded with the aid of a grant from the ministry of higher education in malaysia (grant #frgs/1/2016/skk13/ukm/03/1). references 1. doulatov s, notta f, laurenti e, dick je. hematopoiesis: a human perspective. cell stem cell 2012; 10:120–36. doi: 10. 1016/j.stem.2012.01.006. 2. boisset jc, robin c. on the origin of hematopoietic stem cells: progress and controversy. stem cell res 2012; 8:1–13. doi: 10.1016/j.scr.2011.07.002. 3. dahlberg a, delaney c, bernstein id. ex vivo expansion of human hematopoietic stem and progenitor cells. blood 2011; 117:6083–90. doi: 10.1182/blood-2011-01-283606. 4. bird ga, polsky a, estes p, hanlon t, hamilton h, morton jj, et al. expansion of human and murine hematopoietic stem and progenitor cells ex vivo without genetic modification using myc and bcl-2 fusion proteins. plos one 2014; 9:e105525. doi: 10.1371/journal.pone.0105525. 5. ludin a, gur-cohen s, golan k, kaufmann kb, itkin t, medaglia c et al. reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. antioxid redox signal 2014; 21:1605–19. doi: 10.1089/ars.2014.5941. 6. mantel cr, o’leary ha, chitteti br, huang x, cooper s, hangoc g, et al. enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. cell 2015; 161:1553–65. doi: 10.1016/j.cell.2015.04.054. 7. broxmeyer he, o’leary ha, huang x, mantel c. the importance of hypoxia and extra physiologic oxygen shock/ stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells exvivo. curr opin hematol 2015; 22:273–8. doi: 10.1097/moh. 0000000000000144. 8. shao l, li h, pazhanisamy sk, meng a, wang y, zhou d. reactive oxygen species and hematopoietic stem cell senescence. int j hematol 2011; 94:24–32. doi: 10.1007/s12185-0110872-1. 9. mohyeldin a, garzón-muvdi t, quiñones-hinojosa a. oxygen in stem cell biology: a critical component of the stem cell niche. cell stem cell 2010; 7:150–61. doi: 10.1016/j.stem.2010.07.007. 10. abdul hamid z, lin lin wh, abdalla bj, bee yuen o, latif es, mohamed j, et al. the role of hibiscus sabdariffa l. (roselle) in maintenance of ex vivo murine bone marrow-derived hematopoietic stem cells. scientificworldjournal 2014; 2014:258192. doi: 10.1155/2014/258192. 11. lee j, shieh jh, zhang j, liu l, zhang y, eom jy, et al. improved ex vivo expansion of adult hematopoietic stem cells by over coming cul4-mediated degradation of hoxb4. blood 2013; 121:4082–9. doi: 10.1182/blood-2012-09-455204. 12. amsellem s, pflumio f, bardinet d, izac b, charneau p, romeo ph, et al. ex vivo expansion of human hematopoietic stem cells by direct delivery of the hoxb4 homeoprotein. nat med 2003; 9:1423–7. doi: 10.1038/nm953. 13. ren z, jiang y. umbilical cord blood hematopoietic stem cell expansion ex vivo. j blood disord transfus 2013; s3:004. doi: 10.4172/2155-9864.s3-004. 14. takagi m. cell processing engineering for ex-vivo expansion of hematopoietic cells. j biosci bioeng 2005; 99:189–96. doi: 10.12 63/jbb.99.189. 15. watts kl, adair j, kiem hp. hematopoietic stem cell expansion and gene therapy. cytotherapy 2011; 13:1164–71. doi: 10.3109/ 14653249.2011.620748. 16. berniakovich i, laricchia-robbio l, izpisua belmonte jc. n-acetylcysteine protects induced pluripotent stem cells from in vitro stress: impact on differentiation outcome. int j dev biol 2012; 56:729–35. doi: 10.1387/ijdb.120070ji. 17. luo l, kawakatsu m, guo cw, urata y, huang wj, ali h, et al. effects of antioxidants on the quality and genomic stability of induced pluripotent stem cells. sci rep 2014; 4:3779. doi: 10.1038/srep03779. 18. moslehi a, taghizadeh-ghehi m, gholami k, hadjibabaie m, jahangard-rafsanjani z, sarayani a, et al. n-acetyl cysteine for prevention of oral mucositis in hematopoietic sct: a doubleblind, randomized, placebo-controlled trial. bone marrow trans plant 2014; 49:818–23. doi: 10.1038/bmt.2014.34. 19. hu l, cheng h, gao y, shi m, liu y, hu z, et al. antioxidant n-acetyl-l-cysteine increases engraftment of human hematopoietic stem cells in immune-deficient mice. blood 2014; 124:e45–8. doi: 10.1182/blood-2014-03-559369. https://doi.org/10.1016/j.stem.2012.01.006 https://doi.org/10.1016/j.stem.2012.01.006 https://doi.org/10.1016/j.scr.2011.07.002 https://doi.org/10.1182/blood-2011-01-283606 https://doi.org/10.1371/journal.pone.0105525 https://doi.org/10.1089/ars.2014.5941 https://doi.org/10.1016/j.cell.2015.04.054 https://doi.org/10.1097/moh.0000000000000144 https://doi.org/10.1097/moh.0000000000000144 https://doi.org/10.1007/s12185-011-0872-1 https://doi.org/10.1007/s12185-011-0872-1 https://doi.org/10.1016/j.stem.2010.07.007 https://doi.org/10.1155/2014/258192 https://doi.org/10.1182/blood-2012-09-455204 https://doi.org/10.1038/nm953 https://doi.org/10.4172/2155-9864.s3-004 https://doi.org/10.1263/jbb.99.189 https://doi.org/10.1263/jbb.99.189 https://doi.org/10.3109/14653249.2011.620748 https://doi.org/10.3109/14653249.2011.620748 https://doi.org/10.1387/ijdb.120070ji https://doi.org/10.1038/srep03779 https://doi.org/10.1038/bmt.2014.34 https://doi.org/10.1182/blood-2014-03-559369 the role of n-acetylcysteine supplementation on the oxidative stress levels, genotoxicity and lineage commitment potential of ex vivo murine haematopoietic stem/progenitor cells e136 | squ medical journal, may 2018, volume 18, issue 2 20. liu am, qu ww, liu x, qu ck. chromosomal instability in in vitro cultured mouse hematopoietic cells associated with oxidative stress. am j blood res 2012; 2:71–6. 21. vercelino r, tieppo j, dias as, marroni ca, garcia e, meurer l, et al. n-acetylcysteine effects on genotoxic and oxidative stress parameters in cirrhotic rats with hepatopulmonary syndrome. basic clin pharmacol toxicol 2008; 102:370–6. doi: 10.1111/j. 1742-7843.2007.00181.x. 22. demirel c, kilçiksiz s, ay oi, gürgül s, ay me, erdal n. effect of n-acetylcysteine on radiation-induced genotoxicity and cytotoxicity in rat bone marrow. j radiat res 2009; 50:43–50. doi: 10.1269/jrr.08066. 23. singh np, mccoy mt, tice rr, schneider el. a simple technique for quantification of low levels of dna damage in individual cells. exp cell res 1988; 175:184–91. doi: 10.1016/ 0014-4827(88)90265-0. 24. rydberg b, johanson kj. estimation of dna strand breaks in single mammalian cells. in: hanawalt pc, fox cf, friedberg ec, eds. dna repair mechanisms, 1st ed. new york, usa: academic press, 1978. pp. 465–8. doi: 10.1016/b978-0-12-322650-1.50090-4. 25. glauche i, moore k, thielecke l, horn k, loeffler m, roeder i. stem cell proliferation and quiescence: two sides of the same coin. plos comput biol 2009; 5:e1000447. doi: 10.1371/journal. pcbi.1000447. 26. yahata t, takanashi t, muguruma y, ibrahim aa, matsuzawa h, uno t, et al. accumulation of oxidative dna damage restricts the self-renewal capacity of human hematopoietic stem cells. blood 2011; 118:2941–50. doi: 10.1182/blood-2011-01-330050. 27. beerman i, seita j, inlay ma, weissman il, rossi dj. quiescent hematopoietic stem cells accumulate dna damage during aging that is repaired upon entry into cell cycle. cell stem cell 2014; 15:37–50. doi: 10.1016/j.stem.2014.04.016. 28. seita j, weissman il. hematopoietic stem cell: self-renewal versus differentiation. wiley interdiscip rev syst biol med 2010; 2:640–53. doi: 10.1002/wsbm.86. 29. altinoz e, turkoz y. the protective role of n-acetylcysteine against acrylamide-induced genotoxicity and oxidative stress in rats. gene ther mol biol 2014; 16:35–43. 30. richardson c, yan s, vestal cg. oxidative stress, bone marrow failure, and genome instability in hematopoietic stem cells. int j mol sci 2015; 16:2366–85. doi: 10.3390/ijms16022366. 31. tothova z, kollipara r, huntly bj, lee bh, castrillon dh, cullen de, et al. foxos are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. cell 2007; 128:325–39. doi: 10.1016/j.cell.2007.01.003. https://doi.org/10.1111/j.1742-7843.2007.00181.x https://doi.org/10.1111/j.1742-7843.2007.00181.x https://doi.org/10.1269/jrr.08066 https://doi.org/10.1016/0014-4827%2888%2990265-0 https://doi.org/10.1016/0014-4827%2888%2990265-0 https://doi.org/10.1016/b978-0-12-322650-1.50090-4 https://doi.org/10.1371/journal.pcbi.1000447 https://doi.org/10.1371/journal.pcbi.1000447 https://doi.org/10.1182/blood-2011-01-330050 https://doi.org/10.1016/j.stem.2014.04.016 https://doi.org/10.1002/wsbm.86 https://doi.org/10.3390/ijms16022366 https://doi.org/10.1016/j.cell.2007.01.003 the optimal management of multi-vessel coronary artery disease (cad) is a complex medical decision with significant prognostic implications. despite the advent of clinical and angiographic scores to aid treatment delineation, therapy for multivessel cad should be tailored in each case with regards to the patient’s clinical presentation.1 coronary artery bypass grafting (cabg) surgery and percutaneous coronary intervention (pci) are potential treatment options for patients with advanced cad evaluated using the syntax score, as stated in the european society of cardiology and the european association for cardio-thoracic surgery guidelines on myocardial revascularisation.2 this case describes a patient with multivessel cad who was treated successfully with a combination of drug-eluting stents and bioresorbable vascular scaffolds. case report a 67-year-old male was admitted to the department of cardiac, thoracic & vascular sciences, padua university hospital, padua, italy, in 2014 with a non-st-elevation myocardial infarction. he had t wave inversion in leads v1–4 and mildly increased myocardial necrosis biomarkers (peak troponin i: 2.770 µg/l; upper reference value: 0.015 µg/l). the patient had previously experienced a silent myocardial dipartimento di scienze cardiologiche toraciche e vascolari, università degli studi di padova, padova, italy *corresponding author e-mail: ahmed.almamary@yahoo.com معاجلة امراض الشرايني التاجية متعددة األوعية باستخدام توليفة من الدعامات الدوائية احلديثة اأحمد املعمرى، فيليبو زيليو، ما�صيمو نابودانو abstract: optimal management of multivessel coronary artery disease can be complex. we report a 67-year-old male patient who was admitted to the padua university hospital, padua, italy, in 2014 with a non-st-elevation myocardial infarction. coronary angiography showed diffuse multiple sub-occlusive lesions of the proximal and distal left coronary vessels involving a long segment of the vessel. on intravascular ultrasonography (ivus), the left main artery was moderately diseased with critically stenotic and calcified branch ostia. a successful percutaneous coronary intervention using the t-stenting and small protrusion technique with two drug-eluting stents (des) was performed on the left main artery and its main branches. two bioresorbable vascular scaffolds were also deployed in overlap at the mid to distal segments of the left anterior descending artery and overlapping a previous des at the proximal segment. the full expansion and apposition of the struts and scaffolds to the vessel wall without residual stenosis was confirmed by ivus. keywords: drug-eluting stents; percutaneous coronary intervention; ultrasonography; coronary stenosis; myocardial infarction; case report; italy. اىل ادخل �صنه 67 العمر من بالغ ملري�ض حاله نعر�ض معقده. املتعددة التاجيه القلب �رضايني الأمرا�ض املثلى املعاجلة اإن امللخ�ص: الت�صخي�صية الق�صطرة اأظهرت .st ارتفاع بدون قلبي احت�صاء ب�صبب 2014 عام يف اإيطاليا، بادوفا، مبدينة بادوفا، جامعة م�صت�صفى ل�رضايني القلب التاجيه ت�صيقات ان�صداديه متعددة منت�رضة يف ال�رضايني التاجيه القا�صية والدانية الي�رضى ت�صمل جزء كبري منها. وجد عن طريق ا�صتخدام اال�صعه املوجيه داخل االأوعية الدمويه )ivus( اأن ال�رضيان التاجي الرئي�صي االأي�رض كان م�صابا اإ�صابة متو�صطة بت�صيق اإن�صدادي حاد متكل�ض. اأجري بنجاح راأب الوعاء التاجي من خالل تقنية ت�صمل اإجراء نتوء �صغري يف اجللد بدعامات t با�صتخدام دعاماتني يف مرتاكب ب�صكل الدموية االأوعية �صقاالت من اإثنني اإدخال مت الرئي�صية. وفروعه االأي�رض الرئي�صي ال�رضيان على )des( الدواء الدخال الن�صف االأخري لل�رضيان االأمامي االأي�رض النازل وركب على des �صابق يف اجلزء الداين. مت التاأكد من التو�صع ال�صامل للدعامات وال�صقاالت .ivus جلدار الوعاء الدموي دون ت�صيق متبقي عن طريق حاله؛ تقرير قلبي؛ احت�صاء تاجيه؛ ت�صيقات موجيه؛ اأ�صعه اجللد؛ طريق عن تاجيه عالجيه تدخالت الدوائي؛ النوع من تاجيه دعامه مفتاحية: كلمات اإيطاليا. a combination of drug-eluting stents and bioresorbable vascular scaffolds in the treatment of multivessel coronary artery disease *ahmed al-mamary, filippo zilio, massimo napodano sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e359–363, epub. 19 aug 16 submitted 5 jan 16 revision req. 24 feb 16; revision recd. 22 mar 16 accepted 14 apr 16 case report doi: 10.18295/squmj.2016.16.03.017 a combination of drug-eluting stents and bioresorbable vascular scaffolds in the treatment of multivessel coronary artery disease e360 | squ medical journal, august 2016, volume 16, issue 3 diffuse calcified and atherosclerotic segments with multiple sub-occlusive proximal and distal left cad lesions involving the left main trunk with haziness at the proximal segment of the left circumflex (lcx) artery. despite evaluation from several planes, the angiographic assessment was inconclusive and the stenosis of the proximal lcx artery remained unclear [figure 1]. intravascular ultrasonography (ivus) using a catheter (eagle eye® catheter, volcano corp., san diego, california, usa) revealed that the left main trunk was moderately diseased [figure 2] with critically calcified branch ostia. the angiographic syntax score of the patient was calculated to be 40. due to the anatomical complexity of the distal coronary arteries, the patient was referred for a multiple lesion pci. a decision was made to combine rigid cage stents for the proximal wide lumen segments and bioresorbable vascular scaffolds for the diffuse infarction without significant clinical sequelae as confirmed by echocardiographic follow-up which showed normal dimensions with preserved systolic left ventricular function (left ventricular end-diastolic volume index: 65 ml/m2; ejection fraction: 58%) without wall motion abnormalities. at this time, the patient was asymptomatic without residual ischaemia. this was confirmed by a negative exercise stress test at 150 w. the patient was a smoker and had several other cardiovascular risk factors, including hypertension, dyslipidaemia and type 2 diabetes mellitus. at presentation, the patient was immediately administered 250 mg of intravenous aspirin and 180 mg of oral ticagrelor. as he had a high global registry of acute coronary events risk score (145), an emergency coronary angiogram was carried out using the right radial artery. this revealed non-significant stenosis of the dominant right coronary artery and figure 1a–c: coronary angiography of a 67-year-old male patient from the (a) cranial right anterior oblique (rao), (b) caudal rao and (c) caudal left anterior oblique views showing multiple diffuse critical lesions of the proximal and distal segments of the left coronary arteries involving the left main trunk with a hazy proximal left circumflex artery (lcx) lesion. despite evaluation from several planes, the stenosis of the proximal lcx artery remained unclear. figure 2a–c: intravascular ultrasonography (ivus) of a 67-year-old male patient showing (a) moderate left main trunk disease, (b) multiple significant stenoses of the left anterior descending artery and (c) stenosis of the proximal left circumflex artery with eccentric superficial and deep dense calcific plaque (arrow). mla = minimal lumen area. ahmed al-mamary, filippo zilio and massimo napodano case report | e361 eluting stent (xience prime®) at the level of the left main trunk-proximal segment of the lad artery. this was followed by another 3.5 x 12.0 mm everolimus-eluting stent (xience prime®) at the left main trunk-proximal segment of the lcx artery. kissing balloon postdilation was then performed in the bifurcation of the left main, lad and lcx coronary arteries. finally, after the mid-distal lad artery lesions were prepared using an incremental semi-compliant balloon, excluding the recurrent apical segment, two bioresorbable vascular scaffolds (absorb bioresorbable vascular scaffold, abbott vascular) of 3.0 x 28 mm and 2.5 x 28 mm, respectively, were positioned proximally to the distal segments, with minimal overlap (marker-to-marker implantation) at the midto mid-distal segment of the lad artery and overlapping the metallic cage stent at the proximal segment of the lad artery. following the intervention, a coronary angiogram showed that all vessel side branches were maintained without evidence of any complications. full expansion and complete apposition of the metallic struts to the vessel wall at the proximal segments was confirmed via ivus [figure 3]. similarly, the uniform and full expansion of the bioresorbable scaffolds apposed to the intimo-medial membrane at the mid-distal lad artery was observed without residual stenosis via angiography and ivus [figure 4]. the patient remained asymptomatic without further cardiac events and was discharged one week after admission on a 12-month course of dual antiplatelet therapy. at a six month clinical follow-up, the patient was symptom-free. discussion consideration of the coronary anatomy, disease complexity, the presence of left ventricular dysfunction and syntax risk score, along with any atherosclerotic lesions which involved the long middistal segments of the left anterior descending (lad) artery. due to severe calcifications on the mid-distal lcx artery, percutaneous transluminal coronary angioplasty was performed. instead of a bioresorbable vascular scaffold, a single 2.5 x 23.0 mm everolimuseluting stent (xience prime®, abbott vascular, santa clara, california, usa) was implanted at the middistal lcx artery in order to avoid suboptimal scaffold expansion/apposition. after preparation of the lesions with semi-compliant balloons, a successful two-stent approach using the t-stenting and small protrusion technique was performed at the left main trunk and its main branches using a 3.5 x 33.0 mm everolimus figure 4a–c: a: post-interventional coronary angiography of a 67-year-old male patient following the implantation of two bioresorbable vascular scaffolds at the mid-distal portion of the left anterior descending artery and in overlap with a drug-eluting stent at the proximal portion. b and c: cross-sectional intravascular ultrasonography images corresponding to sections of the coronary angiogram (yellow lines) showing the uniform and full expansion of the struts and scaffolds apposed to the intimo-medial membrane. all three concentric stents and scaffold layers were noted at overlap sites as discrete echo-bright structures. des = drug-eluting stent; bvs = bioresorbable vascular scaffold. figure 3a–c: post-interventional cross-sectional intravascular ultrasonography of a 67-year-old male patient following the implantation of two bioresorbable vascular scaffolds and two drug-eluting stents. the stents were well-apposed and expanded with no signs of dissection at the (a) left main trunk, (b) proximal portion of the left anterior descending artery and (c) proximal portion of the left circumflex artery. a combination of drug-eluting stents and bioresorbable vascular scaffolds in the treatment of multivessel coronary artery disease e362 | squ medical journal, august 2016, volume 16, issue 3 comorbidities, interventional risks, long-term outcomes, local expertise and the patient’s personal preferences, are imperative when making decisions regarding treatment for patients with multivessel cad.1,3 for patients with syntax scores over 22, cabg surgery is associated with better long-term outcomes than pci, barring the presence of excessive preoperative risk factors.3 research indicates that diabetic patients affected by cad respond better to cabg treatment over pci, particularly patients with severe and diffuse cad.4–6 one recent trial involving patients with diabetes mellitus and advanced multivessel cad found that cabg treatment was beneficial in that it significantly reduced rates of death, myocardial infarction and repeated revascularisation at a five-year follow-up, although a higher rate of strokes was observed.6 based on this trial, cabg surgery is recommended as the preferred treatment for patients with multivessel cad, as it has the most favourable long-term outcomes in patients with a high syntax score but without high surgical risk.4,6 alternatively, patients who are at high risk for surgery, or who have low-severity cad, should undergo pci treatment.5 the patient in the current case presented with a high-risk syntax score and angiographic evidence of multivessel cad; treatment with pci was chosen as cabg surgery was deemed unsuitable due to the anatomical complexity of the distal coronary arteries. as distal coronary stenoses may affect adenosine-mediated vasodilation leading to a falsenegative result, the fractional flow reserve technique was not used to evaluate the pci target. the present case illustrates the importance of tomographic techniques—such as ivus imaging— over coronary angiography in the diagnosis and management of complex multivessel cad. in the current case, ivus showed moderate left main trunk disease and critically calcified ostial lesions of the lad and lcx arteries. however, in comparison with conventional intravascular imaging modalities such as ivus, optical coherence tomography has a higher resolution (range: 10–15 μm), allowing for the more accurate detection and quantification of scaffold malapposition, underexpansion, tissue prolapse or stent edge dissection. recently, research has shown that optical coherence tomography can be used to identify adverse cardiac features requiring immediate intervention in a large proportion of patients, resulting in improved clinical outcomes.7 unfortunately, this alternative imaging technology was not available at the padua university hospital at the time of the intervention. the implantation of multiple metallic stents covering long coronary segments can substantially affect vasomotion and may cause vascular inflammation, restenosis, thrombosis and neoatherosclerosis.8–10 permanent metallic platform stents also indefinitely impair the physiological vasomotor functioning of the vessel; hence the coronary geometry and systo-diastolic movement of coronary arteries treated with metallic stents remain similar up to a year after implantation.9,10 bioresorbable vascular scaffolds have the potential to overcome these limitations as they provide a temporary scaffolding which disappears after 2–3 years, liberating the treated vessel, and can help to restore the vessel’s original shape, preserving laminar blood flow, reducing the plaque-to-media ratio and restoring the vasomotion, pulsatility, cyclical strain, adaptive shear stress and mechanotrans duction of the vessel.8,9,11 following pci, the absence of any residual foreign material and restoration of functional endothelial coverage can also reduce the risk of stent thrombosis, myocardial infarction, sudden death and the need for long-term dual antiplatelet therapy; in addition, pci does not exclude the possibility of future graft anastomosis in case the need for future bypass surgery arises.8,9 however, there are as yet no data with regards to the feasibility of performing cabg surgery at coronary sites which have previously undergone implantation of a bioresorbable vascular scaffold. after implantation, the bioresorbable vascular scaffold maintains sufficient radial strength to prevent vessel recoil and releases the drug to inhibit the proliferation of neointima. however, the scaffold’s mass and radial strength gradually decrease over time and it vanishes completely after 2–3 years, leaving the vessel covered with a healthy endothelium and with normal vasomotor function.8 bioresorbable vascular scaffolds should be predominantly used in young patients for whom multiple long stents are required, particularly those with long lesions or diffuse disease; patients with lesions located in the mid-distal portion of the coronary arteries will also benefit because the use of bioresorbable vascular scaffolds does not preclude potential bypass grafting in the future.8 for severely calcified vessels, preparation of the lesion with optimal pre-dilatation or the use of additional devices and procedures such as cutting and scoring balloons or rotational atherectomy is crucial for the successful implantation of the scaffold. even severely calcified vessels will benefit from the disappearance of the scaffold, as this reduces the risk of late stent thrombosis and can lead to late lumen gain.8 no guidelines currently exist on the simultaneous use of drug-eluting stents and bioresorbable vascular scaffolds to manage diffuse critical atherosclerotic multivessel cad. gil et al. recently reported that the ahmed al-mamary, filippo zilio and massimo napodano case report | e363 references 1. parikh pb, kirtane aj, moses jw. management of multivessel coronary artery disease. panminerva med 2013; 55:311–26. 2. kolh p, windecker s, alfonso f, collet jp, cremer j, falk v, et al. 2014 esc/eacts guidelines on myocardial revascularization: the task force on myocardial revascularization of the european society of cardiology (esc) and the european association for cardio-thoracic surgery (eacts) developed with the special contribution of the european association of percutaneous cardiovascular interventions (eapci). eur j cardiothorac surg 2014; 46:517–92. doi: 10.1093/ejcts/ezu366. 3. deb s, wijeysundera hc, ko dt, tsubota h, hill s, fremes se. coronary artery bypass graft surgery vs percutaneous interventions in coronary revascularization: a systematic review. jama 2013; 310:2085–95. doi: 10.1001/ jama.2013.281718. 4. dangas gd, farkouh me, sleeper la, yang m, schoos mm, macaya c, et al. long-term outcome of pci versus cabg in insulin and non-insulin-treated diabetic patients: results from the freedom trial. j am coll cardiol 2014; 64:1189–97. doi: 10.1016/j.jacc.2014.06.1182. 5. nicolini f, agostinelli a, vezzani a, benassi f, gherli t. cabg versus pci in the treatment of diabetic patients affected by coronary artery disease: which is the best option? int heart j 2014; 55:469–73. doi: 10.1536/ihj.14-061. 6. farkouh me, domanski m, sleeper l, siami fs, dangas g, mack m, et al. strategies for multivessel revascularization in patients with diabetes. n engl j med 2012; 367:2375–84. doi: 10.1056/nejmoa1211585. 7. allahwala uk, cockburn ja, shaw e, figtree ga, hansen ps, bhindi r. clinical utility of optical coherence tomography (oct) in the optimisation of absorb bioresorbable vascular scaffold deployment during percutaneous coronary intervention. eurointervention 2015; 10:1154–9. doi: 10.4244/ eijv10i10a190. 8. lesiak m, araszkiewicz a. “leaving nothing behind”: is the bioresorbable vascular scaffold a new hope for patients with coronary artery disease? postepy kardiol interwencyjnej 2014; 10:283–8. doi: 10.5114/pwki.2014.46940. 9. iqbal j, onuma y, ormiston j, abizaid a, waksman r, serruys p. bioresorbable scaffolds: rationale, current status, challenges, and future. eur heart j 2014; 35:765–76. doi: 10.1093/eurheartj/ eht542. 10. gomez-lara j, brugaletta s, farooq v, van geuns rj, de bruyne b, windecker s, et al. angiographic geometric changes of the lumen arterial wall after bioresorbable vascular scaffolds and metallic platform stents at 1-year follow-up. jacc cardiovasc interv 2011; 4:789–99. doi: 10.1016/j.jcin.2011.04.009. 11. tamburino c, latib a, van geuns rj, sabate m, mehilli j, gori t, et al. contemporary practice and technical aspects in coronary intervention with bioresorbable scaffolds: a european perspective. eurointervention 2015; 11:45–52. doi: 10.4244/ eijy15m01_05. 12. gil rj, bil j, pawłowski t, yuldashev n, kołakowski l, jańczak j, et al. the use of bioresorbable vascular scaffold absorb bvs® in patients with stable coronary artery disease: one-year results with special focus on the hybrid bioresorbable vascular scaffolds and drug eluting stents treatment. kardiol pol 2016; 74:627–33. doi: 10.5603/kp.a2015.0250. 13. hahalis g, alexopoulos d. revascularization strategies in multivessel and left main coronary artery disease: syntax and beyond. hellenic j cardiol 2014; 55:328–35. concurrent use of these devices might be safe and effective, with no mortality or incidents of myocardial infarction or stent thrombosis observed at a 12 month follow-up and very few cases of clinically-driven target lesion revascularisation.12 the rationale for using both devices in the current case was to treat the diffuse disease percutaneously while avoiding the use of long metallic stented segments. due to the diffuse disease at the mid-distal lad artery, the patient’s anatomy was not deemed suitable for cabg surgery. on the other hand, the presence of lesions at the left main trunk and proximal lad artery supports coronary revascularisation over medical treatment, especially for acute coronary syndromes such as nonst-elevation myocardial infarctions.2,13 as a result, pci was performed; however, as multiple lesions and segments required treatment, coronary bioresorbable vascular scaffolds were used to avoid mid-to-longterm drug-eluting stent-related adverse events (e.g. stent thrombosis and restenosis).8,9 in addition, implanting a long metallic drug-eluting stent at the distal coronary bed could potentially affect coronary flow or the outcome of future cabg surgeries.9,10 nevertheless, metallic stents were also implanted at proximal sites due to the limitations of bioresorbable vascular scaffolds for large vessels, bifurcations (i.e. the left main trunk lesion in the current patient) and severely calcified lesions.9,11 conclusion lesions in the left main coronary artery are rarely isolated and the coronary anatomy is not always suitable for a cabg surgical approach, regardless of risk scores. as with the current case, a combination of drug-eluting stents and bioresorbable vascular scaffolds can be a feasible treatment option for complex diffuse multivessel cad with left main trunk involvement. the use of non-metallic bioresorbable vascular scaffolds in long diffuse lesions of the middistal vessels, in combination with metallic struts in the proximal segment, may mitigate the adverse effects of metallic stents. this technique ensures adequate and temporary scaffolding while also promoting adequate healing of the vessel wall and allowing for the possibility of future graft anastomosis should the patient subsequently need cabg surgery. http://dx.doi.org/10.1093/ejcts/ezu366 http://dx.doi.org/10.1001/jama.2013.281718 http://dx.doi.org/10.1001/jama.2013.281718 http://dx.doi.org/10.1016/j.jacc.2014.06.1182 http://dx.doi.org/10.1536/ihj.14-061 http://dx.doi.org/10.1056/nejmoa1211585 http://dx.doi.org/10.4244/eijv10i10a190 http://dx.doi.org/10.4244/eijv10i10a190 http://dx.doi.org/10.5114/pwki.2014.46940 http://dx.doi.org/10.1093/eurheartj/eht542 http://dx.doi.org/10.1093/eurheartj/eht542 http://dx.doi.org/10.1016/j.jcin.2011.04.009 http://dx.doi.org/10.4244/eijy15m01_05 http://dx.doi.org/10.4244/eijy15m01_05 http://dx.doi.org/10.5603/kp.a2015.0250 department of dermatology, complejo hospitalario de granada, granada, spain *corresponding author e-mail: ismenios@hotmail.com كيسة كاذبة بصيوان اإلذن بسبب ُمياداة متكررة وغري معتادة هنج سريري فران�س�سكو نافورو-ترايفينو و ريكاردو رويز-فيال فريدي auricular pseudocyst due to unusual repetitive manipulation of the ears clinical approach francisco navarro-triviño and *ricardo ruiz-villaverde a 22-year-old man presented to the complejo hospitalario de granada, granada, spain, in 2006 with an asymptomatic nodule in each ear of several years’ duration. on physical examination, two well-delimited nodules of semi-solid consistency were observed on the helix and scaphoid fossa of each auricular pavilion [figure 1a]. there was no evidence of any local infection or inflammation. the patient had no personal or family history of medical interest, such as previous injuries or frequent use of headphones or contact sports. however, he described a history of unusual repetitive manipulation of the ears since early childhood [figure 1b]. high-frequency ultrasonography of one of the nodules showed an oval cystic lesion with anechoic content and without a capsule or cartilaginous disruption [figure 2]. laboratory testing, including blood count, general biochemistry, thyroid profile, uric acid, complement, autoantibody (e.g. anti-nuclear antibody and extractable nuclear antigen antibody) interesting medical image sultan qaboos university med j, may 2017, vol. 17 iss. 2, pp. e246–247, epub. 20 jun 17 submitted 13 nov 16 revision req. 9 jan 17; revision recd. 15 jan 17 accepted 2 feb 17 figure 1: a: photograph of a well-defined auricular nodular lesion (arrow) on the scaphoid fossa and helix of a 22-yearold man, with no signs of infection or local inflammation. b: photograph of the unnatural manual placement of the upper third of the helix into the interior of the external auditory canal. the patient reported having routinely performed this action since early childhood. doi: 10.18295/squmj.2016.17.02.022 francisco navarro-triviño and ricardo ruiz-villaverde interesting medical image | e247 lesional injections of triamcinolone or sclerosing drugs, such as tetracycline or trichloroacetic acid, are considered the optimal choice of treatment.4–6 surgical excision with local compression (i.e. using shirt buttons or mouldable thermoplastic tablets) also offers effective cosmetic and functional results.6,7 overall, unnecessary procedures should be avoided so as to circumvent unanticipated complications, such as infection, auricular chondritis or related deformities.8 references 1. cohen v, fortier-riberdy g, saliba i, davar s. a case of auricular pseudocyst. j cutan med surg 2016; 20:573–4. doi: 10.1177/1203475416651604. 2. tupker r, toonstra j. auricular pseudocyst in a woman. bmj case rep 2013; 2013:bcr2013010157. doi: 10.1136/bcr-2013010157. 3. kallini jr, cohen pr. rugby injury-associated pseudocyst of the auricle: report and review of sport-associated dermatoses of the ear. dermatol online j 2013; 19:11. 4. miyamoto h, oida m, onuma s, uchiyama m. steroid injection therapy for pseudocyst of the auricle. acta derm venereol 1994; 74:140–2. 5. kim ty, kim dh, yoon ms. treatment of a recurrent auricular pseudocyst with intralesional steroid injection and clip compression dressing. dermatol surg 2009; 35:245–7. doi: 10.1111/j.1524-4725.2008.34416.x. 6. cohen pr, katz be. pseudocyst of the auricle: successful treatment with intracartilaginous trichloroacetic acid and button bolsters. j dermatol surg oncol 1991; 17:255–8. doi: 10.1111/j.1524-4725.1991.tb03639.x. 7. kindem s, sanmartin c, serra-guillén c, guillén c. compression treatment of auricular pseudocyst with thermoplastic splinting (aquaplast®). actas dermosifiliogr 2013; 104:357–9. doi: 10.1016 /j.adengl.2012.07.025. 8. blasco-morente g, arias-santiago s, garrido-colmenero c, pérez-lópez i. sonographic features of auricular pseudocyst. actas dermosifiliogr 2015; 106:840. doi: 10.1016/j.ad.2015. 03.009. and proteinogram tests, indicated no abnormalities. an evaluation of the patient revealed no psychopathological conditions. histology confirmed that the nodule was an intracartilaginous cyst devoid of epithelial lining and that the pseudocystic space was filled with mucinous material [figure 3]. approximately 0.5 ml of straw-coloured fluid was aspirated from the lesion before injection of 0.5 ml of a 5 mg/ml triamcinolone acetonide solution. subsequently, the ear was covered with gauze which was well taped to the skin, resulting in satisfactory compression of the affected area. the patient was evaluated every two days over a 14-day period to check that necrosis had not developed. there was no evidence of recurrence at a four-month follow-up. comment an auricular pseudocyst (ap) is a benign asymptomatic non-inflammatory lesion of unknown aetiology and variable size located in the helix or the triangular or scaphoid fossae of the ear.1,2 both unilateral and bilateral aps have previously been described in the literature.2 a history of ear-related trauma, frequent use of headphones or contact sports such as rugby have been associated with aps.3 the differential diagnosis of this entity includes chondrodermatitis nodularis helicis, epidermal cysts, recurrent perichondritis and rheumatoid nodules.3 for injuries affecting the auricle, the differential diagnosis may be challenging; therefore, caution is required so as to subsequently guide appropriate treatment. incision and drainage of aps is contraindicated, as there is a local recurrence rate of 100%.4 intra figure 2: ultrasonography of the ear of a 22-year-old man showing a hypoechoic cystic lesion without a capsule and with anechoic content (arrows) and poorlydelimited hypoechoic structures compatible with cartilaginous tissue. figure 3: haematoxylin and eosin stain at x4 magnification showing an intracartilaginous cyst devoid of epithelial lining with mucinous material (arrows) filling the pseudocystic space. https://doi.org/10.1177/1203475416651604 https://doi.org/10.1136/bcr-2013-010157 https://doi.org/10.1136/bcr-2013-010157 https://doi.org/10.1111/j.1524-4725.2008.34416.x https://doi.org/10.1111/j.1524-4725.1991.tb03639.x https://doi.org/10.1016/j.adengl.2012.07.025 https://doi.org/10.1016/j.adengl.2012.07.025 https://doi.org/10.1016/j.ad.2015.03.009 https://doi.org/10.1016/j.ad.2015.03.009 department of pathology, maulana azad medical college, new delhi, india *corresponding author’s e-mail: ashutoshrath10@gmail.com سرطان خلية بالزما الدم األولية تقرير حالة ومراجعة األدبيات �شاريكا �شينج، أشوتش راث، �شوريكا ياداف abstract: plasma cell leukaemia (pcl) is one of the most aggressive and rarest forms of plasma cell dyscrasia. how ever, the diagnostic criteria for this condition have not yet been revised and there is no specific treatment to significantly improve the course of the disease. we report a 69-year-old male who presented to the lok nayak hospital, new delhi, india, in 2017 with dyspnoea and chest pain. a peripheral blood smear showed an absolute plasma cell count of 2.16 × 109/l. a bone marrow examination showed 61% atypical plasma cells exhibiting kappa light chain restriction. biochemical investigations were consistent with a diagnosis of primary pcl with renal involvement. bortezomib-based chemotherapy was initiated, which resulted in an improvement in the patient’s haematological and biochemical parameters. this case report includes a comprehensive review of the clinical and diagnostic features, pathobiology and treatment of pcl. keywords: plasma cell leukemia; multiple myeloma; plasma cells; case report; india. امللخ�ص: �رسطان خلية بالزما الدم الأولية هي واحدة من الأ�شكال الأكرث عدوانية واأندر اأعتاللت خلية البالزما. ومع ذلك ، مل يتم بعد تنقيح املعايري الت�شخي�شية لهذه احلالة ول يوجد عالج حمدد لتح�شني م�شار املر�ص ب�شكل كبري. هذا تقرير عن حالة ذكر يبلغ من العمر 69 عاًما قدم اإىل م�شت�شفى لوك ناياك يف نيودلهي بالهند عام 2017 ب�شبب �شيق يف التنف�ص واأمل يف ال�شدر. واأظهر الفح�ص املجهري للدم وجود عدد من خاليا البالزما يبلغ l/109 × 2.16 لرت. كما اأظهر فح�ص لنخاع العظم اأن %61 من خاليا البالزما غري النمطية التي تظهر قيوًدا على �شل�شلة الكابا اخلفيفة لالأج�شام امل�شادة. كانت التحريات البيوكيميائية مت�شقة مع ت�شخي�ص �رسطان خلية بالزما الدم الأولية مع تاأثر الكلى باملر�ص. وبداأ العالج الكيميائي بوا�شطة عقار البورتيزوميب ، مما اأدى اإىل حت�شن يف موؤ�رسات �شورة الدم ونتائج الفحو�شات الكيميائية للمري�ص. يت�شمن تقرير احلالة هذا مراجعة �شاملة للخ�شائ�ص ال�رسيرية والت�شخي�شية ، واملر�شية وطرق عالج �رسطان خلية بالزما الدم الأولية. الكلمات املفتاحية: �رسطان خلية بالزما الدم؛ املايلوما املتعددة؛ خاليا البالزما؛ تقرير حالة؛ الهند. primary plasma cell leukaemia case report and review of the literature sarika singh, *ashutosh rath, surekha yadav sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e397–401, epub. 19 dec 18 submitted 21 jan 18 revisions req. 11 mar & 22 apr 18; revisions recd. 4 & 30 apr 18 accepted 24 may 18 online case report doi: 10.18295/squmj.2018.18.03.024 case report a 69-year-old male presented to a local hospital in new delhi, india, in 2017 with a two-month history of rectal bleeding and dyspnoea during routine activities. heart disease was suspected and the patient was managed accordingly, with minimal investigations. despite transient improvement, he subsequently presented to the lok nayak hospital, new delhi, in 2017 with dyspnoea and chest pain. during a general physical examination, there was evidence of pallor without lymphadenopathy. a systemic examination was unremarkable with no evidence of hepa tosplenomegaly. a complete blood count revealed anaemia with a haemoglobin (hb) level of 72 g/l, mild leukocytosis with a total leukocyte count (tlc) of 12 × 109/l and thrombo cytopaenia with a platelet count of 97 × 109/l. the eryth rocyte sedimentation rate was 70 mm/hour. a peripheral plasma cell leukaemia (pcl) is a rare and aggressive form of plasma cell dyscrasia.1 primary pcl occurs de novo, whereas secondary pcl is the leukaemic transformation of relapsed or refractory multiple myeloma (mm). the incidence of pcl is 2–4%, of which 60–70% of cases are primary and 30–40% are secondary, although the incidence of the latter type is rising.2,3 the median age of patients with primary pcl is younger than those with secondary pcl (52–65 years old versus 65–70 years old).2 in a case series by rajeswari et al., four out of 16 patients with pcl were under the age of 40 years, with the youngest being 25 years old.4 although primary and secondary pcl are considered different clinical entities, both have a poor prognosis. the median survival rate ranges from 6.8–12.6 months without novel therapy, although this increases to over three years after autologous stem cell transplant ation.1,5 primary plasma cell leukaemia case report and review of the literature e398 | squ medical journal, august 2018, volume 18, issue 3 blood smear exhibited normocytic/normochromic to microcytic/hypochromic red blood cells with extensive rouleaux formation. a differential leukocyte count revealed 18% plasma cells with an absolute platelet cell count of 2.16 × 109/l and 15% atypical lymphocytes [figure 1]. mature plasma cells as well as plasma cells with bipolar cytoplasm were present. the atypical lymphocytes had central and eccentrically placed nuclei and a moderate amount of cytoplasm with fuzzy cytoplasmic borders. a bone marrow examination was performed to establish the extent of pcl involvement. a bone marrow aspirate smear and haematoxylin and eosin stain showed 61% atypical plasma cells [figure 2]. the morphological spectrum of these cells included thesaurocytes, plasma cells with bipolar cytoplasm and one to two prominent nucleoli in the nucleus and binucleated plasma cells. the bone marrow was hypercellular for age and showed the near-total replacement of the marrow spaces by the plasma cells, with focal areas of haematopoietic cells. upon immunohistochemical analysis, the plasma cells were immunoreactive for cluster of differentiation (cd)38, showed kappa light chain restriction and reduced lambda light chain expression and demonstrated focal positivity for cd20 [figure 3]. the cells were immunonegative for cd19 and p53. biochemical investigations showed high levels of serum creatinine (3.3 mg/dl; normal range: 0.6–1.2 mg/dl), blood urea (147 mg/dl; normal range: 8–23 mg/dl) and serum uric acid (13.0 mg/dl; normal range: 4–8.5 mg/dl). however, serum calcium levels were slightly low (8.5 mg/dl; normal range: 9.2–11 mg/dl). radiolog ical investigations, including a chest x-ray, abdominal ultrasound and skeletal survey, did not show any lesions. serum protein electrophoresis indicated a total protein level of 15.20 g/dl (normal range: 6.40–8.10 g/dl), albu min level of 3.83 g/dl (normal range: 3.50–5.64 g/dl), α1globulin level of 0.62 g/dl (normal range: 0.17–0.41 g/dl), α2-globulin level of 1.19 g/dl (normal range: 0.31–0.85 g/dl), β-globulin level of 0.59 g/dl (normal range: 0.49–1.32 g/dl), γ-globulin level of 8.97 g/dl (normal range: 0.62–1.53 g/dl) and albumin/globulin ratio of 0.34 (normal ratio: 0.90–2.00). furthermore, the γ-glob ulin region showed a monoclonal spike. the raised glob ulins were found to be immunoglobulin (ig)d on serum immunofixation electrophoresis. bence jones proteins were absent in the urine. a serum free light chain assay revealed kappa light chain restriction with elevated kappa free light chains at 204.00 mg/l (normal range: 3.30–19.40 mg/l) and a kappa/lambda ratio of 27.72 (normal ratio: 0.26–1.65). serum β2-microglobulins were markedly raised at 15,576 ng/ml (normal range: 609–2,366 ng/ml). following confirmation of the diagnosis of primary pcl, the patient decided to undergo treatment at an oncology centre, at which point bortezomib-based chemo therapy was initiated. however, a follow-up haematological profile was performed at the lok nayak hospital. after the first cycle of chemotherapy, the patient’s tlc was 8.72 × 109/l, hb level was 106 g/l, platelet count was 157 × 109/l, serum creatinine level was 1.4 mg/dl and blood urea level was 27 mg/dl. on day 11 of the first cycle, a peripheral blood smear did not show any plasma cells. at the time of writing, the patient was stable; however, a follow-up bone marrow examination had not yet been performed to assess his remission status. figure 1: peripheral blood smears at x200 magnification showing (a) rouleaux formation, plasma cells (arrows) and (b) atypical lymphocytes (arrowhead). figure 3: immunohistochemistry panel at x400 magnif ication showing (a) positivity for cluster of differentiation (cd)38, (b) kappa light chain restriction, (c) reduced lambda light chain expression and (d) focal positivity for cd20. figure 2: a: bone marrow aspirate smear at x1,000 magnif ication showing atypical plasma cells (arrows). b: haemat oxylin and eosin stain at x400 magnification showing plasma cells. sarika singh, ashutosh rath and surekha yadav online case report | e399 patients may also present with other clinical features, such as organomegaly, lymphadenopathy, pleural effusion and central nervous system involvement leading to neuro logical deficits and extramedullary plasmacytomas. in the current case, the patient initially presented with bleeding from the rectum and dyspnoea. renal involvement can also occur, presenting as acute kidney failure, with studies indicating this is more commonly associated with pcl than mm (53–62% versus 22–43%).11,12 a renal biopsy may show interstitial plasma cell infiltration, tubular casts and light chain restriction with direct immunofluorescence.13 the current case also showed renal involvement with raised blood urea and serum creatinine levels which normalised after chemotherapy. certain parameters can help to differentiate pcl from mm, including leukocytosis, relatively high levels of serum lactate dehydrogenase and β2-microglobulins and lower frequencies of lytic bone lesions.1 in addition, patients with pcl usually only secrete free light chains, unlike those with mm. moreover, plasma cells in pcl cases often show varying morphologies, ranging from classic plasma cells, plasmablasts and hairy-cell-like morphology to marked anaplastic features.4,14 in the current case, 15% of the lymphocytes were atypical in that their morphology differed from that of either classic or atypical plasma cells; instead, the cells resembled mature lymphocytes with fuzzy cytoplasmic borders. previous case reports have documented similar lymphocyte-like morphologies in pcl cases.15–17 although flow cytometry can help establish the actual nature of such cells, this could not be performed in the current case as the patient had been referred to an external oncology centre. the diagnostic criteria for pcl were initially laid down by noel et al. in 1974 and include the presence of >20% of plasma cells ascertained to be clonal in nature in the peripheral blood or an absolute plasma cell count of >2 × 109/l.18,19 however, the presence of plasma cells discussion myeloma cells are dependent for their survival on interactions with the bone marrow microenvironment.6 myeloma cells require cd56—a neuronal cell adhesion molecule—to anchor to the bone marrow stroma. as cd56 expression decreases, myeloma cells gain access to the peripheral blood due to loss of contact with the bone marrow stroma. patients with pcl therefore usually show decreased expression of cd56.7 other molecules, such as cd27, cd117 and human leukocyte antigen-dr isotype, are usually negative, whereas cd19, cd20 and cd23 are often positive. in addition, cases of secondary pcl often show cd28 positivity.5 interleukin-6 is considered an important cytokine for pcl proliferation.8 in most primary pcl cases, genetic aberrancies are already present at the time of diagnosis; in contrast, the gradual accumulation of various genetic mutations make mm more aggressive, resulting in secondary pcl.1 hypodiploidy or diploidy are present in 80% of pcl cases and are considered poor prognostic factors comp ared to hyperdiploidy, a common feature of mm.9 both forms of pcl commonly show igh translocations, notably in chromosome 14q32. furthermore, amplifications of chromosome 1q21, myc abnormalities and ras mutations are more frequently seen in pcl than mm.10 in addition, 11q13 (cyclin d1) translocations are almost exclusive to primary pcl.1 however, tp53 inactivation has been observed in both forms of pcl.2 it has been suggested that a phosphatase and tensin homolog deletion is responsible for the transition of mm to pcl.5 due to extensive infiltration of the bone marrow by atypical plasma cells, the most common symptoms of pcl are related to severe anaemia and thrombocytopaenia, notably dyspnoea and haemorrhagic diathesis.1 table 1: remission criteria per category for plasma cell leukaemia cases5 category plasma cells m-protein levels extramedullary disease peripheral blood bone marrow serum urinary complete remission absent <5% negative negative absent stringent complete remission absent undetectable by flow cytometry negative negative absent very good partial response absent <5% ≥90% reduction <100 mg/24 hours absent partial response 1–5% 5–25% ≥50% reduction <200 mg/24 hours ≥50% reduction progressive disease >5% absolute increase >25% increase or absolute increase of ≥10% >25% increase >25% increase definite increase stable disease none of the above criteria are met relapse reappearance >10% increase reappearance reappearance any disease primary plasma cell leukaemia case report and review of the literature e400 | squ medical journal, august 2018, volume 18, issue 3 in peripheral blood can also be seen in other plasma cell dyscrasias and certain non-malignant conditions such as severe sepsis and infectious mononucleosis.20 it has therefore been suggested that the diagnostic criteria of pcl should be revised to >5% plasma cells or an absolute plasma count of >0.5 × 109/l so as to avoid underdiagnosis of the condition.5 however, although the flow cytometric evaluation of pcl and revision of the criteria for diagnosis is currently under consideration, there is no consensus yet as further prospective multicentre analyses are required. in terms of treatment, the proteasome inhibitor bortezomib has shown a relatively good response in both primary and secondary pcl, resulting in some cases in complete remission.21 bortezomib combined with dexa methasone and melphalan has also been documented to show a good response, whereas thalidomide and lena lidomide have only shown a transient partial response.5 allogenic stem cell transplantation can be considered in patients under 50 years of age; however, the risk of trans plantation-related mortality is increased.1,5 nevertheless, high-dose chemotherapy followed by autologous stem cell transplantation improves survival, although mainly for patients with primary pcl.2 seven categories of pcl remission have been proposed by the international myeloma working group, based on the following four main parameters: (1) the plasma cell count in the peripheral blood; (2) the plasma cell count in the bone marrow; (3) serum and urinary m-protein levels; and (4) the assessment of extramedullary disease [table 1].5 in general, a patient is considered to be in complete remission if plasma cells are absent from the peripheral blood and there are <5% of plasma cells in the bone marrow. however, relapse is denoted by a >10% increase in bone marrow plasma cells with the reappearance of peripheral blood plasma cells and m-protein, along with evidence of extramedullary disease.5 jelinek et al. also recommended the assessment of minimal residual disease-negative remission by multicolour flow cytometry or allele-specific oligonucleotide polymerase chain reaction.1 conclusion various significant yet subtle parameters can be used to differentiate primary pcl from mm. as the survival rate is low, such information is necessary to ensure that pcl cases can be diagnosed early and appropriate treat ment regimens initiated. a c k n o w l e d g e m e n t s a poster of the preliminary version of this case report was presented at the 58th annual conference of the indian society of haematology & blood transfusion, from 2–5 november 2017 in guwahati, assam, india. an abstract of this poster presentation was subsequently published in the indian journal of haematology & blood transfusion in november 2017, volume 33, issue s1, pp. s101–2. references 1. jelinek t, kryukov f, rihova l, hajek r. plasma cell leukemia: from biology to treatment. eur j haematol 2015; 95:16–26. doi: 10.1111/ejh.12533. 2. tiedemann re, gonzalez-paz n, kyle ra, santana-davila r, price-troska t, van wier sa, et al. genetic aberrations and survival in plasma cell leukemia. leukemia 2008; 22:1044–52. doi: 10.1038/leu.2008.4. 3. bladé j, kyle ra. nonsecretory myeloma, immunoglobulin d myeloma, and plasma cell leukemia. hematol oncol clin north am 1999; 13:1259–72. doi: 10.1016/s0889-8588(05)70125-8. 4. rajeswari g, paul tr, uppin ms, uppin sg, rao dr, raju dd, et al. plasma cell leukemia: a case series from south india with emphasis on rarer variants. indian j med paediatr oncol 2014; 35:211–14. doi: 10.4103/0971-5851.142037. 5. fernández de larrea c, kyle ra, durie bg, ludwig h, usmani s, vesole dh, et al. plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recom mendations by the international myeloma working group. leuk emia 2013; 27:780–91. doi: 10.1038/leu.2012.336. 6. mitsiades cs, mcmillin dw, klippel s, hideshima t, chauhan d, richardson pg, et al. the role of the bone marrow micro-environment in the pathophysiology of myeloma and its significance in the development of more effective therapies. hematol oncol clin north am 2007; 21:1007–34. doi: 10.1016/j.hoc.20 07.08.007. 7. pellat-deceunynck c, barillé s, jego g, puthier d, robillard n, pineau d, et al. the absence of cd56 (ncam) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma. leukemia 1998; 12:1977–82. 8. zhang xg, bataille r, widjenes j, klein b. interleukin-6 dependence of advanced malignant plasma cell dyscrasias. cancer 1992; 69:1373–6. doi: 10.1002/1097-0142(19920315)69:6<1373::aidcncr2820690612>3.0.co;2-1. 9. garcía-sanz r, orfão a, gonzález m, tabernero md, bladé j, moro mj, et al. primary plasma cell leukemia: clinical, immunophenotypic, dna ploidy, and cytogenetic characteristics. blood 1999; 93:1032–7. 10. chiecchio l, dagrada gp, ibrahim ah, dachs cabanas e, protheroe rk, stockley dm, et al. timing of acquisition of deletion 13 in plasma cell dyscrasias is dependent on genetic context. haematologica 2009; 94:1708–13. doi: 10.3324/haematol.2009. 011064. 11. bernasconi c, castelli g, pagnucco g, brusamolino e. plasma cell leukemia: a report on 15 patients. eur j haematol suppl 1989; 51:76–83. 12. woodruff rk, malpas js, paxton am, lister ta. plasma cell leukemia (pcl): a report on 15 patients. blood 1978; 52:839–45. 13. podduturi v, mohmand h, gill j, zhou xj. plasma cell leukemia presenting as acute kidney injury with heavy proteinuria. world j nephrol urol 2014; 3:129–33. doi: 10.14740/wjnu177w. 14. rastogi p, ahluwalia j, parathan kk, malhotra p. plasma cell leukemia presenting with hyperleukocytosis and anaplasia. indian j hematol blood transfus 2017; 33:128–9. doi: 10.1007/s12288016-0740-5. 15. heerema-mckenney a, waldron j, hughes s, zhan f, sawyer j, barlogie b, et al. clinical, immunophenotypic, and genetic charact erization of small lymphocyte-like plasma cell myeloma: a pot ential mimic of mature b-cell lymphoma. am j clin pathol 2010; 133:265–70. doi: 10.1309/ajcpus3prrt5zxvs. https://doi.org/10.1111/ejh.12533 https://doi.org/10.1038/leu.2008.4 https://doi.org/10.1016/s0889-8588%2805%2970125-8 https://doi.org/10.4103/0971-5851.142037 https://doi.org/10.1038/leu.2012.336 https://doi.org/10.1016/j.hoc.2007.08.007 https://doi.org/10.1016/j.hoc.2007.08.007 https://doi.org/10.1002/1097-0142%2819920315%2969:6%3c1373::aid-cncr2820690612%3e3.0.co%3b2-1 https://doi.org/10.1002/1097-0142%2819920315%2969:6%3c1373::aid-cncr2820690612%3e3.0.co%3b2-1 https://doi.org/10.3324/haematol.2009.011064 https://doi.org/10.3324/haematol.2009.011064 https://doi.org/10.14740/wjnu177w https://doi.org/10.1007/s12288-016-0740-5 https://doi.org/10.1007/s12288-016-0740-5 https://doi.org/10.1309/ajcpus3prrt5zxvs sarika singh, ashutosh rath and surekha yadav online case report | e401 19. swerdlow sh, campo e, harris nl, jaffe es, pileri sa, stein h, et al., eds. who classification of tumours of haematopoietic and lymphoid tissues, 4th ed. from: http://publications.iarc.fr/ book-and-report-series/who-iarc-classification-of-tum ours/who-classification-of-tumours-of-haematopoieticand-lymphoid-tissues-2017 accessed: apr 2018. 20. shtalrid m, shvidel l, vorst e. polyclonal reactive peripheral blood plasmacytosis mimicking plasma cell leukemia in a patient with staphylococcal sepsis. leuk lymphoma 2003; 44:379–80. doi: 10.1080/1042819021000029713. 21. esparís-ogando a, alegre a, aguado b, mateo g, gutiérrez n, bladé j, et al. bortezomib is an efficient agent in plasma cell leukemias. int j cancer 2005; 114:665–7. doi: 10.1002/ijc.20793. 16. loureiro ad, gonçalves mv, ikoma mr, silva mr, colleoni gw, chauffaille ml, et al. plasma cell leukemia with t(11;14)(q13;q32) simulating lymphoplasmacytic lymphoma: a diagnostic challenge solved by flow cytometry. rev bras hematol hemoter 2017; 39:66–9. doi: 10.1016/j.bjhh.2016.10.001. 17. eveillard m, moreau p. atypical plasma cell leukemia mistaken for lymphocytosis on blood count. blood 2015; 126:1965. 18. noel p, kyle ra. plasma cell leukemia: an evaluation of response to therapy. am j med 1987; 83:1062–8. doi: 10.1016/0002-9343 (87)90942-9. https://doi.org/10.1080/1042819021000029713 https://doi.org/10.1002/ijc.20793 https://doi.org/10.1016/j.bjhh.2016.10.001 https://doi.org/10.1016/0002-9343%2887%2990942-9 https://doi.org/10.1016/0002-9343%2887%2990942-9 departments of 1medical microbiology & immunology and 2pediatrics, faculty of medicine, mansoura university, mansoura, egypt *corresponding author’s e-mail: amira110sultan@yahoo.com حتديد عوامل اخلطورة لالصابة بالعدوى املرتبطة بالرعاية الصحية اليت تسببها بكترييا أسينيتوباكرت بوماين املقاومة للكاربابنيم يف وحدة العناية املركزة حلديثي الوالدة اأمرية حممد �سلطان و وائل �سليم abstract: objectives: acinetobacter baumannii is a causative pathogen of various healthcare-associated infections (hais) and is particularly prevalent in high-risk hospital settings. this study aimed to determine risk factors associated with hais caused by carbapenem-resistant a. baumannii (crab) in a neonatal intensive care unit (nicu). methods: this prospective study was performed between january 2013 and june 2014 among nicu patients at the mansoura university children’s hospital, mansoura, egypt. neonates who developed hais due to crab were assigned to a case group, while those infected with carbapenem-sensitive a. baumannii (csab) were assigned to a control group. results: among the 124 neonates who developed a. baumannii-caused hais during the study period, 91 (73.4%) were caused by crab and 33 (26.6%) were caused by csab. prematurity, premature rupture of the membranes (prom), a previous stay in another hospital, prolonged nicu stay, the presence of invasive devices, previous exposure to carbapenems or aminoglycosides and prolonged antibiotic therapy before infection were significantly associated with crab-caused hais. a multivariate logistic regression analysis identified prematurity (adjusted odds ratio [aor] = 25.3; p <0.01), mechanical ventilation (aor = 18.9; p <0.01) and the previous use of carbapenems (aor = 124.7; p <0.01) or aminoglycosides (aor = 22.6; p = 0.04) to be independent risk factors for crab infections. conclusion: various risk factors were significantly associated with crab-caused hais among the studied nicu patients. keywords: healthcare associated infections; antimicrobial drug resistance; carbapenem antibiotics; acinetobacter baumannii; neonatal intensive care units; egypt. امللخ�ص: الهدف: تعترب بكترييا اأ�سينيتوباكرت بوماين اأحد م�سببات العدوى املرتبطة بالرعاية ال�سحية. و حيث اأنها تتواجد ب�سكل خا�ض يف مناطق الرعاية ال�سحية ذات اخلطورة العالية فقد هدفت هذه الدرا�سة اىل حتديد عوامل اخلطورة لال�سابة بالعدوى املرتبطة بالرعاية ال�سحية التي ت�سببها بكترييا اأ�سينيتوباكرت بوماين املقاومة للكاربابنيم يف وحدة العناية املركزة حلديثي الوالدة. الطريقة: اأجريت هذه املن�سورة، اجلامعى، االأطفال مب�ست�سفى الوالدة حلديثي املركزة العناية وحدة يف 2014 ويونيو 2013 يناير بني اال�ستطالعية الدرا�سة م�رص. مت ادراج املر�سى امل�سابني بالعدوى املرتبطة بالرعاية ال�سحية الناجتة عن بكترييا اأ�سينيتوباكرت بوماين املقاومة للكاربابنيم يف جمموعة الدرا�سة يف حني مت ادراج املر�سى امل�سابني بالعدوى املرتبطة بالرعاية ال�سحية الناجتة عن بكترييا اأ�سينيتوباكرت بوماين عن الناجتة ال�سحية بالرعاية املرتبطة بالعدوى م�سابا مري�سا 124 ر�سد مت النتائج: ال�سابطة. املجموعة يف للكاربابنيم احل�سا�سة عن الناجتة ال�سحية بالرعاية املرتبطة بالعدوى امل�سابني املر�سى عدد كان قد و الدرا�سة. فرتة خالل بوماين اأ�سينيتوباكرت بكترييا املرتبطة بالعدوى امل�سابني املر�سى عدد كان بينما )73.4%( مري�سا 91 هو للكاربابنيم املقاومة بوماين اأ�سينيتوباكرت بكترييا اخلطورة عوامل �سملت وقد .)26.6%( مري�سا 33 هو للكاربابنيم احل�سا�سة بوماين اأ�سينيتوباكرت بكترييا عن الناجتة ال�سحية بالرعاية اخلدج، االأطفال من كل للكاربابنيم املقاومة بوماين بكترييا اأ�سينيتوباكرت ت�سببها التي ال�سحية بالرعاية املرتبطة بالعدوى لال�سابة والتمزق املبكر لالأغ�سية املحيطة باجلنني، واالقامة يف م�ست�سفى اآخر، واالإقامة لفرتات طويلة يف وحدة العناية املركزة حلديثي الوالدة، اال�سابة قبل طويلة لفرتات احليوية بامل�سادات والعالج اأمينوغليكوزيد�ض اأو للكاربابنيم ال�سابق والتعر�ض اجتياحية، اأجهزة ووجود ،)p >0.01 25.3؛ = )aor( بالعدوى. وقد بني االنحدار اللوج�ستي متعدد املتغريات اأن كل من االأطفال اخلدج )ن�سبة االأرجحية املعدلة املعدلة االأرجحية )ن�سبة للكاربابنيم ال�سابق واال�ستخدام )p >0.01 18.9؛ = )aor( املعدلة االأرجحية ))ن�سبة امليكانيكية والتهوية م�ستقلة خطورة عوامل ميثلون )p = 0.04 22.6؛ = )aor( املعدلة االأرجحية )ن�سبة اأمينوغليكوزيدز اأو )p >0.01 124.7؛ = )aor( لالإ�سابة بالعدوى املرتبطة بالرعاية ال�سحية التي ت�سببها بكترييا اأ�سينيتوباكرت بوماين املقاومة للكاربابنيم. اخلال�صة: لقد تبني اأنه املقاومة بوماين اأ�سينيتوباكرت بكترييا ت�سببها التي ال�سحية بالرعاية املتعلقة بالعدوى باالإ�سابة مرتبطة خطورة عوامل عدة يوجد للكاربابنيم يف وحدة العناية املركزة حلديثي الوالدة. الكلمات املفتاحية: العدوى املرتبطة بالرعاية ال�سحية؛ امليكروبات املقاومة للم�سادات احليوية؛ م�سادات الكاربابنيم؛ بكترييا اأ�سينيتوباكرت بوماين؛ وحدة العناية املركزة حلديثي الوالدة؛ م�رص. identifying risk factors for healthcare-associated infections caused by carbapenem-resistant acinetobacter baumannii in a neonatal intensive care unit *amira m. sultan1 and wael a. seliem2 clinical & basic research sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e75–80, epub. 4 apr 18 submitted 23 oct 17 revision req. 20 dec 17; revision recd. 24 dec 17 accepted 11 jan 18 doi: 10.18295/squmj.2018.18.01.012 identifying risk factors for healthcare-associated infections caused by carbapenem-resistant acinetobacter baumannii in a neonatal intensive care unit e76 | squ medical journal, february 2018, volume 18, issue 1 healthcare-associated infections (hais) are infections contracted in various health-care settings and are well known to increase morbidity, mortality, length of hospital stay and the cost of medical care.1 intensive care units (icus), including neonatal icus (nicus), constitute high-risk areas for hais as admitted patients are usually critically ill and commonly undergo invasive procedures.2 acinetobacter baumannii is a major causative pathogen of various hais, such as bloodstream infections and pneumonia, particularly in high-risk settings such as icus. unfortunately, recent studies have reported a steady increase in the prevalence of carbapenemresistant a. baumannii (crab) strains isolated from patients with hais.3–5 this study therefore aimed to determine risk factors for the development of crabcaused hais among patients in a nicu in egypt. methods this prospective single-centre study was conducted between january 2013 and june 2014 in the nicu of the mansoura university children’s hospital, man soura, egypt. all patients who developed a. baumannii caused hais of any type following their admission to the nicu were included in the study. the identification of a. baumannii strains was performed using colony morphology, microscopic examination and biochemical tests. the api® 20 ne identification system (biomérieux inc, st. louis, missouri, usa) was used to confirm the diagnosis of an a. baumanniicaused infection. patients who developed hais with a. baumannii isolates showing resistance to imipenem or meropenem were assigned to a case group while those with isolates sensitive to imipenem and meropenem were assigned to a control group. the sensitivity patterns of the isolated a. baumannii strains were detected using the disc diffusion method. all results were interpreted using the guidelines of the clinical and laboratory standards institute.6 surveillance procedures conducted for patients with different types of hais were performed according to the definitions, elements and criteria of the centers for disease control and prevention.7 infections developing during the first two calendar days of hospital stay were deemed to have been present upon admission, while infections developing on or after the third calendar day of hospital stay were considered hais. information regarding the hai was collected by reviewing the patients’ medical records and their clinical and laboratory findings. possible risk factors were documented for each patient, including prematurity (<37 gestational weeks); low birth weight (<2,500 g); premature rupture of the membranes; age; gender; previous stay in another hospital; length of nicu stay prior to infection; the presence of an invasive device; duration of antibiotic therapy before the hai; and previous antibiotic exposure. the latter risk factor was considered present only in cases wherein systemic antibiotics were administered for a minimum of 24 hours within the 14-day period prior to the isolation of the a. baumannii strain. in terms of patient outcome, hai-related mortality was defined as death within 30 days of developing the infection. statistical analysis was performed using the stat istical package for the social sciences (spss), version 22.0 (ibm corp, armonk, new york, usa). nonparametric demographic and clinical parameters were compared using the mann-whitney u test and presented as medians and ranges. categorical variables were compared using the chi-squared test and presented as percentages. a multivariate analysis was performed using binary logistic regression to assess independent risk factors for crab-caused hais. differences were considered statistically significant at p ≤0.05. advances in knowledge the current study identified significant risk factors associated with healthcare-associated infections (hais) caused by carbapenemresistant acinetobacter baumannii (crab) among patients in a neonatal intensive care unit (nicu) in egypt. significant risk factors included prematurity, premature rupture of the membranes, a previous stay in another hospital, prolonged nicu stay, the presence of an invasive device (i.e. an umbilical catheter, urinary catheter or mechanical ventilator), previous exposure to carbapenems or aminoglycosides and prolonged antibiotic therapy prior to the infection. application to patient care the findings of this study may be utilised by nicu staff to decrease risk factors associated with carbapenem resistance among egyptian neonates. table 1: healthcare-associated infections caused by carbapenem-resistant or -sensitive acinetobacter baumannii in a neonatal intensive care unit in egypt (n = 124) type of infection n (%) crab (n = 91) csab (n = 33) blood stream 65 (71.4) 22 (66.7) pneumonia 17 (18.7) 7 (21.2) urinary tract 7 (7.7) 3 (9.1) other 2 (2.2) 1 (3) crab = carbapenem-resistant acinetobacter baumannii; csab = carbapenem-sensitive a. baumannii. amira m. sultan and wael a. seliem clinical and basic research | e77 this study received ethical approval from the institutional review board of the faculty of medicine, mansoura university (#r/17.10.10). informed consent was obtained from a parent or guardian of all of the patients included in the study. results during the study period, 124 neonates in the nicu developed hais caused by a. baumannii. of these, 91 infections (73.4%) were caused by crab and 33 (26.6%) were caused by carbapenem-sensitive a. baumannii (csab). in both groups, bloodstream infections were most common [table 1]. there was no statistically significant difference between the groups in terms of sites of infection. prematurity, premature rupture of the membranes, a previous stay in another hospital and prolonged nicu stay prior to infection were iden tified as significant risk factors for crab-caused hais (p <0.05 each). moreover, the presence of an umbilical catheter, urinary catheter or mechanical ventilator, previous exposure to carbapenems or aminoglycosides and prolonged antibiotic therapy were also significant risk factors (p <0.05 each). prematurity (adjusted odds ratio [aor] = 25.3; p <0.01), mechanical ventilation (aor = 18.9; p <0.01) and the previous use of carbapenems (aor = 124.7; p <0.01) or aminoglycosides (aor = 22.6; p = 0.04) were independent risk factors for crab infections [table 2]. a total of 70 (76.9%) patients with crab infections and eight (24.2%) patients with csab infections died; this difference in mortality rate between the two groups was statistically significant (p = 0.01). significant mortality-related risk factors among patients with table 2: risk factors associated with healthcare-associated infections caused by carbapenem-resistant or -sensitive acinetobacter baumannii in a neonatal intensive care unit in egypt (n = 124) risk factor univariate analysis, n (%) multivariate analysis crab (n = 91) csab (n = 33) p value aor (95% ci) p value postnatal age in days <7 45 (49.5) 18 (54.5) 0.65 ≥7 46 (50.5) 15 (45.5) 0.35 male gender 39 (42.9) 16 (48.5) 0.78 prematurity 54 (59.3) 8 (24.2) 0.03* 25.3 (8.4–784.8) <0.01* lbw 29 (31.9) 10 (30.3) 0.88 prom 42 (46.2) 5 (15.2) 0.01* psah 17 (18.7) 2 (6.1) 0.03* median length of stay in the nicu prior to hai (range) 10 (6.4–15.2) 4 (2.6–7.9) 0.04* presence of an invasive device umbilical catheter 70 (76.9) 11 (33.3) 0.04* ppcl 10 (11) 5 (15.2) 0.85 urinary catheter 66 (72.5) 7 (21.2) <0.01* mv 72 (79.1) 9 (27.3) <0.01* 18.9 (3.5–1,135.1) <0.01* previous antibiotic exposure carbapenems 55 (60.4) 5 (15.2) <0.01* 124.7 (45.2–588.1) <0.01* cephalosporins 24 (26.4) 6 (18.2) 0.07 aminoglycosides 42 (46.2) 4 (12.1) 0.02* 22.6 (1.1–864.9) 0.04* vancomycin 30 (33) 12 (36.4) 0.79 median duration of antibiotic therapy before hai in days (range) 8 (5.7–10.4) 2 (1.2–4.6) <0.05* crab = carbapenem-resistant acinetobacter baumannii; csab = carbapenem-sensitive a. baumannii; aor = adjusted odds ratio; ci = confidence interval; lbw = low birth weight; prom = premature rupture of the membranes; psah = previous stay in another hospital; nicu = neonatal intensive care unit; hai = healthcare-associated infection; ppcl = peripheral percutaneous central line; mv = mechanical ventilator. *considered statistically significant at p ≤0.05. identifying risk factors for healthcare-associated infections caused by carbapenem-resistant acinetobacter baumannii in a neonatal intensive care unit e78 | squ medical journal, february 2018, volume 18, issue 1 crab infections included prolonged nicu stay, the presence of an umbilical catheter or mechanical ventilator and the previous administration of carbapenems (p <0.02 each). independent risk factors for mortality were mechanical ventilation (aor = 17.2; p = 0.04) and the previous use of carbapenems (aor = 79.1; p <0.01) [table 3]. isolates from both the crab and csab groups demonstrated high resistance rates to all antimicrobials except for tigecycline, with no significant differences between the two groups [table 4]. discussion the ability to survive in a hospital environment has resulted in a high incidence of hais attributed to a. baumannii; furthermore, the organism rapidly develops resistance to a broad range of antibiotic classes.8 previous research has indicated that the incidence of a. baumannii-resistant strains is increasing all over the world.3–5 according to surveillance data in the usa, carbapenem resistance increased from 5.2% to 40.8% between 1999 and 2010.9 similarly, in europe, surveillance data from 2012 indicated that 68.8% of a. baumannii strains isolated from icus were resistant to carbapenems.10 these findings support those of the present study which indicated a high rate of carbapenem resistance in the studied egyptian nicu. in terms of invasive procedures, mechanical vent ilation was the only independent risk factor for crabcaused hais in the current study. previous studies have reported similar findings.11,12 mechanical ventilation is indicated for neonates in cases of respiratory distress, table 3: mortality-related risk factors among patients with health-care-associated infections caused by carbapenemresistant or -sensitive acinetobacter baumannii in a neonatal intensive care unit in egypt (n = 124) variable univariate analysis, n (%) multivariate analysis crab (n = 70) csab (n = 8) p value aor (95% ci) p value postnatal age in days <7 32 (45.7) 3 (37.5) 0.38 ≥7 38 (54.3) 5 (62.5) 0.61 male gender 34 (48.6) 4 (50) 0.80 prematurity 33 (47.1) 3 (37.5) 0.21 lbw 25 (35.7) 3 (37.5) 0.89 prom 32 (45.7) 4 (50) 0.42 psah 10 (14.3) 1 (12.5) 0.67 median length of nicu stay prior to hai (range) 12 (8.3–15.2) 5.4 (3.6–7.9) 0.02* presence of an invasive device umbilical catheter 55 (78.6) 1 (12.5) <0.01* ppcl 8 (11.4) 1 (12.5) 0.82 urinary catheter 54 (77.1) 6 (75) 0.87 mv 57 (81.4) 2 (25) 0.02* 17.2 (2.1–129.2) 0.04* previous antibiotic exposure carbapenems 53 (75.7) 1 (12.5) <0.01* 79.1 (32.7–278.9) <0.01* cephalosporins 18 (25.7) 2 (25) 0.94 aminoglycosides 20 (28.6) 2 (25) 0.76 vancomycin 25 (35.7) 3 (37.5) 0.65 median days of antibiotic therapy before hai in days (range) 5.1 (3.8–8.7) 3.2 (2.1–3.5) 0.09 crab = carbapenem-resistant acinetobacter baumannii; csab = carbapenem-sensitive a. baumannii; aor = adjusted odds ratio; ci = confidence interval; lbw = low birth weight; prom = premature rupture of the membranes; psah = previous stay in another hospital; nicu = neonatal intensive care unit; hai = healthcare-associated infection; ppcl = peripheral percutaneous central line; mv = mechanical ventilator. *considered statistically significant at p ≤0.05. amira m. sultan and wael a. seliem clinical and basic research | e79 hypoxaemia or hypercapnia; however, organisms present in the hospital environment frequently attach to the ventilator tube and form a biofilm which is associated with an increased risk of antibiotic resistance.13 further more, ventilated critically-ill neonates often undergo endotracheal intubation which can interrupt immunity barriers.14 therefore, the incidence of hais may potentially be reduced by encouraging the use of noninvasive ventilation among neonates, such as nasal continuous positive pressure ventilation.15 in the current study, a previous stay in another hospital and prolonged nicu stay prior to infection were found to constitute significant risk factors for subsequent crab infections. this may be attributable to prolonged exposure to organisms present in the hospital environment and the extended use of antibiotics that aid in the development of antimicrobial resistance.11,12 rosa et al. reported that exposure to a contaminated hospital environment increased the risk of acquisition of crab isolates.16 baran et al. indicated that patients admitted to the icu had a three-fold higher risk of crab infections.17 playford et al. also observed an association between prolonged icu stay and crab infection.18 unfortunately, the nature of multidrug-resistant microorganisms, including a. bau mannii, in icus is endemic. in addition, the likelihood of antimicrobial therapy increases with the duration of icu stay, thus leading to the colonisation of resistant strains of bacteria. previous exposure to carbapenems was another independent risk factor for hais caused by crab in the present study. sheng et al. also noted that patients with crab infections were significantly more likely to have been exposed to carbapenems.19 such findings emphasise the need for the judicious use of carbapenem antibiotics, which should remain a last resort in the treatment of serious infections so as to control the development of carbapenem-resistant microbes. as with carbapenems, previous exposure to aminoglycosides was another independent risk factor for crab infections in the current study. chen et al. also observed prior exposure to aminoglycosides such as amikacin to be a risk factor for crab.20 treating physicians should therefore consider these findings before prescribing aminoglycosides to icu patients. in the current study, crab isolates showed high resistance rates to other antibiotics. similar findings were reported by falagas et al. among pandrug-resistant a. baumannii infection cases.21 infections caused by multidrug-resistant pathogens have many adverse out comes, including prolonged hospital stay, higher treat ment costs and increased mortality rates.22 the treatment of patients suffering from infections caused by such strains is challenging. adequate knowledge of local a. baumannii resistance patterns is a fundamental element to a successful therapeutic approach.23 in terms of mort ality, the presence of an umbilical catheter or mechanical ventilator, prolonged stay in the nicu and the previous administration of carbapenems resulted in significantly increased mortality among patients with hais caused by crab. similar results were reported by djordjevic et al. among adult patients admitted to a medical-surgical icu.24 this study is subject to certain limitations. generally, nicus in developing countries such as egypt usually have low staff-to-patient ratios, often resulting in a lack of essential infection control precautions like thorough hand hygiene and aseptic procedures. under these conditions, resistant bacteria can more easily spread between patients, resulting in more colonised and infected cases compared to adequately staffed units. in addition, the low number of patients in the control group in comparison to the case group resulted in a wide confidence interval, weakening the findings of the present study. conclusion this study found that prematurity, premature rupture of the membranes, a previous stay in another hosp ital, prolonged nicu stay, the presence of an invasive device, previous exposure to carbapenems or aminoglycosides and prolonged antibiotic therapy were signif table 4: antimicrobial resistance of carbapenem-resistant and -sensitive acinetobacter baumannii isolates in a neonatal intensive care unit in egypt (n = 124) antimicrobial n (%) p value crab (n = 91) csab (n = 33) amoxicillin and clavulanic acid (30 μg/ml) 85 (93.4) 27 (81.8) 0.85 piperacillintazobactam (110 μg/ml) 80 (87.9) 25 (75.8) 0.68 cefotaxime (30 μg/ml) 91 (100) 33 (100) >0.99 cefepime (30 μg/ml) 71 (78) 26 (78.8) 0.98 gentamicin (10 μg/ml) 78 (85.7) 27 (81.8) 0.87 amikacin (30 μg/ml) 87 (95.6) 29 (87.9) 0.69 ciprofloxacin (5 μg/ml)* 86 (94.5) 27 (81.8) 0.85 tigecycline (15 μg/ml) 9 (9.9) 4 (12.1) 0.58 crab = carbapenem-resistant acinetobacter baumannii; csab = carbapenem-sensitive a. baumannii. *not recommended for use in neonates. identifying risk factors for healthcare-associated infections caused by carbapenem-resistant acinetobacter baumannii in a neonatal intensive care unit e80 | squ medical journal, february 2018, volume 18, issue 1 icantly associated with crab-caused hais in an nicu in egypt. moreover, prematurity, mechanical ventilation and previous exposure to carbapenems or aminoglycosides were independent risk factors for the development of hais caused by crab. a c k n o w l e d g e m e n t s the authors wish to acknowledge the consistent and helpful support of the nursing staff at the mansoura university children’s hospital in their provision of professional care to the subjects and implementation of proper research protocols during the study period. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. sydnor er, perl tm. hospital epidemiology and infection control in acute-care settings. clin microbiol rev 2011; 24:141–73. doi: 10.1128/cmr.00027-10. 2. mesiano er, merchán-hamann e. bloodstream infections among patients using central venous catheters in intensive care units. rev lat am enfermagem 2007; 15:453–9. doi: 10.1590/ s0104-11692007000300014. 3. sopirala mm, mangino je, gebreyes wa, biller b, bannerman t, balada-llasat jm, et al. synergy testing by etest, microdilution checkerboard, and time-kill methods for pan-drug-resistant acinetobacter baumannii. antimicrob agents chemother 2010; 54:4678–83. doi: 10.1128/aac.00497-10. 4. jung jy, park ms, kim se, park bh, son jy, kim ey, et al. risk factors for multi-drug resistant acinetobacter baumannii bacteremia in patients with colonization in the intensive care unit. bmc infect dis 2010; 10:228. doi: 10.1186/1471-2334-10228. 5. chuang yc, cheng cy, sheng wh, sun hy, wang jt, chen yc, et al. effectiveness of tigecycline-based versus colistin-based therapy for treatment of pneumonia caused by multidrugresistant acinetobacter baumannii in a critical setting: a matched cohort analysis. bmc infect dis 2014; 14:102. doi: 10.11 86/1471-2334-14-102. 6. clinical and laboratory standard institute. performance standards for antimicrobial susceptibility testing, version m100-s22. wayne, pennsylvania, usa: clinical and laboratory standard institute, 2012. 7. horan tc, andrus m, dudeck ma. cdc/nhsn surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. am j infect control 2008; 36:309–32. doi: 10.1016/j.ajic.2008.03.002. 8. karageorgopoulos de, falagas me. current control and treat ment of multidrug-resistant acinetobacter baumannii infections. lancet infect dis 2008; 8:751–62. doi: 10.1016/s1473-3099(08) 70279-2. 9. adams-haduch jm, onuoha eo, bogdanovich t, tian gb, marschall j, urban cm, et al. molecular epidemiology of carbapenem-nonsusceptible acinetobacter baumannii in the united states. j clin microbiol 2011; 49:3849–54. doi: 10.1128/ jcm.00619-11. 10. european centre for disease prevention and control. surveillance report: annual epidemiological report – antimicrobial resistance and healthcare-associated infections 2014. from: http://ecdc.europa .eu/en/publications/publications/anti microbial-resistance-annual-epidemiological-report .pdf accessed: dec 2017. 11. dizbay m, tunccan og, sezer be, hizel k. nosocomial imipenem-resistant acinetobacter baumannii infections: epidem iology and risk factors. scand j infect dis 2010; 42:741–6. doi: 10.3109/00365548.2010.489568. 12. vaze nd, emery cl, hamilton rj, brooks ad, joshi sg. patient demographics and characteristics of infection with carbapenem-resistant acinetobacter baumannii in a teaching hospital from the united states. adv infect dis 2013; 3:10–16. doi: 10.4236/aid.2013.31002. 13. gil-perotin s, ramirez p, marti v, sahuquillo jm, gonzalez e, calleja i, et al. implications of endotracheal tube biofilm in ventilator-associated pneumonia response: a state of concept. crit care 2012; 16:r93. doi: 10.1186/cc11357. 14. foglia e, meier md, elward a. ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients. clin microbiol rev 2007; 20:409–25. doi: 10.1128/cmr.00041-06. 15. hentschel j, brüngger b, stüdi k, mühlemann k. prospective surveillance of nosocomial infections in a swiss nicu: low risk of pneumonia on nasal continuous positive airway pressure? infection 2005; 33:350–5. doi: 10.1007/s15010-005-5052-x. 16. rosa r, arheart kl, depascale d, cleary t, kett dh, namias n, et al. environmental exposure to carbapenem-resistant acinetobacter baumannii as a risk factor for patient acquisition of a. baumannii. infect control hosp epidemiol 2014; 35:430–3. doi: 10.1086/675601. 17. baran g, erbay a, bodur h, ongürü p, akinci e, balaban n, et al. risk factors for nosocomial imipenem-resistant acinetobacter baumannii infections. int j infect dis 2008; 12:16–21. doi: 10.1016/j.ijid.2007.03.005. 18. playford eg, craig jc, iredell jr. carbapenem-resistant acinetobacter baumannii in intensive care unit patients: risk factors for acquisition, infection and their consequences. j hosp infect 2007; 65:204–11. doi: 10.1016/j.jhin.2006.11.010. 19. sheng wh, liao ch, lauderdale tl, ko wc, chen ys, liu jw, et al. a multicenter study of risk factors and outcome of hospitalized patients with infections due to carbapenemresistant acinetobacter baumannii. int j infect dis 2010; 14:e764–9. doi: 10.1016/j.ijid.2010.02.2254. 20. chen yh, chiueh cc, lee yj. risk factors of carbapenemresistant acinetobacter baumannii infection among hospitalized patients. j exp clin med 2014; 6:143–6. doi: 10.1016/j. jecm.2014.06.003. 21. falagas me, rafailidis pi, matthaiou dk, virtzili s, nikita d, michalopoulos a. pandrug-resistant klebsiella pneumoniae, pseudomonas aeruginosa and acinetobacter baumannii infections: characteristics and outcome in a series of 28 patients. int j antimicrob agents 2008; 32:450–4. doi: 10.1016/j.ijanti micag.2008.05.016. 22. young ls, sabel al, price cs. epidemiologic, clinical, and economic evaluation of an outbreak of clonal multidrug-resis tant acinetobacter baumannii infection in a surgical intensive care unit. infect control hosp epidemiol 2007; 28:1247–54. doi: 10.1086/521660. 23. michalopoulos a, falagas me. treatment of acinetobacter infections. expert opin pharmacother 2010; 11:779–88. doi: 10.1517/14656561003596350. 24. djordjevic zm, folic mm, folic nd, gajovic n, gajovic o, jankovic sm. risk factors for hospital infections caused by carbapanem-resistant acinetobacter baumannii. j infect dev ctries 2016; 10:1073–80. doi: 10.3855/jidc.8231. https://doi.org/10.1128/cmr.00027-10 https://doi.org/10.1590/s0104-11692007000300014 https://doi.org/10.1590/s0104-11692007000300014 https://doi.org/10.1128/aac.00497-10 https://doi.org/10.1186/1471-2334-10-228 https://doi.org/10.1186/1471-2334-10-228 https://doi.org/10.1186/1471-2334-14-102 https://doi.org/10.1186/1471-2334-14-102 https://doi.org/10.1016/j.ajic.2008.03.002 https://doi.org/10.1016/s1473-3099%2808%2970279-2 https://doi.org/10.1016/s1473-3099%2808%2970279-2 https://doi.org/10.1128/jcm.00619-11 https://doi.org/10.1128/jcm.00619-11 https://doi.org/10.3109/00365548.2010.489568 https://doi.org/10.4236/aid.2013.31002 https://doi.org/10.1186/cc11357 https://doi.org/10.1128/cmr.00041-06 https://doi.org/10.1007/s15010-005-5052-x https://doi.org/10.1086/675601 https://doi.org/10.1016/j.ijid.2007.03.005 https://doi.org/10.1016/j.jhin.2006.11.010 https://doi.org/10.1016/j.ijid.2010.02.2254 https://doi.org/10.1016/j.jecm.2014.06.003 https://doi.org/10.1016/j.jecm.2014.06.003 https://doi.org/10.1016/j.ijantimicag.2008.05.016 https://doi.org/10.1016/j.ijantimicag.2008.05.016 https://doi.org/10.1086/521660 https://doi.org/10.1517/14656561003596350 https://doi.org/10.3855/jidc.8231 departments of 1orthopaedics, traumatology & rehabilitation, 2basic medical sciences and 3deanship of research & postgraduate affairs, faculty of medicine, international islamic university malaysia, kuala lumpur, malaysia *corresponding author e-mails: ariffs@iium.edu.my and mdariffs@hotmail.com تقومي النسجيات حلبيبات اهليدروكسي آباتيت يف وجود أو عدم وجود بالزما غنية بالصفائح الدموية مقابل طُْعم عظمي ذايت دراسة مقارنة للمواد احليوية املستخدمة يف دمج الفقرات يف األرانب النيوزلندية البيضاء زمزوري زكريا، �سي نور ز�رد ��سي �سيمان، ز�نريا بيونغ، حممد عارف �رشف �لدين، �أحمد حافظ ذو �لكفل، قمرول �آرفن خالد abstract: objectives: hydroxyapatite (ha) has osteoconductive properties and is widely used as a bone graft substitute. platelet-rich plasma (prp) is an autologous product with osteoinductive effects. hypothetically, a combination of both would augment the bone formation effect of ha and widen its application in spinal fusion surgeries. this study aimed to compare new bone formation with ha granules alone and in combination with prp versus an autologous bone graft during a lumbar intertransverse process spinal fusion. methods: a total of 16 adult new zealand white rabbits underwent single-level bilateral intertransverse process fusion at the l5–l6 vertebrae. one side of the spine received either ha granules alone or a combination of ha granules and prp, while the contralateral side received an autologous bone graft. four animals each from the ha group and the ha plus prp group versus the autograft group were assessed either at six or 16 weeks by undecalcified histology and histomorphometry. the mean percentage of new bone areas over the corresponding fusion masses were compared between groups. results: no significant difference in new bone formation was observed between the ha and ha plus prp groups at six or 16 weeks. the autograft group had significantly more new bone formation at six and 16 weeks (p = 0.004 and <0.001, respectively). conclusion: an autologous bone graft remains superior to ha granules, with or without prp. ha granules demonstrated an excellent osteoconductive scaffold but had poor biodegradability. while prp enhances the properties of ha granules, these biomaterials do not have a synergistic effect. keywords: autografting; hydroxyapatite; lumbar vertebrae; platelet-rich plasma; spinal fusion. �لغنية �لبالزما وتعد �لعظمي. للطعم كبديل كثري� وت�ستخدم �لعظمي، �لتو�سيل خو��ص لها �آباتيت �لهيدروك�سي مادة الهدف: امللخ�ص: بال�سفائح �لدموية منتج ذ�تي ذو �آثار تو�سيل عظمي. ومن ناحية �فرت��سية يوؤدي �جلمع بني �ملادتني معا لتقوية عملية تكوين �لعظام تكوين عملية ملقارنة �لدر��سة هذه وتهدف �لفقر�ت. دمج جر�حات يف تطبيقاتها من وتو�سع �آباتيت، �لهيدروك�سي مادة بها تقوم �لتي عظام جديدة مع ��ستخد�م مادة �لهيدروك�سي �آباتيت مبفردها، و�أي�سا عند جمعها مع �لبالزما �لغنية بال�سفائح �لدموية يف مقابل ُطْعم عظمي ذ�تي �أثناء �إجر�ء عملية دمج �لفقر�ت بني �لناتئتني �مل�ستعر�ستني �لَقَطِنّي. الطريقة: �أجريت عملية ثنائية �جلانب لدمج �لفقر�ت بني �لناتئتني �مل�ستعر�ستني �لَقَطِنّية على 16 من �لأر�نب �لنيوزيلندية �لبي�ساء يف �لفقر�ت l5–l6. و�عطي يف جانب و�حد من �لعمود �لفقري حبيبات مادة �لهيدروك�سي �آباتيت مبفردها، �أو مع مادة �لهيدروك�سي �آباتيتمع �لبالزما �لغنية بال�سفائح �لدموية. بينما عمل يف �جلانب �لآخر �ملقابل من �لعمود �لفقري ُطْعم عظمي ذ�تي. ومت �إجر�ء تقومي ن�سيجي وهي�ستومورفوميرتي بعد 6 �أو 16 �أ�سابيع يف كل �أربعة �أر�نب من �ملجموعتني. ومتت مقارنة ن�سبة م�ساحة �لعظم �جلديد �إىل �أحجام �لفقر�ت �ملدجمة يف �ملجموعتني. النتائج: مل يالحظ �أي فرق معنوي يف تكوين عظم جديد بني �ملجموعتني يف �لأ�سبوعني �ل�ساد�ص و�ل�ساد�ص ع�رش. ومتيزت جمموعة �لطعم �لعظمي �لذ�تي بتكوين عظم �أكرث يف �لأ�سبوعني �ل�ساد�ص و�ل�ساد�ص ع�رش ) p = 0.004 و 0.001< على �لتو�يل(. اخلال�صة: يظل �لُطْعم �لعظمي �لذ�تي متفوقا على حبيبات �لهيدروك�سي �آباتيت، ويف وجود وغياب بالزما غنية بال�سفائح �لدموية. و�أظهرت حبيبات �لهيدروك�سي �آباتيت �أن لها قدرة ممتازة على �أن تكون "�سقالة" للتو�سيل �لعظمي. غري �أن لهذه �ملادة قابلية منخف�سة للتحلل �حليوي. و�أظهرت �لبالزما �لغنية بال�سفائح �لدموية قدرة على تقوية خو��ص مادة �لهيدروك�سي �آباتيت، �إل �أن هذه �ملو�د �حليوية لي�ص لها تاأثري تاآزري. الكلمات املفتاحية: ُطْعم عظمي ذ�تي؛ �لهيدروك�سي �آباتيت؛ فقر�ت َقَطِنّية؛ بالزما غنية بال�سفائح �لدموية؛ دمج �لفقر�ت. histological evaluation of hydroxyapatite granules with and without platelet-rich plasma versus an autologous bone graft comparative study of biomaterials used for spinal fusion in a new zealand white rabbit model zamzuri zakaria,1 che n. z. c. seman,1 zunariah buyong,2 *mohd a. sharifudin,1 ahmad h. zulkifly,1 kamarul a. khalid1,3 clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e422–429, epub. 30 nov 16 submitted 18 feb 16 revisions req. 20 apr & 22 jun 16; revisions recd. 25 may & 6 jul 16 accepted 19 jul 16 doi: 10.18295/squmj.2016.16.04.004 zamzuri zakaria, che n. z. c. seman, zunariah buyong, mohd a. sharifudin, ahmad h. zulkifly and kamarul a. khalid clinical and basic research | e423 bone grafts are used in various clinical fields.1,2 commonly, bone grafts are harvested from the patient’s own bones during surgery. however, serious complications related to the harvesting procedure can arise, such as bleeding, infection and chronic pain at the donor site, as well as increased costs and operating time.1,3,4 as a result, the demand for bone graft substitutes has led to multidisciplinary research designed to develop new biomaterial technology. in malaysia, researchers from a collaborative project have successfully manufactured and commercialised a synthetic bone graft substitute known as granumas® (granulab, kuala lumpur, malaysia); this product is made of locally produced calcium phosphate-based hydroxyapatite (ha) granules fabricated from limestone.5 khadijah et al. tested this bone graft substitute on new zealand white rabbits with non-critical tibial metaphyseal defects; undecalcified bone histology showed new bone formation two weeks after implantation and the defect was completely bridged by new bone at 4–6 weeks.6 as demonstrated in the animal model, ha granules have shown good evidence of bone formation in the weightbearing areas; however, there is currently no scientific evidence that this product is suitable for application in non-weight-bearing areas, such as in lumbar spinal fusion. in lumbar spinal fusion surgeries, an autologous bone graft is still considered the gold standard, as it possesses all of the properties necessary for bone regeneration, such as osteoconductivity, osteoinductivity and the presence of osteogenic cells.3 in comparison, ha granules are solely osteoconductive due to their similarity to the mineral components of bone tissue.7,8 despite this, combining ha granules with growth factors—such as platelet-derived growth factor, transforming growth factor and vascular endothelial growth factor—can augment bone formation.9 the main purpose of this study was therefore to compare new bone formation using an undecalcified histology technique in a lumbar intertransverse process spinal fusion with ha alone and a combination of ha with platelet-rich plasma (prp) versus an autograft control. methods a total of 16 new zealand white rabbits between 10–19 months old and 2.25–3.40 kg were used in this study. the animals were randomly divided into two groups of eight rabbits each to form a ha group and a ha plus prp group. two assessment periods were chosen to show differences in the fusion healing and remodelling changes as a previous study indicated histological evidence of fusion-healing changes at 16 weeks.10 as such, each group was further subdivided into two groups of four rabbits according to the time of observations (at six or 16 weeks, respectively). assumptions for the mean percentage of bone area in subgroups were made according to sample size calculations, since a previous study reporting a similar method of comparison using new bone formation in intertransverse process spinal fusions was performed at 12-week intervals.10 the sample size was calculated using pass software, version 2008 (ncss llc, kaysville, utah, usa), to measure the difference of the mean percentage of bone area in subgroups with 80% power and a significance level of <0.05. in a oneway analysis of variance (anova) test, the means of three samples of four individuals each were compared. the total sample of 16 subjects achieved 91% power to detect differences among the means versus the alternative of equal means using an f-test with a <0.05 significance level. the size of the variation in the means was represented by their standard deviation (24.94). the common standard deviation within a group was assumed to be 20.00 [table 1]. all of the animals underwent a bilateral intertransverse process spinal fusion between the l5 and l6 vertebrae using a previously described lateral approach technique.11 a single orthopaedic surgeon with previous experience in animal studies performed the surgery and a trained laboratory technician administrated the anaesthesia. synthetic granumas® ha granules (granulab) between 1,000–2,500 µm with a tap density of 0.524 g/ml and ~48% porosity were used. the platelet-rich plasma (prp) was obtained from the rabbits’ peripheral blood using a gravitational platelet sequestration technique with a table-top centrifuge machine.12 the processing advances in knowledge calcium phosphate-based hydroxyapatite (ha) granules can be used as bone substitutes in non-weight bearing areas such as in a lumbar intertransverse process spinal fusion. ha granules have excellent osteoconductive properties but lack biodegradability. autologous bone grafts result in significantly more new bone formation in comparison to ha granules, with or without platelet-rich plasma (prp). application to patient care the results of this study showed that ha granules and a combination of ha granules and prp are potentially good bone substitutes in spinal fusion procedures; however, autologous bone grafts result in significantly more new bone formation. histological evaluation of hydroxyapatite granules with and without platelet-rich plasma versus an autologous bone graft comparative study of biomaterials used for spinal fusion in a new zealand white rabbit model e424 | squ medical journal, november 2016, volume 16, issue 4 was done under sterile conditions. the ha granules and platelet gel were prepared prior to implantation following the decortication of the transverse processes. the ha granules were mixed with the platelet gel in a petri dish before being implanted into the fusion bed. one side of the spine was then implanted with either ha granules alone (the ha group) or ha mixed with prp (the ha plus prp group). the contralateral site of the spine acted as a control and received an iliac crest bone graft (the autograft group). the same rabbit was used in both one experimental group and the control group so as to eliminate the confounder of physiological variability between individual rabbits. subsequently, the rabbits were euthanised at either six or 16 weeks post-implantation. their spines were harvested from the l4 to l7 vertebrae en bloc with the adjacent paravertebral muscles. a hard tissue band cutting and microgrinding system (exakt advanced technologies, norderstedt, germany) was used to produce undecalcified tissue sections. retrieved specimens were fixed in 10% neutral buffered formalin, dehydrated in a series of concentrations (70%, 90% and 100%) of ethanol and then cleared in chloroform. the specimens were then infiltrated in various concentrations (10%, 30%, 50%, 70%, 90% and 100%) of hydroxyethyl methacrylate (technovit® 7200, heraeus kulzer, hanau, germany) before being embedded in pure hydroxyethyl methacrylate (technovit® 7200, heraeus kulzer). the tissue sections were then stained using the masson-goldner trichrome staining method and analysed using a transmitted light microscope (olympus® bx61, olympus corp., tokyo, japan). the total area of fusion mass was defined as the area spanning from the upper border of the transverse process of l5 vertebra (tp5) superiorly, the lower border of the transverse process of l6 vertebra inferiorly, the intertransverse membrane ventrally and the ventral border of paraspinal muscles. new bone area was defined as an area with mineralised bone, marrow within the mineralised area and osteoids. unremodelled or native transverse processes, marrow within the transverse processes, cartilaginous tissue, soft tissue stroma, ha granules and the remnants of the autograft were excluded from the measurement of new bone. the total fusion and new bone areas were measured in pixels using photoshop cs4 extended, version 11.0 (adobe systems inc., san jose, california, usa). examples of the calculation of fusion mass, measured total fusion and new bone areas are shown in figure 1. table 1: sample size calculations for assumptions of the mean percentage of bone areas power average k total alpha beta sd of means sd effect size 0.90861 4.00 3 12 0.05000 0.09139 24.94 20.00 1.2472 sd = standard deviation. figure 1: schematic diagrams showing examples of the quantification of areas of (a) full thickness fusion mass, (b) total fusion mass and (c) new bone in a new zealand white rabbit model receiving an autograft and either hydroxyapatite granules or hydroxyapatite granules plus platelet-rich plasma. hag = hydroxyapatite granules; tp5 = transverse process of the l5 vertebra; tp6 = transverse process of the l6 vertebra. zamzuri zakaria, che n. z. c. seman, zunariah buyong, mohd a. sharifudin, ahmad h. zulkifly and kamarul a. khalid clinical and basic research | e425 the percentage of new bone area was calculated from the total number of pixels filled with new bone over the total number of pixels in the fusion mass area. the mean percentage of new bone over the total fusion mass area in the autograft, ha and ha plus prp groups at different periods were analysed using the statistical package for the social sciences (spss), version 16 for macintosh (ibm corp., chicago, illinois, usa). the percentage of new bone was then compared statistically using the one-way anova and tukey’s and dunnett’s post hoc tests. a p value of <0.050 was considered statistically significant. this study was approved by the international islamic university malaysia research ethics committee, international islamic university malaysia, kuala lumpur, malaysia (#iium/305/14/1). results at six weeks post-implantation, the fusion mass in the autograft group was well defined and easily differentiated from the surrounding paraspinal muscle, which was stained brick red. evidence of remodelled woven bone was observed in the fusion mass near the middle of tp5. immature new bone trabeculae or woven bones were seen in the peripheral zones around the transverse processes and adjacent to both decorticated sides of the transverse processes. in the central zone, the fusion mass was made up of immature new bone trabeculae, bone marrow, remnants of old bones (either autografted or grafted bones), cartilage and soft tissue stroma. in the autograft group, the remnants of old bones at six weeks were in close contact and integrated well with the islands of newly formed bone. wellorganised and regularly arranged collagen fibres and osteocyte lacunae characterised the remnants of the old bones. the lacunae appeared empty and contained no osteoids. in this section, the green mineralised old bone appeared brighter than the new bone (woven or newly remodelled bone). in the same way, the undecorticated side of the transverse processes also displayed a green colour similar in intensity to the old bones [figure 2a]. areas of endochondral bone formation in the autograft group at six weeks post-implantation were characterised by a different chondroblast morphology. the chondroblasts in the small lacunae nearest to the stromal tissue were evenly spaced in the matrix of the reserve zone. adjacent to this, the chondroblasts were stacked up in columns in the proliferative zone. next to this zone, the lacunae were hypertrophied in the maturation zone. subsequently, the hyaline cartilages were calcified and resorbed by osteoclasts in the resorption zone. osteoblasts were attached to the calcified hyaline cartilage and secreted osteoids. osteoids were observed scattered in the calcification zones and the adjacent woven bone. new bone trabeculae in these areas appeared less dense compared to the newly formed woven bone. in between bone trabeculae, cells of various sizes—suggestive of bone marrow—were observed [figure 2b]. evidence of adipose cells was noted in the marrow during this observation period. figure 2: photomicrographs of masson-goldner trichrome-stained sagittal sections at either (a & b) six or (c) 16 weeks post-implantation showing the full thickness fusion mass of a new zealand white rabbit receiving an autograft. a: old bone (ob) can be seen in direct contact with the new bone (nb) trabeculae at x100 magnification. b: islets of remodelled bone trabeculae and marrow as well as nb, cartilage and remnants of the autograft or ob are seen across the fusion mass at x200 magnification. c: note the completely remodelled nb and almost complete cortical rim (arrows) bridging the bone between the transverse processes at x40 magnification. there is also visible loss of the normal anatomical structure of the transverse process of the l6 vertebra (tp6) and a common shared marrow cavity with the fusion mass. the soft tissue gap near the tp6 is filled with soft tissue stroma, various stages of endochondral bone cartilage formation and minimal remnants of ob. ob = old bone; m = marrow; nb = new bone; cr = cortical rim; tp5 = transverse process of the l5 vertebra; tp6 = transverse process of the l6 vertebra. histological evaluation of hydroxyapatite granules with and without platelet-rich plasma versus an autologous bone graft comparative study of biomaterials used for spinal fusion in a new zealand white rabbit model e426 | squ medical journal, november 2016, volume 16, issue 4 in the autograft group, minimal grafted bone was observed at 16 weeks post-implantation. the remnants consisted mainly of cortical bone. a striking feature seen at this stage was the almost complete remodelling of the fusion mass, characterised by the presence of a cortical rim encasing cancellous bone and marrow within it. under higher magnification, various sizes of cells were seen, suggestive of the multicellular content of the bone marrow. these cells were separated from each other by empty spaces. remnants of transverse processes underwent total remodelling as part of the fusion mass [figure 2c]. six weeks post-implantation, new bone trabeculae were observed in the peripheral zones of the ha group. in the central zone, new bone trabeculae in between the ha granules almost bridged the transverse processes. areas of soft tissue stroma and adjacent endochondral bone formation were also seen. there was extensive direct bonding between the new bone and the ha granules [figure 3a]. interestingly, new bone trabeculae had formed extensively on the surface of the ha granules in the fusion mass; however, no obvious new bone trabeculae were observed on the surfaces of the ha granules in contact with the margins of the fusion mass, neither at its junction with the paraspinal muscles nor the intertransverse membrane. at higher magnification, bone ingrowth was observed in some of the peripheral pores of the ha granules. no obvious remodelling was seen in the fusion mass at this time [figure 3b]. in the ha group, scattered groups of stromal tissue and endochondral bone formation were seen in between the ha granules in the central region, similar to those observed in the autograft group. at 16 weeks post-implantation, new bone remodelled with the formation of bone marrow was observed [figure 3c]. scattered stromal tissues and on-going endochondral bone formation in the central zone were observed. no obvious evidence of early cortical rim formation was noted, unlike in the autograft group during the same observation period. generally, the ha granules in the ha plus prp group were well defined and contained within the intended fusion site. in addition, fusion masses were better formed and a larger number of ha granules were observed on tissue sections in comparison to the ha group. six weeks post-implantation, new bone trabeculae were seen only near the decorticated transverse processes (i.e. in the peripheral zone). in the central zone, a greater number of ha granules were contained in the fusion mass compared to the ha group. the spaces in between the ha granules were filled with either soft tissue stroma or dense material [figure 4a]. the dense material was more prominent in spaces further from the decorticated transverse processes. similar dense material was not found in either the autograft or the ha groups. the soft tissue stroma in the ha plus prp group was composed of a few blood vessels and spindle-shaped fibroblast-like cells [figure 4b]. some stromal tissue figure 3: photomicrographs of masson-goldner trichrome-stained sagittal sections at either (a & b) six or (c) 16 weeks post-implantation showing the full thickness fusion mass of a new zealand white rabbit receiving hydroxyapatite (ha) granules. a: the ha granules can be seen in direct contact with the new bone (nb) trabeculae at x10 magnification. b: stromal tissue and endochondral bone formation are observed in proximity to the ha granules at x20 magnification. c: there is evidence of nb remodelled with bone marrow formation at x4 magnification. stromal tissue and many loci of on-going endochondral bone formation can be seen in close proximity to the ha granules. evidence of a cartilaginous gap can be observed at the lower third of the fusion mass and there is no obvious cortical rim formation. nb = new bone; hag = hydroxyapatite granules; c = cartilaginous zone; m = marrow; tp5 = transverse process of the l5 vertebra; tp6 = transverse process of the l6 vertebra. zamzuri zakaria, che n. z. c. seman, zunariah buyong, mohd a. sharifudin, ahmad h. zulkifly and kamarul a. khalid clinical and basic research | e427 was also seen in the cavities at the periphery of the granule. in one of the cavities, a multinucleated cell was discernible; however, whether this cavity was caused by osteoclastic activity or not could not be determined. no obvious new bone trabeculae were seen in close proximity. in the ha plus prp group, new bone areas were found only near the transverse processes at 16 weeks post-implantation. in contrast to the six-week samples, areas with endochondral bone formation were located in the peripheral zone. in the central zone, the fusion mass was packed with ha granules. unlike the granules in the ha group, the granules in the ha plus prp group were closer together. the spaces in between the granules were filled with dense material and some stromal tissue, similar in appearance to those observed at six weeks. no obvious new bone growth was seen in the central zone in any of the samples. the mean percentage of new bone area in the autograft group was significantly higher compared to the ha and ha plus prp groups at six weeks post implantation (65.5% versus 33.1% and 9.8%, respectively; p = 0.004). at 16 weeks, the mean percentage of new bone area formed in the autograft group was 86.4% compared to 33.5% in the ha group and only 20.3% in the ha plus prp group (p <0.001) [table 2]. dunnett’s post hoc test showed no statistically significant difference between the ha and ha plus prp groups (p = 0.154). a post hoc test revealed that significant differences existed only between the autograft versus ha groups and the autograft versus ha plus prp groups (p <0.001 each) and no significant differences were observed between mean bone percentages in the ha versus ha plus prp groups (p = 0.487). discussion a lumbar intertransverse fusion is commonly performed on patients with lumbar instability to regenerate bone tissue at sites previously occupied by muscle. recently, ha has been used as a substitute for autologous bone grafting and there have been no detailed reports of intertransverse fusion failure.13,14 calcium phosphate-based ha is well known for its osteoconductive properties; however, studies have revealed that graft materials with osteoconductive properties alone are inadequate to generate new bone at this site.15–17 in its natural form, prp contains growth factors and other cytokines;18,19 these growth table 2: mean percentage of new bone growth between groups receiving an autograft and either hydroxyapatite or hydroxyapatite plus platelet-rich plasma at six and 16 weeks post-implantation in a new zealand white rabbit model (n = 16) six weeks post-implantation 16 weeks post-implantation n mean percentage ± sd n mean percentage ± sd group autograft 8 65.5 ± 28.4 8 86.4 ± 12.0 ha 4 33.1 ± 9.0 4 33.5 ± 12.6 ha plus prp 4 9.8 ± 9.0 4 20.3 ± 9.1 f statistic f(2,10) = 9.808 f(2,12) = 27.004 p value 0.004 <0.001 sd = standard deviation; ha = hydroxyapatite; prp = platelet-rich plasma. figure 4: photomicrographs of masson-goldner trichrome-stained sagittal sections at six weeks post-implantation showing the full thickness fusion mass of a new zealand white rabbit receiving hydroxyapatite (ha) granules plus plateletrich plasma (prp). a: minimal new bone trabeculae are observable at x100 magnification and are adjacent to the transverse processes only. b: by enlarging an area of figure 4a (yellow box) by x20 magnification, a cavity in the periphery of the ha granule can be seen filled with stromal tissue and a multinucleated cell. hag = hydroxyapatite granules; s = stromal tissue. histological evaluation of hydroxyapatite granules with and without platelet-rich plasma versus an autologous bone graft comparative study of biomaterials used for spinal fusion in a new zealand white rabbit model e428 | squ medical journal, november 2016, volume 16, issue 4 factors have been shown to play an important role in promoting bone healing.20 thus, hypothetically, the combination of ha granules and prp would enhance the effect of ha granules on bone formation. in the current study, there was new bone form ation at both ends of the fusion mass near the decorticated transverse processes in the ha group at six weeks. no intervening cartilage was seen in close proximity to this area. areas of cartilage formation were observed in between the granules in the central zone. at 16 weeks, new bone was seen bridging the transverse processes. however, unlike in the autograft group, there was an absence of cortical remodelling and single marrow cavities in the ha group. this presumably occurred because most of the area in the fusion mass consisted of ha granules. in the ha plus prp group, specimens showed almost the same results as those of the ha group. new bone formation was limited at both ends of the fusion mass near the decorticated transverse processes. both of the transverse processes appeared to be healed instead of demonstrating the active bone outgrowth seen in both the autograft and ha groups. moreover, no intervening cartilage was seen in close proximity to this area. the spaces between the granules in the central zone were mainly occupied by connective tissue stroma and no areas of cartilage formation were observed. one sample even demonstrated mature tissue fibrosis at 16 weeks. in contrast, no tissue fibrosis was observed in samples from the autograft or ha groups. furthermore, there was no statistical difference between the ha and the ha plus prp groups; this may be due to the small sample size of the current study as the power to demonstrate a difference between the groups was small. although ha demonstrates good osteoconductivity, the mean percentage of bone area among the ha group in the current study was significantly lower; this may be because the ha granules were minimally resorbed even at 16 weeks post-implantation and they occupied a large volume of the fusion mass. a similar explanation can be applied to the ha plus prp group as well. nevertheless, the results of this study indicate that ha granules and ha plus prp may potentially be used as a good bone graft substitute for spinal fusion. other studies in the literature are in agreement with these findings.2,21,22 the porous characteristics of ha potentially affect the histological outcomes of posterolateral lumbar fusion; motomiya et al. found that the highly interconnected porous structure of ha was a promising environment for spinal fusion in a rabbit model in terms of producing fusion masses with higher cellular viability.23 in addition, bansal et al. reported that ha in combination with β-tricalcium phosphate and bone marrow aspirate was a safe option for spinal fusion and had comparable effectiveness to an autologous bone graft; the major advantage of this option is the avoidance of donor site morbidity.2 based on the results obtained from the current study, it is recommended that future research on ha granules or ha granules plus prp focuses on the use of these materials in combination with spinal fusion instrumentation in larger-sized animal models. in spinal surgery, higher fusion rates are achieved when instrumentation is used.24 one of the limitations of the current study was the absence of macroscopic, radiographical and biomechanical analyses of the fusion areas. conclusion autologous bone grafts remain superior to the implantation of ha granules or ha granules plus prp in terms of new bone formation in intertransverse process spinal fusion. however, ha granules—either in combination with prp or on their own—can be used as alternative bone substitutes to support new bone growth. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was supported by a research grant from the international islamic university malaysia (#frgs 0207-69). references 1. conway jd. autograft and nonunions: morbidity with intramedullary bone graft versus iliac crest bone graft. orthop clin north am 2010; 41:75–84. doi: 10.1016/j.ocl.2009.07.006. 2. bansal s, chauhan v, sharma s, maheshwari r, juyal a, raghuvanshi s. evaluation of hydroxyapatite and betatricalcium phosphate mixed with bone marrow aspirate as a bone graft substitute for posterolateral spinal fusion. indian j orthop 2009; 43:234–9. doi: 10.4103/0019-5413.49387. 3. david r, folman y, pikarsky i, leitner y, catz a, gepstein r. harvesting bone graft from the posterior iliac crest by less traumatic, midline approach. j spinal disord tech 2003; 16:27–30.doi: 10.1097/00024720-200302000-00005. 4. robertson pa, wray ac. natural history of posterior iliac crest bone graft donation for spinal surgery: a prospective analysis of morbidity. spine (phila pa 1976) 2001; 26:1473–6. doi: 10.1097/00007632-200107010-00018. 5. fazan f, besar i, osman a, samsudin ar, khalid ka. successful commercialisation of locally fabricated bioceramics for clinical applications. med j malaysia 2008; 63:49–50. 6. khadijah k, mashita m, saidu mf, fazilah f, khalid ka. histological evaluation of the early bone response to hydroxyapatite (ha) implanted in rabbit tibia. med j malaysia 2004; 59:123–4. zamzuri zakaria, che n. z. c. seman, zunariah buyong, mohd a. sharifudin, ahmad h. zulkifly and kamarul a. khalid clinical and basic research | e429 7. damien cj, parsons jr. bone graft and bone graft substitutes: a review of current technology and applications. j appl biomater 1991; 2:187–208. doi: 10.1002/jab.770020307. 8. saikia kc, bhattacharya td, bhuyan sk, talukdar dj, saikia sp, jitesh p. calcium phosphate ceramics as bone graft substitutes in filling bone tumor defects. indian j orthop 2008; 42:169–72. doi: 10.4103/0019-5413.39588. 9. anitua e, andia i, ardanza b, nurden p, nurden at. autologous platelets as a source of proteins for healing and tissue regeneration. thromb haemost 2004; 9:4–15. doi: 10.1160/ th03-07-0440. 10. boden sd, schimandle jh, hutton wc. an experimental lumbar intertransverse process spinal fusion model: radiographic, histologic, and biomechanical healing characteristics. spine (phila pa 1976) 1995; 20:412–20. 11. zunariah b, zakaria z, zarida cn, rosnani aj. posterolateral intertransverse lumbar arthrodesis in the new zealand white rabbit model: the illustration of an alternative surgical approach. int med j malaysia 2012; 11:19–22. 12. aghaloo tl, moy pk, freymiller eg. evaluation of plateletrich plasma in combination with anorganic bovine bone in the rabbit cranium: a pilot study. int j oral maxillofac implants 2004; 19:59–65. 13. gupta mc, maitra s. bone grafts and bone morphogenetic proteins in spine fusion. cell tissue bank 2002; 3:255–67. doi: 10.1023/a:1024605128411. 14. spivak jm, hasharoni a. use of hydroxyapatite in spine surgery. eur spine j 2001; 10:s197–204. doi: 10.1007/s005860100286. 15. magit dp, maak t, trioano n, raphael b, hamouria q, polzhofer g, et al. healos/recombinant human growth and differentiation factor-5 induces posterolateral lumbar fusion in a new zealand white rabbit model. spine (phila pa 1976) 2006; 31:2180–8. doi: 10.1097/01.brs.0000232823.82106.0a. 16. glazer pa, spencer um, alkalay rn, schwardt j. in vivo evaluation of calcium sulfate as a bone graft substitute for lumbar spinal fusion. spine j 2001; 1:395–401. doi: 10.1016/ s1529-9430(01)00108-5. 17. bozic kj, glazer pa, zurakowski d, simon bj, lipson sj, hayes wc. in vivo evaluation of coralline hydroxyapatite and direct current electrical stimulation in lumbar spinal fusion. spine (phila pa 1976) 1999; 24:2127–33. doi: 10.1097/00007632199910150-00012. 18. eppley bl, woodell je, higgins j. platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. plast reconstr surg 2004; 114:1502–8. doi: 10.1097/01.prs.0000138251.07040.51. 19. weibrich g, kleis wk, hafner g, hitzler we. growth factor levels in platelet-rich plasma and correlations with donor age, sex and platelet count. j craniomaxillofac surg 2002; 30:97–102. doi: 10.1054/jcms.2002.0285. 20. marx re, carlson er, eichstaedt rm, schimmele sr, strauss je, georgeff kr. platelet-rich plasma: growth factor enhancement for bone grafts. oral surg oral med oral pathol oral radiol endod 1998; 85:638–46. doi: 10.1016/s1079-2104(98)90029-4. 21. siebrecht ma, de rooij pp, arm dm, olsson ml, aspenberg p. platelet concentrate increases bone ingrowth into porous hydroxyapatite. orthopedics 2002; 25:169–72. doi: 10.3928/ 0147-7447-20020201-22. 22. el backly rm, zaky sh, canciani b, saad mm, eweida am, brun f, et al. platelet rich plasma enhances osteoconductive properties of a hydroxyapatite-β-tricalcium phosphate scaffold (skelite) for late healing of critical size rabbit calvarial defects. j craniomaxillofac surg 2014; 42:e70–9. doi: 10.1016/j. jcms.2013.06.012. 23. motomiya m, ito m, takahata m, kadoya k, irie k, abumi k, et al. effect of hydroxyapatite porous characteristics on healing outcomes in rabbit posterolateral spinal fusion model. eur spine j 2007; 16:2215–24. doi: 10.1007/s00586-007-0501-0. 24. bridwell kh, sedgewick ta, o’brien mf, lenke lg, baldus c. the role of fusion and instrumentation in the treatment of degenerative spondylolisthesis with spinal stenosis. j spinal disord 1993; 6:461–72. doi: 10.1097/00002517-19930606000001. a schwannoma in the head and neck region may arise from any peripheral, cranial or autonomic nerve, except from the optic and olfactory nerve.1 this tumour arises from the schwann cells, which are the precursor cells of the nerve sheath, and it occurs along the length of the nerves. these tumours are well encapsulated and nerve fibres often splay out on the surface so it never penetrates the capsule.2 in the head and neck region, schwannomas are categorised according the site of the origin nerve. the schwannoma arising from the cervical sympathetic chain (scsc) is a very rare lesion and, until the time of this report, only 60 cases had been reported in english medical literature.3 the scsc typically presents as painless, asymptomatic neck mass. this is due to the fact that the cervical sympathetic chain (csc) runs in a relatively loose fascial compartment and compression is rare. radiological tests and fine needle aspiration cytology (fnac) have only a small contribution in its preoperative diagnosis, histopathological examination being much more useful. on a computed tomography (ct) scan, these tumours show as a well circumscribed, solitary, round or oval shaped hypo-attenuated mass with poor contrast enhancement and are medial to carotid vessels.4 imaging scans usually show anterolateral displacement of carotid vessels and the internal jugular vein. because of lack of specific symptoms and the rarity of this lesion it can be mistaken preoperatively for a branchial cyst, lymphoma or metastatic node.5 the definitive diagnosis has to be made by histopathological examination of the excised specimen. the treatment of choice is surgical excision and recurrence is very rare. we report the first case report of scsc from oman which occurred in a female patient and was excised squ med j, august 2011, vol. 1, iss. 3, pp. 403-406, epub. 15th aug 11 submitted 9th sep 10 revision req. 30th oct 10, revisions recd. 24th nov 10, 26th mar 11 accepted 27th mar 11 departments of 1surgery and 2pathology, sultan qaboos university hospital, muscat, oman. *corresponding author email: sudeshkumar74@gmail.com vìëåá÷]<–fl√÷]<ì◊ä◊â<‡⁄<ífi^àç<›öê ·^€ �¬<ìfl�◊â<ª<ì÷^u<ÿê˘<üëüœi<         :مفتاح الكلمات abstract: schwannomas are benign, encapsulated and slow-growing nerve sheath tumours arising from schwann cells. the schwannoma arising from the cervical sympathetic chain (scsc) is a very rare tumour. it usually presents as a slow growing, painless and asymptomatic neck mass, hence preoperative clinical diagnosis is difficult. radiological investigation and fine needle aspiration cytology make only a small contribution to its preoperative diagnosis, histopathological examination being much more useful. we report here the first case report of scsc from oman. it occurred in a 45 year-old female and was successfully excised. keywords: schwannoma; cervical sympathetic chain; excision; case report; oman schwannoma of the cervical symphathetic chain first case report from oman rashid al-abri,1 *sudesh kumar,1 pradeep chopra,1 p.a.m. saparamadu2 case report schwannoma of the cervical symphathetic chain first case report from oman 404 | squ medical journal, august 2011, volume 11, issue 3 successfully. a review of the literature is also included. case report a forty-five year-old female patient presented to the outpatient department at sultan qaboos university hospital, oman, with a complaint of a painless mass on the left side of the upper lateral part of neck which had been slowly increasing in size for the previous nine months. on examination, there was a 2 x 2.5 cm firm mass in the left side of the upper part of neck under the sternocleidomastoid muscle. the overlying skin was normal and no visible pulsation was seen, nor was there any bruit on auscultation. a flexible nasopharyngolaryngoscopy showed normal nasopharynx, pharynx and larynx. a contrast enhanced ct scan of the neck showed a well encapsulated cystic mass posterior to the carotid vessel and internal jugular vein and was reported as a branchial cyst [figure 1]. the fnac from the swelling was inconclusive and so it was decided to excise the mass. the excision of the mass was done with a longitudinal incision along the posterior border of the sternocleidomastoid muscle. a sub-platysmal flap was elevated and the mass was found to be arising from the cervical sympathetic chain with some cystic consistency. it was carefully separated from the nerve and was excised completely. postoperatively, the patient did well and did not develop horner’s syndrome. histopathological examination of the resected specimen showed a cystic mass with some areas of solid encapsulations. microscopy examinations showed characteristic antoni a and b patterns suggesting the diagnosis of schwannoma [figure 2]. the immunohistochemistry was positive for s-100 thus confirming the diagnosis. at the time of writing, the patient had been free from any locoregional recurrence for one and a half years. discussion scsc is a benign nerve sheath tumour that occurs along the length of the nerves. these tumours are well encapsulated and nerve fibres often splay out on the surface, but never penetrate the capsule. a review of the literature disclosed fewer than 60 figure 1 a & b: preoperative computed tomography scan of (a) axial and (b) coronal sections of the neck showing a well circumscribed cystic mass (arrows) posterior to carotid sheath in middle of neck. figure 2: histological microphotograph showing the typical antoni type a and b pattern of schwannoma (haematoxylin and eosin stain x 40). rashid al abri, sudesh kumar, pradeep chopra, p.a.m. saparamadu case report | 405 cases of schwannomas of the csc to date.2 it is a solitary, slow growing tumour and generally seen in patients between 20 and 50 years of age. as this lesion is so often misdiagnosed, some nondiagnostic and unsuccessful surgical procedures are often performed before a definitive diagnosis is made. frequency is the same in both sexes and malignant change is very rare.6 schwannoma of the head and neck can be divided into those of cochleovestibular and non-vestibular nerve origins.the majority of these schwannomas are of non-vestibular origin and have been reported to arise from various sites including the middle ear, mastoid cavity, sinonasal region, orbit, neck, posterior pharynx, parapharyngeal space, and skull base.6,7 in the neck region, the vagus nerve is the most commonly involved nerve followed by the csc.8 the cervical sympathetic ganglia are part of the sympathetic chain in the neck region and run longitudinally over the longus capitis and longus colli muscles, as far as the pre-vertebral fascia. they are comprised of three ganglia—the superior, middle, and the inferior ganglion. the superior ganglion is largest and most constant and lies at the level of the carotid sinus (c2–c4) .the middle ganglion lies at the level of c6 while the inferior ganglion is variable in position and may fuse with the first thoracic ganglion to form the stellate ganglion. in most cases reported in the literature, the scsc arises from the superior or middle part of the sympathetic chain. the differential diagnoses of scsc include carotid body tumours, deep lobe parotid tumours, minor salivary gland tumours, lymphoma, branchial cleft cyst, vagal schwannoma, distant metastases, sympathicoblastoma, leiomyoma, teratoma, neurofibroma, aneurysm of the internal carotid artery, and rhabdomyoma.9 the presence of horner’s syndrome is very rare before the surgery and, even when present, does not indicate the nerve of origin.10 only in 10 cases of scsc, did patients have horner’s syndrome preoperatively.2 fnac has a limited role and is not useful in diagnosis as it was seen in our case; the majority of studies do not recommend it preoperatively.5 radiological examinations have a definite role in the preoperative diagnosis of this lesion. they help by assessing the extent of the tumour and its relationship with carotid vessels and the internal jugular vein. on a contrast enhanced ct scan, the mass appears as an isodense or hypoattenuated, well circumscribed, round to oval in shape lession with anterior displacement of carotid vessels. there can be heterogeneity due to cystic degeneration, xanthomatous change, or due to areas of relative hypocellularity adjacent to densely cellular or collagenous regions.4 in our case, the heterogeneity on the ct scan was due to cystic degeneration and such changes are very rarely seen. angiography is indicated if the mass is contrast enhancing and if vessels appear to be compressed by the tumour. surgical excision is the treatment of choice and should be done with careful extracapsular dissection or by intracapsular enucleation to preserve the nerve of origin. conclusion scsc, although rare, should be considered as a differential diagnosis in patients presenting with a lateral neck mass. fnac is usually inconclusive, but radiological examination has a definite role in diagnosis. scsc is mainly diagnosed by histopathology and the treatment of choice is surgical excision. references 1. malone jp, lee wj, levin rj. clinical characteristics and treatment outcome for nonvestibular schwannomas of the head and neck. am j otolaryngol 2005; 26:108–112. 2. sedat a, arif s, omer t, aylin ge. horner’s syndrome post excision of a huge cervical sympathetic chain schwannoma. turk j med sci 2007; 37:185–190. 3. bocciolini c, dall’olio d, cavazza s, laudadio p. schwannoma of cervical sympathetic chain: assessment and management. acta otorhinolaryngol ital 2005; 25:191–4. 4. anil g, tan ty. imaging characteristics of schwannoma of the cervical sympathetic chain: a review of 12 cases am j neuroradiol 2010; 31:1408– 12. 5. ganesan s, harar rps, owen ra, dawkins rs, prior aj. horner’s syndrome: a rare presentation of cervical sympathetic chain schwannoma. j laryngol otol 1997; 111:493–5. 6. colreavy mp, lacy pd, hughes j, bouchier-hayes d, brennan p, o’dwyer aj, et al. head and neck schwannoma of the cervical symphathetic chain first case report from oman 406 | squ medical journal, august 2011, volume 11, issue 3 schwannomas – a 10-year review. j laryngol otol 2000; 114:119–24. 7. yoo h, jung h-w, yang hj. jugular foramen schwannomas: surgical approaches and outcome of treatment. skull base surg 1999; 9:243– 52. 8. wanamaker jf, wanamaker hh, kotton b, akers gd, lavertu p, et al. schwannomas of the nose and paranasal sinuses. am j rhinol 1993; 7:59–65. 9. rosner m, fisher w, malligan l. cervical sympathetic schwannoma: case report. neurosurgery 2001; 49:1452–4. 10. mikaelian do, holmes wf, simonian sk. parapharyngeal schwannomas. otolaryngol head neck surg 1981; 89:77–81. 11. furukawa m, furukawa mk, katoh k, tsukuda m. differentiation between schwannoma of vagus nerve and cervical sympathetic chain by imaging diagnosis. laryngoscope 1996; 106:1548–52. التثقيف الصحي يف اململكة العربية السعودية حملة تارخيية اأنوار الها�صم abstract: this article provides a historical overview of the evolution of health education in saudi arabia. it outlines milestones in the development of the health education profession and traces the roles of various health sectors and their achievements in the health education field. additionally, this review seeks to describe the status of health education professionals in saudi arabia. keywords: history; health educators; healthcare sector; health promotion; public health; government agencies; saudi arabia. العالمات اي�صا حتدد وهي ال�صعودية. العربية اململكة يف ال�صحي التثقيف ملهنة التاريخي التطور املقالة هذه ت�صتعر�ض امللخ�ص: املهمة يف تطورهذه املهنة، وتتابع اأدوار القطاعات ال�صحية املختلفة واإجنازاتها يف جمال التثقيف ال�صحي. اإ�صافة اإىل ذلك، ت�صف هذه املقالة حالة العاملني يف جمال التثقيف ال�صحي يف اململكة العربية ال�صعودية. احلكومية؛ الوكاالت العامة؛ ال�صحة ال�صحة؛ تعزيز ال�صحية؛ الرعاية قطاع يني؛ حِّ ال�صِ امُلَثقِِّفني التاريخ؛ مفتاحية: كلمات العربية ال�صعودية. health education in saudi arabia historical overview anwar al-hashem review sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e286–292, epub. 19 aug 16 submitted 23 dec 15 revision req. 31 jan 16; revision recd. 27 feb 16 accepted 13 mar 16 doi: 10.18295/squmj.2016.16.03.004 the world health organization (who) defines health education as “any combination of learning experiences designed to help individuals and communities improve their health, by increasing their knowledge or influencing their attitudes”.1 health education provides opportunities for both individuals and communities to acquire the necessary information/skills required to make health decisions or change health behaviours.2 between the 1970s and 1990s, many gulf corporation council countries witnessed a remarkable growth in their healthcare sectors, including saudi arabia.3 since then, the government of saudi arabia has made efforts to improve healthcare through health education and this remains a focal point of healthcare policies today. in this review, a historical overview of health education in saudi arabia is provided, including more recent milestones in this field, the role of various health sectors in health education and the current status of health education professionals in saudi arabia. historical background of health education initiatives in the early 1900s in saudi arabia, most people sought help from local traditional healers to treat various common health issues, such as back and abdominal pain, flatulence, tooth pain, infertility, depression and headaches. common traditional practices included reciting the holy quran, ingesting certain herbs or teas, cautery and cupping.4,5 before 1925, the territory which now makes up modern-day saudi arabia was not yet completely under the control of the ruler king abdulaziz ibn saud; as a result, some regions were characterised by a lack of political stability and security. during his reign, king abdulaziz established the directorate of public health in the first saudi arabian capital, makkah, in the hejaz region; this directorate was the cornerstone of the saudi arabian healthcare system and aimed to promote health and safety during the hajj season.6 the annual hajj, or pilgrimage season, attracts thousands of muslims to western saudi arabia to practice their faith. due to the large numbers of pilgrims gathering for hajj, both communicable and non-communicable disease outbreaks still occur, including cholera, malaria, poliomyelitis, meningococcal disease, respiratory tract infections, blood-borne diseases, heat exhaustion and heat stroke.7 in 1926, king abdulaziz issued another decree founding the health and emergency department (hed); this department included doctors and other professionals, such as a general inspector, a chief pharmacist and various administrative employees department of health education, king saud medical city, riyadh, saudi arabia e-mail: aalhashem@siu.edu anwar al-hashem review | e287 (e.g. statisticians, record keepers and clerks).6 the hed was responsible for promoting public and environmental health, establishing hospitals and healthcare centres, managing human resources within these centres, legislating policies and procedures to ensure public safety and promoting medicine and pharmacology standards.8 between 1926 and 1949, approximately 25 clinics, 34 health centres and 11 hospitals were established throughout saudi arabia, as well as one microbiology institute in ta’if.6 although the hed played a role in providing and monitoring free healthcare access for hajj pilgrims and the general saudi arabian population, insufficient funding and resources unfortunately limited its overall achievements. epidemics of certain communicable diseases—such as smallpox, measles, meningitis, diphtheria, scarlet fever, cholera, plague and mumps— remained persistently high among both members of the general public and pilgrims.9 in the 1920s, the directorate of public health identified the lack of health awareness among the saudi arabian public as a key issue. specifically, awareness of life-threatening epidemic diseases and their modes of transmission were viewed solely as the focus of health professionals and few health education materials on subjects such as personal hygiene, cleanliness and the prevention of communicable diseases were available at that time.6 as a result, several newspaper articles and announcements on preventative measures, symptoms and causes of communicable diseases as well as general information on protection against malaria epidemics were published in 1925, 1926 and 1930.6 during the hajj season in 1929, the directorate of public health issued a leaflet on various epidemic diseases, including protection and control measures. it also published the first guidelines on health-related personal hygiene, sanitation and cleanliness during the hajj season.6 in the 1940s, several announcements followed with general instructions on the safe preparation/handling of food and the cleanliness of food sale premises as well as health instructions for barbershops (e.g. cleanliness of equipment). concurrently, the hed conducted two free vaccination campaigns against smallpox and typhoid targeted at members of the public and pilgrims alike. additionally, residentassisted cleanliness campaigns were initiated in muna every year before hajj season.6 these health initiatives were significant, as they helped to educate the public without relying on written media—this was important given that the literacy rate in saudi arabia was very low up until the 1970s (approximately 15% for men and 2% for women).10 twenty-five years after the creation of the hed, the saudi arabian ministry of health (moh) was established.8 during the 1950s, malaria control and prevention campaigns/programmes were introduced through the collaborative efforts of the moh, world health organization (who) and arabian american oil company (aramco).11 these nation-wide programmes established a curative and preventative model of healthcare that was then disseminated to the general population. there were over 28 such programmes, whose strategies involved spraying crops with dichlorodiphenyltrichloroethane to reduce the mosquito population as well as administering blood tests and providing antimalarial drugs for infected patients.6 in 1954, school health units were introduced as another health education and prevention effort. to begin with, these units focused only on male pupils, teachers and employees of the ministry of education; at that time, females were not allowed to attend schools. furthermore, school health units were available only in urban areas such as riyadh, makkah and jeddah, and mainly provided curative services and a few preventative services related to immunisation, counselling and health lectures.6 due to the scarcity of resources, the widespread distribution of the population and the vast geographical area of saudi arabia, the healthcare system in the 1960s faced heavy challenges, for example, the high mortality rate among under-five-year-olds (250 deaths per 1,000 live births in 1960).12 however, due to the massive amount of oil revenue generated in the 1970s, the government was subsequently able to dramatically improve the industrial, agricultural, transportation, communication, healthcare and education sectors.3 beginning in 1970, the first five-year development plan greatly improved the national healthcare system and implemented compulsory vaccination plans for infants and children; this in turn helped reduce the under-five mortality rate (19.1 deaths per 1,000 live births in 2011).12 the 1980s were a very successful decade for the saudi arabian healthcare system, during which the third development plan saw the construction of numerous hospitals and primary healthcare centres. from 1985–1987, a total of 377 healthcare facilities were built, of which 65 were hospitals and the rest were primary healthcare centres.13 however, in the late 1980s and mid-1990s, during the course of the fourth and fifth development plans, both governmental and private healthcare growth slowed.13 the two main reasons for this decline were the expenses associated with the curative model and the relatively flat moh budget, which did not allow for price fluctuations. notably, these factors contributed to the suspension of one of the largest medical facilities in saudi arabia, the king fahad medical city.13 although health education in saudi arabia historical overview e288 | squ medical journal, august 2016, volume 16, issue 3 previously the healthcare sector had concentrated on communicable diseases, social and economic factors in the 1980s contributed to a gradual shift in focus to chronic diseases and quality of life-related conditions.6 diabetes, acquired immune deficiency syndrome and heart disease were among the first conditions to be tackled; in 1984 alone, the moh supervised 121 programmes intended to increase health awareness among the public through mass media, symposiums and meetings.6 additionally, public health policy was also changed after a royal decree was issued prohibiting advertisements and publications supporting cigarettes and increasing the duty on tobacco and its derivatives.6 health education activities gradually increased from 1985 to the late 1990s.6 by 1997, health education was perceived much more positively by health professionals and the public alike. this change in perception was due to the success of certain prevention and control programmes (e.g. tuberculosis programmes) and the increased publicity and mass media coverage of health education programmes and activities around the country.6 in 1998, the school health units expanded their services to cover female schools in rural and urban areas. these units provided preventative services by general physicians, dentists, nurses and health educators to promote a healthy lifestyle including information on nutrition and a balanced diet, dental health, personal health/hygiene, smoking cessation, physical activity, safety/injury prevention and mental health.6 by the late 1990s, more than 16 saudi arabian health and medical journals were in circulation, targeting both health professionals and the general public.6 these included the health education journal (1997), a monthly journal published by a security forces hospital; the nutrition bulletin (1997), a monthly leaflet issued by the moh; and the saudi heart association bulletin (1989), a quarterly publication printed by the king saud university. moreover, in 2014 alone, the moh circulated more than four million health booklets, leaflets, posters and announcements and participated in 9,000 national and international health awareness activities to combat smoking, cancer and diabetes.14 modern milestones in the development of health education in 2001, the health education symposium was organised by the king khaled eye specialist hospital in riyadh.15 this was the first national gathering of health educators in saudi arabia and was a significant event in securing support and recognition of the importance of health education. between 2001 and 2011, nine symposiums were held.15 various speakers and workshop instructors at these symposiums were key in influencing health education promotion in the arab world and most attendees were health educators from different sectors. recommendations arising from these symposiums were recognised by the ministry of civil services and the saudi commission for health specialties and helped mobilise efforts to acknowledge health education problems and devise solutions. furthermore, these symposiums facilitated the development of major commissions and organisations, such as the national commission of health education directed by the moh and the charitable society of health communication.15 heightened recognition of the importance of health educators has led to an increased number of health education courses and seminars aiming to further improve the understanding of health education objectives. in 2007, a preventative medicine department of the moh created a programme to provide primary health centre practitioners with greater health education skills; they successfully trained over 100 workers from different primary health centres on health education principles.16 furthermore, in 2007, the moh announced that more than 4,500 health education positions in primary health centres needed to be filled.16 in terms of health education theories, most activities and programmes conducted by health education specialists in hospital settings in saudi arabia since the 1990s have been based on medical concepts.15 these usually involve the identification and ranking of the various causes of mortality and morbidity in a society and then targeting these causes via medical interventions.17 in other settings, most health education activities and interventions are based on behavioural change theories; the dominant model currently used by health education professionals is the health belief model, a psychological model which explains and predicts health-related behaviours at the individual level.15 healthcare sectors and their role in health education healthcare in saudi arabia is divided into two main sectors, governmental and private. in 2012, the moh operated 63% of all hospitals in the country, while 24% were operated by other governmental agencies, such as the ministry of defence and aviation, ministry of education and the national guard. in contrast, 13% of hospitals fell under the private sector.13 anwar al-hashem review | e289 g o v e r n m e n ta l s e c t o r ministry of health the moh is responsible for operating and monitoring health systems in saudi arabia and is the biggest healthcare provider in saudi arabia, receiving 7% of the total governmental annual budget.14 it aims to improve the health of the population by developing health laws, regulatory legislation and policies to serve the health system, conducting health research and training professionals to work in the health system.8 the moh plays a role in establishing, funding, coordinating and delivering health education and public health promotion programmes. in 1998, the moh established the healthy cities project which aimed to promote school and occupational health in 20 cities with a focus on physical activity and nutrition.18 the moh also trains and educates health professionals on health education and health promotion strategies. symposiums have been conducted to educate and share information on health education and its importance in healthcare. recently, the moh has assumed administrative responsibility over school health units, originally governed by the ministry of education.19 health education efforts by the moh face several challenges, most of which are related to the quantity and quality of health education activities. these include the unequal distribution of health education programmes, with most programmes in saudi arabia held in large cities such as riyadh, jeddah and dammam, and only a few located in rural areas. overall, the number of national health education programmes is insufficient to support the high demand in both rural and urban areas.20 moreover, the quality of health education activities/programmes, in particular those managed by primary health centres, suffers from a lack of clearly communicated health goals, theory-based interventions, communication behavioural-related outcomes and comprehensiveness.9 health education activities are usually not based on valid assessment methods but rather on individual perceptions of various health issues and demands.15 even when assessments with valid methods are carried out, they are rarely suitable or rigorous enough to demonstrate programme effectiveness, which can affect the continuity of the programme.15 other concerns include a shortage of human resources, lack of training opportunities for healthcare providers and unmet training demands in health education strategies and programme planning skills. additionally, programmes are not routinely updated with regards to recent advances in the field of health promotion.21 other governmental sectors other governmental healthcare agencies in saudi arabia include the national guard hospitals, aramco hospitals, armed forces hospitals, security forces hospital and royal commission hospitals in jubail and yanbu. research, specialised and university hospitals also exist, such as the king khaled eye specialist hospital, king faisal specialist hospital & research centre in riyadh and jeddah, king abdulaziz university hospitals in riyadh and jeddah, king khalid university hospital in riyadh and king fahad university hospital in al-khobar.9 altogether, over 39 hospitals and hundreds of primary health centres are operated by non-moh governmental agencies, with approximately 10,822 beds.9 most of the patient health education and promotion efforts in saudi arabia are organised by health education departments in these hospitals. in the early 1990s, the king khaled eye specialist hospital, security forces hospital and aramco hospitals were among the first to start health education activities (e.g. patient education and community health awareness activities). afterwards, other hospitals and medical cities followed suit.6,15 previously, most health education in saudi arabia focused on diabetes management, cardiovascular diseases, the early detection and treatment of cancer, diet and weight management, physical activity and the prevention or treatment of the diseases in which each hospital specialised.9 in the early 1990s, most hospitals did not have health education specialists; as a result, other healthcare professionals performed patient and community education tasks.15 only a few hospitals in saudi arabia recruited health educators from different educational backgrounds, such as nursing, social work and other allied health departments, to conduct oneon-one education sessions, lectures and workshops, design printed materials and participate in national and international health events. by providing training and supervision and sharing their experiences, these health educators paved the way for new interns and graduates of health education programmes, many of whom now have official positions working in health education/patient education departments.15 p r i vat e s e c t o r the private sector received strong support from the saudi government in the 1980s. interest-free loans were offered to those interested in establishing healthcare facilities, such as hospitals, private clinics and pharmaceutical care centres.22 currently, there are more than 141 private hospitals with 15,664 beds and 2,412 private polyclinics in saudi arabia; notably, health education in saudi arabia historical overview e290 | squ medical journal, august 2016, volume 16, issue 3 85.6% and 47.5% of these polyclinics and private hospitals, respectively, are located in the urban cities of riyadh and jeddah.14 the role of the private sector in health education in saudi arabia is varied and largely dependent on the quantity and quality of healthcare. only a few private hospitals employ specialised health educators to carry out health education and patient education activities. the responsibility of patient education activities is often left to individual health providers, who spend time in their clinics to educate patients or caregivers on health issues.6 h e a lt h e d u c at i o n c o m m i s s i o n s a n d o r g a n i s at i o n s the first governing body of health education in saudi arabia was the departments of health education, established in 1997.23 this group was comprised of personnel from a number of health institutes, including the king khaled eye specialist hospital, security forces hospital, king faisal specialist hospital & research centre, prince sultan military medical city, moh dental specialist centre, king abdulaziz university hospital, moh general directorate of health affairs, sulaymaniyah children’s hospital, king saud hospital for chest diseases, al-amal complex for mental health and al-salama hospital.15 the goal of the departments of health education was to form a coordinated organisation that could provide health education activities and solve national health education issues. before it was shut down in 2004, the departments of health education was the basis of the subsequent establishment of the charitable society for health communication in 2006.15 the charitable society for health communication was the first health education association in saudi arabia to dedicate itself solely to providing resources on health education and health promotion.23 this organisation provides advisory services—including programme planning, health education research, policy development and general support—to members of the government and private health sectors, teachers and media personnel.23 in 2013, the national committee of health education was founded in riyadh. operating on a similarly large scale as the charitable society for health communication, the national committee of health education was established to provide countrywide health education strategies and policies in relation to health promotion.24 their goal is to prepare national health assessments, prioritise health awareness goals, develop health awareness action plans and evaluation systems and provide laws and procedures to coordinate health activities. all of these efforts fall under the scope of the moh and other health organisations and committees concerned with health education.24 currently, there are 69 charitable and noncharitable health associations in saudi arabia, with 55 charitable health associations registered with the ministry of social affairs and 14 non-charitable health associations affiliated with king saud university.25 all of these associations strive to spread health awareness among professionals and the general public. current status of health educators health educators in saudi arabia can work in the moh, other governmental sectors, the private sector, academic sector or in health associations. the most recent statistics released by the moh in 2014 do not specify health educators as a stand-alone professional category.14 it is therefore difficult to estimate the number of health educators working in various sectors in saudi arabia. in april 2001, the ministry of civil services, which is responsible for creating and updating job classifications, included health education positions under health researcher or health technician positions; graduates with bachelor’s degrees in health education were hence considered qualified to fill these positions.26 in response, advocates of health education recommended that the ministry of civil services create a special health education position that could only be filled by highly qualified health educators. in 2004, the saudi commission for health specialties included health education as a classification of health worker.15 this classification is an important contributor to the recognition of health education as a profession in the field of healthcare. in 2014, the latest update of the health professional classification guide and professional registry approved three levels of classification: specialist, senior specialist and consultant. at each level, certain qualification and work experience requirements must be met.26 specifically, health educators are registered as health education specialists if they have a bachelor’s degree in health education; senior specialists if they have earned a master’s degree along with two years of experience in the field; and consultants if they have a ph.d. and at least three years of work experience.26 regardless of subspecialty, health educators and public health personnel must undergo at least 20 hours of continuous education per year to fulfil requirements. article 15/11 of the saudi commission for health specialties guidelines includes health education within the following subspecialties: behaviour health education, prevention health education, school health education, patient health education, occupational health education and safety, health education in the anwar al-hashem review | e291 mass media, global health education, nutrition health education and environmental health education.26 moreover, the saudi commission for health specialties classifies public health practitioners with similar subspecialties into various domains, including behavioural, environmental, global and nutritional domains. specifically, article 15/12 includes public health as a general specialty with the following subspecialties: behavioural public health, biostatistics, environmental public health, epidemiology, global and international public health, maternal and child public health, nutrition public health, public health laboratory practice, public health policy, public health practice, dental public health and nursing public health.26 p r o f e s s i o n a l q u a l i f i c at i o n s currently, 12 universities in saudi arabia offer either postgraduate or baccalaureate degrees in health education or public health [table 1]. as public education is free for all saudi arabian nationals, none of these universities charge tuition fees, apart from the saudi electronic university. moreover, full-time students who sustain grade point averages of over 2.0 out of 4.0 are allocated a monthly stipend of usd $264.27 the king saud bin abdulaziz university for health sciences offers a master’s degree in public health. their curriculum, which is accredited by the saudi commission for health specialties, is a twoyear programme consisting of 43 credit hours which includes the completion of a research project.28 other universities in saudi arabia that have only been established within the last six years have either started offering or are in the process of developing baccalaureate degrees in public health. most of these universities, excluding king saud university and king saud bin abdulaziz university for health sciences, either offer or plan to offer this degree under the aegis of applied health sciences colleges or public health/health informatics departments. overall, in the coming years, these universities will provide bachelor’s degrees in public health, health education, health promotion or community health. the college of applied medical sciences (cams) at king saud university in riyadh was the first to offer a baccalaureate degree in health education and was also the forerunner in offering this degree to female students in 1981.29 at cams, the degree is undertaken over the course of four and a half years (nine semesters) plus a year-long mandatory internship. students learn basic sciences such as anatomy, physiology, microbiology, epidemiology, biostatistics, physics and biochemistry as well as health sciences such as nutrition, emergency care, childhood growth and development, maternity/childcare and healthcare delivery.29 they also take technology and media in healthcare courses. other basic courses in public health include civilization disease prevention, infectious diseases, demography, occupational health and safety, islamic political system fundamentals, family planning, environmental health, substance abuse and personal health.29 various health education courses are offered every semester, including community health, health education theories, social concepts of health education, the psychological basis of health education, consumer health education, health education methodologies, systems approach to health education, dental health education, school health education, health education management, health education in health services and health education research.29 between 2003–2010, 114 students graduated from cams with baccalaureate degrees in health education, with an average of 16 students per year.29 as with nursing and other health/medical professions, qualifications obtained from outside saudi arabia are reviewed and evaluated by the certificates equivalency committee of the ministry of education to ensure that the obtained degree is the equivalent of its counterpart in the saudi arabian higher education system.29 this generally takes place before the individual is employed as a health education professional.30 table 1: list of saudi arabian universities currently offering public health, health education or community health degree programmes university name and year established programme title and year initiated umm al-qura university (1949) health promotion (2011) king saud university (1957) health education (1981) public health* king faisal university (1975) public health (2011) qassim university (2002) public health (2011) king saud bin abdulaziz university (2005) public health (2010) university of hail (2005) public health* al baha university (2006) community health* king khalid university (2007) public health* princess nourah bint abdulrahman university (2008) health education & promotion (2008) jazan university (2011) health education* prince sattam bin abdulaziz university (2011) public health* saudi electronic university (2011) public health* *programme not yet started or not yet listed on the university website as of 2014. health education in saudi arabia historical overview e292 | squ medical journal, august 2016, volume 16, issue 3 conclusion considerable effort on the part of governmental and private health organisations has led to numerous milestones in the management, administration and leadership of the health education field in saudi arabia. health education has evolved into a profession that requires continuous training to face both current and future challenges. references 1. world health organization. health education. from: www. who.int/topics/health_education/en/ accessed: feb 2016. 2. gold rs, miner kr; 2000 joint committee on health education and promotion terminology. report of the 2000 joint committee on health education and promotion terminology. j sch health 2002; 72:3–7. doi: 10.1111/j.1746-1561.2002. tb06501.x. 3. international hospital online. healthcare in the gulf: challenges remain in spite of investment boom. from: www. ihe-online.com/feature-articles/healthcare-inthe-gulfchallenges-remain-in-spite-of-investment-boom/index.html accessed: feb 2016. 4. qureshi na, al-amri ah, abdelgadir mh, el-haraka ea. traditional cautery among psychiatric patients in saudi arabia. transcult psychiatry 1998; 35:75–83. doi: 10.11 77/136346159803500103. 5. al-rowais n, al-faris e, mohammad ag, al-rukban m, abdulghani hm. traditional healers in riyadh region: reasons and health problems for seeking their advice a household survey. j altern complement med 2010; 16:199–204. doi: 10.1089/acm.2009.0283. 6. al-harthi f. health over a century. riyadh, saudi arabia: ministry of health, 1999. 7. memish za. the hajj: communicable and non-communicable health hazards and current guidance for pilgrims. euro surveill 2010; 15:19671. 8. saudi arabia ministry of health. about the ministry. from: w w w.moh.gov.sa/en/ministr y/about/pages/default .aspx accessed: feb 2016. 9. almalki m, fitzgerald g, clark m. health care system in saudi arabia: an overview. east mediterr health j 2011; 17:784–93. 10. hamdan a. women and education in saudi arabia: challenges and achievements. int educ j 2005; 6:42–64. 11. al-yousuf m, akerele tm, al-mazrou yy. organization of the saudi health system. east mediterr health j 2002; 8:645–53. 12. aldossary a, while a, barriball l. health care and nursing in saudi arabia. int nurs rev 2008; 55:125–8. doi: 10.1111/j.14667657.2007.00596.x. 13. khaliq aa. the saudi health care system: a view from the minaret. world health popul 2012; 13:52–64. doi: 10.12927/ whp.2012.22875. 14. saudi arabia ministry of health. health statistical yearbook 2014. from: www.moh.gov.sa/ministry/statistics/book/pages/ default.aspx accessed: feb 2016. 15. rabah r. personal communication, march 2014. 16. al-houtan a. launch of training sessions on health education. from: www.alriyadh.com/293028 accessed: feb 2016. 17. buchanan dr. perspective: a new ethic for health promotion reflections on a philosophy of health education for the 21st century. health educ behav 2006; 33:290–304. doi: 10.1177/ 1090198105276221. 18. saudi arabia ministry of health. healthy cities project. from: www.moh.gov.sa/depts/environmentalhealth/departments/ pages/healthycities.aspx accessed: feb 2016. 19. abdullah s. the failure of school health units. from: www. alriyadh.com/864190 accessed: feb 2016. 20. mahfouz aa, abdelmoneim i, khan my, daffalla aa, diab mm, al-gelban ms, et al. obesity and related behaviors among adolescent school boys in abha city, southwestern saudi arabia. j trop pediatr 2008; 54:120–4. doi: 10.1093/tropej/ fmm089. 21. al-ahmadi h, roland m. quality of primary health care in saudi arabia: a comprehensive review. int j qual health care 2005; 17:331–46. doi: 10.1093/intqhc/mzi046. 22. royal embassy of saudi arabia, washington dc. the basic law of governance. from: www.saudiembassy.net/about/countryinformation/laws/the_b a sic_l aw_of_g overnance.a spx accessed: feb 2016. 23. the charitable society for health communication. from: www.hayatona.org/mag/ accessed: feb 2016. 24. saudi arabia ministry of culture and information. national commission for health education will hold its first meeting. from: www.info.gov.sa/details.aspx?id=1306 accessed: feb 2016. 25. saudi arabia ministry of social affairs. charities contact information. from: www.gg.org.sa/ accessed: feb 2016. 26. saudi commission for health specialties. guide of professional classification and registration for health practitioners, 6th ed. from: www.scfhs.org.sa/en/registration/classandregister/rer egister/documents/professional%20classification%20manual%20 for%20health%20practitioners.pdf accessed: feb 2016. 27. alkhazim ma. higher education in saudi arabia: challenges, solutions, and opportunities missed. high educ policy 2003; 16:479–86. doi: 10.1057/palgrave.hep.8300035. 28. king saud bin abdulaziz university for health sciences. college of public health & health informatics. from: w w w.ksau-hs .edu.sa/english/academic/colleges/pages/ publichealthandhealthinformatics.aspx accessed: feb 2016. 29. college of applied medical sciences, king saud university. community health sciences department ksu statistics. from: http://cams.ksu.edu.sa/ar/node/1531 accessed: feb 2016. 30. saudi arabia ministry of education. certificate equivalency general guidelines. from: www.mohe.gov.sa/en/ministry/ deputy-ministr y-for-educational-affairs/the-g eneraladministration-for-equiv alenc y -cer tific ations/systemequation/pages/subject-of-study.aspx accessed: feb 2016. http://dx.doi.org/10.1111/j.1746-1561.2002.tb06501.x http://dx.doi.org/10.1111/j.1746-1561.2002.tb06501.x http://dx.doi.org/10.1177/136346159803500103 http://dx.doi.org/10.1177/136346159803500103 http://dx.doi.org/10.1089/acm.2009.0283 http://dx.doi.org/10.1111/j.1466-7657.2007.00596.x http://dx.doi.org/10.1111/j.1466-7657.2007.00596.x http://dx.doi.org/10.12927/whp.2012.22875 http://dx.doi.org/10.12927/whp.2012.22875 http://dx.doi.org/10.1177/1090198105276221 http://dx.doi.org/10.1177/1090198105276221 http://dx.doi.org/10.1093/tropej/fmm089 http://dx.doi.org/10.1093/tropej/fmm089 http://dx.doi.org/10.1093/intqhc/mzi046 http://dx.doi.org/10.1057/palgrave.hep.8300035 multiple myeloma (mm) is an aggressive haematological malignancy arising from the monoclonal expansion of neoplastic plasma cells in the bone marrow.1–3 it tends to occur mostly in older patients, with men being twice as likely to be affected.2,3 mm usually occurs as a result of the progression from earlier conditions known as monoclonal gammopathy of undetermined significance (mgus) and smouldering myeloma.2 it can also evolve from a more localised form of the disease, referred to as solitary plasmacytoma (either bony or soft tissue); tissue samples from both localised plasmacytomas and mms provide identical histopathological pictures.2–4 mm is usually restricted to the bone marrow and may present clinically with a range of complex manifestations, including anaemia, bone pain due to generalised osteoporosis or focal lytic lesions secondary to osteolytic bone destructions, hypercalcaemia, renal dysfunction and a compromised immune system.5,6 malignant plasma cells can escape the bone marrow microenvironment and proliferate at extramedullary sites; various sites such as the eyes, respiratory tract, testes, adrenal and thyroid glands, lymph nodes, skin and subcutaneous tissues, central nervous system and other organs have been reported in the literature.5–7 extramedullary mm (emm) can occur as a primary presentation or, more commonly, in a secondary form during progression or relapse of mm.6 the incidence of emm ranges between 2–20%.6,7 however, the occurrence of emm in the oral and maxillofacial region is rare and infrequently reported, with varying degrees of symptoms including pain, swelling, bleeding, mobility of the teeth and nerve neuropathies.1,3,4 case report a 56-year-old female patient was referred from the haematology department to the oral & maxillofacial surgery unit of sultan qaboos university hospital, muscat, oman, in 2010 due to sudden-onset numbness of the lower lip. the patient had first noticed the numbness 10 days previously. in 2008, the patient had 1oral & maxillofacial surgery residency program, oman medical specialty board, muscat, oman; departments of 2oral health, 3haematology and 4radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: dr.yusra.alriyami@gmail.com اكتشاف انتكاسة ورم نقوي متعدد من خالل ظهور اخدرار للشفة السفلية ي�رسى الري�مية, عبدالعزيز ب�كثري, خليل الف�ر�شي, في�شل العزري abstract: multiple myeloma (mm) is an uncommon malignancy characterised by the proliferation of clonal plasma cells. there are few published reports describing the extramedullary presentation of mm manifesting primarily in the head and neck region. in addition, the occurrence of an isolated relapse of mm in these sites is exceedingly rare. we report a 56-year-old female who presented to the sultan qaboos university hospital, muscat, oman, in 2010 with sudden-onset numbness of the lower lip. she had a history of mm in remission following chemotherapy and a bone marrow transplant. clinical and radiographic examinations were indicative of a possible relapse of mm, which was subsequently confirmed by bone marrow aspiration and histopathological evaluation. this unique case highlights the unusual site of relapse of a haematolymphoid malignancy. keywords: multiple myeloma; relapse; head and neck neoplasms; plasmacytoma; case report; oman. امللخ�ص: الورم النقوي املتعدد هو ورم خبيث ن�در احلدوث ويتميز ب�إنت�ش�ر اخلالي� البالزمية. هن�ك بع�س التق�رير املن�شورة ت�شف حدوث الورم النقوي املتعدد خ�رج النخ�ع بظهور اأويل يف منطقة الراأ�س والعنق. ب�لإ�ش�فة اإىل ذلك, حدوث انتك��شة متفردة من الورم النقوي ال�شلط�ن ج�معة م�شت�شفى اإىل تقدمت ع�م� 56 العمر من تبلغ مري�شة ح�لة التقرير هذا يعر�س جدا. ن�در هو املن�طق هذه يف املتعدد ق�بو�س, م�شقط, �شلطنة عم�ن يف 2010 وهي م�ش�بة ب�خدرار مف�جئ يف ال�شفة ال�شفلية. وك�نت املري�شة م�ش�بة بورم نقوي متعدد يف مرحلة الهداة بعد املع�جلة الكيمي�ئية وزراعة نقي العظم. الفحو�ش�ت ال�رسيرية والإ�شع�عية التي اأجريت ك�نت تدل على اإحتم�لية وجود انتك��شة للورم النقوي املتعدد, وهو م� مت ت�أكيده لحق� عن طريق خزعة �شفط نقي العظم و تقييم مر�شي�ت الأن�شجة. هذه احل�لة الفريدة ت�شلط ال�شوء على اإمك�نية حدوث انتك��ش�ت لالأورام اللمف�وية اخلبيثة يف من�طق غري معت�دة. الكلمات املفتاحية: الورم النقوي املتعدد؛ انتك��شة؛ اأورام الراأ�س والعنق؛ ورم البالزم�وي�ت؛ تقرير ح�لة؛ عم�ن. relapse of multiple myeloma presenting as lower lip numbness *yusra m. al-riyami,1 abdulaziz bakathir,2 khalil al-farsi,3 faisal al-azri4 sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e500–503, epub. 30 nov 16 submitted 7 apr 16 revision req. 31 may 16; revision recd. 29 jun 16 accepted 19 jul 16 doi: 10.18295/squmj.2016.16.04.017 case report yusra m. al-riyami, abdulaziz bakathir, khalil al-farsi and faisal al-azri case report | e501 been diagnosed with immunoglobulin a-λ mm, after presenting with anaemia, hypercalcaemia, acute renal insufficiency and a compression fracture of the t12 vertebra. her initial symptoms included pain related to the long bones and back. she went into complete remission after being treated with bortezomib, dexamethasone and high-dose melphalan followed by an autologous stem cell transplantation in 2009. posttransplant, she remained in complete remission and was prescribed maintenance thalidomide therapy. at referral, the patient was not in any pain and a comprehensive dental examination indicated a good oral status with multiple heavily restored teeth. no evidence of infection or dental pathology was noted. the numbness affected the left side of the lower lip, chin and gingivae of the 32nd to 36th teeth. an orthopantomogram and a computed tomography scan showed no evidence of dental or maxillofacial pathology. based on the clinical presentation, examination and the patient’s medical status, the possibility of a relapse of mm was strongly suspected. an urgent magnetic resonance imaging (mri) examination of the mandible showed an enhancing soft tissue mass in the medial aspect of the left mandibular ramus extending to the bone marrow through the mandibular canal and a soft tissue enhancement near the left mental nerve at the opening of the mental foramen [figure 1]. a bone marrow aspiration revealed the presence of over 24% plasma cells. a biopsy of the oral cavity lesion showed sheets of plasma cells with plasmablastic morphology and a cellular submucosal infiltrate of the neoplastic plasma cells. the cells were positive for cluster of differentiation (cd) 138 and negative for cd20, cd79a and epstein-barr virus, thus excluding a diagnosis of plasmablastic lymphoma. the aggressive nature of the proliferation was supported by the presence of frequent mitosis and a ki67 proliferation index of >90% [figure 2]. in combination, these findings confirmed the diagnosis of a relapse of mm both in the bone marrow as well as at extramedullary sites, as indicated by the numbness of the left mental nerve and the soft tissue mass in the left retromolar area. both the morphological and immunophenotypical features of the oral lesion and bone marrow aspirate histopathology specimens indicated that the relapse was a more aggressive form of the disease. over the course of the following weeks, the retromolar mass continued to enlarge and became erythematous and ulcerated [figure 3]. the patient received lenalidomide and dexamethasone but showed no response to treatment. she was subsequently prescribed a bortezomib-based regimen. however, her condition continued to worsen and she developed multiple infections and extramedullary lesions in the shoulder and lungs. the patient died eight months after the diagnosis of a relapse of mm. figure 1: axial t1-weighted magnetic resonance imaging of a 56-year-old female patient with sudden-onset numbness of the lower lip. the (a) pre-contrast and (b) post-contrast scans show an enhancing mass in the medial left mandibular ramus extending into the bone marrow through the mandibular canal. coronal views at the level of (c) the mandibular ramus and (d) left mental nerve area show soft tissue enhanced signals near the left mandibular foramen (arrows). figure 2: histopathology images of a plasmablastic myelo ma in the oral mucosa. a: haematoxylin and eosin stain at x40 magnification showing a diffuse cellular neoplastic infiltrate (white arrow) beneath the oral mucosa (black arrow). b: haematoxylin and eosin stain at x600 magnification displaying plasmablasts with scant cytoplasm, enlarged nuclei with vesicular chromatin and a single nucleolus and frequent mitosis (arrow) and apoptosis. c: 3,3'-diaminobenzidine immunohistochemistry stain at x400 magnification indicating the immunoreactivity of the cells to cluster of differentiation (cd) 138. d: stain showing the immunoreactivity of the neoplastic cells to cd138 with a ki67 proliferation index of >90%. relapse of multiple myeloma presenting as lower lip numbness e502 | squ medical journal, november 2016, volume 16, issue 4 decreases the adhesion of plasma cells, resulting in the dissemination of plasma cells away from their original environment and into extramedullary sites.5 in the current case, the plasma cells showed aggressive behaviour and diffuse neoplastic infiltration into the oral mucosa via histopathology. these cellular features, along with a loss of the cd138 marker, although this was not seen in the present case, generally result in a high-grade malignancy that responds poorly to treatment.5,8,17 bladé et al. and damaj et al. have reported that progression of mm into emm is seen in 15–20% of patients, with an increased frequency in recent years.18,19 relapsing emm seems to exhibit aggressive behaviour since it manifests as a progression of the disease, leading to a poor prognosis despite various treatment modalities.17,19 in addition, survival following an emm relapse reportedly varies between 4–30 months.20–22 in the current case, the patient responded poorly to treatment, developed new lesions at multiple sites and survived for only eight months following the diagnosis. similar findings have been noted in previous reports.18,20–22 as such, a high index of suspicion is needed when treating patients with a previous history of mm, even during remission. conclusion relapse of mm in the oral and maxillofacial region is rare. dental and maxillofacial surgeons should have a high index of suspicion when treating patients with a previous history of neoplastic disease. such patients should be evaluated by thorough clinical and radiographic examinations to determine the cause of any new symptoms developing, even if they are currently in remission. references 1. ramaiah kk, joshi v, thayi sr, sathyanarayana p, patil p, ahmed z. multiple myeloma presenting with a maxillary lesion as the first sign. imaging sci dent 2015; 45:55–60. doi: 10.5624/ isd.2015.45.1.55. 2. al-farsi k. multiple myeloma: an update. oman med j 2013; 28:3–11. doi: 10.5001/omj.2013.02. 3. nam ku, ahn j, hong j. occurrence of multiple myeloma in the head and neck: a report of two cases. j korean assoc oral maxillofac surg 2013; 39:139–43. doi: 10.5125/ jkaoms.2013.39.3.139. 4. chakravarti a, vishwakarma sk, arora vk. plasmacytoma of the maxilla. indian j otolaryngol head neck surg 1997; 49:44–6. doi: 10.1007/bf02991711. 5. pagella f, canzi p, matti e, benazzo m. sudden clinical course of an unusual ent tumour: clinical pictures of extramedullary plasmacytoma secondary to multiple myeloma. acta otorhinolaryngol ital 2013; 33:347–9. discussion mm is an uncommon haematological malignancy of the plasma cells which accounts for approximately 10% of all haematological malignancies.1,8,9 it is diagnosed following the proliferation of clonal plasma cells in the bone marrow or an extramedullary lesion (i.e. plasmacytoma), the presence of a monoclonal protein or light chain and end-organ damage, indicated by hypercalcaemia, renal insufficiency, anaemia and bony lesions.2,10 the incidence of mm occurring in the maxillofacial region as either a primary manifestation or relapse is low, with few reported cases.4,11–13 usually, mm appears via imaging as radiolucency in the jaw and the patient may also complain of pain, swelling and mobile teeth.3,13 in the present case, the patient was in complete remission when she presented with lip numbness. initial assessment and routine imaging failed to identify the cause of this sudden neuropathy; however, an mri scan revealed an altered soft tissue signal with a mass in relation to the inferior alveolar and mental nerves. similar reported cases of head and neck neuropathies have been observed in patients presenting with primary or secondary emm.8,9,14–16 histopathology of relapsed mm usually reveals numerous immature plasmablastic cells with pleomorphic cellular features indicating its progression and aggressiveness.8 recent advances in therapy—for instance, the introduction of thalidomide and lenalidomide as treatments for mm—may contribute to increases in the incidence of emm.6,8 these drugs have been shown to have antiangiogenic and immunomodulatory effects that alter the production of interleukin-6 and tumour necrosis factor-α; this in turn figure 3: photograph of a 56-year-old female patient with sudden-onset numbness of the lower lip showing an intra-oral erythematous and ulcerated swelling in the left retromolar region. the lesion extended from the distal aspect of the left second molar with involvement of the lingual and lateral pharyngeal area. yusra m. al-riyami, abdulaziz bakathir, khalil al-farsi and faisal al-azri case report | e503 6. besse l, sedlarikova l, greslikova h, kupska r, almasi m, penka m, et al. cytogenetics in multiple myeloma patients progressing into extramedullary disease. eur j haematol 2016; 97:93–100. doi: 10.1111/ejh.12688. 7. fernandez la, couban s, sy r, miller r. an unusual presentation of extramedullary plasmacytoma occurring sequentially in the testis, subcutaneous tissue, and heart. am j hematol 2001; 67:194–6. doi: 10.1002/ajh.1106. 8. cerny j, fadare o, hutchinson l, wang sa. clinicopathological features of extramedullary recurrence/relapse of multiple myeloma. eur j haematol 2008; 81:65–9. doi: 10.1111/j.16000609.2008.01087.x. 9. hogan mc, lee a, solberg la, thomé sd. unusual presentation of multiple myeloma with unilateral visual loss and numb chin syndrome in a young adult. am j hematol 2002; 70:55–59. doi: 10.1002/ajh.10077. 10. al-farsi k, al-haddabi i, al-riyami n, al-sukaiti, r, al-kindi s. myelomatous pleural effusion: case report and review of the literature. sultan qaboos univ med j 2011; 11:259–64. 11. waldron j, mitchell db. unusual presentations of extramedullary plasmacytoma in the head and neck. j laryngol otol 1988; 102:102–4. doi: 10.1017/s002221510010413x. 12. bruce kw, royer rq. multiple myeloma occurring in the jaws: a study of 17 cases. oral surg oral med oral pathol 1953; 6:729–44. doi: 10.1016/0030-4220(53)90199-6. 13. epstein jb, voss nj, stevenson-moore p. maxillofacial manifestations of multiple myeloma: an unusual case and review of the literature. oral surg oral med oral pathol 1984; 57:267–71. doi: 10.1016/0030-4220(84)90182-8. 14. ustuner z, basaran m, kiris t, bilgic b, sencer s, sakar b, et al. skull base plasmacytoma in a patient with light chain myeloma. skull base 2003; 13:167–71. doi: 10.1055/s-2003-43327. 15. chan kp, tam cs. plasmacytoma: report of a case. cancer 1969; 23:694–8. doi: 10.1002/1097-0142(196903)23:3<694::aid-cn cr2820230324>3.0.co;2-8. 16. nobler mp. mental nerve palsy in malignant lymphoma. cancer 1969; 24:122–7. doi: 10.1002/1097-0142(196907) 24:1<122::aid-cncr2820240116>3.0.co;2-x. 17. an sy, an ch, choi ks, heo ms. multiple myeloma presenting as plasmacytoma of the jaws showing prominent bone formation during chemotherapy. dentomaxillofac radiol 2013; 42:20110143. doi: 10.1259/dmfr.20110143. 18. bladé j, kyle ra, greipp pr. presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years. br j haematol 1996; 93:345–51. doi: 10.1046/j.13652141.1996.5191061.x. 19. damaj g, mohty m, vey n, dincan e, bouabdallah r, faucher c, et al. features of extramedullary and extraosseous multiple myeloma: a report of 19 patients from a single center. eur j haematol 2004; 73:402–6. doi: 10.1111/j.16000609.2004.00331.x. 20. nolan kd, mone mc, nelson ew. plasma cell neoplasms: review of disease progression and report of a new variant. surg oncol 2005; 14:85–90. doi: 10.1016/j.suronc.2005.05.001. 21. katodritou e, gastari v, verrou e, hadjiaggelidou c, varthaliti m, georgiadou s, et al. extramedullary (emp) relapse in unusual locations in multiple myeloma: is there an association with precedent thalidomide administration and a correlation of special biological features with treatment and outcome? leuk res 2009; 33:1137–40. doi: 10.1016/j.leukres.2009.01.036. 22. usmani sz, heuck c, mitchell a, szymonifka j, nair b, hoering a, et al. extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. haematologica 2012; 97:1761–7. doi: 10.3324/haematol.2012.065698. stroke is a fairly common medical emergency which can potentially cause long-term disability or even death; furthermore, the incidence of stroke has been increasing in developing countries in recent years.1 there are several different types of stroke according to their specific pathophysio logical mechanisms. large artery atherothrombosis, cardioembolism and lacunar infarction are examples of ischaemic stroke, while an intra-cerebral or subarachnoid haemorrhage are examples of haemorrhagic stroke.1 the effective management of stroke requires diligent evaluation of the patient with a detailed medical history as well as a systemic and neurological examination. overall, the clinical examination and diagnostic work-up of a patient with suspected stroke has multiple objectives, including localising the site of the stroke in the neuraxis, understanding its pathophysiology and cause and determining the most effective form of treatment. moreover, stroke recurrence is a major concern for all patients following the initial stroke event; therefore, choosing appropriate measures to prevent recurrence is a mandatory component of management.1 however, challenges may arise when more than one variety of stroke occurs in the same patient. this continuing medical education article presents an interesting case, wherein a female patient had recurrent stroke, in order to highlight the complex pathophysiology behind cerebrovascular syndromes. readers are encouraged to apply their basic neuroscience knowledge and clinical skills to solve the various diagnostic and management-related dilemmas encountered in this case. 1department of medicine, college of medicine & health sciences, sultan qaboos university; departments of 2medicine and 3radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mails: arunoday@squ.edu.om and grarunoday@hotmail.com “السكتات الدماغية املختلفة” معضالت التشخيص وخطة العالج اأرونودايا ر جوجار، مرت�شى التيجاين، دار�شان لل، اأنوبام كومار كاكاريا، عبد اهلل را�شد العا�شمي abstract: stroke is a common medical emergency resulting from numerous pathophysiological mechanisms and with varied clinical manifestations; as such, the diagnosis of stroke requires diligent clinical assessment. when different stroke syndromes occur in the same patient, it may cause a dilemma in terms of diagnosis and management. this continuing medical education article describes an interesting patient with recurrent neurological events, highlighting the complex pathophysiological processes associated with cerebrovascular syndromes. it offers readers the opportunity to apply their own basic neuroscience knowledge and clinical skills to solve the challenges encountered during the course of diagnosing and treating this patient. specifically, the article aims to familiarise readers with an approach to diagnosing brainstem strokes and the diverse manifestations of a common stroke syndrome. keywords: stroke; lacunar stroke; cerebral hemorrhage; cerebral small vessel disease; continuing medical education. النحو، هذا وعلى خمتلفة؛ �رضيرية اأعرا�ض ولها خمتلفة عوامل عن تنتج �شائعة طبية طوارئ حالت هي الدماغية ال�شكتات امللخ�ص: يتطلب ت�شخي�ض ال�شكتة الدماغية التقييم ال�رضيري الدوؤوب. عندما حتدث متالزمات ال�شكتة الدماغية املختلفة يف نف�ض املري�ض، فاإنه قد ا حدثت له اأعرا�ض ع�شبية متكررة اأثرت على يت�شبب يف مع�شلة من حيث الت�شخي�ض والعالج. ت�شف هذه املقالة التعليمية الطبية مري�شً اجلهاز الع�شبي، وهي تبني مدى �شعوبة وتداخالت العمليات الفيزيولوجية املر�شية امل�شاحبة للمتالزمات الدماغية الوعائية. تتيح هذه املقاله للقراء الفر�شة لتطبيق معلوماتهم الأ�شا�شية يف علم املخ والأع�شاب ومهاراتهم ال�رضيرية من اأجل حل التحديات التي تواجههم الدماغية ال�شكتات لت�شخي�ض ال�شحيح بالنهج القراء تعريف اإىل املقالة تهدف التحديد. وجه على املري�ض هذا وعالج ت�شخي�ض اأثناء والأعرا�ض املتنوعة الناجتة عن متالزمة ال�شكتات الدماغية ال�شائعة التي ت�شيب �شاق املخ. مفتاح الكلمات: ال�شكتة الدماغية؛ ال�شكتة الدماغبة اجلوبية؛ نزف فى املخ؛ اأمرا�ض الأوعية الدموية الدماغية؛ التعليم الطبي امل�شتمر. “different strokes” a management dilemma *arunodaya r. gujjar,1 mortada el-tigani,2 darshan lal,2 anupam k. kakaria,3 abdullah r. al-asmi2 sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e202–207, epub. 9 sep 18 submitted 18 dec 17 revision req. 1 feb 18; revision recd. 12 mar 18 accepted 5 apr 18 doi: 10.18295/squmj.2018.18.02.013 continuing medical education arunodaya r. gujjar, mortada el-tigani, darshan lal, anupam k. kakaria and abdullah r. al-asmi continuing medical education | e203 case study a 55-year-old african woman initially presented to a secondary hospital in muscat, oman, in 2015 with drooping of the left eyelid which had begun a few hours previously. the patient reported a history of double vision. she was being treated for hypertension with amlodipine, which she had taken for the past 20 years, although with poor compliance. upon examination, she was observed to have an elevated blood pressure of 180/120 mmhg. a neurological examination revealed left ptosis with a dilated pupil which reacted sluggishly to light and limited movements of the left eye, except for abduction [figure 1a]. her blood glucose and haemoglobin levels, cell counts and erythrocyte sedimentation rate (esr) were all normal. a computed tomography (ct) scan of the brain showed hypodensities in the brainstem and periventricular regions [figure 1b]. she was prescribed amlodipine, telmisartan, atenolol, aspirin and atorvastatin before being discharged, with advice to take her medication regularly. subsequently, 10 days later, the patient was admitted to the emergency department of the sultan qaboos university hospital, a tertiary hospital in muscat. according to her relatives, she had been speaking on the phone at home before suddenly dropping the phone from her right hand and slumping over. she had remained conscious, but was noted to have right-sided weakness and slurred speech. at presentation, her blood pressure was 165/110 mmhg. she was alert, oriented and appeared able to comprehend and answer questions, although her speech continued to be slurred. the ptosis and ophthalmoparesis in the left eye persisted, while the movement, pupil and visual fields of the right eye were normal. new neurological signs were evident, including right upper motor neuron facial paresis, dense right-sided hemiparesis with a power of 0–1/5 on the medical research council muscle power scale in both the right upper and lower limbs [figure 2], reduced touch and pinprick sensations over the right side of the body and face and right extensor plantar responses. her tendon reflexes on the right side were brisk over the course of the next couple of days. figure 2: photograph of a 55-year-old hypertensive woman with left eye-lid ptosis and right-sided hemiparesis. question 1: based on the patient’s symptoms and signs, which cranial nerve was affected? what was the likely cause of the cranial nerve palsy? overall, the clinical signs are suggestive of left third cranial nerve palsy. isolated palsy of this variety may occur due to involvement anywhere along the course of the affected nerve.2 as the patient had no headaches or signs indicating the involvement of any other cranial nerves, it is likely that the involvement of the left third cranial nerve is localised along the skull base or in the cavernous sinus region. diabetic cranial neuropathy is unlikely as it usually causes pupil-sparing nerve palsy.2 furthermore, the absence of long tract signs at this stage may argue against a sizeable brainstem lesion. the computed tomography brain scan shows midbrain hypodensity—likely a lacunar infarct—with no evidence of another lesion along the course of the third cranial nerve. hence, the possible causes of third nerve palsy are either lacunar stroke in the ventral midbrain or ischaemic neuropathy.2 meningitis, malignancy or autoimmune disorders are unlikely in the context of the patient’s clinical picture and the findings of various investigations. however, an aneurysm, for instance in the posterior communicating artery, may also be possible.2 figure 1: a: photograph of a 55-year-old hypertensive woman with left ptosis and a divergent squint. b: computed tomography scan of the brain showing brainstem and periventricular hypodensities (arrows). question 2: what are the likely locations of the patient’s stroke, considering the new neurological signs of dense right-sided hemiparesis and hemihypoesthesia? the patient had dense right-sided hemiparesis with right hemi hypoesthesia; however, her language functions remained unaffected. this supports the possibility of left subcortical stroke, potentially located at the corona radiata, internal capsule or, less commonly, the ventral midbrain or pons.2 “different strokes” a management dilemma e204 | squ medical journal, may 2018, volume 18, issue 2 the patient’s complete blood count, esr, levels of blood glucose and serum lipids, liver and renal function, coagulation profile and echocardiogram were normal. an electrocardiogram revealed signs of left ventricular hypertrophy. at this stage, a ct scan of the brain showed a hyperdensity in the left thalamocapsular region, suggestive of haemorrhage [figure 3a]. two days later, magnetic resonance imaging (mri) of the brain revealed left thalamocapsular intracerebral haemorrhage as well as scattered hyperintensities in the periventricular white matter and the brainstem [figures 3b–e]. a susceptibility-weighted mri sequence, which is sensitive to haemorrhages, displayed hypointensities scattered in the deep ganglionic and periventricular regions and the brainstem [figure 4a], in addition to a large haematoma. magnetic resonance angiography confirmed that the cervical carotid and vertebral arteries were normal, with some irregularities in the intracranial arteries, suggestive of atherosclerosis [figure 4b]. however, no aneurysms or vascular malformations were observed. following these findings, aspirin and atorvastatin were discontinued and the patient received intravenous labetalol for emergent control of her hypertension; later, other oral antihypertensive agents were prescribed and physiotherapy was initiated. a week after the onset of the right-sided hemiparesis, the patient reported diffuse aching pain over the right side of her body, including the face. the pain was present throughout the day and disturbed her sleep. fortunately, it improved gradually following the administration of oral pregabalin. question 4: what is the likely cause of the sequential ischaemic episodes seen in this case, subsequently followed a few days later by intracerebral haemorrhage? the likely cause is cerebral small vessel disease, presumably due to chronic poorly-controlled hypertension. this diagnosis is supported by the serial occurrence of lacunar infarct in the midbrain followed by hypertensive thalamocapsular haemorrhage, with multiple periventricular hyperintensities seen upon magnetic resonance imaging, microhaemorrhages scattered in the deep ganglionic structures and brainstem as well as the recent haematoma.3,5 while cerebral amyloid angiopathy, central nervous system angiitis, systemic vasculitis and, rarely, a central nervous system lymphoma may be considered in the differential diagnosis, the investigations performed in this case excluded most of these conditions. question 5: in the context of both ischaemic and haemorrhagic stroke, and considering the background of chronic hypertension, which intervention might be beneficial in preventing stroke recurrence in this patient? hypertension control is currently the only intervention recognised to be of some value for patients with cerebral small vessel disease. lacunar infarction due to small vessel disease, as opposed to large artery disease, may not be significantly influenced by antiplatelet therapy.3,6,7 question 3: the combination of left ptosis, ophthalmoparesis and right-sided hemiparesis in this case suggests which specific location of neuraxial involvement? what eponym is used to describe this? the combination of left oculomotor nerve involvement with right-sided hemiparesis indicates a crossed brainstem syndrome, particularly a lesion in the left half of the midbrain at the level of the third nerve nucleus.3 this is known as weber’s syndrome, named after sir hermann david weber who first described this condition in 1863.4 however, the occurrence of two temporally and spatially separated stroke episodes—a lacune and a haematoma— should perhaps instead be labelled pseudo-weber’s syndrome. figure 3: a: computed tomography scan of the brain of a 55-year-old hypertensive woman three hours after the onset of right-sided hemiparesis showing left thalamocapsular haemorrhage (arrow). b–e: magnetic resonance images of the brain two days later showing (b and c) left thalamocapsular intracerebral haemorrhage (arrows), as well as scattered hyperintensities (arrowheads) in the (d) periventricular white matter and (e) brainstem. arunodaya r. gujjar, mortada el-tigani, darshan lal, anupam k. kakaria and abdullah r. al-asmi continuing medical education | e205 the patient was discharged two weeks after admission with persistent right-sided weakness and sensory impairment. at a follow-up appointment one year later, the ophthalmoparesis and lower limb weakness had improved significantly, although she continued to experience weakness in the right arm. discussion the aforementioned case describes a middle-aged woman with a long history of poorly-controlled hypertension who experienced two varieties of stroke sequentially within a few days—ischaemic stroke followed by intracerebral haemorrhage—leading to crossed hemiparesis syndrome causing ptosis and ophthalmoparesis on the left side, followed by hemiparesis and hemihypoesthesia on the right side with preserved speech function. this patient was unique in several aspects. over the course of 10 days, she had sequential neurological deficits which initially seemed consistent with weber’s syndrome, but which were in fact due to a combination of two different stroke mechanisms, with third nerve palsy likely due to a midbrain lacune and contralateral hemiparesis due to a left thalamocapsular haematoma. this unusual sequence of events resulted in a picture of pseudoweber’s syndrome, as the responsible events were distinct and separated by time as well as location. the patient also developed thalamic pain syndrome shortly after an episode of deep ganglionic haemorrhage. cerebral small vessel disease (csvd) is a fairly common vascular syndrome in which hypertension is the main risk factor, with others being age and the presence of diabetes mellitus.3,5,9 while the disease can remain ‘silent’ for long periods of time, it commonly manifests as white matter and periventricular mri hyperintensities, lacunar infarcts, microhaemorrhages and hypertensive intracerebral haemorrhage, as demonstrated in the current case.5,9 such changes are typically clustered deep in the brain in the territory supplied by the penetrating end arteries arising from the circle of willis. in addition, csvd may be associated with progressive cognitive, gait, mood and bladder function changes.3 overall, csvd is the cause of approximately onefifth of all stroke cases and up to 45% of dementias.3 lacunar stroke constitutes 15–25% of all stroke cases, while intracerebral haemorrhage accounts for 10–15%.1 cerebral amyloid angiopathy is the main differential diagnosis and may have similar manifestations.3,5 non hypertensive lobar haemorrhages are often recurrent and typical of amyloid angiopathy, along with mri evidence of white matter hyperintensities and microhaemorrhages which are more prominent in the peripheral subcortical regions of the hemispheres. superficial siderosis on the cortical surface is also a feature of amyloid angiopathy, sometimes leading to focal seizures.3,5 together with hyperintensities, the deposition of amyloid in the brain is known to occur in several degenerative disorders of the brain, the most prominent of which is alzheimer’s disease, with no specific treatment known to date. inherited small vessel disease includes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and fabry disease; autoimmune question 6: what is the likely cause of the patient’s rightsided pain? aching pain involving the right side of the body following dense right-sided hemiparesis and hemihypoesthesia, with evidence of left thalamocapsular haemorrhage upon computed tomography, strongly suggests the possibility of thalamic pain syndrome or central pain syndrome.8 this is reported in 4–9.5% of stroke patients and may occur either a few days, months or even years after the insult. the pain may be due to the spontaneous irritability of surviving neurons or ephaptic transmission.8 pregabalin, gabapentin and carbamazepine are known to be effective in the initial management of thalamic pain.3,6,7 figure 4: a: susceptibility-weighted magnetic resonance image of the brain of a 55-year-old hypertensive woman two days after the onset of right-sided hemiparesis showing additional hypointensities scattered in the deep ganglionic and periventricular regions and the brainstem (arrow). b: magnetic resonance angiography showing irregularities of the intracranial arteries, suggestive of atherosclerosis (arrow). “different strokes” a management dilemma e206 | squ medical journal, may 2018, volume 18, issue 2 vasculitis and irradiation may also cause small vessel disease.3,5 a family history of similar or related manifestations, onset in young non-hypertensive individuals, prominent headaches, imaging evidence of vasculopathy and cerebrospinal fluid abnormalities may assist in the diagnosis. other than for a few specific conditions (i.e. fabry disease or cerebral angiitis), the treatment and prevention of the progression of many of these conditions is still poorly understood.3,5 few studies to date have addressed the manag ement of csvd as a whole. effective long-term hyper tension control is considered the main method of preventing csvd progression.7 several therapeutic trials addressing stroke or dementia have included individual components of csvd, thereby providing some evid ence for the efficacy of certain interventions.3,7 thrombolysis is known to be of benefit for patients with acute lacunar stroke, although csvd may be associated with a higher risk of intracerebral haemorrhage.10 the efficacy of antiplatelet agents among patients with csvd is unclear.3,6,7 in the double-blind secondary prevention of small subcortical strokes trial, no difference in stroke prevention was observed among patients undergoing dual antiplatelet therapy (aspirin with clopidogrel) compared to those taking aspirin and a placebo; in fact, there was a greater risk of haemorrhage and death with dual antiplatelet therapy.6 another study demonstrated a significant reduction in recurrent stroke among patients, most of whom had lacunar stroke, treated with cilostazol rather than a placebo (relative risk: 41.7%; p <0.015).11 thus, it is possible that antiplatelet agents may be of benefit among patients with csvd who present with lacunar stroke. patients with intracerebral haemorrhage due to csvd are treated similarly to those due to other primary causes of intracerebral hemorrhage.11 how-ever, no studies or guidelines have addressed the management of patients with csvd who present with sequential ischaemic and haemorrhagic stroke, as in the current case. in the context of intracerebral haemorrhage, antiplatelet agents are conventionally withheld for a period of between a few weeks to three months. later, the reintroduction of antiplatelet agents may often be indicated by a coexisting risk of ischaemic stroke, ischaemic heart disease or peripheral arterial disease.12 while lacunar stroke is recognised as a risk factor for stroke recurrence and may require antiplatelet therapy, no studies address the issue of whether and when to reintroduce this therapy in cases of sequential ischaemic and haemorrhagic stroke.6,7 therefore, in the absence of other risk factors for ischaemic events and due to the presence of significant cerebral microhaemorrhages as well as a haematoma, management of the patient in the current case consisted solely of hypertension control. no stroke recurrence was observed over the following year. conclusion this article describes a patient with crossed hemiparesis syndrome—left third nerve palsy with rightsided hemiparesis—due to two distinct episodes of ischaemic and haemorrhagic stroke. the underlying causes were a lacunar infarct and thalamocapsular haemorrhage due to csvd, which is a fairly common syndrome with diverse manifestations. for patients with recurrent stroke or multiple stroke syndromes, diligent clinical assessment is important in order to understand the location of each event as well as the underlying pathophysiological mechanism. a c k n o w l e d g e m e n t s the authors wish to acknowledge the cooperation of the patient and her family. the patient consented to the use of all clinical photographs and radiological images included in this article. references 1. hommel m, caplan lr. midbrain infarcts and hematomas. in: caplan lr, van gijn j, eds. stroke syndromes, 3rd ed. cambridge, uk: cambridge university press, 2012. pp. 439–47. 2. brazis pw, masdeu jc, biller j. localization in clinical neurology, 6th ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2011. 3. pantoni l. cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. lancet neurol 2010; 9:689–701. doi: 10.1016/s1474-4422(10)70104-6. 4. weber h. a contribution to the pathology of the crura cerebri. med chir trans 1863; 46:121–40. 5. wardlaw jm, smith c, dichgans m. mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. lancet neurol 2013; 12:483–97. doi: 10.1016/s1474-4422(13) 70060-7. 6. sps3 investigators; benavente or, hart rg, mcclure la, szychowski jm, coffey cs, et al. effects of clopidogrel added to aspirin in patients with recent lacunar stroke. n engl j med 2012; 367:817–25. doi: 10.1056/nejmoa1204133. 7. bath pm, wardlaw jm. pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions. int j stroke 2015; 10:469–78. doi: 10.1111/ijs.12466. 8. canavero s, bonicalzi v. central pain syndrome, 3rd ed. berlin, germany: springer, 2018. doi: 10.1007/978-3-319-56765-5. 9. charidimou a, boulouis g, haley k, auriel e, van etten es, fotiadis p, et al. white matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy. neurology 2016; 86:505–11. doi: 10.1212/wnl.0000000000002362. 10. tsivgoulis g, zand r, katsanos ah, turc g, nolte ch, jung s, et al. risk of symptomatic intracerebral hemorrhage after intravenous thrombolysis in patients with acute ischemic stroke and high cerebral microbleed burden: a meta-analysis. jama neurol 2016; 73:675–83. doi: 10.1001/jamaneurol.2016.0292. https://doi.org/10.1016/s1474-4422%2810%2970104-6 https://doi.org/10.1016/s1474-4422%2813%2970060-7 https://doi.org/10.1016/s1474-4422%2813%2970060-7 https://doi.org/10.1056/nejmoa1204133 https://doi.org/10.1111/ijs.12466 https://doi.org/10.1007/978-3-319-56765-5 https://doi.org/10.1212/wnl.0000000000002362 https://doi.org/10.1001/jamaneurol.2016.0292 arunodaya r. gujjar, mortada el-tigani, darshan lal, anupam k. kakaria and abdullah r. al-asmi continuing medical education | e207 11. gotoh f, tohgi h, hirai s, terashi a, fukuuchi y, otomo e, et al. cilostazol stroke prevention study: a placebo-controlled double-blind trial for secondary prevention of cerebral infarction. j stroke cerebrovasc dis 2000; 9:147–57. doi: 10.1053/ jscd.2000.7216. 12. wijdicks efm. the use of antithrombotic therapy in patients with an acute or prior intracerebral haemorrhage. from: www. uptodate.com/contents/the-use-of-antithrombotic-therapyin-patients-with-an-acute-or-prior-intracerebral-hemorrhage/ print accessed: mar 2018. https://doi.org/10.1053/jscd.2000.7216 https://doi.org/10.1053/jscd.2000.7216 department of medicine, sultan qaboos hospital, salalah, oman *corresponding author e-mail: drakhwand@yahoo.com نتائج اإلنعاش القليب الرئوي وتقدير تكلفة الرعاية الصحية يف حاالت عدم اإلنعاش احملتملة اأخواند �شكيل اأحمد، �شيد مدثر، حممد ن�در خ�ن، ح�فظ جنم الدين ح�شن abstract: objectives: cardiopulmonary resuscitation (cpr) is a life-saving procedure which may fail if applied unselectively. ‘do not resuscitate’ (dnr) policies can help avoid futile life-saving attempts among terminally-ill patients. this study aimed to assess cpr outcomes and estimate healthcare costs in potential dnr cases. methods: this retrospective study was carried out between march and june 2014 and included 50 adult cardiac arrest patients who had undergone cpr at sultan qaboos hospital in salalah, oman. medical records were reviewed and treating teams were consulted to determine dnr eligibility. the outcomes, clinical risk categories and associated healthcare costs of the dnr candidates were assessed. results: two-thirds of the potential dnr candidates were ≥60 years old. eight patients (16%) were in a vegetative state, 39 (78%) had an irreversible terminal illness and 43 (86%) had a low likelihood of successful cpr. most patients (72%) met multiple criteria for dnr eligibility. according to clinical risk categories, these patients had terminal malignancies (30%), recent massive strokes (16%), end-stage organ failure (30%) or were bed-bound (50%). initial cpr was unsuccessful in 30 patients (60%); the remaining 20 patients (40%) were initially resuscitated but subsequently died, with 70% dying within 24 hours. these patients were ventilated for an average of 5.6 days, with four patients (20%) requiring >15 days of ventilation. the average healthcare cost per patient was usd $1,958.9. conclusion: with careful assessment, potential dnr patients can be identified and futile cpr efforts avoided. institutional dnr policies may help to reduce healthcare costs and improve services. keywords: cardiopulmonary resuscitation; medical futility; do not resuscitate orders; persistent vegetative state; terminally ill; healthcare costs; oman. امللخ�ص: الهدف: االإنع��ص القلبي الرئوي يعترب من االإجراءات املنقذة للحي�ة التي قد تف�شل اإذا ُطبِّقت ب�شكل غري اإنتق�ئي.اإن �شي��شة عدم نت�ئج تقييم اإىل تهدف الدرا�شة هذه املجدية. غري للحي�ة اإنق�ذ حم�والت تف�دي يف ي�ش�عد قد املت�أخرة احل�الت ذوي املر�شى اإنع��ص الدرا�شة هذه متت الطريقة: االإنع��ص. عدم �شمن اإدراجه� املحتمل احل�الت عند ال�شحية الرع�ية تكلفة وتقدير الرئوي القلبي االإنع��ص ب�أثٍر رجعي بني �شهري م�ر�ص ويونيو 2014 م، وت�شمنت 50 ح�لة توقف قلب عند الكب�ر من الذين اأُجريت لهم عملية اإنع��ص قلبي رئوي يف م�شت�شفى ال�شلط�ن ق�بو�ص ب�شاللة، عم�ن. لقد متت مراجعة ال�شجالت الطبية وا�شت�ش�رة الفرق الطبية املع�جلة للمر�شى لتحديد اأهلية عدم االإنع��ص.كم� مت تقييم النت�ئج، الفئ�ت املعر�شة للخطر ال�رضيري وتكلفة الرع�ية ال�شحية املتعلقة بذلك عند املر�شى املر�شحني لعدم االإنع��ص. النتائج: وجدن� اأن ُثلثي املر�شى املر�شحني لعدم االإنع��ص ك�نوا يبلغون من العمر 60 ع�م�آ ف�أكرث. 8 مر�شى )%16( ك�نوا يف ح�لة غيبوبة دم�غية م�شتمرة و 39 مري�ش�آ )%78( ك�نت لديهم اأمرا�ص يف مراحل مت�أخرة و 43 مري�ش�آ )%86( ك�ن لديهم اإحتم�ل �شعيف لنج�ح عملية االإنع��ص القلبي. معظم املر�شى)%72( توفرت لديهم عدة مع�يري الأهلية عدم االإنع��ص. ب�لن�شبة لفئ�ت املخ�طر ال�رضيرية، )%30( ك�نت لديهم اأوراما خبيثة، )%16( جلطة دم�غية ح�دة، %30 ف�شل اأع�ش�ء نه�ئي اأو )%50( ك�نوا طريحي الفرا�ص. االإنع��ص القلبي الرئوي االأويل مل يكن ن�جح�آ يف 30 مري�ش�آ )%60(، بينم� ك�ن ن�جح� يف ب�قي املر�شى وهم 20 مري�ش�آ )%40(، لكن %70 منهم م�توا خالل أل 24 �ش�عة االأوىل. هوؤالء املر�شى مت تو�شيلهم ب�أجهزة التنف�ص اال�شطن�عي لفرتة ترتاوح بني 5.6 اأي�م، 4 منهم )%20( ملدة اأكرث من 15 يوم�آ. متو�شط التكلفة لكل مري�ص ك�نت حوايل 1,958.9$ دوالراآ اأمريكي�آ. اخلال�صة: ب�لتقييم الدقيق، ميكن حتديد احل�الت املحتملة لعدم االإنع��ص، ومن ثمَّ تف�دي االإنع��ص القلبي الرئوي غري املجدي. و�شع �شي��ش�ت عدم االإنع��ص يف املوؤ�ش�ش�ت ال�شحية قد ي�ش�عد يف تقليل تكلفة الرع�ية ال�شحية وحت�شني اخلدم�ت يف ذات الوقت. الرع�ي تكلفة ُع�ش�ل؛ مر�ص م�شتمرة؛ دم�غية غيبوبة االإنع��ص؛ بعدم التو�شية الطبية؛ اجلدوي عدم الرئوي؛ القلبي االإنع��ص الكلمات: مفتاح ال�شحية؛ عم�ن. outcomes of cardiopulmonary resuscitation and estimation of healthcare costs in potential ‘do not resuscitate’ cases *akhwand s. ahmad, sayed mudasser, muhammad n. khan, hafiz n. h. abdoun sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e27–34, epub. 2 feb 16 submitted 16 jun 15 revisions req. 26 jul & 27 sep 15; revisions recd. 28 aug & 4 oct 15 accepted 29 oct 15 clinical & basic research doi: 10.18295/squmj.2016.16.01.006 advances in knowledge while cardiopulmonary resuscitation (cpr) techniques have advanced over time, these life-saving measures may still be futile for certain patients. this study indicates very poor cpr outcomes and high associated healthcare costs among potential ‘do not resuscitate’ (dnr) candidates at a secondary care hospital in oman. outcomes of cardiopulmonary resuscitation and estimation of healthcare costs in potential ‘do not resuscitate’ cases e28 | squ medical journal, february 2016, volume 16, issue 1 cardiopulmonary resuscitation (cpr) is an emergency medical procedure whereby external measures, including chest compression, artificial respiration or defibrillation, are carried out in an attempt to restore breathing and spontaneous circulation in a patient whose heart and/or breathing have stopped. important milestones in the history of cpr include the implementation of mouth-to-mouth resuscitation by william tossach in 1732, the first successful closed-chest cardiac massage by friedrich maass in 1892, the first successful openchest defibrillation by claude beck and his team in 1947 and the first successful closed-chest human defibrillation by paul zoll and colleagues in 1955.1–5 chest compressions were established as part of cpr procedures by william kouwenhoven in 1958.6 the american heart association (aha) formally endorsed cpr in 1963 and produced standardised cpr guidelines in 1966.7 prompt cpr is life-saving in select cases. however, the chances of a patient surviving following cpr measures vary depending on the cause and circumstances of the cardiac arrest. with in-hospital cpr, the chances of survival-to-discharge are 15–20%, while out-of-hospital cpr carries an even lower rate of survival-to-discharge (5–10%).8–10 survival rates decrease even further for the elderly, nursing home residents or those with multiple medical problems.11 for advanced cancer patients, survival-to-discharge following in-hospital cpr is approximately 6%.9 furthermore, the process of cpr itself is not without risk. rib fractures, damage to internal organs, hypoxic brain damage and increased risk of physical disability are potential cpr-associated complications.12 following cpr, a patient will normally require support in an intensive care unit (icu); fatal anoxic encephalopathy or respiratory complications may arise from long-term ventilator dependence.13 unsuccessful cpr may also lead to an undignified and/or traumatic death, as well as creating an unnecessary financial burden on the medical services system. by 1976, as the limitations of cpr became known, the potential benefits of ‘do not resuscitate’ (dnr) orders for terminally-ill patients began to be discussed.14 carrying out a dnr order means that no resuscitative measures are undertaken if the patient undergoes a cardiopulmonary arrest. cardiac or respiratory arrest is an inevitable part of dying; thus, theoretically, cpr measures can be used indefinitely on every individual. it is therefore essential to identify patients for whom cardiopulmonary arrest represents the terminal event in their illness, as cpr is inappropriate for these patients. in circumstances where the decision is made not to perform cpr, an order for dnr—sometimes termed ‘do not attempt resuscitation’ or ‘allow natural death’—is inserted into the patient’s records. such orders are intended to prevent inappropriate, futile or undesired cpr attempts. the general medical council of the uk recommends not attempting cpr if resuscitation is likely to be unsuccessful (i.e. if cardiac or respiratory arrest is an expected part of the dying process) or if successful cpr is not clinically appropriate (i.e. due to likely clinical outcomes).15 in wisconsin, usa, legislature exists which permits physicians to dispense dnr orders for the following types of adult patients: those with terminal illnesses; those with medical conditions that indicate cpr would be unsuccessful in restoring cardiac or respiratory function; those who would shortly undergo repeated cardiac or pulmonary failure before death despite cpr measures; or those who would suffer significant pain or harm as a result of the cpr measures, eclipsing the possibility that cpr measures might successfully and indefinitely restore cardiac or respiratory function.16 in essence, dnr orders are implemented if the clinical team believes that cpr is medically futile or if cpr will, at the most, prolong the process of dying. additionally, cpr may not be appropriate if it is unlikely to lead to a meaningful recovery or is carried out on a vegetative patient. in oman, as with many other countries, no legislation regarding dnr orders currently exists. previous research conducted in the country has focused on dnr orders in relation to terminallyill cancer patients and in the neonatal icu of a tertiary care centre.17,18 this study aimed to assess the outcomes and estimate the associated healthcare costs of cpr among potential dnr patients admitted to the sultan qaboos hospital (sqh), a secondary care centre in salalah, oman. methods this retrospective study was carried out from march to june 2014 at sqh and included all admitted adult application to patient care many hospitals and medical institutions still lack official dnr policies or clear guidelines to identify dnr cases. the results of this study indicate that potential dnr patients can be identified according to certain criteria. institutional dnr policies are recommended to save terminally-ill patients from undue trauma and reduce the burden on available healthcare services. akhwand s. ahmad, sayed mudasser, muhammad n. khan and hafiz n. h. abdoun clinical and basic research | e29 medical patients >18 years old who had experienced cardiac arrest, received at least one attempt at cpr (referred to as index cpr) and were potential dnr candidates. patients whose medical history was unknown, who presented with cardiac arrest or those with an uncertain dnr eligibility status were excluded from the study. similarly, patients who were resuscitated in hospital areas other than the general medical ward or medical critical care area (e.g. emergency, surgical or gynaecological departments) were not included. a total of 81 patients at sqh were initially determined to have suffered a cardiac arrest and undergone cpr. of those, 50 met the inclusion criteria and were included in the study. another 19 patients were subsequently identified, but were excluded from the study due to a lack of information on the part of the consulting physician regarding the status of the patient prior to cpr. three criteria were determined to indicate dnr eligibility: (1) the clinical condition of the patient indicated that resuscitation would be medically futile as it would either not restore cardiac and respiratory function or would do so only briefly with a subsequent need for further cpr attempts; (2) the patient was in a persistent vegetative state with no reasonable possibility of regaining cognitive function; or (3) the patient had been diagnosed with an irreversible terminal illness whereby cardiopulmonary arrest was considered a natural consequence of the disease process. the demographic and clinical data of the dnr candidates were collected from medical records and via consultations with the treating teams. in some cases, the researchers had been directly involved in the care of a particular patient and were able to categorise dnr eligibility without further consultation. the potential dnr cases, once identified, were assessed for immediate and long-term cpr outcomes. additionally, the following pre-existing conditions (i.e. present at admission) were deemed clinical risk categories predictive of a poor prognosis and were used to further classify the patients: terminal incurable malignancy, recent massive stroke, end-stage organ failure and being bed-bound. healthcare costs (including expenses related to medications, laboratory investigations, imaging studies, procedures such as tracheostomies or chest tube placements and hospital stay) were approximated using information collected from a comprehensive healthcare information management system (e-government al shifa system, ministry of health, muscat, oman). unfortunately, data on certain items were not available via this system (e.g. screening cultures, nutritional supplements and disposable products such as catheters, central lines, endotracheal and feeding tubes, urinary catheters and drainage bags) and thus the costs of these items were not included in the estimation. data were analysed with simple statistical calculations performed manually using microsoft excel 2010 (microsoft, inc., redmond, washington, usa). ’ this study was approved by the ethical committee of the directorate general of health, ministry of health, salalah. table 1: characteristics of potential ‘do not resuscitate’ patients undergoing at least one attempt at cardiopulmonary resuscitation at sultan qaboos hospital, salalah, oman (n = 50) characteristic n (%) total (n = 50) index cpr survivors (n = 20) gender male 29 (58) 13 (65) female 21 (42) 7 (35) mean age in years (range) 64 (26–98) 61 (26–79) nationality omani 44 (88) 19 (95) other 6 (12) 1 (5) mean hospital stay in days prior to index cpr (range) 33 (0–320) 34 (0–236) dnr eligibility category vegetative state [95% ci] 8 (16) [5.9–26.1] 3 (15) [0–30.6] terminal illness [95% ci] 39 (78) [66.6–79.4] 12 (60) [38.5–81.5] low likelihood of cpr success [95% ci] 43 (86) [76.9–95.6] 16 (80) [62.5–97.5] ventilation before index cpr 22 (44) 6 (30) after index cpr 20 (40) 20 (100) clinical risk category bed-bound [95% ci] 25 (50) [36.1–63.9] 11 (55) [33.2–76.8] malignancy [95% ci] 15 (30) [17.3–42.7] 5 (25) [6.0–44.0] stroke [95% ci] 8 (16) [5.9–26.1] 3 (15) [0–30.6] organ failure [95% ci] 15 (30) [17.3–42.7] 4 (20) [2.5–37.5] cpr = cardiopulmonary resuscitation; dnr = ‘do not resuscitate’; ci = confidence interval. outcomes of cardiopulmonary resuscitation and estimation of healthcare costs in potential ‘do not resuscitate’ cases e30 | squ medical journal, february 2016, volume 16, issue 1 results of the 50 potential dnr cases included in the study, 29 (58%) were male and 21 (42%) were female. the patients ranged in age between 26–98 years old; 33 patients (66%) were ≥60 years old and four patients (8%) were <50 years old. the average hospital stay duration before the index cpr was 33 days (range: three hours–320 days) [table 1]. a total of 22 patients (44%) had already been ventilated for an average of 10 days when index cpr was required (range: 10 minutes–35 days; aggregate: 218 days). three other patients also received non-invasive ventilation, on average for two days prior to index cpr. nine patients (18%) were in the general medical ward when they experienced cardiac arrest, while all other patients (82%) were already in the critical care area. approximately onethird of the patients (n = 17; 34%) were septic on admission and 15 patients (30%) became septic later. in terms of dnr eligibility criteria, eight patients (16%) were in a vegetative state, 39 (78%) had an irreversible terminal illness and 43 (86%) met the criteria of low clinical likelihood of cpr success [figure 1]. however, the majority of the patients (n = 36; 72%) met multiple criteria for dnr eligibility. less than one-third of the patients (n = 14; 28%) met only a single dnr criterion: one patient (2%) was vegetative, three (6%) had been diagnosed with terminal illnesses and 10 (20%) had a low likelihood of cpr success. none of the patients had provided dnr directives in advance. risk factors present on admission which were deemed to predict a poor cpr outcome included endstage malignancies (n = 15; 30%), recent massive strokes (n = 8; 16%), being bed-bound with poor functional status (n = 25; 50%) or chronic end-stage organ failure (n = 15; 30%). these clinical risk categories overlapped with each other. among the eight stroke victims, six (75%) had brain infarcts while two (25%) had intracerebral haemorrhages. four of the stroke victims (50%) had atrial fibrillation, although they had either stopped taking or had never taken anticoagulants. of the patients who were bed-bound, 10 cases (40%) had overlapping risk conditions: recent massive stroke (n = 4; 16%), terminal malignancy (n = 4; 16%) and advanced cardiac failure/crippling chronic obstructive pulmonary disease (n = 2; 8%). however, bed-bound table 2: clinical risk categories of potential ‘do not resuscitate’ patients undergoing at least one attempt of cardiopulmonary resuscitation at sultan qaboos hospital, salalah, oman (n = 50) category n (%) malignancy 15 (30) lung 3 (20) prostate 2 (13) stomach 2 (13) hepatocellular carcinoma 2 (13) rectum 1 (7) colon 1 (7) glioblastoma multiforme 1 (7) chronic lymphocytic leukaemia 1 (7) liver mass* 1 (7) mediastinal mass* 1 (7) organ failure 15 (30) cardiac 6 (40) pulmonary 5 (33) liver 4 (27) bed-bound 25 (50)† multifactorial 12 (48) previous stroke-induced 8 (32) dementia-induced 5 (20) fracture-induced 3 (12) acute or recent stroke 8 (16) massive middle cerebral artery territory infarct 4 (50) intracerebral haemorrhage 2 (25) brain stem/cerebral infarct 2 (25) *these masses were considered malignant although the patients did not give consent for confirmatory biopsies. †these patients had overlapping causes for their bed-bound status. figure 1: frequency of ‘do not resuscitate’ (dnr) eligibility category by gender among potential dnr patients undergoing at least one attempt at cardiopulmonary resuscitation at sultan qaboos hospital, salalah, oman (n = 50). cpr = cardiopulmonary resuscitation. akhwand s. ahmad, sayed mudasser, muhammad n. khan and hafiz n. h. abdoun clinical and basic research | e31 status was a stand-alone risk for the remaining 15 bedbound patients (60%). among all of the bed-bound patients, the overlapping causes of immobility included previous strokes, (n = 8; 32%), advanced dementia (n = 5; 20%), fractures of the femur or pelvis (n = 3; 12%) or a multifactorial cause (n = 12; 48%) including senility, severe osteoarthritis, degenerative spine disease and diabetes with neurovascular complications [table 2]. the majority of patients could not be revived during index cpr (n = 30; 60%). the remaining 20 patients (40%) were resuscitated successfully with index cpr but subsequently died; 14 patients (70%) died within 24 hours and only six (30%) survived more than 24 hours (range: 1–31 days). all of these patients required post-cpr ventilator support and intensive care; they remained on ventilators for an average of 5.6 days (aggregate: 112 days) before dying. four patients (20%) survived >15 days but remained ventilator-dependent. only one of the patients was taken off the ventilator before death; she was a 54-year-old woman who had been vegetative for eight months and had been weaned onto a t-piece after 16 days of ventilation, despite still being on vasopressors. she arrested again four days later and underwent three further cpr attempts in the following 20 hours before dying. all of these patients underwent yet another cpr attempt prior to death; three patients (15%) underwent resuscitation three times following the index cpr. six of the index cpr survivors (30%) had been on a ventilator prior to cardiac arrest for a mean duration of 10 days (range: 4–15 days). table 3 shows the estimated post-resuscitation healthcare costs for the index cpr survivors. the total cost was approximately omani riyals (omr) 15,068.0 (usd $39,178.0), with an average cost of omr 753.0 (usd $1,958.9) per patient. patients with prolonged hospital stays with ventilator support were responsible for most of the costs; one-third of costs were attributed solely to stays in high-care units alone. discussion according to lipsky, four possible indications exist for dispensing a dnr order: futility of treatment, poor quality of life, patient wishes and cost.19 in the current study, three criteria were used to categorise patients as potential dnr cases. while two of these criteria are relatively straightforward to assess (vegetative state or terminal illness), determining whether cpr is likely to be successful depends on the clinical judgment of the treating physician. usually, the decision is not difficult, especially as the patient approaches a terminal state. however, some cases may be more complicated. in the current study, the majority of patients met more than one criterion for dnr eligibility; most of these patients were considered eligible for dnr due to both a terminal illness and a low chance of cpr success. however, no comparative data from other studies could be found. according to wenger et al., dnr orders are more frequently issued to older patients, those with dementia and women.20 while very few of the patients in the current study were below the age of 50 years old, not many of the patients suffered from dementia and there were more male cases than female. in the current study, patients were assessed according to four clinical risk categories deemed predictive of a poor prognosis. half of the cohort were bed-bound, although many of these patients also fell into other risk factors. the term bed-bound is clinically vague; nevertheless, it appears useful for its additive risk due to the predisposition of bed-bound patients to develop severe infections, including aspiration pneumonia, urinary tract infections, infected pressure sores and hospital-acquired infections. bed-bound patients are also prone to other conditions such as venous thromboembolisms, poor nutrition and bleeding due to antithrombotic administration. sepsis was also a major factor among the subjects in the current study. as it is usually treatable, it was not included as a risk category; however, with an underlying critical illness, it can be fatal. while each patient is different, certain negative prognostic features table 3: estimated healthcare costs of potential ‘do not resuscitate’ patients who survived at least one attempt at cardiopulmonary resuscitation at sultan qaboos hospital, salalah, oman (n = 20) total cost in omr (usd) total 25th percentile 75th percentile iqr variable medications 4,698.0 ($12,215.0) 117.5 ($305.5) 117.5 ($305.5) laboratory investigations 4,120.0 ($10,712.0) 285.5 ($742.3) 285.5 ($742.3) imaging studies 710.0 ($1,846.0) 56.5 ($146.9) 56.5 ($146.9) minor procedures 450.0 ($1,170.0) hospital stay in an icu/ hdu 5,090.0 ($13,234.0) 40.0 ($104.0) 300.0 ($780.0) 260.0 ($780.0) aggregate cost 15,068.0 ($39,178.0) average cost per patient 753.4 ($1,958.9) 40.0 ($104.0) 848.0 ($2,204.8) 808.0 ($2,100.8) omr = omani riyals; iqr = interquartile range; icu = intensive care unit; hdu = high dependency unit. outcomes of cardiopulmonary resuscitation and estimation of healthcare costs in potential ‘do not resuscitate’ cases e32 | squ medical journal, february 2016, volume 16, issue 1 such as the ones used in the current study may serve to translate into a simplified dnr score. further research is recommended in this area. it is important to note that none of the potential dnr patients in the current study survived even if they were successfully resuscitated during index cpr. in a study of icu patients who underwent cpr after cardiopulmonary arrest, tian et al. calculated an overall survival-to-discharge rate of 15.9%.21 however, patients on vasopressors were half as likely to survive and mechanical ventilation and older age (≥65 years old) were associated with even lower rates of survival. more than half of the survivors were discharged to rehabilitation centres and only 3.9% were discharged home.21 in comparison, the findings of the current study may seem disappointing; nevertheless, it is important to note that the patients in tian et al.’s study were not categorised as eligible for a dnr order. appropriate case selection is therefore a significant factor in guiding cpr prognosis. in the present study, survivors of the index cpr all required prolonged ventilatory support, with several patients remaining on a ventilator for over 24 hours. prolonged icu care and mechanical ventilation is potentially a source of suffering for both the patient and their family; this type of care is also labourintensive on the part of healthcare staff. additionally, these patients require beds in icus or other high-care areas, which are often in finite supply. almost half of the cohort in the current study had already been on ventilatory support prior to index cpr for a significant duration of time (aggregate: 218 days) and were already in a critical care area before the initiation of index cpr. assuming these patients had had dnr orders to begin with, a ceiling-of-care, short of ventilation, could have been established, potentially increasing available resources for other patients. overall, the estimated cost of post-resuscitation care in the current study was very high; however, it is important to note that the actual total costs involved with futile or inappropriate care of terminally-ill patients is likely much higher. patients with a dnr order deserve the same standard of care as any other patient, short of cpr; in addition, dnr orders should be revoked if clinical conditions change. unfortunately, there is evidence that dnr orders are often broadly applied to other therapies. beach et al. found that patients with a dnr order were less likely to be transferred to an icu or to be intubated and that their treating physicians were less willing to draw blood cultures, place central lines or prescribe blood transfusions.22 brizzi et al. reported that negative prognostic factors such as advanced age, low consciousness levels, history of a previous stroke, midline shift or intraventricular haemorrhage led to a dnr order among patients with intracerebral haemorrhage; moreover, dnr orders were independently associated with a 3.5-fold increase in one-month mortality.23 in this case, early dnr orders may have been used as a justification for an overall decrease in the aggressiveness of care, leading to higher mortality. similarly, scarborough et al. reported that preoperatively-issued dnr orders were a risk factor for mortality after emergency general surgery; this is likely because such patients do not undergo aggressive treatment for major postoperative complications.24 policies and attitudes towards dnr orders vary according to country. in the uk, dnr orders remain clinical decisions; however such decisions should be individualised with an avoidance of blanket policies and attempts should be made to involve patients in the decision-making process.25 in the usa, the situation is different as there is a presumption in favour of resuscitation if a dnr order is not already in place; if made, the orders are established in consultation with the patient or their legal representative.26 the aha recommends resuscitation for all patients in cardiac arrest unless there is a valid dnr order or if resuscitation is physiologically futile (e.g. if a patient shows signs of irreversible death).27 in 1976, the natural death act was enacted in california, usa, to protect a patient’s right to opt for a natural death with out cpr.28 several years later, the patient selfdetermination act was implemented to ensure that healthcare institutions in the usa would recognise and conform to advance dnr directives.28 in taiwan, most terminal patients were taken home to die in accordance with local customs until 2000, when the hospice care law which includes legislation regarding natural death was enacted.29 subsequently, dnr orders were found to be on the rise among taiwanese patients who had been ill for a long period of time or who had solid tumours.30 in japan, physicians can institute dnr orders without consulting the patient’s family if they feel that cpr is unjustified and futile.31 there are no national guidelines regarding dnr orders in denmark; however, patients must generally give informed consent before dnr orders are implemented.32 in saudi arabia, a dnr order can only be applied in consultation with the patient’s family.33 overall, cpr seems to be the only medical intervention whereby consent is automatically assumed—based on implied consent for emergency treatment—and a medical order required in order to withhold its administration. the authors of the current study favour the approach towards dnr implemented in the uk. while cpr is not indicated in every case of cardiac arrest and natural death should be allowed in certain circumstances, the patients and their families should akhwand s. ahmad, sayed mudasser, muhammad n. khan and hafiz n. h. abdoun clinical and basic research | e33 be involved in the discussion. it has been suggested that changing the wording of dnr orders to ‘allow natural death’ may make the order more descriptive and less threatening.34 nevertheless, while communication with patients and their families can facilitate care planning, the extent that the message is understood may be affected by cultural and racial factors; according to mack et al., end-of-life discussions (terminal illness awareness, treatment preferences and dnr orders) benefited caucasian patients but not african american patients.35 one of the major limitations of this study was the retrospective classification of dnr eligibility status based on data collected from medical records and consultations with each patient’s treating team. this process of case selection raises concerns of potential bias in case selection. additionally, as this was a singlecentre study, the results cannot be generalised to other institutions. however, despite these limitations, the findings of this study imply that cpr is ineffective in selected cases which can be identified with a set of predetermined criteria. conclusion although often life-saving, cpr is not beneficial in many cases. allowing death to occur naturally can save undue suffering on the part of a terminally-ill patient and their family and reduce the burden on the healthcare system as a whole. within institutions, the adoption of a dnr policy may reduce healthcare costs both directly and indirectly, as it establishes grounds for the concept of ceiling-of-care and appropriate case-specific treatment options. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. tossach wa. a man dead in appearance recovered by distending the lungs with air. med essays obs 1744; 5:605–8. 2. taw rl jr. dr. friedrich maass: 100th anniversary of “new” cpr. clin cardiol 1991; 14:1000–2. doi: 10.1002/clc.49601 41211. 3. hermreck as. the history of cardiopulmonary resuscitation. am j surg 1988; 156:430–6. doi: 10.1016/s0002-9610(88) 80521-x. 4. beck cs, pritchard wh, feil hs. ventricular fibrillation of long duration abolished by electric shock. j am med assoc 1947; 135:985. doi: 10.1001/jama.1947.62890150005007a. 5. zoll pm, linenthal aj, gibson w, paul mh, norman lr. termination of ventricular fibrillation in man by externally applied electric countershock. n engl j med 1956; 254:727–32. doi: 10.1056/nejm195604192541601. 6. safar p, brown tc, holtey wj, wilder rj. ventilation and circulation with closed-chest cardiac massage in man. jama 1961; 176:574–6. doi: 10.1001/jama.1961.03040200010003. 7. american heart association. history of cpr: highlights of cpr dating back to the 1700’s. from: www.heart.org/heartorg/ cpr andecc/whatiscpr/cprfactsandstats/histor y-ofcpr_ucm_307549_article.jsp accessed: oct 2015. 8. sandroni c, nolan j, cavallaro f, antonelli m. in-hospital cardiac arrest: incidence, prognosis and possible measures to improve survival. intensive care med 2007; 33:237–45. doi: 10.1007/s00134-006-0326-z. 9. reisfield gm, wallace sk, munsell mf, webb fj, alvarez er, wilson gr. survival in cancer patients undergoing in-hospital cardiopulmonary resuscitation: a meta-analysis. resuscitation 2006; 71:152–60. doi: 10.1016/j.resuscitation.2006.02.022. 10. herlitz j, bång a, gunnasson j, engdahl j, karlson bw, lindqvist j, et al. factors associated with survival to hospital discharge among patients hospitalised alive after out of hospital cardiac arrest: change in outcome over 20 years in the community of göteborg, sweden. heart 2003; 89:25–30. doi: 10.1136/heart.89.1.25. 11. ehlenbach wj, bamato ae, curtis jr, kreuter w, koepsell td, deyo ra, et al. the epidemiology of in-hospital cardiopulmonary resuscitation in older adults: 1992-2005. n engl j med 2009; 361:22–31. doi: 10.1056/nejmoa0810245. 12. krischer jp, fine eg, davis jh, nagel el. complications of cardiac resuscitation. chest 1987; 92:287–91. doi: 10.1378/chest. 92.2.287. 13. myerburg rj, conde ca, sung rj, mayorga-cortes a, mallon sm, sheps ds, et al. clinical, electrophysiologic and hemodynamic profile of patients resuscitated from prehospital cardiac arrest. am j med 1980; 68:568–76. doi: 10.1016/00029343(80)90307-1. 14. rabkin mt, gillerman g, rice nr. orders not to resuscitate. new engl j med 1976; 295:364–6. doi: 10.1056/ nejm197608122950705. 15. general medical council. treatment and care towards the end of life: good practice in decision making. from: www.gmc-uk. org/guidance/ethical_guidance/end_of_life_care.asp accessed: oct 2015. 16. wisconsin state legislature. advance directives: subchapter iii do-not-resuscitate orders. from: docs.legis.wisconsin.gov/ statutes/statutes/154/iii/17/4 accessed: oct 2015. 17. faris m. clinical estimation of survival and impact of other prognostic factors on terminally ill cancer patients in oman. support care cancer 2003; 11:30–4. doi: 10.1007/s00520-0020401-0. 18. da costa de, ghazal h, al khusaiby s. do not resuscitate orders and ethical decisions in a neonatal intensive care unit in a muslim community. arch dis child fetal neonatal ed 2002; 86:f115–19. doi: 10.1136/fn.86.2.f115. 19. lipsky ms. indications for dnr orders: a review. resid staff physician 1986; 32:47–51. 20. wenger ns, pearson ml, desmond ka, harrison er, rubenstein lv, rogers wh, et al. epidemiology of do-notresuscitate orders: disparity by age, diagnosis, gender, race, and functional impairment. arch intern med 1995; 155:2056–62. doi: 10.1001/archinte.1995.00430190042006. 21. tian j, kaufman da, zarich s, chan ps, ong p, amoatengadjepong y, et al. outcomes of critically ill patients who received cardiopulmonary resuscitation. am j resp crit care med 2010; 182:501–6. doi: 10.1164/rccm.200910-1639oc. 22. beach mc, morrison rs. the effect of do-not-resuscitate orders on physician decision-making. j am geriatr soc 2002; 50:2057–61. doi: 10.1046/j.1532-5415.2002.50620.x. http://dx.doi.org/10.1002/clc.4960141211 http://dx.doi.org/10.1002/clc.4960141211 http://dx.doi.org/10.1016/s0002-9610%2888%2980521-x http://dx.doi.org/10.1016/s0002-9610%2888%2980521-x http://dx.doi.org/10.1001/jama.1947.62890150005007a http://dx.doi.org/10.1056/nejm195604192541601 http://dx.doi.org/10.1001/jama.1961.03040200010003 http://www.heart.org/heartorg/cprandecc/whatiscpr/cprfactsandstats/history-of-cpr_ucm_307549_article.jsp http://www.heart.org/heartorg/cprandecc/whatiscpr/cprfactsandstats/history-of-cpr_ucm_307549_article.jsp http://www.heart.org/heartorg/cprandecc/whatiscpr/cprfactsandstats/history-of-cpr_ucm_307549_article.jsp http://dx.doi.org/10.1007/s00134-006-0326-z http://dx.doi.org/10.1016/j.resuscitation.2006.02.022 http://dx.doi.org/10.1136/heart.89.1.25 http://dx.doi.org/10.1056/nejmoa0810245 http://dx.doi.org/10.1378/chest.92.2.287 http://dx.doi.org/10.1378/chest.92.2.287 http://dx.doi.org/10.1016/0002-9343%2880%2990307-1 http://dx.doi.org/10.1016/0002-9343%2880%2990307-1 http://dx.doi.org/10.1056/nejm197608122950705 http://dx.doi.org/10.1056/nejm197608122950705 http://www.gmc-uk.org/guidance/ethical_guidance/end_of_life_care.asp http://www.gmc-uk.org/guidance/ethical_guidance/end_of_life_care.asp http://docs.legis.wisconsin.gov/statutes/statutes/154/iii/17/4 http://docs.legis.wisconsin.gov/statutes/statutes/154/iii/17/4 http://dx.doi.org/10.1007/s00520-002-0401-0 http://dx.doi.org/10.1007/s00520-002-0401-0 http://dx.doi.org/10.1136/fn.86.2.f115 http://dx.doi.org/10.1001/archinte.1995.00430190042006 http://dx.doi.org/10.1164/rccm.200910-1639oc http://dx.doi.org/10.1046/j.1532-5415.2002.50620.x outcomes of cardiopulmonary resuscitation and estimation of healthcare costs in potential ‘do not resuscitate’ cases e34 | squ medical journal, february 2016, volume 16, issue 1 23. brizzi m, abul-kasim k, jalakas m, selariu e, pessahrasmussen h, zia e. early do-not-resuscitate orders in intracerebral haemorrhage: frequency and predictive value for death and functional outcome a retrospective cohort study. scand j trauma resusc emerg med 2012; 20:36. doi: 10.1186/1757-7241-20-36. 24. scarborough je, pappas tn. the effect of do-not-resuscitate status on postoperative mortality in the elderly following emergency surgery. adv surg 2013; 47:213–25. doi: 10.1016/j. yasu.2013.04.001. 25. resuscitation council (uk). do not attempt cpr: decisions relating to cardiopulmonary resuscitation (3rd edition). from: www.resus.org.uk/dnacpr/decisions-relating-to-cpr/ accessed: oct 2015. 26. onecle. new york public health: article 29–b orders not to resuscitate for residents of mental hygiene facilities. from: www.law.onecle.com/new-york/public-health/pbh0a29-b_ a29-b.html accessed: oct 2015. 27. american heart association. 2005 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care: part 2 ethical issues. circulation 2005; 112:iv-6–11. doi: 10.1161/circulationaha.105.166551. 28. teno jm, branco kj, mor v, phillips cd, hawes c, morris j, et al. changes in advance care planning in nursing homes before and after the patient self-determination act: report of a 10-state survey. j am geriatr soc 1997; 45:939–44. doi: 10.1111/j.1532-5415.1997.tb02963.x. 29. huang ch, hu wy, chiu ty, chen cy. the practicalities of terminally ill patients signing their dnr orders: a study in taiwan. j med ethics 2008; 34:336–40. doi: 10.1136/ jme.2007.020735. 30. jaing th, tsay pk, fang ec, yang sh, chen sh, yang cp, et al. “do-not-resuscitate” orders in patients with cancer at a children’s hospital in taiwan. j med ethics 2007; 33:194–6. doi: 10.1136/jme.2006.016360. 31. masuda y, fetters m, shimokata h, muto e, mogi n, iguchi a, et al. outcomes of written living wills in japan: a survey of the deceased ones’ families. bioethics forum 2001; 17:41–52. 32. ballin nh. [do-not-resuscitate orders: ethical and legal considerations]. ugeskr laeger 2007; 169:1201–4. 33. the saudi commission for health specialties, department of medical education & postgraduate studies. code of ethics for health care practitioners. from: www.scfhs.org. sa/reglations/cr/uments/%d8%a3%d8%ae%d9%84%d 8 % a 7 % d 9 % 8 2 % d 9 % 8 a % d 8 % a 7 % d 8 % a a % 2 0 % d 8 % a 7 %d9%84%d9%85%d9%85%d8%a7%d8%b1%d8%b3%20 %d8%a7%d9%84%d8%b5%d8%ad%d9%8a.pdf accessed: oct 2015. 34. knox c, vereb ja. allow natural death: a more humane approach to discussing end-of-life directives. j emerg nurs 2005; 31:560–1. doi: 10.1016/j.jen.2005.06.020. 35. mack jw, paulk me, viswanath k, prigerson hg. racial disparities in the outcomes of communication on medical care received near death. arch intern med 2010; 170:1533–40. doi: 10.1001/archinternmed.2010.322. http://dx.doi.org/10.1186/1757-7241-20-36 http://dx.doi.org/10.1016/j.yasu.2013.04.001 http://dx.doi.org/10.1016/j.yasu.2013.04.001 http://dx.doi.org/10.1161/circulationaha.105.166551 http://dx.doi.org/10.1111/j.1532-5415.1997.tb02963.x http://dx.doi.org/10.1136/jme.2007.020735 http://dx.doi.org/10.1136/jme.2007.020735 http://dx.doi.org/10.1136/jme.2006.016360 http://www.scfhs.org.sa/reglations/cr/uments/%25d8%25a3%25d8%25ae%25d9%2584%25d8%25a7%25d9%2582%25d9%258a%25d8%25a7%25d8%25aa%2520%25d8%25a7%25d9%2584%25d9%2585%25d9%2585%25d8%25a7%25d8%25b1%25d8%25b3%2520%25d8%25a7%25d9%2584%25d8%25b5%25d8%25ad%25d9%258a.pdf http://www.scfhs.org.sa/reglations/cr/uments/%25d8%25a3%25d8%25ae%25d9%2584%25d8%25a7%25d9%2582%25d9%258a%25d8%25a7%25d8%25aa%2520%25d8%25a7%25d9%2584%25d9%2585%25d9%2585%25d8%25a7%25d8%25b1%25d8%25b3%2520%25d8%25a7%25d9%2584%25d8%25b5%25d8%25ad%25d9%258a.pdf http://www.scfhs.org.sa/reglations/cr/uments/%25d8%25a3%25d8%25ae%25d9%2584%25d8%25a7%25d9%2582%25d9%258a%25d8%25a7%25d8%25aa%2520%25d8%25a7%25d9%2584%25d9%2585%25d9%2585%25d8%25a7%25d8%25b1%25d8%25b3%2520%25d8%25a7%25d9%2584%25d8%25b5%25d8%25ad%25d9%258a.pdf http://www.scfhs.org.sa/reglations/cr/uments/%25d8%25a3%25d8%25ae%25d9%2584%25d8%25a7%25d9%2582%25d9%258a%25d8%25a7%25d8%25aa%2520%25d8%25a7%25d9%2584%25d9%2585%25d9%2585%25d8%25a7%25d8%25b1%25d8%25b3%2520%25d8%25a7%25d9%2584%25d8%25b5%25d8%25ad%25d9%258a.pdf http://www.scfhs.org.sa/reglations/cr/uments/%25d8%25a3%25d8%25ae%25d9%2584%25d8%25a7%25d9%2582%25d9%258a%25d8%25a7%25d8%25aa%2520%25d8%25a7%25d9%2584%25d9%2585%25d9%2585%25d8%25a7%25d8%25b1%25d8%25b3%2520%25d8%25a7%25d9%2584%25d8%25b5%25d8%25ad%25d9%258a.pdf http://dx.doi.org/10.1016/j.jen.2005.06.020 http://dx.doi.org/10.1001/archinternmed.2010.322 sultan qaboos university med j, may 2015, vol. 15, iss. 2, pp. e202–206, epub. 28 may 15 submitted 9 feb 15 revision req. 19 mar 15; revision recd. 15 apr 15 accepted 16 apr 15 what’s in a name? the history of medicine is replete with eponyms saluting a scientist’s discovery of a disease. however, it is unusual that the strength of this association results in the use of a pioneer’s name for a contrasting disease. perhaps this singular distinction has been achieved through the continued use of the eponymous ‘hodgkin’ for two types of lymphomas: hodgkin and non-hodgkin. the first of this twopart tale of lymphomas is devoted to the original category, which was named hodgkin’s disease, and is today called hodgkin lymphoma (hl). it all began with a basic dilemma: was this disease an infection, inflammation or tumour? the pioneers in 1666, marcell malpighi was one of the first physicians to be credited with describing hl, observed during the autopsy of an 18-year-old female, in his publication: de viscerum structura exercitatio anatomica.1,2 centuries later, in 1832, a paper was read to the medical and chirurgical society in london, uk, on behalf of thomas hodgkin. it described seven patients with painless enlargement of the lymph nodes and included autopsy findings and illustrations from one of the patients given to the author by robert carswell.1,3 the author, thomas hodgkin (1798‒1866) of guy’s hospital, london, went on to publish a paper entitled: on some morbid cases of the absorbent glands and spleen. at this time, autopsies were an irreplaceable source of knowledge for understanding diseases; it is no wonder that in his appointment as ‘inspector of the dead’ hodgkin was an astounding contributor to the museum at guy’s hospital.4 interest in this disease grew when richard bright published observations on abdominal tumours and intumescence illustrated by cases of disease of the spleen in 1838, linking the spleen to the disease beyond its primary nodal origins.2 in 1856, samuel wilks observed similar cases and later, in 1865, published cases of lardaceous diseases and some allied affections with remarks.5 in the true spirit of peer recognition, he honoured hodgkin by eponymously referring to this disease as hodgkin’s lymphoma.6 it is notable that neither hodgkin nor wilks supported the diagnosis of this new disease by its microscopic appearance, something that would be unthinkable today when the diagnostic world demands no less proof than morphology, immunohistochemistry and, in many cases, molecular genetics. from the archival tissues of hodgkin’s original cases available today, only two were authenticated by immunophenotyping.1 in 1872 and 1878, langhan and greenfield, respectively, provided microscopic descriptions of hl; however the cells that came to typify the diagnosis, reed-sternberg (r-s) cells, were attributed to observations and illustrations made by carl sternberg in 1898 and dorothy reed in 1902.7,8 despite reed’s unique diagnostic contribution to pathology, as well as her work in distinguishing hodgkin disease from tuberculosis, reed went on to become a paediatrician. her prospects of joining the academic ranks in pathology at johns hopkins school of medicine as a woman were not in keeping with the prevailing attitudes of the time!9 microscopy, at that time, became the gold standard for diagnosis as reviews of reported cases based on macroscopy alone showed that some cases may have been caused by other lymphomas or other prevalent infections like tuberculosis or syphilis. the dramatic illustration of the bulky lymphadenopathy in a prototype soldier-patient, and the original drawings 1department of pathology, college of medicine & health sciences, sultan qaboos university; 2department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ritu@squ.edu.om قصة تارخيية عن نوعني من أورام الغدد الليمفاوية اجلزء االول: األورام اللمفاوية نوع هودجكني ريتو لكتاكيا و اإكرام بريين medical history a historical tale of two lymphomas part i: hodgkin lymphoma *ritu lakhtakia1 and ikram burney2 ritu lakhtakia and ikram burney medical history | e203 of the r-s cells by reed were sourced from an article in the annals of diagnostic pathology entitled the original illustrations of hodgkin’s disease.9,10 these images remind us of the painstaking methods adopted to preserve medical knowledge only a little over a century ago [figures 1 and 2].10–12 more than a hundred years after these microscopic recordings, generations of pathologist physicians have been avid hunters of the large cells: hodgkin, r-s or their variants. the pathology lexicon offered handy descriptors of these cells, like ‘popcorn’, ‘owl-eye’, ‘mirror-image’, ‘lacunar’ or ‘mummified’, based on nuclear configurations. at a time when cut and dried combinations of lineage-specific immunohistochemical markers and molecular genetics have become the cornerstone of haematolymphoid disease diagnosis, these time-honoured epithets have yet to be relegated to extinction. cell of origin, classifications and cause the neoplastic nature of hl was suggested by gall and mallory (1942), but scientifically grounded through cytogenetics and clonality in 1967 and 1975 by boecker, seif and their collaborators.13–15 in 1999 cossmann and colleagues, through a detailed genomic analysis, narrowed down the origin of the r-s cell to germinal centre b cell type.16 once a disease is identified, the classificationconscious scientific mind wastes no time in devising categories to separate clinically-relevant disease subsets based on appearance and outcome. in 1947, after a lag period of nearly half a century since hl came to be recognised as an entity, the first classification, the jackson and parker classification, appeared. this classification identified three groups: hodgkin’s paragranuloma, granuloma and sarcoma. paragranulomas represented cases with few atypical cells and an indolent course, granulomas described cases with usual appearance and progression, and sarcomas represented bizarre cytology and aggressive behaviour.17 lukes’ and butler’s initial classification recommended six groups: lymphocytic and/or histiocytic, nodular; lymphocytic and/or histiocytic, diffuse; nodular sclerosis; mixed; diffuse fibrosis, and reticular.18 these classifications were later streamlined to four categories: lymphocyte predominance; nodular sclerosis; mixed cellularity, and lymphocytic depletion.19 in 1994, in a dramatic immunophenotypebased approach to haematolymphoid malignancies, the revised european-american lymphoma classification separated nodular lymphocyte-predominant hl (nlphl) from classical hl (chl).20 more recently, in 2001 and 2008, the world health organization classification has endorsed a category of a lymphocyte-rich chl.21,22 much of the evolution in terminology and classification originates from gradual revelation of the lymphoma’s cell of origin. unlike most other malignancies, hl-affected nodes show an interesting admix of several types of inflammatory and lymphoid cells. in the last four decades there has been clarification in the form of the exponential growth of cluster designate (cd) markers, which identify figure 1: an original illustration of a patient with hodgkin’s disease.10,11 figure 2: dorothy reed’s drawings of what came to be referred to as reed-sternberg cells.10,12 a historical tale of two lymphomas part i: hodgkin lymphoma e204 | squ medical journal, may 2015, volume 15, issue 2 treatment: empirical to targeted in 1832, hodgkin tried to treat one of his patients with cascarilla, soda and iodine with an obvious lack of success, since this patient along with six others became the subject of an autopsy.1 in 1894, fowler’s solution, which originally contained potassium arsenite when it was concocted in 1786 by thomas fowler, demonstrated some success,26 and earned its place in osler’s textbook of medicine.2 in the 1940s, nitrogen mustard, the gas that gained notoriety for its wartime usage, was included as a therapeutic option by goodman et al., following its successful use for other haematolymphoid malignancies.27 though radiotherapy was first used for this disease in 1902,28 it was in 1932 that chevalier and bernard recommended radiotherapy for palliation.29 this became popular in the 1940s and reached a pinnacle in the 1960s.29 the important concept that hodgkin’s disease involved lymph nodes by contiguity was proposed by radiotherapists rene gilbert (switzerland) and vera peters (canada) in the 1950s, providing the opportunity to offer planned, targeted coverage to the affected nodes.28 in 1955, henry kaplan, working at stanford university medical center, used a six million volt medical linear accelerator for the first time on a child with retinoblastoma. following its success, he turned his attention to using it for hodgkin’s disease.30 his pioneering efforts with radiotherapy not only changed the cancer landscape but transformed hodgkin’s disease from invariably fatal to near-curable. the dominance of radiotherapy continued until chemotherapy entered the cancer arena and hodgkin’s disease became the ‘poster boy’ for success in cancer treatment. the ground was laid through the discoveries of individual drugs, chlorambucil and vincristine. soon enough the movement was galvanised by the concept of combination chemotherapy to achieve maximum benefit. in 1964, a four-drug combination of mustine hydrochloride, vincristine, procarbazine and prednisone (mopp) was tested at the national cancer institute. by 1970, mopp was shown to achieve cure rates of 70%, even in patients with advanced stage disease.31,32 patients lived longer, and the long-term side-effects became apparent. sterility due to procarbazine and second malignancies due to nitrogen mustard threatened to offset the gains achieved. in 1981, another four-drug combination of doxorubicin, bleomycin, vinblastine and dacarbazine (abvd), designed at the istituto nazionale dei tumori in milan, italy, relegated mopp to history.33 the cure rates were higher with abvd and the long-term antigen-based lineage of haematolymphoid cells, and gene expression profiling. thus far, the fulcrum rests on a follicular centre b cell origin for the nlphl, while the subsets of chl are linked to post-germinal centre b cells.23 it is intriguing to note that these transformed b cells have actually lost their capacity to differentiate or respond to antigenic stimuli. the attendant combination of granulocytes (neutrophils, eosinophils) confer a polymorphic microscopic cocktail. they have been attributed to the secretion of chemoattractant cytokines by the neoplastic cells. inflammation also explains the ‘b’ symptoms that often bring the patient to the hospital in the first place.24 the systematic evolution of understanding pathobiology has shaped clinicopathologic entities and outcome determination in hl, with mixed cellularity hl and lymphocyte depletion hl being the worst. current prognostication, however, relies more emphatically on the disease stage, b symptoms and concurrent association with other conditions, such as immunodeficiency.25 it is certain that the last word on classification has yet to be written, with the spectre of ‘grey-zone’ lymphomas, overlapping hl and non-hl, providing fodder for researchers.25 genome sequencing may provide new historical landmarks for future medical generations. epstein-barr virus (ebv) dna was first reported in the r-s cells of a proportion of hl cases in 1987. since 1990, the identification of ebv-encoded ribonucleotides (rnas) 1 and 2 is the gold standard for its demonstration in clinical tissues.16 the association gained further momentum from the fact that hl associated with human immunodeficiency virus infection has a high frequency of detection of ebv rnas in the r-s cells. surgery-radiology set the stage for staging an important basis of rational treatment was set in motion in the rye (1966) and ann arbor (1971) expert meetings of the committee of staging and classification of hodgkin’s disease, when staging systems and pathological categories determined treatment options and prognoses. initially, radical surgery such as splenectomy, liver biopsy and retroperitoneal lymph node sampling provided proof of infradiaphragmatic involvement. this was further expanded by lymphangiography. only a few decades later, these substantive explorations appear unnecessary and invasive, with the advent of computerised tomography (ct) scans and positron emission tomography (pet). ritu lakhtakia and ikram burney medical history | e205 side-effects were fewer. such was the success that the 10–30% failure rate was considered a major challenge. the last 30 years have seen efforts to refine treatment through the identification of prognostic factors. besides the prognostic factors at presentation,34 early metabolic response to chemotherapy assessed by pet-ct scan has changed the landscape.35 it is now possible to achieve durable responses and high cure rates through strategies such as reduction of doses, drugs and number of cycles of chemotherapy for good prognostic groups.36 on the other hand, more extensive combinations, such as bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone from the german hodgkin study group and the stanford v regimen from the eastern cooperative oncology group have helped to improve the cure rates in poor prognostic groups.37,38 even patients who do not achieve a complete remission at the end of treatment, as well as those who relapse after achieving a complete remission, still stand a chance of being cured. high-dose chemotherapy and autologous stem cell transplantation have been shown to produce lasting remissions in 10–60% of patients.39 optimisation of treatment has continued to evolve both in search of less toxic treatment for good prognostic patients and additional treatment for the poor prognostic patients. examples of history-in-the-making molecules include anti-cd20 antibody rituximab for nlphl,40 and the chemoimmunoconjugate, brentuximab vedotin, for chl and a variety of other cd 30-positive tumours.41 lessons from the history of hodgkin lymphoma the centuries stand witness to the fascinating contributions of physicians, pathologists, radiotherapists and geneticists rising to the challenge of conquering this haematolymphoid malignancy. from clinical manifestations to interesting cell appearances, they are an acknowledgement of the times when discerning physicians used basic tools of observation and analysis to define diseases. they also tell a story of unprecedented forays in cell biology (molecular genetics), opportunity (nitrogen mustard), success (radiotherapy) and cure (chemotherapy)— each a reflection of the rapid evolution in science and technology that is the hallmark of the last two centuries. it is also a promising example of the concept that many cancers are now considered curable or chronic rather than fatal diseases. this tale concludes by urging the reader to learn more about the persona, character, beliefs and global influence of thomas hodgkin, in a brilliant, personalised narrative of his life and times, delivered at his bicentennial in 1998.42 his life is epitomised by the epitaph on his grave: humani nihil a se alienum putabat (nothing of humankind was foreign to him). references 1. banerjee d. recent insights into the biology of hodgkin’s lymphoma. from: cdn.intechopen.com/pdfs-wm/33669.pdf accessed: jan 2015. 2. lymphomainfo.net. hodgkin's disease: historical timeline. from: www.lymphomainfo.net/hodgkins/timeline.html accessed: jan 2015. 3. hodgkin t. on some morbid appearances of the absorbent glands and spleen. med chir trans 1832; 17:68–114. 4. daws jj. thomas hodgkin and the museum at guy’s hospital. cancer treat rev 1999; 25:145–50. doi: 10.1053/ctrv.1998.0110. 5. hummel m. world health organization and beyond: new aspects in the pathology of an old disease. hematol oncol clin north am 2007; 21:769–86. doi: 10.1016/j.hoc.2007.06.015. 6. wilks s. cases with enlargement of the lymphatic glands and spleen (or hodgkin’s disease) with remarks. guys hosp rep 1865; 1:57. 7. sternberg c. über eine eigenartige unter dem bilde der pseudoleukämie verlaufende tuberculose des lymphatischen apparates ztschr heilk 1898; 19:21–90. 8. reed dm. on the pathological changes in hodgkin's disease, with special reference to its relation to tuberculosis. john hopkins hosp rep 1902; 10:133–96. 9. dawson pj. whatever happened to dorothy reed? ann diagn pathol 2003; 7:195–203. doi: 10.1016/s1092-9134(03)00020-0. 10. dawson pj. the original illustrations of hodgkin’s disease. ann diagn pathol 1999; 3:386–93. doi: 10.1016/s10929134(99)80018-5. 11. porter jh. two cases of hodgkin’s disease of the glands: leucocythaemia; lymphadenosis. trans path soc lond 1878; 29:335–41. 12. reed dm. on the pathological changes in hodgkin’s disease, with special reference to its relation to tuberculosis. johns hopkins hosp rep 1902; 10:113–96. 13. gall ea, mallory tb. malignant lymphoma: a clinicopathologic survey of 618 cases. am j pathol 1942; 18:381–429. 14. seif gs, spriggs ai. chromosome changes in hodgkin's disease. j natl cancer inst 1967; 39:557–70. doi: 10.1093/jnci/39.3.557. 15. boecker wr, hossfeld dk, gallmeier wm, schmidt cg. clonal growth of hodgkin cells. nature 1975; 258:235–6. doi: 10.1038/258235a0. 16. kapatai g, murray p. contribution of the epstein barr virus to the molecular pathogenesis of hodgkin lymphoma. j clin pathol 2007; 60:1342–9. doi: 10.1136/jcp.2007.050146. 17. jackson h, parker f, eds. hodgkin’s disease and allied disorders. new york, usa: oxford university press, 1974. 18. lukes rj, butler j, hicks eb. [the prognosis of hodgkin's disease according to the histologic type and the clinical stage. role of the reactions of the host]. nouv rev fr hematol 1966; 6:15–22. 19. lukes rj, butler jj. the pathology and nomenclature of hodgkin's disease. cancer res 1966; 26:1063–83. 20. harris nl, jaffe es, stein h, banks pm, chan jk, cleary ml, et al. a revised european-american classification of lymphoid neoplasms: a proposal from the international lymphoma study group. blood 1994; 84:1361–92. a historical tale of two lymphomas part i: hodgkin lymphoma e206 | squ medical journal, may 2015, volume 15, issue 2 33. bonadonna g, zucali r, monfardini s, de lena m, uslenghi c. combination chemotherapy of hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus mopp. cancer 1975; 36:252–9. doi: 10.1002/1097-0142(197507)36:1<252::aidcncr2820360128>3.0.co;2-7. 34. hasenclever d, diehl v. a prognostic score for advanced hodgkin's disease. international prognostic factors project on advanced hodgkin's disease. n engl j med 1998; 339:1506–14. doi: 10.1056/nejm199811193392104. 35. hutchings m, loft a, hansen m, pedersen lm, buhl t, jurlander j, et al. fdg-pet after two cycles of chemotherapy predicts treatment failure and progression-free survival in hodgkin lymphoma. blood 2006; 107:52–9. doi: 10.1182/ blood-2005-06-2252. 36. engert a, plütschow a, eich ht, lohri a, dörken b, borchmann p, et al. reduced treatment intensity in patients with early-stage hodgkin’s lymphoma. n engl j med 2010; 363:640–52. doi: 10.1056/nejmoa1000067. 37. diehl v, franklin j, hasenclever d, tesch h, pfreundschuh m, lathan b, et al. beacopp: a new regimen for advanced hodgkin’s disease. german hodgkin’s lymphoma study group. ann oncol 1998; 9:s67–71. doi: 10.1093/annonc/9. suppl_5.s67. 38. horning sj, hoppe rt, breslin s, bartlett nl, brown bw, rosenberg sa. stanford v and radiotherapy for locally extensive and advanced hodgkin’s disease: mature results of a prospective clinical trial. j clin oncol 2002; 20:630–7. doi: 10.1200/jco.20.3.630. 39. schmitz n, pfistner b, sextro m, sieber m, carella am, haenel m, et al. aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive hodgkin’s disease: a randomised trial. lancet 2002; 359:2065–71. doi: 10.1016/s0140-6736(02)08938-9. 40. horning sj, bartlett nl, breslin s, advani rh, hoppe rt, ekstrand bc, et al. results of a prospective phase ii trial of limited and extended rituximab treatment in nodular lymphocyte predominant hodgkin’s disease (nlphd). blood 2007; 110:644. 41. younes a, bartlett nl, leonard jp, kennedy da, lynch cm, sievers el, et al. brentuximab vedotin (sgn-35) for relapsed cd30-positive lymphomas. n engl j med 2010; 363:1812–21. doi: 10.1056/nejmoa1002965. 42. kass am. thomas hodgkin remembered. cancer treat rev 1999; 25:133–143. doi: 10.1053/ctrv.1998.0108. 21. jaffe es, harris nl, stein h, vardiman jw. world health organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. ann oncol 2002; 13:490–1. doi: 10.1093/annonc/mdf146. 22. swerdlow sh, campo e, harris nl, jaffe es, pileri sa, stein h, et al. who classification of tumours of haematopoietic and lymphoid tissues. lyon, france: iarc press, 2008. 23. mani h, jaffe es. hodgkin lymphoma: an update on its biology with newer insights into classification. clin lymphoma myeloma 2009; 9:206–16. doi: 10.3816/clm.2009.n.042. 24. allemani c, sant m, de angelis r, marcos-gragera r, coebergh jw; eurocare working group. hodgkin disease survival in europe and the u.s: prognostic significance of morphologic groups. cancer 2006; 107:352–60. doi: 10.1002/ cncr.21995. 25. harris nl. shades of gray between large b-cell lymphomas and hodgkin lymphomas: differential diagnosis and biological implications. mod pathol 2013; 26:s57–70. doi: 10.1038/ modpathol.2012.182. 26. waxman s, anderson kc. history of the development of arsenic derivatives in cancer therapy. oncologist 2001; 6:s3–10. doi: 10.1634/theoncologist.6-suppl_2-3. 27. goodman ls, wintrobe mm, dameshek w, goodman mj, gilman a, mclennan mt. nitrogen mustard therapy: use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. j am med assoc 1946; 132:126–32. doi: 10.1001/ jama.1946.02870380008004. 28. devita vt jr. a selective history of the therapy of hodgkin’s disease. br j haematol 2003; 122:718–27. doi: 10.1046/j.13652141.2003.04541.x. 29. chevalier p, bernard j. la maladie de hodgkin (lymphogranulomatose maligne). paris, france: mason et cie, 1932. 30. jacobs cd. henry kaplan and the story of hodgkin’s disease. redwood city, california, usa: stanford university press, 2010. 31. devita vt jr, serpick aa, carbone pp. combination chemotherapy in the treatment of advanced hodgkin’s disease. ann intern med 1970; 73:881–95. doi: 10.7326/0003-4819-736-881. 32. devita vt jr, simon rm, hubbard sm, young rc, berard cw, moxley jh 3rd, et al. curability of advanced hodgkin’s disease with chemotherapy: long-term follow-up of mopptreated patients at the national cancer institute. ann intern med 1980; 92:587–95. doi: 10.7326/0003-4819-92-5-587. squ med j, august 2010, vol. 10, iss. 2, pp. 249-254, epub. 19th jun 10 submitted: 3rd feb 10 revision req. 30th mar 10, revision recd. 5th may 10 accepted: 11th may 10 cholesterol granulomas (cgs) are also known as cholesterol cysts, unicameral cysts, xanthomas, or chocolate cysts of the temporal bone. they are benign, expansile, round, or ovoid cysts containing cholesterol crystals surrounded by foreign body giant cells and chronic inflammation, all contained within a thick fibrous capsule. the petrous apex is the region of the petrous pyramid bounded medially by the clivus, laterally by the inner ear, anteriorly by the carotid, and posteriorly by the dura of the posterior fossa. the petrous apex cg was not recognized as a distinct entity until the mid-1980s.1 cgs are ten times more common than cholesteatomas and forty times more common than petrous apex mucoceles.2 its occurrence in the petrous portion of the temporal bones is of particular interest because of its effect on a variety of cranial nerves and its surgically challenging location. the exact cause of cgs is unknown, but it is thought to be cause by blocked air cell tracts in well-pneumatised petrous apex spaces. as the mucosa absorbs air negative pressure, hypoxia develops, which leads to mucosal oedema, blood vessel rupture, and haemorrhage. catabolism of haemoglobin leads to the formation and accumulation of blood products such as cholesterol, fibrin, and haemosiderin. these materials subsequently induce a foreign body reaction, resulting in fibrosis, neovascularisation, and cg formation. the granuloma continues to enlarge as new vessels haemorrhage and the cycle repeats itself. mass effects of petrous apex cgs can result in a variety of symptoms such as: unilateral hearing loss, vertigo, headaches, tinnitus, facial numbness, department of otolaryngology, king saud university and king abdulaziz university hospital, riyadh, saudi arabia. email: dhagr90@yahoo.com حتسن السمع بعد استئصال الورم احلبييب الكولسرتولي من قمة العظم الصخري عن طريق استئصال جزئي للتِّيه عبد الرحمن عبد اهلل حجر األعصاب �شعف اأعرا�س مع ال�شخري العظم قمة يف كول�شرتويل حبيبي ورم من يعاين كان 57 عاما عمره رجل حالة هنا نقدم امللخ�ص: نتج عن هذا حتسن وظيفة األعصاب القحفية ومنها عمل الوجه. مت إختيار التدخل اجلراحي إلستئصال الورم عبر التيه. القحفية وصمم األذن اليسرى. كما حتسن السمع في األذن املصابة في غضون ثالثة أشهر بعد اجلراحة. لم يشهد املريض أية مضاعفات بعد اجلراحة. نستنتج أنه ميكن استخدام التدخل اجلراحي إلستئصال الورم احلبيبي الكولسترولي عبر التيه مع إحتمال حتسن السمع. كلمات البحث: التيه ؛ �شمع ؛ كول�شرتول ؛ ورم حبيبي ؛ تقرير حالة ؛ اململكة العربية ال�شعودية. abstract: we present the case of a 57 year-old male presenting with symptomatic petrous apex cholesterol granuloma, multiple cranial nerve weaknesses and deafness of the left ear. the chosen intervention was a cholesterol granuloma resection via the translabyrinthine approach. this resulted in cranial nerve recovery and improved facial functionality. hearing in the operated ear improved within 3 months after surgery. the patient experienced no postoperative complications. we conclude that a translabyrinthine approach can be used for drainage of petrous apex cholesterol granulomas with a chance of hearing loss recovery keywords: labyrinth; hearing; cholesterol; granuloma; case report; saudi arabia hearing improvement after partial labyrinthectomy resection of petrous apex cholesterol granuloma abdulrahman a hagr case report hearing improvement after partial labyrinthectomy resection of petrous apex cholesterol granuloma 250 | squ medical journal, august 2010, volume 10, issue 2 diplopia, and cranial nerve deficits. as the lesions enlarge, signs of cerebellopontine compression can be seen. differential diagnoses of a petrous apex cg include: cholesteatoma, mucocele, chordoma, petrous apicitis, metastasis, and epidermoid cysts. thus, accurate preoperative diagnosis of petrous apex lesions is critical, because the surgical approaches used for this region vary depending on the specific disease process involved. it is best diagnosed by magnetic resonance imaging (mri). partial labyrinthectomy, where only the semicircular canals are drilled without opening of the vestibule, is one option for draining large cg at the petrous apex with hearing preservation. to our knowledge, this case is the first report on improvement in hearing after translabyrinthine surgery for a cg. case report a 57 year-old man presented at king abdulaziz university hospital, riyadh, saudi arabia, with a five-month history of progressive left-sided hearing loss, facial weakness, and numbness. seven months before presentation to our institution, he had undergone subtotal excision and decompression of the cg via a middle fossa approach, which was performed by another surgeon. he had no history of tinnitus, vestibular dysfunction, or middle ear disease. on examination, both ears appeared normal, but left-side grade vi facial weakness (according to the house-brackmann scale) was observed. an audiogram showed severe sensorineural hearing loss in the left ear [figure 1]. a computed tomography (ct) scan revealed extensive erosion of the petrous bone [figure 2]. magnetic resonance imaging (mri) showed that the lesion was hyperintense on both pre-contrast and post0 10 0 0-10 125 250 60 55 55 55 55 40 50 50 75 .5 .75 1 1.5 2 3 4 6 8 12 16 30 40 20 60 70 50 90 100 80 120 110 0 10 0 0-10 125 250 60 55 55 55 55 40 50 50 75 .5 .75 1 1.5 2 3 4 6 8 12 16 30 40 20 60 70 50 90 100 80 120 110 right ff1 db db left ff1 figure 1: preoperative audiogram documenting sensorineural hearing loss in the patient’s left ear. figure 2: axial computed tomography scan of the temporal bone demonstrating a well-defined expansile lesion in the left temporal bone isodense to brain tissue abdulrahman a hagr case report | 251 contrast t1as well as t2-weighted images [figure 3]. we planned a translabyrinthine as well as transcochlear approach for wide excision and drainage of the lesion in view of the hearing loss. a facial nerve monitor was set in place, and a partial labyrinthectomy approach was done where the lateral, posterior and superior semicircular canals are drilled, but the vestibule was left undisturbed. drilling was continued until the gelatinous bluebrown mass was identified. when the mass was opened, it oozed the typical thick, viscous, brownish fluid, which had a characteristic sheen to it. we had wide access to the petrous apex and were able to excise the lesion. thus, the transcochlear approach that was part of the intervention plan was not necessary. the window in the labyrinth was left open for drainage of the petrous apex. no complications or adverse consequences of the petrous apex surgery (e.g. postoperative headache, cerebrospinal fluid leak, and meningitis) were noted. in fact, immediately after the surgery, the patient noticed improved facial functionality, which further improved over time. three months after the operation, the patient reported improved hearing in the operated ear. ear examination revealed an intact tympanic membrane and the weber response lateralised to the operated ear. his audiogram, with masking of air and bone, showed only moderate mixed hearing loss in the operated ear [figure 4]. discussion cholesterol granulomas cannot usually be detected by otoscopic evaluation, and it is difficult to diagnose them before the operation without appropriate imaging. while ct and mri scans have improved the accuracy of preoperative diagnosis of petrous apex pathology, these imaging techniques are most helpful when used in combination. when systematically applied, the combination of contrast ct and mri (with or without gadolinium) permits a narrowing of the extensive differential diagnosis. ct scans of cgs typically show a well-defined, sharply marginated, non-enhancing expansile mass that breaks down the septate structure of the pneumatised petrous apex. it has a density similar to that of brain tissue and it is frequently limited to the petrous apex. remodeling and erosion of the bone can occur. while ct scanning can provide superior evaluation of the bony structures of the temporal bone, mri scanning can aid in the detection of intracranial extension and the involvement of adjacent structures, such as the carotid artery and sigmoid sinus. cg is often unique and diagnostic on figures 3a & 3b: a: magnetic resonance imaging (mri) (t1-weighted) image showing the mass (arrows) to be hyperintense in signal, which is characteristic for cholesterol granulomas (cgs). b: t2-weighted mri scan showing high-signal lobulated masses in the petrous apex compatible with cgs. hearing improvement after partial labyrinthectomy resection of petrous apex cholesterol granuloma 252 | squ medical journal, august 2010, volume 10, issue 2 mri, showing hyperintense t1and t2-weighted images and lacking enhancement with gadolinium infusion, as seen in our patient. moreover, postoperative mri can help in the verification of complete removal of the cg and in the evaluation of complications, as well as recurrence or formation of complicating granulation tissue. in our case, the high-signal characteristics of the cg within the petrous apex allowed reliable distinction of this lesion from other deferential diagnoses. in general, management of cgs includes surgical draining and permanent aeration of the air cell. it is believed that total removal is not necessary in all cases due to the lack of epithelial lining. therefore, the management of cgs is dictated by the location of the lesion relative to adjacent neurovascular structures in the temporal bone, complications, and recurrence, as well as the status of the patient’s hearing. since cgs usually arise in extensively pneumatised temporal bones, several welldeveloped possible access routes usually exist, and many approaches have been used successfully. if hearing is to be preserved, the infra-labyrinthine, infra-cochlear trans-sphenoidal, and middle cranial fossa approaches are the main non-invasive routes. most commonly, the infra-labyrinthine and infra-cochlear approaches are used by otologists. however, recurrences are not uncommon, and may occur in up to 60% of cases, which may require further revision.3 these recurrences may be related to closure of the surgically created tract with new bone formation, granulation tissue, or fibrosis, or may be secondary to obstruction of a surgically placed drainage catheter. although the translabyrinthine approach provides the most direct route and wide exposure for aeration from the mastoid through the surgical defect to the petrous apex, it has previously been considered to be incompatible with hearing preservation and was only used in cases where hearing and vestibular function were absent. however, most patients with cgs have excellent hearing. in this case, a partial labyrinthectomy approach with hearing preservation was used; it is interesting to note that this is led to improvement in hearing after this surgical procedure. in patients with large and multi-loculated petrous apex cgs, there may be extensive critical structure involvement, including the cranial nerve, brain, jugular foramen, carotid canal, and internal auditory canal. in this subset of patients, it may be impossible to remove the cg without wide drainage from multiple access routes, which was the planned approach in our patient, with translabrynthine, as well as transcochlear, approaches. this approach was used because our patient did not meet the well-accepted gardner-robertson preoperative 0 10 0 0-10 .125 .250 .5 .75 1 1.5 2 3 4 6 8 12 16 30 40 20 60 70 50 90 100 80 120 110 0 10 0 0-10 .125 .250 60 55 55 55 55 40 50 50 75 .5 .75 1 1.5 2 3 4 6 8 12 16 30 40 20 60 70 50 90 100 80 120 110 right ff1 db db left ff1 figure 4: postoperative audiogram demonstrating mixed hearing loss on the patient’s operative side. abdulrahman a hagr case report | 253 criteria of the “50/50 rule” for useful hearing, in which subjects with pure-tone audiometry > 50 db and speech discrimination score < 50% are not candidates for hearing preservation. in a previous report in 1991, mcelveen et al.4 modified the traditional translabyrinthine approach for removal of an intracanalicular acoustic schwannoma by sealing the vestibule with bone wax, which allowed hearing function to be preserved in one patient. two years later, the authors reported two cases in which the same technique was used,5 but few other authors have managed to obtain similar results in case reports.6,7 moreover, case series were reported with hearing preservation in all patients8,9 or in some patients.10,11 in these reports, partial labyrinthectomy approaches were used for different lesions at the petrous apex or the cerebellopontine angle. our case is unique because there was marked improvement in inner ear function after partial labyrinthectomy. although our patient was followed up for a short time after surgery, the partial labyrinthectomy approach has been shown to maintain serviceable hearing for a long time.12,13,14 we propose two theories to explain the recovery of hearing observed in our patient, namely, neurovascular compression and ototoxicity. first, it is possible that our patient experienced compression of the arterial or nerve supply to the cochlear, which resulted in transient ischemia or neuropraxia, respectively; this had not yet progressed to irreversible wallerian degeneration. second, toxins from the cg are another theoretical cause of this transient hearing loss, as similar recovery of hearing was also reported with acoustic neuroma after middle fossa tumor resection.15 this case report is instructive in that many otologists would consider hearing to be irretrievably lost, on the basis of the preoperative audiogram, and may thus plan a wide translabyrinthine or transcochlear approach. this case illustrates that a partial labyrinthectomy approach may actually result in recovery of hearing, which is a useful functional result. we therefore believe that this case report is an important contribution to the literature. conclusion partial labyrinthectomy is an option for petrous apex lesion and we recommend consideration of this approach for extensive petrous apex lesions, or for access to the cerebellopontine angle, even in the presence of moderate to severe hearing loss. acknowledgments the author would like to thank the research chair for hearing disability (rchd) at king saud university, riyadh, for its support. references 1. graham md, kemink jl, latack jt, kartush jm. the giant cholesterol cyst of the petrous apex: a distinct clinical entity. laryngoscope 1985; 95:1401–6. 2. arriaga ma, brackmann de. differential diagnosis of primary petrous apex lesions. am j otol 1991; 12:470–4. 3. eisenberg mb, haddad g, al mefty o. petrous apex cholesterol granulomas: evolution and management. j neurosurg 1997; 86:822–9. 4. mcelveen jt jr, wilkins rh, erwin ac, wolford rd. modifying the translabyrinthine approach to preserve hearing during acoustic tumour surgery. j laryngol otol 1991; 105:34–7. 5. mcelveen jt jr, wilkins rh, molter dw, erwin ac, wolford rd. hearing preservation using the modified translabyrinthine approach. otolaryngol head neck surg 1993; 108:671–9. 6. rizvi ss, goyal rn. case report and discussion of hearing preservation after translabyrinthine excision of small acoustic tumors. am j otol 1999; 20:249– 52. 7. smith pg, bigelow dc, kletzker gr, leonetti jp, pugh bk, mishler et. hearing preservation following a transtemporal resection of an acoustic schwannoma: a case report. am j otol 1993; 14:434–6. 8. hirsch be, cass sp, sekhar ln, wright dc. translabyrinthine approach to skull base tumors with hearing preservation. am j otol 1993; 14:533– 43. 9. vrabec jt, lambert pr, arts ha, ruth ra. promontory stimulation following translabyrinthine excision of acoustic neuroma with preservation of the cochlear nerve. am j otol 1995; 16:643–7. 10. magliulo g, parrotto d, stasolla a, marini m. modified translabyrinthine approach and hearing preservation. laryngoscope 2004; 114:1133–8. 11. hong sj, lee jh, jung sh, park ch, hong sm. can cochlear function be preserved after a modified translabyrinthine approach to eradicate a huge cholesteatoma extending to the petrous apex? eur arch otorhinolaryngol 2009; 266:1191–7. hearing improvement after partial labyrinthectomy resection of petrous apex cholesterol granuloma 254 | squ medical journal, august 2010, volume 10, issue 2 12. springborg lk, springborg jb, thomsen j. hearing preservation after classical translabyrinthine removal of a vestibular schwannoma: case report and literature review. j laryngol otol 2007; 121:76–9. 13. tringali s, ferber-viart c, gallego s, dubreuil c. hearing preservation after translabyrinthine approach performed to remove a large vestibular schwannoma. eur arch otorhinolaryngol 2009; 266:147–50. 14. tringali s, bertholon p, chelikh l, jacquet c, prades jm, martin c. hearing preservation after modified translabyrinthine approach performed to remove a vestibular schwannoma. ann otol rhinol laryngol 2004; 113:152–5. 15. shelton c, house wf. hearing improvement after acoustic tumor removal. otolaryngol head neck surg 1990; 103:963–5. sir, recurrent laryngeal nerve (rln) paralysis is a devastating complication after thyroid surgery. although the incidence has decreased from 17% to as low as 1.5% with evolution of surgical technique, it still remains high in cases involving re-exploration, malignancy, radiation exposure, and large goitres.1 some of the important causes of rln injury during thyroid surgery are application of excessive stretch, pressure, suction, electrocautery and ischaemia which may go unnoticed during surgery. symptoms of rln palsy are dysphonia, dysphagia, aspiration, voice alteration and life threatening dyspnoea from airway obstruction.1,2 thus, although the incidence of permanent paresis of the rln after thyroidectomy is low, it can have serious consequences and is of significant medicolegal importance. it is therefore vitally important that during the perioperative period both the anaesthesiologist and the surgeon assess the vocal cord function (vcf) of a patient undergoing thyroidectomy. preoperative indirect laryngoscopy by an otolaryngologist is a simple examination to know the base line vcf.3 similarly, intraoperative neuromonitoring (ionm) is used to localise the rln and prevent impending rln injury during the surgical instrumentation.4 finally, direct laryngoscopy after tracheal extubation can assess the vcf immediately after surgery and rule out the risk of acute airway compromise.3 there is no uniform opinion about the constant question whether laryngoscopy at the end of thyroid surgery is an essential standard or just an unnecessary routine. the answer might depend on the specific hospital protocol and the presence of factors related to the gland itself which increase the risk of rln injury.3 our hospital is a tertiary care referral center and we regularly do difficult thyroid surgeries which include malignancy, big thyroid with retrosternal extension; we also redo thyroidectomy for recurrent nodule or goitre. assessment of vcf is routinely done after these surgeries and our surgeons expect to be provided with the results. the glidescope®, which has recently become a very important piece of equipment in the anaesthesiologist's armamentarium, is a videolaryngoscope. this has a digital camera incorporated into the blade which displays a view of the vocal cords (vcs) on a monitor.5 recently, we have started using a glidescope® to look at the post-extubation vcf after thyroid surgery and found it very advantageous. its exaggerated blade curvature and camera with enhanced optics placed at the inflection point of the blade gives a better magnified view with a larger viewing angle of the glottis even without the proper alignment of the oral and tracheal axis. therefore, the glidescope®, compared to a conventional laryngoscope, requires less forceful displacement of the tongue and less forceful manipulation of the larynx while attempting to view the vcs.5,6 the above features make the glidescope® much more suitable for proper assessment of post-operative vcf when the patient is recovering from the neuromuscular blocker and general anaesthetics and can resist the use of airway instrumentation. a reduced amount of airway manipulation will have lesser systemic side effects such as hypertension, tachycardia, cough, laryngospasm, increased intra-cranial and intraocular pressure. similarly, the risk of disruption to skin sutures in the neck, or bleeding due to laryngeal squ med j, november 2011, vol. 11, iss. 4, pp. 527-528, epub. 25th oct 11 submitted 26th may 11 revision req. 5th sep 11, revision recd. 10th sep11 accepted 26th sep 11 جهازا لرؤيا املنزلق لتقييم سالمة الَعَصُب احلَْنَجريِيُّ ع بعد جراحة الغدة الدرقية الرَّاجيِ glidescope® for assessment of recurrent laryngeal nerve integrity after thyroid surgery letter to editor glidescope® for assessment of recurrent laryngeal nerve integrity after thyroid surgery 528 | squ medical journal, november 2011, volume 11, issue 4 manipulation will also be reduced.5 in addition to patient safety, the glidescope® provides clearer visualisation of the vcs compared to a conventional laryngoscope. its video screen can be shared with other physicians in the operating theatre including the surgeon.6 in addition to confirming the vcf with the surgeon, capturing a video of vc movement can be very useful for documentation purposes. also, in the case of any vcf abnormality, it can be treated as a baseline evaluation for future follow-ups. in patients with established difficult airway, the glidescope® may be the only way to visualise the vcs during intubation and after extubation if a fibreoptic bronchoscope is not available.5,7 in summary, although further randomised clinical trials are required, the glidescope® looks to be a better and safer choice for assessment of post-extubation vocal cord function after thyroid surgery compared to a conventional laryngoscope. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest and are in no way influenced by the manufacturers of any equipment mentioned in this letter. *qutaiba a. tawfic,1 pradipta bhakta,1 pragyandipta mishra,2 mooyad a. ahmed1 1department of anaesthesia & icu, sultan qaboos university hospital, muscat, oman. 2college of medicine, university of florida, jacksonville, usa. *corresponding author email: drqutaibaamir@yahoo.com references 1. randolph gw. surgical anatomy of the recurrent laryngeal nerve. in: randolph gw, ed. surgery of the thyroid and parathyroid glands. philadelphia, pa: elsevier science, 2002. pp. 300–42. 2. shindo m, chheda nn. incidence of vocal paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy. arch otolaryngol head neck surg 2007; 133:481–5. 3. schlosser k, zeuner m, wagner m, slater ep, domínguez fernández e, rothmund m, et al. laryngoscopy in thyroid surgery--essential standard or unnecessary routine? surgery 2007; 142:858–64. 4. chiang fy, lee kw, chen hc, chen hy, lu ic, kuo wr, et al. standardization of intraoperative neuromonitoring of recurrent laryngeal nerve in thyroid operation. world j surg 2010; 34:223-229. 5. rai mr, dering a, verghese c. the glidescope system: a clinical assessment of performance. anaesthesia 2005; 60:60–4. 6. asai t, murao k, shingu k. training method of applying pressure on the neck for laryngoscopy: use of a videolaryngoscope. anaesthesia 2003; 58:602–3. 7. tawfic qa, burad j. the glidescope® for tracheal intubation in patients with grade iv modified cormack and lehane. eur j anaesthesiol 2010; 27:668–70. departments of 1ear, nose & throat and 3radiology, al nahdha hospital, muscat, oman; 2department of paediatrics, nizwa hospital, nizwa, oman; 4department of histopathology, khoula hospital, muscat, oman *corresponding author’s e-mail: salsheibani@gmail.com ورم الغدة اللعابية األنفبلعومية البدائي سبب نادر لالضطراب التنفسي الوليدي �شاملة حممد ال�شيباين، كريان �شوارديكار، �شلوى جعفر حبيب، حنينه حممد الكندي abstract: a salivary gland anlage tumour (sgat) is a very rare type of benign tumour that usually presents in early infancy with respiratory distress which is exacerbated upon feeding. we report a full-term male neonate who was referred to the al nahdha hospital, muscat, oman, in 2015 with severe neonatal respiratory distress due to a nasopharyngeal obstruction immediately after birth. computed tomography and magnetic resonance imaging revealed a well-circumscribed mass in the nasopharynx, without intracranial extension. histopathological analysis of the lesion confirmed a diagnosis of sgat. following excision of the tumour, the postoperative period was uneventful. no recurrence was observed over the next two years. this case report highlights the importance of the early recognition of this extremely rare and potentially life-threatening, yet easily curable, condition. keywords: nasopharyngeal neoplasms; salivary gland neoplasms; neonatal respiratory distress syndrome; case report; oman. على املبكرة الطفولة يف يظهر ما عادة الذي احلميدة الأورام من جدا نادر نوع هو البدائي الأنفبلعومية الغدداللعابية ورم امللخ�ص: عام يف ُعمان، م�شقط، النه�شة، م�شت�شفى اإىل اإحالته مت ذكر مكتمل وليد حالة تقريرعن هذا التغذية. عند تتفاقم تنف�شية �شائقة �شكل بالرنني والت�شوير املقطعي الت�شوير وك�شف مبا�رضًة. الولدة بعد الأنفي البلعوم ان�شداد ب�شبب �شديدة تنف�شية ب�شائقة لأ�شابته 2015 املغناطي�شي وجود كتلة حمددة جيدا يف البلعوم الأنفي، دون امتداد داخل اجلمجمة. واأكد حتليل الأن�شجة املر�شية بعد ا�شتئ�شال الكتلة ت�شخي�ض ورم الغدد اللعابية الأنف بلعومية البدائي. كانت فرتة ما بعد اجلراحة هادئة. وقد لوحظ عدم تكرار الورم على مدى عامني من املتابعه. ي�شلط تقرير احلالة هذا ال�شوء على اأهمية الت�شخي�ض املبكر لهذا ال�شبب النادر للغاية ملتالزمة ال�شائقة التنف�شية الوليدية والذي ُيحتمل اأن يهدد احلياة ، ولكنه �شهل ال�شفاء. الكلمات املفتاحية: الأورام الأنف بلعومية؛ اأورام الغدد اللعابية؛ متالزمة ال�شائقة التنف�شية الوليدية؛ تقرير حالة؛ عمان. nasopharyngeal salivary gland anlage tumour a rare cause of neonatal respiratory distress *salma m. al-sheibani,1 kiran p. sawardekar,2 salwa j. habib,3 hunaina m. al-kindi4 sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e211–214, epub. 9 sep 18 submitted 26 dec 17 revision req. 6 feb 18; revision recd. 11 feb 18 accepted 8 mar 18 case report doi: 10.18295/squmj.2018.18.02.015 as human infants are obligate nasal breathers, any nasal or nasopharyngeal obstruction during early infancy can be life-threatening. such obstructions may be due to congenital malformations, inflammatory conditions, infectious diseases or neoplastic or hamartomatous entities.1 neonates may present with symptoms of nasal discharge, feeding and sleeping difficulties, cyanosis, noisy breathing, respiratory distress or sudden choking.1,2 a salivary gland anlage tumour (sgat) is a very rare benign lesion which usually presents in early infancy with respiratory distress and feeding difficulties.2,3 other symptoms include facial plethora, intermittent apnoea, nasal discharge and epistaxis, which can occur even after gentle nasal manipulation. rarely, coughing and sudden choking may occur due to the dislodgement of the mass; this is sometimes followed by the expulsion of the mass, thus relieving the breathing difficulties.2,3 according to the 2017 world health organization classification of head and neck tumours, sgat is one of the three types of epithelial tumour unique to the nasopharynx.4 to date, more than 30 cases of sgat have been reported in the literature.2,3,5–10 to the best of the authors’ knowledge, this is the first reported case of neonatal sgat from oman. case report a full-term male neonate was born at a district hospital in al-dakhiliyah governorate, oman, in 2015 by vacuum-assisted vaginal delivery. there was no history of antenatal problems or polyhydramnios. the apgar scores at one and five minutes were 7 and 9, respectively. immediately after birth, the neonate developed severe respiratory distress, at which point he was referred to the neonatal intensive care unit of nizwa hospital, nizwa, oman. he maintained a nasopharyngeal salivary gland anlage tumour a rare cause of neonatal respiratory distress e212 | squ medical journal, may 2018, volume 18, issue 2 peripheral blood oxygen saturation of 90% with 3 l of oxygen delivered via nasal catheter. a detailed head and neck assessment did not reveal any abnormalities or features of a craniofacial syndrome and there was no evidence of stridor. anterior rhinoscopy did not reveal any abnormalities. a suction catheter (size 8fg) could be inserted through the left choana; however, attempts to insert the catheter through the right nasal aperture resulted in epistaxis and progressive respiratory distress requiring intubation and ventilation. subsequently, the patient was referred for further evaluation to the al nahdha hospital in muscat, oman. fibreoptic nasopharyngoscopy revealed a large nasopharyngeal mass completely occluding the right choana, while the left one was patent. contrast computed tomography (ct) of the nasopharynx revealed a heterogeneous midline nasopharyngeal mass measuring 37 x 25 x 32 mm. it extended into the right nasal cavity through the right choana, without any signs of bony destruction. magnetic resonance imaging (mri) showed a welldefined lobulated heterogeneous mass occupying the entire nasopharynx and extending into the right nasal cavity. there was no intracranial or parapharyngeal space extension. in comparison to the brain parenchyma, the mass was iso-to-hypointense on t2weighted and mildly hyperintense on t1-weighted images [figure 1]. an endoscopic assessment confirmed that a firm mass attached to the posterior edge of the nasal septum was completely blocking the right choana and nasopharynx. the mass was completely excised and extracted via the oral cavity. a ruptured blood vessel at the posterior edge of the septum was cauterised. the excised mass was 2.5 x 3.5 cm in size with a smooth nodular surface [figure 2]. a histological examination of the mass confirmed microscopic features of sgat [figures 3 and 4]. overall, the outcome of the excision was excellent. the postoperative period was uneventful and there were no signs of recurrence at a two-year follow-up appointment. discussion in 1979, stillwater et al. reported a newborn with a squamous cell proliferative lesion of the nasopharynx.11 subsequently, har-el et al. described a case of congenital pleomorphic adenoma in 1985.12 figure 1: magnetic resonance imaging of the nasopharynx of a full-term male neonate. a: sagittal t2weighted image showing an iso-to-hypointense mass occupying the entire nasopharynx (arrow) and extending to the nasal cavity (arrowhead). b: post-contrast axial t1-weighted image showing a well-demarcated mildlyenhancing heterogeneous mass occupying the entire nasopharynx (arrow). figure 3: haematoxylin and eosin stains at (a) x100 magnification showing a non-keratinising squamous mucosa and (b) at x200 magnification showing an admixture of epithelial groups of duct-like structures and rounded ovoid-to-spindle-shaped cells. figure 4: immunohistochemistry panel at x200 magnification showing positivity for (a) epithelial membrane antigen, (b) cytokeratin ae1/ae3, (c) protein 63 and (d) focal glial fibrillary acidic protein. figure 2: gross photograph of the excised mass. salma m. al-sheibani, kiran p. sawardekar, salwa j. habib and hunaina m. al-kindi case report | e213 both of these entities bore striking histological similarities to sgat.11,12 dehner et al. first coined the current terminology in their description of nine infants with sgat.13 in eight cases, a simple excision of the mass was performed; however, in one case, the mass was spontaneously expelled from the mouth as a result of resuscitative efforts after the infant had gone into respiratory arrest. in all cases, the mucosal surface of the tumour showed features of a budding non-keratinised squamous epithelium with focal ulcerations and a central compact multinodular mesenchyme.13 the submucosal zone consisted of cyli ndrical branching duct-like structures with nests of squamous cells and cysts within a hypocellular stroma of varying thickness. it was continuous with the surface epithelium and extended into the septal zones of the mesenchyme.13 the mesenchyme consisted of densely cellular fascicles of ovoid-to-spindle-shaped cells, with smooth muscle histological and histochemical features; these constituted 50–75% of the entire volume of the mass.13 based on its histological features, dehner et al. claimed that sgat resembles the phase of salivary gland development in which the embryonic ectoderm/ endoderm proliferates into the underling mesenchyme.13 the lesion arises from the nasopharyngeal midline and is tethered by a short thin friable pedicle to either the posterior aspect of the nasal septum, the palate or the nasopharyngeal wall.13–15 in the current case, it was attached to the posterior edge of the septum. overall, sgat has a strong male preponderance.2,5,7,13 boccon-gibod et al. reported a male neonate with sgat in whom the pedunculated mass protruded into the upper part of the oesophagus, completely obstructing both choanae, with a sharp border between the base of the skull and the mass on mri imaging.14 bondeson et al. reported a newborn boy with sgat.15 a clinical examination indicated the presence of a polypoid mass which filled the nasopharynx and protruded one cm below the soft palate. subsequently, a transpalatal exploration procedure with division of the soft palate revealed that the lesion was attached to the posterior edge of the nasal septum by a thin pedicle.15 the tumour was removed without difficulty.15 radhakrishnan et al. reported a case of sgat secondary to polyhydramnios which was detected in utero via fetal mri; a postnatal ct scan confirmed the diagnosis and the lesion was resected when the infant was four days old.9 martin et al. reported a case of sgat in a two-week-old female infant presenting with meningitis.10 a ct scan revealed a homogeneously-enhancing mass within the left nasal cavity, extending through the cribriform plate into the anterior cranial fossa. an mri confirmed the intracranial extension of the mass into the olfactory recess.10 vranic et al. reported a case of sgat in a 12-month-old infant who presented with intermittent airway obstruction and otitis media with bilateral middle ear effusion.8 cytogenetic analysis did not reveal trisomy 12 and 1p deletion—as observed in cases of sinonasal teratocarcinosarcoma—as such, the authors concluded that sgat is a hamartoma rather than a neoplasm.8 this hypothesis is also supported by the midline location, limited growth potential and immunohistopathological features of sgat which resemble those of the embryonic salivary glands.7 the evaluation of neonatal nasal obstruction requires a comprehensive systematic approach.1 a maternal history should include the medications used during pregnancy and any screening for infectious diseases, especially chlamydia, gonorrhoea and syphilis. a comprehensive family history of congenital, developmental or syndromic abnormalities should also be obtained. the birth history may also indicate potential causes of iatrogenic nasal obstruction.1 finally, the physical examination should include an evaluation of associated congenital syndromes that may warrant consultation with a geneticist. anterior rhinoscopy may reveal a deviated septum due to birth trauma, nasal pyriform aperture stenosis, mucosanguinous rhinorrhoea with thick or bloody nasal discharge indicative of congenital syphilis or chlamydia, but very rarely a nasal mass. cohen et al. suggested that it might be prudent for physicians to place their index finger in the oropharynx when inserting a flexible catheter so as to evaluate choanal patency, rule out choanal atresia and identify and dislodge foreign bodies or masses before they cause an unexpected life-threatening obstruction.2 congenital midline masses such as dermoid cysts, nasal gliomas and encephaloceles may have intracranial extension; hence, a biopsy should not be performed before imaging.1 lymphovascular malformations tend to occur more commonly in other head and neck regions in comparison to the nasal cavity.5 malignant neoplasms such as rhabdomyosarcomas, neuroblastomas, chloromas, lymphomas and langerhans cell histiocytosis are extremely rare in neonates and are more commonly seen in older infants and children.6 a fibre optic examination can help in visualising these lesions in the posterior choanae and nasopharynx. contrast ct and/or mri scans are invaluable in delineating the size of a nasopharyngeal mass and defining its characteristics and relationship to surrounding structures.9 in the present case, the nasopharyngeal salivary gland anlage tumour a rare cause of neonatal respiratory distress e214 | squ medical journal, may 2018, volume 18, issue 2 midline location of the mass and the absence of calcium, fat or fluid signal components were strongly suggestive of sgat. a nasopharyngeal teratoma was ruled out due to the lack of distortion of the osseous structures of the skull base or intracranial extension; moreover, there were no foci of high-signal intensity on the t1-weighted images.9 a dermoid was also excluded from the differential diagnosis as there was no relation between the mass and the lateral nasal wall or turbinates and no high-signal intensities on the t1weighted images indicative of fat. most cases of sgat have an excellent outcome, with no cases of recurrence after excision reported to date.7,14 conclusion sgat is a very rare but treatable cause of neonatal respiratory distress. simple excision of the lesion results in an excellent outcome for the patient, with no recurrence reported to date. this entity should be considered in the differential diagnosis of a nasopharyngeal mass presenting in the neonatal period. references 1. gnagi sh, schraff sa. nasal obstruction in newborns. pediatr clin north am 2013; 60:903–22. doi: 10.1016/j.pcl.2013.04.007. 2. cohen eg, yoder m, thomas rm, salerno d, isaacson g. congenital salivary gland anlage tumor of the nasopharynx. pediatrics 2003; 112:e66–9. 3. swayampakula ak, ischander m, zuppan cw, krishnan m, tong k, qureshi s. newborn with congenital salivary gland anlage tumor presenting with respiratory distress. int j pediatr otorhinolaryngol extra 2015; 10:42–4. doi: 10.1016/j.pedex.20 15.03.003. 4. stelow eb, wenig bm. update from the 4th edition of the world health organization classification of head and neck tumours: nasopharynx. head neck pathol 2017; 11:16–22. doi: 10.1007/s12105-017-0787-0. 5. tinsa f, boussetta k, bousnina s, menif k, nouira f, haouet s et al. congenital salivary gland anlage tumor of the naso pharynx. fetal pediatr pathol 2010; 29:323–9. doi: 10.3109/15 513811003796961. 6. mogensen ma, lin ac, chang kw, berry gj, barnes pd, fischbein nj. salivary gland anlage tumor in a neonate presenting with respiratory distress: radiographic and pathologic correlation. ajnr am j neuroradiol 2009; 30:1022–3. doi: 10.31 74/ajnr.a1364. 7. gauchotte g, coffinet l, schmitt e, bressenot a, hennequin v, champigneulle j, et al. salivary gland anlage tumor: a clinicopathological study of two cases. fetal pediatr pathol 2011; 30:116–23. doi: 10.3109/15513815.2010.524690. 8. vranic s, caughron sk, djuricic s, bilalovic n, zaman s, suljevic i, et al. hamartomas, teratomas and teratocarcinosarcomas of the head and neck: report of 3 new cases with clinico-pathologic correlation, cytogenetic analysis, and review of the literature. bmc ear nose throat disord 2008; 8:8. doi: 10.1186/1472-6815-8-8. 9. radhakrishnan r, calvo-garcia ma, lim fy, elluru rg, koch bl. congenital salivary gland anlage tumor: in utero and postnatal imaging. pediatr radiol 2015; 45:453–6. doi: 10.1007/s00247014-3113-y. 10. martin je, tessema b, beshai b, balarezo f. congenital salivary gland anlage tumor: an unusual anterior skull base mass in the neonatal period. pediatr neurosurg 2017; 52:185–8. doi: 10.11 59/000464296. 11. stillwater lb, fee we jr. squamous cell proliferative lesion of the nasopharynx in a newborn. otolaryngol head neck surg (1979) 1980; 88:240–7. doi: 10.1177/019459988008800310. 12. har-el g, zirkin hy, tovi f, sidi j. congenital pleomorphic adenoma of the nasopharynx (report of a case). j laryngol otol 1985; 99:1281–7. doi: 10.1017/s0022215100098546. 13. dehner lp, valbuena l, perez-atayde a, reddick rl, askin fb, rosai j. salivary gland anlage tumor (“congenital pleomorphic adenoma”): a clinicopathologic, immunohistochemical and ultrastructural study of nine cases. am j surg pathol 1994; 18:25–36. doi: 10.1097/00000478-199401000-00003. 14. boccon-gibod la, grangeponte mc, boucheron s, josset pp, roger g, berthier-falissard ml. salivary gland anlage tumor of the nasopharynx: a clinicopathologic and immunohistochemical study of three cases. pediatr pathol lab med 1996; 16:973–83. doi: 10.1080/15513819609168721. 15. bondeson l, andreasson l, olsson m, rausing a. salivary gland anlage tumor: cytologic features in a case examined by fine-needle aspiration. diagn cytopathol 1997; 16:518–21. doi: 10.1002/(sici)1097-0339(199706)16:6<518::aid-dc9>3.0. co;2-5. https://doi.org/10.1016/j.pcl.2013.04.007 https://doi.org/10.1016/j.pedex.2015.03.003 https://doi.org/10.1016/j.pedex.2015.03.003 https://doi.org/10.1007/s12105-017-0787-0 https://doi.org/10.3109/15513811003796961 https://doi.org/10.3109/15513811003796961 https://doi.org/10.3174/ajnr.a1364 https://doi.org/10.3174/ajnr.a1364 https://doi.org/10.3109/15513815.2010.524690 https://doi.org/10.1186/1472-6815-8-8 https://doi.org/10.1007/s00247-014-3113-y https://doi.org/10.1007/s00247-014-3113-y https://doi.org/10.1159/000464296 https://doi.org/10.1159/000464296 https://doi.org/10.1177/019459988008800310 https://doi.org/10.1017/s0022215100098546 https://doi.org/10.1097/00000478-199401000-00003 https://doi.org/10.1080/15513819609168721 https://doi.org/10.1002/%28sici%291097-0339%28199706%2916:6%3c518::aid-dc9%3e3.0.co%3b2-5 https://doi.org/10.1002/%28sici%291097-0339%28199706%2916:6%3c518::aid-dc9%3e3.0.co%3b2-5 departments of 2surgery and 3internal medicine, 1college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia *corresponding author’s e-mail: feras_a_k@yahoo.com ورم خماطي يف الصمام األهبري يعرض كسكتة دماغية تقرير حالة و مراجعة لألدبيات الطبية فرا�س اأحمد الكويتي، يا�رص الغنيمي، �شامي غزال abstract: myxomas originating from the aortic valve are rare. we report a 40-year-old male patient who presented to the king fahd hospital of the university, khobar, saudi arabia, in 2017 with a stroke. transoesophageal echocardiography indicated a mobile mass measuring 6 × 2 mm attached to the right coronary cusp of the aortic valve and a mobile interatrial septum with a small patent foramen ovale (pfo). the patient underwent surgical excision of the mass and direct closure of the pfo. histopathology confirmed the mass to be a myxoma. despite their rarity, the recognition and treatment of valvular myxomas is very important; moreover, clinicians should be aware that affected patients may present with an embolic stroke. keywords: aortic valve; myxoma; patent foramen ovale; stroke; transesophageal echocardiography; case report; saudi arabia. امللخ�ص: يعد الورم املخاطي النا�شئ عن �شمامات القلب حالة نادرة احلدوث. نعر�س هنا حالة مري�س رجل يبلغ من العمر 40 عاًما تقدم اإىل م�شت�شفى امللك فهد اجلامعي، اخُلرب، اململكة العربية ال�شعودية، يف عام 2017 ب�شكتة دماغية. اأ�شار تخطيط �شدى القلب عرب املريء اإىل وجود كتلة متحركة بحجم 2 × 6 مم مت�شلة بال�رصفة التاجية اليمنى لل�شمام الأبهري واحلاجز الأذيني مع وجود ثقب بي�شاوي قلبي �شغري. خ�شع املري�س لالإ�شتئ�شال اجلراحي واإغالق مبا�رص للثقب البي�شاوي القلبي. اأكد تقرير مر�شيات الأن�شجة على اأن الكتلة هي عبارة عن ورم خماطي. على الرغم من ندرة احلالة، اإل اأن معرفة وعالج الورم احلبيبي لل�شمامات يعترب مهمة للغاية؛ عالوة على ذلك، يجب اأن يكون الأطباء على دراية باأن املر�شى امل�شابني قد يظهرون ب�شكتة دماغية �شمّية. اململكة حالة؛ تقرير املريء؛ عرب القلب �شدى تخطيط الدماغية؛ ال�شكتة القلبي؛ البي�شاوي الثقب خماطي؛ ورم الأبهري؛ ال�شمام املفتاحية: الكلمات العربية ال�شعودية. aortic valve myxoma presenting with a stroke a case report and review of the literature *feras a. alkuwaiti,1 yasser elghoneimy,2 sami ghazal3 sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e537–540, epub. 28 mar 19 submitted 27 may 18 revision req. 26 jun 18; revision recd. 25 jul 18 accepted 9 aug 18 case report doi: 10.18295/squmj.2018.18.04.019 myxomas originating from the cardiacvalves are uncommon.1,2 these benign tumours typically occur between the fourth and seventh decades of life and usually affect women more commonly than men.1 the condition is mostly sporadic in nature, but can also be familial.2 myxomas are true neo plasms in that they are derived from primitive multipotent mesenchymal cells which may exist as embryonic rem nants in the heart wall.3 rarely, myxomas may arise from both the ventricular aspect and the margin of the aortic valve cusps; moreover, one or both leaflets may also be affected.4 although transoesophageal echocardiography (tee) aids in the assessment of such masses, histopathology is considered the gold-standard method to confirm a diagnosis.4,5 this report describes an atypical case of aortic valve myxoma and patent foramen ovale (pfo) presenting with a cerebral stroke. such cases serve to increase awareness of the varying presentation of aortic valve myxomas and highlight appropriate investigations and management of this condition. case report a 40-year-old male patient presented to the king fahd hospital of the university (kfhu), khobar, saudi arabia, in 2017 with sudden-onset dysphasia, left ataxia, nausea and vomiting over the preceding two hours. the patient reported having had a previous stroke at the age of 11 years; however, he was unable to provide any information about the event. at presentation, the patient was alert, oriented and had stable vital signs. all laboratory investigation findings were within normal limits and electrocardiography showed normal sinus rhythm. as a result, the case was transferred to the stroke team. urgent computed tomography (ct) of the head showed evidence of the prior ischaemic stroke event in the right occipital lobe and right cerebellum. an intravenous thrombolytic was administered in accordance with hospital guidelines. subsequently, the patient was admitted to the inpatient department and received 150 mg of aspirin and 75 mg of clopidogrel. symptoms improved over the course of the following three days. however, aortic valve myxoma presenting with a stroke a case report and review of the literature e538 | squ medical journal, november 2018, volume 18, issue 4 further investigations were undertaken to determine the source of the stroke. brain magnetic resonance imaging (mri) revealed that the patient had suffered an acute ischaemic stroke, with a multifocal area of diffusion restriction within the right cerebral and superior cerebellar peduncles and both cerebellar hemispheres, as well as hyperintensities on t2-weighted fluid-attenuated inversion recovery mri sequences. however, transthoracic echocardiography (tte) did not show any clear source of emboli. acc ordingly, tee was performed and revealed a small mobile mass measuring 6 × 2 mm attached to the right coronary cusp (rcc) of the aortic valve and a mobile interatrial septum with a small pfo visible with agitated saline contrast [figure 1]. no significant arrhythmia was noted on a holter monitor. a papillary fibroelastoma (pfe) was suspected. after two weeks of stroke management, the decision was made excise the mass along with closure of the pfo to prevent any future embolic events. the surgical procedure was performed while the patient underwent cardiopulmonary bypass. during the surgery, the pfo was visible as an opening between the right and left atria [figure 2]. the mass was success fully excised from the rcc and the pfo was closed. the postoperative period was uneventful and the patient was discharged five days later. a histopathological exam ination of the excised mass showed a paucicellular lesion composed of stellate and oval cells with a moderate amount of eosinophilic cytoplasm, fine chromatin and indistinct cell borders [figure 3]. these features were consistent with a diagnosis of myxoma. discussion to the best of the authors’ knowledge, only 11 cases of aortic valve myxoma have been previously reported in the literature [table 1].4–14 interestingly, nine of these previously reported patients were male, as in the current case; this is contrary to the usual female preponderance of myxoma cases.1,4–9,11,13,14 overall, six aortic valve myxoma patients were symptomatic, with symptoms largely attributable to distal embolisation and ischaemia, including three cases with stroke, two with myocardial infarctions and one with limb ischaemia.4,6,8,11–13 clinicians should therefore be aware of stroke as a potential presentation of aortic valve myxoma. the pathogenesis of ischaemic events in aortic valve myxoma could be due to either embolic debris derived from the tumour itself or from a thrombus around the tumour.12 in the current case, the patient was also diagnosed with pfo, a potential cause of embolic stroke in which a paradoxical embolism may pass through a pfo via right-to-left shunting (rls).15 however, in the current case, the observed pfo was very small in size and therefore would not be able to cause the rls of an embolus. figure 1: transoesophageal echocardiography of a 40 year-old male stroke patient in (a) bi-plane short-axis view showing a small mass in the right coronary cusp of the aortic valve measuring 3 × 5 mm and (b) threedimensional enfaced view showing the mass measuring 6 × 2 mm. figure 2: intraoperative photograph of the heart of a 40-year-old male stroke patient showing an opening between the right and left atria measuring 10 × 10 mm. figure 3: haematoxylin and eosin stains at (a) x40 magnification showing a hypocellular lesion in a myxoid matrix and (b) at x200 magnification showing stellate and oval cells with eosinophilic cytoplasm and indistinct cell borders. feras a. alkuwaiti, yasser elghoneimy and sami ghazal case report | e539 as filiform fronds located near valve closure lines.20 radiologically, tee is superior to tte in identifying a cardiac mass and defining its exact location, attachment to the underlying tissue and relation to surrounding structures.21,22 among previously reported cases of aortic valve myxoma, 10 were identified by tte, of which four were further confirmed via tee.5–14 in one case, an aortic valve abnormality was first revealed via ct.4 in the current case, tee revealed the mass to be located on the rcc of the aortic valve, thus precluding a thrombus or cardiac vegetation; however, the preoperative diagnosis was of a pfe. as with previous cases, the correct diagnosis was eventually confirmed by histopathological examination revealing a myxoid matrix with ovoid myxoma cells.4–14 typically, the management of aortic valve myxoma cases involves the surgical excision of the tumour as well as the surrounding tissue to minimise the risk of local recurrence, as in the present case.4,10–12 during the procedure, the native aortic valve should be conserved as much as possible; however, if the tumour is too large the differential diagnosis of an aortic valve myxoma includes vegetation, a thrombus, pfe and lambl’s excre scences; these conditions can be distinguished by their microscopic and immunohistochemical characteristics.7,10,13 in addition, thrombi and myxomas can be differentiated using two-dimensional echocardiography; the former typically present with a layered appearance, while an area of echolucency may be observed within the tumour in the latter.7 moreover, vegetations of the heart valves are a sign of infective endocarditis; however, this was ruled out in the current case due to a lack of history of this condition.10,16 on imaging, the size, shape, attachment site, mobility and location of a cardiac mass can aid in the exact diagnosis, along with the patient’s clinical presentation.17–19 for example, in pfe cases, the tumour appears as a small mass attached to the mitral or aortic valve, usually located downstream and attached by a small pedicle; such masses are more common and often mobile and appear irregularly-shaped with delicate frond-like surfaces.7,17,18 in contrast, lambl’s excrescences appear table 1: literature review of reported aortic valve myxoma* cases4–14 author and year of case* age/ gender presentation history imaging site size in cm complication surgery kennedy et al.8 (1995) 23/m leg pain none tte rcc and lcc 1.5 limb ischaemia avr watarida et al.9 (1997) 58/m asymptomatic none tte rcc 1.1 × 1 none avr ramsheyi et al.6 (1998) 34/m facial haemiparesis none tte and tee rcc 1 stroke avr okamoto et al.10 (2006) 61/f endocarditis htn and dm tte lcc 1 × 1 none resection dyk et al.11 (2009) 15/m chest pain none tte and tee ncc 4 × 1 mi resection koyalakonda et al.12 (2011) 60/f paroxysmal af af and htn tte and tee rcc 1 × 1 stroke resection fernández et al.13 (2012) 28/m haemiparesis epilepsy tte rcc and lcc 1.5 × 0.7 stroke avr kim et al.7 (2012) 72/m shortness of breath htn tte ncc 1.5 × 0.8 none avr javed et al.4 (2014) 81/m leg pain htn, ckd and pad ct, angiography and tee lcc 1.8 × 1.2 acute mi cabg and resection prifti et al.5 (2015) 13/m dyspnoea and angina none tte and tee rcc and lcc 0.6 × 0.2 none avr ji et al.14 (2017) 17/m heart murmur none tte ncc 2 none avr present case (2018) 40/m dysphasia, ataxia and nausea previous stroke tte and tee rcc 0.6 × 0.2 stroke and pfo excision and pfo closure tte = transthoracic echocardiography; rcc = right coronary cusp; lcc = left coronary cusp; avr = aortic valve replacement; tee = transoesophageal echocardiography; htn = hypertension; dm = diabetes mellitus; ncc = non-coronary cusp; mi = myocardial infarction; af = atrial fibrillation; ckd = chronic kidney disease; pad = peripheral arterial disease; ct = computed tomography; cabg = coronary artery bypass graft; pfo = patent foramen ovale. *in all cases, the diagnosis was confirmed via histopathological examination. aortic valve myxoma presenting with a stroke a case report and review of the literature e540 | squ medical journal, november 2018, volume 18, issue 4 and/or degeneration of the valvular structure occurs, aortic valve replacement (avr) may be necessary. among previously reported cases, seven underwent avr, while resection alone was sufficient in three cases and one required resection and a coronary artery bypass graft.4–14 nevertheless, regardless of treatment option, aortic valve myxoma cases require careful follow-up due to the high probability of local recurrence and distal tumour growth at the site of embolisation.5 conclusion an aortic valve myxoma is uncommon and may present with serious complications, such as stroke. in patients with embolic phenomena, tee should be performed, with special attention to the valvular morphology. for valvular myxomas, aggressive surgical excision is necessary to prevent structural valve degeneration and local recurrence. a c k n o w l e d g e m e n t s the authors express their gratitude for the insightful comments of dr sari alsuhaibani, department of radiology, kfhu, dr mohammed j. alyousef, department of pathology & laboratory medicine, kfhu, and mr ahmed m. alsahlawi, imam abdulrahman bin faisal university, dammam, saudi arabia. references 1. burke a, virmani r. tumors of the heart and the great vessels. in: rosai j, ed. atlas of tumor pathology, 3rd series. washington dc, usa: armed forces institute of pathology, 1996. p. 231. 2. vaideeswar p, butany jw. benign cardiac tumors of the pluripotent mesenchyme. semin diagn pathol 2008; 25:20−8. https://doi.org/10.1053/j.semdp.2007.10.005. 3. orlandi a, ciucci a, ferlosio a, genta r, spagnoli lg, gabbiani g. cardiac myxoma cells exhibit embryonic endocardial stem cell features. j pathol 2006; 209:231−9. https://doi.org/10.1002/path.1959. 4. javed a, zalawadiya s, kovach j, afonso l. aortic valve myxoma at the extreme age: a review of literature. bmj case rep 2014; 2014:bcr2013202689. https://doi.org/10.1136/bcr-2013-202689. 5. prifti e, ademaj f, kajo e, baboci a. a giant myxoma originating from the aortic valve causing severe left ventricular tract obstruction: a case report and literature review. world j surg oncol 2015; 13:151. https://doi.org/10.1186/s12957-0150575-9. 6. ramsheyi a, deleuze p, d’attelis n, bical o, lefort jf. aortic valve myxoma. j card surg 1998; 13:491−3. https://doi.org/10.1 111/j.1540-8191.1998.tb01089.x. 7. kim hy, kwon su, jang wi, kim hs, kim js, lee hs, et al. a rare case of aortic valve myxoma: easy to confuse with papillary fibroelastoma. korean circ j 2012; 42:281−3. https://doi.org/ 10.4070/kcj.2012.42.4.281. 8. kennedy p, parry aj, parums d, pillai r. myxoma of the aortic valve. ann thorac surg 1995; 59:1221−3. https://doi. org/10.1016/0003-4975(94)00969-e. 9. watarida s, katsuyama k, yasuda r, magara t, onoe m, nojima t, et al. myxoma of the aortic valve. ann thorac surg 1997; 63:234−6. https://doi.org/10.1016/s0003-4975(96)00771-0. 10. okamoto t, doi h, kazui t, suzuki m, koshima r, yamashita t, et al. aortic valve myxoma mimicking vegetation: report of a case. surg today 2006; 36:927−9. https://doi.org/10.1007/s005 95-006-3273-y. 11. dyk w, konka m. images in cardiothoracic surgery: unusual complication of aortic valve grape-like myxoma. ann thorac surg 2009; 88:1022. https://doi.org/10.1016/j.athoracsur.2008.12.051. 12. koyalakonda sp, mediratta nk, ball j, royle m. a rare case of aortic valve myxoma: an unusual cause of embolic stroke. cardiology 2011; 118:101−3. https://doi.org/10.1159/000327081. 13. fernández al, vega m, el-diasty mm, suárez jm. myxoma of the aortic valve. interact cardiovasc thorac surg 2012; 15:560−2. https://doi.org/10.1093/icvts/ivs117. 14. ji z, wang l, sun j, ye w, yu y, huang h, et al. aortic valve myxoma in a young man: a case report and review of literature. heart surg forum 2017; 20:e066−8. https://doi.org/10.1532/ hsf.1772. 15. homma s, sacco rl. patent foramen ovale and stroke. circ ulation 2005; 112:1063−72. https://doi.org/10.1161/circula tionaha.104.524371. 16. martinez g, valchanov k. infective endocarditis. bja educ 2012; 12:134−9. https://doi.org/10.1093/bjaceaccp/mks005. 17. shelh m. multiplane transoesophageal echocardiography detection of papillary fibroelastomas of the aortic valve causing a stroke. eur heart j 1997; 18:702−3. https://doi.org/10.1093/ oxfordjournals.eurheartj.a015325. 18. watanabe t, hosoda y, kikuchi n, kawai s. papillary fibroelastoma of the tricuspid valve in association with an atrial septal defect: report of a case. surg today 1996; 26:831−3. https://doi.org/10.1007/bf00311648. 19. rana bs, monaghan mj, ring l, shapiro ls, nihoyannopoulos p. the pivotal role of echocardiography in cardiac sources of embolism. eur j echocardiogr 2011; 12:i25−31. https://doi.org/10. 1093/ejechocard/jer122. 20. aziz f, baciewicz fa jr. lambl’s excrescences: review and recommendations. tex heart inst j 2007; 34:366−8. 21. leibowitz g, keller nm, daniel wg, freedberg rs, tunick pa, stottmeister c, et al. transesophageal versus transthoracic echocardiography in the evaluation of right atrial tumors. am heart j 1995; 130:1224−7. https://doi.org/10.1016/00028703(95)90146-9. 22. mankad r, herrmann j. cardiac tumors: echo assessment. echo res pract 2016; 3:r65−77. https://doi.org/10.1530/erp16-0035. departments of 1surgery and 5behavioural medicine, sultan qaboos university hospital; departments of 2behavioural medicine, 3family medicine & public health, 6physiology and 7surgery, college of medicine & health sciences, sultan qaboos university, muscat, oman; 4department of biostatistics, christian medical college, vellore, india *corresponding author’s e-mail: dr.sanjayjaju@gmail.com تأثري إستئصال اللوزتني وحلمية األنف على مستوى اإلدراك والسلوك لدى األطفال الذين يعانون من الشخري أثناء النوم دراسة مبنية على املالحظة خالد الزعابي، �شمري العدوي، �شاجناي جاجو، لك�شمانن جيا�شيالن، نا�رص ال�شيباين، حممد العلوي، حممد العربي، را�شد العربي abstract: objectives: this study aimed to evaluate cognitive and behavioural changes among 9–14-yearold omani children with obstructive sleep apnoea (osa) after an adenotonsillectomy (at). methods: this naturalistic observational study was conducted at the sultan qaboos university hospital, muscat, oman, between january 2012 and december 2014. omani children with adenotonsillar hypertrophy (ath) underwent overnight polysomnography and those with confirmed osa were scheduled for an at. cognitive and behavioural evaluations were performed using standardised instruments at baseline prior to the procedure and three months afterwards. results: a total of 37 children were included in the study, of which 24 (65%) were male and 13 (35%) were female. the mean age of the males was 11.4 ± 1.9 years, while that of the females was 11.1 ± 1.5 years. following the at, there was a significant reduction of 56% in mean apnoea-hypopnoea index (ahi) score (2.36 ± 4.88 versus 5.37 ± 7.17; p <0.01). there was also a significant positive reduction in osa indices, including oxygen desaturation index (78%), number of desaturations (68%) and number of obstructive apnoea incidents (74%; p <0.01 each). significant improvements were noted in neurocognitive function, including attention/concentration (42%), verbal fluency (92%), learning/recall (38%), executive function (52%) and general intellectual ability (33%; p <0.01 each). there was a significant decrease of 21% in both mean inattention and hyperactivity scores (p <0.01 each). conclusion: these results demonstrate the effectiveness of an at in improving cognitive function and attention deficit hyperactivity disorder-like symptoms among children with ath-caused osa. such changes can be observed as early as three months after the procedure. keywords: adenoidectomy; obstructive sleep apnea; cognitive function; behavior; attention deficit hyperactivity disorders; children; oman. الأطفال لدى وال�شلوك الإدراك م�شتوى على الأنف وحلمية اللوزتني ا�شتئ�شال تاأثري تقييم اإىل تهدف الدرا�شة هذه الهدف: امللخ�ص: العمانيني مبتو�شط عمر 14-9 �شنة والذين يعانون من انقطاع النف�س الإن�شدادي النومي. الطريقة: اأجريت هذه الدرا�شة املبنية على املالحظة مب�شت�شفى جامعة ال�شلطان قابو�س مب�شقط، عمان يف الفرتة املمتدة من �شهر يناير 2012 اىل �شهر دي�شمرب 2014. مت اإخ�شاع جميع الأطفال العمانيني امل�شاركني يف الدرا�شة والذين يعانون من ت�شخم اللوزتني وحلمية الأنف اىل درا�شة للنوم ومت اخ�شاع الأطفال الذين ثبت لديهم انقطاع النف�س الن�شدادي النومي اىل تدخل جراحي متمثل يف ا�شتئ�شال للوزتني وحلمية الأنف. متت درا�شة م�شتوى الدراك وال�شلوك لدى هوؤلء الأطفال قبل وبعد ثالثة اأ�شهر من التدخل اجلراحي. النتائج: بلغ عدد الأطفال امل�شاركني يف الدرا�شة 37 منهم 24 )%65( ذكور و موؤ�رص انخف�س اجلراحي التدخل بعد �شنة. 11.1 ± والإناث 1.5 �شنة 11.4 ± 1.9 الذكور امل�شاركني اعمار متو�شط بلغ اإناث. )35%( 13 انقطاع التنف�س اأثناء النوم مبعدل %56 )4.88 ± 2.36 مقارنة ب 7.17 ± 5.37؛ p >0.01(. كما اأ�شارت النتائج اأي�شا اإىل انخفا�س ملحوظ مرات وعدد )68%( الت�شبع عدد وموؤ�رص )78%( الأك�شجني ت�شبع موؤ�رص مت�شمنا النوم اأثناء النف�س انقطاع ملوؤ�رص الفرعية املوؤ�رصات يف انقطاع النف�س)%74؛ p >0.01 لكل منهما(. كما لحظ الباحثون حت�شنا كبريا يف م�شتوى الإدراك لدى الأطفال مت�شمنا م�شتوى النتباه والرتكيز )%42( وطالقة الل�شان )%92( والتعلم/الذاكرة )%38( ومهارات التنفيذ )%52( ومعدل الذكاء العام )%33؛ p >0.01 لكل منهما(. اأ�شارت الدرا�شة اآي�شا اىل انخفا�س معدل عدم النتباه وفرط احلركة بن�شبة )%21؛ p >0.01 لكل منهما(. اخلال�صة: هذه النتائج تو�شح فعالية التدخل اجلراحي )ا�شتئ�شال اللوزتني واللحمية( يف حت�شن م�شتوى الإدراك وال�شلوك لدى الأطفال الذين يعانون من اأعرا�س فرط احلركة وقلة النتباه ب�شبب انقطاع النف�س الإن�شدادي النومي ب�شبب ت�شخم اللوزتني وحلمية الأنف. من املمكن مالحظة هذه التغريات خالل ثالثة اأ�شهر بعد التدخل اجلراحي. الكلمات املفتاحية: ا�شتئ�شال حلمية الأنف؛ انقطاع النف�س الإن�شدادي النومي؛ م�شتوى الإدراك؛ ال�شلوك؛ ق�شور النتباه وفرط احلركة؛ اأطفال؛ عمان. effects of an adenotonsillectomy on the cognitive and behavioural function of children who snore a naturalistic observational study khalid al-zaabi,1 samir al-adawi,2 *sanjay jaju,3 lakshmanan jeyaseelan,4 nasser al-sibani,2 mohammed al-alawi,5 mohammed al-abri,6 rashid al-abri7 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e455–460, epub. 28 mar 19 submitted 29 may 18 revisions req. 4 & 22 jul 18; revisions recd. 11 & 28 jul 18 accepted 2 aug 18 doi: 10.18295/squmj.2018.18.04.005 effects of an adenotonsillectomy on the cognitive and behavioural function of children who snore a naturalistic observational study e456 | squ medical journal, november 2018, volume 18, issue 4 obstruc tive sleep apnoe a (osa) is estimated to affect between 1.2–5.7% of the paediatric population.1,2 the condition is char acterised by intermittent partial or complete obstruction of breathing during sleep.3 among children, adenotonsillar hypertrophy (ath) can cause narrowing of the airway, leading to symptoms such as snoring, cessation of breathing and sleep fragmentation.4 this in turn reduces oxygen delivery to the terminal alveoli, thus affecting the gas exchange process and leading to tissue hypoxia.5 the neuropsychological sequelae of childhood osa may include compromised cognitive, emotional and social function.6,7 an adenotonsillectomy (at) is considered the first line of treatment for paediatric osa.8,9 findings from the childhood adenotonsillectomy trial (chat) suggest that the procedure has the potential to atten uate certain behavioural problems and enhance cognitive function.10–12 however, to the best of the authors’ knowledge, no studies have yet been conducted among arab children with osa. furthermore, previous studies on this topic have focused on younger children (3–9-yearolds) and longer follow-up periods (≥6 months).13,14 as such, the present study aimed to explore preversus post-at changes in cognitive function, attention deficit hyperactivity disorder (adhd)-like symptoms and osa indices among omani children aged 9–14 years. this study also aimed to determine whether a re-evaluation of cognitive and behavioural measures at three months post-at could provide similar evidence to that noted at 6–12 months. methods this naturalistic observational study was conducted at the sultan qaboos university hospital (squh), muscat, oman, between january 2012 and december 2014. a total of 150 omani children consecutively referred from local health centres with a history of snoring, mouth breathing and sleep disturbance suggestive of osa due to ath were targeted. however, 47 children with craniofacial or neurological abnormalities, a history of persistent and pervasive allergies or asthma, a body mass index not between the 5th and 85th percentile and those on psychotropic medications or deemed clinically unfit for surgical intervention were excluded from the study. the remaining 103 subjects underwent overnight polysomnography; of these, 60 were excluded as their symptoms did not fulfil the criteria for osa. a final sample of 37 subjects were included in the study. the minimum sample size required was calculated to be 35 subjects at a two-sided alpha value of 0.5, power of 80% and expected effect size of 0.5. all of the children underwent in-hospital sleep studies using a portable level 3 sleep machine with an air flow sensor, chest and abdominal effort belt and oximeter.15 during the sleep study, the following five variables were monitored: (1) apnoea-hypopnoea index (ahi) score; (2) oxygen desaturation index (odi) score; (3) the number of desaturations (nod); (4) the number of obstructive apnoea (oa) incidents; and (5) the number of central apnoea (ca) incidents. ahi scores were calcul ated based on the guidelines of the american academy of sleep medicine (aasm), wherein 0–1 obstructive events per hour was considered normal, 2–5 was classified as mild osa, 6–10 was considered moderate osa and >10 was indicative of severe osa.15,16 all children who fulfilled the criteria for mild-to-severe osa were sched uled for an at. those who underwent an at also took part in another sleep study three months after the procedure to document any changes in osa indices. data were manually scored at baseline and three months post-at by a sleep technologist who was blinded to the stage of research and in accordance with the aasm guidelines.15 the children were also evaluated at baseline and three months post-at for adhd indices and cognitive function (i.e. intellectual capacity, verbal fluency, attention/concentration, learning/recall and executive function). a board-certified psychologist who was blinded to the findings of the sleep study conducted cognitive evaluations of the subjects. each child’s parents or caregivers were asked to take a checklist of adhd symptoms from the short version of conners’ teacher rating scale (ctrs) to their child’s school so that their teacher could assess the frequency of certain behaviours associated with adhd.17 the psychometric properties of the ctrs have been previously established among omani children, with a cut-off value of >15 denoting adhd cases.18 advances in knowledge the findings of this study indicate that an adenotonsillectomy (at) has beneficial effects on cognition and attention deficit hyperactivity disorder-like symptoms among children with obstructive sleep apnoea (osa). such changes can be determined as early as three months after the procedure. previous research has focused on 3–10-year-old children; however, this study observed similar results among 9–14-year-olds. application to patient care an at may improve cognitive and behavioural function among older paediatric patients with osa. khalid al-zaabi, samir al-adawi, sanjay jaju, lakshmanan jeyaseelan, nasser al-sibani, mohammed al-alawi, mohammed al-abri and rashid al-abri clinical and basic research | e457 the raven’s coloured progressive matrices test was used to establish the intellectual capacity of the participants. this test has been previously validated in the omani population and consists of 36 items grouped into three sets.19 each item contains a pattern with one part removed and between six and eight pictured inserts, of which the participant must choose the one with the correct pattern. the controlled oral word association test was used to determine verbal fluency by examining lexical ability, executive control and the speed of verbal responses. the score was calculated based on the total number of acceptable words produced in three 30-second periods.20 the digit span test, a subscale of the wechsler intelligence scale for children, was used to measure verbal/auditory attention and short-term memory. the score was based on the participant’s ability to recall seven pairs of random number sequences read aloud by the examiner, with the numbers read both forwards and backwards.21 the respondents’ ability to learn and remember was gauged using the buschke selective reminding test; this consists of lists of 12 words which are read aloud to the participant at the rate of approximately one word every two seconds. the total score was based on the number of words recalled over three trials.22 the tower of london neuropsychological test was used to determine deficits in planning and temporal organisation, which are important constituents of exec utive function.22 the participants were asked to realign coloured beads stacked on poles to three adjacent poles in a minimum number of moves during five trials. after two consecutive failures, the test was stopped. the total score was the sum of all correctly solved trials up to a maximum of 25 moves.23 statistical analysis was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). a paired t-test or wilcoxon test (paired samples) was used to compare the differences between preand post-at indices of osa and neurocognitive and behavioural function. percentage changes were reported separately. this study was approved by the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #749). written informed consent was obtained from the parents or guardians of all of the participants. results a total of 37 children with osa participated in the study, of which 24 (65%) were male and 13 (35%) were female. the mean age was 11.4 ± 1.9 years and 11.1 ± 1.5 years for males and females, respectively. the mean post-at ahi score showed a significant reduction of 56% compared to the mean pre-at ahi score (2.36 ± 4.88 versus 5.37 ± 7.17; p <0.01). similarly, significant reductions were observed for the other osa indices, including odi score (78%), nod (68%) and the number of oa incidents (74%; p <0.01 each). although there was a reduction in the number of ca incidents (14%), this difference was not statistically significant (p = 0.73) [table 1]. following the at, significant improvements were noted in all neurocognitive function parameters, including attention/concentration (42%), verbal fluency (92%), learning/recall (38%), executive function (52%) and general intellectual ability (33%; p <0.01 each). in addition, there was a significant decrease of 21% in both adhd inattention and hyperactivity scores (p <0.01 each); however, the mean post-at hyperactivity score nevertheless remained above a cut-off value of >15 (15.84 ± 4.13) [table 2]. discussion there is a plethora of evidence to suggest that children with cognitive and intellectual deficits and those with adhd-like symptoms tend to have osa.6,7 conversely, osa has also been associated with cognitive and intellectual deficits as well as adhd-like symptoms.24 such findings indicate that clinicians should be vigilant table 1: preand post-adenotonsillectomy changes in obstructive sleep apnoea indices among omani children at the sultan qaboos university hospital, muscat, oman (n = 37) index mean ± sd change, unit (%) 95% ci p value* pre-at post-at ahi score 5.37 ± 7.17 2.36 ± 4.88 −3.00 (−56%) 1.16, 4.86 <0.01 odi score 5.19 ± 8.14 1.14 ± 2.87 −4.05 (−78%) 1.72, 6.39 <0.01 number of desaturations 31.22 ± 57.99 10.05 ± 28.81 −21.16 (−68%) 5.65, 36.67 <0.01 number of oa incidents 16.51 ± 22.51 4.35 ± 13.69 −12.16 (−74%) 4.59, 19.74 <0.01 number of ca incidents 3.32 ± 6.41 2.87 ± 4.93 −0.46 (−14%) 0.84, 1.76 0.73 sd = standard deviation; at = adenotonsillectomy; ci = confidence interval; ahi = apnoea-hypopnoea index; odi = oxygen desaturation index; oa = obstructive apnoea; ca = central apnoea. *using a wilcoxon signed ranks test. effects of an adenotonsillectomy on the cognitive and behavioural function of children who snore a naturalistic observational study e458 | squ medical journal, november 2018, volume 18, issue 4 in excluding osa among children with cognitive and intellectual deficits and adhd or vice versa. a previous study conducted in oman suggested that the prev alence rate of adhd was 8.8% among 9–10-yearolds.25 however, it is not clear what percentage of this population also had osa. in the current study, although there was a significant decrease in mean inattention and hyperactivity scores post-at, this change does not indicate a reversal of adhd-like symptoms, as the mean post-at score remained above the cut-off value of >15 on the ctrs scale.25 longer-term evaluation would perhaps shed more light on this finding. in the current study, indices of neurocognitive and behavioural function and osa were found to improve significantly post-at. these findings concur with those reported in the existing literature.26–30 previous studies on this topic have focused on evaluating cognitive and behavioural changes between 6–12 months after the surgery.13,14,31 in contrast, the current study evaluated cognitive and behavioural function over a much shorter follow-up period. kaditis et al. recommended re-evaluation at six weeks post-at while a 6–12-month range was used by chat researchers.10–13,32 overall, it is still unclear at exactly which point in time neuroplasticity in children with osa is likely to occur after an at. further research on this topic is warranted. in previous research, ats were commonly performed for children between 3–9 years old.13,14 the current study included children aged 9–14 years old; this age group was chosen to ensure the correct diagnosis of adhd-like symptoms, which are more accurately identified in older children.33 additionally, more developmentally appropriate and standardised cognitive measures are available for this population.34 finally, the neurocognitive assessment of very young children can be logistically challenging, thus supporting the assessment of older children in the current study. studies on younger children have been justified based on the assumption that osa can trigger irreversible morbidity and that, therefore, the intervention should be implemented as quickly as possible.35 however, no neurobiological or molecular mechanisms have yet been identified to suggest that the pathological processes triggered by osa can only be reversed in specific age groups. the chat researchers have recommended that ats be performed on 3–10-year-olds.10–12 the current study was subject to certain limitations. first, the study constituted a naturalistic observation of routine medical services provided to children referred to one tertiary care hospital in oman and therefore did not include a control group. while naturalistic observ ational studies have the potential to lay the groundwork for further research with more robust methodologies, generalisation of the findings of such studies should be made with caution. second, using a symptom check list to diagnose adhd is considered suboptimal comp ared to semi-structured interviews in which the diagnosis is based on the international classification of diseases and the diagnostic and statistical manual of mental disorders.36 similarly, brain scans may be of some benefit to more accurately measure cognitive impairment.37 third, this study did not take into account variations of hypoxaemia due to complex fluctuations in the associations between hypoxaemia and cognitive variables.38 fourth, the study may have been affected by various confounders, such as maternal education, maturity, diet, parental supervision, socioeconomic status and spontaneous changes in cognition. finally, a level three sleep study is considered suboptimal compared to level one. however, this type of sleep study machine is widely used in clinical practice and research and is considered an acceptable tool for diagnosing osa.39 table 2: preand post-adenotonsillectomy changes in behavioural and cognitive function indices among omani children with obstructive sleep apnoea at the sultan qaboos university hospital, muscat, oman (n = 37) index mean ± sd change, unit (%) 95% ci p value* pre-at post-at ctrs-ia score 18.76 ± 4.79 14.86 ± 3.65 −3.89 (−21%) 2.39, 5.40 <0.01 ctrs-h score 19.92 ± 6.72 15.84 ± 4.13 −4.08 (−21%) 2.19, 5.97 <0.01 dst score 6.83 ± 2.69 9.70 ± 4.51 +3.00 (+42%) −4.16, −1.84 <0.01 cowat score 6.07 ± 5.45 11.67 ± 8.39 +5.49 (+92%) −7.28, −3.70 <0.01 bsrt score 18.65 ± 5.72 25.65 ± 5.49 +7.00 (+38%) −9.23, −4.77 <0.01 tol score 11.46 ± 4.74 17.43 ± 5.19 +5.97 (+52%) −7.20, −4.74 <0.01 rcpm score 18.03 ± 7.47 23.97 ± 7.19 +5.95 (+33%) −7.35, −4.54 <0.01 sd = standard deviation; at = adenotonsillectomy; ci = confidence interval; ctrs = conners’ teacher rating scale; ia = inattention; h = hyperactivity; dst = digit span test; cowat = controlled oral word association test; bsrt = buschke selective reminding test; tol = tower of london; rcpm = raven’s coloured progressive matrices. *using a paired t-test. khalid al-zaabi, samir al-adawi, sanjay jaju, lakshmanan jeyaseelan, nasser al-sibani, mohammed al-alawi, mohammed al-abri and rashid al-abri clinical and basic research | e459 conclusion the results of this study indicate that an at is effective in improving cognitive function and reducing adhdlike symptoms among children with osa secondary to ath. in addition, a short follow-up period of three months is sufficient to measure such changes. this study also suggests that post-at neurobehavioural improvements extend beyond the previously studied age range of 3–9 years. conflict of interest the authors declare no conflicts of interest. funding no funding was received for this study. references 1. dempsey ja, veasey sc, morgan bj, o’donnell cp. pathophysiology of sleep apnea. physiol rev 2010; 90:47–112. https:// doi.org/10.1152/physrev.00043.2008. 2. delrosso lm. epidemiology and diagnosis of pediatric obstructive sleep apnea. curr probl pediatr adolesc health care 2016; 46:2–6. https://doi.org/10.1016/j.cppeds.2015.10.009. 3. farrell pc, richards g. recognition and treatment of sleepdisordered breathing: an important component of chronic disease management. j transl med 2017; 15:114. https://doi. org/10.1186/s12967-017-1211-y. 4. paul gr, pinto s. sleep and the cardiovascular system in chil dren. sleep med clin 2017; 12:179–91. https://doi.org/10.10 16/j.jsmc.2017.01.004. 5. urquhart ds, hill ea, morley a. sleep-disordered breathing in children. paediatr child health (oxford) 2017; 27:328–36. https://doi.org/10.1016/j.paed.2017.03.004. 6. beebe dw, gozal d. obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. j sleep res 2002; 11:1–16. https://doi.org/10.1046/j.13 65-2869.2002.00289.x. 7. hunter sj, gozal d, smith dl, philby mf, kaylegian j, kheirandish-gozal l. effect of sleep-disordered breathing severity on cognitive performance measures in a large community cohort of young school-aged children. am j respir crit care med 2016; 194:739–47. https://doi.org/10.1164/rccm.201510-2099oc. 8. balaban o, walia h, tumin d, jatana kr, raman v, tobias jd. assessment of adenotonsillar size and caregiver-reported sleep symptoms among 3-6 year old children undergoing adenotonsillectomy. int j pediatr otorhinolaryngol 2016; 91:43–8. https://doi.org/10.1016/j.ijporl.2016.10.001. 9. ali nj, pitson d, stradling jr. sleep disordered breathing: effects of adenotonsillectomy on behaviour and psychological functioning. eur j pediatr 1996; 155:56–62. https://doi.org/10.1007/ bf02115629. 10. marcus cl, moore rh, rosen cl, giordani b, garetz sl, taylor hg, et al. a randomized trial of adenotonsillectomy for childhood sleep apnea. n engl j med 2013; 368:2366–76. https://doi.org/10.1056/nejmoa1215881. 11. mitchell rb, garetz s, moore rh, rosen cl, marcus cl, katz es, et al. the use of clinical parameters to predict obstructive sleep apnea syndrome severity in children: the childhood adenotonsillectomy (chat) study randomized clinical trial. jama otolaryngol head neck surg 2015; 141:130–6. https://doi. org/10.1001/jamaoto.2014.3049. 12. taylor hg, bowen sr, beebe dw, hodges e, amin r, arens r, et al. cognitive effects of adenotonsillectomy for obstructive sleep apnea. pediatrics 2016; 138:e20154458. https://doi.org/10.1 542/peds.2015-4458. 13. redline s, amin r, beebe d, chervin rd, garetz sl, giordani b, et al. the childhood adenotonsillectomy trial (chat): rationale, design, and challenges of a randomized controlled trial evaluating a standard surgical procedure in a pediatric population. sleep 2011; 34:1509–17. https://doi.org/10.5665/sleep.1388. 14. villa mp, malagola c, pagani j, montesano m, rizzoli a, guilleminault c, et al. rapid maxillary expansion in children with obstructive sleep apnea syndrome: 12-month follow-up. sleep med 2007; 8:128–34. https://doi.org/10.1016/j.sleep.20 06.06.009. 15. kapur vk, auckley dh, chowdhuri s, kuhlmann dc, mehra r, ramar k, et al. clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an american academy of sleep medicine clinical practice guideline. j clin sleep med 2017; 13:479–504. https://doi.org/10.5664/jcsm.6506. 16. american academy of sleep medicine. international classification of sleep disorders, 3rd ed. darien, illinois, usa: american academy of sleep, 2014. 17. dupaul gj. parent and teacher ratings of adhd symptoms: psychometric properties in a community-based sample. j clin child psychol 1991; 20:245–53. https://doi.org/10.1207/s15374 424jccp2003_3. 18. al-sharbati m, al-adawi s, ganguly s, al-lawatiya s, al-mshefri f. hyperactivity in a sample of omani schoolboys. j atten disord 2008; 12:264–9. https://doi.org/10.1177/1087054708315136. 19. raven j. the raven’s progressive matrices: change and stability over culture and time. cogn psychol 2000; 41:1–48. https://doi. org/10.1006/cogp.1999.0735. 20. rodriguez-aranda c, martinussen m. age-related differences in performance of phonemic verbal fluency measured by controlled oral word association task (cowat): a meta-analytic study. dev neuropsychol 2006; 30:697–717. https://doi.org/10.1207/ s15326942dn3002_3. 21. inter-university consortium for political and social research. wechsler intelligence scale for children-revised. from: www. icpsr.umich.edu/icpsrweb/phdcn/descriptions/wisc-w1w2-w3.jsp accessed: jul 2018. 22. al-adawi s, powell jh, greenwood rj. motivational deficits after brain injury: a neuropsychological approach using new assessment techniques. neuropsychology 1998; 12:115–24. https://doi. org/10.1037/0894-4105.12.1.115. 23. bull r, espy ka, senn te. a comparison of performance on the towers of london and hanoi in young children. j child psychol psychiatry 2004; 45:743–54. https://doi.org/10.1111/j.1469-761 0.2004.00268.x. 24. song sa, tolisano am, cable bb, camacho m. neurocognitive outcomes after pediatric adenotonsillectomy for obstructive sleep apnea: a systematic review and meta-analysis. int j pediatr otorhinolaryngol 2016; 83:205–10. https://doi.org/10.1016/j. ijporl.2016.02.011. 25. al-ghannami ss, al-adawi s, ghebremeskel k, cramer mt, hussein is, min y, et al. attention deficit hyperactivity disorder and parental factors in school children aged nine to ten years in muscat, oman. oman med j 2018; 33:193–9. https://doi. org/10.5001/omj.2018.37. 26. yu y, chen yx, liu l, yu zy, luo x. neuropsychological functioning after adenotonsillectomy in children with obstructive sleep apnea: a meta-analysis. j huazhong univ sci tech nolog med sci 2017; 37:453–61. https://doi.org/10.1007/s115 96-017-1756-2. 27. youssef na, ege m, angly ss, strauss jl, marx ce. is obstructive sleep apnea associated with adhd? ann clin psychiatry 2011; 23:213–24. effects of an adenotonsillectomy on the cognitive and behavioural function of children who snore a naturalistic observational study e460 | squ medical journal, november 2018, volume 18, issue 4 28. schechter ms. technical report: diagnosis and management of childhood obstructive sleep apnea syndrome. pediatrics 2002; 109:e69. 29. jeon yj, song jj, ahn jc, kong ig, kim jw, park gh, et al. immediate and sustained improvement in behavior and life quality by adenotonsillectomy in children with sleep-disordered breathing. clin exp otorhinolaryngol 2016; 9:136–42. https:// doi.org/10.21053/ceo.2015.00584. 30. korson r, guilleminault c. obstructive sleep apnea syndrome. in: chokroverty s, ed. sleep disorders medicine: basic science, technical considerations and clinical aspects, 4th ed. new york, usa: springer, 2017. pp. 567–96. 31. amiri s, abdollahifakhim s, lotfi a, bayazian g, sohrabpour m, hemmatjoo t. effect of adenotonsillectomy on adhd symptoms of children with adenotonsillar hypertrophy and sleep dis ordered breathing. int j pediatr otorhinolaryngol 2015; 79:1213–17. https://doi.org/10.1016/j.ijporl.2015.05.015. 32. kaditis ag, alonso alvarez ml, boudewyns a, alexopoulos ei, ersu r, joosten k, et al. obstructive sleep disordered breathing in 2to 18-year-old children: diagnosis and management. eur respir j 2016; 47:69–94. https://doi.org/10.1183/13993003.00 385-2015. 33. gustafsson p, holmström e, besjakov j, karlsson mk. adhd symptoms and maturity: a follow-up study in school children. acta paediatr 2010; 99:1536–9. https://doi.org/10.1111/j.16512227.2010.01851.x. 34. archibald sj, kerns ka. identification and description of new tests of executive functioning in children. child neuropsychol 1999; 5:115–29. https://doi.org/10.1076/chin.5.2.115.3167. 35. dehlink e, tan hl. update on paediatric obstructive sleep apnoea. j thorac dis 2016; 8:224–35. https://doi.org/10.3978/j. issn.2072-1439.2015.12.04. 36. mirza h, roberts e, al-belushi m, al-salti h, al-hosni a, jeyaseelan l, et al. school dropout and associated factors among omani children with attention-deficit hyperactivity disorder: a cross-sectional study. j dev behav pediatr 2018; 39:109–15. https://doi.org/10.1097/dbp.0000000000000522. 37. kheirandish-gozal l, sahib ak, macey pm, philby mf, gozal d, kumar r. regional brain tissue integrity in pediatric obstructive sleep apnea. neurosci lett 2018; 682:118–23. https://doi.org/1 0.1016/j.neulet.2018.06.002. 38. hoth kf, zimmerman me, meschede ka, arnedt jt, aloia ms. obstructive sleep apnea: impact of hypoxemia on memory. sleep breath 2013; 17:811–17. https://doi.org/10.1007/s11325-0120769-0. 39. kushida ca, morgenthaler ti, littner mr, alessi ca, bailey d, coleman j jr, et al. practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. sleep 2006; 29:240–3. https://doi.org/10.1093/ sleep/29.2.240. departments of 1radiology and 2pathology, armed forces hospital, muscat, oman *corresponding author e-mail: drphilipsgm@yahoo.com فرط التنسج السدوي متعلق بشبه ورم وعائي حالة نادرة تشبه سرطان الثدي فيليب�س جورج مايكل، طاهرة ال�سعدي، راك�س جاخماندركار، ال�سكيمي راو pseudoangiomatous stromal hyperplasia a rare mimic of breast malignancy *philips g. michael,1 tahra al-saadi,1 rakesh jamkhandikar,1 lakshmi rao2 a 48-year-old premenopausal woman presented to the breast clinic of the armed forces hospital, muscat, oman, in 2015 with a one-year history of a lump in her right breast which was progressively increasing in size. she had no associated fever or nipple discharge. the patient had three children whom she had breastfed normally. she was not lactating at the time of presentation and did not have a history of previous breast-related surgeries or trauma. on clinical examination, the right breast was found to be enlarged and diffusely erythematous with prominent superficial veins and skin changes. there was a palpable non-tender mass measuring approximately 1.5 x 2.5 cm in size which was suspected to be malignant (i.e. an inflammatory carcinoma). the axillary lymph nodes were not palpable. mammography and ultrasonography of both breasts was performed. the mammogram revealed a lesion in the right breast which was rounded with slightly lobulated margins [figure 1]. the lesion was classified as breast imaging-reporting and data system category 4. no microcalcifications were evident. the ultrasound scan showed a 1.5 x 2.5 cm hypoechoic mass in the same location as that of the mammographic abnormality [figure 2]. a colour doppler ultrasound did not show any flow within the lesion. radiologically, the appearance of the lesion was suggestive of a fibroadenoma or phyllodes tumour. however, due to concern that the lesion might be malignant, a histopathological examination was advised. fine-needle aspiration cytology results were equivocal. subsequently, an ultrasound-guided core biopsy of the lesion revealed the presence of spindle cells in a pseudoangiomatous pattern within the fibrous tissue [figure 3]. this confirmed the diagnosis of pseudoangiomatous stromal hyperplasia (pash). the lesion was surgically excised through a small incision with excellent postoperative cosmetic results. the patient was followed-up for two years without evidence of recurrence. figure 1: mammography of the right breast of a 48-year-old premenopausal woman from the (a) mediolateral oblique and (b) craniocaudal views. a round mass with slightly lobulated margins can be observed (arrows). r = right breast; mlo = mediolateral oblique; cc = craniocaudal. interesting medical image sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e248–249, epub. 20 jun 17 submitted 15 dec 16 revision req. 30 jan 17; revision recd. 19 feb 17 accepted 2 mar 17 doi: 10.18295/squmj.2016.17.02.023 radiologically, pash lesions have no pathognomonic or specific diagnostic features. these tumours commonly resemble fibroadenomas or hamartomas on imaging, although more serious pathologies such as angiosarcomas cannot be excluded.1,3,5 large tumours may also be mistaken for phyllodes tumours.3–5 on mammography and ultrasonography, the lesion commonly appears as a well-defined mass or a hypo echoic discrete mass with benign features, respectively.4 however, case reports of lesions with irregular, illdefined or spiculated margins have been described, making it difficult to exclude the possibility of malignancy based on imaging alone.3–5 several factors influence the management of pash. for lesions that are small, asymptomatic and unequivocally confirmed by biopsy, surgical excision can be avoided; in contrast, surgery is indicated for larger lesions, for patients where the preoperative histology cannot confirm a diagnosis or in cases with suspicious clinical or radiological features.2–5 references 1. masannat ya, whitehead s, hawley i, apthorp l, shah ef. pseudoangiomatous stromal hyperplasia: a case report. case rep med 2010; 2010:549643. doi: 10.1155/2010/549643. 2. almohawes e, khoumais n, arafah m. pseudoangiomatous stromal hyperplasia of the breast: a case report of a 12-yearold girl. radiol case rep 2015; 10:1–4. doi: 10.1016/j. radcr.2015.06.007. 3. kutlutürk k, usta s, ünal b, karadağ n, akatlı an. pseudoangiomatous stromal hyperplasia of the breast presenting as a giant breast tumor: a case report. j breast health (2013) 2015; 11:39–41. doi: 10.5152/tjbh.2014.1977. 4. jones kn, glazebrook kn, reynolds c. pseudoangiomatous stromal hyperplasia: imaging findings with pathologic and clinical correlation. ajr am j roentgenol 2010; 195:1036–42. doi: 10.2214/ajr.09.3284. 5. bowman e, oprea g, okoli j, gundry k, rizzo m, gabrammendola s, et al. pseudoangiomatous stromal hyperplasia (pash) of the breast: a series of 24 patients. breast j 2012; 18:242–7. doi: 10.1111/j.1524-4741.2012.01230.x. comment pash refers to a rare benign mesenchymal proliferative lesion of the breast.1 while the precise aetiology of this condition is not yet well understood, a hormonal cause has been proposed.1,2 this is supported by the fact that the majority of patients with pash are premenopausal.2 in addition, the use of oral contraceptives and hormonal replacement therapy have been implicated.2,3 the current case is interesting for several reasons. first, the atypical clinical presentation of pash in the patient initially indicated focal inflammatory or granulomatous mastitis or an inflammatory breast carcinoma. second, the imaging findings primarily resembled a fibroadenoma or phyllodes tumour; however, the possibility of a malignant lesion could not be excluded. third, a final histopathological diagnosis of pash is extremely rare.3 a preoperative diagnosis of pash based on fine-needle aspiration cytology is not possible since the results are non-specific; a core biopsy may help to establish the diagnosis, although in some cases a diagnosis can be made only after surgical excision.4 histologically, pash is composed of complex interanastomosing slit-like spaces within the breast parenchyma lined by spindle cells. the absence of blood cells within these structures and the lack of cellular atypia or mitotic activity can help to differentiate pash from low-grade angiosarcomas.5 differentiation between these two entities is vital due to differences in their management and prognosis.3–5 in equivocal cases, immunohistochemistry also plays a role in diagnosis since pash lesions are positive for vimentin and cluster of differentiation (cd) 34 and negative for cytokeratins and factor viii related antigen.3,4 figure 2: ultrasonography of the right breast of a 48-year-old premenopausal woman from the (a) transverse and (b) sagittal aspects showing an avascular hypoechoic mass (arrows). this mass was in the same location as a clinically palpable lump and mammographic abnormality. tr = transverse; sag = sagittal. figure 3: haematoxylin and eosin stain of a core needle biopsy of a right breast lesion at x200 magnification showing the presence of spindle cells in a pseudoangiomatous pattern (arrow) within the fibrous tissue, in keeping with a diagnosis of pseudoangiomatous stromal hyperplasia. interesting medical image | e249 philips g. michael, tahra al-saadi, rakesh jamkhandikar and lakshmi rao https://doi.org/10.1155/2010/549643 https://doi.org/10.1016/j.radcr.2015.06.007 https://doi.org/10.1016/j.radcr.2015.06.007 https://doi.org/10.5152/tjbh.2014.1977 https://doi.org/10.2214/ajr.09.3284 https://doi.org/10.1111/j.1524-4741.2012.01230.x 2department of haematology, 1college of medicine and health sciences, sultan qaboos university, muscat, oman; departments of 3child health and 4haematology, sultan qaboos university hosptial, muscat, oman *corresponding author’s e-mail: khabori@squ.edu.om تأثري بعد املنزل عن مركز العالج على نتائج زراعة خناع العظم مالك الناعبية، مرت�سى اخلابوري، حممد احلنيني، عبداحلكيم الروا�ض، ديفيد دين�سون abstract: objectives: haematopoietic stem cell transplantation (hsct) in oman started in 1994 at sultan qaboos university hospital (squh), muscat, oman. previous studies have suggested that longer driving time to the trans plant centre (dtc) independently correlates with worse overall survival (os). therefore, this study aimed to examine the impact of dtc on os and acute graft-versus-host disease (agvhd). methods: this retrospective study included all patients who underwent hsct between february 2006 and december 2016 at squh. the dtc was determined using google maps (google llc., mountain view, california, usa). the probability of os was estimated using a kaplan-meier estimator and the impact of dtc on os was compared using a cox model. results: a total of 170 patients were included in this study of which 52% were male and 28% were from the al batinah region. the mean age was 14.2 ± 12.2 years. the mean haemoglobin, platelet and white blood cell counts before the hsct were 10.3 ± 1.7 g/dl, 207 ± 131 × 109/l and 5.1 ± 5.9 × 109/l, respectively. the median dtc for those with agvhd was 84 minutes, which is similar to patients without agvhd (p = 0.918). the hazard ratio for dtc as a predictor of os was 1.0 (p = 0.901). conclusion: in this single centre study, dtc did not impact agvhd or os in patients post-hsct. the study was limited by its retrospective design and the small sample size. it is recommended that these results be confirmed in a prospective study. keywords: hematopoietic stem cell transplantation; graft versus host disease; survival analysis; travel; oman. امللخ�ص: الهدف: بداأت زراعة اخلاليا اجلذعية املكونة للدم يف عمان عام 1994 يف م�ست�سفى جامعة ال�سلطان قابو�ض، م�سقط، عمان. بينت الدرا�سات ال�سابقة اأن زمن الو�سول اإىل مركز زراعة اخلاليا اجلذعية ترتبط ب�سكل �سلبي مع البقاء علي احلياة ب�سكل عام. لذلك، خططنا لدرا�سة تاأثري زمن الو�سول اإىل مركز زراعة اخلاليا اجلذعية على مدى بقاء املري�ض على قيد احلياة وداء الطعم حيال الثوي احلاد. الطريقة: �سملت هذه الدرا�سة ال�ستعادية املر�سى الذين خ�سعوا لزراعة اخلاليا اجلذعية من فرباير 2006 اإىل دي�سمرب 2016 يف م�ست�سفى جامعة ال�سلطان قابو�ض. مت حتديد زمن الو�سول اإىل مركز زراعة اخلاليا اجلذعية باإ�ستخدام خرائط جوجل )جوجل، ماوننت فيو، كاليفورنيا، اأمريكا(. مت تقدير احتمال البقاء علي احلياة ب�سكل عام با�ستخدام مقّدر كابالن ماير ومتت مقارنة تاأثري زمن الو�سول اإىل مركز زراعة اخلاليا اجلذعية على مدى البقاء على قيد احلياة ب�سكل عام با�ستخدام منوذج كوك�ض. النتائج: �سملت هذه الدرا�سة ما جمموعه 170 مري�سا، %52 منهم ذكور و %28 من منطقة الباطنة. كان متو�سط العمر 14.2 ± 12.2 �سنة. كانت معدلت الهيموجلوبني وال�سفائح الدموية وتعداد خاليا الدم البي�ساء قبل الزراعة هي 10.3 ± 1.7 جم/دي�سيلرت، 207 ± 131 × 109/لرت و 5.1 ± 5.9 × 109/لرت، على التوايل. كان متو�سط زمن الو�سول اإىل املركز بالن�سبة لأولئك الذين لديهم داء الطعم حيال الثوي احلاد 84 دقيقة وهو م�سابه للمر�سى دون الداء )p = 0.918(. كانت ن�سبة اخلطر لـزمن الو�سول كموؤ�رس للبقاء على احلياة ب�سكل عام هي 1 والتي مل تكن ذات دللة اإح�سائية )p = 0.901(. اخلال�صة: يف درا�سة هذا املركز الواحد، مل يوؤثر زمن الو�سول اإىل مركز زراعة اخلاليا اجلذعية على معدل داء الطعم حيال الثوي احلاد وعلى مدى بقاء احلياة يف املر�سى الذين خ�سعوا لزراعة اخلاليا اجلذعية. كانت الدرا�سة حمدودة ب�سبب الت�سميم ال�ستعادي وحجم العينة ال�سغري.نو�سي على تاأكيد هذه النتائج يف درا�سة ا�ستباقية. الكلمات املفتاحية: زراعة اخلاليا اجلذعية املكونة للدم؛ داء الطعم حيال الثوي؛ حتليل البقاء على احلياة؛ ال�سفر؛ عمان. impact of home-to-centre distance on bone marrow transplantation outcomes malak al naabi,1 *murtadha al khabori,2 mohammed al-huneini,2 abdulhakeem al-rawas,3 david dennison4 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e15–18, epub. 30 may 19 submitted 11 sep 18 revision req. 4 nov 18; revision recd. 17 dec 18 accepted 3 jan 19 advances in knowledge this study found that home-to-transplant centre distance had no impact on the survival in patients who receive haematopoietic stem cell transplantation or on their risk of acute graft-versus-host disease. application to patient care home-to-transplant centre distance should not impact the decision to proceed with haematopoietic stem cell transplantation (hsct). physicians should ensure adequate follow-up for patients post-hsct regardless of their home-to-transplant centre distance. haematopoietic stem cell transplantation (hsct) includes peripheral blood stem cell, umbilical cord stem cell and bone marrow transplantations. hsct is used as a treatment modality to replace congenital or acquired life-threating abnormal bone marrow with normal haematopoietic stem cells to allow haematopoietic reconstitution after chemotherapy or chemoradiotherapy.1 a number of complications are associated with hsct, including infections, haemorrhage, graft failure, secondary malignancies and chronic and acute graft-versus-host disease (agvhd).2 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.004 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ impact of home-to-centre distance on bone marrow transplantation outcomes e16 | squ medical journal, february 2019, volume 19, issue 1 home-to-transplant centre distance, estimated as driving time to the transplant centre (dtc), has been shown to affect a number of transplant outcomes, albeit not consistently. abou-nassar et al. found that overall survival (os) after hsct was 76% for patients who spent ≤40 minutes driving time and 65% for patients with ≥160 minutes driving time.3 contrary to abou-nassar et al.’s study, graupner et al. found no impact of dtc on post-transplant hospital length of stay, hospital re admission in the first 100 days and os at day 100 and at one year.4 this study hypothesised that frequent early posttransplant follow-up of patients living far from the trans plant centre may be difficult to adhere to and result in patients not attending as advised. this may impact early complications such as agvhd and treatment related mortality. the impact of travelling distance has not been investigated on the outcomes of hsct in oman or in the region. sultan qaboos university hospital (squh), muscat, oman is a tertiary care national institute in the capital city with over 600 beds and serves as the only allogeneic hsct centre in oman, treating patients from the entire country. patients have to travel to the transplant centre for their follow-up, which could be up to twice per week early in the post-transplant period. this study aimed to determine the impact of dtc on os and the probability of developing agvhd for patients under going hsct at squh. methods this retrospective study was conducted between february 2006 and december 2016 and included all patients who received hsct at the transplant centre of squh, regard less of indication. in addition, patients who had received hsct outside the country and had arrived in oman before day 100 of the hsct date were included. patients with missing data on os or on agvhd development were excluded. furthermore, patients who received autologous hsct as the follow-up in the early post-transplant period were also excluded as this is different than allo geneic hsct and there is no risk of developing agvhd. the decision of the preparative regimen was made using a consensus decision during a bone marrow transplantation board discussion. driving distance and time from the primary resid ence of patients to squh was determined using google maps, version 3.32 (google llc., mountain view, calif ornia, u.s.a) and was considered a continuous variable in the analysis of this study. given that the dtc may change during the day as estimated by google maps (google llc.) due to differing traffic conditions, this variable was estimated during the same time of the day and only during working days. clinical and laboratory information were obtained from the patient’s electronic health records. continuous variables were described using means with standard deviations or medians if the variable was not normally distributed. categorical variables were described using frequencies and percentages. the prob ability of os was projected using the kaplan-meier estim ator and the impact of dtc on os was compared using a cox proportional hazard model. dtc was compared between patients with and without agvhd using a t-test. collected data were analysed using statistical package for social science (spss), version 22 (ibm corp., armonk, new york, usa). an alpha threshold of 0.05 was used to determine statistical significance. this study was reviewed and approved by the ethics committee of the college of medicine and health sciences at squh (mrce #1598). results a total of 170 patients were included in this study, with slightly more males than females (52% versus 48%). most patients were from the al batinah region (28%) [figure 1]. the mean age, haemoglobin, platelet, white blood cell count and absolute neutrophil counts at the time of transplant were 14.2 ± 12.2 years, 10.3 ± 1.7 g/dl, 207 ± 131 × 109/l, 5.1 ± 5.9 × 109/l and 2.5 ± 4.8 × 109/l, respectively. patients were transplanted for various indic ations, including acute leukaemia (n = 41), sickle cell disease (n = 28), immunodeficiency (n = 22), thalassaemia major (n = 12), lymphoma (n = 8), fanconi’s anaemia (n = 7), severe aplastic anaemia (n = 7), chronic myeloid leukaemia (n = 4), paroxysmal nocturnal haemoglobinuria (n = 3) and various other indications (n = 38). transplanted stem cells were collected from peripheral stem cells for 120 patients, from bone marrow for 49 patients and from both sources for one patient. all patients received matched sibling donors. the prophylaxis for agvhd was either figure 1: distribution of all patients who received haemato poietic stem cell transplantation at the transplant centre of sultan qaboos university hospital, muscat, oman according to the governorate of residence (n = 170). malak al naabi, murtadha al khabori, mohammed al-huneini, abdulhakeem al-rawas and david dennison clinical and basic research | e17 cyclosporine or tacrolimus with a short course of metho trexate for all patients. the median driving distance and time were 137 km (range: 6.6–997 km) and 84 minutes (range: 11–594 minutes). figure 2 shows the boxplot distribution of the dtc variable in patients with and without agvhd. both distrib utions were similar and had a similar median dtc of 84 minutes with no statistically significant difference (p = 0.918). the mean of the dtc was 106 ± 115 minutes in patients without agvhd and 110 ± 137 minutes in patients with agvhd. the probability of os for all patients at 2 and 5 years after hsct were 89% and 80%, respect ively. figure 3 illustrates the probability of os over time in patients lower and higher than the median dtc. the impact of dtc on os as assessed by a cox proportional hazard model revealed a hazard ratio of 1.0 with no stat istically significant impact of dtc on the os (p = 0.901). given the lack of impact in the univariable analysis of dtc on both os and agvhd, multivariable analyses were not performed in the current study. discussion a number of studies have addressed disparities in cancer survival rates based on geographic proximity to the treat ment center.5,6 however, studies which examine the impact of home-to-transplant centre distances on the os and risk of developing agvhd in patients under going hsct are scarce.3–6 to the best of the authors’ knowledge, this is the first study to address this issue in oman or in the region. a retrospective cohort study from nebraska assessed whether the primary area of residence was an indep endent risk factor for os in patients undergoing auto logous and allogeneic hsct.4 a significant impact was found among patients undergoing autologous hsct, but not with allogeneic hsct. those from rural areas were found to have a significantly lower survival rate (73%) compared to those from urban areas (78%; p = 0.04).4 however, the hazard ratio observed in this study provides evidence that patients from rural areas undergoing allo geneic hsct are not at a greater risk of mortality than patients from urban areas. associations found in other studies may be related to the type of health insurance coverage in urban versus rural areas. in oman, all omanis have governmental health insurance, which covers hsct. this may have led to the lack of impact of dtc on os in this study as all patients, regardless of their area of residence, had equal access to healthcare. the differ ences in the transport system of nebraska and oman may have led to some of the differing outcomes observed between the two studies.4 given the previous literature, dtc was not expected to have an impact on autol ogous hsct and the expected low mortality from this kind of transplantation lead to its exclusion from the current study.4 the gender ratio in the current study was approx imately equal, which is representative of the ratio in the general omani population.7 most of the patients were from the al batinah and muscat regions, which reflects the population distribution in oman. no significant rela tionship was found between the area of residence and os as assessed by the cox regression analysis. additio nally, omani patients receiving hsct are generally younger than those reported in studies from europe and north america.8 therefore, the association between dtc and os may not be as strong in younger patients when compared to older patients. finally, many of the patients who received hsct in the present study were transplanted for benign conditions that generally have a better prognosis than patients transplanted for malig nant conditions.8 figure 2: driving time estimated using google maps (google llc., mountain view, california, usa) of patients who received allogeneic haematopoietic stem cell transplant ation with and without acute graft-versus-host disease from home to the transplant centre of sultan qaboos university hospital, muscat, oman (n = 170). figure 3: overall survival of patients who received haemato poietic stem cell transplantation. the y-axis represents the kaplan-meier estimate of the overall survival probability according to the median driving time from home to the transplant centre at sultan qaboos university hospital, muscat, oman (n = 170). impact of home-to-centre distance on bone marrow transplantation outcomes e18 | squ medical journal, february 2019, volume 19, issue 1 furthermore, data suggests that an increase in dtc is not associated with the development of agvhd (p = 0.918). al-khabori et al.’s study showed that the incidence of agvhd in patients transplanted at squh was 32% while the incidence of chronic gvhd was 16%.8 similar reasons as for the os outcome could also be applicable for the agvhd outcome. the development of agvhd has been inconsistently shown to impact os in international studies.3 there are a number of limitations in the present study. since this was a retrospective study, there is a high chance of selection bias. additionally, the small sample size most likely contributed to the low statistical power and therefore affects the ability to make definitive con clusions. the use of google maps (google llc.) online application to estimate driving time and distance from home to squh is another limitation as the application produced different driving times at different times of the day. this is likely due to the fact that google maps (google llc.) incorporates the current traffic conditions to estimate the driving time. therefore, early morning estimates on working days were used for all patients to improve consistency and accuracy. finally, this study spanned a large time period. the driving conditions and the supportive therapy may have changed during this period. the results of this study should be interpreted in light of these limitations. however, this study is the first to report the lack of impact of home-to-transplant centre distance and driving time on the os of patients undergoing allogeneic hsct in oman as well as the risk of developing agvhd. conclusion this study suggests that driving distance is not assoc iated with the mortality or the development of agvhd. larger and prospective studies should be conducted to more accurately assess the impact of dtc in the future in oman and the region. co n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. wilkinson ib, raine t, wiles k, goodhart a, hall c, o'neill h. oxford handbook of clinical medicine. 10th ed. oxford, uk: oxford university press, 2017. p. 352–62. 2. hoffbrand av, moss pah. essential haematology. 6th ed. new jersey, usa: wiley-blackwell, 2011. p.251–61. 3. abou-nassar ke, kim ht, blossom j, ho vt, soiffer rj, cutler cs, et al. the impact of geographic proximity to transplant center on outcomes after allogeneic hematopoietic stem cell transplantation. biol blood marrow transplant 2012; 18:708–15. https://doi.org/10.1016/j.bbmt.2011.08.022. 4. graupner s, spellman a, jacobson s, bryan l, sportes c, pantin j, et al. impact of socio-economic disparities and distance to bone marrow transplant center on transplantation outcomes. biol blood marrow transplant 2016; 22:s187. https://doi.org/10.1016/j.bb mt.2015.11.567. 5. rao k, darrington dl, schumacher jj, devetten m, vose jm, loberiza fr jr. disparity in survival outcome after hematopoietic stem cell transplantation for hematologic malignancies according to area of primary residence. biol blood marrow transplant 2007; 13:1508–14. https://doi.org/10.1016/j.bbmt.2007.09.006. 6. paulson k, lambert p, bredeson c, demers a, nowatzki j, richardson e, et al. does location matter? rural vs urban out comes after blood and marrow transplantation in a populationbased canadian cohort. bone marrow transplant 2010; 45:1167–73. https://doi.org/10.1038/bmt.2009.332. 7. worldometers. oman population. from: www.worldometers. info/world-population/oman-population/ accessed: dec 2018. 8. al-khabori m, al-huneini m. hematopoietic stem cell transplan tation in the sultanate of oman. hematol oncol stem cell ther 2017; 10:305–7. https://doi.org/10.1016/j.hemonc.2017.05.024. https://doi.org/10.1016/j.bbmt.2011.08.022 https://doi.org/10.1016/j.bbmt.2015.11.567 https://doi.org/10.1016/j.bbmt.2015.11.567 https://doi.org/10.1016/j.bbmt.2007.09.006 https://doi.org/10.1038/bmt.2009.332 https://doi.org/10.1016/j.hemonc.2017.05.024 department of dermatology, thriasio general hospital, athens, greece e-mail: klimel2015@in.gr حالة حمتملة من الطفح اجللدي الثابت لألغشية املخاطية بعد العالج بعقار السيلودوسني اإليني كليمي abstract: a fixed drug eruption consists of erythematous patches that appear on the skin and/or mucous membranes following administration of a drug which, once healed, leaves residual hyperpigmentation. we report a 76-year-old male who presented to the thriasio general hospital, athens, greece, in 2016 with erythema, oedema and blistering of the lower lip and glans penis following the administration of silodosin for benign prostatic hyperplasia. the eruption regressed two weeks after silodosin was discontinued. keywords: drug eruption; mucous membranes; erythema; blister; silodosin; case report; greece. امللخ�ص: يظهر الطفح اجللدي الثابت نتيجة للدواء على هيئة بقع حمراء على اجللد و/اأو الأغ�شية املخاطية بعد اإعطاء الدواء. يرتك هذا الطفح عندما يتم �شفاوؤه، فرط الت�شبغ املتبقي. هذا تقرير حالة عن رجل يبلغ من العمر 76 عاًما قدم اإىل م�شت�شفى ثريا�شيو العام، اأثينا، اليونان، يف عام 2016 مع اأحمرار، وتورم، وبثور يف اجلزء ال�شفلي من ال�شفة وح�شفة الق�شيب بعد اإعطاء عقار ال�شيلودو�شني لعالج ت�شخم الربو�شتاتا احلميد. تراجع الطفح بعد اأ�شبوعني من وقف عقار ال�شيلودو�شني. الكلمات املفتاحية: الطفح اجللدي نتيجة للدواء؛ الأغ�شية املخاطية؛ التهاب اجللد اإلحمرارى؛ بثور؛ ال�شيلودو�شني؛ تقرير حالة؛ اليونان. a probable case of mucosal fixed drug eruption following treatment with silodosin eleni klimi online case report sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e402–404, epub. 19 dec 18 submitted 16 apr 18 revision req. 15 may 18; revision recd. 11 jun 18 accepted 27 jun 18 doi: 10.18295/squmj.2018.18.03.025 a fixed drug eruption (fde) consists of well-circumscribed erythematous patches on the skin and/or mucous membranes that occur between days and a few weeks following the administration of a drug.1 the patches recur on the same body site after the drug is reintroduced and heal leaving hyper pigmentation. although the most common clinical presentation of fde involves the skin, zaouak et al. recently reported a case of mucosal fde due to mefenamic acid.2 to the best of the author’s knowledge, this is the first potential case of mucosal fde following silodosin intake. case report a 76-year-old male presented to the dermatology outpatient clinic of the thriasio general hospital, athens, greece, in 2016 due to lesions on his lower lip and glans penis which had first appeared five days prior. over the preceding 20 days, he reported having taken 8 mg daily of silodosin as prescribed by his urologist for benign prostatic hyperplasia. he was not currently taking any other medications and had no history of atopy, immune disease or cancer. a clinical examination revealed erythema and oedema of the lower lip and a well-circumscribed eryth ematous patch on the glans penis with a blister on one side [figure 1]. the patient reported that a burning sensation had preceded the appearance of both lesions. a fde was suspected; however, he refused a biopsy and a patch test. as a urologist confirmed that no further medication was needed in view of the minor nature of the patient’s urinary symptoms, silodosin was discontinued. within two weeks, regression of the lesions was observed [figure 2]. subsequently, a steroid cream of moderate potency was applied. a rechallenge protocol was not attempted as the patient was wary of the reappearance of the lesions. discussion overall, fde is a rare type of adverse drug reaction.1 the clinical picture of a fde involves a well-circumscribed erythematous patch on the skin and/or mucous membranes, with or without blisters, which recurs at the same site following the re-administration of the responsible drug and leaves hyperpigmentation after regression. in more severe cases, mucosal erosions or eleni klimi online case report | e403 on the other hand, intraepidermal cd8+ t cells function as protective immune cells against bacterial and viral infections. this explains why certain predilection sites for fde, like the oral and genital mucosa, coincide with those of herpes simplex virus infections.9–11 the resolution of the fde lesions occurs when regulatory t cells from other parts of the body are recruited at the affected site. this process accounts for the self-limiting nature of fde in which the tissue damage is minor compared with the extensive and more destructive tissue damage seen in ten cases.9–11 silodosin, an alpha adrenergic receptor blocker, is commonly prescribed to relieve the urinary symptoms of benign prostatic hyperplasia.12 however, adverse skin reactions have been reported with its use, including pruritus, urticaria and maculopapular drug eruptions.13,14 according to the updated french causality assessment method, the likelihood of silodosin being the causative agent of fde in the current case is suggestive, with an imputability value of i3.15 to the best of the author’s knowledge, there have been no previous reports to date of mucosal fde associated either with silodosin or similar drugs like tamsulosin. conclusion the current case increases awareness of the potential occurrence of fde following silodosin administration which could be easily misdiagnosed for other conditions. drug intake history should therefore be taken into account in cases of genital and oral ulceration. references 1. flowers h, brodell r, brents m, wyatt jp. fixed drug eruptions: presentation, diagnosis, and management. south med j 2014; 107:724–7. doi: 10.14423/smj.0000000000000195. ulcerations may appear, resulting in a pseudo-aphthoid appearance.1 a fde may appear as solitary or multiple lesions.3 although the pigmented form is most common, a pure erythematous form as well as a rarer generalised bullous type imitating toxic epidermal necrolysis (ten) has also been described.4,5 a histological analysis reveals a lichenoid reaction, keratinocyte necrosis, vacuolisation of the basal layer of the epidermis, dermal oedema and perivascular lymphohistiocytic and, occasionally, eosin ophilic infiltrate with marked pigmentary incontinence between outbreaks.3 the differential diagnosis of fde includes bullous impetigo in its initial stage, a herpes simplex virus infection, aphthous stomatitis, syphilis and autoimmune disorders such as bullous pemphigoid and pemphigus vulgaris.3 the main differential diagnosis is erythema multiforme which may also be drug-induced; however, the presence of typical target-like lesions in erythema multiforme helps to distinguish these two conditions.3 non-steroidal anti-inflammatory drugs such as mefen amic acid, ibuprofen and oxyphenbutazone are a leading cause of fdes, as well as antibiotics such as trimethoprim, tetracycline and sulfonamide.6 more rarely, meprobamate and oxcarbazepine have also been reported to induce fdes.7,8 intraepidermal resident cluster of differentiation (cd)8+ t cells have been implicated in the pathogenesis of fde.9–11 when activated by certain stimuli, these cells release large amounts of inflammatory cytokines that induce inflammatory findings, such as erythema, blistering and ulceration. they also have memory and effector cell properties which are responsible for the recurrence of fde lesions if the drug is reintroduced.9–11 figure 1: clinical photographs of the (a) lower lip and (b) glans penis of a 76-year-old male showing erythema, oedema and blistering. figure 2: clinical photograph of the glans penis of a 76 year-old male with a suspected fixed drug eruption showing the regression of erythema following the discontinuation of silodosin. https://doi.org/10.14423/smj.0000000000000195 a probable case of mucosal fixed drug eruption following treatment with silodosin e404 | squ medical journal, august 2018, volume 18, issue 3 9. shiohara t, mizukawa y. fixed drug eruption: a disease mediated by self-inflicted responses of intraepidermal t cells. eur j dermatol 2007; 17:201–8. doi: 10.1684/ejd.2007.0149. 10. shiohara t. fixed drug eruption: pathogenesis and diagnostic tests. curr opin allergy clin immunol 2009; 9:316–21. doi: 10.10 97/aci.0b013e32832cda4c. 11. shiohara t, mizukawa y. fixed drug eruption: the dark side of activation of intraepidermal cd8+ t cells uniquely specialized to mediate protective immunity. chem immunol allergy 2012; 97:106–21 doi: 10.1159/000335623. 12. keating gm. silodosin: a review of its use in the treatment of the signs and symptoms of benign prostatic hyperplasia. drugs 2015; 75:207–17. doi: 10.1007/s40265-014-0344-z. 13. romano mv, marino m, cinconze m, nasca mr, furnari r, petralia a, et al. itching skin rash during valproic acid therapy in co-administration with silodosin: a case report and review of literature. j clin exp dermatol res 2016; 7:1000339. doi: 10.4172/2155-9554.1000339. 14. inoue a, sawada y, ohmori s, omoto d, haruyama s, yoshioka m, et al. maculopapular type drug eruption caused by silodosin. allergol int 2016; 65:219–20. doi: 10.1016/j.alit.2015.11.008. 15. miremont-salamé g, théophile h, haramburu f, bégaud b. causality assessment in pharmacovigilance: the french method and its successive updates. therapie 2016; 71:179–86. doi: 10.1016/j. therap.2016.02.010. 2. zaouak a, ben brahim e, ben tanfous a, koubaa w, sahnoun r, hammami h, et al. mucosal fixed drug eruption due to mefenamic acid: report of a case and a review. therapie 2018; 73:433–5. doi: 10.1016/j.therap.2018.01.005. 3. fitzpatrick tb, johnson ra, wolff k, polano mk, suurmond d. fixed drug eruption. in: color atlas and synopsis of clinical dermatology: common and serious diseases, 3rd ed. new york, usa: mcgraw-hill education, 1996. pp. 560–3. 4. ozkaya e, elinç-aslan ms. pseudoephedrine may cause “pigmenting” fixed drug eruption. dermatitis 2011; 22:e7–9. doi: 10.2310/6620.2011.10119. 5. mitre v, applebaum ds, albahrani y, hsu s. generalized bullous fixed drug eruption imitating toxic epidermal necrolysis: a case report and literature review. dermatol online j 2017; 23:7. 6. hoetzenecker w, nägeli m, mehra et, jensen an, saulite i, schmid-grendelmeier p, et al. adverse cutaneous drug eruptions: current understanding. semin immunopathol 2016; 38:75–86. doi: 10.1007/s00281-015-0540-2. 7. zaïem a, kaabi w, badri t, lakhoua g, sahnoun r, kastalli s, et al. meprobamate-induced fixed drug eruption. curr drug saf 2014; 9:161–2. doi: 10.2174/1574886309666140121105737. 8. shuster c, kränke b, aberer w, komericki p. fixed drug eruption on the penis due to oxcarbazepine. arch dermatol 2011; 147:362–4. doi: 10.1001/archdermatol.2011.32. https://doi.org/10.1684/ejd.2007.0149 https://doi.org/10.1097/aci.0b013e32832cda4c https://doi.org/10.1097/aci.0b013e32832cda4c https://doi.org/10.1159/000335623 https://doi.org/10.1007/s40265-014-0344-z https://doi.org/10.4172/2155-9554.1000339 https://doi.org/10.1016/j.alit.2015.11.008 https://doi.org/10.1016/j.therap.2016.02.010 https://doi.org/10.1016/j.therap.2016.02.010 https://doi.org/10.1016/j.therap.2018.01.005 https://doi.org/10.2310/6620.2011.10119 https://doi.org/10.1007/s00281-015-0540-2 https://doi.org/10.2174/1574886309666140121105737 https://doi.org/10.1001/archdermatol.2011.32 although patients admitted to emerg-ency departments often suffer from chest pain, the actual incidence of acute myocardial infarction is relatively low (approximately 2–3%).1,2 the rupture of a papillary muscle is a rare but generally fatal mechanical complication; it is found in 0.5–5% of patients with acute myocardial infarctions.3,4 diagnosing an acute myocardial infarction becomes even more difficult if there is no evidence of acute ischaemia on an electrocardiogram and if echocardiography indicates no regional wall motion abnormalities. one of the current major challenges in emergency medicine is the rapid identification of these patients so as to treat them promptly with appropriate cardiac interventions. this report describes a rare case of severe ischaemic papillary muscle rupture diagnosed via transoesophageal echocardiography. case report a 67-year-old male was admitted to the emergency department of the university hospital bern in switzerland in november 2013 with dyspnoea at rest and a one-hour history of chest pains radiating down both arms. when the ambulance arrived, his oxygen saturation in room air was 84%. during transport to the hospital, the patient became hypotensive (blood pressure: 70/50 mmhg). the patient’s only known cardiovascular risk factor was a history of smoking cigarettes and he reported that he was not currently taking any regular medications. on arrival to the emergency department, the patient’s blood pressure had reduced to 60/40 mmhg. he had a pulse of 110 beats per minute, a respiratory rate of 20 breaths per minute and his oxygen saturation was 96% after the emergency department, university hospital bern, switzerland *corresponding author e-mail: christian.braun@insel.ch تشخيص عسري لتمزق إفقاري يف العضلة احلليمية تقرير حالة من قسم حضري لطب الطوارئ كري�ستيان براون، مرييت ريكلني، اري�ستومين�س اك�ساداكوتلو�س abstract: we present a rare case of severe ischaemic papillary muscle rupture in a 67-year-old male patient who was admitted to the emergency department of the university hospital bern, switzerland, in november 2013 with acute chest pain. on admission, the patient’s blood pressure was 60/40 mm/hg, his pulse was 110 beats per minute and his respiratory rate was 20 breaths per minute. an electrocardiogram was normal and focused assessment with sonography in trauma was negative. transthoracic echocardiography showed possible thickening of the mitral valve leaflet with no indications of severe mitral insufficiency or wall motion abnormalities. triple-ruleout computed tomography angiography revealed no pulmonary emboli or aortic dissection, although coronary atherosclerosis was present. finally, severe insufficiency of the mitral valve with rupture of the papillary muscle, likely due to ischaemia, was observed via transoesophageal echocardiography. the patient underwent a successful surgical intervention and was discharged 10 days later in stable condition. keywords: emergency medicine; shock; myocardial infarction; papillary muscles; heart rupture; echocardiography; case report; switzerland. يف الطوارئ طب لق�سم اأدخل عاما 67 عمره مري�س عند الإقفارية احلليمية الع�سلة لتمزق وحادة نادرة حالة هنا نعر�س امللخ�ص: امل�ست�سفى اجلامعي مبدينة برين يف �سوي�رسا يف نوفمرب 2013م ب�سبب اأمل حاد يف �سدره. وكان �سغط دمه عند اإدخاله للم�ست�سفى 60/40 التخطيط وتقييم طبيعيا، لديه القلب ر�سم وكان الدقيقة. يف مرة 20 تنف�سه ومعدل الدقيقة، يف �رسبة 110 نب�سه ومعدل زئبق، ملم الت�سواتي �سلبيا. واأو�سح تخطيط �سدى القلب عرب ال�سدر اإمكانية حدوث ثخن يف وريقة ال�سمام املرتايل من غري وجود اإ�سارات اإىل حدوث ق�سور مرتايل وخيم، اأو اعتاللت يف حركة اجلدار. واأو�سح ت�سوير الأوعية بوا�سطة الت�سوير املقطعي املحو�سب اأنه ل توجد ان�سمامات رئوية اأو ت�سلخ اأبهري، رغم وجود ت�سلب يف ال�رسايني التاجية. واأخريا مت اكت�ساف وجود ق�سور وخيم يف ال�سمام املرتايل مع متزق اإقفاري يف الع�سلة احلليمية، غالبا ما تكون قد حدثت ب�سبب الإفقار )نق�س الرتوية(، وذلك بوا�سطة تخطيط �سدى القلب عرب املريء. ومت اجراء تدخل جراحي ناجح للمري�س، ومت تخريجه من امل�ست�سفى عقب ا�ستقرار حالته بعد ع�رسة اأيام من اجراء تلك العملية. كلمات مفتاحية: طب الطوارئ؛ ال�سدمة؛ احت�ساء ع�سلة القلب؛ الع�سالت احلليمية؛ متزق القلب؛ تخطيط �سدى القلب؛ تقرير حالة؛ �سوي�رسا. the difficult diagnosis of ischaemic papillary muscle rupture case report from an urban emergency department *christian t. braun, meret e. ricklin, aristomenis k. exadaktylos case report sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 234–237, epub. 15 may 16 submitted 21 jul 15 revisions req. 23 aug & 1 sep 15; revisions recd. 24 aug & 10 sep 15 accepted 8 oct 15 doi: 10.18295/squmj.2016.16.02.016 christian t. braun, meret e. ricklin and aristomenis k. exadaktylos case report | e235 administration of 2 l of oxygen. his temperature was 36.8 °c and consciousness was measured at level 14 of the glasgow coma scale. a physical examination of the patient on arrival indicated regular heart sounds with a systolic murmur; the heart sounds were heard most clearly above erb’s point. auscultation of the lung, examination of the abdomen and a preliminary neurological examination were all normal. an electrocardiogram was normal with no evidence of acute ischaemia. focused assessment with sonography in trauma was negative. transthoracic echocardiography performed by cardiologists revealed a thickened mitral valve leaflet with mild mitral insufficiency and, most importantly, no wall motion abnormalities or pericardial effusion [figure 1]. the left ventricular ejection fraction was estimated to be 65%. creatine kinase (1,319 u/l; normal value: <190 u/l), creatine phosphokinase-mb (119.2 µg/l; normal value: <4.9 µg/l) and high-sensitivity cardiac troponin t (2.150 µg/l; normal value: <0.014 µg/l) levels were all substantially elevated. although the patient was becoming increasingly haemodynamically unstable, the diagnosis remained unclear. consequently, triplerule-out computed tomography was performed. no evidence of pulmonary emboli or aortic dissection was noted, although there were signs of general coronary atherosclerosis with plaques and without any luminal occlusion. the scan also revealed an infiltrate in the left upper lobe, perhaps due to aspiration pneumonia, with a small amount of left pleural effusion. after diagnostic and laboratory testing, the patient was prescribed vasopressin before being intubated and receiving analgaesics. he was in a progressively unstable state and was re-evaluated by an interdisciplinary team, including intensive care physicians, cardiologists and emergency physicians. although there were marked increases in heart enzymes, due to the lack of segmental wall motion abnormalities on transthoracic echocardiography, a coronary angiogram was not immediately performed. the patient was transferred to the intensive care ward for further monitoring. while there, he rapidly developed cardiogenic shock and it was not possible to stabilise him. as a result, transoesophageal echocardiography was performed. this demonstrated severe mitral valve insufficiency with rupture of the papillary muscle, dilatation of the left atrium and severe secondary pulmonary hypertension. the left ventricular ejection fraction remained the same (65%) and there were still no signs of any regional wall motion abnormalities [table 1]. a coronary angiograph was subsequently carried out which showed that the papillary muscle rupture was caused by a distally occluded right coronary artery (rca). as the patient remained unstable, cardiac surgery was performed. the mitral valve was replaced with a biological prosthesis and a coronary artery bypass graft was undertaken. the postoperative course was uneventful and the patient was discharged in a stable condition 10 days later. discussion this report presents an unusual case of ischaemic papillary muscle rupture. firstly, it is rare for cardiogenic shock to develop only a few hours after the onset of symptoms; the highest risk of shock is normally two to seven days after the myocardial infarction, when healing has begun.5 in this particular table 1: comparison of transthoracic and transoesophageal echocardiographic findings for a 67-year-old male patient with ischaemic papillary muscle rupture finding tte toe left ventricular ef normal normal regional wall motion abnormalities none none pericardial effusion none none papillary muscle rupture thickened mitral valve leaflet thickened mitral valve leaflet and rupture of the papillary muscle mitral valve regurgitation* mild insufficiency† severe insufficiency‡ left atrium no dilatation dilatation and severe secondary pulmonary hypertension tte = transthoracic echocardiography; toe = transoesophageal echocardiography; ef = ejection fraction. *using colour doppler imaging. †small jet of mitral regurgitation. ‡large eccentric jet of mitral regurgitation. figure 1: transthoracic echocardiography showing a thickened posterolateral mitral leaflet (arrow) in a 67-year-old male patient with ischaemic papillary muscle rupture. note the lack of wall motion abnormalities or pericardial effusion. the difficult diagnosis of ischaemic papillary muscle rupture case report from an urban emergency department e236 | squ medical journal, may 2016, volume 16, issue 2 patients.10 however, monin et al. found that only 5% of patients required transoesophageal echocardiography to adequately quantify the severity of mitral insufficiency.11 transthoracic echocardiography is therefore an appropriate first-line imaging modality and transoesophageal echocardiography should be reserved for patients with poor-quality transthoracic images or those with continued deterioration and an unclear diagnosis. conclusion corresponding with previous findings in the literature, the current case report supports the view that transoesophageal echocardiography is a valuable tool to confirm the diagnosis of ischaemic papillary muscle rupture. in these cases, several diagnostic measures may often be needed. as such, the utilisation of transoesophageal, rather than transthoracic, echocardiography may lead to a life-saving diagnosis for patients who are cardiovascularly unstable. references 1. cherian ps, clarke aj, burstow dj. unusual case of acute posteromedial papillary muscle rupture after acute anterior myocardial infarction. heart lung circ 2014; 23:e16–19. doi: 10.1016/j.hlc.2013.07.005. 2. bayley md, schwartz js, shofer fs, weiner m, sites fd, traber kb, et al. the financial burden of emergency department congestion and hospital crowding for chest pain patients awaiting admission. ann emerg med 2005; 45:110–17. doi: 10.1016/j. annemergmed.2004.09.010. 3. christ g, siostrzonek p, maurer g, baumgartner h. partial papillary muscle rupture complicating acute myocardial infarction: diagnosis by multiplane transoesophageal echocardiography. eur heart j 1995; 16:1736–8. 4. wei jy, hutchins gm, bulkley bh. papillary muscle rupture in fatal acute myocardial infarction: a potentially treatable form of cardiogenic shock. ann intern med 1979; 90:149–52. doi: 10.7326/0003-4819-90-2-149. 5. thompson cr, buller ce, sleeper la, antonelli ta, webb jg, jaber wa, et al. cardiogenic shock due to acute severe mitral regurgitation complicating acute myocardial infarction: a report from the shock trial registry should we use emergently revascularize occluded coronaries in cardiogenic shock? j am coll cardiol 2000; 36:1104–9. 6. czarnecki a, thakrar a, fang t, lytwyn m, ahmadie r, pascoe e, et al. acute severe mitral regurgitation: consideration of papillary muscle architecture. cardiovasc ultrasound 2008; 18:6:5. doi: 10.1186/1476-7120-6-5. 7. schroeter t, lehmann s, misfeld m, borger m, subramanian s, mohr fw, et al. clinical outcome after mitral valve surgery due to ischemic papillary muscle rupture. ann thorac surg 2013; 95:820–4. doi: 10.1016/j.athoracsur.2012.10.050. 8. bouma w, wijdh-den hamer ij, koene bm, kuijpers m, natour e, erasmus me, et al. predictors of in-hospital mortality after mitral valve surgery for post-myocardial infarction papillary muscle rupture. j cardiothorac surg 2014; 9:171 doi: 10.1186/ s13019-014-0171-z. case, the short interval of time could potentially be explained by a silent ischaemic event occurring one or two days previously. alternatively, the papillary muscle may have already been affected for some unrelated reason.6 secondly, the lack of regional wall motion abnormalities is an uncommon finding, particularly in a hypotensive patient; the only possible explanation for this would be an acute papillary muscle rupture with severe acute mitral regurgitation. as in this case, the posteromedial papillary muscle is often affected during a myocardial infarction in the area perfused by the rca; in comparison, the anterolateral papillary muscle has a dual blood supply and therefore very rarely exhibits ischaemic complications.1 thirdly, it is rare for cases of papillary muscle rupture with severe mitral regurgitation to have an uncomplicated postoperative course, as observed with the current patient. this condition usually carries a high mortality rate; schroeter et al. determined a 30-day postoperative mortality rate of 39.3%, while another study reported rates of 4.2% and 25.0% for intraoperative and in-hospital mortality, respectively.7,8 echocardiography is the imaging modality of choice for the non-invasive assessment of mechanical cardiac complications such as acute mitral regurgitation in the setting of a myocardial infarction.6 in these cases, the appearance of mitral regurgitation, often in relation to papillary muscle rupture, is an important sign of poor prognosis.9 consequently, echocardiography plays an essential role in the early diagnosis, estimation of severity and determination of the pathomechanisms of ischaemic mitral regurgitation in patients with acute myocardial infarctions.9 transoesphageal echocardiography has been well established as the initial diagnostic tool for identifying papillary muscle rupture, with a diagnostic sensitivity of 65–85%.6 due to the close proximity of the ultrasound transducer to the mitral apparatus, transoesophageal echocardiography is often used to improve reliability when diagnosing the cause of mitral regurgitation; it has been found to increase the diagnostic yield to approximately 95–100%.10 christ et al. described a case of partial papillary muscle rupture diagnosed solely by transoesophageal echocardiography; previous transthoracic echocardiographs had shown no pathologies or only posterior mitral leaflet prolapse.3 similar experiences have been reported for patients with acute septal ruptures in the acute stage of a myocardial infarction. maillier et al. found that only eight out of 15 septal ruptures could be visualised directly by conventional transthoracic echocardiography; in contrast, transoesophageal echocardiography successfully diagnosed 14 of the same http://dx.doi.org/10.1016/j.hlc.2013.07.005 http://dx.doi.org/10.1016/j.annemergmed.2004.09.010 http://dx.doi.org/10.1016/j.annemergmed.2004.09.010 http://dx.doi.org/10.7326/0003-4819-90-2-149 http://dx.doi.org/10.1186/1476-7120-6-5 http://dx.doi.org/10.1016/j.athoracsur.2012.10.050 http://dx.doi.org/10.1186/s13019-014-0171-z http://dx.doi.org/10.1186/s13019-014-0171-z christian t. braun, meret e. ricklin and aristomenis k. exadaktylos case report | e237 9. petris ao, iliescu d, alexandrescu dm, costache ii. ischemic mitral regurgitation in patients with acute myocardial infarction. rev med chir soc med nat iasi 2014; 118:618–23. 10. maillier b, metz d, nazeyrollas p, maes d, chapoutot l, jennesseaux c, et al. [value of transesophageal echocardiography in post-infarction septal ruptures.] arch mal coeur vaiss 1996; 89:695–702. 11. monin jl, dehant p, roiron c, monchi m, tabet jy, clerc p, et al. functional assessment of mitral regurgitation by transthoracic echocardiography using standardized imaging planes: diagnostic accuracy and outcome implications. j am coll cardiol 2005; 46:302–9. doi: 10.1016/j.jacc.2005.03.064. http://dx.doi.org/10.1016/j.jacc.2005.03.064 1department of communicable disease surveillance & control, directorate general of health services, ministry of health, al batinah north governorate, oman; 2department of internal medicine, al-nahdha hospital, muscat, oman *corresponding author e-mail: alielgalib@yahoo.co.uk قصور كظر ثانوي نتيجة اعطاء دواء الريتونافري مع خباخ فلوتيكاسون بروبيونات تقرير حالة علي املقبايل، بينا كامبل، �سامل الق�سابي، علي اجلالب abstract: ritonavir is a powerful inhibitor of the cytochrome p450 3a4 (cyp3a4) isoenzyme. it is used as a pharmaceutical enhancer in the management of hiv-positive patients. however, when co-administered with other drugs that are metabolised via the cyp3a4 pathway, ritonavir can potentially cause serious drug-drug interactions. inhaled fluticasone propionate, which is used to treat asthma and chronic obstructive airway disease, is particularly prone to such interactions due to its physiological attributes. we report a hiv-positive 48-year-old male patient who presented to al nahdha hospital, muscat, oman, in 2012 with weight loss, generalised weakness and fatigue and diagnosed with secondary adrenal insufficiency as a result of concomitant ritonavir and inhaled fluticasone. keywords: human immunodeficiency virus; ritonavir; fluticasone; drug interactions; adrenal insufficiency; case report; oman. امللخ�ص: يعترب الريتونافري مثبط قوي لالأيزواأنزمي �سيتوكروم )p450 3a4 )cyp3a4. والذي يتم ا�ستخدامه كعالج للمر�سى امل�سابني بفريو�ص العوز املناعي املكت�سب. اأال اأنه عند ا�ستخدامه مع اأدوية اأخرى تتحلل عن طريق نف�ص عمليات االأي�ص التي يتحلل بها ال�سيتوكروم cyp3a4، حتدث اّثار جانبية نتيجة هذه التفاعالت الدوائية. و من هذه االأدوية بخاخ فلوتيكا�سون بروبيونيت، الذي ي�ستخدم لعالج مر�سى الربو ومر�ص جمرى الهواء االإن�سدادي املزمن، والذي يكون اأكرث عر�سة ب�سكل خا�ص لهذه التفاعالت ب�سبب خ�سائ�سه الف�سيولوجية . قمنا بت�سجيل حالة مري�ص بفريو�ص العوز املناعي املكت�سب والذي يبلغ من العمر 48 عام وح�رص مل�ست�سفى النه�سة مبحافظة م�سقط يف �سلطنة عمان يف عام 2012، وكان ي�ستكي من فقدان يف الوزن، اإعياء وخمول عام، ومت ت�سخي�سه بق�سور الكظر الثانوي نتيجة م�ساحبة اأدوية الريتونافري وبخاخ فلوتيكا�سون بروبيونات. الكلمات املفتاحية: فريو�ص العوز املناعي املكت�سب؛ الريتونافري؛ فلوتيكا�سون؛ تفاعالت اأدوية؛ ق�سور الكظر؛ حالة مر�سية؛ عمان. secondary adrenal insufficiency due to the co-administration of ritonavir and inhaled fluticasone propionate case report ali al-maqbali,1 bina kamble,2 salim al-qassabi,2 *ali elgalib2 sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e339–342, epub. 10 oct 17 submitted 19 feb 17 revision req. 11 apr 17; revision recd. 30 apr 17 accepted 11 may 17 case report doi: 10.18295/squmj.2017.17.03.014 fluticasone propionate is an inhaled steroid used to manage chronic obstructive airway disease and asthma and is a substrate of the cyp3a4 enzyme similar to beclomethasone, budesonide and triamcinolone.5 however, fluticasone propionate is more likely to interact with cyp3a4 inhibitors due to its longer half-life, higher glucocorticoid receptorbinding affinity, greater lipophilicity and larger volume distribution.5 a pharmacokinetic study of healthy volunteers found that ritonavir increased the area under the curve of serum fluticasone by 350-fold.6 this case report describes the development of secondary adrenal insufficiency in an hiv-positive patient as a result of the concomitant administration of ritonavir and inhaled fluticasone propionate. the use of highly-active antiretroviral therapy (haart) has revolutionised the prognosis of hiv-infected patients and ensured that the infection remains a treatable chronic condition. with prompt diagnosis and treatment, hiv infected individuals now have a life expectancy similar to that of the general population.1 ritonavir, a powerful inhibitor of the cytochrome p 450 3a4 (cyp3a4) isoenzyme, is often prescribed once daily in small doses to hiv patients as a pharmacokinetic enhancer of protease inhibitors.2 this allows the use of fewer protease inhibitor tablets, hence improving patient compliance and increasing the potency of haart.3 however, harmful interactions can occur when ritonavir is co-administered with other drugs that are metabolised via the cyp3a4 pathway, such as corticosteroids, macrolides and statins.3,4 secondary adrenal insufficiency due to the co-administration of ritonavir and inhaled fluticasone propionate case report e340 | squ medical journal, august 2017, volume 17, issue 3 case report a 48-year-old man presented to the hiv clinic of al nahdha hospital, muscat, oman, in 2012 for a routine check-up. he had initially been diagnosed with an asymptomatic hiv infection in 1999 with a baseline cluster of differentiation (cd)4 count of >200 cells/ml3. at the time of diagnosis, his only comorbidity was bronchial asthma. subsequently, the patient had developed an atypical mycobacterial infection in 2008 after which haart was initiated in the form of 150 mg of lamivudine and 300 mg of zidovudine twice a day and 600 mg of efavirenz once a day. six months later, due to virological failure, his medication regimen was changed to 400 mg of oral didanosine once a day and 40 mg of oral stavudine and 800/100 mg of oral ritonavir-boosted indinavir/ritonavir twice a day. this resulted in a satisfactory immunological response and complete viral load suppression. however, due to intolerance, these antiretroviral (arv) drugs were again changed in 2010 to 150 mg of oral lamivudine, 300 mg of oral abacavir and 400/100 mg of oral lopinavir/ritonavir twice a day. from 1999 until 2007, the patient also took 200 μg of inhaled salbutamol as required and 100 μg of inhaled beclomethasone twice a day for his asthma. in 2008, the beclomethasone was substituted for 250 μg of inhaled fluticasone propionate twice a day. at presentation, the patient reported a twomonth history of weight loss, generalised weakness and fatigue. his vital signs were normal apart from low blood pressure (90/60 mmhg). his examination results were unremarkable, with no signs of cushing’s syndrome or lipodystrophy. routine investigations, including a complete blood count and urea, electrolyte, liver function, thyroid function and lipid profile tests, were all within normal limits. his cd4 count was 425 cells/ml3 and the hiv viral load was <20 copies/ml. at baseline, his morning serum cortisol levels were 7 nmol/l (normal range: 200–550 nmol/l) on two occasions and his plasma adrenocorticotropic hormone (acth) level was 5.4 pg/ml (normal range: 7–50 pg/ml). one hour after administrating 250 μg of synthetic acth, his cortisol level increased to 71 nmol/l. levels of other pituitary hormones, plasma sodium and potassium were within normal limits. a diagnosis of secondary adrenal insufficiency was made. the administration of inhaled fluticasone propionate was immediately halted and the patient was instead prescribed 20 mg of oral hydrocortisone in two divided doses per day. within four weeks, symptoms of weakness and fatigue had dramatically improved; moreover, the asthma symptoms did not worsen and the patient continued using 200 μg of inhaled salbutamol as required. following the fluticasone withdrawal, basal cortisol levels were 136 nmol/l and 317 nmol/l at 8 and 11 months, respectively. his acth level was 43.1 pg/ml at 11 months. after a period of one year, the hydrocortisone dose was tapered successfully over a three month period. finally, one month after the hydrocortisone was discontinued, the patient’s response to synthetic acth was normal. table 1 shows the patient’s serial basal and stimulated cortisol levels and plasma acth levels over time. discussion previous research has indicated that the concomitant use of inhaled fluticasone propionate and ritonavir leads to the systemic accumulation of fluticasone, consequently causing iatrogenic cushing’s syndrome and secondary adrenal insufficiency.7–14 in a recent literature review, epperla et al. reported a total of 37 cases of iatrogenic cushing’s syndrome and adrenal suppression as a result of concomitant use of fluticasone and ritonavir in which the time between co-administration and the development of symptoms ranged from two weeks to two years.7 another review showed that it took between two weeks and 12 months for patients to experience a complete resolution of symptoms after either drug was discontinued.8 in the current case, the patient had low acth and morning cortisol levels and a subnormal response to synthetic acth. this confirmed the diagnosis of secondary adrenal insufficiency. moreover, the recovery of the hypothalamic-pituitary-adrenal axis after the withdrawal of fluticasone propionate established the cause of the adrenal insufficiency to be a drug-drug interaction. in the present case, the patient initially reported symptoms of adrenal suppression four years after the concurrent use of fluticasone propionate and ritonavir table 1: serial basal and stimulated cortisol and adrenocorticotropic hormone levels of a hiv-positive 48-year-old male patient with secondary adrenal insufficiency basal cortisol level in nmol/l stimulated* cortisol level in nmol/l serum acth in pg/ml at presentation 7 71 5.4 1 month later 11 8 months later 136 11 months later 317 43.1 16 months later 390 880 acth = adrenocorticotropic hormone. *one hour after the administration of 250 μg of synthetic acth. ali al-maqbali, bina kamble, salim al-qassabi and ali elgalib case report | e341 medications that are substrates of the cyp3a4 isoenzyme. it is important that both hiv care providers and primary care physicians are aware of this risk to minimise the occurrence of such events. references 1. gueler a, moser a, calmy a, günthard hf, bernasconi e, furrer h, et al. life expectancy in hiv-positive persons in switzerland: matched comparison with general population. aids 2017; 31:427–36. doi: 10.1097/qad.0000000000001335. 2. abbott laboratories. prescribing information for norvir. from: www.rxabbvie.com/pdf/norvirtab_pi.pdf accessed: apr 2017. 3. hsu a, granneman gr, bertz rj. ritonavir: clinical pharmacokinetics and interactions with other anti-hiv agents. clin pharmacokinet 1998; 35:275–91. doi: 10.2165/00003088199835040-00002. 4. von moltke ll, greenblatt dj, grassi jm, granda bw, duan sx, fogelman sm, et al. protease inhibitors as inhibitors of human cytochromes p450: high risk associated with ritonavir. j clin pharmacol 1998; 38:106–11. doi: 10.1002/j.1552-4604.1998. tb04398.x. 5. winkler j, hochhaus g, derendorf h. how the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. proc am thorac soc 2004; 1:356–63. doi: 10.1513/pats.200403-025ms. 6. mackie a, ventresca gp, fuller rw, bye a. pharmacokinetics of intravenous fluticasone propionate in healthy subjects. br j clin pharmacol 1996; 41:539–42. doi: 10.1046/j.1365-2125. 1996.36110.x. 7. epperla n, mckiernan f. iatrogenic cushing syndrome and adrenal insufficiency during concomitant therapy with ritonavir and fluticasone. springerplus 2015; 4:455. doi: 10.1186/s40064015-1218-x. 8. foisy mm, yakiwchuk em, chiu i, singh ae. adrenal suppression and cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. hiv med 2008; 9:389–96. doi: 10.1111/j.14681293.2008.00579.x. 9. chen f, kearney t, robinson s, daley-yates pt, waldron s, churchill dr. cushing’s syndrome and severe adrenal suppression in patients treated with ritonavir and inhaled nasal fluticasone. sex transm infect 1999; 75:274. 10. soldatos g, sztal-mazer s, woolley i, stockigt j. exogenous glucocorticoid excess as a result of ritonavir-fluticasone interaction. intern med j 2005; 35:67–8. doi: 10.1111/j.14455994.2004.00723.x. 11. gillett mj, cameron pu, nguyen hv, hurley dm, mallal sa. iatrogenic cushing’s syndrome in an hiv-infected patient treated with ritonavir and inhaled fluticasone. aids 2005; 19:740–1. doi: 10.1097/01.aids.0000166102.21391.81. 12. samaras k, pett s, gowers a, mcmurchie m, cooper da. iatrogenic cushing’s syndrome with osteoporosis and secondary adrenal failure in human immunodeficiency virus infected patients receiving inhaled corticosteroids and ritonavirboosted protease inhibitors: six cases. j clin endocrinol metab 2005; 90:4394–8. doi: 10.1210/jc.2005-0036. 13. nocent c, raherison c, dupon m, taytard a. unexpected effects of inhaled fluticasone in an hiv patient with asthma. j asthma 2004; 41:793–5. doi: 10.1081/jas-200038366. 14. johnson sr, marion aa, vrchoticky t, emmanuel pj, lujanzilbermann j. cushing syndrome with secondary adrenal insufficiency from concomitant therapy with ritonavir and fluticasone. j pediatr 2006; 148:386–8. doi: 10.1016/j. jpeds.2005.11.034. was initiated; however, it is difficult to ascertain when the symptoms first appeared. in addition, although the resolution of the symptoms of adrenal insufficiency occurred within four weeks of discontinuing fluticasone propionate and initiating hydrocortisone treatment, it took 11 months for the full recovery of function of the pituitary and adrenal glands. the replacement of lopinavir/ritonavir with another arv drug which does not inhibit the cyp 3a4 pathway, such as raltegravir, would have been an alternative management strategy.15 however, in view of the patient’s history of virological failure with non-nucleoside reverse transcriptase inhib itor-based haart, ritonavir-boosted protease inhibitors were continued to ensure control of the hiv infection. fortunately, the patient’s asthma symptoms did not deteriorate after the withdrawal of fluticasone propionate and he did not require an inhaled steroid. notably, no phenotypic changes indicative of cushing’s syndrome were observed at the time of the initial diagnosis of adrenal insufficiency. the treating physician might have mistaken such features, namely central obesity and the presence of a dorsocervical fat pad, to be those of arv-induced lipodystrophy.7,8 to the best of the authors’ knowledge, this is the first case of secondary adrenal insufficiency as a result of concomitant ritonavir and inhaled fluticasone propionate reported from the middle east and north african region. the joint united nations programme on hiv/aids has advocated for a treatment target of 90% of all hiv-infected people to receive antiretroviral therapy (art) by 2020; it is therefore likely that the use of art in this region will increase as the deadline for this target approaches.16 this expansion of art provision will require support and vigilance from both pharmacists and hiv physicians in order to avoid serious drug-drug interactions between art—especially ritonavir—and the medications used to manage other comorbidities. enhanced communication between hiv clinics and primary healthcare workers is highly recommended to help minimise the frequency of these events. furthermore, where resources allow, the allocation of an hivspecialist pharmacist to hiv clinics would ensure that all drug prescriptions are monitored prior to being filled. if this is unfeasible, a more pragmatic approach would be to provide prescribers with a list of common drug-drug interactions and/or access to computerised software to enable drug-drug interaction screening. conclusion this case highlights the potential for serious drugdrug interactions when prescribing a potent cyp3a4 inhibitor (i.e. ritonavir) with other commonly-used https://doi.org/10.1097/qad.0000000000001335 https://doi.org/10.2165/00003088-199835040-00002 https://doi.org/10.2165/00003088-199835040-00002 https://doi.org/10.1002/j.1552-4604.1998.tb04398.x https://doi.org/10.1002/j.1552-4604.1998.tb04398.x https://doi.org/10.1513/pats.200403-025ms https://doi.org/10.1046/j.1365-2125.1996.36110.x https://doi.org/10.1046/j.1365-2125.1996.36110.x https://doi.org/10.1186/s40064-015-1218-x https://doi.org/10.1186/s40064-015-1218-x https://doi.org/10.1111/j.1468-1293.2008.00579.x https://doi.org/10.1111/j.1468-1293.2008.00579.x https://doi.org/10.1111/j.1445-5994.2004.00723.x https://doi.org/10.1111/j.1445-5994.2004.00723.x https://doi.org/10.1097/01.aids.0000166102.21391.81 https://doi.org/10.1210/jc.2005-0036 https://doi.org/10.1081/jas-200038366 https://doi.org/10.1016/j.jpeds.2005.11.034 https://doi.org/10.1016/j.jpeds.2005.11.034 secondary adrenal insufficiency due to the co-administration of ritonavir and inhaled fluticasone propionate case report e342 | squ medical journal, august 2017, volume 17, issue 3 15. martínez e, larrousse m, llibre jm, gutiérrez f, saumoy m, antela a, et al. substitution of raltegravir for ritonavirboosted protease inhibitors in hiv-infected patients: the spiral study. aids 2010; 24:1697–707. doi: 10.1097/ qad.0b013e32833a608a. 16. unaids. 90-90-90: an ambitious treatment targets to help end the aids epidemic. from: www.unaids.org/sites/default/ files/media_asset/90-90-90_en_0.pdf accessed: apr 2017. https://doi.org/10.1097/qad.0b013e32833a608a https://doi.org/10.1097/qad.0b013e32833a608a since the early 1970s, oman has witnessed a huge leap in development. as part of the modernisation of the country, a wide network of roads was implemented with a significant rise in the use of vehicles at high speeds. this increased motorisation has resulted in an epidemic of traumatic injuries and deaths due to road traffic crashes (rtcs).1 the burden that these rtcs pose on the health system and the economy is significant; in fact, rtc-associated injuries are the leading cause of disability-adjusted life years and years of life lost in oman.2 in particular, the mortality rate is especially high among individuals aged 26–50 years old.3 in october 2009, his majesty sultan qaboos bin said urged the people of oman to identify effective solutions to limit the loss of life on the roads. since then, there have been many efforts to deal with this issue at different levels. a strategic road safety research programme has been established under the umbrella of the research council (trc) to promote scientific research and build national research capacity in road safety, including trauma care services.4 a landmark paper presented in collaboration with the johns hopkins center for injury research and policy in the usa recently provided an overview of the omani health system with the goal of examining its trauma care capabilities and injury control policies.5 the efforts exerted to improve trauma care in the omani health system have been serious and genuine; however, such endeavours have been somewhat fragmented and emergency care services are still lagging behind in their goal of providing timely and effective care to trauma victims.5 the onus is on the ministry of health and other major stakeholders to develop a well-integrated and comprehensive national trauma system. this editorial focuses on the importance of a trauma system and several of its components in the omani health system, including recommendations for future directions. some of the points highlighted in the aforementioned article presented by the johns hopkins center for injury research and policy are reiterated.5 trauma systems are designed to centralise resources and experience and thus assure complete access to definitive trauma care. such systems are intended to maximise efficiency and ensure the rapid delivery of high-quality care, as the early resuscitation of trauma victims within the ‘golden hour’ is essential for improved outcomes.6 trauma systems have been repeatedly shown to be effective in preventing disability and increasing the chance of survival.7–9 in addition to health outcomes, investment in reducing rtc-related morbidity and mortality among relatively young individuals provides significant economic benefit as such individuals usually form the most productive section of society.10 a regional trauma system consists of a public health model designed to reduce morbidity and mortality due to a type of injury within a specified population.11 this system covers the entire relevant period from the time of the injury when pre-hospital care is initiated, through resuscitation and surgical intervention to subsequent rehabilitation.12 emergency medical services (ems) constitute the first component of pre-hospital care within a trauma system. these services must be geographically distributed to ensure the comprehensive coverage of all populated regions and to allow prompt response to emergency situations and the timely transport of trauma patients. in addition, ems personnel provide advanced trauma life support interventions such as airway and haemorrhage control. in oman, the national ems system was officially launched in 2004 and consists of advanced emergency care paramedics stationed at 36 centres across the country.13 currently, the ems system focuses on responding to rtcrelated traumatic injuries. however, there are several limitations to the present ems system, including the department of emergency medicine, khoula hospital, muscat, oman e-mail: ammar.k@moh.gov.om العناية باألصابات يف عمان اين نقف االن و أين ينبغي أن نتوجه؟ عمار الك�صمريي editorial trauma care in oman where do we stand and where should we be heading? ammar al-kashmiri sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e386–388, epub. 10 jan 18 submitted 4 nov 17 revision req. 22 nov 17; revision recd. 1 dec 17 accepted 6 dec 17 doi: 10.18295/squmj.2017.17.04.002 ammar al-kashmiri editorial | e387 absence of a developed medically-oriented dispatch centre and aero-medical ambulances as well as limited coverage of certain areas.13 a previous publication assessing the effectiveness of the omani ems system in reducing rtc-related morbidity and mortality found a non-significant reduction in in-hospital mortality compared with privately transported trauma patients.14 in addition to addressing highlighted deficiencies, there is a need to expand the scope of the ems system in oman to include domestic medical emergencies. trauma centres are hospitals designated to receive severely injured patients that are at increased risk of death. evidence indicates that the outcomes of injured patients admitted to trauma centres are superior to those of patients admitted to other acute care facilities.15 in the usa, once a hospital meets specific criteria as established by the american college of surgeons (acs), it is designated as a trauma centre.16 these criteria define different levels of trauma centres according to the specific capabilities available in each hospital; a level i centre provides the greatest level of care, with comprehensive 24-hour in-house coverage by trauma surgeons while a level v centre provides the lowest level of care, with limited services. the decision as to which level of facility is appropriate for a specific patient is made at the pre-hospital level on the basis of their injury severity score.16 in oman, the highest level trauma hospitals—the sultan qaboos university hospital and khoula hospital—are located in muscat, the capital city. however, according to the acs criteria, the former would be close to a level ii facility and the latter a level iii facility.16 in view of the considerable burden of trauma patients, the country is in need of at least one level i facility to provide total care for every aspect of a patient’s injury from prevention to rehabilitation, accompanied by teaching and research resources to help direct new innovations in trauma care.16,17 in addition, lower level centres distributed in other regions of oman would significantly contribute to the care of trauma victims. in order to optimise the outcomes of initial resuscitation efforts among the severely injured, trauma care should be delivered by qualified and trained providers. developed by the acs, the approach outlined in the advanced trauma life support® (atls) course is accepted as the standard of care in trauma resuscitation, with trained participants demonstrating significant improvements in knowledge and clinical and management skills.18,19 the atls programme was first established in oman in 2011, with 24 courses having been delivered and 378 providers trained so far. however, a large number of providers working in acute care settings remain a target for atls training; unfortunately, a major factor limiting enrolment in the programme is the relatively high fees involved. nevertheless, this course is a necessity, as most providers in acute care settings do not have any structured training in trauma care. there is therefore a dire need to mandate the atls course for all doctors involved in the initial resuscitation of trauma victims in oman. furthermore, in order to ensure optimal out comes, trauma care should be delivered by a multidisciplinary team.20,21 a team approach results in more rapid resuscitation and stabilisation of the patient and reduces the time between injury and critical interventions. the leader of the trauma team is often a qualified surgeon or emergency physician who coordinates the resuscitation efforts and ensures adherence to atls guidelines.22 a recent local study compared the resuscitation of multi-trauma patients led by either trauma surgeons or well-trained general surgeons and indicated that there was no difference in outcome; the authors suggested that although the expansion of the available pool of trauma surgeons in oman may be important, the extent to which this is needed is questionable and that perhaps more attention should be placed on building a cohesive and holistic trauma system.23 this point should be kept in mind by decision-makers, particularly as trauma surgery training is both lengthy and costly. therefore, the recommendation at present to improve oman’s trauma capacity is to invest in atls training and the establishment of trauma teams. a trauma registry is another essential component of an effective trauma system and provides a valuable source of information in analysing and improving the existing quality of trauma care at a national level.24 registry data also helps in determining policy development and resource allocation as well as in the identification of risk factors for different types of injuries. in addition, the economic and social effects of trauma can be documented and research hypotheses can be developed and tested.25 trauma registries are standard in most developed countries and have been successfully implemented in many developing countries as well.26 as part of a strategic project of the trc road safety research programme, a recent pilot study at two hospitals in oman indicated the feasibility of implementing a national, comprehensive and userfriendly electronic trauma registry in oman, based on the use of mobile health tools.27 in conclusion, the health system in oman is in need of a well-developed and integrated trauma system to effectively deal with the morbidity and mortality associated with rtcs. at present, particular attention should be directed towards the components trauma care in oman where do we stand and where should we be heading? e388 | squ medical journal, november 2017, volume 17, issue 4 highlighted above, including pre-hospital care, trauma centres, capacity development and the development of a national trauma registry. references 1. al-reesi h, ganguly ss, al-adawi s, laflamme l, hasselberg m, al-maniri a. economic growth, motorization, and road traffic injuries in the sultanate of oman, 1985-2009. traffic inj prev 2013; 14:322–8. doi: 10.1080/15389588.2012.694088. 2. wang h, dwyer-lindgren l, lofgren kt, rajaratnam jk, marcus jr, levin-rector a, et al. age-specific and sex-specific mortality in 187 countries, 1970–2010: a systematic analysis for the global burden of disease study 2010. lancet 2012; 380:2071–94. doi: 10.1016/s0140-6736(12)61719-x. 3. al-maniri aa, al-reesi h, al-zakwani i, nasrullah m. road traffic fatalities in oman from 1995 to 2009: evidence from police reports. int j prev med 2013; 4:656–63. 4. the research council. road safety research program. from: www.trc.gov.om/trcweb/sites/default/files/2016-12/road_ safety_en.pdf accessed: nov 2017. 5. mehmood a, allen ka, al-maniri a, al-kashmiri a, al-yazidi m, hyder aa. trauma care in oman: a call for action. surgery 2017; 162:s107–16. doi: 10.1016/j.surg.2017.01.028. 6. american college of surgeons. resources for optimal care of the injured patient 2014. from: www.facs.org/qualityprograms/trauma/vrc/resources accessed: nov 2017. 7. sampalis js, denis r, lavoie a, fréchette p, boukas s, nikolis a, et al. trauma care regionalization: a processoutcome evaluation. j trauma 1999; 46:565–79. 8. mullins rj, mann nc. population-based research assessing the effectiveness of trauma systems. j trauma 1999; 47:s59–66. 9. gabbe bj, lyons ra, fitzgerald mc, judson r, richardson j, cameron pa. reduced population burden of road transportrelated major trauma after introduction of an inclusive trauma system. ann surg 2015; 261:565–72. doi: 10.1097/sla.0000 000000000522. 10. kotagal m, agarwal-harding kj, mock c, quansah r, arreola-risa c, meara jg. health and economic benefits of improved injury prevention and trauma care worldwide. plos one 2014; 9:e91862. doi: 10.1371/journal.pone.0091862. 11. royal college of surgeons. regional trauma systems: interim guidance for commissioners. from: www.rcseng.ac.uk/library-andpublications/college-publications/docs/regional-trauma-systemsinterim-guidance-for-commissioners/ accessed: nov 2017. 12. lendrum ra, lockey dj. trauma system development. anaesthesia 2013; 68:30–9. doi: 10.1111/anae.12049. 13. al-shaqsi sz. ems in the sultanate of oman. resuscitation 2009; 80:740–2. doi: 10.1016/j.resuscitation.2009.04.011. 14. al-shaqsi s, al-kashmiri a, al-hajri h, al-harthy a. emergency medical services versus private transport of trauma patients in the sultanate of oman: a retrospective audit at the sultan qaboos university hospital. emerg med j 2014; 31:754–7. doi: 10.1136/emermed-2013-202779. 15. sampalis js, lavoie a, boukas s, tamim h, nikolis a, fréchette p, et al. trauma center designation: initial impact on traumarelated mortality. j trauma 1995; 39:232–7. 16. american trauma society. trauma center levels explained. from: www.amtrauma.org/?page=traumalevels accessed: nov 2017. 17. moore k. understanding trauma systems and trauma centers. j emerg nurs 2015; 41:540–1. doi: 10.1016/j.jen.2015.08.016. 18. van olden gd, meeuwis jd, bolhuis hw, boxma h, goris rj. clinical impact of advanced trauma life support. am j emerg med 2004; 22:522–5. doi: 10.1016/j.ajem.2004.08.013. 19. mohammad a, branicki f, abu-zidan fm. educational and clinical impact of advanced trauma life support (atls) courses: a systematic review. world j surg 2014; 38:322–9. doi: 10.1007/s00268-013-2294-0. 20. tiel groenestege-kreb d, van maarseveen o, leenen l. trauma team. br j anaesth 2014; 113:258–65. doi: 10.1093/bja/ aeu236. 21. petrie d, lane p, stewart tc. an evaluation of patient outcomes comparing trauma team activated versus trauma team not activated using triss analysis: trauma and injury severity score. j trauma 1996; 41:870–3. 22. driscoll pa, vincent ca. organizing an efficient trauma team. injury 1992; 23:107–10. doi: 10.1016/0020-1383(92)90043-r. 23. al-kashmiri a, al-shaqsi sz, al-marhoobi n, hasan m. outcomes of multi-trauma road traffic crashes at a tertiary hospital in oman: does attendance by trauma surgeons versus non-trauma surgeons make a difference? sultan qaboos univ med j 2017; 17:e196–201. doi: 10.18295/squmj.2016.17.02.010. 24. pino sánchez fi, ballesteros sanz ma, cordero lorenzana l, guerrero lópez f; trauma and neurointensive care work group of the semicyuc. quality of trauma care and trauma registries. med intensiva 2015; 39:114–23. doi: 10.1016/j.med in.2014.06.008. 25. zehtabchi s, nishijima dk, mckay mp, mann nc. trauma registries: history, logistics, limitations, and contributions to emergency medicine research. acad emerg med 2011; 18:637–43. doi: 10.1111/j.1553-2712.2011.01083.x. 26. o’reilly gm, joshipura m, cameron pa, gruen r. trauma registries in developing countries: a review of the published experience. injury 2013; 44:713–21. doi: 10.1016/j.injury.2013. 02.003. 27. mehmood a, chan e, allen k, al-kashmiri a, al-busaidi a, al-abri j, et al. development of an mhealth trauma registry in the middle east using an implementation science frame work. glob health action 2017; 10:1380360. doi: 10.1080/ 16549716.2017.1380360. https://doi.org/10.1080/15389588.2012.694088 https://doi.org/10.1016/s0140-6736%2812%2961719-x https://doi.org/10.1016/j.surg.2017.01.028 https://doi.org/10.1097/sla.0000000000000522 https://doi.org/10.1097/sla.0000000000000522 https://doi.org/10.1371/journal.pone.0091862 https://doi.org/10.1111/anae.12049 https://doi.org/10.1016/j.resuscitation.2009.04.011 https://doi.org/10.1136/emermed-2013-202779 https://doi.org/10.1016/j.jen.2015.08.016 https://doi.org/10.1016/j.ajem.2004.08.013 https://doi.org/10.1007/s00268-013-2294-0 https://doi.org/10.1093/bja/aeu236 https://doi.org/10.1093/bja/aeu236 https://doi.org/10.1016/0020-1383%2892%2990043-r https://doi.org/10.18295/squmj.2016.17.02.010 https://doi.org/10.1016/j.medin.2014.06.008 https://doi.org/10.1016/j.medin.2014.06.008 https://doi.org/10.1111/j.1553-2712.2011.01083.x https://doi.org/10.1016/j.injury.2013.02.003 https://doi.org/10.1016/j.injury.2013.02.003 https://doi.org/10.1080/16549716.2017.1380360 https://doi.org/10.1080/16549716.2017.1380360 clear cell meningiomas are a rare variant of meningioma that generally occur in the cerebellopontine angle and the spine.1 despite its bland histological appearance, this tumour is classified as a world health organisation (who) grade ii neoplasm due to its aggressive nature and high propensity for recurrence and spinal seeding.2 although they usually occur in a much younger age group than most other meningiomas, clear cell meningiomas are still rare in infancy.3 this case describes a rare case of meningioma with unusual characteristics, which included a very early age of occurrence and the supratentorial location of the tumour. case report an 8-month-old male infant was referred to the lagos university teaching hospital, lagos, nigeria, in 2015 with persistent vomiting, poor feeding and failure to thrive over a four month period. the vomiting was postprandial and the contents contained recently ingested food. there was no history of loss of consciousness, seizures or fever. the patient’s father reported that the child could not see using his right eye. the pregnancy, delivery and perinatal history had been unremarkable and there was no history of maternal exposure to radiation. on examination, the child was fully conscious and undernourished, weighing 6 kg (60% of his expected weight). he was not pale, cyanosed or dehydrated. his pupils measured 3 mm and were reactive bilaterally; however, a fundoscopic examination revealed bilateral optic atrophy. generalised hypertonia and hyperreflexia were also noted. a computed tomography scan of the brain revealed a huge largely isodense suprasellar mass with a hypodense core. the mass measured 6 x 5 x 4 cm, enhanced non-uniformly with 1department of anatomic & molecular pathology, college of medicine, university of lagos, lagos, nigeria; departments of 2neurosurgery and 3anatomic & molecular pathology, lagos university teaching hospital, lagos, nigeria *corresponding author e-mail: dozieanunobi@yahoo.com ورم السحايا ذي اخلاليا الصافية يف منطقة فوق السرج لطفل رضيع تقرير حالة �صارلز �صيدوزي اأنونوبي، األوفيمي بانكويل، نزي�صوكو زميودو اأيكريي، نورالدين ابيوال اأديليكي abstract: clear cell meningiomas are an uncommon subtype of meningioma rarely seen in infancy. we report a case of clear cell meningioma in an 8-month-old male infant. he presented at the lagos university teaching hospital, lagos, nigeria, in 2015 with persistent vomiting, poor feeding and failure to thrive over a four month period. generalised hypertonia and hyperreflexia were noted on examination. computed tomography of the brain revealed a huge largely isodense suprasellar mass with a hypodense core. the tumour, which measured 6 x 5 x 4 cm, enhanced non-uniformly with contrast injection and extended to occlude the third ventricle. the patient underwent a bifrontal craniotomy with subtotal tumour excision. six hours postoperatively, he went into cardiac arrest and could not be resuscitated. a histological diagnosis of clear cell meningioma was made as the tumour cells were immunoreactive to epithelial membrane antigen, s100 protein and vimentin. this case of clear cell meningioma was unusual due to its early occurrence and supratentorial location. keywords: clear cell meningioma; brain tumor; central nervous system tumors; infant; case report; nigeria. امللخ�ص: تعترب اأورام ال�صحايا ذات اخلاليا ال�صافية من االأورام الغري �صائعة يف االأطفال الر�صع. هذا تقرير حالة لطفل ر�صيع ذكر يبلغ 8 �صهور من العمر. وقد مت تنوميه يف م�صت�صفي الجو�ض اجلامعي التعليمي يف العام 2015م ب�صبب قئ متوا�صل و عدم قابلية للر�صاعة وعدم النمو على مدى اأربعة �صهور متتالية. وعند الفح�ض ال�رضيري للطفل وجد اأنه يعاين من نق�ض عام يف توتر الع�صالت مع وجود فرط يف املنعك�صات الع�صبية. واثبتت االأ�صعة املقطعية على املخ بالكمبيوتر وجود ورم �صخم مت�صاوي الكثافة فوق ال�رضج ومنخف�ض الكثافة يف 6 �صم واأظهر عدم جتان�ض با�صتخدام �صبغة التباين واأمتد الورم ايل البطني الثالث، وقد مت اإجراء عملية x 5 x 4 الو�صط. وقد بلغ حجم الورم ا�صتئ�صال غري كامل للورم عن طريق حج القحف )�صق اجلمجمة( من الناحيتني االأماميتني، وبعد العملية ب�صتة �صاعات توقفت ع�صلة القلب للطفل وف�صلت حماوالت اإنعا�صه، وبالفح�ض الن�صيجي مت ت�صخي�ض ورم خاليا ال�صحايا الوا�صح واأظهرت خاليا الورم تفاعاًل مناعيًا مع بروتني الغ�صاء الظاهري s100 والفاميننت، وهذه احلالة غري عادية نتيجًة حلدوثها يف عمٍر مبكٍر واأي�صًا لتواجدها فوق اخليمة املخية. كلمات مفتاحية: ورم خاليا ال�صحايا الوا�صح؛ ورم خمي؛ اأورام اجلهاز الع�صبي املركزي؛ طفل ر�صيع؛ تقرير حالة؛ نيجرييا. suprasellar clear cell meningioma in an infant case report *charles c. anunobi,1 olufemi bankole,2 nzechukwu z. ikeri,3 nurudeen a. adeleke2 case report sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e364–367, epub. 19 aug 16 submitted 24 dec 15 revision req. 27 jan 16; revision recd. 15 feb 16 accepted 17 mar 16 doi: 10.18295/squmj.2016.16.03.018 charles c. anunobi, olufemi bankole, nzechukwu z. ikeri and nurudeen a. adeleke case report | e365 contrast injection and extended superiorly to efface the third ventricle [figure 1]. a bifrontal craniotomy was performed. intraoperatively, the tumour contained areas which felt hard and gritty to the touch, while other areas were soft and jelly-like in consistency. it was adherent to the optic nerves bilaterally and the optic chiasm and was successfully separated from the left optic nerve and the optic chiasm during surgery. however, attempts to separate the tumour from the right optic nerve proved unsuccessful, resulting in subtotal excision of the tumour. the patient was transfused with 480 ml of blood intraoperatively. he was transferred postoperatively to the intensive care unit where he subsequently developed hyperthermia (temperature: >40 °c) and tachycardia (pulse rate range: 180–240 beats per minute). six hours following the operation, the patient went into cardiac arrest and unfortunately could not be resuscitated. histopathological assessment of the tumour revealed proliferating meningothelial cells, many of which had clear cytoplasm within a densely fibrotic stroma. the cells formed a vague whorled pattern in some foci and had a bland cytological appearance. mitoses were scanty and areas of cystic degeneration and vascular congestion were seen [figure 2a]. the tumour cells showed immunoreactivity to epithelial membrane antigen (ema), vimentin and s100 protein [figures 2b–d]. a diagnosis of clear cell meningioma was made. discussion like other meningiomas, clear cell meningiomas are tumours of meningothelial cells, which are normally scattered in the arachnoid membranes throughout the neuraxis but have their highest concentration at the tips of the arachnoid granulations, where they are called arachnoid cap cells.4 in clear cell meningiomas, the meningothelial cells accumulate glycogen which results in a clear appearance.2 clear cell meningiomas are rare tumours that account for 0.2–0.8% of all meningiomas and thus few cases have been reported in the literature.5 clear cell meningiomas, as with other meningiomas, show a slight female predominance.1 the current case was unusual in view of the very early age of tumour occurrence and the supratentorial location of the tumour. clear cell meningiomas are more commonly seen in younger children and adolescents.3,5,6 in a study of 14 patients ranging from 9 to 82 years old, the mean age of occurrence was 29 years.6 in another study of nine cases diagnosed over an eight year period, the median age of occurrence was 26 years.5 these are much lower than the usual ages of occurrence of other types of meningioma, which have been reported variously to be during the fourth, fifth, sixth and ninth decades in lagos, south africa, egypt and the usa, respectively.7–10 the patient in the current case presented at eight months of age, which is an unusually young age of occurrence for clear cell meningiomas. there are only a few reports of this tumour occurring in infancy; among these, most tumours were located in the intraspinal compartment.11,12 in general, most clear figure 1: brain computed tomography scan showing an isodense suparasellar mass (arrow) in an 8-month-old infant with a suprasellar clear cell meningioma. figure 2a–d: photomicrographs of (a) a haematoxylin and eosin stain at x1,000 magnification showing meningothelial cells with clear cytoplasm within a fibrotic stroma (arrow) and (b) epithelial membrane antigen stain at x1,000 magnification, (c) vimentin stain at x1,000 magnification and (d) s100 stain at x1,000 magnification showing immunoreactivity. suprasellar clear cell meningioma in an infant case report e366 | squ medical journal, august 2016, volume 16, issue 3 conclusion this report described an 8-month-old infant with clear cell meningioma diagnosed postoperatively by histopathological assessment. both the early presentation at infancy and supratentorial location of the tumour were unusual features; most cases occur in younger children or adolescents and the tumours usually have an infratentorial location. the optimal treatment for this rare subtype of meningioma is total surgical resection, with radiotherapy, chemotherapy and receptor-targeted therapy being reserved for recurrent cases. references 1. deb p, datta sg. an unusual case of clear cell meningioma. j cancer res ther 2009; 5:324–7. doi: 10.4103/0973-1482.59902. 2. perry a, louis dn, scheithauer bw, budka h, von deimling a. meningeal tumours. in: louis dn, ohgaki h, wiestler od, cavenee wk, eds. who classification of tumours of the central nervous system, 4th ed. lyon, france: international agency for research on cancer press, 2007. pp. 163–86. 3. kumar r, das kk, jaiswal ak, mehrotra a, sahu rn, srivastava ak, et al. clear cell meningioma in a child: a case report and review of literature. asian j neurosurg 2015; 10:53. doi: 10.4103/1793-5482.151520. 4. brat dj. overview of central nervous system anatomy and histology. in: prayson r. neuropathology, 2nd ed. philadelphia, pennsylvania, usa: saunders, 2011. pp. 1–39. 5. jain d, sharma mc, sarkar c, suri v, garg a, singh m, et al. clear cell meningioma, an uncommon variant of meningioma: a clinicopathologic study of nine cases. j neurooncol 2007; 81:315–21. doi: 10.1007/s11060-006-9237-7. 6. zorludemir s, scheithauer bw, hirose t, van houten c, miller g, meyer fb. clear cell meningioma: a clinicopathologic study of a potentially aggressive variant of meningioma. am j surg pathol 1995; 19:493–505. doi: 10.1097/00000478199505000-00001. 7. anunobi cc, ikeri nz. primary central nervous system tumours in children and adolescents in luth, lagos, nigeria. niger med pract 2015; 68:39–44. 8. ibebuike k, ouma j, gopal r. meningiomas among intracranial neoplasms in johannesburg, south africa: prevalence, clinical observations and review of the literature. afr health sci 2013; 13:118–21. doi: 10.4314/ahs.v13i1.16. 9. zalata kr, el-tantawy da, abdel-aziz a, ibraheim aw, halaka ah, gawish hh, et al. frequency of central nervous system tumours in delta region, egypt. indian j pathol microbiol 2011; 54:299–306. doi: 10.4103/0377-4929.81607. 10. dolecek ta, propp jm, stroup ne, kruchko c. cbtrus statistical report: primary brain and central nervous system tumours diagnosed in the united states in 2005-2009. neuro oncol 2012; 14:1–49. doi: 10.1093/neuonc/nos218. 11. liu pi, liu gc, tsai kb, lin cl, hsu js. intraspinal clear-cell meningioma: case report and review of literature. surg neurol 2005; 63:285–8. doi: 10.1016/j.surneu.2004.03.013. 12. park hc, sohn mj, kim ey, han hs, park hs. spinal clear cell meningioma presented with progressive paraparesis in infancy. childs nerv syst 2000; 16:607–10. doi: 10.1007/pl00007302. 13. pimentel j, fernandes a, pinto ae, fonseca i, moura nunes jf, lobo antunes j. clear cell meningioma variant and clinical aggressiveness. clin neuropathol 1998; 17:141–6. cell meningiomas have an infratentorial location.1 however, in the present case, the tumour was located in the suprasellar region; this location accounted for only 4.3% of meningiomas reported in a previous study conducted at the lagos university teaching hospital.7 other rare tumour locations that have been reported include the foramen magnum and the fourth ventricle.6,13 the histological differential diagnosis of primary central nervous system tumours with a clear cell morphology includes clear cell meningiomas, neurocytomas, oligodendrogliomas, ependymomas and haemangioblastomas.14 clear cell meningiomas are characterised histologically by the presence of polygonal cells with clear glycogen-rich cytoplasm, often in no particular pattern, within a densely fibrotic stroma.2 whorl formation is vague and psammoma bodies are not usually seen.2 the tumour cells are usually immunoreactive to ema, s100 protein and vimentin—as was the case for the current patient— and are usually negative for synaptophysin, glial fibrillary acidic protein, cytokeratins and desmin.1 in ultrastructural studies, the clear cell meningioma cells should have intercellular junctions, interdigitating processes and intermediate vimentin filaments.14 unlike other who grade ii meningiomas, which tend to have a mitotic count greater than four per 10 highpower fields, clear cell meningiomas often have low mitotic activity; moreover, mitosis has been shown to be of no value in predicting the aggressiveness of the neoplasm.1,2,6 jain et al. found that the mib-1 labelling index of clear cell meningiomas ranged from 2–12%.5 deb et al. reported a mib-1 labelling index of <1% in a case of recurrent clear cell meningioma.1 proliferating cell nuclear antigen proliferative indices, percentage s-phase determination and dna ploidy have been linked with aggressiveness in clear cell meningiomas.6,13 closer follow-up is therefore required for these cases. furthermore, germline smarce 1 (switch/sucrose non-fermentable-related matrixassociated actin-dependent regulator of chromatin subfamily e member 1) mutations have been linked with spinal and cranial clear cell meningiomas.15,16 smith et al. identified smarce 1 mutations and loss of smarce 1 proteins in patients and paraffinembedded tissue blocks of spinal and cranial clear cell meningioma cases.15 the treatment of choice for clear cell meningiomas is total surgical resection, with radiotherapy and chemotherapy being reserved for recurrent cases.1 juratli et al. observed increasing overexpression of epidermal growth factor, plateletderived growth factor and vascular endothelial growth factor receptors with each recurrent tumour; receptortargeted therapy was therefore recommended for such tumours.17 http://dx.doi.org/10.4103/0973-1482.59902 http://dx.doi.org/10.4103/1793-5482.151520 http://dx.doi.org/10.1007/s11060-006-9237-7 http://dx.doi.org/10.1097/00000478-199505000-00001 http://dx.doi.org/10.1097/00000478-199505000-00001 http://dx.doi.org/10.4314/ahs.v13i1.16 http://dx.doi.org/10.4103/0377-4929.81607 http://dx.doi.org/10.1093/neuonc/nos218 http://dx.doi.org/10.1016/j.surneu.2004.03.013 http://dx.doi.org/10.1007/pl00007302 charles c. anunobi, olufemi bankole, nzechukwu z. ikeri and nurudeen a. adeleke case report | e367 14. camelo-piragua s. clear cell tumours of the central nervous system: a case-based review. arch pathol lab med 2012; 136:915–26. doi: 10.5858/arpa.2012-0216-cr. 15. smith mj, wallace aj, bennett c, hasselblatt m, elertdobkowska e, evans lt, et al. germline smarce1 mutations predispose to both spinal and cranial clear cell meningiomas. j pathol 2014; 234:436–40. doi: 10.1002/path.4427. 16. evans lt, van hoff j, hickey wf, smith mj, evans dg, newman wg, et al. smarce1 mutations in pediatric clear cell meningioma: case report. j neurosurg pediatr 2015; 16:296–300. doi: 10.3171/2015.3.peds14417. 17. juratli ta, geiger kd, weigel p, von der hagen m, daubner d, pinzer t, et al. a five year-old child with clear cell petro-clival meningioma: case report with clinical and histopathological long-term follow-up. childs nerv syst 2015; 31:2193–8. doi: 10.1007/s00381-015-2782-7. http://dx.doi.org/10.5858/arpa.2012-0216-cr http://dx.doi.org/10.1002/path.4427 http://dx.doi.org/10.3171/2015.3.peds14417 http://dx.doi.org/10.1007/s00381-015-2782-7 التهاب الصفاق املمحفظ املصلب مراجعة نورمان م�سادو abstract: sclerosing encapsulating peritonitis (sep) is a rare chronic inflammatory condition of the peritoneum with an unknown aetiology. also known as abdominal cocoon, the condition occurs when loops of the bowel are encased within the peritoneal cavity by a membrane, leading to intestinal obstruction. due to its rarity and nonspecific clinical features, it is often misdiagnosed. the condition presents with recurrent episodes of small bowel obstruction and can be idiopathic or secondary; the latter is associated with predisposing factors such as peritoneal dialysis or abdominal tuberculosis. in the early stages, patients can be managed conservatively; however, surgical intervention is necessary for those with advanced stage intestinal obstruction. a literature review revealed 118 cases of sep; the mean age of these patients was 39 years and 68.0% were male. the predominant presentation was abdominal pain (72.0%), distension (44.9%) or a mass (30.5%). almost all of the patients underwent surgical excision (99.2%) without postoperative complications (88.1%). keywords: intestinal diseases; peritonitis; sclerosis; membrane tissue; abdominal pain; intestinal obstruction. ال�سبب. معروف وغري املعوي ال�سفاق يف احلدوث نادر املزمن اللتهاب من حالة هو امل�سلب املمحفظ ال�سفاق التهاب امللخ�ص: ويعرف كذلك ب�رسنقة البطن، ويحدث عندما تغطى حلقات من الأمعاء بغ�ساء داخل جوف ال�سفاق مما يوؤدي اإىل ان�سداد معوي. ب�سبب ندرة هذه احلالة و ال�سمات ال�رسيرية الالنوعية، فغالبا ما ي�سخ�س باخلطاأ. التهاب ال�سفاق املمحفظ امل�سلب يظهر كنوائب متكررة من ان�سداد الأمعاء الدقيقة. وقد تكون جمهولة ال�سبب اأو ثانوية، و الأخري له عالقة بالعوامل املوؤهبة مثل الديال ال�سفاقي اأو ال�سل البطني. من املتقدمة للحالت �رسوريا يعترب اجلراحي التدخل فاإن ذلك، ومع املبكرة، املراحل يف للمر�سى التحفظي العالج ا�ستخدام ميكن ان�سداد الأمعاء. مراجعة الأدبيات اأو�سحت و جود 118 حالة من التهاب ال�سفاق املمحفظ امل�سلب، متو�سط عمر املر�سى هو 39 عاما وكان %68.0 منهم ذكورا. كان العر�س ال�سائد هو اأمل البطن )%72.0(، متدد )%44.9( اأو كتلة )%30.5(. معظم هوؤلء املر�سى خ�سعوا لال�ستئ�سال اجلراحي )%99.2( بدون م�ساعفات ما بعد اجلراحة )88.1%(. كلمات مفتاحية: اأمرا�س معوية؛ التهاب ال�سفاق؛ ت�سلب؛ غ�ساء ن�سيجي؛ اأمل بطني؛ ان�سداد الأمعاء. sclerosing encapsulating peritonitis review norman o. machado review sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 142–151, epub. 15 may 16 submitted 3 nov 15 revision req. 26 jan 16; revision recd. 11 feb 16 accepted 25 feb 16 doi: 10.18295/squmj.2016.16.02.003 sclerosing encapsulating peritonitis (sep) is a chronic inflammatory condition of unknown aetiology believed to result from recurrent low-grade or subclinical peritonitis with no specific abdominal signs; this eventually progresses to sclerosis and membrane formation with subsequent cocoon formation.1–6 the condition is characterised by a thick greyish-white fibrotic membrane encasing the contents of the abdomen, predominately the small intestine.1–4 primary sep, known also as an abdominal cocoon, has no obvious associated conditions; however, sep can also be secondary to conditions that cause peritoneum inflammation and fibroblastic proliferation, for example peritoneal dialysis (pd)-related conditions or abdominal tuberculosis.1–4 a clinical diagnosis of sep is difficult in the early stages as symptoms are nonspecific; radiology can hence play a significant role in diagnosing this condition preoperatively.1–6 however, symptoms often present as an acute emergency with an intestinal obstruction and the condition is frequently only diagnosed intra-operatively.1–6 while patients can be managed conservatively in the early stages, when presenting at a later stage with intestinal obstruction, surgical intervention is essential. this review focuses on the aetiopathogenesis, diagnosis and management of this rare condition. terminology and classification first described more than a century ago, sep was initially termed peritonitis chronica fibrosa incapsulata to describe the membrane encasing the intestine; it has since also been named ‘icing sugar’ bowel and fibroplastic peritonitis.7–9 in 1868, an entity known as peritoneal encapsulation was described.2 in 1921, winnen reported the first case of sep, terming department of surgery, sultan qaboos university hospital, muscat, oman e-mail: oneilnorman@gmail.com norman o. machado review | e143 it zuckergussdarm, which translates literally as ‘icing gut’, due to the intestinal surface appearing white from the membrane covering.8 in 1978, foo et al. coined the expression ‘abdominal cocoon’ to describe encapsulation of the abdominal contents.10 several terms are currently used to describe various conditions in which a membrane encases the gut, including peritoneal encapsulation (pe), abdominal cocoon and idiopathic and secondary sep [table 1].2 pe is a developmental anomaly presenting as an accessory peritoneal membrane, derived from the yolk sac peritoneum in the early stages of fetal life.2,11,12 hence, it is not related to an inflammatory process; it is predominately asymptomatic and is generally detected incidentally during a laparotomy performed for some other purpose.2,12–14 the peritoneal membrane is typically found between the mesocolon, omentum and most of the small intestine.13,14 on the other hand, sep is an acquired condition and is a consequence of peritoneal inflammation due to various triggering factors.1–6,12,15 the sep membrane is covered by a dull fibrous structure that contains inflammatory cells, unlike pe whereby the membrane is covered by the mesothelium.1–6,14 sep may enclose the gut partially or completely and may occasionally involve other intraperitoneal organs, including the stomach, liver and colon.1–6 currently, sep is classified as either primary (idiopathic) or secondary, depending on the aetiopathogenesis and the pathological characteristics of the encasing membrane.1–6,12,14 primary sep is often referred to as abdominal cocoon syndrome and is classified into three categories based on the extent of encasement by the membrane [figure 1]. type i and ii involves the encasement of either part of or the complete intestine, respectively, by a fibrocollagenous membrane. in type iii, the appendix, caecum, ascending colon, stomach, liver and ovaries are also encased in addition to the small intestine.1–6,16 aetiology and incidence the aetiology and incidence of sep depend on its classification. primary sep is idiopathic and not associated with any obvious cause. however, cytokines and fibroblasts likely influence the development of table 1: types and features of encapsulating membrane conditions condition aetiopathogenesis pathology symptoms/findings location other peritoneal encapsulation • developmental anomaly • derived from the yolk sac peritoneum in fetal life • non-inflammatory • mesothelium membrane • membrane is usually thin • usually asymptomatic • often detected incidentally during a laparotomy • between the mesocolon, omentum and small intestine primary sep • unknown • thick fibrocollagenous membrane • inflammatory cells • complete mesothelium loss • initially asymptomatic • inflammatory phase: non-specific, including pain, nausea, vomiting, loss of appetite and malnutrition • fibrosclerotic (advanced) phase: intestinal obstruction • type i: part of small intestine • type ii: whole small intestine • type iii: small and large intestine, ovary, liver and stomach • occurs in two forms: adolescent and adult secondary sep • several* • see above • see above • see above sep = sclerosing encapsulating peritonitis.*see table 2. figure 1a‒c: classifications of primary sclerosing encapsulating peritonitis (sep) into (a) type i, (b) type ii and (c) type iii. for types i and ii, the membrane (grey shading) encloses part of and the whole of the small intestine, respectively. type iii sep involves a membrane (grey shading) which encloses the whole of the small bowel and other organs, such as the ovaries and colon. sclerosing encapsulating peritonitis review e144 | squ medical journal, may 2016, volume 16, issue 2 peritoneal fibrosis and neoangiogenesis in some way.2,17,18 several aetiopathogeneses have been proposed to explain primary sep, including retrograde menstruation with a viral infection, retrograde peritonitis via the fallopian tubes and gynaecological infection-inducing cell-mediated immunological tissue damage.1–6,11–19 however, these hypotheses do not explain the aetiopathogenesis for all patients, as 75% of patients with primary sep are men, premenstrual women or children.2,5,16 other theories proposed for the aetiopathogenesis of primary sep include developmental disorders related to vascular anomalies and omental hypoplasia.2,16,19 in contrast, secondary sep is associated with several causes and is therefore more common [table 2]. the predominant cause of secondary sep is pd, due to both its frequency worldwide and the associated peritoneal inflammation that the dialysis fluid induces.2–4 patients on pd are predisposed to developing peritoneal deterioration after prolonged exposure to pd fluids and subsequent bacterial peritonitis.3 long pd duration, acetate-buffered or hypertonic solutions and recurrent episodes of peritonitis may also predispose patients to infection; staphylococcus aureus, various fungi or pseudomonas sp. can also be contributory to the development of sep.20 patients with these infections are at risk of developing intestinal obstructions, in addition to ineffective ultrafiltration caused by the presence of an encasing membrane.2,3,20 a prospective multicentre study in japan reported the overall incidence of sep in patients undergoing pd to be 2.5%.21 interestingly, the incidence increases with prolonged periods of pd; another study reported the incidence as 1.9%, 6.4%, 10.8% and 19.4% among patients undergoing pd of two, five, six and eight years’ duration, respectively.22 several other causes may contribute to secondary sep, including abdominal tuberculosis [figure 2]; autoimmune conditions like systemic lupus erythematosus; recurrent peritonitis; drug use such as chemotherapy or beta-blocker treatment; ovarian disorders such as dermoid cyst rupture or luteinized ovarian thecomas; abdominal surgery; peritoneal shunts; abdominal sarcoidosis; and fibrogenic foreign material.1–6,10–20 table 2: underlying causal factors of secondary sclerosing encapsulating peritonitis aetiopathogenesis specific causes drug-related • beta-blockers (e.g. practolol timolol/propranolol) • chemotherapy (e.g. methotrexate) • asbestos exposure surgical/medical procedures • peritoneal dialysis • peritovenous shunts • ventriculoperitoneal shunts • intraperitoneal chemotherapy • trauma-related • liver transplantation infection • abdominal tuberculosis • cytomegalovirus peritonitis • granulomatous peritonitis due to parasitic infection • recurrent peritonitis inflammatory/ autoimmune • sarcoidosis • systemic lupus erythematosus • familial mediterranean fever • fibrogenic foreign bodies disease • liver cirrhosis • gastrointestinal malignancy • endometriosis • ruptured dermoid cyst • luteinized ovarian thecomas systemic • protein s deficiency figure 2a‒b: laparotomy images revealing (a) the thick membrane (arrow) cocooning the intestine of a patient with sclerosing encapsulating peritonitis and abdominal tuberculosis and (b) multiple exposed tubercles (arrowhead) on the intestinal surface after the membrane has been excised (arrows). norman o. machado review | e145 histopathological features characteristic histopathological features of biopsied peritonea may include fibroconnective tissue proliferation, inflammatory infiltration and dilated lymphatic vessels.2–4 while these non-specific features are not pathognomonic of sep, they support the diagnosis when combined with operative findings. however, foreign body granulomas, giant cells and befringement foreign material are distinctly absent, thus excluding other diagnoses such as tuberculosis.1–3,5 as a condition, sep derives its name from characteristic macroand microscopic pathological findings, including progressive formation of dense collagenous tissue sheets (‘sclerosing’), sheaths of new fibrous tissue which contain and constrict the small bowel (‘encapsulating’) and the ongoing inflammatory process and presence of mononuclear inflammatory infiltrates within the new fibrosing tissue (‘peritonitis’).1–4 one proposed pathological classification of sep progression follows four phases: the pre-sep, inflammatory, progressive and fibrotic phases.23,24 clinical presentation the clinical course of sep usually includes episodes of intermittent and partial small bowel obstruction as a consequence of the kinking and compression of the intestine within the encasing membrane.1–6,10–25 in the initial phase, the symptoms of sep are nonspecific and include fever, ascites, weight loss, loss of appetite and altered bowels; as the disease progresses, intestinal obstruction sets in.1,2,5 the development of the membrane usually occurs over several years; however, it also has been reported to occur rapidly, within 12 weeks of the onset of symptoms.2,23,24 idiopathic sep typically presents in young adolescent girls in tropical and subtropical countries such as those in the indian subcontinent as well as china, malaysia, singapore, nigeria, kenya and south africa.1–6,25 however, it has also been reported in more temperate zones.2 as patients are generally asymptomatic and primary sep is not obviously associated with other conditions, this rare condition is likely to be misdiagnosed. nevertheless, a high index of clinical suspicion is indicated for patients who present with recurrent abdominal pain which cannot be attributed to any other obvious pathology.1–6,16,22,25 a considerable number of primary sep patients present with an intestinal obstruction.2,15 biopsy results from surgical interventions may indicate sep unexpectedly.1–5,16,26,27 li et al. found that 52.3% of a large series of 65 sep patients were diagnosed during surgery in contrast to 47.7% who were diagnosed preoperatively.5 while the majority of sep patients are asymptomatic, some symptoms may include nausea, vomiting, loss of appetite, weight loss and malnutrition as a consequence of acute, subacute or chronic episodes of complete or incomplete gastrointestinal obstruction.1–25 symptomatic patients may present with tell-tale signs, including a painless soft abdominal mass and ascites in those with a severe form of the disease.1–6 however, acute emergencies due to perforation are rare.28 in patients with secondary sep, a clinician may be alerted to the possible diagnosis due to predisposing factors such as pd, intraperitoneal shunts or autoimmune conditions.1–5 diagnostic modalities a diagnosis of sep is facilitated by the patient’s history, existing predisposing factors, various biochemical parameters, radiological imaging and, above all, a high index of clinical suspicion.1–6,10–26 clinical indicators of possible secondary sep include predisposing factors presenting with unexplained abdominal discomfort such as abdominal tuberculosis, systemic lupus erythematosus or pd.1–6,16,20,26 radiological imaging can also support the diagnosis, starting with abdominal x-rays, barium studies and ultrasonography and progressing to abdominal computed tomography (ct) and, in occasional cases, contrast-enhanced magnetic resonance imaging (mri).11,12,17,24,27,29–32 abdominal x-ray findings are likely to be non specific and would indicate features of bowel obstruction, including dilated loops of the small intestine with multiple air fluid levels and, occasionally, bowel wall and peritoneal calcification [figure 3a].1,2,5,24,30 on the other hand, a barium study may show central clumping of the gut—often described as a cauliflower sign or accordion pattern— as a consequence of membrane encasing.1,2,5,16,24,30,32 this encasement may also affect the gut functionally, leading to prolonged intestinal transit time.1,15,32 for obvious reasons, a barium study is not an option for patients presenting with intestinal obstruction. ultrasonography has been reported to facilitate the diagnosis of sep and may reveal dilated bowel segments encased by a dense fibrous membrane.1,33 adherent bowel segments of various diameters may be found arranged in a concertina fashion with a narrow posterior base.1,2,16,24 a thickened peritoneal layer may be noted, appearing as a thick rim of echo-poor tissue with free or loculated abdominal fluid.1,3,4 contrast-enhanced ct is the most reliable investigative method to diagnose sep; features include a central accumulation of the small intestine encased sclerosing encapsulating peritonitis review e146 | squ medical journal, may 2016, volume 16, issue 2 by a dense membrane with a contrast-free periphery [figure 3b].1–3,17,24,27,30 the presence of additional findings may further facilitate the diagnosis, including: intestinal obstruction; ascites; peritoneal or mesenteric thickening; thickening of the small bowel wall; a softtissue density mantle; calcification of the serosal bowel wall over the liver capsule, spleen or peritoneal wall; localised fluid collection; and lymphadenopathy.1–3,17,24 calcification often occurs around blood capillaries and may extend into the serosal and muscular layers; the presence of this feature is important as it could influence both the integrity of the gut and reflect the difficulty in dissecting the membrane from the bowel wall.3 severe adhesions in calcified areas between the bowel wall and membrane makes their identification and separation very hazardous, with the potential risk of perforation.3 a multidetector ct scan with axial, sagittal and coronal reconstruction provides greater accuracy in detecting characteristic findings, excluding other differential diagnoses and facilitating the decision-making process with regards to surgical interventions.1–4,17 as ct scans are relatively cheaper, more widely available and more reliable in detecting certain findings, they are the obvious choice for establishing a diagnosis of sep.1–4,17,24,27 reportedly, ct scans are able to reveal characteristic findings of sep including peritoneal thickening, loculated fluid collection, calcification, congregated small bowel loops in the centre of the abdomen and peritoneal enhancement, with sensitivity rates of 100%, 90%, 70%, 60% and 50%, respectively.24 the role of mri in the diagnosis of sep is limited, although some research indicates that this modality may be marginally superior to ct imaging.29 certain biochemical parameters have been reported as indicators for sep among patients undergoing pd with a catheter in situ. these include haemorrhagic effluent, elevated levels of anti-inflammatory mediators and markers of coagulation-fibrinolysis such as interleukin-6 and fibrin/fibrinogen degradation products.3 a definitive diagnosis is achieved by macroscopically confirming the encapsulation of the intestines via biopsy. in addition, diagnostic laparoscopies are recommended, particularly for patients undergoing pd prior to catheter removal.1–3,16 moreover, a pathological examination will reveal a complete loss of the mesothelium associated with significant interstitial thickening composed of fibroblasts and collagen deposition within the peritoneal membrane.34 inflammatory cells are invariably present but leukocyte infiltration is not a critical part of the diagnosis.34 differential diagnosis recurrent abdominal pain, a predominant feature suggestive of acute, subacute or chronic obstruction, may mimic several other conditions.1,2,5,16 although postoperative adhesions are the most common cause of intestinal obstruction, the absence of other predisposing conditions in cases of idiopathic sep often leads to diagnoses of internal herniation, congenital pe, intestinal malrotation or secondary peritonitis, among others.1–5,11,18,30 patients with secondary sep warrant investigations to confirm the presence of predisposing conditions; these should include measurements of erythrocyte sedimentation rate, sputum tests for tuberculosis, ascetic fluid tests for adenosine deaminase levels, examinations for suspected abdominal tuberculosis and, in some cases, laparoscopies and biopsies.1,2,35,36 similar investigations would be required to rule out other possible diagnoses figure 3a‒b: a: plain abdominal x-ray showing bowel wall calcification (arrow) and peritoneal calcification with centrally clumped dilated small bowel loops (arrowhead) in a patient with sclerosing encapsulating peritonitis. b: abdominal computed tomography revealing encased loops of bowel (arrow) by a distinct membrane (arrowheads) in a patient with sclerosing encapsulating peritonitis. figure 3a reproduced with permission from candido pc, werner af, pereira im, matos ba, pfeilsticker rm, filho rs. sclerosing encapsulating peritonitis: a case report.24 norman o. machado review | e147 including autoimmune conditions or pelvic ovarian inflammatory pathologies.1–4 other differential diagnoses include retractile mesenteritis, sclerosing malignant lymphomas, malignant primary mesenteric tumours and other metastatic neoplasms.1–5,16 features that may help to differentiate sep from other causes of intestinal obstruction are its chronic course, a palpable abdominal mass due to the clustering of the intestines from encapsulation and indolent peritonitis in the absence of a positive peritoneal culture. moreover, among patients undergoing pd, bloody solute, declining small solute clearance and ultrafiltration failure may be noted.3 however, despite various clinical observations, radiological findings and investigations, a preoperative diagnosis of sep may still elude the clinician. in such cases, a definitive diagnosis of sep may only be achieved by laparoscopy or laparotomy and histological confirmation.5,16,26 management c o n s e r vat i v e t r e at m e n t evidence in the literature indicates that it is prudent to manage patients with minimal abdominal symptoms conservatively, with bowel rest, nasogastric decompression and either enteral or parenteral nutritional support.1–6,10–24,37 as a considerable number of patients with recurrent abdominal complaints have nutritional problems, addressing these issues is an important component of management.1–4,24 enteral feeding is recommended for any patient who can tolerate oral nutrition; when this is not feasible, parenteral nutrition should be considered.1–3,37 improving the nutritional status of these patients is of paramount importance as it may improve the response to conservative management or avoid subsequent surgical complications such as infection and fistulae.1–3,5,37 drug therapy may be initiated for patients who fail to respond to conservative treatment, including tamoxifen, steroids, colchicine, azathioprine and mycophenolic acid.1,2,5,15,37–40 tamoxifen acts as an oestrogen receptor modulator that inhibits the fibroblastic production of transforming growth factor beta, while steroids inhibit collagen synthesis and maturation by suppressing the inflammatory process within the peritoneal membrane.1,2,38,40 on the other hand, colchicine inhibits the messenger ribonucleic acid expression of transforming factor beta, thereby exhibiting an anti-inflammatory action.2,38 some reports have described the effectiveness of these medications for patients with idiopathic sep.1,2,38,40 success has also been achieved with these drugs for patients with previous failed surgical interventions in which complete excision and adhesiolysis could not be achieved (e.g. those with type ii or iii sep).38,40 furthermore, patients who continue to have recurrent postoperative symptoms may also benefit from the use of these drugs.2 the role of various drugs in sep treatment, including hormones and immunosuppressive and anti-inflammatories, requires further investigation. s u r g i c a l i n t e r v e n t i o n s patients with severe symptoms of intestinal obstruction, those with virgin abdomens and those who do not respond to conservative management may be candidates for surgical interventions.1–6,10–24,26,27,31,33,34 surgical options include membrane excision plus adhesiolysis or, for patients with a gut injury, resection plus anastomosis with or without a protective enterostomy. an integral part of surgery is the complete excision of the membrane; this ensures a reduction in the recurrence rate.1–6,16,30,31,34 fibrotic membranous sacs which envelop and encase the coiled intestinal loops like thick plastic bags may pose a technical challenge.2,3,6,16,34 separating these sacs from the underlying bowel loops may require multiple longitudinal and transverse incisions; this may facilitate the stripping of the membrane in order to allow the underlying intestines to return to their normal function and length.3,5,16,34 failure to peel off or excise these membranes, or intense difficulties during the removal process, may result in gut perforation.1–6 in most instances, an enterotomy forms the primary repair, while intestinal resection is reserved for cases with extensive injuries or suspected or confirmed loss of the vascular integrity of the gut.2,3,5,16 resection, particularly when not obviously indicated, could result in increased morbidity and mortality for these patients.2,3,5,16 kawanishi et al. reported a mortality rate of 4% among pd-related secondary sep patients undergoing adhesiolysis alone in comparison to 82% for those who underwent an enterectomy and anastomosis in a separate study.3,41 one important factor predicting postsurgical outcomes is peritoneal deterioration, the occurrence of which has been found to increase with the duration of pd, particularly in cases that have extended beyond 10 years.3 in such patients, the capsules are poorly demarcated from the intestinal wall and imprecise enterolysis can hence easily result in intestinal perforation.3 peritoneal calcification around capillaries could also increase the risk of perforation during dissection.3 following complete excision of the membrane, placing anti-adhesive substances between the bowel loops before closing the abdomen sclerosing encapsulating peritonitis review e148 | squ medical journal, may 2016, volume 16, issue 2 ta bl e 3: d em og ra ph ic , c lin ic al a nd tr ea tm en t d et ai ls o f c as es o f s cl er os in g en ca ps ul at in g pe ri to ni ti s* a ut ho r an d ye ar o f c as e se ri es n m ea n ag e in ye ar s (r an ge ) m al eto fe m al e ra ti o sy m pt om du ra ti on sy m pt om s/ si gn s, n (% ) im ag in g m od al it y t im e of di ag n os is , n (% ) t re at m en t, n (% ) su rg er y ty pe , n (% ) in tr ao pe ra ti ve fi n di n gs , n (% ) c om pl ic at io n s, n (% ) li e t a l.5 20 14 65 39 (1 4– 79 ) 57 :8 3. 9 ± 6. 7 ye ar s •a b pa in , 5 6 (8 6. 2) •a b di st en si on , 53 (8 1. 5) •n au se a/ v om iti ng , 35 (5 3. 8) •f ev er , 1 9 (2 9. 2) •a b m as s, 2 1 (3 2. 3) •p re op im ag in g, 31 (4 7. 7) •o pe ra tiv e, 34 (5 2. 3) •s ur ge ry , 65 (1 00 .0 ) -e m er ge nc y, 19 (2 9. 2) -e le ct iv e, 46 (7 0. 7) •m e, a d h a nd in te st in al st en tin g, 4 2 (6 5. 0) •m e an d a d h , 2 3 (3 5. 0) •t yp e i, 16 (2 4. 0) •t yp e ii , 1 6 (2 4. 0) •t yp e ii i, 15 (2 3. 0) •r ec ob st ru ct io n, 4 (6 .1 ) si ng h et a l.2 6 20 13 18 43 (1 6– 70 ) 8: 10 0. 5– 60 m on th s • a b pa in , 1 8 (1 00 .0 ) •a b m as s, 2 (1 1. 1) •a b t b, 9 (5 0. 0) •c t •c on se rv at iv e tr ea tm en t, 1 (5 .6 ) •s ur ge ry , 17 (9 4. 4) •m e an d a d h , 1 5 (8 3. 3) •m e, a d h a nd il eo st om y, 2 (1 1. 1) •t yp e ii , 1 7 (1 00 .0 ) •d ea th d ue to liv er fa ilu re , 1 (5 .6 )† ya ng e t a l.3 9 20 09 6 43 .7 (3 9– 48 ) 4: 2 3– 60 m on th s •a b pa in o nl y, 1 (1 6. 6) •a b pa in a nd in te st in al o bs tr uc tio n, 5 (8 3. 3) •x -r ay •c t •s ur ge ry , 6 (1 00 .0 ) •m e, a d h , m es en te ri c pl ic at io n an d in te st in al st en tin g, 5 (8 3. 3) •m e, a d h a nd je ju nu m re se ct io n, 1 (1 6. 6) •r ec ob st ru ct io n, 2 (3 3. 3) ‡ w ei e t a l.1 6 20 09 24 34 (1 5– 57 ) 9: 15 0. 1– 26 m on th s •i nt es tin al ob st ru ct io n on ly , 11 (4 5. 8) •a b m as s, 1 0 (4 1. 7) •a sy m pt om at ic a b m as s, 3 (1 2. 5) •x -r ay •b ar iu m •u s •c t •p re op , 4 (1 6. 7) •o pe ra tiv e, 20 (8 3. 3) •s ur ge ry , 24 (1 00 .0 ) •m e, a d h a nd a pp en de ct om y, 17 (7 0. 8) •m e, a d h a nd e nt er ot om y, 2 (8 .3 ) •m e, a d h a nd c ec ofi xa tio n, 2 (8 .3 ) •m e an d a d h , 3 (1 2. 5) •t yp e i, 14 (5 8. 3) •t yp e ii , 6 (2 5. 0) •t yp e ii i, 4 (1 6. 6) •i b o , 3 (1 2. 5) •a dh es iv e ile um ob st ru ct io n, 3 (1 2. 5) x u et a l.1 9 20 07 5 37 (2 1– 49 ) 3: 2 0. 5– 12 0 m on th s •r ec ur re nt a b pa in , 5 (1 00 .0 ) •x -r ay •c t •e nd o •p re op c t im ag in g, 4 (8 0% ) • su rg er y, 5 (1 00 .0 ) •m e an d a d h , 4 (8 0) •a d h a nd je ju nu m r es ec tio n, 1 (2 0) •t yp e i, 3 (6 0. 0) •t yp e ii , 2 (4 0. 0) •r ec ob st ru ct io n, 1 (2 0. 0) to ta l 11 8 39 .3 (1 4– 79 ) 81 :3 7 0. 1– 12 0 m on th s •a b pa in , 8 5 (7 2. 0) •a b di st en si on , 53 (4 4. 9) •a b m as s, 3 6 (3 0. 5) •n au se a/ vo m it in g, 35 (2 9. 7) •o th er , 4 3 (3 6. 4) •x -r ay •b ar iu m •u s •c t •e nd o •o pe ra ti ve , 54 (4 5. 7) •p re op , 35 (2 9. 7) •u nk no w n, 29 (2 4. 6) •s ur ge ry , 11 7 (9 9. 2) •o th er , 1 (0 .8 ) •m e, a d h a nd o th er pr oc ed ur es , 7 1 (6 0. 7) •m e an d a d h , 4 5 (3 8. 5) •o th er , 1 (0 .9 ) •t yp e i, 33 (4 3. 4) •t yp e ii , 2 4 (3 1. 6) •t yp e ii i, 19 (2 5. 0) • n on e, 10 4 (8 8. 1) •r ec ob st ru ct io n, 7 (5 .9 ) •o th er , 7 (5 .9 ) a b = ab do m in al ; p re op = p re op er at iv e; m e = m em br an e ex ci sio n; a d h = a dh es io ly sis ; c t = c om pu te d to m og ra ph y; r ec = re cu rr in g; t b = tu be rc ul os is ; u s = ul tr as on og ra ph y; ib o = in fla m m at or y bo w el o bs tr uc tio n; e nd o = en do sc op y. *l ite ra tu re re vi ew in cl ud in g o nl y ca se se ri es w ith fi ve o r m or e c as es . † pa tie nt w as m an ag ed co ns er va tiv el y an d di d no t u nd er go su rg er y. ‡ o ve r a 3 3m on th fo llo w -u p pe ri od . norman o. machado review | e149 may reduce the risk of postoperative adhesions;2,5,16 however, the effect of these substances for patients with partially excised membranes is debatable.2 even though laparoscopies may have both diagnostic and therapeutic purposes, few reports indicate this role clearly.2,35,42–44 technically, laparoscopies may be challenging in patients with an advanced abdominal cocoon, such as those with type iii sep. there is a potential risk of gut injury during the trocar insertion and separation and resection of the membrane from the underlying intestine.2,43 however, the risk of injury during trocar insertion can be reduced or avoided by employing an open technique during the initial insertion for insufflation.43 progressive sclerosing encapsulating peritonitis for patients with secondary pd-related sep, the condition is believed to progress rapidly; hence, it is important to initiate treatment immediately after diagnosis.3 stage one is considered the inflammatory stage, with the inflammation denoted by elevated serum c-reactive protein levels, fibrin/fibrin degradation products and effluent occult blood. treatment during this stage is with corticosteroids.3 in stage two, the encapsulating stage, inflammation is less pronounced, although there is progression of adhesion and encapsulation. symptoms of bowel obstruction usually appear at this point. patients at this stage can be managed with total parenteral nutrition.3 in stage three, the patient experiences bowel obstruction without inflammation; this stage must be managed with complete membrane excision of the membrane and adhesiolysis.3 postoperative complications postoperative complications include early bowel obs truction, intra-abdominal infections, enterocutaneous fistulae, short bowel syndrome and bowel perforation.1–6,16,39,44 predisposing factors that enhance the risk of a postoperative obstruction include significant manipulation of the gut, oedema and prolonged duration of the operation.2,5,35 several methods can be employed to reduce the incidence of postoperative intestinal obstruction, including intestinal intubation through the orifice of the appendix in patients with type ii or iii sep, the use of steroids to reduce oedema, intestinal stasis or bacterial translocation and somatostatin administration to reduce secretion and intestinal distension.1–3,45 inserting long intestinal tube splinting may prevent a potential obstruction; thus, it would be wise to fix the bowel in a favourable position.4 in one report, the postoperative complication rate among patients who underwent enterolysis alone was 9.1% compared to 6.1% among those with internal splinting; moreover, the recurrence rate of intestinal obstruction was significantly higher (40% versus 6.7%; p = 0.02).44 spontaneous complications such as perforation and enterocutaneous fistulae are rare and are usually the sequelae of a missed iatrogenic injury.2 the prognosis of secondary sep depends on the cause of the condition. for patients undergoing pd for end-stage renal disease, the outcome is generally poor with reported mortality rates as high as 69%.3,46 the reported mortality among surgical patients is 45–82% and occurs within a few weeks or months of the interventions.3 however, recent research suggests a good outcome following surgical intervention with either no or minimal perioperative mortality (survival rate: 94%) after three years of follow-up.24,26 summary of literature review a review of case series involving five or more cases of sep revealed a total of 118 cases [table 3].5,16,19,26,39 the mean patient age was 39 years with the majority being male (68.0%). type i sep was the most common finding (43.4%). the predominant symptom of present ation was abdominal pain (72.0%), followed by abdominal distension (44.9%) and abdominal masses (30.5%). the majority of the patients were diagnosed on the operating table (45.7%). almost all of the patients underwent surgical exploration (99.2%); of these, surgery included either excision of the membrane or adhesiolysis (100.0%), along with other procedures such as resection, anastomosis, mesenteric plication or intestinal stenting. outcomes were generally good, with recurrent obstruction seen in only 5.9% of patients. one patient was treated conservatively and died due to liver failure; this was the only death reported (0.8%). patients with abdominal tuberculosis (7.6%) received adequate therapy with antituber cular drugs. conclusion sep is a rare clinical entity and is often encountered unexpectedly in patients with acute intestinal obstruction. a high index of clinical suspicion in susceptible patients is necessary to achieve a preoperative diagnosis. radiological imaging, particularly ct scans, plays a major role in establishing the diagnosis. conservative management is the ideal approach for patients who present with mild sclerosing encapsulating peritonitis review e150 | squ medical journal, may 2016, volume 16, issue 2 symptoms; however, those with severe intestinal obstruction are likely to require surgical intervention, usually comprising of the complete excision of the membrane, adhesiolysis and occasionally resection. references 1. tannoury jn, abboud bn. idiopathic sclerosing encapsulating peritonitis: abdominal cocoon. world j gastroenterol 2012; 18:1999–2004. doi: 10.3748/wjg.v18.i17.1999. 2. akbulut s. accurate definition and management of idiopathic sclerosing encapsulating peritonitis. world j gastroentrol 2015; 21:675–87. doi: 10.3748/wjg.v21.i2.675. 3. kawanishi h, watanabe h, moriishi m, tsuchiya s. successful surgical management of encapsulating peritoneal sclerosis. perit dial int 2005; 25:s39–47. 4. oran e, seyit h, besleyici c, ünsal a, alış h. encapsulating peritoneal sclerosis as a late complication of peritoneal dialysis. ann med surg (lond) 2015; 4:205–7. doi: 10.1016/j. amsu.2015.03.006. 5. li n, zhu w, li y, gong j, gu l, li m, et al. surgical treatment and perioperative management of idiopathic abdominal cocoon: single-center review of 65 cases. world j surg 2014; 38:1860–7. doi: 10.1007/s00268-014-2458-6. 6. maguire d, srinivasan p, o’grady j, rela m, heaton nd. sclerosing encapsulating peritonitis after orthotopic liver transplantation. am j surg 2001; 182:151–4. doi: 10.1016/ s0002-9610(01)00685-7. 7. owtschinnikow pj. peritonitis chronica fibrosa incapsulata. arch klin chir 1907; 83:623–34. 8. winnen p. uber zuckergussdarm (peritonitis chronica fibrosa incapsulata). brunns beitr klin chir 1921; 123:72. 9. hartmann w. [peritonitis fibroplastica]. dtsch z chir 1942; 255:173–207. doi: 10.1007/bf02800697. 10. foo kt, ng kc, rauff a, foong wc, sinniah r. unusual small intestinal obstruction in adolescent girls: the abdominal cocoon. br j surg 1978; 65:427–30. doi: 10.1002/bjs.1800650617. 11. serter a, kocakoç e, çipe g. supposed to be rare cause of intestinal obstruction: abdominal cocoon report of two cases. clin imaging 2013; 37:586–9. doi: 10.1016/j. clinimag.2012.08.010. 12. browne lp, patel j, guillerman rp, hanson ic, cass dl. abdominal cocoon: a unique presentation in an immunodeficient infant. pediatr radiol 2012; 42:263–6. doi: 10.1007/ s00247-011-2135-y. 13. taylor m, clarke mg, jarvis j, booth m. a mystery wrapped in an enigma: the abdominal cocoon syndrome. n z med j 2012; 125:77–80. 14. mordehai j, kleiner o, kirshtein b, barki y, mares aj. peritoneal encapsulation: a rare cause of bowel obstruction in children. j pediatr surg 2001; 36:1059–61. doi: 10.1053/jpsu.2001.24746. 15. da luz mm, barral sm, barral cm, bechara cde s, lacerda-filho a. idiopathic encapsulating peritonitis: report of two cases. surg today 2011; 41:1644‒8. doi: 10.1007/s00595010-4493-8. 16. wei b, wei hb, guo wp, zheng zh, huang y, hu bg et al. diagnosis and treatment of abdominal cocoon: a report of 24 cases. am j surg 2009; 198:348–53. doi: 10.1016/j. amjsurg.2008.07.054. 17. wang q, wang d. abdominal cocoon: multi-detector row ct with multiplanar reformation and review of literatures. abdom imaging 2010; 35:92–4. doi: 10.1007/s00261-008-9489-0. 18. singh o, gupta s, shukla s, mathur r. idiopathic sclerosing encapsulating peritonitis: rare cause of intestinal obstruction. internet j surg 2008; 20:2. 19. xu p, chen lh, li ym. idiopathic sclerosing encapsulating peritonitis (or abdominal cocoon): a report of 5 cases. world j gastroenterol 2007; 13:3649–51. doi: 10.3748/wjg.v13. i26.3649. 20. kawaguchi y, kawanishi h, mujais s, topley n, oreopoulos dg. encapsulating peritoneal sclerosis: definition, etiology, diagnosis, and treatment international society for peritoneal dialysis ad hoc committee on ultrafiltration management in peritoneal dialysis. perit dial int 2000; 20:s43–55. 21. kawanishi h, kawaguchi y, fukui h, hara s, imada a, kubo h, et al. encapsulating peritoneal sclerosis in japan: a prospective, controlled, multicenter study. am j kidney dis 2004; 44:729–37. doi: 10.1016/s0272-6386(04)00953-9. 22. rigby rj, hawley cm. sclerosing peritonitis: the experience in australia. nephrol dial tranplant 1998; 13:154–9. doi: 10.1093/ ndt/13.1.154. 23. kawanishi h, moriishi m. encapsulating peritoneal sclerosis: prevention and treatment. perit dial int 2007; 27:s289–92. 24. candido pc, werner af, pereira im, matos ba, pfeilsticker rm, filho rs. sclerosing encapsulating peritonitis: a case report. radiol bras 2015; 48:56–8. doi: 10.1590/0100-3984.2013.1909. 25. sreevathsa mr, harsha ah. chronic encapsulating peritonitis or cocoon abdomen. trop gastroenterol 2013; 34:204–6. doi: 10.7869/tg.137. 26. singh b, gupta s. abdominal cocoon: a case series. int j surg 2013; 11:325–8. doi: 10.1016/j.ijsu.2013.02.011. 27. taşdelen n, demirağ a, kalaycı m, gürses m, kılıçkesmez no, çomunoğlu n, et al. intestinal obstruction due to abdominal cocoon: ct findings. eur j radiol extra 2009; 70:e79–81. doi: 10.1016/j.ejrex.2008.12.001. 28. akbulut s, yagmur y, babur m. coexistence of abdominal cocoon, intestinal perforation and incarcerated meckel’s diverticulum in an inguinal hernia: a troublesome condition. world j gastrointest surg 2014; 6:51–4. doi: 10.4240/wjgs. v6.i3.51. 29. jovani m, baticci f, bonifacio c, omodei pd, malesci a. abdominal cocoon or idiopathic encapsulating peritoneal sclerosis: magnetic resonance imaging. dig liver dis 2014; 46:192–3. doi: 10.1016/j.dld.2013.08.136. 30. kaur r, chauhan d, dalal u, khurana u. abdominal cocoon with small bowel obstruction: two case reports. abdom imaging 2012; 37:275–8. doi: 10.1007/s00261-011-9754-5. 31. shah my, gedam bs, sonarkar r, gopinath ks. abdominal cocoon: an unusual cause of subacute intestinal obstruction. indian j surg 2013; 75:391–3. doi: 10.1007/s12262-012-0582-9. 32. ndiaye ar, mbengue a, soko to, diémé ep, diagne nm, diouf ct, et al. idiopathic sclerosing encapsulating peritonitis: a case in an adolescent girl. diagn interv imaging 2012; 93:629–31. doi: 10.1016/j.diii.2012.03.017. 33. gurleyik g, emir s, saglam a. the abdominal cocoon: a rare cause of intestinal obstruction. acta chir belg 2010; 110:396–8. 34. hong kd, bae jh, jang yj, jung hy, cho jh, choi jy, et al. encapsulating peritoneal sclerosis: case series from a university center. korean j intern med 2013; 28:587–93. doi: 10.3904/ kjim.2013.28.5.587. 35. gadhire m, singh mb, joshi ma. abdominal cocoon syndrome. j evol med dent sci 2013; 2:1857–61. doi: 10.14260/jemds/473. 36. machado n, grant cs, scrimgeour e. abdominal tuberculosis: experience of a university hospital in oman. acta trop 2001; 80:187–90. doi: 10.1016/s0001-706x(01)00175-9. http://dx.doi.org/10.3748/wjg.v18.i17.1999 http://dx.doi.org/10.3748/wjg.v21.i2.675 http://dx.doi.org/10.1016/j.amsu.2015.03.006 http://dx.doi.org/10.1016/j.amsu.2015.03.006 http://dx.doi.org/10.1007/s00268-014-2458-6 http://dx.doi.org/10.1016/s0002-9610%2801%2900685-7 http://dx.doi.org/10.1016/s0002-9610%2801%2900685-7 http://dx.doi.org/10.1007/bf02800697 http://dx.doi.org/10.1002/bjs.1800650617 http://dx.doi.org/10.1016/j.clinimag.2012.08.010 http://dx.doi.org/10.1016/j.clinimag.2012.08.010 http://dx.doi.org/10.1007/s00247-011-2135-y http://dx.doi.org/10.1007/s00247-011-2135-y http://dx.doi.org/10.1053/jpsu.2001.24746 http://dx.doi.org/10.1007/s00595-010-4493-8 http://dx.doi.org/10.1007/s00595-010-4493-8 http://dx.doi.org/10.1016/j.amjsurg.2008.07.054 http://dx.doi.org/10.1016/j.amjsurg.2008.07.054 http://dx.doi.org/10.1007/s00261-008-9489-0 http://dx.doi.org/10.3748/wjg.v13.i26.3649 http://dx.doi.org/10.3748/wjg.v13.i26.3649 http://dx.doi.org/10.1016/s0272-6386%2804%2900953-9 http://dx.doi.org/10.1093/ndt/13.1.154 http://dx.doi.org/10.1093/ndt/13.1.154 http://dx.doi.org/10.1590/0100-3984.2013.1909 http://dx.doi.org/10.7869/tg.137 http://dx.doi.org/10.1016/j.ijsu.2013.02.011 http://dx.doi.org/10.1016/j.ejrex.2008.12.001 http://dx.doi.org/10.4240/wjgs.v6.i3.51 http://dx.doi.org/10.4240/wjgs.v6.i3.51 http://dx.doi.org/10.1016/j.dld.2013.08.136 http://dx.doi.org/10.1007/s00261-011-9754-5 http://dx.doi.org/10.1007/s12262-012-0582-9 http://dx.doi.org/10.1016/j.diii.2012.03.017 http://dx.doi.org/10.3904/kjim.2013.28.5.587 http://dx.doi.org/10.3904/kjim.2013.28.5.587 http://dx.doi.org/10.14260/jemds/473 http://dx.doi.org/10.1016/s0001-706x%2801%2900175-9 norman o. machado review | e151 37. habib sm, betjes mg, fieren mw, boeschoten ew, abrahams ac, boer wh, et al. management of encapsulating peritoneal sclerosis: a guideline on optimal and uniform treatment. neth j med 2011; 69:500–7. 38. solak a, solak i̇. abdominal cocoon syndrome: preoperative diagnostic criteria, good clinical outcome with medical treatment and review of the literature. turk j gastroenterol 2012; 23:776–9. doi: 10.4318/tjg.2012.0500. 39. yang w, ding j, jin x, wu h, kuang j, tao z, et al. the plication and splinting procedure for idiopathic sclerosing encapsulating peritonitis. j invest surg 2009; 22:286–91. doi: 10.1080/08941930903040072. 40. cornelis t, oreopoulos dg. update on potential medical treatments for encapsulating peritoneal sclerosis: human and experimental data. int urol nephrol 2011; 43:147–56. doi: 10.1007/s11255-010-9744-5. 41. kawanishi h, kawaguchi y. [prevalence and therapeutic outcome of sclerosing encapsulating peritonitis (eps): a multicenter study in japan]. jin to toseki 2000; 49:225–8. 42. ertem m, ozben v, gok h, aksu e. an unusual case in surgical emergency: abdominal cocoon and its laparoscopic management. j minim access surg 2011; 7:184–6. doi: 10.4103/ 0972-9941.83511. 43. hu d, wang r, xiong t, zhang hw. successful delivery after ivf-et in an abdominal cocoon patient: case report and literature review. int j clin exp pathol 2013; 6:994–7. 44. meshikhes aw, bojal s. a rare cause of small bowel obstruction: abdominal cocoon. int j surg case rep 2012; 3:272–4. doi: 10.1016/j.ijscr.2012.03.016. 45. li m, zhu w, li y, jiang j, li j, li n. long intestinal tube splinting prevents postoperative adhesive small-bowel obstruction in sclerosing encapsulating peritonitis. bmc gastroenterol 2014; 14:180. doi: 10.1186/1471-230x-14-180. 46. oulès r, challah s, brunner fp. case-control study to determine the cause of sclerosing peritoneal disease. nephrol dial transplant 1988; 3:66–9. http://dx.doi.org/10.4318/tjg.2012.0500 http://dx.doi.org/10.1080/08941930903040072 http://dx.doi.org/10.1007/s11255-010-9744-5 http://dx.doi.org/10.4103/0972-9941.83511 http://dx.doi.org/10.4103/0972-9941.83511 http://dx.doi.org/10.1016/j.ijscr.2012.03.016 http://dx.doi.org/10.1186/1471-230x-14-180 clinical & basic research squ med j, february 2012, vol. 12, iss. 1, pp. 33-40, epub. 7th feb 12. submitted 6th jul 11 revision req. 15th nov 11, revision recd. 30th nov 11 accepted 7th dec 11 1department of child health, sultan qaboos university hospital, muscat, oman; 2department of family medicine & public health, college of medicine & health sciences, muscat, oman; 3department of pediatrics pondicherry institute of medical sciences, puducherry, india. corresponding author e-mail: amitaaroor@yahoo.co.in بكرة مقابل املتأخرة يف حديثي ُ التغذية الوريدية امل الوالدة ناقصي الوزن جدا دراسة استعادية من ُعمان اأميثا راو اأرور، لليثا كري�سنان ، زينايدا ريي�س، حممد ف�سل اهلل، م�سعود اأحمد، اأ�سفق اأحمد خان، يحيى الفار�سي جدا الوزن ناق�سي الولدة حديثي عند الفو�سفات ومكّمالت العظم وِقّلة الوزن وزيادة احليوية الكيمياء معامل مقارنة الهدف: امللخ�ص: الذين يتلقون التغذية الوريدية املبكرة مقابل تلك التي ُتعطى يف وقت متاأخر. الطريقة: اأجريت درا�سة ا�ستعادية يف امل�ستوى الثالث لوحدة اأعطيت 2008 حيث اأكتوبر 2007 اإىل يناير من للفرتة ُعمان، قابو�س، ال�سلطان جامعة م�ست�سفى يف الولدة حلديثي املركزة العناية التغذية الوريدية املتاأخرة ل 47 طفال، بينما كان عدد الأطفال الذين اأعطوا تلك التغذية بوقت مبكر 44 خالل الفرتة من يناير 2009 اإىل يونيو 2010. مت ا�ستخراج البيانات الدميوغرافية والقيا�سات الب�رصية واملعامل املختربية من نظام ال�سجل الإلكرتوين. النتائج: كان متو�سط عمر البدء بالتغذية الوريدية يف وقت ُمتاأخر 47.3 �ساعة مقابل 14.3 �ساعة.وك�سف حتليل املعامل الكيميائية احليوية خالل الأ�سبوع الأول من احلياة انخفا�سا يف َفْرُط �سوْدُيوِم الدَّم )12.7% مقابل %6.8( وفرط بوتا�سيوم الدم لي�س ب�سبب قلة التبول )12.7 مقابل %6.8( عند الأطفال ذوي التغذية الوريدية املبكرة، مع عدم وجود اختالفات ُمعتّدة يف م�ستويات اليوريا واحلما�س بني املجموعتني. كان ارتفاع الذين من 81 طفال يف الغذائية املعامل وك�سفت املبكرة. الوريدية التغذية يف اأعلى <1000غرام يف الدم< 12 ملمول/لرت يف ال�سكر ا�ستطاعوا العي�س/بقوا يف وحدة الإنعا�س حتى �سن احلمل امُل�سّحح وهو 34اأ�سبوعا )40 يف التغذية الوريدية املتاأخرة و 41 يف التغذية الوريدية املبكرة( انخفا�سا يف اأمرا�س العظام الأي�سية )قلة العظم عند اخُلّدج، 17.5% مقابل%7.3(، واحلاجة اإىل مكمالت الفو�سفات )%22.5 مقابل %7.3( عند الأطفال ذوي التغذية الوريدية املبكرة. مل يكن هناك زيادة يف احلما�س اأو ركود �سفراوي. مل يالحظ اأي اختالف يف م�ستويات الزلل )الألبومني(، ووقت التغذية الكاملة ووقت ا�ستعادة الوزن عند الولدة ومتو�سط زيادة الوزن لكل يوم حتى 34 اأ�سبوعا من �سن احلمل امُل�سّحح. اخلال�صة: ي�ستطيع حديثي الولدة ناق�سي الوزن جدا حَتّمل التغذية الوريدية امُلبكرة، التي تعمل على تقليل فرط ال�سوديوم يف الدم، وتقليل فرط بوتا�سيوم الدم غري الناجت عن قلة التبول، واأخريا تقليل احلاجة اإىل مكمالت الفو�سفات. ع، حديثي الولدة، تغذية وريدية، فرط �سوديوم الدم، فرط بوتا�سيوم الدم، اأمرا�س العظام، الوزن املنخف�س جدا عند الولدة، مفتاح الكلمات: ُر�سّ ُعمان. abstract: objectives: the aim of this study was to compare the biochemical parameters, weight gain, osteopenia and phosphate supplementation in very low birth weight (vlbw) neonates receiving early versus late parenteral nutrition (epn versus lpn). methods: a retrospective study was undertaken in the level iii neonatal intensive care unit at sultan qaboos university hospital, oman: from january 2007 to october 2008 (lpn group, n = 47) and from january 2009 to june 2010 (epn group, n = 44). demographic data, anthropometric and laboratory parameters were extracted from the electronic record system. results: the mean age of pn initiation was lpn = 47.3 hours versus epn = 14.3 hours. biochemical parameters analysed during the first week of life revealed a reduction in hypernatraemia (12.7% versus 6.8%) and non-oliguric hyperkalemia (12.7% versus 6.8%) in epn, with no significant differences in acidosis and urea levels between the two groups. hyperglycemia >12 mmol/l in <1000g was higher in epn. nutritional parameters in 81 babies who survived/stayed in the unit up to a corrected gestational age (cga) of 34 weeks (40 in lpn and 41 in epn), revealed a reduction in metabolic bone disease (osteopenia of prematurity [oop], 17.5% versus 7.3%) and the need for phosphate supplementation (22.5% versus 7.3%) in the epn group. there was no increase in acidosis or cholestasis. no difference was noted in albumin levels, time to full feeds, time to regain birthweight and mean weight gain per day till 34 weeks corrected cga. conclusion: epn in vlbw newborns is well tolerated and reduces hypernatraemia, non-oliguric hyperkalemia, oop and the need for phosphate supplementation. early versus late parenteral nutrition in very low birthweight neonates a retrospective study from oman *amitha r aroor,1 lalitha krishnan,3 zenaida reyes,1 muhammed fazallulah,1 masood ahmed,1 ashfaq a khan,1 yahya al-farsi2 early versus late parenteral nutrition in very low birthweight neonates a retrospective study from oman 34 | squ medical journal, february 2012, volume 12, issue 1 premature very low birthweight (vlbw) infants miss out on fetal accretion of nutrients in the last trimester and have slow postnatal weight gain.1 they are traditionally started on a dextrose infusion and graded to parenteral nutrition (pn) over several days. the goal of epn is to provide an intravenous substrate that promotes protein deposition and increased lean body mass that approximates fetal growth rate and accretion. in recent years, early introduction and aggressive advancement of pn have been shown to be safe and effective.2,3 protein delivery of 3 gm/kg beginning on day one (d1) of life is safe and associated with plasma aa concentrations similar to those of second and third trimester fetuses.4 in the absence of iatrogenic causes of electrolyte and acid base derangements, significant individual variations in nutritional requirements of preterm neonates from pn are rare.5 hypothesising that premature infants might benefit from the anabolic effects of epn without metabolic derangement, we investigated the benefits of epn in vlbw neonates. the objectives of our study were to compare the following between the epn and lpn groups: 1) biochemical disturbances in the first week of life; 2) weight gain/day, mean weight at 34 weeks corrected gestational age (cga), time to full feeds and time to regain birth weight, and 3) incidence of osteopenia, the need for phosphate supplementation, cholestasis and albumin levels. methods inborn neonates, admitted to the neonatal intensive care unit (nicu) at sultan qaboos university hospital (squh), oman, were retrospectively studied over a period of 42 months from 1st january 2007 to 30th june 2010. the time periods were classified as epoch i, lpn (1st january 2007 to 31st october 2008) and epoch 2, epn (1st january 2009 to 30th june 2010). the period from 1st november 2008 to 31st december 2008 was considered a transition period for unit policy change from lpn to epn. the study included all inborn vlbw babies between and including gestational age 25–32weeks and weighing ≤1500 g; those that survived >7days for assessing biochemical parameters; infants who survived/stayed in the nicu until corrected gestational age (cga) of 34 weeks for assessing nutritional parameters, and who received pn for >5 days. excluded from this study were infants with chromosomal and major congenital anomalies; those on pn for >4weeks; babies who died <7 days of age, and cases requiring surgery. lpn group babies were started on intravenous dextrose soon after birth. amino acid (aa), keywords: infants, newborn; parenteral nutrition; hypernatremia; hyperkalemia; bone disease; very low birth weight; oman. advances in knowledge 1. preterm birth results in sudden cessation of nutritional supply for which total parenteral nutrition (tpn) has been used in very low birth weight (vlbw) babies for years. 2. currently, there is a move to introduce parenteral nutrition (pn) soon after birth to reduce the nutritional deficits occurring in the first days of life. 3. the time of commencement of pn in vlbw babies is still controversial and limited studies are available on the safety of early pn (epn) in these babies. 4. our study shows that epn in vlbw is safe and does not cause metabolic derangement or increased incidence of acidosis. 5. in addition, we observed a reduced incidence of hypernatraemia, non-oliguric hyperkalemia and the need for phosphate supplementation in these babies. application to patient care 1. epn for vlbw babies will provide better nutrition as compared to the conventional and current mode of initiating parenteral nutrition. 2. our study shows epn specifically reduces the incidence of metabolic derangements in the first week of life. 3. as parenteral nutrition is not available at weekends and holidays, we overcome this by having a starter tpn, which is stable when stored at 2–8°c for 30 days. 4. approximately 3,000 vlbw are born in oman each year and all these babies may benefit from epn. 5. provision for starter tpn should be made in all neonatal units. amitha r aroor, lalitha krishnan, zenaida reyes, muhammed fazallulah, masood ahmed, ashfaq a khan, yahya al-farsi clinical and basic research | 35 (primene 10%, baxter, newbury, uk) and intralipid (il) emulsion 20% (fresenius kabi ab, uppsala, sweden) were started after day 2 of life, at the discretion of the neonatal team. the prescribing guideline for protein intake was a daily stepwise increment from 0.5 gm/kg/day up to a maximum of 3 gm/kg/day. the il was commenced on day 2 at 1 gm/kg/day and increased by 1 gm/kg/day to a maximum of 3 gm/kg/day. total fluid intake was 80 ml/kg/day on day 1 and increased by 20 ml/kg/ day, up to a maximum of 150 ml/kg/day. epn group babies were started on aa as soon as possible after birth. on day 1, the aa intake was 1.6 g/kg/day, day 2 was 2 g/kg/day and was increased to 2.5 g/kg/day on day 3 and on day four to 3 g/kg/day. the il was started at 1 gm/kg on d1, increased to 2gm/kg on d2 and 3gm/kg on d3. fluid intake was similar to the lpn group. during the transition period, all clinical staff and faculty were instructed on the new standard of care and to commence starter tpn as the first fluid immediately after birth. the starter tpn formulation can be seen in table 1. as the hospital pharmacy works five days a week, tpn was therefore unavailable for babies born after working hours, or during weekends and holidays. to overcome this problem a “starter” tpn was prepared. when kept at 2–8°c this has a stability of 30 days. this was kept in the main pharmacy fridge for use as necessary by nicu staff at any time. the il was preserved as 50 ml aliquots, which are stable for 1 week, for use as necessary. feeding of the infants was trophic, with expressed breast milk commenced on day 2 or 3 if the baby was stable. increments of 2 ml were made every 24 hours after the first week. on the rare occasions when breast milk was unavailable, full term formula was used until full feeds were attained. pooled breast milk is not an option in oman. most babies would reach full feeds by day 14. direct breast feeding was attempted when babies reached 34 weeks cga. in the case of hyperglycemia (>12 mmol/l), a continuous insulin infusion was started at 0.05 u/kg/hr and titrated to achieve normoglycemia. in the study period, there were no major changes in antenatal care, nicu regimens or protocols that could influence the study outcome. the study was approved by the squh ethics committee. individual consent was not considered necessary as it was a retrospective study on de-identified data. patients were identified from a computerised database. the standardised data extraction form included birth weight, gestational age, gender and apgar score. biochemical data were collected from birth through the first 7 days of life. these included mean urea, creatinine, bicarbonate and sodium. biochemical parameters of interest were prevalence of hyperglycemia (blood glucose level >7 mmol/l and >12 mmol/l), non-oliguric hyperkalemia ([nohk] serum k+ >6.5 meq/l), hypernatraemia (na+ >150 mmol/l). nutritional data included age at start of pn, lowest mean phosphate and lowest mean albumin levels. outcomes of interest included age in days at return to birth weight; weight gain per day; weight at 34 weeks; time to reach full feeds; osteopenia of prematurity (oop) defined by alp (alkaline phosphatase) >600 u/l; the need for phosphate supplementation (supplemented when phosphate values reached <1.8 mmol/l on oral feeds), and cholestasis (direct bilirubin >34 mmol/l or >15% of total bilirubin). weight gain per day was computed as the difference in weight at 34 weeks and the birth weight divided by number of days. the statistical package for social sciences (spss, version 16, ibm, chicago, illinois, usa)) software was used to analyse the data. statistical analysis was based on the conservative intentionto-treat approach. differences in the proportions of categorical variables were assessed by chisquare analysis. fisher's exact test was used in case of contingency tables with small counts. for the table 1: composition of starter total parenteral nutrition contents quantity per 100 ml carbohydrates (g) 10 amino acid (g) 2 sodium (mmol) 1.55 potassium (mmol) 0 calcium (mmol) 1 phosphate (mmol) 1.16 acetate (mmol) 0 magnesium (mmol) 0.25 heparin (units) 100 trace elements (ml) 0.66 chloride (mmol) 1.14 early versus late parenteral nutrition in very low birthweight neonates a retrospective study from oman 36 | squ medical journal, february 2012, volume 12, issue 1 assessment of difference in means of continuous variables the student t-test and mann-whitney test were performed as parametric and non-parametric tests, respectively. a p value of <0.05 was used as a cut-off for all tests of statistical significance. results there were a total of 163 babies born at ≤32 weeks and ≤1500 g during the study period. of these a total of 48 babies (29 in the lpn group, 19 in the epn group) were excluded as they did not fit into the inclusion criteria: 15 babies were born at <25 weeks, 10 died at <7 days, 13 received pn for <5 days, 4 received pn for >28 days and 6 had major congenital anomalies. a total of 12 babies were excluded as they were born during the transition period; hence, a total of 103 neonates (54 in lpn and 49 in epn) were enrolled in the study. based on a national estimate of vlbw prevalence of 6.1 per 1,000 live births,6 a sample size of 128 neonates was obtained in order to have 90% power of detecting a 20% difference in body weight between intervention and control groups at an alpha of 0.05. for the total enrollees in the study (103 neonates), the study maintained 84% power at alpha and beta levels of 0.05 and 0.2, respectively. the demographic data are shown in table 2. there were no significant differences in the birth weight, gestational age, 5-minute apgar scores, or male:female ratio in both groups. the majority of babies on lpn (87%) were started on tpn at >24 hours in comparison to epn where tpn was started at <24hrs for the majority (89.8%). a total of 7 out of 54 babies in lpn and 5 table 3: day wise ideal protein, total caloric nonprotein nitrogen (npn) intake in early and late parenteral nutrition (epn and lpn) groups per kg body weight day contents epn lpn p value g/ kg kcal/ kg g/ kg kcal/ kg 1 glucose 8 27.2 8 27.2 protein 1.6 6.4 0 1.0 lipids 20% 1 12 0 total 45.6 27.2 0.04 npn 39.2 27.2 0.05 2 glucose 10 34 10 34 protein 2 8 0.5 2 0.001 lipids 20% 2 24 1 12 total calories 66 48 0.17 npn 58 46 0.67 3 glucose 12 40.8 12 40.8 protein 2.5 10 1 4 0.05 lipids 20% 3 36 2 24 total calories 86.8 68.8 0.06 npn 76.8 64.8 0.09 4 glucose 14 47.6 14 47.6 protein 3 12 1.5 6 0.04 lipids 20% 3 36 3 36 total calories 95.6 89.6 0.71 npn 83.6 83.6 0.87 5 glucose 15 51 15 51 protein 3 12 2 8 0.19 lipids 20% 3 36 3 36 total calories 99 95 0.92 npn 87 87 1.0 table 2: demographic data of the subjects receiving late parenteral nutrition (lpn) or early parenteral nutrition (epn) parameters epoch 1 (lpn) (n = 54) epoch 2 (epn) (n = 49) p value male, n 35 21 0.23 female, n 19 28 0.19 bw <1000g 24 18 0.04 mean bw (kg) 1.1 1.1 0.91 median ga (weeks) 27 28 0.82 aga, n 41 42 0.65 sga, n 13 7 0.04 mean 5 min apgar 7.8 7.6 0.79 mean tpn start (hrs) 47.3 14.3 0.05 tpn start ≤24 hrs, n 7 44 0.001 tpn start >24hrs, n 47 5 0.003 legend: bw = birth weight; ga = gestational age; aga = appropriate for gestational age; sga = small for gestational age; tpn = total parenteral nutrition. amitha r aroor, lalitha krishnan, zenaida reyes, muhammed fazallulah, masood ahmed, ashfaq a khan, yahya al-farsi clinical and basic research | 37 day contents epn lpn p value g/ kg kcal/ kg g/kg kcal/ kg 6 glucose 15 51 15 51 protein 3 12 2.5 10 0.88 lipids 20% 3 36 3 36 total calories 99 97 0.83 npn 87 87 1.0 out of 49 babies in epn were excluded as the time of commencement of tpn was not followed as per the objective of the study. hence, 44 babies in the epn group and 47 babies in the lpn group were considered for further analysis. the mean age at initiation of tpn was much earlier in epn (14.3 hrs) compared to lpn (47.3 hrs) and this was statistically significant. information on ideal total calorie intake per kg/day and non-protein nitrogen (npn) intake in the epn and lpn groups is given in table 3. in each of the first 5 days of life, energy intake was greater in the epn group. the aa supplementation was significantly higher in the epn group on d2, 3 and 4 compared to the lpn group. the biochemical parameters for the first 7 days are shown in table 4. the incidence of hyperglycemia (>7 mmol/l) was similar in the two groups; however, a higher number of babies in epn had hyperglycemia >12 mmol/l requiring insulin infusion. the mean urea, creatinine, sodium and bicarbonate levels were similar in the 2 groups. the incidence of hypernatraemia and nohk was significantly higher in lpn group. the weight gain pattern, incidence of osteopenia, need for phosphorus supplementation, mean albumin level and incidence of cholestasis are shown in table 5. seven babies in the lpn group and 3 babies in the epn one were excluded for assessment of their nutritional parameters. in the lpn group, three of the excluded babies died in the late neonatal period and 4 babies were moved to other hospitals beyond the early neonatal period for various reasons. in the epn group, 3 babies could not be included as they died in the late neonatal period. the time to regain birth weight, the mean weight gain per day till 34 weeks, the mean weight at 34 weeks cga were noted to be similar between the 2 7 glucose 15 51 15 51 protein 3 12 3 12 1.0 lipids 20% 3 36 3 36 total calories 99 99 1.0 npn 87 87 1.0 table 4: biochemical parameters in early and late parenteral nutrition (epn and lpn) in the first week of life lpn epn p value <1000g ≥1000g all <1000 g ≥1000g all n = 14 n = 33 n = 47 n = 23 n = 21 n = 44 hyperglycaemia (>7mmol/l) n (%) 9 (64.2) 15 (45.4) 24 (51.0) 16 (69.5) 9 (42.8) 25 (56.8) 0.79 hyperglycaemia (>12mmol/l) n (%) 1 (7.1) 1 (7.1) 2 (4.2) 6 (26) 1 (4.7) 7 (14.8) 0.03 mean urea (mmol/l) mean (sd) 7 (3.1) 4.5 (2.5) 5 (3.0) 6.6 (2.4) 5 (2.0) 6 (2.3) 0.81 mean creatinine (umol/l), mean (sd) 79 (18) 63 (13.8) 68 (16.6) 72 (14.0) 61 (13.2) 67 (14.5) 0.43 mean sodium (mmol/l) mean (sd) 145 (4.9) 144 (4.2) 145 (4.2) 147 (3.8) 144 (2.5) 146 (3.5) 0.21 hypernatraemia n (%) (>150 mmol/l) 2 (14.2) 4 (12.1) 6 (12.7) 3 (13) 0 3 (6.8) 0.04 nohk, n (%) (.6.5 meq/l) 2 (14.2) 4 (12.1) 6 (12.7) 3 (13) 0 3 (6.8) 0.02 hco3, (mmol/l) mean (sd) 19 (2.1) 17.8 (2.4) 18 (2.4) 16.4 (2.2) 18 (1.5) 17.3 (2.2) 0.54 legend: sd = standard deviation; nohk = non-oliguric hyperkalemia; hco3 = bicarbonate. early versus late parenteral nutrition in very low birthweight neonates a retrospective study from oman 38 | squ medical journal, february 2012, volume 12, issue 1 groups. the phosphate level was better maintained in the epn group compared to the lpn one, but this was not statistically significant. the incidence of oop was higher in the lpn group especially in the subgroup 1–1.5 kg; however, the overall incidence was statistically insignificant. the number of babies requiring phosphate supplementation was significantly higher in the lpn group (22.5%) compared to the epn one (7.3%). the mean albumin levels and the incidence of cholestasis were similar in the 2 groups. discussion tpn plays an important role in the nutritional support of preterm newborns while enteral feeds are gradually being increased. data suggest that long term developmental outcomes in preterm babies may be correlated with early protein intake.7 it has been shown that an aggressive intake of aa and il can be tolerated immediately after birth.8 early administration of aa has been shown to be safe and promotes positive nitrogen balance in preterm infants.2,9 some authors have studied the relationship of epn with the weight gain in preterm infants. a prospective study by valentine et al. compared 308 preterm vlbw infants who received epn supplementation with 132 infants who did not receive epn.1 they observed improved weight gain in the epn group, suggesting that nutrition that includes aas may be critical during the first 24 hours of life. it was also observed that infants in the epn groups had a shorter duration of tpn administration and achieved full enteral feeds earlier despite being smaller and younger. in another study, designed to evaluate preterm infant weight gains at 28 days after aa supplementation, infants were randomly assigned to receive 3.5 or 2.5 g/kg/day of aa. the higher intake of protein resulted in greater aa levels, but no difference was observed in weight gain at 28 days (12.9 g versus. 11.4 g respectively).10 ibrahim compared the nitrogen balance of epn versus lpn in vlbw neonates. all infants in the lpn group had a negative nitrogen balance during the first 48 hours of life, while those in the epn group had a positive balance throughout the sevenday study period.8 in the present study, the use of starter tpn for administering epn resulted in a significantly higher intake of aa in the first week of life [table 3]. in our study, no significant differences were noted in the mean weight gain per day, mean weight at 34 weeks and time to reach full feeds. in both table 5: nutritional parameters in early versus late parenteral nutrition (epn versus lpn) lpn epn p value <1000g ≥1000g all <1000g ≥1000g all n = 11 n = 29 n = 40 n = 20 n = 21 n = 41 time to bw (days of life) mean (sd) 13.6 (4.3) 12.8 (4.8) 13 (5.1) 12 (5.7) 11 (3.3) 11.6 (4.6) 0.30 time to full feeds (days of life) mean (sd) 22.5 (8.8) 11.8 (6.0) 14.7 (8.3) 21 (7.9) 12 (7.1) 16.3 (8.6) 0.89 mw gain/day till 34 weeks cga (gms) 12.1 (4.9) 12.4 (3.8) 12.3 (4.1) 14 (3.8) 12.8 (5) 13.3 (4.5) 0.93 mw at cga 34 (gms) mean (sd) 1479 (357) 1622 (163) 1583 (237) 1533 (310) 1720 (186) 1628 (268) 0.47 lowest mean p(mmol/l) mean (sd) 0.92 (0.3) 1.2 (0.21) 1.1 (0.28) 1.4 (0.44) 1.9 (0.16) 1.6 (0.42) 0.14 oop, n (%) 2 (18.1) 5 (17.2) 7 (17.5) 2 (10) 1 (5) 3 (7.3) 0.06 p supplements, (%) 4 (36.1) 5 (17.2) 9 (22.5) 2 (10) 1 (5) 3 (7.3) 0.04 mean albumin (g/l) mean (sd) 24.5 (2.5) 28.3 (3.84) 27.3 (3.91) 24.5 (3.37) 29 (3.74) 27 (4.16) 0.75 cholestasis, n (%) 2 (18.1) 3 (10.3) 5 (12.5) 3 (15.1) 2 (9.5) 5 (12.1) 0.96 legend: bw = birth weight; sd = standard deviation; mw = mean weight; cga = corrected gestational age; oop = osteopenia of prematurity; p = phosphate. amitha r aroor, lalitha krishnan, zenaida reyes, muhammed fazallulah, masood ahmed, ashfaq a khan, yahya al-farsi clinical and basic research | 39 groups, the weight gain and the weight at 34 weeks were less than if they had stayed in their intrauterine environment. this fall in growth despite epn supplementation may mean that these babies were still protein limited. although early administration of 1.5 g/kg of aas can minimise or prevent the loss of protein stores, significantly higher intake is needed to promote growth11 although clarke showed no benefit of higher aa intakes.10 hyperglycemia is frequent in vlbw infants. murdock, et al. showed that early introduction of aa and lipids lowers serum blood glucose levels.12 they suggested that decrease in blood glucose might be due to the stimulatory effect of aa on insulin secretion. thureen demonstrated higher insulin concentrations in infants receiving aa at 3 gm/ kg/day compared to those receiving 1 gm/kg/day.4 ibrahim showed statistically significant lower serum glucose levels in the epn group compared to the lpn group, though both groups had serum glucose concentrations within normal ranges.8 in our study, the incidence of hyperglycemia (>7 mmol/l) was similar in the 2 groups. this was consistent with the observation of blanco;13 however, in our case more babies in the epn group had hyperglycemia (>12 mmol/l) and required insulin infusion. urea levels have been correlated with aa intakes in vlbw babies. radmacher demonstrated a modest increase in urea as the aa dose was increased.9 blanco demonstrated higher urea levels in the early high amino acid (ehaa) group as compared with the standard amino acid (saa) group during the first week of life.13 braake showed that in conjunction with the higher blood urea nitrogen (bun) levels, the higher amounts of excreted nitrogen in the ehaa group indicated a higher oxidation rate.2 urea is a byproduct of aa oxidation and hence higher bun levels in the absence of renal dysfunction should not be interpreted as a sign of intolerance, but as a reflection of aa utilisation. our study showed no correlation between aa intake and the mean blood urea levels, which was consistent with the findings of thureen.4 it may be due to comparatively lower levels of aa supplementation. metabolic acidosis is common in the vlbw population in the first days of life and may be secondary to a variety of causes (usually between days 2-5) irrespective of dose and duration of aa administration.14 wargo concluded that a total chloride load in excess of 6 meq/kg/day in lbw infants on tpn is associated with metabolic acidosis,15 and improvement in the acid base status was demonstrated when the pn chloride had been replaced with acetate.16 our results did not reveal a higher incidence of acidosis in epn. this may be explained by the low content of chloride in the starter tpn solution (1.14 mmol/100ml) and the fact that acetate was added as required in both epochs at the discretion of the attending neonatal team. disturbances in the fluid and electrolyte balance occur frequently in preterm infants as a result of high insensible water loss and renal immaturity, resulting in higher incidence of hypernatraemia and hyperkalemia.17 elstgeest compared serum sodium values in the first 3 days of life in two cohorts of infants (<28weeks gestation who received early and late tpn) and found no difference in the incidence of hypernatraemia between the two groups.3 in our study, the mean sodium level was similar in the two groups. the lpn group, however, showed an increased incidence of hypernatraemia compared to the epn group. nohk is a common finding in vlbw neonates, occurring in 30–50% of babies during the first 72 hours of life.18,19 a study of 62 extremely low birth weight (elbw) babies demonstrated no difference in peak potassium and insulin levels during the first 3 days in the ehaa group compared to the saa group.13 our study revealed that nohk was significantly less in the epn group. oop refers to the hypomineralised skeleton of the premature infant. the american academy of pediatrics recommends a minimum of 30–40 mg/ kg of elemental calcium and phosphorus in tpn solutions for lbw infants, an amount well below the intrauterine accretion rate. the incidence of osteopenia was not significant in the two groups, but the need for phosphate supplementation was significantly less in the epn group. cholestasis is a common complication of long term tpn in vlbw neonates.20 in our study, the incidence of cholestasis was similar between the two groups. this may be explained by the fact that babies who received tpn for >4 weeks were excluded in both groups. the albumin levels in both groups did not show a difference, although studies by others have shown epn to have a positive effect on albumin levels.21 early versus late parenteral nutrition in very low birthweight neonates a retrospective study from oman 40 | squ medical journal, february 2012, volume 12, issue 1 there were various limitations of this study. first, there was the retrospective nature of the study with comparisons over 42 months. second, there were no assessments of protein kinetics or body composition. more sophisticated measures of nitrogen balance and body composition are needed to define mechanisms of nutrient intake and growth in the preterm infant. conclusion this study shows that epn in vlbw babies is well tolerated. it appears to lead to a reduction in hypernatraemia, nohk, oop and the need for phosphate supplementation. weight gain, time to regain birthweight, mean weight/day upto 34 wks cga and time to full feeds showed no difference between the two study groups. cholestasis and mean serum albumin levels showed no statistical difference between the groups. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest and no funding has been received for this work. references 1. valentine cj, fernandez s, rogers lk, gulati p, hayes j, lore p, et al. early amino-acid administration improves preterm infant weight. j perinatol 2009; 29:428–32. 2. braake fwj, van den akker chp, wattimena djl, huijmans jgm, van goudoever jb. amino acid administration to premature infants directly after birth. j pediatr 2005; 147:457–61. 3. elstgeest le, martens se, lopriore e, walther fj, te pas ab. does parenteral nutrition influence electrolyte and fluid balance in preterm infants in the first days after birth? plos one 2010; 5:e9033. 4. thureen pj, melara d, fennessey pv, hay ww jr. effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. pediatr res 2003; 53:24–32. 5. yeung my, smyth jp, maheshwari r, shah s. evaluation of standardized versus individualized total parenteral nutrition regime for neonates less than 33 weeks gestation. j paediatr child health 2003; 39:613–7. 6. directorate general of planning, ministry of health. annual health report, sultanate of oman, 2008. muscat: ministry of health, 2008. pp. 8–15. 7. lucas a, morley r, cole tj. randomised trial of early diet in preterm babies and later intelligence quotient. bmj 1998; 317:1481–7. 8. ibrahim hm, jeroudi ma, baier rj, dhanireddy r, krouskop rw. aggressive early total parental nutrition in low-birth-weight infants. j perinatol 2004; 24:482–6. 9. radmacher pg, lewis sl, adamkin dh. early amino acids and the metabolic response of elbw infants (≤ 1000 g) in three time periods. j perinatol 2009; 29:433–7. 10. clark rh, chace dh, spitzer ar. effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a randomized, controlled trial. pediatrics 2007; 120:1286–96. 11. denne sc, poindexter bb. evidence supporting early nutritional support with parenteral amino acid infusion. semin j perinatol 2007; 31:56–60. 12. murdock n, crighton a, nelson lm, forsyth js. low birthweight infants and total parenteral nutrition immediately after birth. ii. randomised study of biochemical tolerance of intravenous glucose, amino acids, and lipid. arch dis child fetal neonatal ed 1995; 73:f8–12. 13. blanco cl, falck a, green bk, cornell je, gong ak. metabolic responses to early and high protein supplementation in a randomized trial evaluating the prevention of hyperkalemia in extremely low birth weight infants. j pediatr 2008; 153:535–40. 14. jadhav p, parimi ps, kalhan sc. parenteral amino acid and metabolic acidosis in premature infants. jpen j parenter enteral nutr 2007; 31:278–83. 15. groh-wargo s, ciaccia a, moore j. neonatal metabolic acidosis: effect of chloride from normal saline flushes. jpen j parenter enteral nutr 1988; 12:159–61. 16. richards ce, drayton m, jenkins h, peters tj. effect of different chloride infusion rates on plasma base excess during neonatal parenteral nutrition. acta paediatr 1993; 82:678–82. 17. bhatia j. fluid and electrolyte management in the very low birth weight neonate. j perinatol 2006; 26:s19–21. 18. mildenberger e, versmold ht. pathogenesis and therapy of non-oliguric hyperkalaemia of the premature infant. eur j pediatr 2002; 161:415–22. 19. lorenz jm, kleinman li, markarian k. potassium metabolism in extremely low birth weight infants in the first week of life. j pediatr 1997; 131:81–6. 20. yip yy, lim ak, r j, tan kl. a multivariate analysis of factors predictive of parenteral nutrition-related cholestasis (tpn cholestasis) in vlbw infants. j singapore paediatr soc 1990; 32:144–8. 21. van den akker chp, te braake fwj, schierbeek h, rietveld t, wattimena djl, bunt je, et al. albumin synthesis in premature neonates is stimulated by parenterally administered amino acids during the first days of life. am j clin nutr 2007; 86:1003–8. 1department of child health, sultan qaboos university hospital, muscat, oman; 5department of family medicine & public health, 2college of medicine and health sciences, sultan qaboos university, muscat, oman; 3department of respiratory therapy and child health evaluative sciences, hospital for sick children, toronto, canada; 4faculty of health sciences, ontario tech university, oshawa, canada *corresponding author’s e-mail: drhilal@squ.edu.om risk factors of extubation failure in intubated preterm infants at a tertiary care hospital in oman *hilal al mandhari,1 buthina al riyami,2 ashfaq khan,1 mika nonoyama,3,4 syed g. a. rizvi5 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 247–252, epub. 26 may 22 submitted 8 sep 20 revisions req. 28 dec 20 & 24 feb 21; revisions recd. 10 feb & 10 mar 21 accepted 7 apr 21 https://doi.org/10.18295/squmj.8.2021.122 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to determine extubation failure (ef) rate among intubated preterm infants (<37 weeks gestational age [ga]) admitted to a tertiary care neonatal intensive care unit (nicu) in oman and identify the risk factors associated with ef. methods: this retrospective study included all intubated preterm infants (<37 weeks ga) admitted to the nicu at sultan qaboos university hospital (squh) from january 2013 to december 2017. ef was defined as reintubation within seven days of planned extubation. demographics, ventilation parameters, blood gas values and other possible risk factors of ef were collected. statistical analysis included comparisons between ef and extubation success (es) groups and a binary logistic regression analysis. results: a total of 190 preterm infants were intubated during the study period with 140 eligible for analysis. a total of 106 infants (75.7%) were successfully extubated while 34 (24.3%) failed extubation. ga <28 weeks (p = 0.029), lower 1-minute apgar score (p = 0.023) and patent ductus arteriosus diagnosis (p = 0.018) were significantly associated with ef. after the multivariate analysis, only ga <28 weeks predicted ef with an adjusted odds ratio of 2.621 (95% confidence interval: 1.118 – 6.146). conclusion: ef rate in preterm infants admitted at the nicu of squh was within international rates. ga <28 weeks was the only predictor of the identified extubation failure. neonatal practitioners need to seriously consider extreme prematurity in the extubation process and consider implementing strategies to decrease extubation failure in this group of fragile infants. keywords: premature infants; neonate; airway extubation; risk factors; oman. advances in knowledge this study identified a neonatal extubation failure rate of 24.3% and reaffirmed that extreme prematurity (gestational age <28 weeks) is an important predictor in intubated preterm infants admitted to a level iii neonatal intensive care unit (nicu) in oman. application to patient care health-care professionals in nicus need to seriously consider extreme prematurity prior to extubation of preterm infants and implement strategies that may help decrease extubation failure. these include formal assessment of extubation readiness and use of positive pressure ventilation as post-extubation respiratory support. invasive mechanical ventilation is a life-supporting intervention used for patients with respiratory failure, including preterm infants in neonatal intensive care units (nicus). despite this advantage, extubation failure (ef) is a recurrent issue. ef occurs in approximately 40% of intubated extremely low birth weight infants globally, but is highly variable between 10–30%.1,2 this is partly due to the absence of a consistent definition for and standardised criteria to determine ef.2 ef has been defined as reintubation within 24, 48 and 72 hours; however, some patients have required reintubation up to seven days postextubation.2,3 it is of utmost importance to extubate infants as soon as they are ready. prolonged intubation and mechanical ventilation in preterm infants are associated with significant adverse effects including ventilator-associated pneumonia, bronchopulmonary dysplasia, sepsis and subglottic stenosis.3,4 however, this is a tenuous balancing act because premature extubation may lead to ef, which itself is associated with serious complications such as prolonged mechanical ventilation, prolonged hospital stay, higher mortality rate and complications related to the reintubation procedure itself.5–8 in order to find an optimal strategy for successful extubation in preterm infants, there must be an awareness of potential risk and success factors. previous studies had identified predictors of ef such as lower 5-minute apgar score, poor acid-base homeostasis, lower gestational age (ga; ≤28 weeks), post-extubation lung collapse, patent ductus arteriosus (pda) and acquired pneumonia.9–12 similarly, chawla et al. identified markers of successful extubation in preterm infants, including higher 5-minute apgar score and arterial ph prior to extubation, lower peak fractional concentration of inspired oxygen (fio2) on the first day of life and prior to extubation, lower https://creativecommons.org/licenses/by-nd/4.0/ risk factors of extubation failure in intubated preterm infants at a tertiary care hospital in oman 248 | squ medical journal, may 2022, volume 22, issue 2 arterial partial pressure of carbon dioxide prior to extubation and “non-small” for ga.13 currently, there are no studies regarding ef in preterm infants in middle eastern countries. this study aimed to describe the ef rate among intubated preterm infants in a tertiary care nicu in oman and determine the risk factors associated with ef. it is anticipated that this study will provide specific criteria that neonatal practitioners can use to assess extubation readiness in preterm infants in order to optimise success. methods this retrospective case-control study was conducted at a level iii nicu of sultan qaboos university hospital (squh), in muscat, oman. squh is a tertiary and academic perinatal hospital and has approximately 5,000 deliveries per year; its nicu has a 24-bed capacity. eligible infants were intubated preterm infants (<37 weeks) admitted over a period of five years from january 2013 to december 2017. infants who died prior to extubation, extubated for palliative care/comfort care, transferred to another hospital with an endotracheal tube (ett), had an unplanned/ accidental extubation or were tracheostomised were excluded. only the first planned extubation attempt for each patient was assessed for this study. ef was defined as the need for reintubation within seven days of a planned extubation.2,3 the patients’ electronic charts were reviewed and specific predefined clinical variables including patient’s demographic data, preextubation ventilation parameters (mode, respiratory rate [rr], peak inspiratory pressure [pip], peak end expiratory pressure [peep], tidal volume [vt in ml/ kg], fio2), blood gas values (ph, partial pressure of carbon dioxide, bicarbonate [hco3-] and base excess [be]) and other risk factors of ef were collected. blood gas values included a mix of arterial, venous and capillary samples. all infants were ventilated using dräger babylog® vn500 or sle5000 ventilators (dräger, lübeck, germany). the primary ventilation mode was pressure control conventional ventilation from 2013 until 2016 and volume-targeted conventional ventilation in 2017. high frequency oscillatory ventilation was used as a rescue mode. infants were extubated once they were on minimal ventilatory parameters (pip/peep: 16/5, rr: 30/min, fio2 <0.35), had normal blood gases and were deemed ready by the medical team (established spontaneous breathing, hemodynamically stable). post-extubation interventions included bubble nasal, nasal non-invasive positive pressure ventilation for infants <1,000 g and high flow nasal cannula for late preterm. pre-and post-extubation blood gas tests were performed one to two hours prior to and after extubation, respectively. the study population was classified into two groups: ef and extubation success (es). descriptive statistics included mean ± standard deviation (sd) or median and interquartile range (iqr) for continuous variables and counts and percentages for categorical variables. normality of continuous variables was tested using the one-sample kolmogorov-smirnov test. the differences in patient characteristics and possible risk factors between the es and ef groups were tested using the chi-squared test for categorical variables, independent sample t-test for normally distributed continuous variables and mann-whitney u test for non-normally distributed continuous variables. adjusted binary logistic regression analysis was performed to determine predictors of ef using clinical variables that were significantly different between the two groups (ef versus es). after obtaining the results of these statistical analyses (post-hoc), the analyses in the sub-group of infants <28 weeks ga (multivariate regression analysis) was repeated; however, it was not completed as the sample size was small and only one variable was significant in the univariate analysis. missing data was excluded from the data analyses. statistical package for the social sciences (spss), version 23.0 (ibm corp., chicago, illinois, usa) was used for data analysis. a p value of ≤ 0.05 was considered statistically significant. ethical approval was obtained through the institution’s medical research ethics committee (mrec#1699). results a total 140 infants were included in this study, out of which 34 (24.3%) failed extubation [figure 1]. the mean ga was higher in the es group compared to the ef group (31.6 ± 3.0 versus 26.1 ± 1.2 weeks). approximately 75% of infants were <32 gestational weeks, which was equally distributed between the es (74%) and ef (79%) groups (p = 0.649). the most common reasons for reintubation were desaturation and bradycardia (50%) followed by apnoea (17.7%) and respiratory failure (11.8%) [figure 2]. the majority of extubation failures occurred within the first three days of extubation (79.4%) [figure 3]. there were significant differences between the ef and es groups for the following three clinical variables: ga <28 weeks (p = 0.029), 1-minute apgar score (p = 0.023) and pda (p = 0.018). infants with ef hilal al mandhari, buthina al riyami, ashfaq khan, mika nonoyama and syed g. a. rizvi clinical and basic research | 249 had significantly higher total mechanical ventilation (mv) days as well as longer length of hospital stay compared to those with es (16 versus 3 days; p <0.001 and 67 versus 54.5 days; p = 0.01, respectively) [table 1]. there were no significant differences in other clinical variables (5-minute apgar score, birth weight [bw], weight at intubation and extubation, day of life at intubation and extubation, caffeine use, preextubation haemoglobin [hb] level), intraventricular haemorrhage rate, pre-extubation ventilatory variables (mode, vt, pip, peep, rr, fio2) and pre-extubation blood gas results [tables 1 and 2]. after extubation, ph (p <0.001), hco3(p <0.001) and be (p <0.001) were significantly lower in the ef compared to the es group [table 2]. most infants (81.4%) had a fiveminute apgar score >6. after the multivariate analysis, only the variable ga <28 weeks remained as a significant predictor of ef; the 1-minute apgar score and pda were no longer associated with ef [table 3]. for the post-hoc subgroup analysis of infants of ga <28 weeks (n = 54), 35 (64.8%) had es and 19 (35.2%) had ef. given the results of the multivariate analyses on the whole cohort, it is not surprising that the presence of pda in infants was significantly higher in the ef group (n = 15 out of 19, 78.9%) compared to the es group (n = 14 out of 35, 40.0%; p = 0.03). similar to the whole group, the median (iqr) of total mv days was higher in the ef group (20 [23] versus 5 [10] days; p <0.001), but not significantly different for the length of hospital stay (87 [53] versus 70 [15] days; p = 0.142) compared to the es group. the median length of stay for the entire subgroup was 72.5 days. all other variables were not significantly different between the es and ef groups. figure 1: flowchart showing the study population selection. figure 2: reported reason for reintubation of infants in the neonatal intensive care unit (n = 34). figure 3: cumulative extubation failure per day of infants in the neonatal intensive care unit (n = 34). risk factors of extubation failure in intubated preterm infants at a tertiary care hospital in oman 250 | squ medical journal, may 2022, volume 22, issue 2 discussion this study determined the ef rate (and associated risk factors) among intubated preterm infants in a tertiary care nicu in oman. the ef rate was found to be on the upper boundary of the 10–30% ef rate range found by al-mandari et al.; however, the majority of respondents (93%) in that study defined ef as occurring within 72 hours.2 the longer the period of time after extubation, the higher the risk of reintubation.1 thus, the researchers’ definition of reintubation within seven days may be a more accurate reflection of ef rate. compared with other ef studies using 5–7 days post-extubation as their benchmark, the present study’s ef rate was similar to hermeto et al. (23.1%) and wang et al. (23.5%) but lower than chawla et al. (42%) and stefanescu et al. (40%).1,10,11,13 however, it is important to consider the differences in ga in these studies as they may have contributed to the difference in ef rates as well. the association of ef with extreme prematurity (exclusively <28 weeks ga) table 1: characteristics of extubation failure and extubation success groups (n = 140) characteristic n (%) p value es (n = 106) ef (n = 34) gestational age <28 weeks 35 (33.0) 19 (55.9) 0.029* male gender 58 (54.7) 20 (58.8) 0.825* mean 1-minute apgar ± sd 5.98 ± 2.22 4.88 ± 2.38 0.023† mean 5-minute apgar ± sd 8.10 ± 1.62 7.72 ± 1.63 0.117† mean birth weight in kg ± sd 1.44 ± 0.82 1.34 ± 0 .73 0.448† mean weight at intubation in kg ± sd 1.46 ± 0.85 1.32 ± 0.70 0.481† mean weight at extubation in kg ± sd 1.45 ± 0.82 1.33 ± 0.76 0.370† patent ductus arteriosus‡ 39 (36.8) 21 (61.8) 0.018* intraventricular haemorrhage‡ 14 (13.2) 5 (14.7) 1.000* caffeine 78 (73.6) 27 (79.4) 0.649* median day of life at intubation (iqr) 1 (0) 1 (0) 0.798§ median day of life at extubation (iqr) 3 (5) 2.5 (6) 0.965§ median total mechanical ventilation in days (iqr) 3 (4) 16 (26.5) 0>.001§ median length of hospital stay in days (iqr) 54.5 (38.8) 67 (54.3) 0.01§ es = extubation success; ef = extubation failure; sd = standard deviation; iqr = interquartile range. *using chi-square test. †using independent sample t-test. ‡grade and diagnosis data were not collected. §using mann-whitney u test. table 2: ventilator and blood gas parameters 1–2 hours prior to and after extubation of infants (n = 140) variable n (%) p value es (n = 106) ef (n = 34) prior to extubation mode of ventilation i.e. simv 68 (64.2) 20 (58.8) 0.722* median rr in breaths/min (iqr) 30 (10) 25 (5) 0.093† median pip in cmh2o (iqr) 15 (1) 15 (2) 0.461† median peep in cmh2o (iqr) 6.0 (0) 6.0 (0.05) 0.021† median vt in ml/kg (iqr) 4.9 (3.6) 4.9 (2.5) 0.640† median fio2 in % (iqr) 23 (4) 25 (7.5) 0.228† median ph (iqr) 7.39 (0.08) 7.38 (0.1) 0.644† median pco2 (iqr) 37.5 (13.4) 35.5 (13.9) 0.513† median hco3 (iqr) 22.4 (3.7) 21.4 (2.6) 0.057† median be (iqr) ‒2.5 (4.8) ‒3.3 (4.05) 0.126† median hb in g/dl (iqr) 13.5 (3.1) 13.9 (3.6) 0.363† after extubation respiratory support i.e. cpap 77 (72.6) 28 (82.4) 0.720* median ph (iqr) 7.36 (0.08) 7.32 (0.13) <0.001† median pco2 (iqr) 41.2 (1 3.97) 41.7 (18) 0.298† median hco3 (iqr) 21.7 (3.4) 19.6 (2.9) <0.001† median be (iqr) ‒3.0 (4.2) ‒5.9 (4.4) <0.001† es = extubation success; ef = extubation failure; simv = synchronised intermittent mandatory ventilation; rr = respiratory rate; iqr = inter quartile range; pip = peak inspiratory pressure; peep = positive end expir atory pressure; fio2 = fraction of inspired oxygen; hb = haemoglobin; hco3= bicarbonate ; pco2 = par tial pre ssure of carbon dioxide ; vt = tidal volume. *using chi-squared test. †using mann-whitney u test. hilal al mandhari, buthina al riyami, ashfaq khan, mika nonoyama and syed g. a. rizvi clinical and basic research | 251 has been inconsistent in the literature as some studies showed an association while others did not.9–14 costa et al. as well as other authors found that the 5-minute apgar score was significantly lower for those with ef compared to es.9,10,13 this association was absent in the present study probably because most infants (81.4%) had a high 5-minute apgar score of >6 [table 1]. in addition, the 5-minute apgar score was missing for five infants (3.6%). loss of impact of pda diagnosis on the extubation outcome on multivariate regression is likely due to the influence of ga, as the present study’s post-hoc subgroup analyses of infants <28 weeks showed a significant difference in pda presence between the ef and es groups. the impact of pda on extubation outcomes continues to be a controversial issue. hermeto et al. and chawla et al. found significant associations between ef and the presence of pda, while wang et al. and szymankiewicz et al. did not.6,10,11,15 similarly, the association between bw and ef is aligned with previously published studies, but contrasts with the findings of other studies which showed that lower bw is associated with an increased chance of ef.10–12,14,16 in the present study, median bws were not associated with ef, likely because the bws were consistently larger (>1,000 g). randomised trials of prophylactic use of caffeine showed increased chances of successful extubation in preterm infants within one week since birth.17 the lack of difference in caffeine use in this study was most likely because the present study’s nicu routinely uses caffeine in all preterm infants <32 weeks ga. this constitutes approximately 75% of the present study’s sample size and was equally distributed between the es (74%) and ef (79%) groups (p = 0.649). the absence of differences in pre-extubation ventilation parameters and blood gas results between ef and es groups in the present study was similar to wang et al. but differed from chawla et al. who found that lower ph, higher co2 and higher fio2 prior to extubation were significantly associated with ef.10,11 in addition, shalish et al. found a significant correlation between lower pre-extubation peep and ef.16 as expected, the present study found significantly worse post-extubation blood gas values in the ef compared to the es group; this is similar to wang et al.’s study.11 however, these factors cannot be used to predict the risk of extubation failure. brix et al. found that hb <8.5 mmol/l was associated with ef.18 the present study showed no significant difference in pre-extubation hb level between the ef and es groups, likely because the study population had normal mean hb levels >8.5 mmol/l prior to extubation (related to the unit’s transfusion policy). the longer duration of mv and hospital length of stay in the ef group are expected morbidities of ef. this is consistent with many previous studies.6,9,12,16 the duration of mv for the ef group was also significantly higher for the subgroup of infants <28 weeks ga, but not significantly different for hospital length of stay. it is speculated that, in the <28 weeks ga subgroup, other complications impacted and balanced out their hospital length of stay, because the median for the whole <28 weeks ga subgroup was high at 72.5 (iqr = 33.75%) days (e.g. bronchopulmonary dysplasia). these subgroup results also support that ga (especially <28 weeks) impacted es and the length of hospital stay for all the infants included in the present study. prospective, clinical trials with larger sample sizes are needed to confirm these results. a number of limitations in this study need to be considered. this study had a retrospective design which has more biases associated with confounding factors and causality.19 moreover, some of the data were not documented in patients’ electronic charts, resulting in missing data and a smaller sample size, which could have negatively affected the results. the subgroup analysis on infants <28 weeks ga was done post-hoc and resulted in a decrease in the sample size. this was done for exploratory reasons; inferences on these results should be made with caution. blood gas values were arterial, venous or capillary; these could not be distinguished as they were not categorised separately in patients’ charts. finally, this study only reviewed the charts of preterm infants of a single tertiary centre in oman and may not be generalisable to other settings. conclusion ef rate (within seven days of extubation) in preterm infants admitted to a tertiary care nicu in oman, was found to be 24.3%; this is within reported international rates. ga <28 weeks was found to be the main predictor table 3: predictors of infant extubation failure variable or (95% ci) univariate multivariate* pda 2.775 (1.251–6.154 2.326 (0.967–5.592) ga<28 weeks 2.570 (1.168–5.655) 2.621 (1.118–6.146) 1-minute apgar 2.997 (1.190–7.548) 2.533 (0.958–6.695) or = odds ratio; ci = confidence interval; pda = patent ductus arteriosus; ga = gestational age. *adjusted binary logistic regression analysis performed. risk factors of extubation failure in intubated preterm infants at a tertiary care hospital in oman 252 | squ medical journal, may 2022, volume 22, issue 2 of ef. neonatal practitioners need to seriously consider extreme prematurity before extubation. it may be beneficial to implement strategies known to help decrease ef such as formal assessment of extubation readiness and post-extubation non-invasive positive pressure ventilation in this group of infants. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n hm conceptualised the study while hm and br prepared the research proposal. br and ak collected the data. br, mn and sr analysed the data. all authors contributed to the drafting of the manuscript and approved the final version. references 1. stefanescu bm, murphy wp, hansell bj, fuloria m, morgan tm, aschner jl. a randomized, controlled trial comparing two diffe rent continuous positive airway pressure systems for the successful extubation of extremely low birth weight infants. pediatrics 2003; 112:1031–8. https://doi.org/10.1542/peds.112.5.1031. 2. al-mandari h, shalish w, dempsey e, keszler m, davis pg, sant'anna g. international survey on periextubation practices in extremely preterm infants. arch dis child fetal neonatal ed 2015; 100:f428–31. https://doi.org/10.1136/archdischild-20 15-308549. 3. miller jd, carlo wa. pulmonary complications of mechanical ventilation in neonates. clin perinatol 2008; 35:273–81, x-xi. https://doi.org/10.1016/j.clp.2007.11.004. 4. kamlin co, davis pg, morley cj. predicting successful extubation of very low birthweight infants. arch dis child fetal neonatal ed 2006; 91:f180–3. https://doi.org/10.1136/adc.2005.081083. 5. baisch sd, wheeler wb, kurachek sc, cornfield dn. extubation failure in pediatric intensive care incidence and outcomes. pediatr crit care med 2005; 6:312–18. https://doi.org/10.1097/01.pcc. 0000161119.05076.91. 6. chawla s, natarajan g, gelmini m, kazzi sn. role of sponta neous breathing trial in predicting successful extubation in premature infants. pediatr pulmonol 2013; 48:443–8. https:// doi.org/10.1002/ppul.22623. 7. kurachek sc, newth cj, quasney mw, rice t, sachdeva rc, patel nr, et al. extubation failure in pediatric intensive care: a multiple-center study of risk factors and outcomes. crit care med 2003; 31:2657–64. https://doi.org/10.1097/01. ccm.0000094228.90557.85. 8. guardia cg, moya fr, sinha s, gadzinowski j, donn sm, simmons p, et al. reintubation and risk of morbidity and mortality in preterm infants after surfactant replacement therapy. j neonatal-perinatal med 2011; 4:101–9. https://doi. org/10.3233/npm-2011-2736. 9. costa ac, schettino rde c, ferreira sc. [predictors of extubation failure and reintubation in newborn infants subjected to mechanical ventilation]. rev bras ter intensiva 2014; 26:51–6. https://doi.org/10.5935/0103-507x.20140008. 10. hermeto f, martins bm, ramos jr, bhering ca, sant'anna gm. incidence and main risk factors associated with extubation failure in newborns with birth weight < 1,250 grams. j pediatr (rio j) 2009; 85:397–402. https://doi.org/10.1590/s0021-7557 2009000500005. 11. wang sh, liou jy, chen cy, chou hc, hsieh ws, tsao pn. risk factors for extubation failure in extremely low birth weight infants. pediatr neonatol 2017; 58:145–50. https://doi.org/10.10 16/j.pedneo.2016.01.006. 12. hiremath gm, mukhopadhyay k, narang a. clinical risk factors associated with extubation failure in ventilated neonates. indian pediatr 2009; 46:887–90. 13. chawla s, natarajan g, shankaran s, carper b, brion lp, keszler m, et al. markers of successful extubation in extremely preterm infants, and morbidity after failed extubation. j pediatr 2017; 189:113–19.e2. 14. dimitriou g, greenough a, endo a, cherian s, rafferty gf. pred iction of extubation failure in preterm infants. arch dis child fetal neonatal ed 2002; 86:f32–5. https://doi.org/10.1136/ fn.86.1.f32. 15. szymankiewicz m, vidyasagar d, gadzinowski j. predictors of successful extubation of preterm low-birth-weight infants with respiratory distress syndrome. pediatr crit care med 2005; 6:44–9. https://doi.org/10.1097/01.pcc.0000149136.28598.14. 16. shalish w, latremouille s, papenburg j, sant'anna gm. predictors of extubation readiness in preterm infants: a systematic review and meta-analysis. arch dis child fetal neonatal ed 2019; 104:f89–97. https://doi.org/10.1136/archdischild-2017-313878. 17. henderson-smart dj, davis pg. prophylactic methylxanthines for endotracheal extubation in preterm infants. cochrane data base syst rev 2010:cd000139. https://doi.org/10.1002/146518 58.cd000139.pub2. 18. brix n, sellmer a, jensen ms, pedersen lv, henriksen tb. pred ictors for an unsuccessful intubation-surfactant-extubation procedure: a cohort study. bmc pediatr 2014; 14:155. https:// doi.org/10.1186/1471-2431-14-155. 19. hulley sb, cummings sr, newman tb. designing crosssectional and cohort studies. in: hulley sb, cummings sr, browner ws, grady dg, newman tb. designing clinical research. 4th ed. philadelphia: lippincott williams & wilkins, 2013. pp. 85–96. https://doi.org/10.1542/peds.112.5.1031 https://doi.org/10.1136/archdischild-2015-308549 https://doi.org/10.1136/archdischild-2015-308549 https://doi.org/10.1016/j.clp.2007.11.004 https://doi.org/10.1136/adc.2005.081083 https://doi.org/10.1097/01.pcc.0000161119.05076.91 https://doi.org/10.1097/01.pcc.0000161119.05076.91 https://doi.org/10.1002/ppul.22623 https://doi.org/10.1002/ppul.22623 https://doi.org/10.1097/01.ccm.0000094228.90557.85 https://doi.org/10.1097/01.ccm.0000094228.90557.85 https://doi.org/10.3233/npm-2011-2736 https://doi.org/10.3233/npm-2011-2736 https://doi.org/10.5935/0103-507x.20140008 https://doi.org/10.1590/s0021-75572009000500005 https://doi.org/10.1590/s0021-75572009000500005 https://doi.org/10.10 16/j.pedneo.2016.01.006 https://doi.org/10.10 16/j.pedneo.2016.01.006 https://doi.org/10.1136/fn.86.1.f32 https://doi.org/10.1136/fn.86.1.f32 https://doi.org/10.1097/01.pcc.0000149136.28598.14 https://doi.org/10.1136/archdischild-2017-313878 https://doi.org/10.1002/14651858.cd000139.pub2 https://doi.org/10.1002/14651858.cd000139.pub2 https://doi.org/10.1186/1471-2431-14-155 https://doi.org/10.1186/1471-2431-14-155 squ med j, november 2011, vol. 11, iss. 4, pp. 455-461, epub. 25th oct 11 submitted 3rd feb 11 revision req. 24th may 11, revision recd. 25th jun 11 accepted 28th aug 11 it is about 20 years since the first cord blood transplant (cbt) was performed in a young patient with fanconi's anaemia. since then, due to technological advances, there has being a tremendous progress in the utilisation and application of cbt, both in terms of quantity and quality.1 the use of cbt has risen following the understanding that cord blood (cb), which is normally wasted following delivery of a baby, 1department of haematology, college of medicine & health sciences, muscat, oman; 2department of haematology, sultan qaboos university hospital, muscat, oman. *corresponding author email: sskindi@yahoo.com جتميع وزراعة دم احلبل الُسري مراجعة قصرية �ضلم الكندي و ديفيد دين�ضون اخلال�صة: مّر اأكرث من ع�رسين �ضنة على اأول زراعة من دم احلبل ال�رسي، وجاءت هذه العملية بعد التحقق من اأّن دم احلبل ال�رسي )الذي عادة ما كان ُيهدر( غني باخلليا الأ�ضلية )اجلذعية( التي ميكن ال�ضتفادة منها يف اإعادة منو اإنتاج خليا الدم. ومنذ ذلك احلني مت التعرف على كثري من خ�ضائ�س دم احلبل ال�رسي، التي من �ضمنها قدرته على اإ�ضعاف املري�س املحتاج لزراعة هذا الدم دون احلاجة اإىل اأن يكون هناك تطابقا كامل مل�ضت�ضد اخلليا الليمفاوية. كذلك فاإن دم احلبل ال�رسي متوفر، ويكون خاليا من الكائنات املجهرية امل�ضببة للعدوى ن�ضبيا، كما اأنه ل ي�ضكل اأي خطر على ال�ضخ�س الذي اأخذ منه. غري اأن كمية دم احلبل ال�رسي قليلة ولذلك فاإن اإ�ضتخداماته حمدودة للأطفال اأو الكبار الذين هم بحاجة اإىل وحدتني معا. ويف ُعمان، كان هناك اهتمام كبري مبو�ضوع البحوث يف اخلليا اجلذعية اأو العظمي للنخاع متربع لهم يتوفر ل الذين املر�ضى من لكثري مدخل متثل الأن�ضطة هذه مثل وارتاأينا اأن ال�رسي، احلبل دم وزراعة احلبل لدم التطوعي الوطني امل�رسف تاأ�ضي�س اإىل �ضجعنا ما وهذا لهم. اآخر خمرجا ال�رسي احلبل دم ي�ضكل وبالتايل اخلارجي للدم ال�رسي، والذي �ضيكون خيارا ممتازا لبع�س املر�ضى، بعك�س امل�رسف التجاري لدم احلبل ال�رسي الذي حتوم حوله ال�ضبهات. �ضيحوي هذا امل�رسف الوطني متطلبات املنطقة من التطابق لأنواع م�ضت�ضد اخلليا الليمفاوية و�ضيكون مفيدا لعتماده على م�ضارف م�ضابهة يف دول اأخرى. وبالنظر حلاجة البلد اإىل زراعة اخلليا اجلذعية والعلج بها فاإن اإن�ضاء م�رسف كهذا �ضوف يخدم بع�س املتطلبات الوطنية. مفتاح الكلمات: دم احلبل ال�رسي، زراعة دم احلبل ال�رسي، اخلليا اجلذعية يف دم احلبل ال�رسي، جتميع دم احلبل ال�رسي، امل�رسف الوطني لدم احلبل ال�رسي، امل�رسف اخلا�س لدم احلبل ال�رسي، ُعمان. abstract: it is more than 20 years since the first cord blood transplant (cbt) was performed, following the realisation that cord blood (cb), which is normally wasted, is rich in progenitor cells and capable of rescuing haematopoiesis. since then it has been appreciated that cb is rich in stem cells, and has many other features not the least of which is its ability to rescue the transplanted patient without a rigid need for full human lymphocyte antigen (hla) compatibility. also it is easily accessible, relatively free from infections and poses no medical risk to the donor. however, the quantity of the stem cells is rather small, thus predominantly restricting its use to children or adults requiring double units. in oman, we have taken a keen interest in stem cell research and also cbt. we see such activities as an avenue for our patients, for whom a compatible bone marrow (bm) or a peripheral blood donor cannot be found, to have an alternative in the form of cbt. this has encouraged us to establish a national voluntary cord blood bank (cbb) which is a valuable option open to a selected group of patients, as compared to the controversial private cbb. this national cbb will have a better representation of hla-types common in the region, an improvement on relying on banks in other countries. considering the need for stem cell transplant/therapy in this country, it is only appropriate that this sort of bank is established to cater for some of these requirements. keywords: umbilical cord blood; cord blood transplantation; cord blood stem cell; cord blood banking; private cord blood bank; national cord blood bank. review umbilical cord blood banking and transplantation a short review *salam alkindi1 and david dennison2 umbilical cord blood banking and transplantation a short review 456 | squ medical journal, november 2011, volume 11, issue 4 contains large quantities of pluripotential stem cells that could be utilised to regenerate or rescue haematopoietic stem cells (hsc), following their exposure to accidental or therapeutic ablative therapy. pleuripotent stem cells are undifferentiated cells that are capable of dividing, self-renewal, and generating progeny of highly specialised cells, upon exposure to optimal environmental stimuli in what is termed a bone marrow microenvironment.2,3 this microenvironment is under the influence of various biomolecules, with interplay between adhesions molecules, cytokines and their receptors.3 the stem cells found in cb are also similar to those found in the bone marrow and are responsible for the regenerative capacity of the bone marrow’s haematopoietic activities. the initial experiments centered on a severe combined immune deficiency (scid) mouse model that could be rescued by giving these stem cells. the progress that was made in this area was paralleled by progress in the ability to define these stem cells through the process of antibody labelling using flowcytometry, combining both functional and phenotypic assays.4 more recently, the focus has also been on the stromal support cells as they are found to play a crucial role in maintaining the integrity of the haematopoietic cellular milieu.5 these cells originate from mesenchymal stem cells that are not only necessary for the integrity of other marrow stem cells, but are capable of giving rise to many tissue types including cartilage, fat, muscle and bones.5,6 subsequently, it has been demonstrated that cord blood units (cbu) have a number of features which makes them a highly favourable source of stem cells in the ever expanding range of stem cell therapy. having realised the potential uses of cbus, it was deemed necessary to establish cord blood banks (cbbs) in order to collect and store these units until the need for them arose. advantages of cord blood transplants a cbu contains a large number of progenitor cells that can be used to transplant most paediatric and some adult patients who require this form of therapy. these units have a low risk of viral infection (although this is not completely eliminated as epstein-barr virus [ebv] cases has been reported), in particular from cytomegalovirus [cmv].7 moreover, cbus are accessible and secured, so that they could be used at any time. this means that cbu units are ready for use when the recipient is ready for them, and so the transplant can be scheduled at the convenience of the recipient (patient) and not that of the donor. furthermore, it is also known that the incidence of graft-versus-host disease (gvhd) is lower compared with bone marrow or peripheral blood transplantation. this may be related to the immaturity of the immune system at birth and the decreased potential of alloreactive lymphocytes.8 as a result, it is not strictly necessary to have a complete hla match in cbu selection compared to peripheral blood or bone marrow selection. at the same time, the graft-versus-leukaemia (gvl) effect is maintained, fulfilling one of the main purposes of any allogeneic stem cell transplant procedure. additional advantages, include zero risk to the donor since this blood is normally not used and wasted [table1]. disadvantages of cord blood transplants there are, however, some obstacles to the widespread use of cbu [table 2], including the sometimes small number of stem cells in each unit, which leads to a delayed engraftment, and may be reflected in the increased transplant related mortality/morbidity and reduced survival. this is table 1: advantages of cord blood transplantation advantage comments rich in progenitor cells capable of durable engraftment and long-term haematopoiesis in adults and children relatively free from infections translates to reduced transplant mortality/ morbidity cbus are accessible transplantation scheduled to recipient convenience gvhd is less improved survival gvl is maintained achieves transplantation purposes zero risk to the donor positive utilisation of cbu less stringent hla matching requirements with easy access to rare haplotypes transplant possible for many recipients legend: cbu = cord blood unit; gvhd = graft-versus-host disease; gvl = graft-versus-leukaemia; hla = human lymphocyte antigen salam alkindi and david dennison review | 457 tests could be improved by taking a detailed family history from the parents. despite all of the above difficulties, cbt is growing, and cbu storage is rising worldwide. the increasing interest in cbu has therefore necessitated the need for cbbs of which there are currently two types. national voluntary cord blood banks national voluntary cbbs generally cater for mothers who have children with a disease that is cured by bone marrow transplant (bmt) such as thalassaemia, sickle cell disease or leukaemia. in these cases, mothers are encouraged to collect their babies' cb for possible future related umbilical cbt. these cbus are collected and a process of hla matching is done. it is also now possible in some centres to make a selection of disease-free offspring and hla-matched babies as part of preimplantation genetic determination (pgd).12 parents also can elect to donate the cbu of their baby to the national cbb to be used for patients where donors could not be found from their own family, allowing many matched but unrelated cbts to be performed. with the average family size declining in the western world, it is estimated that only about 25% of caucasians will have a fully matched unrelated donor, and cbt has become in this regard an attractive source of stem cells.13 recent statistics suggest that more than 400,000 cbu units are stored in banks in about 40 countries worldwide for use in unrelated transplants; of these, around 20,000 cbus have been used for transplant so far worldwide, contributing to the cure of many children with haematological malignancies and bone marrow failure disorders who do not have matched family donors.14 interestingly in fact, cbt has become more popular, particularly in children, and in 2009 more unrelated cbts were performed than unrelated bmts worldwide.15,13 public banks store cbus free of charge, samples are used to treat any patient without a donor and these banks are financed by public money.16 probably the most important limitation in cbt.9 furthermore, since these units are small, (with reduced volume and quantity of stem cells), they may not be sufficient for large patients, although this could be augmented by using two human lymphocyte antigen (hla) matched units at the same time. efforts are being made to enhance the number, potency and engrafting capabilities of the collected stem cells through ex-vivo and in vivo manoeuvres, by modulating the microenvironment, cell receptors, and signalling pathways that control them.2 there are also efforts to enhance engraftment, including enhancing homing of the transfused cells as well as direct intra-bone marrow injections.10,11 the stored unit is not known for any severe haematologic or immune disorders, which may be transferred by the transplant process, and only for this reason, the donor is examined carefully after 6 months and the unit is also tested for haematologic and immune deficiency syndromes which may manifest only in the adult life. extensive testing for common hereditary disorders, although very relevant to a country such as oman, would be quite expensive, and the predictive value of such table 2: disadvantages of cord blood transplantation disadvantages consequences reduced cell dose may delay engraftment/ reduce survival units may be small large adult recipients (>60 kg) require two units haematologic and immunologic disorders may not be apparent at birth requires careful donor screening and testing for common hereditary blood and immune disorders inherited disorders 84 (48%) haematological malignancy 81 (46%) aplastic anaemia 11 (6%) figure 1: indications for bone marrow transplantation, sultan qaboos university hospital, oman, june 1995 to oct 2010. umbilical cord blood banking and transplantation a short review 458 | squ medical journal, november 2011, volume 11, issue 4 private cord blood banking upon requests from interested parents, cbus are also collected for personal use of that newborn in the future and, although the odds ratio for their utilisation has risen with time, it remains between 1 in 25,000 to 1 in 200,000 in the first 20 years of life.17 this has resulted in the proliferation of private (for-profit) cbbs that store these units. their number is rising worldwide, capitalising on the idea that cb usage is expanding daily, beyond the currently available indications. these banks charge a fee to store cbus exclusively for that neonate’s family only and only this family may access them. there are about 900,000 cbus stored in private banks and more than 100 reports of successful autologous cbts done worldwide by this method. although the use of such cbus for non-malignant conditions is reasonable, their use for the treatment of malignant conditions such as leukaemia will be limited by the lack of gvl—one of the main reasons for having allogeneic transplants. caution has to be exercised in unrestrictedly advocating the widespread use of such banks, one of the many reasons being the limited future clinical utility of cbus; for example, the european group for blood and marrow transplantation (embt) reported 544 cord blood transplants in 2006, but none of them was autologous.18 furthermore, the professional reluctance to accept private cbbs stems from the fact that the amount of total nucleated cells (tnc) in these units is small allowing at most only paediatric transplants. it is also possible that these cbus are contaminated with leukaemogenic cells prohibiting the most important indications for cord transplant in childhood leukaemia.19 the yield of cbus as well as their utilisation for mesenchymal stem cell therapy remains controversial.20 arguments for lack of support for private (for profit) banks from academic and scientific community, rest on the lack of clinical justifications for autologous banking, poor quality standards regarding collection and storage, no guarantees in case of bankruptcy and misleading advertising from cb companies.20 recent studies from european countries suggest a strong preference for public cbb as opposed to private blood banking.16,21 hybrid banks are also gaining popularity, where companies are collecting units for a fee for a private family use, and at the same time collect units for national use. this enables local health authorities to cover some of the costs of storing these public units.19 what are the indications for cord blood transplantation? cbus contain a large number of stem cells that could be used in transplanting many diseases including sickle cell anaemia: 8 blackfan diamond syndrome: 1 glanzmanns thrombasthaenia: 2 fanconi’s anaemia: 5 mucopolysaccharidosis type i: 1 chronic granulomatous disease: 4 haemaphagocytic lymphohistiocytosis: 5 severe combined immunodeficiency syndrome: 4 mhc class ii deficiency: 2 chediak higashi syndrome: 1 congenital neutropaenia: 1 interferon gamma receptor deficiency: 2thalassaemia major: 47 primary immunodeficiency figure 2: bone marrow transplantation for hereditary blood disorders at sultan qaboos university hospital, oman, june 1995 to oct 2010. salam alkindi and david dennison review | 459 response. however, more recently we have started reduced intensity conditioning transplantations (ric) allowing us to include older patients with malignant conditions as well as more complicated patients with non-malignant disease such as scd patients. ric, particularly in scd, has been used following the understanding of improved survival of healthy donor erythrocytes as compared to the recipient abnormal cells. furthermore, as ineffective erythropoiesis lends a competitive advantage to donor erythroid progenitors, this creates a mixed donor/recipient chimera to co-habilitate together first. later the donor clone eventually dominates and replaces the recipient’s original clone. ric has also allowed many patients who could not tolerate a fully myeloablative therapy to have a stem cell transplant, allowing appropriate disease control with acceptable transplant related morbidity/ mortality.27 the spectrum of the conditions that we have treated in our centre is shown in figure 1, whereas figure 2 outlines in detail the transplantations for hereditary blood disorders and is reflective of pattern of diseases that are prevalent in oman. our cbb was established as the first national cbb in the country to cater for parents who have a child suffering from one of the disorders that are cured by bmt and who wanted their newborn baby’s cbu to be collected and processed for possible matched related transplant for their offspring. we have also created a voluntary cb banking system for those who want to donate their baby’s cb to our national cbb. having obtained local ethical approval, our counsellors approach expectant mothers and their partners in the antenatal clinic for consent to collect cord blood. this is then collected by trained midwifes in the delivery ward, and undergoes red cell depletion at our stem cell processing laboratory. samples are taken for hla typing, serology for hepatitis and hiv as well as microbial cultures. also the sample undergoes cell counts and, in related (sibling) cord samples, any count is acceptable; however, in voluntary cord blood samples, only units with total nucleated cells above 6 x 108/kg are cryopreserved, other units being discarded.28 so far we have collected cord blood from 81 siblings and >40 unrelated cb units. the number of the frozen cbus is increasing and our aim is to establish a fully fledged cbb according to the international regulations of the foundation for accreditation acute and chronic leukaemia, other malignancies such as lymphoma, hereditary blood disorders such as sickle cell disease (scd), thalassaemia and many bone marrow failure syndromes as well as immune deficiency states. the reports of disease free survival in various conditions range from 40–80% in paediatric unrelated transplants and 20–57% in adults transplants with varying times of follow-up.12,22-24 according to the most recent data from multicentre registries, there are several factors that determine the outcome of transplants including the cell dose, age, gender, cmv status and stage of the disease at the time of the transplant.24-25 in the presence of in vitro expansion, there may be a role for cb in the treatment of degenerative diseases such as cardiac, neurological and rheumatic diseases in what is known as cellular regenerative therapy, an argument used by the advocates for private cbb groups.26 umbilical cord blood banking and stem cell transplantation in oman stem cell transplantation (bone marrow [bm], peripheral blood [pb] and cb), has been carried out at sultan qaboos university hospital since 1995. although the start was modest in terms of numbers, over the years more has been achieved, and results are now comparable with the best transplant centres worldwide. currently, having done over 200 transplants of bm, pb, and cbt for leukaemia, myeloma, lymphoma, hereditary blood disorders and immune deficiency syndromes, the programme is gaining strength. diversification was achieved in the programme by the use of bm, pb, and cb both in related and, more recently, unrelated donors, as well autologous transplantations. the programme aims to address the unique disease distributions seen in our country by catering for transplants in haemoglobin disorders such as thalassaemia and sickle cell disease, as well as immune deficiency syndromes, and malignant disorders such as leukaemia, lymphoma and myeloma. furthermore, for successful stem cell transplantation, traditionally a full myeloablative conditioning therapy using chemotherapy, radiotherapy or both has been used. this helps to create a less hostile bm environment, eradicates any residual abnormal clone and suppresses the recipient’s immune umbilical cord blood banking and transplantation a short review 460 | squ medical journal, november 2011, volume 11, issue 4 10. campbell tb, hangoc g, liu y, pollok k, broxmeyer he. inhibition of cd 26 in human cord blood cd34+ cells enhance their engraftment of non obese-diabetic/severe combined immunodeficiency mice. stem cell dev 2007; 16:347–54. 11. frassoni f, gualandi f, podestà m, raiola am, ibatici a, piaggio g, et al. direct intrabone transplant of umbilical cord-blood cells in acute leukaemia phase i/ii study. lancet oncol 2008; 9:831–9. 12. locatelli f, rocha v, reed w, bernauudin f, ertem m, grafakos s, et al. related umbilical cord blood transplantation in patients with thalassaemia and sickle cell disease. blood 2003; 101:2137–43. 13. rocha v. lacatelli f. searching for alternative hematopoietic stem cell donors for pediatric patients. bone marrow transplantat 2008; 41:207–14. 14. ballen k. challenges in umbilical cord blood stem cell banking for stem cell reviewers and reports. stem cell rev 2010; 6:8–14. 15. broxmeyer he. umbilical cord transplantation epilogue. semin hematol 2010; 47:97–103. 16. katz g, mills a, garcia j, hooper k, mcguckin c, platz a, rebulla p, et al. banking cord blood stem cells: attitude and knowledge of pregnant women in five european countries. transfusion 2011; 51:578–86. 17. ballen k, barker jn, stewart sk, greene mf, lane ta. collection and preservation of cord blood for personal use. biol blood marrow transplant 2008; 14:356–63. 18. gratwohl a, baldomero h, frauendorfer k, rocha v, apperley j, niederwieser d. the embt activity survey 2006 on haematopoietic stem cells transplantation: focus on the use of cord blood products. bone marrow transplant 2008; 41:687–705. 19. fisk nm, atun r. public-private partnerships in cord blood banking. bmj 2008; 336:642–4. 20. fisk nm, roberts ia, markwald r, mironov v. can routine commercial cord blood banking be scientifically and ethically justified? plos med 2005; 2:e44. 21. edozien lc. nhs maternity units should not encourage commercial banking of umbilical cord blood. bmj 2006; 333:801–4. 22. kurtzberg j, laughlin m, graham ml, smith c, olson jf, halperin ec, et al. placental blood as a source of hematopoetic stem cells for transplantation into unrelated recipients. new engl j med 1996; 335:157–66. 23. laughlin mj, barker j, bambach b, koc on, rizzieri da, wagner je, et al. hematopeitic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. n engl j med 2001; 344:1815–22. 24. laughlin mj, eapen m, rubinstein p, wagner je, on cell therapy (fact). this foundation edits the netcord-fact international standards for cb collection, processing, testing and banking selection.29 conclusion stem cells derived from cb, bm, and pb are contributing significantly to the curative treatment potential available for many acquired and congenital disorders in oman and worldwide. national cbbs remain the preferred option, on economic, scientific and ethical grounds, until there are further advances in knowledge on the use of autologous cbt. our strategy is to make stem cell therapy accessible to our patients, employing well established procedures for stem cell collection, storage, in vitro expansion and manipulation in order to achieve a successful national, culturally accepted cbb. references 1. brunstein cg, setubal dc, wagner je. expanding the role of umbilical cord blood transplantation. br j haematol 2007; 137:20–35. 2. broxymeyer he. cord blood hematopoietic stem cell transplantation. in: stem cells (internet), cambdrige (ma): harvard stem cell institute; update 20082010, 26 may 2010. 3. bryder d, rossi dj, weissman il. hematopoietic stem cells: the paradigmatic tissue-specific stem cell. am j pathol 2006; 169:338–46. 4. scadden dt. the stem-cell niche as an entity of action. nature 2006; 1075–79. 5. bhatia m, bonnet d, murdoch b, gan oi, dick je. a newly discovered class of human hematopoietic cells with scid-repopulating activity. nat med 1998; 4:1038–45. 6. pittenger mf, mackay am, beck sc, jaiswal rk, douglas r, mosca jd, et al. multi-lineage potential of adult human mesenchymal stem cells. science 1999; 284:143–7. 7. kogler g, calleias j, hakenbern p, enczmann j, adams o, daubener w, et al. hematopoietic transplant potential of unrelated cord blood: critical issues. j hematother 1996; 5:105–16. 8. eapen m. outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukemia: a comparison study. lancet 2007; 369:1947–54. 9. gluckman e, rocha v. donor selection for unrelated cord blood transplants. curr opin immunol 2006; 18:565–70. salam alkindi and david dennison review | 461 processors for the treatment of myocardial infarction. j am coll cardiol 2010; 55:2244–53. 27. diaconescu r, flowers cr, storer b, sorror ml, maris mb, maloney dg, et al. mortality and morbidity with nonmyeloablative compared to myeloablative conditioning before haematopoietic cell transplantations from hla matched related donors. blood 2004; 104:1550–8. 28. barker jn, byan c, scaradavou a. how i treat: the selection and acquisition of unrelated cord blood grafts. blood 2011; 117:2332–9. 29. wall da. regulatory issues in cord blood banking and transplantation. best pract res clin haematol 2010; 23:171–7. zhang mj, charnplin re, et al. outcome after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. n engl j med 2004; 351:2265–75. 25. cohen yc, scaradayou a, stevens ce, rubinstein p, gluckman e, rocha v, et al. factors affecting mortality following myeloablative cord blood transplantation in adults: a pooled analysis of three international registries. bone marrow transplant 2011; 46:70–6; doi:10.1038/bmt.2010.83; epub 3 may 2010. 26. arminan a, gandia c, garcia-verduqo jm, liedo e, triqueros c, ruiz-sauri a, et al. mesenchymal stem cells provide better results than hematopieetic a hydatidiform mole coexisting with a normal live fetus in a twin pregnancy is an extremely rare phenomenon, with a worldwide incidence ranging from one in 22,000 to one in 100,000 pregnancies.1,2 this condition presents a significant management challenge for physicians due to its associated complications, including heavy vaginal bleeding, severe pre-eclampsia, intrauterine fetal death or growth restriction, miscarriage, preterm birth and hyperthyroidism, as well as ovarian cyst rupture or torsion in cases with theca lutein cysts.1 twin molar pregnancies may also have an increased risk of persistent trophoblastic disease compared to a single molar pregnancy.2 case report a 32-year-old gravida 3, para 2 woman was admitted to the emergency department of the sultan qaboos university hospital (squh), muscat, oman, in march 2012 at 13 gestational weeks with lower abdominal pain and vaginal spotting. upon examination, she was haemodynamically stable and not in distress. abdominal palpation indicated mild tenderness and a uterine size corresponding to 16 gestational weeks. an ultrasound examination revealed a twin pregnancy, including one normal fetus with the placenta covering the cervical opening and one molar pregnancy [figure 1a]. both ovaries were enlarged with multiple theca lutein cysts; the right ovary measured 12.2 x 8.1 x 6.9 cm while the left measured 13.3 x 7.3 x 10.6 cm [figure 1b]. the patient’s serum β-human chorionic gonadotropin (hcg) level was 1,386,570 iu/l. chest x-ray findings were normal as were the results of the thyroid function tests and coagulation profile. the patient and her husband were counselled in detail regarding the risks associated with this type of pregnancy; opinions from international experts departments of 1obstetrics & gynaecology, 3radiology & molecular imaging and 4pathology, sultan qaboos university hospital, muscat, oman; 2department of obstetrics & gynaecology, kasturba medical college, manipal, india *corresponding author e-mail: drshahila@gmail.com احلمل التوأم باحلمل العنقودي الكامل مع جنني حي حالة نادرة �سهيلة ال�سيخ، نهال الريامية، ناميثا را�سيل ماثيو، را�سد ال�سكيتي، عا�سم قري�سي، مرمي ماثيو abstract: a hydatidiform mole with a coexisting live fetus is a rare occurrence and the optimal management for this condition is not yet known. we report the case of a 32-year-old woman (gravida 3, para 2) who presented to the sultan qaboos university hospital, muscat, oman, in march 2012 at 13 gestational weeks with abdominal pain and vaginal bleeding. an ultrasound examination revealed a hydatidiform mole pregnancy coexisting with a live fetus. after extensive counselling, the patient and her husband opted for a conservative management approach. unfortunately, a hysterotomy had to be performed at 17 gestational weeks due to severe haemorrhage. the postoperative period was uneventful and histopathology results confirmed one complete mole with a coexisting fetus and normal placenta. the patient’s serum β-human chorionic gonadotropin level remained normal for 18 months following her surgery. keywords: hydatidiform mole; twin pregnancy; fetus; hysterotomy; placenta; human chorionic gonadotropin; case report; oman. امللخ�ص: احلمل العنقودي الكامل مع جنني حي هو حالة نادرة احلدوث والعالج الأمثل لهذه احلالة غري معروف حتى الآن. نحن نبلغ عن حالة لإمراأه يف 32 من عمرها )يف حملها الثالث وولدتني �سابقتني( والتي جاءت اإىل م�ست�سفى جامعة ال�سلطان قابو�ض يف م�سقط، عمان، يف مار�ض 2012 يف الإ�سبوع 13 من احلمل بالآم يف البطن ونزيف مهبلي.الأ�سعة الفوق ال�سوتية اأو�سحت حمل عنقودي مع جنني حي. وبعد امل�سورة وا�سعة النطاق اختارت املري�سة وزوجها املحافظة والإ�ستمرار يف احلمل. لالأ�سف كان لبد من اإجراء عملية اإنزال للجنني يف الأ�سبوع 17 من احلمل عن طريق فتحة يف الرحم ب�سبب نزيف حاد. كانت فرتة ما بعد اجلراحة خالية من الأحداث واأكد الت�رسيح املخربي حمل تواأم بحمل عنقودي واحد وجنني اآخر مع م�سيمة طبيعية. ظل م�ستوى هرمون احلمل طبيعي لفرتة 18 �سهر بعد العملية. مفتاح الكلمات: حمل عنقودي؛ حمل تواأم؛ جنني؛ فتح الرحم؛ م�سيمة؛ هرمون احلمل؛ تقرير حالة؛ عمان. twin pregnancy with a complete hydatidiform mole and a coexisting live fetus rare entity *shahila sheik,1 nihal al-riyami,1 namitha r. mathew,2 rashid al-sukaiti,3 asim qureshi,4 mariam mathew1 online case report sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e550–553, epub. 23 nov 15 submitted 26 feb 15 revision req. 14 may 15; revision recd. 30 may 15 accepted 18 jun 15 doi: 10.18295/squmj.2015.15.04.019 shahila sheik, nihal al-riyami, namitha r. mathew, rashid al-sukaiti, asim qureshi and mariam mathew online case report | e551 were elicited and the couple was informed that a review of the literature indicated a 25% chance of a live birth and a 40% chance of early fetal loss.3 a multidisciplinary team including a consultant haematologist, an anaesthetist, an interventional radiologist and several obstetricians were involved in the decision-making process. after consideration, the couple opted to continue the pregnancy with close follow-up and the patient was discharged after three days. despite close follow-up, the patient was readmitted at 17 gestational weeks with vaginal bleeding and tachycardia. a significant drop in haemoglobin from 10 g/dl to 7 g/dl was also noted, requiring a transfusion of two units of packed red blood cells. at this time, the uterine size corresponded to 28 gestational weeks. the couple were advised that the maternal risks had now increased significantly and they agreed to have the pregnancy terminated. bilateral uterine artery balloon catheters were placed prophylactically and inflated to control the intraoperative blood loss; this provision would also enable the postoperative embolisation of the uterine arteries if required. a hysterotomy was performed under general anaesthesia via a lower segment transverse incision. molar tissue weighing 1,040 g was evacuated, along with a fetus weighing 105 g and a normal placenta of 65 g [figure 2]. the ovaries were enlarged with bilateral theca lutein cysts. the intraoperative blood loss was 800 ml. the uterine artery balloon catheters were removed six hours after the operation as there was no active bleeding and embolisation was not deemed necessary. the postoperative recovery period was uneventful. histopathology results confirmed a complete hydatidiform mole with a coexisting fetus and normal placenta [figure 3]. three months after the surgery, the patient’s serum β-hcg level had returned to normal without any cytotoxic therapy. the enlarged ovaries with multiple theca lutein cysts took six months to return to a normal size. there was no evidence of any persistent trophoblastic disease one year later and the serum β-hcg level remained normal for 18 months following the surgery. at the time of writing, the patient was planning her next pregnancy. discussion complete hydatidiform moles form part of the tumour spectrum of gestational trophoblastic disease. molar pregnancies are subdivided into either complete or partial types based on genetic and histological features. a complete hydatidiform mole consists of oedematous villous tissue and trophoblastic hyperplasia with no fetal tissue.1,3 while a complete mole is diploid, its chromosomes are entirely of paternal origin, following the duplication of a single sperm fertilising an empty ovum.1 however, the majority of partial moles are triploid in origin and contain two sets of paternal and one set of maternal haploid genes. this occurs following the fertilisation of a normal ovum by two sperm cells. in a partial mole, a fetus or fetal red blood figure 1a & b: ultrasound scans of a patient with a complete hydatidiform mole and coexisting live fetus showing (a) the junction between the normal placenta and the molar tissue (white arrow) and the normal fetus in the gestational sac (red arrow) and (b) the enlarged left ovary with multiple theca lutein cysts (red arrow). figure 2: photograph of the normal fetus and placenta and the molar tissue following a hysterotomy in a pregnant patient with a complete hydatidiform mole and a coexisting live fetus. twin pregnancy with a complete hydatidiform mole and a coexisting live fetus rare entity e552 | squ medical journal, november 2015, volume 15, issue 4 past decade, clinicians have supported the option of conservation, providing that the patient remains under strict hospital-based observation and followup.8,9 with the current medical facilities available, most expected complications can be diagnosed early and managed appropriately. although the risk of persistent trophoblastic disease cannot be excluded in cases of conservative management, this risk does not seem to increase with gestational age.10,11 conservative management in a tertiary care environment is indicated if a multi-disciplinary team is present and able to quickly respond in the event of an emergency. close surveillance of the patient is also recommended to detect early signs of maternal and fetal complications. termination of the pregnancy should be considered only if the patient develops severe pre-eclampsia, thyrotoxicosis or significant vaginal bleeding, or if there is evidence of trophoblastic embolisation.12 measures to minimise blood loss during surgery for complete hydatidiform twin molar pregnancies with live co-twins are not described in the literature, although torrential haemorrhage is an expected complication. as such, the authors of this report strongly recommend preoperative placement of bilateral uterine artery balloon catheters for patients at centres with interventional radiology facilities. this will assist in decreasing the intraand postoperative blood loss and minimise the need for blood and blood product transfusions. conclusion in twin pregnancies with one complete hydatidiform mole, the likelihood of delivering a healthy viable fetus is low. this type of pregnancy creates a cells are evident.2 the current patient is the first case of a complete hydatidiform mole coexisting with a live fetus at squh. a conservative approach was initially deemed possible due to the availability of resources and high standard of care. however, close monitoring of the patient and timely intervention were crucial. the incidence of gestational trophoblastic disease is higher among women of asian, west african and south american origin, compared to those from europe and north america.4 it is normally seen in the very young and elderly. a previous molar pregnancy increases the chance of a repeat molar pregnancy by 1‒3%.4 however, with two previous molar pregnancies, the risk goes up to almost 15%.4 aside from ethnicity, none of the risk factors mentioned above were relevant to the patient described in the current report. twin pregnancy with a complete hydatidiform mole and a coexisting live fetus is also known as sad fetus syndrome, because the coexisting fetus is usually chromosomally normal and potentially viable.5,6 in the present case, amniocentesis could not be performed for the purposes of fetal karyotyping as the molar tissue was covering the entire anterior wall of the uterus, pushing the live fetus into a posterior position. the pregnancy had to be terminated due to haemorrhage, which is a known and potentially fatal complication associated with this condition. sebire et al. assessed 77 twin pregnancies with complete hydatidiform moles and healthy co-twins to ascertain the risk of continuing the pregnancy as opposed to termination.7 they concluded that there was a 40% chance of a live birth with a very low chance of serious obstetric complications, including the development of persistent gestational trophoblastic disease, if the pregnancy was continued.7 in the figure 3a & b: haematoxylin and eosin stains of the molar tissue showing (a) normal trophoblasts (arrow) at x10 magnification and (b) avascular oedematous villi (arrow) in a pregnant patient with a complete hydatidiform mole and a coexisting live fetus. shahila sheik, nihal al-riyami, namitha r. mathew, rashid al-sukaiti, asim qureshi and mariam mathew online case report | e553 significant management dilemma for the treating physician, especially if the pregnancy was planned. comprehensive counselling, close follow-up and timely intervention are imperative during the conservative management of this rare clinical entity. a c k n o w l e d g e m e n t s a poster presentation of this case was displayed at the 9th singapore international congress of obstetrics & gynecology in singapore in august 2013. an abstract of the poster was published in the singapore journal of obstetrics & gynaecology in 2013 (vol. 44, iss. 2, p. 120). references 1. yarandi f, eftekhar z, izadi-mood n, elahi-panah z, shojaei h. twin pregnancy with hydatidiform mole and coexisting fetus: report of three cases and review of literature. j family reprod health 2009; 3:31–4. 2. steller ma, genest dr, bernstein mr, lage jm, goldstein dp, berkowitz rs. natural history of twin pregnancy with complete hydatidiform mole and coexisting fetus. obstet gynecol 1994; 83:35–42. doi: 10.1016/0020-7292(94)90494-4. 3. royal college of obstetricians & gynaecologists. green-top guideline no.3: gestational trophoblastic disease. from: www. rcog.org.uk/en/guidelines-research-services/guidelines/gtg38/ accessed: feb 2015. 4. lurain jr. gestational trophoblastic disease i: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. am j obstet gynecol 2010; 531–39. doi: 10.1016/j. ajog.2010.06.073. 5. malinowski w, biskup i, dec w. sad fetus syndrome: gestational trophoblastic disease concurrent with a living fetus or fetuses. acta genet med gemellol (roma) 1995; 44:193–202. 6. moini a, ahmadi f, eslami b, zafarani f. dizygotic twin pregnancy with a complete hydatidiform mole and a coexisting viable fetus. iran j radiol 2011; 8:249–52. doi: 10.5812/ iranjradiol.4488. 7. sebire nj, foskett m, paradinas fj, fisher ra, francis rj, short d, et al. outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. lancet 2002; 359:2165–6. doi: 10.1016/s0140-6736(02)09085-2. 8. shazly sa, ali mk, abdel badee ay, alsokkary ab, khodary mm, mostafa na. twin pregnancy with complete hydatidiform mole and coexisting fetus following ovulation induction with a non-prescribed clomiphene citrate regimen: a case report. j med case rep 2012; 6:95. doi: 10.1186/17521947-6-95. 9. piura b, rabinovich a, hershkovitz r, maor e, mazor m. twin pregnancy with a complete hydatidiform mole and surviving co-existent fetus. arch gynecol obstet 2008; 278:377–82. doi: 10.1007/s00404-008-0591-x. 10. massardier j, golfier f, journet d, frappart l, zalaquett m, schott am, et al. twin pregnancy with complete hydatidiform mole and coexistent fetus: obstetrical and oncological outcomes in a series of 14 cases. eur j obstet gynecol reprod biol 2009; 143:84–7. doi: 10.1016/j.ejogrb.2008.12.006. 11. matsui h, sekiya s, hando t, wake n, tomoda y. hydatidiform mole coexistent with a twin live fetus: a national collaborative study in japan. hum reprod 2000; 15:608–11. doi: 10.1093/ humrep/15.3.608. 12. kushtagi p, hegde t. unusual twins: a case of intrauterine pregnancy with complete molar pregnancy. internet j gynecol obstet 2009; 10:11. http://dx.doi.org/10.1016/0020-7292%2894%2990494-4 http://dx.doi.org/10.1016/j.ajog.2010.06.073 http://dx.doi.org/10.1016/j.ajog.2010.06.073 http://dx.doi.org/10.5812/iranjradiol.4488 http://dx.doi.org/10.5812/iranjradiol.4488 http://dx.doi.org/10.1016/s0140-6736%2802%2909085-2 http://dx.doi.org/10.1186/1752-1947-6-95 http://dx.doi.org/10.1186/1752-1947-6-95 http://dx.doi.org/10.1007/s00404-008-0591-x http://dx.doi.org/10.1016/j.ejogrb.2008.12.006 http://dx.doi.org/10.1093/humrep/15.3.608 http://dx.doi.org/10.1093/humrep/15.3.608 departments of 1pharmacology & clinical pharmacy and 2biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3department of laboratory medicine & pathology, royal hospital, muscat, oman; 4department of small animal health, directorate general of veterinary services, royal court affairs, muscat, oman; 5department of basic medical sciences, dubai healthcare city, dubai, united arab emirates *corresponding author e-mail: mme51@squ.edu.om تكرار التعدد اجليين ملورثات arg16gly, gln27glu and thr164ile يف مستقبالت بيتا 2 األدرينريجية عند العمانيني خالد البلو�سي، فهد الزدجايل، �سو�سن ال�سنانية، املعت�سم الزدجايل، ريا�ض بيومي abstract: objectives: this study aimed to assess the distribution of missense mutations in the adrenoceptor β2 (adrb2) gene in an omani cohort. methods: this study was carried out between may 2014 and march 2015 at the sultan qaboos university, muscat, oman. blood samples were taken from 316 unrelated omani subjects. genotyping for rs1042713 (c.46a>g, p.arg16gly), rs1042714 (c.79c>g, p.gln27glu) and rs1800888 (c.491c>t, p.thr164ile) polymorphisms was performed by real-time polymerase chain reaction using single nucleotide polymorphism (snp) genotyping assays. the allelic frequencies of these polymorphisms were estimated on the basis of the observed numbers of specific alleles from the genotype data for male and female subjects. the genotype frequencies for each polymorphism were tested for deviation from the hardy-weinberg equilibrium. results: gly16 and glu27 were the most frequent variants found among the cohort (63% and 75%, respectively). the ile164 variant was not detected in the study population. there was a significant linkage disequilibrium between the rs1042713 and rs1042714 snps (r2 = 0.209; p ≤0.001). the most observed haplotypes were gly16-gln27 and arg16-gln27 (0.37 and 0.38, respectively). the frequency of gly16-glu27 was 0.25, comprising all glu27 carriers. conclusion: the allelic distribution of variants in this omani cohort was similar to distributions reported among caucasian populations. keywords: beta-2 adrenergic receptor; genetic polymorphisms; single nucleotide polymorphisms; allele frequencies; genotype; oman. امللخ�ص: الهدف: هدف هذا البحث اإىل درا�سة توزيع الطفرات املغلطة يف مورثات م�ستقبالت بيتا 2 الأدرينريجية )adrb2( يف جمموعة من العمانيني. الطريقة: اأجريت الدرا�سة بني مايو 2014م ومار�ض 2015م بجامعة ال�سلطان قابو�ض مب�سقط يف عمان. متجمع عينات دم من p.gln27glu( ،rs1042713 )c.46a<g, p.arg16gly( 316 فرد من العمانيني الغري اأقارب. ومتت درا�سة منط التعدد اجليني يف مورثات احلقيقي( )الوقت الت�سل�سلي البلمرة تفاعل جهاز بوا�سطة rs1800888 )c.491c<t, p.thr164ile( and rs1042714 )c.79c<g, وبا�ستخدام مقاي�سة التنميط اجليني للتعدد اجليني للنيوكليوتايد الواحد )snp(. ومت تقدير هذه التعددات اجلينية بح�سب الأرقام املالحظة انحراف وقي�ض البحث. هذا يف والإناث الذكور عينات يف اجلينية الأمناط معلومات من عليها املتح�سل املحددة الأليات تعدادات من تكراركل تعدد جيني من توازن هاردي–فاينبريغ. النتائج: كانت اأكرث املتفاوتات تكرارا هي gly16 و glu27 يف املجموعة التي متت درا�ستها %63 و%75، على التوايل(. ومل يوجد متفاوت ile164 يف تلك املجموعة. وكان هنالك اختالل توازن معنوي اإح�سائيا يف الرتباط 0.37( arg16-gln27 و gly16-gln27 وكان اأكرث منط فرداين هو يف .rs1042713 و rs1042714 snps )r2 = 0.209 ; p ≤0.001( بني ال و 0.38 على التوايل(. وبلغ تواتر gly16-glu27 0.25، وي�سمل ذلك حوامل glu27. اخلال�صة: كان التوزيع الأليلي ملختلف املتفاوتات يف املجموعة العمانية التي در�ست م�سابهة لتوزيعها عند ال�سعوب القوقازية. مفتاح الكلمات: م�ستقبالت بيتا 2 الأدرينريجية؛ التعدد اجليني؛ التعدد اجليني للنيككليوتايد الواحد؛ تكرارالأليات؛ النمط اجليني؛ عمان. frequencies of the arg16gly, gln27glu and thr164ile adrenoceptor β 2 polymorphisms among omanis *khalid al-balushi,1 fahad zadjali,2 sawsan al-sinani,3 al-muatasim al-zadjali,4 riad bayoumi5 clinical & basic research advances in knowledge this study explores the distribution of the major missense mutations of the adrenoceptor β2 (adrb2) gene in the omani population. the p.arg16gly and p.gln27glu variants occurred most frequently among this omani cohort. application to patient care variations in the adrb2 gene can affect responses to drug actions, thereby impacting diseases in which adrb2 plays a role, such as asthma, obesity and hypertension. the results of this study could therefore be of importance for the clinical management of these diseases. sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e486–490, epub. 23 nov 15 submitted 5 apr 15 revisions req. 24 may & 14 jul 15; revisions recd. 22 jun & 25 jul 15 accepted 30 jul 15 doi: 10.18295/squmj.2015.15.04.007 khalid al-balushi, fahad zadjali, sawsan al-sinani, al-muatasim al-zadjali and riad bayoumi clinical and basic research | e487 genetic variation in the human β2-adrenergic receptor (β2ar) has been the subject of much experimental and pharmacoclinical research, especially in the treatment of asthma. initially cloned, sequenced and reported by kobilka et al., β2ar encodes a 413 amino acid protein belonging to the family of g-protein coupled receptors.1 the receptor is the product of the 1,242base pair intronless adrenoceptor β2 (adrb2) gene located on the long arm of chromosome 5 (q31.q32).1 adrb2 has been linked to asthma, asthma-related phenotypes and diseases such as hypertension and obesity.2–5 β2ar is expressed in different types of cells in the lung, including airway smooth muscle cells, the vascular endothelium, alveolar walls, immune cells and presynaptic cholinergic nerve terminals.6 reihsaus et al. described nine single nucleotide polymorphisms (snps) in the coding region of adrb2.7 four of these snps were nonsynonymous mutations leading to changes in the amino acid sequence: rs1042713 (c.46a>g, p.arg16gly), rs104 2714 (c.79c>g, p.gln27glu), rs1800888 (c.491c>t, p.thr164ile) and rs1141370 (c.100g>a, p.val34met). the first three of the nonsynonymous snps demonstrated in vivo functional effects on the receptor activity.7 the rs1800888 and rs1141370 snps were infrequent and found only in the heterozygous state. arg16gly and glyn27glu were the most common nonsynonymous polymorphisms reported in the adrb2 gene.7 the arg16gly polymorphism is the most common and functionally relevant snp at the amino terminus of the receptor; it occurs with allelic frequencies of between 67–72% in different populations.8 the frequency of the gln27glu polymorphism is approximately 29% in caucasian populations.7 the thr164ile polymorphism, which is located in the fourth transmembrane domain of β2ar, exhibits an allelic frequency of 2–5% in caucasian populations; however, it has only been reported in the heterozygous state so far.7 allelic frequencies of adrb2 polymorphisms, especially the snps in the coding region, have been studied in different ethnic groups. studies on african american, european american, saudi, southwest asian, kenyan and chinese populations all show inter-ethnic variation in the frequency of gln27glu and arg16gly polymorphisms.9,10 since β2ar is an important target for many asthma drugs, these variations in the frequency of adrb2 genotypes may influence disease susceptibility and drug responses in different populations.11 jamil et al. reported that the prevalence of asthma in the usa was lower among arabs in comparison to non-middle eastern caucasians, independent of environmental factors.12 this further suggests the role of ethnic-specific gene-environment interactions in the predisposition to asthma. therefore, the current study aimed to determine the frequencies of alleles and haplotypes of major missense mutations in the adrb2 gene in an omani cohort. methods this study was carried out between may 2014 and march 2015 at the sultan qaboos university (squ), muscat, oman. a total of 316 unrelated omani subjects were recruited either as volunteers from the community or from patients visiting the family medicine & community clinic at squ hospital for regular medical check-ups. the inclusion criteria for the subjects were omani nationality and an age of ≥35 years old. a minimum sample size of 261 was calculated based on 5.5% precision, 5% type i error and the reported proportion of gln27glu in a caucasian population (0.29).8 blood was collected from all participants for the purposes of dna extraction. genomic dna was isolated from 200 µl of whole blood using a dna kit (qiagen gmbh, hilden, germany) according to the protocols provided by the manufacturer. genotyping for the rs1042713, rs1042714 and rs1800888 snps was performed by real-time polymerase chain reaction using snp genotyping assays (taqman®, applied biosystems, thermo fisher scientific inc., wilmington, delaware, usa) according to the manufacturer’s instructions. statistical analyses were performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa). data were compiled by genotype and the derived allelic frequencies were estimated based on the observed numbers of the specific alleles from the genotype data for male and female subjects. the genotype frequencies for each polymorphism were tested for deviation from the hardy-weinberg equilibrium (hwe) using a chi-squared goodness-of-fit analysis with one degree of freedom. haplotypes were constructed from the combination of both polymorphisms. frequencies were inferred using phase 2.1.1 software (matthew stephens laboratory, department of human genetics, university of chicago, chicago, illinois, usa).13,14 ethical permission to conduct this study was obtained from the medical research & ethics committee of the college of medicine & health sciences at squ (mrec #284-a). all participants gave informed consent before inclusion in the study. frequencies of the arg16gly, gln27glu and thr164ile adrenoceptor β 2 polymorphisms among omanis e488 | squ medical journal, november 2015, volume 15, issue 4 results among the omani cohort, there were 129 male and 187 female subjects. the overall mean age was 46.0 ± 8.0 years, with a mean age of 45.0 ± 9.0 years for males and 46.0 ± 7.9 years for females (p = 0.291). three variants of the adrb2 gene were genotyped: rs1042713 (p.arg16gly), rs1042714 (p.gln27glu) and rs1800888 (p.thr164ile). no significant differences were observed in the genotype frequencies between genders [table 1]. the rare rs1800888 snp was not detected in the cohort; all individuals were homozygous for the wild-type allele. gly16 and gln27 were the most frequent variants in the study population (63% and 75%, respectively), with average frequencies of 0.63 and 0.75, respectively [table 2]. the p values for observed and expected genotype frequencies of the rs1042713 and rs1042714 snps were 0.171 and 0.708, respectively, with no deviation from the hwe distribution. allelic frequencies for the rs1042713, rs1800888 and rs1042714 snps were 0.63/0.37, 1.00/0.00 and 0.75/0.25, respectively [table 3]. there was a significant linkage disequilibrium between the rs1042713 and rs1042714 snps (r2 = 0.209; p ≤0.001). random segregation of alleles showed that the arg16 allele did not occur together with glu27, as shown in the distribution of the ag haplotype. the most observed haplotypes in the cohort were gly16gln27 (gc) and arg16-gln27 (ac) with frequencies of 0.38 and 0.37, respectively. the frequency of gly16glu27 (gg) was also common (0.25), comprising all glu27 carriers [table 4]. table 1: genotype distributions of adrenoceptor β2 genetic polymorphisms by gender among an omani cohort (n = 316) snp n (%) p value male (n = 129) female (n = 187) rs1042713 g>a 0.937 gg 54 (41.9) 77 (41.2) ag 56 (43.4) 80 (42.8) aa 19 (14.7) 30 (16.0) rs1800888 c>t cc 129 (100.0) 187 (100.0) ct 0 (0.0) 0 (0.0) tt 0 (0.0) 0 (0.0) rs1042714 c>g 0.715 cc 70 (54.3) 109 (58.3) cg 49 (38.0) 67 (35.8) gg 10 (7.8) 11 (5.9) snp = single nucleotide polymorphism. table 2: allelic frequencies and percentages of adrenoceptor β-2 genetic polymorphisms among an omani cohort (n = 316) snp allelic frequency allelic percentage rs1042713 ga 0.63/0.37 63/37 rs1800888 ct 1.00/0.00 100/0 rs1042714 cg 0.75/0.25 75/25 table 3: observed and expected genotype distributions and allelic frequencies of the adrenoceptor β-2 gene among an omani cohort (n = 316) snp n (%) 95% ci hwe p value observed expected rs1042713 g>a 1.88 0.171 gg 131 (41.5) 125.3 (39.7) 34.4–45.1 ag 136 (43.0) 147.4 (46.6) 41.2–52.2 aa 49 (15.5) 43.3 (13.7) 10.3–18.0 rs1800888 c>t cc 316 (100.0) 316 (100.0) ct 0 (0.0) 0 (0.0) tt 0 (0.0) 0 (0.0) rs1042714 c>g 0.14 0.708 cc 179 (56.6) 177.8 (56.3) 50.8–61.7 cg 116 (36.7) 118.5 (37.5) 32.2–42.8 gg 21 (6.6) 19.8 (6.3) 3.6–8.9 snp = single nucleotide polymorphism; ci = confidence interval; hwe = hardy-weinberg equilibrium. table 4: haplotype frequencies and linkage disequilibrium pattern of adrenoceptor β-2 genetic polymorphisms (rs1042713/rs1042714) among an omani cohort (n = 316) haplotype n frequency linkage r2 χ2 p value gg 158 0.25 0.209 127.54 ≤0.001 gc 240 0.38 ag 0 0.00 ac 233 0.37 khalid al-balushi, fahad zadjali, sawsan al-sinani, al-muatasim al-zadjali and riad bayoumi clinical and basic research | e489 discussion in the current study, gly16 and gln27 were the most common alleles among the omani cohort. there were no differences in the genotype frequencies between genders, suggesting random selection; this was further supported by the lack of deviation from the hwe distribution. previous research in different populations has suggested inter-ethnic differences in adrb2 gene polymorphisms. the allelic frequencies of two snps (rs1042713 and rs1042714) in the current omani cohort were compared with those of various ethnic groups reported in the literature [table 5].9,10,15–21 gly16 and gln27 polymorphisms occur with high allelic frequency in caucasian populations;7,8 the frequencies of gly16 and gln27 polymorphisms in the current omani cohort were similar. however, regardless of population, the frequency of the gln27 variant showed higher inter-ethnic variation than the gly16 variant (standard deviation: 0.14 versus 0.07). the haplotype distributions in the population of the current study were similar to those reported in a previous study of the turkish population.15 there is strong linkage disequilibrium between snps in the adrb2 gene since limited sets of haplotypes are observed in different ethnic groups. drysdale et al. reported three common haplotypes in caucasians and four common haplotypes in african americans based on 13 adrb2 snps.22 examinations of the results of genetic association studies between adrb2 and diseases like asthma should take into account differences in genotype frequencies between populations and the existence of the strong linkage disequilibrium between adrb2 snps. variations in the adrb2 gene affect patient responses to drug actions; therefore, these variations could be of importance for the clinical management of diseases in which β2ar plays a role, such as asthma, obesity and hypertension. inter-ethnic differences in this receptor have been proposed to explain differences in responses to drugs such as terbutaline, isoproterenol and albuterol.23 conclusion the present study provides further evidence of interethnic differences in adrb2 gene polymorphisms. the allelic distribution of variants in this omani population was similar to distributions reported in caucasian populations. a c k n o w l e d g e m e n t this study was funded by the research council, oman (#rd/med/phar/12/01). c o n f l i c t o f i n t e r e s t the authors report no conflicts of interest. table 5: comparative analysis of allelic frequencies of gly16 (rs1042713) and gln27 (rs1042714) polymorphisms in various ethnic groups reported in the literature author and year of study population frequency of polymorphism total sample size gly16 gln27 maxwell et al.9 2005 saudi 0.53 0.83 100 maxwell et al.9 2005 ghanaian 0.47 0.90 100 maxwell et al.9 2005 kenyan 0.43 0.91 100 maxwell et al.9 2005 sudanese 0.57 0.84 52 maxwell et al.9 2005 filipino 0.46 0.91 78 maxwell et al.9 2005 chinese 0.41 0.93 99 xie et al.10 1999 african american 0.51 0.79 123 maxwell et al.9 2005 southwest asian 0.46 0.84 99 maxwell et al.9 2005 scottish 0.59 0.54 100 kato et al.17 2001 japanese 0.51 0.93 1,681 ehrenborg et al.18 2000 swedish 0.59 0.62 180 hall et al.19 2006 british 0.64 0.55 8,018 hamdy et al.16 2002 egyptians 0.43 0.76 240 aynacioglu et al.15 1999 turkish 0.60 0.68 104 ramasy et al.20 1999 australian 0.54 0.60 332 xie et al.10 1999 american caucasian 0.62 0.58 212 candy et al.21 2000 south african 0.52 0.83 123 present study omani 0.63 0.75 316 mean of all populations ± sd 0.53 ± 0.07 0.77 ± 0.14 sd = standard deviation. frequencies of the arg16gly, gln27glu and thr164ile adrenoceptor β 2 polymorphisms among omanis e490 | squ medical journal, november 2015, volume 15, issue 4 references 1. kobilka bk, dixon ra, frielle t, dohlman hg, bolanowski ma, sigal is, et al. cdna for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. proc natl acad sci u s a 1987; 84:46–50. 2. turki j, pak j, green sa, martin rj, liggett sb. genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma: evidence that gly16 correlates with the nocturnal phenotype. j clin invest 1995; 95:1635–41. doi: 10.1172/jci117838. 3. yako yy, echouffo-tcheugui jb, balti ev, matsha te, sobngwi e, erasmus rt, et al. genetic association studies of obesity in africa: a systematic review. obes rev 2015; 16:259–72. doi: 10.1111/obr.12260. 4. ortega ve. pharmacogenetics of beta2 adrenergic receptor agonists in asthma management. clin genet 2014; 86:12–20. doi: 10.1111/cge.12377. 5. johnson ad, newton-cheh c, chasman di, ehret gb, johnson t, rose l, et al. association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. hypertension 2011; 57:903–10. doi: 10.1161/ hypertensionaha.110.158667. 6. green sa, turki j, bejarano p, hall ip, liggett sb. influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. am j respir cell mol biol 1995; 13:25–33. doi: 10.1165/ajrcmb.13.1.7598936. 7. reihsaus e, innis m, macintyre n, liggett sb. mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. am j respir cell mol biol 1993; 8:334–9. doi: 10.1165/ajrcmb/8.3.334. 8. fenech a, hall ip. pharmacogenetics of asthma. br j clin pharmacol 2002; 53:3–15. doi: 10.1046/j.0306-5251.2001.01509.x. 9. maxwell tj, ameyaw mm, pritchard s, thornton n, folayan g, githang’a j, et al. beta-2 adrenergic receptor genotypes and haplotypes in different ethnic groups. int j mol med 2005; 16:573–80. 10. xie hg, stein cm, kim rb, xiao zs, he n, zhou hh, et al. frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among african-american, caucasian and chinese individuals. pharmacogenetics 1999; 9:511–16. 11. liggett sb. the pharmacogenetics of beta2-adrenergic receptors: relevance to asthma. j allergy clin immunol 2000; 105:s487–92. doi: 10.1016/s0091-6749(00)90048-4. 12. jamil h, raymond d, fakhouri m, templin t, khoury r, fakhouri h,et al. self-reported asthma in chaldeans, arabs, and african americans: factors associated with asthma. j immigr minor health 2011; 13:568–75. doi: 10.1007/s10903010-9390-0. 13. stephens m, smith nj, donnelly p. a new statistical method for haplotype reconstruction from population data. am j hum genet 2001; 68:978–89. doi: 10.1086/319501. 14. stephens m, donnelly p. a comparison of bayesian methods for haplotype reconstruction from population genotype data. am j hum genet 2003; 73:1162–9. doi: 10.1086/379378. 15. aynacioglu as, cascorbi i, güngör k, ozkur m, bekir n, roots i, et al. population frequency, mutation linkage and analytical methodology for the arg16gly, gln27glu and thr164ile polymorphisms in the beta2-adrenergic receptor among turks. br j clin pharmacol 1999; 48:761–4. doi: 10.1046/j.1365-2125.1999.00082.x. 16. hamdy si, hiratsuka m, narahara k, el-enany m, moursi n, ahmed ms, et al. allele and genotype frequencies of polymorphic dcp1, cetp, adrb2, and htr2a in the egyptian population. eur j clin pharmacol 2002; 58:29–36. doi: 10.1007/s00228-002-0423-z. 17. kato n, sugiyama t, morita h, kurihara h, sato t, yamori y, et al. association analysis of beta(2)-adrenergic receptor polymorphisms with hypertension in japanese. hypertension 2001; 37:286–92. doi: 10.1161/01.hyp.37.2.286. 18. ehrenborg e, skogsberg j, ruotolo g, large v, eriksson p, arner p, et al. the q/e27 polymorphism in the beta2adrenoceptor gene is associated with increased body weight and dyslipoproteinaemia involving triglyceride-rich lipoproteins. j intern med 2000; 247:651–6. doi: 10.1046/j.13652796.2000.00669.x. 19. hall ip, blakey jd, al balushi ka, wheatley a, sayers i, pembrey me, et al. beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the british 1958 birth cohort: a genetic association study. lancet 2006; 368:771–9. doi: 10.1016/s0140-6736(06)69287-8. 20. ramsay ce, hayden cm, tiller kj, burton pr, goldblatt j, lesouef pn. polymorphisms in the beta2-adrenoreceptor gene are associated with decreased airway responsiveness. clin exp allergy 1999; 29:1195–203. doi: 10.1046/j.13652222.1999.00570.x. 21. candy g, samani n, norton g, woodiwiss a, radevski i, wheatley a, et al. association analysis of beta2 adrenoceptor polymorphisms with hypertension in a black african population. j hypertens 2000; 18:167–72. 22. drysdale cm, mcgraw dw, stack cb, stephens jc, judson rs, nandabalan k, et al. complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. proc natl acad sci u s a 2000; 97:10483–8. doi: 10.1073/pnas.97.19.10483. 23. litonjua aa, gong l, duan ql, shin j, moore mj, weiss st, et al. very important pharmacogene summary adrb2. pharmacogenet genomics 2010; 20:64–9. doi: 10.1097/ fpc.0b013e328333dae6. http://dx.doi.org/10.1172/jci117838 http://dx.doi.org/10.1111/obr.12260 http://dx.doi.org/10.1111/cge.12377 http://dx.doi.org/10.1161/hypertensionaha.110.158667 http://dx.doi.org/10.1161/hypertensionaha.110.158667 http://dx.doi.org/10.1165/ajrcmb.13.1.7598936 http://dx.doi.org/10.1165/ajrcmb/8.3.334 http://dx.doi.org/10.1046/j.0306-5251.2001.01509.x http://dx.doi.org/10.1016/s0091-6749%2800%2990048-4 http://dx.doi.org/10.1007/s10903-010-9390-0 http://dx.doi.org/10.1007/s10903-010-9390-0 http://dx.doi.org/10.1086/319501 http://dx.doi.org/10.1086/379378 http://dx.doi.org/10.1046/j.1365-2125.1999.00082.x http://dx.doi.org/10.1007/s00228-002-0423-z http://dx.doi.org/10.1161/01.hyp.37.2.286 http://dx.doi.org/10.1046/j.1365-2796.2000.00669.x http://dx.doi.org/10.1046/j.1365-2796.2000.00669.x http://dx.doi.org/10.1016/s0140-6736%2806%2969287-8 http://dx.doi.org/10.1046/j.1365-2222.1999.00570.x http://dx.doi.org/10.1046/j.1365-2222.1999.00570.x http://dx.doi.org/10.1073/pnas.97.19.10483 http://dx.doi.org/10.1097/fpc.0b013e328333dae6 http://dx.doi.org/10.1097/fpc.0b013e328333dae6 despite recent outstanding break-throughs in thrombosis research, venous thromboembolisms (vtes)—notably pulmonary embolisms (pes)—continue to be a major health concern around the world. possibly due to its abrupt onset, non-specific symptoms and relatively difficult diagnosis, pe is the most common cause of in-hospital death worldwide.1 in addition, it is a major cause of preventable mortality in hospitalised trauma patients.2 although pes are preventable through a variety of prophylactic and therapeutic measures, data from the usa suggests that pe is the cause of 50,000– 100,000 deaths each year.3 in 1961, sevitt et al. reported an incidence of 65% and 20.3% of deep venous thrombosis (dvt) and pe, respectively, among a cohort of trauma and burn patients.4 moreover, a study published in 1990 by shackford et al. found a vte incidence of 7% among trauma patients, despite the use of mechanical or pharmacological prophylactic measures.5 however, more recent data have suggested lower incidences of vte. a cohort study from the uk of acute trauma patients admitted between 2010–2011 found the incidence of pe to be 0.8%; most of these patients had lower limb fractures.6 ho et al. found that fatal pes accounted for 11.9% of all deaths among 971 consecutive trauma patients.7 one reason for the variability in reported vte incidences could be differences in the techniques used to confirm or diagnose the condition, while another explanation could be under-reporting, perhaps due to a reluctance to perform autopsies in cases of sudden death.8 several studies have attempted to identify risk factors for vtes following trauma.9,10 in 1994, a comprehensive prospective study of 349 patients by geerts et al. showed various associations between developing vte and older age, scores on the abbreviated injury scale, lower limb orthopaedic injuries and fractures, spinal cord injuries, blood transfusions within 24 hours of admission and surgical interventions.9 similar factors were associated with the risk of developing vte in a study by kudsk et al. in 1989, including spinal, pelvic or lower limb fractures, age (>45 years old), bed rest (>3 days) and previous venous repairs.10 inferior vena cava (ivc) filters interrupt the vena cava flow and the migration of a potential thrombus. trauma patients usually present with multiple injuries involving organs such as the brain or spinal cord which leaves them at risk of fatal bleeding if pharmacological anticoagulation is attempted. in addition, to further complicate matters, extremity injuries in trauma are often severe enough to render the use of mechanical 1department of surgery, college of medicine & health sciences, sultan qaboos university; departments of 2radiology & molecular imaging and 3surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ahmedanaiem@gmail.com االستخدام الوقائي ملرشحات الوريد األجوف السفلي يف حاالت الصدمة اأحمد اأ�رضف نعيم، الرمي خ�لد الهن�ئي، را�شد ال�شكيتي، ه�ين الق��شي abstract: venous thromboembolisms, specifically pulmonary embolisms (pes), represent a significant burden on healthcare systems worldwide, particularly within the setting of trauma. according to the literature, pes are the most common cause of in-hospital death; however, this condition can be prevented with a variety of prophylactic and therapeutic measures. this article aimed to examine current evidence on the use, indications for prophylaxis, outcomes and complications of prophylactic inferior vena cava filters in trauma patients. keywords: inferior vena cava filters; trauma; veins; thromboembolisms. اأنح�ء جميع يف ال�شحية الرع�ية نظم على كبريا عبئ� الرئوية، االإن�شم�م�ت خ��شة الوريدية، اخلث�رية االإن�شم�م�ت متثل امللخ�ص: الع�مل،وب�شورة خ��شة يف ح�الت ال�شدمة وبح�شب م� ج�ء يف االأدبي�ت الع�ملية، ف�إن االإن�شم�م�ت الرئوية هي من اأهم االأ�شب�ب ال�ش�ئعة لبحث املق�ل هذا ويهدف عديدة. وعالجية وق�ئية بطرق حدوثه� منع ميكن احل�لة هذه اأن غري ب�مل�شت�شفى. املقيمني املر�شى ملوت الدليل احل�يل فيم� يخ�ص ا�شتخدام مر�شح�ت الوريد االأجوف ال�شفلي عند امل�ش�بني ب�ل�شدمة وا�شتطب�ب�ته� الوق�ئية، ونت�ئج ا�شتخدامه�، وامل�ش�عف�ت التي قد حتدث عند ا�شتخدامه�. مفتاح الكلمات: الوريد االأجوف ال�شفلي؛ الصدمة؛ االأوردة؛ االإن�شم�م�ت اخلث�رية. use of prophylactic inferior vena cava filters in trauma *ahmed a. naiem,1 alreem k. al-hinai,1 rashid al-sukaiti,2 hani al-qadhi3 continuing medical education sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e82–85, epub. 2 feb 16 submitted 8 jan 15 revision req. 9 apr 15; revision recd. 12 aug 15 accepted 27 aug 15 doi: 10.18295/squmj.2016.16.01.015 ahmed a. naiem, alreem k. al-hinai, rashid al-sukaiti and hani al-qadhi continuing medical education | e83 pneumatic compression devices unsuitable.5 two types of ivc filter exist: permanent and non-permanent. permanent filters are designed to function indefinitely while non-permanent filters are subdivided into temporary filters which must be removed or retrievable filters that can either be removed or left in place as a permanent implant, depending on the patient’s clinical condition.6 since the introduction of percutaneously-inserted ivc filters approximately 30 years ago, there has been extensive development of filter designs aiming to improve success rates and lower complication rates.11 this article aimed to examine the available published literature on the use of prophylactic ivc filters in trauma patients and their effect on reducing morbidity and mortality. articles were identified through a search on the medline and cochrane central register of controlled trials databases using the following keywords: “inferior”; “vena”; “cava”; “filter”; and “trauma”. choice of placement the placement of ivc filters is usually done in an angiography suite by an interventional radiologist or in an operating room by a vascular surgeon. venous access is gained via the femoral or internal jugular vein.12 the ideal position for the placement of an ivc filter depends on the extent of the thrombus within the inferior vena cava; deployment at an infrarenal position is often chosen to protect against renal vein thrombosis in the event of an ivc occlusion. another approach involves using intravascular ultrasound probes.12 this technique offers some advantages as it can be performed at the patient’s bedside and avoids exposing trauma patients to the effects of an iodinated contrast injection; however, this approach is relatively expensive.12 indications for prophylaxis considerable controversy exists regarding the use of ivc filters in vte prevention, despite a reported vte prevention rate of 98%.13 in 2002, the eastern association for the surgery of trauma (east) recommended that insertion of a prophylactic ivc filter should be considered only in extremely high-risk trauma patients who were unable to receive anticoagulation treatment because of their increased risk of bleeding.14 in addition, eligible patients included those who would remain immobile for prolonged periods of time, potentially due to one of the following: severe closed head injuries (glasgow coma scale score <8); incomplete spinal cord injuries with paraplegia or quadriplegia; complex pelvic fractures with associated long bone fractures; or multiple long bone fractures.14 in addition, the east guidelines also state that patients at high risk for bleeding complications for 5–10 days after injury have an increased need for prophylactic ivc filters, particularly those with intracranial haemorrhage, ocular injuries with associated haemorrhage, solid intraabdominal organ injuries and/or pelvic or retroperitoneal haematomas requiring transfusion.14 in contrast, the american college of chest physicians recommended against the use of prophylactic ivc filters regardless of vte risk in 2012.15 this recommendation was based on low-quality evidence (grade 2c) suggesting frequent complications with ivc filters and unclear long-term benefits.15 these conflicting recommendations, which were issued 10 years apart, exist due to the continuing absence of high-quality evidence to either support or refute the prophylactic use of ivc filters. as a result, the final decision as to ivc filter insertion in a critical trauma patient remains with the treating physician. outcomes there are very limited data in the form of randomised controlled trials to ascertain the outcomes of the prophylactic use of ivc filters to prevent pes. to date, the only evidence available is in the form of observational studies, the majority of which were conducted before 2010.16 since then, the use of lowmolecular-weight heparin has become a widely accepted method of thromboprophylaxis against dvts and pes.15 a meta-analysis of seven observational studies on the prophylactic use of ivc filters in trauma patients reported that the pooled odds ratio of developing a pe was significantly lower (or = 0.21; 95% ci = 0.09– 0.49) among patients who received an ivc filter in comparison to matched control subjects.16 in contrast, a clinical trial observed an increase in the odds of dvt with ivc filter placement, reaching up to 87%.17 in weighing these outcomes, the absolute risk reduction of pe is compared to the absolute increased risk of dvt. such reported outcomes further contribute to the controversy regarding ivc filter use.18 complications early and late complications can occur at various stages during and after the placement of ivc filters. access-site thrombosis is an early complication which has been found to occur in 1–3% of cases with low-profile filter delivery systems.19 delivery system complications, such as sheath kinking or air emboluse of prophylactic inferior vena cava filters in trauma e84 | squ medical journal, february 2016, volume 16, issue 1 isms, penetration of the ivc filter into neighbouring organs and post-procedural bleeding are other early complications.20–22 late complications include filter fracture, migration, ivc occlusion, venous stasis, chronic venous insufficiency and pe recurrence.23–25 the risk of fracture rises the longer a filter is in place; research shows a 40% risk of filter fracture after 5.5 years.23 the incidence of migration varies with the type of filter used. for one of the most extensively used filters, the greenfield™ filter (boston scientific corp., marlborough, massachusetts, usa), the migration rate is 8–15%.24 recurrence of pe has been reported to be as high as 4%.24 an increased risk of ivc occlusion and distant embolism despite ivc filter use has also been previously reported.25 conclusion trauma is a major risk factor for vte. trauma patients usually present with multiple injuries that preclude the use of pharmacological or mechanical thromboprophylaxis. thus, ivc filters are sometimes used to prevent the occurrence of a fatal pe in highrisk trauma patients. however, there is a lack of highquality evidence available to standardise protocols for ivc filter use. in addition, there remain concerns over the long-term benefits of ivc filters. the final decision as to whether ivc filter insertion is suitable for a severely injured trauma patient remains a decision best guided by clinical judgment and available evidence. references 1. stein pd, henry jw. prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. chest 1995; 108:978–81. doi: 10.1378/chest.108.4.978. 2. o’donnell m, weitz ji. thromboprophylaxis in surgical patients. can j surg 2003; 46:129–35. 3. horlander kt, mannino dm, leeper kv. pulmonary embolism mortality in the united states, 1979-1998: an analysis using multiple-cause mortality data. arch intern med 2003; 163:1711–17. doi: 10.1001/archinte.163.14.1711. 4. sevitt s, gallagher n. venous thrombosis and pulmonary em bolism: a clinico-pathological study in injured and burned patients. br j surg 1961; 48:475–89. doi: 10.1002/bjs.180 04821103. 5. shackford sr, davis jw, hollingsworth-fridlund p, brewer ns, hoyt db, mackersie rc. venous thromboembolism in patients with major trauma. am j surg 1990; 159:365–9. doi: 10.1016/ s0002-9610(05)81272-3. 6. gudipati s, fragkakis em, ciriello v, harrison sj, stavrou pz, kanakaris nk, et al. a cohort study on the incidence and outcome of pulmonary embolism in trauma and orthopedic patients. bmc med 2014; 12:39. doi: 10.1186/1741-7015-12-39. 7. ho km, burrell m, rao s, baker r. incidence and risk factors for fatal pulmonary embolism after major trauma: a nested cohort study. br j anaesth 2010; 105:596–602. doi: 10.1093/bja/ aeq254. 8. sandler da, martin jf. autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? j r soc med 1989; 82:203–5. doi: 10.1177/014 107688908200407. 9. geerts wh, code ki, jay rm, chen e, szalai jp. a prospective study of venous thromboembolism after major trauma. n engl j med 1994; 331:1601–6. doi: 10.1056/nejm199412153312401. 10. kudsk ka, fabian tc, baum s, gold re, mangiante e, voeller g. silent deep vein thrombosis in immobilized multiple trauma patients. am j surg 1989; 158:515–19. doi: 10.1016/00029610(89)90182-7. 11. kinney tb. update on inferior vena cava filters. j vasc interv radiol 2003; 14:425–40. doi: 10.1097/01.rvi.0000064 860.87207.77. 12. wellons ed, matsuura jh, shuler fw, franklin js, rosenthal d. bedside intravascular ultrasound-guided vena cava filter placement. j vasc surg 2003; 38:455–7. doi: 10.1016/s07415214(03)00471-3. 13. greenfield lj, proctor mc. recurrent thromboembolism in patients with vena cava filters. j vasc surg 2001; 33:510–14. doi: 10.1067/mva.2001.111733. 14. rogers fb, cipolle md, velmahos g, rozycki g, luchette fa. practice management guidelines for the prevention of venous thromboembolism in trauma patients: the east practice management guidelines work group. j trauma 2002; 53:142–64. doi: 10.1097/00005373-200207000-00032. 15. gould mk, garcia da, wren sm, karanicolas pj, arcelus ji, heit ja, et al. prevention of vte in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. chest 2012; 141:e227s–77s. doi: 10.1378/chest.11-2297. 16. rajasekhar a, lottenberg r, lottenberg l, liu h, ang d. pulmonary embolism prophylaxis with inferior vena cava filters in trauma patients: a systematic review using the meta-analysis of observational studies in epidemiology (moose) guidelines. j thromb thrombolysis 2011; 32:40–6. doi: 10.1007/s11239010-0544-7. 17. decousus h, leizorovicz a, parent f, page y, tardy b, girard p, et al. a clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis: prévention du risque d’embolie pulmonaire par interruption cave study group. n engl j med 1998; 338:409–15. doi: 10.1056/nejm199802123380701. 18. greenfield lj. the prepic study group: eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism the prepic (prevention du risque d’embolie pulmonaire par interruption cave) randomized study. perspect vasc surg endovasc ther 2006; 18:187–8. doi: 10.1177/1531003506290863. 19. rosenthal d, wellons ed, levitt ab, shuler fw, o’conner re, henderson vj. role of prophylactic temporary inferior vena cava filters placed at the icu bedside under intravascular ultrasound guidance in patients with multiple trauma. j vasc surg 2004; 40:958–64. doi: 10.1016/j.jvs.2004.07.048. 20. lorch h, welger d, wagner v, hillner b, strecker ep, herrmann h, et al. current practice of temporary vena cava filter insertion: a multicenter registry. j vasc interv radiol 2000; 11:83–8. doi: 10.1016/s1051-0443(07)61287-1. 21. campbell jj, calcagno d. aortic pseudoaneurysm from aortic penetration with a bird's nest vena cava filter. j vasc surg 2003; 38:596–9. doi: 10.1016/s0741-5214(03)00325-2. 22. ray ce jr, kaufman ja. complications of inferior vena cava filters. abdom imaging 1996; 21:368–74. doi: 10.1007/ s002619900084. http://dx.doi.org/10.1378/chest.108.4.978 http://dx.doi.org/10.1001/archinte.163.14.1711 http://dx.doi.org/10.1002/bjs.18004821103 http://dx.doi.org/10.1002/bjs.18004821103 http://dx.doi.org/10.1016/s0002-9610%2805%2981272-3 http://dx.doi.org/10.1016/s0002-9610%2805%2981272-3 http://dx.doi.org/10.1186/1741-7015-12-39 http://dx.doi.org/10.1093/bja/aeq254 http://dx.doi.org/10.1093/bja/aeq254 http://dx.doi.org/10.1177/014107688908200407 http://dx.doi.org/10.1177/014107688908200407 http://dx.doi.org/10.1056/nejm199412153312401 http://dx.doi.org/10.1016/0002-9610%2889%2990182-7 http://dx.doi.org/10.1016/0002-9610%2889%2990182-7 http://dx.doi.org/10.1097/01.rvi.0000064860.87207.77 http://dx.doi.org/10.1097/01.rvi.0000064860.87207.77 http://dx.doi.org/10.1016/s0741-5214%2803%2900471-3 http://dx.doi.org/10.1016/s0741-5214%2803%2900471-3 http://dx.doi.org/10.1067/mva.2001.111733 http://dx.doi.org/10.1097/00005373-200207000-00032 http://dx.doi.org/10.1378/chest.11-2297 http://dx.doi.org/10.1007/s11239-010-0544-7 http://dx.doi.org/10.1007/s11239-010-0544-7 http://dx.doi.org/10.1056/nejm199802123380701 http://dx.doi.org/10.1177/1531003506290863 http://dx.doi.org/10.1016/j.jvs.2004.07.048 http://dx.doi.org/10.1016/s1051-0443%2807%2961287-1 http://dx.doi.org/10.1016/s0741-5214%2803%2900325-2 http://dx.doi.org/10.1007/s002619900084 http://dx.doi.org/10.1007/s002619900084 ahmed a. naiem, alreem k. al-hinai, rashid al-sukaiti and hani al-qadhi continuing medical education | e85 23. tam md, spain j, lieber m, geisinger m, sands mj, wang w. fracture and distant migration of the bard recovery filter: a retrospective review of 363 implantations for potentially life-threatening complications. j vasc interv radiol 2012; 23:199–205.e1. doi: 10.1016/j.jvir.2011.10.017. 24. greenfield lj, proctor mc. twenty-year clinical experience with the greenfield filter. cardiovasc surg 1995; 3:199–205. doi: 10.1016/0967-2109(95)90895-c. 25. greenfield lj, proctor mc, michaels aj, taheri pa. prophylactic vena caval filters in trauma: the rest of the story. j vasc surg 2000; 32:490–5. doi: 10.1067/mva.2000.108636. cme quiz questions 1. how is venous access for an ivc filter gained? a. basilic vein b. femoral veins c. internal jugular veins d. femoral or internal jugular veins e. all of the above 2. what are possible indications for prophylactic use of ivc filters in trauma patients? a. severe closed head injury b. incomplete spinal cord injury with paraplegia or quadriplegia c. complex pelvic fractures with associated long bone fractures d. multiple long bone fractures e. all of the above f. none of the above 3. what are potential short-term complications of ivc filter use? check all correct answers. a. migration b. thrombosis c. air embolisms d. post-procedure bleeding e. chronic venous insufficiency 4. what are potential long-term complications of ivc filter use? check all correct answers. a. fracture b. solid intra-abdominal organ injury c. migration d. lower limb venous stasis e. chronic venous insufficiency 5. what is the risk of ivc occlusion and distant embolism despite ivc filter use? a. decreased b. increased c. the same ivc = inferior vena cava. answers: 1: d; 2: e; 3: b, c, d; 4: a, c, d, e; 5: b. http://dx.doi.org/10.1016/j.jvir.2011.10.017 http://dx.doi.org/10.1016/0967-2109%2895%2990895-c http://dx.doi.org/10.1067/mva.2000.108636 نقل الدم يف أمراض الدم الوراثية مراجعة و توصيات لبنوك الدم احمللية وخدمات نقل الدم يف عمان اأروى زكريا الريامي و �ساهينا دار abstract: sickle cell disease and homozygous β-thalassaemia are common haemoglobinopathies in oman, with many implications for local healthcare services. the transfusions of such patients take place in many hospitals throughout the country. indications for blood transfusions require local recommendations and guidelines to ensure standardised levels of care. this article summarises existing transfusion guidelines for this group of patients and provides recommendations for blood banks and transfusion services in oman. this information is especially pertinent to medical professionals and policy-makers developing required services for the standardised transfusion support of these patients. keywords: hemoglobinopathies; sickle cell disease; thalassemia major; blood transfusion; blood banks; oman. امللخ�ص: يعترب مر�ض اخلاليا املنجلية والثال�سيميا النوع بيتا املتماثل من امرا�ض الدم الوراثية ال�سائعة يف عمان، والتي لها العديد من االآثار على خدمات الرعاية ال�سحية املحلية. تتم عمليات نقل الدم لهوؤالء املر�سى يف العديد من امل�ست�سفيات يف جميع اأنحاء البالد. تتطلب حمددات نقل الدم عمل تو�سيات واإر�سادات حملية ل�سمان معايري موحدة من الرعاية. تلخ�ض هذه املقالة املبادئ التوجيهية لنقل الدم احلالية لهذه املجموعة من املر�سى وتقدم تو�سيات ب�ساأن بنوك الدم وخدمات نقل الدم يف عمان. وتعد هذه املعلومات مالئمة ب�سكل خا�ض للمهنيني الطبيني و�سانعي �سيا�سات تطوير اخلدمات املطلوبة لدعم نقل الدم العياري املوحد لهوؤالء املر�سى. الكلمات املفتاحية: امراض الدم؛ مر�ض فقر الدم املنجلي؛ الثال�سيميا العظمى؛ نقل الدم؛ بنوك الدم؛ عمان. transfusion in haemoglobinopathies review and recommendations for local blood banks and transfusion services in oman arwa z. al-riyami1 and *shahina daar2 review sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e3–12, epub. 4 apr 18 submitted 11 oct 17 revision req. 14 nov 17; revision recd. 6 dec 17 accepted 11 jan 17 1department of haematology, sultan qaboos university hospital, muscat, oman; 2wallenberg research centre, stellenbosch institute for advanced study, stellenbosch university, stellenbosch, south africa *corresponding author’s e-mail: sf.daar@gmail.com doi: 10.18295/squmj.2018.18.01.002 sickle cell disease (scd) and transfusion-dependent thalassaemia, also known as thalassaemia major (tm), are complex haemoglobinopathies common in oman, with estimated carrier prevalence rates of 5.8% and 2.2%, respectively.1,2 the rate of scd is 3.7 per 1,000 live births and, in a community-based survey of 6,342 children, the prevalence rates of scd and homozygous β-thalassaemia were reported to be 0.2% and 0.07%, respectively, among children under five years of age.2 this high prevalence can partly be explained by the previous endemic of plasmodium falciparum malaria in the country and other parts of the mediterranean region, the middle east, africa, india and southwest asia.3,4 an additional factor is the high prevalence of consanguineous marriages in oman.5 a previous study on the genetic epidemiology of the sickle haemoglobin (hbs) mutation showed that the three major haplotypes—benin (typical and atypical), arab indian and bantu—coexist in oman, reflecting the influence of gene migration in the past from neighbouring countries.6 the management of scd and tm has a strong economic impact on the available national health services and the quality of life of the local population, raising the need for immediate public health action.7 a hospital-based study of ≤12-year-old omani children with scd reported a severe morbidity profile, defined as either six or more vaso-occlusive crises, hospitalisation for 11 days or longer, three or more blood transfusions or a life-threatening event, such as a haemoglobin (hb) level of <5 g/dl, acute chest syndrome (acs), acute splenic sequestration crises, septicaemia or stroke.8 another study of thalassaemic children aged 5–18 years old found that those with higher pre-transfusion haemoglobin levels (i.e. ≥9 g/dl) and those who received red blood cell (rbc) transfusions at intervals of over three weeks had better overall scores according to the pediatric quality of life inventory™.9 low scores in the school function domains were associated with pre-transfusion hb levels of <9 g/dl and increased transfusion frequency (every ≤3 weeks).9 the former has been attributed to fatigue, general weakness and decreased mental alertness. transfusion is also transfusion in haemoglobinopathies review and recommendations for local blood banks and transfusion services in oman e4 | squ medical journal, february 2018, volume 18, issue 1 associated with risks of alloimmunisation which has been reported among 31.6% of omani patients with scd.10 moreover, according to unpublished data, the rate of alloimmunisation is 9.3% among tm patients in oman. clinical manifestations and optimal treatment modalities differ for patients with scd and tm. nevertheless, rbc transfusion is an important component in the management of both conditions. patients with tm require life-long rbc transfusions for survival, while those with scd require transfusions in specific clinical settings.11 moreover, transfusionrelated complications, such as acute and delayed transfusion reactions, alloimmunisation and iron overload, can create additional challenges. for patients with scd, the medication hydroxyurea is indicated in different settings, including recurrent moderateto-severe pain crises, a history of severe and/or recurrent acs and symptomatic chronic anaemia, among others.12 this article summarises the existing literature and recommendations for transfusing patients with scd and tm and discusses the potential impact of these recommendations on local blood banks and transfusion services in oman. however, it is important to note that these recommendations serve only as a guide and should not replace clinical judgment in individual situations. consultation with a haematologist with expertise in managing scd and tm patients is advised. transfusion in sickle cell disease transfusions in scd patients can occur in either acute care settings or as part of long-term transfusion therapy. in some cases, transfusions are strongly recommended, while in others insufficient evidence exists to support use of this procedure. however, it is worth mentioning that few randomised clinical trials (rcts) are available to direct clinicians as to when a transfusion should be considered.13–16 for patients in whom the indications for transfusion have limited evidence, the decision as to whether to transfuse should be based on a clinical assessment of the individual patient by an experienced team. a c u t e s e t t i n g s acute stroke transfusions are often beneficial in the management of ischaemic stroke. urgent transfusion is required in patients with acute neurological symptoms, with the aim of achieving an hbs proportion of <30%.17,18 while this often requires an exchange transfusion, an initial top-up transfusion may be necessary, depending on the patient’s hb level.17 it is important to avoid hypervolaemia during the procedure and to keep the patient’s post-transfusion hb level at 10 g/dl, as a high haematocrit (hct) level may worsen the neurological insult.17,18 no data are available at present to support transfusion in the acute management of haemorrhagic stroke or in preventing its recurrence.18 however, transfusion is warranted and may be a life-saving procedure for other scd complications, such as acute haemolytic anaemia, aplastic crises, acs and splenic and hepatic sequestration crises.18 acute anaemia top-up transfusions may be necessary for scd patients admitted with acute anaemia, especially symptomatic patients, those who show signs of imminent or established cardiovascular compromise or when accompanied by reticulocytopaenia suggestive of a parvovirus b19 infection.17 the threshold level for transfusion will depend on the patient’s baseline hb level and clinical status, while the target hb level should be the patient’s own steady-state hb level.17 an exchange transfusion is also indicated for patients with exacerbated anaemia due to acute multiorgan failure and mesenteric syndrome.18,19 acute chest syndrome in cases of suspected acs, it is advisable to ensure the availability of blood for an exchange transfusion ahead of time, as acute respiratory failure can develop rapidly and a blood transfusion can be life-saving.18 depending on the clinical severity of the case, either a simple or exchange transfusion may be warranted. in scd patients with an hb level of <9 g/dl, an early topup transfusion may be all that is necessary. however, an exchange transfusion is recommended for patients who have an initial hb level of >9 g/dl, those who do not respond to an initial simple transfusion or in cases of severe or rapid acs progression as manifested by an oxygen saturation level of <90% despite supplemental oxygen, increasing respiratory distress, progressive pulmonary infiltrates and/or declining hb levels despite having undergone a simple transfusion.12,18,20 although a target hbs proportion of 30–40% is often used, it is more important that the physician be guided by the patient’s clinical response.20 splenic and hepatic sequestration crises in scd patients with splenic and hepatic sequestration crises, transfusions should be performed cautiously with small volumes following fluid resuscitation; this is so as to avoid hyperviscosity due to the return of the sequestered rbcs to the circulation system.18 for this reason, it is recommended that hb levels of 8 g/dl arwa z. al-riyami and shahina daar review | e5 are not exceeded. a splenectomy should be considered in patients with recurrent episodes of two or more splenic sequestration crises.18 vaso-occlusive crises transfusion is not recommended for scd patients with uncomplicated painful vaso-occlusive crises, if no other indications for transfusion are present.12 however, it should be considered if the baseline hb level has dropped substantially or there is haemodynamic compromise or concern of impending critical organ complications.18 hydroxyurea is recommended as a first-line treatment for repeated painful crises, alth ough it may take some time before the effect is perceived; transfusions can therefore be useful in the interim.18 priapism to date, no rcts have been conducted to evaluate the efficacy of transfusion in acute priapism. for priapic episodes, transfusions are not recommended as an immediate treatment modality; early interventions should instead include analgaesia and oral or intravenous hydration. however, if the episode lasts for longer than four hours, scd patients may require transfusion in preparation for a shunt or drainage procedure under general anaesthesia, if the latter is recommended by a urologist.12 long-term transfusion has been shown to reduce the incidence of priapism.21 patients may also benefit from an exchange transfusion to reduce the hbs proportion if there is no response to these procedures.13,18 other indications there is insufficient evidence to support the benefit of blood transfusions in the management of scd patients with leg ulcers, pulmonary hypertension, end-stage liver disease or progressive sickle cell retinopathy.18 it is therefore important to consult an experienced haematologist for a full risk assessment and to create a plan for managing such patients. however, an exchange or simple transfusion may be useful in cases of severe sepsis.18,22 l o n g-t e r m s e t t i n g s stroke prevention long-term rbc transfusion is the mainstay of primary and secondary ischaemic stroke prevention in scd patients.18 multiple rcts in paediatric scd patients have assessed the benefit of transfusions in primary stroke prevention and in the secondary prevention of silent cerebral infarcts.14,21,23 annual transcranial doppler (tcd) ultrasound assessments are recommended for children with scd from the age of two years, based on the benefits of regular transfusions among children with raised cerebral blood flow velocities (≥200 cm/second).14,17 in these chronic transfusion programmes, the aim is to maintain an hbs proportion of <30%.17,18 these transfusions should be continued throughout child-hood as a significant number revert to high tcd velocities or develop overt stroke after the transfusions are discontinued.18,23 in children with scd and high cerebral blood flow velocities without new magnetic resonance imaging-related changes, severe magnetic resonance angiography (mra)-defined cerebral vasculopathy or prior transient ischaemic attacks, hydroxyurea should be considered after initiating a regular trans fusion programme for primary stroke prevention for a minimum of one year. data from the transcranial doppler with transfusions changing to hydroxyurea (twitch) trial indicated that hydroxyurea was efficacious and not inferior to blood transfusions for primary stroke prevention in children.15 however, transfusions should be continued in patients with severe mra-defined cerebral vasculopathy and are effective in reducing recurrence among scd children with silent cerebral infarcts.21 no studies have been conducted to assess the efficacy of regular transfusions for primary stroke prevention in adult scd patients or in patients undergoing long-term transfusion programmes since childhood. moreover, tcd has not been validated in adults; therefore, its utility in assessing stroke risk in this patient group is unknown.18 according to the results of the stroke with transfusions changing to hydroxyurea (switch) rct, monthly transfusions and iron chelation were more effective than hydroxyurea in preventing ischaemic stroke recurrence among scd children with a history of stroke, with seven stroke events occurring in the hydroxyurea group compared to no events in the transfusion group.16 long-term transfusions to maintain an hbs proportion of < 30% rather than hydroxyurea are therefore recommended for secondary stroke prevention. transfusions may be needed indefinitely, although they do not completely abolish the risk of recurrence; as such, risk factors should be reviewed regularly with patients and/or their parents or guardians.18 as with primary stroke prevention, there is no evidence of the benefit of transfusions for secondary stroke prevention among adult scd patients. however, based on paediatric trials, long-term regular transfusions are recommended to maintain an hbs proportion of <30%.18 other indications for long-term transfusions include patients with contraindications for hydroxyurea and those with progressive organ failure, recurrent acs or vasoocclusive crises not prevented by hydroxyurea.17,18 the specific management approach for these patients should be decided on an individual case-by-case basis. transfusion in haemoglobinopathies review and recommendations for local blood banks and transfusion services in oman e6 | squ medical journal, february 2018, volume 18, issue 1 preoperative indications there is currently no consensus as to which scd patients require preoperative transfusions.17 the trans fusion alternatives preoperatively in sickle cell disease trial provides the most compelling evidence to support the use of preoperative transfusions.13 in this trial, patients undergoing lowor medium-risk surgeries were randomised to receive either a preoperative transfusion—a simple transfusion if hb levels were <9 g/dl or an exchange transfusion if hb levels were ≥9 g/dl—or no transfusion at all. patients in the non-transfused group had significantly higher rates of complications and serious adverse events, particularly acs, as compared to the transfused patients.13 while the optimal method of transfusion is debatable, currently available evidence indicates that simple transfusions are not inferior to exchange transfusions.13,24 vichinsky et al. reported that conservative transfusions aiming to raise hb levels to 10 g/dl were as effective in preventing postoperative complications as aggressive exchange transfusions intending to reduce hbs proportions to <30%.24 both simple (in patients with hb levels of <9 g/dl) and exchange (in patients with hb levels of ≥9 g/dl) transfusions for an hb target level of 10 g/dl are recommended for scd patients undergoing low(e.g. adenectomies and dental procedures) or medium-risk (e.g. tonsillectomies and abdominal or orthopaedic surgeries) procedures. how ever, exchange transfusions are recommended for patients undergoing high-risk surgeries such as cardiovascular operations.18 for patients requiring emergency surgeries, as long as they are not unduly delayed, simple transfusions can be given preoperatively with the aim of achieving an hb level of 10 g/dl.18 pregnancy prophylactic transfusions should be considered in pregnant patients with previous or current medical, obstetric or fetal scd-related complications, patients who were previously taking hydroxyurea for severe scd and those with multiple-gestation pregnancies.18 however, routine prophylactic transfusions are not recommended during pregnancy as there is insufficient evidence to substantiate their role.25,26 women receiving long-term transfusions for other indications should continue regular transfusions throughout their pregnancy.27 transfusions in homozygous β-thalassaemia homozygous β-thalassaemia is a genetic disorder that affects the synthesis of β-globin chains, leading to chronic anaemia and ineffective erythropoiesis due to imbalanced globin synthesis. it can be broadly categorised clinically as either tm or thalassemia intermedia (ti). in tm, hb production is markedly reduced and regular transfusions from infancy are critical to keep the patient alive.28 in ti, patients can survive without lifelong regular transfusions; however, certain indications may necessitate transfusion.29 transfusion therapy in β-thalassaemia is effective in supplying normal erythrocytes and suppressing ineffective erythropoiesis to a large extent.30 t h a l a s s a e m i a m a j o r regular blood transfusions every 3–4 weeks are the standard therapy for tm.11 once an infant is diagnosed with homozygous β-thalassaemia, close monitoring from the age of three months is required to detect clinical signs indicative of the need to initiate regular transfusions, with hb levels checked on at least a monthly basis. the current guidelines of the thalassemia international federation for initiating regular transfusions include severe anaemia (<7 g/dl on two occasions one to two weeks apart) or hb levels of >7 g/dl accompanied by inappropriate fatigue, poor feeding, developmental delay or regression or symptoms of heart failure, after excluding contributing causes such as infections.11 other reasons to initiate transfusion regardless of hb levels include a failure to thrive, progressive splenomegaly, fractures, clinicallysignificant extramedullary haematopoiesis and/or the appearance of thalassaemic facies.11,31 it is important to reassess infants after the initial transfusion; if hb levels fall again, it is reasonable to assume long-term dependency necessitating a regular transfusion programme.31,32 the decision to begin regular transfusions usually occurs within the first two years of life.11 where possible, this decision should not be delayed beyond three years as the risk of alloimmunisation increases with age, as does the difficulty of finding suitable rbc units.31 regular transfusion programmes in children should aim for trough pre-transfusion hb levels of 9–10.5 g/dl.31,33 occasionally, tm patients with cardiac disease, extramedullary haematopoiesis and/or inadequate bone marrow suppression benefit from higher transfusion hb thresholds of 11–12 g/dl, although there is limited evidence to support this approach.31 once initiated, transfusions are usually given every 2–4 weeks.31 with older patients, a transfusion every two weeks may be necessary to maintain a trough hb level of 9–10.5 g/dl.31,34 a splenectomy is sometimes indicated for patients with hypersplenism and for those with high transfusion requirements.35 a transfusion record should be maintained and arwa z. al-riyami and shahina daar review | e7 include the volume or weight of administered units, the hb/hct level of the units, the patient’s weight, the occurrence of any transfusion reactions and if any rbc antibodies have formed.11,36 transfusion requirements are likely to increase in pregnant patients.27 in patients undergoing elective surgery, a preoperative assessment should include the transfusion history and preand perioperative transfusions should be planned to ensure an hb level of 10–12 g/dl. post-transfusion hb levels should not be higher than 14–15 g/dl to avoid the risk of hyperviscosity and stroke.11 t h a l a s s a e m i a i n t e r m e d i a patients with ti have mild or moderate haemolytic anaemia and can maintain an hb level of >7 g/dl without regular transfusion support.32 these patients may have worsening anaemia, particularly upon exposure to physiological stress or other triggers. the decision to transfuse in ti cases depends on several factors beyond hb level.37 children should be monitored carefully for evidence of thalassaemic features resulting from ineffective erythropoiesis, bone marrow expansion, a reduction in growth or progressive splenomegaly. if there is evidence of any of the above, the child should receive regular transfusions until they have reached their full adult height and the bones are fused.31 older children, adolescents and adults should continue to be monitored regularly for any indications that may arise. some adolescents require transfusions because of poor growth, delayed/absent puberty or complications due to bone expansion.38 during adulthood, periodic transfusions may be indicated during acute episodes of anaemia, especially for pregnant patients, those suffering from infections or prior to surgery.38–40 transfusions should be consid ered in the management of certain conditions, for primary prevention in high-risk populations and for secondary prevention in some settings. indications include the development of thrombotic or cerebrovascular disease, pulmonary hypertension with or without secondary heart failure, extramedullary haematopoietic pseudotumours and leg ulcers.38 although transfusions have been shown to protect against these complications, increased risks due to iron overload, endocrinopathies and alloimmunisation should be taken into account when deciding the optimal time to transfuse such patients.41 during pregnancy, transfusions should be considered in mothers with ti and worsening anaemia or if there is evidence of fetal growth retardation; the aim should be to maintain a pre-transfusion hb level of >10 g/dl.42 once the transfusion programme is initiated, patients should be closely monitored and therapy should be individually tailored to meet their needs.38 some patients with ti may need to continue regular transfusions. such a decision should be made in consultation with a specialist with experience in managing ti patients.31,43 alloimmunisation a major complication of transfusion in patients with scd and homozygous β-thalassaemia is the risk of alloimmunisation. risk factors for alloimmunisation are complex and involve at least three contributing elements: (1) rbc antigenic differences between the blood donor and the recipient, (2) the recipient’s immune status and (3) the immune-modulatory effects of the transfused rbcs on the recipient.44 increased systemic inflammation and dysregulation of the immune system may also be responsible for alloimmunisation in scd patients.45,46 several studies have shown a rising risk of alloimmunisation among scd patients corresponding with an increase in the number of transfusions received.47–49 red cell alloimmunisation presents a challenge to blood banks, especially when trying to find compatible blood for affected patients. following alloimmunisation, serious complications may occur such as life-threatening delayed haemolytic transfusion reactions and transfusion delays due to difficulties in finding compatible units. alloimmunisation further triggers autoantibody formation in transfused scd and thalassaemic patients, with a cumulative incidence of 6–10%.44,50–52 although the development of these autoantibodies is less frequent compared to the development of alloantibodies, they can cause clinically significant haemolysis and difficulty in obtaining compatible rbc units.53 the most common antibodies observed in patients with scd and homozygous β-thalassaemia are those against the rhesus (rh), particularly the c and e antigens, and the kell (k) systems.54 other antibodies that tend to develop are against the kidd, duffy, lewis and mns systems.54 reported alloimmunisation rates in scd vary. in patients with scd receiving only aboand d-matched rbcs, the rate of alloimmunisation ranges from 18% to as high as 76%.47,48,52,55–59 the exact rate is dependent on many factors, including the extent of rbc antigen matching, the degree of homogeneity between the recipients’ and donors’ ethnic backgrounds and the frequency of transfusion. the rh and anti-k antibodies comprise over two-thirds of the rbc antibodies encountered.60 the risk of alloimmunisation has been shown to be reduced to 5–11% with additional limited antigen phenotype matching for c, e and k antigens and to 0–7% with extended phenotype-matched rbcs.45,59,61,62 therefore, compatible rbcs which have transfusion in haemoglobinopathies review and recommendations for local blood banks and transfusion services in oman e8 | squ medical journal, february 2018, volume 18, issue 1 been fully cross-matched for all rh and k antigens is the minimum recommended standard of transfusion care for patients with scd.17,18,60,63 extended rbc phenotypes should ideally be performed in the first year of life, before the start of a regular transfusion programme.31,36 if the patient has been recently transfused, dna-based methods can be used to determine the predicted phenotype.64 if alloantibodies are identified, the rbcs used for the transfusion should be negative for the corresponding antigen. extended rbc phenotype-match ing for duffy, kidd and mns antigens has also been recommended to reduce the risk of alloimmunisation against these antigens.65 however, this can be problem atic, as such additional testing increases costs and is dependent upon the availability of the necessary inventory, laboratory personnel and resources. that being said, establishing a limited inventory of o group rbcs negative for the c, c, e, e and k antigens in blood banks may be cost-effective, as well as decreasing the need to process blood on an urgent basis and shortening the time to transfusion.66 molecular methods are particularly useful in patients with recent transfusions and no baseline phenotype as well as patients with autoantibodies and complex alloimmunisation.67 comp arative studies show that alloimmunisation and delayed haemolytic transfusion reactions are less frequent in automated rbc exchange transfusions compared to chronic simple transfusions, despite increased blood exposure.68–70 however, this finding may be due to the fact that some patients receive rbcs with a higher degree of phenotype-matching during automated exchange transfusions.71 these types of transfusions also have the advantage of limiting iron overload in these patients, a variable which has been associated with increased morbidity.72 according to various reports, the rate of alloimmunisation among tm patients ranges from 5.2–37%, although it appears to be lower among more homogeneous populations.44,60,73–78 this variation has been linked to the extent of the homogeneity between the donor-recipient populations, divergent testing methods and differences in the patient population of each study.75,79 other factors include the use of non-leuko reduced rbc units and differences in providing antigenmatched blood.67 the lower rates of alloimmunisation in tm compared to scd are probably due to the fact that transfusions for thalassaemic patients begin at a relatively younger age and are continued on a regular basis. no consensus exists on the provision of extended antigen-matching in tm patients due to limited data on the impact of rbc-matching policies on alloimmunisation rates in such patients. research has been published regarding the impact on the rate of alloimmunisation of providing limited c, e and k antigen-matched rbcs in comparison to abo and d antigen phenotype-matched rbcs.44,80 nevertheless, this approach has been questioned considering the low rate of alloimmunisation in this population.79 however, clinical standards recommend antigen-matching for all rh and k antigens in order to minimise the risk of alloimmunisation in patients with homozygous β-thalassaemia.11,31,34,36 alloimmunisation is more common in ti than in tm.80,81 risk factors for alloimmunisation in ti patients include a history of splenectomy, pregnancy and patients who have never been transfused or have been only minimally transfused before.31,39,43,82 previous research has demonstrated the value of providing extended rbc antigen-matching for the rh (c, c, e and e), k (k, kpa and kpb), kidd (jka and jkb), duffy (fya and fyb), s and s antigens in reducing alloimmunisation rates among patients with ti.82 as rbc alloimmunisation is common in ti, phenotypematched units are recommended.31,39,43,82 the association between leukoreduction and rbc alloimmunisation has not been well established.75 it has been hypothesised that leukoreduction lowers the frequency of rbc alloimmunisation.83 hussein et al. reported a higher rate of rbc alloimmunisation among patients receiving non-leukoreduced rbcs compared to those always receiving leukoreduced rbcs.84 due to its benefit in reducing the risk of febrile reactions and cytomegalovirus transmission, leukoreduction has become an increasingly common procedure and standard of care in many centres caring for patients with scd and thalassaemia.67,85 other transfusion requirements for both scd and tm patients, the rbc units to be transfused should be fresh (between <7–14 days old) and, in the case of scd patients, negative for sickle cells.17,31 if possible, a hepatitis b immunisation course should be completed prior to the first transfusion. serological testing for hepatitis a, b and c and hiv should also be performed to obtain baseline values. it is recommended that all patients who lack serological immunity to the hepatitis b virus begin a vaccination programme and show evidence of immunity before the start of the transfusion.17,34,36 following the start of the transfusion programme, patients should be regularly screened for hepatitis and hiv. arwa z. al-riyami and shahina daar review | e9 recommendations in oman in oman, patients with haemoglobinopathies are managed and treated at various regional hospitals throughout the country. implementation of the aforementioned recommendations will necessitate that all blood banks have the required testing facilities for extended rbc phenotyping, antibody screening and identification. in addition, healthcare institutions will need to have access to pre-storage leukoreduced rbc units, maintain an accurate and comprehensive patient record database and develop facilities for automated rbc exchange transfusions. accordingly, the development of an interconnected blood bank system through out oman is recommended, from which information on blood groups, baseline extended phenotypes and existing alloand autoantibodies can be shared between different blood banks. until these measures are implemented, patients should be provided with an up-to-date transfusion card detailing their blood group, baseline extended phenotype, existing antibodies and date of antibody formation, if any, as well as baseline hb levels for patients with scd. such a measure would aid in ensuring that these patients receive adequate management and standard levels of care when presenting to different hospitals in oman. moreover, an active donor recruitment programme is required to ensure the availability of blood for omani patients with scd or thalassaemia. a limited antigen-negative rbc inventory should be established in major hospitals treating patients with these haemoglobinopathies. a centralised database of phenotyped blood donors accessible to all blood banks is also needed to allow the identification of suitable rbc units for transfusing potentially problematic alloimmunised patients. in addition, a frozen blood facility of rare rbc phenotypes for use in difficult situations should be established, along with molecular testing methods in major centres to facilitate the immediate management of complex alloimmunised cases. table 1 summarises recommendations for blood banks and transfusion services in oman. table 1: recommendations for blood banks and transfusion services in oman category recommendation phenotyping and antigen-matching • extended rbc phenotyping for rh (c, c, e and e), k (k, kpa and kpb), kidd (jka and jkb), duffy (fya and fyb), s and s antigens should be performed before the start of a regular transfusion programme, ideally within the first year of life. if this is not available, then extended rbc phenotyping can be performed on a pre-transfusion sample after a minimum of three months following an rbc transfusion. • if the patient has been recently transfused, dna-based methods can be used to determine the predicted phenotype. • rbc antigen matching for rh and k antigens is recommended as a standard of care in non-alloimmunised scd cases due to the increased risk of alloimmunisation to these antigens. • rbc antigen matching for rh and k antigens is recommended in tm patients to minimise the risk of alloimmunisation. • extended rbc antigen matching is recommended in ti patients since they have an increased risk of alloimmunisation compared to tm patients. • if alloantibodies are identified in scd or tm patients, extended rbc phenotype matching is recommended. the selected units should be serologically cross-match compatible with the patient’s serum and tested to ensure negativity to the corresponding antigens. • if extended phenotype matching is unavailable, transfused rbcs in alloimmunised patients should be at the very least serologically cross-matched and tested to ensure negativity to the corresponding antigen. screening • antibody screening should be performed before each transfusion. serology and immunity • serological testing for hepatitis a, b and c and hiv should be performed at baseline and every six months thereafter. • all patients who do not have serological immunity to the hepatitis b virus should start a vaccination programme and show evidence of immunity before the start of the transfusion, if possible. monitoring • due to the risk of iron overload and related cardiac, hepatic and endocrinological complications, patients should be closely monitored and chelation therapy should be initiated when indicated. blood bank records • every patient should have a complete and up-to-date blood bank record of antigen typing, antibodies and transfusion reactions. this information should be used to assess the blood type and phenotype needed prior to each transfusion. other • rbc units for both scd and tm patients should be fresh (<7–14 days old). • rbcs for scd patients should be sickle cell-negative. • pre-storage leukoreduced rbc components should be used as much as possible for patients with scd and homozygous β-thalassaemia. • an automated rbc exchange transfusion facility is recommended in centres that care for larger numbers of scd patients as this transfusion method is a more efficient way to perform exchange transfusions and reduces the degree of iron overload. rbc = red blood cell; rh = rhesus; k = kell; scd = sickle cell disease, tm = thalassaemia major; ti = thalassaemia intermedia. transfusion in haemoglobinopathies review and recommendations for local blood banks and transfusion services in oman e10 | squ medical journal, february 2018, volume 18, issue 1 conclusion major haemoglobinopathies such as scd and tm have specialised transfusion requirements. this article provides various recommendations to enhance exist ing blood banks and transfusion services in oman, based on a review of the current literature regarding the transfusion practices for such patients. the provision of such services will require additional funding, administrative support, expertise, training and human resources, as well as the development of an active donor recruitment programme and interconnected blood bank system within the country. references 1. al-riyami aa, suleiman aj, afifi m, al-lamki zm, daar s. a community-based study of common hereditary blood disorders in oman. east mediterr health j 2001; 7:1004–11. 2. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 3. hamamy h, alwan a. hereditary disorders in the eastern mediterranean region. bull world health organ 1994; 72:145–54. 4. white jm, byrne m, richards r, buchanan t, katsoulis e, weerasingh k. red cell genetic abnormalities in peninsular arabs: sickle haemoglobin, g6pd deficiency, and alpha and beta thalassaemia. j med genet 1986; 23:245–51. doi: 10.1136/ jmg.23.3.245. 5. rajab a, patton ma. major factors determining the frequencies of hemoglobinopathies in oman. am j med genet 1997; 71:240–2. doi: 10.1002/(sici)1096-8628(19970808)71:2<240::aid-ajmg 26>3.0.co;2-d. 6. daar s, hussain hm, gravell d, nagel rl, krishnamoorthy r. genetic epidemiology of hbs in oman: multicentric origin for the bs gene. am j hematol 2000; 64:39–46. doi: 10.1002/ (sici)1096-8652(200005)64:1<39::aid-ajh7>3.0.co;2-#. 7. beaudevin c. old diseases and contemporary crisis: inherited blood disorders in the sultanate of oman. anthropol med 2013; 20:175–89. doi: 10.1080/13648470.2013.805317. 8. jaiyesimi f, pandey r, bux d, sreekrishna y, zaki f, krishna moorthy n. sickle cell morbidity profile in omani children. ann trop paediatr 2002; 22:45–52. doi: 10.1179/027249302125 000148. 9. mevada st, al saadoon m, zachariah m, al rawas ah, wali y. impact of burden of thalassemia major on health-related quality of life in omani children. j pediatr hematol oncol 2016; 38:384–8. doi: 10.1097/mph.0000000000000565. 10. alkindi s, almahrooqi s, alhinai s, almarhoobi a, al-hosni s, daar s, et al. alloimmunization in patients with sickle cell disease and thalassemia: experience of a single centre in oman. mediterr j hematol infect dis 2017; 9:e2017013. doi: 10.4084/ mjhid.2017.013. 11. thalassaemia international federation. guidelines for the management of transfusion dependent thalassaemia, 3rd edition (2014). from: https://thalassaemia.org.cy/publications/tif-publi cations/guidelines-forthe-management-oftransfusiondependent-thalassaemia-3rd-edition-2014/ accessed: dec 2017. 12. yawn bp, buchanan gr, afenyi-annan an, ballas sk, hassell kl, james ah, et al. management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. jama 2014; 312:1033–48. doi: 10.1001/jama.2014.10517. 13. howard j, malfroy m, llewelyn c, choo l, hodge r, johnson t, et al. the transfusion alternatives preoperatively in sickle cell disease (taps) study: a randomised, controlled, multicentre clinical trial. lancet 2013; 381:930–8. doi: 10.1016/s0140-6736 (12)61726-7. 14. adams rj, mckie vc, hsu l, files b, vichinsky e, pegelow c, et al. prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial doppler ultrasonography. n engl j med 1998; 339:5–11. doi: 10.1056/ nejm199807023390102. 15. ware re, davis br, schultz wh, brown rc, aygun b, sarnaik s, et al. hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia: tcd with transfusions changing to hydroxyurea (twitch) a multicentre, open-label, phase 3, non-inferiority trial. lancet 2016; 387:661–70. doi: 10.1016/s0 140-6736(15)01041-7. 16. ware re, helms rw. stroke with transfusions changing to hydroxyurea (switch). blood 2012; 119:3925–32. doi: 10.11 82/blood-2011-11-392340. 17. uk national health service. sickle cell disease in childhood: standards and guidelines for clinical care. from: www.gov. uk/government/uploads/system/uploads/attachment_data/ file/408961/1332-sc-clinical-standards-web.pdf accessed: dec 2017. 18. davis ba, allard s, qureshi a, porter jb, pancham s, win n, et al. guidelines on red cell transfusion in sickle cell disease: part ii indications for transfusion. br j haematol 2017; 176:192–209. doi: 10.1111/bjh.14383. 19. hassell kl, eckman jr, lane pa. acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. am j med 1994; 96:155–62. doi: 10.10 16/0002-9343(94)90136-8. 20. howard j, hart n, roberts-harewood m, cummins m, awogbade m, davis b. guideline on the management of acute chest syndrome in sickle cell disease. br j haematol 2015; 169:492–505. doi: 10.1111/bjh.13348. 21. debaun mr, gordon m, mckinstry rc, noetzel mj, white da, sarnaik sa, et al. controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. n engl j med 2014; 371:699–710. doi: 10.1056/nejmoa1401731. 22. ohene-frempong k. indications for red cell transfusion in sickle cell disease. semin hematol 2001; 38:5–13. doi: 10.1016/ s0037-1963(01)90055-1. 23. adams rj, brambilla d. discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. n engl j med 2005; 353:2769–78. doi: 10.1056/nejmoa050460. 24. vichinsky ep, haberkern cm, neumayr l, earles an, black d, koshy m, et al. a comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease: the preoperative transfusion in sickle cell disease study group. n engl j med 1995; 333:206–13. doi: 10.1056/ nejm199507273330402. 25. royal college of obstetricians and gynaecologists. greentop guideline no. 61: management of sickle cell disease in pregnancy. from: www.rcog.org.uk/globalassets/documents/ guidelines/gtg_61.pdf accessed: dec 2017. 26. mahomed k. prophylactic versus selective blood transfusion for sickle cell anaemia during pregnancy. cochrane database syst rev 2000; 2:cd000040. doi: 10.1002/14651858.cd000040. 27. boga c, ozdogu h. pregnancy and sickle cell disease: a review of the current literature. crit rev oncol hematol 2016; 98:364–74. doi: 10.1016/j.critrevonc.2015.11.018. 28. weatherall dj, clegg jb. the thalassaemia syndromes, 4th ed. hoboken, new jersey, usa: wiley-blackwell, 2008. pp. 630–85. 29. musallam km, rivella s, vichinsky e, rachmilewitz ea. nontransfusion-dependent thalassemias. haematologica 2013; 98:833–44. doi: 10.3324/haematol.2012.066845. https://doi.org/10.1136/jmg.23.3.245 https://doi.org/10.1136/jmg.23.3.245 https://doi.org/10.1002/%28sici%291096-8628%2819970808%2971:2%3c240::aid-ajmg26%3e3.0.co%3b2-d https://doi.org/10.1002/%28sici%291096-8628%2819970808%2971:2%3c240::aid-ajmg26%3e3.0.co%3b2-d https://doi.org/10.1002/%28sici%291096-8652%28200005%2964:1%3c39::aid-ajh7%3e3.0.co%3b2-%23 https://doi.org/10.1002/%28sici%291096-8652%28200005%2964:1%3c39::aid-ajh7%3e3.0.co%3b2-%23 https://doi.org/10.1080/13648470.2013.805317 https://doi.org/10.1179/027249302125000148 https://doi.org/10.1179/027249302125000148 https://doi.org/10.1097/mph.0000000000000565 https://doi.org/10.4084/mjhid.2017.013 https://doi.org/10.4084/mjhid.2017.013 https://doi.org/10.1001/jama.2014.10517 https://doi.org/10.1016/s0140-6736%2812%2961726-7 https://doi.org/10.1016/s0140-6736%2812%2961726-7 https://doi.org/10.1056/nejm199807023390102 https://doi.org/10.1056/nejm199807023390102 https://doi.org/10.1016/s0140-6736%2815%2901041-7 https://doi.org/10.1016/s0140-6736%2815%2901041-7 https://doi.org/10.1182/blood-2011-11-392340 https://doi.org/10.1182/blood-2011-11-392340 https://doi.org/10.1111/bjh.14383 https://doi.org/10.1016/0002-9343%2894%2990136-8 https://doi.org/10.1016/0002-9343%2894%2990136-8 https://doi.org/10.1111/bjh.13348 https://doi.org/10.1056/nejmoa1401731 https://doi.org/10.1016/s0037-1963%2801%2990055-1 https://doi.org/10.1016/s0037-1963%2801%2990055-1 https://doi.org/10.1056/nejmoa050460 https://doi.org/10.1056/nejm199507273330402 https://doi.org/10.1056/nejm199507273330402 https://doi.org/10.1002/14651858.cd000040 https://doi.org/10.1016/j.critrevonc.2015.11.018 https://doi.org/10.3324/haematol.2012.066845 arwa z. al-riyami and shahina daar review | e11 30. cazzola m, de stefano p, ponchio l, locatelli f, beguin y, dessi c, et al. relationship between transfusion regimen and suppression of erythropoiesis in beta-thalassaemia major. br j haematol 1995; 89:473–8. doi: 10.1111/j.1365-2141.1995.tb0 8351.x. 31. united kingdom thalassaemia society. standards for the clinical care of children and adults with thalassaemia in the uk: 3rd edition, 2016. from: http://ukts.org/standards/standards2016final.pdf accessed: dec 2017. 32. rachmilewitz ea, giardina pj. how i treat thalassemia. blood 2011; 118:3479–88. doi: 10.1182/blood-2010-08-300335. 33. cazzola m, borgna-pignatti c, locatelli f, ponchio l, beguin y, de stefano p. a moderate transfusion regimen may reduce iron loading in beta-thalassemia major without producing excessive expansion of erythropoiesis. transfusion 1997; 37:135–40. doi: 10.1046/j.1537-2995.1997.37297203514.x. 34. children’s hospital & research center oakland. standards of care guidelines for thalassemia. from: http://thalassemia.com/ documents/socguidelines2012.pdf accessed: dec 2017. 35. rebulla p, modell b. transfusion requirements and effects in patients with thalassaemia major: cooleycare programme. lancet 1991; 337:277–80. doi: 10.1016/0140-6736(91)90881-o. 36. thalassemia foundation of canada. guidelines for the clinical care of patients with thalassemia in canada. from: www. thalassemia.ca/wp-content/uploads/thalassemia-guidelines_ lr.pdf accessed: dec 2017. 37. taher at, musallam km, cappellini md, weatherall dj. optimal management of β thalassaemia intermedia. br j haematol 2011; 152:512–23. doi: 10.1111/j.1365-2141.2010.0 8486.x. 38. thalassaemia international federation. guidelines for the management of non transfusion dependent thalassaemia (ntdt). from: http://thalassemia.com/documents/ntdttif-guidelines.pdf accessed: dec 2017. 39. taher at, radwan a, viprakasit v. when to consider transfusion therapy for patients with non-transfusiondependent thalassaemia. vox sang 2015; 108:1–10. doi: 10.1111/ vox.12201. 40. haidar r, mhaidli h, taher at. paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia. eur spine j 2010; 19:871–8. doi: 10.1007/s00586-010-1357-2. 41. taher at, musallam km, karimi m, el-beshlawy a, belhoul k, daar s, et al. overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the optimal care study. blood 2010; 115:1886–92. doi: 10.1182/blood-2009-09-243154. 42. royal college of obstetricians and gynaecologists. greentop guideline no. 66: management of beta thalassaemia in pregnancy. from: www.rcog.org.uk/globalassets/documents/ guidelines/gtg_66_thalassaemia.pdf accessed: dec 2017. 43. karimi m, cohan n, de sanctis v, mallat ns, taher a. guidelines for diagnosis and management of beta-thalassemia intermedia. pediatr hematol oncol 2014; 31:583–96. doi: 10.31 09/08880018.2014.937884. 44. singer st, wu v, mignacca r, kuypers fa, morel p, vichinsky ep. alloimmunization and erythrocyte autoimmunization in transfusion-dependent thalassemia patients of predominantly asian descent. blood 2000; 96:3369–73. 45. lasalle-williams m, nuss r, le t, cole l, hassell k, murphy jr, et al. extended red blood cell antigen matching for transfusions in sickle cell disease: a review of a 14-year experience from a single center (cme). transfusion 2011; 51:1732–9. doi: 10.1111/ j.1537-2995.2010.03045.x. 46. bao w, zhong h, li x, lee mt, schwartz j, sheth s, et al. immune regulation in chronically transfused allo-antibody responder and nonresponder patients with sickle cell disease and β-thalassemia major. am j hematol 2011; 86:1001–6. doi: 10.1002/ajh.22167. 47. vichinsky ep, earles a, johnson ra, hoag ms, williams a, lubin b. alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. n engl j med 1990; 322:1617–21. doi: 10.1056/nejm199006073222301. 48. rosse wf, gallagher d, kinney tr, castro o, dosik h, moohr j, et al. transfusion and alloimmunization in sickle cell disease: the cooperative study of sickle cell disease. blood 1990; 76:1431–7. 49. sarnaik s, schornack j, lusher jm. the incidence of development of irregular red cell antibodies in patients with sickle cell anemia. transfusion 1986; 26:249–52. doi: 10.1046/ j.1537-2995.1986.26386209381.x. 50. castellino sm, combs mr, zimmerman sa, issitt pd, ware re. erythrocyte autoantibodies in paediatric patients with sickle cell disease receiving transfusion therapy: frequency, characteristics and significance. br j haematol 1999; 104:189–94. doi: 10.1046/j.1365-2141.1999.01127.x. 51. garratty g. autoantibodies induced by blood transfusion. transfusion 2004; 44:5–9. doi: 10.1111/j.0041-1132.2004.00658.x. 52. aygun b, padmanabhan s, paley c, chandrasekaran v. clinical significance of rbc alloantibodies and autoantibodies in sickle cell patients who received transfusions. transfusion 2002; 42:37–43. doi: 10.1046/j.1537-2995.2002.00007.x. 53. do valle netoa og, alves vm, de araújo pereira g, moraessouzaa h, martins pr. clinical and epidemiological profile of alloimmunized and autoimmunized multi-transfused patients against red blood cell antigens in a blood center of minas gerais. hematol transfus cell ther 2018; in press. doi: 10.1016/j.htct.2017.08.001. 54. borgna-pignatti c. modern treatment of thalassaemia intermedia. br j haematol 2007; 138:291–304. doi: 10.1111/ j.1365-2141.2007.06654.x. 55. davies sc, mcwilliam ac, hewitt pe, devenish a, brozovic m. red cell alloimmunization in sickle cell disease. br j haematol 1986; 63:241–5. doi: 10.1111/j.1365-2141.1986.tb05546.x. 56. ambruso dr, githens jh, alcorn r, dixon dj, brown lj, vaughn wm, et al. experience with donors matched for minor blood group antigens in patients with sickle cell anemia who are receiving chronic transfusion therapy. transfusion 1987; 27:94–8. doi: 10.1046/j.1537-2995.1987.27187121485.x. 57. olujohungbe a, hambleton i, stephens l, serjeant b, serjeant g. red cell antibodies in patients with homozygous sickle cell disease: a comparison of patients in jamaica and the united kingdom. br j haematol 2001; 113:661–5. doi: 10.1046/j.13652141.2001.02819.x. 58. castro o, sandler sg, houston-yu p, rana s. predicting the effect of transfusing only phenotype-matched rbcs to patients with sickle cell disease: theoretical and practical implications. transfusion 2002; 42:684–90. doi: 10.1046/j.15372995.2002.00126.x. 59. sakhalkar vs, roberts k, hawthorne lm, mccaskill dm, veillon dm, caldito gc, et al. allosensitization in patients receiving multiple blood transfusions. ann n y acad sci 2005; 1054:495–9. doi: 10.1196/annals.1345.072. 60. chou st, liem ri, thompson aa. challenges of alloimmunization in patients with haemoglobinopathies. br j haematol 2012; 159:394–404. doi: 10.1111/bjh.12061. 61. tahhan hr, holbrook ct, braddy lr, brewer ld, christie jd. antigen-matched donor blood in the transfusion management of patients with sickle cell disease. transfusion 1994; 34:562–9. doi: 10.1046/j.1537-2995.1994.34794330008.x. 62. vichinsky ep, luban nl, wright e, olivieri n, driscoll c, pegelow ch, et al. prospective rbc phenotype matching in a stroke-prevention trial in sickle cell anemia: a multicenter transfusion trial. transfusion 2001; 41:1086–92. doi: 10.1046/j. 1537-2995.2001.41091086.x. https://doi.org/10.1111/j.1365-2141.1995.tb08351.x https://doi.org/10.1111/j.1365-2141.1995.tb08351.x https://doi.org/10.1182/blood-2010-08-300335 https://doi.org/10.1046/j.1537-2995.1997.37297203514.x https://doi.org/10.1016/0140-6736%2891%2990881-o https://doi.org/10.1111/j.1365-2141.2010.08486.x https://doi.org/10.1111/j.1365-2141.2010.08486.x https://doi.org/10.1111/vox.12201 https://doi.org/10.1111/vox.12201 https://doi.org/10.1007/s00586-010-1357-2 https://doi.org/10.1182/blood-2009-09-243154 https://doi.org/10.3109/08880018.2014.937884 https://doi.org/10.3109/08880018.2014.937884 https://doi.org/10.1111/j.1537-2995.2010.03045.x https://doi.org/10.1111/j.1537-2995.2010.03045.x https://doi.org/10.1002/ajh.22167 https://doi.org/10.1056/nejm199006073222301 https://doi.org/10.1046/j.1537-2995.1986.26386209381.x https://doi.org/10.1046/j.1537-2995.1986.26386209381.x https://doi.org/10.1046/j.1365-2141.1999.01127.x https://doi.org/10.1111/j.0041-1132.2004.00658.x https://doi.org/10.1046/j.1537-2995.2002.00007.x https://doi.org/10.1016/j.htct.2017.08.001 https://doi.org/10.1111/j.1365-2141.2007.06654.x https://doi.org/10.1111/j.1365-2141.2007.06654.x https://doi.org/10.1111/j.1365-2141.1986.tb05546.x https://doi.org/10.1046/j.1537-2995.1987.27187121485.x https://doi.org/10.1046/j.1365-2141.2001.02819.x https://doi.org/10.1046/j.1365-2141.2001.02819.x https://doi.org/10.1046/j.1537-2995.2002.00126.x https://doi.org/10.1046/j.1537-2995.2002.00126.x https://doi.org/10.1196/annals.1345.072 https://doi.org/10.1111/bjh.12061 https://doi.org/10.1046/j.1537-2995.1994.34794330008.x https://doi.org/10.1046/j.1537-2995.2001.41091086.x https://doi.org/10.1046/j.1537-2995.2001.41091086.x transfusion in haemoglobinopathies review and recommendations for local blood banks and transfusion services in oman e12 | squ medical journal, february 2018, volume 18, issue 1 63. sickle cell society. standards for the clinical care of adults with sickle cell disease in the uk. from: http://sicklecellsociety. org/wp-content/uploads/2016/02/standards-for-the-clinicalcare-of-adults-with-sickle-cell-disease-inthe-uk .pdf accessed: dec 2017. 64. veldhuisen b, van der schoot ce, de haas m. blood group genotyping: from patient to high-throughput donor screening. vox sang 2009; 97:198–206. doi: 10.1111/j.14230410.2009.01209.x. 65. yazdanbakhsh k, ware re, noizat-pirenne f. red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. blood 2012; 120:528–37. doi: 10.1182/blood-2011-11-327361. 66. le n, harach me, kay jk, brown rp, everetts jn, herman jh. establishing an antigen-negative red blood cell inventory in a hospital-based blood bank. transfusion 2014; 54:285–8. doi: 10.1111/trf.12270. 67. matteocci a, pierelli l. red blood cell alloimmunization in sickle cell disease and in thalassaemia: current status, future perspectives and potential role of molecular typing. vox sang 2014; 106:197–208. doi: 10.1111/vox.12086. 68. venkateswaran l, teruya j, bustillos c, mahoney d jr, mueller bu. red cell exchange does not appear to increase the rate of allo-and auto-immunization in chronically transfused children with sickle cell disease. pediatr blood cancer 2011; 57:294–6. doi: 10.1002/pbc.22985. 69. wahl sk, garcia a, hagar w, gildengorin g, quirolo k, vichinsky e. lower alloimmunization rates in pediatric sickle cell patients on chronic erythrocytapheresis compared to chronic simple transfusions. transfusion 2012; 52:2671–6. doi: 10.1111/j.1537-2995.2012.03659.x. 70. michot jm, driss f, guitton c, moh klaren j, lefebvre f, chamillard x, et al. immunohematologic tolerance of chronic transfusion exchanges with erythrocytapheresis in sickle cell disease. transfusion 2015; 55:357–63. doi: 10.1111/trf.12875. 71. kelly s, quirolo k, marsh a, neumayr l, garcia a, custer b. erythrocytapheresis for chronic transfusion therapy in sickle cell disease: survey of current practices and review of the literature. transfusion 2016; 56:2877–88. doi: 10.1111/trf.13800. 72. vichinsky e, butensky e, fung e, hudes m, theil e, ferrell l, et al. comparison of organ dysfunction in transfused patients with scd or beta thalassemia. am j hematol 2005; 80:70–4. doi: 10.1002/ajh.20402. 73. saied da, kaddah am, badr eldin rm, mohaseb ss. alloimmunization and erythrocyte autoimmunization in transfusion-dependent egyptian thalassemic patients. j pediatr hematol oncol 2011; 33:409–14. doi: 10.1097/mph.0b013e31 82208154. 74. pahuja s, pujani m, gupta sk, chandra j, jain m. alloimmunization and red cell autoimmunization in multitransfused thalassemics of indian origin. hematology 2010; 15:174–7. doi: 10.1179/102453309x12583347114013. 75. thompson aa, cunningham mj, singer st, neufeld ej, vichinsky e, yamashita r, et al. red cell alloimmunization in a diverse population of transfused patients with thalassaemia. br j haematol 2011; 153:121–8. doi: 10.1111/j.1365-2141.2011. 08576.x. 76. economidou j, constantoulakis m, augoustaki o, adinolfi m. frequency of antibodies to various antigenic determinants in polytransfused patients with homozygous thalassaemia in greece. vox sang 1971; 20:252–8. doi: 10.1111/j.1423-0410.1971. tb00436.x. 77. ameen r, al-shemmari s, al-humood s, chowdhury ri, al-eyaadi o, al-bashir a. rbc alloimmunization and autoimmunization among transfusion-dependent arab thal assemia patients. transfusion 2003; 43:1604–10. doi: 10.1046/j. 1537-2995.2003.00549.x. 78. ho hk, ha sy, lam ck, chan gc, lee tl, chiang ak, et al. alloimmunization in hong kong southern chinese transfusion-dependent thalassemia patients. blood 2001; 97:3999–4000. doi: 10.1182/blood.v97.12.3999. 79. sirchia g, zanella a, parravicini a, morelati f, rebulla p, masera g. red cell alloantibodies in thalassemia major: results of an italian cooperative study. transfusion 1985; 25:110–12. doi: 10.1046/j.1537-2995.1985.25285169198.x. 80. spanos t, karageorga m, ladis v, peristeri j, hatziliami a, kattamis c. red cell alloantibodies in patients with thalassemia. vox sang 1990; 58:50–5. doi: 10.1111/j.1423-0410.1990.tb02055.x. 81. taher at, musallam km, karimi m, cappellini md. contemporary approaches to treatment of beta-thalassemia intermedia. blood rev 2012; 26:s24–7. doi: 10.1016/s0268-960x (12)70008-5. 82. al-riyami az, al-mahrooqi s, al-hinai s, al-hosni s, almadhani a, daar s. transfusion therapy and alloimmunization in thalassemia intermedia: a 10 year experience at a tertiary care university hospital. transfus apher sci 2014; 51:42–6. doi: 10.1016/j.transci.2014.04.009. 83. blumberg n, heal jm, gettings kf. wbc reduction of rbc transfusions is associated with a decreased incidence of rbc alloimmunization. transfusion 2003; 43:945–52. doi: 10.1046/j.1537-2995.2003.00443.x. 84. hussein e, ahmed eldesoukey n, rihan a, kamal a. predictors of red cell alloimmunization in multitransfused egyptian patients with β-thalassemia. arch pathol lab med 2014; 138:684–8. doi: 10.5858/arpa.2013-0016-oa. 85. spinella pc, dressler a, tucci m, carroll cl, rosen rs, hume h, et al. survey of transfusion policies at us and canadian children’s hospitals in 2008 and 2009. transfusion 2010; 50:2328–35. doi: 10.1111/j.1537-2995.2010.02708.x. https://doi.org/10.1111/j.1423-0410.2009.01209.x https://doi.org/10.1111/j.1423-0410.2009.01209.x https://doi.org/10.1182/blood-2011-11-327361 https://doi.org/10.1111/trf.12270 https://doi.org/10.1111/vox.12086 https://doi.org/10.1002/pbc.22985 https://doi.org/10.1111/j.1537-2995.2012.03659.x https://doi.org/10.1111/trf.12875 https://doi.org/10.1111/trf.13800 https://doi.org/10.1002/ajh.20402 https://doi.org/10.1097/mph.0b013e3182208154 https://doi.org/10.1097/mph.0b013e3182208154 https://doi.org/10.1179/102453309x12583347114013 https://doi.org/10.1111/j.1365-2141.2011.08576.x https://doi.org/10.1111/j.1365-2141.2011.08576.x https://doi.org/10.1111/j.1423-0410.1971.tb00436.x https://doi.org/10.1111/j.1423-0410.1971.tb00436.x https://doi.org/10.1046/j.1537-2995.2003.00549.x https://doi.org/10.1046/j.1537-2995.2003.00549.x https://doi.org/10.1182/blood.v97.12.3999 https://doi.org/10.1046/j.1537-2995.1985.25285169198.x https://doi.org/10.1111/j.1423-0410.1990.tb02055.x https://doi.org/10.1016/s0268-960x%2812%2970008-5 https://doi.org/10.1016/s0268-960x%2812%2970008-5 https://doi.org/10.1016/j.transci.2014.04.009 https://doi.org/10.1046/j.1537-2995.2003.00443.x https://doi.org/10.5858/arpa.2013-0016-oa https://doi.org/10.1111/j.1537-2995.2010.02708.x sir, i read with interest the published article by al-shamahy et al. in your journal.1 it is an important report which encourages health policy makers to control hepatitis b virus (hbv) infections more effectively. i would like to add some information which may improve the understanding of the situation. hbv is a common cause of liver disease in the world and most of the sufferers are asians.2 universal vaccination in iran since 1993 of all neonates against hepatitis b virus has changed the epidemiology of this infection. similar experiences have been reported from other countries such as saudi arabia and china.3,4 improvement of people's knowledge about hbv risk factors, national vaccination programmes for all neonates, vaccination of high risk groups, such as health care workers, and the introduction of disposable syringes for use in vaccinations, hospitals and clinics might explain this decrease.4 it is important for a country such as yemen with hbsag positivity of more than 6% in pregnant women, to formulate a better policy for the control of hbv infection. the age at which hbv infection occurs influences the rate of transmission, the long-term outcome and determines the primary targets of a vaccination programme. thus, perinatal transmission from mother to child at or soon after birth results in about 90% chronic carriage, with its long-term complications of chronic hepatitis, cirrhosis and hepatocellular carcinoma, leading to death in middle age. this has serious economic consequences for the family and for the country as a whole. the contribution of each mode of transmission to morbidity and mortality must be known in order to develop the optimal vaccination programme.4 the authors excluded the anti-hbcab positive subjects from the vaccinated group in order differentiate them from those with naturally occurring to hbv infection. however, as we have reported before about the outcome after hbv vaccination in infants of hbsag mothers, 23% of these infants were anti hbcab positive.3 this means that the hbv vaccine prevented hbv infection. the authors recommend that children who were non-responders to hbv vaccine be re-vaccinated, but i think the first strategy should be to focus on increasing the coverage of hbv vaccination in infants. the world health organization (who) recommended that all countries which have reached a satisfactory coverage level of hepatitis b immunisation through routine vaccination develop other strategies for the control of hbv infection in their community. finally, i would like to mention that hbv vaccine is a temperature-sensitive biological product and exposure to heat shortens its shelf life, while freezing causes irreversible loss of potency.5 i therefore recommend the evaluation of an outside-the-cold-chain vaccine delivery system in yemen. i hope for better prospects for hbv infection control in the future in our region. seyed-moayed alavian baqiyatallah research center for gastroenterology and liver disease, tehran, iran squ med j, november 2011, vol. 11, iss. 4, pp. 529-530, epub. 25th oct 11 submitted 6th apr accepted 28th aug تغطية التطعيم ضد التهاب الكبد الفريوسي البائي واالستجابة املناعية له عند االطفال حتت سن العاشرة مبدينة صنعاء )اليمن( حنتاج اىل جهد أكرب للسيطرة على العدوى بفايروس الكبد البائي يف الدول النامية re: hepatitis b vaccine coverage and the immune response in children under ten years old in sana'a, yemen—we need to work much harder to control hepatitis b virus infection in developing countries letter to editor re: hepatitis b vaccine coverage and the immune response in children under ten years old in sana'a, yemen—we need to work much harder to control hepatitis b virus infection in developing countries 530 | squ medical journal, november 2011, volume 11, issue 4 email: alavian@thc.ir references 1. al-shamahy ha, hanash sh, rabbad ia, al-madhaji nm, naser sm. hepatitis b vaccine coverage and the immune response in children under ten years old in sana'a, yemen. sultan qaboos univ med j 2011; 11:77–82. 2. uyar y, cabar c, balci a. seroprevalence of hepatitis b virus among pregnant women in northern turkey. hepat mon 2009; 9:146–9. 3. adibi p, ghassemian r, alavian sm, ranjbar m, mohammadalizadeh ah, nematizadeh f, et al. effectiveness of hepatitis b vaccination in children of chronic hepatitis b mothers. saudi med j 2004; 25:1414–18. 4. alavian sm. ministry of health in iran is serious about controlling hepatitis b. hepat mon 2007; 7:3–5. 5. ren q, xiong h, li y, xu r, zhu c. evaluation of an outside-the-cold-chain vaccine delivery strategy in remote regions of western china. public health rep 2009; 124:745–50. author's response dr. alavian's careful reading of our article and his subsequent comments are acceptable. he raises several points and we would like to respond to each of them. first, dr. alavian added some information which may improve the understanding of the situation and change the epidemiology of this infection by improvement of people's knowledge about hbv risk factors. national vaccination programmes for all neonates, vaccination of high risk groups such as health care workers and the introduction of disposable syringes for use in vaccinations, hospitals and clinics might explain the decrease in hbv rates in some countries.1 i agree with him, but often there are many obstacles which suddenly rise up like the situation now in yemen where the national vaccination programme is stopped due to what is called a revolution (civil war). also i agree with his second point as a high rate of liver cancer in yemen is now occurring in individuals in their early forties.2 the third point was why we excluded the antihbcab positive subjects from the vaccinated group in order to differentiate them from those with naturally occurring hbv infection. we did this because the anti-hbsag might be due to natural infection and not due to vaccine.3 the fourth point was where we recommended that children who were non-responders to hbv vaccine be re-vaccinated; in addition, we have also recommended increasing the coverage of hbv vaccination in infants. however, just increasing the vaccination coverage may still lead to a high rate of failure because of non-response rates. finally, we agree with him about the effect of temperature on the failure of the vaccine as hbv vaccine is a temperature-sensitive biological product and exposure to heat shortens its shelf-life, while freezing causes irreversible loss of potency. thus we agree with his recommendation of the evaluation of an outside-thecold-chain vaccine delivery system in yemen. hassan a. al-shamahy department of medical microbiology, faculty of medicine & health sciences, sana’a university, yemen email: shmahe@yemen.net.ye references 1. alavian sm. ministry of health in iran is serious about controlling hepatitis b. hepat mon 2007; 7:3–5. 2. ministry of health (yemen). news letter 2007, 20:4–7. 3. ayerbe m c, pe’rez-rivilla a, icovahb group. assessment of long-term efficacy of hepatitis b vaccine. eur j epidemiol 2001; 17:151–6. osteopetrosis is a congenital clinical syndrome characterised by failure of osteoclasis resulting in impaired bone remodelling. the resultant bony defect leads to bone fragility (with a resultant propensity to fractures despite increased bone mass), haemopoietic insufficiency, nerve entrapment syndromes and growth impairment. osteopetrosis was first described by a german radiologist, albersschonberg in 1904.1 it is a heterogeneous disorder describing a cluster of clinical entities sharing a common pathogenic nexus in the osteoclast.2 this rare condition is often missed; it presents with multiple fractures and osteosclerotic bones of no known cause and without any prior traumatic events. three forms of the disease are diagnosed in infancy, childhood and adulthood.3 we hereby describe the first case from eastern africa of the adolescent-onset form of osteopetrosis. case report a 23 year-old lady presented in nairobi, kenya for admission with a 2-week history of headaches, general malaise and body weakness. over the 3 days prior to admission, she had gone blind and had to drop out of her college work in order to visit the hospital for care. six month prior to presentation she had been seen elsewhere for episodes of severe temporal headaches associated with some visual disturbance and nausea/vomiting. the diagnosis was optic neuritis and she was put on methylprednisolone for 6 months until her presentation with blindness. for the 4 months prior to admission, she noted increased weight; she also had a previous history of fractured tibia, fibula and humerus for which internal fixation had been done. on examination, she was pyrexic and had obvious cushinoid features. neurologically, she was fully awake with glasgow coma scale (gcs) scale of 15/15. the only findings wree those of quadriparesis (motor power 3, all limbs) and the optic fundii being oedematous with raised obscuring everted margins and bilateral optic atrophy. she had suprapubic tenderness and epigastric guarding with marked tenderness and hepatosplenomegaly. squ med j, august 2011, vol. 1, iss. 3, pp. 407-411, epub. 15th aug 11 submitted 7th jan 11 revision req. 15th feb 11, revision recd. 25th mar 11 accepted 3rd apr 11 1aga khan university hospital, nairobi, kenya; 2management sciences for health, nairobi, kenya; departments of 3medicine and 4surgery, school of medicine, university of nairobi, kenya. *corresponding author email: drmajidwangai@yahoo.co.uk ‹ø√÷]<ü �~íi<ª<ü � � }`jπ]<üíf÷]<·]眠     32    :مفتاح الكلمات abstract: late-onset visual loss is a complication of nerve entrapment and increased intracranial pressure. we hereby describe the first case in eastern africa. a 23 year-old lady presented with sudden blindness, headaches and body weakness. she had previously had treatment for multiple unexplained fractures. findings of optic nerve entrapment explained this blindness. this case highlights the need to have a high index of suspicion in cases of unexplained fractures with late-onset blindness. keywords: osteopetrosis; blindness; late onset; case report; eastern africa late-onset visual loss in osteopetrosis *abdul-majid wangai,1 sheila waa,1 maryam wangai,2 erastus amayo,3 oluoch olunya4 case report late-onset visual loss in osteopetrosis 408 | squ medical journal, august 2011, volume 11, issue 3 she had frontal bossing and nystagmus. during the physical examination she had a grand mal seizure. only limited investigations could be done due to the financial limitations of the family. the pertinent ones were as follows. the urine culture sensitivity parameters showing increased pus cells and white blood cells (wbc) at 20–40 /hpf; 48 hours incubation yielded a growth of escherichia coli organisms sensitive to all quinolines. a full haemogram showed haemoglobin of 9.5 gm and wbc count of 23 with a neutrophilic preponderance. the peripheral film showed a microcytic hypochromic picture. liver function tests showed raised transaminases. renal function tests, uric acid and thyroid function tests were all normal; however, the calcium levels were low at 1.8 mmol/l. serial blood sugars remained elevated and were controlled on a sliding scale of insulin therapy tailored to a glycaemic level of 4–7 mmol/l. the glycaemic excursions remained erratic throughout the admission period with sporadic high levels (26 mmol/l), but mainly an average of 16 mmol/l as the highest peak. glycated haemoglobin was elevated at 12%. both c reactive protein and d-dimers were elevated (15 and 23 respectively), but there were unreactive serum hiv antigens. a previous antibody test had been inconclusive. the electroencephalogram (eeg) reading was unremarkable. a lumbar puncture was done under aseptic condition at lumbar levels 3/4 regions with one pass. the cerebrospinal fluid (csf) was under pressure (240 mm of water) and appeared clear on observation. the csf sample was sent for cytology, biochemistry and microbiology testing. the only significant finding was an increased glucose level of 14 mmol/l. blood lipids were markedly elevated (both figure 1: computed tomography scans of head showing gross thickening and sclerosis of cranial vault and skull base. also noted is the internal acoustic meatal narrowing. figure 2: (a) thickening of base of skull causing narrowing of optic canal (arrow), and (b) compression of the optic nerve, resulting in bulbous dilatation of the retrobulbar optic nerve sheath and posterior scleral flattening (arrow). abdul-majid wangai, sheila waa, maryam wangai, erastus amayo, oluoch olunya case report | 409 total and low density lipoprotein cholesterol and triglyceride levels). blood cultures were done as part of the septic screening and no growth was obtained. anti-nuclear antibodies and factors, hepatitis a, b, c, and tuberculosis polymerase chain reaction tests were all negative. the chest radiograph showed generalised osteoporosis with a visible humerus fracture and metallic implant in situ. generalised bone osteosclerosis was noted. the abdominal ultrasound was normal with the exception of hepatosplenomegaly. no other abnormalities were seen. an enhanced computed tomography (ct) scan of the head showed gross hyperdensity of the cranial vault and the base of skull consistent with osteopetrosis [figure 1]. also visible was a narrowing of the optic canals and internal auditory meatus. a ct scan of the orbits showed bilateral dense sclerosis of the bones consistent with osteopetrosis with reduced optic canal circumference (4.4 mm x 3.7 mm right and 4.0 mm x 3.5 mm left) [figure 2]. magnetic resonance (mr) imaging showed multiple subacute infarcts with thickening of the orbital bones at the optic canal causing narrowing of the optic nerve [figure 3]. the optic nerve was tortuous causing the flattening of sclera posteriorly as well as bilateral bulbous dilatation of the retrobulbar optic nerve sheath. this had led to bilateral optic canal stenosis causing optic nerve atrophy. an mr angiography showed bilateral segmental narrowing of the distal vertebral arteries and proximal basilar artery and, to a milder extent, of both internal carotid arteries at the level of the siphon [figure 4]. focal narrowing of proximal right middle cerebral artery was also observed. this was a clear case of late-onset osteopetrosis with the long term steroid use associated conditions of cushing’s disease, diabetes, dyslipidaemia, peptic ulcer syndrome and osteoporosis. the osteopetrosis had caused anaemia, internal carotid compression and narrowing of vertebral arteries, cerebral infarcts, multiple fractures, and bilateral optic canal stenosis causing bilateral optic atrophy. the patient was treated with sodium valproate to prevent seizures, enteric-coated aspirin with clopidegrol, rosuvastatin, insulin, iron supplement, ciprofloxacin, sertralline, metformin, glimepiride, calcitriol supplement, oxybral, vitamin d, gamma interferon, erythropoietin, diclofenac and physiotherapy. calcitriol use is controversial, but in this index case it was also given for the assumed short-term benefit. the patient made a moderate improvement and was able to be ambulated with minimal support and could feed herself as well as figure 3: (a & b) axial flair images and (c & d) diffusion weighted images showing multiple subacute infarcts. skull thickening is also noted in the flair sequences (a & b ). late-onset visual loss in osteopetrosis 410 | squ medical journal, august 2011, volume 11, issue 3 undertake basic living activities unaided. an intraventricular catheter was placed showing an intracranial pressure of 32 mmhg. via the same catheter, the cerebral spinal fluid was drained until the levels reached 8 mmhg. the catheter was left in situ as further surgical options were being discussed with the patient’s family. the visual acuity remained poor (with only finger movements visible) and she thus became very depressed, as she had to discontinue college work and start learning braille. on antidepressants and psychosocial counselling support this depressive component of her condition improved well. unfortunately, the patient’s family was unable to pay for the much needed definitive optic canal decompression and cranial vault expansion surgery. the hospital did not have the ability at the time to offer complimentary care. hence a referral to the public hospital system was the only option. a surgical widening of the optic canal and decompression of the vertebral arteries was considered to be too dangerous in a public hospital due to their lack of equipment and level of postoperative care. consequently, the consensus was to abandon the option of surgical intervention and refer the patient to a public hospital for conservative and supportive management. figure 4: (a & b) magnetic resonance angiography source and reformatted images showing segmental narrowing of distal verterbral arteries (b, arrows) and proximal basilar arteries and to a milder extent of both internal carotid arteries at the level of the siphon. focal narrowing of the proximal right middle cerebral artery is also noted. discussion in 1999, baron reviewed what is known in cell biology of bone remodelling4 and the process of bone remodeling was further elucidated by plow et al.5 osteoblasts are of fibroblastic origin whose function is to synthesise bone matrix in new osteocytes. in contrast, osteoclasts are derived from macrophage/monocyte lineage and they function in solubilisation of bone mineral causing bone resorption. bone modelling is the process of changing bone shape and is prominent in childhood causing growth. remodelling, on the other hand, is the degradation of bone tissue from existing bony structures and replacing these with newly synthesised bony cells. osteopetrosis is the failure of modelling leading to improper growth and overgrowth of bony surfaces. this causes constriction of other structures, which leads to the myriad of conditions that constitute the disease process. the primary underlying defect in osteopetrosis is failure of the osteoclasts to reabsorb bone. the exact molecular or genetic defect and site of these mutations are largely unknown. osteopetrosis is thought to be autosomal dominant in adult-onset disease, but recessive in both infantileand intermediate-onset. the condition is often diagnosed incidentally (usually before age 1 year) due to the effects on other tissues affected by the bone modeling limitations of the disease. overall, the global incidence is unknown because no epidemiological studies have been conducted; however, one estimate suggested 1 case in 100,000–500,000 in the population.6 untreated, the infantile form results in death by the first abdul-majid wangai, sheila waa, maryam wangai, erastus amayo, oluoch olunya case report | 411 decade of life due to severe anaemia, resultant cardiac failure, bleeding and/or severe sepsis. in its adult form, osteopetrosis is usually a milder form of disease with good prognosis. from the history, our patient had the childhood form with the consequences of bony defects: neuropathies due to nerve entrapment (in our case optic canal stenosis/atrophy/blindness), frontal bossing and paraparesis; haemopoetic consequences (anaemia, hepatosplenomegaly), and infections (in our case urinary tract infection and septicaemia). medical care with high dose calcitriol (vitamin d) helps by stimulating dormant osteoclasts and thus stimulating bone resorption.7 although controversial, this treatment usually produces a dramatic result which unfortunately is not sustained after the therapy ceases. gamma interferon produces long-term benefits especially in combination with calcitriol. erythropoietin corrects anaemia, and corticosteroids have been used to correct the anaemia and stimulate bone resorption. in our index case, the patient was put on steroids for too long (6 months) prior to our seeing her and she had thus developed steroid therapy side effects. definitive treatment also involves novel approaches such as bone marrow transplants, although these are unavailable in the eastern africa region. in several case series where this has been possible, there has been proven success in altering the course of the disease; however, visual improvement rarely occurs.8 conclusion in osteopetrosis, surgical treatment is often necessary for the constellation of problems related to bony defects,9 usually to manage fractures. prior to presentation, our patient had had four surgeries for internal fixation of fractures. there is a definite benefit from intracranial surgery to decompress soft tissue (vessels and nerve) entrapment syndromes. such definitive optic canal decompression and cranial vault expansion surgery would have assisted this case. unfortunately, a surgical widening of the optic canal and decompressing the vertebral arteries was considered to be too dangerous in a public hospital with resource constraints, yet the parents could not afford the care at the private facility where she was admitted. we were unwilling to refer the patient for surgery in a public hospital. although the facilities are there, the surgical supplies, equipment and, more importantly, postsurgical care were wanting in a public facility. we thus had to defer surgery in the private hospital and refer her to a public health facility for conservative care. references 1. albers-schonberg h. roentgenbilder einer seltenen knochennerkrankung (x-rays of an unusual bone disease). munch med wochenschr 1904; 51:365. 2. stark z, savarirayan r. osteopetrosis. orphanet j rare dis 2009; 4:5. 3. tolar j. teitelbaunn sl, orcahrd pj. osteopetrosis. n engl j med 2004; 351:2839–49. 4. baron r. anatomy and ultrastructure of bone. in: favus mj, ed. primer on the metabolic bone diseases and disorders of mineral metabolism. 4th ed. philadelphia: lippincott williams & wilkins, 1999. pp. 3–10. 5. plow ef, qin j, byzova t. kindling the flame of integrin activation and function with kindlins. curr opin hematol 2009; 16:323–8. 6. beighton p, hamersma h, cremin bj. osteopetrosis in south africa. the benign, lethal and intermediate forms. s afr med j 1979; 55:659–65. 7. key l, carnes d, cole s. treatment of congenital osteopetrosis with high dose calcitriol. n engl j med 1984; 310:409–15. 8. kulkarni ml marakkanavar sn, sushanth s, pradeep n, ashok c, balaji md, et al. osteopetrosis with arnold chiari malformation type i and brain stem compression. indian j paediatr 2007; 74:412-5. 9. amstrong dg, newfield jt, gillespie r. orthopaedic management of osteopetrosis: results of a survey and review of the literature. j paed orthop 1999; 19:122–32. 1college of medicine and 2sharjah institute of medical research, university of sharjah, sharjah, united arab emirates *corresponding author e-mail: a7md13@gmail.com فتق أريب صفين مزمن عدمي األعراض أمحد نقد و مشوس نقد long-standing asymptomatic inguinoscrotal hernia *ahmed a. nugud1 and shmous nugud2 a 67-year-old man presented to the emergency department of kuwait hospital, sharjah, united arab emirates, in 2016 after multiple episodes of biliary vomiting with abdominal pain over the preceding 24 hours. he had had no bowel motion during the previous 10 days. on examination, he was found to have a long-standing asymptomatic inguinoscrotal mass which had first been noticed 30 years before; since then, it had been increasing in size and had recently become irreducible. he was retired and had a history of atrial fibrillation, hypertension, scoliosis, gout and peptic ulcer disease. in addition, he had smoked one pack of cigarettes daily for 25 years and sometimes drank alcohol socially. an abdominal x-ray revealed degenerative changes in his right hip [figure 1]. computed tomography showed a hugely dilated stomach with the distal part of the stomach herniating through the left inguinal canal to the scrotum, along with loops of the small bowel and sigmoid colon [figures 2 and 3]. the patient refused surgery and was subsequently lost to follow-up. comment hernias are usually treated with surgical repair in order to prevent possible complications (i.e. hernia incarceration or strangulation) which can lead to bowel obstruction and, eventually, to intestinal ischaemia.1 the estimated annual risk of a hernia is approximately three per thousand patients.1 direct inguinal hernias usually occur only among older men, as ageing and stress/strain weaken the abdominal muscles around the inguinal canal; in comparison, women rarely suffer from this type of hernia.2 a recent study by isik et al. interesting medical image sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e250–251, epub. 20 jun 17 submitted 2 jan 17 revision req. 5 feb 17; revision recd. 27 feb 17 accepted 16 mar 17 figure 1: pelvic x-ray of a 67-year-old man with a long-standing asymptomatic inguinoscrotal mass showing extensive inguinal herniation (arrow) in addition to degenerative changes in the right hip joint (asterisk). doi: 10.18295/squmj.2016.17.02.024 ahmed a. nugud and shmous nugud interesting medical image | e251 has suggested that inguinal hernias develop as a result of changes at the tissue level involving matrix metalloproteinases.3 the current case describes a patient with an asymptomatic inguinal hernia in which a large part of the abdominal content had herniated into the scrotum without strangulation. in such cases, surgery is indicated to relieve the symptoms, cosmetically correct the defect and to prevent future complications.4,5 references 1. fitzgibbons rj jr, giobbie-hurder a, gibbs jo, dunlop dd, reda dj, mccarthy m jr, et al. watchful waiting vs repair of inguinal hernia in minimally symptomatic men: a randomized clinical trial. jama 2006; 295:285–92. doi: 10.1001/jama. 295.3.285. 2. quintas ml, rodrigues cj, yoo jh, rodrigues junior aj. agerelated changes in the elastic fiber system of the interfoveolar ligament. rev hosp clin fac med sao paulo 2000; 55:83–6. doi: 10.1590/s0041-87812000000300003. 3. isik a, gursul c, peker k, aydın m, fırat d, yılmaz i̇. metalloproteinases and their inhibitors in patients with inguinal hernia. world j surg 2017 [epub ahead of print]. doi: 10.1007/s00268-016-3858-6. 4. fitzgibbons rj jr, ramanan b, arya s, turner sa, li x, gibbs jo, et al. long-term results of a randomized controlled trial of a nonoperative strategy (watchful waiting) for men with minimally symptomatic inguinal hernias. ann surg 2013; 258:508–15. doi: 10.1097/sla.0b013e3182a19725. 5. o’dwyer pj, norrie j, alani a, walker a, duffy f, horgan p. observation or operation for patients with an asymptomatic inguinal hernia: a randomized clinical trial. ann surg 2006; 244:167–73. doi: 10.1097/01.sla.0000217637.69699.ef. figure 2: horizontal computed tomography of a 67-year-old man with a long-standing asymptomatic inguinoscrotal mass showing large bowel loops passing into the scrotum (arrow). figure 3: three-dimensional reconstructed computed tomography of a 67-year-old man with a long-standing asymptomatic inguinoscrotal mass showing a hugely dilated fluid-filled stomach with the distal part of the stomach herniating through the left inguinal canal into the left scrotum. in addition, the stomach displaced the small bowel loops on the right side which, along with most of the sigmoid, descending and transverse colon, passed through the left inguinal canal. https://doi.org/10.1001/jama.295.3.285 https://doi.org/10.1001/jama.295.3.285 https://doi.org/10.1590/s0041-87812000000300003 https://doi.org/10.1007/s00268-016-3858-6 https://doi.org/10.1097/sla.0b013e3182a19725 https://doi.org/10.1097/01.sla.0000217637.69699.ef departments of 1family medicine & public health and 2medicine, sultan qaboos university hospital, muscat, oman; 3directorate general of primary health care, ministry of health, muscat, oman; departments of 4pharmacology & clinical pharmacy and 5medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mails: ial_zakwani@yahoo.com and azakwani@squ.edu.om عيادات عالج مرض الربو يف مراكز الرعاية الصحية األولية يف عمان هل حتدث فرقا؟ عبد العزيز املحرزي، �شو�شن بّدار، �شيخه ال�شيابية، �شفاء الكندية، اإبراهيم الزكواين، عمر الروا�ض abstract: objectives: this study aimed to determine the effect of newly established asthma clinics (acs) on asthma management at primary healthcare centres (phcs) in oman. methods: this retrospective crosssectional study was conducted between june 2011 and may 2012 in seven phcs in the seeb wilayat of muscat, oman. all ≥6-year-old asthmatic patients visiting these phcs during the study period were included. electronic medical records were reviewed to determine which clinical assessment and management components had been documented. results: a total of 452 asthmatic patients were included in the study. the mean age was 35 ± 21 years old (range: 6–95 years) and the majority (57%) were female. in total, 288 (64%) cases were managed at acs and 164 (36%) were managed at general clinics (gcs). significant differences were noted in the documentation of cases managed at acs compared to those at gcs, including history-taking information regarding signs and symptoms (91% versus 19%; p <0.001), trigger factors (79% versus 16%; p <0.001) and a history of atopy (81% versus 17%; p <0.001), smoking (61% versus 7%; p <0.001), asthma exacerbations (73% versus 10%; p <0.001) or previous admissions (63% versus 10%; p <0.001). furthermore, prescription rates of inhaled corticosteroids (72% versus 61%; p = 0.021) and short-acting β-agonists (93% versus 82%; p = 0.001) were significantly higher at acs compared to gcs. conclusion: overall, the findings indicated that acs have had a positive impact on asthma management at the studied phcs. keywords: asthma; disease management; patient compliance; medical history taking; medical records; documentation; oman. امللخ�ص: الهدف: حتديد اأثر عيادات الربو املن�شاأة حديثًا لعالج الربو يف مراكز الرعاية ال�شحية الأولية يف عمان. الطريقة: مت عمل حتليل رجعي، مقطعي عر�شي لل�شجالت الطبية الإلكرتونية ملر�شى الربو الذين تلقواالعالج بني يونيو 2011 و مايو 2012 يف �شبعة مراكز للرعاية ال�شحية الأولية يف ولية ال�شيب من حمافظة م�شقط. مت جتميع بيانات جميع مر�شى الربو الذين ترتاوح اأعمارهم من 6 �شنوات وما فوق، والذين مت عالجهم خالل ال�شنة الأوىل منذ ان�شاء عيادات الربو يف هذه املراكز ال�شحية. مت ت�شميم ا�شتمارة بيانات خا�شة م�شتوحاة من الدليل الوطني العماين للربو لتجميع البيانات و قد احتوت ال�شتمارة على الأق�شام الأربعة التالية: معلومات دميوغرافية، التاريخ املر�شي، مري�شا، 452 جمموعه ما درا�شة مت النتائج: املتغري. اأحادية الإح�شائيات با�شتخدام الدرا�شة حتليل اإجراء مت العالج. الطبي، التقييم مبتو�شط عمر 21 ± 35 )95-6( �شنة و )%57( منهم كانوا من الإناث.باملجموع 288 )%64( ع من احلالت مت عالجها يف عيادات الربو و 164 )%36( يف العيادات. كان هناك اختالف وا�شح يف توثيق التقييم الطبي بني الأطباء الذين عملوا يف عيادات الربو والأطباء الذين عملوا يف العيادات العامة يف نف�ض املراكز ال�شحية )اأعرا�ض املر�ض: %91 مقارنة ب %19؛ p >0.001(، )العوامل املهيجة: %79 مقارنة ب %16؛ p >0.001(، )تاريخ احل�شا�شية: %81 مقارنه ب %17؛ p >0.001(، )التدخني: %61 مقارنة ب %7؛ p >0.001(، )حالت تفاقم الربو: %73 مقارنة ب %10؛ p >0.001( اأو )الرتقيد ال�شابق: %63 مقارنة ب %10؛ p >0.001(. كان هناك اأي�شا اختالفات يف توثيق و�شف .)p = 0.001 ( وو�شف اأدوية مو�شع ال�شعب الهوائية )%93 مقارنة ب %82؛p = 0.021 اأدوية ا�شتن�شاق الكورتيزون )%72 مقارنة ب %61؛ اخلال�صة: ت�شري نتائج الدرا�شة اإىل الأثر الإيجابي لتاأ�شي�ض عيادات الربو يف مراكز الرعاية ال�شحية الأولية. الكلمات املفتاحية: الربو؛ عالج املر�ض؛ مواظبة املري�ض؛ ت�شجيل التاريخ الطبي؛ال�شجالت الطبية؛ التوثيق؛ عمان. asthma clinics in primary healthcare centres in oman do they make a difference? abdulaziz al-mahrezi,1 sawsan baddar,2 sheikha al-siyabi,3 safaa al-kindi,3 *ibrahim al-zakwani,4 omar al-rawas5 clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e137–142, epub. 9 sep 18 submitted 17 jan 18 revision req. 26 feb 18; revision recd. 7 mar 18 accepted 25 mar 18 advances in knowledge this study found that the management of asthmatic patients at newly established asthma clinics (acs) in oman resulted in significantly greater documentation of various clinical assessment and management components compared to cases seen at general clinics. application to patient care the findings of this study highlight the need for the establishment of more specialised acs in oman so as to improve management protocols and patient outcomes. doi: 10.18295/squmj.2018.18.02.003 asthma clinics in primary healthcare centres in oman do they make a difference? e138 | squ medical journal, may 2018, volume 18, issue 2 asthma is a common chronic disease and a major cause of morbidity worldwide.1–4 it is a challenging disease that requires a systematic approach as, if not appropriately controlled, the condition can have negative consequences for patients, their families and the healthcare system.5–8 physicians are expected to possess the essential knowledge and skills to continually assess, monitor and adjust management plans in order to prevent future exacerbations and achieve satisfactory asthma control.9 however, several studies have indicated that most children and adults do not have well controlled asthma and do not comply with recommended treatment regimens.10–14 previous research has also highlighted poor adherence to asthma care protocols and the insufficient documentation of various management components among general practitioners (gps).15–19 training health care providers, providing them with necessary resources and encouraging adherence to standardised manage ment protocols can lead to a significant improvement in asthma control and reduction in management costs.20–23 moreover, the introduction of nurse-led asthma clinics (acs) has been shown to be cost-effective, with similar clinical outcomes to cases managed at physician-led clinics.24 in oman, patients with acute complaints can receive medical care at any time at a network of primary healthcare centres (phcs). each phc has specialised clinics for diabetes, hypertension, antenatal and immun isation care and is staffed by one or two family physicians as well as gps from various medical backgrounds. however, the majority of asthmatics are managed by different physicians and at different clinics.19 in 2009, the second edition of the national asthma guidelines was released and made available to phc physicians; subsequently, a programme was launched to establish specialised acs in phcs in the muscat governorate in 2010.25,26 in addition, all phcs in the muscat governorate also have access to essential resources required to manage mild and moderate asthma cases, such as peak flow metres, spacer devices and asthma medications, including salbutamol inhalers with long acting or short-acting β-agonists (sabas), inhaled corti costeroids (ics), oral and intravenous corticosteroids and theophylline.19 in line with the national asthma guidelines, the main aim of the ac programme was to improve the management of asthmatic patients in phcs by training healthcare providers on the practical aspects of asthma management, including both theoretical and practical sessions on the management of asthmatic children and adults.25,26 however, subsequent research conducted in 2010 revealed no immediate improvement in asthma management following the launch of the national guidelines.19 therefore, the aim of this study was to compare asthma management between cases seen at the newly established acs and those at general clinics (gcs) within the same phcs. methods this retrospective cross-sectional study was conducted between june 2011 and may 2012 at seven phcs located in the seeb wilayat of muscat governorate, including al-koudh, al-shadi, al-seeb, al-mawa leh north, al-mawaleh, al-maabela north and al-maa bela south clinics. all of these acs were newly established at some point during the study period. all patients aged ≥6 years old with mild or moderate asthma-related symptoms visiting the phcs during this period were included in the study. however, patients who presented with acute asthmatic exacerbations requiring emergency management, those who were diagnosed with other chronic respiratory diseases and patients requiring only repeat prescriptions or receiving routine care at other healthcare institutions were excluded. the sample size was calculated to be 387 patients based on an average prevalence of 50% (range: 2–77%) of complete documentation of management components by gps in gcs and assuming the difference in documentation completion by gps in acs to be at least 10%.19 the alpha and power values were maintained at 5% and 80%, respectively. subsequently, at each of the seven phcs, the electronic medical records of 100 consecutive asthmatic patients were reviewed and included in the study. a data collection form derived from the national asthma guidelines was utilised.26 the information collected consisted of demographic characteristics and the type of clinic visited; in addition, various history-taking (i.e. signs and symptoms of asthma, trigger factors and a history of atopy, smoking, asthma exacerbations or previous admissions), clinical assessment (i.e. peak expiratory flow rate [pefr], level of asthma control, inhaler technique and patient compliance) and manage ment (i.e. prescription of ics, inhaled sabas and antihistamines and a scheduled date for the next follow-up appointment) components were analysed and marked as either documented or undocumented according to the contents of the records. documentation was considered complete if both positive and negative information was recorded (e.g. inability to use a peak flow metre, satisfactory inhaler technique, etc.) and considered incomplete if the required component was missing. so as to avoid bias, every phc was given a unique identification code and medical staff at the centres were not involved in the data collection process. abdulaziz al-mahrezi, sawsan baddar, sheikha al-siyabi, safaa al-kindi, ibrahim al-zakwani and omar al-rawas clinical and basic research | e139 the data were analysed using stata® data analysis and statistical software, version 13.1 (statacorp llc, college station, texas, usa). descriptive statistics were used to describe the data, with frequencies and percentages reported for categorical variables and means and standard deviations for continuous variables. medians and interquartile ranges were used to present non-normally distributed data. differences between the ac and gc groups were analysed using pearson’s chi-squared test or fisher’s exact test for categorical variables and the student’s t-test or mann-whitney u test for continuous variables, as appropriate. an a priori two-tailed level of significance was set at p ≤0.050. ethical approval for this study was obtained from the research and ethical review and approval committee of the directorate of primary health affairs, ministry of health, oman (#mh/dg ps/33). results a total of 452 patients were seen by 74 gps at the phcs during the study period. the overall mean age of the patients was 35 ± 21 years old (range: 6–95 years) and 256 (57%) were female. in total, 288 (64%) cases were managed at acs and 164 (36%) were managed at gcs. overall, 87 patients (19%) were managed by gps who worked only at the acs, 84 (19%) by gps who worked only at the gcs and 281 (62%) by gps who worked at both types of clinics. significant differences were noted in the documentation of clinical historytaking, assessment and management components for cases managed at acs and gcs. overall, physicians at acs were significantly more likely to complete history-taking documentation comp ared to those at gcs, including information regarding signs and symptoms (91% versus 19%; p <0.001), trigger factors (79% versus 16%; p <0.001) and a history of atopy (81% versus 17%; p <0.001), smoking (61% versus 7%; p <0.001), asthma exacerbations (73% versus 10%; p <0.001) or previous admissions (63% versus 10%; p <0.001) [figure 1]. moreover, documentation regarding the clinical assessment of the patient’s inhaler technique (88% versus 14%; p <0.001), asthma control (86% versus 19%; p <0.001), treatment compliance (86% versus 19%; p <0.001) and pefr (85% versus 12%; p <0.001) was significantly higher among cases managed at acs compared to those managed at gcs [figure 2]. in terms of management, cases managed at acs had significantly higher prescription rates of ics (72% versus 61%; p = 0.021) and inhaled sabas (93% versus 82%; p = 0.001) compared to gc cases. however, physicians at gcs were significantly more likely to prescribe antihistamines than physicians at acs (34% figure 2: chart showing the percentage of complete documentation of various clinical assessment components in the medical records of asthma cases seen at asthma clinics versus general clinics in seeb wilayat, oman (n = 452). acs = asthma clinics; gcs = general clinics; pefr = peak expiratory flow rate. figure 3: chart showing the frequency of prescriptions and follow-up appointments for asthma cases seen at asthma clinics versus general clinics in seeb wilayat, oman (n = 452). acs = asthma clinics; gcs = general clinics; ics = inhaled corticosteroids; sabas = short-acting β-agonists; fuas = follow-up appointments. figure 1: chart showing the percentage of complete documentation of various history-taking components in the medical records of asthma cases seen at asthma clinics versus general clinics in seeb wilayat, oman (n = 452). acs = asthma clinics; gcs = general clinics; hx = history. asthma clinics in primary healthcare centres in oman do they make a difference? e140 | squ medical journal, may 2018, volume 18, issue 2 versus 19%; p = 0.001). nevertheless, gps at acs were significantly more likely to schedule follow-up appointments (69% versus 39%; p = 0.001) [figure 3]. among the 281 cases seen by the 25 gps who worked at both types of clinics (i.e. acs and gcs), the documentation of all components was significantly greater when the physician worked at the ac rather than the gc (p <0.050 each), except for antihistamine prescription rates [table 1]. however, in gcs, no significant differences were noted in documentation completeness when comparing gps who worked only at gcs and those who worked at both types of clinics [table 2]. discussion overall, the current study found that the completeness of documentation of various history-taking, clinical assessment and management components was significantly greater among asthma cases seen at acs compared to those seen at gcs in selected phcs in muscat. this finding might be due to the intensive training that most physicians received prior to the establishment of the acs; alternatively, it could be due to the structured management approach followed at these clinics. previous research has indicated that the management of asthmatic patients is easier and more effective when gps are guided by a standardised management protocol.27 however, a study in oman reported that junior gps had greater documentation rates compared to junior pulmonologists, despite both groups following the same management protocol.28 a previous study comparing asthma management in two different settings within the same healthcare institution reported better documentation of symptoms by residents compared to medical officers (64% versus 35%).19 to the best of the authors’ knowledge, the current study is the first to assess differences in documentation among the same gps working in two different settings. both control and preventative medications are important in order to achieve better control of the disease and improve the quality of life of asthmatic patients. in this regard, ics are considered the cornerstone of management and should be prescribed to all asthmatic patients upon discharge.12,29 in this study, ics were prescribed to 72% and 61% of patients managed at acs and gcs, respectively. in contrast, arnold et al. found that only 47% of hospitalised adult asthmatic patients had received ics prior to table 1: documentation completeness of asthma cases seen by the same doctors working at both types of clinics* at asthma clinics versus general clinics in seeb wilayat, oman (n = 281) component documentation, n (%) p value cases seen at acs (n = 201) cases seen at gcs (n = 80) signs and symptoms 178 (89) 53 (66) <0.001 trigger factors 152 (76) 18 (23) <0.001 history of smoking 106 (53) 8 (10) <0.001 history of atopy 156 (78) 17 (21) <0.001 history of asthma exacerbations 142 (71) 10 (13) <0.001 history of previous admissions 130 (65) 10 (13) <0.001 pefr 166 (83) 12 (15) <0.001 compliance 173 (86) 15 (19) <0.001 inhaler technique 176 (88) 15 (19) <0.001 asthma control 173 (86) 15 (19) <0.001 ics prescription 147 (73) 52 (65) 0.046 saba prescription 186 (93) 66 (83) 0.009 antihistamine prescription 36 (18) 20 (25) 0.120 follow-up appointment 114 (57) 26 (33) 0.046 acs = asthma clinics; gcs = general clinics; pefr = peak expiratory flow rate; ics = inhaled corticosteroids; saba = short-acting β-agonist. *a total of 25 doctors worked at both types of clinics. table 2: documentation completeness of asthma cases seen at general clinics (gcs) by doctors working either only at gcs* or at both types of clinics† in seeb wilayat, oman (n = 164) component documentation, n (%) p value cases seen by doctors at both types of clinics (n = 84) cases seen by gc-only doctors (n = 80) signs and symptoms 50 (60) 53 (66) 0.421 trigger factors 13 (15) 18 (23) 0.319 history of smoking 4 (5) 8 (10) 0.239 history of atopy 11 (13) 17 (21) 0.213 history of asthma exacerbations 6 (7) 10 (13) 0.298 history of previous admissions 7 (8) 10 (13) 0.268 pefr 8 (10) 12 (15) 0.343 compliance 16 (19) 15 (19) 1.000 inhaler technique 8 (10) 15 (19) 0.116 asthma control 16 (19) 15 (19) 1.000 ics prescription 48 (57) 52 (65) 0.339 saba prescription 68 (81) 66 (83) 0.842 antihistamine prescription 36 (43) 20 (25) 0.120 follow-up appointment 37 (44) 26 (33) 0.150 gc = general clinic; pefr = peak expiratory flow rate; ics = inhaled corticosteroids; saba = short-acting β-agonist. *a total of 37 doctors worked only at gcs. †a total of 25 doctors worked at both types of clinics. abdulaziz al-mahrezi, sawsan baddar, sheikha al-siyabi, safaa al-kindi, ibrahim al-zakwani and omar al-rawas clinical and basic research | e141 admission, potentially causing asthma exacerbations and subsequent admission to the hospital.18 furthermore, in a study of 100 consecutive children admitted with episodes of acute asthma exacerbation in kuwait, none of the children were prescribed ics.30 in a tertiary care hospital in oman, a previous study of all asthmatic patients presenting with acute exacerbations reported that only 33% of patients had been prescribed ics in the three months prior to the episode; additionally, this medication was subsequently prescribed after admission to only 58% of cases.19 the same study also showed low levels of therapy-related documentation, with 73% of patients having no record of a post-nebulisation assessment and 23% having poor documentation of follow-up appointments—with the latter finding lower compared to those of the current study at both gcs (39%) and acs (69%).19 in the current study, when analysing the records of patients seen by gps who worked at both acs and gcs, the documentation of follow-up appointments was higher when patients were seen at the ac rather than the gc (57% versus 33%, respectively). a relative lack of consultation time could account for the differences in management components noted between the two types of clinics in the current study. generally, gps who work in gcs are expected to attend to more patients with a much wider range of conditions compared to those in acs. in addition, both nurses and pharmacists were included in the intensive training programme prior to the launch of the acs in muscat and thus expected to be able to assess a patient’s pefr, inhaler technique and asthma control without the assistance of a physician. consequently, the gps who worked in the acs may have had more time to assess patients and document the required information in their medical records.21,24 this could also explain the current study’s finding that the same doctors performed significantly differently when managing patients seen at acs and gcs, particularly in the documentation of most analysed components. moreover, without previous knowledge of the patient’s medical history, it can be extremely difficult for a physician seeing a patient for the first time to assess control levels and initiate an appropriate management plan. therefore, adequate documentation of such information is essential for good clinical practice and high-quality patient care. the current study is subject to certain limitations. due to the retrospective and cross-sectional nature of the study, these findings may only be relevant to a specific period of time. furthermore, this study mainly assessed the documentation of various clinical assessment and management components within the electronic medical records of asthma cases; while this is an essential part of clinical practice and generally expected to reflect greater clinical judgment and better patient outcomes, some doctors may have adequately documented their clinical and management notes but lacked other important clinical skills. it is also possible that some physicians may have performed specific assessment or history-taking actions, but not have documented these steps due to lack of time. however, it is important to highlight that the electronic medical record system used at many phcs in oman does not allow physicians to execute certain management actions without the documentation of specific information like prescriptions, referrals and follow-up appointments. it is therefore likely that the electronic records represent a true account of what was assessed or took place during the patient’s visit. conclusion the findings of this study demonstrate the positive impact of newly established acs at several phcs in muscat. specifically, the documentation of various assessment and management components in the electronic medical records of asthmatic patients was significantly better at acs compared to gcs. future studies are recommended to determine whether better documentation is correlated with better patient outcomes and whether management at acs has an effect on the patient’s level of asthma control. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. global asthma network. the global asthma report 2014. from: www.globalasthmareport.org/resources/global_asthma_ report_2014.pdf accessed: mar 2018. 2. world health organization. asthma. from: www.who.int/ mediacentre/factsheets/fs307/en/ accessed: mar 2018. 3. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. a relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirology 2003; 8:69–76. doi: 10. 1046/j.1440-1843.2003.00426.x. 4. al-rawas oa, al-riyami bm, al-kindy h, al-maniri aa, al-riyami aa. regional variation in the prevalence of asthma symptoms among omani school children: comparisons from two nationwide cross-sectional surveys six years apart. sultan qaboos univ med j 2008; 8:157–64. 5. al-busaidi n, soriano jb. asthma control in oman: national results within the asthma insights and reality in the gulf and the near east (airgne) study. sultan qaboos univ med j 2011; 11:45–51. https://doi.org/10.1046/j.1440-1843.2003.00426.x https://doi.org/10.1046/j.1440-1843.2003.00426.x asthma clinics in primary healthcare centres in oman do they make a difference? e142 | squ medical journal, may 2018, volume 18, issue 2 6. nunes c, pereira am, morais-almeida m. asthma costs and social impact. asthma res pract 2017; 3:1. doi: 10.1186/s40733016-0029-3. 7. masoli m, fabian d, holt s, beasley r; global initiative for asthma (gina) program. the global burden of asthma: executive summary of the gina dissemination committee report. allergy 2004; 59:469–78. doi: 10.1111/j.1398-9995.2004. 00526.x. 8. seung sj, mittmann n. urgent care costs of uncontrolled asthma in canada, 2004. can respir j 2005; 12:435–6. doi: 10. 1155/2005/478764. 9. partridge mr. living with a variable disease. pulm pharmacol ther 2002; 15:491–6. doi: 10.1006/pupt.2002.0399. 10. al busaidi n, al mukhaini s. level control of asthma patients in chest specialist clinics. oman med j 2009; 24:195–8. doi: 10.5001/omj.2009.38. 11. al-rawas oa, jayakrishnan b, ben abid f, george j, baddar sa, al-riyami bm. management and control of asthma in patients attending a specialist centre in oman. sultan qaboos univ med j 2009; 9:132–9. 12. peters sp, jones ca, haselkorn t, mink dr, valacer dj, weiss st. real-world evaluation of asthma control and treatment (react): findings from a national web-based survey. j allergy clin immunol 2007; 119:1454–61. doi: 10.1016/j.jaci. 2007.03.022. 13. fitzgerald d. non-compliance in adolescents with chronic lung disease: causative factors and practical approach. paediatr respir rev 2001; 2:260–7. doi: 10.1053/prrv.2001.0149. 14. baddar s, jayakrishnan b, al-rawas oa. asthma control: importance of compliance and inhaler technique assessments. j asthma 2014; 51:429–34. doi: 10.3109/02770903.2013.871558. 15. meng yy, leung km, berkbigler d, halbert rj, legorreta ap. compliance with us asthma management guidelines and spec ialty care: a regional variation or national concern? j eval clin pract 1999; 5:213–21. doi: 10.1046/j.1365-2753.1999.00177.x. 16. finkelstein ja, lozano p, shulruff r, inui ts, soumerai sb, ng m, et al. self-reported physician practices for children with asthma: are national guidelines followed? pediatrics 2000; 106:886–96. 17. baddar s, jayakrishnan b, al-rawas o, george j, al-zeedy k. is clinical judgment of asthma control adequate? a prospective survey in a tertiary hospital pulmonary clinic. sultan qaboos univ med j 2013; 13:63–8. 18. arnold lb, usery jb, finch ck, wallace jl, deaton pr, self th. inadequate documentation of asthma management in hospitalized adult patients. south med j 2009; 102:510–14. doi: 10.10 97/smj.0b013e31819ecb03. 19. baddar sa, al-ismaili ai, al-taie ma, al-mahrezi am, al-rawas oa. documentation of the management of asthma exacerbation in adults by primary health care physicians in a teaching hospital in oman. sultan qaboos univ med j 2010; 10:335–40. 20. cabana md, slish kk, evans d, mellins rb, brown rw, lin x, et al. impact of physician asthma care education on patient outcomes. health educ behav 2014; 41:509–17. doi: 10.1177/ 1090198114547510. 21. guevara jp, wolf fm, grum cm, clark nm. effects of educational interventions for self management of asthma in children and adolescents: systematic review and meta-analysis. bmj 2003; 326:1308–9. doi: 10.1136/bmj.326.7402.1308. 22. suh dc, shin sk, okpara i, voytovich rm, zimmerman a. impact of a targeted asthma intervention program on treatment costs in patients with asthma. am j manag care 2001; 7:897–906. 23. elward k, blackburn b, peterson le, greenawald m, hagen md. improving quality of care and guideline adherence for asthma through a group self-assessment module. j am board fam med 2014; 27:391–8. doi: 10.3122/jabfm.2014.03.130241. 24. kamps aw, roorda rj, kimpen jl, overgoor-van de groes aw, van helsdingen-peek lc, brand pl. impact of nurse-led outpatient management of children with asthma on healthcare resource utilisation and costs. eur respir j 2004; 23:304–9. doi: 10.1183/09031936.03.00052203. 25. baddar s. asthma clinic programme at primary health care level. abstract in: oman thoracic conference 2013: the oman respiratory society and sultan qaboos university. sultan qaboos univ med j 2014; 14:e418. 26. oman ministry of health. guidelines for the manag ement of asthma: second edition, 2009. from: www.moh.gov. o m / d o c u m e n t s / 2 7 2 9 2 8 / 1 3 1 4 7 6 3 / g u i d e l i n e s + f o r + management+of+asthma+second+edition+2009+%281%29.pdf/ c5e8ff0c-d937-4c57-bc2b-d225c26be727 accessed: mar 2018. 27. ting s. multicolored simplified asthma guideline reminder (msagr) for better adherence to national/global asthma guide lines. ann allergy asthma immunol 2002; 88:326–30. doi: 10. 1016/s1081-1206(10)62016-9. 28. baddar s, worthing ea, al-rawas oa, osman y, al-riyami bm. compliance of physicians with documentation of an asthma management protocol. respir care 2006; 51:1432–40. 29. global initiative for asthma. 2017 gina report: global strategy for asthma management and prevention. from: https:// ginasthma.org/wp-content/uploads/2016/01/wms-gina2017-main-report-tracked-changes-for-archive.pdf accessed: mar 2018. 30. hijazi z, abdulmalek ak, al-taweel f, al-shareda s. hospital management of children with acute asthma exacerbations in kuwait: adherence to international guidelines. med princ pract 2002; 11:126–30. doi: 10.1159/000063244. https://doi.org/10.1186/s40733-016-0029-3 https://doi.org/10.1186/s40733-016-0029-3 https://doi.org/10.1111/j.1398-9995.2004.00526.x https://doi.org/10.1111/j.1398-9995.2004.00526.x https://doi.org/10.1155/2005/478764 https://doi.org/10.1155/2005/478764 https://doi.org/10.1006/pupt.2002.0399 https://doi.org/10.5001/omj.2009.38 https://doi.org/10.1016/j.jaci.2007.03.022 https://doi.org/10.1016/j.jaci.2007.03.022 https://doi.org/10.1053/prrv.2001.0149 https://doi.org/10.3109/02770903.2013.871558 https://doi.org/10.1046/j.1365-2753.1999.00177.x https://doi.org/10.1097/smj.0b013e31819ecb03 https://doi.org/10.1097/smj.0b013e31819ecb03 https://doi.org/10.1177/1090198114547510 https://doi.org/10.1177/1090198114547510 https://doi.org/10.1136/bmj.326.7402.1308 https://doi.org/10.3122/jabfm.2014.03.130241 https://doi.org/10.1183/09031936.03.00052203 https://doi.org/10.1016/s1081-1206%2810%2962016-9 https://doi.org/10.1016/s1081-1206%2810%2962016-9 https://doi.org/10.1159/000063244 the use of small doses of midazolam and fentanyl is standard practice during day case surgery for providing sedation and analgaesia during minor procedures under local anaesthetic infiltration. although both midazolam and fentanyl are known to produce respiratory depression in the occasional patient,1 complete apnea with total loss of train-of-four response on peripheral nerve stimulation has, as yet, been unreported. we here report a very unusual case of midazolam and fentanyl induced apnea with total skeletal muscle paralysis in a patient undergoing a small lipoma excision under local anaesthesia. case report a 44 year-old, american society of anesthesiologist class i (asa i), female patient weighing 62 kg was scheduled for elective excision of a small lipoma of the left thigh in the supine position at khoula tertiary hospital, oman. the patient had undergone uneventful general anaesthesia on three previous occasions. her last anaesthetic exposure was for lower segment caesarean section 9 years previously. we could not elicit any details about the nature of the anaesthetic used from her file or computer records. no abnormality was detected during the clinical examination and all her investigations were within acceptable limits. her preoperative heart rate (hr) and blood pressure (bp) were 78/min and squ med j, august 2010, vol. 10, iss. 2, pp. 255-261, epub. 19th jun 10 submitted: 26th aug 09 revision req. 23rd nov 09, revision recd. 2nd jan 10 accepted: 3rd feb 10 department of anesthesia & icu, khoula hospital, muscat, oman *corresponding author email: nassn@omantel.net.om توقف التنفس والشلل الكامل للعضالت بتأثري عقاري الفنتانيل وامليدازوالم أثناء إجراء اجلراحة يف الرعاية اليومية تقرير حالة را�شد خان، ناري�س كول، نيال كنثان، بنوفيال هريهارا عملية لإجراء الأمريكية التخدير اأطباء جمعية ح�شب الأوىل الدرجة على ت�شنف 44 �شنة العمر من تبلغ مري�شة حالة ت�شجيل مت امللخ�ص: اإ�شتئ�شال ورم �شحمي �شغري من الفخذ الأي�رش. حدث توقف عن التنف�س مع �شلل كامل للع�شالت اإ�شتغرق قرابة 90 دقيقة ثم ت�شجيله عن طريق والتهدئة. الأمل ت�شكني لغر�س بالوريد جهاز حتفيز الأع�شاب بعد اإعطاء املري�شة جرعة ميدازولم )1 ملجم( وقينتانيل )100 مايكروجم( بعد ذلك كانت الإفاقة طبيعية، ومل تكن هناك اأية عالقة بني ال�شبب والتاأثري بني العقاقري والإ�شتجابة غري الطبيعية ملفعولها. مفتاح الكلمات: جراحة الرعاية اليومية ، ميد ازولم ،فنتانيل ، توقف التنف�س ، �شلل الع�شالت ، تقرير حالة ، عمان. abstract: we report a 44 year-old, american society of anesthesiologist class i (asa i), female patient scheduled for elective excision of a small lipoma of the left thigh. she went into a 90 minute apnea and complete muscle paralysis as evidenced by the absence of all stimulatory responses by a peripheral nerve stimulator after receiving midazolam (1.0 mg) and fentanyl (100 µg) intravenously for sedation and analgaesia. the patient made an uneventful recovery after 90 minutes. no cause and effect relationship could be established between the administered drugs and this unusual response. keywords: day case surgery; midazolam, fentanyl; apnea; muscle paralysis; case report; oman fentanyl and midazolam induced respiratory arrest and neuromuscular paralysis during day care surgery a case report rashid m khan, *naresh kaul, punnuvella h neelakanthan case report fentanyl and midazolam induced respiratory arrest and neuromuscular paralysis during day care surgery a case report 256 | squ medical journal, august 2010, volume 10, issue 2 126/64 mmhg respectively. on the day of surgery, the patient received 7.5 mg of midazolam orally at 8:30am. the patient was taken to the operating theatre at 10:00am. after initiating non-invasive blood pressure, cardioscopic electrocardiography, peripheral oxygen saturation monitoring and intravenous (iv) infusion, the patient was administered 1.0 mg of midazolam and 50 + 50 µg of fentanyl iv. a venturi mask (35% o2) was applied and the surgeon told to commence cleaning the surgical site. over the next 3-4 minutes, the patient’s respiratory pattern gradually changed, the oxygen saturation started falling and before the venturi mask was removed, she had stopped breathing. her respiration was immediately supported by positive pressure mask ventilation. our immediate diagnosis was respiratory depression secondary to midazolam and/or fentanyl, especially keeping in mind the possible cumulative effect of 7.5 mg oral (premedication) and 1.0 mg intravenous midazolam. the patient’s pupils were 2 mm and reactive to light. two doses of naloxone (an opioid antagonist) 100 + 100 µg were administered 2–3 minutes apart. no positive response was noted. while flumazenil (a benzodiazepine antagonist) was being loaded and diluted for possible administration, a peripheral nerve stimulator (pns) was applied for recording the level of neuromuscular blockade. surprisingly, there was complete absence of response to train-of-four (tof), double burst stimulation (dbs) and post tetanic count (ptc). at this juncture, the index of consciousness (ioc) monitor (ioc – viewtm, version 2.1, morpheus medical, barcelona) was attached to the patient and the depth of sedation was noted to be 57. the ioc level transiently increased to 62 after the administration of 0.2 mg of flumazenil and subsequent doses of 0.1mg each to a total of 1.0 mg. during this brief period of 5-7 minutes, patient was noted to make shallow respiratory efforts. surprisingly, the patient showed no response to tof stimulation which was kept on a 12-second repeat mode. she went back to apnea thereafter. it was now decided to withhold all drug administration, pass a #4 laryngeal mask airway (lma) and commence intermittent positive pressure ventilation with a tidal volume of 400 ml, respiratory rate of 12/min and a mixture of 2:l each of air and oxygen. the patient continued to show absence of any response to peripheral nerve stimulation over the next 60 minutes. during this period, her ioc level fluctuated between 54 and 67, bp and hr varied between 116/64–144/84 mmhg and 74–94/min respectively. this range of ioc suggested a borderline case between anaesthesia and a deep level of sedation (ioc level 99 = awake; 80 = sedation; 60-40 = general anesthesia; 0 = isoelectric). oxygen saturation remained between 98–100% and end tidal co2 38–46 mmhg. nearly 75 minutes after the administration of midazolam and fentanyl, the patient started making weak respiratory efforts and attempted to open her eyes. over the next 30 minutes, she started breathing adequately (tidal volume 300–360 ml). peripheral nerve stimulation now showed a weak response to tof without a fade, but demonstrated a better response to dbs. her ioc level was now 87. the lma was soon removed on the patient’s request and she was transferred to the recovery room for further observation. a fully restored tof stimulation response was documented in the recovery room. unfortunately, during the episode, no blood samples were collected to analyse drug levels to rule out any drug error. viewed in retrospect, this should have been done. with the approval of the attending anaesthesiologist, the surgeon removed the small lipoma after local infiltration with 5 ml of 0.25% bupivacaine. the surgery lasted 15 minutes. the patient made an uneventful recovery and was discharged from hospital the next day. a detailed interview with the patient in the ward afterwards brought to light her tendency to feel weak and exhausted on returning from school where she was a teacher. unfortunately, no evidence of myasthenia gravis or other skeletal muscle abnormalities could be detected as the patient refused further investigations. discussion midazolam is frequently used in combination with opioids for anaesthesia and sedation.2 though respiratory arrest after low dose fentanyl alone has been rarely reported,3 depression is most common when combined with a sedating agent such as midazolam or propofol.4,5 our patient had also received a combination of midazolam and fentanyl 3-4 minutes before she went into respiratory arrest. the duration of the respiratory depression was over one hour. this unexpectedly long duration of respiratory depression may be explained by rashid m khan, naresh kaul and punnuvella h neelakanthan case report | 257 the fact that fentanyl is known to competitively inhibit metabolism of midazolam by cytochrome p450 3a4 (cyp3a4) activity2 leading to prolonged apnea.1 however the most interesting aspect of this case was the complete absence of neuromuscular junction activity as evident from total loss of tof, dbs and ptc response by electrical stimulation with pns. inadvertent administration of muscle relaxants was ruled out as only the two drugs in question (midazolam and fentanyl) were prepared and administered before she went into apnea. as per operating theatre policy, all syringes of previous cases are always discarded. the fentanyl was undiluted, while 1 ml midazolam containing 5 mg was diluted to 1 mg/ml in distilled water. no other drug was administered which could have led to muscle paralysis and loss of pns stimulation response. moreover, had she received an accidental administration of muscle relaxant, a transient restoration of shallow respiration in response to flumazenil would not have been possible. however, in any future case, we would advocate collecting a blood sample to check blood levels for any drug error. this leads us to an unexplored area of a possible interaction between the two drugs in question, especially midazolam, with any form of myopathy which the patient might have had. however, an exhaustive search of literature yielded no documentation or reference to interactions with midazolam and any form of myopathy leading to muscle paralysis. midazolam by itself is known to possess a mild muscle-relaxant property, but it is mediated at the spinal cord level, not at the neuromuscular junction.6 interestingly, fujii, uemura and toyooka7,8 have reported midazolam induced diaphragmatic dysfunction in dogs in the form of reduced contractility and inhibited electrical activity, but how far this finding can be extrapolated to human beings is uncertain. conclusion the present case highlights the possibility that monitored anaesthesia care under sedation (midazolam) and analgaesia (fentanyl) for minor surgical procedure under local infiltration anesthesia may produce profound central nervous system depression with resultant loss of consciousness, diaphragmatic dysfunction, and muscle tone necessitating respiratory support until full recovery. references 1. bailey pl, pace nl, ashburn ma, moll jwb, east ka, stanley th. frequent hypoxemia and apnea after sedation with midazolam and fentanyl. anesthesiology 1990; 73:826–30. 2. hase i, oda y, tanaka k, mizutani k, nakamoto t, asada a. i.v. fentanyl decreases the clearance of midazolam. br j anaesth 1997; 79:740–3. 3. topacoglu h, karcioglu o, cimrin ah, arnold j. respiratory arrest after low-dose fentanyl. ann saudi med 2005; 25:508–10. 4. jagoda as, campbell k karas s. clinical policy for procedural sedation and analgesia in the emergency department. ann emerg med 1998; 31:663–7. 5. proudfoot j. analgesia, anesthesia, and conscious sedation. emerg med clin north am 1995; 13:357– 79. 6. morgan jr ge, mikhail ms, murray mj. nonvolatile anesthetic agents. in: clinical anesthesiology. 4th ed. philadelphia: mcgraw-hill companies, inc., 2006. 7. fujii y, uemura a, toyooka h. midazolam-induced muscle dysfunction and its recovery in fatigued diaphragm in dogs. anesth analg 2003; 97:755–8. 8. fujii y, uemura a, toyooka h. flumazenil recovers diaphragm muscle dysfunction caused by midazolam in dogs. anesth analg 2002; 95:944–7. departments of 1maternal & child health nursing and 4fundamentals & administration, college of nursing and 2department of family medicine, college of medicine, sultan qaboos university, muscat, oman; 3department of sociology, college of arts & social sciences, yarmouk university, irbid, jordan *corresponding author e-mails: esra@squ.edu.om and emanursing@yahoo.com تطوير والتحقق من صحة برنامج تعليم صحي خاص بسرطان الثدي مصمم خصيصا لتثقيف املرأة العربية اإ�رشاء من�سور اخل�ساونة، يحيى الفار�سي، فايز ال�سمادي، مايكل ليوكاديو abstract: objectives: this study aimed to develop and validate a health education programme to encourage breast cancer awareness and early detection behaviours among arab women. methods: this study took place between december 2015 and march 2016. the enabling systems raising awareness model was used to develop a breast cancer health education programme which was subsequently implemented by trained health educators at three female-only fitness clubs in muscat, oman. breast cancer knowledge among 53 women was assessed using the breast module of the cancer awareness measure before and after each health education session. overall preand post-session knowledge scores were then compared. additionally, three focus group discussions were conducted with 10 participants from each location. thematic analysis was used to analyse the transcribed discussions and collect feedback on the programme. results: the health education sessions resulted in a statistically significant increase in overall mean knowledge scores (p <0.001). participants also reported significantly improved intentions to undertake early detection practices (p <0.001). the focus group discussions yielded distinct themes and valuable feedback which can be utilised in the future to create an improved version of the programme. conclusion: while the health education programme significantly improved breast cancer and early detection knowledge among a cohort of arab women, it still required critical improvements in terms of structure and administration. additional studies are required in order to evaluate long-term behavioural outcomes resulting from the improved programme. keywords: breast cancer; preventive health services; health behavior; health education; health promotion; validation studies; oman. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل تطوير برنامج التثقيف ال�سحي والتحقق من �سحته من اأجل رفع الوعي ب�رشطان الثدي و�سلوك منوذج ا�ستخدام مت .2016 ومار�س 2015 دي�سمرب بني ما الفرتة يف الدرا�سة هذه اأجريت الطريقة: العربيات. الن�ساء لدى املبكر الك�سف التوعية بالنظم التمكينية لتطوير برنامج التثقيف ال�سحي ل�رشطان الثدي والذي مت تنفيذه الحقا من قبل مثقفني �سحيني مدربني يف ثالث نوادي للياقة البدنية لل�سيدات يف م�سقط، عمان. مت تقييم معلومات الن�ساء حول �رشطان الثدي ل 53 امراأة با�ستخدام جم�سم للثدي وبعدها. الدورة قبل للمعرفة العامة النتائج مقارنة متت ثم ال�سحي. التثقيف دورات من دورة كل وبعد قبل بال�رشطان الوعي لقيا�س املناق�سات لتحليل املو�سوعي التحليل وا�ستخدم موقع. كل من م�ساركني 10 مع جماعية مناق�سات ثالث اأجريت ذلك، اإىل وباالإ�سافة درجات متو�سط يف اإح�سائية داللة ذات زيادة عن ال�سحي التثقيف جل�سات اأ�سفرت النتائج: الربنامج. على التعليقات وجمع املكتوبة املعرفة )p <0.001(. كما اأفاد امل�ساركون بتح�سن كبري يف رغباتهم الإجراء ممار�سات الك�سف املبكر )p <0.001(. وقد اأظهرت مناق�سات جمموعات الرتكيز عن موا�سيع متميزة وردود فعل قيمة، ميكن ا�ستخدامها يف امل�ستقبل الإن�ساء ن�سخة حم�سنة من الربنامج. اخلال�صة: يف حني اأن برنامج م�ستوى الوعي ال�سحي قد حت�سن ب�سكل كبري وكذلك م�ستوى املعرفة ب�رشطان الثدي والك�سف املبكر لدى الن�ساء، اإال اأنه يلزم اإجراء درا�سات اإ�سافية لتقييم النتائج ال�سلوكية الطويلة االأجل للربنامج املح�سن. درا�سات ال�سحية؛ التوعية ال�سحي؛ التثقيف ال�سحي؛ الت�رشف الوقائية؛ ال�سحية اخلدمات الثدي؛ �رشطان املفتاحية: الكلمات حتقيقية؛ عمان. development and validation of a culturally-tailored breast cancer health education programme for arab women *esra alkhasawneh,1 yahya al-farsi,2 fayez al-simadi,3 michael leocadio4 clinical & basic research sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e181–190, epub. 20 jun 17 submitted 3 may 16 revisions req. 21 jun & 22 sep 16; revisions recd. 8 aug & 11 oct 16 accepted 13 oct 16 advances in knowledge this study developed and validated a breast cancer health education programme for use among arab women. the health education programme significantly improved overall knowledge of breast cancer risk factors, symptoms and early detection methods among a cohort of omani women. the findings of this study resulted in valuable qualitative feedback to be used in the development of an improved version of the programme; this improved version could then potentially be implemented nationwide in oman. application to patient care enhanced awareness of breast health among omani women may help to improve early detection of breast cancer and the use of early detection services such as mammography. doi: 10.18295/squmj.2016.17.02.008 development and validation of a culturally-tailored breast cancer health education programme for arab women e182 | squ medical journal, may 2017, volume 17, issue 2 breast cancer is the most common causeof cancer-related deaths among women world-wide.1 in addition, the burden of breast cancer is higher in less developed countries, constituting 58–65% of all breast cancer-related deaths.1,2 in oman, women are diagnosed with breast cancer at a younger age and at a more advanced stage compared to developed countries.3,4 nevertheless, breast cancer awareness remains low in arab societies, mostly due to fear, modesty, lack of health education, limited access to breast health services and common misconceptions.3,5 in terms of awareness, omani women show similar characteristics in comparison to those from other arab countries, such as qatar, saudi arabia and jordan.6–10 a previous qualitative study has highlighted various factors that influence breast cancer awareness among omani women and the desire among this population for enhanced breast cancer information systems and programmes.6 various studies have recognised the need for breast cancer health education programmes.11–15 however, it is necessary to address barriers to breast cancer awareness and early detection in the context of the local population’s presiding social and cultural beliefs.9,10,16,17 health education interventions therefore need to be culturally and linguistically tailored, while still portraying breast cancer as a treatable disease.14,18–20 learning strategies, activities and tools should also be aligned with the local cultural context.21,22 in bangladesh, china, saudi arabia, egypt and iran, health education campaigns have resulted in a significant positive impact on breast cancer awareness levels and early detection practices, with improved awareness, positive health beliefs and increased early detection activities and suitable follow-up practices after abnormal examination results.12,23–26 the enabling systems raising awareness (esra) model is based on the following four premises: (1) that individuals can actively regulate their own behaviours; (2) that they interact with the environment on multiple biopsychosocial levels, eventually shaping and being shaped by the environment over time; (3) that health practitioners greatly affect individuals by exerting influence on them; and (4) that self-initiated reconstruction or empowerment of person-environment interactive patterns is essential to change behaviours.6,27 additionally, the esra model emphasises specific systems which either enable or inhibit arab women in terms of health awareness. according to modifiability, these include personal (e.g. cultural, religious or fatalistic beliefs), interpersonal (e.g. familial or environmental factors) and healthcare-related systems [table 1].6 furthermore, the model highlights the complete influence of external enabling systems on each other, known as the “pouring-in” process, while the influence of omani women across systems to initiate interventions to increase awareness is an “out-pouring” process (i.e. an empowering internal enabling system). as such, each arab woman is considered an instrument or enabler for other women in the advocacy for breast cancer awareness [figure 1].6 this framework therefore suggests a sustainable method of improving breast cancer awareness in arab countries, in that public health programmes can use existing enabling systems to improve awareness levels among groups of women, after which empowered women can then spread their knowledge to other women, resulting in a multiplier effect. this study aimed to develop and validate a breast cancer health education programme for arab women based on the esra model.6 an asset-mapping exercise prior to development of the programme did not identify any existing formal or standardised breast health programmes that had been previously implemented in oman. it is hoped that the findings of this study will enable public health practitioners, table 1: systems, concepts and relevant content objectives of the enabling systems of raising awareness breast cancer model6 system concepts content objectives cultural/religious/fatalistic •self-empowerment by addressing sociocultural factors seen as facilitators/ barriers to breast cancer awareness •cancer fatalism •encourage familiarity and comfort with breast selfexamination, i.e. “knowing your own breasts” •stress that breast cancer can be cured if detected early and that a diagnosis of breast cancer is not a death sentence personal/familial/environmental •social stigma/taboos associated with breast cancer •highlight the importance of breast cancer awareness in family and society •encourage awareness of breast cancer risk factors, signs and symptoms •stress the importance of taking immediate and appropriate action when the risk of breast cancer is high •emphasise the prioritisation of one’s own health healthcare-related •familiarity with early detection and medical resources •availability of local resources •accessibility of local resources •describe the different forms of early detection practices •disclose provisions for breast health and early detection in the local healthcare system esra alkhasawneh, yahya al-farsi, fayez al-simadi and michael leocadio clinical and basic research | e183 health professionals and policy-makers in oman to better understand the role of health education in breast cancer awareness and early detection. in addition, the results of this study may guide similar health education models for future breast cancer-related programmes in arab populations. methods this study took place between december 2015 and march 2016. based on the previously described esra model, a breast cancer health education programme was developed in both arabic and english.6 primary and secondary research was conducted on breast cancer education programmes and barriers to breast cancer awareness and early detection among omani women. three academics from sultan qaboos university (squ), muscat, oman, and the university of jordan (uj), amman, jordan, who were familiar with breast cancer awareness programmes were consulted. focus group discussions were held with omani women recruited from three female-only fitness clubs regarding local factors that influence breast cancer awareness and early detection levels. in addition, four health professionals were interviewed regarding breast cancer screening and diagnosis services at local health facilities. all content, materials, learning strategies and evaluation techniques utilised in the programme were designed in consultation with these experts. a literature review was undertaken of previously published evidence-based breast cancer health education programmes and recent studies assessing breast cancer awareness levels among arab women.3,4,6,28,29 the development of the programme was an iterative process, leading to multiple versions of the programme until the final version was ready for implementation. the content was reviewed to improve its linguistic and cultural sensitivity as well as the visual design, content, flow of ideas and structure of the programme. in particular, the health education programme was designed to desensitise the notion of examining/touching breasts by emphasising that breasts are an important part of the body and should be treated with the same respect as other body parts. as all breasts are different, it was necessary to stress the importance of “knowing your own breasts” so that each woman would be able to recognise any potential abnormalities, for instance by noting changes in the appearance or texture of their breasts. the health education programme was also designed to be as interactive as possible. each section started with a few open-ended questions to initiate discussion, followed by information to be shared by the health educator. an effective learning activity called the ‘myth and fact game’ was developed, which aimed to dispel common local misconceptions such as “breast cancer cannot be treated”, “breast cancer is always painful”, “a small lump in your breast can be ignored” and “the evil eye is a risk factor for breast cancer”.6 the content of the programme was designed to be understandable to a layperson with no prior medical knowledge and included breast cancer statistics (e.g. incidence rates) and knowledge regarding the definition of the disease, specific diseases stage, risk factors, signs/symptoms, early detection practices and treatments [table 2]. each section of the programme used specific learning strategies that suited the topic being discussed. some sections were explained using pictographs, as facts presented with pictures are not only easily understandable but also better retained.30 cultural, religious or fatalistic beliefs and interpersonal or familial factors affecting breast health were addressed during an open discussion, as these topics required more in-depth interaction with the participants. images and a breast model were used figure 1: diagram of the enabling systems of raising awareness (esra) breast cancer model. note the increasing modifiability of the factors moving closer towards the centre of the model. reproduced with permission from alkhasawneh e, siddiqui st, leocadio m, seshan v, al-farsi y, al-moundhri ms. i do not even say “it”: a mixed methods study on breast cancer awareness of omani women.6 development and validation of a culturally-tailored breast cancer health education programme for arab women e184 | squ medical journal, may 2017, volume 17, issue 2 to demonstrate the appearance and texture of breast changes. in line with the esra model, the health education programme ended with the participants taking part in a vocal and signed pledge to prioritise their breast health and promote breast cancer awareness at the personal, familial and community levels.6 the entire programme was designed to be delivered via a printed handout with an accompanying multimedia powerpoint presentation, version 2010 (microsoft corp., redmond, washington, usa). four omani nursing students were trained to deliver the health education programme using a training manual developed by the research team. these trainee health educators were bilingual in arabic and english and their nationality ensured that cultural sensitivity was maintained. the trainee health educators underwent 10 hours of training on the content of the programme, the research method being used, research ethics, various strategies and activities for delivering the programme and effective public speaking skills. the final training session included rehearsals and role-playing exercises to gauge the effectiveness of the training, ensure standardised delivery of the programme and simulate potential issues and questions. rehearsals were attended by the research team, an oncologist and nursing faculty members specialising in community health. the attendees included both arabic speakers to judge content delivery and non-arabic speakers to judge body language and the method of delivery. during the final training session, the trainee health educators were explicitly instructed to avoid behaviours that could influence the results of the study, including providing additional explanations or clarifications not included in the content of the programme. four health education sessions using the programme were conducted by the trained health educators over a one-week period in february 2016 at three female-only fitness clubs in muscat. the sessions were advertised several days beforehand via social media, text messages and posters. the sessions were open to all women regardless of their membership to the fitness club. each session was conducted at the publicised time by two of the trained health educators. women already present at the location at the time of each session were invited to participate in upcoming sessions. as the sample size for each session needed to be manageable for subsequent discussion groups table 2: outline of a breast cancer health education programme for arab women based on the enabling systems of raising awareness breast cancer model6 learning objective content learning strategy clarify the incidence of breast cancer and associated risk factors among omani women •what is breast cancer and how does it affect you, your family and society? •what can you do about it? •multimedia presentation •short discussion correct personal beliefs or local misconceptions related to breast cancer and discuss fatalism and breast cancer with regards to islamic teachings •which of the following statements about breast cancer are true and which are false? •what are some of the other breast cancer-related risk factors or facts that you have heard of? •how do you think women get breast cancer? can you change your fate of getting breast cancer? can you take action towards maintaining your own health? •“myth or fact” game •multimedia presentation •short discussion identify challenges to breast health •what are the issues that women face in looking after their breast health? •have you personally faced any of these? •what would you do in these situations? •how might women take proactive measures towards maintaining their breast health? •discussion of challenges/ factors enumerate the signs and symptoms of breast cancer and possible results of non-action •how can you tell if you might have a tumour? •what are the signs and symptoms of breast cancer? •multimedia presentation •short discussion list possible early detection practices •how can you detect breast cancer early? •where can you go to have your breasts examined? •did you know that mammography services are available at tertiary hospitals? have you heard of the oman cancer association? did you know there is a walk-in breast cancer clinic at the sultan qaboos university hospital? •multimedia presentation •short discussion describe different ways to promote breast health •what are some of the things you can do to improve your overall health? •discussion of healthy habits encourage participants to sign a motivational contract to promote breast health as positive reinforcement •should we take a pledge of commitment towards breast health? •recitation of pledge in unison •signing of pledge esra alkhasawneh, yahya al-farsi, fayez al-simadi and michael leocadio clinical and basic research | e185 while also sufficient for preand post-test quantitative evaluation of the programme, up to 15 women were recruited for each session via a convenience sampling method.6,10 women ≤20 years old were included in the study due to the relatively high incidence of young women being diagnosed with breast cancer in oman.3,4 a convenience sampling technique was used to find willing participants who were easily accessible and to minimise the attrition rate between preand postsession surveys. during the session, each participant was provided with a structured handout to record information on breast cancer signs and symptoms, risk factors and early detection practices. a previously translated and adapted arabic version of the breast module of the cancer awareness measure (bcam) was used to determine the effectiveness of the programme as an interventional tool for improving breast cancer awareness and early detection practices.31,32 the bcam tool assesses awareness of breast cancer risk factors, signs and symptoms as well as knowledge and intentions regarding early detection practices.31 the modified translated survey has shown acceptable reliability and internal consistency (cronbach’s alpha values of 0.856 and 0.890 for the risk factors and warning signs subscales, respectively).32 the modified translated bcam survey was distributed before and after each health education session. in addition, demographic information such as age, marital status, education and income level was recorded. participants were requested not to discuss the survey questions among themselves and the health educators stressed the importance of completing both the preand post-session surveys. if a participant was unable to read arabic or english, the trained health educators read the questions to them out loud in private and asked the participant to answer using one of the multiple-choice responses. before the end of the session, the participants were informed that they might be invited at a later date to take part in focus group discussions in order to provide feedback on the sessions. each session was audio-recorded by one of the health educators and an accompanying research assistant. feedback on the session was analysed by the research team and the three academic experts from squ and uj during post-session debriefing meetings with the health educators. following this, focus group discussions were conducted in arabic at each of the three fitness centres with groups of 10 women from each centre. participants were randomly selected from the signup sheets of those who had previously taken part in the health education sessions. two research assistants were trained to conduct the discussions, with one actively moderating the discussion and the other recording important observations and comments. the discussions focused on the organisation, time management, setting, content, flow, clarity, teaching style and delivery of the sessions. in addition, the participants were encouraged to voice their questions and concerns, remark on any unanswered questions and discuss the availability of information and resources about breast health in oman. each discussion was audio-recorded, transcribed and translated into english for qualitative analysis. however, the transcripts of the discussions were initially prepared in arabic in order to improve the reliability of the feedback and to ensure that no information was lost during the translation process. quantitative data analysis was conducted using the statistical package for the social sciences (spss), version 21 (ibm corp., armonk, new york, usa). mean overall preand post-session knowledge and positive intention scores were compared using a paired t-test at a 95% confidence level. intentions to practice early detection behaviours were analysed using descriptive statistics. qualitative data from the focus group discussions were analysed using thematic synthesis in which data were organised into essential themes, thus providing a more holistic view of the programme. thematic consistency was ensured through peer review and expert consultations. ethical approval for this study was granted by the ethics committee of the college of nursing, squ (#sr/con/mchh/13/01). informed consent was provided by all participants during the health education sessions. all women who wanted to take part in the health education sessions were allowed to participate, even if they subsequently chose not to complete the surveys or join the focus group discussions. verbal consent to record the sessions and focus group discussions was given by all of the participants. results of the 53 participants, the majority were younger than 40 years old (83.0%), were married (54.7%), had been educated beyond the 12th grade (79.2%) and were employed (62.3%) [table 3]. a total of 30 women (56.6%) participated in the preand post-session surveys to estimate the effectiveness of the health education programme as a tool to improve breast cancer awareness and knowledge. the overall mean knowledge score increased significantly following the health education session (8.43 ± 6.10 versus 23.43 ± 5.54; p <0.001). in addition, there was also a statistically significant increase in the women’s mean scores regarding positive intentions to undertake early development and validation of a culturally-tailored breast cancer health education programme for arab women e186 | squ medical journal, may 2017, volume 17, issue 2 detection practices (1.42 ± 1.31 versus 2.41 ± 1.03; p <0.001) [table 4]. thematic analysis was undertaken of the feedback gathered from the health educators, research team, focus group discussions and audio recordings of the health education sessions. as a result of their experience and interactions with the participants, the health educators noted that the women appeared to have poor awareness of breast cancer signs and symptoms, risk factors and early detection practices. nevertheless, the participants showed interest in the sessions, were engaged during the different sections of the programme and were curious, active and unreserved during discussions, openly sharing their personal issues, stories, experiences and questions. most women reported that they were satisfied with the sessions overall, but expressed a need for more interaction or discussion time. table 5 provides a summary of the themes and feedback that emerged from the focus group discussions. in line with this feedback, the recommendations of the participants, health educators and the research team were used to modify the health education programme. table 6 illustrates the outline of a modified health education programme which is more interactive and allows for more discussion and questions, moving away from the previous lecture-focused programme. discussion according to the findings of the current study, the health education programme was found to significantly improve breast cancer knowledge scores among a cohort of omani women. in addition, there was a significant increase in the number of women who intended to undertake early detection practices following the health education sessions. based on the principles of the health promotion model, the programme was tailored to the individual characteristics, cultural values, behaviours and experiences of muslim omani women.27 by including certain tenets of motivational interviewing, the programme emphasised the integration of interpersonal and situational influences on the capacity of female omanis to act positively for their own health, the intensification of their self-efficacy and empowerment and their intentions to detect breast cancer at an early stage and seek adequate breast health.33 as there is currently no official breast cancer screening programme in oman, specific data on the use table 3: demographic and socioeconomic characteristics of omani women participating in a breast cancer health education programme (n = 53) characteristic n (%) age in years 20–29 24 (45.3) 30–39 20 (37.7) 40–49 7 (13.2) ≥50 1 (1.9) no response 1 (1.9) nationality omani 45 (84.9) other 8 (15.1) marital status single 24 (45.3) married 29 (54.7) education level up to 12th grade 9 (17.0) beyond 12th grade 42 (79.2) no response 2 (3.8) employment status employed 33 (62.3) unemployed 19 (35.8) no response 1 (1.9) monthly income in omr ≤500 2 (3.8) 501–1,000 22 (41.5) 1,001–1,500 7 (13.2) 1,501–2,000 2 (3.8) 2,001–2,500 3 (5.7) ≥2,501 9 (17.0) no response 8 (15.1) omr = omani riyals. table 4: knowledge and positive intentions to undertake early detection practices before and after health education sessions among omani women participating in a breast cancer health education programme (n = 30) mean score ± sd difference (95% ci) t p value knowledge pre-session 8.43 ± 6.10 15.0 (12.2–17.8) 11.12 <0.001 post-session 23.43 ± 5.54 positive intention pre-session 1.42 ± 1.31 1.0 (0.6–1.4) 4.71 <0.001* post-session 2.41 ± 1.03 *calculated using a non-parametric approach. esra alkhasawneh, yahya al-farsi, fayez al-simadi and michael leocadio clinical and basic research | e187 of screening methods such as mammography services are not readily available due to the voluntary nature of mammograms and clinical breast examinations; thus, it was impossible to compare the findings of the current study with any baseline use of these services in oman. in the current study, feedback from the participants, health educators and research team indicated certain modifications to the health education programme which might improve its effectiveness in increasing breast cancer awareness in oman. based on these recommendations, the improved programme would need to target a larger sample of women, including those who belong to lower socioeconomic and less educated backgrounds. in addition, the participants should be motivated to remain for the entire session, as well as participate more actively in any associated education or research activities. the health education programme should also incorporate answers to questions raised during the sessions and health educators should undergo more rigorous training in technical breast cancer knowledge and public speaking. novel learning strategies and activities were recommended such as the use of relatable “real life” stories and the inclusion of actual breast cancer survivors and religious experts in the sessions. in table 5: qualitative feedback from focus group discussions among selected omani women following their participation in a breast cancer health education programme (n = 30) theme issues challenges positives feedback target audience and location of the health education sessions •sessions were conducted in locations mostly accessed by well-educated and moderately highearning women •the participants were mostly well-educated and belonged to middle-income households •there was little diversity in the participant pool •none •future sessions should be conducted at more diverse locations in order to be accessible to women from lower socioeconomic and less educated backgrounds content of the health education sessions •the participants had specific queries and required clarifications during sessions •not all queries could be answered by the health educators, who were limited for time and needed to stay on topic and keep to the content of the programme •the health educators were able to deal with most queries •health educators should be trained in more detail regarding aspects of breast cancer, breast health service delivery and early detection resources specific to the omani healthcare system training of the health educators •health educators were trained in basic breast cancer knowledge and public speaking skills •in a few instances, the health educators were limited by their lack of technical knowledge or inadequate public speaking skills •the level of knowledge of the health educators was nevertheless appreciated by participants •health educators should be trained to improve their technical knowledge of breast cancer, disease stages, treatment modalities and treatment concerns •additional training in public speaking should also be conducted learning strategies, activities and materials •n/a •there were no “real-world” stories from breast cancer survivors •the health educators did not have formal religious training and could not address certain queries •there was a lack of summarised material/handouts •the information on early detection resources was inadequate and too general •there was not enough time spent on tactile learning with the breast model •the participants appreciated many of the learning strategies, including the ‘myth or fact’ game, the open discussions and the use of images and the breast model as learning strategies •future sessions should involve breast cancer survivors who can talk about their experiences and motivate the participants •future sessions should include a discussion on the responsibility of muslims towards their own health and self-care •future sessions should provide pamphlets with summarised session information, including additional specific information on early detection resources in oman •at the end of future sessions, a token gift should be given to participants in gratitude of their participation and to act as a memento/reminder of the sessions attrition rate •the programme had a high attrition rate as many women were unable to stay for the entire session or left before the post-session test •the target audience of the sessions consisted primarily of walk-ins •many women had prior commitments and left when the sessions went over the time limit •none •the venue of future sessions should be made more convenient/specific to the session •publicity tactics and duration for future sessions should be improved •in future sessions, participants should be persuaded and motivated to remain present throughout the entire session •tangible incentives should be provided to participants at the end of future sessions mode of delivery •the sessions relied heavily on multimedia presentation slides and lectures •the structure of the sessions was found to be overly restrictive and did not allow enough time for open discussion •discussion topics did not include discussion of breast health resources in oman •the interactive components of the sessions were appreciated, as they allowed for conversation and gave importance to participants’ personal experiences •to allow for more flexibility, future sessions should focus on interactive discussions with presentation slides as minor learning aids •future sessions should incorporate “real life” stories and personal experiences to enhance interaction and accessibility of the material n/a = not applicable. development and validation of a culturally-tailored breast cancer health education programme for arab women e188 | squ medical journal, may 2017, volume 17, issue 2 addition, other strategies for future health education sessions include the use of a breast model to teach comprehensive breast self-examination techniques, dissemination of information on local breast cancer screening facilities in oman and distribution of physical tokens/mementoes to remind participants of their pledge to maintain and promote breast health. in the new health education programme, an emphasis on participant interaction would improve the fidelity of the programme content to the original esra breast cancer model, which is based on empowerment through awareness and identifies the main barriers present within three enabling systems.6 as women were the target population in the current study, the previous health education programme was able to extensively address cultural/religious/fatalistic barriers, although factors related to the personal/familial/environmental and healthcare-related systems were addressed only to a limited extent. it is recommended that the future health education programme involve stakeholders related to these two enabling systems, including family members, men, religious leaders and healthcare professionals, in order to enable these systems to support breast cancer awareness and early detection practices in oman. moreover, as this study measured only the immediate effects of a health education programme on breast cancer awareness, future studies should evaluate long-term behavioural effects. this is due to the fact that any changes in factors related to the three enabling systems—such as changes in personal beliefs, cultural values, social taboos and interpersonal relationships along with systematic improvements in breast health resources in oman—would take place over time. as such, collecting evidence soon after the implementation of a health education programme would not provide an accurate depiction of its effects. despite the encouraging results of the present study, caution should be exercised before generalising the results to the omani community as a whole. the study design relied on a convenience sampling method to recruit participants from three specific locations, since previous experience with random sampling in table 6: outline of a modified health education programme for future use based on improvements gathered from feedback from health educators, participants and the research team section content learning strategy “real life” story •an incomplete story describing a young omani woman who discovers changes in her breast, in which the participants are encouraged to finish the story themselves •the character is named “amal” which means hope •the sociodemographic features of the character are consistent with the majority of breast cancer cases in oman (i.e. young and married with children and with a family history of breast cancer) •participants are encouraged to empathise with amal •discussion of how each participant would complete the story introduction •what do you associate with the term “breast cancer”? •what prior knowledge do you have about breast cancer? •introduction to breast cancer with definitions and global/ local statistics •emphasis on the fact that breast cancer can be cured if detected early •discussion of associations with the term “breast cancer” •discussion of prior knowledge of breast cancer •pictographs depicting facts, definitions and statistics about breast cancer breast cancer signs and symptoms •what breast cancer signs and symptoms are you aware of? •illustration of signs and symptoms •emphasis on “knowing your own breasts” to identify abnormalities •discussion of one sign/symptom of breast cancer that each participant may be aware of •multimedia presentation slides to illustrate the various signs and symptoms of breast cancer risk factors for breast cancer •what are the factors that make some women more vulnerable to breast cancer than others? •what are some healthy habits that can reduce your breast cancer risk? •emphasis on a generally healthy lifestyle •discussion of one risk factor of breast cancer that each participant may be aware of •discussion of breast cancer facts, myths/misconceptions and known risk factors •multimedia presentation slides to illustrate known risk factors as a retention aid •discussion of healthy habits and preventative measures to reduce breast cancer risk early detection and screening practices •what measures can you take to detect breast cancer early? •emphasis on “knowing your own breasts” to identify abnormalities •what are the health responsibilities of muslims? •discussion of each early detection practice (e.g. bse, cbe and mammograms) and the importance of being familiar with one’s own breasts •discussion of muslims’ responsibility towards their own health •extension of amal’s story to relate a scenario in which amal visits the doctor and is referred for mammography services pledge to promote breast health •encourage participants to sign a pledge of commitment to healthy practices and breast health awareness with accompanying tokens/mementoes of the programme (e.g. pink ribbons) •recitation of pledge in unison •signing of pledge •distribution of tokens/mementoes as positive reinforcement bse = breast self-examination; cbe = clinical breast examination. esra alkhasawneh, yahya al-farsi, fayez al-simadi and michael leocadio clinical and basic research | e189 this topic has led to high attrition rates. this resulted in a cohort whom were primarily 20–39 years old and either regularly accessed or visited fitness clubs or were intending to become regular members. as such, the majority of the study sample were relatively more affluent and educated than the general population of oman. conclusion breast cancer is a global healthcare challenge and there is a need to improve awareness and early breast cancer detection practices. in the current study, a culturallytailored breast cancer health education programme was developed based on a previously described model. the programme was found to significantly increase breast cancer awareness and positive intentions to undertake early detection practices among a cohort of omani women. recommendations arising from feedback obtained from the health education sessions may be used to revise and improve the structure, content and delivery of the programme in the future. however, long-term behavioural outcomes need to be evaluated to ensure the effectiveness of this modified programme in promoting breast health among omani women. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by a grant from his majesty sultan qaboos as part of the strategic research fund, muscat, oman (#sr/con/mchh/13/01). references 1. world health organization. breast cancer: prevention and control. from: www.who.int/cancer/detection/breastcancer/ en/index1.html accessed: oct 2016. 2. international agency for research on cancer, world health organization. all cancers (excluding non-melanoma skin cancer): estimated incidence, mortality and prevalence worldwide in 2012. from: globocan.iarc.fr/pages/fact_sheets_ cancer.aspx accessed: oct 2016. 3. kumar s, burney ia, al-ajmi a, al-moundhri ms. changing trends of breast cancer survival in sultanate of oman. j oncol 2011; 2011:316243. doi: 10.1155/2011/316243. 4. al-moundhri m, al-bahrani b, pervez i, ganguly ss, nirmala v, al-madhani a, et al. the outcome of treatment of breast cancer in a developing country: oman. breast 2004; 13:139–45. doi: 10.1016/j.breast.2003.10.001. 5. al-azri m, al-awisi h, al-rasbi s, el-shafie k, al-hinai m, al-habsi h, et al. psychosocial impact of breast cancer diagnosis among omani women. oman med j 2014; 29:437–44. doi: 10.5001/omj.2014.115. 6. alkhasawneh e, siddiqui st, leocadio m, seshan v, al-farsi y, al-moundhri ms. i do not even say “it”: a mixed methods study on breast cancer awareness of omani women. asian pac j cancer prev 2016; 17:2247–54. doi: 10.7314/apjcp. 2016.17.4.2247. 7. donnelly tt, al khater ah, al-bader sb, al kuwari mg, al-meer n, malik m, et al. beliefs and attitudes about breast cancer and screening practices among arab women living in qatar: a cross-sectional study. bmc womens health 2013; 13:49. doi: 10.1186/1472-6874-13-49. 8. radi sm. breast cancer awareness among saudi females in jeddah. asian pac j cancer prev 2013; 14:4307–12. doi: 10.7314/apjcp.2013.14.7.4307. 9. alkhasawneh im. knowledge and practice of breast cancer screening among jordanian women. oncol nurs forum 2007; 34:1211–17. doi: 10.1188/07.onf.1211-1217. 10. alkhasawneh im, akhu-zaheya lm, suleiman sm. jordanian nurses’ knowledge and practice of breast self-examination. j adv nurs 2009; 65:412–16. doi: 10.1111/j.1365-2648.2008.04891.x. 11. parsa p, kandiah m, abdul rahman h, zulkefli nm. barriers for breast cancer screening among asian women: a mini literature review. asian pac j cancer prev 2006; 7:509–14. 12. islam rm, bell rj, billah b, hossain mb, davis sr. awareness of breast cancer and barriers to breast screening uptake in bangladesh: a population based survey. maturitas 2016; 84:68–74. doi: 10.1016/j.maturitas.2015.11.002. 13. ramathuba du, ratshirumbi ct, mashamba tm. knowledge, attitudes and practices toward breast cancer screening in a rural south african community. curationis 2015; 38:1–8. doi: 10.4102/curationis.v38i1.1172. 14. gangane n, anshu, manvatkar s, ng n, hurtig ak, san sebastián m. prevalence and risk factors for patient delay among women with breast cancer in rural india. asia pac j public health 2016; 28:72–82. doi: 10.1177/1010539515620630. 15. yip ch, buccimazza i, hartman m, deo vs, cheung ps. improving outcomes in breast cancer for low and middle income countries. world j surg 2015; 39:686–92. doi: 10.1007/ s00268-014-2859-6. 16. othman ak, kiviniemi mt, wu yw, lally rm. influence of demographic factors, knowledge, and beliefs on jordanian women’s intention to undergo mammography screening. j nurs scholarsh 2012; 44:19–26. doi: 10.1111/j.1547-5069. 2011.01435.x. 17. othman a, ahram m, obeidat rf, obeidat n, al-tarawneh mr. barriers for mammography among non-adherent women in jordan: a national survey. life sci j 2013; 10:2268–74. 18. ramos ak, correa a, trinidad n. perspectives on breast health education and services among recent hispanic immigrant women in the midwest: a qualitative study in lancaster county, nebraska. j cancer educ 2016; 31:666–72. doi: 10.10 07/s13187-015-0886-0. 19. shirazi m, bloom j, shirazi a, popal r. afghan immigrant women’s knowledge and behaviors around breast cancer screening. psychooncology 2013; 22:1705–17. doi: 10.1002/ pon.3216. 20. bickell na, weidmann j, fei k, lin jj, leventhal h. underuse of breast cancer adjuvant treatment: patient knowledge, beliefs, and medical mistrust. j clin oncol 2009; 27:5160–7. doi: 10.12 00/jco.2009.22.9773. 21. hall cp, wimberley pd, hall jd, pfriemer jt, hubbard em, stacy as, et al. teaching breast cancer screening to african american women in the arkansas mississippi river delta. oncol nurs forum 2005; 32:857–63. doi: 10.1188/05.onf. 857-863. https://doi.org/10.1155/2011/316243 https://doi.org/10.1016/j.breast.2003.10.001 https://doi.org/10.5001/omj.2014.115 https://doi.org/10.7314/apjcp.2016.17.4.2247 https://doi.org/10.7314/apjcp.2016.17.4.2247 https://doi.org/10.1186/1472-6874-13-49 https://doi.org/10.7314/apjcp.2013.14.7.4307 https://doi.org/10.1188/07.onf.1211-1217 https://doi.org/10.1111/j.1365-2648.2008.04891.x https://doi.org/10.1016/j.maturitas.2015.11.002 https://doi.org/10.4102/curationis.v38i1.1172 https://doi.org/10.1177/1010539515620630 https://doi.org/10.1007/s00268-014-2859-6 https://doi.org/10.1007/s00268-014-2859-6 https://doi.org/10.1111/j.1547-5069.2011.01435.x https://doi.org/10.1111/j.1547-5069.2011.01435.x https://doi.org/10.1007/s13187-015-0886-0 https://doi.org/10.1007/s13187-015-0886-0 https://doi.org/10.1002/pon.3216 https://doi.org/10.1002/pon.3216 https://doi.org/10.1200/jco.2009.22.9773 https://doi.org/10.1200/jco.2009.22.9773 https://doi.org/10.1188/05.onf.857-863 https://doi.org/10.1188/05.onf.857-863 development and validation of a culturally-tailored breast cancer health education programme for arab women e190 | squ medical journal, may 2017, volume 17, issue 2 22. kline kn. cultural sensitivity and health promotion: assessing breast cancer education pamphlets designed for african american women. health commun 2007; 21:85–96. doi: 10.10 80/10410230701283454. 23. ouyang yq, hu x. the effect of breast cancer health education on the knowledge, attitudes, and practice: a community health center catchment area. j cancer educ 2014; 29:375–81. doi: 10.10 07/s13187-014-0622-1. 24. gandeh bs, milaat wa. effect of a breast cancer health education program on the awareness and practice of jeddah female secondary school students. j family community med 2000; 7:31–6. 25. abd el aziz hm, akl oa, ibrahim hk. impact of a health education intervention program about breast cancer among women in a semi-urban area in alexandria, egypt. j egypt public health assoc 2009; 84:219–43. 26. rezaeian m, sharifirad g, mostafavi f, moodi m, abbasi mh. the effects of breast cancer educational intervention on knowledge and health beliefs of women 40 years and older, isfahan, iran. j educ health promot 2014; 3:43. doi: 10.41 03/2277-9531.131929. 27. pender nj, murdaugh cl, parsons ma. health promotion in nursing practice, 6th ed. upper saddle river, new jersey, usa: pearson, 2010. pp. 250–355. 28. world education health literacy special collection. health education and adult literacy: breast & cervical cancer heal:bcc curriculum. from: http://healthliteracy.worlded. org/heal/healbcchtml/index.htm accessed: oct 2016. 29. john snow inc. jsi adolescent breast cancer curriculum. from: w w w.jsi.com/jsiinternet/inc/common/_download_pub. cfm?id=11148&lid=3 accessed: oct 2016. 30. roberts nj, ghiassi r, partridge mr. health literacy in copd. int j chron obstruct pulmon dis 2008; 3:499–507. doi: 10.21 47/copd.s1088. 31. stubbings s, robb k, waller j, ramirez a, austoker j, macleod u, et al. development of a measurement tool to assess public awareness of cancer. br j cancer 2009; 101:s13–7. doi: 10.1038/ sj.bjc.6605385. 32. al-khasawneh em, leocadio m, seshan v, siddiqui st, khan an, al-manaseer mm. transcultural adaptation of the breast cancer awareness measure. int nurs rev 2016; 63:445–54. doi: 10.1111/inr.12265. 33. miller wr, rollnick s. motivational interviewing: preparing people for change, 2nd ed. new york, usa: guilford press, 2002. pp. 305–414. https://doi.org/10.1080/10410230701283454 https://doi.org/10.1080/10410230701283454 https://doi.org/10.1007/s13187-014-0622-1 https://doi.org/10.1007/s13187-014-0622-1 https://doi.org/10.4103/2277-9531.131929 https://doi.org/10.4103/2277-9531.131929 https://doi.org/10.2147/copd.s1088 https://doi.org/10.2147/copd.s1088 https://doi.org/10.1038/sj.bjc.6605385 https://doi.org/10.1038/sj.bjc.6605385 https://doi.org/10.1111/inr.12265 division of endocrinology, david geffen school of medicine, university of california los angeles, los angeles, california, usa e-mail: runyu@mednet.ucla.edu امتصاص متعدد البؤر للفلوروديوكسي جلوكوز يف جلد مريض لديه كتلة كبرية يف البطن ران يو multifocal skin fluorodeoxyglucose uptake in a patient with a large abdominal mass run yu a 30-year-old male patient presented tothe emergency room of a community hospital in california, usa, in 2018 with lower abdom inal pain. abdominal computed tomography (ct) revealed a 9-cm mass in the left adrenal gland. subsequently, the patient became very anxious and stressed and developed chest and abdominal pain, which resulted in more than 10 emergency room visits over the next few months. the pain reportedly subsided once the patient was prescr ibed benzodiazepine. he was then referred to the ronald reagan university of california los angeles medical center, los angeles, california, for management of the mass. at referral, the patient was currently taking esom eprazole and lorazepam. his past medical history included mild hypertension, obesity and kidney stones. multiple family members had a history of malignancy. a physical examination indicated tachycardia and multiple acne lesions on the back [figure 1a]. biochemical tests revealed normal levels of catecholamines, metadrenalines, aldosterone, renin, potassium, dehydroepiandrosterone sulfate and cortisol. a dedicated adrenal ct scan showed an 8.2 × 6.9 × 9.5 cm mass in the left adrenal gland, with a pre-contrast attenuation of 28 hounsfield units and delayed enhanc ement after contrast administration. fluorodeoxyglucose (fdg)-positron emission tomography (pet)/ct imaging indicated heterogeneous moderate-to-intense fdg uptake in the mass (standard uptake value [suv]: 6.4) [figure 1b] as well as multifocal and diffuse fdg uptake in the back (suv: 1.9–3.9) and facial (suv: 7.8) skin, respectively [figures 1c and d]. the patient underwent surgical resection of the mass which was subsequently histologically diagnosed as a benign ganglioneuroma, with a normal left adrenal gland. comment an adrenocortical carcinoma is a serious concern among patients with a large unilateral mass in or near the adrenal glands.1 therefore, fdg-pet imaging is required to identify potential local invasion, tumour thrombi and remote metastasis. multifocal skin fdg uptake in the interesting medical image sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e405–406, epub. 19 dec 18 submitted 17 apr 18 revision req. 5 jun 18; revision recd. 9 jun 18 accepted 5 jul 18 figure 1: a: photograph of the back of a 30-year-old male patient with a large abdominal mass showing multiple acne lesions. b–d: fused fluorodeoxyglucose (fdg) positron emission tomography/computed tomography imaging in the (b) coronal and (c & d) sagittal views showing heterogeneous moderate-to-intense fdg uptake in the abdominal mass (arrowhead) as well as multifocal fdg uptake in the back skin (white arrows) and diffuse fdg uptake in the facial skin (red arrows). doi: 10.18295/squmj.2018.18.03.026 multifocal skin fluorodeoxyglucose uptake in a patient with a large abdominal mass e406 | squ medical journal, august 2018, volume 18, issue 3 absence of visceral or bony metastasis is very unusual because most skin metastases from adrenocortical carci nomas occur after hepatic and pulmonary metastases.1 multiple benign skin lesions, including infectious and inflammatory lesions, are often seen incidentally on fdg-pet imaging.2 acne vulgaris is a common skin condition in which the associated lesions are often positive on fdg-pet imaging, leading to suspicion of skin malignancy, such as melanomas.2,3 a simple physical examination will easily ensure the correct diagnosis, as in the current case, in which the patient had a few purulent acne lesions on his back corresponding to locations of fgd uptake. however, the diffuse facial skin fdg uptake was intriguing and, to the best of the author’s knowledge, has not been reported previously. various emotional states such as stress, anger, anxiety and fear increase blood flow to the facial skin.4,5 in the present case, the patient was under extreme stress due to the recent diagnosis of a potentially malignant abdom inal mass and was very anxious during the fdg-pet procedure. however, upon physical examination, his facial skin appeared completely normal. it is therefore likely that the diffuse facial skin fdg uptake was due to emotional stress. while it is unknown if emotional stress can cause hyperaemia in the chest and abdominal skin, fdg uptake in these areas was normal. this case illustrates that multifocal skin fdg uptake can be due to benign lesions in patients with suspected malignancies and that diffuse facial skin fdg uptake may be due to emotional stress. references 1. else t, kim ac, sabolch a, raymond vm, kandathil a, caoili em, et al. adrenocortical carcinoma. endocr rev 2014; 35:282−326. doi: 10.1210/er.2013-1029. 2. metser u, tau n. benign cutaneous and subcutaneous lesions on fdg-pet/ct. semin nucl med 2017; 47:352−61. doi: 10.1053/ j.semnuclmed.2017.02.007. 3. pawlik tm, erasmus jj, truong mt, macapinlac h, ross mi, gershenwald je. acne vulgaris: false-positive finding on integrated 18f-fdg pet/ct in a patient with melanoma. ajr am j roentgenol 2006; 187:w117−19. doi: 10.2214/ajr.04.1986. 4. drummond pd, quah sh. the effect of expressing anger on cardiovascular reactivity and facial blood flow in chinese and caucasians. psychophysiology 2001; 38:190−6. doi. 10.1111/14698986.3820190. 5. engert v, merla a, grant ja, cardone d, tusche a, singer t. exploring the use of thermal infrared imaging in human stress research. plos one 2014; 9:e90782. doi: 10.1371/journal.pone. 0090782. https://doi.org/10.1210/er.2013-1029 https://doi.org/10.1053/j.semnuclmed.2017.02.007 https://doi.org/10.1053/j.semnuclmed.2017.02.007 https://doi.org/10.2214/ajr.04.1986 https://doi.org/10.1111/1469-8986.3820190 https://doi.org/10.1111/1469-8986.3820190 https://doi.org/10.1371/journal.pone.0090782 https://doi.org/10.1371/journal.pone.0090782 1residency programme, kuwaiti board of physical medicine & rehabilitation, andalous, kuwait; 2department of internal medicine, mubarak al kabeer hospital, jabriya, kuwait; 3almanara child psychiatry unit, kuwait center for mental health, sabah health region, kuwait *corresponding author’s e-mail: dr.ahmad.j.abdulsalam@gmail.com املعارف املتعلقة بالسكري واملمارسات الوقائية بني املوظفني احلكوميني املصابني بالسكري يف الكويت اأحمد جا�صم عبدال�صالم، عبداهلل اإبراهيم الديحاين، كو�صتانتينيو�ض فران�صي�ض abstract: objectives: diabetes mellitus (dm)-related knowledge and preventative practices are vital for the successful management of this condition. in kuwait, few studies have been conducted to evaluate the knowledge and preventative practices of dm patients. this study aimed to assess dm-related knowledge and preventative practices among government employees with dm in kuwait and to examine associations between dm knowledge, preventative practices and other variables. methods: this cross-sectional study was conducted in june 2015 and involved 345 employees with dm from 15 government ministries in kuwait. a self-administered arabic-language questionnaire was designed to assess dm-related knowledge and preventative practices based on the diabetes knowledge test and the recommendations of the american diabetes association, respectively. results: a total of 312 ministry employees agreed to participate in the study (response rate: 90.4%). the mean age was 45.6 ± 10.6 years. a total of 63.4% were male and 64.1% were kuwaiti. the median dm knowledge score was 9 out of 14 and the median preventative practice score was 5 out of 14. high knowledge scores were significantly associated with education (β = 1.510; p ≤0.001) and income (β = 0.896; p ≤0.001). high preventative practice scores were significantly associated with income (β = 1.376; p = 0.002), dm duration (β = 0.919; p = 0.026) and knowledge scores (β = 1.783; p = 0.015). conclusion: government employees in kuwait were found to have average dm knowledge and poor preventative practices. it is therefore imperative that policy-makers develop educational and health-promoting campaigns to target government employees with dm in kuwait. keywords: diabetes mellitus; knowledge; primary prevention; lifestyle risk reduction; health education; kuwait. امللخ�ص: الهدف: املعارف املتعلقة بال�صكري واملمار�صات الوقائية امران مهمان لنجاح عالج املر�ض.يف الكويت اأجريت درا�صات قليلة احلكومة ملوظفي الوقائية واملمار�صات املعارف تقييم اإىل الدرا�صة هذة تهدف ال�صكري. ملر�صى الوقائية واملمار�صات املعارف لتقييم امل�صابون بال�صكري يف الكويت واأختبار مدى ارتباطها بعوامل اأخرى. الطريقة: اأجريت هذة الدرا�صة املقطعية العر�صية يف يونيو 2015 املعرفة لتقييم العربية باللغة ذاتي ا�صتبيان ت�صمم مت الكويت. يف وزارة 15 يف بال�صكري م�صابون حكوميا موظفا 345 على و�صملت بال�صكري وطرق الوقاية منه مبني على اأختبار املعرفة بال�صكري وتو�صيات اجلمعية الأمريكية لل�صكري. النتائج: وافق 312 موظفا على امل�صاركة بال�صتبيان )معدل ال�صتجابة: %90.4(. كان متو�صط العمر 10.6 ± 45.6 �صنه. و %63.4 من الذكور و %64.1 من الكويتيني. و�صيط درجة املعرفة بال�صكري كان 9 من 14 ومتو�صط املعرفة بطرق الوقاية كان 5 من 14. الن�صب العالية للمعرفة بال�صكري كانت مرتبطة ب�صكل كبري مع امل�صتوى التعليمي )β = 1.510؛ p ≤0.001( والدخل ال�صهري )β = 0.896؛ p ≤0.001(. بينما الن�صبة العالية للمعرفة بالطرق الوقائية كانت مرتبطة ب�صكل كبري بالدخل )β = 1.376؛ p = 0.002(، ومدة ال�صابة بال�صكري )β = 0.919؛ p = 0.026( ودرجة املعرفة.)β = 1.783؛ p = 0.015(. اخلال�صة: موظفو القطاع احلكومي امل�صابون بال�صكري يف الكويت لديهم م�صتوى متو�صط للمعرفة عن مر�ض ال�صكري وم�صتوى امل�صابني احلكوميني املوظفني ت�صتهدف و�صحية تثقيفية حمالت تطوير ال�صيا�صات �صناع على يتحتم لذلك الوقائية. للطرق �صعيف بال�صكري يف الكويت. الكلمات املفتاحية: ال�صكري؛ املعرفة؛ الوقاية الأولية؛ تقليل الختطار عن طريق اأمناط احلياة؛ التثقيف ال�صحي؛ الكويت. diabetes-related knowledge and preventative practices among government employees with diabetes in kuwait *ahmad j. abdulsalam,1 abdullah e. al-daihani,2 kostantinos francis3 clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e444–451, epub. 10 jan 18 submitted 9 apr 17 revision req. 11 jun 17; revision recd. 7 jul 17 accepted 27 jul 17 advances in knowledge the findings of this study revealed average diabetes mellitus (dm)-related knowledge and poor adherence to preventative practices among government employees with dm in kuwait. application to patient care this study emphasises the importance of improving current dm knowledge and preventative practices among government employees with diabetes in kuwait. doi: 10.18295/squmj.2017.17.04.011 ahmad j. abdulsalam, abdullah e. al-daihani and kostantinos francis clinical and basic research | e445 diabetes mellitus (dm) is an increasingly prevalent economic burden worldwide.1,2 a study conducted in kuwait in 1998 estimated the prevalence of dm among adults to be 14.8%.3 in 2013, another kuwaiti study estimated the prevalence at 25.4% among adults, indicating it to be a major public health problem.4 well-designed educational programmes have been developed worldwide for patients with dm in order to improve their knowledge of this chronic condition as an essential aspect of promoting self-care and selfmanagement behaviours.5,6 high levels of dm-related knowledge have been associated with improved clinical outcomes, fewer complications and enhanced glycaemic control and quality of life.7–10 several studies have been conducted worldwide to determine dm-related knowledge among different populations.11–13 in canada, a community telephone survey among adults in the general population revealed a low level of general dm knowledge.11 kheir et al. also reported relatively poor knowledge levels among 54 patients attending a diabetic clinic in qatar; these findings were similar to those of a study of saudi arabian female patients with dm.12,13 interestingly, most studies have evaluated patients with access to dm-related healthcare services who would therefore be expected to have greater dm knowledge than patients in the general community.2,7 in 2004, a kuwaiti study revealed low levels of dm knowledge among 5,114 people with diabetes attending 24 primary healthcare clinics, with only 9.7% demonstrating adequate knowledge.7 in addition, the study reported that a younger age, higher levels of education and higher incomes were significantly associated with higher knowledge scores; however, the study did not assess preventative practices and their association with dm knowledge.7 in 2013, research from the united arab emirates revealed that 31% of patients had poor dm knowledge and 72% had negative attitudes towards the disease, concluding that low levels of dm awareness were prevalent in the region.14 however, a more recent study testing dm knowledge in oman found that patients displayed satisfactory knowledge and good preventative practices, apart from low adherence to a regular exercise regimen.15 the objective of the current study was to assess levels of dm-related knowledge and adherence to preventative practices among people with dm employed in the kuwaiti public workforce. in addition, the study also aimed to examine associations between these two variables and to identify associations with other factors. it was hypothesised that a higher dm knowledge score would be associated with greater adherence to preventative practices. methods this cross-sectional study took place in june 2015 and included all 5,417 employees working at 15 government ministries in kuwait. the ministries of defence, the interior and foreign affairs were not included as permission from the authorities to screen employees at these sites could not be secured. two doctors visited all of the employees working in each ministry building to screen all those with self-reported type 1 or type 2 dm. only individuals who were govern ment employees, those who claimed to have been diagnosed with type 1 or type 2 dm by a doctor and those who were fluent in arabic were included in the study. a self-administered questionnaire was designed to collect sociodemographic data, medical history, levels of dm knowledge and adherence to preventative practices. for the items involving dm knowledge, a modified version of the diabetes knowledge test was used.16 these questionnaire items were previously translated into arabic and validated in a kuwaiti population by al-adsani et al.7 for the knowledge items, each of 14 questions was scored as either 1 or 0 for correct and incorrect/missing responses, respectively, for a total score of 14. scores of ≤6, 7–11 and ≥11 were considered to indicate low, average and high dm knowledge, repectively.7 the preventative practice section of the questionnaire was developed based on the recommendations of the american diabetes association (ada).17 the preventative practice items were translated into arabic and a panel of local diabetes experts confirmed the translated items to be appropriate for a kuwaiti population. as with the knowledge items, the 14 preventative practice items were assigned a score of 1 or 0 for correct and inappropriate/missing responses, respectively, for a total score of 14. scores of <5, 5–6 and ≥6 were deemed to indicate poor, average and high adherence to preventative practices, respectively. education level was categorised based on the completion of various degrees as high (bachelor’s degree or postgraduate diploma), average (diploma) or low (elementary, middle or high school certificates). all collected data were crosschecked by inspecting the frequencies of the variables and correcting inaccurate values. means, standard deviations, medians, ranges and proportions were used to present the variables, as appropriate. the 95% confidence interval for proportions was obtained using the binomial method with stata® data analysis and statistical software, version 13.0 (statacorp llc, college station, texas, usa). a chi-squared test was used to assess the significance of associations between categorical diabetes-related knowledge and preventative practices among government employees with diabetes in kuwait e446 | squ medical journal, november 2017, volume 17, issue 4 variables. knowledge and preventative practice scores were used as outcome variables for the binary logistic regression models. odds ratios were calculated from the binary logistic regression analysis. for multivariate logistic regression, the analysis was adjusted for age, gender and other factors found to be significantly associated with each outcome during the crude analysis; as such, age, gender, education and income were adjusted in the knowledge model, while age, gender, income and smoking status were adjusted in the preventative practice model. pearson’s correlation coefficient was used to evaluate the relationship between knowledge and practice scores and a simple linear regression analysis was used to assess the strength of the unadjusted association between the two variables. a p value of <0.050 was considered the cut-off value for significance. table 1: sociodemographic characteristics of kuwaiti ministry employees with diabetes (n = 312) characteristic n (%) age in years* ≤40 86 (31.3) 41–49 87 (31.6) ≥50 102 (37.1) mean ± sd 45.6 ± 10.6 gender† male 196 (63.4) female 113 (36.6) nationality kuwaiti 200 (64.1) non-kuwaiti 112 (35.9) marital status‡ single 27 (8.7) married 265 (85.5) divorced/widowed 18 (5.8) place of residence kuwait city 83 (26.6) hawalli 113 (36.2) farwaniya 58 (18.6) mubarak al-kabeer 30 (9.6) al-ahmadi/al-jahra 28 (9.0) education level‡ low 77 (24.8) average 82 (26.5) high 151 (48.7) monthly income in kd§ <1,000 133 (43.8) 1,000–2,000 114 (37.5) >2,000 57 (18.8) sd = standard deviation; kd = kuwaiti dinar. *total dataset for this variable was 275 due to missing data for 37 subjects. †total dataset for this variable was 309 due to missing data for three subjects. ‡total dataset for these variables was 310 due to missing data for two subjects. §total dataset for this variable was 304 due to missing data for eight subjects. table 2: clinical characteristics of kuwaiti ministry employees with diabetes (n = 312) characteristic n (%) dm duration in years* ≤3 100 (34.6) 4–10 105 (36.3) >10 84 (29.1) median (range) 6.0 (0.1–36.9) comorbidities† high cholesterol 162 (59.8) high blood pressure 145 (53.5) diabetic retinopathy 68 (25.1) diabetic foot problems 47 (17.3) diabetic kidney disease 19 (7.0) heart attack 12 (4.4) stroke 9 (3.3) number of dm complications 0 211 (67.6) 1 61 (19.6) 2 29 (9.3) 3 11 (3.5) smoking status‡ current smoker 74 (24.6) previous smoker 50 (16.6) nonsmoker 177 (58.8) bmi in kg/m2§ ≤25.00 42 (14.8) 25.01–30.00 110 (38.9) ≥30.01 131 (46.3) dm = diabetes mellitus; bmi = body mass index. *total dataset for this variable was 289 due to missing data for 23 subjects. †percentages for this variable add up to more than 100% as some subjects may have reported multiple comorbidities. total dataset for this variable was 271 due to missing data for 41 subjects. ‡total dataset for this variable was 301 due to missing data for 11 subjects. §bmi was calculated from selfreported height and weight measurements. total dataset for this variable was 283 due to missing data for 29 subjects. ahmad j. abdulsalam, abdullah e. al-daihani and kostantinos francis clinical and basic research | e447 this study was approved by the kuwait ministry of health and the ethical committee of the kuwait institute for scientific research. written consent was obtained from all of the participants prior to their enrollment. all subjects were informed that their participation was voluntary and that any data collected would remain anonymous and confidential. results of the 5,417 employees screened, 345 (6.4%) reported having previously received a dm diagnosis; of these, 312 agreed to participate in the study (response rate: 90.4%). a total of 29 employees (0.3%) had type 1 dm while 283 (90.7%) had type 2. the mean age was 45.6 years. most participants were of kuwaiti nationality (64.1%), male (63.4%) and had a high education level (48.7%) and a low monthly income (43.8%) [table 1]. the median dm duration was 6.0 years and the most prevalent comorbidities were high cholesterol levels (59.8%), high blood pressure (53.5%) and diabetic retinopathy (25.1%). according to self-reported height and weight measurements, many individuals were either overweight (38.9%) or obese (46.3%) [table 2]. the mean dm knowledge score was 8.33 ± 2.20 (median score: 9) and the mean preventative practice score was 5.62 ± 2.60 (median score: 5). only 6.1% of participants had high levels of dm-related knowledge, with the remaining 74.0% and 17.6% demonstrating average and low knowledge levels, respectively. specifically, knowledge questions regarding diet, the treatment of low glucose levels and the nature of the glycated haemoglobin (hba1c) test were answered correctly by less than half of the participants (range: 24.4–47.4%). while 49.4% of the participants claimed to attend follow-up appointments with their doctors every three months or more often, 18.9% of the patients indicated that they did not attend regular follow-up appointments with their doctors or only did so on an annual basis. between 63.8–73.4% of participants reported owning a glucometer and checking their cholesterol levels regularly. moreover, between 40.4–51.9% of the participants indicated that they adhered to recommended guidelines related to kidney function and micro-albuminuria testing and knew their latest hba1c level, visited a dietician, controlled their blood glucose levels and underwent eye examinations and regular checkups. of the participants, 31.7% reported appropriately examining their feet, 23.3% reported exercising regularly, 19.9% underwent hba1c testing and 11.9% had regular diabetic neuropathy examinations. a total of 32.3% and 20.5% of the subjects, respectively, indicated that they checked table 3: associations between diabetes-related knowledge* and sociodemographic characteristics among kuwaiti ministry em-ployees with diabetes (n = 312) characteristic mean dm knowledge score ± sd p value β† (95% ci) p value age in years ≤40 8.2 ± 2.2 0.740 41–49 8.3 ± 2.0 0.095 (-0.5–0.7) 0.761 ≥50 8.5 ± 2.2 0.162 (-0.5–0.8) 0.610 gender male 8.2 ± 2.3 0.440 female 8.4 ± 1.9 0.347 (-0.2–1.0) 0.230 nationality‡ kuwaiti 8.2 ± 2.1 0.240 non-kuwaiti 8.5 ± 2.2 0.153 (-0.5–01) 0.620 marital status married 8.4 ± 2.2 0.227 single 7.6 ± 2.4 0.885 (-0.1–1.9) 0.077 divorced/ widowed 8.3 ± 2.0 0.970 (0.0–2.4) 0.170 place of residence kuwait city 8.1 ± 2.3 0.067 hawalli 8.7 ± 2.2 0.524 (-0.2–1.2) 0.110 farwaniya 8.4 ± 2.0 0.521 (-0.2–1.3) 0.180 mubarak al-kabeer 7.4 ± 2.2 -0.854 (-1.8–0.0) 0.061 al-ahmadi al-jahra 8.4 ± 1.6 0.333 (-0.6–1.2) 0.470 education level low 7.5 ± 2.1 <0.001§ average 7.9 ± 2.2 0.313 (-0.4–1.0) 0.387 high 9.0 ± 1.9 1.510 (0.9–2.1) <0.001 monthly income in kd <1,000 7.9 ± 2.1 <0.001§ 1,000–2,000 8.5 ± 2.2 0.521 (0.0–1.1) 0.060 >2,000 9.3 ± 1.9 0.896 (0.2–1.6) <0.001 dm = diabetes mellitus; sd = standard deviation; ci = confidence interval; kd = kuwaiti dinar. *knowledge levels were assessed using an arabic version of the 14-item diabetes knowledge test.7,16 †difference in mean score. ‡adjusted for age, gender and education level (income was not included due to the collinearity of this variable). §using a chi-squared test. diabetes-related knowledge and preventative practices among government employees with diabetes in kuwait e448 | squ medical journal, november 2017, volume 17, issue 4 their blood glucose regularly and took the hba1c test appropriately. in the crude analysis, education level and income were significantly associated with high dm knowledge (p <0.001 each). although both nationality and place of residence were significantly associated with income, these factors did not have a significant table 4: associations between preventative practices* and sociodemographic factors among kuwaiti ministry employees with diabetes (n = 312) characteristic mean preventative practice score ± sd p value β† (95% ci) p value age in years ≤40 5.7 ± 2.6 0.296 4–49 5.3 ± 2.3 -0.343 (-1.1–0.4) 0.382 ≥50 5.9 ± 2.8 0.475 (-0.3–1.3) 0.243 gender male 5.5 ± 2.7 0.196 female 5.9 ± 2.4 0.603 (0.0–1.3) 0.094 nationality‡ kuwaiti 5.8 ± 2.6 0.196 non-kuwaiti 5.4 ± 2.5 -0.514 (-1.3–0.2) 0.172 marital status married 5.7 ± 2.6 0.862 single 5.5 ± 2.7 -0.262 (-1.5–1.0) 0.681 divorced/widowed 5.4 ± 2.3 -1.04 (-2.8–0.7) 0.254 place of residence kuwait city 5.9 ± 2.9 0.294 hawalli 5.6 ± 2.5 -0.092 (-0.9–0.7) 0.831 farwaniya 5.1 ± 2.2 0.022 (-0.9–1.0) 0.962 mubarak alkabeer 6.2 ± 2.9 0.409 (-0.8–1.6) 0.494 al-ahmadi/aljahra 5.3 ± 2.5 -0.186 (-1.4–1.0) 0.751 education level low 5.5 ± 2.7 0.183 average 5.3 ± 2.7 -0.587 (-1.5–0.3) 0.195 high 5.9 ± 2.4 0.193 (-0.6–1.0) 0.633 monthly income in kd <1,000 5.3 ± 2.5 0.012 1000–2000 5.7 ± 2.6 0.657 (0.0–1.3) 0.057 >2,000 6.5 ± 2.4 1.376 (0.5–2.3 0.002 sd = standard deviation; ci = confidence interval; kd = kuwaiti dinar. *preventative practices were assessed using a 14-item arabic-language questionnaire based on the recommendations of the american diabetes association.17 †difference in mean score. ‡adjusted for age, gender and smoking status. table 5: associations between preventative practices* and clinical characteristics among kuwaiti ministry employees with diabetes (n = 312) characteristic mean preventative practice score ± sd p value β† (95% ci) p value dm duration in years ≤3 5.0 ± 2.2 0.006 3–10 6.0 ± 2.6 0.805 (0.0–1.6) 0.037 >10 6.0 ± 2.9 0.919 (0.0–1.7) 0.026 number of dm complications 0 5.6 ± 2.4 0.781 1 5.7 ± 2.8 0.328 (-0.5–1.1) 0.411 2 5.9 ± 3.3 0.446 (-0.8–1.7) 0.473 3 6.3 ± 2.3 0.989 (-0.7–2.7) 0.261 smoking status current smoker 4.8 ± 2.6 0.005 previous smoker 5.9 ± 2.6 -0.999 (-1.8–0.0) 0.019 nonsmoker 5.9 ± 2.5 -0.199 (-1.1–0.7) 0.671 bmi in kg/m2‡ ≤25.00 5.8 ± 3.1 0.839 25.01–30.00 5.6 ± 2.6 -0.179 (-1.1–0.8) 0.709 ≥30.01 5.5 ± 2.3 -0.083 (-1.0–0.8) 0.859 knowledge level§ low 4.6 ± 2.7 <0.001 average 5.8 ± 2.5 0.713 (0.0–1.6) 0.092 high 6.9 ± 2.6 1.783 (0.4–3.2) 0.015 sd = standard deviation; ci = confidence interval; dm = diabetes mellitus; bmi = body mass index. *preventative practices were assessed using a 14-item arabic-language questionnaire based on the recommendations of the american diabetes association.17 †difference in mean score. ‡adjusted for age, gender and income. §knowledge levels were assessed using an arabic version of the 14-item diabetes knowledge test, with scores of ≤6, 7–11 and ≥11 indicating low, average and high knowledge levels, respectively.7,16 ahmad j. abdulsalam, abdullah e. al-daihani and kostantinos francis clinical and basic research | e449 impact on knowledge scores [table 3]. only income was significantly associated with higher preventative scores (p = 0.012), even after adjusting for age and gender [table 4]. knowledge score was the only significant factor associated with high preventative practice scores in both the crude and adjusted analyses (p <0.050) [table 5]. discussion this cross-sectional study assessed the level of dm knowledge and adherence to ada-recommended prev entative practices among government employees with dm in kuwait.17 the estimated prevalence of diabetes in the sample (6.3%) was much lower than that estimated for the general population (25.4%); this may be due to the fact that younger and geriatric individuals were omitted from the current study.4 in addition, individuals in kuwait with severe diabetes are usually exempted from work and so were not included in the study population. the characteristics of the current sample also differed from the general population in terms of nationality, gender and education; according to the 2011 national census, kuwaitis represented only approximately one-third of the total population, there was a preponderance of males (56.7%) due to the presence of male immigrant workers and only 15.9% of the population had a high education level.18 in the current study, the mean dm knowledge score was slightly lower than that noted in a previous study involving patients with type 2 dm attending diabetes clinics in kuwait, although both mean scores fell within the average range (8.33 versus 8.93).7 to some extent, this finding is to be expected as the current sample was recruited from a community setting and therefore included individuals who did not attend regular follow-up appointments with healthcare practitioners and would accordingly have less knowledge of their condition. however, it should be noted that participants in the current study were younger (mean age of 45.6 versus 55.6 years), more highly educated (48.7% versus 4.4% with a university education) and had a lower disease severity (32.4% versus 57% with dm-related complications) than those of the previous study.7 nevertheless, it is alarming that only 6% of participants in the current sample had high levels of dm-related knowledge, revealing a considerable knowledge gap. moreover, less than half of the participants could correctly answer several specific knowledge questions, particularly those regarding diet, the treatment of low glucose levels and the nature of the hba1c test; these results are comparable to those reported previously.7 the current study evaluated levels of dm knowledge using a modified version of the diabetes knowledge test.16 a previous study using the same assessment tool found that age, smoking status, number of dm-related complications and dm duration were significantly associated with dm knowl edge scores.7 these associations were not observed in the current study, possibly because the ages of the participants spanned a relatively narrow range, smoking was more infrequent and the sample was derived from a community setting and therefore had fewer complications. al-qazaz et al. reported a significant association between diabetes knowledge and education levels among 505 type 2 diabetics in a tertiary institute in malaysia; this finding was consistent with that observed in the current study.8 overall, education and income levels seem to be factors which are unaffected by selection bias. adherence to preventative practices is important to reduce the risk of developing dm-related complications, such as neuropathy, nephropathy and retinopathy.9 high preventative practice scores were associated with both income and education levels in the current study. in general, individuals with higher education levels and incomes have increased general knowledge regarding their health and greater access to health facilities, which often translates to greater dm-related knowledge and adherence to preventative practices.2,19 similarly to a previous study conducted in india, high knowledge scores were significantly correlated with preventative practice scores in the present study, suggesting that people who are more aware of the disease and its associated complications are more likely to adhere to recommended preventative practices.20 another study reported significantly lower levels of adherence to preventative practices among newly diagnosed patients, indicating an association with dm duration.9 greater adherence to preventative practices has also been reported among nonsmokers, which is appropriate as such individuals tend to be more health conscious than smokers.21 in the current study, the median preventative practice score was 5, indicating that participants followed only approximately one-third of the preventative practices recommended by the ada.17 critically, only 32.3% of the current sample reported regularly an unsatisfactory level of adherence to recommended guidelines among 5,000 subjects with dm visiting a tertiary hospital in south korea; however, 84.9% of patients reported having undergone an hba1c test in comparison to only 20% of participants in the current study.9 this difference could be due to the fact that dm patients recruited from a tertiary hospital diabetes-related knowledge and preventative practices among government employees with diabetes in kuwait e450 | squ medical journal, november 2017, volume 17, issue 4 probably received more detailed information about the importance of achieving glycaemic control and had closer contact with their healthcare providers. however, less than 46% of the korean sample adhered to guidelines about lipid profiles, renal function testing, and eye examinations, which is comparable to the findings of the present study.9 the findings of the current study indicate the need for extensive educational and health-promoting dm campaigns in the kuwaiti community, with special outreach tactics to target individuals of a lower socioeconomic status.22 moreover, healthcare providers caring for diabetics (such as diabetes educators, primary care doctors and diabetes specialists) should be made aware that members of the general public may demonstrate average dm-related knowledge and poor adherence to preventative practices. in addition, healthcare providers should implement various screening and monitoring tests, including hba1c, micro-albuminuria, diabetic retinopathy and diabetic peripheral neuropathy tests; this will not only improve dm management but may also positively affect their patients’ dm-related knowledge levels and adherence to preventative practices. to this end, healthcare providers should educate all patients and encourage preventative practices such as daily blood sugar measurements and exercise schedules.14,15,23 a major limitation of the current study was that the sample was not representative of the general kuwaiti population; it is therefore expected that the results would differ from those of a more representative sample. similar to other research, the data in this study were self-reported and subject to expectation bias.24 these findings may overestimate the level of adherence to preventative practices and underestimate the severity of dm cases. finally, the current study did not address different patient and health system-related barriers to adherence for recommended preventative practices.17,25 conclusion this study found that a community sample of government employees in kuwait with either type 1 or type 2 dm demonstrated average dm-related knowledge levels and poor adherence to recommended preventative practices. these findings are alarming even considering the potential for estimation error due to sample bias. there is therefore an urgent need for healthcare providers and policy-makers in kuwait to design, implement and promote various dm prevention strategies targeting diabetic government employees, in particular those of lower socioeco nomic status. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. wild s, roglic g, green a, sicree r, king h. global prevalence of diabetes: estimates for the year 2000 and projections for 2030. diabetes care 2004; 27:1047–53. doi: 10.2337/ diacare.27.5.1047. 2. karbalaeifar r, kazempour-ardebili s, amiri p, ghannadi s, tahmasebinejad z, amouzegar a. evaluating the effect of knowledge, attitude and practice on self-management in patients with type 2 diabetes. acta diabetol 2016; 53:1015–23. doi: 10.1007/s00592-016-0905-6. 3. abdella n, al arouj m, al nakhi a, al assoussi a, moussa m. non-insulin-dependent diabetes in kuwait: prevalence rates and associated risk factors. diabetes res clin pract 1998; 42:187–96. doi: 10.1016/s0168-8227(98)00104-1. 4. channanath am, farran b, behbehani k, thanaraj ta. state of diabetes, hypertension, and comorbidity in kuwait: showcasing the trends as seen in native versus expatriate populations. diabetes care 2013; 36:e75. doi: 10.2337/dc12-2451. 5. hartayu ts, mi mi, suryawati s. improving of type 2 diabetic patients’ knowledge, attitude and practice towards diabetes self-care by implementing community-based interactive approach-diabetes mellitus strategy. bmc res notes 2012; 5:315. doi: 10.1186/1756-0500-5-315. 6. padma k, bele sd, bodhare tn, valsangkar s. evaluation of knowledge and self care practices in diabetic patients and their role in disease management. natl j community med 2012; 3:3–6. 7. al-adsani am, moussa ma, al-jasem li, abdella na, alhamad nm. the level and determinants of diabetes knowledge in kuwaiti adults with type 2 diabetes. diabetes metab 2009; 35:121–8. doi: 10.1016/j.diabet.2008.09.005. 8. al-qazaz hkh, sulaiman sa, hassali ma, shafie aa, sundram s, al-nuri r, et al. diabetes knowledge, medication adherence and glycemic control among patients with type 2 diabetes. int j clin pharm 2011; 33:1028–35. doi: 10.1007/ s11096-011-9582-2. 9. oh sw, lee hj, chin hj, hwang ji. adherence to clinical practice guidelines and outcomes in diabetic patients. int j qual health care 2011; 23:413–19. doi: 10.1093/intqhc/mzr036. 10. bains ss, egede le. associations between health literacy, diabetes knowledge, self-care behaviors, and glycemic control in a low income population with type 2 diabetes. diabetes technol ther 2011; 13:335–41. doi: 10.1089/dia.2010.0160. 11. mcmanus rm, stitt lw, bargh gj. population survey of diabetes knowledge and protective behaviours. can j diabetes 2006; 30:256–63. doi: 10.1016/s1499-2671(06)03009-7. 12. kheir n, greer w, yousif a, al geed h, al okkah r. knowledge, attitude and practices of qatari patients with type 2 diabetes mellitus. int j pharm pract 2011; 19:185–91. doi: 10. 1111/j.2042-7174.2011.00118.x. 13. abahussain na, el-zubier ag. diabetes knowledge among self reported diabetic female teachers: al-khobar, saudi arabia. j family community med 2005; 12:43–8. 14. al-maskari f, el-sadig m, al-kaabi jm, afandi b, nagelkerke n, yeatts kb. knowledge, attitude and practices of diabetic patients in the united arab emirates. plos one 2013; 8:e52857. doi: 10.1371/journal.pone.0052857. https://doi.org/10.2337/diacare.27.5.1047 https://doi.org/10.2337/diacare.27.5.1047 https://doi.org/10.1007/s00592-016-0905-6 https://doi.org/10.1016/s0168-8227%2898%2900104-1 https://doi.org/10.2337/dc12-2451 https://doi.org/10.1186/1756-0500-5-315 https://doi.org/10.1016/j.diabet.2008.09.005 https://doi.org/10.1007/s11096-011-9582-2 https://doi.org/10.1007/s11096-011-9582-2 https://doi.org/10.1093/intqhc/mzr036 https://doi.org/10.1089/dia.2010.0160 https://doi.org/10.1016/s1499-2671%2806%2903009-7 https://doi.org/10.1111/j.2042-7174.2011.00118.x https://doi.org/10.1111/j.2042-7174.2011.00118.x https://doi.org/10.1371/journal.pone.0052857 ahmad j. abdulsalam, abdullah e. al-daihani and kostantinos francis clinical and basic research | e451 15. al bimani zs, khan sa, david p. evaluation of t2dm related knowledge and practices of omani patients. saudi pharm j 2015; 23:22–7. doi: 10.1016/j.jsps.2013.12.006. 16. fitzgerald jt, funnell mm, hess ge, barr pa, anderson rm, hiss rg, et al. the reliability and validity of a brief diabetes knowledge test. diabetes care 1998; 21:706–10. doi: 10.2337/ diacare.21.5.706. 17. american diabetes association. executive summary: standards of medical care in diabetes 2012. diabetes care 2012; 35:s4–10. doi: 10.2337/dc12-s004. 18. kuwait central statistical bureau. annual statistical abstracts. from: www.csb.gov.kw/socan_statistic_en.aspx?id=18 accessed: jul 2017. 19. agardh e, allebeck p, hallqvist j, moradi t, sidorchuk a. type 2 diabetes incidence and socio-economic position: a systematic review and meta-analysis. int j epidemiol 2011; 40:804–18. doi: 10.1093/ije/dyr029. 20. balasubramaniyan n, ganesh kumar s, ramesh babu k, subitha l. awareness and practices on eye effects among people with diabetes in rural tamil nadu, india. afr health sci 2016; 16:210–17. doi: 10.4314/ahs.v16i1.28. 21. kelly mp, barker m. why is changing health-related behaviour so difficult? public health 2016; 136:109–16. doi: 10.1016/j. puhe.2016.03.030. 22. rhee mk, cook cb, el-kebbi i, lyles rh, dunbar vg, panayioto rm, et al. barriers to diabetes education in urban patients: perceptions, patterns, and associated factors. diabetes educ 2005; 31:410–17. doi: 10.1177/0145721705277022. 23. pirdehghan a, poortalebi n. predictors of adherence to type 2 diabetes medication. j res health sci 2016; 16:72–5. 24. guess nd, caengprasath n, dornhorst a, frost gs. adherence to nice guidelines on diabetes prevention in the uk: effect on patient knowledge and perceived risk. prim care diabetes 2015; 9:407–11. doi: 10.1016/j.pcd.2015.04.005. 25. zgibor jc, songer tj. external barriers to diabetes care: addressing personal and health systems issues. diabetes spectr 2001; 14:23–8. doi: 10.2337/diaspect.14.1.23. https://doi.org/10.1016/j.jsps.2013.12.006 https://doi.org/10.2337/diacare.21.5.706 https://doi.org/10.2337/diacare.21.5.706 https://doi.org/10.2337/dc12-s004 https://doi.org/10.1093/ije/dyr029 https://doi.org/10.4314/ahs.v16i1.28 https://doi.org/10.1016/j.puhe.2016.03.030 https://doi.org/10.1016/j.puhe.2016.03.030 https://doi.org/10.1177/0145721705277022 https://doi.org/10.1016/j.pcd.2015.04.005 https://doi.org/10.2337/diaspect.14.1.23 both stroke and diabetes mellitus (dm)are increasingly common conditions that contribute to worldwide morbidity and mortality, thus necessitating urgent action. globally, there were 33 million estimated cases of stroke in 2013, with a loss of 39.4 and 62.8 million disability-adjusted life years (dalys) due to ischaemic and haemorrhagic stroke, respectively.1,2 furthermore, stroke was the second most common cause of death (11.8%) and the third most common cause of disability (4.5%).2 a systematic review of 64 studies from the middle east indicated incidence and prevalence rates of 22.7–250 and 508–777 per 100,000 people per year, respectively.3 over the next 20 years, stroke-related mortality is predicted to triple in africa, the middle east and in latin american countries.4 in 2014, an estimated 422 million adults worldwide had dm, with the prev alence almost doubling from 4.7% in 1980 to 8.5% in 2014, the greatest burden of which was in lowand middle-income countries.5,6 in the eastern mediterranean region, the prevalence of dm is particularly high (3.5–30%), with gulf cooperation council countries observed to have some of the highest dm prevalence rates in the region.7 diabetes is associated with several neurological disorders, with stroke being the most well-recognised and, likely, the most common. diabetes is known to influence almost all varieties of stroke, including large artery stroke due to atherosclerosis, lacunar stroke and, possibly, intracerebral haemorrhage due to microvascular injury and embolic stroke due to diabetes; the latter of which is a significant risk factor for atrial fibrillation and hence part of risk factor assessment.8 diabetic indiv iduals have a 2.5–3.6-times higher risk of stroke compared to non-diabetics, with diabetic women at an increased risk compared to men.5,9–11 rammal et al. estimated the prev alence of diabetes in ischaemic stroke to be 37.5% in the arab world, based on an analysis of 29 studies of 10,242 patients.12 in an unpublished case-control study conducted in oman, the prevalence of dm was 62.3% versus 44.7% among ischaemic stroke cases compared to controls (p <0.001).13 in another study from oman based on stroke registry data, 52% of 600 patients with ischaemic stroke had diabetes.14 a growing body of literature in recent decades has recognised the link between dm and cerebral atrophy, as well as cognitive dysfunction.8,15–18 the strong inter relationship between dm and stroke may be due not only to microand macrovascular injuries associated with dm, but also to other shared risk factors such as genetic, demographic and lifestyle factors that are likely influenced by age and gender.8 in terms of the mechanism of vascular injury in diabetes, evidence indic ates that hyperglycaemia (and possibly insulin resistance) leads to oxidative stress and the overproduction of reactive oxygen species, triggering multiple biochemical path ways and, ultimately, endothelial dysfunction and vasc ular injury.8,15 early endothelial changes may lead to accel erated macrovascular atherosclerosis as well as changes in microvascular blood flow control and permeability.16 the phenomenon of ‘metabolic memory’ complicates the course of dm, with a prolonged progression of micro and macrovascular complications observed, even after prompt and intensive glycaemic control.17 currently, mechanisms of nonvascular brain injury are still being explored. several of the above mechanisms as well as endothelial dysfunction, alterations in blood brain barrier function and inflammation may contribute to nonvascular neurological injury.18 in view of the strong relationship between diabetes and stroke, it is natural to explore various methods of cerebrovascular evaluation to better understand the pathophysiology of these conditions or to predict epis odes of cerebrovascular injury. carotid doppler ultrasonography is a relatively simple and noninvasive method of visualising the superficial blood vessels and can be used to clinically evaluate the cervical carotid and parts of the vertebral arteries in the context of stroke. using doppler ultrasonography, the carotid intima media thick department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: arunoday@squ.edu.om مرض السكري والسكتة الدماغية أكثر من جمرد تسارع تصلب الشرايني؟ اأرونوداي جوجار editorial diabetes and stroke more than just accelerated atherosclerosis? arunodaya r. gujjar sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e261–263, epub. 19 dec 18 submitted 16 oct 18 revision req. 24 oct 18; revision recd. 18 nov 18 accepted 19 nov 18 doi: 10.18295/squmj.2018.18.03.001 diabetes and stroke more than just accelerated atherosclerosis? e262 | squ medical journal, august 2018, volume 18, issue 3 ness (cimt) can be measured and used as surrogate evidence of vascular injury as thickening of the tunica intima is known to be a precursor of atherosclerosis.19,20 the cervical carotid arteries are a fairly easy and convenient location to study this, particularly as they are also the location of the atherosclerotic plaques that lead to stroke. vascular ultrasonography is another simple method of quantifying the extent of arterial narrowing, as measured by the diameter or cross-sectional area of the lumen or by recognising turbulent changes in blood flow.19,20 in this issue of squmj, nazish et al. have published a retrospective study in which they report a relationship between glycated haemoglobin (hba1c) and cimt and carotid plaques among adult ischaemic stroke patients who underwent carotid doppler ultrasonography in addition to brain imaging.21 the authors found a signif icant association between mean hba1c levels and incr eased cimt, but not with the presence of carotid plaques. a regression analysis indicated that dyslipidaemia and age were independently correlated with high cimt, but not with hba1c levels.21 the results of this study are similar to those of other studies exploring the role of carotid ultrasound cimt and plaque findings as surrogate risk factors for stroke in general, as well as among patients with diabetes.20,22,23 however, the strength of the relationship between cimt and stroke among diabetic patients has not yet been determined. increased cimt has been associated with other factors influencing stroke, such as hypertension, hyperlipidaemia, smoking, obesity, advanced age and genetic factors.24 in addition, while some studies have demonstr ated cimt to be a risk factor for diabetes, others have demonstrated only an association on univariate analysis and not as an independent risk factor.23 nevertheless, community-based studies of vascular changes are of value because they enhance our understanding of the underlying pathophysiological mechanisms of these conditions; in addition, such research may inform future targets of therapy or be used as markers of treatment efficacy.19,20,25 apart from vascular ultrasonography, other methods may be of use when exploring the complex interactions between diabetes and brain dysfunction. as mentioned earlier, diabetes is a risk factor for other mechanisms of brain injury leading to cerebral small vessel disease (csvd), non-stroke brain atrophy and cognitive dysf unction.18 with magnetic resonance imaging (mri), csvd is now recognised to comprise a spectrum of brain changes including periventricular hyperintensities, lacunar stroke, intracerebral microand macrohaemorrhage, enlarged perivascular spaces and cortical siderosis.26,27 several studies have demonstrated an assoc iation between diabetic retinopathy and lacunar stroke as well as cognitive dysfunction, although the relation between csvd and diabetic microangiopathy is not yet clear.26–28 apart from conventional changes observed in diabetic retinopathy, such as retinal haemorrhage and changes in vascular diameter, novel methods such as optical coherence tomography, retinal vasculature fractal dimension and laser flowmetry are being explored as methods of detecting brain injury.18,29 using video capillaroscopy, microvasculature changes in the nail bed can be quantified and have been utilised to demonstrate a relationship with diabetic microangiopathy; this method could potentially be explored as a surrogate marker for brain injury.30 skin autofluorescence, which reflects the accumulation of advanced glycation endproducts in diabetes, has been associated with brain cortical atrophy.31 overall, mri is a sensitive method of studying structural changes in the brain. a review of studies addressing mri findings among diabetic subjects indicated that diffuse brain atrophy as well as increased csvd changes were associated with diabetes; such changes are only explained in part by age and the presence of other adverse vascular risk factors.32 mri is also useful in the detection of microstructural brain lesions among diabetic subjects.32,33 attempts to link mri findings of structural brain abnormalities to histology results may, for example, advance our understanding of the role of diabetic microvascular disease in the context of brain injury. while such methods of studying the relation between diabetes and brain injury may help predict neurological dysfunction, a more attractive application would be to monitor novel treatments. in conclusion, large artery stroke due to accelerated atherosclerosis is only one mechanism of neurological injury associated with diabetes, with several other mech anisms well recognised in relation to diabetes. cerebro vascular atherosclerosis can be easily explored using vascular doppler ultrasonography and angiography. however, csvd as well as nonvascular diabetic encephalopathy are conditions that may also be explored clinically based on other methods such as retinal or skin vascular changes or utilising advanced brain mri modalities. more studies are necessary to explore the utility of the latter approach in predicting neurobehavioural changes in patients with diabetes, enhancing our understanding of its pathophysiology and developing better methods of managing these conditions. references 1. krishnamurthi rv, feigin vl, forouzanfar mh, mensah ga, connor m, bennett da, et al. global and regional burden of first-ever ischaemic and haemorrhagic stroke during 19902010: findings from the global burden of disease study 2010. lancet glob health 2013; 1:e259–81. doi: 10.1016/s2214-10 9x(13)70089-5. https://doi.org/10.1016/s2214-109x%2813%2970089-5 https://doi.org/10.1016/s2214-109x%2813%2970089-5 arunodaya r. gujjar editorial | e263 2. feigin vl, forouzanfar mh, krishnamurthi r, mensah ga, connor m, bennett da, et al. global and regional burden of stroke during 1990–2010: findings from the global burden of disease study 2010. lancet 2014; 383:245–54. doi: 10.1016/ s0140-6736(13)61953-4. 3. el-hajj m, salameh p, rachidi s, hosseini h. the epidemiology of stroke in the middle east. eur stroke j 2016; 1:180–98. doi: 10.1177/2396987316654338. 4. world heart federation. stroke. from: www.world-heart-federa tion.org/cardiovascular-health/stroke accessed: nov 2018. 5. world health organization. global report on diabetes. from: www.who.int/diabetes/global-report/en/ accessed: nov 2018. 6. international diabetes federation. key messages. from: www. diabetesatlas.org/key-messages.html accessed: nov 2018. 7. world health organization. world health statistics 2015. from: www.who.int/gho/publications/world_health_statistics/2015/ en/ accessed: nov 2018. 8. luitse mj, biessels gj, rutten ge, kappelle lj. diabetes, hyperglycaemia, and acute ischaemic stroke. lancet neurol 2012; 11:261–71. doi: 10.1016/s1474-4422(12)70005-4. 9. karapanayiotides t, piechowski-jozwiak b, van melle g, bogousslavsky j, devuyst g. stroke patterns, etiology, and prog nosis in patients with diabetes mellitus. neurology 2004; 62:1558–62. doi: 10.1212/01.wnl.0000123252.55688.05. 10. writing group members, mozaffarian d, benjamin ej, go as, arnett dk, blaha mj, et al. heart disease and stroke statistics: 2016 update a report from the american heart association. circulation 2016; 133:e38–360. doi: 10.1161/cir.00000000000 00350. 11. emerging risk factors collaboration, sarwar n, gao p, seshasai sr, gobin r, kaptoge s, et al. diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. lancet 2010; 375:2215–22. doi: 10.1016/s0140-6736(10)60484-9. 12. rammal sa, almekhlafi ma. diabetes mellitus and stroke in the arab world. j taibah univ med sci 2016; 11:295–300. doi: 10.1016/j.jtumed.2016.05.001. 13. ganguly ss, al-harthi h, gujjar ar, kumar s, al-hashmi a, al-asmi ar. risk factors for ischemic stroke in an omani community: a case-control study. abstract presented at the 5th international conference on neurology & epidemiology, 18–20 november 2015, griffith university, gold coast, australia. 14. gujjar a, ramachandiran n, al-asmi a, ganguly s, shoaib r, al-asmi a. ischemic stroke outcomes in oman: experience of a university hospital based stroke registry. neurology 2017; 88:6.278. 15. qiu c, sigurdsson s, zhang q, jonsdottir mk, kjartansson o, eiriksdottir g, et al. diabetes, markers of brain pathology and cognitive function: the age, gene/environment susceptibilityreykjavik study. ann neurol 2014; 75:138–46. doi: 10.1002/ ana.24063. 16. brownlee m. the pathobiology of diabetic complications: a unifying mechanism. diabetes 2005; 54:1615–25. doi: 10.2337/ diabetes.54.6.1615. 17. ceriello a, ihnat ma, thorpe je. clinical review 2: the “meta bolic memory” is more than just tight glucose control nece ssary to prevent diabetic complications? j clin endocrinol metab 2009; 94:410–15. doi: 10.1210/jc.2008-1824. 18. umemura t, kawamura t, hotta n. pathogenesis and neuro imaging of cerebral large and small vessel disease in type 2 diabetes: a possible link between cerebral and retinal microvascular abnormalities. j diabetes investig 2017; 8:134–48. doi: 10.1111/jdi.12545. 19. kasliwal rr, bansal m, desai d, sharma m. carotid intimamedia thickness: current evidence, practices, and indian exp erience. indian j endocrinol metab 2014; 18:13–22. doi: 10.41 03/2230-8210.126522. 20. touboul pj, hennerici mg, meairs s, adams h, amarenco p, bornstein n, et al. mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011): an update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th european stroke conferences, mannheim, germany, 2004, brussels, belgium, 2006, and hamburg, germany, 2011. cerebrovasc dis 2012; 34:290–6. doi: 10.1159/000343145. 21. nazish s, zafar a, shahid r, albakr a, alkhamis fa, aljaafari d, et al. relationship between glycated haemoglobin and carotid atherosclerotic disease among patients with acute ischaemic stroke. sultan qaboos univ med j 2018; 18:e311–17. doi: 10.182 95/squmj.2018.18.03.008. 22. o’leary dh, polak jf, kronmal ra, manolio ta, burke gl, wolfson sk jr. carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: cardiovascular health study collaborative research group. n engl j med 1999; 340:14–22. doi: 10.1056/nejm19990107340 0103. 23. lee ej, kim hj, bae jm, kim jc, han hj, park cs, et al. relevance of common carotid intima-media thickness and carotid plaque as risk factors for ischemic stroke in patients with type 2 diabetes mellitus. ajnr am j neuroradiol 2007; 28:916–19. 24. touboul pj, labreuche j, vicaut e, amarenco p; genic invest igators. carotid intima-media thickness, plaques, and fram ingham risk score as independent determinants of stroke risk. stroke 2005; 36:1741–5. doi: 10.1161/01.str.0000174490. 23495.57. 25. crouse jr 3rd, raichlen js, riley wa, evans gw, palmer mk, o’leary dh, et al. effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the meteor trial. jama 2007; 297:1344–53. doi: 10.1001/jama.297.12.1344. 26. pantoni l. cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. lancet neurol 2010; 9:689–701. doi: 10.1016/s1474-4422(10)70104-6. 27. shi y, wardlaw jm. update on cerebral small vessel disease: a dynamic whole-brain disease. stroke vasc neurol 2016; 1:83–92. doi: 10.1136/svn-2016-000035. 28. cheung cy, ikram mk, klein r, wong ty. the clinical implic ations of recent studies on the structure and function of the retinal microvasculature in diabetes. diabetologia 2015; 58:871–85. doi: 10.1007/s00125-015-3511-1. 29. grauslund j, green a, kawasaki r, hodgson l, sjølie ak, wong ty. retinal vascular fractals and microvascular and macrovascular complications in type 1 diabetes. ophthalmology 2010; 117:1400–5. doi: 10.1016/j.ophtha.2009.10.047. 30. kuryliszyn-moskal a, zarzycki w, dubicki a, moskal d, kosztyła-hojna b, hryniewicz a. clinical usefulness of video capillaroscopy and selected endothelial cell activation markers in people with type 1 diabetes mellitus complicated by microangiopathy. adv med sci 2017; 62:368–73. doi: 10.1016/j.advms. 2016.11.007. 31. moran c, münch g, forbes jm, beare r, blizzard l, venn aj, et al. type 2 diabetes, skin autofluorescence, and brain atrophy. diabetes 2015; 64:279–83. doi: 10.2337/db14-0506. 32. biessels gj, reijmer yd. brain changes underlying cognitive dysfunction in diabetes: what can we learn from mri? diabetes 2014; 63:2244–52. doi: 10.2337/db14-0348. 33. van harten b, de leeuw fe, weinstein hc, scheltens p, biessels gj. brain imaging in patients with diabetes: a systematic review. diabetes care 2006; 29:2539–48. doi: 10.2337/dc06-1637. https://doi.org/10.1016/s0140-6736%2813%2961953-4 https://doi.org/10.1016/s0140-6736%2813%2961953-4 https://doi.org/10.1177/2396987316654338 https://doi.org/10.1016/s1474-4422%2812%2970005-4 https://doi.org/10.1212/01.wnl.0000123252.55688.05 https://doi.org/10.1161/cir.0000000000000350 https://doi.org/10.1161/cir.0000000000000350 https://doi.org/10.1016/s0140-6736%2810%2960484-9 https://doi.org/10.1016/j.jtumed.2016.05.001 https://doi.org/10.1002/ana.24063 https://doi.org/10.1002/ana.24063 https://doi.org/10.2337/diabetes.54.6.1615 https://doi.org/10.2337/diabetes.54.6.1615 https://doi.org/10.1210/jc.2008-1824 https://doi.org/10.1111/jdi.12545 https://doi.org/10.4103/2230-8210.126522 https://doi.org/10.4103/2230-8210.126522 https://doi.org/10.1159/000343145 https://doi.org/10.18295/squmj.2018.18.03.008 https://doi.org/10.18295/squmj.2018.18.03.008 https://doi.org/10.1056/nejm199901073400103 https://doi.org/10.1056/nejm199901073400103 https://doi.org/10.1161/01.str.0000174490.23495.57 https://doi.org/10.1161/01.str.0000174490.23495.57 https://doi.org/10.1001/jama.297.12.1344 https://doi.org/10.1016/s1474-4422%2810%2970104-6 https://doi.org/10.1136/svn-2016-000035 https://doi.org/10.1007/s00125-015-3511-1 https://doi.org/10.1016/j.ophtha.2009.10.047 https://doi.org/10.1016/j.advms.2016.11.007 https://doi.org/10.1016/j.advms.2016.11.007 https://doi.org/10.2337/db14-0506 https://doi.org/10.2337/db14-0348 https://doi.org/10.2337/dc06-1637 anterior ischaemic optic neuropathy (aion) is characterised by sudden vision loss as a result of an infarction of the optic nerve head due to an impairment of blood flow.1 the majority of cases are non-arteritic (90%); non-arteritic aion (naion) is associated with numerous risk factors, including diabetes mellitus, atherosclerosis and arterial hypotension, all of which compromise the blood supply of the optic nerve head.1 the main features of naion include unilateral vision loss usually occurring upon waking, ocular pain and headaches.2,3 bilateral naion is rare but can occur among patients on dialysis, individuals who experience blood loss and those on medications such as phosphodiesterase type 5 inhibitors and interferon-α.4,5 patients with end-stage renal disease are often managed via continuous peritoneal dialysis (cpd). episodes of systemic hypotension occur frequently among patients on cpd, thus predisposing these 1ophthalmology and 3orthopaedics residency programs, oman medical specialty board, muscat, oman; departments of 2opthamology and 4child health, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: aj.alkaabi@hotmail.com اإلعتالل العصيب البصري األمامي غري الشرياين بسبب نقص الرتوية الدموية لدى طفلة جتري الغسيل الربيتوين املستم تقرير حالة و مراجعة لألدبيات عبداهلل الكعبي, اآغ� �شه�ب حيدر, حممد �شفيق, حممد النج�ري, ابت�ش�م النور, انورادا غ�ني�س abstract: non-arteritic anterior ischaemic optic neuropathy (naion) is a serious complication of continuous peritoneal dialysis (cpd) which can lead to poor vision and blindness. we report a five-year-old girl who had undergone a bilateral nephrectomy at the age of one year and was on home cpd. she was referred to the paediatric ophthalmology unit of sultan qaboos university hospital, muscat, oman, in 2013 with acute bilateral vision loss, preceded by a three-day history of poor oral intake. at presentation, the patient had severe systemic hypotension. an ophthalmological examination revealed severe bilateral visual impairment and naion. she was treated with intravenous methylprednisolone and normal saline boluses. at a five-month follow-up, the visual acuity of the right eye had improved but vision in the left eye remained the same. acute bilateral blindness due to naion while on cpd is a rare condition in childhood. paediatricians should be aware of this complication in order to ensure prompt management. keywords: anterior ischemic optic neuropathy; blindness; hypotension; pediatrics; continuous ambulatory peritoneal dialysis; case report; oman. امللخ�ص: يعد العتالل الع�شبي الب�رسي الأم�مي غري ال�رسي�ين ب�شبب نق�س الرتوية الدموية من امل�ش�عف�ت اخلطرية للغ�شيل الربيتوين عندم� كليت�ه� ا�شتوؤ�شلت �شنوات خم�س العمر من تبلغ طفلة ح�لة هن� نعر�س والعمى. الب�رس �شعف اإىل يوؤدي قد اأنه حيث امل�شتمر ك�نت يف ال�شنة الأوىل من العمر وبقيت على الغ�شيل الربيتوين امل�شتمر ب�ملنزل. وقد مت حتويل الطفلة يف ع�م 2013 اإىل وحدة طب العيون لالأطف�ل مب�شت�شفى ج�معة ال�شلط�ن ق�بو�س مب�شقط, عم�ن بعد اإ�ش�بته� ب�نخف��س ح�د ومف�جئ يف الب�رس. وقد ك�نت الطفلة وملدة ثالثة اأي�م قبل فقدانه� الب�رس تع�ين من اإنخف��س معدل تن�ول ال�رساب والطع�م عن طريق الفم. وعند فح�س الطفلة ب�مل�شت�شفى ك�نت تع�ين من هبوط ح�د يف �شغط الدم. واأظهر فح�س العينني عن �شعف ح�د يف الب�رس واإعتالل الع�شب الب�رسي الأم�مي غري ال�رسي�ين ب�شبب نق�س الرتوية الدموية. عوجلت الطفلة ب�إ�شتخدام دواء امليثيل بريدنيزولون الوريدي وجرع�ت كبرية من املحلول امللحي النظ�مي. وبعد خم�شة اأ�شهر من املت�بعة لوحظ حت�شن يف حدة الب�رس يف العني اليمنى بينم� بقيت العني الي�رسى على ح�له�. وجتدر الإ�ش�رة اإىل اأن النخف��س احل�د يف الب�رس ب�شبب العتالل الع�شبي الب�رسي الأم�مي غري ال�رسي�ين ب�شبب نق�س الرتوية الدموية ملر�شى للغ�شيل الربيتوين امل�شتمر تعد ح�لة ن�درة يف مرحلة الطفولة. وينبغي اأن يكون اأطب�ء الأطف�ل على بينة من هذا الت�شخي�س يف مثل هوؤلء املر�شى من اأجل �شم�ن تدخل �رسيع وفع�ل. الكلمات املفتاحية: العتالل الع�شبي الب�رسي غري ال�رسي�ين ب�شبب نق�س الرتوية الدموية؛ العمي؛ انخف��س �شغط الدم؛ الأطف�ل؛ الغ�شيل الربيتوين امل�شتمر املتنقل؛ عر�س ح�لة طبية؛ عم�ن. bilateral anterior ischaemic optic neuropathy in a child on continuous peritoneal dialysis case report and literature review *abdullah al-kaabi,1 agha s. haider,2 mohammed o. shafeeq,3 mohammed a. el-naggari,4 ibtisam el-nour,4 anuradha ganesh2 sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e504–507, epub. 30 nov 16 submitted 13 apr 16 revision req. 18 may 16; revision recd. 16 jun 16 accepted 19 jul 16 doi: 10.18295/squmj.2016.16.04.018 case report abdullah al-kaabi, agha s. haider, mohammed o. shafeeq, mohammed a. el-naggari, ibtisam el-nour and anuradha ganesh case report | e505 individuals to naion.6 this report describes a fiveyear-old child who developed acute bilateral blindness due to naion while on cpd and presents a review of the literature of this serious ophthalmic complication among children undergoing dialysis. case report a five-year-old girl was referred from the paediatric nephrology unit to the paediatric ophthalmology unit of the sultan qaboos university hospital, muscat, oman, in 2013 due to acute bilateral vision loss, noted upon waking from sleep. the mother of the patient reported a history of poor oral intake, dizziness and blurred vision for three days prior to the acute deterioration of vision. there was no history of vomiting or diarrhoea. the patient had undergone a bilateral nephrectomy at the age of one year due to congenital nephrotic syndrome which had been diagnosed when she was 20 days old. following the procedure, the patient had been on home cpd using dianeal pd4 glucose 2.27% (baxter healthcare ltd., thetford, norfolk, uk) at six cycles per day for a total duration of 12 hours with a fill volume of 450 ml. since then, she had suffered periodic episodes of systemic hypotension for which she had been admitted to hospital several times. six months prior to the current presentation, the patient had been admitted to hospital for the management of posterior reversible encephalopathy syndrome. at referral, the patient showed no signs of dehydration, although her blood pressure (bp) was very low for her age and height (50/25 mmhg). she received intravenous fluids until her bp returned to normal. a neurological examination was unremarkable apart from the visual impairment. in terms of visual acuity, an ophthalmological examination revealed light perception in the right eye and counting fingers close to face in her left eye. visual field testing using the confrontation method was not possible for the right eye due to her low visual acuity; however, the left eye showed superior and nasal field constriction. the pupils were dilated bilaterally, fixed with no direct light reaction in the right eye and sluggishly reacting to light in the left eye. a funduscopy showed bilateral pale optic disc oedema with blurred margins. there was an obscured peripapillary nerve fibre layer and tort uous vessels with flame-shaped haemorrhage close to the disc margin in the right eye, while the disc pallor was more severe in the left eye [figure 1]. blood investigations showed haemoglobin levels of 10.4 g/dl and urea levels of 21.4 µmol/l, which were considered appropriate as the patient was on cpd; as such, anaemia and uraemia were excluded as causes of the naion. a magnetic resonance imaging (mri) scan of the brain showed features consistent with posterior reversible encephalopathy syndrome. no other lesions were observed, thus ruling out infiltrative optic neuropathy and intracranial causes of naion [figure 2]. there was no evidence of optic nerve drusen on optical coherence tomography. the patient was treated with intravenous methylprednisolone at 20 mg/kg/day for five days, followed by oral prednisolone at 2 mg/kg/day for one month as a tapering dose. to prevent anaemia, erythropoietin was also prescribed at an optimised dose. normal saline boluses were administered to control the hypotension. dialysis was continued at six cycles per day; however, the duration of each cycle was reduced from one hour to half an hour for two days. an ophthalmological review prior to discharge showed no significant changes. funduscopy images revealed figure 1: funduscopy images of a five-year-old child on continuous peritoneal dialysis with acute bilateral vision loss. bilateral pallid disc oedema with blurred margins was observed in both the (a) right and (b) left eyes. the right eye had an obscured peripapillary nerve fibre layer and tortuous vessels with flame-shaped haemorrhage close to the disc margin (arrow). the disc pallor was more severe in the left eye. bilateral anterior ischaemic optic neuropathy in a child on continuous peritoneal dialysis case report and literature review e506 | squ medical journal, november 2016, volume 16, issue 4 and bilateral mydriasis unreactive to bright light.12−15 in general, naion is associated with low bp and hypovolemia.12−16 it can occur following parainfectious or post-vaccine optic neuritis as well; however, visual loss in these cases is usually bilateral and more severe at onset.17 naion has also been documented among children undergoing major surgical procedures.16 it is important to rule out other possible causes of naion, such as uremic optic neuropathy, increased intracranial pressure and drug toxicity.8–10 nanji et al. reported an association with optic nerve drusen, which are calcific deposits that form in the optic nerve head secondary to abnormalities in axonal metabolism and degeneration.7 all of these factors were ruled out in the current patient; however, she had had periodic episodes of hypotension preceding the vision loss. as such, the cause of naion was attributed to hypotension-induced low perfusion and ischaemia of the optic nerve. the pathophysiology of aion is due to the susceptibility of the optic nerve to ischaemia and the tendency of the retina to develop an ischaemic injury; any increase in intraocular pressure or decrease in profusion may lead to ischaemia of the optic nerve and retina.18 moreover, the condition has also been reported in association with local anatomical and systemic factors such as the presence of a small optic nerve head with little cupping, intraocular hypertension, systemic hypertension, hypovolemia and anaemia.13 hypotension is considered among the main causes of decreased perfusion to the microcirculation of the optic disc and retina.1 chronic hypotension has been reported in children with naion.14 hypotension has also been shown to occur during sleep; among 925 cases of naion, 73% reported visual loss on waking from sleep.19 in the present case, the patient was found to be hypotensive on admission and reported the loss of vision upon waking from sleep. many causes can lead to chronic hypotension among patients on cpd, including hypovolemia, the use of anti-hypertensive medications and removal of vasopressors during dialysis.20 poor visual outcomes following naion have been reported among both children and adults on cpd.6,10,21 the treatment of aion involves the reversal of hypotension in order to maintain adequate perfusion to the optic nerve. the use of steroids is controversial, with some studies showing a positive outcome.3,22,23 the use of combined levodopa and carbidopa has been found to improve visual acuity in patients with aion.24 in addition, significant improvement in vision has been reported with steroids and levodopa.12 steroids and prostaglandins have also been reported to be effective.25 the current patient was managed that the naion was resolving with persistent bilateral disc pallor that was still more severe in the left eye compared to the right eye. upon discharge, the patient’s parents were advised of the importance of keeping their child hydrated and monitoring her bp in order to prevent further cpd complications. at a five-month follow-up, improvement was noted in the visual acuity of the right eye (0.6). however, vision in the left eye remained at counting fingers close to face. discussion apart from naion, other causes of acute bilateral vision loss include giant cell arteritis, optic nerve drusen, uremic optic neuropathy, infiltrative optic neuropathy and intracranial space-occupying lesions leading to optic nerve compression.7–10 however, the age of the patient in the current case was not consistent with a diagnosis of giant cell arteritis, which typically presents in old age.11 moreover, naion secondary to anaemia or uremic optic neuropathy were excluded following blood investigations while optic nerve drusen, infiltrative optic neuropathies and intracranial space-occupying lesions were ruled out via optical coherence tomography and mri. due to the presentation, naion was considered to be the underlying aetiology for the visual impairment. although bilateral naion is a rare disease among children, a few cases have been previously described in the literature; most children present with loss of light perception, visual fixation, ocular pursuit movements figure 2: magnetic resonance imaging of the brain of a five-year-old child on continuous peritoneal dialysis with acute bilateral vision loss. hypotense t1 and hyperintense t2 signals were noted in the bilateral parietal, occipital cortical and subcortical areas, consistent with vasogenic oedema suggestive of posterior reversible encephalopathy syndrome (white arrow). bifrontal and bilateral basal ganglionic hyperintensities were also present, likely due to calcification (black arrow). there was no evidence of cerebral venous thrombosis. abdullah al-kaabi, agha s. haider, mohammed o. shafeeq, mohammed a. el-naggari, ibtisam el-nour and anuradha ganesh case report | e507 with intravenous saline in addition to intravenous methylprednisolone followed by oral prednisolone. since the main aetiology of the condition in this case was hypotension, her parents were counselled to pay close attention to her hydration and bp levels after discharge in order to identify hypovolemia and prevent complications. conclusion children undergoing cpd are at risk of sudden blindness due to naion, mainly as a result of chronic hypotension. visual outcomes after treatment are generally poor. therefore, prompt management of hypotension and hypovolemia in children on cpd is necessary in order to prevent the development of this serious complication. references 1. hayreh ss. ischemic optic neuropathies: where are we now? graefes arch clin exp ophthalmol 2013; 251:1873−84. doi: 10.1007/s00417-013-2399-z. 2. hayreh ss, podhajsky pa, zimmerman b. nonarteritic anterior ischemic optic neuropathy: time of onset of visual loss. am j ophthalmol 1997; 124:641−7. doi: 10.1016/s00029394(14)70902-x. 3. swartz ng, beck rw, savino pj, sergott rc, bosley tm, lam bl, et al. pain in anterior ischemic optic neuropathy. j neuroophthalmol 1995; 15:9−10. doi: 10.1097/00041327199503000-00002. 4. pomeranz hd, bhavsar ar. nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. j neuroophthalmol 2005; 25:9−13. doi: 10.1097/00041327-200503000-00003. 5. lohmann cp, kroher g, bogenrieder t, spiegel d, preuner j. severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma. lancet 1999; 353:1326. doi: 10.1016/s0140-6736(99)00403-1. 6. chutorian am, geffner m. [anterior ischemic optic neuropathy in children]. rev neurol 1999; 29:366−75. 7. nanji aa, klein ks, pelak vs, repka mx. nonarteritic anterior ischemic optic neuropathy in a child with optic disk drusen. j aapos 2012; 16:207−9. doi: 10.1016/j.jaapos.2011.10.016. 8. knox dl, hanneken am, hollows fc, miller nr, schick hl jr, gonzales wl. uremic optic neuropathy. arch ophthalmol 1988; 106:50−4. doi: 10.1001/archopht.1988.01060130056027. 9. chang d, nagamoto g, smith we. benign intracranial hypertension and chronic renal failure. cleve clin j med 1992; 59:419−22. doi: 10.3949/ccjm.59.4.419. 10. dukar o, barr cc. visual loss complicating okt3 monoclonal antibody therapy. am j ophthalmol 1993; 115:781−5. doi: 10.10 16/s0002-9394(14)73648-7. 11. cullen jf. occult temporal arteritis: a common cause of blindness in old age. br j ophthalmol 1967; 51:513−25. doi: 10.1136/bjo.51.8.513. 12. lapeyraque al, haddad e, andré jl, brémond-gignac d, taylor cm, rianthavorn p, et al. sudden blindness caused by anterior ischemic optic neuropathy in 5 children on continuous peritoneal dialysis. am j kidney dis 2003; 42:e3−9. doi: 10.1016/j.ajkd.2003.07.009. 13. chutorian am, winterkorn jm, geffner m. anterior ischemic optic neuropathy in children: case reports and review of the literature. pediatr neurol 2002; 26:358−64. doi: 10.1016/s08878994(02)00398-3. 14. kim js, deputy s, vives mt, aviles dh. sudden blindness in a child with end-stage renal disease. pediatr nephrol 2004;19:691−3. doi: 10.1007/s00467-004-1447-7. 15. dufek s, feldkoetter m, vidal e, litwin m, munk m, reitner a, et al. anterior ischemic optic neuropathy in pediatric peritoneal dialysis: risk factors and therapy. pediatr nephrol 2014; 29:1249−57. doi: 10.1007/s00467-013-2747-6. 16. sivaswamy l, vanstavern gp. ischemic optic neuropathy in a child. pediatr neurol 2007; 37:371−2. doi: 10.1016/j.pediat rneurol.2007.06.023. 17. behbehani r. clinical approach to optic neuropathies. clin ophthalmol 2007; 1:233−46. 18. bates cm, baum m, hunchik m, quan a. acute vision loss in children with autosomal recessive polycystic kidney disease. am j kidney dis 1999; 34:1125−8. doi: 10.1016/s0272-6386 (99)70019-3. 19. hayreh ss, podhajsky p, zimmerman mb. role of nocturnal arterial hypotension in optic nerve head ischemic disorders. ophthalmologica 1999; 213:76−96. doi: 10.1159/000027399. 20. shetty a, afthentopoulos ie, oreopoulos dg. hypotension on continuous ambulatory peritoneal dialysis. clin nephrol 1996; 45:390−7. 21. jackson tl, farmer ck, kingswood c, vickers s. hypotensive ischemic optic neuropathy and peritoneal dialysis. am j ophthalmol 1999; 128:109−11. doi: 10.1016/s0002-9394(99) 00026-4. 22. hayreh ss, zimmerman mb. non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. graefes arch clin exp ophthalmol 2008; 246:1029−46. doi: 10.1007/s00417-008-0805-8. 23. rebolleda g, pérez-lópez m, casas-llera p, muñoz-negrete fj. treatment of non-arteritic anterior ischemic optic neuropathy with high-dose systemic corticosteroids. graefes arch clin exp ophthalmol 2013; 251:1031−2. doi: 10.1007/s00417-0122063-z. 24. johnson ln, guy me, krohel gb, madsen rw. levodopa may improve vision loss in recent-onset, nonarteritic anterior ischemic optic neuropathy. ophthalmology 2000; 107:521−6. 25. steigerwalt rd jr, cesarone mr, belcaro g, pascarella a, de angelis m, bacci s. nonarteritic anterior ischemic optic neuropathy treated with intravenous prostaglandin e1 and steroids. int j angiol 2008; 17:193−6. doi: 10.1055/s-00311278308. departments of 1haematology, 3child health and 6surgery, sultan qaboos university hospital; 4department of haematology, 2college of medicine & health sciences, sultan qaboos university, muscat, oman; 5department of planning & studies, oman medical specialty board, muscat, oman *corresponding author e-mail: arwa.alriyami@gmail.com أول تنفيذ لسياسة املوافقة املسبقة لعملية نقل الدم يف ُعمان دراسة تدقيقة على مدى اإللتزام يف مستشفى جامعي للرعاية الثالثية اأروى الريامية، نايف الغافري، فهميدة �صياء، حممد احلنيني، عبد-احلكيم الروا�ض، �صالم الكندي، �صا�صني خو�صيه، مرت�صى اخلابوري، هالل ال�صبتي، �صاهينا دار abstract: objectives: transfusions are a common medical intervention. discussion of the benefits, risks and alternatives with the patient is mandated by many legislations prior to planned transfusions. at the sultan qaboos university hospital (squh), muscat, oman, a written transfusion consent policy was introduced in march 2014. this was the first time such a policy was implemented in oman. this study therefore aimed to assess adherence to this policy among different specialties within squh. methods: the medical records of patients who underwent elective transfusions between june and august 2014 were reviewed to assess the presence of transfusion consent forms. if present, the consent forms were examined for completeness of patient, physician and witness information. results: in total, the records of 446 transfused patients (299 adult and 147 paediatric patients) were assessed. haematology patients accounted for 50% of adult patients and 71% of paediatric patients. consent was obtained for 75% of adult and 91% of paediatric patients. the highest adherence rate was observed among adult and paediatric haematology specialists (95% and 97%, respectively). consent forms were correctly filled out with all details provided for 51% and 52% of adult and paediatric patients, respectively. among inadequately completed forms, the most common error was a lack of witness details (20–25%). conclusion: in most cases, the pre-transfusion consent policy was successfully adhered to at squh. however, further work is required to ensure full compliance with the consent procedure within different specialties. implementation of transfusion consent in other hospitals in the country is recommended. keywords: blood transfusion; informed consent; policy compliance; clinical audit; oman. الدم نقل عملية اإجراء قبل املري�ض مع والبدائل واملخاطر املنافع مناق�صة �صائعًا. طبيًا تدخاًل الدم نقل عملية تعترب اأهداف: امللخ�ص: �صيا�صة اإدخال مت عمان، �صلطنة م�صقط، ،)squh( قابو�ض ال�صلطان جامعة م�صت�صفى يف الت�رضيعات، من العديد فر�صته اإجراء ب�صفته املوافقة اخلطيِّة امل�صبقة لعملية نقل الدم يف مار�ض 2014م. كانت هذه هي املرة االأوىل التي تنفذ فيها هذه ال�صيا�صة يف عمان. تهدف هذه الدرا�صة اإىل تقييم االلتزام بهذه ال�صيا�صة بني التخ�ص�صات املختلفة يف squh. منهجية: متت مراجعة ال�صجالت الطبية للمر�صى الذين خ�صعوا لعمليات نقل الدم بني يونيو واأغ�صط�ض عام 2014م لتقييم وجود ا�صتمارات املوافقة، مت فح�ض مناذج املوافقة اإن وجدت �صمن معلومات املري�ض، الطبيب وال�صهود. نتائج: يف املجموع، مت تقييم �صجالت 446 مري�صا مت نقل الدم اإليهم )299 بالغ و 147 طفل مري�ض(. �صكل امل�صابون باأمرا�ض الدم %50 من املر�صى البالغني و %71 من االأطفال. ومت احل�صول على املوافقة لدى %75 من البالغني و 91% من االأطفال املر�صى. لوحظ اأن اأعلى ن�صبة لاللتزام ب�صيا�صة اقتناء املوافقة اخلطيِّة قبل عملية نقل الدم كانت بني اأطباء ق�صم الدم للبالغني واالأطفال )%95 و %97 على التوايل(. مت تعبئة ا�صتمارات املوافقة ب�صكل �صحيح بجميع التفا�صيل اخلا�صة بـ %51 و %52 من املر�صى البالغني واالأطفال على التوايل. من بني النماذج غري املكتملة كان اخلطاأ االأكرث �صيوعًا عدم وجود تفا�صيل ال�صهود )%25-20(. خامتة: يف معظم احلاالت، مت االلتزام ب�صيا�صة موافقة ما قبل نقل الدم بنجاح يف squh. ومع ذلك، هناك حاجة اإىل مزيد من العمل ل�صمان االلتزام الكامل الإجراءات املوافقة امل�صبقة يف خمتلف التخ�ص�صات، ويو�صى بتنفيذ موافقة عملية نقل الدم يف امل�صت�صفيات االأخرى يف البلد. كلمات مفتاحية: نقل الدم؛ موافقة م�صبقة؛ االمتثال لل�صيا�صات؛ املراجعة ال�رضيرية؛ عمان. first implementation of transfusion consent policy in oman audit of compliance from a tertiary care university hospital *arwa z. al-riyami,1 naif al-ghafri,2 fehmida zia,1 mohammed al-huneini,1 abdul-hakeem al-rawas,3 salam al-kindi,4 sachin jose,5 murtadha al-khabori,1 hilal al-sabti,6 shahina daar4 advances in knowledge this study assessed adherence to transfusion consent policy at the sultan qaboos university hospital, the first centre in oman to implement transfusion consent. application to patient care written patient consent and discussion of the risks and benefits of transfusion procedures has become increasingly important. the authors of this study advocate wide implementation of transfusion consent in all hospitals in oman as an integral part of patient autonomy. clinical & basic research sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e293–297, epub. 19 aug 16 submitted 10 jan 16 revision req. 24 feb 16; revision recd. 7 mar 16 accepted 17 mar 16 doi: 10.18295/squmj.2016.16.03.005 first implementation of transfusion consent policy in oman audit of compliance from a tertiary care university hospital e294 | squ medical journal, august 2016, volume 16, issue 3 blood transfusion is a frequent inter-vention which should only be performed to avoid significant morbidity or mortality if not given.1 although blood transfusions are safe in comparison to other medical and surgical interventions, they nevertheless carry certain risks, such as transfusion reactions, alloimmunisation, immunomodulation and transfusion-transmitted infections.2 patient consent for blood transfusions is a topic that has long stimulated debate among healthcare practitioners.2,3 previously, verbal informed consent for a blood transfusion was often considered sufficient to authorise the procedure; however, with the recognition of transfusion hazards, effective and documented counselling of risks and benefits has become increasingly important.2,3 as such, patients receiving blood transfusions should be provided with sufficient information regarding the purpose, anticipated benefits, alternatives to the blood trans fusion and their expected outcome without the transfusion. additionally, patients should be made aware of frequent and significant transfusion-related risks.4 following this, the caregiver must obtain patient consent which must be given voluntarily by the patient or a parent or legally appointed guardian, when applicable.5,6 ideally, there should be witnessed verification of the patient’s signature.6 worldwide variation exists regarding the practice of obtaining informed consent from patients prior to a blood transfusion. while in many countries this practice is not routine, it is mandated in others, with the prescribing physician being responsible for obtaining consent.6–9 concerns regarding transfusiontransmitted infections have resulted in legislation in some jurisdictions in the usa which requires physicians to obtain written informed consent for blood transfusions.10 in the uk, there is a widespread recommendation that patients must be informed about blood transfusions, although this is not routinely practiced.9,11 in canada, requirements to inform patients about blood transfusions are stated in justice krever’s recommendation for the blood system.8,12 this recommendation mandates that patients should be informed about the benefits, risks and alternatives to allogeneic blood transfusions and that this discussion needs to be documented in patients’ medical records.12 transfusion consent in oman was first introduced at the sultan qaboos university hospital (squh), muscat, oman, in march 2014. the transfusion consent policy mandates that all patients—or their eligible guardians in paediatric cases or with adult patients unable to give informed consent—provide pre-transfusion written consent by signing a consent form which confirms that they have been given information on transfusion of blood and/or blood components by a qualified physician. the physician must explain the risks and benefits of and alternatives to blood transfusion prior to obtaining the consent. the consent process should be witnessed by another healthcare provider, such as a physician or a nurse, and all information, including any refusal of blood and blood components, should be documented in the patient’s electronic medical records. for nonchronically transfused patients, consent is renewed upon each patient admission. furthermore, the policy requires that consent be obtained prior to a planned elective transfusion during the same admission period. patients on long-term blood support (e.g. patients with underlying haemoglobinopathies and those undergoing chemotherapy) should provide consent annually with an option to withdraw their consent at any time during that period. in emergency situations where the patient or their guardian is unable or unavailable to provide consent, pre-transfusion consent requirements are waived; in these cases, patients or guardians are retroactively informed about the requirements of and reasons for performing the blood transfusion. prior to implementation of the policy, hospitalwide educational sessions were initiated to raise awareness of the new policy, procedures for transfusion consent, patient rights, the elements of consent, how consent is given and the validity of consent and its documentation. a pocket guide was made available and distributed to all nurses and physicians in the hospital to aid implementation of the policy. this study therefore aimed to assess adherence to the transfusion consent policy among different specialties at squh. methods this cross-sectional retrospective quantitative study included all chronically and non-chronically transfused patients who underwent elective transfusions between june and august 2014. the medical records of these patients were examined for the presence of a transfusion consent form. in addition, the forms were examined for completeness of patient, physician and witness information and medical records were examined for any documentation of refusal of consent. blood bank records of all blood components transfused during june–august 2014 were reviewed for information regarding issued blood components to ensure the inclusion of all patients during the study period. data collected were entered into microsoft excel, version 2010 (microsoft corp., redmond, washington, usa) and analysed using the statistical package for arwa z. al-riyami, naif al-ghafri, fehmida zia, mohammed al-huneini, abdul-hakeem al-rawas, salam al-kindi, sachin jose, murtadha al-khabori, hilal al-sabti and shahina daar clinical and basic research | e295 the social sciences (spss), version 22.0 (ibm corp., chicago, illinois, usa). descriptive statistics were used to summarise the results and associations were tested using fisher’s exact test. a p value of <0.0500 was considered statistically significant. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #961). results during the study period, 446 transfused patients from different specialties were assessed, including 299 adult and 147 paediatric patients. of these, 49% of the adult and 70% of the paediatric patients were on chronic transfusion support. haematology patients accounted for 50% of adult patients, while the remaining adults were admitted by general medicine, surgery or obstetrics and gynaecology teams. the majority of transfused patients in the paediatric age group were haematology patients (71%), with the rest admitted under the care of general paediatric, paediatric surgery and neonatology teams [table 1]. consent was obtained for a total of 359 subjects (75% of adult and 91% of paediatric patients) [table 2]. paediatric and adult haematology specialists demonstrated the greatest adherence to the policy (97% and 95%, respectively). in contrast, only 55% of transfused patients under the care of adult nonhaematology services had documented transfusion consent forms. however, paediatric non-haematology specialists showed a higher adherence rate (76%). upon assessment of the completeness of the consent forms among paediatric patients, 52% were filled out adequately with all of the required information. adult and paediatric haematology specialists had correctly filled out consent forms in 77% and 66% of cases, respectively [table 2]. a statistically significant difference was found between haematology and non-haematological specialists with regards to the completeness of consent forms for both adults and paediatric patients (p = 0.0001 each). in both patient groups, the most common error was a lack of witness name and/or signature (20–25%). in paediatric consent forms, 26% lacked the physicians’ name in comparison to 13% of adult consent forms [figure 1]. the names and signatures of the patients’ parents or guardians were present in 95% and 97% of paediatric consents, respectively. discussion over recent years, patients have become more involved in their medical and surgical treatments. despite table 1: characteristics of patients who underwent elective transfusions at the sultan qaboos university hospital, muscat, oman, by admitting department* (n = 446) patient group n (%) adults (n = 299) haematology 149 (50) non-haematology 150 (50) surgery 54 (36) gynaecology and obstetrics 50 (33) medicine 48 (32) paediatric (n = 147) haematology 105 (71) non-haematology 42 (29) neonatology 22 (52) general paediatrics 11 (26) paediatric surgery 9 (21) *assessed for the presence of transfusion consent in their clinical records. table 2: transfusion consent and degree of completeness of consent forms among patients who underwent elective transfusions at the sultan qaboos university hospital, muscat, oman, by admitting department (n = 446) patient group n (%) consent taken completeness of form adults (n = 299) 225 152 haematology 142 (95) 114 (77) non-haematology 83 (55) 38 (25) paediatrics (n = 147) 134 76 haematology 102 (97) 69 (66) non-haematology 32 (76) 7 (17) figure 1: chart showing the degree of completeness of various components of consent forms among patients who underwent elective transfusions at the sultan qaboos university hospital, muscat, oman (n = 359). mrn = medical record number. first implementation of transfusion consent policy in oman audit of compliance from a tertiary care university hospital e296 | squ medical journal, august 2016, volume 16, issue 3 this, inconsistencies have been reported in the practice of obtaining consent for blood transfusions. transfusion consent has been mandated in some countries, while obtaining specific consent for a transfusion remains a novel concept in others. furumaki et al. found that patients who were provided with information were more likely to have a better understanding of the risks and benefits of transfusion.13 however, research indicates that only 50–60% of transfusion patients recall having a discussion with their physicians or giving their consent for a blood transfusion; this indicates that current processes to aid informed patient decision-making fall short.7,9,14 court et al. reported limited patient awareness of a transfusion having occurred at all, indicating a lack of communication between healthcare providers and their patients.7 in oman, written patient consent for blood transfusions was not in practice at any government hospital before 2014 and squh was the first hospital in the country to implement a transfusion consent policy. the findings of the current study show excellent adherence to the consent policy in the squh haematology specialty for both adult and paediatric cases. further effort is hence required to enhance adherence in other specialties at squh. one explanation for the lower adherence to consent policy observed among non-haematology specialties in the current study could be a failure in documenting consent in medical records. similar audits at other institutions have shown a lack of documentation of transfusion consent, raising the need for efforts to improve the documentation process.15 at squh, the preliminary results of the current survey were presented to heads of departments and members of the blood transfusion committee; action plans were put in place for the reeducation of staff hospital-wide. in addition, a quarterly nursing-specific course on transfusion practices was initiated, with emphasis on aspects related to transfusion reactions and the consent process. an introductory session of transfusion policies in the hospital was prepared specifically for new physicians and residents. moreover, re-assessment of policy adherence via a second survey is planned following the implementation of these remedial actions. in addition, the findings of the present study have highlighted issues relating to the proper completion of transfusion consent forms. lack of witness information was a common issue and the importance of this element should be emphasised in future policies. this finding may potentially be due to language or cultural barriers. it is important that the witness understands the language in which the consent explanation is given in order to be able to document consent properly. in many healthcare settings, the witness is usually the nurse responsible for administering the blood components; at squh, the feasibility of this approach is limited as nurses do not always speak the same language as their patients. this problem is applicable to other aspects of the consent process as well and raises the need for specific hospital policies to address this issue. recently, the distribution of transfusion information pamphlets has been recommended as a means of improving information delivery, since patient rarely report being informed of the specifics of the transfusion or its benefits/risks.6,7 nevertheless, it is important to note that these pamphlets cannot be given to illiterate patients or those with sight disabilities; furthermore, court et al. found that although patients reportedly valued pamphlets as a source of information, over half of the patients who remembered discussing blood transfusions with their caregivers felt that the best source of information was a physician.7 educational pamphlets were recently designed for distribution at squh in order to aid physicians during informed consent discussions. however, it was emphasised to the healthcare providers that written information should not replace verbal discussion with the patient during the consent process. implementation of the consent process in other hospitals in oman is advocated by the researchers as a vital step towards patient autonomy and to establish a method for the on-going monitoring of transfusion processes. there is a lack of published data assessing the amount of information given to patients before obtaining transfusion consent or patients’ levels of understanding of the information provided during the consent process.7 informed consent for transfusion presumes that the patient has been given sufficient information, was able to comprehend the information provided and was given the opportunity to ask questions before making their decision. furthermore, patients need to agree to undergo the intervention based on the information provided. in the current study, the degree of information provided or the patients’ comprehension of the provided information was not assessed. previous studies have shown that there is variability in the amount of information delivered to patients during the informed consent discussion.16,17 the current study lays the groundwork for further assessment of these aspects in the future. although blood transfusion consent policies have been applied in nearby countries as a result of accreditation requirements, to the best of the authors’ knowledge, this study is the first from oman to assess the degree of adherence to an informed consent policy. however, a few limitations of the study should arwa z. al-riyami, naif al-ghafri, fehmida zia, mohammed al-huneini, abdul-hakeem al-rawas, salam al-kindi, sachin jose, murtadha al-khabori, hilal al-sabti and shahina daar clinical and basic research | e297 be considered. first, the generalisability of this study may be limited since the subjects consisted of a patient cohort from a single institution. however, transfusion consent in oman was only implemented at squh at the time of writing. the extent to which these findings can be replicated in a wider patient and physician population remains to be determined pending implementation of the policy at other hospitals. second, the policy was introduced at squh relatively recently and it will thus understandably take further education of physicians and patients before a better level of adherence can be achieved. third, the study assessed neither the degree of patient comprehension of information provided during the consent process, nor the details of what the physicians discussed with their patients. further studies on these aspects are recommended. conclusion this study describes the first experience of transfusion consent policy application in oman and found high adherence among haematology specialties. further effort is required to expand adherence in other medical and surgical specialties. greater efforts should be made to provide information to patients about the benefits and risks of and alternatives to blood transfusion. distribution of information pamphlets at squh is in process and will be followed by a second survey to assess the effectiveness of this in policy adherence. however, the adequacy of communication delivered and patient understanding during the consent process has yet to be assessed. the authors advocate implementation of the consent process in other hospitals in oman as a vital step towards increased patient autonomy and to establish a method for ongoing monitoring of the transfusion process. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s this study was previously presented as a poster abstract at the american association of blood banks (aabb) annual meeting in anaheim, california, usa, on 24–27 october 2015. an abstract of the poster was published in transfusion in 2015 (vol. 55, iss. s3, p. 166a). references 1. world health organization. the clinical use of blood: handbook. from: www.who.int/bloodsafety/clinical_use/en/ handbook_en.pdf accessed: mar 2016. 2. williams fg. consent for transfusion. bmj 1997; 315:380–1. doi: 10.1136/bmj.315.7105.380. 3. farrell am, brazier m. consent for blood transfusion. bmj 2010; 341:c4336. doi: 10.1136/bmj.c4336. 4. holland pv. consent for transfusion: is it informed? transfus med rev 1997; 11:274–85. doi: 10.1016/s0887-7963(97)80093-4. 5. willett de. the duty to warn about transfusion risks. arch pathol lab med 1989; 113:307–10. 6. rock g, berger r, filion d, touche d, neurath d, wells g, et al. documenting a transfusion: how well is it done? transfusion 2007; 47:568–72. doi: 10.1111/j.1537-2995.2007.01157.x. 7. court el, robinson ja, hocken db. informed consent and patient understanding of blood transfusion. transfus med 2011; 21:183–9. doi: 10.1111/j.1365-3148.2011.01069.x. 8. capen k. there’s more to krever’s report than the blood issue: much more. cmaj 1998; 158:92–4. 9. davis r, vincent c, sud a, noel s, moss r, asgheddi m, et al. consent to transfusion: patients’ and healthcare professionals’ attitudes towards the provision of blood transfusion information. transfus med 2012; 22:167–72. doi: 10.1111/j.1365-3148.2012.01148.x. 10. eisenstaedt rs, glanz k, smith dg, derstine t. informed consent for blood transfusion: a regional hospital survey. transfusion 1993; 33:558–61. doi: 10.1046/j.1537-2995.1993. 33793325050.x. 11. wilkinson j, wilkinson c. administration of blood transfusions to adults in general hospital settings: a review of the literature. j clin nurs 2001; 10:161–70. doi: 10.1111/j.13652702.2001.00444.x. 12. government of canada. final report: commission of inquiry on the blood system in canada. from: http://publications. gc.ca/site/eng/72717/publication.html accessed: mar 2016. 13. furumaki h, fujihara h, yamada c, watanabe h, shibata h, kaneko m, et al. involvement of transfusion unit staff in the informed consent process. transfus apher sci 2016; 54:150–7. doi: 10.1016/j.transci.2015.12.002. 14. chan t, eckert k, venesoen p, leslie k, chin-yee i. consenting to blood: what do patients remember? transfus med 2005; 15:461–6. doi: 10.1111/j.1365-3148.2005.00622.x. 15. moog r. lessons learned from transfusion audits. transfus apher sci 2016; 54:377–9. doi: 10.1016/j.transci.2015.11.017. 16. friedman m, arja w, batra r, daniel s, hoehn d, paniz am, et al. informed consent for blood transfusion: what do medicine residents tell? what do patients understand? am j clin pathol 2012; 138:559–65. doi: 10.1309/ajcp2tn5odjlygqr. 17. cheung d, lieberman l, lin y, callum j. consent for blood transfusion: do patients understand the risks and benefits? transfus med 2014; 24:269–73. doi: 10.1111/tme.12141. http://dx.doi.org/10.1136/bmj.315.7105.380 http://dx.doi.org/10.1136/bmj.c4336 http://dx.doi.org/10.1016/s0887-7963%2897%2980093-4 http://dx.doi.org/10.1111/j.1537-2995.2007.01157.x http://dx.doi.org/10.1111/j.1365-3148.2011.01069.x http://dx.doi.org/10.1111/j.1365-3148.2012.01148.x http://dx.doi.org/10.1046/j.1537-2995.1993.33793325050.x http://dx.doi.org/10.1046/j.1537-2995.1993.33793325050.x http://dx.doi.org/10.1111/j.1365-2702.2001.00444.x http://dx.doi.org/10.1111/j.1365-2702.2001.00444.x http://dx.doi.org/10.1016/j.transci.2015.12.002 http://dx.doi.org/10.1111/j.1365-3148.2005.00622.x http://dx.doi.org/10.1016/j.transci.2015.11.017 http://dx.doi.org/10.1309/ajcp2tn5odjlygqr http://dx.doi.org/10.1111/tme.12141 1department of dermatology, complejo hospitalario de granada, granada, spain; 2department of dermatology, hospital universitario reina sofia, córdoba, spain; 3department of dermatology, hospital universitario campus de la salud, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com ردود الفعل االلتهابية ألحبار الوشم االمحر ثالث حاالت تسلط الضوء على مشكلة مستجدة ريكاردو رويز-فيالفريدي، بابلو فرنانديز-كراويت، باول اأغوايو-كاريرا�ض، خو�شيه لوي�ض هرينانديز-�شينتينو، كارلو�ض كوينكا-بارالي�ض abstract: in recent years, tattoos have become more commonplace. however, this can result in various inflammatory processes, the management of which can be challenging in daily clinical practice. tattoo-related inflammatory reactions can comprise different patterns, including acute and immediate reactions, foreign body granulomas, sarcoid granulomas, isomorphic lesions, allergic contact dermatitis and photosensitivity. we report three cases who were referred to the dermatology outpatient clinic of the hospital universitario san cecilio, granada, spain, in 2017 with various skin reactions in the red-ink areas of their tattoos. screening was performed for infectious diseases like atypical mycobacterial infections and systemic processes such as sarcoidosis. a good therapeutic response was achieved in all cases. an adequate differential diagnosis is essential for the therapeutic management of this emerging health problem. keywords: non-therapeutic body modification; tattooing, adverse effects; inks; foreign body reaction; inflammation; case report; spain. عالجها ميثل والتي اللتهابية، الفعل ردود من العديد اإىل الو�شم يوؤدي قد و الأخرية. ال�شنوات يف �شيوعا اأكرث الو�شم اأ�شبح امللخ�ص: حتديا كبريا يف املمار�شة ال�رضيرية اليومية. ميكن اأن ت�شمل ردود الفعل اللتهابية املرتبطة بالو�شم اأمناًطا خمتلفة، مبا يف ذلك التفاعالت التح�ش�شي التما�شي اجللد التهاب املت�شابهة، الآفات ال�شاركانية، احلبيبية الأورام للج�شم، اخلارجية احلبيبية الأورام والفورية، احلادة واحل�شا�شية لل�شوء. هذا تقرير عن ثالث حالت مت اإحالتها اإىل عيادة الأمرا�ض اجللدية اخلارجية مب�شت�شفى يونيفر�شيتاريو �شان �شي�شيليو، غرناطة، اإ�شبانيا، يف عام 2017 وبها العديد من ردود اأفعال اجللد يف املناطق التي مت حقنها باحلرب الأحمر لعمل الو�شم اخلا�ض بهم. مت اإجراء الفحو�شات الالزمة لالأمرا�ض املعدية مثل التهابات امليكوبكترييا غري النمطية واي�شا الأمرا�ض العامة مثل ال�شاركويد. مت حتقيق ا�شتجابة عالجية جيدة يف جميع احلالت. الت�شخي�ض التفريقي املنا�شب �رضوري لالإدارة العالجية لهذه امل�شكلة ال�شحية امل�شتجدة. الكلمات املفتاحية: تعديل �شكل اجل�شم الغريعالجي؛ الو�شم؛ الآثار ال�شارة؛ الأحبار؛ تفاعل ج�شم غريب؛ التهاب؛ تقرير حالة؛ اإ�شبانيا. inflammatory reactions to red tattoo inks three cases highlighting an emerging problem *ricardo ruiz-villaverde,1 pablo fernandez-crehuet,2 paula aguayo-carreras,3 jose l. hernandez-centeno,2 carlos cuenca-barrales3 sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e215–218, epub. 9 sep 18 submitted 22 nov 17 revision req. 18 feb 18; revision recd. 18 feb 18 accepted 8 mar 18 case report doi: 10.18295/squmj.2018.18.02.016 the popularity of tattoos has increased in recent years.1 inflammatory reactions to red tattoo inks may be due to the pigment itself, auxiliary ingredients in the ink (i.e. preservatives, binders or thickeners) or impurities generated during the manufacturing process.2 nowadays, 80% of the colour pigments used in tattoo inks are synthetic azo or polycyclic compounds which enhance the brightness, stability and duration of the tattoo.3 most inflammatory reactions to red tattoo inks occur as a response to the red pigment and can have hyperkeratotic, nodular, plaque, exudative or ulcerative manifestations.4 such reactions may have a latency period varying from weeks to months or even years after the tattoo is inked.2,5 the majority of such reactions usually occur in tattoos located on the extremities, possibly due to their greater exposure to ultraviolet (uv) radiation, and result in intense pruritus.6 we present three patients who developed inflammatory reactions to red tattoo inks and discuss the potential differential diagnoses of such reactions. case one a 38-year-old female patient was referred to the dermatology outpatient clinic of the hospital universitario san cecilio, granada, spain, in 2017. she had gotten a tattoo on the right leg seven months previously. however, two weeks after receiving the tattoo, she began to develop hyperkeratotic papules and nodules on the parts of the tattoo impregnated with red ink [figure 1]. she reported no relevant medical history, apart from being allergic to sulph onamides. an ultrasound revealed a poorly demarcated hypoechoic epidermal tumour of variable echogenicity without artefacts. there was evidence of abundant intralesional vascularisation in doppler mode. all complementary tests and investigations were normal, including a complete blood count (cbc), biochemistry panel, thyroid hormone and angiotensin-converting enzyme (ace) levels, a chest x-ray and an autoimmunity study. inflammatory reactions to red tattoo inks three cases highlighting an emerging problem e216 | squ medical journal, may 2018, volume 18, issue 2 a histological examination of the lesion confirmed an intense lymphohistiocytic inflammatory reaction. a ziehl-neelsen stain demonstrated the presence of multinucleated foreign body giant cells, with an absence of fungal structures and acid-alcohol-resistant bacilli. the red pigment of the tattoo was curiously enhanced [figure 2]. a polymerase chain reaction (pcr) analysis for mycobacterium tuberculosis was also negative. initially, the patient was treated with topical mometasone furoate for six weeks to promote occlusive healing. unfortunately, this was not successful. subsequently, she was prescribed 300 mg/day of allopurinol and 100 mg/day of doxycycline, to which she demonstrated a good therapeutic response after two months. case two a 34-year-old female patient was referred to the dermatology outpatient clinic of the hospital universitario san cecilio, granada, in 2017. she had an indurated erythematous painful nodule with welldefined borders on a six-month-old back tattoo. the lesion was confined to the areas of red pigmentation [figure 3]. the patient reported a history of malaise, anorexia and weight loss over the previous month. complementary tests and investigations—including a cbc, biochemistry panel, thyroid hormone and ace levels, chest x-ray and pcr analysis for m. tuberculosis—were all normal. a punch biopsy was obtained from the indurated area of the tattoo. a histological examination of the sample revealed dense subepithelial lymphoid infiltration, consisting of lymphocytes and histiocytes without germinal centres, eosinophils, large cells or granulomas. there was an absence of cellular atypia. the patient was initially prescribed topical mometasone furoate for six weeks, without improvement. he was then advised to take 0.5 mg/kg/day of oral prednisone. a medium response to therapy was noted after two months. however, the patient refused further systemic treatment. case three a 35-year-old male was referred to the dermatology outpatient clinic of the hospital universitario san cecilio, granada, in 2017. he presented with a wartlike lesion located on a three-month-old tattoo on the back of his right wrist. the lesion was confined to the part of the skin tattooed with red ink [figure 4]. these was no visible evidence of any trauma or injury. complementary tests and investigations were normal, including a cbc, biochemistry panel, thyroid hormone and ace levels, chest x-ray and pcr analysis for m. tuberculosis. a histological examination revealed a granulomatous foreign body reaction, most likely due to the red ink in the tattoo. following an unsuccessful sixweek course of treatment with topical mometasone furoate, the patient demonstrated a good therapeutic response after three months of therapy with 100 mg/day of doxycycline and 300 mg/day of allopurinol. figure 1: clinical photographs of the right leg of a 38-yearold female patient (case one) showing an inflammatory reaction to the red ink in a skeleton tattoo. figure 3: clinical photograph of the back of a 34-year-old female patient (case two) showing an inflammatory reaction to the red ink in a butterfly tattoo. figure 2: ziehl-neelsen stain at x40 magnification showing the enhancement of red pigment in tattoo ink. ricardo ruiz-villaverde, pablo fernandez-crehuet, paula aguayo-carreras, jose l. hernandez-centeno and carlos cuenca-barrales case report | e217 discussion from a clinical viewpoint, inflammatory reactions can present in different patterns—including acute and immediate reactions after the tattooing process, foreign body granulomas, sarcoid granulomas, isomorphic reactions due to the phenomenon of koebner, allergic contact dermatitis and photosensitivity.4 as such, the diagnosis of an inflammatory reaction to red tattoo ink is not straightforward, since the cutaneous lesions are not specific and the histological findings are not characteristic. likewise, epicutaneous tests are not informative in most cases.5 even when the original ink used by the tattoo artist is available, the allergen is usually generated as a result of the degradation of the primary components of the ink, rather than because of the ink itself.6 for example, azo pigments become chemically unstable when subjected to uv radiation for long periods of time, which causes fragmentation, degradation and diffusion of the ink. in such cases, solar exposure and sunburn considerably increase the risk of developing an inflammatory reaction.6 unfortunately, determining the exact chemical composition of the tattoo inks of the three cases presented in this report was not possible. a biopsy is essential in cases in which the patient has an inflammatory reaction to red tattoo inks. although not always conclusive, a biopsy can offer relevant information regarding the type of reaction developed, for example, regarding whether the react ion is granulomatous, pseudolymphomatous, lichenoid, fibrosing or due to a tumour or infection.4,7–9 a sarcoid granuloma appearing on a tattoo may be the first or only manifestation of systemic sarcoidosis; this must therefore be excluded from the differential diagnosis as quickly as possible.4 in cases of suspected atypical mycobacterial infections, special stains such as a ziehlneelsen stain must be used to determine the presence of mycobacteria, as well as a specific pcr analysis.10 the clinical course of an inflammatory reaction to red tattoo ink is unpredictable and sometimes dis concerting. foreign body reactions may resolve spontaneously or the transepidermal elimination of the pigment may take place.11,12 for persistent reactions, optimal treatment varies according to the patient’s response. topical potent corticosteroids have been previously reported as a form of occlusive treatment; however, once the lesion has been flattened, the frequency of application should be decreased.5 intralesional corticoids may also be used on a monthly basis.4 in terms of systemic treatment, allopurinol is indicated in granulomatous lesions at a dose of 300–600 mg/day for two months.7 in addition, effective results have been reported with hydroxychloroquine (200 mg/day for two months).9 oral corticosteroids are recommended in cases with intense pruritus or recurrence, especially if associated with uveitis.4,5 excision of the cutaneous lesion is only useful for patients with small tattoos (<2 cm in diameter). however, satisfactory results have been reported for those with larger tattoos when using a dermatome to obtain a graft that covers the entire dermis.13 mohs surgery has also been successfully utilised in more complicated cases.14 laser therapy is another promising therapeutic approach, with a number of successful outcomes and no reports of any significant adverse effects.15 in particular, q-switched potassium titanyl phosphate laser treatment at 532 nm may be useful in the treatment of red tattoo ink reactions.2 conclusion inflammatory reactions to red tattoo inks are an emerging health problem. unfortunately, the diagnosis of such reactions can be challenging due to the varied nature of the cutaneous and histological findings. it is therefore important to rule out other differential diagnoses in order to determine an appropriate therapeutic approach. references 1. kluger n. epidemiology of tattoos in industrialized countries. curr probl dermatol 2015; 48:6–20. doi: 10.1159/000369175. 2. forbat e, al-niaimi f. patterns of reactions to red pigment tattoo and treatment methods. dermatol ther (heidelb) 2016; 6:13–23. doi: 10.1007/s13555-016-0104-y. 3. de cuyper c, d’hollander d. materials used in body art. in: de cuyper c, cotapos ml, eds. dermatologic complications with body art: tattoos, piercings and permanent make-up. berlin, germany: springer, 2010. pp. 13–28. doi: 10.1007/978-3-64203292-9_2. 4. kluger n. cutaneous complications related to tattoos: 31 cases from finland. dermatology 2017; 233:100–9. doi: 10.1159/ 000468536. figure 4: clinical photograph of the right wrist of a 35-year old male patient (case three) showing a verrucous reaction to the red ink of a strawberry tattoo. https://doi.org/10.1159/000369175 https://doi.org/10.1007/s13555-016-0104-y https://doi.org/10.1007/978-3-642-03292-9_2 https://doi.org/10.1007/978-3-642-03292-9_2 https://doi.org/10.1159/000468536 https://doi.org/10.1159/000468536 inflammatory reactions to red tattoo inks three cases highlighting an emerging problem e218 | squ medical journal, may 2018, volume 18, issue 2 5. haber r, farid s. [granulomatous tattoo reaction confined to red pigment]. ann dermatol venereol 2016; 143:79–80. doi: 10. 1016/j.annder.2015.09.001. 6. serup j. how to diagnose and classify tattoo complications in the clinic: a system of distinctive patterns. curr probl dermatol 2017; 52:58–73. doi: 10.1159/000450780. 7. godinho mm, aguinaga f, grynszpan r, lima vm, azulay dr, cuzzi t, et al. granulomatous reaction to red tattoo pigment treated with allopurinol. j cosmet dermatol 2015; 14:241–5. doi: 10.1111/jocd.12149. 8. almodovar-real a, sánchez-lópez j, navarro-triviño f, fernández-pugnaire ma. [lichenoid reaction to red pigment in a tattoo]. semergen 2016; 42:e115–17. doi: 10.1016/j.semerg. 2015.12.016. 9. patrizi a, raone b, savoia f, bacci f, pileri a, gurioli c, et al. tattoo-associated pseudolymphomatous reaction and its succ essful treatment with hydroxychloroquine. acta derm venereol 2009; 89:327–8. doi: 10.2340/00015555-0639. 10. wolf r, wolf d. a tattooed butterfly as a vector of atypical mycobacteria. j am acad dermatol 2003; 48:s73–4. doi: 10.10 67/mjd.2003.166. 11. fang hy, wu py, hsieh hj. generalized lichenoid tattoo reaction with spontaneous resolution after skin biopsy. dermatolo sinica 2013; 31:38–40. doi: 10.1016/j.dsi.2012.04.003. 12. høgsberg t, thomsen bm, serup j. histopathology and immune histochemistry of red tattoo reactions: interface dermatitis is the lead pathology, with increase in t-lymphocytes and langerhans cells suggesting an allergic pathomechanism. skin res technol 2015; 21:449–58. doi: 10.1111/srt.12213. 13. mlakar b. successful removal of hyperkeratotic-lichenoid reaction to red ink tattoo with preservation of the whole tattoo using a skin grafting knife. acta dermatovenerol alp pannonica adriat 2015; 24:81–2. doi: 10.15570/actaapa.2015.21. 14. kim ym, taylor d, weiss e, saleeby er. mohs micrographic surgery for a red tattoo reaction. dermatol surg 2018; 44:120–2. doi: 10.1097/dss.0000000000001137. 15. millán-cayetano jf, alegre-sánchez a, boixeda p. treatment of red tattoo reaction using co2 laser. lasers med sci 2018; 33:1171–3. doi: 10.1007/s10103-017-2229-3. https://doi.org/10.1016/j.annder.2015.09.001 https://doi.org/10.1016/j.annder.2015.09.001 https://doi.org/10.1159/000450780 https://doi.org/10.1111/jocd.12149 https://doi.org/10.1016/j.semerg.2015.12.016 https://doi.org/10.1016/j.semerg.2015.12.016 https://doi.org/10.2340/00015555-0639 https://doi.org/10.1067/mjd.2003.166 https://doi.org/10.1067/mjd.2003.166 https://doi.org/10.1016/j.dsi.2012.04.003 https://doi.org/10.1111/srt.12213 https://doi.org/10.15570/actaapa.2015.21 https://doi.org/10.1097/dss.0000000000001137 https://doi.org/10.1007/s10103-017-2229-3 1department of radiology, pusat perubatan universiti kebangasaan malaysia, kuala lumpur, malaysia; 2department of radiology diagnostic imaging, hospital kuala lumpur, kuala lumpur, malaysia; 3department of radiology, hospital tengku ampuan rahimah, klang, malaysia *corresponding author’s e-mail: dr.leechungyuen@gmail.com خطأ يف تشخيص عرض متأخر لتشوه جمرى اهلواء الرئوي اخللقي على أنه فقاعة كبرية منتنه �شوجن يون يل، �شيازارينا �رصي�س عثمان، حلمي حممد نور، نور �شفريا عبد عي�شى abstract: a congenital pulmonary airway malformation (cpam) is a rare cystic anomaly that may occur during development of the fetal airways. the vast majority of cpams are detected in neonates; as such, it is unusual for diagnosis to occur in adulthood. we report a 21-year-old male patient who presented to the emergency department of the hospital ampang, kuala lumpur, malaysia, in 2015 with chest pain, breathlessness and tachypnoea. based on an initial chest x-ray, the patient was misdiagnosed with pneumothorax and underwent urgent chest tube insertion; however, his condition deteriorated over the course of the next three days. further imaging was suggestive of infected bullae or an undiagnosed cpam. the patient therefore underwent video-assisted thoracoscopic surgery, during which a large infected bulla was resected. a diagnosis of an infected cpam was confirmed by histopathological examination. following the surgery, the patient recovered quickly and no bullae remnants were found at a one-month follow-up. keywords: respiratory system abnormalities; congenital cystic adenomatoid malformation of lung; adult; respiratory tract infection; pneumothorax; video-assisted thoracic surgery; case report; malaysia. امللخ�ص: الت�شوه الهوائي الرئوي اخللقي هو ت�شوه حو�شلي نادر قد يحدث اأثناء تطور جمرى الهواء اجلنيني. يتم ت�شخي�س الغالبية العظمى من احلالت يف حديثي الولدة ولكن من غري املعتاد اأن يحدث الت�شخي�س يف مرحلة البلوغ. هذا تقريرحالة ملري�س يبلغ من العمر 21 عاًما قدم اإىل ق�شم الطوارئ يف م�شت�شفى اأمباجن، كوال لمبور، ماليزيا، يف عام 2015 باأمل يف ال�شدر و�رصعة �شيق يف التنف�س. وقد مت ت�شخي�س املري�س باخلطاأً ا�شتناداً اإىل �شورة اأولية لل�شدر بالأ�شعة ال�شينية، على اأنه حالة هواء يف الغ�شاء البلوري للرئة )ا�شرتواح ال�شدر( ومت و�شع اأنبوب الق�شبة الهوائية ب�شورة �رصيعة؛ ومع ذلك، تدهورت حالته على مدى الأيام الثالثة التالية. وبعمل املزيد من الأ�شعات وجد اأنها حالة ت�شوه هوائي رئوي خلقي غري م�شخ�شة. ولذلك خ�شع املري�س جلراحة باملنظار ال�شدري مب�شاعدة الفيديو، حيث مت ازالة الفقاعة الكبرية امل�شابة. مت تاأكيد ت�شخي�س الت�شوه الهوائي الرئوي اخللقي عن طريق الفح�س الن�شيجي. بعد اجلراحة، تعافى املري�س ب�رصعة ومل يتم العثور على اأي بقايا من الفقاعات اأثناء املتابعة بعد �شهر واحد. الكلمات املفتاحية: ت�شوهات اجلهاز التنف�شي؛ الت�شوه الهوائي الرئوي اخللقي؛ الكبار؛ عدوى اجلهاز التنف�شي؛ ا�شرتواح ال�شدر؛ جراحة ال�شدر مب�شاعدة الفيديو؛ تقرير حالة؛ ماليزيا. a missed late presentation of a congenital pulmonary airway malformation as a large infected bulla *chung y. lee,1 syazarina s. osman,1 helmee m. noor,2 nur s. a. isa3 sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e541–544, epub. 28 mar 19 submitted 26 jun 18 revisions req. 2 & 29 jul 18; revisions recd. 4 jul & 1 aug 18 accepted 16 aug 18 case report doi: 10.18295/squmj.2018.18.04.020 pain, breathlessness and tachypnoea. on examination, the patient was tachypnoeic with reduced air entry in the left lung on auscultation. there was no recent history of acute illnesses or cough. his leukocyte count was 15,000/mm3. a chest x-ray revealed a large lucency in the left hemithorax with depression of the left hemidiaphragm and a mediastinal shift to the right [figure 1]. this finding was initially misinterpreted as indicative of left-sided tension pneumothorax; as such, a chest tube was immediately inserted. however, the patient’s condition deteriorated over the following three days and he developed sepsis with coagulopathy. repeat chest x-rays appeared to show non-resolving pneumothorax. computed tomography (ct) of the thorax revealed large air-filled lesions in the left upper hemithorax containing fluids and septations causing a mediastinal a congenital pulmonary airway malformation (cpam)—formerly known as a congenital cystic adenomatoid malformation—accounts for 25% of all congenital lung lesions.1,2 the vast majority of cases are diagnosed via ultrasonography during the immediate neonatal period.2 this report describes a rare case of cpam first diagnosed in a young adult presenting with dyspnoea secondary to a large infected bulla. the patient was initially misdiagnosed as having pneumothorax based on findings from a chest x-ray. case report a 21-year-old male patient with a history of smoking presented to the emergency department of the hospital ampang, kuala lumpur, malaysia, in 2015 with chest a missed late presentation of a congenital pulmonary airway malformation as a large infected bulla e542 | squ medical journal, november 2018, volume 18, issue 4 shift [figures 2 and 3]. these findings were suggestive of an infected bulla, an undiagnosed cpam or congenital lobar overinflation (clo). accordingly, the patient under went left video-assisted thoracoscopic surgery (vats), during which a large infected bulla was identified in the left upper lobe supplied by multiple vessels from the chest wall. the bulla was resected and a histological analysis confirmed a diagnosis of a cpam with secondary inf ection [figure 4a]. after the surgery, the patient quickly recovered following treatment with antibiotics and was discharged. at a one-month follow-up appointment, a chest x-ray showed no bullae remnants [figure 4b]. discussion a cpam is a hamartomatous lesion comprising both cystic and adenomatous elements of tracheobronchial and alveolar tissue and is characterised by intracystic communication with and connection to the tracheobronchial tree.2,3 the prevalence of cpam has been estimated to be approximately one in 7,200 pregnancies.2 after birth, the lesions may regress, persist or remain stable.3 stocker et al. first described three types of cpam; however, more recently, these classifications have been expanded to five types reflecting developmental progression through the tracheobronchial tree, from the large airways to the bronchioles and alveoli [table 1].4,5 an alternate classification of cpam was proposed by adzick et al., dividing cpam cases into macrocystic, microcystic or solid lesions based on prenatal ultrasongraphy.6 in most cases, cpam presents in the neonatal period with acute respiratory distress and is characterised by unilateral lower lobe involvement.7 diagnosis in adulthood is rare and can occur either as a result of infection, malignant transformation or discovered incidentally on chest x-ray.8 adult patients with undiagnosed cpams can present with recurrent pneumonia, pneumothorax, bullae, haemoptysis or dyspnoea.7,9,10 the differential diagnosis in adults includes acquired cystic lesions (i.e. pulmonary tuberculosis [tb]) or congenital lesions (i.e. bronchogenic cysts and pulmonary sequestration).11,12 other renal and cardiac anomalies may also be associated with cpam. pulmonary sequestration can be radiologically ruled out as this type of malformation has an anomalous systemic arterial supply, unlike cpam.13 histological analysis is crucial as this enables identification of the cause of the multicystic mass and excludes pulmonary tb.14 in the current case, a retrospective review of the initial chest x-ray indicated a large left-sided bulla causing a contralateral mediastinal shift; however, at the time, the bulla was mistaken for pneumothorax, resulting in the unwarranted insertion of a chest tube. subseq figure 1: chest x-ray of a 21-year-old male patient with chest pain, breathlessness and tachypnoea showing lucency (arrow) with reduced lung markings in the left hemi thorax and a corresponding increase in lung volume (arrowhead) evidenced by the contralateral mediastinal shift. figure 3: post-chest tube insertion computed tomography scans of the thorax of a 21-year-old male patient in the (a) sagittal and (b) coronal views showing a septated cystic lesion (arrows) replacing the normal left upper lobe. figure 4: a: haematoxylin and eosin stain at x100 magnif ication showing a cystic lesion lined by columnar epith elium. b: postoperative chest x-ray of a 21-year-old male patient showing thickened left apical pleura (arrow) and the complete resolution of an ipsilateral upper lobe bulla. figure 2: post-chest tube insertion axial computed tomography scans of the thorax of a 21-year-old male patient showing an air-filled lesion with atelectasis in the left upper lobe (arrow). note the tip of the chest tube (arrowhead) and the corresponding fluid level. chung y. lee, syazarina s. osman, helmee m. noor and nur s. a. isa case report | e543 conclusion the initial identification and presentation of a cpam in adulthood is rare; as such, the diagnosis and treatment of such cases is challenging for unsuspecting clinicians and radiologists. nevertheless, as many cases remain asymptomatic, the prevalence of adult cpam may be under-reported. long-term research is needed to assess treatment outcomes in adult cpam patients. references 1. ch’in ky, tang my. congenital adenomatoid malformation of one lobe of a lung with general anasarca. arch pathol (chic) 1949; 48:221–9. 2. lau ct, kan a, shek n, tam p, wong kk. is congenital pulmo nary airwa y malformation really a rare disease? result of a prospective registry with universal antenatal screening program. pediatr surg int 2017; 33:105–8. https://doi.org/10.1007/s003 83-016-3991-1. 3. langston c. new concepts in the pathology of congenital lung malformations. semin pediatr surg 2003; 12:17–37. https://doi. org/10.1053/spsu.2003.00001. 4. stocker jt, madewell je, drake rm. congenital cystic adeno matoid malformation of the lung: classification and morphologic spectrum. hum pathol 1977; 8:155–71. https://doi.org/ 10.1016/s0046-8177(77)80078-6. 5. stocker jt, mani h, husain an. the respiratory tract. in: stocker jt, dehner lp, husain an (eds). stocker and dehner’s pediatric pathology, 3rd ed. philadelphia, pennsylvania, usa: lippincott, williams & wilkins, 2010. pp. 441–515. 6. adzick ns, harrison mr, glick pl, golbus ms, anderson rl, mahony bs, et al. fetal cystic adenomatoid malformation: pre natal diagnosis and natural history. j pediatr surg 1985; 20:483–8. https://doi.org/10.1016/s0022-3468(85)80470-x. uently, ct scans revealed multicystic air-filled lesions, some of which contained fluid and enhanced the septa; at this point, clo was suspected due to the unusual involvement of the left upper lobe. however, following vats, a large infected bulla was identified and histologically confirmed to be a cpam, likely type 1 as it occupied almost the entire left upper lobe.5 radiology and histology ruled out pulmonary sequestration and pulmonary tb, respectively; however, an association with other renal and cardiac anomalies could not be excluded as this type of screening was not performed in the current case. among symptomatic infants with cpams, urgent surgical excision is usually advocated because segmental resection may be incomplete, resulting in recurrent infections or persistent pneumothorax.15–18 among 19 surgically-treated infants and children, pinter et al. reported respiratory infections and chest deformities occurring in seven and eight patients, respectively, over an average follow-up period of 7.7 years.18 however, in the current case, the patient underwent vats diss ection of the left upper lobe bulla. in such cases, the risk of recurrent infection-related complications is unknown as there is minimal published research reg arding the long-term outcomes of adult patients with resected cpam lesions. nevertheless, most cpam patients remain asymptomatic and otherwise healthy.16 previous research has shown post-lobectomy lung volumes in asymptomatic cpam patients to be 90% that of predicted normal values.19 table 1: expanded classification of congenital pulmonary airway malformations5 characteristic type 0 type 1 type 2 type 3 type 4 frequency in % 1–3 50–65 20–25 8 10 size in cm ≤0.5 2–10 <2–2.5 0.2–1.5 0.5–7 location tracheobronchial bronchial/ bronchiolar bronchiolar bronchiolar/ alveolar duct distal acinar onset birth prenatal* postnatal prenatal* postnatal clinical presentation • lethal pulmonary hypoplasia • absence or lack of alveoli • none (asymptomatic) • immediate or delayed respiratory distress or infection • respiratory issues† • development of hydrops in prenatal cases • respiratory distress‡ in postnatal cases • none (asymptomatic) • pneumonia or pneumothorax risk of malignancy unknown risk of bronchioloalveolar carcinoma unknown unknown risk of pleuropulmonary blastoma association with other congenital anomalies or conditions • cardiovascular anomalies • renal hypoplasia unknown • renal agenesis or dysgenesis • pulmonary sequestration • congenital cardiac anomalies unknown unknown *particularly with large cysts. †these are often less significant than associated anomalies. ‡depending on the size of the cyst. a missed late presentation of a congenital pulmonary airway malformation as a large infected bulla e544 | squ medical journal, november 2018, volume 18, issue 4 7. taştekin e, usta u, kaynar a, ozdemır c, yalçin o, ozyilmaz f, et al. congenital pulmonary airway malformation type 2: a case report with review of the literature turk patoloji derg 2014; 32:200–4. https://doi.org/10.5146/tjpath.2013.01208. 8. smith ja, koroscil mt, hayes ja. congenital pulmonary airway malformation in the asymptomatic adult: a rare presentation. respir med case rep 2018; 25:280–1. https://doi.org/10.1016/j. rmcr.2018.10.009. 9. shupe mp, kwon hp, morris mj. spontaneous pneumothorax in a teenager with prior congenital pulmonary airway malformation. respir med case rep 2014; 11:18–21. https://doi.org/10.1 016/j.rmcr.2013.03.003. 10. mcdonough rj, niven as, havenstrite ka. congenital pulmo nary airway malformation: a case report and review of the literature. respir care 2012; 57:302–6. https://doi.org/10.4187/ respcare.00727. 11. baral d, adhikari b, zaccarini d, dongol rm, sah b. congenital pulmonary airway malformation in an adult male: a case report with literature review. case rep pulmonol 2015; 2015:743452. https://doi.org/10.1155/2015/743452. 12. ankers d, sajjad n, green p, mcpartland jl. antenatal management of pulmonary hyperplasia (congenital cystic adenomatoid malformation). bmj case rep 2010; 2010:bcr0120102679. https://doi.org/10.1136/bcr.01.2010.2679. 13. katzenstein aa. katzenstein and askin’s surgical pathology of non-neoplastic lung disease, 3rd ed. philadelphia, pennsylvania, usa: saunders, 1997. pp.468–90. 14. marshall kw, blane ce, teitelbaum dh, van leeuwen k. congenital cystic adenomatoid malformation: impact of prenatal diagnosis and changing strategies in the treatment of the asymptomatic patient. ajr am j roentgenol 2000; 175:1551–4. https://doi.org/10.2214/ajr.175.6.1751551. 15. wong kk, flake aw, tibboel d, rottier rj, tam pk. congenital pulmonary airway malformation: advances and controversies. lancet child adolesc health 2018; 2:290–7. https://doi.org/10. 1016/s2352-4642(18)30035-x. 16. leblanc c, baron m, desselas e, phan mh, rybak a, thouvenin g, et al. congenital pulmonary airway malformations: state-of the-art review for pediatrician’s use. eur j pediatr 2017; 176:1559–71. https://doi.org/10.1007/s00431-017-3032-7. 17. wong a, vieten d, singh s, harvey jg, holland aj. longterm outcome of asymptomatic patients with congenital cystic adenomatoid malformation. pediatr surg int 2009; 25:479–85. https://doi.org/10.1007/s00383-009-2371-5. 18. pinter a, kalman a, karsza l, verebely t, szemledy f. longterm outcome of congenital cystic adenomatoid malformation. pediatr surg int 1999; 15:332–5. https://doi.org/10.1007/s003 830050593. 19. frenckner b, freyschuss u. pulmonary function after lobectomy for congenital lobar emphysema and congenital cystic adeno matoid malformation: a follow-up study. scand j thorac cardiovasc surg 1982; 16:293–8. https://doi.org/10.3109/1401 7438209101066. 1physiotherapy program, school of rehabilitation sciences, faculty of health sciences and departments of 4orthopaedics & traumatology, faculty of medicine and 5electrical, electronic & systems engineering, faculty of engineering & built environment, universiti kebangsaan malaysia, kuala lumpur, malaysia; 2ministry of health, putrajaya; 3myphysio ficomo specialist centre, petaling jaya, malaysia *corresponding author e-mail: devinderkas@gmail.com; devinder@ukm.edu.my احلركات يف منطقة الفقرات القطنية أسفل الظهر والعجز الوظائفي واملعتقدات املتعلقة بتجنب اخلوف بني البالغني الذين يعانون من آالم مزمنة وغري حمددة ملنطقة أسفل الظهر ن�ن�شي جورج جيتي, يي لني ليم, هوي لينج ليم, �ش�ب�رول اأفي�ن خمت�ر, كوك بنج ج�ن, ديفيندر كور اأجيت �شينج abstract: objectives: this study aimed to examine correlations between lumbar kinematics, functional disability and fear avoidance beliefs among adults with nonspecific chronic low back pain (lbp). methods: this crosssectional study was conducted between march and december 2014. a total of 32 adults diagnosed with nonspecific chronic lbp were recruited from outpatients attending either an orthopaedic clinic at a university hospital or a private physiotherapy clinic in malaysia. lumbar kinematics were measured using sensors attached at the first lumbar (l1) and second sacral (s2) vertebrae levels. the oswestry disability index (odi) and fear-avoidance beliefs questionnaire (fabq) were used to assess degree of functional disability and fear avoidance beliefs, respectively. results: for maximum range of motion, positive correlations were observed between odi scores and right lateral flexion and right rotation (p = 0.01 each), although there was a negative correlation with left rotation (p = 0.03). with maximum angular velocity, odi scores were positively correlated with right and left lateral flexion l1 (p = 0.01 and <0.01, respectively) but negatively correlated with left lateral flexion l2 (p = 0.04). regarding minimum angular velocity, odi scores were positively correlated with left lateral flexion s2 (p <0.01) but negatively correlated with right and left lateral flexion l1 (p = 0.02 each), right rotation l1 (p = 0.02) and left rotation s2 (p = 0.01). no significant correlations were found between lumbar kinematics and fabq scores. conclusion: these findings suggest that certain lumbar kinematic parameters are correlated with functional disability, but not with fear avoidance beliefs. keywords: low back pain; lumbar vertebrae; kinematics; disability evaluation; fear. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل فح�س العالق�ت املتب�دلة بني احلرك�ت يف منطقة الفقرات القطنية اأ�شفل الظهر والعجز الوظ�ئفي هذه اأجريت الطريقة: الظهر. اأ�شفل منطقة يف حمدد وغري مزمن اأمل من يع�نون الذين الب�لغني بني اخلوف بتجنب املتعلقة واملعتقدات ب�آلم امل�شخ�شني الب�لغني من فرداً 32 من مكونة جمموعة تخ�شي�س مت ,2014 لع�م ودي�شمرب م�ر�س �شهري بني امل�شتعر�شة الدرا�شة اأ�شفل الظهر املزمنة وغري حمددة من املر�شى املراجعني يف عي�دة العظ�م مب�شت�شفى تعليمي ج�معي اأو من مراجعِي عي�دة خ��شة للعالج الطبيعِي يف م�ليزي�, مت قي��س احلرك�ت يف املنطقة القطنية للظهر ب��شتخدام جم�ش�ت معلَّقة يف م�شتوى الفقرة القطنية الأوىل والفقرة العجزية الثَّ�نية اأ�شفل الظهر, كم� مت ا�شتخدام موؤ�رس اأو�س وي�شرتي لقي��س مدى العجز وا�شتبي�ن املعتقدات املتعلقة بتجنب اخلوف وذلك لتقييم درجة العجز الوظ�ئفي واملعتقدات املدرو�شة على التوايل. النتائج: اأظهرت الدرا�شة اأنه فيم� يتعلق ب�ملدى الأق�شى للحركة, ك�نت هن�ك عالقة طردية بني موؤ�رس اأو�س وي�شرتي لقي��س الإع�قة والنحن�ء للج�نب الأمين والدوران جلهة اليمني )p = 0.01 لكل منهم�(, ب�لرغم من كون العالقة مع حركة الدوران جلهة الي�ش�ر ك�نت عك�شية )p = 0.03(, كم� اأظهرت الدرا�شة اأنه من ن�حية �رسعة الزاوية الق�شوى, ك�ن هن�ك ارتب�ط اإيج�بي ملوؤ�رس اأو�س وي�شرتي مع حركة النحن�ء اجل�نبي جلهتي اليمني والي�ش�ر يف م�شتوى الفقرة القطنية الأوىل )0.01 = p و 0.01< على التوايل(, وك�ن الرتب�ط عك�شي� مع حركة النحن�ء اجل�نبي جلهة الي�ش�ر يف الفقرة العجزية الث�نية )p = 0.04(, اأم� فيم� يتعلق ب�حلد الأدنى لل�رسعة الزاوية, ك�ن ارتب�ط موؤ�رس اأو�س وي�شرتي اإيج�بي� مع حركة النحن�ء اجل�نبي جلهة الي�ش�ر يف منطقة الفقرة القطنية الفقرة ملنطقة والي�ش�ر اليمني جلهتي اجل�نبي النحن�ء حركة مع عك�شي� ك�ن الرتب�ط هذا ولكن ,)p >0.01( الث�نية العجزية الأوىل )p = 0.02 لكل منهم�(, وحركة الدوران جلهة اليمني يف م�شتوى الفقرة القطنية الأوىل )p = 0.02(, وحركة الدوران جلهة الي�ش�ر يف م�شتوى الفقرة العجزية الث�نية )p = 0.01(, ومل يكن هن�ك اأي ارتب�ط كبري بني احلرك�ت يف منطقة الفقرات القطنية للظهر مع نت�ئج ا�شتبي�ن املعتقدات املتعلقة بتجنب اخلوف. اخلال�صة: ت�شري هذه النت�ئْج اإىل اأن هن�ك عالقة ارتب�ط بني بع�س موؤ�رسات احلرك�ت ملنطقة الفقرات القطنية اأ�شفل الظهر مع العجز الوظ�ئفي, ولكن لي�س مع املعتقدات املتعلقة ب�أ�ش�ليب جتنب اخلوف. الكلمات املفتاحية: اآلم منطقة اأ�شفل الظهر؛ الفقرات القطنية؛ علم احلرك�ت؛ تقييم مدى العجز والإع�قة؛ اخلوف. lumbar kinematics, functional disability and fear avoidance beliefs among adults with nonspecific chronic low back pain nancy g. jette,1,2 yi l. lim,1,3 hui l. lim,1 sabarul a. mokhtar,4 kok b. gan,5 *devinder k. a. singh1 clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e430–436, epub. 30 nov 16 submitted 21 apr 16 revision req. 6 jun 16; revision recd. 3 jul 16 accepted 11 aug 16 doi: 10.18295/squmj.2016.16.04.005 nancy g. jette, yi l. lim, hui l. lim, sabarul a. mokhtar, kok b. gan and devinder k. a. singh clinical and basic research | e431 low back pain (lbp) is the term used to indicate lumbosacral pain originating between the bottom of the twelfth rib and above the gluteal fold.1 it is a global health problem with a lifetime prevalence of over 80%; moreover, 11–12% of adults with lbp suffer from physical disabilities.1,2 acute lbp is defined as pain that occurs suddenly after a minimum of six months without pain and lasting for six weeks or less, whereas chronic lbp denotes periodic pain persisting for more than three months with increased risk of recurrence.1,2 the prevalence of chronic lbp is approximately 23%.2 in general, acute lbp has an organic pathology; however, biopsychosocial factors that can predispose an individual to chronic lbp are often present at the time of onset.3 lumbar kinematic measurements include an assessment of the range of motion (rom), movement velocity and acceleration of the lumbar spine.4 these variables may assist in the identification of adults at risk of lbp as adults with chronic lbp have shown variations in lumbar biomechanical parameters, including reduced rom, velocity and acceleration.5,6 however, the current focus on structural and biomechanical abnormalities is inadequate to explain chronic lbp and its associated disabilities, with previous research supporting the inclusion of biopsychosocial factors.7,8 studies have shown an association between pain-related fear of movement and reduced lumbar flexion among adults with chronic lbp and indicated that pain-related fear of movement can lead to disabilities.9–12 however, it is unclear whether adults with lbp who have pain-related fear of movement deliberately avoid movements of increased velocity and acceleration. pain-related fear of movement can be measured using the fear-avoidance beliefs questionnaire (fabq), which quantifies an individual’s fear of pain as a result of alterations in behaviour to avoid pain.8 a positive correlation has been reported between fabq scores and disability measures; however, inconsistent results have been found regarding the relationship between pain-related fear and decreased activity.12,13 the oswestry disability index (odi) has been deemed suitable for determining an individual’s disability in relation to chronic pain, with higher scores indicating greater levels of disability.14,15 nevertheless, findings of correlations between lumbar rom measurements and functional impairment in adults with chronic lbp have not been consistent.16 although a weak relationship between flexion rom and disability in adults with lbp has been found, rom and the angular velocity of flexion and extension movements have shown an inconsistent relationship with odi scores.4,17 overall, there are limited and conflicting data regarding the correlations between lumbar kinematics and functional disability and fear avoidance. further studies on this topic may assist clinicians in the management and care of adults with chronic lbp. the current study therefore aimed to examine the correlation between lumbar kinematics, functional disability and fear avoidance beliefs among adults with chronic lbp. methods this cross-sectional study was conducted between march and december 2014. a total of 32 adults with chronic lbp persisting for more than three months were recruited from a list of outpatients at either an orthopaedic clinic at the pusat perubatan universiti kebangsaan malaysia hospital, kuala lumpur, malaysia, or a private physiotherapy clinic in petaling jaya, malaysia. the inclusion criteria included outpatients between 20–45 years old with pain originating between the lower ribs and inferior gluteal fold who had been diagnosed by a doctor as having chronic lbp. patients were excluded from the study if they were currently taking any medications or if they had referred or radicular pain, overt neurological signs (i.e. sensory deficits or motor paralysis), psychological illnesses or “red-flag” disorders (e.g. neoplasms, inflamm atory disease, fractures or infections). women who were pregnant were also excluded. a power analysis for a bivariate normal model was performed using g*power software, version 3.1.9.2 (heinrich heine university, dusseldorf, germany); this indicated that the sample size was sufficient for the purposes of the study (effect size = 0.50; power = 0.80; p <0.05).18 advances in knowledge the current study identified significant correlations between several lumbar kinematic parameters and functional disability as determined using the oswestry disability index among adults with nonspecific chronic low back pain (lbp). however, no correlations were observed between lumbar kinematic parameters and fear avoidance beliefs. application to patient care the findings of this study indicate that both lumbar kinematics and functional impairment should be taken into consideration during the assessment and management of adults with nonspecific chronic lbp. lumbar kinematics, functional disability and fear avoidance beliefs among adults with nonspecific chronic low back pain e432 | squ medical journal, november 2016, volume 16, issue 4 lumbar kinematic parameters, including lumbar rom, velocity and acceleration, were measured using an inertial measurement system (mtx human motion tracker, xsens technologies b.v., enschede, netherlands). this system provides an accurate and drift-free 360° view with a three-dimensional spinal range of movement and coupled motion measurements. the first lumbar (l1) and second sacral (s2) spinous processes were identified by palpating the spine when the participant was in a standing position. two sensors set at 50 hz were attached perpendicularly to each other and the spinous processes of the l1 and s2 vertebrae and secured to the trunk with an elastic strap. participants were then requested to move to their full rom, while limiting pelvic movements as much as possible. the rom of six physiological movements was then obtained by calculating the relative angles between the two sensors using a direction cosine matrix that transforms vectors in the body frame to reference frame analysis (matlab software, mathworks inc., natick, massachusetts, usa). each participant was requested to perform three repetitions of flexion, extension, lateral flexion (left and right) and rotation (left and right) with their feet shoulder-width apart and knees extended. the averages of the three measurements were taken as rom and velocity results. participants were given a demonstration of this process before official recording of the data began. the sociodemographic characteristics of the participants were obtained, including age, gender and employment status. weight and height were measured to calculate body mass index (bmi). back pain was evaluated using a visual analogue scale (vas), which has a 10 cm horizontal line numbered from 0 to 10 with 0 signifying no pain, 5 signifying moderate pain and 10 signifying the worst possible pain.19 participants were required to mark the point on the scale that they felt represented their current pain status. the 10-item odi questionnaire was used to quantify the severity of disability for each participant, with a score between 0–5 being assigned for each of the following items: pain intensity, personal care, lifting, walking, sitting, standing, sleeping, sex life, social life and travelling.14 the total score of the 10-item odi questionnaire was recorded as a percentage. fear avoidance beliefs were assessed using the 5-item physical activity (fabq-pa) and 11-item work (fabq-w) subscales of the fabq, with scores ranging on a likert scale of 0–6.8 a score of 6 was taken to denote the highest level of fear avoidance belief.8 both the odi and fabq questionnaires were completed by the researchers in english during interviews with the participants. all data analysis was performed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). a shapiro-wilk test indicated that most of the kinematic variables were not normally distributed; thus, spearman’s rank correlation coefficient was used to determine correlations between the variables. a p value of <0.05 was considered to be statistically significant. ethical approval for this study was obtained from the secretariat for research & ethics of the universiti kebangsaan malaysia, kuala lumpur (ukm #1.5.3.5/244/nn-147-2013). all participants were provided with written and verbal information about the study procedures and gave informed verbal consent for participation. table 2: mean maximum range of motion variables among adults with chronic low back pain (n = 32) rom in degrees mean ± sd flexion 37.52 ± 9.25 extension 9.33 ± 7.61 right lateral flexion 13.72 ± 10.23 left lateral flexion 11.67 ± 13.62 right rotation 8.23 ± 12.76 left rotation 11.05 ± 11.77 rom = range of motion; sd = standard deviation. table 1: demographic characteristics, degree of functional disability* and fear avoidance belief† scores among adults with chronic low back pain (n = 32) variable mean ± sd gender, n (%) male 13 (40.6) female 19 (59.4) age in years 32.94 ± 7.83 vas score 2.00 ± 1.42 bmi in kg/m2 23.77 ± 3.21 employment status, n (%) unemployed 6 (18.8) employed 26 (81.3) odi score 19.02 ± 8.72 fabq-pa score 15.84 ± 4.32 fabq-w score 17.41 ± 8.60 overall fabq score 33.25 ± 9.48 sd = standard deviation; vas = visual analogue scale; bmi = body mass index; odi = oswestry disability index; fabq-pa = physical activity subscale of the fear-avoidance beliefs questionnaire; fabq-w = work subscale of the fear-avoidance beliefs questionnaire. *functional disability was assessed using the oswestry disability index.14 †fear avoidance beliefs were assessed using the fear-avoidance beliefs questionnaire.8 nancy g. jette, yi l. lim, hui l. lim, sabarul a. mokhtar, kok b. gan and devinder k. a. singh clinical and basic research | e433 results the sociodemographic characteristics and mean odi and fabq scores of the participants are shown in table 1. the mean lumbar rom for flexion and extension was 37.52 ± 9.25 degrees and 9.33 ± 7.61 degrees, respectively. mean rotation and lateral flexion were between 11.67–13.72 degrees and 8.23–11.05 degrees, respectively [table 2]. table 3 depicts the mean minimum and maximum angular velocity measurements. there were significant moderate positive correl ations between odi scores and the right lateral flexion and right rotation (p = 0.01 each) variables of maximum rom, the right and left lateral flexion l1 (p = 0.01 and <0.01, respectively) variables of maximum angular velocity and the left lateral flexion s2 (p <0.01) variable of minimum angular velocity. significant weak-to-moderate negative correlations were observed between odi scores and the left rotation (p = 0.03) variable of maximum rom, the left lateral flexion s2 (p = 0.04) variable of maximum angular velocity and the right and left lateral flexion l1 (p = 0.02 each), right rotation l1 (p = 0.02) and left rotation s2 (p = 0.01) variables of minimum angular velocity. there were no significant correlations between lumbar kinematics and either fabq-pa or fabq-w scores [table 4]. discussion this study aimed to examine potential correlations between lumbar kinematics, functional disability and fear avoidance beliefs among adults with chronic lbp. however, only functional disability was found to be significantly correlated with certain lumbar kinematic parameters, suggesting that greater perceived funct ional disability was correlated to a decrease or increase in certain aspects of lumbar rom and angular velocity. using an electrogoniometer and torsio meter, bible et al. previously reported mean full active rom measurements for flexion (54.6 degrees), extension (26.6 degrees), left and right lateral bending (17.5–19.5 degrees) and left and right axial rotation (16.7–17.6 degrees) for adults without lbp.20 in comparison, participants in the current study had lower lumbar rom measurements, with approximately 30% reduced flexion and rotation, 65% reduced extension and 35% reduced rotation. these differences in findings may be due to variations in measurement instruments and study protocols. however, it is noteworthy that extension rom was the most limited movement in the current study, followed by rotation and side flexion. in the current study, mean maximum right lateral flexion and right rotation variables of rom had a positive correlation with odi scores, whereas there was a negative correlation between left rotation and odi scores. these results demonstrate an inconsistent correlation between lumbar movements and disability. clinically, these results are acceptable as both declined and increased mobility may be related to functional ability.21 in a previous study, parks et al. concluded that the association between lumbar motions and functional ability was either weak or absent.22 moreover, a negative correlation between odi and left rotation rom has also been described in an earlier report.23 movement impairment among adults with chronic lbp may be due to an associated cocontraction of the lumbar-pelvic muscles and muscle spasms which can lead to limited motion and injury.24 on the other hand, hypermobility may also exist in certain spinal segments, causing spinal instability and impaired neuromuscular control, eventually affecting an individual’s ability to function normally.25 table 3: mean minimum and maximum angular velocity variables among adults with chronic low back pain (n = 32) angular velocity in degrees/second mean ± sd minimum maximum flexion l1 -84.22 ± -25.78 83.65 ± -26.93 s2 -59.59 ± -20.05 56.72 ± -20.63 extension l1 -30.37 ± -25.78 33.23 ± -18.33 s2 -22.35 ± -21.20 21.77 ± -16.62 right lateral flexion l1 -17.76 ± -10.31 17.76 ± -10.89 s2 -12.61 ± -5.16 12.03 ± -5.16 left lateral flexion l1 -17.76 ± -10.31 18.33 ± -9.74 s2 -12.03 ± -4.58 12.03 ± -5.16 right rotation l1 -25.21 ± -43.54 23.49 ± -39.53 s2 -20.63 ± -42.40 18.91 ± -38.39 left rotation l1 -8.02 ± -4.58 14.32 ± -14.32 s2 -8.59 ± -6.88 10.31 ± -9.74 l1 = first lumbar vertebra level; s2 = second sacral vertebra level; sd = standard deviation. lumbar kinematics, functional disability and fear avoidance beliefs among adults with nonspecific chronic low back pain e434 | squ medical journal, november 2016, volume 16, issue 4 as with rom, inconsistent results were also observed in the current study with regards to lumbar velocity. the authors of the current study speculate that this may be due to the complex relationship of lumbar kinematics with functional impairment. other factors may have influenced the results, such as limb dominance, laterality of pain, level of pain and disability. adults with lbp have been found to move more slowly compared to healthy individuals.26 it is also noteworthy that the mean odi score of participants in the current study indicated minimal disability (19.2%), while the mean vas score (2/10) suggested only mild-to-moderate disability.14 thus, the results of the present study could have been influenced by the lack of severity of lbp symptoms among the participants. in addition, asymmetries in lumbar motion have been noted among adults without lbp which were unrelated to any limitations and were believed to be derived from daily habitual movements.27 pain-related fear is believed to be an important factor in determining disability in chronic lbp, rather than pain or physical impairment alone.22 the present study found that lumbar kinematic variables were not associated with fabq-pa or fabq-w scores. similarly, demoulin et al. reported that painrelated fear measures were not significantly related to the physical capacity of the spine.28 however, these findings are contradictory to those of earlier studies reporting associations between physical ability and table 4: correlations between lumbar kinematic variables and functional disability* and fear avoidance beliefs† among adults with chronic low back pain (n = 32) variable odi score fabq-pa score fabq-w score rs p value rs p value rs p value maximum rom in degrees flexion 0.07 0.72 -0.03 0.86 -0.22 0.23 extension 0.10 0.60 0.00 0.98 -0.16 0.39 right lateral flexion 0.48 0.01‡ -0.11 0.55 -0.16 0.40 left lateral flexion -0.33 0.07 -0.35 0.05 -0.04 0.82 right rotation 0.48 0.01‡ 0.04 0.83 -0.11 0.56 left rotation -0.39 0.03‡ -0.29 0.11 -0.21 0.25 maximum angular velocity in degrees/second flexion l1 0.10 0.57 -0.09 0.63 -0.18 0.34 s2 0.15 0.40 -0.17 0.35 0.22 0.23 extension l1 -0.16 0.37 0.01 0.95 -0.34 0.06 s2 -0.31 0.09 -0.09 0.64 -0.24 0.20 right lateral flexion l1 0.44 0.01‡ -0.05 0.79 -0.13 0.47 s2 -0.28 0.12 -0.12 0.52 0.13 0.49 left lateral flexion l1 0.52 <0.01‡ 0.07 0.72 -0.18 0.32 s2 -0.37 0.04‡ -0.12 0.52 -0.08 0.69 right rotation l1 0.26 0.15 -0.12 0.50 -0.25 0.16 s2 0.34 0.06 -0.10 0.60 -0.10 0.60 left rotation l1 0.24 0.19 -0.19 0.30 -0.06 0.76 s2 0.31 0.09 -0.31 0.09 -0.15 0.43 minimum angular velocity in degrees/second flexion l1 0.06 0.76 0.17 0.35 0.20 0.27 s2 0.19 0.30 0.20 0.28 0.11 0.55 extension l1 -0.01 0.95 0.08 0.65 0.27 0.14 s2 0.11 0.55 0.01 0.96 0.20 0.28 right lateral flexion l1 -0.42 0.02‡ -0.02 0.93 0.10 0.58 s2 0.26 0.15 0.08 0.68 0.09 0.62 left lateral flexion l1 -0.42 0.02‡ -0.01 0.97 0.13 0.50 s2 0.51 <0.01‡ 0.16 0.37 -0.15 0.41 right rotation l1 -0.42 0.02‡ 0.05 0.80 0.28 0.13 s2 -0.29 0.11 0.11 0.56 0.20 0.27 left rotation l1 0.25 0.16 0.30 0.09 0.07 0.72 s2 -0.47 0.01‡ 0.03 0.88 0.11 0.54 odi = oswestry disability index; fabq-pa = physical activity subscale of the fear-avoidance beliefs questionnaire; fabq-w = work subscale of the fear-avoidance beliefs questionnaire; rs = spearman’s rank correlation coefficient; rom = range of motion; l1 = first lumbar vertebra level; s2 = second sacral vertebra level. *functional disability was assessed using the oswestry disability index.14 †fear avoidance beliefs were assessed using the fear-avoidance beliefs questionnaire.8 ‡significant at p <0.05. nancy g. jette, yi l. lim, hui l. lim, sabarul a. mokhtar, kok b. gan and devinder k. a. singh clinical and basic research | e435 fear avoidance beliefs.9,11,29 in one study, geisser et al. observed a significant correlation between pain-related fear and decreased lumbar flexion among participants with chronic lbp.9 vaisy et al. reported that rom and angular velocity were associated with psychological characteristics, including fear of movement.11 grotle et al. found that fear avoidance beliefs were significantly related to disability after controlling for sociodemographic, pain-related and clinical variables and excluding distress variables.30 another study found that a combination of psychological factors, including fear avoidance beliefs, anxiety and pain catastrophising, determined functional disability in adults with chronic lbp.31 nevertheless, other sociodemographic and psychosocial factors such as income, education level, type of management received, selfefficacy and motivation may need to be accounted for when considering a relationship between pain-related fear of movement and functional ability. the findings of the present study add to existing controversy in the literature regarding the correlation between lumbar motion, functional ability and fear avoidance beliefs. differences in findings may be due to inter-study variations in measurement instruments, protocols, participant selection and analysis systems. despite this, the results of the current study may be of interest to clinicians in the assessment and management of adults with nonspecific chronic lbp. it is important to note that observation of lumbar rom through visual estimations may not show small differences. however, measurements of higher order kinematics, such as movement velocity and acceleration, may not be feasible in clinical settings as they often require costly instrumentation. physiotherapists should provide individually tailored exercises focusing on lumbar rotation and lateral flexion movements as well as lumbar extension when treating adults with nonspecific chronic lbp. there are a few limitations to this study. firstly, the sample size was limited and confined to adults with nonspecific chronic lbp. secondly, data regarding quality of movement, specific locations of pain and range of pain were not analysed. therefore, the results of this study cannot be generalised to other types of lbp with symptoms that include unilateral pain, hypomobility or hypermobility. further studies are required assessing lumbar kinematics among patients with different types of lbp in comparison to a control group.32 there is also a need for future research to examine the relationship between lumbar kinematics and sustained prolonged functional activities among adults with nonspecific chronic lbp. conclusion the results of this study suggest that certain components of rotation and lateral flexion are correlates of functional disability, but not fear avoidance beliefs. lumbar rotation and lateral flexion movements should therefore be emphasised in addition to lumbar extension during rehabilitation therapy for adults with nonspecific chronic lbp. in addition, both lumbar kinematics and functional impairment should be taken into consideration in the assessment and management of adults with nonspecific chronic lbp. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by a grant from the ministry of higher education, malaysia, through universiti kebangsaan malaysia (#ergs/1/2012/skk10/ukm/02/2). references 1. hoy d, brooks p, blyth f, buchbinder r. the epidemiology of low back pain. best pract res clin rheumatol 2010; 24:769–81. doi: 10.1016/j.berh.2010.10.002. 2. balagué f, mannion af, pellisé f, cedraschi c. non-specific low back pain. lancet 2012; 379:482–91. doi: 10.1016/s01406736(11)60610-7. 3. koho p, aho s, watson p, hurri h. assessment of chronic pain behaviour: reliability of the method and its relationship with perceived disability, physical impairment and function. j rehabil med 2001; 33:128–32. doi: 10.1080/165019701750165970. 4. lehman gj. biomechanical assessments of lumbar spinal function: how low back pain sufferers differ from normals implications for outcome measures research: part i kinematic assessments of lumbar function. j manipulative physiol ther 2004; 27:57–62. doi: 10.1016/j.jmpt.2003.11.007. 5. williams jm, haq i, lee ry. a novel approach to the clinical evaluation of differential kinematics of the lumbar spine. man ther 2013; 18:130–5. doi: 10.1016/j.math.2012.08.003. 6. trost z. pain-related fear, pain and harm appraisal, and kinematic avoidance among healthy participants following delayed onset muscle soreness. phd thesis. athens, ohio, usa: ohio university, 2010. 7. leeuw m, goossens me, linton sj, crombez g, boersma k, vlaeyen jw. the fear-avoidance model of musculoskeletal pain: current state of scientific evidence. j behav med 2007; 30:77–94. doi: 10.1007/s10865-006-9085-0. 8. waddell g, newton m, henderson i, somerville d, main cj. a fear-avoidance beliefs questionnaire (fabq) and the role of fear-avoidance beliefs in chronic low back pain and disability. pain 1993; 52:157–68. doi: 10.1016/0304-3959(93)90127-b. 9. geisser me, haig aj, wallbom as, wiggert ea. pain-related fear, lumbar flexion, and dynamic emg among persons with chronic musculoskeletal low back pain. clin j pain 2004; 20:61–9. doi: 10.1097/00002508-200403000-00001. lumbar kinematics, functional disability and fear avoidance beliefs among adults with nonspecific chronic low back pain e436 | squ medical journal, november 2016, volume 16, issue 4 10. thomas js, france cr, lavender sa, johnson mr. effects of fear of movement on spine velocity and acceleration after recovery from low back pain. spine (phila pa 1976) 2008; 33:564–70. doi: 10.1097/brs.0b013e3181657f1a. 11. vaisy m, gizzi l, petzke f, consmüller t, pfingsten m, falla d. measurement of lumbar spine functional movement in low back pain. clin j pain 2015; 31:876–85. doi: 10.1097/ ajp.0000000000000190. 12. george sz, fritz jm, mcneil dw. fear-avoidance beliefs as measured by the fear-avoidance beliefs questionnaire: change in fear-avoidance beliefs questionnaire is predictive of change in self-report of disability and pain intensity for patients with acute low back pain. clin j pain 2006; 22:197–203. doi: 10.1097/01.ajp.0000148627.92498.54. 13. van weering m, vollenbroek-hutten mm, kotte em, hermens hj. daily physical activities of patients with chronic pain or fatigue versus asymptomatic controls: a systematic review. clin rehabil 2007; 21:1007–23. doi: 10.1177/0269215 507078331. 14. fairbank jc, pynsent pb. the oswestry disability index. spine (phila pa 1976) 2000; 25:2940–52. doi: 10.1097/00007632200011150-00017. 15. vianin m. psychometric properties and clinical usefulness of the oswestry disability index. j chiropr med 2008; 7:161–3. doi: 10.1016/j.jcm.2008.07.001. 16. nattrass cl, nitschke je, disler pb, chou mj, ooi kt. lumbar spine range of motion as a measure of physical and functional impairment: an investigation of validity. clin rehabil 1999; 13:211–18. 17. vlaeyen jw, linton sj. fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. pain 2000; 85:317–32. doi: 10.1016/s0304-3959(99)00242-0. 18. faul f, erdfelder e, buchner a, lang ag. statistical power analyses using g*power 3.1: tests for correlation and regression analyses. behav res methods 2009; 41:1149–60. doi: 10.3758/ brm.41.4.1149. 19. bijur pe, silver w, gallagher ej. reliability of the visual analog scale for measurement of acute pain. acad emerg med 2001; 8:1153–7. doi: 10.1111/j.1553-2712.2001.tb01132.x. 20. bible je, biswas d, miller cp, whang pg, grauer jn. normal functional range of motion of the lumbar spine during 15 activities of daily living. j spinal disord tech 2010; 23:106–12. doi: 10.1097/bsd.0b013e3181981823. 21. key j. back pain: a movement problem a clinical approach incorporating relevant research and practice. london, uk: churchill livingstone, 2010. pp. 152–63. doi: 10.1016/b978-07020-3079-6.00004-6. 22. parks ka, crichton ks, goldford rj, mcgill sm. a comparison of lumbar range of motion and functional ability scores in patients with low back pain: assessment for range of motion validity. spine (phila pa 1976) 2003; 28:380–4. doi: 10.1097/01. brs.0000048466.78077.a6. 23. beazell jr, mullins m, grindstaff tl. lumbar instability: an evolving and challenging concept. j man manip ther 2010; 18:9–14. doi: 10.1179/106698110x12595770849443. 24. michel a, kohlmann t, raspe h. the association between clinical findings on physical examination and self-reported severity in back pain: results of a population-based study. spine (phila pa 1976) 1997; 22:296–303. doi: 10.1097/00007632199702010-00013. 25. o’sullivan p. diagnosis and classification of chronic low back pain disorders: maladaptive movement and motor control impairments as underlying mechanism. man ther 2005; 10:242–55. doi: 10.1016/j.math.2005.07.001. 26. simmonds mj, lee ce, etnyre br, morris gs. the influence of pain distribution on walking velocity and horizontal ground reaction forces in patients with low back pain. pain res treat 2012; 2012:214980. doi: 10.1155/2012/214980. 27. gomez tt. symmetry of lumbar rotation and lateral flexion range of motion and isometric strength in subjects with and without low back pain. j orthop sports phys ther 1994; 19:42–8. doi: 10.2519/jospt.1994.19.1.42. 28. demoulin c, huijnen ipj, somville pr, grosdent s, salamun i, crielaard jm, et al. relationship between different measures of pain-related fear and physical capacity of the spine in patients with chronic low back pain. spine j 2013; 13:1039–47. doi: 10.1016/j.spinee.2013.02.037. 29. vlaeyen jw, linton sj. fear-avoidance model of chronic musculoskeletal pain: 12 years on. pain 2012; 153:1144–7. doi: 10.1016/j.pain.2011.12.009. 30. grotle m, vøllestad nk, brox ji. clinical course and impact of fear-avoidance beliefs in low back pain: prospective cohort study of acute and chronic low back pain ii. spine (phila pa 1976) 2006; 31:1038–46. doi: 10.1097/01.brs.0000214878.01709.0e. 31. dubois jd, abboud j, st-pierre c, piché m, descarreaux m. neuromuscular adaptations predict functional disability independently of clinical pain and psychological factors in patients with chronic non-specific low back pain. j electromyogr kinesiol 2014; 24:550–7. doi: 10.1016/j.jelekin.2014.04.012. 32. nancy gj, singh dk, nordin na, ha th, mokhtar sa, chang sh, et al. lumbar kinematic pattern among adults with low back pain: a study protocol. j teknol 2016; 78:101–6. doi: 10.11113/jt.v78.9061. departments of 1medicine and 3radiology & molecular imaging, sultan qaboos university hospital; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mails: arunoday@squ.edu.om and grarunoday@hotmail.com أنواع التجلط الوعائي الوريدي الدماغي يف سلطنة عمان دار�شان لل، اأرونودايا غوجار، نانداجوبال راما�شاندران، عمار عبيدي، �شونيل كومار، مرت�شى التيجاين، في�شل العزري، عبد اهلل را�شد العا�شمي abstract: objectives: cerebral venous thrombosis (cvt) can have varied and life-threatening manifestations. this study aimed to examine the spectrum of its clinical presentations and outcomes in a tertiary hospital in oman. methods: this retrospective study was conducted at the sultan qaboos university hospital, muscat, oman, between january 2009 and december 2017. the medical records of all patients with cvt were reviewed to determine demographic characteristics, clinical features and patient outcomes. results: a total of 30 patients had cvt. the mean age was 36.8 ± 11 years and the male-to-female ratio was 2:3. common manifestations included headache (83%), altered sensorium (50%), seizures (43%) and hemiparesis (33%). underlying risk factors were present in 16 patients (53%). computed tomography or magnetic resonance imaging of the brain was abnormal in all patients, with indications of infarcts (40%) and major sinus thrombosis (100%). there were five cases (20%) of deep cvt. the patients were treated with low-molecular-weight heparin, mannitol and anticonvulsants. the majority (77%) had no residual neurological deficits at follow-up. conclusion: these findings indicate that cvt is a relatively uncommon yet treatable disorder in oman. a high index of suspicion, early diagnosis, prompt anticoagulation treatment and critical care may enhance favourable patient outcomes. keywords: venous thrombosis; cerebral thrombosis; cranial venous sinuses; neurological manifestations; patient outcome assessment; oman. امللخ�ص: الهدف: التجلط الوريدي الدماغي له مظاهر متنوعة قد تهدد احلياة. هدفت هذه الدرا�شة اإىل معرفة اأنواع هذه اجللطات واأعرا�شها ونتائج عالجها يف ُعمان. الطريقة: اأجريت هذه الدرا�شة الرجعية يف م�شت�شفى جامعة ال�شلطان قابو�ص، م�شقط، عمان، بني يناير 2009 الدميوغرافية، اخل�شائ�ص لتحديد الدماغي الوريدي بالتجلط امل�شابني املر�شى جلميع الطبية ال�شجالت ا�شتعرا�ص مت .2017 ودي�شمرب ± 11 العمر متو�شط كان الدماغي. الوريدي بالتجلط مري�شا 30 جمموعه ما ا�شيب النتائج: ونتائجها. للجلطات ال�رسيرية والأعرا�ص 36.8 �شنة وكانت ن�شبة الذكور اإىل الإناث 2:3. و�شملت الأعرا�ص الكلينيكية ال�شائعة ال�شداع )%83(، وتغري يف حوا�ص املري�ص )50%(، والت�شنجات )%43( و وال�شعف الن�شفي )%33(. كانت عوامل اخلطورة الأ�شا�شية موجودة يف 16 مري�شا )%53(. كان نتائج الت�شوير بالرنني املغناطي�شي للدماغ غري طبيعيه يف جميع املر�شى، مع وجود موؤ�رسات على جلطة دماغية يف )%40( وجتلط الأوردة الدماغية الرئي�شية يف )%100( من احلالت. كانت هناك خم�ص حالت )%20( من التجلط الوريدي الدماغي العميق. مت عالج جميع املر�شى بالهيبارين منخف�ص الوزن اجلزيئي، مع املانيتول اأو م�شادات الت�شنجات ال�رسعية. ظهر اأن غالبية املر�شى )%77( لي�ص لديهم اأي خلل اأوعجز ع�شبي عند املتابعة. اخلال�صة: ت�شري هذه النتائج اإىل اأن التجلط الوريدي الدماغي هو ا�شطراب غري �شائع ن�شبيا يف عمان وممكن عالجه بنجاح. اإن وجود قدرة عالية لتوقع املر�ص يعزز من فر�ص الت�شخي�ص املبكر وبداأ العالج الفوري مب�شادات التجلط والرعاية املركزة قد يعزز من النتائج الإيجابية ل�شفاء املري�ص. الكلمات املفتاحية: التجلط الوريدي؛ اجللطة الدماغية؛ اجليوب الوريدية الدماغية؛ الأعرا�ص الع�شبية؛ تقييم نتائج املر�شى؛ عمان. spectrum of cerebral venous thrombosis in oman darshan lal,1 *arunodaya r. gujjar,2 nandagopal ramachandiran,2 ammar obaidi,1 sunil kumar,1 mortada el-tigani,1 faizal al-azri,3 abdullah r. al-asmi1 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e329–337, epub. 19 dec 18 submitted 18 dec 17 revisions req. 28 jan & 26 mar 18; revisions recd. 7 mar & 6 apr 18 accepted 12 apr 18 advances in knowledge this study reports the spectrum of cerebral venous thrombosis (cvt) in a tertiary hospital in oman. the approximate prevalence of cvt in the hospital-based cohort was 3%. the cvt survivors had a relatively low incidence of residual neurological deficits (14.8%). application to patient care this study emphasises the need for greater awareness of the wide range of clinical manifestations of cvt and highlights the use of imaging to ensure the prompt diagnosis of this condition. doi: 10.18295/squmj.2018.18.03.011 cerebral venous thrombosis (cvt)—also known as cerebral sinovenous thrombosis or dural sinus thrombosis—constitutes approximately 0.5% of all stroke syndromes.1 the diverse manif estations of cvt can cause difficulties in diagnosis. moreover, the disease is potentially dangerous, with a large proportion of patients experiencing raised intracranial pressure (icp), focal infarcts and intracerebral haemorrhage.1 due to advances in the diagnostic sensit ivity of imaging methods and the overall quality of spectrum of cerebral venous thrombosis in oman e330 | squ medical journal, august 2018, volume 18, issue 3 management, cvt-related mortality has decreased from >30% in 1960 to 5–15% in recent years.2 this study aimed to examine the spectrum of cvt in a tertiary hospital in oman, including its clinical presentations and outcomes. in addition, representative cases are described to highlight various manifestations of cvt and challenges in the management of this condition. methods this retrospective study was conducted at the sultan qaboos university hospital (squh), muscat, oman, between january 2009 and december 2017. all adult patients (>18 years old) diagnosed with cvt and entered into the hospital stroke registry were included in the study. cases of cavernous sinus thrombosis were excluded due to their relation to infective conditions. in addition, patients with sinovenous disease related to trauma or local malignancy were also excluded. electronic medical records were systematically reviewed to collect demographic, clinical, imaging, treat ment and outcome data. a cvt diagnosis was based on clinical features such as headaches, seizures, altered sensorium and focal neurological deficits, supported by imaging findings typical of sinovenous thrombosis. all patients were investigated for possible underlying thromboses. other investigations included a complete blood count (cbc) and coagulation profile as well as tests for autoimmune conditions and procoagulant states such as proteins c, s and antithrombin iii deficiencies and antiphospholipid syndrome. this study received ethical approval from the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #1062). results a total of 900 patients with cerebrovascular disease were treated at squh during the study period, of which 30 (3%) were diagnosed with cvt. the male-to-female ratio was 2:3 and the mean age was 36.8 ± 11 years old. the mean duration of symptoms was 7.4 ± 3 days, with 28 patients (93%) having symptoms of 1–14 days duration, while the remaining two patients had symptoms which evolved over a period of 30 and 45 days, respectively. the 28 patients were evaluated initially by the emergency medical services, while the two patients with a longer duration of symptoms were admitted to the hospital ward. headache was the most common symptom (83%), followed by altered sensorium (50%), seizures (43%) and hemiparesis (33%). the initial differential diagnosis incl uded status epilepticus, arterial strokes, neuroinfections, intracerebral haemorrhage, mass lesions and cerebral angiitis, in addition to cvt. risk factors were present in 16 patients (53%), including pregnancy/puerperium (17%), systemic malignancy (13%), oral contraceptive use (7%), systemic lupus erythematosus (3%) and protein table 1: sociodemographic and clinical characteristics of cerebral venous thrombosis patients at the sultan qaboos university hospital, muscat, oman (n = 30) characteristic n (%) mean age in years ± sd 36.8 ± 11 gender male 12 (40) female 18 (60) symptoms* headache 25 (83) altered sensorium 15 (50) seizures 13 (43) hemiparesis 10 (33) mean duration of symptoms in days ± sd 7.4 ± 3 risk factors* 16 (53) pregnancy/puerperium 5 (17) systemic malignancy 4 (13) oral contraceptive use 2 (7) sle 1 (3) protein c/anti-thrombin iii deficiency 2 (7)† none 14 (47) treatment* lmwh 27 (90) iv mannitol 13 (43) anticonvulsant 11 (37) icu care 6 (20) warfarin 21 (70) short-term outcome died during hospital stay 3 (10) survived 27 (90) long-term outcome complete recovery 23 (77) neurological deficit 4 (13) sd = standard deviation; sle = systemic lupus erythematosus; lmwh = low-molecular-weight heparin; iv = intravenous; icu = intensive care unit. *percentages do not add up to 100% as some patients may have had more than one risk factor, symptom or treatment. †including one patient with a protein c deficiency and one patient with an antithrombin iii deficiency. darshan lal, arunodaya r. gujjar, nandagopal ramachandiran, ammar obaidi, sunil kumar, mortada el-tigani, faizal al-azri and abdullah r. al-asmi clinical and basic research | e331 c and anti-thrombin iii deficiencies (7%). despite ext ensive investigations, no underlying cause could be established in the remaining 14 patients (47%) [table 1]. either computed tomography (ct) or magnetic resonance imaging (mri) of the brain was performed in all 30 patients, with the majority (67%) undergoing both modalities. a total of 25 patients (83%) underwent ct scans, which were abnormal in 21 patients (84%). parenchymal haemorrhage and infarcts were observed in 28% and 40% of patients, respectively. using contrast ct venography, transverse sinus (trs) thrombosis was seen in 48% of patients, superior sagittal sinus (sss) thrombosis in 44%, sigmoid sinus (sigs) thrombosis in 32%, internal jugular vein (ijv) thrombosis in 16% and straight sinus (ss) and cortical vein thrombosis were each seen in 8% of patients. empty delta sign was seen in eight patients (32%). the mri scans of all patients were abnormal. infarcts were the most common mri abnormality (40%), followed by haemorrhage (12%). magnetic resonance venography (mrv) revealed trs thrombosis in 52% of patients, sss and sigs thrombosis in 44% each, cortical vein thrombosis in 20% and ijv and ss thrombosis in 8% each. empty delta sign was observed in five patients (20%) [table 2]. with regards to treatment, 27 patients (90%) rec eived low-molecular-weight heparin (lmwh) in therapeutic doses over an initial 7–14-day period. a total of 13 patients (43%) received intravenous (iv) mannitol and 11 (37%) received anticonvulsants. six patients (20%) required intubation and ventilation in the intensive care unit (icu) due to either an altered mental status or status epilepticus. a total of 21 patients (70%) were prescribed warfarin for the purposes of long-term anti coagulation, adjusted to a target international normalised ratio (inr) of 2.3. this treatment was continued for periods ranging from three months for puerperal cvt cases to a year or longer for other conditions. patients with either recurrent cvt or high-risk procoagulant states were advised to continue taking anticoagulation medications indefinitely. overall, 27 patients (90%) survived. the remaining three patients (10%) died due to either extensive thromb osis with malignant brain oedema, advanced malignancy or sepsis complicating a central nervous system infection. one patient underwent surgical evacuation of a hemispheric haematoma with perioperative recogn ition of the thrombosed veins; after one year, he was readmitted with recurrent cvt after having discontinued anticoagulation medications. at follow-up, 23 patients (77%) showed complete neurological recovery. the following subsections highlight four different pres entations of cvt seen during the study period. p u e r p e r a l c e r e b r a l v e n o u s t h r o m b o s i s a 23-year-old woman underwent an emergency caes arean section due to severe pre-eclampsia at 29 gestational weeks. she had a family history of venous thrombotic events with a history of deep vein thrombosis (dvt) on her mother’s side. although she recovered promptly following the procedure, she presented 10 days later with a headache, left-sided weakness and recurrent generalised seizures progressing to status epilepticus. the seizures were controlled with iv phenytoin. an examination revealed drowsiness and left hemiparesis. table 2: imaging features of cerebral venous thrombosis patients at the sultan qaboos university hospital, muscat, oman (n = 30)* feature n (%)† ct 25 (83) abnormal 21 (84) parenchymal haemorrhage 7 (28) non-haemorrhagic/haemorrhagic infarct 10 (40)‡ contrast ctv 25 (83) trs thrombosis 12 (48) sss thrombosis 11 (44) sigs thrombosis 8 (32) ijv thrombosis 4 (16) ss thrombosis 2 (8) cortical vein thrombosis 2 (8) empty delta sign 8 (32) mri 25 (83) abnormal 25 (100) haemorrhage 3 (12) non-haemorrhagic/haemorrhagic infarct 10 (40)§ mrv 25 (83) trs thrombosis 13 (52) sss thrombosis 11 (44) sigs thrombosis 11 (44) cortical vein thrombosis 5 (20) ijv thrombosis 2 (8) ss thrombosis 2 (8) empty delta sign 5 (20) ct = computed tomography; ctv = computed tomography venography; trs = transverse sinus; sss = superior sagittal sinus; sigs = sigmoid sinus; ijv = internal jugular vein; ss = straight sinus; mri = magnetic resonance imaging ; mrv = magnetic resonance venography. *all patients had either ct or mri brain scans, with 20 patients (67%) undergoing both imaging modalities. †percentages do not add up to 100% as some patients may have had more than one imaging feature. ‡comprising five patients with non-haemorrhagic infarcts and five patients with haemorrhagic infarcts. §comprising three patients with non-haemorrhagic infarcts and seven patients with haemorrhagic infarcts. spectrum of cerebral venous thrombosis in oman e332 | squ medical journal, august 2018, volume 18, issue 3 a ct scan of the brain revealed bifrontal mixeddensity lesions suggestive of haemorrhagic venous infarcts [figure 1a]. a contrast ct scan showed evidence of a filling defect in the sss and left trs, suggestive of dural venous thrombosis. extensive investigations, including a factor viii assay and tests for protein c, protein s and anti-thrombin iii deficiencies, were normal or negative. the patient was diagnosed with puerperal cvt and received a weight-based dosage of subcutaneous lmwh. however, an mri scan of the brain two days later revealed diffuse oedema and an increase in the size of the right hemispheric infarction [figure 1b]. an mrv confirmed thrombosis of the anterior part of the sss and right trs [figure 1c]. after further treatment, the left hemiparesis impr oved gradually. the patient was discharged on warfarin treatment adjusted to an inr of 2.3, which she continued taking for one year. at a one-year follow-up, she appeared normal. later, she received lmwh prophy lactically during two subsequent uneventful pregnancies. r e c u r r e n t c e r e b r a l v e n o u s t h r o m b o s i s a 60-year-old man presented with a two-day history of generalised severe headaches associated with vomiting and a generalised tonic-clonic seizure. he remained unresponsive after the seizure, with normal reactive pupils, left facial paresis and dense left-sided hemiparesis. there was no evidence of recent weight loss, trauma or alcohol abuse. the results of blood investigations, such as plasma glucose, cbc, biochemistry and coagulation parameters, were normal. a ct scan of the brain performed at admission showed patchy right parietal haemorrhage, a streak of blood in the left parietal cortical region and hyperdensity along the sss [figure 2a]. he received iv levetiracetam and mannitol and was managed in the icu. the altered sensorium further worsened the next day. an mri scan showed an increase in the size of the right parietal haematoma with mass effects and a midline shift [figure 2b]. an mrv confirmed thrombosis of the sss extending to the trs, ss and further into the right ijv [figure 2c]. the patient underwent an emergency craniotomy with decompression of the right parietal haematoma. during the surgery, thrombosis of the cortical veins was confirmed. he received an enoxaparin sodium injection as well as iv mannitol and phenytoin. further investigations for autoimmune conditions, procoagulant states and occult malignancies were negative. despite the cont inuation of anticoagulation treatment, his icu stay was complicated by dvt leading to extensive lower limb oedema, requiring the placement of an inferior vena cava filter. over the next two weeks, the patient’s altered sensorium and left hemiplegia improved. he was advised to take warfarin on a long-term basis; however, he stopped after two years. a year later, he presented with a sudden onset severe headache, disorientation and generalised seizures without focal deficits. brain ct and mri scans showed a left temporal haemorrhagic infarct with surrounding oedema due to thrombosis of the vein of labbé as well as the major sinuses. he was treated with levetiracetam, lmwh and iv mannitol. the patient improved with no overt neurological deficits and good functional recovery. he was advised to continue taking warfarin indefinitely. d e e p v e i n t h r o m b o s i s a 41-year-old woman presented to the emergency department with a one-day history of left-sided weakness, impaired speech and altered sensorium. there were no seizures. she reported having a history of oral contraceptive use of unspecified duration. upon presentation, the patient was conscious but had difficulty finding words. both pupils and optic fundi appeared normal. figure 1: imaging of the brain of a 23-year-old woman with puerperal cerebral venous thrombosis showing (a) mixed-density bifrontal venous infarcts on computed tomography, (b) increased involvement of the right hemi sphere two days later on magnetic resonance imaging and (c) thrombosis of the anterior two-thirds of the superior sagittal sinus (arrow) and right transverse sinus upon magnetic resonance venography. figure 2: imaging of the brain of a 60-year-old man with recurrent cerebral venous thrombosis showing (a) right parietal patchy haemorrhage, a thrombosed cortical vein in the left parietal region (arrow) and hyperdensity along the superior sagittal sinus (arrowhead) on computed tomography, (b) an increase in the size of the right parietal haematoma upon magnetic resonance imaging the next day and (c) thrombosis of the superior sagittal sinus extending to the transverse and sigmoid sinuses and further into the right internal jugular vein (arrow) upon magnetic resonance venography. darshan lal, arunodaya r. gujjar, nandagopal ramachandiran, ammar obaidi, sunil kumar, mortada el-tigani, faizal al-azri and abdullah r. al-asmi clinical and basic research | e333 she had left hypotonic hemiplegia but normal power on the right side. her tendon reflexes were brisk and she had bilateral extensor plantar responses. blood investigations revealed a haemoglobin level of 15.2 g/dl with mild neutrophilic leukocytosis and a c-reactive protein level of 22 mg/dl. the results of biochemistry tests were normal. one day after the onset of symptoms, a brain ct scan showed mild diffuse oedema without acute infarcts or haemorrhage. however, the sss was prominent and hyperintense, suggesting sinus thrombosis, with suspected cortical vein thrombosis in the left frontal and parietal regions [figure 3a]. therapeutic doses of lmwh were administered. however, the altered sensorium worsened the next day. the patient was drowsy and only opened her eyes in reaction to pain. an mri of the brain showed bilateral parasagittal and frontoparietal hyperintensities as well as symmetrical hyperintensities in the basal ganglia and thalamus, typical of cvt involving the deep venous system [figures 3b and c]. an mrv showed extensive thrombosis of the sss and left trs, sigs, bilateral parasagittal cortical veins as well as of the deep venous system [figure 3d]. the patient received iv mannitol and a levetiracetam injection along with lmwh. a work-up for antinuclear antibodies (anas), antiphospholipid antibodies and thrombophilia was negative. gradually, the patient’s speech and motor functions improved with time. event ually, the lmwh anticoagulant treatment was replaced with warfarin at a target inr of 2–3. at discharge, she was ambulant with no focal neurological deficits. r a i s e d i n t r a c r a n i a l p r e s s u r e a 21-year-old man was admitted with a severe general ised headache of six days’ duration, recurrent vomiting and double vision. he did not report any focal weakness, seizures or loss of consciousness. upon examination, the patient was alert, with restricted abduction of the right eye and bilateral florid papilloedema, suggestive of raised icp. at admission, a brain ct scan revealed no parenchymal changes; however, there was evidence of thrombosis of the sss and trs and empty delta sign [figures 4a and b]. additionally, mri scans showed normal brain parenchyma as well as extensive thrombosis involving the sss and trs [figures 4c and d]. the patient’s haemoglobin level was 17.9 g/dl and his haematocrit percentage was 49%, consistent with a diagnosis of polycythaemia. however, his anas and antiphospholipid antibodies were normal and tests for cprotein, s-protein and antithrombin iii deficiencies and the janus kinase 2 mutation were negative. no specific cause for the polycythaemia could be determined. the patient was treated with iv tramadol and subcut aneous lmwh. repeated venesections were performed figure 3: imaging of the brain of a 41-year-old woman with deep cerebral venous thrombosis showing (a) thrombosis of the superior sagittal sinus (sss) as well as the left frontal and parietal cortical veins (arrows) on computed tomography, (b) biconvex hyperintensities in the thalamus-basal ganglionic region (arrow) as well as (c) cortical venous infarcts (arrow) upon magnetic resonance imaging the next day and (d) the absence of flow void in the deep venous system as well as the sss (arrowheads) upon magnetic resonance venography. figure 4: imaging of the brain of a 21-year-old man with thrombosis restricted to the major dural venous sinuses showing (a) empty delta sign in the superior sagittal sinus (sss) with surrounding contrast (arrow) and (b) thrombosis of the transverse sinus (trs) (arrow) on computed tomography, (c) normal parenchyma upon magnetic resonance imaging and (d) thrombosis of the sss and trs upon magnetic resonance venography (arrowhead). spectrum of cerebral venous thrombosis in oman e334 | squ medical journal, august 2018, volume 18, issue 3 to reduce his haematocrit percentage. one week later, the patient reported that his headache had improved remarkably. the papilloedema and sixth cranial nerve palsy improved gradually. he was discharged with a prescription for warfarin. discussion this study explores patterns of cvt presentation, diagn osis and outcomes among patients at a tertiary hospital in oman. despite the small number of cases, the majority of patients resembled previously reported series in most respects, such as onset in young adulthood, a female predominance, the rapid evolution of symptoms over a few days, a relatively low mortality rate and complete improvement among most survivors.1,3,4 as illustrated in the four representative cases described, cvt may present in certain recognisable syndromes which often correlate with patterns of cerebral vein or dural sinus involvement.4–7 such presentations may include raised icp/space-occupying lesion, acute stroke-like presentations, status epilepticus/seizures, diffuse encephalopathy, comas and, rarely, a posterior fossa syndrome. the first case had puerperal cvt, the most common form of cvt in developing countries.4,8 despite its monomorphic clinical profile, no specific cause for puerperal cvt is yet recognised.8 the second and third cases illustrate the rapid evolution of cvt symptoms. the overall risk of relapse in cvt cases is 6.5%, decreasing to 3% for patients with puerperal cvt.9,10 recurrent cvt generally occurs more often among males, such as in the second case.6 in the third case, the patient developed cvt due to oral contraceptive use. this progressed to encephalopathy and altered sensorium and pyramidal signs signifying dien cephalic dysfunction due to deep cvt. other manifestations of deep venous system involvement include ophthalmoparesis, ptosis, decerebrate posturing, coma and movement disorders reflecting the regions drained by the affected veins. the fourth patient had isolated major dural sinus thrombosis without parenchymal changes, with symptoms of headache, papilloedema and sixth cranial nerve palsy; the latter is a classic example of a false localising sign. every patient with cvt should be investigated for an underlying cause or risk factor.11 ovarian hormonal changes related to the puerperium, oral contraceptive use, haematological disorders, prothrombotic states and malignancy constitute common risk factors. in the context of pregnancy or soon after labour, changes in the coagulation cascade may play a role in cvt devel opment; anaemia and dehydration may also be influencing factors, although puerperal cvt has not been associated with any specific procoagulant risk factor.4,8 the presence of certain risk factors may influence the duration of anticoagulation treatment. however, in most cvt series, there is no underlying cause or predisposing condition. ideally, mri plus mrv is the preferred imaging approach to confirm a diagnosis of cvt.9,12,13 however, a cranial ct scan is often the initial investigation perf ormed in emergency cases and can provide several indic ations of the correct diagnosis. changes involving the venous structures as well as parenchymal changes may be seen on ct brain scans. cord sign, dense triangle sign and empty delta sign are well-known direct signs of cvt.9,12,13 cord sign appears as a linear hyperdensity on a non-contrast scan, usually on the cortical surface due to thrombosis of the cortical veins. a thrombus in the ss or vein of galen may be similarly visualised.9,12,13 a dense triangle sign on a non-contrast ct scan is typically seen along the thrombosed sss. on contrastenhanced ct scans, an empty delta sign—wherein the contrast flows around a central and relatively hypodense thrombus—can be observed in the dural venous sinus region in up to 60% of cvt cases.7 indirect signs of cvt on ct occur due to the effects of venous or sinus thrombosis on the brain parenchyma. although common, the specificity of such signs is low; thus, they may not be sufficient for a definitive diagnosis of cvt. multiple non-haemorrhagic infarcts not conforming to an arterial territory or multifocal or confluent areas of haemorrhage are suggestive of cvt. extensive brain oedema, compressed ventricles or bihemispheric hypodensities may be caused by thrombosis of the major sinuses or cortical veins; these features are seen in 25–42% of cvt cases.12 deep cvt gives rise to fairly typical biconvex diencephalic hypodensities with cord sign in the internal cerebral veins or ss.14,15 when used together, mri and magnetic resonance angiography (mra) have a high degree of sensitivity and specificity in the diagnosis of cvt.12 a gyriform pattern of venous infarcts, thrombosed cortical veins or venous sinuses, different temporal stages of haemorrhagic infarcts or haematomas and associated brain oedema may be observed. acute parenchymal haemorrhage as well as thrombi located within the dural sinuses may vary in appearance over time, appearing isointense on t1 and t2 sequences in the first few days (due to the predominance of deoxyhaemoglobin in the clot), then hyperintense between days 5–15 (due to the formation of methaemoglobin), before becoming isointense again.6 mrv has the advantage of depicting most of the cerebral venous system noninvasively. thrombosis most comm only affects the sss (62%) and trs (41%), while the ss (18%), deep venous system (11%) and ijv (12%) are less frequently involved.16 two direct signs of cvt darshan lal, arunodaya r. gujjar, nandagopal ramachandiran, ammar obaidi, sunil kumar, mortada el-tigani, faizal al-azri and abdullah r. al-asmi clinical and basic research | e335 on mra images are the absence of high flow in the dural sinus region which is not hypoor aplastic and a ‘frayed’ flow signal in the sinus region after partial recanalisation. dilated collateral medullary veins and prominent emissary veins crossing the skull may also be observed in later stages.4 conventional angiography, preferably digital subtraction angiography, is useful in patients with equivocal signs on other modes of imaging. the management of cvt has evolved significantly in the last few decades.2 prompt diagnosis and treatment have been shown to drastically reduce mortality and improve outcomes, even in the presence of intracerebral haemorrhage, as in the first case described in the current study.4 anticoagulation treatment, typically with lmwh, is the standard of care, despite limited evidence to support its use.11,13,17,18 weight-based dosing for anti coagulants significantly improves outcomes and reduces mortality, even among patients with haemorrhagic infarcts or haematomas.11,13,17,18 overall, lmwh may be safer than unfractionated heparin, although the latter may be preferable perioperatively.17 patients should be monitored closely for evidence of haemorrhage or heparin-induced thrombocytopaenia. anticerebral oedema measures such as mannitol, hypertonic saline or hyperventilation may be required for the emergent control of raised icp, particularly for patients with extensive infarctions involving the major dural sinuses; however, the benefits of these measures have not yet been systematically evaluated.18,20 anticonvulsants are clearly indicated among patients with seizures; moreover, due to the high incidence of seizures in cvt (35–50%), some researchers recommend prescribing these prophylactically.5,11,19 steroids and acetazolamide are not beneficial in cvt treatment.9 novel approaches such as surgical decompression and intrasinus thrombolysis or thrombectomies have been explored in select cases of cvt.11,18 patients with lateral or focal brain oedema due to infarction/haemorrhage or thrombosed veins causing mass effects and impending herniation should be considered in a timely manner for an emergency decompressive craniectomy. such surgical interventions may require the transient interruption of anticoagulation measures. in a previous series of 56 cvt patients with large infarcts causing significant mass effects, decompressive craniectomies resulted in good outcomes in 54% of cases.20 however, 25% of the patients died. poor outcomes were associated with coma at admission, advanced age, a need for ventilation and severe neurological deficits.20 other studies have reported better mortality and functional recovery rates following surgical intervention.21,22 endovascular interventions such as thrombolysis or a thrombectomy have been utilised in thrombosis mainly involving the major dural venous sinuses causing raised icp and not improving following an initial anti coagulation trial.20–26 an endovascular catheter is placed inside the clot to deliver an infusion of actilyse for thrombolysis or a mechanical clot-retrieving instrument may be used for mechanical throbectomy.25 a multicentre randomised clinical trial was initiated in 2013 to compare the effectiveness of endovascular thrombectomy in comparison with anticoagulant therapy; unfortunately, it was prematurely terminated in 2016.25 a retrospective study found that the intrasinus infusion of a thrombolytic agent with mechanical thrombectomy in 29 patients with dural sinus thrombosis resulted in similar 90-day outcomes to those of 37 patients treated with anticoagulants alone.26 long-term anticoagulation treatment, usually involving warfarin titrated to an inr of 2–3, is recommended to prevent recurrent venous thrombosis as well as other complications such as a pulmonary embolism.9,13 however, due to a lack of randomised trials, recommendations for long-term anticoagulation are mostly based on expert consensus. in puerperal or oral contraceptive-associated cvt, anticoagulants are recommended for 12 weeks after an initial course of heparin; thereafter, subcutaneous lmwh is recomm ended during subsequent pregnancies to prevent recurrence.27 patients with cvt provoked by specific triggers (e.g. infections, medication or catheter placement) or those with no risk factors for possible recurrence should be treated with anticoagulants for 6–12 months. in contrast, oral anticoagulants are continued indefinitely among patients with recurrent cvt or those with severe prothrombotic states such as antiphospholipid syndrome or genetic thrombophilias. while newer oral anticoagulants have been studied, there is currently insufficient evidence to recommend their use.28 in recent decades, the overall prognosis for patients with cvt has improved, likely due to early anticoagulation measures and improvements in the quality of critical care.2,4,29 although cvt is three times more common among women, the prognosis is worse for men.3 additionally, cvt cases related to pregnancy/puerperium or hormonal changes have a much better prognosis than those associated with thrombophilia or internal malignancy.8,27 furthermore, those who improve after acute cvt episodes often recover with very few neurological deficits in contrast to arterial stroke cases. however, death or a state of dependency occurs in about 15% of cvt cases.21 of all cvt syndromes, dvt has the highest mortality rate.5,6,15 conclusion although an uncommon condition, the prompt diagnosis and treatment of cvt can prevent serious and spectrum of cerebral venous thrombosis in oman e336 | squ medical journal, august 2018, volume 18, issue 3 potentially fatal outcomes. this study illustrates the varied manifestations of cvt at a tertiary hospital in oman and highlights the usefulness of prompt imaging to ensure a timely diagnosis. effective anticoagulation measures ensured good outcomes among the survivors, despite severe neurological deficits at presentation. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a d d e n d u m for a complete table detailing the age, gender, aetiology, symptom duration, clinical features, imaging findings, treatment and outcome of each patient included in this study, please contact the corresponding author. references 1. bousser mg, ferro jm. cerebral venous thrombosis: an update. lancet neurol 2007; 6:162–70. doi: 10.1016/s1474-4422(07)7 0029-7. 2. coutinho jm, zuurbier sm, stam j. declining mortality in cerebral venous thrombosis: a systematic review. stroke 2014; 45:1338–41. doi: 10.1161/strokeaha.113.004666. 3. zuurbier sm, middeldorp s, stam j, coutinho jm. sex differ ences in cerebral venous thrombosis: a systematic analysis of a shift over time. int j stroke 2016; 11:164–70. doi: 10.1177/174 7493015620708. 4. narayan d, kaul s, ravishankar k, suryaprabha t, bandaru vc, mridula kr, et al. risk factors, clinical profile, and long-term outcome of 428 patients of cerebral sinus venous thrombosis: insights from nizam’s institute venous stroke registry, hyderabad (india). neurol india 2012; 60:154–9. doi: 10.4103/00283886.96388. 5. ferro jm, canhão p. cerebral venous sinus thrombosis: update on diagnosis and management. curr cardiol rep 2014; 16:523. doi: 10.1007/s11886-014-0523-2. 6. bushnell c, saposnik g. evaluation and management of cerebral venous thrombosis. continuum (minneap minn) 2014; 20:335–51. doi: 10.1212/01.con.0000446105.67173.a8. 7. coutinho jm, gerritsma jj, zuurbier sm, stam j. isolated cortical vein thrombosis: systematic review of case reports and case series. stroke 2014; 45:1836–8. doi: 10.1161/strokeaha. 113.004414. 8. nagaraja d, taly ab, das s. puerperal cerebral venous thrombosis in india. in: sinha kk, chandra p, eds. progress in clinical neurosciences. ranchi, india: catholic press, 1989. pp. 165–77. 9. saposnik g, barinagarrementeria f, brown rd jr, bushnell cd, cucchiara b, cushman m, et al. diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the american heart association/american stroke association. stroke 2011; 42:1158–92. doi: 10.1161/str. 0b013e31820a8364. 10. palazzo p, agius p, ingrand p, ciron j, lamy m, berthomet a, et al. venous thrombotic recurrence after cerebral venous thrombosis: a long-term follow-up study. stroke 2017; 48:321–6. doi: 10.1161/strokeaha.116.015294. 11. einhäupl k, bousser mg, de bruijn sf, ferro jm, martinelli i, masuhr f, et al. efns guideline on the treatment of cerebral venous and sinus thrombosis. eur j neurol 2006; 13:553–9. doi: 10.1111/j.1468-1331.2006.01398.x. 12. leach jl, fortuna rb, jones bv, gaskill-shipley mf. imaging of cerebral venous thrombosis: current techniques, spectrum of findings, and diagnostic pitfalls. radiographics 2006; 26:s19–41. doi: 10.1148/rg.26si055174. 13. ferro jm, bousser mg, canhão p, coutinho jm, crassard i, dentali f, et al. european stroke organization guideline for the diagnosis and treatment of cerebral venous thrombosis: endorsed by the european academy of neurology. eur j neurol 2017; 24:1203–13. doi: 10.1111/ene.13381. 14. arunodaya gr, nagaraja d, srikanth sg, yasha tc, vani s, jayakumar pn, et al. deep cerebral venous thrombosis: clinical, ct and autopsy study of 58 cases. in: american academy of neurology. 52nd annual meeting abstracts: san diego, california, usa april 29-may 6, 2000. neurology 2000; 54:a1–557. 15. crawford sc, digre kb, palmer ca, bell da, osborn ag. thrombosis of the deep venous drainage of the brain in adults: analysis of seven cases with review of the literature. arch neurol 1995; 52:1101–8. doi: 10.1001/archneur.1995.00540350095021. 16. ferro jm, canhão p, stam j, bousser mg, barinagarrementeria f. prognosis of cerebral vein and dural sinus thrombosis: results of the international study on cerebral vein and dural sinus thrombosis (iscvt). stroke 2004; 35:664–70. doi: 10.1161/01. str.0000117571.76197.26. 17. pillai lv, ambike dp, nirhale s, husainy sm, pataskar s. cerebral venous thrombosis: an experience with anticoagulation with low molecular weight heparin. indian j crit care med 2005; 9:14–18. doi: 10.4103/0972-5229.16263. 18. ferro jm, canhão p. acute treatment of cerebral venous and dural sinus thrombosis. curr treat options neurol 2008; 10:126–37. doi: 10.1007/s11940-008-0014-0. 19. kalita j, chandra s, misra uk. significance of seizure in cerebral venous sinus thrombosis. seizure 2012; 21:639–42. doi: 10.1016/j. seizure.2012.07.005. 20. gujjar ar, srikanth s, mohanty a, satish s, srikanth sg, nagaraja d. efficacy of decompressive craniectomy for cerebral venous thrombosis with massive infarction: a case series. in: abstracts of the 5th world stroke conference. stroke 2018; 35:e225–41. 21. ferro jm, crassard i, coutinho jm, canhão p, barinagarrementeria f, cucchiara b, et al. decompressive surgery in cerebrovenous thrombosis: a multicenter registry and a systematic review of individual patient data. stroke 2011; 42:2825–31. doi: 10.1161/strokeaha.111.615393. 22. aaron s, alexander m, moorthy rk, mani s, mathew v, patil ak, et al. decompressive craniectomy in cerebral venous thrombosis: a single centre experience. j neurol neurosurg psychiatry 2013; 84:995–1000. doi: 10.1136/jnnp-2012-303356. 23. siddiqui fm, dandapat s, banerjee c, zuurbier sm, johnson m, stam j, et al. mechanical thrombectomy in cerebral venous thrombosis: systematic review of 185 cases. stroke 2015; 46:1263–8. doi: 10.1161/strokeaha.114.007465. 24. mokin m, lopes dk, binning mj, veznedaroglu e, liebman km, arthur as, et al. endovascular treatment of cerebral venous thrombosis: contemporary multicenter experience. interv neu roradiol 2015; 21:520–6. doi: 10.1177/1591019915583015. 25. coutinho jm, ferro jm, zuurbier sm, mink ms, canhão p, crassard i, et al. thrombolysis or anticoagulation for cerebral venous thrombosis: rationale and design of the to-act trial. int j stroke 2013; 8:135–40. doi: 10.1111/j.1747-4949.2011. 00753.x. https://doi.org/10.1016/s1474-4422%2807%2970029-7 https://doi.org/10.1016/s1474-4422%2807%2970029-7 https://doi.org/10.1161/strokeaha.113.004666 https://doi.org/10.1177/1747493015620708 https://doi.org/10.1177/1747493015620708 https://doi.org/10.4103/0028-3886.96388 https://doi.org/10.4103/0028-3886.96388 https://doi.org/10.1007/s11886-014-0523-2 https://doi.org/10.1212/01.con.0000446105.67173.a8 https://doi.org/10.1161/strokeaha.113.004414 https://doi.org/10.1161/strokeaha.113.004414 https://doi.org/10.1161/str.0b013e31820a8364 https://doi.org/10.1161/str.0b013e31820a8364 https://doi.org/10.1161/strokeaha.116.015294 https://doi.org/10.1111/j.1468-1331.2006.01398.x https://doi.org/10.1148/rg.26si055174 https://doi.org/10.1111/ene.13381 https://doi.org/10.1001/archneur.1995.00540350095021 https://doi.org/10.1161/01.str.0000117571.76197.26 https://doi.org/10.1161/01.str.0000117571.76197.26 https://doi.org/10.4103/0972-5229.16263 https://doi.org/10.1007/s11940-008-0014-0 https://doi.org/10.1016/j.seizure.2012.07.005 https://doi.org/10.1016/j.seizure.2012.07.005 https://doi.org/10.1161/strokeaha.111.615393 https://doi.org/10.1136/jnnp-2012-303356 https://doi.org/10.1161/strokeaha.114.007465 https://doi.org/10.1177/1591019915583015 https://doi.org/10.1111/j.1747-4949.2011.00753.x https://doi.org/10.1111/j.1747-4949.2011.00753.x darshan lal, arunodaya r. gujjar, nandagopal ramachandiran, ammar obaidi, sunil kumar, mortada el-tigani, faizal al-azri and abdullah r. al-asmi clinical and basic research | e337 26. nyberg em, case d, nagae lm, honce jm, reyenga w, seinfeld j, et al. the addition of endovascular intervention for dural venous sinus thrombosis: single-center experience and review of literature. j stroke cerebrovasc dis 2017; 26:2240–7. doi: 10.1016/j.jstrokecerebrovasdis.2017.05.006. 27. aguiar de sousa d, canhão p, crassard i, coutinho j, arauz a, conforto a, et al. safety of pregnancy after cerebral venous thrombosis: results of the iscvt (international study on cerebral vein and dural sinus thrombosis)-2 pregnancy study. stroke 2017; 48:3130–3. doi: 10.1161/strokeaha.117.018829. 28. mendonça md, barbosa r, cruz-e-silva v, calado s, vianabaptista m. oral direct thrombin inhibitor as an alternative in the management of cerebral venous thrombosis: a series of 15 patients. int j stroke 2015; 10:1115–18. doi: 10.1111/ijs.12462. 29. hiltunen s, putaala j, haapaniemi e, tatlisumak t. long-term outcome after cerebral venous thrombosis: analysis of functional and vocational outcome, residual symptoms, and adverse events in 161 patients. j neurol 2016; 263:477–84. doi: 10.1007/ s00415-015-7996-9. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.05.006 https://doi.org/10.1161/strokeaha.117.018829 https://doi.org/10.1111/ijs.12462 https://doi.org/10.1007/s00415-015-7996-9 https://doi.org/10.1007/s00415-015-7996-9 2department of pharmaceuticals, 1faculty of pharmacy, university of indonesia, depok, west java, indonesia *corresponding author’s e-mails: vina.anasthasia@ui.ac.id and vinanasthasia@gmail.com تقومي فعالية تدخل الصيدالين السريري حلل املشاكل السريرية والدوائية عند املرضى الداخليني املصابني مبرض القلب التاجي دراسة استباقية قبل-جتريبية يف مستشفى عام بإندونيسيا فينا اأنا�ستازيا �ساجتا، اأنتون بهتيار، ريتنو�ساري اندراجاتي abstract: objectives: this study aimed to evaluate the role of a clinical pharmacist intervention in decreasing subsequent clinical and drug-related problems (drps) among coronary heart disease (chd) inpatients with at least one previous drp. methods: this pre-experimental study with a pre-post design was carried out from january to april 2017 among inpatients with at least one previous drp at a general hospital in tangerang district, banten, indonesia. clinical and drps were documented prospectively by a clinical pharmacist, with drps classified using version 6.2 of the drp classification scheme of the pharmaceutical care network europe foundation. the intervention consisted of a discussion of identified drps with physicians, patients, pharmaceutical logistics clerks, nurses and nutritionists. following this, any subsequent clinical and drps were re-identified and further interventions were conducted as necessary. results: a total of 75 inpatients were included in the study. pre-intervention, there were 443 drps and 202 clinical problems. the most frequent drps were adverse drug reactions (52.6%), followed by drug effects (41.8%). most drps were of moderate severity and would have resulted in moderate consequences had the pharmacist not intervened. the interventions resulted in a significant reduction in the number of drps, type of drps and number of clinical problems (p <0.05 each). patients with complications were 26.047 times more likely to have no reduction or an increased number of clinical problems compared to patients without complications (p <0.05). conclusion: clinical pharmacist interventions were found to reduce subsequent drps and clinical problems among chd patients with at least one previous drp. keywords: coronary heart disease; drug interactions; adverse drug reactions; pharmacists; indonesia. امللخ�ص: الهدف: تهدف هذه الدرا�سة لتقومي دور ال�سيدالين ال�رصيري يف التدخل لتقليل امل�ساكل ال�رصيرية والدوائية الالحقة عند املر�سى الداخليني امل�سابني مبر�ض القلب التاجي الذين تعر�سوا من قبل لنوبة واحدة من ذلك املر�ض، على االأقل. الطريقة: اأجريت هذه الدرا�سة اال�ستباقية قبل-التجريبية يف الفرتة من يناير اإىل اأبريل من عام 2017م على مر�سى اأ�سيبوا من قبل بنوبة واحدة على االأقل بهذا املر�ض، وذلك يف م�ست�سفى عام يف منطقة تاجنارانق ببانتنج يف اإندوني�سيا. وقد �سجلت و�سنفت كل م�ساكل املر�سى ال�رصيرية والدوائية بوا�سطة �سيدالين �رصيري با�ستخدام الن�سخة رقم 6.2 من نظام ت�سنيف امل�ساكل الدوائية الذي اأ�سدرته �سبكة الرعاية ال�سيدالنية االأوروبية. و�سمل التدخل مناق�سة للم�ساكل املتعرف عليها مع االأطباء واملر�سى وكتبة اخلدمات اللوج�ستية ال�سيدالنية واملمر�سات واخت�سا�سي التغذية. وعقب ذلك مت التعرف على اأي م�ساكل �رصيرية اأو دوائية الحقة، ومت التدخل فيها عند ال�رصورة. النتائج: �سمت هذه الدرا�سة 75 مري�سا. )52.6%( اجلانبية االآثار هي حدوثا الدوائية امل�ساكل اأكرث وكانت �رصيرية. م�سكلة 202 و دوائية م�سكلة 443 التدخل قبل هنالك وكان وتلتها اآثار الدواء )%41.8(. وكانت معظم امل�ساكل الدوائية متو�سطة ال�سدة، وكان من املمكن اأن حتدث نتائج ذات اآثار متو�سطة ال�سدة لوال تدخل ال�سيديل ال�رصيري، اإذ اأف�سى ذلك التدخل خلف�ض معنوي يف اأعداد واأنواع امل�ساكل ال�رصيرية والدوائية عند املر�سى )p >0.05، يف احلالتني(. وكان احتمال زيادة امل�ساكل ال�رصيرية اأو عدم نق�سان عددها اأكرب مبقدار 26.047 مرة اأ عند املر�سي الذين تعر�سوا مل�ساعفات من الذين مل يتعر�سوا مل�ساعفات )p >0.05(. اخلال�صة: وجدنا اأن تدخل ال�سيديل ال�رصيري يقلل من امل�ساكل ال�رصيرية والدوائية الالحقة عند املر�سى الداخليني امل�سابني مبر�ض القلب التاجي الذين تعر�سوا من قبل لنوبة واحدة من املر�ض على االأقل. الكلمات املفتاحية: مر�ض القلب التاجي؛ تفاعل االأدوية؛ االآثار ال�سارة لالأدوية؛ ال�سيادلة؛ اأند ون�سيا. evaluation of a clinical pharmacist intervention on clinical and drug-related problems among coronary heart disease inpatients a pre-experimental prospective study at a general hospital in indonesia *vina a. sagita,1 anton bahtiar,2 retnosari andrajati2 clinical & basic research sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e81–87, epub. 4 apr 18 submitted 5 jul 17 revisions req. 12 aug & 4 oct 17; revisions recd. 7 sep & 17 oct 17 accepted 26 oct 17 advances in knowledge a clinical pharmacist intervention was found to significantly reduce clinical and drug-related problems (drps) among coronary heart disease (chd) inpatients with at least one previous drp at a general hospital in indonesia. the most frequent type of potential drps observed in the study were adverse drug reactions. most drps were of moderate severity and, without intervention, were forecast to result in moderate consequences with regards to the health of the patients. doi: 10.18295/squmj.2018.18.01.013 evaluation of a clinical pharmacist intervention on clinical and drug-related problems among coronary heart disease inpatients a pre-experimental prospective study at a general hospital in indonesia e82 | squ medical journal, february 2018, volume 18, issue 1 nearly one-third of all deaths worldwide are due to cardiovascular diseases (cvds), with coronary heart disease (chd) the leading cause of cvd-related deaths.1,2 in 2015, the world health organization estimated that approximately 17.7 million people died globally as a result of chd.3 in europe, cvd was responsible for four million deaths in 2015, with chd the cause of 19% and 20% of deaths among men and women, respectively.4 a total of 15.5 million people in the usa were found to be living with chd in 2016.5 in indonesia, the overall prevalence of chd in 2013 for individuals aged 15 years and over was 0.5% based on an official diagnosis and 1.5% based on a diagnosis or related symptoms; this increased to 1.7% and 3.2%, respectively, in those over 75 years old.6 for those in the 15–24-year-old age group, the prevalence was 0.1% based on a diagnosis and 0.7% based on a diagnosis or symptoms.6 in chd, the coronary arteries that supply oxygen to the heart become narrower due to a build-up of plaque. the disease may clinically manifest as stable angina (i.e. chest pain) or acute coronary syndrome (acs).7 the goal of chd treatment is to control these symptoms and prevent progression of the disease by reducing relevant risk factors such as hypertension and dyslipidaemia.8 it is common for patients to take five or more drugs simultaneously as part of lifelong therapy. unfortunately, polypharmacy increases the risk of a drug-related problem (drp), defined as an event or circumstance involving drug therapy that can interfere with a desired health outcome.9 the occurrence of drps can reduce the benefits of drugs and cause increased morbidity and mortality.10 according to the classification scheme of the pharmaceutical care network europe foundation (pcnef), four types of drps exist, including drug effects, adverse drug reactions (adrs), treatment cost-related problems and other problems.11 cases involving inappropriate drug dosages, regimens or drug interactions and poor adherence to a drug regimen may result in drug treat ments having non-optimal effects or no effect. other drps include non-allergic adrs, unnecessary drug treatment and patient dissatisfaction with therapy.12 the detection and prevention of drps can enhance the quality of life of patients and optimise healthcare costs.10 in 2004, a study from norway found that 81% of hospitalised patients had drps.13 other research has indicated that between 69–78% of cvd patients have drps.14,15 in 2011, a study reported that cardiovascular drugs were one of the major causes of all drps.16 identified risk factors for adrs include age, gender, polypharmacy, drug administration with a narrow therapeutic index, decreased renal elimination and the use of oral anti-coagulants and diuretics.17 pharmacists can help to identify and resolve drps through appropriate interventions.10 examples of phar macist interventions include advising patients of drug information and instructions for use or changing the drug prescription, dosage, formulation or regimen. in addition, if needed, pharmacists can also provide medi cation counselling and education for patients regarding adr presentations and drug interactions.12 research has shown that involving pharmacists in multidisciplinary teams decreases morbidity and mortality.18 a study performed in indonesia evaluated the role of pharmacist interventions in decreasing drps among cvd and stroke inpatients.19 this study aimed to eval uate the number and type of drps and clinical problems following a clinical pharmacist intervention among chd inpatients with at least one previous drp at a general hospital in tangerang district, banten, indonesia. it was hypothesised that the intervention would result in a reduction in drps and an improvement in the inpatients’ clinical condition. methods this pre-experimental prospective study with a prepost design was carried out from january to april 2017 at a general hospital in tangerang district. only inpatients aged ≥35-years-old with national health insurance, who had been diagnosed with chd, were receiving chd medications and had experienced at least one drp previously were included in the study. patients with infectious diseases and pregnant or lactating women were excluded, as well as patients with incomplete medical records or those who were unwilling to participate or lost to follow-up during the study period. out of 111 inpatients, 21 patients were unwilling to participate, three did not have a drp and 12 patients were diagnosed with infections, resulting in a total sample of 75 inpatients. the drug therapy details, laboratory parameters and demographic details of all inpatients were prospectively reviewed by a clinical pharmacist. during ward rounds, drug and dose selection, drug regimens and patients’ drug use patterns were evaluated in application to patient care the findings of this study may be used by physicians, pharmacists and other healthcare workers in order to reduce drps and clinical problems among chd inpatients. vina a. sagita, anton bahtiar and retnosari andrajati clinical and basic research | e83 order to identify drps as per version 6.2 of the pcnef classification scheme.11 interventions consisted of reporting and discussing identified drps during interviews with various recipients, including physicians, patients, pharmaceutical logistics clerks, nurses and nutritionists. the type of intervention was classified as either independent (i.e. specifically tailored to an individual recipient) or concurrent (i.e. provided to several or all recipients at the same time). it is important to note that each drp could be targeted with more than one intervention. after the interventions, the pharmacist continued monitoring the patient until discharge, conducting further interventions as necessary for any subsequent drps. the overall number of clinical problems and the overall number and subtypes of drps before and after the intervention were calculated for every patient. a specific subtype of drp could occur as a result of different drugs. the severity of identified drps was classified as major, moderate or minor.20 major drps were defined as those requiring intervention to prevent major or irreversible detrimental effects or due to lack of appropriate therapy in circumstances where evidence-based options were available. moderate drps included drps whereby interventions would result in moderate benefit for the patient, while minor drps were defined as those requiring only minor adjustments, such as modifications to dosage timings.20 harmful, unpleasant and unintended responses to drugs at normal doses were considered to constitute adrs.17 the probable consequences of a lack of intervention were categorised as insignificant, minor, moderate, major or catastrophic.20 for example, insignificant con sequences referred to circumstances where no harm or injury to the patient and a low financial loss would result as a lack of intervention. minor consequences included minor injuries, minor treatment, no prolonged length of stay (los) or re-admission to the hospital and the potential for minor financial loss, while moderate consequences included major temporary injuries, prolonged los or re-admission to the hospital, a cancellation or delay in planned treatments/ procedures and the potential for financial loss. major consequences included major permanent injuries, prolonged los or re-admission to the hospital, morbidity upon discharge and the potential for significant financial loss. finally, catastrophic consequences of a lack of intervention included the death of the patient, the potential for large financial losses and/or threat to the patient’s goodwill or reputation.20 data were analysed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). a wilcoxon signed rank test was used to assess the differences between preand post-intervention drps and clinical problems. a chi-squared test was used to assess the relationship between drps and risk factors such as age, gender, clinical manifestations, los, comorbidities, complications from other cvds and the number of drugs administered. logistic regression was used for the multi variate analysis of risk factors (advance test). a p value of <0.05 was considered statistically significant. ethical approval for this study was obtained from the ethics committee of the faculty of medicine at the university of indonesia (#956/un2.f1/etik/2016). informed consent was provided by all patients and/or table 1: demographic and clinical characteristics of coronary heart disease inpatients in indonesia (n = 75) characteristic n (%) age in years 35–59 48 (64) ≥60 27 (36) gender male 53 (70.7) female 22 (29.3) clinical manifestation non-acs symptoms 50 (66.7) acs 25 (33.3) number of comorbidities 1–2 50 (66.7) >2 25 (33.3) presence of complications yes 15 (20) no 60 (80) los in days 1–5 69 (92) >5 6 (8) number of drugs prescribed 1–5 19 (25.3) >5 56 (74.7) acs = acute coronary syndrome; los = length of stay. table 2: acceptance of a clinical pharmacist intervention for clinical and drug-related problems among coronary heart disease inpatients in indonesia (n = 459) acceptance of intervention n (%) no intervention 2 (0.4) not accepted 14 (3.1) accepted 443 (96.5) evaluation of a clinical pharmacist intervention on clinical and drug-related problems among coronary heart disease inpatients a pre-experimental prospective study at a general hospital in indonesia e84 | squ medical journal, february 2018, volume 18, issue 1 their relatives. data confidentiality and security were ensured throughout the study period. results the mean age of the patients was 56.4 ± 8.4 years, with the majority being 35–59 years old (64%). most of the patients were male (70.7%). the most frequent clinical manifestations of chd among the patients were nonacs symptoms (66.7%) [table 1]. the median los was two days (interquartile range [iqr]: 2–4 days), with 92% staying 1–5 days. the median number of comorbidities was two (iqr: 1–3). hypertension (96%), cholesterol (38.7%) and type 2 diabetes mellitus (30.7%) were the most common comorbidities. the majority of the patients had no complications (80%). overall, a total of 561 different kinds of drugs were prescribed, falling into 44 drug classes. the most common class was antihypertensives (33.6%), followed by antiplatelets (21.6%) and anticholesterol medications (12.8%). patients received a median of seven different types of drugs (iqr: 5–9 types). the pharmacist interventions were not fully accepted (96.5%) [table 2]. initially, a total of 443 drps and 202 clinical problems were identified and received interventions. patients had a median of five drps (iqr: 4–8 drps). there were 199 different subtypes of drps, with patients experiencing a median of three subtypes (iqr: 2–3 subtypes) [table 3]. nonoptimal drug effects (37.5%), non-allergic adrs (39.1%) and unnecessary drug treatments (1.8%) were the dominant subtypes of drps [table 4]. post-percutaneous coronary intervention hand pain (27.2%), chest pain (21.8%) and shortness of breath (11.4%) were the dominant pre-intervention clinical problems [table 5]. pre-intervention drps varied in terms of severity, with 35 minor (7.9%), 336 moderate (75.8%) and 72 major (16.3%) drps. interventions were performed for 138 actual (31.2%) and 305 potential (68.8%) drps. of the actual drps, 107 (77.5%) were attributable to drug effects, 22 (15.9%) were attributable to adrs and nine (6.5%) were due to treatment cost-related problems. for the potential drps, 77 (25.2%) and 228 (74.8%) were due to drug effects and adrs, respectively [table 6]. the most predominant type of intervention for drps was concurrent (n = 310; 70%). the consequences of a lack of intervention for drps were projected to be insignificant in two cases (0.5%), minor in 33 cases (7.4%), moderate in 336 cases (75.8%), major in 71 cases (16%) and catastrophic in one case (0.2%). following the intervention, there were 53 drps, 37 subtypes of drps and 26 clinical problems [table 3]. table 3: drug-related and clinical problems before and after a clinical pharmacist intervention among coronary heart disease inpatients in indonesia (n = 75) pre-intervention post-intervention p value* n mean ± sd median (iqr) n mean ± sd median (iqr) clinical problems 202 2.69 ± 0.97 2 (2–4) 26 0.35 ± 0.73 0 (0) <0.01 number of drps 443 5.91 ± 3.22 5 (4–8) 53 0.71 ± 1.30 0 (0–1) <0.01 types of drps 199 2.65 ± 0.78 3 (2–3) 37 0.49 ± 0.66 0 (0–1) <0.01 sd = standard deviation; iqr = interquartile range; drp = drug-related problem. *using a wilcoxon signed-rank test. table 4: number and subtype of drug-related problems before and after a clinical pharmacist intervention among coronary heart disease inpatients in indonesia (n = 443) drp n (%) pre-intervention (n = 443) post-intervention* (n = 53) drug effects 184 (41.5) 28 (6.3) none 0 (0) 0 (0) nonoptimal 166 (37.5) 22 (4.5) wrong effect 0 (0) 0 (0) indication untreated 18 (4.1) 8 (1.8) adrs 250 (55.8) 25 (5.6) non-allergic 173 (39.1) 22 (5) allergic 0 (0) 0 (0) toxic 77 (17.4) 3 (0.7) treatment costrelated 9 (2) 0 (0) more costly than necessary 1 (0.2) 0 (0) unnecessary treatment 8 (1.8) 0 (0) other 0 (0) 0 (0) patient dissatisfaction† 0 (0) 0 (0) unclear‡ 0 (0) 0 (0) drp = drug-related problem; adr = adverse drug reaction. *post-intervention percentages are calculated out of the total number of pre-intervention drps. there was an 88% reduction in the overall number of drps following the intervention. †despite optimal clinical and economic treatment outcomes. ‡more clarification necessary. vina a. sagita, anton bahtiar and retnosari andrajati clinical and basic research | e85 overall, the number and subtypes of drps significantly decreased by 88% and 81.4%, respectively, while clinical problems significantly decreased by 87.1% (p <0.01 each). clinical manifestations of chd were associated with a reduction in clinical problems, although this difference was not statistically significant (p = 0.21). in addition, the effect of age and comorbidity on the number of drps was also not significant (p = 0.18 and 0.16, respectively). while clinical problems were significantly affected by age (p = 0.02), the effect of comorbidities was not significant (p = 0.21). conversely, there was a significant reduction in the number of drps, subtypes of drps and clinical problems among patients with complications (p = 0.04 each). in the advance test, patients with complications were 26.047 times more likely to have an increase or no reduction in the number of clinical problems compared to patients without complications (p <0.05). discussion advanced age is a major risk factor of myocardial infarction, a cause of acs-related chd.21,22 according to previous research, the majority of chd patients in indonesia are elderly (>75 years old).6 however, most of the patients in the current study were middleaged; this is likely due to the high proportion of non acs-related chd cases. according to the american heart association, nearly half of all males and onethird of all females between 40–60 years old in the usa will develop some manifestation of chd.5 this finding is in agreement with the results of the current study. moreover, the majority of the patients in the current study did not have complications; once again, this may be because most were not elderly and therefore still had well-functioning organs. the los varied from 1–5 days for the majority of patients. this is in accordance with the unpublished clinical protocols of the studied hospital, which recommends a treatment plan of five days. in the current study, patients received a median of seven drugs. a previous study reported a range of 6–16 cardiovascular drugs prescribed to patients in india.10 antihypertensives, antiplatelets and anticholesterol medications are the primary treatments for chd.23 accordingly, these drugs were the most frequently prescribed classes of drugs in the present study. however, while the majority of patients in the current study did not have acs-related symptoms or complications, it was noted upon review that more acs drugs were prescribed than non-acs drugs.23 in terms of severity, most of the drps in the present study were moderate; similarly, shareef et al. noted that 58.5% of drps among chd patients in a hospital in table 5: number of clinical problems before and after a clinical pharmacist intervention among coronary heart disease inpatients in indonesia (n = 202) clinical problem n (%) preintervention (n = 202) postintervention* (n = 26) chest and hand pain 6 (3) 0 (0) chest pain and a burning sensation 3 (1.5) 0 (0) chest pain and a sensation of heaviness 4 (2) 0 (0) chest, back and shoulder pain 21 (10.4) 0 (0) chest pain 44 (21.8) 1 (0.5) palpitations 4 (2) 1 (0.5) epigastric pain 5 (2.5) 0 (0) nausea 10 (5) 1 (0.5) vomiting 2 (1) 0 (0) cold sweat 7 (3.5) 0 (0) coughing 4 (2) 3 (1.5) shortness of breath 23 (11.4) 6 (3) headache/vertigo 4 (2) 1 (0.5) post-pci/ca hand pain 55 (27.2) 1 (0.5) swallowing pain 1 (0.5) 0 (0) joint pain 2 (1) diarrhoea 1 (0.5) constipation 1 (0.5) 0 (0) melaena 1 (0.5) 0 (0) easily fatigued 4 (2) 5 (2.5) haematuria 1 (0.5) 0 (0) back and shoulder pain 2 (1) restless sleep 1 (0.5) 1 (0.5) oedema 2 (1) pci = percutaneous coronary intervention; ca = coronary angiography. *post-intervention percentages are calculated out of the total number of preintervention clinical problems. there was an 87.1% reduction in the overall number of drps following the intervention. table 6: pre-intervention drug-related problems among coronary heart disease inpatients in indonesia (n = 443) drps n (%) drug effects adrs treatment cost-related problems total actual 107 (77.5) 22 (15.9) 9 (6.5) 138 (31.2) potential 77 (25.2) 228 (74.8) 0 (0) 305 (68.8) total 184 (41.8) 250 (56.2) 9 (2) 443 (100) drp= drug-related problem; adr = adverse drug reaction. evaluation of a clinical pharmacist intervention on clinical and drug-related problems among coronary heart disease inpatients a pre-experimental prospective study at a general hospital in indonesia e86 | squ medical journal, february 2018, volume 18, issue 1 india were moderately severe.24 the most common type of drps in the present study were potential adrs. these likely occurred because the recommended drug therapies for chd patients are antianginal, fibrinolytic and anticoagulant medications, which can have many drug interactions and therefore result in a higher risk of adrs.23,25 in contrast, drug effects caused the greatest number of actual drps; such problems may be due to the inappropriate timing and/or dosing intervals of drugs or failure on the part of the patient to take the drugs as prescribed. most interventions for drps in the present study were given concurrently to multiple recipients in order to increase awareness of potential drug interactions. in order to properly manage potential drps caused by drug interactions, separate and specifically timed doses of different drugs are recommended.23,25 although clinicians in the current study seemed aware of these recommendations, the task of administering medications fell primarily to nurses who may not have been as equally well-informed. in addition, there was often not enough time to re-check correct drug dosages and certain dietary instructions regarding potential fooddrug interactions were not properly communicated to nutritionists. such logistical shortcomings should be addressed. the consequences of a lack of pharmacist intervention for most drps in the present study were deemed to be moderate as it was assumed that no in tervention would have risked the health of the inpatients. gattis et al. found that the inclusion of a pharmacist on multidisciplinary teams significantly reduced mortality and heart failure events among patients with cvds.18 the results of the current study similarly underline the importance of pharmacists, in that the intervention significantly decreased the number and type of drps and the number of clinical problems among chd inpatients. this was in line with a comparable study of cvd patients in india, which demonstrated that a clinical pharmacist inter vention positively influenced cardiovascular healthcare management by preventing and resolving drps.24 another study in indonesia also observed that a pharmacist intervention significantly decreased drps among stroke and cvd patients in an intensive care unit.19 in the current study, only age significantly affected the number of clinical problems post-intervention, while complications affected the number and subtypes of drp and number of clinical problems. since the type of chd can influence the drug treatment required, it may also have affected the number of drps.23 age-related physiological changes can also affect the pharmacokinetic and pharmacodynamic properties of medication.26 in the current study, the presence of complications was found to significantly increase the chance of an increase or no reduction in clinical problems by 26.047 compared to patients without complications. cardiovascular complications causing heart remodelling or aortic stenosis could result in a deterioration of the patient’s clinical condition.25 this study was subject to certain limitations. the identification and evaluation of drps and the content of the interventions were based solely on information from the available literature and the authors’ experience as pharmacists. in addition, the study took place under conditions in which many of the clinicians involved did not fully support the research. furthermore, no control group was included to compare drp prevalence between cases with and those without pharmacist intervention. as a result, it was difficult to ascertain whether the intervention was the sole cause of the observed reduction in drps and clinical problems. additionally, treatment costrelated drps could not be accurately evaluated in the study, as all treatments were covered by the patients’ national health insurance. conclusion this prospective study found that drps and clinical problems among chd inpatients with at least one previous drp were significantly reduced following a clinical pharmacist intervention. in most cases, drps were moderately severe; furthermore, the consequences of not intervening in the majority of drps was projected to be moderate, potentially risking the health of the inpatients. these findings indicate that a pharmacist intervention can optimise therapy and improve the clinical conditions of chd inpatients. a c k n o w l e d g e m e n t s the authors wish to acknowledge the aid of the director and the head of pharmaceutical installation for granting permission for the study to be performed at the hospital. in addition, the authors would like to thank all of the cardiologists who cooperated in this study, especially siti e. nauli, cardiologist supervisor, and yulian rahmadini and dewi fatmawati, pharmacist supervisors. all other parties who assisted with this study are also acknowledged. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. vina a. sagita, anton bahtiar and retnosari andrajati clinical and basic research | e87 references 1. gaziano ta, bitton a, anand s, abrahams-gessel s, murphy a. growing epidemic of coronary heart disease in lowand middle-income countries. curr probl cardiol 2010; 35:72–115. doi: 10.1016/j.cpcardiol.2009.10.002. 2. wong nd. epidemiological studies of chd and the evolution of preventive cardiology. nat rev cardiol 2014; 11:276–89. doi: 10.1038/nrcardio.2014.26. 3. world health organization. cardiovascular diseases (cvds): fact sheet. from: www.who.int/mediacentre/factsheets/fs317/ en/ accessed: oct 2017. 4. townsend n, nichols m, scarborough p, rayner m. cardiovascular disease in europe: epidemiological update 2015. eur heart j 2015; 36:2696–705. doi: 10.1093/eurheartj/ehv428. 5. mozaffarian d, benjamin ej, go as, arnett dk, blaha mj, cushman m, et al. heart disease and stroke statistics: 2016 up date a report from the american heart association. circulation 2016; 133:e38–360. doi: 10.1161/cir.0000000000000350. 6. national institute of health research and development, indonesia ministry of health. [indonesia basic health research 2013]. from: http://labmandat.litbang.depkes.go.id/riset-badan litbangkes/menu-riskesnas/menu-riskesdas/374-rkd-2013 accessed: oct 2017. 7. sayols-baixeras s, lluís-ganella c, lucas g, elosua r. pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants. appl clin genet 2014; 7:15–32. doi: 10.2147/tacg.s35301. 8. aaronson pi, ward jp. the cardiovascular system at a glance, 3rd ed. hoboken, new jersey, usa: wiley-blackwell, 2007. pp. 74–117. 9. urbina o, ferrández o, luque s, grau s, mojal s, pellicer r, et al. patient risk factors for developing a drug-related problem in a cardiology ward. ther clin risk manag 2014; 11:9–15. doi: 10.2147/tcrm.s71749. 10. abraham rr. drug related problems and reactive pharmacist interventions for inpatients receiving cardiovascular drugs. int j basic med sci pharm 2013; 3:42–8. 11. pharmaceutical care network europe foundation. classification for drug-related problems, version 6.2. from: www.pcne. org/upload/files/11_pcne_classification_v6-2.pdf accessed: oct 2017. 12. dipiro jt, talbert rl, yee gc, matzke gr, wells bg, posey lm. pharmacotherapy: a pathophysiologic approach, 8th ed. new york, usa: mcgraw hill medical, 2011. pp. 9–10. 13. blix hs, viktil kk, reikvam a, moger ta, hjemaas bj, pretsch p, et al. the majority of hospitalised patients have drug-related problems: results from a prospective study in general hospitals. eur j clin pharmacol 2004; 60:651–8. doi: 10.1007/s00228-0040830-4. 14. niquille a, bugnon o. relationship between drug-related problems and health outcomes: a cross-sectional study among cardiovascular patients. pharm world sci 2010; 32:512–19. doi: 10.1007/s11096-010-9401-1. 15. gastelurrutia p, benrimoj si, espejo j, tuneu l, mangues ma, bayes-genis a. negative clinical outcomes associated with drugrelated problems in heart failure (hf) outpatients: impact of a pharmacist in a multidisciplinary hf clinic. j card fail 2011; 17:217–23. doi: 10.1016/j.cardfail.2010.10.009. 16. andreazza rs, silveira de castro m, sippel köche p, heineck i. causes of drug-related problems in the emergency room of a hospital in southern brazil. gaceta sanit 2011; 25:501–6. doi: 10.1016/j.gaceta.2011.05.016. 17. kaufmann cp, stämpfli d, hersberger ke, lampert ml. deter mination of risk factors for drug-related problems: a multidisciplinary triangulation process. bmj open 2015; 5:e006376. doi: 10.1136/bmjopen-2014-006376. 18. gattis wa, hasselblad v, whellan dj, o’connor cm. reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the pharmacist in heart failure assessment recommendation and monitoring (pharm) study. arch intern med 1999; 159:1939–45. doi: 10.1001/archinte.159.16.1939. 19. simarmata m. [pharmacist intervention on drug-related problems in patients with stroke and cardiovascular disorders the the intensive care unit, dr.mintohardjo navy hospital, jakarta]. msc thesis, 2010, university of indonesia, depok, jakarta, indonesia. 20. shpa committee of specialty practice in clinical pharmacy. shpa standards of practice for clinical pharmacy. j pharm pract res 2005; 35:122–48. doi: 10.1002/j.2055-2335.2005.tb00322.x. 21. wilson pw, douglas ps. epidemiology of coronary heart disease. from: www.uptodate.com/contents/epidemiology-ofcoronary-heart-disease accessed: nov 2017. 22. roffi m, patrono c, collet jp, mueller c, valgimigli m, andreotti f, et al. 2015 esc guidelines for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation of the european society of cardiology (esc). eur heart j 2016; 37:267–315. doi: 10.1093/ eurheartj/ehv320. 23. montalescot g, sechtem u, achenbach s, andreotti f, arden c, budaj a, et al. 2013 esc guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the european society of cardiology. eur heart j 2013; 34:2949–3003. doi: 10.1093/ eurheartj/eht296. 24. shareef j, sandeep b, shastry cs. assessment of drug related problems in patients with cardiovascular diseases in a tertiary care teaching hospital. j pharm care 2014; 2:70–6. 25. o’gara pt, kushner fg, ascheim dd, casey de jr, chung mk, de lemos ja, et al. 2013 accf/aha guideline for the management of st-elevation myocardial infarction: a report of the american college of cardiology foundation/american heart association task force on practice guidelines. circulation 2013; 127:e362–425. doi: 10.1161/cir.0b013e3182742cf6. 26. chan dc, chen jh, kuo hk, we cj, lu is, chiu ls, et al. drug-related problems (drps) identified from geriatric medication safety review clinics. arch gerontol geriatr 2012; 54:168–74. doi: 10.1016/j.archger.2011.02.005. https://doi.org/10.1016/j.cpcardiol.2009.10.002 https://doi.org/10.1038/nrcardio.2014.26 https://doi.org/10.1093/eurheartj/ehv428 https://doi.org/10.1161/cir.0000000000000350 https://doi.org/10.2147/tacg.s35301 https://doi.org/10.2147/tcrm.s71749 https://doi.org/10.1007/s00228-004-0830-4 https://doi.org/10.1007/s00228-004-0830-4 https://doi.org/10.1007/s11096-010-9401-1 https://doi.org/10.1016/j.cardfail.2010.10.009 https://doi.org/10.1016/j.gaceta.2011.05.016 https://doi.org/10.1136/bmjopen-2014-006376 https://doi.org/10.1001/archinte.159.16.1939 https://doi.org/10.1002/j.2055-2335.2005.tb00322.x https://doi.org/10.1093/eurheartj/ehv320 https://doi.org/10.1093/eurheartj/ehv320 https://doi.org/10.1093/eurheartj/eht296 https://doi.org/10.1093/eurheartj/eht296 https://doi.org/10.1161/cir.0b013e3182742cf6 https://doi.org/10.1016/j.archger.2011.02.005 situs inversus totalis (sit) is a rare autosomal recessive anomaly whereby the organs are located on the opposite side of the body to their normal positions; the condition was first reported by fabricius in 1600.1,2 the incidence of sit is estimated to vary between 1 in 5,000 and 1 in 20,000 individuals.1 when patients with this anomaly present with a surgical emergency—such as appendicitis—diagnosis can be challenging.3 acute appendicitis requires prompt surgical intervention and the laparoscopic appendectomy is the current gold-standard surgical treatment. even for patients with sit, a multi-port laparoscopic appendectomy allows minimal access surgery by positioning the ports and monitor in a mirror-image fashion on the opposite side. however, one of the most popular recent advances in minimal access surgery is the single-incision multi-port surgery.4 this technique is more technically demanding due to the loss of triangulation; however, it allows for an improved postsurgical cosmetic appearance and a faster recovery time.4 this case report describes a young male patient with sit who presented with acute appendicitis and successfully underwent a single-incision multi-port appendectomy. case report a 22-year-old male presented to the lifeline institute of minimal access surgery, chennai, india, in april 2015 with pain and discomfort in the left iliac fossa, which had begun around the umbilicus and moved to department of surgery, lifeline institute of minimal access surgery, chennai, tamil nadu, india *corresponding author e-mail: sm_akbars@yahoo.co.in استئصال الزائدة متعددة األبواب بشق واحد يف مريض مصاب حبالة أعضاء مقلوبة الوضع أول تقرير حالة جي �سي راجكومار، �سيد اأكرب، جي. اأنربيد، �سي كي�سور، قان�س ديبا abstract: situs inversus totalis (sit) is a rare autosomal recessive condition involving the complete lateral transposition of the organs. when individuals with this condition suffer from appendicitis, associated pain and symptoms are usually present on the left side, resulting in diagnostic difficulties. moreover, the laparoscopic removal of the left-sided appendix may pose practical problems during surgery. removal of an inflamed appendix is generally performed using a multiple-port laparoscopy. we report a 22-year-old male who presented to the lifeline institute of minimal access surgery in chennai, india, in april 2015 with pain in the left iliac fossa. chest x-rays and ultrasonography confirmed sit with an acutely inflamed appendix on the left side. the patient underwent a single-incision multi-port laparoscopic appendectomy with a successful outcome. to the best of the authors’ knowledge, this is the first report in the literature of a single-incision multi-port appendectomy in a patient with sit. keywords: laparoscopy; appendectomy; situs inversus; case report; india. امللخ�ص: حالة الأع�ساء مقلوبة الو�سع هي حالة �سبغية ج�سدية متنحية نادرة يحدث فيها تغيري )قلب( و�سع الأع�ساء باأكملها. وعندما ي�ساب من تكون عندهم هذه احلالة بالتهاب الزائدة، فاإن الأمل والأعرا�س امل�ساحبة لهذا اللتهاب تظهر عادة يف اجلانب الأي�رس، مما قد ي�سبب �سعوبة يف الت�سخي�س. وبالإ�سافة لذلك، فاإن الإزالة اجلراحية باملنظار للزائدة يف اجلانب الأي�رس قد ت�سبب م�ساكل عملية اأثناء اجلراحة. وتزال، وب�سورة عامة، الزائدة امللتهبة با�ستخدام جراحة املناظري متعددة الأبواب. ويف هذا التقرير نقدم حالة رجل عمره 22 عاما اأح�رس مل�ست�سفى ليف لين ريجد يف �سيناي بالهند يف اأبريل عام 2015م، وهو ي�سكو من اأمل يف احلفرة احلرقفية. واأكدت الأ�سعة اأجريت الأي�رس. جانبه يف الزائدة التهاب من ويعاين الو�سع، مقلوبة الأع�ساء حالة عنده املري�س اأن ال�سوتية فوق واملوجات ال�سينية بنجاح للمري�س عملية ا�ستئ�سال الزائدة متعددة الأبواب ب�سق واحد، دون حدوث اأي م�ساعفات. ومبلغ علمنا فاإن هذا التقرير هو التقرير الأول يف الأدب العلمي لو�سف مثل هذه احلالة يف مري�س م�ساب بحالة اأع�ساء مقلوبة الو�سع. كلمات مفتاحية: جراحة املناظري؛ اإزالة الزائدة؛ تغيري و�سع الأع�ساء؛ تقرير حالة؛ الهند. single-incision multi-port appendectomy for a patient with situs inversus totalis first case report rajkumar j. s., *akbar syed, anirudh j. r., kishor c. m., deepa ganesh case report sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 242–245, epub. 15 may 16 submitted 27 apr 15 revisions req. 21 jul 15 & 15 jan 16; revisions recd. 21 aug 15 & 9 mar 16 accepted 14 mar 16 doi: 10.18295/squmj.2016.16.02.018 rajkumar j. s., akbar syed, anirudh j. r., kishor c. m. and deepa ganesh case report | e243 the left lower quadrant of the abdomen. there was no pain in his right side or anywhere else in the abdomen. the patient suffered from loss of appetite and vomiting. a physical examination revealed that the patient was mildly tachycardic, febrile and had severe localised tenderness in the left iliac fossa in addition to rebound tenderness and abdominal guarding. when asked for his medical history, the patient informed the physician that his heart was on the other side. a chest x-ray and ultrasound confirmed the diagnosis of sit with an acutely inflamed appendix in the left iliac fossa. consequently, a single-incision multi-port appendectomy was performed. a thorough laparoscopy of the internal organs was performed using a telescope inserted through a supraumbilical incision of 10 mm, including an examination of the terminal 90 cm section of the ileum in the small bowel. the inflamed appendix was observed along the left paracolic gutter. a second port was introduced by extending the incision by an additional 5 mm and inserting a 5 mm trocar directed towards the left iliac fossa, away from the lateral edge of the incision [figure 1a]. the appendix was gently lifted up using alligator needle/grasper forceps (alligator™ retrieval device, medtronic, fridley, minneapolis, usa) [figure 1b]. the appendix was coiled upon itself and was carefully released [figure 2a]. a small amount of purulent fluid was removed from the left iliac fossa by suctioning. an ultrasonic scalpel was used to dissect the complete mesoappendix, with the alligator needle/ grasper forceps elevating the shaft of the appendix. two endoloop® ligatures (ethicon inc., johnson & johnson, somerville, new jersey, usa) were looped around the appendix from the port with the support of the alligator needle/grasper forceps [figure 2b]. for the third tie, a cobbler’s suture needle was used to suture the appendix base through the needle hole of the alligator needle/grasper forceps with dissecting forceps (laparoscopic maryland dissecting forceps, medline industries inc., mundelein, illinois, usa) in the port. the appendix was cut between the ties. the fluid was suctioned out and the appendix was removed through the incision from the lateral port with camera assistance. the patient made a smooth postoperative recovery and was healthy at a 20-day follow-up. figure 1 a&b: intrasurgical photographs of (a) the single-incision multi-port appendectomy performed on a patient with situs inversus totalis using (b) alligator needle/grasper forceps. figure 2 a&b: intrasurgical photographs of (a) the coiled and inflamed appendix in the left iliac fossa of a patient with situs inversus totalis and (b) the looping of the ligature around the base of the appendix. single-incision multi-port appendectomy for a patient with situs inversus totalis first case report e244 | squ medical journal, may 2016, volume 16, issue 2 appendix through the port. additionally, detailed examination of the terminal end of the small bowel was possible using solely the bowel-holding forceps in the port. several reports have recommended alligator needle/grasper forceps in single-port or reducedport cholecystectomies.11,19 using the alligator forceps in one hand and the energy device (e.g. harmonic scalpels, monopolar or bipolar electrosurgical devices or electrocautery devices) in the other also reduces the potential triangulation problems that may arise during a single-port surgery. in the present case, a cobbler’s needle was used to suture the appendix base through the needle hold of the alligator needle/grasper forceps with dissecting forceps in the port. this type of intracorporeal suturing is usually deployed in single-port fundoplication surgeries and single-port sleeve gastrectomies.4 despite concerns regarding triangulation, the authors would recommend the combination of alligator needle/grasper forceps and a 10 and 5 mm port through the same incision. although two ports were used in the current case, both ports were implanted through a single 15 mm incision; the most accurate term for this procedure is therefore a single-incision double-port appendectomy. the alligator needle/grasper forceps and the cobbler’s needle were both passed through a single needle hole of 1.5 mm in diameter, justifying the use of the aforementioned term. although a singleport device might have facilitated the handling and removal of the appendix, it is departmental policy at the lifeline institute of minimal access surgery to perform single-incision multi-port surgeries so as to decrease patient costs. conclusion a single-incision appendectomy is a viable alternative to multi-port appendectomies in patients with sit. to the best of the authors’ knowledge, this is the first case to be reported in the english medical literature. references 1. phothong n, akaraviputh t, chinswangwatanakul v, trakarnsanga a. simplified technique of laparoscopic cholecystectomy in a patient with situs inversus: a case report and review of techniques. bmc surg 2015; 15:23. doi: 10.1186/ s12893-015-0012-6. 2. dalal js, kalsey g, rai h, chanana a, mittal s, dalal v, et al. situs inversus totalis. j punjab acad forensic med toxicol 2004; 1:35–6. 3. oh js, kim kw, cho hj. left-sided appendicitis in a patient with situs inversus totalis. j korean surg soc 2012; 83:175–8. doi: 10.4174/jkss.2012.83.3.175. discussion appendectomies among sit patients have previously been reported, with 69 cases to date in the scientific literature.5 when patients with sit present with acute appendicitis, the diagnosis can be confusing.6,7 in cases of a straightforward and total contralateral transposition of the viscera, the appendix and caecum can easily be identified on the left side. however, in patients with malrotation of the viscera, the appendix may be in the subhepatic or subsplenic positions which can cause diagnostic problems during surgery.8 disconcertingly, up to 15% of sit patients with appendicitis report pain on the right side.3 a small proportion of those without neural situs inversus complain of appendicular pain on the right side as well.5,7,9,10 this anomaly occurs due to a failure in the transposition of the nervous system, with the leftsided appendix still causing right iliac fossa pain. as a result, ultrasonography or computed tomography should be performed to confirm the diagnosis of sit, as was done in the present case. the commonly recommended strategy for treating patients with a left-sided appendix due to intestinal malrotation, sit or a similar abnormality is a diagnostic laparoscopy in the periumbilical area, after which ports can be placed strategically depending upon the pathology observed and on the quadrant affected.11 commonly placed trocar positions for laparoscopic appendectomies include umbilical and suprapubic trocars and trocars placed in the left upper quadrant. in some patients, particularly those with a slightly elevated caecum on the left side, the left upper quadrant port is replaced by an epigastric port.11 very few surgeries for left-sided appendicitis have been carried out laparoscopically (10.2%).5 while there are several reports of single-incision or single-port cholecystectomies in patients with sit, the present case report appears to be the first in the medical literature of a single-incision appendectomy in a patient with sit, although the technique has been mentioned previously.12–17 the single-incision procedure described in the current case report took only a few minutes longer than a standard multi-port appendectomy. ultrasonic shears are not normally used for appendectomies as they increase the cost of the procedure;11,18 however, in the present case, they were deemed suitable as alligator needle/grasper forceps would not be able to coagulate the tissues if mesoappendix bleeding occurred with cautery. moreover, use of the alligator needle/grasper forceps permitted traction of the appendix during the mesoappendix dissection as well as the looping of the ligatures around the base of the http://dx.doi.org/10.1186/s12893-015-0012-6 http://dx.doi.org/10.1186/s12893-015-0012-6 http://dx.doi.org/10.4174/jkss.2012.83.3.175 rajkumar j. s., akbar syed, anirudh j. r., kishor c. m. and deepa ganesh case report | e245 4. canes d, desai mm, aron m, haber gp, goel rk, stein rj, et al. transumbilical single-port surgery: evolution and current status. eur urol 2008; 54:1020–9. doi: 10.1016/j. eururo.2008.07.009. 5. naik mb, roa ks. laparoscopic appendicectomy in situs inversus totalis. j evol med dent sci 2015; 4:5064–7. doi: 10.14260/jemds/2015/738. 6. golash v. laparoscopic management of acute appendicitis in situs inversus. j minim access surg 2006; 2:220–1. doi: 10.4103/0972-9941.28184. 7. akbulut s, caliskan a, ekin a, yagmur y. left-sided acute appendicitis with situs inversus totalis: review of 63 published cases and report of two cases. j gastrointest surg 2010; 14:1422–8. doi: 10.1007/s11605-010-1210-2. 8. palanivelu c, rangarajan m, john sj, senthilkumar r, madhankumar mv. laparoscopic appendectomy for appendicitis in uncommon situations: the advantages of a tailored approach. singapore med j 2007; 48:737–40. 9. machado no, chopra p. laparoscopic cholecystectomy in a patient with situs inversus totalis: feasibility and technical difficulties. jsls 2006; 10:386–91. 10. franklin me jr, almeida ja, pérez er, michaelson rl, majarrez a. cholecystectomy and appendectomy by laparoscopy in a patient with situs inversus totalis: a case report and review of the literature. assoc mex surg endoscóp 2001; 2:150–3. 11. kollmar o, z’graggen k, schilling mk, buchholz bm, büchler mw. the suprapubic approach for laparoscopic appendectomy. surg endosc 2002; 16:504–8. doi: 10.1007/ s00464-001-9027-4. 12. han hj, choi sb, kim cy, kim wb, song tj, choi sy. singleincision multiport laparoscopic cholecystectomy for a patient with situs inversus totalis: report of a case. surg today 2011; 41:877–80. doi: 10.1007/s00595-010-4387-9. 13. de campos martins mv, pantaleão falcão jl, skinovsky j, de faria gm. single-port cholecystectomy in a patient with situs inversus totalis presenting with cholelithiasis: a case report. j med case rep 2012; 6:96. doi: 10.1186/1752-1947-6-96. 14. uludag m, yetkin g, kartal a. single-incision laparoscopic cholecystectomy in situs inversus totalis. jsls 2011; 15:239–43. doi: 10.4293/108680811x13071180407032. 15. bozkurt s, coskun h, atak t, kadioglu h. single incision laparoscopic cholecystectomy in situs inversus totalis. j surg tech case rep 2012; 4:129–31. doi: 10.4103/2006-8808.110264. 16. khiangte e, newme i, patowary k, phukan p. single-port laparoscopic cholecystectomy in situs inversus totalis using e.k. glove port. j minim access surg 2013; 9:180–2. doi: 10.41 03/0972-9941.118838. 17. zachariah sk. feasibility of single-incision laparoscopic surgery for appendicitis in abnormal anatomical locations: a single surgeon’s initial experience. j minim access surg 2013; 9:13–18. doi: 10.4103/0972-9941.107128. 18. ignacio rc, burke r, spencer d, bissell c, dorsainvil c, lucha pa. laparoscopic versus open appendectomy: what is the real difference? results of a prospective randomized double-blinded trial. surg endosc 2004; 18:334–7. doi: 10.1007/ s00464-003-8927-x. 19. blanco fc, kane td. single-port laparoscopic surgery in children: concept and controversies of the new technique. minim invasive surg 2012; 2012:232347. doi: 10.1155/ 2012/232347. http://dx.doi.org/10.1016/j.eururo.2008.07.009 http://dx.doi.org/10.1016/j.eururo.2008.07.009 http://dx.doi.org/10.14260/jemds/2015/738 http://dx.doi.org/10.4103/0972-9941.28184 http://dx.doi.org/10.1007/s11605-010-1210-2 http://dx.doi.org/10.1007/s00464-001-9027-4 http://dx.doi.org/10.1007/s00464-001-9027-4 http://dx.doi.org/10.1007/s00595-010-4387-9 http://dx.doi.org/10.1186/1752-1947-6-96 http://dx.doi.org/10.4293/108680811x13071180407032 http://dx.doi.org/10.4103/2006-8808.110264 http://dx.doi.org/10.4103/0972-9941.118838 http://dx.doi.org/10.4103/0972-9941.118838 http://dx.doi.org/10.4103/0972-9941.107128 http://dx.doi.org/10.1007/s00464-003-8927-x http://dx.doi.org/10.1007/s00464-003-8927-x http://dx.doi.org/10.1155/2012/232347 http://dx.doi.org/10.1155/2012/232347 multiple sclerosis (ms) is a chronic demyelinating neurological disease result-ing from the predominately t cell-mediated autoimmune destruction of oligodendrocytes which synthesise myelin.1 the disease affects women twice as often as men and symptoms usually present when patients are between 20 and 40 years old, which means that women of reproductive age are the most susceptible.1 several disease-modifying drugs (dmds) have been reported to reduce the frequency of clinical ms attacks and are prescribed with the intent of slowing disability progression; these medications include interferon (ifn)-β 1a and 1b, glatiramer acetate, natalizumab, mitoxantrone and fingolimod, with ifn-β and glatiramer acetate currently considered first-line therapies.1 many newer agents are also being introduced, including tyrosine kinase inhibitors.2,3 unfortunately, recent evidence has emerged regarding the potential pregnancy-related adverse effects of dmds.4 in general, dmd therapy is discontinued during pregnancy, although the actual risk of adverse effects occurring due to ifn-β and glatiramer acetate appears to be low.5 this report describes a pregnant woman who took ifn-β throughout her first trimester and subsequently developed severe placental complications. case report a 30-year-old gravida 2 para 1 woman presented to the tawam hospital, al ain, united arab emirates, in 2013. she had been diagnosed with relapsing-remitting ms five years previously, after she had developed unilateral optic neuritis with frequent relapses. these symptoms had progressed two years later to epilepsy and left-sided haemiplegia and her ms was re-classified as secondary progressive ms. she was prescribed ifn-β 1a at a dose of 30 µg weekly as a lifelong 1department of pharmacy, sheikh zayed hospital, abu dhabi, united arab emirates; 2department of obstetrics & gynaecology, tawam hospital, al ain, united arab emirates *corresponding author e-mail: ssdocpharm@gmail.com األدوية املغرية للمرض قد تؤدي إىل قصور املشيمة مضاعفات حادة يف مشيمِة امرأٍة حامٍل ومصابٍة مبرض التصلب املتعدد �صلطان حممد �صالح الدين و موزيبوني�صا بيجام abstract: disease-modifying drugs (dmds) such as interferon (ifn)-β and glatiramer acetate are often prescribed to slow disability progression in patients with multiple sclerosis (ms). however, adverse pregnancy outcomes have been reported with these medications. we report the rare occurrence of severe placental complications in a 30-yearold pregnant woman with ms who continued to take ifn-β during her first trimester. she presented at the tawam hospital, al ain, united arab emirates, in 2013 with early-onset fetal growth restriction. at 30 gestational weeks, she developed severe pre-eclampsia. the baby was delivered via emergency caesarean section and was discharged at the age of two months. continuation of ifn-β during pregnancy may have contributed to the development of placental insufficiency in this patient. increased education regarding the risks of dmds for pregnant patients with ms is very important to ensure successful pregnancy outcomes. keywords: multiple sclerosis; interferon beta; pre-eclampsia; fetal growth retardation; placental insufficiency; case report; united arab emirates. امللخ�ص: يعترب عقاري البيتا انتريفريون وا�صيتات اجللتيمرات من االأدوية امل�صتخدمة الإبطاء االإعاقة يف مر�صى الت�صلب املتعدد، وهناك ت�صارب يف البيانات اخلا�صة بتاأثري هذه االأدوية علي احلمل، هذا تقرير حالة عن حدوث م�صاعفات �صديدة يف م�صيمة اأمراأة حامل يف 2013م عام املتحدة العربية االإمارات يف بالعني توام مل�صت�صفى املري�صة ح�رضت املتعدد، الت�صلب مبر�ض م�صابة العمر من الثالثني مع نق�ض مبكر يف منو اجلنني، يف االأ�صبوع الثالثني من احلمل تعر�صت املراأة مل�صاعفات احلمل ومت توليد الطفل ب�صكل طارئ عن طريق العملية القي�رضية، ومت ترخي�ض الطفل بعد �صهرين، اإن ا�صتمرار تعاطي عقاقري املر�ض يف الثالثة �صهور االأوىل من احلمل اأّدى ذلك اإىل حدوث ق�صور يف امل�صيمة، يجب االإهتمام بتثقيف وتوعية املر�صى امل�صابني بالت�صلب املتعدد عن هذه املخاطر من اأجل نتائج ناجحة للحمل. كلمات مفتاحية: الت�صلب املتعدد؛ انرتفريون بيتا؛ ا�صيتات اجللتيمرات؛ ت�صمم احلمل؛ تاأخر منو اجلنني؛ ق�صور امل�صيمة؛ تقرير حالة. disease-modifying drug possibly linked to placental insufficiency severe placental complications in a pregnant woman with multiple sclerosis *sultan m. salahudheen1 and muzibunnisa a. begam2 case report sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e368–370, epub. 19 aug 16 submitted 8 feb 16 revision req. 21 mar 16; revision recd. 30 mar 16 accepted 7 apr 16 doi: 10.18295/squmj.2016.16.03.019 sultan m. salahudheen and muzibunnisa a. begam case report | e369 prophylactic therapy as well as levetiracetam at a dose of 750 mg twice daily to control her epilepsy. in 2013, she conceived spontaneously; however, the medication was discontinued only at 13 gestational weeks after her first visit to an obstetrician. levetiracetam was continued throughout her pregnancy. during her pregnancy, the patient remained stable; however, a fetal ultrasound at 22 gestational weeks indicated that all fetal growth parameters had decreased. severe early-onset fetal growth restriction (fgr) was diagnosed. the results of a detailed anatomic survey, karyotyping by amniocentesis and a virology screening test were normal. however, prenatal ultrasonography revealed that the fetus had an echogenic mildly dilated bowel [figure 1], most probably due to ischaemia. a uterine artery doppler ultrasound revealed high-resistance flow with early diastolic notching [figure 2a] and an umbilical artery doppler ultrasound showed absent end-diastolic flow [figure 2b]. additionally, the patient suffered from oligohydramnios. these findings were suggestive of placental insufficiency as the cause for early-onset fgr. the patient was subsequently monitored with a series of biophysical tests. at 30 gestational weeks, the patient developed severe pre-eclampsia that was further complicated by hellp (haemolysis, elevated liver enzymes and low platelets) syndrome. as a result, an emergency caesarean section was performed and the patient was given full high-intensive care to manage the preeclampsia, including magnesium sulphate infusions, serial monitoring of vitals and renal and respiratory function tests. post-delivery, the patient had an uneventful recovery and was discharged eight days after the caesarean section in stable condition with the advice to continue ifn-β as lifelong prophylactic therapy. in this case, the placenta was not sent for histopathology examination; it is recommended to do so in future cases. at birth, the female baby weighed 980 g and was admitted to the neonatal unit of tawam hospital. a physical examination did not reveal any malformations or abnormalities. the neonate required a postnatal course of surfactant for respiratory distress. she also required total parenteral nutrition initially but subsequently tolerated enteral feeds. she was discharged at the age of two months. discussion there are four clinical types of ms, including relapsing-remitting ms, secondary progressive ms, primary progressive ms and progressive-relapsing ms. generally, dmds are recommended for patients who suffer from relapsing forms of ms, such as relapsing-remitting ms or secondary progressive ms with exacerbations; the prescription criteria include abnormal neurological examinations, several ms attacks and a high burden of disease as assessed by magnetic resonance imaging of the brain.1 the patient in the current case was an ideal candidate for dmds as she was first diagnosed with relapsing-remitting ms, which then progressed to secondary progressive ms with permanent neurological complications. hence, she was on lifelong prophylactic therapy with ifn-β 1a. figure 1: prenatal ultrasonography of a pregnant woman with multiple sclerosis showing a fetus with a mildly dilated echogenic bowel. figure 2a & b: doppler ultrasonography of (a) the uterine arteries revealing high-resistance flow with early diastolic notching (arrow) and (b) the umbilical artery showing absent end-diastolic flow in a pregnant woman with multiple sclerosis. edn = early diastolic notching ; rt = right; aedf = absent end-diastolic flow. disease-modifying drug possibly linked to placental insufficiency severe placental complications in a pregnant woman with multiple sclerosis e370 | squ medical journal, august 2016, volume 16, issue 3 conclusion this case describes severe placental complications in a pregnant woman with ms who continued taking ifn-β during her first trimester. the continuation of this dmd well into the period of full placental development may have contributed to the development of early-onset fgr and pre-eclampsia in this patient. however, further research into this issue is required to determine whether these factors are related. it is advisable that women who continue taking dmds during their pregnancies should be followed-up closely to assess and prevent the development of fetal and maternal complications. references 1. hauser sl, goodin ds. multiple sclerosis and other demyelinating diseases. in: longo d, fauci a, kasper d, hauser s, jameson j, loscalzo j. harrison’s principles of internal medicine, 18th ed. new york, usa: mcgraw-hill professional, 2012. pp. 3395–409. 2. mirshafiey a, ghalamfarsa g, asghari b, azizi g. receptor tyrosine kinase and tyrosine kinase inhibitors: new hope for success in multiple sclerosis therapy. innov clin neurosci 2014; 11:23–36. 3. azizi g, mirshafiey a. imatinib mesylate: an innovation in treatment of autoimmune diseases. recent pat inflamm allergy drug discov 2013; 7:259–67. doi: 10.2174/1872213 x113079990021. 4. lu e, wang bw, guimond c, synnes a, sadovnick d, tremlett h. disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. neurology 2012; 79:1130–5. doi: 10.1212/ wnl.0b013e3182698c64. 5. cunningham fg, leveno kj, bloom sl, spong cy, dashe js, hoffman bl, et al. williams obstetrics, 24th ed. new york, usa: mcgraw-hill education/medical, 2013. pp. 1187–1203. 6. mawhinney e, craig j, morrow j, russell a, smithson wh, parsons l, et al. levetiracetam in pregnancy: results from the uk and ireland epilepsy and pregnancy registers. neurology 2013; 80:400–5. doi: 10.1212/wnl.0b013e31827f0874. 7. hellwig k, brune n, haghikia a, müller t, schimrigk s, schwödiauer v, et al. reproductive counselling, treatment and course of pregnancy in 73 german ms patients. acta neurol scand 2008; 118:24–8. doi: 10.1111/j.1600-0404.2007.00978.x. 8. stuart m, bergstrom l. pregnancy and multiple sclerosis. j midwifery womens health 2011; 56:41–7. doi: 10.1111/j.15422011.2010.00008.x. 9. parham p, moffett a. variable nk cell receptors and their mhc class i ligands in immunity, reproduction and human evolution. nat rev immunol 2013; 13:133–44. doi: 10.1038/nri3370. 10. moffett-king a. natural killer cells and pregnancy. nat rev immunol 2002; 2:656–63. doi: 10.1038/nri886. 11. mifsud w, sebire nj. placental pathology in early-onset and late-onset fetal growth restriction. fetal diagn ther 2014; 36:117–28. doi: 10.1159/000359969. 12. salafia cm, minior vk, pezzullo jc, popek ej, rosenkrantz ts, vintzileos am. intrauterine growth restriction in infants of less than thirty-two weeks’ gestation: associated placental pathologic features. am j obstet gynecol 1995; 173:1049–57. doi: 10.1016/0002-9378(95)91325-4. 13. manaster i, mandelboim o. the unique properties of uterine nk cells. am j reprod immunol 2010; 63:434–44. doi: 10.11 11/j.1600-0897.2009.00794.x. in the current case, the patient was prescribed levetriacetam monotherapy to control her epilepsy during pregnancy. with levetriacetam, the risk of major congenital malformations is comparable with that of the non-epileptic population, indicating the relative safety of the drug.6 on the other hand, a systematic review reported that ifn-β exposure was associated with lower mean birth weight, shorter mean birth length and preterm birth, although the drug was not associated with increased risk of low birth weight infants (<2,500 g), caesarean section delivery, congenital anomalies or spontaneous abortion.4 due to the limited data regarding the effect of dmds on pregnancy outcomes, women are advised to stop taking the drug either three months or at least one month prior to conception.7,8 close follow-up is recommended for patients who continue taking dmds during their pregnancies in order to assess and prevent the development of any fetal or maternal complications. women with ms should be given more education regarding the risks of dmds in pregnancy. extra-villous trophoblast (evt) cells are fetal cells that invade the mother’s uterus, where they transform the spiral arteries into large vessels capable of conducting sufficient blood to the placenta.9 early trophoblast invasion is important for placental function and the extent of arterial transformation by the trophoblasts affects successful reproductive outcomes.9 severe early-onset fgr overlapping with severe pre-eclampsia, as in the present case, is mainly associated with features of impaired maternal uteroplacental perfusion secondary to defective evt invasion, which results in insufficient blood supply to the placenta.10,11 placental histopathological findings generally reflect abnormal uteroplacental flow with secondary chronic fetal vasoconstriction and distal villous changes.11,12 trophoblast invasion is controlled by the uterine natural killer cells (unk cells), the most common uterine leukocyte.9,13 the efficacy of ifn-β in patients with ms is due to its immunomodulatory properties; the drug downregulates major histocompatibility molecules on antigen-presenting cells, inhibits proinflammatory cytokine levels, increases regulatory cytokine levels, inhibits t cell proliferation and limits the trafficking of inflammatory cells in the nervous system.1 these properties evidently oppose the effects of unk cells.9,13 the patient in the current case took ifn-β until the 13th week of her pregnancy, which is when evt invasion and placental development occurs.9 however, further research is required to determine whether dmds are related to placental insufficiency. studies using experimental animal models are recommended to assess the relationship between ifn-β and evt invasion or placental development. http://dx.doi.org/10.2174/1872213x113079990021 http://dx.doi.org/10.2174/1872213x113079990021 http://dx.doi.org/10.1212/wnl.0b013e3182698c64 http://dx.doi.org/10.1212/wnl.0b013e3182698c64 http://dx.doi.org/10.1212/wnl.0b013e31827f0874 http://dx.doi.org/10.1111/j.1600-0404.2007.00978.x http://dx.doi.org/10.1111/j.1542-2011.2010.00008.x http://dx.doi.org/10.1111/j.1542-2011.2010.00008.x http://dx.doi.org/10.1038/nri3370 http://dx.doi.org/10.1038/nri886 http://dx.doi.org/10.1159/000359969 http://dx.doi.org/10.1016/0002-9378%2895%2991325-4 http://dx.doi.org/10.1111/j.1600-0897.2009.00794.x http://dx.doi.org/10.1111/j.1600-0897.2009.00794.x sultan qaboos university med j, august 2015, vol. 15, iss. 3, pp. e317–321, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.003. submitted 2 jun 15 revision req. 28 jun 15; revision recd. 12 jul 15 accepted 14 jul 15 in 1865, thomas hodgkin was immortalised by his peer, samuel wilks, in the annals of medical literature through the eponymous use of the term ‘hodgkin’s disease’.1,2 consequently, it must have seemed logical for the medical community of the time to name the other, more heterogeneous group of neoplastic lymph node enlargements as non-hodgkin lymphoma (nhl). a century and a half later, nhl has emerged from those shadows and is now recognised as the leading haematological malignancy worldwide.3 the second of this two-part medical history article provides a succinct narrative of what transpired in these 150 years to pique scientific curiosity and establish nhl in the centre stage. it follows the trail of classifications, aetiology and epidemiology, prognostic factors and, finally, the elusive holy grail of treatment which marked this period of medical history. the mother of all classifications: confusion and logic it would not be an understatement to assert that the classifications of nhl are the outright frontrunners in terms of their complexity when compared with other tumour classifications. this is a reflection of the transition of pathological diagnosis from an ‘eyes-only’ morphological basis in the 19th century, to the more sophisticated tools of immunology and genetics that exist today. in 1864 and 1865, virchow and cohnheim had recognised the diseased enlargement of lymph nodes as lymphosarcoma and pseudoleukaemia, respectively, although the term ‘malignant lymphoma’ was first used by bilroth in 1871.4 it appears that the diseases thus identified had resulted from a mix of neoplastic, infective and miscellaneous causes of lymph node enlargement. between the end of the 19th century and the middle of the 20th century, little headway was made in identifying nhl, with the sporadic additions of reticulum cell sarcoma by oberling in 1928 and giant follicular lymphoma by brill and symmers in 1925.4,5 the first organised classification appeared through the efforts of rappaport in 1956, with a modified version being published in an armed forces institute of pathology fascicle in 1966.6 the categorisation of nhls into nodular, diffuse and histiocytic, each with subtypes, was based on architectural organisation and the cell size of the neoplastic lymphoid infiltrate.6 in subsequent years, the histiocytic category of nhls was lost, as true histiocytic lymphomas were found to be exceedingly rare once immunomarker-based identification became possible. the 1960s saw an ever increasing evolution in the science of immunology and associated tools. scientists on both sides of the atlantic ocean drew on these resources to breathe new life into the concepts of lymphoid differentiation, trying to relate neoplastic cells to their normal counterparts in lymphoid tissue.7–10 in the usa in 1974, lukes and collins’ classifications combined the presumed cell of origin (b, t or histiocytic), site of origin (follicular) and state of transformation as evidenced by combinations of cell size (small/large) and nuclear shape (round/cleaved).7,8 in europe, the kiel classification by lennert and luke (proposed in 1974 and extensively modified in 1988) introduced the concept of tumour grading, suffixing low grade tumour cells with “-cytic” and higher grades with “-blastic” (e.g. centrocytic, centroblastic and immunoblastic).9 the kiel classification continued to be updated with accumulating data, adding extranodal and t cell lymphomas. yet another schema, the british national lymphoma investigation (bnli) classification, was propounded in 1974 by bennett et al.10 1department of pathology, college of medicine & health sciences, sultan qaboos university; 2department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ritu@squ.edu.om قصة تارخيية عن نوعني من أورام الغدد الليمفاوية اجلزء الثاين: أورام الغدد اللمفاوية نوع هودجكني ريتو لكتاكيا و اإكرام بريين medical history a historical tale of two lymphomas part ii: non-hodgkin lymphoma *ritu lakhtakia1 and ikram burney2 a historical tale of two lymphomas part ii: non-hodgkin lymphoma e318 | squ medical journal, august 2015, volume 15, issue 3 to assuage the increasing frustration among clinicians, lost in a maze of classifications with questionable clinical relevance, a working formula for clinical usage was created by a group of experts appointed by the national cancer institute in the usa in 1978.11 six experts and six non-experts reviewed a thousand nhl cases with adequate clinical follow-up. they drew on previous classifications and separated lowand high-grade groups (respectively showing small and large cells) by an intermediate grade. however, this new grade was contentious because of the inclusion of ‘mixed-bag’ entities. moreover, the universal application of the classification came into question as nhl subtypes varied in frequency in different parts of the world and the cases studied represented only those seen in the usa.11 however, this remained a working formula until it was succeeded by later classifications. the 1970s and 1980s saw a trifurcated practice of nhl classification in the western world: the working formulation favoured in the usa, the bnli in the uk and the kiel classification in europe.9–11 founded in 1990 by stein and isaacson, the international lymphoma study group tried to unify transatlantic opinions in its revised europeanamerican lymphoma (real) classification of 1994.12 this schema tapped newly emerging data and combined clinical features, morphology and immunophenotyping and genetic information. notably, the group was comprised of 19 histopathologists from around the world in an inclusive approach so as to encompass diversity in disease and scientific opinion.12 the group emphasised the acronym of the classification, real, by endorsing the recognition of true clinico biological entities.12 the world health organization classifications of haematopoeitic and lymphoid tissue tumours of 2001 and 2008 emerged from this foundation, grouping established and provisional categories of nhl under a broad umbrella based on cell lineage and differentiation (precursor/mature and b/t/natural killer/histiocytic/ dendritic cell types).13 subtypes of hodgkin lymphoma were also listed. in these now well-established and revised classifications, a close intertwining of clinicopathological features and definitive cytogenetics brought order and improved understanding. notable examples of specific diagnostic entities determined by their genotype include follicular lymphoma (t[14:18]), burkitt lymphoma (t[8:14]) and anaplastic large cell lymphoma (t[2:5]).13 the emerging era of targeted therapy demands standardised reporting on potential targets in tumour cells, like cluster of differentiation twenty (cd20) and anaplastic lymphoma kinase (alk); the diagnostic pathologist now has the onerous responsibility of being both a predictor and prognosticator. aetiology of non-hodgkin lymphoma: immune dysregulation when lymphoma came to be recognised as a clinical entity, it was difficult to separate its neoplastic origin and intent from other causes of lymphadenopathy, especially infection. the distinction became easier once diagnostic patterns could be established via microscopy. in the last century, rapid advances in microbiological, immunological and molecular tech niques have brought epidemiological evidence of risk and aetiology to light. stimulation of the lymphoid cells or integration of the infectious agent with cellular dna may provide the opportunity for uncontrolled proliferation—associations of hepatitis c and human immunodeficiency virus with multiple nhl-subtypes; epstein barr virus with burkitt lymphoma; and helicobacter pylori with gastric mucosa-associated lymphoid tissue lymphomas are established examples.14–16 altered regulation of immunological processes (autoimmune diseases) or their suppression (post-transplantation) provide the milieu for neoplastic lymphoid clones to grow without the usual checks.17,18 large-scale case-control studies from multiple continents under the international lymphoma epidemiology consortium will provide additional data for future historians.19 prognostic factors: towards precision medicine consistent with the history of the evolution of nhl classifications, a plethora of literature has emerged attempting to describe prognostic factors for the more common forms of nhl. the complexity of nhl does not end with descriptions of new subsets at major scientific meetings, but continues to evolve with new clinical and molecular features of each major subtype. these features help to describe prognostic groups or prognostic features within selected nhl subtypes. three major prognostic systems deserve special mention. the first was a predictive model for aggressive nhl developed in 1993 and known as the international prognostic index.20 the index used clinical features including age, clinical stage, serum lactate dehydrogenase level, number of extranodal sites and performance status to stratify patients into low-, low-intermediate-, high-intermediateand highrisk categories.20 the second major system describes two major types of b cell lymphomas at the molecular level. alizadeh et al. used dna microarrays to systematically characterise gene expression in b cell lymphomas.21 ritu lakhtakia and ikram burney medical history | e319 (methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone); macop-b (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin); and promace-cytabom (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate and folinic acid). by the mid-1990s, a stalemate had been reached. at the turn of the century, two significant strides were made. research indicated that a second attempt at a cure was possible for a majority of patients with aggressive nhl: high-dose chemotherapy with autologous stem cell transplantation could cure 45% of patients, as compared to 12% of those who were treated with a second-line chemotherapy regimen.29 secondly, knowledge of the molecular structure and expression of cell surface antigens changed the face of treatment for almost all forms of nhl forever. a monoclonal antibody (rituximab) was engineered, targeting the cd20 antigen expressed on the surface of b lymphocytes (especially activated b cells) and a new paradigm of treatment emerged.30 a combination of cytotoxic chemotherapy with the anti-cd20 antibody improved remission rates and cure rates.31 what has followed since this discovery has been nothing less than spectacular. the use of a monoclonal antibody as a single agent to induce remission and prolong remission and in combination to enhance the effect of salvage chemotherapy before high-dose treatment and autologous stem cell transplantation are options which have changed the outlook for patients with nhl.32–34 more recently, radioimmunoconjugates, monoclonal antibodies against different antigens and molecule inhibitors, such as bruton tyrosine kinase inhibitors, have been added to the armamentarium of physicians treating nhl.35 while the chances of a cure continue to improve with the advent of targeted therapy, parallel efforts are underway to reduce the short and long-term toxicity of these treat ment options. lessons from the history of non-hodgkin lymphoma pathological diagnostic challenges are often mirrored in taxonomic riddles that create a bewildering maze of classifications. for over a century and half, nhl classifications have been a prime example of the disconnect between the lexicon of the microscopist and the clinical relevance of the resultant diagnostic entity. the search for clarity is achieved most often through insight, pragmatism, the bridging of geographical divides and collaboration between they described two forms of molecularly distinct diffuse large b cell lymphoma (dlbcl); one type expressed genes characteristic of germinal centre b cells and the other expressed genes induced during the in vitro activation of peripheral blood b cells (activated b-like dlbcl). the former had a better outcome compared to the latter.21 the third major attempt at disease prognostication came with the advent and widespread use of positron emission tomography (pet) scans in 2005.22 functional imaging with 18f-fluorodeoxyglucose pet scans, and subsequently with combined pet/computed tomography, was found to increase the sensitivity and specificity of disease assessment and also predict outcomes.22 numerous studies have confirmed that mid-treatment pet scans are predictive of clinical outcomes, especially when the negative predictive value is very high.23 treatment: a tale of discovery, stalemate and invention at least 80 different forms of nhl have been described, the details of which are consequently beyond the scope of this article. two entities representing the polar ends of the spectrum of biological behaviour— aggressive b cell nhl and indolent b cell nhl—are addressed below. the treatment of nhl came into the limelight through serendipity. towards the end of world war ii, alkylating agents used in chemical warfare were observed to cause ulcers, infections and alopecia amongst the inmates of concentration camps. subsequently, nitrogen mustard gas and its derivatives were used for the treatment of lymphoproliferative disorders as well as many other cancers in the 1950s.24 since the 1960s, alkylating agents used individually (chlorambucil) and in combination (cyclophosphamide, hydroxydaunomycin, vincristine and prednisolone [chop]) became the standard of care for the majority of patients with indolent and aggressive nhl, respectively, for the next 30 years.25 chlorambucil induced stable remission in a significant number of patients with symptomatic indolent nhl and chop not only induced remissions in the majority of patients with aggressive nhl, but also ‘cured’ a significant number. further efforts to cure either indolent or aggressive forms of nhl met with disappointing results.26 newer generations of alkylating agents or combinations with additional and different cytotoxic agents or dose-dense chemotherapy did not improve chances of a cure and were more toxic.27,28 chemotherapy combinations included m-bacod a historical tale of two lymphomas part ii: non-hodgkin lymphoma e320 | squ medical journal, august 2015, volume 15, issue 3 pathologists and physicians. today, technology and advances in tumour biology may provide the missing links in our understanding, hopefully leading to diagnostic precision and tailored therapies. for crude classifications and false generalisations are the curse of all organised human life. h. g. wells.36 references 1. wilks s. cases with enlargement of the lymphatic glands and spleen (or hodgkin’s disease) with remarks. guy’s hosp rep 1865; 11:57–67. 2. lakhtakia r, burney i. a historical tale of two lymphomas: part i: hodgkin lymphoma. sultan qaboos univ med j 2015; 15:e202–6. 3. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin 2011; 61:69–90. doi: 10.3322/caac.20107. 4. norton aj. classification of non-hodgkin’s lymphomas. ballieres clin haematol 1996; 9:641–52. doi: 10.1016/s09503536(96)80046-1. 5. van besien k, schouten h. follicular lymphoma: a historical review. leuk lymphoma 2007; 48:232–43. doi: 10.10 80/10428190601059746. 6. rappaport h. tumors of the haematopoeitic system: section 3 3, fascicle 8. in: atlas of tumor pathology. washington dc, usa: united states armed forces institute of pathology, 1966. p.442. 7. lukes rj, collins rd. a functional approach to the classification of malignant lymphoma. recent results cancer res 1974; 46:18–30. doi: 10.1007/978-3-642-80829-6_4. 8. lukes rj, collins rd. immunologic characterization of human malignant lymphomas. cancer 1974; 34:1488–503. doi: 10.1002/1097-0142(197410)34:8+<1488::aid-cncr2820 340822>3.0.co;2-c. 9. stansfeld ag, diebold j, noel h, kapanci y, rilke f, kelényi g, et al. updated kiel classification for lymphomas. lancet 1988; 1:292–3. doi: 10.1016/s0140-6736(88)90367-4. 10. bennett mh, farrer-brown g, henry k, jaliffe am, gerardmarchant r, hamlin i, et al. classification of non-hodgkin’s lymphomas. lancet 1974; 405–6. doi: 10.1016/s0140-6736 (74)91786-3. 11. national cancer institute sponsored study of classifications of non-hodgkin’s lymphomas: summary and description of a working formulation for clinical usage the non-hodgkin's lymphoma pathologic classification project. cancer 1982; 49:2112–35. doi: 10.1002/1097-0142(19820515)49:10<2112::aidcncr2820491024>3.0.co;2-2. 12. harris nl, jaffe es, stein h, banks pm, chan jk, cleary ml, et al. a revised european-american classification of lymphoid neoplasms: a proposal from the international lymphoma study group. blood 1994; 84:1361–92. 13. swerdlow sh, campo e, harris nl, jaffe es, pileri sa, stein h, et al., eds. who classification of tumours of haematopoietic and lymphoid tissues. 4th ed. lyon, france: iarc press, 2008. 14. suarez f, lortholary o, hermine o, lecuit m. infectionassociated lymphomas derived from marginal zone b cells: a model of antigen-driven lymphoproliferation. blood 2006; 107:3034–44. doi: 10.1182/blood-2005-09-3679. 15. dal maso l, franceschi s. epidemiology of non-hodgkin lymphomas and other haemolymphopoietic neoplasms in people with aids. lancet oncol 2003; 4:110–19. doi: 10.1016/ s1470-2045(03)00983-5. 16. de sanjose s, benavente y, vajdic cm, engels ea, morton lm, bracci pm, et al. hepatitis c and non-hodgkin lymphoma among 4784 cases and 6269 controls from the international lymphoma epidemiology consortium. clin gastroenterol hepatol 2008; 6:451–8. doi: 10.1016/j.cgh.2008.02.011. 17. ekström smedby k, vajdic cm, falster m, engels ea, martinez-maza o, turner j, et al. autoimmune disorders and risk of non-hodgkin lymphoma subtypes: a pooled analysis within the interlymph consortium. blood 2008; 111:4029–38. doi: 10.1182/blood-2007-10-119974. 18. clarke ca, morton lm, lynch c, pfeiffer rm, hail ec, gibson tm, et al. risk of lymphoma subtypes after solid organ transplantation in the united states. br j cancer 2013; 109:280–8. doi: 10.1038/bjc.2013.294. 19. morton lm, sampson jn, cerhan jr, turner jj, vajdic cm, wang ss, et al. rationale and design of the international lymphoma epidemiology consortium (interlymph) nonhodgkin lymphoma subtypes project. j natl cancer inst monogr 2014; 2014:1–14. doi: 10.1093/jncimonographs/lgu005. 20. a predictive model for aggressive non-hodgkin’s lymphoma: the international non-hodgkin’s lymphoma prognostic factors project. n engl j med 1993; 329:987–94. doi: 10.1056/ nejm199309303291402. 21. alizadeh aa, eisen mb, davis re, ma c, lossos is, rosenwald a, et al. distinct types of diffuse large b-cell lymphoma identified by gene expression profiling. nature 2000; 403:503–11. doi: 10.1038/35000501. 22. haioun c, itti e, rahmouni a, brice p, rain jd, belhadj k, et al. [18f]fluoro-2-deoxy-d-glucose positron emission tomography (fdg-pet) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. blood 2005; 106:1376–81. doi: 10.1182/blood-2005-01-0272. 23. cheson bd. role of functional imaging in the management of lymphoma. j clin oncol 2011; 29:1844–54. doi: 10.1200/ jco.2010.32.5225. 24. devita jr vt, chu e. a history of cancer chemotherapy. cancer res 2008; 68:8643–53. doi: 10.1158/0008-5472.can-07-6611. 25. devita vt jr, canellos gp, chabner b, schein p, hubbard sp, young rc. advanced diffuse histiocytic lymphoma, a potentially curable disease. lancet 1975; 305:248–50. doi: 10.1016/s0140-6736(75)91142-3. 26. armitage jo. treatment of non-hodgkin’s lymphoma. n engl j med 1993; 328:1023–30. doi: 10.1056/nejm199304083281409. 27. fisher ri, gaynor er, dahlberg s, oken mm, grogan tm, mize em, et al. comparison of a standard regimen (chop) with three intensive chemotherapy regimens for advanced non-hodgkin’s lymphoma. n engl j med 1993; 328:1002–6. doi: 10.1056/nejm199304083281404. 28. pfreundschuh m, trümper l, kloess m, schmits r, feller ac, rudolph c, et al. two-weekly or 3-weekly chop chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal ldh) aggressive lymphomas: results of the nhl-b1 trial of the dshnhl. blood 2004; 104:626–33. doi: 10.1182/blood-2003-06-2094. 29. philip t, guglielmi c, hagenbeek a, somers r, van der lelie h, bron d, et al. autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-hodgkin’s lymphoma. n engl j med 1995; 333:1540–5. doi: 10.1056/nejm199512073332305. 30. maloney dg, grillo-lópez aj, white ca, bodkin d, schilder rj, neidhart ja, et al. idec-c2b8 (rituximab) anticd20 monoclonal antibody therapy in patients with relapsed low-grade non-hodgkin’s lymphoma. blood 1997; 90:2188–95. 31. coiffier b, lepage e, briere j, herbrecht r, tilly m, bouabdallah r, et al. chop chemotherapy plus rituximab compared with chop alone in elderly patients with diffuse large-b-cell lymphoma. n engl j med 2002; 346:235–42. doi: 10.1056/ nejmoa011795. http://dx.doi.org/10.3322/caac.20107 http://dx.doi.org/10.1016/s0950-3536%2896%2980046-1 http://dx.doi.org/10.1016/s0950-3536%2896%2980046-1 http://dx.doi.org/10.1080/10428190601059746 http://dx.doi.org/10.1080/10428190601059746 http://dx.doi.org/10.1007/978-3-642-80829-6_4 http://dx.doi.org/10.1002/1097-0142%28197410%2934:8%2b%3c1488::aid-cncr2820340822%3e3.0.co%3b2-c http://dx.doi.org/10.1002/1097-0142%28197410%2934:8%2b%3c1488::aid-cncr2820340822%3e3.0.co%3b2-c http://dx.doi.org/10.1016/s0140-6736%2888%2990367-4 http://dx.doi.org/10.1016/s0140-6736%2874%2991786-3 http://dx.doi.org/10.1016/s0140-6736%2874%2991786-3 http://dx.doi.org/10.1002/1097-0142%2819820515%2949:10%3c2112::aid-cncr2820491024%3e3.0.co%3b2-2 http://dx.doi.org/10.1002/1097-0142%2819820515%2949:10%3c2112::aid-cncr2820491024%3e3.0.co%3b2-2 http://dx.doi.org/10.1182/blood-2005-09-3679 http://dx.doi.org/10.1016/s1470-2045%2803%2900983-5 http://dx.doi.org/10.1016/s1470-2045%2803%2900983-5 http://dx.doi.org/10.1016/j.cgh.2008.02.011 http://dx.doi.org/10.1182/blood-2007-10-119974 http://dx.doi.org/10.1038/bjc.2013.294 http://dx.doi.org/10.1093/jncimonographs/lgu005 http://dx.doi.org/10.1056/nejm199309303291402 http://dx.doi.org/10.1056/nejm199309303291402 http://dx.doi.org/10.1038/35000501 http://dx.doi.org/10.1182/blood-2005-01-0272 http://dx.doi.org/10.1200/jco.2010.32.5225 http://dx.doi.org/10.1200/jco.2010.32.5225 http://dx.doi.org/10.1158/0008-5472.can-07-6611 http://dx.doi.org/10.1016/s0140-6736%2875%2991142-3 http://dx.doi.org/10.1056/nejm199304083281409 http://dx.doi.org/10.1056/nejm199304083281404 http://dx.doi.org/10.1182/blood-2003-06-2094 http://dx.doi.org/10.1056/nejm199512073332305 http://dx.doi.org/10.1056/nejmoa011795 http://dx.doi.org/10.1056/nejmoa011795 ritu lakhtakia and ikram burney medical history | e321 35. tees mt, sokol l. novel pharmacotherapies for b-cell lymphomas and leukemias. am j ther 2014; epub ahead of print. doi: 10.1097/mjt.0000000000000164. 36. wells hg. a modern utopia. london, uk: penguin modern classics, 2005. p.205. 32. gribben jg. how i treat indolent lymphoma. blood 2007; 109:4617–26. doi: 10.1182/blood-2006-10-041863. 33. salles g, seymour jf, offner f, lópez-guillermo a, belada d, xerri l, et al. rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (prima): a phase 3, randomised controlled trial. lancet 2011; 377:42–51. doi: 10.1016/s01406736(10)62175-7. 34. kewalramani t, zelenetz ad, nimer sd, portlock c, straus d, noy a, et al. rituximab and ice as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large b-cell lymphoma. blood 2004; 103:3684–8. doi: 10.1182/blood-2003-11-3911. http://dx.doi.org/10.1097/mjt.0000000000000164 http://dx.doi.org/10.1182/blood-2006-10-041863 http://dx.doi.org/10.1016/s0140-6736%2810%2962175-7 http://dx.doi.org/10.1016/s0140-6736%2810%2962175-7 http://dx.doi.org/10.1182/blood-2003-11-3911 squ med j, august 2011, vol. 11, iss. 3, pp. 412-414, epub. 15th aug 11 submitted 21st nov 10 revision req. 11th apr 11, revision recd. 5th may 11 accepted 24th may 11 deep dermal burns and full thickness burns are generally managed by excision and split thickness skin grafting. the skin graft has certain disadvantages. it may lead to unacceptable colour changes in certain skin types and be aesthetically unacceptable. also, there may be a contour defect and, furthermore, the graft is followed by varying degrees of contracture. the keystone design perforator island flap was first described by behan in 2003.1 since then, there have been number of articles on this flap. most of them reported its use to cover defects created after the excision of malignant lesions.2,3,4 we have used this flap to cover defects resulting from full thickness burns as the primary surgery instead of skin grafting. the use of this flap in certain areas like hands has a superior aesthetic result in term of colour and contour compared with a skin graft. in addition, contracture formation is reduced. the keystone sliding skin flap is made in the following manner. the defect is converted to an elliptical defect. a curvilinear incision is made parallel to the defect with two incisions at a 90 degree angle at either end of the defect which meet the curvilinear line. this results in a keystone design flap. the width of the flap is equal to the width of the defect. the length of the flap is determined by the size of the excisional defect. careful teasing of the circumferential tissues is performed without any flap undermining so as to preserve the integrity of perforators.1 we report here two cases with defects resulting from excision of full thickness burns which were covered with a keystone design sliding skin flap. case one a 28 year-old male sustained an accidental full thickness electrical burn of his hypothenar 1barka polyclinic, oman; 2department of plastic & reconstructive surgery, khoula hospital, muscat, oman. *corresponding author email: khallott@omantel.net.om t¯¬<ª<ì蜘àfi]<ìëç◊q<ì◊ëçâ<‹è€íi ‘ �€ �ä÷]<ì◊⁄^“<ï4«í÷]<—êü£]<       2003       :مفتاح الكلمات abstract: deep dermal burns and full thickness burns are generally managed by excision and split thickness skin grafting. the skin graft may lead to unacceptable colour changes and be aesthetically unacceptable. also, there may be a contour defect and, furthermore, it is followed by varying degrees of contracture. the keystone design sliding flap, first described in 2003, avoids the need for grafting and is not associated with any skin graft problems. we report two cases of the use of this flap as the primary surgery in reconstruction of small full thickness burn defects. keywords: burns; skin grafting; keystone flap; case report; oman keystone design sliding skin flap for the management of small full thickness burns azher a. al-busaidi,1 nirannanilathu semalesan,2 *said s. al-busaidi2 case report azher a. al-busaidi, nirannanilathu semalesan, said s. al-busaidi case report | 413 eminence [figure 1]. he underwent excision of the full thickness burnt skin. as the defect was small (about 1.5 x 1.5cm) and it was on the hand, a keystone design sliding skin flap was mobilised to cover the defect. the postoperative course was uneventful. on follow-up, the flap was settling well and the aesthetic result was good. case two a 19 year-old male sustained electrical burns when he was holding an iron rod which touched an electric wire [figure 2]. he had full thickness burns over the anteromedial aspect of his right forearm (about 2 x 4 cm in size) with ulnar nerve palsy. the patient was referred for surgery where the distal forearm burns were excised. the ulnar nerve was explored and found to be oedematous and was decompressed in the guyon’s canal. the defect was covered with a keystone design sliding skin flap. on subsequent follow-up, the keystone flap was settling well and the aesthetic result was good. the ulnar nerve completely recovered. discussion the keystone design sliding skin flap is very useful as it is easy and fast to raise. it minimises or abolishes the use of skin grafting and gives a better contour. also it can be raised in areas where other flaps are difficult to raise. the skin graft in omani patients (fitzpatrick scale types iv, v and vi)5 invariably becomes hyperpigmented and aesthetically unacceptable, especially if used on hands [figure 3]. furthermore, as skin grafts may result in contour defects and contractures, we started using the keystone design sliding skin flap cover as the primary surgery to cover the small full thickness burns after excision. the two cases described above had defects on the hand. covering these defects with a keystone flap resulted in a normal contour and normal skin figure 1: case one (a) the defect with marking for keystone flap; (b) after closure with keystone flap; (c) the appearance one day postoperative. figure 2: case two (a) full thickness burns; (b) defect after debridement; (c) planning of the flap; (d) after closure of the defect; (e) after 6 days; (f) after 3 months. keystone design sliding skin flap for the management of small full thickness burns 414 | squ medical journal, august 2011, volume 11, issue 3 colour which would not be possible with a skin graft. in both of the cases, it was easy to raise the flap. there was no flap loss and there were no complications. in both of the cases, we used a type i keystone flap. the keystone flap has been classified by behan into four types: type i: the keystone flap is a skin island based on subcutaneous perforators. the lateral deep fascia margin may be left intact; type ii: division of the deep fascia along the outer curvilinear line to obtain adequate advancement of the flap and facilitate closure. the donor site is either primarily closed [type iia] or skin grafted [type iib] if undue tension exists; type iii: this is used for larger defects, two identical opposing keystone flaps are mobilised; type iv: up to 50% of the flap can be undermined subfascially to maintain the perforator support in order to facilitate its rotation.1,6 the flap is sensate which gives it an advantage over the skin graft. it has a dual blood supply from the superficial vascular network and the perforators.6 also it was found that vascular perfusion is augmented in the keystone flaps. this phenomenon is still unexplained. one of the possible explanations is that as the sympathetic nerve is divided, catecholamines are released from the nerve terminal.7 as a result the keystone flap is very reliable. in reconstructive surgery, aesthetic appearance is not given much attention as the priority is to provide tissue cover, but the deformity always has a psychological impact on the patient. combining reconstructive surgery with an aesthetic approach when treating a tissue defect improves the final result and reduces the negative psychological impact. conclusion the use of the keystone flap type i for small full thickness burn defects results in normal colour and contour. it avoids the use of grafts that invariably become hyperpigmented and aesthetically unacceptable. the flap is sensate and this is a great advantage over the skin graft. another advantage over the graft is that there is no contracture formation. references 1. behan fc. the keystone design perforator island flap in reconstructive surgery. anz j surg 2003; 73:112– 20. 2. moncrieff md, bowen f, thompson jf, saw rp, shannon kf, spillone aj et al. keystone flap reconstruction of primary melanoma excision defects of the leg—the end of the skin graft? ann surg oncol 2008; 15:2867–73. 3. behan f, sizeland a, gilmour f, hui a, seel m, lo ch. use of the keystone island flap for advanced head and neck cancer in the elderly a principle of amelioration j plast reconstr aesthet surg 2009; 62:551-3. 4. pelissier p, gardet h, pinsolle v, casoli v, behan f. the keystone design perforator island flap. part ii: clinical applications. j plast reconstr aesthet surg 2007; 60:888–91. 5. fitzpatrick tb. soleil et peau. j med esthet 1975; 2:330–4. 6. pelissier p, santoul m, pinsolle v, casoli v, behan f. the keystone design perforator island flap. part i: anatomic study. j plast reconstr aesthet surg 2007; 60:883–7. 7. behan fc, lo ch, sizeland a. the interpretation of vascular changes observed in keystone island flaps: a hypothesis. j plast reconstr aesthet surg 2009; doi:10.1016/j.bjps.2009.02.063 figure 3: example of hyperpigmented skin graft. departments of 1neurosurgery and 3anaesthesia, intensive care unit & pain management, khoula hospital, muscat, oman; 2department of cardiac anaesthesia, royal hospital, muscat, oman; 4anaesthesia residency programme, oman medical speciality board, muscat, oman *corresponding author e-mail: nilay.chatt@gmail.com إستخدام طريقة غري باضعة ملراقبة النتاج القليب لتحسني ديناميكا الدم ملريض صمام مرتايل خضع جلراحة دماغية وعائية علي حماد املع�سني، نرياجنان واجي، نرياج �سالهوترا، �ساماريت�ص داز، ميالن �سوري، را�سد اأحمد ال�سهيمي، نيالي �ساترجي abstract: patients with mitral valve disease undergoing cerebrovascular surgery face increased inherent risks due to their associated cardiac comorbidities. as such, the anaesthetic management of such patients is distinctly challenging. simultaneous consideration of both the cerebrovascular and underlying cardiac conditions determines key anaesthetic issues, as fluids and vasopressors or inotropes need to be titrated according to haemodynamic variables in order to optimise cerebral blood flow without compromising cardiac function. we report a 45-yearold female patient with mild mitral stenosis and moderate-to-severe mitral regurgitation who presented to the khoula hospital, muscat, oman, in 2016 following a ruptured anterior communicating artery aneurysm requiring urgent surgical intervention. as highlighted in this case, the volumeview ev1000™ (edwards lifesciences, irvine, california, usa) system is a minimially invasive haemodynamic monitor that can help immensely in the perioperative management of such patients. keywords: anesthesia; cerebral aneurysm; mitral valve stenosis; mitral valve regurgitation; hemodynamics; cardiac output; case report; oman. امللخ�ص: مر�سى ال�سمام املرتايل الذين يخ�سعون جلراحة الدماغ الوعائية يكونون عر�سة خلطر متاأ�سل نتيجة عوامل املرا�سة القلبية امل�سرتكة. لذا، فاإن اإدارة التخدير لهوؤالء املر�سى ي�سكل حتديا وا�سحا. النظر يف وقت واحد حلالة الدماغ الوعائية والقلب يحدد ق�سايا التخدير االأ�سا�سية، الأن ال�سوائل وروافع التوتر الوعائي اأو موؤثرات التوتر الع�سلي حتتاج اإىل معايرة وفقا ملتغريات ديناميكا الدم من اأجل حت�سني الرتوية الدماغية دون التاأثري على وظيفة القلب. نعر�ص حالة مري�سة عمرها 45 عاما م�سابة بت�سيق ب�سيط يف ال�سمام املرتايل وقل�ص مرتايل معتدل اإىل �سديد تقدمت اإىل م�ست�سفى خولة، م�سقط، عمان، عام 2016، بعد متزق اأم الدم يف ال�رصيان املو�سل االأمامي والذي اأرفن، �ساين�ص، اليف )اأدوارد ev1000 احلجم عر�ص نظام جهاز يعترب احلالة، هذه يف مبني هو ما مثل عاجل. جراحي لتدخل تطلب باجلراحة املحيطة الفرتة اأثناء كثريا ي�ساعد والذي الدم ديناميكا ملراقبة با�سع غري جهاز االأمريكية( املتحدة الواليات كاليفورنيا، لهوؤالء املر�سى. الكلمات املفتاحية: التخدير؛ اأم الدم املخية؛ ت�سيق ال�سمام املرتايل؛ قل�ص ال�سمام املرتايل؛ ديناميكا الدم؛ النتاج القلبي؛ تقرير حالة؛ عمان. use of a minimally invasive cardiac output monitor to optimise haemodynamics in a patient with mitral valve disease undergoing cerebrovascular surgery ali m. al-mashani,1 niranjan d. waje,2 neeraj salhotra,1 samaresh das,3 neelam suri,3 rashid a. al-sheheimi,4 *nilay chatterjee3 sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e343–347, epub. 10 oct 17 submitted 24 dec 16 revisions req. 19 feb & 18 apr 17; revisions recd. 24 mar & 27 apr 17 accepted 18 may 17 case report doi: 10.18295/squmj.2017.17.03.015 subarachnoid haemorrhage secondary to a ruptured intracerebral aneurysm and the sub-sequent surgery for clipping of the aneurysm is associated with its own inherent risks.1 however, such intraoperative risks are increased when the patient also has valvular heart disease or an associated cardiac comorbidity. simultaneous consideration of both the cerebrovascular and cardiac conditions is particularly challenging for anaesthesiologists as key issues in the perioperative management of haemodynamic goals are contradictory at times and require precise and continuous monitoring of cardiac output and other related variables.1 the use of the volumeview ev1000™ (edwards lifesciences, irvine, california, usa) system in a neurosurgical setting has not yet been described in the literature. however, it may be a useful monitoring tool for goal-directed therapy in such cases. the volumeview ev1000™ (edwards lifesciences) system is a minimally invasive device that measures haemodynamic parameters and guides the use of fluids and vasopressors for patient-specific goaldirected therapy. it provides pulse contour analysis derived calibrated haemodynamic parameters—inclu ding stroke volume variation (svv), cardiac output and systemic vascular resistance (svr)—as well as use of a minimally invasive cardiac output monitor to optimise haemodynamics in a patient with mitral valve disease undergoing cerebrovascular surgery e344 | squ medical journal, august 2017, volume 17, issue 3 parameters for fluid responsiveness derived from a transpulmonary thermodilution algorithm, such as the global end-diastolic volume index (gedvi), extravascular lung water index (evlwi), pulmonary vascular permeability index (pvpi) and contractility (i.e. cardiac output, stroke volume, global ejection fraction and svr).2 the physiological parameters derived by the volumeview ev1000™ system (edwards lifesciences) help to determine the precise titration of fluid and vasopressors or inotropes; moreover, its accuracy is comparable to that of more invasive monitors.3 this case report describes the anaesthetic management of a patient with mitral valve disease who underwent a craniotomy for clipping of an anterior communicating artery aneurysm. the role of a minimally invasive cardiac output monitor in achieving targeted haemodynamic goals in such patients is highlighted. case report a 45-year-old woman presented to the khoula hospital, a tertiary care neurosurgical centre in muscat, oman, in 2016 with a sudden-onset, severe, holocranial headache of seven days’ duration. she had no history of vomiting, loss of consciousness or altered sensorium. however, she reported a history of shortness of breath on exertion (grade ii dyspnoea) over the previous four years. on examination, she was found to be conscious, cooperative and alert, with a glasgow coma scale score of 15, a heart rate of 65 beats/minute and a respiratory rate of 20 breaths/ minute. her blood pressure was 124/80 mmhg. a neurological examination was unremarkable and the headache symptoms were categorised as hunt and hess grade ii. a computed tomography (ct) scan revealed evidence of a subarachnoid haemorrhage (fisher grade ii) and an angiogram showed an anterior communicating artery aneurysm measuring 5.7 x 6.2 x 7.0 mm. the a1 segment of the right anterior cerebral artery showed evidence of vasospasm. transthoracic echocardiography revealed thickened calcific mitral valve leaflets with mild mitral stenosis (mitral valve area: 1.6 cm2), moderate-to-severe mitral regurgitation (vena contracta width: 0.5 cm; effective regurgitant orifice area: 0.4 cm2) with an eccentric jet hugging the posterior wall of the left atrium and an ejection fraction of 50% with adequate biventricular function. the pulmonary vein flow pattern on the contralateral side showed systolic blunting without reversal and the mitral regurgitation was graded as moderate-tosevere.4 all other haematological and biochemical investigations were within normal limits. an urgent craniotomy was planned to clip the aneurysm. in the operating room, standard monitoring equipment including electrocardiography, pulse oximetry and non-invasive blood pressure equipment was set up as per the recommendations of the american society of anesthesiologists.1 the baseline pre-induction blood pressure was 124/55 mmhg. since the patient had a high perioperative cardiac risk and a narrow therapeutic window for fluid administration, a volumeview ev1000™ (edwards lifesciences) arterial catheter with a temperature sensor was inserted in the right femoral artery and a triple lumen central venous catheter was placed in the right internal jugular vein while she was under sedation and local anaesthesia. subsequently, the volumeview ev1000™ (edwards lifesciences) cardiac output monitor was connected. following preoxygenation, general endotracheal anaesthesia was administered using propofol, fentanyl, sevoflurane and vecuronium. a decrease in blood pressure following induction was managed judiciously with various aliquots of ephedrine. the anaesthesia was maintained with airoxygen-isoflurane-propofol and supplemental doses of vecuronium-fentanyl, as required. the ventilation parameters were as follows: volume-guaranteed pressure-controlled ventilation, a peak inspiratory pressure of 20 cm, tidal volume of ~450 ml (for 8 ml/kg of ideal body weight) and a respiratory rate of 14 breaths/minute (for a partial pressure of carbon dioxide [co2] of 32–35 mmhg). intraoperatively, judicious fluid administration (including lactated ringers solution and 0.9% sodium chloride) and inotrope/vasopressor therapy were strictly guided by the physiological parameters derived by the volumeview ev1000™ (edwards lifesciences) system. the perioperative haemodynamic goals consisted of a low-to-normal svr index and an augmented cardiac output. the use of colloids was avoided entirely. optimum brain relaxation was achieved with 20% mannitol and controlled hyperventilation to maintain end-tidal co2 at 30–32 mmhg. systolic blood pressure was allowed to fall to 95 mmhg immediately before the clipping of the aneurysm. a temporary clip application to the feeding arteries of the aneurysm was not required during the surgery. following the application of a permanent clip, blood pressure was augmented for a target mean arterial pressure (map) of 110 mmhg as the maximum upper limit using titrated doses of a noradrenaline infusion. however, this was associated with a significant fall in cardiac output, an increase in svr index, a simultaneous drop in oxygen saturation (from 100% to 91%) with a rise in ali m. al-mashani, niranjan d. waje, neeraj salhotra, samaresh das, neelam suri, rashid a. al-sheheimi and nilay chatterjee case report | e345 the augmentation of arterial blood pressure during temporary clip application to curtail the impact of ischaemia in regions of the brain located upstream to the clamped artery and the suppression of cerebral metabolism with titrated doses of propofol or other volatile anaesthetic agents. finally, the arterial blood pressure should be raised (systolic blood pressure: 160–200 mmhg; map: >100 mmhg) following permanent clip application, thereby preventing ischaemia in vasospastic segments.6,7 formerly, triple-h therapy (i.e. hypertension, hypervolaemia and haemodilution) was a popular technique for managing vasospasm and related complications; however, hypervolaemia and haemodilution have since fallen out of favour due to their inherent complications, although induced hypertension (systolic blood pressure of 160–200 mmhg once the aneurysm is secured) is still routinely employed to ensure adequate cerebral blood flow.7 cardiac output monitoring is an important tool in goal-directed therapy for critically ill patients.3 while a pulmonary artery catheter was formerly the goldstandard monitoring approach, its use is associated with various complications and increased mortality; accordingly, it has been progressively replaced by less invasive monitoring techniques.8–10 a reliable cardiac output monitor, ideally a minimally invasive one, could be of immense use for monitoring patients with cardiac comorbidities undergoing cerebrovascular surgery. due to her pre-existing heart condition, the patient in the current case required precise monitoring of her left ventricular function. in addition, flow augmentation management had significant limitations due to the mild mitral stenosis and moderate-to-severe mitral regurgitation. moreover, increasing the svr with noradrenaline to achieve the target map adversely affected the cardiac output, regurgitant fraction and myocardial function because of the concomitant mitral regurgitation. peak airway pressure (from 19 to 24 cm) and increases in evlwi and gedvi [table 1]. at this point, low-dose dobutamine was administered at 5 μg/kg/minute to augment forward flow with concomitant titration of the noradrenaline infusion in order to attain an acceptable map.5 in this way, the patient’s blood pressure increased to 160/82 mmhg (mean: 108 mmhg). the svr index was relatively low after the induction of the anaesthesia, possibly due to anaesthesia-mediated vasodilation; the baseline svr index was 1,680 dynes.second/cm5, which fell to approximately 1,460 dynes.second/cm5 after induction and then 1,100–1,300 dynes.second/cm5 before the clipping of the aneurysm (normal range: 2,000–2,400 dynes.second/cm5). throughout the course of the surgery, any changes in the haemodynamic variables were continuously monitored, including heart rate, map, svv, cardiac output and svr index. the extubation of the patient and the postoperative course were uneventful. on the third postoperative day, a repeat ct scan was essentially normal, with evidence that the subarachnoid haemorrhage was resolving. there was no indication of a cerebral infarction following the surgery. discussion the presence of valvular cardiac disease increases the anaesthetic and perioperative risks of noncardiac surgery.1 there are three key haemodynamic targets in the perioperative management of a cerebral aneurysm. firstly, haemodynamic perturbations should be prevented when inducing anaesthesia and deliberate hyperventilation or hypocania should be avoided before the opening of the dura, as both of these circumstances may cause the aneurysm to rupture secondary to sudden changes in the transmural pressure gradient.6,7 secondly, cerebral perfusion pressure should be preserved, including table 1: haemodynamic parameters derived by a minimally invasive cardiac output monitor* during an aneurysm clipping surgery for a patient with mitral valve disease time point svv gedvi in ml/m2 evlwi in ml/kg pvpi co in l/ minute svri in dynes. second/cm5 immediately post-induction 22 690 9.2 2.3 4.8 1,460 immediately before clipping of the aneurysm 28 675 8.7 2.4 4.5 1,123 post-aneurysm clipping with noradrenaline infusion 17 790 14.2 3.3 2.8 3,460 post-aneurysm clipping with dobutamine and noradrenaline infusions 13 689 11.7 2.6 4.8 2,043 svv = stroke volume variation; gedvi = global end-diastolic volume index; evlwi = extravascular lung water index; pvpi = pulmonary vascular permeability index; co = cardiac output; svri = systemic vascular resistance index. *using the volumeview ev1000™ (edwards lifesciences, irvine, california, usa) system. use of a minimally invasive cardiac output monitor to optimise haemodynamics in a patient with mitral valve disease undergoing cerebrovascular surgery e346 | squ medical journal, august 2017, volume 17, issue 3 on the other hand, augmenting cardiac output using inotropes (i.e. dobutamine) could have potentially caused excessive tachycardia and worsened the transmitral pressure gradient and pulmonary congestion (due to increased evlwi).5 this could have led to a deterioration in oxygenation. arguably, common practices to augment cerebral blood flow in vasospastic areas without compromising myocardial function and oxygenation are not themselves free of complications.7 as the mitral stenosis was mild, it was hypothesised that the patient would be better able to tolerate a higher heart rate rather than increased svr. hence, the aim was to perfuse the patient so as to augment cardiac output without excessively increasing the afterload, thus maintaining a low-to-normal svr index and avoiding tachycardia for a target heart rate of 80–90 beats/minute. this was expected to maintain the forward flow and limit the transmitral pressure gradient, thus minimising the regurgitant volume (i.e. a lower evlwi, gedvi and svv). as such, a reliable monitoring tool was needed to achieve these haemodynamic targets without adversely affecting cardiac output, regurgitant fraction and myocardial function. transoesophageal echocardiography is another useful tool for the perioperative monitoring of cardiac output in neurosurgical patients.11 it has been validated in comparison to pulmonary artery catheters with a good outcome.12 however, transesophageal echocardiography requires a skilled operator and its use is limited by the cost and availability of the equipment. the volumeview ev1000™ (edwards lifesciences) system requires both central and arterial cannulation via the internal jugular and femoral artery, respectively. central venous pressure does not adequately reflect the preload status and is therefore unsuitable for predicting the ventricular response to fluid loading; the gedvi, a volumetric preload variable, more adequately reflects cardiac preload changes.13 a supranormal gedvi and evlwi indicates excessive fluid balance with pulmonary congestion, whereas a pvpi of >3 indicates increased pulmonary vascular permeability and thereby potentially differentiates cardiogenic oedema from acute respiratory distress syndrome.13,14 an evlwi of >10 is associated with increased morbidity and mortality.14 in the present patient, the use of a vasopressor to increase the map after clipping resulted in a significant fall in cardiac output, with a concomitant increase in volume parameters (i.e. gedvi and evlwi) which suggested an increase in the regurgitant fraction. this was instantly recognised by the cardiac output monitor, enabling prompt use of an inodilator to augment the forward flow. intraoperatively, due to the mild mitral stenosis and moderate-to-severe mitral regurgitation, the current patient required a comparatively high heart rate with a low-to-normal svr index to augment the forward flow. among the different options available to augment cerebral perfusion following clipping of the aneurysm, the continuous infusion of noradrenaline (a βand α-agonist) was the preferred choice over phenyl ephrine (a pure α-agonist). this was in view of the ability of noradrenaline to prevent the reflex bradycardia associated with a raised map.5 however, the physiological parameters worsened (i.e. increased svr index and evlwi with decreased cardiac output) following the augmentation of the map using a noradrenaline infusion alone. initiating titrated doses of dobutamine resulted in a further increase in heart rate with a drop in svr index. this was deemed appropriate in order to augment cerebral perfusion to the targeted level and was subsequently reflected in the physiological parameters (i.e. a decreased svr index and evlwi with increased cardiac output). the fall in the svr index probably resulted in a reduction in the regurgitant fraction of the mitral regurgitation and augmentation of the cardiac output following the dobutamine infusion. although temporary clipping was not necessary, dobutamine and noradrenaline infusions were titrated to achieve augmented perfusion as well as an appropriate map postoperatively. conclusion conflicting haemodynamic goals can complicate the anaesthetic management of patients with mitral valve diseases undergoing surgical clipping of a cerebral aneurysm. minimally invasive cardiac output monitoring devices, such as the volumeview ev1000™ (edwards lifesciences) system, are useful in such situations to aid in the accurate titration of fluids and inotropes/vasopressors according to myocardial performance, thus greatly enhancing patient safety while under anaesthesia. references 1. fleisher la, beckman ja, brown ka, calkins h, chaikof e, fleischmann ke, et al. acc/aha 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary a report of the american college of cardiology/american heart association task force on practice guidelines. circulation 2007; 116:1971–96. doi: 10.1161/circulationaha.107.185700. 2. kiefer n, hofer ck, marx g, geisen m, giraud r, siegenthaler n, et al. clinical validation of a new thermodilution system for the assessment of cardiac output and volumetric parameters. crit care 2012; 16:r98. doi: 10.1186/cc11366. https://doi.org/10.1161/circulationaha.107.185700 https://doi.org/10.1186/cc11366 ali m. al-mashani, niranjan d. waje, neeraj salhotra, samaresh das, neelam suri, rashid a. al-sheheimi and nilay chatterjee case report | e347 10. bendjelid k, marx g, kiefer n, simon tp, geisen m, hoeft a, et al. performance of a new pulse contour method for continuous cardiac output monitoring: validation in critically ill patients. br j anaesth 2013; 111:573–9. doi: 10.1093/bja/aet116. 11. chatterjee n, koshy t, misra s, suparna b. changes in left ventricular preload, afterload, and cardiac output in response to a single dose of mannitol in neurosurgical patients undergoing craniotomy: a transesophageal echocardiographic study. j neurosurg anesthesiol 2012; 24:25–9. doi: 10.1097/ ana.0b013e3182338b11. 12. perrino ac jr, harris sn, luther ma. intraoperative determination of cardiac output using multiplane transesophageal echocardiography: a comparison to thermodilution. anesthesiology 1998; 89:350–7. 13. marik pe, cavallazzi r. does the central venous pressure predict fluid responsiveness? an updated meta-analysis and a plea for some common sense. crit care med 2013; 41:1774–81. doi: 10.1097/ccm.0b013e31828a25fd. 14. jozwiak m, teboul jl, monnet x. extravascular lung water in critical care: recent advances and clinical applications. ann intensive care 2015; 5:38. doi: 10.1186/s13613-015-0081-9. 3. mehta y, arora d. newer methods of cardiac output monitoring. world j cardiol 2014; 6:1022–9. doi: 10.4330/wjc. v6.i9.1022. 4. lancellotti p, moura l, pierard la, agricola e, popescu ba, tribouilloy c, et al. european association of echocardiography recommendations for the assessment of valvular regurgitation: part 2 mitral and tricuspid regurgitation (native valve disease). eur j echocardiogr 2010; 11:307–32. doi: 10.1093/ejechocard/ jeq031. 5. overgaard cb, dzavík v. inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. circulation 2008; 118:1047–56. doi: 10.1161/circulationa ha.107.728840. 6. priebe hj. aneurysmal subarachnoid haemorrhage and the anaesthetist. br j anaesth 2007; 99:102–18. doi: 10.1093/bja/aem119. 7. pomg rp, lam am. anesthetic management of cerebral aneurysm surgery. in: cottrell je, young wl, eds. cottrell and young’s neuroanesthesia, 5th ed. philadelphia, pennsylvania, usa: mosby elsevier, 2010. pp. 218–46. 8. robin ed. death by pulmonary artery flow-directed catheter: time for a moratorium? chest 1987; 92:727–31. doi: 10.1378/ chest.92.4.727. 9. connors af jr, speroff t, dawson nv, thomas c, harrell fe jr, wagner d, et al. the effectiveness of right heart catheterization in the initial care of critically ill patients: support invest igators. jama 1996; 276:889–97. doi: 10.1001/jama.1996.0354 0110043030. https://doi.org/10.1093/bja/aet116 https://doi.org/10.1097/ana.0b013e3182338b11 https://doi.org/10.1097/ana.0b013e3182338b11 https://doi.org/10.1097/ccm.0b013e31828a25fd https://doi.org/10.1186/s13613-015-0081-9 https://doi.org/10.4330/wjc.v6.i9.1022 https://doi.org/10.4330/wjc.v6.i9.1022 https://doi.org/10.1093/ejechocard/jeq031 https://doi.org/10.1093/ejechocard/jeq031 https://doi.org/10.1161/circulationaha.107.728840 https://doi.org/10.1161/circulationaha.107.728840 https://doi.org/10.1093/bja/aem119 https://doi.org/10.1378/chest.92.4.727 https://doi.org/10.1378/chest.92.4.727 https://doi.org/10.1001/jama.1996.03540110043030 https://doi.org/10.1001/jama.1996.03540110043030 1department of medicine, college of medicine, hawler medical university, erbil, iraq; 2department of clinical haematology, nanakaly hospital for blood diseases & oncology, erbil, iraq e-mail: mah_kawa@yahoo.com اجلوانب السريرية )اإلكلينيكية(، حتليل النمط املناعي الظاهري ومعدل البقاء على قيد احلياة ملرضى سرطان الدم الليمفاوي املزمن يف مدينة أربيل، العراق كاوه حممدامني ح�شن abstract: objectives: chronic lymphocytic leukaemia (cll) is characterised by an accumulation of clonal b cells in the blood, bone marrow and lymphatic tissue. this study aimed to evaluate the clinical and immunophenotypic characteristics and survival rate of cll patients. methods: this retrospective study was conducted at the nanakaly hospital for blood diseases & oncology in erbil, iraq, between january 2011 and december 2017. a total of 105 cll patients were assessed to determine clinical presentation and staging, immunophenotype and survival rate. results: the median age of the patients was 65 years and 63.8% were male. the main clinical presentations were splenomegaly (64.8%), pallor (61.9%) and lymphadenopathy (60%). more than half of the patients presented at an advanced clinical stage according to the rai and binet staging systems (59.1% and 55.2%, respectively). all cll cases expressed both cluster of differentiation (cd)19 and cd5, 67.6% had monoclonal kappa light chains and 21% expressed cd38. the five-year overall survival (os) rate was 61.3%. the mean duration of five-year survival was 41.3 months (95% confidence interval: 36.4–46.3 months). there were no correlations between survival and sociodemographic, clinical or laboratory characteristics. conclusion: in comparison to the existing western literature, iraqi cll patients more frequently presented with hepatosplenomegaly and at a more advanced clinical stage. in addition, the five-year os rate was much lower. keywords: lymphoproliferative disorders; chronic lymphocytic leukemia; immunophenotyping; survival rates; iraq. هدفت الليمفاوي. والن�شيج العظام ونخاع الدم يف الن�شيلة ب خاليا برتاكم املزمن الليمفاوي الدم �رصطان يتميز الهدف: امللخ�ص: هذه الدرا�شة ايل تقييم اخل�شائ�س ال�رصيرية و النمط املناعي الظاهري ومعدل البقاء على قيد احلياة للمر�شى امل�شابني ب�رصطان الدم الليمفاوي املزمن. الطريقة: اأجريت هذه الدرا�شة الأ�شرتجاعية يف م�شت�شفى ناناكايل لأمرا�س الدم والأورام يف اأربيل، العراق، بني يناير 2011 ودي�شمرب 2017. مت تقييم ما جمموعه 105 م�شابا مبر�س �رصطان الدم الليمفاوي املزمن لتحديد العر�س ال�رصيري و مرحلة املر�س وكانت الذكور. من بينهم 63.8% �شنة املر�شى 65 عمر متو�شط كان احلياة. النتائج: قيد على البقاء ومعدل الظاهري املناعي النمط و العالمات ال�رصيرية الرئي�شية عبارة عن ت�شخم الطحال )%64.8(، �شحوب )%61.9( واعتالل العقد اللمفاوية )%60(. كان اأكرث من ن�شف املر�شى يف مرحلة �رصيرية متقدمة وفقا جلداول راي وبينيت )%59.1 و %55.2 على التوايل(. اأظهر حتليل النمط املناعي الظاهري جلميع املر�شى كال من جمموعة التمايز 19 و 5، بينما اأظهر %67.6 من املر�شى �شال�شل كابا اخلفيفة وحيدة الن�شيلة و %21 منهم كان لديهم جمموعة التمايز 38. وكان املعدل العام للبقاء على قيد احلياة ملدة خم�س �شنوات هو %61.3. وكان متو�شط مدة البقاء على قيد احلياة 36.4–46.3 اأ�شهر(. مل تكن هناك ارتباط بني معدل البقاء على قيد احلياة وال�شفات ملدة خم�س �شنوات 41.3 �شهرا )فا�شل الثقة 95%: الجتماعية والدميوغرافية وال�رصيرية واملخربية للمر�شى. اخلال�صة: باملقارنة مع املطبوعات الغربية احلالية، فاإن مر�شى �رصطان الدم الليمفاوي املزمن العراقيني لديهم بن�شبة اكرث من ت�شخم الطحال والكبد ويتم ت�شخي�شهم يف مرحلة �رصيرية اأكرث تقدًما. بالإ�شافة اإىل ذلك، كان معدل البقاء على قيد احلياة ملدة خم�س �شنوات فيهم اأقل بكثري. الكلمات املفتاحية: ال�شطرابات التكاثرية الليمفاوية؛ �رصطان الدم الليمفاوي املزمن؛ النمط املناعي الظاهري؛ معدلت البقاء على قيد احلياة؛ العراق. clinical aspects, immunophenotypic analysis and survival rate of chronic lymphocytic leukaemia patients in erbil city, iraq kawa m. hasan1,2 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e461–467, epub. 28 mar 19 submitted 18 jul 18 revision req. 3 sep 18; revision recd. 27 sep 18 accepted 18 oct 18 doi: 10.18295/squmj.2018.18.04.006 advances in knowledge this study provides the clinical and immunophenotypic findings and the survival rate of chronic lymphocytic leukaemia (cll) patients in erbil city, iraq. the current sample of cll patients more frequently presented with hepatosplenomegaly, although less frequently with lymphadenopathy, compared to populations reported from western countries. in addition, the iraqi patients tended to present at a more advanced clinical stage and had lower survival rates than western patients. application to patient care the current results highlight the importance of implementing more advanced work-up tools for iraqi cll patients, such as a thorough cytogenetic evaluation. clinical aspects, immunophenotypic analysis and survival rate of chronic lymphocytic leukaemia patients in erbil city, iraq e462 | squ medical journal, november 2018, volume 18, issue 4 chronic lymphocytic leukaemia (cll) is the most common type of leukaemia among adults in western countries; however, it is relat ively rare in asia.1,2 it is characterised by the build-up of lymphocytes in the blood, bone marrow and lymphatic tissue. the median age at diagnosis ranges from 67–72 years and the condition is more common in males.1,2 the clinical course of cll is highly variable, ranging from no symptoms to the rapid development of features of high-risk disease.3 lymph node swelling is the most common presenting feature of cll, although fever, night sweats and weight loss are sometimes seen. the most common physical findings are lymphadenopathy, splen omegaly and, less frequently, hepatomegaly.3 a diagnosis of cll can be established via a complete blood count (cbc) showing the progressive accumulation of clonal b cells (>5,000 b lymphocytes/ml) over a period of at least three months and an immunophenotypic study demonstrating clonal lymphocytes expressing b cell mar kers and cluster of differentiation (cd)5.4 both the mod ified rai and binet clinical staging systems are widely used to classify cll patients into different prognostic groups according to the extent of lymph node involvement, enlargement of the liver and/or spleen and blood findings (i.e. anaemia and thrombocytopaenia).5,6 the median survival rate for patients with cll ranges from 18 months to more than 10 years, depending on prognostic factors like age, gender, disease stage, performance status, lymphocyte doubling time, absolute lymphocyte count (alc) and β-2 microglobulin serum levels.7 furthermore, the expression of certain biological markers such as cd38 or cd49d, deletion of chromo some 17p13 and the mutation status of the immunoglobulin heavy-chain variable region, tumour protein 53 (tp53), notch homolog 1, splicing factor-3b subunit-1 (sf3b1), baculoviral inhibitor of apoptosis protein-1 repeat-containing protein-3 (birc3), myeloid different iation primary response 88 and zeta chain t cell receptor associated protein kinase-70 (zap70) genes also have a prognostic impact.8 the current study aimed to assess and compare the clinical characteristics, immunopheno typic findings and survival rate of cll patients in erbil, iraq, with previously reported international and regional data. methods this retrospective study was carried out between january 2011 and december 2017 at the nanakaly hospital for blood diseases & oncology, a regional referral hospital for adult and paediatric patients with benign and malig nant haematology and solid oncology disorders in erbil, iraq. all patients attending the hospital during the study period and diagnosed with cll as confirmed by cbc and immunophenotyping were invited to participate in the study. the main clinical presentation and characteristics of each patient was documented, including the presence of lymphadenopathy, pallor, hepatomegaly and spleno megaly. in addition, the patients underwent a cbc and immunophenotyping study by flow cytometry using a facscanto ii flow cytometer device (bd biosciences, san jose, california, usa) and/or immunohistochemistry. the laboratory analysis included a reticulocyte count, erythrocyte sedimentation rate, direct antiglobulin test (dat), bone marrow examination, serology tests (i.e. to determine lactate dehydrogenase [ldh] levels) and liver and renal function tests. in indicated cases, patients also underwent various imaging studies, including ultra sonography of the abdomen, a chest x-ray and computed tomography. in each case, clinical stage was determined table 1: baseline characteristics of chronic lymphocytic leukaemia patients in erbil, iraq (n = 105) characteristic n (%) age in years <50 10 (9.5) 50–59 21 (20) 60–69 40 (38.1) ≥70 34 (32.4) gender male 67 (63.8) female 38 (36.2) clinical presentation* splenomegaly† 68 (64.8) pallor 65 (61.9) peripheral lymphadenopathy 63 (60) hepatomegaly 23 (21.9) rai clinical stage 0 14 (13.3) i 9 (8.6) ii 20 (19) iii 19 (18.1) iv 43 (41) binet clinical stage a 29 (27.6) b 18 (17.1) c 58 (55.2) *percentages do not add up to 100% as some patients may have had more than one clinical presentation. †for patients with splenomegaly, the mean longitudinal axis of the spleen was 14.7 ± 3.4 cm. kawa m. hasan clinical and basic research | e463 according to both the rai and binet staging systems.5,6 survival rates were calculated, including the overall survival (os) rate over the study period and the fiveyear os rate. data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). a chi-squared test was used to compare associations between proportions. kaplanmeier survival curves were plotted and the log-rank mantel-cox test was used to compare mean survival times. a p value of ≤0.050 was considered statistically significant. this study was approved by the scientific and ethical committees of the college of medicine, hawler medical university, erbil. results a total of 143 cll patients attended the hospital during the study period. however, 38 patients were excluded due to a lack of adequate data or follow-up. as such, figure 1: immunophenotypic findings of chronic lymphocytic leukaemia patients in erbil, iraq (n = 105). cd = cluster of differentiation; bcl2 = b cell lymphoma 2; fmc7 = flinder medical centre-7. table 2: laboratory results of chronic lymphocytic leukaemia patients in erbil, iraq (n = 105) investigation mean ± sd median range normal range haemoglobin in g/dl 10.6 ± 2.3 11 5–15.4 13.5–17.5/11.5–15.5* whole blood count × 109/l 94.8 ± 106.6 65 8.9–491 4–11 absolute lymphocyte count × 109/l 87 ± 104.5 58.5 6–462.5 1–4.8 absolute neutrophil count × 109/l 6.7 ± 5.7 6 0.2–54 1.8–7.7 platelet count × 109/l 140 ± 74.2 115 30–382 150–400 reticulocytes, % 2.1 ± 2.0 1.7 0.1–10 0.5–1.5 erythrocyte sedimentation rate in mm/hour 44.3 ± 33.3 37 2–145 0–10/3–15* lactate dehydrogenase in u/l 400.1 ± 159.9 378 108–905 100–250 aspartate aminotransferase in u/l 24 ± 10.9 22 8.9–99 8–48 alanine transaminase in u/l 18.1 ± 9.9 17 4–50.3 7–55 blood urea in mg/dl 44.2 ± 21.3 41 16.3–160 15–40 serum creatinine in mg/dl 1 ± 0.4 1 0.3–3 0.7–1.3 sd = standard deviation. *males/females. table 3: treatment provided to chronic lymphocytic leukaemia patients in erbil, iraq (n = 105) treatment* n (%) fcr 24 (22.9) br 19 (18.1) fc 2 (1.9) chlorambucil 9 (8.6) chlorambucil plus prednisolone 10 (9.5) rituximab and chlorambucil 10 (9.5) cop 4 (3.8) rituximab and cop 5 (4.8) rituximab and chop 7 (6.7) rituximab 2 (1.9) no treatment 17 (16.2) fcr = fludarabine, cyclophosphamide and rituximab; br = bendamustine plus rituximab; fc = fludarabine plus cyclophosphamide; cop = cyclo phosphamide, oncovin and prednisolone; chop =cyclophosphamide, hydro xydaunomycin, oncovin and prednisolone. *percentages do not add up to 100% as four patients were treated with more than one protocol. clinical aspects, immunophenotypic analysis and survival rate of chronic lymphocytic leukaemia patients in erbil city, iraq e464 | squ medical journal, november 2018, volume 18, issue 4 105 patients were included in the final analysis. of these, 67 (63.8%) were male and 38 (36.2%) were female. the mean age at presentation was 63.3 ± 10.7 years. most patients (70.5%) were ≥60 years, with only 9.5% <50 years. the age at diagnosis ranged from 28–81 years old, with a median of 65 years. the main clinical presentations were splenomegaly (64.8%) pallor (61.9%) and lymphadenopathy (60%). hepatomegaly was observed in 21.9% of patients. modified rai staging showed a high risk (stage iii or iv) of cll in 59.1%, an intermediate risk (stage i or ii) in 27.6% and a low risk (stage 0) in 13.3% of patients. in terms of binet staging, 55.2% of patients were stage c, 17.1% were stage b and 27.6% were stage a [table 1]. most patients (72.4%) were from erbil and other cities in the kurdistan region of iraq, while the rest were from other northern and western iraqi cities. the mean haemoglobin level was 10.6 ± 2.3 g/dl (range: 5–15.4 g/dl). mean platelet and white blood cell counts were 140 ± 74.2 × 109/l (range: 30–382 × 109/l) and 94.8 ± 106.6 × 109/l (range: 8.9–491 × 109/l), respectively. the mean alc was 87 ± 104.5 × 109/l (range: 6–462.5 × 109/l) [table 2]. overall, ldh levels were elevated in 82.8% of patients and 11.4% had autoimmune haemolytic anaemia (aiha) with positive dat results. anaemia was observed in 83 (79.1%) patients, comprising 83.6% and 71.1% of male and female patients, respectively. a total of 63 (60%) and 28 (26.7%) patients presented with thrombocytopaenia and incidental lymph ocytosis, respectively. none of the patients had richter’s syndrome. all patients underwent immunophenotyping an alysis via flow cytometry and/or immunohistochemistry from either peripheral blood (79.1%) or bone marrow (21%) samples. all cases expressed both cd19 and cd5, while the vast majority expressed cd23 (94.3%), cd45 (84.8%) and b cell lymphoma 2 (82.9%). about twothirds of the patients (67.6%) expressed monoclonal kappa light chains, while just under one-third (32.4%) expressed lambda chains. only 21% of cases expressed cd38 [figure 1]. in terms of treatment, most patients received either fludarabine, cyclophosphamide and rituximab (22.9%) or bendamustine plus rituximab (18.1%). the rest underwent various other chemotherapy protocols (46.7%) or did not receive any treatment at all (16.2%) [table 3]. the mean follow-up period was 27.7 months. a total of 34 (32.4%) patients died during the study period, of which 24 (70.6%) were male and 10 (29.4%) were female, resulting in an os rate of 67.6%. although survival was greater among those aged 50–59 years (90.5% versus 60–62.5% in other age groups) and among females (73.7% versus 64.2% in males), these differences were not statistically significant (p = 0.098 and 0.163, table 4: correlation between survival rate and selected characteristics among chronic lymphocytic leukaemia patients in erbil, iraq (n = 105) characteristic n (%) p value survived (n = 71) died (n = 34) age in years <50 6 (60) 4 (40) 0.098 50–59 19 (90.5) 2 (9.5) 60–69 25 (62.5) 15 (37.5) ≥70 21 (61.8) 13 (38.2) gender male 43 (64.2) 24 (35.8) 0.163 female 28 (73.7) 10 (26.3) lymphadenopathy yes 41 (65.1) 22 (34.9) 0.496 no 30 (71.4) 12 (28.6) splenomegaly yes 46 (67.6) 22 (32.4) 0.993 no 25 (67.6) 12 (32.4) hepatomegaly yes 14 (60.9) 9 (39.1) 0.434 no 57 (69.5) 25 (30.5) rai clinical stage 0 12 (85.7) 2 (14.3) 0.190 i 4 (44.4) 5 (55.6) ii 15 (75) 5 (25) iii 14 (73.7) 5 (26.3) iv 26 (60.5) 17 (39.5) binet clinical stage a 21 (72.4) 8 (27.6) 0.648b 13 (72.2) 5 (27.8) c 37 (63.8) 21 (36.2) hb level in g/dl ≤11 54 (65.9) 28 (34.1) 0.465 >11 17 (73.9) 6 (26.1) wbc × 109/l <65 37 (69.8) 16 (30.2) 0.628 ≥65 34 (65.4) 18 (34.6) platelet count × 109/l <150 44 (69.8) 19 (30.2) 0.551 ≥150 27 (64.3) 15 (35.7) ldh in u/l <250 17 (81) 4 (19) 0.144 ≥250 54 (64.3) 30 (35.7) hb = haemoglobin; wbc = white blood cells; ldh = lactate dehydrogenase. kawa m. hasan clinical and basic research | e465 respectively). other clinical and laboratory characteristics were also not significantly correlated with survival (p >0.050 each) [table 4]. the five-year os rate was 61.3%. the mean duration of five-year survival was 60 months (95% confidence interval: 36.4–46.3 months); however, the median survival could not be estimated and could have occurred beyond the study period. the mean duration of survival was longer among females and those aged 50–59 years old; however, these differences were not statistically significant (p = 0.185 and 0.163, respectively) [figure 2]. discussion in the current study, the median age at diagnosis of cll patients in erbil, iraq, was similar to that reported in neighbouring countries such as iran and turkey (65 years versus 60.73 and 64 years, respectively).2,9 in contrast, the median age at diagnosis in western countries is much higher, ranging from 67–72 years old.1,10,11 however, the frequency of male cll patients in the current study was identical to that reported in italy (64%).12 in terms of clinical presentation, splenomegaly (64.8% versus 54%) and hepatomegaly (21.9% versus 14%) were reported more frequently in the current study compared to western patients, while lymphadenopathy was less frequent (60% versus 87%).3 in turkey, rates of splenomegaly, hepatomegaly and lymphadenopathy differed at 55.4%, 54.6% and 79.2%, respectively.9 in iran, payandeh et al. also reported varying rates of organomegaly (34%) and lymphadenopathy (38.7%).2 the diversity of clinical presentations in cll and correlations with ethnicity have been well documented in previous research.13 the incidence of anaemia and aiha in the current study (78.1% and 11%, respectively) was comp arable to that reported in previous research in which aiha was documented in up to 11% of late-stage cll patients, with positive dat results seen in up to 15% of patients.14 in the present study, 60% of patients had thrombocytopaenia; this finding is understandable given that most patients presented at an advanced clinical stage, such as rai stage iii or iv (59.1%) or binet stage c (55.2%). according to data from other developing countries such as iran, turkey and india, patients in this region are often first seen at more advanced stages (38.5%, 33.3% and 41%, respectively).2,15,16 however, in developed countries, only 10–20% of patients present at an advanced stage.17 these findings may indicate that routine cbc analysis is less frequently performed in developing countries or that hospitals in this region lack proper evaluation and management protocols or experience delays in the referral of patients with incidental lymphocytosis. it is also possible that there is a difference in the biology of the disease (e.g. in terms of such patients having a less mutated subtype of cll).4 in the present study, most cases expressed cd19, cd5 and cd23, with cd79b less frequently expressed; these findings are consistent with the characteristic profile of cll disease.18 for those patients not expressing cd23—considered atypical cll cases—other markers could help to differentiate cll from mantle cell lymph oma, such as the negative expression of flinder medical figure 2: kaplan-meier survival curves showing (a) fiveyear overall survival (os), (b) five-year os by age group (p = 0.185) and (c) five-year os by gender (p = 0.163) among chronic lymphocytic leukaemia patients in erbil, iraq (n = 105). clinical aspects, immunophenotypic analysis and survival rate of chronic lymphocytic leukaemia patients in erbil city, iraq e466 | squ medical journal, november 2018, volume 18, issue 4 centre-7.19 overall, cd38 expression at any level is regarded as a poor prognostic indicator; it was expressed in 21% of cases in the present study, which is comparable to the findings of hojjat farsangi et al. (27.6%).20 in the current study, 67.6% of patients had monoclonal kappa light chains, with 32.4% expressing lambda chains. hojjat fersangi et al. reported rates of expression of kappa and lambda chains to be 71.3% and 28.7%, respectively, among iranian cll patients.20 stamatopoulos et al. also reported similar findings in greece.21 the os (67.6%) in the current study was comparable to data reported from iran (64%), although the five-year os rate (61.3%) was higher than results from turkey (36.5%) and india (51%).2,22,23 however, data from germany and the usa indicate much higher five-year relative survival rates (80.2% and 82.4%, respectively).24 the mean duration of five-year survival in the current study was 41.3 months, which is similar to data reported from iran (38.5 months).2 this may be related to variations in a number of patient-related characteristics, such as clinical stage at diagnosis. the reason why the five-year os rate in the present study was lower than the overall os is likely because patients whom were more recently diagnosed (i.e. in 2015–2017) had not yet received their five-year follow-up at the time of the analysis. early diagnosis plays a major role in improving survival in cll patients.25 other possible causes for low five-year os rates are the lack of availability of equipment to conduct thorough cytogenetic evaluations for factors known to have a prognostic impact—such as deletions of chromosomes 11q, 13q, 17p and trisomy 12 as well as tp53, notch1, sf3b1 and birc3 gene mutations.8 in addition, insufficient access to adequate or novel chemotherapy agents like obinutuzumab, ibru tinib, idelalisib and venetoclax as a frontline treatment or for relapsed/refractory cases may negatively affect survival.26 no significant correlations were noted between survival rates and selected sociodemographic, clinical or laboratory characteristics in the present study. these findings partially agree with those previously reported by shvidel et al.; however, they contradict de faria et al.’s study.27,28 the difference between these findings is probably due to variations in sample size, the lack of genetic assessment conducted in the current study and the well-known impact of ethnicity.13 in addition, data regarding cd49d and zap70 expression, which have a major prognostic impact on cll patients, were not available.8 further research is therefore recommended to evaluate these factors. conclusion the median age, male-to-female ratio and clinical and immunophenotypic characteristics of iraqi cll patients in the current study did not differ greatly from previous regional and international data; however, patients more frequently presented at an advanced stage and had a lower five-year os rate compared to western populations. in addition, iraqi patients more frequently presented with organomegaly, including hepatomegaly, although less frequently with lymphadenopathy. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. watson l, wyld p, catovsky d. disease burden of chronic lymph ocytic leukaemia within the european union. eur j haematol 2008; 81:253–8. https://doi.org/10.1111/j.1600-0609.2008.01114.x. 2. payandeh m, sadeghi e, sadeghi m. survival and clinical aspects for patients with chronic lymphocytic leukemia in ker manshah, iran. asian pac j cancer prev 2015; 16:7987–90. https://doi.org/10.7314/apjcp.2015.16.17.7987. 3. abbott bl. chronic lymphocytic leukemia: recent advances in diagnosis and treatment. oncologist 2006; 11:21–30. https://doi. org/10.1634/theoncologist.11-1-21. 4. hallek m. chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. am j hematol 2017; 92:946–65. https://doi.org/10.1002/ajh.24826. 5. rai kr, sawitsky a, cronkite ep, chanana ad, levy rn, pasternack bs. clinical staging of chronic lymphocytic leukemia. blood 1975; 46:219–34. 6. binet jl, auquier a, dighiero g, chastang c, piguet h, goasguen j, et al. a new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. cancer 1981; 48:198–206. https://doi.org/10.1002/1 097-0142(19810701)48:1<198:: aid-c n c r2820480131> 3.0.co;2-v. 7. wierda wg, o’brien s, wang x, faderl s, ferrajoli a, do ka, et al. characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. j clin oncol 2009; 27:1637–43. https://doi.org/10.1 200/jco.2008.18.1701. 8. puente xs, pinyol m, quesada v, conde l, ordóñez gr, villamor n, et al. whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. nature 2011; 475:101–5. https://doi.org/10.1038/nature10113. 9. üsküdar teke h, üsküdar cansu d, akay om, gündüz e, bal c, gülbaş z. clinico-hematological evaluation of 13 chronic lymph ocytic leukemia patients in the central anatolia region in turkey. turk klin tip bilimleri dergisi 2009; 29:64–9. 10. eichhorst b, robak t, montserrat e, ghia p, hillmen p, hallek m, et al. chronic lymphocytic leukaemia: esmo clinical practice guidelines for diagnosis, treatment and follow-up. ann oncol 2015; 26:v78–84. https://doi.org/10.1093/annonc/mdv303. kawa m. hasan clinical and basic research | e467 11. mulligan sp, tam cs. chronic lymphocytic leukemia: diagnosis and clinical staging. in: keating mj, tam cs, eds. advances in the treatment of b-cell chronic lymphocytic leukemia. london, uk: future medicine ltd., 2012. pp. 6–15. https://doi. org/10.2217/9781780840444. 12. molica s. sex differences in incidence and outcome of chronic lymphocytic leukemia patients. leuk lymphoma 2006; 47:1477–80. https://doi.org/10.1080/10428190600555819. 13. nabhan c, ascherbrook-kilfoy b, chiu bc, smith sm, shanafelt td, evens am, et al. the impact of race, ethnicity, age and sex on clinical outcome in chronic lymphocytic leukemia: a comprehensive surveillance, epidemiology, and end results analysis in the modern era. leuk lymphoma 2014; 55:2778–84. https://doi.org/10.3109/10428194.2014.898758. 14. diehl lf, ketchum lh. autoimmune disease and chronic lymphocytic leukemia: autoimmune anemia, pure red cell aplasia, and autoimmune thrombocytopenia. semin oncol 1998; 25:80–97. 15. tombak a, tiftik n, dogu mh, sari i, akay mo, karagulle m, et al. the clinical characteristics and therapeutic outcomes of elderly patients with chronic lymphocytic leukemia: a retrospective multicenter study. blood 2014; 124:5644. 16. gogia a, sharma a, raina v, kumar l, vishnubhatla s, gupta r, et al. assessment of 285 cases of chronic lymphocytic leukemia seen at single large tertiary center in northern india. leuk lymphoma 2012; 53:1961–5. https://doi.org/10.3109/1042819 4.2012.672734. 17. delgado j, santacruz r, baumann t, montserrat e. new developments in chronic lymphocytic leukaemia diagnosis. eur oncol haematol 2013; 9:114–18. https://doi.org/10.17925/eo h.2013.09.2.114. 18. rodrigues ca, gonçalves mv, ikoma mr, lorand-metze i, pereira ad, farias dl, et al. diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the brazilian group of chronic lymphocytic leukemia. rev bras hematol hemoter 2016; 38:346–57. https://doi.org/10.1016/j.bjhh.2016.07.004. 19. delgado j, matutes e, morilla am, morilla rm, owusuankomah ka, rafiq-mohammed f, et al. diagnostic significance of cd20 and fmc7 expression in b-cell disorders. am j clin pathol 2003; 120:754–59. https://doi.org/10.1309/fngcyemj-e3ma-e5l2. 20. hojjat farsangi m, jeddi-tehrani m, razavi sm, sharifian ra, shamsian khoramabadi a, rabbani h, et al. immunophenotypic characterization of the leukemic b-cells from iranian patients with chronic lymphocytic leukemia: association between cd38 expression and disease progression. iran j immunol 2008; 5:25–35. 21. stamatopoulos k, belessi c, hadzidimitriou a, smilevska t, kalagiakou e, hatzi k, et al. immunoglobulin light chain repertoire in chronic lymphocytic leukemia. blood 2005; 106:3575–83. https://doi.org/10.1182/blood-2005-04-1511. 22. pamuk on, pamuk ge, soysal t, ongören s, başlar z, ferhanoğlu b, et al. chronic lymphocytic leukemia in turkey: experience of a single center in istanbul. south med j 2004; 97:240–5. https://doi.org/10.1097/01.smj.0000053674.03385.b7. 23. gogia a, raina v, gupta r, gajendra s, kumar l, sharma a, et al. prognostic and predictive significance of smudge cell percentage on routine blood smear in chronic lymphocytic leukemia. clin lymphoma myeloma leuk 2014; 14:514–17. https://doi.org/10.1016/j.clml.2014.02.007. 24. pulte d, castro fa, jansen l, luttmann s, holleczek b, nennecke a, et al. trends in survival of chronic lymphocytic leukemia patients in germany and the usa in the first decade of the twenty-first century. j hematol oncol 2016; 9:28. https://doi. org/10.1186/s13045-016-0257-2. 25. molica s, levato d. what is changing in the natural history of chronic lymphocytic leukemia? haematologica 2001; 86:8–12. 26. barrientos jc. management of chronic lymphocytic leukemia in the elderly. cancer control 2015; 22:17–23. https://doi.org/1 0.1177/107327481502204s04. 27. shvidel l, braester a, bairey o, rahimi-levene n, klepfish a, herishanu y, et al. survival trends among 1,325 patients with chronic lymphocytic leukemia seen over the past 40 years in israel. am j hematol 2011; 86:985–92. https://doi.org/10.1002/ ajh.22160. 28. de faria jr, de oliveira js, delbone de faria rm, silva mr, goihman s, yamamoto m, et al. prognosis related to staging systems for chronic lymphocytic leukemia. sao paulo med j 2000; 118:83–8. https://doi.org/10.1590/s1516-318020000004 00002. 1department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2directorate general of primary health care, ministry of health, muscat, oman; 3department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 4the research council, muscat, oman *corresponding author e-mail: mhalazri@squ.edu.om االكتئاب يف فرتة احلمل معدل انتشاره وأسبابه يف النساء العمانيات يف جمال الرعاية الصحية األولية دراسة مستعرضة حممد العزري، امي�ن اللواتية، ري� الكمي�نية، م�ي�شة الكيومية، ع�ئ�شة الرواحية، روبن ديفد�شون، عبداهلل املنريي abstract: objectives: this study aimed to identify the prevalence of antenatal depression and the risk factors associated with its development among omani women. no previous studies on antenatal depression have been conducted in oman. methods: this descriptive cross-sectional study was carried out between january and november 2014 in muscat, oman. pregnant omani women ≥32 gestational weeks who were attending one of 12 local primary care health centres in muscat for routine antenatal care were invited to participate in the study (n = 986). an arabic version of the validated self-administered edinburgh postnatal depression scale questionnaire was used to measure antenatal depression. a cut-off score of ≥13 was considered to indicate probable depression. results: a total of 959 women participated in the study (response rate: 97.3%). of these, 233 were found to have antenatal depression (24.3%). a bivariate analysis showed that antenatal depression was associated with unplanned pregnancies (p = 0.010), marital conflict (p = 0.001) and a family history of depression (p = 0.019). the adjusted odds ratio (or) after logistic multivariate regression analysis showed that antenatal depression was significantly associated with unplanned pregnancies (or: 1.37; 95% confidence interval [ci]: 1.02–1.86) and marital conflict (or: 13.83; 95% ci: 2.99–63.93). conclusion: the prevalence of antenatal depression among the studied omani women was high, particularly in comparison to findings from other arab countries. thus, antenatal screening for depression should be considered in routine primary antenatal care. couples should also be encouraged to seek psychological support should marital conflicts develop during pregnancy. keywords: pregnancy; depression; prevalence; risk factors; women; primary health care; oman. امللخ�ص: الهدف: تهدف هذه الدرا�شة اإىل التعرف على مدى انت�ش�ر االإكتئ�ب يف فرتة احلمل وعلى العوامل املرتبطة بتطوره عند الن�ش�ء العم�ني�ت حيث مل جترى درا�ش�ت �ش�بقة عن االكتئ�ب يف فرتة احلمل يف �شلطنة عم�ن. الطريقة: اأجريت هذه الدرا�شة املقطعية الو�شفية قبل م� لفح�ص ح�رضن واللواتي اأ�شبوع� 32 من الأكرث احلوامل الن�ش�ء دعوة متت عم�ن. م�شقط، حم�فظة يف 2014 نوفمرب و ين�ير بني الوالدة يف واحدة من 12 مركز �شحي للرع�ية ال�شحية االأولية يف م�شقط للم�ش�ركة يف هذا البحث )n = 986(. مت ا �شتخدام الن�شخة العربية لال�شتبي�ن املعب�أ ذاتي� ملقي��ص أدنربه الكتئ�ب م� بعد احلمل )epds( جلمع البي�ن�ت. كذالك مت ا�شتخدام درجة قطع 13≤ نقطه لتحديد احتم�ل وجود االكتئ�ب يف فرتة احلمل. النتائج: �ش�ركت جمموعة من 959 إمراأة ح�مل دعيت للدرا�شة )معدل اال�شتج�بة = %97.3(. ومن بني هوؤالء، مت العثور على 233 إمراه ح�مل يع�نني من االكتئ�ب قبل الوالدة )%24.3(. واأظهر التحليل الثن�ئي املتغري اأن االكتئ�ب قبل الوالدة مرتبط مع احلمل غري املخطط له )p = 0.010(، امل�ش�كل الع�ئلية بني الزوجني )p = 0.001( وت�ريخ الع�ئلة ملر�ص االكتئ�ب )0.019 = p(. اأظهرت ن�شبة االأرجحية املعدلة )or( بعد حتليل االنحدار اللوج�شتي املتعدد اأن االكتئ�ب قبل الوالدة يرتبط ب�شكل كبري مع احلمل غري .)ci: 2.99-63.93 :95% ،or: 13.83( امل�ش�كل الع�ئلية بني الزوجني )1.86-1.02 :]ci[ 95، الثقة الف��شلة% ،or: 1.37( املخطط له اخلال�صة: ك�نت ن�شبة معدل االكتئ�ب قبل الوالدة بني الن�ش�ء العم�ني�ت مرتفعة ال �شيم� ب�ملق�رنة مع النت�ئج يف الدول العربية االأخرى لهذا ينبغي النظر يف تطبيق عمل فح�ص ب�شكل دائم يف الرع�ية ال�شحية االأولية يف فرتة احلمل ملعرفة وجود االكتئ�ب وتوفري العالج الالزم. كم� ينبغي اأي�ش� ت�شجيع االأزواج على التم��ص الدعم والعالج النف�شي عند ظهور م�ش�كل زوجية اأثن�ء فرتة احلمل. مفتاح الكلمات: احلمل؛ االكتئ�ب؛ املعدل؛ عوامل اخلطر؛ الن�ش�ء؛ الرع�ية ال�شحية االأولية؛ عم�ن. prevalence and risk factors of antenatal depression among omani women in a primary care setting cross-sectional study *mohammed al-azri,1 iman al-lawati,2 raya al-kamyani,2 maisa al-kiyumi,2 aisha al-rawahi,2 robin davidson,3 abdullah al-maniri4 clinical & basic research sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e35–41, epub. 2 feb 16 submitted 10 sep 15 revision req. 22 oct 15; revision recd. 10 nov 15 accepted 10 dec 15 doi: 10.18295/squmj.2016.16.01.007 prevalence and risk factors of antenatal depression among omani women in a primary care setting cross-sectional study e36 | squ medical journal, february 2016, volume 16, issue 1 depression is a common although often misdiagnosed disorder that can affect women during the antenatal period.1 while the prevalence of antenatal depression varies between countries, it is generally more common than postnatal depression.2,3 antenatal depression is often associated with considerable medical and psychological morbidities which affect both the mother and baby. research has shown that antenatal depression increases the risk of pre-eclampsia, operative deliveries (e.g. caesarean sections or instrumental vaginal deliveries), use of epidural analgaesics during delivery, spontaneous preterm births, postnatal depression and suicidal ideation.4–6 for the baby, antenatal depression is known to increase the risk of slower fetal activity, low birth weight, subsequent admission to the neonatal care unit and sudden death.6 in addition, the infants of women with antenatal depression may receive suboptimal physical and psychological care after birth and older children and/or spouses can also suffer from the secondary effects of maternal depression.7,8 consequently, increased awareness and early identification of antenatal depression with appropriate psychotherapeutic interventions could reduce the risk of adverse effects for the mother, child and family.1,7,8 several sociodemographic, psychiatric and medical factors have been associated with an increased risk of developing antenatal depression. low socioeconomic and educational status, low levels of social support, unplanned pregnancies and spousal violence have been associated with the condition.9–11 psychological and psychiatric factors include the existence of psychosocial problems such as depression, stress, anxiety, low self-esteem, poor partner relationships, forced sexual relations and a history of traumatic abuse; these factors may either affect the woman herself or other family members.3,11,12 finally, excessive consumption of alcohol and iron deficiency anaemia have been linked to the development of antenatal depression.11 oman is a developing country located on the southeastern tip of the arabian peninsula. in 2010, the national census recorded a total population of 2.7 million, of which 1.9 million were omani.13 approximately 35% of omanis were aged below 15 years and only 3.5% were aged above 65 years (median age: 22 years).13 in 2010, approximately 21% of the total population resided in the capital city, muscat, which is the most populated city in oman.13 primary healthcare is considered the first port of entry to all levels of healthcare in oman. by means of the ministry of health (moh), the omani government funds and provides free healthcare services to all omanis, as well as non-omanis working in the government sector. in muscat, standard antenatal services are available in the antenatal clinics of 27 local primary care health centres, each of which provides care to the population in their specific catchment area.14 in general, a total of six visits are required during a normal low-risk pregnancy while higher-risk pregnancies are referred to antenatal clinics in secondary or tertiary hospitals depending on the severity of the condition.15 however, no screening measures currently exist within moh antenatal care protocols to identify women with antenatal depression.15 to the best of the authors’ knowledge, no studies have yet been conducted in oman to identify the prevalence of antenatal depression and its potential sociodemographic correlates. the aim of this study, therefore, was to assess the prevalence of antenatal depression among omani women and explore associated clinical and demographic risk factors. methods this descriptive cross-sectional study was carried out between january and november 2014 in muscat, oman. the required sample size for the current study was estimated to be approximately 1,600, based on an assumed 20% prevalence of antenatal depression, a 95% confidence interval (ci) and a 10% error in estimating the prevalence of depression. of the 27 local primary care health centres in muscat, 12 centres were randomly selected for inclusion in the study. a advances in knowledge this study is the first in oman to investigate the prevalence and risk factors of antenatal depression. the rate of antenatal depression among the studied omani women was high in comparison to rates observed in other countries in the middle eastern region. among the cohort of omani pregnant women, antenatal depression was significantly associated with unplanned pregnancies, marital conflict and a family history of depression. application to patient care due to the high rate of antenatal depression found in this study, depression screening should be considered as part of routine antenatal care. this will allow women with antenatal depression to be identified earlier and provided with adequate treatment and support. considering that marital conflict was a significant risk factor for antenatal depression, omani couples should be encouraged to seek psychological support if this type of conflict arises during pregnancy. mohammed al-azri, iman al-lawati, raya al-kamyani, maisa al-kiyumi, aisha al-rawahi, robin davidson and abdullah al-maniri clinical and basic research | e37 total of 986 pregnant omani women ≥32 gestational weeks attending one of these 12 centres for routine antenatal care during the study period were invited to participate in the study. women who were nonomani, currently receiving treatment for depression, or diagnosed with gestational diabetes, hypertension or pregnancy-induced hypertension were excluded. the arabic version of the self-administered edinburgh postnatal depression scale (epds) ques tionnaire was used to measure antenatal depression.3,16 mohammad et al. first translated into arabic, validated and successfully used the epds questionnaire in a study conducted in jordan, an arab country with similar cultural and sociodemographic characteristics to oman.3 the epds is a widely validated questionnaire used to identify and measure depression in the antenatal and postnatal periods.3,5,17 the first part of the questionnaire included 12 items designed to determine the sociodemographic and medical characteristics of the participants, including age, occupation, education level, monthly income, gravidity, gestational age, anaemia status (haemoglobin levels <11.0 gm/dl), history of miscarriage, history of depression, family history of depression, whether the pregnancy was planned or spontaneous and marital conflict. the second part constituted 10 questions to determine the presence of antenatal depression. each question was scored from 0–3 with a total score ranging from 0–30. a cut-off score of ≥13 was considered to indicate probable antenatal depression.3,5 three nurses in each of the primary care health centres included in the study were trained to distribute and collect the questionnaires from the study subjects, although the questionnaires were completed solely by the participants. the reliability of the items was tested on a sample of 30 women, which indicated a cronbach’s alpha value of 0.75. these women were subsequently included in the study. data were analysed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). all variables were subjected to univariate analysis using pearson’s chi-squared test to determine associations between antenatal depression and sociodemographic characteristics. a p value of ≤0.050 was considered statistically significant. to adjust for possible confounding factors, a second analysis table 1: sociodemographic and clinical characteristics of pregnant omani women receiving antenatal care in local primary care health centres (n = 959). characteristic* n (%) age in years 957 (100.0) <24 261 (27.3) 25–30 451 (47.1) >30 245 (25.6) occupation 959 (100.0) housewife 609 (63.5) employed 350 (36.5) education level 957 (100.0) primary and secondary 519 (54.2) university 438 (45.8) monthly income in omani riyals 957 (100.0) <500 298 (31.1) 500–1,000 488 (51.0) >1,000 171 (17.9) gravidity 959 (100.0) primigravida 373 (38.9) multigravida 465 (48.5) grand multigravida 121 (12.6) gestational age in weeks 959 (100.0) 32–34 399 (41.6) 35–37 376 (39.2) >37 184 (19.2) anaemia status† 958 (100.0) normal 255 (26.6) mild anaemia 488 (50.9) moderate-to-severe anaemia 215 (22.4) history of miscarriage 959 (100.0) yes 170 (17.7) no 789 (82.3) history of depression 959 (100.0) yes 10 (1.0) no 949 (99.0) family history of depression 959 (100.0) yes 19 (2.0) no 940 (98.0) planned pregnancy 958 (100.0) yes 560 (58.5) no 398 (41.5) marital conflict 958 (100.0) yes 13 (1.4) no 945 (98.6) *the total of each characteristic corresponds to the number of respondents for each question. †haemoglobin levels of <11.0 gm/dl. prevalence and risk factors of antenatal depression among omani women in a primary care setting cross-sectional study e38 | squ medical journal, february 2016, volume 16, issue 1 was conducted using multivariate logistic regression for variables that showed significant associations with antenatal depression at the p ≤0.050 level. this study was approved by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #572). written consent was obtained from each of the subjects before their participation in the study. results a total of 959 pregnant omani women participated in the study (response rate: 97.3%). the mean age of the participants was 27 ± 4.8 years (range: 17–43 years old). the majority of participants were housewives (63.5%). more than half of the participants (54.2%) had only completed primary and secondary education while 45.8% had a university qualification. in terms of gravidity, 48.5% were multigravidae, 12.6% were grand multigravidae and 38.9% were primigravidae. a total of table 2: associations between antenatal depression* and sociodemographic variables among pregnant omani women receiving antenatal care in local primary care health centres (n = 959). variable† n (%) p value depressed (n = 233) not depressed (n = 726) age in years (n = 957) 0.917 <24 66 (25.3) 195 (74.7) 25–30 108 (23.9) 343 (76.1) >30 59 (24.1) 186 (75.9) occupation (n = 959) 0.399 housewife 154 (25.3) 455 (74.7) employed 80 (22.9) 270 (77.1) education level (n = 957) 0.127 primary and secondary 137 (26.4) 382 (73.6) university 97 (22.1) 341 (77.9) monthly income in omani riyals (n = 957) 0.078 <500 86 (28.9) 212 (71.1) 500–1,000 106 (21.7) 382 (78.3) >1,000 42 (24.6) 129 (75.4) gravidity (n = 959) 0.923 primigravida 89 (23.9) 284 (76.1) multigravida 114 (24.5) 351 (75.5) grand multigravida 31 (25.6) 90 (74.4) gestational age in weeks (n = 959) 0.338 32–34 107 (26.8) 292 (73.2) 35–37 85 (22.6) 291 (77.4) >38 42 (22.8) 142 (77.2) anaemia status‡ (n = 958) 0.941 normal 64 (25.1) 191 (74.9) mild anaemia 117 (24.0) 371 (76.0) moderate-tosevere anaemia 53 (24.7) 162 (75.3) history of miscarriage (n = 959) 0.765 yes 43 (25.3) 127 (74.7) no 191 (24.2) 598 (75.8) history of depression (n = 959) 0.058 yes 5 (50.0) 5 (50.0) no 229 (24.1) 720 (75.9) table 3: logistic regression analysis of risk factors for antenatal depression* among pregnant omani women receiving antenatal care in local primary care health centres (n = 959) variable adjusted or 95% ci p value family history of depression 2.04 0.76–5.47 0.159 unplanned pregnancy 1.37 1.02–1.86 0.040† marital conflict 13.83 2.99–63.93 0.000† or = odds ratio; ci = confidence interval. *antenatal depression was self-assessed by respondents using the arabic version of the 22-item edinburgh postnatal depression scale questionnaire.3,16 a score of ≥13 was considered to indicate probable antenatal depression.3,5 †statistically significant at p ≤0.050. family history of depression (n = 959) 0.019§ yes 9 (47.4) 10 (52.6) no 225 (23.9) 715 (76.1) planned pregnancy (n = 958) 0.010§ yes 120 (21.4) 440 (78.6) no 114 (28.6) 284 (71.4) marital conflict (n = 958) 0.001§ yes 11 (84.6) 2 (15.4) no 223 (23.6) 722 (76.4) *antenatal depression was self-assessed by respondents using the arabic version of the 22-item edinburgh postnatal depression scale questionnaire.3,16 a score of ≥13 was considered to indicate probable antenatal depression.3,5 †the total of each variable corresponds to the number of respondents for each question ‡haemoglobin levels of <11.0 gm/dl. §statistically significant at p ≤0.050. mohammed al-azri, iman al-lawati, raya al-kamyani, maisa al-kiyumi, aisha al-rawahi, robin davidson and abdullah al-maniri clinical and basic research | e39 pregnancies and a lack of partner support.25 in oman, most women marry at a younger age, some as young as 16 years old, which may explain the higher prevalence of antenatal depression noted in the current study.26 also, oman, like many other developing countries, has a high fertility rate.27 previous research shows that the more children in a family, the greater the prevalence of depression, as a result of increased psychosocial and financial demands.28 nevertheless, neither maternal age nor gravidity were identified as factors significantly associated with antenatal depression in the current study. unplanned pregnancy was a significant risk factor for antenatal depression in the present cohort of omani women. a planned pregnancy ensures that the woman is more prepared for the realities of pregnancy and childbearing whereas unplanned or unintended pregnancies may increase the risk of antenatal depression because of difficulties in balancing maternal needs and other responsibilities at home or work.29 women experiencing unplanned pregnancies are more likely to have an unstable psychosocial environment or feel a lack of security and attachment with their spouse.30 a previous study also indicated that couples with unplanned pregnancies experienced higher levels of marital conflict following delivery than couples with planned pregnancies.31 women experiencing unplanned pregnancies are often unaware of their condition; as a result they do not initiate early prenatal care and may be more likely to engage in risky behaviours, such as drinking, smoking or illicit drug use. kuroki et al. found that women with unplanned pregnancies had a lower vitamin intake during early pregnancy, which increased the risk of premature birth, low birth weight babies, infant abuse and neonatal death.32 furthermore, one unplanned pregnancy was identified as a risk factor for subsequent unplanned pregnancies, particularly among young women with low education levels.33 increased education about appropriate methods of contraception and approaches towards pregnancy planning are recommended in oman. the other significant risk factor for antenatal depression observed in the current study was marital conflict. the physiological and psychological changes that occur during pregnancy often influence women to seek out intimate partner support; consequently, the lack of such support may increase the likelihood of antenatal depression.34 indeed, difficult or strained marital relationships marked by violence and disharmony have been shown to increase rates of antenatal depression.35,36 likewise, greater marital distress has been reported by couples where the wife is depressed; these couples also resort to less constructive tactics to resolve their conflicts.35 further exploration is needed 41.6% of the women were between 32–34 gestational weeks while 58.4% were ≥35 gestational weeks. a history of miscarriage was reported by 17.7% of the participants. more than half the women (58.5%) stated that their pregnancies were planned. a previous history or family history of depression was reported by 1.0% and 2.0% of the participants, respectively. the majority of the participants (98.6%) reported no marital conflict. mean haemoglobin levels were 10.9 gm/dl. the majority of the participants were anaemic (73.3%) [table 1]. the epds scores ranged from 0–23 (mean: 9 ± 4.8). a total of 233 women had antenatal depression (24.3%). a bivariate analysis showed that antenatal depression was significantly associated with unplanned pregnancies (p = 0.010), marital conflict (p = 0.001) and a family history of depression (p = 0.019) [table 2]. logistic multivariate regression analysis revealed that antenatal depression was significantly associated with unplanned pregnancies (or: 1.37; 95% ci: 1.02–1.86) and marital conflict (or: 13.83; 95% ci: 2.99–63.93) [table 3]. the model fit 77.0% of cases correctly. discussion the prevalence of antenatal depression in the studied group of omani pregnant women was similar to that of a cohort in brazil (24.3%), but higher than findings from other countries with similar cultural and sociodemographic characteristics, such as jordan (19.0%) and morocco (19.2%).3,18 additionally, the prevalence was higher than results reported from bangladesh, turkey, australia and the uk, but lower than the rate observed in south africa (39.0%).14,19–22 the high antenatal depression rate in south africa has been attributed to a lack of partner support, high rates of intimate partner violence, low household incomes and the younger age of women during their pregnancies.23 screening for antenatal depression has been recommended for developed countries by the american college of obstetricians and gynecologists.24 considering the relatively high rate of antenatal depression observed in the current study, the moh in oman should consider implementing routine screening for the presence of antenatal depression as part of regular antenatal care services. identifying women with antenatal depression would enable healthcare professionals to provide psychological support to those affected and hence potentially reduce the rate of antenatal depression and its related complications in oman.3,17 rich-edwards et al. found that young maternal age was the strongest predictor of antenatal depression, as it was associated with financial hardship, unwanted prevalence and risk factors of antenatal depression among omani women in a primary care setting cross-sectional study e40 | squ medical journal, february 2016, volume 16, issue 1 regarding the nature of such conflicts and their role in the development of antenatal depression. in addition, future research is recommended to identify anxiety and depression among omani women in the antenatal or postnatal periods, perhaps through the use of structured clinical interviews to validate the reliability of the epds questionnaire as a screening tool. although a previous history of depression was initially found to represent a risk factor for antenatal depression in the current study, this association was not significant after multivariate analysis. this may perhaps be due to the low reported rates of past or family history of depression; as is the case in several other arab countries, many women in oman believe that psychiatric illness is a social stigma.37 they may feel ashamed to be known to have a psychiatric illness and may hide their condition and refuse to seek medical help. some women prefer to rely on their faith or turn to religious leaders for help.38 al-adawi et al. noted that omanis tend to express their psychological problems in terms of physical symptoms in order to avoid the stigma attached to a psychiatric diagnosis.37 the current study is subject to certain limitations. first, as data were gathered from responses to a self-reported questionnaire, the true prevalence of antenatal depression may have been overor underestimated. additionally, the choice of cutoff value for epds scores was based on jordanian research; although oman has a similar culture, there may have been other differences between cohorts which could have affected the results.3 indeed, it is not clear if the epds questionnaire has yet been established to have cross-cultural construct and criterion validity. second, this study was descriptive and did not use objective criteria to diagnose antenatal depression; while the epds screens for antenatal depression, it is not intended as a diagnostic tool.16 third, the crosssectional design of this study may have resulted in the inclusion of patients with pre-existing undiagnosed depression unrelated to pregnancy, although those with a known history of depression were excluded as far as possible. conclusions about causative factors for depressive symptoms cannot be formulated based on the findings of this cross-sectional study; carefully designed prospective studies are recommended to identify possible causal relationships. fourth, although the sample was large, the study was not designed to be truly epidemiological and the results reflect only women who presented to primary care centres. fifth, women with previous diagnoses of depression, diabetes and hypertension were excluded; however, the presence of a pre-existing condition does not diminish the possibility that such women may develop antenatal depression. finally, the required sample size calculated to estimate the prevalence of antenatal depression was not achieved due to a number of constraints. conclusion this study was the first to assess the prevalence of antenatal depression and associated risk factors among a group of pregnant women in oman. findings indicated that antenatal depression was higher in oman compared to other countries in the middle eastern region. screening for the presence of antenatal depression should be included as a routine part of antenatal care. this will ensure that sufficient support can be provided to those affected. antenatal depression was also significantly associated with unplanned pregnancies and marital conflict. as such, omani women should be educated regarding appropriate methods of contraception and psychological support is recommended for couples experiencing marital conflict. further large-scale research is required to determine the true rate of antenatal depression among omani women. a c k n o w l e d g e m e n t s the authors are grateful to dr. khitam. i. mohammad, professor jenny gamble and professor debra k. creedy for permission to use the arabic version of the epds in this research. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. breedlove g, fryzelka d. depression screening during pregnancy. j midwifery womens health 2011; 56:18–25. doi: 10.1111/j.1542-2011.2010.00002.x. 2. moses-kolko el, roth ek. antepartum and postpartum depression: healthy mom, healthy baby. j am med womens assoc 2004; 59:181–91. 3. mohammad ki, gamble j, creedy dk. prevalence and factors associated with the development of antenatal and postnatal depression among jordanian women. midwifery 2011; 27:e238–45. doi: 10.1016/j.midw.2010.10.008. 4. chung tk, lau tk, yip as, chiu hf, lee dt. antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. psychosom med 2001; 63:830–4. doi: 10.1097/00006842-200109000-00017. 5. heron j, o’connor tg, evans j, golding j, glover v; alspac study team. the course of anxiety and depression through pregnancy and the postpartum in a community sample. j affect disord 2004; 80:65–73. doi: 10.1016/j.jad.2003.08.004. 6. dailey de, humphreys jc. social stressors associated with antepartum depressive symptoms in low-income african american women. public health nurs 2011; 28:203–12. doi: 10.1111/j.1525-1446.2010.00912.x. http://dx.doi.org/10.1111/j.1542-2011.2010.00002.x http://dx.doi.org/10.1016/j.midw.2010.10.008 http://dx.doi.org/10.1097/00006842-200109000-00017 http://dx.doi.org/10.1016/j.jad.2003.08.004 http://dx.doi.org/10.1111/j.1525-1446.2010.00912.x mohammed al-azri, iman al-lawati, raya al-kamyani, maisa al-kiyumi, aisha al-rawahi, robin davidson and abdullah al-maniri clinical and basic research | e41 23. hartley m, tomlinson m, greco e, comulada ws, stewart j, le roux i, et al. depressed mood in pregnancy: prevalence and correlates in two cape town peri-urban settlements. reprod health 2011; 8:9. doi: 10.1186/1742-4755-8-9. 24. american college of obstetricians and gynecologists committee on health care for undeserved women. acog committee opinion no. 343: psychosocial risk factors perinatal screening and intervention. obstet gynecol 2006; 108:469–77. doi: 10.1097/00006250-200608000-00046. 25. rich-edwards jw, kleinman k, abrams a, harlow bl, mclaughlin tj, joffe h, et al. sociodemographic predictors of antenatal and postpartum depressive symptoms among women in a medical group practice. j epidemiol community health 2006; 60:221–7. doi: 10.1136/jech.2005.039370. 26. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32–42. doi: 10.12816/0003193. 27. dorvlo as, bakheit cs, al-riyami a, morsi m, al-adawi s. a study of fertility patterns of ever married women in oman. sultan qaboos univ med j 2006; 6:33–40. 28. mirza i, jenkins r. risk factors, prevalence, and treatment of anxiety and depressive disorders in pakistan: systematic review. bmj 2004; 328:794. doi: 10.1136/bmj.328.7443.794. 29. najman jm, morrison j, williams g, andersen m, keeping jd. the mental health of women 6 months after they give birth to an unwanted baby: a longitudinal study. soc sci med 1991; 32:241–7. doi: 10.1016/0277-9536(91)90100-q. 30. bouchard gd. adult couples facing a planned or an unplanned pregnancy: two realities. j fam issues 2005; 26:619–37. doi: 10.1177/0192513x04272756. 31. bouchard gd. boudreau jd, hébert r. transition to parenthood and conjugal life: comparisons between planned and unplanned pregnancies. j fam issues 2006; 27:1512–31. doi: 10.1177/0192513x06290855. 32. kuroki lm, allsworth je, redding ca, blume jd, peipert jf. is a previous unplanned pregnancy a risk factor for a subsequent unplanned pregnancy? am j obstet gynecol 2008; 199:517.e1–7. doi: 10.1016/j.ajog.2008.03.049. 33. noble re. depression in women. metabolism 2005; 54:49–52. doi: 10.1016/j.metabol.2005.01.014. 34. johanson r, chapman g, murray d, johnson i, cox j. the north staffordshire maternity hospital prospective study of pregnancy-associated depression. j psychosom obstet gynaecol 2000; 21:93–7. doi: 10.3109/01674820009075614. 35. lancaster ca, gold kj, flynn ha, yoo h, marcus sm, davis mm. risk factors for depressive symptoms during pregnancy: a systematic review. am j obstet gynecol 2010; 202:5–14. doi: 10.1016/j.ajog.2009.09.007. 36. coyne jc, thompson r, palmer sc. marital quality, coping with conflict, marital complaints, and affection in couples with a depressed wife. j fam psychol 2002; 16:26–37. doi: 10.1037/0893-3200.16.1.26. 37. al-adawi s, dorvlo as, al-ismaily ss, al-ghafry da, al-noobi bz, al-salmi a, et al. perception of and attitude towards mental illness in oman. int j soc psychiatry 2002; 48:305–17. doi: 10.1177/002076402128783334. 38. al-krenawi a. mental health practice in arab countries. curr opin psychiatry 2005; 18:560–4. doi: 10.1097/01.yco.00 00179498.46182.8b. 7. larsson c, sydsjö g, josefsson a. health, sociodemographic data, and pregnancy outcome in women with antepartum depressive symptoms. obstet gynecol 2004; 104:459–66. doi: 10.1097/01.aog.0000136087.46864.e4. 8. patel v, rodrigues m, desouza n. gender, poverty, and postnatal depression: a study of mothers in goa, india. am j psychiatry 2002; 159:43–7. doi: 10.1176/appi.ajp.159.1.43. 9. nasreen he, kabir zn, forsell y, edhborg m. prevalence and associated factors of depressive and anxiety symptoms during pregnancy: a population based study in rural bangladesh. bmc womens health 2011; 11:22. doi: 10.1186/1472-6874-11-22. 10. dibaba y, fantahun m, hindin mj. the association of unwanted pregnancy and social support with depressive symptoms in pregnancy: evidence from rural southwestern ethiopia. bmc pregnancy childbirth 2013; 13:135. doi: 10.1186/1471-2393-13-135. 11. melo ef jr, cecatti jg, pacagnella rc, leite df, vulcani de, makuch my. the prevalence of perinatal depression and its associated factors in two different settings in brazil. j affect disord 2012; 136:1204–8. doi: 10.1016/j.jad.2011.11.023. 12. ritter c, hobfoll se, lavin j, cameron rp, hulsizer mr. stress, psychosocial resources, and depressive symptomatology during pregnancy in low-income, inner-city women. health psychol 2000; 19:576–85. doi: 10.1037/0278-6133.19.6.576. 13. ministry of national economy. oman census summary 2010. from: 85.154.248.117/ mone2010/#view=viewcensus summar y&sele cte dwafers=0&sele cte dcolumns=0,1,2,3 &selectedrows=2,5,7,8,9 accessed: nov 2015. 14. directorate general health services of muscat, ministry of health. from: www.moh.gov.om/en/web/directorate-generalhealth-services-muscat/facilities accessed: nov 2015. 15. el aty ma, meky fa, morsy m, el sayed mk. overall adequacy of antenatal care in oman: secondary analysis of national reproductive health survey data, 2008. east mediterr health j 2015; 20:781–8. 16. cox jl, holden jm, sagovsky r. detection of postnatal depression: development of the 10-item edinburgh postnatal depression scale. br j psychiatry 1987; 150:782–6. doi: 10.1192/ bjp.150.6.782. 17. bergink v, kooistra l, lambregtse-van den berg mp, wijnen h, bunevicius r, van baar a, et al. validation of the edinburgh depression scale during pregnancy. j psychosom res 2011; 70:385–9. doi: 10.1016/j.jpsychores.2010.07.008. 18. alami km, kadri n, berrada s. prevalence and psychosocial correlates of depressed mood during pregnancy and after childbirth in a moroccan sample. arch womens ment health 2006; 9:343–6. doi: 10.1007/s00737-006-0154-8. 19. gulseren l, erol a, gulseren s, kuey l, kilic b, ergor g. from antepartum to postpartum: a prospective study on the prevalence of peripartum depression in a semiurban turkish community. j reprod med 2006; 51:955–60. 20. nasreen he, kabir zn, forsell y, edhborg m. low birth weight in offspring of women with depressive and anxiety symptoms during pregnancy: results from a population based study in bangladesh. bmc public health 2010; 10:515. doi: 10.1186/1471-2458-10-515. 21. leigh b, milgrom j. risk factors for antenatal depression, postnatal depression and parenting stress. bmc psychiatry 2008; 8:24. doi: 10.1186/1471-244x-8-24. 22. pawlby s, hay df, sharp d, waters cs, o’keane v. antenatal depression predicts depression in adolescent offspring: prospective longitudinal community-based study. j affect disord 2009; 113:236–43. doi: 10.1016/j.jad.2008.05.018. http://dx.doi.org/10.1186/1742-4755-8-9 http://dx.doi.org/10.1097/00006250-200608000-00046 http://dx.doi.org/10.1136/jech.2005.039370 http://dx.doi.org/10.12816/0003193 http://dx.doi.org/10.1136/bmj.328.7443.794 http://dx.doi.org/10.1016/0277-9536%2891%2990100-q http://dx.doi.org/10.1177/0192513x04272756 http://dx.doi.org/10.1177/0192513x06290855 http://dx.doi.org/10.1016/j.ajog.2008.03.049 http://dx.doi.org/10.1016/j.metabol.2005.01.014 http://dx.doi.org/10.3109/01674820009075614 http://dx.doi.org/10.1016/j.ajog.2009.09.007 http://dx.doi.org/10.1037/0893-3200.16.1.26 http://dx.doi.org/10.1177/002076402128783334 http://dx.doi.org/10.1097/01.yco.0000179498.46182.8b http://dx.doi.org/10.1097/01.yco.0000179498.46182.8b http://dx.doi.org/10.1097/01.aog.0000136087.46864.e4 http://dx.doi.org/10.1176/appi.ajp.159.1.43 http://dx.doi.org/10.1186/1472-6874-11-22 http://dx.doi.org/10.1186/1471-2393-13-135 http://dx.doi.org/10.1016/j.jad.2011.11.023 http://dx.doi.org/10.1037/0278-6133.19.6.576 http://85.154.248.117/%20mone2010/%23view%3dviewcensus%0asummary%26selectedwafers%3d0%26selectedcolumns%3d0%2c1%2c2%2c3%0a%26selectedrows%3d2%2c5%2c7%2c8%2c9 http://85.154.248.117/%20mone2010/%23view%3dviewcensus%0asummary%26selectedwafers%3d0%26selectedcolumns%3d0%2c1%2c2%2c3%0a%26selectedrows%3d2%2c5%2c7%2c8%2c9 http://85.154.248.117/%20mone2010/%23view%3dviewcensus%0asummary%26selectedwafers%3d0%26selectedcolumns%3d0%2c1%2c2%2c3%0a%26selectedrows%3d2%2c5%2c7%2c8%2c9 http://www.moh.gov.om/en/web/directorate-general-health-services-muscat/facilities http://www.moh.gov.om/en/web/directorate-general-health-services-muscat/facilities http://dx.doi.org/10.1192/bjp.150.6.782 http://dx.doi.org/10.1192/bjp.150.6.782 http://dx.doi.org/10.1016/j.jpsychores.2010.07.008 http://dx.doi.org/10.1007/s00737-006-0154-8 http://dx.doi.org/10.1186/1471-2458-10-515 http://dx.doi.org/10.1186/1471-244x-8-24 http://dx.doi.org/10.1016/j.jad.2008.05.018 septic arthritis is a purulent joint infection occurring when microorganisms invade the joint space, either through the haematological spread of a distant infection or postiatrogenic direct joint inoculation.1,2 the latter can occur either due to traumatic joint exposure to a microorganism invasion or contiguous odontogenic, ear or skin infections.1,2 as the joint synovium is highly vascular and has no limiting basement membrane, it is more vulnerable to infection by haematological spread.3 most infections are monoarticular; however, 10‒20% are polyarticular, with the knee being the most commonly involved joint.1 septic arthritis usually affects the knee and the hip; it rarely affects smaller joints, such as the temporomandibular joint (tmj).2,4,5 septic arthritis of the tmj is not commonly reported in the literature.2‒4,6 delayed management of tmj septic arthritis often leads to irreversible damage of the joint structure with subsequent longterm complications of bony deformity and ankylosis. this report presents two rare cases of tmj ankylosis following a neonatal septic arthritis infection. both patients were diagnosed with tmj ankylosis between one to five years after the infection and presented clinically with facial asymmetry and trismus. 1oral & maxillofacial surgery programme, oman medical specialty board, muscat, oman; 2department of oral health, sultan qaboos university hospital, muscat, oman; 3department of oral & maxillofacial surgery, al-nahda hospital, muscat, oman; 4department of oral & maxillofacial surgery, oman dental college, muscat, oman *corresponding author e-mail: dr.noorjabbar@ymail.com تصلب املفصل الصدغي الفكي كُمضاعفة لإللتهاب اإلنْتاين للمْفصل يف األطفال حديثي الوالدة تقرير عن حالتني نور ال�ساعدية، عبدالعزيز باكثري، اأحمد الها�سمي، حممد ال�سماعيلي abstract: temporomandibular joint (tmj) ankylosis as a complication of neonatal septic arthritis is rarely reported in the literature. we report two clinical cases of unilateral tmj ankylosis occurring in paediatric patients subsequent to neonatal septic arthritis. the first case was a 15-month-old male infant who presented to the sultan qaboos university hospital, muscat, oman, in may 2010. according to the published english scientific literature, he is the youngest person yet to be diagnosed with this condition. the second case was a five-year-old female who presented to the al-nahda hospital, muscat, oman, in october 2011. both cases presented with facial asymmetry and trismus. they subsequently underwent gap arthroplasty and interpositional temporalis muscle and fascia grafts which resulted in an immediate improvement in mouth opening. postoperatively, the patients underwent active jaw physiotherapy which was initially successful. both patients were followed up for a minimum of two years following their surgeries. keywords: temporomandibular joint; ankylosis; septic arthritis; children; case report; oman. امللخ�ص: َق�َسط املف�سل ال�سدغي الفكي كُم�ساعفة لالإلتهاب الإْنتايِن للمف�سل ال�سدغي الفكي يف الطفال حديثي الولدة نادراً ما ُيذكر يف الأدب الطبي. يف هذا التقرير نعر�ض حالتني من َق�سٍط اأحادي اجلهة للمف�سل ال�سدغي الفكي لطفلني حديثي الولدة كاأحد م�ساعفات �ست احلالة الوىل لطفل يبلغ من العمر 15 �سهراً يف م�ست�سفى جامعة ال�سلطان قابو�ض يف اللتهاب الإنتاين للمف�سل ال�سدغي الفكي. �ُسخِّ مايو 2010، ومبراجعة الأدب الطبي املذكور باللغة الجنليزية ُيعترب هذا املري�ض اأ�سغر طفل يتم ت�سخي�سه بهذه احلالة، اأما احلالة الثانية فهي لطفلة تبلغ من العمر 5 �سنوات �ُسِخ�ست يف م�ست�سفى النه�سة يف اكتوبر 2011. كلتا احلالتني عانت من فقدان التناظر بني ن�سفي ل واحداث فجوة بني العظمتني الوجه ومن ال�زضز. مت اجراء عملية جراحية لفتح الق�سط ال�سدغي الفكي لكلتا احلالتني عن طريق َراأِْب امَلْف�سِ �ُسن وا�سح يف فتح الفم وحتريكه. مت اأخ�ساع املري�سني للعالج امللتحمتني ثم و�سع فا�سل من الع�سلة واللفافة ال�سدغية، مما نتج عنه حَتَ ية، ثم متت متابعة كلتا احلالتني ملدة �سنتني على الأقل بعد العملية. الطبيعي مبا�رسة بعد العملية مع نتائج اأولية ُمر�سِ مفتاح الكلمات: املف�سل ال�سدغي الفكي؛ الق�سط؛ التهاب املف�سل الإنتاين؛ اأطفال؛ تقرير حالة؛ عمان. temporomandibular joint ankylosis as a complication of neonatal septic arthritis report of two cases *noor j. al-saadi,1 abdulaziz a. bakathir,2 ahmed k. al-hashmi,3 mohammad i. al-ismaili3,4 online case report sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e554–558, epub. 23 nov 15 submitted 8 feb 15 revision req. 25 may 15; revision recd. 19 jun 15 accepted 28 jun 15 doi: 10.18295/squmj.2015.15.04.020 noor j. al-saadi, abdulaziz a. bakathir, ahmed k. al-hashmi and mohammad i. al-ismaili online case report | e555 case 1 a 15-month-old boy presented to the oral health department at sultan qaboos university hospital, muscat, oman, in may 2010 with trismus and a chin misalignment [figure 1a]. his medical history indicated that he had developed neonatal septic arthritis due to an umbilical cord infection at the age of 10 days old. at the time, the neonate had multiple joint swelling and pain involving both knees and hand joints. in addition, there were multiple subcutaneous infections at various sites, including the skin of the right pre-auricular region. microbiological tests revealed the growth of staphylococcus aureus. the infant recovered well following treatment with intravenous antibiotics. the patient presented again at the age of 10 months due to a recurrence of the infection in both knees and in multiple subcutaneous areas. he again responded well to intravenous antibiotics. there was no reported history of facial trauma or a fall at this time. a clinical examination showed that the 15-monthold child had a maximum mouth opening of 8 mm with facial asymmetry and chin deviation to the right. maxillofacial computed tomography (ct) showed gross enlargement and deformation of the right condylar head with evidence of fusion with the base of the skull. this led to a diagnosis of right tmj ankylosis [figures 1b & c]. at the age of 16 months, the child underwent gap arthroplasty with interpositional temporalis muscle and fascia grafts with removal of the ipsilateral coronoid process under general anaesthesia to release the right tmj ankylosis. the mouth opening was increased intraoperatively from 8 mm to 24 mm. recovery during the postoperative period was uneventful and the patient immediately began jaw exercises and physiotherapy. at a six-month postoperative review, the patient was able to maintain a mouth opening of 30 mm with satisfactory lateral movement. when he was three years old, the patient was found to have a maximum mouth opening of 22 mm. a ct scan revealed growth of the condylar head on the mediolateral aspect and a u-shaped condylar head on the coronal aspect. a bony overgrowth was seen extending from the cranial aspect into the condylar depression [figure 2a]. his parents were reluctant to proceed with any further surgical interventions, so the patient was closely monitored with continuous physiotherapy and jaw exercises. at five years of age, the trismus had worsened with a maximum mouth opening of 13 mm. an orthopantomogram showed that the bony mass of the deformed right condyle had increased and the gap space had decreased, indicating a recurrence of the right tmj ankylosis [figure 2b]. the patient was operated on again to release the ankylosis under figure 1a–c: a 15-month-old boy presented with (a) trismus and chin misalignment. computed tomography scans in the (b) coronal and (c) sagittal aspects revealed severe bony deformation and ankylosis of the right temporoman dibular joint. temporomandibular joint ankylosis as a complication of neonatal septic arthritis report of two cases e556 | squ medical journal, november 2015, volume 15, issue 4 improved and the patient could open her mouth to 40 mm. discussion tmj septic arthritis is an infection of the joint space that can lead to many complications, including intracranial abscesses, growth impairment and deformity of the condyle and destruction of the joint. subsequent tmj ankylosis can be a long-term complication.4 tmj ankylosis is the replacement of normal joint articulation with fibrous, fibro-osseous or bony tissues which results in partial or complete fusion of the mandibular condyle to the base of the skull.5 it is the most severe long-term complication of septic arthritis and has a devastating presentation. the long-term effect of joint deformity and ankylosis is unpredictable, depending on the degree of joint damage, type of ankylosis and age of the patient.5 as such, each case is unique and should be assessed individually. in the paediatric population, patients with bilateral tmj ankylosis usually present with facial deformity, trismus and dysmasesis.5 deviation of the jaw when the mouth is open and facial asymmetry are the usual presentations of unilateral tmj.5,7 owing to the gradual nature of the joint deformity and ankylosis, it may take several months or years before the facial deformity is noticed and medical treatment is sought, as was the case for the patients described in the current report. both cases presented with facial asymmetry due to the tmj deformity, growth deficiency of the affected condyle and ramus, misalignment of the chin and mandible to the affected side and trismus. these findings are in line with previously published cases.5,7 according to the available english literature, there were 29 reported cases of septic arthritis involving general anaesthesia and the intraoperative mouth opening was increased from 13 mm to 32 mm. the postoperative recovery period was uneventful and the patient again began jaw exercises and physiotherapy. case 2 a five-year-old girl presented to the oral & maxillofacial surgery unit of al-nahda hospital, muscat, oman, in october 2011 with a complaint of longstanding trismus [figure 3a]. her medical history indicated neonatal septic arthritis occurring on the second day post-delivery and manifesting as a high fever with painful swelling of the left knee. there was no record of the causative microorganism for the infection. the neonate was treated with intravenous antibiotics for three weeks, followed by a one-month oral antibacterial course. she recovered well but suffered a recurrence of the knee swelling one year later which was again successfully treated with antibiotics. at the age of five years, the patient had a maximum mouth opening of 5 mm, restriction of the lateral jaw movements and clinically apparent facial asymmetry with chin misalignment [figure 3b]. ct scans showed a bony deformation of the left tmj with reduced joint space and partial fusion of the condylar head with the base of the skull, which confirmed the diagnosis of left tmj ankylosis [figures 3c & d]. the patient underwent a gap arthroplasty with interpositional temporalis muscle and fascia grafts. this improved her mouth opening ability from 5 mm to 27 mm. postoperatively, the recovery period was uneventful and was followed by immediate jaw exercises and physiotherapy. at a six-month postoperative review, the patient maintained satisfactory mouth opening and lateral mandibular movements. at a two-year follow-up, the mouth opening had further figure 2a & b: a: coronal computed tomography scan of the patient at three years old showing mediolateral temporomandibular joint (tmj) bony overgrowth resulting in a u-shaped deformity, shortening of the mandibular ramus and downward overgrowth of the cranial bone into the deformed u-shaped condyle. b: orthopantomogram of the patient at five years old showing right tmj bony deformity and a reduced gap with a short ramus in comparison to the normal left side. noor j. al-saadi, abdulaziz a. bakathir, ahmed k. al-hashmi and mohammad i. al-ismaili online case report | e557 the tmj from 1931–2011, with only four cases of ankylosis subsequent to septic arthritis in neonates.7,8 the current report adds two rare cases of neonatal septic arthritis that resulted in tmj ankylosis after the haematogenous spread of a distant systemic infection involving multiple joints. in addition, to the best of the authors’ knowledge, the first case represents the youngest child so far to be diagnosed and treated for tmj ankylosis due to neonatal septic arthritis. septic arthritis can be caused by bacteria, viruses, fungi or parasites. the most common isolated causative bacteria are gram-positive s. aureus and streptococcus.1,4 gram-negative bacilli are found in 20‒50% of neonates, the elderly, intravenous drug users and the immunocompromised.1,4 s. aureus was found to be the causative agent in the first case of the current report. unfortunately, the microorganism in the second case was unknown. joint infections initiate an inflammatory response in the host which is responsible for much of the joint destruction. inflammation leads to synovial hyperplasia and subsequent intra-articular abscess formation. this, in turn, leads to increased intraarticular pressure with subsequent diminished joint blood flow, ischaemia and necrosis of the cartilage.1,6 intra-articular cartilage damage may be seen after only three days, with irreversible changes in joint structure occurring as early as seven days.1,6 acute tmj infections manifest clinically as severe joint pain, trismus, acute malocclusion, contralateral deviation on opening, preauricular erythema and swelling.4,6 radiographical assessment is essential in evaluating the extent and nature of the tmj ankylosis following septic arthritis. the ankylosis will usually appear as an ill-defined radiopaque mass with partial or complete fusion between the mandibular condyle, glenoid fossa, articular eminence and base of the skull with an irregular overgrowth. a plain radiograph can underestimate the extent of the ankylotic mass as it gives no information about the anatomy medial to the condyle.9 a ct scan is more diagnostically useful and was hence used to evaluate the extent of ankylosis in both of the cases reported here. surgical management of tmj ankylosis continues to be a challenge in children. different surgical techniques have been reported in the literature, including gap or interpositional arthroplasty and wide excision of the ankylotic mass with varying methods of reconstruction.5,7 however, no single method has yet reported complete success. this is likely due to the challenging nature of this condition, poor compliance with postoperative physiotherapy and the unavoidable figure 3a–d: a five-year-old girl presented with (a) trismus and (b) a deviated chin to the left. computed tomography scans in the (c) coronal and (d) sagittal aspects showed left temporomandibular joint bone deformity and ankylosis with a shortened left mandibular ramus. temporomandibular joint ankylosis as a complication of neonatal septic arthritis report of two cases e558 | squ medical journal, november 2015, volume 15, issue 4 arthritis is critical in preventing and avoiding such complications. references 1. ohl ca, forster d. infectious arthritis of native joints. in: bennett e, dolin r, blaser m, eds. mandell, douglas, and bennett’s principles and practice of infectious diseases. 8th ed. philadelphia, pennsylvania, usa: saunders, 2015. pp. 1302–17. 2. cai xy, yang c, zhang zy, qiu wl, chen mj, zhang sy. septic arthritis of the temporomandibular joint: a retrospective review of 40 cases. j oral maxillofac surg 2010; 68:731–8. doi: 10.1016/j.joms.2009.07.060. 3. lynn mm, mathews cj. advances in the management of bacterial septic arthritis. int j clin rheumatol 2012; 7:335–42. doi: 10.2217/ijr.12.11. 4. leighty sm, spach dh, myall rw, burns jl. septic arthritis of the temporomandibular joint: review of the literature and report of two cases in children. int j oral maxillofac surg 1993; 22:292–7. doi: 10.1016/s0901-5027(05)80519-3. 5. kaban lb, bouchard c, troulis mj. a protocol for management of temporomandibular joint ankylosis in children. j oral maxillofac surg 2009; 67:1966–78. doi: 10.1016/j.joms.2009 .03.071. 6. goldschmidt mj, butterfield kj, goracy es, goldberg mh. streptococcal infection of the temporomandibular joint of hematogenous origin: a case report and contemporary therapy. j oral maxillofac surg 2002; 60:1347–53. doi: 10.1053/ joms.2002.35736. 7. chaves netto hd, nascimento ff, chaves md, chaves lm, negreiros lyrio mc, mazzonetto r. tmj ankylosis after neonatal septic arthritis: literature review and two case reports. oral maxillofac surg 2011; 15:113–19. doi: 10.1007/ s10006-010-0210-4. 8. sembronio s, albiero am, robiony m, costa f, toro c, politi m. septic arthritis of the temporomandibular joint successfully treated with arthroscopic lysis and lavage: case report and review of the literature. oral surg oral med oral pathol oral radiol endod 2007; 103:e1–6. doi: 10.1016/j. tripleo.2006.08.028. 9. sanders r, macewen cj, mcculloch as. the value of skull radiography in ophthalmology. acta radiol 1994; 35:429–33. doi: 10.1177/028418519403500506. complication of relapse and recurrence of the ankylosis, as with the first case reported here. most published reports of tmj ankylosis following septic arthritis only provide short-term follow-up periods of less than one year.7 however, the patients in the present case report were followed up for a minimum of two years following surgical release of the tmj ankylosis. longterm follow-up will continue with these patients until they reach early adulthood in order to monitor facial growth and to detect any further complications. conclusion tmj neonatal septic arthritis is uncommon and early recognition is crucial. delayed diagnosis and management can lead to devastating functional and aesthetic complications of facial deformity, trismus and dysmasesis due to the progressive and permanent joint distortion, overgrowth and gradual fusion with the base of the skull. the management of such complications is challenging with low success rates and a high likelihood of relapse and recurrence of the ankylosis. rapid diagnosis and treatment of the tmj septic http://dx.doi.org/10.1016/j.joms.2009.07.060 http://dx.doi.org/10.2217/ijr.12.11 http://dx.doi.org/10.1016/s0901-5027%2805%2980519-3 http://dx.doi.org/10.1016/j.joms.2009.03.071 http://dx.doi.org/10.1016/j.joms.2009.03.071 http://dx.doi.org/10.1053/joms.2002.35736 http://dx.doi.org/10.1053/joms.2002.35736 http://dx.doi.org/10.1007/s10006-010-0210-4 http://dx.doi.org/10.1007/s10006-010-0210-4 http://dx.doi.org/10.1016/j.tripleo.2006.08.028 http://dx.doi.org/10.1016/j.tripleo.2006.08.028 http://dx.doi.org/10.1177/028418519403500506 sir, we compliment al-araimi and colleagues for recommending prospective awareness for medical personnel about different travel-related tropical diseases including dengue fever.1 their 38 year-old sri lankan patient1 tested negative with polymerase chain reaction giving an equivocal result for dengue igm. serum sample(s) collected after two or more months should be tested for dengue igg. in all probability, the levels of igm and dengue virus ribonucleic acid had reached undetectable levels. the demonstration of dengue virus igg would reconfirm the initial diagnosis.1 in countries known to be free of dengue virus infection, travel-related importation would be a problem for clinicians and laboratory personnel. a point-of-care assay for dengue virus non-structural protein1 (ns1) antigen, anti-dengue igm and igg would be very practical. during the initial phase of illness, ns1 would be the earliest datable marker in any primary or secondary infection. that would be followed by an appearance of igm in a primary infection or igg in a secondary infection. the results of the 23 dengue-virus positive cases detected at the narita airport quarantine station, japan are of interest in this regard.2 there was almost identical sensitivity of the dengue virus (denv) ns1 antigen detection by the elisa and the rapid test. the igm/igg detection, employing either the antibody-capture elisa or the rapid test, was not found to be suitable to identify any denv-carrying individuals arriving in countries reported to be dengue free. the utility of a single-step immunochromatograhic one step dengue ns1 ag and igg/igm test, (dengue duo; standard diagnostics, inc, st.ingbert, germany: www.standard.com) was immense during the 2010 denv outbreak in delhi, india. among 175 suspected cases, 86 were ns1 positive and 89 were ns1 negative. among 86 ns1-positive patients, 23 were igm positive, four were igg positive and six were positive for all three markers. the 89 ns1-negative patients included two who were igm positive, eight who were igg positive and seven who were positive for both igm and igg: 72 were negative for all three markers and 53 patients were positive exclusively for ns1. using the dengue duo test, it was possible to diagnose 61 additional patients: these ns1 positives included 57 who were negative for igm and four who were positive for igg only.3 to conclude, awareness among medical and health care personnel in dengue free countries1 as well rapid disease diagnosis would ensure better clinical management and public health response to halt any local dengue transmission. *subhash c. arya and nirmala agarwal sant parmanand hospital, delhi, india *corresponding author email: subhashbhapaji@gmail.com references 1. al-araimi h, al-jabri a, mehmoud a, al-abri s. dengue haemorrhagic fever presenting as acute abdomen. sultan qaboos univ med j 2011; 11:265–8, epub. 15 may 2011. 2. sugimoto m, haseyama m, ishida y, yoshida s, kamiya k. evaluation of nonstructural 1 protein rapid test for dengue virus at the narita airport quarantine station, japan. jpn j infect dis 2011; 64:169–70. 3. arya sc, agarwal n, parikh sc. usefulness of detection of dengue ns1 antigen alongside igm plus igg, and concurrent platelet enumeration during an outbreak. trans r soc trop med hyg 2011; 105:358–9. squ med j, november 2011, vol. 11, iss. 4, pp. 531, epub. 25th oct 11 submitted 5th jun 11 accepted 14th sep 11 رد على: البطن احلادة كعرض حلمى الدنك النزفية re: dengue haemorrhagic fever presenting as acute abdomen letter to editor department of cardiothoracic surgery, minia university hospital, el-minia, egypt *corresponding author’s e-mail: yaser_ali_kamal@yahoo.com خثرة كبرية يف الصمام التاجي الصناعي أثناء احلمل املبكر يا�رس علي كمال، حممد زهران، اأحمد عريبي large thrombus on a prosthetic mitral valve during early pregnancy *yasser a. kamal, mohamed zahran, ahmed oreiby a 28-year-old primigravida female presented at 12 gestational weeks to the emergency department of minia university hospital, elminia, egypt, in 2017 with severe dyspnoea upon exert ion. five years earlier, she had undergone mitral valve replacement with a mechanical prosthesis. after her pregnancy had been confirmed, she had discontinued anticoagulant warfarin therapy before taking low-molec ular-weight heparin. there was no significant history of medical diseases or prescription of any other medications. transoesophageal echocardiography (tee) revealed a large thrombus of approximately 4 cm2 on the mitral prosthesis, with near total obstruction of the prosthetic mitral valve [figure 1a]. an abdominal ultrasound revealed that the fetus was non-viable. three days after admission, the patient underwent surgery. this revealed a large thrombus on the atrial aspect of the mitral prosthesis projected away from the valve disc [figure 1b]. both the prosthetic valve and the entire thrombus were removed surgically and another valve was inserted [figure 2]. an obstetrician performed a dilation and evacuation procedure on the fifth day after the open-heart surgery. at a six-month follow-up, the patient had recovered well and was healthy. comment prosthetic valve thrombosis (pvt) during pregnancy is a rare but life-threatening complication following mech anical heart valve replacement.1,2 most cases occur during the second or third trimester. the underlying mechan isms of pvt during pregnancy include a hypercoagulable state and poor anticoagulation when warfarin is replaced with heparin injections to avoid its harmful effects during the first trimester and last two weeks of interesting medical image sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e407–408, epub. 19 dec 18 submitted 16 may 18 revision req. 5 jun 18; revision recd. 6 jun 18 accepted 21 jun 18 figure 1: a: transoesophageal echocardiograph of a 28-year-old primigravida female patient showing a thrombus on the left atrial aspect of a prosthetic mitral valve (arrow). b: perioperative photo showing left atriotomy with a thrombus on the prosthetic mitral valve (arrow). la = left atrium; pmv = prosthetic mitral valve; lv = left ventricle. doi: 10.18295/squmj.2018.18.03.027 large thrombus on a prosthetic mitral valve during early pregnancy e408 | squ medical journal, august 2018, volume 18, issue 3 pregnancy.1,2 in order to prevent thromboembolic compl ications during pregnancy, patients with mechanical valves should undergo continuous anticoagulation therapy and monitoring. according to the american college of cardi ology and american heart association, warfarin should be replaced with heparin between six and 12 gestational weeks to avoid the risk of fetal defects; however, heparin increases maternal risks of pvt, systemic embolisation, infection, osteoporosis and heparin-induced thrombocytopaenia.3 the management of pvt during pregnancy is chall enging and no specific guidelines are currently available.1 acute symptoms, particularly dyspnoea and embolic events, should increase the index of suspicion for pvt. emergency surgery may be necessary for patients with left-sided pvt and new york heart association (nyha) functional class iii–iv symptoms or a large clot burden, while thrombolysis is the first line of therapy for patients with nyha class i–ii symptoms and a small clot burden.3 fluoroscopy or tee is indicated to assess valve motion and clot burden and to differentiate the formation of a thrombus from that of a pannus.3,4 the current case increases awareness of the need for detailed discussion before and after pregnancy for childbearing women with prosthetic heart valves. for such patients, preconception counselling—involving an obstetrician, cardiologist and, possibly, a haematologist—is crucial in minimising the risk of pvt. such counselling should include pregnancy planning, pregn ancy-related complications, prematurity and the possib ility of discontinuing and replacing teratogenic medic ations.5 bioprosthesis is also a reliable option for women who wish to become pregnant as anticoagulation therapy is generally not required; however, re-operation may be undesirable as the associated mortality rate ranges from 4−9%.3,6 regular and careful monitoring of prosthetic heart valves is crucial during the first trimester of preg nancy to avoid life-threatening complications. references 1. biteker m, ozkan m. treatment of obstructive prosthetic heart valve thrombosis in pregnancy. j card surg 2010; 25:206. doi: 10.1111/j.1540-8191.2009.00822.x. 2. choi c, midwall s, chaille p, conti cr. treatment of mechanical valve thrombosis during pregnancy. clin cardiol 2007; 30:271−6. doi: 10.1002/clc.20054. 3. bonow ro, carabello ba, chatterjee k, de leon ac jr, faxon dp, freed md, et al. 2008 focused update incorporated into the acc/aha 2006 guidelines for the management of patients with valvular heart disease: a report of the american college of cardiology/american heart association task force on practice guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease). j am coll cardiol 2008; 52:e1−142. doi: 10.1016/j.jacc.2008.05.007. 4. dogan v, basaran o, altun i, biteker m. transesophageal echo cardiography guidance is essential in the management of prosthetic valve thrombosis. int j cardiol 2014; 177:1103−4. doi: 10.10 16/j.ijcard.2014.09.193. 5. nanna m, stergiopoulos k. pregnancy complicated by valvular heart disease: an update. j am heart assoc 2014; 3:e000712. doi: 10.1161/jaha.113.000712. 6. pieper pg, balci a, van dijk ap. pregnancy in women with prosth etic heart valves. neth heart j 2008; 16:406−11. doi: 10.1007/bf03 086187. figure 2: postoperative photo of a thrombus on the resected mechanical valve of a 28-year-old primigravida female patient. https://doi.org/10.1111/j.1540-8191.2009.00822.x https://doi.org/10.1002/clc.20054 https://doi.org/10.1016/j.jacc.2008.05.007 https://doi.org/10.1016/j.ijcard.2014.09.193 https://doi.org/10.1016/j.ijcard.2014.09.193 https://doi.org/10.1161/jaha.113.000712 https://doi.org/10.1007/bf03086187 https://doi.org/10.1007/bf03086187 clinical & basic research squ med j, february 2012, vol. 12, iss. 1, pp. 41-47, epub. 7th feb 12. submitted 7th jul 11 revision req. 10th sep 11, revision recd. 1sth nov11 accepted 16th nov 11 1department of genetics, sultan qaboos university hospital, muscat, oman; 2department of family & community medicine, ministry of health, dhakhiliya region, oman; 3department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman corresponding author e-mail: almaawali@squ.edu.om شاكلة املنشورات الطبية احليوية واجتاهاهتا يف ُدَول جملس الّتعاون اخلليجي املنذر املعويل، اأحمد البو�سعيدي، �سمري العدوي امللخ�ص: الهدف: هناك ُندرة يف الدرا�سات التي تك�سف العالقة بني خُمرجات البحوث وغريها من املوؤ�رّصات الدميوغرافية والجتماعية يف دول جمل�س التعاون اخلليجي )ُعمان، البحرين، الكويت، قطر، اململكة العربية ال�سعودية، الإمارات العربية املتحدة).كانت الأهداف الثالثة املرتابطة لهذه الدرا�سة كالآتي، اأول التاأكد: من عدد املن�سورات الطبية احليوية يف دول جمل�س التعاون اخلليجي للفرتة من �سنة 1970اإىل �سنة 2010. ثانيا: حتديد ُمعّدل اإ�سدار املن�سورات الطبية احليوية مقارنة بحجم ال�سكان خالل نف�س الفرتة. ثالثا: قيا�س العالقة بني عدد املن�سورات الطبية وبع�س املعامل الجتماعية والقت�سادية. الطريقة: مت البحث يف قاعدة البيانات ميدلين يف اأكتوبر 2010 ح�سب نوع النتماء، وال�ّسنة، ثم نوعية املن�سورات للفرتة من �سنة 1970حتى �سنة 2010. مت ت�سوية النتائج مع املن�سورات الطبية لكل مليون من ال�سكان، وح�سب الناجت املحلي الإجمايل، ثم عدد الأطباء يف كل بلد. النتائج: كان عدد من املقالت التي ُن�رصت يف دول جمل�س التعاون اخلليجي خالل فرتة الـ 40�سنة هي 25،561. كانت اململكة العربية ال�سعودية اأكرث الدول من حيث عدد املن�سورات الطبية تليها الكويت، ثم الإمارات العربية املتحدة، ثم ُعمان. �سجلت الكويت اأعلى عدد من املن�سورات عند مقارنتها مع حجم ال�سكان، تليها قطر،اأما ُعمان فهي الأدنى يف هذا الرتتيب. وعموما، اأظهرت الدول ال�ست اجتاها متزايدا يف اأعداد املن�سورات مع وجود زيادة اأكرب يف ُعمان يف الفرتة من 1990 �سنة اإىل �سنة 2005. هناك عالقة ُمعتّدة بني عدد الأطباء وعدد املن�سورات. اخلال�صة: �سهدت الإنتاجية البحثية يف دول جمل�س التعاون اخلليجي منوا معقداً ومتقلبًا يف ال�سنوات ال 40 املا�سية. مَتّ مناق�سة الآفاق امل�ستقبلية لزيادة معدل اإنتاج البحوث مع اإ�سارة خا�سة اإىل الو�سع يف ُعمان. مفتاح الكلمات: من�سورات، ُعمان، جمل�س التعاون اخلليجي، �سبه اجلزيرة العربية، بحوث طبية حيوية. abstract: objectives there is a dearth of studies examining the relationship between research output and other socio-demographic indicators in the gulf cooperation council (gcc) countries (bahrain, kuwait, oman, qatar, saudi arabia, and the united arab emirates). the three interrelated aims of this study were, first, to ascertain the number of biomedical publications in the gcc from 1970 to 2010; second, to establish the rate of publication according population size during the same period and, third, to gauge the relationship between the number of publications and specific socio-economic parameters. methods: the medline database was searched in october 2010 by affiliation, year and publication type from 1970 to 2010. data obtained were normalised to the number of publications per million of the population, gross domestic product, and the number of physicians in each country. results: the number of articles from the gcc region published over this 40 year period was 25,561. saudi arabia had the highest number followed by kuwait, uae, and then oman. kuwait had the highest profile of publication when normalised to population size, followed by qatar. oman is the lowest in this ranking. overall, the six countries showed a rising trend in publication numbers with oman having a significant increase from 1990 to 2005. there was a significant relationship between the number of physicians and the number of publications. conclusion: the research productivity from ggc has experienced complex and fluctuating growth in the past 40 years. future prospects for increasing research productivity are discussed with particular reference to the situation in oman. keywords: publications; oman; gulf cooperation council; arabian peninsula; biomedical research. biomedical publications profile and trends in gulf cooperation council countries *almundher al-maawali,1 ahmed al busadi,2 samir al-adawi3 advances in knowledge this study sheds light on the biomedical research productivity profile of the gulf cooperation council countries, its growth and fluctuations and its relations to specific socio-economic parameters. biomedical publications profile and trends in gulf cooperation council countries 42 | squ medical journal, february 2012, volume 12, issue 1 health related research determines the extent and burden of health problems, establishes the clinical and epidemiological profiles of different diseases, and determines the efficacy of therapies.1 such research leads to a better formulation of health policy planning and management, and has a direct impact on improving patient care.2 globally, there is a huge gap in research output between industrialised countries and emerging economies.3 the usa, the uk, some western european countries and japan contribute the majority of papers published in high impact journals. research papers produced in these geographical regions are likely to be highly cited.4,5 this is a paradox since 80% of the global population lives outside the countries which contribute 98% of scientific output.6 in general, compared to other countries, arab countries do not fare well in international comparisons of biomedical research.7–9 this has been attributed to the political instability that is besetting the region which does not create an environment conducive to progress in science and the development of a knowledge-based society.10 according to fergany, “the arab region also has far fewer researchers and engineers, and produces fewer scientific publications, than any other world region, apart from sub-saharan africa” (p. 33).9 however, to put all arab countries into one category is erroneous, despite their common heritage and language, given that the multiplicity of factors contributing to growth in medical research will vary from country to country. given this diversity among arab countries, it would be better to compare those countries that may have some socio-economic characteristics in common. health care facilities and research institutes in the arabian gulf countries (bahrain, kuwait, oman, qatar, saudi arabia, and united arab emirates [uae]), formally known as the gulf cooperation council (gcc), have witnessed significant growth in the last 40 years. in the case of oman, the world health organization has ranked it as the most “efficient” health care system in the world.11 postnatal care and coverage is the highest among the arab nations12 and the country has generally triumphed over the traditional enemies of health such as communicable diseases,13 even though it is now facing the emerging challenge of ‘diseases of civilization’.14 such a trend has coincided both with an increased number of physicians in the country and an improved standard of living, a result of growth in gross domestic product (gdp).15 however, to our knowledge, no study has been done in the gcc to document the relationship between current trends in biomedical publications output and socio-economic factors. previous studies have either focused on an individual country16 or have compared the gcc region with non-gcc countries.8 similarly, earlier attempts to quantify trends in publication output in the gcc were limited to descriptive analysis.16–18 gcc countries represent a fertile ground for examining the relationship between economic indicators and research output. these countries share sociopolitical outlooks, but their stage of economic development varies. therefore, studies are needed to evaluate medical research against demographic and economic indicators. in the past four decades, these countries, like other emerging economies, have witnessed unprecedented economic growth fueled by the exploitation of hydrocarbons. the interrelated aims of the present study are to ascertain the number of biomedical publications from the gcc in the period 1970 to 2010 in order to calculate the rate of publication per million of the population (ppmp) per year in this period, and to examine the relationship between the number of publications (ppmp) and the number of physicians per 1,000 and gdp per capita. additionally, this study endeavours to extrapolate the trends in the gcc with some reflection on the situation in oman. methods electronic databases provide a good estimate of biomedical publication productivity. medline is the most widely used international database for health research. the medline database was searched during the last week of october 2010. the search strategy included search by affiliation, years and publication application to patient care studying biomedical research profile and improving research productivity has a direct impact on improving patient care. many research studies lay the groundwork for evidence-based medicine and the formulation of health policy, planning and management almundher al-maawali, ahmed al busadi, samir al-adawi clinical and basic research | 43 type. affiliation included the country names written in different forms (e.g. saudi arabia, ksa, or saudi). the time period investigated was 1970 to 2010 as there were very few articles published before 1970. the trends in publication numbers for each five year period were extrapolated using the period interface limits in medline. we limited the publication type to journal articles. data obtained were normalised to the number of publications per million of the population (ppmp), gdp, and the number of physicians (per hundred of the population) in each of the countries. these demographic and economic indicators were retrieved from the world bank.19 the data were analysed using microsoft excel (microsoft office 2007). results the number of articles for the gcc published over the 40 year period 1970 to 2010 was 25,561. saudi arabia had the highest number of publications followed by kuwait, the uae, and then oman. figure 1 presents the absolute number of publications retrieved from the medline database. the average size of the population for each country from 1970 to 2010 was calculated and the normalisation to ppmp per year is presented in figure 2. kuwait had the highest number of publications when normalised to population size, followed by qatar. oman was the lowest in this ranking. overall, all the countries showed a positive trend. medical research output has been blooming in qatar, showing a strong positive trend for the period 2000 to 2010. oman had a significant increase in the number of publications in the period 1990 to 2005; however, the trend has plateaued in the last five years. a similar observation was noted in both saudi arabia and the united arab emirates for the last 10 years [figure 3]. in kuwait, there was a negative trend in the early and mid 1990s, probably due to the second gulf war. the third interrelated aim of this study was to gauge the research output (ppmp) against the number of physicians per 100 and gdp. the gdp per capita averages for every five year interval and the average number of physicians per 100 of the population for the same interval were calculated, and then the correlation between these parameters examined independently and the ppmp extrapolated. there was a significant positive correlation between the number of publications and number of physicians (r = 0.69, p <0.05) and a similar positive correlation between ppmp and gdp per capita (r = 0.26, p = 0.08), but it was not statistically significant. figure 4 shows the comparison in respect to the 40 year averages of these three parameters. discussion this study is, to our knowledge, the first detailed analysis of publication productivity in the gcc which traces the research trend over the last 40 years. there are several factors that determine the medical bibliometric productivity in any country, which include, but are not limited to, population size, the number of physicians, and economic status. figure 1: the absolute number of publications retrieved from medline database over the period january 1970 to october 2010. biomedical publications profile and trends in gulf cooperation council countries 44 | squ medical journal, february 2012, volume 12, issue 1 we corrected the total number of publications with some of these parameters in order to elicit national differences. these parameters have been used by several studies in order to normalise bibliometric productivity.20 saudi arabia had the highest overall publication rate followed by kuwait, the uae and then oman. in order to audit the present findings, we used the scimago journal & country rank, to retrieve the citations of all documents published in the period 1996–2010 from gcc countries.21 table 1 shows the rank of each of these countries according to the citations. it is observed that the citation ranking is similar to our initial approach as depicted in figure 1. the percentage of self-citations of these countries is lower than 14%. the h index (hirsch index) measures both the productivity and impact of the work published, integrates the number of publications and the number of citations per publication and serves as a very good tool for examining the quality of research. saudi arabia has had the highest h index while bahrain has had the lowest h index. when the publication rates were scrutinised against socio-economic indicators, the productivity changed. kuwait had the highest rate and oman the lowest. all the countries showed a positive trend in general over the past 40 years. the trend changed in the period 2001–2005 in oman when it increased to become equal to that of the uae. the trend has remained the same for the last ten years in both saudi arabia and the uae.22 it is very interesting to note that the rate became linear for all countries after 2005 with the exception of qatar. this was period when qatar instituted massive investment in research and development (r&d).23 however, the relatively small absolute number of publications from qatar, together with a surprisingly large number of physicians in that country, compared to the rest of the gcc, may make this a spurious result. future studies need to provide mechanisms to counter such inherent limitations. nonetheless, it is possible that this significant change may have stemmed from the fact that, in qatar, r&d has been given preference over tourism and real estate development.24,25 in addition to ppmp, there is an indication that many social and economic factors play a pivotal role in research output. these include gnp, the number of physicians, public expenditure in the health sector, health expenditure per capita, expenditure on r&d, the number of personnel (scientists and engineers) in the r&d sector, and the number of indexed journals published. rahman and fukui surveyed global research productivity in 166 countries right across the economic divide and showed that there is a critical relationship between gnp, resources allocated to r&d, and the quality and quantity of biomedical publications.1 such a link was indirectly explored in figure 2: the average number of publications per million population (ppmp) per year over a 40 year period from 1970 to 2010. table 1: scimago journal & country rank: citations of all articles published 1996-2000 in gulf cooperation council countries country articles citations selfcitations percentage of self citations citations per articles hirsch index saudi arabia 12,303 71,843 8,813 12% 6.31 80 kuwait 3,101 19,835 2,254 11% 7.13 48 united arab emirates 2,776 16,754 1,498 9% 7.05 45 oman 1,518 6,710 610 9% 5.15 29 qatar 1,179 3,841 416 11% 4.49 24 bahrain 1,075 3,184 431 14% 3.65 22 almundher al-maawali, ahmed al busadi, samir al-adawi clinical and basic research | 45 the present study. qatar had the highest gdp per capita compared to other gcc countries, while oman had the lowest. however, the paradox here is that despite the fact that these countries are ‘high income’ according to global standards, the number of publications they produce leaves much to be desired, with the exception of some medical research subspecialties.26 within the gcc, the differences could be a result of resource allocation. in 2010, for those countries where information is available, qatar spent 2.8% of gdp on r&d, while saudi arabia and kuwait spent 0.05 and 0.09%, respectively. an additional reason for qatar’s success may be that the country has the highest number of physicians per 100 of the population. this, in turn, may also explain the presently noted linear growth in qatar’s publication numbers. there are some obvious limitations to the present study that need to be acknowledged. first, while medline is a premier database for biomedical sciences, there are a number of medical publications that are not featured in it. with a few exceptions, figure 3: the trend in numbers of publications corrected to publication per million of the population over interval periods between 1970 and 2010. figure 4: comparison across countries for the period 1970 to 2010 giving the average number of publications per million population (ppmp), gross domestic product (gdp) and physicians. biomedical publications profile and trends in gulf cooperation council countries 46 | squ medical journal, february 2012, volume 12, issue 1 many of the medical publications in the gcc region are not indexed in medline. there is also a concern that research from developing countries, including those in this study, do not get favourable editorial consideration in the major journals featured in medline.6 if this is really the case, then it could be extrapolated that the visibility of articles from the gcc would be inevitably be affected. this would also mean that the number of publications and their impact on scientometrics is likely underestimated.27 however, even if such misgivings are accepted, the present quest has heuristic value since the aim was to compare the biomedical research trends among gcc countries. secondly, in order to compare adequately the trend in gcc countries, it would be essential to include local journals; however, many of the local journals are not yet indexed. this is a paradoxical situation for biomedical research in this region. on one hand, the local journals are finding it extremely difficult to get indexed while, on the other hand, research from this part of the world does not get international exposure. despite such caveats, some gcc countries have benefitted from having their local medical journals indexed by medline, thus adding to the total number of publications. in the period under review, saudi arabia published 4,197 articles in indexed gcc journals, kuwait published 411 articles, qatar published 69 articles, the uae 32, bahrain 88 and oman 138 articles. the third limitation worth considering is that, although the present study has examined trends in publications against certain socio-economic indicators, in the parlance of scientometrics, the citation index or impact factor is the sine qua non of good research. the present study has not taken on board either the citation index or the impact factors of the articles in the medline from the gcc region. it would also have been helpful to consider the relationship between the number and history of medical schools in the region and their relationship to the number of publications. common sense teaches us that more research centres or, in the present parlance, a greater number of medical schools, would translate into more research activity and hence, an increased number of publications. it is also possible, however, that most of the academic centres in the region are more interested in teaching than pursuing academic research.6 however, since such a line of thought was not central to the present study, it would need to be addressed in a future study. last but not least, it is possible that generalisation of the present study could be hampered by the fact that the search for the publications was partly based on the affiliations of the authors. in some journals, an affiliation is only provided for the corresponding author. therefore, the possibility remains that there are more publications that originated from gcc countries than were reported in this study. despite the aforementioned caveats, it is right to acknowledge the achievements so far and delineate the hurdles still to be overcome in the gcc region. there is an urgent need to increase institutional support for r&d following the model of qatar.28 in the context of oman, allocating more research funding would be essential, if not paramount. such an undertaking should be enshrined in the policies for r&d development. there are already some good examples in this regard, for example, oman established a research council in 2005.29 despite its infancy, this body has funded some strategic research projects that have a direct bearing on biomedical sciences.30 the expected outcome of these projects is an increase in the number of publications which should further help to put oman on the world map of biomedical publications. in tandem with the oman research council, the oman medical specialty board and the college of medicine & health sciences at sultan qaboos university encourage research in all phases of medical education. the explicit goal here is to equip the future cadre of oman health professionals with research skills. conversely, and relevant to oman, there are some issues to be contemplated. first, it should be acknowledged that there are a number of biomedical journals in oman and, as in other gcc countries, concerted efforts should be made to feature these journals in various indexes, especially medline, so that gcc publications are accessible to the global audience. second, it is essential to improve the existing research culture in the region. health professionals and those in allied fields should be given incentives to pursue research as a career option, and the path towards tenure should be based on merit rather than on the existing form of ‘academic nepotism’. another constraint on the development of biomedical research is the idea that health care should focus on dispensing services. notwithstanding such a view, research could contribute to the betterment of just those services. the establishment of a knowledgealmundher al-maawali, ahmed al busadi, samir al-adawi clinical and basic research | 47 based health care system would have many positive implications. for example, a medical curriculum could be developed to reflect the prevailing sociodemographic and epidemiological trends in the country. this would likely result in evidence-based allocation of resources and the establishment of an enlightened health care system in the country. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest and stated that no funding was received for this work. references 1. rahman m, fukui t. biomedical publication global profile and trend. public health. 2003; 117:274−80. 2. hyder aa, corluka a, winch pj, el-shinnawy a, ghassany h, malekafzali h, et al. national policymakers speak out: are researchers giving them what they need? health policy plan 2011; 26:73−82. 3. patel v, kim yr. contribution of low and middleincome countries to research published in leading general psychiatry journals 2002-2004. br j psychiatry 2007; 190:777. 4. garg kc. an overview of cross-national, national, and institutional assessment as reflected in the international journal scientometrics. scientometrics 2003; 56:169−99. 5. karageorgopoulos de, lamnatou v, sardi ta, gkegkes id, falagas me. temporal trends in the impact factor of european versus usa biomedical journals. plos one 2011; 6:e16300. 6. aladawi sh, ali bh. west is west, east is east. the divide in science. saudi med j. 2010; 31:1093−4. 7. benamer ht, bakoush o. arab nations lagging behind other middle eastern countries in biomedical research: a comparative study. bmc med res methodol 2009; 9:26. 8. tadmouri go, bissar-tadmouri n. biomedical publications in an unstable region: the arab world, 1988-2002. lancet 2003; 362:1766. 9. fergany n. islam and science: steps towards reform. nature 2006; 444:33−4. 10. arab human development report 2009: challenges to human security in the arab countries. from: http://www.arab-hdr.org/contents/index. aspx?rid=5. accessed: oct 2010. 11. lauer ja, knox lovell ca, murray cj, evans db. world health system performance revisited: the impact of varying the relative importance of health system goals. bmc health serv res 2004; 4:19. 12. unicef. the state of the world’s children 2010. oxford: oxford university press, 2010. 13. ganguly ss, al-lawati a, alshafaee ma, duttagupta kk. epidemiological transition of some diseases in oman: a situational analysis. world hosp health serv 2009; 45:2631. 14. aladawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos univ med j 2006; 6:3−9. 15. ghosh b. health workforce development planning in the sultanate of oman: a case study. hum resour health 2009; 7:47. 16. alkhader aa, aljondeby ms, shaheen fa. impact of nephrology publications from saudi arabia in the last decade. saudi med j 2002; 23:1177–80. 17. deleu d, northway mg, hanssens y. geographical distribution of biomedical publications from the gulf corporation council countries. saudi med j 2001; 22:10–2. 18. shaban sf, abu-zidan fm. a quantitative analysis of medical publications from arab countries. saudi med j 2003; 24:294–6. 19. the world bank. oman report. from: http://data. worldbank.org/country/oman. accessed: january 2012. 20. king da. the scientific impact of nations. nature 2004; 430:311–16. 21. scimago. scimago journal & country rank 2007. from: http://www.scimagojr.com. accessed: oct 2011. 22. neves k, lammers wj. growth in biomedical publications and scientific institutions in the emirates (1998-2004): an arabian renaissance? health info libr j 2007; 24:41–9. 23. chouchane l, mamtani r, al-thani mh, al-thani aa, ameduri m, sheikh ji. medical education and research environment in qatar: a new epoch for translational research in the middle east. j transl med 2011; 9:16. 24. el amrousi m, john biln. muscat emerging: tourism and cultural space. j tourism cult change 2010; 8:254–66. 25. steiner c. political instability, transnational tourist companies and destination recovery in the middle east after 9/11. tourism plan & develop 2007; 4:169−90. 26. lammers wj, karam sm. emerging excellence in neurogastroenterology and motility research in the arabian peninsula. neurogastroenterol motil 2010; 22:946−9. 27. fava ga, ottolini f. impact factors versus actual citations. psychother psychosom 2000; 69:285−6. 28. chouchane l, mamtani r, althani mh, althani aa, ameduri m, sheikh ji. medical education and research environment in qatar: a new epoch for translational research in the middle east. j transl med 2011; 27:9−16. 29. oman research council. from: http://www.trc.gov. om/trcwebsite/decree.htm accessed: apr 2011. 30. oman daily observer. squ college of medicine contemplates research. 9 may 2010. from: http:// main.omanobserver.om/node/8968. accessed: apr 2010. 1department of epidemiology, ministry of health affairs, jeddah, saudi arabia; 2department of postgraduate studies, suliman alfaqih college, jeddah, saudi arabia; 3department of family & community medicine, princess nourah bint abdulrahman university, riyadh, saudi arabia *corresponding author’s e-mail: smalhabib@yahoo.com العنف يف مكان العمل ضد طاقم التمريض يف مستشفيات األمراض النفسية وجهات نظر من اململكة العربية السعودية وفاء با�سفر، اأحالم حمدان، �سامية احلبيب abstract: objectives: workplace violence (wpv) has become a world-wide concern. this study aimed to measure the prevalence of wpv among nurses working in psychiatric hospitals in saudi arabia. methods: this cross-sectional study was conducted at three psychiatric hospitals in saudi arabia between march and may 2017. participants compl eted a self-reported questionnaire which was used to measure the prevalence and explore the associated factors of wpv. a multivariate logistic regression analysis was also performed. results: a total of 310 nurses (response rate: 62%) were included in this study. the prevalence of wpv against nurses was 90.3%, of which 57.7% had been exposed to both physical and verbal abuse. more nurses were exposed to wpv during the morning shift than the evening shift (58.4% versus 42.3%). violent behaviour was exhibited mostly by the patients themselves (81.3%). over half of the nurses (57.4%) required medical intervention in such cases. the majority of nurses felt either stressed (64.2%) or anxious (53.5%) and 34.2% felt depressed after the incident. multivariate logistic regression analysis revealed that time of violence, source of violence, patient dissatisfaction with medical care and lack of organisational support for nurses were significantly associated with the occurrence of wpv in psychiatric units. conclusion: wpv has reached an alarming rate among nurses in psychiatric hospitals in saudi arabia. it is crucial to invest in the prevention of wpv by constant training of workers and a mutual policy with the police and the civic prosecutor in saudi arabia on how to respond to violent psychiatric patients. keywords: workplace violence; psychiatry; nurse; mental health; saudi arabia. امللخ�ص: الهدف: اأ�سبح العنف يف مكان العمل م�سدر قلق عاملي. تهدف هذه الدرا�سة اإىل قيا�ض معدل انت�سار العنف �سد طاقم التمري�ض العاملني يف م�ست�سفيات الأمرا�ض النف�سية يف اململكة العربية ال�سعودية الطريقة: اأجريت هذه الدرا�سة امل�ستعر�سة يف ثالثة م�ست�سفيات لالأمرا�ض النف�سية يف اململكة العربية ال�سعودية بني مار�ض 2017 ومايو 2017. اأكمل امل�ساركون ا�ستبيانا ذاتيا والذي مت ا�ستخدامه لقيا�ض انت�سار وا�ستك�ساف العوامل املرتبطة بالعنف يف اأماكن العمل. ومت اإجراء حتليل النحدار املتعدد. النتائج: مت ت�سمني ما جمموعه 310 ممر�ض وممر�سة )مبعدل ا�ستجابة: %62( يف هذه الدرا�سة. بلغت ن�سبة انت�سار العنف يف مكان العمل �سد املمر�سني %90.3، منهم 57.7% تعر�سوا لالإيذاء اجل�سدي واللفظي. تعر�ض عدد اأكرب من املمر�سني للعنف خالل مناوبة ال�سباح اأكرث من مناوبة امل�ساء )%58.4 مقابل %42.3(. مت ت�سجيل ال�سلوك العنيف يف الغالب من قبل املر�سى اأنف�سهم )%81.3(. ويف اأكرث من ن�سف املمر�سني )%57.4( تطلب التدخل احلادث. بعد بالكتئاب �سعروا 34% و )53.5%( القلق اأو )64.2%( بالإجهاد �سعروا للعنف تعر�سوا الذين غالبية اليذاء. لعالج الطبي للممر�سني التنظيمي الدعم ونق�ض الطبية الرعاية من املر�سى وا�ستياء العنف، وم�سدر العنف، وقت اأن املتعدد النحدار حتليل ك�سف ارتبط ب�سكل كبري مع حدوث العنف يف الوحدات النف�سية. اخلال�صة: لقد و�سلت ن�سبة العنف �سد طاقم التمري�ض اإىل معدل ينذر باخلطر يف م�ست�سفيات الأمرا�ض النف�سية باململكة العربية ال�سعودية. من الأهمية مبكان الإ�ستثمار يف الوقاية من العنف من خالل التدريب امل�ستمر لطاقم التمري�ض و�سيا�سة التعاون امل�سرتك مع ال�رسطة والأدعاء العام يف اململكة العربية ال�سعودية لدعم التمري�ض يف كيفية ال�ستجابة لعنف مر�سى الطب النف�سي. الكلمات املفتاحية: العنف يف مكان العمل؛ الطب النف�سي؛ التمري�ض؛ ال�سحة النف�سية؛ اململكة ال�سعودية. workplace violence against nurses in psychiatric hospital settings perspectives from saudi arabia wafa basfr,1 ahlam hamdan,2 *samia al-habib3 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e19–25, epub. 30 may 19 submitted 2 sep 18 revision req. 30 sep 18; revision recd. 11 nov 18 accepted 19 dec 18 advances in knowledge this study provided an insight into the estimate, associated factors and characteristics of workplace violence (wpv) amongst nurses working in three psychiatric hospitals in saudi arabia. it highlighted the possible contextual factors surrounding workplace violence and the interactions with these factors. application to patient care the present study emphasised the importance of patients’ characteristics and their dissatisfaction of nurses and medical care, which might contribute to the occurrence of wpv. the results of this study could help in tackling wpv with particular emphasis on the training of nurses on how to deal with and react to such violence safely and with special consideration to patients’ mental health status. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.005 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ workplace violence against nurses in psychiatric hospital settings perspectives from saudi arabia e20 | squ medical journal, february 2019, volume 19, issue 1 workplace violence (wpv) has been apersistent problem that is accepted and generally overlooked by the public and professional organisations.1 there has been an increasing concern worldwide about the rise in wpv. it has been defined by the national institute for occupational safety and health “as violent acts (including physical assaults and threats of assaults) directed toward persons at work or on duty” and it “ranges from offensive or threatening language to homicide”.2 the world health organization highlighted that wpv includes “incidents where staff are abused, threatened or assaulted in circumstances related to their work, including commuting to and from work, involving an explicit or implicit challenge to their safety, well-being or health”.3 on an international level, it has been noticed that the highest number of these assaults are directed towards healthcare workers.4 a study in canada found that the overall patient violence rate over a one year period was 1.52 incidents per 100,000 worked hours.5 studies have emphasised that the well-being of healthcare staff and a healthy workplace are considered key components of effective healthcare systems. this should be applied to all sectors in any healthcare setting. this is particularly important among psychiatric nurses, who may be exposed to verbal, physical, emotional and psychological abuse.2,6 a systematic review by iozzino et al. emphasised that almost one in five patients admitted to acute psychiatric units may commit an act of violence towards nurses working within these units.7 it is possible that these mentally unstable patients might be stressed and there fore express their anger towards the nurses who care for them. iozzino et al. also found that factors associated with levels of violence in psychiatric units—including male gender, diagnosis of schizophrenia, substance use and a lifetime history of violence—were similar to factors associated with violence among individual patients.7 in turkey, wpv is considered an important issue that adversely affects the personal lives of healthcare professionals and leads to a high staff turnover.8,9 these studies found that such violence is particularly common among nurses compared to other healthcare providers. furthermore, among healthcare workers in iran, it was found that nurses reported the highest rate of violence; 74.7% of the participants were subjected to psychological violence.10 in saudi arabia, wpv has been explored in primary healthcare and studies have revealed a wide range of wpv prevalence (28–67.5% in 12 months), especially among nurses working in outpatient primary health care settings.11,12 however, this study proposes that wpv is more serious in other inpatient hospital settings, such as in psychiatric care units where patients are mentally unstable and might be more aggressive. the safety of hospital staff is of paramount importance for the continuity and quality of care in all healthcare settings. therefore, this study aimed to measure the prevalence and explore the associated factors of wpv among nurses working in mental-care hospitals in saudi arabia. methods this cross-sectional study was conducted between march and may 2017 at three main psychiatric hospitals loc ated in the western region of saudi arabia. a total of 938 nurses worked in these three hospitals and it was initially intended to include all nurses. however, it was only possible to distribute 500 questionnaires due to a high turn-over of nurses between hospitals, some nurses being on holiday, attending courses or being assigned to administrative work. the questionnaires were distributed to all participants via their hospital postal system. nurses working in direct contact with psychiatric patients were included. participants were asked to complete a self-reported questionnaire, which has previously been used in several countries with a similar cultural context as saudi arabia.11,13–15 the language of the questionnaire was english in order to ensure its originality and avoid language-based distortions related to measurements of violence. the questionnaire was composed of 32 items under four sections: 1) sociodemographic variables; 2) questions measuring the freq uency and type of wpv; 3) items asking participants on how they respond to such violence; and 4) open-ended questions exploring their needs in managing wpv the scale was scored with ‘yes’ or ‘no’ and participants were asked to tick the choices that applied to their situation. the explanation of the nature of each type of wpv (physical, verbal or both) was provided to all participants in a covering letter attached to the questionnaire, incl uding examples of types of wpv. the questionnaire was reviewed by two epidemiol ogists, four researchers and three professors in the nursing college of suliman alfaqih in order to check its consistency, appropriateness and the relevance of the items. furthermore, a pilot study including 30 nurses was conducted to ensure questionnaire applicability, wording and to identify any ambiguities in the items, after which the suggested changes were implemented and the quest ionnaire was modified accordingly. this pilot study is not reported here and was excluded from the results and analysis of the present study. completed questionnaires were returned to a dedicated postal box in each hospital. all written materials were protected in secure closed cabinets accessible only to the researchers. data were analysed using statistical package for social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the level of statistical significance was set wafa basfr, ahlam hamdan and samia al-habib clinical and basic research | e21 at p ≤0.05. a multivariate logistic regression model using a forward (wald) model was also performed. a consent form was signed by all participants and confidentiality was ensured by maintaining a completely anonymous involvement in the study. approval for this study was obtained from the instructional review board ethics committee of fakeeh college for medical sciences, riyadh, saudi arabia. results a total of 310 nurses (response rate: 62%) completed the questionnaire and were included in the study. during the study period, many nurses were in transition between various departments, on leave or not interested in parti cipating. the majority of the participants were middleaged married saudi females, mainly working in the inpatient department, with a diploma degree in nursing and an experience of 1–10 years [table 1]. the prevalence of wpv against nurses was 90.3%; 43.2% were exposed to wpv more than three times in the last year and 57.7% had experienced both physical and verbal abuse. most nurses were exposed to wpv during their morning shift (58.4%) followed by the after noon (50.3%), evening (42.3%) and night shift (33.9%). the majority of violence originated from the patients themselves (81.3%) and some wpv came from their relatives (30%), visitors (26.1%), or co-workers (25.8%) [table 2]. the majority of participants were rarely (24.2%) or sometimes (32.3%) concerned about wpv. after exposure to wpv, 57.4% of nurses required medical intervention and 15.8% experienced life-threatening acts that required emergency care. the majority felt either stress (64.2%) or anxiety (53.5%), while 34.2% felt depressed and few (8.4%) were not interested in attending work and were considering leaving their job [table 2]. nurses differed in their response to wpv and many selected more than one option when reacting to such acts. over half of the nurses (54.2%) would report the wpv to their manager, 40.6% spoke to colleagues and 30% requested to be transferred to another department [table 3]. participants perceived that psychological problems (69.7%), shortage of staff (44.8%), denial of patients’ request for admission (41%), smoking prohibition in thepsychiatric inpatient wards (37.1%), overcrowding of the inpatient wards (33.9%), long waiting times in the outpatient clinics (29.7%) and violation of visiting hours (28.4%) contributed to wpv [table 4]. participants also selected options from a range of preventive measures and the required resources to tackle wpv. the majority (61%) chose to train nurses on managing wpv and how to cope with stress associated with such violence. additionally, over half of the participants (56%) selected the option that addressed the importance of policies related to wpv. many (45%) also chose the option of awareness programmes to the public and staff with regards to unacceptable violent behaviour in a hospital environment. some (39.4%) selected the option of the role of organisational support for victims of violence. univariate analysis of wpv occurrence revealed significant associations with several factors. however, a multivariate logistic regression revealed the dependent table 1: characteristics of nurses working at psychiatric hospitals in saudi arabia (n = 310) characteristic n (%) age 20–29 95 (30.6) 30–39 158 (51) 40–49 40 (12.9) 50–59 17 (5.5) gender male 142 (45.8) female 168 (54.2) marital status single 95 (30.6) married 193 (62.3) divorced 14 (4.5) widow 8 (2.6) nationality saudi arabian 214 (69) not saudi arabian 96 (31) qualification in nursing diploma 190 (61.3) bachelor 103 (33.2) master 17 (5.5) experience in psychiatric units in years <1 31 (10) 1–5 85 (27.4) 6–10 105 (33.9) 11–15 43 (13.9) >15 46 (14.8) working shift day 132 (42.6) evening 35 (11.3) night 19 (6.1) rotating days and nights 46 (14.8) rotating days, evenings and nights 78 (25.2) psychiatric department emergency 54 (17.4) inpatient 204 (65.8) outpatient 52 (16.8) workplace violence against nurses in psychiatric hospital settings perspectives from saudi arabia e22 | squ medical journal, february 2019, volume 19, issue 1 variables that were significantly associated with wpv after controlling for other socio-demographic variables and other possible confounders, such as age and years of experience. wpv mostly occurred during the evening time (odds ration [or]: 2.91; 95% confidence interval [ci]: 1.19–7.09; p = 0.02). patients (or: 2.99; 95% ci: 1.26–7.08; p = 0.01) and their relatives (or: 0.29; 95% ci: 0.11–0.74; p = 0.01) were the main sources of violence. patients’ dissatisfaction with nursing or med ical care was significantly associated with more wpv table 2: prevalence, types and characteristics of work place violence experienced by nurses working at psychiatric hospitals in saudi arabia (n = 310) wpv characteristic n (%) experienced violence at work yes 280 (90.3) no 30 (9.7) numbers of violent attacks in the previous year once 59 (19) twice 47 (15.2) three times 43 (13.9 more than three times 134 (43.2) type of violence physical abuse 44 (14.2) verbal abuse 61 (19.7) both 179 (57.7) consequence of violence medical intervention required 176 (57.4) life-threatening 49 (15.8) both 53 (17.1) concerned regarding violence at work never 23 (7.4) rarely 75 (24.2) sometimes 100 (32.3) usually 72 (23.2) always 40 (12.9) timing of wpv morning yes 181 (58.4) no 129 (41.6) afternoon yes 156 (50.3) no 154 (49.7) evening yes 131 (42.3) no 179 (57.7) night yes 105 (33.9) no 205 (66.1) source of violence patient's relative yes 93 (30) no 217 (70) patient yes 252 (81.3) no 58 (18.7) co-worker yes 80 (25.8) no 230 (74.2) visitor yes 81 (26.1) no 229 (73.9) feeling after exposure to wpv stress yes 199 (64.2) no 111 (35.8) anxiety yes 166 (53.5) no 144 (46.5) depression yes 106 (34.2) no 204 (65.8) no interest in going to work; consider leaving job yes 26 (8.4) no 284 (91.6) wpv = workplace violence. table 3: participants’ response to workplace violence at psychiatric hospitals in saudi arabia (n = 310) response after exposure to a wpv incident n (%)* no response 89 (28.7) talking to family and friends 73 (23.5) request to be transferred to another department 93 (30) pretending nothing happened 50 (16.1) getting professional help 98 (31.6) getting help from the police 21 (6.8) warning the patient 79 (25.5) talking with colleagues 126 (40.6) reporting incident to the manager 168 (54.2) reacting with violence 46 (14.8) getting legal help 26 (8.4) wpv = workplace violence. *participants had the option of choosing more than one item. wafa basfr, ahlam hamdan and samia al-habib clinical and basic research | e23 (or: 2.70; 95% ci: 1.03–7.09; p = 0.04). the lack of organisational support to nurses exposed to such viol ence was significantly associated with the occurrence of wpv (or: 0.33; 95% ci: 0.14–0.79; p = 0.01) [table 5]. discussion the results of the present study showed that nurses in saudi arabia were exposed to wpv, similar to other nurses who work in psychiatric hospitals worldwide. however, there are some differences in terms of frequency and type of wpv as well as other associated factors. in the present study, the prevalence of wpv (90.3%) was higher than that reported in studies from china (50–76%), egypt (27.7%) and taiwan (49.6%).16–19 the high prevalence in the present study may be due to the lack of policies related to wpv in saudi arabian hospitals, which could contribute to the continuity of such violence. it was previously reported in a study by hatchmaillette et al. that 100% of the nurses experienced wpv at some point in their careers.20 such variability may be due to the different instruments used to measure wpv in various countries with diverse laws and health system regulations. moreover, this might be because of differences in the definitions of violence and variations in the levels of under-reporting of wpv episodes by mental healthcare personnel. the high prevalence of wpv in the current study could also be explained by the nurses’ lack of awareness of wpv, which reflects the lack of training and support from their hospital; this may subsequently lead to the occurrence of wpv. these concerns should be explored further using in-depth interviews and/or focus groups in order to elaborate the dimensions and factors underlying their perceptions about wpv. the current study’s participants were exposed to both physical and verbal abuse, mostly during morning and afternoon shifts. this is consistent with other studies that showed a high level of both verbal abuse and physical violence towards healthcare professionals, in particular, mental healthcare workers.10,21,22 the current study showed that the source of wpv was mainly the psychiatric patients themselves followed by their relatives. this is similar to other studies which revealed that the main perpetrators of wpv were patients followed by their relatives.23,24 in addition to possible physical consequences, psych ological consequences may also be significant.1 tonso et al. reported that almost one in three victims of violence (33%) rated themselves as being in psychological distress, while in the current study almost two in three felt the same (64.2%).25 a study by van leeuwen et al. in the dutch mental health system revealed that one in five healthcare professionals working in psychiatric inpatient units experienced mental health complications as a consequence of wpv.26 in addition, some (8.4%) of the current study’s participants expressed a lack of interest to go to work or considered leaving their job. this is consistent with nijman et al.’s study that indicated that wpv was associated with a decrease in productivity and higher rates of work non-attendance.27 violence against nurses is thought to contribute to low morale, high rates of sick leave and increased turnover.28 this may instigate a cycle, as decreased staffing levels and table 4: participants’ perception of causes of workplace violence at psychiatric hospitals in saudi arabia (n = 310) perceived causes of wpv n (%)* violation of visiting hours 88 (28.4) long waiting periods in outpatient clinics 92 (29.7) psychological problems 216 (69.7) smoking prohibition in inpatient wards 115 (37.1) denial of patients' admission to the hospital 127 (41) delays in nursing care provision 54 (17.4) delays in medical care provision 65 (21) patient dissatisfaction with nursing or medical care 64 (20.6) shortage of staff 139 (44.8) the patients' requests not satisfied 84 (27.1) poor organisation 68 (21.9) overcrowded inpatient ward 105 (33.9) patients' health condition 138 (44.5) wpv = workplace violence. *participants had the option of choosing more than one item. table 5: multivariate logistic regression model using for ward (wald) model of factors associated with workplace violence towards nurses in psychiatric hospitals in saudi arabia variable or (95% ci) p value time violent incident occurred evening 2.91 (1.19–7.09) 0.02 source of violence relatives 0.29 (0.11–0.74) 0.01 patients 2.99 (1.26–7.08) 0.01 cause patient dissatisfaction with nursing or medical care 2.70 (1.03–7.09) 0.04 organisational support for victims of violence 0.33 (0.14–0.79) 0.01 constant 3.08 0.005 or = odds ratio; ci = confidence interval. workplace violence against nurses in psychiatric hospital settings perspectives from saudi arabia e24 | squ medical journal, february 2019, volume 19, issue 1 the presence of temporary staff can lead to more episodes of violence.29 the majority of the current participants responded to the wpv by reporting the incident to their manager (54.2%), which is comparable with speroni et al.’s study where nurses reported incidents to managers or super visors.30 while several nurses (40.6%) chose to talk to their colleagues about their exposure to such violence, 30% requested to be transferred to another department. participants’ perceptions of the causes of wpv rev ealed multiple reasons, including psychological problems of patients, shortage of staff, denial of patients’ request for admission, smoking prohibition in the psychiatric inpatient wards, overcrowded inpatient wards, long waiting times in outpatient clinics and during visiting hours. park et al.’s study showed that heavy work man dates under time pressure caused by shortage of staff, less trust and justice and a high patient turn-over created stressful situations for patients, families and healthcare workers.23 there were some limitations in the current study. there was a relatively low response rate (62%), but this could be due to several factors such as during the recr uitment period, there was a high turn-over of nurses between hospitals and some were also on leave, attending courses or assigned to administrative work. however, it should be noted that other studies have reported an even lower response rate (25–26%).15,25 there were discr epancies between the simple prevalence statistics and the regression statistics. this could be due to missing data in some of the items in the questionnaire. add itionally, some of the questionnaire sections allowed participants to choose more than one option and, hence, some estimates reflect these selections. moreover, some healthcare workers who experienced serious physical or mental injuries due to wpv have left their jobs in mental healthcare and could not be reached. in addition, there might be a selection bias, resulting in more nurses who experienced wpv disproportionately completing the survey. the current findings should be seen in light of these limitations. in future research, comparable methodologies, instruments and definitions could be used to establish a clearer conceptual framework. the authors’ also suggest that in order to decrease the frequency of wpv, it is crucial to invest in its prevention by constant training of healthcare professionals to improve their verbal comm unication skills and other necessary techniques that are implemented in psychiatric units. however, even if staff are well-trained, wpv may still occur. hence, it is of utmost importance that workers communicate that violence against them will not be tolerated under any circumstance and it may also have legal consequences. for that purpose, it is fundamental for all mental health organisations to have a mutual policy, which may involve the police and the judicial system, on how to react to violent psychiatric patients. conclusion in healthcare settings, wpv is an occupational hazard with detrimental effects on work-related health. such violence has reached an alarming rate among nurses working in three psychiatric hospitals in saudi arabia. workplace characteristics and the interface between patients and healthcare professionals are important contextual factors that can contribute to the development of wpv. this study revealed that important factors associated significantly with wpv included lack of organisational support for nurses as wpv victims, staffing levels and patients’ and/or relatives’ dissatisfaction with the psychiatric care. these factors must be kept in mind to create policies and manage violence in a psychiatric healthcare setting. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. phillips jp. workplace violence against health care workers in the united states. n engl j med 2016; 374:1661–9. https://doi.org/10. 1056/nejmra1501998. 2. centers for disease control and prevention. violence occupational hazards in hospitals. from: https://www.cdc.gov/niosh/docs/20 02-101/default.html accessed: dec 2018. 3. world health organization. workplace violence: world health organisation 2005 from: https://www.who.int/violence_injury_ prevention/injury/work9/en/index2.html accessed: dec 2018. 4. federal bureau of investigation, u.s. department of justice. work place violence: issues in response. from: https://www.fbi.gov/sta ts-services/publications/workplace-violence accessed: dec 2018. 5. kling rn, yassi a, smailes e, lovato cy, koehoorn m. charac terizing violence in health care in british columbia. j adv nurs 2009; 65:1655–63. https://doi.org/10.1111/j.1365-2648.20 09.05020.x. 6. chapman r, styles i, perry l, combs s. nurses' experience of adjusting to workplace violence: a theory of adaptation. int j ment health nurs 2010; 19:186–94. https://doi.org/10.1111/j.14 47-0349.2009.00663.x. 7. iozzino l, ferrari c, large m, nielssen o, de girolamo g. preva lence and risk factors of violence by psychiatric acute inpatients: a systematic review and meta-analysis. plos one 2015; 10:e0128536. https://doi.org/10.1371/journal.pone.0128536. 8. aytac s, bozkurt v, bayram n, yildiz s, aytac m, akinci fs, et al. workplace violence: a study of turkish workers. int j occup saf ergon 2011; 17:385–402. https://doi.org/10.1080/10803548.20 11.11076902. https://doi.org/10.1056/nejmra1501998 https://doi.org/10.1056/nejmra1501998 https://doi.org/10.1111/j.1365-2648.2009.05020.x https://doi.org/10.1111/j.1365-2648.2009.05020.x https://doi.org/10.1111/j.1447-0349.2009.00663.x https://doi.org/10.1111/j.1447-0349.2009.00663.x https://doi.org/10.1371/journal.pone.0128536 https://doi.org/10.1080/10803548.2011.11076902 https://doi.org/10.1080/10803548.2011.11076902 wafa basfr, ahlam hamdan and samia al-habib clinical and basic research | e25 9. st-pierre i, holmes d. the relationship between organizational justice and workplace aggression. j adv nurs 2010; 66:1169–82. https://doi.org/10.1111/j.1365-2648.2010.05281.x. 10. fallahi khoshknab m, oskouie f, najafi f, ghazanfari n, tamizi z, ahmadvand h. psychological violence in the health care settings in iran: a cross-sectional study. nurs midwifery stud 2015; 4:e24320. https://doi.org/10.17795/nmsjournal24320. 11. algwaiz wm, alghanim sa. violence exposure among health care professionals in saudi public hospitals. a preliminary invest igation. saudi med j 2012; 33:76–82. 12. el-gilany ah, el-wehady a, amr m. violence against primary health care workers in al-hassa, saudi arabia. j interpers violence 2010; 25:716–34. https://doi.org/10.1177/0886260509 334395. 13. tiruneh bt, bifftu bb, tumebo aa, kelkay mm, anlay dz, dachew ba. prevalence of workplace violence in northwest ethiopia: a multivariate analysis. bmc nurs 2016; 15:42. https://doi.org/10.1186/s12912-016-0162-6. 14. fallahi khoshknab m, oskouie f, ghazanfari n, najafi f, tamizi z, afshani s, et al. the frequency, contributing and preventive factors of harassment towards health professionals in iran. int j community based nurs midwifery 2015; 3:156–64. 15. di martino v. workplace violence in the health sector. from: https://www.who.int/violence_injury_prevention/injury/en/ wvsynthesisreport.pdf accessed: dec 2018. 16. kwok rp, law yk, li ke, ng yc, cheung mh, fung vk, et al. prevalence of workplace violence against nurses in hong kong. hong kong med j 2006; 12:6–9. 17. wu s, zhu w, li h, lin s, chai w, wang x. workplace violence and influencing factors among medical professionals in china. am j ind med 2012; 55:1000–8. https://doi.org/10.1002/ajim. 22097. 18. abbas ma, fiala la, abdel rahman ag, fahim ae. epidemiology of workplace violence against nursing staff in ismailia governorate, egypt. j egypt public health assoc 2010; 85:29–43. 19. wei cy, chiou st, chien ly, huang n. workplace violence against nurses--prevalence and association with hospital organ izational characteristics and health-promotion efforts: crosssectional study. int j nurs stud 2016; 56:63–70. https://doi.org/10. 1016/j.ijnurstu.2015.12.012. 20. hatch-maillette ma, scalora mj, bader sm, bornstein bh. a gender-based incidence study of workplace violence in psychiatric and forensic settings. violence vict 2007; 22:449–62. https://doi.org/10.1891/088667007781553982. 21. swain n, gale c, greenwood r. patient aggression experienced by staff in a new zealand public hospital setting. n z med j 2014; 127:10–18. 22. mckinnon b, cross w. occupational violence and assault in mental health nursing: a scoping project for a victorian mental health service. int j ment health nurs 2008; 17:9–17. https://doi.org/10. 1111/j.1447-0349.2007.00499.x. 23. park m, cho sh, hong hj. prevalence and perpetrators of workplace violence by nursing unit and the relationship between violence and the perceived work environment. j nurs scholarsh 2015; 47:87–95. https://doi.org/10.1111/jnu.12112. 24. spector pe, zhou ze, che xx. nurse exposure to physical and non physical violence, bullying, and sexual harassment: a quantitative review. int j nurs stud 2014; 51:72–84. https://doi.org/10.1016/j. ijnurstu.2013.01.010. 25. tonso ma, prematunga rk, norris sj, williams l, sands n, elsom sj. workplace violence in mental health: a victorian mental health workforce survey. int j ment health nurs 2016; 25:444–51. https://doi.org/10.1111/inm.12232. 26. van leeuwen me, harte jm. violence against mental health care professionals: prevalence, nature and consequences. j forens psychiatry psychol 2017; 28:581–98. https://doi.org/10.1080/14 789949.2015.1012533. 27. nijman h, bowers l, oud n, jansen g. psychiatric nurses' exper iences with inpatient aggression. aggress behav 2005; 31:217–27. https://doi.org/10.1002/ab.20038. 28. needham i, abderhalden c, halfens rj, dassen t, haug hj, fischer je. the effect of a training course in aggression management on mental health nurses’ perceptions of aggression: a cluster randomised controlled trial. int j nurs stud 2005; 42:649–55. https://doi.org/10.1016/j.ijnurstu.2004.10.003. 29. bowers l, simpson a, alexander j, hackney d, nijman h, grange a, et al. the nature and purpose of acute psychiatric wards: the tompkins acute ward study. j ment health 2005; 14:625–35. https://doi.org/10.1080/09638230500389105. 30. speroni kg, fitch t, dawson e, dugan l, atherton m. incidence and cost of nurse workplace violence perpetrated by hospital patients or patient visitors. j emerg nurs 2014; 40:218–28. https://doi.org/10.1016/j.jen.2013.05.014. https://doi.org/10.1111/j.1365-2648.2010.05281.x https://doi.org/10.17795/nmsjournal24320 https://doi.org/10.1177/0886260509334395 https://doi.org/10.1177/0886260509334395 https://doi.org/10.1186/s12912-016-0162-6 https://doi.org/10.1002/ajim.22097 https://doi.org/10.1002/ajim.22097 https://doi.org/10.1016/j.ijnurstu.2015.12.012 https://doi.org/10.1016/j.ijnurstu.2015.12.012 https://doi.org/10.1891/088667007781553982 https://doi.org/10.1111/j.1447-0349.2007.00499.x https://doi.org/10.1111/j.1447-0349.2007.00499.x https://doi.org/10.1111/jnu.12112 https://doi.org/10.1016/j.ijnurstu.2013.01.010 https://doi.org/10.1016/j.ijnurstu.2013.01.010 https://doi.org/10.1111/inm.12232 https://doi.org/10.1080/14789949.2015.1012533 https://doi.org/10.1080/14789949.2015.1012533 https://doi.org/10.1002/ab.20038 https://doi.org/10.1016/j.ijnurstu.2004.10.003 https://doi.org/10.1080/09638230500389105 https://doi.org/10.1016/j.jen.2013.05.014 squ med j, august 2010, vol. 10, iss. 2, pp. 103-106, epub. 19th jun 10 submitted: 26th oct 09 revision req. 11th jan 10, revision recd. 7th feb 10 accepted: 22nd mar 10 cantharidin, from the greek word kantharos (‘beetle’),1 is an intoxicant produced by beetles in the family meloidae (coleoptera). the spanish fly (lytta cantharis vesicatoria linnaeus, 1758) is the most well known species. spanish flies and other meloids have historically been used medicinally as aphrodisiacs, skin irritants, vesicants and abortifacients.2 many species of meloidae produce cantharidin,2 including hycleus maculiventris (klug, 1845). the species recovered in both cases reported here [figure 1] was identified by dr. marco bolonga, university of roma tre, italy who has great experience in studying the meloidae of the arabian peninsula. cantharidin, a bicyclic terpenoid, has an inhibitory effect on protein phosphatase 1 (pp1) and protein phosphatase 2a (pp2a). it is stored in the haemolymph, genitalia and other tissues.3,4 the systemic manifestations of a paediatric cantharidin poisoning have been reported previously.5,7 our purpose in reporting the clinical presentations of these two cases is to increase awareness of the signs and symptoms of meloid beetle ingestion. case reports c a s e o n e an otherwise healthy eight month-old saudi male child ingested a beetle, later identified in the infant vomitus as hycleus maculiventris [figure1]. thirty minutes after ingestion, he developed haematemesis and four hours later he presented to the emergency room (er) at aseer central hospital, abha, saudi arabia, with impaired consciousness. there was no history of fever, ecchymosis, diarrhea, seizure, photophobia or weakness. there was also no history of cardiovascular or respiratory systems involvement. in the er, he was stuporous with a glasgow 1department of child health, college of medicine, king khalid university, saudi arabia; 2department of pediatrics, aseer central hospital, abha, saudi arabia *corresponding author email: aalbinali@yahoo.com تسمم الكانثرادين بسبب ابتالع اخلنفساء اإلسبانية عند األطفال تقرير حالتني مع مراجعة األعراض السريرية علي حممد اآل بن علي، مدحت �شبانة، �شليمان الفيفي، �شامي داود، عامر ال�شهري، اأحمد البارقي قد الأطفال بع�س قبل من احل�رشة وابتالع الإ�شبانية. اخلنف�شاء ح�رشة يف املوجودة ال�شمية املواد اأهم من الكانرثادين مادة اإن امللخ�ص: يوؤدي اإىل ت�شمم يف اجل�شم ب�شبب مادة الكانرثادين التي قد توؤدي اإىل تقيوؤ الدم وانخفا�س م�شتوى الوعي وا�شطراب اأمالح الدم والتبول الدموي وتدهور وظائف الكلى. اننا يف هذه املقالة نعطي و�شفًا ملا ح�شل لطفلني مت تنوميهما بامل�شت�شفى اإثر ابتالعهما لهذه احل�رشة ونبني يف هذا ال�شياق الو�شف ال�رشيري حلالتيهما وذلك لإحاطة املهتمني ب�شحة الطفل حول هذه احل�رشة وما قد ت�شببه من اأعرا�س خطرية. مفتاح الكلمات: الكانرثادين ، ت�شمم ، اأطفال ، اخلنف�شانة ال�شبانية. abstract: cantharidin is an intoxicant found in beetles in the meloidae (coleoptera) family. ingestion may result in haematemesis, impaired level of consciousness, electrolyte disturbance, haematurea and renal impairment. here, we report two paediatric cases of meloid beetle ingestion resulting in cantharidin poisoning and the clinical presentation of the ensuing intoxication. keywords: cantharidin; intoxication; meloidae; paediatric; blister beetle; case report; saudi arabia. cantharidin poisoning due to blister beetle ingestion in children two case reports and a review of clinical presentations *ali m. al-binali,1 medhat shabana,1 suliman al-fifi,1 sami dawood,2 amer a. shehri2 and ahmed albarki2 case report ali m al-binali,medhat shabana,suliman al-fifi,sami dawood,amer a. shehri and ahmed al-barki case report | 259 coma score (gcs) of 12/15. his heart rate was 140/ min, respiratory rate 30/min, temperature 38oc, and oxygen saturation 92% in room air. on physical examination, his respiratory, cardiovascular, and gastrointestinal systems assessments were normal. there were no skin lesions or musculoskeletal abnormalities. a central nervous system evaluation revealed hypertonia and hyperreflexia of both upper and lower limbs. the child was admitted to the paediatric intensive care unit and shortly after admission he developed gross haematuria. a blood work-up revealed a white cell count of 17,700/cc; red blood cell count of 4,100,000/ cc; platelet count of 131,000/cc, and haemoglobin of 10.1 gm/dl. blood urea nitrogen was initially 47 mg/dl and serum creatinine was 0.4 mg/dl. on day two, his kidney function deteriorated, with urea increasing to 68 mg/dl and serum creatinine increasing to 1.2 mg/dl. serum electrolytes and blood sugar were within normal ranges. initial venous blood gas was ph 7.32; pc02 29.5; po2 61.2; hco3 14.9; abe -10 and oxygen pulse oxymeter was 95%. serum aspartate aminotransferase (ast) was 64 u/l; serum alanine aminotransferase (alt) 20 u/l; alkaline phosphatase 253 u/l (normal range [nr] = 145–420); creatine phosphokinase (cpk) 226 u/l (nr = 0–170), and lactate dehydrogenase 409 u/l (nr = 135-225). his total bilirubin was 0.4 mg/ dl; direct bilirubin 0.0; total serum protein 5.4 gm/ dl and albumin 3.4 gm/dl. the serum calcium level was 6 mg/dl, and urinalysis showed numerous red blood cells, granular casts, proteins and glucose. over the next 4 days, the child's condition improved steadily with a return to normal consciousness. the haematuria cleared up gradually with renormalisation of complete blood count (cbc) and renal function. c a s e t w o an otherwise healthy eleven months-old saudi female ingested a beetle which the father found in the child’s vomitus and brought to the hospital for recognition, it was later identified as hycleus maculiventris [figure 1]. two hours after ingestion of the insect, she developed haematemesis associated with decreased consciousness and was brought to the local hospital. her temperature was 40oc. she developed an attack of generalised tonic-clonic convulsion which was aborted by a diazepam injection of 0.3 mg/kg/dose followed by a loading dose of phenobarbitone 15 mg/kg intravenously. the initial blood work-up showed a white blood cell count of 45,000/cc; platelets of 51,000/cc; red blood cells (rbcs) of 4,600,000/cc, and haemoglobin of 11 gm/dl. her blood urea nitrogen was 79 mg/dl and serum creatinine 2.1 mg/dl. she was managed at the local hospital with concerns about possible encephalitis. she was started on ceftriaxone 100 mg/kg/day in two divided doses; phenobarbitone 5 mg/kg/day in two divided doses, and calcium gluconate intravenously at a dose of 70 mg elemental ca/kg. she was kept nil per os (nothing per mouth) and given intravenous fluids, and 05% dextrose with ½ normal saline. mannitol of 0.25 g/kg was given for possible increased intracranial pressure, since there was no cranial scanning (computed tomography [ct] scan) facility at the local hospital. two days later, she was referred to our hospital for brain imaging and proper intensive care management. her initial assessment revealed that she was moderately dehydrated. her temperature was 38oc rectally, respiratory rate was 40/min, pulse rate 156/min, and blood pressure 90/55 mmhg. she was not pale or jaundiced and not in distress. a central nervous system (cns) examination revealed a conscious, non-irritable child. her cranial nerves, motor and sensory systems evaluation were normal. examination of chest (cardio vascular system), abdomen, skin and musculoskeletal systems were within normal limits as well. results of repeated blood tests revealed a white blood cell count of 84,800/cc, and a platelet count of 43,000/cc. her initial blood gas was ph 7.28; figure 1: hycleus maculiventris (1.5 cm in length) insect ingested by the child cantharidin poisoning due to blister beetle ingestion in children two case reports and a review of clinical presentations 260 | squ medical journal, august 2010, volume 10, issue 2 pc02 27.2; hco3-13; abe -10. this abnormality was corrected over 24 hours. the patient started to have haematuria and her blood urea nitrogen peaked to 143 mg/dl, while serum creatinine increased to 2.4 mg/dl. the serum sodium level was 123 mmol/l; potassium 5.6 mmol/l; calcium 5.3 mg/ dl; phosphorus 6.1 mg/dl and chloride 92 mmol/dl. a ct scan of the brain was normal. the patient remained on ceftriaxone and acyclovir was added to her management. the results of a septic work up, including a cerebral spinal fluid (csf) examination (including protein, sugar, culture and cell count), were normal. the antibiotics were discontinued and the patient managed conservatively with intravenous fluids and phenobarbitone. over the following three days all symptoms resolved with normalisation of her laboratory values. by the end of the 6 day she was back to normal status and was discharged in good condition. discussion these cases describe the clinical presentations of cantharidin intoxication following ingestion of blister beetles. once the insect is disturbed it exudes cantharidin in a milky oral fluid, however the adult beetle reflexively secretes the toxin from the leg joints.8 the amount of cantharidin found in the blister beetle varies from 0.2 mg to 0.7 mg among different species. some species like e. immaculate have larger amounts of 4.8 mg per beetle. females have a significantly lower concentration.9 symptoms begin within 2–4 hours of ingestion with sudden onset of haematemesis of fresh blood, which is likely due to local irritation by the toxin. haematemesis is either associated with, or followed by, agitation impaired consciousness or convulsions. these symptoms are followed by haematuria either on the first or second day.5,7 fever was a presenting feature in both cases, similar to observations reported in other cases.7 presentation is also associated with leukocytosis and thrombocytopenia with a mild drop in haemoglobin. initially, there was only mild impairment of renal function, but over 24 hours the impairment became more pronounced, with creatinine increasing to 2.1 mg/dl. in spite of renal impairment, the blood pressure remained in within the normal range. the exact amount of cantharidin which causes intoxication in children is unknown, but a minimal amount of cantharidin causes severe intoxication. the fatal dose is estimated to range from 10–65 mg with a minimal lethal dose being approximately 1 mg/kg . fatality usually result from renal failure.4 serum electrolytes may also be affected, manifesting as hyponatraemia, hyperkalaemia and hypocalcaemia.8 it is not clear why electrolytes are affected, but it might be due to renal impairment secondary to the local toxin effect. there was a mild elevation of ast to 64 u/l, but there was no jaundice associated with this presentation. gross and microscopic haematurea with a granular cast is a prominent feature of cantharidin toxicity, and was also present in the cases discussed here.5,7 there is no specific antidote for cantharidin intoxication. management, therefore, has to be supportive in nature, including iv fluid at maintenance rate and correction of electrolyte and blood gas abnormalities. the use of intravenous proton pump inhibitors or h2 blockers may enhance the healing of the ulceration that results from the local effect of the toxin on the gastric mucosa. these clinical presentations are similar to those described for adults10,13 and animals.5,11,12 there is currently no clear explanation for these clinical presentations, but they are likely secondary to the local toxic effect of cantharidin on different organ systems. for topical exposure, the affected area should be cleaned with acetone, ether, fatty soap or alcohol, which helps to dissolve and dilute the cantharidin. topical steroids may be applied to intact skin if it is symptomatic.14 conclusion there is no pathognomonic feature of cantharidin intoxication in children, but a careful history and examination, combined with the sequence of events, should alert the medical team to this rare event. acknowledgement we would like to express our thanks to dr marco bologna, university of roma tre, italy, the taxonomist who identified the beetle. ali m al-binali,medhat shabana,suliman al-fifi,sami dawood,amer a. shehri and ahmed al-barki case report | 261 references 1. cantharidin and meloids: a review of classical history, biosynthesis, and function. from www.colostate.edu. accessed feb 2010. 2. dolson cj, tattersall rn. cantharides wasp, bee, and scorpion stings. clin toxicol 1969; 30:475–84. 3. international veterinary information service. in: v. beasley, ed. veterinary toxicology. from www.ivis. org. accessed feb 2010. 4. rauh r, kahl s, boechzelt h, bouer r, kaina b, efferth t. molecular biology of cantharidin in cancer cells. chin med 2007; 2:8. 5. wertelecki w, vietti tj, kulapongs p. cantharidin poisoning from ingestion of a "blister beetle". pediatrics 1967; 39:287–9. 6. mallari rq, saif m, elbualy ms, sapru a. ingestion of a blister beetle (mecoidae family). pediatrics 1996; 98:458–9. 7. tagwireyi d, ball de, loga pj, moyo s. cantharidin poisoning due to "blister beetle" ingestion. toxicon 2000; 38:1865–9. 8. carrel je, mccairel mh, slagel aj, doom jp, bril j, mccormick jp. cantharidin production in a blister beetle. experientia 1993; 49:171–4. 9. capinera jl, gardner dr, stermitz fr. j echonom entemol 1985; 78:1052–5. 10. al-rumikan a, al-hamdan na. indirect cantharidin food poisoning caused by eating wild birds. saudi epidemiol bull 1999; 6:26. 11. karras dj, farrel se, harrigan ra, henretig fm, gealt l. poisoning from "spanish fly" (cantharidin). am j emerg med 1996; 14:478–83. 12. fisch hp, reutter fw, gloor f. lesions of the kidney and the efferent urinary tract due to cantharidin (german). schweiz med wochenschr 1978; 108:1664–7. 13. ewart wb, rabkin sw, mintenko pa. poisoning by cantharides. cma journal 1978; 118:1199. 14. lisa moed ba, tor a, shwayder md, mary wu chang. a blistering defence of an ancient medicine arch dermatol 2001; 137:1357–60. departments of 1dermatology and 3pathology, college of medicine, university of baghdad, baghdad, iraq; 2department of dermatology, jena university hospital, jena, germany; 4department of dermatology, baghdad teaching hospital, baghdad, iraq *corresponding author e-mail: amarfaisal1976@yahoo.com الرتابط بني أعداد النسخ اجلينومية املرتفعة لربوتني ديفنسني بيتا defb4( 4( وبني داء هبجت عند املرضى العراقيني عمار حميد، �سامح جردات، ب�سام املو�سوي، خليفة ال�رسقي، مازن اإبراهيم، رافع احلياين، جونز نورقوار abstract: objectives: behçet’s disease (bd) is an immune-mediated small vessel systemic vasculitis. human β-defensins are antimicrobial peptides associated with many inflammatory diseases and are encoded by the β-defensin family of multiple-copy genes. however, their role in bd necessitates further investigation. the aim of the present study was to investigate the possible association of bd in its various clinical forms with defensin β-4 (defb4) genomic copy numbers. methods: this case-control study was conducted from january to september 2011 and included 50 control subjects and 27 unrelated iraqi bd patients registered at baghdad teaching hospital, bagdad, iraq. copy numbers of the defb4 gene were determined using the comparative cycle threshold method by duplex real-time polymerase chain reaction technology at the department of dermatology of jena university hospital, jena, germany. results: defb4 genomic copy numbers were significantly higher in the bd group compared to the control group (p = 0.010). however, no statistically significant association was found between copy numbers and clinical variables within the bd group. conclusion: the defb4 copy number polymorphism may be associated with bd; however, it is not associated with different clinical manifestations of the disease. keywords: behçet disease; beta-defensins; genetic polymorphisms; gene copy numbers; iraq. امللخ�ص: الهدف: داء بهجت هو التهاب مناعي جهازي ي�سيب الأوعية الدموية ال�سغرية. وبيتا ديفن�سني هي بيبتيدات م�سادة للميكروبات ترتبط بكثري من الأمرا�ض اللتهابية، وتكون م�سفرة يف عائلة بيتا ديفين�سني املكونة من مورثات )جينات( متعددة الن�سخ. غري اأن الدور الذي قد تلعبه تلك املورثات يف داء بهجت ما زال يحتاج ملزيد من الدرا�سة. ويهدف هذا البحث لدرا�سة الرتابط املمكن بني داء بهجت ب�سوره الإكلينيكية املختلفة وبني اأعداد الن�سخة اجلينومية defb4. الطريقة: اأجريت هذه الدرا�سة ال�ستعادية من يناير اإىل �سبتمرب 2011م و�سملت 50 فردا �سحيحا )جمموعة �سابطة( و27 مري�سا عراقيا )لي�سوا باأقرباء( م�سابني بداء بهجت من امل�سجلني مب�ست�سفى بغداد التعليمي يف العراق. وحددت اأرقام مورثات defb4 بتقنية تفاعل الت�سل�سل البلومريزي بق�سم الأمرا�ض اجللدية يف م�ست�سفى اجلامعة بجينا يف اأملانيا. النتائج: وجد اأن اأرقام الن�سخة اجلينومية defb4 كانت اأعلى معنويا عند مر�سى داء بهجت عند املقارنة مع املجموعة ال�سابطة )0.010 = p(. غري اأنه مل تكن هنالك اأي فروقات معنوية بني ن�سخ اأرقام مورثات defb4 والأعرا�ض الإكلينيكية للم�سابني باملر�ض. اخلال�صة: هنالك ارتباط بني تعدد اأ�سكال اأرقام defb4 وبني داء بهجت، رغم عدم وجود اأي ارتباط لها مع الأعرا�ض الإكلينيكية. مفتاح الكلمات: داء بهجت؛ بيتا ديفن�سني؛ تعدد الأ�سكال الوراثية؛ اأعداد ن�سخ املورثات؛ العراق. association of higher defensin β-4 genomic copy numbers with behçet’s disease in iraqi patients *ammar f. hameed,1 sameh jaradat,2 bassam m. al-musawi,3 khalifa sharquie,1 mazin j. ibrahim,3 raafa k. hayani,4 johannes norgauer2 clinical & basic research advances in knowledge as part of its genetic pathogenesis, behçet’s disease (bd) may be associated with the presence of a high number of human defensin β-4 (defb4) genomic copy numbers, as observed among this sample of unrelated iraqi bd patients. the defb4 genomic copy numbers in the healthy iraqi control group were comparable to those observed in other populations. application to patient care bd has neither a specific diagnostic test nor a targeted course of therapy. as such, exploring the genetic basis of this autoimmune disease could improve understanding of its pathological mechanisms and promote the development of a more accurate diagnostic and therapeutic approach. sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e491–495, epub. 23 nov 15 submitted 13 feb 15 revision req. 4 jun 15; revision recd. 11 jun 15 accepted 21 jul 15 doi: 10.18295/squmj.2015.15.04.008 behçet’s disease (bd) is a chronic auto-immune disease characterised by multiple inflammatory lesions of the orogenital mucosa, eyes and skin with additional involvement of other organs in the body.1 bd is prevalent in the mediterranean region and eastern asia;2 iraq is also known to have a relatively high prevalence of the disease.3 although the precise pathogenesis association of higher defensin β-4 genomic copy numbers with behçet’s disease in iraqi patients e492 | squ medical journal, november 2015, volume 15, issue 4 of bd remains unknown, genetic, immunological and environmental factors have been suggested to contribute to its development.2 a genetic basis for bd is supported by its high prevalence in certain geographic areas, the familial aggregation of cases and a strong association with human leukocyte antigen-b51.4,5 moreover, single nucleotide polymorphism studies have revealed associations with several genes, including interferon regulatory factor 1 and tumour necrosis factor-α (tnf-α).6,7 human β-defensins (hbds) are antimicrobial peptides expressed by various epithelial tissues. they are encoded by the multiple-copy β-defensin gene family, copies of which are clustered on the short arm of chromosome eight, including the human defensin β-2 gene synthesised by defensin β-4 (defb4).8 this β-defensin cluster has a genomic copy number of between two and 12 copies per genome, with a mode of four copies.9 such variation in genomic copy numbers may play a role in innate immunity; research has shown that hbd-2 has the ability to function as a chemokine that attracts inflammatory cells, such as dendritic cells and t lymphocytes, to the inflamed tissues.10,11 thus, it is possible that variations in the defb4 gene might influence an individual’s susceptibility to immune-mediated diseases. the antimicrobial and proinflammatory nature of these β-defensins has led many researchers to hypothesise that variations in gene dosage may affect the pathogenesis of many immunological diseases.12 hence, the present study aimed to investigate genomic copy numbers of defb4 in iraqi bd patients in comparison with normal healthy controls. various clinical manifestations of bd were also studied in association with defb4 genomic copy numbers. methods this case-control study was conducted between january and september 2011 and included all unrelated iraqi patients registered at the bd clinic in baghdad teaching hospital, baghdad, iraq (n = 27), and randomly selected healthy control subjects (n = 50). all of the bd patients fulfilled the international study group criteria for a diagnosis of bd, which requires the presence of recurrent oral ulcers plus at least two of the following symptoms: recurrent genital ulcerations, typical defined eye or skin lesions or a positive skin pathergy test (a skin hypersensitivity reaction to a non-specific physical insult).13,14 any patient who did not fulfil these criteria was excluded from the study. the control group included healthy individuals who donated their blood to the central blood bank after confirmation that they were free from any symptoms or signs suggestive of bd. blood was collected from all of the subjects and genomic dna was extracted from peripheral blood mononuclear cells by a standard phenol-chloroform method at the department of pathology in baghdad medical college, baghdad. samples were then stored at -20 °c and delivered to the department of dermatology at jena university hospital, jena, germany. dna concentrations and quality were then determined with a nanodrop 1000 spectrophotometer (nanodrop technologies inc., thermo fisher scientific inc., wilmington, delaware, usa) using the following settings: optical density (od) at 260/280 ~1.8 and od at 260/230 = 2.0–2.2. samples were anonymised and the genomic copy number analysis was performed by individuals who were blinded to the relevant clinical information. diploid defb4 genomic copy numbers (genbank: af040153.1)15 were determined by a duplex realtime polymerase chain reaction (pcr) technique as described by jaradat et al.16 briefly, pcr was performed in 96-well microplates (applied biosystems, thermo fisher scientific inc.) in a 7500 real-time pcr system (applied biosystems, thermo fisher scientific inc.). all assays were performed in quadruplicate. each plate included templates for genomic dna, negative controls and na07048hm calibrator dna (coriell institute for medical research, camden, new jersey, usa) at four copies per genome. each well contained a 20 µl reaction mixture including 4 µl of genomic dna (5 ng/µl), 10 µl of taqman® genotyping master mix (thermo fisher scientific inc.) 1 µl of taqman® copy number assay mix (applied biosystems, thermo fisher scientific inc.), 1 µl of taqman® copy number rnase p reference assay mix (applied biosystems, thermo fisher scientific inc.) and 4 µl of nuclease-free water (ambion® gmbh, thermo fisher scientific inc.). the reaction conditions were as follows: 95 °c for 10 minutes for initial denaturation and enzyme activation followed by 40 cycles of 95 °c for 15 seconds and 60 °c for one minute. cycle threshold values were calculated using the abi prism® 7700 sequence detection system, version 1.3 (applied biosystems, thermo fisher scientific inc.). relative quantitation was performed using copy callertm software (applied biosystems) to estimate the genomic copy number in each sample according to the comparative cycle threshold method (∆∆ct). statistical analysis was performed using the statistical package for the social sciences (spss), version 16.0, (ibm corp., chicago, illinois, usa). ammar f. hameed, sameh jaradat, bassam m. al-musawi, khalifa sharquie, mazin j. ibrahim, raafa k. hayani and johannes norgauer clinical and basic research | e493 data were presented as the mean estimated copy numbers of defb4. each single genomic copy number estimate was rounded to the nearest integer number. comparisons between the study groups were performed using an unpaired student’s t-test to assess the differences in the means ± standard deviation of defb4 genomic copy number values. pearson’s chisquared test was used to analyse categorical data. all p values were two-sided and statistical significance was set at p ≤0.05. this study was approved by the ethical committee of the iraqi board for medical specializations (approval #3) according to the principles of the declaration of helsinki. all subjects gave informed consent for inclusion in this study. results a total of 27 bd patients were recruited along with 50 healthy controls. no significant difference in age (p = 0.33) or gender (p = 0.57) was found between the groups [table 1]. the defb4 integer genomic copy number range was 3–7 copies per diploid genome in bd cases compared with 2–6 copies in the control group. the mean was 4.44 ± 1.15 copies versus 3.80 ± 0.92 copies in the bd and control groups, respectively. the defb4 genomic copy number was significantly higher in bd cases than in controls (p = 0.01) [figure 1]. no association was found between the clinical presentations of bd and defb4 genomic copy numbers [table 2]. discussion high defb4 genomic copy number values have been reported in patients with psoriasis and chronic obstructive pulmonary disease.17,18 previous studies have also demonstrated increased defb4 messenger ribonucleic acid expression of these copy number variations on the cellular level and in the mucosal tissues of the colon, upper airways and psoriatic skin.9,18–20 in a large chinese sample, significantly higher defb4 gene numbers were observed among patients with systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated small vasculitis with a mean genomic copy number of 3.98 and 4.05, respectively.21 jansen et al. presented evidence that both genomic copy number and pro-inflammatory cytokines affect the biological levels of hbd-2.20 bd is a good example of a disease rooted in immunological disturbance mediated by cytokines derived from t-helper lymphocytes, such as tnf-α, which acts as a mediator in the initiation and propagation of bd.22 in this context, tnf-α is a common inducer of defb4 expression.18 possible mechanisms underlying the uncontrolled inflammatory response seen in bd to infection or other environmental triggers are either a high basal level of hbd-2 occurring in table 2: defensin β-4 genomic copy numbers by clinical variables among patients with behçet’s disease in baghdad, iraq (n = 27) clinical variable present absent p value* n mean gcn ± sd n mean gcn ± sd genital ulcer 17 4.39 ± 9.94 10 4.18 ± 1.19 0.21 ocular lesion 7 4.15 ± 0.20 20 4.36 ± 1.17 0.64 skin lesion 18 4.21 ± 1.03 9 4.46 ± 0.09 0.47 arthritis 23 4.53 ± 1.09 4 4.46 ± 1.02 0.72 positive skin pathergy test 20 4.47 ± 1.11 7 3.79 ± 0.10 1.22 gcn = gene copy number; sd = standard deviation. *determined using the unpaired student’s t-test. figure 1: frequency of defensin β-4 (defb4) genomic copy numbers among iraqi patients with behçet's disease (n = 27) in comparison to healthy controls (n = 50). the mean defb4 genomic copy number was significantly higher in the bd group (p = 0.01). table 1: demographic variables of patients with behçet’s disease in comparison to healthy controls in baghdad, iraq (n = 77) variable control group (n = 50) bd group (n = 27) p value mean age in years ± sd 34.20 ± 8.88 36.39 ± 10.00 0.33* gender, n female male 20 30 9 18 0.57† bd = behçet’s disease; sd = standard deviation. *calculated using the unpaired student’s t-test. †calculated using the pearson’s chi-squared test. association of higher defensin β-4 genomic copy numbers with behçet’s disease in iraqi patients e494 | squ medical journal, november 2015, volume 15, issue 4 genetically susceptible individuals with high defb4 genomic copy numbers or high levels of hbd-2 induced through the stimulation of tnf-α. it is notable that the oral epithelium, the main site of involvement in bd, has enriched hbd-2 expression.23 the bd patients in the present study showed significantly higher defb4 copy numbers than the healthy controls. such an association between defb4 copy numbers and bd has not been previously reported. however, no significant relationship was observed between genomic copy number variations of defb4 and the various clinical manifestations of bd. the results obtained from the current study were not consistent with previous research from south korea, which found no significant correlation between defb4 copy numbers and bd.24 these contradictory results could be due to several reasons. it is well known that the effect of variation in β-defensin genomic copy numbers is regarded as complex, rather than simple, copy number variation; this is difficult to evaluate in smallor moderate-sized case-control studies. as a result, very few good candidate genes have been accurately studied in genomic association trials.25 the results of aldhous et al. support this observation; in spite of a large sample size, they failed to replicate both the previously reported high and low genomic copy numbers of defb4 among patients with crohn’s disease.19,26,27 in addition, discrepancies in assay reliability could play a role in explaining differences in the obtained results as well as the difference between the paralog ratio test used in the korean study and the quantitative pcr assay used in the present study.24 however, fernandez-jimenez et al. demonstrated that both techniques can produce comparable defb4 results with the use of optimum dna normalisation and high-quality genomic dna.28 nevertheless, it is known that defb4 copy numbers vary between ethnicities;29 this might account for the differences observed between the studied iraqi and korean populations.24 genetic heterogeneity was observed in the β-defensin gene cluster among 67 populations; this may have been due to selection.30 such genetic heterogeneity may differ along geographical or racial lines in different populations. one of the limitations of this study was the small sample size. it is important to note that the current study simply presents the significantly higher counts of mean defb4 genomic copies in bd, drawing attention to a possible pathological association. further research should focus on the influence of these results on hbd-2 levels both in the peripheral tissues (especially the orogenital mucosa) and serum of bd individuals. nevertheless, the present study is the first to analyse defb4 in a cohort of healthy iraqi men and women. the median genomic copy number found among this group was similar to the modal diplotype genomic copy numbers observed in seven different populations.12 a large-scale multicentre study is recommended to validate the results of the present study and to investigate the functional consequences of these copy number variations in terms of hbd-2 protein expression. conclusion there was an association between bd and defb4 genomic copy numbers among the studied iraqi subjects, with bd patients having significantly higher defb4 genomic copy numbers than the control group. this suggests that high defb4 genomic copy numbers may be associated with susceptibility to bd. however, no association was found between defb4 genomic copy numbers and the different clinical manifestations of bd. among the healthy iraqi control group, the median defb4 genomic copy number was comparable to numbers observed in other populations. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. sibley c, yazici y, tascilar k, khan n, bata y, yazici h, et al. behçet syndrome manifestations and activity in the united states versus turkey: a cross-sectional cohort comparison. j rheumatol 2014; 41:1379–84. doi: 10.3899/jrheum.131227. 2. hatemi g, seyahi e, fresko i, talarico r, hamuryudan v. behçet’s syndrome: a critical digest of the 2013-2014 literature. clin exp rheumatol 2014; 32:s112–22. 3. tappuni ar, tbakhi a, sharquie ke, hayani rk, alkaisi a, lafi a, et al. a comparative study of the genetics of behcet’s disease in iraq: international collaboration to transfer clinical and laboratory skills to baghdad medical school and hospitals. med confl surviv 2013; 29:57–68. doi: 10.1080/13623699.2013.765201. 4. demirseren dd, ceylan gg, akoglu g, emre s, erten s, arman a, et al. hla-b51 subtypes in turkish patients with behçet’s disease and their correlation with clinical manifestations. genet mol res 2014; 13:4788–96. doi: 10.4238/2014.july.2.8. 5. gul a, ohno s. hla-b*51 and behçet disease. ocul immunol inflamm 2012; 20:37–43. doi: 10.3109/09273948.2011.634978. 6. lee yj, kang sw, song jk, baek hj, choi hj, bae yd, et al. associations between interferon regulatory factor-1 polymorphisms and behcet’s disease. hum immunol 2007; 8:770–8. doi: 10.1016/j.humimm.2007.06.002. 7. akman a, sallakci n, coskun m, bacanli a, yavuzer u, alpsoy, et al. tnf-alpha gene 1031 t/c polymorphism in turkish patients with behcet’s disease. br j dermatol 2006; 155:350–6. doi: 10.1111/j.1365-2133.2006.07348.x. 8. groth m, szafranski k, taudien s, huse k, mueller o, rosenstiel p, et al. high-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes. hum mutat 2008; 29:1247–54. doi: 10.1002/humu.20751. http://dx.doi.org/10.3899/jrheum.131227 http://dx.doi.org/10.1080/13623699.2013.765201 http://dx.doi.org/10.4238/2014.july.2.8 http://dx.doi.org/10.4238/2014.july.2.8 http://dx.doi.org/10.3109/09273948.2011.634978 http://dx.doi.org/10.1016/j.humimm.2007.06.002 http://dx.doi.org/10.1111/j.1365-2133.2006.07348.x http://dx.doi.org/10.1002/humu.20751 ammar f. hameed, sameh jaradat, bassam m. al-musawi, khalifa sharquie, mazin j. ibrahim, raafa k. hayani and johannes norgauer clinical and basic research | e495 9. hollox ej, armour ja, barber jc. extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. am j hum genet 2003; 73:591–600. doi: 10.1086/378157. 10. schneider jj, unholzer a, schaller m, schäfer-korting m, korting hc. human defensins. j mol med (berl) 2005; 83:587–95. doi: 10.1007/s00109-005-0657-1. 11. yang d, biragyn a, kwak lw, oppenheim jj. mammalian defensins in immunity: more than just microbicidal. trends immunol 2002; 23:291–6. doi: 10.1016/s1471-4906(02)02246-9. 12. hollox ej. copy number variations of beta-defensins and relevance to disease. cytogenet genome res 2008; 123:148–55. doi: 10.1159/000184702. 13. international study group for behçet’s disease. criteria for diagnosis of behçet’s disease. lancet 1990; 335:1078–80. doi: 10.1016/0140-6736(90)92643-v. 14. scherrer ma, de castro lp, rocha vb, pacheco l. [the dermatoscopy in the skin pathergy testing: case series in patients with suspected behçet’s disease.] rev bras reumatol 2014; 54:494–8. doi: 10.1016/j.rbr.2014.06.003. 15. national center for biotechnology information. homo sapiens beta-defensin 2 (defb2) gene, complete cds: genbank af040153.1. from: www.ncbi.nlm.nih.gov/nuccore/af040153 accessed: jun 2015. 16. jaradat sw, hoder-przyrembel c, cubillos s, krieg n, lehmann k, piehler s, et al. beta-defensin-2 genomic copy number variation and chronic periodontitis. j dent res 2013; 92:1035–40. doi: 10.1177/0022034513504217. 17. hollox ej, huffmeier u, zeeuwen pl, palla r, lascorz j, rodijk-olthuis d, et al. psoriasis is associated with increased beta-defensin genomic copy number. nat genet 2008; 40:23–5. doi: 10.1038/ng.2007.48. 18. janssens w, nuytten h, dupont lj, van eldere j, vermeire s, lambrechts d, et al. genomic copy number determines functional expression of {beta}-defensin 2 in airway epithelial cells and associates with chronic obstructive pulmonary disease. am j respir crit care med 2010; 182:163–9. doi: 10.1164/rccm.200905-0767oc. 19. bentley rw, pearson j, gearry rb, barclay ml, mckinney c, merriman tr, et al. association of higher defb4 genomic copy number with crohn’s disease. am j gastroenterol 2010; 105:354–9. doi: 10.1038/ajg.2009.582. 20. jansen pa, rodijk-olthuis d, hollox ej, kamsteeg m, tjabringa gs, de jonph gj, et al. beta-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin. plos one 2009; 4:e4725. doi: 10.1371/journal.pone.0004725. 21. zhou xj, cheng fj, lv jc, luo h, yu f, chen m, et al. higher defb4 genomic copy number in sle and anca-associated small vasculitis. rheumatology (oxford) 2012; 51:992–5. doi: 10.1093/rheumatology/ker419. 22. sayinalp n, ozcebe oi, ozdemir o, haznedaroğlu ic, dündar s, kirazli s. cytokines in behçet’s disease. j rheumatol 1996; 23:321–2. 23. joly s, organ cc, johnson gk, mccray pb jr, guthmiller jm. correlation between beta-defensin expression and induction profiles in gingival keratinocytes. mol immunol 2005; 42:1073–84. doi: 10.1016/j.molimm.2004.11.001. 24. park jj, oh br, kim jy, park ja, kim c, lee yj, et al. copy number variation of β-defensin genes in behçet’s disease. clin exp rheumatol 2011; 29:s20–3. 25. olsson lm, holmdahl r. copy number variation in autoimmunity: importance hidden in complexity? eur j immunol 2012; 42:1969–76. doi: 10.1002/eji.201242601. 26. fellermann k, stange de, schaeffeler e, schmalzl h, wehkamp j, bevins cl, et al. a chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to crohn’s disease of the colon. am j hum genet 2006; 79:439–48. doi: 10.1086/505915. 27. aldhous mc, abu bakar s, prescott nj, palla r, soo k, mansfield jc, et al. measurement methods and accuracy in copy number variation: failure to replicate associations of betadefensin copy number with crohn’s disease. hum mol genet 2010; 19:4930–8. doi: 10.1093/hmg/ddq411. 28. fernandez-jimenez n, castellanos-rubio a, plaza-izurieta l, gutierrez g, irastorza i, castaño l, et al. accuracy in copy number calling by qpcr and prt: a matter of dna. plos one 2011; 6:e28910. doi: 10.1371/journal.pone.0028910. 29. li j, yang t, wang l, yan h, zhang y, guo y, et al. whole genome distribution and ethnic differentiation of copy number variation in caucasian and asian populations. plos one 2009; 4:e7958. doi: 10.1371/journal.pone.0007958. 30. hardwick rj, machado lr, zuccherato lw, antolinos s, xue y, shawa n, et al. a worldwide analysis of beta-defensin copy number variation suggests recent selection of a high-expressing defb103 gene copy in east asia. hum mutat 2011; 32:743–50. doi: 10.1002/humu.21491. http:/dx.doi.org/10.1086/378157 http://dx.doi.org/10.1007/s00109-005-0657-1 http://dx.doi.org/10.1016/s1471-4906%2802%2902246-9 http://dx.doi.org/10.1159/000184702 http://dx.doi.org/10.1016/0140-6736%2890%2992643-v http://dx.doi.org/10.1016/j.rbr.2014.06.003 http://dx.doi.org/10.1177/0022034513504217 http://dx.doi.org/10.1038/ng.2007.48 http://dx.doi.org/10.1164/rccm.200905-0767oc http://dx.doi.org/10.1038/ajg.2009.582 http://dx.doi.org/10.1371/journal.pone.0004725 http://dx.doi.org/10.1093/rheumatology/ker419 http://dx.doi.org/10.1016/j.molimm.2004.11.001 http://dx.doi.org/10.1002/eji.201242601 http://dx.doi.org/10.1086/505915 http://dx.doi.org/10.1093/hmg/ddq411 http://dx.doi.org/10.1371/journal.pone.0028910 http://dx.doi.org/10.1371/journal.pone.0007958 http://dx.doi.org/10.1002/humu.21491 the diagnosis and treatment of cancer continues to pose profound challenges. over the past 50–60 years, significant advances have been made in the screening, early detection, diagnosis and treatment of cancer, resulting in the current cure rate of 40–60%.1–3 together with surgery and radiotherapy, systemic chemotherapy has been the mainstay of cancer treatment for over half a century. however, conventional cytotoxic chemotherapy is fraught with both shortand longterm side-effects, to the extent that many patients and caregivers consider the option of cancer treatment to represent a choice between ‘the devil and the deep sea’. although combinations of cytotoxic chemotherapy are developed following rigorous evidence-based testing, a significant number of patients may not benefit from the combination and develop side-effects due to the non-selective nature of the treatment. personalised and individualised treatment therefore remains a much desired but elusive goal for cancer patients, caregivers and healthcare professionals alike. precision or personalised medicine aims to overcome the ‘one-size-fits-all’ approach to cancer care and tries to match the treatment with specific genotypic and/or phenotypic targets on the tumour so as to maximise efficacy and minimise side-effects.4 notably, the genetic profile of the cancer may change over time and hence this method of treatment also needs to be dynamic. another important aspect of the personalised approach, beyond the individual tailoring of therapy, is the capacity to provide prognostic information. with gene-on-a-chip technology, the analysis of multiple biological determinants such as growth, metastatic potential and microenvironment regulators can be used to stratify tumour behavior. the seminal work by perou et al. on the molecular characteristics of breast cancer opened the floodgates for genomic signature determinants to enable prognostication.5 there are several dimensions of personalised medicine. first and foremost, it is important to ask ourselves whether, in the prevailing bio-psychosocial model of health and illness, we can rely solely on genetic code to inform the choice of treatment, or if we also need to take into account other factors, such as environment and lifestyle, which have a very strong influence on overall health. secondly, it may be prudent to distinguish between prognostic and predictive markers, although this may not always be possible. whereas the intrinsic characteristics of the patient or disease are known as prognostic biomarkers which identify the likelihood of a clinical event, predictive biomarkers indicate whether a favourable or unfavourable effect would result from exposure to a certain therapeutic agent. while both of these aspects are important, for the purposes of this article, the focus of discussion will lie on predictive biomarkers which help not only in predicting the response to treatment, but also to tailor the treatment itself. so, what is our current understanding of an individual’s predictive biomarkers? in general, cancer denotes a heterogeneous group of diseases. since the outcomes of treatment are overtly different in different patients, attempts have been made to classify and subclassify cancers based on either histological or biological characteristics and, more recently, molecular phenotype. as a result, some common cancers, such as breast cancer, colon cancer and non-hodgkin’s lymphoma are no longer considered a single disease entity, but have been classified into several molecular types [table 1].5–8 these molecular subtypes may provide either prognostic or predictive information, or both. a further refinement is that ‘actionable’ predictive targets have been identified in many cancers, including non-small-cell lung cancer, hodgkin’s lymphoma, melanomas and gastric, ureteral and uterine cancers [table 2].9,10 for certain other cancers, molecular aberrations have become the sine 1department of medicine, sultan qaboos university hospital, muscat, oman; 2college of medicine, mohammed bin rashid university, dubai healthcare city, dubai, united arab emirates *corresponding author e-mail: ikramburney@hotmail.com الطب الدقيق إىل أين وصلنا و إىل أين نتجه؟ اإكرام بريين و ريتو لكتاكيا editorial precision medicine where have we reached and where are we headed? *ikram a. burney1 and ritu lakhtakia2 sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e255–258, epub. 10 oct 17 submitted 6 sep 17 revision req. 18 sep 17; revision recd. 24 sep 17 accepted 25 sep 17 doi: 10.18295/squmj.2017.17.03.001 precision medicine where have we reached and where are we headed? e256 | squ medical journal, august 2017, volume 17, issue 3 qua non for diagnosis, for example the breakpoint cluster region-abelson murine leukaemia (bcr-abl) translocation in chronic myeloid leukaemia and the c-kit mutation in gastrointestinal stromal tumours.11,12 these are only a few examples, with the list of such cancers continuing to grow. these molecular targets not only guide treatment using targeted therapy, but may also help to determine the choice of conventional cytotoxic chemotherapy. therefore, it became possible to treat a subtype of tumour with a drug which has been specifically tailored to the tumour target. the first two drugs in this class of targeted therapy are monoclonal antibodies against the receptors expressed on the cell surface. trastuzumab, a monoclonal antibody directed against epidermal growth factor receptor (egfr)-2 or human epidermal growth factor receptor (her)-2/neu, was found to improve progression-free survival in patients with breast cancer expressing the protein.13,14 moreover, rituximab, a monoclonal antibody directed against the cluster of differentiation (cd)20 antigen expressed on activated b lymphocytes, was shown to improve both progression-free and overall survival in several types of b cell non-hodgkin’s lymphoma.15,16 at almost the same time, a small-molecule tyrosine kinase inhibitor (tki), later christened imatinib, was described; this agent inhibits phosphorylation at the adenosine triphosphate-binding site of the protein translated as a result of the bcr-abl translocation in chronic myeloid leukaemia.11 the introduction of imatinib in 2001 forever changed the landscape of treatment and outcomes for patients with chronic myeloid leukaemia as allogeneic bone marrow transplantations, with their attendant morbidity and significant mortality, were replaced by a tablet with very few, if any, significant side-effects and an equal degree of efficacy.17,18 these three drugs are regarded as the frontrunners of modern day precision medicine. since then, a plethora of monoclonal antibodies and tkis have been investigated, reported and approved for use in a variety of cancers and have resulted in improved response rates and progression-free and overall survival, in addition to reducing and, in some cases, alleviating toxicities associated with conventional cytotoxic chemotherapy.19 nevertheless, although the side-effect profile of monoclonal antibodies and tkis is different from that of conventional cytotoxic chemotherapy, it may sometimes be just as devastating. in addition to improving survival rates of common cancers, these medicines have also provided opportunities for therapy for individuals with otherwise difficult-totreat cancers.19 however, challenges remain and treatment is often ‘hit or miss’, as not all patients with a certain target respond, or respond similarly, to a specific drug. for example, braf inhibitors produce remarkable responses in cases of metastatic malignant melanoma, but so far have not proved particularly effective in braf-mutant colon cancer.20 some tumours continue to exhibit primary resistance to the specific molecularly-targeted drug and may even develop table 1: molecular subtypes of common cancer5–8 type of cancer molecular subtype breast cancer er/pgr-positive and her-2/ neu-negative er/pgr-positive and her-2/ neu-positive er/pgr-negative and her2/neu-positive triple-negative colon cancer wild-type ras mutant ras non-hodgkin’s lymphoma b cell, cd19 and cd20 t cell and cd52 anaplastic large-cell and cd30 er = estrogen receptor; pgr = progesterone receptor; her = human epidermal growth factor receptor; cd = cluster of differentiation. table 2: actionable targets and targeted therapy in selected cancers9,10 type of cancer target treatment non-small-cell lung cancer egfr mutations egfr tkis alk translocation alk tkis ros1 fusion ros1 tki anaplastic largecell lymphoma cd30 expression anti-cd30 antibody alk translocation alk tki hodgkin’s lymphoma cd30 expression anti-cd30 antibody melanoma braf mutation braf inhibitors gastric cancer her-2/neu expression anti-her-2 antibodies uterine cancer microsatellite instability immune checkpoint inhibitors ovarian cancer brca1 and brca2 mutations parp inhibitors egfr = epidermal growth factor receptor; tki = tyrosine kinase inhibitor; alk = anaplastic lymphoma kinase; cd = cluster of differentiation; her = human epidermal growth factor receptor; brca = breast cancer; parp = polyadenosine diphosphate-ribose polymerase. ikram a. burney and ritu lakhtakia editorial | e257 secondary resistance during the course of treatment. there are several reasons for this; some cancers may have more than one pathway of oncogenesis and others, especially solid tumors, may not have one specific driver mutation leading to oncogenesis.20 these cancers may be dependent on tumour-environment interactions for progression. furthermore, infiltration, invasion and metastasis remain the primary reason for dissemination in some cancers. invariably, a metastatic tumour may harbor a different type of mutation and the elimination of one clone of cells may not be sufficient.20 nevertheless, the paradigm of cancer care is changing. instead of classifying tumours by histological or biological behaviour, molecular targets are now being employed to classify tumors. because of a common target, and the availability of tailored treatment for the target, different tumour types charcterised by the same molecular target respond similarly. for example, in addition to breast cancer, her-2/neu is overexpressed in gastric, bladder and several other cancers and trastuzumab (the monoclonal antibody binding to the egfr-2 receptor) has been shown to improve survival in cases of her-2/neu overexpressing gastric cancer, although not to the same extent as in breast cancer.21 similarly, patients with tumours with mutations in the breast cancer (brca) 1 and brac2 genes, such as highgrade epithelial ovarian cancer, triple-negative breast cancer and prostate cancer, have exhibited prolonged progression-free survival when treated with the polyadenosine diphosphate-ribose polymerase inhibitor, olaparib, which induces a state of synthetic lethality.22 another example is microsatellite instability in mismatch repair (mmr) genes. data are beginning to emerge that mmr-deficient tumours may be more responsive to immunotherapy using anti-programmed cell death protein 1 (anti-pd1) antibodies, even if the mutation occurs in tumours as diverse as those seen in cancers of the colon, uterus, bladder or ureter.23 although molecular targets provide an opportunity for cancers to be treated with target-specific drugs, a significant number of tumours do not respond. is personalised therapy therefore ‘illusive’ or ‘elusive’? it may be crucial to clearly distinguish between targeted therapy and precision medicine. on the one hand, targeted therapy is directed towards a molecular target in an individual, albeit one shared by a significant number of patients with a particular type of tumour or even across multiple types of tumours; therefore, it may be not be necessarily personalised in the true sense of the word. on the other hand, if personalised medicine needs to be precise enough to be individualised, then treatment such as chimeric antigen receptor t cell therapy may be an example. this first-of-its-kind drug was recently approved for the treatment of relapsed acute lymphoblastic leukaemia in children and young adults and has shown remarkable response and longterm survival rates among patients whose disease relapsed after a bone marrow transplant.24 however, the drug is prohibitively expensive at the moment and may produce side-effects requiring transfer to the intensive care unit. also, there may be an economic dichotomy in the implementation of precision medicine. on the one hand, precision medicine is likely to identify susceptibility, preventative strategies, prognosis and appropriate targets for treatment, and hence may be cost-effective. as former usa president barak obama said in the mission statement for his precision medicine initiative: “it must enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward the development of individualized care”.25 on the other hand, precision medicine initiatives require vast resources, such as the incorporation of extensive molecular profiling tests into clinical practice, which is clearly beyond the means of many healthcare programmes around the world, especially those in lowand middle-income countries. in conclusion, the journey to personalised cancer treatment continues and, happily, this goal may no longer be quite so elusive. the advent of immunohistochemistry and monoclonal antibodies were torchbearers for tailored treatment. gene sequencing, the identification of genetic mutations and the development of small-molecule tkis have also allowed us to move away from the beaten path of cytotoxic chemotherapy.26 the identification of other targets such as proteasomes and cyclin-dependent kinases has also helped significantly in this regard. other areas of research in precision medicine include the cancer genome atlas, integrated proteogenomic analysis, next-generation sequencing, clustered regu larly interspaced short palindromic repeat (crispr) mechanisms and translational research; these may result in designer drugs that pave the way for the near future.26 nevertheless, while we seem to be moving in the right direction, we are still not past the winning post. critically, all new drugs need to be validated in proper trials before they can be considered for clinical use, particularly as the detection of a target and the availability of a drug to hit that target does not guarantee clinically relevant efficacy.26 precision medicine where have we reached and where are we headed? e258 | squ medical journal, august 2017, volume 17, issue 3 references 1. cancer research uk. cancer survival statistics. from: www. cancerresearchuk.org/health-professional/cancer-statistics/ survival accessed: sep 2017 2. american cancer society. cancer facts & figures: 2017. from: www.cancer.org/content/dam/cancer-org/research/cancerfacts-and-statistics/annual-cancer-facts-and-figures/2017/ cancer-facts-and-figures-2017.pdf accessed: sep 2017. 3. siegel rl, miller kd, jemal a. cancer statistics, 2017. ca cancer j clin 2017; 67:7–30. doi: 10.3322/caac.21387. 4. whitcomb dc. what is personalized medicine and what should it replace? nat rev gastroenterol hepatol 2012; 9:418–24. doi: 10.1038/nrgastro.2012.100. 5. perou cm, sørlie t, eisen mb, van de rijn m, jeffrey ss, rees ca, et al. molecular portraits of human breast tumours. nature 2000; 406:747–52. doi: 10.1038/35021093. 6. guinney j, dientsmann r, wang x, de reyniès a, schliker a, soneson c, et al. the consensus molecular subtypes of colorectal cancer. nat med 2015; 21:1350–6. doi: 10.1038/ nm.3967. 7. lukes rj, collins rd. immunologic characterization of human malignant lymphomas. cancer 1974; 34:1488–503. doi: 10.1002/1097-0142(197410)34:8+<1488::aid-cncr2820 340822>3.0.co;2-c. 8. alizadeh aa, eisen mb, davis re, ma c, lossos is, rosenwald a, et al. distinct types of diffuse large b-cell lymphoma identified by gene expression profiling. nature 2000; 403:503–11. doi: 10.1038/35000501. 9. furrukh m, al-moundhri m, zahid kf, kumar s, burney i. customized, individualised treatment of metastatic non-smallcell lung carcinoma (nsclc). sultan qaboos univ med j 2013; 13:202–17. 10. ciriello g, miller ml, aksoy ba, senbabaoglu y, schultz n, sander c. emerging landscape of oncogenic signatures across human cancers. nat genet 2013; 45:1127–33. doi: 10.1038/ ng.2762. 11. druker bj, talpaz m, resta dj, peng b, buchdunger e, ford jm, et al. efficacy and safety of a specific inhibitor of bcrabl tyrosine kinase in chronic myeloid leukemia. n engj med 2001; 344:1031–7. doi: 10.1056/nejm200104053441401. 12. heinrich mc, blanke cd, druker bj, corless cl. inhibition of kit tyrosine kinase activity: a novel molecular approach to the treatment of kit-positive malignancies. j clin oncol 2002; 20:1692–703. doi: 10.1200/jco.2002.20.6.1692. 13. ross js, fletcher ja, linette gp, stec j, clark e, ayers m, et al. the her-2/neu gene and protein in breast cancer: biomarker and target of therapy. oncologist 2003; 8:307–25. doi: 10.1634/ theoncologist.8-4-307. 14. slamon dj, leyland-jones b, shak s, fuchs h, paton v, bajamonde a, et al. use of chemotherapy plus a monoclonal antibody against her2 for metastatic breast cancer that overexpresses her2. n eng j med 2001; 344:783–92. doi: 10.1056/nejm200103153441101. 15. maloney dg, grillo-lópez aj, white ca, bodkin d, schilder rj, neidhart ja, et al. idec-c2b8 (rituximab) anti-cd20 monoclonal antibody therapy in patients with relapsed lowgrade non-hodgkin’s lympohoma. blood 1997; 90:2188–95. 16. coiffier b, lepage e, brierie j, herbrecht r, tilly m, bouabdallah r, et al. chop chemotherapy plus rituximab compared with chop alone in elderly patients with diffuse large b-cell lymphoma. n eng j med 2002; 346:235–42. doi: 10.1056/ nejmoa011795. 17. goldman jm. therapeutic strategies for chronic myeloid leukemia in the chronic (stable) phase. semin hematol 2003; 40:10–17. doi: 10.1053/shem.2003.50028. 18. burney ia, al-moundhri ms. from transplant to tablets: a paradigm shift in oncology. sultan qaboos univ med j 2012; 12:402–5. 19. ke x, shen l. molecular targeted therapy of cancer: the progress and future prospect. front lab med 2017; 1:69–75. doi: 10.1016/j.flm.2017.06.001. 20. tannock if, hickman ja. limits to personalized cancer medicine. n eng j med 2016; 375:1289–94. doi: 10.1056/ nejmsb1607705. 21. bang yj, van custem e, feyereislova a, chung hc, shen l, sawaki a, et al. trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of her2-positive advanced gastric or gastro-oesophageal junction cancer (toga): a phase 3, open-label, randomised controlled trial. lancet 2010; 376:687–97. doi: 10.1016/s01406736(10)61121-x. 22. ledermann j, harter p, gourley c, friedlander m, vergote i, rustin g, et al. olaparib maintenance therapy in platinumsensitive relapsed ovarian cancer. n eng j med 2012; 366:1382–92. doi: 10.1056/nejmoa1105535. 23. le dt, uram jn, wang h, bartlett br, kemberling h, eyring ad, et al. pd-1 blockade in tumors with mismatch-repair deficiency. n eng j med 2015; 372:2509–20. doi: 10.1056/nejmoa1500596. 24. national institutes of health. fda approves first car-t cell therapy for pediatric acute lymphoblastic leukemia. from: https ://directorsblog .nih.gov/2017/08/30/fda-approvesfirst-car-t-cell-therapy-for-pediatric-acute-lymphoblasticleukemia/ accessed: sep 2017. 25. the white house archives. the precision medicine initiative. from: https://obamawhitehouse.archives.gov/node/3 33101 accessed: sep 2017. 26. shin sh, bode am, dong z. precision medicine: the foundation of future cancer therapeutics. npj precis oncol 2017; 1:12. doi: 10.1038/s41698-017-0016-z. https://doi.org/10.3322/caac.21387 https://doi.org/10.1038/nrgastro.2012.100 https://doi.org/10.1038/35021093 https://doi.org/10.1038/nm.3967 https://doi.org/10.1038/nm.3967 https://doi.org/10.1002/1097-0142%28197410%2934:8%2b%3c1488::aid-cncr2820340822%3e3.0.co%3b2-c https://doi.org/10.1002/1097-0142%28197410%2934:8%2b%3c1488::aid-cncr2820340822%3e3.0.co%3b2-c https://doi.org/10.1038/35000501 https://doi.org/10.1038/ng.2762 https://doi.org/10.1038/ng.2762 https://doi.org/10.1056/nejm200104053441401 https://doi.org/10.1200/jco.2002.20.6.1692 https://doi.org/10.1634/theoncologist.8-4-307 https://doi.org/10.1634/theoncologist.8-4-307 https://doi.org/10.1056/nejm200103153441101 https://doi.org/10.1056/nejmoa011795 https://doi.org/10.1056/nejmoa011795 https://doi.org/10.1053/shem.2003.50028 https://doi.org/10.1016/j.flm.2017.06.001 https://doi.org/10.1056/nejmsb1607705 https://doi.org/10.1056/nejmsb1607705 https://doi.org/10.1016/s0140-6736%2810%2961121-x https://doi.org/10.1016/s0140-6736%2810%2961121-x https://doi.org/10.1056/nejmoa1105535 https://doi.org/10.1056/nejmoa1500596 https://doi.org/10.1038/s41698-017-0016-z the respiratory syncytial virus (rsv) belongs to the paramyxoviridae family and, along with the recently identified human metapneumovirus, belongs to the pneumovirinae subfamily. rsv is further classified into subtypes a and b; subtype a usually causes a more severe form of the disease.1 both subtypes occur more commonly in cold weather and rainy seasons.2 around the world, it has been noted that rsv is highly prevalent in fiveyear-old children.3 in the united states, 4–5 million children younger than four years of age annually contract rsv infections and 125,000 require hospital admission.4 in most cases, the virus is not fatal; however, in certain groups of high-risk patients, an rsv infection can lead to a more severe morbidity or result in death.5 in order to manage affected patients appropriately, clinicians need to be aware of severe intrapulmonary and extrapulmonary manifestations of rsv infections.6 rsv mainly causes lower respiratory tract infections in children younger than two years of age or upper respiratory tract infections in older children and adults.5,6 rsv rarely causes severe extrapulmonary manifestations like cerebellitis, encephalitis, fatal interstitial myocarditis, hepatitis or reye’s syndrome.6–9 this case series reports four children admitted to the critical care area of the royal hospital, muscat, oman, in december 2013 with severe and rare manifestations of rsv. all patients had a positive outcome and made a full recovery. case one a previously healthy 11-month-old female infant was admitted to the royal hospital in december 2013 with a three-day history of fever, a runny nose and cough followed by drowsiness and respiratory distress. she had been in contact with her sibling who had an upper respiratory tract infection. a physical examination revealed fever, drowsiness and response only to painful stimuli. she was tachypnoeic, had marked hepatomegaly (8 cm below the costal margin with a liver span of 13 cm) and her spleen was not palpable. investigations showed a normal complete blood count (cbc), high aspartate transaminase (ast) departments of 1paediatric infectious diseases, 2microbiology and 3child health, royal hospital, muscat, oman *corresponding author e-mail: nawal.almaskari@gmail.com حاالت شاذة من اإلصابة بالفريوس املخلوي التنفسي سلسلة من احلاالت نوال امل�شكرية، جليلة حم�شن، اأمل املع�نية، نبيل مكي، �شع�د االإ�شم�عيلية abstract: the respiratory syncytial virus (rsv) usually causes a lower respiratory tract infection in affected patients. rsv has also been infrequently linked to extrapulmonary diseases in children. we report four children who had unusually severe clinical manifestations of rsv infections requiring critical care admission. these patients presented to the royal hospital, muscat, oman, in december 2013 with acute necrotising encephalopathy (ane), acute fulminant hepatic failure with encephalopathy, pneumatoceles and croup. a unique presentation of ane has not previously been reported in association with an rsv infection. all patients had a positive outcome and recovered fully with supportive management. keywords: respiratory syncytial virus infections; epidemiology; encephalitis; hepatitis; croup; case series; oman. امللخ�ص: الفريو�ص املخلوي التنف�شي )rsv( ع�دة م� ي�شيب اجله�ز التنف�شي ال�شفلي للمر�شى. كم� اأنه ن�درا م�ي�شيب اأع�ش�ء غري الرئة يف االأطف�ل. نقدم �شل�شلة ح�الت الأربعة اأطف�ل لديهم اأعرا�ش� �رضيرية �شديدة غري ع�دية من عدوى ال rsv تتطلب الدخول للعن�ية املركزة. قدم هوؤالء املر�شى اإىلامل�شت�شفى ال�شلط�ين، م�شقط، عم�ن، يف دي�شمرب 2013 مع اعتالل الدم�غ التقرحي احل�د )ena(، وف�شل كبدي مداهم ح�د مع اعتالل الدم�غ والقيلة الهوائية واخل�نوق. مل ي�شبق اأن قدمت ح�لة ena م�ش�حبة للعدوى بrsv. ك�ن جلميع املر�شى نتيجة اإيج�بية وتع�فوا مت�م� مع الدعم الطبي. مفتاح الكلمات: الته�ب�ت الفربو�ص املخلوي التنف�شي؛ علم االأوبئة؛ الته�ب الدم�غ؛ الته�ب الكبد؛ اخل�نوق؛ �شل�شلة ح�الت؛ عم�ن. atypical presentations of respiratory syncytial virus infection case series *nawal al-maskari,1 jalila mohsin,2 amal al-maani,1 nabil al-macki,3 suad al-ismaili1 case series sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e86–91, epub. 2 feb 16 submitted 16 jun 15 revisions req. 15 jul & 1 sep 15; revisions recd. 6 aug & 9 sep 15 accepted 22 sep 15 doi: 10.18295/squmj.2016.16.01.016 nawal al-maskari, jalila mohsin, amal al-maani, nabil al-macki and suad al-ismaili case series | e87 levels of 9,000 iu/l (normal range: 5–60 iu/l), normal alkaline phosphatase levels of 163 iu/l (normal range: 90–210 iu/l), high alanine transaminase levels of 52 iu/l (normal range: 0–40 iu/l) and normal albumin levels of 37 g/l (normal range: 35–50 g/l). the patient had a deranged coagulation profile, a prothrombin time of 27.9 seconds (normal range: 9.1–11.6 seconds), activated partial thromboplastin time of 40.4 seconds (normal range: 27.3–39.1 seconds), fibrinogen 1 levels of 0.03 g/l (normal range: 1.5–4.2 g/l) and a thrombin time of 23.80 seconds (normal range: 12–16 seconds). she was diagnosed with acute fulminant hepatic failure with encephalopathy. a nasopharyngeal swab viral multiplex polymerase chain reaction (pcr) test revealed a positive result for rsv and a negative result for other respiratory viruses, including influenza a and b, coronaviruses, parainfluenza viruses, rhinoviruses, adenoviruses, enteroviruses, paraechoviruses, human metapneumovirus, bocavirus and mycoplasma pneumoniae. plasma pcr tests were negative for herpes simplex virus and human immunodeficiency virus. hepatitis e immunoglobulin (ig) m, hepatitis a igg and igm, hepatitis b surface antigen and hepatitis c virus antibodies were negative. no growth was observed on blood and urine cultures. the metabolic work-up showed normal ammonia and urine organic acid with mildly elevated levels of methionine and phenylalanine; these were likely secondary to the hepatic dysfunction. five days after admission, a repeat cbc showed leukocytosis with lymphocytosis. a chest x-ray (cxr) revealed right upper lobe consolidation [figure 1a]. computed tomography (ct) of the head was normal. the patient was stabilised in the paediatric intensive care unit (picu) and did not require ventilation. she was prescribed cefotaxime and acyclovir empirically. five days later, her ast levels dropped to 1,500 iu/l. she improved gradually and regained a normal level of consciousness. within seven days her liver had returned to a normal size and her cxr showed complete resolution of the consolidation [figure 1b]. case two a nine-year-old boy diagnosed with a recurrent medulloblastoma was admitted to the royal hospital in december 2013 with a two-day history of fever, figure 1 a&b: chest x-rays of an 11-month-old female infant (case one) with respiratory syncytial virus infection showing (a) right upper lobe consolidation and (b) complete consolidation resolution five days after admission. figure 2 a&b: chest x-rays of a nine-year-old boy (case two) with respiratory syncytial virus infection showing (a) upper airway narrowing which required (b) intubation. atypical presentations of respiratory syncytial virus infection case series e88 | squ medical journal, february 2016, volume 16, issue 1 day. the endotracheal secretion showed positive haemophilus influenzae growth. a nasopharyngeal swab viral multiplex pcr test was positive for rsv and negative for other viruses. for a period of two weeks, he received intravenous ceftriaxone and clindamycin followed by oral clindamycin. a repeat cxr on the 12th day of admission showed resolved pneumonia and a pneumatocele. on the 14th day of admission, another cxr showed complete resolution of the pneumatoceles [figure 3b]. on the same day, he was discharged on oral clindamycin to complete the fourweek course of treatment. case four a previously healthy six-year-old female was admitted to a peripheral hospital in oman in december 2013 with a one-day history of fever, runny nose, cough and lethargy, followed by altered sensorium and an inability to walk. one day prior to admission, she received an oral antibiotic from a local health centre. on examination, she was drowsy, mute, febrile and unable to stand or walk without support. she did not have any meningeal signs, although a lumbar puncture showed significant leukocytosis (red blood cell count [rbc]: 10,000/ul; white blood cell count [wbc]: 50/ul; neutrophils: 70%). her cerebrospinal fluid (csf) glucose level was 4.5 mmol/l and her protein level was 0.4 g/l. her csf gram stain, bacterial antigen and culture stains were negative. a viral study was not performed. a nasopharyngeal swab viral multiplex pcr test was positive for rsv and negative for other viruses and mycoplasma. the patient was suspected to have meningoencephalitis and was prescribed ceftriaxone, vancomycin and acyclovir empirically. on the same day, the patient developed recurrent abnormal movements—sudden twisting of the head to the right side, blankness in the eyes and generalised stridor, a barking cough and respiratory distress. on examination, he was febrile with bilateral equal breath sounds and an expiratory wheeze. he had received high-dose chemotherapy seven days prior to admission. his investigations showed high levels of c-reactive protein. a nasopharyngeal swab viral multiplex pcr test was positive for rsv and negative for other viruses. the patient’s cbc showed severe leukopenia 0.1 x 109/l (normal range: 1.4‒9.0 x 109/l) with no neutrophils. his cxr showed a narrowing of the upper third of the trachea [figure 2a] with compensatory hyperinflation and no consolidation. the patient was diagnosed with croup and was prescribed adrenaline and dexamethasone. he had severe stridor requiring intubation [figure 2b] and a three-day course of ventilation. six days later, a repeat cbc, neck x-ray and cxr showed resolution of the aforementioned signs. he completely recovered and was discharged seven days after admission. case three a 33-day-old male infant was admitted to the picu at the royal hospital in december 2013 with a twoday history of fever, cough and poor feeding. on examination, he was febrile, tachycardic, tachypnoeic and required 3 l of oxygen via nasal prongs for maintained saturation. investigations showed a normal cbc, urea electrolyte panel, bone profile and urine analysis. a cxr revealed bronchopneumonia with multiple pneumatoceles [figure 3a]. the day after admission, he became distressed and was found to be hypotensive with right pneumothorax. he required intubation, ventilation, intercostal drainage (icd) catheter insertion and inotropic support for three days. he began to improve on the fourth day of admission and the icd catheter was removed and the inotropic support discontinued. he was extubated on the same figure 3 a&b: chest x-rays of a 33-day-old male infant (case three) with respiratory syncytial virus infection showing (a) right-side pneumatoceles on admission and (b) the resolution of the pneumatoceles four days after admission. nawal al-maskari, jalila mohsin, amal al-maani, nabil al-macki and suad al-ismaili case series | e89 body stiffness which would last for a few seconds. these movements were eased by the administration of diazepam. when assessed, the patient scored between 8–11 on the glasgow coma scale. on the subsequent day, the patient was transferred to the picu at the royal hospital for further evaluation and management. on arrival, she was obtunded, only opened her eyes to painful stimuli, did not respond to verbal commands and showed some withdrawal of the flexor response of the limbs to deep painful stimuli. there were bilateral pyramidal tract signs involving both the upper and lower limbs. she was ventilated due to her low glasgow coma score and a depressed gag reflex. she developed a severe allergic skin reaction to ceftriaxone and was subsequently prescribed meropenem instead, although she continued to receive acyclovir. upon her admission to the picu, results of a brain ct scan were normal. fluid attenuated inversion recovery magnetic resonance t2 imaging of the brain on the second day of admission revealed multiple subcortical white matter hyperintense lesions involving the periventricular white matter, internal capsule, left anterior midbrain, corpus callosum, posterior brainstem tract, cerebellar peduncles and left optic nerve [figure 4]. this was suggestive of acute necrotising encephalopathy (ane). she was treated with intravenous methylprednisolone pulse therapy for five days. as no improvement was seen from the methylprednisolone treatment, this was followed by intravenous immunoglobulin at a dosage of 2 g/kg over the next five days. the patient had multiple episodes of generalised tonic posturing and was treated with phenytoin and levetiracetam. as there were no clinical signs of improvement, a lumbar puncture was repeated on day nine of admission, which showed a negative culture with normal analysis (wbc: 5/ul; rbc: 20/ul; glucose: 4.6 mmol/l; proteins: 0.2 g/l). the patient’s csf viral pcr study was negative for herpes simplex viruses 1 and 2, enteroviruses, varicella zoster virus and mumps virus. blood serology showed positive mycoplasma igg and negative igm and iga. on the 11th day of admission, the patient received five sessions of plasmapheresis over the following seven days. she showed dramatic clinical improvement and was extubated at the end of the third week of admission. with an extensive rehabilitation programme, the patient made excellent progress. when she was discharged, despite mild left upper limb weakness, she had normal speech, cognitive function and could walk with support. she was advised to continue physiotherapy. three months after discharge, she was seen in a paediatric neurology outpatient clinic and was found to have no neurological deficits. discussion almost all children acquire a rsv infection by the second year of life. a minority (0.5–2.0%) of infected children will require admission and most of them will be less than six months old.5 all of the patients in this case series were asymptomatic apart from upper respiratory tract infections for two days prior to admission. three of the children were unique in that they had a complicated course with an extrapulmonary manifestation of rsv infection, while the remaining patient had such a severe lower respiratory tract infection that he was found to have a pneumatocele in association with rsv. only one child was known to be immunocompromised; the other three had no known risk factors. pneumatoceles are caused primarily by staphylococcus aureus, although they may also be associated with other pathogens like streptococcus pneumoniae, h. influenzae and klebsiella pneumoniae.10 pneumatoceles are a very rare complication of rsv bronchiolitis.11 figure 4 a&b: axial fluid-attenuated inversion recovery magnetic resonance images of the brain in a six-year-old female (case four) with respiratory syncytial virus infection showing (a) non-confluent white matter hyperintense foci involving the centrum semiovale, periventricular white matter and internal capsules, (b) hyperintense lesions involving the anterior midbrain and (c) hyperintense lesions involving the cerebellar peduncles. atypical presentations of respiratory syncytial virus infection case series e90 | squ medical journal, february 2016, volume 16, issue 1 it has been shown that treatments for ane have limited efficacy.17 a recent report showed that treatment with steroids within the first 24 hours for three children without brainstem involvement improved outcomes, whereas the use of non-steroidal anti-inflammatory drugs has been associated with a poor prognosis and increased mortality rates.17 methylprednisolone pulse therapy and high-dose γ-globulin treatment have been used to modulate immune-mediated neurovascular and cell injury.17 plasma exchange can be used in patients who respond poorly to corticosteroids in order to modulate immune-mediated neurovascular and cell injuries. although no data from randomised trials are available, successful treatment with plasma exchange has been reported.17,22,23 alternative treatments for rsv infections that have been initiated in an attempt to improve mitochondrial function include carnitine, coenzyme q10 and pyridoxine; hypothermia has also been tried as a treatment modality.17 the use of these interventions has been associated with a decrease in mortality rate (30% to 15%).17 currently, there is no clear evidence that the use of ribavirin improves the clinical outcome of critically ill infants with rsv infections.24 one patient in this case series (case four) had encephalopathy which rapidly progressed within 48 hours preceded by an upper respiratory tract infection. the respiratory viral panel showed positive rsv pcr results with negative findings for other viruses and m. pneumoniae. the patient was managed with methylprednisolone, plasmapheresis and extensive physiotherapy. she improved gradually and had fully recovered within three months. in this case, the most likely cause of ane was the rsv infection. it is very difficult to confirm that ane is caused only by rsv in the absence of a brain biopsy. a brain biopsy was not performed on this patient as it was thought to be an invasive procedure and the patient was in an unstable condition. clinicians should consider ane in cases of rsv infection with rapid progressive encephalopathy and start aggressive management accordingly. conclusion in healthy children, an rsv infection usually causes a mild respiratory tract infection; however, some patients present with rare atypical and severe manifestations. testing for rsv in these cases is therefore indicated. clinicians should have a high suspicion of ane when treating a patient with a respiratory infection and acute neurological manifestations. early recognition of ane is important for the initiation of effective supportive treatment in order to improve patient outcomes. almost 85% of rsv pneumatoceles resolve completely and spontaneously.12 lobar emphysema may also be associated with rsv pneumonia.12 one patient (case three) had symptoms of a viral infection with a runny nose and cough, then developed pneumonia and a pneumatocele which completely resolved within two weeks. endotracheal secretions were positive for rsv pcr findings and h. influenzae non-type b culture, but his blood culture was negative. in this patient, it is likely that rsv was the primary infection; h. influenzae may have been a colonisation or secondary infection. previous research has shown that serious bacterial infections are present in 0.6–1.2% of children admitted with rsv infections.13 to determine the aetiology of the pneumatoceles and pneumonia in the previously reported patient (case three), a lung biopsy was necessary. however, it was not carried out as the patient had improved; as such, a biopsy would not have added to the clinical management of the case. acute laryngeal croup is most often associated with parainfluenza viruses, rsv, rhinoviruses and enteroviruses.14 usually croup presents in children of five years of age or younger. unusually, one patient in this case series (case two) had severe croup due to rsv at the age of nine years; this can be explained by his secondary immunodeficiency following chemotherapy. acute fulminant hepatic failure with encephalopathy is another rare atypical manifestation of rsv infection.15 acute hepatitis can be a manifestation of other viruses such as the hepatitis, epsteinbarr, cytomegalovirus and influenza viruses. one patient in this series (case one) had acute fulminant hepatic failure with encephalopathy and deranged coagulation. a liver biopsy was not performed; with supportive management, she recovered both clinically and biochemically within one week. ane is a rare, rapidly progressive, potentially fatal, parainfectious encephalopathy with specific neuroimaging findings that affect mainly healthy children between five months and 11 years of age. ane seems to be more prevalent in children from japan.16 it has a high mortality rate, reaching up to 30%, with a severe neurological handicap occurring in 15% of survivors.17 ane has been reported in patients with influenza types a and b, parainfluenza viruses, enteroviruses, reoviruses and m. pneumoniae.16–20 however, to the best of the authors’ knowledge, ane has not previously been reported in the english literature in association with rsv infections. the pathogenesis of rsv-related encephalitis is still not yet fully understood. however, it has been hypothesised that rsv may enter into the central nervous system through the haematogenous/blood-brain barrier route or through invasion with the release of several humoral neurotoxic cytokine mediators.21 nawal al-maskari, jalila mohsin, amal al-maani, nabil al-macki and suad al-ismaili case series | e91 references 1. collins pl, graham bs.viral and host factors in human respiratory syncytial virus pathogenesis. j virol 2008; 82:2040–55. doi: 10.1128/jvi.01625-07. 2. omer sb, sutanto a, sarwo h, linehan m, djelantik ig, mercer d, et al. climatic, temporal, and geographic characteristics of respiratory syncytial virus disease in a tropical island population. epidemiol infect 2008; 136:1319–27. doi: 10.1017/ s0950268807000015. 3. khamis fa, al-kobaisi mf, al-areimi ws, al-kindi h, al-zakwani i. epidemiology of respiratory virus infections among infants and young children admitted to hospital in oman. j med virol 2012; 84:1323–9. doi: 10.1002/jmv.23330. 4. hall cb, weinberg ga, iwane mk, blumkin ak, edwards km, staat ma, et al. the burden of respiratory syncytial virus infection in young children. n engl j med 2009; 360:588–98. doi: 10.1056/nejmoa0804877. 5. dawson-caswell m, muncie hl jr. respiratory syncytial virus infection in children. am fam physician 2011; 83:141–6. 6. eisenhut m. extrapulmonary manifestations of severe respiratory syncytial virus infection: a systematic review. crit care 2006; 10:r107. doi: 10.1186/cc4984. 7. ng yt, cox c, atkins j, butler ij. encephalopathy associated with respiratory syncytial virus bronchiolitis. j child neurol 2001; 16:105–8. doi: 10.1177/088307380101600207. 8. playfor sd, khader a. arrhythmias associated with respiratory syncytial virus infection. pediatr anesth 2005; 15:1016–18. doi: 10.1111/j.1460-9592.2005.01580.x. 9. hirayama k, sakazaki h, murakami s, yonezawa s, fujimoto k, seto t, et al. sequential mri, spect and pet in respiratory syncytial virus encephalitis. pediatr radiol 1999; 29:282–6. doi: 10.1007/s002470050589. 10. imamoğlu m, cay a, koşucu p, ozdemir o, cobanoğlu u, orhan f, et al. pneumatoceles in postpneumonic empyema: an algorithmic approach. j pediatr surg 2005; 40:1111–17. doi: 10.1016/j.jpedsurg.2005.03.048. 11. fujii am, moulton s. percutaneous catheter evacuation of a pneumatocele in an extremely premature infant with respiratory failure. j perinatol 2003; 23:516–8. doi: 10.1038/sj.jp.7210964. 12. fujii am, moulton s. vats management of an enlarging multicystic pneumatocele. j perinatol 2008; 28:445–7. doi: 10. 1038/sj.jp.7211928. 13. randolph ag, reder l, englund ja. risk of bacterial infection in previously healthy respiratory syncytial virus-infected young children admitted to the intensive care unit. pediatr infect dis j 2004; 23:990–4. doi: 10.1097/01.inf.0000143647.88873.66. 14. rihkanen h, ronkko e, nieminen t, komsi kl, räty r, saxen h, et al. respiratory viruses in laryngeal croup of young children. j pediatr 2008; 152:661–5. doi: 10.1016/j.jpeds.2007.10.043. 15. kirin bk, topić rz, dodig s. hepatitis during respiratory syncytial virus infection: a case report. biochem med (zagreb) 2013; 23:112–6. doi: 10.11613/bm.2013.014. 16. kim yn, you sj. a case of acute necrotizing encephalopathy associated with parainfluenza virus infection. korean j pediatr 2012; 55:147–50. doi: 10.3345/kjp.2012.55.4.147. 17. marco ej, anderson je, neilson de, strober jb. acute necrotizing encephalopathy in 3 brothers. pediatrics 2010; 125:e693–8. doi: 10.1542/peds.2009-1984. 18. martin a, reade ep. acute necrotizing encephalopathy progressing to brain death in a pediatric patient with novel influenza a (h1n1) infection. clin infect dis 2010; 50:e50–2. doi: 10.1086/651501. 19. tabarki b, thabet f, al shafi s, al adwani n, chehab m, al shahwan s. acute necrotizing encephalopathy associated with enterovirus infection. brain dev 2013; 35:454–7. doi: 10.1016/j.braindev.2012.07.001. 20. ashtekar cs, jaspan t, thomas d, weston v, gayatri na, whitehouse wp. acute bilateral thalamic necrosis in a child with mycoplasma pneumoniae. dev med child neurol 2003; 45:634–7. doi: 10.1111/j.1469-8749.2003.tb00969.x. 21. park a, suh si, son gr, lee yh, seo hs, eun bl, et al. respiratory syncytial virus-related encephalitis: magnetic resonance imaging findings with diffusion-weighted study. neuroradiology 2014; 56:163–8. doi: 10.1007/s00234-013-1305-z. 22. tunkel ar, glaser ca, bloch kc, sejvar jj, marra cm, roos kl, et al. the management of encephalitis: clinical practice guidelines by the infectious diseases society of america. clin infect dis 2008; 47:303–27. doi: 10.1086/589747. 23. wu x, wu w, pan w, wu l, liu k, zhang hl. acute necrotizing encephalopathy: an underrecognized clinicoradiologic disorder. mediators inflamm 2015; 2015:792578. doi: 10.1155/ 2015/792578. 24. davison c, ventre km, luchetti m, randolph ag. efficacy of interventions for bronchiolitis in critically ill infants: a systematic review and meta-analysis. pediatr crit care med 2004; 5:482–9. doi: 10.1097/01.pcc.0000128891.54799.67. http://dx.doi.org/10.1128/jvi.01625-07 http://dx.doi.org/10.1017/s0950268807000015 http://dx.doi.org/10.1017/s0950268807000015 http://dx.doi.org/10.1002/jmv.23330 http://dx.doi.org/10.1056/nejmoa0804877 http://dx.doi.org/10.1186/cc4984 http://dx.doi.org/10.1177/088307380101600207 http://dx.doi.org/10.1111/j.1460-9592.2005.01580.x http://dx.doi.org/10.1007/s002470050589 http://dx.doi.org/10.1016/j.jpedsurg.2005.03.048 http://dx.doi.org/10.1038/sj.jp.7210964 http://dx.doi.org/10.1038/sj.jp.7211928 http://dx.doi.org/10.1038/sj.jp.7211928 http://dx.doi.org/10.1097/01.inf.0000143647.88873.66 http://dx.doi.org/10.1016/j.jpeds.2007.10.043 http://dx.doi.org/10.11613/bm.2013.014 http://dx.doi.org/10.3345/kjp.2012.55.4.147 http://dx.doi.org/10.1542/peds.2009-1984 http://dx.doi.org/10.1086/651501 http://dx.doi.org/10.1016/j.braindev.2012.07.001 http://dx.doi.org/10.1111/j.1469-8749.2003.tb00969.x http://dx.doi.org/10.1007/s00234-013-1305-z http://dx.doi.org/10.1086/589747 http://dx.doi.org/10.1155/2015/792578 http://dx.doi.org/10.1155/2015/792578 http://dx.doi.org/10.1097/01.pcc.0000128891.54799.67 1department of pathology & laboratory medicine, sultan qaboos hospital, salalah, oman; 2department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: rajib562@yahoo.com مرض روزاي-دورفمان املعزول يف األنسجة الرخوة تقرير حالة روبياث �صودري رايب، راجا�صيخاران بيالي، اإبراهيم عدنان �صليمان، اإبراهيم الهدابي abstract: rosai-dorfman disease (rdd) is a rare benign proliferative histiocytic disorder characterised by massive lymphadenopathy. while extranodal involvement can occur in generalised rdd, isolated soft tissue rdd (strdd) is extremely rare. we report a 17-year-old male patient who presented to the maxillofacial outpatient department of the sultan qaboos hospital, salalah, oman, in 2015 with a painless cheek mass which had been slowly growing over the previous two months. routine histopathological examinations and immunohistochemistry confirmed a diagnosis of strdd. currently, surgical excision is considered to be the most effective curative treatment for strdd, as the outcomes of other treatment modalities are still unknown. despite its rarity, strdd should be considered in the differential diagnosis of histiocytic soft tissue lesions. keywords: histiocytosis; rosai-dorfman disease; emperipolesis; s100 proteins; case report; oman. ملفاوية عقد بوجود ويتميز الهي�صتيو�صايت خاليا ا�صطراب تكاثرو عن ناجت حميد نادر مر�ض هو دورفمان روزاي مر�ض امللخ�ص: مر�ض حدوث جدا النادر من انه ال الليمفية الغقد خارج املعمم روزاي-دورفمان مر�ض حدوث امكانية من وبالرغم �صخمة. اخلارجية العيادات ق�صم اإىل قدم عاما 17 العمر من يبلغ مري�ض عن حالة تقرير هذا الرخوة. الأن�صجة يف املعزول روزاي-دورفمان للوجه والفكني يف م�صت�صفى ال�صلطان قابو�ض، �صاللة، عمان، يف عام 2015 مع كتلة خديه غري موؤملة كانت تنمو ببطء خالل ال�صهرين حاليا، الرخوة. الأن�صجة يف املعزول روزاي-دورفمان ت�صخي�ض الكيميائية واملناعية املر�صية الأن�صجة فحو�صات واأكدت املا�صيني. يعترب ال�صتئ�صال اجلراحي هو العالج الأكرث فعالية لهذا املر�ض حيث اأن نتائج ا�صاليب العالج الأخرى ل تزال غري معروفة. على الرغم من ندرته، ينبغي و�صع مر�ض الروزاي-دورفمان املعزول يف الأن�صجة الرخوة يف الت�صخي�ض التفريقي لأمرا�ض الأن�صجة الرخوة خلاليا الهي�صتيو�صايت. الكلمات املفتاحية: اأمرا�ض الهي�صتيو�صيتوزي�ض؛ مر�ض روزاي-دورفمان؛ اخرتاق اخللية؛ الربوتينات s100؛ تقرير احلالة؛ عمان. soft tissue rosai-dorfman disease case report *rubyath c. rajib,1 rajasekharan pillai,1 ibrahim a. sulaiman,1 ibrahim al-haddabi2 case report sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e452–454, epub. 10 jan 18 submitted 3 jun 17 revision req. 17 jul 17; revision recd. 8 aug 17 accepted 24 aug 17 doi: 10.18295/squmj.2017.17.04.012 also known as sinus histiocytosis with massive lymphadenopathy, rosai-dorfman disease (rdd) was first described as a unique clinicopathological entity in 1969.1 clinically, it is characterised by massive bilateral painless lymphadenopathy of the head and neck region, with affected patients often presenting with fever, leukocytosis, an elevated erythrocyte sedimentation rate and polyclonal hypergammaglobulinaemia.2 isolated soft tissue rdd (strdd) may occur as part of a generalised process involving the lymph nodes or may involve extranodal sites independent of lymph node status.3,4 the clinical presentation is similar to that of nodal rdd.5 nodalbased rdd usually regresses spontaneously, whereas isolated strdd is indolent in nature and may recur years or even decades later.6 this report describes a case of isolated strdd which presented initially as a painless nodular cheek mass. the importance of including this rare entity in the differential diagnosis of histiocytic soft tissue lesions is highlighted. case report a 17-year-old male patient presented to the maxillofacial outpatient department of the sultan qaboos hospital, salalah, oman, in 2015 with a firm painless nodular mass in his right cheek which had been progressively increasing in size over the previous two months. in addition, he had mild proptosis of the right eye. there were no significant findings in the patient’s medical history or laboratory investigations. on clinical examination, the cheek mass measured 4 cm in diameter and was not associated with any lymph node enlargement. the differential diagnosis was of either a neoplastic or inflammatory soft tissue lesion. an excisional biopsy was performed. the excised mass was formed of two separate pieces of tissue with a firm whitish cut surface. the larger piece measured 1.7 x 0.8 x 0.3 cm and the smaller one measured 1.5 x 0.7 x 0.4 cm. a microscopic examination revealed fibrocollagenous and adipose rubyath c. rajib, rajasekharan pillai, ibrahim a. sulaiman and ibrahim al-haddabi case report | e453 lesion was continuous with another mass measuring 3.2 x 3.4 cm in the right infratemporal fossa, with obliteration of the fat planes. the optic nerve and extraocular muscles were in contact with the mass, but the globe was still intact. clinically, this lesion was considered to be of the same disease as the cheek lesion and no specific treatment or biopsy was attempted. after two years of follow-up, there was no evidence of disease progression in either lesion. discussion while rdd has been reported worldwide, it is more common among patients of african descent.7 up to 80% of cases occur among individuals in the first two decades of life, although other age groups can also be affected; in addition, rdd tends to occur more frequently among males.7,8 in the largest known study of rdd, 43% of 423 patients had associated extranodal disease along with lymphadenopathy; in comparison, only 3% of patients had no detectable lymphadenopathy.2 the skin and the paranasal sinuses are the most common sites for extranodal involvement.9 in an extensive review of the literature, komaragiri et al. identified only 36 strdd cases reported between 1969 and 2012.10 the current report adds an additional case to the existing literature concerning this rare entity. two large case series of strdd have been reported from the usa; the first described 17 cases of strdd, of which four presented with lymphadenopathy, whereas the second found that only one of 18 patients with strdd had associated lymph node involvement from a single node.5,11 in both series, strdd was more common in the trunk and proximal extremities and tended to grow rapidly, although the actual size of the lesion varied. the age of the affected patients also ranged widely and there was a slight female predominance.5,11 multifocal strdd is extremely uncommon but recurs more frequently than a solitary lesion.11,12 the rate of recurrence of strdd after excision has been reported to range from 21.4–54%.5,11 immunohistochemistry is key to differentiating soft tissue lesions in order to determine the correct diagnosis. morphologically, strdd is similar to nodal rdd in exhibiting the diffuse subcutaneous infiltration of large polygonal histiocytes, which in turn demonstrate emperipolesis predominantly of lymphocytes, although sometimes plasma cells, erythrocytes and neutrophils are also affected.5 infiltration of lymphocytes, plasma cells and neutrophils may also occur, along with the histiocytes. however, mitosis and necrosis are rare.5 while some researchers have tissue with nodular infiltration of lymphocytes, plasma cells, eosinophils, neutrophils and foamy histiocytes. many of the histiocytes showed ingested lymphocytes, plasma cells, eosinophils or neutrophils in the cytoplasm [figure 1]. no necrosis or mitosis was noted and the histiocytes were immunoreactive to s100 proteins [figure 2]. as a result, a diagnosis of rdd was made. the patient was subsequently referred to a tertiary hospital in oman for further examination and management. additional immunostaining of the mass revealed that the histiocytes were positive for s100 proteins and cluster of differentiation (cd)68, but negative for cd1a, cd30 and cd15. the plasma cells were polyclonal on both kappa and lambda light chain stains. moreover, even though a few cells were stained by immunoglobulin g (igg)4, the igg4:igg ratio did not increase. these findings confirmed the diagnosis of extranodal rdd, with a final diagnosis of isolated strdd. the patient was followed up continuously without any active treatment. five months later, a computed tomography scan of the right eye showed an enhancing lesion in the posteroinferior and lateral aspect of the right orbit measuring 3 x 2 cm. this figure 1: haematoxylin and eosin stain at x400 magnification showing lymphoid aggregates of mixed inflammatory cells including mature lymphocytes, neutrophils and plasma cells. note the evidence of emperipolesis as shown by the histiocytes engulfing the intact lymphocytes, neutrophils and plasma cells (arrow). figure 2: immunohistochemistry stain at x400 magnification showing the s100 protein positivity of large histiocytes (arrow). soft tissue rosai-dorfman disease case report e454 | squ medical journal, november 2017, volume 17, issue 4 3. rosai j, dorfman rf. sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder analysis of 34 cases. cancer 1972; 30:1174–88. doi: 10.1002/ 1097-0142(197211)30:5<1174::aid-cncr2820300507>3.0. co;2-s. 4. wenig bm, abbondanzo sl, childers el, kapadia sb, heffner dr. extranodal sinus histiocytosis with massive lymphadenopathy (rosai-dorfman disease) of the head and neck. hum pathol 1993; 24:483–92. doi: 10.1016/00468177(93)90160-i. 5. montgomery ea, meis jm, frizzera g. rosai-dorfman disease of soft tissue. am j surg pathol 1992; 16:122–9. doi: 10.1097/00000478-199202000-00004. 6. costa al, silva no, motta mp, athanazio ra, athanazio da, athanazio pr. soft tissue rosai-dorfman disease of the posterior mediastinum. j bras pneumol 2009; 35:717–20. doi: 10.1590/s1806-37132009000700015. 7. sodhi ks, suri s, nijhawan r, kang m, gautam v. rosaidorfman disease: unusual cause of diffuse and massive retroperitoneal lymphadenopathy. br j radiol 2005; 78:845–7. doi: 10.1259/bjr/23127241. 8. potts ca, bozeman ap, walker an, floyd we 3rd. cutaneous rosai-dorfman disease of the forearm: case report. j hand surg am 2008; 33:1409–13. doi: 10.1016/j.jhsa.2008.04.003. 9. brenn t, calonje e, granter sr, leonard n, grayson w, fletcher cd, et al. cutaneous rosai-dorfman disease is a distinct clinical entity. am j dermatopathol 2002; 24:385–91. doi: 10.1097/00000372-200210000-00001. 10. komaragiri m, sparber ls, santos-zabala ml, dardik m, chamberlain rs. extranodal rosai-dorfman disease: a rare soft tissue neoplasm masquerading as a sarcoma. world j surg oncol 2013; 11:63. doi: 10.1186/1477-7819-11-63. 11. al-daraji w, anandan a, klassen-fischer m, auerbach a, marwaha js, fanburg-smith jc. soft tissue rosai-dorfman disease: 29 new lesions in 18 patients, with detection of polyomavirus antigen in 3 abdominal cases. ann diagn pathol 2010; 14:309–16. doi: 10.1016/j.anndiagpath.2010.05.006. 12. young pm, kransdorf mj, temple ht, mousavi f, robinson pg. rosai-dorfman disease presenting as multiple soft tissue masses. skeletal radiol 2005; 34:665–9. doi: 10.1007/s00256005-0906-y. 13. rosai j. rosai and ackerman’s surgical pathology, 10th ed. new york, usa: mosby, 2011. pp. 1771–900. 14. govender d, chetty r. inflammatory pseudotumour and rosaidorfman disease of soft tissue: a histological continuum? j clin pathol 1997; 50:79–81. doi: 10.1136/jcp.50.1.79. 15. lu d, estalilla oc, manning jt jr, medeiros j. sinus histiocytosis with massive lymphadenopathy and malignant lymphoma involving the same lymph node: a report of four cases and review of the literature. mod pathol 2000; 13:414–19. doi: 10.1038/modpathol.3880071. 16. falk s, stutte hj, frizzera g. hodgkin’s disease and sinus histiocytosis with massive lymphadenopathy-like changes. histopathology 1991; 19:221–4. doi: 10.1111/j.1365-2559.1991. tb00025.x. reported frequent spindling of the histiocytes, others have claimed this is uncommon.5,11 in cases with histiocyte spindling, strdd may be confused with a sarcoma.10 in terms of immunohistochemistry, rdd histiocytes are consistently positive for s100 proteins and cd68 and negative for cd1a.13 the microscopic appearance of an inflammatory pseudotumour can resemble strdd; however, the histiocytes of inflammatory pseudotumours are negative for s100. these lesions may reflect a histological continuum.14 another differential diagnosis of strdd is langerhans cell histiocytosis, in which the histiocytes are positive for both s100 proteins and cd1a.15 the histogenesis of rdd is still unclear, but may be the result of an aberrant immunoresponse.7 the disease has also been associated with lymphoproliferative disorders.2 in cases of hodgkin’s lymphoma, certain cytokines have been found to alter the morphology of histiocytes to that seen in rdd.16 a relationship between polyomavirus infections and intra-abdominal strdd has also been postulated.11 due to its rarity, there is as yet no definitive treatment strategy for patients with strdd; however, surgical excision has been proven effective in preventing disease recurrence.10 further studies are required to establish evidence-based treatment strategies for this disease and to increase our understanding of its outcomes and natural history. conclusion strdd is a very rare benign proliferative histiocytic disorder. morphologically, it may mimic an inflammatory pseudotumour, sarcoma or langerhans cell histiocytosis. as such, it is important that strdd be considered in the differential diagnosis of histiocytic soft tissue lesions. references 1. rosai j, dorfman rf. sinus histiocytosis with massive lymphadenopathy: a newly recognized benign clinico-pathological entity. arch pathol 1969; 87:63–70. 2. foucar e, rosai j, dorfman r. sinus histiocytosis with massive lymphadenopathy (rosai-dorfman disease): review of the entity. semin diagn pathol 1990; 7:19–73. https://doi.org/10.1002/1097-0142%28197211%2930:5%3c1174::aid-cncr2820300507%3e3.0.co%3b2-s https://doi.org/10.1002/1097-0142%28197211%2930:5%3c1174::aid-cncr2820300507%3e3.0.co%3b2-s https://doi.org/10.1002/1097-0142%28197211%2930:5%3c1174::aid-cncr2820300507%3e3.0.co%3b2-s https://doi.org/10.1016/0046-8177%2893%2990160-i https://doi.org/10.1016/0046-8177%2893%2990160-i https://doi.org/10.1097/00000478-199202000-00004 https://doi.org/10.1590/s1806-37132009000700015 https://doi.org/10.1259/bjr/23127241 https://doi.org/10.1016/j.jhsa.2008.04.003 https://doi.org/10.1097/00000372-200210000-00001 https://doi.org/10.1186/1477-7819-11-63 https://doi.org/10.1016/j.anndiagpath.2010.05.006 https://doi.org/10.1007/s00256-005-0906-y https://doi.org/10.1007/s00256-005-0906-y https://doi.org/10.1136/jcp.50.1.79 https://doi.org/10.1038/modpathol.3880071 https://doi.org/10.1111/j.1365-2559.1991.tb00025.x https://doi.org/10.1111/j.1365-2559.1991.tb00025.x the stomach is less commonly affected by hollow viscus injuries (hvis) following blunt trauma, making up 4.3% of total cases.1 it is estimated that trauma surgery departments only encounter approximately 14 cases of hvis annually, with a prevalence of 0.3−1.2%.1−3 despite this, hvis account for 17.8% of all missed injuries in blunt trauma in comparison to solid organs such as the spleen (8.9%) and liver (3.3%); as such, a hvi is the most frequently missed organ injury.4 following blunt abdominal trauma (bat), gastric injuries have a higher mortality rate compared to other hvis, reaching up to 28.2% in cases with stomach injuries compared to 15.2% for small bowel injuries and 19.4% for injuries to the colon and rectum.1 case report a 39-year-old male pedestrian was hit by a vehicle and brought by the emergency medical services to the emergency medicine department of the sultan qaboos university hospital, muscat, oman, in 2015. the patient was managed according to advanced trauma life support® protocols (american college of surgeons, chicago, illinois, usa). the primary survey was unremarkable and the secondary survey was normal apart from an externally rotated right foot. after initial resuscitation with fluids, computed tomography (ct) imaging of the patient revealed a moderate amount of free intraperitoneal air [figure 1], suggestive of a bowel perforation. in addition, a lower limb x-ray revealed a comminuted open fracture of the right tibia. the patient underwent an exploratory laparotomy followed by intramedullary nailing of the tibial fracture and debridement of the wound. the laparotomy indicated free fluid and blood in the peritoneal cavity and a 2 cm serosal laceration on the posterior aspect of the distal stomach with a contained haematoma. primary wound closure was performed using 3-0 vicryl® sutures (ethicon inc., johnson & johnson, somerville, new jersey, usa). a non-bleeding liver 1general surgery residency program, oman medical specialty board, muscat, oman; 2department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: ahmed-naiem@hotmail.com إصابات املعدة غري املشخصة يف رضوح البطن الكليلة تقرير حلالة مع مراجعة للدراسات اأحمد اأ�رسف نعيم, ك�ظم م�شطفى تقي, بدرية حمود الكندية, ه�ين الق��شي abstract: hollow viscus injuries of the digestive tract are an uncommon occurrence in blunt abdominal trauma. we report a 39-year-old male who was hit by a vehicle as a pedestrian and admitted to the sultan qaboos university hospital, muscat, oman, in 2015. he underwent an exploratory laparotomy which revealed injuries to the distal stomach, liver and descending colon. postoperatively, the patient was febrile, tachycardic and hypotensive. abdominal examination revealed distention and tenderness. the next day, a repeat laparotomy identified a gastric injury which had not been diagnosed during the initial laparotomy. although the defect was repaired, the patient subsequently died as a result of multiorgan failure. missed gastric injuries are rare and are associated with a grave prognosis, particularly for trauma patients. delays in diagnosis, in addition to associated injuries, contribute to a high mortality rate. keywords: abdominal injuries; blunt injuries; trauma; diagnostic errors; laparotomy; case report; oman. امللخ�ص: تعترب اإ�ش�ب�ت الأح�ش�ء املجوفة للجه�ز اله�شمي من الإ�ش�ب�ت غري ال�ش�ئعة يف الر�شوح البطنية الكليلة. نعر�س يف هذا التقرير ح�لة مري�س يبلغ من العمر 39 ع�م� اأ�شيب يف ح�دث ده�س ومت تنوميه يف م�شت�شفى ج�معة ال�شلط�ن ق�بو�س مب�شقط, عم�ن ع�م 2015. اأجريت لهذا املري�س جراحة فتح بطن ا�شتك�ش�فية اأظهرت اإ�ش�ب�ت يف اجلزء الأق�شى من املعدة, والكبد, والقولون الن�زل. ويف فرتة م� بعد العملية, ظل املري�س يع�ين من ت�رسع القلب, وانخف��س �شغط الدم, و احلمى, م�شحوبً� ب�نتف�خ و وجع يف البطن. وقد اأظهرت يف اليوم الت�يل جراحة فتح بطن ا�شتك�ش�فية ُمع�دة اإ�ش�بة يف املعدة مل تكن قد �شخ�شت يف اجلراحة الأوىل. مع اأن الإ�ش�بة مت اإ�شالحه�, اإل اأن املري�س توفى نتيجة ف�شل وظيفي متعدد لالأع�ش�ء. تعد اإ�ش�ب�ت املعدة غري امل�شخ�شة ن�درة وذات خطورة ع�لية٬ خ��شة يف مر�شى الر�شوح. ويعترب الت�أخري يف الت�شخي�س, اإىل ج�نب تزامنه� مع اإ�ش�ب�ت متعددة من العوامل امل�ش�همة يف ارتف�ع معدل الوفي�ت. الكلمات املفتاحية: اإ�ش�ب�ت البطن؛ الإ�ش�ب�ت الكليلة؛ ر�شوح؛ اأخط�ء ت�شخي�شية؛ فتح البطن؛ تقرير ح�لة؛ عم�ن. missed gastric injuries in blunt abdominal trauma case report with review of literature *ahmed a. naiem,1 kadhim m. taqi,1 badriya h. al-kendi,1 hani al-qadhi2 case report sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e508–510, epub. 30 nov 16 submitted 9 apr 16 revision req. 10 may 16; revision recd. 7 jun 16 accepted 30 jun 16 doi: 10.18295/squmj.2016.16.04.019 ahmed a. naiem, kadhim m. taqi, badriya h. al-kendi and hani al-qadhi case report | e509 injury and a serosal tear of the descending colon were also observed. no bowel perforation was identified upon running the bowel three times from the stomach to the rectum, both anteriorly and posteriorly. the abdomen was subsequently closed and the patient was extubated and transferred to the intensive care unit (icu). the next day, the patient was febrile, tachycardic and hypotensive. abdominal examination revealed distention and tenderness. a repeat ct scan of the chest and abdomen showed increased pneumoperitoneum [figure 2], necessitating a repeat exploratory laparotomy carried out on the same day. this revealed that the abdominal cavity was soiled with bowel content and inflammatory fluid. there was a 3 x 3 cm perforation with necrotic edges at the distal greater curvature of the stomach. the edges of the perforation were resected and the defect closed with a single interrupted 3-0 vicryl® suture (ethicon inc.). the patient was transferred back to the icu after the repeat laparotomy. four days after the initial exploratory laparotomy, he developed multiple episodes of asystole and was resuscitated. post-resuscitation, there was evidence of multiorgan failure manifesting as a severe hypoxic brain injury, acute respiratory distress syndrome, liver failure and an acute kidney injury requiring continuous venovenous haemodialysis and vasopressors. the patient subsequently died on the 10th postoperative day following the initial laparotomy. discussion blunt trauma can result in injuries to the gastrointestinal tract via different mechanisms. an external force against the thorax and abdomen, such as that of a seatbelt or steering wheel, can crush a distended part of the gastrointestinal tract against the vertebral column, resulting in rupture of the bowel and its mesentery.5 moreover, deceleration forces encountered while in a sharply braking vehicle can disrupt bowel integrity at the junctions between the freely mobile and fixed segments of the gastrointestinal tract, giving rise to varying degree of tears and devascular ising injuries.3 missed injuries and delayed diagnoses are attributed to many causes, most of which are multifactorial.1 common patient-related factors include an altered level of consciousness, delayed presentation, haemodynamic abnormalities and the presence of other distracting injuries.2 the most frequent physicianrelated factors include deficiencies in clinical assessment or judgment as well as the inaccurate interpretation of results and imaging studies.6 in addition, an initially low index of suspicion for hvis and incomplete surgical exploration are significant contributing factors.6 in the current case, the primary and secondary surveys focused more on the distracting lower limb injury and the presence of ct-proven pneumoperitoneum. the initial exploratory laparotomy revealed nothing to explain the radiological findings. these factors could have contributed to a delayed diagnosis. tertiary surveys may detect significant injuries missed during primary and secondary surveys.7 gastric injuries are usually associated with a high injury severity score.1 moreover, although rare in bat, these injuries carry the highest mortality rate among hvis.1,6−8 the most commonly affected part of the stomach is the anterior stomach wall (40% of total gastric injuries), followed by the greater (23%) or lesser (15%) curvature of the stomach and the posterior stomach wall (15%).7 most gastric injuries are superficial haematomas and serosal tears, whereas full thickness perforations occur less commonly (0.3%).1 a proposed classification for traumatic gastric figure 1: computed tomography scan with contrast of a 39-year-old male with blunt abdominal trauma. there is evidence of a moderate amount of free intraperitoneal air as well as fluid in the left upper quadrant between the stomach and the spleen and more surrounding the stomach. fluid can also be seen around the duodenum. figure 2: repeat computed tomography scan with contrast following an explorative laparotomy and stomach laceration repair of a 39-year-old male with blunt abdominal trauma. there is evidence of increased pneumoperitoneum, necessitating a repeat laparotomy. missed gastric injuries in blunt abdominal trauma case report with review of literature e510 | squ medical journal, november 2016, volume 16, issue 4 1. watts dd, fakhry sm; east multi-institutional hollow viscus injury research group. incidence of hollow viscus injury in blunt trauma: an analysis from 275,557 trauma admissions from the east multi-institutional trial. j trauma 2003; 54:289–94. doi: 10.1097/01.ta.0000046261.06976.6a. 2. sung ck, kim kh. missed injuries in abdominal trauma. j trauma 1996; 41:276–82. doi: 10.1097/00005373-19960800000013. 3. tejerina alvarez ee, holanda ms, lópez-espadas f, dominguez mj, ots e, díaz-regañón j. gastric rupture from blunt abdominal trauma. injury 2004; 35:228–31. doi: 10.1016/ s0020-1383(03)00212-2. 4. lawson cm, daley bj, ormsby cb, enderson b. missed injuries in the era of the trauma scan. j trauma 2011; 70:452–6. doi: 10.1097/ta.0b013e3182028d71. 5. shinkawa h, yasuhara h, naka s, morikane k, furuya y, niwa h, et al. characteristic features of abdominal organ injuries associated with gastric rupture in blunt abdominal trauma. am j surg 2004; 187:394–7. doi: 10.1016/j.amjsurg.2003.12.018. 6. allen gs, moore fa, cox cs jr, wilson jt, cohn jm, duke jh. hollow visceral injury and blunt trauma. j trauma 1998; 45:69–75. doi: 10.1097/00005373-199807000-00014. 7. rodríguez-hermosa ji, roig j, sirvent jm, codina-cazador a, gironès j, puig j, et al. gastric perforations from abdominal trauma. dig surg 2008; 25:109–16. doi: 10.1159/000121906. 8. brooks a, holroyd b, riley b. missed injury in major trauma patients. injury 2004; 35:407–10. doi: 10.1016/s0020-1383(03) 00219-5. 9. moore ee, jurkovich gj, knudson mm, cogbill th, malangoni ma, champion hr, et al. organ injury scaling: vi extrahepatic biliary, esophagus, stomach, vulva, vagina, uterus (nonpregnant), uterus (pregnant), fallopian tube, and ovary. j trauma 1995; 39:1069–70. doi: 10.1097/00005373-19951200000009. 10. pikoulis e, delis s, tsatsoulis p, leppäniemi a, derlopas k, koukoulides g, et al. blunt injuries of the stomach. eur j surg 1999; 165:937–9. doi: 10.1080/110241599750008035. injuries is detailed in table 1.9 patients with gastric injuries secondary to bat usually have a nonspecific presentation, possibly due to shock; as such, abdominal tenderness or rigidity and fevers are less likely to be clinically evident.1 diagnostic tools range from plain films to ultrasonography and ct; in addition, a diagnosis can be made during a diagnostic or exploratory laparotomy.8 the management of such injuries involves initial fluid resuscitation followed by laparoscopic or open debridement of the wound with primary closure or a partial gastrectomy.10 conclusion traumatic hvis, when missed, are a major cause of morbidity and mortality. in a trauma setting, injuries usually involve multiple systems, many of which can complicate clinical assessment and diagnosis. moreover, the presentation of gastric injuries is generally nonspecific. trauma teams should therefore have a high index of suspicion for hvis when treating severely injured patients. references table 1: classification of traumatic gastric injuries9 grade injury type description of injury i haematoma or contusion •haematoma or contusion without devascularisation •partial thickness laceration of the stomach wall ii laceration •laceration of ≤2 cm in the gastroesophageal junction or pylorus •laceration of ≤5 cm in the proximal third of the stomach •laceration of ≤10 cm in the distal two-thirds of the stomach iii laceration •laceration of >2 cm in the gastroesophageal junction or pylorus •laceration of >5 cm in the proximal third of the stomach •laceration of >10 cm in the distal two-thirds of the stomach iv vascular injury tissue loss or devascularisation of two-thirds of the stomach or less v vascular injury tissue loss or devascularisation of more than two-thirds of the stomach e447 | squ medical journal, may 2015, volume 15, issue 2 إشعار بنشر مزدوج الفوائد املتصورة من التدريب باحملاكاة يف ما قبل املرحلة السريرية على حصيلة التدريب السريري عند طالب التمريض العمانيني notice of duplicate publication notice of duplicate publication perceived benefits of pre-clinical simulation-based training on clinical learning outcomes among omani undergraduate nursing students the editors of sultan qaboos university medical journal (squmj) have been informed that an article by madhavanprabhakaran et al. in the february 2015 issue of squmj overlaps significantly with the content of an article published by madhavanprabhakaran et al. in nurse education in practice in april 2015.1,2 the editors of squmj wish to notify the readers of both journals of this issue. upon examination of the above two articles, there was evidence of major duplication/overlap with neither article referencing the other. the levels of similarity and duplication between the articles contravened the policies of ethical publication as defined by the international committee of medical journal editors and the committee on publication ethics.3,4 for the reasons stated herein, the article by madhavanprabhakaran et al. in nurse education in practice has now been retracted.2 the article by madhavanprabhakaran et al. will not be retracted from squmj.1 the authors have agreed to the publication of this notice. the corresponding author takes sole responsibility for the duplicate publication and would like to apologise to the readers, reviewers and editors of nurse education in practice and squmj. furthermore, the corresponding author would like to assure all concerned parties that the duplicate publication was unintentional. references 1. madhavanprabhakaran g, al-khasawneh e, wittmann l. perceived benefits of pre-clinical simulation-based training on clinical learning outcomes among omani undergraduate nursing students. sultan qaboos univ med j 2015; 15:e105–11. 2. madhavanprabhakaran gk, al-khasawneh e, ramasubramaniam s, akintola aa. students’ perceived benefits of pre-clinical simulation based training (psbt) on enhancing patient safety and clinical learning outcomes. nurse educ pract 2015; pii: s1471-5953(15)00055-4. doi: 10.1016/j.nepr.2015.03.009. 3. international committee of medical journal editors. overlapping publications. from: www.icmje.org/recommendations/browse/ publishing-and-editorial-issues/overlapping-publications.html accessed: jul 2015. 4. committee on publication ethics. flowcharts. from: www.publicationethics.org/resources/flowcharts accessed: jul 2015. n o t i c e o f d u p l i c at e p u b l i c at i o n f o r: m a d h ava n p r a b h a k a r a n e t a l. p e r c e i v e d b e n e f i t s o f p r e-c l i n i c a l s i m u l at i o n-b a s e d t r a i n i n g o n c l i n i c a l l e a r n i n g o u t c o m e s a m o n g o m a n i u n d e r g r a d u at e n u r s i n g s t u d e n t s. s u lta n q a b o o s u n i v m e d j 2015; 15:e 105–11. sultan qaboos university med j, august 2015, vol. 15, iss. 3, p. e447, epub. 24 aug 15. doi: 10.18295/squmj.2015.15.03.028. http://dx.doi.org/10.1016/j.nepr.2015.03.009 department of emergency medicine, faculty of medicine, mara university of technology, selangor, malaysia *corresponding author’s e-mail: alif_1979@yahoo.com نقطة الرعاية للمسلك اهلوائي بتخطيط الصدى قبل عملية بضع الغشاء احللقي الدرقي الطارئة تقرير حالة حممد اإقبال، جولينا حممد نور، نور عبدالكرمي، اإيزات اإ�شماعيل، حليم �شنيب، حممد اأمني خمتار، �شفريدا �شامل abstract: the use of ultrasonography in acute and critical care medicine is becoming increasingly common. however, use of an airway ultrasound as an adjunct to determine the type of intervention needed and assess complications is not common practice. we report a 56-year-old male who presented to the emergency department of the sungai buloh hospital, selangor, malaysia, in 2015 with hoarseness, stridor and impending respiratory failure. a point-of-care ultrasound performed to assess the neck and vocal cords indicated a heterogeneous echogenic mass in the larynx, thus ruling out a cricothyroidotomy. the patient was therefore referred for an emergency tracheostomy. this case highlights the importance of point-of-care airway ultrasonography in the assessment of patients with stridor. this imaging technique not only helps to detect the cause of the stridor, but also to determine the feasibility of a cricothyroidotomy in emergency cases. keywords: emergency medicine; stridor; ultrasonography; airway management; tracheostomy; case report; malaysia. فوق املوجات ا�شتخدام اأن، ومع متزايد. ب�شكل �شائعًا اأمراً واحلرجة احلادة الرعاية طب يف ال�شدى تخطيط ا�شتخدام اأ�شبح امللخ�ص: حالة نعر�ض ال�شتخدام. �شائعة غري اأنها اإل امل�شاعفات وتقييم املطلوب التدخل نوع لتحديد م�شاعدة تعترب الهوائي للم�شلك ال�شوتية مري�ض ذكر عمره 56 عامًا تقدم لق�شم الطوارئ مب�شت�شفى �شونغاي بوله، �شيلنجور، ماليزيا، يف 2015 باأعرا�ض بحة، �رضير و ف�شل تنف�شي و�شيك. مت تقدمي نقطة الرعاية با�شتخدام املوجات فوق ال�شوتية لتقييم الرقبة واحلبال ال�شوتية والتي اأظهرت وجود كتلة متغايرة مولدة لل�شدى يف البلعوم، وبالتايل مت اأ�شتبعاد اإجراء ب�شع الغ�شاء احللقي الدرقي. مت بذلك حتويل املري�ض لإجراء فغر الرغامى الطارئ. هذه احلالة ت�شلط ال�شوء على اأهمية تخطيط ال�شدى يف نقطة الرعاية للم�شلك الهوائي عند تقييم املر�شى الذين يعانون من �رضير. هذه التقنية الت�شويرية ل ت�شاعد فقط على اكت�شاف �شبب ال�رضير، ولكن اأي�شا حتدد جدوى عملية ب�شع الغ�شاء احللقي الدرقي يف احلالت الطارئة. الكلمات املفتاحية: طب الطوارئ؛ �رضير؛ تخطيط ال�شدى؛ عالج امل�شلك الهوائي؛ فغر الرغامى؛ تقرير حالة؛ ماليزيا. point-of-care airway ultrasonography prior to an emergency cricothyroidotomy case report *mohamad iqhbal, julina m. noor, nur a. karim, izzat ismail, halim sanib, mohd a. mokhtar, safreeda s. f. salim case report sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e219–222, epub. 9 sep 18 submitted 6 nov 17 revision req. 12 dec 17; revision recd. 8 jan 18 accepted 1 feb 18 doi: 10.18295/squmj.2018.18.02.017 the presence of stridor indicates anupper airway obstruction.1 in emergency departments, patients with stridor are often treated emergently according to strict management protocols. in such cases, the attending physician must be able to evaluate the patient and determine the type of airway management intervention required, such as a cricothyroidotomy.1 however, with the high rate of success of newer airway management techniques, such as orotracheal intubation, rates of cricothyroidotomies have declined over the past decade to approximately 0.4–1.2%.2–5 unfortunately, as this procedure is uncommon, the prevalence of complications during a cricothyroidotomy can vary from 6.1–54.5%, depending on the clinical circumstances of the case, technique employed and experience of the surgeon.6,7 although pointof-care ultrasonography (pocus) is very useful in critical care and acute medicine, its role in airway management is not routine, even though several studies have advocated its use.8–10 the current case demonstrates the benefits of pocus in assessing the airway of a patient with stridor and informing the choice of emergency airway intervention. case report a 56-year-old male presented to the emergency department of the sungai buloh hospital, selangor, malaysia, in 2015 with shortness of breath, stridor and hoarseness. he had started experiencing breathing difficulties and coryzal symptoms a few months prev iously. the patient reported that the hoarseness had begun about six months prior to presentation and point-of-care airway ultrasonography prior to an emergency cricothyroidotomy case report e220 | squ medical journal, may 2018, volume 18, issue 2 was associated with weight loss, loss of appetite and dysphagia. however, he was still able to eat and drink. he had seen a local general practitioner but these symptoms had not been investigated. one week prior to presentation, he started to experience noisy breathing precipitated by an upper respiratory tract infection and he reported feeling breathless upon exertion. at presentation, the patient could sit upright and was mildly tachypnoeic with inspiratory stridor. his breathing sounds were normal and he was able to talk in a hoarse voice without drooling. his blood pressure was 118/80 mm hg and he had a pulse rate of 70 beats per minute. oxygen saturation was at 98% with a nasal cannula. a clinical examination revealed no visible mass in the head, neck or chest region and the trachea appeared to be centrally located. there were also no signs of venous distension of the neck or chest wall or evidence of facial or upper extremity oedema. an airway ultrasound was performed to investigate the structure of the airway and identify the cause of the stridor. notably, this revealed a hyperechoic artefact extending throughout the cricoid cartilage, which was inconsistent with the structure of a normal airway [figure 1]. the mass had ill-defined borders with heterogeneous echogenicity [figure 2]. anticipating that airway management would be difficult and potentially involve intubation or a cricothyroidotomy, the patient was referred to the otorhinolaryngology team for further assessment and definitive management. flexible laryngoscopy revealed a fungating mass involving the false vocal cords and extending to the subglottic region [figure 3]. as the patient was stable and able to maintain oxygenation, he underwent an emergency tracheostomy. later, a computed tomography scan was suggestive of a laryngeal carcinoma [figure 4], which was successfully removed. figure 3: flexible laryngoscopic image of the airway of a 56-year-old male showing an intraluminal fungating mass (arrow). figure 1: longitudinal point-of-care airway ultrasonography of (a) a 56-year-old male with stridor showing a distorted cricothyroid membrane with a mass underneath (arrow) in comparison to (b) an example of a normal airway. tc = thyroid cartilage; ctm = cricothyroid membrane; cc = cricoid cartilage. figure 2: transverse point-of-care airway ultrasonography of (a) the airway of a 56-year-old male with stridor showing intraluminal heterogeneous echogenic mass (arrow) in comparison to (b) an example of a normal airway. sm = sternohyoid muscle; ctm = cricothyroid membrane; t = trachea. mohamad iqhbal, julina m. noor, nur a. karim, izzat ismail, halim sanib, mohd a. mokhtar and safreeda s. f. salim case report | e221 thyroidotomy skills in emergency medicine and critical care training, particularly in view of the reliability of this technique and its association with fewer complications compared to conventional methods.16 conclusion routine pocus should be considered in certain high risk situations requiring emergency airway management, such as stridor and neck haematomas and masses. in such cases, the identification of an abnormal anat omical structure in the airway would make a conven tional cricothyroidotomy unfeasible; hence, an alternative approach is required, such as a tracheostomy. references 1. nemeth j, maghraby n, kazim s. emergency airway management: the difficult airway. emerg med clin north am 2012; 30:401−20. doi: 10.1016/j.emc.2011.12.005. 2. bushra js, mcneil b, wald da, schwell a, karras dj. a comparison of trauma intubations managed by anesthesiologists and emergency physicians. acad emerg med 2004; 11:66−70. doi: 10.1197/j.aem.2003.08.013. 3. tayal vs, riggs rw, marx ja, tomaszewski ca, schneider re. rapid-sequence intubation at an emergency medicine residency: success rate and adverse events during a two-year period. acad emerg med 1999; 6:31−7. doi: 10.1111/j.1553-2712.1999. tb00091.x. 4. sakles jc, laurin eg, rantapaa aa, panacek ea. airway management in the emergency department: a one-year study of 610 tracheal intubations. ann emerg med 1998; 31:325−32. doi: 10.1016/s0196-0644(98)70342-7. 5. levitan rm, rosenblatt b, meiner em, reilly pm, hollander je. alternating day emergency medicine and anesthesia resident responsibility for management of the trauma airway: a study of laryngoscopy performance and intubation success. ann emerg med 2004; 43:48−53. doi: 10.1016/s0196-0644(03)00638-3. 6. bair ae, panacek ea, wisner dh, bales r, sakles jc. cricothyrotomy: a 5-year experience at one institution. j emerg med 2003; 24:151−6. doi: 10.1016/s0736-4679(02)00715-1. 7. brantigan co, grow jb sr. cricothyroidotomy: elective use in respiratory problems requiring tracheotomy. j thorac cardiovasc surg 1976; 71:72−81. discussion in acute care medicine, delays in airway management can result in poor outcomes.11 emergency airway inter ventions range from laryngoscopy to a cricothyroidotomy, with the latter being a last life-saving resort when all other measures fail. traditionally, a cricothyroidotomy is performed blindly as a form of emergent airway management.12 prior to the procedure, the cricothyroid membrane is identified based on surface landmarks and palpation. however, elliott et al. demonstrated that this membrane was only correctly identified by 30% of anaesthetists, of which only 11% could locate the midline.13 in such cases, the cricothyroidotomy tube can be misplaced due to the inaccurate identification of these anatomical landmarks. in addition, technical problems in 40% of cases have been noted during cricothyroidotomies performed using the seldinger technique.14 in comparison, pocus is a noninvasive and readily available technique. furthermore, it can provide detailed information regarding the anatomy of the airway as all of the internal structures can be visualised in a short period of time by placing the linear probe at the centre of the neck.15 prior to an emergency cricothyroidotomy, an ultrasound allows for the reliable and rapid identification of the cricothyroid membrane and trachea, unaffected by the patient’s body mass index.16,17 the current case highlights the importance of pocus, not only in the accurate localisation of anatomical landmarks, but also in the identification of any internal structural abnormalities and, consequently, the feasibility of performing a cricothyroidotomy. while it may be argued that pocus is not expedient in a time-sensitive situation, failure and complication rates remain high for emergency cricothyroidotomies performed blindly, thus delaying critical life-saving interventions in any case.18 as such, the authors advocate the incorporation of pocus-guided crico figure 4: computed tomography scans of the airway of a 56-year-old male in the (a) sagittal view showing an irregular mass obstruction (arrow) extending to the lower border of the cricoid cartilage and (b) axial view showing the severely stenosed airway. tc = thyroid cartilage; cc = cricoid cartilage; tt = tracheostomy tube. https://doi.org/10.1016/j.emc.2011.12.005 https://doi.org/10.1197/j.aem.2003.08.013 https://doi.org/10.1111/j.1553-2712.1999.tb00091.x https://doi.org/10.1111/j.1553-2712.1999.tb00091.x https://doi.org/10.1016/s0196-0644%2898%2970342-7 https://doi.org/10.1016/s0196-0644%2803%2900638-3 https://doi.org/10.1016/s0736-4679%2802%2900715-1 point-of-care airway ultrasonography prior to an emergency cricothyroidotomy case report e222 | squ medical journal, may 2018, volume 18, issue 2 14. eisenburger p, laczika k, list m, wilfing a, losert h, hofbauer r, et al. comparison of conventional surgical versus seldinger technique emergency cricothyrotomy performed by inexperienced clinicians. anesthesiology 2000; 92:687−90. doi: 10.1097/ 00000542-200003000-00012. 15. singh m, chin kj, chan vw, wong dt, prasad ga, yu e. use of sonography for airway assessment: an observational study. j ultrasound med 2010; 29:79−85. doi: 10.7863/jum.2010.29.1.79. 16. nicholls se, sweeney tw, ferre rm, strout td. bedside sonography by emergency physicians for the rapid identification of landmarks relevant to cricothyrotomy. am j emerg med 2008; 26:852−6. doi: 10.1016/j.ajem.2007.11.022. 17. curtis k, ahern m, dawson m, mallin m. ultrasoundguided, bougie-assisted cricothyroidotomy: a description of a novel technique in cadaveric models. acad emerg med 2012; 19:876−9. doi: 10.1111/j.1553-2712.2012.01391.x. 18. mcgill j, clinton je, ruiz e. cricothyrotomy in the emergency department. ann emerg med 1982; 11:361−4. doi: 10.1016/ s0196-0644(82)80362-4. 8. whitson mr, mayo ph. ultrasonography in the emergency department. crit care 2016; 20:227. doi: 10.1186/s13054-0161399-x. 9. osman a, sum km. role of upper airway ultrasound in airway management. j intensive care 2016; 4:52. doi: 10.1186/s40560016-0174-z. 10. kristensen ms, teoh wh, graumann o, laursen cb. ultrasonography for clinical decision-making and intervention in airway management: from the mouth to the lungs and pleurae. insights imaging 2014; 5:253−79. doi: 10.1007/s13244-014-0309-5. 11. bauer pr, gajic o, nanchal r, kashyap r, martin-loeches i, sakr y, et al. association between timing of intubation and outcome in critically ill patients: a secondary analysis of the icon audit. j crit care 2017; 42:1–5. doi: 10.1016/j.jcrc.2017.06.010. 12. shannon nj, shannon gd. “blind” emergency cricothyrotomy in patients with complicating factors under adverse conditions. wilderness environ med 1998; 9:260–1. doi: 10.1580/ 1080-6032(1998)009[0260:ltte]2.3.co;2. 13. elliott ds, baker pa, scott mr, birch cw, thompson jm. accuracy of surface landmark identification for cannula cricothyroidotomy. anaesthesia 2010; 65:889−94. doi: 10.1111/ j.1365-2044.2010.06425.x. https://doi.org/10.1097/00000542-200003000-00012 https://doi.org/10.1097/00000542-200003000-00012 https://doi.org/10.7863/jum.2010.29.1.79 https://doi.org/10.1016/j.ajem.2007.11.022 https://doi.org/10.1111/j.1553-2712.2012.01391.x https://doi.org/10.1016/s0196-0644%2882%2980362-4 https://doi.org/10.1016/s0196-0644%2882%2980362-4 https://doi.org/10.1186/s13054-016-1399-x https://doi.org/10.1186/s13054-016-1399-x https://doi.org/10.1186/s40560-016-0174-z https://doi.org/10.1186/s40560-016-0174-z https://doi.org/10.1007/s13244-014-0309-5 https://doi.org/10.1016/j.jcrc.2017.06.010 https://doi.org/10.1580/1080-6032%281998%29009%5b0260:ltte%5d2.3.co%3b2 https://doi.org/10.1580/1080-6032%281998%29009%5b0260:ltte%5d2.3.co%3b2 https://doi.org/10.1111/j.1365-2044.2010.06425.x https://doi.org/10.1111/j.1365-2044.2010.06425.x squ med j, november 2011, vol. 11, iss. 4, pp. 462-469, epub. 25th oct 11 submitted 2nd may 11 revision req. 30th may 11, revision recd. 9th jul 11 accepted 7th sep 11 1department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of haematology, sultan qaboos university hospital, muscat, oman; 3department of medicine, sohar hospital, sohar, oman; 4department of obstetrics & gynecology, sultan qaboos university hospital, muscat, oman; 5hôpital robert debré, inserm u763, paris, france. corresponding author email: sskindi@yahoo.com فرز )حتري( حديثي الوالدة املعدالت املرجعية ملؤشرات اخلاليا احلمراء ومتوسط اهليموغلوبني يف دم احلبل السري عند األطفال الُعمانيني حديثي الوالدة �ضلم الكندي، انيل بثاري، علي املدحاين، �ضعيب الزدجايل، حمود الهدابي، قمرية العربي، ديفيد جرافل، مرمي ماثيو، راجو جوبال كر�ضنا مورثي يف الأداء عايل اِئل ال�ضَّ اُب ِت�رسرْ وال�ضرْ الكامل العددي الدم فح�س يف احلمراء الدم خليا معدلت موؤ�رسات من التحقق الهدف: امللخ�ص: عينات من دم احلبل ال�رسي عند الُعمانيني حديثي الولدة. الطريقة: مت فح�س 7837 عينة من دم احلبل ال�رسي للأطفال حديثي الولدة وذلك بالقيام بفح�س الدم العددي الكامل وفح�س ال�ضت�رساب ال�ضائل عايل الأداء با�ضتخدام الربنامج الق�ضري للثال�ضيميا "بيتا". مت اإجراء اجلودة. عايل ال�ضائل ال�ضت�رساب نتائج من للتحقق و)�ضي( و)اأي( و)دي( )ا�س( للهيموغلوبني الطبيعية غري للعينات املبا�رس الت�ضل�ضل اإ�ضافة لذلك فقد مت اإجراء الفح�س اجليني يف احلالت التي وجد فيها كمية هيموغلوبني )اأي( اأقل من 10% لتاأكيد وجود طفرة. النتائج: – هيموغلوبني ،8.03±22.88 – اأي )هيموغلوبني طبيعيا ال�ضائل ال�ضت�رساب حتليل عندهم كان )%51.58( 4042 وليدا اأن ثبت حالة اأية على نح�ضل ومل ،)%48.42( البقية يف األفا – بالثل�ضيميا بالإ�ضابة توؤ�رس النتيجة كانت بينما ،) 8.04±77.02 اف لهيموغلوبني – اأت�س. كانت نتائج املجموعة ال�ضابقة كما يلي: متو�ضط الهيموغلوبني )15.38±2.04 جرام/ لرت(، وتعداد كريات الدم هيموغلوبنُي ،(7.75±107.66( الَو�َضِطّي الُكَريِويُّ ُم احَلجرْ ،)%7.18±50.5( الدَّم َدا�ُس ِمكرْ لرت(، /1012 x 0.68±4.69 ( احلمراء اخلليا توزيع عر�س لرت(، جرام/دي�ضي 3.44±30.98( الكريوي الهيموغلوبني متو�ضط بيكوجرام(، 4.07±33.31( الَو�َضِطّي ِة الُكَريَّ بينما كانت يف املجموعة الثانية امل�ضابة بالثال�ضيميا )األفا( كما ياأتي وعلى التوايل: )14.79±2.90 احلمراء )%2.17±17.01(، 30.39±3.6(; بيكوجرام( 29.74±11.80(; )97.29±13.8(; )%49.7±7.40(; لرت( /1012 x 5.09±0.77(; لرت( جرام/ الدم فح�س نتائج يوؤكد اأن ميكن الطبيعي غري للهيموغلوبني للعينات النووي احلم�س ت�ضل�ضل جرام/دي�ضي لرت( ;)%18.09±2.56( اِئل عايل الأداء يف جميع احلالت. اخلال�صة: هذه هي اأول درا�ضة ملقارنة الهيموغلوبني وموؤ�رسات خليا اُب ال�ضَّ ِت�رسرْ العددي الكامل وال�ضرْ الدم احلمراء يف دم احلبل ال�رسي حلديثي الولدة الُعمانيني مع مثيلتها من بلدان اأخرى يف املنطقة، والتي تبني نتائج مماثلة لتلك التي اُب ِت�رسرْ ظهرت عند حديثي الولدة ال�ضعوديني. كما قمنايف هذه الدرا�ضة اأي�ضا بالتحقق من �ضحة تف�ضريات فح�س الدم العددي الكامل وال�ضرْ اِئل عايل الأداء ملوؤ�رسات دم احلبل ال�رسي عند حديثي الولدة الُعمانيني. كان وقوع الثل�ضيميا )األفا( التي مت ت�ضخي�ضها عن طريق ال�ضَّ الهيموجلوبني يف دم احلبل ال�رسي حلديثي الولدة %48.42. مفتاح الكلمات: وليدي، فرز، حتري، تق�ضي، هيموغلوبني، متغريات، ثتل�ضيميا األفا، ُعمان. abstract: objectives: the aim of this study was to validate the interpretation of red blood cell indices in complete blood count (cbc) and high performance liquid chromatography (hplc) results on cord blood samples in consecutive omani neonates. methods: cord blood samples from 7,837 neonates, were analysed with cbc and hplc using the β-thalassaemia short programme. direct sequencing of abnormal samples with hbs, hbd, hbe and hbc was performed to validate the hplc results. additionally, in cases with hba <10%, the β-globin gene was directly sequenced for β-thalassaemia mutation analysis. results: overall, 4,042 subjects (51.58%) had normal hplc (hba 22.88±8.03; hbf 77.02±8.04), whereas the presence of hb barts in the remaining 3,795 cases (48.42%) indicated the presence of α-thalassaemia. no case of hbh was detected. in the former subgroup respectively, the mean hb (15.38±2.04 g/dl) red blood cell (rbc) count (4.69±0.68 x 1012/l), hct (50.5±7.18%), mean corpuscular volume (mcv) (107.66±7.75 fl), mean corpuscular haemoglobin (mch) (33.31±4.07 pg), mean corpuscular haemoglobin concentration (mchc) (30.98±3.44 g/dl), red cell distribution width (rdw) (17.01±2.17%) whereas, in the latter group with α-thalassaemia, it was (14.79±2.90 g/dl); (5.09±0.77 x 1012/l); (49.7±7.40%); (97.29±13.8 fl); (29.74±11.80 pg); (30.39±3.6 g/dl), and (18.09±2.56%) respectively. dna sequencing of samples with abnormal neonatal screening mean haemoglobin and red cell indices in cord blood from omani neonates *salam alkindi,1 anil pathare,2 ali al-madhani,3 shoaib al-zadjali,2 hamood al-haddabi,2 qamariya alabri,2 david gravell,2 mariam mathew,4 rajagopal krishnamoorthy5 clinical & basic research salam alkindi, anil pathare, ali al-madhani, shoaib al-zadjali, hamood al-haddabi, qamariya al-abri, david gravell, mariam mathews and rajagopal krishnamoorthy clinical and basic research | 463 several studies have shown that inherited haemoglobinopathies are widespread in oman and are at a sufficiently high level to be of considerable national concern.1,2 specifically, oman has a relatively high prevalence of α and β-thalassaemia, g6pd deficiency and sickle cell syndromes compared to other arabian gulf countries.3-6 a community based survey carried out in 1995 in oman showed a significantly high prevalence of haemoglobinopathy.5 the reported prevalence of sickle cell trait was 6% and β-thalassaemia trait was 2%, whereas the prevalence of homozygous sickle cell and β-thalassaemia was 0.2% and 0.07% respectively. the prevalence of other abnormal haemoglobins namely hbd, hbe and hbc were 0.6%, 0.3% and 0.02% respectively. enzyme deficiency of g6pd was also prevalent (18%). our own report in 2010 also showed comparatively high prevalence rates.6 interestingly, a high incidence of inherited haemoglobinopathies has also been reported in mediterranean and middle eastern contries.3,7,8 the prevalence of α-thalassaemia was reported as 39.99% and the sickle cell gene was seen in 23.4% of cord blood neonatal samples from saudi arabia.8 it has been postulated that the likelihood of children being born with a major haemoglobinopathy in oman would be about 3 per 1,000 births.5 thus, with an annual birth rate of 35.76 births/1,000 population,9 there would approximately be 106 new cases every year. therefore, with this burden of haemoglobinopathy, the establishment of neonatal reference ranges is extremely important. this study was undertaken under the auspices of his majesty’s research directive to screen neonates by implementing a universal newborn screening at the sultan qaboos university hospital (squh), oman. cord blood samples from newborns at squh (representing the muscat governorate), and from the sohar hospital (representing the batinah costal region) were collected. the objectives of our study were twofold. the first objective was to screen the newborn omani subjects to establish the current prevalence of haemoglobinopathy and to see the effect of the decade long measures that were implemented following the first community study in 1995. the second objective was to validate the cbc and hplc interpretations of the cord blood red cell indices in the omani neonate. hplc is a powerful tool for the simultaneous screening of newborn samples for haemoglobinopathies and to detect the presence of haemoglobin barts.10,11 it is extremely accurate, reliable with reproducible results and has thus become the method of choice due to its speed and precision. the objective of this study was therefore to validate the cbc and hplc interpretations of the cord blood red cell indices in the omani neonate and by a universal newborn cord blood screening in the omani population. advances in knowledge 1. this study validates the cord blood red cell indices obtained from omani newborn subjects without any underlying haemoglobinopathy. 2. it validates the cord blood red cell indices in omani newborn subjects with α-thalassaemia. 3. finally, it validates the abnormal haemoglobins in omani newborn subjects. application to the patient care 1. the results of this study will benefit patient care by comparative analysis of omani cord blood red cell indices in subjects without any underlying haemoglobinopathy with those from other countries in the region. 2. it will improve patient care by comparative analysis of omani cord blood red cell indices with α-thalassaemia with those from other countries in the region. 3. it will also improve patient care by comparing the influence of α-thalassaemia on cord red cell indices in the different subsets with variant haemoglobins amongst omani newborn subjects. haemoglobin could validate the cbc and hlpc interpretations in all cases. conclusion: this is the first study comparing the hemoglobin and red cell indices in the cord blood from newborn omani subjects with those from other countries in the region, showing comparable results to those seen in saudi neonates. the study also validates the cbc and hplc interpretations of the cord blood red cell indices in the omani neonate. the incidence of α-thalassaemia diagnosed by the presence of hb barts in cord blood of neonates was 48.42%. keywords: neonatal; screening; reference range, haemoglobin; variants; alpha-thalassaemia. neonatal screening mean haemoglobin and red cell indices in cord blood from omani neonates 464 | squ medical journal, november 2011, volume 11, issue 4 methods this study was conducted under the auspices of his majesty’s strategic research project initiated and funded between the years 2005 to 2008. the study was approved by the institutional review board and conformed to the declaration of helsinki. the study enrolled a total of 3,740 subjects from squh in muscat and 4,097 neonates from sohar hospital, oman. all data was archived in a microsoft excel database. statistical analysis was performed using the student’s t test with a value <0.05 considered significant. between april 2005 and march 2007 and after informed consent was obtained, a total of 7,837 consecutive cord blood samples were table 1: comparative analysis of cord blood red cell indices (mean ± sd) in newborn omani neonates compared with saudi neonates8 haemoglobins n hb gm/dl rbc 1012/l hct % mcv fl mch pg mchc g/dl rdw % hba % hbf % ab. hb s,d,e,c omani hbaf 3, 765 15.38 2.04* 4.69 0.68* 50.5 7.18* 107.66 7.75* 33.31 4.07* 30.98 3.44* 17.01 2.17* 22.88 8.03* 77.02 8.04* -saudi hbaf8 243 15.1 1.65 4.5 0.52 47.4 5.32 106.0 8.0 33.6 2.36 31.8 1.7 17.9 1.7 27.2 7.1 72.8 7.7 omani hbaf barts 3,505 14.79 2.9* 5.09 0.77* 49.7 7.4* 97.29 13.8* 29.74 11.8* 30.39 3.6* 18.09 2.56* 25.74 9.05* 73.96 8.91* -saudi hbaf barts8 136 14.3 1.98 5.03 0.68 46.4 5.9 92.5 9.9 28.6 2.9 30.7 2.2 19.2 2.0 28.1 8.2 67.8 8.3 -omani hbafs 188 15.09 1.56 4.91 0.62 48.59 5.5 103.34 9.6* 32.92 2.9* 30.5 2.96* 16.65 1.5 13.13 7.8* 76.7 11.4* 8.18 2.9* saudi hbafs8 57 14.97 1.47 4.66 0.5 47.1 5.2 101.2 6.2 32.3 2.1 31.9 1.7 17.7 1.4 18.5 3.8 73.6 5.4 7.9 2.57 omani hbafs barts 218 15.02 2.0 4.73 0.66 47.0 7.6 96.51 8.04* 30.12 4.2* 30.26 3.51* 17.33 2.1 14.28 5.2 * 78.73 8.3* 6.97 3.4* saudi hbafs barts8 50 13.88 1.37 5.03 0.57 45.2 5.3 89.3 8.24 27.7 2.2 31.1 1.94 19.6 4.2 18.7 5.56 70.1 5.8 6.8 2.02 omani hbfs 9 16.45 0.21* 5.06 0.37 48.5 8.09* 104.52 5.9* 32.55 2.8* 30.81 3.26 14.95 0.49* -89.55 3.78* 12.9 4.7* saudi hbfs8 3 14.13 0.1 4.26 0.1 44.8 3.6 105.2 7.8 33.2 0.57 31.7 2.7 17.5 0.5 -89.2 3.8 10.8 3.8 omani hbfs barts 14 12.89 2.4* 4.40 1.04 45.57 5.5* 97.5 4.4* 30.63 6.8* 30.85 3.24 17.16 0.97* -86.85 5.2* 10.8 5.2* saudi hbfs barts8 4 12.9 1.6 4.7 0.4 41.1 9.1 87.2 14.8 27.5 1.9 31.8 2.76 20.03 2.31 -83.7 5.6 11.87 5.9 omani hbafd 45 14.86 1.3 4.4 0.39* 43.3 3.8 104.7 7.6* 33.84 3.5 30.77 2.66 16.75 2.01 13.91 7.41 78.76 8.3* 8.66 3.6 omani hbafd barts 28 15.0 1.5 4.76 0.64* 49.47 7.5 101.4 10.23* 31.8 3.4 30.22 2.9 18.24 3.57 12.7 4.8 87.24 4.8* 8.42 3.8 omani hbafe 29 16.63 1.8* 5.31 0.91 57.6 5.07 104.77 7.88* 31.67 3.4 30.89 3.05 17.95 2.26 20.3 9.91* 75.36 6.5* 6.78 3.21 omani hbafe barts 30 15.17 1.57* 4.9 0.99 50.9 11.0 99.6 6.8* 30.57 8.2 30.15 3.55 18.85 6.93 13.29 5.32* 86.7 5.32* 6.54 2.84 omani hbafc 3 15.7 1.19 4.24 0.78 42.12 6.78 101.5 7.8* 32.55 4.5 30.99 2.34 15.35 1.67 13.5 3.4 77.9 5.33* 7.8 2.67 omani hbafc barts 3 15.05 1.62 4.62 0.8 44.9 9.32 99.75 5.6* 32.2 5.6 30.2 3.89 16.65 0.56 11.31 4.6 85.13 6.45* 6.21 3.24 legend: * p <0.05 between red cell indices, with and without α-thalassemia (hb barts) in omani neonates; rbc = red blood cell; hct = haematocrit; mcv = mean cell volume; mch = mean corpuscular haemoglobin; mchc = mean corpuscular haemoglobin concentration; rdw = red cell distribution width; hbaf = hb a+f; hbafs = hb a+f+s; hbfs = hb f+s; hbafd = hb a+f+d; hbafe = hb a+f+e; hbafc = hb a+f+c. salam alkindi, anil pathare, ali al-madhani, shoaib al-zadjali, hamood al-haddabi, qamariya al-abri, david gravell, mariam mathews and rajagopal krishnamoorthy clinical and basic research | 465 screened prospectively, for the presence of possible haemoglobinopathies by a full blood count followed by hplc using the biorad variant ιι β-thalassaemia short programme. the cbc was performed using edta cord blood samples on cell dyn 4000tm automated blood cell counter (abbot diagnostics, abbot laboratories, il, usa) within 4–12 hours of collection. hplc was performed within 12–24 hours of collection using the β-thalassaemia short programme on the bio-rad variant iitm instrument (bio-rad laboratories, hercules, ca, usa) using the manufacturer’s instructions and controls. the samples were refrigerated from the time of collection up to the time of analysis. all samples were then processed to isolate and store mononuclear leukocytes for subsequent confirmatory molecular diagnostics. direct sequencing of abnormal samples with hbs, hbd, hbe and hbc was performed on the abi prismtm 3100 genetic analyser (applied biosystems, foster city, ca, usa) to assign the genotype status to these subjects and validate the hplc results. the dna sequencing was performed by polymerase chain reaction (pcr)-amplified β-globin gene segment to look for the following mutations, namely hbs (β6 glu-val), hbd (β121 glu-gln), hbe (β26 glu-lys) and hbc (β6glu-lys) as per the manufacturer’s instructions and pcr conditions. additionally, in samples with hba below 10%, the β-globin gene was directly sequenced including the promoter, all exons and introns in these samples to look for all the known mutations reported for β-thalassaemia. results on the basis of a cbc and hplc, all samples were characterised as either normal (hba+hbf), 4,042 cases; or α–thalassaemia, (hba+hbf+hb barts) 3,795 cases. in the former group, 200 cases also had hbs, 45 cases had hbd, 29 cases had hbe, and 3 cases had hbc. whereas in the latter group, 229 cases additionally also had hbs, 28 cases had hbd, 30 cases had hbe, and 3 cases had hbc. table 1 shows the comparative analysis of cord blood red cell indices (mean ± standard deviation [sd]) from newborn omani neonates compared with saudi neonates.8 in a subset of the omani neonates without any abnormal haemoglobin (hba+hbf) (n = 3,765), the mean (±sd) hb(g/ dl), red blood cell count (rbc) count (x 1012/l), haematocrit (hct) (%), mean cell volume (mcv) (fl), mean corpuscular haemoglobin (mch) (pg), mean corpuscular haemoglobin concentration (mchc) (g/dl), red cell distribution width (rdw) (%), were 15.38±2.04; 4.69±0.68; 50.5±7.18; 107.66±7.75; 33.31±4.07, 30.98±3.44, and 17.01±2.17 respectively. whereas in the subset of subjects with hba, hbf, hb barts (n = 3,505), the study observed a 48.42% incidence of α-thalassaemia, based on low mcv and mch on the cbc and significant amounts of hb barts on hplc based on the manufacturer’s cutoff limit. their mean (±sd) hb(g/dl), rbc count (x 1012/l), hct (%), mcv (fl), mch (pg), mchc (g/dl), rdw (%), were 14.79±2.90; 5.09±0.77; 49.7±7.40; 97.29±13.8; 29.74±11.80; 30.39±3.6, and 18.09±2.56 respectively. there was a statistically significant reduction in the mcv, mch, mchc, hct, hb and an increase in the rbc count. furthermore, mcv was the best discriminator between the two table 2: incidence of abnormal haemoglobinopathies observed in this study (n = 7,837) haemoglobins number (%) high performance liquid chromatography (hplc) direct sequencing concordance numbers % numbers % % normal (a+f) 7,837 (100) 4042 51.57 α-thalassemia(a+f+barts) 3795 48.42 hbs (f+s+a) 773 (9.86) 429 5.47 428 5.46 99.8 hbd (f+d+a) 73 0.93 73 0.93 100 hbe (f+e+a) 59 0.75 59 0.75 100 hbc (f+c+a) 6 0.08 6 0.08 100 low hba,<10% 206 2.62 202 2.57 98.1 neonatal screening mean haemoglobin and red cell indices in cord blood from omani neonates 466 | squ medical journal, november 2011, volume 11, issue 4 groups (p = 7.0e-118). since hplc cannot diagnose the presence of the β-thalassaemia gene at birth, in samples with hba below 10%, the β-globin gene was directly sequenced including the promoter, all exons and introns in the abnormal samples (as per the manufacturer’s technical report) [table 2]. in 105 of the 206 cases, an underlying known and previously reported mutation described in β-thalassaemia cases could be documented in this cohort of newborn cases.6 on complete analysis of the remaining cases, amongst the 206 cases we could demonstrate a known β-thalassaemia mutation in a total of 202 cases (98.1%). additionally, in cases with an abnormal haemoglobin on hplc, direct sequencing of abnormal samples with hbs (n = 429), hbd (n = 73), hbe (n = 59), and hbc (n = 6) was also performed on an abi prism 3100 genetic analyser to assign the genotype status to these subjects and validate the hplc results [table 2 and figure 1]. in 428 of the 429 cases with hplc showing hbs, the β6glu—˃val mutation could be documented by direct sequencing of the relative region of the β-gene, (99.76%) whereas, in the single sample with hbs in cord blood, but no β6glu—˃val mutation, we found an abnormality in codon 16 of the delta chain. furthermore, direct sequencing results in all cases of hbd, hbe and hbc showed complete concordance (100%) [table 2]. population reference range for various haemoglobins (%) in cord blood from newborn omani subjects (n = 7,837) are shown in table 3. the mean hba, hbf, hbs, hbd, hbe, hbc (±sd) were 22.88±8.04; 77.02±8.04; 13.6±6.96; 8.88±4.87; 6.64±2.98, and 6.21±3.41 respectively. the overall incidence of other haemoglobinopathies was 9.86% (n = 773), with 5.46% (n = 428) incidence of sickle haemoglobin. discussion oman is a country with a population comprising a wide range of ethnic groups, and high rates of consanguinous marriages.12 this is a significant reason for the increased prevalence of haemoglobinopathies, which is of growing importance as knowledge of the population structure can be a unique aid in planning genetic services. hplc is a powerful tool to screen newborns for haemoglobinopathies. cord blood sampling offers an easy, simple and practical method for demonstrating the coexistence of α-thalassaemia by detecting the presence of hb barts. we were able to identify these subjects very well with the biorad variant ii© system, using the β-thalassaemia short programme which works on the principle of cation exchange high pressure liquid chromatography. since each haemoglobin has a characteristic retention time, hb barts being a fast moving haemoglobin, is easily separated and eluted from the other haemoglobins present in the neonatal cord blood samples. the precision is further improved by running a chromatographic calibrator with an assigned value for hb barts at the beginning of each run. thus, using the presence of hb barts as an indicator of α-thalassaemia, we found that 51.57% subjects had normal hplc (absence of hb barts). before the availability of molecular diagnostic methods for the diagnosis of α-thalassaemia, there was good evidence that the presence of hb barts in the neonatal period indicated the presence of α-thalassaemia.13,14 however, the relationship between the amounts of hb barts and the underlying molecular defect was not clear. most surveys using assays that detect 0.5% to 1% hb barts in cord blood detect a large proportion of neonates with α-thalassaemia, but not all; hence, surveys solely based on the presence of hb barts in cord table 3: reference range for various haemoglobins (%) in cord blood from newborn omani subjects (n = 7,837) hba % (n = 7837) hbf % (n = 7837) hbs % (n = 429) hbd % (n = 73) hbe % (n = 59) hbc % (n = 6) mean 22.88 77.02 13.6 8.88 6.64 6.21 standard deviation 8.04 8.05 6.96 4.87 2.98 3.41 median 22.0 78.0 12.6 9.15 5.8 5.7 range 4–50 25.1–96 2.1–21.9 3.7–19.1 2.2–14.6 2.7–11.6 95% confidence interval 22.62–23.13 76.75–77.29 12.7–14.5 6.94–9.83 5.47–8.05 2.64–9.79 salam alkindi, anil pathare, ali al-madhani, shoaib al-zadjali, hamood al-haddabi, qamariya al-abri, david gravell, mariam mathews and rajagopal krishnamoorthy clinical and basic research | 467 blood consistently under-reported the frequency of α-thalassaemia.15 moreover, although the levels of hb barts are related to the degree of α-chain deficit, there is no way to distinguish the various α-thalassaemia syndromes solely on the basis of hplc.16 a comparative analysis of the red cell indices in these two groups revealed that α-thalassaemia resulted in a lower mean hb, hct, mcv, mch, mchc and hbf whereas it resulted in a higher mean red cell count and hba concentration [table 1]. furthermore, all these differences were statistically strongly significant. the best discriminator was found to be mcv followed by red cell count, mch and hb concentration. similar observations have been also made by other investigators; however, the degree of abnormality varies amongst these parameters.7,8 the greatest difference reported has been seen in mch as individuals with α-thalassaemia clearly make less haemoglobin per cell than their normal counterparts. however, subjects with α-thalassaemia trait maintain adequate haemoglobin levels, the main compensatory mechanism being via the increased red cell numbers. the presence of α-thalassaemia was found to reduce the amount of hba both in hbs heterozygous as well as homozygous hbss subjects [table 1]. thus the presence of α-thalassaemia not only resulted in anatomically smaller rbcs, but also a cell which carried less hba making it rheologically more adapted to flow through the small capillaries, thereby increasing the disease severity.7,8,17 in subjects with hbd, the presence of α-thalassaemia also resulted in lower hba, hbd, mcv, and mch; whereas the hb, red cell count, hct and hbf were higher. the differences in rbc count, mcv and hbf were statistically significant [table 1]. in subjects with hbe the presence of α-thalassaemia resulted in lower hba, hbe, mcv, mch, hb, rbc counts and hct, whereas only the hbf was higher [table 1]. the differences in hb, mcv and hbf were statistically significant. overall, α-thalassaemia appears to influence all the red cell indices when it is the only abnormality. in the presence of abnormal haemoglobin, its influence was marginal unless the abnormal haemoglobin was present in a homozygous state, as in subjects who showed homozygous hbs. thus with the presence of α-thalassaemia leading to a reduction in α-chains, the additional presence of a β structural variant will lead to a variable situation the outcome of which depends on the net globin chain synthesis rate. some β-globin variants like hbe are synthesised less efficiently than hba and represent less than 50% of the haemoglobin in the heterozygote. furthermore, the rate of assembly of the αβ-chain complexes also would affect the final product. therefore, the formation of the αβ-dimer is the rate limiting step in the assembly of haemoglobin. sickle cell trait β6 a>t [heterozygous] sickle cell disease β6 a>t [homozygous] hb e trait β26 g>c [heterozygous] hb c trait β6 g> a a>t [both hetero] hb d trait β121 c>g [heterozygous] β thal. trait β ivs 1-5 c>g [hetero] β thal. trait β ivs 1,-2 t>g [hetero] β thal. trait β44(-c) [heterozygous] figure 1: capillary electropherogram results of dna sequencing by pcr-amplified β-globin gene segment to document hbs (β6 glu-val) (a,b), hbd (β121 glu-gln) (e), hbe (β26 glu-lys) (c), hbc (β6 glu-lys) (d) and the common β-thalassemia mutations (f,g,h). neonatal screening mean haemoglobin and red cell indices in cord blood from omani neonates 468 | squ medical journal, november 2011, volume 11, issue 4 direct sequencing of samples with abnormal haemoglobin was used to validate the interpretation of the cbc and hplc results and was found to be quite accurate [figure 1]. all cases with hbd, hbe, hbc were documented to show hbd (β121 glu-gln), hbe (β26 glu-lys) and hbc (β6glu-lys) mutation respectively. all cases with hbs were shown to carry the hbs (β6 glu-val) except in one case which had the delta chain codon 16 mutation, and is known to show a small abnormal haemoglobin band in the hbs window on hplc in the β-thalassaemia short programme hplc runs. furthermore, in cases with low hba (below 10%), 98.1% of subjects were documented to have one of the known mutations described as causative of β-thalassaemia, consistent with the recommendations of the manufacturer (bio-rad laboratories, hercules, ca, usa ). thus, the significantly high prevalence of haemoglobinopathies in newborns from oman emphasises the value of neonatal cord blood screening. this should be implemented as the first step in the national strategy towards total management of haemoglobinopathies—including early diagnosis, comprehensive clinical care and counselling of the affected families. in the light of the results of the current study, this initiative is being taken forward to encompass all the regions of oman. the results of this large study would indicate that using hplc is a cost effective method (<2 us $ per sample).18 conclusion in this study, for the first time, we were able to establish and validate the neonatal cord blood red cell indices and the prevalence of underlying abnormal haemoglobin by a universal newborn cord blood screening in the omani population. the study observed that approximately 10% of the population still carries an abnormal haemoglobinopathy with significant clinical consequences, like hb s, hb d, hb c and the β-thalassaemia gene. furthermore, we have also established the prevalence of α-thalassaemia in this cohort and its potential to alter the red cell indices as well as its ameliorating effect when co-associated with the presence of other haemoglobin variants, which are highly prevalent in oman. the comparative analysis of cord blood red cell indices and mean haemoglobins showed similar results to those seen with neonates from other countries in the region. therefore, as a direct result of this study, it is suggested that “targeted screening” with prescreening of both parents, and then selecting only the samples of neonatal cord blood from newborns with one parent having an underlying genetic trait for haemoglobinopathy, would result in a huge cost saving compared to the universal neonatal cord blood screening undertaken in this study. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g e m e n t s this study was supported by a grant from his majesty’s research project ig/med/haem/05/01. we would like to thank the parents who consented to the use of the cord blood samples. we would also thank the nurses, midwives and attending doctors who helped in the sample collection and in making this project a success. references 1. white jm, byrne m, richards r, buchanan t, katsoulis e, weerasingh k. red cell genetic abnormalities in peninsular arabs: sickle hemoglobin, g6pd deficiency, and alpha and beta thalassemia. j med genet 1986; 23:245–51. 2. white jm, christie bs, nam d, daar s, higgs dr. frequency and clinical significance of erythrocyte genetic abnormalities in omanis. j med genet 1993; 30:396–400. 3. el-hazmi ma, al-swailem ar, al-faleh fz, warsy as. frequency of glucose-6-phosphate dehydrogenase, pyruvate kinase and hexokinase deficiency in the saudi population. hum hered 1986; 36:45–9. 4. al-awamy bh, al-muzan m, al-turki m, serjeant gr. neonatal screening for sickle cell disease in the eastern province of saudi arabia. trans r soc trop med hyg 1984; 78:792–4. 5. al-riyami aa, suleiman aj, afifi m, al-lamki zm, daar s. a community-based study of common hereditary blood disorders in oman. east mediterr health j 2001; 7:1004–11. 6. al kindi s, zadjali s, al madhani a, daar sd, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. 7. nasserullah z, al-jame a, abu srair h, al-qatari g, al-naim s, al-aqib a, et al. neonatal screening salam alkindi, anil pathare, ali al-madhani, shoaib al-zadjali, hamood al-haddabi, qamariya al-abri, david gravell, mariam mathews and rajagopal krishnamoorthy clinical and basic research | 469 for sickle cell disease, glucose-6-phosphate dehydrogenase deficiency and α-thalassemia in qatif and al hasa. ann saudi med 1998; 18:289–92. 8. quadri mi, islam siam, nasserullah z. the effect of α-thalassemia on cord blood red cell indices and interaction with sickle cell gene, ann saudi med 2000; 20:367–70. 9. birth rate in oman. from: http://www.nationmaster. com/country/mu-oman/peo-people accessed: apr 2011. 10. rogers bb, wessels ra, ou cn, buffone gj. highperformance liquid chromatography in the diagnosis of hemoglobinopathies and thalassemias. report of three cases. am j clin pathol 1985; 84:671–4. 11. lorey f, cunningham g, shafer f, lubin b, vichinsky e. universal screening for hemoglobinopathies using high-performance liquid chromatography: clinical results of 2.2 million screens. eur j hum genet 1994; 24:262–71. 12. rajab a, patton ma. a study of consanguinity in the sultanate of oman. ann hum biol 2000; 27:321–6. 13. weatherall dj. abnormal hemoglobins in the neonatal period and their relationship to thalassemia. br j haematol 1963; 9:265–77. 14. wasi p, na-nakorn s, pootrakul s. the α-thalassemias. clin haematol 1974; 3:383–410. 15. higgs dr, pressley l, clegg jb, weatherall dj, higgs s, carey p, et al. detection of beta-thalassemia in negro infants. br j haematol 1980; 46:39–46. 16. higgs dr, vickers ma, wilkie aom, pretorius i-m, jarman ap, weatheral dj. a review of the molecular genetics of the human α-globin gene cluster. blood 1989; 73:1091–108. 17. weatheral dj. the thalassemias. in: beutler e, litchmen ma, coller bs, kipps tj, eds. william’s hematology. 5th ed, (international ed.). new york: mcgraw-hill inc, health professions division, 1995. pp. 581–615. 18. pathare av, al kindi s, al zadjali s, al abri q, al haddabi h, muralitharan s, et al. newborn hemoglobinopathy carrier screening: towards comprehensive and improved patient care of sickle cell disease in oman, a cost effective analysis (abstr. 806) hematol j 2006; 91:296–7. 1department of clinical physiology, sultan qaboos university hospital; departments of 2behavioural medicine and 5family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3department of basic sciences, school of basic & biomedical sciences, university of health & allied sciences, ho, ghana; 4department of mathematics & statistics, college of science, sultan qaboos university, muscat, oman *corresponding author’s e-mail: malabri@squ.edu.om النعاس النهاري بني الشباب البالغني سائقي املركبات يف عمان حممد عبد اهلل العربي، �شمري العدوي، اإبراهيم العربي، في�شل العربي، اأت�شو دورڤلو، رونالد و�شونغا، �شانچاي چاچو abstract: objectives: sleepiness and fatigue play significant roles in exacerbating the occurrence of car crashes. however, there is a dearth of studies examining the prevalence of sleepiness while driving among omanis. this study aimed to determine the proportion of young omani adults who confess to daytime sleepiness while driving and to investigate associations between gender, daytime sleepiness and risk of obstructive sleep apnoea syndrome (osas). methods: this cross-sectional study took place at the sultan qaboos university hospital, muscat, oman, between may and july 2014 and included 600 young adult omani non-commercial drivers. the berlin questionnaire and epworth sleepiness scale (ess) were distributed among the participants, along with additional questions about their sleeping habits. associations between daytime sleepiness while driving and nocturnal sleep duration, risk of osas and gender were determined. results: a total of 492 private vehicle drivers took part in the study (response rate: 82%), of which 50.4% were male. overall, 124 omanis (25.2%) reported experiencing daytime sleepiness while driving at least once per month. there was a significant association between nocturnal sleep duration of <6 hours and sleepiness while driving (p = 0.042). female participants were significantly more likely to score >10 on the ess, indicating a greater propensity for daytime sleepiness (p = 0.006). however, male drivers were significantly more likely to report sleepiness while driving (p = 0.001). conclusion: sleepiness while driving was common among young male drivers in oman and might be due to nocturnal sleep deprivation. further studies are needed so that preventative measures can be developed. keywords: motor vehicles; traffic accidents; sleep; fatigue; obstructive sleep apnea syndrome; oman. امللخ�ص: يعترب النعا�ض والإرهاق �شببًا رئي�شيًا يف وقوع حوادث املركبات، ومع ذلك، فاإن هناك ندرة يف الدرا�شات التي ُتعنى بدرا�شة مدى انت�شار النعا�ض اأثناء قيادة املركبة بني العمانيني، لذلك هدفت هذه الدرا�شة اإىل حتديد ن�شبة ال�شباب العماين الرا�شدين الذين يعرتفون التنف�ض انقطاع متالزمة وخطر النهاري والنعا�ض اجلن�ض بني الرتابط من وللتحقق النهار اأثناء فرتة القيادة اأثناء بالنعا�ض باإ�شابتهم 2014 ويوليو مايو بني عمان، يف مب�شقط قابو�ض ال�شلطان جامعة م�شت�شفى يف امل�شتعر�شة الدرا�شة هذه اأجريت الطريقة: النوم. اأثناء و�شملت عدد 600 من ال�شائقني العمانيني ال�شباب الغري عاملني يف مهنة �شياقة املركبات ب�شكل جتاري، مت توزيع ا�شتبيان برلني ومعيار اإبورث ملقيا�ض النعا�ض )epworth sleepiness scale( على امل�شاركني، بالإ�شافة اإىل اأ�شئلة اإ�شافية حول عادات نومهم، مت حتديد مدى اأثناء التنف�ض انقطاع متالزمة خماطر وكذلك امل�شاء، فرتة النوم ومدة املركبات قيادة اأثناء النهار فرتة اأثناء النعا�ض بني الرتباطات النوم ونوع اجلن�ض. النتائج: �شارك يف الدرا�شة ما جمموعه 492 من �شائقي املركبات اخلا�شة )معدل ال�شتجابة: %82( ، منهم %50.4 من الذكور، وب�شكل عام، اأفاد 124 �شاب عماين )%25.2( اأنهم يعانون من النعا�ض خالل النهار اأثناء القيادة مرة واحدة على الأقل كل �شهر، وكان هناك ارتباط كبري بني مدة النوم الليلي الأقل عن 6 �شاعات والنعا�ض اأثناء قيادة املركبة )p = 0.042(، كما كانت امل�شاركات من الإناث اأكرث احتماًل بكثري يف ت�شجيل معدل اأكرث من 10 ح�شب معيار اإبورث ملقيا�ض النعا�ض، مما يدل على زيادة امليل لالإ�شابة بالنعا�ض اأثناء فرتة النهار )p = 0.006(، ومع ذلك، كان ال�شائقون الذكور اأكرث عر�شة لالإبالغ عن النعا�ض اأثناء القيادة )p = 0.001(. اخلال�صة: كان النعا�ض اأثناء القيادة اأمراً �شائعًا بني ال�شائقني ال�شباب الذكور يف ُعمان ورمبا يعود ذلك اإىل نق�ض النوم اأثناء فرتة الليل، هناك حاجة اإىل مزيد من الدرا�شات حول هذا املو�شوع حتى ميكن و�شع التدابري الوقائية الالزمة. الكلمات املفتاحية: املركبات؛ حوادث املرور؛ نوم؛ اإعياء؛ متالزمة توقف التنف�ض اأثناء النوم؛ عمان. daytime sleepiness among young adult omani car drivers *mohammed a. al-abri,1 samir al-adawi,2 ibrahim al-abri,1 faisal al-abri,1 atsu dorvlo,3 ronald wesonga,4 sanjay jaju5 clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e143–148, epub. 9 sep 18 submitted 2 jan 18 revision req. 31 jan 18; revision recd. 21 feb 18 accepted 8 mar 18 advances in knowledge to the best of the authors’ knowledge, this study is the first to illustrate the prevalence of sleepiness while driving among young adult omanis. these findings may be of use in legislative and educational measures for road traffic safety and the prevention of motor vehicle crashes. application to patient care sleepiness while driving can result in significant morbidity and mortality. as such, the results of this study may encourage physicians to refer sleepy drivers for further tests and early medical intervention. doi: 10.18295/squmj.2018.18.02.004 daytime sleepiness among young adult omani car drivers e144 | squ medical journal, may 2018, volume 18, issue 2 sleepiness and fatigue can decrease mentalalertness and increase the likelihood of errors and unintentional injuries among children, adolesc ents and adults.1,2 in particular, fatigue and daytime sleepiness have been shown to impair cognitive function while driving, which results in a higher risk of road traffic crashes.3 extended work shifts can also disrupt the sleep-wake cycle and therefore heighten the risk of occupational injuries and motor vehicle crashes.4 in the uk, it is estimated that daytime sleepiness causes approximately 16% and 20% of all car crashes and those occurring on motorways, respectively.5 nocturnal sleep deprivation and poor sleep hygiene are well-known causes of daytime sleepiness and tiredness, particularly among younger individuals.6,7 in addition to lack of sleep, there is evidence to suggest that sleep disorders such as obstructive sleep apnoea syndrome (osas) can trigger excessive daytime sleepiness.8 as such, patients with osas are at a 1.3–7-fold greater risk of having car crashes than the general population.8,9 car crashes are one of the most common causes of mortality and morbidity among young people in oman, a country of approximately 4.5 million individuals.10,11 in a review of epidemiological studies available in the literature, the prevalence of excessive daytime sleepiness ranged between 4–20.6%, depending on the methods and definitions used.12 however, no studies have yet been conducted in oman to determine the prevalence of daytime sleepiness among young adult drivers. this study therefore aimed to determine the proportion of young omani drivers who confess to daytime sleepiness and to study the association of certain key risk factors such as gender, osas, body mass index (bmi) and snoring. methods this cross-sectional study was conducted among 600 young adults visiting the sultan qaboos university hospital in muscat, oman, between may and july 2014. a systematic sampling technique was used to select every fifth omani bystander or patient’s relative between 20–40 years old passing through the main entrance of the hospital during outpatient clinic opening hours. there were 10 subjects approached per day for a total of 200 participants per month. only apparently healthy individuals who drove noncommercial vehicles were included in the study. subjects working night-shifts and commercial drivers (e.g. truck or taxi drivers) were excluded. in order to ascertain the prevalence of daytime sleepiness among young adult omani drivers, the necessary sample size was determined based on a hypothesis testing a single proportion, with an alpha value set at 0.05 and a power of 80%. based on the findings of an earlier study in which 23% of drivers initially reported driving impairment due to sleepiness, daytime sleepiness while driving was assumed to be 26% in the current study, leading to a total required sample size of 369 drivers.3 validated english or arabic versions of the epworth sleepiness scale (ess) were distributed to the participants in order to determine daytime sleepiness.13,14 the ess is scored on a 3-point likert scale, with the total score ranging from 0–24; a propensity towards daytime sleepiness is indicated at scores of >10.13 subsequently, participants were requested to complete either an english or arabic version of the 10-item berlin questionnaire (bq) to determine various symptoms of osas, such as the presence of snoring (category 1), daytime somnolence (category 2) and hypertension and high bmi (category 3).15,16 participants were classified as being at either high or low risk of osas based on their responses to individual items and their overall bq scores in each category, with those who scored positive in two or more categories classified as high-risk.15 the psychometric properties of the arabic versions of both the ess and bq tools have been found to be adequate in arab populations.14,16 in addition, participants were asked specific questions to gauge their average nocturnal sleep duration and the occurrence of daytime sleepiness over the preceding month. the height and weight of all subjects was also measured to calculate their bmi. statistical analyses were performed using the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). summary stat figure 1: diagram illustrating the various factors used in the current study to determine associations with daytime sleepiness while driving among young adult omani drivers. bmi = body mass index; ess = epworth sleepiness scale; bq = berlin questionnaire; osas = obstructive sleep apnoea syndrome. *bmi category was classified as underweight (<20 kg/m2), normal weight (20–25 kg/m2) or overweight (>25 kg/m2). †nocturnal sleep duration was categorised as adequate (≥6 hours) or inadequate (<6 hours).17 ‡ess scores were categorised as normal (0–10) or abnormal (>10). §bq scores were categorised as high risk of osas (positive scores in two or more categories) or low risk of osas (positive scores in one or zero categories). mohammed a. al-abri, samir al-adawi, ibrahim al-abri, faisal al-abri, atsu dorvlo, ronald wesonga and sanjay jaju clinical and basic research | e145 istics and two sample t-tests were computed and p values provided where appropriate. a chi-squared test was used to determine associations between categorical variables such as age, gender, bmi, snoring, ess scores, risk of osas and sleepiness while driving [figure 1]. a cut-off time of 6 hours was deemed to indicate adequate nocturnal sleep, with anything under this deemed to constitute nocturnal sleep deprivation.17 the level of statistical significance was set at p ≤0.050 (α = 0.05). this study was approved by the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university (#mrec 963). participants provided informed written consent prior to their enrolment in the study. results a total of 492 drivers agreed to participate in this study (response rate: 82%). of these, 248 (50.4%) were male and 244 (49.6%) were female. the mean age of the male drivers was 30.0 ± 8.5 years and the mean age of the female drivers was 32.5 ± 5.0 years. the mean bmi was 25.6 ± 4.0 kg/m2 and 24.6 ± 4.2 kg/m2 for male and female drivers, respectively. there were significant differences noted in terms of age and bmi according to gender (p <0.050 each). overall, 127 young drivers (25.8%) had experienced daytime sleepiness while driving. male drivers reported significantly greater daytime sleepiness compared to females (33.5% versus 18%; p = 0.001). however, no gender difference was noted in terms of average nocturnal sleep duration [table 1]. there was a significant association between daytime sleepiness while driving and nocturnal sleep deprivation (p = 0.041), bmi (p = 0.009) and snoring (p <0.001). among those who reported sleepiness while driving, the majority had fewer than 6 hours of sleep per night (69.3%) and were overweight (59.1%). furthermore, the proportion of those with daytime sleepiness was doubled among those who snored compared to those who did not snore (36.2% versus 16.4%) [table 2]. signif icantly more females than males were found to have a propensity towards daytime sleepiness as per their ess scores (43.9% versus 31.9%; p = 0.006). however, although more males than females were categorised as at high-risk of osas based on their bq scores, this difference was not significant (12.9% versus 8.2%; p = 0.093) [table 3]. table 1: prevalence of daytime sleepiness and nocturnal sleep deprivation according to gender among young adult omani drivers (n = 492) factor n (%) p value male drivers (n = 248) female drivers (n = 244) mean age in years ± sd 30.0 ± 8.5 32.5 ± 5.0 <0.001 mean bmi in kg/m2 ± sd 25.6 ± 4.0 24.6 ± 4.2 0.007 daytime sleepiness while driving yes 83 (33.5) 44 (18) 0.001 no 165 (66.5) 200 (82) nocturnal sleep duration in hours <6 157 (63.3) 147 (60.2) 0.485 ≥6 91 (36.7) 97 (39.8) sd = standard deviation; bmi = body mass index. table 2: risk factors associated with daytime sleepiness while driving among young adult omani drivers (n = 492) risk factor daytime sleepiness while driving, n (%) p value yes (n = 127) no (n = 365) nocturnal sleep duration in hours <6 88 (69.3) 216 (59.2) 0.041 ≥6 39 (30.7) 149 (40.8) bmi in kg/m2 <20 5 (3.9) 10 (2.7) 0.00920–25 47 (37) 193 (52.9) >25 75 (59.1) 162 (44.4) snoring no 67 (52.8) 268 (73.4) <0.001yes 46 (36.2) 60 (16.4) unknown 14 (11) 37 (10.1) bmi = body mass index. table 3: associations between gender and epworth sleepiness scale and berlin questionnaire scores among young adult omani drivers (n = 492) score n (%) p value male drivers (n = 248) female drivers (n = 244) ess 0–10 169 (68.1) 137 (56.1) 0.006 >10 79 (31.9) 107 (43.9) bq high risk* 32 (12.9) 20 (8.2) 0.093 low risk† 216 (87.1) 224 (91.8) ess = epworth sleepiness scale; bq = berlin questionnaire. *positive scores in two or more categories. †positive scores in one or zero categories. daytime sleepiness among young adult omani car drivers e146 | squ medical journal, may 2018, volume 18, issue 2 overall, sleepiness while driving was significantly associated with ess and bq scores (p = 0.023 and <0.001, respectively). female drivers who reported daytime sleepiness while driving had significantly higher ess scores in comparison to those who did not report daytime sleepiness (61.4% versus 38.6%; p = 0.010). moreover, in terms of bq scores, there were significantly more women who reported daytime sleepiness at high risk of osas than at low risk (81.8% versus 18.2%; p = 0.014). among the men who reported daytime sleepiness while driving, there was a significant association with bq scores, with most being classified as low rather than high risk (22.9% versus 77.1%; p = 0.001) [table 4]. discussion sleepiness while driving is a leading cause of car crashes.18 the findings of the current study indicated that sleepiness while driving was fairly common among private car drivers in oman, with just over onequarter of the drivers reporting that they experienced daytime sleepiness while driving at least once a month. in addition, a significantly greater proportion of male drivers experienced daytime sleepiness while driving compared to females. despite this, females had ess scores of >10 significantly more frequently. therefore, young males were found to carry a higher risk of daytime sleepiness while driving compared to females, despite the latter having a greater propensity towards daytime sleepiness in general. multiple factors were observed to contribute to daytime sleepiness among drivers in the current study. almost two-thirds of the sample had an inadequate nocturnal sleep duration of <6 hours per night, with a significant association between nocturnal sleep deprivation and daytime sleepiness while driving. a previous study found that 57.6% of omani adolescents had fewer than 7 hours of sleep per night.19 this lack of sleep could be due to socialor work-related reasons, particularly in a society wherein most social events take place late at night.20 earlier research from other parts of the world has indicated that nocturnal sleep deprivation is an important contributing factor to car crashes; for example, valent et al. found that sleep deprivation and long working hours increased the risk of car crashes in italy.21 philip et al. reported that sleep deprivation negatively affected the vigilance and concentration necessary for safe driving under both real-life and simulated conditions.22 almost half of the participants in the present study had an ess score of >10, indicative of a greater propensity towards daytime sleepiness. there was also a significant association between sleepiness while driving and ess score. these findings suggest that this scale could potentially be used as a screening tool to assess daytime sleepiness among driving licence aspirants. a study from the uk found that self-reported excessive daytime sleepiness was common among bus drivers, with 20% reporting an ess score of >10 and 8% admitting that they had fallen asleep at the wheel within the previous month.23 in a similar study, anund et al. found that 19% of bus drivers in sweden experienced severe sleepiness, to the point that the affected individual had to fight to stay awake while driving at least two or three times per week.24 the bq is a useful tool to screen for osas and has been used in previous epidemiological research targeting the omani population.20 young et al. previously demonstrated that individuals with osas are at greater risk of having car crashes due to the symptoms of daytime sleepiness associated with the disorder.25 in the present study, there was a significant association between being at high risk of osas, according to bq score, and sleepiness while driving; however, the actual number of subjects who were at risk of osas was relatively low. this could be explained by the fact that the studied population was relatively young and most were not overweight, as both of these factors (i.e. older age and high bmi) are associated with osas.26 nevertheless, the prevalence of osas in this sample was 10.6%, which is within the range reported by previous research (9–24%).25 table 4: associations between daytime sleepiness while driving and epworth sleepiness scale and berlin questionnaire scores according to gender among young adult omani drivers (n = 492) score daytime sleepiness while driving, n (%) p value yes (n = 127) no (n = 365) es s male 0–10 51 (61.4) 118 (71.5) 0.108 >10 32 (38.6) 47 (28.5) female 0–10 17 (38.6) 120 (60) 0.010 >10 27 (61.4) 80 (40) b q male high risk* 19 (22.9) 13 (7.9) 0.001 low risk† 64 (77.1) 152 (92.1) female high risk* 8 (18.2) 12 (6) 0.014 low risk† 36 (81.8) 188 (94) ess = epworth sleepiness scale; bq = berlin questionnaire. *positive scores in two or more categories. †positive scores in one or zero categories. mohammed a. al-abri, samir al-adawi, ibrahim al-abri, faisal al-abri, atsu dorvlo, ronald wesonga and sanjay jaju clinical and basic research | e147 this study was subject to certain limitations, particularly as the findings were based solely on selfreported data. future research should be performed in which the drivers are asked to maintain sleep and driving diaries to report their level of sleepiness every day. such an investigation could also include objective measures such as the duration, approximate temperature and time of day or night during which each drive takes place. additionally, this study did not precisely quantify the frequency of daytime sleepiness among the studied drivers and relied on general questions regarding the drivers’ perceptions of their average level of sleepiness while driving over the previous month. further studies should be conducted including objective measures of daytime sleepiness, such as multiple sleep latency or maintenance of wakefulness tests. nocturnal sleep duration should also be measured more precisely via actigraphy. finally, instead of relying on bq responses, participants could undergo polysomnography in order to determine osas risk. conclusion this study revealed that daytime sleepiness was fairly common among young omani drivers. various characteristics were found to be associated with daytime sleepiness while driving, including gender, bmi category, nocturnal sleep deprivation and snoring. these relationships should be explored further using psychometric tests. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. akerstedt t, fredlund p, gillberg m, jansson b. a prospective study of fatal occupational accidents: relationship to sleeping difficulties and occupational factors. j sleep res 2002; 11:69–71. doi: 10.1046/j.1365-2869.2002.00287.x. 2. findley lj, suratt pm, dinges df. time-on-task decrements in “steer clear” performance of patients with sleep apnea and narcolepsy. sleep 1999; 22:804–9. doi: 10.1093/sleep/22.6.804. 3. engleman hm, hirst ws, douglas nj. under reporting of sleep iness and driving impairment in patients with sleep apnoea/ hypopnoea syndrome. j sleep res 1997; 6:272–5. doi: 10.1111/j. 1365-2869.1997.00272.x. 4. dembe ae, erickson jb, delbos rg, banks sm. the impact of overtime and long work hours on occupational injuries and illnesses: new evidence from the united states. occup environ med 2005; 62:588–97. doi: 10.1136/oem.2004.016667. 5. horne j, reyner l. vehicle accidents related to sleep: a review. occup environ med 1999; 56:289–94. doi: 10.1136/oem.56.5.289. 6. vorona rd, szklo-coxe m, lamichhane r, ware jc, mcnallen a, leszczyszyn d. adolescent crash rates and school start times in two central virginia counties, 2009-2011: a follow-up study to a southeastern virginia study, 2007-2008. j clin sleep med 2014; 10:1169–77. doi: 10.5664/jcsm.4192. 7. calhoun sl, vgontzas an, fernandez-mendoza j, mayes sd, tsaoussoglou m, basta m, et al. prevalence and risk factors of excessive daytime sleepiness in a community sample of young children: the role of obesity, asthma, anxiety/depression, and sleep. sleep 2011; 34:503–7. doi: 10.1093/sleep/34.4.503. 8. terán-santos j, jiménez-gómez a, cordero-guevara j. the association between sleep apnea and the risk of traffic accidents: cooperative group burgos-santander. n engl j med 1999; 340:847–51. doi: 10.1056/nejm199903183401104. 9. young t, blustein j, finn l, palta m. sleep-disordered breathing and motor vehicle accidents in a population-based sample of employed adults. sleep 1997; 20:608–13. doi: 10.1093/sleep/20. 8.608. 10. al-maniri aa, al-reesi h, al-zakwani i, nasrullah m. road traffic fatalities in oman from 1995 to 2009: evidence from police reports. int j prev med 2013; 4:656–63. 11. al-reesi h, ganguly ss, al-adawi s, laflamme l, hasselberg m, al-maniri a. economic growth, motorization, and road traffic injuries in the sultanate of oman, 1985-2009. traffic inj prev 2013; 14:322–8 doi: 10.1080/15389588.2012.694088. 12. ohayon mm. from wakefulness to excessive sleepiness: what we know and still need to know. sleep med rev 2008; 12:129–41. doi: 10.1016/j.smrv.2008.01.001. 13. johns mw. a new method for measuring daytime sleepiness: the epworth sleepiness scale. sleep 1991; 14:540–5. doi: 10.10 93/sleep/14.6.540. 14. al-abri m, al-hamhami a, al-nabhani h, al-zakwani i. validation of the arabic version of the epworth sleepiness scale in oman. oman med j 2013; 28:454–6. doi: 10.5001/omj. 2013.126. 15. netzer nc, stoohs ra, netzer cm, clark k, strohl kp. using the berlin questionnaire to identify patients at risk for the sleep apnea syndrome. ann intern med 1999; 131:485–91. doi: 10.7326/0003-4819-131-7-199910050-00002. 16. saleh ab, ahmad ma, awadalla nj. development of arabic version of berlin questionnaire to identify obstructive sleep apnea at risk patients. ann thorac med 2011; 6:212–16. doi: 10.4103/1817-1737.84775. 17. hirshkowitz m, whiton k, albert sm, alessi c, bruni o, doncarlos l, et al. national sleep foundation’s updated sleep duration recommendations: final report. sleep health 2015; 1:233–43. doi: 10.1016/j.sleh.2015.10.004. 18. filtness aj, armstrong ka, watson a, smith ss. sleep-related crash characteristics: implications for applying a fatigue definition to crash reports. accid anal prev 2017; 99:440–4. doi: 10. 1016/j.aap.2015.11.024. 19. kilani h, al-hazzaa h, waly mi, musaiger a. lifestyle habits: diet, physical activity and sleep duration among omani adolescents. sultan qaboos univ med j 2013; 13:510–19. 20. al-abri ma, jaju d, al-sinani s, al-mamari a, albarwani s, al-resadi k, et al. habitual sleep deprivation is associated with type 2 diabetes: a case-control study. oman med j 2016; 31:399–403. doi: 10.5001/omj.2016.81. 21. valent f, di bartolomeo s, marchetti r, sbrojavacca r, barbone f. a case-crossover study of sleep and work hours and the risk of road traffic accidents. sleep 2010; 33:349–54. doi: 10.1093/ sleep/33.3.349. 22. philip p, sagaspe p, taillard j, valtat c, moore n, akerstedt t, et al. fatigue, sleepiness, and performance in simulated versus real driving conditions. sleep 2005; 28:1511–16. doi: 10.1093/ sleep/28.12.1511. https://doi.org/10.1046/j.1365-2869.2002.00287.x https://doi.org/10.1093/sleep/22.6.804 https://doi.org/10.1111/j.1365-2869.1997.00272.x https://doi.org/10.1111/j.1365-2869.1997.00272.x https://doi.org/10.1136/oem.2004.016667 https://doi.org/10.1136/oem.56.5.289 https://doi.org/10.5664/jcsm.4192 https://doi.org/10.1093/sleep/34.4.503 https://doi.org/10.1056/nejm199903183401104 https://doi.org/10.1093/sleep/20.8.608 https://doi.org/10.1093/sleep/20.8.608 https://doi.org/10.1080/15389588.2012.694088 https://doi.org/10.1016/j.smrv.2008.01.001 https://doi.org/10.1093/sleep/14.6.540 https://doi.org/10.1093/sleep/14.6.540 https://doi.org/10.5001/omj.2013.126 https://doi.org/10.5001/omj.2013.126 https://doi.org/10.7326/0003-4819-131-7-199910050-00002 https://doi.org/10.4103/1817-1737.84775 https://doi.org/10.1016/j.sleh.2015.10.004 https://doi.org/10.1016/j.aap.2015.11.024 https://doi.org/10.1016/j.aap.2015.11.024 https://doi.org/10.5001/omj.2016.81 https://doi.org/10.1093/sleep/33.3.349 https://doi.org/10.1093/sleep/33.3.349 https://doi.org/10.1093/sleep/28.12.1511 https://doi.org/10.1093/sleep/28.12.1511 daytime sleepiness among young adult omani car drivers e148 | squ medical journal, may 2018, volume 18, issue 2 23. vennelle m, engleman hm, douglas nj. sleepiness and sleeprelated accidents in commercial bus drivers. sleep breath 2010; 14:39–42. doi: 10.1007/s11325-009-0277-z. 24. anund a, ihlström j, fors c, kecklund g, filtness a. factors associated with self-reported driver sleepiness and incidents in city bus drivers. ind health 2016; 54:337–46. doi: 10.2486/ indhealth.2015-0217. 25. young t, palta m, dempsey j, skatrud j, weber s, badr s. the occurrence of sleep-disordered breathing among middleaged adults. n engl j med 1993; 328:1230–5. doi: 10.1056/ nejm199304293281704. 26. deng x, gu w, li y, liu m, li y, gao x. age-group-specific associations between the severity of obstructive sleep apnea and relevant risk factors in male and female patients. plos one 2014; 9:e107380. doi: 10.1371/journal.pone.0107380. https://doi.org/10.1007/s11325-009-0277-z https://doi.org/10.2486/indhealth.2015-0217 https://doi.org/10.2486/indhealth.2015-0217 https://doi.org/10.1056/nejm199304293281704 https://doi.org/10.1056/nejm199304293281704 https://doi.org/10.1371/journal.pone.0107380 department of orthopaedics, armed forces hospital, salalah, oman *corresponding author’s e-mail: sumrani123@yahoo.com سرطان عظم الفخذ األدىن مشابه إللتهاب مفصل الورك املتقيح معضلة تشخيصية �شليل عمراين و يعقوب املفرجي abstract: septic arthritis is a surgical emergency requiring prompt drainage of the accumulation of pus in the joint. we report an eight-year-old boy who was referred to the armed forces hospital, salalah, oman, in 2016 with limping and pain in his right hip along with an abduction deformity. he was initially diagnosed with synovitis and underwent conservative management. however, two weeks later, he presented to another centre due to persistent pain. magnetic resonance imaging was suggestive of septic arthritis or osteomyelitis. eight weeks later, the patient presented again to the armed forces hospital. an arthrotomy was performed, during which an amount of what appeared to be frank pus was drained; however, cultures of the intraoperative samples returned no growth. a histopathological analysis revealed an osteosarcoma. the patient was subsequently referred elsewhere and underwent neoadjuvant chemotherapy and limb salvage surgery. several months later, he relapsed and developed extensive pulmonary metastasis and died as a result of progressive deterioration. keywords: osteosarcoma; hip joint; septic arthritis; osteomyelitis; differential diagnosis; case report; oman. يف املرتاكم القيح لت�رصيف �رصيعًا جراحيًا تدخالًّ تتطلب التي احلرجة الطوارئ حالت من التقيحي املفا�شل اإلتهاب يعترب امللخ�ص: ،2016 �شنة يف عمان، ب�شاللة، امل�شلحة القوات م�شت�شفى اإىل حتويله مت �شنوات ثماين العمر من يبلغ لطفل حالة هنا ن�شيف املف�شل. وكان يعاين من عرج واأمل يف خ�رصه ووركه اإ�شافة اإىل ت�شوه اإبعادي. بدايًة مت ت�شخي�شه باإلتهاب الغ�شاء الزليلي ومت عالجه حتفظيًا. لكن بعد اأ�شبوعني، راجع املري�س يف مركز اآخر ب�شبب ا�شتمرار الأمل. مت اإخ�شاعه لفح�س الت�شوير بالرنني املغناطي�شي الذي اأظهر ما يقرتح وجود لإلتهاب املف�شل التقيحي اأو الإلتهاب العظمي النخاعي. بعد ثمانية اأ�شابيع، رجع املري�س اإىل م�شت�شفى القوات امل�شلحة. على اإثرها مت اإجراء عملية ل�شق املف�شل، وخاللها لوحظ ا�شتخراج كمية ال�شائل ي�شتبه اأنه قيح؛ ودرا�شة امليكروبات ا�شتخرجت خالل هذا الإجراء مل تظهر وجود اأي منو ميكروبي. اإل اأن حتليل الفح�س املجهري للخاليا املر�شية اأ�شار لوجود �رصطان العظم )�شاركوما(، مت التن�شيق مبا�رصة لإجراء العالج الكيميائي و عملية جراحة لإنقاذ الطرف ال�شفلي. بعد عدة اأ�شهر رجع املري�س بانتكا�شة يف املر�س مع انت�شار �رصطاين يف الرئة ومات نتيجة تدهور يف حالته. الكلمات املفتاحية: �رصطان عظمي؛ مف�شل الورك؛ اإلتهاب املفا�شل التقيحي؛ اإلتهاب العظمي النخاعي؛ الت�شخي�س التفريقي؛ تقرير حالة؛ عمان. osteosarcoma of the proximal femur mimicking septic arthritis of the hip a diagnostic dilemma *salil umrani and yaqoub al-mufargi case report sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e545–548, epub. 28 mar 19 submitted 18 may 18 revisions req. 28 may & 26 jun 18; revisions recd. 4 jun & 8 jul 18 accepted 2 aug 18 doi: 10.18295/squmj.2018.18.04.021 osteosarcomas are characterised by theproduction of osteoid material by malignant cells.1 primary osteosarcomas can be classified into conventional, low-grade intramedullary, parosteal, periosteal, high-grade surface, telangiectatic and small cell types and are the second most common type of primary bone malignancy, with an incidence of 1–3 cases per million people per year. onset can occur at any age and patients usually present with pain which improves initially and then worsens, particularly at night.1 the differential diagnosis of an osteosarcoma includes benign bone tumours, infections and other malignant disorders.2 among these differential diagnoses, septic arthritis in particular can present very similarly to an osteosarcoma.2,3 this condition involves the accumulation of pus in a joint and can potentially result in severe sequelae such as the destruction or occlusion of the epiphysis; as such, urgent diagnosis and drainage of the accumulated pus is required.3 this report describes an osteosarcoma case which initially presented with features of septic arthritis and highlights various aspects of these two conditions to allow for prompt differentiation and treatment. case report an eight-year-old boy was referred to the orthopaedic clinic of the armed forces hospital, salalah, oman, in 2016 with pain in his right hip and noticeable limping following a trivial fall. the pain was constant, abating only intermittently with analgaesics. there was diffuse tenderness in the right hip with limited flexion (30–90 degrees), fixed abduction (30 degrees), restricted rotation, osteosarcoma of the proximal femur mimicking septic arthritis of the hip a diagnostic dilemma e546 | squ medical journal, november 2018, volume 18, issue 4 apparent leg lengthening and pelvic obliquity. his white blood cell count (wbc), erythrocyte sedimentation rate (esr) and c-reactive protein (crp) levels (5.43 × 109/l, 6 mm/hour and 1.04 mg/l, respectively) were within normal ranges (4.8–10.8 × 109/l, 0–20 mm/hour and 0–5 mg/l, respectively). an x-ray confirmed the pelvic obliquity and an abduction deformity in the right hip [figure 1]. an initial working diagnosis of synovitis was made and conservative management was advised. however, the patient was subsequently lost to follow up. two weeks later, he was admitted elsewhere and underwent magnetic resonance imaging (mri); this revealed joint effusion in the right hip with marrow signal changes [figure 2]. he was again treated conservatively for syno vitis and subsequently discharged. as the pain persisted, the patient presented to yet another centre after one month, at which point he was suspected to have histiocytosis or infective synovitis. however, a repeated blood work-up indicated that his wbc, esr and crp levels were normal. nevertheless, mri revealed moderate effusion in the right hip with thickening of the femur neck and bone marrow oedema, suggestive of septic arthritis of the right hip and osteomyelitis of the proximal femur [figure 3]. the patient was discharged without treatment. eight weeks later, the patient presented once again to the armed forces hospital with persistent complaints of pain and limping. there was no history of fever, dysuria or involvement of any joints other than the hip during this period. his wbc, esr and crp levels were still normal (5.13 × 109/l, 20 mm/hour and 1.66 mg/l, resp ectively). blood and urine cultures revealed no bacterial growth. however, an x-ray revealed periarticular osteo paenia and a possible lytic lesion in the proximal femur of the right hip [figure 4]. the patient was referred to the paediatric orthopaedic unit of the armed forces hospital in muscat, oman. at this time, repeat investig ations indicated raised esr and crp levels (32.97 mg/l and 51 mm/hour, respectively). an arthrotomy was immediately performed, revealing what appeared to be thick pus originating from the hip joint and the neck of the femur along with unhealthy tissue around the latter. following thorough curettage and copious saline lavage (approximately 6 l), samples of the pus-like material were sent for gram staining and cultures for routine bacteria as well as acid-fast bacilli and fungi. a histopathological exam ination was also requested. in the meantime, antibiotic therapy was initiated; however, although the patient appeared to improve clinically in the initial postoperative period, he subsequently reverted to his preoperative status. while his wbc remained normal (range: 5.8–7.4 × 109/l) and his crp levels gradually returned to normal (from 12.2 mg/l to 3.1 mg/l), his esr remained elevated (range: 45–55 mm/hour) throughout the post operative period. subsequently, the biopsy results revealed that none of the intraoperative cultures had resulted in growth. the histopathological analysis confirmed a diagnosis of an osteosarcoma (chondroblastic variant). however, postoperative x-rays revealed the same findings as those performed preoperatively and a postoperative chest x-ray was normal. the patient was referred to a paediatric oncology unit in muscat, where a staging work-up revealed single bilateral pulmonary metastases. neoad juvant chemotherapy was initiated as per institutional protocols. a few months later, following completion of the neoadjuvant chemotherapy regimen, he under went limb salvage surgery in india; at this time, a histol ogical analysis revealed 50–60% tumour response to treat figure 2: magnetic resonance imaging of an eight-year-old boy with persistent right hip pain showing joint effusion in the right hip with marrow signal changes (arrows). the patient was provisionally diagnosed with synovitis. figure 1: x-ray of the pelvis of an eight-year-old boy with right hip pain at presentation showing pelvic obliquity and an abduction deformity in the right hip (arrow). salil umrani and yaqoub al-mufargi case report | e547 early detection of septic arthritis—including synovial procalcitonin estimations, combined leukocyte esterase/ glucose strip tests, α-defensin synovial fluid measurements and next-generation dna sequencing—were unavailable at the time of presentation.7–10 kocher et al. proposed certain criteria to help diagnose septic arthritis, with at least three of the following four conditions indicating a 93–99% risk of septic arthritis: (1) lack of weight-bearing on the affected side; (2) esr of >40 mm/hour; (3) fever of >38.5 °c; and (4) wbc of >12,000 cells/mm3.11,12 the risk falls to 40% if only two of the criteria are met, dwindling to 3% if only one criterion is met.11,12 kang et al. similarly confirmed that an inability to bear weight, fever and a raised wbc are diagnostic of septic arthritis, with a sensitivity of >98%.13 in the current case, the patient met only the first criterion in that he could not bear weight on the affected side. in addition, repeated x-rays did not demonstrate any sequelae of septic arthritis, such as destruction or occlusion of the epiphysis.3 as a result, there was no suspicion of septic arthritis at initial presentation. however, following an increase in esr and crp levels, an arthrotomy was immediately performed. on radiology, septic arthritis has typical imaging features, including periarticular soft tissue swelling, effacement with blurring of the periarticular fat planes, effusion and periarticular osteopaenia in the early stages, followed by narrowing and destruction of the joint space with premature osteoarthritis and shortening of the limb in the later stages.14 in contrast, an osteosarcoma appears as an aggressive metaphyseal blastic or lytic lesion, with areas of bone production and bone destruction; in addition, a permeative ill-defined soft tissue mass may be visible.1 the periosteal reaction forms either codman’s triangle, sunburst or ‘hair-on-end’ patterns. in the present case, plain x-rays showed consistent evidence of persistent periarticular osteopaenia and a lytic lesion in the proximal femur over a three-month period, even after the arthrotomy was performed. ment. adjuvant chemotherapy was resumed after the surgery; however, the patient relapsed and developed multiple bilateral pulmonary metastases and septic shock. unfortunately, although he recovered from the shock with intensive treatment, the patient died a few months later as his condition progressively deteriorated. discussion in the current case, the patient was initially diagnosed with synovitis, followed by septic arthritis and osteo myelitis, before the correct diagnosis of an osteosarcoma was made based on the histopathological findings. transient synovitis is a common self-limiting condition which improves rapidly with conservative treatment.4 in the present case, this was eventually ruled out in view of the patient’s prolonged illness. children with acute septic arthritis of the lower limbs usually present with fever, pain and limping; moreover, they often refuse to put weight on the affected leg or hold the affected joint in a position of comfort.5 although the current patient presented initially with pain and refused to bear weight on the affected limb, he did not have fever. furthermore, blood cultures as well as arthrotomy samples yielded no growth of nongonococcal bacteria or evidence of polymorphonuclear predominance.6 unfortunately, recent advances in the figure 3: magnetic resonance imaging of an eight-year-old boy with persistent right hip pain showing moderate effusion in the right hip with thickening of the femur neck and bone marrow oedema (arrows). figure 4: x-ray of the pelvis of an eight-year-old boy with persistent right hip pain after eight weeks showing periarticular osteopaenia (white arrow) and a possible lytic lesion in the proximal femur of the right hip (black arrow). osteosarcoma of the proximal femur mimicking septic arthritis of the hip a diagnostic dilemma e548 | squ medical journal, november 2018, volume 18, issue 4 ultrasonography may also be helpful to diagnose septic arthritis and guide aspiration.14 the fluid in the joint may either be hypoechoic and clearly separated from or hyperechoic and adjacent to the joint capsule. furthermore, in children, the capsule is >5 mm away from the femoral cortex and/or >2 mm thicker than that of the normal side.14 power doppler sonography may also show increased capsular vascularity. however, in the current case, ultrasonography was not requested as the patient had already undergone repeated mri scans and x-rays. most osteosarcomas begin in an intramedullary location but may pierce through the cortex to form a soft tissue mass.1 histologically, they can be osteoblastic, fibroblastic or chondroblastic. the diagnosis is usually delayed since common musculoskeletal conditions need to be excluded first. pan et al. reported an average delay of approximately 17 weeks from the onset of symptoms to diagnosis.15 both patientand physicianrelated factors may be responsible for this delay; the latter include a failure to obtain x-rays at presentation and/or after symptoms persist or worsen.1 in the present case, x-rays were taken at both initial and follow-up visits; however, these did not demonstrate evidence of any lumps, masses or significant changes indicative of an osteosarcoma. unfortunately, although the correct diagnosis was made in under 17 weeks, it is likely that the patient would have been diagnosed much earlier and possibly had a better prognosis if he had been followed-up regularly at a single centre. the long-term survival rate reported for high grade osteosarcomas without metastasis at presentation is 60–70%, rising to 90% for low-grade lesions; however, this decreases rapidly to 20% if there are detectable pulmonary metastases at diagnosis.1 although the current patient had a clear chest x-ray when the diagn osis was made, the staging work-up revealed bilateral single pulmonary metastatic nodules. most patients with high-grade osteosarcomas have non-detectable micrometastases at presentation.1 even with neoadjuvant or adjuvant chemotherapy, approximately 50% of patients relapse after initial treatment, as seen in the current case.1 conclusion this case report describes a patient who was initially diagnosed with synovitis, followed by septic arthritis and osteomyelitis, before the correct diagnosis of an osteosarcoma was made based on histopathological findings. infection is a known differential diagnosis of malignancy but must be identified quickly and treated promptly. physicians should be aware that osteosarcomas may present with features suggestive of septic arthritis and osteomyelitis. references 1. heck rk jr. malignant tumors of bone. in: canale st, beaty jh, eds. campbell’s operative orthopaedics, 12th ed. philadelphia, pennsylvania, usa: elsevier mosby, 2008. pp. 909–14. 2. esmo/european sarcoma network working group. bone sarcomas: esmo clinical practice guidelines for diagnosis, treat ment and follow-up. ann oncol 2014; 25:iii113–23. https://doi. org/10.1093/annonc/mdu256. 3. shaw ba, kasser jr. acute septic arthritis in infancy and childhood. clin orthop relat res 1990; 257:212–25. 4. luhmann sj, jones a, schootman m, gordon je, schoenecker pl, luhmann jd. differentiation between septic arthritis and transient synovitis of the hip in children with clinical prediction algorithms. j bone joint surg am 2004; 86-a:956–62. 5. gutierrez k. bone and joint infections in children. pediatr clin north am 2005; 52:779–94. https://doi.org/10.1016/j. pcl.2005.02.005. 6. goldenberg dl. septic arthritis. lancet 1998; 351:197–202. https://doi.org/10.1016/s0140-6736(97)09522-6. 7. wang c, zhong da, liao q, kong l, liu a, xiao h. procalcitonin levels in fresh serum and fresh synovial fluid for the differential diagnosis of knee septic arthritis from rheumatoid arthritis, osteoarthritis and gouty arthritis. exp ther med 2014; 8:1075–80. https://doi.org/10.3892/etm.2014.1870. 8. omar m, ettinger m, reichling m, petri m, lichtinghagen r, guenther d, et al. preliminary results of a new test for rapid diagnosis of septic arthritis with use of leukocyte esterase and glucose reagent strips. j bone joint surg am 2014; 96:2032–7. https://doi.org/10.2106/jbjs.n.00173. 9. deirmengian c, kardos k, kilmartin p, cameron a, schiller k, parvizi j. combined measurement of synovial fluid α-defensin and c-reactive protein levels: highly accurate for diagnosing periprosthetic joint infection. j bone joint surg am 2014; 96:1439–45. https://doi.org/10.2106/jbjs.m.01316. 10. tarabichi m, shohat n, goswami k, alvand a, silibovsky r, belden k, et al. diagnosis of periprosthetic joint infection: the potential of next-generation sequencing. j bone joint surg am 2018; 100:147–54. https://doi.org/10.2106/jbjs.17.00434. 11. kocher ms, zurakowski d, kasser jr. differentiating between septic arthritis and transient synovitis of the hip in children: an evidence-based clinical prediction algorithm. j bone joint surg am 1999; 81:1662–70. 12. kocher ms, mandiga r, zurakowski d, barnewolt c, kasser jr. validation of a clinical prediction rule for the differentiation between septic arthritis and transient synovitis of the hip in children. j bone joint surg am 2004; 86-a:1629–35. 13. kang sn, sanghera t, mangwani j, paterson jm, ramchandran m. the management of septic arthritis in children: systematic review of the english language literature. j bone joint surg br 2009; 91:1127–33. https://doi.org/10.1302/0301-620x.9 1b9.22530. 14. chau cl, griffith jf. musculoskeletal infections: ultrasound appearances. clin radiol 2005; 60:149–59. https://doi.org/10.10 16/j.crad.2004.02.005. 15. pan kl, chan wh, chia yy. initial symptoms and delayed diagnosis of osteosarcoma around the knee joint. j orthop surg (hong kong) 2010; 18:55–7. https://doi.org/10.1177/2309 49901001800112. this is an image of the chest wall of a 57 year-old male, who presented with a painless mass in the left subscapular region of the chest which he had for more than ten years. the mass had recently increased in size causing discomfort when lying down. examination revealed a mass on the back side of the left chest wall deep to the angle of the scapula which became prominent on abduction of the arm [figure 1]. the mass was firm, but became hard on shoulder adduction. a similar mass became visible on the right infrascapular region during the abduction of the right arm, but this mass had not been noticed by the patient. the differential diagnoses considered were intramuscular lipoma, sarcoma, desmoid tumour, fibromuscular tumour besides other soft tissue tumours. a magnetic resonance (mr) scan of both periscapular regions showed a very well-defined oval soft tissue mass measuring 6 cm in oblique diameter, 2 cm in depth and 9 cm in cranio-caudal length which was located posterolaterally in the left side deep into the serratus anterior muscle and attached to the rib. another identical mass of squ med j, august 2011, vol. 11, iss. 3, pp. 415-416, epub. 15th aug 11 submitted 25th sep 10 revision req. 28th nov 11, revision recd. 20th dec 11 accepted 8th feb 11 departments of 1surgery and 2pathology, sultan qaboos university hospital, muscat, oman. *corresponding author email: sureshkannan18@yahoo.com gfi^¢]<íò^fl� m<îü„æ<· �ü⁄̌<íàè÷<›ö̌ê̌  bilateral elastofibroma dorsi mooyad a. ahmed,1 *sureshkannan k. subramanian,1 intisar al-hashmi,1 sreedharanv. koliyadan,1 nayil al-kindi,1 p.a.m saparamadu2 interesting medical image figure 1: clinical photograph showing the mass on the back of the left side of the chest wall deep to the angle of scapula. a similar smaller mass is seen on the right side. bilateral elastofibroma dorsi 416 | squ medical journal, august 2011, volume 11, issue 3 smaller size was detected on right side. the serratus anterior muscle was displaced laterally, but the ribs and overlying muscle were unaffected. both masses had a striated appearance with multiple linear septae of alternating highand low-signal intensity due to interlacing of linear streaks of fat. both masses showed a significant soft tissue component enhancement [figure 2]. the diagnosis suggested by mr scan was bilateral fibrolipoma. core needle biopsy reported fragments of fibrocollagenous and fibroadipose tissue only. the patient underwent complete excision of both the masses. grossly, the tumours were firm non-encapsulated, firmly adherent to the scapula and ribs, the left one 10 x 6 x 3 cm and the right one 7 x 5 x 2 cm in size. microscopically, both lesions were ill-defined and non-encapsulated comprised of adipose tissue, blood vessels and fibroconnective tissues. thick eosinophilic fragmented material was present within areas of connective tissues of fragmented elastic fibres [figure 3], and scattered fibrillar material with staining affinity similar to elastic fibres (so called elastofibroma fibres). elastofibroma dorsi [efd] is a slow growing benign lesion of unknown pathogenesis. it is most commonly seen in the sub-scapular region in elderly women as an ill-defined mass located within the muscles attached to the inferior angle of the scapula.1 the majority of patients are asymptomatic; rare symptoms include periscapular pain and discomfort, clunking of the scapula or restriction of shoulder movements. the findings in computed tomography (ct) and mr imaging in a typical infrascapular location are very characteristic to efd, hence obviating the need for biopsy and surgery in asymptomatic patients.2,3,4 although only 320 cases have been reported in medical literature, the prevalence of asymptomatic efd detected by ct scan in elderly populations was 2%.1,5 subclinical cases of small lesions (2–3 cm) have been found in autopsy series in 24% of females and 11% of males older than 55 years.1,5 the pathogenesis of this lesion remains unclear; whether these lesions are true neoplastic or reactive pseudotumours is still a controversy. references 1. fibla j, molins l, marco v, pérez j, vidal g. bilateral elastofibroma dorsi. joint bone spine 2007; 74:194– 6. 2. alouini r, allani m, harzallah l, bahri m, kraiem c, tlili-graies k. elastofibroma: imaging features. j radiol 2005; 86:1712–15. 3. mortman kd, hochheiser gm, giblin em, manon-matos y, frankel km. elastofibroma dorsi: clinicopathologic review of 6 cases. ann thorac surg 2007; 83:1894–7. 4. daigeler a, vogt pm, busch k, pennekamp w, weyhe d, lehnhardt m, et al. elastofibroma dorsidifferential diagnosis in chest wall tumours. world j surg oncol 2007; 5:15. 5. brandser ea, goree jc, el-khoury gy. elastofibroma dorsi: prevalence in an elderly patient population as revealed by ct. ajr am j roentgenol 1998; 171:977–80. figure 2: magnetic resonance scan of both mass with striated appearance and multiple linear septae of alternating high and low signal intensity due to the interlacing of linear streaks of fat. figures 3a to 3d: histopathology of both masses showing an ill-defined non-encapsulated lesion comprising of adipose tissue, blood vessels and fibroconnective tissue. there is thick eosinophilic fragmented material within the areas of connective tissue of fragmented elastic fibers. a: haematoxylin and eosin stain, low power; b: haematoxylin and eosin stain, high power; c: elastic van gieson stain, d: masson’s trichrome stain. 1department of emergency medicine, rustaq hospital, rustaq, oman; departments of 2statistics & health information and 3emergency medicine, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: u038664@gmail.com دقة شريط الطوارئ بروسلو لألطفال لتقدير أوزان األطفال العمانيني اأزهر بن اأحمد البو�سعيدي، الك�سمنان جايا�سالن، هالل بن حممد الربواين abstract: objectives: this study aimed to evaluate the accuracy of the broselow™ pediatric emergency tape (bt) for estimating weight in an omani paediatric population at a tertiary care hospital. methods: this retrospective cross-sectional study was conducted during july 2015. the electronic medical records of omani outpatients <14 years old attending the sultan qaboos university hospital, muscat, oman, between july 2009 and june 2013 were reviewed for recorded height and weight data. the bt version 2002a was used to predict weight based on actual height measurements. predicted weight measurements were then compared with actual weight to determine the accuracy of the estimation. results: a total of 3,339 children were included in the study, of which 43.5% were female and 56.5% were male. the mean age was 6.4 ± 3.1 years and the mean height was 93.2 ± 23.5 cm. the mean actual weight was 13.9 ± 6.7 kg while the mean bt-predicted weight was 14.4 ± 6.9 kg. the bt-predicted weight estimations correlated significantly with actual weight measurements (intraclass correlation coefficient: 0.97; p <0.001). a bland-altman analysis indicated that the bt performed well when estimating weight among omani children, with an overestimation of only 0.5 kg for the entire cohort. conclusion: the bt was found to be an effective tool for estimating weight according to body length in an omani paediatric population. it should therefore be considered for use in emergency situations when actual weight cannot be determined. keywords: paediatrics; body weight; body height; emergency medicine; oman. امللخ�ص: الهدف: هدفت الدرا�سة لتقييم دقة �رشيط برو�سلو يف تقدير اأوزان االأطفال العمانيني يف م�ست�سفى رعاية ثالثية. الطريقة: مت اإجراء هذه الدرا�سة امل�ستعر�سة باأثر رجعي خالل �سهر يوليو 2015. متت مراجعة ال�سجالت الطبية االإلكرتونية للمر�سى اخلارجيني العمانيني الذين تقل اأعمارهم عن 14 عاما والذين كانوا يعاجلون يف م�ست�سفى جامعة ال�سلطان قابو�س، م�سقط، عمان، بني يوليو 2009 ويونيو 2013 وا�ستخال�س بيانات مقارنة متت الفعلي. الطول قيا�سات اأ�سا�س على بالوزن للتنبوؤ )2002a )الن�سخة برو�سلو �رشيط ا�ستخدام مت امل�سجلة. والوزن الطول املائة يف 43.5% منهم طفال، 3,339 الدرا�سة �سملت النتائج: التقدير. دقة لتحديد الفعلي الوزن مع ذلك بعد املتوقعة الوزن قيا�سات من االإناث و %56.5 يف املائة من الذكور.متو�سط العمر يف العينة 3.1 ± 6.4 �سنة و متو�سط االأطوال 23.5 ± 93.2 �سم ومتو�سط االأوزان بالوزن ملحوظ ب�سكل بر�سلو ل�رشيط املقدر الوزن يرتبط كجم. 14.4 ± 6.9 برو�سلو ب�رشيط املقدرة االأوزان ومتو�سط كجم 13.9 ± 6.7 احلقيقي )p <0.001؛ intraclass correlation coefficient: 0.97(. حتليل بالند-األتمان أظهر اأن اأداء �رشيط برو�سلو يقارب قيا�س الوزن احلقيقي وال يزيد عن الوزن احلقيقي اإال بقدار 0.5 كجم يف كامل عينات الدرا�سة. اخلال�صة: اأثبتت الدرا�سة دقة �رشيط برو�سلو كاأداة لتقدير اأوزان االأطفال العمانيني با�ستخدام الطول. ولذلك ينبغي النظر يف ا�ستخدامها يف حاالت الطوارئ عندما ال ميكن حتديد الوزن الفعلي. الكلمات املفتاحية: اأطفال؛ وزن اجل�سم؛ طول اجل�سم؛ طب الطوارئ؛ عمان. the accuracy of the broselow™ pediatric emergency tape for weight estimation in an omani paediatric population *azher a. al-busaidi,1 lakshmanan jeyaseelan,2 hilal m. al-barwani3 clinical & basic research sultan qaboos university med j, may 2017, vol. 17, iss. 4, pp. e191–195, epub. 20 jun 17 submitted 25 aug 16 revisions req. 18 oct & 5 dec 16; revisions recd. 7 nov 16 & 18 jan 17 accepted 5 feb 17 doi: 10.18295/squmj.2016.17.02.009 advances in knowledge to the best of the authors’ knowledge, this is the first study from oman to investigate the accuracy of the broselow™ pediatric emergency tape (bt) in a paediatric population. application to patient care: the results of this study indicate that the bt can be used to accurately predict the weight of omani paediatric patients; this may be useful in emergency situations or during resuscitation. in paediatric emergencies, an accurate andrapid estimation of a child’s weight is critical as it allows physicians to determine appropriate drug doses, use proportionately sized equipment and establish the level of defibrillation energy necessary.1–3 inaccurate weight estimations may have adverse effects, such as causing the patient to become unresponsive or experience toxicity during certain interventions.4 however, it is often extremely difficult to use tra ditional methods to determine a paediatric patient’s weight during a critical or emergency situation. a variety of methods have therefore been developed over the years to rapidly estimate a child’s weight.5–7 the accuracy of the broselow™ pediatric emergency tape for weight estimation in an omani paediatric population e192 | squ medical journal, may 2017, volume 17, issue 2 the broselow™ pediatric emergency tape (bt) was developed in the late 1970s as a tool to determine a child’s weight based on height calculated by measuring the head-to-heel body length while the patient is in a supine position.8,9 subsequently, the tool sorts children into weight categories based on their length, with each category assigned a colour that corresponds to a list of proportionally-sized equipment, appropriate doses of emergency drugs and safe levels of defibrillation energy.8,9 the bt is now the standard method for estimating paediatric weight in many emergency departments, as it reduces the need for recalling complicated weight estimation equations or calculations in an emergency situation.10–12 it has been recommended by both the american college of surgeons and the american heart association for use in their advanced trauma life support® and pediatric advanced life support® courses.13,14 although originally developed using data from a western population, recent studies from the usa and canada now indicate that the bt may significantly underestimate weight due to the rising prevalence of childhood obesity.15,16 in addition, to the best of the authors’ knowledge, no studies have yet been performed to assess the accuracy of the bt in estimating weight in an omani paediatric population. nevertheless, the bt is still used in oman to gauge weight during paediatric emergencies. as such, this study therefore aimed to determine the accuracy of the bt version 2002a in estimating weight among an omani paediatric population. methods this retrospective cross-sectional study took place in july 2015 at the sultan qaboos university hospital (squh), a tertiary care institution in muscat which receives referrals from all over oman. all paediatric omani patients <14 years old who visited the general outpatient clinic at squh between july 2009 and june 2013 were included in the study. children were excluded if their weight was >35 kg or their height was outside the recommended range (50–150 cm).8,9 patients were also excluded if they had any medical conditions that would substantially affect their weight and/or height, such as an amputation, dwarfism, a growth hormone deficiency, metabolic disease, severe joint contractures or neurological defects like cerebral palsy. in order to obtain an intraclass correlation (icc) of 0.8 to compare bt weight estimations with actual weight, the required sample size was calculated to be 300 subjects, assuming an icc of 0.7, with α and β errors at 5% and 10%, respectively, and an expected dropout rate of 10%. however, as many subgroup analyses were planned, a minimum of 3,000 subjects was deemed necessary. hospital electronic medical records were reviewed to collect data for all eligible subjects during their initial outpatient visit. all children were weighed on a standard calibrated paediatric scale and their height was measured using a stadiometer. for children <2 years old, recumbent length was measured using a standard medical measuring tape and weight was calculated using an electronic infant scale while the child was wearing diapers. weight and body length/height were measured to the nearest 0.1 kg and 1 cm, respectively. during the retrospective chart review, patient information was collected using a data sheet, including their name, medical record number, age in years, gender, body length/height and weight. the 2002a version of the bt was then used to estimate the weight of each patient based on actual body length/height measurements collected from medical records. a regression analysis was used to predict weight using the bt. subsequently, actual weight measurements were compared with bt-predicted weight estimates using icc calculations and a scatter plot. a bland-altman plot was also used to determine whether differences were randomly distributed over the range of average weight, with averages of the actual weight and btpredicted weight plotted on the x-axis and differences between the actual weight and bt-predicted weight plotted on the y-axis.17–19 to ensure accurate results, other indices such as bias, precision and percentage errors were also calculated.20 statistical software including r software, version 3.2.2 (r foundation for statistical table 1: mean age, height and weight according to gender of omani paediatric outpatients at the sultan qaboos university hospital, muscat, oman (n = 3,339) characteristic mean ± sd female (n = 1,451) male (n = 1,888) total age in years 6.4 ± 3.2 6.3 ± 3.2 6.4 ± 3.1 height in cm 92.7 ± 24.2 93.6 ± 23.0 93.2 ± 23.5 actual weight in kg 13.7 ± 7.0 14.1 ± 6.6 13.9 ± 6.7 bt-predicted weight in kg 14.3 ± 6.9 14.5 ± 6.9 14.4 ± 6.9 weight difference in kg* -0.5 ± 2.2 -0.4 ± 1.8 -0.5 ± 1.9 average weight in kg† 14.0 ± 6.9 14.3 ± 6.7 14.1 ± 6.7 sd = standard deviation; bt = broselow™ pediatric emergency tape. *difference between actual weight and bt-predicted weight. †average of actual weight and bt-predicted weight. azher a. al-busaidi, lakshmanan jeyaseelan and hilal m. al-barwani clinical and basic research | e193 computing, vienna, austria) and the statistical package of the social sciences (spss), version 22 (ibm corp., armonk, new york, usa) was used for the analysis. this study received ethical approval from the research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #1024). results a total of 3,339 children were included in the study. of these, 1,451 (43.5%) were female and 1,888 (56.5%) were male. the majority of the participants were 5–9 years old (53.9%), while 28.8% were ≤5 years old and 17.0% were ≥10 years old. the mean age was 6.4 ± 3.1 years and the mean height was 93.2 ± 23.5 cm. the mean actual weight was 13.9 ± 6.7 kg, while the mean bt-predicted weight was 14.4 ± 6.9 kg. the mean difference between actual weight and btpredicted weight was -0.5 ± 1.9 kg. the combined average of both actual and bt-predicted weight was 14.1 ± 6.7 kg [table 1]. the icc of the actual weight and bt-predicted weight measurements was 0.97 (icc coefficient: 0.97–0.98; p <0.001). a scatter plot of actual weight measurements and bt-predicted weight estimates is shown in figure 1. the linear regression equation was as follows: where w is the actual weight. this equation implies that a 1 kg increase in actual weight results in a 0.9 kg increase in bt-predicted weight, with a near-perfect correlation between the two measurements. the bland altman plot is shown in figure 2. the mean bias was -0.49 ± 1.98 (95% confidence interval: -2.46–1.50) with the limits of agreement at -4.37 and 3.40. a total of 53.7% and 85.4% of the bt-predicted weight estimates fell within 10% and 20% of the actual weights, respectively. the precision of the bt-predicted weight estimates was 3.9% and the percentage of error was 27.9%. for children weighing <15 kg, the overestimation was negligible; however, when the actual weight was 15–25 kg, a small difference between actual and bt-predicted weight was observed. nevertheless, as the percentage of error was within 30%, bt-predicted weight estimation was deemed very reliable and comparable to actual weight measurements.18,19 discussion in emergency situations, the accurate measurement or estimation of weight is a difficult yet crucial task to select proportionately sized equipment and administer the correct drug doses for paediatric patients.1–3 the bt is an accessible and unbiased tool to estimate a child’s weight based on their body length/height and is useful during paediatric resuscitation.8,9 however, as the bt was not specifically developed for omani children, it is important to determine its accuracy among this specific population. using the bt version 2002a, the results of this study confirmed that btpredicted weight estimates correlate with actual weight in an omani paediatric population. these findings are in agreement with those reported by other studies conducted in various parts of the world, including saudi arabia, korea, the usa, india and kenya.2,8,21–24 furthermore, other indices also suggested that the figure 1: scatterplot comparing actual weight measurements with predicted weight estimates using the broselow™ pediatric emergency tape among omani paediatric outpatients at the sultan qaboos university hospital, muscat, oman (n = 3,339). bt = broselow™ pediatric emergency tape. figure 2: bland-altman plot comparing the mean weights of actual weight measurements and predicted weight estimates using the broselow™ pediatric emergency tape (bt) with the differences between actual weight and bt predicted weight among omani paediatric outpatients at the sultan qaboos university hospital, muscat, oman (n = 3,339). bt = broselow™ pediatric emergency tape; sd = standard deviation. predicted weight = 0.81 + 0.98 × w the accuracy of the broselow™ pediatric emergency tape for weight estimation in an omani paediatric population e194 | squ medical journal, may 2017, volume 17, issue 2 bt sufficiently predicts actual weight. although the bt slightly overestimated the actual weight of the population in the current study by 0.5 kg, the percentage of error still fell within acceptable limits at <30%.18,19 nevertheless, while overestimation was negligible in smaller children weighing <15 kg, it was more pronounced in children weighing between 15–25 kg. this implies that the bt performs better in lighter children, a finding which has also been reported in other studies.2,7,8,21,23–27 the bt has been shown to perform differently in various populations. two studies from india and a study from south sudan have reported that the bt overestimates weight.28–30 as a result, some researchers have advised that certain adjustments be made to the bt to improve its accuracy for these particular populations.28,29 conversely, studies from more economically developed countries have found that the bt tends to underestimate weight among paediatric populations.5,15,25,31,32 these contradictory data may reflect the increasing prevalence of obesity in more developed countries.15,16 the strengths of the current study include its large sample size and the collection of data from a tertiary care centre which receives referrals from all over the country. therefore, the subjects included in this study may be considered representative of the general omani paediatric population. however, a potential limitation of this study was the assumption that the sample population were of the same weight as children who require resuscitation. furthermore, the most recent version of the bt, the bt version 2011, was not used to estimate weight. this is because the bt version 2002a is currently used at squh in emergency settings. moreover, intra-rater reliability was also not estimated and the study was conducted in only one hospital. conclusion the bt was found to accurately predict weight in an omani paediatric population. as such, it can be considered an effective tool to estimate paediatric weight in emergency situations where the actual weight of the child cannot be easily determined. accurate weight estimation allows physicians to administer the correct drug doses, use proportionately sized instruments and determine safe shock levels for defibrillation when treating critically ill children. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. ecc committee, subcommittees and task forces of the american heart association. 2005 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. circulation 2005; 112: iv1–203. doi: 10.11 61/circulationaha.105.166550. 2. hofer ck, ganter m, tucci m, klaghfer r, zollinger a. how reliable is length-based determination of body weight and tracheal tube size in the paediatric age group? the broselow tape reconsidered. br j anaesth 2002; 88:283–5. doi: 10.1093/ bja/88.2.283. 3. davis d, barbee l, ririe d. pediatric endotracheal tube selection: a comparison of age-based and height-based criteria. aana j 1998; 66:299–303. 4. shah an, frush k, luo x, wears rl. effect of an intervention standardization system on pediatric dosing and equipment size determination: a crossover trial involving simulated resuscitation events. arch pediatr adolesc med 2003; 157:229–36. doi: 10.1001/archpedi.157.3.229. 5. black k, barnett p, wolfe r, young s. are methods used to estimate weight in children accurate? emerg med (fremantle) 2002; 14:160–5. doi: 10.1046/j.1442-2026.2002.00311.x. 6. dubois d, baldwin s, king wd. accuracy of weight estimation methods for children. pediatr emerg care 2007; 23:227–30. doi: 10.1097/pec.0b013e31803f5aca. 7. argall ja, wright n, mackway-jones k, jackson r. a comparison of two commonly used methods of weight estimation. arch dis child 2003; 88:789–90. doi: 10.1136/ adc.88.9.789. 8. lubitz ds, seidel js, chameides l, luten rc, zaritsky al, campbell fw. a rapid method for estimating weight and resuscitation drug dosages from length in the pediatric age group. ann emerg med 1988; 17:576–81. doi: 10.1016/s01960644(88)80396-2. 9. luten rc, wears rl, broselow j, zaritsky a, barnett tm, lee t, et al. length-based endotracheal tube and emergency equipment in pediatrics. ann emerg med 1992; 21:900–4. doi: 10.1016/s0196-0644(05)82924-5. 10. agarwal s, swanson s, murphy a, yaeger k, sharek p, halamek lp. comparing the utility of a standard pediatric resuscitation cart with a pediatric resuscitation cart based on the broselow tape: a randomized, controlled, crossover trial involving simulated resuscitation scenarios. pediatrics 2005; 116:e326–33. doi: 10.1542/peds.2005-0320. 11. chavez h, peterson re, lo k, arel m. weight estimation in an inner-city pediatric ed: the effect of obesity. am j emerg med 2015; 33:1364–7. doi: 10.1016/j.ajem.2015.07.040. 12. khouli m, ortiz mi, romo-hernández g, martínez-licona d, stelzner sm. use of the broselow tape in a mexican emergency department. j emerg med 2015; 48:660–6. doi: 10.1016/j.jemer med.2014.12.082. 13. american college of surgeons. advanced trauma life support: atls® student course manual, 9th ed. chicago, illinois, usa: american college of surgeons, 2012. p. 250. 14. leon c, samson ra, schexnayder sm, hazinski mf. pediatric advanced life support: provider manual. dallas, texas, usa: american heart association, 2012. p. 91. 15. milne wk, yasin a, knight j, noel d, lubell r, filler g. ontario children have outgrown the broselow tape. cjem 2012; 14:25–30. doi: 10.2310/8000.2011.110523. https://doi.org/10.1161/circulationaha.105.166550 https://doi.org/10.1161/circulationaha.105.166550 https://doi.org/10.1093/bja/88.2.283 https://doi.org/10.1093/bja/88.2.283 https://doi.org/10.1001/archpedi.157.3.229 https://doi.org/10.1046/j.1442-2026.2002.00311.x https://doi.org/10.1097/pec.0b013e31803f5aca https://doi.org/10.1136/adc.88.9.789 https://doi.org/10.1136/adc.88.9.789 https://doi.org/10.1016/s0196-0644%2888%2980396-2 https://doi.org/10.1016/s0196-0644%2888%2980396-2 https://doi.org/10.1016/s0196-0644%2805%2982924-5 https://doi.org/10.1542/peds.2005-0320 https://doi.org/10.1016/j.ajem.2015.07.040 https://doi.org/10.1016/j.jemermed.2014.12.082 https://doi.org/10.1016/j.jemermed.2014.12.082 https://doi.org/10.2310/8000.2011.110523 azher a. al-busaidi, lakshmanan jeyaseelan and hilal m. al-barwani clinical and basic research | e195 16. nieman ct, manacci cf, super dm, mancuso c, fallon wf jr. use of the broselow tape may result in the underresuscitation of children. acad emerg med 2006; 13:1011–19. doi: 10.1197/j. aem.2006.06.042. 17. bland jm, altman dg. statistical methods for assessing agreement between two methods of clinical measurement. lancet 1986; 1:307–10. doi: 10.1016/s0140-6736(86)90837-8. 18. bland jm, altman dg. comparing methods of measurement: why plotting difference against standard method is misleading. lancet 1995; 346:1085–7. doi: 10.1016/s0140-6736(95)91748-9. 19. bland jm, altman dg. measuring agreement in method comparison studies. stat methods med res 1999; 8:135–60. doi: 10.1177/096228029900800204. 20. cecconi m, rhodes a, poloniecki j, della rocca g, grounds rm. bench-to-bedside review: the importance of the precision of the reference technique in method comparison studies – with specific reference to the measurement of cardiac output. crit care 2009; 13:201. doi: 10.1186/cc7129. 21. varghese a, vasudevan vk, lewin s, indumathi ck, dinakar c, rao sd. do the length-based (broselow) tape, apls, argall and nelson’s formulae accurately estimate weight of indian children? indian pediatr 2006; 43:889–94. 22. jang hy, shin sd, kwak yh. can the broselow tape be used to estimate weight and endotracheal tube size in korean children? acad emerg med 2007; 14:489–91. doi: 10.1111/j.1553-2712. 2007.tb01814.x. 23. house dr, ngetich e, vreeman rc, rusyniak de. estimating the weight of children in kenya: do the broselow tape and agebased formulas measure up? ann emerg med 2013; 61:1–8. doi: 10.1016/j.annemergmed.2012.07.110. 24. alharbi tm, algarni a, algamdi f, jawish m, wani ta, abu-shaheen ak. the accuracy of broselow tape weight estimate among paediatric population. biomed res int 2016; 2016:7042947. doi: 10.1155/2016/7042947. 25. theron l, adams a, jansen k, robinson e. emergency weight estimation in pacific island and maori children who are largefor-age. emerg med australas 2005; 17:238–43. doi: 10.11 11/j.1742-6723.2005.00729.x. 26. so ty, farrington e, absher rk. evaluation of the accuracy of different methods used to estimate weights in the pediatric population. pediatrics 2009; 123:e1045–51. doi: 10.1542/peds. 2008-1968. 27. mishra dg, kole t, nagpal r, smith jp. a correlation analysis of broselow™ pediatric emergency tape-determined pediatric weight with actual pediatric weight in india. world j emerg med 2016; 7:40–3. doi: 10.5847/wjem.j.1920-8642.2016.01.007. 28. ramarajan n, krishnamoorthi r, strehlow m, quinn j, mahadevan sv. internationalizing the broselow tape: how reliable is weight estimation in indian children. acad emerg med 2008; 15:431–6. doi: 10.1111/j.1553-2712.2008.00081.x. 29. asskaryar f, shankar r. an indian pediatric emergency weight estimation tool: prospective adjustment of the broselow tape. int j emerg med 2015; 8:78. doi: 10.1186/s12245-015-0078-z. 30. clark mc, lewis rj, fleischman rj, ogunniyi aa, patel ds, donaldson ri. accuracy of the broselow tape in south sudan, “the hungriest place on earth”. acad emerg med 2016; 23:21–8. doi: 10.1111/acem.12854. 31. anstett d, bawden j, moylette e, milne wk. abstract 126: does the broselow tape accurately estimate the weight of healthy irish children? in: 2009 caep/acmu scientific abstracts, june 6–10, 2009, calgary, alta. cjem 2009; 11:289. doi: 10.1017/s1481803500011301. 32. bourdeau s, copeland j, milne wk. accuracy of the broselow tape in estimating the weight of first nations children. can j rural med 2011; 16:121–5. https://doi.org/10.1197/j.aem.2006.06.042 https://doi.org/10.1197/j.aem.2006.06.042 https://doi.org/10.1016/s0140-6736%2886%2990837-8 https://doi.org/10.1016/s0140-6736%2895%2991748-9 https://doi.org/10.1177/096228029900800204 https://doi.org/10.1186/cc7129 https://doi.org/10.1111/j.1553-2712.2007.tb01814.x https://doi.org/10.1111/j.1553-2712.2007.tb01814.x https://doi.org/10.1016/j.annemergmed.2012.07.110 https://doi.org/10.1155/2016/7042947 https://doi.org/10.1111/j.1742-6723.2005.00729.x https://doi.org/10.1111/j.1742-6723.2005.00729.x https://doi.org/10.1542/peds.2008-1968 https://doi.org/10.1542/peds.2008-1968 https://doi.org/10.5847/wjem.j.1920-8642.2016.01.007 https://doi.org/10.1111/j.1553-2712.2008.00081.x https://doi.org/10.1186/s12245-015-0078-z https://doi.org/10.1111/acem.12854 https://doi.org/10.1017/s1481803500011301 globally, obesity has now reached epidemic proportions. although the prevalence is highest in developed countries, obesity has become an important health issue in many developing countries, often coexisting with undernutrition. concomitant with the increased rates of obesity in the general population, rates during pregnancy have also escalated, and obesity is now a common high-risk obstetric condition. information is limited on the prevalence of overweight and obesity during pregnancy in various countries. according to this book, the reported prevalence of maternal obesity in different cities and states of the usa ranged from10% to 26%. obesity is not only a health issue, but also has economic consequences. total costs involve both direct costs related to medical expenditure on obesity-related diseases (including type 2 diabetes, cardiovascular diseases, several types of cancers and musculoskeletal disorders) as well as indirect costs related to absenteeism, reduced productivity, and disability. studies from many countries have reported on the substantial and increased economic burden of obesity. recognition of this problem has led to an explosion of research into causes and solutions, from the genetic to the population level and all points in between. the pregnancy care of obese and overweight women provides a unique set of challenges. excess weight affects fertility, pregnancy, delivery and the postpartum period. a specialised knowledge base and skill set are required to provide competent pre-pregnancy, obstetric and postnatal care to obese women. the aim of this book is to supply this knowledge to busy clinicians facing just such challenges. the reader will find collected in one location information covering every aspect of pregnancy in obese women beginning with the epidemiological scope of the problem and ending with postpartum care. this is the first edition of the book, edited by deborah l.conway of the احلمل يف املرأة البدينة العالج السريري املحرر: ديبورا كونواي book review pregnancy in the obese woman clinical management editor: deborah conway publisher: wiley-blackwell, 1st edition, 2011 isbn: 978-1-4051-9648-2 orders: www.wiley.com/wiley-blackwell squ med j, november 2011, vol. 11, iss. 4, pp. 532-533, epub. 25th oct 11 submitted 20th aug deborah conway book review | 533 department of obstetrics & gynecology at the university of texas school of medicine, there is a growing body of evidence to suggest that obese women experience more psychological stressors and psychological disorders than normal weight women. in this book, composed of 14 chapters, the second one describes the psychological aspects of obesity in women outside of and during pregnancy and offers pragmatic screening tools for use in clinical assessment during pregnancy. in addition to the typical obstetrics topics like prenatal care, fetal surveillance and delivery, in chapter 4 the book addresses bariatric surgery (vertical banded gastroplasty and roux-en-y gastric bypass). this surgery is recommended for women with a body mass index of 40 kg/m2 or over who have failed at conventional weight loss attempts, have been properly educated and are motivated for surgery. chapter 5 deals with post-bariatric surgery pregnancy-related complications like hypertensive disorders and gestational diabetes. caesarean sections are more prevalent in women who have undergone bariatric surgery. however, there is no difference between them and the general population in intra-partum complications like placental abruption, labour dystocia and meconiumstained amniotic fluid. chapter 5 also covers fetal malformation and birth weight problems like small for gestational age neonates and macrosomia. the reader will find covered in this book the special considerations needed in prenatal care for obese women and the limitations of ultrasound in anomaly detection as well the difficulty of invasive testing. it also covers late pregnancy and intrapartum care, especially breech presentation and trial of labour in obese women. other chapters address the adverse consequences of maternal obesity during pregnancy, as well the adverse effects on child health outcomes later in life such as: child, adolescent and adult obesity; high blood pressure; metabolic syndrome, and cardiometabolic complications. chapter 13 focuses on the preparation of the obese pregnant women for surgery and anaesthetic considerations as well antibiotics and pre-operative and post-operative care. the last chapter, the most interesting one in my opinion, focuses on how obesity affects breastfeeding and contraception. the various contraception methods are described in detail. since obesity increases the failure rates of several methods, the book proposes that there is a need for in depth evaluation, which should take into consideration the woman’s personal, social, family and medical history. this book is unique on several scores. it focuses on a problem that has now reached epidemic proportions and uses evidence-based medicine to cover many aspects of obesity in pregnancy in one volume. it is an excellent source of up-to-date information and, in addition, it is very easy to read and digest. overall, this book is therefore a useful resource for medical students, obstetric residents, and general and high-risk obstetricians. i will definitely use this book for reference and i highly recommend it to others. rahma al-haddabi department of obstetrics & gynaecology sultan qaboos university hospital, muscat, oman email: rahmahamed@hotmail.com departments of 1anaesthesia and 2surgery, ibri regional hospital, ibri, oman *corresponding author e-mail: mmelawdy@gmail.com العبء الناجم عن إلغاء العمليات اجلراحية وعدم حضور املرضى حسب مواعيدهم دراسة إلدارة اجلودة من مستشفى إقليمي كبري يف عمان �صيفا �صوبرامانيان ثريومايل، �صامل مرهون ال�صكيلي، اأحمد حممد ال�رضيف، حممد حممد العو�صي abstract: objectives: the operating theatre (ot) is a vital facility that utilises a considerable portion of the hospital’s budget; thus proper ot utilisation is essential. surgical cancellation is a leading cause of ot underutilisation. this study aimed to report the rate and reasons for surgical cancellations and no-shows in a large regional hospital in oman. methods: this study took place as part of a retrospective quality management project at the ibri regional hospital, ibri, oman. all elective surgical procedures scheduled between january and december 2014 were included. cancelled procedures were reviewed to determine the reasons for cancellation. results: a total of 4,814 elective procedures were scheduled during the study period; of these, 1,235 (26%) were cancelled. patient no-shows were the most prevalent reason for surgical cancellation (63%), followed by surgical reasons (17%); in contrast, ot-associated reasons were responsible for only 2% of cancellations. according to speciality, general surgery had the highest percentage of total cancellations (65%), while ear, nose and throat had the highest rate of surgical cancellations among their scheduled cases (42%). conclusion: ibri regional hospital had a higher surgical cancellation rate due to no-shows than those reported in the literature. regular audits, quality management projects and the appointment of a dedicated procedure booking coordinator may enhance proper utilisation of the ot, potentially saving funds, conserving resources and alleviating the burden of cancellations. keywords: elective surgical procedures; appointments and schedules; operating rooms; hospital financial management; oman. امللخ�ض: اأهداف: تعدُّ غرف العمليات من اأهم املرافق احليوية التي ت�صتخدم جزءاً كبرياً من ميزانية امل�صت�صفى. ولذا يعد اال�صتخدام االأمثل وال�صليم للوقت املتاح للعمليات اأمراً �رضوريًا، اإلغاء العمليات اجلراحية هو ال�صبب الرئي�صي لعدم كفاءة االإ�صتخدام، هدفت هذه الدرا�صة اإىل تقرير معدل واأ�صباب اإلغاء العمليات اجلراحية وعدم ح�صور املر�صى يف مواعيدهم املحددة وذلك يف م�صت�صفى اإقليمي كبري بُعمان بُعمان. منهجية: كانت هذه الدرا�صة االإ�صتعدادية جزء من م�رضوع الإدارة اجلودة يف م�صت�صفى عربي املرجعي التابع لوزارة ال�صحة يف عمان. �صملت العينة جميع العمليات اجلراحية االختيارية املقررة بني يناير ودي�صمرب 2014م، ومت ا�صتعرا�ض العمليات اجلراحية امللغاة و حتديد اأ�صباب اإلغاءها. نتائج: بلغ املجموع االإجمايل للعمليات االختيارية الداخلة يف العينة ما جمموعه 4,814 خالل فرتة الدرا�صة. األغيت 1,235 عملية )%26( خالل هذه الفرتة. كان ال�صبب االأكرث انت�صارا الإلغاء العمليات اجلراحية هو عدم ح�صور املري�ض ملوعده املحدد )%63( تليه االأ�صباب اجلراحية )%17(؛ و يف املقابل، كانت االأ�صباب املرتبطة بغرفة العمليات م�صوؤولة عن %2 فقط من احلاالت امللغاة. ووفقا للتخ�ص�ض، كانت واحلنجرة واالأنف االأذن حاالت اأن حني يف )65%( التخ�ص�صات بقية بني من االإلغاءات اإجمايل من ن�صبة اأعلى العامة اجلراحة حاالت حققت اأعلى معدل لالإلغاء بني احلاالت املجدوله )%42(. خامتة: حقق م�صت�صفى عربي املرجعي معدالت عالية الإلغاء للعمليات اجلراحية االختيارية ب�صبب عدم احل�صور مقارنة باملعدالت العاملية املعروفة، ومن املمكن تقليل الفاقد و تعزيز اال�صتخدام ال�صليم للوقت املتاح اإجراءات ملتابعة خمت�ض من�صق بتعيني وكذلك اجلودة، اإدارة وم�صاريع املنتظمة، التدقيقية االإجراءات و املراجعة طريق عن للعمليات حتديد احلجز، مما �صيوفر الكثري من االأموال، وي�صاعد على احلفاظ على املوارد وتخفيف عبء هذه االإلغاءات. كلمات مفتاحية: العمليات اجلراحية االختيارية؛ املواعيد واجلداول؛ غرف العمليات؛ االإدارة املالية للم�صت�صفى؛ عمان. the burden of surgical cancellations and no-shows quality management study from a large regional hospital in oman sivasubramanian t. appavu,1 salim m. al-shekaili,1 ahmed m. al-sharif,1 *mohamed m. elawdy2 clinical & basic research sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e298–302, epub. 19 aug 16 submitted 23 dec 15 revision req. 29 feb 16; revision recd. 20 mar 16 accepted 7 apr 16 doi: 10.18295/squmj.2016.16.03.006 advances in knowledge to the best of the authors’ knowledge, no studies on rates of surgical cancellation have yet been published from governmental hospitals in oman. the majority of surgical cancellations at the ibri regional hospital, ibri, oman, were attributed to patient no-shows, with very few cancellations due to facilityor operating theatre-related reasons. findings from the current study indicated a higher rate of surgical cancellations due to no-shows in comparison to reports from the international literature. sivasubramanian t. appavu, salim m. al-shekaili, ahmed m. al-sharif and mohamed m. elawdy clinical and basic research | e299 the operating theatre (ot) is an integral part of any hospital and utilises con-siderable economic resources and manpower. the ot requires an assembly of staff from the surgery, anaesthesia and nursing teams in addition to surgical instruments and equipment. for elective surgeries, preoperative protocols can include laboratory and radiological work-ups, pre-anaesthetic clinic (pac) assessments and the booking of intensive care unit beds. however, both hospitals and patients can be negatively affected if the surgery is subsequently cancelled following these preparations. from an administrative perspective, surgical cancellation leads to ot underutilisation; in 2001, the cost of unused ot time was estimated to be usd $1,400–2,000 per hour.1 moreover, surgical cancellation inconveniences patients, as cancelled cases will need to be rescheduled. patients may have travelled long distances and taken leave from work in order to come into the hospital; they may therefore feel emotional and psychological distress if their surgeries are cancelled or delayed.2 although surgical cancellation has been extensively studied, reported rates of surgical cancellation are inconsistent (4.5–30.3%).3–7 furthermore, there is a lack of agreement in the literature regarding the most prevalent reasons for cancellations. common causes include previous surgeries running beyond their allotted ot time, hospital-initiated factors and the development of upper respiratory infections (uris) among patients scheduled for surgery.4–8 however, other studies have identified patient-related reasons as the most common causes of surgical cancellation.3,9 to the best of the authors’ knowledge, no previous studies focusing on surgical cancellation have been carried out at ministry of health (moh) healthcare centres in oman. in light of this gap in the literature, this study aimed to analyse the rate of surgical cancellations in an moh hospital in oman, identifying not only the reasons for surgical cancellations but also the rate of surgical cancellations within different medical specialties. these results may potentially aid the implementation of policies designed to minimise surgical cancellations and subsequently improve health services in oman. methods this retrospective analysis included all elective surgical procedures scheduled between january and december 2014 at the ibri regional hospital, ibri, oman. this is a 270-bed secondary level moh hospital with four operating rooms, including one designated solely for obstetrics and gynaecology cases. the hospital operates five days a week, with an average of 15 elective surgeries scheduled daily. emergency surgery cases and second surgeries scheduled in double-entry cases were excluded from the study. after data for all scheduled surgeries had been collected, the rate of cancellations was determined. surgical cancellation was defined as any surgery that was scheduled but not carried out for any reason. following this, the rate of surgical cancellations within different medical specialties was determined to identify specific departments with high cancellation rates. electronic records from the al-shifa® healthcare information system, version 2 (ministry of health, oman), were reviewed to determine the reasons for cancellation in all surgical cancellation cases. documentation of the reason for surgical cancellation is a mandatory step in this system. in rare cases where reasons were not mentioned, doctors’ and/or nurses’ notes were used to deduce the cause of the cancellation. if a deduction could not be made from the notes, the cancellation reason was documented as unknown. reasons for surgical cancellation were categorised into the following groups: patient noshows; surgical (i.e. the procedure was cancelled by surgeons); acute conditions (e.g. uri or uncontrolled hypertension or diabetes mellitus); ot-related; administrative; improved patient condition; and unknown. patients who were assessed by an anaesthesiologist and surgeon and scheduled for surgery, but who did not show up on the day of surgery without previously cancelling, were classified as no-shows. data were collected in a microsoft excel spreadsheet, version 2007 (microsoft corp., redmond, washington, usa). after coding, the data were transferred to the statistical package for the social application to patient care understanding the burden of surgical cancellation is a necessary step for the implementation of policies to minimise cancellations. as such, the results of the current study may help local healthcare administrators and lead to a better health service in oman. additionally, the resulting economic savings from such steps may help to cover other hospital expenditures, potentially improving patient care. furthermore, a decrease in surgical cancellations could also reduce the psychological impact of cancellations and subsequent rescheduling of operations on patients and their families. the burden of surgical cancellations and no-shows quality management study from a large regional hospital in oman e300 | squ medical journal, august 2016, volume 16, issue 3 sciences (spss), version 16 (ibm corp., chicago, illinois, usa) for further analysis. nominal noncontinuous data were reported as frequencies and percentages. this study was granted ethical approval from the studies & research committee of the directorate general of health services, ministry of health, aldhahira governorate, oman. results during the study period, a total of 4,814 elective surgeries were scheduled by six different surgical specialties. of these, 1,235 (26%) surgeries were cancelled, averaging nearly five cases daily. patient no-shows were the most prevalent reason for surgical cancellation (63%). the second most common reason was surgical (17%), including changes in surgical plans. acute conditions were the third most common cause (14%). very few cancellations occurred due to administrative causes or because of an improved patient condition (1% each) [table 1]. according to the distribution of cancelled cases by speciality, the highest frequency of cancellations in total were attributed to general surgery (65%), followed by ear, nose and throat (ent; 8%) and orthopaedics (7%). in comparison, ent had the highest frequency of cancellations out of their scheduled cases (42%). dental surgery had the lowest surgical cancellation rate in total (>1%); however, they also had the lowest number of scheduled cases (35 cases) [table 2]. discussion many procedures involving a considerable amount of work are usually undertaken to prepare a patient for surgery, including routine laboratory and radiology work-ups and pac consultations. patients sometimes require further clearance for surgery from general medicine, cardiology and paediatric clinicians due to uncontrolled illnesses. certain surgeries may require not only coordination between anaesthesiologists, surgeons and nurses, but also the booking, preparation and assembly of specialist equipment, which can be costly. technicians, interns and medical students may also need to attend surgeries. surgical cancellation therefore results in a significant waste of time, energy and both financial and human resources. at the personal level, patients may have to change their schedules to accommodate a surgery date, take unpaid leave from work and/or arrange for childcare and long-distance travel. additionally, patients may be instructed to abstain from or modify medication regimens before surgery. the ramifications of surgical cancellation thus extend beyond the misuse of financial resources for the hospital. the social, economic and psychological burden imposed upon patients should table 1: reasons for surgical cancellations at the ibri regional hospital, ibri, oman (n = 1,235) reason for cancellation n (%) patient no-shows 783 (63) surgical reasons 215 (17) acute conditions (e.g. uri or uncontrolled htn or dm) 174 (14) ot-associated reasons (e.g. over-booking, full ot or technical reasons) 23 (2) hospital transfers/administrative causes 16 (1) improved patient condition 17 (1) unknown 7 (1) total 1,235 (100) uri = upper respiratory infection; htn = hypertension; dm = diabetes mellitus; ot = operating theatre. table 2: rate of completed surgeries and surgical cancellations by specialty at the ibri regional hospital, ibri, oman (n = 4,814) specialty surgeries completed surgeries cancelled total overall cancellation rate cancellation rate per specialty general surgery 2,345 802 3,147 65% 25% ent 274 201 475 16% 42% ob/gyn 437 39 476 3% 8% ophthalmology 245 89 334 7% 27% orthopaedics 240 94 334 8% 28% dental 32 3 35 >1% 9% other 6 7 13 1% 54% total 3,579 1,235 4,814 26% ent = ear, nose and throat; ob/gyn = obstetrics/gynaecology. sivasubramanian t. appavu, salim m. al-shekaili, ahmed m. al-sharif and mohamed m. elawdy clinical and basic research | e301 not be underestimated; indeed, surgical cancellation can result in dissatisfaction among patients and their families.2 from the perspective of quality management, a low surgical cancellation rate is a fair indicator of the efficient use of an ot as well as the hospital’s financial resources. in a large study comprised of 329,784 surgical cases scheduled by nine different surgical specialties at 40 hospitals in the usa, the overall surgical cancellation rate was 12.4%; medical causes were responsible for 28% of cancellations, while facility unavailability led to 20% of the cancellations.10 in another study of 7,913 surgeries scheduled at a hospital in australia, the over-running of previous surgeries and bed unavailability were responsible for 18.7% and 18.1% of surgical cancellations, respectively, while 17.5% were due to patient cancellations.11 regular audits as part of quality management or improvement activities are recommended to determine the current rate of surgical cancellations at specific health care facilities. no-shows are defined as individuals who have made but neither keep nor cancel their reservation, booking or appointment.12 in the current study, noshows were included among surgical cancellations because these patients unnecessarily occupied ot schedules, preventing other patients from being operated upon at that time. cancellations due to noshows occurred in 63% of cases in the current study; this is much higher than the reported international standard (7.6–30.3%).4,5,7,13 many factors may contribute to the high prevalence of no-shows at ibri regional hospital, including patient dissatisfaction, the preference to undergo surgical procedures at a tertiary hospital and the existence of a relatively long waiting list. these factors should be investigated further in a prospective study. as an moh facility, ibri regional hospital provides free services to omani nationals. very few patients require private funding or insurance for medical procedures; thus, high costs or insurance concerns are unlikely to contribute to the rate of surgical cancellations observed at this institution. there are several ways in which the high rate of noshows observed in the current study could potentially be reduced. one method would be to schedule operations one day prior to the surgery instead of days or weeks ahead of time. as a result, the ot can be used for the next patient listed if a scheduled patient does not show up. this would reduce underutilisation of ots. for day care or outpatient surgeries, a booking coordinator can be assigned to ensure patient attendance. pratap et al. reported a quality improvement trial at a children’s hospital aimed at reducing patient-related causes of surgical cancellation using additional communication techniques such as simplified colourful instruction sheets and call/text message reminders; these interventions successfully reduced wasted ot time from 5.7 to 3.6 hours per day.14 some institutions have also recommended charging patients for no-shows, although this would be difficult to implement in governmental hospitals.12 while financial penalties are an attractive option to prevent patient-related surgical cancellations, the authors of the current study do not believe that this option should be considered until hospital-associated reasons that may lead to patient noncompliance have been identified and managed appropriately. surgeries may also be cancelled due to medical reasons. in the current study, 14% of cancellations were due to acute conditions such as uris. a similar rate of uri-related cancellations was reported by palomero rodríguez et al.; however, this decreased from 12.9% in 2001 to 7.2% in 2003 through enhanced communication of simple and appropriate information to parents.8 knox et al. reported a significant reduction in medical-related surgical cancellations after the establishment of a preoperative assessment clinic (p = 0.013).15 the use of preoperative clinics to ensure patients’ fitness before surgery is recommended in oman. currently, patients with known comorbidities are evaluated first by their primary physicians before being referred to pacs. nevertheless, surgeries are inevitably cancelled for medical reasons, for example due to patient noncompliance regarding their medication regimens or the development of respiratory tract infections before surgery. in the current study, ent cases had the highest rate of surgical cancellation according to specialty; this was similar to findings reported by schofield et al.11 although uris may be responsible for cancellations among ent cases, it does not explain why the cancellation rate was so high in comparison with other departments. upon further investigation, it was found that the ent team at the ibri regional hospital intentionally overbooked surgeries to enhance ot utilisation. in terms of the overall rate of surgical cancellations in the current study, the greatest frequency of cancellations was reported from general surgery, followed by ent and orthopaedics. comparable results were reported by chiu et al.4 surprisingly, facility-related cancellations were very low in the current study; other studies have reported facility-related reasons (e.g. previous surgeries running over time and a lack of ot time and bed availability) as the most prevalent causes of cancellations (59.7–73%).4,5 these findings are common in busy hospitals with rapid turnover, long waiting lists or heavy emergency loads. this may also explain the low the burden of surgical cancellations and no-shows quality management study from a large regional hospital in oman e302 | squ medical journal, august 2016, volume 16, issue 3 rate of patient-related surgical cancellations in these hospitals (10–16.2%).4,5 the limited availability of ot time could make patients in busier hospitals more compliant due to increased awareness of the difficulty in rescheduling surgeries. the current study is limited by its retrospective design. additionally, specific reasons for no-shows could not be assessed. further studies are needed from other moh hospitals in oman to increase the reliability of these findings and better understand patient reasons for no-shows. a prospective study at ibri regional hospital is planned to assess the impact of quality improvement activities designed to minimise surgical cancellations. with these limitations in mind, this study assessed for the first time in oman an important worldwide issue in hospital management. hopefully, the results of this study will increase awareness of the burden of surgical cancellations and encourage similar audits to be performed in other hospitals in oman. conclusion a higher rate of surgical cancellations due to no-shows was found in comparison to those reported in the international literature. measures to minimise surgical cancellations are highly recommended, potentially resulting in proper ot utilisation, the conservation of hospital funds and the alleviation of the psychological distress of cancelling and rescheduling surgeries on patients and their families. the results of this study may serve to increase awareness of the burden of surgical cancellation and encourage similar audits in other hospitals in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. macario a, dexter f, traub rd. hospital profitability per hour of operating room time can vary among surgeons. anesth analg 2001; 93:669–75. doi: 10.1097/00000539-20010900000028. 2. tait ar, voepel-lewis t, munro hm, gutstein hb, reynolds pi. cancellation of pediatric outpatient surgery: economic and emotional implications for patients and their families. j clin anesth 1997; 9:213–19. doi: 10.1016/s0952-8180(97)00032-9. 3. laisi j, tohmo h, keränen u. surgery cancelation on the day of surgery in same-day admission in a finnish hospital. scand j surg 2013; 102:204–8. doi: 10.1177/1457496913492626. 4. chiu ch, lee a, chui pt. cancellation of elective operations on the day of intended surgery in a hong kong hospital: point prevalence and reasons. hong kong med j 2012; 18:5–10. 5. garg r, bhalotra ar, bhadoria p, gupta n, anand r. reasons for cancellation of cases on the day of surgery: a prospective study. indian j anaesth 2009; 53:35–9. 6. haana v, sethuraman k, stephens l, rosen h, meara jg. case cancellations on the day of surgery: an investigation in an australian paediatric hospital. anz j surg 2009; 79:636–40. doi: 10.1111/j.1445-2197.2009.05019.x. 7. lacqua mj, evans jt. cancelled elective surgery: an evaluation. am surg 1994; 60:809–11. 8. palomero rodríguez ma, sanabria carretero p, rodriguez pérez e, goldman tarlousky l, nodal ramos a, díaz gonzález c. [upper respiratory tract infections in children: impact on surgical scheduling at a pediatric hospital]. rev esp anestesiol reanim 2005; 52:597–602. 9. sanjay p, dodds a, miller e, arumugam pj, woodward a. cancelled elective operations: an observational study from a district general hospital. j health organ manag 2007; 21:54–8. doi: 10.1108/14777260710732268. 10. argo jl, vick cc, graham la, itani km, bishop mj, hawn mt. elective surgical case cancellation in the veterans health administration system: identifying areas for improvement. am j surg 2009; 198:600–6. doi: 10.1016/j.amjsurg.2009.07.005. 11. schofield wn, rubin gl, piza m, lai yy, sindhusake d, fearnside mr, et al. cancellation of operations on the day of intended surgery at a major australian referral hospital. med j aust 2005; 182:612–15. 12. metropolitan ent & facial plastic surgery. cancellation policy/ no show policy for doctor appointments and surgery. from: www.metropolitanent.com/webdocuments/cancellationpolicy-auth-release.pdf accessed: mar 2016. 13. kumar r, gandhi r. reasons for cancellation of operation on the day of intended surgery in a multidisciplinary 500 bedded hospital. j anaesthesiol clin pharmacol 2012; 28:66–9. doi: 10. 4103/0970-9185.92442. 14. pratap jn, varughese am, mercurio p, lynch t, lonnemann t, ellis a, et al. reducing cancelations on the day of scheduled surgery at a children’s hospital. pediatrics 2015; 135:e1292–9. doi: 10.1542/peds.2014-2418. 15. knox m, myers e, hurley m. the impact of pre-operative assessment clinics on elective surgical case cancellations. surgeon 2009; 7:76–8. doi: 10.1016/s1479-666x(09)80019-x. http://dx.doi.org/10.1097/00000539-200109000-00028 http://dx.doi.org/10.1097/00000539-200109000-00028 http://dx.doi.org/10.1016/s0952-8180%2897%2900032-9 http://dx.doi.org/10.1177/1457496913492626 http://dx.doi.org/10.1111/j.1445-2197.2009.05019.x http://dx.doi.org/10.1108/14777260710732268 http://dx.doi.org/10.1016/j.amjsurg.2009.07.005 http://dx.doi.org/10.4103/0970-9185.92442 http://dx.doi.org/10.4103/0970-9185.92442 http://dx.doi.org/10.1542/peds.2014-2418 http://dx.doi.org/10.1016/s1479-666x%2809%2980019-x brain abscesses are a challenging emergency and any delay in diagnosis or treatment may result in poor health outcomes for affected patients. the incidence of this infectious disease is approximately 0.4–0.9 per 100,000 individuals worldwide, with much higher rates among immunocompromised patients.1 brain abscesses can be caused by bacteria, fungi or parasites.1 aspergillus sp. is an opportunistic ubiquitous fungus that usually enters the body by inhalation of airborne spores; it can then invade the central nervous system (cns) via the haematogenous route, from direct extension through the paranasal sinuses or by direct inoculation during trauma or surgical procedures.2,3 invasive intracranial aspergillosis is unusual, accounting for 10–20% of all cases of invasive aspergillosis.4 most patients with this condition have immune defects, usually in the form of neutrophil or macrophage dysfunction.5,6 invasive intracranial aspergillosis is associated with high morbidity and mortality rates; the latter can be as high as 88% in bone marrow transplant recipients and for those with disseminated or cerebral aspergillosis.2,7,8 cns-invasive aspergillosis may present with meningitis, cerebritis, infarctions, abscesses, granulomas or mycotic aneurysms.9 the exact pathology depends upon the disease pathway and the host’s immunity. the most frequent pathological findings are haemorrhage, infarctions and abscesses.10 rarely, aspergillus infections present as spaceoccupying lesions in immunocompetent patients.3,10 1department of paediatric infectious disease, royal hospital, muscat, oman; departments of 2child health, 3paediatric infectious disease and 4neurosurgery, king faisal specialist hospital & research centre, riyadh, saudi arabia *corresponding author e-mail: nawal.almaskari@gmail.com ارشاشيات فالفس املستحثة للخراج يف دماغ طفل ذو كفاءة مناعية تقرير احلالة نوال امل�سكرية، ابراهيم بن ح�سني، �سليمان جمعه، ع�سام ال�سهيل abstract: intracranial aspergillosis is an extremely rare manifestation of invasive aspergillosis in immunocompetent children and is associated with high morbidity and mortality. we report a 12-year-old immunocompetent male child who was referred to the king faisal specialist hospital & research centre, riyadh, saudi arabia, in may 2010 after a sudden-onset headache and loss of consciousness. brain imaging revealed a large right space-occupying occipital lesion and the patient underwent a craniotomy and resection. histopathology of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes. two days later, a computed tomography scan showed debulking of the fungal mass and the patient was discharged on oral voriconazole. however, imaging at a six-week follow-up showed progression of the abnormality. a residual or persistent fungal brain lesion was suspected. further neurosurgical resection of the lesion was performed and cultures showed growth of aspergillus flavus. the patient was treated successfully with antifungal therapy over the following two years. keywords: brain abscess; fungus disease; aspergillus flavus; antifungal agents; immunocompetence; case report; saudi arabia. وتكون املناعية الكفاءة ذوي الأطفال يف الجتياحية الر�سا�سيات من للغاية نادر مظهر الدماغي القحف داخل الر�سا�سيات امللخ�ص: التخ�س�سي في�سل امللك م�ست�سفى اإىل اأحيل عاما 12 العمر من بالغ طفل باأن نفيدكم مرتفعة. لذلك نتيجة والوفيات العتالل معدلت ومركز الأبحاث يف مايو 2010 حيث اأن املري�س اأ�سيب ب�سداع مفاجئ وفقدان للوعي. ك�سف ت�سوير الدماغ الأمين اآفة قذايل حتتل م�ساحة من العديد مع تقرحي حبيبي فطري دماغ التهاب بوجود امل�ستاأ�سل الن�سيج درا�سة وك�سفت الآفة. ل�ستئ�سال املري�س وخ�سع كبرية اخليوط املحاطة مبن�سجات عمالقة متعددة النوى. بعد يومني، اأظهر امل�سح املقطعي املحو�سب خلو املخ من الكتلة الفطرية وخرج املري�س على دواء فوريكونازول. ومع ذلك، اأظهر الت�سوير املغناطي�سي خالل �ستة اأ�سابيع تطور الفطريات يف الدماغ مرة اأخرى. مت تنفيذ مزيد من البرت لالآفة يف جراحة الأع�ساب واأظهرت زارعة الن�سجه منو فطريات الفالف�س.ومت عالج املري�س بنجاح بالأدوية امل�سادة للفطريات على مدى العامني التاليني. كلمات مفتاحية: خراج الدماغ؛ الأمرا�س الفطرية؛ ار�سا�سيات فالف�س؛ الأدوية امل�سادة للفطريات؛ الكفاءة املناعية؛ تقرير حالة؛ العربية ال�سعودية. aspergillus flavus-induced brain abscess in an immunocompetent child case report *nawal al-maskari,1 ibrahim hussain,2 suleiman jumaa,3 essam a. al-shail4 sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 246–249, epub. 15 may 16 submitted 9 jun 15 revisions req. 26 jul & 27 sep 15; revisions recd. 31 aug & 6 oct 15 accepted 29 oct 15 case report doi: 10.18295/squmj.2016.16.02.019 nawal al-maskari, ibrahim hussain, suleiman jumaa and essam a. al-shail case report | e247 were requested as the lesion was believed to be a tumour. the patient was prescribed daily intravenous liposomal amphotericin b (5 mg/kg/dose). two days after the surgery, a brain ct scan showed debulking of the right-sided occipital fungal mass. the extent of the perilesional reactive changes had regressed with a persistent mild midline shift to the left and regression of the right trigone effacement [figure 1b]. blood assays showed high (1,3)-beta-d-glucan levels (272 picogrammes [pg]/ml; normal range: 0‒60 pg/ml) and non-reactive aspergillus galactomannan. an eye examination, abdominal ultrasound and echocardiogram were unremarkable. the results of an immun ological work-up were normal, including serum immunoglobulin levels, lymphocyte markers, blastogenic response, complement deficiency, oxida-tive burst and polymorphonuclear chemotaxis. a human immunodeficiency virus infection test was negative. the patient was discharged on oral voriconazole (6 mg/kg every 12 hours). at a six-week follow-up appointment, the patient underwent ct and mri scans of the brain which showed a progression of the dense solid marginal tissue abnormality. the enhancement was consistent with a granulomatous tissue abnormality [figure 2a]. a residual or persistent fungal brain lesion was suspected and the patient subsequently underwent surgical exploration with further resection of the lesion. the histopathology remained consistent with that of the first resected brain lesion; however, cultures showed a. flavus growth. oral administration of voriconazole was substituted for intravenous administration (6 mg/kg every 12 hours). two days later, a postoperative ct scan showed a slight nonspecific enhancement in the periphery of the resected area. the patient was discharged with a prescription for oral voriconazole (6 mg/kg every 12 hours). this report describes an invasive aspergillus-induced brain abscess in an immunocompetent patient with no history of trauma. case report a previously healthy 12-year-old male child was referred to the king faisal specialist hospital & research centre, riyadh, saudi arabia, in may 2010 after a sudden-onset headache and loss of consciousness for 15 minutes. he had no convulsions, abnormal movements, eye abnormalities, vision impairment, fever, vomiting or skin rashes. in addition, he had no history of trauma. on examination, the patient was stable and interactive with no obvious neurological deficits. computed tomography (ct) of the brain showed a right occipital space-occupying lesion, suspected to be a tumour. the nasal sinuses were clear. his complete blood count (haemoglobin: 135 g/l; white blood cell count: 6.4 x 109/l; neutrophil count: 2.51 x 109/l; eosinophils: 0.47 x 109/l; platelet count: 333 x 109/l) and erythrocyte sedimentation rate (3 mm/hour) were normal. magnetic resonance imaging (mri) of the brain revealed a large right occipital mass with heterogeneous enhancement and perifocal oedema in the right temporal and parietal lobes. the right occipital horn was compressed and there was a midline shift to the left [figure 1a]. a preoperative diagnosis of a brain tumour was made. the patient underwent a craniotomy and resection of the brain lesion. histopathology examination of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes. no cultures figure 1a&b: a: magnetic resonance imaging of the brain of a 12-year-old immunocompetent child showing a large right occipital mass (arrow) with heterogeneous enhancement, perifocal oedema in the right temporal and parietal lobes and a midline shift to the left. the nasal sinuses were clear. b: post-resection computed tomography showing debulking of the rightsided occipital fungal mass (arrow) two days later. note the regression of the perilesional reactive changes with a persistent mild midline shift to the left and regression of the right trigone effacement. figure 2a&b: a: magnetic resonance imaging (mri) of the brain of a 12-year-old immunocompetent child six weeks after an initial resection of a right occipital fungal mass showing progression of the dense solid marginal tissue abnormality (arrow) and enhancement consistent with a granulomatous tissue abnormality. b: brain mri one month after the second resection showing partial resolution of the solid parenchymal abnormality (arrow). aspergillus flavus-induced brain abscess in an immunocompetent child case report e248 | squ medical journal, may 2016, volume 16, issue 2 in the current case, the patient had invasive cns aspergillosis without paranasal sinus involvement and with no identifiable immune defects. although he had negative aspergillus serum galactomannan antigens, this negative result does not exclude a diagnosis of invasive aspergillosis.13 culture supernatants of a. flavus have demonstrated lower reactivity, with lower galactomannan concentrations.14 negative results could be due to factors related to the host, the assay or the fungus itself. one of the blood investigations which can be used to detect aspergillus is the enzyme-linked immunosorbent assay platelia™ aspergillus eia (bio-rad laboratories, california, usa); this assay is most favourable in patients with haematological malignancies, especially those who have undergone a haematopoietic stem cell transplant and are neutropaenic.15 it is not clear how the patient in the present case developed the brain abscess. although no immune defects were identified, he may nevertheless have been suffering from a rare form of immunodeficiency, such as an interleukin (il)-4 or il-6 deficiency; suppression of monocytes and t helper cells and interferon-gamma (ifn-γ) responses can lead to severe aspergillus infections.13,16 a previous case report has indicated the beneficial role of ifn-γ treatment in combination with antifungal drugs in managing a patient with an a. fumigatus-induced brain abscess.17 conclusion persistent cerebral aspergillus-induced abscesses in immunocompetent patients are extremely rare and the clinical and radiological features of these cases may be similar to primary or secondary neoplasms or other forms of infection. health professionals should therefore be aware of the symptoms of aspergillusinduced brain abscesses, as early detection and appropriate treatment is necessary to ensure positive patient outcomes. references 1. brouwer mc, tunkel ar, mckhann gm 2nd, van de beek d. brain abscess. n engl j med 2014; 371:447–56. doi: 10.1056/ nejmra1301635. 2. chen s, pu jl, yu j, zhang jm. multiple aspergillus cerebellar abscesses in a middle-aged female: case report and literature review. int j med sci 2011; 8:635–9. doi: 10.7150/ijms.8.635. 3. köse s, çavdar g, senger ss, akkoçlu g. central nervous system aspergillosis in an immunocompetent patient. j infect dev ctries 2011; 5:313–15. doi: 10.3855/jidc.1461. 4. wannasirikul v, chayakulkeeree m. multiple brain abscesses caused by aspergillus fumigatus in a patient with systemic lupus erythematous. j infect dis antimicrob agents 2012; 29:17–20. a one-month follow-up mri scan of the patient showed resolution of the solid enhancing parenchymal abnormality [figure 2b]. subsequent mri scans were performed at regular intervals, including four, six, 18 and 24 months after the second resection. after eight months of oral voriconazole treatment, (1,3)-beta-d-glucan levels were undetectable. repeated assays for aspergillus galactomannan also revealed undetectable levels. antifungal treatment was discontinued after two years as there was on-going evidence of the complete resolution of the brain lesion by may 2013. discussion in general, cns aspergillosis—particularly invasive aspergillosis—is rarely observed in immunocompetent patients.2 the brain is remarkably resistant to fungal infections due to its abundant blood supply and the relatively impermeable blood-brain barrier. nevertheless, despite the existence of anatomical and functional barriers which protect the brain and subarachnoid space, fungal pathogens can breach these barriers under certain conditions.2 persistent cerebral aspergillus abscesses in immunocompetent patients may exhibit clinical and radiological features similar to primary or secondary neoplasms or other forms of infection.10 only a few cases of invasive aspergillus brain abscesses have been reported; of these, most involved adult rather than paedia tric patients.11 the management of cerebral fungal abscesses remains controversial. antifungal therapy alone reportedly has a poor outcome for patients with cns aspergillosis, with a high mortality rate of >90%; this is likely due to the poor penetration of the cns by the antifungal drugs.2 other research has indicated that surgical resection of focal cns aspergillosis lesions reduces the mortality rate from 64% to 39%.2 overall, voriconazole seems to be the drug of choice for the treatment of aspergillosis.2 in the current case, the patient showed clinical and radiological improvement with intravenous voriconazole administration and surgical resection. however, imaging scans at a six-week follow-up revealed that the lesion had progressed despite the continued administration of oral voriconazole; this is unusual due to the high bioavailability level (82.6%) of oral voriconazole.12 this uncommon occurrence may have been due to poor medication compliance on the part of the patient or incomplete resection which resulted in the slow progression of the remnant lesion. unfortunately, no facilities were available to monitor the patient’s exact voriconazole drug levels. http://dx.doi.org/10.1056/nejmra1301635 http://dx.doi.org/10.1056/nejmra1301635 http://dx.doi.org/10.7150/ijms.8.635 http://dx.doi.org/10.3855/jidc.1461 nawal al-maskari, ibrahim hussain, suleiman jumaa and essam a. al-shail case report | e249 5. sundaram c, murthy jm. intracranial aspergillus granuloma. patholog res int 2011; 2011:157320. doi: 10.4061/2011/157320. 6. andrews t, sullivan ke. infections in patients with inherited defects in phagocytic function. clin microbiol rev 2003; 16:597–621. doi: 10.1128/cmr.16.4.597-621.2003. 7. mohindra s, mukherjee kk, chhabra r, gupta sk, gupta r, kosla vk. invasive intracranial aspergillosis: the management dilemmas. surg neurol 2008; 69:496–505. doi: 10.1016/j. surneu.2007.03.025. 8. shamim ms, enam sa, ali r, anwar s. craniocerebral aspergillosis: a review of advances in diagnosis and management. j pak med assoc 2010; 60:573–9. 9. shuper a, levitsky hi, cornblath dr. early invasive cns aspergillosis: an easily missed diagnosis. neuroradiology 1991; 33:183–5. doi: 10.1007/bf00588266. 10. sidani c, freiser me, saigal g, sklar e. unusual case of cerebral aspergillosis with clinical and imaging findings mimicking lymphoma. neuroradiol j 2013; 26:290–6. doi: 10.1177/197140091302600306. 11. dotis j, iosifidis e, roilides e. central nervous system aspergillosis in children: a systematic review of reported cases. int j infect dis 2007; 11:381–93. doi: 10.1016/j.ijid.2007.01.013. 12. scholz i, oberwittler h, riedel kd, burhenne j, weiss j, haefeli we, et al. pharmacokinetics, metabolism and bioavail ability of the triazole antifungal agent voriconazole in relation to cyp2c19 genotype. br j clin pharmacol 2009; 68:906–15. doi: 10.1111/j.1365-2125.2009.03534.x. 13. cenci e, mencacci a, casagrande a, mosci p, bistoni f, romani l. impaired antifungal effector activity but not inflammatory cell recruitment in interleukin-6-deficient mice with invasive pulmonary aspergillosis. j infect dis 2001; 184:610–17. doi: 10.1086 /322793. 14. verweija pe, mennink-kerstena ma. issues with galactomannan testing. med mycol 2006; 44:179–83. doi: 10.1080/1369 3780600904918. 15. dutkiewicz r, hage ca. aspergillus infections in the critically ill. proc am thorac soc 2010; 7:204–9. doi: 10.1513/ pats.200906-050al. 16. monneret g, venet f, kullberg bj, netea mg. icuacquired immunosuppression and the risk for secondary fungal infections. med mycol 2011; 49:s17–23. doi: 10.3109 /13693786.2010.509744. 17. saulsbury ft. successful treatment of aspergillus brain abscess with itraconazole and interferon-gamma in a patient with chronic granulomatous disease. clin infect dis 2001; 32:e137–9. doi: 10.1086/320158. http://dx.doi.org/10.4061/2011/157320 http://dx.doi.org/10.1128/cmr.16.4.597-621.2003 http://dx.doi.org/10.1016/j.surneu.2007.03.025 http://dx.doi.org/10.1016/j.surneu.2007.03.025 http://dx.doi.org/10.1007/bf00588266 http://dx.doi.org/10.1177/197140091302600306 http://dx.doi.org/10.1177/197140091302600306 http://dx.doi.org/10.1016/j.ijid.2007.01.013 http://dx.doi.org/10.1111/j.1365-2125.2009.03534.x http://dx.doi.org/10.1086/322793 http://dx.doi.org/10.1086/322793 http://dx.doi.org/10.1080/13693780600904918 http://dx.doi.org/10.1080/13693780600904918 http://dx.doi.org/10.1513/pats.200906-050al http://dx.doi.org/10.1513/pats.200906-050al http://dx.doi.org/10.3109/13693786.2010.509744 http://dx.doi.org/10.3109/13693786.2010.509744 http://dx.doi.org/10.1086/320158 التحديات العالجية والسريرية يف عالج مرضى حب الشباب اأنور احلمداين، عبلة الإ�سماعلية، �سمري العلي، راجي�س رامادوراي، ري�سى جني، لني ماكنلي جرانت، طارق موجال abstract: acne vulgaris is one of the most common chronic inflammatory skin disorders among adolescents and young adults. it is associated with substantial morbidity and, rarely, with mortality. the exact worldwide incidence and prevalence are currently unknown. current challenges involve improving understanding of the underlying pathophysiology of acne vulgaris and developing a practical treatment consensus. expert panel discussions were held in 2013 and 2014 among a group of scientists and clinicians from the omani and united arab emirate dermatology societies to ascertain the current optimal management of acne vulgaris, identify clinically relevant end-points and construct suitable methodology for future clinical trial designs. this article reviews the discussions of these sessions and recent literature on this topic. keywords: acne vulgaris; molecular biology; diagnosis; therapeutics; benzoyl peroxide; retinoids; isotretinoin; antibiotics. امللخ�ص: حب ال�سباب هو اأحد اأمرا�س األتهابات اجللد املزمنة الأكرث �سيوعا بني املراهقني وال�سباب. وله اأرتباط بالإ�سابة بالأمرا�س ونادرا ما يوؤدى اإىل الوفيات. املعدل العاملي لالإ�سابة والأنت�سار غري معروف حاليا. التحديات الراهنة ت�سمل حت�سني فهم الفيزيولوجيا املر�سية حلب ال�سباب والعمل على تطوير عالج عملي مبني على توافق الأراء. ويف اللقاء بني اخلرباء الذي عقد يف 2013 و 2014 بني جمموعة من الأخت�سا�سيني والأطباء من جمعيات اأمرا�س اجللد يف �سلطنة عمان ودولة الأمارات العربية املتحدة دارت نقا�سات للتاأكد من طرق العالج الأمثل حلب ال�سباب، حتديد نقطة النهاية ذات ال�سلة ال�رسيرية وبناء منهجية منا�سبة لت�سميم التجارب ال�رسيرية يف امل�ستقبل. ي�ستعر�س هذا املقال مناق�سات هذة اجلل�سات والدرا�سات احلديثة املن�سورة حول هذا املو�سوع. امل�سادات ايزوتريتينوين؛ الرتينويدات؛ بريوك�سايد؛ بنزويل العالجات؛ الت�سخي�س؛ اجلزيئية؛ البيولوجيا ال�سباب؛ حب مفتاحية: كلمات احليوية. topical, biological and clinical challenges in the management of patients with acne vulgaris anwar al-hammadi,1 abla al-ismaily,2 sameer al-ali,3 rajesh ramadurai,4 rishi jain,4 lynn mckinley-grant,5 *tariq i. mughal6 review sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 152–160, epub. 15 may 16 submitted 27 sep 14 revisions req. 19 nov 14 & 5 jul 15; revisions recd. 2 jul 15 & 17 jan 16 accepted 18 jan 16 doi: 10.18295/squmj.2016.16.02.004 acne vulgaris is a common chronic inflammatory disorder of the pilosebaceous unit among adolescents and young adults.1 it is associated with substantial morbidity and sometimes mortality due to associated disorders.2 the term acne was introduced by the greek philosopher celsus in the second century c.e. to describe the presence of pustules/papules on the skin, although the ancient roman physician pliny had previously used the word ‘varus’ to describe similar pustules.3 the condition is part of a heterogeneous group of skin disorders, the precise aetiology of which is unknown; however, several potential aggravating factors have been identified.4 the main feature is a chronic process leading to excessive sebum production (seborrhoea), altered keratinisation and bacterial colonisation by propionibacterium acnes within the pilosebaceous units or hair follicles.4 the natural history is that of a non-inflammatory process, resulting in open and closed comedones and widespread inflammatory lesions including papules, pustules [figure 1], nodules, cysts and scarring.1 these lesions can evolve rapidly in some patients and are likely androgen-induced.2 the current challenge in treating acne vulgaris is improving the understanding of its precise underlying cellular and molecular biology, identifying any potential candidate trigger factors and developing treatment guidelines within a regional and demographic context. the latter concept is of particular interest in view of several recent reports suggestive of diverse causal factors, such as seasonal variations, unique dietary and ethnic factors and comorbidities.5,6 other factors which need to be addressed include the precise methods and timing of treatment and which strategies 1department of dermatology, rashid hospital, dubai, united arab emirates; 2department of dermatology, al nahdha hospital, muscat, oman; 3department of dermatology, abu dhabi dermatology clinic, abu dhabi, united arab emirates; 4department of clinical & medical affairs, glenmark pharmaceuticals private ltd., mumbai, india; 5department of dermatology, george washington university hospital, washington d.c., usa; 6department of hematology & oncology, tufts university medical center, boston, massachusetts, usa *corresponding author e-mails: tmughal911@hotmail.com and tmughal@tuftsmedicalcenter.org anwar al-hammadi, abla al-ismaily, sameer al-ali, rajesh ramadurai, rishi jain, lynn mckinley-grant and tariq i. mughal review | e153 yield optimal longand short-term clinical outcomes. little, if any, high-quality evidence exists to support the effectiveness and safety of many existing therapies, particularly topical therapies. evidently, new research is urgently required to better understand the biology and treatment of acne. recent efforts have also identified potential genetic and molecular abnormalities; concepts of how best to integrate such advances into treatment algorithms will also therefore need to be addressed.7,8 in addition, new research is needed to assess the comparative therapeutic effectiveness and safety of the many available medications for acne treatment, determine the best preventive strategies and investigate the natural history, subtypes and triggers of this condition. this review seeks to clarify some of these challenges and the natural history of treatment in order to help improve clinical outcomes for patients with acne vulgaris. an international panel of scientific and clinical experts was formed under the aegis of the united arab emirates (uae) and omani dermatology societies to review current knowledge regarding the biology and diagnosis of acne vulgaris and novel therapeutic approaches. an independent panel convened on 11 october 2013 in dubai, uae, 12 october 2013 in muscat, oman, and on 16 september 2014 in dubai. this review reflects the results of these discussions as well as information collected from literatures searches on the medline, google scholar and cochrane library databases using the terms acne and acne vulgaris. epidemiology the precise worldwide incidence and prevalence of acne vulgaris is currently unknown; this is unusual given that it is considered a common disease globally. hospital-based dermatology registries in the usa suggest that approximately 40–50 million people and 80% of adolescents and young adults are affected by this condition.9 in the uk, recent estimates suggest that acne accounts for more than 3.5 million annual visits to general practioners.10 a kuwaiti study assessing over 3,700 patients with skin disorders indicated that approximately 75% of the study cohort had non-infectious disorders compared to 25% with infection-related skin ailments; the researchers found that acne was the second most common skin disorder (9.41%) after atopic dermatitis (11.07%).11 a saudi arabian study revealed similar findings in a cohort of 3,051 patients with skin disorders.12 further research from saudi arabia confirmed that acne vulgaris was a common dermatological condition, accounting for 20–30% of all skin disorders.13 in the uae, acne vulgaris anecdotally comprises 30% of all chronic skin conditions; other research has indicated that this condition is the cause of 9% of all dermatology outpatient visits.14–16 acne vulgaris appears to affect more pubescent boys than girls; in contrast, when the disorder affects adults, more women than men appear to be affected.4 a western study among arab americans reported a peak incidence of acne vulgaris occurring figure 1: photograph of a young female patient with moderate to severe acne vulgaris with pustular formation. topical, biological and clinical challenges in the management of patients with acne vulgaris e154 | squ medical journal, may 2016, volume 16, issue 2 in adolescents at puberty.17 an iranian communitybased study involving individuals aged 12–20 years old reported an overall acne prevalence of 93.2%; the prevalence was higher in females, with a female-tomale ratio of 1:0.4.18 the researchers speculated that this ratio perhaps reflected gender-based perceptions of overall body image, with females more likely to seek dermatological assessment than adolescent boys.18 acne can have profound psychosocial effects as well as result in permanent skin scarring;19 these can act as a motivation for acne patients to seek medical attention. a recent syrian study found that the prevalence of acne increased with body mass index.20 pathophysiology the precise pathogenesis of acne vulgaris has remained enigmatic, although overproduction of sebum, altered keratinisation and bacterial colonisation by p. acnes within the pilosebaceous units are generally agreed upon as causal factors.4 the significant role of androgens is also recognised.2 the gram-positive bacterium p. acnes, which is part of the normal skin microbiome, is present in the pilosebaceous units and uses lipid-rich sebum as a nutrient source; its growth is therefore increased in the presence of acne-associated excessive sebum production.21 lipid-rich sebum is hydrophobic in nature and it facilitates lubrication and protection of the skin while p. acnes hydrolyses triglycerides in the sebum, causing the release of free fatty acids which increase the chance of bacterial adherence. the potential association of demodex mites and acne vulgaris has been speculated upon, but definitive evidence remains elusive.9 i n f l a m m at o r y fa c t o r s agak et al. suggested that p. acnes plays an important role in eliciting an inflammatory response by activating inflammasomes, which in turn results in the production of interleukin (il)-1β and other inflammatory cytokines.22 p. acnes was a potent inducer of t helper (th) 17 and th1; however, it did not induce th2 responses in human peripheral blood mononuclear cells. in addition, p. acnes was found to stimulate the expression of key th17-related genes, including il-17a, retinoid-related orphan receptor (ror) α, ror c, il-17a receptor and il-17c receptor, as well as trigger il-17 secretion from cluster of differentiation (cd) 4+ cells, but not from cd8+ t cells.22 agak et al. also noted that the combination of il-1β, il-6 and transforming growth factor-βneutralising antibodies completely inhibited p. acnesinduced il-17 production.22 this is of considerable interest since il-17-expressing cells were present in skin biopsies from patients with acne vulgaris but not in healthy controls. furthermore, it was observed that all-trans-retinoic acid and 1,25-dihydroxyvitamin d3 inhibits p. acnes-induced th17 differentiation. 22 collectively, these observations support the notion of using both retinoids and 1,25-dihydroxyvitamin d3 in inhibiting the above inflammatory cascades. kistowska et al. also confirmed the idea that p. acnes activates inflammasomes, resulting in the production of il-1β.23 the investigators were able to decipher the underlying mechanisms which contribute to the inflammatory lesions in acne by demonstrating that il-1β messenger ribonucleic acid and the active processed form of il-1β are abundant in these lesions in a murine model. they hypothesised that p. acnes activates the monocytemacrophage nucleotide-binding domain leucine-rich repeat family pyrin domain containing-3 (nlrp3) inflammasome and activates a cascade reaction involving il-1β processing, lysosomal destabilisation, reactive oxygen species and cellular potassium efflux.23 if confirmed independently, the nlrp3 inflammasome and il-1β appear to be candidate therapeutic targets for acne treatment. g e n o m i c l a n d s c a p e a recent genomic analysis of over 1,000 chinese patients with severe acne vulgaris revealed two new genetic factors that could potentially play a role in the pathogenesis of this condition.7 the study found that two genetic loci—11p11.2 (for the damage-specific dna binding protein 2 gene) and 1q24.2 (for the selectin l gene)—were involved in androgen metabolism, inflammation processes and scar formation.7 yaykasli et al. recently demonstrated the importance of extracellular matrix remodelling, which is regulated by matrix metalloproteinases and tissue inhibitors of metalloproteins (timp), in the pathogenesis of acne vulgaris.24 the investigators analysed polymorphisms in 85 patients with acne vulgaris and noted that the timp-2 (-418 g>c) genotype was twice as prevalent in the study cohort in comparison to normal controls.24 f u t u r e r e s e a r c h recently, there has been interest expressed in other molecular abnormalities, such as toll-like receptor 2 (tlr2) activation and comedogenesis. selway et al. observed the expression of tlr2 in basal and infundibular keratinocytes and sebaceous glands and determined that tlr2 activation led to the release of il-1α from primary human keratinocytes.8 in addition, selway et al. suggested that the release of il-1α from infundibular keratinocytes in response to p. acnesanwar al-hammadi, abla al-ismaily, sameer al-ali, rajesh ramadurai, rishi jain, lynn mckinley-grant and tariq i. mughal review | e155 mediated tlr2 activation could be the initiating steps in comedogenesis and acne formation.8 additionally, il-1α may cause sebaceous hypercornification, a feature of acne.8 increased fibroblast growth factor receptor-2 (fgfr2) signalling has been proposed in the pathogenesis of acne and related disorders, following initial observations in patients with apert syndrome and acneiform nevus with a gain-of-function mutation in the fgfr2 gene.25,26 furthermore, several studies have provided in vitro evidence of many anti-acne agents, including benzoyl peroxide (bpo), antiandrogens and retinoids, attenuating fgfr2 signal transduction in murine models.27,28 collectively, these inflammatory, genetic and molecular findings are of considerable interest and may pave the way to the identification of candidate pathways and targets for acne vulgaris treatment (e.g. nlrp3 inflammasomes and il-1β) in future clinical trials. clinical features most acne patients present with localised lesions on the face, neck [figure 2] and truncal areas. however, acne vulgaris can affect all areas of the body except the palms of the hands and soles of the feet, as these regions do not have sebaceous glands. even ocular areas can be involved; the meibomian glands (also known as tarsal glands) are sebaceous and produce the lipid layer of tears. additionally, with severe acne vulgaris, in particular the nodulocystic type, pilosebaceous units on the eyelids may sometimes produce ocular symptoms.4,29 a range of diverse factors have been found to clinically impact acne vulgaris, including stress levels, diet and even seasonal variation; these factors might be affected by prevailing regional geographical and cultural elements and therefore merit further study and validation.5,6 additionally, there appears to be some causal evidence supporting a link between acne and hyperglycaemic diets, certain dairy products and refined sugars.5 there is little doubt that acne vulgaris results in significant morbidity, in particular with regards to its impact on quality of life (qol). however, this condition can also result in mortality by affecting self-esteem and increasing the risk of suicide, particularly in cases of severe acne.30 severe acne appears to be more prevalent in older age and among females, caucasians and those with a higher socioeconomic status.4 studies from iran and saudi arabia have confirmed the symptom burden associated with severe acne vulgaris.19,31,32 research has demonstrated an association between severe acne and several other conditions, ranging from sinopulmonary to gastrointestinal and psychological comorbidities; the latter includes depression, insomnia and attention deficit and hyperactivity disorders.33 scarring is a serious complication of acne vulgaris and occurs commonly despite the high availability of acne treatment options. the scars occur due to skin damage during the healing process. acne scars are often atrophic and are sometimes accompanied by hyperpigmentation; they can therefore have considerable psychological impact, often affecting qol.34 these observations indicate the importance figure 2: photograph of a young female patient with moderate acne vulgaris. topical, biological and clinical challenges in the management of patients with acne vulgaris e156 | squ medical journal, may 2016, volume 16, issue 2 of multidisciplinary assessment for acne patients, preferably by a team which includes dermatologists, psychologists and psychiatrists. clinical management in the absence of well-defined aetiological factors, the principle objective for optimal clinical management of acne vulgaris is to identify potential precipitating and/or aggravating factors and to prevent significant associated morbidities.2 additionally, it is important to prevent new acneiform lesions and associated scarring and hyperpigmentation [figure 3]. most experts advocate the use of a stepwise treatment algorithm in accordance with the severity of the disorder, typically combining non-pharmacological and pharmacological agents concomitantly with counselling and support.9,10 topical agents, including bpo, retinoids, azelaic acid and antibiotics are used to control mild to moderate acne. systemic therapy, such as oral antibiotics and oral retinoids, tend to be reserved for patients with severe acne; they are often combined with bpo or topical retinoids such as adapalene and tretinoin. although there are a lack of randomised trials comparing topical versus oral treatments, several consensusbased recommendations and treatment algorithms are available.1 figure 4 depicts a potential treatment flowchart for adult patients with mild, moderate or severe acne. t o p i c a l t h e r a p i e s for topical therapy, most specialists tend to use bpo or adapalene, a third-generation topical retinoid, or a combination of the two for the treatment of mild to moderate acne. first introduced in 1934 for the treatment of papulopustular acne, bpo appears to have diverse mechanisms of action, including antibacterial mechanisms by virtue of its oxidative effect and sebostatic and comedolytic properties.2,4 bpo is effective, rapid and substantially reduces p. acnes colonies while also reducing the risk of resistance when used in combination with topical antibiotics.35 adapalene has been in clinical use for over two decades; research has confirmed its efficacy figure 3: photograph of a young female patient with post-acne vulgaris hyperpigmentation and scarring. figure 4: flowchart detailing a potential treatment algorithm for patients with mild, moderate or severe forms of acne vulgaris. anwar al-hammadi, abla al-ismaily, sameer al-ali, rajesh ramadurai, rishi jain, lynn mckinley-grant and tariq i. mughal review | e157 and safety, both as a monotherapy and when combined with topical antibiotics.36 both tretinion and adapalene are anti-inflammatory agents; however, adapalene works by inhibiting keratinocyte differentiation and comedone formation. topical antibiotics are known to inhibit p. acnes and reduce inflammation.4 azelaic acid appears to have antimicrobial and anticomedonal properties.37 in addition, it can cause hypopigmentation which might help patients to counteract any post-inflammatory hyperpigmentation. other topical agents include salicylic acid, which is also an exfoliant, and dapsone. there is some evidence supporting the use of combinations of topical treatments with different mechanisms of action.37‒39 both bpo and adapalene are available in a variety of strengths. although the efficacy is generally similar, higher concentrations are often associated with increased side-effects, such as skin peeling and irritation.40 a fixed-dose combination of 0.1% adapalene and 2.5% bpo is also available.36 in addition to topical bpo and adapalene, the treatment guidelines of the american academy of dermatology (aad) also recommend topical antibacterials, such as erythromycin and clindamycin.41 evidence from several randomised studies supports the use of a combination of topical antibacterial and bpo therapy.37‒39 in a double-blind controlled study involving 378 patients, dréno et al. demonstrated the clinical benefit of combining adaplene or bpo with lymecycline in comparison to treatment with bpo and a placebo.37 a turkish clinical trial among young adults with mild to moderate facial acne vulgaris found that combination 5% bpo lotion was significantly more effective in the reduction of inflammatory lesions compared with 1% nadifloxacin cream alone.38 furthermore, it has been shown that combination therapy is also more effective in preventing relapse compared to monotherapy.39 currently, most specialists advocate the use of 0.02–0.05% topical retinoids on all affected areas for mild to moderate forms of acne.42 o r a l t h e r a p i e s oral retinoids, in particular isotretinoin, reduce the size of the sebaceous glands and reduce sebum production which helps to normalise follicular epithelial desquamation; topical retinoids also appear to have these characteristics, although to a lesser degree.4 according to the current aad guidelines, both topical and oral formulations have a strong evidence-based recommendation (category ia).41 in general, most patients appear to achieve longer-term positive responses with both formulations.40 oral retinoids are generally reserved for more severe forms of acne or for patients who are resistant/refractory to conventional therapy, regardless of severity. while side-effects—including skin irritation and peeling— are common, these effects are usually mild and easily managed.43 retinoids are rarely associated with other potentially serious adverse side-effects, such as psychiatric issues and, in particular, depressive illnesses.4,43 the association between psychiatric issues and retinoids is challenging to address since such side-effects are often already present among patients with acne vulgaris, especially those with moderate or severe forms.30–32 a study from the uae found that oral isotretinoin was effective in improving psychiatric comorbidities and body image among adolescents and young adults with severe acne.44 another study noted that certain patients undergoing oral isotretinoin therapy sometimes demonstrated abnormalities in liver function tests and serum lipids, especially lowdensity lipoproteins and triglycerides; however, this was generally reversible upon discontinuation of the therapy.45 oral antibiotics, such as tetracyclines, erythromycin and clindamycin, are often utilised as part of a combination regimen for patients with severe acne, particularly in the presence of inflammatory lesions.46–48 antimicrobials should be discontinued once the inflammatory lesions abate and other treatments, such as topical agents, should be used as maintenance therapy thereafter. while antibiotics are generally well-tolerated, they are occasionally associated with severe adverse events.40 there appears to be no important difference in the efficacy of the choice or dose of antibiotics; the decision is often based on patient preference, cost and side-effect profile.44,45 however, there is considerable concern regarding antibiotic resistance; as such, their use for extended periods should be avoided.49,50 concomitant bpo use helps to reduce the risk of resistance, possibly by eliminating resistant bacteria.4,40 h o r m o n a l a n d o p t i c a l t h e r a p i e s combined oral oestrogen and progesterone hormonal therapy is sometimes used as an adjunctive therapy for women with moderate to severe acne who also need oral contraception.4 oestrogen helps to suppress sebaceous gland activity in addition to suppressing androgen synthesis; in contrast, progesterone, if used alone, can worsen acne.4 optical treatments, particularly fractionated laser and photodynamic therapies, and selective photothermolysis can be useful in improving post-acne scarring; however, formal comparative studies have not yet been conducted.51,52 topical, biological and clinical challenges in the management of patients with acne vulgaris e158 | squ medical journal, may 2016, volume 16, issue 2 c h a l l e n g e s i n m a n a g e m e n t additional challenges in management include determining the definitive timing of topical acne treatments and optimal management of post-acne scarring and hyperpigmentation as well as maintaining patient adherence to treatment.53 the time taken between the initiation of topical therapy and clinicallyrelevant improvement is an important factor. in a systematic review on acne treatment, jacobs et al. noted that different concentrations of bpo and adapalene did not seem to influence the time taken for resolution of inflammatory lesions; however, both agents produced earlier responses when compared to retinoids, particularly isotretinoin.54 in addition, combined clindamycin and bpo produced faster responses in comparison to adapalene alone.54 it is therefore necessary for clinicians to offer longerterm management plans in order to be sure that the treatments are successful in resolving the acne. the management of acne in pregnant women is challenging largely due to the potential teratogenicity associated with retinoids, which considerably limits treatment options for patients with moderate to severe acne.55,56 women of childbearing age with acne should therefore be counselled and offered effective contraception before beginning treatment. most specialists tend to use non-retinoid topical agents and add azelaic acid in an effort to improve efficacy and, more specifically, to help reduce the post-acneassociated hyperpigmentation. conclusion acne vulgaris is a chronic inflammatory disorder which occurs worldwide. various effective and welltolerated options are available for the management of acne vulgaris, although none are optimal. for the management of mild to moderate acne, evidencebased guidelines advocate topical therapies, in particular bpo or adapalene, sometimes combined with antibiotics. patients with severe acne can benefit from oral tretinoin; however, the drug is associated with potentially challenging side-effects. it is important for clinicians to recognise acne as a potentially serious medical condition and offer prompt management, appropriate counselling and support when indicated. the importance of a longer-term multi-disciplinary management plan in order to evoke a response to treatment should be emphasised. in addition, new clinical research is needed to assess the comparative effectiveness and safety of the many treatments available and the impact of patient compliance. further research regarding the natural history, subtypes and triggers of acne is also required. a c k n o w l e d g e m e n t s the excellence in dermatology global initiative (edge) continuing medical education programme in dubai was chaired by anwar al-hammadi and included sameer al-ali, salah al-azawi, hanish babu, vidya kharkar, lynn mckinley-grant, tariq mughal and mohammed salah as faculty members. the edge continuing medical education programme in muscat was chaired by abla al-ismaily and included fatima al-balushi, abdullah al-taie, damodar bandodkar, lynn mckinley-grant and tariq mughal as faculty members. the authors would like to thank the global webrx team for their assistance with the programme logistics. in addition, the authors are grateful to glenmark pharmaceuticals private ltd., india, for funding the project. c o n f l i c t o f i n t e r e s t rajesh ramadurai and rishi jain were employees of glenmark pharmaceuticals private ltd. until early 2016. the other authors declare no conflicts of interest. references 1. knutsen-larson s, dawson al, dunnick ca, dellavalle rp. acne vulgaris: pathogenesis, treatment, and needs assessment. dermatol clin 2012; 30:99–106. doi: 10.1016/j.det.2011.09.001. 2. fisk wa, lev-tov ha, sivamani rk. epidemiology and management of acne in adult women. curr dermatol rep 2014; 3:29–39. doi: 10.1007/s13671-014-0071-4. 3. grant rn. the history of acne. proc r soc med 1951; 44:647–52. 4. williams hc, dellavalle rp, garner s. acne vulgaris. lancet 2012; 379:361–72. doi: 10.1016/s0140-6736(11)60321-8. 5. aksu ae, metintas s, saracoglu zn, gurel g, sabuncu i, arikan i, et al. acne: prevalence and relationship with dietary habits in eskisehir, turkey. j eur acad dermatol venereol 2012; 26:1503–9. doi: 10.1111/j.1468-3083.2011.04329.x. 6. veith wb, silverberg nb. the association of acne vulgaris with diet. cutis 2011; 8:84–91. 7. he l, wu wj, yang jk, cheng h, zuo xb, lai w, et al. two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne. nat commun 2014; 5:2870. doi: 10.1038/ncomms3870. 8. selway jl, kurczab t, kealey t, langlands k. toll-like receptor 2 activation and comedogenesis: implications for the pathogenesis of acne. bmc dermatol 2013; 13:10 doi: 10.1186/1471-5945-13-10. 9. bhate k, williams hc. what’s new in acne? an analysis of systematic reviews published 2011-2012. clin exp dermatol 2014; 39:273–7. doi: 10.1111/ced.12270. 10. dawson al, dellavalle rp. acne vulgaris. bmj 2013; 346:f2634. doi: 10.1136/bmj.f2634. 11. al-mutairi n, zaki a, shiltawi m, manchanda y, nouridin o, sharma ak. pattern of skin diseases in farwaniya region in kuwait. gulf j dermatol 2004; 11:5–13. http://dx.doi.org/10.1016/j.det.2011.09.001 http://dx.doi.org/10.1007/s13671-014-0071-4 http://dx.doi.org/10.1016/s0140-6736%2811%2960321-8 http://dx.doi.org/10.1111/j.1468-3083.2011.04329.x http://dx.doi.org/10.1038/ncomms3870 http://dx.doi.org/10.1186/1471-5945-13-10 http://dx.doi.org/10.1111/ced.12270 http://dx.doi.org/10.1136/bmj.f2634 anwar al-hammadi, abla al-ismaily, sameer al-ali, rajesh ramadurai, rishi jain, lynn mckinley-grant and tariq i. mughal review | e159 12. al shobaili ha. the pattern of skin diseases in the qassim region of saudi arabia: what the primary care physician should know. ann saudi med 2010; 30:448–53. doi: 10.4103/02564947.72263. 13. al-ameer am, al-akloby om. demographic features and seasonal variations in patients with acne vulgaris in saudi arabia: a hospital-based study. int j dermatol 2002; 41:870–1. doi: 10.1046/j.1365-4362.2002.01669.x. 14. al-hammadi a. personal communication, 2013. 15. abu shareeah am. united arab emirates. in: parish lc, millikan le, global dermatology: diagnosis and management according to geography, climate, and culture. new york, usa: springer-verlag, 1994. pp. 301–5. 16. abu share’ah am, abdel dayem h. the incidence of skin diseases in abu dhabi (united arab emirates). int j dermatol 1991; 30:121–4. 17. el-essawi d, musial jl, hammad a, lim hw. a survey of skin disease and skin-related issues in arab americans. j am acad dermatol 2007; 56:933–8. doi: 10.1016/j.jaad.2007.01.031. 18. ghodsi sz, orawa h, zouboulis cc. prevalence, severity, and severity risk factors of acne in high school pupils: a communitybased study. j invest dermatol 2009; 129:2136–41. doi: 10.1038/ jid.2009.47. 19. ismail kh, mohmmed-ali kb. quality of life in patients with acne in erbil city. health qual life outcomes 2012; 10:60. doi: 10.1186/1477-7525-10-60. 20. al-kubaisy w, abdullah nn, kahn sm, zia m. sociodemographic characteristics of acne among university students in damascus, syria. epidemiol res int 2014; 2014:974019. doi: 10.1155/2014/974019. 21. marples rr, downing dt, kligman am. control of free fatty acids in human surface lipids by corynebacterium acnes. j invest dermatol 1971; 56:127–31. doi: 10.1111/1523-1747. ep12260695. 22. agak gw, qin m, nobe j, kim mh, krutzik sr, tristan gr, et al. propionibacterium acnes induces an il-17 response in acne vulgaris that is regulated by vitamin a and vitamin d. j invest dermatol 2014; 134:366–73. doi: 10.1038/jid.2013.334. 23. kistowska m, gehrke s, jankovic d, kerl k, fettelschoss a, feldmeyer l, et al. il-1β drives inflammatory responses to propionibacterium acnes in vitro and in vivo. j invest dermatol 2014; 134:677–85. doi: 10.1038/jid.2013.438. 24. yaykasli ko, turan h, kaya e, hatipoglu of. polymorphisms in the promoters of mmp-2 and timp-2 genes in patients with acne vulgaris. int j clin exp med 2013; 6:967–72. 25. melnik bc, schmitz g, zouboulis cc. anti-acne agents attenuates fgfr2 signal transduction in acne. j invest dermatol 2009; 129:1868–77. doi: 10.1038/jid.2009.8. 26. benjamin lt, trowers ab, schachner la. successful acne treatment in apert syndrome twins. pediatr dermatol 2005; 22:561–5. doi: 10.1111/j.1525-1470.2005.00141.x. 27. belleudi f, leone l, nobili v, raffa s, francesganceli f, maggio m, et al. keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways. traffic 2007; 8:1854–72. doi: 10.1111/j.1600-0854.2007.00651.x. 28. pu y, huang l, birch l, prins gs. androgen regulation of prostate morphoregulatory gene expression: fgf10-dependent and -independent pathways. endocrinology 2007; 148:1697–706. doi: 10.1210/en.2006-1113. 29. ozdemir m, ozdemir g, sasmaz s, arican o. ocular surface disorders and tear function changes in nodulo-cystic acne. j dermatol 2005; 32:174–8. doi: 10.1111/j.1346-8138.2005. tb00740.x. 30. silverberg ji, silverberg nb. epidemiology and extracutaneous comorbidities of severe acne in adolescence: a u.s. populationbased study. br j dermatol 2014; 170:1136‒42. doi: 10.1111/ bjd.12912. 31. al mashat s, al sharif n, zimmo s. acne awareness and perception among population in jeddah, saudi arabia. j saudi soc dermatol dermatol surg 2013; 17:47–9. doi: 10.1016/j. jssdds.2013.05.003. 32. golchai j, khani sh, heidarzadeh a, eshkevari ss, alizade n, eftekhari h. comparison of anxiety and depression in patients with acne vulgaris and healthy individuals. indian j dermatol 2010; 55:352–4. doi: 10.4103/0019-5154.74539. 33. gollnick hp. from new findings in acne pathogenesis to new approaches in treatment. j eur acad dermatol venereol 2015; 29:1–7. doi: 10.1111/jdv.13186. 34. al ameer am, al akioby om, al omran it. acne scarring and its incidence in saudi arabia (a clinical evaluation study). gulf j dermatol 2003; 10:23. 35. strauss js, krowchuk dp, leyden jj, lucky aw, shalita ar, siegfried ec, et al. guidelines of care for acne vulgaris management. j am acad dermatol 2007; 56:651–63. doi: 10. 1016/j.jaad.2006.08.048. 36. thiboutot dm, weiss j, bucko a, eichenfield l, jones t, clark s, et al. adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. j am acad dermatol 2007; 57:791–9. doi: 10.1016/j.jaad.2007.06.006. 37. dréno b, kaufmann r, talarico s, torres lozada v, rodríguezcastellanos ma, gómez-flores m, et al. combination therapy with adapalene-benzoyl peroxide and oral lymecycline in the treatment of moderate to severe acne vulgaris: a multicentre, randomized, double-blind controlled study. br j dermatol 2011; 165:383–90. doi: 10.1111/j.1365-2133.2011.10374.x. 38. özgen zy, gürbüz o. a randomized, double-blind comparison of nadifloxacin 1% cream alone and with benzoyl peroxide 5% lotion in the treatment of mild to moderate facial acne vulgaris. marmara med j 2013; 26:17–20. doi: 10.5472/mmj/2012.02649. 39. poulin y, sanchez np, bucko a, fowler j, jarratt m, kempers s, et al. a 6-month maintenance therapy with adapalene-benzoyl peroxide gel prevents relapse and continuously improves efficacy among patients with severe acne vulgaris: results of a randomized controlled trial. br j dermatol 2011; 164:1376–82. doi: 10.1111/j.1365-2133.2011.10344.x. 40. zaenglein al, thiboutot dm. expert committee recommendations for acne management. pediatrics 2006; 118:1188–99. doi: 10.1542/peds.2005-2022. 41. american academy of dermatology. clinical guidelines. from: www.aad.org/practice-tools/quality-care/clinical-guidelines accessed: jan 2016. 42. jones dh, king k, miller aj, cunliffe wj. a dose-response study of i3-cis-retinoic acid in acne vulgaris. br j dermatol 1983; 108:333–43. doi: 10.1111/j.1365-2133.1983.tb03973.x. 43. gollnick hh, cunliffe w, berson d, dreno b, finlay a, leyden jj, et al. management of acne: a report from a global alliance to improve outcomes in acne. j am acad dermatol 2003; 49:s1–37. doi: 10.1067/mjd.2003.618. 44. bener a, lestringant gg, ehlayel ms, saarinen k, takiddin ah. treatment outcome of acne vulgaris with oral isotretinoin. j coll physicians surg pak 2009; 19:49–51. doi: 01.2009/jcpsp. 4951. 45. zane lt, leyden wa, marqueling al, manos mm. a population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. arch dermatol 2006; 142:1016–22. doi: 10.1001/archderm.142.8.1016. 46. akman a, durusoy c, senturk m, koc ck, soyturk d, alpsoy e. treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study. arch dermatol res 2007; 299:467–73. doi: 10.1007/s00403-0070777-2. 47. amichai b, shemer a, grunwald mh. low-dose isotretinoin in the treatment of acne vulgaris. j am acad dermatol 2006; 54:644–6. doi: 10.1016/j.jaad.2005.11.1061. http://dx.doi.org/10.4103/0256-4947.72263 http://dx.doi.org/10.4103/0256-4947.72263 http://dx.doi.org/10.1046/j.1365-4362.2002.01669.x http://dx.doi.org/10.1016/j.jaad.2007.01.031 http://dx.doi.org/10.1038/jid.2009.47 http://dx.doi.org/10.1038/jid.2009.47 http://dx.doi.org/10.1186/1477-7525-10-60 http://dx.doi.org/10.1155/2014/974019 http://dx.doi.org/10.1111/1523-1747.ep12260695 http://dx.doi.org/10.1111/1523-1747.ep12260695 http://dx.doi.org/10.1038/jid.2013.334 http://dx.doi.org/10.1038/jid.2013.438 http://dx.doi.org/10.1038/jid.2009.8 http://dx.doi.org/10.1111/j.1525-1470.2005.00141.x http://dx.doi.org/10.1111/j.1600-0854.2007.00651.x http://dx.doi.org/10.1210/en.2006-1113 http://dx.doi.org/10.1111/j.1346-8138.2005.tb00740.x http://dx.doi.org/10.1111/j.1346-8138.2005.tb00740.x http://dx.doi.org/10.1111/bjd.12912 http://dx.doi.org/10.1111/bjd.12912 http://dx.doi.org/10.1016/j.jssdds.2013.05.003 http://dx.doi.org/10.1016/j.jssdds.2013.05.003 http://dx.doi.org/10.4103/0019-5154.74539 http://dx.doi.org/10.1111/jdv.13186 http://dx.doi.org/10.1016/j.jaad.2006.08.048 http://dx.doi.org/10.1016/j.jaad.2006.08.048 http://dx.doi.org/10.1016/j.jaad.2007.06.006 http://dx.doi.org/10.1111/j.1365-2133.2011.10374.x http://dx.doi.org/10.5472/mmj/2012.02649 http://dx.doi.org/10.1111/j.1365-2133.2011.10344.x http://dx.doi.org/10.1542/peds.2005-2022 http://dx.doi.org/10.1111/j.1365-2133.1983.tb03973.x http://dx.doi.org/10.1067/mjd.2003.618 http://dx.doi.org/01.2009/jcpsp.4951 http://dx.doi.org/01.2009/jcpsp.4951 http://dx.doi.org/10.1001/archderm.142.8.1016 http://dx.doi.org/10.1007/s00403-007-0777-2 http://dx.doi.org/10.1007/s00403-007-0777-2 http://dx.doi.org/10.1016/j.jaad.2005.11.1061 topical, biological and clinical challenges in the management of patients with acne vulgaris e160 | squ medical journal, may 2016, volume 16, issue 2 48. veltri kt. acne pharmacotherapy: a review. u.s. pharm 2013; 38:43–6. 49. nakase k, nakaminami h, takenaka y, hayashi n, kawashima m, noguchi n. relationship between the severity of acne vulgaris and antimicrobial resistance of bacteria isolated from acne lesions in a hospital in japan. j med microbiol 2014; 63:721–8. doi: 10.1099/jmm.0.067611-0. 50. luk nm, hui m, lee hc, fu lh, liu zh, lam ly, et al. antibiotic-resistant propionibacterium acnes among acne patients in a regional skin centre in hong kong. j eur acad dermatol venereol 2013; 27:31–6. doi: 10.1111/j.1468-3083. 2011.04351.x. 51. webster gf. light and laser therapy for acne: sham or science? facts and controversies. clin dermatol 2010; 28:31–3. doi: 10.1016/j.clindermatol.2009.04.002. 52. paithankar d, sakamoto fh, farinelli wa, kositratna g, blomgren rd, meyer tj, et al. acne treatment based on selective photothermolysis of sebaceous follicles with topically delivered light-absorbing gold microparticles. j invest dermatol 2015; 135:1727–34. doi: 10.1038/jid.2015.89. 53. layton a, eady ea, peat m, whitehouse h, levell n, ridd m, et al. identifying acne treatment uncertainties via a james lind alliance priority setting partnership. bmj open 2015; 5:e008085. doi: 10.1136/bmjopen-2015-008085. 54. jacobs a, starke g, rosumeck s, nast a. systematic review on the rapidity of the onset of action of topical treatments in the therapy of mild-to-moderate acne vulgaris. br j dermatol 2014; 170:557–64. doi: 10.1111/bjd.12706. 55. meredith fm, ormerod ad. the management of acne vulgaris in pregnancy. am j clin dermatol 2013; 14:351–8. doi: 10.1007/ s40257-013-0041-9. 56. zouboulis cc, bettoli v. management of severe acne. br j dermatol 2015; 172:27–36. doi: 10.1111/bjd.13639. http://dx.doi.org/10.1099/jmm.0.067611-0 http://dx.doi.org/10.1111/j.1468-3083.2011.04351.x http://dx.doi.org/10.1111/j.1468-3083.2011.04351.x http://dx.doi.org/10.1016/j.clindermatol.2009.04.002 http://dx.doi.org/10.1038/jid.2015.89 http://dx.doi.org/10.1136/bmjopen-2015-008085 http://dx.doi.org/10.1111/bjd.12706 http://dx.doi.org/10.1007/s40257-013-0041-9 http://dx.doi.org/10.1007/s40257-013-0041-9 http://dx.doi.org/10.1111/bjd.13639 فك رموز دور اجلسم بار يف السرطان نظرة ثاقبة يف سرطان الرأس والرقبة ديبتي �صارما، جورج كو�صي، �رشتي جوبتا، بو�صان �صارما، �صونال جروفر abstract: x chromosome inactivation is the epitome of epigenetic regulation and long non-coding ribonucleic acid function. the differentiation status of cells has been ascribed to x chromosome activity, with two active x chromosomes generally only observed in undifferentiated or poorly differentiated cells. recently, several studies have indicated that the reactivation of an inactive x chromosome or x chromosome multiplication correlates with the development of malignancy; however, this concept is still controversial. this review sought to shed light on the role of the x chromosome in cancer development. in particular, there is a need for further exploration of the expression patterns of x-linked genes in cancer cells, especially those in head and neck squamous cell carcinoma (hnscc), in order to identify different prognostic subpopulations with distinct clinical implications. this article proposes a functional relationship between the loss of the barr body and the disproportional expression of x-linked genes in hnscc development. keywords: sex chromatin; x chromosome; lyonization; x-linked genes; cell differentiation; cancer; squamous cell carcinoma, head and neck. احلم�ض يف م�صفر غري طويل جزء وجود وظيفة وتو�صيح اجليني التنظيم لعملية الأو�صح املثال هو x كرومو�صوم تعطيل امللخ�ص: النووي الريبوزي. وقد عزيت حالة متايز اخلاليا اإىل ن�صاط الكرومو�صوم x، حيث لوحظ وجود اثنان من كرومو�صوم x ن�صطني ب�صكل عام فقط يف اخلاليا غري املتمايزة اأو فقرية التمييز. وقد اأ�صارت العديد من الدرا�صات يف الآونة الأخرية، ايل اأن اإعادة تن�صيط كرومو�صوم x غري الن�صط اأوتعدد وجود كرومو�صوم x يرتبط مع حدوث الأورام اخلبيثة. ومع ذلك، فاإن هذا املفهوم ل يزال مثريا للجدل. �صعى هذا ال�صتعرا�ض اإىل ت�صليط ال�صوء على دور الكرومو�صوم x يف حدوث مر�ض ال�رشطان. على وجه اخل�صو�ض، هناك حاجة لأ�صتك�صاف املزيد )�رشطان والعنق الراأ�ض يف املوجودة تلك وبخا�صة ال�رشطانية، اخلاليا يف x بالكرومو�صوم املرتبطة اجلينات يف التعبري اأمناط من اخلاليا احلر�صفية(، من اأجل حتديد جمموعات اجلينات املختلفة ذات النذير ال�صئ ومايرتتب عليها من الآثار ال�رشيرية. تقرتح هذه املقالة وجودعالقة وظيفية بني فقدان اجل�صم بار وحدوث تعبري غريمتنا�صب للجينات املرتبطة بالكرومو�صوم x قد تت�صبب يف ن�صوء �رشطان اخلاليا احلر�صفية يف الراأ�ض والعنق. اخلاليا؛ متايز x؛ بكرومو�صوم املرتبطة اجلينات x؛ لكرومو�صوم ال�صبغي التعطيل x؛ كرومو�صوم اجلن�ض؛ كروماتني املفتاحية: الكلمات �رشطان؛ �رشطان اخلاليا احلر�صفية، الراأ�ض والعنق. deciphering the role of the barr body in malignancy an insight into head and neck cancer *deepti sharma,1 george koshy,1 shruti gupta,2 bhushan sharma,1 sonal grover1 review sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e389–397, epub. 10 jan 18 submitted 5 jun 17 revision req. 6 jul 17; revision recd. 3 aug 17 accepted 24 aug 17 1department of oral & maxillofacial pathology, christian dental college, ludhiana, punjab, india; 2department of oral anatomy, postgraduate institute of dental sciences, rohtak, haryana, india *corresponding author’s e-mail: deepti_dentist@yahoo.co.in doi: 10.18295/squmj.2017.17.04.003 genetic and epigenetic processes resultin heritable changes in the expression of cancer cells; consequently, the molecular targets of malignancy include critical tumour-associated genes—such as tumour suppressor genes (tsgs) or oncogenes—along with their mutations, amplifications, deletions, loss of heterozygosity or other epigenetic modifications.1 recently, researchers have confirmed the role of dna methylation and histone modification of the cytosine-guanine (cpg) site in malignancy as well as the interrelation between nuclear architecture, chromatin packaging, heterochromatin organisation, epigenome and noncoding ribonucleic acid (rna).2 many x-linked potential tsgs and oncogenes have been attributed to the distinctive biology of the x chromosome and its specific implications in malignancy.3 the exclusivity of tsgs to the x chromosome can be attributed to their inactivation by a single referred loss of function mutation (i.e. hit); in other words, if a tumour suppressor gene is localised on the x chromosome, one hit is sufficient to induce tumorigenesis because the other allele on the x chromosome is inactivated by epigenetic modification. moreover, the reactivation of the inactive x chromosome (xi) could ultimately lead to oncogene overexpression.4 in female somatic cells, an xi is referred to as the barr body. in malignant cells, the disappearance of the deciphering the role of the barr body in malignancy an insight into head and neck cancer e390 | squ medical journal, november 2017, volume 17, issue 4 barr body results in misregulation of the centromereassociated satellite heterochromatin and the peripheral heterochromatic compartment, potentially causing broad epigenetic instability.5 as such, the barr body is considered an epigenetic nuclear landmark in cancer development. recent interest in exploring the loss of the barr body in different malignancies has been encouraged by the high frequency of this phenomenon in aggressive breast cancers.6 nevertheless, the association between barr body disappearance and genetic loss, epigenetic instability or transcriptional reactivation is still ambiguous.7 head and neck squamous cell carcinoma (hnscc) is the sixth most common cancer worldwide and has been associated with conventional aetiological factors including tobacco and alcohol consumption.8 however, the growing incidence of oropharyngeal squamous cell carcinoma in western countries in the absence of a corresponding rise in smoking and alcohol consumption points towards the involvement of additional behavioural and environmental factors, such as human papilloma virus (hpv) infection and epigenetic instability.9 strong evidence exists that altered dna methylation profiles in hnscc cases reflect the aberrant epigenetic regulation of tsgs and oncogenes.10 as such, it is imperative that researchers concentrate on epigenetic pathways because of their reversible nature when seeking new approaches to the molecular diagnosis and targeted treatment of cancer. while x chromosome perturbations have been reported in breast, uterine, cervical, ovarian, renal and colon cancers, they are rarely documented in hnscc cases.7,11–14 this article focuses on reviewing variations in barr body frequency in different malignancies and proposing its hypothetical involvement in hnscc development. there is a need to further explore the role of sex chromosomes in hnscc development in order to determine potential clinical implications. the barr body and x inactivation during early embryonic development in females, the random inactivation of one of the two x chromosomes occurs and is maintained subsequently through out further cell division.15 the term barr body was first used to describe this transcriptionally inert, heterochromatic and late-replicating chromatin mass by barr et al. in 1949.16 this inactivation of an x chromosome results in equivalent gene dosage (i.e. xx and xy) between the sexes by the synchronised transcriptional silencing of genes; thus, both sexes have one copy of an active x chromosome (xa), which is necessary for the embryo to survive.17 critically, x inactivation represents numerous epigenetic mechanisms that result in the formation and maintenance of facultative heterochromatin in mammals.14 the x-inactive specific transcript (xist) gene is the linchpin of x inactivation, whereby heterochromatin silencing is mediated via xist expression and stabilisation of its non-coding rna transcript.18 the xist gene is located in the x inactivation centre and belongs to a class of rna molecules known as non-coding transcripts.19 with the exception of 3–15%, 1,500 genes located on the human x chromosome undergo transcriptional silencing due to x inactivation.6 distinct x chromosome perturbations in malignancy the differentiation status of cells is determined by x chromosome activity, whereby undifferentiated or poorly differentiated cells have been ascribed to the presence of two xa.20 variations in xi frequency have been reported with age, pregnancy, the use of oral contraceptives, fluctuations in menstrual cycle and neoplasia.21–25 moore et al. found that the frequency of the sex chromatin in the nuclei of female hosts was low in malignant tissues, appearing in only about one-third of tumours in comparison to non-malignant tissues; this finding was attributed to the diverse chromosomal abnormalities that occur in malignancy.26 straub et al. suggested that there was apparent reversion to the early embryonic state and loss of the barr body in some female mammalian tumours wherein the condensed x chromosome may become partially or fully extended, altering its genetic activity.27 thus, x chromosomes could be considered as existing in a dynamic state rather than a permanent or invariant one.28 it therefore appears that cancer is linked to an unusual escape from x inactivation. however, the extent of xi perturbations and disruptions to the epigenetic state in cancer have not yet been systematically explored. barring head and neck cancers, there is no dearth of literature reporting xi reactivation in malignant tumours.29 sirchia et al. noted that the lack of x inactivation in breast oncogenesis occurs independently from breast cancer 1 gene status and xist expression and is due to the loss of the xi and replication of the xa, without the reactivation of the native xi (i.e. the x chromosome predestined to be inactivated from the beginning), which results in the gain of an additional xa together with the lack of an xi.18 according to kaur et al., barr body frequency in buccal mucosal cells was significantly lower among menstruating patients with cervical cancer as compared to those who were deepti sharma, george koshy, shruti gupta, bhushan sharma and sonal grover review | e391 cancer-free; however, the findings were non-significant among breast cancer patients.30 this suggests that low barr body frequency occurs only in the tissue directly involved with the change. in breast cancer patients, a significantly low incidence of inactive x chromatins has been observed among menstruating as well as menopausal women, indicating that this low incidence is due to xi reactivation.21 jäger et al. observed that dna replication stress during oncogenesis led to xi hypermutations in aberrantly proliferating cells; moreover, mutation rates were comparatively higher in late replicating regions due to the lack of transcription-coupled dna repair.31 furthermore, vijay kumar et al. reported a significant association between sex chromatin status and the histopathological grading of breast carcinomas, in which there was a lower frequency of sex chromatins in tumours with a higher microscopic grade.32 another study found increased expression of cancer/testis antigens and loss of x inactivation in endometrial carci noma cases which was attributed to global hypomethylation and a high number of copy number variations (cnvs);33 this might indicate that other cancers with a high degree of cnv, such as colorectal cancer, nonsmall-cell lung cancer and hnscc could also present with loss of x inactivation. moreover, kobayashi et al. reported that xist expression could be used to predict the survival rate and prognosis of patients with cervical squamous cell carcinoma.11 overall chromatin state is determined by dna and histone modifications which maintain whether genes are transcriptionally active or inactive.2,3 the structure and function of chromatins and subsequent x inactivation can potentially become disrupted by environmental, toxicological and/or disease conditions; for example, recent research has indicated that xist function may be severely affected by defects in heterochromatin stability and epigenetic modifications.34,35 the misexpression of xist may potentially be a mechanism underlying oncogenesis and low xist levels may reduce x inactivation with contin uous x reactivation.20 however, the molecular cascade that alters x inactivation and x chromosome copy numbers in both female and male cancer cells remains undetermined.14 several plausible explanations for xi reactivation are proposed in figure 1. weakley et al. described three patterns of xi loss in that certain cells lose xi without xa, others lose xi and undergo xa multiplication and a few undergo xi reactivation.4 significant epigenetic changes could also be caused by viral oncoproteins, which potentially lead to abnormal cellular growth, transformation and, in some cases, oncogenesis.36,37 thus, virus-mediated transformation could be another explanation which has yet to be completely understood. x-linked genes in head and neck squamous cell carcinoma the role of various x-linked genes in different cancers has been previously documented.14 consistent genetic abnormalities have been found to be associated with the development and/or progression of hnscc in various karyotyping and molecular analyses.38 martin et al. previously published a thorough description of specific genetic changes involving autosomes in oral squamous cell carcinoma cases, which included the loss of chromosomal segments 3p, 5q, 7q, 8p, 9p, 11q and 18q in addition to the gain of 3q, 5p, 7p, 8q and 11q figure 1: possible mechanisms of x chromosome perturbations leading to the altered expression of x-linked genes in malignancy. xa = active x chromosome; xi = inactive x chromosome. deciphering the role of the barr body in malignancy an insight into head and neck cancer e392 | squ medical journal, november 2017, volume 17, issue 4 table 1: x-linked genes involved in the development of head and neck squamous cell carcinoma and other malignancies8,37,41–65 gene type function locus role in hnscc and other malignancies fhl1 tsg regulates muscle development, structural maintenance and signalling xq26 • fhl1 mrna and protein expression are frequently decreased in hnscc cases, with fhl1 modulating hnscc proliferation via the dysregulated expression of cyclin d1, cyclin e1 and p27.41 • fhl1 silencing notably enhances the proliferation of hnscc cells, whereas forced fhl1 expression dramatically represses hnscc cell growth.41 • the dna hypermethylation of fhl1 has been detected in certain types of cancer.41 bex genes (including bex1, bex2, bex3, bex4 and bex5) tsgs potential regulators of the cell cycle and apoptotic signalling xq22 • bex4 controls oscc proliferation and growth.42 • reduced bex4 expression occurs early on in oscc development.42 • bex genes are epigenetically silenced in oscc cases.43 • bex1 and bex3 are involved in modulating the nf-κb signalling pathway and have been implicated in cell death and the cell cycle.44 foxp3 hnscc oncogene involved in immune system responses and the development and function of regulatory t cells xp11.23 • the foxp3 gene modulates the expression of various other genes implicated in cancer development (i.e. tsgs and oncogenes).45 • immune evasion via foxp3 expression in tumour cells may represent the main mechanism of cancer progression.45 • high foxp3 expression in tumours has been found to be significantly associated with poor prognosis in oscc cases (e.g. decreased survival and lymph node metastasis).46 atrx chromatin regulator gene involved in transcriptional regulation and chromatin remodelling xq21.1 • atrx is one of the most frequently mutated chromatin factors in cancers.45 • atrx mutations promote telomere lengthening, increased genomic instability and cellular proliferation.45 • atrx loss-of-function mutations have been associated with cancers that exhibit alt phenotypes, including oesophageal scc.47 • atrx mutations have also been associated with abnormal dna methylation patterns.47 mecp2 oncogene acts as a transcriptional activator, likely by binding to another epigenetic dna modifier, and induces the mapk and pi3k growth factor signalling pathways xq28 • mecp2 amplification/overexpression has been linked to cancer.48 ddx3x* tsg implicated in cell cycle regulation, cell differentiation, cell survival and apoptosis xp11.4 • ddx3x expression has been evaluated in breast, lung, colon, oral and liver cancers and a positive correlation has been recently reported between high ddx3x levels and poor prognosis in human tumours.49 • ddx3x inhibits apoptosis by reducing caspase 3 activation.49 • an inverse relation between cytoplasmic ddx3x expression and survival rate has been found in smokers with oscc.49 • missense ddx3x mutations have been reported in hnscc and hpv patients.49 mage genes 50, 51, 52 and 53 oncogenes encode certain tumourassociated antigens recognised by cytotoxic t lymphocytes xq26–28 xp21† • several magea subgroups contribute to malignancy. • one study found that 71% of hnscc cases expressed at least one of six different mage genes.50 • mage1 and mage4 were the most frequently expressed genes in poorly differentiated scc cases.50 • the transcription of mage genes may be linked to a transformation event; various viruses (such as hpv and ebv) have easy access to the head and neck region, which might influence cell transformation.51 • in hnscc cases, magea2 expression is regulated by promoter demethylation, which interacts with the p53 pathway by increasing cellular proliferation and decreasing cell cycle arrest.52 • as a result of promoter demethylation, mageb2 overexpression was reported almost exclusively in tumours, with growth-promoting effects.53 araf1 protooncogene potentially involved in cell growth and development xp11.3 • araf1 may be involved in malignancy as a component gene of the mapk pathway.54 deepti sharma, george koshy, shruti gupta, bhushan sharma and sonal grover review | e393 fancb tsg involved in dna repair xp22.2 • patients with fanconi’s anaemia have been reported to have an increased susceptibility to early-onset hnscc.55 • fancb hypermethylation has been observed sporadically in hnscc tumours.55 col4a6 and col4a5 genes collagen genes involved in synthesising col4, an important protective component against invasion and metastasis xq22 • in carcinogenesis, col4 is gradually fragmented, collapsed or even dissolved completely, thus providing channels for cancer cells to invade the lamina propria.56 • as they become less differentiated, scc cells were found to lose their ability to form basement membrane components.56 elk1‡ transcription activator gene involved in determining the cellular response to extracellular signals and controlling the expression of genes involved in cell cycle progression, differentiation and apoptosis§ xp11.23 • elk1 proteins are a nuclear target for the ras-raf-mapk signalling cascade which is important for the control of growth signals, differentiation and cell survival.57 • elk1 is involved in the hypoxic induction of hif2αdependent genes, which can facilitate tumour cell survival by making them more resistant to therapeutic intervention.58 g6pd oncogene encodes the g6pd enzyme which produces nadph and pentoses involved in reductive biosynthetic activity xq28 • increased g6pd activity has been found in cancer cells.59 • g6pd inhibition has been reported to decrease cancer cell survival and nadph levels and increase ros production.59 • some researchers consider high g6pd activity to be an independent negative prognostic marker in cancer.60 • in breast cancer patients, g6pd overexpression is considered a predictor of high risk of recurrent metastasis.61 • g6pd becomes hyperactive in tumours with p53 inactivation, such as hnscc.60 • g6pd activity ensures a steady supply of pentoses and stabilisation of the nadph equilibrium which is an essential prerequisite for uncontrolled cell growth and proliferation, particularly for tumour cells.61 ldoc1 tsg able to induce apoptosis in various kinds of human cancer cells xq27 • ldoc1 downregulation due to epigenetic silencing by promoter hypermethylation has been observed in oral, cervical and ovarian cancers.43 ssx genes¶ oncogenes expression of these genes is restricted to malignant tumours xp11.1–11.2 • expression of at least one ssx subfamily member was most frequently observed in head and neck cancer (75%), followed by ovarian cancer (50%), malignant melanomas (43%), lymphomas (36%), colorectal cancer (27%) and breast cancer (23%).62 xiap oncogene encodes a protein that belongs to a family of apoptotic suppressor proteins/caspase inhibitors xq25 • the elevated expression of potent apoptotic inhibitor xiap is a significant biomarker for hnscc, with high xiap expression predicting poor prognosis.63 • xiap overexpression in tumour cells has been shown to inhibit cell death induced by a variety of apoptotic stimuli and induce resistance to chemotherapy.63 • the xiap gene was found to be hypomethylated in oral tumours.63 kdm6a and kdm6b genes tsgs act as the only enzymes displaying histone diand tridemethylase activity and are required for the reactivation of epigenetically silenced genes xp11.3 • hpv type 16 e7 expression has been reported to cause kdm6a and kdm6b upregulation, resulting in epigenetic reprogramming as evidenced by the aberrant expression of homeobox genes which are frequently dysregulated during carcinogenesis.37,64 • these genes have been found to be mutated in >10% of hnscc cell lines, although not in human hnscc tumours.65 apex2 and trex2 genes dna repair genes dna repair xp11.21 • apex2 and trex2 genes are hypomethylated in cancer tissues.8 • screening suggests dna repair genes, which are located on the x chromosome, have a propensity for aberrant methylation.8 fhl1 = four-and-a-half lim domains; tsg = tumour suppressor gene; mrna = messenger ribonucleic acid; hnscc = head and neck and squamous cell carcinoma; bex = brain-expressed x-linked; oscc = oral squamous cell carcinoma; nf-κb = nuclear factor kappa b; foxp3 = forkhead box p3; atrx = α-thalassemia mental retardation syndrome, x-linked; alt = alternative lengthening of telomeres; scc = squamous cell carcinoma; mecp2 = methyl cytosine guanine dinucleotide-binding protein 2; mapk = mitogen-activated protein kinase; pi3k = phosphoinositide 3-kinase; ddx3x = dead-box helicase 3, x-linked; hpv = human papillomavirus; mage = melanoma-associated antigen; ebv = epstein-barr virus; araf1 = a-raf proto-oncogene, serine/threonine kinase; fancb = fanconi’s anaemia complementation group b; col4 = collagen type iv; elk1 = e26 transformation-specific domain-containing protein elk-1; hif2α = hypoxia-inducible factor 2α; g6pd = glucose-6-phosphate dehydrogenase; nadph = nicotinamide adenine dinucleotide phosphate; ros = reactive oxygen species; ldoc1 = leucine zipper downregulated in cancer 1; ssx = synovial sarcoma, x chromosome-related; xiap = x-linked inhibitor of apoptosis; kdm6 = lysine-specific demethylase 6; apex2 = apurinic/ apyrimidinic endodeoxyribonuclease 2; trex2 = three prime repair exonuclease 2. *ddx3x is a highly conserved subfamily of dead-box proteins, the largest group of rna helicases. †type i mage genes in the magea, mageb and magec subfamilies are clustered on chromosome x. type ii mage genes in the maged, magee, magef, mageh, magel and necdin-like protein subfamilies are clustered on chromosome x as well as a few autosomes. ‡a member of the e26 transformation-specific oncogene family. §nf-κb regulates vascular endothelial growth factor expression through elk1 and activator protein 1 transcription factors. ¶ssx genes comprise six members of the recently described cancer/testis antigen class. deciphering the role of the barr body in malignancy an insight into head and neck cancer e394 | squ medical journal, november 2017, volume 17, issue 4 segments.39 however, a sex link was dubious; the loss of the short arm of the xi was a common observation in females and y loss was observed in about 50% of males.39 in hnscc cases, xi reactivation can potentially be considered a marker of heterochromatin instability associated with poor prognosis as, much like cervical cancer, the disease may be associated with epigenetic modifications as well as oncoviruses that could alter the x-linked genes.11,36,37 thus, the destabilised genomic repertoire in hnscc appears to be further undermined by epigenetic events.39,40 however, before considering an association between the barr body and hnscc, a causal relation between x-linked tsgs and hnscc development must be established. a summary of the x-linked genes involved in hnscc development and their various loci, functions and mechanisms can be found in table 1.8,37,41–65 the involvement of x-linked genes in hnscc, which bears similarities to the molecular pathogenesis of cervical carcinomas and other epithelial malignancies, indicate that there is a potential association between altered barr body frequency and hnscc development. probable contributors leading to xi reactivation in hnscc cases are documented in table 2.3,5–7,14,66 however, these hypothetical conclusions can only be confirmed or negated by experimental research. major disruptions in the dna methylation profiles of malignant cells—including the hypermethylation of gene promoters, global hypomethylation and increased mutation rates at methylated cpg dinucleotides—have been observed in both hpv-positive and -negative patients with hnscc.67 additionally, fang et al. found that individual genes and gene expression programmes are regulated by various long non-coding rnas by either implicating epigenetic control or altering basal transcriptional machinery.68 according to goedert et al., long non-coding rnas induced by viral oncoproteins play critical roles in tumour initiation and progression.69 as previously mentioned, increased xist expression—which contains a long non-coding rna transcript—has been found to predict a favourable prognosis in cases of cervical squamous cell carcinoma.11 since the transcriptional capacity of host cell chromatins can be regulated by hpv e6 and e7 oncoproteins, further research is needed to fully comprehend hpv-induced modulation of long non-coding rnas.70 clinical implications xi reactivation is an emerging topic of interest with potential clinically relevant applications which may pave the way for further understanding of chromatin changes and other drivers of tumour development. x-linked genes can serve as potential targets for the genetic and epigenetic alterations observed in malignant cells. therefore, considering heterochromatin defects and the involvement of epigenetic processes in switching on or off transcriptional cell machinery in malignancy, attempts have been made to delineate specific drug targets.71 epimutations could potentially be reversed via chemical agents known as epidrugs, such as dna methyltransferase or histone deacetylase inhibitors which help to re-establish the expression of tumour suppressors that have been suppressed by hypermethylation or repressive chromatin marks.72 the upregulation of oncogenes and cancer/testis antigens located on the x chromosome are induced by the loss of x inactivation, which leads to increased tumour aggressiveness; this could therefore be a susceptible target for immunotherapy.73 other options for reactivating x-linked tsgs in cancer therapy also deserve further investigation.4 advanced genomic techniques, single-cell profiling and other highly specific tools could be utilised to explore epigenetic changes and x inactivation, thus opening new horizons for hnscc treatment.74 conclusion previous research has elucidated in detail the physiological phenomenon of x inactivation and subsequent reactivation in various malignancies, particularly breast, ovarian and cervical cancers in females. this article reviewed the distinct perturbations of the x chromosome in various malignancies and suggested a similar hypothesis for hnscc development. the careful profiling of x-linked gene expression in tumour cells could help to elucidate the x chromosome-related events which lead to oncogenesis. table 2: hypothesised mechanisms leading to x reactivation in the development of head and neck squamous cell carcinoma3,5–7,14,66 mechanism loss of xi via deletion chromosomal segregation errors reactivation of xi through epigenetic changes (i.e. hypomethylation or heterochromatin instability) hpv oncoproteins influencing xist expression dna replicating stress in proliferating malignant cells translocations involving regions of the x chromosome to autosomes and vice versa hpv = human papilloma virus; xi = inactive x chromosome; xist = x-inactive specific transcript. deepti sharma, george koshy, shruti gupta, bhushan sharma and sonal grover review | e395 references 1. herceg z, hainaut p. genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis. mol oncol 2007; 1:26–41. doi: 10.1016/j.molonc.2007.01.004. 2. clark sj. action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis. hum mol genet 2007; 16:r88–95. doi: 10.1093/hmg/ddm051. 3. weakley sm, wang h, yao q, chen c. expression and function of a large non-coding rna gene xist in human cancer. world j surg 2011; 35:1751–6. doi: 10.1007/s00268-010-0951-0. 4. liu y, wang l, zheng p. x-linked tumor suppressors: perplexing inheritance, a unique therapeutic opportunity. trends genet 2010; 26:260–5. doi: 10.1016/j.tig.2010.03.004. 5. carone dm, lawrence jb. heterochromatin instability in cancer: from the barr body to satellites and the nuclear periphery. semin cancer biol 2013; 23:99–108. doi: 10.1016/j. semcancer.2012.06.008. 6. chaligné r, popova t, mendoza-parra ma, saleem ma, gentien d, ban k, et al. the inactive x chromosome is epigenetically unstable and transcriptionally labile in breast cancer. genome res 2015; 25:488–503. doi: 10.1101/gr.18 5926.114. 7. pageau gj, hall ll, ganesan s, livingston dm, lawrence jb. the disappearing barr body in breast and ovarian cancers. nat rev cancer 2007; 7:628–33. doi: 10.1038/nrc2172. 8. chaisaingmongkol j, popanda o, warta r, dyckhoff g, herpel e, geiselhart l, et al. epigenetic screen of human dna repair genes identifies aberrant promoter methylation of neil1 in head and neck squamous cell carcinoma. oncogene 2012; 31:5108–16. doi: 10.1038/onc.2011.660. 9. koffler j, sharma s, hess j. predictive value of epigenetic alterations in head and neck squamous cell carcinoma. mol cell oncol 2014; 1:e954827. doi: 10.1080/23723548.2014.954827. 10. bakhtiar sm, ali a, barh d. epigenetics in head and neck cancer. methods mol biol 2015; 1238:751–69. doi: 10.1007/9781-4939-1804-1_39. 11. kobayashi r, miyagawa r, yamashita h, morikawa t, okuma k, fukayama m, et al. increased expression of long non-coding rna xist predicts favorable prognosis of cervical squamous cell carcinoma subsequent to definitive chemoradiation therapy. oncol lett 2016; 12:3066–74. doi: 10.3892/ol.2016.5054. 12. jiang f, richter j, schraml p, bubendorf l, gasser t, sauter g, et al. chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes. am j pathol 1998; 153:1467–73. doi: 10.1016/s0002-9440(10)65734-3. 13. sadikovic b, al-romaih k, squire ja, zielenska m. cause and consequences of genetic and epigenetic alterations in human cancer. curr genomics 2008; 9:394–408. doi: 10.2174/ 138920208785699580. 14. spatz a, borg c, feunteun j. x-chromosome genetics and human cancer. nat rev cancer 2004; 4:617–29. doi: 10.1038/ nrc1413. 15. hysolli e, jung yw, tanaka y, kim ky, park ih. the lesser known story of x chromosome reactivation: a closer look into the reprogramming of the inactive x chromosome. cell cycle 2012; 11:229–35. doi: 10.4161/cc.11.2.18998. 16. barr ml, bertram eg. a morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. nature 1949; 163:676. doi: 10.1038/163676a0. 17. chow jc, yen z, ziesche sm, brown cj. silencing of the mammalian x chromosome. annu rev genomics hum genet 2005; 6:69–92. doi: 10.1146/annurev.genom.6.080604.162350. 18. sirchia sm, ramoscelli l, grati fr, barbera f, coradini d, rossella f, et al. loss of the inactive x chromosome and replication of the active x in brca1-defective and wildtype breast cancer cells. cancer res 2005; 65:2139–46. doi: 10.1158/0008-5472.can-04-3465. 19. kalantry s. recent advances in x-chromosome inactivation. j cell physiol 2011; 226:1714–18. doi: 10.1002/jcp.22673. 20. vallot c, ouimette jf, rougeulle c. establishment of x chromosome inactivation and epigenomic features of the inactive x depend on cellular contexts. bioessays 2016; 38:869–80. doi: 10.1002/bies.201600121. 21. natekar pe, desouza fm. reactivation of inactive x chromosome in buccal smear of carcinoma of breast. indian j hum genet 2008; 14:7–8. doi: 10.4103/0971-6866.42320. 22. chhabra v, siddiqui ms, singh u, srivastava an, sahai a, sharma pk. sex chromatin & primary amenorrhoea: a correlation study. j anat soc india 2002; 51:145–7. 23. ghosh sn, shah pn. probable mechanism for the loss of barr body in human female tumor with special reference to breast cancer. med hypotheses 1981; 7:1099–104. doi: 10.1016/03069877(81)90106-7. 24. fischer ah, zhao c, li qk, gustafson ks, eltoum ie, tambouret r, et al. the cytologic criteria of malignancy. j cell biochem 2010; 110:795–811. doi: 10.1002/jcb.22585. 25. ørstavik kh. skewed x inactivation in healthy individuals and in different diseases. acta paediatr suppl 2006; 95:24–9. doi: 10.1080/08035320600618783. 26. moore kl, barr ml. the sex chromatin in human malignant tissues. br j cancer 1957; 11:384–90. 27. straub dg, lucas la, mcmahon nj, pellett ol, teplitz rl. apparent reversal of x-condensation mechanism in tumors of the female. cancer res 1969; 29:1233–43. 28. brown cj. role of the x chromosome in cancer. j natl cancer inst 1996; 88:480–2. doi: 10.1093/jnci/88.8.480. 29. deng x, berletch jb, nguyen dk, disteche cm. x chromosome regulation: diverse patterns in development, tissues and disease. nat rev genet 2014; 15:367–78. doi: 10.1038/nrg3687. 30. kaur s, sambyal v, sharma a, kaur p. buccal mucosal x-chromatin frequency in breast and cervix cancer. anthropol 2006, 8:223–5. 31. jäger n, schlesner m, jones dt, raffel s, mallm jp, junge km, et al. hypermutation of the inactive x chromosome is a frequent event in cancer. cell 2013; 155:567–81. doi: 10.1016/j. cell.2013.09.042. 32. vijay kumar b, ravneet k, manjit singh b, ranjeev b, kalyan gs, nishit g, et al. correlation between sex chromatin and female breast tumour in paraffin sections, buccal smears and peripheral blood films. j clin diagn res 2014; 8:92–5. doi: 10.7860/jcdr/2014/8289.4117. 33. kang j, lee hj, jun sy, park es, maeng ls. cancer-testis antigen expression in serous endometrial cancer with loss of x chromosome inactivation. plos one 2015; 10:e0137476. doi: 10.1371/journal.pone.0137476. 34. de la fuente r, baumann c, viveiros mm. role of atrx in chromatin structure and function: implications for chromosome instability and human disease. reproduction 2011; 142:221–34. doi: 10.1530/rep-10-0380. 35. cerase a, pintacuda g, tattermusch a, avner p. xist localization and function: new insights from multiple levels. genome biol 2015; 16:166. doi: 10.1186/s13059-015-0733-y. 36. kawakami t, zhang c, taniguchi t, kim cj, okada y, sugihara h, et al. characterization of loss-of-inactive x in klinefelter syndrome and female-derived cancer cells. oncogene 2004; 23:6163–9. doi: 10.1038/sj.onc.1207808. 37. mclaughlin-drubin me, crum cp, münger k. human papillomavirus e7 oncoprotein induces kdm6a and kdm6b histone demethylase expression and causes epigenetic reprogramming. proc natl acad sci u s a 2011; 108:2130–5. doi: 10.10 73/pnas.1009933108. 38. veiga lc , bérgamo na, kowalski lp, rogatto sr. classical and molecular cytogenetic analysis in head and neck squamous cell carcinomas. genet mol biol 2003; 26:121–28. doi: 10.1590/ s1415-47572003000200003. https://doi.org/10.1016/j.molonc.2007.01.004 https://doi.org/10.1093/hmg/ddm051 https://doi.org/10.1007/s00268-010-0951-0 https://doi.org/10.1016/j.tig.2010.03.004 https://doi.org/10.1016/j.semcancer.2012.06.008 https://doi.org/10.1016/j.semcancer.2012.06.008 https://doi.org/10.1101/gr.185926.114 https://doi.org/10.1101/gr.185926.114 https://doi.org/10.1038/nrc2172 https://doi.org/10.1038/onc.2011.660 https://doi.org/10.1080/23723548.2014.954827 https://doi.org/10.1007/978-1-4939-1804-1_39 https://doi.org/10.1007/978-1-4939-1804-1_39 https://doi.org/10.3892/ol.2016.5054 https://doi.org/10.1016/s0002-9440%2810%2965734-3 https://doi.org/10.2174/138920208785699580 https://doi.org/10.2174/138920208785699580 https://doi.org/10.1038/nrc1413 https://doi.org/10.1038/nrc1413 https://doi.org/10.4161/cc.11.2.18998 https://doi.org/10.1038/163676a0 https://doi.org/10.1146/annurev.genom.6.080604.162350 https://doi.org/10.1158/0008-5472.can-04-3465 https://doi.org/10.1002/jcp.22673 https://doi.org/10.1002/bies.201600121 https://doi.org/10.4103/0971-6866.42320 https://doi.org/10.1016/0306-9877%2881%2990106-7 https://doi.org/10.1016/0306-9877%2881%2990106-7 https://doi.org/10.1002/jcb.22585 https://doi.org/10.1080/08035320600618783 https://doi.org/10.1093/jnci/88.8.480 https://doi.org/10.1038/nrg3687 https://doi.org/10.1016/j.cell.2013.09.042 https://doi.org/10.1016/j.cell.2013.09.042 https://doi.org/10.7860/jcdr/2014/8289.4117 https://doi.org/10.1371/journal.pone.0137476 https://doi.org/10.1530/rep-10-0380 https://doi.org/10.1186/s13059-015-0733-y https://doi.org/10.1038/sj.onc.1207808 https://doi.org/10.1073/pnas.1009933108 https://doi.org/10.1073/pnas.1009933108 https://doi.org/10.1590/s1415-47572003000200003 https://doi.org/10.1590/s1415-47572003000200003 deciphering the role of the barr body in malignancy an insight into head and neck cancer e396 | squ medical journal, november 2017, volume 17, issue 4 39. martin cl, reshmi sc, ried t, gottberg w, wilson jw, reddy jk, et al. chromosomal imbalances in oral squamous cell carcinoma: examination of 31 cell lines and review of the literature. oral oncol 2008; 44:369–82. doi: 10.1016/j. oraloncology.2007.05.003. 40. brown cj, carrel l, willard hf. expression of genes from the human active and inactive x chromosomes. am j hum genet 1997; 60:1333–43. doi: 10.1086/515488. 41. cao w, liu j, xia r, lin l, wang x, xiao m, et al. x-linked fhl1 as a novel therapeutic target for head and neck squamous cell carcinoma. oncotarget 2016; 7:14537–50. doi: 10.18632/ oncotarget.7478. 42. gao w, li jz, chen sq, chu cy, chan jy, wong ts. decreased brain-expressed x-linked 4 (bex4) expression promotes growth of oral squamous cell carcinoma. j exp clin cancer res 2016; 35:92. doi: 10.1186/s13046-016-0355-6. 43. lee ch, wong ts, chan jy, lu sc, lin p, cheng aj, et al. epigenetic regulation of the x-linked tumour suppressors bex1 and ldoc1 in oral squamous cell carcinoma. j pathol 2013; 230:298–309. doi: 10.1002/path.4173. 44. fernandez em, díaz-ceso md, vilar m. brain expressed and x-linked (bex) proteins are intrinsically disordered proteins (idps) and form new signaling hubs. plos one 2015; 10:e0117206. doi: 10.1371/journal.pone.0117206. 45. liu r, kain m, wang l. inactivation of x-linked tumor suppressor genes in human cancer. future oncol 2012; 8:463–81. doi: 10.2217/fon.12.26. 46. song jj, zhao sj, fang j, ma d, liu xq, chen xb, et al. foxp3 overexpression in tumor cells predicts poor survival in oral squamous cell carcinoma. bmc cancer 2016; 16:530. doi: 10. 1186/s12885-016-2419-6. 47. watson la, goldberg h, bérubé ng. emerging roles of atrx in cancer. epigenomics 2015; 7:1365–78. doi: 10.2217/epi.15.82. 48. neupane m, clark ap, landini s, birkbak nj, eklund ac, lim e, et al. mecp2 is a frequently amplified oncogene with a novel epigenetic mechanism that mimics the role of activated ras in malignancy. cancer discov 2016; 6:45–58. doi: 10.11 58/2159-8290.cd-15-0341. 49. bol gm, xie m, raman v. ddx3, a potential target for cancer treatment. mol cancer 2015; 14:188. doi: 10.1186/s12943-0150461-7. 50. eura m, ogi k, chikamatsu k, lee kd, nakano k, masuyama k, et al. expression of the mage gene family in human head-andneck squamous-cell carcinomas. int j cancer 1995; 64:304–8. doi: 10.1002/ijc.2910640504. 51. zakut r, topalian sl, kawakami y, mancini m, eliyahu s, rosenberg sa. differential expression of mage-1, -2 and -3 messenger rna in transformed and normal human cell lines. cancer res 1993; 53:5–8. 52. glazer ca, smith im, bhan s, sun w, chang ss, pattani km, et al. the role of magea2 in head and neck cancer. arch otolaryngol head neck surg 2011; 137:286–93. doi: 10.1001/ archoto.2011.2. 53. peche ly, ladelfa mf, toledo mf, mano m, laiseca je, schneider c, et al. human mageb2 expression enhances e2f activity, cell proliferation and resistance to ribotoxic stress. j biol chem 2015; 290:29652–62. doi: 10.1074/jbc.m115.671982. 54. rauch j, vandamme d, mack b, mccann b, volinsky n, blanco a, et al. differential localization of a-raf regulates mst2-mediated apoptosis during epithelial differentiation. cell death differ 2016; 23:1283–95. doi: 10.1038/cdd.2016.2. 55. smith im, mithani sk, mydlarz wk, chang ss, califano ja. inactivation of the tumor suppressor genes causing the hereditary syndromes predisposing to head and neck cancer via promoter hypermethylation in sporadic head and neck cancers. orl j otorhinolaryngol relat spec 2010; 72:44–50. doi: 10.1159/000292104. 56. gouse s, girish hc, sangamad r. role of type iv collagen in oral squamous cell carcinoma. res j pharm biol chem sci 2016; 7:2737–41. 57. roberts pj, der cj. targeting the raf-mek-erk mitogenactivated protein kinase cascade for the treatment of cancer. oncogene 2007; 26:3291–310. doi: 10.1038/sj.onc.1210422. 58. salnikow k, aprelikova o, ivanov s, tackett s, kaczmarek m, karaczyn a, et al. regulation of hypoxia-inducible genes by ets1 transcription factor. carcinogenesis 2008; 29:1493–9. doi: 10.1093/carcin/bgn088. 59. hu t, li ys, chen b, chang yf, liu gc, hong y, et al. elevated glucose-6-phosphate dehydrogenase expression in the cervical cancer cases is associated with the cancerigenic event of highrisk human papillomaviruses. exp biol med (maywood) 2015; 240:1287–97. doi: 10.1177/1535370214565971. 60. jiang p, du w, wu m. regulation of the pentose phosphate pathway in cancer. protein cell 2014; 5:592–602. doi: 10.1007/ s13238-014-0082-8. 61. cernaj ie. simultaneous dual targeting of par-4 and g6pd: a promising new approach in cancer therapy? quintessence of a literature review on survival requirements of tumor cells. cancer cell int 2016; 16:87. doi: 10.1186/s12935-016-0363-9. 62. türe ci o, chen yt, sahin u, güre ao, zwick c, villena c, et al. expression of ssx genes in human tumors. int j cancer 1998; 77:19–23. doi: 10.1002/(sici)1097-0215(199 80703)77:1<19::aid-ijc4>3.0.co;2-2. 63. yang hx, liu l, xu jh, hu yj, zhang p, qiu jx. co-expression of xiap and ciap1 play synergistic effect on patient’s prognosis in head and neck cancer. j mol biomark diagn 2016; 8:314. doi: 10.4172/2155-9929.1000314. 64. hyland pl, mcdade ss, mccloskey r, dickson gj, arthur k, mccance dj, et al. evidence for alteration of ezh2, bmi1, and kdm6a and epigenetic reprogramming in human papillomavirus type 16 e6/e7-expressing keratinocytes. j virol 2011; 85:10999–1006. doi: 10.1128/jvi.00160-11. 65. li h, wawrose js, gooding we, garraway la, lui vw, peyser nd, et al. genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. mol cancer res 2014; 12:571–82. doi: 10.1158/1541-7786.mcr-13-0396. 66. wang j. method to analyze x-chromosomal genetic data. from: http://grantome.com/grant/nih/r03-ca192197-02 accessed: aug 2017. 67. worsham mj, stephen jk, chen km, havard s, shah v, gardner g, et al. delineating an epigenetic continuum in head and neck cancer. cancer lett 2014; 342:178–84. doi: 10.1016/j. canlet.2012.02.018. 68. fang y, fullwood mj. roles, functions, and mechanisms of long non-coding rnas in cancer. genomics proteomics bioinformatics 2016; 14:42–54. doi: 10.1016/j.gpb.2015.09.006. 69. goedert l, plaça jr, nunes em, debom gn, espreafico em. long noncoding rnas in hpv-induced oncogenesis. adv tumor virol 2016; 6:1–9. doi: 10.4137/atv.s29816. 70. plesa a, iancu iv, botezatu a, huica i, stoian m, anton g. the involvement of epigenetic mechanisms in hpv-induced cervical cancer. in: rajkumar r, ed. human papillomavirus: research in a global perspective. london, uk: intechopen, 2016. pp. 191–239. 71. mund c, brueckner b, lyko f. reactivation of epigenetically silenced genes by dna methyltransferase inhibitors: basic concepts and clinical applications. epigenetics 2006; 1:7–13. doi: 10.4161/epi.1.1.2375. 72. timp w, feinberg ap. cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. nat rev cancer 2013; 13:497–510. doi: 10.1038/nrc3486. https://doi.org/10.1016/j.oraloncology.2007.05.003 https://doi.org/10.1016/j.oraloncology.2007.05.003 https://doi.org/10.1086/515488 https://doi.org/10.18632/oncotarget.7478 https://doi.org/10.18632/oncotarget.7478 https://doi.org/10.1186/s13046-016-0355-6 https://doi.org/10.1002/path.4173 https://doi.org/10.1371/journal.pone.0117206 https://doi.org/10.2217/fon.12.26 https://doi.org/10.1186/s12885-016-2419-6 https://doi.org/10.1186/s12885-016-2419-6 https://doi.org/10.2217/epi.15.82 https://doi.org/10.1158/2159-8290.cd-15-0341 https://doi.org/10.1158/2159-8290.cd-15-0341 https://doi.org/10.1186/s12943-015-0461-7 https://doi.org/10.1186/s12943-015-0461-7 https://doi.org/10.1002/ijc.2910640504 https://doi.org/10.1001/archoto.2011.2 https://doi.org/10.1001/archoto.2011.2 https://doi.org/10.1074/jbc.m115.671982 https://doi.org/10.1038/cdd.2016.2 https://doi.org/10.1159/000292104 https://doi.org/10.1038/sj.onc.1210422 https://doi.org/10.1093/carcin/bgn088 https://doi.org/10.1177/1535370214565971 https://doi.org/10.1007/s13238-014-0082-8 https://doi.org/10.1007/s13238-014-0082-8 https://doi.org/10.1186/s12935-016-0363-9 https://doi.org/10.1002/%28sici%291097-0215%2819980703%2977:1%3c19::aid-ijc4%3e3.0.co%3b2-2 https://doi.org/10.1002/%28sici%291097-0215%2819980703%2977:1%3c19::aid-ijc4%3e3.0.co%3b2-2 https://doi.org/10.4172/2155-9929.1000314 https://doi.org/10.1128/jvi.00160-11 https://doi.org/10.1158/1541-7786.mcr-13-0396 https://doi.org/10.1016/j.canlet.2012.02.018 https://doi.org/10.1016/j.canlet.2012.02.018 https://doi.org/10.1016/j.gpb.2015.09.006 https://doi.org/10.4137/atv.s29816 https://doi.org/10.4161/epi.1.1.2375 https://doi.org/10.1038/nrc3486 deepti sharma, george koshy, shruti gupta, bhushan sharma and sonal grover review | e397 73. kang j, lee hj, kim j, lee jj, maeng ls. dysregulation of x chromosome inactivation in high grade ovarian serous adenocarcinoma. plos one 2015; 10:e0118927. doi: 10.1371/ journal.pone.0118927. 74. agrelo r, wutz a. context of change: x inactivation and disease. embo mol med 2010; 2:6–15. doi: 10.1002/ emmm.200900053. https://doi.org/10.1371/journal.pone.0118927 https://doi.org/10.1371/journal.pone.0118927 https://doi.org/10.1002/emmm.200900053 https://doi.org/10.1002/emmm.200900053 الوهن العضلي الوبيل قضايا العالج السريري قبل وأثناء وبعد احلمل علي ح�سن و زكية حممد ي�ساوي abstract: myasthaenia gravis (mg) is an autoimmune neuromuscular disorder which is twice as common among women, often presenting in the second and third decades of life. typically, the first trimester of pregnancy and first month postpartum are considered high-risk periods for mg exacerbations. during pregnancy, treatment for mg is usually individualised, thus improving its management. plasma exchange and immunoglobulin therapies can be safely used to treat severe manifestations of the disease or myasthaenic crises. however, thymectomies are not recommended because of the delayed beneficial effects and possible risks associated with the surgery. assisted vaginal delivery—either vacuum-assisted or with forceps—may be required during labour, although a caesarean section under epidural anaesthesia should be reserved only for standard obstetric indications. myasthaenic women should not be discouraged from attempting to conceive, provided that they seek comprehensive counselling and ensure that the disease is under good control before the start of the pregnancy. keywords: myasthenia gravis; pregnancy; postpartum period; neonatal myasthenia gravis; disease management. يف الن�ساء ي�سيب ما وغالبا الن�ساء بني �سيوعا اأكرث وهو ذاتي. مناعي ع�سلي ع�سبي ا�سطراب هو الوبيل الع�سلي الوهن امللخ�ص: العقدين الثاين والثالث من العمر. عادة، تعترب االأ�سهر الثالثة االأوىل من احلمل و ال�سهر االأول بعد الوالدة فرتات عالية املخاطر لتفاقم مر�ص الوهن الع�سلي الوبيل. ويكون عالج هذا املر�ص خالل فرتة احلمل خمتلفا من فرد الأخر مما يح�سن من فر�ص االأ�ستجابة للعالج. وميكن عالج املظاهر ال�سديدة للمر�ص او االأنتكا�سة با�ستخدام تغيري البالزما واملعاجلات املناعية ب�سكل اآمن اثناء احلمل. ومع ذلك، ال ين�سح با�ستئ�سال الغدة ال�سعرتية ب�سبب االآثار املتاأخرة واملخاطر املحتملة املرتبطة باجلراحة. واأثناء املخا�ص ميكن اجراء الوالدة بالطريقة املهبلية العادية اأو ا�ستخدام و�سائل م�ساعدة لها مثل امللقاط او ال�سفاط. كما ميكن اي�سا اجراءعملية قي�رصية حتت التخدير من فوق اجلافية عند احلاجة اليها. ال ينبغي تثبيط الن�ساء امل�سابات باملر�ص عن حماولة احلمل مع االأخذ يف االأعتبار تهيئة احل�سول على امل�سورة ال�ساملة و�سمان اأن يكون هذا املر�ص حتت ال�سيطرة اجليدة قبل حدوث احلمل. الكلمات املفتاحية: الوهن الع�سلي الوبيل؛ حمل؛ فرتة ما بعد الوالدة؛ الوهن الع�سلي الوليدي؛ عالج املر�ص. myasthaenia gravis clinical management issues before, during and after pregnancy *ali hassan and zakia m. yasawy review sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e259–267, epub. 10 oct 17 submitted 21 nov 16 revisions req. 5 jan & 20 feb 17; revisions recd. 29 jan & 6 mar 17 accepted 9 mar 17 department of neurology, king fahd hospital, university of dammam, khobar, saudi arabia *corresponding author e-mail: ahrajput@uod.edu.sa doi: 10.18295/squmj.2017.17.03.002 myasthaenia gravis (mg) is an acquired organ-specific autoimmune disease in which autoantibodies are directed against the post-synaptic nicotinic acetylcholine receptor (achr) on the neuromuscular endplate of skeletal muscles, leading to fatigable weakness of the diaphragm and the ocular, oropharyngeal and/or limb muscles.1–3 in western countries, the prevalence of mg is 50–125 cases per million individuals and can present at any age.1 however, the incidence is twice as common among women (ratio: 3:2) and typically occurs during the second and third decades of life; in contrast, the disease most commonly presents in males during the sixth and seventh decades of life.2 the majority of myasthaenic patients are seropositive for achr antibodies, while seronegative patients may have antibodies to other targets at the neuromuscular junction (nmj), such as muscle-specific kinase (musk).3 clinical presentation of myasthaenia gravis patients with mg may have a wide range of clinical symptoms. the characteristic presentation is fatigability, usually in the form of exercise intolerance, with fluctuating skeletal muscle weakness that worsens throughout the day and improves with rest.4 ocular symptoms of ptosis and diplopia are presenting symptoms in over 50% of patients, whereas up to 15% of patients present with bulbar muscle weakness manifesting as dysphagia, dysarthria or difficulty in chewing.5 among patients with ocular myasthenia, the progression of the disease to generalised muscle weakness usually occurs within two years of onset.5 a myasthaenic crisis is a life-threatening exacerbation of the disease which occurs in 15–20% of patients.6 it can sometimes result in severe myasthaenia gravis clinical management issues before, during and after pregnancy e260 | squ medical journal, august 2017, volume 17, issue 3 respiratory and bulbar weakness requiring intubation and mechanical ventilation; as such, affected patients should be treated in an intensive care unit (icu).6 due to improvements in the management of myasthaenic crises in icus over the last four decades, the mortality rate has dropped from 75% to the current rate of <5%.7 known triggers of acute mg exacerbations include infections, surgery, general anaesthesia, hypo or hyperthyroidism, physical or emotional stress, the menstrual cycle, pregnancy, a postpartum state, extreme temperatures and exposure to certain medications that may increase muscle weakness.6 in mg, the thymus performs an important role in the pathological breakdown of immune tolerance towards self-antigens. as such, magnetic resonance imaging or computed tomography is advisable to see if the thymus is enlarged. approximately 75% of patients with mg have thymic abnormalities.6 of these, 65% have hyperplasia with active germinal centres full of plasma cells expressing the achr α-subunit on their surface, resulting in the production of autoantibodies to achrs, while 10% have thymomas, mostly in the form of benign tumors.6,8 diagnosis of myasthaenia gravis a diagnosis of mg is essentially clinical, as fatigability is considered a reliable indicator of the disease.6 subsequently, serological, electrodiagnostic and pharm acological tests are used to confirm the diagnosis. serum anti-achr antibodies, which are highly specific for mg, are detected in 80–85% of generalised and 50–60% of isolated ocular mg cases.3,6 serum antimusk antibodies are found in 70% of seronegative generalised mg cases and should therefore be measured when an achr antibody test is negative.9 repetitive nerve stimulation (rns) and single fibre electromyography (sf-emg) are electrophysiological tests to assess nmj function. these electrophysiological tests should be considered to confirm the diagnosis, particularly among seronegative patients. at a low frequency (3–5 hz), rns shows a gradual decrease in the amplitude of the compound muscle action potential, with a >10% decrement from the fourth response considered pathological.3,6 when performed in the weak distal muscles, the test is nearly always positive in generalised mg cases; however, in patients with isolated ocular myasthaenia, a rns test may be negative in 50% of cases.3 on the other hand, sf-emg is a more sophisticated and highly sensitive (95–99%) test for detecting neuromuscular transmission abnormalities. abnormal jitters (>100 ms) are found in all myasthaenic patients when tested on clinically weak muscles.9 both of these neurophysiological investigations can be performed safely on pregnant women.10 the tensilon test consists of administering 10 mg of intravenous edrophonium, a short-acting acetylcholine esterase inhibitor, under a set protocol to improve muscle weakness and sometimes to confirm a diagnosis of mg; it is positive in >90% of myasthaenic patients, but has a relatively low sensitivity (60%).6 as such, the results of this test should be interpreted in the context of the patient’s clinical features and other investigative findings, as the results may also be positive for brain stem lesions, third nerve palsy, motor neuron disease and mitochondrial myopathies.3 during testing, intravenous atropine (0.2–4 mg) and electrocardiography monitoring facilities should be available to counter serious muscarinic sideeffects, like bradycardia or syncope. administration of oral pyridostigmine over several days may result in a subjective improvement in muscle strength and fatigability which might not otherwise be evident after a single dose of edrophonium.11 treatment of myasthaenia gravis treatment of mg aims to both increase acetylcholine neurotransmission at the nmj and reduce autoantibody production. current treatments include a thymectomy, acetylcholinesterase inhibitors (i.e. pyridostigmine and neostigmine), immunosuppressants (i.e. corticosteroids, azathioprine [aza], mycophenolate mofetil [mmf] and ciclosporin a) and plasma exchange (pe) and intravenous immunoglobulin (ig) therapies.2 acetylcholinesterase inhibitors act on the parasympathetic nervous system and therefore may cause hypersecretion, bronchoconstriction and gastro intestinal tract hypermotility; these side-effects therefore limit their use in patients with asthma, chronic bronchitis and/or diarrhoea.3,12 pyridostigmine is the most commonly prescribed acetylcholinesterase inhibitor and acts by inhibiting the synaptic enzyme, resulting in an increase in the concentration of acetylcholine neurotransmitters at the postsynaptic membrane. this form of treatment is purely symptomatic, is usually effective in the early stages of mg and may be sufficient to treat the mildest form of the disease.6 corticosteroids (e.g. prednisone) are usually used in conjunction with pyridostigmine to treat mild ali hassan and zakia m. yasawy review | e261 refractory disease or moderate-to-severe mg. initially, if administered at a high dose, the patient’s symptoms may worsen; therefore, gradual escalation of the steroid dose over one to two months is recommended, with patients initially prescribed low doses of 10 mg/day which are gradually increased up to 60 mg/day.3 once clinical remission is achieved, the dose is tapered over several months and is kept on an alternating day cycle.6 in the long term, nonsteroidal immunosuppressive medications are usually incorporated into the medication regimen, such as aza and mmf. as aza requires between 3–6 months to take effect, it should be prescribed concurrently with corticosteroids.6 in comparison to other immunosuppressants, the relatively low-level toxicity and rapid-onset therapeutic effects of mmf, which can occur as early as two weeks among patients who respond to the therapy, is a distinct advantage.6 in addition, mmf has been shown to play a potential role in the treatment of refractory mg.13 while pe and intravenous ig therapies result in rapid improvement for mg patients by removing/ interacting with the circulating autoantibodies against achrs, the effects are unfortunately only temporary (approximately 4–10 weeks’ duration).14 as such, these therapies are indicated in cases of severe disease, myasthaenic crises, perioperative management prior to thymic surgery and mg refractory to immunosuppressant therapy.6 a thymectomy is mandatory treatment for patients with thymomas, as 30% of thymomas are locally invasive.15 although the therapeutic effects of a thymectomy can take years to become apparent, it is often associated with an improvement in disease severity.6 therefore, it is frequently performed for patients with generalised mg occurring before the age of 50 years.9 a recent international randomised controlled trial among 126 non-thymomatous patients with earlyor late-onset mg has confirmed the clear benefit over a three-year period of an early thymectomy in comparison to medical treatment alone.16 moreover, patients who underwent thymectomies demonstrated significant clinical improvement in terms of the reduced need for immunosuppressive therapy and hospitalisation to treat myasthaenic exacerbations.16 in total, 80% of mg patients show symptomatic improvement after undergoing a thymectomy.17,18 one year after a thymectomy, the mg remission rate is <20%, although this rises to 50% after 7–10 years.19 the association of british neurologists have previously published detailed clinician guidelines to inform the management and treatment of mg patients.20,21 the effect of pregnancy on myasthaenia gravis pregnancy has an unpredictable and variable effect on the clinical course of mg and the experience of previous pregnancies cannot predict the clinical course during subsequent pregnancies.22,23 in patients with pre-existing mg, the severity of the disease at the beginning of the pregnancy may not remain the same throughout the rest of the pregnancy; as such, the disease can go into remission, become exacerbated or remain static.22 however, clinical improvement during the second and third trimesters is noted in approximately 20–40% of pregnancies, most likely due to the immunosuppressive effect of late pregnancy.24 according to batocchi et al. and djelmis et al., 19% and 14.5% of mg cases, respectively, worsened during pregnancy with a further 28% and 15.9% experiencing disease exacerbation during the first six weeks postpartum; in comparison, the course of the disease remained unchanged throughout the pregnancy in 39% and 42% of cases, respectively.22,23 in pregnant women, both hypoventilation due to respiratory muscle weakness and diaphragm elevation due to the growing fetus reduce the capacity of the lungs to inflate fully, hence compromising respiratory function.10 as such, myasthaenic women should be monitored closely throughout their pregnancies for breathing problems to avoid respiratory crises which would require mechanical ventilation. moreover, changes in blood volume, increased renal clearance, frequent vomiting and delayed gastric emptying during pregnancy may interfere with the intestinal absorption of mg medications and thus necessitate frequent dose adjustments.10 puerperal respiratory and urinary tract infections may exacerbate symptoms of mg; therefore, prompt diagnosis and treatment of these infections is required with antibiotics appropriate for use in pregnancy and mg. it is crucial to recognise that selected groups of antibiotics—such as fluoroquinolones (e.g. moxifloxacin and ciprofloxacin), macrolides (e.g. azithromycin and erythromycin) and aminoglycosides (e.g. streptomycin and gentamicin)—may exacerbate myasthaenic-related muscle weakness and should hence be avoided.10 the risk of mortality for a myasthaenic pregnant woman is inversely correlated to the duration of the disease, with the highest risk occurring in the first year following onset of the disease and reaching its lowest level after seven years.24 the physiological stress of pregnancy can also precipitate a myasthaenic crisis.24 myasthaenia gravis clinical management issues before, during and after pregnancy e262 | squ medical journal, august 2017, volume 17, issue 3 treatment of myasthaenia gravis during pregnancy therapeutic regimens for pregnant myasthaenic women should be individualised and based on the severity of the symptoms and distribution of muscle weakness in the mother, while considering the potential side-effects of the medication on the fetus. myasthaenic patients with the mildest form of weakness may only require close follow-up without treatment. however, involvement of the bulbar and respiratory muscles requires a more aggressive treatment approach because of the potential for lifethreatening myasthaenic exacerbations.6 due to its delayed therapeutic effect and possible surgical risks, a thymectomy shoud not be considered during pregnancy; therefore, both the surgery and thymic imaging should be postponed until after delivery to avoid teratogenic complications.10 if the pregnancy is planned, a thymectomy can be performed before conception or after delivery, if required. acetylcholinesterase inhibitors are the drug of choice for the symptomatic treatment of mg among pregnant women. during pregnancy, pyridostigmine is considered safe at a recommended dosage of <600 mg/day.9 however, frequent dose adjustments may be needed because of frequent vomiting or other pregnancy-related changes in intestinal absorption.10 in cases of severe vomiting, intravenous administration may be required; however, this may cause increased uterine contractions and premature labour.9 immunosuppressant corticosteroids are effective in the majority of pregnant myasthaenic patients and should be considered when the severity of symptoms necessitates their use.9 however, corticosteroids may result in carbohydrate intolerance among pregnant women, with an increased risk of cleft palate in newborn infants when used by their mothers during the first trimester.25 as such, corticosteroids should be maintained at the lowest possible dose whenever possible. premature rupture of the membranes and preterm delivery have also been associated with high doses of corticosteroids.24 in addition, the transient worsening of myasthaenic symptoms has been reported to occur with the initiation of corticosteroid therapy.4 while the initiation of immunosuppressive drugs should be avoided before and during pregnancy, the risk of triggering a myasthaenic crisis or exacerbation by dose reduction or discontinuation in pregnant myasthaenic women needs to be balanced against the teratogenic risk to the fetus.21 however, recent best practice guidelines support the use of aza at therapeutic dosages throughout pregnancy and during the breastfeeding period.21,26 although aza crosses the placenta, the immature fetal liver has a deficiency of the enzyme responsible for the conversion of aza to its active metabolites; hence, the fetus is relatively protected from the harmful effects of the drug.21 nevertheless, reversible leucopenia, thrombocytopaenia, anaemia, thymic atrophy and decreased ig levels have been reported among infants exposed to aza.24,27 in addition, newborns whose mothers were treated with aza may also have an increased risk of myeloand immunosuppression.24 although considered safe for use during pregnancy and breastfeeding, ciclosporin a may cause prematurity, spontaneous abortions and low birth weight among newborn infants.21,24 in contrast, mmf is considered teratogenic, causing a clinical syndrome which includes hypoplastic nails, shortened fifth fingers, oral cleft, microtia, diaphragmatic hernia and micrognathia.21 contraception is required before, during and for up to six weeks after mmf therapy.28 treatment of acute myasthaenic exacerbations during pregnancy both pe and intravenous ig therapies have been proven to be effective, safe and well tolerated during pregnancy.10 although these therapies result in a rapid improvement in mg symptoms, the benefits are short-lived and retreatment may be required; as such, they should be reserved for patients experiencing myasthaenic crises or to manage severe myasthaenic symptoms when conventional therapy has failed.4,14 however, the hyperviscosity and volume overloading associated with intravenous ig may be dangerous during pregnancy and should be carefully monitored.24 during pe sessions, the occurrence of hypotension must also be carefully monitored and corrected; placing the patient in a left lateral decubitus position may be helpful. in addition, pe may cause premature labour by removing the circulating hormones vital for the integrity of pregnancy.24 although both treatment modalities have been found to have equivalent efficacy in the treatment of myasthaenic exacerbations, pe should be considered a second-line option to intravenous ig therapy due to its effect on blood volume, circulating hormones and coagulation factor changes in pregnancy.2 table 1 summarises the safety and potential side-effects of medications used to treat mg during pregnancy.10,21,24 ali hassan and zakia m. yasawy review | e263 labour and delivery considerations for myasthaenia gravis cases typically, mg does not affect the first stage of labour because of the involvement of smooth muscles. in contrast, during the second stage, maternal fatigability may be pronounced because the voluntary striated muscles are involved.24 at this point, the patient may become exhausted, potentially precipitating a myasthaenic crisis; hence, the obstetrician should be prepared for an assisted vaginal delivery if necessary (e.g. via vacuum extraction or with forceps).10,23 acetylcholinesterase inhibitors can minimise myasthaenic fatigue during labour and should be administered parenterally to avoid erratic gastrointestinal absorption.24 intravenous doses of pyridostigmine and neostigmine are equivalent to about one-thirtieth of the usual oral dose.29 neostigmine (1.5 mg intramuscularly or 0.5 mg intravenously every 3–4 hours) is preferrable to pyridostigmine, which may cause the formation of sterile abscesses.24 surgery is very stressful and can cause acute worsening of myasthaenic symptoms; therefore, a caesarean section procedure should be reserved only for standard obstetric indications. as myasthaenic patients are especially sensitive to certain anaesthetic drugs, an anaesthesiologist should be consulted at the beginning of the pregnancy.24 epidural anaesthesia not exceeding the 10th thoracic veterbra level is preferrable in both vaginal and surgical deliveries to provide adequate analgaesia.2 however, this should be confined to amide-type local anaesthetic agents (e.g. lidocaine, mepivacaine and bupivacaine) because these agents do not affect myasthaenia, whereas ester-type medications (such as benzocaine, tetracaine and procaine) should be avoided because of the risk of exacerbation of the underlying myasthaenia.2 nonsteroidal anti-inflammatory drugs (such as ketorolac tromethamine) and paracetamol (acetaminophen) can be used for postpartum or postoperative pain, while narcotic analgaesic agents that may cause respiratory depression should be avoided.4 magnesium sulphate inhibits acetylcholine release by blocking the presynaptic calcium influx at the nerve terminals; however, it is contraindicated for table 1: maternal and fetal side-effects and safety of drugs used to treat myasthaenia gravis during pregnancy10,21,24 drug maternal side-effects fda category* teratogenic side-effects safety during pregnancy pyridostigmine abdominal cramps, excessive oral and bronchial secretions, diarrhoea and bradycardia c respiratory distress and microcephaly (dose >600 mg/day) safe prednisone weight gain, hyperglycaemia, gastritis, gastric ulcers, mood changes, osteoporosis and myopathy c cleft palate safe azathioprine bone marrow suppression, gastrointestinal disturbances, hepatotoxicity, leukaemia and possible increased risk of lymphomas d reversible leukopaenia, anaemia, thrombocytopaenia, thymic atrophy, sporadic congenital defects such as cerebral palsy, cerebral haemorrhage and cardiovascular defects safe† ciclosporin renal toxicity, hypertension, seizures, myopathy, tremors, increased body hair and gingival hyperplasia c prematurity, low birth weight, spontaneous abortions, transient neonatal thrombocytopaenia, neutropaenia and lymphopaenia safe† mycophenolate mofetil gastrointestinal disturbances, white blood count reduction and a possible increased risk of lymphomas and other malignancies such as skin cancer d pregnancy loss in the first trimester, cleft lip and palate, micrognathia, ocular hypertelorism, microtia and agenesis of the corpus callosum unsafe intravenous immunoglobulin therapy headache, aseptic meningitis, acute kidney injury, venous thrombosis and stroke c unknown safe plasma exchange therapy hypotension, tachycardia, electrolyte imbalances, sepsis and venous thrombosis n/a unknown safe fda = food and drug administration; n/a = not applicable. *fda pregnancy risk classification using the following scores: a (no fetal risk), b (no evidence of risk in humans, hence the chance of fetal harm is remote but possible), c (chance of fetal harm, but the potential benefits to the mother outweigh the risk) and d (evidence of fetal risk, but the potential benefits to the mother outweigh the risk). †recent guidelines from the uk consider these immunosuppressive agents safe during pregnancy and breastfeeding.21 myasthaenia gravis clinical management issues before, during and after pregnancy e264 | squ medical journal, august 2017, volume 17, issue 3 use in the management of eclampsia in myasthaenic women since it can cause acute worsening of mg symptoms.10 levetiracetam and valproic acids are acceptable alternatives for seizure prophylaxis, while phenytoin should be reserved for refractory seizures because it can potentially exacerbate myasthaenicrelated weakness.4 the treatment of hypertension is a cornerstone of pre-eclampsia management; methyldopa and oral hydralazine can be considered the initial drugs of choice to control non-severe hypertension, while intravenous hydralazine should be used to reduce acute blood pressure in severe hypertensives (systolic pressure of >160 mmhg or diastolic pressure of >110 mmhg).30 however, in comparison to hydralazine, intravenous urapidil has shown better tolerability and controllability and is a promising alternative.31 both β-blockers and calcium channel blockers can potentially worsen myasthaenic symptoms and thus should be avoided.30 neonatal considerations for myasthaenia gravis cases among neonates whose mothers have mg, between 10–20% develop transient neonatal mg (tnmg) shortly after birth because of the transplacental passage of maternal achr antibodies.10,32 commonly, this occurs in cases wherein the mothers are positive for achr and/or anti-musk antibodies, but is rarely seen in neonates with seronegative myasthaenic mothers.33,34 symptoms of tnmg appear within the first few days of life, most commonly 12–48 hours after delivery and characteristically resolve within four weeks (18–21 days); occasionally, symptoms persist for as long as four months.9,34,35 symptoms of tnmg include a weak cry, ptosis, facial weakness, poor sucking, generalised hypotonia and respiratory distress; however, the severity of these symptoms differs from newborn to newborn, with some showing only mild hypotonia and others requiring mechanical ventilation due to significant breathing problems.24,32,34 thus, neonatal icu facilities should be available at the time of delivery and infants born to myasthaenic mothers should be carefully monitored during their first 48–72 hours for signs of respiratory difficulty and muscle weakness. ventilatory support and pyridostigmine (0.5–1.0 mg/kg in divided doses) should be administered as necessary until the neuromuscular symptoms have resolved, with pe therapy to be considered in more severe cases.10 rarely, the babies of myasthaenic mothers may develop arthrogryposis multiplex congenita, a syndrome characterised by nonprogressive contractures of multiple joints throughout the body at the time of birth.32 a likely mechanism that leads to the development of this condition is reduced fetal movements in utero, possibly due to the placental transfer of maternal achr antibodies that selectively inhibit fetal achr function.32 infants born to mothers with a high quantity of achr antibodies in relation to the fetal γ-subunit of achr may develop severe fetal arthrogryposis.21 ultrasonography should therefore be performed to detect this condition in utero by monitoring fetal movement. postpartum considerations for myasthaenia gravis cases during the first postpartum month, close followup is recommended to monitor the potential exacerbation of myasthenic symptoms such as weakness and respiratory distress. breastfeeding is not contraindicated in myasthaenic mothers, but can worsen cases of tnmg as achr antibodies are secreted in breast milk; it is therefore advisable to avoid breastfeeding symptomatic newborns.24 symptoms of mg also intensify in the setting of infection; therefore, myasthaenic mothers should be advised to promptly report any symptoms consistent with infections (e.g. urinary, respiratory tract, uterine or wound infections).2 in lactating myasthaenic mothers, choosing a medication regimen is challenging because of the potential teratogenic risks to the infant. pyridostigmine is considered safe during lactation unless high doses are required, which may cause gastrointestinal symptoms in breastfed infants. glucocorticoids and aza can also be used safely by nursing mothers; however, for infants breastfeeding from mothers taking aza, it is advisable to monitor complete blood count and conduct a liver function test.21,24 breastfeeding is contraindicated in myasthaenic women taking mmf.2 infant care can be particularly difficult for myasthaenic mothers; the increased fatigue associated with a lack of sleep due to nighttime feedings and the increased exertion related to caring for a newborn may cause a worsening of mg symptoms. in patients for whom immunosuppressive therapy is to be initiated or restarted after delivery, contraceptive counselling is strongly recommended. an effective contraceptive should be prescribed at least four weeks before immunosuppressive therapy begins and should be maintained for six months before a new pregnancy.10 the cyclic withdrawal of oral contraceptives is well documented to cause exacerbation of myasthaenic symptoms.2 continuous hormonal contraception or an intrauterine device may therefore be better options for myasthaenic women.2 ali hassan and zakia m. yasawy review | e265 pre-pregnancy counselling for women with myasthaenia gravis all myasthaenic women who are considering having children should be advised to undergo pre-pregnancy counselling with a neurologist before conception to optimise their myasthaenic status, reduce the use of immunosuppressive medications and assess the need for a thymectomy. during counselling, patients should also receive information about the risks of pregnancy and make an informed decision based on the most current data available. a patient who has been newly diagnosed with ocular mg potentially risks developing severe generalised mg within two years.5 it is therefore prudent to delay conceiving during this period so as to avoid potential worsening of the disease due to pregnancy. as pyridostigmine is safe for use during pregnancy and among women with the mildest form of the disease, it can be initiated as a symptomatic treatment even before conception for women planning to get pregnant.9 however, immunosuppressive medications other than corticosteroids and aza should typically be avoided because of their teratogenic risk.21 a preconception thymectomy might decrease the need for such medications during the course of the pregnancy; however, the patient should be informed that it may take years before the full therapeutic effects of the surgery become evident.6 the patient should also be cautioned that mg severity at the beginning of their pregnancy does not predict the same disease course throughout the rest of the pregnancy and that the course of previous pregnancies does not forecast the outcome of any subsequent pregnancies.10,22,23 it should also be noted that the absence of symptoms of mg before or during pregnancy does not guarantee the delivery of a healthy infant.36 as such, the possibility of their newborn developing arthrogryposis multiplex congenita or tnmg should always be discussed with mg patients who wish to have children. table 2 summarises recommendations for management among women with mg of childbearing age.21 table 2: recommendations for the management of women of childbearing age with myasthenia gravis21 time period recommendations pre-pregnancy • counselling by a neurologist • effective contraception advice for pregnacy planning • advice on the safety of different mg treatments during pregnancy (i.e. prednisone, aza, pyridostigmine and ciclosporin) • mg drugs should not be discontinued without medical consultation • thyroid function tests • thymectomy (if necessary) during pregnancy • counselling on the possible teratogenic effects of immunosuppressive agents (i.e. methotrexate or mmf) as well as the risk of disease exacerbation with abrupt withdrawal • interdisciplinary care from neurologists, obstetricians and anaesthesiologists • consultation with an obstetric anaesthesiologist before the early third trimester • prompt treatment with suitable antibiotics for infections (i.e. utis) • fetal monitoring • thymectomy is not advised during labour and delivery • delivery at hospitals/birth centres with on-site general icu and nicu facilities • multidisciplinary team from an obstetrician, obstetric anesthesiologist, neonatologist and neurologist • women with well-controlled mg should aim to have a vaginal delivery with spontaneous onset of labour • caesarean deliveries should be performed only if necessary • intravenous hydrocortisone should be given in stress doses (i.e. 100 mg three times a day) to patients on long-term oral steroids • medications to treat preeclampsia, eclampsia and postpartum pain should be carefully selected • treatment with magnesium sulphate should be avoided • epidural analgaesia is preferable to general anaesthesia postpartum • breastfeeding should be encouraged for patients receiving pyridostigmine, prednisone or aza • early consultation with a neurologist • all infants should be monitored for at least 48 hours for symptoms of tnmg, preferably in the nicu • for infants with tnmg, pyridostigmine should be prescribed until the neuromuscular symptoms resolve • intravenous ig and pe therapies should be considered in severe tnmg cases mg = myasthaenia gravis; aza = azathioprine; mmf = mycophenolate mofetil; uti = urinary tract infection; icu = intensive care unit; nicu = neonatal icu; tnmg = transient neonatal myasthaenia gravis; pe = plasma exchange; ig = immunoglobulin. myasthaenia gravis clinical management issues before, during and after pregnancy e266 | squ medical journal, august 2017, volume 17, issue 3 conclusion treatment of mg during pregnancy is challenging because the disease course is unpredictable and highly variable. medication regimens must balance the teratogenic risk to the fetus with the potential therapeutic benefits to the myasthaenic patient. immunosuppressive therapy should be discontinued before conception, although corticosteroids, aza and intravenous ig and pe therapies can be used safely throughout the pregnancy. forceps or vacuum extraction is often necessary to reduce the length of the second stage of labour, although a caesarean delivery should be conducted only if necessary according to standard obstetrical indications. intensive care facilities should be available for newborns due to the risk of tnmg. throughout their pregnancy, during delivery and in the postpartum period, women with mg require personalised care from a multidisciplinary team comprising neurologists, obstetricians, neonatologists and anaesthesiologists. references 1. al-moallem ma, alkali nh, hakami ma, zaidan rm. myasthenia gravis: presentation and outcome in 104 patients managed in a single institution. ann saudi med 2008; 28:341–5. doi: 10.4103/0256-4947.51686. 2. varner m. myasthenia gravis and pregnancy. clin obstet gynecol 2013; 56:372–81. doi: 10.1097/grf.0b013e31828e92c0. 3. turner c. a review of myasthenia gravis: pathogenesis, clinical features and treatment. trends anaesth crit care 2007; 18:15–23. doi: 10.1016/j.cacc.2007.01.006. 4. bird sj, stafford ip, dildy ga. management of myasthenia gravis in pregnancy. from: www.uptodate.com/contents/managementof-myasthenia-gravis-in-pregnancy accessed: mar 2017. 5. meriggioli mn, sanders db. autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. lancet neurol 2009; 8:475–90. doi: 10.1016/s1474-4422(09)70063-8. 6. khadilkar sv, sahni ao, patil sg. myasthenia gravis. j assoc physicians india 2004; 52:897–904. 7. juel vc. myasthenia gravis: management of myasthenic crisis and perioperative care. semin neurol 2004; 24:75–81. doi: 10.1055/s-2004-829595. 8. spring pj, spies jm. myasthenia gravis: options and timing of immunomodulatory treatment. biodrugs 2001; 15:173–83. doi: 10.2165/00063030-200115030-00004. 9. ciafaloni e, massey jm. myasthenia gravis and pregnancy. neurol clin 2004; 22:771–82. doi: 10.1016/j.ncl.2004.06.003. 10. massey jm, de jesus-acosta c. pregnancy and myasthenia gravis. continuum (minneap minn) 2014; 20:115–27. doi: 10.1212/01.con.0000443840.33310.bd. 11. meriggioli mn, sanders db. myasthenia gravis: diagnosis. semin neurol 2004; 24:31–9. doi: 10.1055/s-2004-829594. 12. echaniz-laguna a, pistea c, philippi n, enache i, oswaldmammosser m, de sèze j, et al. asthma as a cause of persistent dyspnea in treated myasthenia gravis patients. eur neurol 2012; 68:300–3. doi: 10.1159/000341834. 13. ciafaloni e, massey jm, tucker-lipscomb b, sanders db. mycophenolate mofetil for myasthenia gravis: an open-label pilot study. neurology 2001; 56:97–9. doi: 10.1212/wnl.56.1.97. 14. chiu hc, chen wh, yeh jh. the six-year experience of plasmapheresis in patients with myasthenia gravis. ther apher 2000; 4:291–5. doi: 10.1046/j.1526-0968.2000.004004291.x. 15. stafford ip, dildy ga. myasthenia gravis and pregnancy. clin obstet gynecol 2005; 48:48–56. 16. wolfe gi, kaminski hj, aban ib, minisman g, kuo hc, marx a, et al. randomized trial of thymectomy in myasthenia gravis. n engl j med 2016; 375:511–22. doi: 10.1056/nejmoa1602489. 17. budde jm, morris cd, gal aa, mansour ka, miller ji jr. predictors of outcome in thymectomy for myasthenia gravis. ann thorac surg 2001; 72:197–202. doi: 10.1016/s0003-4975(01)02678-9. 18. remes-troche jm, téllez-zenteno jf, estañol b, garduñoespinoza j, garcía-ramos g. thymectomy in myasthenia gravis: response, complications, and associated conditions. arch med res 2002; 33:545–51. doi: 10.1016/s0188-4409(02)00405-8. 19. bird sj. thymectomy for myasthenia gravis. from: www. uptodate.com/contents/thymectomy-for-myasthenia-gravis accessed: mar 2017. 20. sussman j, farrugia me, maddison p, hill m, leite mi, hiltonjones d. myasthenia gravis: association of british neurologists’ management guidelines. pract neurol 2015; 15:199–206. doi: 10.1136/practneurol-2015-001126. 21. norwood f, dhanjal m, hill m, james n, jungbluth h, kyle p, et al. myasthenia in pregnancy: best practice guidelines from a u.k. multispecialty working group. j neurol neurosurg psychiatry 2014; 85:538–43. doi: 10.1136/jnnp-2013-305572. 22. batocchi ap, majolini l, evoli a, lino mm, minisci c, tonali p. course and treatment of myasthenia gravis during pregnancy. neurol 1999; 52:447–52. doi: 10.1212/wnl.52.3.447. 23. djelmis j, sostarko m, mayer d, ivanisevic m. myasthenia gravis in pregnancy: report on 69 cases. eur j obset gynecol reprod biol 2002; 104:21–5. doi: 10.1016/s0301-2115(02)00051-9. 24. ferrero s, pretta s, nicoletti a, petrera p, ragni n. myasthenia gravis: management issues during pregnancy. eur j obstet gynecol reprod biol 2005; 121:129–38. doi: 10.1016/j. ejogrb.2005.01.002. 25. rodríguez-pinilla e, martínez-frías ml. corticosteroids during pregnancy and oral clefts: a case-control study. teratology 1998; 58:2–5. doi: 10.1002/(sici)1096-9926(199807)58:1<2::aid-te ra2>3.0.co;2-4. 26. ostensen m, brucato a, carp h, chambers c, dolhain rj, doria a, et al. pregnancy and reproduction in autoimmune rheumatic diseases. rheumatology (oxford) 2011; 50:657–64. doi: 10.1093/rheumatology/keq350. 27. armenti vt, moritz mj, davison jm. drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. drug saf 1998; 19:219–32. doi: 10.2165 /00002018-199819030-00005. 28. ebpg expert group on renal transplantation. european best practice guidelines for renal transplantation: section iv longterm management of the transplant recipient: iv.10 pregnancy in renal transplant recipients. nephrol dial transplant 2002; 17:50–5. doi: 10.1093/ndt/17.suppl_4.50. 29. national health service. medicine q&as: how do you convert an oral pyridostigmine dose to a parenteral neostigmine dose? from: www.medicinesresources.nhs.uk/upload/nhse_ 248.2final.doc accessed: mar 2017. 30. ozcan j, balson if, dennis at. new diagnosis myasthenia gravis and preeclampsia in late pregnancy. bmj case rep 2015; 2015:bcr2014208323. doi: 10.1136/bcr-2014-208323. https://doi.org/10.4103/0256-4947.51686 https://doi.org/10.1097/grf.0b013e31828e92c0 https://doi.org/10.1016/j.cacc.2007.01.006 https://doi.org/10.1016/s1474-4422%2809%2970063-8 https://doi.org/10.1055/s-2004-829595 https://doi.org/10.2165/00063030-200115030-00004 https://doi.org/10.1016/j.ncl.2004.06.003 https://doi.org/10.1212/01.con.0000443840.33310.bd https://doi.org/10.1055/s-2004-829594 https://doi.org/10.1159/000341834 https://doi.org/10.1212/wnl.56.1.97 https://doi.org/10.1046/j.1526-0968.2000.004004291.x https://doi.org/10.1056/nejmoa1602489 https://doi.org/10.1016/s0003-4975%2801%2902678-9 https://doi.org/10.1016/s0188-4409%2802%2900405-8 https://doi.org/10.1136/practneurol-2015-001126 https://doi.org/10.1136/jnnp-2013-305572 https://doi.org/10.1212/wnl.52.3.447 https://doi.org/10.1016/s0301-2115%2802%2900051-9 https://doi.org/10.1016/j.ejogrb.2005.01.002 https://doi.org/10.1016/j.ejogrb.2005.01.002 https://doi.org/10.1002/%28sici%291096-9926%28199807%2958:1%3c2::aid-tera2%3e3.0.co%3b2-4 https://doi.org/10.1002/%28sici%291096-9926%28199807%2958:1%3c2::aid-tera2%3e3.0.co%3b2-4 https://doi.org/10.1093/rheumatology/keq350 https://doi.org/10.2165/00002018-199819030-00005 https://doi.org/10.2165/00002018-199819030-00005 https://doi.org/10.1093/ndt/17.suppl_4.50 https://doi.org/10.1136/bcr-2014-208323 ali hassan and zakia m. yasawy review | e267 31. wacker jr, wagner bk, briese v, schauf b, heilmann l, bartz c, et al. antihypertensive therapy in patients with preeclampsia: a prospective randomised multicentre study comparing dihydralazine with urapidil. eur j obstet gynecol reprod biol 2006; 127:160–5. doi: 10.1016/j.ejogrb.2005.09.013. 32. polizzi a, huson s, vincent a. teratogen update: maternal myasthenia gravis as a cause of congenital arthrogryposis. teratology 2000; 62:332–41. doi: 10.1002/1096-9926(200011) 62:5<332::aid-tera7>3.0.co;2-e. 33. o’carroll p, bertorini te, jacob g, mitchell cw, graff j. transient neonatal myasthenia in a baby born to a mother with new-onset anti-musk-mediated myasthenia gravis. j clin neuromuscul dis 2009; 11:69–71. doi: 10.1097/cnd.0b0 13e3181a78280. 34. niks eh, verrips a, semmekrot ba, prick mjj, vincent a, van tol mjd, et al. a transient neonatal myasthenic syndrome with anti-musk antibodies. neurology 2008; 70:1215–16. doi: 10.1212/01.wnl.0000307751.20968.f1. 35. berlit s, tuschy b, spaich s, sütterlin m, schaffelder r. myasthenia gravis in pregnancy: a case report. case rep obstet gynecol 2012; 2012:736024. doi: 10.1155/2012/736024. 36. hoff jm, daltveit ak, gilhus ne. asymptomatic myasthenia gravis influences pregnancy and birth. eur j neurol 2004; 11:559–62. doi: 10.1111/j.1468-1331.2004.00900.x. https://doi.org/10.1016/j.ejogrb.2005.09.013 https://doi.org/10.1002/1096-9926%28200011%2962:5%3c332::aid-tera7%3e3.0.co%3b2-e https://doi.org/10.1002/1096-9926%28200011%2962:5%3c332::aid-tera7%3e3.0.co%3b2-e https://doi.org/10.1097/cnd.0b013e3181a78280 https://doi.org/10.1097/cnd.0b013e3181a78280 https://doi.org/10.1212/01.wnl.0000307751.20968.f1 https://doi.org/10.1155/2012/736024 https://doi.org/10.1111/j.1468-1331.2004.00900.x department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com ورم حبييب متقيح يف موقع غري طبيعي بعد العالج باأليزوتريتينوين كارلو�ص كوينكا-بارالي�ص، ترييزا رودينا�ص-هريانز، لورا ليناري�ص-غونزالي�ص، ريكاردو رويز-فيالفريد pyogenic granuloma in an atypical location following isotretinoin treatment carlos cuenca-barrales, teresa ródenas-herranz, laura linares-gonzalez, *ricardo ruiz-villaverde an 18-year-old woman presented to theoutpatient dermatology clinic of the hospital universitario san cecilio, granada, spain, in 2017 for a scheduled three-month follow-up appointment after having been prescribed 30 mg/day of oral isotretinoin for the control of severe acne. at the follow-up appointment, she reported multiple ulcer ated exophytic dome-shaped lesions prone to haemorrh age in the intergluteal fold and pubic region [figure 1]. she had no significant past medical history and did not report ever having had hidradenitis in the affected location nor any past trauma following hair removal. the results of complementary tests, including a complete blood count, general biochemistry tests and urinalysis, were within normal limits. a histological examination of the largest lesion was compatible with a diagnosis of pyogenic granuloma (pg) [figure 2]. sub sequently, the isotretinoin dose was reduced to 15 mg/day and a topical application of clobetasol propionate twice daily was administered. the patient reported the comp lete resolution of the lesions within three weeks. comment also known as capillary lobular haemangioma, pg is a benign vascular lesion that can compromise the skin or mucous membranes and usually occurs in children or adolescents.1 it was first described in 1979 following high doses of vitamin a.2 it has also been reported after treatment with topical and/or systemic retinoids—such as isotretinoin—between two weeks and six months after the initiation of treatment.3,4 most cases reported in the literature are located in the periungual area (i.e. lateral and distal nail folds), although it can also affect the chest, back, face, scalp and, less frequently, the genital area, as in the present case.5–8 interesting medical image sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e409–410, epub. 19 dec 18 submitted 16 may 18 revision req. 19 jul 18; revision recd. 20 jul 18 accepted 2 aug 18 figure 1: clinical photographs of an 18-year-old patient with multiple ulcerated exophytic dome-shaped lesions located on the (a) inner side of both groins and (b) intergluteal fold. doi: 10.18295/squmj.2018.18.03.028 pyogenic granuloma in an atypical location following isotretinoin treatment e410 | squ medical journal, august 2018, volume 18, issue 3 the pathophysiology of pg is still not clear. isotre tinoin may increase skin fragility and increase vascular proliferation. alternatively, retinoids promote early stages of wound healing, cause the accumulation of mononuclear cells in the dermis and stimulate collagen synthesis, all of which may contribute to pg formation.3,5 different triggering factors have also been postulated, including local trauma, bacterial infections and skin fragility.5,6 such factors can lead to the formation of granulation tissue.9 other causative factors may include the intake of other drugs, such as oral contraceptives, or pregnancy-related hormonal changes.10 from a therapeutic point of view, there is no need to discontinue isotretinoin treatment, although the dose should be modified temporarily.7 in addition, the topical application of corticosteroids and/or antibiotics is common to promote occlusive healing for 2−3 weeks. following this, if there is no clinical response, surgical removal is recommended.7 references 1. patrice sj, wiss k, mulliken jb. pyogenic granuloma (lobular capillary hemangioma): a clinicopathologic study of 178 cases. pediatr dermatol 1991; 8:267−76. doi: 10.1111/j.1525-1470.19 91.tb00931.x. 2. hagedorn m, kirchner s. [multiple granulomata pyogenica in a patient with acne vulgaris (author’s transl)]. dermatologica 1979; 158:93−8. doi: 10.1159/000250749. 3. simmons bj, chen l, hu s. pyogenic granuloma association with isotretinoin treatment for acne. australas j dermatol 2016; 57:e144−5. doi: 10.1111/ajd.12418. 4. figueiras dde a, ramos tb, marinho ak, bezerra ms, cauas rc. paronychia and granulation tissue formation during treatment with isotretinoin. an bras dermatol 2016; 91:223−5. doi: 10.15 90/abd1806-4841.20163817. 5. armstrong k, weinstein m. pyogenic granulomas during isotre tinoin therapy. j dermatol case rep 2011; 5:5−7. doi: 10.3315/ jdcr.2011.1062. 6. türel a, oztürkcan s, sahin mt, türkdogan p. a rare side-effect of systemic isotretinoin treatment: pyogenic granuloma. j eur acad dermatol venereol 2003; 17:609−11. doi: 10.1046/j.14683083.2003.00620.x. 7. exner jh, dahod s, pochi pe. pyogenic granuloma-like acne lesions during isotretinoin therapy. arch dermatol 1983; 119:808−11. doi: 10.1001/archderm.1983.01650340018012. 8. gupta s, radotra bd, kumar b. multiple, genital lobular capillary haemangioma (pyogenic granuloma) in a young woman: a diag nostic puzzle. sex transm infect 2000; 76:51−2. doi: 10.1136/ sti.76.1.51. 9. campbell jp, grekin rc, ellis cn, matsuda-john ss, swanson na, voorhees jj. retinoid therapy is associated with excess granulation tissue responses. j am acad dermatol 1983; 9:708−13. doi: 10.1016/s0190-9622(83)70184-2. 10. mussalli ng, hopps rm, johnson nw. oral pyogenic granuloma as a complication of pregnancy and the use of hormonal contraceptives. int j gynaecol obstet 1976; 14:187−91. doi: 10.10 02/j.1879-3479.1976.tb00592.x. figure 2: haematoxylin and eosin stain at x2 magnification showing capillaries and venules with plump endo thelial cells (arrowhead) separated into lobules by fibromyxoid stroma (arrow). https://doi.org/10.1111/j.1525-1470.1991.tb00931.x https://doi.org/10.1111/j.1525-1470.1991.tb00931.x https://doi.org/10.1159/000250749 https://doi.org/10.1111/ajd.12418 https://doi.org/10.1590/abd1806-4841.20163817 https://doi.org/10.1590/abd1806-4841.20163817 https://doi.org/10.3315/jdcr.2011.1062 https://doi.org/10.3315/jdcr.2011.1062 https://doi.org/10.1046/j.1468-3083.2003.00620.x https://doi.org/10.1046/j.1468-3083.2003.00620.x https://doi.org/10.1001/archderm.1983.01650340018012 https://doi.org/10.1136/sti.76.1.51 https://doi.org/10.1136/sti.76.1.51 https://doi.org/10.1016/s0190-9622%2883%2970184-2 https://doi.org/10.1002/j.1879-3479.1976.tb00592.x https://doi.org/10.1002/j.1879-3479.1976.tb00592.x departments of 1medicine and 2pathology, sultan qaboos university hospital; 3department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: drsaifak@yahoo.com جناح العالج اإلنقاذي بإأليكوليزوماب لرفض كلوي حاد ومقاوم متعلق بتفاعل جسم مناعي مضاد �صيف خان، داوود الريامي، يا�رض املالعبد، �صجى حممد، مروة الريامي، نبيل اللواتيا abstract: antibody-mediated rejection (abmr) jeopardises shortand long-term transplant survival and remains a challenge in the field of organ transplantation. we report the first use of the anticomplement agent eculizumab in oman in the treatment of a 61-year-old female patient with abmr following a living unrelated kidney transplant. the patient was admitted to the sultan qaboos university hospital in muscat, oman, in 2013 on the eighth day post-transplantation with serum creatinine (cr) levels of 400 µmol/l which continued to rise, necessitating haemodialysis. a biopsy indicated abmr with acute cellular rejection. no improvement was observed following standard abmr treatment and she continued to require dialysis. five doses of eculizumab were administered over six weeks with a subsequent dramatic improvement in renal function. the patient became dialysis-free with serum cr levels of 119 µmol/l within four months. this case report indicates that eculizumab is a promising agent in the treatment of abmr. keywords: kidney transplantation; transplantation rejection; complement activation; eculizumab; case report; oman. امللخ�ص: يهدد رف�ض زرع الكلى احلاد بوا�صطة اجل�صم امل�صاد بقاء الزرعه لفرتات ق�صرية وطويلة االأجل ويبقى من التحديات يف جمال زرع االأع�صاء. هذا تقرير حالة عن اأول ا�صتخدام لعقار االإيكوليزوماب يف عمان يف عالج مري�صة تبلغ من العمر 61 عاما حدث لها رف�ض حاد بعد زرع الكلى من متربع حي من غري االأقارب. مت ترقيد املري�ض يف م�صت�صفى جامعة ال�صلطان قابو�ض يف م�صقط، عمان، بتاريخ 2013 يف اليوم الثامن بعد الزراعه حيث و�صل معدل كرياتينني الدم ايل 400 ميكرومول/لرت م�صتمرا يف االأرتفاع حتي و�صل ايل قيم حتتاج الغ�صيل الكلوي. واأ�صارت خزعة الكلي ايل وجود رف�ض خلوي حاد باجل�صم امل�صاد. مل يوجد اأي حت�صن ملحوظ بعد العالج بالطرق القيا�صية املعتادة، واأ�صتمرت احلاجه ايل الغ�صيل الكلوى. اعطيت املري�صة خم�ض جرعات من عقار االإيكوليزوماب على مدى �صتة اأ�صابيع مع حدوث حت�صن كبري الحق يف وظيفة الكلى. و�صل معدل كرياتينني الدم ايل 119 ميكرومول/لرت يف غ�صون خم�صة اأ�صابيع ومل يحتاج املري�ض ايل غ�صيل الكلى بعد ذلك. ي�صري هذا التقرير ايل اأن عقاراالإيكوليزوماب واعد يف عالج رف�ض زرع الكلي اخللوي احلاد بوا�صطة اجل�صم امل�صاد. كلمات مفتاحية: زراعة الكلى؛ رف�ض الزرعه؛ تن�صيط الكومبليمنت؛ عقار االإيكوليزوماب؛ تقريرحالة؛ ُعمان. successful salvage treatment of resistant acute antibody-mediated kidney transplant rejection with eculizumab *saif a. khan,1 dawood al-riyami,1 yasser w. al-mula abed,1 saja mohammed,1 marwa al-riyami,2 nabil m. al-lawati3 sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e371–374, epub. 19 aug 16 submitted 29 apr 15 revisions req. 16 jun & 14 dec 15; revisions recd. 24 aug 15 & 9 may 16 accepted 2 jun 16 doi: 10.18295/squmj.2016.16.03.020 case report many advances have been made inthe last 50 years in the field of kidney transplantation due to improved understanding of the role of the immune system in allograft rejection. additionally, the introduction of powerful immunosuppressive agents like calcineurin inhibitors has significantly reduced acute cellular rejection rates and substantially improved oneyear transplant survival rates.1 despite this, organ rejection is still a major obstacle and long-term posttransplantation outcomes (≥10 years) have not shown much improvement.2 hyper acute rejection caused by preformed donorspecific antibodies (dsas) is now extremely rare due to the universal implementation of pre-transplant crossmatching. antibody-mediated rejection (abmr) has proven to play a critical role in the shortand longterm survival of kidney allografts. when untreated or insufficiently treated, abmr may lead to chronic changes that ultimately result in graft loss.3 this case report demonstrates the successful recovery of renal function due to the administration of eculizumab in a patient with abmr following a living unrelated transplant. case report a 61-year-old omani woman with end-stage renal disease due to hypertension was admitted to the sultan qaboos university hospital in 2013 eight days postsuccessful salvage treatment of resistant acute antibody-mediated kidney transplant rejection with eculizumab e372 | squ medical journal, august 2016, volume 16, issue 3 transplantation. she had no history of spontaneous abortions or venous thromboem-bolisms. she had been on regular haemodialysis at a local dialysis centre for three years before undergoing a living unrelated kidney transplant abroad. unfor-tunately, details regarding tissue typing, cross-matching, immune suppression induction and the operative procedure were unavailable. at presentation, she had serum creatinine levels of >400 µmol/l which increased to 607 µmol/l a few days later. ultrasonography of the transplanted kidney showed a normal-sized graft with a resistive index of 0.91. four days after admission, on the 12th postoperative day, an ultrasound-guided renal transplant biopsy showed glomerular thrombosis, mild peritubular capillaritis, interstitial haemorrhage, strong complement component 4 (c4) d positivity in the peritubular capillaries, mild to moderate focal lymphocytic tubulitis and mild interstitial inflammation [figure 1]. the arteries and arterioles were normal. these findings were consistent with acute class ii abmr and t cell-mediated acute cellular rejection (acr). the patient was treated with 250 mg of intravenous methylprednisolone for three days, 1.5 mg/kg of rabbit anti-thymocyte globulin for a total cumulative dose of 980 mg, 2 g/kg of intravenous immunoglobulin (ivig) and five cycles of plasma exchange (plex) at 2.5 l per exchange. she also received maintenance immunosuppression with oral prednisolone, tacrolimus and mycophenolate. the patient showed no improvement in renal function and remained dialysis-dependent after four weeks of conventional treatment. a second biopsy was performed on the 32nd day post-transplantation which indicated on-going abmr (acute thrombotic microangiopathy, peritubular capillaritis and strong c4d positivity) and features of chronic abmr, but no evidence of significant acr. intimal fibrosis was seen in the arteries as the result of an earlier acute rejection. these findings were believed to indicate resistance to conventional treatment; as a result, the decision was made to proceed with eculizumab administration. other treatment options such as rituximab and bortezomib were not considered in view of the strong c4d staining in the peritubular capillaries and persistent findings of abmr indicative of complement pathway activation. the patient received a meningococcal vaccine two weeks prior to the initiation of the eculizumab treatment as per the manufacturers’ recommendations. she received a total of five doses of eculizumab, with the first four doses of 900 mg administered on a weekly basis and the fifth dose of 1,200 mg given two weeks after the fourth dose. a dramatic response in renal function was observed following the first dose [figure 2]. her serum creatinine levels continued to improve and had decreased to 119 µmol/l four months after the eculizumab treatment. discussion abmr occurs in 5–7% of all renal transplants and 20–48% of pre-sensitised positively cross-matched patients.4 graft dysfunction usually manifests within a few days of the transplant procedure; however, allograft dysfunction with a resultant increase in serum creatinine may not be present in all cases.4 dsas play a major role in transplant rejection; figure 1a‒c: a: haematoxylin and eosin stain at x200 magnification showing an area of interstitial haemorrhage with acute inflammation. b: jones’ stain at x400 magnification showing glomerular thrombosis with intraluminal neutrophils. c: complement component 4d stain at x200 magnification showing strong diffuse positive staining. figure 2: serum creatinine levels in a 61-year-old omani woman with antibody-mediated rejection following a kidney transplant. the patient showed no improvement after six weeks of conventional therapy and was treated with five doses of eculizumab; she became dialysis-free after the first dose. the dotted lines represent the timing of the first and final doses of eculizumab, respectively. saif a. khan, dawood al-riyami, yasser w. al-mula abed, saja mohammed, marwa al-riyami and nabil m. al-lawati case report | e373 (10‒50%) and minimal (<10%) staining.8 the goal of abmr treatment is the reduction and removal of dsas and the elimination of the b cell and plasma cell population responsible for the production of these antibodies. the international guidelines do not outline any evidence-based treatments for acute abmr.11 historically, ivig and plex therapy have been used as first-line treatments for abmr.11 these therapies are difficult to assess because treatment options, doses and regimens are not standardised. moreover, no randomised control studies have supported the use of ivig in acute abmr despite its common utilisation in this context.12 although the role of plex has not been confirmed, studies have shown it to be beneficial especially in combination with other agents.13,14 other strategies for managing abmr include the use of rituximab, which targets pre-b cells and b cells, and bortezomib, which is a proteasome inhibitor.15,16 uncontrolled randomised studies have shown benefit in both rituximab and bortezomib.11,17 these agents are usually used in conjunction with ivig and/or plex.11 eculizumab is a humanised monoclonal antibody directed against complement protein-c and has recently been used as a new therapeutic agent for abmr with emerging data supporting its applicability and efficacy in kidney transplantation.11,18 it is a term inal complement inhibitor initially approved for the management of paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome.19,20 it targets complement component 5, thus blocking the complement cascade and the formation of the complement membrane attack complex.21 to the best of the authors’ knowledge, the present case report is the first to detail the use of eculizumab to treat abmr in oman. in this case, eculizumab was administered after a failed response to conventional treatment (ivig, plex, steroids and anti-thymocyte globulin) and histological evidence of persistent abmr on a repeated graft biopsy four weeks post-transplantation. the patient exhibited a dramatic improvement in renal function following five doses of eculizumab. gonzález-roncero et al. confirmed the efficacy of this agent in the treatment of two cases of abmr, especially when the biopsy shows c4d staining.22 several other reports also endorse the use of eculizumab in the treatment of abmr.23,24 however, these findings need to be confirmed by randomised control trials. the current case report highlights a common dilemma arising from commercial transplants, particularly as these surgeries may be carried out without optimal preparation and with limited peri-operative information available following the procedure. they are either preformed or develop de novo after transplantation.5 these antibodies are most commonly directed against the human leukocyte antigen (hla) or major histocompatibility complex (mhc) class i and ii. the former is expressed in all nucleated cells while the latter is restricted to endothelial cells and antigen-presenting cells like dendritic cells and b-lymphocytes. the antibodies can also be directed against other dsas/non-hla-like platelets, specific antigens, renin-angiotensin pathways and mhc class i-related chain a. previous transplantations, pregnancy and blood transfusions are major risk factors leading to sensitisation against mhc.6 anti-mhc antibodies either result in direct injury to the capillary endothelium or indirect injury via complement activation which is the major mechanism leading to the formation of a membrane attack complex. this formation results in cell injury and manifests histologically as glomerulitis, peritubular capillaritis and vascular endothelial injury. endothelial damage also causes platelet activation and microthrombus formation. the banff foundation for allograft pathology has proposed that at least two of the following criteria indicate a diagnosis of abmr: (1) the presence of dsas; (2) a positive c4d stain; and (3) histological evidence of glomerulitis, peritubular capillaritis and vascular endothelial injury.7,8 in the present case, two of the above criteria were met. however, the patient was not tested for panel-reactive antibodies or dsas; the latter was due to the unavailability of the technique at that time in oman. however, it is an established practice to initiate treatment of abmr in circumstances where the criteria are not entirely fulfilled due to multiple factors, including an inability to measure dsas due to the presence of non-hla antibodies or the possibility of dsa adsorption into the allograft.9 on the other hand, c4d stains may be falsely negative in areas of necrosis or with less sensitive immunohistochemistry techniques. protocol biopsies have also demonstrated c4d variability in staining over time from positive to negative.8 the complement split product c4d results from the breakdown of c4b into c4d and c4c. it has a high affinity for endothelial and basement mem branes and is expressed in the normal kidney mesangium and vascular pool owing to the constant complement turnover.10 in cases of immune-mediated glomerulopathy, it extends into the glomerular capillaries and deposits in the peritubular capillaries in a transplanted kidney. immunohistochemistry and immunofluorescence are two methods to detect c4d, the latter of which is more sensitive. diffuse staining of c4d (more than 50% of a peritubular capillary stain) is highly suggestive of abmr, in comparison to focal successful salvage treatment of resistant acute antibody-mediated kidney transplant rejection with eculizumab e374 | squ medical journal, august 2016, volume 16, issue 3 conclusion abmr is a serious complication that can occur following organ transplantation. it can have a grave impact on long-term kidney transplant survival. several non-evidence-based strategies exist to treat abmr. this case report presents the first use of eculizumab in oman to treat abmr. the successful outcome of this case indicates that eculizumab may be a promising agent in the treatment of this condition. however, randomised control trials are needed to confirm the efficacy of this agent. references 1. watson cj, dark jh. organ transplantation: historical perspective and current practice. br j anaesth 2012; 108:i29–42. doi: 10.1093/bja/aer384. 2. coll e, crespo m, solé m, campistol jm, cofàn f, esforzado n, et al. lessons from cyclosporine monotherapy in renal transplantation: the impact of acute rejection on longterm allograft outcome. transplant proc 2004; 36:114s–6s. doi: 10.1016/j.transproceed.2004.01.116. 3. amore a. antibody-mediated rejection. curr opin organ transplant 2015; 20:536–42. doi: 10.1097/mot.00000000000 00230. 4. puttarajappa c, shapiro r, tan hp. antibody-mediated rejection in kidney transplantation: a review. j transplant 2012; 2012:193724. doi: 10.1155/2012/193724. 5. stastny p, zou y, fan y, qin z, lavingia b. the emerging issue of mica antibodies: antibodies to mica and other antigens of endothelial cells. contrib nephrol 2009; 162:99–106. doi: 10.1159/000170842. 6. picascia a, grimaldi v, sabia c, napoli c. comprehensive assessment of sensitizing events and anti-hla antibody development in women awaiting kidney transplantation. transpl immunol 2016; 36:14–19. doi: 10.1016/j.trim.2016.03.002. 7. solez k, racusen lc. the banff classification revisited. kidney int 2013; 83:201–6. doi: 10.1038/ki.2012.395. 8. haas m. the revised (2013) banff classification for antibodymediated rejection of renal allografts: update, difficulties, and future considerations. am j transplant 2015; 16:1352–7. doi: 10.1111/ajt.13661. 9. burton sa, amir n, asbury a, lange a, hardinger kl. treatment of antibody-mediated rejection in renal transplant patients: a clinical practice survey. clin transplant 2015; 29:118–23. doi: 10.1111/ctr.12491. 10. feucht he. complement c4d in graft capillaries: the missing link in the recognition of humoral alloreactivity. am j transplant 2003; 3:646–52. doi: 10.1034/j.1600-6143.2003.00171.x. 11. yilmaz vt, suleymanlar g, koksoy s, ulger bv, ozdem s, akbas h, et al. therapy modalities for antibody mediated rejection in renal transplant patients. j invest surg 2016; 1–7 [epub ahead of print]. doi: 10.3109/08941939.2016.1154626. 12. archdeacon p, chan m, neuland c, velidedeoglu e, meyer j, tracy l, et al. summary of fda antibody-mediated rejection workshop. am j transplant 2011; 11:896–906. doi: 10.1111/j.1600-6143.2011.03525.x. 13. rocha pn, butterly dw, greenberg a, reddan dn, tuttle-newhall j, collins bh, et al. beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. transplantation 2003; 75:1490–5. 14. al-badr w, kallogjeri d, madaraty k, oliver d, bastani b, grossman bj. a retrospective review of the outcome of plasma exchange and aggressive medical therapy in antibody mediated rejection of renal allografts: a single center experience. j clin apher 2008; 23:178–82. doi: 10.1002/jca.20181. 15. kaposztas z, podder h, mauiyyedi s, illoh o, kerman r, reyes m, et al. impact of rituximab therapy for treatment of acute humoral rejection. clin transplant 2009; 23:63–73. doi: 10.1111/j.1399-0012.2008.00902.x. 16. flechner sm, fatica r, askar m, stephany br, poggio e, koo a, et al. the role of proteasome inhibition with bortezomib in the treatment of antibody-mediated rejection after kidney-only or kidney-combined organ transplantation. transplantation 2010; 90:1486–92. doi: 10.1097/tp.0b013e3181fdd9b0. 17. everly mj, everly jj, susskind b, brailey p, arend lj, alloway rr, et al. bortezomib provides effective therapy for antibodyand cell-mediated acute rejection. transplantation 2008; 86:1754– 61. doi: 10.1097/tp.0b013e318190af83. 18. johnson ck, leca n. eculizumab use in kidney transplantation. curr opin organ transplant 2015; 20:643–51. doi: 10.1097/ mot.0000000000000249. 19. emadi a, brodsky ra. successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. am j hematol 2009; 84:699–701. doi: 10.1002/ajh.21506. 20. nürnberger j, philipp t, witzke o, opazo saez a, vester u, baba ha, et al. eculizumab for atypical hemolytic-uremic syndrome. n engl j med 2009; 360:542–4. doi: 10.1056/ nejmc0808527. 21. frémeaux-bacchi v, legendre cm. the emerging role of complement inhibitors in transplantation. kidney int 2015; 88:967–73. doi: 10.1038/ki.2015.253. 22. gonzález-roncero f, suñer m, bernal g, cabello v, toro m, pereira p, et al. eculizumab treatment of acute antibody-mediated rejection in renal transplantation: case reports. transplant proc 2012; 44:2690–4. doi: 10.1016/j. transproceed.2012.09.038. 23. legendre c, sberro-soussan r, zuber j, rabant m, loupy a, timsit mo, et al. eculizumab in renal transplantation. transplant rev (orlando) 2013; 27:90–2. doi: 10.1016/j. trre.2013.04.002. 24. locke je, margo cm, singer al, segev dl, haas m, hillel at, et al. the use of antibody to complement protein c5 for salvage treatment of severe antibody-mediated rejection. am j transplant 2009; 9:231–5. doi: 10.1111/j.16006143.2008.02451.x. doi:%2010.1093/bja/aer38410.1093/bja/aer384 http://dx.doi.org/10.1016/j.transproceed.2004.01.116 http://dx.doi.org/10.1097/mot.0000000000000230 http://dx.doi.org/10.1097/mot.0000000000000230 http://dx.doi.org/10.1155/2012/193724 http://dx.doi.org/10.1159/000170842 http://dx.doi.org/10.1016/j.trim.2016.03.002 http://dx.doi.org/10.1038/ki.2012.395 http://dx.doi.org/10.1111/ajt.13661 http://dx.doi.org/10.1111/ctr.12491 http://dx.doi.org/10.1034/j.1600-6143.2003.00171.x http://dx.doi.org/10.3109/08941939.2016.1154626 http://dx.doi.org/10.1111/j.1600-6143.2011.03525.x http://dx.doi.org/10.1002/jca.20181 http://dx.doi.org/10.1111/j.1399-0012.2008.00902.x http://dx.doi.org/10.1097/tp.0b013e3181fdd9b0 http://dx.doi.org/10.1097/tp.0b013e318190af83 http://dx.doi.org/10.1097/mot.0000000000000249 http://dx.doi.org/10.1097/mot.0000000000000249 http://dx.doi.org/10.1002/ajh.21506 http://dx.doi.org/10.1056/nejmc0808527 http://dx.doi.org/10.1056/nejmc0808527 http://dx.doi.org/10.1038/ki.2015.253 http://dx.doi.org/10.1016/j.transproceed.2012.09.038 http://dx.doi.org/10.1016/j.transproceed.2012.09.038 http://dx.doi.org/10.1016/j.trre.2013.04.002 http://dx.doi.org/10.1016/j.trre.2013.04.002 http://dx.doi.org/10.1111/j.1600-6143.2008.02451.x http://dx.doi.org/10.1111/j.1600-6143.2008.02451.x departments of 1child health and 2pediatric cardiology, royal hospital, muscat, oman *corresponding author e-mail: kholoud_saeed@hotmail.com تعاكس الشرايني الكربى وتضيق الشريان األهبر يف رضيع مصاب بالتهاب القصيبات اهلوائية إكتشاف عرضي خلود �سعيد املخينية وعالء م�سطفى حممد abstract: the transposition of the great arteries (tga) is a complex congenital heart disease which usually presents as cyanosis in neonates with limited mixing between the systemic and pulmonary circulatory systems. a delayed diagnosis of tga can lead to ventricular failure. we report a six-week-old infant who was admitted to the paediatric intensive care unit of the royal hospital, muscat, oman, in 2016 for bronchiolitis. during admission, she was incidentally diagnosed with tga and coarctation of the aorta. postnatal screening, including the use of pulse oximetry, plays a significant role in avoiding a late diagnosis of tga; however, this screening tool is not widely used in oman. moreover, the common practice of applying a pulse oximetry probe only to the foot may have been limited in the current case due to the reverse differential saturation between the upper and lower limbs caused by this particular combination of lesions. keywords: transposition of great arteries; cyanosis; neonatal screening; pulse oximetry; case report; oman. امللخ�ص: تعاك�ص ال�رصايني الكربى من اأمرا�ص القلب اخللقية املعقدة التي ت�سبب ازرقاق اللون يف حديثي الوالدة مع اختالط حمدود بني الدورةالدمويه اجل�سميه والرئوية. الت�سخي�ص املتاأخر لهذه احلالة ممكن اأن يوؤدي اإىل ف�سل البطني القلبي. هنا نعر�ص حالة ر�سيع يبلغ من العمر �ستة اأ�سابيع اأدخل اإىل وحدة العناية املركزة لالأطفال يف امل�ست�سفى ال�سلطاين يف م�سقط، عمان، عام 2016، ب�سبب التهاب الق�سيبات الهوائية. مت عن طريق امل�سادفة ت�سخي�ص احلالة بتعاك�ص ال�رصايني الكربى وت�سيق ال�رصيان االأبهر. هذا يربهن ان فح�ص ما بعد الوالدة، مبا يف ذلك ا�ستخدام قيا�ص النب�ص، يلعب دورا هاما يف الت�سخي�ص املبكرلتعاك�ص ال�رصايني الكربى، ومع ذلك، فاإن هذه االأداة ال ت�ستخدم على نطاق وا�سع يف عمان. واأي�سا، فاإن املمار�سة ال�سائعة لتطبيق م�سبار قيا�ص التاأك�سج النب�سي فقط على القدم قد تكون حمدودة النتائج يف احلالة احلالية ب�سبب الت�سبع التفا�سلي العك�سي بني االأطراف العلوية وال�سفلية الناجمة عن جمموع االأ�سباب املر�سية. الكلمات املفتاحية: تعاك�ص ال�رصايني الكربى؛ ازرقاق؛ فح�ص حديثي الوالدة؛ التاأك�سج النب�سي؛ تقرير حالة؛ عمان. transposition of the great arteries and coarctation of the aorta in an infant presenting with bronchiolitis an incidental finding *khaloud s. al-mukhaini1 and ala m. mohamed2 sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e348–351, epub. 10 oct 17 submitted 1 mar 17 revision req. 27 mar 17; revision recd. 29 apr 17 accepted 18 may 17 case report doi: 10.18295/squmj.2017.17.03.016 moderate to severe congenital heart diseases occur in approximately six in 1,000 live births.1 of these, the transposition of the great arteries (tga) is a major condition in which the aorta and pulmonary arteries do not arise from their respective ventricles, resulting in ventriculoarterial discordance and parallel pulmonary and systemic circulation.2 while most infants are diagnosed with tga in the neonatal period, a subgroup of children are diagnosed at a much later stage. a delayed presentation of tga carries additional complications—such as congestive heart failure in patients with increased pulmonary blood flow and systemic ventricular failure in those with an intact ventricular septum—leading to a need for ventricular support devices and longer stays in the intensive care unit (icu).2,3 as such, the early diagnosis of this major lesion can avoid associated morbidity and mortality.4 case report a six-week-old infant girl was admitted to the paediatric icu of the royal hospital, muscat, oman, in 2016 with symptoms of respiratory distress. the infant had been born at term with a birthweight of 2.38 kg. the postnatal course was uneventful and she was discharged and sent home on the second day of life. there was no maternal history of diabetes and no history of cardiac diseases among the family members. at the age of one month, the infant had been evaluated khaloud s. al-mukhaini and ala m. mohamed case report | e349 for a febrile illness and respiratory distress and diagnosed with bronchiolitis. at admission, her weight and length was 3.00 kg and 52 cm, respectively. due to difficulties in breathing, noninvasive ventilation in the form of continuous positive airway pressure was initiated; however, as the breathing difficulties persisted, she was later intubated. following admission, the patient was noted to have a wide pulse pressure and a pansystolic murmur with peripheral pulses of adequate volume, including femoral pulses. in addition, she had features of congestive heart failure with cardiomegaly and congested lungs [figure 1]. given these clinical features, an echocardiogram was performed which showed discordant ventriculoarterial connections, good biventricular function, a large unrestrictive ventricular septal defect (vsd) measuring 8 x 7 mm, coarctation of the aorta and a large patent ductus arteriosus (pda) of 6.7 mm, supplying the distal aorta with a bidirectional shunt [figure 2]. notably, she had reversed differential saturation between the upper and lower limbs with oxygen saturation of 80% in the right hand and 100% in the lower limb. her fraction of inspired oxygen level was 0.45. a respiratory viral panel was positive for a rhinovirus infection. on the ninth day following admission, a singlestage surgery was performed combining an arterial switch operation with an aortic arch repair and vsd closure. the bypass and cross-clamp time was 240 and 137 minutes, respectively. the postoperative period was complicated by low cardiac output, renal impairment requiring peritoneal dialysis and a left-sided diaphragm weakness necessitating diaphragmatic plication. follow ing a period of noninvasive ventilatory support, the patient was discharged one month after admission while breathing room air. at a two-month follow-up visit, she was healthy. discussion in tga cases, the clinical presentation is affected by the presence of atrial, ventricular or ductal connections and the degree of mixing between the two circulatory systems.2 some infants without circulatory mixing present earlier in shock, often urgently requiring a prostaglandin infusion and an atrial septostomy as a palliative measure while awaiting corrective surgery. in contrast, infants with significant defects (including large vsds, atrial septal defects and pdas) may present later with features of congestive heart failure and mild cyanosis following a decrease in pulmonary vascular resistance.2 in the current case, the patient had adequate-volume peripheral pulses due to a large pda, despite the concomitant presence of a coarctation of the aorta. an interesting observation in the current patient was the reversed differential cyanosis. the term figure 2: echocardiograms of a six-week-old female infant in the (a) suprasternal and (b) parasternal long axis views showing coarctation (arrow) and the continuation of the arterial duct (arrowhead) into the descending aorta. note the anterior aorta arising from the right ventricle and the posterior pulmonary artery. ao = ascending aorta; pa = pulmonary artery; lv = left ventricle; rv = right ventricle; la = left atrium. figure 1: anteroposterior chest x-ray of a six-week-old female infant showing plethoric lung fields. transposition of the great arteries and coarctation of the aorta in an infant presenting with bronchiolitis an incidental finding e350 | squ medical journal, august 2017, volume 17, issue 3 however, not all institutions incorporate screening at both the preand post-ductal sites; instead, some test only the post-ductal site in the foot, since most lesions have lower saturations in the foot due to a right-to-left shunt at the ductal level.10 this approach would miss a complex defect, as seen in the current patient who had higher saturation in the foot due to reversed differential saturation. unfortunately, pulse oximetry screening is not mandatory in omani health institutions and, when performed, may be restricted to the post-ductal site. as such, the researchers strongly recommend that these limitations be addressed in future screening practices in the country. at birth, the left ventricle is of normal thickness in infants with tga who have an intact ventricular septum; however, since it supports only low-pressure pulmonary circulation, the ventricle loses its muscle mass and becomes thin-walled by the time the child is 2–4 months old.13 in cases such as the current one, the systemic ventricle has a reduced risk of deconditioning due to the presence of a large vsd that exposes the ventricle to systemic or near-systemic pressure.2 nevertheless, the presence of aortic arch abnormalities requires early surgery.2 an arterial switch operation is the surgical procedure of choice for tga cases.14 however, a primary tga repair can be still performed at 3–8 weeks of age, with similar results to those found for surgical repairs undertaken at an earlier age.3 in children with tga and a large vsd, as in the present case, the surgery of choice is also an arterial switch operation.2 edwin et al. reported that surgical correction in infants over two months old with tga and an intact ventricular septum resulted in prolonged mechanical ventilation and increased hospital stays due to the deconditioning of the systemic ventricles.3 conclusion this case describes a patient with a significant congenital heart lesion diagnosed incidentally following her admission for bronchiolitis. as she had been asymptomatic at birth and no postnatal screening for cardiac anomalies was undertaken, the condition had gone undiagnosed. neonatal and postnatal screening has been shown to play a major role in reducing undiagnosed cases of congenital heart diseases. the current case demonstrates that even a combination of two complex cardiac lesions can be missed both antenatally and postnatally. it is therefore recommended that universal postnatal pulse oximetry screening be implemented in healthcare institutions throughout oman, with screening of both the preand post-ductal sites to include the right hand and one of the feet. differential cyanosis refers to the discrepancy between upper and lower limb saturation where the former is higher compared to the latter.5 this finding is often observed in children with a left-to-right shunt at the ductal level, either due to pulmonary hypertension or an obstruction in aortic blood flow anywhere proximal to the ductus. reversed differential cyanosis, on the other hand, is seen in children with tga in association with aortic arch abnormalities and pulmonary hypertension.2,5 in such cases, the deoxygenated blood from the right ventricle is pumped into the systemic circulatory system through the aorta to supply the head, neck and upper limbs while the oxygenated blood from the left ventricle is pumped into the pulmonary circulation via the pulmonary artery.2 the presence of a coarctation between the left subclavian artery and the ductus allows for the shunting of a portion of this blood—while the rest is ejected to the lungs—from the pulmonary artery to the descending aorta which supplies the rest of the torso and lower limbs. this leads to higher saturation in the lower limbs in comparison to the arms.2,5 while reversed differential cyanosis is pathognomonic in children with tga, a pda and elevated pulmonary vascular resistance or aortic arch abnormalities, it has also been reported in an infant presenting with a supracardiac total anomalous pulmonary venous connection.6 in recent years, fetal echocardiography has become an important tool for antenatal care. patients with critical congenital heart lesions diagnosed antenatally have a better prognosis than those diagnosed postnatally, including a reduced risk of brain injury, as they can be rapidly transferred to a tertiary surgical centre and receive early intervention.4,7,8 various international guidelines recommend antenatal anomaly screening, including the need for certain imaging views such as four chamber and ventricular outflow tract assessments.9 staff training in obstetric ultrasonography techniques is therefore crucial to improve the antenatal detection of congenital heart diseases. in addition, neonatal screening for congenital cardiac anomalies should include pulse oximetry as a part of the clinical examination. this method of postnatal testing has been incorporated into numerous newborn screening programmes worldwide and is recommended by the american academy of pediatrics, american heart association and the american college of cardiology.10,11 overall, the percentage of severe congenital heart diseases diagnosed postnatally has increased from 58% with clinical examinations alone to 72% with pulse oximetry.10,12 asymptomatic neonates should be screened after 24 hours of life or before discharge at two sites, including the right hand and foot.10 khaloud s. al-mukhaini and ala m. mohamed case report | e351 references 1. hoffman ji, kaplan s. the incidence of congenital heart disease. j am coll cardiol 2002; 39:1890–900. doi: 10.1016/s07351097(02)01886-7. 2. latham gj, joffe dc, eisses mj, richards mj, geiduschek jm. anesthetic considerations and management of transposition of the great arteries. semin cardiothorac vasc anesth 2015; 19:233–42. doi: 10.1177/1089253215581852. 3. edwin f, mamorare h, brink j, kinsley r. primary arterial switch operation for transposition of the great arteries with intact ventricular septum: is it safe after three weeks of age? interact cardiovasc thorac surg 2010; 11:641–4. doi: 10.1510/ icvts.2010.243832. 4. eckersley l, sadler l, parry e, finucane k, gentles tl. timing of diagnosis affects mortality in critical congenital heart disease. arch dis child 2016; 101:516–20. doi: 10.1136/ archdischild-2014-307691. 5. buckley mj, mason dt, ross j jr, braunwald e. reversed differential cyanosis with equal desaturation of the upper limbs: syndrome of complete transposition of the great vessels with complete interruption of the aortic arch. am j cardiol 1965; 15:111–15. doi: 10.1016/0002-9149(65)90609-0. 6. yap sh, anania n, alboliras et, lilien ld. reversed differential cyanosis in the newborn: a clinical finding in the supracardiac total anomalous pulmonary venous connection. pediatr cardiol 2009; 30:359–62. doi: 10.1007/s00246-008-9314-0. 7. hunter le, simpson jm. prenatal screening for structural congenital heart disease. nat rev cardiol 2014; 11:323–34. doi: 10.1038/nrcardio.2014.34. 8. peyvandi s, de santiago v, chakkarapani e, chau v, campbell a, poskitt kj, et al. association of prenatal diagnosis of critical congenital heart disease with postnatal brain development and the risk of brain injury. jama pediatr 2016; 170:e154450. doi: 10.1001/jamapediatrics.2015.4450. 9. sharland g. fetal cardiac screening: why bother? arch dis child fetal neonatal ed 2010; 95:f64–8. doi: 10.1136/ adc.2008.151225. 10. oster me, kochilas l. screening for critical congenital heart disease. clin perinatol 2016; 43:73–80. doi: 10.1016/j. clp.2015.11.005. 11. kemper ar, mahle wt, martin gr, cooley wc, kumar p, morrow wr, et al. strategies for implementing screening for critical congenital heart disease. pediatrics 2011; 128:e1259–67. doi: 10.1542/peds.2011-1317. 12. valmari p. should pulse oximetry be used to screen for congenital heart disease? arch dis child fetal neonatal ed 2007; 92:f219–24. doi: 10.1136/adc.2005.090282. 13. planche c, lacour-gayet f, serraf a. arterial switch. pediatr cardiol 1998; 19:297–307. doi: 10.1007/s002469900313. 14. tchervenkov ci. surgical management of transposition in the setting of obstruction within the aortic arch. cardiol young 2005; 15:106–10. doi: 10.1017/s1047951105001125. https://doi.org/10.1016/s0735-1097%2802%2901886-7 https://doi.org/10.1016/s0735-1097%2802%2901886-7 https://doi.org/10.1177/1089253215581852 https://doi.org/10.1510/icvts.2010.243832 https://doi.org/10.1510/icvts.2010.243832 https://doi.org/10.1136/archdischild-2014-307691 https://doi.org/10.1136/archdischild-2014-307691 https://doi.org/10.1016/0002-9149%2865%2990609-0 https://doi.org/10.1007/s00246-008-9314-0 https://doi.org/10.1038/nrcardio.2014.34 https://doi.org/10.1001/jamapediatrics.2015.4450 https://doi.org/10.1136/adc.2008.151225 https://doi.org/10.1136/adc.2008.151225 https://doi.org/10.1016/j.clp.2015.11.005 https://doi.org/10.1016/j.clp.2015.11.005 https://doi.org/10.1542/peds.2011-1317 https://doi.org/10.1136/adc.2005.090282 https://doi.org/10.1007/s002469900313 https://doi.org/10.1017/s1047951105001125 department of otorhinolaryngology, bahrain defence force hospital, ar-rifaa, bahrain *corresponding author’s e-mail: heshambdf@hotmail.com فعالية العالج بالبيسيبانيل )ok-432( لإلزالة الغري جراحية ألورام منطقة الرأس والرقبة التكيسية سلسلة حاالت ه�سام يو�سف علي ح�سن و حممد عامر ر�سوان abstract: head and neck masses can present in different pathologies that usually vary according to the age of the patient. we report five cases of benign head or neck masses occurring among patients of different ages who were managed at the bahrain defence force royal medical services hospital, ar-rifaa, bahrain, between 2005–2014. all of the patients were treated using the sclerotherapeutic agent ok-432. although surgical removal is usually considered optimal treatment in the management of such cases, ok-432 appears to be a promising alternative. keywords: sclerotherapy; ok-432; lymphatic abnormalities; branchial cyst; thyroglossal cyst; cystic hygroma; case series; bahrain. امللخ�ص: تظهر اأورام الراأ�ض والرقبة ب�سبب اأمرا�ض خمتلفة تختلف اأنواعها عادًة ح�سب عمر املري�ض، ن�ستعر�ض هنا خم�ض حاالت اأ�سيبت دفاع لقوة التابع امللكية الطبية اخلدمات م�ست�سفى يف عالجهم ومت خمتلفة الأعمار ينتمون الرقبة اأو الراأ�ض منطقة يف حميدة باأورام البحرين، منطقة الرفاع، مملكة البحرين يف الفرتة من عام، 2014–2005. ومت عالج جميع احلاالت با�ستخدام الدواء املحفز للت�سلب من ok-432 وبالرغم من اأن االإزالة اجلراحية تعترب االأف�سل يف عالج مثل هذه احلاالت، اإال اأن العالج الت�سلبي با�ستخدام ،ok-432 نوع قد يوفر بدياًل منا�سبًا وناجحًا. الكي�سي؛ املائي الورم الل�ساين؛ الدرقي التكي�ض اخلي�سومي؛ التكي�ض اللمفاوي؛ اجلهاز عيوب ok-432؛ الت�سلبي؛ العالج املفتاحية: الكلمات �سل�سلةحاالت؛ البحرين. efficacy of ok-432 therapy for the incisionless treatment of head and neck cystic masses case series *hesham y. a. hasan and muhammad a. rizwan case series sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e88–92, epub. 4 apr 18 submitted 25 aug 17 revision req. 31 oct 17; revision recd. 26 nov 17 accepted 21 dec 17 doi: 10.18295/squmj.2018.18.01.014 a m i x t u r e o f b a c t e r i a i n a h e at attenuated form was first used to treat in-operable malignancies in 1891.1 subsequently, in 1967, a streptococcus pyogenes strain was found to have a positive anticancer effect.2 these experiments led to the development of ok-432, a freezedried product prepared from the su strain of the group a streptococcus pyogenes species. upon exposure to benzylpenicillin and heat treatment, the toxinproducing capacity of the bacterium is eliminated and its anticancer properties are enhanced.3 this process involves heating the su strain in the presence of benzylpenicillin at 37 °c for 20 minutes and then 45 °c for 30 minutes. at this stage, the product is known as pc-b-45 or ok-431, before becoming ok-432 after being freeze-dried.3 the product contains an intact bacterial cell wall devoid of its toxin-producing properties, consequently eliminating its ability to cause infection and proliferate. each dose is measured in klinische einheit (ke), of which one ke equals 0.1 mg of freeze-dried streptococci containing approximately 1 x 108 cells.3 cystic neck masses can be either congenital or acquired. branchial cleft cysts, thyroglossal duct cysts, cystic lymphangiomas, dermoid cysts, ranulae and laryngoceles are common congenital neck masses, while acquired neck cysts include laryngoceles, cystic schwannomas and parotid cysts.4 a provisional diag nosis can be made based on the age and clinical presentation of the patient, which can subsequently be confirmed using radiological and pathological investigations. in general, benign cystic neck masses such as branchial cleft cysts, lymphangiomas and plunging ranulae are usually amenable to surgical excision; however, the lesions may recur due to the technicallychallenging nature of the surgical intervention or inadequate excision to avoid nerve or vessel injury.5 classically, residual disease and subsequent recurrence is more commonly encountered with lymphatic malformations and branchial cystic masses.6 hesham y. a. hasan and muhammad a. rizwan case series | e89 alternative non-surgical modalities—including cryotherapy, diathermy, radiofrequency ablation and laser treatment—have been employed in the treatment of cystic head and neck lesions, with varying degrees of success.7 a more appealing alternative is sclerotherapy, including bleomycin, ethanol and sodium tetradecyl sulphate.8 in 1986, ogita et al. first noted that ok-432 injections were effective in reducing or even completely resolving unresectable paediatric lymph angiomas.9 since then, ok-432 has been investigated to determine its potential benefits in treating head and neck cystic masses in both children and adults.10 patients who fail to respond to surgical management are often successfully treated with ok-432, with even more promising results in conjunction with surgery.11 overall, ok-432 has proven effective in the treatment of malignant ascites, pleural effusion and lymphatic malformations.12 this case series describes five patients with cystic head or neck lesions who were successfully treated with ok-432 therapy at the bahrain defence force royal medical services hospital, ar-rifaa, bahrain. case one a 54-year-old woman presented in 2014 with a recurrent branchial cyst following a previous surgical excision at another hospital. postoperatively, she had suffered from temporary palsy of the marginal mandibular branch. at presentation, the cyst measured 3.9 x 1.5 cm and was located in the left lateral region of the upper neck [figure 1]. the patient feared undergoing a second, potentially more difficult surgery with an increased risk of complications. for this reason, intra lesional ok-432 treatment was initiated. after two sessions, the cyst had regressed and was no longer visible or palpable. the patient experienced no complic ations. she was followed up for two years after the treat ment, with no evidence of recurrence. unfortunately, longer-term follow-up was not possible as the patient moved abroad. case two a two-year-old male child presented in 2012 with a three-month history of a cyst in the left upper neck, measuring 5.2 x 3.5 cm [figure 2]. the patient underwent nine sessions of ok-432 sclerotherapy, with no complications, resulting in complete resolution of the lesion. the patient was followed up for four years with no evidence of recurrence. case three an eight-month-old female child presented in 2005 with a congenital mass measuring 6.21 x 4.52 x 3.92 cm in the right supraclavicular fossa [figure 3]. clinically and radiologically, the mass appeared consistent with a cystic hygroma. three sessions of ok-432 sclerotherapy resulted in the total dissolution of the cyst. the patient had no complications and was followed up for nine years with no recurrence. case four a 30-year-old woman presented in 2011 with a five month history of a midline neck swelling that moved upon swallowing or extension of the tongue. computed tomography of the neck showed a cystic mass measuring 2.5 x 1.5 x 2.7 cm, consistent with a thyroglossal cyst. figure 1: photographs of a 54-year-old woman with a left branchial cyst which had (a) recurred following surgery but (b) resolved following ok-432 treatment. figure 3: photographs of an eight-month-old female child with a cystic hygroma (a) before and (b) after treatment with ok-432 sclerotherapy. figure 2: photographs of a two-year-old male child with a left branchial cyst (a) before and (b) after treatment with ok-432 sclerotherapy. efficacy of ok-432 therapy for the incisionless treatment of head and neck cystic masses case series e90 | squ medical journal, february 2018, volume 18, issue 1 as the patient did not wish to undergo a surgery which might potentially cause scarring, ok-432 treatment was her preferred option. she completed a total of four sessions of ok-432 sclerotherapy uneventfully, with no subsequent recurrence over the next three years. case five a 44-year-old man presented in 2013 with a left parotid cystic swelling that had persisted for a year. ultrasound-guided fine needle aspiration cytology confirmed the benign nature of the cystic mass, with a final diagnosis of an idiopathic benign cyst. the patient was given a single dose of intralesional ok-432 under ultrasound guidance and the swelling resolved completely without any complications. none of the five patients demonstrated any allergic reactions to the treatment or untoward side-effects. in addition, all of the patients were compliant with the planned treatment and participated in each session as scheduled. a summary of the cases is provided in table 1. discussion overall, the outcome of ok-432 treatment for all five patients reported in the current case series was positive, with no undue adverse reactions observed. several previous reports have indicated the effectiveness of ok-432 sclerotherapy as treatment for a variety of cystic neck lesions, usually resulting in total or near complete resolution of the lesion with no recurrence.10–12 in their original research, ogita et al. reported an overall cure rate of 91.3%.9 in the current case series, all five of the patients were cured as a result of ok-432 sclerotherapy; moreover, the treatment was able to resolve the postoperative recurrence of a branchial cyst in case one. differences in the patients’ ages at the time of treatment did not seem to affect the efficacy of the treatment. additionally, none of the patients reported any skin discoloration or local scarring during or after ok-432 treatment. this is consistent with the findings of ohta et al.13 during embryological development, the failed closure of the branchial cleft can lead to the formation of either a branchial cyst (75%) or a sinus fistula (25%).14 in the current case series, two patients (cases one and two) had unilocular branchial cysts. interestingly, the first case involved an adult who had previously undergone surgical excision and subsequent recurrence of the lesion. neither cases had residual masses after treatment, yielding a 100% response rate to ok-432 sclerotherapy alone. kim et al. reported that 60.8% of patients with unilocular branchial cysts experienced total regression following ok-432 treat ment, with no or partial response in cases of multilocular cysts.7 in another study, roh et al. found that seven out of 12 patients with branchial cysts experienced full resolution following ok-432 treatment, while three patients exhibited a partial response and the treatment failed in two patients.15 in both of the aforementioned studies, patients who did not respond to ok-432 treatment subsequently underwent surgical excision, thus indicating that this may be a potential salvage option in such cases.7,15 lymphatic malformations are classified into microcystic, macrocystic and combined types. in 50% of cases, the malformations are present at birth, with another 40% emerging by the age of two years.16 the spontaneous resolution of cystic hygromas is rare and occurs in less than 12.5% of cases.17 surgical management is complicated by the high risk of injury to the surrounding neurovascular structures, scarring and recurrence. various sclerotherapy agents have been used to treat macrocystic lymphatic malformations, including alcoholic solution of zein, pure ethanol, bleomycin a5, doxycycline, acetic acid and polidocanol.18 in the third case reported in the present series, the patient responded well to ok-432 therapy with no residual mass or recurrence of the cystic hygroma after three doses. in their study of massive macrocystic lymphatic malformations, chen et al. observed excellent outcomes with a combination of fibrin glue, ok-432 and bleomycin in 53% of patients, in comparison to good and partial outcomes in 33% and 13% of cases, respectively.19 none of the patients required surgical excision.19 table 1: summary of five cases of benign cystic head or neck masses treated with ok-432 sclerotherapy case diagnosis age in years size in cm number of treatment sessions outcome 1 branchial cyst 54 3.9 x 1.5 2 resolved 2 branchial cyst 2 5.2 x 3.5 9 resolved 3 cystic hygroma 0.6 6.21 x 4.52 x 3.92 3 resolved 4 thyroglossal cyst 30 2.5 x 1.5 x 2.7 4 resolved 5 benign parotid cyst 44 6.0 x 1.4 1 resolved hesham y. a. hasan and muhammad a. rizwan case series | e91 thyroglossal duct cysts account for 70% of congenital neck masses; these lesions have a bimodal age distribution in which 90% of patients present by the age of 10 years, with a second peak in young adulthood.4 surgery in the form of a classic sistrunk procedure is the preferred method of management.20 kim et al. reported reduction in the volume of the cyst in 81.3% of patients undergoing ethanol sclerotherapy ablation.21 the same authors reported that 41.4% of thyroglossal duct cysts treated with ok-432 showed complete regression.22 ohta et al. reported that ok-432 therapy had better results for patients with thyroglossal cysts compared to branchial cysts.23 however, in the current case series, there was complete regression in both cases one and four, regardless of the type of cyst. cystic lesions in the parotid gland can be either bilateral or unilateral and congenital or acquired. congenital cysts can present at birth but most often reveal themselves in adulthood.4 occasionally, systemic diseases such as sjögren’s syndrome and hiv may present with bilateral benign parotid cysts.24 while benign parotid cysts are usually managed surgically, there has been recent evidence supporting the use of sclerotherapy. for example, monama et al. reported the complete resolution of parotid cysts without morbidity in three adult patients following bleomycin sclerotherapy.25 in the current case series, the fifth patient underwent aspiration of a parotid cyst under ultrasonic guidance in order to exclude malignancy before commencing ok-432 treatment. this resulted in complete regression with no recurrence within the subsequent follow-up period. conclusion sclerotherapy is the optimal therapeutic choice for a variety of benign cystic neck masses. the safety, effectiveness and economic and cosmetic advantages of the sclerotherapeutic agent ok-432 make this modality a favourable alternative to surgery in the management of various otolaryngological cystic head and neck masses, including lymphatic cystic lesions as well as thyroglossal duct and branchial cysts. furthermore, surgery can be reserved as a salvage procedure following ok-432 treatment in cases of postsurgical recurrence or residual disease. references 1. wiemann b, starnes co. coley’s toxins, tumor necrosis factor and cancer research: a historical perspective. pharmacol ther 1994; 64:529–64. doi: 10.1016/0163-7258(94)90023-x. 2. okamoto h, shoin s, koshimura s, shimizu r. studies on the anticancer and streptolysin s-forming abilities of hemolytic streptococci. jpn j microbiol 1967; 11:323–36. doi: 10.1111/ j.1348-0421.1967.tb00350.x. 3. okamoto h, shoin s, koshimura s. streptolysin s-forming and antitumor activities of group a streptococci. in: jeljaszewicz j, wadstrom t, eds. bacterial toxins and cell membranes. new york, usa: academic press inc., 1978. p. 259. 4. mittal mk, malik a, sureka b, thukral bb. cystic masses of neck: a pictorial review. indian j radiol imaging 2012; 22:334–43. doi: 10.4103/0971-3026.111488. 5. bloom dc, perkins ja, manning sc. management of lymphatic malformations. curr opin otolaryngol head neck surg 2004; 12:500–4. doi: 10.1097/01.moo.0000143971.19992.2d. 6. kim kh, sung mw, roh jl, han mh. sclerotherapy for congenital lesions in the head and neck. otolaryngol head neck surg 2004; 131:307–16. doi: 10.1016/j.otohns.2004.02.018. 7. kim mg, lee nh, ban jh, lee kc, jin sm, lee sh. sclerotherapy of branchial cleft cysts using ok-432. otolaryngol head neck surg 2009; 141:329–34. doi: 10.1016/j.otohns.2009.05.022. 8. bajpai h, bajpai s. comparative analysis of intralesional sclerotherapy with sodium tetradecyl sulfate versus bleomycin in the management of low flow craniofacial soft tissue vascular lesions. j maxillofac oral surg 2012; 11:13–20. doi: 10.1007/ s12663-011-0325-7. 9. ogita s, tsuto t, deguchi e, tokiwa k, nagashima m, iwai n. ok-432 therapy for unresectable lymphangiomas in children. j pediatr surg. 1991; 26:263-8. doi: 10.1016/0022-3468(91)90500-s. 10. smith mc, zimmerman mb, burke dk, bauman nm, sato y, smith rj, et al. efficacy and safety of ok-432 immunotherapy of lymphatic malformations. laryngoscope 2009; 119:107–15. doi: 10.1002/lary.20041. 11. kim sy, lee s, seo jm, lim sy. postoperative adjuvant ok432 sclerotherapy for treatment of cervicofacial lymphatic malformations: an outcomes comparison. int j pediatr otorhinolaryngol 2015; 79:570–5. doi: 10.1016/j.ijporl.2015.01.030. 12. kitsuki h, katano m, ikubo a, morisaki t, annan k, tanaka m, et al. induction of inflammatory cytokines in effusion cavity by ok-432 injection therapy for patients with malignant effusion: role of interferon-gamma in enhancement of surface expression of icam-1 on tumor cells in vivo. clin immunol immunopathol 1996; 78:283–90. doi: 10.1006/clin.1996.0040. 13. ohta n, fukase s, watanabe t, ito t, aoyagi m. effects and mechanism of ok-432 therapy in various neck cystic lesions. acta otolaryngol 2010; 130:1287–92. doi: 10.3109/ 00016489.2010.483480. 14. deane sa, telander rl. surgery for thyroglossal duct and branchial cleft anomalies. am j surg 1978; 136:348–53. doi: 10.1016/0002-9610(78)90292-1. 15. roh jl, sung mw, hyun kim k, il park c. treatment of branchial cleft cyst with intracystic injection of ok-432. acta otolaryngol 2006; 126:510–4. doi: 10.1080/00016480500437443. 16. mulligan pr, prajapati hj, martin lg, patel th. vascular anomalies: classification, imaging characteristics and implications for interventional radiology treatment approaches. br j radiol 2014; 87:20130392. doi: 10.1259/bjr.20130392. 17. kennedy tl. cystic hygroma-lymphangioma: a rare and still unclear entity. laryngoscope 1989; 99:1–10. doi: 10.1288/0000 5537-198910001-00001. 18. farnoosh s, don d, koempel j, panossian a, anselmo d, stanley p. efficacy of doxycycline and sodium tetradecyl sulfate sclerotherapy in pediatric head and neck lymphatic malformations. int j pediatr otorhinolaryngol 2015; 79:883–7. doi: 10.1016/j.ijporl.2015.03.024. https://doi.org/10.1016/0163-7258%2894%2990023-x https://doi.org/10.1111/j.1348-0421.1967.tb00350.x https://doi.org/10.1111/j.1348-0421.1967.tb00350.x https://doi.org/10.4103/0971-3026.111488 https://doi.org/10.1097/01.moo.0000143971.19992.2d https://doi.org/10.1016/j.otohns.2004.02.018 https://doi.org/10.1016/j.otohns.2009.05.022 https://doi.org/10.1007/s12663-011-0325-7 https://doi.org/10.1007/s12663-011-0325-7 https://doi.org/10.1016/0022-3468%2891%2990500-s https://doi.org/10.1002/lary.20041 https://doi.org/10.1016/j.ijporl.2015.01.030 https://doi.org/10.1006/clin.1996.0040 https://doi.org/10.3109/00016489.2010.483480 https://doi.org/10.3109/00016489.2010.483480 https://doi.org/10.1016/0002-9610%2878%2990292-1 https://doi.org/10.1080/00016480500437443 https://doi.org/10.1259/bjr.20130392 https://doi.org/10.1288/00005537-198910001-00001 https://doi.org/10.1288/00005537-198910001-00001 https://doi.org/10.1016/j.ijporl.2015.03.024 efficacy of ok-432 therapy for the incisionless treatment of head and neck cystic masses case series e92 | squ medical journal, february 2018, volume 18, issue 1 19. chen wl, huang zq, chai q, zhang dm, wang yy, wang hj, et al. percutaneous sclerotherapy of massive macrocystic lymphatic malformations of the face and neck using fibrin glue with ok-432 and bleomycin. int j oral maxillofac surg 2011; 40:572–6. doi: 10.1016/j.ijom.2011.01.009. 20. al-thani h, el-menyar a, sulaiti ma, el-mabrok j, hajaji k, elgohary h, et al. presentation, management, and outcome of thyroglossal duct cysts in adult and pediatric populations: a 14-year single center experience. oman med j 2016; 31:276–83. doi: 10.5001/omj.2016.54. 21. kim sm, baek jh, kim ys, sung jy, lim hk, choi h, et al. efficacy and safety of ethanol ablation for thyroglossal duct cysts. ajnr am j neuroradiol 2011; 32:306–9. doi: 10.3174/ ajnr.a2296. 22. kim mg, kim sg, lee jh, eun yg, yeo sg. the therapeutic effect of ok-432 (picibanil) sclerotherapy for benign neck cysts. laryngoscope 2008; 118:2177–81. doi: 10.1097/mlg. 0b013e3181864acf. 23. ohta n, fukase s, suzuki y, ishida a, aoyagi m. treatments of various otolaryngological cystic diseases by ok-4321: its indications and limitations. laryngoscope 2010; 120:2193–6. doi: 10.1002/lary.21141. 24. shanti rm, aziz sr. hiv-associated salivary gland disease. oral maxillofac surg clin north am 2009; 21:339–43. doi: 10.1016/j.coms.2009.04.002. 25. monama gm, tshifularo mi. intralesional bleomycin injections in the treatment of benign lymphoepithelial cysts of the parotid gland in hiv-positive patients: case reports. laryngoscope 2010; 120:243–6. doi: 10.1002/lary.20577. https://doi.org/10.1016/j.ijom.2011.01.009 https://doi.org/10.5001/omj.2016.54 https://doi.org/10.3174/ajnr.a2296 https://doi.org/10.3174/ajnr.a2296 https://doi.org/10.1097/mlg.0b013e3181864acf https://doi.org/10.1097/mlg.0b013e3181864acf https://doi.org/10.1002/lary.21141 https://doi.org/10.1016/j.coms.2009.04.002 https://doi.org/10.1002/lary.20577 strongyloidiasis is caused by an infection with strongyloides stercoralis.1 the diagnosis of strongyloidiasis is often difficult since stool examination is negative in up to 50–70% of the cases.2 the role of the histopathological examination of the surgical and cytology specimens is important in the diagnosis and exclusion of a wide range of infectious diseases. case report a 52 year-old man from salalah region was referred to sultan qaboos university hospital, oman, complaining of pyrexia of unknown origin of 6 weeks duration. upon admission, he was diagnosed to have hairy cell leukemia on both blood film and bone marrow aspirate. the patient was a known case of type 2 diabetes mellitus of 15 years duration and had a previous history of treatment for helicobacter pylori induced chronic gastritis. the patient also complained of epigastric pain with nausea and loss of appetite as well as loss of weight; however, no skin manifestations, indicative of cutaneous infestations, were present. the peripheral blood oesinophilic count was normal. a repeated routine stool examination was negative for parasites. a serology test for detection of strongyloides infection was not done. an oesophageogastroduodenoscopy was performed and the findings showed gastritis with multiple duodenal ulcers and hypertrophied mucosa. gastric and duodenal biopsies (2 and 3 mm across respectively) were taken and separately submitted for histopathological examination. on gross examination, the fragments were received fixed in formalin and separately labelled as gastric and duodenal biopsies. the specimens were routinely processed and stained with haematoxylin and eosin staining. microscopic examination of the samples squ med j, august 2010, vol. 10, iss. 2, pp. 262-265, epub. 19th jun 10 submitted: 31st oct 09 revision req. 9th dec 09, revision recd. 3rd jan 10 accepted: 9th jan 10 department of pathology, sultan qaboos university hospital, muscat, oman corresponding author email: d.alsaji@yahoo.co.uk داء األسطوانيات يف املعدة واالثنى عشر �شحى حممود علوان ال�شاجي، عائ�شة احلمدانية ظهور دون الأمعاء يف العدوى من مزمنة حالت ت�شبب التي َرة( امُلَدوَّ )الدِّيداُن امَلْم�شودات من الربازية الأ�شطوانية الدودة تعترب امللخ�ص: اأعرا�س مر�شية. اأما عند املر�شى الذين يعانون �شعفا يف املناعة فيمكن اأن ت�شبب تلك الديدان تهديدا ًللحياة مع وجود اأمرا�س اأخرى. ي�شعب ت�شخي�س حالة العدوى بالديدان عن طريق الفح�س املجهري لعينة برازية بالك�شف عن يرقات الديدان حتت املجهر لأن الريقات تكون قليلة جدا مت وقد ، من مدينة �شاللة مبحافظة ظفار، ي�شكو من داء ال�شكري )النوع الثاين( ملدة 15 عاما . ن�شتعر�س هنا حالة ل�شخ�س عمره 52 عاما نق�س مع ال�شهية وفقدان البطن يف واأوجاع الغثيان من املري�س ي�شكو حديثا. امل�شعرة اخللية ذي الدم ابي�شا�س مبر�س اإ�شابته ت�شخي�س الوزن . بعد اإجراء ناظور املريء واملعدة والأمعاء واأخذ اخلزعات للفح�س الن�شيجي املر�شي، مت ت�شخي�س احلالة بالإ�شابة بداء ال�شطوانيات. امللخ�ص: الدودة الأ�شطوانية الربازية، عدوى الأمعاء، تقرير حالة ،عمان. abstract: strongyloides stercoralis is a nematode parasite which causes a protracted asymptomatic intestinal infection. it is considered a life threatening condition in immunocompromised patients when hyperinfection is associated with disseminated disease. the diagnosis by routine stool examination is very limited since the larval output in stools is very low. we present the case of a 52 year-old omani man from salalah, in the southern region of oman, with a 15-year history of type 2 diabetes mellitus and recently discovered to have hairy cell leukaemia, who complained of nausea, abdominal pain, loss of appetite and loss of weight. an oesophagogastroduodoscopic biopsy was obtained and histopathologic examination revealed gastrointestinal strongyloidiasis. keywords: strongyloides stercoralis; intestinal infection; case report; oman. a case of gastric and duodenal strongyloidiasis *dhuha m a al-sajee and aisha al-hamdani case report dhuha m a al-sajee and aisha al-hamdani case report | 263 obtained by the gastric biopsy showed gastric antral mucosa [figure 1] with cross-sections of many parasitic worms, morphologically consistent with strongyloides stercoralis, seen within the crypts, in the glandular epithelium and within the lamina propria with associated chronic inflammatory cell infiltration in the lamina propria. there was no intestinal metaplasia, malignancy or h. pylori organisms sections from the duodenal biopsy showed small bowel mucosa [figure 2] with numerous cross as well as longitudinal sections of strongyloides stercoralis. the lamina propria showed active chronic inflammatory cell infiltrate consisting of eosinophils, plasma cells and lymphocytes. the patient was treated with albendazole 400 mg orally twice daily for ten days and he was found to be completely cured of strongyloidiasis when the gastric and duodenal biopsies were repeated. discussion infection with strongyloides stercoralis is known as strongyloidiasis or threadworm infection. the global prevalence is 30–100 million with the highest prevalence in the developing countries of asia, africa and latin america.2 it is endemic in tropical and sub-tropical areas of the world.2,3 in oman, the weather is predominantly hot and dry in most of the areas except in the salalah region, where it is relatively cool and rainy, thus encouraging parasitic intestinal helminthiasis; nonetheless, strongyloidiasis is considered to be of low prevalence in oman.4,5 strongyloides stercoralis can alternate between parasitic and free-living life cycles. in the free-living cycle, the rhabditiform larvae are shed in the stool into the soil were they grow into adult worms that produce eggs which will hatch to larvae. these larvae can either grow to adult worms or penetrate the human skin to start the parasitic life cycle. in humans, the larvae are transported to the lungs through the blood stream and then through the alveoli and bronchi they reach the pharynx where they are swallowed into the stomach and the small intestine. in the small intestine, the larvae grow into adult female worms. by parthenogenesis, the female worms produce eggs that hatch to larvae and causeautoinfection.6 the diagnosis of strongyloidiasis by routine stool examination is very limited since the output of the parasite in the stool is low and thus 50–70% of a single figure 1: haematoxylin and eosin (h&e) stain, gastric mucosa x 40 showing cross-sections of strongyloides stercoralis (arrows) a case of gastric and duodenal strongyloidiasis 264 | squ medical journal, august 2010, volume 10, issue 2 general stool examination is unrewarding.2,4,5 it is also worth mentioning that the eosinophilic count is not a reliable indicator of parasitic infection.6 although the serological test enzyme-linked immunosorbent assay (elisa) for diagnosing strongyloidiasis is highly sensitive (reaching up to 90%), the test is not always available, does not discriminate recent from old infections, and shows cross-reaction with other helminth infections. thus the pathological examination of tissue sections and aspirate material gives the definitive diagnosis.6 nonetheless, in order to reach a correct diagnosis of a specific helminthic infection, the pathologist needs to have a wide knowledge of the types of helminthes that localise within body tissues and fluids together with the stages of development and the morphological features to avoid misdiagnosing them as an arthropod or artifacts. a definite diagnosis is made by finding one or more stages of the parasites in faeces, an intestinal aspirate, peritoneal fluid, peripheral blood or in tissue sections. the haematoxylin and eosin (h&e) stained section plays two roles in tissue diagnosis of parasitic infections. first, it allows detection of most parasites or their eggs. second, for those which are not readily visualised, the pattern of inflammation, in conjunction with the clinical history, may provide a clue to their presence and thus initiate a more careful search and further evaluation using special stains.7 for the diagnosis of strongyloidiasis no special stains are required. however, difficulties in the diagnosis of strongyloidiasis may arise in mixed infections with gram-negative bacteria.7 early diagnosis is very important especially in immunocompromised patients or patients on steroids and chemotherapy in order to lower the fatality due to hyperinfection.4 in our case, the patient had a long history of gastrointestinal symptoms consisting of abdominal pain, nausea and loss of appetite which were relieved following the treatment of strongyloidiasis. the risk of hyperinfection in this case is high because of his associated medical illnesses and hairy cell leukaemia. conclusion although strongyloides stercoralis infection is usually asymptomatic and routine stool examination may be negative, histopathological identification of figure 2: haematoxylin and eosin (h&e) stain, duodenal mucosa x 60 showing cross and longitudinal sections of strongyloides stercoralis (arrows) dhuha m a al-sajee and aisha al-hamdani case report | 265 the parasite in tissue sections provides the definite diagnosis. early diagnosis of such parasitic infection in immunocompromised patients is life saving and avoids fatality caused by hyperinfection or systemic dissemination. we therefore recommend that strongyloidiasis should be on the top of the differential diagnosis list for any patient who is immunocompromised and complaining of gastrointestinal symptoms in order to avoid the dramatic complication of hyperinfection. a c k n o w l e d g e m e n t we authors wish to thank the doctors in the department of medicine of sultan qaboos university hospital for the concurrent medical management of this case. references 1. marty am, andersen em. helminthology in tropical pathology. in: doerr w, seifert g, uehlinger e, eds. 2nd ed. berlin: springer-verlag, 1995. pp. 801–982. 2. davila pm, fortun j, velez rl, norman f, montes de oca m, zamarron p, et al. transmission of tropical and geographically restricted infections during solidorgan transplantation. clin microbiol rev 2008; 21:60–96. 3. hotez pj, brindley pj, bethony jm, king chh, pearce ej, jacobson j. helminth infections: the great neglected tropical diseases. j clin invest 2008; 118:1311–21. 4. patel pk, khandekar r. intestinal parasitic infections among school children of dhahira region of oman. saudi med j 2006; 27:627–32. 5. scrimgeour em, mehta fr, suleiman amj. infectious and tropical diseases in oman: a review. am j trop med hyg 1999; 61:920–5. 6. agrawal v, agarwal t, ghoshal uc. intestinal strongyloidiasis: a diagnosis frequently missed in the tropics. trans r soc trop med hyg 2009; 103:242–6. 7. woods gl, walked dh. detection of infection and infectious agents by use of cytologic and histologic stains. clinl microbiol rev 1996; 9:382–404. departments of 1pathology and 2obstetrics & gynaecology, hamdard institute of medical sciences & research, new delhi, india *corresponding author e-mail: jaseemamu@gmail.com سرطان اخلاليا احلرشفية األويل يف موقع بطانة الرحم تقرير تشخيص نادر �سوجاتا جيتلي، زيبا �ساميم، حممد جا�سم ح�سن، جارميا مادان، رينا جاين abstract: squamous cell carcinoma (scc) of the endometrium, whether primary or secondary to cervical cancer, is a rare entity. primary endometrial squamous cell carcinoma in situ is even more uncommon; it usually occurs in postmenopausal women and has a strong association with pyometra. we report a 60-year-old multiparous postmenopausal woman who presented to the hakeem abdul hameed centenary hospital, new delhi, india, in may 2014 with a lower abdominal swelling corresponding in size to a pregnancy of 26 gestational weeks and vaginal discharge of one year’s duration. a total abdominal hysterectomy with a bilateral salpingooophorectomy was performed, which revealed an enlarged uterus with pyometra. histopathology showed that the entire endometrial lining had been replaced with malignant squamous cells without invasion of the myometrium. immunohistochemistry revealed that the tumour cells were positive for p63 with a high ki-67 labelling index. no adjuvant therapy was required and the patient was disease-free at a seven-month follow-up. keywords: squamous cell carcinoma; endometrium; pyometra; case report; india. امللخ�ص: �رسطان اخلاليا احلر�سفية )scc( لبطانة الرحم، �سواء كان اأويل اأو ثانوي ل�رسطان عنق الرحم، نادر احلدوث. و�رسطان اخلاليا احلر�سفية الأ�سا�سي النا�سيء يف موقع بطانة الرحم نف�سه اأكرث ندرة. وعادة ما يحدث يف الن�ساء بعد �سن الياأ�ض، وله عالقة قوية مع تقيح الرحم. نعر�ض حالة امراأة يف �سن الياأ�ض ،متعددة الولدات تبلغ من العمر 60 عاما قدمت اإىل م�ست�سفى الذكرى املئوية حلكيم عبد احلميد، نيو دلهي، الهند، مايو 2014 ومعها تورم اأ�سفل البطن ي�سابه حمل 26 اأ�سبوعا وافرازات مهبلية ملدة �سنة واحدة. مت اإجراء ا�ستئ�سال كلي للرحم مع قناتي فالوب واملبي�سني، وكان الرحم مت�سخما مع تقيح واأظهر الت�رسيح اأنه قد مت ا�ستبدال خاليا بطانة الرحم باأكملها بخاليا حر�سفية خبيثة دون انت�سار اىل الن�سيج الع�سلي. وك�سف فح�ض الن�سيج املناعي اأن اخلاليا ال�رسطانية كانت ايجابية لp63 مع ارتفاع قيا�ض موؤ�رسki-67. مل يكن العالج امل�ساعد مطلوبا واأ�سبحت املري�سة خالية من الأمرا�ض عند متتبعتها بعد �سبعة اأ�سهر. مفتاح الكلمات: خاليا ال�رسطان احلر�سفية؛ بطانة الرحم؛ تقيح الرحم؛ تقرير حالة؛ الهند. primary endometrial squamous cell carcinoma in situ report of a rare disease sujata jetley,1 zeeba s. jairajpuri,1 *mohammad j. hassan,1 garima madaan,1 reena jain2 online case report hospital, new delhi, india, in may 2014 with abdominal swelling and vaginal discharge which had been occurring for the past year. there was no history of vaginal bleeding, the obstetric history was uneventful and the patient had been postmenopausal for 16 years. an abdominal examination revealed a soft and nontender lump corresponding to the size of a pregnancy of 26 gestational weeks. a speculum examination showed a healthy cervix. ultrasonography revealed a mass in the pelvic region measuring 14.2 x 10.8 cm, suggestive of a postmenopausal simple ovarian cyst. contrast-enhanced computed tomography of the lower abdomen showed a large pelvic-abdominal cystic lesion, likely of left adnexal origin. a papanicolaou smear of the cervix was suggestive of atrophy and was negative for intraepithelial lesions or invasive cancers. an exploratory laparotomy and total abdominal hysterectomy with bilateral salpingo-oophorectomy cancer of the endometrium is acommon gynaecological malignancy in the developed world and is second only to cervical cancer in the developing world.1 most endometrial cancers are adenocarcinomas. primary endometrial squamous cell carcinomas (pesccs) are extremely rare although the exact prevalence is not yet known. the majority of squamous cell carcinoma (scc) cases represent an extension from the cervix, where scc spreads superficially to the inner surface of the uterus and replaces the endometrium with carcinoma cells.2 however, whether primary or secondary, endometrial scc is rare and pescc in situ even rarer. case report a 60-year-old multiparous postmenopausal woman presented to hakeem abdul hameed centenary sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e559–562, epub. 23 nov 15 submitted 13 jan 15 revisions req. 16 jun & 13 jul 15; revisions recd. 30 jun & 20 aug 15 accepted 27 aug 15 doi: 10.18295/squmj.2015.15.04.021 primary endometrial squamous cell carcinoma in situ report of a rare disease e560 | squ medical journal, november 2015, volume 15, issue 4 was performed. on gross examination, the uterus was enlarged and the uterine cavity was filled with approximately 1,500 ml of pus. the inner surface of the cavity had a slightly irregular appearance [figure 1]. the cervix had thinned but showed no growth. microscopy of multiple sections from different areas of the uterine wall revealed that the entire endometrial lining had been replaced by sheets of atypical squamous cells with marked pleomorphism and bizarre forms [figure 2]. the changes were limited to the epithelial lining and extensive sampling did not reveal any invasion into the myometrium. in view of the chronic pyometra, the presence of ichthyosis uteri was suspected but samples taken from multiple sections did not yield evidence of the condition. despite extensive sampling, no evidence of normal endometrial glandular epithelium was found. sections from the cervix did not show any abnormalities and there was no evidence of atypia or dysplasia. both ovaries and the myometrium were unremarkable. positive immunohistochemical staining for p63 confirmed the squamous nature of the lesion and a high ki67 labelling index was noted [figure 3]. a diagnosis of pescc in situ was made. the patient was not given any adjuvant therapy and was disease-free during the seven-month follow-up period. discussion endometrial scc usually occurs in postmenopausal women (mean age: 67 years).2 the condition has been strongly associated with pyometra, cervical stenosis, multiparity and chronic inflammation.2 clinically, the majority of patients present with vaginal bleeding. endometrial scc usually originates from the uterine cervix and extends in a superficial spreading pattern.3 an extensive review of the literature by marwah et al. revealed 26 cases of cervical carcinoma with endometrial surface involvement; ishida et al. reported two more cases the following year.3,4 in all of these cases, the women were over the age of 50 years and presented with vaginal bleeding.3,4 pescc is defined as a primary carcinoma of the endometrium composed of squamous cells with varying degrees of differentiation.5 although a few reports of pescc are available in the literature, the prevalence of this condition is unknown. while the exact pathogenesis is unclear, the cellular origin of pescc has been proposed to be “reserve or stem cells located between the glandular basement membrane and the endometrial columnar cell layer, squamous metaplasia of the normal endometrium, or heterotopic cervical tissue”.6 further research supports this finding.7–9 human papilloma virus is known to have a definite role in the pathogenesis of scc of the uterine cervix; however, its role in endometrial scc is still to be determined.6 in cases of pescc, it is important to exclude cervical scc extension into the endometrium and squamous differentiation of an endometrioid adenocarcinoma.6,10 it is also essential to differentiate pescc from endometrial scc involvement based on the following strict pathological criteria recommended by fluhmann: (1) no evidence of a coexisting endometrial adenocarcinoma or primary cervical scc; (2) no connection between the endometrial tumour and squamous epithelium of the cervix; or figure 1: cut-open hysterectomy specimen showing the greyish-yellow irregular uterine cavity of a patient with primary endometrial squamous cell carcinoma in situ. no cervical growth was seen. figure 2a & b: haematoxylin and eosin stains at (a) x40 and (b) x400 magnification showing extensive replacement of the entire endometrial lining by sheets of atypical squamoid cells with marked pleomorphism in a patient with primary endometrial squamous cell carcinoma in situ. no invasion of the myometrium was seen. figure 3a & b: immunohistochemistry stains at x100 magnification showing (a) tumour cells positive for p63 and (b) a high ki-67 labelling index in a patient with primary endometrial squamous cell carcinoma in situ. sujata jetley, zeeba s. jairajpuri, mohammad j. hassan, garima madaan and reena jain online case report | e561 labelling index has also been reported, demonstrating the aggressive and malignant nature of the lesion.18 lee et al. found a positive immunoreactivity for the cytokeratin 7, p63 and p16ink4a proteins, but not for cytokeratin 20 or the oestrogen and progesterone receptors.6 as a prognostic indicator of pescc, the role of these receptors is still uncertain; however, lack of oestrogen cannot be completely ruled out as an aetiological factor since most patients diagnosed with pescc are postmenopausal.6 the prognosis for patients with scc depends mainly on the stage of the tumour. pescc has been reported to show a poorer prognosis than endometrioid carcinomas.18 management for this condition usually consists of a surgical hysterectomy with adnexectomy and radiotherapy.2 conclusion few cases of pescc have been reported in the literature. as the disease usually presents with vaginal bleeding and is most commonly seen in postmenopausal women, pescc should be considered (3) no connection between any existing cervical in situ carcinoma and the independent endometrial neoplasm.10 these criteria were later modified by other authors.11,12 the present case conformed to fluhmann’s criteria and also displayed sequential changes of dysplasia and carcinoma in situ, although there were no signs of an invasive carcinoma despite extensive sampling. to the best of the authors’ knowledge, only five cases of pescc in situ have been reported to date [table 1].13–17 radhika et al. reported a case of pescc in situ associated with a prolapsed uterus, while mitchell et al. noted an association with the long-term use of intrauterine devices.13,14 zidi et al. described a case of pescc in situ with extensive squamous metaplasia and dysplasia along with a serous cystadenoma of the right ovary.15 pescc in situ was also reported by kairys et al., while a rare case with extensive ichthyosis uteri was described by pailoor et al. in a postmenopausal woman with pyometra.16,17 the role of immunohistochemistry is limited, with most studies demonstrating a mutation of the p53 tumour suppressor gene.18,19 a high ki-67 table 1: comparative analysis of cases of endometrial squamous cell carcinoma in situ in the literature author and year of report patient age in years clinical presentation gross findings microscopy findings associated pathology kairys et al.16 1964 57 asymptomatic pelvic mass which appeared 3.5 years after undergoing apparently successful radiation therapy for stage ii scc of the cervix multiple myomas with replacement of the endometrium by a pyogenic membrane endometrial scc in situ multiple leiomyomas with pyometra radhika et al.13 1993 50 complete prolapse of the uterus normal uterine cavity with wall thickness of 1.3 cm pescc in situ squamous metaplasia of the surface mucosal lining and involvement of some of the superficial glands by scc in situ mitchell et al.14 1999 65 vaginal bleeding haemorrhagic and granular endometrium endometrial scc in situ extensive squamous metaplasia of the endometrium and in situ carcinoma of the cervix uteri zidi et al.15 2003 75 pelvic pain and vaginal discharge thickened and epidermalised endometrium with pyometra pescc in situ extensive squamous metaplasia of the endometrium with foci of dysplasia and pyometra pailoor et al.17 2014 52 pelvic pain widened endometrial cavity lined by irregular, shaggy, membrane-like material pescc in situ extensive ichthyosis uteri present case 60 abdominal swelling and vaginal discharge irregular appearance of the endometrial surface with pyometra pescc in situ pyometra and replacement of the endometrial lining with atypical squamous cells without invasion of the myometrium scc = squamous cell carcinoma; pescc = primary endometrial squamous cell carcinoma. primary endometrial squamous cell carcinoma in situ report of a rare disease e562 | squ medical journal, november 2015, volume 15, issue 4 in the differential diagnosis for these patients, despite its rarity. the exact pathogenesis is unclear and diagnosis is based on strict pathological criteria. this report presents a case of pescc in situ in a 60-year-old multiparous postmenopausal woman with pyometra and without invasion of the myometrium. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin 2011; 61:69–90. doi: 10.3322/caac.20107. 2. bagga pk, jaswal ts, datta u, mahajan nc. primary endometrial squamous cell carcinoma with extensive squamous metaplasia and dysplasia. indian j pathol microbiol 2008; 51:267–8. doi: 10.4103/0377-4929.41686. 3. marwah n, garg m, singh s, sethi d, sen r. unusual form of squamous cell carcinoma of the cervix extending in situ into the endometrium: three case reports and review of literature. int j appl basic med res 2012; 2:139–41. doi: 10.4103/2229516x.106359. 4. ishida m, okabe h. superficial spreading squamous cell carcinoma of the uterine cervix involving the endometrium: report of two cases with emphasis on the likely molecular mechanism. oncol lett 2013; 5:31–4. doi: 10.3892/ol.2012.953. 5. kennedy as, demars lr, flannagan lm, varia ma. primary squamous cell carcinoma of the endometrium: a first report of adjuvant chemoradiation. gynecol oncol 1995; 59:117–23. doi: 10.1006/gyno.1995.1277. 6. lee sj, choi hj. primary endometrial squamous cell carcinoma: a case report and review of relevant literature on korean women. korean j pathol 2012; 46:395–8. doi: 10.4132/ koreanjpathol.2012.46.4.395. 7. baggish ms, woodruff jd. the occurrence of squamous epithelium in the endometrium. obstet gynecol surv 1967; 22:69–115. doi: 10.1097/00006254-196702000-00008. 8. seltzer vl, klein m, beckman em. the occurrence of squamous metaplasia as a precursor of squamous cell carcinoma of the endometrium. obstet gynecol 1977; 49:34–7. 9. yamamoto y, izumi k, otsuka h, kishi y, mimura t, okitsu o. primary squamous cell carcinoma of the endometrium: a case report and a suggestion of new histogenesis. int j gynecol pathol 1995; 14:75–80. doi: 10.1097/00004347-19950100000013. 10. fluhmann cf. the histogenesis of squamous cell metaplasia of the cervix and endometrium. surg gynecol obstet 1953; 97:45–58. 11. kay s. squamous cell carcinoma of the endometrium. am j clin pathol 1974; 61:264–9. 12. jeffers md, mcdonald gs, mcguinness ep. primary squamous cell carcinoma of the endometrium. histopathology 1991; 19:177–9. doi: 10.1111/j.1365-2559.1991.tb00010.x. 13. radhika s, dey p, gupta sk. primary squamous cell carcinomain-situ of the endometrium: a case report. indian j cancer 1993; 30:92–5. 14. mitchell s, fletcher h, williams np, coard k. in situ squamous cell carcinoma of the endometrium associated with long-term intrauterine device (dalkon shield) usage. j obstet gynaecol 1999; 19:88–9. doi: 10.1080/01443619966119. 15. zidi ys, bouraoui s, atallah k, kchir n, haouet s. primary in situ squamous cell carcinoma of the endometrium, with extensive squamous metaplasia and dysplasia. gynecol oncol 2003; 88:444–6. doi: 10.1016/s0090-8258(02)00105-1. 16. kairys lr, dougherty cm, mickal a. squamous cell carcinoma in situ of the endometrial cavity. am j obstet gynaecol 1964; 88:548–9. doi: 10.1016/0002-9378(64)90516-2. 17. pailoor k, pai mr, gatty rc, fernandes h, jayaprakash cs, marla nj. a rare case of primary insitu squamous cell carcinoma of the endometrium with extensive icthyosis uteri. online j health allied sci 2014; 13:10. 18. terada t, tateoka k. primary pure squamous cell carcinoma of the endometrium: a case report. int j clin exp pathol 2013; 6:990–3. 19. giordano g, d’adda t, merisio c, gnetti l. primary squamous cell carcinoma of the endometrium: a case report with immunohistochemical and molecular study. gynecol oncol 2005; 96:876–9. doi: 10.1016/j.ygyno.2004.11.019. http://dx.doi.org/10.3322/caac.20107 http://dx.doi.org/%2010.4103/0377-4929.41686 http://dx.doi.org/10.4103/2229-516x.106359 http://dx.doi.org/10.4103/2229-516x.106359 http://dx.doi.org/10.3892/ol.2012.953 http://dx.doi.org/10.1006/gyno.1995.1277 http://dx.doi.org/10.4132/koreanjpathol.2012.46.4.395 http://dx.doi.org/10.4132/koreanjpathol.2012.46.4.395 http://dx.doi.org/10.1097/00006254-196702000-00008 http://dx.doi.org/10.1097/00004347-199501000-00013 http://dx.doi.org/10.1097/00004347-199501000-00013 http://dx.doi.org/10.1111/j.1365-2559.1991.tb00010.x http://dx.doi.org/10.1080/01443619966119 http://dx.doi.org/10.1016/s0090-8258%2802%2900105-1 http://dx.doi.org/10.1016/0002-9378%2864%2990516-2 http://dx.doi.org/10.1016/j.ygyno.2004.11.019 pendant on a necklace – case of sertoli-leydig cell tumour shabnam saquib,1 vaidyanathan gowri,2 aisha al-hamdani,3 ikram burney4 and rajeev jain5 departments of 1obstetrics and gynaecology, 3pathology, 4medicine, sultan qaboos university hospital, muscat, oman; departments of 2obstetrics and gynaecology, 5radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: gowri@squ.edu.om a 23 year-old lady was referred to our institution as a case of primary infertility lasting two years. she had had an irregular menstrual cycle since menarche (8/60-90) associated with dysmenorrhea. she had gained 15 kg in weight since her marriage. a systemic examination was unremarkable except for excessive fine hair all over the body and face. abdominal and pelvic examinations were unremarkable. a routine vaginal scan showed a normal uterus, normal ovaries, and a hyperechoic mass of 4 x 4 cm near the left ovary with minimal free fluid in the pouch of douglas. the differential diagnosis was a haemorrhagic or dermoid cyst of the left ovary. a routine infertility work-up showed raised testosterone of 4.2 nmol/l, but tumour markers were all normal. a magnetic resonance imaging (mri) scan was requested as the mass was persistent after 3 months. the mri revealed a normal uterus and ovaries with free fluid in the pouch of douglas, a 4.2 x 3.2 x 4.1 cm heterogeneous solid mass with necrotic areas and intense contrast enhancement with high cellularity seen in the pouch of douglas. there was no evidence of continuity of the mass or infiltration into the left ovary. there was no evidence of pelvic lymphadenopathy. the provisional mri diagnosis was a malignant mass in the pouch of douglas not infiltrating the ovaries. further investigations for a possible primary source of malignancy were negative. a diagnostic laparoscopy revealed a pedunculated ovarian mass of 7 x 5 x 3 cm, dark in colour with solid and cystic components attached to the left ovary by a thick pedicle of 1 cm, a normal uterus and ovaries with ascitic fluid in the pouch of douglas. the pedicle was ligated, cut and the mass was removed intact. both ovaries were left in situ. the ascitic fluid was sent for cytology. the couple did not consent to removal of the affected ovary. the histopathology result for the mass was an intermediate to poorly differentiated sertoli-leydig cell tumor without heterogeneous elements. peritoneal fluid was positive for malignant cells. the couple was counselled in detail about staging laparotomy and chemotherapy, but they refused. a testosterone and pelvic scan after 3 months were normal. ovarian sertoli-leydig cell tumours are rare sex cord stromal tumour, accounting for less than 1% of ovarian tumors.1 the majority of these tumors are benign, unilateral, only 3–5% being bilateral. these patients present with clinical features of virilisation due to excessive secretion of testosterone from the tumour, however 50% may have no endocrine symptoms.2 the important prognostic factors for sertoli-leydig cell tumors are age of patient, degree of differentiation and stage of the tumour. malignant potential as given by young et al. is none in a well–differentiated tumour, about 11% in the intermediate type, 59% in a poorly differentiated tumour and about 19% in tumours with heterologous elements.3 as these tumours are mostly unilateral, conservative treatment with unilateral salpingo-oophorectomy and evaluation of the contralateral ovary is recommended at reproductive age. for patients who have completed their family, hysterectomy and bilateral salpingo-oophorectomy is appropriate. for patients with poorly differentiated tumours, postoperative chemotherapy is recommended. in our case the histopathology of the tumour showed an intermediate to poorly differentiated sertoli-leydig cell, but the couple refused staging surgery or chemotherapy. she is still being followed up clinically. r e f e r e n c e s 1. choong cs, fuller pj, chu s, jeske y, bowling f, brown r, et al. sertoli-leydig cell tumor of the ovary, a rare cause of precocious puberty in a 12-month-old infant. j clin endocrinol metab 2002; 87:49–56. 2. oliva e, alvarez t, young rh. sertoli cell tumors of the ovary: a clinicopathologic and immunehistochemical study of 54 cases. am j surg pathol 2005; 29:143–56. 3. young rh, scully re. ovarian sertoli-leydig cell tumors. a clinico-pathological analysis of 207 cases. am j surg pathol 1985; 9:543–69. this case was presented at the sultan qaboos university clinical-pathological conference on 4th february 2009 with the title “pendant on a necklace”. abstracts squ med j, august 2010, vol. 10, iss. 2, pp. 296-298, epub. 19th jun 10 وقائع مؤمترات علم األمراض السريري يف جامعة السلطان قابوس 2010 – 2009 proceedings of sultan qaboos university clinical pathological conferences 2009-2010 abstracts 2009-2010 abstracts | 297 abrupt onset of unilateral third nerve palsy secondary to central nervous system relapse in acute myeloid leukaemia abdullah al-mujaini,1 rana al-senwai,1 humoud al-dhuhli2 and david dennison3 departments of 1ophthalmology, 2radiology and 3haematology, sultan qaboos university hospital, muscat, oman. email: mujainisqu@hotmail.com isolated central nervous system (cns) relapse following allogeneic stem cell transplantation (allo-sct) is rare and poses a major therapeutic obstacle to cure in acute myelogenous leukaemia (aml). cns relapse in a leukaemic patient ranges widely from less than 10% to 30% and is associated with a high rate of treatment failure when it occurs following allo-sct. acute unilateral third nerve palsy is an unusual early manifestation of such an event. a 25 year-old male patient with a diagnosis of aml was referred to the sultan qaboos university hospital eye clinic with a 3 days history of inability to move his left eye inwards. there was history of double vision associated with his problem. the patient was subjected to detailed ocular, medical and radiologic evaluations. ophthalmic examination of the right eye was unremarkable. examination of the left eye showed partial blepharoptosis of the upper eyelid and absent adduction and elevation of the eyeball. depression was moderately reduced. abduction was normal. the pupil was mildly dilated with absent direct and consensual reaction to light. the patient maintained an intact corneal reflex and normal looking optic disc. neurological examination revealed no neurological deficits apart from above-mentioned features of left 3rd cranial nerve palsy. four months prior to the presenting problem, the patient had had allo-sct, but from that time there had been no evidence of cns involvement. a magnetic resonance imaging (mri) examination with intravenous gadolinium diethylenetriamine penta-acetic acid (gd-dtpa) of the orbit and brain showed enlargement and enhancement of the cisternal and cavernous portions of the left third cranial nerve. there was no meningeal enhancement or parenchymal brain lesion. a lumbar puncture to evaluate the cerebrospinal fluid (csf) showed the presence of myeloblasts. based on the above findings, a diagnosis of cns relapse was made and treatment with intrathecal methotrexate was initiated. although most cranial nerves may be difficult to visualise with mri scanning due to their small diameter and complex anatomic course, the oculomotor cranial nerves can be visualised and reliably assessed by standard mri sequences, not only in the subarachnoid space and cavernous sinus but also in the orbit. rapid developments in the mri have enabled evaluation of the entire course of normal as well as abnormal cranial nerves. indeed, imaging has been dramatically improved with the use of high resolution mri. this case highlights the value of mri in the early detection and accurate evaluation of cranial nerve lesions, thereby aiding in the clinical diagnosis, treatment and prognosis assessment of patients with cns relapse in leukaemia. this case was presented at the sultan qaboos university clinical-pathological conference on 21st october 2009 with the title “is it frozen?”, and was published as follows: al-mujaini a, al-duhli h, dennison d. acute unilateral third nerve palsy as an early manifestation of central nervous system relapse in a patient with acute myeloid leukemia. saudi med j 2009; 30:961-963. successful management of a case of gestational trophoblastic neoplasia in a young woman mariam mathew,1 shabnam saquib,1 shiyam kumar,2 dilani lokuhetty3 and rajeev jain4 departments of 1obstetrics and gynaecology, 2medicine, 3pathology, sultan qaboos university hospital, muscat, oman; 4department radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat, oman. email:mariamm@squ.edu.om a 23 year-old, recently married omani lady was admitted with 7 weeks of amenorrhoea, abdominal pain and bleeding per vagina. her abdominal examination was unremarkable; a bimanual examination showed a uterine size of 12 weeks gestation with a closed cervix. serum β hcg was 284, 263 iu on admission. an ultrasonogram revealed a “snowstorm pattern” diagnostic of a complete hydatidiform mole. suction evacuation and curettage was performed after the initial work-up. a histopathological examination confirmed complete hydatidiform mole. weekly follow-up showed rising β hcg 3 weeks after evacuation. staging investigations like computerised tomography (ct) of the chest and magnetic resonance imaging (mri) of the abdomen and pelvis showed two tiny deposits in the lung and a myometrial invasion of 2 cm size, confirming low risk gestational trophoblastic neoplasia. after counselling, single agent chemotherapy was started with methotrexate. actinomycin d was added later due to poor response to treatment as evidenced by suboptimal β hcg regression. β hcg returned to normal in 10 weeks time and remains negative on follow-up. gestational trophoblastic diseases (gtd) include a spectrum of diseases with wide range of biologic behaviour. it includes the benign form, hydatidiform mole; locally malignant form, invasive mole, and frankly malignant form, choriocarcinoma. although persistent, gestational trophoblastic tumours develop most commonly after a molar pregnancy, they may follow any gestation. the incidence of hydatidiform moles varies from 0.1 to 1%; 8–15% of them develop malignant sequelae.1 β hcg is the tumour marker used for the diagnosis and follow up of gtd. hydatidiform moles need close follow-up due to their malignant potential. recommended follow-up is weekly β hcg testing until 3 negative values, followed by monthly for another 6 months. pregnancy should be avoided during this period. invasive moles are characterised by local invasion into the myometrium with or without lung metastasis and present with persistently elevated β hcg, as in our case. choriocarcinoma usually presents with symptoms of metastases like cough, dyspnoea, haemoptysis, headache, convulsion, stroke, and vaginal bleeding.2 the world health organization (who) scoring system based on prognostic factors is used for the risk stratification of the disease. a score of 6 or less is low risk disease and is treated with single agent chemotherapy. a score of 7 or greater is high-risk disease, which needs multiagent chemotherapy with or without local radiation/surgery.3 choriocarcinoma is potentially curable and future fertility is unaffected if promptly treated. women can conceive 1 year after completion of chemotherapy; there is no increased risk of pregnancy complications or congenital anomalies. the risk of recurrence of molar pregnancy is 1–3%, which should be ruled out by an early ultrasound.4 r e f e r e n c e s 1. berkowitz rs, goldstein dp. chorionic tumours. n engl j med 1996; 335:1740–8. 2. khoo sk, sidhu m, baartz d, yip wl, tripcony l. persistence and malignant sequelae of gestational trophoblastic disease: clinical proceedings of sultan qaboos university clinical pathological conferences 298 | squ medical journal, august 2010, volume 10, issue 2 presentation, diagnosis, treatment and outcome. aust n z j obstet gynaecol 2010; 50:81–6. 3. ngan hys, benedet jl, jones 111 hw, bender hg, pecorelli s. figo staging and risk factor scoring for trophoblastic neoplasia. int j gynecol obstet 2002; 77:285–7. 4. the mangement of gestational trophoblastic disease. rcog guideline no 38, feb 2010. this case was presented at the sultan qaboos university clinical-pathological conference on 28th october 2009 with the title “through the vine (vain) yard” pre-eclampsia or acute fatty liver of pregnancy nihal al-riyami,1 abdullah al-harthy2 and femida zia3 departments of 1obstetrics and gynaecology, 2surgery, 3haematology, sultan qaboos university hospital, muscat, oman. email:drriyami@hotmail.com we report the case of a 36 year-old gravida 3 para 2 woman who presented at 34 weeks gestation with malaise, nausea, vomiting and feeling unwell. she underwent an emergency caesarean section for non-reassuring foetal heart status. the postoperative course was complicated by severe postpartum haemorrhage and disseminated intravascular coagulation requiring multiple blood transfusions. the patient developed chronic hypoalbuminaemia and jaundice. a presumptive diagnosis of acute fatty liver was made and supportive care resulted in a good outcome. acute fatty liver of pregnancy (aflp) was first described by sheehan in 1940.1 it is a life threatening obstetrical emergency that can lead to high maternal and perinatal morbidity and mortality. the aetiology of the disease is unknown with an incidence of 1 in 10,000 to 1 in 15,000.2 the most common presentation is malaise, nausea, vomiting and epigastric pain followed by jaundice. the laboratory findings are usually of mild to moderate increase in serum transaminases, hyperbilirubinaemia, hypoglycaemia and deranged coagulation profile.3 liver biopsy is the gold standard for diagnosing aflp, but due to the presence of coagulation abnormalities, the diagnosis is usually made by clinical and laboratory findings.1 bleeding and disseminated intravascular coagulation (dic) are one of most common complications of aflp. other complications include hepatic encephalopathy, sepsis, ascites, acute renal failure, respiratory distress syndrome and pancreatitis. due to the high maternal and perinatal mortality, early diagnosis, prompt delivery and supportive care are required. r e f e r e n c e s 1. vigil-de gracia p, lavergne ja. acute fatty liver of pregnancy. int j gynaecol obstet 2001; 72:193–5. 2. castro ma, goodwin tm, shaw kj, ouzounian jg, mcghee wg. disseminated intravascular coagulation and antithrombin iii depression in acute fatty liver of pregnancy. am j obstet gynecol 1996; 174:211–6. 3. sibai bm. imitators of severe pre-eclampsia. semin perinatol 2009; 33:196–205. this case was presented at the sultan qaboos university clinical-pathological conference on 28th april 2010 with the title “the mysterious fountain” the concept of maternal glucose levels predicting birth weight in diabetic pregnancies is well known and has been extensively investigated. this notion however seems to overshadow the understanding of the effect of other maternal factors on birth weight in non-diabetic pregnancies. here, we emphasise that, in healthy non-diabetic pregnancies, postprandial and fasting glucose levels at late gestation are in the normal range.1,2 on the other hand, marked lipemia, mainly hypertriglyceridemia is a marked feature of late gestation.2 in spite of this fact, maternal triglyceride (tg) levels appear to be underestimated in this debate. notably, recent studies reported highly significant positive correlations between fasting maternal tg levels at late gestation and birth weight in non-diabetic mothers independent of glucose levels or maternal weight.3,4 also, in diabetic mothers, tg levels were shown to be better predictors of birth weight than glucose levels.5 in spite of these highly significant associations, the number of human studies that describe the effect of increased maternal tg levels on birth weight in normal pregnancies are surprisingly limited. this may be due to the understanding that maternal tg does not cross the maternal-fetal placental barrier unless hydrolysed into fatty acids that have not been proven readily to cross the maternal-fetal placental barrier as glucose. in this commentary, we bring into focus maternal tg levels as potential independent predictors of birth weight that may contribute to early fetal programming events predisposing to childhood obesity and metabolic derangements later in life. this is of particular importance in light of expanding epigenetic research that may overcome maternal-fetal placental barrier considerations and may therefore contribute to the understanding of the specific effect of maternal tg and dietary fat on the expression of obesity related genes. references 1. deierlein al, siega-riz am, chantala k, herring ah. the association between maternal glucose concentration and child bmi at age 3 years. diabetes care 2011; 34:480–4. epub jan 7 2011. 2. butte n. carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. am j clin nutr 2000; 71: 1256–61s. 3. di cianni g, miccoli r, volpe l, lencioni c, ghio a, giovannitti m, et al. maternal triglyceride levels and newborn weight in pregnant women with normal glucose tolerance. diabetic med 2005; 22:21–5. 4. saleh j, al-riyami h, chaudhary t, cianflone k. cord blood asp is predicted by maternal lipids and correlates with fetal birth weight. obesity 2008; 16:1193–8. 5. son g, kwon y, kim h, park w. maternal serum triglycerides as predictive factors for large-for-gestational age newborns in women with gestational diabetes mellitus. acta obstet gynecol scand 2010; 89:700–4. squ med j, august 2011, vol. 11, iss. 3, pp. 417, epub. 15th aug 11 submitted 29th may 11 accepted 27th june 11 ì�è⁄á⁄ � ˘]<ìèm¯n÷]<·á‚ç÷] ïå˜á÷]<oëçu<ÿà�÷]<·áê<l]üçˆ≤<õ^à~jâ˜]  ì�è⁄á⁄ � ˘]<ìèm¯n÷]<·á‚ç÷]ì�è⁄á⁄ � ˘]<ìèm¯n÷]<·á‚ç÷] maternal triglycerides underestimated predictors of neonatal birth weight jumana saleh letter to editor department of biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: jumanasaleh@hotmail.com department of rheumatology, mongi slim hospital, tunis, tunisia; university tunis el manar, tunis, tunisia *corresponding author’s e-mail: yasmine.mkhlouf@gmail.com zoledronate-associated seizure in chronic recurrent multifocal osteomyelitis saoussen miladi, *yasmine makhlouf, alia fazaa, mariem sallemi, selma chekili, kawther ben abdelghani, ahmed laatar sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 570–573, epub. 7 nov 22 submitted 5 may 21 revisions req. 16 jun & 25 jul 21; revisions recd. 27 jun & 25 jul 21 accepted 29 jul 21 a limp in her right leg. the erythrocyte sedimentation rate (esr) was 50 mm/h (reference range: 0–6 mm/h). she had negative antinuclear antibodies, rheumatoid factor and anti-citrullinated protein antibodies. other laboratory investigations such as human leukocyte antigen b-27, lyme’s disease, anti-streptolysin o serology and tuberculosis were also negative. a radiograph of the hip showed a lytic lesion in the right acetabular roof [figure 1]. a magnetic resonance imaging (mri) scan of the whole body showed low signal on t1-weighted images. a high signal was seen on the t2 short-tau inversion recovery (stir) sequence in the left greater trochanter at the point of insertion in the gluteus medius and obturator externus muscles with trochanteric bursitis and edema of the entire right iliac wing [figure 2]. a scintigraphy was then performed and it illustrated an intense uptake of radioisotopes in the left ilium, femurs and seventh right costo-vertebral junction. at this stage two possible diagnoses were discussed: histiocytosis and crmo. the bone biopsy of the hip ruled out chronic infection and malignancies and showed bone remodelling and non-specific inflammatory changes, all supporting the diagnosis of crmo. the patient was treated with a non-steroidal antiinflammatory drug (nsaid)—diclofenac— at a dose of 75 mg twice a day, resulting in the control of pain and regression of acute phase reactants (esr: 7, c-reactive protein: 4). she maintained a prompt response until 2018, when she returned to the current department complaining of a sterno-clavicular joint swelling and right hip pain. chronic recurrent multifocal osteomyelitis (crmo) or chronic non-bacterial osteitis is an auto-inflammatory rather than an autoimmune disease characterised by sterile bone lesions. described in 1972 by giedion et al., this disease is characterised by recurrent inflammation of multiple bones reflecting the presence of aseptic osteitis.1 crmo is considered by many medical researchers as the paediatric form of synovitis, acne, pustulosis, hyperostosis and osteitis (sapho) syndrome.2 this inflammatory condition results from an activation of the innate immune system leading to the presence of pro-inflammatory cytokines.3 the diagnosis of crmo depends on the clinical and radiographic data. bone biopsy is often required in order to exclude infection, neoplasia or langerhans’ cell histiocytosis.1 although, the treatment of crmo is currently not classified, the most promising results have been observed in patients under treatment with bisphosphonates (bps).4 here we describe the case of a patient with crmo who developed a seizure post-bp administration. case report a seven-year-old female child presented to the department of rheumatology at a university hospital in september 2010, with symptoms of insidious pain in the right hip and scapula as well as swelling affecting the left ankle. there were no extraarticular manifestations, cutaneous involvement or inflammatory bowel disease. subsequently, the patient’s physical activity decreased as she developed this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.111 case report abstract: chronic recurrent multifocal osteomyelitis (crmo) is an auto-inflammatory disease characterised by sterile bone lesions. we report a case of a seven-year-old female patient who presented at a university hospital in 2010 and 2018 with crmo. while the most promising results have been observed in patients under treatment with bisphosphonates (bps), the initial decision to treat the current patient with a dose of zoledronic acid every six months was recalled as the patient developed tonic-clonic seizures immediately following the second dose bp administration. following recall, the patient maintained a prompt response at follow-up and her disease remained controlled with non-steroidal anti-inflammatory drugs. the current case report speculates a possible relationship between bp use and a possible seizure threshold reduction, thereby emphasising the need for closer monitoring when bps are used. keywords: chronic recurrent multifocal osteomyelitis; bisphosphonate; tonic-clonic seizure; case report; tunisia. https://creativecommons.org/licenses/by-nd/4.0/ saoussen miladi, yasmine makhlouf, alia fazaa, mariem sallemi, selma chekili, kawther ben abdelghani and ahmed laatar case report | 571 a whole-body mri scan showed sacroiliitis with erosions in the sacral rim and an edema at the left ischium. a trial of two other nsaids and prednisolone with a maximum dose of 40 mg/day for 10 days offered the patient limited symptomatic improvement. following the consensus treatment for crmo refractory to nsaids, a decision was made to switch to administering an intravenous dose of zoledronic acid (za) at 0.025 mg/kg every six months.5 the first dose was given in 2018. a good response was obtained with resumption of mobility of the right hip and reduction of pain from 8 to 6, according to the visual analogue scale. after six months, the patient relapsed, experiencing pain in the hip and sterno-clavicular joint. as soon as the infusion of the second dose of za was initiated, the patient developed generalised tonic-clonic seizures and retrovulsion of the eyeballs that lasted less than one minute. there were no signs of tongue biting, urinary incontinence or a postictal status. the infusion was stopped immediately. the blood pressure reading—initially recorded as 80/60 mmhg—was rechecked and stood at 110/60 mmhg and the blood glucose stood at 5 mmol/l with a heart rate of 60 beats per minute. the electrocardiogram showed no disturbances. laboratory tests taken before and after the event, such as those taken for blood sugar and serum calcaemia levels were normal. furthermore, the patient had a brain mri that ruled out not only the common causes of seizures but also neurological involvement due to crmo. an electroencephalogram was not performed. the role of the drug was suspected due to the suggestive delay and spontaneous resolution of symptoms after it was stopped. at follow-up, the patient maintained a prompt response and her disease remained controlled with nsaids. methotrexate would be considered if the patient experiences future flares. more importantly, the patient did not experience any other episodes of seizure and hence did not justify introducing an anticonvulsant medication. written consent was obtained from the patient’s father for publication of this report. discussion chronic non-bacterial osteomyelitis encompasses a wide clinical spectrum of “monofocal bone inflammation to severe chronically active or recurrent multifocal bone inflammation”.4 crmo represents some of the most severe presentations. due to the variability of symptoms, epidemiological data is sparse and taken from small case series and cohorts. crmo mostly affects children and adolescents with the peak age of onset ranging between 7 and 12 years of age.6 in the absence of diagnostic criteria, experts rely on exclusion of other differential diagnosis including infection, malignancy and langerhans cell histiocytosis for the diagnosis of crmo.4 in the current case, the diagnosis was made based on a clinical assessment in conjunction with acute phase reactants, mri data and biopsy ruling out differential diagnosis. presently, there is no consensus regarding the treatment of patients with crmo. it usually involves nsaids, corticosteroids (cs), disease-modifying antirheumatic drugs, anti-tumour necrosis factor agents or bisphosphonates.4 however, the most efficient treatment and its duration is yet to be determined as large prospective clinical trials are lacking. the figure 1: x-ray of the hip showing a lytic lesion with surrounding sclerosis in the right acetabular roof (arrow) of a seven-year-old female patient. figure 2: a magnetic resonance imaging scan in t2 sequence showing signal abnormalities in the left greater trochanter and right acetabulum (arrow) of a seven-year-old female patient. zoledronate-associated seizure in chronic recurrent multifocal osteomyelitis 572 | squ medical journal, november 2022, volume 22, issue 4 current patient was treated with nsaids as a firstline treatment but the condition intensified after eight years. in the literature, a relapse after two years was observed in more than half of the cases.7 although cs appeared to decrease pain and control inflammation activity, they were ineffective in maintaining longterm remission as symptoms reoccurred once cs were stopped.4 recently, the childhood arthritis and rheumatology research alliance (carra) developed a consensual treatment plan for patients’ refractory to nsaids.5 one of the consensual plans included a monthly dosage of pamidronate at 1 mg/kg/dose or za with an initial dose of 0.0125–0.025 mg/kg every 3–6 months. an increase in the per pulse dosage to 0.05 mg/kg/dose (maximum: 4 mg/dose) may be required depending on disease activity.5 the current patient was treated with za (following the above recommendations) and showed marked improvement after the first infusion. however, the beneficial effect could not be fully evaluated as the treatment was stopped when she developed a side-effect at the second infusion. to the best of the authors’ knowledge, this is the first reported case of seizure associated with bp administration in children with crmo. indeed, treatment-related cases of seizures occur mainly due to za infusion in connection with low level of calcium or glucose in elderly patients.8–10 overall, five cases of seizures occurring soon after bp administration have been reported.11 one case reported a seizure in an 87-year-old man with metastatic prostate cancer receiving za, with the patient’s symptoms normalising rapidly after correction of serum calcium levels.9 in another case, an 80-year-old woman suffering from post-menopausal osteoporosis developed a hypoglycaemic seizure 30 minutes after the infusion.10 the remaining za was infused after the glucose level was corrected with good outcomes. in another case, the patient developed a febrile seizure due to a central nervous system infection.11 notably, all of the patients had a pre-existing vitamin d deficiency, a well-known risk factor for bp-induced hypocalcaemia. unlike previously reported cases, shalit and tripto-shkolnik described a seizure after za infusion in a 63-yearold woman with a history of well-controlled epileptic disorder.11 her creatinine, calcium, parathyroid hormone and vitamin d levels were all normal. similar to the current case, mineral metabolism abnormality and infection as the precipitating factors for the seizure were unlikely. the role of the drug was suspected due to the suggestive delay and spontaneous resolution of symptoms after it was stopped. as part of the prevention of side-effects, the carra has recommended prescribing a supplement of calcium and vitamin d before initiating za, especially in patients at risk of failure of compensatory mechanisms as vitamin d deficiency.5 the current case report, along with the other scarcely available reports, raises questions about a possible relationship between bp use and a possible seizure threshold reduction. this would impact the clinical management of these children as it stresses on the need for closer monitoring when bps are used. conclusion the present case suggests that although bp therapy can be of benefit to patients with crmo, adverse events may occur. a close surveillance for the occurrence of this phenomenon would be required for adequate clinical management. a u t h o r s’ c o n t r i b u t i o n all authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work. all authors approved the final version of the manuscript. references 1. giedion a, vischer d, masel lf, holthuse w. subacute and chronic symmetrical osteomyelitis. ann radiol 1972;15:329–42. 2. jelušić m, čekada n, frković m, potočki k, skerlev m, muratsušić s, et al. chronic recurrent multifocal osteomyelitis (crmo) and synovitis acne pustulosis hyperostosis osteitis (sapho) syndrome two presentations of the same disease. acta dermatovenerol croat 2018; 26:212–19. 3. hedrich cm, hofmann sr, pablik j, morbach h, girschick hj. pediatr rheumatol 2013; 11:47. https://doi.org/10.1186/15460096-11-47. 4. hofmann sr, kapplusch f, girschick hj, morbach h, pablik j, ferguson pj, et al. chronic recurrent multifocal osteomyelitis (crmo): presentation, pathogenesis, and treatment. curr osteoporos rep. 2017;15:542–4. https://doi.org/10.1007/s1191 4-017-0405-9. 5. zhao y, wu ey, oliver ms, cooper am, basiaga ml, vora ss et al. consensus treatment plans for chronic nonbacterial osteomyelitis refractory to nonsteroidal antiinflammatory drugs and/or with active spinal lesions. arthritis care res (hoboken) 2018; 70:1228–37. https://doi.org/10.1002/acr.23462. 6. hedrich cm, hahn g, girschick hj, morbach h. a clinical and pathomechanistic profile of chronic nonbacterial osteomyelitis/ chronic recurrent multifocal osteomyelitis and challenges facing the field. expert rev clin immunol 2013; 9:845–54. https://doi.org/10.1586/1744666x.2013.824670. 7. schnabel a, range u, hahn g, berner r, hedrich cm. treatment response and longterm outcomes in children with chronic nonbacterial osteomyelitis. j rheumatol 2017; 44:1058–65. https://doi.org/10.3899/jrheum.161255. 8. maclsaac rj, seeman e, jerums g. seizures after alendronate. j r soc med 2002; 95:615–16. https://doi.org/10.1258/jrsm.9 5.12.615. https://doi.org/10.1186/1546-0096-11-47. https://doi.org/10.1186/1546-0096-11-47. https://doi.org/10.1007/s11914-017-0405-9 https://doi.org/10.1007/s11914-017-0405-9 https://doi.org/10.1002/acr.23462 https://doi.org/10.1586/1744666x.2013.824670 https://doi.org/10.3899/jrheum.161255 https://doi.org/10.1258/jrsm.95.12.615 https://doi.org/10.1258/jrsm.95.12.615 saoussen miladi, yasmine makhlouf, alia fazaa, mariem sallemi, selma chekili, kawther ben abdelghani and ahmed laatar case report | 573 11. shalit r, tripto-shkolnik l. seizures associated with zoledronic acid (za) therapy: a case report and review of the literature. aace clin case rep 2020; 6:e315–18. https://doi.org/10.4158/accr-2020-0234. 9. navarro m, lopez r, alana m, ocaa a, leno r, sa´nchez f et al. tonic-clonic seizure as the presentation symptom of severe hypocalcemia secondary to zoledronic acid administration. j palliat med 2007; 10:1226–7. https://doi.org/10.1089/jpm.20 07.0113. 10. tsourdi e, rachner td, gruber m, hamann c, ziemssen t, hofbauer lc. seizures associated with zoledronic acid for osteoporosis. j clin endocrinol metab. 2011; 96:1955–9. https://doi.org/10.1210/jc.2011-0418. https://doi.org/10.4158/accr-2020-0234 https://doi.org/10.1089/jpm.2007.0113. https://doi.org/10.1089/jpm.2007.0113. https://doi.org/10.1210/jc.2011-0418 1canterbury district health board, christchurch hospital, christchurch, new zealand; 2directorate general of planning & studies, ministry of health, muscat, oman; 3edgar diabetes & obesity research centre, dunedin school of medicine, university of otago, dunedin, new zealand *corresponding author’s e-mail: ibra.3sk@gmail.com أحباث مرض القدم السكري يف دول جملس التعاون اخلليجي حتليل ببليوغرايف اإبراهيم �شالح البو�شعيدي، نادية نور عبد الهادي، كري�شنت كوبيل abstract: objectives: countries in the gulf cooperation council (gcc) have some of the highest prevalence rates of diabetes mellitus (dm) in the world; however, dm-related research activity in this region is limited. this study aimed to examine trends in published diabetic foot disease (dfd) research undertaken in gcc countries. methods: this bibliometric study was conducted in december 2016. standardised criteria were used to search the medline® database (national library of medicine, bethesda, maryland, usa) for dfd-related publications authored by gcc researchers between january 1990 and december 2015. various details such as the type of publication, journal impact factor and number of article citations were analysed. results: a total of 96 research articles were identified. the number of publications per year significantly increased from nil prior to 1991 to 15 in 2015 (p <0.01). basic/clinical research articles accounted for 96.9% of publications, with three randomised controlled trials and no systematic reviews/meta-analyses. when adjusted for population size, kuwait had the highest number of published papers per year, followed by bahrain and qatar. the number of authors per publication significantly increased during the study period (p = 0.02). however, 16 articles (16.7%) had no citations. the median journal impact factor was 0.15 ± 1.19 (range: 0–6.04). conclusion: the number of publications authored by gcc researchers has risen in recent years. increasing research funding and promoting collaboration between local and international researchers and institutes are recommended to bolster research regarding dfd prevention and management in gcc countries. keywords: bibliometric analysis; diabetes mellitus; diabetic foot; research; publications; arab countries; gulf cooperation council. فاإن ذلك، ومع العامل. دول ببقية مقارنة عاليا اخلليجي التعاون جمل�ص دول يف ال�شكري مر�ص انت�شار معدل يعترب الهدف: امللخ�ص: القدم مر�ص جمال يف املن�شورة الأبحاث حتليل اإىل الدرا�شة هذه تهدف حمدودة. املنطقة هذه يف بال�شكري املتعلقة البحثية الأن�شطة ال�شكري يف دول جمل�ص التعاون اخلليجي. الطريقة: مت اإجراء هذه الدرا�شة الببليوغرافية يف دي�شمرب 2016. با�شتخدام معايري بحثيه موحدة املقالت جميع لتحديد الأمريكية( املتحدة الوليات ماريالند، بيثي�شدا، للطب، الوطنية )املكتبة ميدلين البيانات قاعدة يف البحث مت املتعلقة مبر�ص القدم ال�شكري التي ن�رسها باحثني من دول جمل�ص التعاون اخلليجي بني يناير 1990 ودي�شمرب 2015. مت جمع وحتليل عدد من البيانات من �شمنها نوع املن�شورة الطبية، عامل تاأثري املجلة، ومعدل القتبا�ص. النتائج: مت حتديد ما جمموعه 96 بحثا من�شورا. مت مالحظة ازدياد عدد املن�شورات ب�شكل كبري من ل �شيء يف �شنة 1991 اإىل 15 يف �شنة p >0.01( 2015(. �شكلت البحوث املخربية/ال�رسيرية %96.9 من اإجمايل املن�شورات فيما كان هناك ثالثة جتارب ع�شوائية حمكومة وعدم وجود اأي مراجعات منهجية/حتاليل تلوية. كانت الكويت اأكرث الدول من حيث عدد املن�شورات الطبية عند مقارنتها مع حجم ال�شكان، تليها البحرين وقطر. لقد لوحظ ازدياد عدد املوؤلفني لكل من�شور مع الوقت خالل فرتة الدرا�شة )p = 0.02(. ومع ذلك، كان 16 )%16.7( بحثا من�شورا بدون اقتبا�ص. كان متو�شط عامل تاأثري املجلة 1.19 ± 0.15 )جمال: 6.04-0(. اخلال�صة: لقد زادت عدد املن�شورات يف دول جمل�ص التعاون اخلليجي على مدى ال�شنوات املا�شية. دعم الأن�شطة البحثية املتعلقة بعالج والوقاية من مر�ص القدم ال�شكري يف دول جمل�ص التعاون اخلليجي يتطلب زيادة متويل البحوث الطبية وت�شجيع التعاون بني الباحثني ومراكز البحوث داخليا وخارجيا. الكلمات املفتاحية: حتليل ببليوغرايف؛ ال�شكري؛ القدم ال�شكري؛ بحث؛ من�شورات؛ الدول العربية؛ جمل�ص التعاون اخلليجي. diabetic foot disease research in gulf cooperation council countries a bibliometric analysis *ibrahim s. al-busaidi,1 nadia n. abdulhadi,2 kirsten j. coppell3 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e338–343, epub. 19 dec 18 submitted 20 dec 17 revision req. 6 feb 18; revision recd. 6 mar 18 accepted 29 mar 18 advances in knowledge this study presents a systematic bibliometric analysis of diabetic foot disease (dfd) research originating from the gulf cooperation council (gcc) region. although the number of dfd-related publications showed a slow but significant increase between 1990 and 2015, gcc countries still lag behind other countries in this field, despite having some of the highest diabetes mellitus (dm) prevalence rates worldwide. application to patient care the findings of this study are intended to highlight and promote research related to the epidemiology, management and prevention of dfd in gcc countries. such research efforts would help to inform patient care, policy planning and dm management in this region. doi: 10.18295/squmj.2018.18.03.012 ibrahim s. al-busaidi, nadia n. abdulhadi and kirsten j. coppell clinical and basic research | e339 diabetes mellitus (dm) is a public health challenge in the arabian gulf region.1 with an estimated population of 53 million, the gulf cooperation council (gcc) consists of the member states of bahrain, kuwait, oman, qatar, saudi arabia and the united arab emirates (uae), all of which share similar demographic characteristics, socioeconomic profiles and healthcare systems.2 over the past five decades, these countries have undergone rapid economic growth and urbanisation, facilitating lifestyle changes which have contributed to a marked rise in the prevalence of obesity and nutrition-related noncommunicable diseases, such as type 2 dm.3 overall, gcc countries have some of the highest global age-adjusted dm prevalence rates among adults, ranging from 14.8% in oman to 20% in kuwait, qatar and saudi arabia.1 moreover, the health care systems of gcc countries are inadequately resourced and structured to tackle the growing dm burden, resulting in suboptimal care.4,5 poorly-controlled dm increases the risk of complications such as diabetic foot disease (dfd), a group of heterogeneous conditions which cause deformity, ulcer ation and infection due to peripheral neuropathy and vascular disease in the lower limbs.6 worldwide, dfd is associated with significant morbidity and mortality, in addition to being a major financial burden to both individuals and healthcare systems.7,8 the lifetime risk of an individual with dm developing a foot ulcer is approximately 25%.8 foot ulceration increases the risk of lower limb amputation, one of the most debilitating complications of dm. more than 50% of non-traumatic lower limb amputations are attributable to dfd.8 population-based studies conducted in high-income countries have shown the prevalence of active diabetic foot ulcers to be 1–5%, which is much lower than rates reported in certain middleand low-income countries (>11%).7,8 marked differences have also been observed in gcc countries, with the prevalence of diabetic foot ulcers ranging from 0.2% in the uae to 5.9% in bahrain.9 while dm-related lower limb amputations are reportedly uncommon (1.1%) among patients attending primary care centres in saudi arabia, 47.3% of all lower limb amputations in oman are performed on dm patients.10,11 current understanding of dfd has become possible as a result of decades of international research and collab oration.7 nevertheless, locally driven dm-related research, particularly regarding dfd, appears to be limited in the gcc region, despite the high dm prevalence rates.5,11,12 publication in peer-reviewed journals is generally reg arded as one of the key indicators of research productivity.13,14 in a recent bibliometric analysis, alzahrani et al. examined the research contributions of 22 arab countries to the dfd literature and found that only 11.6% of 906 dm publications were related to dfd, although the highest number of publications originated from gcc countries.15 however, this study had methodological limitations. only articles published between january 1996 and april 2012 were examined; in addition, nonoriginal research studies were included.15 moreover, publication-related characteristics (e.g. the quality of the publications and extent of local and international collab oration) were not evaluated. the aim of the current study was to provide an updated analysis of dfd-related publications emanating from gcc countries and to examine trends in publication quality and quantity. specifically, the study aimed to determine the total number and type of gccproduced dfd-related publications, country-specific contributions, the degree of local and international research collaboration and the impact of the published research. methods this study was conducted in december 2016 and inv olved a bibliometric analysis of dfd-related publications authored or co-authored by researchers from the gcc region. a comprehensive literature search for relev ant publications was conducted using the medline® database (national library of medicine, bethesda, mary land, usa), the largest and most widely used biomedical indexing database in the world.16 two search strategies were employed—the first using medical subject headings (mesh) classifications and the second based on freetext searching—to ensure maximal retrieval of relevant articles. in both strategies, the following search terms were used in combination with the boolean operator “or”: “diabetes”, “diabetes complications”, “diabetic foot”, “diabetic foot disease”, “diabetic foot ulcer”, “peripheral arterial disease”, “peripheral neuropathy”, “diabetic foot ulceration” and “amputation”. the boolean operator “and” was then used to link these terms to the ethnogeographical terms “gulf cooperation council”, “gcc”, “arabian gulf”, “arab”, “arabs”, “bahrain”, “kuwait”, “oman”, “qatar”, “saudi arabia” and “united arab emirates”. the reference lists of identified articles, as well as any scopus® citations (elsevier, amsterdam, the netherlands), were also scanned to find additional publications. subsequently, the titles and abstracts of identified publications were reviewed. for an article to be included in the study, the research had to have been conducted in one or more of the gcc countries and the author(s) based in the gcc region (i.e. affiliated with a gcc medical or research centre). furthermore, only english-language articles related to dfd and its comp onents (e.g. dm-related peripheral neuropathy, peripheral vascular disease, infections, deformity, ulceration and/or amputation) published between january 1990 diabetic foot disease research in gulf cooperation council countries a bibliometric analysis e340 | squ medical journal, august 2018, volume 18, issue 3 and december 2015 were included in the study. nonoriginal research publications, including reviews, case reports, commentaries, letters and editorials, were excl uded from the study. thereafter, the remaining publications were classified into three general categories—basic/ clinical research papers, systematic reviews/meta analyses and randomised controlled trials (rcts)—based on their level of evidence as defined by the oxford centre for evidence-based medicine.17 for each included publication, various authorand article-related data were extracted, including the number of authors, their institutional affiliations, the year and type of publication and the name of the publishing journal at the time of publication. in addition, the degree of local (defined as the presence of authors affiliated with two or more gcc countries) and international (defined as the presence of one or more author(s) affil iated with a non-gcc country) collaboration was determined. as a measure of research quality, the imp act factor of the publishing journal was obtained using the journal citation reports tool (clarivate analytics, philadelphia, pennsylvania, usa).18 the number of citations per article was determined using the scopus® database (elsevier). the number of dfd-related articles from each gcc country per year was normalised according to the population size of the respective country for an estimation of the number of publications per million population (ppmp) per year.19,20 collected data were entered into a pre-designed excel spreadsheet, version 2016 (microsoft corp., red mond, washington, usa). descriptive statistics were used to analyse the data. comparisons were conducted using an independent samples student’s t-test. the cox stuart test was performed to identify significant trends over the investigated publication period. statistical significance was based on a type i error rate of <5% (p <0.05). all analyses were performed using r statistical software (r foundation for statistical computing, vienna, austria). results a total of 105 publications from the gcc region were initially identified, of which six (5.7%) were excluded due to unrelated content (non-dfd-related research) and three (2.9%) due to article type (two letters and one case series). of the remaining 96 articles, the vast majority (96.9%) focused on basic/clinical research. only three (3.1%) rcts were published, examining the effect of different treatments for chronic diabetic foot ulcers, peripheral neuropathy and wet gangrene prevention. these were published between 2013–2015 and had small sample sizes (23–112 patients). no systematic reviews/ meta-analyses were identified. collaborative research was reported in 19 publications (19.8%), with one instance (5.3%) of local collaboration between kuwait and the uae, 16 cases (84.2%) of international collaboration and two (10.5%) involving both local and international collaboration. there were three (3.1%) international multicentre studies. none of the collaborative studies were rcts. overall, the number of publications per year showed a gradual yet significant upward trend, increasing from zero publications prior to 1991 to 15 in 2015 (p <0.01) [figure 1]. the number of authors per publication also significantly increased during the study period (p = 0.02), with a median of three authors per publication. the country with the highest absolute number of publications was saudi arabia (62.5%), followed by kuwait (19.8%) and the uae (7.3%). however, after adjusting for population, kuwait had the highest ppmp per year (7.66), followed by bahrain (4.55) and qatar (3.85). there were no publications identified from oman [table 1]. figure 1: chart showing the number of diabetic foot disease-related publications per year originating from gulf cooperation council countries between 1990–2015 (n = 96). there was a significant increase in publications per year during the study period (p <0.01). ibrahim s. al-busaidi, nadia n. abdulhadi and kirsten j. coppell clinical and basic research | e341 the articles were published in 65 different journals, of which the saudi medical journal (9.4%) and diabetes research and clinical practice (4.2%) were most common. the majority of journals (72.3%) had only one published article. in total, 20 articles (20.8%) were published in gcc based journals, including the saudi medical journal, bahrain medical bulletin, journal of king abdulaziz university medical sciences, annals of saudi medicine, saudi journal of kidney diseases & transplantation and the journal of family & community medicine. data regarding the impact factor of the publishing journal was only available for 52 articles (54.2%). the median impact factor was 0.15 ± 1.19 (range: 0–6.04). as of december 2015, the articles had a total of 1,097 citations, with an average of 11.43 citations per article (range: 0–98 citations). in total, 80 papers (83.3%) were cited at least once; however, 16 articles (16.7%) were uncited. moreover, the five most cited articles represented 32.8% of all citations. the most frequently cited paper was a cross-sectional population-based study examining the prevalence of dm and its complications in the uae. the other four most cited articles were laboratory-based studies from kuwait and saudi arabia related to the pathogenesis of diabetic wound healing and the bacteriology of diabetic foot infections [table 2].21–25 discussion bibliometric analyses can help to identify trends in the quantity (i.e. publication output, areas of research focus and trends over time) and quality (i.e. the level of evidence, degree of collaboration, impact factor and citation rates) of published research.14,16 such analyses are crucial when identifying gaps in knowledge and directing research efforts to answer pertinent unaddressed issues, whether on an international or local scale. in the present study, kuwait was the most productive gcc country after adjusting for population size, while oman had no publications during the study period. these findings are consistent with those of two other recent bibliometric analyses of biomedical and dfdrelated publications from gcc countries.15,26 in the gcc region, dfd-related research has become a growing topic of interest among researchers. the current study observed a gradual but significant increase in the annual number of dfd-related publications originating from gcc countries between 1990–2015, most noticeably from 2007 onwards. a table 1: country-specific rate of diabetic foot diseaserelated publications originating from gulf cooperation council countries between 1990–2015 (n = 96) country n (%) population per year in millions* estimated ppmp per year bahrain 4 (4.2) 0.88 4.55 kuwait 19 (19.8) 2.48 7.66 oman 0 (0) 2.65 0.00 qatar 4 (4.2) 1.04 3.85 saudi arabia 60 (62.5) 23.70 2.53 uae 7 (7.3) 4.89 1.43 total 94 (97.9)† 35.64 2.64 ppmp = publications per million population; uae = united arab emirates. *population data sourced from the world bank.20 †two publications were not included as they involved both local and international collaboration. table 2: most cited diabetic foot disease-related publications originating from gulf cooperation council countries between 1990–2015 (n = 96)21–25 author and year of publication publication title country journal number of citations* saadi et al.21 (2007) prevalence of diabetes mellitus and its complications in a population-based sample in al ain, united arab emirates uae diabetes research and clinical practice 98 bitar et al.22 (1996) transforming growth factor-beta and insulin-like growth factor-i in relation to diabetes-induced impairment of wound healing kuwait journal of surgical research 86 abdulrazak et al.23 (2005) bacteriological study of diabetic foot infections kuwait journal of diabetes and its complications 74 el-tahawy24 (2000) bacteriology of diabetic foot saudi arabia saudi medical journal 56 bitar25 (1997) insulin-like growth factor-1 reverses diabetes-induced wound healing impairment in rats kuwait hormone & metabolic research 46 uae = united arab emirates. *citation data sourced from the scopus® database (elsevier, amsterdam, the netherlands). diabetic foot disease research in gulf cooperation council countries a bibliometric analysis e342 | squ medical journal, august 2018, volume 18, issue 3 number of factors could explain this observation. before the 1990s, healthcare systems in the region were under developed, with limited opportunities for medical education and minimal institutional support and investment in biomedical research.27 in addition, the health burden in gcc countries prior to 1990 was still dominated by infectious diseases.27,28 more recently, the burden of noncommunicable diseases has increased substantially in this region, thus prioritising dm research.9–12 furthermore, politically-stable gcc counties have recently increased spending on research and development, along with the establishment of independent organisations to fund biomedical research.26 in the current study, there was evidence of a growing body of basic/clinical research articles, including three rcts published between 2013–2015. in addition, a considerable proportion of the published articles represented local or international collaboration and the number of authors per publication significantly increased over the study period. both of these factors are indicators of the exchange of knowledge and research skills among researchers, reflecting a trend towards increasingly collaborative research. however, according to the oxford centre for evidence-based medicine, the three rcts were classified as level 2 evidence, which is insufficient to change clinical practice.17 the findings of the present study indicated that the majority of the dfd-related publications originating from the gcc region were of poor quality, particularly in light of the low citation rate. the five most cited articles represented a relatively large proportion of all citations and were classified as level 3 or 4 evidence.17 moreover, 20.8% of the articles were published in gcc based journals, the majority of which are not medline® indexed.29 improving the quality of dfd-related research will require the provision of further training opportunities so that researchers in the gcc region can conduct impactful high-quality research.5 to this end, the alloc ation of additional funding to support strategic research projects examining noncommunicable diseases in general, and dm specifically, is crucial. in the current study, the median journal impact factor of the publications was fairly low. however, the validity and utility of the impact factor as a measure of research quality has been vigorously debated.18,30,31 the value of published research to a specific population or in a certain context is not necessarily reflected by its publication in high-impact factor journals.32 it is possible that the authors may have deemed publication in a local journal more appropriate than in a higher-ranked international journal in light of the intended audience. therefore, while the impact factor remains the most common and, arguably, the best existing metric for evaluating the bibliometric impact of published research to date, caution must be exercised when using it as the sole indicator of research quality and impact, especially for research originating from low-income countries and those with emerging economies.33 the current study was subject to several limitations. first, the methods used in the analysis may have underestimated the publication rate of dfd-related research originating from gcc countries. as the search strategy was restricted to the medline® database (national library of medicine), articles published in journals not included in this database would have been omitted. additionally, while publication in peer-reviewed journals is usually the preferred vehicle for the dissemination of medical research, it is possible that certain dfd-related studies, such as those conducted by governmental entities, may have been disseminated by other means (i.e. internal reports).13 second, some article types not included in the analysis, such as reviews and case reports, may nevertheless represent valuable contributions to the literature. however, it is widely acknowledged that original research articles are an accurate reflection of research activity in a particular field and represent higher-quality evidence when compared to other types of publications.17 finally, it was outside the scope of this study to estimate the contribution of gcc-researchers to international literature. despite these limitations, the findings from this study are a reliable representation of gcc-based dfd-related research activity and may help to inform future efforts in this region. conclusion the current study found that the number of dfd-related publications authored by gcc researchers increased significantly during the study period. nevertheless, gcc countries lag behind other countries in terms of output and quality of dfd-related research, despite having some of the highest dm prevalence rates worldwide. this undoubtedly leaves gaps in knowledge related to the burden and management of dfd. improving research funding and infrastructure and promoting local and international collaboration is crucial to enhancing dfd related research in this region. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. ibrahim s. al-busaidi, nadia n. abdulhadi and kirsten j. coppell clinical and basic research | e343 references 1. international diabetes federation. idf diabetes atlas: seventh edition, 2015. from: http://diabetesatlas.org/resources/previous editions.html accessed: mar 2018. 2. world health organization. global health observatory (gho) data: country statistics. from: www.who.int/gho/countries/en/ accessed: mar 2018. 3. ng sw, zaghloul s, ali hi, harrison g, popkin bm. the prevalence and trends of overweight, obesity and nutrition-related non-communicable diseases in the arabian gulf states. obes rev 2011; 12:1–13. doi: 10.1111/j.1467-789x.2010.00750.x. 4. klautzer l, becker j, mattke s. the curse of wealth: middle eastern countries need to address the rapidly rising burden of diabetes. int j health policy manag 2014; 2:109–14. doi: 10.15171/ijhpm. 2014.33. 5. alhyas l, mckay a, balasanthiran a, majeed a. quality of type 2 diabetes management in the states of the cooperation council for the arab states of the gulf: a systematic review. plos one 2011; 6:e22186. doi: 10.1371/journal.pone.0022186. 6. bakker k, apelqvist j, schaper nc; international working group on diabetic foot editorial board. practical guidelines on the management and prevention of the diabetic foot 2011. diabetes metab res rev 2012; 28:225–31. doi: 10.1002/dmrr.2253. 7. boulton aj. the diabetic foot: grand overview, epidemiology and pathogenesis. diabetes metab res rev 2008; 24:s3–6. doi: 10.1002/dmrr.833. 8. boulton aj, vileikyte l, ragnarson-tennvall g, apelqvist j. the global burden of diabetic foot disease. lancet 2005; 366:1719–24. doi: 10.1016/s0140-6736(05)67698-2. 9. abuyassin b, laher i. diabetes epidemic sweeping the arab world. world j diabetes 2016; 7:165–74. doi: 10.4239/wjd.v7.i8.165. 10. al-rubeaan k, al derwish m, ouizi s, youssef am, subhani sn, ibrahim hm, et al. diabetic foot complications and their risk factors from a large retrospective cohort study. plos one 2015; 10:e0124446. doi: 10.1371/journal.pone.0124446. 11. al-busaidi is, abdulhadi nn, coppell kj. care of patients with diabetic foot disease in oman. sultan qaboos univ med j 2016; 16:e270–6. doi: 10.18295/squmj.2016.16.03.002. 12. al-busaidi is. diabetic foot disease in oman: a call for more research. oman med j 2017; 32:354–5. doi: 10.5001/omj.2017.68. 13. al-busaidi is, alamri y. publication rates and characteristics of undergraduate medical theses in new zealand. n z med j 2016; 129:46–51. 14. deshazo jp, lavallie dl, wolf fm. publication trends in the medical informatics literature: 20 years of “medical informatics” in mesh. bmc med inform decis mak 2009; 9:7. doi: 10.1186/ 1472-6947-9-7. 15. alzahrani oh, badahdah ys, bamakrid ms, alfayez as, alsaeedi ms, mansouri am, et al. the diabetic foot research in arabs’ countries. open j endocr metab dis 2013; 3:157–65. doi: 10.4236/ojemd.2013.33023. 16. jenuwine es, floyd ja. comparison of medical subject headings and text-word searches in medline to retrieve studies on sleep in healthy individuals. j med libr assoc 2004; 92:349–53. 17. oxford centre for evidence-based medicine. 2011 levels of evid ence. from: www.cebm.net/2016/05/ocebm-levels-of-evidence/ accessed: mar 2018. 18. saha s, saint s, christakis da. impact factor: a valid measure of journal quality? j med libr assoc 2003; 91:42–6. 19. king da. the scientific impact of nations. nature 2004; 430:311–16. doi: 10.1038/430311a. 20. the world bank. countries and economies. from: data.world bank.org/country accessed: mar 2018. 21. saadi h, carruthers sg, nagelkerke n, al-maskari f, afandi b, reed r, et al. prevalence of diabetes mellitus and its complications in a population-based sample in al ain, united arab emirates. diabetes res clin pract 2007; 78:369–77. doi: 10.1016/ j.diabres.2007.04.008. 22. bitar ms, labbad zn. transforming growth factor-beta and insulin-like growth factor-i in relation to diabetes-induced impair ment of wound healing. j surg res 1996; 61:113–19. doi: 10.1006/ jsre.1996.0090. 23. abdulrazak a, bitar zi, al-shamali aa, mobasher la. bacter iological study of diabetic foot infections. j diabetes complications 2005; 19:138–41. doi: 10.1016/j.jdiacomp.2004.06.001. 24. el-tahawy at. bacteriology of diabetic foot. saudi med j 2000; 21:344–7. 25. bitar ms. insulin-like growth factor-1 reverses diabetes-induced wound healing impairment in rats. horm metab res 1997; 29:383–6. doi: 10.1055/s-2007-979060. 26. al-maawali a, al busadi a, al-adawi s. biomedical publications profile and trends in gulf cooperation council countries. sultan qaboos univ med j 2012; 12:41–7. 27. world health organization regional office for the eastern mediterranean. country cooperation strategy for who and oman: 2010-2015. from: apps.who.int/iris/bitstream/10665/11 3221/1/ccs_oman_2010_en_14485.pdf accessed: mar 2018. 28. mokdad ah, jaber s, aziz mi, albuhairan f, alghaithi a, alhamad nm, et al. the state of health in the arab world, 1990-2010: an analysis of the burden of diseases, injuries, and risk factors. lancet 2014; 383:309–20. doi: 10.1016/s0140-6736 (13)62189-3. 29. al-busaidi is. medline® indexing of the sultan qaboos university medical journal: a great leap forward for biomedical research and publishing in the gulf region. sultan qaboos univ med j 2017; 17:e123–4. doi: 10.18295/squmj.2016.17.01.025. 30. garfield e. the history and meaning of the journal impact factor. jama 2006; 295:90–3. doi: 10.1001/jama.295.1.90. 31. seglen po. why the impact factor of journals should not be used for evaluating research. bmj 1997; 314:498–502. doi: 10.11 36/bmj.314.7079.497. 32. al-busaidi is. re: neurology research in saudi arabia urgent call for action. sultan qaboos univ med j 2017; 17:e491–2. doi: 10.18295/squmj.2017.17.04.023. 33. hoeffel c. journal impact factors. allergy 1998; 53:1225. doi: 10.11 11/j.1398-9995.1998.tb03848.x. https://doi.org/10.1111/j.1467-789x.2010.00750.x https://doi.org/10.15171/ijhpm.2014.33 https://doi.org/10.15171/ijhpm.2014.33 https://doi.org/10.1371/journal.pone.0022186 https://doi.org/10.1002/dmrr.2253 https://doi.org/10.1002/dmrr.833 https://doi.org/10.1016/s0140-6736%2805%2967698-2 https://doi.org/10.4239/wjd.v7.i8.165 https://doi.org/10.1371/journal.pone.0124446 https://doi.org/10.18295/squmj.2016.16.03.002 https://doi.org/10.5001/omj.2017.68 https://doi.org/10.1186/1472-6947-9-7 https://doi.org/10.1186/1472-6947-9-7 https://doi.org/10.4236/ojemd.2013.33023 https://doi.org/10.1038/430311a https://doi.org/10.1016/j.diabres.2007.04.008 https://doi.org/10.1016/j.diabres.2007.04.008 https://doi.org/10.1006/jsre.1996.0090 https://doi.org/10.1006/jsre.1996.0090 https://doi.org/10.1016/j.jdiacomp.2004.06.001 https://doi.org/10.1055/s-2007-979060 https://doi.org/10.1016/s0140-6736%2813%2962189-3 https://doi.org/10.1016/s0140-6736%2813%2962189-3 https://doi.org/10.18295/squmj.2016.17.01.025 https://doi.org/10.1001/jama.295.1.90 https://doi.org/10.1136/bmj.314.7079.497 https://doi.org/10.1136/bmj.314.7079.497 https://doi.org/10.18295/squmj.2017.17.04.023 https://doi.org/10.1111/j.1398-9995.1998.tb03848.x https://doi.org/10.1111/j.1398-9995.1998.tb03848.x squ med j, december 2010, vol. 10, iss. 3, pp. 377-381, epub. 14th nov 10 submitted 9th jan 10 revision req. 14th june 10, revision recd. 24th june 10 accepted 13th july 10 college of medicine, taibah university, almadinah almuhawwarah, saudi arabia *corresponding author email: dr.manaalb@hotmail.com <á^èj⁄˜]<^fõ_<â^ü<<ìëç◊¢]<l]å^è√÷]<ª<óïüπ]<ãœ]á⁄ ìëåá√ä÷]<ìèeü√÷]<ì”◊€π]<hïöáflπ]<<ìflëçπ]<ª<g�÷]<h¯õê      112 2009   112  31%44.9 44  %26.5%61.2     abstract: objectives: outpatient clinics are a key element in dermatology health service provision thus making them an excellent place for intern and medical student rotations. however, this requires that patients are willing to interact with these trainees. this study assessed the attitudes of patients towards interns and medical students rotating in dermatology clinics. methods: all 112 patients interacting with medical students and interns at dermatology clinics at king fahad specialist hospital in almadinah almunawwarah region, saudi arabia, from september to november 2009 completed a cross-sectional survey, which assessed their acceptance of these trainees. results: ninety-eight of 112 patient responses were valid. a total of 44 (44.9%) of these 98 patients had a chance to interact with 1–3 medical students or interns during their visit. the majority of the patients preferred the treating physician to be present during history taking by the interns and students. a majority of patients preferred that their physical examination be done by the physician alone (61.2%), whereas others (26.5%) preferred an intern with the physician. both male and female patients preferred that their health care provider be of the same sex. conclusion: the patients in dermatology clinics accept the services of interns and students, while also expecting privacy. therefore, interns and students should be confident when taking patient histories and performing physical examinations. keywords: attitude; dermatology; medical students brief communicationbrief communication patient attitudes towards interns and medical students rotating in dermatology clinics in almadinah almunawwarah region, saudi arabia *mana al-harbi and khalid al-harbi advances in knowledge 1. this study showed that patients have favorable attitudes toward medical students and teaching processes even in the most conservative cultures in saudi arabia. 2. it also highlighted some points which increase patients' acceptance of medical students: 1. the physician should explain to patients the importance of clinical experience in medical student teaching ; 2. health care should be provided by a trainee/physician of the same sex, especially for female patients; 3. the number of students interacting with each patient should be minimised; 4. patient examination should be performed by a physician, with student participation possibly requested from cooperative patients. patient attitudes towards interns and medical students rotating in dermatology clinics in almadenah almunawwarah region, saudi arabia 378 | squ medical journal, december 2010, volume 10, issue 3 brief communication | 378 application to patient care 1. students should have more confidence in dealing with patients when they realise that patients have a favorable attitude towards them; this will make the teaching and health care process go more smoothly. 2. in order to increase patient satisfaction and minimise their rejection by patients, students should avoid examining patients alone without presence of the treating physician. 3. more clinical exposure for students will result in better doctors participating in a positive way in health care. outpatient clinics are a key element in dermatology health service provision thus making them an excellent place for intern and medical student learning.1 thus, medical students who are rotating in dermatology obtain considerable benefit from their learning experience in these clinics. this also gives them more opportunity to interact with patients and their relatives than in any other specialty. a large number of patients in our dermatology clinic are females so they might refuse student participation in their care due to concerns about privacy or because of their conservative cultural background. the latter is especially true in the almadinah almunawwarah region location of al madinah, the second most important islamic city in saudi arabia. interestingly, several investigators have found patient attitudes toward medical students to be favourable in internal medicine and surgery clinics.1,2,3 similar studies conducted in dermatology clinics inside and outside saudi arabia have shown that a large percentage of patients accept the participation of medical students in their care.4,5 prior information about the presence of a medical students and their specific role during clinical examination was felt to be essential by a significant number of patients.6 however, the patient acceptance of medical students and interns has not been studied in the almadinah region of saudi arabia. this region has a medical college with the medical students undertaking their formal and elective rotations in both king fahad specialist hospital (kfsh) and auhd hospital. the objective of this research was therefore to study attitudes of patients toward interns and medical students who rotate in the dermatology clinics in almadinah region. methods this cross-sectional survey was conducted at kfsh in almadinah almunawwarah region in the two month period, september to november 2009. the survey consisted of 15 questions on patient demographic information and preferences regarding medical student participation in providing health services and participating in clinical examination. the questionnaire and study protocol were obtained from a previous study, the authors also providing us with an arabic translation.1 we then modified the questionnaire to include medical interns, to see if there would be any difference in patient acceptance of students as compared to the interns (see questionnaire in annexe). we tested the questionnaire in a pilot study which included 15 patients. data were collected by distributing the self-reported questionnaires in consultation rooms in dermatology clinics at kfsh and auhd hospital. the questionnaires were distributed to all those patients who were managed by interns and medical students. the respondents were asked to choose the most relevant response. the 112 returned questionnaires, of which 14 were discarded due to incomplete data, were analysed using the statistical package for social sciences (spss) for windows, version 17.0 (spss inc., chicago, il, usa). a p value of <0.05 was used for statistical significance. approval for this study was obtained from the medical college of taibah university, saudi arabia. results ninety-eight patients from dermatology clinics were included in this study. their mean age was 24.3 ± 6.2 years; 59% were female and all had received some education with 52.6% having college education or above. during their visit to the dermatology clinics, forty-four patients (44.9%) interacted with 1–3 medical students, while 15.3% interacted with 3–4 students [table 1]. regarding patient preferences for intern and medical student participation in outpatient dermatology clinics, 60.2% of respondents preferred to see students with the physician while mana al-harbi and khalid al-harbi brief communication | 379 21.4% preferred to see the physician alone. similar figures were obtained for intern participation: 57.1% preferred to see interns with the physician and 23.5% preferred to see the physician alone [table 2]. regarding participation of students in the physical examination, 61.2% of respondents preferred to see the physician alone and 26.5% preferred interns in the presence of the treating physician; only 4.1% preferred to see students with the physician as shown in the table 2. patient responses to a variety of preference questions are listed in table 3. as shown, 78.6% preferred to see students of the same sex, whereas 21.4% did not mind about the sex of the student. all female patients wanted a same sex health care provider, whereas 63.8% of male patients wanted male students and interns. this difference between males and females was statistically significant (p = 0.00). of the study participants, 77.5% wanted to discuss their health problems alone with their physician, while 39.7% agreed to disclose personal health information in front of medical students and interns. the majority of the patients (67.4%) stated that they enjoyed interacting with medical students in outpatient dermatology clinics. out of those who were involved in the study, 42.9% felt that they got more attention from their physician in the presence of the medical students, and 56.1% felt that the students understood their health needs. the chisquare test showed a statistically insignificant relationship between number of medical students and patient acceptance of them participating in the clinic (p = 0.18). on the other hand, there was a statistically significant relationship between the number of the students and their acceptance by patients during clinical examination (p = 0.00). also the sex of the patient and that of the care giver was a significant factor during the examination (p = 0.01). discussion the attention given to patient-medical student interaction in medical literature is very much deserved and needs to be sustained.7 medical student participation in outpatient clinics is an integral component of their medical school education and the patients are often the focal point of the teaching process. patient’s willingness and comfort level table 1: demographic data of dermatology clinic patients no. (%) age (mean ± standard deviation) female male 24.3 ± 6.2 58 (59.2) 40 (40.8) education intermediate or less secondary technical school college graduate postgraduate study 12 (12.2) 31 (31.6) 4 (4.1) 38 (38.8) 13 (13.8) number of students seen in previous visit none 1–3 4–5 >5 39 (39.8) 44 (44.9) 15 (15.3) 0 table 2: patient preferences in regards to medical students and interns total n (%) male n (%) female n (%) p value medical student participation physician alone student with physician no preference 98 (100) 21 (21.4) 59 (60.2) 18 (18.4) 58 (59.2) 12 (57.1) 30 (50.8) 16 (88.9) 40 (40.8) 9 (42.9) 29 (49.1) 2 (11.1) < 0.016 intern participation physician alone intern with physician no preference 98 (100) 23 (23.5) 56 (57.1) 19 (19.4) 58 (59.2) 9 (39.1) 30 (53.6) 19 (100) 40 (40.8) 14 (60.9) 26 (46.4) 0 <0.00 physical examination physician alone intern with physician student with physician no preference 98 (100) 60 (61.2) 26 (26.5) 4 (4.1) 8 (8.2) 58 (59.2) 38 (63.3) 11(42.3) 1(25) 8 (100) 40 (40.8) 22 (36.7) 15 (57.7) 3 (75) 0 < 0.012 patient attitudes towards interns and medical students rotating in dermatology clinics in almadenah almunawwarah region, saudi arabia 380 | squ medical journal, december 2010, volume 10, issue 3 regarding the involvement of a medical trainee in their care may be affected by their previous experience with trainees, their understanding of the role and responsibilities of trainees, and the nature of the medical problem.8 our study showed that patients had a favorable attitude toward medical student and intern participation in their health care. the majority of patients preferred the presence of the treating physician alongside the trainees, and preferred to undergo physical examination by the physician alone. the attitude toward interns was more favourable compared to medical students. all of the female patients wanted to deal with female students, whereas over 60% of males preferred to deal with male students. amongst the study participants, 39.7% did not mind disclosing personal information to the students. the majority of patients enjoyed interacting with the students and felt that the students understood their health needs. although the results of attitudes of the patients were positive for acceptance of the student participation in the dermatology clinics, the figures were less than those in the study by townsend et al. which was carried out in the usa.2 this might be due to cultural differences between the two countries as saudi arabia has a more conservative culture. it could also be due to the large percentage of female patients (59.2%) in our study. based on the results of our study, we would like to suggest some points that might make medical student and intern participation in dermatology clinics easier and more acceptable. the physician should try to explain to the patients the importance of direct interaction with patients in medical student teaching. health care should also preferably be provided by a trainee/physician of the same sex, especially for the physical examination of female patients. the number of trainees interacting with each patient should be minimised. examination of patients, especially of the private organs, should be performed by a physician alone, but student/ intern participation in physical examination may be requested from cooperative patients. conclusion in the al-madenah al-munawwarah region, medical student and intern participation is generally accepted by patients in dermatology clinics and therefore they should be confident during history taking and examination, while making efforts to maintain patient privacy. a c k n o w l e d g m e n t s we are grateful to dr. i bukhari4 for her help with data collection sheets and to all those who helped us in preparing this manuscript. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. simons rj, imboden e, martel jk. patient attitudes toward medical student participation in a general internal medicine clinic. j gen intern med 1995; 10:251–4. 2. york nl, da rosa da, markwell sj, niehaus ah, folse r. patients' attitudes toward the involvement of medical students in their care. am j surg 1995; 169:421–3. 3. alsultnan a, parashar s, alghamdi a. electives during medical internship. saudi med j 2003; 24:1006–9. table 3: distribution of patient preferences towards the medical trainees strongly agree agree undecided disagree strongly disagree 1. prefer same sex 39 (39.8) 38 (38.8) 5 (5.1) 16 (16.3) 0 2. wanted time alone with physician 54 (55.1) 22 (22.4) 21(21.4) 1(1) 0 3. will disclose personal info in front of trainees 17 (17.3) 22 (22.4) 34 (34.7) 7 (7.1) 18 (18.4) 4. enjoyed interacting with trainees 27 (27.6) 39 (39.8) 6 (6.1) 21(21.4) 5 (5.1) 5. received more attention when trainee present 24 (24.5) 18 (18.4) 42 (42.9) 12 (12.2) 2 (2) 6 trainees understood my health needs 25 (25.5) 30 (30.6) 24 (24.5) 12 (12.2) 7 (7.1) mana al-harbi and khalid al-harbi brief communication | 381 4. bukhari i, alakloby o, al saeed w. patients' attitude towards medical students rotating in the dermatology clinic. indian j dermatol 2008; 53:12–4. 5. townsend b, marks j, mauger d, miller j. patients attitudes towards medical student participation in a dermatology clinic. j am acad dermatol 2003; 49:709–11. 6. thompson ja, anderson jl. patient preferences and the bedside manner. med educ 1982, 16:17–21. 7. richardson ph, curzen p, fonagy p. patients' attitudes to student doctors. med educ 1986; 20:314–17. 8. salisbury k, farmer ea, vnuk a. patients' views on the training of medical students in australian general practice settings. aust fam physician 2004; 33:281– 3. it is well established that mitochondrial disorders (mids) may phenotypically mimic motor neuron disease.1–3 these similarities fade with disease progression and the development of mitochondrial multiple organ dysfunction syndrome (mimods).4,5 however, if progression is slow and mimods is mild, a mid may still be misinterpreted as amyotrophic lateral sclerosis (als), as with the case presented below. case report a 48-year-old caucasian male presented to the neurological hospital rosenhügel, vienna, austria, in february 2001. the patient had first noticed occasional weakness of the left brachial biceps muscle at 36 years of age. four years later, fasciculations occurred for the first time in the shoulder girdle muscles which spread bilaterally to other muscles and the lower limbs during the following years. by the age of 46 years, the patient’s muscle weakness had spread to the left intrinsic hand muscles, particularly those of the left thumb and fifth finger. the muscle weakness increased when it was cold and led to involuntary muscle contractions. he was an amateur cyclist, regularly cycling 4,000 km per year. after cycling, he often experienced aching of the neck extensor muscles which prevented him from sleeping. previous creatine kinase values for the patient were unavailable. one year before presentation, the patient was diagnosed with als by a neurologist based on clinical and electrophysiological findings. there was 1department of neurology, krankenanstalt rudolfstiftung, vienna, austria; 2genomics platform, pasteur institute of tunis, tunis, tunisia *corresponding author e-mail: fipaps@yahoo.de اضطرابات املايتوكندريا قد حتاكي التصلب اجلانيب الضموري يف بداياته جوزيف فين��شرتر و �شندا زروق-حمجوب abstract: similarities between a mitochondrial disorder (mid) and amyotrophic lateral sclerosis (als) fade with disease progression and the development of mitochondrial multiple organ dysfunction syndrome (mimods). however, with mild mimods, a mid may still be misinterpreted as als. we report a 48-year-old male who presented to the neurological hospital rosenhügel, vienna, austria, in february 2001 with slowly progressive weakness, wasting and left upper limb fasciculations which spread to the shoulder girdle and lower limbs. additionally, he developed tetraspasticity and bulbar involvement. he had been diagnosed with als a year previously due to electrophysiological investigations indicative of a chronic neurogenic lesion. however, a muscle biopsy revealed morphological features of a mid and a combined complex-ii/iii defect. nerve conduction studies were performed over subsequent years until february 2011. this case demonstrates that mids may mimic als at onset and begin as a mono-organ disorder but develop into a multi-organ disease with long-term progression. a combined complex ii/iii defect may manifest with bulbar involvement. keywords: motor neuron disease; mitochondrial disorders; amyotrophic lateral sclerosis; mtdna; oxidative phosphorylation; case report; austria. ظهور ومع املر�ص، تقدم مع )als( ال�شموري اجل�نبي والت�شلب )mid( املتقدرة ا�شطراب�ت بني الت�ش�به تدريجي� يختفي امللخ�ص: als على اأنه mid املعتدلة، فقد ي�شخ�ص mimods غري اأنه يف ح�الت .)mimods( متالزمة االختالل املتعدد االأع�ش�ء املتقدري عن طريق اخلط�أ. ونعر�ص هن� حل�لة رجل عمره 48 ع�م� يف م�شت�شفى روزنهيقل لالأمرا�ص الع�شبية يف مدينة فيينا ب�لنم�ش� يف فرباير من ع�م 2001م ك�ن ي�شكو من �شعف تدريجي، وهزال، وارجت�ف حزمي يف الطرف العلوي االأي�رض، امتد الحق� اإىل حزام الكتف واالأطراف ال�شفلى. ثم اأظهر املري�ص �شن�ج� رب�عي� مع اكتن�ف ب�شلي. وك�نت ح�لة املري�ص قد �شخ�شت قبل ع�م على اأنه� als بن�ء على فحو�ش�ت على دلت مورفولوجية خ�ش�ئ�ص اأن اأو�شح الع�شل من خزعة فح�ص اأن اإال املن�ش�أ. ع�شبية مزمنة اآفة اإىل اأ�ش�رت كهربية–فيزيولوجية االإ�ش�بة بـ mid، متزامنة مع عيب يف مركب – ii/iii. واأجريت درا�ش�ت حول النقل الع�شبي بعد �شنوات من الفحو�ش�ت ال�ش�بقة حتى ع�م 2011م. تو�شح هذه احل�لة اإىل اأن ح�الت الـ mid قد حت�كي als يف بداية املر�ص، وتبداأ يف ع�شو واحد، ولكنه� تتطور اإىل اأن ت�شبح اختالال متدرج� يف عدد من االأع�ش�ء. وقد يحدث عيب يف مركب – ii/iii مع اكتن�ف ب�شلي. مفتاح الكلمات: مر�ص الع�شبون احلركي؛ ا�شطراب�ت املتقدرة؛ الت�شلب اجل�نبي ال�شموري؛ احلم�ص الريبي النووي منزوع االأك�شجني؛ فسفرة ت�أك�شدية؛ تقرير ح�لة؛ النم�ش�. mitochondrial disorders may mimic amyotrophic lateral sclerosis at onset *josef finsterer1 and sinda zarrouk-mahjoub2 case report sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e92–95, epub. 2 feb 16 submitted 19 may 15 revisions req. 29 jun & 17 aug 15; revisions recd. 22 jul & 17 aug 15 accepted 27 aug 15 doi: 10.18295/squmj.2016.16.01.017 josef finsterer and sinda zarrouk-mahjoub case report | e93 slight wasting of the shoulder girdle muscles and diffuse wasting of the left upper limb muscles with predominance of the left intrinsic hand muscles. fasciculations were seen in all muscles of the left upper limb and the shoulder girdle, tendon reflexes were exaggerated and pyramidal signs were bilaterally positive. cerebral magnetic resonance imaging (mri) was normal and an mri scan of the cervical spine showed only mild degenerative alterations. the diagnosis of als was confirmed by other neurologists. the patient was prescribed riluzole and high-dose vitamin d without effect. immunoglobulins were prescribed without rationale or beneficial effect. following the initiation of riluzole treatment, the patient developed muscle cramps in the distal lower limb muscles and his resting pulse occasionally reached 130 beats/minute. although levothyroxine was prescribed by endocrinologists to prevent growth of diffuse multinodular goitres, the patient was noncompliant with the treatment. at presentation to the neurological hospital rosenhügel, the patient had developed liquid dysphagia and chewing difficulties. he had often complained of hyperhidrosis over the preceding years. additionally, his history was positive for hyperlipidaemia and there was a family history of hypoacusis and gibbus deformity from his paternal grandfather. re-examination of the patient revealed wasting of the tongue edges, frequent fasciculations of the tongue, distal weakness with leftsided predominance, diffuse wasting, exaggerated tendon reflexes, positional tremors with left-sided predominance, fasciculations in all muscles and positive pyramidal signs for the upper limbs. with regards to the lower limbs, there was weakness of the left foot extensors (grade m5-), exaggerated tendon reflexes and bilateral positive pyramidal signs. the results of multiple nerve conduction studies performed over the following years are shown in table 1. needle electromyography of the right brachial biceps muscle showed fibrillations and fasciculations with bizarre morphology at 20/20 sites, increased mean motor unit action potential duration, increased polyphasia and satellite potentials and a reduced interference pattern at maximal voluntary contractions. his creatine kinase levels were slightly elevated (maximal value: 97 u/l; normal value: <70 u/l) and he had hypercholesterolaemia. however, the results of a lactate stress test were normal. transcranial magnetic stimulation revealed increased central motor conduction time (cmct) of the c8 motor neuron on the right side, normal cmct of the c8 motor neuron on the left side and normal cmct of the s1 nerve root bilaterally. ganglioside gm1 antibodies were normal. an abdominal ultrasound revealed a double kidney on the right side. based on the patient’s history and the existence of atypical clinical features—including hyperhidrosis, goitre and hyperlipidaemia—mimods involving the central nervous system, the peripheral motor, sensory and vegetative nerves, the endocrine system and the skeletal muscles was suspected. a muscle biopsy from the lateral vastus muscle showed neurogenic features with grouped atrophic fibres and a fibretype grouping; however, the biopsy also showed indications for a mid, including a coarsening of the mitochondrial pattern on oxidative enzyme and gomori trichrome stains. immunohistochemistry revealed cytochrome c oxidase-hyporeactive/negative fibres and electron microscopy indicated the subsarcolemmal accumulation of abnormally-shaped mitochondria. biochemical investigations of the muscle homogenate revealed a combined complex-ii/iii defect consisting of succinate cytochrome c-oxidoreductase related to non-collagen protein and citrate synthase. no tests for coenzyme-q activity were carried out. screening for common mitochondrial dna (mtdna) mutations causing the following conditions was noninformative: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; myoclonic epilepsy with red-ragged fibres; chronic progressive external ophthalmoplegia; leber hereditary optic neuropathy; neuropathy, ataxia and retinitis pigmentosa; maternally-inherited leigh syndrome; non-syndromic myopathy; cardiomyopathy; dementia; diabetes; or encephalopathy. despite repeated attempts to contact the patient for further investigations, he was subsequently lost to follow-up. discussion misinterpretation of a mid as als may occur with mild or unnoticeable mimods or when the mid starts primarily with motor manifestations and spasticity due to additional cerebral involvement.4–6 in the presented case, the implications of the thyroid dysfunction, hyperhidrosis, hyperlipidaemia and autonomic and sensory involvement were neglected. in order to avoid misdiagnosis, clinical manifestations should not be ignored and a common cause of seemingly unrelated manifestations should not be excluded. under these circumstances, patients with suspected als should be investigated for a mid. since most mids develop into mimods during the disease course, it is usually just a matter of time before mimods becomes evident.4,5 nevertheless, it is important to note that als may also show morphological evidence of a mitochondrial defect. hirano et al. reported a 65-year-old als patient whose muscle biopsy showed 10% raggedmitochondrial disorders may mimic amyotrophic lateral sclerosis at onset e94 | squ medical journal, february 2016, volume 16, issue 1 and alterations of the mitochondrial genome and transcriptome.8–14 there are also indications that mtdna deletions are more common in individuals with sporadic als as compared to healthy controls.15 mitochondrial dysfunction in als is often regarded as secondary following the exposure of mtdna to increased oxidative stress.16 in the current case, the diagnosis of als was eventually excluded due to the long duration of red fibres and 3% cytochrome c oxidase-negative fibres.7 however, contrary to the present case, no biochemical abnormalities were detected.7 a number of other reports have described mitochondrial dysfunction in als, including decreased complex-i activity, decreased superoxide dismutase 1 function and energy production, increased apoptosis, abnormal calcium homeostasis, impaired axonal transport of mitochondria, respiratory chain dysfunction table 1: nerve conduction study results of a patient with a mitochondrial disorder mimicking amyotrophic lateral sclerosis at onset nerve may 2009 august 2009 october 2009 january 2010 november 2010 february 2011 l r l r l r l r l r l r m ed ia n motor dl in ms 4.8 np 6.3 4.4 4.8 4.3 6.0 4.6 np 6.3 5.9 np cmap in mv 3.0 np 0.9 4.2 1.8 4.6 0.8 3.2 np 1.5 1.3 np ncv in m/s 48.0 np 41/52* 49/51 52.0 59.0 41.0 56.0 np 57.0 41.2 np sensory snap in μv 40.0 np np np 28.8 15.5 55.0 40.0 np 34.0 np np ncv in m/s 56.0 np np np 59.0 60.0 63.0 56.0 np 50.0 np np f-wave persistence np np np np 0/10 1/10 np np np np 0/10 np u ln ar motor dl in ms 3.3 np 3.8 3.2 2.3 3.4 3.8 3.3 4.2 4.0 np np cmap in mv 3.0 np 2.8 3.2 6.2 8.3 2.7 2.9 0.9 1.9 np np ncv in m/s 59/43* np 56/45 53/58 62/51 43/41 60/33 47/53 48/38 46/28 np np sensory snap in μv 20.0 np 20.0 5.0 18.8 9.5 11.0 np np np np np ncv in m/s 61.0 np 55.0 np 51.0 54.0 48.0 np np 30.0 np np f-wave persistence np np np np 9/10 9/10 np np np np np np pe ro ne al motor dl in ms np np np 5.5 4.5 4.0 4.5 5.1 4.8 np np np cmap in mv np np np 4.0 8.9 10.1 np 3.0 3.0 np np np ncv in m/s np np np np 50.0 46.0 np np np 44.0 np np ti bi al motor dl in ms np np np np 3.9 3.4 np np np 4.8 np np cmap in mv np np np np 18.5 12.7 np np np 6.8 np np ncv in m/s np np np np 50.0 46.0 np np np 44.0 np np su ra l sensory snap in μv np np np 5.5 np 6.1 2.0 6.0 np np np np ncv in m/s np np np 40.0 np 42.0 43.0 38.0 np np np np l = left; r = right; dl = distal latency; ms = milliseconds; cmap = compound muscle action potential; mv = millivolt; ncv = nerve conduction velocity; m/s = metres per second; snap = sensory nerve action potential; μv = microvolts; np = not performed. *values represent the distal and proximal measurements. josef finsterer and sinda zarrouk-mahjoub case report | e95 the clinical course, the multisystemic nature of the phenotype (mimods), the muscle biopsy findings, the normal cerebral mri scan and the biochemical findings. the strongest arguments in favour of a diagnosis of a primary mitochondrial defect were the multi-organ phenotype and the presence of a complex ii/iii defect. on the other hand, the histochemical findings did not match the biochemical findings. since no mtdna mutations could be detected, the complex ii/iii defect may have instead been due to a mutation in a nuclear dna-located gene rather than a mtdnalocated gene. however, the precise genetic defect still requires confirmation. another point of interest with regards to the current case is the late onset of the disease and its slow progression. the frequency and severity of mids are usually increased in children and the disease usually progresses slowly in adults.17,18 often, only a single organ is initially affected and other organs are consecutively affected after long periods of time.19 there is no consistent pattern of organ involvement and no regular sequence among the organs which are affected. factors which drive the pattern of organ involvement and the speed of progression may include the type of mutation (e.g. protein, transfer/ribosomal ribonucleic acid, helicase or polymerase mutations) or modifying genes and the heteroplasmy rate or the threshold effect in the case of mtdna mutations.20 conclusion this case suggests that a mid can mimic als at the onset of the disease and that it may start as a monoorgan disorder and subsequently turn into a multiorgan disease after slow progression over a prolonged period of time. the exclusion of als may indicate the presence of a mid and a complex ii/iii defect may manifest with bulbar involvement. patients with apparent als should be investigated for a mid if atypical manifestations have been noted. references 1. finsterer j. mitochondriopathy mimicking amyotrophic lateral sclerosis. neurologist 2003; 9:45–8. doi: 10.1097/01.nrl. 0000038589.58012.a8. 2. finsterer j. mitochondriopathy as a differential diagnosis of amyotrophic lateral sclerosis. amyotroph lateral scler other motor neuron disord 2002; 3:219–24. 3. cohen bh. neuromuscular and systemic presentations in adults: diagnoses beyond merrf and melas. neurotherapeutics 2013; 10:227–42. doi: 10.1007/s13311-013-0188-3. 4. finsterer j, stöllberger c. plec1 mutation associated with left ventricular hypertrabeculation/noncompaction. neuromuscul disord 2015; 25:447–8. doi: 10.1016/j.nmd.2015.02.005. 5. finsterer j, frank m. haematological abnormalities in mitochondrial disorders. singapore med j 2015; 56:412–19. doi: 10.11622/smedj.2015112. 6. finsterer j, stöllberger c. noncompaction in alleged motor neuron disease suggests myopathy. int j cardiol 2014; 177:639–40. doi: 10.1016/j.ijcard.2014.09.183. 7. hirano m, angelini c, montagna p, hays ap, tanji k, mitsumoto h, et al. amyotrophic lateral sclerosis with ragged-red fibers. arch neurol 2008; 65:403–6. doi: 10.1001/archneurol.2007.65. 8. ghiasi p, hosseinkhani s, noori a, nafissi s, khajeh k. mitochondrial complex i deficiency and atp/adp ratio in lymphocytes of amyotrophic lateral sclerosis patients. neurol res 2012; 34:297–303. doi: 10.1179/1743132812y.0000000012. 9. faes l, callewaert g. mitochondrial dysfunction in familial amyotrophic lateral sclerosis. j bioenerg biomembr 2011; 43:587–92. doi: 10.1007/s10863-011-9393-0. 10. pizzuti a, petrucci s. mitochondrial disfunction as a cause of als. arch ital biol 2011; 149:113–19. doi: 10.4449/aib.v149i 1.1266. 11. kawamata h, manfredi g. mitochondrial dysfunction and intracellular calcium dysregulation in als. mech ageing dev 2010; 131:517–26. doi: 10.1016/j.mad.2010.05.003. 12. crugnola v, lamperti c, lucchini v, ronchi d, peverelli l, prelle a, et al. mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis. arch neurol 2010; 67:849–54. doi: 10.1001/archneurol.2010.128. 13. artuso l, zoccolella s, favia p, amati a, capozzo r, logroscino g, et al. mitochondrial genome aberrations in skeletal muscle of patients with motor neuron disease. amyotroph lateral scler frontotemporal degener 2013; 14:261–6. doi: 10.3109/ 21678421.2012.735239. 14. ladd ac, keeney pm, govind mm, bennett jp jr. mitochondrial oxidative phosphorylation transcriptome alterations in human amyotrophic lateral sclerosis spinal cord and blood. neuromolecular med 2014; 16:714–26. doi: 10.1007/s12017014-8321-y. 15. ro ls, lai sl, chen cm, chen st. deleted 4977-bp mitochondrial dna mutation is associated with sporadic amyotrophic lateral sclerosis: a hospital-based case-control study. muscle nerve 2003; 28:737–43. doi: 10.1002/mus.10504. 16. vielhaber s, kunz d, winkler k, wiedemann fr, kirches e, feistner h, et al. mitochondrial dna abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. brain 2000; 123:1339–48. doi: 10.1093/brain/123.7.1339. 17. schaefer am, mcfarland r, blakely el, he l, whittaker rg, taylor rw, et al. prevalence of mitochondrial dna disease in adults. ann neurol 2008; 63:35–9. doi: 10.1002/ana.21217. 18. béhin a, jardel c, claeys kg, fagart j, louha m, romero nb, et al. adult cases of mitochondrial dna depletion due to tk2 defect: an expanding spectrum. neurology 2012; 78:644–8. doi: 10.1212/wnl.0b013e318248df2b. 19. finsterer j, bastovansky a. multiorgan disorder syndrome (mods) in an octagenarian suggests mitochondrial disorder. rev med chil 2015; 143:1210–14. doi: 10.4067/s0034-9887 2015000900016. 20. chinnery pf. mitochondrial disease in adults: what’s old and what’s new? embo mol med 2015; 7:1503–12. doi: 10.15252/ emmm.201505079. http://dx.doi.org/10.1097/01.nrl.0000038589.58012.a8 http://dx.doi.org/10.1097/01.nrl.0000038589.58012.a8 http://dx.doi.org/10.1007/s13311-013-0188-3 http://dx.doi.org/10.1016/j.nmd.2015.02.005 http://dx.doi.org/10.11622/smedj.2015112 http://dx.doi.org/10.1016/j.ijcard.2014.09.183 http://dx.doi.org/10.1001/archneurol.2007.65 http://dx.doi.org/10.1179/1743132812y.0000000012 http://dx.doi.org/10.1007/s10863-011-9393-0 http://dx.doi.org/10.4449/aib.v149i%0a1.1266 http://dx.doi.org/10.4449/aib.v149i%0a1.1266 http://dx.doi.org/10.1016/j.mad.2010.05.003 http://dx.doi.org/10.1001/archneurol.2010.128 http://dx.doi.org/10.3109/21678421.2012.735239 http://dx.doi.org/10.3109/21678421.2012.735239 http://dx.doi.org/10.1007/s12017-014-8321-y http://dx.doi.org/10.1007/s12017-014-8321-y http://dx.doi.org/10.1002/mus.10504 http://dx.doi.org/10.1093/brain/123.7.1339 http://dx.doi.org/10.1002/ana.21217 http://dx.doi.org/10.1212/wnl.0b013e318248df2b http://dx.doi.org/10.4067/s0034-98872015000900016 http://dx.doi.org/10.4067/s0034-98872015000900016 http://dx.doi.org/10.15252/emmm.201505079 http://dx.doi.org/10.15252/emmm.201505079 1department of radiology, hospital university kebangsaan malaysia, kuala lumpur, malaysia; 2division of paediatric surgery, department of surgery, university of malaya, kuala lumpur, malaysia; 3department of paediatric surgery, sabah women & children hospital, sabah, malaysia; 4department of paediatric surgery, institut pediatrik hospital kuala lumpur, kuala lumpur, malaysia *corresponding author’s e-mail: hooi525@yahoo.com تقرير عن حالة مصابة باجليب البويل املستمر املزالق والتحديات يف التشخيص هوي هوي تان، �صونغ كني تان، راجح �صومنوجان، روزمان زكريا، زكريا زهاري abstract: persistent urogenital sinus (pugs) is a rare anomaly whereby the urinary and genital tracts fail to separate during embryonic development. we report a three-year-old female child who was referred to the sabah women & children hospital, sabah, malaysia, in 2016 with a pelvic mass. she had been born prematurely at 36 gestational weeks via spontaneous vaginal delivery in 2013 and initially misdiagnosed with neurogenic bladder dysfunction. the external genitalia appeared normal and an initial sonogram and repeat micturating cystourethrograms did not indicate any urogenital anomalies. she therefore underwent clean intermittent catheterisation. three years later, the diagnosis was corrected following the investigation of a persistent cystic mass posterior to the bladder. at this time, a clinical examination of the perineum showed a single opening into the introitus. magnetic resonance imaging of the pelvis revealed gross hydrocolpos and a genitogram confirmed a diagnosis of pugs, for which the patient underwent surgical separation of the urinary and genital tracts. keywords: urogenital abnormalities; congenital defects; clean intermittent catheterization; hydrocolpos; cystography; case report; malaysia. امللخ�ص: اجليب البويل امل�صتمر هو �صذوذ نادر حيث تف�صل امل�صالك البولية والتنا�صلية للف�صل خالل التطور اجلنيني. هذا ثقرير حالة عن طفلة تبلغ من العمر ثالث �صنوات مت اإحالتها اإىل جامعة امل�صت�صفى كيباجن�صان ماليزيا، كوالملبور، ماليزيا، يف عام 2016 لوجود ورم يف منطقة احلو�ض. كانت الطفلة قد ولدت قبل الأوان يف 36 اأ�صابيع احلمل عن طريق الولدة املهبلية العفوية يف عام 2013 ومت ت�صخي�صها خطاأ يف البداية غلى اأنها حالة خلل وظيفي ع�صبي يف املثانة. بالك�صف الظاهري وجدت الأع�صاء التنا�صلية اخلارجية طبيعية، ومل يظهر ال�صونار اأو اعادة الفح�ض بالأ�صعه علي املثانة، وجمرى البول اأثناء التبول وجود اأي �صذوذ بويل اأو تنا�صلي. لذلك مت عالجها بعمل ق�صطرة خلف احلو�ض منطقة يف م�صتمر كي�صي ورم لوجود الطفلة فح�ض اأثناء الت�صخي�ض ت�صحيح مت �صنوات، ثالث بعد للبول. نظيفة متقطعة املثانة البولية. يف هذا الوقت، اأظهر الفح�ض ال�رشيري للعجان وجود فتحة واحدة يف مقدمة. ك�صف الت�صوير بالرنني املغناطي�صي للحو�ض عن وجود جتمع مائي )موه( يف املهبل واأظهرت الأ�صعة على الأع�صاء التنا�صبية وجود اجليب البويل امل�صتمر، وخ�صعت الطفلة لعملية ف�صل جراحي للم�صالك البولية والتنا�صلية. الكلمات املفتاحية: ت�صوهات اجلهاز البويل التنا�صلي؛ العيوب اخللقية؛ ق�صطرة نظيفة متقطعة؛ موه املهبل؛ ت�صوير املثانة؛ تقرير حالة؛ ماليزيا. a case of persistent urogenital sinus pitfalls and challenges in diagnosis *hooi h. tan,1 shung k. tan,2,3 rajah shunmugan,3 rozman zakaria,1 zakaria zahari4 case report sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e455–459, epub. 10 jan 18 submitted 3 oct 17 revision req. 31 oct 17; revision recd. 11 nov 17 accepted 23 nov 17 doi: 10.18295/squmj.2017.17.04.013 a persistent urogenital sinus (pugs) occurs as a result of the arrested migration of the müllerian ducts from the müller tubercle to the vestibule.1 the incidence of this rare congenital anomaly is estimated to be six in every 100,000 female births.2 while pugs can present as an isolated anomaly, it has also been associated with other diseases, including congenital adrenal hyperplasia or mckusick-kaufman syndrome.3–5 the presence of pugs along with digit anomalies, retinitis pigmentosa, obesity, learning disabilities and male hypogenitalism are phenotypical characteristics of bardet-biedl syndrome.6 in addition, pugs may also be seen in handfoot-genital syndrome, in which affected males have hypospadias and females have both müllerian and limb abnormalities.7 case report a three-year-old female child was referred to the paediatric surgical clinic of the sabah women & children hospital, sabah, malaysia, in 2016. she had been born prematurely at 36 gestational weeks via spontaneous vaginal delivery in 2013. at 35 gestational weeks, an antenatal ultrasound had shown a distended bladder with a thickened wall. at birth, the neonate had a distended abdomen and appeared tachypnoeic with intermittent grunting sounds. consequently, she underwent bladder catheterisation during which 100 ml of urine was drained, which resulted in an improvement of her symptoms. however, she subse quently developed urinary retention with incomplete voiding after the catheter was removed. initial blood a case of persistent urogenital sinus pitfalls and challenges in diagnosis e456 | squ medical journal, november 2017, volume 17, issue 4 investigations showed renal impairment with urea levels of 6.3 mmol/l and creatinine levels of 161 mmol/l. she was diagnosed with neurogenic bladder dysfunction and underwent clean intermittent catheterisation (cic) every six hours, with approximately 30–40 ml of residual urine being drained each time. seven days after birth, an ultrasound of the kidneys, ureter and bladder showed bilateral mild hydronephrosis with no evidence of hydroureter. the bladder appeared normal. at three weeks of age, a micturating cystourethrogram (mcug) did not reveal any vesicoureteral reflux and the contours of the bladder seemed normal. at two months, a technetium-99m mercaptoacetyltriglycine scan indicated a differential function of 46% and 54% for the left and right kidneys, respectively, with no evidence of a urinary outflow obstruction. at three months, a magnetic resonance imaging (mri) scan of the spine appeared normal. the patient attended regular followup appointments at the paediatric outpatient clinic due to her presumed neurogenic bladder dysfunction. her mother continued to ensure that cic was performed every six hours. the patient appeared to be well and thriving during this period without any history of urinary tract infections. however, serial ultrasounds of the kidneys, ureters and bladder at seven, 19 and 31 months of age indicated a persistent cystic structure posterior to the bladder. in 2016, the patient was referred to the paediatric surgical clinic at the age of three years for an investigation of the persistent cystic mass. at this time, a clinical examination of the perineum revealed a single opening into the introitus, with a normal anus [figure 1a]. a cystic mass was felt anteriorly upon rectal examination. she was also found to have bilateral upper and lower limb postaxial polydactyly. a repeat mcug did not show any abnormalities; however, a genitogram revealed a pugs with a common channel measuring 2 cm in length [figure 1b]. an mri of the pelvis showed a large cystic mass posterior to the bladder suggestive of gross hydrocolpos [figure 2]. based on the clinical and radiological findings of a pugs in combination with the bilateral limb postaxial polydactyly, the child was diagnosed with mckusickkauffman syndrome. the decision was subsequently made to surgically separate the child’s urinary and genital tracts. intraoperatively, the vagina appeared grossly distended, although the uterus was normal [figure 3]. the vagina was surgically detached from the urogenital sinus and a tube vaginoplasty was performed, created from an inverted u-flap taken from the posterior vaginal wall. the common channel was preserved as the urethra. postoperatively, the patient recovered well. at the time of writing, she demonstrated normal bladder emptying without requiring any further cic. figure 1: a: clinical photograph of the perineal region of a three-year-old female showing a single opening at the introitus (arrow). b: genitogram of a three-year-old female showing a common channel (arrow) bifurcating anteriorly into the urinary bladder and posteriorly into the vagina. v = vagina; b = bladder. figure 3: intraoperative photograph of the perineal region of a three-year-old female undergoing corrective surgery for a persistent urogenital sinus showing hydrocolpos and a normal uterus. u = uterus; h = hydrocolpos. figure 2: t2-weighted magnetic resonance imaging scans of the pelvis of a three-year-old female in the (a) axial and (b) sagittal views showing a large welldefined thin-walled cystic lesion (arrow) posterior to the urinary bladder, suggestive of hydrocolpos. hooi h. tan, shung k. tan, rajah shunmugan, rozman zakaria and zakaria zahari case report | e457 lumen. the pathophysiology of this phenomenon can be explained by the location of the vaginal confluence above the bladder sphincter, the formation of a cusp in the sinus by the posterior lip of the hymen and the contraction of the puborectalis muscle sling.1 as observed in the current patient, massive urocolpos may be mistaken for a distended bladder in certain cases. hence, a thorough clinical examination of the perineum is crucial as the finding of a single opening in the introitus is pathognomonic of a pugs diagnosis. ultrasonography is the diagnostic modality of choice in the detection of a pugs because of the ubiquitous and minimally invasive nature of this imaging technique. the presence of a cystic lesion with internal debris posterior to the fetal bladder—which can be detected by sonogram as early as the second trimester of pregnancy—is suggestive of a pugs.11 a postnatal ultrasound with similar findings may also help to confirm the diagnosis. in the present case, a postnatal ultrasound when the patient was seven days old did not show any abnormalities; however, this might be due to the fact that the urocolpos had been drained as a result of cic having been performed prior to the ultrasound. structural anomalies of the ureter, bladder and urethra may also be revealed using a mcug, which is a dynamic fluoroscopic method.12 during the micturating phase, a lower urinary tract abnormality can be demonstrated after the removal of the catheter if the contrast medium flows into the urethra. however, performing an mcug on a child can be challenging. younger patients may need to be coaxed into following instructions and bladder catheterisation can be difficult among patients with abnormal urinary tracts.13 among female patients with pugs, there is also a risk of accidentally catheterising the vagina instead of the bladder. furthermore, the child may refuse to void their bladder once the catheter has been removed.13 the outcome of the procedure is therefore discussion during embryonic development, the urogenital sinus forms as a common channel into which both the urinary and genital tracts enter before subsequently being separated later on by the migration of the müllerian ducts [figure 4]. the arrested migration of the müllerian ducts at an early stage of development results in a long urogenital sinus with a short vagina and a high urethral opening, while arrested migration at a late stage results in a short urogenital sinus with a vaginal vestibule of almost normal length and a low urethral opening.1 consequently, pugs can be classified into high and low anomalies according to the length of the common channel (>3 cm or <3 cm, respectively).8 in general, short urogenital sinuses are more common, as observed in the current case.8 furthermore, pugs patients can be divided into those with confluence above or below the neck of the bladder.9 an additional classification can be made based on the distance of the vaginal confluence from the bladder neck and perineal meatus; this is often crucial for both clinical management and surgical recon structive purposes.10 a diagnosis of pugs is challenging due to the complexity and rarity of this condition. as demonstrated by the present case, the presence of a urogenital tract anomaly can be easily overlooked by unsuspecting practitioners when inspecting essentially normal-looking external genitalia with typical labial folds and a normally positioned anus. however, a high index of suspicion for this anomaly is necessary, especially among newborns with grossly distended abdomens and lower urinary tract symptoms for whom an antenatal ultrasound reveals a pelvic cystic mass.1 among infants with pugs, the presence of such a mass occurs due to the storage of urine in the vagina (i.e. urocolpos) when the common channel is partially blocked, causing the urine to flow up into the vaginal figure 4: diagram showing the normal embryological development of the female genitourinary system. a: at four gestational weeks, the urogenital sinus and rectum enter a common cavity known as the cloaca. b: at six gestational weeks, the urorectal septum grows in a caudal direction, separating the cloaca into a ventral urogenital sinus and a dorsal rectum. c: at eight gestational weeks, a pair of müllerian ducts develop lateral to the mesonephric ducts, crossing ventromedially to fuse in the midline and join the urogenital sinus to form an elevation known as the müllerian tubercle. d: between the eighth and twelfth gestational weeks, the müllerian ducts migrate caudally from the müllerian tubercle to the vestibule. e: from the twelfth gestational weeks onwards, the development of the genitourinary system is complete. c = cloaca; us = urogenital sinus; r = rectum; md = müllerian ducts; b = bladder; v = vagina. a case of persistent urogenital sinus pitfalls and challenges in diagnosis e458 | squ medical journal, november 2017, volume 17, issue 4 dependent on the experience of the operator. in the current case, both mcugs failed to demonstrate a pugs; this was most likely because the urocolpos failed to drain spontaneously after the catheter was removed. in certain cases, a distended vagina may be mistaken for the bladder on a mcug, since the two organs are difficult to distinguish. in such instances, an ascending genitogram may constitute a better imaging modality since it can clearly delineate the length of the common channel and the level of vaginal confluence.14 however, it is important to place the tip of the catheter just above the perineal opening as there is a risk of either the bladder or vagina alone being opacified if the catheter penetrates too deeply. in addition, an ascending genitogram may help the surgeon to choose a suitable approach and method of surgical repair.14 besides conventional imaging methods, the use of mri has gained popularity in the paediatric field over the last decade due to advances in resolution, reduced motion artefacts, volumetric imaging and imaging time.15 an mri scan of the pelvis can effectively depict the relationship between urogenital structures, the pelvic muscle complex and any associated spinal or renal abnormalities.16 additionally, a combination of multidetector computed tomography, mri and fluoro scopy of the urogenital tract can help to clearly illustrate the anatomy of associated structures in a three dimensional reconstruction.17–19 however, although the advantages of this technique are undeniable, the risks of increased radiation exposure and prolonged general anaesthesia should not be overlooked. moreover, a cystovaginoscopy assessment prior to surgery is still needed to definitely delineate the anatomy of the genitourinary tract.20,21 as a result of various conditions such as pugs, the vagina can distend and reach a potentially massive size, causing gross abdominal distension and respiratory distress if it splints the diaphragm.22 in such cases, management consists of drainage and decompression by catheterising the common channel or, if catheterisation fails, performing an ultrasound-guided percutaneous tube vaginostomy, an open vaginostomy/vesicostomy or a ureterostomy/nephrostomy.9,21,23,24 in the event of a rupture, a laparotomy, peritoneal drainage and open vaginostomy are temporary solutions prior to definitive surgical correction. for example, urocolpos drainage may prevent urinary tract obstructions, infections, pyocolpos or, in severe cases, rupture and peritonitis.23,24 fortunately, cic was effective in draining the hydrocolpos for the current patient, thus avoiding other more invasive procedures such as a vaginostomy or vesicostomy which can cause scarring and adhesions, potentially complicating subsequent surgeries.20 conclusion a pugs is a very rare developmental anomaly which can be easily misdiagnosed as neurogenic bladder dysfunction or overlooked entirely, especially if the external genitalia appear normal. as such, a thorough examination of the perineal orifices of a newborn is necessary to rule out complex urogenital abnormalities, particularly among those who present with a pelvic mass and urinary symptoms. falsenegative ultrasound and mcug findings may lead to a delay in diagnosis; however, genitograms and mri modalities are useful to clearly visualise the anatomy of the genitourinary tract. references 1. stephens fd, smith ed, hutson jm. congenital anomalies of the kidney, urinary and genital tracts, 2nd ed. london, uk: martin dunitz ltd., 2002. pp. 3–12, 53–4. 2. singh s, singh p, singh rj. persistent urogenital sinus. j anat soc india 2010; 59:242–4. doi: 10.1016/s0003-2778(10)80034-6. 3. ganesan a, smith gh, broome k, steinberg a. congenital adrenal hyperplasia: preliminary observations of the urethra in 9 cases. j urol 2002; 167:275–8. doi: 10.1016/s0022-5347(05) 65448-1. 4. marei mm, fares ae, abdelsattar ah, abdullateef ks, seif h, hassan mm, et al. anatomical measurements of the urogenital sinus in virilized female children due to congenital adrenal hyperplasia. j pediatr urol 2016; 12:282.e1–8. doi: 10.1016/j. jpurol.2016.02.008. 5. slavotinek am. mckusick-kaufman syndrome. in: adam mp, ardinger hh, pagon ra, wallace se, bean lj, mefford hc, et al., eds. genereviews®. from: www.ncbi.nlm.nih.gov/books/ nbk1502/ accessed: nov 2017. 6. suspitsin en, imyanitov en. bardet-biedl syndrome. mol syndromol 2016; 7:62–71. doi: 10.1159/000445491. 7. innis jw. hand-foot-genital syndrome. in: adam mp, ardinger hh, pagon ra, wallace se, bean lj, mefford hc, et al., eds. genereviews®. from: www.ncbi.nlm.nih.gov/books/ nbk1423/ accessed: nov 2017. 8. bischoff a. the surgical treatment of cloaca. semin pediatr surg 2016; 25:102–7. doi: 10.1053/j.sempedsurg.2015.11.009. 9. hendren wh. cloaca, the most severe degree of imperforate anus: experience with 195 cases. ann surg 1998; 228:331–46. doi: 10.1097/00005392-199907000-00103. 10. rink rc, adams mc, misseri r. a new classification for genital ambiguity and urogenital sinus anomalies. bju int 2005; 95:638–42. doi: 10.1111/j.1464-410x.2005.05354.x. 11. valentini al, giuliani m, gui b, laino me, zecchi v, rodolfino e, et al. persistent urogenital sinus: diagnostic imaging for clinical management what does the radiologist need to know? am j perinatol 2016; 33:425–32. doi: 10.1055/s-0035-1565996. 12. zerin jm. morphologic studies of the urinary tract. in: gearhart jg, rink rc, mouriquand pd, eds. pediatric urology, 2nd ed. philadelphia, pennsylvania, usa: saunders, 2009. pp. 56–83. 13. traubici j, lim r. imaging the pediatric urinary tract. in: geary df, schaefer f, eds. comprehensive pediatric nephrology. maryland heights, missouri, usa: mosby, 2008. pp. 1–38. https://doi.org/10.1016/s0003-2778%2810%2980034-6 https://doi.org/10.1016/s0022-5347%2805%2965448-1 https://doi.org/10.1016/s0022-5347%2805%2965448-1 https://doi.org/10.1016/j.jpurol.2016.02.008 https://doi.org/10.1016/j.jpurol.2016.02.008 https://doi.org/10.1159/000445491 https://doi.org/10.1053/j.sempedsurg.2015.11.009 https://doi.org/10.1097/00005392-199907000-00103 https://doi.org/10.1111/j.1464-410x.2005.05354.x https://doi.org/10.1055/s-0035-1565996 hooi h. tan, shung k. tan, rajah shunmugan, rozman zakaria and zakaria zahari case report | e459 20. hendren wh. urogenital sinus and anorectal malformation: experience with 22 cases. j pediatr surg 1980; 15:628–41. doi: 10.1016/s0022-3468(80)80514-8. 21. levitt ma, peña a. cloacal malformations: lessons learned from 490 cases. semin pediatr surg 2010; 19:128–38. doi: 10.1053/j.sempedsurg.2009.11.012. 22. khan ar, ghani i, wahab s. hydrometrocolpos due to persistent urogenital sinus mimicking neonatal ascites. iran j pediatr 2008; 18:67–70. 23. vanderbrink ba, reddy pp. early urologic considerations in patients with persistent cloaca. semin pediatr surg 2016; 25:82–9. doi: 10.1053/j.sempedsurg.2015.11.005. 24. chalmers dj, rove ko, wiedel ca, tong s, siparsky gl, wilcox dt. clean intermittent catheterization as an initial management strategy provides for adequate preservation of renal function in newborns with persistent cloaca. j pediatr urol 2015; 11:211.e1–4. doi: 10.1016/j.jpurol.2015.05.014. 14. chavhan gb, parra da, oudjhane k, miller sf, babyn ps, pippi salle fl. imaging of ambiguous genitalia: classification and diagnostic approach. radiographics 2008; 28:1891–904. doi: 10.1148/rg.287085034. 15. church dg, vancil jm, vasanawala ss. magnetic resonance imaging for uterine and vaginal anomalies. curr opin obstet gynecol 2009; 21:379–89. doi: 10.1097/gco. 0b013e3283307c3e. 16. mohammad sa, abouzeid aa. mri of persistent cloaca: can it substitute conventional imaging? eur j radiol 2013; 82:241–51. doi: 10.1016/j.ejrad.2012.09.020. 17. adams me, hiorns mp, wilcox dt. combining mdct, micturating cystography, and excretory urography for 3d imaging of cloacal malformation. ajr am j roentgenol 2006; 187:1034–5. doi: 10.2214/ajr.05.0117. 18. patel mn. use of rotational fluoroscopy and 3-d reconstruction for pre-operative imaging of complex cloacal malformations. semin pediatr surg 2016; 25:96–101. doi: 10.1053/j.semp edsurg.2015.11.008. 19. jarboe md, teitelbaum dh, dillman jr. combined 3d rotational fluoroscopic-mri cloacagram procedure defines luminal and extraluminal pelvic anatomy prior to surgical reconstruction of cloacal and other complex pelvic malformations. pediatr surg int 2012; 28:757–63. doi: 10.1007/ s00383-012-3122-6. https://doi.org/10.1016/s0022-3468%2880%2980514-8 https://doi.org/10.1053/j.sempedsurg.2009.11.012 https://doi.org/10.1053/j.sempedsurg.2015.11.005 https://doi.org/10.1016/j.jpurol.2015.05.014 https://doi.org/10.1148/rg.287085034 https://doi.org/10.1097/gco.0b013e3283307c3e https://doi.org/10.1097/gco.0b013e3283307c3e https://doi.org/10.1016/j.ejrad.2012.09.020 https://doi.org/10.2214/ajr.05.0117 https://doi.org/10.1053/j.sempedsurg.2015.11.008 https://doi.org/10.1053/j.sempedsurg.2015.11.008 https://doi.org/10.1007/s00383-012-3122-6 https://doi.org/10.1007/s00383-012-3122-6 1department of dermatology, hospital alcalá la real, jaén, spain; 2department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: fntmed@gmail.com مرض الذئبة املزمنة سبب غري مألوف لضمور الظفر فران�شي�شكو خو�شيه نافارو-تريفينيو و ريكاردو رويز-فيالفريد chronic discoid lupus an uncommon cause of nail atrophy *francisco j. navarro-triviño1 and ricardo ruiz-villaverde2 a 45 year-old woman presented to the outpatient dermatology clinic of the hospital alcalá la real, jaén, spain, in 2017 complaining of recent changes to the distal phalanx of the third and fourth finger of her right hand and the fourth finger of her left one. she had a history of discoid lupus erythematosus (dle) and sjögren syndrome (ss) without raynaud’s phenomenon. a clinical examination revealed atrophic changes associated with milky-red patches on the affected areas [figure 1]. the status of the toenails was normal. the patient did not show palmoplantar hyper keratosis and there was no evidence of mucous membrane ulceration. the patient underwent a series of laboratory tests which revealed an antinuclear antibody titre of 1/640 with granular and nuclear patterns, anti-ss-related antigen a/ ro52 level of >240 u/ml, anti-ss-related antigen b/la level of >320 u/ml and rheumatoid factor level of 72.7 ui/ml. however, complement, anti-histidyl trans fer ribonucleic acid synthetase, antiscleroderma 70, antiphospholipid and thrombophilia tests were normal. in addition, thyroid function was normal. nailfold capillaroscopy was performed using a 3gen dermlite® dermascope (3gen inc., san juan capistrano, california, usa) in polarised mode at x10 magnification. this showed dilated and elongated capillaries, increased tortuosities and avascular areas [figure 2]. these changes were associated with nail pterygium. onychomycosis was ruled out by a negative dermatophyte culture. comment first described by gilliam et al. in 1981, dle is a chronic scarring skin condition and a common form of cutaneous lupus in european populations.1–3 the condition usually has a severe effect on quality of life and emotional well being.2,3 dermoscopy of facial and extra-scalp dle lesions shows varying features according to disease stage. erythematous perifollicular whitish ‘halos’, follicular keratotic plugs, red dots and white scaling are common features in early lesions, while whitish structureless areas and hyperpigmentation (e.g. in a ‘honeycomb’ or peri interesting medical image sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e411–412, epub. 19 dec 18 submitted 22 mar 18 revision req. 14 may 18; revision recd. 11 jun 18 accepted 27 jun 18 figure 1: photograph of the fourth fingernail of the left hand of a 45 year-old woman with discoid lupus erythematosus and sjögren syndrome showing atrophic changes and whitish cuticles. doi: 10.18295/squmj.2018.18.03.029 chronic discoid lupus an uncommon cause of nail atrophy e412 | squ medical journal, august 2018, volume 18, issue 3 nail dystrophy in dle may allow for the identification of patients with severe conditions and high dam age indices. the differential diagnosis of dle-related nail dystrophy should include onychomycosis—ruled out in the current case—psoriasis, lichen planus, darier’s disease and nail trauma.10 a skin biopsy is often not necessary if other discoid skin lesions are present, as in the current case; however, it can be performed in cases wherein the clinical diagnosis is not consistent with dle. in terms of topical treatment, clobetasol propionate lacquer, tazarotene cream and tacrolimus ointment may result in a partial therapeutic response.11 however, combining this approach with systemic treatment such as methotrexate has produced better response rates. in addition, antiplatelets and/or anticoagulant agents should be considered.5 references 1. gilliam jn, sontheimer rd. distinctive cutaneous subsets in the spectrum of lupus erythematosus. j am acad dermatol 1981; 4:471−5. doi: 10.1016/s0190-9622(81)80261-7. 2. grönhagen cm, fored cm, granath f, nyberg f. cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in sweden. br j dermatol 2011; 164:1335−41. doi: 10.1111/j.13652133.2011.10272.x. 3. ogunsanya me, kalb sj, kabaria a, chen s. a systematic review of patient-reported outcomes in patients with cutaneous lupus erythematosus. br j dermatol 2017; 176:52−61. doi: 10.1111/bjd. 14868. 4. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb) 2016; 6:471–507. doi: 10.1007/s13555-016-0141-6. 5. trüeb rm. hair and nail involvement in lupus erythematosus. clin dermatol 2004; 22:139−47. doi: 10.1016/j.clindermatol.20 03.12.021. 6. cutolo m, melsens k, wijnant s, ingegnoli f, thevissen k, de keyser f, et al. nailfold capillaroscopy in systemic lupus erythematosus: a systematic review and critical appraisal. autoimmun rev 2018; 17:344−52. doi: 10.1016/j.autrev.2017.11.025. 7. higuera v, amezcua-guera lm, montoya h, massó f, patlán m, paez a, et al. association of nail dystrophy with accrued damage and capillaroscopic abnormalities in systemic lupus erythematosus. j clin rheumatol 2016; 22:13−18. doi: 10.1097/rhu.0000 000000000336. 8. bărbulescu al, vreju af, bugă am, sandu re, criveanu c, tudoraşcu dr, et al. vascular endothelial growth factor in systemic lupus erythematosus: correlations with disease activity and nailfold capillaroscopy changes. rom j morphol embryol 2015; 56:1011−16. 9. urowitz mb, gladman dd, chalmers a, orgyzio ma. nail lesions in systemic lupus erythematosus. j rheumatol 1978; 5:441−7. 10. tully as, trayes kp, studdiford jc. evaluation of nail abnormalities. am fam physician 2012; 85:779−87. 11. winkelmann rr, kim gk, del rosso jq. treatment of cutaneous lupus erythematosus: review and assessment of treatment benef its based on oxford centre for evidence-based medicine criteria. j clin aesthet dermatol 2013; 6:27−38. follicular pattern) are frequently observed in late phases.4 ungual involvement is not common. clinically, dle usually presents as a well-delimited plaque with red and white areas and is associated with skin and nail trophic changes.5 capillaroscopy is considered the gold-standard technique to evaluate the microvasculature in the prox imal area of the nailfold.6 giant capillaries, haemorrhage, avascular areas and neoangiogenesis are considered scleroderma-type features of systemic lupus erythematosus (sle), rather than dle.7 correlations have been demonstrated between capillaroscopic abnormalities in sle and raynaud’s phenomenon, disease activity, endo thelial cell activation markers and certain autoantibodies, such as anticardiolipin, anti-u1-ribonucleoprotein, anti smith and anti-double stranded dna antibodies.6,8 in affected cases where capillaroscopy is not feasible, examination of the nail via routine dermoscopy may provide important information. although nailfold dermo scopic features may not be specific to dle, these feat ures have been associated with higher disease activity and internal organ involvement and suggest an important role for chronic microvascular damage in the clinical development of systemic autoimmune disease.7 urowitz et al. described common nail features among patients affected by sle.9 however, little has been published regarding nail trophic changes among patients with dle. figure 2: capillaroscopy images of the fingernail of a 45 year-old woman with discoid lupus erythematosus and sjögren syndrome showing (a) dystrophic tent-shaped changes in the nail (arrow) as well as distal onycholysis associated with fine superficial desquamation and pointed vessels in the hyponychium (arrowhead) and (b) white avascular areas (arrow) and elongated tortuous capillaries (arrowhead) in the eponychium. https://doi.org/10.1016/s0190-9622%2881%2980261-7 https://doi.org/10.1111/j.1365-2133.2011.10272.x https://doi.org/10.1111/j.1365-2133.2011.10272.x https://doi.org/10.1111/bjd.14868 https://doi.org/10.1111/bjd.14868 https://doi.org/10.1007/s13555-016-0141-6 https://doi.org/10.1016/j.clindermatol.2003.12.021 https://doi.org/10.1016/j.clindermatol.2003.12.021 https://doi.org/10.1016/j.autrev.2017.11.025 https://doi.org/10.1097/rhu.0000000000000336 https://doi.org/10.1097/rhu.0000000000000336 1department of family medicine & public health, college of medicine & health sciences, sultan qaboos university; 2directorate general of primary health care, ministry of health, muscat, oman; 3department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 4department of community medicine, psg institute of medical sciences & research, coimbatore, tamil nadu, india *corresponding author e-mail: mhalazri@squ.edu.om املعرفة واملعتقدات حول مرض فقر الدم املنجلي لدى العمانيني يف مراكز الرعاية الصحية األولية دراسة مستعرضة حممد العزري, رج�ء البلو�شية, منى املعمرية, روبن ديفيد�شون, اأنيل م�ثيو abstract: objectives: sickle cell disease (scd) is a global health concern associated with high childhood morbidity and mortality; in oman, the prevalence of scd is 0.2%. public awareness of scd and the need for premarital screening (pms) are essential to reduce the incidence of this disease. this study aimed to assess awareness of and beliefs regarding scd and pms among omanis in a primary healthcare setting. methods: this cross-sectional study took place in five health centres located in al-seeb province, muscat, oman, between june and august 2015. a total of 500 omanis aged ≥18 years old attending the clinics were invited to participate in the study. a previously described questionnaire by gustafson et al. was used to measure awareness of and beliefs regarding scd and pms. results: a total of 450 omani adults completed the questionnaire (response rate: 90.0%). the majority (67.8%) were aware that scd is genetically inherited and 85.1% believed in the value of pms; however, only 24.4% reported having undergone pms previously. few participants were aware that scd can be very painful (20.2%) and can cause strokes, infections and organ damage (20.0%). more than half (56.7%) reported that the availability of educational material on scd or pms in oman was inadequate. participants’ education levels were positively associated with accurate scd knowledge (p <0.05). conclusion: despite the free availability of pms services in local health centres, few omanis reported having undergone pms previously. health promotion and education programmes are therefore needed in oman in order to increase public awareness of scd and the value of pms. keywords: sickle cell disease; awareness; genetic screening; primary health care; oman. امللخ�ص: الهدف: يعترب مر�س فقر الدم املنجلي مر�س مثري للقلق يف الع�مل ومرتبط بزي�دة معدل العتالل و الوفي�ت بني الأطف�ل يف �شلطنة عم�ن. معدل حدوث مر�س فقر الدم املنجلي يف عم�ن هو %0.2. ان الوعي الع�م ملر�س فقر الدم املنجلي واحل�جة للفح�س م� قبل الزواج �رسوري للحد من انت�ش�ر هذا املر�س. تهدف هذه الدرا�شة اإىل تقييم مدى الوعي الع�م واملعتقدات حول مر�س فقر الدم املنجلي والفح�س الطبي يف مرحلة م� قبل الزواج لدى العم�نيني الذين ح�رسوا لتلقي العالج يف مراكز الرع�ية ال�شحية الأولية. الطريقة: اأجريت هذه الدرا�شة امل�شتعر�شة يف خم�شة مراكز �شحية يف ولية ال�شيب يف حم�فظة م�شقط ع�م 2015 يف الفرتة بني يونيو واأغ�شط�س. مت دعوة واملعتقد املعرفة لقي��س جو�شت�ف�شون اأ�شتبي�ن ا�شتخدام مت الدرا�شة. هذه يف للم�ش�ركة فوق وم� �شنة 18 اأعم�رهم العم�نيني من 500 .)90.0% = ال�شتج�بة )معدل ال�شتبي�ن يف �شخ�ش� 450 �ش�رك الزواج. النتائج: قبل م� الطبي والفح�س املنجلي الدم فقر مر�س حول ك�نت غ�لبية امل�ش�ركني )%67.8( تدرك على اأن مر�س فقر الدم املنجلي �شببه جين�ت وراثيه وكذلك %85.1 من امل�ش�ركني يعتقدوا يف اأهمية الفح�س الطبي م� قبل الزواج, لكن %24.4 فقط ح�رسوا لفح�س الطبي م� قبل الزواج. ك�ن هن�ك عدد اأقل من امل�ش�ركني على علم ب�أن مر�س فقر الدم املنجلي ميكن اأن تكون له اأعرا�س موؤملة جدا )%20.2( وقد ي�شبب ال�شكتة الدم�غية, اللته�ب�ت و تلف اع�ش�ء اجل�شم املنجلي الدم فقر مر�س حول ك�فية توعية و �شحي تثقيف برامج توفر عدم على )56.7%( امل�ش�ركني ن�شف من اأكرث اأف�د .)20.0%( �شحة مع )p >0.05( اإيج�بي� يرتبط امل�ش�ركني لدى التعليم م�شتوى اأن النت�ئج اظهرت كم� عم�ن. يف الزواج قبل م� الطبي والفح�س املراكز يف الزواج قبل م� ملرحلة املج�ين الطبي الفح�س خدم�ت توفر من ب�لرغم املنجلي. اخلال�صة: الدم فقر مر�س حول املعلوم�ت ال�شحية املحلية ف�إن عدد قليل من العم�نيني قد خ�شع له� �ش�بق�. ب�لت�يل هن�ك ح�جه اإىل تعزيز برامج التثقيف ال�شحي وزي�دة الوعي الع�م يف املجتمع العم�ين حول مر�س فقر الدم املنجلي والفح�س الطبي يف مرحلة م� قبل الزواج. الكلمات املفتاحية: مر�س فقر الدم املنجلي؛ التوعية؛ الرع�ية ال�شحية الأولية؛ عم�ن. knowledge and health beliefs regarding sickle cell disease among omanis in a primary healthcare setting cross-sectional study *mohammed h. al-azri,1 rajaa al-belushi,2 muna al-mamari,2 robin davidson,3 anil c. mathew4 sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e437–444, epub. 30 nov 16 submitted 4 apr 16 revisions req. 10 may & 26 jun 16; revisions recd. 2 jun & 28 jun 16 accepted 19 jul 16 clinical & basic research doi: 10.18295/squmj.2016.16.04.006 knowledge and health beliefs regarding sickle cell disease among omanis in a primary healthcare setting cross-sectional study e438 | squ medical journal, november 2016, volume 16, issue 4 the world health organization reco-gnises sickle cell disease (scd) as a global public health problem.1 approximately 5% of the global population and over 7% of pregnant women worldwide are carriers of haemoglobin disorders such as scd.2 moreover, the burden of scd and other haemoglobin disorders is expected to increase in developing countries; in such countries, scd is associated with high childhood mortality; many children with scd die before five years of age, mainly due to infectious complications and severe anaemia.3,4 in oman, the local population is comprised of a wide range of ethnic groups; however, the prevalence of consanguineous marriages is 58%.5 three infants per 1,000 live births in oman have major haemoglobin disorders and there are approximately 106 new cases annually.6 a community-based study conducted in 2001 reported the prevalence of the sickle cell trait (sct) in the omani population to be 5.8%.7 in 2003, another study reported that the prevalence of scd was 0.2% while incidences of scd and sct in omani neonates were 0.3% and 4.8%, respectively.5 sickle haemoglobin (hbs) is the most common structural mutation of normal adult haemoglobin (hba), which is inherited as a mendelian trait.8 heterozygous carriers who inherit one hbs allele and one hba allele are usually asymptomatic; in contrast, homozygous carriers who inherit hbs alleles from both parents suffer from scd, which often causes intermittent vaso-occlusive crises resulting in tissue ischaemia, acute and chronic pain and organ damage.8,9 thus, knowledge of the genetic inheritance of scd is essential for couples where one or both individuals are carriers in order to make informed decisions about marriage and family planning. however, public knowledge of scd is often limited; one study conducted in the usa showed that, although the majority of african-american women knew that scd was a hereditary blood disorder, few of them understood its inheritance pattern.10 in contrast, another study from the usa showed that 86.2% of the respondents had adequate knowledge of the genetic causes and severity of scd.11 in muscat, the capital city of oman, a premarital screening (pms) programme was introduced in 1999; from 2001 onwards, the programme was gradually extended to cover other regions.12 currently, the pms programme includes free optional screening, counselling, health education and advice for carriers of common haemoglobin disorders (e.g. thalassaemia, scd and sct). however, a study conducted in 2011 among omani university students showed that although the majority of the students (79%) were aware of the pms programme, only half believed that it should be obligatory before marriage.12 to the best of the authors’ knowledge, no previous studies have measured public awareness of and beliefs regarding scd and pms in oman, despite the high prevalence of scd in the country. this study therefore aimed to assess public awareness and beliefs regarding scd and pms in oman as well as determine associations between demographic factors and knowledge of scd. methods this cross-sectional study was conducted between june and august 2015 in al-seeb province, muscat. in 2010, the population of muscat was over 1.15 million, including both local omanis and expatriates;13 there are currently 32 local health centres providing primary healthcare services for those living in the catchment areas. eight of these health centres are located in al-seeb, which had a total population of 223,449 in 2010, of which 47% were omani.13 for the purposes of this study, five health centres were randomly selected for the recruitment of participants. as no previous studies have yet established baseline awareness of scd in the omani population, the sample size was calculated by assuming that 50% of the participants had adequate scd awareness, with 10% allowable error. according to these calculations, the required sample size was 400. as advances in knowledge to the best of the authors’ knowledge, this is the first study conducted in oman to assess public awareness of and beliefs regarding sickle cell disease (scd) and premarital screening (pms). while the majority of participants in this study were aware that scd is a serious genetic disease and were alarmed by the thought of having a child with scd, few participants were aware that scd can be very painful and can cause organ damage, stroke and infections. moreover, many participants reported that there was a lack of educational material about scd or pms in oman. in the current study, only a minority of omanis reported previously undergoing pms, even though the majority indicated that they might reconsider a marriage if they were aware that their children might be affected by scd. application to patient care the findings of the current study indicate that more health promotion and education programmes are needed in oman in order to increase public awareness of scd and utilisation of pms services. promoting the currently available pms programme and counselling couples who are scd carriers are essential steps to help reduce the incidence of scd in oman. mohammed h. al-azri, rajaa al-belushi, muna al-mamari, robin davidson and anil c. mathew clinical and basic research | e439 such, with an expected non-response rate of 20%, 500 adult omanis ≥18 years old attending the selected local health centres were invited to participate in the study. gustafson et al. previously examined the health beliefs of african-american women regarding genetic testing and counselling for scd using a 12-item questionnaire based on the health belief model (hbm).14 the same questionnaire was used to deter-mine awareness of and beliefs about scd and pms among participants in the current study.14 the hbm is a widely used psychosocial tool designed to analyse health-related behaviours—including public attitudes towards screening and prevention programmes—and has been used in scd-related research to explore public understanding of the disease and approaches to its management.15,16 gustafson et al.’s questionnaire consists of three sections to elicit the following information: socio demographic characteristics; knowledge and awareness of scd; and individual health beliefs (including perceptions of susceptibility and disease seriousness as well as benefits and barriers to a specific behaviour).14 in the original questionnaire, a five-point likert scale is used to assess the health beliefs of participants, with the following responses: strongly agree, agree, neither agree nor disagree, disagree and strongly disagree. however, for the purposes of the current analysis, strongly agree and agree responses and disagree and strongly disagree responses were combined. the questionnaire was translated into arabic and back into english by two different groups of translators to ensure that the original meaning was preserved. a pilot study was conducted on 50 participants to check the clarity and reliability of the arabic version of the questionnaire; these participants were later included in the full study. based on standardised items, the cronbach’s alpha of the translated questionnaire was 0.70. a research assistant was in charge of data collection and was trained to administer the questionnaire to illiterate participants and to help those requiring assistance during completion of the questionnaire. data were analysed using the statistical package for the social sciences (spss), version 20 (ibm corp., chicago, illinois, usa). means, median modes and standard deviations were calculated for continuous variables and percentages were calculated for categorical variables. sociodemographic variables considered in the analysis included age, marital status, number of children and education level. to determine knowledge of scd, a score of 1 was assigned to each correct response and the total score was calculated. mean total knowledge scores were then compared with sociodemographic factors using either a t-test to compare the mean values of two variables or an f-test to compare the mean values for more than two variables, as appropriate. a multiple regression analysis was performed to find associations between sociodemographic variables and total knowledge scores. a chi-squared test was used to determine significant associations between sociodemographic variables and mean total knowledge scores. the normal distribution of the variables was checked graphically. a p value of <0.050 was considered statistically significant. this study was approved by the medial research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #902). medical officers in charge of the selected health centres gave permission for their centres to be involved in the study. the purpose of the study was explained and written consent was obtained from all participants before they took part in the study. results a total of 450 omani adults participated in the study (response rate: 90.0%). of these, 201 were male (44.7%) and 249 were female (55.3%). participants ranged in age between 18–58 years old (median: 29.0 years; mode: 26.0 ± 8.0 years). more than half of the participants (n = 242; 53.8%) were between 18–29 years old, 191 (42.4%) were between 30–49 years old and 17 (3.8%) table 1: health beliefs regarding premarital screening and sickle cell disease education* among omani adults in a primary healthcare setting (n = 450) questionnaire item n (%) yes no/unsure do you believe in the value of premarital screening? 383 (85.1) 67 (14.9) have you ever been tested for sickle cell trait? 110 (24.4) 340 (75.6) if you have been tested, were you found to have sickle cell trait?† 21 (19.1) 89 (80.9) if you were planning to get married and discovered that there was a chance of having a child with scd, would you proceed with the marriage? 85 (18.9) 365 (81.1) is health education regarding scd adequate in the community (e.g. via television, radio, school or your health centre)? 195 (43.3) 255 (56.7) *health beliefs were self-reported by participants using an arabic version of gustafson et al.’s questionnaire.14 †total dataset for this question was 110 as only those who had been tested for sickle cell trait were included. knowledge and health beliefs regarding sickle cell disease among omanis in a primary healthcare setting cross-sectional study e440 | squ medical journal, november 2016, volume 16, issue 4 were ≥50 years old. the majority (n = 321; 71.3%) were married, 115 (25.6%) were single and 14 (3.1%) were divorced. a total of 230 participants (51.1%) had between one and three children, 138 (30.7%) had no children and 82 (18.2%) had four or more children. the majority (n = 242; 53.8%) had a secondary school education, 136 (30.2%) had a university education and 72 (16.0%) had no formal education. when asked about screening for scd, 383 participants (85.1%) believed that pms was valuable, but only 110 (24.4%) reported having previously had such screening performed. of those who had undergone pms, 21 (19.1%) reported having been diagnosed with sct. overall, 365 participants (81.1%) reported that they might reconsider getting married if their future children were at risk of having scd. only 195 participants (43.3%) reported receiving adequate scd education from the media, school or their local health centre [table 1]. in terms of health beliefs, 334 participants (74.2%) believed that scd was a serious disease, 307 (68.2%) felt scared by the thought of having a child with scd, 300 (66.7%) believed that scd could affect a child’s school performance and 260 (57.8%) felt that a scd-affected child would have an effect on the parents’ personal lives. however, fewer participants believed that their child was at risk of having scd (n = 77; 17.1%), that their partner might be a carrier (n = 113; 25.1%) or that scd could occur in their family (n = 144; 32.0%). the majority believed that it would be useful to know if they had sct (n = 363; 80.7%) or if their partner had sct (n = 350; 77.8%); in addition, 294 participants reported that knowing the risk of having a child with scd would change their pregnancy plans (65.3%). many participants believed that sct testing was painful and difficult (n = 157; 34.9%) and that it would be hard to persuade their partner to get tested (n = 155; 34.4%) [table 2]. in terms of scd knowledge, 305 participants (67.8%) were correctly aware that scd is caused by genes inherited from parents and 270 (60.0%) knew that scd carriers could be identified via a simple blood test. however, fewer participants were aware table 2: health beliefs regarding sickle cell disease* among omani adults in a primary healthcare setting (n = 450) questionnaire item n (%) disagree neither agree nor disagree agree severity sickle cell disease is a serious disease 334 (74.2) 84 (18.7) 32 (7.1) having a child with sickle cell disease would be very scary 307 (68.2) 97 (21.6) 46 (10.2) scd can impact school performance 300 (66.7) 98 (21.8) 52 (11.6 ) my life would change if i had a child with sickle cell disease 260 (57.8) 113 (25.1) 77 (17.1) susceptibility sickle cell disease could happen in my family 144 (32.0) 215 (47.8) 91 (20.2) my partner may be a carrier of sickle cell trait 113 (25.1) 185 (41.1) 152 (33.8) my child is at risk of sickle cell disease 77 (17.1) 222 (49.3) 151 (33.6) benefits it is useful to know whether i have the sickle cell trait 363 (80.7) 64 (14.2) 23 (5.1) it is useful to know whether my partner has the sickle cell trait 350 (77.8) 71 (15.8) 29 (6.4) knowing the risk of having a child with sickle cell disease would change how i plan a pregnancy 294 (65.3) 101 (22.4 ) 55 (12.2) barriers testing for the sickle cell trait is painful and difficult 157 (34.9) 131 (29.1) 162 (36.0) my partner would be hard to convince to get tested 155 (34.4) 125 (27.8) 170 (37.8) *health beliefs were self-reported by participants using an arabic version of gustafson et al.’s questionnaire.14 table 3: levels of accurate* knowledge of sickle cell disease† among omani adults in a primary healthcare setting (n = 450) questionnaire item n (%) sickle cell disease is caused by inheriting genes from parents 305 (67.8) to have sickle cell disease, someone must inherit two genes (one from the mother and one from the father) 133 (29.6) sickle cell disease can cause severe debilitating pain, strokes, infections and organ damage 90 (20.0) sickle cell pain can feel worse than a broken bone, a headache and a gunshot wound 91 (20.2) sickle cell disease makes red blood cells hard and sickle-shaped 119 (26.4) you can tell if someone carries the gene for sickle cell disease with a simple blood test 270 (60.0) *using correct responses only. †knowledge was self-assessed by participants using an arabic version of gustafson et al.’s questionnaire.14 mohammed h. al-azri, rajaa al-belushi, muna al-mamari, robin davidson and anil c. mathew clinical and basic research | e441 that scd is inherited by one gene from each parent (n = 133; 29.6%), that it can be extremely painful (n = 91; 20.2%), that it makes red blood cells hard and sickle-shaped (n = 119; 26.4%) or that it can cause debilitating pain, strokes, infections and organ damage (n = 90; 20.0%) [table 3]. total knowledge scores ranged from 0.00–6.00, with a mean score of 2.24 ± 1.59. mean knowledge scores were significantly lower among those with no formal education compared to those with formal education (p <0.001) [table 4]. a multiple regression analysis revealed that education level was the only sociodemographic factor significantly associated with mean total knowledge scores (p <0.001) [table 5]. on further analysis, significant differences according to level of education were observed in several of the knowledge and health belief questionnaire items [table 6]. discussion to the best of the authors’ knowledge, this is the first study determining awareness of and health beliefs regarding scd among an omani population. level of knowledge of scd, including its genetic causes (67.8%) and the fact that it can be diagnosed by a simple blood test (60.0%), was lower than that reported in other countries; one study conducted in the usa found that 91% of african-american women were aware that scd is a hereditary blood disorder while 89% of members of the public in a bahraini study knew that scd could be diagnosed by a blood test.10,17 certain beliefs reported by the majority of participants in the current study—that scd is serious, that it is frightening to have an scd-affected child, that the disease can have an impact on school performance and that having a child with scd can affect the parents’ personal lives—are supported by findings from other studies in the literature.18–21 parents of children with chronic illnesses such as scd have reported significantly greater stress than the parents of healthy children.18,19 research has shown that stress is significantly related to poor psychological adjustment on the part of the parents to the increased demands of children with scd, including frequent pain and frequent use of both routine and urgent healthcare services, as well as realisation of the short life expectancy of their child.18,20 a study conducted in nigeria found that children with scd reported more frequent absences from school and poorer academic achievement compared to their healthy siblings.21 parents of children with scd have shown increased scd knowledge compared to parents of children without scd; moreover, the absence of family discussion about scd was associated with lower knowledge levels and awareness of scd and the value of pms.16,22 education levels were significantly and positively associated with accurate knowledge of scd in the current study; this positive association is to be expected, as education is an essential component in promoting health, screening behaviours and healthier table 5: multiple regression analysis of associations between sociodemographic variables and mean total sickle cell disease knowledge* scores among omani adults in a primary healthcare setting (n = 450) variable standardised regression coefficient p value gender 0.061 0.201 age 0.052 0.338 marital status 0.028 0.630 number of children -0.053 0.401 educational status 0.196 <0.001 *knowledge was self-assessed by participants using an arabic version of gustafson et al.’s questionnaire.14 table 4: mean total sickle cell disease knowledge scores* by sociodemographic characteristic among omani adults in a primary healthcare setting (n = 450) characteristic n (%) mean score ± sd p value gender 0.207 male 201 (44.7) 2.13 ± 1.61 female 249 (55.3) 2.32 ± 1.57 number of children 0.138 0 138 (30.7) 2.18 ± 1.57 1–3 230 (51.1) 2.36 ± 1.63 ≥4 82 (18.2) 1.97 ± 1.48 age in years 0.242 18–29 242 (53.8) 2.18 ± 1.61 30–49 191 (42.4) 2.35 ± 1.55 ≥50 17 (3.8) 1.76 ± 1.71 marital status 0.249 single 115 (25.6) 2.14 ± 1.52 married 321 (71.3) 2.29 ± 1.62 divorced 14 (3.1) 1.64 ± 1.33 educational status <0.001 no formal education 72 (16.0) 1.52 ± 1.62 formal education 378 (84.0) 2.37 ± 1.78 *knowledge was self-assessed by participants using an arabic version of gustafson et al.’s questionnaire.14 knowledge and health beliefs regarding sickle cell disease among omanis in a primary healthcare setting cross-sectional study e442 | squ medical journal, november 2016, volume 16, issue 4 lifestyles.14,23 it is well known that enhancing public understanding of the genetic causes of scd and providing scd information to the public reduces scd-related morbidity and mortality rates.24,25 however, over half of the participants in the current study reported a lack of educational resources concerning scd. although the educational curriculum in oman covers many health-related topics, none are specifically related to scd.26 secondary school and higher education students are the most suitable targets for information about the prevention and control of scd.27 however, health information delivered by physicians is most trusted by the public, despite the availability of other resources.28 in the current study, although the majority of omani adults believed in the value of pms screening, very few reported having taken part in pms previously. in a study of 400 omani adults, al-farsi et al. reported that while 84.5% believed that premarital carrier screening was necessary, 30.5% were not in favour of taking a blood screening test themselves.29 the ministry of health (moh) in oman offers free optional pms for haemoglobin disorders; low attendance at these services might therefore reflect a lack of health promotion of the availability or need for pms or insufficient motivation on the part of the individual to take advantage of the services. according to the hbm hypothesis, individuals must believe that they are at risk of the disease in order to be motivated to pursue health screening behaviours.30 alarmingly, very few participants in the current study believed that scd could affect their families personally, that they were at risk of having a child with scd or that their partner could be a carrier of the scd gene. to this end, the authors of the current study recommend that the moh in oman implements and promotes media and education campaigns in order to increase young people’s awareness of the importance of pms for scd. table 6: significant differences in health beliefs and accurate* knowledge of sickle cell disease† according to education level among omani adults in a primary healthcare setting (n = 450) questionnaire item n (%) p value‡ total education level non-formal secondary school university knowledge sickle cell disease is caused by inheriting genes from parents 305 (67.8) 36 (10.3) 157 (44.9) 112 (32.0) <0.001 sickle cell disease can cause severe debilitating pain, strokes, infections and organ damage 90 (20.0) 7 (7.8) 46 (51.1) 37 (41.1) 0.025 to have sickle cell disease, someone must inherit two genes (one from the mother and one from the father) 133 (29.6) 19 (14.3) 67 (50.4) 47 (35.3) 0.36 sickle cell disease makes red blood cells hard and sickle-shaped 119 (26.4) 7 (5.9) 53 (44.5) 59 (49.6) <0.001 you can tell if someone carries the gene for sickle cell disease with a simple blood test 270 (60.0) 31 (11.5) 134 (49.6) 105 (38.9) <0.001 health beliefs sickle cell disease is a serious disease 334 (74.2) 38 (11.4) 175 (52.4) 121 (36.2) <0.001 having a child with sickle cell disease would be very scary 307 (68.2) 31 (10.1) 157 (51.1) 119 (38.8) <0.001 my life would change if i had a child with sickle cell disease 260 (57.8) 32 (12.3) 134 (51.5) 94 (36.2) 0.002 sickle cell disease can impact school performance 300 (66.7) 32 (10.7) 159 (53.0) 109 (36.3) <0.001 it is useful to know whether i have the sickle cell trait 363 (80.7) 50 (13.8) 184 (50.7) 129 (35.5) <0.001 it is useful to know whether my partner has the sickle cell trait 350 (77.8) 43 (12.3) 181 (51.7) 126 (36.0) <0.001 knowing the risk of having a child with sickle cell disease would change how i plan a pregnancy 294 (65.3) 35 (11.9) 147 (50.0) 112 (38.1) <0.001 *using correct responses only. †health beliefs and knowledge was self-assessed by participants using an arabic version of gustafson et al.’s questionnaire.14 ‡using a chi-squared test. mohammed h. al-azri, rajaa al-belushi, muna al-mamari, robin davidson and anil c. mathew clinical and basic research | e443 these campaigns could involve the distribution of leaflets and posters in hospitals, local health centres and schools. despite the recent decline in consanguineous marriages in oman, the practice is still relatively common; in 2000, the rate of first-cousin and secondcousin marriages was 35.9% and 20.4%, respectively.31 individuals still adhere to cultural norms despite an awareness of the associated risks of congenital and genetic disorders.32,33 furthermore, cultural, legal and religious restrictions limit the control of genetic disorders in many arab countries; for example, termination of a pregnancy is not allowed, even for couples with an affected fetus.34 thus, without the option to terminate a pregnancy, couples expecting a child are more likely to go ahead with a planned marriage.34 these factors may explain why some participants in the current study reported that they would get married even if there was a risk that their future children would have scd. alternatively, these individuals might not have been sufficiently aware of the physical, emotional and social impact of scd.35 it is therefore essential that omani couples who are scd carriers are made fully aware of the medical, psychological and financial consequences of deciding to proceed with the marriage. however, it is important that the counselling of these couples takes place with cultural sensitivity and support from religious leaders within the community. the current study has several limitations. first, although the study was conducted in one of the largest provinces in muscat, the results might not be generalisable to the whole of oman. nonetheless, the authors believe that these results are likely to have some national relevance as most primary care health centres in oman are very similar and many patients travel from different regions of the country in order to seek healthcare in muscat. second, the study was conducted among omanis in a primary healthcare setting and this sample may therefore not be representative of the population as a whole. studies with larger sample sizes conducted among the general public or in communities from different regions of oman are needed for the purposes of generalisability. finally, although the majority of participants reported that they had not undergone pms previously, some of these individuals might not have gotten married yet or may only have had plans to get married. conclusion despite the availability of free pms services in all local health centres in oman, few participants in the current study reported having undergone screening themselves. this is alarming considering the high incidence of scd in oman. it is essential that every effort is made to increase awareness of the consequences of intermarriages between scd carriers, including the possible medical, psychological and financial problems often experienced by parents with scd-affected children. health promotion and education programmes are therefore needed in order to increase public awareness of scd and the value of pms among the omani public. government-mediated media and education campaigns will benefit not only scd patients but the omani community as a whole. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization regional office for africa. sicklecell disease: a strategy for the who african region report of the regional director. from: www.afro.who.int/index. php?option=com_docman&task=doc_download&gid=5436 accessed: jun 2016. 2. modell b, darlison m. global epidemiology of haemoglobin disorders and derived service indicators. bull world health organ 2008; 86:480–7. doi: 10.2471/blt.06.036673. 3. weatherall dj. the inherited diseases of hemoglobin are an emerging global health burden. blood 2010; 115:4331–6. doi: 10.1182/blood-2010-01-251348. 4. aygun b, odame i. a global perspective on sickle cell disease. pediatr blood cancer 2012; 59:386–90. doi: 10.1002/pbc.24175. 5. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 6. alkindi s, pathare a, al-madhani a, al-zadjali s, al-haddabi h, al-abri q, et al. neonatal screening: mean haemoglobin and red cell indices in cord blood from omani neonates. sultan qaboos univ med j 2011; 11:462–9. 7. al-riyami aa, suleiman aj, afifi m, al-lamki zm, daar s. a community-based study of common hereditary blood disorders in oman. east mediterr health j 2001; 7:1004–11. 8. bender ma, seibel gd. sickle cell disease. in: pagon ra, adam mp, ardinger hh, wallace se, amemiya a, bean lj, et al., eds. genereviews. from: www.ncbi.nlm.nih.gov/books/ nbk1377/ accessed: jun 2016. 9. williams tn, obaro sk. sickle cell disease and malaria morbidity: a tale with two tails. trends parasitol 2011; 7:315–20. doi: 10.1016/j.pt.2011.02.004. 10. boyd jh, watkins ar, price cl, fleming f, debaun mr. inadequate community knowledge about sickle cell disease among african-american women. j natl med assoc 2005; 97:62–7. 11. treadwell mj, mcclough l, vichinsky e. using qualitative and quantitative strategies to evaluate knowledge and perceptions about sickle cell disease and sickle cell trait. j natl med assoc 2006; 98:704–10. 12. al kindi r, al rujaibi s, al kendi m. knowledge and attitude of university students towards premarital screening program. oman med j 2012; 27:291–6. doi: 10.5001/omj.2012.72. knowledge and health beliefs regarding sickle cell disease among omanis in a primary healthcare setting cross-sectional study e444 | squ medical journal, november 2016, volume 16, issue 4 13. national centre for statistics & information. dashboards: population. from: www.data.gov.om/en/dashboards accessed: jun 2016. 14. gustafson sl, gettig ea, watt-morse m, krishnamurti l. health beliefs among african american women regarding genetic testing and counseling for sickle cell disease. genet med 2007; 9:303–10. doi: 10.1097/gim.0b013e3180534282. 15. champion vl. instrument development for health belief model constructs. ans adv nurs sci 1984; 6:73–85. doi: 10.10 97/00012272-198404000-00011. 16. acharya k, lang cw, ross lf. a pilot study to explore knowledge, attitudes, and beliefs about sickle cell trait and disease. j natl med assoc 2009; 101:1163–72. doi: 10.1016/ s0027-9684(15)31113-5. 17. al arrayed s, al hajeri a. public awareness of sickle cell disease in bahrain. ann saudi med 2010; 30:284–8. doi: 10.4103/02564947.65256. 18. cousino mk, hazen ra. parenting stress among caregivers of children with chronic illness: a systematic review. j pediatr psychol 2013; 38:809–28. doi: 10.1093/jpepsy/jst049. 19. casey r, brown rt, bakeman r. predicting adjustment in children and adolescents with sickle cell disease: a test of the risk-resistance-adaptation model. rehabil psychol 2000; 45:155–78. doi: 10.1037/0090-5550.45.2.155. 20. barakat lp, patterson ca, weinberger bs, simon k, gonzalez er, dampier c. a prospective study of the role of coping and family functioning in health outcomes for adolescents with sickle cell disease. j pediatr hematol oncol 2007; 29:752–60. doi: 10.1097/mph.0b013e318157fdac. 21. ogunfowora ob, olanrewaju dm, akenzua gi. a comparative study of academic achievement of children with sickle cell anemia and their healthy siblings. j natl med assoc 2005; 97:405–8. 22. long ka, thomas sb, grubs re, gettig ea, krishnamurti l. attitudes and beliefs of african-americans toward genetics, genetic testing, and sickle cell disease education and awareness. j genet couns 2011; 20:572–92. doi: 10.1007/s10897-011-9388-3. 23. cutler dm, lleras-muney a. education and health: evaluating theories and evidence. from: www.nber.org/papers/w12352 accessed: jun 2016. 24. day ll, murray e, treadwell mj, lubin bh. teaching about genetics and sickle cell disease in fifth grade. j natl med assoc 2015; 107:4–10. doi: 10.1016/s0027-9684(15)30003-1. 25. yusuf hr, lloyd-puryear ma, grant am, parker cs, creary ms, atrash hk. sickle cell disease: the need for a public health agenda. am j prev med 2011; 41:s376–83. doi: 10.1016/j. amepre.2011.09.007. 26. ambusaidi a, al-balushi s. health education in the sultanate of oman: towards sustainable health for students. in: taylor n, littledyke m, quinn f, coll rk, eds. health education in context: an international perspective on health education in schools and local communities. rotterdam, the netherlands: sense publishers, 2012. pp. 17–25. doi: 10.1007/978-94-6091876-6_3. 27. adewuyi jo. knowledge of and attitudes to sickle cell disease and sickle carrier screening among new graduates of nigerian tertiary educational institutions. niger postgrad med j 2000; 7:120–3. 28. hesse bw, nelson de, kreps gl, coyle rt, arora nk, rimer bk, et al. trust and sources of health information: the impact of the internet and its implications for health care providers: findings from the first health information national trends survey. arch intern med 2005; 165:2618–24. doi: 10.1001/archinte.165.22.2618. 29. al-farsi oa, al-farsi ym, gupta i, ouhtit a, al-farsi ks, al-adawi s. a study on knowledge, attitude, and practice towards premarital carrier screening among adults attending primary healthcare centers in a region in oman. bmc public health 2014; 14:380. doi: 10.1186/1471-2458-14-380. 30. rosenstock im, strecher vj, becker mh. social learning theory and the health belief model. health educ q 1988; 15:175–83. doi: 10.1177/109019818801500203. 31. rajab a, patton ma. short report: a study of consanguinity in the sultanate of oman. ann hum biol 2000; 27:321–6. doi: 10.1080/030144600282208. 32. hamamy h. consanguineous marriages: preconception consultation in primary health care settings. j community genet 2012; 3:185–92. doi: 10.1007/s12687-011-0072-y. 33. tadmouri go, nair p, obeid t, al ali mt, al khaja n, hamamy ha. consanguinity and reproductive health among arabs. reprod health 2009; 6:17. doi: 10.1186/1742-4755-6-17. 34. al-gazali l, hamamy h, al-arrayad s. genetic disorders in the arab world. bmj 2006; 333:831–4. doi: 10.1136/bmj.38 982.704931.ae. 35. o’connor am, bennett cl, stacey d, barry m, col nf,eden kb, et al. decision aids for people facing health treatment or screening decisions. cochrane database syst rev 2009; 3:cd001431. doi: 10.1002/14651858.cd001431.pub2. departments of 1child health and 2medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mails: koul@squ.edu.om, roshankoul@hotmail.com and koulroshan@gmail.com العالج بعقار الريتوكسيماب يف الوهن العضلي الشديد تقرير عن طفلني مصابني رو�شان كول، اآمنة الفطي�شي، رنا عبد الرحيم، رينجيث ماين، رمي عبدواين، عبداهلل العا�شمي abstract: myasthaenia gravis (mg) is an autoimmune disease involving the postsynaptic receptors in the neuromuscular junction. the condition is characterised by fatigable weakness of the skeletal muscles and is uncommon in children. acetylcholinesterase inhibitors and immune-modifying medications are usually considered the mainstay of treatment. however, these medications have to be given on a lifelong basis so that patients remain in remission; furthermore, drug-related side-effects can have a major impact on quality of life. we report two paediatric cases who were treated for mg at the sultan qaboos university hospital, muscat, oman, in 2007 and 2008, respectively. rituximab was eventually administered to each patient after their condition failed to improve despite several years of standard treatment with acetylcholinesterase inhibitors and immune-modifying medications. overall, rituximab resulted in complete remission in one case and significant clinical improvement in the other case. keywords: myasthenia gravis; rituximab; children; cholinergic receptors; case report; oman. الع�شلية. الع�شبية الو�شلة يف امل�شبك بعد ما م�شتقبالت ت�شيب التي الذاتية املناعة اأمرا�ض اأحد هو ال�شديد الع�شلي الوهن امللخ�ص: للمناعة املعدلة والأدوية اأ�شتيل مثبطات تعترب ما وعادة الأطفال. يف �شائع وهوغري الهيكلية الع�شالت يف جهد ب�شعف احلالة تتميز الدعامة الأ�شا�شية للعالج. ومع ذلك ، يجب اإعطاء هذه الأدوية على مدى احلياة حتى يظل املر�ض يف حالة �شكون. عالوة على ذلك ، ميكن الوهن مبر�ض م�شابني لالأطفال حالتني عن تقرير هذا احلياة. جودة على كبري تاأثري لها يكون اأن بالعقاقري املرتبطة اجلانبية لالآثار الع�شلي ال�شديد ومت عالجهم يف م�شت�شفى جامعة ال�شلطان قابو�ض، م�شقط، عمان، يف عام 2007 و 2008. ويف وقت لحق، اأعطي عقار اأدى فقد وعموما �شنوات. لعدة كولين�شرتيز الأ�شيتيل ومثبطات املناعة مبثبطات للعالج ي�شتجيبا مل املراهقني كلتا اإىل الريتوك�شيماب الريتوك�شيماب ايل �شكون كامل يف احلالة الأوىل والتح�شن ال�رضيري الكبري يف احلالة الثانية. الكلمات املفتاحية: الوهن الع�شلي ال�شديد؛ ريتوك�شيماب؛ الأطفال؛ امل�شتقبالت الكولينية؛ تقرير حالة؛ عمان. rituximab treatment in myasthaenia gravis report of two paediatric cases *roshan koul,1 amna al-futaisi,1 rana abdelrahim,1 renjith mani,1 reem abdwani,1 abdullah al-asmi2 sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e223–227, epub. 9 sep 18 submitted 17 nov 17 revisions req. 28 dec 17, 5 feb & 1 mar 18; revisions recd. 17 jan, 18 feb & 4 mar 18 accepted 8 mar 18 case report doi: 10.18295/squmj.2018.18.02.018 case one a seven-year-old female patient presented to squh in 2007 and was diagnosed with mg. she was prescribed prednisolone, pyridostigmine and azathioprine and underwent a thymectomy in 2009. her acetylcholine receptor (achr) antibody levels were 85,000 nmol/l in 2007 and 292 nmol/l in 2013 (normal range: 0–0.25 nmol/l). an anti-muscle-specific kinase (musk) antibody test was not performed. for several years, she continued taking pyridostigmine, prednisolone and azathioprine; however, she still had minimal ptosis and was easily fatigued. she could not participate in active games and, according to the myasthenia gravis foundation of america (mgfa) scale, her muscular weakness was categorised as class iva.8 the patient was the elder sister of another previously reported female child with mg.9 in 2012, five years after her initial mg diagnosis, the patient was prescribed rituximab. although she myasthaenia gravis (mg) is an auto-immune neuromuscular disease often presenting as generalised weakness.1 the condition is most often seen in the adult population; in a previously reported series of mg patients from oman, only 10% were children.2 acetylcholinesterase inhibitors and immune-modifying medications such as steroids, mycophenolate, azathioprine, intravenous immunoglobulins (ivigs) and plasmapheresis are considered the mainstay of treatment for mg; however, these treatments must be maintained over the course of the patient’s life.1 in addition, thymectomies are reported to be effective for a large number of patients.1,3 recently, various reports have shown remarkable improvements in mg cases following treatment with rituximab.4–7 this case report describes two children with severe mg who were refractory to conventional treatment. both children responded well to rituximab therapy, resulting in marked improvement in one case and complete remission in the second case. rituximab treatment in myasthaenia gravis report of two paediatric cases e224 | squ medical journal, may 2018, volume 18, issue 2 demonstrated significant clinical improvement, it was necessary to continue treatment with the other drugs. at the time of writing, she was taking 50 mg of azathioprine twice a day, 30 mg of pyridostigmine three times a day and 5 mg of prednisolone once a day. her cluster of differentiation (cd)19 count remained below 0.1 x 109/l (normal range: 0.2–0.5 x 109/l) for almost five years. case two a five-year old girl presented to squh in 2008 with ptosis, difficulty swallowing and mild generalised weakness. clinical investigations confirmed a diagnosis of mg. the results of achr antibody tests performed in 2008 and 2013 were negative. an anti-musk antibody test was not performed. she was prescribed pyridostigmine, 2 mg/kg/day of prednisolone, azathio prine and atenolol (due to steroid-related hypertension). she also developed severe cushingoid features and osteopaenia with reduced bone density requiring vitamin d therapy. she was on regular monthly ivig therapy (1 g/kg). a thymectomy was advised but not performed, as her father did not consent to the procedure. according to the mgfa scale, her muscular weakness was categorised as class ivb.8 as the patient’s symptoms did not improve, rituximab treatment was initiated in 2014, more than five years after her initial mg diagnosis. clinical improvement was evident after the second dose. after three months, once all four doses of rituximab had been administered, prednisolone was tapered off and all other drugs were discontinued, including the azathioprine, pyridostigmine and atenolol. at the time of writing, the patient had been asymptomatic for two years. she was given one additional dose of rituximab in 2016 after her cd19 count had normalised. a summary of the clinical characteristics and management plans of both cases is shown in table 1. discussion rituximab is an anti b-cell cd20 monoclonal antibody used in the treatment of several autoimmune neurological disorders, including neuromyelitis optica, opsoclonus ataxia syndrome and autoimmune neuropathies.10,11 the drug was first used for the treatment of mg in 2003.12 since then, several reports have been published indicating a good clinical response to the drug.4,5,13–15 in a recent systematic review, tandan et al. reported that 71% of mg patients have shown improvement with rituximab therapy.6 currently, a multi-centre phase ii rituximab trial is being undertaken among mg patients in the usa, with preliminary results to be reported soon.16 in a 10year open-label study, rituximab was well-tolerated, resulting in sustained clinical improvement and the eventual tapering off of other immune therapies.7 although the majority of mg cases demonstrate an effective and sustained response with rituximab with few complications, the potential adverse effects of the drug should be considered prior to treatment.7,9 rituximab can cause serious side-effects, including progressive multifocal leukoencephalopathy, the reactivation of dormant hepatitis and epidermal necro lysis.5,10,11 however, as the current cases were asymptomatic, they were not screened for these side-effects. in the first case, the patient was the elder sister of another previously reported female child with class v mg who presented to squh in 2012 at the age of four years.9 the younger sister was prescribed incremental doses of prednisolone and pyridostigmine, but her table 1: clinical characteristics and management plans of two paediatric cases of myasthaenia gravis treated with rituximab case one case two age at mg onset in years 7 5 gender female female year of presentation 2007 2008 mg severity* iva ivb initial treatment prd, pyd, ivigs and aza prd, pyd, ivigs, aza, vitamin d and atenolol number of mg crises 1 3 thymectomy yes no achrab status positive† negative rituximab dosage four doses of 375 mg/m2 four doses of 375 mg/m2 response to treatment after the fourth dose after the second dose number of cycles 1 full cycle 1 full cycle plus one dose current treatment prd, pyd and aza none outcome significant clinical improvement in remission mg = myasthenia gravis; prd = prednisolone; pyd = pyridostigmine; ivigs = intravenous immunoglobulins; aza = azathioprine; achrab = acetylcholine receptor antibody. *according to the myasthenia gravis foundation of america scale.8 †initially, her achrab levels were 85,000 nmol/l in 2007 before dropping to 292 nmol/l in 2013. roshan koul, amna al-futaisi, rana abdelrahim, renjith mani, reem abdwani and abdullah al-asmi case report | e225 condition progressively worsened over time and she was intubated six times.9 nine months later, rituximab treatment was initiated at weekly intervals, as per standard squh protocols [table 2]. three days after the first dose, her ventilatory parameters began to improve, with all baseline symptoms of weak ness resolving after the fourth dose.9 after 14 months, her cd19 count normalised and she remained asymptomatic for 20 months; however, she subsequently relapsed and underwent a second cycle of rituximab in 2013.9 her cd19 count normalised again in 2016 and she was given another single dose of rituximab. the patient remained asymptomatic, with no clinical evidence of any further relapse.9 rituximab was thus administered to the first case in light of the successful outcome achieved for her younger sister. at present, there are no indicators other than cd19 count to guide rituximab use following the first round of treatment. although the cd19 count is initially suppressed by rituximab, it normalises once the effect of the drug wears off.13 rituximab treatment should therefore be repeated once the cd19 count normalises to avoid clinical relapse.17 in the second case, the rituximab dose was repeated once the patient’s cd19 count had normalised, before the recurrence of any clinical weakness. for the first case, table 2: standard protocols for paediatric rituximab treatment at the sultan qaboos university hospital, muscat, oman protocol dosage • 375 mg/m2 once weekly for four weeks, with subsequent doses depending on the patient’s initial response to treatment. dilution • add a solution of 0.9% sodium chloride or 5% glucose for a final concentration of 1–4 mg/ml. • mix gently to avoid foaming. pre-treatment • the following medications should be administered orally 30–60 minutes prior to each infusion: a) 15 mg/kg of paracetamol (up to a maximum of 1 g) b) chlorpheniramine at dosages of: (i) 1 mg twice for patients between 1 month and 2 years old (ii) 1 mg every four to six hours for patients between 2–6 years old (iii) 2 mg every four to six hours for patients between 6–12 years old (iv) 4 mg every four to six hours for patients between 12–18 years old. • intravenous corticosteroids may also be given if required (e.g. two doses of 0.1 mg/kg of dexamethasone). • consider withholding antihypertensive medications for 24 hours to prevent hypotension. • screen for hepatitis b before starting rituximab, as this treatment can reactivate dormant infections. • for patients with pre-existing pulmonary disease, concomitant nebulised salbutamol should be considered. administration • the drug should be infused over an 8-hour period at an initial rate of 10 ml/hour, before increasing to 15 ml/hour, 20 ml/hour, 30 ml/hour and 40 ml/hour for half-hour intervals each. the infusion rate should then be maintained at 50 ml/hour until the entire dose has been administered. compatibility • apart from 0.9% sodium chloride and 5% glucose, rituximab should not be mixed with any other fluids or drugs. • the catheter should be flushed with saline or glucose before and after the rituximab infusion. potential adverse effects • fever and chills/rigors may occur in up to 50% of patients. • infusion-related symptoms include nausea, vomiting, urticaria, headaches, bronchospasms, dyspnoea, angioedema and hypotension. • severe gastrointestinal adverse effects including obstruction and perforation have been reported; complaints of abdominal pain, especially early in the treatment course, should be investigated. • patients with pre-existing pulmonary disease may be at greater risk of respiratory adverse effects. • rituximab can exacerbate or induce arrhythmias or angina. • adverse reactions are usually more severe during the first infusion; however, anaphylaxis can occur at any time and at any stage of treatment. • in case of anaphylaxis, emergency treatment (i.e. adrenaline and corticosteroids) should be readily available. observation and monitoring • the patient’s vital signs and the site of the infusion should be checked every 15 minutes during the first hour of the infusion, then every hour until the infusion is complete. • routine observation should continue at 30-minute intervals for two hours following the completion of the infusion in order to monitor any delayed reactions. • the infusion should be halted immediately if any adverse effects arise; if the effects are mild and the symptoms resolve, the infusion may be restarted at half the previous rate of infusion. • cardiac monitoring may be required for patients with cardiac dysfunction. • continue to monitor patients for signs of hepatitis b infection during and for several months after treatment; rituximab must be discontinued if fulminant hepatitis develops. follow-up • a complete blood count, including differential and platelet counts, should be obtained at weekly intervals for inpatients and fortnightly intervals for outpatients. • lymphocyte subset panels should be undertaken every three months. • urea and electrolyte levels should be monitored on a daily basis for inpatients and prior to every infusion for outpatients. rituximab treatment in myasthaenia gravis report of two paediatric cases e226 | squ medical journal, may 2018, volume 18, issue 2 the cd19 count remained suppressed and had still not reached normal values more than four years after the initial rituximab treatment. the duration of the period of cd19 suppression is variable.13 in this case, the patient was asymptomatic and hence was not screened for progressive multifocal leukoencephalopathy or a john cunningham virus infection. tandan et al. noted that rituximab resulted in a better response among patients with anti-musk antibodies compared to those with anti-achr antibodies.6 in the current report, the second patient was negative for achr antibodies and seemed to respond most positively to the rituximab treatment. the first patient had positive achr antibody test results, which, despite a significant decline between 2007 and 2013, never normalised; furthermore, this patient did not respond as well to rituximab treatment as the achr antibody-negative patient. negative achr antibody test results may therefore be a good marker for predicting remission with rituximab treatment. however, it is important to note that achr antibody levels appear to increase with age and that cases of childhood-onset mg may initially appear to be achr antibody-negative.17 it is not yet clear whether there is any correlation between the duration of mg and the efficacy of rituximab therapy. in the first case, rituximab did not appear to result in the complete resolution of mg symptoms, although the therapy was not initiated until five years after her initial mg diagnosis. rituximab treatment was also far more effective for her younger sister when administered within a year of the onset of the symptoms.9 however, the second case also received rituximab after having had mg for five years, resulting in the complete amelioration of her mg symptoms. future studies may therefore reveal more information in this context. a thymectomy is often performed as part of mg treatment for adults; however, while it is sometimes used in childhood mg as well, the effect of the procedure is slow and takes place over time.1,3 in the first case, the patient had undergone a thymectomy seven years prior to rituximab treatment, with seemingly little improvement. as such, the authors suggest that rituximab therapy be considered for paediatric patients with mg from the time of onset of clinical symptoms, except in cases of ocular mg. however, local experience using rituximab is advised. additionally, the long-term outcomes of rituximab in mg patients with primary disease is unknown. therefore, the long-term follow-up of such patients is recommended to ensure sustained remission and to monitor for possible side-effects. conclusion this report describes two cases of paediatric mg in which the use of rituximab therapy resulted in remission or significant clinical improvement. rituximab should therefore be considered in similar cases from the time of disease onset. however, the authors highly recommend the continuous followup of these patients as the long-term outcome of this treatment has not yet been established. a c k n o w l e d g e m e n t s the squh protocols for rituximab therapy in mg cases are adapted from the 2007 and 2009 protocols of the john hunter children’s hospital, newcastle, new south wales, australia, and the brain institute at miami children’s hospital, miami, florida, usa, respectively. references 1. sanders db, wolfe gi, benatar m, evoli a, gilhus ne, illa i, et al. international consensus guidance for management of myasthenia gravis: executive summary. neurology 2016; 87:419–25. doi: 10.1212/wnl.0000000000002790. 2. jacob pc, tharakan jt, chand pr, koul rl, chacko ap. clinical profile of myasthenia gravis in the sultanate of oman. saudi med j 2003; 24:774–5. 3. heng hs, lim m, absoud m, austin c, clarke d, wraige e, et al. outcome of children with acetylcholine receptor (achr) antibody positive juvenile myasthenia gravis following thymectomy. neuromuscul disord 2014; 24:25–30. doi: 10.1016/j.nmd. 2013.09.013. 4. hayashi r, tahara m, oeda t, konishi t, sawada h. [a case of refractory generalized myasthenia gravis with anti-acetylcholine receptor antibodies treated with rituximab]. rinsho shinkeigaku 2015; 55:227–32. doi: 10.5692/clinicalneurol.55.227. 5. iorio r, damato v, alboini pe, evoli a. efficacy and safety of rituximab for myasthenia gravis: a systematic review and metaanalysis. j neurol 2015; 262:1115–19. doi: 10.1007/s00415-0147532-3. 6. tandan r, hehir mk 2nd, waheed w, howard db. rituximab treatment of myasthenia gravis: a systematic review. muscle nerve 2017; 56:185–96. doi: 10.1002/mus.25597. 7. stieglbauer k, pichler r, topakian r. 10-year-outcomes after rituximab for myasthenia gravis: efficacy, safety, costs of inhospital care, and impact on childbearing potential. j neurol sci 2017; 375:241–4. doi: 10.1016/j.jns.2017.02.009. 8. jazetzki a 3rd, barohn rj, ernstoff rm, kaminski hj, keesey jc, penn as, et al. myasthenia gravis: recommendations for clinical research standards task force of the medical scientific advisory board of the myasthenia gravis foundation of america. neurology 2000; 55:16–23. doi: 10.1212/wnl.55.1.16. 9. koul r, al futaisi a, abdwani r. rituximab in severe sero negative juvenile myasthenia gravis: review of the literature. pediatr neurol 2012; 47:209–12. doi: 10.1016/j.pediatrneurol. 2012.05.017. 10. kosmidis ml, dalakas mc. practical considerations on the use of rituximab in autoimmune neurological disorders. ther adv neurol disord 2010; 3:93–105. doi: 10.1177/1756285609356135. https://doi.org/10.1212/wnl.0000000000002790 https://doi.org/10.1016/j.nmd.2013.09.013 https://doi.org/10.1016/j.nmd.2013.09.013 https://doi.org/10.5692/clinicalneurol.55.227 https://doi.org/10.1007/s00415-014-7532-3 https://doi.org/10.1007/s00415-014-7532-3 https://doi.org/10.1002/mus.25597 https://doi.org/10.1016/j.jns.2017.02.009 https://doi.org/10.1212/wnl.55.1.16 https://doi.org/10.1016/j.pediatrneurol.2012.05.017 https://doi.org/10.1016/j.pediatrneurol.2012.05.017 https://doi.org/10.1177/1756285609356135 roshan koul, amna al-futaisi, rana abdelrahim, renjith mani, reem abdwani and abdullah al-asmi case report | e227 11. pescovitz md. rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action. am j transplant 2006; 6:859–66. doi: 10.1111/j.1600-6143.2006.01288.x. 12. wylam me, anderson pm, kuntz nl, rodriguez v. successful treatment of refractory myasthenia gravis using rituximab: a pediatric case report. j pediatr 2003; 143:674–7. doi: 10.1067/ s0022-3476(03)00300-7. 13. collongues n, casez o, lacour a, tranchant c, vermersch p, de seze j, et al. rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study. muscle nerve 2012; 46:687–91. doi: 10.1002/mus.23412. 14. lindberg c, bokarewa m. rituximab for severe myasthenia gravis: experience from five patients. acta neurol scand 2010; 122:225–8. doi: 10.1111/j.1600-0404.2010.01345.x. 15. baek ws, bashey a, sheean gl. complete remission induced by rituximab in refractory, seronegative, muscle-specific, kinase positive myasthenia gravis. j neurol neurosurg psychiatry 2007; 78:771. doi: 10.1136/jnnp.2006.093567. 16. national institutes of health. beatmg: phase ii trial of rituximab in myasthenia gravis. from: https://clinicaltrials.gov/ ct2/show/nct02110706 accessed: mar 2018. 17. andrew pi, massey jm, sanders db. acetylcholine receptor antibodies in juvenile myasthenia gravis. neurology 1993; 43:977–82. doi: 10.1212/wnl.43.5.977. https://doi.org/10.1111/j.1600-6143.2006.01288.x https://doi.org/10.1067/s0022-3476%2803%2900300-7 https://doi.org/10.1067/s0022-3476%2803%2900300-7 https://doi.org/10.1002/mus.23412 https://doi.org/10.1111/j.1600-0404.2010.01345.x https://doi.org/10.1136/jnnp.2006.093567 https://doi.org/10.1212/wnl.43.5.977 1department of ear, nose & throat, suliaman al habib hospital, dubai, uae; departments of 2microbiology and 3ear, nose & throat, al zahra hospital, dubai, uae; 4center of advanced research in medical mycology, postgraduate institute of medical education & research, chandigarh, india *corresponding author’s e-mail: drlevente.deak@gmail.com حالة عدوي بفطر كونيديوبولوس كوروناتوس يف األنف والوجه ظهرت كورم يف داخل األنف ليفنتي ديك، �شافيثا مودالقريييابا، انيلي�س بالن، ديفيد �شاكتون، اآرونالوك �شاكارباتي abstract: conidiobolomycosis is a rare fungal infection that affects adults in tropical regions. we report a 42-year-old male patient who was referred to the sulaiman al habib hospital, dubai, united arab emirates (uae), in 2013 with excessive nasal bleeding and a suspected nasal tumour. he reported having briefly visited central india nine months previously. computed tomography and magnetic resonance imaging showed a highly vascularised mass in the nasal cavity. however, after surgical excision, initial treatment with amphotericin b deoxycholate was unsuccessful and the disease progressed, leading to external and internal nasal deformation and necessitating further excision and facial reconstruction. histopathological analysis of the second biopsy revealed splendorehoeppli changes consistent with a fungal infection. microbiological findings subsequently confirmed conidiobolus coronatus. subsequently, the patient was successfully treated with a combination of itraconazole and fluconazole. to the best of the authors’ knowledge, this is the first report of a case of rhinofacial conidiobolomycosis from the uae. keywords: nasal obstruction; conidiobolus; zygomycosis; antifungal agents; case report; united arab emirates. بحالة تقريرا هنا ونقدم املدارية. املناطق يف البالغني وي�شيب احلدوث، نادر داء لالأنف املجاورة واجليوب الأنف ُفَطار داء امللخ�ص: رجل يف 42 من العمر مت حتويله اإىل م�شت�شفى �شليمان حبيب يف دبي بالأمارات العربية املتحدة يف عام 2013م لإ�شابته بنزف اأنفي ويٌر املْقَطِعيٌّ امُلَحو�َشب مفرط، ولل�شك يف اإ�شابته بورم يف الأنف. ذكر املري�س اأنه زار و�شط الهند ملدة ق�شرية قبل ت�شعة اأ�شهر. واأظهر الَت�شْ والرنني املغنطي�شي كتلة غنية بالأوعية الدموية يف التجويف الأنفي. ومتت اإزالة تلك الكتلة جراحيا واأعطى املري�س دواء امفوتري�شني ب ديوك�شي كوليت؛ غري اأن ذلك العالج مل ينجح، وازداد تطور املر�س و�شبب ت�شوها خارجيا وداخليا يف الأنف، مما ا�شتدعى اإجراء عملية ا�شبيلندور)تغريات َماِنّية جَنْ اأج�شام وجود ثانية خلزعة الهي�شتوباثلوجي الفح�س واأثبت للوجه. ا�ْشِتْبناء وعمل الورم لإزالة جراحية هوبلي( دالة على وجود عدوى فطرية. واأثبتت الختبارات امِلْكروبيولوجية لحقا وجود فطر كونيديوبولوس كوروناتوس. وعقب ذلك عولج املري�س بدوائي اتراكونازول وفلوكونازول. ونح�شب-مبلغ علمنا-اأن هذا التقرير هو اأول تقرير حلالة مري�س م�شاب ب داء ُفَطار الأنف والوجه يف الإمارات العربية املتحدة. الكلمات املفتاحية: ان�شداد اأنفي؛ كونيديوبولو�س؛ فطار عفني؛ دواء م�شاد للفطريات؛ تقرير حالة؛ الإمارات العربية املتحدة. a rhinofacial conidiobolus coronatus fungal infection presenting as an intranasal tumour *levente deak,1 savitha mudalagiriyappa,2 annelyse ballin,3 david saxton,1 arunaloke chakrabarti4 case report sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e549–552, epub. 28 mar 19 submitted 30 may 18 revision req. 17 jul 18; revision recd. 9 sep 18 accepted 27 sep 18 doi: 10.18295/squmj.2018.18.04.022 first identified in mammals such as horses, dolphins and chimpanzees, conidiobolus coronatus is an opportunistic pathogen which causes rhinofacial conidiobolomycosis in humans.1,2 initially, cases were restricted to areas with tropical and subtr opical climates; however, due to climate change and modern advances in global travel, the disease can now be found on almost every continent.1 the main symptoms of c. coronatus infections are facial deformation with extensive nasal blockage and bleeding due to the presence of subcutaneous granulomatous lesions.1,3,4 the fungus usually infects healthy male farm workers between 20–60 years old.1,2 in humans, c. coronatus infections likely occur due to inhalation of the fungal spores which imbed into the nasal mucosa; subsequently, as a result of enzymatic activity, they can penetrate into the subcutaneous area of the face as well as the nasal cavity and sinuses.1 swelling inside the nasal cavity is usually localised to the lower turbinate and nasal mucosa.1,2 more fulminant progression has been reported in immunocompromised hosts, with invasion into the blood vessels; however, in otherwise healthy patients, the infection is non-fatal and localised to the subcutaneous and mucocutaneous tissues.2,5 case report a 42-year-old male patient was referred to the sulaiman al habib hospital, dubai, united arab emirates (uae), in 2013 with excessive nasal bleeding and a suspected nasal tumour. nine months previously, the patient had a rhinofacial conidiobolus coronatus fungal infection presenting as an intranasal tumour e550 | squ medical journal, november 2018, volume 18, issue 4 under general anaesthesia, resectioning of the lower turbinate was performed and a biopsy of the mass and the involved mucosa was taken. significant bleeding was encountered and controlled by laser vaporisation of the mucosa edges. a fresh frozen section examination of the biopsy suggested a fungal infection; however, a fungal culture did not yield any growth. the patient was there fore suspected of having aspergillosis. following extensive nasal debridement, the patient was treated with 2.5 mg/kg/day of intravenous amphotericin b deoxycholate and was monitored for all necessary blood parameters. however, after 10 days of treatment, the mass regrew rapidly. a further tissue biopsy and culture were performed, followed by a radical turbinectomy and excision of the mucosa from the floor of the nose together with the mid-portion of the cartilaginous nasal septum. the vestibular skin was also found to be affected and was removed [figure 2]. the second biopsy was sent for histopathological and microbiological analysis. a haematoxylin and eosin stain of the biopsy specimen showed eosinophilic deposits surrounded by hyphae (i.e. splendore-hoeppli phenomenon), while gram staining showed broad sparsely septate hyphae. the biopsy specimen was cultured using both sabouraud dextrose agar (sda) with chloramphenicol and cycloheximide and plain sda and incubated at 30 °c and 37 °c. after five days of incubation at 30 °c, the plates with the plain sda medium showed multiple flat, white, glabrous, slightly powdery-to-granular and radially furrowed colonies of mould with several peripheral satellite col onies [figure 3]. as these features were highly indicative of a conidiobolus species, the lid of the plate was secured with a thermoplastic self-sealing film to prevent cont agion (parafilm®, bemis co. inc., neenah, wisconsin, usa). in addition, a lactophenol cotton blue stain prep aration showed broad hyaline sparsely septate hyphae with a few spherical conidia with hair-like appendages (i.e. villae), also characteristic of a zygomycetes species. the cultured fungus was sent for molecular ident ification and antifungal susceptibility testing at a reputable visited central india for a few days; subsequently, three months after returning to the uae, he had noticed swelling and tenderness above his nasal dorsum, with progressive nasal blockage. six months later, he developed recurrent epistaxis, resulting in admission to another healthcare facility. however, following failed conventional management, he was referred to the sulaiman al habib hospital. upon physical examination, there was thickening of the right nasal vestibule as well as occlusion of the nasal cavity due to highly vascularised granulomatous tissue growth involving the right inferior turbinate, the floor of the nasal cavity and the right side of the nasal septum. no airway could be established, despite the administration of xylometazoline as a decongestant. in addition, the left nasal cavity was narrowed due to a deviated septum. the nasal mucosa was intact and the nasal dorsum was slightly tender and widened. the patient was otherwise in good health with no evidence of underlying disease. computed tomography and magnetic resonance imaging scans of the nose and paranasal sinuses revealed a highly vascularised mass occupying the entire nasal cavity. the sinuses were intact without bony erosion or extension to the adjacent anatomical areas [figure 1]. figure 2: endoscopic photograph of the nasal cavity of a 42-year-old male patient showing the spread of a highly vascularised mass to both the nasal mucosa and vestibular skin, indicating subcutaneous fat involvement. ns = nasal mucosa; vs = vestibular skin. figure 1: imaging of a 42-year-old male patient with excessive nasal bleeding and a suspected nasal tumour. a & b: computed tomography scans confirming the intact nasal bony wall (arrows). c: magnetic resonance imaging showing increased t2 signals in the nasal cavity alone (arrow), without intracranial spread or extension to the sinuses. levente deak, savitha mudalagiriyappa, annelyse ballin, david saxton and arunaloke chakrabarti case report | e551 discussion as in the current case, most published reports of rhino facial c. coronatus infections have occurred in males with normal immune status who have recently travelled to a tropical region.5,9–11 overall, very few cases of rhinofacial c. coronatus infections have been reported in the liter ature; as such, early identification of the organism remains challenging.1,3,4 to the best of the authors’ knowledge, the current case is the first report of a patient with rhinofacial conidiobolomycosis from the uae. the diagnosis of a c. coronatus infection is based on a tissue biopsy in which eosinophilic deposits surr ounding the hyphae can be seen (i.e. splendore-hoeppli phenomenon).1,2 however, physicians often face diffic ulties in obtaining a positive culture in order to dem onstrate antimicrobial susceptibility; as such, the disease has a high morbidity and mortality rate.1,2,9,12 currently, there is no standard recommended therapy for conidiobolomycosis cases. generally, treatment ranges from conservative options to the radical resectioning of infected tissues, with approaches varying according to individual cases and local drug resistance patterns.1,4,13,14 in the current case, the initial culture was negative and histopathologically misdiagnosed as aspergillosis. following disease progression and unsucc essful treatment with amphotericin b deoxycholate, the patient required extensive surgical debridement. at this point, a repeated culture confirmed a diagnosis of a c. coronatus infection and a detailed antifungal susceptib ility profile was established. the patient was then success fully treated with prolonged combination therapy involving itraconazole and fluconazole. other researchers have reported similar success using potassium iodide, trimethoprim/sulfamethoxazole, amphotericin b, ketoconazole and itraconazole, either individually or in combination.1,3,15,16 blumentrath et al. proposed a treatment strategy according to stages of disease progression; based on these classifications, the current case would be considered intermediate due to the incubation period and vestibular skin involvement and a surgical approach would not be recommended.17 however, the current patient had non-responsive bleeding and a blocked airway; as such, his quality of life immediately improved following surgical debridement. conclusion due to climate change and increasing global travel, rhino facial c. coronatus infections are no longer restricted to tropical regions. however, successful management of such cases remains challenging due to the low laboratory affiliated with the postgraduate institute of medical education & research, chandigarh, india. mol ecular typing and an antifungal susceptibility profile was performed as per standard methods and the recommendations of the clinical & laboratory standards inst itute (clsi).6–8 briefly, the macrobroth was diluted according to m61 clsi standards and a final concentration of 3.5 × 102 colony forming units/ml was used as the inoculum, before being incubated at 35 °c for 48 hours.8 based on these findings, the fungus was identified to be c. coronatus. as per the antifungal susceptibility profile, oral anti fungal treatment was initiated with 200 mg/day of itra conazole combined with 100 mg/day of fluconazole [table 1]. after six months of treatment, only a small granulomatous lesion remained which was subseq uently removed under local anaesthesia. the nasal def ormation resulting from the nostril retraction was corrected with a skin flap rotation procedure. the prev iously noted enlargement of the nasal dorsum reduced without the need for surgical intervention. antifungal therapy was continued for a total of 18 months. there was no sign of disease recurrence at a three-year follow-up. table 1: antifungal susceptibility profile of a cultured fungus identified as conidiobolus coronatus antifungal agent mic in µg/ml amphotericin b deoxycholate 2 voriconazole >16 itraconazole >16 posaconazole >16* caspofungin >64 anidulafungin 8 micafungin >8 mic = minimal inhibitory concentration. *80% inhibition at 4 µg/ml. figure 3: photograph of a nasal mass culture showing multiple, flat, white, glabrous, slightly powdery-to-granular and radially furrowed colonies of fungus with several peripheral satellite colonies. a rhinofacial conidiobolus coronatus fungal infection presenting as an intranasal tumour e552 | squ medical journal, november 2018, volume 18, issue 4 7. gil-lamaignere c, roilides e, hacker j, müller fm. molecular typing for fungi: a critical review of the possibilities and limitations of currently and future methods. clin microbiol infect 2003; 9:172–85. https://doi.org/10.1046/j.1469-0691.2003.00649.x. 8. clinical and laboratory standards institute. m61: performance standards for antifungal susceptibility testing of filamentous fungi, 1st edition. from: https://clsi.org/standards/products/mi crobiology/documents/m61/ accessed: sep 2018. 9. gonzalez ce, rinaldi mg, sugar am. zygomycosis. infect dis clin north am 2002; 16:895–914. https://doi.org/10.1016/s0 891-5520(02)00037-5. 10. yang x, li y, zhou x, wang y, geng s, liu h, et al. rhinofacial conidiobolomycosis caused by conidiobolus coronatus in a chinese rice farmer. mycoses 2010; 53:369–73. https://doi.org/ 10.1111/j.1439-0507.2009.01716.x. 11. moncada dc, montes m, molina v, velásquez jb, gómez ci. orofacial infection by conidiobolus coronatus. biomedica 2016; 36:15–22. https://doi.org/10.7705/biomedica.v36i2.2806. 12. gilbert ef, khoury gh, pore rs. histopathological identification of entomophthora phycomycosis: deep mycotic infection in an infant. arch pathol 1970; 90:583–7. 13. kimura m, yaguchi t, sutton da, fothergill aw, thompson eh, wickes bl. disseminated human conidiobolomycosis due to conidiobolus lamprauges. j clin microbiol 2011; 49:752–6. https://doi.org/10.1128/jcm.01484-10. 14. fischer n, ruef ch, ebnöther c, bächli eb. rhinofacial conidiobolus coronatus infection presenting with nasal enlargement. infection 2008; 36:594–6. https://doi.org/10.1007/s15 010-008-8056-5. 15. cherian lm, varghese l, panchatcharam bs, parmar hv, varghese gm. nasal conidiobolomycosis: a successful treatment option for localized disease. j postgrad med 2015; 61:143–4. https://doi.org/10.4103/0022-3859.153112. 16. mukhopadhyay d, ghosh lm, thammayya a, sanyal m. entomophthoromycosis caused by conidobolus coronatus: clinicomycological study of a case. auris nasus larynx 1995; 22:139–42. https://doi.org/10.1016/s0385-8146(12)80113-1. 17. blumentrath cg, grobusch mp, matsiégui pb, pahlke f, zoleko-manego r, nzenze-aféne s, et al. classification of rhinoentomophthoromycosis into atypical, early, intermediate, and late disease: a proposal. plos negl trop dis 2015; 9:e0003984. https://doi.org/10.1371/journal.pntd.0003984. incidence of the disease, difficulties in confirming the diagnosis and the lack of established treatment strategies. as highlighted by the current case, physicians should bear this fungal infection in mind when encount ering nasal obstructions or a nasal tumour of uncertain aetiology. early identification of the infection is crucial to reduce morbidity. a c k n o w l e d g e m e n t s a preliminary version of this case report was presented at the international meeting on clinical case reports on 18–20 april 2016 in dubai, uae. an abstract of this presentation was subsequently published in the journal of clinical case reports in 2016, volume 6, issue s2, p. 40. references 1. isa-isa r, arenas r, fernández rf, isa m. rhinofacial conidiobolomycosis (entomophthoramycosis). clin dermatol 2012; 30:409–12. https://doi.org/10.1016/j.clindermatol.2011.09.012. 2. el-shabrawi mh, arnaout h, madkour l, kamal nm. entomophthoromycosis: a challenging emerging disease. mycoses 2014; 57:132–7. https:/doi.org/10.1111/myc.12248. 3. gupta m, narang t, kaur rj, manhas a, saikia un, dogra s. a prospective case series evaluating efficacy and safety of combination of itraconazole and potassium iodide in rhinofacial conidio bolomycosis. int j dermatol 2016; 55:208–14. https://doi.org/10.1 111/ijd.12966. 4. bento dp, tavares r, martins mda l, faria n, maduro ap, araújo c, et al. atypical presentation of entomophthoromycosis caused by conidiobolus coronatus. med mycol 2010; 48:1099–104. https://doi.org/10.3109/13693786.2010.497973. 5. youssef nm, shaheen ma, zu-el fakkar n, ghadiry g, el-darouty m, massoud ma, et al. a clinicopathological and mycological study of chronic rhinofacial zygomycosis (rhinoentomophthoromycosis). egypt dermatol online j 2005; 1:4. 6. baghela a, thungapathra m, shivaprakash mr, chakrabarti a. multilocus microsatellite typing for rhizopus oryzae. j med microbiol 2010; 59:1449–55. https://doi.org/10.1099/jmm.0.023002-0. departments of 1child health and 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author e-mails: koul@squ.edu.om and roshankoul@hotmail.com صور الرنني املغناطيسي لدى طفل مصاب بالتهاب املخيخ احلاد رو�سان كول، اأنور حامد حممد العمريي، رنا عبد الرحيم، رجنيث ماين، ديليب �سنكله magnetic resonance imaging abnormalities in a child with acute cerebellitis *roshan koul,1 anwar h. m. al-omairi,1 rana a. rahim,1 renjith mani,1 dilip sankhla2 figure 1a &b: axial fluid-attenuated inversion recovery magnetic resonance images of the brain of a child with acute cerebellitis showing diffuse hyperintense changes in the cerebellar hemispheres and vermis. interesting medical image a three-year-old girl was admitted to the emergency department of the sultan qaboos university hospital, muscat, oman, in august 2014 with a three-day history of an acute unsteady gait. she had had an upper respiratory infection one week prior to admission. there was no history of headaches, vomiting or loss of consciousness, nor a history of similar illnesses in the past or within the patient’s family. on examination, the cranial nerves and optic fundi were normal with no pyramidal signs, nystagmus or opsoclonus. the patient had truncal ataxia, a severe unsteady gait and was not able to walk unsupported. an urgent non-contrast computed tomography scan of the brain revealed a hypoattenuating area involving both cerebellar hemispheres and the vermis, associated with effaced cerebellar and vermis folia. magnetic resonance imaging (mri) of the brain showed hyperintense changes in the cerebellar hemispheres and vermis [figure 1]. the mri showed evidence of mild diffusion restriction in the lesion. there was no significant enhancement of the lesion after the administration of contrast media and no perilesional oedema was noted. baseline blood investigations, tandem mass spectrometry and lactate and ammonia tests were normal. a lumbar puncture revealed 25 lymphocytes/mm3 with normal glucose and protein levels. polymerase chain reaction tests of the cerebrospinal fluid were negative for herpes simplex virus, enteroviruses, varicella zoster virus and mumps. the patient was prescribed 30 mg/kg of methylprednisolone once sultan qaboos university med j, november 2015, vol. 15, iss. 4, pp. e563–564, epub. 23 nov 15 submitted 14 nov 14 revisions req. 15 dec 14 & 4 mar 15; revisions recd. 13 jan & 8 mar 15 accepted 15 mar 15 doi: 10.18295/squmj.2015.15.04.022 magnetic resonance imaging abnormalities in a child with acute cerebellitis e564 | squ medical journal, november 2015, volume 15, issue 4 also been reported following varicella cerebellitis.3 mri findings in acute cerebellitis have been reported in several cases.4 acute cerebellitis is usually a mild condition; affected patients generally recover over time without treatment. however, there are as yet no guidelines for treating severe cases with imaging abnormalities. as demonstrated by the current patient, intravenous methylprednisolone is very useful and potentially life-saving in severe fulminant cases with abnormal imaging. this short course of treatment should be considered after other infections and mass lesions have been excluded from the differential diagnosis. references 1. ryan mm, engle ec. acute ataxia in childhood. j child neurol 2003; 18:309–16. doi: 10.1177/08830738030180050901. 2. levy ei, harris ae, omalu bi, hamilton rl, branstetter bf 4th, pollack if. sudden death from fulminant acute cerebellitis. pediatr neurosurg 2001; 35:24–8. doi: 10.1159/000050381. 3. göhlich-ratmann g, wallot m, baethmann m, schaper j, roggendorf m, roll c, et al. acute cerebellitis with near-fatal cerebellar swelling and benign outcome under conservative treatment with high dose steroids. eur j paediatr neurol 1998; 2:157–62. doi: 10.1016/s1090-3798(98)80032-9. 4. de bruecker y, claus f, demaerel p, ballaux f, sciot r, lagae l, et al. mri findings in acute cerebellitis. eur radiol 2004; 14:1478–83. doi: 10.1007/s00330-004-2247-y. daily for three days followed by 1 mg/kg/day of oral prednisolone for one week which was subsequently tapered over the second week. after treatment, a 10-week follow-up t2-weighted fluid-attenuated inversion recovery mri brain scan showed complete resolution of the cerebellar and vermis hyperintense lesions. the patient showed remarkable improvement with steroids and had totally recovered within a month. comment acute cerebellar ataxia (acute cerebellitis) in children is usually seen following viral infections (particularly of the upper respiratory tract), immunisation, drug intoxication or overdose, cerebrovascular accidents, trauma and immunological diseases.1 rarely, patients with bleeding in a posterior fossa tumour present with acute-onset ataxia.1 post-viral cerebellitis is self-limiting and imaging is not normally required. however, when a child presents with severe cerebellar signs, imaging should be performed to rule out other potential causes of cerebellar dysfunction, particularly a posterior fossa mass lesion. a number of deaths have been reported due to fulminant cerebellitis.2 acute cerebellar swelling has http://dx.doi.org/10.1177/08830738030180050901 http://dx.doi.org/10.1159/000050381 http://dx.doi.org/10.1016/s1090-3798%2898%2980032-9 http://dx.doi.org/10.1007/s00330-004-2247-y behçet’s disease is a chronic inflamm-atory disease diagnosed by recurrent aphthous ulcers, genital ulcers and eye involvement in the form of uveitis.1 cerebrovascular involvement with arterial aneurysm rupture is an exceedingly rare phenomenon in patients with behçet’s disease and is only found in 1.6–10% of all vascular lesions in these patients.2,3 cerebral artery aneurysms, brain parenchymal inflammatory disease, pseudotumour cerebri, intimal hyperplasia of the cerebral artery and vasculitis are the main symptoms of neurobehçet’s disease.4 cardiac involvement leads to inflammatory endocardial disease, coronary artery stenosis, pericarditis, cardiomyopathy and thrombus formation.4 however, the combination of an intracardiac thrombus with rupture of a cerebral artery aneurysm is a very rare occurrence.5 case report a 35-year-old female known to have behçet’s disease was referred to the imam ali hospital, kermanshah, iran, in july 2014 from the neurosurgery ward for evaluation of postoperative dyspnoea. seven days previously, she had undergone a cranial surgery for a ruptured cerebral artery aneurysm and the removal of parenchymal haemorrhagic lesions. upon admission to the neurosurgery ward, an initial diagnosis of a ruptured cerebral artery aneurysm was made based on the parenchymal changes observed on computed tomography [figure 1]. cerebral angiography confirmed haemorrhagic sequelae in the left cerebral artery branch due to the rupture of the aneurysm [figure 2]. seven days after the neurosurgery, the patient complained of vertigo, dysarthria, dyspnoea, fever, 1preventive cardiovascular research centre kermanshah and 2department of neurology, kermanshah university of medical sciences, kermanshah, iran *corresponding author e-mail: r.faraji61@gmail.com جلطة يف البطني األمين ومتدد الشريان الدماغي يف مريضة مبرض هبجت فريدون �سابزي، �سامانه مريزايي، ر�سا فرجي abstract: we report a 35-year-old woman referred to the imam ali hospital, kermanshah, iran, in july 2014 for evaluation of postoperative dyspnoea after neurosurgery performed seven days previously for a ruptured cerebral artery aneurysm. she was known to have behçet’s disease with a history of recurrent oral and genital aphthous ulcers and uveitis. at referral, her symptoms included vertigo, dysarthria, palpitations and chest pain. transthoracic echocardiography (tte) revealed a large thrombus in her right ventricle outflow tract and open-heart surgery was performed eight days after the previous surgery to remove the clot. the postoperative period was complicated by transient acute renal failure, which resolved spontaneously. the patient was discharged 13 days after the cardiac surgery on warfarin, prednisolone, azathioprine and cyclophosphamide. cyclophosphamide and azathioprine were discontinued after three months as the symptoms had completely resolved; however, prednisolone was continued due to recurrent uveitis. a 10-month follow-up tte scan revealed no thrombus recurrence and treatment with warfarin and prednisolone was continued. keywords: behçet disease; thrombus; fusiform aneurysm; case report; iran. امللخ�ص: هذا تقرير حالة لأمراأة تبلغ من العمر 35 عاما مت حتويلها اإىل م�ست�سفى الإمام علي، كرمان�ساه، اإيران، يف يوليو 2014 لتقييم �سيق التنف�س بعد اإجراء جراحة لتمدد �رسياين دماغي منفجر منذ �سبعة اأيام قبل التنومي. كانت املري�سة م�سابة مبر�س بهجت مع تاريخ تلعثم، دوار، من تعاين املري�سة كانت التحويل عند القزحية. والتهاب التنا�سلية والأع�ساء الفم يف املتكررة القالعية للقرح مر�سي وخفقان واأمل يف ال�سدر. ك�سف تخطيط �سدى القلب عرب ال�سدر )tte( عن وجود جلطة كبرية يف تدفق جماري البطني الأمين. مت اإجراء جراحة قلب مفتوح بعد ثمانية اأيام من اجلراحة ال�سابقة. تعقدت فرتة ما بعد اجلراحة بحدوث الف�سل الكلوي احلاد، الذي �سفي من تلقاء نف�سه. غادرت املري�سة بعد 13 يوما من عملية القلب املفتوح على عقاقري الوارفارين، الربيدنيزولون، الآزوثيوبرين وال�سيكلوفو�سفاميد. مت ايقاف عقاري ال�سيكلوفو�سفاميد والآزوثيوبرين بعد ثالثة اأ�سهر نتيجة لأختفاء كل الأعرا�س متاما. ومع ذلك، ا�ستمر عقار الربيدنيزولون بالوارفارين العالج وا�ستمر اجللطات عودة عن �سهور ع�رسة بعد tte ال فح�س اعادة تك�سف مل املتكررة. القزحية التهابات ب�سبب والربيدنيزولون. كلمات مفتاحية: مر�س بهجت؛ جلطة؛ متدد الأوعية الدموية املغزيل؛ تقرير حالة؛ اإيران. right ventricular thrombus and cerebral artery aneurysm in a patient with behçet’s disease feridoun sabzi,1 samaneh mirzaei,2 *reza faraji1 case report sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 250–253, epub. 15 may 16 submitted 28 jun 15 revisions req. 13 aug, 28 sep & 25 nov 15; revisions recd. 31 aug, 3 nov & 13 dec 15 accepted 31 dec 15 doi: 10.18295/squmj.2016.16.02.020 feridoun sabzi, samaneh mirzaei and reza faraji case report | e251 with 91% neutrophils; platelet count: 90,000/mm-3 (nr: 150,000–450,000/mm-3); haemoglobin count: 10 g/dl (nr: 13–18 g/dl); c-reactive protein levels: 54 mg/dl (nr: ≤0.8 mg/dl); erythrocyte sedimentation rate: 80 mm/hour (nr: 0–20 mm/hour); blood urea nitrogen levels: 35 mg/dl (nr: 7–25 mg/dl); and creatinine levels: 2.9 mg/dl (nr: 0.6–1.2 mg/dl). the thrombocytopaenia was treated with prednisolone and her platelet levels had normalised when a repeat platelet count was performed three weeks later. urinalysis revealed proteinuria without haematuria. anti-nuclear, anti-neutrophil cytoplasmic, anti-double strand and anticardiolipin antibodies were negative, as were rheumatoid factor and lupus anticoagulants. test results for other thrombophilia factors were normal, including hyperhomocysteinemia, antiphospholipid antibodies, protein s, protein c and antithrombin iii levels and factor v leiden. transthoracic echocardiography (tte) revealed a mobile thrombus in the right ventricle outflow tract (rvot) of the subtricuspid apparatus [figure 3]; this was believed to have been the cause of the patient’s respiratory symptoms. eight days after the neurosurgery and one day after admission to the cardiac surgery ward, open cardiac surgery was performed to remove the clot. intraoperatively, the thrombus was observed to be located in the rvot with a single site of attachment to the perimembranous septum and septal tricuspid valve [figure 4]. surgical exploration of the pulmonary artery and its main branches revealed no other thrombi. a pulmonary thromboembolism was suspected; however, no facilities for lung perfusion scans were available and the patient could not be transferred to another centre due to her general condition. postoperatively, the patient suffered from acute renal dysfunction and nephrologists were consulted. heart palpitations and chest pain and was referred to the cardiac surgery ward. in the ward, her medical history revealed classic features of behcet’s disease, including four occurrences of mouth and genital ulcers in the previous year and ophthalmologist-confirmed uveitis. a physical examination revealed signs of the former cranial surgery, multiple aphthous mouth and genital ulcers and left haemiparesis. there were no signs of thrombophlebitis or lower limb oedema. chest radiography was normal. the results of laboratory tests on admission were as follows: white blood cell count: 19,000/mm-3 (normal range [nr]: 4,300–10,800/mm-3) figure 1: preoperative computed tomography of a 35-year-old female patient with behçet’s disease showing a haemorrhagic mass in the right cranial hemisphere (arrow) indicative of a ruptured cerebral artery aneurysm. figure 2: postoperative cerebral angiography of a 35-year-old female patient with behçet’s disease with a ruptured cerebral artery aneurysm in the left middle cerebral artery branch (circle), with aneurysm clip in situ (arrow). figure 3: transthoracic echocardiography of a 35-yearold female patient with behçet’s disease showing a large thrombus (arrows) in the right ventricular outflow tract. la = left atrium; ra = right atrium; lv = left ventricle; rv = right ventricle. right ventricular thrombus and cerebral artery aneurysm in a patient with behçet’s disease e252 | squ medical journal, may 2016, volume 16, issue 2 however, the condition resolved spontaneously. a few days later, the patient was treated with immunosuppressive therapy for symptoms of behcet’s disease. symptoms of oral and genital aphthous ulcers and uveitis were relieved using a combination of oral corticosteroids, prednisolone, azathioprine and cyclophosphamide. nine days after the cardiac surgery, she was prescribed anticoagulation therapy (heparin and warfarin) to prevent further thrombus formation. the patient was discharged on the 13th postoperative day on warfarin, prednisolone, azathioprine and cyclophosphamide. after three months of treatment, the cyclophosphamide and azathioprine were discont inued due to resolution of the symptoms. at a 10-month follow-up, the patient’s general condition was satisfactory and tte indicated no thrombus recurrence. however, prednisolone was continued indefinitely due to recurrent eye involvement. warfarin was also continued due to prolonged bedrest caused by haemiparesis which increases the risk of thromboemboli in the extremities. discussion this report presents a patient with behçet’s disease with right ventricle thrombus formation after a previous cerebral artery aneurysm rupture. cardiac involvement in behçet’s disease is very rare and consists mainly of thrombus formation. while any chamber of the heart may be involved in clot formation, the right atrium, with its unique haemodynamic characteristics, is the most commonly affected chamber.5 all of the layers of the heart are involved in the inflammatory process of behçet’s disease.6 endothelial inflammation can cause luminal irregularities and thickening which is revealed as thrombi, loeffler endocarditis and arterial aneurysm formation. thrombi of the superior and inferior vena cava (ivc) may cause superior vena cava syndrome and budd-chiari syndrome. systemic lupus erythematosus (sle) can be associated with cardiac thrombosis and cerebral complications;6 ruling out sle as a diagnosis was therefore necessary in the current case. aneurysms of the large and medium arteries— such as the aorta, pulmonary and peripheral arteries including the femoral, popliteal, brachial and subclavian arteries—can form part of the vascular involvement in behçet’s disease.6 one important medium-sized artery involved in aneurysm formation is the cerebral artery. although vascular inflammatory disease is observed in only 25% of patients with behçet’s disease, it is nonetheless the most important predictive factor of behçet’s disease-related mortality.6 the combination of cerebral and cardiac manifestations of behçet’s disease is a very uncommon phenomenon.7 intracardiac thrombus formation may be caused by cardiac endothelial inflammation or may arise from an extracardiac thrombus that has broken off from the thromboembolism source in a peripheral vein and dislodged into the cardiac chamber. however, emboli that originate from a cardiac chamber are a relatively uncommon occurrence.7 mogulkoç et al. detected 13 cases of pulmonary emboli among 25 subjects with behçet’s disease; in approximately 50% of these cases, thrombosis in the inferior and superior vena cavae and deep lower extremity veins may have been the source of the embolism.5 most emboli in behçet’s disease patients begin in the cardiac chambers.8 in patients without behçet’s disease, deep vein thrombosis in the lower extremities is usually associated with pulmonary emboli, as thrombi formed in the veins in the absence of inflammation can easily break off and travel to the heart and lungs. contrary to conventional thromboemboli, the combination of a pulmonary thromboembolism with lower extremity phlebitis is a rare event in patients with behçet’s disease.8 thrombi formed in inflamed vessels are strongly adherent to the endothelium; therefore, these patients have a low risk of thromboembolism.9,10 houman et al. observed vascular involvement in 43.3% of 113 behçet’s disease cases; of those, 89.8% had deep vein thrombosis.11 involvement of the deep venous system is more common in men than women.10 luo et al. evaluated the clinical features of patients with behçet’s disease and cardiac chamber thrombi; they found that intracardiac thrombus formation frequently occurred in young male patients and usually involved the right cardiac chambers.12 in the present case report, the patient was treated with immunosuppressive and antithrombotic drugs following the surgical removal of the cardiac thrombus. figure 4: intraoperative photograph of a thrombus in the right ventricular outflow tract of the subtricuspid apparatus (arrow) of a 35-year-old female with behçet’s disease. feridoun sabzi, samaneh mirzaei and reza faraji case report | e253 metabolomic evaluation of behcet’s disease with arthritis and seronegative arthritis using synovial fluid. plos one 2015; 10:e0135856. doi: 10.1371/journal.pone.0135856. 4. erkan f, gül a, tasali e. pulmonary manifestations of behçet’s disease. thorax 2001; 56:572–8. doi: 10.1136/thorax.56.7.572. 5. mogulkoç n, burgess mi, bishop pw. intracardiac thrombus in behçet’s disease: a systematic review. chest 2000; 118:479–87. doi: 10.1378/chest.118.2.479. 6. aşker s, aşker m, gürsu o, mercan r, timuçin ob. a behcet’s disease patient with right ventricular thrombus, pulmonary artery aneurysms, and deep vein thrombosis complicating recurrent pulmonary thromboembolism. case rep pulmonol 2013; 2013:492321. doi: 10.1155/2013/492321. 7. franco-macías e, roldán-lora f, martínez-agregado p, cerdáfuertes n, moniche f. neuro-behçet: pons involvement with longitudinal extension to midbrain and hypertrophic olivary degeneration. case rep neurol 2015; 7:148–51. doi: 10.1159/000435804. 8. düzgün n, küçükşahin o, atasoy kç, togay işıkay c, gerede dm, erden a, et al. behçet’s disease and intracardiac thrombosis: a report of three cases. case rep rheumatol 2013; 2013:637015. doi: 10.1155/2013/637015. 9. bouali e, kaabachi w, hamzaoui a, hamzaoui k. interleukin-37 expression is decreased in behçet’s disease and is associated with inflammation. immunol lett 2015; 167:87–94. doi: 10.1016/j.imlet.2015.08.001. 10. joo hj, hong sj, yu cw. transcatheter aortic valve-in-valve implantation for severe bioprosthetic stenosis after bentall operation using a homograft in a patient with behçet’s disease. j heart valve dis 2015; 24:217–19. 11. houman mh, ben ghorbel i, khiari ben salah i, lamloum m, ben ahmed m, miled m. deep vein thrombosis in behçet’s disease. clin exp rheumatol 2001; 19:s48–50. 12. luo l, ge y, liu zy, liu yt, li ts. [a report of eight cases of behcet’s disease with intracardiac thrombus and literatures review]. zhonghua nei ke za zhi 2011; 50:914–17. cyclophosphamide, azathioprine and prednisolone were prescribed. prior to starting treatment with cyclophosphamide and azathioprine, routine baseline assessments were performed, including a complete blood cell count and liver and renal function tests; regular monitoring continued throughout treatment. to prevent urinary toxicity such as haemorrhagic cystitis, patients need to be adequately hydrated and pass urine frequently. as such, patients should be instructed to increase their fluid intake 24 hours before, during and at least 24 hours after receiving cyclophosphamide.12 conclusion in the present case, a large intracardiac thrombus was detected in a patient with behçet’s disease who had previously undergone neurosurgery for a ruptured cerebral artery aneurysm. the patient underwent openheart surgery for the removal of the thrombus before undergoing immune suppression and antithombotic therapy. at a 10-month follow-up, she was healthy with no evidence of further thrombus formation. references 1. mahfoudhi m, turki s. [giant aneurysm of the pulmonary artery revealing behçet syndrome]. pan afr med j 2015; 20:411. doi: 10.11604/pamj.2015.20.411.5941. 2. mahfoudhi m, goucha r. [behçet syndrome associated with iga nephropathy]. pan afr med j 2015; 20:410. doi: 10.11604/ pamj.2015.20.410.5956. 3. ahn jk, kim s, kim j, hwang j, kim kh, cha hs. a comparative http://dx.doi.org/10.1371/journal.pone.0135856 http://dx.doi.org/10.1136/thorax.56.7.572 http://dx.doi.org/10.1378/chest.118.2.479 http://dx.doi.org/10.1155/2013/492321 http://dx.doi.org/10.1159/000435804 http://dx.doi.org/10.1155/2013/637015 http://dx.doi.org/10.1016/j.imlet.2015.08.001 http://dx.doi.org/10.11604/pamj.2015.20.411.5941 http://dx.doi.org/10.11604/pamj.2015.20.410.5956 http://dx.doi.org/10.11604/pamj.2015.20.410.5956 first described in 1839, a ruptured sinus of valsalva aneurysm (rsva) is a rare but well-known clinical condition, with the rupture usually occurring in the right-sided cardiac chamber.1,2 these types of aneurysms are thin-walled sac cular or tubular outpouchings of the aortic sinuses and can be either congenital or acquired.2 echocardiography can accurately identify these lesions and confirm a diagnosis of rsva. cardiac surgical repair is the conventional method of treatment; however, trans-catheter closure has more recently been deemed the optimal choice of treatment.3 this report presents two cases of rsva in which transcatheter closure was used. complete closure of the defect was achieved in the first case. for the second case, which involved a patient with a multifenestrated aneurysmal defect, two devices were used during catheterisation. however, complete closure could not be achieved. case 1 a 45 year-old female with no known medical conditions presented to the emergency department of the royal hospital, muscat, oman, in 2014 with a one-day history of chest pain and shortness of breath. there was no history of fever. her blood pressure was 120/55 mmhg and her heart rate was 85 beats per minute. a clinical examination revealed normal heart sounds, although a continuous murmur was audible over the third left intercostal space. an electrocardiogram and chest x-ray were normal with no features suggestive of a myocardial infarction. her 1department of child health, sultan qaboos university hospital, muscat, oman; departments of 2paediatric cardiology and 3anaesthesia, royal hospital, muscat, oman *corresponding author e-mail: alsineidiksk@hotmail.com إغالق متزق جيب فالسالفا الوعائي املتمدد بطريقة القسطرة التداخلية تقرير حلالتني خلف�ن �ش�مل ال�شنيدي, عبداللة الفرق�ين, م�دان م�دايل, �ش�مل امل�شكري abstract: a ruptured sinus of valsalva aneurysm (rsva) is a rare cardiac anomaly. traditionally, rsvas were repaired surgically; however, percutaneous transcatheter closure is the current treatment of choice. we report two cases of rsva which were closed using this approach. the first case was a 45-year-old female who presented to the royal hospital, muscat, oman, in 2014 with a rsva in the right ventricle. the second case was a 39-year-old male who was admitted to the sultan qaboos university hospital, muscat, in 2015 with a large multifenestrated rsva extending into the right ventricle outflow tract. each patient underwent transcutaneous cardiac catheterisation using three-dimensional echocardiography. both interventions were technically successful; however, the second patient required a subsequent surgery due to the continuing presence of a significant shunt. transcatheter closure of rsvas is an effective alternative to surgical repair, although large multifenestrated rsvas should be repaired surgically to ensure complete closure. keywords: sinus of valsalva; ruptured aneurysm; cardiac catheterization; three-dimensional echocardiography; case report; oman. امللخ�ص:متزق جيب ف�ل�ش�لف� الوع�ئي الدموي املتمدد هو عيب خلقي ن�در يحدث يف القلب, ويف الع�دة يتم اإ�شالح هذا التمزق جراحي� يف احلديثة الطريقة ا�شتخدام مت حل�لتني �رسح التقرير هذا يف نعر�س التداخلية. الق�شطرة بوا�شطة اإغالقه ميكن الراهن الوقت يف ولكن العالج, احل�لة الأوىل هي ملري�شة تبلغ من العمر 45 ع�مً� متت مع�ينته� ب�مل�شت�شفى ال�شلط�ين يف ع�م 2015 ومت ت�شخي�شه� بتمزق يف جيب ف�ل�ش�لف� الوع�ئي الدموي املتمدد يف منطقة البطني الأمين للقلب, اأم� احل�لة الث�نية فهي ملري�س يبلغ من العمر 39 ع�م� مت تقييمه يف م�شت�شفى ج�معة ال�شلط�ن ق�بو�س ووجد لديه متزق كبري يف جيب ف�ل�ش�لف� متمدد وذو فتح�ت متعددة جهة خمرج البطني الأمين, كال احل�لتني خ�شعت� لإجراء ق�شطرة تداخلية لإ�شالح التمزق وذلك مب�ش�ندة تخطيط ال�شدى ثالثي الأبع�د للقلب, ك�نت التدخالت للح�لتني ن�جحة من الن�حية الفنية, اإل اأن املري�س الث�ين تطلب اإجراء عملية جراحية لحقة نتيجة ل�شتمرار تدفق الدم للبطني الأمين نتيجة لوجود عدة فتح�ت �شغرية. اإن اأغالق متزق جيب ف�ل�ش�لف� الوع�ئي املتمدد بطريقة الق�شطرة التداخلية هو بديل فع�ل عن التدخل اجلراحي اإل اأنه يف ح�لت التمزق متعدد الفتح�ت والأكرب حجم� ف�إنه ين�شح ب�أن يع�لج جراحي� ل�شم�ن الإغالق الك�مل ملك�ن التمزق. الكلمات املفتاحية: متزق جيب ف�ل�ش�لف�, متدد ف�ل�ش�لف� الوع�ئي, ق�شطرة قلبية, تخطيط القلب ب�ل�شدى ثالثي الأبع�د, تقرير ح�لة, عم�ن. transcatheter closure of ruptured sinus of valsalva aneurysm report of two cases *khalfan s. al-senaidi,1 abdullah al-farqani,2 madan maddali,3 salim al-maskary2 sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e511–515, epub. 30 nov 16 submitted 7 feb 16 revision req. 21 mar 16; revision recd. 10 may 16 accepted 9 jun 16 doi: 10.18295/squmj.2016.16.04.020 case report transcatheter closure of ruptured sinus of valsalva aneurysm report of two cases e512 | squ medical journal, november 2016, volume 16, issue 4 troponin t levels were within the expected range (<5 pg/ml). transthoracic echocardiography (tte) and transoesophageal echocardiography (toe) revealed a rsva extending from the right sinus into the right ventricle under the septal leaflet of the tricuspid valve. the aneurysm had a windsock appearance, with the aortic end measuring 10 mm and the opening into the right ventricle measuring 6 mm [figure 1a]. she had a trileaflet aortic valve with no regurgitation. no ventricular septal defects, pericardial effusions or intracardiac vegetations were seen. the right and left ventricles were not dilated and demonstrated normal systolic function. after discussion with cardiothoracic surgeons, a transcutaneous cardiac catheterisation intervention was performed. the patient was put under general anaesthesia, with the right femoral artery and vein punctured and a 6f short sheath secured. unfractionated heparin and cefradine were administered intravenously at doses of 100 iu/kg and 1,000 mg, respectively. twoand three-dimensional toe scans confirmed the previous echocardiographic findings and haemodynamic data showed an increased left ventricular end-diastolic pressure of 15 mmhg and a pulmonary to systemic blood flow (qp:qs) ratio of 3:1. an aortic root angiogram clearly delineated the rsva, which was located far away from the right coronary artery with similar measurements to those observed via toe. the rsva was closed using a size 12/10 cocoon duct occluder (aeon world group corp., taguig city, manila, philippines), which was inserted antegradely from the venous side. the rsva was crossed from the aortic side with a 5f cordis™ judkins right jr4 catheter (cordis corp., california, usa) using 0.89 mm x 260 cm of guidewire (terumo interventional systems, terumo medical corp., tokyo, japan). an arteriovenous loop was established after the wire was snared from the left pulmonary artery. a 7f mullins sheath (cook group, bloomington, indiana, usa) was placed into the ascending aorta before the occluder was introduced; the skirt of the device was opened in the ascending aorta under fluoroscopic and toe guidance. the device was pulled as one unit into the rsva and the sheath retracted over the cable to deploy the rest of the device. threedimensional toe and an angiogram confirmed that the device was in a satisfactory position, with minimal flow through the device and no aortic valve regurgitation [figures 1b and c]. the following day, tte confirmed that the device was well-positioned, with total occlusion of the rsva and no aortic or tricuspid valve regurgitation. the patient was discharged and prescribed a six-month course of aspirin (5 mg/kg per day) and a two-month course of clopidogrel (75 mg per day), with close follow-up. case 2 a 39-year-old man was admitted to the sultan qaboos university hospital, muscat, in 2015 with a two-month history of chest pain, shortness of breath and exercise intolerance. clinically, he showed signs of aortic regurgitation, with an early diastolic murmur along the left sternal border. using tte, a rsva extending into the right ventricular outflow tract (rvot) was observed, with a dilated left ventricle. a mitral annulus (5 cm) and mild mitral and aortic valve regurgitation were also noted. the aneurysm had two large fenestrations of 8 mm in diameter each, in addition to multiple smaller defects. the mouth of the main aneurysm was 17 mm in diameter and the right coronary artery was in close proximity to the opening of the aneurysm. the aneurysm protruded into the rvot but did not obstruct it. the patient underwent transcutaneous cardiac catheterisation of the ruptured aneurysm under toe guidance with on-site surgical back-up. a toe scan figure 1: a: two-dimensional transoesophageal echocardiography (toe) in the short axis view showing a right sinus of valsalva aneurysm (rsva) extending into the right ventricle (arrow) of a 45-year-old female patient. b: post-closure three-dimensional toe in the short axis view showing the position of a cardiac catheter device (arrow) across the aneurysm. c: post-closure lateral fluoroscopy showing the satisfactory position of the device (arrow), with no residual shunts or aortic valve regurgitation. rv = right ventricle. khalfan s. al-senaidi, abdullah al-farqani, madan maddali and salim al-maskary online case report | e513 figure 2: a: two-dimensional transoesophageal echocardiography (toe) in the short axis view showing a multifenestrated right sinus of valsalva aneurysm (rsva) into the right ventricular outflow tract (arrow) of a 39-year-old male patient. b: post-closure three-dimensional toe in the short axis view showing the position of two cardiac catheter devices (short arrow) across the aneurysm, with the right ventricular outflow tract wide open. c: post-closure lateral fluoroscopy showing the position of the devices. rvot = right ventricular outflow tract. discussion congenital rsvas account for 0.1–3.5% of congenital heart defects and have a higher incidence in asian versus western populations.3,4 these aneurysms usually rupture into the right side of the heart, producing a left-to-right shunt which has a profound haemodynamic effect.3 drainage sites can be single or multiple, with the right ventricle being the most common.5 previous research has described a wide spectrum of presentations, ranging from an asymptomatic murmur to cardiogenic shock or even sudden cardiac death.5 lillehei et al. reported the first successful repair of rsvas for three patients in 1957.6 traditionally, surgical closure has been the mainstay of treatment for rsvas, with an operative mortality rate of <5% and excellent long-term outcomes.4,7 nevertheless, these patients remain at risk of prolonged hospital stays and postoperative complications such as chest pain and septicaemia, making percutaneous device closure an attractive alternative.4 the transcatheter closure of a rsva was first reported by cullen et al. in 1994 using a rashkind umbrella device.8 advances in cardiac catheterisation technology have resulted in a wide range of devices and coils which can be used to close a rsva.9–15 retrograde and combined minimally invasive surgery hybrid approaches have been described in certain cases.16,17 based on a retrospective review of 257 patients, guo et al. proposed a new system of simple surgical classification for right-sided defects according to rupture site.18 this classification system identifies four types of rupture: type i, a rupture or protrusion into the right atrium; type ii, a rupture or protrusion into the right atrium or right ventricle, near or at the tricuspid annulus; type iii, a rupture or protrusion into the right ventricular outflow tract, under the pulmonary valve; and type iv, other types of ruptures or protusions.18 another system of angiographic classification uses the shape of the left-to-right shunt confirmed the tte findings and showed that the rsva was 3.4 cm with a 17 mm mouth [figure 2a]. the right femoral artery and vein as well as the left femoral artery were accessed using 8f, 10f and 6f sheaths, respectively. the coronary arteries were normal and the qp:qs ratio was 5.2:1, with a pulmonary vascular resistance index of 1.6 wood units. as previously described for the first patient, the fenestrated defect was crossed and an arteriovenous loop established. the first fenestration was closed with a 23/25 mm occlutech® figulla® pfo occluder (occlutech gmbh, jena, germany), inserted antegradely from the venous side. a large shunt in the second fenestration was identified via toe, necessitating the use of a second device; hence, an 18mm amplatzer™ pfo occluder (st. jude medical inc., st. paul, minnesota, usa) was deployed retrogradely from the arterial side. this device was deployed retrogradely in order to close the aneurysm from the rvot towards the left ventricle and to secure the two devices in a more stable position. the right coronary artery was not affected by the devices and both devices were placed in suitable positions [figures 2b and c]. following the intervention, the qp:qs ratio decreased to 2.2:1 and tee revealed mild aortic regurgitation. the patient was discharged the following day, after a tte scan confirmed the position of the devices. however, a mild-to-moderate shunt was present across the aneurysm, with no rvot obstruction. the mild aortic regurgitation persisted. the patient was prescribed 75 mg of aspirin daily for six months and 75 mg of clopidogrel daily for two months. on followup, the patient reported significant improvement in his symptoms. echocardiography confirmed that the two devices were still in a satisfactory position across the aneurysm with no rvot obstruction; however, there was a significant shunt across the other small defects. the patient subsequently underwent successful surgical correction of the aneurysm a few months later. transcatheter closure of ruptured sinus of valsalva aneurysm report of two cases e514 | squ medical journal, november 2016, volume 16, issue 4 jet in order to facilitate the selection of occluders for percutaneous closure.19 the four types of shunt jets identified are: type i, window-like; type ii, aneur ysmal; type iii, tubular; and type iv, other rare conditions.19 with regards to the current cases, the first patient had a type iii shunt jet and the second patient had a type ii shunt jet. the current report describes two patients with rsvas in which a transcatheter approach was used to close the aneurysms. in the first case, the rsva was closed using an occluder made of platinumcoated nitinol wires. this is a self-expanding doubledisk device connected by a joint at the centre of the disks, which are filled with polypropylene fabric to increase thrombogenicity. complete closure of the defect was achieved in this case. the second patient had a complex multifenestrated rsva with two large defects and additional smaller defects. the rsva penetrated into the rvot and required two devices to close the larger defects. initially, the interventionist intended to close the aneurysm at its entry point; however, due to the close proximity of the right coronary ostia to the mouth of the aneurysm, it was decided to close the rsva at the exit point instead. patent foramen ovale occluders were used as they have large retention discs on both sides which are nearly equal in size. as the aneurysm was multifenestrated, the devices were positioned in order to cover as many of the smaller defects as possible. nevertheless, the patient continued to experience a significant shunt through the small defects and was referred for further surgical correction. these two cases demonstrate the two extremes of rsva in terms of complexity. as observed with the second patient, large multifenestrated rsvas should be closed surgically—if closure at the point of entry is not possible—in order to prevent the occurrence of smaller defects. in most cases of rsva, the coronary ostia are quite high and device impingement occurs rarely. ventricular septal defects often coexist with rsvas, especially in patients with significant aortic valve regurgitation.20 thankfully, neither patient in the current report had a ventricular septal defect. conclusion transcatheter closure is a safe and effective treatment option for patients with rsvas. real-time three-dimensional echocardiography allows easy visualisation of the defect and is helpful in guiding deployment of the device. however, surgical repair is recommended for large multifenestrated defects to prevent the development of further small defects after closure. the long-term follow-up of rsva patients is mandatory to ensure complete closure of the aneurysm. references 1. perloff jk. the clinical recognition of congenital heart disease, 5th ed. philadelphia, pennsylvania, usa: saunders, 2003. pp. 457–70. 2. goldberg n, krasnow n. sinus of valsalva aneurysms. clin cardiol 1990; 13:831–6. doi: 10.1002/clc.4960131204. 3. chang cw, chiu sn, wu et, tsai sk, wu mh, wang jk. transcatheter closure of a ruptured sinus of valsalva aneurysm. circ j 2006; 70:1043–7. doi: 10.1253/circj.70.1043. 4. chu sh, hung cr, how ss, chang h, wang ss, tsai ch, et al. ruptured aneurysms of the sinus of valsalva in oriental patients. j thorac cardiovasc surg 1990; 99:288–98. 5. shah rp, ding zp, ng as, quek ss. a ten-year review of ruptured sinus of valsalva: clinico-pathological and echodoppler features. singapore med j 2001; 42:473–6. 6. lillehei cw, stanley p, varco rl. surgical treatment of ruptured aneurysms of the sinus of valsalva. ann surg 1957; 146:459–72. doi: 10.1097/00000658-195709000-00014. 7. van son ja, danielson gk, schaff hv, orszulak ta, edwards wd, seward jb. long-term outcome of surgical repair of ruptured sinus of valsalva aneurysm. circulation 1994; 90:ii20–9. 8. cullen s, somerville j, redington a. transcatheter closure of ruptured aneurysm of the sinus of valsalva. br heart j 1994; 71:479–80. doi: 10.1136/hrt.71.5.479. 9. rao ps, bromberg bi, jureidini sb, fiore ac. transcatheter occlusion of ruptured sinus of valsalva aneurysm: innovative use of available technology. catheter cardiovasc interv 2003; 58:130–4. doi: 10.1002/ccd.10394. 10. tong s, zhong l, liu j, yao q, guo y, shu m, et al. the immediate and follow-up results of transcatheter occlusion of the ruptured sinus of valsalva aneurysm with duct occluder. j invasive cardiol 2014; 26:55–9. 11. kerkar pg, lanjewar cp, mishra n, nyayadhish p, mammen i. transcatheter closure of ruptured sinus of valsalva aneurysm using the amplatzer duct occluder: immediate results and mid-term follow-up. eur heart j 2010; 31:2881–7. doi: 10.1093/ eurheartj/ehq323. 12. bialkowski j, akdeniz c, celebi a. transcatheter closure in two rare cases of left-to-right shunt with cardio-o-fix occluders. cardiol young 2012; 22:96–9. doi: 10.1017/s1047951 111000680. 13. rittger h, gundlach u, koch a. transcatheter closure of ruptured sinus of valsalva aneurysm into the right ventricle with an amplatzer vascular plug ii. catheter cardiovasc interv 2015; 85:166–9. doi: 10.1002/ccd.25382. 14. altekin re, karakas ms, er a, yanikoglu a, ozbek s, yilmaz h. percutaneous closure of ruptured sinus of valsalva aneurysm with amplatzer ductal occluder. acta cardiol 2011; 66:657–60. doi: 10.2143/ac.66.5.2131095. 15. arora r, trehan v, rangasetty um, mukhopadhyay s, thakur ak, kalra gs. transcatheter closure of ruptured sinus of valsalva aneurysm. j interv cardiol 2004; 17:53–8. doi: 10.11 11/j.1540-8183.2004.01714.x. 16. jayaranganath m, subramanian a, manjunath cn. retrograde approach for closure of ruptured sinus of valsalva. j invasive cardiol 2010; 22:343–5. khalfan s. al-senaidi, abdullah al-farqani, madan maddali and salim al-maskary online case report | e515 19. liu s, xu x, chen f, zhao z, zhang y, wang c, et al. angiographic features of ruptured sinus of valsalva aneurysm: new classification. j cardiol 2014; 64:139–44. doi: 10.1016/j. jjcc.2013.12.004. 20. sakakibara s, konno s. congenital aneurysm of the sinus of valsalva associated with ventricular septal defect: anatomical aspects. am heart j 1968; 75:595–603. doi: 10.1016/00028703(68)90320-7. 17. cao x, zhang f, wang l, jing h, li n. transthoracic minimally invasive closure for the treatment of ruptured sinus of valsalva aneurysm: a case report. j cardiothorac surg 2014; 9:27. doi: 10.1186/1749-8090-9-27. 18. guo hw, xiong h, xu jp, wang xq, hu ss. a new and simple classification for sinus of valsalva aneurysms and the corresponding surgical procedure. eur j cardiothorac surg 2013; 43:1188–93. doi: 10.1093/ejcts/ezs673. رنوالزين هل هو دواء حقيقي حمفز القلب واألوعية الدموية أو جاك له مجيع الصفات، ولكنه سيد ال شيء؟ األي�ض ميزين�سكو، كارتيكيان، �سونيل نادر abstract: cardiovascular disease (cvd) is a leading cause of morbidity and mortality worldwide. although the majority of patients with cvd are treated with interventional procedures, a substantial number require medical therapy in terms of both prognosis and symptomatic relief. however, commonly used agents such as β-blockers and calcium channel blockers reduce blood pressure in patients whose resting pressures are often already low. ranolazine is a promising agent that does not have significant effects on blood pressure or heart rate. use of this drug has been documented in various cardiovascular conditions, including ischaemic heart disease, heart failure and arrhythmias. this review article aimed to examine current evidence on the use of ranolazine in various cardiovascular conditions in order to determine whether it is a true pluripotent cardiovascular agent or, on the other hand, a “jack of all trades, master of none.” keywords: drug therapy; cardiovascular agents; ranolazine; cardiovascular diseases; ischemic heart disease. امللخ�ص: تعترب اأمرا�ض القلب واالأوعية الدموية ال�سبب الرئي�سي للمرا�سه والوفيات يف جميع اأنحاء العامل. وعلى الرغم من اأن غالبية املر�سى الذين يعانون من االأمرا�ض القلبية الوعائية يتم التعامل معهم باإجراءات تدخلية، اإال اأن عدًدا كبرًيا منهم يحتاجون اإىل عالج طبي لالأعرا�ض واأي�سا للتنبوؤ مب�سار املر�ض. ومع ذلك، فاإن العوامل امل�ستخدمة ب�سكل �سائع مثل حا�رصات م�ستقبالت بيتا وحا�رصات قنوات الكال�سيوم تقلل من �سغط الدم لدى املر�سى الذين تكون عندهم �سغوط الراحة منخف�سة بالفعل. رانوالزين هو دواء جديد واعد و لي�ض له اأثار كبرية على �سغط الدم اأو معدل �رصبات القلب. وقد مت توثيق ا�ستخدام هذا الدواء يف خمتلف احلاالت القلبية الوعائية، مبا يف ذلك مر�ض نق�ض تروية القلب، وف�سل القلب وعدم انتظام �رصبات القلب. هدفت هذه املقالة املرجعية اإىل فح�ض االأدلة احلالية على ا�ستخدام دواء الرانوالزين يف خمتلف احلاالت القلبية الوعائية من اأجل حتديد ما اإذا كان هذا الدواء متعدد القدرات فعال اأم، من ناحية اأخرى، انه ”جاك له جميع ال�سفات، ولكنه �سيد ال �سيء.“ الكلمات املفتاحية: العالج بالعقاقري؛ رانوالزين؛ عقاقري القلب واالأوعية الدموية؛ اأمرا�ض القلب واالأوعية الدموية؛ مر�ض القلب االإقفاري. ranolazine a true pluripotent cardiovascular drug or jack of all trades, master of none? alice mezincescu,1 v. j. karthikeyan,2 *sunil k. nadar3 review sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e13–23, epub. 4 apr 18 submitted 2 oct 17 revision req. 7 dec 17; revision recd. 18 dec 17 accepted 8 jan 18 1cardiovascular & diabetes research unit, university of aberdeen, aberdeen, uk; 2royal albert edward infirmary, wrightington wigan & leigh nhs foundation trust, wigan, uk; 3department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com doi: 10.18295/squmj.2018.18.01.003 cardiovascular disease (cvd) is a leading cause of mortality worldwide; moreover, according to the british heart foundation, cvd-related morbidity continues to represent a main cause of hospital admission.1 chest pain and stable angina are common manifestations of ischaemic heart disease (ihd), while breathlessness is the main presentation of heart failure.2 other cardiovascular conditions that result in hospital admission and out patient visits include arrhythmias, such as atrial fibrillation (af) or supraventricular tachycardia. certain cardiovascular agents—such as β-blockers, calcium (ca) channel blockers and angiotensin-converting enzyme inhibitors—can be used for both patients with ihd and those with heart failure; however, most of these agents lower blood pressure and heart rate among patients who often have low blood pressure to begin with, thus limiting their use.2 recently, ranolazine has been increasingly prescribed in ihd cases, in part due to the fact that it does not affect blood pressure. mihos et al. recently summarised ongoing clinical trials of ranolazine for various indications worldwide.3 this review article aimed to examine the current role of ranolazine in ihd cases and its potential role in other cardiovascular conditions such as heart failure and af. administration and pharmacokinetics the chemical name of ranolazine is n-(2,6-dimethylphenyl)-2-(4-(2-hydroxy-3-(2-methoxyphenoxy) propyl)piperazin-1-yl) acetamide.4 its molecular formula is c24h33n3o4. ranolazine was initially approved by the usa food and drug administration in 2006 and by the european medicine agency in 2008; it is currently available in the form of oral prolonged-release tablets at doses of 375, 500 and 750 mg, with twice daily administration recommended.3 ranolazine is an ranolazine a true pluripotent cardiovascular drug or jack of all trades, master of none? e14 | squ medical journal, february 2018, volume 18, issue 1 acetanilide and piperazine derivative with a molecular weight of 427.545 g/mol.3 the drug has poor water solubility; after the oral administration of prolongedrelease tablets, peak plasma concentration occurs within 2–6 hours but it can take up to three days to reach a steady state.5 in the human body, approximately 62% of rano lazine is bound to plasma proteins; as such, haemodialysis is not effective in clearing the drug in cases of an overdose.4 ranolazine is eliminated primarily by the metabolism, with less than 5% of the dose excreted unchanged in the urine and faeces. more than 40 and 100 metabolites have been identified in the plasma and urine, respectively, following administration.3 ranolazine is metabolised in the hepatocytes and the intestinal tract, primarily via cytochrome p450 3a (cyp3a) but also by cyp2d6.6 clearance is dosedependent, decreasing with an increase in dose. the half-life of slow-release preparations is 7–9 hours and excretion is 75% renal and 25% intestinal.6 when prescribing ranolazine to patients with mild-to-moderate renal impairment, it is important to remember that the peak serum concentration is increased by 40–50%; therefore, the dose should be adjusted accordingly.5,6 mechanism of action it was initially thought that ranolazine exhibits its anti-anginal effects by selectively inhibiting fatty acid oxidation and improving the efficiency of glucose oxidation.7,8 however, more recent data have invalidated these theories and demonstrated that the anti-anginal effect is mainly due to inhibition of the late inward sodium (na) ion current (ina). 9,10 in the presence of ischaemia, a decrease in mitochondrial adenosine triphosphate production in the myocyte leads to reduced excitation-contraction coupling and impaired ion homeostasis. as a result, there is increased accumulation of intracellular na+ due to disruption in the opening of the ina channel, na + influx through the na/hydrogen pump and the lack of na+ elimination through the na/potassium pump.9,10 the increase in intracellular na+ disrupts the na-ca exchanger, leading to an intracellular ca2+ overload causing impaired relaxation of the myocytes, diastolic dysfunction and impaired coronary blood flow in the diastole, thereby worsening the ischaemia and creating a dangerous feedback loop. ranolazine selectively inhibits the late ina, reducing na+ overload and the subsequent intracytosolic ca2+ accumulation and leading to a reduction in diastolic wall stress and improved coronary blood flow.11,12 in animal studies, ranolazine also exhibited weak β1 and β2 and ca channel antagonist activity.13,14 however, in clinical trials, ranolazine doses had no clinically significant effect on resting heart rate or arterial blood pressure.15 recommendations and guidelines in the european society of cardiology (esc) guide lines on the management of stable angina, ranolazine is given a class iia (level of evidence b) recommendation as a second-line agent for the relief of angina and ischaemia.2 its use is also suggested for patients with low blood pressure and those with microvascular angina. the national institute for health and care excellence guidelines from the uk also recommend the use of ranolazine either as monotherapy or in combination with other agents in stable angina cases where β-blockers and ca channel blockers are either contraindicated or cannot be tolerated.16 the american college of cardiology (acc)/american heart association (aha) guidelines for the management of stable angina give ranolazine a class iia recommendation either as a substitute for β-blockers when β-blockers are either not tolerated or contraindicated (level of evidence b), or in combination with β blockers where the initial use of β-blockers alone has not proven effective (level of evidence a).17 ranolazine is not included in the esc or acc/ aha guidelines for the management of non-st-segment elevation myocardial infarctions (nstemis).18,19 however, the acc/aha guidelines for the management of nstemis mention that ranolazine is indicated in chronic stable angina (csa) and that it can be used to control ischaemia and symptoms in the post-acute phase. neither the acc/aha nor the esc mention ranolazine in their guidelines for the management of heart failure.20–22 although they provide a summary of the existing clinical data regarding ranolazine, the esc guidelines for af management state that there is currently insufficient evidence to recommend the drug either on its own or in combination with an anti-arrhythmic agent.23 similarly, while the esc guidelines for managing ventricular arrhythmias do mention that ranolazine has been used in combination with other anti-arrhythmic agents to suppress drug-resistant ventricular arrhythmias, they also note that it is currently not approved for this indication.24 the acc/aha guidelines on af and supraventricular tachycardias do not mention ranolazine at all.25,26 alice mezincescu, v. j. karthikeyan and sunil k. nadar review | e15 treatment efficacy i s c h a e m i c h e a r t d i s e a s e while ihd is often treated with interventional techniques such as percutaneous coronary intervention (pci) or coronary artery bypass grafting (cabg), such interventions are unsuitable for patients with certain types of coronary anatomy or those who remain symptomatic due to microvascular disease despite adequate revascularisation.2 drugs such as nitrates, β-blockers and ca channel blockers are the mainstay of medical therapy in these patients. however, an important and unfortunate side-effect of most of these agents is hypotension, often leading to the discontinuation of treatment.2 therefore, an anti-anginal agent is needed that is effective, well-tolerated and does not affect blood pressure. multiple randomised placebo-controlled trials have shown that ranolazine is a cost-effective treatment for patients with csa.27 it decreases the frequency of the angina episodes and improves functional capacity whilst having no clinically significant effects on resting heart rate or arterial blood pressure. in the combination assessment of ranolazine in stable angina (carisa) study, a randomised three-group parallel double-blind placebo-controlled trial was perf ormed in which 823 patients with symptomatic chronic angina received either 750 or 1,000 mg of slow-release ranolazine twice daily or a placebo in addition to standard anti-anginal therapy (atenolol, amlodipine and diltiazem) for a period of three months.28 the effects of the therapy were assessed by treadmill testing at two and six weeks at trough levels and two and 12 weeks at peak levels. the study demonstrated that ranolazine significantly increased the patient’s exercise capacity (mean treadmill time increase: 24–34 seconds; p <0.05) and reduced angina attacks and nitroglycerin use by approximately one per week (p <0.02) in comparison to a placebo.28 in the carisa trial and its associated long-term open-label study, the survival rate of patients taking ranolazine was 98.4% at one year and 95.9% at two years.28,29 using a randomised double-blind four-period crossover study design, the monotherapy assessment of ranolazine in stable angina (marisa) study assessed the relationship between ranolazine dose and anti-anginal effects among patients with stable angina.30 after discontinuing their usual angina medications, 191 patients with treadmill-inducible stable angina of more than three months’ duration received either 500, 1,000 or 1,500 mg sustained-release doses of ranolazine or placebo monotherapy twice daily for one week. exercise testing according to a modified bruce protocol was performed at baseline, at the end of each period, at trough levels (12 hours post-dose) and at peak levels (four hours post-dose).30 plasma levels of ranolazine were assessed to determine the dose-response relationship. the study demonstrated a significant increase in exercise duration in a dosedependent fashion among patients treated with ranolazine versus those receiving a placebo (p <0.005).30 both the marisa trial and its open-label follow-up study showed a survival rate of 96.3 ± 1.7% at one year.30,31 within the cohort, 24% were diabetic; an analysis of the efficacy of ranolazine therapy between diabetic and non-diabetic patients showed that a history of diabetes did not have a statistically relevant impact on the anti-anginal effect of ranolazine (p = 0.77).30 moreover, the frequency of adverse reactions and sideeffects was comparable in both subgroups. asthaenia, constipation, dizziness and nausea were the most common side-effects reported in both subgroups.30 the efficacy of ranolazine in chronic angina (erica) study was a multinational double-blind randomised trial comparing the effects of ranolazine to a placebo among 565 patients with csa who had more than three angina attacks per week despite receiving a maximal dose of amlodipine (10 mg/day).32 a total of 281 patients were randomly assigned to the ranolazine group, while the remaining 284 subjects formed the placebo group. the patients received either 1,000 mg of ranolazine twice per day or a placebo for a period of six weeks.32 the primary endpoint was the weekly frequency of angina attacks, with responses to the seattle angina questionnaire (saq) and nitroglycerin consumption levels also used to assess the efficiency of the treatment.33 the erica trial demonstrated that ranolazine was well-tolerated and significantly reduced the frequency of angina attacks compared to a placebo (mean: 2.88 ± 0.19 attacks versus 3.31 ± 0.22 attacks; p = 0.028).32 patients who had more frequent weekly angina attacks at baseline seemed to benefit from more pronounced treatment effects. nitroglycerin use was also reduced in the ranolazine group versus the placebo group (mean: 2.03 ± 0.20 doses versus 2.68 ± 0.22 doses; p = 0.014).24 however, it is worth noting that patients with a corrected qt interval of >500 ms at baseline and those with class iii or iv heart failure, recent unstable angina, acute coronary syndrome (acs) or revascularisation within two months of the study period were excluded from both the erica and marisa trials.30,32 known as the type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina (terisa) study, an international double-blind random ised trial was conducted to evaluate the efficacy of ranolazine versus a placebo among 949 patients with ranolazine a true pluripotent cardiovascular drug or jack of all trades, master of none? e16 | squ medical journal, february 2018, volume 18, issue 1 type 2 diabetes, coronary artery disease and stable angina already receiving one or two other anti-anginal agents.34 initially, all patients were single-blinded and received a placebo during a four-week period. subsequently, the cohort was randomised and received either ranolazine (1,000 mg twice daily) or a placebo in a double-blind fashion for eight weeks.34 the primary outcome of the study was the average number of angina attacks per week during the final six weeks of the study period, with the frequency of angina attacks and the use of nitroglycerin documented daily. the study demonstrated that ranolazine significantly reduced the frequency of angina attacks versus a placebo (3.8 versus 4.3 attacks/week; p = 0.008) and also reduced nitroglycerin use (1.7 versus 2.1 doses/week; p = 0.003).34 the incidence of serious adverse events was similar in both groups. in the terisa trial, the benefits of ranolazine appeared more prominent in patients with high glycated haemoglobin levels.34 the metabolic efficiency with ranolazine for less ischaemia in non-st elevation acute coronary synd rome thrombolysis in myocardial infarction 36 (mer lin-timi 36) trial was a multinational randomised double-blind placebo-controlled parallel group study table 1: clinical trials investigating the anti-anginal and anti-ischaemic effects of ranolazine28,30,32,34,35,37–39 clinical trial n study design and type ranolazine dosage endpoints conclusions carisa28 823 patients with chronic angina randomised, db, pc trial either 750 or 1,000 mg bid • exercise duration according to an ett • time before angina symptoms • time to ecg changes (st-segment depression of 1 mm) • increased exercise duration and time before angina symptoms • reduction in angina frequency and ntg use per week • no difference in mortality marisa30 191 patients with stable angina db, pc crossover study either 500, 1,000 or 1,500 mg bid • exercise duration according to ett • time before angina symptoms • time to ecg changes (st-segment depression of 1 mm) • increased exercise duration and time before angina symptoms • reduction in angina frequency erica32 565 patients with coronary disease randomised, db, pc, multinational trial 1,000 mg as well as 10 mg of amlodipine bid • angina frequency per week • qol • reduction in angina frequency and ntg use per week • improved qol terisa34 949 type 2 diabetics with coronary artery disease and stable angina randomised, db, pc, international trial 1,000 mg bid • average number of angina episodes per week • average ntg use per week • number of angina episode-free days (i.e. ≥50% reduction in angina frequency) • qol • reduction in angina frequency and ntg use per week • more patients achieved a ≥50% reduction in weekly angina frequency • no change in qol merlintimi 3635,37,38 6,560 patients with nstemis randomised, db, pc, multinational trial 200 mg iv infusion over one hour, followed by 80 mg iv infusion over 12–96 hours and 1,000 mg extended-release oral tablets bid* • composite of cv death, mi or recurrent ischaemia • recurrent ischaemia • documented symptomatic arrhythmia • all-cause mortality • no change in composite cv death, mi or recurrent ischaemia • reduction in recurrent ischaemia and symptomatic documented arrhythmias • no change in all-cause mortality river-pci39 2,651 patients with incomplete revascularisation after pci randomised, db, pc, international trial 1,000 mg bid • time to first occurrence of ischaemia-driven revascularisation or ischaemia-driven hospitalisation without revascularisation • no difference in primary endpoint carisa = combination assessment of ranolazine in stable angina; db = double-blind; pc = placebo-controlled; bid = twice daily; ett = exercise tolerance test; ecg = electrocardiography; ntg = nitroglycerin; marisa = monotherapy assessment of ranolazine in stable angina; erica = efficacy of ranolazine in chronic angina; qol = quality of life; terisa = type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina; merlin-timi 36 = metabolic efficiency with ranolazine for less ischaemia in non-st elevation acute coronary syndrome thrombolysis in myocardial infarction 36; nstemi = non-st-segment elevation myocardial infarction; iv = intravenous; cv = cardiovascular; mi = myocardial infarction; river-pci = ranolazine in patients with incomplete revascularisation after pci; pci = percutaneous coronary intervention. *plus standard non-st-elevation acute coronary syndrome therapy. alice mezincescu, v. j. karthikeyan and sunil k. nadar review | e17 analysing the efficacy of ranolazine in the treatment of high-risk acs.35 in total, 6,560 patients with nstemis received either ranolazine (initially intravenous and then an oral preparation) or a placebo; the baseline characteristics of the two groups were well-matched. the study had a primary composite endpoint of cardio vascular death, myocardial infarction (mi) or recurrent ischaemia at 30 days.35 the secondary endpoint was the first occurrence of a major cardiovascular event, in which the mi had to be distinct from the index event. in addition, the patient’s quality of life was assessed four months after treatment using the saq.33,36 patients were followed up at four and eight months and ischaemia was assessed via an exercise tolerance test.35 in the ranolazine group, 21.8% and 23.5% of the ranolazine and placebo groups, respectively, experienced cardiovascular death, mi or recurrent ischaemia (p = 0.11). the secondary endpoint occurred in 18.7% of the ranolazine group versus 19.2% of the placebo group (p = 0.5).35 accordingly, the merlin-timi 36 study demonstrated that ranolazine was not an effective add-on therapy for patients presenting with acs. however, approximately one half of the merlin-timi 36 cohort had angina; a subgroup analysis demonstrated that patients treated with ranolazine could exercise for 32 seconds longer than the placebo group (p = 0.002).37 the saq responses demonstrated a significant decrease in the frequency of angina attacks in the ranolazine group versus the placebo group (p <0.001).33,36 overall, ranolazine had a favourable safety profile.35–38 recently, the ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (river-pci) study evaluated the use of ranolazine in 2,651 patients with incomplete revascularisation following a pci procedure.39 the river-pci study had a composite endpoint of ischaemia-driven revascularisation or hospitalisation without revascularisation. in comparison to a placebo, ranolazine showed no benefit.39 table 1 provides details of the clinical trials investigating the anti-anginal and anti-ischaemic effects of ranolazine.28,30,32,34,35,37–39 h e a r t fa i l u r e in experimental models of heart failure, ranolazine significantly improved left ventricular (lv) performance by the late inhibition of the ina. 40,41 ranolazine has also been shown to significantly reduce lv end diastolic pressure and increase lv ejection fraction in dogs in the absence of any haemodynamic effects.42 in a normal dog model, there was no effect on lv func tion.43 in human subjects with decreased lv function, infusions of ranolazine did not improve lv function but appeared to improve regional diastolic function.44 in an open-label trial during which ranolazine was given to patients with either diastolic or systolic heart failure on top of guideline-driven therapy, there appeared to be an improvement in lv systolic function and autonomic measures; however, clinical parameters were not investigated.45 a prospective single-centre randomised doubleblind placebo-controlled proof-of-concept study termed the ranolazine for the treatment of diastolic heart failure (rali-dhf) study was conducted to determine if ranolazine would be more effective in improving diastolic function among patients with heart failure table 2: in vitro and in vivo studies investigating the effects of ranolazine on atrial arrhythmia models51–54 author and year of study study type study objective conclusions kumar et al.51 (2008) porcine in vivo model investigation of surface ecg and electrophysiological parameters in normal closed-chest anaesthetised pigs following ranolazine administration • ranolazine produced a mild increase in qt intervals and a marked increase in vf thresholds • ranolazine does not augment and may improve ventricular repolarisation dispersion • ranolazine potentially triggers an antiarrhythmic action burashnikov et al.52 (2010) canine in vitro model investigation of the electrophysiological effects of ranolazine and dronedarone in canine-isolated coronary-perfused atrial and ventricular preparations and pulmonary vein preparations • low concentrations of ranolazine or dronedarone alone resulted in weak af suppression • combined ranolazine and dronedarone resulted in a potent synergistic effect causing atrial-selective depression of ina-dependent parameters and effective suppression of af burashnikov et al.53 (2007) canine in vitro model investigation of the electrophysiological effects of ranolazine in canine-isolated coronary-perfused atrial and ventricular preparations • ranolazine blocked ina-dependent parameters in the atrial, but not the ventricular preparations, suppressing and preventing the induction of af sossalla et al.54 (2010) human in vitro model investigation of the electrophysiological effects of ranolazine on isolated human right atrial appendages from patients with either af or normal sinus rhythm • the inhibition of ina with ranolazine had anti-arrhythmic effects and resulted in improved diastolic function ecg = electrocardiography; vf = ventricular fibrillation; af = atrial fibrillation; ina = sodium ion current. ranolazine a true pluripotent cardiovascular drug or jack of all trades, master of none? e18 | squ medical journal, february 2018, volume 18, issue 1 with preserved ejection fraction compared to a placebo.46 however, despite improving haemodynamic parameters, the rali-dhf study found no improve ment in relaxation parameters according to echocardiography findings.46 larger studies with long-term follow-up are required to see whether ranolazine results in clinical benefits for patients with diastolic heart failure. table 3: clinical trials, studies and case series investigating the efficacy of ranolazine in atrial fibrillation35,37,38,55–63 clinical trial/ author and year of study n study design and type ranolazine dosage findings conclusions merlin-timi 3635,37,38,55 6,560 patients with nstemis randomised, db, pc, multinational trial 200 mg iv infusion over one hour, followed by 80 mg iv infusion over 12–96 hours and 1,000 mg extended-release oral tablets bid* • decreased new-onset af (1.7% versus 2.4%; p = 0.08) • lower af burden in patients with paroxysmal af (4.4% versus 16.1%; p = 0.015) • ranolazine resulted in a trend in decreased new-onset af, although the study focused on nstemi ischaemia harmony56 134 patients with paroxysmal af and permanent pacemakers randomised, pc, db, parallel trial 750 mg in combination with either 150 or 225 mg of dronedarone bid • reduced af burden in combination with 225 mg of dronedarone compared to patients receiving a placebo (p = 0.008) • however, af burden was not reduced in combination with 250 mg of dronedarone compared to patients receiving a placebo (p = 0.072) • ranolazine has a synergistic effect with dronedarone and this combination can be used to reduce the af burden in patients with paroxysmal af koskinas et al.57 (2014) 121 patients with recentonset af undergoing ec prospective, sb, randomised study 1,500 mg in combination with iv amiodarone or iv amiodarone alone prior to ec • conversion within 24 hours (87% versus 70%; p = 0.024) and 12 hours (52% versus 32%; p = 0.021) was achieved more frequently compared to patients receiving amiodarone alone • time to conversion was significantly shorter (10.2 ± 3.3 hours versus 13.3 ± 4.1 hours; p = 0.001) • the addition of ranolazine to amiodarone significantly improved the success rate of ec miles et al.58 (2011) 393 cabg patients retrospective cohort study 1.5 g preoperatively and then 1 g bid for 10–14 days • decreased af occurrence compared to patients receiving amiodarone (17.5% versus 26.5%; p = 0.035) • ranolazine was more useful than amiodarone in preventing postoperative af in patients undergoing cabg raffaello59 241 patients with persistent af prospective, multicentre, randomised, db, pc parallel trial 375, 500 or 750 mg • af recurrence occurred in 56.9% of patients taking 375 mg, 41.7% of patients taking 500 mg and 39.7% taking 750 mg of ranolazine compared to 56.4% of patients receiving a placebo • no specific dose of ranolazine significantly reduced the time to af recurrence • however, higher doses of ranolazine reduced af recurrence murdock et al.60 (2009) 18 patients with paroxysmal af off-label uc study single 2,000 mg dose using a ‘pill in the pocket’ approach • following treatment at the time of af onset, 72% of patients reverted to normal sinus rhythm • ranolazine can be useful in converting paroxysmal af to normal sinus rhythm murdock et al.61 (2012) 25 ecresistant patients uc case series 2,000 mg prior to cardioversion • normal sinus rhythm was successfully maintained in 76% of patients • ranolazine can be useful in the pretreatment of patients undergoing ec fragakis et al.62 (2012) 51 patients with af undergoing ec prospective randomised pilot study 1,500 mg in combination with iv amiodarone or iv amiodarone alone prior to ec • conversion was achieved more frequently compared to patients receiving amiodarone alone (88% versus 65%; p = 0.056) • the combination of ranolazine and amiodarone can improve the rate of cardioversion tagarakis et al.63 (2013) 102 patients scheduled for cabg prospective, randomised, sb, singlecentre trial 375 mg bid for three days prior to cabg until discharge • reduced postoperative af incidence compared to patients receiving a placebo (8.8% versus 30.8%; p <0.001) • ranolazine is useful in preventing postoperative af in patients undergoing cabg merlin-timi 36 = metabolic efficiency with ranolazine for less ischaemia in non-st elevation acute coronary syndrome thrombolysis in myocardial infarction 36; nstemi = non-st-segment elevation myocardial infarction; db = double-blind; pc = placebo-controlled; iv = intravenous; bid = twice daily; af = atrial fibrillation; harmony = study to evaluate the effect of ranolazine and dronedarone when given alone and in combination in patients with paroxysmal atrial fibrillation; ec = electrical cardioversion; sb = single-blind; cabg = coronary artery bypass grafting ; raffaello = ranolazine in atrial fibrillation following an electrical cardioversion; uc = uncontrolled. *plus standard non-st-elevation acute coronary syndrome therapy. alice mezincescu, v. j. karthikeyan and sunil k. nadar review | e19 a r r h y t h m i a s atrial arrhythmias the anti-atrial arrhythmic properties of ranolazine have been demonstrated in both animal and human experiments.9,10 the threshold for potential atrial firing is lowered by enhanced ina in atrial myocytes, leading to increased excitability and atrial arrhythmias. rano lazine inhibits various ca2+ channels that block both peak and late ina, thereby affecting the automaticity and excitability of the myocardium.47,48 it is beyond the scope of this review article to go into the details of the possible mechanism of action of ranolazine in arrhythmias; however, several excellent reviews on this topic are available in the literature.49,50 table 2 summarises several experimental studies investigating the effects of ranolazine on myocardial electrophysiology.51–54 clinically, the results of ranolazine among patients with af are limited. a subgroup analysis of the merlin-timi 36 study found that patients treated with ranolazine had fewer episodes of newonset af versus patients in the placebo group; however, these findings were not significant (1.7% versus 2.4%; p = 0.08).38 further analysis of the data showed that, among patients with paroxysmal af, the overall burden was significantly lower with ranolazine than with a placebo (4.4% versus 16.1%; p = 0.015).55 similarly, over a one-year period, patients treated with ranolazine had fewer af events compared to those receiving a placebo (2.9 versus 4.1 events; p = 0.01). however, this trial was designed to focus on clinical endpoints in nstemi management rather than af; therefore, def initive conclusions on this topic cannot be drawn.55 it could be that the lower rate of ischaemic events resulted in the lower af burden. the study to evaluate the effect of ranolazine and dronedarone when given alone and in combination in patients with paroxysmal atrial fibrillation (harmony) trial compared the efficacy of either ranolazine or dronedarone alone or combined in reducing the af burden among 134 patients with paroxysmal af and permanent pacemakers.56 the harmony trial found that a combination of both drugs significantly reduced the af burden as compared to a placebo (p = 0.008), whilst either agent on its own was unsuccessful (p ≥0.49). ranolazine has also been shown to result in a higher conversion rate of af to normal sinus rhythm when used in combination with amiodarone in comparison to amiodarone alone.57 ranolazine has also been shown to reduce the incidence of postoperative af in patients undergoing cabg as compared to those receiving a placebo or amiodarone.58 the ranolazine in atrial fibrillation following an electrical cardioversion (raffaello) trial demonstrated a decreased recurrence rate in 241 successfully cardioverted patients with persistent af at high doses of ranolazine.59 however, there was no significant reduction in the time to recurrence in the raffaello trial. the ‘pill in the pocket’ approach—involving the administration of a single dose of oral ranolazine at the time of onset of the af—has been attempted in a small number of patients, with a success rate of approximately 72%.60 various clinical trials, studies and case series involving ranolazine as a treatment for af are detailed in table 3.35,37,38,55–63 ventricular arrhythmias some experimental evidence exists to suggest the benefit of ranolazine in treating ventricular arrhythmias.47,51,64 however, in the clinical setting, data are limited. in patients with ventricular arrhythmias, rano lazine has been shown to significantly shorten qtc intervals and reduce the burden of ventricular tachy cardia (vt) and the number of shocks required for patients with implantable cardioverter defibrillators.65,66 it has also been shown to reduce the qtc in patients with congenital long-qt syndrome.67 in the merlin timi 36 trial, intravenous ranolazine also significantly reduced the frequency of vt lasting eight or more beats over a 24-hour period as compared to a placebo.38 in the ranolazine implantable cardioverterdefibrillator (raid) trial, 1,012 patients with an implantable cardioverter defibrillator were randomised to receive either ranolazine or a placebo.68 although there was no difference in terms of the frequency of the composite endpoint of vt, ventricular fibrillation or death, patients receiving ranolazine experienced a significant reduction in vt events requiring antitachycardia pacing.68 the various clinical trials and studies investigating the use of ranolazine in ventricular arrhythmias are summarised in table 4.38,65,66,68 side-effects and tolerability ranolazine is contraindicated in patients with severe renal impairment (creatinine clearance of <30 ml/ minute).4,5 given the three-fold increased risk of qt prolongation, ranolazine is also contraindicated in patients with hepatic impairment.4 furthermore, patients taking strong cyp3a inhibitors (i.e. clarithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, hiv protease inhibitors, telithromycin or nefazodone) or cyp3a4 inducers (i.e. rifampicin, phenytoin, phenobarbital, carbamazepine or st. john’s wort) should not be prescribed ranolazine.69 if ranoranolazine a true pluripotent cardiovascular drug or jack of all trades, master of none? e20 | squ medical journal, february 2018, volume 18, issue 1 lazine is concomitantly administrated with moderate cyp3a inhibitors (e.g. diltiazem, macrolide antibiotics or fluconazole) or p-glycoprotein inhibitors (e.g. verapamil or cyclosporin), the dose should be carefully titrated up to a maximum of 500 mg twice daily.4 grapefruit products also have a moderate cyp3ainhibiting effect and should therefore be avoided.4 data derived from a phase iii clinical trial and the marisa, erica and terisa studies suggest that patients over 75 years old seem to have a higher incidence of ranolazine-related adverse events.29,30,32,34 these trials also indicate that ranolazine-associated side-effects are more frequent at higher dosages. the main treatment-related adverse events observed were dizziness, headaches, nausea, vomiting, blurred vision, visual disturbance, diplopia, hypotension, fatigue, peri pheral oedema and acute renal failure; however, such side-effects were rare.29,30,32,34 cost-effectiveness several studies have analysed the cost-effectiveness of ranolazine.70–72 in a systematic review of the existing evidence, vellopoulou et al. found that ranolazine, when added to a standard of care, appeared to be cost-effective primarily due to its ability to decrease angina-related hospitalisation and marginally improve quality of life.73 conclusion ranolazine appears to be a fairly versatile cardiovascular agent with other potential indications beyond that of angina control, which was its original purpose. it is a well-tolerated drug and can be used in patients with low blood pressure for whom β-blockers and ca channel blockers are not advised. due to its mechanism of action, ranolazine may also have a promising role in the management of heart failure and arrhythmias, particularly af. its role in ventricular arrhythmias is also very promising, although the drug is not yet included in the international management guidelines for this condition. references 1. townsend n, wilson l, bhatnagar p, wickramasinghe k, rayner m, nichols m. cardiovascular disease in europe: epidemiological update 2016. eur heart j 2016; 37:3232–45. doi: 10.1093/eurheartj/ ehw334. table 4: clinical trials and studies investigating the efficacy of ranolazine in ventricular arrhythmias38,65,66,68 clinical trial/author and year of study n study design and type ranolazine dosage findings conclusions merlintimi 3638 6,560 patients with nstemis randomised, db, pc, multinational trial 200 mg iv infusion over one hour, followed by 80 mg iv infusion over 12–96 hours and 1,000 mg extended-release oral tablets bid* • reduced incidence of vt lasting ≥8 beats compared to patients receiving a placebo (5.3% versus 8.3%; p <0.001) • ranolazine can reduce ventricular arrhythmias in the setting of nstemi moss et al.65 (2008) 5 patients with congenital lqts cohort study 45 mg/hour iv infusion for three hours followed by 90 mg/hour for five hours • digital 24-hour holter recordings indicated that qtc was shortened in comparison to baseline parameters by 26 ± 3 minutes (p <0.0001) • ranolazine can shorten qtc duration in patients with congenital lqts bunch et al.66 (2011) 12 patients with drugresistant vt and recurrent icd shocks prospective cohort study 1,000 mg bid in combination with other antiarrhythmic agents • there was a reduction in icd shocks and vt burden in comparison to baseline data in 92% of patients • ranolazine can reduce the vt burden in patients with drugresistant vt raid68 1,012 patients with icds randomised, db, pc trial 1,000 mg bid • there was no difference in the combined frequency of vt, vf or death • however, there was a reduction in vt events requiring antitachycardia pacing • ranolazine can reduce vt events in patients with an icd merlin-timi 36 = metabolic efficiency with ranolazine for less ischaemia in non-st elevation acute coronary syndrome thrombolysis in myocardial infarction 36; nstemi = non-st-segment elevation myocardial infarction; db = double-blind; pc = placebo-controlled; iv = intravenous; bid = twice daily; vt = ventricular tachycardia; lqts = long-qt syndrome; icd = implantable cardioverter defibrillator; raid = ranolazine implantable cardioverter-defibrillator; vf = ventricular fibrillation. *plus standard non-st-elevation acute coronary syndrome therapy. https://doi.org/10.1093/eurheartj/ehw334 https://doi.org/10.1093/eurheartj/ehw334 alice mezincescu, v. j. karthikeyan and sunil k. nadar review | e21 2. montalescot g, sechtem u, achenbach s, andreotti f, arden c, budaj a, et al. 2013 esc guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the european society of cardiology. eur heart j 2013; 34:2949–3003. doi: 10.1093/eurhea rtj/eht296. 3. mihos cg, krishna rk, kherada n, larrauri-reyes m, tolentino a, santana o. the use of ranolazine in non-anginal cardiovascular disorders: a review of current data and ongoing randomized clinical trials. pharmacol res 2016; 103:49–55. doi: 10.1016/j.phrs.2015.10.018. 4. european medicines agency. ranexa (previously latixa): ranolazine. from: www.ema.europa.eu/ema/index.jsp?curl= pages/medicines/human/medicines/000805/human_med_001009. jsp&mid=wc0b01ac058001d124 accessed: dec 2017. 5. jerling m, abdallah h. effect of renal impairment on multipledose pharmacokinetics of extended-release ranolazine. clin pharmacol ther 2005; 78:288–97. doi 10.1016/j.clpt.2005.05.004. 6. jerling m. clinical pharmacokinetics of ranolazine. clin pharma cokinet 2006; 45:469–91. doi: 10.2165/00003088-200645050-00003. 7. mccormack jg, barr rl, wolff aa, lopaschuk gd. ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. circulation 1996; 93:135–42. doi: 10.1161/01.cir.93.1.135. 8. mccormack jg, baracos ve, barr r, lopaschuk gd. effects of ranolazine on oxidative substrate preference in epitrochlearis muscle. j appl physiol (1985) 1996; 81:905–10. doi: 10.11 52/jappl.1996.81.2.905. 9. antzelevitch c, belardinelli l, zygmunt ac, burashnikov a, di diego jm, fish jm, et al. electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. circulation 2004; 110:904–10. doi: 10.1161/01.cir.00 00139333.83620.5d. 10. antzelevitch c, belardinelli l, wu l, fraser h, zygmunt ac, burashnikov a, et al. electrophysiologic properties and anti arrhythmic actions of a novel antianginal agent. j cardiovasc pharmacol ther 2004; 9:s65–83. doi: 10.1177/107424840400900106. 11. bers dm, barry wh, despa s. intracellular na+ regulation in cardiac myocytes. cardiovasc res 2003; 57:897–912. doi: 10.10 16/s0008-6363(02)00656-9. 12. murphy e, cross h, steenbergen c. sodium regulation during ischemia versus reperfusion and its role in injury. circ res 1999; 84:1469–70. doi: 10.1161/01.res.84.12.1469. 13. allen tj, chapman ra. effects of ranolazine on l-type calcium channel currents in guinea-pig single ventricular myocytes. br j pharmacol 1996; 118:249–54. doi: 10.1111/j.1476-5381.1996. tb15395.x. 14. létienne r, vié b, puech a, vieu s, le grand b, john gw. evidence that ranolazine behaves as a weak beta1and beta2 adrenoceptor antagonist in the rat [correction of cat] cardiovascular system. naunyn schmiedebergs arch pharmacol 2001; 363:464–71. doi: 10.1007/s002100000378. 15. chaitman br. ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. circulation 2006; 113:2462–72. doi: 10.1161/ circulationaha.105.597500. 16. national institute for health and care excellence. clinical guideline no. cg126: stable angina management. from: www. nice.org.uk/guidance/cg126 accessed: dec 2017. 17. fihn sd, gardin jm, abrams j, berra k, blankenship jc, dallas ap, et al. 2012 accf/aha/acp/aats/pcna/scai/ sts guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the american college of cardiology foundation/american heart association task force on practice guidelines, and the american college of physicians, american association for thoracic surgery, preventive cardiovascular nurses association, society for cardiovascular angiography and interventions, and society of thoracic surgeons. circulation 2012; 126:e354–471. doi: 10.1161/ cir.0b013e318277d6a0. 18. roffi m, patrono c, collet jp, mueller c, valgimigli m, andreotti f, et al. 2015 esc guidelines for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation of the european society of cardiology (esc). eur heart j 2016; 37:267–315. doi: 10.1093/ eurheartj/ehv320. 19. amsterdam ea, wenger nk, brindis rg, casey de jr, ganiats tg, holmes dr jr, et al. 2014 aha/acc guideline for the management of patients with non-st-elevation acute coronary syndromes: a report of the american college of cardiology/american heart association task force on practice guidelines. j am coll cardiol 2014; 64:e139–228. doi: 10.1016/j. jacc.2014.09.017. 20. yancy cw, jessup m, bozkurt b, butler j, casey de jr, drazner mh, et al. 2013 accf/aha guideline for the management of heart failure: a report of the american college of cardiology foundation/american heart association task force on practice guidelines. j am coll cardiol 2013; 62:e147–239. doi: 10.1016/j.jacc.2013.05.019. 21. yancy cw, jessup m, bozkurt b, butler j, casey de jr, colvin mm, et al. 2017 acc/aha/hfsa focused update of the 2013 accf/aha guideline for the management of heart failure: a report of the american college of cardiology/ american heart association task force on clinical practice guidelines and the heart failure society of america. j am coll cardiol 2017; 70:776–803. doi: 10.1016/j.jacc.2017.04.025. 22. ponikowski p, voors aa, anker sd, bueno h, cleland jg, coats aj, et al. 2016 esc guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (esc) developed with the special contribution of the heart failure association (hfa) of the esc. eur heart j 2016; 37:2129–200. doi: 10.1093/eurheartj/ ehw128. 23. kirchhof p, benussi s, kotecha d, ahlsson a, atar d, casadei b, et al. 2016 esc guidelines for the management of atrial fibrillation developed in collaboration with eacts. eur heart j 2016; 37:2893–962. doi: 10.1093/eurheartj/ehw210. 24. priori sg, blomström-lundqvist c. 2015 european society of cardiology guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs. eur heart j 2015; 36:2757–9. doi: 10.1093/eurheartj/ehv445. 25. january ct, wann ls, alpert js, calkins h, cigarroa je, cleveland jc jr, et al. 2014 aha/acc/hrs guideline for the management of patients with atrial fibrillation: a report of the american college of cardiology/american heart association task force on practice guidelines and the heart rhythm society. j am coll cardiol 2014; 64:e1–76. doi: 10.1016/j.jacc.2014.03.022. 26. page rl, joglar ja, caldwell ma, calkins h, conti jb, deal bj, et al. 2015 acc/aha/hrs guideline for the management of adult patients with supraventricular tachycardia: a report of the american college of cardiology/american heart association task force on clinical practice guidelines and the heart rhythm society. j am coll cardiol 2016; 67:e27–115. doi: 10.1016/j. jacc.2015.08.856. 27. vellopoulou k, kourlaba g, maniadakis n, vardas p. a literature review to evaluate the economic value of ranolazine for the symptomatic treatment of chronic angina pectoris. int j cardiol 2016; 211:105–11. doi: 10.1016/j.ijcard.2016.02.140. 28. chaitman br, pepine cj, parker jo, skopal j, chumakova g, kuch j, et al. effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. jama 2004; 291:309–16. doi: 10.1001/jama.291.3.309. 29. koren mj, crager mr, sweeney m. long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the ranolazine open label experience (role). j am coll cardiol 2007; 49:1027–34. doi: 10.1016/j.jacc.2006.10.067. https://doi.org/10.1093/eurheartj/eht296 https://doi.org/10.1093/eurheartj/eht296 https://doi.org/10.1016/j.phrs.2015.10.018 https://doi.org/10.1016/j.clpt.2005.05.004 https://doi.org/10.2165/00003088-200645050-00003 https://doi.org/10.1161/01.cir.93.1.135 https://doi.org/10.1152/jappl.1996.81.2.905 https://doi.org/10.1152/jappl.1996.81.2.905 https://doi.org/10.1161/01.cir.0000139333.83620.5d https://doi.org/10.1161/01.cir.0000139333.83620.5d https://doi.org/10.1177/107424840400900106 https://doi.org/10.1016/s0008-6363%2802%2900656-9 https://doi.org/10.1016/s0008-6363%2802%2900656-9 https://doi.org/10.1161/01.res.84.12.1469 https://doi.org/10.1111/j.1476-5381.1996.tb15395.x https://doi.org/10.1111/j.1476-5381.1996.tb15395.x https://doi.org/10.1007/s002100000378 https://doi.org/10.1161/circulationaha.105.597500 https://doi.org/10.1161/circulationaha.105.597500 https://doi.org/10.1161/cir.0b013e318277d6a0 https://doi.org/10.1161/cir.0b013e318277d6a0 https://doi.org/10.1093/eurheartj/ehv320 https://doi.org/10.1093/eurheartj/ehv320 https://doi.org/10.1016/j.jacc.2014.09.017 https://doi.org/10.1016/j.jacc.2014.09.017 https://doi.org/10.1016/j.jacc.2013.05.019 https://doi.org/10.1016/j.jacc.2017.04.025 https://doi.org/10.1093/eurheartj/ehw128 https://doi.org/10.1093/eurheartj/ehw128 https://doi.org/10.1093/eurheartj/ehw210 https://doi.org/10.1093/eurheartj/ehv445 https://doi.org/10.1016/j.jacc.2014.03.022 https://doi.org/10.1016/j.jacc.2015.08.856 https://doi.org/10.1016/j.jacc.2015.08.856 https://doi.org/10.1016/j.ijcard.2016.02.140 https://doi.org/10.1001/jama.291.3.309 https://doi.org/10.1016/j.jacc.2006.10.067 ranolazine a true pluripotent cardiovascular drug or jack of all trades, master of none? e22 | squ medical journal, february 2018, volume 18, issue 1 30. chaitman br, skettino sl, parker jo, hanley p, meluzin j, kuch j, et al. anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. j am coll cardiol 2004; 43:1375–82. doi: 10.1016/j.jacc. 2003.11.045. 31. milne hc, vallerand ah. chronic angina and the treatment with ranolazine: facts and recommendations. prog cardiovasc nurs 2009; 24:90–5. doi: 10.1111/j.1751-7117.2009.00041.x. 32. stone ph, gratsiansky na, blokhin a, huang iz, meng l. antianginal efficacy of ranolazine when added to treatment with amlodipine: the erica (efficacy of ranolazine in chronic angina) trial. j am coll cardiol 2006; 48:566–75. doi: 10.1016/j. jacc.2006.05.044. 33. spertus ja, winder ja, dewhurst ta, deyo ra, prodzinski j, mcdonell m, et al. development and evaluation of the seattle angina questionnaire: a new functional status measure for coronary artery disease. j am coll cardiol 1995; 25:333–41. 34. kosiborod m, arnold sv, spertus ja, mcguire dk, li y, yue p, et al. evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the terisa randomized clinical trial (type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina). j am coll cardiol 2013; 61:2038–45. doi: 10.1016/j.jacc.2013.02.011. 35. morrow da, scirica bm, karwatowska-prokopczuk e, murphy sa, budaj a, varshavsky s, et al. effects of ranolazine on recurrent cardiovascular events in patients with non-st-elevation acute coronary syndromes: the merlin-timi 36 randomized trial. jama 2007; 297:1775–83. doi: 10.1001/jama.297.16.1775. 36. arnold sv, morrow da, wang k, lei y, mahoney em, scirica bm, et al. effects of ranolazine on disease-specific health status and quality of life among patients with acute coronary syndromes: results from the merlin-timi 36 randomized trial. circ cardiovasc qual outcomes 2008; 1:107–15. doi: 10.11 61/circoutcomes.108.798009. 37. wilson sr, scirica bm, braunwald e, murphy sa, karwatowska-prokopczuk e, buros jl, et al. efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled merlintimi (metabolic efficiency with ranolazine for less ischemia in non-st-segment elevation acute coronary syndromes) 36 trial. j am coll cardiol 2009; 53:1510–16. doi: 10.1016/j. jacc.2009.01.037. 38. scirica bm, morrow da, hod h, murphy sa, belardinelli l, hedgepeth cm, et al. effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non st-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non st-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (merlin-timi 36) randomized controlled trial. circulation 2007; 116:1647–52. doi: 10.1161/circulationaha.107.724880. 39. weisz g, généreux p, iñiguez a, zurakowski a, shechter m, alexander kp, et al. ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (river-pci): a multicentre, randomised, double-blind, placebo controlled trial. lancet 2016; 387:136–45. doi: 10.1016/s01406736(15)00459-6. 40. doshi d, morrow jp. potential application of late sodium current blockade in the treatment of heart failure and atrial fibrillation. rev cardiovasc med 2009; 10:s46–52. 41. doshi d, marx so. ion channels, transporters, and pumps as targets for heart failure therapy. j cardiovasc pharmacol 2009; 54:273–8. doi: 10.1097/fjc.0b013e3181a1b9c7. 42. chandler mp, stanley wc, morita h, suzuki g, roth ba, blackburn b, et al. short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. circ res 2002; 91:278–80. doi: 10.1161/01.res.0000031 151.21145.59. 43. sabbah hn, chandler mp, mishima t, suzuki g, chaudhry p, nass o, et al. ranolazine, a partial fatty acid oxidation (pfox) inhibitor, improves left ventricular function in dogs with chronic heart failure. j card fail 2002; 8:416–22. doi: 10.1054/ jcaf.2002.129232. 44. hayashida w, van eyll c, rousseau mf, pouleur h. effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. cardiovasc drugs ther 1994; 8:741–7. doi: 10.1007/bf00877121. 45. murray gl, colombo j. ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure. heart int 2014; 9:66–73. doi: 10.5301/heartint.5000219. 46. maier ls, layug b, karwatowska-prokopczuk e, belardinelli l, lee s, sander j, et al. ranolazine for the treatment of diastolic heart failure in patients with preserved ejection fraction: the rali-dhf proof-of-concept study. jacc heart fail 2013; 1:115–22. doi: 10.1016/j.jchf.2012.12.002. 47. song y, shryock jc, wu l, belardinelli l. antagonism by ranolazine of the pro-arrhythmic effects of increasing late ina in guinea pig ventricular myocytes. j cardiovasc pharmacol 2004; 44:192–9. 48. wu l, shryock jc, song y, li y, antzelevitch c, belardinelli l. antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-qt syndrome. j pharmacol exp ther 2004; 310:599–605. doi: 10.1124/jpet.104.066100. 49. saad m, mahmoud a, elgendy iy, richard conti c. ranolazine in cardiac arrhythmia. clin cardiol 2016; 39:170–8. doi: 10.1002/ clc.22476. 50. sossalla s, maier ls. role of ranolazine in angina, heart failure, arrhythmias, and diabetes. pharmacol ther 2012; 133:311–23. doi: 10.1016/j.pharmthera.2011.11.003. 51. kumar k, nearing bd, bartoli cr, kwaku kf, belardinelli l, verrier rl. effect of ranolazine on ventricular vulnerability and defibrillation threshold in the intact porcine heart. j cardiovasc electrophysiol 2008; 19:1073–9. doi: 10.1111/j.1540-8167.2008.01204.x. 52. burashnikov a, sicouri s, di diego jm, belardinelli l, antzelevitch c. synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation. j am coll cardiol 2010; 56:1216–24. doi: 10.1016/j.jacc.2010.08.600. 53. burashnikov a, di diego jm, zygmunt ac, belardinelli l, antzelevitch c. atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. circulation 2007; 116:1449–57. doi: 10.1161/ circulationaha.107.704890. 54. sossalla s, kallmeyer b, wagner s, mazur m, maurer u, toischer k, et al. altered na(+) currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium. j am coll cardiol 2010; 55:2330–42. doi: 10.1016/j.jacc.2009.12.055. 55. scirica bm, belardinelli l, chaitman br, waks jw, volo s, karwatowska-prokopczuk e, et al. effect of ranolazine on atrial fibrillation in patients with non-st elevation acute coronary syndromes: observations from the merlin-timi 36 trial. europace 2015; 17:32–7. doi: 10.1093/europace/euu217. 56. reiffel ja, camm aj, belardinelli l, zeng d, karwatowskaprokopczuk e, olmsted a, et al. the harmony trial: combined ranolazine and dronedarone in the management of paroxysmal atrial fibrillation mechanistic and therapeutic synergism. circ arrhythm electrophysiol 2015; 8:1048–56. doi: 10.1161/circep.115.002856. 57. koskinas kc, fragakis n, katritsis d, skeberis v, vassilikos v. ranolazine enhances the efficacy of amiodarone for conversion of recent-onset atrial fibrillation. europace 2014; 16:973–9. doi: 10.1093/europace/eut407. https://doi.org/10.1016/j.jacc.2003.11.045 https://doi.org/10.1016/j.jacc.2003.11.045 https://doi.org/10.1111/j.1751-7117.2009.00041.x https://doi.org/10.1016/j.jacc.2006.05.044 https://doi.org/10.1016/j.jacc.2006.05.044 https://doi.org/10.1016/j.jacc.2013.02.011 https://doi.org/10.1001/jama.297.16.1775 https://doi.org/10.1161/circoutcomes.108.798009 https://doi.org/10.1161/circoutcomes.108.798009 https://doi.org/10.1016/j.jacc.2009.01.037 https://doi.org/10.1016/j.jacc.2009.01.037 https://doi.org/10.1161/circulationaha.107.724880 https://doi.org/10.1016/s0140-6736%2815%2900459-6 https://doi.org/10.1016/s0140-6736%2815%2900459-6 https://doi.org/10.1097/fjc.0b013e3181a1b9c7 https://doi.org/10.1161/01.res.0000031151.21145.59 https://doi.org/10.1161/01.res.0000031151.21145.59 https://doi.org/10.1054/jcaf.2002.129232 https://doi.org/10.1054/jcaf.2002.129232 https://doi.org/10.1007/bf00877121 https://doi.org/10.5301/heartint.5000219 https://doi.org/10.1016/j.jchf.2012.12.002 https://doi.org/10.1124/jpet.104.066100 https://doi.org/10.1002/clc.22476 https://doi.org/10.1002/clc.22476 https://doi.org/10.1016/j.pharmthera.2011.11.003 https://doi.org/10.1111/j.1540-8167.2008.01204.x https://doi.org/10.1016/j.jacc.2010.08.600 https://doi.org/10.1161/circulationaha.107.704890 https://doi.org/10.1161/circulationaha.107.704890 https://doi.org/10.1016/j.jacc.2009.12.055 https://doi.org/10.1093/europace/euu217 https://doi.org/10.1161/circep.115.002856 https://doi.org/10.1093/europace/eut407 alice mezincescu, v. j. karthikeyan and sunil k. nadar review | e23 58. miles rh, passman r, murdock dk. comparison of effectiveness and safety of ranolazine versus amiodarone for prev enting atrial fibrillation after coronary artery bypass grafting. am j cardiol 2011; 108:673–6. doi: 10.1016/j.amjcard.2011.04.017. 59. de ferrari gm, maier ls, mont l, schwartz pj, simonis g, leschke m, et al. ranolazine in the treatment of atrial fibrillation: results of the dose-ranging raffaello (rano lazine in atrial fibrillation following an electrical cardioversion) study. heart rhythm 2015; 12:872–8. doi: 10.1016/j. hrthm.2015.01.021. 60. murdock dk, kersten m, kaliebe j, larrain g. the use of oral ranolazine to convert new or paroxysmal atrial fibrillation: a review of experience with implications for possible “pill in the pocket” approach to atrial fibrillation. indian pacing electrophysiol j 2009; 9:260–7. 61. murdock dk, kaliebe j, larrain g. the use of ranolazine to facilitate electrical cardioversion in cardioversion-resistant patients: a case series. pacing clin electrophysiol 2012; 35:302–7. doi: 10.1111/j.1540-8159.2011.03298.x. 62. fragakis n, koskinas kc, katritsis dg, pagourelias ed, zografos t, geleris p. comparison of effectiveness of ranolazine plus amiodarone versus amiodarone alone for conversion of recent-onset atrial fibrillation. am j cardiol 2012; 110:673–7. doi: 10.1016/j.amjcard.2012.04.044. 63. tagarakis gi, aidonidis i, daskalopoulou ss, simopoulos v, liouras v, daskalopoulos me, et al. effect of ranolazine in preventing postoperative atrial fibrillation in patients under going coronary revascularization surgery. curr vasc pharmacol 2013; 11:988–91. doi: 10.2174/157016111106140128123506. 64. kloner ra, dow js, bhandari a. the antianginal agent ranolazine is a potent antiarrhythmic agent that reduces ventricular arrhythmias: through a mechanism favoring inhibition of late sodium channel. cardiovasc ther 2011; 29:e36–41. doi: 10.1111/j.1755-5922.2010.00203.x. 65. moss aj, zareba w, schwarz kq, rosero s, mcnitt s, robinson jl. ranolazine shortens repolarization in patients with sus-tained inward sodium current due to type-3 long-qt syndrome. j cardiovasc electrophysiol 2008; 19:1289–93. doi: 10.1111/j.1540-8167.2008.01246.x. 66. bunch tj, mahapatra s, murdock d, molden j, weiss jp, may ht, et al. ranolazine reduces ventricular tachycardia burden and icd shocks in patients with drug-refractory icd shocks. pacing clin electrophysiol 2011; 34:1600–6. doi: 10.11 11/j.1540-8159.2011.03208.x. 67. chorin e, hu d, antzelevitch c, hochstadt a, belardinelli l, zeltser d, et al. ranolazine for congenital long-qt syndrome type iii: experimental and long-term clinical data. circ arrhythm electrophysiol 2016; 9:e004370. doi: 10.1161/circ ep.116.004370. 68. zareba w, daubert jp, beck ca, huang dt, alexis j, brown m, et al. abstract c-lbct02-01: ranolazine in high risk icd patients (raid) trial. in: 38th annual scientific sessions of the heart rhythm society, 10–13 may 2017, chicago, illinois, usa. heart rhythm 2017; 14:944–7. doi: 10.1016/j. hrthm.2017.05.010. 69. jerling m, huan bl, leung k, chu n, abdallah h, hussein z. studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. j clin pharmacol 2005; 45:422–33. doi: 10.1177/0091270004273992. 70. hidalgo-vega a, ramos-goñi jm, villoro r. cost-utility of ranolazine for the symptomatic treatment of patients with chronic angina pectoris in spain. eur j health econ 2014; 15:917–25. doi: 10.1007/s10198-013-0534-8. 71. kohn cg, parker mw, limone bl, coleman ci. costeffectiveness of ranolazine added to standard-of-care treatment in patients with chronic stable angina pectoris. am j cardiol 2014; 113:1306–11. doi: 10.1016/j.amjcard.2014.01.407. 72. coleman ci, freemantle n, kohn cg. ranolazine for the treatment of chronic stable angina: a cost-effectiveness analysis from the uk perspective. bmj open 2015; 5:e008861. doi: 10.11 36/bmjopen-2015-008861. 73. vellopoulou k, kourlaba g, maniadakis n, vardas p. a literature review to evaluate the pharmacoeconomic value of ranolazine for the treatment of symptomatic chronic stable angina. value health 2015; 18:a395. doi: 10.1016/j.jval.2015.09.893. https://doi.org/10.1016/j.amjcard.2011.04.017 https://doi.org/10.1016/j.hrthm.2015.01.021 https://doi.org/10.1016/j.hrthm.2015.01.021 https://doi.org/10.1111/j.1540-8159.2011.03298.x https://doi.org/10.1016/j.amjcard.2012.04.044 https://doi.org/10.2174/157016111106140128123506 https://doi.org/10.1111/j.1755-5922.2010.00203.x https://doi.org/10.1111/j.1540-8167.2008.01246.x https://doi.org/10.1111/j.1540-8159.2011.03208.x https://doi.org/10.1111/j.1540-8159.2011.03208.x https://doi.org/10.1161/circep.116.004370 https://doi.org/10.1161/circep.116.004370 https://doi.org/10.1016/j.hrthm.2017.05.010 https://doi.org/10.1016/j.hrthm.2017.05.010 https://doi.org/10.1177/0091270004273992 https://doi.org/10.1007/s10198-013-0534-8 https://doi.org/10.1016/j.amjcard.2014.01.407 https://doi.org/10.1136/bmjopen-2015-008861 https://doi.org/10.1136/bmjopen-2015-008861 https://doi.org/10.1016/j.jval.2015.09.893 beal’s syndrome (online mendelian inheritance in man® entry #121050), also known as congenital contractural arachnodactyly, is an autosomal dominantly inherited connective tissue disorder characterised by multiple flexion contractures, arachnodactyly, severe kyphoscoliosis, abnormal pinnae and muscular hypoplasia.1,2 the syndrome was first described in 1971 by beal et al.3 this report describes a case of beal’s syndrome with seizures as a potential feature. to the best of the authors’ knowledge, seizures have not previously been reported as a characteristic of beal’s syndrome. this case also highlights the importance of genetic screening for family members of patients with beal’s syndrome. case report a seven-year-old omani male was admitted to the sultan qaboos university hospital, muscat, oman, in 2014 with seizures. he had been born at fullterm gestation by caesarean section due to nonprogression of the second stage of labour. at birth, he had a good apgar score and his growth parameters were normal. there were no antenatal or perinatal concerns and no significant maternal illness or history of drug intake. however, as a newborn, contractures in both lower limbs were observed; these were treated by orthopaedic specialists with plaster of paris cast applications. the patient’s developmental progress was appropriate for his age. he displayed delayed gross motor development and stood up late; however, his parents showed no concern and he began walking without support at 18 months. a hearing test was normal and a vision test showed a refractive error, for which he was prescribed glasses. the patient was in grade 1 at school and had no learning difficulties, although he experienced minor difficulties in holding his pen due to finger contractures. his mother reported that he had been bullied at school because department of genetics, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: nazreenarif@hotmail.com نوبات التشنج مسة غري شائعة يف متالزمة بيلز نازرين بانو كمار�ض جمان و عبري ال�صائغ abstract: congenital contractural arachnodactyly, commonly known as beal’s syndrome, is an extremely rare genetic disorder caused by mutations in the fibrillin-2 (fbn2) gene located on chromosome 5q23. it is an autosomal dominant inherited connective tissue disorder characterised by a marfan-like body habitus, contractures, abnormally shaped ears and kyphoscoliosis. we report a seven-year-old omani male who presented to the sultan qaboos university hospital, muscat, oman, in 2014 with seizures. he was noted to have certain distinctive facial features and musculoskeletal manifestations; he was subsequently diagnosed with beal’s syndrome. sequencing of the fbn2 gene revealed that the patient had a novel mutation which was also present in his mother; however, she had only a few facial features indicative of beal’s syndrome and no systemic involvement apart from a history of childhood seizures. to the best of the authors’ knowledge, this is the first report of beal’s syndrome with seizure symptoms as a potential feature. keywords: congenital contractural arachnodactyly; marfan syndrome; fibrillin-2; seizures; case report; oman. امللخ�ص: عنكبية االأ�صابع التقفعية اخللقية واملعروفة اأي�صا با�صم متالزمة بيلز هو ا�صطراب وراثي نادر للغاية ت�صببه طفرات جينية يف ويتميز ال�صام الن�صيجي باجلهاز املتعلقة ال�صائدة ال�صفة ذوات من املر�ض هذا .5q23 ال�صبغي املوقع على )fbn2( فربيلني-2 اجلني ب�صمات ج�صمية م�صابهة ملتالزمة مارفان، من تقفع يف االأطراف واختالفات خلقية يف االأذن وتقو�ض يف الظهر. نعر�ض يف هذا التقرير اإكلينيكيا و�صخ�ض الهيكلي باجلهاز متعلقة واأعرا�ض مميزة وجه ومالمح بت�صنجات جاء العمر من ال�صابعة يف ذكر عماين لطفل حالة يف ت�صبهه فقط كانت التي واأمه املري�ض هذا يف fbn2 جني يف جديد جيني اختالف وجود اجلينية الفحو�ض اأثبتت بيلز، مبتالزمة مالمح الوجه بدون االأعرا�ض االأخرى املتعلقة باملر�ض ولكنها كانت م�صابة بالت�صنجات يف ال�صغر. ح�صب علمنا هذه اأول حالة م�صخ�صة مبتالزمة بيلز تعر�ض الت�صنجات ك�صمة حمتملة يف متالزمة بيلز. كلمات مفتاحية: عنكبية االأ�صابع التقفعية اخللقية؛ متالزمة مارفان؛ فربيلن 2؛ الت�صنجات؛ تقرير حالة؛ عمان. seizures as an atypical feature of beal’s syndrome *nazreen b. k. jaman and abeer al-sayegh case report sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e375–378, epub. 19 aug 16 submitted 7 oct 15 revisions req. 26 nov 15 & 13 jan 16; revisions recd. 20 dec 15 & 21 jan 16 accepted 14 feb 16 doi: 10.18295/squmj.2016.16.03.021 seizures as an atypical feature of beal’s syndrome e376 | squ medical journal, august 2016, volume 16, issue 3 of his physical appearance. for this reason, the patient had undergone counselling, which both the patient and his parents reported to be helpful. at admission, the patient was referred to the clinical genetics team as he was noted to have certain features suggestive of beal’s syndrome. a clinical examination revealed that he had a broad forehead, arched eyebrows, a broad and flat nasal bridge, facial asymmetry with a small mouth, retrognathia, a high arched palate, low posterior hairline and a short neck. his ears were low set, fanning laterally. camptodactyly was noted in both hands as well as contractures in both feet [figure 1]. the patient was observed to have both pectus carinatum with a small excavation in the mid sternum along with a café au lait spot of more than 1 cm on the right leg. he had big prominent eyes with ptosis, which was mainly present in the left eye. with regards to growth parameters, the patient was below the 25th percentile for height and below the 10th percentile for weight. his head circumference was smaller than average (below the mean 50%). he scored 70 on an intelligence quotient test, which was classified as borderline deficiency. computed tomography of the brain was normal; however, an electroencephalogram showed right occipital lobe spikes and spike wave discharges suggestive of partial seizures. a skeletal survey indicated that the bones and joints of the lower extremities had a normal appearance. an ophthalmology examination showed hypermetropia in both eyes and an echocardiogram showed aortic root dilatation. in view of his physical features, the patient was diagnosed with beal’s syndrome. with regards to family pedigree, he was the eldest son of consanguineous first cousin parents [figure 2]. he had a healthy younger sister who did not share his physical characteristics. while he resembled both parents, his mother also had a small mouth, small chin and high arched palate. she reported that she had a history of childhood epilepsy, which improved with age; she was currently not on any anti-epileptic drugs at the time. in addition, she also revealed that most of the members of her family— figure 1a & b: photographs demonstrating (a) upper limb camptodactyly and (b) lower limb contractures in a patient with beal’s syndrome. figure 2: family pedigree chart of a patient with beal’s syndrome (arrow). nazreen b. k. jaman and abeer al-sayegh case report | e377 including her parents, siblings and cousins as well as cousins on her husband’s side of the family—shared the same facial features but had no systemic involvement indicative of beal’s syndrome, other than a history of childhood epilepsy in the patient’s maternal uncle and aunt. the latter family member had also suffered a stroke at a young age. molecular sequencing of the fibrillin-2 (fbn2) gene showed that the patient had a new mutation in exon 46, c.5847a>g (p.lys1949lys). five splice site prediction programs were used in the testing process. of these, the alamut® visual (interactive biosoftware, rouen, france), sorting intolerant from tolerant, align-gvgd (huntsman cancer institute, salt lake city, utah, usa) and multivariate analysis of protein polymorphism programs suggested that the c.5847a>g variant would activate a cryptic guaninethymine donor site upstream.4,5 subsequent genetic testing of the patient’s parents showed that his mother was a carrier of the same fbn2 mutation. despite this, she had only a few facial features indicative of beal’s syndrome and no systemic involvement apart from the history of seizures. molecular genetic testing of the patient’s father did not show any mutation of the fbn2 gene. discussion a diagnosis of beal’s syndrome is mainly based on clinical findings.6 marfan’s syndrome and homocystinuria can be considered in the differential diagnosis for beal’s syndrome. patients with beal’s syndrome may display similar skeletal features to those with marfan’s syndrome, such as marfanoid habitus, arachnodactyly, camptodactyly and kyphoscoliosis.2 however, the ear helix of patients with beal’s syndrome often has a crumpled appearance; in addition, patients have congenital contractures and do not typically have the same ocular and cardiovascular complications seen in marfan’s syndrome.2 although the presence of contractures is specific to beal’s syndrome, there have been reports of patients with marfan’s syndrome with mild contractures.2 patients with marfan’s syndrome have lens subluxation, which is not a typical feature of beal’s syndrome.6 moreover, it is estimated that general ocular complications are only present in 20% of beal’s syndrome patients.2 aortic root dilatation and mitral valve prolapse are the most common cardiovascular complications in marfan’s syndrome, whereas cardiac findings in beal’s syndrome include aortic enlargement and/or mitral valve regurgitation.2 clinical features overlap between beal’s syndrome and marfan’s syndrome because each of these conditions result from mutations in two highly similar but distinct homologous genes, fbn2 and fbn1, respectively, situated in chromosomes 5q23-31 and 15q15-21.3, respectively.7 the fbn2 gene is located on chromosome 5q23 and is responsible for encoding the extracellular matrix microfibril fibrillin-2.6 previous research has found that over 20 mutations in the fbn2 gene can cause beal’s syndrome; these mutations can change the amino acid structure of the fibrillin-2 protein—such as the replacement of cysteine with a different amino acid—which may lead to either structural or functional changes in the protein.8 in the present case, the patient was admitted with seizures and subsequently diagnosed with beal’s syndrome. there is the possibility that the seizures may be an unrelated finding; to the best of the authors’ knowledge, seizures are not a typical finding in reported cases of beal’s syndrome in the literature. the management of beal’s syndrome is largely symptomatic. the joint contractures may resolve with time, with residual camptodactyly persisting.2,6 however, spine curvature problems may be seen at birth or during early childhood.6 an early diagnosis and multidisciplinary management with physiotherapy and occupational therapy can help to prevent the progression of these orthopaedic issues, enabling patients to carry on with their day-to-day activities with ease. routine physical examinations for spinal deformities and early intervention for scoliosis can prevent morbidity later in life.6 an initial cardiac evaluation with serial echocardiography is recommended, as cardiac complications may arise.6 a thorough ophthalmological evaluation is also recommended to rule out any ocular involvement. individuals with beal’s syndrome are usually able to live normal lives unless they suffer from cardiac problems or severe deformities of the vertebrae. many patients with beal’s syndrome also have an affected parent, although occasionally beal’s syndrome can be caused by a de novo gene mutation.6 the risk to the patient’s siblings can be estimated after assessing the genetic status of the parents. if one of the parents is found to have clinical features, then there is a 50% chance that their children will also have beal’s syndrome due to its pattern of autosomal dominant inheritance.6 there have been reported cases of beal’s syndrome associated with germline mosaicism. if a beal’s syndrome-causing mutation is found in one member of the family, prenatal testing can be offered to other family members.6 conclusion this is the first reported case of beal’s syndrome with a feature of seizures, although there is a possibility seizures as an atypical feature of beal’s syndrome e378 | squ medical journal, august 2016, volume 16, issue 3 that the seizures were an unrelated finding. molecular sequencing of the patient’s fbn2 gene showed a new mutation in exon 46, c.5847a>g (p.lys1949lys). while his mother carried the same variant, she shared only a few facial features and none of the classic features of beal’s syndrome. this report indicates the importance of early genetic screening of other family members to assess the risk of recurrence. references 1. online mendelian inheritance in man. entry #121050: arthrogryposis, distal, type 9. from: www.omim.org/entry/ 121050 accessed: jan 2016. 2. tunçbilek e, alanay y. congenital contractural arachnodactyly (beals syndrome). orphanet j rare dis 2006; 1:20. doi: 10.11 86/1750-1172-1-20. 3. beals rk, hecht f. congenital contractural arachnodactyly: a heritable disorder of connective tissue. j bone joint surg am 1971; 53:987–93. 4. j. craig venter institute. sorting intolerant from tolerant (sift). from: sift.jcvi.org/ accessed: jan 2016. 5. stone ea, sidow a. physicochemical constraint violation by missense substitution mediates impairment of protein function and disease severity. genome res 2005; 15:978–86. doi: 10.1101/ gr.3804205. 6. godfrey m. congenital contractural arachnodactyly. in: pagon ra, adam mp, ardinger hh, wallace se, amemiya a, bean lj, et al., eds. genereviews®. seattle, washington, usa: university of washington, 2016. 7. callewaert bl, loeys bl, ficcadenti a, vermeer s, landgren m, kroes hy, et al. comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature. hum mutat 2009; 30:334–41. doi: 10.1002/ humu.20854. 8. ramos arroyo ma, weaver dd, beals rk. congenital contractural arachnodactyly: report of four additional families and review of literature. clin genet 1985; 27:570–81. doi: 10.1111/j.1399-0004.1985.tb02042.x. http://dx.doi.org/10.1186/1750-1172-1-20 http://dx.doi.org/10.1186/1750-1172-1-20 http://dx.doi.org/10.1101/gr.3804205 http://dx.doi.org/10.1101/gr.3804205 http://dx.doi.org/10.1002/humu.20854 http://dx.doi.org/10.1002/humu.20854 http://dx.doi.org/10.1111/j.1399-0004.1985.tb02042.x 1department of biochemistry & molecular biology, sana'a university, sana'a, yemen; 2department of parasitology, liverpool school of tropical medicine, liverpool, uk *corresponding author e-mails: faiza.issa@uta.edu and f_eyssa@hotmail.com تأثري استخدام القات )كاثا أدليس( على التوافر احليوي، مستويات البالزما ونشاط الكلوروكني املضاد للمالريا فايزة عي�سى، ملهم احلبوري، مايكل �سان�س abstract: objectives: this study aimed to evaluate the effect of khat (catha edulis) on chloroquine (cq) bioavailability in healthy yemeni adults and its effect on cq plasma levels and parasite clearance among malaria patients. methods: this study took place between january and april 2007 in bajil and sana’a, yemen. two cq doses (600 mg each) were given to 15 healthy males on separate occasions; the first dose was followed by a khat-chewing session (phase one) while controls abstained from khat-chewing for the second (phase two). additionally, 103 patients with plasmodium falciparum-induced malaria, including both regular khat chewers (n = 57) and non-khat chewers (n = 46), were treated with cq (25 mg/kg) over three days. pharmacokinetic parameters were analysed among both controls and malaria patients. parasite clearance was also investigated for the latter group. results: the mean area under the concentration-time curve (auc) was 2,108.9 versus 2,797.4 ng/hour/ml, mean peak plasma concentration (cmax) was 415.6 versus 508.7 ng/ml and mean time to reach cmax was 3.8 versus 3.6 hours for controls in phase one versus phase two, respectively; both auc and cmax levels were significantly reduced by khat-chewing (p <0.050). for khatversus non-khat-chewing malaria patients, mean plasma cq concentrations were 266.4 ng/ml versus 427.5 ng/ml (p <0.001). furthermore, cq was effective in 71.7% and 75.4% of non-khat and khat-chewing malaria patients, respectively (p = 0.823). conclusion: khat-chewing was found to significantly reduce plasma cq levels among healthy volunteers and malaria patients. while receiving cq treatment, patients should be advised not to chew khat. keywords: khat; catha edulis; malaria; plasmodium falciparum; chloroquine; yemen. امللخ�ص: اأهداف: هدفت هذه الدرا�سة اإىل تقييم تاأثري القات على التوافر البيولوجي لعقار الكلوروكني )cq( يف البالغني الأ�سحاء اليمنيني وتاأثريها على م�ستويات البالزما للكلوروكني وقدرته على اإزالة الطفيليات بني مر�سى املالريا. منهجية: اأجريت هذه الدرا�سة يف الفرتة يف الأ�سحاء للذكور 15 اإىل منهما لكل ملغ 600 الكلوروكني من جرعتني اأعطيت اليمن. و�سنعاء باجل يف 2007 واأبريل يناير بني ما القات م�سغ عن ال�سابطة املجموعة امتنعت بينما الأوىل(، )املرحلة القات مل�سغ جل�سة الأوىل اجلرعة واأعقبت منف�سلة منا�سبات عدة )املرحلة الثانية(. بالإ�سافة اإىل ذلك، مت عالج 103 مري�سا باملالريا التي ي�سببها البالزموديوم املنجلي و�سملت املر�سى الذين مي�سغون القات بانتظام )ن = 57( والذين لمي�سغون القات )ن = 46(، بوا�سطة جرعة 25 ملغ/كلغ من عقار الكلوروكني على مدى ثالثة اأيام. وقد مت حتليل حركية الدواء يف كل من املجموعة ال�سابطة و مر�سى املالريا. ومت التحقق من اإزالة الطفيليات اأي�سا للمجموعة الثانية. نتائج: كان متو�سط املنطقة حتت منحنى الرتكيز الزمني هو 2,108.9 مقابل 2,797.4 نانوغرام/�ساعة/مل، بينما كان متو�سط ذروة تركيز البالزما )cmax( 415.6( مقابل 508.7 نانوغرام/مل ومتو�سط وقت الو�سول اإىل cmax كان 3.8 مقابل 3.6 �ساعة للمجموعة ال�سابطة يف املرحلة الأوىل مقابل املرحلة الثانية، على التوايل. انخف�س متو�سط املنطقة حتت منحنى الرتكيز الزمني و ال cmax ب�سكل ملحوظ اح�سائيا مع م�سغ القات )p >0.050(. كانت متو�سط تركيزات البالزما للكلوروكني هي 427.5 نانوغرام/مل املر�سى الذين لمي�سغون القات مقابل 266.4 نانوغرام/مل يف يف املر�سى ما�سغي القات )p >0.001(. وعالوة على ذلك، كان عقار الكلوروكني فعال يف%71.7 يف املر�سى الذين لمي�سغون القات مقابل و %75.4 من مر�سى املالريا ما�سغي القات على التوايل )p = 0.823(. اخلامتة: مل�سغ القات تاثري كبري على انحفا�س تركيز عقار الكلوروكني يف الذكور الأ�سحاء ومر�سى املالريا. لذلك يجب ن�سح هوؤلء املر�سى بالتوقف عن م�سغ القات اثناء تلقي العالج. كلمات مفتاحية: قات؛ كاثا اأدلي�س؛ املالريا؛ البالزموديوم املنجلي؛ الكلوروكني؛ اليمن. effect of khat (catha edulis) use on the bioavailability, plasma levels and antimalarial activity of chloroquine *faiza h. issa,1 molhem al-habori,1 michael l. chance2 clinical & basic research sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 182–188, epub. 15 may 16 submitted 18 sep 15 revision req. 21 dec 15; revision recd. 19 jan 16 accepted 14 feb 16 doi: 10.18295/squmj.2016.16.02.008 advances in knowledge this is the first study to reveal that the use of khat (catha edulis) significantly reduces plasma chloroquine (cq) levels among malaria patients receiving cq treatment. the results of this study may be used as a reference for future research on possible interactions between khat and other drugs. faiza h. issa, molhem al-habori and michael l. chance clinical and basic research | e183 application to patient care chewing khat was found to significantly reduce plasma cq levels among malaria patients. health workers and medication manufacturers should be educated regarding the potential risk of cq and khat co-administration and patients should be advised to abstain from khat-chewing whilst undergoing cq treatment. the rate of cq resistance noted in this study was above the threshold recommended by the world health organization. this indicates that current antimalarial drug practices in yemen need to be modified. certain dietary substances can affect the absorption of medications, including antimalarial drugs.1–6 drug-food, drug-drug and drug-herb interactions are factors that can alter the pharmacokinetic activity of a drug; these interactions can occur during absorption, distribution, metabolism or excretion.7 catha edulis of the celastraceae family, also known as khat, is a plant widely cultivated in east africa (e.g. kenya and ethiopia) and the arabian peninsula.8 the main active substances in fresh khat leaves are alkaloids with amphetamine-like properties which have euphoric and stimulatory effects.9 in yemen, khat-chewing is a widespread habit; approximately 80–85% of male and 50–60% of female adults in northern yemen chew khat at least once a week.8 the concurrent use of khat with standard medications is anecdotally purported to be common practice in yemen. attef et al. found that khat-chewing among healthy yemeni adults significantly reduced the bioavailability of the antibiotics ampicillin and amoxicillin.10 another study observed a significant reduction in the pharmacokinetic parameters of tetracycline-hydrochloride among healthy yemeni adults after a khat-chewing trial.11 malaria is a serious health concern in yemen, with an estimated 800,000–900,000 malaria cases occurring each year.12 the disease is responsible for significant child morbidity and mortality; 1% of deaths among yemeni children under five years of age are attributed to malaria.13 recently, a study revealed that repeated dosing with extracts of khat reduced parasite loads among swiss albino mice with malaria infections.14 however, ketema et al. found that khat exhibited only mild antimalarial activity among khat chewers in ethiopia.15 chloroquine (cq) is one of the most common antimalarial drugs prescribed by yemeni physicians.16 consequently, determining whether khat-chewing has an effect on cq is of great importance. this study was undertaken to investigate the effect of khat use on cq bioavailability in both healthy volunteers and malaria patients. in addition, the effect of khat use on parasitaemia and parasite clearance among the latter group was also examined. methods this study was carried out between january and april 2007 in bajil and sana’a, yemen. healthy volunteers and malaria patients made up the control and patient groups, respectively. a total of 15 healthy males >18 years old and between 45‒64 kg were recruited from sana’a, the capital city of yemen, which is free of malaria.16 the healthy volunteers were selected from a group of respondents to an advertisement requesting participants for an unpaid pharmacological study. volunteers with blood film examinations negative for malaria parasites, normal standard laboratory test results (including haemoglobin [hb] levels, a complete blood count and kidney and liver function tests) and who were otherwise healthy with no history of clinical illness were included in the control group. individuals with a history of taking antimalarial or prophylactic drugs over the preceding 12 months and those who were unwilling to abstain from khatchewing for a period of 72 hours were excluded. for the patient group, all patients >18 years old who presented to the national malaria control centre in bajil, al-hudaydah governorate, west yemen, with microscopy-confirmed plasmodium falciparuminduced malaria were recruited (n = 103). this area was identified as a mesoto hyperendemic area for malaria between january−april 2007.17 all patients had a p. falciparum-positive thick or thin blood smear and were seeking treatment for uncomplicated malaria with no signs of severe malaria, such as an inability to drink/eat or sit/stand upright, repeated vomiting, convulsions, lethargy or unconsciousness and hb levels of <7 g/dl. the presence of a documented fever was not required for enrolment in the study. the control group underwent two phases of cq administration. in the first phase, a single dose of cq (600 mg) was administered orally to the healthy volunteers immediately before a khat-chewing session which involved chewing ~250 g of fresh khat leaves for 4–5 hours. the second phase occurred four weeks later; participants received a second single dose of cq (600 mg) after having been instructed to abstain from khat-chewing for the preceding 48 hours. in addition, they were also requested to refrain from khat-chewing for 24 hours on the day of dosing. all of the participants clearly understood the purpose of the study and had agreed to abstain from khatchewing for the required period of time. the principle investigator contacted all of the volunteers two days before their second cq dose to reiterate the necessity of abstaining from khat-chewing. for both stages, 3 effect of khat (catha edulis) use on the bioavailability, plasma levels and antimalarial activity of chloroquine e184 | squ medical journal, may 2016, volume 16, issue 2 ml of venous blood was collected from the subjects before and during cq administration, at 0.5, one, two, three, four, six, eight, 12 and 24 hours after each dose. samples were transferred to heparinised tubes and the plasma was separated and stored at -75 °c until analysis. several studies have shown that cq levels are negligible four weeks after a single dose.18,19 furthermore, active components of khat, cathine and cathinone are reportedly undetectable 24 hours after chewing.20 as a result, residual levels of either the first dose of cq or khat would not interact with the cq dose administered during the second phase. malaria patients were divided into regular khat chewers and non-khat chewers. patients were considered khat chewers if they reported chewing khat more than three days a week. for khat-chewing patients, the amount and type of khat used and the timing of the khat-chewing sessions was not controlled by the researchers. on average, khat chewers reported using 230–350 g of fresh khat leaves for 4–5 hours per session. all of the malaria patients received oral cq tablets administered over three days, at 10 mg/kg for the first two days and 5 mg/kg on day three, resulting in a total dose of 25 mg/kg. the full dose was readministered if the patient vomited within 30 minutes of the initial dose. a total of 3 ml of venous blood was drawn and transferred into heparinised tubes the day before cq dosing (day zero) and during cq treatment (days 1–3), 24 hours after the dose had been administered. body temperature was recorded during treatment as a marker of illness/ clinical cure. in addition, parasitaemia was routinely assessed on each visit by counting the number of asexual parasites against at least 200 white blood cells (wbcs) in thick blood films, assuming a normal wbc count of 8,000/µl.21 patients were followed-up for three days after the first dose of cq. a validated high-performance liquid chromatography (hplc) method was used to determine plasma cq concentrations in the blood samples of both healthy controls and malaria patients using the lc-2010ht system (shimadzu corp., kyoto, japan) with an auto sampler.22 ultraviolet detection of eluted peaks was performed at 340 nm. chromatographic separation was carried out using the reversed-phase 150 mm x 4.6 mm hypersiltm bds c18 hplc columns (thermo fisher scientific inc., waltham, massachusetts, usa) with a 5 µm particle size. the mobile phase contained a mixture of water and acetonitrile (ratio: 85:15%) as well as 1% triethylamine adjusted to a ph of 2.8 with concentrated phosphoric acid and a flow rate of 1 ml/minute. the pharmacokinetic parameters of cq were determined by measuring the area under the concentration-time curve (auc) from time zero (before the cq dosing) to 24 hours after cq dosing, maximal plasma drug concentration (cmax) and time taken to reach maximum plasma concentration (tmax). these parameters were calculated using the compartmental/trapezoidal method with kinetica software for pk/pd data analysis, simulation and reporting, version 4.4 (thermo fisher scientific inc.). values were reported as means ± standard deviation. among the malaria patients, parasitological and clinical responses to cq treatment were classified according to different treatment protocols devised by the world health organization (who) and osorio et al.23–25 in terms of parasitological response, the 1973 who protocol was utilised—patients were deemed to exhibit sensitivity (s)/resistance level i (ri) if the p. falciparum parasites had cleared by day two of cq treatment; rii if there was incomplete clearance of parasites by day two; and riii if parasite density on day two was ≥25% that of the parasite density observed on day zero.23 clinical responses to cq were classified according to definitions used within the 1996 who treatment protocols and methods of osorio et al.24,25 early treatment failure (etf) was defined as (1) the development of any danger signs, such as fever and vomiting, severe malaria or parasite positivity on days 1–3 of cq administration; (2) higher parasitaemia levels on day two than day zero; or (3) parasite density on day three ≥25% that of day zero.24 treatment success (ts) was classified as negative parasitaemia on day three.24 late treatment failure (ltf) was defined as the development of any danger signs, severe malaria, parasitaemia or fever after day three or an unscheduled return to seek medical help because of clinical deterioration or parasitaemia on any scheduled follow-up day on or after day seven.25 in this study, follow-up after three days was not possible. patients who failed to respond to cq treatment were prescribed sulfadoxine/pyrimethamine. during follow-up, patients received a single dose of primaquine (0.75 mg/kg) at the end of the follow-up period if they were found to have gametocytaemia. the t-test for paired values was used to compare pharmacokinetic parameters of cq obtained after the two phases of the control group trial and to compare results between khat-chewing and non-khat-chewing malaria patients. geometric means were used to summarise parasite densities for malaria patients. parasite clearance and the association with khat use were analysed with a two-sided fisher’s exact test. a p value of <0.050 was used as the level of significance. this study was approved by the institutional review boards of the faculty of medicine & health sciences at sana’a university and the national malaria control programme (nmcp) in sana’a. in addition, ethical faiza h. issa, molhem al-habori and michael l. chance clinical and basic research | e185 permission was granted by the liverpool school of tropical medicine in liverpool, uk. informed consent was obtained from all individuals before participation in the study. results the control group ranged in age from 20–30 years old and had a mean hb level of 16.2 g/dl and mean body weight of 62.86 kg. in phase two versus phase one, there was a significant reduction in mean cmax and auc among the healthy controls (415.6 versus 508.7 ng/ml and 2,108.9 versus 2,797.4 ng/hour/ml; p <0.001 and 0.002, respectively) [figure 1]. however, no significant difference was seen in mean tmax (3.8 versus 3.6 hours; p = 0.81) [table 1]. the malaria patient group ranged in age from 20–45 years old and there were 57 khat chewers and 46 non-khat chewers. of the khat and non-khat chewers, 25 (43.9%) and 27 (58.7%) were female and 32 (56.1%) and 19 (41.3%) were male, respectively. all patients had a temperature of >37 °c prior to treatment and had normal axillary temperatures by day three of cq treatment. plasma cq levels among khatand non-khat-chewing malaria patients according to day of treatment are presented in table 2. plasma cq levels were significantly reduced among khat-chewing malaria patients compared to their non-khat-chewing counterparts (266.4 ± 164.3 and 427.5 ± 125.6, respectively; p <0.001). before cq treatment, parasite density among the malaria patients ranged from 48–256,800 to 32–111,760/µl for non-khat and khat chewers, respectively. no danger signs or severe malaria symptoms were recorded for any of the patients. geometric mean parasitaemia before treatment was 1,494/µl (95% confidence interval [ci]: 771–3,837/µl) and 1,861/µl (95% ci: 902–2,890/µl) for khat and non-khat chewers, respectively. on day three of cq treatment, the geometric mean parasite density was 3/µl (95% ci: 1.7–5.2/µl) and 4/µl (95% ci: 1.9–7.9/µl) for khat and non-khat chewers, respectively. there was no significant difference in mean parasite density (p = 0.652 and 0.563, respectively) and axillary temperature (p = 0.140 and 0.145, respectively) between khat and non-khat chewers before treatment and on day three [table 3]. among the malaria patients, parasitaemia had cleared completely (s/ri) by day two of cq treatment for 61 patients (59.2%) while the remaining 42 patients (40.8%) showed resistance at either the rii or riii levels. among non-khat chewers, 27 (58.7%) patients were completely clear of parasites by day two, while 19 (41.3%) showed parasitological resistance. however, cq was effective for 34 khat chewers (59.6%) while 23 non-khat chewers (40.4%) were not clear of parasites by day two. there was no significant difference in overall resistance (rii and riii) between the two groups (p = 0.394). among the patient group, 76 (73.8%) had table 1: effect of khat-chewing on the pharmacokinetic parameters of chloroquine* among healthy adult males in yemen (n = 15) parameter mean ± sd p value after 48-hour khat-chewing abstinence period after khatchewing session† auc in ng/ hour/ml 2,797.4 ± 845.9 2,108.9 ± 682.3 0.002 cmax in ng/ml 508.7 ± 106.4 415.6 ± 103.1 <0.001 tmax in hours 3.6 ± 0.5 3.8 ± 0.4 0.810 sd = standard deviation; auc = area under the time-concentration curve; cmax = peak plasma concentration; tmax = time to reach peak concentration. *single dose of 600 mg. †approximately 250 g of fresh khat leaves for 4–5 hours. table 2: effect of khat-chewing on chloroquine plasma levels among malaria patients in yemen after chloroquine treatment* (n = 103) day of treatment mean plasma level ± sd p value non-khat chewers (n = 46) khat chewers (n = 57) day one 216.5 ± 94.8 145.4 ± 73.8 <0.001 day two 313.3 ± 123.4 202.7 ± 130.1 <0.001 day three 427.5 ± 125.6 266.4 ± 164.3 <0.001 sd = standard deviation. *total dose of 25 mg/kg over three days. figure 1: mean plasma concentration-time curves of chloroquine* after a khat-chewing session† and after a 48-hour khat-chewing abstinence period among healthy adult males in yemen (n = 15). cq = chloroquine; vcqk = after a khat-chewing session; vcq = after a 48-hour khat-chewing abstinence period. *single dose of 600 mg. †approximately 250 g of fresh khat leaves for 4–5 hours. effect of khat (catha edulis) use on the bioavailability, plasma levels and antimalarial activity of chloroquine e186 | squ medical journal, may 2016, volume 16, issue 2 ts/ltf while 27 (26.2%) had etf. overall, rates of ts/ ltf were 71.7% and 75.4% among non-khatand khatchewing malaria patients, respectively (p = 0.823). there was no significant difference between khat and non-khat chewers in terms of etf (p = 0.823) [table 4]. discussion the co-administration of cq and khat was found to significantly affect the pharmacokinetics of cq among both healthy controls and malaria patients in yemen. this was comparable to reported reductions in the pharmacokinetic activity of tetracycline hydrochloride and the low bioavailability of ampicillin and amoxicillin when co-administered with khat.10,11 a possible drug-plant cq-khat interaction exists, as indicated by the significantly reduced cq auc and cmax values observed with khat use in the present study. the mechanisms underlying this interaction are unknown; however, one possible mechanism may relate to the interaction of the drug with some of khat’s components—tannic acid, cathinone and cathine— which are known to cause the formation of insoluble complexes and non-absorbable compounds.10,11 in particular, it has been hypothesised that tannins in khat may interfere with absorption processes in the gastrointestinal tract.10 changes in gastric acidity and motility or the delay of gastric emptying may slow absorption of cq, as these changes will prolong the duration of time that the drug remains in the stomach.3,26 finally, increased diuresis is often reported among khat chewers, possibly due to fluid intake during khat-chewing sessions;26 this may lead to increased urinary excretion of cq. other possible mechanisms of pharmacokinetic interactions between khat and cq require further investigation. in the current study, cq plasma levels were significantly reduced among khat-chewing malaria patients in comparison to non-khat-chewing patients. this may be associated with the general health of this patient group with regards to malnutrition, anaemia and parasitic infestation; tulpule et al. found faster clearance of cq in undernourished subjects.5 in general, khat-chewing-induced symptoms include loss of appetite and malnutrition.9 this may also affect digestion or absorption of cq. in addition, differences in plasma cq levels between healthy controls and malaria patients could be related to the age differences between the two groups. edwards et al. reported that cq blood concentrations and auc were significantly higher in malaria patients receiving oral cq treatment than in healthy subjects, suggesting that malaria induces absorption changes and increases systemic exposure to cq.27 in the current study, reduction in the plasma cq levels among khat-chewing malaria patients could be related to impaired gastrointestinal absorption due to the effect of khat on cq absorption. in the current study, the rate of cq resistance among the malaria patients was above the acceptable level of resistance determined by the who.24 several studies conducted in different governorates of yemen have also demonstrated high to medium rates of cq treatment failure, including rates of 61% in the table 4: in vivo plasmodium falciparum response to chloroquine treatment* in khatand non-khat-chewing malaria patients in yemen (n = 103) n (%) s/ri† rii† riii† overall r† ts‡/ltf§ etf‡ khat chewers (n = 57) 34 (59.6)¶ 17 (29.8) 6 (10.6) 23 (40.4)¶ 43 (75.4)// 14 (24.6)// non-khat chewers (n = 46) 27 (58.7) 10 (21.7) 9 (19.6) 19 (41.3) 33 (71.7) 13 (28.3) total 61 (59.2) 27 (26.2) 15 (14.6) 42 (40.8 ) 76 (73.8) 27 (26.2) s = sensitivity; r = resistance level; ts = treatment success; ltf = late treatment failure; etf = early treatment failure. *total dose of 25 mg/kg over three days. †according to the 1973 treatment protocol of the world health organization.23 ‡according to values obtained on day three of treatment and the 1996 treatment protocol of the world health organization.24 §according to values obtained on day three of treatment and the methods of osorio et al.25 ¶p = 0.394. //p = 0.823. table 3: parasitaemia and axillary temperature before (day zero) and after (day three) chloroquine treatment* among khatand non-khat-chewing malaria patients in yemen (n = 103) mean† parasitaemia per µl (95% ci) mean axillary temperature in °c ± sd day 0 day 3 day 0 day 3 khat chewers (n = 57) 1,494 (771–3,837) 3 (1.7–5.2) 37.5 ± 0.54 36.8 ± 0.11 nonkhat chewers (n = 46) 1,861 (902–2,890) 4 (1.9–7.9) 37.4 ± 0.66 36.8 ± 0.14 p value 0.653 0.563 0.140 0.145 ci = confidence interval; sd = standard deviation. *total dose of 25 mg/kg over three days. †geometric mean. faiza h. issa, molhem al-habori and michael l. chance clinical and basic research | e187 al-musaimeer district of lahj governorate and 16.1% in the hethran and al-mafatch districts of taiz governorate.28,29 in addition, al-mekhlafi et al. observed a high frequency of p. falciparum cq resistance transporter t76 mutations, suggesting considerable cq resistance among cases of p. falciparum-induced malaria in yemen.30 in the current study, parasite densities differed between khatand non-khat-chewing malaria patients, although this finding was not significant. ketema et al. similarly observed the mildly antiplasmodial characteristics of khat leaves.15 antimicrobial activity has also been reported.31 several studies have shown that plant alkaloids, flavonoids and tannins demonstrate in vivo and in vitro antimalarial activity against cqsensitive and -resistant strains of p. falciparum.32,33 however, further studies are needed to investigate the antimalarial activity of khat. the limited reduction in parasite densities observed in the current study might be attributed to the antiplasmodial activity of certain compounds in khat leaves. with regards to treatment outcomes, no significant differences were found between khatand nonkhat-chewing malaria patients in the current study. however, rates of successful treatment may have been overestimated, as certain patients might have been classified as cases of ltf instead of ts had they been followed-up for a longer period of time (e.g. 14–28 days). the lack of follow-up and utilisation of non-age-matched control and patient groups are limitations of the present study. additionally, the difference between cases of s or ri could not be distinguished at day two; cq resistance may therefore have been underestimated due to the short follow-up period. a further limitation was the use of cq over artemisinin-based combination therapy (act). in 2005, the nmcp in yemen replaced cq with act as the first line of antimalarial therapy. unfortunately, however, this policy was not implemented in practice until 2009.16,17 nevertheless, regardless of current antimalarial treatment guidelines, cq remains the second most common antimalarial drug prescribed by physicians in public and private health facilities in yemen.16 as such, the results of this study should be utilised to educate health workers and medication manufacturers in yemen as to the potential risk of cq co-administration among khat-chewing patients. current anti-malarial drug practices in yemen should be modified accordingly and physicians should advise patients not to chew khat whilst undergoing cq treatment. conclusion the findings of this study revealed that cq plasma levels were significantly reduced by khat-chewing; however, khat-chewing had no significant influence on rates of p. falciparum parasite clearance among malaria patients. the rate of cq resistance among the patient group was above the acceptable levels determined by the who, indicating high cq resistance in these areas of yemen. based on these preliminary findings, patients should be advised not to chew khat whilst undergoing cq treatment. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. references 1. ali bh, al-qarawi a, mousa hm. effect of grapefruit juice on plasma chloroquine kinetics in mice. clin exp pharmacol physiol 2002; 29:704–6. doi: 10.1046/j.1440-1681.2002.03722.x. 2. crevoisier c, handschin j, barré j, roumenov d, kleinbloesem c. food increases the bioavailability of mefloquine. eur j clin pharmacol 1997; 53:135–9. doi: 10.1007/s002280050351. 3. mahmoud bm, ali hm, homeida mm, bennet jl. significant reduction in chloroquine bioavailability following coadministration with the sudanese beverages aradaib, karkadi and lemon. j antimicrob chemother 1994; 33:1005–9. doi: 10.1093/jac/33.5.1005. 4. rolan pe, mercer aj, weatherley bc, holdich t, meire h, peck rw, et al. examination of some factors responsible for a food-induced increase in absorption of atovaquone. br j clin pharmacol 1994; 37:13–20. doi: 10.1111/j.1365-2125.1994. tb04232.x. 5. tulpule a, krishnaswamy k. effect of food on bioavailability of chloroquine. eur j clin pharmacol 1982; 23:271–3. doi: 10.1007/bf00547567. 6. welling pg. effects of food on drug absorption. pharmacol ther 1989; 43:425‒41. doi: 10.1016/0163-7258(89)90019-3. 7. izzo aa. herb-drug interactions: an overview of the clinical evidence. fundam clin pharmacol 2005; 19:1–16. doi: 10.1111 /j.1472-8206.2004.00301.x. 8. kennedy jg. the flower of paradise: the institutionalized use of the drug qat in north yemen. dondreoht, netherlands: springer, 1987. pp. 783–9. 9. kalix p. khat: a plant with amphetamine effects. j subst abuse treat 1988; 5:163–9. doi: 10.1016/0740-5472(88)90005-0. 10. attef oa, ali aa, ali hm. effect of khat chewing on the bioavailability of ampicillin and amoxycillin. j antimicrob chemother 1997; 39:523–5. doi: 10.1093/jac/39.4.523. 11. hamed ff, ali ao, ahmed aa. the influence of khat on the in-vitro and in-vivo availability of tetracycline-hcl. res j pharm dosage forms technol 2015; 7:1–6. doi: 10.5958/09754377.2015.00001.4. 12. middle east health. regional profile: yemen the burden of poverty. from: www.middleeasthealthmag.com/jan2006/ yemen_profille.htm accessed: jan 2016. http://dx.doi.org/10.1046/j.1440-1681.2002.03722.x http://dx.doi.org/10.1007/s002280050351 http://dx.doi.org/10.1093/jac/33.5.1005 http://dx.doi.org/10.1111/j.1365-2125.1994.tb04232.x http://dx.doi.org/10.1111/j.1365-2125.1994.tb04232.x http://dx.doi.org/10.1007/bf00547567 http://dx.doi.org/10.1016/0163-7258%2889%2990019-3 http://dx.doi.org/10.1111/j.1472-8206.2004.00301.x http://dx.doi.org/10.1111/j.1472-8206.2004.00301.x http://dx.doi.org/10.1016/0740-5472%2888%2990005-0 http://dx.doi.org/10.1093/jac/39.4.523 http://dx.doi.org/10.5958/0975-4377.2015.00001.4 http://dx.doi.org/10.5958/0975-4377.2015.00001.4 effect of khat (catha edulis) use on the bioavailability, plasma levels and antimalarial activity of chloroquine e188 | squ medical journal, may 2016, volume 16, issue 2 13. world health organization. yemen: neonatal and child health profile. from: www.who.int/maternal_child_adolescent/epidem iology/profiles/neonatal_child/yem.pdf accessed: jan 2016. 14. ketema t, yohannes m, alemayehu e, ambelu a. effect of chronic khat (catha edulis, forsk) use on outcome of plasmodium berghei anka infection in swiss albino mice. bmc infect dis 2015; 15:170. doi: 10.1186/s12879-015-0911-2. 15. ketema t, bacha k, alemayehu e, ambelu a. incidence of severe malaria syndromes and status of immune responses among khat chewer malaria patients in ethiopia. plos one 2015; 10:e0131212. doi: 10.1371/journal.pone.0131212. 16. bin ghouth as. availability and prescription practice of antimalaria drugs in the private health sector in yemen. j infect dev ctries 2013; 7:404–12. doi: 10.3855/jidc.2528. 17. national malaria control programme of yemen. report on the final results of the national malaria indicator survey: 2009. from: www.mophp-ye.org/arabic/docs/report2009.pdf accessed: jan 2016. 18. na-bangchang k, limpaibul l, thanavibul a, tan-ariya p, karbwang j. the pharmacokinetics of chloroquine in healthy thai subjects and patients with plasmodium vivax malaria. br j clin pharmacol 1994; 38:278–81. doi: 10.1111/j.13652125.1994.tb04354.x. 19. walker o, salako la, alván g, ericsson o, sjöqvist f. the disposition of chloroquine in healthy nigerians after single intravenous and oral doses. br j clin pharmacol 1987; 23:295–301. doi: 10.1111/j.1365-2125.1987.tb03048.x. 20. halket jm, karasu z, murray-lyon im. plasma cathinone levels following chewing khat leaves (catha edulis forsk). j ethnopharmacol 1995; 49:111–13. doi: 10.1016/0378-8741(95) 90038-1. 21. world health organization. basic malaria microscopy: part 1 learner’s guide. 2nd ed. from: apps.who.int/iris/ bitstream/10665/44208/1/9789241547826_eng.pdf accessed: jan 2016. 22. bell dj, nyirongo sk, molyneux me, winstanley pa, ward sa. practical hplc methods for the quantitative determination of common antimalarials in africa. j chromatogr b analyt technol biomed life sci 2007; 847:231–6. doi: 10.1016/j. jchromb.2006.10.020. 23. world health organization. chemotherapy of malaria and resistance to antimalarials: report of a who scientific group. world health organ tech rep ser 1973; 529:1‒121. 24. world health organization. assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria, december 2003. from: www.who.int/malar ia/publications/atoz/whohtmrbm200350/en/ accessed: jan 2016. 25. osorio le, giraldo le, grajales lf, arriaga al, andrade al, ruebush tk 2nd, et al. assessment of therapeutic response of plasmodium falciparum to chloroquine and sulfadoxinepyrimethamine in an area of low malaria transmission in colombia. am j trop med hyg 1999; 61:968–72. doi: 10.1590/ s0074-02762002000400020. 26. halbach h. medical aspects of the chewing of khat leaves. bull world health organ 1972; 47:21–9. 27. edwards g, looareesuwan s, davies aj, wattanagoon y, phillips re, warrell da. pharmacokinetics of chloroquine in thais: plasma and red-cell concentrations following an intravenous infusion to healthy subjects and patients with plasmodium vivax malaria. br j clin pharmacol 1988; 25:477–85. doi: 10.1111/j.1365-2125.1988.tb03332.x. 28. mubjer ra, adeel aa, chance ml, hassan aa. molecular markers of anti-malarial drug resistance in lahj governorate, yemen: baseline data and implications. malar j 2011; 10:245. doi: 10.1186/1475-2875-10-245. 29. alkadi ho, al-maktari mt, nooman ma. chloroquineresistant plasmodium falciparum local strain in taiz governorate, republic of yemen. chemotherapy 2006; 52:166– 70. doi: 10.1159/000093592. 30. al-mekhlafi am, mahdy ma, al-mekhlafi hm, azazy aa, fong my. high frequency of plasmodium falciparum chloroquine resistance marker (pfcrt t76 mutation) in yemen: an urgent need to re-examine malaria drug policy. parasit vectors 2011; 4:94. doi: 10.1186/1756-3305-4-94. 31. al-hebshi n, al-haroni m, skaug n. in vitro antimicrobial and resistance-modifying activities of aqueous crude khat extracts against oral microorganisms. arch oral biol 2006; 51:183–8. doi: 10.1016/j.archoralbio.2005.08.001. 32. françois g, bringmann g, dochez c, schneider c, timperman g, aké assi l. activities of extracts and naphthylisoquinoline alkaloids from triphyophyllum peltatum, ancistrocladus abbreviatus and ancistrocladus barteri against plasmodium berghei (anka strain) in vitro. j ethnopharmacol 1995; 46:115– 20. doi: 10.1016/0378-8741(95)01240-e. 33. garavito g, rincón j, arteaga l, hata y, bourdy g, gimenez a, et al. antimalarial activity of some colombian medicinal plants. j ethnopharmacol 2006; 107:460–2. doi: 10.1016/j. jep.2006.03.033. http://dx.doi.org/10.1186/s12879-015-0911-2 http://dx.doi.org/10.1371/journal.pone.0131212 http://dx.doi.org/10.3855/jidc.2528 http://dx.doi.org/10.1111/j.1365-2125.1994.tb04354.x http://dx.doi.org/10.1111/j.1365-2125.1994.tb04354.x http://dx.doi.org/10.1111/j.1365-2125.1987.tb03048.x http://dx.doi.org/10.1016/0378-8741%2895%2990038-1 http://dx.doi.org/10.1016/0378-8741%2895%2990038-1 http://dx.doi.org/10.1016/j.jchromb.2006.10.020 http://dx.doi.org/10.1016/j.jchromb.2006.10.020 http://dx.doi.org/10.1590/s0074-02762002000400020 http://dx.doi.org/10.1590/s0074-02762002000400020 http://dx.doi.org/10.1111/j.1365-2125.1988.tb03332.x http://dx.doi.org/10.1186/1475-2875-10-245 http://dx.doi.org/10.1159/000093592 http://dx.doi.org/10.1186/1756-3305-4-94 http://dx.doi.org/10.1016/j.archoralbio.2005.08.001 http://dx.doi.org/10.1016/0378-8741%2895%2901240-e http://dx.doi.org/10.1016/j.jep.2006.03.033 http://dx.doi.org/10.1016/j.jep.2006.03.033 department of orthodontics, paedodontics and preventive dentistry, faculty of dentistry, university of khartoum, khartoum, sudan *corresponding author’s e-mails: m73827842@gmail.com and maalqadi@nu.edu.sa موثوقّية طريقيت دميريجيان وفيشمان يف التنبؤ بالعمر الزمين لدى أطفال اليمن مكتوم القا�سي و اآمال اأبو عفان abstract: objectives: there has been an increasing need for reliable chronological age (ca) estimation in several aspects, including orthodontic treatment needs and legal, civil and forensic purposes. this study aimed to assess the validity of the demirjian and fishman methods in predicting the ca of yemeni children. methods: this descriptive cross-sectional study was conducted at seven schools in sana’a, yemen, between december 2016 and december 2017. one orthopantomograph and one left hand-wrist x-ray were obtained for each child to calculate the dental age (da) and skeletal age (sa) which were correlated and compared with the ca. results: a total of 358 yemeni children aged 8–16 years were included in this study. the mean ca, da and sa were 12.00 ± 2.25, 11.34 ± 2.42 and 12.39 ± 1.65 years, respectively. the demirjian method significantly underestimated the ca by 0.58 ± 1.25 years in the total sample and 0.73 ± 1.30 and 0.40 ± 1.17 years in males and females, respectively (p <0.001). the fishman method significantly underestimated the ca by 0.23 ± 1.19 and 0.44 ± 1.26 years in the total sample and in males, respectively (p ≤0.02). the fishman method insignificantly underestimated the females ca by 0.02 ± 1.08 years (p = 0.898). conclusions: yemeni ca is highly correlated to da and sa estimated by the demirjian and fishman methods, respectively. the fishman method was more accurate amongst yemeni females. results showed that yemeni children are delayed in dental development and skeletal maturity. keywords: age determination by teeth; age determination by skeleton; children; adult children; diagnostic imaging; yemen. الأ�سنان تقومي عالج احتياجات تت�سمن وهذه جوانب. عدة من املوثوق الزمني العمر لتقدير متزايدة حاجة هناك الهدف: امللخ�ص: تقدير يف وفي�سمان دميريجيان طريقتي من لكل املوثوقية لتقييم الدرا�سة هذه هدفت ال�رسعي. والطب واملدنية القانونية والأغرا�ض العمر الزمني لدى الأطفال اليمنيني. الطريقة: اأجريت هذه الدرا�سة الو�سفية امل�ستعر�سة يف �سبع مدار�ض يف �سنعاء، اليمن بني دي�سمرب 2016 ودي�سمرب 2017. ومت تقدير عمر الفرد بوا�سطة الفح�ض ال�سعاعي حلالة تطور الأ�سنان اأو م�ستوى الن�سج لعظام الكف والر�سغ. اأخذت العمر مع ومقارنتهما العظمي والعمر ال�سني العمر حل�ساب الدرا�سة، يف طفل لكل والر�سغ للكف �سينية واأ�سعة للفكني بانورامية �سورة والعظمي وال�سني الزمني العمر متو�سط كان عاًما. 16 و 8 بني اأعمارهم ترتاوح مينًيا طفاًل 358 على الدرا�سة متت النتائج: الزمني. 12.00 ± 2.25، 11.43 ± 2.42 و 12.39 ± 1.65 �سنة، على التوايل. اأظهرت طريقة دميريجيان تقديرا منخف�سا ذا دللة اإح�سائّية للعمر .)p >0.001( الزمني مبقدار 0.58 ± 1.25 �سنة يف العينة الكاملة و 0.73 ± 1.30 و 0.40 ± 1.17 �سنة لكل من البنني والبنات على التوايل كما اأظهرت طريقة في�سمان انخفا�سا ذا دللة اإح�سائّية للعمر الزمني مبقدار 0.23 ± 1.19 و 0.44 ± 1.26 �سنة يف العينة الكلّية والبنني على التوايل)p ≤0.02(، بينما اأظهرت طريقة في�سمان انخفا�سا طفيفا غري دال اإح�سائّيا للعمر الزمني لدى البنات مبقادر 0.02 ± 1.08 �سنة )p = 0.898(. اخلال�صة: اأظهرت النتائج اأّن العمر الزمني يرتبط ب�سكل قوّي بكٍل من العمر ال�سني والعمر العظمي املقّدر بطريقة دميريجيان وطريقة في�سمان على التوايل. وظهر اأّن طريقة في�سمان اكرث دقة عند البنات اليمنيات. كما اأت�سح باأّن لدى الأطفال اليمنيني تاأخر زمني يف التطور ال�سني والن�سج العظمي. الكلمات املفتاحية: العمر ال�سني؛ العمر العظمي؛ اأطفال؛ اأطفال بالغني؛ الت�سوير الت�سخي�سي؛ اليمن. validity of the demirjian and fishman methods for predicting chronological age amongst yemeni children *maktoom a. alqadi and amal h. abuaffan clinical & basic research sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e26–31, epub. 30 may 19 submitted 1 nov 18 revisions req. 6 dec & 24 dec 18; revisions recd. 9 dec & 27 dec 18 accepted 10 jan 19 advances in knowledge yemeni children are delayed in skeletal maturation and dental development in relation to demirjian and fishman standards. to the best of the authors’ knowledge, this is the first study investigating the applicability of chronological age estimating methods in the yemeni population. application to patient care orthodontists should not rely on yemeni chronological age to assign the proper age for growth modification using functional appliances. the demirjian and fishman methods are not applicable for clinical orthodontic implementations but can be acceptable for legal, civil and forensic purposes. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.006 https://creativecommons.org/licenses/by-nd/4.0/ maktoom a. alqadi and amal h. abuaffan clinical and basic research | e27 prediction of chronological age (ca) hasbecome important for orthodontic diagnosis and treatment as well as for civil purposes.1,2 different methods have been suggested to predict the ca based on skeletal maturity or dental development.3,4 dental and skeletal age estimation methods are valuable approaches in predicting the ca when birth data are missing.5 the validity of these methods will have clinical importance in the reliability of orthodontic diagnosis and treatment planning. the demirjian method is a dental age (da) estimating technique which uses a radiographic assessment of dental development of the left mandibular teeth, excl uding the third molar.4 several studies have been cond ucted to assess the applicability of the demirjian method to predict the ca amongst different populations; the method has shown an overestimation of ca of turkish, indian and saudi children and an underestimation of tunisian, kuwaiti and chinese children.6–11 however, the demirjian method has been accurate in ca pred iction for sudanese and omani children.12,13 jayaraman et al. found that the demirjian method tends to over estimate the age of both genders (overestimation of 0.60 and 0.65 years for males and females, respectively).14 the fishman method is based on skeletal maturity indicators (smi) and is widely used to estimate the skeletal age (sa) by hand-wrist x-ray.3 the sa is closely related to child growth and considered to be the most reliable method for assessing maturation status, although affected by ethnicity.15,16 definite variations between genders and races were found in the ca and in the timing of skeletal maturity. the smi method, which is related to the over all maxillofacial growth velocity, was found to have high discriminant validity between individuals’ pubertal stages and is clinically acceptable to predict the peak growth of the mandible.17,18 however, studies aimed at validating the smi method for predicting the ca showed incon sistent results.19–21 the fishman method was accurate when predicting the ca of indian children and was inacc urate for indonesian and lebanese children; this method was more accurate when compared to the demirjian method.19–21 the applicability of the demirjian and/or fishman methods will help to accurately determine the ca of children without a birth certificate for functional ortho dontic intervention without the need of hand-wrist radiographs. to the best of the authors’ knowledge, no study has been conducted on yemeni children to invest igate the applicability of the demirjian, fishman or any age estimating methods. this study aimed to val idate the fishman and demirjian methods in pred icting the ca of yemeni children. methods this descriptive cross-sectional study was conducted between december 2016 and december 2017. partic ipants were aged 8–16 years, resided in sana’a, yemen, and both parents were yemeni. the exclusion criteria for this study were as follows: 1) presence of any congenital, nutritional or systemic disorder; 2) presence of peri apical lesion or trauma to the lower jaw or left handwrist; 3) congenitally missing or supernumerary teeth; and 4) children who were at the time or had previously had orthodontic or oral surgical treatment. the sample size was calculated using the following equation: where α is the type one error (probability of rejecting standard normal distribution table set at 1.96, 1-β is the power of the test sets at 80%, z1-β is the critical value from standard normal distribution table set as 0.84, is the difference in means for matched groups and sd is the standard deviation calculated from a previous study.22 the sample size was calculated based on a previous study conducted on a turkish population.22 therefore, the effective minimum sample size calculated was 238 children [equation 1]. the sample in the current study was increased to a total of 358 children for more precision and collected via a cluster random sampling technique in three out of the ten directorates of sana’a. two public schools from the first directorate, two public schools from the second directorate and three private schools from the third directorate were randomly selected by the authors and the head office of education in sana’a. students from each school were conveniently sampled and stratified according to age and gender, with a one year interval [table 1]. table 1: distribution of the study sample according to age and gender (n = 358) age group in years (age range) n (%) male female total 8 (8–8.999) 21 (10.9) 23 (13.9) 44 (12.3) 9 (9–9.999) 17 (8.8) 18 (10.9) 35 (9.8) 10 (10–10.999) 28 (14.5) 21 (12.7) 49 (13.7) 11 (11–11.999) 35 (18.1) 24 (14.5) 59 (16.5) 12 (12–12.999) 29 (15) 22 (13.3) 51 (14.2) 13 (13–13.999) 21 (10.9) 21 (12.7) 42 (11.7) 14 (14–14.999) 16 (8.3) 14 (8.5) 30 (8.4) 15 (15–15.999) 26 (13.5) 22 (13.3) 48 (13.4) total 193 (53.9) 165 (46.1) 358 (100) [equation 1] true hypothesis) set at 0.05, is the critical value from n = 2(z1z1d (d/sd)2 α α 2 2 + z1-β) 2 validity of the demirjian and fishman methods for predicting chronological age amongst yemeni children e28 | squ medical journal, february 2019, volume 19, issue 1 one orthopantomograph (opg) and one left hand wrist radiograph (hwr) were obtained for each child by the same operator and with the same machine (paxflex3d, vatech, republic of korea) in accordance with the manufacturer’s instructions. all x-rays were assessed for their anatomical clearness and for age prediction by the authors. the date of birth of each child was obtained from the child’s birth certificate. the ca was calculated in years by subtracting the date of birth from the date of radiographing divided by 365. the da was calculated according to the demirjian method from the digital opg. each of the seven lower left teeth, excluding the third molar, was represented by a letter (a–h) based on its developmental stage.4 each letter was matched with its specific self-weighted score in tooth gender-specific tables. the total score of the seven teeth was converted to da according to the gender-specific tables of the demirjian method.4 the sa was calculated in accordance with the fishman method. each child’s left hwr was assessed for assignment of the smi, as shown in a scheme suggested by fishman.3 the assigned smi was matched to the corresponding sa. the first stage of skeletal maturation in the fishman method using the smi of the proximal phalanx of the third finger (pp3) begins at ages 11.01 and 9.94 years for males and females, respectively. the lower limit of the childrens’ ages in this study was eight years; the children who did not reach the lower limit for pp3 stage were excluded from statistical comparisons because they cannot be scored by the fishman method. the data were statistically described and analysed with the statistical package for the social sciences (spss), version 21 (ibm corp., armonk, new york, usa). descriptive statistics were determined for the total ca, da and sa. comparative analysis was conducted for the assessment of the statistically significant differences between the means for the children and within age groups for both genders. the kolmogorov-smirnov test showed a non-normal distribution of data. nonparametric tests were used for the correlation and comparison among the measurement methods within age groups and by genders. a value of p <0.05 was considered statistically significant. in addition, the ca was subtracted from the da and sa. a positive value indicated overestimation, whereas a negative value indicated an underestimation of ca by the method. regression models were used to predict the ca by da and sa. after six weeks, 60 randomly selected part icipants were rescored to evaluate the reliability of the demirjian and fishman methods by using the dahlberg equation. an ethical approval was obtained from the faculty of dentistry, university of khartoum, khartoum, sudan as this study was part of a doctoral thesis. letters were sent by the author via the selected schools to children’s parents to be signed for informed consent. results a total of 358 yemeni children were included in this study. the mean ca for the total sample was 12.00 ± 2.25 years (12.06 ± 2.24 years for males and 11.94 ± 2.46 years for females). the lowest mean age of 11.43 ± 2.42 years for the total sample was found using the demirjian method (11.33 ± 2.40 and 11.54 ± 2.46 years for males and females, respectively), whereas the highest mean age of 12.39 ± 1.65 years was noted using the fishman method (12.53 ± 1.50 and 12.25 ± 1.77 years for males and females, respectively). a wilcoxon signed-rank test showed significant differences between the ca and sa for males (p = 0.001) and between the ca and da for both genders (p <0.001 each) [table 2]. the ca for males was underestimated by both methods, yet the fishman method was closer to the ca than the demirjian method (−0.44 ± 1.26 versus −0.73 ± 1.30; p ≤0.001). for females, the da showed a significant age underestimation (p <0.001), while no significant difference was noted between the ca and sa (p = 0.898). intraclass correlation coefficient (icc) showed a strong correlation amongst the ca, da and sa for the total sample and gender; the correl table 2: correlation and comparison of chronological, dental and skeletal age of yemeni children (n = 358) comparison mean difference ± sd p value* icc (95% ci) p value* ca (total) da (n = 358) −0.58 ± 1.25 <0.001 0.923 (0.906–0.938) <0.001 sa (n = 292)† −0.23 ± 1.19 0.02 0.882 (0.852–0.906) <0.001 ca (males) da (n = 193) −0.73 ± 1.30 <0.001 0.915 (0.888–0.936) <0.001 sa (n = 142)† −0.44 ± 1.26 0.001 0.831 (0.765–0.879) <0.001 ca (females) da (n = 165) −0.40 ± 1.17 <0.001 0.935 (0.911–0.952) <0.001 sa (n = 150)† −0.02 ± 1.08 0.898 0.917 (0.885–0.940) <0.001 sd = standard deviation; icc = intraclass correlation coefficient; ci = confidence interval; ca = chronological age; da = dental age; sa = skeletal age. *using the wilcoxon signed-rank test and intraclass correlation coefficient. †sample size varies from total due to exclusion of some children for not reaching the lower limit for analysis of the proximal phalanx of the third finger. maktoom a. alqadi and amal h. abuaffan clinical and basic research | e29 ation value was higher amongst females in both methods (p <0.001 each) [table 2]. there were significant differences found between ca and da in all age groups (p <0.05), except in the 13-year-olds age group, the male 8-year-olds age group and the female 9-, 10and 14-year-olds age group. signif icant differences between the ca and sa were found in all age groups, except in the 11-year-olds and the female 12-, 13and 14-year-olds age groups. for the sa, the males in the age groups 8 and 9 years were not compared as there were only two and zero males in these groups, respectively [table 3]. the regression models showed very narrow conf idence intervals for the intercept and slope, for both methods and both genders (p <0.001) [table 4]. during preliminary testing on the study sample, the models yielded adjusted r2 values of 71% and 78% for males and females, respectively, using the demirjian method. for the fishman method, the regression models yielded adjusted r2 values of 61% and 55% for males and females, respectively. the dahlberg equation showed minimum error values (0.30 and 0.34 year) for the demirjian and fishman methods representing relative errors of 2.6% and 3.8%, respectively. this showed that the two methods are highly reproducible. discussion this study aimed to assess the validity of the demirjian and fishman methods in predicting the ca of yemeni children. the results of the current study could aid clinical orthodontists in predicting the ca of children with no birth certificates and, therefore, appropriately timing intervention therapy to avoid the development of malocclusion. in the current study, the demirjian method app eared to be more accurate for females than for males when comparing ca to da. the demirjian method underestimated the ca for both genders with a higher deviation in males. this result indicates that yemeni children are delayed in dental maturity relative to children from other regions.14 ca underestimation and overest imation by the demirjian method has been observed in other studies.11,23–25 however, the demirjian method has shown applicability in other populations.12,26 the differences in the obtained results amongst the different populations may be attributed to the statistical tests, sample size, age groups and study population. in the current study, the regression models used to predict the ca through da estimated by the demirjian method were highly significant. based on the results of this study, a high correlation coefficient value was found between the ca and sa, with a higher value in females than males; this finding is in agreement with previous studies.19,21 the fishman method significantly overestimated ca for age groups table 3: comparison between chronological, dental and skeletal age for yemeni children (n = 358) age group in years gender mean ± sd p value ca da sa* ca versus da ca versus sa 8 m (n = 21) 8.5 ± 0.26 8.28 ± 0.8 11.01 ± 0† 0.075 nc f (n = 23) 8.63 ± 0.29 8.22 ± 0.9 10.22 ± 0.34‡ 0.048 0.008 9 m (n = 17) 9.43 ± 0.24 8.79 ± 0.99 na§ 0.022 na f (n = 18) 9.61 ± 0.33 9.74 ± 1.09 10.46 ± 0.34¶ 0.616 <0.001 10 m (n = 28) 10.56 ± 0.27 9.90 ± 1.09 11.17 ± 0.29¶ 0.003 <0.001 f (n = 21) 10.54 ± 0.34 10.35 ± 1.16 10.96 ± 0.6 0.715 0.002 11 m (n = 35) 11.48 ± 0.27 10.78 ± 1.16 11.58 ± 0.42\\ 0.004 0.357 f (n = 24) 11.35 ± 0.26 10.58 ± 1.13 11.1 ± 0.86 0.002 0.17 12 m (n = 29) 12.59 ± 0.28 11.52 ± 1.37 12.12 ± 0.83 <0.001 0.005 f (n = 22) 12.56 ± 0.32 12.06 ± 1.09 12.33 ± 0.84 0.02 0.095 13 m (n = 21) 13.58 ± 0.26 13.29 ± 1.54 12.8 ± 1.22 0.394 0.017 f (n = 21) 13.57 ± 0.31 13.45 ± 1.22 13.53 ± 1.21 0.781 0.689 14 m (n = 16) 14.62 ± 0.29 13.66 ± 1.47 13.32 ± 1.49 0.026 0.005 f (n = 14) 14.52 ± 0.29 14.09 ± 1.47 13.84 ± 1.2 0.433 0.096 15 m (n = 26) 15.62 ± 0.29 14.53 ± 1.51 14.46 ± 1.44 0.004 <0.001 f (n = 22) 15.46 ± 0.28 14.81 ± 1.31 14.63 ± 1.06 0.036 0.001 sd = standard deviation; ca = chronological age; da = dental age; sa = skeletal age; m = male; nc = not computed; f = female; na = not applicable. *sample size may vary between age groups due to some children not reaching the lower limit for analysis of the proximal phalanx of the third finger. †n = 2. ‡n = 9. §n = 0. ¶n = 17. \\n = 31. table 4: regression analysis using demirjian and fishman methods showing adjusted r2 amongst yemeni children (n = 358) method g param coef se 95% ci p value adj. r2 demirjian m intercept 3.12 0.42 2.294–3.950 <0.001 0.71 slope 0.79 0.04 0.718–0.861 <0.001 f intercept 2.50 0.40 1.719–3.289 <0.001 0.78 slope 0.82 0.03 0.751–0.884 <0.001 fishman m intercept 9.21 0.19 8.833–9.589 <0.001 0.61 slope 0.31 0.02 0.274–0.343 <0.001 f intercept 7.14 0.36 6.431–7.846 <0.001 0.55 slope 0.43 0.03 0.371–0.491 <0.001 g = gender; param = parameter; coef = coefficient; se = standard error; ci = confidence intervals; adj. = adjusted; m = male; f = female. validity of the demirjian and fishman methods for predicting chronological age amongst yemeni children e30 | squ medical journal, february 2019, volume 19, issue 1 of 8, 9 and 10 years for females and age group of 10 years for males. this overestimation by the fishman method may be attributed to the inability of the method to estimate the sa for children under 10 and 11 years of age for females and males, respectively. mohammed et al. found no significant difference between ca and sa amongst indian females of 12, 13 and 14 years; this is in agreement with the current results.19 however, saade et al. found a significant over estimation for the age groups of 8–16 years amongst lebanese children; this differs from the current study’s findings and may be attributed to the differences in sample size, group age intervals or other environmental and genetic factors.21 the variations amongst different populations may be partially attributed to methodological factors or to other factors, such as changes in socio economic condition or a large malnutritional range.27,28 world health organization reported that yemen is one of the top countries suffering from poor nutrition.29 the demirjian and fishman methods showed more accurate estimations amongst females than males. the biggest difference in mean ca amongst the age groups was observed with the fishman method. the r2 for the line of best fit was higher with the demirjian method than the fishman method for both genders and the minimum constant value and highest slope value (closest to 1) were also found with the demirjian method for both genders. a one-year difference between ca and da was considered acceptable for legal authorities and forensic purposes.30 therefore, both the demirjian and the fish man method can be used for predicting the ca of yemeni children with no birth certificate, for legal pur poses such as school enrolment and marriage age determ ination as well as for forensic purposes. the yemeni ca is not a strong diagnostic aid for assigning the proper timing for orthodontic growth modification by functional appliances. the main limitation of this study is that the regression models used to predict the ca through sa and da estimated by the fishman and demirjian methods, respectively, still need to be validated. conclusions there is a strong correlation between ca and da estimated by the demirjian method and between ca and sa estimated by the fishman method. however, both methods underestimated the ca of yemeni children. although the underestimation was less for females than for males, orthodontists should not rely on the ca of yemeni children to assign the proper age for growth modification by functional appliances; however, sa is the more suitable method to allocate the correct timing for orthodontic functional treatment. both the demirjian and fishman methods are considered acceptable for predicting the ca of yemeni children with no birth certificate for legal, civil and forensic purposes. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. krailassiri s, anuwongnukroh n, dechkunakorn s. relationships between dental calcification stages and skeletal maturity indicators in thai individuals. angle orthod 2002; 72:155–66. 2. willems g. a review of the most commonly used dental age estimation techniques. j forensic odontostomatol 2001; 19:9–17. 3. fishman ls. radiographic evaluation of skeletal maturation. a clinically oriented method based on hand-wrist films. angle orthod 1982; 52:88–112. 4. demirjian a, goldstein h, tanner jm. a new system of dental age assessment. hum biol 1973; 45:211–27. 5. maber m, liversidge hm, hector mp. accuracy of age estimation of radiographic methods using developing teeth. forensic sci int 2006; 159 suppl 1:s68–73. https://doi.org/10.1016/j.fors ciint.2006.02.019. 6. apaydin bk, yasar f. accuracy of the demirjian, willems and cameriere methods of estimating dental age on turkish children. niger j clin pract 2018; 21:257–63. 7. hegde s, patodia a, dixit u. a comparison of the validity of the demirjian, willems, nolla and häävikko methods in determination of chronological age of 5–15 year-old indian children. j forensic leg med 2017; 50:49–57. https://doi.org/10.1016/j.jf lm.2017.07.007. 8. alshihri am, kruger e, tennant m. dental age assessment of 4–16 year old western saudi children and adolescents using demirjian’s method for forensic dentistry. egypt j forensic sci 2016; 6:152–6. https://doi.org/10.1016/j.ejfs.2015.03.003. 9. aissaoui a, salem nh, mougou m, maatouk f, chadly a. dental age assessment among tunisian children using the demirjian method. j forensic dent sci 2016; 8:47–51. https://doi.org/10. 4103/0975-1475.176956. 10. qudeimat ma, behbehani f. dental age assessment for kuwaiti children using demirjian's method. ann hum biol 2009; 36:695–704. https://doi.org/10.3109/03014460902988702. 11. zhai y, park h, han j, wang h, ji f, tao j. dental age assessment in a northern chinese population. j forensic leg med 2016; 38:43–9. https://doi.org/10.1016/j.jflm.2015.11.011. 12. hasan bm, abuaffan ah. correlation between chronological age, dental age and skeletal maturity in a sample of sudanese children. global j med res 2016; 16:12–21. 13. al balushi s, thomson wm, al-harthi l. dental age estimation of omani children using demirjian's method. saudi dent j 2018; 30:208–13. https://doi.org/10.1016/j.sdentj.2018.04.005. 14. jayaraman j, wong hm, king nm, roberts gj. the frenchcanadian data set of demirjian for dental age estimation: a systematic review and meta-analysis. j forensic leg med 2013; 20:373–81. https://doi.org/10.1016/j.jflm.2013.03.015. https://doi.org/10.1016/j.forsciint.2006.02.019 https://doi.org/10.1016/j.forsciint.2006.02.019 https://doi.org/10.1016/j.jflm.2017.07.007 https://doi.org/10.1016/j.jflm.2017.07.007 https://doi.org/10.1016/j.ejfs.2015.03.003 https://doi.org/10.4103/0975-1475.176956 https://doi.org/10.4103/0975-1475.176956 https://doi.org/10.3109/03014460902988702 https://doi.org/10.1016/j.jflm.2015.11.011 https://doi.org/10.1016/j.sdentj.2018.04.005 https://doi.org/10.1016/j.jflm.2013.03.015 maktoom a. alqadi and amal h. abuaffan clinical and basic research | e31 15. kiran s, sharma vp, tandon p, tikku t, verma s, srivastava k. to establish the validity of dental age assessment using nolla's method on comparing with skeletal age assessed by hand-wrist radiographs. j orthod res 2013; 1:11–15. https://doi.org/10.41 03/2321-3825.112250. 16. mansourvar m, ismail ma, raj rg, kareem sa, aik s, gunalan r, et al. the applicability of greulich and pyle atlas to assess skeletal age for four ethnic groups. j forensic leg med 2014; 22:26–9. https://doi.org/10.1016/j.jflm.2013.11.011. 17. flores-mir c, nebbe b, major pw. use of skeletal maturation based on hand-wrist radiographic analysis as a predictor of facial growth: a systematic review. angle orthod 2004; 74:118–24. 18. soegiharto bm, moles dr, cunningham sj. discriminatory ability of the skeletal maturation index and the cervical vertebrae maturation index in detecting peak pubertal growth in indonesian and white subjects with receiver operating charac teristics analysis. am j orthod dentofacial orthop 2008; 134:227–37. https://doi.org/10.1016/j.ajodo.2006.09.062. 19. mohammed rb, kalyan vs, tircouveluri s, vegesna gc, chirla a, varma dm. the reliability of fishman method of skeletal matur ation for age estimation in children of south indian population. j nat sci biol med 2014; 5:297–302. https://doi.org/10.4103/09 76-9668.136170. 20. soegiharto bm, cunningham sj, moles dr. skeletal maturation in indonesian and white children assessed with hand-wrist and cervical vertebrae methods. am j orthod dentofacial orthop 2008; 134:217–26. https://doi.org/10.1016/j.ajodo.2006.07.037. 21. saadé a, baron p, noujeim z, azar d. dental and skeletal age estimations in lebanese children: a retrospective cross-sectional study. j int soc prev community dent 2017; 7:90–7. 22. kırzıoğlu z, ceyhan d. accuracy of different dental age estimation methods on turkish children. forensic sci int 2012; 216:61–7. https://doi.org/10.1016/j.forsciint.2011.08.018. 23. cruz-landeira a, linares-argote j, martínez-rodríguez m, rodríguez-calvo ms, otero xl, concheiro l. dental age estim ation in spanish and venezuelan children. comparison of demir jian and chaillet’s scores. int j legal med 2010; 124:105–12. https://doi.org/10.1007/s00414-009-0380-5. 24. mani sa, naing l, john j, samsudin ar. comparison of two methods of dental age estimation in 7-15-year-old malays. int j paediatr dent 2008; 18:380–8. https://doi.org/10.1111/j.1365263x.2007.00890.x. 25. gungor oe, kale b, celikoglu m, gungor ay, sari z. validity of the demirjian method for dental age estimation for south ern turkish children. niger j clin pract 2015; 18:616–19. https://doi.org/10.4103/1119-3077.154216. 26. burt nm, sauer n, fenton t. testing the demirjian and the international demirjian dental aging methods on a mixed ancestry urban american subadult sample from detroit, mi. j forensic sci 2011; 56:1296–301. https://doi.org/10.1111/j.15564029.2011.01833.x. 27. ozer bk. growth reference centiles and secular changes in turkish children and adolescents. eco hum biol 2007; 5:280–301. https://doi.org/10.1016/j.ehb.2007.03.007. 28. garn sm, lewis ab, kerewsky rs. genetic, nutritional, and maturational correlates of dental development. j dent res 1965; 44:228–42. https://doi.org/10.1177/00220345650440011901. 29. world health organization. annual report 2017-yemen. cairo, egypt: world health organization regional office for the eastern mediterranean 2018. cc bync-sa 3.0 igo p. 22. 30. chaillet n, nyström m, kataja m, demirjian a. dental maturity curves in finnish children: demirjian's method revisited and polynomial functions for age estimation. j forensic sci 2004; 49:1324–31. https://doi.org/10.1520/jfs2004211. https://doi.org/10.4103/2321-3825.112250 https://doi.org/10.4103/2321-3825.112250 https://doi.org/10.1016/j.jflm.2013.11.011 https://doi.org/10.1016/j.ajodo.2006.09.062 https://doi.org/10.1016/j.ajodo.2006.07.037 https://doi.org/10.1016/j.forsciint.2011.08.018 https://doi.org/10.1007/s00414-009-0380-5 https://doi.org/10.1111/j.1365-263x.2007.00890.x https://doi.org/10.1111/j.1365-263x.2007.00890.x https://doi.org/10.4103/1119-3077.154216 https://doi.org/10.1111/j.1556-4029.2011.01833.x https://doi.org/10.1111/j.1556-4029.2011.01833.x https://doi.org/10.1177/00220345650440011901 https://doi.org/10.1520/jfs2004211 1department of clinical pharmacy, jordan university of science & technology, irbid, jordan; 2department of clinical pharmacy & therapeutics, applied science private university, amman, jordan; 3department of biopharmaceutics & clinical pharmacy, university of jordan, amman, jordan; 4clinical pharmacy & practice research group, school of pharmacy, queen’s university belfast, belfast, uk *corresponding author’s e-mail: tlmukattash@just.edu.jo الرعاية الصيدالنية لألطفال املعرفة و التوجهات والقدرات لدى طالب السنة األخرية يف كليات الصيدلة يف األردن طارق لوي�س مقّط�س، عنان �شادق جّراب، رنا كمال اأبو فرحة، اإميان العفي�شات، جيم�س ماكيلناي abstract: objectives: pharmacists require a baseline level of knowledge in paediatric pharmaceutical care in order to be able to adequately care for paediatric patients and counsel their families. this study aimed to explore the self-reported knowledge, attitudes and competency of final-year pharmacy students in jordan regarding paediatric pharmaceutical care. methods: this study took place in jordan between november 2016 and may 2017. a 28-item questionnaire was designed and administered to 400 students from all pharmacy programmes in jordan during their final year of training. results: a total of 354 students agreed to take part in the study (response rate: 88.5%). most respondents (95.2%) were aware of the term ‘paediatrics’. however, almost one-third of the respondents (30.5%) reported never having taken paediatric dose calculation courses and more than half (55.6%) were unfamiliar with the term ‘off-label medicines’. moreover, most respondents (65.1%) had low knowledge scores (≤2 out of 5) when presented with realistic paediatric case scenarios. there were no significant differences in knowledge and attitudes between undergraduate and doctoral students or between those from public or private universities (p >0.05). conclusion: the findings of this study highlight an alarming deficiency in paediatric pharmaceutical knowledge among final-year pharmacy students in jordan. as such, paediatric-related content should be emphasised in the pharmacy curricula of jordanian universities so that pharmacy students receive more formalised education and more extensive training in this area. keywords: pharmaceutical care; pediatrics; pharmacy students; knowledge; attitudes; competency-based education; jordan. الرعاية تقدمي من يتمكنوا حتى لالأطفال ال�شيدلنية الرعاية يف املعرفة من اأ�شا�شي م�شتوى اإىل ال�شيادلة يحتاج الهدف: امللخ�ص: الكافية لالأطفال املر�شى واإر�شاد عائالتهم. هدفت هذه الدرا�شة اإىل ا�شتك�شاف املعرفة و التوجهات والقدرات املتعلقة بالرعاية ال�شيدلنية لالأطفال لدى طالب ال�شنة الأخرية يف كليات ال�شيدلة يف الأردن. الطريقة: اأجريت هذه الدرا�شة يف الأردن يف الفرتة ما بني نوفمرب 2016 الأردن. يف ال�شيدلة برامج جميع �شمن الأخرية ال�شنة يف طالب 400 على توزيعه ومت بنًدا 28 من مكون ا�شتبيان �شمم .2017 ومايو معرفة على كانوا )95.2%( امل�شاركني معظم اأن تبنّي .)88.5% ال�شتجابة: )معدل الدرا�شة يف امل�شاركة على طالبًا 354 وافق النتائج: مب�شطلح "طب الأطفال". بينما اأفاد ما يقارب ثلث املجيبني )%30.5( باأنهم مل يتلقوا اأي دورات �شابقة حول طرق ح�شاب اجلرعات الدوائية لالأطفال وتبنّي اأن اأكرث من ن�شف املجيبني )%55.6( مل يكونوا على دراية مب�شطلح "ال�شتخدام غري امل�رصح لالأدوية". وعالوة على ذلك، ح�شل معظم امل�شتجيبني )%65.1( على ن�شب معرفة منخف�شة )2≥ من 5( عندما تعر�شوا ل�شيناريوهات. اقعية تتعلق بطب الأطفال ومل تكن هناك اختالفات كبرية مب�شتويات املعرفة والتوجهات بني الطالب اجلامعيني وطالب الدكتوراه اأو بني طالب اجلامعات احلكومية وطالب اجلامعات اخلا�شة )p <0.05(. اخلال�صة: تو�شح نتائج هذه الدرا�شة اأنه يوجد نق�س مثري للقلق مب�شتويات املعرفة ال�شيدلنية لالأطفال بني طالب ال�شنة الأخرية يف كليات ال�شيدلة يف الأردن. لذلك، يجب التاأكيد على املحتوى املتعلق بطب الأطفال يف مناهج ال�شيدلة يف اجلامعات الأردنية حتى يح�شل طالب ال�شيدلة على درجة اأعلى من التعليم الر�شمي والتدريب املكثف يف هذا املجال. الكلمات املفتاحية: الرعاية ال�شيدلنية؛ طب الأطفال؛ طالب ال�شيدلة؛ املعرفة؛ التوجهات؛ التعليم القائم على الكفاءة؛ الأردن. pharmaceutical care in children self-reported knowledge, attitudes and competency of final-year pharmacy students in jordan *tareq l. mukattash,1 anan s. jarab,1 rana k. abu-farha,2 eman alefishat,3 james c. mcelnay4 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e468–475, epub. 28 mar 19 submitted 4 apr 18 revision req. 21 may 18; revision recd. 31 may 18 accepted 5 jul 18 doi: 10.18295/squmj.2018.18.04.007 advances in knowledge to the best of the authors’ knowledge, this study is the first to explore the self-reported knowledge, attitudes and competency of final-year pharmacy students regarding paediatric pharmaceutical care. the present study highlights a perceived lack of specialised paediatric education and training in the pharmacy curricula at jordanian universities. application to patient care the findings of the current study highlight the importance of incorporating more specialised paediatric content within the pharmacy curricula in jordan; this will hopefully lead to the provision of safer and more effective pharmaceutical care to paediatric patients. tareq l. mukattash, anan s. jarab, rana k. abu-farha, eman alefishat and james c. mcelnay clinical and basic research | e469 children represent a significant proportion of the population requiring pharmacy services in a variety of hospital and community settings; as such, pharmacists play an essential role in paediatric care.1–4 due to advances in paediatric medicine, the increasing complexity of childhood diseases and unique dosing and pharmacokinetic challenges, there is growing need to educate pharmacists in basic paediatric competencies. furthermore, it is estimated that the use of prescription medications among paediatric patients is substantial; according to the centers for disease control and prevention, 14–20% of patients under 19 years old surveyed in 2008 reported having used at least one prescription drug in the preceding month.5,6 as a result, pharmacy curricula should emphasise a minimum level of paediatric pharmacotherapy competence; this could potentially help to lower the rate of paediatric medication errors.1,7 the provision of pharmaceutical care to children can be challenging, especially with regards to the appr opriate drug, dosage and route of administration. because of their relative lack of chronic ailments, children usually require fewer medications compared to adults; this, compounded with the various ethical and logistical barriers to studying the effects of medications among children, means that there are very few medications licensed for use among children.4 medications without the proper marketing authorisation are referred to as ‘unlicensed’, while off-label medications indicate licensed medicines which are prescribed or used in a manner not consistent with recommendations, for instance in terms of dose, route of administration or recommended age. according to the united nations, 37.7% of the popul ation in jordan is under 14 years old.8 moreover, pharm acists in jordan often act as primary care providers as, for financial reasons, they are often the first and only port of call for healthcare advice and medicine use by patients. wazaify et al. also reported that pharmacists in jordan often dispense non-prescribed medications, including antibiotics.9 as such, it is imperative that pharmacists in jordan have the necessary knowledge to provide safe and adequate care to paediatric patients, including the information needed to dispense medic ations and counsel paediatric patients or their guardians.7,10 however, due to a lack of national guidelines regarding paediatric care, pharmacists often rely on knowledge received during their education and training. the present study aimed to explore the self-reported knowledge, attitudes and competency of final-year pharmacy students in jordan regarding paediatric pharmaceutical care, including assessment, treatment and dosage. to the best of the authors’ knowledge, this is the first study to directly explore pharmacy students’ perceptions and attitudes regarding this topic. methods this study took place in jordan between november 2016 and may 2017 and involved all 400 final-year undergraduate (bachelor of science) and postgraduate (doctor of pharmacy) students from all pharmacy programmes in jordan. only students who had completed ≥85% of the credit-hours required for graduation at their specific university were included. a survey was designed to assess the students’ knowledge, attitudes and competency regarding paediatric pharmaceutical care. the content of the survey was based on the findings of an extensive literature review, in addition to one-on-one interviews conducted with staff members at all pharmacy faculties in jordan to assess the paediatric-related content of the existing curricula.11–17 subsequently, the survey was examined by experts in the fields of clinical pharmacy, pharmacy practice and paediatrics to determine the fitness for purpose and face and content validity of the instrument. the final version of the questionnaire was then tested in a pilot group of 50 final-year pharmacy students who were not included in the full study. the instrument was deemed valid, with a cronbach’s alpha coefficient of 0.87 for internal consistency. the final english-language questionnaire consisted of 28 items and was divided into four sections. the first section (items 1–7) collected the participants’ demographic information to allow for the examination of variability in responses according to various characteristics. section two (items 8–14) aimed to explore respondents’ knowledge of paediatric treatment and dosing. the third section (items 15–22) explored resp ondents’ perceptions of their abilities regarding paediatric treatment and dosing. the final section (items 23–28) consisted of five realistic case scenarios covering common paediatric complaints [table 1]. these case scenarios were chosen based on the recommendations of colleagues specialising in paediatric therapeutics and were assessed by a panel of experts prior to their inclusion in the survey. for each case scenario, the participants had to choose the single correct response out of five multiple-choice options; each correct answer received one point while wrong answers were scored as zero. the total knowledge score for the section was calculated by summing the correct answers, with five being the highest score, indicating perfect knowledge, and zero the lowest, indicating a complete lack of knowledge. the students were invited to take part in the survey at the end of specific lectures, as determined by appropriate members of the administration at each university. before distributing the questionnaire, one of the researchers introduced the study to the students and briefly described the contents and purpose of pharmaceutical care in children self-reported knowledge, attitudes and competency of final-year pharmacy students in jordan e470 | squ medical journal, november 2018, volume 18, issue 4 the survey. students were informed that completion of the questionnaire would take approximately 10 minutes in order to avoid duplicate responses, all students who had previously completed the questionnaire were asked to leave the room. the questionnaires were collected as soon as they were completed. following data collection, the survey responses were coded and entered into a customised database using the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). descriptive results were presented as means and standard deviations for continuous variables and percent ages for qualitative variables. a simple linear regression analysis was performed to identify factors significantly affecting knowledge scores. all tests were two-tailed. a p value of ≤0.05 was considered statistically significant. this study received ethical approval from the instit utional review board of king abdullah university hospital, ar ramtha, jordan (#20160191). all students were informed that participation in the study was voluntary in nature. all participants provided informed written consent before completing the questionnaire and were assured of the anonymity and confidentiality of their data. results a total of 354 students took part in the study (response rate: 88.5%). the majority were female (81.1%) and jordanian (78.8%). in addition, most students (76.3%) were enrolled in public universities, such as the university of jordan (37%) and the jordan university of science & technology (39.3%). as students in jordan are able to register for more credit-hours in order to graduate earlier, there was a range of fourth-, fifthand sixth-year students [table 2]. most respondents (95.2%) were aware of the term ‘paediatrics’, with 86.7% reporting having gained this knowledge during their pharmacy education. however, table 1: five realistic case scenarios to assess paediatric pharmaceutical knowledge among final-year pharmacy students in jordan case scenario correct answer a six-month-old girl has become inc reasingly irritable and has been waking up four-to-five times each night. she also seems to be drooling excessively and biting on hard objects constantly. a brief examination of her mouth shows red tender gums. no teeth are present and she is afebrile. what would you recommend? topical benzocaine would be effective/ safe a three-month-old infant has had a severe rash for the past four days. it is confined to the diaper area and is very inflamed and tender. vesicular satellite lesions are present on the periphery of the main erythematous area. the mother uses only cloth diapers and has not changed soaps or normal methods of diaper care since her child was born. what would you recommend to treat this child? topical clotrimazole or miconazole cream a three-month-old female has had nasal congestion, rhinorrhoea and a cough since yesterday. she has not had a fever and is eating well but did not sleep well last evening. her mother called her paed iatrician and was told that her daughter most likely has a cold caused by a virus. how can the child’s symptoms be treated? using a cold mist humidifier you receive a call from a mother asking about her child’s constipation. all of the following are true regarding paediatric constipation, except which of the following? liquid intake should be restricted the mother of a 12-month-old baby weighing 10 kg has stated that her son has been warm for the last 12 hours. his rectal temperature taken 15 minutes ago was 38.7 ºc. which of the follow ing would be an appropriate recommendation? administer 100 mg of acetaminophen every 6–8 hours as needed table 2: demographic characteristics of final-year pharmacy students in jordan (n = 354) characteristic n (%) gender male 67 (18.9) female 287 (81.1) nationality jordanian 279 (78.8) other 75 (21.2) type of university public 270 (76.3)* private 84 (23.7) type of degree bachelor/undergraduate 179 (50.6) doctoral/postgraduate 175 (49.4) year of study fourth 73 (20.6) fifth 224 (63.3) sixth 57 (16.1) gpa excellent 70 (19.8) very good 117 (33.1) good 129 (36.4) satisfactory 38 (10.7) gpa = grade point average. *comprising 131 (37%) students from the university of jordan and 139 (39.3%) from the jordan university of science & technology. tareq l. mukattash, anan s. jarab, rana k. abu-farha, eman alefishat and james c. mcelnay clinical and basic research | e471 almost one-third of the respondents (30.5%) reported having had no exposure to paediatric dosing or dose calculation courses during their education. moreover, 55.6% were unfamiliar with the concept of off-label or unlicensed paediatric medicine use. overall, the majority of the students (81.1%) reported that there was a need for more paediatric-related topics to be incorporated into the curriculum [table 3]. in terms of their perceived ability to deal with and treat paediatric patients after graduation, many respondents were either unsure or believed that they would not be able to recommend treatment for paediatric patients (55.7%), calculate paediatric doses (40.1%), counsel the parents or guardians of paediatric patients (44.9%) or monitor side-effects in children (49.2%) [table 4]. with regards to their responses to realistic paediatric case scenarios, most students scored either one (33.9%) or two (28.2%) points out of five [figure 1a]. in addition, there was a greater percentage of incorrect compared to correct responses for each case scenario, except for the case scenario involving fever [figure 1b]. overall, there were no significant differences in the students’ knowledge, attitudes or competency according to type of degree or university attended (p >0.05). discussion the present study sheds light on the self-reported knowledge, attitudes and competency of final-year pharmacy students in jordan regarding paediatric phar maceutical care, including assessment, treatment and dosage. although a previous study investigated the paediatric content of pharmacy curricula in different countries, the current study is, to the best of the authors’ knowledge, the first to directly explore pharmacy students’ perceptions and attitudes regarding this topic.18 overall, the current study exposed a perceived lack of paediatricrelated content in the pharmacy curricula of jordanian universities, with most students highlighting the need for the inclusion of more paediatric-related topics in their courses. this raises concerns regarding the ability of newly-graduated pharmacists to deal with paediatric cases. table 3: knowledge and attitudes of final-year pharmacy students in jordan regarding paediatric pharmaceutical care (n = 354) item response, n (%) are you aware of the term ‘paediatrics’? yes 337 (95.2) no 17 (4.8) where did you first hear this term? during my pharmacy studies 307 (86.7) during my hospital training 12 (3.4) during my community pharmacy training 6 (1.7) other 26 (7.3) i have never heard of the term 3 (0.8) if familiar with the term ‘paediatrics’ through your education, in which course did you learn this term? many 140 (39.5) pharmacokinetics and dose calculation 12 (3.4) medicinal chemistry and organic chemistry 3 (0.8) pharmacotherapy and pharmacology 152 (42.9) pharmacy practice 18 (5.1) physical pharmacy, industrial pharmacy and dosage formulation 10 (2.8) other 16 (4.5) none 3 (0.8) during your education, did you take any courses on paediatric dosing or paediatric dose calculation? yes 229 (64.7) no 108 (30.5) i don’t know 17 (4.8) have you been taught anything about off-label and unlicensed medicine in paediatrics? yes 157 (44.4) no 197 (55.6) do you think that your curriculum should have more paedia tric courses? yes 287 (81.1) no 44 (12.4) i don’t know 23 (6.5) table 4: self-reported competency of final-year pharmacy students in jordan regarding paediatric pharmaceutical care (n = 354) item response, n (%) yes no i don’t know when you graduate, will you be able to deal with paediatric patients and give treatment recommendations? 157 (44.4) 77 (21.8) 120 (33.9) do you think that you will be able to calculate paediatric doses? 212 (59.9) 86 (24.3) 56 (15.8) do you think that you have the training and ability to counsel paediatric patients’ parents or guardians? 195 (55.1) 100 (28.2) 59 (16.7) do you think that you have the ability to monitor side-effects in children? 180 (50.8) 99 (28) 75 (21.2) pharmaceutical care in children self-reported knowledge, attitudes and competency of final-year pharmacy students in jordan e472 | squ medical journal, november 2018, volume 18, issue 4 pharmacists should be sufficiently knowledgeable of paediatric pharmaceutical care so as to ensure that paediatric patients are prescribed suitable, safe and effective medications.19 this is especially important in light of the fact that up to 70% and 95% of medicines prescribed to paediatric patients and neonates, respectively, are unlicensed or off-label; moreover, the risk of adverse drug events in the paediatric population is three times greater than for adults.20–22 several studies have reported high rates of pharmacy-related medication errors when treating children, including a retrospective study of outof-hospital medication errors among young children in the usa between 2002–2012.23–25 generally, the majority of pharmacy-related errors occur when a pharmacist is not able to identify prescription errors, gives incorrect drug administration instructions or mislabels a medication.26 there is considerable evidence to suggest that a well-trained pharmacist can reduce the rate of medication errors, specifically in younger children, for whom such errors can be fatal.27,28 in the current study, more than half of the students reported being unfamiliar with the concept of off-label or unlicensed paediatric medicine use during the course of their education. many healthcare professionals have similarly reported being unfamiliar with the off-label or unlicensed use of medicine among children in their own practices.29–31 a previous study in scotland found that 30% of pharmacists were unaware of off-label med icine use in children, with the majority of respondents having gained such knowledge in clinical practice rather than during their formal education.30 both general pract itioners and paediatricians have reported receiving insufficient information regarding off-label and unlicensed medicine use in children during undergraduate education.29,31 almost one-third of respondents in the current study reported not having taken any paediatric dose calculation courses during their education. dosing mistakes—such as 10-fold dose calculation errors, in which wrong dose calculations result from missing one or more decimal points—are amongst the most fatal drug-related problems in paediatric care.32–34 compared to adults, dosing in paediatric patients is individualised and may depend on different factors for each case.35 accordingly, extra caution should be taken when dealing with paediatric dosages, especially when dispensing medications with a narrow therapeutic index.36 overall, respondents in the current study had grave concerns regarding their ability to deal with and treat paediatric patients. this highlights the importance of covering such topics in pharmacy courses. previous studies have indicated that healthcare professionals fail to adequately communicate with paediatric patients or convey treatment information to the child’s parents.29–31 pharmacy students should therefore be trained to deal with paediatric patients and their parents in communication courses. furthermore, dose calculations and adjust ments should be covered extensively in pharmacokinetics courses to ensure that future pharmacists are able to dispense medicine in accurate doses and reduce the frequency of dosing errors in children. another important factor is the ability to monitor side-effects in children; previous research has shown that pharmacists often fail to detect and report adverse drug reactions.37 further education regarding pharmacovigilance, specif ically in paediatric patients, will optimise the role of future pharmacists in paediatric pharmaceutical care. another suggestion is to mandate postgraduate certification courses in paediatrics prior to actual practice. worldwide, there is growing recognition that phar macy education needs to be developed and improved so as to better prepare graduates to provide paediatric pharmaceutical care.11,38 in the current study, most resp ondents had low knowledge scores when faced with basic real-life paediatric scenarios. alarmingly, although the cases covered only simple ailments which are very common in paediatric care (e.g. diaper rash, teething, constipation, etc.), most students were unable to answer figure 1: distribution of (a) total knowledge scores* and (b) correct and incorrect responses among final-year pharmacy students in jordan presented with realistic paediatric case scenarios (n = 354). *for each of the five case scenarios, correct responses were given a score of one, with total scores of zero and five corresponding to no or perfect knowledge, respectively. tareq l. mukattash, anan s. jarab, rana k. abu-farha, eman alefishat and james c. mcelnay clinical and basic research | e473 correctly. moreover, such students were in their final year of study and would very soon be registered pharmacists. this finding is therefore of major concern and highlights the importance of hands-on paediatric training along with formal education.39 a didactic educational approach that fails to include a research component and incorporates only minimal hands-on training may lead to pharmacists lacking real-world experience and being unable to deal with general and primary care cases.40,41 one obstacle in jordan may be the large number of students per class in pharmacy schools, especially in public universities. the implementation of a pre-regis tration year of practice for pharmacy graduates may positively influence their ability to deal with different patient populations, such as children.41 in the present study, no significant differences in knowledge or attitudes were noted between final-year pharmacy undergraduate and doctoral students according to type of degree. this finding was unexpected as doctoral students undergo more specialised paediatric education in the form of a compulsory course in paediatric therapeutics and a hospital rotation in paediatric wards. given this additional training, it might be supposed that such students should display greater knowledge or enhanced clinical abilities when faced with paediatric case scenarios.42 furthermore, no significant diff erences were observed between pharmacy students at public or private universities. it should be noted that all university programmes and curricula in jordan are subject to the guidelines and recommendations of the accreditation and quality assurance commission for higher education institutions, thereby leading to similar curricula for the majority of pharmacy programmes in the country. this study was subject to several limitations. firstly, no measures were taken to ensure that students did not consult or refer to external sources when answering knowledge questions; however, this is unlikely considering the low knowledge scores. secondly, the participants’ knowledge was scored on a likert rather than a binomial scale; the latter might have allowed for more in-depth analysis of the responses in comparison to the participants’ demographic characteristics and potentially reduced bias. thirdly, some of the questions may have been difficult to answer due to the wording, which could have been clearer; thus, clarity may have affected the validity of the findings. furthermore, items in the questionnaire were perhaps too general—for example when inquiring about respondents’ knowledge of the term ‘paediatrics’—however, this was deemed necessary as the study took place in an arabic-speaking country where laypeople may not be aware of such terms. nevertheless, the current study was exploratory in nature and these findings could be considered a benchmark for further in-depth studies in paediatric pharmacy education. conclusion pharmacists play a vital role in assuring the safe and effective administration of medications to paediatric patients. the results of this study revealed that, according to final-year pharmacy students, the current pharmacy curricula taught during undergraduate and doctoral programmes in jordan is insufficient with regards to paediatric pharmaceutical care. the students had low confidence regarding their ability to deal with paediatric patients, with most not able to make correct recommend ations during basic case scenarios, counsel children and their parents/guardians or calculate correct drug dosages. pharmacy students should therefore undergo more extensive education and training in these areas, perhaps during a mandatory pre-registration year of practice. a c k n o w l e d g e m e n t s the preliminary version of this study was presented at the health services research and pharmacy practice conference on 12–13 april 2018 at the university of newcastle, newcastle upon tyne, uk. an abstract of this oral presentation was published in the international journal of pharmacy practice in march 2018, volume 26, issue s1, pp. 9–10. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded with the aid of a grant from the deanship of research at jordan university of science & technology (grant #20160191). references 1. bhatt-mehta v, buck ml, chung am, farrington ea, hagemann tm, hoff ds, et al. recommendations for meeting the pediatric patient’s need for a clinical pharmacist: a joint opinion of the pediatrics practice and research network of the american college of clinical pharmacy and the pediatric pharmacy advocacy group. pharmacotherapy 2013; 33:243–51. https://doi.org/10.1002/phar.1246. 2. condren me, haase mr, luedtke sa, gaylor as. clinical activ ities of an academic pediatric pharmacy team. ann pharmacother 2004; 38:574–8. https://doi.org/10.1345/aph.1d384. 3. larochelle jm, ghaly m, creel am. clinical pharmacy faculty interventions in a pediatric intensive care unit: an eight-month review. j pediatr pharmacol ther 2012; 17:263–9. https://doi. org/10.5863/1551-6776-17.3.263. pharmaceutical care in children self-reported knowledge, attitudes and competency of final-year pharmacy students in jordan e474 | squ medical journal, november 2018, volume 18, issue 4 4. feudtner c, dai d, hexem kr, luan x, metjian ta. prevalence of polypharmacy exposure among hospitalized children in the united states. arch pediatr adolesc med 2012; 166:9–16. https://doi.org/10.1001/archpediatrics.2011.161. 5. lasky t. estimates of pediatric medication use in the united states: current abilities and limitations. clin ther 2009; 31:436–45. https://doi.org/10.1016/j.clinthera.2009.02.003. 6. gu q, dillon cf, burt vl. prescription drug use continues to increase: u.s. prescription drug data for 2007-2008. nchs data brief 2010; 42:1–8. 7. prescott wa jr, dahl em, hutchinson dj. education in pediatrics in us colleges and schools of pharmacy. am j pharm educ 2014; 78:51. https://doi.org/10.5688/ajpe78351. 8. kharmeh s. evaluating the quality of health care services in the hashemite kingdom of jordan. int j bus manag 2012; 7:195–205. https://doi.org/10.5539/ijbm.v7n4p195. 9. wazaify m, abood e, tahaineh l, albsoul-younes a. jordanian community pharmacists’ experience regarding prescription and nonprescription drug abuse and misuse in jordan: an update. j subst use 2017; 22:463–8. https://doi.org/10.1080/14659891. 2016.1235734. 10. cho hj, hong sj, park s. knowledge and beliefs of primary care physicians, pharmacists, and parents on antibiotic use for the pediatric common cold. soc sci med 2004; 58:623–9. https://doi. org/10.1016/s0277-9536(03)00231-4. 11. aucoin rg, buck ml, dupuis ll, dominguez kd, smith kp. pediatric pharmacotherapeutic education: current status and recommendations to fill the growing need. pharmacotherapy 2005; 25:1277–82. https://doi.org/10.1592/phco.2005.25.9.1277. 12. lavoie a, gerber p. pediatric pharmacotherapy content of canadian undergraduate pharmacy curricula. can pharm j (ott) 2008; 141:228–33. https://doi.org/10.3821/1913701x200 8141228ppcocu20co2. 13. meyers rs, costello-curtin j. implementing a pediatric pharmacy educational program for health-system pharmacists. am j pharm educ 2011; 75:205. https://doi.org/10.5688/ajpe7 510205. 14. small l, schuman a, reiter pd. training program for pharmacists in pediatric emergencies. am j health syst pharm 2008; 65:649–54. https://doi.org/10.2146/ajhp070353. 15. benavides s, huynh d, morgan j, briars l. approach to the pediatric prescription in a community pharmacy. j pediatr pharmacol ther 2011; 16:298–307. https://doi.org/10.5863/15 51-6776-16.4.298. 16. boucher ea, burke mm, johnson pn, klein kc, miller jl; advocacy committee for the pediatric pharmacy advocacy group. minimum requirements for core competency in pediatric pharmacy practice. j pediatr pharmacol ther 2015; 20:481–4. https://doi.org/10.5863/1551-6776-20.6.481. 17. munzenberger pj, thomas rl, edwin sb, tutag-lehr v. pharmacists’ perceived knowledge and expertise in selected pediatric topics. j pediatr pharmacol ther 2011; 16:47–54. 18. horton er, belliveau p. pediatric pharmacotherapy in the pharmd curriculum: course design and student self-assessment of learning outcomes achievement. curr pharm teach learn 2014; 6:277–83. https://doi.org/10.1016/j.cptl.2013.11.008. 19. hepler cd, strand lm. opportunities and responsibilities in pharmaceutical care. am j hosp pharm 1990; 47:533–43. 20. pandolfini c, bonati m. a literature review on off-label drug use in children. eur j pediatr 2005; 164:552–8. https://doi.org/ 10.1007/s00431-005-1698-8. 21. conroy s, mcintyre j, choonara i. unlicensed and off label drug use in neonates. arch dis child fetal neonatal ed 1999; 80:f142–5. https://doi.org/10.1136/fn.80.2.f142. 22. kaushal r, bates dw, landrigan c, mckenna kj, clapp md, federico f, et al. medication errors and adverse drug events in pediatric inpatients. jama 2001; 285:2114–20. https://doi. org/10.1001/jama.285.16.2114. 23. costa la, valli c, alvarenga ap. medication dispensing errors at a public pediatric hospital. rev lat am enfermagem 2008; 16:812–17. https://doi.org/10.1590/s0104-11692008000500003. 24. smith md, spiller ha, casavant mj, chounthirath t, brophy tj, xiang h. out-of-hospital medication errors among young children in the united states, 2002-2012. pediatrics 2014; 134:867–76. https://doi.org/10.1542/peds.2014-0309. 25. miller mr, robinson ka, lubomski lh, rinke ml, pronovost pj. medication errors in paediatric care: a systematic review of epidemiology and an evaluation of evidence supporting reduction strategy recommendations. qual saf health care 2007; 16:116–26. https://doi.org/10.1136/qshc.2006.019950. 26. jeetu g, girish t. prescription drug labeling medication errors: a big deal for pharmacists. j young pharm 2010; 2:107–11. https://doi.org/10.4103/0975-1483.62218. 27. matsui d. current issues in pediatric medication adherence. paediatr drugs 2007; 9:283–8. https://doi.org/10.2165/0014858 1-200709050-00001. 28. eisenhut m, sun b, skinner s. reducing prescribing errors in paediatric patients by assessment and feedback targeted at pres cribers. isrn pediatr 2011; 2011:545681. https://doi.org/10. 5402/2011/545681. 29. ekins-daukes s, helms pj, taylor mw, mclay js. off-label prescribing to children: attitudes and experience of general practitioners. br j clin pharmacol 2005; 60:145–9. https://doi. org/10.1111/j.1365-2125.2005.02397.x. 30. stewart d, rouf a, snaith a, elliott k, helms pj, mclay js. attitudes and experiences of community pharmacists towards paediatric off-label prescribing: a prospective survey. br j clin pharmacol 2007; 64:90–5. https://doi.org/10.1111/j.1365-2125. 2007.02865.x. 31. mukattash tl, wazaify m, khuri-boulos n, jarab a, hawwa af, mcelnay jc. perceptions and attitudes of jordanian paediatricians towards off-label paediatrics prescribing. int j clin pharm 2011; 33:964–73. https://doi.org/10.1007/s11096-011-9569-z. 32. yin hs, dreyer bp, moreira ha, van schaick l, rodriguez l, boettger s, et al. liquid medication dosing errors in children: role of provider counseling strategies. acad pediatr 2014; 14:262–70. https://doi.org/10.1016/j.acap.2014.01.003. 33. cohen m, vaida a, litman rs, jenkins rh. error-prone abbreviations and dose expressions. anesth analg 2016; 122:581. https://doi.org/10.1213/ane.0000000000000984. 34. scott cs, deloatch kh. advanced pediatric pharmacotherapy: an elective course with service-learning. am j pharm educ 1998; 62:420–6. https://doi.org/aj620410.pdf. 35. cella m, danhof m, della pasqua o. adaptive trials in paediatric development: dealing with heterogeneity and uncertainty in pharmacokinetic differences in children. br j clin pharmacol 2012; 74:346–53. https://doi.org/10.1111/j.1365-2125.2012.04187.x. 36. mukattash tl, hayajneh wa, ibrahim sm, ayoub a, ayoub n, jarab as, et al. prevalence and nature of off-label antibiotic prescribing for children in a tertiary setting: a descriptive study from jordan. pharm pract (granada) 2016; 14:725. https://doi. org/10.18549/pharmpract.2016.03.725. 37. pellegrino p, carnovale c, cattaneo d, perrone v, antoniazzi s, pozzi m, et al. pharmacovigilance knowledge in family paediatricians: a survey study in italy. health policy 2013; 113:216–20. https://doi.org/10.1016/j.healthpol.2013.08.006. 38. eiland ls, benner k, gumpper kf, heigham mk, meyers r, pham k, et al. ashp-ppag guidelines for providing pediatric pharmacy services in hospitals and health systems. am j health syst pharm 2018; 75:1151–65. https://doi.org/10.2146/ajhp170827. tareq l. mukattash, anan s. jarab, rana k. abu-farha, eman alefishat and james c. mcelnay clinical and basic research | e475 39. johnson tj. pharmacist work force in 2020: implications of requiring residency training for practice. am j health syst pharm 2008; 65:166–70. https://doi.org/10.2146/ajhp070231. 40. mukattash tl, alattar m, abu-farha rk, alsous m, jarab as, darwish elhajji fw, et al. evaluating scientific research knowledge and attitude among medical representatives in jordan: a cross-sectional survey. curr clin pharmacol 2017; 12:245–52. https://doi.org/10.2174/1574884712666170828124950. 41. jee s, schafheutle e, noyce pr. changes in behavioural prof essionalism during pre-registration training and early pharmacy practice. in: abstracts of the papers presented at the health services research & pharmacy practice conference, 3-4 april 2014, university of aberdeen, aberdeen, uk. int j pharm pract 2014; 22:s41–2. 42. mukattash tl, nuseir kq, biltaji e, jarab as, alefan q. students’ perceptions of pharmacy as a specialization and their future career, a cross sectional study of final year pharmacy students in jordan. jordan j pharm sci 2015; 8:195–204. clinical & basic research squ med j, february 2012, vol. 12, iss. 1, pp. 48-54, epub. 7th feb 12. submitted 28th may 11 revision req. 6th sep 11, revision recd. 25th sep 11 accepted 30th nov 11 1department of medical microbiology, faculty of medicine & health sciences, sana’a university, yemen; 2al-thawra university hospital, sana’a university, sana’a, republic of yemen corresponding author e-mail: shmahe@yemen.net.ye أنواع البكترييا املرتبطة باإلنتان الوليدي يف مستشفى جامعة الثورة، صنعاء ، اليمن وشاكلة مضادات امليكروبات ح�سن عبد الوهاب ال�سماحي، اأمل عبد الكرمي �سربة، عبدالباقي عبداهلل الربا�سي، �سمرية مثنى نا�رص امللخ�ص: الهدف: حتديد البكترييا امل�سببة لالإنتانات بني حديثي الولدة يف م�ست�سفى الثورة مبدينة �سنعاء، بالإ�سافة اإىل حتديد مقاومة البكترييا للم�سادات احليوية، وو�سع تو�سية للعالج التجريبي بناء على ذلك. الطريقة: ت�سمنت هذه الدرا�سة 158 طفال حديثي الولدة )ترتاوح اأعمارهم بني 0 و28 يوما(عانوا من واحد اأو اأكرث من اأعرا�س الإنتانات. مت اأخذ عينة من الدم الوريدي من كل احلالت، وثم مت واأظهرت ،)75%( 09 طفال يف اإيجابيا اجلرثومي الزرع فح�س كان النتائج: املعزولة. للجراثيم احل�سا�سية اختبارات وحتديد زرعها اإ�سابات الإنتان املبكرة اأعلى النتائج الإيجابية للزرع اجلرثومي )%61.7( منه يف الإ�سابات املتاأخرة )%32(. وجدت نتائج الزرع �سالبة البكترييا �سّكلت .)78.6%( جرام 2 كيلو 0.9 اإىل بني الولدة عند وزنهم يرتاوح الذين الأطفال جمموعة عند املهمة اليجابي تليها ،)36.7%( بن�سبة فيها ال�سائدة هي الرئوية الكلب�سيلة بكترييا كانت حيث اجلرثومي، الزرع اإجمايل من )97.8%( ن�سبة اجلرام تالها احلالت، من )72.2%( بن�سبة التنف�س �سيق فكان امل�سابني بني �سيوعا الأعرا�س اأكرث اأما .)30.0%( بن�سبة الزَّاِئَفة البكترييا �سالبة البكرتيا لكل الزرع نتائج كانت .)27.8%( فبلغ الوفيات معدل اأما .)47.8%( والُنوام )51.1%( والُزراق )62.2%( الريقان لأكرث ُمقاومة كانت الزرع نتائج معظم لكن ال�سيفالو�سبورين، من الرابع للجيل ح�سا�سا كان وبع�سها اميبينيم، للدواء ح�سا�سة اجلرام مدينة يف الولدة حلديثي البكتريية لالإنتانات الرئي�سية امل�سببة هي اجلرام �سالبة البكترييا اخلال�صة: امل�ستخدمة. احليوية امل�سادات باأن ال�ستنتاج ميكن جدا. املنخف�س الوزن ذوي املواليد بني خا�سة الولدة، حلديثي واملر�س الوفاة يف رئي�سيا �سببا وكانت �سنعاء، امل�ساد احليوي اميبينيم واجليل الرابع من ال�سيفالو�سبورينات ميكن اأن تكون اخليار الأول للعالج التجريبي للحالت املر�سية بالإنتان البكتريي . مفتاح الكلمات: اأنتان، وليدي، مبكر، متاأخر، مقاومة دواء، عالج، عالج جتريبي، �سنعاء، اليمن. abstract: objectives: this study was undertaken to investigate the organisms causing sepsis in the neonatal unit at al-thawra hospital, sana’a, yemen, determine their resistance to antibiotics, and recommend policy for empirical treatment. methods: a total of 158 neonates having one or more signs of sepsis, and aged from 0 to 28 days, were enrolled in this study. a blood sample was taken from each subject, cultured, and then antibacterial susceptibility tests were performed for isolates. results: 90 (57%) cases yielded positive cultures. early-onset sepsis showed higher positive culture results (61.7%) than late-onset sepsis (32%). significant positive culture results were found among the group with birth weight 0.9–2 kg (78.6%). gram negative bacteria constituted 97.8% of the total isolates, of which klebsiella pneumoniae was the predominant pathogen (36.7%), followed by pseudomonas species (30.0%). the commonest symptoms among the cases were respiratory distress (72.2%), jaundice (62.2%), cyanosis (51.1%), and lethargy (47.8%); the mortality rate was 27.8%. all gram negative bacterial isolates were sensitive to imipenem and some isolates were sensitive to fourth-generation cephalosporins, but most isolates were highly resistant to the majority of other antibiotics tested. conclusion: gram negative organisms were the most frequent causative agents of bacterial sepsis, which is a significant cause of mortality and morbidity in the newborn, and particularly in those of very low birth weight. it can also be concluded that imipenem and fourth-generation cephalosporins can be used for empirical treatment of bacterial sepsis. keywords: sepsis; neonatal; early-onset; late-onset; drug resistance; treatment, empirical; sanaa; yemen. types of bacteria associated with neonatal sepsis in al-thawra university hospital, sana’a, yemen, and their antimicrobial profile hassan a al-shamahy,1 amal a sabrah,2 abdul baki al-robasi,1 samarih m naser1 hassan a al-shamahy, amal a sabrah, abdul baki al-robasi, samarih m naser clinical and basic research | 49 sepsis is a significant cause of mortality and morbidity in the newborn, particularly among those of very low birth weight and premature infants.1,2 the world health organization (who) estimates that worldwide 1.6 million newborn babies die every year from neonatal infections. individual units have reported case fatality rates as low as 2–3% and as high as 50%,3 but the average overall mortality from neonatal sepsis reported from many neonatal intensive care units in developed countries is around 20%.4 despite recent advances in neonatal intensive care and current strategies to treat neonatal sepsis, mortality rates have not fallen for over three decades4 except in babies born to mothers who have received intrapartum prophylaxis (iap) for group b streptococcus (gbs).5 whilst iap has been successful in significantly reducing the incidence of early onset gbs disease in the newborn it has led to an increase in gram negative infections in institutions where antibiotics other than penicillin are used for iap.6 worryingly, both short and long term neurodevelopmental morbidity in survivors of neonatal sepsis is also significant.7 the study by stoll et al. in 2002 showed that neonatal infection is associated with a 30–80% increase in neurodevelopmental impairment and a 30–100% increase in odds for poor head growth which is a very good predictor of long-term morbidity.6 this study aimed to determine the types of bacteria associated with neonatal sepsis in neonatal unit of al-thawra university hospital in sana’a, yemen, and their antibiotic profile. methods this prospective study was carried out during a 12 month period from april 2008 to march 2009. the study proposal was approved by the department of medical microbiology, in the faculty of medicine & health sciences at sana’a university, yemen. a total of 158 hospital-born neonates with a clinical diagnosis of septicaemia, and admitted to the neonatal unit of al-thawra university hospital in sana’a city, were included in this study. a consent form was completed by the parents for each subject. early-onset sepsis (eos) was defined as sepsis occurring within the first week of life. late-onset sepsis (los) was defined as sepsis that occurred any time after the first week of life until the end of the neonatal period (28 days of age). a full history was taken from doctors and files, and the findings were recorded in a predesigned questionnaire. the data collected included: any complications during delivery, characteristics of the infant, sex, birth weight, temperature, other medical conditions in the infant, major signs and symptoms and other necessary data for the research. blood culture was preformed for all neonates suspected of having septicaemia. septicaemia was suspected in the following settings: 1) at birth: all neonates born to mothers with maternal fever, prolonged rupture of membranes for more than 24 hours, or foul-smelling or meconium-stained liquor, and those having severe prematurity or birth asphyxia necessitating active resuscitation; 2) after birth: all newborns with lethargy, poor feeding, abdominal distension, respiratory distress, instability in temperature, pathological jaundice, and convulsions. the collected data and the results of this study were statistically analysed for means of significance by the epi info computer programme, version 6 (epi info, centers for disease control (cdc), atlanta, georgia, usa). the specimens were collected as follows: one blood culture at least was obtained for each neonate with signs of sepsis, by the method described by buttery.8 blood from peripheral venous or arterial punctures was collected under sterile conditions as described by hall and lyman.9 the blood specimen was then inoculated into a bactec vial (bactec, rochester, uk) and the advances in knowledge 1. this study provides current data on the organisms causing sepsis in neonatal units and the resistance of the sepsis-causing organisms to the relevant antibacterial drugs. it was found that gram negative organisms were the most frequent causative agents of bacterial sepsis (97.8%). 2. this information is important in order to recommend policy for empirical treatment. 3. this is one of only a few studies from arabic countries focused on neonatal sepsis. application to patient care 1. the research reported here could aid in the prevention of neonatal sepsis and build a treatment policy for neonatal bacterial sepsis. 2. this study alerts physicians to the defective hygiene in neonatal units and the high rate of resistance to antibiotics. types of bacteria associated with neonatal sepsis in al-thawra university hospital, sana’a, yemen, and their antimicrobial profile 50 | squ medical journal, february 2012, volume 12, issue 1 inoculated culture bottles were incubated as soon as possible in the bactec brand fluorescent series instrument (bactec 9120) for up to 5 days, as recommended by becton dickinson microbiological systems.10 positive blood culture vials were sub-cultured into blood agar, chocolate agar, macconkey agar, and sabouraud agar (for yeast), then the media were inspected for the presence of bacterial growth. the isolated bacteria were defined by colonial morphology, gram stain reaction, biochemical reactions and confirmed by api-20e biotyping (api 20e system, analytab products, plainview, new york, usa). finally, the sensitivity of isolated bacteria to various antibiotics was assessed according to the modified kirby and bauer method on mueller-hinton agar. the concentrations of the antibiotics used (µg/disc) were as follows: ampicillin (amp) ˗ 10; gentamycin (cn) ˗ 10; amikacin (ak) ˗ 30; ceftazidime (caz) ˗ 30; ceftriaxone (cro) ˗ 30; cefepime (fep) ˗ 30; piperacillin (p) ˗ 100; imipenem (ipm) -10; and aztreonam (atm) ̠ 30. the clinical and laboratory standards institute (clsi) guidelines were used to determine antimicrobial resistance. results this study included 158 neonates, their ages ranging from 0 to 28 days with a mean age of 5.2 days. the standard deviation (sd) was equal to 6.1 days, mode equal to 1 day and median equal to 3 days. there were 96 (60.8%) males and 62 (39.2%) females. the detailed results of this study are presented in tables 1 to 6. table 1 shows the distribution of positive bacterial culture according to sex. a total of 90 (57%) of patients had a positive culture for bacterial growth. the rate of positive culture among females (62.9%) was higher compared to males (53.1%), but the variation was not statistically significant in which χ2 = 1.47 and p = 0.22. the eos showed higher positive culture results (61.7%) than los (32%), with the relative risk of contracting eos bacterial infection 2.2 times that of los, but the difference was not statistically significant in which χ2 = 2.7 and p = 0.1 [table 2]. table 3 shows that highly significant positive cultures results were found among the group with birth weight 0.9–2 kg (78.6%, χ2 = 5.7, p = 0.01). the commonest symptoms among the cases studied were respiratory distress (72.2%), jaundice (62.2%), cyanosis (51.1%) and lethargy (47.8%). on the other hand, lethargy, apnoea, poor feeding and unconsciousness occurred significantly less frequently among positive bacterial culture cases in which χ2 > 3.7 and p <0.05. however, the mortality rate was higher among positive culture cases (27.8%), than negative ones (2.9%) and the variation was statistically significant in which χ2 = 16.86 and p = 0.0004 [table 4]. table 1: the rate of positive bacterial culture among male and female neonates. sex: total cases cases with positive culture χ2 p no. % no. % male 96 60.8 51 53.1 1.47 0.22 female 62 39.2 39 62.9 crude rate 158 100.0 90 57 legend: χ2 = chi square; p = probability value. note: χ2 > 3.7 and p <0.05 are significant. table 2: the rate of positive bacterial culture in earlyonset (eos) and late-onset of sepsis (los) and their relative risks for contracting bacteria, confidence interval and test of significance type of sepsis positive bacterial culture rr ci χ2 p no. % eos ≥ 7 days n =133 82 61.7 2.2 (0.77–6.3) 2.7 0.10 los < 7 days n = 25 8 32 0.7 (0.4–1.2) 2.7 0.10 total 90 57 legend: rr = relative risk; ci = confidence interval; χ2 = chi square, p = probability value note: χ2 > 3.7 and p < 0.05 are significant table 3: the rate of positive bacterial culture and its relationship to birth weight birth weight (kg) total cases cases with positive culture χ2 p no. % no. % 0.9–2 73 46.2 50 68.5 5.7 0.01 2.1–3 63 39.9 31 49.2 3.7 0.05 3.1–4 19 12 08 42.1 0.2 0.68 <4 3 1.9 1 33.3 0.7 0.4 legend: χ2 = chi square; p = probability value. note: χ2 > 3.7 and p <0.05 are significant hassan a al-shamahy, amal a sabrah, abdul baki al-robasi, samarih m naser clinical and basic research | 51 gram negative bacteria constituted 97.8% of the total isolates, of which klebsiella pneumoniae was the predominant pathogen with 36.7%, followed by pseudomonas species with 30.0%. citrobacter species was the least common isolate of gram negative bacteria with a percentage of 4.4%, while gram positive bacteria rates were very low (1.1%) [table 5]. all gram negative bacterial isolates were sensitive to imipenem and some isolates were sensitive to fourth-generation cephalosporins (cefepime), but most isolates were highly resistant to the majority of other antibiotics tested [table 6]. discussion in this study, blood culture obtained from 158 neonates yielded positive results in 57% of cases, while the remaining 43% gave negative results. a similar result was reported by ako-nai and others in nigeria in 1999 with a positive percentage of 55%.11 slightly higher positive results were reported by rohsiswatmo (65.3%) in indonesia,12 rahman et al.13 in pakistan (62.8%) and by macharashvili et al. 14 in georgia (63%). in contrast, much lower positive results were reported from iran (5.6%),15 kuwait (8.7%)16 and saudi arabia (5%).17 these variations can be attributed to many different factors of which antibiotic therapy prior to the laboratory diagnosis may have had the most important influence on the low culture results. the eos rates (61%) were higher than the los rates (32%) in this study. this result is compatible table 4: presenting clinical symptoms and mortality rate among total patients compared with positive bacterial culture. symptoms negative culture n = 68 positive culture n = 90 χ2 p no. % no. % fever, n = 20 8 11.8 12 13.3 0.09 0.76 lethargy, n = 64 21 31 43 47.8 4.6 0.03 jaundice, n = 98 36 53 56 62.2 0.00 0.95 apnoea, n = 15 3 4.4 12 13.3 3.6 0.05 respiratory distress, n = 116 51 75 65 72.2 0.15 0.7 poor feeding, n = 19 2 2.9 17 18.9 9.3 0.002 cyanosis, n = 76 30 44.1 46 51.1 0.76 0.38 abdominal distention, n = 7 4 5.8 3 3.3 0.6 0.4 pallor, n = 20 5 7.3 15 16.7 3.04 0.08 convulsion, n = 5 1 1.5 4 4.4 1.12 0.29 birth asphyxia, n = 8 4 5.9 4 4.4 0.17 0.68 unconscious, n = 21 5 7.3 16 17.8 3.65 0.05 mortality rate, n = 27 2 2.9 25 27.8 16.86 0.0004 legend: χ2 = chi square; p = probability value. note: χ2 > 3.7 and p <0.05 are significant table 5: the frequency and percentage of bacterial species that isolated from neonate sepsis cases organism no. % gram negative bacteria 88 97.8 klebsiella pneumoniae 33 36.7 pseudomonas species 27 30 enterobacter species 14 15.6 acinetobacter species 10 11.1 citrobacter species 4 4.4 gram positive bacteria 1 1.1 staphylococcus aureus 1 1.1 fungi 1 1.1 candida species 1 1.1 total positive bacteria 90 100.0 types of bacteria associated with neonatal sepsis in al-thawra university hospital, sana’a, yemen, and their antimicrobial profile 52 | squ medical journal, february 2012, volume 12, issue 1 with the reports from iran and pakistan,18,19 but it contrasts with a report from bangladesh, where los was more common than eos.20 however, the most common organism in eos was k. pneumoniae; the same finding was recorded in many developing countries.21–23 in the present study, females showed slightly higher positive results than males, which is similar to findings reported from iran.24 the commonest symptoms among the cases studied were respiratory distress (72.2%), jaundice (62.2%), cyanosis (51.1%, and lethargy (47.8%). on the other hand, lethargy, apnoea, poor feeding and unconsciousness showed significantly low rates of occurrence among positive bacterial culture cases. in general, the presenting clinical symptoms and signs in our study agreed with the who clinical criteria for neonatal sepsis.25 there was a significant correlation between low birth weight and the incidence of neonatal sepsis with, statistically significant values of χ2 = 5.7 and a p value equal to 0.01. the same finding was observed in the studies of al-umran and twumdanso in saudi arabia and jeong in korea.17,26 mortality rate among positive culture cases in this study was 27.8%, which was similar to that found in zimbabwe,27 pakistan28 and georgia.14 the most common organisms which caused eos and los in the present study were gram negative bacteria, with a percentage of 97.8%. this result agreed with other related studies in many developing countries,13,14,23,29 but differed from those reported by huda et al.16 in kuwait, haque et al.4 in the uk and hyde et al.30 in the usa where gram positive bacteria were more predominant. k. pneumoniae was the predominant isolate in the present study, representing 36.7% of the total isolates. similar findings were reported by macharashvili in georgia,14, mehdinejad et al. in iran (33.5%)15 and by kumhar et al. in india (33.8%),21 but lower results were reported from nepal (18.3%) and pakistan (7.6%).31,13 moreover, it was found in this study that pseudomonas species were the second most common isolate; similar findings were reported in pakistan.13,32 the overwhelming majority of gram negative organisms isolated in this study and among the other studies reviewed suggests that these infections may in fact be acquired from the hospital or community environment, due to poor hygienic practices during delivery and postnatal care, rather than reflecting vertical transmission to the infant from exposure to vaginal tract flora.33,34 another possible explanation of the predominance of gram negative bacteria in our study is that asymptomatic colonised patients, the contaminated environment, or both can serve as reservoirs for these pathogens, which are then spread by the hands of health care workers.35,36 furthermore, a limitation of our study was that there is insufficient sterility testing or wipe testing of the neonatal wards to confirm if the conditions are unhygienic which could mean that contaminating bacteria might also be recovered from the environment. table 6: resistant pattern of the isolates to some antibiotics antibiotic klebsiella spp (n = 33) pseudomonas spp (n = 27) enterobacter spp (n = 13) citrobacter spp (n = 4) acinetobacter spp (n = 10) amp 29 (87.8) 23 (85.2) 12(92.3) 3 (75.0) 5 (50) aml 31 (93.9) 19 (70.3) 13 (100) 4 (100) 9 (90) atm 30 (90.9) 20 (74.0) 10(76.9) 4 (100) 7 (70) prl 29 (87.8) 3 (11.1) 8 (61.5) 1 (25.0) 1 (10) caz 30 (90.9) 10 (37.0) 12(92.3) 4 (100) 5 (50) fep 12 (36.4) 4 (14.8) 0 1 (25.0) 0 cro 32 (96.9) 19 (70.3) 13 (100) 4 (100) 9 (90) ipm 0 0 0 0 0 ak 13 (39.3) 12 (44.4) 8 (61.5) 0 5 (50) cn 9 (27.2) 17 (62.9) 5 (38.4) 0 5 (50) legend: amp = ampicillin; aml = amoxicillin; atm = azteronam; prl = pipracillin; ak = amikacin; cn = gentamicin; caz = ceftazidim; cro = ceftriaxon; fep = cefipime = c; ipm = imipenem. hassan a al-shamahy, amal a sabrah, abdul baki al-robasi, samarih m naser clinical and basic research | 53 multi-drug resistance of the causative organisms of sepsis is a rapidly emerging and potentially disastrous problem. infection with resistant organisms has been associated with treatment failure, higher morbidity and mortality and increased costs. the present study shows a very high degree of resistance of gram negative organisms to commonly used antibiotics (amp and cn) as well as third-generation cephalosporins. these results agree with many other studies.12,18,37,,38 the high burden of infection and the degree of antibiotic resistance seen in this study population may signify an emerging trend among sepsis isolates recovered from neonates in developing countries. in a review of data from developing countries, zaidi et al. found rates of neonatal infection in hospitalised infants to be 3–20 times higher than those in developed countries, and approximately 70% of these infections would not be susceptible to conventional empirical antibiotic regimens, such as amp with cn.39 all gram negative organisms in this study were sensitive to imp; the same results were reported by shaw et al., al-tawfiq and antony, rohsiswatmo, and waseem et al.31,40,12,23 in contrast, a study in the philippines reported 20% resistance to imp.36 in the present study, there was increasing resistance to third-generation cephalosporins, probably attributable to extended spectrum beta-lactamase (esbl) production by gram negative bacteria, especially klebsiella, as also observed in another studies on neonates. 31,39,41 the lack of culturedriven antimicrobial therapy and limited, consistent infection control practices is likely to be responsible for the resistance of gram negative organisms in this study. conclusion gram negative organisms were the most common causative agents of bacterial sepsis in this study. in turn, they are a significant cause of mortality and morbidity in the newborn, particularly in very low birth weight infants. ipm and fourth-generation cephalosporins such as fep can be used for the empirical treatment of bacterial sepsis in sana’a city, yemen. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. stoll bj, hansen n. infections in vlbw infants: studies from nichd neonatal network. semin perinatol 2003; 27:293−301. 2. stoll bj, hansen n, chapman ai. neuro-development and growth impairment among extremely low birth weight infant with neonatal infections. jama 2004; 292:2357−65. 3. bizzarro mj, raskind c, baltimore rd, gallagher pc. seventy-five years of neonatal sepsis at yale: 1928-2003. pediatrics 2005; 116:595−602. 4. haque kn, khan ma, kerry s, stephenson j, woods g. pattern of culture-proven neonatal sepsis. a district general hospital in the united kingdom. infect control hosp epidemiol 2004; 25:759−64. 5. isaacs d, doyle ja. intrapartum antibiotics and early onset sepsis caused by group b streptococcus and other organisms in australia. pediatr inf dis j 1999; 8:524−8. 6. stoll bj, hansen n, fanaroff aa. changes in pathogens causing early onset sepsis in very low birth weight infants. n engl j med 2002; 347:240−7. 7. nelson kb, willoughby re. infection, inflammation and the risk of cerebral palsy. curr opinion neurol 2000; 13:133−9. 8. buttery jp. blood cultures in newborns and children: optimizing an everyday test. arch dis child fetal neonatal ed 2002; 87: f25−8. 9. hall kk, lyman ja. updated review of blood culture contamination. clin microbiol rev 2006; 788−802. 10. becton dickinson microbiological systems. bectec peds plus/f culture vials: instruction leaflet. sparks, maryland: becton dickinson company, 2000. 11. ako-nai ak, adejuyigbe ea, ajayi fm, onipede ao. the bacteriology of neonatal septicaemia in i1eife, nigeria. j trop pediatr 1999; 45:146−51. 12. rohsiswatmo r. multi-drug resistance in the neonatal unit and its therapeutic implications. paediatr indones 2006; 46:25−31. 13. rahman s, hameed a, roghani m t, ullah z. multidrug resistant neonatal sepsis in peshawar, pakistan. arch dis child fetal neonatal 2002; 87: f52–4. 14. macharashvili n, kourbatova e, butsashvili m, tsertsvadze t, mcnutt la, leonard mk. etiology of neonatal blood stream infections in tbilisi, republic of georgia. int j infect dis 2009; 13:499−505. 15. mehdinejad m, khosravi ad, morvaridi a. study of prevalence and antimicrobial susceptibility pattern of bacteria isolated from blood cultures. j biol sci 2009; 9:249−53. 16. huda ha, edet ge, rajaram uu. neonatal septicemia in al-jahra hospital, kuwait: etiologic agents and antibiotic sensitivity patterns. med principles pract 2001; 10:145–50. types of bacteria associated with neonatal sepsis in al-thawra university hospital, sana’a, yemen, and their antimicrobial profile 54 | squ medical journal, february 2012, volume 12, issue 1 17. alumran dk, twum-danso k. a case control study of neonatal sepsis: experience from saudi arabia. j trop pediatr 1997; 43:84−8. 18. movahedian ah, moniri r, mosayebi z. bacterial culture of neonatal sepsis. iran j publ health 2006; 35:84−9. 19. rasu ch, hassan ma, habibullah m. neonatal sepsis and use of antibiotic in a tertiary care hospital. pak j med sci 2007; 23:78−81. 20. ahmed as, chowdhury ma, hoque m, darmstadt gl. clinical and bacteriological profile of neonatal septicemia in tertiary level pediatric hospital in bangladesh. indian pediatr 2002; 39:34−9. 21. kumhar gd, ramachandran vg, gupta p. bacteriological analysis of blood culture isolates from neonates in a tertiary care hospital in india. j health popul nutr 2002; 20:343−7. 22. world health organization. explore simplified antimicrobial regimens for the treatment of neonatal sepsis. geneva: who. who/fch/ cah/04.1. 30 sep–1 oct 2002. 23. waseem r, khan m, izhar ts, qureshi aw. neonatal sepsis. professional med j 2005; 12:451−6. 24. salamati p, rahbarimanesh aa, yunesian m, naseri m. neonatal nosocomial infections in bahrami children hospital. indian j pediatr 2006; 73:25–31. 25. world health organization. management of the young child with an acute respiratory infection. geneva: world health organization: program for control of acute respiratory infections, 1990. 26. jeong is, jeong js, choi eo. nosocomial infection in a newborn intensive care unit (nicu), south korea. bmc infectious diseases, 2006; 6:103. 27. nanthoo k, mason p, gwanzura l. severe klebsiella infection as a cause of mortality in neonates in harare, zimbabwe: evidence from postmortem blood cultures. pediatr inf dis j 1993; 12:840–4. 28. bhutta za, yusuf k. neonatal sepsis in karachi, factors determining outcome and mortality. j trop pediatr 1997; 43:65−70. 29. sundaram v, kumar p, dutta s. blood culture confirmed bacterial sepsis in neonates in a north indian tertiary care center: changes over the last decade. jpn j infect dis 2009; 62:46−50. 30. hyde tb, hilger tm, reingold a, farley mm, o’brien kl, schuchat a. trends in incidence and antimicrobial resistance of early-onset sepsis: population-based surveillance in san francisco and atlanta. pediatrics 2002; 110:690−5. 31. shaw ck, shaw p, thapalial a. neonatal sepsis bacterial isolates and antibiotic susceptibility patterns at a nicu in a tertiary care hospital in western nepal: a retrospective analysis. kathmandu uni med j 2007; 5:153−60. 32. pawa ak, ramji s, prakash k, thirupuram s. neonatal nosocomial infection: profile and risk factors. indian pediatr 1997; 34:297−02. 33. zaidi akm, thaver smd, ali sa, khan ta. pathogens associated with sepsis in newborns and young infants in developing countries. pediatr infect dis j 2009; 28:s10–18. 34. litzow jm, gill cj, mantaring jbv. high frequency of multi-drug-resistant gram-negative rods in 2 neonatal intensive care units in the philippines. infect control hosp epidemiol 2009; 30:543−9. 35. gupta a, della-latta pd, todd b. outbreak of extended-spectrum beta-lactamase–producing klebsiella pneumonia in a neonatal intensive care unit linked to artificial nails. infect control hosp epidemiol 2004; 25:210−15. 36. artemio gv, dolores ac, cuauhtli m. multiresistant extended-spectrum b-lactamase producing klebsiella pneumoniae causing an outbreak of nosocomial bloodstream infection. infect control hosp epidemiol 2001; 22:723−5. 37. vergnano s, sharland m, kazembe p, mwansambo c, heath pt. neonatal sepsis: an international perspective. arch dis child fetal neonatal ed 2005; 90:220−4. 38. thaver d, ali sa, zaidi akm. antimicrobial resistance among neonatal pathogens in developing countries. pediatr infect dis j 2009; 28:s19−21. 39. zaidi akm, huskins wc, thaver d, bhutta za, abbas z, goldmann da. hospital-acquired neonatal infections in developing countries. lancet 2005; 365:1175−88. 40. altawfiq ja, antony a. antimicrobial resistance of klebsiella pneumoniae in a saudi arabian hospital: results of a 6-year surveillance study 1998–2003. j infect chemother 2007; 13:230−4. 41. bindayna km, jamsheer a, farid e, botta ga. neonatal sepsis 1991–2001: prevalent bacterial agents and antimicrobial susceptibilities in bahrain. med princ pract 2006; 15:131−6. squ med j, february 2011, vol. 11, iss. 1, pp. 112-114, epub. 12th feb 11 submitted 20th jun 10 revision req. 21st sept 10, revision recd. 7th oct 10 accepted 27th oct 10 s tump appendicitis (sa) is a rare post-appendectomy complication whose exact incidence and prevalence are not clearly defined.1 the incidence of sa may be increasing, possibly because of widespread utilisation of laparoscopic appendectomy. this may result in a long appendiceal stump which is the commonest aetiology for stump appendicitis.2,3 confirmation is either by imaging studies or diagnostic laparoscopy. only a few cases of sa have been reported in english medical literature.3 case report an eighteen-year-old boy who had undergone laparoscopic appendectomy one year previously presented at kasturba medical college hospital, manipal, india. he had lower abdominal pain of three days duration which was most acute in the right iliac fossa. it was not associated with fever and vomiting. he had had a similar episode six months previously, which had subsided with conservative treatment. the general physical examination was unremarkable. per abdominal examination revealed healed scars of laparoscopic surgery, along with tenderness in the right iliac fossa with no palpable mass. laboratory investigations were within normal limits. a contrast enhanced computed tomography (cect) scan of the abdomen and pelvis showed a short length tubular structure at the caput caecum with enhancing wall and stranding of adjacent periappendiceal fat consistent with an inflamed appendiceal stump [figure 1]. a preoperative diagnosis of stump appendicitis was made and an open ‘completion’ appendectomy was performed with an uneventful postoperative period. discussion stump appendicitis is rare following previous appendectomy, the known causative factor being a long residual stump. the true incidence and prevalence of sa are not known largely due to under-reporting and its poor definition.3 the first case of sa was reported by rose in 1945 and since then thirty-seven cases of ‘residual appendicitis’ departments of 1surgery and 2radiology, kasturba medical college, manipal university, manipal, karnataka, india. *corresponding author email: rodricksgaby@yahoo.co.in döáj�f� π]< �õǚ ��÷]<‡̌ �⁄<ìè̌ �ë^œ÷]<ì̌ë^„� fl÷]e<ïçò]à÷]<ì¬̌ç̌q̌<h^„j÷] ö^øflπ^e<ïçò]à÷]<ƒ ö<ìè◊€¬<ç√e<       :مفتاح الكلمات abstract: stump appendicitis (sa) is a rare clinicopathologic entity characterised by inflammation of the appendiceal remnant after incomplete appendectomy. the diagnosis is not routinely suspected in patients who have previously undergone appendectomy. we report a case of sa in an adolescent boy who had previously undergone laparoscopic appendectomy. the case necessitated surgical completion of the appendectomy. keywords: appendicitis; stump; surgery; case report; india stump appendicitis following laparoscopic appendectomy suresh parameshwarappa,1 *gabriel rodrigues,1 raghunath prabhu,1 charudutt sambhaji2 case report suresh parameshwarappa, gabriel rodrigues, raghunath prabhu and charudutt sambhaji case report | 113 have been reported in english medical literature.2 the age at presentation of sa ranged from 11 to 72 years (mean 39 years) with an equal incidence in both sexes. the time of onset ranged from two weeks to decades after the appendectomy. although no relationship between laparoscopic appendectomy and sa has yet been conclusively demonstrated, the occurrence of sa is more prevalent following laparoscopic appendectomy than conventional appendectomy.4,5 the causes of sa are insufficient inversion of the stump, a long proximal remnant of the appendix, incomplete removal of the distal remnant and partial laparoscopic or laparotomic appendectomy. the growing utilisation of laparoscopic appendectomy may increase the frequency of stump appendicitis due to the potential limitations of this technique. these include a smaller field of vision, lack of three-dimensional perspective and the absence of tactile feedback, thus potentially leaving a longer stump.6 other causes reported in the literature include inadequate identification of the appendiceal base because of severe local inflammation; a retrocecal or sub-serous appendix; simple ligation of the appendix without invagination of the stump; leaving a long stump due to fear of caecal injury, and difficult dissection and local ulceration due to faecolith.3,6 a stump longer than 5 mm serves as a reservoir for the faecolith, becomes ischaemic and eventually perforates. inversion of the long stump into the caecal wall does not necessarily prevent sa and other complications.7 clinically, sa patients present with signs and symptoms similar to those of appendicitis or acute abdomen and with a previous history of appendectomy. the presence of an appendectomy scar does not absolutely rule out the possibility of sa.4 ultrasonography (usg) and a ct scan of the abdomen constitute the modalities of choice for preoperative diagnosis of sa. usg can reveal a thickened appendix stump, fluid in the right iliac fossa and caecal oedema.8 a ct scan of the abdomen and pelvis is more useful than usg for the accurate preoperative diagnosis of sa, as it also excludes other aetiologies.1 the ct features of sa are similar to those of acute appendicitis, which include pericecal inflammatory changes, abscess formation, fluid in the right paracolic gutter, cecal wall thickening, and an ileocecal mass. a specific diagnosis of sa can be made preoperatively when inflammatory changes surround a distended appendiceal stump.3,5 barium studies and colonoscopy have also been reported as being helpful in diagnosing sa.9,10 diagnostic laparoscopy is gaining popularity and can be helpful for the diagnosis of sa.6 sa is most commonly treated by an open operation, but cases successfully treated using laparoscopic intervention, have been reported.3 very rarely, an aggressive surgery such as ileocolic resection may be obligatory. laparoscopy seems to be more successful than conventional laparotomy as it permits a global inspection of the abdominal cavity and an easier adhesiolysis.3 accurate visualisation of the base and leaving a stump less than 3 mm in depth can minimise the incidence of sa.11 use of angled scopes may provide good visualisation of the appendix.12 conclusion the diagnosis of sa is often missed or delayed. it should be considered in patients presenting with right lower abdominal pain and a history of previous appendectomy. ct imaging studies help in preoperative diagnosis of sa. completion of the appendectomy by conventional or laparoscopic means is the treatment of choice for sa. figure 1: distended residual appendicular stump (white arrow) at the caput cecum with periappendiceal fat stranding (black arrow) suggesting inflammation. stump appendicitis following laparoscopic appendectomy 114 | squ medical journal, february 2011, volume 11, issue 1 references 1. shin lk, halpern d, weston sr, meiner em, katz ds. prospective ct diagnosis of stump appendicitis. ajr am j roentgenol 2005; 184:s62–4. 2. aschkenasy mt, rybicki fj. acute appendicitis of the appendiceal stump. j emerg med 2005; 28:41–3. 3. gasmi m, fitouri f, sahli s, jemai r, hamzaoui m. a stump appendicitis in a child: a case report. ital j pediatr 2009; 35:35. 4. al-dabbagh ak, thomas nb, haboubi n. stump appendicitis. a diagnostic dilemma. tech coloproctol 2009; 13:734. 5. o'leary dp, myers e, coyle j, wilson i. case report of recurrent acute appendicitis in a residual tip. cases j 2010; 3:14. 6. walsh dc, roediger we. stump appendicitis. a potential problem after laparoscopic appendicectomy. surg laparosc endosc percut tech 1997; 7:357–8. 7. uludag m, isgor a, basak m. stump appendicitis is a rare delayed complication of appendectomy: a case report. world j gastroenterol 2006; 12:5401–3. 8. baldisserotto m, cavazzola s, cavazzola lt, lopes mh, mottin cc. acute edematous stump appendicitis diagnosed preoperatively on sonography. ajr am j roentgenol 2000; 175:503–4. 9. de u, de kk. stump appendicitis. j ind med assoc 2004; 102:329. 10. nahon p, nahon s, hoang jm, traissac l, delas n. stump appendicitis diagnosed by colonoscopy. am j gastroenterol 2002; 97:1564–5. 11. mangi aa, berger dl. stump appendicits. am surg 2000; 66:739–41. 12. durgun av, baca b, ersoy y, kapan m. stump appendicitis and generalized peritonitis due to incomplete appendectomy. tech coloproctol 2003; 7:102–4. departments of 1radiology and 2orthopaedics & traumatology, national university of malaysia medical centre, kuala lumpur, malaysia *corresponding author’s e-mail: windhoe2@hotmail.com ورم وعائي دموي زليلي يف املرفق حالة نادرة يف طفل، ومعضلة تشخيص إشعاعي هان قوان هو، فايز حممد زكي، عبد احلليم عبد الرا�سد abstract: synovial haemangiomas are rare benign vascular proliferations arising in synovium-lined surfaces. while the knee is by far the joint most commonly involved, this condition can also occur in the elbow. we report an eight-year-old boy who presented to the national university of malaysia medical centre, kuala lumpur, malaysia, in 2016 with a left elbow swelling of one year’s duration. magnetic resonance imaging showed a lobulated intraarticular mass with intermediate signal intensity on t1-weighted imaging and low signal punctate and linear structures within the hyperintense mass on t2-weighted imaging. in addition, there was heterogeneous yet avid contrast enhancement on post-gadolinium contrast images. the mass had juxta-articular extension and bony erosion to the coronoid process and the head of the radius. synovial haemangiomas present a diagnostic dilemma. this report highlights certain imaging characteristics to distinguish this entity from other differential diagnoses. keywords: synovial membrane; hemangioma; sarcoma; magnetic resonance imaging; diagnostic imaging; case report; malaysia. امللخ�ص: تعد االأورام الوعائية انت�سارات وعائية حميدة ونادرة احلدوث تن�ساأ من اأ�سطح الغ�ساء الزليلي. وحتدث هذه احلاالت يف الغالب يف الركبة، اإال اأنها قد حتدث اأي�سا يف املرفق. نعر�ض هنا حلالة طفل عمره ثماين �سنوات اأح�رص اإىل املركز الطبي جلامعة ماليزيا الوطنية يف كواال المبور مباليزيا يف عام 2016. وكان ذلك الطفل م�سابا بورم يف مرفقه االأي�رص منذ عام كامل. وتبني من ت�سوير الرنني املغنطي�سي طة وجود كتلة مف�س�سة بني املفا�سل كانت لها اإ�سارة متو�سطة الكثافة على ت�سل�سل الت�سوير يف t1 املرجحة، واإ�سارة قليلة الكثافة ُمَنقَّ و�سديد متغاير ت�سخيم هنالك كان لذلك وباالإ�سافة املرجحة. t2 يف الت�سوير بت�سل�سل الكثافة عالية الكتلة داخل يف اخلطية البنيات احلدة للتباين يف �سور ما بعد عن�رص الغادولينيوم. وكان للكتلة امتداد جماور للمف�سل، وتـاآكل للعظم يف النَّاِتُئ االإِْكلياَليّن وَراأْ�ُض الُكْعرُبَة. متثل االأورام الوعائية الدموية الزاللية مع�سلة ت�سخي�سية. ويربز تقرير احلالة هذه بع�ض خوا�ض ال�سور التي متيز هذه احلالة من غريها بالت�سخي�ض التفريقي. الكلمات املفتاحية: غ�ساء زليلي؛ ورم وعائي دموي؛ �ساركوما؛ ت�سوير الرنني املغنطي�سي؛ الت�سوير الت�سخي�سي؛ تقرير حالة؛ ماليزيا. synovial haemangioma of the elbow a rare paediatric case and imaging dilemma *han g. hoe,1 faizah m. zaki,1 abdul h. a. rashid2 case report sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e93–96, epub. 4 apr 18 submitted 22 oct 17 revision req. 18 dec 17; revision recd. 2 jan 18 accepted 18 jan 18 doi: 10.18295/squmj.2018.18.01.015 synovial haemangiomas are rare benign vascular lesions first described by bouchut in 1856.1 most cases involve young adults and children; moreover, men are affected more often than women.2 due to their potential for significant morbid ity, synovial haemangiomas require early diagnosis and treatment.2,3 this case report describes the clinical presentation, differential diagnosis and imaging findings of a histologically-proven case of synovial haemangioma of the elbow. case report an eight-year-old boy presented to the national university of malaysia medical centre, kuala lumpur, malaysia, in 2016 with a swelling in his left elbow that his parents had first noticed one year prior. there was no history of antecedent trauma to the affected elbow. the patient had been previously seen by a general practitioner who treated the swelling as an infection and prescribed a course of antibiotics. due to a lack of improvement following completion of the antibiotic course, the patient was referred to an orthopaedic surgeon who prescribed a course of non-steroidal antiinflammatory drugs to which he responded positively. at this stage, the probable working diagnosis was of an osteoid osteoma. upon physical examination, there was fixed flexion of the elbow to approximately five degrees. the mass measured 5 x 3 cm and was oval, soft, non-tender, immobile, not warm and had a smooth surface with ill-defined margins. a plain radiograph of the left elbow showed a mass or effusion causing signs of a posterior fat pad and anterior sail [figure 1]. no abnormal calcification was seen. in view of the persistent swelling, a magnetic resonance imaging (mri) examination was performed. the mri scans showed an ill-defined multilobulated intra-articular lesion with an epicentre proximal to synovial haemangioma of the elbow a rare paediatric case and imaging dilemma e94 | squ medical journal, february 2018, volume 18, issue 1 [figure 2c]. post-gadolinium administration, the mass demonstrated avid yet heterogeneous enhancement [figure 2d]. further t2wi scans indicated the presence of a tubular-like hyperintense structure within the lesion, potentially representing a vascular component [figure 3]. a cortical breach into the intramedullary region at the level of the coronoid process of the ulna and into the proximal radius shaft was also noted. the lesion extended posteriorly to infiltrate the anconeus muscle and was relatively large in comparison to the cortical breach [figures 4a–c]. a core biopsy confirmed features of a benign vascular neoplasm, with a final diagnosis of a synovial haemangioma [figure 4d]. there was no evid ence of calcification, atypical cells, multinucleated giant cells, granulomas or malignancy. an ultrasound showed the lesion to be a diffuse hypervascular mass. since there was no worsening of the symptoms, the parents of the patient opted for follow-up imaging, after being informed of the risks and benefits of resection surgery. discussion while most synovial haemangiomas tend to involve the knee joint, this type of lesion can occur in any joint of the body, including the intra-articular space, ankle, tempo romandibular joint and bursae.2–5 devaney et al. reported 20 cases of synovial haemangioma, of which only six had originated from within the elbow.2 such patients can present with multiple symptoms, the intramedullary region of the left elbow with extraarticular extension. it involved the supinator muscle in the posteromedial compartment of the left proximal forearm. it was slightly hyperintense on t1-weighted imaging (t1wi) and hyperintense on t2-weighted imaging (t2wi), with internal serpentine linear and punctate hypodensities [figures 2a and b]. the signal intensity was not suppressed upon fat saturation figure 1: plain radiographs of the left elbow of an eight year-old boy from the (a) anteroposterior and (b) lateral views. signs of a posterior fat pad (arrow) and anterior sail (arrowhead) indicated an effusion or mass in the left elbow joint. a lucent/lytic lesion (circle) was seen on the proximal left ulna, potentially representing a cortical bony erosion. figure 3: t2-weighted magnetic resonance imaging scans of the left elbow of an eight year-old boy in the superior to inferior positions. a hyperintense tubular structure could be seen arising from a lobulated mass in the posteromedial part of the left elbow and crossing the proximal left ulna anteriorly to the anterior compartment of the forearm (arrows). figure 2: magnetic resonance imaging scans of the left elbow of an eight year-old boy from the axial view showing an ill-defined and multilobulated lesion, including (a) t1-weighted, (b) t2-weighted, (c) t1weighted fat-saturated and (d) t1-weighted postgadolinium contrast images. the epicentre of the mass was located in the proximal intramedullary region involving the supinator muscle in the posteromedial compartment of the left proximal forearm. the lesion was slightly hyperintense on t1-weighted imaging and hyperintense on t2-weighted imaging, with internal linear and punctate hypodensities. the signal intensity was not suppressed on fat saturation. post-gadolinium administration, the lesion demonstrated avid yet heterogeneous enhancement (arrow) with a well-defined oval calcification (arrowhead). han g. hoe, faizah m. zaki and abdul h. a. rashid case report | e95 as extremity x-rays is usually performed in more than half of synovial haemangioma cases.7 radiographs commonly show a non-specific soft tissue mass. local ised phleboliths may also be seen and are fairly specific indications of a haemangioma.7 the precise diagnosis of synovial tumours is often difficult due to the non-specific nature of the patient’s clinical symptoms and physical examination findings. the differential diagnoses of an elbow mass include synovial sarcomas, synovial haemangiomas, pigmented villonodular synovitis (pvns), synovial chondromatosis, chronic infections of mycobacterial origin, inflammatory arthritis with pannus formation, ganglion cysts or lipoma arborescens.7 in the present case, the lesion was unlikely to be pvns as the condition usually demonstrates low signals on all sequences as a result of a ‘blooming’ phenomenon in gradient echo sequences.11,12 moreover, even though the patient presented with an intra-articular nodular ossified body, synovial chondromatosis usually occurs in adults rather than in young children; moreover, juvenile rheumatoid arthritis is rare before the age of 10 years.7 a chronic mycobacterial infection was also considered improbable as there was no evidence of necrosis or marrow oedema.7 ganglion cysts demonstrate a low signal intensity on t1wi and a high signal intensity on t2wi; in addition, low signal intensity structures may be present within the lesion.13 however, this was not considered in the differential diagnosis for the current case as ganglion cysts usually have peripheral rim enhancement, which was not evident. lipoma arborescens is a monoarticular condition that most commonly occurs in the suprapatellar recess and the knee joint.13 it has frond-like synovial projections of fat signal intensity on mri, which were not seen in the present case, and rarely has bony erosions. despite the use of gadolinium contrast, differentiating synovial sarcomas and haemangiomas on radiology images can be challenging. in particular, the characteristic mri features of a synovial haemangioma may coincide with those of malignant lesions such as intra-articular synovial sarcomas.12,13 however, synovial sarcomas are associated with calcification in one-third of cases and are not commonly encountered in children. moreover, although synovial sarcomas arise near the joint, it is rare for them to originate or extend intra-articularly.13 in the present case, the epicentre of the mass arose from the elbow joint with juxta-articular extension, lowering the likelihood of a synovial sarcoma. in the current case, there was a cortical breach of the coronoid process of the left ulna and proximal radius. this therefore made it challenging to determine whether the bony erosion was due to the presence of including persistent elbow pain, swelling, loss of range of movement either in terms of flexion or extension and posterior interosseous nerve palsy secondary to a haemangioma.6–9 despite its rarity, the early diagnosis of a synovial haemangioma is important as recurrent haemarthrosis may lead to irreversible joint damage and chronic inflammatory synovitis.10 chronic synovial haemangioma can also result in pressure erosion or remodelling of the adjacent bones.11 the characteristic mri features of a synovial haemangioma include homogeneous, low or iso-intense signals upon t1wi.11,12 however, with t2wi, synovial haemangiomas have lobulated, well-defined margins with heterogeneous high signal intensity. moreover, multiple low signal punctates or linear structures may be present within the lesion.11,12 following the administration of gadolinium, synovial haemangiomas usually demonstrate heterogeneous enhancement. magnetic resonance angiography is a suitable noninvasive imaging method that can be used to evaluate the relationship of the haemangioma to adjacent feeding vessels for better surgical planning.11,12 conventional radiography such figure 4: a & b: t1-weighted magnetic resonance imaging (mri) scan in the axial view and t2-weighted scan in the coronal view of the left elbow of an eight year-old boy showing a cortical breach into the intramedullary region at the level of the coronoid process into the proximal radius shaft (arrows) and extending posteriorly to infiltrate the anconeus muscle (arrowheads). c: t1-weighted mri scan in the coronal view showing the large size of the lesion (arrow) compared to the cortical breach. d: haematoxylin and eosin stain at x20 magnification showing predominantly fibrous tissue, adipose tissue and skeletal muscle fibres. note the numerous admixtures of dilated vascular spaces interspersed between the connective tissue matrix (arrow) consisting of both thick-walled, thinwalled and capillary-sized vessels lined by blandlooking endothelial cells. synovial haemangioma of the elbow a rare paediatric case and imaging dilemma e96 | squ medical journal, february 2018, volume 18, issue 1 references 1. bouchut me. [erectile tumor of the knee joint]. gaz hop (paris) 1856; 29:379. 2. devaney k, vinh tn, sweet de. synovial hemangioma: a report of 20 cases with differential diagnostic considerations. hum pathol 1993; 24:737–45. doi: 10.1016/0046-8177(93)90010-e. 3. mcneill tw, ray rd. hemangioma of the extremities: review of 35 cases. clin orthop relat res 1974; 101:154–66. 4. wen dw, tan tj, rasheed s. synovial haemangioma of the knee joint: an unusual cause of knee pain in 14-month old girl. skeletal radiol 2016; 45:827–31. doi: 10.1007/s00256-0162356-0. 5. atkinson tj, wolf s, anavi y, wesley r. synovial hemangioma of the temporomandibular joint: report of a case and review of the literature. j oral maxillofac surg 1988; 46:804–8. doi: 10.1016/0278-2391(88)90195-4. 6. mohammadi a, rosa m, wolfson d. synovial hemangioma of the elbow: an uncommon lesion to be considered. internet j pathol 2008; 7:3. 7. chatha ds, rybak ld, wittig jc, desai p. orthopaedicradiology-pathology conference: elbow mass in a 9-year-old girl. clin orthop relat res 2007; 463:237–43. doi: 10.1097/ blo.0b013e3180463089. 8. banks db, hay sm. intra-articular synovial haemangioma of the elbow in an adolescent male. shoulder elbow 2014; 6:57–9. doi: 10.1111/sae.12034. 9. busa r, adani r, marcuzzi a, caroli a. acute posterior interosseous nerve palsy caused by a synovial haemangioma of the elbow joint. j hand surg br 1995; 20:652–4. doi: 10.1016/ s0266-7681(05)80128-7. 10. akgün i, kesmezacar h, oğüt t, dervişoğlu s. intra-articular hemangioma of the knee. arthroscopy 2003; 19:e17. doi: 10.10 53/jars.2003.50068. 11. de filippo m, rovani c, sudberry jj, rossi f, pogliacomi f, zompatori m. magnetic resonance imaging comparison of intra-articular cavernous synovial hemangioma and cystic synovial hyperplasia of the knee. acta radiol 2006; 47:581–4. doi: 10.1080/02841850600767724. 12. llauger j, monill jm, palmer j, clotet m. synovial hemangioma of the knee: mri findings in two cases. skeletal radiol 1995; 24:579–81. doi: 10.1007/bf00204855. 13. kim sj, cho sh, ko dh. arthroscopic excision of synovial hemangioma of the hip joint. j orthop sci 2008; 13:387–9. doi: 10.1007/s00776-007-1232-0. 14. price nj, cundy pj. synovial hemangioma of the knee. j pediatr orthop 1997; 17:74–7. doi: 10.1097/01241398-19970 1000-00017. a bone tumour which had infiltrated into the adjacent soft tissue or because of a soft tissue tumour that had eroded the adjacent bone. in this case, as the soft tissue lesion was much larger than the cortical erosion, a primary soft tissue abnormality with secondary involvement of the bone was deemed more probable. it is important to note that although the radiographical and mri features of the present case pointed towards the diagnosis of a synovial haemangioma, it is a rare disease entity and some imaging features may coincide with other differential diagnoses as described above. therefore, while the presence of the aforementioned imaging features indicate a likely diagnosis of a synovial haemangioma, a definitive diagnosis requires histopathological confirmation via biopsy, as in the present case. the treatment of synovial haemangiomas depends on the extent of the lesion and should therefore be individualised. currently, the gold standard of treatment is surgery. arthroscopic resection may be performed in lesions that are pedunculated or welldefined.14 if the synovial haemangioma is large and involves intraand extra-articular regions, then removal via open surgery with local excision or a total synovectomy is preferable. recurrence rates after surgical removal are higher for lesions with diffuse involvement.14 conclusion synovial haemangiomas are rare tumours requiring early diagnosis and treatment to prevent long-term morbidity. however, the diagnosis is challenging due to a myriad of similar conditions. currently, an accurate diagnosis depends upon a combination of mri scans, early arthroscopic assessment and histopathological confirmation following a core biopsy. both clinicians and radiologists should consider this entity in the differential diagnosis of patients who present with synovial lesions. https://doi.org/10.1016/0046-8177%2893%2990010-e https://doi.org/10.1007/s00256-016-2356-0 https://doi.org/10.1007/s00256-016-2356-0 https://doi.org/10.1016/0278-2391%2888%2990195-4 https://doi.org/10.1097/blo.0b013e3180463089 https://doi.org/10.1097/blo.0b013e3180463089 https://doi.org/10.1111/sae.12034 https://doi.org/10.1016/s0266-7681%2805%2980128-7 https://doi.org/10.1016/s0266-7681%2805%2980128-7 https://doi.org/10.1053/jars.2003.50068 https://doi.org/10.1053/jars.2003.50068 https://doi.org/10.1080/02841850600767724 https://doi.org/10.1007/bf00204855 https://doi.org/10.1007/s00776-007-1232-0 https://doi.org/10.1097/01241398-199701000-00017 https://doi.org/10.1097/01241398-199701000-00017 1department of emergency medicine, khoula hospital, muscat, oman; 2division of plastic & reconstructive surgery, university of toronto, toronto, ontario, canada; 3ear, nose & throat residency programme, oman medical specialty board, muscat, oman; 4emergency medicine royal college residency training programme, mcgill university, montreal, quebec, canada *corresponding author e-mail: drsultanalshaqsi@gmail.com نتائج حاالت الرضوح املتعدد يف حوادث املرور يف مستشفى ثالثي عمان هل مثة فرق بني حضور جراحي الرضوح وحضور غريهم من اجلراحني؟ عمار الك�سمريي، �سلطان ال�سق�سي، ندى املرهوبي، حممود ح�سن abstract: objectives: trauma surgeons are essential in hospital-based trauma care systems. however, there are limited data regarding the impact of their presence on the outcome of multi-trauma patients. this study aimed to assess the outcomes of multi-trauma road traffic crash (rtc) cases attended by trauma surgeons versus those attended by non-trauma surgeons at a tertiary hospital in oman. methods: this retrospective study was conducted in december 2015. a previously published cohort of 821 multi-trauma rtc patients admitted between january and december 2011 to the sultan qaboos university hospital, muscat, oman, were reviewed for demographic, injury and hospitalisation data. in-hospital mortality constituted the main outcome, with admission to the intensive care unit, operative management, intubation and length of stay constituting secondary outcomes. results: a total of 821 multi-trauma rtc cases were identified; of these, 60 (7.3%) were attended by trauma surgeons. there was no significant difference in mortality between the two groups (p = 0.35). however, patients attended by trauma surgeons were significantly more likely to be intubated, admitted to the icu and undergo operative interventions (p <0.01 each). the average length of hospital stay in both groups was similar (2.6 versus 2.8 days; p = 0.81). conclusion: no difference in mortality was observed between multi-trauma rtc patients attended by trauma surgeons in comparison to those cared for by non-trauma surgeons at a tertiary centre in oman. keywords: multiple trauma; resuscitation; patient outcome assessment; surgeons; trauma centers; oman. امللخ�ص: الهدف: يعد وجود جراحي الر�سح اأمرا الزما يف امل�ست�سفيات التي بها اأنظمة رعاية للر�سوح. غري اأنه ال تتوفر معلومات كافية عن مدى تاأثري وجودهم على نتائج املر�سي امل�سابني بر�سوح متعددة. وتهدف هذه الدرا�سة لتقومي نتائج حوادث املرور على الطرق التي يقوم عليها جراحو الر�سوح مقارنة مع تلك التي يقوم عليها غريهم من اجلراحني يف م�ست�سفى ثالثي عمان. الطريقة: اأجريت هذه الدرا�سة 821 حلاالت واال�ست�سفاء واالإ�سابة بالدميغرافيا اخلا�سة املخزنة املعلومات مراجعة ومتت 2015م، عام من دي�سمرب يف االإ�ستعادية مري�سا اأدخلوا مل�ست�سفى جامعة ال�سلطان قابو�س يف م�سقط عمان بني يناير ودي�سمرب 2011م. وكانت الوفاة يف امل�ست�سفى هي النتيجة الرئي�سة، اأما النتائج الثانوية فكانت هي االإدخال يف العناية املركزة، والعالج اجلراحي، والتنبيب، ومدة البقاء بامل�ست�سفى. النتائج: بلغ عدد امل�سابني بر�سوح متعددة يف حوادث املرور على الطرق يف فرتة الدرا�سة 821 مري�سا، قام على رعاية 60 منهم )%7.3( جراحو ر�سح. ومل يكن هنالك فرق اإح�سائي معتد )معنوي( يف معدل الوفاة بني هذه املجموعة وغريها )p = 0.35(. اإال اأن معدل املر�سى الذين قام على رعايتهم جراحو الر�سح كانوا اأكرث تنبيبا واإدخاال للعناية املركزة وخ�سوعا للتدخالت اجلراحية من غريهم )p <0.01 يف كل حالة(. ومل يكن هنالك فرق اإح�سائي معنوي يف فرتة البقاء يف امل�ست�سفى بني املجموعتني )2.6 يوما يف مقابل 2.8 يوما، p = 0.81(. اخلال�صة: مل يكن هنالك فرق اح�سائي معنوي يف معدل الوفاة عند امل�سابني الذين قام على رعايتهم جراحو الر�سح مقارنة بامل�سابني الذي قام على رعايتهم جراحون اآخرون يف م�ست�سفى رعاية ثالثية بعمان. الكلمات املفتاحية: ر�سوح متعدد؛ اإنعا�س؛ تقومي نتائج املر�سى؛ اجلراحون؛ مراكز الر�سح؛ عمان. outcomes of multi-trauma road traffic crashes at a tertiary hospital in oman does attendance by trauma surgeons versus non-trauma surgeons make a difference? ammar al-kashmiri,1 *sultan z. al-shaqsi,2 nada al-marhoobi,3 mahmood hasan4 clinical & basic research sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e196–201, epub. 20 jun 17 submitted 25 jan 17 revision req. 27 feb 17; revision recd. 13 mar 17 accepted 19 mar 17 doi: 10.18295/squmj.2016.17.02.010 advances in knowledge in oman, multi-trauma road traffic crash (rtc) cases attended by non-trauma surgeons were found to have similar outcomes to those cared for by trauma surgeons. application to patient care many of the multi-trauma rtc cases in the current study were attended by non-trauma surgeons. as such, non-trauma surgeons in oman should be trained in the management and resuscitation of multi-trauma patients in order to strengthen overall trauma care services in the country. ammar al-kashmiri, sultan z. al-shaqsi, nada al-marhoobi and mahmood hasan clinical and basic research | e197 trauma injuries represent a significant global burden, particularly in middleand lowincome countries; the world health organization (who) has estimated that approximately five million people die every year from injuries, most often due to road traffic crashes (rtcs), violence or burns.1 the physical effects of such injuries can be classified as either immediate, secondary (i.e. within hours of the event) or delayed (i.e. long-term complications). most trauma-related deaths occur either at the scene of the injury or en route to or within hours of arrival at a healthcare facility.1 therefore, pre-hospital and initial hospital-based trauma systems focus on reducing the immediate effects of injuries on mortality and morbidity by promptly providing essential life-saving trauma interventions, such as securing a patient’s airway, maintaining adequate ventilation and controlling bleeding.1 the who has advocated for the establishment of trauma care systems globally in order to mitigate the mortality and morbidity of trauma injuries.2 moreover, the american college of surgeons recommend that trauma surgeons be present upon the initial arrival of a seriously injured patient to the emergency department.3 oman has one of the highest rates of rtcs globally; in 2015, there were approximately 6,279 rtcs and this type of accident was the direct cause of 675 deaths and 3,624 injuries.4 moreover, the rtcrelated fatality rate in 2013 was 30.4 per 100,000 people annually compared to the global yearly average of 18 per 100,000 people.5 an increase in car ownership as a result of rapid modernisation and the development of new roads and highways due to urbanisation processes have contributed to a dramatic increase in rtcs.6–8 other complex behavioural issues related to modernisation, such as increased use of mobile phones while driving, may also be partially responsible for the high rate of rtcs in oman.6,9 in some cases, traffic enforcement and legal authorities have failed to keep up with rapid modernisation, resulting in more lenient and less than optimal law enforcement. the trauma system in oman consists of a pre-hospital emergency system and the emergency medical services (ems) run by the public authority of civil defence and ambulances.10,11 hospitals in oman vary in size and resources, ranging from rural health centres staffed by junior non-specialist doctors to tertiary hospitals with qualified trauma and non-trauma surgeons. the sultan qaboos university hospital (squh) in muscat is the only national tertiary hospital in the country which has board-certified trauma surgeons with training in trauma and critical and acute care surgeries, excluding emergency craniotomies.10,11 at squh, the emergency department receives an average of 900 trauma patients annually.11 trauma teams consist of a team leader (either a trauma or non-trauma surgeon), an anaesthetist, an emergency physician, residents in emergency or general surgery and allied health personnel. however, while some of the trauma teams are led by board-certified trauma surgeons, others are led by non-trauma surgeons for whom the scope of emergency procedures is limited to abdominal damage control. it is therefore not clear whether the presence of board-certified trauma surgeons affects the outcome of injured patients. this study aimed to assess differences in outcomes among multitrauma patients injured in rtcs who were attended by board-certified trauma surgeons compared to those attended by non-trauma surgeons. methods this retrospective study took place in december 2015 and utilised the same cohort as that of a previously published study.11 the electronic medical records of all rtc multi-trauma patients admitted to the emergency department of squh between january and december 2011 were reviewed. data for all cases were collected, including the demographic characteristics of the patient and whether they were attended by a board-certified trauma surgeon or a non-trauma surgeon.11 additionally, information regarding patient outcome, length of hospital stay and injury details, severity and management was recorded.11 the primary outcome was in-hospital mortality, with secondary outcomes constituting of admission to the intensive care unit (icu), surgical interventions and length of hospital stay. data were analysed using the statistical package for the social sciences (spss), version 22.1 (ibm corp., armonk, new york, usa). differences between variables were initially determined using a univariate analysis. for continuous variables, a student’s t-test or mann-whitney u test was used whereas a yates’ chi-squared test or fisher’s exact test was used for categorical variables, as appropriate.12 a p value of <0.05 was considered statistically significant. a general linear multivariate regression analysis was performed to determine if the primary and secondary outcomes were the same between the two groups, after controlling for variables with potential confounding effects, such as age, gender, ethnicity, time of injury, admissions over the weekend, triage status, injury severity score (iss) and the presence of a head injury. this study received ethical approval from the ethics committee of the ministry of health in oman. outcomes of multi-trauma road traffic crashes at a tertiary hospital in oman does attendance by trauma surgeons versus non-trauma surgeons make a difference? e198 | squ medical journal, may 2017, volume 17, issue 2 results a total of 821 multi-trauma rtc cases were admitted during the study period.11 of these, 60 (7.3%) were attended by trauma surgeons and 761 (92.7%) were attended by non-trauma surgeons. the average age of patients attended by trauma surgeons was similar to that of patients attended by non-trauma surgeons; however, significantly more of the trauma patients attended by trauma surgeons were male compared to those attended by other surgeons (85.0% versus 65.8%; p = 0.01). a similar proportion of patients in both groups were of omani ethnicity. almost onethird of the patients in both groups were admitted to the hospital during weekends and approximately twothirds were transported to the hospital by the ems. patients admitted between 8 a.m. and 3 p.m. were significantly more likely to be attended by trauma surgeons (35.0% versus 25.4%; p = 0.04) while those admitted between 4 p.m. and 11 p.m. were significantly more likely to be seen by non-trauma surgeons (51.5% versus 38.3%; p = 0.03). in terms of triage status, significantly more patients in the ‘resuscitation’ (16.7% versus 8.3%) and ‘emergency’ (33.3% versus 9.6%) triage categories were attended by trauma surgeons (p <0.01) [table 1]. the majority of cases in both groups had an iss of 0–15. however, 26.7% of cases attended by trauma surgeons had head injuries compared to 8.7% of cases attended by non-trauma surgeons (p <0.01). nevertheless, when patients with severe head injuries were compared using the abbreviated injury score (ais) for injuries of >3 ais severity, there was still no difference in outcome between the two groups. after controlling for potential confounders in the regression analysis, no significant differences were noted with regards to in-hospital mortality between patients attended by trauma surgeons and those attended by non-trauma surgeons (p = 0.35), even when stratified by head trauma ais or iss scores (p = 0.42 and 0.50, respectively). in addition, no significant difference was observed with regards to the length of stay between the two groups (2.8 versus 2.6 days; p = 0.81) however, patients attended by trauma surgeons were significantly more likely to be intubated (relative risk [rr]: 13.3; confidence interval [ci]: 7.76–22.7; p <0.01), admitted to the icu (rr: 7.2; ci: 4.16–12.62; p <0.01) and undergo surgical interventions (rr: 3.5; ci: 2.64–5.48) [table 2]. discussion the burden of trauma in oman has been steadily rising over the last few decades, thus highlighting the need for a well-established trauma system.6,11 a well-resourced trauma system is known to improve mortality rates.13–17 however, the trauma system in oman has not kept pace with modernisation and rapid population growth in the country. furthermore, a non-holistic approach has led to a lack of integration of trauma care services within the existing healthcare system; for example, as the pre-hospital trauma care system has developed faster than existing hospital systems, there can be a decline in care once the patient is transferred to a medical facility. at present, squh is the only facility in the country with qualified trauma surgeons who have undergone structured training. however, within established hospital trauma systems, it remains to be seen whether all trauma cases require table 1: demographic and injury characteristics of multitrauma road traffic crash cases admitted to the sultan qaboos university hospital, muscat, oman (n = 821) characteristic n (%) p value patients attended by trauma surgeons (n = 60) patients attended by non-trauma surgeons (n = 761) mean age in years (range) 29.8 (1–67) 27.6 (2–79) 0.20 male gender 51 (85.0) 521 (68.5) 0.01 omani ethnicity 40 (66.7) 495 (65.0) 0.20 admitted during the weekend 19 (31.7) 220 (28.9) 0.05 transported to hospital by ems 40 (66.7) 508 (66.8) 0.60 time of arrival to ed 12 a.m. to 7 a.m. 16 (26.7) 176 (23.1) 0.05 8 a.m. to 3 p.m. 21 (35.0) 193 (25.4) 0.04 4 p.m. to 11 p.m. 23 (38.3) 392 (51.5) 0.03 triage category <0.01 urgent 30 (50.0) 625 (82.1) emergency 20 (33.3) 73 (9.6) resuscitation 10 (16.7) 63 (8.3) iss 0.12 0–15 53 (88.3) 665 (87.4) 16–30 6 (10.0) 43 (5.7) 31–75 1 (1.7) 53 (7.0) presence of a head injury 16 (26.7) 66 (8.7) <0.01 ems = emergency medical services; ed = emergency department; iss = injury severity score. ammar al-kashmiri, sultan z. al-shaqsi, nada al-marhoobi and mahmood hasan clinical and basic research | e199 a trauma surgeon. in settings where a trauma system is still in its infancy, such as oman, determining whether this factor affects outcomes can potentially guide policy-makers in the hiring of additional human resources, if necessary, and to anticipate training requirements. in the current study, the outcomes of multitrauma rtc patients attended by trauma surgeons were compared with those of patients cared for by non-trauma surgeons at squh. the primary practice of the non-trauma surgeons was elective general surgery and subspecialties other than trauma; however, they were all certified in the advanced trauma life support® (american college of surgeons, chicago, illinois, usa) training course and were aware of the written resuscitative protocols for trauma care set by the hospital’s trauma committee. in addition, all nontrauma surgeons were included within the trauma case schedule and had a similar amount of exposure to trauma patients. no criteria currently exist at squh to decide which trauma patients should be attended by trauma surgeons; the presence of a trauma surgeon is instead determined by their call schedule, which covers a minimum of two days a week. the findings of the present study indicated that multi-trauma rtc patients attended by trauma surgeons at squh had similar mortality rates to those cared for by non-trauma surgeons. in addition, the severity of injuries was similar between the two groups. these findings would suggest that—in hospitals with established trauma systems—trauma patients may not always require a trauma surgeon, as this factor did not play a significant role in improving patient outcomes. however, an interesting finding of the present study was that trauma patients attended by trauma surgeons were significantly more likely to undergo surgical interventions than those attended by non-trauma surgeons. this finding is probably a reflection of the confidence of trauma surgeons in operative trauma management compared to a potentially more conservative approach among non trauma surgeons. the findings of the present study are in line with some of those reported in the literature. a recent study from a rural trauma centre in the usa similarly found no difference in the mortality rate of trauma patients attended by trauma surgeons versus those attended by other surgeons.18 podnos et al. also reported no difference in mortality among 1,427 patients at a level i trauma centre cared for either by trauma specialists or general surgeons.19 however, other researchers have obtained different results; haut et al. reported significantly better outcomes among patients with severe head injuries treated by full-time trauma surgeons compared to those cared for by parttime trauma surgeons.14 in the present study, analysis of the outcomes of patients with head injuries did not indicate statistically significant differences. this finding may have been the result of grouping together all types of head injuries, including moderate head table 2: outcomes of multi-trauma road traffic crash cases admitted to the sultan qaboos university hospital, muscat, oman (n = 821) outcome n (%) rr (ci) p value patients attended by trauma surgeons (n = 60) patients attended by non-trauma surgeons (n = 761) mortality 2 (3.3) 49 (6.4) 0.5 (0.13–2.10) 0.35 head injury ais >3 1 (1.7) 24 (3.2) 0.2 (0.03–1.12) 0.42 iss >15 1 (1.7) 40 (5.3) 0.2 (0.02–1.02) 0.50 intubation 22 (37) 21 (2.8) 13.3 (7.76–22.7) <0.01 head injury ais >3 10 (46) 1 (0.6) 76.6 (82.3–41.2) <0.01 no tbi 12 (54) 20 (94) 0.7 (1.3–0.34) 0.56 icu admission 16 (27) 28 (3.7) 7.2 (4.16–12.62) <0.01 head injury ais >3 3 (15.8) 3 (1.2) 13.2 (17.3–4.9) <0.01 no tbi 13 (84.2) 25 (98.8) 0.9 (1.9–0.43) 0.34 surgical interventions 25 (41.7) 88 (11.8) 3.5 (2.64–5.48) <0.01 transferred from hospital 4 (6.7) 49 (6.4) 1.1 (0.39–2.77) 0.94 mean los in days (range) 2.8 ± 5.4 (1–75) 2.6 ± 5.5 (1–83) 0.81 rr = relative risk; ci = confidence interval; ais = abbreviated injury score; iss = injury severity score; tbi = traumatic brain injury; icu = intensive care unit; los = length of stay. outcomes of multi-trauma road traffic crashes at a tertiary hospital in oman does attendance by trauma surgeons versus non-trauma surgeons make a difference? e200 | squ medical journal, may 2017, volume 17, issue 2 injuries. in addition, no significant results were found when stratifying patients by iss category. employing full-time surgeons dedicated exclusively to trauma surgery and surgical critical care, such as those employed in the setting described by haut et al., is not yet feasible in oman.14 currently, there are no centres in oman busy enough to support a surgical practice dedicated exclusively to trauma care; this could account for the differences in findings reported by this study. moreover, it may be that the volume of multi-trauma patients seen by non-trauma surgeons at squh allows them sufficient opportunities to improve their skills to the level of that of specialised trauma surgeons. indeed, smith et al. have demonstrated an inverse relationship between patient volume and mortality rates at trauma centres in the usa.20 konvolinka et al. also affirmed that increased surgeon experience with seriously injured patients was associated with improved outcomes while haut et al. reported that surgeons with vastly different levels of training could safely provide trauma care and obtain equivalent patient outcomes.15,21 based on these findings, it seems that more emphasis should be placed on building a cohesive trauma system rather than focusing on capacitybuilding individual components within the system. as such, all components in a hospital trauma system require equal development to assure that a satisfactory level of trauma care is provided, including institutional policies governing clinical and operational processes, round-the-clock availability of a structured trauma team, a dedicated trauma admitting unit and adequate training and qualification standards for healthcare providers involved in trauma care and the provision of essential equipment and services. education and the application of evidence-based protocols and guide lines should also be prioritised among non-trauma surgeons in oman. another important component is the expansion of the available pool of trauma surgeons; however, the extent to which this is needed remains debatable. nevertheless, trauma surgeons may act as advocates for better trauma care at the national level. the current study has several limitations which may have affected the results. first, the study design was retrospective and the cohort was from a single institution. second, the glasgow coma scale of the patients at admission was not assessed, thus precluding further analysis of patients with severe head injuries. this limitation was minimised as much as possible by stratifying outcomes based on ais categorisation; nevertheless, patients with head injuries may still have significantly improved outcomes when cared for by trauma surgeons. third, the low rate of penetrating trauma injuries in the present study population may have resulted in a less defined outcome difference between the two groups. as such, it is possible that a more significant difference would have been evident had the study population been larger and included more severe trauma cases. a multicentre study is recommended for more accurate results. finally, this study focused primarily on mortality and did not investigate morbidity, for which the presence of an attending trauma surgeon may potentially affect patient outcomes. conclusion no significant difference was noted in the mortality rates of multi-trauma rtc cases attended by trauma surgeons compared to those attended by non-trauma surgeons. these findings indicate that addressing only one component of a trauma system (i.e. the presence of trauma surgeons) is not sufficient to achieve better patient outcomes. as such, better outcomes for trauma patients in oman may potentially be achievable by developing all components of a trauma system to ensure that it is both effective and cohesive. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. prehospital trauma care systems. from: whqlibdoc.who.int/publications/2005/924159294x.pdf accessed: mar 2017. 2. toroyan t. global status report on road safety. inj prev 2009; 15:286. doi: 10.1136/ip.2009.023697. 3. american college of surgeons committee on trauma. resources for optimal care of the injured patient: 2014. from: www.facs.org/~/media/files/quality%20programs/trauma/ vrcresources.ashx accessed: mar 2017. 4. times of oman. road accidents drop but fatalities rise in oman. from: www.timesofoman.com/article/101115/oman/ oman-road-accident-rates-down-but-expat-deaths-up-by-16per-cent accessed: mar 2017. 5. world health organization. global status report on road safety 2013: reporting a decade of action. from: www.who. int/violence_injury_prevention/road_safety_status/2013/en/ accessed: mar 2017. 6. al-reesi h, ganguly ss, al-adawi s, laflamme l, hasselberg m, al-maniri a. economic growth, motorization, and road traffic injuries in the sultanate of oman, 1985-2009. traffic inj prev 2013; 14:322–8. doi: 10.1080/15389588.2012.694088. 7. al-kharusi w. update on road traffic crashes: progress in the middle east. clin orthop relat res 2008; 466:2457–64. doi: 10.1007/s11999-008-0439-5. 8. peterson je. oman’s diverse society: southern oman. middle east j 2004; 58:254–69. doi: 10.3751/58.2.15. https://doi.org/10.1136/ip.2009.023697 https://doi.org/10.1080/15389588.2012.694088 https://doi.org/10.1007/s11999-008-0439-5 https://doi.org/10.3751/58.2.15 ammar al-kashmiri, sultan z. al-shaqsi, nada al-marhoobi and mahmood hasan clinical and basic research | e201 9. belwal r, belwal s. mobile phone usage behavior of university students in oman. in: international conference on new trends in information and service science proceedings, 2009. pp. 954–62. doi: 10.1109/niss.2009.65. 10. al-shaqsi sz. ems in the sultanate of oman. resuscitation 2009; 80:740–2. doi: 10.1016/j.resuscitation.2009.04.011. 11. al-shaqsi s, al-kashmiri a, al-hajri h, al-harthy a. emergency medical services versus private transport of trauma patients in the sultanate of oman: a retrospective audit at the sultan qaboos university hospital. emerg med j 2014; 31:754–7. doi: 10.1136/emermed-2013-202779. 12. daly le, bourke gj. interpretation and uses of medical statistics, 5th ed. hoboken, new jersey, usa: wiley-blackwell, 2000. pp. 202–67. 13. mains c, scarborough k, bar-or r, hawkes a, huber j, bourg p, et al. staff commitment to trauma care improves mortality and length of stay at a level i trauma center. j trauma 2009; 66:1315–20. doi: 10.1097/ta.0b013e31819d96d8. 14. haut er, chang dc, efron dt, cornwell ee 3rd. injured patients have lower mortality when treated by “full-time” trauma surgeons vs. surgeons who cover trauma “part-time”. j trauma 2006; 61:272–8. doi: 10.1097/01.ta.0000222939.51147.1c. 15. haut er, chang dc, hayanga aj, efron dt, haider ah, cornwell ee 3rd. surgeonand system-based influences on trauma mortality. arch surg 2009; 144:759–64. doi: 10.1001/ archsurg.2009.100. 16. papa l, langland-orban b, kallenborn c, tepas jj 3rd, lottenberg l, celso b, et al. assessing effectiveness of a mature trauma system: association of trauma center presence with lower injury mortality rate. j trauma 2006; 61:261–6. doi: 10.1097/01.ta.0000221789.53864.ba. 17. margulies dr, cryer hg, mcarthur dl, lee ss, bongard fs, fleming aw. patient volume per surgeon does not predict survival in adult level i trauma centers. j trauma 2001; 50:597–601. 18. louras n, fortune j, osler t, hyman n. nontrauma surgeons can safely take call at an academic, rural level i trauma center. am j surg 2016; 211:129–32. doi: 10.1016/j.amjsurg.2015.05.020. 19. podnos yd, wilson se, williams ra. effect of surgical panel composition on patient outcome at a level i trauma center. arch surg 1998; 133:847–54. doi: 10.1001/archsurg.133.8.847. 20. smith rf, frateschi l, sloan ep, campbell l, krieg r, edwards lc, et al. the impact of volume on outcome in seriously injured trauma patients: two years’ experience of the chicago trauma system. j trauma 1990; 30:1066–75. 21. konvolinka cw, copes ws, sacco wj. institution and persurgeon volume versus survival outcome in pennsylvania’s trauma centers. am j surg 1995; 170:333–40. doi: 10.1016/ s0002-9610(99)80299-2. https://doi.org/10.1109/niss.2009.65 https://doi.org/10.1016/j.resuscitation.2009.04.011 https://doi.org/10.1136/emermed-2013-202779 https://doi.org/10.1097/ta.0b013e31819d96d8 https://doi.org/10.1097/01.ta.0000222939.51147.1c https://doi.org/10.1001/archsurg.2009.100 https://doi.org/10.1001/archsurg.2009.100 https://doi.org/10.1097/01.ta.0000221789.53864.ba https://doi.org/10.1016/j.amjsurg.2015.05.020 https://doi.org/10.1001/archsurg.133.8.847 https://doi.org/10.1016/s0002-9610%2899%2980299-2 https://doi.org/10.1016/s0002-9610%2899%2980299-2 congenital anomalous origin of the right coronary artery from the left coronary sinus is rare and many patients often present with sudden death or myocardial ischaemia.1 thus, aggressive management is usually recommended at diagnosis. this case report describes a 19-year-old man with an anomalous origin of the right coronary artery from the left coronary sinus who underwent successful surgical management. case report a 19-year-old morbidly obese male patient was referred from a peripheral hospital to the cardiology service at the sultan qaboos university hospital, muscat, oman, in 2015 with a seven-month history of intermittent substernal exertional chest pain (canadian cardiovascular society grade ii) associated with diaphoresis, palpitations and dizziness. in addition, he also suffered from insulin-dependent diabetes mellitus and adult-onset still’s disease. at the previous hospital, he had initially been treated as a case of acute coronary syndrome as his echocardiography results were reportedly normal. however, 24-hour holter monitoring had shown seven premature supraventricular ectopic beats and an exercise stress test had been prematurely terminated due to the patient’s poor exercise tolerance. since the findings were inconclusive and the patient had a history of recurrent chest pain, a cardiac computed tomography (ct) scan was performed which showed an anomalous origin of the right coronary artery (rca) from the left coronary sinus. the rca passed between the root of the aorta and the main pulmonary artery. moderate narrowing of the proximal segment and the ostium was noted [figure 1]. considering the ct findings and the patient’s history of ischaemic heart disease, a coronary angiogram and a myocardial perfusion scan were carried out. the coronary angiogram showed a codominant system with no other apparent abnormalities apart from the anomalous rca. the patient subsequently underwent a technetium-99m stress test which showed normal myocardial uptake. however, the anomalous course 1general surgery residency programme, oman medical speciality board, muscat, oman; 2department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: khan.md89@gmail.com أصل شاذ للشريان التاجي األمين من اجليب التاجي األيسر تقرير حالة ذياب خان �سارفاراز، حممد �سلمان �سدقي، عادل ها�سم الكندي، طارق علم الدين abstract: the anomalous origin of the right coronary artery from the left coronary sinus is a rare congenital disorder and can often result in sudden death upon initial presentation. we report a 19-year-old male patient who was referred to the sultan qaboos university hospital, muscat, oman, in 2015 with multiple episodes of exertional angina. he was diagnosed as having an anomalous right coronary artery arising from the left coronary sinus following an intraoperative transesophageal echocardiogram. an unroofing ostioplasty of the anomalous right coronary artery was successful. details of the surgical management of this anomaly are discussed. keywords: congenital abnormalities; coronary artery; coronary sinus; anatomic variation; myocardial ischemia; case report; oman. امللخ�ص: يعد االأ�سل ال�ساذ لل�رصيان التاجي االأمين من اجليب التاجي االأي�رص ا�سطرابا خلقيا نادرا، ولكنه قد يف�سي اإىل املوت املفاجئ عند جتلي اال�سطراب يف البداية. نعر�ص هنا تقرير ملري�ص عمره 19 �سنة حول اإىل م�ست�سفى جامعة ال�سلطان قابو�ص يف م�سقط بعمان يف عام 2015م ب�سبب نوبات متكررة من ذبحة االجهاد. وبعد القيام بعمل خمطط ل�سدى القلب عرب املريء اأثناء العملية، مت ت�سخي�ص احلالة وترميم لراأب ناجحة بعملية القيام ومت االأي�رص. التاجي اجليب من االأمين التاجي لل�رصيان �ساذا اأ�سال للمري�ص اأن من ناجتة اأنها على ناجحة لفتحة لل�رصيان التاجي ال�ساذ. ونناق�ص اأي�سا هنا تفا�سيل التدابري اجلراحية لتلك احلالة ال�ساذة. الكلمات املفتاحية: اال�رصابات اخللقية؛ ال�رصيان التاجي؛ اجليب التاجي؛ اختالف ت�رصيحي؛ اإقفار ع�سلي قلبي؛ تقرير حالة؛ عمان. anomalous origin of the right coronary artery from the left coronary sinus case report *ziyab k. sarfaraz,1 mohammad s. siddiqi,2 adil h. al-kindi,2 tarek alameddine2 case report sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e352–354, epub. 10 oct 17 submitted 12 feb 17 peer-reviewed accepted 13 apr 17 doi: 10.18295/squmj.2017.17.03.017 ziyab k. sarfaraz, mohammad s. siddiqi, adil h. al-kindi and tarek alameddine case report | e353 of the rca, together with the narrowing of the proximal segment, made the patient more susceptible to ischaemic events and sudden death. the patient was referred to the sultan qaboos university hospital for further management. an intraoperative transoesophageal echocardiogram was done in which the rca was clearly visualised as arising from the left coronary sinus [figure 2]. accordingly, an unroofing ostioplasty of the anomalous rca was undertaken. the intraoperative period went smoothly. the aortic cross-clamp and cardiopulmonary bypass time was 45 and 144 minutes, respectively. the postoperative period was uneventful and the patient was discharged five days after the surgery. at a one-year follow-up visit to the outpatient clinic, he denied any further episodes of chest pain and a cardiac ct scan showed that the proximal part of the rca was wide open with no signs of narrowing. discussion to the best of the authors’ knowledge, this is the first reported case from oman of an anomalous origin of the right coronary artery from the left coronary sinus. in a prospective angiographic study of 1,950 consecutive adult cases, angelini et al., reported the incidence of anomalous coronary arteries to be 5.6%; of these, the incidence of the rca arising from the left coronary sinus was 0.92%.1 however, even though the incidence is relatively low, the consequences of this type of anomaly are often fatal.1 as with the current case, the diagnosis of an anomalous rca is often made incidentally as physical examinations or tests like electrocardiograms, stress tests and perfusion scans are usually non-revealing.2 a precise diagnosis is often made as the result of cardiac ct imaging which can provide numerous threedimensional image reconstructions that allow precise evaluation of the origin and course of the anomalous coronary artery.3 other diagnostic modalities, such as coronary angiography, are of limited value because they provide only two-dimensional pictures and cannulation of the aberrant coronary artery can be difficult.4 in view of these limitations, cardiac ct is recommended as the imaging modality of choice in diagnosing such anomalies.2,3 various treatment modalities have been suggested for treating coronary artery anomalies. kaku et al. proposed conservative therapy, such as figure 1: a: cardiac computed tomography (ct) scan of a 19-year-old male patient showing the anomalous course of the right coronary artery (rca) arising from the left coronary sinus. b: three-dimensional cardiac ct reconstruction of the anomalous rca. rca = right coronary artery; lcs = left coronary sinus; lmca = left main coronary artery; mpt = main pulmonary trunk; lada = left anterior descending artery. figure 2: intraoperative transesophageal echocardiography of a 19-year-old male patient demonstrating the anomalous origin of the right coronary artery from the left coronary sinus. lcs = left coronary sinus; lmca = left main coronary artery; rca = right coronary artery. anomalous origin of the right coronary artery from the left coronary sinus case report e354 | squ medical journal, august 2017, volume 17, issue 3 conclusion the anomalous origin of the rca is a potentially fatal congenital condition. an unroofing surgery is the procedure of choice when the course is malignant and intramural. in the current case, a one-year postoperative follow-up indicated that the procedure was successful, with the patient reporting the complete resolution of his symptoms. references 1. angelini p, villason s, chan av jr, diez jg. normal and anomalous coronary arteries in humans. in: angelini p, ed. coronary artery anomalies: a comprehensive approach. philadelphia, pennsylvania, usa: lippincott williams & wilkins; 1999. pp. 27–150. 2. basso c, maron bj, corrado d, thiene g. clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. j am coll cardiol 2000; 35:1493–501. doi: 10.1016/s0735-1097(00)00566-0. 3. shi h, aschoff aj, brambs hj, hoffmann mh. multislice ct imaging of anomalous coronary arteries. eur radiol 2004; 14:2172–81. doi: 10.1007/s00330-004-2490-2. 4. de jonge gj, van ooijen pma, piers lh, dikkers r, tio ra, willems tp, et al. visualization of anomalous coronary arteries on dual-source computed tomography. eur radiol 2008; 18:2425–32. doi: 10.1007/s00330-008-1110-y. 5. kaku b, shimizu m, yoshio h, ino h, mizuno s, kanaya h, et al. clinical features of prognosis of japanese patients with anomalous origin of the coronary artery. jpn circ j 1996; 60:731–41. 6. gulati r, reddy vm, culbertson c, helton g, suleman s, reinhartz o, et al. surgical management of coronary artery arising from the wrong coronary sinus, using standard and novel approaches. j thorac cardiovasc surg 2007; 134:1171–8. doi: 10.1016/j.jtcvs.2007.02.051. 7. mustafa i, gula g, radley-smith r, durrer s, yacoub m. anomalous origin of the left coronary artery from the anterior aortic sinus: a potential cause of sudden death anatomic characterization and surgical treatment. j thorac cardiovasc surg 1981; 82:297–300. 8. davies je, burkhart hm, dearani ja, suri rm, phillips sd, warnes ca, et al. surgical management of anomalous aortic origin of a coronary artery. ann thorac surg 2009; 88:844–8. doi: 10.1016/j.athoracsur.2009.06.007. 9. thomas d, salloum j, montalsescot g, drobinski g, artigou jy, grosgogeat y. anomalous coronary arteries coursing between the aorta and pulmonary trunk: clinical indications for coronary artery bypass. eur heart j 1991; 12:832–4. doi: 10.10 93/eurheartj/12.7.832. 10. karimi m, murdison k, blackwood w, davis w. reimplantation of anomalous right coronary artery from left main coronary artery: a surgical option. interact cardiovasc thorac surg 2010; 10:642–4. doi: 10.1510/icvts.2009.226464. limited exercise and drug therapy (i.e. nitrates, calcium or β-blockers and antiarrhythmic drugs), with 69.2% of cases treated using this approach reporting symptomatic improvement.5 however, the surgical correction of an anomalous rca is generally indicated when the anomalous artery traverses interarterially between the aortic root and the pulmonary artery.6 this is commonly termed the ‘malignant’ course, with the artery often passing proximally within the aorta wall (i.e. the intramural segment). during exertion, this intramural segment can transiently narrow due to changes in the pressure and diameter of the pulmonary artery and aorta.6 the surgical method of correcting such anomalies remains controversial, with many techniques recommended over the years, including a coronary artery bypass, coronary reimplantation and unroofing of the intramural segment.7–10 in 1981, mustafa et al. first described the use of an unroofing procedure to correct an anomalous left coronary artery anomaly.7 this technique has since become the procedure of preference for many surgeons, especially if the course of the anomalous coronary artery is intramural.8 using the unroofing approach, a neo-ostium is created in the correct sinus and the course between the pulmonary artery and aorta is eliminated, as well as the intramural course within the aortic wall. this moves the coronary lumen away from the interarterial position and effectively relieves the stenosis.6,7 other techniques such as coronary artery bypass grafting using a saphenous vein or ipsilateral internal mammary artery have been proposed; however, they may be more suitable for older patients with associated atherosclerotic changes.9 performing this type of surgery on younger patients, such as in the present case, may be counterintuitive because the long-term patency of the graft has not been established and the graft may theoretically compete with the normal antegrade flow of the anomalous artery, leading to concerns of graft thrombosis.9 instead, a coronary reimplantation can be considered in which the anomalous coronary artery is ligated and transected proximally and anastomosed in the correct sinus of valsalva.10 https://doi.org/10.1016/s0735-1097%2800%2900566-0 https://doi.org/10.1007/s00330-004-2490-2 https://doi.org/10.1007/s00330-008-1110-y https://doi.org/10.1016/j.jtcvs.2007.02.051 https://doi.org/10.1016/j.athoracsur.2009.06.007 https://doi.org/10.1093/eurheartj/12.7.832 https://doi.org/10.1093/eurheartj/12.7.832 https://doi.org/10.1510/icvts.2009.226464 less than 1 % of ingested foreign bodies cause perforation of the gastrointestinal tract,1 even rarer is an aortic pseudoaneurysm with the consequence of an aortoesophageal fistula (aef) caused by foreign body. aef has a high fatality rate; only a few cases of aef caused by foreign bodies were treated successfully in the world.2,3,4,5 a 42 year-old previously healthy male presented to a local health centre with odynophagia of 5 days duration. the initial x-ray was normal and the patient was discharged home [figure 1]. the following day, the patient started vomiting with blood clots in the vomitus. he continued to have odynophagia, but no dysphagia, and was only able to tolerate liquids. the patient returned to his local health centre and was admitted. during admission he became febrile, hypotensive, tachycardic and developed episodes of haematemesis. he was started on antibiotics. he became irritable, so he was sedated squ med j, august 2010, vol. 10, iss. 2, pp. 266-268, epub. 19th jun 10 submitted: 20th oct 09 revision req. 22nd dec 09, revision recd. 7th mar 10 accepted: 28th mar 10 1department of radiology & molecular imaging, sultan qaboos university hospital, muscat, oman; 2department of radiology, division of medical imaging, royal hospital, muscat, oman; 3department of radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: b_saqri@hotmail.com ناسور أبهري مريئي سببه جسم غريب بدرية ال�شقري، اأثيل كمونة ، نايلة اللمكي aortoesophageal fistula caused by a foreign body *badriya al-saqri,1 atheel kamona,2 neela al-lamki3 interesting medical image figure 1: chest x-ray showing the widened mediastinum and lung infiltrates. the black arrow indicates the possible foreign body lying perpendicular to the mediastinum badriya al-saqri, atheel kamona and naila al-lamki interesting medical image | 267 and intubated and sent by ambulance to our institution, the royal hospital, oman, which is a tertiary care centre. an esophagogastroduodenoscopy (ogd) was done which revealed considerable mucosal oedema in the esophagus with ulceration and what looked like friable fleshy material distally. the ogd was stopped at this stage and the patient was referred for a computed tomography (ct) examination of the chest. the chest ct showed pneumomediastinum, bilateral moderate pleural effusions with left upper lobe consolidation and atelectasis of the right lung lower lobe. there was a linear 1 cm dense structure lying in perpendicular position in the mediastinum communicating with the right main bronchus. in addition, there was a pseudoaneurysm of the descending thoracic aorta [figures 2 and 3]. the patient was immediately taken to the operating theatre. a right-sided thoracotomy was performed. during surgery severe mediastinitis was found with approximately 1l of dirty infected fluid in the right side of the chest and around 1l of haemoserous fluid in the left side of the chest. there was 2 cm sharp piece of bone centered in the mediastinum. a thin false aneurysm of the thoracic aorta was seen contained in the wall of the oesophagus. figure 2a: axial contrast enhanced computed tomography scan: pneumomediastinum, left upper lobe consolidation. white arrow = foreign body, black arrow = aortic pseudoaneurysm figure 2b: aortic pseudoaneurysm figure 3a: coronal reformat of the computed tomography scan of the chest showing aortic pseodoaneursm, extensive mediastinitis and left lung consolidation figure 3b: sagittal reformat of the computed tomography scan showing aortic pseodoaneurysm aortoesophageal fistula caused by a foreign body 268 | qu medical journal, august 2010, volume 10, issue 2 there was a 1.5 mm defect in the aorta and 1 cm mucosal defect in the oesophagus denoting double perforation. the false aneurysm was opened and the defect in the aorta as well as the oesophageal defect were located and closed. the patient survived the surgery; however, he died in the post-operative period because of circulatory arrest. aef is an extremely rare cause of upper gastrointestinal haemorrhage. ct scanning is an essential diagnostic tool for these cases as it helps to assess a suspected aortic pseudoaneurysm, mediastinitis and the extent of soft tissue involvement. it is also helpful in planning for therapeutic drainage or aspiration.6 references 1. hunter tb, taljanovic ms. foreign bodies. radiographics. 2003; 23:731–57. 2. yamada t, sato h, seki m, kitagawa s, nakagawa m, shimazaki h. successful salvage of aortoesophageal fistula caused by fish bone. ann thorac surg 1996; 61:1843–5. 3. amin s, luketich j, wald a. aortoesophageal fistula case report and review of the literature. dig dis sci 1998; 43:1665–71. 4. eren e, keles c, toker me, ersahin s, erentug v, guler m, et al. surgical treatment of aortobronchial and aortoesophageal fistulae due to thoracic aortic aneurysm. tex heart inst j 2005; 32:522–8. 5. inoue t, nishino t, peng y-f, saga t. successful one-stage operation of aortoesophageal fistula from thoracic aneurysm using a rifampicin – soaked synthetic graft. interact cardiovasc thorac surg 2008; 7:322–4. 6. gimenez a, franquet t, eramus jj, martinez s, estrada p. thoracic complications of esophageal disorders. radiographics 2002; 22:s247–58. squ med j, november 2011, vol. 11, iss. 4, pp. 470-476, epub. 25th oct 11 submitted 7th may 11 revision req. 14th jun 11, revision recd. 27th jun 11 accepted 5th sep 11 sant parmanand hospital, delhi, india. *corresponding author email: subhashbhapaji@gmail.com الكشف املتزامن عن املستضد الال بنيوي حلمى الدنك، باإلضافة إىل الغلوبولني املناعي g والغلوبولني املناعي m وتعداد الصفائح الدموية خالل تفشي الوباء �ضوبا�س اأريا، نرمال اأجاروال، �ضاتب باريخ، �ضيخار اأجاروال امللخ�ص: الهدف: خلل عام 2010 ، كانت هناك زيادة يف حالت العدوى بفريو�س حمى الدنك يف نيودلهي، الهند، مقارنة بعام 2009. اأجريت هذه الدرا�ضة يف م�ضت�ضفى �ضانت بارماناند خلل تف�ضي ذلك الوباء لتحديد فائدة "حزمة حمى الدنك" من اأجل الت�ضخي�س املبكر للحالت، واإجراء العلج الأف�ضل واتخاذ الإجراءات ال�رسيعة اللزمة من ناحية ال�ضحة العامة، وت�ضمل احلزمة الك�ضف املتزامن للربوتني الل بنيوي للدنك )1(، الغلوبولني املناعي امل�ضاد حلمى الدنك )m( و )g( وتعداد ال�ضفيحات الدموية، والعلج الأف�ضل للحالت وال�ضتجابة )m( والغلوبولني املناعي امل�ضاد حلمى الدنك ،)ال�رسيعة ال�ضحية العامة. الطريقة: مت اختبار عينات الدم للربوتني الل بنيوي للدنك )1 و )g( با�ضتخدام تقنية الر�ضم املناعي امللون بخطوة واحدة، ومت تعداد ال�ضفائح الدموية باأجهزة التحليل التلقائي التي تعطي النتائج يف فرتة ل تزيد عن �ضاعتني. النتائج: من اأ�ضل 1886 مري�ضا مت فح�ضهم ب "حزمة حمى الدنك، ظهرت النتائج اإيجابية للربوتني الل بنيوي للدنك )1( يف 678 منهم فقط يف تركيبات خمتلفة. ويف 394 حالة كان الربوتني الل بنيوي حلمى الدنك )1( اإيجابيا ح�رسا، يف حني كانت 29 حالة اإيجابية اأي�ضا للغلوبولني املناعي امل�ضاد حلمى الدنك )g(. ويف 942 حالة كانت النتائج �ضلبية للربوتني الل بنيوي للدنك )1(، والغلوبولني املناعي امل�ضاد حلمى الدنك )m( و )g(. اأما تعداد ال�ضفيحات فكان اأقل عند املر�ضى الذين كان عندهم فح�س 66.6–74.1 و الثقة فرتة الربوتني الل بنيوي حلمى الدنك )1( اإيجابيا )املتو�ضط والنحراف املعياري x 70.2±116.8 109/ليرت( الل للربوتني موجب فح�س ذي 20 مري�ضا x 20< يف ل ال�ضفيحات109/ تعداد كان .)p>0.0001 109/ل x 94.3±167.2( بنيوي حلمى الدنك )1( و 42 مري�ضا ذي فح�س �ضالب لذلك الربوتني. اخلال�صة: خلل وباء �ضنة 2010 �ضاعد التطبيق ال�رسيع "حلزمة حمى الدنك" يف علج املر�ضى، ونقل ال�ضفيحات، تنفيذ طرق مكافحة النواقل و اإخطارات ال�ضحة العامة. فح�س الربوتني الل بنيوي حلمى الدنك �ضاعد يف ت�ضخي�س 22.4% من احلالت الإ�ضافية، لدى 394 منهم عدوى اأولية بينما كان لدى 29 اآخرين عدوى ثانوية. كانت فيها. امل�ضتبه احلالت معاجلة يف الدنك" مفيدة حمى "حزمة ِدلة ؛ امل�ضت�ضدات الفريو�ضية ؛ �ضفائح الدم ؛ عدد َتعرْ ك ؛ الربوتني الفريو�ضي الَلِبنرَْيِوّي؛ الأج�ضام امل�ضادة امُل�ضرْ ى الدَّنرْ مفتاح الكلمات: فريو�س ُحمَّ �ضفائح الدم. abstract: objectives: during 2010, there was an increase in dengue virus infections in new delhi, india compared to 2009. this study was conducted at sant parmanand hospital during this outbreak to determine the utility of a ‘dengue package’, comprising simultaneous detection of dengue non-structural protein 1 (ns1), antidengue igm, anti-dengue igg and platelet enumeration for early diagnosis, better case management and faster public health response. methods: blood samples were tested for dengue ns1, igm and igg using the singlestep immunochromatigrahic one-step dengue ns1 ag and igg/igm test, while platelets were enumerated with automatic analysers yielding results within 1–2 hours. results: of the 1,886 patients screened with the ‘dengue package’, 678 and 1208 were ns1-positive and -negative respectively, in different combinations. in 394 cases, ns1 was exclusively positive while 29 were also igg positive. in 942 cases ns1, igm and igg were negative (triple negative). the platelet counts in the ns1 positives were lower than the ns1 negatives, mean and standard deviation (sd) 116.8±70.2 x 109/l: 95% confidence interval (ci) 66.6–74.1 and 167.2±94.0 x 109/l, p<0.0001. platelet counts were <20 x 109/l in 20 ns1 antigen-positives and 42 ns1 antigen-negatives. conclusion: during the 2010 outbreak, swift availability of the ‘dengue package’ assisted patient management, platelet transfusions, implementation of anti-vector measures and public health notifications. testing for ns1 assisted the diagnosis of an additional 22.4% cases; of these 394 had evidence of primary infection and 29 of secondary infection. the ‘dengue package’ was useful in tackling the rise in suspected cases. simultaneous detection of dengue ns1 antigen, igm plus igg and platelet enumeration during an outbreak *subhash c arya, nirmala agarwal, satibh c parikh, shekhar agarwal clinical & basic research subhash c arya, nirmala agarwal, satibh c parikh and shekhar agarwal clinical and basic research | 471 during the late incubation period, or initial phase of dengue virus infection, laboratory disease confirmation is through viral isolation in cell culture and/or molecular investigations, or immunofluorescence, or immunohistochemistry.1 the dengue virus nonstructural antigen non-structural protein 1 (ns1) that develops right at the beginning of the feverish period and before the appearance of dengue igm and/or igg is emerging as a suitable option for dengue diagnosis.2 consequent to a multi-country evaluation of two commercially available ns1 enzyme-linked immunoabsorbent assay (elisa) assays, a combination of ns1 and igm detection in samples during the first few days of illness was recommended to increase overall dengue diagnostic sensitivity.3 platelet therapy is a standard clinical practice for dengue patients with severe thrombocytopenia.4 however, during introductory screening, a platelet count is not done in many cases. this results in delays in staring platelet therapy. during the 2010 spurt in the incidence of dengue in new delhi,5 simultaneous screening for ns1, igm and igg and platelet enumeration was launched at the sant parmanand hospital, a 140-bed tertiary care, multidisciplinary, private hospital in delhi which caters to populations in the national capital and adjoining townships. the study was aimed to assess the utility of a concurrent identification of ns1, igm, igg, and platelet counting offered as the ‘dengue package’ for patients, clinicians and community. methods during the period august to november 2010, samples from 1,886 suspected dengue patients were taken for testing by the combined ‘dengue package’ that included assays for ns1, igm, igg and automated platelet enumeration. blood samples were collected by venipuncture in the hospital laboratory. they were drawn into ethylene diamine tetraacetic acid (edta) coated tubes and tested for dengue components employing the single-step immunochromatigrahic one-step dengue ns1 ag and igg/igm test, dengue duo, in accordance with the manufacturer’s instructions (standard diagnostics, inc., st. ingbert, germany). the platelet enumeration was in the 5or 3-differential analyzers, coulter®ac. t5diff al (beckman coulter, fullerton, ca, usa) or bc-3000plus (mindary, shenzhen, china). the individual reports were authenticated by two technologists and were available within 1–2 hours. apart from the in-built controls in the one-step dengue ns1 ag and igg/ igm test, dengue duo, no independent controls from ns1 antigen, igm and igg were used. data were entered and analysed using the statistical package for social sciences (spss inc, chicago, il, usa, version 11.5). non-parametric testing was advances in knowledge 1. concurrent assays for dengue virus non-structural protein 1 (ns1), anti-dengue igm, anti-dengue igg along with platelet enumeration in the ‘dengue package’ is immensely beneficial for patients, clinicians and public health officials. 2. cases with a primary or secondary dengue virus infection in the initial febrile phase of illness will not escape detection with the ‘dengue package’. 3. notifications to public health officials based on the results obtained by using the ‘dengue package’ would help in prompt initiation of anti-vector measures. application to patient care 1. the ‘dengue package’ produces an earlier differential diagnosis in suspected cases enabling appropriate intervention and prevention of any death from shock. 2. patients with severe thrombocytopenia, when diagnosed as positive by use of the ‘dengue package’, can be offered platelet infusions immediately. 3. clinicians can discontinue the empirical use of antibiotics in patients who test positive for dengue virus infection by use of the ‘dengue package’. 4. it should be possible to implement anti-vector measures around hospitalised patients found positive by use of the ‘dengue package’. such measures will protect against any cross-infection on hospital premises. keywords: dengue virus; viral nonstructural protein ns1; neutralizing antibody; viral antigens; blood platelets; platelet count. simultaneous detection of dengue ns1 antigen, igm plus igg and platelet enumeration during an outbreak 472 | squ medical journal, november 2011, volume 11, issue 4 carried out. p <0.05 was considered significant. the performance of this study was approved by the director of our hospital. results the patients tested by the ‘dengue package” were aged between 2 and 92 years, mean age 31.2 years: standard deviation (si) 15.5 years, 95% confidence interval (ci) 2–62 years, 5th percentile 9 years and 95th percentile 62 years. in 678 patients, the ns1 antigen was detected with igm and/or igg while 1,208 were likewise ns1-negative. among the 678 ns1-positive, 394 were exclusively positive for ns1, 145 were also positive for igm, and 29 for igg and 110 were positive for igm and igg (triple positive). the 1,208 ns1-negatives included 48 igm-positives and 96 igg-positives, while 122 were igm-positive and igg-positive and 942 were igm and igg negatives [tables 1 and 2]. the platelet counts among the 678 ns1-positives were lower than the 1,208 ns1-negatives: the respective mean and sd were 116.8±70.2 x 109/l; 95% ci 66.6–74.1 and 167.2±94.0 x 109/l 95% ci 90.7–98.2 [figure 1]; the mann-whitney, 2-tailed test gave p = 0.002. the average platelet counts were highest among 394 who were exclusively positive for ns1, 140.0±72.6 x 109/l. they were lowest among 29 who were co-positive for igg, 66.8±48.6 x 109/l; the mann-whitney, 2-tailed test p < 0.0001 [figures 2 and 3]. there was no significant difference in platelet counts in cases who were positive for all three markers, 69.2±40 x 109/l, or those positive for ns1 and igg: and 66.8±48 x 109/l. the counts in 145 igm co-positives, 100±52 x 109/l were higher than 110 triple-positives, 69.2±45 x 109/l; the mann-whitney, 2-tailed test gave p < 0.0001. among 1,208 ns1-negative cases, the average platelet counts were highest among 942 triplenegatives, mean 84.7±90.25 x 109/l and lowest among 122 positives for igm and igg, mean 86.1±77.7 x 109/l; the mann-whitney 2-tailed test gave p < 0.0001. the counts among 48 positive for igm, 136.5±63.5 x 109/l were higher than for the 96 co-positives for igg and igm, 114.3±84.7 x 109/l; the mann-whitney 2-tailed test p = 0.028 [figure 3]. discussion we initiated this feasibility study in august 2010 to ascertain the utility of concurrent testing of dengue virus ns1, igm, igg and platelet enumeration. the response was encouraging. initial data on 175 suspected cases of dengue showed that just a single laboratory visit was sufficient both for serology and platelet enumeration;6 consequently, the ‘dengue package’ was chosen by clinicians for patients with table 1: platelet counts as 109/l in 678 cases screened ns1 positive by ‘dengue package’ testing at sant parmanand hospital delhi during the 2010 dengue outbreak category cases mean ± standard deviation standard error minimum platelet count maximum platelet count cases with counts <20 x 109/l igm negative igg negative 394 139.9±72.6 3.66 10 481 4 igm positive igg negative 145 100.0±52.9 4.39 11 2.74 1 igm negative igg positive 29 66.8±48.6 9.04 10 210 3 igm positive igg positive 110 69.6±45.1 4.3 10 206 12 table 2: platelet counts as 109/l in 1208 cases screened ns1 negative by ‘dengue package’ testing at sant parmanand hospital during the 2010 dengue outbreak category cases mean ± standard deviation standard error minimum platelet count maximum platelet count cases with counts <20 x 109/l igm negative igg positive 96 114.3±84.7 8.65 9 364 12 igm positive igg negative 48 136.5±63.5 9.71 13 302 3 igm positive igg positive 122 86.1±77.7 7.03 7 339 15 igm negative igg negative 942 184.7±90.2 29.4 5 693 12 subhash c arya, nirmala agarwal, satibh c parikh and shekhar agarwal clinical and basic research | 473 febrile illness. while working with the one step dengue ns1 ag and igg/igm test, dengue duo, the in-built controls were used. for enumeration of platelets using different analysers, both internal quality control and external quality assessment were implemented. the performance of the bc-3000plus (mindary, shenzhen, china) matched the results obtained on coulter®ac. ttm 5diff autoloader (beckman coulter, fullerton, ca, usa).7 the laboratory has participated in the randox international quality assessment (riqas) programme for biochemistry for over three years;8 consequently, laboratory technologists are well trained in constant quality control. the platelet counts among the 678 ns1positives were lower than the 1,208 ns1-negatives: the respective mean and sd were 116.8±70.2 x 109/l, 95%, ci 66.6–74.1 and 167.2±94.0 x 109/l, 95% ci 90.7–98.2 [figure 1]; mann whitney, 2-tailed test gave p = 0.002. on average, the counts in exclusive ns1-positive cases were the highest, and lowest in those who were also igg positives: 139.8±3.6 x109/l and 66.8±9.04 x 109/l [table 1], p < 0.0001. there was no significant difference in the counts in cases that were positive for all three markers and those positive for ns1 and igg: 69.2±4 x 109/l and 66.8±9 x 109/l. among 1,208 ns1-negative cases, the average platelet counts were highest among those who were negative for igg and igm, mean 184.7±90.3 x 109/l and lowest among 122 positives for igm and igg, mean 86.1±77.7 x 109/l. mann-whitney, 2-tailed test gave p = 0.0001. the counts among 48 positives for igm 136.5±63.5 x 109/l were higher than the 96 co-positives for igg and igm, 114.3±84.7 x 109/l; mann-whitney, 2-tailed, p = 0.0228 [figure 3]. among the 678 ns1-positive patients there were 394 who were negative for igm [table 1] and these would have otherwise been missed. they were suffering from a primary infection in the early phase of illness and were also viremic, i.e. they could transmit the virus if bitten by a mosquito. the 29 patients who were exclusively igg positives, with a secondary viral infection, would have also been overlooked. without ns1 screening they would have been labelled as “dengue negative”. they could have been infectious for mosquitoes during the earlier phase of illness. the concurrent ns1positive and igm-positive status of 145 patients [table 1] reinforced the utility of antigen detection during the earlier phase of illness. furthermore, 110 patients who were positive for ns1, igm and igg (triple-positives) [table 1] were in the late stage of either a primary or a secondary infection and might have been infectious for mosquitoes. the ns1 test in the ‘dengue package’ helped in diagnosing an additional 423 (394 ns1 and 35 igg positives) otherwise igm negative cases. those would have been labelled negative if the dengue igm alone had been used. the ns1 negatives included 48 igm positives [table 2] who had a primary infection presenting a later phase of illness. they were most likely igg negative. it is unlikely that dengue igg antibody levels became undetectable in the convalescent phase of illness. furthermore, there were 96 cases that were positive only for igg [table 2] who might have presented themselves for ‘dengue package’ fairly early during a secondary infection. a cell culture or reverse transcription polyermerase chain reaction (rt-pcr) would be required to 0.00 139.9 n = 394 97.8 n =145 66.8 n = 29 69.2 n = 110 50.00 100.00 150.00 1.00 2.00 category error bars show 95.0% ci of mean bars show means 3.00 4.00 co un ts figure 2: platelet counts as 109/l in ns1-positive as tested by the ‘dengue package’ at sant parmanand hospital, delhi. legend: 1 = ns 1 positive; 2 = igm positive; 3 = igg positive; 4 = triple positive. 0.00 116.8 n = 678 167.2 n = 1208 50.00 100.00 150.00 1.00 category error bars show 95.0% ci of mean bars show means 2.00 co un ts figure 1: platelet counts as 109/l in ns 1-positives and n 1-negatives tested by the ‘dengue package’ at sant parmanand hospital, delhi. legend: 1 = ns 1 positive; 2 = ns 1 negative simultaneous detection of dengue ns1 antigen, igm plus igg and platelet enumeration during an outbreak 474 | squ medical journal, november 2011, volume 11, issue 4 exclude dengue virus replication. furthermore, 122 cases were positive for igm and igg [table 2]. such patients with a primary or secondary infection had presented in a later stage of illness. dengue viruses are generally extruded from the host when igm antibodies are present. among the 1,208 cases who were ns1-negative there were 942 triple-negative cases. it would not be possible to rule out dengue infection in the negative cases without testing for viral replication in cell culture and/or molecular investigations or immunofluorescence, or immunohistochemistry;1 facilities for these are not available in our hospital. such patients should be investigated for acute febrile illnesses including malaria, urinary tract infection, enteric fever, chikungunya virus and the influenza virus h1n1 infection. thrombocytopenia is observable in several patients with dengue virus infection. cases with severe thrombocytopenia, platelet counts ≤30 x 109/l (normal range = platelet counts of 150 to 400 x 109/l), would need hospitalisation and/or platelet infusions.4 with the ‘dengue package’, it was possible to recognise 19 cases, four ns1 and igm positive and three igg positives [table 1], and 12 triple-negatives [table 2]. they would have missed detection during any one-tier combined screening for ns1, igg and igm. platelet counts were generally higher in ns1positives than the ns1-negatives [figure 1]. the average platelet counts in triple-negatives were highest. the counts were lowest among those with a secondary infection who were positive for ns1and igg [figure 2]. in both ns1 positive and negatives, they declined further upon production of igm and igg antibodies. there was a progressive decline in counts in cases presenting in later stages of illness. the platelet count in 12 ns1, igm and iggnegatives was <20 x 109/l. it would not be possible to rule out dengue infection in such cases without testing for viral replication in cell culture and/or molecular investigations or immunofluorescence, or immunohistochemistry.1 this would help to differentiate between patients with dengueassociated thrombocytopenia and those with severe bleeding episodes associated with trauma, invasive intensive care procedures or emergency surgery. moreover, in patients with platelet count <20 x 109/l, investigation for decreased megakaryocytic production, splenic sequestration, non-immune or immune destruction of platelets would need to be carried out. the wide variation in the platelet counts of the patients [tables 1 and 2] is natural since the mechanism of dengue related thrombocytopenia and coagulopathy is complex. it would involve platelet activation, pro-coagulant and anticoagulant arms of the coagulation system, complement, cytokines, and endothelial cells.7 moreover, symptomatic thrombocytopenia would require platelet transfusion though platelet counts might not correlate well with clinical bleeding. public health officials were not notified about the 394 ns1-positive cases that were viremic and infectious to mosquitoes. notifications are based on clinical and laboratory categorisation of a probable or confirmed case. as a rule rather than exception, who guidelines are applicable in dengue-endemic countries, including india.8 nevertheless, igm and/or igg positive patients were notified as probable cases. a mandate for ns1-based notification is awaited. that would be ideal for future comprehensive reporting of every probable case of dengue. the ‘dengue package’ was beneficial during the outbreak since a single laboratory visit for serology and platelet enumeration was an asset for clinicians and patients. based on results obtained with the ‘dengue package’, platelet transfusion could be started straightaway. those who were exclusively ns1-positives could be offered appropriate supportive therapy, thus avoiding any irrational usage of antibiotics. the patients and their attendants could be briefed regarding the basics of vector biology and provided with mosquito nets during hospitalisation.11 moreover, with concurrent 0.00 184.63 n = 942 114.32 n = 96 86.07 n = 122 136.52 n = 48 50.00 100.00 150.00 200.00 1.00 2.00 category error bars show 95.0% ci of mean bars show means 3.00 4.00 cou nts figure 3: platelet counts as 109/l in ns1-negtives as tested by the ‘dengue package’ at sant parmanand hospital, delhi. legend: 1 = triple negatives; 2 = igg positives; 3 = igg and igm positive; 4 = igm positive. subhash c arya, nirmala agarwal, satibh c parikh and shekhar agarwal clinical and basic research | 475 ns1 testing in the ‘dengue package’, one could even distinguish between a secondary or past infection in a patient positive only for igg antibody; the demonstrable ns1 will indicate a secondary infection. there were limitations in the present study, conducted during an outbreak of dengue with a three-fold higher than normal workload. there was no gold standard obtainable for authentication. apart from the in-built controls in the one-step dengue ns1 ag and igg/igm test, dengue duo, no independent third-party controls were employed during the outbreak. facilities for molecular testing or cell culture were not available. some of the ns1-negative, but igg and igm positive cases, might have evolved from a ns1-positive status to a ns1-negative stage when examined by the ‘dengue package’. alternatively, there might have been other patients who had previously suffered from dengue virus infection. unfortunately, none of them was available later to evaluate any seroconversion. furthermore, precise details about the duration of fever and allied clinical presentations were not made available prior to the individual’s ‘dengue package’ testing in the hospital. the ‘dengue package’ has substantiated the earlier utility of enhanced diagnostic sensitivity of the combined antigen-antibody testing protocols. to our knowledge, there are no reports that contradict the simultaneous use of the dengue ns1 antigen and antibody testing for disease diagnosis. a combined antibody and ns1 diagnostic protocol was reported during the 2007 dengue outbreak in puerto rico. employing a 90% plaquereduction neutralisation test with dengue virus igg depletion and ns1 antigen elisa, it was possible to diagnose 85% of the 43 samples which could not be diagnosed using the standard diagnostic methods.12 during the multi-country evaluation of two commercially available ns1 elisa assays, a combination of ns1 and igm detection in samples during the first few days was recommended to increase the overall dengue diagnostic sensitivity.3 evaluation of the dengue duo rapid test kit for detection of the ns1 antigen, igm/ igg antibody at the university of malaysia on 320 dengue acute or convalescent sera in comparison with an in-house igm capture elisa, haemagglutination-inhibition test, or to real-time reverse transcriptionpolymerase chain reaction (rt-pcr) was more affirmative. the rapid test kit was highly sensitive (88.65%) and highly specific (98.7%). ns1 and igm detection by a rapid combined kit gave detection rates which were comparable to testing either by serology or rt-pcr.13 the circulation of dengue ns1, igm and igg antibodies was examined by using an in-house dengue type 1 (denv1)-specific ns1 capture elisa and the commercial panbio dengue igm and igg capture elisa in guangzhou in china. in a panel of 313 acute and early convalescent-phase sera from 140 denv1 primary infected patients, ns1 detection was established in 81.8–91.1% samples during the first 7 days. the anti-dengue igm antibody was detectable on the third day of onset with the positive rate of 42.9%, and rapidly increasing to 100% by the 8th day of illness. the anti-dengue igg antibody was detectable on the fifth day of onset, with a low level in the first week of onset, and slowly increasing to 100% by the 15th day of illness. combining the results of ns1 and igm antibody detection allowed positive diagnosis in 96.9–100% of samples taken after day 3 of onset. a combination of dengue ns1 antigen and igm antibody testing enhanced the rates of the disease diagnosis.14 the performance of the standard diagnostics (sd, south korea) dengue virus sd dengue ns1 ag elisa for dengue diagnosis on 320 dengue sera in malaysia was compared with parallel real-time pcr, igm capture elisa and a haemagglutinationinhibition assay. the ns1 antigen detection had a sensitivity and specificity of 76.76% and 98.31%, respectively. the assay was able to detect ns1 antigen in the convalescent phase sera till the 14th day of illness. a combined assay with igm and/or igg was speculated to increase the ns1 sensitivity of detection still further.15 conclusion utilisation of the ‘dengue package’ can be important in the diagnosis of dengue virus infection in health care centres lacking sophisticated laboratory facilities as it means that one laboratory session would rule out dengue virus infection and also identify cases with severe thrombocytopenia who might have otherwise escaped detection. the ‘dengue package’ would enable physicians to offer rational therapy to their patients. they could simultaneous detection of dengue ns1 antigen, igm plus igg and platelet enumeration during an outbreak 476 | squ medical journal, november 2011, volume 11, issue 4 ask appropriate government agencies to initiate vector control measures including active disease surveillance. last but not least, the one-stage ‘dengue package’ should emerge as the ideal option for the management of patients with dengue since it would be economical during dengue outbreaks even at secondary or tertiary care health centres. dengue outbreaks overpower outpatient and inpatient facilities in hospitals and both medical and health care personnel are rapidly exhausted. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g e m e n t s the technical assistance of mr. john d kutty, ms cg sherin, mr. hawa singh and mr. jaldeep singh is acknowledged. references 1. centers for disease prevention and control. dengue: laboratory criteria for diagnosis for case definitions. from http://www.cdc.gov/dengue/ clinicallab/casedef.html accessed sep 10. 2. thomas l, najioullah f, verlaeten o, martial j, brichler s, kaidomar s, et al. relationship between nonstructural protein 1 detection and plasma virus load in dengue patients. am j trop med hyg 2010; 83:696–9. 3. guzman mg, jaenisch t, gaczkowski r. multi-country evaluation of the sensitivity and specificity of two commercially-available ns1 elisa assays for dengue diagnosis. plos negl trop dis 2010; 4:e811. 4. thomas l, kaidomar s, kerob-bauchet b, moravie v, brouste y, king jp, et al. prospective observational study of low thresholds for platelet transfusion in adult dengue patients. transfusion 2009; 49:1400–11. epub 20 mar 2009. 5. bbc news south asia. disease threat at delhi commonwealth games site. from: http://www. b b c . c o . u k / n e w s / w o r l d s o u t h a s i a 1 1 2 4 1 2 1 8 . accessed: sep 2010. 6. arya sc, agarwal n, parikh sc. usefulness of detection of dengue ns1 antigen alongside igm plus igg, and concurrent platelet enumeration during an outbreak. trans r soc trop med hyg 2011; 105:384–5. 7. arya sc, agarwal n. evaluation of automated blood count analyzers for utility in resource poor laboratories. clin chim acta 2009; 401:187. 8. arya sc, agarwal n, agarwal s, michael b. external quality assessment of clinical biochemical assays in a medium non-academic, non-research hospital laboratory. saudi m j 2011; 32:87–8. 9. schexneider ki, reedy ea. thrombocytopenia in dengue fever. curr hematol rep 2005; 4:145–8. 10. world health organization. dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. geneva: world health organization, 1997. 11. arya sc, rajagopal s, agarwal n, kaushik m, maheshwari p, agarwal s, et al. private sector hospital response to 2003 dengue outbreak in indian capital metropolis. am j infect control 2004: 32:489–92. 12. hunsperger e, beltran m, acosta ln et al. serological evaluation of suspected west nile virus human cases following its introduction during a dengue outbreak in puerto rico in 2007. clin vaccine immunol 2011; 18:978–83. 13. wang sm, sekaran sd. early diagnosis of dengue infection using a commercial dengue duo rapid test kit for the detection of ns1, igm, and igg. am j trop med hyg 2010; 83:690–5. 14. hu d, di b, ding x, wang y, chen y, pan y, et al. kinetics of non-structural protein 1, igm and igg antibodies in dengue type 1 primary infection. virol j 2011; 8:47. 15. wang sm, sekaran sd. evaluation of a commercial sd dengue virus ns1 antigen capture enzyme-linked immunosorbent assay kit for early diagnosis of dengue virus infection. j clin microbiol 2010; 48:2793–7. epub 23 jun 2010. department of oral & maxillofacial pathology & microbiology, dr d. y. patil dental college & hospital, mumbai, maharashtra, india *corresponding author’s e-mail: sandhya.tamgadge@gmail.com تقييم اإلنقسام التفتلي والبنية اخللوية والنووية لعدة درجات مرضية نسيجية من سرطان اخلاليا احلرشفية يف الفم دراسة مقارنة ما بني صبغيت البنفسج البلوري و صبغة الفلوجني كا�شمريا كي�شاركار، اأفينا�ض تاجمادج، تريفيل برييرا، �شانديا تاجمادج، �شواتي جومتاري، بوجا كامات abstract: objectives: the objectives of this study were to quantitatively estimate the number of mitotic figures (mfs) and evaluate the cellular and nuclear features of various histological grades of oral squamous cell carcinoma (oscc) using feulgen and 1% crystal violet stains. methods: this case-control study took place at the dr d. y. patil dental college & hospital in mumbai, maharashtra, india, between june and december 2016. a total of 51 samples were retrieved from the hospital archives. of these, 15 well-differentiated, 15 moderately-differentiated and six poorly-differentiated oscc samples formed the case group while 15 samples of normal gingival mucosa constituted the control group. each sample was dyed using feulgen and 1% crystal violet stains and the mitotic count, nuclear area (na), cellular area (ca), nuclear perimeter (np), cellular perimeter (cp) and nuclear-to-cytoplasmic (n/c) ratio was calculated using computeraided morphometry techniques. results: the number of mfs visible per field was significantly higher in feulgen-stained sections as compared to those stained with crystal violet (p = 0.050). in addition, the na, np, ca and cp values and n/c ratios of samples in the experimental group increased significantly in accordance with an increase in oscc grade (p <0.001). conclusion: the feulgen stain is more reliable than 1% crystal violet in terms of the selective staining of mfs. moreover, the findings of this study indicate that computer-based morphometric analysis is an effective tool for differentiating between various grades of oscc. keywords: crystal violet; feulgen stain; mitotic index; image cytometry; squamous cell carcinoma; oral cancers. امللخ�ص: الهدف: الهدف من هذه الدرا�شة هو التقييم الكمي لعدد الت�شكالت الإنق�شامية بالإ�شافة اإىل تقييم اخل�شائ�ض اخللوية والنووية لعدة درجات ن�شيجية من �رضطان اخلاليا احلر�شفية الفموي با�شتخدام �شبغتي البنف�شج البلوري و�شبغة الفلوجني. الطريقة: اقيمت هذه الدرا�شة يف كلية و م�شت�شفى الدكتور د. باتل يف مومباي يف مهار�شرتا بالهند، بني �شهري يونيو ودي�شمرب من عام 2016، مت ح�رض جمموع 51 عينة من �شجالت امل�شت�شفى، من هذه العينات ُوجدت 15 عينة وا�شحة التمايز، و 15 عينة متو�شطة التمايز، و 6 عينات �شعيفة التمايز من �رضطان اخلاليا احلر�شفية الفموي ممثلة جمموعة احلالت، كما اختريت 15 عينة لأن�شجة طبيعية من الغ�شاء املخاطي املبطن للفم لتمثل جمموعة ال�شواهد، كل عينة مت �شبغها با�شتخدام اإما �شبغة الفلوجني اأو تركيز %1 من �شبغة البنف�شج البلوري، مت ح�شاب معدل الإنق�شام اخللوي، واملناطق اخللوية، واملحيط النووي، واملحيط اخللوي، بالإ�شافة اإىل الن�شبة النووية حلجم الهالم مقابل النواة باإ�شتخدام تقنيات مقيا�ض الأ�شكال مب�شاعدة احلا�شوب. النتائج: الدرا�شة اأظهرت اأن عدد الت�شكالت الإنق�شامية التي ترى يف احلقل الواحد املحدد كانت اأعلى ب�شكل كبري يف القطع امللونة ب�شبغة الفلوجني مقارنة بالقطع امللونة ب�شبغة البنف�شج البلوري )p = 0.050(، كما اأظهرت اأي�شًا اأن معدلت كل من املناطق اخللوية، املحيط النووي، املحيط اخللوي، والن�شبة النووية حلجم الهالم مقابل النواة يف جمموعة احلالت زادت اأكرث الفلوجني �شبغة اخلال�صة: .)p >0.001( الفموي احلر�شفية اخلاليا ل�رضطان اخللوي التمايز �شعف درجة زيادة مع وا�شح ب�شكل موثوقية من �شبغة البنف�شج البلوري )تركيز %1( عند ا�شتخدامه قي ال�شبغ الإنتقائي للت�شكالت الإنق�شامية، بال�شافة اىل ذلك ت�شري نتائج هذه الدرا�شة اإىل اأن ا�شتخدام حتليل قيا�ض الأ�شكال مب�شاعدة احلا�شوب ُيعد اأداة فعالة للتفريق بني الدرجات التمايزية املختلفة ل�رضطان اخلاليا احلر�شفية الفموي. الكلمات املفتاحية: �شبغة البنف�شج البلوري؛ �شبغة الفلوجني؛ موؤ�رض الإنق�شام؛ ال�شورة اخللوية؛ �رضطان اخلاليا احلر�شفية؛ �رضطان الفم. evaluation of mitotic figures and cellular and nuclear morphometry of various histopathological grades of oral squamous cell carcinoma comparative study using crystal violet and feulgen stains kashmira kesarkar, avinash tamgadge, treville peirera, *sandhya tamgadge, swati gotmare, pooja kamat clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e149–154, epub. 9 sep 18 submitted 14 nov 17 revisions req. 13 dec 17 & 18 jan 18; revisions recd. 29 dec 17 & 25 jan 18 accepted 1 feb 18 doi: 10.18295/squmj.2018.18.02.005 advances in knowledge feulgen staining was found to provide a more reliable estimation of tumour aggressiveness and progression in comparison to crystal violet stains. moreover, there was a consistent increase in the mitotic count and cellular and nuclear measurements of oral squamous cell carci noma cells according to histological grade. evaluation of mitotic figures and cellular and nuclear morphometry of various histopathological grades of oral squamous cell carcinoma comparative study using crystal violet and feulgen stains e150 | squ medical journal, may 2018, volume 18, issue 2 cancer develops from a series of uncontrolled cellular events known as atypia in which cellular and nuclear morphometric changes occur as a result of excessive alterations in dna synthesis accompanied by proliferation and apoptosis.1 mitosis is defined as a process of cell division wherein a single mother cell divides to produce two identical daughter cells; this process occurs in four distinct phases known as prophase, metaphase, anaphase and telophase.2 excessive cell proliferation due to increased abnormal mitosis is the hallmark of cancerous and precancerous lesions. as such, quantitatively evaluating the number of cells undergoing mitosis—also known as mitotic figures (mfs)—can serve as a prognostic indicator for such lesions.2,3 unfortunately, routine histochemical procedures cannot differentiate between pyknotic nuclei, apoptotic cells and mfs, posing a diagnostic problem.4 to date, light microscopy remains the gold standard for mf identification, among various other methods such as morphometry, immunohistochemistry, flow cytometry, dna ploidy and nucleotide radiolabelling.5 malignant cells also exhibit considerable variations in terms of their morphology and dimensions, including pleomorphism, nuclear hyperchromatism and increased nuclear-to-cytoplasmic (n/c) ratios.6 various morphometric parameters including the shape and size of cells or cellular structures (i.e. the cellular area [ca], cellular perimeter [cp], nuclear area [na] and nuclear perimeter [np]) as well as the n/c ratio have proven useful in differentiating between normal tissues and potentially malignant disorders such as leukoplakia, lichen planus and oral squamous cell carcinoma (oscc).7 previous studies have deduced that computer-assisted image analysis allows for the assessment of large numbers of specimens with high reproducibility as well as sensitivity and accuracy rates exceeding 99%.8,9 this method also allows for precise measurement of the size, shape, organisation and quantity of cells and their nuclei, while reducing interobserver discrepancies, thus increasing the reliability of accurate histopathological grading of the lesion.9 special stains such as feulgen and 1% crystal violet stains which depend on the acid hydrolysis of dna can be used to identify chromosomal material in cells and tissues.10 previous studies have utilised haematoxylin and eosin (h&e), giemsa, crystal violet, toluidine blue and feulgen stains to investigate chromatin patterns and identify mfs in brain, uterus and breast tissue.2,5,11 however, few studies have employed feulgen stains to stain paraffin-embedded sections of oral dysplasia and oscc cells.8,10 this study aimed to compare the number of mfs assessed quantitatively in normal mucosa and oscc samples using feulgen and 1% crystal violet stains. a secondary objective was to evaluate the mitotic count among various grades of oscc. in addition, the study aimed to evaluate other nuclear and cellular morphometric variables among various grades of oscc, including ca, cp, na, np and n/c ratio. methods this case-control study was conducted between june and december 2016 in the department of oral & maxillofacial pathology & microbiology at the dr d. y. patil dental college & hospital, mumbai, maharashtra, india. a total of 51 samples were retrieved from the hospital archives. the experimental group comprised 15 samples of well-differentiated, 15 samples of moderately-differentiated and six samples of poorlydifferentiated oscc collected from surgical biopsies sent for diagnosis, while the control group consisted of 15 samples of normal gingival mucosa willingly donated by patients undergoing minor oral and periodontal surgeries. the gingival mucosa was chosen as the control tissue because the gingival epithelium is active and would thus be an adequate comparison for the highly active and proliferative epithelia of oral cancers and precancers.5 two sections from each sample were prepared and stained with feulgen and 1% crystal violet stains as per established methods.12,13 slides were observed under a leica microsystems led laboratory microscope (model dm1000, meyer instruments inc., houston, texas, usa) and assessed using image analysis software (version 3.8.0, leica microsystems image organizer software, meyer instruments inc.). the sections were subsequently evaluated for mfs along with other cellular and nuclear features. the four phases of mitosis were identified as follows. cells lacking a nuclear membrane indicated that the prophase stage had begun; subsequently, the metaphase stage was characterised by condensed chromosomes forming clear hair-like extensions of nuclear material in either a clot or along a single equatorial plane. anaphase was denoted by the clots beginning to separate into two separate parallel chromo application to patient care feulgen stains offer an objective basis for grading oral squamous cell carcinomas which may be otherwise missed in routine histopathological examinations, thereby aiding healthcare providers in the provision of appropriate treatment plans. kashmira kesarkar, avinash tamgadge, treville peirera, sandhya tamgadge, swati gotmare and pooja kamat clinical and basic research | e151 searched for mfs, excluding areas of inflammation, necrosis, tissue folds and calcification. after reviewing the number of mfs in the tissue sections, the samples were evaluated for nuclear and cellular morphometric features. the final image of the representative cells in the basal cell layer was captured at x10 magnification using the leica microsystems image organizer software (meyer instruments inc.), avoiding areas of basal cell hyperplasia and overlapping cells. the outlines of the cells and nuclei were traced on a black and white monitor and the size of the cell and nucleus was calculated by measuring the area and perimeter of the outline.8 afterwards, the cellular and nuclear outlines of 5–7 cells with the largest dimensions and the clearest outlines were traced. the ca, cp, na and np were then automatically calculated by the leica microsystems image organizer software (meyer instruments inc.), based on the number of boundary pixels detected. the n/c ratio of the cell was calculated using the following formula:6 differential and inferential statistical analyses were undertaken using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa) and microsoft excel, version 2007 (microsoft inc., redmond, washington, usa). continuous measurements were presented as means and standard deviations. the level of significance was set at p ≤0.050. continuous parameters were compared between two groups using an unpaired two-tailed student’s t-test, while comparisons between three or more groups were performed using an analysis of variance test which, if significant, was followed by a post hoc analysis. ethical approval for this study was obtained from the institutional review board of the dr d. y. patil dental college & hospital (#dypusod/gs-opsat/28/2017). written consent to collect oral samples was obtained from all donors in both the control and case groups. somes, while the movement of the chromosomes to separate poles of the cell signified the telophase stage. each mf was identified as per criteria reported by van diest et al.1 the mfs were analysed at various magnifications and counted in ‘step-ladder’ fashion using an oculometer grid of 15 fields at x40 magnification. the entire stretch of the epithelium was n/c ratio = cytoplasmic area na na figure 2: paraffin-embedded oil immersion sections at x100 magnification showing the (a and b) anaphase and (c and d) telophase stages of mitosis and (e and f) tripolar mitosis in well-differentiated oral squamous cell carcinoma cells using 1% crystal violet and feulgen stains, respectively. figure 1: paraffin-embedded oil immersion sections at x100 magnification showing the (a and b) prophase and (c and d) metaphase stages of mitosis in welldifferentiated oral squamous cell carcinoma cells using 1% crystal violet and feulgen stains, respectively. table 1: mean mitotic figure count using feulgen and 1% crystal violet stains in samples of normal gingival mucosa and various grades of oral squamous cell carcinoma (n = 51) stain mean mf count per field ± sd t value p value* feulgen 3.51 ± 2.93 1.938 0.050 crystal violet 2.47 ± 2.47 mf = mitotic figure; sd = standard deviation. *using an unpaired two-tailed student’s t-test. evaluation of mitotic figures and cellular and nuclear morphometry of various histopathological grades of oral squamous cell carcinoma comparative study using crystal violet and feulgen stains e152 | squ medical journal, may 2018, volume 18, issue 2 results in terms of mf assessment, all four phases of mitosis were visible in the samples, with prophase being the most difficult to detect [figures 1a and b]. the most commonly seen phases of mitosis were metaphase, anaphase and telophase [figures 1c and d and 2a–d]. a few abnormal mfs, such as tripolar nuclei, were seen in various grades of oscc using both stains [figures 2e and f]. the frequency of mfs was significantly higher in the samples stained with feulgen in comparison to 1% crystal violet (3.51 ± 2.93 per field versus 2.47 ± 2.47 per field; p = 0.050) [table 1]. the ca, cp, na, np and n/c ratio of the cells increased steadily from the normal gingival mucosa samples to the welldifferentiated and moderately-differentiated oscc samples, before reaching their highest value in the poorly-differentiated oscc samples, with statistically significant results (p <0.001 each) [table 2]. discussion the feulgen stain is a modified histochemical stain that is simple, cost-effective, reliable and allows for differentiation between apoptotic bodies, karyorrhexis and mfs, thereby excluding false-positive results.2,5,10,11 furthermore, the purple-coloured chromatin material against a green cytoplasm facilitates the identification of mfs, even at lower magnifications. multiple studies have reported using feulgen staining to study nuclear and cellular morphometry and chromatin frameworks in oral cytosmears or paraffin-embedded tissue sections of various potentially malignant lesions, such as oral hyperplasia, dysplasia and oscc.6–8,14–18 in the present study, different mean mitotic counts were calculated using different stains, with a significantly greater frequency of mfs observed among samples stained with feulgen stains compared to those stained with 1% crystal violet, regardless of oscc grade. similarly, rao et al. also noted a significant increase in the number of mfs in feulgenstained sections as compared to 1% crystal violetstained samples.10 a similar study by palaskar et al. evaluating the effectiveness of h&e, toluidine blue, giemsa, crystal violet and feulgen stains in oral epithelial dysplasia samples concluded that all of the aforementioned stains were useful in the identification of mfs, although feulgen stains yielded superior results.19 in a study evaluating oral epithelial dysplasia and oscc, nikita et al. reported that feulgen stains provided a greater contrast when staining mfs as compared to h&e, toluidine blue, giemsa and crystal violet stains; in addition, the mfs were easier to see at lower magnifications in comparison to the other stains.20 the current study also found a consistent increase in basal cellular and nuclear measurements beginning with the normal gingival mucosa samples and increasing with each grade of oscc, thereby indicating heightened biological activity in the nucleus and cytoplasm. nandini et al. proposed a new grading system for various nuclear features (na, np and nuclear form factor) based on their observations of a steady increase in all three features corresponding to increasing grades of oscc in feulgen-stained buccal mucosa samples.8 similarly, smitha et al. studied the nuclear and cellular morphometry of oral leukoplakia and oscc cells in the basal layer using computeraided image analysis, concluding that the mean ca, cp, na and np steadily increased from normal oral buccal mucosa to leukoplakia, reaching their highest values in oscc cells.6 an increased n/c ratio is a common feature of oscc.21 as with the mf count and cellular and nuclear measurements, an increase in the n/c ratio in the present study was also found to correlate with the oscc grade. shabana et al. likewise reported table 2: mean cellular area, cellular perimeter, nuclear area, nuclear perimeter and nuclear-to-cytoplasmic ratio of samples of normal gingival mucosa and various grades of oral squamous cell carcinoma (n = 51) sample group mean ca in mm2 ± sd* mean cp in mm2 ± sd* mean na in mm2 ± sd* mean np in mm2 ± sd* mean n/c ratio ± sd* p value† normal mucosa (n = 15) 78.68 ± 7.96 30.27 ± 2.01 26.35 ± 20.07 20.07 ± 1.17 0.515 ± 0.132 <0.001 wd oscc (n = 15) 123.03 ± 6.91 47.33 ± 4.81 60.32 ± 32.89 32.89 ± 3.34 0.965 ± 0.271 md oscc (n = 15) 134.18 ± 8.45 54.45 ± 6.33 66.00 ± 39.45 39.45 ± 6.91 0.971 ± 0.164 pd oscc (n = 6) 156.02 ± 12.39 57.32 ± 7.58 74.66 ± 43.87 43.87 ± 7.17 1.018 ± 0.353 ca = cellular area; sd = standard deviation; cp = cellular perimeter; na = nuclear area; np = nuclear perimeter; n/c = nuclear-to-cytoplasmic; wd = well-differentiated; oscc = oral squamous cell carcinoma; md = moderately-differentiated; pd = poorly-differentiated. *of both feulgenand 1% crystal violet-stained samples combined. †using an analysis of variance test. kashmira kesarkar, avinash tamgadge, treville peirera, sandhya tamgadge, swati gotmare and pooja kamat clinical and basic research | e153 an increase in n/c ratio to be consistent with the progression of oral lesions from a benign to malignant state.22 similarly, another cytomorphometric analysis of oral lichen planus, oral submucous fibrosis, oscc and normal oral mucosa indicated that the n/c ratio was increased in potentially malignant lesions and oscc cells.23 based on the findings of the present study, it can be concluded that nuclear cytomorphometric para meters using computer-aided morphometry are a sophisticated tool to objectively assess and differentiate various grades of oscc. as such, nuclear and cellular morphometric analysis can be utilised to quantitatively predict the rate of malignancy, thereby avoiding subjective errors and potentially informing treatment decisions. however, a prospective study involving a larger sample group should be performed in order to determine the validity and practicality of utilising such analyses for this purpose. conclusion the authors strongly recommend the use of feulgen stains for the distinct and selective staining of mfs. in addition, the authors further advise using computeraided morphometry to evaluate a combination of nuclear and cellular variables as a method of determining tumour aggressiveness. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. van diest pj, brugal g, baak jp. proliferation markers in tumours: interpretation and clinical value. j clin pathol 1998; 51:716–24. doi: 10.1136/jcp.51.10.716. 2. chinthu sk, prasad h, kumar gs, mohan rm, anuthama k, yoithapprabhunath tr. comparison of mitotic figures using hae matoxylin & eosin with crystal violet, toluidine blue, and giemsa stain in oral epithelial dysplasia and in oral squamous cell carcinoma. baoj dent 2016; 2:007. doi: 10.24947/baojd/2/1/107. 3. kapoor k, puri a, prakash a, jazib, sharma g. mitotic counting and its significance in histopathological grading of oscc & oral epithelial dysplasia. heal talk 2013; 5:35–7. 4. tolbert pe, shy cm, allen jw. micronuclei and other nuclear anomalies in buccal smears: methods development. mutat res 1992; 271:69–77. doi: 10.1016/0165-1161(92)90033-i. 5. jadhav kb, ahmed mujib br, gupta n. crystal violet stain as a selective stain for the assessment of mitotic figures in oral epithelial dysplasia and oral squamous cell carcinoma. indian j pathol micobiol 2012; 55:283–7. doi: 10.4103/0377-4929.101731. 6. smitha t, sharada p, girish h. morphometry of the basal cell layer of oral leukoplakia and oral squamous cell carcinoma using computer-aided image analysis. j oral maxillofac pathol 2011; 15:26–33. doi: 10.4103/0973-029x.80034. 7. christopher v, murthy s, sr a, singh s, cp a, shivaram sk, et al. morphometry as a diagnostic tool for potentially malignant lesions. j clin diagn res 2015; 9:zc22–5. doi: 10.7860/ jcdr/2015/15838.6959. 8. nandini db, subramanyam rv. nuclear features in oral squamous cell carcinoma: a computer-assisted microscopic study. j oral maxillofac pathol 2011; 15:177–81. doi: 10.4103/ 0973-029x.84488. 9. abdel-salam m, mayall bh, hansen ls, chew kl, greenspan js. nuclear dna analysis of oral hyperplasia and dysplasia using image cytometry. j oral pathol 1987; 16:431–5. doi: 10.1111/ j.1600-0714.1987.tb00713.x. 10. rao rs, patil s, agarwal a. comparison and evaluation of mitotic figures in oral epithelial dysplasia using crystal violet and feulgen stain. j contemp dent pract 2014; 3:273–7. doi: 10.50 05/jp-journals-10024-1527. 11. ankle mr, kale ad, chandrimath s. comparison of staining of mitotic figures by hematoxylin and eosin-crystal violet stains, in oral epithelial dysplasia and squamous cell carcinoma. indian j dent res 2007; 18:101–5. doi: 10.4103/0970-9290.33784. 12. bancroft jd, gamble m, eds. theory and practice of histological techniques, 5th ed. london, uk: churchill livingstone, 2001. pp. 224–5. 13. godkar pb, godkar dp, eds. textbook of medical laboratory technology: clinical laboratory science and molecular diagnosis, 2nd ed. mumbai, india: bhalani publishing house, 2005. pp. 1009–11. 14. gadiwan m, madhushankari g, mandana d, praveen s, selvamani m, pradeep d. nuclear features in different grades of epithelial dysplasia in leukoplakia: a computer assisted microscopic study. j oral maxillofac pathol 2014; 18:194–200. doi: 10.4103/0973-029x.140747. 15. hannen ej, van der laak ja, manni jj, pahlplatz mm, freihofer hp, slootweg pj, et al. an image analysis study on nuclear morphology in metastasized and non-metastasized squamous cell carcinomas of the tongue. j pathol 1998; 185:175–83. doi: 10.1002/(sici)1096-9896(199806)185:2<175::aid-path6 9>3.0.co;2-u. 16. sharma d, sandhu sv, bansal h, gupta s. distinct perturbations of oral squamous cell carcinoma patients: a quantitative cytomorphometric analysis. int j health sci (qassim) 2015; 9:283–91. 17. abdel-salam m, mayall bh, chew k, silverman s jr, greenspan js. prediction of malignant transformation in oral epithelial lesions by image cytometry. cancer 1988; 62:1981–7. doi: 10.1002/1097-0142(19881101)62:9<1981::aidcncr2820620918>3.0.co;2-o. 18. kasten fh. the feulgen-deoxyribonucleic acid absorption curve in normal and tumorous tissues. j histochem cytochem 1957; 5:398–402. doi: 10.1177/5.4.398. 19. palaskar sj, patil s, narang b, prabhu p, kathuriya p, pawar r. efficacy of various stains to study mitotic figures in oral epithelial dysplasia: a pilot study. j dent allied sci 2013; 2:46–8. doi: 10.4103/2277-4696.159281. 20. nikita g, navneet kb, akanksha b, maiunita b, devi cs, ajit r. abstract: special stains to highlight mitotic figures in oral epithelial dysplasia and squamous cell carcinoma. j oral maxillofacial pathol 2014; 18:s17. 21. shilpi, chandra s, samadi fm, sreedhar g, george j, thippeswamy sh. comparison of morphometric parameters in suprabasal cells in epithelial hyperplasia, leukoplakia and squamous cell carcinoma: an image analysis. int j contemp med res 2016; 3:2307–9. https://doi.org/10.1136/jcp.51.10.716 https://doi.org/10.24947/baojd/2/1/107 https://doi.org/10.1016/0165-1161%2892%2990033-i https://doi.org/10.4103/0377-4929.101731 https://doi.org/10.4103/0973-029x.80034 https://doi.org/10.7860/jcdr/2015/15838.6959 https://doi.org/10.7860/jcdr/2015/15838.6959 https://doi.org/10.4103/0973-029x.84488 https://doi.org/10.4103/0973-029x.84488 https://doi.org/10.1111/j.1600-0714.1987.tb00713.x https://doi.org/10.1111/j.1600-0714.1987.tb00713.x https://doi.org/10.5005/jp-journals-10024-1527 https://doi.org/10.5005/jp-journals-10024-1527 https://doi.org/10.4103/0970-9290.33784 https://doi.org/10.4103/0973-029x.140747 https://doi.org/10.1002/%28sici%291096-9896%28199806%29185:2%3c175::aid-path69%3e3.0.co%3b2-u https://doi.org/10.1002/%28sici%291096-9896%28199806%29185:2%3c175::aid-path69%3e3.0.co%3b2-u https://doi.org/10.1002/1097-0142%2819881101%2962:9%3c1981::aid-cncr2820620918%3e3.0.co%3b2-o https://doi.org/10.1002/1097-0142%2819881101%2962:9%3c1981::aid-cncr2820620918%3e3.0.co%3b2-o https://doi.org/10.1177/5.4.398 https://doi.org/10.4103/2277-4696.159281 evaluation of mitotic figures and cellular and nuclear morphometry of various histopathological grades of oral squamous cell carcinoma comparative study using crystal violet and feulgen stains e154 | squ medical journal, may 2018, volume 18, issue 2 22. shabana ah, el-labban ng, lee kw. morphometric analysis of basal cell layer in oral premalignant white lesions and squamous cell carcinoma. j clin pathol 1987; 40:454–8. doi: 10.1136/jcp.40.4.454. 23. hegde v. cytomorphometric analysis of squames from oral premalignant and malignant lesions. j clin exp dent 2011; 5:e441–4. doi: 10.4317/jced.3.e441. https://doi.org/10.1136/jcp.40.4.454 https://doi.org/10.4317/jced.3.e441 squ med j, december 2010, vol. 10, iss. 3, pp. 301-305, epub. 14th nov 10 submitted 6th oct 10 accepted 10th oct 10 the year 2000 was a special milestone for the global agenda to improve quality of life and especially important for developing countries. in that year, 192 nations of the world met at the united nations (un) and signed the “millennium declaration”. in the declaration, 8 millennium development goals (mdgs) were identified to be achieved by 2015.1 the hope is that they will reduce poverty, hunger and disease in developing nations, and provide universal access to health care and education, with emphasis on gender equality in both areas and access to political representation. the 8 goals (g1-g8) are accompanied by 18 targets and 62 indicators. as oman is marking 40 years of its 'renaissance', it is relevant to reflect how the country has fared in relation to the mdg benchmarks. this editorial focuses on those mdgs that are germane to health issues. help from affluent industrialised countries should be a pivotal incentive for developing countries to accomplish the mdgs by the deadline. an essential prerequisite is that affluent countries provide more aid to developing nations. although generous amounts were pledged, unfortunately most of the 10 year aid targets have not been reached. to compound the problem, the efforts of many developing countries can hardly be described as stellar. however, the un has not given up on the mdgs. it organised a summit in september 2010, attended by most world leaders, to celebrate the 10th anniversary of the declaration and to check on the progress of developed and developing nations towards the 8 goals. among the nations with success stories is oman.2,3 sayyid badr bin hamed al busaidy, secretary-general of the oman foreign ministry,4 spoke to the world leaders of oman’s many successes in the last 10 years. he also drew attention to the negative impact of natural disasters, epidemics and civil unrest on progress in several developing countries. oman’s development and progress towards the mdgs is a matter of rejoicing as we celebrate the 40th anniversary of his majesty, sultan qaboos bin said al said's enlightened leadership since 1970. our development in the last 40 years has exceeded all expectations as will become apparent in the following paragraphs. with respect to the first goal (g1), “eradicate extreme poverty and hunger”, oman has reduced extreme poverty to beyond the target set by the un. this goal has 2 targets, halving both the number of people living in extreme poverty and those who suffer from hunger by 2015. while it is clear that oman is winning the war against extreme poverty and hunger, some challenges still persist. the editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, oman email: mjournal@squ.edu.om <ïçvjπ]<‹⁄˙÷<ìèà÷˘]<ìè€flj÷]<õ]ç‚_ <;õá÷]<çè√◊÷<∞√eö˘]<ôü“ñ÷]<ª<·^€�√÷<ç.]  editorialeditorial un millennium development goals and oman kudos to oman on its 40th national day lamk al-lamki “and i say that life is indeed darkness save when there is urge, and all urge is blind save when there is knowledge, and all knowledge is vain save when there is work...” khalil gibran (1883-1931) un millennium development goals and oman kudos to oman on its 40th national day 302 | squ medical journal, december 2010, volume 10, issue 3 number of underweight children below 5 years is still unacceptably high in oman at 17.9%;3,5 this is a matter of concern given our other positive achievements. however, there is some evidence from health centre patients, that it may have declined to 16.5% or even 10.8%,5 but these figures cannot perhaps be generalised as they refer only to clinic registered patients. nonetheless, the mortality rate among children under 5 has fallen by 29% since 1990.6 thus many g1 targets have been met and we still have 5 more years for complete achievement. with respect to g2, “achieve universal primary education”, oman, with universal free education up to and including tertiary level, has been paying particular attention to the quality of education from early childhood onwards. indeed, ministry of education efforts have boosted primary school enrolment to almost 100% in oman; however, there is a gradual drop-out during primary and secondary school and in tertiary education. this hinders the fulfillment of one target of this goal which is for children to complete a full course of primary schooling. another indicator in this target is the illiteracy rate among the 15–24 year-olds. a barrier to achieving this in oman, considering the number of high school graduates, is that more opportunities for higher education are still needed. this is despite the fact that the country has instituted major initiatives in developing higher education aiming to increasing vocational skills as well as academic learning. this is an increasing need given oman's young population. as for g3, “promote gender equality and empower women”, the target is to eliminate gender disparity in primary and secondary school. the indicators are the ratio of girls to boys in primary, secondary and tertiary education, and ratio of literate women to men. there may still be some way to go in addressing the gender gap in primary and secondary education, but the target should be fully achieved before 2015. on the contrary, in the tertiary education, female enrolment is about to exceed that of males and women also play a significant role in the public and private sector workforces. another indicator is the portion of seats held by women in national parliaments. women, in oman, have taken over many leadership positions with the continued encouragement, support and care of his majesty, sultan qaboos bin said. for example, we currently have three female government ministers in oman, and 14 (19.4%) of the 72 seats in our senate are held by women.7 with respect to g4, “reduce child mortality”, oman has successfully reduced child mortality rates, both for under 5 year-olds and infant mortality. the former dropped a staggering 94% from 181 per 1,000 live births in 1972 to 11 in 2008.6,7 this more than meets the mdg target to reduce the under-5 mortality rate by two-thirds by 2015, but globally, murray christopher et al. concluded, “we are not doing a better job of reducing child mortality now compared with three decades ago.”8 the other target is the proportion of one year-olds immunized against measles. our immunization rate in oman is at 99%, well above the mdg indicators.6 there have been significant advances in g5, “improve maternal health.” in oman. the mdg target is to reduce maternal mortality ratio (mmr) by 75% by 2015. indicators are the mmr and the proportion of births attended by skilled health personnel. the proportion of births attended by skilled medical staff in oman is close to 99%. in addition, oman currently has almost 100% coverage for antenatal care,6 reflecting an outstanding development of child and maternal health care infrastructure in the last 40 years. oman has made efforts to tackle hiv/aids to meet g6 “combat hiv/aids, malaria and other diseases”. the target is to halt the disease by 2015 and begin reversing the spread of hiv/aids. the number of reported hiv/aids cases in oman fell to 116 in 2009 from 145 in 1990.3 another target is the percent of population with comprehensive and correct knowledge of hiv and aids. oman has also gone out of its way to educate young people about hiv/aids with the help of unicef officials.3,4 malaria has been almost completely eliminated in oman with only 965 cases in 2008 compared to 32,720 in 1990,6 and most of those likely to have contracted malaria outside oman. in ensuring the fulfillment of g7, “ensure environmental sustainability”, oman is playing its role by trying to green the country and reduce carbon dioxide emissions by ensuring no old cars are on the road. the ministry of environment is setting high standards for all new factories. one indicator is carbon dioxide emissions and consumption of ozone-depleting cholorofluorocarbons (cfcs). there is now only limited consumption of substances such as cfcs in oman, with a drop from 452 tons lamk al-lamki editorial | 303 in 1992 to 29 tons in 1997.9 the other targets of this goal are to halve by 2015 the proportion of people without sustainable access to safe drinking water and sanitation; and to significantly improve the lives of at least a 100 million slum-dwellers. oman has not fully achieved sustainable access to safe drinking water and sanitation in all regions, but the authorities are working diligently on this issue and winning ground. as for g8, “develop a global partnership for development”, oman cooperates with the private sector to make available new information and communications technologies, exactly one of the g8 targets. another target includes commitment to good governance, development and poverty reduction. oman is on track for all 4 targets of g8 “through national and international measures”, under the visionary direction of the sultan. where does the rest of the world stand in achieving the goals of the united nations? according to laila gad, the unicef representative in oman,3,9 several countries have achieved success in combating extreme poverty and hunger, improving school enrolments, children’s health, expanding access to clean water, controlling diseases, and treating hiv. thus, the mdgs can be achieved with the appropriate policies, investment and international support. oman is an "exemplary success story". gad pointed out that the government of oman has already adopted programmes to combat the problem of underweight children under 5 years old, and that oman has achieved many successes towards the goals, but she also pointed out that progress has been uneven and the focus on equality is the biggest challenge to advancement. the rural-urban and gender gaps need to be addressed (in oman) in order to avoid uneven development and this applies to many nations. there is also concern about mortality rates among young pregnant women, like in many other countries. fortunately, our policy-makers are targeting interventions for this. in oman, there are other relatively major problems such as road accidents and noncommunicable diseases such as diabetes. road accidents and non-communicable diseases remain the two greatest challenges for oman as the country continues to strive to meet the millennium development goals.2,10,11 we need to take a hard look into these problems as they cause 15% and 60% (respectively) of premature deaths around the world.4 in oman, significant efforts are being made to improve road safety including public education and research support;10 a new national diabetes centre will aid in our struggle with noncommunicable diseases. given sufficient resources and political will, the mdgs are thus achievable in oman and elsewhere. if achieved, they would lead to a world with less poverty, hunger and disease and more people with access to better health care and education. apart from the shortfall of the target in the second goal, namely, the “underweight children under 5 years”, oman has been very successful and ahead of many nations in attaining the 1st, 3rd and 4th goals, as well as the 5th and 6th goals, and there is clear visible progress in environmental sustainability and developing global partnership for development, which are the 7th and 8th goals. with the impressive way the sultanate has progressed, it is clear that we will achieve the un targets by 2015.12,13 where do we go from here? the problem is to get the developed nations to stick to their commitments. the un goal for each of the developed nations is to contribute 0.7% of their gross national income (gni) towards helping developing countries achieve these goals by the year 2015. unfortunately, several countries in europe, except for the uk, are very far behind this goal.14 "we have no right to do less than what we have decided to do," french president, nicolas sarkozy, told the assembled leaders. the united nations secretary-general, ban ki-moon, stressed that the world has to raise us$ 20 billion for humanitarian aid this year if we are to meet the mdgs by 2015. the bbc news analysed global progress towards achieving the mdgs.15 they pointed out that the 7th target has not been achieved. we have not improved the lives of 100 million slum-dwellers neither have the donor nations reached the target of donating 0.56% of their gross national income by the year 2010, and it is unlikely, they will reach the 0.7% target by 2015. while it is true that the richest countries have failed to reach their targets, there is hope for reversal of this as of this year. us president obama, following his speech to the un, announced that us is adopting a new foreign policy to help developing countries.16 he announced initiatives on global climate change, global food security, and global health when he un millennium development goals and oman kudos to oman on its 40th national day 304 | squ medical journal, december 2010, volume 10, issue 3 signed a presidential policy directive on global development. this is the first time an american administration has ever made such a commitment. us leadership and international development had taken a hit in recent years and, hopefully, this effort can begin to reverse that trend. sarkozy, also made an impassioned plea to developed countries to join france in raising their contributions to meeting the mdgs, and said that france would increase its contribution by 20% over the next three years.14 the developing countries must, however, play their role adequately. the african development bank group17 points out that african countries can achieve the mdgs if they re-dedicate and re-commit themselves to them and implement the 7-point agenda for action which is intended to strengthen cooperation, both in the private sector and at national level. statistics from arab nations are not much better18 although oman is doing very well compared to many neighbours and other arab countries. in fact, oman topped all the arab nations in the 2003 literacy statistics for g2.18 the un reports that the world has more than one billion under-nourished people this year. it is estimated that 10.5 million children aged under 5 years die every year from largely preventable conditions.8 about 40% of these deaths occur within the first month of life, thus oman is not alone in facing the problem of undernourished children. about half a million women die each year as a result of pregnancy. these statistics are stark, but improved economic conditions are expected to reduce the number of hungry people to just over 900 million from the one billion. the question is what can we do as a medical community? what should be our role in all of this? unfortunately, the medical community in oman, in general, has left the responsibility of “health advocacy” to the ministry of health. no question, the ministry of health has the prime responsibility for the health of oman, but we, as physicians, can and must play a direct role by educating the public in the better nourishment of their young. we also need to play a more active role in educating the public regarding sanitation, good nutrition and disease prevention. indeed, we are privileged as university faculty and staff, and it is our social and moral obligation to take positive and definitive steps to improve the health of our fellow citizens and in particular our young ones. the 2009 oman national nutrition report,5 which alerted us to the 17.9% of our children under 5 years who are under-nourished, should be a wakeup call to all medical personnel, physicians and nurses alike, to play their role in health advocacy in oman. indeed, the country will have to tighten its belt in other areas since oman currently spends far too little on health care, the health care share of gross domestic product (gdp) being only 2% in 2009.6,19 this is only 4% of total government expenditure.19 the ministry of health has to be congratulated on what it has achieved on this limited budget, but more needs to be spent to catch up with gulf neighbours and other developed countries and cope with emerging health care challenges. almost all the developed western countries spend 7–10% of gdp on health care, except usa, which spends about 16%.20 we are now trying to teach our young physicians at the oman medical specialty board (omsb) that “health advocacy” is one of the seven basic competencies that they are expected to have upon graduation in their specialisation. we have to teach by example. to achieve the un mdgs, all parents in oman should enrol their sons and daughters in school and ensure they remain in education to secondary and tertiary levels. while oman vaccinates 99% of the new generation, we have still not quite fully reached the maternal care targets. let us celebrate the success story of oman, but not be complacent. let us be determined to exceed the mdgs under the wise and visionary leadership of his majesty sultan qaboos bin said on this 40th year of the renaissance of oman. references 1. un millennium development goals. from: http:// www.un.org/millenniumgoals/ accessed: oct 2010. 2. millennium development goals: oman. from: http://www.indexmundi.com/oman/millenniumdevelopment-goals.html accessed: oct 2010. 3. oman on track to achieve development goals by 2015. khaleej times. from: http://www.khaleejtimes. com/displayarticle.asp?xfile=data/middleeast/2010/ s e p t e m b e r / m i d d l e e a s t _ s e p t e m b e r 4 2 8 . xml&section=middleeast&col= accessed: oct 2010. 4. oman succeeds in implementing millennium development goals. editorial: 40th anniversary in oman and mdgs. from: http://main.omanobserver. om/node/23844 accessed: oct 2010. lamk al-lamki editorial | 305 5. national nutrition surveillance report 2009. from:http://www.moh.gov.om/reports/national n u t r i t i o n _ s u r v e i l l a n c e _ r e p o r t . p d f accessed: oct 2010. 6. annual health report & moh health facts 2009. from: http://www.moh.gov.om/stat/2009/index.htm accessed: oct 2010. 7. women in parliaments: world classification. from: http://www.ipu.org/wmn-e/classif.htm). accessed: oct 2010. 8. can we achieve millennium development goal 4? new analysis of country trends and forecasts of under-5 mortality to 2015. murray cjl, laakso t, shibuya k, hill k, lopez ad. lancet 2007; 370:1040–54. 9. consumption of ozone-depleting substances in opd metric tons. index mundi. from: http://indexmundi. com/oman/consumption-of-ozone-de ple tingsubstances.html accessed: oct 2010. 10. lamki l. life loss and disability from traffic accidents: it is imperative we all act now. squ med j 2010; 10:1–5. 11. road accidents, non-communicable diseases pose biggest challenge for oman. the gulf news – 22 september 2010. from: http://gulfnews.com/news/ gulf/oman/road-accidents-non-communicablediseases-pose-biggest-challenge-for-oman-1.685764 accessed: oct 2010. 12. oman on track: millennium development goals by 2015. oman observer. from” http://main. omanobserver.om/node/23590 accessed: oct 2010. 13. millennium goals. oman tribune. from: http:// www.omantribune.com/index.php?page=editorial_ details&id=1735&heading=editorial accessed: oct 2010. 14. plea to refocus un millennium goals. f r o m : h t t p : / / e n g l i s h . a l j a z e e r a . n e t / n e w s / americas/2010/09/2010920151454657766.html accessed: oct 2010. 15. uneven progress of un millennium development goals. bbc world news. from: http://www.bbc. co.uk/news/world-11364717 accessed: oct 2010. 16. obama’s speech to the un mdg summit. un dispatch. from:http://undispatch.com/obama s sp e e ch to-the-un-mdg-summit accessed: oct 2010. 17. african development bank group. from: http:// www.afdb.org/en/topics-sectors/topics/milleniumdevelopment-goals-mdgs/ accessed: oct 2010. 18. the millennium development goals in arab c o u n t r i e s . f r o m : h t t p : / / w w w. a r a b h d r. o r g publications/other/undp/mdgr/regional/arab/mdgarab-03e.pdf accessed: oct 2010. 19. national statistics: ministry of national economy, oman. from: http://www.moneoman.gov. om/ accessed: oct 2010. 20. healthcare costs around the world. from: http:// w w w. v i s u a l e co n o m i c s . co m / h e a l th c a re co s t s around-the-world_2010-03-01/ accessed: oct 2010. إلقاء الضوء على سياسة حتول املهام أستكشاف فرص ا لتكيف يف برامج إدارة األمراض غري املعدية بأوغندا جود فري كتندي و ماري دونايل abstract: in terms of disease burden, many lowand middle-income countries are currently experiencing a transition from infectious to chronic diseases. in uganda, non-communicable diseases (ncds) have increased significantly in recent years; this challenge is compounded by the healthcare worker shortage and the underfunded health system administration. addressing the growing prevalence of ncds requires evidence-based policies and strategies to reduce morbidity and mortality rates; however, the integration and evaluation of new policies and processes pose many challenges. task-shifting is the process whereby specific tasks are transferred to health workers with less training and fewer qualifications. successful implementation of a task-shifting policy requires appropriate skill training, clearly defined roles, adequate evaluation, an enhanced training capacity and sufficient health worker incentives. this article focuses on task-shifting policy as a potentially effective strategy to address the growing burden of ncds on the ugandan healthcare system. keywords: health workforce; physician shortage area; community health planning; delivery of health care; uganda. امللخ�ص: من حيث عبء املر�س، تواجه حاليا الكثري من الدول ذات الدخل املنخف�س واملتو�سط حتول من الأمرا�س املعدية اإىل الأمرا�س يف العاملني نق�س ب�سبب التحدي هذا ويتفاقم ، الأخرية ال�سنوات يف ملحوظ ب�سكل املعدية غري الأمرا�س زادت اأوغندا يف املزمنة. قائمة �سيا�سات اإىل يحتاج املعدية غري لالأمرا�س املتزايد النت�سار معاجلة ال�سحي. النظام لإدارة التمويل ونق�س ال�سحية الرعاية العديد تطرح اجلديدة والعمليات ال�سيا�سات وتقييم التكامل فاإن ذلك، ومع والوفيات، الإ�سابة معدلت حلفظ وا�سرتاتيجيات علىاأدلة من التحديات. حتويل املهام هو عملية يتم مبوجبها نقل مهام حمددة للعاملني ال�سحيني باأقل تدريب وعدد اأقل من املوؤهالت. يتطلب التنفيذ الناجح ل�سيا�سة حتويل املهام اإىل التدريب املنا�سب، واأدوار حمددة ووا�سحة، تقييم منا�سب، القدرة على التدريب املعزز ووجود حوافز كافية للعاملني. يركز هذا املقال على �سيا�سة حتول املهام كا�سرتاتيجية فعالة ملعاجلة زيادة الأعباء املرتتبة على الأمرا�س غري املعدية على نظام الرعاية ال�سحية يف اأوغندا. كلمات مفتاحية: القوى العاملة ال�سحية؛ منطقة نق�س الأطباء؛ تخطيط �سحة املجتمع؛ تقدمي الرعاية ال�سحية؛ اأوغندا. shining a light on task-shifting policy exploring opportunities for adaptability in non-communicable disease management programmes in uganda *godfrey katende1 and mary donnelly2 special contribution sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 161–167, epub. 15 may 16 submitted 27 sep 15 revision req. 8 nov 15; revision recd. 5 dec 15 accepted 31 dec 15 doi: 10.18295/squmj.2016.16.02.005 nearly 80% of the nine milliondeaths worldwide among individuals under 60 years old occur in lowand middle income countries (lmics).1 in these developing countries, non-communicable diseases (ncds) have emerged relatively unnoticed while the international community focused on combating human immunodeficiency virus (hiv), acquired immune deficiency syndrome (aids), malaria and tuberculosis.2 furthermore, ncds have long been under-recorded and were omitted from the millennium development goals.2 consequently, there are numerous knowledge, policy, and implementation gaps regarding the treatment of ncds.2,3 as a result, strategies for the treatment and management of ncds have traditionally struggled to gain significant financing. in general, ncds share common risk factors (e.g. tobacco use, excessive alcohol consumption, unhealthy diets and physical inactivity) and socioeconomic determinants of health (e.g. poverty, lack of education and urbanisation) with cardiovascular diseases (cvds).2,4,5 in uganda, a low-income country in east sub-saharan africa, the double burden of both communicable diseases and ncds is a challenge to the underfunded health system administration.2,3,6 over the last decade, the prevalence of ncds in uganda has increased significantly, with ncds estimated to account for 27% of total deaths.2 the world health organization (who) estimates that cvds account for 9% of total deaths in uganda.1 recent statistics have also shown an increase in mortality from cancers (5%), chronic respiratory diseases (2%), type 2 diabetes 1department of adult health & critical care, college of nursing, sultan qaboos university, muscat, oman; 2department of acute & chronic care, school of nursing, johns hopkins university, baltimore, maryland, usa *corresponding author e-mail: katendeg@yahoo.com shining a light on task-shifting policy exploring opportunities for adaptability in non-communicable disease management programmes in uganda e162 | squ medical journal, may 2016, volume 16, issue 2 mellitus (1%), injuries (13%) and other ncds (10%); chronic, communicable, maternal, perinatal and nutritional conditions are responsible for 60% of all deaths.3 the rise in ncds in uganda is compounded by numerous factors such as an increasing elderly population as well as unplanned urbanisation, which can lead to increased blood pressure and increased consumption of unhealthy foods.2–5 while sub-saharan africa accounts for 11% of the world’s population and 24% of the global burden of disease, only 3% of the world’s health workers are based in this region.7 in 2008, the who noted a regional critical shortage of more than four million trained health workers.5,8,9 in 2015, 31 countries in sub-saharan africa reported an increased need for trained health personnel.10 as there is a direct relationship between the health worker-to-population ratio and ncd health outcomes, this is a serious concern.7,11–13 in uganda, the increasing demand for healthcare services, a steadily growing population and the continued burden of morbidity and mortality from infectious diseases have led to significant health workforce shortages.8 numerous knowledge, social, economic, legislative, policy and implementation gaps have also affected the workforce shortage and this problem has been exacerbated by the emigration of trained professionals to europe and the usa.14–16 these issues have significantly affected the delivery of healthcare services in uganda and highlight the need for the implementation and development of policies that consider both an efficient and effective use of existing human resources through planned resource allocation.8,10,17,18 the who recommends task-shifting as a national strategy to combat the health human resource crisis and to aid in the implementation of national ncd management programmes.8,10,11,13,17–19 this article examines task-shifting policy in uganda within the current political and economic context. healthcare structure and delivery currently, uganda has a population of more than 36 million people, although only 22.5% of the population is between 30–70 years old.2 the majority of ugandans live in rural provinces and only 15.6% live in urban areas.2 healthcare services in uganda are provided through both governmental and non-governmental resources. in uganda, the decentralised healthcare system is categorised by the level of healthcare delivery; public healthcare is provided at the local, district, regional and national levels. the district health service is responsible for all healthcare structures within that district, except for the national and regional referral hospitals. health centre i is the name given to the most basic level of healthcare provision in uganda, operating within villages. a health centre ii is the first physical centre at which a patient can be seen; from here, patients are referred to a health centre iii, which can then refer patients to a health centre iv. communities and facilities served at the health centre iv level make up a health sub-district. the fifth level of care is provided at a district or general hospital, which then refers patients to regional hospitals, and from there to national referral hospitals. as yet, uganda has no evidence-based national guidelines, protocols or standards for the management of major ncds.2,5 healthcare professionals manage ncd patients with minimal local epidemiological data, as few studies include sub-saharan african populations in determining optimal medications for specific ncds.3 considering the lack of ncd surveillance systems and inadequate financial resources, addressing and reporting ncds to meet the nine global ncd targets of the who will continue to pose a challenge.2,5 given its limited resources, the government of uganda has set in place an operational unit within the ministry of health to address the health burden caused by ncds.3 this will require moving away from siloed programmes towards diagonally oriented and integrated health service delivery platforms.11 uganda continues to face problems in the recruitment and retention of trained health workers to serve its growing population and the healthcare worker shortage is characterised by an inadequate number of personnel with the required skills, low motivation, poor performance and high attrition rates.8,10,13,17 during the 2010–2011 fiscal year, only 56% of approved positions in the public sector at the national level were filled by trained health professionals, which is well below established norms.20 currently, over 51% of all staff positions at all levels of the healthcare delivery system in uganda are unfilled.21,22 uganda’s national development plan for 2010/2011–2014/2015 estimated the health worker-to-population ratio to be 1:1,298; this is much higher than the ratio in most countries in the east african region.23 in 2010, data showed that the doctor-to-patient ratio in uganda was 1:24,725 while the nurse-to-patient ratio was 1:1,000.23 in 2011, data collected by the ugandan ministry of health indicated significant gaps in health staffing at all levels [table 1].24 staff shortages were reportedly more acute in rural health facilities. as such, a large proportion of the available health workforce is urbanbased while the majority of uganda’s low-income population lives in rural areas.14 godfrey katende and mary donnelly special contribution | e163 according to the uganda nurses and midwives council (unmc), the national licensing body for nurses and midwives, there are 11,673 nurses and midwives in uganda, 6,405 of whom have attained a certificate level of nursing education.25 fewer nurses obtain a specialised nursing education as there are only three graduate nursing programmes available in uganda.25 other factors affecting staff recruitment and retention include a lack of promotion opportunities, unequal remuneration of healthcare workers compared to other professionals, inadequate training/facilities, poor leadership, inadequate staff accommodation and staff fatalities due to hiv/aids, accidents and malaria.14,16,26,27 task-shifting policy fulton et al. define task-shifting as the delegation of tasks to an existing or new cadre of health workers with either less training or disease-/skill-specific training.10 the who describes task-shifting as the process whereby specific tasks are transferred, in a structured manner, to health workers with less training and fewer qualifications than normally required to provide a certain service or perform a specific task.8 task-shifting strategies have the potential to meet the demands of ncd programmes since management principles for these diseases are based on screening, health promotion, initiation of treatment and referral of high-risk patients to physicians.28 proponents of task-shifting point to significant positive outcomes for patients with hiv, obstetric care requirements, mental health issues and malaria.8,10,13,20 trained table 1: number of units and percentage of staffing positions filled at various health facilities in uganda facility units positions filled, % mulago hospital 1 87 butabika hospital 1 93 regional referral hospitals 13 72 general hospitals 39 63 district health offices 112 57 health centres iv 164 60 health centres iii 803 60 health centres ii 1,321 45 urban authorities 155 50 total 2,609 58 adapted from uganda ministry of health. human resources for health bi-annual report: improving hrh evidence for decision making april–september 2011.24 non-physician healthcare workers (nphws) have also successfully screened and treated individuals for various ncds, such as asthma, cancer, hypertension, diabetes, depression and epilepsy.9,15,28–30 additionally, nphws can also encourage medication adherence among patients requiring chronic care.7 task-shifting interventions by nurses and nursing assistants in lmics have reportedly helped to reduce the burden of cvds and there is considerable evidence supporting the effectiveness of task-shifting implementation for chronic disease management.9,19 the who recommends task-shifting as a strategy for lmics to address the global human resource crisis.8 without a policy on task-shifting, uganda may not attain the benefits and viability of ncd programme implementation reported by other countries.20 taskshifting has been present in uganda for decades as nurses have been known to undertake a range of tasks that were formerly the responsibility of doctors.14,20 however, at the national level, there are no policies on task-shifting to address the growing burden of ncds.2,5 although task-shifting is not a new concept, it has faced criticism due to its unstructured approach and lack of systematic follow-up and monitoring.17,20 a qualitative study on task-shifting in uganda found nphws were perceived by health managers and policy-makers as incompetent, overworked and lacking support or supervision.14 barriers to taskshifting in uganda include, but are not limited to: reluctance to change; protection of professional ‘turf ’; institutional regulations; heavy workloads; lack of time to provide necessary supervision and training; and the high disease burden.20 other challenges include poor planning, inadequate guidelines and high unemployment rates, as well as the lack of taskshifting advocates in uganda.20 successful task-shifting interventions are potentially effective and affordable; some of the benefits include mitigation of the health workforce shortage by increasing the number of nphws and thus providing increased access to life-saving treatment, improving health workforce skills and increasing the efficiency and sustainability of healthcare delivery.28 these elements form the core principles of primary ncd management.14 at the same time, challenges to task-shifting implementation need to be identified and addressed. these challenges include the identification of the right health workers with the necessary competencies, effective supervision of nphws and sufficient support from policy-makers, professional bodies and managers. shining a light on task-shifting policy exploring opportunities for adaptability in non-communicable disease management programmes in uganda e164 | squ medical journal, may 2016, volume 16, issue 2 political and legal environment analysis of the ugandan national development plan 2010/2011–2014/2015 revealed many existing gaps in achieving its intended results.23,31 however, the ugandan government, private partners and donor agencies are all committed to solving the on-going human resource crisis.31 to ensure that the united nations millennium development goals are met, the government of uganda has prioritised their response by addressing the uneven distribution of health workers.21–23,32,33 the majority of trained healthcare providers are educated in state-sponsored universities; thus, a loss of trained personnel is an investment loss on the part of the government.21 it is therefore imperative for the government of uganda, healthcare leaders and policy-makers to extend their political commitment to support and allocate adequate budgets for training, incentivising, hiring and retaining healthcare workers in the public sector. currently, several policies are being implemented in various sectors, including agriculture, health and education. within the health sector, the national development plan and national health policies have been put in place to guide the achievement of health indicators.23,24 professional councils and licensure bodies in uganda are responsible for controlling health worker professional practices, with published codes of conduct;23,25 however, no specific guidelines exist regarding task-shifting in the management of ncds in uganda. in addition, no policies have been developed to stop the emigration of healthcare providers.34 as such, it is recommended that healthcare professional councils work in collaboration with universities or institutions and other government agencies in uganda to institute a formal legal framework that will support contractual employment for retention purposes.14 it is important that policies and standards for managing ncds, considering the barriers to taskshifting implementation, are established.17 the who recommends that countries facing a growing ncd burden, as well as a human resource crisis, undertake a fast-track strategy to produce essential revisions to their regulatory policies, enabling existing healthcare staff to work with an extended scope of practice without compromising quality or patient safety.8 social and economic influences disparities in salaries are strongly linked to health workforce shortages, leading to a significant maldistribution of healthcare providers and inequitable healthcare service provision.21,31 in the public sector, attrition among health workers and low productivity have reportedly led to low salaries and delayed payments.31 research indicates that uganda’s budget allocation for the health sector is inadequate to provide liveable salaries for health workers serving in the public sector.14,30 consequently, the remaining healthcare providers are overworked, resulting in some choosing to leave the profession altogether.34 other healthcare providers often look for additional employment to supplement their wages, causing uncontrolled absenteeism.31 these factors have signifi cantly affected the provision of high-quality healthcare services.22,31,33,35 the world bank reported absenteeism as the single largest waste factor in the public sector, leading to an estimated loss of 26 billion ugandan shillings.23,31 similarly, social pressure and increased responsibilities have forced more healthcare providers in rural areas to leave their families and work in urban areas.21,31 national reports in uganda indicate that healthcare providers in the public sector and in rural settings are more likely to work without incentives or motivation compared to their private sector counterparts, leading to a significant maldistribution of healthcare workers.14,21 rural areas do not have the capacity to attract and retain health workers; as such, recruitment efforts should be focused on these regions.14 the term ‘brain drain’ is used to describe the phenomenon whereby highly trained personnel migrate to another country, usually for social and/or economic reasons. due to the high cost of living, many healthcare workers from uganda emigrate in an effort to attain a better quality of life.31 tsolekile et al. found that 22% of medical school graduates from sub-saharan africa had migrated outside of africa five years post-graduation.7 to address this challenge, health trainees sponsored by the government should be contractually obligated to serve the ugandan health sector for a five-year period before receiving their academic transcripts and certificates.14 in order for ncd management programmes to be both successfully implemented and sustainable, social and economic factors affecting healthcare provider retention and efficiency need to be addressed through improved salary packages, including allowances for housing, transportation to work facilities and other social amenities.30 such benefits could result in major improvement to the lives of healthcare workers in rural settings and thus contribute to their retention.14 an opportunity that may present with a ncd taskshifting policy is the potential to create demand for better pay for nphws who accept these new roles.15 furthermore, the government of uganda should godfrey katende and mary donnelly special contribution | e165 increase budget allocations to purchase the drugs required for the management of ncds. adapting task-shifting strategies to non-communicable disease programmes in order for uganda to pursue its goal of improving the health of its population, both the existing health workforce crisis as well as the growing burden of ncds need to be addressed.31 task-shifting from physicians to nphws, if accompanied by the restructuring of the health system, is a potentially effective and affordable strategy.28 specifically, successful task-shifting should include workforce skill-mix changes, worker incentives and an increase in training capacity and supportive oversight. w o r k f o r c e s k i l l-m i x c h a n g e s notably, task-shifting in ncd programmes requires the skill mix of various healthcare providers working collaboratively with regards to management, screen ing, prevention, lifestyle modification health education, treatment and referrals for specialised care.30 ugandan nurses are among those envisioned to take up the task-shifting role in the detection and management of ncds; as a result, these nurses will require additional training in ncd management as well as supportive supervision, mirroring the use of nphws in the detection and management of hiv.9,14,15,18,26,29 unfortunately, the scope of practice for nurses and midwives often limits their roles. at present, only midwives in uganda are allowed to administer drugs during obstetric care. the unmc is currently developing a scope of practice for all cadres of nurses and midwives in uganda which will extend their prescriptive role.25 policies governing prescriptive roles need to be put in place and disseminated nationally to protect and facilitate the nphw’s extended role in treatment. encouraging consensus among the relevant stakeholders within the ugandan healthcare sector would be beneficial in successfully implementing ncd programmes.3 t r a i n i n g c a pa c i t y a n d s u p p o r t i v e o v e r s i g h t focused training and intensive support of nphws by experienced health workers is essential to maintain quality standards.14,17,28 healthcare workers taking up new roles in identifying and managing ncds need to be adequately prepared through formal training, enabling them to successfully carry out their new duties.8 adequate training, evaluation, clinical mentoring and supportive supervision will also counteract the number of health workers leaving the country.8 however, training health workers to meet the current demands of both communicable diseases and ncds poses a significant challenge to many countries.8,36 training nphws to take up expanded roles will require introducing them to evidence-based guidelines, protocols and strategies in the management of ncds;37 approved treatment algorithms may be useful in this respect. re-training, supportive supervision and mentoring of nphws need to be considered as quality-monitoring approaches to the implementation of an effective task-shifting policy. h e a lt h w o r k e r i n c e n t i v e s considerable evidence suggests that incentives play a significant role in increasing the retention, productivity and motivation of health workers.8,14 the who advises healthcare policy-makers to consider both financial and non-financial incentives predicated on performance-based measures, particularly with respect to encouraging nphws in their new or increased responsibilities.8,37 however, these incentives should be matched with available resources to ensure sustainability.8,17 similarly, it has been suggested that incentivising health workers enhances their responsiveness to patient needs and is associated with improved healthcare outcomes.8 further recommendations in addition to the above recommendations, further operational research is needed to understand barriers to the successful implementation of task-shifting policies in uganda. the role of incentives and remuneration in retaining an optimal health workforce should not be underestimated. further investigation is necessary to understand how role expansion for nphws might affect patient safety. moreover, additional studies are needed to assess the acceptance of existing task-shifting strategies among communities and professionals. conclusion in uganda, the growing ncd burden is complicated by a severe shortage of healthcare personnel. taskshifting may potentially be an effective model for the management of ncds. successful implementation of the task-shifting model of care requires policy changes to include standardised protocols, enhanced training capacity and the incentivisation and integration of nphws as part of a multidisciplinary team of health workers. further studies are needed to assess the shining a light on task-shifting policy exploring opportunities for adaptability in non-communicable disease management programmes in uganda e166 | squ medical journal, may 2016, volume 16, issue 2 effectiveness of and barriers towards task-shifting in ncd programmes in uganda. a c k n o w l e d g m e n t s the authors would like to acknowledge the management team of the mulago hospital, kampala, uganda, among whom the idea for this article was first conceived. in addition, the authors are grateful to the medical outpatient nursing staff at the mulago hospital for supporting ideas. references 1. world health organization western pacific region. noncommunicable diseases. from: www.wpro.who.int/media centre/factsheets/fs_20120926e/en/ accessed: dec 2015. 2. world health organization. noncommunicable diseases country profiles 2014: uganda. from: www.who.int/nmh/coun tries/uga_en.pdf?ua=1 accessed: dec 2015. 3. siddharthan t, ramaiya k, yonga g, mutungi gn, rabin tl, list jm, et al. noncommunicable diseases in east africa: assessing the gaps in care and identifying opportunities for improvement. health aff (millwood) 2015; 34:1506–13. doi: 10.1377/hlthaff.2015.0382. 4. addo j, smeeth l, leon da. hypertension in sub-saharan africa: a systematic review. hypertension 2007; 50:1012–18. doi: 10.1161/hypertensionaha.107.093336. 5. world health organization. noncommunicable diseases country profiles 2011. from: www.who.int/nmh/publications/ ncd_profiles2011/en/ accessed: dec 2015. 6. labhardt nd, balo jr, ndam m, grimm jj, manga e. task shifting to non-physician clinicians for integrated management of hypertension and diabetes in rural cameroon: a programme assessment at two years. bmc health serv res 2010; 10:339. doi: 10.1186/1472-6963-10-339. 7. tsolekile lp, abrahams-gessel s, puoane t. healthcare professional shortage and task-shifting to prevent cardiovascular disease: implications for low-and middle-income countries. curr cardiol rep 2015; 17:115. doi: 10.1007/s11886015-0672-y. 8. world health organization. task shifting: global recommendations and guidelines. from: www.who.int/ w o rk fo rce a l l i a n ce / k n o w l e d ge / re s o u rce s / t a s k s h i f t i n g _ guidelines/en/ accessed: dec 2015. 9. ogedegbe g, gyamfi j, plange-rhule j, surkis a, rosenthal dm, airhihenbuwa c, et al. task shifting interventions for cardiovascular risk reduction in low-income and middleincome countries: a systematic review of randomised controlled trials. bmj open 2014; 4:e005983. doi: 10.1136/ bmjopen-2014-005983. 10. fulton bd, scheffler rm, sparkes sp, auh ey, vujicic m, soucat a. health workforce skill mix and task shifting in low income countries: a review of recent evidence. hum resour health 2011; 9:1. doi: 10.1186/1478-4491-9-1. 11. schwartz ji, dunkle a, akiteng ar, birabwa-male d, kagimu r, mondo ck, et al. towards reframing health service delivery in uganda: the uganda initiative for integrated management of non-communicable diseases. glob health action 2015; 8:26537. doi: 10.3402/gha.v8.26537. 12. maher d, waswa l, baisley k, karabarinde a, unwin n. epidemiology of hypertension in low-income countries: a crosssectional population-based survey in rural uganda. j hypertens 2011; 29:1061–8. doi: 10.1097/hjh.0b013e3283466e90. 13. katende g, groves s, becker k. hypertension education intervention with ugandan nurses working in hospital outpatient clinic: a pilot study. nurs res pract 2014; 2014:710702. doi: 10.1155/2014/710702. 14. baine so, kasangaki a. a scoping study on task-shifting: the case of uganda. bmc health serv res 2014; 14:184. doi: 10.1186/1472-6963-14-184. 15. foster n, mcintyre d. economic evaluation of task-shifting approaches to the dispensing of anti-retroviral therapy. hum resour health 2012; 10:32. doi: 10.1186/1478-4491-10-32. 16. islam sm, purnat td, phuong nt, mwingira u, schact k, fröshl g. non-communicable diseases (ncds) in developing countries: a symposium report. global health 2014; 10:81. doi: 10.1186/s12992-014-0081-9. 17. callaghan m, ford n, schneider h. a systematic review of task-shifting for hiv treatment and care in africa. hum resour health 2010; 8:8. doi: 10.1186/1478-4491-8-8. 18. world health organization. global status report on noncommunicable diseases 2010. from: www.who.int/nmh/ publications/ncd_report_full_en.pdf accessed: dec 2015. 19. wouters e, van damme w, van rensburg d, masquillier c, meulemans h. impact of community-based support services on antiretroviral treatment programme delivery and outcomes in resource-limited countries: a synthetic review. bmc health serv res 2012; 12:194. doi: 10.1186/1472-6963-12-194. 20. dambisya ym, matinhure s. policy and programmatic implications of task shifting in uganda: a case study. bmc health serv res 2012; 12:61. doi: 10.1186/1472-6963-12-61. 21. kirby ke, siplon p. push, pull, and reverse: self-interest, responsibility, and the global health care worker shortage. health care anal 2012; 20:152–76. doi: 10.1007/s10728-0110178-8. 22. gross jm, riley pl, kiriinya r, rakuom c, willy r, kamenju a, et al. the impact of an emergency hiring plan on the shortage and distribution of nurses in kenya: the importance of information systems. bull world health organ 2010; 88:824–30. doi: 10.2471/blt.09.072678. 23. uganda ministry of health. national development plan (2010/11 2014/15). from: www.undp-alm.org/sites/default/ files/downloads/uganda-national_de velopment_plan.pdf accessed: dec 2015. 24. uganda ministry of health. human resources for health bi-annual report: improving hrh evidence for decision making april–september 2011. from: library.health.go.ug/ publications/health-workforce/human-resource-manage m e nt / hu m a n re s o u rce s h e a l th b i a n nu a l re p o r t2 0 1 1 accessed: dec 2015. 25. uganda nurse and midwives council. performance report:fy 2014 2015 (july 2014 to june 2015). from: unmc.ug/download/ unmc%20perfomance%20report%20fy-14-15.pdf accessed: dec 2015. 26. africa health workforce observatory. human resources for health: country profile uganda. from: www.hrh-observatory. afro.who.int/images/document_centre/uganda_country_ profile.pdf?ua=1 accessed: dec 2015. 27. zachariah r, ford n, philips m, lynch s, massaquoi m, janssens v, et al. task shifting in hiv/aids: opportunities, challenges and proposed actions for sub-saharan africa. trans r soc trop med hyg 2009; 103:549–58. doi: 10.1016/j.trstmh.2008.09.019. 28. joshi r, alim m, kengne ap, jan s, maulik pk, peiris d, et al. task shifting for non-communicable disease management in low and middle income countries: a systematic review. plos one 2014; 9:e103754. doi: 10.1371/journal.pone.0103754. http://dx.doi.org/10.1377/hlthaff.2015.0382 http://dx.doi.org/10.1161/hypertensionaha.107.093336 http://dx.doi.org/10.1186/1472-6963-10-339 http://dx.doi.org/10.1007/s11886-015-0672-y http://dx.doi.org/10.1007/s11886-015-0672-y http://dx.doi.org/10.1136/bmjopen-2014-005983 http://dx.doi.org/10.1136/bmjopen-2014-005983 http://dx.doi.org/10.1186/1478-4491-9-1 http://dx.doi.org/10.3402/gha.v8.26537 http://dx.doi.org/10.1097/hjh.0b013e3283466e90 http://dx.doi.org/10.1155/2014/710702 http://dx.doi.org/10.1186/1472-6963-14-184 http://dx.doi.org/10.1186/1478-4491-10-32 http://dx.doi.org/10.1186/s12992-014-0081-9 http://dx.doi.org/10.1186/1478-4491-8-8 http://dx.doi.org/10.1186/1472-6963-12-194 http://dx.doi.org/10.1186/1472-6963-12-61 http://dx.doi.org/10.1007/s10728-011-0178-8 http://dx.doi.org/10.1007/s10728-011-0178-8 http://dx.doi.org/10.2471/blt.09.072678 http://dx.doi.org/10.1016/j.trstmh.2008.09.019 http://dx.doi.org/10.1371/journal.pone.0103754 godfrey katende and mary donnelly special contribution | e167 29. beaglehole r, epping-jordan j, patel v, chopra m, ebrahim s, kidd m, et al. improving the prevention and management of chronic disease in low-income and middle-income countries: a priority for primary health care. lancet 2008; 372:940–9. doi: 10.1016/s0140-6736(08)61404-x. 30. lekoubou a, awah p, fezeu l, sobngwi e, kengne ap. hypertension, diabetes mellitus and task shifting in their management in sub-saharan africa. int j environ res public health 2010; 7:353–63. doi: 10.3390/ijerph7020353. 31. uganda ministry of health. national health policy: reducing poverty through promoting people’s health. from: library.heal th.go.ug/publications/leadership-and-governance-governance/ p o l i c y d o c u m e n t s / n a t i o n a l h e a l t h p o l i c y r e d u c i n g accessed: dec 2015. 32. united nations. millennium development goals and beyond 2015: background. from: www.un.org/millenniumgoals/bkgd.shtml accessed: dec 2015. 33. zuin p, dolea c, stilwell b; world health organization. issue paper 4: nurse retention and recruitment developing a moti vated workforce. from: www.icn.ch/images/stories/documen ts/publications/gnri/issue4_retention.pdf accessed: dec 2015. 34. record r, mohiddin a. an economic perspective on malawi’s medical “brain drain”. global health 2006; 2:12. doi: 10.1186/1744-8603-2-12. 35. mullan f. the metrics of the physician brain drain. n engl j med 2005; 353:1810–18. doi: 10.1056/nejmsa050004. 36. scheffler rm, mahoney cb, fulton bd, dal poz mr, preker as. estimates of health care professional shortages in sub-saharan africa by 2015. health aff (millwood) 2009; 28:w849–62. doi: 10.1377/hlthaff.28.5.w849. 37. long l, brennan a, fox mp, ndibongo b, jaffray i, sanne i, et al. treatment outcomes and cost-effectiveness of shifting management of stable art patients to nurses in south africa: an observational cohort. plos med 2011; 8:e1001055. doi: 10.1371/journal.pmed.1001055. http://dx.doi.org/10.1016/s0140-6736%2808%2961404-x http://dx.doi.org/10.3390/ijerph7020353 http://dx.doi.org/10.1186/1744-8603-2-12 http://dx.doi.org/10.1056/nejmsa050004 http://dx.doi.org/10.1377/hlthaff.28.5.w849 http://dx.doi.org/10.1371/journal.pmed.1001055 رد: تصّورات االنتحال بني طالب الطب والتمريض يف أربيل، العراق re: perceptions of plagiarism among medical and nursing students in erbil, iraq dear editor, we read with great interest the recent study by ismail published in the may 2018 issue of squmj.1 in this study, the author concluded that “there is an urgent need to increase students’ understanding of plagiarism and its consequences so as to reduce the incidence of this type of academic misconduct”.1 we agree that further education would be a good preventative action to deter unethical publications. however, an interesting question is whether unethical publication problems are due to a lack of knowledge or arise from other factors.2 many cases of plagiarism as well as other unethical publication practices involve senior professors or scientists.3 undoubted, such individuals should already be knowledgeable regarding plagiarism by this point in their careers. when plagiarism is detected, the individual responsible often claims that they were unaware of the infraction, but whether this response is believable should be judged based on evidence.3 nevertheless, we agree with ismail that further education regarding acceptable publication practices and ethics is a necessity for medical and nursing students.1 *sora yasri1 and viroj wiwanitkit2 1department of primary care, kmt primary care center, bangkok, thailand; 2department of community medicine, dr. d.y. patil university, pune, maharashtra, india *corresponding author’s e-mail: sorayasri@outlook.co.th references 1. ismail kh. perceptions of plagiarism among medical and nursing students in erbil, iraq. sultan qaboos univ med j 2018; 18:e196–201. doi: 10.18295/squmj.2018.18.02.012. 2. wiwanitkit v. letter on the article: plagiarism in medical schools, and its prevention. presse med 2012; 41:887–8. doi: 10.1016/j.lpm. 2012.07.006. 3. wiwanitkit s, wiwanitkit v. responses of authors accused of plagiarism by journal editors. sci eng ethics 2017; 23:309–11. doi: 10.1007/ s11948-016-9752-7. letter to the editor sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e413, epub. 19 dec 18 submitted 26 sep 18 accepted 11 oct 18 doi: 10.18295/squmj.2018.18.03.030 letter to the editor | e413 https://doi.org/10.18295/squmj.2018.18.02.012 https://doi.org/10.1016/j.lpm.2012.07.006 https://doi.org/10.1016/j.lpm.2012.07.006 https://doi.org/10.1007/s11948-016-9752-7 https://doi.org/10.1007/s11948-016-9752-7 squ med j, december 2010, vol. 10, iss. 3, pp. 382-387, epub. 14th nov 10 submitted 5th dec 09, reformat recd. 24th apr 10 revision req. 5th july 10, revision recd. 7th aug 10 accepted 8th sept 10 sialolithiasis, the formation of stones in the salivary gland, results in a mechanical obstruction of the salivary duct, causing recurrent glandular swellings during meals which are transitory, or complicated by bacterial infections accompanied by fever, purulent discharge at the papilla, and painful glandular swelling. salivary stones occasionally form in a salivary gland or duct, usually by deposition of calcium salts around a nidus of organic material, and have a layered microscopic structure. in contrast to urolithiasis and cholelithiasis, the aetiology of sialolithiasis is unknown.1 and various hypotheses have been proposed.2,3 salivary stones can be either solitary or multiple, particularly in the parotid gland. they vary in size and shape, being either round or irregular [figure 1]. they can either float in the lumen, or become partially fixed due to an irregular shape, or even attach to the ductal wall. a less frequent diagnosis is intraductal stenosis, which might be localised [figure 2], or diffuse on a portion of the main duct. sialolithiasis is estimated to affect 1:10–20,0004 and the incidental ratio of submandibular/parotid is described as 90/10, but in the geneva experience is a ratio of 60/40; this difference is possibly explained by the sensitivity of the new detection methods, and local recruitment.5,6 in the classical approach, distal stones close to the papilla are simply extracted,7 whereas glandular resection is indicated for deeply located stones. in submandibular glands, sialolithiasis surgery still represents 70–90% of all actual indications8 for surgery, which may carry a risk of facial nerve injury.9 parotidectomy is rarely performed for 1department of surgery, sultan qaboos university hospital, muscat, oman; 2department of otorhinolaryngology, head & neck surgery, university hospital, geneva, switzerland. *corresponding author email: ralabri@hotmail.com ö^øflπ]<–ëüõ<‡¬<<ìèe^√◊÷]<åç«÷]<óíu<<t¯√÷<çëçq<üí¬          abstract: sialendoscopy is one of the innovations introduced in the last few years in the field of otolaryngology, head and neck surgery. sialolithiasis and sialadenitis are two of the most frequently presenting disorders of the salivary glands. the diagnosis is most frequently confirmed by radiology and the treatment of sialolithiasis ranges from the use of surgery, intra-oral extraction or external lithotripsy, to the more frequent external excision of the gland. sialendoscopy uses minimal invasive surgical techniques which allows for optical exploration of the salivary ductal system and extraction of the stones by a basket under endoscopic view. sialendoscopy incorporates diagnostic with therapeutic procedures, as dictated by the clinical findings. this technique can be performed in most cases as an ambulatory, outpatient procedure under local anaesthesia. keywords: sialolithiasis; sialendoscopy; salivary glands new era of endoscopic approach for sialolithiasis: sialendoscopy *rashid al-abri1 and francis marchal2 technical note rashid al-abri and francis marchal technical note | 383 inflammatory conditions in parotid glands, because it remains a tedious procedure and involves a higher incidence of postoperative paresis.10 a possible reason for this high rate of submandibular resections might be the common belief that a gland suffering from long standing sialolithiasis is no longer functional. in a clinicalhistopathological study on 48 patients afflicted with sialolithiasis and treated with glandular resection, half of the patients had subnormal histology patterns, and there was no correlation between the number of infectious episodes and the alteration of the gland.11 therefore, numerous infectious episodes or a long duration of symptoms cannot be used to predict the degree of glandular alteration, and thus a minimally invasive approach towards sialolithiasis appears justified. several new techniques have been developed since 1990 to fragment sialoliths such as extracorporeal lithotripsy.12 success rates for extracorporeal lithotripsy vary from 40–75% for the submandibular and parotid glands, respectively. performed on an outpatient basis, this technique is now widely practised, but often requires multiple sessions. the main problem remains the clearance of fragments, which can be incomplete and could become the cause of recurrent sialolithiasis. the classical investigation methods of salivary glands are radiography, including x-rays, ultrasound and computed tomography scans and sialography.13 ultrasound remains an excellent primary diagnostic method for the detection of salivary stones; however, calculi with a size less than 3 mm can hardly be visualised.14 another new non-invasive diagnostic option is nuclear magnetic resonance tomography, which provides scans of the salivary ducts by opacification of the natural salivary pathway without the need for administration of contrast medium and without exposing the patient to ionising irradiation.5 these procedures aim to visualise the ductal system for the diagnosis of obstructive pathologies, typically stones or other rarer diseases. sialendoscopy is a new procedure, aiming to visualise the lumen of the salivary ducts and their pathologies. the first reported attempts to visualise the ducts were conducted in the early 1990s.15,16 major advances in optical technologies and the development of semirigid sialendoscopies are responsible for significant progress in salivary gland endoscopy.17 this procedure, by allowing the complete exploration of the salivary ductal system, is positioned to replace sialography and other radiological studies15 because of its higher specificity and cost-effectiveness. patients with suspected sialolithiasis comprise the major population for whom sialendoscopy is indicated. this technique can be performed in most cases as an ambulatory, outpatient procedure18 with advantages of no scar, elimination of facial nerve paralysis of the marginal mandibular branch, and lower morbidity, especially for older patients with co-occurring disorders. they are two types of sialenoscopy, diagnostic and interventional. the diagnostic and figure 1: salivary stones can be unique or multiple and vary in size and shape, and be either round or irregular as demonstrated in this endoscopic view figure 2: endoscopic view of a concentric stenosis in the second branch of stensen’s duct as shown by sialendoscopy new era of endoscopic approach for sialolithiasis: sialendoscopy 384 | squ medical journal, december 2010, volume 10, issue 3 interventional sialendoscope (1.33 mm2 surface, 1.3 mm diameter) [figure 3] provides excellent vision and is recommended both for diagnostic and interventional procedures as it has a rinsing channel as well as a working channel. recently new generations of all-in-one endoscopes became available to be used for the same purposes. diagnostic sialendoscopy the endoscopic technique described19,20 allows almost complete exploration of the ductal system (main duct, secondary and tertiary branches) [figure 4], mainly because of the small diameter of the scopes (0.9 and 1.3 mm). diagnostic sialendocopy was used to classify ductal lesions into sialolithiasis, stenosis, sialodochitis, and polyps. over the last 1,000 endoscopies performed, diagnostic sialendoscopy could be achieved in 98% of cases and reduced the need for radiological investigations. rare limitations include convoluted sections that are impassable with a rigid endoscope.18,1 mobility of the endoscope is also limited at the distal end of the gland. diagnostic findings showed that mucous plugs are found in cases of sialolithiasis and also in cases of sjögren syndrome and in several cases of chronic parotitis in children [figure 5]. interventional sialendoscopy interventional sialendoscopy is used to treat disorders discovered during diagnostic sialendoscopy. the attitude is the same for the submandibular and parotid glands,1 although the diameter of the ductal system is smaller in the parotid duct. for small stones less than 4 mm in diameter in submandibular cases and less than 3 mm for parotid cases [figure 6], extraction is performed with custom designed wire baskets of various sizes [figure 7]. in cases of bigger stones, a priori fragmentation is necessary, using a laser system [figure 8], or possibly an extracorporeal lithotripter. stenoses are treated with metallic dilators or with balloon catheters. all these techniques of fragmentation and stone retrieval are performed under endoscopic control, as described by others.21 we do not recommend the “semi-blind” technique, consisting of introducing the basket after the removal of the optic fibre, because of its lack of precision and the potential danger of perforation. in recent published studies, the overall success rates were above 85%.17,1,22 it is important to keep in mind that a combined endoscopic-external approach may be required in cases with larger size stones especially the ones positioned deeper in the salivary ducts and not easily retrievable or fragmented by laser. figure 3: diagnostic and interventional marchal sialendoscope (inset – wire basket and laser fibre) figure 4: endoscopic view shows the salivary ductal system (main duct, secondary and tertiary branches) rashid al-abri and francis marchal technical note | 385 technique indications and contraindications the indications for sialendoscopy are all salivary gland swellings of unclear origin.23 there are no specific contraindications, mostly because sialendoscopy is a minimally invasive outpatient procedure performed under local anaesthesia. all ages can benefit from this technique.24,3 the interventional sialendoscopy is a technically challenging procedure. operating the rigid sialendoscope is delicate, requires experience and might be hazardous due to the theoretical risks of perforation and vascular or neural damage. progression in the canal should be performed only under adequate vision. perforations of iatrogenic origin can lead to diffuse swellings of the floor of mouth, with potential risks of life-threatening swellings. operative technique sialendoscopy can be done as an outpatient procedure with the patient sitting in a chair or partially recumbent. anaesthesia is purely local, but occasionally general anaesthsia (ga) may be required for some cases. progressive dilatation of the papilla is performed with salivary sounds of progressively larger diameters. endoscopy is performed with progressive endoluminal irrigation using a local anaesthetic solution and, if ga is administered, irrigation is performed using normal saline solution. limitations the writhing course of the canal puts certain limitations on semi-rigid endoscopy, especially in cases of sharply bent curvatures. also, manoeuvering within the small salivary ducts has to be absolutely atraumatic because of possible ductal perforation of yet uncertain consequences. significant trauma to the ductal wall could result in later stenosis. marsupialisation of the ductal papillae should either be completely avoided, or kept as small as possible to prevent retrograde passage of air and aliments. efficacy in the reviewed literature, the procedural success rate of sialendoscopy (resolution of obstruction) ranged from 82% (90/110)25 to 87% (47/54).26 in a study of 72 patients, 8% (n = 6) had clinical or subjective problems which did not improve after the procedure and required removal of the gland. in another study of 129 patients, 110 of whom underwent interventional sialendoscopy, sialendoscopy treatment in 18% (n = 20) of patients was considered a failure, with five patients requiring gland resection.25 recurrence of obstructive symptoms were reported in two other studies with rates of 2% (4/236)27 and 5% (3/55),17 respectively. all recurrences occurred between 15 and 24 months after the procedure. figure 5: endoscopic view demonstrates the presence of a mucosal plug in a salivary gland ductal system figures 6: stone being removed by use of a wire basket new era of endoscopic approach for sialolithiasis: sialendoscopy 386 | squ medical journal, december 2010, volume 10, issue 3 safety few complications were reported in the reviewed literature. the most common complication reported by patients following sialendoscopy was temporary swelling of the gland. in one study of 129 patients,25 ductal wall perforation occurred in 11 patients (9%), with two of these patients requiring hospitalisation and one patient undergoing gland resection. three other studies reported cases of perforation with an incidence of 3/55,17 1/103,28 1/23627 respectively. one patient (1/236) suffered from lingual nerve paraesthesia caused by the perforation, and ductal strictures were also reported in seven patients in a case series study of 236 patients.27 five of these underwent successful dilatation with two requiring further surgery. other complications included wire basket blockages, infection and ductal avulsion. conclusion as the most frequent ductal pathology is sialolithiasis, interventional sialendoscopy aims to retrieve salivary stones following their fragmentation and allows almost complete exploration of the ductal system (main duct, secondary and tertiary branches), mainly because of the small diameter of the scopes (0.9 and 1.3 mm).18 diagnostic sialendoscopy is a low morbidity minimally invasive technique, which becomes the investigational procedure of choice for salivary duct pathologies in all ages and especially in elderly patients with concurrent diseases. interventional sialendoscopy allows the treatment of sialolithasis and stenosis, and help therefore to prevent salivary gland excisions and to minimise postoperative complications. finally, it should be noted that in the early phases of sequential learning complications rates are significant. however, major complications are infrequent and in general can be rectified by standard salivary gland surgery.29 references 1. marchal f, kurt am, dulguerov p, becker m, lehmann w. histopathology of submandibular glands removed for sialolithiasis. ann otol rhinol laryngol 2001; 464–9. 2. marchal f, kurt am, lehmann w. retrograde theory in sialolithiasis formation: role of an anatomical sphincter. arch otolaryngol 2001; 15:11–13. 3. ödman m, pichard c, marchal f. does calcium intake proceeding influence sialogenesis? first international congress on salivary gland diseases, 2002. p. 81. 4. marchal f, dulguerov p. sialolithiasis management. arch otolaryngol 2003; 129:951. 5. becker m, marchal f, becker c, dulguerov p, georgeakopoulos g, lehmann w, et al. mrsialography using 3d-extended phase conjugate symmetry rapid spin echo (express) sequence: diagnostic accuracy for assessing sialolithiasis and salivary duct stenosis. radiology 2000; 217:347–58. 6. marchal f, becker m, dulguerov p, lehmann w, terrier t. sialolithiasis: ultrasound versus conventional sialography. eur radiol. accepted for publication. 7. zenk j, constantinidis j, al-kadah b, iro h. transoral removal of submandibular stones. arch otolaryngol 200; 127:432–6. 8. hald j, andreassen uk. sub-mandibular gland excision: shortand long-term complications. orl j 1994; 56:87–91. figure 7: wire basket for endoscopy figures 8: view of bigger stones in the salivary ducts, which required fragmentation using a laser system prior to removal. rashid al-abri and francis marchal technical note | 387 9. klintworth n, zenk j, koch m, iro h. postoperative complications after extracapsular dissection of benign parotid lesions with particular reference to facial nerve function. laryngoscope 2010; 120:484– 90. 10. dulguerov p, marchal f, wang d, gysin c. objective evaluation of facial nerve function: a review. am j otol 1999; 20:672–8. 11. marchal f, kurt am, dulguerov p, becker m, lehmann w. histopathology of submandibular glands removed for sialolithiasis. ann otol rhinol laryngol 2001; 464–9. 12. iro h, zenk j,waldfahrer f, benzel w, schneider t, ell c. extracorporeal shock wave lithotripsy of parotid stones. results of a prospective clinical trial. ann otol rhinol laryngol 1998; 107:860–4. 13. som pm, sugar gma, train gb, biller hf. manifestations of parotid gland enlargement. radiographic, pathologic and clinical correlations. part i: the autoimmune pseudosialectasias. radiology 1981; 141:415–9. 14. marchal f, dulguerov p. sialolithiasis management: the state of the art. arch otolaryngol 2003; 129:951– 6. 15. gundlach p, scherer h, hopf j, leege n, müller g. die endoskopisch kontrollierte laserlithotripsie von speichelsteinen. in-vitro-untersuchungen und erster klinischer einsatz. hno 1990; 38:247–50. 16. katz p. nouvelle thérapeutique des lithiases salivaires. inf dent 1991; 73:3975–9. 17. marchal f, dulguerov p, becker m, barki g, disant f, lehmann w. specificity of parotid sialendoscopy. larygoscope 2001; 111:264–71. 18. faure f, boem a, taffin c, badot f, disant f, marchal f. diagnostic and interventional sialendoscopy. rev stomatol chir maxillofac 2005; 106:250–2. 19. marchal f, dulguerov p, lehmann w. sialendoscopy. n engl j med 1999; 341:1242–3. 20. marchal f, dulguerov p, becker m, lehmann w. how i do it: interventional sialendoscopy. laryngoscope 2000; 110:318–20. 21. ito h, baba s. pulsed dye laser lithotripsy of submandibular gland salivary calculus. j laryngol otol 1996; 110:942–6. 22. al-abri r, marchal f. sialendoscopy in old patients: a new tool or a revolution? europ geriatric med 2010:95–8 23. marchal f, dulguerov p, becker m, lehmann w. interventional sialendoscopy. in: wackym p, rice dh, schaefer sd, eds. minimally invasive surgery of the head, neck, and cranial base. philadelphia: lippincott williams & wilkins, 2002; pp. 416–26. 24. nahlieli o, eliav e, hasson o, zagury a, baruchin am. pediatric sialolithiasis. oral surg oral med oral pathol oral radiol endod 2000 dec; 90:709–12. 25. marchal f, dulguerov p, becker m, barki g, disant f, lehmann w. submandibular diagnostic and interventional sialendoscopy: new procedure for ductal disorders. ann otol rhinol laryngol 2002; 111:27–35. 26. ziegler cm, steveling h, seubert m, mühling j. endoscopy: a minimally invasive procedure for diagnosis and treatment of diseases of the salivary glands. six years of practical experience. br j oral maxillofac surg 2004; 42:1–7. 27. nahlieli o, baruchin am. long-term experience with endoscopic diagnosis and treatment of salivary gland inflammatory diseases. laryngoscope 2000; 110:988–93. 28. koch m, zenk j, bozzato a, bumm k, iro h. sialoscopy in cases of unclear swelling of the major salivary glands. otolaryngol head neck surg 2005; 133:863–8. 29. walvekar rr, razfar a, carrau rl, schaitkin b. sialendoscopy and associated complications: a preliminary experience. laryngoscope 2009; 118:776–9. department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com فحص مستوى الرتوبونني يف قسم الطوارئ جتربة من الواقع حممد امل�صكري، حممود املكدمي، حامت اللواتي، حفيظ الهادي، �صونيل نادر abstract: objectives: the aim of this study was to examine patterns of troponin testing in the emergency department of a large tertiary care hospital in oman and to determine its effect on patient management, including length of hospital stay (los). methods: this retrospective study analysed the medical records of all adult patients undergoing troponin testing in the emergency department of the sultan qaboos university hospital, muscat, oman, during the month of july 2015. patients who presented with an st-elevation myocardial infarction were excluded. results: a total of 4,845 patients attended the emergency department during the study period; of these, troponin tests were ordered for 588 patients. the majority of the patients had negative troponin test results (81.3%). chest pain, palpitations and breathlessness were the most common presenting complaints for those with positive troponin results. however, 41.8% of patients did not have any cardiac symptoms. individuals with positive troponin tests had a significantly longer los compared to those with negative tests (mean: three versus one day; p = 0.001). in total, only 28.2% of those with positive troponin test results had final diagnoses associated with a cardiac condition, such as heart failure, an acute coronary syndrome (acs), atrial fibrillation or other types of arrhythmia. conclusion: a positive troponin test was associated with increased los; however, only a small proportion of these patients had a final diagnosis associated with a cardiac condition. guidelines should be provided to ensure that troponin testing is performed only in cases where an acs is suspected. keywords: emergency department; troponin; cardiovascular abnormality; acute coronary syndrome; length of stay; oman. امللخ�ص: الهدف: تهدف هذه الدرا�صة لدرا�صة منط اإجراء فح�ض الرتوبونني يف ق�صم الطواري مب�صت�صفى كبري يف عمان يقدم الرعاية ال�صحية الثالثية وذلك لتحديد تاأثري هذه الفحو�صات على عالج املري�ض ومدة مكوثه بامل�صت�صفى. الطريقة: �صملت هذة الدرا�صة ال�صتعادية حتليل قابو�ض، ال�صلطان جامعة مب�صت�صفى الطوارئ ق�صم يف الرتوبونني مل�صتوى فح�ض على ح�صلوا الذين البالغني املر�صى جميع �صجالت 4,845 عدد ح�رش النتائج: مرتفع. st مقطع ذات قلبية بنوبة امل�صخ�صني املر�صى ا�صتثناء مت .2015 يوليو �صهر خالل عمان م�صقط، ا. الغالبية العظمى من املر�صى جاءوا بنتيجة فح�ض مري�صا اإىل ق�صم الطوارئ خالل فرتة الدرا�صة، ُعمل اختبار الرتوبونني لـ 588 مري�صً �صلبية )%81.3(. اأمل ال�صدر، اخلفقان، و�صعوبة التنف�ض كانت اأكرث الأعرا�ض �صيوعًا بني املر�صى ذوي النتائج املوجبة للفح�ض، يف حني اأن %41.8 من املر�صى مل ي�صكوا من اأي اأعرا�ض قلبية. كما ظهر اأي�صًا اأن املر�صى ذوي النتائج املوجبة كانت فرتة بقائهم يف امل�صت�صفى اأطول مقارنة باملر�صى ذوي النتائج ال�صلبية )متو�صط 3 مقابل 1 يوم؛ p = 0.001(. باملجمل، فقط %28.2 من املر�صى ذوي النتائج املوجبة مت ت�صخي�صهم باأمرا�ض مرتبطة بالقلب مثل الف�صل القلبي، متالزمة ال�رشيان التاجي احلادة، الرجفان الأذيني واأنواع اأخرى من عدم النتظام. اخلال�صة: النتائج الإيجابية لفح�ض الرتوبونني جاءت مرتبطة بزيادة فرتة البقاء يف امل�صت�صفى، بالرغم من ذلك وجد اأن ن�صبة املر�صى الذين مت ت�صخي�صهم لحقا باأمرا�ض قلبية قليلة. القواعد الإر�صادية يجب اأن تو�صع للتاأكد من اأن فح�ض الرتوبونني يجرى يف احلالت املتوقعة ملتالزمة ال�رشيان التاجي احلادة فقط. الكلمات املفتاحية: ق�صم الطوارئ؛ الرتوبونني؛ ت�صوه قلبي وعائي؛ متالزمة ال�رشيان التاجي احلادة؛ فرتة البقاء بامل�صت�صفى؛ عمان. troponin testing in the emergency department real world experience mohammed al-maskari, mahmoud al-makhdami, hatim al-lawati, hafidh al-hadi, *sunil k. nadar clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e398–403, epub. 10 jan 18 submitted 2 oct 17 revision req. 2 nov 17; revision recd. 12 nov 17 accepted 16 nov 17 doi: 10.18295/squmj.2017.17.04.004 advances in knowledge emergency department patients should not undergo troponin testing unless an acute coronary syndrome is suspected. in this study, a high degree of inappropriate troponin testing was observed. application to patient care the findings of this study highlight the need for protocols to guide troponin testing as, unless indicated, it can lead to unnecessary investigations and delayed patient discharge. accordingly, a thoroughly clinical evaluation should be conducted prior to a test request. chest pain is one of the most common reasons for emergency department (ed) attendance.1 as there are many causes of chest pain, the emergency physician has the responsibility of ruling out potentially life-threatening and serious conditions, such as a myocardial infarction (mi), aortic dissection or pulmonary embolism. necessary diagnostic investigations include a thorough patient mohammed al-maskari, mahmoud al-makhdami, hatim al-lawati, hafidh al-hadi and sunil k. nadar clinical and basic research | e399 history and physical examination, chest x-rays, 12lead electrocardiography (ecg) and blood tests for myocardial injury biomarkers. of these, the most widely used and extensively validated biomarkers for detecting cardiac cellular injury are cardiac troponins t and i (ctn-i) as they have a high sensitivity to and specificity for myocardial damage.2,3 however, because the troponin test is very sensitive, an inevitable number of false-positive results is to be expected.4 as the main reason for testing cardiac troponin is to rule out an acute coronary syndrome (acs), it is thus essential that troponin is only checked in circumstances where the probability of ischaemic heart disease is high and an acs is suspected, especially as indiscriminate troponin testing can lead to unnecessary investigations or a misdiagnosis.5,6 this study therefore aimed to review patterns of troponin testing among patients attending the ed of the sultan qaboos university hospital (squh) in muscat, oman, and to examine whether initial troponin test results had an effect on patient management, especially length of hospital stay (los). methods this retrospective study included all adult patients ≥18 years old undergoing ctn-i testing following their admission to the ed of squh during july 2015. patients who presented with a st-elevation mi (stemi) were excluded. the month of july was chosen at random for the study period. patient data were obtained from the hospital’s electronic records. troponin levels were considered positive at ≥0.04 μg/ml and negative at <0.04 μg/ml, as per the reference levels recommended by the manufacturer of the assay kit (accutnl+3 reagent kit, beckman coulter inc., brea, california, usa). the presenting complaints of the patients were classified as either cardiac or non-cardiac, with presenting cardiac complaints including chest pain, palpitations, breathlessness and epigastric pain. epigastric pain was included as a cardiac symptom as it is potentially indicative of an atypical presentation of angina; furthermore, it is often difficult to distinguish between epigastric and retrosternal discomfort.7 the final diagnosis of each patient was categorised as either cardiac or non-cardiac, with cardiac diagnoses including heart failure, an acs, atrial fibrillation or other forms of arrhythmia. all statistical analyses were performed using the statistical package for the social science (spss), version 21.0 (ibm corp., armonk, new york, usa). a p value of <0.050 was considered statistically significant. all categorical variables were presented as frequencies and percentages. means and standard deviations were used to describe continuous normally distributed variables, while non-normally distributed variables were described as medians and interquartile ranges. a chi-squared test was used to compare categorical variables between groups and a t-test was used to compare mean ages. a mann-whitney test was used to compare associations with los. ethical approval for this study was obtained from the medical ethics & research committee of the college of medicine & health sciences, sultan qaboos university (mrec #1122). results during the study period, a total of 4,845 patients attended the ed of squh. of these, 599 adult patients underwent ctn-i testing as part of their evaluation; however, 11 patients with stemis were excluded from the analysis. accordingly, a total of 588 patients underwent 681 troponin tests. the mean age of the participants was 56.6 ± 16.7 years and 53.9% were male. a total of 110 (18.7%) and 478 (81.3%) patients had positive and negative initial troponin results, table 1: demographic and clinical characteristics of emergency department patients undergoing troponin testing at the sultan qaboos university hospital, muscat, oman (n = 588) characteristic n (%) p value* positive troponin findings (n = 110) negative troponin findings (n = 478) gender male 66 (60.0) 251 (52.5) 0.094 female 44 (40.0) 227 (47.5) age mean ± sd 61.6 ± 15.9 55.5 ± 16.8 0.001† comorbidities‡ stroke 8 (7.3) 12 (2.5) 0.020 cabg 6 (5.5) 27 (5.6) 0.574 pci 11 (10.0) 30 (6.3) 0.123 renal failure 8 (7.3) 9 (1.9) 0.007 mi 9 (8.2) 11 (2.3) 0.006 htn 56 (50.9) 215 (45.0) 0.158 diabetes 40 (36.4) 170 (35.6) 0.484 sd = standard deviation; cabg = coronary artery bypass grafting ; pci = percutaneous coronary intervention; mi = myocardial infarction; htn = hypertension. *calculated using a chi-squared test. †calculated using a student’s t-test. ‡percentages do not add up to 100% as patients may have had more than one comorbidity. troponin testing in the emergency department real world experience e400 | squ medical journal, november 2017, volume 17, issue 4 respectively. patients with positive troponin results were significantly older and more likely to have renal failure and mis as comorbidities (p <0.050 each). however, there was no association between elevated troponin results and coronary artery bypass grafting, percutaneous coronary interventions, hypertension or diabetes (p >0.050) [table 1]. a total of 342 patients (58.1%) presented with cardiac symptoms. of these, chest pain was the most frequent (n = 135; 39.5%), followed by breathlessness (n = 118; 34.5%), epigastric pain (n = 74; 21.6%) and palpitations (n = 15; 4.4%). interestingly, a large proportion of the patients (n = 246; 41.8%) did not present with any cardiac symptoms. overall, only 65 (19.0%) of those with cardiac symptoms had initial positive troponin test results, including 6.8% with epigastric pain. in addition, 18.3% of patients with non-cardiac symptoms also had raised troponin levels [table 2]. in terms of management, 494 patients (84.0%) did not have a repeat troponin test and 93 (15.8%) underwent at least one repeat troponin test. of those with initial positive troponin findings, 39 (35.5%) underwent multiple repeat troponin tests as compared to 54 (11.3%) with initial negative results. only 33 (30.0%) and 10 (9.1%) patients with positive troponin results were referred to a cardiologist or underwent acs management, respectively. all 10 of these acs patients received an angiogram, of which four were normal. of those with initial negative troponin results, 31 (6.5%) were referred to a cardiologist, seven (1.5%) underwent acs management and four (0.8%) had an angiogram, of which two were normal. patients with table 2: presenting complaints among emergency department patients undergoing troponin testing at the sultan qaboos university hospital, muscat, oman (n = 588) complaint n (%) p value positive troponin findings (n = 110) negative troponin findings (n = 478) chest pain 20 (14.8) 115 (85.2) 0.001 breathlessness 35 (29.7) 83 (70.3) 0.001 palpitations 5 (33.3) 10 (66.7) 0.001 epigastric pain 5 (6.8) 69 (93.2) 0.001 non-cardiac complaints 45 (18.3) 201 (81.7) 0.001 table 3: management and length of stay of emergency department patients undergoing troponin testing at the sultan qaboos university hospital, muscat, oman (n = 588) management n (%) p value positive troponin findings (n = 110) negative troponin findings (n = 478) treated as acs 10 (9.1) 7 (1.5) <0.001 angiography 10 (9.1) 4 (0.8) <0.001 referred to a cardiologist 33 (30.0) 31 (6.5) <0.001 initial troponin test only 71 (64.5) 424 (88.7) <0.001 at least one repeat troponin test 39 (35.5) 54 (11.3) median los in days (iqr) 3 (1–8) 1 (1–2) 0.001 acs = acute coronary syndrome; los = length of hospital stay; iqr = interquartile range. table 4: final diagnoses of emergency department patients undergoing troponin testing at the sultan qaboos university hospital, muscat, oman (n = 588) final diagnosis n (%) p value* positive troponin findings (n = 110) negative troponin findings (n = 478) cardiac† 31 (28.2) 66 (13.8) <0.001 non-cardiac 79 (71.8) 412 (86.2) *calculated using a chi-squared test. †including heart failure, an acute coronary syndrome, atrial fibrillation or other forms of arrhythmia. table 5: correlations between presenting complaints and final diagnoses among emergency department patients undergoing troponin testing at the sultan qaboos university hospital, muscat, oman (n = 588) presenting complaint n (%) p value cardiac diagnoses* (n = 97) non-cardiac diagnoses (n = 491) chest pain 35 (36.1) 100 (20.4) <0.001 breathlessness 27 (27.8) 91 (18.5) <0.001 palpitations 5 (5.2) 10 (2.0) <0.001 epigastric pain 9 (9.3) 65 (13.2) <0.001 non-cardiac symptoms 21 (21.6) 225 (45.8) <0.001 *including heart failure, an acute coronary syndrome, atrial fibrillation or other forms of arrhythmia. mohammed al-maskari, mahmoud al-makhdami, hatim al-lawati, hafidh al-hadi and sunil k. nadar clinical and basic research | e401 positive troponin test results had a significantly greater los compared to those with negative troponin findings (mean: one versus three days; p <0.050) [table 3]. a total of 97 patients (16.5%) had a final diagnosis related to a cardiac condition, consisting of 31 patients (32.0%) with positive troponin tests and 66 (13.8%) with negative results [table 4]. specifically, six patients (5.5%) with positive troponin test results and two (0.4%) with negative findings were diagnosed with acs. overall, 76 (22.2%) of patients with cardiac symptoms had a final cardiac diagnosis, including nine patients with epigastric pain [table 5]. while a small proportion (n = 21; 8.5%) of those patients presenting with non-cardiac complaints also had a cardiac diagnosis, most of these cases did not have an acs. discussion to the best of the authors’ knowledge, this study is the first of its kind in the region to study the pattern of troponin testing in the ed of a large tertiary care centre. while the results indicated that cardiac troponin testing was performed mainly for patients with chest pain or in cases where an acs was suspected, it was also occasionally requested for patients with non-cardiac-related symptoms. it is possible that the attending doctor in these cases requested troponin testing because they felt that the patient’s presentation might be the result of an atypical manifestation of an acs. moreover, not all of the patients with positive troponin results in the current study were treated for an acs, while a small number of patients with negative troponin results underwent acs management based on their clinical presentation. this finding is in keeping with the guidelines of the european society of cardiology which specify that while troponin testing has a role in diagnosing a mi, a negative test does not always rule out other forms of acs, such as unstable angina.8 although troponin tests are widely available, not all hospitals have clear guidelines or protocols as to when a troponin test should be requested, which can inadvertently lead to the inappropriate use of this diagnostic investigation.5,6,9 while troponin tests are mainly used to diagnose an acs, troponin levels can also be elevated in other cardiac conditions such as heart failure, tachyarrhythmias and post-cardiac arrest and direct current cardioversion as well as noncardiac conditions such as cerebrovascular accidents, head injuries, sepsis and pulmonary emboli.2–4 in these circumstances, a troponin test should only be performed if there is strong suspicion of an acs—such as prior chest pain or ecg changes—as a positive result can be misleading.5,6 interestingly, although 97 patients in the current study had a final cardiac-related diagnosis, only eight of these patients (8.2%) were diagnosed with an acs. this number is relatively low and might reflect the short study period. in addition, there may have been a high incidence of type 2 mis (i.e. infarctions due to demand-supply mismatch rather than plaque rupture), which are often overlooked.10,11 unfortunately, patients with stemis were not included in the current analysis and it was beyond the scope of this study to examine the incidence of type 2 mis. as expected, patients with positive troponin test results in the present study had a significantly longer los than those with negative findings. these patients were also significantly more likely to be treated for acs, be referred to a cardiologist and undergo angiography. however, only 30.0% of patients with positive troponin results were referred to cardiologists; it is likely that the remaining 70.0% of patients were not considered to have a significant cardiac condition and were therefore not referred. in these cases, it is unclear why the troponin test was requested if such patients were not subsequently referred to a cardiologist despite their raised troponin levels. this finding may perhaps reflect the routine ordering of blood tests rather than requests made based on the patient’s clinical presentation. rehmani et al. similarly showed that 62.2% of blood tests requested from an ed at a large tertiary centre were considered inappropriate and that only 3.8% influenced patient management.12 along the same lines, only 6.5% of patients with negative troponin findings in the current study were referred to a cardiologist although 13.8% had a final cardiacrelated diagnosis. this apparent discrepancy could be due to the fact that cardiac diagnoses included atrial fibrillation, arrhythmias and heart failure. as such, some patients may have presented to the ed with noncardiac symptoms but nevertheless received a cardiac diagnosis; for example, patients with coexisting atrial fibrillation may have received a cardiac diagnosis despite this not being the main reason for their attendance at the ed. a final diagnosis of an acs was only made in a very small percentage of patients. if an acs is suspected and the initial troponin test result is negative, it is recommended that a repeat test be performed within six hours to completely rule out mis and improve diagnostic accuracy.3,13 however, in the current sample, only a small number of patients underwent a second test and this proportion was even lower among those with an initial negative result. research from other centres also indicates that these recommendations are not being followed.14,15 on the whole, the results of the current study confirmed those of similar studies conducted in other parts of the world.16,17 such findings highlight the need for proper troponin testing in the emergency department real world experience e402 | squ medical journal, november 2017, volume 17, issue 4 ed guidelines and protocols for troponin test requests. triage nurses or physicians often request a wide array of blood tests while the patient is waiting to be seen by a doctor.18,19 although these measures may help reduce patient wait times, it often results in unnecessary tests being ordered.11,20,21 for economic reasons, it is prudent to limit such requests for unnecessary tests, in turn reducing unnecessary hospital stays and admissions.6 this study was subject to certain limitations due to its retrospective nature and the method of data collection using patient records. the ctn-i tests were requested by various ed doctors or triage nurses without standard protocols to guide requests for troponin testing or to screen for an acs or myocardial injuries or infarctions. in addition, patients with negative ctn-i results were not followed up during their subsequent stay in the ed or hospital. the final diagnosis of a cardiac or non-cardiac abnormality was based solely on documentation from the initial ed visit. similarly, final cardiac diagnoses were not subcategorised according to the specific condition as this was beyond the scope of this study; the focus of the analysis lay in determining the pattern of ctn-i test requests and not in studying the prevalence of individual cardiac conditions. moreover, the sample size of the study was small due to the short study period. finally, a major limitation of this study was the unavailability of ecg data for most patients. conclusion in the current study, a large number of patients attending the ed were found to have undergone troponin testing despite presenting without cardiacrelated symptoms. moreover, only a small proportion of patients with initial positive troponin test results received a final cardiac-related diagnosis upon discharge. such unnecessary testing may lead to increased los and unnecessary referrals to the cardiology department. hospital protocols regarding the appropriate use of troponin testing are therefore needed to guide emergency physicians and triage nurses. a c k n o w l e d g e m e n t s the authors wish to thank the ed staff at squh for their cooperation during this study and for their help during the data collection process. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. pitts sr, niska rw, xu j, burt cw. national hospital ambulatory medical care survey: 2006 emergency department summary. natl health stat report 2008:1–38. 2. babuin l, jaffe as. troponin: the biomarker of choice for the detection of cardiac injury. cmaj 2005; 173:1191–202. doi: 10.1503/cmaj/051291. 3. newby lk, jesse rl, babb jd, christenson rh, de fer tm, diamond ga, et al. accf 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the american college of cardiology foundation task force on clinical expert consensus documents. j am coll cardiol 2012; 60:2427–63. doi: 10.1016/j.jacc.2012.08.969. 4. sandoval y, smith sw, schulz km, murakami mm, love sa, nicholson j, et al. diagnosis of type 1 and type 2 myocardial infarction using a high-sensitivity cardiac troponin i assay with sex-specific 99th percentiles based on the third universal definition of myocardial infarction classification system. clin chem 2015; 61:657–63. doi: 10.1373/clinchem.2014.236638. 5. fraga or, sandoval y, love sa, mckinney zj, murakami mm, smith sw, et al. cardiac troponin testing is overused after the rule-in or rule-out of myocardial infarction. clin chem 2015; 61:436–8. doi: 10.1373/clinchem.2014.232694. 6. nilsson s, andersson a, janzon m, karlsson je, levin lå. cost consequences of point-of-care troponin t testing in a swedish primary health care setting. scand j prim health care 2014; 32:241–7. doi: 10.3109/02813432.2014.984901. 7. bösner s, haasenritter j, becker a, hani ma, keller h, sönnichsen ac, et al. heart burn or angina? differentiating gastrointestinal disease in primary care patients presenting with chest pain: a cross sectional diagnostic study. int arch med 2009; 2:40. doi: 10.1186/1755-7682-2-40. 8. roffi m, patrono c, collet jp, mueller c, valgimigli m, andreotti f, et al. 2015 esc guidelines for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation. rev esp cardiol (engl ed) 2015; 68:1125. doi: 10.1016/j.rec.2015.10.009. 9. love sa, mckinney zj, sandoval y, smith sw, kohler r, murakami mm,et al. electronic medical record-based performance improvement project to document and reduce excessive cardiac troponin testing. clin chem 2015; 61:498–504. doi: 10.1373/clinchem.2014.234310. 10. thygesen k, alpert js, jaffe as, simoons ml, chaitman br, white hd. third universal definition of myocardial infarction. j am coll cardiol 2012; 60:1581–98. doi: 10.1016/j. jacc.2012.08.001. 11. sandoval y, smith sw, thordsen se, apple fs. supply/demand type 2 myocardial infarction: should we be paying more attention? j am coll cardiol 2014; 63:2079–87. doi: 10.1016/j. jacc.2014.02.541. 12. rehmani r, amanullah s. analysis of blood tests in the emergency department of a tertiary care hospital. postgrad med j 1999; 75:662–6. doi: 10.1136/pgmj.75.889.662. 13. edwards b, washington i, pretlow l, passmore g, dias j, wise s. sequential assessment of troponin in the diagnosis of myocardial infarction. clin lab sci 2013; 26:95–9. 14. kalim s, nazir s, khan zu. high sensitivity troponin t: an audit of implementation of its protocol in a district general hospital. j ayub med coll abbottabad 2013; 25:9–11. https://doi.org/10.1503/cmaj/051291 https://doi.org/10.1016/j.jacc.2012.08.969 https://doi.org/10.1373/clinchem.2014.236638 https://doi.org/10.1373/clinchem.2014.232694 https://doi.org/10.3109/02813432.2014.984901 https://doi.org/10.1186/1755-7682-2-40 https://doi.org/10.1016/j.rec.2015.10.009 https://doi.org/10.1373/clinchem.2014.234310 https://doi.org/10.1016/j.jacc.2012.08.001 https://doi.org/10.1016/j.jacc.2012.08.001 https://doi.org/10.1016/j.jacc.2014.02.541 https://doi.org/10.1016/j.jacc.2014.02.541 https://doi.org/10.1136/pgmj.75.889.662 mohammed al-maskari, mahmoud al-makhdami, hatim al-lawati, hafidh al-hadi and sunil k. nadar clinical and basic research | e403 15. rajappan k, murphy e, amber v, meakin f, muller b, fox kf, et al. usage of troponin in the real world: a lesson for the introduction of biochemical assays. qjm 2005; 98:337–42. doi: 10.1093/qjmed/hci052. 16. groarke jd, browne l, margey r, mccann ha, blake gj, sugrue dd, et al. a multicentre analysis of troponin use in clinical practice. ir j med sci 2013; 182:185–90. doi: 10.1007/ s11845-012-0853-2. 17. yiadom my, jarolim p, jenkins c, melanson se, conrad m, kosowsky jm. diagnostic implications of an elevated troponin in the emergency department. dis markers 2015; 2015:157812. doi: 10.1155/2015/157812. 18. ebrahimi m, mirhaghi a, mazlom r, heydari a, nassehi a, jafari m. the role descriptions of triage nurse in emergency department: a delphi study. scientifica (cairo) 2016; 2016:5269815. doi: 10.1155/2016/5269815. 19. andersson ak, omberg m, svedlund m. triage in the emergency department: a qualitative study of the factors which nurses consider when making decisions. nurs crit care 2006; 11:136–45. doi: 10.1111/j.1362-1017.2006.00162.x. 20. holroyd br, bullard mj, latoszek k, gordon d, allen s, tam s, et al. impact of a triage liaison physician on emergency department overcrowding and throughput: a randomized controlled trial. acad emerg med 2007; 14:702–8. doi: 10.11 97/j.aem.2007.04.018. 21. seaberg dc, macleod ba. correlation between triage nurse and physician ordering of ed tests. am j emerg med 1998; 16:8–11. doi: 10.1016/s0735-6757(98)90057-2. https://doi.org/10.1093/qjmed/hci052 https://doi.org/10.1007/s11845-012-0853-2 https://doi.org/10.1007/s11845-012-0853-2 https://doi.org/10.1155/2015/157812 https://doi.org/10.1155/2016/5269815 https://doi.org/10.1111/j.1362-1017.2006.00162.x https://doi.org/10.1197/j.aem.2007.04.018 https://doi.org/10.1197/j.aem.2007.04.018 https://doi.org/10.1016/s0735-6757%2898%2990057-2 1pistachio safety research center, rafsanjan university of medical sciences, rafsanjan, iran; 2ameretat shimi pharmaceutical co., tehran, iran; 3department of toxicology & pharmacology, school of pharmacy and 4razi drug research center, iran university of medical sciences, tehran, iran *corresponding author e-mails: shetab.v@iums.ac.ir and vshetab@gmail.com التفاعل الكيميائي بني محض البوريك والفسفني يشري إىل أن محض البوريك يعمل كرتياق مضاد لتسمم فوسفيد األلومنيوم مطهره �صلطاين، �صيد فريد �صتاب-بو�صهري، �صيد وحيد �صتاب-بو�صهري abstract: objectives: aluminium phosphide (alp) is a fumigant pesticide which protects stored grains from insects and rodents. when it comes into contact with moisture, alp releases phosphine (ph3), a highly toxic gas. no efficient antidote has been found for alp poisoning so far and most people who are poisoned do not survive. boric acid is a lewis acid with an empty p orbital which accepts electrons. this study aimed to investigate the neutralisation of ph3 gas with boric acid. methods: this study was carried out at the baharlou hospital, tehran university of medical sciences, tehran, iran, between december 2013 and february 2014. the volume of released gas, rate of gas evolution and changes in ph were measured during reactions of alp tablets with water, acidified water, saturated boric acid solution, acidified saturated boric acid solution, activated charcoal and acidified activated charcoal. infrared spectroscopy was used to study the resulting probable adduct between ph3 and boric acid. results: activated charcoal significantly reduced the volume of released gas (p <0.01). although boric acid did not significantly reduce the volume of released gas, it significantly reduced the rate of gas evolution (p <0.01). a gaseous adduct was formed in the reaction between pure alp and boric acid. conclusion: these findings indicate that boric acid may be an efficient and non-toxic antidote for ph3 poisoning. keywords: antidotes; aluminum phosphide; poisoning; boric acid; phosphine; activated charcoal. للنداوة التعر�ض عند والقوار�ض. احل�رضات من املخزنة احلبوب يحمي للهوام م�صتدخن مبيد هو االألومينيوم فو�صفيد اأهداف: امللخ�ص: يطلق فو�صفيد االألومينيوم الف�صفني وهو غاز �صديد ال�صمية. مل يتم العثور على ترياق فعال لت�صمم فو�صفيد االألومينيوم حتى االآن ومعظم النا�ض الذين يتعر�صون للت�صمم يفقدون احلياة. حم�ض البوريك هو حم�ض لوي�ض مع فارغة p املدارية التي تقبل االإلكرتون. الهدف من طهران جامعة بهارلو، م�صت�صفى يف الدرا�صة هذه اأجريت البوريك. منهجية: حم�ض مع الف�صفني غاز حتييد من التحقق هو الدرا�صة هذة ودرجة والتغريات الغاز، تطور ومعدل املنبعث، الغاز حجم قيا�ض مت 2014م. وفرباير 2013م دي�صمرب بني اإيران، طهران، الطبية، للعلوم احلمو�صة خالل تفاعل اأقرا�ض فو�صفيد االألومينيوم مع املاء، واملاء املحم�ض، وحملول حم�ض البوريك امل�صبع، و حملول حم�ض البوريك املحم�ض امل�صبع، والفحم املن�صط، و الفحم املن�صط املحم�ض. مت ا�صتخدام تنظري طيف االأ�صعة حتت احلمراء لدرا�صة ناجت االإ�صافة املحتمل بني الف�صفني وحم�ض البوريك. نتائج: الفحم املن�صط خف�ض ب�صكل كبري حجم الغاز املنبعث )p >0.01(. على الرغم من اأن حم�ض البوريك مل يقلل اإىل حد كبري انبعاث الغاز اإال انه �صاعد على خف�ض معدل تطور الغاز )p >0.01(. مت ت�صكيل ناجت اإ�صافة غازي من التفاعل بني فو�صفيد االألومينيوم النقي وحم�ض البوريك. خامتة: ت�صري هذة النتائج اإىل اأن حم�ض البوريك ميكن اأن يكون ترياق فعال وغري �صام حلاالت ت�صمم الف�صفني. كلمات مفتاحية: الرتياق؛ فو�صفيد االألومينيوم؛ ت�صمم؛ حم�ض البوريك؛ الف�صفني؛ الفحم املن�صط. chemical reaction between boric acid and phosphine indicates boric acid as an antidote for aluminium phosphide poisoning motahareh soltani,1 seyed f. shetab-boushehri,2 *seyed v. shetab-boushehri3,4 advances in knowledge the results of the present study show that phosphine (ph3 ) reacts with boric acid and produces a gaseous adduct. activated charcoal was found to significantly reduce the volume of released ph3 gas, while boric acid significantly reduced the rate of gas evolution. the time taken for the production of a lethal volume of ph3 gas was 6.5–21 minutes. application to patient care the results of this study may be utilised by emergency medicine and poisoning centre staff to treat aluminium phosphide (alp)poisoned patients for the adsorption of released ph 3 and to prevent further ph3 absorption. treatment should comprise emergency oral administration of activated charcoal during a ‘golden’ time period of no longer than 20 minutes post-alp ingestion. the present study proposes boric acid as a new antidote for alp poisoning ; however, extensive in vivo studies are needed to confirm its effectiveness in animals and humans. clinical & basic research sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e303–309, epub. 19 aug 16 submitted 20 mar 16 revision req. 8 may 16; revision recd. 13 may 16 accepted 9 jun 16 doi: 10.18295/squmj.2016.16.03.007 chemical reaction between boric acid and phosphine indicates boric acid as an antidote for aluminium phosphide poisoning e304 | squ medical journal, august 2016, volume 16, issue 3 aluminium phosphide (alp) is a fumigant pesticide often utilised to protect stored grains from insects and rodents. although alp is not toxic per se, the pesticide releases phosphine (ph3)—a colourless, water insoluble, flammable and highly toxic gas—after coming into contact with water.1–3 the gas is produced according to the following chemical equation:4 while odourless in its pure form, ph3 can smell of garlic or decaying fish due to the presence of impurities such as substituted phosphines and diphosphines.1,2 ph3 is a lewis base and a strong nucleophile. it is a reducing agent with a lone-pair electron which reduces cytochrome c oxidase and interferes with the electron transfer from complex iii to complex iv of the mitochondrial respiratory chain, ultimately resulting in the inhibition of oxidative phosphorylation, adenosine triphosphate depletion and cell death.1 alp is a multiorgan poison which has toxic effects on the cardiovascular, respiratory, hepatic and gastrointestinal systems and induces acid-base disturbances.1,5–9 myocardial damage is reported to be the primary cause of death in alp poisoning.10,11 alp poisoning is more prevalent in iran and india.2,3 many reports have proposed experimental or individual case treatments for a1p poisoning, includ ing digoxin; n-acetylcysteine; hyperbaric oxygen; magnesium (25mg2+)-carrying nanoparticles; intragastric irrigation with sweet almond oil; a combination of vitamin c and methylene blue; extensive gastric lavage with coconut oil and a sodium bicarbonate solution with simultaneous aspiration; perfusion with an intraaortic balloon pump; nω-nitro-l-arginine methyl ester; a combination of atropine and pralidoxime; and trimetazidine.12–21 however, no specific antidote has yet been found for the routine treatment of alp poisoning and unfortunately most people who are poisoned do not survive.2–4 recently, boric acid has been theoretically proposed as an antidote for alp poisoning.1 with the formula b(oh)3, boric acid is a lewis acid with an empty p orbital which can accept electrons. it is nontoxic with a median lethal oral dose of 5.14 g kg-1 in rats.1 the present study aimed to investigate the feasibility of a chemical reaction between ph3 and boric acid. adsorption of evolved gas by activated charcoal was also studied. the main objective of the present study was to determine whether boric acid could be suitable as a specific and efficient antidote for alp poisoning. methods this study was carried out at the baharlou hospital, tehran university of medical sciences, tehran, iran, between december 2013 and february 2014. the following compounds and materials were pur chased: boric acid (merck kgaa, darmstadt, germany); disodium tetraborate (merck kgaa); 37% hydrochloric acid (merck kgaa); activated charcoal with a 45–150 μm particle size and 850 m2g-1 specific surface (colorsorb® m5, jacobi carbons ab, permatang tinggi, penang, malaysia); alp tablets (phostoxin®, alcan, bucharest, romania); pure alp (mp biomedicals llc, santa ana, california, usa); and ammonium carbamate (merck kgaa). a gascollecting apparatus was assembled as follows: by a transparent flexible rubber tube, the side arm of an erlenmeyer vacuum flask, placed on a magnetic stirrer, was connected to an upside-down water-filled graduated glass cylinder in a water basin. a combined ph meter electrode which simultaneously measured ph and temperature was tightly fitted to the mouth of the erlenmeyer flask by means of a drilled gas-tight annular rubber stopper. the apparatus was placed under a ventilating laboratory hood to prevent the toxic gas from spreading. six experiments were performed as follows: a 1 g alp tablet as an unbroken piece was added separately to 200 ml each of (1) distilled water (dw); (2) acidified dw; (3) 1% (weight [w]/volume [v]) activated charcoal in dw; (4) 1% (w/v) activated charcoal in acidified dw; (5) a saturated boric acid solution; and (6) an acidified saturated boric acid solution. for acidification of the solutions, 100 μl of concentrated 37% hydrochloric acid was added to the solutions to bring the ph to approximately 2.0, which is the approximate ph of the human stomach.1 after the addition of an alp tablet to each of the respective solutions, the gas-tight annular rubber stopper containing the combined ph meter electrode was immediately fitted tightly to the mouth of the erlenmeyer flask and the mixtures were gently stirred by the magnetic stirrer. each experiment was repeated five times. the volume of evolved gas and ph were recorded every minute and every 10 seconds, respectively, until the end of the reaction. the rate of gas evolution was determined by taking the first derivative of equations of respective released gas curves. as each experiment was carried out at different times and with different ambient temperatures and pressures, all gas volumes were corrected for 310.15 kelvin (k) or 37 °c and 101.325 kilopascal (kpa) or alp + 3h2o → al(oh)3 + ph3↑ motahareh soltani, seyed f. shetab-boushehri and seyed v. shetab-boushehri clinical and basic research | e305 used in powdered form. to study the effect of water on pure dry alp, pure dry boric acid and a mixture of pure dry alp and pure dry boric acid, the respective infrared spectra were obtained by spraying one puff (approximately 5 µl) of double dw on the respective dry samples. data were analysed using the statistical package for the social sciences (spss), version 19 (ibm corp., chicago, illinois, usa). the maximum volume (vmax) of released gas from each of the experiments was compared using a one-way analysis of variance with scheffe’s post hoc test. differences were regarded as significant at p <0.05. differences between rates of gas evolution in the experiments were determined by comparing the slopes of the respective rate curves using the student t-test with the slopes of two lines considered as b1 and b2. the null hypothesis was that there would be no difference between these slopes (b1 = b2) and the alternative hypothesis was that there would be a difference (b1 ≠ b2). in order to perform this analysis, a dummy variable (method) was first made and was coded one for line one and zero for line two. an additional variable (mettim, the product of method and time) was also made. subsequently, method, time and mettim were used as predictors for slope comparisons. in the spss syntax editor window (ibm corp.,), a programme was written and a statistical analysis was performed for two-by-two comparisons of the experimental groups. results the vmax, maximum time needed to release vmax, slopes of rate curves, difference between the initial and final temperatures of the reaction medium and the difference between the initial and final ph of the reaction medium of all experiments are summarised in table 1. one alp tablet produced 150.5 ± 2.2 ml of total gas and a maximum of 174.2 ± 1.5 ml of gas in 200 ml of dw and acidic dw, respectively, at 37 °c and 101.325 kpa. the approximate time needed for the production of a lethal volume of gas was 6.5–21 minutes. an alp tablet in acidified dw produced signifi cantly more gas than an alp tablet in dw (p <0.01). moreover, the rate of gas evolution in acidified dw was significantly higher than in dw (t = 11.76; p <0.01). the suspension of 1% (w/v) activated charcoal in dw significantly reduced the volume of released gas in comparison to the alp tablet in dw (p <0.01). however, the rate of gas evolution in a suspension of 1% (w/v) activated charcoal in dw was significantly higher than that of an alp tablet in dw 1 atmosphere; these values represent the normal temperature and the standard pressure, respectively, of and around the human body. this permitted a statistical comparison between the experimental groups. correction of the evolved gas volume was done by using the following ideal gas law equation: where p1, v1 and t1 are the initial pressure in pascal, volume in ml and temperature in k of the released gas, respectively, and p2, v2 and t2 are 101.325 kpa, corrected volume in ml and temperature of 310.15 k, respectively. the ambient temperature and pressure of each experiment was measured using a multifunction digital altimeter (model kt808, dealextreme, hong kong, china). because ph3 is a base, the ph of the reaction media was monitored continuously to evaluate the increase in ph of the mixtures. complementary experiments using the aforementioned apparatus were performed as follows: 0.56 g of pure alp and 0.44 g of pure ammonium carbamate were separately added to 200 ml of dw, acidified dw, saturated boric acid and acidified saturated boric acid. the volume of released gas (if any) and ph were continuously recorded in these experiments. each 1 g alp tablet contained approximately 56% pure alp and 44% ammonium carbamate by weight, which produces carbon dioxide (co2) and ammonia (nh3) gases according to the following chemical equation:4 thus, one alp tablet was expected to produce 236.3 ml of ph3, 137.8 ml of co2 and 275.6 ml of nh3 and 650.0 ml of total gas at 25 °c and 101.325 kpa.1 due to the water solubility of ph3 (26 ml per 100 ml of water at 20 °c and 101.325 kpa), co2 (88 ml per 100 ml of water at 20 °c and 101.325 kpa) and nh3 (34 ml per 100 ml of water at 20 °c and 101.325 kpa), it was predicted that one alp tablet would produce approximately 184.0 ml of ph3, 0.0 ml of co2 and 208.0 ml of nh3, for 392.0 ml of total gas in 200 ml of dw at 20 °c and 101.325 kpa if the reactions were complete. infrared spectroscopy was used to confirm the reaction between boric acid and ph3 gas and the formation of a phosphorous-boron bond. the infrared spectra of pure dry alp, pure dry boric acid, a dry mixture of pure alp and pure boric acid at a ratio of 1:1 (w/w) were obtained with an infrared spectroscope (ftir-8400s, shimadzu corp., kyoto, japan) in a transmission mode between 500–4700 cm-1 with a resolution of 0.85 cm-1. all materials were p1v1 t1 t2 p2v2 = nh2coonh4 → co2↑ + 2nh3↑ chemical reaction between boric acid and phosphine indicates boric acid as an antidote for aluminium phosphide poisoning e306 | squ medical journal, august 2016, volume 16, issue 3 (t = 32.28; p <0.01). a suspension of 1% (w/v) activated charcoal in acidified dw significantly reduced the volume of released gas in comparison to an alp tablet in acidified dw (p <0.01). the rate of gas evolution in a suspension of 1% (w/v) activated charcoal in acidified dw was significantly higher than that of an alp tablet in acidified dw (t = 9.64; p <0.01). saturated boric acid solution did not significantly reduce the volume of released gas in comparison to an alp tablet in dw (p = 0.99). however, the rate of gas evolution in a saturated boric acid solution was significantly slower than that of an alp tablet in dw (t = -11.50; p <0.01). the acidified saturated boric acid solution significantly reduced the volume of released gas in comparison to an alp tablet in acidified dw (p <0.01). the rate of gas evolution in the acidified saturated boric acid solution was also significantly slower than that of an alp tablet in acidified dw (t = -38.22; p <0.01). gas evolution in the acidic saturated boric acid solution was significantly less than that in a saturated boric acid solution (p <0.01). the rate of gas evolution in the acidic saturated boric acid solution was significantly lower than in the saturated boric acid solution (t = -19.74; p <0.01). the infrared spectra of the pure dry and wet alp, pure dry and wet boric acid and a dry and wet 1:1 mixture of pure alp and pure boric acid were measured. for the pure dry alp [figure 1a], a weak peak was observed at 2,280–2,440 cm-1, which was intensified after wetting the alp [figure 1b]. a comparison of pure dry [figure 2a] and wet [figure 2b] boric acid showed the production of no new peak in the latter spectrum. a comparison of the dry [figure 3a] and wet [figure 3b] mixture of pure alp and boric acid indicated the production of three new peaks at 1,250 cm-1, 1,350 cm-1 and 1,440 cm-1 in the latter wet mixture. an intensified peak at 2,280–2,440 cm-1 was noted for the wet mixture in comparison to the dry mixture. discussion previous research has shown that ph3 reacts with boron trichloride (bcl3) through a lewis base-acid reaction and produces a gaseous product (h3p-bcl3). 22 the reaction between ph3 and boric acid is comparable. as a reducing agent with a standard electrode potential (e0) of -1.18 v, ph3 gives electrons table 1: vmax, tmax, slopes of rate curves, temperature differences and ph differences of all experiments experiment mean vmax in ml ± sd tmax in minutes slope of rate curve in ml min-1 mean ∆t in °c ± sd mean δph ± sd 1. alp tablet with dw 150.5 ± 2.2 64.5 -0.0736 1.8 ± 0.0 2.2 ± 0.1 2. alp tablet with acidified dw 174.2 ± 1.5* 67.4 -0.0786§ 3.6 ± 1.2 5.4 ± 0.3 3. alp tablet with 1% activated charcoal in dw 114.4 ± 2.0* 52.2 -0.0939§ 5.0 ± 1.6 1.9 ± 0.1 4. alp tablet with 1% activated charcoal in acidified dw 129.8 ± 0.5† 56.3 -0.0838¶ 4.8 ± 0.4 4.9 ± 0.3 5. alp tablet with saturated boric acid 149.0 ± 5.6 67.2 -0.0683§ 6.7 ± 1.3 1.6 ± 0.2 6. alp tablet with acidified saturated boric acid 136.3 ± 2.4†‡ 71.2 -0.0558¶ 6.8 ± 0.2 2.8 ± 0.4 7. pure alp with dw nd nm nc 0.9 ± 0.1 2.8 ± 0.1 8. pure alp with acidified dw nd nm nc 0.8 ± 0.1 1.5 ± 0.1 9. pure alp with saturated boric acid nd nm nc 1.3 ± 0.1 1.2 ± 0.1 10. pure alp with acidified saturated boric acid nd nm nc 1.7 ± 0.1 2.0 ± 0.1 11. ammonium carbamate in dw nd\\ nm nc 1.2 ± 0.1 2.6 ± 0.1 12. ammonium carbamate in acidified dw nd\\ nm nc 1.4 ± 0.1 0.5 ± 0.1 13. ammonium carbamate in saturated boric acid nd\\ nm nc 0.9 ± 0.1 1.9 ± 0.1 14. ammonium carbamate in acidified saturated boric acid nd\\ nm nc 0.7 ± 0.1 3.0 ± 0.1 vmax = maximum of released gas in each experiment; tmax = maximum time needed to release vmax; ∆t = difference between initial and final temperatures of reaction medium in each experiment; δph = difference between initial and final ph of reaction medium in each experiment; sd = standard deviation; alp = aluminium phosphide; dw = distilled water; nd = not detected; nm = could not be measured; nc = not calculable. *significantly different from experiment 1 (p <0.01). †significantly different from experiment 2 (p <0.01). ‡significantly different from experiment 5 (p <0.01). §significantly different from experiment 1 (p <0.01). ¶significantly different from experiment 2 (p <0.01). \\gas evolution was too rapid and small to be detected. motahareh soltani, seyed f. shetab-boushehri and seyed v. shetab-boushehri clinical and basic research | e307 p orbital, boric acid seems to adequately fulfil this theory.1 the possibility of a reaction between ph3 and boric acid forming an adduct of h3p-b(oh)3 has been recently proposed; in this theoretical reaction, ph3, as a nucleophile and lewis base, neutralises boric acid, as an electrophile and lewis acid, and a h3p-b(oh)3 adduct is formed.1 one alp tablet was predicted to produce approximately 392.0 ml of total gas in 200 ml of dw at 20 °c and 101.325 kpa.4 however, in the present study, one alp tablet produced less total gas in 200 ml of dw and acidic dw, respectively, at 37 °c and 101.325 kpa. this may be due to the incompleteness of this reaction at these conditions. the results also showed that activated charcoal significantly reduced the volume of released gas from alp tablets. previous studies have shown that activated charcoal is a universal antidote which adsorbs many poisons as well as some gases; as such, it is often used in poisoning emergency centres for gastrointestinal decontamination.23–25 although it was expected that more gas would evolve in the saturated boric acid solution as the solubilities of co2 and nh3 in this solution are less than those in dw, this did not occur. it seems that boric acid reacts with these gases and traps them in solution.1,26 another explanation may be the production of less co2 and nh3 in this solution due to reduced water molecules around the alp tablet.1,26 to cytochrome c oxidase (e0 = +0.29 v) and interferes with electron transfer in the mitochondrial respiratory chain.10 theoretically, an electron acceptor stronger than cytochrome c oxidase can protect cytochrome c oxidase against ph3, which might prevent or reduce the inhibition of cellular respiration.10 with an empty figure 1a & b: infrared spectrum of (a) pure dry aluminium phosphide (alp) and (b) pure wet alp. note the weak peak at 2,280–2,440 cm-1 for the dry alp, which increased after wetting. figure 2a & b: infrared spectrum of (a) pure dry boric acid and (b) pure wet boric acid. note that no new peak is produced. figure 3a & b: infrared spectrum of (a) a 1:1 dry mixture of pure aluminium phosphide (alp) and pure boric acid and (b) a 1:1 wet mixture of pure alp and pure boric acid. note the three new peaks at 1,250 cm-1, 1,350 cm-1 and 1,440 cm-1 in the wet mixture. chemical reaction between boric acid and phosphine indicates boric acid as an antidote for aluminium phosphide poisoning e308 | squ medical journal, august 2016, volume 16, issue 3 in general, ph3 gas has two infrared peaks at between 950–1,250 cm-1 and 2,280–2,440 cm-1 which are related to the bending and stretching of the phosphorus-hydrogen bond.22 in the current study, pure wet alp showed a more intensified peak at 2,280–2,440 cm-1 than dry pure alp. this may be due to the production of more ph3 gas after wetting pure dry alp. the peak at 950–1,250 cm-1 related to the phosphorus-hydrogen bond bending of ph3 also seemed to be overlapped by the alp peak. for the 1:1 (w/w) mixture of pure alp and pure boric acid, an intensified peak at 2,280–2,440 cm-1 was noted for the wet mixture in comparison to the dry mixture; this seems to be due to an overlap of a boric acid peak in this region with that of ph3. the production of three new peaks after wetting the dry mixture strongly suggests the formation of a new chemical product. along with this infrared spectroscopic data, the gentler slope of the gas evolution rate curve in the boric acid solution suggests the formation of a gaseous adduct during the reaction between ph3 and boric acid, which is comparable to the reaction of ph3 and bcl3 and subsequent production of a h3p-bcl3 adduct. 22 the reaction product of alp (ph3) and boric acid in the present study had very similar infrared spectroscopic absorption peaks (in the region of 1,250–1,450 cm-1) to the reaction product of ph3 and bcl3, indicating the formation of a phosphorous-boron bond.22 in addition, the authors of the current study found that breaking the alp tablet into fragments reduced ph3 gas evolution in comparison to an equiweight unfragmented alp tablet, with more fragments producing less ph3 gas. however, the powdered form of the alp tablet produced too little gas which the gas-collecting assembly was unable to collect and hence the data were not presented. this greatly reduced production of gas may be due to the surface chemistry of alp tablets and may also explain why reduced mortality and fewer systemic effects have been reported among individuals who have ingested fragmented or powdered forms of alp.2,27,28 in nearly all animal studies, the alp tablet is administered by gastric gavage in powdered form in a carrier such as peanut oil, almond oil or normal saline;15,16,29 this method of poisoning may therefore be incorrect because fragmentation or powdering interferes with ph3 gas evolution. thus, examining oral alp poisoning in animal studies is very difficult; instead, it is recommended that the animals be poisoned by ph3 gas. in addition, alp tablets contain ammonium carbamate which produces nh3 and co2 gasses when in contact with water;4 these gasses also interfere with the results of alp poisoning studies and should subsequently be excluded. it has been previously shown that ingestion of alp in as low a dose as 150–500 mg is lethal to human beings.2 these amounts are equivalent to 49.3–164.2 mg of ph3 gas. therefore, 150–500 mg of alp was deemed approximately equivalent to 26–87 ml of gas in the acidic environment of the stomach, at 37 °c and under 101.325 kpa. according to the current study, the approximate time needed for the production of a lethal volume of ph3 gas was 6.5–21 minutes. as such, the optimal or ‘golden’ time period to save a poisoned human seems to be up to 20 minutes post-ingestion of 150–500 mg of alp, which is a very short time frame to ensure that the patient receives an antidote. after this, a lethal amount of ph3 is released and absorbed and it is unlikely that any therapy will be effective. treatment should therefore comprise emergency oral administration of activated charcoal during this ‘golden’ time period. the present study indicates that boric acid may be a new antidote for alp poisoning; however, extensive in vivo studies are needed to confirm its effectiveness in animals and humans. overall, the current study showed that although saturated boric acid solution did not significantly reduce the volume of released gas in comparison to dw, acidified saturated boric acid solution significantly reduced the volume of released gas in comparison to acidified dw. these results, along with a higher rate of gas evolution in the former solution and infrared spectroscopic data, indicate the formation of a gaseous product with a stronger hydrogen bond in acidic boric acid than in boric acid. this suggests that this gaseous product has a high vapour pressure. a limitation of the current study was that neither the volume of ph3 consumed nor the amount of product produced was measured; these should be taken into account during future research. conclusion the results of this study indicate that ph3 reacts with boric acid and produces a gaseous adduct. the approximate time needed for the production of a lethal volume of ph3 gas was 6.5–21 minutes. activated charcoal significantly reduced the volume of released gas. these findings suggest that alp-poisoned individuals should be treated with emergency oral administration of activated charcoal during a ‘golden’ time period of up to 20 minutes post-ingestion for adsorption of released ph3 and the prevention of further ph3 absorption. the present study indicates that boric acid may be a new antidote for alp poisoning, although further research is needed to confirm its effectiveness. motahareh soltani, seyed f. shetab-boushehri and seyed v. shetab-boushehri clinical and basic research | e309 15. baeeri m, shariatpanahi m, baghaei a, ghasemi-niri sf, mohammadi h, mohammadirad a, et al. on the benefit of magnetic magnesium nanocarrier in cardiovascular toxicity of aluminum phosphide. toxicol ind health 2013; 29:126–35. doi: 10.1177/0748233711425074. 16. saidi h, shojaie s. effect of sweet almond oil on survival rate and plasma cholinesterase activity of aluminum phosphideintoxicated rats. hum exp toxicol 2012; 31:518–22. doi: 10.1177/0960327111407229. 17. soltaninejad k, nelson ls, khodakarim n, dadvar z, shadnia s. unusual complication of aluminum phosphide poisoning: development of hemolysis and methemoglobinemia and its successful treatment. indian j crit care med 2011; 15:117–19. doi: 10.4103/0972-5229.83021. 18. bajwa sj, bajwa sk, kaur j, singh k, panda a. management of celphos poisoning with a novel intervention: a ray of hope in the darkest of clouds. anesth essays res 2010; 4:20–4. doi: 10.4103/0259-1162.69301. 19. siddaiah l, adhyapak s, jaydev s, shetty g, varghese k, patil c, et al. intra-aortic balloon pump in toxic myocarditis due to aluminum phosphide poisoning. j med toxicol 2009; 5:80–3. doi: 10.1007/bf03161093. 20. mittra s, peshin ss, lall sb. cholinesterase inhibition by aluminium phosphide poisoning in rats and effects of atropine and pralidoxime chloride. acta pharmacol sin 2001; 22:37–9. 21. dueñas a, pérez-castrillon jl, cobos ma, herreros v. treatment of the cardiovascular manifestations of phosphine poisoning with trimetazidine, a new antiischemic drug. am j emerg med 1999; 17:219–20. doi: 10.1016/s07356757(99)90075-x. 22. tierney pa, lewis dw, berg d. some physical properties of boron trichloride-phosphine. j inorg nucl chem 1962; 24:1163–9. doi: 10.1016/0022-1902(62)80263-2. 23. olson kr. activated charcoal for acute poisoning: one toxicologist’s journey. j med toxicol 2010; 6:190–8. doi: 10.1007 /s13181-010-0046-1. 24. mohammad-khah a, ansari r. activated charcoal: preparation, characterization and applications: a review article. int j chemtech res 2009; 1:859–64. 25. bond gr. the role of activated charcoal and gastric emptying in gastrointestinal decontamination: a state-of-the-art review. ann emerg med 2002; 39:273–86. doi: 10.1067/mem.2002. 122058. 26. guo d, thee h, da silva g, chen j, fei w, kentish s, et al. borate-catalyzed carbon dioxide hydration via the carbonic anhydrase mechanism. environ sci technol 2011; 45:4802–7. doi: 10.1021/es200590m. 27. chugh sn, arora v, kaur s, sood ak. toxicity of exposed aluminium phosphide. j assoc physicians india 1993; 41:569–70. 28. verma rk, gupta sn, bahl dv, gupta a. aluminium phosphide poisoning: late presentation as oesophageal stricture. jk sci 2006; 8:235–6. 29. dua r, kumar v, sunkaria a, gill kd. altered glucose homeostasis in response to aluminium phosphide induced cellular oxygen deficit in rat. indian j exp biol 2010; 48:722–30. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. soltani m, shetab-boushehri sf, mohammadi h, shetabboushehri sv. proposing boric acid as an antidote for aluminium phosphide poisoning by investigation of the chemical reaction between boric acid and phosphine. j med hypotheses ideas 2013; 7:21–4. doi: 10.1016/j.jmhi.2012.11.001. 2. moghadamnia aa. an update on toxicology of aluminum phosphide. daru 2012; 20:25. doi: 10.1186/2008-2231-20-25. 3. bumbrah gs, krishan k, kanchan t, sharma m, sodhi gs. phosphide poisoning: a review of literature. forensic sci int 2012; 214:1–6. doi: 10.1016/j.forsciint.2011.06.018. 4. mehrpour o, jafarzadeh m, abdollahi m. a systematic review of aluminium phosphide poisoning. arh hig rada toksikol 2012; 63:61–73. doi: 10.2478/10004-1254-63-2012-2182. 5. akkaoui m, achour s, abidi k, himdi b, madani a, zeggwagh aa, et al. reversible myocardial injury associated with aluminum phosphide poisoning. clin toxicol (phila) 2007; 45:728–31. doi: 10.1080/15563650701517350. 6. chugh sn, ram s, mehta lk, arora bb, malhotra kc. adult respiratory distress syndrome following aluminium phosphide ingestion: report of 4 cases. j assoc physicians india 1989; 37:271–2. 7. saleki s, ardalan fa, javidan-nejad a. liver histopathology of fatal phosphine poisoning. forensic sci int 2007; 166:190–3. doi: 10.1016/j.forsciint.2006.05.033. 8. chhina rs, thukral r, chawla ls. aluminum phosphideinduced gastroduodenitis. gastrointest endosc 1992; 38:635–6. doi: 10.1016/s0016-5107(92)70546-x. 9. mehrpour o, alfred s, shadnia s, keyler de, soltaninejad k, chalaki n, et al. hyperglycemia in acute aluminum phosphide poisoning as a potential prognostic factor. hum exp toxicol 2008; 27:591–5. doi: 10.1177/0960327108096382. 10. solgi r, abdollahi m. proposing an antidote for poisonous phosphine in view of mitochondrial electrochemistry facts. j med hypotheses ideas 2012; 6:32–4. doi: 10.1016/j. jmhi.2012.03.011. 11. nath ns, bhattacharya i, tuck ag, schlipalius di, ebert pr. mechanisms of phosphine toxicity. j toxicol 2011; 2011:494168. doi: 10.1155/2011/494168. 12. mehrpour o, farzaneh e, abdollahi m. successful treatment of aluminum phosphide poisoning with digoxin: a case report and review of literature. int j pharmacol 2011; 7:761–4. doi: 10.3923/ijp.2011.761.764. 13. azad a, lall sb, mittra s. effect of n-acetylcysteine and l-name on aluminium phosphide induced cardiovascular toxicity in rats. acta pharmacol sin 2001; 22:298–304. 14. saidi h, shokraneh f, ghafouri hb, shojaie s. effects of hyperbaric oxygenation on survival time of aluminum phosphide intoxicated rats. j res med sci 2011; 16:1306–12. http://dx.doi.org/10.1177/0748233711425074 http://dx.doi.org/10.1177/0960327111407229 http://dx.doi.org/10.4103/0972-5229.83021 http://dx.doi.org/10.4103/0259-1162.69301 http://dx.doi.org/10.1007/bf03161093 http://dx.doi.org/10.1016/s0735-6757%2899%2990075-x http://dx.doi.org/10.1016/s0735-6757%2899%2990075-x http://dx.doi.org/10.1016/0022-1902%2862%2980263-2 http://dx.doi.org/10.1007/s13181-010-0046-1 http://dx.doi.org/10.1007/s13181-010-0046-1 http://dx.doi.org/10.1067/mem.2002.122058 http://dx.doi.org/10.1067/mem.2002.122058 http://dx.doi.org/10.1021/es200590m http://dx.doi.org/10.1016/j.jmhi.2012.11.001 http://dx.doi.org/10.1186/2008-2231-20-25 http://dx.doi.org/10.1016/j.forsciint.2011.06.018 http://dx.doi.org/10.2478/10004-1254-63-2012-2182 http://dx.doi.org/10.1080/15563650701517350 http://dx.doi.org/10.1016/j.forsciint.2006.05.033 http://dx.doi.org/10.1016/s0016-5107%2892%2970546-x http://dx.doi.org/10.1177/0960327108096382 http://dx.doi.org/10.1016/j.jmhi.2012.03.011 http://dx.doi.org/10.1016/j.jmhi.2012.03.011 http://dx.doi.org/10.1155/2011/494168 http://dx.doi.org/10.3923/ijp.2011.761.764 department of dermatology & venereology, virgen de las nieves hospital, granada, spain *corresponding author e-mail: gonzaloblascomorente@gmail.com املليساء املعدية على اجللد املوشوم جونزالو بال�سكو-مورينتى، ماريا خو�سيه ناراجن-دياز، اإ�رسائيل برييز-لوبيز، اأنطونيو مارتينيز لوبيز، كري�ستينا غاريدو-كوملينريو molluscum contagiosum over tattooed skin *gonzalo blasco-morente, maria jose naranjo-díaz, israel pérez-lópez, antonio martínez-lópez, cristina garrido-colmenero a 33-year-old spanish male presented to the department of dermatology & venereology at the virgen de las nieves hospital, granada, spain, in february 2015 with pruritic skin lesions located over a tattoo on his right arm. the tattoo had been completed three months earlier without protective measures by the patient’s friend at his home. at presentation, the patient was not suffering from any known illnesses. a physical examination showed several pearled papules of 0.3–0.5 cm located over the tattoo [figure 1a]. the papules were umbilicated and occurred over the lines of the tattoo [figure 1b]. biochemical tests and a haemogram were normal. serology for hepatitis b and c, human immunodeficiency virus (hiv) and syphilis was negative. the patient was diagnosed with molluscum contagiosum (mc) and treated with curettage, with a subsequent healing time of three weeks. figure 1a & b: a: photograph showing several pearled molluscum contagiosum papules of 0.3–0.5 cm (arrows) located over a tattoo on the arm of a 33-year-old male patient. b: dermoscopic image showing the umbilicated papules occurring on the inked lines of the tattoo. interesting medical image sultan qaboos university med j, may 2016, vol. 16, iss. 2, pp. 257–258, epub. 15 may 16 submitted 23 jul 15 revision req. 16 sep 15; revision recd. 3 oct 15 accepted 29 oct 15 doi: 10.18295/squmj.2016.16.02.022 molluscum contagiosum over tattooed skin 258 | squ medical journal, may 2016, volume 16, issue 2 however, these conditions were not detected in the current patient. the differential diagnosis for mc includes common warts, condylomata acuminata and granulomatous or inflammatory reactions, such as lichen planus, lichenoid reactions or cutaneous lupus erythematosus-like reactions.1,2,4 deep fungal infections should also be excluded in immunocompromised patients as they can have a similar presentation.3 to confirm a diagnosis of mc, a skin biopsy should be performed.2 treatment options include curettage, cryotherapy, topical keratolytics, topical potassium hydroxide and imiquimod.2,4 otherwise, papules may spontaneously resolve in certain cases.4 references 1. molina l, romiti r. molluscum contagiosum on tattoo. an bras dermatol 2011; 86:352–4. doi: 10.1590/s0365-0596201100 0200022. 2. grillo e, urech m, vano-galvan s, jaén p. lesions on tattooed skin: a case study. aust fam physician 2012; 41:308–9. 3. de giorgi v, grazzini m, lotti t. a three-dimensional tattoo: molluscum contagiosum. cmaj 2010; 182:e382. doi: 10.1503/ cmaj.091480. 4. ruiz-villaverde r, sánchez-cano d. pearled papules over tattoo: molluscum cotagiosum. pan afr med j 2013; 16:49. doi: 10.11604/pamj.2013.16.49.3442. 5. thappa dm. the isomorphic phenomenon of koebner. indian j dermatol venereol leprol 2004; 70:187–9. comment mc is an infection caused by a virus of the poxviridae family; it occurs commonly in children although only occasionally in adults.1,2 it presents as small, umbilicated, rose-coloured pearly papules generally located on the trunk and within body folds.2 on certain occasions, mc may occur over tattoos in the form of a pseudo-koebner phenomenon, affecting the ink lines weeks after the tattoo’s completion.1‒4 the koebner or isomorphic phenomenon occurs when identical clinical and histological lesions develop on traumatised uninvolved areas of skin among patients who already have cutaneous diseases such as psoriasis, vitiligo or lichen planus.2,5 when these lesions develop with infections such as mc, it is deemed a pseudo-koebner phenomenon.2,5 in the present case, the patient’s tattoo was performed at home by an unqualified tattoo artist; it is very likely that the instruments used were not sterilised which would have increased the risk of secondary infections. the mc virus may have been transmitted via instruments used during the tattooing process or through contaminated ink.2 furthermore, black pigment has been suggested to reduce cellular and humoural immunity.1 syphilis, atypical mycobacteria, hepatitis, hiv, tuberculosis and viral warts may potentially be transmitted during the application of a tattoo.2 http://dx.doi.org/10.1590/s0365-05962011000200022 http://dx.doi.org/10.1590/s0365-05962011000200022 http://dx.doi.org/10.1503/cmaj.091480 http://dx.doi.org/10.1503/cmaj.091480 http://dx.doi.org/10.11604/pamj.2013.16.49.3442 جدل يف األورام سنية املنشأ مراجعة بوجا �سوا�ص، تابيا جوي، جادي�ص توبكاري، اأرو�ص ثاكر abstract: odontogenic tumours are lesions that occur solely within the oral cavity and are so named because of their origin from the odontogenic (i.e. tooth-forming) apparatus. odontogenic tumours comprise a variety of lesions ranging from non-neoplastic tissue proliferations to benign or malignant neoplasms. however, controversies exist regarding the pathogenesis, categorisation and clinical and histological variations of these tumours. the recent 2017 world health organization classification of odontogenic tumours included new entities such as primordial odontogenic tumours, sclerosing odontogenic carcinomas and odontogenic carcinosarcomas, while eliminating several previously included entities like keratocystic odontogenic tumours and calcifying cystic odonogenic tumours. the aim of the present review article was to discuss controversies and recent concepts regarding odontogenic tumours so as to increase understanding of these lesions. keywords: neoplasms; oral cavity; odontogenic tumors; hamartomas; classification; world health organization. امللخ�ص: االأورام �سنية املن�ساأ هي اآفات حتدث بالتحديد يف جوف الفم وح�سب الت�سمية تن�ساأ من اخلاليا املن�ساأة لالأ�سنان. ت�سم االأورام �سنية املن�ساأ على العديد من االآفات ترتاوح من تكاثر االأن�سجة غري ال�رصطانية اإىل االأورام احلميدة واخلبيثة. على الرغم من هذا، توجد اإختالفات يف االإمرا�ص والت�سنيف والتنوع االأكلينيكي واملجهري لهذه االأورام. �سمل الت�سنيف اجلديد 2017 لالأورام �سنية املن�ساأ ملنظمة ال�سحة العاملية على كيانات جديدة مثل اأورام اأولية �سنية املن�ساأ، �رصطانات م�سلبة �سنية املن�ساأ، و�ساركومة �رصطانية �سنية املن�ساأ، مع اإ�ستبعاد العديد من الكيانات املدرجة �سابقا كاأورام الكي�سة الكرياتينية �سنية املن�ساأ واالأورام الكي�سية املكل�سة �سنية املن�ساأ. تهدف هذه املراجعة اإىل مناق�سة هذه االإختالفات واملفاهيم احلديثة املتعلقة باالأورام �سنية املن�ساأ لزيادة فهم هذه االأورام. الكلمات املفتاحية: اأورام؛ جوف الفم؛ اأورام �سنية املن�ساأ؛ اأورام عابية؛ ت�سنيف؛ منظمة ال�سحة العاملية. controversies in odontogenic tumours review *pooja siwach, tabita joy, jagdish tupkari, arush thakur review sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e268–276, epub. 10 oct 17 submitted 8 feb 17 revisions req. 15 mar & 1 may 17; revisions recd. 12 apr & 8 may 17 accepted 25 may 17 doi: 10.18295/squmj.2017.17.03.003 many lesions, both intraosseous and extraosseous, can involve the maxillary and mandibular regions of the jaw; of these, odontogenic tumours are unique to the oral cavity and do not occur elsewhere in the body. these tumours originate from tissues involved in odontogenesis (i.e. tooth development) and include a wide variety of lesions ranging from hamartomas to non-neoplastic tissue proliferations and both benign and malignant neoplasms.1,2 due to this wide range of biological behaviour, there is currently much debate regarding the pathogenesis, classification and clinical and histological variations of odontogenic tumours.1 the present review aimed to provide insight into different controversies and recent developments in this field, particularly with regards to the recent 2017 world health organization (who) classification of odontogenic tumours.2 awareness of such controversies may aid in a better understanding of these pathological entities as well as enhancing their diagnosis and management. a brief overview of the main controversies associated with different odontogenic lesions is shown in table 1. classification odontogenic lesions were first classified by broca in 1868.3 in 1971, the who included these lesions in its first histological classification of such tumours and provided the clinicopathological criteria necessary for diagnosis.1 due to subsequent advancements in diagnostic immunohistochemistry, molecular biology and genetics, as well as clinical and epidemiological follow-up, modifications were made to the previous 2005 who classification in 2017 wherein some lesions were newly added, removed or reclassified; in addition, attempts were made to simplify the classification system, discarding subtypes or suffixes that lacked clinical relevance.2,4,5 table 2 provides a summary of the entities which were either newly included or excluded from the who 2017 classification.2,4 department of oral pathology & microbiology, government dental college & hospital, mumbai, maharashtra, india *corresponding author e-mail: poojasiwach127@gmail.com pooja siwach, tabita joy, jagdish tupkari and arush thakur review | e269 nevertheless, researchers have argued that classifying odontogenic tumours as either benign or malignant does not encompass the reported range of behaviours shown by these lesions.6 as such, classifying these lesions in a manner similar to the who bone and soft tissue tumour classification—with the addition of intermediate (locally aggressive) and intermediate (rarely metastasising) categories—may be more appropriate.6,7 in 2016, singh et al. proposed a classification for odontogenic tumours based on histopathological patterns; unfortunately, some of the classified lesions had overlapping histological features, thus limiting their diagnostic utility.8 the current review article categorises benign odontogenic lesions as either epithelial, mixed or mesenchymal lesions while malignant lesions are divided into carcinomas, sarcomas and carcinosarcomas. benign epithelial odontogenic tumours due to their odontogenic potential, oral epithelial tissues may give rise to epithelial odontogenic tumours. these tumours can originate from the remnants of odontogenic epithelia such as reduced enamel epithelium and the respective epithelial cell rests of malassez and serres.9 table 1: key controversies in the pathogenesis, categorisation and clinical and histological variations of odontogenic tumours entity controversy benign epithelial odontogenic tumours peripheral ameloblastoma this lesion may be either a hamartoma or a benign neoplasm peripheral ameloblastomas and intraoral basal cell carcinomas these may be separate entities or variants of the same entity calcifying epithelial odontogenic tumour the biochemical nature and origin of the amyloid-like material in this lesion is not yet understood keratocystic odontogenic tumour/ odontogenic keratocyst there is debate as to whether this lesion is a cyst or tumour adenomatoid odontogenic tumour this lesion may be either a hamartoma, cyst or neoplasm squamous odontogenic tumour this lesion may be either a hamartoma or a neoplasm benign mixed epithelial and mesenchymal odontogenic tumours complex and compound odontomas there seems to be little clinical relevance in distinguishing these lesions as two separate entities ameloblastic fibroma both a neoplastic and hamartomatous line of development have been proposed for this entity primordial odontogenic tumour there is doubt as to whether this is a new entity or a variant of ameloblastic fibromas, odontogenic fibromas or myxomas calcifying cystic odontogenic tumour/ calcifying odontogenic cyst this lesion may be either a cyst or a tumour benign mesenchymal odontogenic tumours odontogenic fibroma there is doubt regarding the subcategorisation of this entity into epithelium-rich and epithelium-poor variants odontogenic myxoma there is controversy regarding the pathogenesis of this lesion and whether it is truly odontogenic in nature cementoblastoma this lesion may have either an odontogenic or osteogenic origin cemento-ossifying fibroma this lesion may have either an odontogenic or fibro-osseous nature malignant odontogenic tumours clear cell odontogenic carcinomas and clear cell ameloblastomas these may be separate entities or variants of the same entity ghost cell odontogenic carcinoma there is doubt as to whether the presence of ghost cells would cause malignancy sclerosing odontogenic carcinoma there is as yet no confirmation of the metastatic potential of this lesion odontogenic carcinosarcoma the existence of this lesion is questionable controversies in odontogenic tumours review e270 | squ medical journal, august 2017, volume 17, issue 3 a m e l o b l a s t o m a in the categorisation of conventional ameloblastomas in the 2017 who classification, solid/multicystic adjectives were eliminated as they were deemed to have no biological implications and could be confused with unicystic ameloblastomas.4 desmoplastic ameloblastomas, which had been sub-categorised under ameloblastomas in the previous 2005 who classification, were also removed as they were considered a histological variant similar to conventional ameloblastomas.4,5 metastasising amelo blastomas were reclassified as benign tumours rather than malignant odontogenic tumours as these tumours show benign histopathology in spite of their metastatic potential, rendering them difficult to differentiate histo pathologically from conventional ameloblastomas.2 based on the innocuous nature of peripheral ameloblastomas (pas), philipsen et al. questioned whether such lesions were analogous to solid multicystic ameloblastomas (smas) or hamartomatous lesions.10 indeed, the biological behaviour of a pa has been deemed more indicative of a hamartomatous proliferation or persistent hyperplasia than neoplasia.11 marx et al. defined a pa as a hamartomatous proliferation of odontogenic epithelia arising from the rests of serres or perhaps from the basal cells of the oral mucosa.12 however, the occurrence of intraoral basal cell carcinomas (bccs) in the mucous membranes or tooth-bearing areas is not accepted by some investigators; thus, debate exists as to whether bccs and pas actually represent two distinct entities or the same lesion.13 in spite of many histological similarities between pas and bccs, reichart et al. and sciubba have claimed that pas deserved to be recognised as a separate entity.9,14 in addition, brierley et al. believed that while pas may resemble bccs histopathologically, a distinction was possible using immunohistochemical stains for berep4 and cytokeratin (ck) 19.6 c a l c i f y i n g e p i t h e l i a l o d o n t o g e n i c t u m o u r to date, the biochemical mechanism and the origin of amyloid material in calcifying epithelial odontogenic tumours (ceots) is still unknown. immunohistochemical and electron microscope research has suggested a possible degenerative process involving ck intermediate filaments in tumour cells, while other investigators consider that the degeneration of type iv collagen associated with the basement membrane is responsible for amyloid derivation.15 murphy et al. determined through immunological and chemical analysis that amyloid associated with ceots is formed by the n-terminal fragments of a 153-residue protein coded by exons 5–10 of the odontogenic ameloblast-associated protein; this protein, along with green birefringent congophilic material, was detected in unerupted tooth follicles.16 k e r at o c y s t i c o d o n t o g e n i c t u m o u r/o d o n t o g e n i c k e r at o c y s t the renaming of odontogenic keratocysts (okcs) as keratocystic odontogenic tumours (kcots) has been one of the most controversial changes in the nomenclature of odontogenic lesions in recent years.17 this entity shows characteristics of both a cyst and a benign tumour and differs from other odontogenic cysts due to the appearance of mural growth with proliferation of the lining into the cancellous bone, instead of centripetal growth and expansion; thus, such lesions may reach a considerable size before the bony expansion becomes clinically apparent. furthermore, the high recurrence rate suggests the aggressive table 2: summary of lesions either newly excluded, included or recategorised in the 2017 world health organization classification of odontogenic tumours2,3 lesion reason entities excluded keratocystic odontogenic tumour now considered an odontogenic cyst and renamed odontogenic keratocyst calcifying cystic odontogenic tumour now considered an odontogenic cyst and renamed calcifying odontogenic cyst primary intraosseous squamous cell carcinoma now considered a primary intraosseous carcinoma ameloblastic fibrodentinoma and ameloblastic fibroodontoma now grouped together under the category of ameloblastic fibroma and no longer considered separate entities newer entities included primordial odontogenic tumour this previously undescribed entity has been newly included as an odontogenic tumour following evidence that the periphery of the lesion resembles that of inner enamel epithelia (i.e. primordial epithelia) sclerosing odontogenic carcinoma this tumour has been proposed to be a distinct entity from other odontogenic carcinomas due to its hyalinized or sclerosing stroma odontogenic carcinosarcoma new research has reconfirmed the existence of this lesion cemento-ossifying fibroma this lesion has been included due to its exclusive occurrence within tooth-bearing areas and probable periodontal origin changes in category metastasising ameloblastoma this lesion has been recategorised as benign due to its benign histopathology pooja siwach, tabita joy, jagdish tupkari and arush thakur review | e271 behaviour and inherent potential for growth of this lesion.18 however, the association of kcots/okcs with bccs in nevoid bcc syndrome, along with the fact that a subset of okcs have similar patched homolog (ptch) gene mutations to those found in bcc cases, is suggestive of a neoplastic nature.18 for this reason, in 2005 the who categorised okc as a benign odontogenic neoplasm and changed the nomenclature of okc to kcot.2 this classification was not fully accepted and many authors continued using the older terminology.12,19,20 nevertheless, although ptch gene alterations can be found in up to 85% of okcs associated with nevoid bcc syndrome, they are only found in 30% of sporadic cysts.21 in addition, such genetic alterations have been reported among several non-neoplastic lesions, including dentigerous and orthokeratinised odontogenic cysts, thus indicating that neoplasia cannot be defined on the basis of a single genetic event.21 these molecular/genetic alterations may influence the biological behaviour of okcs without the need to define the cyst as a neoplasm, particularly as the classification of a lesion as a cyst or tumour has a direct impact on its treatment.21,22 for example, cystic lesions require more conservative management than neoplasms; as such, most kcot/okc cases are treated using marsupialisation and enucleation rather than surgical resection so as to reduce morbidity.21 even extensive kcots respond to marsupialisation and may resolve completely, with the characteristic neoplastic epithelial lining being replaced by epithelia similar to oral mucosa.23 the resolution of such cysts following marsupialisation is not typical of neoplastic lesions.21 pogrel found that initial decompression of a kcot followed by aggressive curettage and peripheral ostectomy with methylene blue staining resulted in no recurrences of the lesion; however, the longest follow-up period in the study was only six years.23 similarly, leung et al. concluded that enucleation of kcots along with the application of carnoy’s solution resulted in comparatively low rates of surgical morbidity and recurrence.24 hence, these lesions were reclassified as cystic lesions rather than odontogenic tumours in the 2017 who classification.2,21 while both okcs and orthokeratinised odontogenic cysts are considered developmental cysts, okcs behave more aggressively.20 adenomatoid odontogenic tumour the true nature of adenomatoid odontogenic tumours (aots) has always been controversial, particularly as to whether these lesions should be considered hamartomatous growths, true benign neoplasms or cystic lesions. this may be due to difficulties regarding the precise definitions and overlapping features of hamartomas, cysts and cystic neoplasms.25 an aot is sometimes considered to be a hamartoma due to its limited size, occurrence at an early age (during the second decade of life) and lack of recurrence even following incomplete removal. however, the arrangement of odontogenic tissue within the lesional area is not in line with that of a developmental anomaly.25 researchers who consider aots to be non-aggressive non-invasive benign neoplasms claim that the limited size of most aot cases is due to the fact that they are detected early and removed before reaching a clinically-noticeable size.25 in contrast, marx et al. proposed that aots should not be considered tumours but cysts with a hamartomatous intraluminal proliferation of epithelial cells derived from the hertwig epithelial root sheath.12 however, rick stated that aots were benign embryonal neoplasms; he disagreed with the change in terminology as the majority of lesions have a predominantly solid component instead of a fluidfilled cavity.25 similarly, thakur et al. proposed that the term aot was most apt for this entity.26 a molecular study by razavi et al. showed that the ki-67 labelling index was lower in aots as compared to smas, signifying a hamartomatous nature.27 however, using a human androgen receptor gene polymorphism assay, gomes et al. found that aots are monoclonal and therefore neoplastic.28 s q u a m o u s o d o n t o g e n i c t u m o u r the 2005 who classification defined squamous odontogenic tumours (sots) as locally infiltrative neoplasms;5 however, marx et al. considered them to be a hamartomatous proliferation of mature epithelial cells probably arising from the epithelial cell rests of malassez.12 the occurrence of multicentric sots may also be indicative of a hamartomatous nature, with leider et al. reporting three cases of familial multicentric sots among siblings.29 benign mixed epithelial and mesenchymal odontogenic tumours as the name implies, these tumours are composed of both epithelial and mesenchymal tissue. o d o n t o m a philipsen et al. suggested that complex and compound odontomas be regarded as two separate entities; this position is in contrast to that of regezi et al., who suggested that the classification of complex and compound odontomas should be combined controversies in odontogenic tumours review e272 | squ medical journal, august 2017, volume 17, issue 3 for therapeutic reasons.30,31 nonetheless, as these entities differ in their relative frequency, location and radiographical presentation, their separation as two distinct entities seems to be justified, regardless of the fact that both types of odontoma are treated conservatively.9 cases of odontomas have shown microscopic features of both types; however, clinical data and histological evaluations will, in most cases, lead to a diagnosis of either a complex or compound odontoma.9 in general, however, there seems to be little clinical justification for differentiating these two entities. a m e l o b l a s t i c f i b r o m a in agreement with the 1992 who classification, philipsen et al. confirmed that ameloblastic fibromas (afs)—in particular, those 22.3% developing after the age of 20 years—are true benign neoplasms.30,32 additionally, afs which grow during the entire odontogenesis period of childhood and adolescence may represent non-neoplastic or hamartomatous lesions that develop into ameloblastic fibro-odontomas (afos) or odontomas. both afos and odontomas go through stages of mineralisation and calcification; none of them arise de novo as calcified lesions.9 on these grounds, philipsen et al. proposed some hypothetical theories on the pathogenesis and relationship between mixed odontogenic tumours and odontomas and suggested that both a neoplastic and hamartomatous line of development should be considered to explain how mixed odontogenic tumours are formed.30 as the histopathological appearance of an af in its neoplastic form is indistinguishable from that of a developing odontoma, buchner et al. recommended the use of clinical and radiological features in distinguishing these lesions.33 large expansile multilocular lesions that exhibit extensive bone destruction and cortical perforation in young individuals are more likely to be of a neoplastic nature, while asymptomatic small unilocular lesions in children, when they lie directly over the crown of an unerupted tooth with no or minimal expansion of bone, are likely to be developing odontomas.33 in the 2017 classification, the who ceased classifying ameloblastic fibrodentinomas and afos as separate entities, with only afs considered a separate entity.2 p r i m o r d i a l o d o n t o g e n i c t u m o u r mosqueda-taylor et al. reported six cases of a previously undescribed odontogenic tumour that presented as well-circumscribed pericoronal radiolucencies with a dentigerous relationship.34 microscopically, the tumour was composed of immature loose fibrous connective tissue resembling dental papillae and the periphery was lined by columnar or cuboidal epithelia resembling the inner enamel epithelium of a developing tooth.34 due to the unique clinical, radiographical, histopathological and immunohistochemical presentation of primordial odontogenic tumours, this entity was included in the 2017 who classification.2 however, ide et al. questioned the exact nature of this tumour, particularly as to whether it was truly a newly recognised embryonal tumour of immature dental tissue exhibiting neoplastic characteristics of progressive growth or merely an architectural morphological variant of an af or odontogenic fibroma (of)/dentigerous myxoma arising during active dental development.35 future case reports may shed more light on this new lesion. c a l c i f y i n g c y s t i c o d o n t o g e n i c t u m o u r/c a l c i f y i n g o d o n t o g e n i c c y s t calcifying odontogenic cysts (cocs) were first identified as a specific type of odontogenic lesion by gorlin et al.36 however, controversy has since arisen regarding the association between non-neoplastic cystic lesions and solid tumour masses with similar cellular and histomorphological features. the 1971 who classification described coc tumours as a non-neoplastic cystic lesion, while the description was updated to state that “most lesions appear to be non-neoplastic” in the 1992 edition.32,37 reichart et al. theorised that the lesion had been wrongly classified as an epithelial-ectomesenchymal lesion because the stroma was not characterised by ectomesenchyme, but rather by mature collagenous connective tissue.9 the nature of the dentinoid material produced in cocs has not been fully clarified; however, its production is probably not the outcome of true induction via a sequence of reciprocal epithelialectomesenchymal interactions but rather as a result of the metaplastic process.9 in 2005, the who grouped cocs with all of their variants as an odontogenic tumour rather than a cyst and defined it as a benign cystic neoplasm of odontogenic origin characterised by ameloblastoma-like epithelia with ghost cells that may calcify.12 dentinogenic ghost cell tumours were classified as a separate entity and defined as locally invasive neoplasms characterised by ameloblastomalike islands of epithelial cells in mature connective tissue stroma.5 however, in a multicentre review of ghost cell lesions, ledesma-montes et al. found that over 85% of calcifying cystic odontogenic tumours were simple cysts occurring either alone (65%) or in association with odontomas (20%); only a few lesions showed ameloblastomatous proliferations, with merely 5% pooja siwach, tabita joy, jagdish tupkari and arush thakur review | e273 of lesions found to be solid and described as true neoplastic dentinogenic ghost cell tumours.38 similar results were observed by hong et al., who found that lesions which presented as simple cysts rarely recurred and had a completely benign course.39 martin et al. proposed that simple cystic lesions should be considered developmental cysts that may arise alone or in association with other developmental lesions, such as odontomas, whereas solid lesions showing ameloblastomatous proliferations should be regarded as neoplasms due to their high recurrence rates.21 subsequently, the who reclassified dentinogenic ghost cell tumours as odontogenic tumours in 2017, while excluding cystic lesions such as cocs.2 benign mesenchymal odontogenic tumours these tumours are derived from mesenchymal tissue of dental origin, such as periodontal ligaments, dental papillae or dental follicles.9 o d o n t o g e n i c f i b r o m a due to their rarity and uncertainty regarding distinct types, ofs are often considered to be controversial.9 it is worth mentioning that the current widely accepted terms—simple type or who type/complex central ofs—were not used in either the first or second editions of the who classification; both terms were proposed by gardner.40 doyle et al. further recommended the term complex of as an alternative to who type of.41 in 2005, the who divided ofs according to two histological types of lesions: epithelium-poor (formerly termed simple type ofs) and epitheliumrich (formerly termed complex or who type ofs) lesions.5 in 2017, the who abandoned the epithelium-poor subtype as it was poorly defined and documented, with of instead described as “a rare neoplasm of mature fibrous connective tissue, with variable amounts of inactive-looking odontogenic epithelium with or without evidence of calcification”.4 o d o n t o g e n i c m y x o m a considerable confusion exists regarding the patho genesis of jaw myxomas and whether they are odontogenic (i.e. derived from odontogenic mesenchyme) or osteogenic (i.e. presumably derived from primitive bone tissue).19 while myxomas do occur in the long bones, they are rare and are thought to arise from the pluripotent mesenchymal stem cells. the jaws also contain a small population of non-odontogenic pluripotent mesenchymal stem cells that may generate myxomas.12,42 although it is as yet unproven, jaw myxomas are thought to originate from the odontogenic rather than somatic mesenchyme.12 on the other hand, myxomas have been reported in nonodontogenic sites, such as the sinonasal tract, facial bones, extracranial skeleton, upper ramus and the condyle of the mandible.42 according to johnson et al., true myxoid tissue is a specific fundamental primary tissue in humans and not merely an embryonic connective tissue as it performs many functions, is an essential component of the mucoperiosteum of the paranasal sinuses, cranial sutures and dental papillae and may also be responsible for the development of myxomas.43 subclassifying myxomas derived from the facial skeleton into odontogenic myxomas (oms) and true osteogenic myxomas may therefore better reflect their histogenesis.42 the dental papillae, dental follicles and periodontal tissues have been implicated as possible germ centres of oms.1 however, oms differ from dental papillae or dental follicle lesions due to differences in the amount and types of proteoglycan present. hyaluronic acid concentrations in oms have been found to be four times higher than other glycosaminoglycans, such as chondroitin sulphate.1 this finding is contrary to those of mesenchymal tissues from dental pulp, the gingivae and the periodontal ligament.1 adekeye et al. suggested that the characteristic histopathology of this neoplasm could be due to myxoid changes within a pre-existing mesenchymatous lesion or that it may represent a degenerative form of of.44 c e m e n t o b l a s t o m a cementoblastomas are considered the only true neoplasms of cemental (odontogenic) origin.9 however, some researchers have pointed out that the histopathological features of jaw cementoblastomas are identical to those of osteoblastomas.19 the only differentiating feature seems to be that a cementoblastoma is attached to the apex of a tooth and grows in an expansile pattern with radiating osteoid columns growing outwards.18,19 c e m e n t o-o s s i f y i n g f i b r o m a in the 2005 who classification, ossifying fibromas were incorporated under bone-related lesions; however, the 2017 who classification included this entity under the category of mesenchymal odontogenic tumours instead.2,5 this may be because their exclusive occurrence within the jaws and probable periodontal origin are suggestive of an odontogenic nature. despite the fact that definitions of cementum include its anatomical association with tooth roots, wright et al. proposed that cementoossifying fibroma was the best name for this entity because it is a well-understood term and laboratory controversies in odontogenic tumours review e274 | squ medical journal, august 2017, volume 17, issue 3 evidence indicates that periodontal ligament stem cells can produce both bone and cementum.22 morover, the term cemento-ossifying fibroma also emphasises that the lesion occurs exclusively within the tooth-bearing areas of the jaws. however, confusion may still arise when differentiating cemento-ossifying fibromas from ossifying fibromas of other bones. malignant odontogenic tumours these lesions are extremely rare as the majority of odontogenic tumours are either completely benign or only locally aggressive.22 o d o n t o g e n i c c a r c i n o m a in the 2017 who classification, carcinomas derived from the odontogenic epithelia have been categorised in a number of ways, including as ameloblastic carcinomas (acs), primary intraosseous carcinomas, sclerosing odontogenic carcinomas, clear-cell odontogenic carcinomas (ccocs) and odonto genic ghost cell carcinomas.2 metastasising ameloblastomas, which were previously considered to be malignant odontogenic neoplasms in the 2005 who classification, are now designated as benign odontogenic tumours (i.e. ameloblastomas).2,5 the practice of subtyping carcinomas as acs or primary intraosseous carcinomas has been abandoned as there seems to be no advantage to dividing these rare lesions.4 however, some researches have highlighted the difficulty in differentiating these two entities because of their overlapping histopathological and clinical features.22,45,46 c l e a r c e l l o d o n t o g e n i c c a r c i n o m a the existence of a relationship between clear-cell ameloblastomas (ccas) and ccocs is an interesting proposition which has yet to be fully elucidated. piattelli et al. were the first to postulate that ccocs are a distinct and separate entity of ameloblastomas and not simply a clear cell variant, whereas waldron et al. maintained that ccocs and ccas were part of the same histopathological spectrum.47,48 slater also regarded cca to be a synonym for ccoc, although reichart et al. believed that these lesions should be differentiated as two different entities based on their distinct demographic, clinical and histological features.9,49 future studies with large sample sizes may reveal whether these lesions should be viewed as separate entities or variants along a spectrum. o d o n t o g e n i c g h o s t c e l l c a r c i n o m a these lesions have been described in a variety of ways, including as malignant cocs, odontogenic ghost cell carcinomas, carcinomas arising in cocs, aggressive epithelial odontogenic ghost cell tumours, dentinogenic ghost cell ameloblastomas and malignant calcifying ghost cell odontogenic tumours.9 slater considered this entity to be a variant of an ac with evidence of ghost cell keratinisation.49 however, the mere presence of ghost cells does not necessarily dictate the biological behaviour of a lesion; prognosis is determined by the tissue that surrounds the ghost cells. for example, a benign lesion containing ghost cells will exhibit benign biological behaviour, while a carcinoma containing ghost cells will behave malignantly.49 s c l e r o s i n g o d o n t o g e n i c c a r c i n o m a these tumours were not included in the 2005 who classification of odontogenic carcinomas and were first proposed as a distinct entity by koutlas et al.5,50 the characteristic histopathology includes infiltrating ‘single file’ thin cords and strands of polyhedral neoplastic cells within a stroma of dense sclerosis. koutlas et al. described the tumour as having an odontogenic origin, as the immunohistochemical profile of the tumour cells exhibited positive ck markers (ck5/6, ck19 and weak ck7 stains).50 despite its bland cytological features, the tumour exhibits extensive local infiltrative growth into the muscles and nerves.51 this newer entity has been included in the 2017 who classification; however, metastasis has not been reported in any of the seven cases described to date.2,51 hence, further study of its biological behaviour is required to confirm its placement within the category of odontogenic carcinomas. o d o n t o g e n i c s a r c o m a the 2005 who classification made a distinction between odontogenic sarcomas with (i.e. amelo-blastic fibrodentinosarcomas and ameloblastic odonto sarcomas) and without (i.e. ameloblastic fibrosarcomas) formation of dental hard structures, which is useful when making a histopathological diagnosis.5 however, this concept has been questioned as the biological profile and prognosis of ameloblastic fibrodentinosarcomas, ameloblastic odontosarcomas and ameloblastic fibrosarcomas appear to be identical.52 in the 2017 who classification, only odontogenic sarcomas were mentioned, thereby simplifying this category.2 pooja siwach, tabita joy, jagdish tupkari and arush thakur review | e275 o d o n t o g e n i c c a r c i n o s a r c o m a this entity was excluded from the 2005 who classification as evidence supporting its inclusion was questionable; however, recent research has reconfirmed its existence and it was once again incorporated in the 2017 who classification.4,5,53–55 conclusion there are a number of controversies currently under debate within the field of odontogenic tumours, particularly regarding their nomenclature, incidence, pathogenesis and histopathological characteristics. it is hoped that the elucidation of key controversies and recent concepts regarding odontogenic tumours presented in this article may help to enhance the understanding, diagnosis and treatment of these unique lesions. references 1. mosqueda-taylor a. new findings and controversies in odontogenic tumors. med oral patol oral cir bucal 2008; 13:e555–8. 2. el-naggar ak, chan jk, grandis jr, takata t, slootweg pj, eds. who classification of head and neck tumours, 4th ed. lyon, france: iarc press, 2017. 3. broca p. [invesitgations into a new group of tumours known as odontomes]. gaz hebd sci med 1868; 5:70. 4. wright jm, vered m. update from the 4th edition of the world health organization classification of head and neck tumours: odontogenic and maxillofacial bone tumors. head neck pathol 2017; 11:68–77. doi: 10.1007/s12105-017-0794-1. 5. barnes l, eveson jw, reichart p, sidransky d, eds. who/iarc classification of tumors: pathology and genetics of head and neck tumours. lyon, france: iarc press, 2005. 6. brierley dj, hunter kd. odontogenic tumours. diagn histopathol 2015; 21:370–9. doi: 10.1016/j.mpdhp.2015.07.003. 7. fletcher cd, bridge ja, hogendoorn pc, mertens f, eds. who classification of tumours of soft tissue and bone, 4th ed. lyon, france: iarc press, 2013. 8. singh e, pujari rk, murgod s, girish hc. odontogenic tumour patterns: an introspective analysis. br j med med res 2016; 11:1–17. doi: 10.9734/bjmmr/2016/20162. 9. reichart pa, philipsen hp. odontogenic tumors and allied lesions. london, uk: quintessence publishing co. inc., 2004. pp. 25–270. 10. philipsen hp, reichart pa, nikai h, takata t, kudo y. peripheral ameloblastoma: biological profile based on 160 cases from the literature. oral oncol 2001; 37:17–27. doi: 10.1016/s1368-8375 (00)00064-6. 11. reichart pa, philipsen hp, sonner s. ameloblastoma: biological profile of 3677 cases. eur j cancer b oral oncol 1995; 31:86–99. doi: 10.1016/0964-1955(94)00037-5. 12. marx re, stern d. oral and maxillofacial pathology: a rationale for diagnosis and treatment, 2nd ed. chicago, illinois, usa: quintessence publishing co. inc., 2012. pp. 667–717. 13. curran ae. peripheral odontogenic tumours. oral maxillofacial surg clin north am 2004; 16:399–408. doi: 10.1016/j.coms.2004.03.008. 14. sciubba jj. discussion: peripheral ameloblastoma a clinical and histologic study of 11 cases. j oral maxillofac surg 1991; 49:974–5. doi: 10.1016/0278-2391(91)90062-q. 15. goode rk. calcifying epithelial odontogenic tumor. oral maxillofac surg clin north am 2004; 16:323–31. doi: 10.1016/j. coms.2004.03.002. 16. murphy cl, kestler dp, foster js, wang s, macy sd, kennel sj, et al. odontogenic ameloblast-associated protein nature of the amyloid found in calcifying epithelial odontogenic tumors and unerupted tooth follicles. amyloid 2008; 15:89–95. doi: 10.1080/ 13506120802005965. 17. morgan pr. odontogenic tumors: a review. periodontol 2000 2011; 57:160–76. doi: 10.1111/j.1600-0757.2011.00393.x. 18. jordan rc, speight pm. current concepts of odontogenic tumours. diagn histopathol 2009; 15:303–10. doi: 10.1016/j.mp dhp.2009.03.002. 19. neville bw, damm dd, allen cm, bouquot je. oral and maxillofacial pathology, 3rd ed. philadelphia, pennsylvania, usa: saunders, 2008. pp. 678–740. 20. shear m, speight pm. cysts of the oral and maxillofacial regions, 4th ed. singapore: wiley-blackwell, 2007. pp. 6–58. 21. martin l, speight pm. odontogenic cysts. diagn histopathol 2015; 21:359–69. doi: 10.1016/j.mpdhp.2015.07.005. 22. wright jm, odell ew, speight pm, takata t. odontogenic tumors, who 2005: where do we go from here? head neck pathol 2014; 8:373–82. doi: 10.1007/s12105-014-0585-x. 23. pogrel ma. the keratocystic odontogenic tumour (kcot): an odyssey. int j oral maxillofac surg 2015; 44:1565–8. doi: 10. 1016/j.ijom.2015.03.008. 24. leung yy, lau sl, tsoi ky, ma hl, ng cl. results of the treatment of keratocystic odontogenic tumours using enucleation and treatment of the residual bony defect with carnoy’s solution. int j oral maxillofac surg 2016; 45:1154–8. doi: 10.1016/j.ijom.2016.02.002. 25. rick gm. adenomatoid odontogenic tumor. oral maxillofac surg clin north am 2004; 16:333–54. doi: 10.1016/j.coms.20 04.04.001. 26. thakur a, tupkari jv, joy t, hanchate av. adenomatoid odontogenic tumor: what is the true nature? med hypotheses 2016; 97:90–3. doi: 10.1016/j.mehy.2016.10.024. 27. razavi sm, tabatabaie sh, hoseini at, hoseini et, khabazian a. a comparative immunohistochemical study of ki-67 and bcl-2 expression in solid ameloblastoma and adenomatoid odontogenic tumor. dent res j (isfahan) 2012; 9:192–7. 28. gomes cc, oliveira cda s, castro wh, de lacerda jc, gomez rs. clonal nature of odontogenic tumours. j oral pathol med 2009; 38:397–400. doi: 10.1111/j.1600-0714.2008.00744.x. 29. leider as, jonker la, cook he. multicentric familial squamous odontogenic tumor. oral surg oral med oral pathol 1989; 68:175–81. doi: 10.1016/0030-4220(89)90189-8. 30. philipsen hp, reichart pa, praetorius f. mixed odontogenic tumours and odontomas: considerations on interrelationship review of the literature and presentation of 134 new cases of odontomas. oral oncol 1997; 33:86–99. doi: 10.1016/s09641955(96)00067-x. 31. regezi ja, kerr da, courtney rm. odontogenic tumors: analysis of 706 cases. j oral surg 1978; 36:771–8. 32. kramer ir, pindborg jj, shear m, eds. histological typing of odontogenic tumours, 2nd ed. berlin, germany: springerverlag, 1992. 33. buchner a, vered m. ameloblastic fibroma: a stage in the development of a hamartomatous odontoma or a true neoplasm? critical analysis of 162 previously reported cases plus 10 new cases. oral surg oral med oral pathol oral radiol 2013; 116:598–606. doi: 10.1016/j.oooo.2013.06.039. https://doi.org/10.1007/s12105-017-0794-1 https://doi.org/10.1016/j.mpdhp.2015.07.003 https://doi.org/10.9734/bjmmr/2016/20162 https://doi.org/10.1016/s1368-8375%2800%2900064-6 https://doi.org/10.1016/s1368-8375%2800%2900064-6 https://doi.org/10.1016/0964-1955%2894%2900037-5 https://doi.org/10.1016/j.coms.2004.03.008 https://doi.org/10.1016/0278-2391%2891%2990062-q https://doi.org/10.1016/j.coms.2004.03.002 https://doi.org/10.1016/j.coms.2004.03.002 https://doi.org/10.1080/13506120802005965 https://doi.org/10.1080/13506120802005965 https://doi.org/10.1111/j.1600-0757.2011.00393.x https://doi.org/10.1016/j.mpdhp.2009.03.002 https://doi.org/10.1016/j.mpdhp.2009.03.002 https://doi.org/10.1016/j.mpdhp.2015.07.005 https://doi.org/10.1007/s12105-014-0585-x https://doi.org/10.1016/j.ijom.2015.03.008 https://doi.org/10.1016/j.ijom.2015.03.008 https://doi.org/10.1016/j.ijom.2016.02.002 https://doi.org/10.1016/j.coms.2004.04.001 https://doi.org/10.1016/j.coms.2004.04.001 https://doi.org/10.1016/j.mehy.2016.10.024 https://doi.org/10.1111/j.1600-0714.2008.00744.x https://doi.org/10.1016/0030-4220%2889%2990189-8 https://doi.org/10.1016/s0964-1955%2896%2900067-x https://doi.org/10.1016/s0964-1955%2896%2900067-x https://doi.org/10.1016/j.oooo.2013.06.039 controversies in odontogenic tumours review e276 | squ medical journal, august 2017, volume 17, issue 3 34. mosqueda-taylor a, pires fr, aguirre-urízar jm, carlosbregni r, de la piedra-garza jm, martínez-conde r, et al. primordial odontogenic tumour: clinicopathological analysis of six cases of a previously undescribed entity. histopathology 2014; 65:606–12. doi: 10.1111/his.12451. 35. ide f, kikuchi k, kusama k, muramatsu t. primordial odontogenic tumour: is it truly novel? histopathology 2015; 66:603–4. doi: 10.1111/his.12595. 36. gorlin rj, pindborg jj, redman as, williamson jj, hansen ls. the calcifying odontogenic cyst: a new entity and possible analogue of the cutaneous epithelioma of malherbe. cancer 1964; 17:723–9. doi: 10.1002/1097-0142(196406)17:6<723::aidcncr2820170606>3.0.co;2-a. 37. pindborq jj, kramer ir, eds. histological typing of odontogenic tumours, jaw cysts and allied lesions. berlin, germany: springer-verlag, 1971. 38. ledesma-montes c, gorlin rj, shear m, prae torius f, mosqueda-taylor a, altini m, et al. international collaborative study on ghost cell odontogenic tumours: calcifying cystic odontogenic tumour, dentinogenic ghost cell tumour and ghost cell odontogenic carcinoma. j oral pathol med 2008; 37:302–8. doi: 10.1111/j.1600-0714.2007.00623.x. 39. hong sp, ellis gl, hartman ks. calcifying odontogenic cyst: a review of ninety-two cases with reevaluation of their nature as cysts or neoplasms, the nature of ghost cells, and subclassification. oral surg oral med oral pathol 1991; 72:56–64. doi: 10.1016/0030-4220(91)90190-n. 40. gardner dg. the central odontogenic fibroma: an attempt at classification. oral surg oral med oral pathol oral radiol 1980; 50:425–32. doi: 10.1016/s0030-4220(80)80011-9. 41. doyle jl, lamster ib, baden e. odontogenic fibroma of the complex (who) type: report of six cases. j oral maxillofac surg 1985; 43:666–74. doi: 10.1016/0278-2391(85)90191-0. 42. brannon rb. central odontogenic fibroma, myxoma (odontogenic myxoma, fibromyxoma), and central odontogenic granular cell tumor. oral maxillofac surg clin north am 2004; 16:359–74. doi: 10.1016/j.coms.2004.03.004. 43. johnson lc, yousefi m, vinh tn, heffner dk, hyams vj, hartman ks. juvenile active ossifying fibroma: its nature, dynamics, and origin. acta otolaryngol suppl 1991; 488:1–40. 44. adekeye eo, avery bs, edwards mb, williams hk. advanced central myxoma of the jaws in nigeria: clinical features, treatment and pathogenesis. int j oral surg 1984; 13:177–86. doi: 10.1016/s0300-9785(84)80001-0. 45. corio rl, goldblatt li, edwards pa, hartman ks. ameloblastic carcinoma: a clinicopathologic study and assessment of eight cases. oral surg oral med oral pathol 1987; 64:570–6. doi: 10. 1016/0030-4220(87)90063-6. 46. bruce ra, jackson it. ameloblastic carcinoma: report of an aggressive case and review of the literature. j craniomaxillofac surg 1991; 19:267–71. doi: 10.1016/s1010-5182(05)80068-x. 47. piattelli a, sesenna e, trisi p. clear cell odontogenic carcinoma: report of a case with lymph node and pulmonary metastases. eur j cancer b oral oncol 1994; 30b:278–80. doi: 10.1016/09 64-1955(94)90010-8. 48. waldron ca, small ia, silverman h. clear cell ameloblastoma: an odontogenic carcinoma. j oral maxillofac surg 1985; 43:707–17. doi: 10.1016/0278-2391(85)90198-3. 49. slater lj. odontogenic malignancies. oral maxillofac surg clin north am 2004; 16:409–24. doi: 10.1016/j.coms.2004.03.009. 50. koutlas ig, allen cm, warnock gr, manivel jc. sclerosing odontogenic carcinoma: a previously unreported variant of a locally aggressive odontogenic neoplasm without apparent meta static potential. am j surg pathol 2008; 32:1613–19. doi: 10.1097 /pas.0b013e31817a8a58. 51. richardson ms, muller s. malignant odontogenic tumors: an update on selected tumors. head neck pathol 2014; 8:411–20. doi: 10.1007/s12105-014-0584-y. 52. altini m, thompson sh, lownie jf, berezowski bb. ameloblastic sarcoma of the mandible. j oral maxillofac surg 1985; 43:789–94. doi: 10.1016/0278-2391(85)90336-2. 53. kunkel m, ghalibafian m, radner h, reichert te, fischer b, wanger w. ameloblastic fibrosarcoma or odontogenic carcinosarcoma: a matter of classification? oral oncol 2004; 40:444–9. doi: 10.1016/j.oraloncology.2003.09.010. 54. slater lj. odontogenic sarcoma and carcinosarcoma. semin diagn pathol 1999; 16:325–32. 55. delair d, bejarano pa, peleg m, el-mofty sk. ameloblastic carcinosarcoma of the mandible arising in ameloblastic fibroma: a case report and review of the literature. oral surg oral med oral pathol oral radiol endod 2007; 103:516–20. doi: 10.1016 /j.tripleo.2006.02.025. https://doi.org/10.1111/his.12451 https://doi.org/10.1111/his.12595 https://doi.org/10.1002/1097-0142%28196406%2917:6%3c723::aid-cncr2820170606%3e3.0.co%3b2-a https://doi.org/10.1002/1097-0142%28196406%2917:6%3c723::aid-cncr2820170606%3e3.0.co%3b2-a https://doi.org/10.1111/j.1600-0714.2007.00623.x https://doi.org/10.1016/0030-4220%2891%2990190-n https://doi.org/10.1016/s0030-4220%2880%2980011-9 https://doi.org/10.1016/0278-2391%2885%2990191-0 https://doi.org/10.1016/j.coms.2004.03.004 https://doi.org/10.1016/s0300-9785%2884%2980001-0 https://doi.org/10.1016/0030-4220%2887%2990063-6 https://doi.org/10.1016/0030-4220%2887%2990063-6 https://doi.org/10.1016/s1010-5182%2805%2980068-x https://doi.org/10.1016/0964-1955%2894%2990010-8 https://doi.org/10.1016/0964-1955%2894%2990010-8 https://doi.org/10.1016/0278-2391%2885%2990198-3 https://doi.org/10.1016/j.coms.2004.03.009 https://doi.org/10.1097/pas.0b013e31817a8a58 https://doi.org/10.1097/pas.0b013e31817a8a58 https://doi.org/10.1007/s12105-014-0584-y https://doi.org/10.1016/0278-2391%2885%2990336-2 https://doi.org/10.1016/j.oraloncology.2003.09.010 https://doi.org/10.1016/j.tripleo.2006.02.025 https://doi.org/10.1016/j.tripleo.2006.02.025 1department of adult health nursing, ibra nursing institute, ibra, oman; 2school of nursing, widener university, chester, pennsylvania, usa *corresponding author’s e-mail: mohammed.almaskari20@gmail.com االجتاهات حنو و التصورات لتنفيذ املمارسات القائمة على األدلة بني املمرضات العمانيات حممد عامر امل�شكري و باربرة باتر�شون abstract: objectives: this study aimed to explore the attitudes of omani nurses towards evidence-based practice (ebp) and their perceptions of the barriers to and facilitators of ebp implementation in oman. in addition, the attitudes and perceptions of nurse leaders and staff nurses were compared. methods: this descriptive cross-sectional study was conducted between august and october 2016 in three suburban governmental hospitals in northern oman. a demographic questionnaire and two ebp instruments were used to collect data from 282 registered omani nurses, including the evidence-based nursing attitude questionnaire and the developing evidence-based practice questionnaire. results: a total of 260 omani nurses took part in the study (response rate: 92.2%). on the whole, the nurses had positive attitudes towards ebp, with no significant difference in mean attitude scores per item between staff nurses and nurse leaders (3.98 ± 0.46 versus 4.03 ± 0.50; p = 0.431). however, in comparison to staff nurses, nurse leaders had higher scores per item for the barriers to changing practice and finding and reviewing evidence subsections, with lower scores for the facilitators to changing practice section. conclusion: in accordance with the international literature, omani nurses had positive attitudes towards ebp as well as similar perceptions of barriers and facilitators to ebp implementation. these findings may help to inform recommendations for the integration of ebp in educational programmes and clinical settings in oman, as well as to facilitate necessary changes in nursing practice. keywords: evidence-based practice; nurses; attitudes; perceptions; oman. عن وت�شوراتهم الأدلة على القائمة املمار�شة من العمانيات املمر�شات مواقف ا�شتك�شاف اإىل الدرا�شة هذه هدفت الهدف: امللخ�ص: العوائق واملي�رسات لتنفيذ املمار�شة القائمة على الأدلة يف عمان. بالإ�شافة اإىل ذلك، متت مقارنة املواقف واملفاهيم من قادة املمر�شات واملمر�شات املوظفني. الطريقة: اأجريت هذه الدرا�شة الو�شفية امل�شتعر�شة بني اأغ�شط�ص واأكتوبر 2016 يف ثالثة م�شت�شفيات حكومية يف ممر�شة 282 من البيانات جلمع الأدلة على القائمة املمار�شة اأدوات من واثنان الدميوغرايف ال�شتبيان ا�شُتخدم عمان. �شمال �شواحي �شارك عمانية م�شجلة، مبا يف ذلك ا�شتبيان �شلوك التمري�ص القائم على الأدلة وا�شتبيان تطوير املمار�شة امل�شتندة اإىل الأدلة. النتائج: ما جمموعه 260 ممر�شة عمانية يف الدرا�شة )معدل ال�شتجابة: %92.2(. على العموم، كان للممر�شات مواقف اإيجابية جتاه املمار�شة املمر�شات وقادة التمري�شية الهيئة اأع�شاء بني عن�رس لكل املوقف درجات متو�شط يف كبري فرق وجود عدم مع الأدلة، على القائمة )0.46 ± 3.98 مقابل 0.50 ± 4.03؛ p = 0.431(. ومع ذلك، باملقارنة مع اأع�شاء الهيئة التمري�شية، ح�شل قادة املمر�شات على درجات املي�رسين للم�شوؤولني الدرجات انخفا�ص مع الأدلة، ومراجعة واإيجاد املمار�شة تغيري دون حتول التي للعوائق بالن�شبة بند لكل اأعلى الأدلة على القائمة املمار�شة جتاه اإيجابية مواقف العمانيات للممر�شات كان الدولية، لالأدبيات بالتوافق اخلال�صة: املمار�شة. لتغيري وكذلك ت�شورات مماثلة عن احلواجز واملي�رسات لتنفيذ املمار�شة القائمة على الأدلة. قد ت�شاعد هذه النتائج يف اإبالغ التو�شيات اخلا�شة بتكامل برنامج املمار�شة القائمة على الأدلة يف الربامج التعليمية والإعدادات ال�رسيرية يف ُعمان، وكذلك لت�شهيل التغيريات ال�رسورية يف ممار�شة التمري�ص. الكلمات املفتاحية: املمار�شة القائمة على الأدلة؛ املمر�شات؛ الجتاهات؛ الت�شورات؛ عمان. attitudes towards and perceptions regarding the implementation of evidence-based practice among omani nurses *mohammed a. al-maskari1 and barbara j. patterson2 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e344–349, epub. 19 dec 18 submitted 7 feb 18 revisions req. 18 feb & 3 apr 18; revisions recd. 25 feb & 30 apr 18 accepted 24 may 18 advances in knowledge this study demonstrates that there is a need to explore factors that may act as barriers to or facilitators for the implementation of evidence-based practice (ebp) in oman. recommendations are suggested to facilitate the adoption of ebp and improve the quality of nursing practice in oman. application to patient care the integration of ebp in nursing education and clinical practice may improve the quality of nursing care provided to patients and, ultimately, positively influence patient outcomes. doi: 10.18295/squmj.2018.18.03.013 mohammed a. al-maskari and barbara j. patterson clinical and basic research | e345 evidence-based practice (ebp) is a problemsolving approach to the delivery of healthcare that seeks to integrate the best available evidence from existing research with clinician expertise and patient preferences.1,2 in this way, patients can receive the highest quality of care and achieve the best outcomes. for nurses, ebp is considered an effective way of enhancing confidence in clinical decision-making.2–4 additionally, ebp can enhance clinical judgment, keep nurses’ knowledge up-to-date and increase the accountability of healthcare workers.5–8 nevertheless, despite the significant benefits of ebp, many factors may act as barriers to the implementation of ebp, with some researchers arguing that the global application of ebp continues to advance slowly for these reasons.9 as in other middle eastern countries, nurses in oman face many challenges when implementing ebp, including a lack of time and resources, high workload volume and the lack of authority to make changes in current practice.10,11 the ministry of health (moh) in oman has recognised the significance of implementing ebp in clinical settings and has provided multiple work shops and in-service training programmes for nurses; however, many nurses still lack essential knowledge and skills for ebp implementation.11 to the best of the authors’ knowledge, only one previous study has documented the attitudes of nurses working in oman towards the implementation of ebp.11 this study therefore aimed to explore the attitudes of omani nurses towards the implementation of ebp and their perceptions of barriers to and facilitators of ebp implementation. in addition, this study aimed to compare differences in the attitudes and perceptions of omani nurse leaders and staff nurses as these individuals hold key roles in the provision of high-quality nursing care. methods this descriptive cross-sectional study was conducted between august and october 2016. a convenience sample was recruited of omani nurses working in three suburban governmental hospitals in northern oman. all registered full-time nurses with two or more years’ experience and who could speak, read and write english fluently were included in the study. however, nurses with less than two years of experience and who were not omani nationals were excluded. subjects were classified as nurse leaders based on their role, at least six months of leadership experience and job title (i.e. nurse-in-charge, nurse manager or head of a unit). the nurses were recruited from all hospital units, including medical/surgical units, paediatric/maternity units, crit ical care, administration, staff development and infection control departments and outpatient clinics. a power analysis, based on a medium effect size of 0.50, a twotailed p value of ≤0.050, and a power of 0.80, was cond ucted; according to this calculation, the required sample size was 128 participants. a demographic questionnaire and two ebp tools were used for data collection. all instruments were administered in english. the demographic questionnaire consisted of 11 items including age, gender, job title, level of education, years of nursing leadership experience, work setting and their prior experience of ebp in nursing education, continuing education and in the workplace. subsequently, the evidence-based nursing attitude questionnaire (ebnaq) was used to measure nurses’ attitude towards ebp in light of its clear and concise language and relevance to nursing practice.12 this tool consists of 15 items grouped into three dim ensions (cognitive, affective and behavioural). responses were scored on a five-point likert scale, ranging from one for ‘strongly disagree’ to five for ‘strongly agree’.12 finally, the developing evidence-based practice (debp) questionnaire was used to measure barriers and facilitators of ebp.13 the debp tool consists of 49 items categorised into five sections: (1) bases of practice knowl edge; (2) barriers to finding and reviewing evidence; (3) barriers to changing practice on the basis of evidence; (4) facilitation and support in changing practice; and (5) skills in finding and reviewing evidence. responses were scored on a five-point likert scale, with items scored differently in each section. for the first section, one indicated ‘never’ and five ‘always’, while one denoted ‘strongly agree’ and five ‘strongly disagree’ in sections two, three and four and one was ‘complete beginner’ and five ‘expert’ in the final section.13 for the purposes of this study, cronbach’s alpha values indicated good reliability for various subsections of the ebnaq and debp [table 1]. introductory sessions to introduce nurses to the study were conducted at each hospital; these sessions were also used as a tool to answer any questions from potential subjects. in addition, flyers were distributed to all hospital units. both the introductory sessions and the flyers included information regarding the study, such as the inclusion and exclusion criteria, directions on how to complete the questionnaires, the distribution and coll ection procedures of the questionnaires and the contact information of the researchers. after the flyers were distributed, subjects were approached and invited to participate in the study. a total of 282 questionnaires were distributed. the statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa), was used for data analysis. descriptive and inferential attitudes towards and perceptions regarding the implementation of evidence-based practice among omani nurses e346 | squ medical journal, august 2018, volume 18, issue 3 statistics were used to analyse the findings. an indep endent t-test was used to compare differences in the mean attitude scores of nurse leaders and staff nurses, as well as differences in barriers to finding and reviewing evidence (e.g. insufficient resources, insufficient time at work and lack of authority to implement change in practice), barriers to changing practice (e.g. insufficient time to find research reports, lack of confidence and difficulty understanding research reports) and facilitators to changing practice (e.g. support from nursing colleagues, nurse managers and doctors). additional analyses using pearson’s correlation coefficient were conducted to deter mine correlations with age, gender, years of nursing experience and ebp variables. a p value of ≤0.050 was deemed statistically significant. this study received ethical approval from the institutional review board of the moh (#mh/dgp/ r&s/21/2016). all data were anonymised and kept confidential and participation was voluntary in nature. in addition, information about the aims and procedures of the study, the estimated time to complete the quest ionnaire and the rights of the participants was provided to all subjects. table 1: reliability of the evidence-based nursing attitude questionnaire12 and developing evidence-based practice questionnaire13 among omani staff nurses and nurse leaders at three hospitals in northern oman (n = 260) instrument subsection cronbach’s alpha coefficient nurse leaders (n = 98) staff nurses (n = 162) ebnaq 0.84 0.82 beliefs and expectations towards ebp 0.72 0.81 intention of conduct towards ebp 0.51 0.45 feelings towards ebp 0.78 0.62 debp knowledge of ebp 0.83 0.89 barriers to finding and reviewing evidence 0.79 0.81 barriers to changing practice 0.65 0.72 facilitators to changing practice 0.81 0.82 skills in finding and reviewing evidence 0.86 0.91 ebnaq = evidence-based nursing attitude questionnaire; ebp = evid ence-based practice; debp = developing evidence-based practice quest ionnaire. table 2: demographic characteristics of omani staff nurses and nurse leaders at three hospitals in northern oman (n = 260) characteristic n (%) total nurse leaders (n = 98) staff nurses (n = 162) gender male 45 (17.3) 21 (21.4) 24 (14.8) female 215 (82.7) 77 (78.6) 138 (85.2) age in years mean ± sd 32.7 ± 4.7 35.0 ± 5.0 30.4 ± 4.5 range 24−50 24−50 24−43 job title nurse incharge 74 (28.5) 74 (75.5) 0 (0) nurse supervisor 3 (1.2) 3 (3.1) 0 (0) unit nurse 17 (6.5) 17 (17.3) 0 (0) head of nursing 4 (1.5) 4 (4.1) 0 (0) staff nurse 162 (62.3) 0 (0) 162 (100) education level diploma 159 (61.2) 51 (52) 108 (66.7) specialised diploma 58 (22.3) 33 (33.7) 25 (15.4) bachelor’s degree 42 (16.2) 14 (14.3) 28 (17.3) master’s degree 1 (0.4) 0 (0) 1 (0.6) prior exposure to ebp in nursing education no 17 (6.5) 6 (6.1) 11 (6.8) yes 184 (70.8) 67 (68.4) 117 (72.2) unsure 59 (22.7) 25 (25.5) 34 (21) prior exposure to ebp at cne activities* no 114 (43.8) 30 (30.6) 84 (51.9) yes 146 (56.2) 68 (69.4) 78 (48.1) prior implementation of ebp at work no 34 (13.1) 9 (9.2) 25 (15.4) sometimes 181 (69.6) 75 (76.5) 106 (65.4) always 18 (6.9) 9 (9.2) 9 (5.6) unsure 27 (10.4) 5 (5.1) 22 (13.6) sd = standard deviation; ebp = evidence-based practice; cne = continuous nursing education. *previous attendance at ebp-related conferences, workshops or seminars. mohammed a. al-maskari and barbara j. patterson clinical and basic research | e347 results a total of 282 questionnaires were distributed, of which 269 were completed; however, nine questionnaires were excluded due to missing data. therefore, a total of 260 nurses were included in the analysis (response rate: 92.2%). of these, 162 (62%) were staff nurses and 98 (38%) were nurse leaders. the majority of the nurses were female (82.7%). most had a diploma in nursing (61.2%), with 22.3% holding a specialised degree in nursing and 16.2% a bachelor’s degree in nursing. only one nurse had a master’s degree in nursing (0.4%). although 70.8% of the subjects had learned about ebp during their nursing education, 6.5% had not and 22.7% could not remember. a total of 145 nurses (56.2%) had previously attended ebp-related conferences, workshops or seminars and 69.6% reported occasional implementation of ebp at their workplace [table 2]. overall, the omani nurses had positive attitudes towards ebp. there were no significant differences in mean score per item in the attitudes subsection between staff nurses and nurse leaders (p = 0.431). this was also the case for the barriers to changing practice and facilitators to changing practice subsections (p = 0.176 and 0.096, respectively). however, there was a significant difference in the mean score per item for the barriers to finding and reviewing evidence subsection (p = 0.015) [table 3]. there was no significant relationship between age, gender, years of nursing experience and ebp variables for either group. however, the groups differed significantly in terms of education level and their mean score per item in the attitude subsection (p <0.001) [table 4]. more over, nurses who had had prior exposure to ebp in nursing education and via cne sessions differed signif icantly in their overall attitudes towards ebp compared to those without prior exposure (p = 0.004 and 0.014, respectively). furthermore, there was a significant diff erence in the barriers to finding and reviewing evidence (p = 0.015), barriers to changing practice (p <0.001) and facilitators of ebp (p = 0.007) scores between nurses who did and those who did not report prior ebp implementation at their workplace. table 3: mean total scores and scores per item for attitudes towards evidence-based practice* and perceived barriers and facilitators† among omani staff nurses and nurse leaders at three hospitals in northern oman (n = 260) questionnaire section mean total score ± sd mean score per item ± sd p value nurse leaders (n = 98) staff nurses (n = 162) nurse leaders (n = 98) staff nurses (n = 162) attitudes towards ebp 60.40 ± 7.48 59.68 ± 6.91 4.03 ± 0.50 3.98 ± 0.46 0.431 barriers to changing practice 28.59 ± 5.59 26.85 ± 5.52 2.57 ± 0.62 2.45 ± 0.71 0.176 barriers to finding and reviewing evidence 12.84 ± 3.11 12.27 ± 3.57 2.86 ± 0.56 2.68 ± 0.55 0.015 facilitators to changing practice 10.41 ± 3.22 11.12 ± 3.38 2.60 ± 0.80 2.78 ± 0.84 0.096 sd = standard deviation; ebp = evidence-based practice. *self-assessed using the english-language 15-item evidence-based nursing attitude questionnaire.12 †self-assessed using the english-language 49-item developing evidence-based practice (debp) questionnaire.13 table 4: association between education level and mean score per item for attitudes towards evidence-based practice* and perceived barriers and facilitators† among omani staff nurses and nurse leaders at three hospitals in northern oman (n = 259)‡ questionnaire section mean score per item ± sd p value§ attitudes towards ebp diploma holders 3.88 ± 0.47 <0.001specialised diploma holders 4.16 ± 0.44 bachelor’s degree holders 4.20 ± 0.41 barriers to finding and reviewing evidence diploma holders 2.70 ± 0.53 0.092specialised diploma holders 2.79 ± 0.61 bachelor’s degree holders 2.90 ± 0.60 barriers to changing clinical practice diploma holders 2.47 ± 0.68 0.331specialised diploma holders 2.61 ± 0.68 bachelor’s degree holders 2.43 ± 0.66 facilitators to changing practice diploma holders 2.65 ± 0.81 0.198specialised diploma holders 2.78 ± 0.95 bachelor’s degree holders 2.89 ± 0.68 sd = standard deviation; ebp = evidence-based practice. *self-assessed using the english-language 15-item evidence-based nursing attitude questionnaire.12 †self-assessed using the englishlanguage 49-item developing evidence-based practice (debp) questionnaire.13 ‡excluding one nurse with a master’s degree. §using a one-way analysis of variance. attitudes towards and perceptions regarding the implementation of evidence-based practice among omani nurses e348 | squ medical journal, august 2018, volume 18, issue 3 discussion to the best of the authors’ knowledge, this is the second study to examine attitudes of omani nurses towards ebp and perceived barriers to ebp implementation.11 the present study had a high response rate, which may be due to three possible explanations. first, the omani culture incorporates a strong sense of community in which helpfulness is highly valued. second, there is a possibility that the nurses felt proud to be part of a research project and to play a role in advancing the nursing profession in oman. third, there may have been a perceived sense of obligation to participate despite the anonymous approach to data collection. nevertheless, the findings of this study add to the existing body of knowledge related to ebp implementation in oman and the importance of establishing appropriate nursing strategies in a clinical setting. this information could be of use in other countries which share similar cultures and nursing practices. additionally, the results of this study provide directions for future research aimed at optimising the implementation of ebp in oman, for example by integrating ebp modules into the pre-licensure nursing curricula. overall, the findings of the current study indic ated that the omani nurses held positive attitudes tow ards ebp. these findings are consistent with those of other studies conducted in both western and eastern countries.1,9,14–16 positive attitudes towards ebp are a good foundation for appropriate nursing strategies to be developed to promote its implementation in oman. however, the effect of frequent exposure to ebp work shops and training programmes and/or the hawthorne observer effect might have played a major role in influencing nurses’ attitudes towards ebp and increasing awareness of its significance in clinical settings.1,5 in recent years, the omani moh has conducted multiple workshops and training programmes for nurses to improve ebp-related knowledge and skills and to be consistent with the standards of international healthrelated organisations such as the quality and safety education for nurses institute. such factors may have played a role in promoting positive attitudes towards ebp. nurses in the present study had higher scores in the barriers to finding and reviewing evidence subsection compared to the barriers to and facilitators of changing practice sections. these findings are consistent with those of other studies, which found that nurses perceived barriers to finding and reviewing evidence to be more problematic than those relating to changing practice, mainly due to a lack of ebp knowledge/skills, time and resources.11,13 nurse leaders play an important role in ebp implementation by promoting a supportive environment as well as providing the necessary resources required for its successful application. additionally, nurse leaders can create policies and guidelines that promote ebp impl ementation as well as collaborate with experts to provide additional ebp training workshops for staff nurses. in accordance with previous studies, there was no significant difference in mean attitude scores between staff nurses and nurse leaders.6,9,10,14,15 however, nurse leaders had higher scores in the barriers to changing practice subsection and lower scores in the facilitators to changing practice section compared to staff nurses. this may have been due to a lack of ebp-related knowledge and skills among nurse leaders. alternatively, as nurse leaders are usually more experienced than staff nurses and may have a better understanding of the organisational context of their institution, they might simply recognise that they have limited resources for ebp implementation.1,9 in the current study, there was a significant difference between the two groups in terms of educational level and their ebp attitude scores, indicating that incr eased education levels had a positive effect on overall attitudes towards ebp. this is consistent with the results reported in other studies.1,10,11 this finding provides evidence for the importance of educational programmes for omani nurses which focus on promoting ebp knowl edge and skills. furthermore, understanding differences in the perceptions of ebp barriers and facilitators between staff nurses and nurse leaders may lead to targeted progr ammes for each group. the results of the current study should be interpreted in light of its limitations. a convenience sampling method was used to recruit participants from three hospitals in northern oman; as such, the findings may not be representative of nurses in other regions. therefore, it would be useful to conduct further research with a larger and more representative sample. also, as the instruments used in this study were disseminated in english, there was a potential risk that some subjects were not able to understand some of the items. however, the english-language ebnaq and debp instruments have high validity and reliability; additionally, the partic ipants underwent an english-language proficiency check as part of the inclusion and exclusion criteria.13,14 additionally, most of the cohort were diploma holders and would not have been prepared for ebp during their diploma; therefore, such nurses may perceive greater barriers towards its implementation. finally, since the responses to the questionnaires were based on self-reported data, the data may have been affected by response bias and/or the hawthorne observer effect. mohammed a. al-maskari and barbara j. patterson clinical and basic research | e349 conclusion both omani staff nurses and nurse leaders had positive attitudes towards ebp. the importance of nurse leaders in ebp implementation should not be underestimated, as such individuals may act as role models and play a key role in ensuring a supportive environment. the findings of this study may be useful in developing strategies to integrate ebp into the nursing curricula in oman, ultimately improving patient care outcomes. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. williamson km, almaskari m, lester z, maguire d. utilization of evidence-based practice knowledge, attitude, and skill of clin ical nurses in the planning of professional development programming. j nurses prof dev 2015; 31:73–80. doi: 10.1097/nnd. 0000000000000140. 2. melnyk bm, fineout-overholt e, gallagher-ford l, stillwell sb. evidence-based practice, step by step: sustaining evidence-based practice through organizational policies and an innovative model. am j nurs 2011; 111:57–60. doi: 10.1097/01.naj.0000405063. 97774.0e. 3. al hadid la, hasheesh ma, al momani m. validating a tool that explores factors influencing the adoption of principles of evidence-based practice. j nurs educ 2011; 50:681–7. doi: 10.39 28/01484834-20110930-03. 4. malik g, mckenna l, plummer v. perceived knowledge, skills, attitude and contextual factors affecting evidence-based prac tice among nurse educators, clinical coaches and nurse specialists. int j nurs pract 2015; 21:46–57. doi: 10.1111/ijn.12366. 5. melnyk bm, fineout-overholt e. evidence-based practice in nursing & healthcare: a guide to best practice, 2nd ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2010. pp. 3–39. 6. facchiano l, snyder ch. evidence-based practice for the busy nurse practitioner: part one: relevance to clinical practice and clinical inquiry process. j am acad nurs pract 2012; 24:579–86. doi: 10.1111/j.1745-7599.2012.00748.x. 7. upton d, upton p, scurlock-evans l. the reach, transferability, and impact of the evidence-based practice questionnaire: a methodological and narrative literature review. worldviews evid based nurs 2014; 11:46–54. doi: 10.1111/wvn.12019. 8. varaei s, salsali m, cheraghi ma. implementation of evidencebased nursing practice for diabetic patients: an iranian experience. int j nurs pract 2013; 19:73–80. doi: 10.1111/ijn.12170. 9. melnyk bm, gallagher-ford l, long le, fineout-overholt e. the establishment of evidence-based practice competencies for practicing registered nurses and advanced practice nurses in real-world clinical settings: proficiencies to improve healthcare quality, reliability, patient outcomes, and costs. worldviews evid based nurs 2014; 11:5–15. doi: 10.1111/wvn.12021. 10. adib-hajbaghery m. evidence-based practice: iranian nurses’ perceptions. worldviews evid based nurs 2009; 6:93–101. doi: 10.1111/j.1741-6787.2009.00149.x. 11. ammouri aa, raddaha aa, dsouza p, geethakrishnan r, noronha ja, obeidat aa, et al. evidence-based practice: know ledge, attitudes, practice and perceived barriers among nurses in oman. sultan qaboos univ med j 2014; 14:e537−45. 12. ruzafa-martínez m, lópez-iborra l, madrigal-torres m. attitude towards evidence-based nursing questionnaire: development and psychometric testing in spanish community nurses. j eval clin pract 2011; 17:664–70. doi: 10.1111/j.1365-2753.2011.01677.x. 13. gerrish k, ashworth p, lacey a, bailey j. developing evidencebased practice: experiences of senior and junior clinical nurses. j adv nurs 2008; 62:62–73. doi: 10.1111/j.1365-2648.2007.04579.x. 14. ez elarab hs, el salam sa, behalik sg, eltayeb he. nurses’ practice, knowledge and attitude towards evidence-based practice at yanbu general hospital, kingdom of saudi arabia. life sci j 2012; 9:1062–71. 15. gallagher-ford l. the influence of nurse leaders and nurse educators on registered nurses’ evidence-based practice. phd. thesis, 2012, widener university, chester, pennsylvania, usa. 16. linton mj, prasun ma. evidence-based practice: collaboration between education and nursing management. j nurs manag 2013; 21:5–16. doi: 10.1111/j.1365-2834.2012.01440.x. https://doi.org/10.1097/nnd.0000000000000140 https://doi.org/10.1097/nnd.0000000000000140 https://doi.org/10.1097/01.naj.0000405063.97774.0e https://doi.org/10.1097/01.naj.0000405063.97774.0e https://doi.org/10.3928/01484834-20110930-03 https://doi.org/10.3928/01484834-20110930-03 https://doi.org/10.1111/ijn.12366 https://doi.org/10.1111/j.1745-7599.2012.00748.x https://doi.org/10.1111/wvn.12019 https://doi.org/10.1111/ijn.12170 https://doi.org/10.1111/wvn.12021 https://doi.org/10.1111/j.1741-6787.2009.00149.x https://doi.org/10.1111/j.1365-2753.2011.01677.x https://doi.org/10.1111/j.1365-2648.2007.04579.x https://doi.org/10.1111/j.1365-2834.2012.01440.x a hypercoagulable state has been desc-ribed in patients with tuberculosis (tb), with a reported incidence of deep vein thrombosis (dvt) in 3−4% of adults with pulmonary tb.1,2 how ever, cases of extrapulmonary tb complicated by thrombotic events are rare and only two cases of childhood abdominal tb complicated by dvt have been previously described in the literature.3,4 moreover, tb complicated by cerebral venous thrombosis is very rarely reported.5 to the best of the authors’ knowledge, this is the first report of a case of childhood tb with intracranial sinus thrombosis. case report a 13-year-old female presented to the department of pediatrics at the postgraduate institute of medical sciences in rohtak, india, in 2012 with a five-month history of intermittent fever and pain in the abdomen. the fever was of a low-to-moderate grade and became more pronounced in the evening, while the abdominal pain was diffuse and moderate in intensity. there was a history of reduced appetite and a documented weight loss of 14 kg over the previous five months. the patient had no history of contact with known cases of tb. she had been immunised with the bacillus calmetteguérin vaccine at birth. at presentation, the patient was pale and emaciated. her weight was 24 kg and her height was 124 cm (both values below the 3rd centile for her age). the abdomen was distended with tenderness in the right iliac fossa and a palpable lump. the liver was non-tender with a span of 10 cm. the results of blood investigations were as follows: haemoglobin count of 6.7 g/dl; leukocyte count of 7,000/mm3; differential of 60% polymorphs and 36% lymphocytes; platelet count of 250,000/mm3; a dimorphic blood picture with predominantly microcytic anaemia; and an erythrocyte sedimentation rate of 50 mm/hour. her mantoux test result with 5 tuberculin units was 18 mm/72 hours. liver and renal function tests were normal and a human immunodeficiency virus department of pediatrics, postgraduate institute of medical sciences, rohtak, haryana, india *corresponding author e-mail: drpoonam12@yahoo.com حالة خثار وريدي عميق وخثار جييب داخل القحف مضاعفات نادرة ممكنة يف حالة السل البطين عند الطفولة جيت� ج�تواثال, بون�م دلل, فرييندر جيالوات, ج��شرب �شينج, ف�ندان� اأري� abstract: severe pulmonary tuberculosis (tb) complicated by deep vein thrombosis (dvt) in adults has been reported previously in the medical literature; however, childhood extrapulmonary tb complicated by dvt is rare. we report a 13-year-old girl who presented to the department of pediatrics at the postgraduate institute of medical sciences in rohtak, india, in 2012 with abdominal tb complicated by dvt and intracranial sinus thrombosis. she was treated with a course of four antitubercular drugs and short-term anticoagulation therapy with a positive outcome over the next six months. to the best of the authors’ knowledge, no previous reports have yet suggested a possible association between childhood tb and intracranial sinus thrombosis. keywords: deep vein thrombosis; intracranial sinus thrombosis; gastrointestinal tuberculosis; case report; india. امللخ�ص: ذكرت الأدبي�ت الطبية ت�شجيل ح�لت �شل رئوي وخيمة, حدثت فيه� م�ش�عف�ت خث�ر وريدي عميق. غري اأن ح�لت ال�شل غري الرئوي عند الأطف�ل التي حتدث م�ش�عف�ت خث�ر وريدي عميق هي ن�درة احلدوث. نعر�س هن� ح�لة طفلة يف الث�لثة ع�رسة من العمر عر�شت لق�شم الأطف�ل مبعهد الدرا�ش�ت الطبية العلي� يف روت�ك ب�لهند يف ع�م 2012. وك�نت م�ش�به ب�شل بطني وم�ش�عف�ت خث�ر وريدي عميق مع خث�ر جيبي داخل القحف. ومت عالج الطفلة ب�أربعة اأنواع من اأدوية عالج ال�شل ب�لإظ�فة لعالج التخرث ملدة ق�شرية. وك�نت نتيجة العالج يف ال�شهور ال�شتة التي اأعقبت العالج اإيج�بية. وبح�شب علم موؤلفى هذا التقرير, مل يتم ت�شجيل اأي ارتب�ط �ش�بق بني مر�س ال�شل عند الأطف�ل واخلث�ر اجليبي داخل القحف يف الأدبي�ت الطبية. الكلمات املفتاحية: خث�ر وريدي عميق؛ خث�ر جيبي داخل القحف؛ �شل معدي معوي؛ ت�شجيل ح�لة؛ الهند. a case of deep vein thrombosis and intracranial sinus thrombosis possible rare complications of childhood abdominal tuberculosis geeta gathwala, *poonam dalal, virender gehlawat, jasbir singh, vandana arya case report sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e516–519, epub. 30 nov 16 submitted 20 apr 16 revisions req. 17 may & 23 jun 16; revisions recd. 11 & 28 jun 16 accepted 19 jul 16 doi: 10.18295/squmj.2016.16.04.021 geeta gathwala, poonam dalal, virender gehlawat, jasbir singh and vandana arya case report | e517 of pitting oedema and swelling, along with calf tenderness. on ultrasonography, the common femoral, superficial, deep femoral and popliteal veins were non-compressible with echogenic thrombi. no flow was observed on a colour doppler ultrasound, confirming the diagnosis of dvt. a detailed coagulation profile revealed protein c levels of 68% (reference value [rv]: 60−120%), protein s levels of 77% (rv: 60−120%), d-dimer levels of 137 ng/ml (rv: <500 ng/ml), prothrombin time of 15 seconds (rv: 13 seconds), activated partial thromboplastin time of 34 seconds (rv: 28 seconds) and an international normalised ratio (inr) of 1.2. levels of fibrin degradation products were 3.6 µg/ml (rv: 0−1.34 µg/ml) while antithrombin iii levels were 62% (rv: 80−130%). test results for factor v leiden and antinuclear antibodies were normal. the patient was administered low-molecular-weight heparin and warfarin. the warfarin was initially prescribed at a dose of 0.1 mg/kg/day with the dose adjusted every third day to achieve an inr of 2−3. the inr was frequently monitored to avoid the possible enzyme induction effects of rifampicin.1 on the tenth day of admission, the patient developed sudden-onset altered sensorium, aphasia and right-sided haemiparesis. a lumbar puncture was performed to rule out tubercular meningitis; how-ever, examination of the cerebrospinal fluid revealed no abnormalities. a magnetic resonance imaging (mri) scan of the brain revealed no abnormal findings in the brain parenchyma. there was no evidence of ventricular enlargement, basal exudates or infarcts. there was a hyperintense signal in the left transverse sinus on a t2-weighted fluid attenuated inversion recovery mri scan. in addition, there was a narrowing of the corresponding sinus on a magnetic resonance venogram [figure 2], suggestive of intracranial sinus thrombosis. after excluding systemic causes or seizures as possible causes of the altered sensorium and focal deficits, the possibility of cerebral vein thrombosis was considered. the altered sensorium improved over the following two days and the haemiparesis improved over the next 5−7 days, without any residual neurological deficits. the patient made an uneventful recovery while undergoing the antitubercular and anticoagulation therapy. she became afebrile within two weeks, while the limb oedema and pain improved within four weeks. her fibrinogen degradation product and antithrombin iii levels were normal at four weeks. a repeat ultrasound of the left leg revealed a residual thrombus; however, evidence of partial re-canalisation and flow on a colour doppler mri suggested that it was in the process of resolving. she continued to take serology test was non-reactive. her serum protein levels were 5.1 g/dl. while a chest x-ray was normal, an abdominal x-ray revealed multiple air-fluid levels. ultrasonography of the abdomen revealed free fluid, matting of the bowel loops, pelvic septations and multiple enlarged mesenteric nodes. a computed tomography scan of the abdomen revealed enlarged mesenteric lymph nodes with stranding of the mesentery [figure 1], indicating a tubercular aetiology. there was no evidence of compression of the inferior vena cava by the lymph nodes. a gastric lavage was positive for acid-fast bacilli. consequently, a diagn osis of probable abdominal tb was made and the patient was prescribed four-drug antitubercular therapy three days after admission, comprised of rifampicin, isoniazid, pyrazinamide and ethambutol. later that day, the patient developed pain and swelling in the left leg and thigh. there was evidence figure 1: contrast-enhanced computed tomography scan of the abdomen of a 13-year-old girl with intermittent fever and abdomen pain showing enlarged lymph nodes (arrow) in the pre-aortic region and stranding of the mesentery. figure 2: a: magnetic resonance (mr) venogram of the brain of a 13-year-old girl with probable abdomi nal tuberculosis and sudden-onset altered sensorium, aphasia and right-sided haemiparesis. note the thinn ing of the left transverse sinus (arrow), suggestive of intracranial sinus thrombosis. b: t2-weighted fluidattenuated inversion recovery mr image showing hyperintensity in the region of the thrombosed left transverse sinus (arrowhead). a case of deep vein thrombosis and intracranial sinus thrombosis possible rare complications of childhood abdominal tuberculosis e518 | squ medical journal, november 2016, volume 16, issue 4 low-molecular-weight heparin for 10 days, warfarin for three months and antitubercular drugs for six months. regular follow-up appointments over the next six months indicated that she was in good health and had gained 11 kg. unfortunately, the patient was subsequently lost to follow-up. discussion severe tb is known to induce an acute phase response which leads to the activation of mononuclear cells; the interaction of mycobacterial products with activated mononuclear cells subsequently induces increased synthesis of tumour necrosis factor-α and interleukin-6.6,7 these proinflammatory cytokines activate the vascular intima, rendering the endothelial surface thrombogenic. the cytokines also induce a hepatic acute phase response leading to deranged levels of coagulation proteins and a subsequent hypercoagulable state.6,7 there are very few reports of thrombotic complications among children with tb, possibly due to under-reporting.3,4 this type of rare but serious complication can further increase the morbidity and mortality associated with tb in young children;8 as such, clinicians should keep a high index of suspicion of dvt. to the best of the authors’ knowledge, this is the first reported case of childhood abdominal tb with dvt and intracranial sinus thrombosis. robson et al. reported 35 cases of pulmonary tb and dvt in adults; of these, venous thrombosis occurred seven days after diagnosis for 33 patients, while two had dvt upon presentation.6 the patient in the present case developed symptoms of dvt on the third day of admission, before the commencement of antitubercular therapy. elevated plasma fibrinogen, impaired fibrinolysis, decreased levels of antithrombin iii and reactive thrombocytosis can lead to the development of dvt among patients with pulmonary tb.6 a hypercoagulable state in patients with tb has been reported to improve within four weeks with the use antitubercular drugs.7 in the current case, the patient had elevated levels of fibrin degradation products and decreased levels of antithrombin iii which resolved within a month of antitubercular therapy. tb can predispose to dvt due to a hypercoagulable state.6 retroperitoneal tubercular lymphadenitis leading to compression of the inferior vena cava has also been reported to cause dvt in the absence of any haemostatic abnormalities.9 immobility can further exacerbate the effects of a hypercoagulable state. although the patient in the present case was diagnosed with probable abdominal tb with mesenteric lymphadenitis, there was no evidence of inferior vena cava compression. thus, the dvt and intracranial sinus thrombosis were possibly due to the patient’s hypercoagulable state. isoniazid and rifampicin can exacerbate the thrombogenic potential of tb by killing mycobacteria and enhancing the release of interleukin-6 from the peripheral blood mononuclear cells.1 rifampicin is a potent inducer of cytochrome p450 proteins and thus enhances metabolism of oral anticoagulants;1 as a result, adjustments to the dosage of warfarin may be necessary to maintain its therapeutic efficacy. doses and durations of anticoagulant treatment for patients with tb have not yet been standardised. the recommended duration of anticoagulants for children with secondary and idiopathic venous thrombosis is three and six months, respectively.10 it has been suggested that the hypercoagulable state and haemostatic changes stabilise within four weeks of antitubercular therapy.7 in the current patient, the dvt resolved within a month of antitubercular treatment, which provides further evidence of a correlation between tb and venous thrombosis. conclusion while dvt is a rare complication associated with pulmonary and extrapulmonary tb in adult patients, reports of this complication occurring with childhood tb are scarce. there is a need to keep a high index of suspicion of this rare but serious complication as it can further increase the morbidity and mortality associated with tb in young children. in addition, the current case highlights for the first time a possible association between childhood tb and intracranial sinus thrombosis. references 1. white nw. venous thrombosis and rifampicin. lancet 1989; 2:434−5. doi: 10.1016/s0140-6736(89)90603-x. 2. ambrosetti m, ferrarese m, codecasa lr, besozzi g, sarassi a, viggiani p, et al. incidence of venous thromboembolism in tuberculosis patients. respiration 2006; 73:396. doi: 10.1159/ 000091188. 3. gupta r, brueton m, fell j, lyall h. an afghan child with deep vein thrombosis. j r soc med 2003; 96:289−91. doi: 10.1258/ jrsm.96.6.289. 4. havaldar pv, mogale kd, koppad am, haravi r. spontaneous deep vein thrombosis. indian pediatr 1998; 35:657−63. 5. fiorot júnior ja, felício ac, fukujima mm, rodrigues ca, morelli vm, lourenço dm, et al. tuberculosis: an uncommon cause of cerebral venous thrombosis? arq neuropsiquiatr 2005; 63:852−4. doi: 10.1590/s0004-282x2005000500025. geeta gathwala, poonam dalal, virender gehlawat, jasbir singh and vandana arya case report | e519 9. gogna a, pradhan gr, sinha rs, gupta b. tuberculosis presenting as deep vein thrombosis. postgrad med j 1999; 75:104−6. doi: 10.1136/pgmj.75.880.104. 10. chalmers e, ganesen v, liesner r, maroo s, nokes t, saunders d, et al. guideline on the investigation, management and prevention of venous thrombosis in children. br j haematol 2011; 154:196−207. doi: 10.1111/j.1365-2141.2010.08543.x. 6. robson sc, white nw, aronson i, woollgar r, goodman h, jacobs p. acute-phase response and the hypercoagulable state in pulmonary tuberculosis. br j haematol 1996; 93:943−9. doi: 10.1046/j.1365-2141.1996.d01-1722.x. 7. turken o, kunter e, solmazgul e, cerrahoglu k, bozkanat e, ozturk a, et al. hemostatic changes in active pulmonary tuberculosis. int j tuberc lung dis 2002; 6:927−32. 8. dentan c, epaulard o, seynaeve d, genty c, bosson jl. active tuberculosis and venous thromboembolism: association according to international classification of diseases, ninth revision hospital discharge diagnosis codes. clin infect dis 2014; 58:495−501. doi: 10.1093/c id/cit780. 1department of radiology, edirne sultan 1. murat state hospital, edirne, turkey; 2department of pediatric radiology faculty of medicine, erciyes university, kayseri, turkey *corresponding author e-mail: msaitdogan@hotmail.com القولون اإلثين عشر املنقلب نتائج من صور متتالية للجهاز اهلضمي العلوي مهمت دوغان، �صليم دوغاناي، جونكا كوك، �صوريا جوركم، عبداحلكيم كو�صكون duodenum inversum findings from an upper gastrointestinal series *mehmet s. dogan,1 selim doganay,2 gonca koc,2 sureyya b. gorkem,2 abdulhakim coskun2 interesting medical image a 12-year-old girl with a history of occasional nausea and vomiting for the previous 4‒5 years was admitted to the erciyes university children’s hospital, kayseri, turkey, in 2014 after the frequency of these symptoms had increased. for the previous six weeks, she had been vomiting 6‒7 times per day and had lost 3 kg in weight. the laboratory findings and a physical examination were unremarkable except for non-specific epigastric tenderness. an upper gastrointestinal series (ugis) was performed using a fluoroscopy device and barium contrast medium; this revealed that the third part of the duodenum was vertically oriented and subsequently crossed the midline to the left to form the duodenojejunal junction in the normal location, at the level of the bulb [figure 1]. based on these findings, a diagnosis of duodenum inversum was made. in addition, gastroesophageal reflux was observed. an endoscopic biopsy revealed peptic oesophagitis and chronic gastritis. there was no evidence sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e379–380, epub. 19 aug 16 submitted 17 feb 16 revision req. 21 mar 16; revision recd. 29 mar 16 accepted 14 apr 16 doi: 10.18295/squmj.2016.16.03.022 figure 1a–f: sequential images from an upper gastrointestinal series of a 12-year-old girl showing the (a) normal appearance of the first and second parts of the duodenum and the (b) third part of the duodenum bending over the second part and (c) continuing with a vertical orientation. subsequently, the (d) duodenum crosses the midline to the left and the (e) duodenojejunal junction is located normally at the level of the bulb. finally, the (f) proximal jejunal intestines are located in the left upper quadrant. the arrows show the route of the barium contrast medium. duodenum inversum findings from an upper gastrointestinal series e380 | squ medical journal, august 2016, volume 16, issue 3 predispose patients to diseases such as cholecystitis, pancreatitis and peptic ulcers.1–6 these symptoms and comorbidities are thought to be due to stasis in the duodenum.6 clinicians must therefore be aware of possible comorbidities in patients with duodenum inversum. for symptomatic patients with peptic ulcers and without duodenal obstruction, pharmacological treatments are advised, including antacids, antispasmodics and anti-ulcer agents; however, if a duodenal obstruction is present, surgery is the treatment of choice.1 although limited in number, studies have shown favourable outcomes for both surgical and pharmacological interventions.1,3,4 references 1. kim me, fallon sc, bisset gs, mazziotti mv, brandt ml. duodenum inversum: a report and review of the literature. j pediatr surg 2013; 48:e47–9. doi: 10.1016/j.jpedsurg.2012. 10.066. 2. fallon m. duodenum inversum. ir j med sci 1940; 15:256–60. doi: 10.1007/bf02952945. 3. long fr, mutabagani kh, caniano da, dumont rc. duodenum inversum mimicking mesenteric artery syndrome. pediatr radiol 1999; 29:602–04. doi: 10.1007/s002470050658. 4. menchise an, mezoff ea, lin tk, saaed sa, towbin aj, white cm, et al. medical management of duodenum inversum presenting with partial proximal intestinal obstruction in a pediatric patient. j pediatr gastroenterol nutr 2016; 62:e64–5. doi: 10.1097/mpg.0000000000000519. 5. childress mh. duodenum inversum. j natl med assoc 1979; 71:515–16. 6. rozek ec, graney cm. duodenum inversum: a report of two cases. radiology 1951; 57:66–9. doi: 10.1148/57.1.66. of duodenal obstruction, only duodenum inversum as seen during the ugis. the patient was therefore prescribed 20 mg of oral omeprazole daily. her symptoms gradually resolved and she was noted to have gained 4 kg at a three-month follow-up evaluation. comment duodenum inversum, also known as inverted duodenum or duodenum reflexum, is a rare congenital anomaly of duodenal configuration which results in the third part of the duodenum bending over onto the second part posteriorly and crossing the midline at a more cephalic level than expected, subsequently forming the duodenojejunal junction at its original site.1–6 in an ugis, radiological signs of duodenum inversum following the introduction of a contrast substance are as follows: (1) return of the contrast substance from the second into the first part of the duodenum and then into the bulb more frequently; (2) stasis in the duodenum; and (3) rapid passage of the contrast medium through the third stage.2 while the aetiology of duodenum inversum is unknown, it is believed to be due to the persistence of the dorsal mesentery with a mobile duodenum.5 determining the normal location of the duodenojejunal junction is important in differentiating duodenum inversum from intestinal malrotation.1–3 patients with duodenum inversum are often asymptomatic, although they may present with obstructive symptoms, epigastric pain, bloating, nausea and vomiting. furthermore, duodenum inversum may http://dx.doi.org/10.1016/j.jpedsurg.2012.10.066 http://dx.doi.org/10.1016/j.jpedsurg.2012.10.066 http://dx.doi.org/10.1007/bf02952945 http://dx.doi.org/10.1007/s002470050658 http://dx.doi.org/10.1097/mpg.0000000000000519 http://dx.doi.org/10.1148/57.1.66 squ med j, april 2010, vol. 10, iss. 1, pp. 111-113, epub. 17th apr 10 sumbitted 25th july 09 revision req. 14th sept 09, revision recd. 10th oct 09 accepted 11th nov 09 oculocutaneous albinism and mesodermal dysgenesis of the anterior segment are two distinct disorders with different types of inheritance. oculocutaneous albinism presents as an autosomal recessive disorder and mesodermal dysgenesis as an autosomal dominant disorder. although there are several studies reporting an association between the two inherited disorders, in each of these case reports, only one case has been reported as having this association.1,2,3,4,5 in a study by izquierdo et al.,6 four patients with hermansky-pudlak syndrome were described as having axenfeld anomaly. in our cases, all the three siblings had oculocutaneous albinism with nystagmus, iris transillumination, foveal and optic nerve hypoplasia and poor vision. all of them showed axenfeld anomaly with prominent schwalbe’s line and iridocorneal processes. case reports three of the eight children of a family with a history of consanguinity, [figure 1] who attended the low vision clinic of sur hospital, oman, were diagnosed as having oculocutaneous albinism and were worked up for evaluation of low vision and management. c a s e o n e a boy aged 13 years had been wearing high hypermetropic glasses for the previous three years. on examination, he had a best-corrected visual actuity of 0.2 in each eye. refraction revealed the following: right eye +9.00sph/-3.0 at 15 degrees, left eye +9.50/-2.0 at 160 degrees pendular nystagmus, and poliosis. biomicroscopy revealed an anteriorly displaced irregularly thickened posterior embryotoxon (schwalbe’s) in both eyes with iris processes extending to the peripheral cornea [figure 2]. the iris transillumination was positive, intraocular pressure was 14mm hg in both eyes and the fundus showed gross choroidal department of ophthalmology, sur hospital, oman *to whom correspondence should be addressed. email keshavraj2000@gmail.com املهق البصري اجللدي املرتبط بُشذوِذ أكِْسينِفيلد تقرير ثالث حاالت كي�شاف، حمم�د حممد، نا�رس حمم�د ط االأمامي حالتان وراثيتان معروفتان، لكن ح�ش�لهما بنف�س ال�قت يعترب نادرا كما اخلال�صة: املهق الب�رسي اجللدي وخلل تك�ن االأَدمُي امُلَتَ��شِّ ظهر يف التقارير. ندرج هنا ثالث حاالت لعائلة بعر�س متماثل قد يدل على اأن حدوثهما اأكرث من جمرد �شدفة. هكذا ترابط ي�شتحق املالحظة الأنه ميكن اأن يك�ن اأحد اأ�شباب ملر�س العني و�شعف الب�رس يف املهق الب�رسي اجللدي. مفتاح الكلمات: املهق، الب�رسي اجللدي، �شذوذ اأك�شينفيلد، وراثة، قرابة، ترابط. abstract: oculocutaneous albinism and anterior mesodermal dysgenesis are well-known heritable conditions, but their occurrence in association has only been rarely reported. we present cases of three siblings of a family with identical presentation suggesting that this association may be more than just a coincidence. this association is worth noting, as this could be one of the causes of ocular morbidity and poor vision in oculocutaneous albinism. keywords: albinism; oculocutaneous; axenfeld anomaly; hereditary; consanguinity; association. oculocutaneous albinism associated with axenfeld’s anomaly three case reports *b r keshav, mahmood j mohammed, nasir mahmood case report oculocutaneous albinism associated with axenfeld’s anomaly three case reports 112 | squ medical journal, april 2010, volume 10, issue 1 hypopigmentation, small hypoplastic discs and absent foveal reflex suggestive of foveal hypoplasia [figure 3]. his systemic history was unremarkable with regard to any evidence of bleeding diathesis or recurrent infections or respiratory problems. c a s e t w o a boy aged 9 years presented, also with a history of wearing high hypermetropic glasses. his systemic history revealed that he had an extra digit, which was excised. on examination, he had a visual actuity of 0.1 in the right eye and 0.05 in the left one. refraction showed: right eye +8.00/-3.00 @ 10 degrees, left eye +8.00sph/-3.00 at 165 degrees. intraocular pressure (iop) 15mm hg right eye, 14mm hg left eye. the rest of the anterior and posterior segments were remarkably similar to his brother’s eyes. blood investigations were negative for sickling. prothrombin time (pt) and activated partial thromboplastin time (aptt) were 17.2 secs and 33.0 secs respectively and international normalised ratio (inr) was 1.38. c a s e t h r e e a girl aged 6 years, sister of the two other siblings mentioned above, presented without a history of wearing glasses with other ocular findings very similar to her those of her brothers. her uncorrected visual acuity was counting fingers 3m in both eyes. refraction showed: right eye +8.00sph/-1.00 at 10 degrees, left eye +7.00sph/-2.00 at 160 degrees. discussion albinism refers to a group of hereditary disorders that involve an abnormality of melanin synthesis or distribution. the term albinism comes from the latin word albus, which means white, and, in 1908, garrod figure 1: family tree showing the three of the 8 children affected. first scientifically described it.7 clinically, albinism presents as a pigmentation abnormality of the skin, the hair, and/or the eyes. albinism can be divided into two broad categories, as follows: oculocutaneous albinism and ocular albinism. oculocutaneous albinism involves both the skin and the eyes, whereas ocular albinism mainly affects the eyes with minimal to no skin involvement. the primary morbidity of both oculocutaneous albinism and ocular albinism is eye related. signs and symptoms include photophobia, refractive errors, monocular vision, strabismus, pendular nystagmus, iris transillumination defects, foveal hypoplasia, and abnormal decussation of the optic nerve fibres. these ocular manifestations are almost always present in both forms of albinism; however, the degree of their presentation can vary depending on the type of albinism and the racial background of the patient.7 oculocutaneous albinism mostly presents in an autosomal recessive form and is mainly of two types, namely tyrosine negative and tyrosine positive albinism. mesodermal dysgenesis is an autosomal dominant disorder characterised by iridogonio dysgenesis with iris hypopiasia and may be associated with glaucoma and systemic features.8 of the various types of mesodermal dysgenesis, the axenfield anomaly is the least severe and presents as an anteriorly displaced schwalbe’s line and iridocorneal processes with or without glaucoma. only a few studies in the literature have shown the association of albinism and iridocorneal dysgenesis. 1,2,3,4,5 lubin et al. published a case of a tyrosine negative albino having mesodermal dysgenesis of the axenfeld type and thought that the association could be coincidental.1 another study by hayakawa et al. showed an association of ocular albinism with an axenfeld type of mesodermal dysgenesis in one japanese patient and postulated that there could be a common defective factor leading to these two disorders.2 in our report, the occurrence of this association in three siblings in an identical fashion shows that the association is more than coincidental. it has been speculated that mesodermal deficiency is a developmental anomaly that is related to lack of pigmentation in the tissues thus connecting the two diseases.4 it has been postulated that a developmental arrest, in the third trimester of gestation, of tissues derived from the neural crest cells accounts for the b r keshav, mahmood j mohammed and nasir mahmood case report | 113 ocular and most of the nonocular abnormalities in this group.8 even the melanocytes are of neural crest origin thus supporting their occurrence in a single individual. our cases also conform to other reports of the common type of mesodermal dysgenesis associated with albinism, which is the axenfeld anomaly. it is important to be aware of this particular ocular association of anterior mesodermal dysgenesis with albinism. this is because it could be one of the causes of ocular morbidity and loss of vision in albinism, apart from other inherent factors namely: foveal hypoplasia, nystagmus, optic nerve hypoplasia, and increased number of crossed fibres in the optic tract leading to defective cortical projection and squinting.7 conclusion several case reports have been published hitherto on the association of oculocutaneous albinism and ocular albinism with anterior mesodermal dysgenesis. our case report of three siblings with a similar association not only supports this but also goes a step further in proving that the association is more than coincidental and could be caused by a common defective factor. a further insight into the genetics of both the disorders may throw light on the possible genetic linkage between them. references 1. lubin jr. oculocutaneous albinism associated with mesodermal dysgenesis. am j ophthalmol 1981; 91:347–50. 2. hayakawa m, kato k, nakajima a,yoshiike t, ogawa h. nettleship–falls x-linked albinism with axenfeld anomaly: a case report. ophthalmic paed genet 1986; 7:109–14. 3. benson w. oculocutaneous albinism associated with axenfeld anomaly. am j ophthalmol 1981; 92:133. 4. ricci b, lazerra f. ocular albinism and corneal mesodermal dysgenesis. am j ophthalmol 1981; 92:587. 5. vandorp bd, delleman jw, loewer-sieger dh. oculocutaneous albinism and anterior chamber cleavage syndrome not a coincidence. clin genet 1984; 26:440–4. 6. izquierdo nj, townsend w, hussels ie. ocular findings in hermansky-pudlak syndrome. trans am ophthalmol soc 1995; 93:191–202. 7. grønskov k, jakob ek, brondum-nielsen k. ocular manifestations of albinism. orphanet j rare dis 2007; 2:43. 8. shields mb, buckley e, klintworth gk, thresher r. axenfeld-rieger syndrome a spectrum of dev disorder. surv ophthalmol 1985; 29:387–409 figure 2: anteriorly displaced irregularly thickened posterior embryotoxon (schwalbe’s) in both eyes with iris processes extending to the peripheral cornea figure 3: fundus showed gross choroidal hypopigmentation, small hypoplastic discs and absent foveal reflex suggestive of foveal hypoplasia departments of 1pathology and 2surgery, maulana azad medical college, new delhi, india *corresponding author’s e-mail: dr.surekhay@gmail.com حالة ورم خبيث متكرر للنسيج الليفي اجللدي الناتئ مع تصبغ ومتايز عضلي �شوريكا ياداڤ، نيدي ڤريما، نيتا كورانا، �شو�شانت نيوجي abstract: dermatofibrosarcomas protuberans (dfsp) are rare low-grade tumours with various subtypes and usually occur among middle-aged adults. however, myoid differentiation is very rare. we report a 44-year-old woman who presented to the lok nayak jai prakash hospital, new delhi, india, in 2017 with a recurrent pigmented dfsp presenting as an arm swelling. upon histological and immunohistochemical analysis, myoid differentiation was confirmed. a literature review of the clinical and histopathological features of this rare entity is presented. keywords: dermatofibrosarcoma protuberans; melanocytes; pigmentation; cell differentiation; case report; india. امللخ�ص: تعترب الأورام اخلبيثة للن�شيج الليفي اجللدي الناتئ من الأورام النادرة ذات ال�رضا�شة املنخف�شة ولها اأنواع عدة، وحتدث غالبًا عند البالغني يف منت�شف العمر، اإل اأن حدوث متايز خلاليا الورم اإىل النوع الع�شلي يعترب نادر احلدوث، ن�شجل هنا حالة ملري�شة يف العقد الرابع من العمر عوينت يف م�شت�شفى لوك ناياك جاي بركا�ض يف منطقة نيودلهي يف عام 2017، وكانت م�شابة بورم متكرر يف الذراع من نوع الن�شيج الليفي اجللدي اخلبيث الناتئ وامل�شاحب بالت�شبغ، واأظهرت التحاليل املجهرية وفحو�ض الأن�شجة با�شتخدام الكيميائية املناعية وجود متايز للخاليا اإىل اأن�شجة ع�شلية داخل الورم، كما يتم عر�ض املن�شورات ال�شابقة عن اخلوا�ض ال�رضيرية واملجهرية ملثل هذه احلالة النادرة احلدوث. الكلمات املفتاحية: ورم الن�شيج الليفي اجللدي اخلبيث الناتئ؛ اخلاليا ال�شبغية؛ الت�شبغ، متايز اخلاليا؛ تقرير حالة؛ الهند. recurrent dermatofibrosarcoma protuberans with pigmentation and myoid differentiation *surekha yadav,1 nidhi verma,1 nita khurana,1 sushant neogi2 case report sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e228–230, epub. 9 sep 18 submitted 30 aug 17 revisions req. 15 oct, 10 dec 17 & 11 jan 18; revisions recd. 25 nov 17, 3 jan & 24 jan 18 accepted 1 feb 18 doi: 10.18295/squmj.2018.18.02.019 dermatofibrosarcomas protuberans (dfsp) are rare low-grade sarcomas involv-ing the dermis and subcutaneous tissue.1,2 this type of tumour has a low rate of distant metastasis, but a higher rate of local recurrence. histological sub types of dfsp include giant-cell, pigmented, sclerosing, atrophic, myoid and fibrosarcomatous types.1,2 of these, pigmented dfsp are characterised by interspersed melanin-rich dendritic cells and are very rare, account ing for less than 5% of all reported cases of dfsp.1 however, the origin of myoid differentiation in dfsp and its clinical significance is unknown. this case report describes a case of myoid differentiation in recurrent pigmented dfsp presenting as an arm swelling in an adult female patient. case report a 44-year-old woman presented to the lok nayak jai prakash hospital, new delhi, india, in 2017 with a recurrent mass on her right upper arm. the tumour had regrown since being surgically removed three years prior, at which time it had been histopathologically diagnosed as a dfsp. at presentation, the lesion was attached to the overlying skin, measuring 8 x 7 x 6 cm. a computed tomography (ct) scan showed a homo geneously-enhancing soft tissue lesion in the subcutaneous plane of the lateral aspect of the middle-third of the right arm, measuring 7 x 6 x 4.5 cm [figure 1a]. the lesion had well-defined margins except medially, where it was abutting the deltoid muscle with the loss of the intervening fat planes. however, ct scans of the chest, abdomen and head and neck region were normal. there was no evidence of organomegaly or lymphadenopathy. the patient subsequently underwent wide surgical excision of the lesion. upon gross examination, the excised soft tissue mass measured 13 x 11 x 5 cm. the surface of the lesion showed a firm homogenous polypoidal greyish-white growth of 6 x 6 x 4.5 cm, which extended deep into the underlying dermis [figure 1b]. there were no areas of haemorrhage or necrosis. histologically, the overlying skin was unremarkable. the tumour itself was located in the dermis and was composed of monomorphic spindle cells arranged in a storiform and fascicular pattern with a parallel arrangement of cells [figure 2a]. in certain areas, the tumour was more cellular and composed of elongated cells with moderate cytoplasm and elongated-to-plump nuclei, which were mostly perivascular [figure 2b]. the eosinophilic cells were surekha yadav, nidhi verma, nita khurana and sushant neogi case report | e229 patient was symptom-free and there was no sign of disease recurrence. discussion in general, dfsp occur mostly in middle-aged adults, but have been reported in patients between 8–87 years old.3 men are affected more often than women at a ratio of 2.3:1.4 this type of tumour is usually painless and presents as a long-standing solitary multinodular mass. commonly affected sites include the trunk, particularly the back, and the limbs, chest and head and neck region.1,3 the tumour is locally aggressive and usually infiltrates the deep dermis and subcutaneous fat.3 a genetic study found that 89% of dfsp cases had collagen type i alpha 1 platelet-derived growth factor β fusion transcripts.4 a classical histological feature of dfsp is a storiform growth pattern of benign-looking spindle cells. histopathologically, cd34 is considered a highly-specific marker of dfsp.5 the origin of muscle differentiation in dfsp is debatable. calonje et al. first described myoid differen tiation in five cases of dfsp either with or without fibrosarcomatous components; because the myoid areas were distributed throughout the tumour, the authors concluded that these cells form their own areas.6 o’connell et al. studied two cases of fibrosarcoma arising in dfsp and came to a similar conclusion.7 other researchers have claimed that myoid differentiation is solely a reactive phenomenon, with stromal myofibroblasts showing some degree of hyperplasia.8,9 sanz trelles et al. concluded the myoid areas in dfsp to be the result of vascular smooth muscle cell hyperplasia or the proliferation of pericytes.10 another study demonstrated a close relationship between blood vessels in the tumour and areas of myoid differentiation.11 ohtani et al. found smooth muscle actin expressing myoid cells in a case of fibrosarcomatous dfsp which had metastasised to the lung; the researchers suggested that myoid differentiation may therefore be neoplastic in origin.12 however, no relationship between the myoid areas and the blood vessels was found; furthermore, these areas differed in appearance from the pericytes.12 bland-looking without pleomorphism or mitotic fig ures. the focal tumour cells contained brown intracellular pigment [figure 2c]. the tumour had infiltrated the underlying soft tissue; however, all of the resected margins, including the circumferential resected margins and deep resection plane, were tumour-free. there was no evidence of mitosis, cellular atypia or necrosis. an immunohistochemical panel of the tumour cells showed diffuse expression of vimentin and cluster of differentiation (cd)34 [figure 3a]. the cells with eosinophilic cytoplasm showed immunohistochemical expression of smooth muscle actin, indicative of myoid differentiation [figure 3b]. these areas were negative for cd34 [figure 3c]. the final diagnosis was of a recurrent dfsp with pigmentation and myoid differentiation. at a six-month follow-up appointment, the figure 1: a: contrast-enhanced computed tomography of a recurrent swelling in the right arm of a 44-year-old woman showing a homogenously-enhancing mass. b: gross photograph of the excised lesion showing a greyish-white mass with stretching of the overlying skin. figure 2: haematoxylin and eosin stains at (a) x100 magnification and (b) x200 magnification showing areas of myoid differentiation and (c) at x400 magnification showing monomorphic spindle cells with interspersed pig mented cells. figure 3: immunohistochemical panel at x200 magnification showing (a) diffuse positivity for cluster of differentiation (cd)34 and (b) smooth muscle actin expression in areas of myoid differentiation and (c) negativity for cd34. recurrent dermatofibrosarcoma protuberans with pigmentation and myoid differentiation e230 | squ medical journal, may 2018, volume 18, issue 2 the pigmented subtype of dfsp, also known as a bednar tumour or storiform neurofibroma, contains varying amounts of melanotic pigment.13 this subtype is different from conventional dfsp and has specific chromosomal abnormalities.14 however, the origin of pigmented dfsp is still unknown. some researchers advocate a neuroectodermal origin due to the presence of cells of schwannian differentiation along with dendritic melanocytes, while others believe that such tumours arise after trauma, scarring from vaccinations or insect and animal bites.15,16 although several cases of dfsp with fibrosarcomatous differentiation are available in the literature, the current case appears to be the first report of recurrent dfsp with myoid differentiation and pigmentation.17–19 conclusion myoid differentiation is a morphological variant of dfsp. in the current case, myoid differentiation was found around the blood vessels in the tumour, distributed irregularly without forming a specific stromal pattern. it is possible that hyperplastic myofibroblasts occur due to a reactive process to proliferating tumour cells. however, further studies are needed to enhance our understanding of myoid differentiation and its clinical prognosis in dfsp cases. references 1. zhang j, zhang rs, wei x, shi ql, zhou xj, ma j. [pigmented dermatofibrosarcoma protuberance: a clinicopathologic analysis of 7 cases]. zhonghua bing li xue za zhi 2013; 42:810–14. doi: 10.3760/cma.j.issn.0529-5807.2013.12.005. 2. laskin wb. dermatofibrosarcoma protuberans. ca cancer j clin 1992; 42:116–25. doi: 10.3322/canjclin.42.2.116. 3. mentzel t, beham a, katenkamp d, dei tos ap, fletcher cd. fibrosarcomatous (“high-grade”) dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. am j surg pathol 1998; 22:576–87. doi: 10.1097/00000478-199 805000-00009. 4. llombart b, sanmartin o, lopez-guerrero ja, monteaqudo c, serra c, requena c, et al. dermatofibrosarcoma protuberans: clinical, pathological, and genetic (col1a1-pdgfb ) study with therapeutic implications. histopathology 2009; 54:860–72. doi: 10.1111/j.1365-2559.2009.03310.x. 5. goldblum jr, tuthill rj. cd34 and factor-xiiia immunoreactivity in dermatofibrosarcoma protuberans and dermatofibroma. am j dermatopathol 1997; 19:147–53. doi: 10.1097/ 00000372-199704000-00008. 6. calonje e, fletcher cd. myoid differentiation in dermatofibrosarcoma protuberans and its fibrosarcomatous variant: clinic opathologic analysis of 5 cases. j cutan pathol 1996; 23:30–6. doi: 10.1111/j.1600-0560.1996.tb00774.x. 7. o’connell jx, trotter mj. fibrosarcomatous dermatofibrosarcoma protuberans with myofibroblastic differentiaion: a histologically distinctive variant. mod pathol 1996; 9:273–8. 8. morimitsu y, hisaoka m, okamoto s, hashimoto h, ushijima m. dermatofibrosarcoma protuberans and its fibrosarcomatous variant with areas of myoid differentiation: a report of three cases. histopathology 1998; 32:547–51. doi: 10.1046/j.1365-2559.1998. 00428.x. 9. sanz-trelles a. myoid cells in the fibrosarcomatous variant of dermatofibrosarcoma protuberans. are they neoplastic? histopathology 1999; 34:179–80. 10. sanz-trelles a, ayala-carbonero a, rodrigo-fernández i, weil-lara b. leiomyomatous nodules and bundles of vascular origin in the fibrosarcomatous variant of dermatofibrosarcoma protuberans. j cutan pathol 1998; 25:44–9. doi: 10.1111/j.16000560.1998.tb01688.x. 11. diaz-cascajo c. myoid differentiation in dermatofibrosarcoma protuberans and its fibrosarcomatous variant. j cutan pathol 1997; 24:197–8. doi: 10.1111/j.1600-0560.1997.tb01577.x. 12. ohtani n, fukusato t, tezuka f. sarcomatous dermatofibrosarcoma protuberans metastasized to the lung: preservation of cd34 expression in tumor cells. pathol int 1998; 48:989–93. doi: 10.1111/j.1440-1827.1998.tb03872.x. 13. bednar b. storiform neurofibromas of the skin, pigmented and nonpigmented. cancer 1957; 10:368–76. doi: 10.1002/1097-0142 (195703/04)10:2<368::aid-cncr2820100218>3.0.co;2-3. 14. sirvent n, maire g, pedeutour f. genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. genes chromosomes cancer 2003; 37:1–19. doi: 10.1002/gcc.10202. 15. elder de, massi d, scolyer ra, wilemze r, eds. dermatofibrosarcoma protuberans and variants. in: world health organization classification of skin tumours, 4th ed. lyon, france: iarc press, 2018. pp. 304–6. 16. llombart b, serra-guillén c, monteagudo c, lópez guerrero ja, sanmartín o. dermatofibrosarcoma protuberans: a comprehensive review and update on diagnosis and management. semin diagn pathol 2013; 30:13–28. doi: 10.1053/j.semdp.20 12.01.002. 17. porter c, vincetic a, saleh me, goldstein h. pigmented dermatofibrosarcoma protuberans of the foot with fibrosarcomatous changes: a review and case presentation. j foot ankle surg 2002; 41:186–91. doi: 10.1016/s1067-2516(02)80070-9. 18. suehara y, yazawa y, hitachi k. metastatic bednar tumor (pigmented dermatofibrosarcoma protuberans) with fibrosarcomatous change: a case report. j orthop sci 2004; 9:662–5. doi: 10.1007/s00776-004-0831-2. 19. kini h, raghuveer cv, pai mr, sk. fibrosarcomatous bednar tumor with distant metastases: a case report. indian j pathol microbiol 2004; 47:26–9. https://doi.org/10.3760/cma.j.issn.0529-5807.2013.12.005 https://doi.org/10.3322/canjclin.42.2.116 https://doi.org/10.1097/00000478-199805000-00009 https://doi.org/10.1097/00000478-199805000-00009 https://doi.org/10.1111/j.1365-2559.2009.03310.x https://doi.org/10.1097/00000372-199704000-00008 https://doi.org/10.1097/00000372-199704000-00008 https://doi.org/10.1111/j.1600-0560.1996.tb00774.x https://doi.org/10.1046/j.1365-2559.1998.00428.x https://doi.org/10.1046/j.1365-2559.1998.00428.x https://doi.org/10.1111/j.1600-0560.1998.tb01688.x https://doi.org/10.1111/j.1600-0560.1998.tb01688.x https://doi.org/10.1111/j.1600-0560.1997.tb01577.x https://doi.org/10.1111/j.1440-1827.1998.tb03872.x https://doi.org/10.1002/1097-0142%28195703/04%2910:2%3c368::aid-cncr2820100218%3e3.0.co%3b2-3 https://doi.org/10.1002/1097-0142%28195703/04%2910:2%3c368::aid-cncr2820100218%3e3.0.co%3b2-3 https://doi.org/10.1002/gcc.10202 https://doi.org/10.1053/j.semdp.2012.01.002 https://doi.org/10.1053/j.semdp.2012.01.002 https://doi.org/10.1016/s1067-2516%2802%2980070-9 https://doi.org/10.1007/s00776-004-0831-2 1department of internal medicine, sohar hospital, sohar, oman; 2department of neurology, royal hospital, muscat, oman *corresponding author’s e-mail: santosh.balagopal@yahoo.ca اعتالل عصيب متعلق بالتسمم الدرقي حالة نادرة لشلل سفلي رخو اأمين خمي�ض الوهيبي، �صانتو�ض كومار، علي الري�صي، فاروق وايل abstract: acute polyneuropathy is a rare manifestation of severe hyperthyroidism. we report a 22-year-old omani male who presented to the sohar hospital, sohar, oman, in 2016 with acute-onset rapidly progressive flaccid areflexic paraplegia as the presenting manifestation of thyrotoxicosis. nerve conduction studies revealed mixed axonal and demyelinating polyneuropathy in both the motor and sensory nerves. treatment of the hyperthyroidism with β-blockers and carbimazole along with physiotherapy resulted in the patient’s full recovery and the alleviation of his symptoms. besides highlighting this rare association, this report underscores the importance of including thyroid function tests in the evaluation of patients with acute polyneuropathy. keywords: thyrotoxicosis; polyneuropathy; hyperthyroidism; flaccid paraplegia; case report; oman. امللخ�ص: يعد العتالل الع�صبي املتعدد احلاد عر�صا نادرا لفرط الدرقية الوخيم. ونعر�ض هنا حالة مري�ض عماين عمره 22 عاما اأح�رش وقد و�رشيعة. حادة ب�صورة وت�صاعف ترقى رخو �صفلي �صلل من ي�صكو وهو ،2016 عام يف عمان يف �صحار مبدينة �صحار، مل�صت�صفى كانت تلك الأعرا�ض دالة على ت�صمم درقي. واأو�صحت درا�صات التو�صيل الع�صبي عن حالة اعتالل ع�صبي متعدد حمواري ومزيل للميالني يف الأع�صاب احلركية واحل�صية معًا. ومت عالج فرط الدرقية با�صتخدام م�صادات م�صتقبالت بيتا وكارمبازول، وبالعالج الطبيعي. واأف�صى العالج ل�صفاء املري�ض �صفاء تاما من الأعرا�ض املذكورة. وتو�صح هذه احلالة الرتباط النادر بني الت�صمم الدرقي وال�صلل ال�صفلي الرخو، وتبني اأي�صا اأهمية قيا�ض موؤ�رشات وظائف الغدة الدرقية عند تقومي حالة املر�صى امل�صابني باعتالل ع�صبي متعدد حاد. الكلمات املفتاحية: الت�صمم الدرقي؛ العتالل الع�صبي املتعدد؛ فرط الدرقية؛ ال�صلل ال�صفلي الرخو؛ تقرير حالة؛ عمان. thyrotoxic neuropathy a rare cause of acute flaccid paraplegia aiman k. al-wahaibi,1 *santosh kumar,1 ali al-risi,1 farook wali2 case report sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e460–463, epub. 10 jan 18 submitted 13 jul 17 revision req. 5 sep 17; revision recd. 28 oct 17 accepted 16 nov 17 doi: 10.18295/squmj.2017.17.04.014 thyrotoxicosis is associated with various neuromuscular illnesses like myopathy, periodic paralysis, ophthalmoplegia and myasthaenia gravis.1,2 in contrast to muscles, the involvement of the peripheral nerves in hyperthyroidism has received little attention.3,4 even though the association between these two disorders has been questioned, electron microscopic studies of sural nerve biopsies have shown changes compatible with thyrotoxicosis.5,6 this report describes a case of acute flaccid paraplegia which resolved upon treatment of the underlying hyperthyroidism. case report a 22-year-old omani male presented to the sohar hospital, sohar, oman, in 2016 with a three-day history of progressive weakness in both lower limbs, resulting in him becoming bed-bound. there were no symptoms in the upper limbs or evidence of sphincter dysfunction. on examination, he was anxious, diaphoretic and had bilateral exophthalmos with lid lag. his pulse rate was 110 beats per minute and blood pressure was 130/82 mmhg. motor weakness and reflex changes were confined to both of the lower extremities. the lower limbs were hypotonic and areflexic with a power grade of 2/5 both proximally and distally; there was no wasting or fasciculations. an examination of the feet revealed normal flexor plantar reflexes. the results of routine blood tests were unremarkable, including serum electrolyte, creatine phosphokinase and antiganglioside antibody tests. a cerebrospinal fluid examination and electrocardiogram were normal. his serum thyroxine (t4) level was >100 pmol/l (normal range: 12–22 pmol/l), his triiodothyronine level was 11.77 pmol/l (normal range: 3.1–6.8 pmol/l) and his thyroid stimulating hormone (tsh) level was <0.005 iu/ml (normal range: 0.27–4.2 iu/ml). levels of antithyroid peroxidase and tsh receptor antibodies were 16.2 iu/ml (normal range: <6 iu/ml) and 5.9 iu/l (normal range: ≥1.57 iu/l), respectively. plain and contrast magnetic resonance imaging (mri) of the brain and spine was essentially normal, although an mri scan of the lumbosacral plexus was not performed. tests aiman k. al-wahaibi, santosh kumar, ali al-risi and farook wali case report | e461 improvement in nerve conduction was noted after 12 weeks, coinciding with the patient’s clinical and biochemical recovery [table 1].7 discussion this case report describes a patient who presented with acute-onset rapidly progressive polyradiculoneuropathy involving only the lower limbs, without evidence of cranial nerve dysfunction or sphincter involvement. the absence of cranial nerve involvement, a normal cerebrospinal fluid examination and the presence of striking sensory involvement on electrophysiological studies made a diagnosis of guillain-barré syndrome unlikely.8 thyrotoxic periodic paralysis (tpp) was subsequently considered, since the patient’s clinical signs correlated with hyperthyroidism. patients with tpp usually present with muscle cramps with the lower extremities more often affected than the upper extremities in a proximalto-distal pattern of involvement.9 the attack can last for hours to days and improve with treatment of the thyrotoxicosis. however, the majority of patients with tpp have precipitating factors such as a carbohydraterich diet or muscle cooling immediately following exercise; moreover, hypokalaemia (serum potassium levels of <2.5 μmol/l) is also often detected, along with low tsh levels together with reduced-amplitude for collagen vascular diseases (i.e. systemic lupus erythematosus or polyarteritis nodosa) were negative. epstein-barr virus, cytomegalovirus, hepatitis b and retroviral infections were also excluded by appropriate serology. two weeks after the onset of the patient’s illness, nerve conduction studies revealed mixed axonal and demyelinating polyneuropathy in both the motor and sensory nerves. concentric needle electromyography (emg) showed moderate-to-severe active denervation in the bilateral extensor digitorum brevis, tibialis anterior, gastrocnemius and vastus medialis muscles. in contrast, nerve conduction was normal in the upper extremities. according to the emg findings, there were no fasciculations in the lower extremities and the motor unit action potentials were of high amplitude with incomplete recruitment. the patient was pres cribed a combination of a β-blocker (120 mg/day of propranolol) and 40 mg/day of carbimazole alongside intensive physiotherapy. after three weeks of treatment, thyroid function tests revealed t4 and tsh levels of 35.4 pmol/l and 0.01 iu/ml, respectively. after six weeks, the patient’s tremors disappeared, the tachycardia stabilised and the motor power of the lower limbs improved to grade 4/5; moreover, reflexes were elicited as normal and the patient became ambulant. at this time, the t4 levels had decreased to 23.36 pmol/l and tsh levels remained at 0.01 iu/ml. table 1: sequential nerve conduction studies in a patient with acute-onset rapidly progressive flaccid areflexic paraplegia associated with hyperthyroidism nerve* at baseline after 12 weeks of antithyroid treatment distal latency in ms amplitude conduction velocity in m/s distal latency in ms amplitude conduction velocity in m/s peroneal left nr 0.0 mv nr 6.0 3.5 mv 46.0 right 9.0 0.6 mv 39.3 4.0 4.1 mv 44.0 tibial left 3.7 2.1 mv 31.5 right 3.2 2.5 mv 36.0 sural left 3.8 9.0 µv 36.8 right 3.9 9.7 µv 35.9 superficial peroneal left 4.8 0.6 µv 43.8 4.5 2.8 µv 45.6 right 6.0 0.0 µv na na na na nr = not reproducible; na = not assessed. *normal ranges for motor nerves are as follows: distal latency: 3.4–6.2 ms; amplitude: 6–15 mv; and conduction velocity: 42–55 m/s. normal ranges for sensory nerves are as follows: distal latency: 2.5–3.6 ms; amplitude: >10 µv; and conduction velocity: 38–55 m/s.7 m ot or n er ve s se ns or y ne rv es thyrotoxic neuropathy a rare cause of acute flaccid paraplegia e462 | squ medical journal, november 2017, volume 17, issue 4 compound motor action potentials during clinical attacks.9 such features were not present in the current case; the patient’s serum potassium levels were normal and his nerve conduction findings were not typical for tpp, although provocative tests were not carried out. eventually, the patient’s gradual clinical and electrophysiological response to antithyroid treatment confirmed the diagnosis of neuropathy. common causes of acute polyneuropathy aside from hyperthyroidism are presented in table 2.3,5,8 in the current case, these causes were considered but eventually excluded as a result of various investigations. heavy metal poisoning was deemed unlikely from the patient’s history, the electrophysiological findings and his rapid recovery. spinal epidural abscesses, haemorrhage into the spinal cord and spinal cord injuries were also excluded by mri. acute porphyric neuropathy is rare in this geographical region of the world and neurosarcoidosis even more so.5 tick paralysis was also not considered in the present patient as, to the best of the authors’ knowledge, this disease has never been reported in oman. however, an acute polyneuropathy-like illness could also be a presenting feature of poliomyelitis, botulism, critical illness neuromyopathy and diphtheria.5,8 moreover, anterior horn cell syndrome secondary to hyperthyroidism (i.e. thyroid amyotrophy) may be possible.3 the association of thyrotoxicosis with acute peripheral neuropathy simulating guillain-barré syn drome has been reported in previous research; moreover, chronic subclinical peripheral neuropathy has been previously reported in hyperthyroidism, although less frequently than in hypothyroidism.10,11 paraplegia related to severe hyperthyroidism was first described by charcot in 1889.12 however, the association between hyperthyroidism and acute polyneuropathy has been questioned, with the muscle weakness believed to be secondary to a myopathic process rather than a polyneuropathy.5 however, pandit et al. reported a patient for whom electron microscopic studies on sural nerve biopsies revealed changes consistent with thyrotoxicosis, but different from guillain-barré syndrome.6 other researchers have also concluded that thyrotoxic myopathy is actually a neuropathic disorder in its early stage of denervation.3 a prospective study of hyperthyroid patients found that 14% had numbness and paresthaesia and 19% had signs of distal sensory disturbances in the limbs with depressed ankle jerks.13 electrophysiological findings confirmed predominantly sensory axonal neuropathy among 24%; moreover, with treatment of the hyperthyroidism, the sensory symptoms resolved within seven months.13 surprisingly, acute thyrotoxic neuropathy has not been reported in children.14 the pathogenesis of neuropathy in hyperthyroidism is still obscure. it has been postulated to be either a direct effect of excessive thyroid hormones, immune-mediated or due to a hypermetabolic state depleting the nerves of essential nutrients.3 a high index of suspicion of thyroid dysfunction is of paramount importance when evaluating a patient with acute polyneuropathy, even in the absence of overt thyromegaly or a history of thyroid disorders. thyroid function tests should therefore be included in the routine work-up of acute polyneuropathy cases. conclusion acute polyneuropathy in hyperthyroidism is relatively rare. this report describes a patient who presented with acute polyradiculoneuropathy as the primary manifestation of thyrotoxicosis and for whom antithyroid treatment coincided with his clinical recovery. references 1. engel ag. neuromuscular manifestations of graves’ disease. mayo clin proc 1972; 47:919−25. 2. swanson jw, kelly jj jr, mcconahey wm. neurologic aspects of thyroid dysfunction. mayo clin proc 1981; 56:504−12. 3. mccomas aj, sica re, mcnabb ar, goldberg wm, upton ar. neuropathy in thyrotoxicosis. n engl j med 1973; 289:219−20. doi: 10.1056/nejm197307262890420. 4. fisher m, mateer je, ullrich i, gutrecht ja. pyramidal tract deficits and polyneuropathy in hyperthyroidism: combination clinically mimicking amyotrophic lateral sclerosis. am j med 1985; 78:1041−4. doi: 10.1016/0002-9343(85)90231-1. table 2: other causes of acute polyneuropathy aside from hyperthyroidism3,5,8 cause periodic paralysis (i.e. hypokalaemia) botulism collagen vascular diseases (i.e. sle/pan) lead poisoning poliomyelitis critical illness neuromyopathy cmv, ebv and hepatitis b infections diphtheria retroviral infections (i.e. hiv) neurosarcoidosis tick paralysis spinal cord haemorrhage/epidural abscesses sle = systemic lupus erythematosus; pan = polyarteritis nodosa; cmv = cytomegalovirus; ebv = epstein-barr virus. https://doi.org/10.1056/nejm197307262890420 https://doi.org/10.1016/0002-9343%2885%2990231-1 aiman k. al-wahaibi, santosh kumar, ali al-risi and farook wali case report | e463 5. dyck pj. neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. in: dyck pj, thomas pk, griffin jw, low pa, poduslo jf, eds. peripheral neuropathy, 3rd ed. philadelphia, pennsylvania, usa: saunders, 1993. pp. 1065−93. 6. pandit l, shankar sk, gayathri n, pandit a. acute thyrotoxic neuropathy: basedow’s paraplegia revisited. j neurol sci 1998; 155:211−14. doi: 10.1016/s0022-510x(97)00313-4. 7. lee hj, delisa ja. manual of nerve conduction study and surface anatomy for needle electromyography, 4th ed. philadelphia, pennsylvania, usa: lippincott williams, 2004. p. 43. 8. wijdicks ef, klein cj. guillain-barré syndrome. mayo clin proc 2017; 92:467−79. doi: 10.1016/j.mayocp.2016.12.002. 9. burge ja, hanna mg. novel insights into the pathomechanisms of skeletal muscle channelopathies. curr neurol neurosci rep 2012; 12:62−9. doi: 10.1007/s11910-011-0238-3. 10. ropper ah, wijdicks ef, truax bt. guillain-barré syndrome. in: contemporary neurology series, 5th ed. oxford, uk: oxford university press, 1991. p. 232. 11. feibel jh, campa jf. thyrotoxic neuropathy (basedow’s paraplegia). j neurol neurosurg psychiatry 1976; 39:491−7. doi: 10.1136/jnnp.39.5.491. 12. charcot j. [new signs of graves’ disease]. bull med 1889; 3:147−9. 13. duyff rf, van den bosch j, laman dm, van loon bj, linssen wh. neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. j neurol neurosurg psychiatry 2000; 68:750−5. doi: 10.1136/jnnp.68.6.750. 14. nandi-munshi d, taplin ce. thyroid-related neurological disorders and complications in children. pediatr neurol 2015; 52:373−82. doi: 10.1016/j.pediatrneurol.2014.12.005. https://doi.org/10.1016/s0022-510x%2897%2900313-4 https://doi.org/10.1016/j.mayocp.2016.12.002 https://doi.org/10.1007/s11910-011-0238-3 https://doi.org/10.1136/jnnp.39.5.491 https://doi.org/10.1136/jnnp.68.6.750 https://doi.org/10.1016/j.pediatrneurol.2014.12.005 in our paper published in squ medical journal in december 2009, we presented our early experience with radial artery catheterisation as an alternative route to the femoral artery for coronary angiography.1 most of our findings were compatible with many previously published papers, but there where also disagreements, especially about the cross-over rate from the radial to the femoral approach which was higher (17.1%) in our study. we pointed out, however, that the cross-over was less in the second half of the study indicating developing technical expertise, nonetheless, the figure of 17.1% was still high and required explanation. in our study we compared 116 patients (femoral group) with 105 patients (radial group). the reasons for the cross-over from radial to femoral are illustrated in the flow chart [figure 1]. first, as explained below, three patients (2.9% of total patients and 17.5% of all cross-over patients) had a positive allen’s test indicative of incomplete palmar arch flow and were considered as failed procedures. the study by greenwood et al. carefully assessed the relative contribution of collateral palmar circulation during 30 minutes of radial artery occlusion.2 their conclusion was an abnormal allen's test is not valid as a contraindication to trans-radial cardiac catheterisation. moreover, ghuran et al. ceased screening the palmar flow (allen’s test) before radial access,3 negating its importance as a preliminary safety test before radial artery puncture. in our study, in patients with a positive allen’s test we did not attempt the radial approach and planned straightaway for a femoral approach. these patients were erroneously considered as cross-overs from the radial to the femoral approach. second, ten patients in whom we failed to access the radial artery constituted the main bulk of crossovers (58.8%). this figure was dramatically reduced in the second half of the study. these failed procedures squ med j, august 2010, vol. 10, iss. 2, pp. 269-271, epub. 19th jun 10 submitted: 29th apr 10 internally reviewed املعدل العالي لتصوير األوعية التاجية عرب الشريان الكعربي مقارنة بالشريان الفخذي هل لدينا تعليل ؟ من�شور �شالم وحفيظ الهادي the higher cross-over rate from transradial to transfemoral coronary angiography do we have the explanation? *mansour sallam and hafidh al-hadi letter to editor department of medicine & health sciences, sultan qaboos university hospital, muscat, oman. *corresponding author email:mansoursallam@yahoo.com positive allen's test 3 (2.9%) 3 (2.9%) 10 (9.37%) 2 (1.93%) access site failure spasm tortuosity figure 1: the various causes in numbers and (percentages) for the crossover from the radial to the femoral approach. the higher cross-over rate from trans-radial to trans-femoral coronary angiography do we have the explanation? 270 | squ medical journal, august 2010, volume 10, issue 2 occurred despite improving experience and in the presence of good radial pulse. currently, as part of an ongoing study, we are doing brachial artery angiography to assess the feasibility of using both radial and ulnar arteries as access sites for coronary angiography and intervention and to exclude procedural vascular complications. this study disclosed many anatomic variations including an absent radial artery and the radial area supplied by microvessels [figure 2]. it would have been impossible to cannulate such radial arteries, despite the not infrequent presence of a good peripheral radial pulse. moreover, we routinely cannulated the ipsilateral ulnar artery if we failed to engage the radial artery, definitely reducing the crossover rate from arm to groin. third, two patients experienced severe radial artery spasm (1.93% of total patients and 11. 7% of all crossovers). in the initial phase of the study we tended to abandon the procedure prematurely if there was severe spasm. with further experience we learned to mange this problem successfully by an additional bolus doses of the routine vasodilatory cocktail glyceryle trinitrate 200 mcg and verapamil 2.5 mg. fourth, three patients (2.9% of total patients and 17.5% of all cross-over) had significant vessel tortuosity [figure 3]. currently, we have acquired extra support exchange guide wires to overcome this problem. in summary, we have found that the following, as possible confounding factors, led us to conclude a higher rate of cross-over from the transradial to the transfemoral approach: 1) abnormal allen’s test; 2) severe spasm; 3) severe tortousity, and 4) anatomical variation of the radial artery. the elimination of some of these patients from the study would have reduced the cross-over rate. if we apply the strategy of successful ulnar artery cannulation after failure of radial artery access, and eliminate those with positive allen’s test from the study, our rate of cross-over will be decreased further and match the international standard (from 3–8%). we have also acquired the necessary tools to overcome some of the obstacles encountered before, e.g. severe spasm and tortousity. for the time being, the radial artery approach has become the standard preferred access site method for both diagnostic and interventional coronary procedures in our institutition. based on the last 307 procedures of radial artery catheterisations performed after the completion of the figure 2: dashed arrow: radial artery is thread-like and the radial area is supplied by collateral circulation from ulnar artery (continuous arrow). it was immposible to cannulate an artery which was less than the size of the access sheath figure 3: markedly tortuous right subclavian artery and aortic arch. we could overcome this not uncommon anatomic finding, especially in elderly patients, by using extrasupport guidewire and asking the patient to take deep breath and hold it during catheter advancement mansour sallam and hafidh al-hadi letter to editor | 271 above study, and consideration of the above factor, our current rate of cross-over is 6.8%, which is consistent with international standards (7.7%).4 references: 1. sallam m, al hadi h, rattinasekar s, chandy s. comparative study of the radial and femoral artery approaches for diagnostic coronary angiography. squ med j 2009; 9:272–9. 2. greenwood mj, della-siega aj, fretz eb, kinloch d, klinke p, mildenberger r, et al. vascular communications of the hand in patients being considered for trans-radial coronary angiography: is the allen's test accurate? j am coll cardiol 2005; 46:2013–17. 3. ghuran a, dixon g, de belder a, holmberg s, hildick-smith d. transradial coronary intervention without prescreening for a dual palmar blood supply (abstr). heart 2005; 91 suppl: a5–i122. 4. hetherington sl, adam z, morley r, de belder ma, hall ja, muir df, et al. primary percutaneous coronary intervention for acute st-segment elevation myocardial infarction: changing patterns of vascular access, radial versus femoral artery. heart 2009; 95:1612–8. congenital diaphragmatic agenesis (cda) is an extreme congenital defect which occurs due to the complete absence of the septum transversum and pleuroperitoneal membranes with an associated impaired development of the thoracic intercostal muscles.1,2 the incidence of cda is one in 250,000 births.1–6 cda forms a rare part of the of the congenital diaphragmatic hernia (cdh) spectrum. in comparison, the prevalence of cdh is one in 2,200–2,450 births.3–6 the mortality rate of cdh is high (85–95%) due to lung hypoplasia, pulmonary hypertension and associated cardiac anomalies.3–8 however, the survival rate of children with large congenital diaphragmatic defects has increased due to recent advances in neonatal care.9 reconstruction of a functional diaphragm among young patients with large diaphragmatic defects can be a difficult surgical procedure. the neodiaphragm should be an intact compliant functional muscular entity that grows with the child and ensures pleuroperitoneal separation. the disadvantages of a synthetic mesh repair include recurrence of the defect, patch migration or infection, progressive chest wall deformities and restrictive pulmonary function.2,6–11 in previous reports, diaphragms with large defects have been reconstructed in two or more stages.2,3,6,7,9 1department of surgery, medcare hospital, dubai, united arab emirates; 2department of neonates, nmc specialty hospital, dubai, united arab emirates *corresponding author e-mail: madan.samuel@yahoo.co.uk إصالح أويل لعيب خلقي يف اجلانب األمين للحجاب احلاجز بألواح عضلية من الظهرية العريضة مشرتكة مع املنشارية األمامية يف املولود �ش�موئيل م�دان و راجيف ب�رابوراث abstract: large diaphragmatic defects can be repaired with latissimus dorsi and serratus anterior muscle flaps. we report the first successful primary repair of complete congenital diaphragmatic agenesis using a combination of autologous living bio-tissue and synthetic mesh in a neonate born in the nmc specialty hospital in dubai, united arab emirates, in may 2014. poor apgar scores, a scaphoid abdomen and absent breath sounds over the right hemithorax were observed at birth. chest and abdominal x-rays revealed a diaphragmatic hernia. the neonate was stabilised using high-frequency oscillatory ventilation, nitric oxide and sildenafil. the right diaphragm was reconstructed using combined latissimus dorsi and serratus anterior muscle flaps reinforced by a flexible composite mesh. at 12 months old, the infant had normal respiratory function and the diaphragm was intact. no disabilities of the shoulder or scapula were observed. this case indicates that a combination of living tissue and synthetic mesh can be used to reconstruct a functional diaphragm with efficient pleuroperitoneal separation. keywords: congenital diaphragmatic hernia; neonate; reconstructive surgical procedures; autologous transplantation; surgical mesh; sildenafil citrate; case report; united arab emirates. هن� اأول نعر�ص واملن�ش�رية االأم�مية. العري�شة الظهرية من ع�شلية ب�ألواح احل�جز احلج�ب يف الكبرية العيوب ميكن اإ�شالح امللخ�ص: ح�لة اإ�شالح ابتدائية اأجريت بنج�ح ك�مل حلج�ب ح�جزغري مكتمل ب�شبب عيب خلقي ب��شتخدام مزيج من ن�شيج بيولوجي متكون ذاتي� ون�شيج ا�شطن�عي يف حديثي الوالدة الذين ولدو يف م�شت�شفى nmc التخ�ش�شي يف دبي، االإم�رات العربية املتحدة يف م�يو 2014. القيم املتدنية لعالمة اأبغ�ر والبطن الزورقي وغي�ب اأ�شوات تنف�ص �شق ال�شدر االأمين لوحظت عند الوالدة. االأ�شعة ال�شينية لل�شدر والبطن اأظهرت بن�ء اأعيد و�شيلدين�فيل. النيرتيك اأك�شيد الرتدد، ع�لية التذبذبية التهوية ب��شتخدام املولود و�شع ا�شتقر وقد احل�جز. احلج�ب يف فتق احلج�ب احل�جز االأمين ب��شتخدام األواح ع�شلية من الظهرية العري�شة م�شرتكة مع املن�ش�رية االأم�مية تعززه� �شبكة مرنة مركبة. عند بلوغ الر�شيع 12 �شهرا من عمره اأ�شبحت وظيفة اجله�ز التنف�شي ع�دية وك�ن احلج�ب احل�جز �شليم�. مل يالحظ اأي اإع�قة يف الكتف اأو العظم الكتفي. ت�شري هذه احل�لة اإىل اأن تركيبة من االأن�شجة احلية وال�شبك�ت اال�شطن�عية ميكن ا�شتخدامه� الإع�دة بن�ء حج�ب ح�جز وظيفي مع . ف�ِقيُّ ف�شل فع�ل للَجْنِبيُّ ال�شِّ مفتاح الكلمات: فتق احلج�ب احل�جز اخللقي؛ مولود؛ العملي�ت اجلراحية الرتميمية؛ زرع ذاتي؛ �شبكة جراحية ؛ �شيرتات ال�شيلدين�فيل؛ تقرير ح�لة؛ االإم�رات العربية املتحدة. primary combined latissimus dorsi and serratus anterior flap repair of right-sided congenital diaphragmatic agenesis in a neonate *madan samuel1 and rajiv parapurath2 sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e96–100, epub. 2 feb 16 submitted 9 jul 15 revision req. 13 aug 15; revision recd. 31 aug 15 accepted 17 sep 15 case report doi: 10.18295/squmj.2016.16.01.018 madan samuel and rajiv parapurath case report | e97 a primary neonatal synthetic patch is usually subsequently replaced by a reversed latissimus dorsi muscle flap in childhood; the secondary reconstructed autologous living tissue flap provides a high-quality and functional diaphragm.2,9,12 primary reconstruction of a diaphragm utilising combined latissimus dorsi and serratus anterior muscle flaps on a matrix of flexible composite mesh has not yet been reported in the literature. this report describes the preoperative stabilisation and primary reconstruction of the diaphragm of a neonate with complete cda utilising living autologous bio-tissue and synthetic mesh. case report a 26-year-old primigravida woman gave birth at 39 gestational weeks to a full-term male infant weighing 2,580 g via supervised vaginal delivery at the nmc specialty hospital in dubai, united arab emirates, in may 2014. the infant was born to consanguineous parents who were first cousins with an inbreeding coefficient of >0.0156. poor apgar scores, a scaphoid abdomen and absent breathing sounds over the right hemithorax were observed at birth. combined chest and abdominal x-rays revealed a right-sided diaphragmatic hernia [figure 1]. cytogenetic analysis indicated a normal male karyotype (46,xy). further neonatal and metabolic screening tests were also normal. despite optimal mechanical ventilation, preductal partial pressure of oxygen and carbon dioxide in the arterial blood were 6.6–7.8 kilopascals (kpa) and ≥6.0 kpa, respectively. the persistent hypoxia was associated with severe pulmonary hypertension with a three-dimensional (3d) echocardiogram showing a mean pulmonary artery versus mean systemic artery pressure ratio of >1. the illness severity and mortality risk of the neonate was assessed using the validated score for neonatal acute physiologyperinatal extension-ii (snappe-ii) [figure 2].13 at six hours old, the infant required high-frequency oscillatory ventilation and 20 parts per million of inhaled nitric oxide due to persistent hypoxia, severe pulmonary hypertension and a high snappe-ii score (67). haemodynamic instability necessitated inotropic support with dobutamine (10.0 µg/kg/minute) and dopamine (20.0 µg/kg/minute). a high oxygenation index of >45 prompted the administration of sildenafil (1 mg/kg every six hours). subsequently, a postloading dose infusion of 0.6 µg/kg/minute of milrinone was administered. the neonate was gradually stabilised over a period of 15 days and was weaned onto conventional mechanical ventilation by the age of 18 days. the neonate underwent a right-sided thoracotomy through the eighth intercostal space at 22 days old. the three lobes of the right lung were atelectatic, hypoplastic and consolidated. the diaphragm was absent in the anterior, posterior and lateral aspects. the phrenic nerve was identified along the pericardium and was traced to the small fibrous rim of tissue in the medial aspect of the posterior costophrenic recess and subsequently preserved [figure 3a]. the right adrenal gland, kidney, liver and small and large bowel formed the hernial contents. the appendix had herniated through the mesoappendix causing a partial cecal volvulus and was attached to the posterior chest wall by fibrovascular adhesions. adhesiolysis freed the inflamed appendix and caecum and an appendectomy was performed. the non-rotated intestines and solid viscera were returned to the peritoneal cavity. figure 1 a&b: combined chest and abdomen x-rays of a male infant with right-sided congenital diaphragmatic agenesis in the (a) anteroposterior and (b) lateral aspects. a diaphragmatic hernia with herniation of the liver and intestinal loops into the right hemithorax was observed with complete absence of aeration in the right lung. the left diaphragm was intact with the stomach located in the peritoneal cavity. note the marked mediastinal shift and impaired left lung with early signs of bronchopulmonary dysplasia. figure 2: illness severity and mortality risk* of a male infant with right-sided congenital diaphragmatic agenesis between six hours and 18 days since birth. snappe-ii = score for neonatal acute physiology-perinatal extension-ii; h = hours; d = days. *illness severity and mortality risk were assessed using the snappe-ii instrument with high scores correspondingly reflecting high illness severity and risk of mortality.13 primary combined latissimus dorsi and serratus anterior flap repair of right-sided congenital diaphragmatic agenesis in a neonate e98 | squ medical journal, february 2016, volume 16, issue 1 were sutured to the periosteum using 3-0 nonabsorbable polypropylene sutures with a double-loop mattress interrupted suture technique.14 the suture line was reinforced by subcostal anchoring sutures. an end-to-side neural co-optation of the thoracodorsal nerve and phrenic nerve was performed using 9-0 polypropylene sutures. the nerve supply to the upper slips of the serratus anterior was meticulously maintained throughout the reconstruction in order to prevent winging of the scapula. the postoperative recovery period was uneventful and the neonate was extubated on the third postoperative day. at two months of age, he was breathing room air with normal respiratory function and had achieved full oral feeds. administration of sildenafil was tapered and subsequently stopped when the infant was three months old. by the time he was 12 months old, neurological developmental, hearing and ophthalmic evaluations were normal. anthropometric measurements of weight (50th percentile), length (75th percentile) and head circumference (75th percentile) were all age-appropriate. results of the denver developmental screening test ii were normal (75th percentile). an intact right hemidiaphragm with uniform non-paradoxical movements during respiration and complete right lung expansion was observed via ultrasonography and fluoroscopy [figure 4]. electromyography showed normal function of the skeletal muscles with a phrenic nerve conduction the dermo-adipose skin flaps were raised to allow visualisation of the right hemithorax and the neurovascular and muscular anatomy. the head of the latissimus dorsi was transected and the muscle was freed from the chest wall. the thoracodorsal artery, vein and nerve were identified and maintained with the flap. the latissimus dorsi flap also had an intact wide-based vascular pedicle observed through the lumbar perforators. following the harvesting of the latissimus dorsi, the thoracodorsal vascular pedicle supplying the lower three slips of the serratus anterior muscle was observed along with the long thoracic nerve. the slips were exposed from their origin on the inferior angle of the scapula to the rib insertions. the artery and nerve to the serratus were dissected proximally and mobilised by intrafascicular dissection. the thoracodorsal artery was divided into two large branches. these two branches, the thoracodorsal vein and the circumflex scapular vascular bundle were identified and preserved. the lower edge of the serratus was delineated at the ninth rib. the posterior plane was developed up to the angle of the scapula. posterior insertions of the muscle to the scapula and anterior insertions to the seventh, eighth and ninth ribs were detached using monopolar cautery. the absence of a distinct plane required cauterisation of several small perforating vessels from the intercostal muscles. this allowed the isolation of the major vascular pedicle (≥15 cm) up to the subcapular artery. the superior border of the 10th rib was retracted and the intercostal muscles were freed. a combined tension-free flap was placed into the chest through the space created. to avoid the possibility of pedicle torsion, the latissimus dorsi and serratus anterior tissue formed the posterolateral dorsal and anterolateral ventral aspects of the neo-diaphragm, respectively [figure 3b]. a flexible composite mesh (ethicon physiomesh® #phy1515q, johnson & johnson medical gmbh, norderstedt, germany) formed the matrix. the composite muscle and mesh figure 3 a&b: perioperative photographs of a male infant with right-sided congenital diaphragmatic agenesis demonstrating the (a) absent right diaphragm with a small fibrotic oesophageal mesenteric rim in the medial aspect and (b) reconstruction of the diaphragm with serratus anterior and latissmus dorsi flaps. figure 4: fluoroscopy image showing the small hypoplastic right lung and normal domed right diaphragm of a male infant following reconstruction of the diaphragm due to right-sided congenital diaphragmatic agenesis. note that the mediastinum has returned to the midline, which is a normal feature of post-diaphragmatic repairs. madan samuel and rajiv parapurath case report | e99 velocity of 20–22 metres/second. the heart was normal as per a 3d echocardiograph. there was no winging of the scapula or any other chest deformities and the right shoulder and arm had normal function. discussion cda is a rare anomaly occurring in 5% of neonates diagnosed with cdh.2–7,9 in 98% of reported cases, cda is a left-sided defect with a high mortality rate of 85–95%.3–7 right-sided cda has a high mortality rate in comparison to right-sided cdh (95–98% versus 50–70%).2–7,9,10 the present report details a unique case of right-sided cda with complete hemidiaphragmatic agenesis associated with impaired development of the thoracic intercostal muscles and oesophageal mesentery. the defect was repaired using an autologous living bio-tissue flap to facilitate the development of a compliant neo-diaphragm that would provide effective pleuroperitoneal separation. in the current case, preoperative stabilisation of the patient was enhanced by the use of selected vasodilators and phosphodiesterase type five and type three enzyme inhibitors. these agents increase the levels of cyclic guanosine monophosphate, resulting in vascular smooth muscle relaxation and increased pulmonary blood flow.15 the synergistic action of inhaled nitric oxide, sildenafil and milrinone therefore improve circulatory haemodynamics.15 the uncomplicated postoperative recovery course was likely due to improved lung angiogenesis and alveolar growth in association with a compliant diaphragm. sildenafil may also have prevented any worsening of the contralateral bronchopulmonary dysplasia.15 in most instances, large diaphragmatic defects in neonates are primarily repaired using a synthetic mesh which invariably leads to recurrence due to mesh migration, abscess formation/sepsis due to infection, progressive chest wall deformities due to mesh constriction or deterioration of pulmonary function due to noncompliance.2,9–12 synthetic durable patches and acellular collagen matrices that can be remodelled by the host tissue cannot be used as neo-diaphragms due to poor compliance.16 primary reconstruction with living bio-tissue avoids the complications of synthetic mesh repairs. the serratus anterior muscle originates from the lateral scapula and fans anteriorly into the first nine ribs. a medium-sized flap can be obtained by harvesting the lower three slips which have an independent blood and nerve supply. the latissimus dorsi and serratus anterior muscle flaps are nourished by a substantial anatomically reliable subscapular-thoracodorsal vascular pedicle and lumbar perforators. double-loop mattress interrupted sutures also help to form a compliant resilient hemidiaphragm.14 approximately 25% of the population have two thoracodorsal arteries.17 in the current case, this phenomenon may have helped to sustain good vascularity to the harvested flaps. neuroanastomosis between the phrenic and the thoracodorsal nerve also ensured function. additionally, the domed neo-diaphragm was both vascular and tensile to ensure growth and retain compliance and function, respectively; this resulted in efficient pleuroperitoneal separation and adequate cardiopulmonary function. utilising a similar procedure with left-sided latissimus dorsi and serratus anterior muscle flaps may potentially repair left-sided cda. conclusion this is the first report of a successful primary reconstruction utilising combined latissimus dorsi and serratus anterior muscle flaps on a matrix of flexible composite mesh in a neonate with complete right-sided cda. at a 12-month follow-up, the neodiaphragm was functional and the infant had no disabilities of the shoulder or scapula. references 1. tsang tm, tam pk, dudley ne, stevens j. diaphragmatic agenesis as a distinct clinical entity. j pediatr surg 1995; 30:16–18. doi: 10.1016/0022-3468(95)90599-5. 2. samarakkody u, klaassen m, nye b. reconstruction of congenital agenesis of hemidiaphragm by combined reversed latissimus dorsi and serratus anterior muscle flaps. j pediatr surg 2001; 36:1637–40. doi: 10.1053/jpsu.2001.27937. 3. neville hl, jaksic t, wilson jm, lally pa, hardin wd jr, hirschl rb, et al. bilateral congenital diaphragmatic hernia. j pediatr surg 2003; 38:522–4. doi: 10.1053/jpsu.2003.50092. 4. ruano r, takashi e, da silva mm, campos ja, tannuri u, zugaib m. prediction and probability of neonatal outcome in isolated congenital diaphragmatic hernia using multiple ultrasound parameters. ultrasound obstet gynecol 2012; 39:42–9. doi: 10.1002/uog.10095. 5. tudorache s, chiuţu lc, illiescu dg, georgescu r, stoica ga, simionescu ce, et al. prenatal diagnosis and perinatal outcome in congenital diaphragmatic hernia: single tertiary center report. rom j morphol embryol 2014; 55:823–33. 6. jani p, bidarkar ss, walker k, halliday r, badawi n, cohen rc. right-sided congenital diaphragmatic hernia: a tertiary centre’s experience over 25 years. j neonatal perinatal med 2014; 7:39–45. doi: 10.3233/npm-1474313. 7. fisher jc, jefferson ra, arkovitz ms, stolar cj. redefining outcomes in right congenital diaphragmatic hernia. j pediatr surg 2008; 43:373–9. doi: 10.1016/j.jpedsurg.2007.10.049. 8. koziarkiewicz m, taczalska a, piaseczna-piotrowska a. longterm follow-up of children with congenital diaphragmatic hernia: observations from a single institution. eur j pediatr surg 2014; 24:500–7. doi: 10.1055/s-0033-1357751. http://dx.doi.org/10.1016/0022-3468%2895%2990599-5 http://dx.doi.org/10.1053/jpsu.2001.27937 http://dx.doi.org/10.1053/jpsu.2003.50092 http://dx.doi.org/10.1002/uog.10095 http://dx.doi.org/10.3233/npm-1474313 http://dx.doi.org/10.1016/j.jpedsurg.2007.10.049 http://dx.doi.org/10.1055/s-0033-1357751 primary combined latissimus dorsi and serratus anterior flap repair of right-sided congenital diaphragmatic agenesis in a neonate e100 | squ medical journal, february 2016, volume 16, issue 1 14. biddlestone j, samuel m, creagh t, ahmad t. the double loop mattress suture. wound repair regen 2014; 22:415–23. doi: 10.1111/wrr.12159. 15. noori s, friedlich p, wong p, garingo a, seri i. cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. neonatology 2007; 91:92–100. doi: 10.1159/000097125. 16. mayer s, decaluwe h, ruol m, manodoro s, kramer m, till h, et al. diaphragm repair with a novel cross-linked collagen biomaterial in a growing rabbit model. plos one 2015; 10:e0132021. doi: 10.1371/journal.pone.0132021. 17. majumdar s, bhattacharya s, chatterjee a, dasgupta h, bhattacharya k. a study on axillary artery and its branching pattern among the population of west bengal, india. ital j anat embryol 2013; 118:159–71. 9. barbosa rf, rodrigues j, correia-pinto j, costa-ferreira a, cardoso a, reis jc, et al. repair of a large congenital diaphragmatic defect with a reverse latissimus dorsi muscle flap. microsurgery 2008; 28:85–8. doi: 10.1002/micr.20455. 10. zardo p, zhang r, wiegman b, haverich a, fischer s. biological materials for diaphragmatic repair: initial experience with the periguard repair patch®. thorac cardiovasc surg 2011; 59:40–4. doi: 10.1055/s-0030-1250499. 11. bekdash b, singh b, lakhoo k. recurrent late complications following congenital diaphragmatic hernia repair with prosthetic patches: a case series. j med case rep 2009; 26:7237. doi: 10.1186/1752-1947-3-7237. 12. sydorak rm, hoffman w, lee h, yingling cd, longaker m, chang j, et al. reversed latissimus dorsi muscle flap for repair of recurrent congenital diaphragmatic hernia. j pediatr surg 2003; 38:296–300. doi: 10.1053/jpsu.2003.50097. 13. richardson dk, corcoran jd, escobar gj, lee sk. snapii and snappe-ii: simplified newborn illness severity and mortality risk scores. j pediatr 2001; 138:92–100. doi: 10.1067/ mpd.2001.109608. http://dx.doi.org/10.1111/wrr.12159 http://dx.doi.org/10.1159/000097125 http://dx.doi.org/10.1371/journal.pone.0132021 http://dx.doi.org/10.1002/micr.20455 http://dx.doi.org/10.1055/s-0030-1250499 http://dx.doi.org/10.1186/1752-1947-3-7237 http://dx.doi.org/10.1053/jpsu.2003.50097 http://dx.doi.org/10.1067/mpd.2001.109608 http://dx.doi.org/10.1067/mpd.2001.109608 1department of medicine & rheumatology, kunhitharuvai memorial charitable trust medical college, kozhikode, india; 2department of internal medicine, government medical college, kozhikode, india *corresponding author’s e-mail: raveendranav@yahoo.co.in بنت مراهقة مصابة بتضخم مرتق يف األصابع تقرير حالة ومعايري تشخيصية مقرتحة لفرط النمو الالمتناسب الورمي الشحمي بينوي بول و رافني دران abstract: macrodystrophia lipomatosa (ml) is a rare congenital non-hereditary condition caused by an increase in all mesenchymal elements. we report a 14-year-old girl who presented to the medical outpatient department, kunhitharuvai memorial charitable trust medical college, kozhikode, india, in 2017 with progressive enlargement of digits. an x-ray and t1-weighted magnetic resonance imaging scan showed enlargement of the phalanges of the middle and index finger of the left hand with an overgrowth of soft tissues. the patient was subsequently diagnosed with ml. as the condition is benign and usually asymptomatic, no medical treatment was deemed necessary. this report describes a case of ml and proposes a set of diagnostic criteria to aid clinicians in the differential diagnosis of the condition. keywords: congenital disorders; gigantism; macrodactyly of the hand; differential diagnosis; case report; india. كل يف لزيادة نتيجة املر�س النادرة. الوراثية غري اخللقية الأمرا�س من واحداً ال�شحمي الورمي الالمتنا�شب النمو فرط يعد امللخ�ص: الوقفي كونهتهاريوفاي مل�شت�شفى اخلارجي الطب لق�شم ح�رصت عاما �شنها فتاة بحالة تقريرا هنا ونقدم املتو�شطة. اللحمة عنا�رص اخلريي لكلية الطب التذكارية يف كوزيكود بالهند يف عام 2017م، وهي م�شابة بت�شخم متطور يف الأ�شابع. واأظهرت نتيجة فح�س الأ�شعة ال�شينية و�شورة الرنني املغنطي�شي )t1-weighted( ت�شخما يف �شالميات الأ�شبع الأو�شط وال�شبابة، مع منو مفرط يف الأن�شجة الرخوة. م�شحوبة وغري حميدة احلالة اأن ومبا . ْحِميُّ ال�شَّ الَوَرِميُّ ُمَتَنا�شُب الالَّ النُُّموِّ َفْرُط اأنها على الفتاة تلك حالة ت�شخي�س مت ذلك على وبناء ْحِميُّ و ونقرتح ُمَتَنا�شُب الَوَرِميُّ ال�شَّ باأعرا�س، راأينا اأنه لي�س هنالك داع لأي عالج طبي للحالة. نقدم يف هذا التقرير حالة لَفْرُط النُُّموِّ الالَّ اأي�شا عددا من املعايري الت�شخي�شية مل�شاعدة الأطباء ال�رصيريني يف الت�شخي�س التفريقي لها. الكلمات املفتاحية: الأمرا�س اخللقية؛ عملقة؛ �شخامة الأ�شابع/اليد؛ الت�شخي�س التفريقي؛ تقرير حالة؛ الهند. an adolescent with progressive enlargement of digits case report and proposed diagnostic criteria for macrodystrophia lipomatosa binoy j. paul1 and *raveendran a. v.2 case report sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e553–556, epub. 28 mar 19 submitted 10 jun 18 revision req. 8 jul 18; revision recd. 17 jul 18 accepted 2 aug 18 doi: 10.18295/squmj.2018.18.04.023 first described in 1926, macrodystrophia lipomatosa (ml) is a rare congenital non-hereditary condition characterised by the progressive enlargement of one or more digits of the extremities, resulting in unilateral localised gigantism.1,2 the condition is usually present at birth and stops at puberty.3–5 a variety of terms are often used to describe ml cases, such as macromelia, digital or limited gigantism, megaloor macro dactyly, partial acromegaly, dactylomegaly, macroceir and club finger.3,4,6 the hallmark of ml is an increase in all mesenchymal elements of the affected digits, particularly the fibro-fatty tissue.4 in addition to the subcutaneous tissue, this condition can also affect the nerve sheath, muscle, periosteum and bone marrow.7 usually, ml affects the median nerve distribution area of the upper limbs and the medial plantar nerve distribution area of the lower limbs.3–5 most commonly, it affects the middle and index fingers; in the lower limbs, it usually causes enlargement of the first-to-third toes.2–5 like proteus syndrome, ml is a form of true macro dactyly where there is progressive hypertrophy of all mesenchymal elements, whereas an increase in a single mesenchymal element results in pseudo-macro dactyly, such as in neurofibromatosis type 1, fibrolipomatous hamartoma (flh) of the median or ulnar nerves and certain vascular malformations and acquired cond itions (i.e. chronic hyperaemia).3–5 although the exact pathogenesis of ml is unknown, proposed mechanisms include lipomatous degeneration, disturbed fetal circul ation, an imbalance in growth-inhibiting factors, the trophic influence of a tumefied nerve and errors in segment ation.6,8,9 this report describes a case of ml and proposes a set of diagnostic criteria to aid clinicians in the differential diagnosis of this condition. case report a 14-year-old girl presented to the medical outpatient department, kunhitharuvai memorial charitable trust medical college, kozhikode, india, in 2017 with progr essive enlargement of her left middle and index fingers over the previous three years [figure 1]. no systemic symptoms were reported. at birth, her parents had an adolescent with progressive enlargement of digits case report and proposed diagnostic criteria for macrodystrophia lipomatosa e554 | squ medical journal, november 2018, volume 18, issue 4 no evidence of any tenderness or cutaneous changes. the rest of the systemic examination was normal and the results of routine blood examinations were within normal limits. an x-ray of the left hand showed enlargement of the phalanges of the middle and index fingers with overgrowth of soft tissues [figure 2]. a t1-weighted magnetic resonance imaging (mri) scan showed enlarged phalanges with increased thickness of the subcutaneous fat planes [figure 3]. sagittal short-tau inversion recovery images confirmed the increased subcutaneous fat by signal suppression. these findings were consistent with a diagnosis of ml. the benign nature of the condition was explained to the patient and her parents. no cosmetic treatment was requested. discussion the differential diagnosis of ml includes flh, neurofibr omatosis (e.g. plexiform neurofibroma), haemangioma tosis, lymphangiomatosis, ollier disease and proteus, beckwith-wiedemann, maffucci and klippel-trénaunay weber syndromes.4,5 overall, flh can be differentiated from ml as the former usually produces isolated nerve lesions associated with intramuscular fat deposition, whereas fat deposition in the latter occurs in the nerve sheath as well as the subcutaneous and muscle compartments.4,5 in ml, there is also periosteal involvement resulting in bony changes like hypertrophy, exostosis and ankylosis in the interphalangeal joint and fatty invasion of the medullary cavity.4,5 in contrast, macro dactyly secondary to hyperaemia due to haemangiomatous or lymphangiomatous overgrowth produces only soft tissue hypertrophy. in addition, the absence of cutaneous and vascular abnormalities help to eliminate the possibility of klippel-trénaunay-weber syndrome, while the absence of enchondromas precludes ollier disease.4,5 in plexiform neurofibromatosis, overgrowth is often bilateral and either continues after puberty or stops prior to this stage due to the premature fusion of the growth plate as a result of haemangiomatous elements; in comp arison, ml cases are rarely bilateral and growth ceases at puberty.4 moreover, ml predominantly affects the distal phalanges. in neurofibromatosis, the enlarged osseous structures have a wavy cortex and an elongated sinuous appearance contrasting with that of ml cases; additionally, soft-tissue lucencies due to the neuro cutaneous manifestations of neurofibromatosis are absent in ml.10 the authors propose a set of diagnostic criteria to help clinicians in the differential diagnosis of ml cases [table 1]. the presence of essential clinical criteria along noticed a slight enlargement of her left middle finger. however, there was no family history of similar conditions or a personal history of any significant illnesses. an examination of her left hand showed diffuse overgrowth of the middle and index fingers. the affected fingers had the same consistency as her other fingers, with figure 1: photograph of the hands of a 14-year-old girl showing enlargement of the left middle and index fingers. figure 3: t1-weighted magnetic resonance imaging scan of the left hand of a 14-year-old girl showing enlargement of the phalanges of the middle and index fingers, with excess fibro-fatty tissue around the affected digits. figure 2: x-ray of the left hand of a 14-year-old girl showing enlargement of the phalanges of the middle and index fingers, with bony and soft tissue overgrowth. binoy j. paul and raveendran a. v. case report | e555 appearance of fat within a nerve sheath excludes the possibility of neurofibromatosis.5 in addition, neurofibr omas demonstrate marked hyperintensity close to the nerves in t2-weighted images; in flh, mri scans show enlargement of the fusiform nerve due to thickened nerve fibre embedded in fatty tissue.15 patients with ml are usually asymptomatic, although some can develop mechanical problems resulting from secondary degenerative changes in the joint and the compression of the neurovascular structure (i.e. carpel or tarsal tunnel syndromes).4 patients may also have functional issues, such as difficulty in grasping objects or, rarely, abnormal gait due to overgrowth of the affected region.4,6,16 other problems seen in ml cases include lipomatous growths in the intestines as well as other tissues, naevus pigmentation, calvarial abnormalities, pulmonary cysts, syndactyly, polydactyly, clinodactyly, brachydactyly and symphalangism.4 as ml is usually benign, medical attention is gener ally only necessary for cosmetic or aesthetic reasons.4 for those requiring surgical treatment, multiple debulking procedures, epiphysiodesis and osteotomies can be performed; however, such procedures can be challenging as there is a 33–60% risk of recurrence and a 30–50% risk of nerve injury due to overzealous debulking.2,17 for patients with severe ml-related functional and aesthetic concerns, amputation is an option.2 in children, the rate of growth of the affected digit can be slowed by destroying, stapling or wiring the epiphyseal plate.18 with either histopathological or radiological criteria is required for the diagnosis of ml. the histopathological analysis of ml cases generally reveals an increase in adipose tissue scattered in fine mesh-like fibrous tissue.4,11 plain x-rays show an overgrowth of soft tissue and bony elements, along with radiolucent areas due to the presence of adipose tissue. soft tissue overgrowth is usually seen more in the volar aspect, resulting in dorsal deviation, while bony overgrowth increases the width and length of the affected phalanges with distal splaying, resulting in a mushroom-like appearance.7 secondary osteoarthritis changes—like joint space narrowing, sub chondral cysts and osteophytes—may also be seen in adult patients.12 ultrasonography typically shows diffuse echogenicity consistent with increased fat accumulation in the subcutaneous and muscle tissues; this results in a loss of soft tissue detail and a decrease in grayscale reflectivity between soft tissue structures.13 computed tomography reveals bony overgrowth, excessive fat proliferation and, with muscle involvement, separation of the muscle fibres due to fatty infiltration.14 typically, mri scans show fatty infiltration of the muscles, cortical thickening and bony overgrowth.14 they may also show abundant fat tissue in the affected area, with the same low signal intensity as that of normal sub cutaneous fat on t1and t2-weighted mri sequences. linear hypointense bands in redundant adipose tissue represent fibrous strands.5 the absence of encapsulation helps to differentiate ml from a lipoma, while the table 1: proposed diagnostic criteria for cases of macrodystrophia lipomatosa type of criteria diagnostic necessity/certainty description clinical essential • unilateral localised gigantism, most commonly involving the median nerve area (first three fingers) in the upper limbs or the medial planter nerve area (first three toes) in the lower limbs • lack of family history of similar conditions • no cutaneous changes • no systemic symptoms • cessation of digit enlargement at puberty optional • presence of digit enlargement at birth • presence of related issues (i.e. syndactyly, polydactyly, clinodactyly, brachydactyly, etc.) histopathological confirmatory • evidence of an increase in all mesenchymal elements • evidence of increased adipose tissue scattered in a fine mesh-like fibrous tissue • evidence of both soft tissue and bony elements, with predominant fibro-fatty tissue hypertrophy radiological possible • x-ray evidence of overgrowth of both soft tissue and bony elements probable • ct evidence of bony overgrowth, excessive fatty proliferation and separation of the muscle fibres confirmatory • mri evidence of fatty infiltration of the muscles, cortical thickening and bony overgrowth of the affected area • mri evidence of increased thickness of the subcutaneous fat planes with linear hypointense fibrous bands in the adipose tissue without encapsulation • mri evidence of fat within the nerve sheath ct = computed tomography; mri = magnetic resonance imaging. an adolescent with progressive enlargement of digits case report and proposed diagnostic criteria for macrodystrophia lipomatosa e556 | squ medical journal, november 2018, volume 18, issue 4 7. gupta sk, sharma op, sharma sv, sood b, gupta s. macrodystrophia lipomatosa: radiographic observations. br j radiol 1992; 65:769–73. https://doi.org/10.1259/0007-1285-65-777-769. 8. kelikan h. congenital deformities of the hand and forearm. philadelphia, pennsylvania, usa: saunders, 1974. pp. 610–60. 9. barsky aj. macrodactyly. j bone joint surg am 1967; 49:1255–66. https://doi.org/10.2106/00004623-196749070-00001. 10. pitt mj, mosher jf, edeiken j. abnormal periosteum and bone in neurofibromatosis. radiology 1972; 103:143–6. https://doi. org/10.1148/103.1.143. 11. rohilla s, jain n, sharma r, dhaulakhandi db. macrodystrophia lipomatosa involving multiple nerves. j orthop traumatol 2012; 13:41–5. https://doi.org/10.1007/s10195-011-0159-6. 12. van den heever aj. macrodystrophia lipomatosa. s afr j radiol 2014; 18:a667. https://doi.org/10.4102/sajr.v18i2.667. 13. sone m, ehara s, tamakawa y, nishida j, honjoh s. macro dystrophia lipomatosa: ct and mr findings. radiat med 2000; 18:129–32. 14. cerofolini e, landi a, desantis g, maiorana a, canossi g, romagnoli r. mr of benign peripheral nerve sheath tumors. j comput assist tomogr 1991; 15:593–7. https://doi.org/10.1097 /00004728-199107000-00013. 15. soler r, rodríguez e, bargiela a, martĩnez c. mr findings of macrodystrophia lipomatosa. clin imaging 1997; 21:135–7. https://doi.org/10.1016/0899-7071(95)00095-x. 16. wu kk. macrodactylia fibrolipomatosis of the foot. j foot surg 1991; 30:402–5. 17. brodwater bk, major nm, goldner rd, layfield lj. macrodystrophia lipomatosa with associated fibrolipomatous hamartoma of the median nerve. pediatr surg int 2000; 16:216–18. https://doi.org/10.1007/s003830050728. 18. tsuge k. treatment of macrodactyly. plast reconstr surg 1967; 39:590–9. https://doi.org/10.1097/00006534-19670600000008. conclusion in summary, ml is a rare congenital non-hereditary condition resulting in localised gigantism. the condition is usually asymptomatic and treatment is for cosmetic reasons. this report describes a case of ml and proposes a set of diagnostic criteria to aid clinicians in accurately differentiating ml from other conditions with similar presentations. references 1. feriz h. [progressive macrodystrophia lipomatosa]. virchows arch pathol anat physiol klin med 1926; 260:308–68. https://doi.org/10.1007/bf01888444. 2. prasetyono to, hanafi e, astriana w. a review of macrodystrophia lipomatosa: revisitation. arch plast surg 2015; 42:391–406. https://doi.org/10.5999/aps.2015.42.4.391. 3. tuzuner t, parlak ah, kavak a, alper m. a neglected case of macrodystrophia lipomatosa of the foot in an elderly man. j am podiatr med assoc 2005, 95:486–90. https://doi.org/10.75 47/0950486. 4. khan ra, wahab s, ahmad i, chana rs. macrodystrophia lipomatosa: four case reports. ital j pediatr 2010; 36:69. https://doi.org/10.1186/1824-7288-36-69. 5. boren wl, henry re jr, wintch k. mr diagnosis of fibrolipomatous hamartoma of nerve: association with nerve territory-oriented macrodactyly (macrodystrophia lipomatosa). skeletal radiol 1995; 24:296–7. https://doi.org/10.1007/bf001 98419. 6. littler wj, cramer lm, smith jw, eds. symposium on reconstructive hand surgery: proceedings of the symposium of the educational foundation of the american society of plastic and reconstructive surgeons. st louis, missouri, usa: mosby, 1974. pp. 218–20. to the editor, i read with great interest your editorial in the squmj august issue “plagiarism and other types of publication misconduct”.1 it seems from your article that the main reason for the rise in plagiarism is the increasing pressure on faculty and staff in various institutions to publish, whatever their aptitude for research. in this “publish or perish” culture, a good clinician or a good teacher with no interest or aptitude for research is destined to lag behind his/her colleagues. this would be regardless of any other qualities and advantages s/he may bring to the hospital or institution. the situation s/he would face is to get left behind, or try his/her hand at activities that are not of personal interest, thus distracting him/her from more productive areas. digressing a little from the main thrust of your editorial, i wish to introduce the idea of a paradigm shift in the way we assess our medical personnel. perhaps it is time to broaden our assessment portfolio to include qualities other than research and publications for assessing the worth of individuals. these may include objective criteria for assessing the individual’s contribution to patient care, undergraduate and postgraduate teaching, and participation in departmental and interdepartmental activities or contributions in other areas. if proper assessment and weighting of these other types of contribution were done, it would both reduce the pressure on individuals to publish as well as enabling people who are interested in research to utilise the space left free by those who are not. this would lead to staff maximising their potential in the areas which interest them the most without hindering their upward mobility. i feel this would reduce the extent of plagiarism and possibly improve the quality of publications as they would be submitted by people who are genuinely interested in research. this may also help in retaining good clinicians and teachers in teaching institutions as, free of the pressure of publishing, they could devote more time and attention to what they are good at thus improving the quality of work across the board. anupam kakaria department of radiology & molecular imaging sultan qaboos university hospital muscat, sultanate of oman email: bittanupam@yahoo.com reference 1. al lamki l. plagiarism and other types of publication misconduct a case for teaching publication ethics in medical schools. squ med j 2009; 9:1-4. squ med j, december 2009, vol. 9, iss. 3, pp. 361, epub. 19th dec 2009 received 4th nov 09 رد: االنتحال وغريه من إساءات التصرف يف النشر العلمي re: plagiarism and other types of publication misconduct letter to editor department of orthopaedics & traumatology, universiti kebangsaan malaysia, kuala lumpur, malaysia *corresponding author’s e-mail: drashraffariff@gmail.com التهاب كيس األنسريين املؤمل بعد جراحة استبدال الركبة الكلي حالتني حممد اأ�رصاف حممد عارف، حممد عزت اأر�سالن ت�سي رو�ض، نور حمدان حممد يحيى abstract: pes anserine bursitis (pab) is an inflammation of the bursa located between the medial aspect of the tibia and the hamstring muscles. it is common in patients with degenerative or inflammatory knee arthritis, usually has a self-limiting course and tends to respond well to conservative treatment. however, painful pab directly following total knee replacement surgery is rare. we report two such cases who were diagnosed via ultrasonography at the universiti kebangsaan malaysia medical centre, kuala lumpur, malaysia, in 2015. both patients were treated locally with triamcinolone acetonide under ultrasound guidance and responded well to treatment. keywords: total knee replacement; bursitis; pain; case report; malaysia. امللخ�ص: يقع كيس االأن�سريين بني اجلانب االإن�سي من عظمة ال�ساق وع�سالت الرباط. ويكون التهاب هذا الكيس �سائعا يف املر�سى الذين يعانون من التهاب املفا�سل التنك�سية اأو التهابات الركبة، وعادة ما يتم شفاؤه ذاتيا ومييل إىل اإلستجابة بشكل جيد للعالج التحفظي. ومن مت احلاالت هذه من حالتني عن تقرير هذا الكلي. الركبة ا�ستبدال جراحة بعد مبا�رصة يفالساق االأن�سريين كيس التهاب حدوث النادر ت�سخي�سهما باستخدام املوجات فوق ال�سوتية يف مركز كيبانغ�سان املاليزي اجلامعي يف كواال ملبور مباليزيا يف عام 2015. ومتت معاجلة املري�سني باحلقن املو�سعي لعقار االأ�سيتونيد تريام�سينولون با�ستخدام املوجات فوق ال�سوتية وا�ستجابا جيدا للعالج. الكلمات املفتاحية: ا�ستبدال الركبة الكلي؛ التهاب اجلراب؛ امل؛ تقرير حالة؛ ماليزيا. painful pes anserine bursitis following total knee replacement surgery two cases *mohamed a. m. ariff, mohd i. a. c. ros, nor h. m. yahaya case report sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e97–99, epub. 4 apr 18 submitted 17 aug 17 revision req. 15 oct 17; revision recd. 12 nov 17 accepted 7 dec 17 doi: 10.18295/squmj.2018.18.01.016 pes anserine bursitis (pab) is a self-limiting condition whereby the bursa located between the tibia and the three tendons of the hamstring muscle becomes inflammed.1 patients norm ally present with medialised knee pain which is aggravated upon climbing stairs. the condition has been reported to respond well to exercise and stretching programmes.1 the main underlying cause of pab is thought to be due to short hamstrings causing a frictional bursal irritation.2 other common causes include direct trauma and degenerative and inflammatory knee diseases.3 generally, pab as a cause of pain directly following total knee replacement surgery is rare; to the best of the authors’ knowledge, only one previous case has been reported which was ultimately found to have been caused by polyethylene wear debris.4 this case report describes two patients who developed pab following total knee replacement surgeries performed by the same surgeon. case one a 70-year-old woman with a body mass index (bmi) of 29.6 kg/m2 presented to the universiti kebangsaan malaysia medical centre, kuala lumpur, malaysia, in 2015 for a follow-up appointment. she had previously undergone a total knee replacement surgery in 2014 due to well-controlled rheumatoid arthritis of the left knee joint. at her 12-month follow-up appointment, she complained of a nagging pain in the left medial joint line of her knee which she had first noted shortly after the surgery and which was present only when climbing stairs. she denied any history of falls after the surgery. a physical examination revealed a wellhealed anterior midline longitudinal surgical scar over the left knee. there was no obvious swelling of the area and the range of motion of the knee was 0–120 degrees. upon light palpation of the knee, the patient complained of pain extending distally from the left knee medial joint line to a point 3–4 cm medial to the tibial tubercle. there was no obvious erythema or fluctuapainful pes anserine bursitis following total knee replacement surgery two cases e98 | squ medical journal, february 2018, volume 18, issue 1 tion over the tender area. radiographs of the knee showed no evidence of osteolysis or loosening of the prosthetic components [figure 1]. the biomechanical axis of the affected limb appeared well restored. blood and knee aspirate tests for infective markers did not indicate any signs of infection. an ultrasound showed mild peritendinous effusion of the pes anserinus tendons and thickening of the sheath [figure 2]. the patient was treated with the local administration of 1 ml of 40 mg/ml of triamcinolone acetonide into the bursa under ultrasonography guidance. at periodic three-monthly outpatient follow-up appointments, the patient reported the complete resolution of her symptoms. she continued to be symptom-free three years following the treatment. case two a 77-year-old woman with a bmi of 26.4 kg/m2 presented to the universiti kebangsaan malaysia medical centre in 2015 for a follow-up appointment. eight months earlier, she had undergone a total knee replacement surgery in 2014 due to kellgren-lawrence grade 3 osteoarthritis of the right knee. at presentation, she was relatively pain-free except for right-sided medialised knee pain whenever she climbed stairs. on examination, there was a well-healed longitudinal scar anterior to the knee and the range of motion of the knee was 0–130 degrees. there was pinpoint tenderness and localised swelling over the medial aspect of the knee just below the joint line. radiographs showed no evidence of osteolysis or loosening of the prosthetic components and the postoperative biomechanical axis of the limb seemed adequately restored [figure 3]. as with the former case, a lack of infective blood and knee aspirate markers excluded infection. an ultrasound showed a fluid-filled bursa with peritendinous effusion of the pes anserinus tendons [figure 4]. a total of 1 ml of 40 mg/ml of triamcinolone acetonide was locally administered into the bursa under ultrasonography guidance. periodic three-monthly outpatient follow-up visits confirmed the complete resolution of the patient’s symptoms and there was no evidence of recurrence three years later. discussion the pes anserinus bursa is one of the 13 bursae around the knee; it is located approximately 5 cm below the medial knee joint line.5 patients in whom the bursa has a circumscribed anechoic fluid collection of 2 mm or greater on ultrasonography can be considered to have bursitis.6 the inflammation of this conjoined insertion of tendons was first recognised as a unique condition in 1937.7 most cases of pab have been reported among patients with underlying degenerative or inflammatory figure 1: x-ray images of a 70-year-old woman with intermittent pain in the left medial knee joint line following total knee replacement surgery. there was no evidence of osteolysis or loosening of the prosthetic components. figure 3: x-ray images of a 77-year-old woman with right-sided medialised knee pain following total knee replacement surgery. no signs of osteolysis or loosening of the prosthetic components could be seen. figure 2: ultrasound of a 70-year-old woman with intermittent pain in the left medial knee joint line following total knee replacement surgery. note the thickened appearance of the pes anserinus insertion (arrow). mohamed a. m. ariff, mohd i. a. c. ros and nor h. m. yahaya case report | e99 to place two hoffman’s retractors on either side of the tibia while making the tibial bone cut with the saw. the retractors allow for good visualisation of the tibia and keep any soft tissue safely away from the saw blades. it is possible that manipulation during the surgery, the placement of the retractors and over zealous retraction may have contributed to the subsequent development of the pab. hence, caution should be taken when placing and withdrawing retractors during total knee replacement surgeries, especially on the medial side of the knee. conclusion patients who complain of persistent medial knee pain following total knee replacement surgery may have developed pab. steroids such as triamcinolone acetonide are a safe and effective way of relieving pain. the use of ultrasonography is recommended as a diagnostic aid as well as to guide the local administration of treatment injections to the affected bursae. references 1. handy jr. anserine bursitis: a brief review. south med j 1997; 90:376–7. 2. rennie wj, saifuddin a. pes anserine bursitis: incidence in symptomatic knees and clinical presentation. skeletal radiol 2005; 34:395–8. doi: 10.1007/s00256-005-0918-7. 3. larsson lg, baum j. the syndrome of anserina bursitis: an overlooked diagnosis. arthritis rheum 1985; 28:1062–5. doi: 10.10 02/art.1780280915. 4. huang tw, wang cj, huang sc. polyethylene-induced pes anserinus bursitis mimicking an infected total knee arthroplasty: a case report and review of the literature. j arthroplasty 2003; 18:383–6. doi: 10.1054/arth.2003.50062. 5. chatra ps. bursae around the knee joints. indian j radiol imaging 2012; 22:27–30. doi: 10.4103/0971-3026.95400. 6. yoon hs, kim se, suh yr, seo yi, kim ha. correlation between ultrasonographic findings and the response to corticosteroid injection in pes anserinus tendinobursitis syndrome in knee osteoarthritis patients. j korean med sci 2005; 20:109–12. doi: 10.3346/jkms.2005.20.1.109. 7. moschcowitz e. bursitis of sartorius bursa: an undescribed malady simulating chronic arthritis. jama 1937; 109:1362. doi: 10.1001/jama.1937.92780430001009. 8. finnoff jt, nutz dj, henning pt, hollman jh, smith j. accuracy of ultrasound-guided versus unguided pes anserinus bursa injections. pm r 2010; 2:732–9. doi: 10.1016/j.pmrj.2010.03.014. joint diseases.3 in the current case report, both patients were diagnosed with pab via ultrasonography. in order to accurately confirm the diagnosis, the affected lower leg was placed in external rotation with the knee flexed at a 30 degree angle. the transducer was first positioned longitudinally relative to the anterior fibres of the medial collateral ligament and then in an oblique trans verse position relative to the pes anserinus tendons. in terms of treatment, the ultrasound image was maintained while the triamcinolone acetonide was administered via a 22g 38 mm needle. the needle was introduced through the skin until the needle tip could be visualised between the middle of the pes anserinus and the medial collateral ligament. ultrasonography was considered preferable to other imaging modalities as it is cost-effective, easily accessible and useful in aiding the administration of the treatment. ultrasonography-guided injections permit injected substances to be delivered with up to 92% accuracy.8 it is important to note that neither of the two patients reported in the current case report experienced pab-related symptoms prior to the total knee replacement surgery. moreover, the researchers were unable to ascertain exactly why these symptoms developed postoperatively. during the total knee replacement, the surgeon used an anterior midline medial parapatellar approach and the same type of implant for both patients. neither patient had any intraoperative complications and their operative times were not prolonged. however, at the universiti kebangsaan malaysia medical centre, it is common practice figure 4: ultrasound of a 77-year-old woman with right-sided medialised knee pain following total knee replacement surgery. the peritendinous effusion of the pes anserinus tendons with a fluid-filled bursa was noted (arrow). https://doi.org/10.1007/s00256-005-0918-7 https://doi.org/10.1002/art.1780280915 https://doi.org/10.1002/art.1780280915 https://doi.org/10.1054/arth.2003.50062 https://doi.org/10.4103/0971-3026.95400 https://doi.org/10.3346/jkms.2005.20.1.109 https://doi.org/10.1001/jama.1937.92780430001009 https://doi.org/10.1016/j.pmrj.2010.03.014 1department of obstetrics & gynaecology, sultan qaboos university hospital; departments of 2obstetrics & gynaecology and 3family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: drriyami@hotmail.com استخدام قثطار فويل داخل عنق الرحم لتحريض املخاض حلاالت القيصرية السابقة جتربة أحد مراكز الرعاية الثالثية يف عمان ه�زل غون�ش�لفي�س, نه�ل الري�مية, متيمة الدغي�شية, فيداي�ن�ث�ن غوري, حممد العزري, ع�ئ�شة �شالح الدين abstract: objectives: this study aimed to evaluate rates of success and perinatal complications of labour induction using an intracervical foley catheter among women with a previous caesarean delivery at a tertiary centre in oman. methods: this retrospective cohort study included 68 pregnant women with a history of a previous caesarean section who were admitted for induction via foley catheter between january 2011 and december 2013 to the sultan qaboos university hospital, muscat, oman. patient data were collected from electronic and delivery ward records. results: most women were 25–35 years old (76.5%) and 20 women had had one previous vaginal delivery (29.4%). the most common indication for induction of labour was intrauterine growth restriction with oligohydramnios (27.9%). most women delivered after 40 gestational weeks (48.5%) and there were no neonatal admissions or complications. the majority experienced no complications during the induction period (85.3%), although a few had vaginal bleeding (5.9%), intrapartum fever (4.4%), rupture of the membranes (2.9%) and cord prolapse shortly after insertion of the foley catheter (1.5%). however, no cases of uterine rupture or scar dehiscence were noted. overall, the success rate of vaginal birth after a previous caesarean delivery was 69.1%, with the remaining patients undergoing an emergency caesarean section (30.9%). conclusion: the use of a foley catheter in the induction of labour in women with a previous caesarean delivery appears a safe option with a good success rate and few maternal and fetal complications. keywords: vaginal birth after cesarean; induced labor; catheters; pregnancy complications; oman. امللخ�ص: الهدف: تهدف هذه الدرا�شة اإىل تقييم معدلت النج�ح وم�ش�عف�ت فرتة م� حول الولدة لتحري�س املخ��س ب��شتخدام قثط�ر فويل داخل عنق الرحم بني الن�ش�ء اللواتي ولدن �ش�بق� بعملي�ت قي�رسية يف اأحد مراكز الرع�ية الث�لثية يف �شلطنة عم�ن. الطريقة: �شملت هذه الدرا�شة ال�شتع�دية لالتراب على 68 امراأة من اللواتي خ�شعن لعملي�ت قي�رسية يف ال�ش�بق و مت قبولهن للولدة املحر�شة عربا�شتخدام قثط�ر فويل داخل عنق الرحم بني ين�ير 2011 ودي�شمرب ع�م 2013 مب�شت�شفى ج�معة ال�شلط�ن ق�بو�س, م�شقط, عم�ن. النتائج: مت جمع بي�ن�ت املر�شى من �شجالت جن�ح الولدة. ك�نت معظم الن�ش�ء من الفئة العمرية 35-25 �شنة )%76.5( و 20 امراأة ك�ن له� ولدة طبيعية �ش�بقة )%29.4(. اإن املوؤ�رسات الأكرث �شيوع� لتحري�س املخ��س هو قلة وزن اجلنني مع قلة ال�ش�ئل ال�شلوي )%27.9(. متت الولدة يف معظم الن�ش�ء بعد 40 اأ�شبوع� من احلمل )%48.5( ومل تتواجد اي م�ش�عف�ت حلديثي الولدة. مل ت�شهد معظم احلوامل اأي م�ش�عف�ت خالل دور التحري�س )%85.3(, ولكن حدثت بع�س امل�ش�عف�ت يف عدد قليل وت�شمنت النزيف املهبلي )%5.9(, واحلمى اأثن�ء الولدة )%4.4(, ومتزق الأغ�شية )%2.9( وهبوط احلبل ال�رسي بعد فرتة وجيزة من اإدخ�ل قثط�ر فويل )%1.5(. ومع ذلك, مل يالحظ اأي ح�لت متزق الرحم اأو تفزر قي�رسية لعملي�ت املر�شى بقية خ�شوع مع ,69.1% ال�ش�بقة القي�رسية الولدة بعد الطبيعية الولدة جن�ح معدل ك�ن وعموم�, الندبة. ط�رئة )%30.9(. النتائج: اإن ا�شتخدام قثط�ر فويل يف حتري�س املخ��س يف الن�ش�ء ذوات الولدات القي�رسية ال�ش�بقة يبدو خي�را اآمن� مع ن�شبة جن�ح جيدة وم�ش�عف�ت قليلة لالأم واجلنني. الكلمات املفتاحية: الولدة املهبلية بعد القي�رسية؛ ولدة حمر�شة؛ قثط�ر؛ م�ش�عف�ت احلمل؛ عم�ن. use of intracervical foley catheter for induction of labour in cases of previous caesarean section experience of a single tertiary centre in oman hazel gonsalves,1 *nihal al-riyami,1 tamima al-dughaishi,1 vaidayanathan gowri,2 mohammed al-azri,3 ayesha salahuddin1 clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e445–450, epub. 30 nov 16 submitted 8 mar 16 revision req. 8 may 16; revision recd. 19 jul 16 accepted 2 aug 16 doi: 10.18295/squmj.2016.16.04.007 advances in knowledge to the best of the authors’ knowledge, this is the first time a study of this kind has been conducted in oman. pregnant women who have previously undergone a caesarean section are at risk of various complications during subsequent labour. the findings of this study indicate that the use of a foley catheter for induction of labour may be a safe option for this population. use of intracervical foley catheter for induction of labour in cases of previous caesarean section experience of a single tertiary centre in oman e446 | squ medical journal, november 2016, volume 16, issue 4 for subsequent pregnancies, women witha previous history of a caesarean delivery may be offered either a trial of vaginal birth after caesarean section (vbac) or an elective repeat caesarean section.1 the former option is well accepted as a practical and safe means of decreasing caesarean delivery rates.2,3 women who have previously delivered via caesarean section have subsequent vaginal delivery rates of 50–85%.4 the induction of labour in women with a prior caesarean delivery is more likely to result in a subsequent caesarean delivery.5 in a prospective observational study of 11,778 women, induction of labour was associated with a significantly higher risk of unsuccessful vbac (i.e. requiring an emergency caesarean section) than spontaneous labour.6 in contrast, a previous history of vaginal delivery and a favourable cervical status were found to significantly increase chances of success.6 uterine rupture is a major concern for women with a prior caesarean section; a population-based retrospective cohort study found that the rate of uterine rupture following a previous caesarean delivery was 1.6 per 1,000 women.7 higher rates of rupture are associated with induced labour rather than spontaneous labour; other risk factors include an unfavourable cervix and the method of cervical ripening used.5 the safest and most efficacious method of cervical ripening and/or induction of labour in women with previous caesarean deliveries has not yet been established. induction with oxytocin appears to have a lower risk of uterine rupture than prostaglandins.7 although data regarding mechanical methods of cervical ripening in this population are limited by low sample sizes and the retrospective nature of the analyses, favourable outcomes have been reported.7 the advantages of a mechanical method include a decreased risk of uterine tachysystole and fetal distress, stability at room temperature and low cost.8 several trials have presented evidence of the efficacy of the intracervical foley catheter in comparison to prostaglandins for pre-induction cervical ripening.9,10 a meta-analysis of randomised trials comparing mechanical versus pharmacological methods showed mechanical devices to be associated with a lower risk of uterine hyperstimulation and fetal heart rate abnormalities.11 the guidelines of the society of obstetricians and gynecologists of canada state that “a foley catheter may be safely used to ripen the cervix in a woman planning a trial of labour after caesarean section”.4 in contrast, the american congress of obstetricians and gynecologists believe that, given a lack of compelling data and the increased risk of mechanical dilatation, such interventions should only be an option for trial of vbac delivery among candidates with an unfavourable cervix.12 therefore, the aim of the current study was to evaluate the safety and efficacy of induction of labour using an intracervical foley catheter among pregnant women with a previous history of caesarean delivery admitted to a tertiary centre in oman. methods this retrospective cohort study included 68 pregnant women with a previous history of caesarean delivery who were admitted from january 2011 to december 2013 to the sultan qaboos university hospital, muscat, oman, for labour induction via foley catheter for a vbac trial. women who refused trial of labour, those who were induced via other methods (e.g. oxytocin administration or artificial rupture of the membranes) and patients with missing data were excluded from the study. patient data were collected from the hospital information system and delivery ward records, including: age; parity; body mass index (bmi); a prior history of vaginal delivery; bishop scores at the time of insertion and removal of the catheter; indications for the induction of labour; mode of delivery; and the duration of labour. postnatal outcomes were also noted, including the gestational age at delivery, birth weight and apgar scores of the baby and the presence of any neonatal complications. in all cases, a size 18 single balloon foley catheter was used for induction of labour. the catheter was introduced under sterile conditions into the intracervical canal past the internal opening of the cervix and the bulb was inflated with 30–60 cm3 of water. the catheter was kept in place for 24 hours unless other centres in oman use prostaglandins for the induction of labour in cases of previous caesarean delivery. further studies are required to compare modes of induction, success rates, complications and perinatal outcomes in order to inform delivery practices in oman. application to patient care the results of this study may encourage obstetricians to use a foley catheter as the main mode of induction of labour in patients who have previously had a caesarean section. thorough patient assessment and counselling is critical before deciding on the mode of delivery, as this choice may affect perinatal outcomes and future pregnancies. hazel gonsalves, nihal al-riyami, tamima al-dughaishi, vaidayanathan gowri, mohammed al-azri and ayesha salahuddin clinical and basic research | e447 it fell out spontaneously beforehand. the primary outcome measure of the study was the success rate of vbac while the secondary outcomes were perinatal complications such as uterine scar dehiscence, uterine rupture and perinatal mortality. uterine rupture was defined as a disruption of the uterine muscle extending to and involving the uterine serosa or disruption of the uterine muscle with extension to the bladder or broad ligament, while uterine dehiscence was defined as disruption of the uterine muscle with intact uterine serosa.13 factors affecting the success rate of vbac, such as a previous normal vaginal delivery and bishop scores, were also studied; the bishop scoring system used included five determinants—dilatation, effacement, station, position and consistency.14 the statistical package for the social sciences (spss), version 19 (ibm corp., chicago, illinois, usa) was used for data entry and analysis. all data and field notes were first transcribed into the spss program. a p value of <0.050 was deemed to be statistically significant. ethical approval of this study was granted by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #562). all women opted for induction of labour with a foley catheter after appropriate counselling and assessment by a senior obstetrician. results a total of 68 women were included in the study. most of the women were 25–35 years old (76.5%) and were primiparous (63.2%). due to missing height records, bmi could only be calculated for 48 women; of these, 58.3% were obese and 27.1% were overweight. only 20 women (29.4%) had had a previous vaginal delivery. most women delivered after 40 gestational weeks (48.8%) [table 1]. table 1: sociodemographic variables of pregnant women with a history of a previous caesarean section admitted for induction via foley catheter (n = 68) variable n (%) age in years <25 4 (5.9) 25–35 52 (76.5) >35 12 (17.6) bmi in kg/m2* 18.5–24.9 7 (14.6) 25.0–29.9 13 (27.1) ≥30.0 28 (58.3) gravidity† multigravida 56 (82.4) grand multigravida 12 (17.6) parity‡ primiparous 43 (63.2) multiparous 21 (30.9) grand multiparous 2 (2.9) great grand multiparous 2 (2.9) previous vaginal delivery yes 20 (29.4) no 48 (70.6) gestational age at delivery in weeks <37 6 (8.8) 37–40 29 (42.6) >40 33 (48.5) *total dataset for this variable was 48 due to missing data. †women who had had two to four previous pregnancies were defined as multigravida while woman who had had five to six previous pregnancies were considered grand multigravida. ‡women who had delivered one live infant were defined as primiparous, while those who had had delivered two to four live infants, five to six live infants and seven or more live infants were considered multiparous, grand multiparous and great grand multiparous, respectively. table 2: indications for labour induction and complications during induction among pregnant women with a history of a previous caesarean section admitted for induction via foley catheter (n = 68) n (%) indication for labour induction pregnancy duration of ≥40 gestational weeks 18 (26.5) iugr with oligohydramnios 19 (27.9) iufd 5 (7.4) gdm with polyhydramnios 12 (17.6) poor bpp 5 (7.4) uncontrolled epilepsy 2 (2.9) pih 6 (8.8) unknown 1 (1.5) complication during induction none 58 (85.3) rupture of membrane 2 (2.9) fever 3 (4.4) cord prolapse 1 (1.5) vaginal bleeding 4 (5.9) iugr = intrauterine growth restriction; iufd = intrauterine fetal death; gdm = gestational diabetes mellitus; bpp = biophysical profile; pih = pregnancy-induced hypertension. use of intracervical foley catheter for induction of labour in cases of previous caesarean section experience of a single tertiary centre in oman e448 | squ medical journal, november 2016, volume 16, issue 4 table 2 shows the various indications for induction of labour and the complications observed during the induction period. labour was most commonly induced due to intrauterine growth restriction with oligohydramnios (27.9%). no complications were noted during the induction period in the majority of women (85.3%). there were no cases of uterine rupture or scar dehiscence. three women had intrapartum fever which subsided postpartum without evidence of chorioamnionitis on placental histopathology. four women experienced vaginal bleeding following the insertion of the foley catheter; three had minimal bleeding and subsequently underwent a successful vbac, but one had heavy vaginal bleeding and fetal bradycardia, resulting in an emergency caesarean section. there was no evidence of placenta previa or abruptio in the latter case. one patient had an emergency caesarean section 30 minutes after the insertion of the foley catheter due to rupture of the membranes and cord prolapse; this 26-year-old gravida 2, para 1 woman had had a caesarean section two years previously due to fetal distress. she underwent labour induction with a foley catheter at 38 gestational weeks and four days due to gestational diabetes with polyhydramnios (amniotic fluid index = 263 mm). her bishop score before the insertion of the catheter was 2. all women went into labour when the catheter was removed; however, 46 women (67.6%) and 42 women (61.8%) required oxytocin and artificial rupture of the membranes, respectively, to augment labour. the overall success rate of vbac was 69.1%, with 47 women successfully giving birth via vaginal delivery. for the remaining 21 women (30.9%), emergency caesarean sections were performed due to failure to progress (n = 11; 52.4%), non-reassuring fetal status (n = 9; 42.9%) and cord prolapse (n = 1; 4.8%). women with a successful vbac had a mean duration of labour of 8.04 ± 4.57 hours (range: 3–25 hours) for stage one labour and 22.74 ± 27.00 minutes (range: 2–165 minutes) for stage two labour. there was a significant difference in mean maternal age between women who had a successful vbac and those who underwent an emergency caesarean section (p = 0.007). no significant differences were noted between the groups in terms of gestational age of delivery, bishop scores at foley’s insertion and removal, mean neonatal birth weights or apgar scores at one and five minutes. there was a significant difference in mode of delivery between those who had had a previous vaginal delivery and those who had not (p = 0.019) [table 3]. table 4 shows the success rate of vbac among patients who had had a previous vaginal delivery versus a previous caesarean delivery in their earlier pregnancy. the vbac success rate was 85.0% among those with a previous vaginal birth in comparison to 62.5% for those with a previous caesarean section (p = 0.067). table 3: comparison of demographic, maternal and fetal variables between successful vaginal births versus emergency caesarean section deliveries among pregnant women with a history of a previous caesarean section admitted for induction via foley catheter (n = 68) variable successful vbac emergency caesarean section p value n (%) mean ± sd n (%) mean ± sd age in years 47 (69.1) 29.62 ± 4.32 21 (30.9) 33.66 ± 5.27 0.007 bmi in kg/m2* 32 (66.7) 32.34 ± 8.13 16 (33.3) 31.09 ± 4.70 0.575 gestational age at delivery in weeks 48 (70.6) 38.89 ± 2.73 20 (29.4) 38.86 ± 1.70 0.969 bishop score at insertion 47 (69.1) 2.40 ± 0.54 21 (30.9) 2.19 ± 0.40 0.075 bishop score at removal 47 (69.1) 4.40 ± 1.10 21 (30.9) 4.00 ± 1.18 0.175 parity† 47 (69.1) 1.98 ± 1.51 21 (30.9) 1.62 ± 1.47 0.365 previous vaginal delivery 47 (69.1) 0.51 ± 0.91 21 (30.9) 0.14 ± 0.36 0.019 birth weight in kg 47 (69.1) 3.05 ± 0.65 21 (30.9) 3.16 ± 0.46 0.478 apgar score at 1 minute‡ 44 (67.7) 8.36 ± 1.98 21 (32.3) 8.24 ± 1.30 0.792 apgar score at 5 minutes‡ 44 (67.7) 9.43 ± 2.12 21 (32.3) 9.71 ± 0.64 0.553 vbac = vaginal birth after caesarean section; sd = standard deviation; bmi = body mass index. *total dataset for this variable was 48 due to missing data. †women who had delivered one live infant were defined as primiparous, while those who had had delivered two to four live infants, five to six live infants and seven or more live infants were considered multiparous, grand multiparous and great grand multiparous, respectively. ‡total dataset for this variable was 65 due to missing apgar data for three neonates. hazel gonsalves, nihal al-riyami, tamima al-dughaishi, vaidayanathan gowri, mohammed al-azri and ayesha salahuddin clinical and basic research | e449 discussion among the various predictors for a successful vbac, a previous vaginal birth is the most promising, yielding a success rate of 87–90%.15,16 other factors, such as induced labour or increased bmi, may reduce the success rate to 40%.17 according to previous research, the overall success rate of vbac is 72–76%.18–20 few studies have looked into the success rate of vbac following induction of labour via foley catheter. one recent study included 208 women with a previous history of caesarean delivery who were induced using a foley catheter; the success rate was 71%, with two perinatal deaths (1.0%), one of which was due to uterine rupture (0.5%).21 in the current study, the success rate of vbac was 69.1% with no cases of uterine rupture or perinatal death. all women who have previously undergone a caesarean delivery should be counselled appropriately and offered both vbac and an elective repeat caesarean section as options for trial of labour. the risks and benefits of both approaches should be explained, including associated perinatal morbidity and mortality rates. women who opt for a vbac should be thoroughly assessed so as to better predict the chances of success with this method. maternal age, bmi, bishop score at foley insertion and removal, gestational age at delivery, birth weight and previous vaginal births were examined as predictors for successful vbac in the present study. however, the only statistically significant differences noted were with maternal age and a previous vaginal birth. patients who had a better bishop score at insertion of the foley catheter had slightly higher success rates for vbac, but this association was not statistically significant. this could be attributed to the small sample size of the current study. in a casecontrol study of 101 successful vbac cases and 103 unsuccessful controls at three major hospitals, birara et al. found that a previous history of successful vbac and cervical dilatation of more than 3 cm at table 4: comparison of delivery modes between those with a previous vaginal versus caesarean section delivery in earlier pregnancy among pregnant women with a history of a previous caesarean section admitted for induction via foley catheter (n = 68) previous method of delivery n (%) p value emergency caesarean vbac total caesarean 18 (37.5) 30 (62.5) 48 (100.0) 0.067 vaginal 3 (15.0) 17 (85.0) 20 (100.0) total 21 (30.9) 47 (69.7) 68 (100.0) vbac = vaginal birth after caesarean section. admission were the best predictors for successful vbac.22 srinivas et al. similarly investigated predictors of failed vbac among 13,706 women; gestational age at delivery, maternal age, maternal race, labour type (spontaneous versus induced), lack of a prior vaginal delivery and cephalopelvic disproportion or failed induction as the prior caesarean section indication were significantly associated with vbac failure (failure rate: 24.5%).23 having a prior vaginal delivery was the factor most indicative of a successful vbac attempt (odds ratio: 0.21, 95% confidence interval: 0.19–0.24) and labour induction had the highest association with vbac failure.23 yokoi et al. also concluded that the best predictor for a successful vbac was a previous vbac in their study of 664 women with one previous caesarean delivery.24 to the best of the authors’ knowledge, this study is the first of its kind to be conducted in oman. the sultan qaboos university hospital was one of the first centres in oman to induce labour using a foley catheter in cases of previous caesarean delivery; the majority of other centres in oman use prostaglandins for the induction of labour. to this end, further research is necessary to compare success rates and complications of vbac in patients induced with prostaglandins versus a foley catheter. the current study was limited by its small sample size and retrospective nature. it is recommended that future prospective studies utilise a multicentre approach with a larger number of patients. conclusion induction of labour via foley catheter in women who have previously undergone a caesarean section delivery appears to be a safe option with a good success rate and few complications for both mother and fetus. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. royal college of obstetricians and gynaecologists. birth after previous caesarean birth: green-top guideline no. 45. from: www.rcog.org.uk/globalassets/documents/guidelines/gtg_45. pdf accessed: jul 2016. 2. national institutes of health. nih consensus developed conference statement on vaginal birth after cesarean: new insights. from: www.consensus.nih.gov/2010/images/vbac/ vbac_statement.pdf accessed: jul 2016. 3. american college of obstetricians and gynecologists. acog practice bulletin no. 115: vaginal birth after previous cesarean delivery. obstet gynecol 2010; 116:450–63. doi: 10.1097/aog. 0b013e3181eeb251. 4. martel mj, mackinnon cj; clinical practice obstetrics committee, society of obstetricians and gynaecologists of canada. guidelines for vaginal birth after previous caesarean birth. j obstet gynaecol can 2005; 27:164–88. 5. biswas a. management of previous cesarean section. curr opin obstet gynecol 2003; 15:123–9. 6. grobman wa, gilbert s, landon mb, spong cy, leveno kj, rouse dj, et al. outcomes of induction of labour after one prior caesarean. obstet gynecol 2007; 109:262–9. doi: 10.1097/01. aog.0000254169.49346.e9. 7. lydon-rochelle m, holt vl, easterling tr, martin dp. risk of uterine rupture during labor among women with a prior cesarean delivery. n engl j med 2001; 345:3–8. doi: 10.1056/ nejm200107053450101. 8. bujold e, blackwell sc, gauthier rj. cervical ripening with transcervical foley catheter and the risk of uterine rupture. obstet gynecol 2004; 103:18–23. doi: 10.1097/01. aog.0000109148.23082.c1. 9. dalui r, suri v, ray p, gupta i. comparison of extraamniotic foley catheter and intracervical prostaglandin e gel for preinduction cervical ripening. acta obstet gynecol scand 2005; 84:362–7. doi: 10.1111/j.0001-6349.2005.00662.x. 10. prager m, eneroth-grimfors e, edlund m, marions l. a randomised controlled trial of intravaginal dinoprostone, intravaginal misoprostol and transcervical balloon catheter for labour induction. bjog 2008; 115:1443–50. doi: 10.1111/j. 1471-0528.2008.01843.x. 11. boulvain m, kelly a, lohse c, stan c, irion o. mechanical methods for induction of labour. cochrane database syst rev 2001; 4:cd001233. doi: 10.1002/14651858.cd001233. 12. american college of obstetricians and gynecologists committee on obstetric practice. acog practice bulletin #54: vaginal birth after previous caesarean. obstet gynecol 2004; 104:203–12. doi: 10.1097/00006250-200407000-00060. 13. landon mb, hauth jc, leveno kj, spong cy, leindecker s, varner mw, et al. maternal and perinatal outcomes associated with a trial of labor after prior cesarean delivery. n engl j med 2004; 351:2581–9. doi: 10.1056/nejmoa040405. 14. bishop eh. pelvic scoring for elective induction. obstet gynecol 1964; 24:266–8. 15. smith gc, white ir, pell jp, dobbie r. predicting caesarean section and uterine rupture among women attempting vaginal birth after prior cesarean section. plos med 2005; 2:e252. doi: 10.1371/journal.pmed.0020252. 16. gyamfi c, juhasz g, gyamfi p, stone jl. increased success of trial of labor after previous vaginal birth after cesarean. obstet gynecol 2004; 104:715–19. doi: 10.1097/01.aog.00 00139516.43748.1b. 17. landon mb, leindecker s, spong cy, hauth jc, bloom s, varner mw, et al. the mfmu cesarean registry: factors affecting the success of trial of labor after previous cesarean delivery. am j obstet gynecol 2005; 193:1016–23. doi: 10.1016/j.ajog.2005.05.066. 18. guise jm, berlin m, mcdonagh m, osterweil p, chan b, helfand m. safety of vaginal birth after cesarean: a systematic review. obstet gynecol 2004; 103:420–9. doi: 10.1097/01. aog.0000116259.41678.f1. 19. wen sw, rusen id, walker m, liston r, kramer ms, baskett t, et al. comparison of maternal mortality and morbidity between trial of labor and elective cesarean section among women with previous cesarean delivery. am j obstet gynecol 2004; 191:1263–9. doi: 10.1016/j.ajog.2004.03.022. 20. chauhan sp, martin jn jr, henrichs ce, morrison jc, magann ef. maternal and perinatal complications with uterine rupture in 142,075 patients who attempted vaginal birth after cesarean delivery: a review of the literature. am j obstet gynecol 2003; 189:408–17. doi: 10.1067/s0002-9378(03)00675-6. 21. jozwiak m, van de lest ha, burger nb, dijksterhuis mg, de leeuw jw. cervical ripening with foley catheter for induction of labor after cesarean section: a cohort study. acta obstet gynecol scand 2014; 93:296–301. doi: 10.1111/ aogs.12320. 22. birara m, gebrehiwot y. factors associated with success of vaginal birth after one caesarean section (vbac) at three teaching hospitals in addis ababa, ethiopia: a case control study. bmc pregnancy childbirth 2013; 13:31. doi: 10.1186/1471-2393-13-31. 23. srinivas sk, stamilio dm, stevens ej, odibo ao, peipert jf, macones ga. predicting failure of a vaginal birth attempt after cesarean delivery. obstet gynecol 2007; 109:800–5. doi: 10.1097/01.aog.0000259313.46842.71. 24. yokoi a, ishikawa k, miyazaki k, yoshida k, furuhashi m, tamakoshi k. validation of the prediction model for success of vaginal birth after cesarean delivery in japanese women. int j med sci 2012; 9:488–91. doi: 10.7150/ijms.4682. use of intracervical foley catheter for induction of labour in cases of previous caesarean section experience of a single tertiary centre in oman 450 | squ medical journal, november 2016, volume 16, issue 4 departments of 1child health and 2genetics, sultan qaboos university hospital, muscat, oman *corresponding author e-mails: koul@squ.edu.om, roshankoul@hotmail.com and koulroshan@gmail.com ضمور عضلي شوكي قطعي متموضع يف األطراف السفلى أول حالة تسجل يف عمان رو�سان كول، اآمنة الفطي�سية، خالد الذهلي، زاندر بروير، باترك �سكوت abstract: spinal muscular atrophy (sma) is a genetic lower motor neuron disease. it usually involves all of the skeletal muscles innervated by the anterior horn cells of the spinal cord. in rare cases, there is also localised involvement of the spinal cord. we report a 10-year-old boy who presented to the sultan qaboos university hospital, muscat, oman, in 2015 with muscle weakness restricted to the lower limbs. the presence of a homozygous deletion within the survival of motor neuron 1 gene confirmed the diagnosis of sma. to the best of the authors’ knowledge, this is the first report of an omani patient with segmental sma involving only the lower limbs. treatment for this rare and relatively benign form of sma is symptomatic and includes physiotherapy. keywords: spinal muscular atrophies of childhood; spinal muscular atrophy, segmental; muscle weakness; pes cavus; case report; oman. الهيكلية الع�سالت كل عادة املر�ص وي�سيب ال�سفلي. احلركي بالع�سبون وراثيا مر�سا القطعي ال�سوكي الع�سلي ال�سمور يعد امللخ�ص: التي تع�سبها اخلاليا القرنية االأمامية يف احلبل النخاعي. وتوجد نادرا حاالت اكتناف متمو�سعة يف احلبل النخاعي. ون�سجل هنا حالة طفل عمره 10 �سنوات اأدخل مل�ست�سفى جامعة ال�سلطان قابو�ص يف م�سقط، عمان يف عام 2015م ب�سبب �سعف يف الع�سالت حم�سور يف االأطراف ال�سفلى. ومت اكت�ساف وجود َخنْب زايجوتي متماثل االأالئل يف داخل جني "بقاء اخلاليا الع�سبية احلركية 1" مما اأكد ت�سخي�ص املر�ص على اأنه �سمور ع�سلي �سوكي. ومبلغ علمنا، فهذه هي احلالة االأوىل التي ت�سجل عن مري�ص عماين م�ساب ب�سمور ع�سلي �سوكي ع فقط يف االأطراف ال�سفلى. ومت عالج هذه ال�سكل النادر واحلميد ن�سبيا لهذا املر�ص عالجا اأعرا�سيا �سمل العالج الطبيعي. قطعي ُمتمو�سِ الكلمات املفتاحية: حاالت ال�سمور الع�سلي ال�سوكي عند االأطفال؛ �سمور ع�سلي �سوكي، قطعي؛ �سعف ع�سلي؛ قدم خم�سية؛ ت�سجيل حالة؛ عمان. segmental spinal muscular atrophy localised to the lower limbs first case from oman *roshan koul,1 amna al-futaisi,1 khalid al-thihli,2 zandre bruwer,2 patrick scott2 case report sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e355–357, epub. 10 oct 17 submitted 12 feb 17 revision req. 19 mar 17; revision recd. 18 apr 17 accepted 4 may 17 doi: 10.18295/squmj.2017.17.03.018 of sma are seen every year at the sultan qaboos university hospital (squh), a tertiary hospital in muscat, oman. furthermore, staff at squh have observed that these children often have an acute presentation with a significant progression of weakness within days of onset. the majority of children in oman with type i sma have a homozygous smn1 gene deletion.5 this case report describes a young male patient with muscle weakness restricted to the lower limbs who was found to have sma. to the best of the authors’ knowledge, this is the first case reported from oman of segmental sma involving only the lower limbs. case report a 10-year-old boy from salalah, oman, presented to squh in 2015 with muscular weakness confined to the lower limbs. the patient had had a delayed onset of walking, with his parents noting the lower limb weakness only when he first began to walk. at autosomal recessive spinal muscular atrophy (sma) is a genetic disorder of the lower motor neurons classified into four types based on clinical features, age of onset and the motor functions affected.1 all four types of sma involve almost all of the skeletal muscles; only the muscles innervated by cranial nerves are unaffected, excluding those innervated by the hypoglossal nerve.1 rarely, there is also localised involvement of the spinal cord.2 type i sma may present from birth, within the first three months of life or after three months with patients having a limited ability to sit upright.2,3 in the majority of cases, the main cause of sma is a homozygous deletion of the survival of motor neuron 1 (smn1) gene.4 in oman, autosomal recessive sma is the most common genetic disease of the lower motor neurons.5 in addition, the country has one of the highest incidences of this disease worldwide, with approximately every one in 6,000 live births affected.5 according to unreported data, between 6–8 new cases segmental spinal muscular atrophy localised to the lower limbs first case from oman e356 | squ medical journal, august 2017, volume 17, issue 3 the results of a routine blood work-up were normal, although the patient’s serum creatine kinase level was slightly elevated at 600 iu/l (normal range: 50–350 iu/l). motor and sensory nerve conduction studies in the upper limbs were normal. in the lower limbs, distal motor latency was mildly delayed in all nerves, although sensory nerve conduction was normal. the compound muscle action potential was reduced overall as compared to the upper limbs. magnetic resonance imaging (mri) scans of the brain, spine and pelvis were normal. genetic testing revealed the homozygous absence of the smn1 gene, confirming the diagnosis of sma. unfortunately, the family refused to consent to further genetic testing of any other family members. at the time of writing, the patient was undergoing physiotherapy at a local hospital in oman. discussion this case report describes an omani boy with localised weakness of the lower limbs in whom a homozygous smn1 gene deletion was identified via genetic testing. to the best of the authors’ knowledge, this type of sma has not previously been reported from this country; moreover, no cases with similar presentations of segmental sma with homozygous smn1 gene deletions are available in the current literature. further genetic testing of the patient’s family would have helped to determine the nature of inheritance of the condition as well as the carrier status; unfortunately, this could not be performed due to lack of consent. patients with autosomal dominant distal sma predominantly involving the upper limbs have been previously reported.6 several variants of sma not linked to the smn1 gene exist, including scapuloperoneal sma, sma with pontocerebellar hypoplasia, x-linked infantile sma with arthrogryposis, sma with respiratory distress type 1, congenital distal sma and distal sma type v/ presentation, he was able to sit up on his own, but had difficulty getting up and needed support from both hands. after standing, he was able to walk with a wide-based waddling gait and foot drop in both feet. when walking, he could only move slowly, frequently fell and had difficulty climbing stairs. there were no complaints regarding his upper limbs. moreover, he had no problems swallowing and there were no respiratory symptoms. the patient seemed intelligent and had been ranked first in his class at school. his parents reported that the weakness in the lower limbs had remained the same over the past three years. his routine day-to-day activities were not affected, although he could not take part in various school activities or sports. in terms of family history, his parents mentioned that his maternal uncle aged 32 years old had had a similar presentation in early childhood. the patient had four siblings, none of whom displayed similar symptoms. on examination, the patient’s higher mental functions and cranial nerves were normal, with no tongue fasciculation. the power and tone of the upper limbs was normal. the hands had normal grip and power and the shoulder girdle muscles had normal power, with no winging of the scapula at rest or with resistance. the deep tendon reflexes were preserved in the upper limbs. the lower limbs looked bulky but were weak and the patient had difficulty lifting his legs up from the bed. there was no evidence of any wasting of the hip girdle or thigh muscles; however, there was wasting of the small muscles of both feet. the abduction and adduction power at the hips was 4/5, flexion and extension at the knees was 3/5 and dorsiflexion and planter flexion at the ankles was 3/5. he had bilateral pes cavus and the long toe flexors and extensors were weak with a power of 2/5 [figure 1]. he could walk on his heels but not on his toes and gowers’ sign was positive. both knee and ankle reflexes were absent; however, sensation was normal all over the lower limbs. figure 1: photographs of a 10-year-old omani boy with muscle weakness restricted to the lower limbs showing (a) bilateral pes cavus and (b) normal hands. the presence of a homozygous deletion within the survival of motor neuron 1 gene confirmed a diagnosis of spinal muscular atrophy. roshan koul, amna al-futaisi, khalid al-thihli, zandre bruwer and patrick scott case report | e357 charcot-marie-tooth disease type 2d.2 of these, distal sma with autosomal dominant inheritance involving the upper limbs is most common.2 sma type iii with smn1 gene deletion may present in early childhood; affected children usually survive till adulthood and have a very slow progression of the disease.7,8 with regards to the present case, it is possible that the patient had a differing phenotype of sma type iii resulting in weakness of only the lower limbs.9 as such, there may be a progression of weakness over time, eventually spreading to the upper limbs. there are reports of isolated upper limb or lower limb weakness related to anterior horn cell loss.8–10 benign juvenile focal amyotrophy of the upper limbs, also known as benign focal amyotrophy disorders of the limbs or hirayama disease, was initially reported in japan.10 schröder et al. reported a case of intrinsic motor neuron disease of the lower cervical spinal cord in which an mri revealed localised spinal cord atrophy and flattening.11 in another case, huang et al. reported that movement-induced myelopathy could also be an underlying mechanism of hirayama disease; however, an autopsy revealed only loss of the anterior horn cells without any other changes.12 hirayama disease is a sporadic disorder, although familial cases have been reported.6 similar to cases of upper limb atrophy, researchers have also reported amyotrophy restricted to the lower limbs, particularly the calf muscles.13 however, this disease is usually seen in adults, does not progress and there is no evidence of sensory loss; moreover, there are no upper motor neuron features or smn1 gene deletions in such patients and mri scans of the spine are normal.13 clinically, segmental sma resulting in weakness of the lower limbs should be differentiated from hereditary motor sensory neuropathy, chronic immune mediated demyelinating neuropathy, distal myopathy, cauda equina syndrome and myeloradiculopathy. exam inations of the spine and any sensory abnormalities, nerve conduction and genetic tests and, if required, muscle/nerve biopsies can aid in confirming a diagnosis. to date, physiotherapy remains the main mode of treatment for sma. however, the antisense oligonucleotide gene therapy drug nusinersen has recently been approved as treatment to prevent the progression of the disease.14 conclusion to the best of the authors’ knowledge, this is the first case of segmental sma with smn1 gene deletion reported from oman. this form of sma, with involvement of only one part of the body, is a rare condition. physiotherapy is currently the mainstay of treatment although recent advances in gene therapy could be beneficial. references 1. munsat tl, davies ke. international sma consortium meeting: (26-28 june 1992, bonn, germany). neuromuscul disord 1992; 2:423–8. doi: 10.1016/s0960-8966(06)80015-5. 2. d’amico a, mercuri e, tiziano fd, bertini e. spinal muscular atrophy. orphanet j rare dis 2011; 6:71. doi: 10.1186/17501172-6-71. 3. bertini e, burghes a, bushby k, estournet-mathiaud b, finkel rs, hughes ra, et al. 134th enmc international workshop: outcome measures and treatment of spinal muscular atrophy, 11-13 february 2005, naarden, the nether-lands. neuromuscul disord 2005; 15:802–16. doi: 10.1016/j.nmd. 2005.07.005. 4. lefebvre s, bürglen l, reboullet s, clermont o, burlet p, viollet l, et al. identification and characterization of a spinal muscular atrophy-determining gene. cell 1995; 80:155–65. doi: 10.1016/0092-8674(95)90460-3. 5. koul r, al futaisi a, chacko a, rao v, simsek m, muralitharan s, et al. clinical and genetic study of spinal muscular atrophies in oman. j child neurol 2007; 22:1227–30. doi: 10.1177/088 3073807306268. 6. andreadou e, christodoulou k, manta p, karandreas n, loukaidis p, sfagos c, vassilopoulos d. familial asymmetric distal upper limb amyotrophy (hirayama disease): report of a greek family. neurologist 2009; 15:156–60. doi: 10.1097/ nrl.0b013e31818d6717. 7. dastur rs, gaitonde ps, khadilkar sv, udani vp, nadkarni jj. correlation between deletion patterns of smn and naip genes and the clinical features of spinal muscular atrophy in indian patients. neurol india 2006; 54:255–9. doi: 10.4103/00283886.27147. 8. al-jumah m, majumdar r, al-rajeh s, awada a, chavescarbello e, salih m, et al. molecular analysis of the spinal muscular atrophy and neuronal apoptosis inhibitory protein genes in saudi patients with spinal muscular atrophy. saudi med j 2003; 24:1052–4. 9. deymeer f, serdaroğlu p, poda m, gülşen-parman y, ozçelik t, ozdemir c. segmental distribution of muscle weakness in sma iii: implications for deterioration in muscle strength with time. neuromuscul disord 1997; 7:521–8. doi: 10.1016/s09608966(97)00113-2. 10. hirayama k. [juvenile muscular atrophy of the distal upper limb: three decades of description and it’s treatment]. rinsho shinkeigaku 1993; 33:1235–43. 11. schröder r, keller e, flacke s, schmidt s, pohl c, klockgether t, et al. mri findings in hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease? j neurol 1999; 246:1069–74. doi: 10.1007/s004150050514. 12. huang yl, chen cj. hirayama disease. neuroimaging clin n am 2011; 21:939–50. doi: 10.1016/j.nic.2011.07.009. 13. felice kj, whitaker ch, grunnet ml. benign calf amyotrophy: clinicopathologic study of 8 patients. arch neurol 2003; 60:1415–20. doi: 10.1001/archneur.60.10.1415. 14. food and drug adminitsration, u.s. department of health and human services. fda approves first drug for spinal muscular atrophy. from: www.fda.gov/newsevents/newsroom/ pressannouncements/ucm534611.htm accessed: apr 2017. https://doi.org/10.1016/s0960-8966%2806%2980015-5 https://doi.org/10.1186/1750-1172-6-71 https://doi.org/10.1186/1750-1172-6-71 https://doi.org/10.1016/j.nmd.2005.07.005 https://doi.org/10.1016/j.nmd.2005.07.005 https://doi.org/10.1016/0092-8674%2895%2990460-3 https://doi.org/10.1177/0883073807306268 https://doi.org/10.1177/0883073807306268 https://doi.org/10.1097/nrl.0b013e31818d6717 https://doi.org/10.1097/nrl.0b013e31818d6717 https://doi.org/10.4103/0028-3886.27147 https://doi.org/10.4103/0028-3886.27147 https://doi.org/10.1016/s0960-8966%2897%2900113-2 https://doi.org/10.1016/s0960-8966%2897%2900113-2 https://doi.org/10.1007/s004150050514 https://doi.org/10.1016/j.nic.2011.07.009 https://doi.org/10.1001/archneur.60.10.1415 the paediatric handbook evolved from the 1960s as a management guide intended for in-house use by medical officers at the royal children’s hospital in melbourne, a leading clinical and training centre for paediatric medicine in australia. this new eighth edition is the fruit of the tireless efforts and contributions of its staff team. it was developed from evidencebased practice and longstanding clinical experience as a succinct and relevant guide to those who care medically for children from infancy through adolescence. this new edition has been updated from the last (2003) edition and is available both in print and pda version online. the current edition contains new and revised chapters aligned with the hospital clinical practice guidelines. it comprises a table of contents with a list of contributors, editorial committee, forward, preface and health problems divided into seven parts followed by appendices and finally the index. the different parts are: emergencies, with up-to-date guidelines and algorithms regarding resuscitation; procedures and pain management; fluids and nutrition; child public health; development; psychosocial problems and, lastly, important paediatric conditions in medicine and surgery. each of the parts has from 2 to 20 chapters. there are four appendices: growth charts; pharmacopoeia; antimicrobial guidelines and formulae. a resuscitation guide and australian immunization schedule are also included on the front and back pages for easy reference. new topics for this edition include sleep problems, continence, slow weight gain (failure to thrive), obesity, continuous sc insulin infusion pumps, cystic fibrosis and illicit drug poisoning. chapters on renal conditions, pain management, management of stroke, immigrant health and the immunisation schedule have been extensively revised. each chapter provides useful web links to assist the reader with further references. the illustrations, diagnostic and management algorithms greatly enhance the accessibility of the information. the handbook would be further enhanced by including a chapter on history taking and physical examination in children. in addition, a darker font would minimise strain on the eyes and make for easier and more rapid reading. كتاب طب األطفال اليدوي امل�ؤلف�ن: كيت ت�م�ش�ن، دين تي ، مايكل مارك book review paediatric handbook editors: kate thomson, dean tey, michael marks publisher: wiley-blackwell, 8th edition, 2009 isbn: 978-1-405-7400-8 orders: www3.interscience.wiley.com squ med j, april 2010, vol. 10, iss. 1, pp. 152-153, epub. 17th apr 10 submitted 3rd feb 10 kate thomson, dean tey and michael marks book review | 153 the paediatric handbook, with its concise descriptions, is a useful source of quick revision for medical students and paediatric residents. practising general physicians and busy nurses will also find it a ready reference tool for clinical management and fast decisions making at the point of care. being comprehensive, it is easy to use, thus providing a practical guide to the diagnosis and management of common and serious health problems in children. it also complements and extends information in the clinical practice guidelines. the book will have a wide appeal as a comprehensive and clear guide to managing common and serious disorders of childhood. to conclude, this is an excellent handbook which serves the needs of all health professionals involved in the day-to-day care of paediatric patients. it emphasises the community-based approach to the practical management of children’s problems and paediatric pharmacopoeia as well as covering the current significant advances in paediatric practice. r e v i e w e r zakiya al-lamki department of child health college of medicine & health sciences sultan qaboos university muscat, oman email: zakiya@squ.edu.om directorate general of primary health care, ministry of health, muscat, oman *corresponding author’s e-mail: amel.albulushi@gmail.com هل جيب أن يكون فحص أمراض الدم الوراثية قبل الزواج إجراًء إلزامياً يف عمان؟ اأمل اأحمد البلو�سي و بدور الهنائي abstract: due to the high rate of consanguineous marriages in oman, there is a correspondingly high prevalence of hereditary blood disorders, particularly sickle cell disease and β-thalassaemia. this article proposes the possibility of implementing mandatory premarital carrier screening for blood disorders in oman, while giving due consideration to potential social and cultural obstacles. although the implementation of such legislation would require collaboration between different sectors and may negatively affect the autonomy of certain individuals, mandatory premarital screening would help to alleviate the burden of hereditary blood disorders on the national health care system, as well as reduce avoidable suffering among carriers and their families. keywords: consanguinity; premarital examinations; genetic carrier screening; mandatory screening; sickle cell trait; beta-thalassemia; oman. نظراً عمان يف وبيتا-ثال�سيما املنجلية اخلاليا دم فقر مر�ض وخا�سة الوراثية، الدم اأمرا�ض انت�سار معدل يف ارتفاع هناك امللخ�ص: اأعاله املذكورة الدم اأمرا�ض اأجل من الزواج قبل االإلزامي الفح�ض تطبيق اإمكانية الدرا�سة هذه تقرتح االأقارب. زواج معدل الرتفاع بني التعاون يتطلب الت�رصيع هذا مثل تنفيذ اأن من الرغم وعلى املحتملة. والثقافية االجتماعية العقبات مراعاة مع عمان، يف التخفيف على �سي�ساعد الزواج قبل االإلزامي الفح�ض فاإن االأفراد، بع�ض ا�ستقاللية على �سلبًا يوؤثر اأن املمكن ومن املختلفة القطاعات هذا حاملي بني جتنبها ميكن التي املعاناة تقليل عن ف�ساًل الوطني، ال�سحية الرعاية نظام على الوراثية الدم ا�سطرابات عبء من املر�ض الوراثي واأ�رصهم. الكلمات املفتاحية: قرابة؛ فح�ض ما قبل الزواج؛ الفح�ض اجليني؛ الفح�ض االإلزامي؛ �سفة نق�ض الدم املنجلي؛ بيتا-ثال�سيميا؛ عمان. should premarital screening for blood disorders be an obligatory measure in oman? *amal a. al-balushi and budoor al-hinai sounding board sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e24–29, epub. 4 apr 18 submitted 21 aug 17 revisions req. 15 oct & 7 dec 17; revisions recd. 6 nov & 17 dec 17 accepted 27 dec 17 doi: 10.18295/squmj.2018.18.01.004 as with many arab countries, consang-uineous marriages are fairly common in oman, accounting for 58% of all marriages.1,2 of these consanguineous marriages, 75% are firstcousin marriages.3 unfortunately, such unions can result in offspring with hereditary blood disorders, such as sickle cell disease (scd) and β-thalassaemia.4 as health care services in oman are free for the local population, hereditary blood disorders present a significant economic burden on the healthcare system. there is an urgent need to prioritise health services and concentrate on preventative cost-effective measures. to this end, heredi tary blood disorders might be avoided if a couple is made aware of their carrier status prior to marriage using a simple premarital screening test. this article discusses the possibility of reducing the burden of hereditary blood disorders like scd and β-thalassaemia by implementing mandatory premarital screening. in addition, the prospect of applying disincentives to atrisk couples who wish to get married is considered from an ethical standpoint. the burden of hereditary diseases in oman the most common hereditary blood disorders in oman are scd, β-thalassaemia and glucose-6-phosphate dehydrogenase (g6pd) deficiency; such diseases constitute a significant source of morbidity in addition to consuming valuable national health resources.1,5 in 2003, the genetic blood disorders survey found that approx imately 6% and 2% of omani children under five years old carried the sickle cell and β-thalassaemia genes, resp ectively; moreover, the prevalence of scd was 0.2% and homozygous β-thalassaemia was 0.07%.2 a retros pective study at a tertiary hospital in oman showed the prevalence of the sickle cell trait and scd to be 7.5% and 0.46%, respectively.6 patients with hereditary blood disorders often experience higher rates of absenteeism and reduced academic performance due to frequent hospitalisation and follow-up appointments.7 the effects of such disorders are not only multi-systemic on the part of the individual patient, but may also affect the psychosocial amal a. al-balushi and budoor al-hinai sounding board | e25 well-being of the entire family, leading to stress and anxiety as well as a disruption of the normal family dynamic.8 for example, healthy children may feel neglected by their parents as affected siblings receive greater care and attention or ill adults may not be able to fully fulfil their role as a caregiver or financial provider due to disease-related morbidity. existing premarital screening measures in oman a premarital carrier screening service has been in place in oman since 1999 and is available on an optional free-of-charge basis at all governmental healthcare institutions; the service includes a blood test involving carrier testing for sickle cell, β-thalassaemia and g6pd deficiency for those planning to get married.9,10 subsequently, a counselling session is provided during which the couple receives the results of the blood test and are informed about the risk and consequences of having affected children if they are both carriers.10 they are also provided with information about possible solutions to avoid passing on the trait to their offspring, such as in vitro fertilisation combined with preimp lantation genetic diagnosis. any family history of common genetic disorders is also collected and indiv iduals are offered additional testing, as required.10 the provision of adequate health information precedes the testing, including information regarding the diseases for which the couple will be tested, the chances that they might carry other diseases for which they will not be tested and the implications of positive or negative test results. awa r e n e s s a n d u t i l i s at i o n o f e x i s t i n g s e r v i c e s according to a survey by al-farsi et al. conducted on a section of the omani population, 89.3% of adults were aware of the availability of premarital carrier screening in oman; however, 30.5% were opposed to actually taking the test themselves, regardless of whether they were married or single.10 reasons for this reluctance might be related to fears that positive carrier results could lead to the cancellation of the marriage, with various social, cultural, psychological and financial implications. as such screening in oman is advertised on a premarital basis, people rarely under take them before a marriage proposal. following the proposal, excitement about the prospect of getting married may outweigh fear of the consequences of a positive carrier test result and couples may therefore neglect to take the test and decide to proceed with the wedding regardless. a study from saudi arabia found that knowledge about premarital testing was associated with higher educational and income levels; thus, there is a need to increase awareness of the availability and importance of premarital screening among members of the general public who may be of lower socioeconomic status or less educated.11 al-farsi et al. also suggested unifying counselling and educational efforts in order to develop protocols to standardise clinical practice at primary healthcare centres and encourage knowledge and aware ness of premarital screening among omani patients.10 this recommendation might help to increase the effect iveness of the current premarital screening programme. because they have experienced the disease themselves, scd or β-thalassaemia patients are often more motivated than asymptomatic carriers to ask their potential partners to undergo premarital testing as they do not wish to see their children suffer in the same way.12,13 however, the aim of premarital screening is to screen all individuals planning to get married in order to identify asymptomatic carriers who may produce a symptomatic child. making premarital screening compulsory is one way to achieve this goal. mandating premarital carrier screening s o c i a l a n d h e a lt h-r e l at e d b e n e f i t s the objective of a successful mandatory premarital screening programme is to reduce the number of individuals with hereditary disorders by minimising marriages between carriers and increasing the use of reproductive technologies that eliminate the risk of having a sick child. in turkey, a mandatory premarital screening programme resulted in the cancellation of 53% of at-risk marriages and an 80% reduction in at-risk births.14 similarly, mandatory premarital screen ing in bahrain led to a 58% cancellation rate of atrisk marriages.14 in saudi arabia, the prevalence of β-thalassaemia dropped from 32.9% to 9.0% following the implementation of mandatory premarital screening; in addition, there was a 60% reduction in the number of at-risk couples and a 51.9% cancellation rate of at-risk marriages.15 there are many potential advantages to making premarital screening an obligatory measure for omani couples planning to get married. social benefits of mandatory premarital screening include the possibility of increased family bonding, decreased absenteeism from school or work and a better quality of life (qol), although these factors are often difficult to assess quan should premarital screening for blood disorders be an obligatory measure in oman? e26 | squ medical journal, february 2018, volume 18, issue 1 titatively. mandatory premarital screening would also prevent the inconvenience or potential social awkwardness of individuals having to ask their partner to get tested. couples who are interested in marrying each other would be able to immediately determine their carrier status and thus make informed decisions regard ing the potential union. al-farsi et al. reported that 49.5% of omani adults in their study agreed that premarital testing should be compulsory.10 in another study, 53% of omani university students preferred mandated premarital screening and 36% were of the opinion that high-risk marriages should be prevented by law.9 a study conducted in saudi arabia indicated that 60.3% of participants encouraged obligatory premarital screening.16 e c o n o m i c b e n e f i t s on average, the annual cost of haemoglobinopathy man agement is estimated to be $4,425–7,000 usd per patient.17 inclusive of the financial costs associated with new cases arising each year, the overall economic burden of these disorders on the national healthcare system can reach $1.36 million usd.18 on the other hand, the cost of carrier screening, including personnel costs, is $20–30 usd per test; testing the entire omani population aged 15–19 years old over a five-year period would therefore amount to $800,000 usd annually.17,19 this annual cost is approximately equivalent to that currently being spent on treating haemoglobinopathy patients; however, this figure does not represent other financial costs related to the psychological and social aspects of hereditary diseases, such as qol. l e g i s l at i v e a n d p r a c t i c a l b a r r i e r s nevertheless, the implementation of a mandatory scree ning programme may also have several disadvantages. one difficulty would lie in regulating the entire marriage and screening process—which would require the involve ment of several governmental bodies, including the ministries of health, education, justice, legal affairs, religious affairs and civil services as well as the national youth committee—in a way that is comprehensive and yet still convenient for the public. second, it might be argued that mandatory screening restricts personal autonomy by forcing individuals to get tested regardless of their personal inclinations and may violate confidentiality by exposing private carrier status infor mation to possible future partners. however, it is important to determine whether an individual’s right to privacy eclipses another’s right to know their partner’s carrier status and the preventable risks to which their offspring may be exposed. moreover, every individual also has the right to enjoy their share of public health services; these are potentially reduced by the manage ment of preventable diseases consuming valuable health related resources. if the incidence of such diseases could be reduced, members of the public would be more able to benefit from other health services such as dental care, which is not easily available due to long waiting lists. therefore, implementing such a measure can be considered generally beneficial to the omani community at large. another potential obstacle that might arise with a mandatory screening policy is the decision by some at-risk couples to go ahead with the marriage despite the knowledge that each pregnancy would have a 50% chance of producing an affected child. of those at-risk couples who underwent premarital testing in saudi arabia, ibrahim et al. found that 40% subsequently cancelled their marriage plans.11 in contrast, al-farsi et al. found that 14.8% of surveyed omanis would marry even if they found out their future spouse was a carrier; moreover, 37.5% stated that they would not be willing to change their decision to marry based on premarital screening results.10 however, this issue could potentially be solved by increasing awareness of the importance of premarital screening and the consequences of passing on hereditary blood disorders. other factors affecting this issue might be an incomplete understanding of the potential risks of consanguinity due to inadequate counselling provided by healthcare workers.14,15 healthcare workers therefore need to have adequate time and training devoted to enhancing their genetic counselling skills. a combination of two models could be used to change an individual’s behaviour with regards to the acceptance of premarital screening. the cognitive model is concerned with influencing conscious thoughts, while the contextual model aims to make the intended behaviour more favourable under the assumption that people are affected by various factors in their environment and that their choices are therefore not always rational.20 instead of focusing efforts solely on awareness, as per the cognitive model, a contextual change could involve adjusting the time point at which the test is performed, particularly as this may play an important role in the outcome.14,21 currently, those who undergo premarital screening in oman are usually already engaged to be married and may therefore choose to ignore unfavourable screening results.10,21,22 mandatory screening should be carried out well before the individual is likely to get engaged, preferably during high school or university.10,15,23 moreover, providing premarital screening to individuals in late adolescence or early adulthood would allow for better comprehension of the implications of the amal a. al-balushi and budoor al-hinai sounding board | e27 results and might allow an individual to direct their search for a partner instead of, for example, offering testing alongside childhood vaccinations. even though the latter option would allow for greater coverage of the local population, neonatal screening for haemoglobinopathies would have limited success due to the likelihood of false-positive results arising from the presence of fetal haemoglobin in infants under six months of age.24 in the researchers’ opinion, mandatory premarital screening should be performed at the age of 16 years at primary healthcare institutions where optional screening is already being provided. students in the 10th grade can undertake mandatory premarital screen ing as part of their general health check-up. for those who do not undergo screening at this time, an alert reminding the physician to perform the test should appear on the patient’s electronic health record whenever they subsequently seek medical care. c u lt u r a l, r e l i g i o u s a n d s o c i a l b a r r i e r s religious beliefs, cultural attitudes and education are important determinants of the success of a premarital screening programme.14,25 current cultural norms in some parts of the country are encouraging as to the acceptance of premarital screening, while many individuals in other regions still view screening as a possible obstacle to a fruitful marriage. reproduction in oman is socially and religiously acceptable only within the context of marriage. however, it is important to mention that the implementation of a mandatory premarital screening programme is not intended to prevent consanguineous marriages, as carriers can still marry non-carrier partners within their family circle; rather, the aim is to give people with abnormal genes the chance to make an informed decision regarding their reproductive health and the health of their offspring.26 nevertheless, the implementation of such a policy might encounter resistance from the public as it might be interpreted as a method of forcing them to marry outside of their own family. despite the wide range of ethnic diversity in oman, there are various cultural barriers to banning consanguineous marriages. many omanis view consanguineous marriage to be economically beneficial since it helps to retain a family’s wealth or property.3,27 moreover, it is often perceived as an ideal method of strengthening relationships within a tribe.27,28 in addition, wedding arrangements tend to be less complicated and the financial burden is reduced if the couple is from the same family.27,29 such marriages are also deemed to increase the chances of suitability between couples and decrease the likelihood of divorce.27 therefore, prior to its implementation, members of the omani public should be assured that a mandatory premarital screening policy is not aimed at preventing consanguineous marriages, but rather at promoting good health. in many islamic societies, including oman, the term ination of a pregnancy is not accepted as it is believed to be a form of murder.27 at-risk couples who choose to get married regardless of the possibility of having an affected child would therefore not have the option to selectively terminate affected fetuses. however, such couples could choose to refrain from having biological children and adopt instead, or undergo preimplantation genetic diagnosis prior to in vitro fertilisation.4 preimplantation genetic diagnosis is welcomed in islamic societies as a method of preventing hereditary diseases as it is not perceived as terminating a living being.27 however, such services are not offered at govern mental institutions in oman; couples seeking this service would therefore have to visit a private health institution either locally or abroad. the obligatory nature of premarital screening might also result in social stigma, with the families of carriers potentially ostracised or unable to find a non-carrier partner for their child within their community.1,15 however, this should not be a major obstacle provided that effective awareness and educational programmes are promoted to address such fears.30 emphasis should be placed on the prevalence of these diseases and the duty of members of society to prevent suffering in the next generation of children. in addition, the public needs to be educated regarding the precise medical implications of carrier status, as some individuals might associate being a carrier as equivalent to having the disease. moreover, some individuals may interpret the islamic belief in predestination to signify acceptance of having an ill child.14 however, it is important to note that islamic beliefs also encourage taking the causes of ill health into consideration and making healthy choices accordingly.14 disincentives for at-risk couples patients need to be involved within the healthcare process and must therefore be made responsible for their choices. from a liberal egalitarian perspective, individuals should have access to equal health resources for diseases that are outside of their control, but not for those arising from their own choices.31 this argument would hold the parents of offspring with scd or β-thalassaemia responsible for their child’s illness due to their having neglected premarital screening or having failed to act on the test results of such screening. policy-makers could therefore apply financial disincentives to the parents of patients with hereditary blood diseases. these could be should premarital screening for blood disorders be an obligatory measure in oman? e28 | squ medical journal, february 2018, volume 18, issue 1 in the form of paying all or part of the cost of treatment and management of an affected child or instituting fines for all at-risk married couples, even if they do not give birth to an affected child. nevertheless, neither carriers nor those affected by hereditary disorders are responsible for their genetic material. disincentives may therefore unequally discriminate against such individuals and it would not be fair to penalise or deny patients necessary healthcare because of a decision made by someone else (i.e. their parents). one can argue that such patients are already penalised enough by virtue of their ill health and therefore do not need an additional penalty in the form of disincentives. on the other hand, financial deterrents will spare the government from having to fund the treatment of certain hereditary disorders, thereby allowing for the more efficient allocation of already limited resources. moreover, such disincentives will not affect an individual’s liberty as the decision to marry remains up to the couple; should they nevertheless opt to take the risk and marry, knowing that they are both carriers, they will still be able to do so at an additional cost. however, one might argue that a couple’s autonomy is nevertheless restricted by such a measure. moreover, individuals with low incomes may not be able to go ahead with a marriage in view of the potential financial deterrents. therefore, this measure may unfairly disadvantage those with lower incomes. the implementation of any deterrent or disincen tive measures should be delayed until after the mandatory premarital screening programme has been put into effect, as it may subsequently be found that such measures are not necessary. however, if unavoidable, policy-makers should take certain factors into account when deciding to apply disincentive measures, possibly by excluding or reducing the fines or co-payments of low-income individuals. one way to make this policy more equitable would be to base the amount on a predetermined proportion of the household’s income. in general, disincentives may be deemed necessary by experts on the behalf of the entire community, in that the ideal wellbeing of a few individuals is a justifiable sacrifice in view of the best interests of the public. conclusion mandating premarital screening could alleviate the un necessary burden of hereditary blood disorders in oman. compulsory premarital screening is recommended for all omani adolescents at approximately 16 years old so as to cover the entire target population at an early age; this could also help avoid the potential incon venience associated with learning of positive screening results after becoming engaged. however, in order to implement such legislation, multilevel collaboration is needed among various institutions in oman. in addition, various awareness and educational programmes may be necessary to ensure compliance and understanding of the goals of the programme within the omani population. a c k n o w l e d g e m e n t s the authors would like to thank the editors and anonymous reviewers for their valuable comments on this article. references 1. world health organization regional office for the eastern medi terranean. community control of genetic and congenital disorders. from: apps.who.int/iris/handle/10665/119571 accessed: dec 2017. 2. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 3. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571–94. doi: 10.1017/s0021932012000016. 4. howard j, telfer p. sickle cell disease in clinical practice. london, uk: springer, 2015. pp. 18–28. doi: 10.1007/978-1-44 71-2473-3. 5. aneke jc, okocha ce. sickle cell disease genetic counseling and testing: a review. arch med health sci 2016; 4:50–7. doi: 10.4103/2321-4848.183342. 6. adly g, rajappa a. haemoglobinopathies encountered at khoula hospital, oman: a retrospective study. sultan qaboos univ med j 2008; 8:59–62. 7. al-saqladi am. the impact of sickle cell disease severity on school performance in affected yemeni children. j appl hematol 2016; 7:124–30. doi: 10.4103/1658-5127.198506. 8. rees dc, williams tn, gladwin mt. sickle-cell disease. lancet 2010; 376:2018–31. doi: 10.1016/s0140-6736(10)61029-x. 9. al kindi r, al rujaibi s, al kendi m. knowledge and attitude of university students towards premarital screening program. oman med j 2012; 27:291–6. doi: 10.5001/omj.2012.72. 10. al-farsi oa, al-farsi ym, gupta i, ouhtit a, al-farsi ks, al-adawi s. a study on knowledge, attitude, and practice towards premarital carrier screening among adults attending primary healthcare centers in a region in oman. bmc public health 2014; 14:380. doi: 10.1186/1471-2458-14-380. 11. ibrahim nk, bashawri j, al bar h, al ahmadi j, al bar a, qadi m, et al. premarital screening and genetic counseling program: knowledge, attitude, and satisfaction of attendees of governmental outpatient clinics in jeddah. j infect public health 2013; 6:41–54. doi: 10.1016/j.jiph.2012.05.001. 12. ross pt. motivations of women with sickle cell disease for asking their partners to undergo genetic testing. soc sci med 2015; 139:36–43. doi: 10.1016/j.socscimed.2015.06.029. 13. gallo am, wilkie d, suarez m, labotka r, molokie r, thompson a, et al. reproductive decisions in people with sickle cell disease or sickle cell trait. west j nurs res 2010; 32:1073–90. doi: 10.1177/ 0193945910371482. 14. saffi m, howard n. exploring the effectiveness of mandatory premarital screening and genetic counselling programmes for β-thalassaemia in the middle east: a scoping review. public health genomics 2015; 18:193–203. doi: 10.1159/000430837. https://doi.org/10.1017/s0021932012000016 https://doi.org/10.1007/978-1-4471-2473-3 https://doi.org/10.1007/978-1-4471-2473-3 https://doi.org/10.4103/2321-4848.183342 https://doi.org/10.4103/1658-5127.198506 https://doi.org/10.1016/s0140-6736%2810%2961029-x https://doi.org/10.5001/omj.2012.72 https://doi.org/10.1186/1471-2458-14-380 https://doi.org/10.1016/j.jiph.2012.05.001 https://doi.org/10.1016/j.socscimed.2015.06.029 https://doi.org/10.1177/0193945910371482 https://doi.org/10.1177/0193945910371482 https://doi.org/10.1159/000430837 amal a. al-balushi and budoor al-hinai sounding board | e29 15. alhamdan na, almazrou yy, alswaidi fm, choudhry aj. pre marital screening for thalassemia and sickle cell disease in saudi arabia. genet med 2007; 9:372–7. doi: 10.1097/gim.0 b013e318065a9e8. 16. el-hazmi ma. pre-marital examination as a method of preven tion from blood genetic disorders: community views. saudi med j 2006; 27:1291–5. 17. world health organization. guidelines for the control of haemo globin disorders. from: http://apps.who.int/iris/handle/10665/ 66665 accessed: dec 2017. 18. alkindi s, al zadjali s, al madhani a, daar s, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. doi: 10.3109/03630261003677213. 19. national centre for statistics and information. data portal: population. from: http://data.gov.om/ompop2016/population? age-group=1000410 accessed: dec 2017. 20. institute for government cabinet office. mindspace: influen cing behaviour through public policy. from: www.institutefor government.org.uk/sites/default/files/publications/mindsp ace-practical-guide-final-web_1.pdf accessed: dec 2017. 21. al-aama jy. attitudes towards mandatory national premarital screening for hereditary hemolytic disorders. health policy 2010; 97:32–7. doi: 10.1016/j.healthpol.2010.02.009. 22. alswaidi fm, memish za, o’brien sj, al-hamdan na, al-enzy fm, alhayani oa, et al. at-risk marriages after compulsory premarital testing and counseling for β-thalassemia and sickle cell disease in saudi arabia, 2005-2006. j genet couns 2012; 21:243–55. doi: 10.1007/s10897-011-9395-4. 23. memish za, saeedi my. six-year outcome of the national prema rital screening and genetic counseling program for sickle cell disease and β-thalassemia in saudi arabia. ann saudi med 2011; 31:229–35. doi: 10.4103/0256-4947.81527. 24. giordano p. newborn screening for haemoglobinopathies. in: old j, ed. prevention of thalassaemias and other haemoglobin disorders, 2nd ed. nicosia, cyprus: thalassaemia international federation, 2013. 25. hashemizadeh h, noori r. premarital screening of beta thalassemia minor in north-east of iran. iran j ped hematol oncol 2012; 3:210–15. 26. modell b, kuliev a. the history of community genetics: the contribution of the haemoglobin disorders. community genet 1998; 1:3–11. doi: 10.1159/000016129. 27. hamamy h, bittles ah. genetic clinics in arab communities: meeting individual, family and community needs. public health genomics 2009; 12:30–40. doi: 10.1159/000153428. 28. kilshaw s, al raisi t, alshaban f. arranging marriage, negotiating risk: genetics and society in qatar. anthropol med 2015; 22:98–113. doi: 10.1080/13648470.2014.976542. 29. bittles ah, mason wm, greene j, rao na. reproductive behavior and health in consanguineous marriages. science 1991; 252:789–94. doi: 10.1126/science.2028254. 30. al-gazali l, hamamy h, al-arrayad s. genetic disorders in the arab world. bmj 2006; 333:831–4. doi: 10.1136/bmj.38 982.704931.ae. 31. cappelen aw, norheim of. responsibility, fairness and rationing in health care. health policy 2006; 76:312–19. doi: 10.1016/j.healthpol.2005.06.013. https://doi.org/10.1097/gim.0b013e318065a9e8 https://doi.org/10.1097/gim.0b013e318065a9e8 https://doi.org/10.3109/03630261003677213 https://doi.org/10.1016/j.healthpol.2010.02.009 https://doi.org/10.1007/s10897-011-9395-4 https://doi.org/10.4103/0256-4947.81527 https://doi.org/10.1159/000016129 https://doi.org/10.1159/000153428 https://doi.org/10.1080/13648470.2014.976542 https://doi.org/10.1126/science.2028254 https://doi.org/10.1136/bmj.38982.704931.ae https://doi.org/10.1136/bmj.38982.704931.ae https://doi.org/10.1016/j.healthpol.2005.06.013 التصورات واملمارسات البحثية خلرجيي الطب دراسة مقطعية تقارن بني خرجيي جامعة امللك عبد العزيز لعامي 2015 و 2017 اأحمد با�سكران، مي�ساء بنجري، مالك املرغوب، اإيالف الزرنوقي abstract: objectives: this study aimed to compare changes in medical students’ research practices and perceptions of two cohorts of graduates. methods: this cross-sectional comparative study was conducted from november 2014 to december 2017 and included the 2015 and 2017 medical graduates of king abdulaziz university, jeddah, saudi arabia. a validated self-administrated questionnaire, which included questions about participants’ age and gender, research activities, and obstacles to and motivators for research involvement was used. results: a total of 484 graduates were included in this study (response rate: 96.8%). a significant difference was found between the 2015 and 2017 graduates who had not started any research project (48.4% versus 35%; p <0.001) and a 20% increase in the 2017 graduates’ conf idence in their abilities to start their own projects was observed (p <0.001). significantly more 2017 graduates were engaged in various research roles, other than 'author', compared to 2015 graduates (71.3% versus 55.4%; p <0.001). career progression was the main motivator for both the 2015 and 2017 medical graduates to participate in research (79.5%). reported obstacles to research included a lack of dedicated time for research and methodology training and a shortage of research project opportunities. conclusion: this study highlights positive changes in attitudes towards and perceptions of research among medical graduates. keywords: medical students; research; professional practice; attitude; perception; medical education; saudi arabia. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل مقارنة التغريات يف الت�سورات واملمار�سات البحثية لطالب الطب على مدار عامني. الطريقة: اأجريت درا�سة مقطعية امتدت من نوفمرب 2014 اإىل دي�سمرب 2017 و�سملت مقارنة خريجي الطب لعامي 2015 و 2017 بجامعة امللك عبد العزيز ، جدة ، اململكة العربية ال�سعودية. وللمقارنة مت ا�ستخدام ا�ستبيان تقييم ذاتي معتمد م�سبقا، والذي ت�سمن اأ�سئلة حول عمر وجن�ض امل�ساركني واأن�سطتهم البحثية ودوافعهم للم�ساركة يف البحوث بال�سافة اىل العقبات التي حتول دون تلك امل�ساركة. النتائج: �سملت هذه الدرا�سة 484 خريجا )معدل ال�ستجابة: %96.8(. مت العثور على فرق ذو دللة اح�سائية بني خريجي 2015 و 2017 من حيث ن�سبة الطلبة الذين مل يبداأوا اأي م�رسوع بحثي بعد )p >0.001؛ %35 مقابل %48.4( غري انه لوحظت زيادة بن�سبة %20 يف ثقة خريجي عام 2017 بقدراتهم على البدء بامل�ساريع البحثية اخلا�سة بهم )p >0.001(. �سارك عدد اأكرب من خريجي عام 2017 يف اأدوار بحثية خمتلفة ، بخالف دورهم كموؤلفني ، مقارنة بخريجي عام p > 0.001( 2015؛ %55.4 مقابل %71.3(. كان التدرج الوظيفي هو الدافع الرئي�سي لكل من خريجي الطب عامي 2015 و 2017 للم�ساركة يف البحوث )%79.5(. �سملت معوقات البحث التي مت ذكرها قلة الوقت املخ�س�ض للبحث وعدم توفرالتدريب الكايف على منهجية البحث ونق�ض امل�ساريع البحثية املتاحة. اخلال�صة: ت�سلط هذه الدرا�سة ال�سوء على التغريات الإيجابية يف مواقف وت�سورات خريجي الطب جتاه البحث. الكلمات املفتاحية: طلبة الطب؛ بحث؛ املمار�سة املهنية؛ موقف؛ ت�سور؛ التعليم الطبي؛ اململكة ال�سعودية. medical graduates’ research practices and perceptions a comparative cross-sectional study between 2015 and 2017 graduates of king abdulaziz university ahmed m. basakran,1 *maysaa a. banjari,2 malak a. almarghoub,3 elaf m. alzarnougi4 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e32–37, epub. 30 may 19 submitted 19 jul 18 revisions req. 29 jul & 13 sep 18; revisions recd. 5 aug & 16 oct 18 accepted 21 nov 18 advances in knowledge positive changes in medical graduates’ perceptions of research and practice is an indication of the importance of awareness to research involvement. the main barriers affecting research activities were a lack of dedicated time and methodology training as well as a lack of research project availability. application to patient care understanding evolving changes in perceptions and practice associated with research will help to focus efforts to ensure more research involvement among medical graduates. improving perceptions of research and practice among medical graduates can help them properly implement evidence-based medicine in a clinical setting. 1faculty of medicine, university of jeddah, jeddah, saudi arabia; departments of 2pediatrics and 3obstetrics & gynecology, king abdulaziz university, jeddah, saudi arabia; 4department of internal medicine, king faisal specialist hospital and research centre, jeddah, saudi arabia *corresponding author’s e-mail: maysaa.ban@live.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.007 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ ahmed m. basakran, maysaa a. banjari, malak a. almarghoub and elaf m. alzarnougi clinical and basic research | e33 research is an essential component of medicine as it plays a vital role in advancing scientific knowledge.1 clinicians are required to make decisions based on the best available evidence. this practice can only be accomplished with optimum understanding of research principles.2 in order to imp rove medical practice and scientific knowledge, research activities should be encouraged and implemented in the undergraduate years.3 encouraging medical students to participate in research can help them develop skills associated with communication, teamwork, time management and indep endent learning. as students gain research experience, they in turn are motivated to pursue a career in research. further, participating in research at an early stage in education could help students establish a positive pers pective towards science and scientific methodologies.4–7 understanding the attitude of undergraduate students and graduates towards research can improve research practice in the postgraduate period.8 shahbaz et al.’s study conducted in lahore with undergraduate university students found that 86% believed research was an essential aspect of their field of study; however, only 33% had previous research experience.9 in addition, ibrahim et al.’s study in egypt revealed that 69% of medical students believed that research experience would greatly help their long-term career objectives, yet only 11% had publ ished a paper.10 several studies have been conducted in saudi arabia to understand medical students’ perceptions of their research practice. a study conducted in makkah’s umm al-qura university with undergraduate students in the health colleges revealed that only 6.6% had published research-based writing.11 another study conducted in jeddah in 2010 with medical graduates of king abdulaziz university found that 31% had co-authored research papers, with only 3.2% being first authors.12 at king abdulaziz university, research is an essential part of the undergraduate curriculum. at the time of this paper’s writing, students had no graduation requirements to participate in a research project. how ever, during their third, fourth and fifth years of medical school, the university offered lectures and assignments designed to teach undergraduates the basics of research, such as idea formation, data acquisition and analysis, manuscript writing and how to appraise research articles. the current study aimed to compare research practices and perceptions among undergraduate medical students who graduated in 2015 and 2017 from king abdulaziz university. these two groups were chosen because of increased efforts around improving research awareness over the two years preceding this study, in part due to a new unit established to deliver free workshops emphasising the importance of research. in addition, in jeddah in 2016, a summer school was established to encourage undergraduate students to participate in research by providing them with research opportunities. finally, the saudi commission for health specialties (scfhs), the organisation responsible for postgraduate studies in saudi arabia, announced that conducting research, authoring papers and presenting at conferences would improve a medical graduate’s likelihood of admission into postgraduate programmes. methods this comparative cross-sectional study was conducted at king abdulaziz university in jeddah, saudi arabia, between november 2014 and december 2017. the study included 2015 and 2017 medical school graduates who had completed six years of an undergraduate medical programme and were in their internship years during the data collection phase. both groups were approached in person or through mobile phone text messages. this population was chosen due to ease of access and because the graduates were in the process of applying to postgraduate programmes and would therefore be aware of research. this study used a validated, self-administered, online questionnaire that was originally used in a study conducted in the same setting; permission was taken from the primary author to use this tool in the current study.12 the questionnaire comprised 29 questions, including questions about age, gender and grade point average (gpa). further questions sought information about research activities, motivators to be active in research, obstacles affecting research progress and measures to improve research involvement. graduates’ answers were classified according to a likert scale and were rated from strongly disagree to strongly agree (1–5, respectively). data were analysed using statistical package for the social science (spss), version 16 (ibm corp., armonk, new york, usa) and were expressed as numbers and percentages. a chi-squared test was used to assess whether the data followed a random distribution. a p value of <0.005 was considered statistically significant. consent was collected after the purpose of the study was thoroughly explained to the participants. ethical approval was received for this study from the ethical committee of king abdulaziz university (62261\39\d). results a total of 500 medical graduates were contacted and 484 completed the questionnaire (response rate: 96.8%) medical graduates’ research practices and perceptions a comparative cross-sectional study between 2015 and 2017 graduates of king abdulaziz university e34 | squ medical journal, february 2019, volume 19, issue 1 of which 51.4% were females. females and those with higher gpas were more likely to begin research during their undergraduates’ education [table 1]. more 2015 graduates had not started a research project compared to 2017 graduates (48.4% versus 35%; p <0.001) [table 2]. moreover, a significant increase was seen in the number of 2017 graduates compared to 2015 graduates engaging in research in a role other than author such as data collector, etc. (71.3% versus 55.4%; p <0.001). less 2015 graduates published papers as a first author than 2017 graduates (8.7% versus 22.67%; p <0.001). more 2017 graduates felt confident to start their own research project (62% versus 42.4%; p <0.001) and submit an article without supervision (37.3% versus 13.6%; p <0.001) than 2015 graduates [table 2]. table 1: comparison of the research activities, grade point averages, genders and ages between 2015 and 2017 medical graduates from king abdulaziz university, jeddah, saudi arabia (n = 484) characteristic n (%) p value n (%) p value 2015 graduates 2017 graduates started research (n = 95) did not start research (n = 89) started research (n = 195) did not start research (n = 105) gender male 31 (32.6) 54 (60.7) <0.001 86 (44.1) 64 (61) 0.005 female 64 (67.4) 35 (39.3) 109 (55.9) 41 (39) gpa 4–5 61 (64.2) 55 (61.8) 0.085 165 (84.6) 42 (40) <0.001 3–3.99 14 (14.7) 23 (25.8) 25 (12.8) 62 (59) ≤2.99 0 (0) 0 (0) 1 (0.5) 0 (0) undisclosed by students 20 (21.1) 11 (12.4) 4 (2.1) 1 (1) age in years ≥24 56 (58.9) 34 (38.2) 0.005 94 (48.2) 44 (41.9) 0.296 <24 39 (41.5) 55 (61.8) 101 (51.8) 61 (58.1) gpa = grade point average. table 2: comparison of research activity between 2015 and 2017 medical graduates from king abdulaziz university, jeddah, saudi arabia (n = 484) graduates’ research involvement n (%) p value 2015 graduates (n = 184) 2017 graduates (n = 300) 1. graduates who had not yet started a research project 89 (48.4) 105 (35) <0.001 2. graduates who had started a research project 95 (51.6) 195 (65) <0.001 3. graduates who had started a research project but stopped 51 (27.7) 58 (19.3)* <0.001 4. graduates who had completed a research project 44 (23.9) 145 (48.3)* <0.001 role in research other than author† (n = 102) (n = 214) <0.001 hypothesis creation 32 (17.4) 60 (20) data collection 80 (43.5) 204 (68) data analysis 33 (18) 69 (23) manuscript writing 31 (16.8) 63 (21) graduates who had submitted their papers for publication 31 (30.4) 111 (37) <0.001 graduates who had published a research paper 16 (8.7) 68 (22.7) <0.001 graduates who felt confident enough to start their own project 78 (42.4) 186 (62) <0.001 graduates who felt confident in submitting an article without supervision 25 (13.6) 112 (37.3) <0.001 *some participants chose both options three and four as they had participated in more than one research project. †participants could choose more than one option. ahmed m. basakran, maysaa a. banjari, malak a. almarghoub and elaf m. alzarnougi clinical and basic research | e35 graduates identified career progression as the main motivator to participate in research (79.5%), followed by a motivation to improve academic performance (60%) and pursue research interests (33.5%). in addition, peer pressure to carry out research was significantly higher among the 2017 graduates than the 2015 graduates (18% versus 7.6%; p <0.001) [table 3]. in terms of barriers to active research, a lack of dedicated time (73.4%) and methodology training (69.6%) were identified as major obstacles by the 2015 graduates. on the other hand, the 2017 graduates reported that the main barriers to being more active in research was a lack of dedicated research time (66.3%) and a paucity of available research projects (60%) [table 4]. the majority (60.8%) believed that including a one month rotation devoted to research during the internship period could be an effective approach to enhancing research activities. in addition, 60.3% agreed that a 2–3-month rotation would have the same benefit. discussion this study aimed to compare research practice and perception among 2015 and 2017 graduates of an under graduate medical programme in saudi arabia. the findings highlight the effect of increased awareness of the importance of research and a change in researchspecific criteria for post-graduate programme acceptance. two main findings emerged from this study. first, significantly more 2017 graduates were active in research compared to 2015 graduates (p <0.001). second, the researchers noted a pronounced boost in graduates’ confidence in their ability to author and submit research independently, demonstrating a positive change in attit udes and perceptions. in this study, 65% of the 2017 graduates indicated they had begun their own research project in comparison to 51.6% of the 2015 graduates. this finding could be explained by an increased awareness of the importance of involvement in research through the activities of student research units and the changes that occurred in the scfhs criteria of admission into postgraduate programmes. it is worth noting that research involvement of both the 2015 and 2017 graduates is higher than other studies done in sweden and brazil.13,14 however, both of these studies were conducted on medical students, while our study was conducted on medical graduates, who had more time to be involved in research. in the current study, the confidence of the graduates to start their own projects without supervision increased significantly in 2017, possibly due to those graduates’ increased involvement in research-promoting activities (p <0.001). past research has noted that students’ active participation in research can improve their confidence in and understanding of research, in addition to increasing their interest in pursuing research-based careers in the postgraduate period.15 however, graduates expressed concerns about not having sufficient research opportunities in their university. this finding could indicate that even though barriers were present, students found alternative solutions to increasing research involve ment, such as eliciting support from supervisors from different universities and attending summer schools or focused workshops that provided research opportunities. this observed high level of confidence and increased research practice could be a result of reporting table 3: factors motivating 2015 and 2017 medical graduates from king abdulaziz university, jeddah, saudi arabia, to actively participate in research (n = 484) factor* n (%) p value 2015 graduates (n = 184) 2017 graduates (n = 300) total (n = 484) career progression 138 (75) 247 (82.3) 385 (79.5) 0.052 improved academia 101 (54.9) 189 (63) 290 (59.9) 0.077 personal interest 54 (29.3) 108 (36) 162 (33.5) 0.132 supervisor encouragement 32 (17.4) 38 (12.7) 70 (14.5) 0.151 peer pressure 14 (7.6) 54 (18) 68 (14) 0.001 no motivation 4 (2.2) 16 (5.3) 20 (4.1) 0.090 *participants could choose more than one factor. table 4: factors preventing 2015 and 2017 medical grad uates from king abdulaziz university, jeddah, saudi arabia, from being active in research (n = 484) factors* n (%) p value 2015 graduates (n = 184) 2017 graduates (n = 300) lack of dedicated research time 135 (73.4) 199 (66.3) 0.014 lack of methodology training 128 (69.6) 172 (57.3) 0.040 lack of available projects to join 117 (63.6) 180 (60) 0.168 lack of workshops on research 112 (60.9) 143 (47.7) 0.023 lack of convenient data systems 87 (47.3) 166 (55.3) 0.007 faculty members not providing assistance 77 (41.8) 154 (51.3) <0.001 difficulty writing in english 62 (33.7) 108 (36) 0.427 lack of financial rewards 62 (33.7) 98 (32.7) 0.053 *participants could choose more than one factor. medical graduates’ research practices and perceptions a comparative cross-sectional study between 2015 and 2017 graduates of king abdulaziz university e36 | squ medical journal, february 2019, volume 19, issue 1 bias or sample bias, as the students may have wanted to over-represent their achievements and the sample of this study only included medical programme graduates. a study conducted in madinah, saudi arabia revealed a direct relationship between students’ academic year and their research involvement.3 therefore, further research is needed to analyse research practices among students of all academic years to better understand students’ perceptions at all levels of education. career progression was one of the main motivators for research involvement for both the 2015 and the 2017 graduates, which is similar to findings from studies conducted in king abdulaziz university, univ ersity college cork and universiti sains malaysia.16,17 furthermore, peer pressure to carry out research was found to have significantly increased in the 2017 cohort comparing to the 2015 cohort (p <0.001). this increase may be attributed to increasing competition between graduates or the more stringent research recommend ations implemented by the scfhs in 2017. graduates identified many barriers affecting their research participation. both 2015 and 2017 graduates agreed that lack of time negatively impacted their research practice (73.4% and 66.3%). similar obstacles to research were reported by medical students in another saudi arabian study conducted in five medical schools.18 these findings also concur with those of a study done in the united kingdom, where 74% of their sample reporting that time constraints acted as a crippling barrier to their research activities.19 the persistence of this obstacle indicates the importance of allocating time dedicated specifically to research. the majority (60%) of the 2017 graduates believed that there was a shortage in the number of available research projects, indicating a need for more enthusiastic faculty members and summer schools to provide more research opportunities for interested students. it is worth noting that starting from 2021, authoring a research project will become a prerequisite for graduation from king abdulaziz university. this positive change can play an important role in improving students’ future participation in research. the current study noted an improvement in knowl edge regarding the existence of research methodology training, possibly because of the free workshops conducted by the students’ research unit. this positive change indicates that plans to improve students’ research practice are succeeding; however, more efforts are needed to ensure the adequacy of the given lectures and workshops. this obstacle represents a serious barrier to students’ research practice, as reported in similar studies conducted in saudi arabia and pakistan.9,12 the primary limitation of this study is that the data was collected from the graduates via a data collection tool and not through one-on-one interviews. qualitative interview-based studies can help researchers better understand graduates’ perceptions of research and find solutions to increase their research involvement. add itionally, conducting this study with a larger sample and including graduates and students from several universities and different academic years could give more insight into how to improve students’ and graduates’ practices and perceptions of research. conclusion this study highlighted positive changes in attitudes and perceptions of research among graduates of a medical programme in jeddah, saudi arabia. however, it still demonstrates the importance of providing more research opportunities and research-based lectures as well as matching supervisors with medical students and recent graduates in order to ensure the quality of their conducted research. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. kasulkar aa, gupta m, chari s, kanade ht. assessment of medical students’ interest in research in central india. j evol med dent sci 2013; 2:5375–81. https://doi.org/10.14260/jemds/997. 2. murdoch-eaton d, drewery s, elton s, emmerson c, marshall m, smith ja, et al. what do medical students understand by research and research skills? identifying research opportunities within undergraduate projects. med teach 2010; 32:e152–60. https://doi.org/10.3109/01421591003657493. 3. noorelahi mm, soubhanneyaz aa, kasim ka. perceptions, barriers, and practices of medical research among students at taibah college of medicine, madinah, saudi arabia. adv med educ pract 2015; 6:479–85. https://doi.org/10.2147/amep.s83978. 4. burgoyne ln, o'flynn s, boylan gb. undergraduate medical research: the student perspective. med educ online 2010; 15:5212. https://doi.org/10.3402/meo.v15i0.5212. 5. reinders jj, kropmans tj, cohen-schotanus j. extracurricular research experience of medical students and their scientific out put after graduation. med educ 2005; 39:237. https://doi.org/10. 1111/j.1365-2929.2004.02078.x. 6. vujaklija a, hren d, sambunjak d, vodopivec i, ivanis a, marusić a, et al. can teaching research methodology influence students’ attitude toward science? cohort study and nonrandomized trial in a single medical school. j investig med 2010; 58:282–6. https://doi.org/10.2310/jim.0b013e3181cb42d9. 7. buckley s, coleman j, davison i, khan ks, zamora j, malick s, et al. the educational effects of portfolios on undergraduate student learning: a best evidence medical education (beme) systematic review. beme guide no. 11. med teach 2009; 31:282–98. https://doi.org/10.1080/01421590902889897. https://doi.org/10.14260/jemds/997 https://doi.org/10.3109/01421591003657493 https://doi.org/10.2147/amep.s83978 https://doi.org/10.3402/meo.v15i0.5212 https://doi.org/10.1111/j.1365-2929.2004.02078.x https://doi.org/10.1111/j.1365-2929.2004.02078.x https://doi.org/10.2310/jim.0b013e3181cb42d9 https://doi.org/10.1080/01421590902889897 ahmed m. basakran, maysaa a. banjari, malak a. almarghoub and elaf m. alzarnougi clinical and basic research | e37 8. alghamdi km, moussa na, alessa ds, alothimeen n, al-saud as. perceptions, attitudes and practices toward research among senior medical students. saudi pharm j 2014; 22:113–17. https://doi.org/10. 1016/j.jsps.2013.02.006. 9. shahbaz t, masooma n, naeem m, siddiqui h, nawaz i, firdous z. perception and attitude towards research: a comparative study among medical and non-medical undergraduate students at university of lahore. pakistan j med health sci 2016; 10:122–6. 10. ibrahim si, afifi am, zahran a. knowledge, attitudes and practices of medical students towards research in two public universities in egypt. proceedings of the ires 23rd international conference, dubai, uae, 29th december 2015. 11. nour mo, natto ha, faden bs, almghrabi na, alqurashi aa, alaiafi aa, et al. participation of health colleges’ students in research at umm al-qura university, saudi arabia: a crosssectional study. imp j interdiscip res 2017; 3:429–35. 12. alsayed n, eldeek b, tayeb s, ayuob n, al-harbi a. research practices and publication obstacles among interns at king abdulaziz university hospital, jeddah, saudi arabia, 2011-2012. j egypt pub health assoc 2012; 87:64–70. https://doi.org/10.10 97/01.epx.0000417978.44502.61. 13. stockfelt m, karlsson l, finizia c. research interest and activity among medical students in gothenburg, sweden, a cross-sectional study. bmc med educ 2016; 16:226. https://doi.org/10.1186/ s12909-016-0749-3. 14. oliveira cc, de souza rc, abe eh, silva móz le, de carvalho lr, domingues ma, undergraduate research in medical education: a descriptive study of students’ views. bmc med educ 2014; 14:51. https://doi.org/10.1186/1472-6920-14-51. 15. robertson j, blackler g. students’ experiences of learning in a research environment. high educ res dev 2006; 25:215–29. https://doi.org/10.1080/07294360600792889. 16. ibrahim nkr, fetyani dm, bashwari j. assessment of the research-oriented knowledge, attitude and practice of medical students and interns of the king abdulaziz university, jeddah and the adoption of a research-intervention educational program. rawal med j 2013; 38:432–9. 17. ismail im, bazli my, o’flynn s. study on medical student’s attitude towards research activities between university college cork and universiti sains malaysia. procedia soc behav sci 2014; 116:2645–9. https://doi.org/10.1016/j.sbspro.2014.01.628. 18. al-hilali sm, al-kahtani e, zaman b, khandekar r, al-shahri a, edward dp. attitudes of saudi arabian undergraduate medical students towards health research. sultan qaboos univ med j 2016; 16:e68–73. https://doi.org/10.18295/squmj.2016.16.01.012. 19. nikkar-esfahani a, jamjoom aa, fitzgerald je. extracurricular participation in research and audit by medical students: opportunities, obstacles, motivation and outcomes. med teach 2012; 34:e317–24. https://doi.org/10.3109/0142159x.2012.670324. https://doi.org/10.1016/j.jsps.2013.02.006 https://doi.org/10.1016/j.jsps.2013.02.006 https://doi.org/10.1097/01.epx.0000417978.44502.61 https://doi.org/10.1097/01.epx.0000417978.44502.61 https://doi.org/10.1186/s12909-016-0749-3 https://doi.org/10.1186/s12909-016-0749-3 https://doi.org/10.1186/1472-6920-14-51 https://doi.org/10.1080/07294360600792889 https://doi.org/10.1016/j.sbspro.2014.01.628 https://doi.org/10.18295/squmj.2016.16.01.012 https://doi.org/10.3109/0142159x.2012.670324 squ med j, february 2012, vol. 12, iss. 1, pp. 55-61, epub. 7th feb 12. submitted 2nd july 11 revision req. 7th sep 11, revision recd. 1st oct 11 accepted 26th oct 11 1department of clinical pharmacy, college of pharmacy, university of mosul, mosul, iraq; 2department of pharmacology, college of medicine, university of mosul, mosul, iraq. *corresponding author e-mail: imadpharma@yahoo.com مقارنة تأثريات الكليبنكالميد مع امليتفورين على الربوتني التفاعلي نوع )ج( وحالة األكسدة/ مضادات األكسدة عند مرضى السكري من النوع الثاين عالء اأبو بكر، عماد ثانون امللخ�ص: الهدف: تهدف هذه الدرا�سة اىل مقارنة تاأثريات امليتفورمني والكليبنكالميد على الربوتني التفاعلي عايل احل�سا�سية نوع )ج( حديثي الثاين النوع من ال�سكري مر�سى عند الدم م�سل يف الكلّية( الأك�سدة ُم�سادات وحالة باملالونديليهايد )ممثال الأك�سدة و�سغط 103 مري�سا الدرا�سة هذه يف تطّوع الطريقة: ال�سابطة. املجموعة مع باملقارنة العالج من �سهرين مرور وبعد البداية، يف الت�سخي�س م�سابا بال�سكري من النوع الثاين حديثي الت�سخي�س من مركز الوفاء للبحوث وعالج ال�سكري، للفرتة من ت�رصين الثاين/نوفمرب 2009 �سّمت الكليبنكالميد. دواء )50 مري�سا( الباقون اأعطي بينما امليتفورمني، بدواء 53 منهم عالج مت ،2011 الثاين/يناير كانون اإىل وقيا�س امل�سول عينات عزل ومت الليل، �سيام بعد امل�ساركني من الدم عّينات �ُسحبت الأ�سحاء. من 40متطوعا ال�سابطة املجموعة م�ستويات الربوتني التفاعلي عايل احل�سا�سية نوع )ج( ، املالونديليهايد وحالة م�سادات الأك�سدة الكلّية. بعد �سهرين من العالج الأحادي بامليتفورمني امُلعاجلني املر�سى بني ُمعتّدة اإح�سائية فروقا هناك كانت النتائج: اأعاله. الفحو�سات واإعادة ثانية دم عينة �سحب مت م�سادات وحالة واملالونديليهايد )ج(، نوع احل�سا�سية عايل التفاعلي الربوتني من لكل بالن�سبة ال�سابطة واملجموعة والكليبنكالميد الك�سدة الكلّية، حيث كان هناك انخفا�سا اإح�سائيا ُمعتّدا يف م�ستوى املالونديليهايد مع ارتفاع ُمعتد من الناحية الإح�سائية يف م�ستوى م�سادات الأك�سدة الكلّية مع عدم وجود تاثري معتّد اإح�سائيا على م�ستوى الربوتني التفاعلي عايل احل�سا�سية نوع ج بعد امليتفورمني ولكن مل يكن هنالك تاثري ُمعتّد على تلك املفردات بعد الكليبنكالميد. ن�سبة الختالف يف هذه املفردات بعد العقارين اأظهرت ارتفاعا معتّدا يف م�ستوى م�سادات الأك�سدة الكلّية مع عالج امليتفورمني وتاأثري غري معتد على م�ستوى املالونديلهايد والربوتني التفاعلي عايل احل�سا�سية نوع )ج(. اخلال�صة: اأظهر امليتفورمني تاثريا اإيجابيا على املوازنة بني الك�سدة/م�سادات الك�سدة يف مر�سى ال�سكري من النوع الثاين حديثي الت�سخي�س مع عدم وجود تاأثري معتّد على م�ستوى الربوتني التفاعلي عايل احل�سا�سية نوع )ج(. من جهة اأخرى مل يكن للكليبنكالميد تاأثري معتّد على حالة املوازنة بني الأك�سدة/م�سادات الأك�سدة وم�ستوى الربوتني التفاعلي عايل احل�سا�سية نوع )ج(. مفتاح الكلمات: مر�س ال�سكري، امليتفورمني، الكليبنكالميد، املالونديليهايد، حالة م�سادات الأك�سدة الكلّية، الربوتني التفاعلي عايل احل�سا�سية نوع )ج(. abstract: objectives: this study aimed to compare the effects of metformin and glibenclamide on high sensitivity serum c-reactive protein (hs-crp) and oxidative stress, represented by serum malondialdehyde (mda) and total antioxidant status (tas) in newly-diagnosed patients with type 2 diabetes mellitus (dm) at baseline and after 2 months of therapy in comparison to controls. methods: the subjects, recruited from al-wafaa centre for diabetes management and research, iraq, november 2009 to january 2011, were 103 newly-diagnosed type 2 dm patients; 53 were prescribed metformin and 50 glibenclamide. the control group was 40 apparently healthy volunteers. blood samples were taken from all subjects after overnight fasting. sera were separated and assays of hs-crp, mda and tas were done. after 2 months monotherapy, the blood samples and assays were repeated. results: there were significant differences between patients prescribed metformin and glibenclamide and the controls with regard to serum hs-crp, mda and tas. there was a significant reduction in the serum mda and a significant raise in the serum tas levels, with no significant effects on serum hs-crp levels after metformin therapy, but no significant effects on these parameters after glibenclamide therapy. the percentage of variation in these parameters after both drugs, showed a significant raise in serum tas levels with the metformin therapy with no significant effects in serum mda and hs-crp. conclusion: metformin positively affected the oxidant/antioxidant balance in newlydiagnosed type 2 dm patients with no significant effects on acute phase reaction protein. glibenclamide had no comparative effects of glibenclamide and metformin on c-reactive protein and oxidant/antioxidant status in patients with type ii diabetes mellitus alaa a.a. abdulkadir1 and *imad a-j. thanoon2 clinical & basic research comparative effects of glibenclamide and metformin on c-reactive protein and oxidant/antioxidant status in patients with type ii diabetes mellitus 56 | squ medical journal, february 2012, volume 12, issue 1 type ii diabetes mellitus (dm) is extremely common and increasing rapidly worldwide. the diabetes epidemic is driven, in part, by a parallel epidemic of obesity.1 inflammation has been strongly implicated in type ii dm.2 long-term cytokine-mediated acute-phase response has been postulated to play an important role in the pathogenesis of type ii dm.3 oxidative stress (os) has been suggested to play an important role in the development and progression of diabetes mellitus.4,5 it has been suggested that in diabetic patients a major factor responsible for enhanced free radical generation is hyperglycaemia6 through auto-oxidation of glucose7 and production of advanced glycation end products (ages),8 which is known to progress at an extremely accelerated rate in type ii dm.9 metformin is recommended as an oral hypoglycemic core therapy in diabetes management worldwide and the guidelines of the american diabetes association (ada) and the european association for the study of diabetes (easd) recommend its use in patients irrespective of age, body weight and degree of baseline hyperglycaemia, due to its favourable effect on metabolic indices of glucose, lipid, and weight control.10 on the other hand, glibenclamide is a well-known second generation sulfonylurea (su) that has been the mainstay for treatment of patients with type ii dm for years.11 the aim of this study was to assess and compare the effects of metformin and glibenclamide on acute phase protein (represented by high sensitivity serum c-reactive protein [hs-crp]) and on oxidative/antioxidant status (represented by serum malondialdehyde [mda] and total antioxidant status [tas]) in newlydiagnosed patients with type ii dm at baseline and after 2 months of therapy. methods the study was conducted at al-waffaa center of diabetes management and research in mosul city, iraq, from november 2009 to january 2011. it was approved by the regional research committee of mosul health administration, a follow-up design was adopted for the study. fifty-three patients newly-diagnosed with type ii dm were selected and prescribed metformin monotherapy (dialon, julphar, united arab emirates). they were 23 females and 30 males with a mean age of 51.27±9.07 years, and a body mass index (bmi) of 29.18±2.86. another 50 newly-diagnosed patients with type ii dm were also recruited in this study and were prescribed glibenclamide monotherapy (glibesyn, medochemie, cyprus). they were 25 females and 25 males with a mean age of 49.40±7.81 years, with a mean bmi of 26±2.70. inclusion criteria included: newly-diagnosed cases of type ii dm with fasting glucose ≥7.00 mmol/l (126 mg/dl, or 2-hour post-load glucose ≥11.1 mmol/l [200 mg/dl]) in accordance with the ada and the world health organization (who) diagnostic criteria for type ii dm.12,13 patients excluded from this study were pregnant or lactating women, those requiring insulin, or a combination of oral hypoglycemic therapy, or those known to have hypertension, or cardiac, renal or hepatic disorders. forty apparently healthy volunteers were also recruited as a control group. they were 21 females and 19 males, with a mean age of 46.90±11.91 years and a mean bmi of 26.90±2.77. the sampling was performed as follows. at 8.30 am, 5 ml venous blood samples were taken from both the diabetic patients and control subjects after overnight fasting. sera were separated and measurements of hs-crp, mda and tas were significant effects on oxidant/antioxidant balance and acute phase reaction protein. keywords: diabetes mellitus; metformin; glibenclamide; malondialdehyde (mda); total antioxidant status (tas); high sensitivity serum c-reactive protein (hs-crp). advances in knowledge 1. type ii diabetes mellitus is shown by this study to be associated with oxidative stress and metformin (an oral hypoglycaemic agent) to have a positive effect on oxidant/antioxidant balance. applications to patient care 1. metformin possesses an advantage over glibenclamide with regard to the effects on oxidant/antioxidant status. alaa a.a. abdulkadir1 and imad a-j. thanoon2 clinical and basic research | 57 done. after 2 months of monotherapy, repeated blood samples were taken and the same parameters measured using the same kits and the same analytical methods: 1) hs-crp was measured by enzyme–linked immunosorbent assay (elisa), using biocheck hs-crp elisa kit (biocheck inc., california, usa); 2) serum mda was measured using the thiobarbituric acid (tba) assay method;14 3) serum tas was measured according to the method of miller et al.15 using a kit supplied by randox laboratories (co. antrim, ireland), and 4) bmi was calculated according to the following equation: bmi = weight (kg)/height (m2).16 standard statistical methods were used to determine the mean and standard deviation (sd). the unpaired t-test was used to compare the results of various parameters between diabetic patients and controls and to between diabetic patients on metformin and those on glibenclamide monotherapy. the paired t-test was used to compare the results of various parameters between diabetic patients before and after therapy. a p value of ≤0.05 was considered to be statistically significant.17 results there were significant differences between patients prescribed metformin [table 1], glibenclamide therapy [table 2] and the control subjects with regard to serum hs-crp, mda and tas. there was a significant reduction in serum mda with a significant rise in the serum tas levels and an insignificant effect on serum hscrp after metformin therapy [table 3]. patients on glibenclamide therapy showed non-significant differences with regard to serum levels of mda,tas and hs-crp [table 4]. there was a significant rise in the serum tas levels after metformin therapy compared to glibenclamide therapy, while no significant effects on serum mda and hs-crp levels were found [table 5]. discussion the results of the present study showed no significant decrease in serum hs-crp levels in newly-diagnosed patients with type ii dm after two months metformin therapy, and only insignificant differences in serum hs-crp levels in diabetic patients on glibenclamide therapy. in regard to metformin therapy, our findings were in accordance with the results of previous studies,18-20 while the results of the glibenclamide therapy were in agreement with the study conducted by yudkin, et al. who found that markers of acute phase activation measured by concentrations of crp in patients with type ii dm were not significantly influenced by su.21 moreover, these findings were in concordance with those reported by derosa et al. who reported that no variations in hs-crp levels were observed in patients with type ii dm treated with glibenclamide.22 on the other hand, akbar found that serum crp level in well-controlled type ii dm patients with metabolic syndrome was significantly lower in patients using metformin compared with those using glibenclamide; he concluded that metformin table 1: comparison between patients prescribed metformin therapy and controls with regards to serum levels of high sensitivity serum c-reactive protein (hscrp), malondialdehyde (mda) and total antioxidant status (tas) parameters mean ± standard deviation p value controls patients prescribed metformin hs-crp (μg/ml) 1.66±0.81 6.95±3.19 <0.05 mda (µmol/ l) 1.09±0.13 1.70±0.36 <0.05 tas (mmol/ l) 2.41±0.30 2.17±0.41 <0.05 note: comparison done using unpaired t-test. table 2: comparison between patients prescribed glibenclamide therapy and controls with regards to serum levels of high sensitivity serum c-reactive protein (hs-crp), malondialdehyde (mda) and total antioxidant status (tas) parameters mean ± standard deviation p value controls patients prescribed glibenclamide hs-crp (µg/ml) 1.66±0.81 4.95±2.71 <0.05 mda (µmol/ l) 1.09±0.13 1.76±0.26 <0.05 tas (mmol/ l) 2.41±0.30 1.33±0.31 <0.05 note: comparison done using unpaired t-test. comparative effects of glibenclamide and metformin on c-reactive protein and oxidant/antioxidant status in patients with type ii diabetes mellitus 58 | squ medical journal, february 2012, volume 12, issue 1 produces a greater decrease in the level of circulating crp than glibenclamide.23 kahn, et al. reported that the reduction in serum hs-crp in patients recently diagnosed with type ii dm was greater with metformin monotherapy (26%) versus glyburide (10%) after 12 months of therapy.24 this study showed a significant elevation in serum mda levels (p <0.001) in patients with type ii dm prescribed metformin therapy compared to their matched healthy controls. os is proposed to be an early event in the pathology of dm and may influence the onset and progression of late complications.25 furthermore, elevated levels of serum mda, as a marker of os, have been reported in type ii dm.26 conflicting data were obtained regarding the effects of metformin on os in diabetic patients.27 the present work revealed a significant decrease in serum mda levels in newly-diagnosed type ii dm patients after a 2-month therapy with metformin. these results were in agreement with the study conducted by pavlovic, et al. who reported a significant reduction in mda levels in both erythrocytes and plasma in newly-diagnosed patients with type ii dm who had been on metformin therapy for a period of 4 weeks.28 these results were also in line with those reported by tessier et al. who observed that metformin therapy significantly decreased serum mda levels in adult patients with type ii dm after a period of treatment for 24 weeks.29 conversely, skrha et al. observed that 3-month therapy with metformin was accompanied by significantly increased plasma mda levels in type ii dm patients.30 they concluded that initiation of metformin treatment in such patients was associated with activation of os. gupta et al., observed no change in mda levels at the end of the 12 weeks treatment with metformin, in newlydiagnosed type ii dm patients.31 the present study also revealed a significant increase (p <0.05) in tas of newly-diagnosed type ii dm patients after a 2-month metformin therapy, which is consistent with those reported by tessier et al.29 they observed that a 24-week therapy with metformin significantly increased serum levels of antioxidant vitamin e in adult patients with type ii dm. this is in agreement with the results of pavlovic et al. who reported that metformin significantly increased the erythrocyte activities of copper, zinc, superoxide dismutase, catalase and glutathione (gsh) levels, and decreased erythrocyte susceptibility to os in patients with type ii dm.28 in line with these studies, skrha et al. observed that 3 months of metformin treatment table 3: comparison of serum levels of high sensitivity serum c-reactive protein (hs-crp), malondialdehyde (mda) and total antioxidant status (tas) for patients before and after metformin therapy parameters mean ± standard deviation p value patients before metformin therapy patients after metformin therapy hs-crp (μg/ml) 6.95±3.19 6.12±2.71 ns mda (μmol/ l) 1.70±0.36 1.57±0.31 <0.05 tas (mmol/ l) 2.17±0.41 2.35±0.43 <0.05 ns = not significant using paired t-test table 5: percentage of variations in measured parameters after metformin and glibenclamide therapy parameters ( % variations after therapy) mean ± standard deviation p value glibenclamide group metformin group hs-crp (μg/ ml) 0.51±2.94 -0.83±1.9 ns mda (μmol/ l) -0.03±0.09 -0.13±0.20 ns tas (mmol/ l) 0.01±0.07 0.19±0.33 <0.05 ns = not significant using unpaired t-test table 4: comparison of serum levels of high sensitivity serum c-reactive protein (hs-crp), malondialdehyde (mda) and total antioxidant status (tas) for patients before and after glibenclamide therapy. parameters mean ± standard deviation p value patients before glibenclamide therapy patients after glibenclamide therapy hs-crp (μg/ml) 4.95± 2.71 5.46± 2.76 ns mda (μmol/ l) 1.76± 0.26 1.73± 0.26 ns tas (mmol/ l) 1.33± 0.31 1.35± 0.26 ns ns = not significant using paired t-test alaa a.a. abdulkadir1 and imad a-j. thanoon2 clinical and basic research | 59 was accompanied by significantly increased ascorbic acid concentrations and concluded that initiation of metformin treatment in type ii dm patients was associated with activation of the antioxidant system.30 with regards to glibenclamide therapy, this study showed an insignificant decrease in serum mda levels in newly-diagnosed type ii dm patients after a 2-month therapy. these findings were in agreement with those reported by stefanovic et al.32 they reported no significant decrease in the plasma mda levels of patients treated with glibenclamide at the end of 3 months treatment. on the other hand, chugh et al. reported a significant fall in serum mda levels in patients with type ii dm at the end of 12 weeks using glibenclamide, although the mda levels were not normalised and stayed higher than those in controls.33 this study also showed an insignificant increase in tas levels of newly-diagnosed type ii dm patients after therapy with glibenclamide. these results were in line with those mentioned by jennings et al. who found no significant difference in red blood cell superoxide dismutase activity, or in plasma thiols (psh) levels, in type ii dm patients with retinopathy after 3 months of treatment with glibenclamide.34 similarly, chugh et al. reported increased levels of gsh in patients with type ii dm at the end of a 12-week glibenclamide treatment period and concluded that this revealed beneficial effects on os, although normalisation was not achieved.33 the present study showed an insignificant decrease in serum mda levels, with a significant increase in tas in patients treated with metformin compared with those treated with glibenclamide. this is in line with the findings of the study conducted by faure et al.35 they found that the mda levels were significantly lower in metformin-treated type ii dm patients compared to those treated with su. it is possible that the short-term treatment durations in our study may have influenced the endpoints of the present study.36 with regard to antioxidant status, our findings were in agreement with faure et al.35 where there was a significant increase in antioxidant protection, as shown by tas, total blood gsm and plasma thiols in patients with type ii dm receiving metformin compared with those receiving su, and those authors concluded that a significant protection of serum albumin was found in patients with type ii dm treated with metformin, and that this leads to an increased antioxidant protection. conclusion this study has shown that metformin therapy for 2 months in newly-diagnosed type ii dm patients positively affected the oxidant/antioxidant balance while having insignificant effects on acute phase reaction protein. on the other hand, glibenclamide had insignificant effects on the oxidant/antioxidant balance and on acute phase reaction protein. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g m e n t s this study was conducted at the al-wafaa centre for diabetes management and research, mosul, iraq, during the period november 2009 to january 2011. the laboratory work was done in the department of pharmacology, college of medicine, university of mosul, iraq. references 1. meigs jb, larson mg, fox cs, keaney jf, vasan rs, benjamin ej. association of oxidative stress, insulin resistance and diabetes. risk phenotype: the framingham offspring study. diabetes care study. diabetes care 2007; 30:2529-35. 2. wang z, hoy eh. creactive protein and the risk of developing type 2 diabetes in aboriginal australians. diabetes res clin pract 2007; 76:37-43. 3. wen j, liang y, wang f,sun l, guo y, duan x, et al. c-reactive protein, gamma-glutamyltransferase and type 2 diabetes in a chinese population. clin chim acta 2010; 411:198-203. 4. jin y, han g, hu y, bi y, li l, zhu d. tea consumption and risk of type 2 diabetes: a meta-analysis of cohort studies. j gen intern med 2009; 24:557-62. 5. medina-navarro r, duran-reyes g, diaz-flores m, vilar-rojas c. protein antioxidant response to the stress and the relationship between molecular structure and antioxidant function. plos one 2010; 5:8971. 6. yamanouchi t, taniguchi a, fukushima m, nakai y, nagasaka s,ohgushi m, et al. leptin, triglyceride, and interleukin 6 are independently associated with c-reactive protein in japanese type 2 diabetic patients. diabetes rese clin pract 2007; 75:2-6. 7. ahmed ka,muniandy s, ismail is. n ε-(carboxymethyl) lysine and coronary comparative effects of glibenclamide and metformin on c-reactive protein and oxidant/antioxidant status in patients with type ii diabetes mellitus 60 | squ medical journal, february 2012, volume 12, issue 1 atherosclerosis-associated low density lipoprotein abnormalities in type 2 diabetes: current status. j clin biochem nutr 2009; 44:14-27. 8. nistala r, whaley-connell a, sower jr. redox control of renal function and hypertension. antioxid redox signal 2008; 10:2047-89. 9. levy j, cobas ra, gomes mb. assessment of efficacy and tolerability of once daily extended release metformin in patients with type 2 diabetes mellitus. diabet metab syndr 2010; 2:16. 10. shimabukuro mt, higa n, takasu n. comparison of the antioxidant and vascular effects of gliclazide and glibenclamide in type 2 diabetic patients. a randomized crossover study. j diabet complications 2006; 20:179-83. 11. who (world health organization). definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a who/ idf consultation. geneva: who document production services, 2006. pp. 1-41. 12. ada (american diabetes association). standards of medical care in diabetes, 2010: position statement. diabet care 2010; 33:s11-61. 13. cummings pj. immunoassay. in: appleton and lange's outline review: clinical chemistry. new york: mcgraw-hill companies 2001. pp. 310-15. 14. buege ja, aust sd. thiobarbituric acid assay. methods enzymol 1978; 52:306-07. 15. miller nj, rice-evans c, davies mj, gopinathanv, milner a. a novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. clin sci 1993; 84:407-12. 16. leermarkers ea, dunn al, blaire sn. exercise management of obesity. med clin north am 2000; 84:419-25. 17. kirkwood br. essentials of medical statistics.1st ed. oxford: blackwell scientific publications, 1988. pp. 43-56. 18. jager jd, kooy a, lehert ph, bets d, wulffele mg, teerlink t, et al. effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo controlled trial. j int med 2005; 257:100–9. 19. stocker dj, taylor aj, langley rw, jezior mr, vigersky ra. a randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. am heart j 2007; 153:445e1-6. 20. pradhan ad, everett bm, cook nr, rifai n, ridker pm. effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the lancet randomized trial. jama 2009; 302: 1186-94. 21. yudkin js, panahloo a, stehouwer c, emeis jj, bulmer k, mohamed-ali v, et al. the influence of improved glycemic control with insulin and sulphonylureas on acute phase and endothelial markers in type 2 diabetic subjects. diabetologia 2000; 43:1099-106. 22. derosa g, maffioli p, salvadeo sa, ferrari i, ragonesi pd, querci f, et al. exenatide versus glibenclamide in patients with diabetes. diabetes technol ther 2010; 12:233-40. 23. akbar dh. effect of metformin and sulfonylurea on c-reactive protein level in well-controlled type 2 diabetes with metabolic syndrome. endocrine 2003; 20:215-18. 24. kahn se, haffner sm,viberti g, herman wh, lachin jm, kravitz bg, et al. rosiglitazone decreases c-reactive protein to a greater extent relative to glyburide and metformin over 4 years despite greater weight gain: observation from a diabetes outcome progression trial (adopt). diabet care 2010; 33:177-183. 25. singh u, jialal i. alpha-lipoic acid supplementation and diabetes. nutr rev 2008; 66:646-57. 26. mahreen r, mohsin m, nasreen z, siraj m, ishaq m. significantly increased levels of serum malondialdehyde in type 2 diabetes with myocardial infarction. int j diabetes dev ctries 2010; 30:40-51. 27. yilmaz m, bukan n, ayvaz g, karakoç a, törüner f, çakir n, et al. the effects of rosiglitazone and metformin on oxidative stress and homocystine levels in lean patients with polycystic ovary syndrome. human reproduct 2005; 20:3333-40. 28. pavlović d, kocić r, kocić g, jevtović t, radenković s, mikić d, et al. effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. diabetes obes metab 2000; 2:251-256. 29. tessier d, maheux p, khalil a, fülöp t. effects of gliclazide versus metformin on the clinical profile and lipid peroxidation markers in type 2 diabetes. metabolism 1999; 48:897-903. 30. skrha j, prázný m, hilgertová j, kvasnicka j, kalousová m, zima t. oxidative stress and endothelium influenced by metformin in type 2 diabetes mellitus. eur j clin pharmacol 2007; 63:1107-14. 31. gupta rk, rehan hs, rohatagi a, bhatacharjee j, chopra d. the effect of glipizide, metformin and rosiglitazone on nontraditional cardiovascular risk factors in newly diagnosed patients with type 2 diabetes mellitus. int j diabetes dev ctries 2010; 30:123-8. 32. stefanovic v, antic s, milojkovic m, lazarević g, vlahovic p. lymphocyte ecto-5-nucleotidase in obese type 2 diabetic patients treated with gliclazide. diabetes metab 2006; 32:166-70. 33. chugh sn, dhawan r, kishore k, sharma a, chugh k. glibenclamide vs gliclazide in reducing oxidative stress in patients of non insulin dependent diabetes alaa a.a. abdulkadir1 and imad a-j. thanoon2 clinical and basic research | 61 mellitus. a double blind randomized study. j assoc physicians india 2001; 49:803-7. 34. jennings pe, scott na, saniabadi ar, belch jj. effects of gliclazide on platelet reactivity and free radicals in type 2 diabetic patients: clinical assessment. metabol 1992; 41:36-9. 35. faure p, wiernsperger n, polge c, favier a, halimi s. impairment of the antioxidant properties of serum albumin in patients with diabetes: protective effects of metformin. clin sci 2008; 114:251-6. 36. lima lma,wiernsperger n, kraemer-aguiar lg, bouskela e. short-term treatment with metformin improves the cardiovascular risk profile in firstdegree relatives of subjects with type 2 diabetes mellitus who have a metabolic syndrome and normal glucose tolerance without changes in c-reactive protein or fibrin. clin sci 2009; 64:415-20. to the editor, i read with great interest the article “i found it on the internet” preparing for the e-patient in oman,1 published in squmj in august 2010. briefly, this article reviews the e-patient, medical student and the relationship between them. i would like to share with you and the readers my views regarding the above article. in my opinion, an e-patient is easy to deal with as he/she listens, understands and does what his/ her doctor asks him/her to do properly. he/she is not difficult. this is because i find e-patients similar to university students. university students have high levels of knowledge and good communication skills and therefore cooperate well. their unanswerable questions may be of great benefit as they may lead the teacher to undertake more research. in my opinion, the issue of preparing medical students for the e-patient in oman is not a demanding one. in general, medical students, from squ or the oman medical college, are well educated and have wide training experience. in addition, there is no specific data on the number of omani patients seeking for health information via the internet as dr masters only gave figures for general internet use in oman. on the other hand, non-university students, like non-e-patients, have less understanding and are less inclined to cooperate. i also think that e-patients should be faced with e-doctors. in addition to their existing knowledge, e-doctors can enhance and increase their medical knowledge using various and wide internet resources. thus they will strengthen their ability to answer many questions posed by either e-patients or regular patients. thanks to the various number of medical websites, the e-doctor can now play an even more beneficial role in the consultation than the e-patient, in particular as regards the treatment plan. a far more pressing concern in oman is the number of patients going abroad for treatment, even for appendicitis or tonsillitis. the number of patients that are treated abroad at ministry of health expenses in 2009 was 4522 and the number is on rise. governmental and non-governmental sponsorships for medical travel abroad are limited. it is important to note that the majority of omani patients who go abroad for treatment therefore do so at their own expense. e-doctors can play a major role in reducing the number of these patients. if i can trust my doctor, then he can start treating me. trust in treatment starts with a patient or e-patient, and then it goes to friends and family, then community and finally the whole country. trust is an easy word to say, but it is very hard to achieve and takes a longer time to take root. prospective and retrospective studies should be undertaken to highlight currently hidden information about e-patients and e-doctors in oman. nasar alwahaibi department of pathology college of medicine & health sciences sultan qaboos university, muscat, oman e-mail: nasarsidab@yahoo.com squ med j, february 2011, vol. 11, iss. 1, pp. 129-131, epub. 12th feb 11 submitted: 10th nov 2010 <>ìè÷êç÷]<ì”fé÷]<ó◊¬<^„içqê<çœ÷><v<åö ·^€ �¬<ª<ífiê3”÷˝]<òëü€◊÷<å]ç√jâ˜]  re: i found it on the internet” preparing for the e-patient in oman nasar alwahaibi letter to editor re: i found it on the internet” preparing for the e-patient in oman 130 | squ medical journal, february 2011, volume 11, issue 1 references 1. masters k, ng’ambi d, todd g. “i found it on the internet”: preparing for the e-patient in oman. squ med j 2010; 10:169–79. 2. ministry of health, oman. annual health report. morbidity and mortality. muscat: ministry of health, 2009. ch 9, pp. 9–92. authors’ response dr. alwahaibi’s close reading of our article, and the resultant comments, are appreciated. he raises several points, and we would like to respond to each of them. first, dr. alwahaibi’s experience with e-patients is encouraging, and reflects a similar pattern that has been found elsewhere. in my own research,1 i found some doctors relishing these consultations, finding them stimulating, and one even likened it to an enjoyable objective structured clinical examination (osce). to get patients to this stage, however, frequently requires patience and guidance from the doctor. it is this patience and guidance that our article wishes to encourage. in addition, unfortunately, my own and other research has found that e-patients are not always like this. for example, some patients who would normally be confrontational have used the information found on the internet to raise the confrontation to a new level, in an attempt to intimidate the doctor. patients can also become confused or misled by the information they find on the internet if their searches are not guided. and then, there are the so-called “cyberchondriacs.” our article is aimed at ensuring that medical students are alerted to these issues, and can manage the resultant situations competently. second, we agree wholeheartedly that e-patients should be faced with e-doctors. indeed, the medical informatics courses taught to sultan qaboos university students in both phase i and ii are aimed at equipping the students with these skills. i currently teach on those courses, and i will gladly share the curriculum outline with dr. alwahaibi (or any other reader) on request. third, as dr. alwahaibi points out, our article does not provide figures on the number of omani patients seeking health information on the internet. unfortunately, no research has yet been published on that topic. indeed, part of the motivation for the paper was to provide the impetus for a research project to do just that. until we have such data, however, there is no reason to believe that the proportion of e-patients (compared to internet users) is significantly different in oman from other countries, so proportions of total internet users can be used as a guide. moreover, in our article, we made the prediction that the number of omani internet users would follow roger’s diffusion curve,2 and was set to increase at an accelerated pace in the very near future. the latest figures3 indicate that this acceleration has occurred. our article used 2009 figures, which estimated the number of omani internet users at a little less than 500,000. by 2010, this figure had increased to more than 1.2 million.3 in the light of this dramatic increase, the need to accommodate the e-patient is possibly of greater urgency than was the case when the article was written. finally, i am not qualified to comment on the reasons for omani patients seeking medical treatment elsewhere, but i certainly agree with dr. alwahaibi that a student who has been well trained to deal with the information will undoubtedly inspire confidence in any e-patient. further, i agree that studies of e-patients and e-doctors should be undertaken in oman; if dr. alwahaibi would like to collaborate on such a project, i would welcome further correspondence on the subject. ken masters medical education unit faculty of medicine & health sciences sultan qaboos university email: kmasters@ithealthed.com nasar alwahaibi letter to editor | 131 references 1. masters k. the diffusion of the internet amongst south african primary care doctors: an activity systems view. unpublished phd thesis. university of cape town, south africa, 2009. 2. rogers e. diffusion of innovations. 5th ed. new york: free press, 2003. 3. internet world stats. internet usage in the middle east. from: http://www.internetworldstats.com/stats5.htm. accessed: january 2011. submitted 3 jan 23 1 revision req. 16 mar 23; revision recd. 17 mar 23 2 accepted 4 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.028 5 6 predictors of quality of life among omani family caregivers for 7 traumatic brain injury patients 8 devakirubai jacob,1 *joshua k. muliira,2 eilean r. lazarus,1 hema 9 roslin1 10 11 1department of adult health & critical care, college of nursing, sultan qaboos 12 university, muscat, oman; 2school of nursing, ball state university, muncie, usa. 13 *corresponding author’s e-mail: joshua.muliira@bsu.edu 14 15 abstract 16 objective: after acute care, the burden of caring for patients with traumatic brain injury 17 (tbi) is mainly shouldered by the family caregivers (fcs). we aimed to explore the quality 18 of life (qol) of omani fcs for patients with tbi. methods: a total of 36 fcs and patients 19 with tbi were recruited from one hospital. data was collected at discharge time and eight 20 weeks post-discharge in the period from april 2019 to december 2021. the sf-12 general 21 health survey and preparedness for caregiving scale were used to measure the caregivers’ 22 qol and preparedness, respectively. the disability rating scale and the tbi symptom scale 23 were used to measure the patient’s disability and symptoms, respectively. paired t-test and 24 multiple linear regression analysis were performed. results: most caregivers were the 25 parent (41.7%) or child (27.8%) of the patient with tbi. overall the caregivers had good 26 physical qol (pqol) and mental health qol (mhqol) but low caregiving preparedness 27 at the time of discharge. at eight weeks post-discharge, there were significant 28 improvements in caregiving preparedness (p< 0.01), patient disability (p< 0.05), and 29 about:blank depreciation in caregivers’ mhqol (p< 0.05), but no change in the pqol. the modifiable 30 predictors of pqol were the caregiver’s employment status and the severity of the patient’s 31 sleep and mood problems. the predictors of mhqol were caregiving preparedness, the 32 patient’s inability to live independently, and the severity of mood and behavioral problems. 33 conclusion: omani fcs for patients with tbi experience a negative impact on qol, and 34 this is correlated with the physical, emotional, and mental health symptoms of the patient. 35 keywords: caregiving, family, quality of life, caregiving burden, traumatic brain 36 injury, caregivers’ preparedness, oman. 37 38 advances in knowledge 39 • most omani family caregivers for patients with tbi have low caregiving 40 preparedness and are not ready to adequately meet the patient care needs when the 41 patient is discharged from the acute care hospital. 42 • within a period of eight weeks, the family caregivers self-teach and improve their 43 abilities and caregiving preparedness as they spend more time with the patients 44 and in the caregiver role. 45 • the process of adapting to the caregiving demands negatively impacts the family 46 caregivers and is associated with a decline in the caregivers’ mental health at 47 eight weeks post-discharge. 48 49 application to patient care 50 • the study highlights the importance of discharge planning that ensures family 51 caregiver involvement, training, skilling, and support. 52 • there is a need for supportive care programs that ensure caregiver readiness for 53 caregiving responsibilities and personal health promotion while performing the 54 caregiver role. 55 • further research focusing on family-centered interventional programs may help to 56 develop culturally sensitive and cost-effective programs for supporting, educating, 57 and empowering caregivers for patients with tbi. 58 59 60 introduction 61 traumatic brain injury (tbi) is an alteration in brain function or evidence of brain 62 pathology caused by an external force.1 tbi is a significant cause of death or disability 63 with a wide spectrum of symptoms and sequelae.2 one of the leading causes of tbi is 64 road traffic injuries arising from crashes and accidents (rtis). annually, approximately 65 1.3 million people succumb to death due to rtis, and these (rtis) are projected to be a 66 leading contributor to global fatalities by 2030.3 reports by the world health 67 organization show that rtis cause 3.55% of deaths in oman, the age-adjusted death rate 68 due to rtis is 12.63 per 100,000 population, and the country ranks 113th in the world for 69 the highest number of rtis.4 70 71 in oman, the rtis are attributed to the rise in urbanization, nocturnal driving, speeding, 72 alcohol use, mobile phone usage, and vehicle ownership.5 the other causes of tbi 73 include unintentional falls, intentional self-harm, gunshots, violence, assaults, and 74 others.6 the increasing population of older adult omanis that experience falls and other 75 forms of injuries has also been reported to be contributing to a rise in tbi.7 the patients 76 that survive the acute phase of tbi live with sequelae such as cognitive decline, 77 functional impairment, physical disability, psychological and behavioral disturbances, 78 and overall changes in personality.8 irrespective of the severity of the injury, tbi is 79 associated with neurocognitive deficits such as amnesia, insomnia, mood disorders, and 80 others.9 81 82 in the acute phase, patients with tbi are managed in specialist trauma centers and are 83 later transferred to neuro-rehabilitation facilities. in countries where rehabilitation, long-84 term care, and/or home care services are negligible, the family caregiver (fc) takes up 85 the responsibility for the patient’s rehabilitation, home care, and reinstitution into society 86 when the patients with tbi emerge out of the acute phase. trauma care is available in all 87 tertiary hospitals in oman, but the country has one specialized tertiary neuro-trauma care 88 center and a ratio of 1.25 physiotherapists per 10,000 population.10 therefore, access to 89 specialized neuro-rehabilitation facilities is feasible in urban settings but limited in other 90 locations, and this puts more burden on the shoulders of the fcs. 91 92 caregiving is a multi-faceted role that leads the fcs to provide physical, psychological, 93 emotional, social, and financial support while simultaneously experiencing strain and 94 stress.11 due to a lack of well-established rehabilitation services10, omani fcs for 95 patients with tbi are likely to assume caregiving roles without any support or training to 96 help them meet the new demands and responsibilities. considering the physical, 97 cognitive, behavioral, and psychosocial sequelae of tbi, the fcs taking care of such 98 patients at home tend to be overwhelmed if they are not supported.12 99 100 studies conducted in other countries and focusing on fcs for patients with tbi show that 101 family members assuming the caregiver role without any formal training and support 102 system experience a high caregiving burden, poor family functioning, poor mental health, 103 and emotional distress.13 the fcs also experience a lack of time for self-care, interrupted 104 life, poor physical health, social isolation, sleep disturbances, depression, exhaustion, and 105 anger.14 the most common physical symptoms among caregivers of patients with tbi 106 include low energy, trouble sleeping, digestive problems, back pain, and joint pain.15 107 108 a study conducted in turkey showed that the caregiving burden is higher among fcs that 109 are older and unemployed or with financial difficulties, and both factors affected the care 110 given to the patient with tbi.16 one of a few studies that focused on omani fcs of 111 patients with tbi found a limited availability of rehabilitative resources, lack of support 112 services for fcs, and utilization of personal religious faith and beliefs to cope with the 113 caregiving strain.17 despite the problem of tbi in oman4,7 and its impact on the family, 114 no study has focused on the qol of omani fcs of patients with tbi. our study aimed to 115 explore the qol of omani fcs for patients with tbi and the predictors of qol. 116 117 methods 118 a cross-sectional design was used to collect data from fcs and patients with tbi at the 119 time of discharge from the hospital and at eight (8) weeks post-discharge (april 2019120 december 2021). the fcs and patients with tbi (participants) were recruited from one 121 hospital (khoula hospital). the patients were omanis of age ≥18 years, with a confirmed 122 diagnosis of tbi, able to state their names, positively identify family members, and with 123 a minimum modified rankin scale for neurologic disability of at least +1. the fcs 124 were any family member scheduled to provide regular day-to-day care at home for the 125 patient after discharge from the hospital. the fcs were included if they met the inclusion 126 criteria of being the main person responsible for the care of a patient with tbi at home; 127 omani by nationality; the age of ≥18 years; able to speak arabic or english; live in the 128 same household as the patients with tbi; and has no formal training as a healthcare 129 profession. a convenience sampling approach was used to identify patients with tbi and 130 their fcs. a convenience sampling technique allowed us to access patients with tbi, 131 which is a very hard-to-access population. many studies of patients with tbi have used 132 samples ranging from 30 to 100 participants.18 a total of 36 fcs and their patients with 133 tbi were recruited for the study. 134 135 study instrument 136 an interview questionnaire (iq) was used to collect data. the iq was comprised of six 137 sections of the fc and patient demographic characteristics (see table 1); caregivers’ qol 138 (sf-12 general health survey); preparedness for caregiving scale (pcs); the disability 139 rating scale (drs); and the tbi symptom severity scale. the sf-12 health survey (sf-140 12) has internal consistency and test-retest reliabilities ranging from 0.67 to 0.82.19 a 141 score of 50 and 42 have been recommended as a cut-off for the physical health qol 142 (pqol) and mental health qol (mhqol), respectively.19 the family caregiver’s 143 preparedness to care for a patient with tbi at home was measured using the pcs.20,21 the 144 pcs has eight (8) items assessing preparedness in multiple domains of caregiving.20,21 145 the participants’ responses are rated on a 5-point likert scale ranging from 0 (not at all 146 prepared) to 4 (very well prepared). the items are summed to generate total scores 147 (ranging from 0 to 32). high scores on the pcs indicate a high level of preparedness. the 148 pcs has a cronbach’s alpha of ≥ 0.8820,21 in the current study, the pcs cronbach’s alpha 149 at the time of discharge and eight weeks post-discharge were 0.94 and 0.96, respectively 150 151 the disabilities of patients with tbi were measured using the drs. the drs (8 items) 152 measures and tracks tbi disability from the state of coma to the community.22 the drs 153 focuses on impairments, disabilities, and handicaps related to eye-opening, 154 communication ability, motor response, feeding, toileting, grooming ability, level of 155 functioning, and employability or level of handicap.22 the drs total scores range from 0 156 (no disabling impairments) to 29 (extreme vegetative state). the total scores are further 157 classified as no disability (0), mild (1), partial (2-3), moderate (4-6), moderately severe 158 (7-11), severe (12-16), extremely severe (17-21), vegetative state (22-24), and extreme 159 vegetative state (25-29).22 the drs has an inter-rater reliability of ≥ 0.97.22 the drs 160 was used when the patients were not under the influence of any mind-altering drugs or 161 influence of complications of a recent seizure. the cronbach’s alpha of the drs at the 162 time of discharge and eight weeks post-discharge were 0.71 and 0.75, respectively 163 164 the tbi patient symptom scale was used to assess the severity of symptoms of sequelae 165 associated with tbi. the symptoms recorded include loss of muscle strength (paralysis, 166 limited physical mobility, or poor coordination); blurred vision or loss of vision; loss of 167 hearing or ringing in the ears; loss of memory and concentration; changes in speech or 168 difficulty being understood; mood problems (such as depression, anxiety, denial, and 169 frequent change in emotions); insomnia; changes in behaviors (aggression, anger, and 170 being impulsive); and ability to live independently. the severity of the symptoms was 171 rated on a scale (developed by the investigators) ranging from 1 to 5 (1= no difficulty, 3 172 = mild difficulty, 4 = moderate difficulty, and 5 = severe difficulty). the cronbach’s 173 alpha of the tbi patient symptom scale at the time of discharge and eight weeks post-174 discharge were 0.90 and 0.91, respectively 175 176 data collection procedures 177 the study was approved by the research and ethics committees of the hospital and the 178 investigators’ institutions. all the participants received a detailed explanation of the study 179 procedures and signed the consent form prior to data collection. the investigators 180 approached the charge nurses of units that admit patients with tbi to identify those 181 scheduled for discharge. during the in-patient period, all the patients with tbi are 182 followed by the neurology team and other teams according to medical care needs, 183 comorbidities, and complications. the medical team determines the discharge date and 184 time. the nurse assigned to the patient notified the study research assistant (a nurse) of 185 the time of discharge and when the fc was available to take the patient home. 186 187 on the day of discharge, the research assistant (ra) screened the fc and patient for 188 eligibility. on the day of discharge, the ra also collected time 1 data about the patient’s 189 symptoms, the patient’s level of disability, the caregiver’s preparedness for caregiving, 190 and the caregiver’s qol. during the meeting (on the day of discharge), the fcs were 191 informed that additional data about caregiving preparedness, qol, and the patient’s 192 symptoms and disabilities would be collected when the patient is brought for the follow-193 up appointment in the neurology clinic at eight weeks. patients with tbi return for 194 follow-up care and review in the neurology clinic every two months. data collection at 195 eight weeks post-discharge helped to ensure that fcs get a reasonable amount of time to 196 experience the caregiving demands. a total of 36 fc and patients with tbi were 197 recruited for the study at discharge time, but 35 fcs and patients showed up for the first 198 appointment at eight weeks. one fc did not show up because the patient died before the 199 first follow-up appointment (see figure 1). 200 201 data analysis 202 data were analyzed using statistical package for the social sciences (spss), version 23 203 (ibm corp., armonk, new york, usa). descriptive statistics were used to describe the 204 tbi patients’ symptoms and disabilities, the fcs’ preparedness for caregiving, and qol. 205 the paired t-test was used to examine the difference in patients’ disability, fcs’ 206 caregiving preparedness, pqol, and mhqol at the time of discharge and eight weeks 207 post-discharge. multiple linear regression analyses (backward method) were used to 208 examine predictors of qol. multicollinearity was tested using the variance inflation 209 factor and tolerance. a p-value of ≤ 0.05 was considered to be statistically significant. 210 211 results 212 a total of 36 fcs and their patients with tbi participated in the study at the time of 213 discharge from the hospital, and their characteristics are presented in table 1. the mean 214 age of the fcs was 38.44 ± 9.23 years. the majority of fcs were female (52.8%), and the 215 parent (41.7%) or child (27.8%) of the patient with tbi. the mean age of patients with 216 tbi was 59.58 ± 20.57 years. the main causes of tbi were motor vehicle accidents, 217 falls, and assaults. the majority of patients were male (52.8%) and had a glasgow coma 218 scale score (≤ 8) equivalent to severe injury at the time of admission (52.8%). the 219 average glasgow coma scale score on admission and discharge was 7.92 ± 2.40 (severe 220 injury status) and 14.20 ± 2.32 (mild injury status), respectively. 221 222 symptom profile of patients at the time of discharge 223 at the time of discharge from the hospital, all patients were found to have multiple 224 symptoms (see table 2). the most severe symptoms were inability to live independently 225 (97.2%), loss of muscle strength, paralysis, limited physical mobility or poor 226 coordination (77.5%), mood problems such as depression, anxiety, denial, and frequent 227 change in emotions (66.7%), and loss or memory and concentration (63.9%). the mean 228 scores show that in this sample, the symptoms that were most common and severe to deal 229 with were the inability to live independently, loss of muscle strength, mood problems, 230 and change in speech or difficulty being understood by others. 231 232 change in patient’s disability and caregiver’s preparedness and quality of life 233 the results in table 3 show that overall the fcs had a good pqol (m= 71.91 ± 25.69) 234 and mhqol (m= 63.05 ± 16.96) and low caregiving preparedness (m= 19.74 ± 9.04) at 235 the time of discharge. at eight weeks post-discharge, there was a significant 236 improvement in caregiving preparedness (p < 0.01) and patient’s disability (p < 0.05). at 237 eight weeks post-discharge, there was a significant depreciation in the mhqol (p < 238 0.05). there was a decrease in pqol from 71.91 at discharge to 68.93 at eight weeks, but 239 this change was not significant. 240 241 predictors of caregiver quality of life 242 the results of the multiple regression analysis to determine the predictors of caregivers’ 243 qol are presented in table 4. the significant predictors of the pqol were the age of the 244 caregiver (p < 0.001), the age of the patient (p = 0.013), the caregiver’s employment 245 status (p= 0.001), the severity of patient symptoms related to mood (p= 0.003) and 246 insomnia (p= 0.025). the final regression model showed that five factors were 247 responsible for approximately 56.4% of the variance in the caregivers’ pqol [f (5, 29) = 248 9.80, p < 0.001, r2 = 0.628, r2adjusted = 0.564]. the significant predictors of the 249 caregivers’ mhqol were the caregiver’s age (p= 0.003), the patient’s age (p < 0.001), 250 caregiving preparedness (p= 0.05), the severity of the patient’s mood problems (p = 251 0.001), behaviors problems (p= 0.007), and inability to live independently (p= 0.034). 252 the final model showed that the six factors were responsible for approximately 44.9% of 253 the variance in caregivers’ mhqol [f (6, 28) = 5.62, p= 0.001, r2 = 0.546, r2adjusted = 254 0.449]. 255 256 discussion 257 traumatic brain injury (tbi) is a common health problem in oman, and the risk factors 258 are abundant due to the high percentage of youths in the population, the increasing 259 geriatric population, increasing urbanization, and motor vehicle ownership.7,23,24 despite 260 the problem of tbi and associated sequelae, there has been no study about the qol of 261 fcs caring for patients with tbi in oman or the greater middle east region. the majority 262 of other studies that have focused on fc in oman included caregivers of cancer patients 263 and children with autism and found high caregiver burden and low qol.25,26 264 265 the findings of our study show that the fcs of patients with tbi were mostly female, the 266 parent or child of the patient with tbi, and assumed caregiving responsibilities for a 267 patient with tbi with severe injury (52.8%) and multiple severe symptoms. the 268 symptoms that were most common include the inability to live independently (97.2%), 269 loss of muscle strength, paralysis, limited physical mobility or poor coordination 270 (77.5%), mood problems such as depression, anxiety, denial, and frequent change in 271 emotions (66.7%), and loss or memory and concentration (63.9%). the fcs started the 272 caregiving responsibilities for patients with tbi while in good physical and mental health 273 but with low levels of caregiving preparedness. 274 275 the low level of caregiving preparedness could be due to inadequacies in discharge 276 planning and a lack of programs to prepare fcs for caregiving responsibilities before the 277 patient with tbi is discharged home. a similar study conducted in new south wells 278 (australia) found that the majority of caregivers (72%) for patients with tbi felt well 279 prepared or very well prepared overall for caregiving, especially in regard to the patient’s 280 physical needs and responding to patient needs in an emergency.27 the caregivers in the 281 new south wells were least prepared to get help and information from the health system 282 and to deal with the stress of caregiving.27 the caregivers in the australian study had 283 been caring for the tbi patients for at least one year, and the country’s healthcare system 284 has established discharge planning processes, neurorehabilitation facilities, and long-term 285 care facilities.27 it is important to note that even in countries with highly established 286 healthcare systems fcs of patients with tbi have challenges related to caregiving stress 287 and seeking help and information from the healthcare system. 288 289 the findings of our study show that in a period of only eight weeks post-discharge, there 290 was significant depreciation in the caregivers’ mental health qol (p < 0.05). these 291 findings are closely similar to those of a study from iran, which found that the qol of 292 fcs of patients with spinal cord injury (sci) was mainly poor in the mental health 293 dimension.28 consistent with our findings, a study conducted in the netherlands showed 294 that the mean mental health score of fcs for patients with tbi significantly depreciated 295 from 63.07 at the time of discharge to 58.41 at eight weeks post-discharge.29 the above 296 findings demonstrate that caregiving for patients with tbi is difficult and promptly 297 impacts the caregivers’ qol if support and interventions to increase caregiving 298 preparedness are not provided. hence, the need for interventions to teach, support, and 299 increase the fcs’ preparedness before the patients are discharged and across the 300 caregiving trajectory. literature shows interventions focusing on skill building, peer 301 support, support groups, advocacy training, and other community-based services targeted 302 at the fc or dyad (fc and patient with tbi) improve health outcomes.30 303 304 our findings also show that at eight weeks post-discharge, there was a significant 305 improvement in caregiving preparedness (p < 0.01) and the patients with tbi disability (p 306 < 0.05) but no significant change in the fcs’ physical health qol. this shows that 307 without support or efforts by the healthcare system to prepare the fcs, caregivers use 308 inherent intuition, life experiences, and other resources to provide care to the patient with 309 tbi while also learning how to address the patient’s needs and symptoms. this is likely a 310 very stressful and emotionally draining task that compromises mental health qol. we 311 recommend more longitudinal studies of the resources fcs use to meet the needs of the 312 patient at home and to assess and monitor the health and health promotion practices of 313 fcs as they adjust to the demands of caring for patients with tbi beyond the eight weeks 314 period. 315 316 the significant modifiable predictors of the fcs’ mental health qol were caregiving 317 preparedness and the severity of the patient’s symptoms related to mood problems, 318 change in behaviors, and inability to live independently. these findings are consistent 319 with those of other recent studies, which reported that the caregivers of patients with tbi 320 have low mental health qol due to the patient’s mental health issues and ongoing care 321 needs.31,32 the significator modifiable predictors of the physical qol were the fcs’ 322 employment status, the severity of symptoms related to mood problems, and insomnia. 323 these findings demonstrate that interventions focusing on training the fc to increase 324 caregiving preparedness, skills needed to care for the patient with tbi with behavioral 325 problems, home-based care-led health professionals such as nurses to assist with 326 symptom management and other community-based services may enhance the caregivers’ 327 qol and outcomes of the patients with tbi. 328 329 the findings of studies conducted among fcs of patients with tbi in the usa (mainly 330 veterans) show that caregivers report lower qol in the mental health dimension than the 331 physical.28,31,32 the low mental health qol is mainly attributed to factors such as 332 perceived social stigma regarding the sequelae of tbi, inappropriate behaviors of patients 333 with tbi, anticipated future financial problems, social isolation, unhealthy family 334 functioning, dissatisfaction with intimate relationships, responsibility overload, sleep 335 deprivation, and suppression of personal needs and emotions.28,31,32 336 337 regarding caregiving preparedness, the current study revealed that overall, the fcs had 338 low caregiving preparedness at the time of patient discharge from the hospital. at eight 339 weeks post-discharge, there was a significant improvement in the fcs’ caregiving 340 preparedness. similar findings have been reported by a longitudinal study conducted 341 among danish fc of patients with tbi.33 however, the fcs in the danish study received 342 initial support from healthcare providers that helped patients with activities of daily 343 living.33 therefore, healthcare facilities in oman must prioritize the implementation of 344 tailored pre-discharge teaching and education and other interventions to increase 345 caregiving preparedness and mitigate poor health outcomes among fc and patients with 346 tbi. 347 348 the study’s findings need to be interpreted in view of its limitations, such as small 349 sample size (increase the risk of a type ii error), convenience sampling, and lack of data 350 about caregiver outcomes of depression, anxiety, and coping. the sample was mostly 351 comprised of fcs caring for patients with severe tbi-related disabilities, and this limits 352 the generalizability of the results. despite its limitations, the study highlights that 353 caregiving for patients with tbi promptly impacts the caregiver’s qol in the absence of 354 interventions to enhance support and preparedness. we recommend longitudinal and 355 interventional studies focusing on caregiver education, skilling, and support throughout 356 the caregiving trajectory. there is also a need for acute care hospitals to augment 357 discharge planning with interventions that enhance caregiver preparedness before the 358 patient is sent home. nurses could implement such interventions through community-359 based services such as home care, which can be tailored to the oman culture and social 360 context. 361 362 conclusion 363 this is the first study to explore the qol of fcs of patients with tbi in oman. the 364 omani fcs of patients with tbi experience a negative impact on their mental qol as a 365 result of assuming caregiving responsibilities. the modifiable predictors of qol were the 366 caregivers’ employment status and caregiving preparedness and patient symptoms related 367 to mood, insomnia, behaviors, and disability. the modifiable factors can be targeted to 368 enhance fcs preparedness and to mitigate poor health outcomes of the dyad (caregiver 369 and patients with tbi). 370 authors’ contribution 371 dj and jkm conceptualized and designed the study. erl, dj, and hr collected the data. 372 jkm analyzed and interpreted the data. all authors were involved in the study 373 investigation. erl, dj, hr, and jkm handled the project administration. jkm and dj 374 drafted the manuscript. erl and hr reviewed and edited the manuscript. jkm, dj, and 375 hr supervised the study and acquired the funding. all authors approved the final version 376 of the manuscript. 377 378 conflict of interest 379 the authors declare that there is no conflict of interest. 380 381 funding 382 the study was funded by the sultan qaboos university internal grant 383 ig/con/ahcc/19/03. 384 385 references 386 1. menon d k, schwab k, wright dw, maas ai. position statement: definition of 387 traumatic brain injury. arch phys med rehabil 2010; 91(11):1637-40. 388 https://doi.org/10.1016/j.apmr.2010.05.017 389 2. caplan b, bogner j, brenner l, manskow us, sigurdardottir s, røe c, et al. factors 390 affecting caregiver burden 1 year after severe traumatic brain injury: a prospective 391 nationwide multicenter study. j head trauma rehabil 2015; 30(6): 411-23. 392 https://doi.org/10.1097/htr.0000000000000085 393 3. world health organization. road traffic injuries. world health organization. from 394 https://www.who.int/violence_injury_prevention/road_traffic/en accessed on 395 december 14, 2022. 396 4. world health organization. world health rankings: oman, road traffic accidents. 397 from https://www.worldlifeexpectancy.com/oman-road-traffic-accidents accessed on 398 december 15, 2022 399 5. al-aamri ak, padmadas ss, zhang lc, al-maniri aa. disentangling age–gender 400 interactions associated with risks of fatal and non-fatal road traffic injuries in the 401 https://doi.org/10.1016/j.apmr.2010.05.017 https://doi.org/10.1097/htr.0000000000000085 https://www.who.int/violence_injury_prevention/road_traffic/en https://www.worldlifeexpectancy.com/oman-road-traffic-accidents sultanate of oman. bmj glob health 2017; 2(3): e000394. 402 http://dx.doi.org/10.1136/bmjgh-2017-000394 403 6. peterson ab, xu l, daugherty j, breiding mj. surveillance report of traumatic brain 404 injury-related emergency department visits, hospitalizations, and deaths, united 405 states, 2014. (2019) 406 7. al-saadi t, al-mirza a, al-taei o, al-saadi, h. (2022). geriatric neurosurgery in 407 high-income developing countries: a sultanate of oman experience. psychiatry 408 international 2022; 3(4): 264-272. https://doi.org/10.3390/psychiatryint3040021 409 8. pavlovic d, pekic s, stojanovic m, popovic v. traumatic brain injury: 410 neuropathological, neurocognitive and neurobehavioral sequelae. pituitary 411 2019; 22(3):270-82. https://doi.org/10.1007/s11102-019-00957-9 412 9. jourdan c, azouvi p, genêt f, selly n, josseran l, schnitzler a. disability and 413 health consequences of traumatic brain injury: national prevalence. am j phys med 414 rehabil 2018; 97(5):323-31. https://doi.org/10.1097/phm.0000000000000848 415 10. al-balushi t, al-badi ah, ali s. prevalence of disability in oman: statistics and 416 challenges. canadian journal of applied sciences 2011;1(3):81-96. 417 11. hudson c, radford k, kettlewell j. a qualitative study to understand the impact of 418 caring for traumatic injury survivors. int j environ res public health 2022; 419 19(23):16202. https://doi.org/10.3390/ijerph192316202 420 12. oberholzer m, müri rm. neurorehabilitation of traumatic brain injury (tbi): a 421 clinical review. med sci 2019; 7(3). https://doi.org/10.3390/medsci7030047 422 13. baker a, barker s, sampson a, martin c. caregiver outcomes and interventions: a 423 systematic scoping review of the traumatic brain injury and spinal cord injury 424 literature. clin rehabil 2017; 31(1):45-60. 425 https://doi.org/10.1177/0269215516639357 426 14. brickell ta, cotner ba, french lm, carlozzi ne, o'connor dr, nakase-427 richardson r, et al. severity of military traumatic brain injury influences caregiver 428 health-related quality of life. rehabil psychol 2020; 65(4), 377. 429 https://doi.org/10.1037/rep0000306 430 http://dx.doi.org/10.1136/bmjgh-2017-000394 https://doi.org/10.3390/psychiatryint3040021 https://doi.org/10.1007/s11102-019-00957-9 https://doi.org/10.1097/phm.0000000000000848 https://doi.org/10.3390/ijerph192316202 https://doi.org/10.3390/medsci7030047 https://doi.org/10.1177/0269215516639357 https://doi.org/10.1037/rep0000306 15. saban kl. perceived health, caregiver burden, and quality of life in women partners 431 providing care to veterans with traumatic brain injury. j rehabil r d 2016; 53(6). 432 https://doi.org/10.1682/jrrd.2015.07.0143 433 16. tezel n, umay e, çakcı a. factors affecting the caregiver burden following 434 traumatic brain injury. gulhane med j 2021;63(3):186-92. 435 https://doi.org/10.4274/gulhane.galenos.2021.1460 436 17. mccall rk. understanding family caregiving for individuals with traumatic brain 437 injury after a road traffic crash in oman (doctoral dissertation, queensland 438 university of technology). 2020. 439 18. al-kashmiri am, al-shaqsi sz, al-kharusi as, al-tamimi la. save the patient a 440 trip. outcome difference between conservatively treated patients with traumatic brain 441 injury in a nonspecialized intensive care unit vs. a specialized neurosurgical intensive 442 care unit in the sultanate of oman. j crit care 2015; 30(3):465-68. 443 https://doi.org/10.1016/j.jcrc.2015.02.010 444 19. lam et, lam cl, fong dy, huang ww. is the sf‐12 version 2 health survey a 445 valid and equivalent substitute for the sf‐36 version 2 health survey for the 446 chinese? j eval clin pract 2013;19(1): 200-8. https://doi.org/10.1111/j.1365-447 2753.2011.01800.x 448 20. zwicker d. preparedness for caregiving scale. mov disord 2010; 28:1-2. 449 21. henriksson a, andershed b, benzein e, arestedt k. adaptation and psychometric 450 evaluation of the preparedness for caregiving scale, caregiver competence scale and 451 rewards of caregiving scale in a sample of swedish family members of patients with 452 life-threatening illness. palliat med 2012; 26(7): 930-38. 453 https://doi.org/10.1177/0269216311419987 454 22. bellon k, wright j, jamison l, kolakowsky-hayner s. disability rating scale. j head 455 trauma rehabil 2012; 27(6):449-51. 456 https://doi.org/10.1097/htr.0b013e31826674d6 457 23. al-adawi s, dorvlo as, burke dt, huynh cc, jacob l, et al. apathy and depression 458 in cross-cultural survivors of traumatic brain injury. j neuropsychiatry clin neurosci 459 2004;16(4):435-42. https://doi.org/10.1176/jnp.16.4.435 460 https://doi.org/10.1682/jrrd.2015.07.0143 https://doi.org/10.4274/gulhane.galenos.2021.1460 https://doi.org/10.1016/j.jcrc.2015.02.010 https://doi.org/10.1111/j.1365-2753.2011.01800.x https://doi.org/10.1111/j.1365-2753.2011.01800.x https://doi.org/10.1177/0269216311419987 https://doi.org/10.1097/htr.0b013e31826674d6 https://doi.org/10.1176/jnp.16.4.435 24. daradkeh g, essa mm, ali al, al-adawi s, koshi r, arabawi s, et al. assessment 461 of nutritional status and macronutrients adequacy of traumatic brain injury 462 patients attending tertiary health care in oman. acta scientific nutritional health 463 2020; 4(2):144-50. https://doi.org/10.31080/asnh.2020.04.0625 464 25. al-balushi n, al-alawi m, al shekaili m, al-balushi m, mirza h, al-huseini s, et 465 al. predictors of burden of care among caregivers of drug-naive children and 466 adolescents with adhd: a cross-sectional correlative study from muscat, oman. j 467 atten disord 2019; 23(5):517-26. https://doi.org/10.1177/1087054718808 468 26. chan mf, al‐dhawyani am, al hinai k, al‐azri m. a cluster analysis to explore 469 the burden of primary caregivers of children with cancer in oman. j spec pediatr 470 nurs 2022; 27(3): e12389. https://doi.org/10.1111/jspn.12389 471 27. lieshout k, oates j, baker a, unsworth ca, cameron id, schmidt j, lannin na. 472 burden and preparedness amongst informal caregivers of adults with moderate to 473 severe traumatic brain injury. int j environ res public health 2020; 17(17): 6386. 474 https://doi.org/10.3390/ijerph17176386 475 28. farajzadeh a, akbarfahimi m, maroufizadeh s, miri lavasani n. factors associated 476 with quality of life among caregivers of people with spinal cord injury. occup ther 477 int 2021. https://doi.org/10.1155/2021/9921710 478 29. backx apm, spooren aif, bongers-janssen hmh, bouwsema h. quality of life, 479 burden and satisfaction with care in caregivers of patients with a spinal cord injury 480 during and after rehabilitation. spinal cord 2018; 56(9):890-99. 481 https://doi.org/10.1038/s41393-018-0098-7 482 30. kreitzer n, kurowski bg, bakas t. systematic review of caregiver and dyad 483 interventions after adult traumatic brain injury. arch phys med rehabil 2018; 99(11): 484 2342-2354. https://doi.org/10.1016/j.apmr.2018.04.016 485 31. brickell ta, wright mm, lippa s, sullivan jk, bailie jm, french lm, et al. 486 resilience is associated with health-related quality of life in caregivers of service 487 members and veterans following traumatic brain injury. quality of life research 488 2020; 29(10):2781-92. https://doi.org/10.1007/s11136-020-02529-y 489 32. bermejo-toro l, sánchez-izquierdo m, calvete e, roldán ma. quality of life, 490 psychological well-being, and resilience in caregivers of people with acquired brain 491 https://doi.org/10.31080/asnh.2020.04.0625 https://doi.org/10.1177/1087054718808 https://doi.org/10.1111/jspn.12389 https://doi.org/10.3390/ijerph17176386 https://doi.org/10.1155/2021/9921710 https://doi.org/10.1038/s41393-018-0098-7 https://doi.org/10.1016/j.apmr.2018.04.016 https://doi.org/10.1007/s11136-020-02529-y injury (abi). brain inj 2020; 34(4):480-88. 492 https://doi.org/10.1080/02699052.2020.1725127 493 33. norup a, snipes dj, siert l, mortensen el, perrin pb, arango-lasprilla jc. 494 longitudinal trajectories of health-related quality of life in danish family members of 495 individuals with severe brain injury. the australian journal of rehabilitation 496 counselling 2013;19(2):71-83. https://doi.org/10.1017/jrc.2013.12 497 498 https://doi.org/10.1080/02699052.2020.1725127 https://doi.org/10.1017/jrc.2013.12 figure 1: study flow 499 abbreviations: fcs, family caregiver; tbi, traumatic brain injury 500 s c re e n in g e li g ib il it y in c lu si o n a n a ly si s total number of fc of tbi patients screened at the time of discharge n= 63 not eligible fcs = 17 (paid to provide care = 11; patient not willing to participate = 4; fc is also a trained health care professional = 2) total number of eligible fcs (and their patients) = 46 patient status changed and transferred to another unit = 10 total number of fcs consented = 36 total number of patients with tbi= 36 total number of fcs at the time of discharge = 36 n total number of patients with tbi at the time of discharge = 36 total number of fcs after 8 weeks = 35 total number of patients with tbi after 8 weeks = 35 (death = 1) table 1: characteristics of the family caregivers and patients with tbi 501 characteristic fcs (n = 36) patients (n = 36) % % gender male female 47.2 52.8 52.8 47.2 age in years 18-40 ≥ 41 69.4 29.6 25 75 marital status single married separated/divorced/widowed 8.3 88.9 2.8 13.9 63.9 22.2 level of education ≤ high school ≥ post-secondary 80.6 19.4 94.4 5.6 employment status full-time unemployed 61.1 38.9 36.1 63.9 relationship to patient parent spouse child sibling legal guardian 41.7 16.7 27.8 11.1 2.8 cause of injury or patient diagnosis fall motor vehicle accident assault other forms of trauma 36.1 50 11.1 2.7 glasgow coma scale on admission 9-12 (moderate) ≤ 8 (severe) 47.2 52.8 glasgow coma scale at the point of discharge mild (14–15) moderate (9–13) 64.2 35.8 fcs, family caregivers502 oman family caregivers of tbi patients 20 table 2: symptom profile of patients with tbi at the time of discharge 503 symptom rating (n =36) m ± sd no difficulty mild difficulty moderate difficulty severe difficulty % % % % loss of muscle strength (paralysis, limited physical mobility, or poor coordination) -2.8 19.4 77.5 4.75 ± 0.50 blurred or loss of vision 11.1 11.1 25 52.8 4.08 ± 1.30 loss of hearing or ringing in the ears 19.4 11.1 16.7 52.8 3.83 ± 1.56 loss of memory and concentration 8.3 16.7 11.1 63.9 4.22 ± 1.25 change in speech or difficulty being understood 2.8 11.1 11.1 75 4.56 ± 0.91 mood problems (include depression, anxiety, denial, and frequent change in emotion) 8.3 8.3 16.7 66.7 4.33 ± 1.20 insomnia 22.2 8.3 13.9 55.6 3.81 ± 1.64 changes in behavior (aggression, anger, impulsiveness, etc.) 13.9 11.1 22.2 52.8 4.00 ± 1.39 ability to live independently --2.8 97.2 4.97 ± 0.17 504 oman family caregivers of tbi patients 21 table 3: changes in patient disability, caregiver quality of life, and caregiving preparedness at 8 weeks post-discharge (n = 35) 505 variable level n m sd sem t p-value md 95% ci tbi patient’s disability rating scale score at the time of discharge 35 16.74 4.15 0.70 2.33 0.026 1.40 0.18-2.62 at eight weeks postdischarge 35 15.34 5.00 0.85 family caregiver’s caregiving preparedness at the time of discharge 35 19.74 9.04 1.53 -4.33 < 0.001 -3.00 -4.41 -1.59 at eight weeks postdischarge 35 22.74 6.71 1.14 family caregivers’ sf-12 physical quality of life (pqol) at the time of discharge 35 71.91 25.69 4.34 1.02 0.316 2.98 -2.97 – 8.92 at eight weeks postdischarge 35 68.93 27.66 4.68 family caregivers’ sf-12 mental health quality of life (mhqol) at the time of discharge 35 63.05 16.96 2.87 2.11 0.042 4.64 0.18 – 9.11 at eight weeks postdischarge 35 58.41 17.98 3.04 sem, standard error of the mean; md, mean difference 506 oman family caregivers of tbi patients 22 table 4: predictors of caregivers’ quality of life at 8 weeks post-discharge 507 dependent variable factor unstandardized coefficient t p-value 95% ci β se family caregivers’ sf-12 physical quality of life (pqol) constant 152.26 23.69 6.43 < 0.001 103.81-200.71 family caregiver age (years) -1.59 0.39 -4.14 < 0.001 -2.38 -0.81 patient age (years) 0.44 0.17 2.64 0.013 0.10 – 0.78 family caregiver employment status -13.27 3.66 -3.62 0.001 -20.75 -5.78 severity of mood problems (depression, anxiety, denial, and frequent change in emotion) -10.34 3.16 -3.27 0.003 -16.80 3.88 severity of insomnia 5.36 2.29 2.34 0.026 0.68 -10.04 family caregivers’ sf-12 mental health quality of life (mhqol) constant 228.64 73.53 3.22 0.004 78.02 – 379.27 family caregiver age (years) -0.94 0.29 -3.29 0.003 -1.53 -0.36 patient age (years) 0.45 0.16 3.96 < 0.001 0.22 – 0.69 family caregiver’s caregiving preparedness 0.59 0.29 2.02 0.050 0.00 -1.20 severity of mood problems (depression, anxiety, denial, and frequent change in emotion) -11.61 3.18 -3.65 0.001 -18.13 -5.09 severity of behavior changes (aggression, anger, impulsiveness, etc.) 8.33 2.86 2.91 0.007 2.47 – 14.20 severity of the inability to live independently -13.39 14.04 -2.24 0.034 -60.16 -2.63 ci, confidence interval; se, standard error 508 ischemic infarction is a rare cause of acute myelopathy.1 the unique vascular supply predisposes the spinal cord to potential ischaemic insults in the perioperative setting of complicated abdominal surgery. epidural analgesia is a common and relatively safe procedure to alleviate pain and to speed up recovery after abdominal surgery. the incidence of acute myelopathy due to central neural blockade after epidural analgesia is extremely rare. in view of the rarity of neurological complications following epidural analgesia alone, careful consideration should be paid to other medical or surgical causes (other than postoperative epidural injection as such) to account for post-operative acute myelopathy. in addition, it is important to recognise the signs of myelopathy rather than attributing the findings to delayed wearing-off of the analgesic effect. we report the unusual case of a young adult who developed spinal cord infarction in the setting of surgical evacuation of intra-abdominal (liver) haematoma and thoracic epidural analgaesia. case report a 28-year-old woman, admitted to a hospital in oman, tested positive for hepatitis c viral (genotype 4) infection by polymerase chain reaction assay. she had no vascular risk factors such as hypertension, diabetes mellitus, atrial fibrillation, and hyperlipidemia. to establish the extent of liver pathology and to plan further management she underwent an elective liver biopsy in another institution. two days after the procedure, she developed right upper abdominal pain and vomiting. the haemoglobin (hb) dropped from squ med j, december 2010, vol. 10, iss. 3, pp. 396-400, epub. 14th nov 10 submitted 26th june 10 revision req. 18th july 09, revision recd. 26th july 10 accepted 2nd aug 2010 departments of 1medicine, 2anaesthesia; 3formerly: department of radiology & molecular imaging, college of medicine & health sciences,sultan qaboos university, muscat, oman, current affiliation: department of radiology, medanta medicity, gurgaon, india *corresponding author email: rnandagopal@yahoo.com <‡�f÷]<ª<ìèu]üq<ìè◊€¬<]üqc<ç√e<í“áé÷]<ÿf£]<^éju] ìè ^¢]<ÿáu<∞”äiê                 abstract: ischemic infarction is a rare cause of acute myelopathy. we report the case of a young woman admitted to sultan qaboos university hospital, oman, who developed extensive spinal cord infarction in the setting of surgical evacuation and packing of liver haematoma and post-operative epidural analgesia. she had no vascular risk factors for stroke. the vascular mechanism underlying ischemic myelopathy and the relationship to abdominal surgery and epidural analgesia are discussed. keywords: myelopathy; spinal cord infarction; abdominal surgery; epidural analgesia; magnetic resonance imaging; liver hematoma; liver packing; radiculomedullary artery; case report; oman spinal cord infarction following abdominal surgery and postoperative epidural analgaesia abdullah al-asmi,1 rosanna john,2 *ramachandiran nandhagopal,1 povathoor c jacob,1 karin nollain,2 rajeev jain3 case report abdullah al-asmi, rosanna john, ramachandiran nandhagopal, pc jacob, karin nollain, and rajeev jain case report | 397 12 to 10 gm/l. an abdominal sonogram showed a hepatic subcapsular haematoma and she received 3 units of packed red cell transfusion. despite the blood transfusion, the hb remained low. persistent intra-abdominal bleeding was suspected and an urgent abdominal computed tomography (ct) scan confirmed extensive haemorrhage in the peritoneal cavity and the pelvis. the following day (third day after the biopsy), she was transferred to our institution for further management including emergency laparotomy. at pre-operative assessment in our centre, the blood pressure was 130/82 mmhg, and the heart rate ranged from 130 to 140 beats per minute. hb remained stable at 10 gm/l and the coagulation profile was within normal limits. the neurological examination was unremarkable. intra-operatively she remained haemodynamically stable and there was no episode of hypotension. to arrest the continual oozing of blood from the liver surface, surgical packing of the liver was performed. at the end of the procedure, an epidural catheter was inserted at the thoracic (t)11-12 intervertebral space as per the standard technique of postoperative analgesia. a bolus of 10ml of 0.125% bupivacaine along with fentanyl 20 mcg was injected initially, followed by an infusion at 6ml/hr. she was extubated successfully in the intensive care unit an hour later and the rate of infusion was increased to 10ml/hr as she continued to experience pain. figure 1a: sagittal t2 weighted magnetic resonance imaging (initial scan) demonstrating diffuse bright signal (horizontal arrow) in the distal part of spinal cord. the corresponding transverse extent of the lesion with involvement of central gray on the left side (vertical arrow) is illustrated in 1b: follow-up scans at 2 months 1c: (sagittal image) and 1d: (corresponding transverse image) and at 3 years1e: (sagittal image) and 1f: (corresponding transverse image) demonstrate progressive atrophy of the cord with myelomalacia (arrows) in the affected segments. spinal cord infarction following abdominal surgery and postoperative epidural analgaesia 398 | squ medical journal, december 2010, volume 10, issue 3 she did not demonstrate hypotension during the procedure. eight hours after the initiation of epidural analgesia, she complained of an inability to move her lower limbs and the epidural infusion was withheld. neurologically, she demonstrated flaccid paraplegia (power of 0/5 in legs), sensory level at t8 dermatome (below which the primary modalities of sensation were lost) and areflexia in the lower limbs along with extensor plantar response and bowel and bladder disturbances. emergent magnetic resonance imaging (mri) of the spine revealed diffuse hyperintensity of the distal spinal cord, but sparing the terminal end and the conus [figure 1a]. on the transverse t2 weighted image, it was observed that the signal abnormality corresponded to the central grey matter on the left side, while sparing the peripheral white matter [figure 1b]. the ischaemic nature of the lesion was confirmed on diffusion weighted mr images. there was no evidence of epidural mass/compression, fluid collection, bone changes or acute traumatic injury. serial clinical examination demonstrated persistent weakness and sensory signs indicating that the sensory changes were not due to delayed wearing-off of the analgesic effect. a lumbar tap showed clear cerebrospinal fluid (csf). csf findings included glucose of 5.3 mmol/l (serum glucose 6 mmol/l), protein of 0.42 g/l, igg 0.07 g/l and cell count of 28 cell/mm3 with 80% polymorphic lymphocytes. auto-antibody screening for collagen vascular disease was negative. in view of recent recurrent surgical procedures, a course of intravenous immunoglobulin was preferred over high dose methylprednisolone to avoid the emergence of intra-abdominal sepsis, bowel perforation and in view of seropositivity for hepatitis c virus. she was re-explored surgically after 48 hrs and the liver packs were removed. the thrombophilia work-up (results obtained at a later date) was normal except for mild protein s deficiency. haematological consultation was sought and it was felt that protein s deficiency was an incidental finding and not a causative factor for the cord infarction. a follow-up mri study performed two months later showed interval atrophy of the spinal cord as compared to the previous study with myelomalacia of the involved left central column [figures 1c and 1d]. at a clinical follow-up a few months later, she had significant spastic paraparesis with ankle clonus and a sensory level at t6-7. the patient was placed on regular physiotherapy. a subsequent follow-up mri performed three years later showed progressive marked atrophy with persistent long segment t2 hyperintense lesions consistent with myelomalacia [figure 1e]. these changes are also illustrated on the transverse t2 weighted images in figure 1f. discussion in this communication, we report the case of a young woman who developed extensive spinal cord infarction following surgical evacuation and packing for liver haematoma and epidural analgesia. it is to be noted that she did not have the conventional vascular risk factors for stroke. the extensive ischaemic myelopathy was unlikely to be due to the epidural analgesia per se and probably, the extensive intraabdominal haemorrhage prior to our hospital admission having set the stage for the ischemic injury. the tight packing of the liver (performed to arrest continual oozing of blood from the liver surface), may have compromised cord perfusion. although venous stasis subsequent to the tight liver packing might also have contributed to congestive myelopathy, imaging studies did not demonstrate significant cord swelling, haemorrhagic lesions, or congestive changes in the intra-abdominal organs. regarding the vascular supply, the spinal cord is perfused by 3 main arteries that course vertically over its surface. the anterior two-thirds of the cord is supplied by a single anterior spinal artery and the posterior one-third by two anastomosing posterior spinal arteries. the anterior spinal artery is formed by the union of a branch from each vertebral artery. along its course, the anterior spinal artery receives input from 6–9 unpaired radicular arteries in variable locations. these arteries are compromised in aortic lesions, but our patient did not demonstrate any aortic lesion. the major radiculo-medullary artery, the arteria radicularis magna (artery of adamkiewicz) supplies the lower thoracic cord and lumbar enlargement; this site is particularly vulnerable to hypoperfusion and is referred to as the water shed area of the cord.2-4 in a multidetector row ct angiogram study, acquisition of longitudinal imaging volume from the dome of liver at the level of eighth thoracic vertebra to the tip of the liver at the level of third lumbar vertebra abdullah al-asmi, rosanna john, ramachandiran nandhagopal, pc jacob, karin nollain, and rajeev jain case report | 399 covered the location of artery of adamkiewicz.5 with regards to the laterality of this radiculomedullary artery, the artery arises from the lower intercostal and upper lumbar arteries on the left side in about two-thirds of cases and from the right side in one-third of cases.5 it is, therefore, conceivable that the unique vascular supply of the spinal cord and the anatomical proximity of vessels, such as the artery of adamkiewicz, to abdominal organs like the liver render the cord particularly vulnerable to ischemia and infarction in the setting of complicated liver/abdominal surgery. most spinal cord infarcts are located in the central territory of the anterior spinal artery with predominant involvement of the central grey matter and the adjacent central white matter, though some may have a more prominent involvement of the anterior grey matter.6 this central grey involvement was also observed more prominently on the left side in our patient. occlusion of the arteria radicularis magna due to the pressure effect of tight liver packing and intraabdominal haemorrhage was the most likely vascular mechanism based on the extent of anatomical lesion on the sagittal imaging [figures 1a, 1c and 1e]. the sequential changes with progressive atrophy of the cord and myelomalacia [figure 1c to 1f ] confirmed the initial diagnosis of spinal cord infarction. other focal non-mitotic intramedullary lesions of the cord, e.g. transverse myelitis, were unlikely to be limited to the central cord, and usually progressive improvement in the imaging appearances and neurological status of the patient might be expected in those conditions. another technique that may be used for ascertaining the ischemic nature of the lesion is diffusion-weighted mri of the spinal cord. as in the brain, acute spinal cord infarction demonstrates restricted diffusion.7 in keeping with this finding, severe diffusion restriction was also observed in the acute stage of cord infarction in our patient. in the late stage, the myelomalacic segment showed increased diffusivity. spinal cord ischemia following epidural anaesthesia is rare and usually a direct causal relationship is unlikely.8-14 possible mechanisms of epidural analgesia-related myelopathy include cord compression due to epidural haematoma, cord trauma, injury to arteries supplying the cord, chemical contamination and iatrogenic meningitis.8-11 our patient did not have any evidence of compressive myelopathy, nor did her csf findings support chemical or iatrogenic meningitis.8-11 moreover, our patient did not have risk factors for premature atherosclerosis, in which setting a hyperlordotic or laterally flexed position may be a more common cause of spinal cord injury.12,13 continuous infusion of local anaesthetic with sympathomimetics has been implicated in vasoconstriction and subsequent cord ischemia.14,15 this was less likely in our case as epinephrine was not used. hypotension has been cited as a major contributor in the majority of reports of paraplegia complicating epidural anesthesia;15-19 however, the patient did not demonstrate systemic hypotension during the procedure. the presence of vasculitis and atherosclerotic and thrombogenic risk factors render the cord more susceptible to a hypoperfusion insult.20 our patient did not have any clinical or serological evidence of vasculitis. moreover, she was relatively healthy, apart from the hepatitis c infection prior to the liver biopsy. on many occasions, the association between epidural anaesthesia and serious neurological sequelae is only a temporal coincidence and might be inappropriately suspected as causative factor.21-23 however, it is to be noted that in the post-operative setting the epidural analgesia may obscure the neurological assessment, especially the sensory examination. conclusion in summary, we have described a young patient who developed ischemic myelopathy following surgical evacuation and packing of liver haematoma and postoperative epidural analgesia. we believe that tight packing of liver injury, apart from intraabdominal haemorrhage might have compromised the blood supply and contributed to the ischemic injury of the cord. our report underscores the importance of considering various possible mechanisms underlying spinal cord infarction, especially surgical factors, rather than attributing the signs of myelopathy to the delayed wearing-off of post-operative epidural analgesia. references 1. cheng my, lyu rk, chang yj, chen rs, huang cc, wu t, et al. spinal cord infarction in chinese patients. clinical features, risk factors, imaging and prognosis. cerebrovasc dis 2008; 26:502–8. spinal cord infarction following abdominal surgery and postoperative epidural analgaesia 400 | squ medical journal, december 2010, volume 10, issue 3 2. silver jr, buxton ph. spinal stroke. brain 1974; 97:539–50. 3. marcus l, heistad dd, ehrhardt jc. regulation of total and regional spinal cord blood flow. circ res 1977; 41:128–34. 4. duggal n, lach b. selective vulnerability of the lumbosacral spinal cord after cardiac arrest and hypotension. stroke 2002; 33:116–21. 5. kudo k, terae s, asano t, oka m, kaneko k, ushikoshi s, et al. anterior spinal artery and artery of adamkiewicz detected by using multi-detector row ct. ajnr am j neuroradiol 2003; 24:13–7. 6. pattany pm, saraf-lavi e, bowen bc. mr angiography of the spine and spinal cord. top magn reson imaging 2003; 14:444–60. 7. kuker w, weller m, klose u, krapf h, dichgans j, nagele t. diffusion-weighted mri of spinal cord infarction-high resolution imaging and time course of diffusion abnormality. j neurol 2004; 251:818–24. 8. kane re. neurologic deficits following epidural or spinal anesthesia. anesth analg 1981; 60:150–61. 9. brull r, mccartney cj, chan vw, el-beheiry h. neurological complications after regional anesthesia. contemporary estimate of risk. anesth analg 2007; 104:965–74. 10. bromage pr, benumof jl. paraplegia following intracord injection during attempted epidural anesthesia under general anesthesia. reg anesth pain med 1998; 23:104–7. 1. kao mc, tsai sk, tsou my, lee hk, guo wy, hu js. paraplegia after delayed detection of inadvertent spinal cord injury during thoracic epidural catheterization in an anesthetized elderly patient. anesth analg 2004; 99:580–3. 12. lee la, posner kl, domino kb, caplan ra, cheney fw. injuries associated with regional anesthesia in the 1980’s and 1990’s: a closed claims analysis. anesthesiology 2004; 101:143–52. 13. borgeat a, blumenthal s. nerve injury and regional anaesthesia. curr opin anaesthesiol 2004; 17:417– 21. 14. usubiaga je. neurological complications following epidural anesthesia. int anaesthesiol clin 1975; 13:1–153. 15. kozody r, palahniuk rj, wade jg, cumming mo, pucci wr. the effect of subarachnoid epinephrine and phenylephrine on spinal cord bood flow. can anaesth soc j 1984; 31:503–8. 16. weinberg l, harvey wr, marshall rj. post operative paraplegia following spinal cord infarction. acta anaestheiol scand 2002; 46:469–72. 17. sing u, silver jr, welply nc. hypotensive infarction of the spinal cord. paraplegia 1994; 32:314–22. 18. cekic g, de kock m, kremer y, scholtes jl. paraplegia after combined general and epidural anesthesia. a case report. acta anaesthesiol belg 2008; 59:95–8. 19. bhuiyan ms mallick a, parsloc m. post thoracotomy paraplegia coincident with epidural anaesthesia. anaesthesia 1998; 53:583–6. 20. linz sm, charbonnet c, mikhail ms, vadehra n, zelman v, katz rl. spinal artery syndrome masked by postoperative epidural analgesia. can j anaesth 1997; 44:1178–81. 21. levstad r z, steen p a, forsman m. paraplegia after thoracotomy – not caused by the epidural catheter. acta anaesth scand 1999; 43:230–2. 22. raz a, avramovich a, saraf-lavi e, saute m, eidelman la. spinal cord ischemia following thoracotomy without epidural anesthesia. can j anaesth 2006; 53:551–5. 23. rutter sv, jeevananthan v, souter r, cowen mj. ‘shared spinal cord’ scenario. paraplegia following abdominal aortic surgery under combined general and epidural anaesthesia. eur j anaesthiol 1999; 16:646–9. مصادر اخلاليا اجلذعية الوسيطة واستخداماهتا السريرية مراجعة حديثة روبرتو برييبت�شيز-فريدمان و بابلو رودريغو مونتريو-اأولفريا abstract: first discovered by friedenstein in 1976, mesenchymal stem cells (mscs) are adult stem cells found throughout the body that share a fixed set of characteristics. discovered initially in the bone marrow, this cell source is considered the gold standard for clinical research, although various other sources—including adipose tissue, dental pulp, mobilised peripheral blood and birth-derived tissues—have since been identified. although similar, mscs derived from different sources possess distinct characteristics, advantages and disadvantages, including their differentiation potential and proliferation capacity, which influence their applicability. hence, they may be used for specific clinical applications in the fields of regenerative medicine and tissue engineering. this review article summarises current knowledge regarding the various sources, characteristics and therapeutic applications of mscs. keywords: mesenchymal stem cells; adult stem cells; regenerative medicine; cell differentiation; tissue engineering. امللخ�ص: اخلاليا اجلذعية الو�شيطة التي مت اكت�شافها لأول مرة بوا�شطة فريدن�شتاين يف عام 1976 هي اخلاليا اجلذعية البالغة املوجودة يف جميع اأنحاء اجل�شم والتي ت�شرتك يف جمموعة ثابتة من اخل�شائ�ص. مت اكت�شاف هذه اخلالايا يف البداية يف نخاع العظام، ويعترب هذا امل�شدر اخللوي هو املعيار الذهبي للبحوث ال�رسيرية، على الرغم من اأنه مت منذ ذلك احلني حتديد م�شادر اأخرى متنوعة-مبا يف ذلك الأن�شجة الدهنية، ولب الأ�شنان، وخاليا الدم الطرفية املحركة والأن�شجة امل�شتقة من م�شيمة الولدة. وعلى الرغم من كونها مت�شابهة، يف اإمكاناتها ذلك يف مبا وعيوب، ومزايا مميزة خ�شائ�ص متتلك خمتلفة امل�شادر تلك من امل�شتمدة الو�شيطة اجلذعية اخلاليا فاإن التمايز وقدرتها على النت�شار، والتي توؤثر على قابليتها للتطبيق. ومن ثم، ميكن ا�شتخدامها يف تطبيقات �رسيرية حمددة يف جمالت الطب التجديدي وهند�شة الأن�شجة. تلخ�ص هذه املقالة املعرفة احلالية فيما يتعلق مبختلف امل�شادر واخل�شائ�ص والتطبيقات العالجية للخاليا اجلذعية الو�شيطة. الكلمات املفتاحية: اخلاليا اجلذعية الو�شيطة؛ اخلاليا اجلذعية للبالغني؛ الطب التجديدي؛ متايز اخلاليا؛ هند�شة الن�شجة. sources and clinical applications of mesenchymal stem cells state-of-the-art review *roberto berebichez-fridman1,2 and pablo r. montero-olvera2 review sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e264–277, epub. 19 dec 18 submitted 20 feb 18 revision req. 18 mar 18; revision recd. 16 apr 18 accepted 10 may 18 1department of orthopaedic surgery, american british cowdray medical center, mexico city, mexico; 2tissue engineering, cell therapy & regenerative medicine unit, national institute of rehabilitation, mexico city, mexico *corresponding author’s e-mail: berebichezmd@gmail.com doi: 10.18295/squmj.2018.18.03.002 stem cells can be distinguished based on their differentiation potential and source within the human body. embryonic stem cells are totipotent, because they can form both embryonic and extra embryonic structures.1 furthermore, embryonic stem cells can proliferate indefinitely under specific culture conditions and retain the ability to differentiate into cell types of the three embryonic germ layers.1,2 in contrast, adult stem cells are undifferentiated multipotent stem cells obtained from adult individuals and differentiate into the cell types that constitute their respective source tissues; accordingly, cells originating from neuronal tissue can differentiate into neurons, oligodendrocytes or astrocytes. this characteristic plasticity is an attribute of mesenchymal stem cells (mscs), which are unspecialised cells with the ability to self-renew.3,4 human mscs are plastic-adherent cells that differ entiate into cells that originate from the ectoderm and endoderm.3–5 moreover, they can abandon their unspec ialised or undifferentiated states and transform into other mesenchymal lineages. thus, they can regenerate bone, cartilage and fat and even become endothelial cells, muscle cells or neurons under physiological and experimental conditions.3,4 while evidence suggests that mscs are present in almost all human tissues, they were first isolated from mononuclear cells derived from bone marrow (bm).3,6 as mscs are responsible for tissue repair, growth, wound healing and cell substitution resulting from physiological or pathological causes, they have various therapeutic applications such as in the treatment of central nervous system afflictions like spinal cord lesions.4 roberto berebichez-fridman and pablo r. montero-olvera review | e265 moreover, because of their differentiation ability, mscs have become the de facto model for regenerative medicine research.3,5,6 in the field of regenerative medicine, mscs have several advantages over other types of stem cells. for example, from an ethical standpoint, the contr oversy that surrounds the procurement of embryonic stem cells is virtually nonexistent in the case of induced pluripotent stem cells or mscs, although teratogenicity limits the widespread use of the former cell type.3,4,6 the objective of the current review was to highlight the available information regarding msc sources and their potential applications in the treatment of a variety of diseases. however, in order to present a comprehensive overview of the possible clinical applications of mscs, it is first necessary to understand their unique characteristics, including their differentiation potential, activity and therapeutic effects in various human systems and tissues. differentiation potential mscs can differentiate into different cell types, although they require an array of differentiation factors. in an in vitro environment, the specific growth medium allows them to reach their osteogenic, chondrogenic or adipo genic potential.7,8 however, due to the use of different isolation and culture techniques, there are conflicting data regarding the specific characteristics used to define mscs. since these cells can be isolated from almost any tissue, it has been proposed that mscs from various sources might not be similar enough to be grouped together under a single classification.6 however, this issue has been resolved following the establishment of universally accepted laboratory criteria allowing for the identification of common msc characteristics.8 according to the international society for cellular therapy, multipotent mscs must meet the following three criteria: plastic adherence to culture flasks; expres sion of cluster of differentiation (cd)105, cd73 and cd90 and lack of expression of cd45, cd34, cd14/ cd11b, cd79α/cd19 and human leukocyte antigen (hla) class ii by ≥95% and ≤2% of the cell population, respectively; and the ability to differentiate into osteoblasts, chondroblasts or adipocytes.8 in addition, under specific culture conditions, mscs can differentiate into non-mesodermal lineages such as hepatocytes, neurons, pancreatic cells, cardiac muscle cells or astrocytes.9 sources and clinical applications stem cells can be isolated from various sources in the human body, the selection of which should ideally be based on their logistical, practical and in vitro characteristics. currently, the main sources of mscs are bm and adipose tissue (at).6 although mscs can hypothetically be obtained from almost any tissue within the human body, there are practical limitations concerning the difficulty and invasiveness of the procurement process and various donor characteristics. to select an adequate cell source, the practitioner must consider the difficulty of procuring the samples and the potential adverse effects of harvesting the cells on the donor. obtaining bm-mscs, for example, can result in pain, bleeding or infection, thus making harvesting mscs from this source more problematic than harvesting cells from peripheral blood or surgical remnants such as at or birth-derived tissues.9 table 1 describes current sources of mscs along with their character istics, advantages, disadvantages and clinical applications.7,9–30 b o n e m a r r o w initially discovered in 1976 by friedenstein, bm-mscs were first described as undifferentiated mscs in 1987.31,32 subsequently, bm became the main source of multipotent stem cells. however, their procurement requires a highly invasive and painful procedure involving heavy use of anaesthesia; moreover, the cell yield, longevity and potential for differentiation diminishes with donor age.9 compared with mscs derived from other sources, bm-mscs possess a longer duplication period, reach senescence earlier and constitute only 0.01–0.001% of nucleated marrow cells.9,10 nevertheless, one advantage of bm-mscs over other cell types is their relatively short culture time.11,33 the role of inflammation in the pathogenesis of arterial hypertension, particularly in activating the sympathetic nervous system, has been recently identified in a study using a murine model.34 penn et al. observed that bm transplantation from spontaneously hypertensive rats into normotensive rats resulted in a marked increase in blood pressure; however, treating the rats with minocycline, a second-generation semi synthetic tetracycline and microglial activation inhibitor with anti-inflammatory effects, reversed the hyper tension.34 the underlying mechanism involves an inc rease in the production of inflammatory cells and cytokines which translates into a stronger neuroinflammatory response and increased activity of the sympathetic nervous system. the association between haematopoietic (i.e. bm-derived) stem cells and hyper tension indicates that bm-msc therapy may have poten tial applications in treating obesity, diabetes mellitus (dm) and hypertension.34 in a clinical context, attempts have been made to use bm-mscs to alleviate heart failure, address cardiosources and clinical applications of mesenchymal stem cells state-of-the-art review e266 | squ medical journal, august 2018, volume 18, issue 3 ta bl e 1: c om pa ri so n of m es en ch ym al s te m c el l s ou rc es a nd th ei r ch ar ac te ri st ic s7 ,9 – 30 so ur ce d iff er en ti at io n po te nt ia l m et ho d of pr oc ur em en t a dv an ta ge s d is ad va nt ag es c li n ic al a pp li ca ti on s p ro li fe ra ti on ca pa ci ty o th er bm 7, 9– 12 ,3 0 • a di po cy te s • a st ro cy te s • c ar di om yo cy te s • c ho nd ro cy te s • h ep at oc yt es • m es an gi al c el ls • m us cl e ce lls • n eu ro ns • o st eo bl as ts • st ro m al c el ls • em br yo ni c tis su e is ol at ed fr om bm a sp ir at e • st em c el ls fr om th is so ur ce h av e th e po te nt ia l to d iff er en tia te in to he pa to cy te s, m uc h lik e a t m sc s. • th es e ce lls e xp re ss cy to ch ro m e p4 50 . • m ul tip le c lin ic al tr ia ls h av e co nfi rm ed th e sa fe ty a nd eff ec tiv en es s of th is ty pe o f st em c el l. • pr oc ur em en t o f ce lls fr om th is s ou rc e is o ft en p ai nf ul a nd ca rr ie s th e ri sk o f in fe ct io n. • c el l y ie ld a nd di ffe re nt ia tio n po te nt ia l is d ep en de nt o n do no r ch ar ac te ri st ic s (e .g . a ge ). • g en er at io n of p an cr ea tic c el ls in v it ro . • t re at m en t o f o rt ho pa ed ic co nd iti on s ch ar ac te ri se d by la rg e bo ne d ef ec ts , i nc lu di ng a rt ic ul ar ca rt ila ge r ep ai r an d os te oa rt hr iti s, rh eu m at oi d ar th ri tis , r ot at or c uff in ju ri es a nd te nd on , s pi na l c or d an d m en is cu s l es io ns . • bm -m sc s m ay a ls o be u se d to tr ea t n on -u ni on s, o st eo ne cr os is o f th e fe m or al h ea d an d to p ro m ot e gr ow th in o st eo ge ne si s im pe rf ec ta . • po te nt ia lly p ro m is in g tr ea tm en t fo r m yo ca rd ia l i nf ar ct io n, a s w el l a s g v h d , s le a nd m s. • in a ni m al m od el s, b m -m sc s ha ve b ee n st ud ie d in th e co nt ex t of a ut oi m m un e en ce ph al om ye lit is , as th m a, a lle rg ic r hi ni tis , p ul m on ar y fib ro si s an d pe ri ph er al n er ve re ge ne ra tio n. • m ea n do ub lin g tim e of 4 0 ho ur s. • pr ol ife ra tio n ca pa ci ty in cr ea se s af te r pa ss ag e si x. • c on ta ct in hi bi tio n of pr ol ife ra tio n. • se ne sc en ce b y pa ss ag e se ve n. • th is ty pe o f s te m c el l is th e m os t e xt en si ve ly in ve st ig at ed a nd is co ns id er ed to b e th e go ld st an da rd . a t 7, 9, 10 ,1 2, 13 ,3 0 • a di po cy te s • c ho nd ro cy te s • o st eo cy te s • m us cl e ce lls is ol at ed fr om lip os uc tio n, lip op la st y or lip ec to m y m at er ia ls • th is s ou rc e re su lts in th e is ol at io n of u p to 5 00 ti m es m or e st em c el ls th an b m (i. e. 5 × 10 3 c el ls fro m 1 g o f a t ). • a t is a cc es si bl e an d ab un da nt a nd s ec re te s se ve ra l a ng io ge ni c an d an tia po pt ot ic c yt ok in es . • th e im m un os up pr es si ve eff ec ts o f a t -m sc s ar e st ro ng er th an th os e of b m m sc s. • c el ls fr om th is s ou rc e ha ve in fe ri or o st eo ge ni c an d ch on dr og en ic po te nt ia l i n co m pa ri so n to b m -m sc s. • im m un os up pr es si ve g v h d th er ap y. • po te nt ia l f or c el lba se d th er ap y fo r ra di cu lo pa th y, m i a nd n eu ro pa th ic pa in . • c os m et ic /d er m at ol og ic al ap pl ic at io ns . • su cc es sf ul ly u se d in th e tr ea tm en t of s ke le ta l m us cl e in ju ri es , m en is cu s da m ag e an d te nd on , r ot at or c uff a nd pe ri ph er al n er ve r eg en er at io n. • m ea n do ub lin g tim e of 4 ± 1 d ay s (5 ± 1 d ay s fo r om en ta l f at ). • c el ls p ro lif er at e fa st er th an b m m sc s. • r eg io nde pe nd en t (s ub cu ta ne ou s) . d en ta l p ul p1 4– 17 • o do nt ob la st s • o st eo bl as ts • a di po cy te s • c ho nd ro cy te s • n eu ro ge ni c ce lls • m yo ge ni c ce lls is ol at ed fr om to ot h ex tr ac tio n (i. e. w is do m , ec to pi c or ev en d ec ay ed te et h) o r ro ot ca na l s ur ge ry m at er ia ls • a s de nt al s ur ge ri es a re fa ir ly c om m on , t he s ou rc e m at er ia ls fo r th es e ce lls a re ea si ly a cc es si bl e. • th e fr eq ue nc y of c ol on yfo rm in g ce lls fr om d en ta l pu lp is h ig h co m pa re d to th os e fr om b m (2 2– 70 co lo ni es v er su s 2. 4– 3. 1 co lo ni es /1 04 c el ls p la te d) . • th e pr oc ur em en t of th es e ce lls c an b e di ffi cu lt an d in va si ve . • ec to m es en ch ym al an d pe ri od on ta l t is su es aff ec t m sc p ro pe rt ie s. • o ro fa ci al , b on e an d ne ur al re ge ne ra tio n. • m ea n do ub lin g tim e of 3 0– 40 ho ur s. • th es e ce lls h av e an ec to m es en ch ym al o ri gi n (i. e. a re d er iv ed fr om ne ur al c re st c el ls ). • d en ta l p ul pde ri ve d st em c el ls c an d iff er en tia te in to m es en ch ym al li na ge s bo th in v it ro a nd in v iv o. • pc ym sc s ha ve r ec en tly at tr ac te d in te re st b ec au se of th ei r ne ur al a nd b on e di ffe re nt ia tio n po te nt ia l. • d en ta l p ul p an d pe ri od on ta l l ig am en t st ro m al c el ls a re th e m ai n ty pe s of c el ls . roberto berebichez-fridman and pablo r. montero-olvera review | e267 ta bl e 1 (c on td .): c om pa ri so n of m es en ch ym al s te m c el l s ou rc es a nd th ei r ch ar ac te ri st ic s7 ,9 – 30 so ur ce d iff er en ti at io n po te nt ia l m et ho d of pr oc ur em en t a dv an ta ge s d is ad va nt ag es c li n ic al a pp li ca ti on s p ro li fe ra ti on ca pa ci ty o th er bi rt hde ri ve d tis su es 7, 10 ,1 1, 18 ,2 1 u c bm sc s: • a di po cy te s • c ho nd ro cy te s w jm sc s: • d op am in er gi c ne ur on s • c ho nd ro cy te s is ol at ed fr om th e pl ac en ta , am ni on a nd u c b af te r bi rt h • th e be ne fit s of th is s ou rc e in cl ud es h ig h av ai la bi lit y an d th e av oi da nc e of in va si ve pr oc ed ur es a nd e th ic al is su es . • th es e st em c el ls de m on st ra te h ig he r ex pa ns io n an d en gr af tm en t ca pa ci ty th an b m -m sc s. • u c bm sc s al so p os se ss os te og en ic d iff er en tia tio n ca pa bi lit ie s. • u c bm sc s p ro du ce 2 .5 -f ol d m or e in su lin th an b m -m sc s. • u c bm sc s m ay no t h av e ad ip og en ic po te nt ia l. • in te rm s of os te og en es is p ot en tia l, th is s ou rc e is n ot a s us ef ul a s bm , b lo od o r th e liv er . u c bm sc s: • p an cr ea tic is le t c el l g en er at io n in v itr o. • su cc es sf ul tr ea tm en t f or g v h d an d sl e. w jm sc s: • t re at m en t o f m i. • pe ri ph er al n er ve r eg en er at io n. • m ea n do ub lin g tim e is 3 0 ho ur s (t hi s re m ai ns co ns ta nt fo r pa ss ag es 1 – 10 ). • m ul til ay er ed pr ol ife ra tio n. • u c bm sc s do n ot a ge o ve r pa ss ag es (i .e . se ne sc en ce ). • w jm sc s ha ve h ig h pr ol ife ra tiv e po te nt ia l. a f an d pl ac en ta 19 ,2 0 a fm sc s: • n eu ra l s te m ce lls (f or m in g n s) • a di po cy te s • o st eo bl as ts • c ho nd ro cy te s • h ep at oc yt es pm sc s: • pa nc re at ic c el ls o bt ai ne d fo llo w in g de liv er y • b ot h a fm sc s an d pm sc s ca n be h ar ve st ed w ith m in im al in va si ve ne ss . • n o cl in ic al tr ia ls h av e ye t b ee n co nd uc te d to as se ss th e sa fe ty a nd eff ec tiv en es s of th es e st em c el ls . a fm sc s: • po te nt ia l t re at m en t f or n er ve in ju ri es o r ne ur on al d eg en er at iv e di se as es . • b la dd er r eg en er at io n an d ki dn ey , lu ng , h ea rt , h ea rt v al ve , d ia ph ra gm , bo ne , c ar til ag e an d bl oo d ve ss el fo rm at io n. pm sc s: • t re at m en t f or s ki n an d oc ul ar di se as es , i nfl am m at or y bo w el di se as e, lu ng in ju ri es , c ar til ag e de fe ct s, d uc he nn e m us cu la r dy st ro ph y, s tr ok e an d d m . • pe ri ph er al n er ve r eg en er at io n. • h ig h se lfre ne w al ca pa ci ty (> 30 0 ce ll di vi si on s) . • d ou bl in g tim e of 36 h ou rs . • th es e ce lls m ai nt ai n a no rm al ka ry ot yp e, e ve n at la te p as sa ge s. • th e ph en ot yp e of th es e ce lls is s im ila r to th at o f bm -m sc s. • th es e ce lls p ro du ce im m un os up pr es si ve fa ct or s an d ex pr es s ce rt ai n hu m an e m br yo ni c st em ce ll m ar ke rs . pe ri ph er al bl oo d1 0, 12 ,2 1 • a di po cy te s • fi br ob la st s • o st eo bl as ts • o st eo cl as ts • c ho nd ro cy te s o bt ai ne d vi a de ns ity gr ad ie nt ce nt ri fu ga tio n • c ol on yfo rm in g effi ci en cy ra ng es fr om 1 .2 –1 3 co lo ni es pe r m ill io n m on on uc le ar c el ls . • a la rg e vo lu m e of b lo od an d, th er ef or e, a g re at er qu an tit y of m sc s ca n be co lle ct ed c om pa re d to b m m sc s (u p to 1 .9 1 ± 0. 21 m l of m ob ili se d pe ri ph er al b lo od yi el ds 1 97 .8 ± 2 4. 9 × 10 6 ce lls /m l ve rs us 2 1. 6 ± 2. 7 × 10 6 c el ls /m l of b m ). • th e am ou nt o f m sc s ob ta in ed fr om th is so ur ce v ar ie s gr ea tly (0 .0 01 – 0. 01 % ). • c el ls fr om th is s ou rc e ha ve lo w er o st eo ge ni c an d ch on dr og en ic po te nt ia l a nd h ig he r ad ip og en ic p ot en tia l th an b m -m sc s. • n o cl in ic al tr ia ls h av e be en c on du ct ed to as se ss th e sa fe ty a nd eff ec tiv en es s of th is ty pe o f s te m c el l. • in tr ac or on ar y in fu si on in a cu te o r ol d m yo ca rd ia l i nf ar ct io n. • c ho nd ra l a nd m en is cu s re ge ne ra tio n. • d ou bl in g tim e of 95 h ou rs . sources and clinical applications of mesenchymal stem cells state-of-the-art review e268 | squ medical journal, august 2018, volume 18, issue 3 ta bl e 1 (c on td .): c om pa ri so n of m es en ch ym al s te m c el l s ou rc es a nd th ei r ch ar ac te ri st ic s7 ,9 – 30 so ur ce d iff er en ti at io n po te nt ia l m et ho d of pr oc ur em en t a dv an ta ge s d is ad va nt ag es c li n ic al a pp li ca ti on s p ro li fe ra ti on ca pa ci ty o th er sy no vi um a nd sy no vi al fl ui d2 2, 23 • a di po cy te s • c ho nd ro cy te s • o st eo bl as ts is ol at ed fr om th e sy no vi um an d sy no vi al flu id • th es e ce lls h av e hi gh di ffe re nt ia tio n an d pr ol ife ra tio n ca pa ci ty . • c el ls fr om th is s ou rc e ar e su pe ri or to s ke le ta l m us cl e an d a t -m sc s. • th e ha rv es tin g of ce lls fr om th is s ou rc e re qu ir es a n in va si ve pr oc ed ur e. • in a ni m al m od el s, th es e ce lls h av e be en u se d to r ep ai r ch on dr al d ef ec ts an d fo r os te oa rt hr iti s an d lig am en t re ge ne ra tio n. • th es e ce lls r et ai n th ei r pr ol ife ra tiv e ab ili ty u p to pa ss ag e 10 . • c el ls fr om th is so ur ce h av e hi gh in vi tr o ex pa nd ab ili ty , di ffe re nt ia tio n po te nt ia l an d ep ito pe p ro fil e. en do m et ri um 24 ,2 5 • c ho nd ro cy te s • a di po cy te s • o st eo bl as ts • sm oo th m us cl e ce lls • m yo ca rd ia l c el ls • h ep at oc yt es is ol at ed fr om m en st ru al bl oo d or en do m et ri al bi op si es • if is ol at ed fr om m en st ru al bl oo d, th is s ou rc e is m in im al ly in va si ve . • u se o f t he se c el ls m ay fa ci lit at e un de rs ta nd in g of gy na ec ol og ic al d is ea se s su ch as e nd om et ri al c ar ci no m a an d en do m et ri os is . • th e po te nt ia l c lin ic al ap pl ic at io ns o f t he se st em c el ls a re li m ite d, as o nl y pr ec lin ic al st ud ie s ha ve b ee n co nd uc te d. • t re at m en t f or d uc he nn e m us cu la r dy st ro ph y, m us cl e re pa ir, lim b is ch ae m ia a nd m yo ca rd ia l in fa rc tio n. • o th er ap pl ic at io ns in cl ud e ty pe 1 d m , st ro ke , u lc er at iv e co lit is , en do m et ri os is , e nd om et ri al ca rc in om a, p el vi c pr ol ap se a nd ca rd ia c fa ilu re . • h ig h pr ol ife ra tio n ca pa ci ty o f 6 × 1 01 1 ce lls fr om a s in gl e ce ll. • d ou bl in g tim e of 18 – 36 h ou rs . • th es e ce lls ca n m ai nt ai n a re la tiv el y st ab le ka ry ot yp e ov er 4 0 pa ss ag es . • st em c el ls fr om th is so ur ce d em on st ra te si m ila r pr op er tie s to th os e of a t an d bm -m sc s. sk in 26 ,2 7 • c ho nd ra l c el ls • b on e ce lls • a di po cy te s • n eu ra l c el ls • g lia l c el ls • pa nc re at ic c el ls • sm oo th m us cl e ce lls c an b e ha rv es te d fr om h um an fo re sk in a nd sk in b io ps ie s • th es e ce lls h av e a hi gh pr ol ife ra tio n ra te ; i n pa rt ic ul ar , n eo na ta l s ki nde ri ve d m sc s ex hi bi t h ig he r pr ol ife ra tio n ra te s th an a t m sc s. • a n in va si ve p ro ce du re is r eq ui re d to o bt ai n th es e ce lls . • n o cl in ic al tr ia ls h av e ye t b ee n pe rf or m ed to an al ys e th e sa fe ty a nd eff ec tiv en es s of th is ty pe o f s te m c el l. • a pp lic at io ns in cl ud e ne ur al ti ss ue , pe ri ph er al n er ve , h ae m at op oi et ic lin ea ge a nd p an cr ea tic c el l a nd s ki n re ge ne ra tio n af te r in ju ry . • in su lin p ro du ct io n. • t re at m en t f or a lo pe ci a an d sp in al co rd in ju ri es . • b la dd er r ec on st ru ct io n. • h ig h pr ol ife ra tio n ra te . • d ou bl in g tim e of 7– 8 da ys . m us cl e2 8, 29 • b on e ce lls • a di po cy te s • c ho nd ro cy te s • m us cl e ce lls • n eu ra l c el ls • h ep at oc yt es • b lo od c el ls is ol at ed fr om s ke le ta l m us cl e tis su e • so m e su bt yp es o f th es e st em c el ls , s uc h as m yo en do th el ia l a nd tr au m at is ed m us cl em sc s, ar e ch ar ac te ri se d by lo ng te rm p ro lif er at io n an d hi gh se lfre ne w al . • m us cl em sc s ca n be ob ta in ed fr om v ir tu al ly a ny m us cl e in th e bo dy . • th e pr oc ur em en t o f th es e ce lls is u su al ly in va si ve . • b on e, c ho nd ra l a nd c ra ni of ac ia l re ge ne ra tio n. • t re at m en t o f r ot at or c uff te ar s an d ne rv e in ju ri es . • r eg en er at io n of s ke le ta l ( es pe ci al ly in m us cu la r dy st ro ph y ca se s an d af te r tr au m at ic in ju ri es ) a nd c ar di ac m us cl e. • v as cu la r re ge ne ra tio n, u ri na ry in co nt in en ce tr ea tm en t a nd r ep ai r of v ag in al ti ss ue . • h ig h pr ol ife ra tio n ra te . • d ou bl in g tim e of 40 h ou rs . bm = b on e m ar ro w ; a t = a di po se ti ss ue ; m sc s = m es en ch ym al st em ce lls ; g v h d = g ra ftve rs us -h os t d is ea se ; s le = sy st em ic lu pu s e ry th em at os us ; m s = m ul tip le sc le ro sis ; m i = m yo ca rd ia l i nf ar ct io n; p c y = pe ri ap ic al c ys t; u c b = um bi lic al co rd b lo od ; w j = w ha rt on ’s je lly ; a f = am ni ot ic fl ui d; n s = ne ur os ph er es ; p = p la ce nt ade ri ve d; d m = d ia be te s m el lit us . roberto berebichez-fridman and pablo r. montero-olvera review | e269 myocyte loss to improve heart function and prevent end stage heart failure. although clinical trials in both human and animal models have been promising, a meta-analysis of 10 large-scale randomised phase two trials using bmderived cells showed negligible benefits after an acute myocardial infarction.35–42 in preclinical and clinical studies, intravenous, intracoronary or intramyocardial routes represent the main options for cell delivery within minutes to a few months after a myocardial infarction.37–42 however, protocol variations impede the accurate inter pretation of preclinical and clinical trial results.41,42 forest et al. compared cellular retention and engraftment with in vivo imaging in a porcine model using different admin istration routes.40 following an intracoronary injection, the safest and easiest delivery method, 34.8 ± 9.9% of cells were detected in the heart after one hour; this proportion declined precipitously to 6.0 ± 1.7% after 24 hours.40 inconsistent results regarding the benefits of bm cell therapy in cardiac function may be due to variability in cell survival, engraftment and differentiation.39 currently, several ongoing clinical trials are being conducted to establish the usefulness of bm-mscs, especially in the context of ischaemic heart failure. diastolic left ventricular (lv) dysfunction represents a frequent complication after acute myocardial infarction and a major risk factor for the development of heart failure, independent of preserved lv ejection fraction.41 schaefer et al. conducted a follow-up study of 60 patients with st-segment elevation acute myocardial infarction treated by bm-msc transfer.42 the time trend of the diastolic function and the e/a ratio remained unchanged in the experimental bm-msc group relative to the control group, in which the e/a ratio decreased over the course of 60 months. however, the duration of the improvement noted in the experimental group did not exceed five years.42 importantly, no arrhyth mogenic or tumourigenic effects have been observed in the treatment of myocardial infarction with bm-mscs.7 in allogeneic (i.e. haematopoietic) stem cell transpl antation, graft-versus-host disease (gvhd)—in which immunocompetent donor cells recognise and attack tissues in an immunocompromised host—is a significant cause of morbidity and mortality.11 traditional manage ment entails immunosuppression with corticosteroids as first-line therapy, a treatment that produces sustained responses in <40–50% of patients with gvhd.43 however, corticosteroid-refractory patients require effective secondand third-line treatment options.44 the allogeneic transplantation of bm-mscs can, when obt ained from major histocompatibility complex-matched donors (i.e. a mother or twin), induce immunosuppression in the recipient and thus be used to treat gvhd. this effect was initially evaluated in murine models wherein mscs inhibited naive and memory antigen-specific t cells.45 bm-mscs have also been used to treat systemic lupus erythematosus (sle), multiple sclerosis (ms), autoimmune encephalomyelitis, asthma, allergic rhinitis and pulmonary fibrosis. except for sle and ms, these applications have all been tested in animal models.7 the efficacy and safety of using bm-mscs in gvdh patients is being tested in on going clinical trials based on growing evidence highlighting the key role of bm-mscs in modulating inflammation.46 in the digestive system, bm-mscs can improve liver cirrhosis and liver failure caused by hepatitis b infections, with positive changes according to chronic liver disease staging and prognostic scales.47 other important applications of bm-mscs are in orthopaedics. for example, bm aspirates from the iliac crest have been used to treat atrophic diaphyseal non-unions, leading to callus formation.9,12 placing bm-mscs on scaffolds has been shown to regenerate meniscus tissue in rabbits and bm-mscs placed on conduits or grafts have been used to treat nerve defects, with better results than cell-depleted grafts.9 furthermore, bm-mscs have been transplanted to various injured tendon sites, resulting in enhanced tissue repair, especially for injuries of the patellar tendon.9 another important application of bm-mscs is in the treatment of spinal cord injuries. when mixed with minocycline, bm-mscs have resulted in improved spinal cord injuries in a rat model.9 as such, these cells may represent a promising approach for neuroprotection following spinal cord injury. bm-mscs have also been used to treat osteogenesis imperfecta in a mouse model, in which bm-mscs from a diseasefree mouse were infused into an affected mouse.9 this treatment promoted the differentiation of migrated cells into osteocytes and synthesised standard amounts of type i collagen, partially reverting the disease phenotype. other bm-msc applications include muscular dystrophy, physical defects and rotator cuff injuries.9 a d i p o s e t i s s u e the main advantage of using at as an msc source is convenience, as human subcutaneous at is usually abundant throughout the body and is a byproduct of cosmetic and therapeutic liposuction procedures. it is estimated that approximately 98–100% of cells obtained from at are viable.5,48 the morphological, phenotypical and functional characteristics of at-mscs are similar to those of bm-mscs.48 besides their stability in longterm cell cultures, at-mscs can expand effectively in vitro and possess high multilineage differentiation pot ential. the stromal vascular at fraction produces more stromal elements than the mononuclear bm fraction, sources and clinical applications of mesenchymal stem cells state-of-the-art review e270 | squ medical journal, august 2018, volume 18, issue 3 even though these stromal elements may represent other lineages, such as endothelial, haematopoietic and pericyclic origins.48–50 thus, at represents a more pract ical autologous source of mscs for tissue engineering than bm. however, one limitation of at-mscs is that certain donor characteristics, such as age, can affect the expansion and differentiation of at-mscs, particularly into osteogenic and chondrogenic lineages, although the adipogenic lineage is not affected.48 besides their ability to differentiate and self-renew, at-mscs secrete several cytokines and growth factors with anti-inflammatory, antiapoptotic and immunomodulatory properties. examples include vascular endo thelial growth factor, hepatocyte growth factor and insulin-like growth factor, all of which are involved in angiogenesis and tissue repair. these characteristics render at-mscs prime candidates for treating ischaemic diseases.5 additionally, due to the immunomodulatory effects of human at-mscs, at is an excellent source of mscs for allogeneic transplants and, as at-mscs do not express major histocompatibility complex type ii antigens, the risk of rejection is minimised.11 atmscs regulate the function of t cells by promoting the induction of suppressor t cells and inhibiting the production of cytotoxic t cells, natural killer cells and proinflammatory cytokines (including tumour necrosis factor-α, interferon-γ and interleukin [il]-12). furthermore, these cells secrete soluble factors, such as il-10, transforming growth factor-β and prostaglandin e2, making these cells immunosuppressive.5,11 it should be noted that the p53 protein plays a key role in the differentiation of human at-mscs cells, affecting their osteogenic and adipogenic potential by suppressing the osterix, runt-related transcription factor and peroxisome proliferator-activated receptor (ppar) genes.51 in various malignancies, p53 function is limited, thus offering the possibility of using cancer cells from mutant mscs to investigate treatment targets.51,52 a recent study by inatani et al. compared the differentiation potential of mscs from normal at and atypical lipomatous tumour/well-differentiated liposarcoma (alt/wdl).49 the osteogenic differentiation potential in alt/wdl-mscs was greater than that of the normal at group, although normal at produced more fatty acid droplets during adipogenic differentiation than alt/wdl.49 this type of study offers an interesting approach to therapeutics in that it postulates using differentiation as a means of treatment. this concept has also been explored with the use of troglitazone in patients with liposarcoma, defective proliferation, apoptosis and differentiation.50 histological tumour changes were observed in a small follow-up study of patients with myxoid and pleomorphic liposarc omas; six months after the administration of ppar-γ ligand, troglitazone, the researchers observed microves icular cytoplasmic lipid accumulation and diminished proliferation according to ki-67 expression.50 although imaging indicated that the tumour size increased as a result of intracellular lipid accumulation, with a corresponding increase in cellular volume, no new tumour sites were found. thus, it may be possible to modify the pathophysiology of cancer and reduce the proliferation of malignant cells by promoting cellular differentiation.50 additionally, at-mscs may be useful for myocardial regeneration. in one trial, at-msc application resulted in improved cardiac function, elevated per fusion and a reduction in the extension of scar tissue.7 at-mscs have also been used extensively for dermatological and cosmetic purposes. these cells promote wound healing by enhancing the secretion of type i collagen, upregulating the expression of type iii collagen and fibronectin and downregulating matrix metallopro teinase-1 in fibroblasts.13 they have also been shown to accelerate granulation tissue and capillary formation and epithelisation in dm-induced tissue damage. more over, at-mscs have been used for wrinkle reduction, skin whitening (by inhibiting melanin synthesis), as anti oxidants and for the promotion of hair growth.13 furthermore, at-mscs have accelerated skeletal muscle regeneration in a rat model.9 interestingly, at mscs express various neuronal and schwann cell markers, such as myelin protein zero, myelin basic protein and peripheral myelin 22, suggesting that they may possess a myelin-generating capacity. these cells have also been used to treat nerve defects and neuropathic pain in rats with promising results.9 finally, at-mscs have been used to treat collagenase-induced tendinitis in horses, improving tendon organisation and successfully treating rotator cuff injuries.9 d e n ta l p u l p dental pulp (dp)-derived mscs specialise into odont oblasts, which produce dentin.14 these cells are obtained from pulp tissue from the third molar and are extracted by an enzymatic digestive process. overall, dp-mscs are easy to cryopreserve and, similarly to at-mscs, possess immunomodulatory properties.14 since dpmscs are derived from the neural crest, they have ectomesenchymal origins and both ectodermal and mesenchymal lineages. hence, in addition to differentiating into osteo/chondroblasts and adipocytes, dp mscs can also differentiate into neuronal lineages. when cultured in a three-dimensional (3d) dentin scaffold, dp-mscs can differentiate into corneal epithelial cells, melanocytes and induced pluripotent stem cells, rendering them highly useful in regenerative medicine research.14,15,53 roberto berebichez-fridman and pablo r. montero-olvera review | e271 the most promising clinical applications for this stem cell source involve the correction of metabolic diseases and the treatment of liver diseases with high mortality rates, such as cirrhosis and hepatocellular carcinoma.54,55 over time, dp-mscs have become the preferred alternative to harvesting stem cells during hepatic transplantation.15 dp-mscs have also been used in the field of bone regeneration. when dp-mscs are cultured on hydrogels, they can spontaneously differ entiate into both odontogenic and osteogenic phenotypes.55,56 a specific type of dp-mscs, known as periapical cyst (pcy)-mscs, have gained special attention because of their extensive proliferative potential, cell surface marker profile and ability to differentiate into various cell types, such as osteoblasts, adipocytes and neurons.16,17,55,56 importantly, these cells are easily collected from surgically removed pcys, thus allowing for the reuse of biological waste. they have also been used in the field of bone regeneration. due to their neural plasticity, these cells represent an interesting option for treating neurodegenerative diseases.16 b i r t h-d e r i v e d t i s s u e s currently, umbilical cord blood (ucb) is not universally accepted as a source of mscs.57 nevertheless, the vast abundance of ucb, availability of donors, ease of procurement and reliability of sample collection and lack of transmission of herpesviridae viruses are advantages of this particular cell source.57 furthermore, as ucb mscs are less mature than other types of adult stem cells, they do not elicit a strong immune rejection response in an allogeneic recipient, tolerating mismatches of hlas. conveniently, ucb-mscs can be cryopreserved in vast quantities for later cultivation and research.57 the doubling time of these cells is similar to that of bm-mscs (i.e. every 30 hours). overall, ucb-mscs possess osteogenic, chondrogenic, adipogenic and myo genic differentiation potential.57 in humans, the intrav enous administration of ucb-mscs has been successfully used to treat gvhd and sle.11 additionally, ucb mscs have been implanted to treat sciatic nerve defects and in post-crush and transection animal models with good results.9 recently, wharton’s jelly (wj) has garnered attention as a potential source of mscs. the properties of wj mscs are different from those derived from other sources, with wj-mscs exhibiting a higher proliferative potential independent of culture conditions.18 never theless, when cultured in the presence of serum, these cells produce fewer extracellular matrix components than bm-mscs and at-mscs. in terms of clinical applications, wj-mscs have been shown to be beneficial and safe in the treatment of myocardial infarctions, positively affecting the size of the infarction and lv function.7 in one study, human wj-mscs were placed on a 3d scaffold in a conditioned medium obtained from a culture of human articular chondrocytes.18 the wj mscs underwent chondrogenic differentiation without the need for growth factors, with a high accumulation of glycosaminoglycans and expression of cartilage-related genes. these observations indicate that wj-mscs may be a good option for regenerating articular cartilage.18 a m n i o t i c f l u i d a n d p l a c e n ta according to immunophenotypical analyses, the pheno type of cultured cells obtained from amniotic fluid (af) is similar to that of bm-mscs.58 cultured cells obtained from this source can differentiate into mesenchymal lineages. the expansion of afand amnion-derived mscs is similar, with no marked differences in cell counts, although the latter grow at a slower pace and with a lower yield than bm-mscs.19,58 af-mscs demonstrate high self-renewal capacity (>300 cell divisions) and a doubling time of 36 hours. furthermore, they have been shown to maintain a normal karyotype even at late passages.58 interestingly, af-mscs express octamer-binding transcription factor-4 (oct-4) and stage-specific embryonic antigen-4 (ssea-4) human embryonic stem cell markers, which is typical for underdifferentiated embryonic stem cells; this means that af-mscs are not primitive embryonic stem cells but maintain greater differentiation potential than most adult stem cells.19,58 in addition to common mesodermal lineages, af-mscs can also differentiate into hepatocytes and neurons under specific culture conditions.19 while no human investigations using af-mscs have yet been reported, several animal models have studied various clinical applications, including bladder formation using af-mscs differentiated into muscle cells, the treatment of nerve injuries, blood vessel and heart valve formation and regeneration of the diaphragm, kidney, bone, lung, heart and cartilage.19,20,58 as with ucb-mscs, af-mscs have also been successfully implanted in sciatic nerve defects and post-crush and transection animal models.9 the basement membrane of the amnion contains mscs derived from the inner cell mass of blastocysts. in addition to not expressing hla class ii, human amnion derived mscs possess immunosuppressive factors.58 other parts of the placenta, such as the decidua basalis and decidua parietalis, also contain mscs; upon cultiv ation, these cells exhibit similar characteristics to amnionderived mscs. placenta-derived mscs (p-mscs) also express embryonic stem cell markers such as c-kit, sex determining region y-box 2, oct-4 and ssea-4 and are able to differentiate into mesenchymal as well sources and clinical applications of mesenchymal stem cells state-of-the-art review e272 | squ medical journal, august 2018, volume 18, issue 3 as hepatic, pancreatic and neuronal lineages.59 p-mscs have been shown to improve lung function and reduce pulmonary fibrosis in animal models and have been used in the treatment of skin and ocular diseases.20,59 interestingly, these cells have also been used to create an artificial amnion within a collagen scaffold.19 other clinical applications of p-mscs in animal models incl ude the formation of cardiac tissue and treatment of bleomycin-induced lung injuries, cartilage defects, inflammatory bowel disease, duchenne muscular dys trophy, ischaemic stroke, inflammation and dm.20 one of the main benefits of p-mscs is that they can be easily obtained following delivery without the need for a specific procedure; they also offer distinct advantages in terms of proliferation and plasticity.20 m o b i l i s e d p e r i p h e r a l b l o o d specific factors that control haematopoiesis were initially identified by their ability to support progenitor cells in culture assays. these factors have since been isolated and purified, allowing for the development of therapeutic agents, including colony-stimulating factors (csfs).60,61 filgrastim, a granulocyte-csf, is a bacterially-synthesised recombinant protein that acts on neutrophils. it was first used in cancer patients in 1991 as an adjunct for ameliorating chemotherapy-induced neutropaenia. filgrastim has since been approved in over 70 countries for mobilising peripheral blood progenitor cells for transplantation.60,61 granulocyte-csf binds selectively to specific cell-surface receptors, triggering the phosphorylation of janus kinase (jak)1 and jak2 protein tyrosine kinases and activating the ras/mitogen-activated protein kinase pathway. a subcutaneous dose of filgrastim (10 µg/kg) results in a six-fold increase in neutrophil levels within 24–48 hours.62 furthermore, filgrastim treatment reduces the neutrophil maturation time from five days to one day.61,62 peripheral blood stem cells may be mobilised from healthy donors using granulocyte-csfs.9 the underlying mechanism involves a number of adhesion molecules, including lymphocyte function-associated antigen 1, very late antigen-4, c-x-c motif chemokine receptor 4, c-kit, cd44 and macrophage-1. these molecules facil itate the binding of stem cells to bm and their disruption allows for their release into the circulation. while the underlying mechanism is unclear, this process is mainly regulated by cytokines.63,64 as a replacement for bm-mscs, granulocytecsf-mobilised peripheral blood stem cells are convenient and easily accessible. they are similar to bmmscs in most aspects, as they can differentiate into mesenchymal lineages and have a strong capacity to adhere to plastic culture flasks.21 however, mscs mobilised from the blood using granulocyte-csf exhibit a 95-hour duplication time, which is longer than that of mscs from other sources. moreover, they adhere in a monolayer and to different scaffolds.21 their surface expression profile is similar to that of bm-mscs with specific msc markers. their capability to differentiate into chondral and bone lineages is lower than that of bm-mscs, while their capability to differentiate into an adipose lineage is higher.21 as yet, no clinical trial on the use of these cells has been published. s y n o v i u m a n d s y n o v i a l f l u i d in humans, cartilage and synovium originate from a common pool of cells during synovial joint development. in the treatment of musculoskeletal injuries, synovial mscs are an attractive method of meniscus regeneration. synovium-derived mscs (s-mscs) are far superior to cells derived from the skeletal muscle and at, as determined by their in vitro expandability, differentiation potential and epitope profiles.65 when replated at a density of 50 cells/cm2, these cells retain their proliferative ability up to passage 10, whereas cells from other sources proliferate only until passage seven. furthermore, these cells possess remarkable adipogenic, chondrogenic and osteogenic potential comparable to that of bmand periosteum-derived mscs.65 interestingly, in vivo evidence suggests that the intra-articular injection of endogenous cells from the synovial membrane can contribute to the repair of partial-thickness cartilage defects in a mouse injury model.22 s-mscs have also promoted ligament regeneration in another animal model.23 interestingly, in one study, when s-mscs were implanted into the deeper aspect of an osteochondral defect, they differentiated into osteocytes; however, when they were implanted into the superficial aspect, the cells differentiated into chondrocytes.9 these observations suggest that the microenvironment may play an important role in the multilineage differ entiation potential of mscs.9 furthermore, s-mscs may play a role in the endogenous repair of intra-articular injuries because the number of s-mscs in synovial fluid are elevated in patients with osteoarthritic knees, cartilage defects, meniscus damage or intra-articular ligament injuries.9 e n d o m e t r i u m in 2004, chan et al. hypothesised that because the human endometrium regenerates from the lower basalis layer, it might contain small populations of epithelial and stromal cells that exhibit clonogenicity.66 human clonogenic endometrial cells exhibit the same in vitro properties as bm-mscs. human endometrial stromal cell cultures can differentiate in vitro, unlike other non endometrial gynaecological tissues.67,68 roberto berebichez-fridman and pablo r. montero-olvera review | e273 there are three types of endometrial stem cells (enscs): epithelial progenitor cells, mscs and endothelial progenitor cells.68 enscs can be isolated from the menstrual blood or from endometrial biopsies without the need for invasive procedures.68,69 furthermore, enscs have similar properties to those of atand bm derived mscs. the functional dysregulation of these cells may contribute to a range of pathologies, from endometriosis to endometrial carcinomas.24 the prolif eration potential of enscs is 6 × 1011 cells from a single cell and these cells can differentiate into adipogenic, chondrogenic and osteogenic lineages.67,68 enscs have several clinical applications, albeit limited to preclinical studies. current models include duchenne muscular dystrophy, muscle repair by ensc transplantation into atrophied muscle fibres, limb ischaemia and myocardial infarction.68 the proliferative ability of menstrual blood-derived mscs (men-mscs) is very high and they can maintain a relatively stable karyotype over 40 passages. the doubling time of these cells is 18–36 hours, which is fast when compared with other types of mscs.69–71 men-mscs can be induced into multiple lineages, including chondrocytes, osteoblasts, adipocytes, smooth muscle cells, myo cardial cells and hepatocytes. in an animal model of type 1 dm, the intravenous administration of these cells improved hyperglycaemia.72 in another animal model, men-mscs were shown to secrete various neuroprotective factors (e.g. vascular endothelial growth factor and brain-derived neurotrophic factor) which promote neuron survival and mitigate behavioural and histolog ical changes, making them applicable for stroke treatment.25 other potential applications of men-mscs include ulcerative colitis, endometriosis, endometrial carcinomas, pelvic organ prolapse and cardiac failure.25 s k i n skin-derived precursors are able to differentiate into both neural and mesodermal cells. these cells can be harvested from the human foreskin or even from skin biopsies.73 when cultured, they differentiate into neurons, glia and smooth muscle cells, including cells of the peripheral neural phenotype (consistent with cells originating from the neural crest), but hold limited potential for mesen chymal lineage differentiation.26,73 one of the main adv antages of this cell type is its proliferation rate. the skinderived mscs (s-mscs) of human newborns exhibit a higher proliferation rate during long-term cultures than human at-mscs and skin stromal cells.68,73 furthermore, stem cells can be obtained from several regions of the skin, including the epidermis (epidermal stem cells), interfollicular epidermis, hair follicles, sebaceous glands and subcutaneous at. each of these stem cell types expresses different markers.26,27 although s-mscs are able to differentiate into neurons, from a functional point of view, these cells present an immature electrophysiological profile.27 the implantation of s-mscs into an adult mouse brain led to the discovery that these cells are capable of differentiating into astrocytes as well as insulinproducing pancreatic cells.27 an important application of s-mscs is skin regeneration after serious skin damage, such as that caused by burns, chronic ulcers and deep wounds, as well as anti-ageing therapy and repigmentation in vitiligo, alopaecia and melanoma cases. other potential clinical applications of s-mscs currently being studied include spinal cord injuries, regeneration of the haematopoietic lineage after radiotherapy, bladder reconstruction and alopecia.27 undifferentiated hair follicle stem cells have also been used in murine models of sciatic and tibial nerve tran sections and crush injuries, with the animals exhibiting improved functional outcomes after cell administration.9 m u s c l e the skeletal muscle and bone share a common mesodermal origin and these tissues exhibit regenerative capacities due to the presence of endogenous muscle stem cells, satellite cells and skeletal stem cells.74 it is important to distinguish between satellite cells and muscle-derived mscs (m-mscs), as the former are committed to a myogenic lineage while the latter are satellite cell predecessors capable of multilineage differentiation. other subtypes of m-mscs include myoendothelial cells—which express surface markers of both endothelial and satellite cells—and traumatised m-mscs which are rapidly adherent.74 m-mscs differ entiate into mesenchymal tissues, including osteogenic, myogenic and even chondrogenic lineages. the most important and extensively researched clinical application of this cell type is for use in the treatment of muscular dystrophy.75 overall, m-mscs have many clinical applications; for instance, upon transfection with the bone morphogenetic protein-4 gene, m-mscs were able to differentiate into osteoblasts and fill a critical femoral defect in an animal model.28 these cells have also been used in a similar fashion for craniofacial regeneration. in an animal model, the implantation of m-mscs with fibrin glue directly into osteochondral defects resulted in persistent repair of the defect site after 24 weeks.29 these cells, when differentiated, express type ii collagen and proteoglycan-rich extracellular matrix. m-mscs may also promote peripheral nerve reg eneration, as shown in animal models of sciatic nerve injuries.9 another therapeutic application of m-mscs is the promotion of skeletal and cardiac muscle regen sources and clinical applications of mesenchymal stem cells state-of-the-art review e274 | squ medical journal, august 2018, volume 18, issue 3 eration. several studies have supported the possibility that m-mscs can augment muscle healing following injury; another study found that the injection of m-mscs into the infarcted region of cardiac tissue resulted in improved function.28 additionally, m-mscs can mediate a secondary mechanism of regeneration by promoting angiogenesis.28,30 other potential applications of m-mscs include vascular regeneration, the treatment of urinary incontinence and the repair of vaginal tissue. m-mscs have also been successfully used for treating rotator cuff injuries.9 legal implications and future research the wide array of possibilities engendered by stem cell therapy have generated expectations that exceed our current understanding and regulations regarding their use. to meet these expectations, the food and drug administration (fda) in the usa has advocated further studies to assess the risks and benefits of stem cell therapy and develop evidence-based therapeutic approaches.76 thus far, the fda has only approved stem cell treatments sourced from bm aspirate concentrate.9 while haematopoietic reconstitution using bmor peripheral blood-derived mscs is a well-known, safe and effective treatment, there is a lack of research regarding the safety and efficacy of other sources of mscs. in some cases, these sources may be used with only minimal clinical evidence.76–78 some of the arguments used to justify these practices include the capacity of mscs to repair damage; the extremely high cost of clinical trials necessitating large industrial sponsors; and the assumption that stem cell therapies are safe, especially when derived from an auto logous source.76,77 the modern clinician should under stand the basis of regenerative medicine, the clinical options at their disposal and the potential of such therapies to drive medical decisions. however, they must also protect patients from pseudomedical treatments that have been widely popularised to constitute stem cell therapies. most clinical options for stem cell therapy focus on chronic conditions because of the relatively slow pace of transplantable stem cell generation. in general, such procedures require the procurement, isol ation, expansion, differentiation and implantation of a sufficient number of cells before a therapeutic response is noted.76–78 in different countries, regulations for regenerative medicine products allow for exceptions to long established safety rules. for example, in japan, such products can be marketed based on preliminary evid ence and are only required to meet reduced thresholds for therapeutic efficacy.74 in the usa, the 21st century cures act of 2016 saw the inception of the term ‘regenerative advanced therapy’ for the purpose of expediting regulatory processes.77 nevertheless, clinical trials should be performed to ensure the safe and effective use of therapies involving mscs, regardless of cell source or clinical application. moreover, specific laws should be implemented for further control over the use of these cells.78 in the future, once the aforementioned challenges have been resolved, it might be possible to replicate the exact function of native tissues by differentiating mscs identical to the organs in need of replacement. furthermore, the differentiation process might be perf ormed in vivo, leading to standardised stem cell therapies for various ailments. conclusion although bm-mscs have been the main source of stem cells for many years, the inconvenience and risk of procuring these cells has fuelled research for alternative and more practical sources. as shown in this review, mscs have many clinical applications, with an important role in almost all medical and surgical specialties. it is important to recognise that the therapeutic use of mscs is not an unrealistic goal, as stem cells already offer a promising option in the treatment of several diseases. nevertheless, the safety and efficacy of all types of mscs, regardless of source, should be carefully assessed prior to their application, first in animal models and subsequently in clinical trials. references 1. choo a, ngo as, ding v, oh s, kiang ls. autogeneic feeders for the culture of undifferentiated human embryonic stem cells in feeder and feeder-free conditions. methods cell biol 2008; 86:15–28. doi: 10.1016/s0091-679x(08)00002-2. 2. hiew vv, simat sfb, teoh pl. the advancement of biomaterials in regulating stem cell fate. stem cell rev 2018; 14:43–57. doi: 10.1007/s12015-017-9764-y. 3. lv fj, tuan rs, cheung km, leung vy. concise review: the surface markers and identity of human mesenchymal stem cells. stem cells 2014; 32:1408–19. doi: 10.1002/stem.1681. 4. wei x, yang x, han zp, qu ff, shao l, shi yf. mesenchymal stem cells: a new trend for cell therapy. acta pharmacol sin 2013; 34:747–54. doi: 10.1038/aps.2013.50. 5. liras a. future research and therapeutic applications of human stem cells: general, regulatory, and bioethical aspects. j transl med 2010; 8:131. doi: 10.1186/1479-5876-8-131. 6. stanko p, kaiserova k, altanerova v, altaner c. comparison of human mesenchymal stem cells derived from dental pulp, bone marrow, adipose tissue, and umbilical cord tissue by gene expression. biomed pap med fac univ palacky olomouc czech repub 2014; 158:373–7. doi: 10.5507/bp.2013.078. https://doi.org/10.1016/s0091-679x%2808%2900002-2 https://doi.org/10.1007/s12015-017-9764-y https://doi.org/10.1002/stem.1681 https://doi.org/10.1038/aps.2013.50 https://doi.org/10.1186/1479-5876-8-131 https://doi.org/10.5507/bp.2013.078 roberto berebichez-fridman and pablo r. montero-olvera review | e275 7. majka m, sułkowski m, badyra b, musiałek p. concise review: mesenchymal stem cells in cardiovascular regeneration emerging research directions and clinical applications. stem cells transl med 2017; 6:1859–67. doi: 10.1002/sctm.16-0484. 8. dominici m, le blanc k, mueller i, slaper-cortenbach i, marini f, krause d, et al. minimal criteria for defining multipotent mesenchymal stromal cells: the international society for cellular therapy position statement. cytotherapy 2006; 8:315–17. doi: 10.1080/14653240600855905. 9. berebichez-fridman r, gómez-garcía r, granados-montiel j, berebichez-fastlicht e, olivos-meza a, granados j, et al. the holy grail of orthopedic surgery: mesenchymal stem cells their current uses and potential applications. stem cells int 2017; 2017:2638305. doi: 10.1155/2017/2638305. 10. cheng hy, ghetu n, wallace cg, wei fc, liao sk. the impact of mesenchymal stem cell source on proliferation, differentiation, immunomodulation and therapeutic efficacy. j stem cell res ther 2014; 4:237. doi: 10.4172/2157-7633.1000237. 11. cagliani j, grande d, molmenti ep, miller ej, rilo hlr. immunomodulation by mesenchymal stromal cells and their clinical applications. j stem cell regen biol 2017; 3:1–26. doi: 10.15436/2471-0598.17.022. 12. mafi r, hindocha s, mafi p, griffin m, khan ws. sources of adult mesenchymal stem cells applicable for musculoskeletal applications: a systematic review of the literature. open orthop j 2011; 5:242–8. doi: 10.2174/1874325001105010242. 13. yang ja, chung hm, won ch, sung jh. potential application of adipose-derived stem cells and their secretory factors to skin: discussion from both clinical and industrial viewpoints. expert opin biol ther 2010; 10:495–503. doi: 10.1517/14712591003610598. 14. gronthos s, mankani m, brahim j, robey pg, shi s. postnatal human dental pulp stem cells (dpscs) in vitro and in vivo. proc natl acad sci u s a 2000; 97:13625–30. doi: 10.1073/pnas.240 309797. 15. kushnerev e, shawcross sg, sothirachagan s, carley f, brahma a, yates jm, et al. regeneration of corneal epithelium with dental pulp stem cells using a contact lens delivery system. invest ophthalmol vis sci 2016; 57:5192–9. doi: 10.1167/iovs.15-17953. 16. tatullo m, codispoti b, pacifici a, palmieri f, marrelli m, pacifici l, et al. potential use of human periapical cyst-mesenchymal stem cells (hpcy-mscs) as a novel stem cell source for regenerative medicine applications. front cell dev biol 2017; 5:103. doi: 10.3389/fcell.2017.00103. 17. vasandan ab, shankar sr, prasad p, sowmya jahnavi v, bhonde rr, jyothi prasanna s. functional differences in mesenchymal stromal cells from human dental pulp and periodontal ligament. j cell mol med 2014; 18:344–54. doi: 10.1111/jcmm.12192. 18. alves da silva ml, costa-pinto ar, martins a, correlo vm, sol p, bhattacharya m, et al. conditioned medium as a strategy for human stem cells chondrogenic differentiation. j tissue eng regen med 2015; 9:714–23. doi: 10.1002/term.1812. 19. joo s, ko ik, atala a, yoo jj, lee sj. amniotic fluid-derived stem cells in regenerative medicine research. arch pharm res 2012; 35:271–80. doi: 10.1007/s12272-012-0207-7. 20. pipino c, shangaris p, resca e, zia s, deprest j, sebire nj, et al. placenta as a reservoir of stem cells: an underutilized resource? br med bull 2013; 105:43–68. doi: 10.1093/bmb/lds033. 21. tondreau t, meuleman n, delforge a, dejeneffe m, leroy r, massy m, et al. mesenchymal stem cells derived from cd133positive cells in mobilized peripheral blood and cord blood: proliferation, oct4 expression, and plasticity. stem cells 2005; 23:1105–12. doi: 10.1634/stemcells.2004-0330. 22. mak j, jablonski cl, leonard ca, dunn jf, raharjo e, matyas jr, et al. intra-articular injection of synovial mesenchymal stem cells improves cartilage repair in a mouse injury model. sci rep 2016; 6:23076. doi: 10.1038/srep23076. 23. mcgonagle d, jones e. a potential role for synovial fluid mesenchymal stem cells in ligament regeneration. rheumatology (oxford) 2008; 47:1114–16. doi: 10.1093/rheumatology/ken236. 24. gargett ce, masuda h. adult stem cells in the endometrium. mol hum reprod 2010; 16:818–34. doi: 10.1093/molehr/gaq061. 25. xu y, zhu h, zhao d, tan j. endometrial stem cells: clinical application and pathological roles. int j clin exp med 2015; 8:22039–44. 26. toma jg, mckenzie ia, bagli d, miller fd. isolation and characterization of multipotent skin-derived precursors from human skin. stem cells 2005; 23:727–37. doi: 10.1634/stemcells. 2004-0134. 27. niezgoda a, niezgoda p, nowowiejska l, białecka a, męcińskajundziłł k, adamska u, et al. properties of skin stem cells and their potential clinical applications in modern dermatology. eur j dermatol 2017; 27:227–36. doi: 10.1684/ejd.2017.2988. 28. jackson wm, nesti lj, tuan rs. potential therapeutic applic ations of muscle-derived mesenchymal stem and progenitor cells. expert opin biol ther 2010; 10:505–17. doi: 10.1517/147 12591003610606. 29. gates cb, karthikeyan t, fu f, huard j. regenerative medicine for the musculoskeletal system based on muscle-derived stem cells. j am acad orthop surg 2008; 16:68–76. 30. hass r, kasper c, böhm s, jacobs r. different populations and sources of human mesenchymal stem cells (msc): a comparison of adult and neonatal tissue-derived msc. cell commun signal 2011; 9:12. doi: 10.1186/1478-811x-9-12. 31. friedenstein aj. precursor cells of mechanocytes. int rev cytol 1976; 47:327–59. 32. friedenstein aj, chailakhyan rk, gerasimov uv. bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. cell tissue kinet 1987; 20:263–72. 33. kern s, eichler h, stoeve j, klüter h, bieback k. comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. stem cells 2006; 24:1294–301. doi: 10.1634/stemcells.2005-0342. 34. penn ms, swaminath d. novel role of bone marrow stem cells in systemic disease. circ res 2015; 117:119–20. doi: 10.1161/ circresaha.117.306852. 35. jackson l, jones dr, scotting p, sottile v. adult mesenchymal stem cells: differentiation potential and therapeutic applications. j postgrad med 2007; 53:121–7. doi: 10.4103/0022-3859.32215. 36. lipinski mj, biondi-zoccai gg, abbate a, khianey r, sheiban i, bartunek j, et al. impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. j am coll cardiol 2007; 50:1761–7. doi: 10.1016/j.jacc.2007.07.041. 37. lloyd-jones d, adams rj, brown tm, carnethon m, dai s, de simone g, et al. heart disease and stroke statistics: 2010 update a report from the american heart association. circul ation 2010; 121:e46–215. doi: 10.1161/circulationaha. 109.192667. 38. segers vf, lee rt. stem-cell therapy for cardiac disease. nature 2008; 451:937–42. doi: 10.1038/nature06800. 39. nguyen pk, lan f, wang y, wu jc. imaging: guiding the clinical translation of cardiac stem cell therapy. circ res 2011; 109:962–79. doi: 10.1161/circresaha.111.242909. 40. forest vf, tirouvanziam am, perigaud c, fernandes s, fusellier ms, desfontis jc, et al. cell distribution after intracoronary bone marrow stem cell delivery in damaged and undamaged myocardium: implications for clinical trials. stem cell res ther 2010; 1:4. doi: 10.1186/scrt4. https://doi.org/10.1002/sctm.16-0484 https://doi.org/10.1080/14653240600855905 https://doi.org/10.1155/2017/2638305 https://doi.org/10.4172/2157-7633.1000237 https://doi.org/10.15436/2471-0598.17.022 https://doi.org/10.2174/1874325001105010242 https://doi.org/10.1517/14712591003610598 https://doi.org/10.1073/pnas.240309797 https://doi.org/10.1073/pnas.240309797 https://doi.org/10.1167/iovs.15-17953 https://doi.org/10.3389/fcell.2017.00103 https://doi.org/10.1111/jcmm.12192 https://doi.org/10.1002/term.1812 https://doi.org/10.1007/s12272-012-0207-7 https://doi.org/10.1093/bmb/lds033 https://doi.org/10.1634/stemcells.2004-0330 https://doi.org/10.1038/srep23076 https://doi.org/10.1093/rheumatology/ken236 https://doi.org/10.1093/molehr/gaq061 https://doi.org/10.1634/stemcells.2004-0134 https://doi.org/10.1634/stemcells.2004-0134 https://doi.org/10.1684/ejd.2017.2988 https://doi.org/10.1517/14712591003610606 https://doi.org/10.1517/14712591003610606 https://doi.org/10.1186/1478-811x-9-12 https://doi.org/10.1634/stemcells.2005-0342 https://doi.org/10.1161/circresaha.117.306852 https://doi.org/10.1161/circresaha.117.306852 https://doi.org/10.4103/0022-3859.32215 https://doi.org/10.1016/j.jacc.2007.07.041 https://doi.org/10.1161/circulationaha.109.192667 https://doi.org/10.1161/circulationaha.109.192667 https://doi.org/10.1038/nature06800 https://doi.org/10.1161/circresaha.111.242909 https://doi.org/10.1186/scrt4 sources and clinical applications of mesenchymal stem cells state-of-the-art review e276 | squ medical journal, august 2018, volume 18, issue 3 41. poulsen sh, jensen se, egstrup k. longitudinal changes and prognostic implications of left ventricular diastolic function in first acute myocardial infarction. am heart j 1999; 137:910–18. doi: 10.1016/s0002-8703(99)70416-3. 42. schaefer a, zwadlo c, fuchs m, meyer gp, lippolt p, wollert kc, et al. long-term effects of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: 5-year results from the randomized-controlled boost trial an echocardiographic study. eur j echocardiogr 2010; 11:165–71. doi: 10.1093/ejechocard/jep191. 43. saliba rm, de lima m, giralt s, andersson b, khouri if, hosing c, et al. hyperacute gvhd: risk factors, outcomes, and clinical implications. blood 2006; 109:2751–8. doi: 10.1182/ blood-2006-07-034348. 44. le blanc k, rasmusson i, sundberg b, götherström c, hassan m, uzunel m, et al. treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. lancet 2004; 363:1439–41. doi: 10.1016/s0140-6736(04)16104-7. 45. krampera m, glennie s, dyson j, scott d, laylor r, simpson e, et al. bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific t cells to their cognate peptide. blood 2003; 101:3722–9. doi: 10.1182/blood-2002-07-2104. 46. wang lt, ting ch, yen ml, liu kj, sytwu hk, wu kk, et al. human mesenchymal stem cells (mscs) for treatment towards immuneand inflammation-mediated diseases: review of current clinical trials. j biomed sci 2016; 23:76. doi: 10.1186/s12929016-0289-5. 47. houlihan dd, hopkins lj, suresh sx, armstrong mj, newsome pn. autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis b: short-term and long term outcomes. hepatology 2011; 54:1891–2. doi: 10.1002/hep.24722. 48. choudhery ms, badowski m, muise a, pierce j, harris dt. donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. j transl med 2014; 12:8. doi: 10.1186/1479-5876-12-8. 49. inatani h, yamamoto n, hayashi k, kimura h, takeuchi a, miwa s, et al. do mesenchymal stem cells derived from atypical lipomatous tumors have greater differentiation potency than cells from normal adipose tissues? clin orthop relat res 2017; 475:1693–701. doi: 10.1007/s11999-017-5259-z. 50. demetri gd, fletcher cd, mueller e, sarraf p, naujoks r, campbell n, et al. induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. proc natl acad sci u s a 1999; 96:3951–6. doi: 10.1073/pnas.96.7.3951. 51. artigas n, gámez b, cubillos-rojas m, sánchez-de diego c, valer ja, pons g, et al. p53 inhibits sp7/osterix activity in the transcriptional program of osteoblast differentiation. cell death differ 2017; 24:2022–31. doi: 10.1038/cdd.2017.113. 52. reya t, morrison sj, clarke mf, weissman il. stem cells, cancer, and cancer stem cells. nature 2001; 414:105–11. doi: 10.1038/35102167. 53. sanz ar, carrión es, chaparro ap. mesenchymal stem cells from the oral cavity and their potential value in tissue engineering. periodontol 2000 2015; 67:251–67. doi: 10.1111/prd.12070. 54. ohkoshi s, hara h, hirono h, watanabe k, hasegawa k. regen erative medicine using dental pulp stem cells for liver diseases. world j gastrointest pharmacol ther 2017; 8:1–6. doi: 10.4292/ wjgpt.v8.i1.1. 55. ishkitiev n, yaegaki k, calenic b, nakahara t, ishikawa h, mitiev v, et al. deciduous and permanent dental pulp mesenchymal cells acquire hepatic morphologic and functional features in vitro. j endod 2010; 36:469–74. doi: 10.1016/j.joen.2009.12.022. 56. lei m, li k, li b, gao ln, chen fm, jin y. mesenchymal stem cell characteristics of dental pulp and periodontal ligament stem cells after in vivo transplantation. biomaterials 2014; 35:6332–43. doi: 10.1016/j.biomaterials.2014.04.071. 57. gang ej, hong sh, jeong ja, hwang sh, kim sw, yang ih, et al. in vitro mesengenic potential of human umbilical cord blood-derived mesenchymal stem cells. biochem biophys res commun 2004; 321:102–8. doi: 10.1016/j.bbrc.2004.06.111. 58. koike c, zhou k, takeda y, fathy m, okabe m, yoshida t, et al. characterization of amniotic stem cells. cell reprogram 2014; 16:298–305. doi: 10.1089/cell.2013.0090. 59. in’t anker ps, scherjon sa, kleijburg-van der keur c, de groot-swings gm, claas fh, fibbe we, et al. isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. stem cells 2004; 22:1338–45. doi: 10.1634/ stemcells.2004-0058. 60. demetri gd, griffin jd. granulocyte colony-stimulating factor and its receptor. blood 1991; 78:2791–808. 61. chao nj, schriber jr, grimes k, long gd, negrin rs, raimondi cm, et al. granulocyte colony-stimulating factor “mobilized” peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy. blood 1993; 81:2031–5. 62. welte k, gabrilove j, bronchud mh, platzer e, morstyn g. filgrastim (r-methug-csf): the first 10 years. blood 1996; 88:1907–29. 63. craddock cf, nakamoto b, andrews rg, priestley gv, papayannopoulou t. antibodies to vla4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice. blood 1997; 90:4779–88. 64. kikuta t, shimazaki c, ashihara e, sudo y, hirai h, sumikuma t, et al. mobilization of hematopoietic primitive and committed progenitor cells into blood in mice by anti-vascular adhesion molecule-1 antibody alone or in combination with granulocyte colony-stimulating factor. exp hematol 2000; 28:311–17. doi: 10.1016/s0301-472x(99)00151-4. 65. sakaguchi y, sekiya i, yagishita k, muneta t. comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. arthritis rheum 2005; 52:2521–9. doi: 10.1002/art.21212. 66. chan rw, schwab ke, gargett ce. clonogenicity of human endometrial epithelial and stromal cells. biol reprod 2004; 70:1738–50. doi: 10.1095/biolreprod.103.024109. 67. wolff ef, wolff ab, hongling du, taylor hs. demonstration of multipotent stem cells in the adult human endometrium by in vitro chondrogenesis. reprod sci 2007; 14:524–33. doi: 10.1177/ 1933719107306896. 68. verdi j, tan a, shoae-hassani a, seifalian am. endometrial stem cells in regenerative medicine. j biol eng 2014; 8:20. doi: 10.1186/1754-1611-8-20. 69. gargett ce. uterine stem cells: what is the evidence? hum reprod update 2007; 13:87–101. doi: 10.1093/humupd/dml045. 70. schüring an, schulte n, kelsch r, röpke a, kiesel l, götte m. characterization of endometrial mesenchymal stem-like cells obtained by endometrial biopsy during routine diagnostics. fertil steril 2011; 95:423–6. doi: 10.1016/j.fertnstert.2010.08.035. 71. pittenger mf, mackay am, beck sc, jaiswal rk, douglas r, mosca jd, et al. multilineage potential of adult human mesenchymal stem cells. science 1999; 284:143–7. doi: 10.1126/science. 284.5411.143. 72. wu x, luo y, chen j, pan r, xiang b, du x, et al. transplantation of human menstrual blood progenitor cells improves hyperglycemia by promoting endogenous progenitor differentiation in type 1 diabetic mice. stem cells dev 2014; 23:1245– 57. doi: 10.1089/scd.2013.0390. 73. al-nbaheen m, vishnubalaji r, ali d, bouslimi a, al-jassir f, megges m, et al. human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. stem cell rev 2013; 9:32–43. doi: 10.1007/s12015-012-9365-8. https://doi.org/10.1016/s0002-8703%2899%2970416-3 https://doi.org/10.1093/ejechocard/jep191 https://doi.org/10.1182/blood-2006-07-034348 https://doi.org/10.1182/blood-2006-07-034348 https://doi.org/10.1016/s0140-6736%2804%2916104-7 https://doi.org/10.1182/blood-2002-07-2104 https://doi.org/10.1186/s12929-016-0289-5 https://doi.org/10.1186/s12929-016-0289-5 https://doi.org/10.1002/hep.24722 https://doi.org/10.1186/1479-5876-12-8 https://doi.org/10.1007/s11999-017-5259-z https://doi.org/10.1073/pnas.96.7.3951 https://doi.org/10.1038/cdd.2017.113 https://doi.org/10.1038/35102167 https://doi.org/10.1111/prd.12070 https://doi.org/10.4292/wjgpt.v8.i1.1 https://doi.org/10.4292/wjgpt.v8.i1.1 https://doi.org/10.1016/j.joen.2009.12.022 https://doi.org/10.1016/j.biomaterials.2014.04.071 https://doi.org/10.1016/j.bbrc.2004.06.111 https://doi.org/10.1089/cell.2013.0090 https://doi.org/10.1634/stemcells.2004-0058 https://doi.org/10.1634/stemcells.2004-0058 https://doi.org/10.1016/s0301-472x%2899%2900151-4 https://doi.org/10.1002/art.21212 https://doi.org/10.1095/biolreprod.103.024109 https://doi.org/10.1177/1933719107306896 https://doi.org/10.1177/1933719107306896 https://doi.org/10.1186/1754-1611-8-20 https://doi.org/10.1093/humupd/dml045 https://doi.org/10.1016/j.fertnstert.2010.08.035 https://doi.org/10.1126/science.284.5411.143 https://doi.org/10.1126/science.284.5411.143 https://doi.org/10.1089/scd.2013.0390 https://doi.org/10.1007/s12015-012-9365-8 roberto berebichez-fridman and pablo r. montero-olvera review | e277 74. abou-khalil r, yang f, lieu s, julien a, perry j, pereira c, et al. role of muscle stem cells during skeletal regeneration. stem cells 2015; 33:1501–11. doi: 10.1002/stem.1945. 75. peng h, huard j. muscle-derived stem cells for musculoskeletal tissue regeneration and repair. transpl immunol 2004; 12:311–19. doi: 10.1016/j.trim.2003.12.009. 76. marks pw, witten cm, califf rm. clarifying stem-cell therapy’s benefits and risks. n engl j med 2017; 376:1007–9. doi: 10.1056/nejmp1613723. 77. daley gq. polar extremes in the clinical use of stem cells. n engl j med 2017; 376:1075–7. doi: 10.1056/nejme1701379. 78. marks p, gottlieb s. balancing safety and innovation for cellbased regenerative medicine. n engl j med 2018; 378:954–9. doi: 10.1056/nejmsr1715626. https://doi.org/10.1002/stem.1945 https://doi.org/10.1016/j.trim.2003.12.009 https://doi.org/10.1056/nejmp1613723 https://doi.org/10.1056/nejme1701379 https://doi.org/10.1056/nejmsr1715626 1department of medical records, college of health sciences, public authority of applied education & training, kuwait city, kuwait; 2institute of health informatics, university college london, london, uk *corresponding author’s e-mails: baa.almutairi@paaet.edu.kw and dr.bashayer.almutairi@gmail.com آراء األطباء عن الوصفة اإللكرتونية بالسجالت الطبية اإللكرتونية يف مراكز الرعاية الصحية األولية يف الكويت ب�شاير عبدهلل املطريي، هرني بوت�س، �شعدون فار�س العازمي abstract: objectives: this study aimed to evaluate physicians’ perceptions of electronic prescribing in kuwaiti primary healthcare centres. methods: this cross-sectional study was conducted between june and august 2017 among 368 physicians from 25 primary healthcare centres in kuwait. data were collected from the participants using a selfreported questionnaire, including sociodemographic characteristics, previous experience with computers and awareness, knowledge and use of e-prescribing systems and their functional features. in addition, perceptions of the benefits and levels of satisfaction associated with e-prescribing were explored. results: a total of 306 physicians completed the survey (response rate: 83%). the majority had positive perceptions regarding the use of e-prescribing, particularly in terms of time-savings (86%), healthcare quality (84%), productivity (80%) and clinical workflow and efficiency (83%). however, many respondents indicated that e-prescribing systems required additional improvements in terms of functionality. conclusion: most physicians in primary healthcare centres in kuwait recognised the importance of e-prescribing to improve the quality of patient care, streamline workflow, increase productivity and reduce medical errors. however, there is a need to improve the design and infrastructure of e-prescribing systems, which may aid in the adoption of such systems in kuwait. keywords: computer-assisted drug therapies; electronic prescribing; electronic medical records; physicians; primary healthcare; kuwait. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل تقييم اآراء الأطباء حول تقدمي الو�شفات اإلكرتونيًا يف مراكز الرعاية ال�شحية الأولية يف الكويت. طبيبًا 368 عدد وا�شتهدف الأولية ال�شحية للرعاية مركًزا 25 يف 2017 اأغ�شط�س اإىل يونيو من مقطعي م�شح درا�شة اإجراء مت الطريقة: بطريقة اختيار ع�شوائية بعد دعوتهم للم�شاركة يف الدرا�شة. مت جمع البيانات عن طريق ا�شتبيان ذاتي يت�شمن املعلومات الدميوغرافية، الإلكرتونية الو�شفة اأنظمة الطبيبباإ�شتخدام ومعرفة ادراك مدى عن ومعلومات الكمبيوتر، اأجهزة ا�شتخدام يف اخلربة عن ومعلومات وم�شتويات الإلكرتوين بالو�شف املرتبطة الفوائد حول الأطباء وت�شورات باآراء تتعلق معلومات جمع مت كما الوظيفية. وخ�شائ�شها ر�شاهم عن النظام. النتائج: ا�شتكمل امل�شح ما جمموعه 306 طبيًبا )معدل ا�شتجابة: %83(. قد كانت الإجابات ب�شكل عام اإيجابية يف ما يتعلق با�شتخدام الو�شفات الإلكرتونية، خا�شة فيما يتعلق بتوفريالوقت )%86(، وجودة الرعاية ال�شحية )%84(، والإنتاجية )%80(، و�شري العمل ال�رصيري والكفاءة )%83(. كما اأ�شار معظم امل�شاركني اإىل اأن اأنظمة الو�شف الإلكرتونية حتتاج اإىل ادخال وظائف حم�شنة. اخلال�صة: �شهولة و�شمان املر�شى رعاية جودة لتح�شني الإلكرتونية الدواء و�شف اأنظمة باأهمية الكويتية الأولية الرعاية مراكز يف الأطباء يقر �شري العمل والإنتاجية والتقليل من الأخطاء الطبية. مع ذلك، هناك حاجة لتح�شني ت�شميم البنية التحتية لنظام الو�شفة الإلكرتونية، مما �شي�شهم يف اإعتمادها بفعالية يف الكويت. الأولية؛ ال�شحية الرعاية الأطباء؛ الإلكرتونية؛ ال�شحية ال�شجالت الكرتونية؛ الو�شفة باحلا�شوب؛ املدعومة الدوائية العالجات املفتاحية: الكلمات الكويت. physicians’ perceptions of electronic prescribing with electronic medical records in kuwaiti primary healthcare centres *bashair a. almutairi,1 henry w. w. potts,2 saadoun f. al-azmi1 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e476–482, epub. 28 mar 19 submitted 22 jun 18 revision req. 29 jul 18; revision recd. 19 sep 18 accepted 11 oct 18 advances in knowledge this study found that physicians in kuwait were generally accepting of the introduction of electronic prescribing as part of an electronic medical record system, recognising the value and potential of such systems to improve efficiency, reduce medical errors and improve patient safety. however, physicians in kuwait identified several deficiencies in the implemented e-prescribing systems. application to patient care there is a need to address identified deficiencies in e-prescribing systems being implemented in kuwait in order to optimise the quality of care provided to patients and reduce the potential for prescription errors. doi: 10.18295/squmj.2018.18.04.008 bashair a. almutairi, henry w. w. potts and saadoun f. al-azmi clinical and basic research | e477 prescribing medicines is an important part of public healthcare services; as such, systems that optimise the prescription process are ess ential.1 electronic prescribing is defined as a computer based method of creating, transferring, sorting and doc umenting prescriptions electronically.2 a successful e-pre scribing system functions as an interoperational plat form between physicians and pharmacies to facilitate the exchange of treatment information.3 e-prescribing systems often form part of a larger electronic medical record (emr) system allowing physicians access to a broad range of patient information, including medical histories and details of diagnoses and treatment, in addition to prescription information.4 prescription errors are a common yet avoidable cause of increased morbidity and mortality.5–7 although the implementation of new technologies may initially be challenging, adopting e-prescribing systems can help to reduce the frequency of medication errors, thereby enhancing patient safety and the overall quality of treat ment, particularly in primary care settings and for patients with long-term drug regimens.8–10 the successful adopt ion of e-prescribing systems has been reported in many regions worldwide, including the usa, uk, european union and canada.10,11 the main barriers to implement ation include cost, time, lack of efficiency, negative per ceptions of technology and its impact on care, lack of prior experience with computers, low computer literacy, limitations in interoperability, difficulty of data entry/ correction and the ability of the system to complete desired tasks.11–15 furthermore, there may be concerns regarding differences in healthcare policies and the enforcement of local privacy and data protection laws.16 according to sicotte et al., preferred style of information acquisition, successful integration of e-prescribing into day-to-day practice and previous computer experience all contribute to a better understanding of technology and can positively influence the usage and adoption of e-prescribing systems.17 in kuwait, healthcare services are offered at the primary, secondary and tertiary level via health centres, regional general hospitals and specialty hospitals. there are a total of 97 primary healthcare centres located throughout the country.18 each residential area has at least one primary healthcare centre, with some centres also incorporating specialised clinics catering to patients with diabetes, dermatological and ophthalmological prob lems and those requiring antenatal care, among others. although these centres operate on an independent basis, they are overseen by the central directorate of primary healthcare in the kuwaiti ministry of health (moh).18,19 in 2000, a national health information emr system was developed by the moh and subsequently implemented in all primary healthcare centres in 2001. the emr system was specifically designed to support end-users (i.e. physicians, nurses and pharmacists) by providing access to a complete and accurate database of relevant patient information.20 this study aimed to evaluate phys icians’ perceptions of e-prescribing in kuwaiti primary healthcare centres. methods this cross-sectional study was conducted between june and august 2017 in 25 primary healthcare centres in kuwait. the required sample size for the study was based on a finite population of 1,685 physicians. as a conservative estimate, it was assumed that 50% of users would be satisfied with the current e-prescribing system. taking into account a 4.6% error, the number of participants was calculated to be 350 at a 95% confidence level. adjusting for a 5% non-response rate, a total of 368 kuwaiti physicians were selected by a two-stage stratified random sampling method, considering the proportional allocation of the total population in the study area. in the first stage, a total of 25 primary healthcare centres were randomly selected, comprising five centres from each of the five main regions of kuwait (ahmadi, asmimah, farwaniya, hawalli and jahra). subsequently, during the second stage, physicians from each of the selected centres were randomly chosen and invited to participate in the survey. a two-part english-language questionnaire was developed to elicit information from the participants. the first section focused on sociodemographic factors and computer experience (13 items), while the second consisted of 48 items to determine the physicians’ per ceptions of e-prescribing in four categories: knowledge (four items), functionality (18 items), benefits (18 items) and satisfaction (eight items). all of the questions were closed-ended and were scored on a three-point likert scale, with one indicating disagreement with the item, two neither agreement nor disagreement and three agreement. a pilot study of 10 physicians who were not included in the final study pre-tested the questionnaire to ensure the clarity and relevance of the items. the quest ionnaires were physically distributed to the selected physicians during their work shifts and collected one week later by the same researcher. data were analysed using the statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa). responses for each item in the second section of the questionnaire were averaged over the total number of items in the category. as the scores for each dimension were not normally distributed, the results were expressed as minimums, maximums, medians and interquartile ranges (iqrs), with an overall unweighted or weighted score. mann-whitney u, physicians’ perceptions of electronic prescribing with electronic medical records in kuwaiti primary healthcare centres e478 | squ medical journal, november 2018, volume 18, issue 4 kruskal-wallis and spearman’s rank correlation tests were used to calculate associations at a 5% significance level. the study was approved by the standing committee for the coordination of medical & health research at the kuwaiti moh (#537/2017). all participants were informed of the study’s purpose, the anonymity of their data and that participation was voluntary in nature. written consent was obtained from all participants prior to their inclusion in the study. results a total of 306 participants took part in the survey (response rate: 83%). most respondents were female (59%), 30–39 years old (49%), married (84%), had a postgraduate degree (58%) and had worked for between 6–11 years (40%). the majority (71%) had received their medical education outside of kuwait and 61% had taken computer courses during medical school. more than half (56%) reported having average computer literacy. awareness of e-pres cribing systems was high (94%), with 94% indicating that they understood how to use the system. the vast majority (95%) were currently using an e-prescribing system, with between 1–17 years of previous experience (median: 7 years; iqr: 5–11 years). the number of daily prescriptions was between 15–54 prescriptions (median: 42 prescriptions; iqr: 36–47 prescriptions) [table 1]. the overall weighted median score for the knowledge dimension of the questionnaire was 3, while the median score for functionality was 2.3. median weighted scores for the benefits and satisfaction dimensions were 2.7 and 2.5, respectively [table 2]. generally, the majority of physicians had positive perceptions regarding the concept of e-prescribing, reporting that the emr system was easy to use (85%), efficient (88%) and provided easy access to prescriptions services (81%). notable benefits of e-prescribing were time-savings (86%), increased healthcare quality (84%), productivity (80%) and clinical workflow and efficiency (83%). however, many of the respondents indicated that e-prescribing systems should have better functionality, table 1: sociodemographic characteristics of physicians in primary healthcare centres in kuwait (n = 306) characteristic n (%) age in years 20–29 23 (8) 30–39 149 (49) 40–49 68 (22) 50–59 44 (14) >60 22 (7) gender male 124 (41) female 182 (59) marital status single 50 (16) married 256 (84) education level bachelor’s degree 129 (42) postgraduate degree 177 (58) location of medical education kuwait 89 (29) abroad 217 (71) previous work experience in years <6 64 (21) 6–11 123 (40) 12–17 46 (15) 18–23 38 (12) >24 35 (11) prior computer training at medical school yes 186 (61) no 120 (39) level of computer literacy basic 98 (32) average 172 (56) excellent 36 (12) awareness of e-prescribing modules yes 287 (94) no 19 (6) use of e-prescribing modules yes 291 (95) no 15 (5) awareness of how to use e-prescribing modules yes 288 (94) no 18 (6) previous experience using e-prescribing modules in years median (interquartile range) 7 (5–11) range 1–17 number of prescriptions per day median (interquartile range) 42 (36–47) range 15–54 table 2: dimension scores for a survey assessing perceptions of electronic prescribing systems among physicians in primary healthcare centres in kuwait (n = 306) dimension unweighted score weighted score range med (iqr) range med (iqr) knowledge 4–12 12 (11–12) 1–3 3 (2.8–3) functionality 18–54 42 (37–48) 1–3 2.3 (2.1–2.7) benefits 18–54 49 (43–53) 1–3 2.7 (2.4–2.9) satisfaction 8–24 20 (19–21) 1–3 2.5 (2.4–2.6) med = median; iqr = interquartile range. bashair a. almutairi, henry w. w. potts and saadoun f. al-azmi clinical and basic research | e479 table 3: perceptions of electronic prescribing systems among physicians in primary healthcare centres in kuwait (n = 306) item n (%) disagree neither agree knowledge the emr e-prescribing system is easy to use 8 (3) 37 (12) 261 (85) it is easy to access e-prescription services and prescribe medications with this system 12 (4) 46 (15) 248 (81) i use the emr e-prescribing system efficiently for most prescriptions 10 (3) 28 (9) 268 (88) the emr e-prescribing system clearly displays patient demographic information 23 (8) 80 (26) 203 (66) functionality the emr e-prescribing system allows me to create new prescriptions 48 (16) 45 (15) 213 (70) the emr e-prescribing system allows me to detect prescribing errors 74 (24) 77 (25) 155 (51) the emr e-prescribing system allows me to receive medication interaction alerts 162 (53) 44 (14) 100 (33) the emr e-prescribing system allows me to receive medication allergy alerts 41 (13) 34 (11) 231 (75) the emr e-prescribing system allows me to review patient medication histories 15 (5) 39 (13) 252 (82) the emr e-prescribing system allows me to track health maintenance items 44 (14) 98 (32) 164 (54) the emr e-prescribing system allows me to select medications 13 (4) 28 (9) 265 (87) the emr e-prescribing system allows me to view current medications 20 (7) 34 (11) 252 (82) the emr e-prescribing system allows me to add an electronic signature 174 (57) 55 (18) 77 (25) the emr e-prescribing system allows me to obtain medication information 89 (29) 66 (22) 151 (49) the emr e-prescribing system allows me to review medication reference information 101 (33) 70 (23) 135 (44) the emr e-prescribing system allows me to prescribe medication safely 80 (26) 81 (26) 145 (47) the emr e-prescribing system allows me to request repeat medications 52 (17) 64 (21) 190 (62) the emr e-prescribing system allows me to review formula information 92 (30) 68 (22) 146 (48) the emr e-prescribing system allows me to print patient information sheets 48 (16) 35 (11) 223 (73) the emr e-prescribing system allows me to print medical information sheets 36 (12) 44 (14) 226 (74) the emr e-prescribing system allows me to perform dosing calculations 143 (47) 73 (24) 90 (29) the emr e-prescribing system allows me to search by medication name 39 (13) 37 (12) 230 (75) benefits the emr e-prescribing system helps to control patient medication lists 68 (22) 66 (22) 172 (56) the emr e-prescribing system leads to increased prescription accuracy 62 (20) 84 (27) 160 (52) the emr e-prescribing system helps to streamline workflow and increase efficiency 17 (6) 35 (11) 254 (83) the emr e-prescribing system contributes to financial savings 29 (9) 77 (25) 200 (65) the emr e-prescribing system improves communication with pharmacists 32 (10) 50 (16) 224 (73) the emr e-prescribing system improves communication with patients 37 (12) 69 (23) 200 (65) the emr e-prescribing system leads to greater patient satisfaction 22 (7) 97 (32) 187 (61) the emr e-prescribing system results in better security and confidentiality 16 (5) 77 (25) 213 (70) the emr e-prescribing system results in better protection of the patient’s privacy 21 (7) 68 (22) 217 (71) the emr e-prescribing system leads to greater patient safety 24 (8) 76 (25) 206 (67) the emr e-prescribing system contributes to time-savings 13 (4) 31 (10) 262 (86) the emr e-prescribing system reduces medication errors 28 (9) 79 (26) 199 (65) the emr e-prescribing system leads to greater efficiency in physician practice 16 (5) 67 (22) 223 (73) the emr e-prescribing system contributes to higher-quality healthcare 7 (2) 43 (14) 256 (84) the emr e-prescribing system leads to greater productivity 14 (5) 46 (15) 246 (80) the emr e-prescribing system improves flexibility without much mental effort 25 (8) 95 (31) 186 (61) the emr e-prescribing system results in faster task accomplishment 19 (6) 45 (15) 242 (79) the emr e-prescribing system allows me to treat more patients 21 (7) 68 (22) 217 (71) satisfaction the emr e-prescribing system is useful for my job 7 (2) 13 (4) 286 (93) the emr e-prescribing system makes my job easier 9 (3) 18 (6) 279 (91) the emr e-prescribing system is not time-consuming 46 (15) 48 (16) 212 (69) the emr e-prescribing system improves the speed and efficiency of processing orders 12 (4) 41 (13) 253 (83) the emr e-prescribing system maintains data accuracy 10 (3) 39 (13) 257 (84) the emr e-prescribing system makes my job much more difficult 214 (70) 45 (15) 47 (15) i require more training to use the emr e-prescribing system 92 (30) 91 (30) 123 (40) an on-staff support technician is needed to maintain and resolve technical problems 59 (19) 68 (22) 179 (58) emr = electronic medical record. physicians’ perceptions of electronic prescribing with electronic medical records in kuwaiti primary healthcare centres e480 | squ medical journal, november 2018, volume 18, issue 4 table 4: dimension scores for a survey assessing perceptions of electronic prescribing systems among physicians in primary healthcare centres in kuwait according to sociodemographic characteristics (n = 306) characteristic median score (iqr) knowledge functionality benefits satisfaction gender male 3 (2.8–3) 2.3 (2.1–2.7) 2.7 (2.4–2.9) 2.5 (2.3–2.8) female 3 (2.5–3) 2.3 (2.1–2.6) 2.8 (2.4–2.9) 2.5 (2.4–2.6) marital status single 2.8 (2.5–3) 2.4 (2.1–2.6) 2.7 (2.4–2.9) 2.5 (2.3–2.6) married 3 (2.8–3) 2.3 (2.1–2.7) 2.7 (2.4–2.9) 2.5 (2.4–2.6) education level bachelor’s degree 3 (2.8–3) 2.4 (2.1–2.8) 2.7 (2.4–2.9) 2.5 (2.4–2.6) postgraduate degree 3 (2.5–3) 2.3 (2.1–2.6) 2.7 (2.4–2.9) 2.5 (2.4–2.6) location of medical education kuwait 3 (2.8–3) 2.2 (2–2.5) 2.7 (2.3–2.9) 2.5 (2.3–2.6) abroad 2.8 (2.5–3) 2.4 (2.1–2.7) 2.7 (2.4–2.9) 2.5 (2.4–2.6) prior computer training at medical school yes 3 (2.8–3) 2.4 (2.1–2.7) 2.8 (2.4–2.9) 2.5 (2.4–2.6) no 2.8 (2.5–3) 2.3 (2.1–2.6) 2.7 (2.3–2.9) 2.5 (2.3–2.6) awareness of e-prescribing modules yes 3 (2.8–3) 2.4 (2.1–2.7) 2.7 (2.4–2.9) 2.5 (2.4–2.6) no 2.8 (2.5–3) 2.1 (1.6–2.6) 2.4 (2.1–3) 2.5 (2.2–2.7) use of e-prescribing modules yes 3 (2.8–3) 2.4 (2.1–2.7) 2.7 (2.4–2.9) 2.5 (2.4–2.6) no 2.8 (2–3) 2.1 (1.8–2.6) 2.6 (2.1–3) 2.4 (2–2.5) awareness of how to use e-prescribing modules yes 3 (2.8–3) 2.4 (2.1–2.7) 2.7 (2.4–2.9) 2.5 (2.4–2.6) no 2.8 (2.5–3) 2 (1.5–2.6) 2.4 (2.2–2.9) 2.4 (2.3–2.6) iqr = interquartile range. table 5: relationship between sociodemographic variables and dimension scores for a survey assessing perceptions of electronic prescribing systems among physicians in primary healthcare centres in kuwait (n = 306) variable knowledge functionality benefits satisfaction r/z score p value r/z score p value r/z score p value r/z score p value age −0.041* 0.474 0.102* 0.075 0.000* 0.999 −0.104* 0.068 gender 0.170* 0.865 0.461† 0.645 0.408† 0.683 0.596† 0.551 marital status 1.142† 0.253 0.635† 0.525 0.722† 0.470 1.088† 0.277 education level 0.092† 0.927 1.524† 0.128 0.066† 0.947 0.820† 0.412 location of medical education 1.205† 0.228 2.434† 0.015 1.473† 0.141 0.168† 0.866 prior computer training at medical school 0.958† 0.338 1.546† 0.122 2.223† 0.026 0.998† 0.318 computer literacy 0.050* 0.387 0.015* 0.797 0.071* 0.214 0.011* 0.849 awareness of e-prescribing modules 1.726† 0.084 2.069† 0.039 1.123† 0.258 0.359† 0.720 use of e-prescribing modules 2.386† 0.017 1.792† 0.073 0.859† 0.391 2.066† 0.039 awareness of how to use e-prescribing modules 1.932† 0.053 2.656† 0.008 1.269† 0.204 0.887† 0.375 previous experience using e-prescribing modules −0.003* 0.958 0.005* 0.353 −0.005* 0.937 0.070* 0.219 number of prescriptions per day 0.028* 0.629 0.091* 0.112 −0.016* 0.718 −0.049* 0.396 iqr = interquartile range; emr = electronic medical record. *using spearman’s rank correlation coefficient. †using a mann-whitney u test. bashair a. almutairi, henry w. w. potts and saadoun f. al-azmi clinical and basic research | e481 for instance regarding the ability to add electronic sign atures (57%), receive medication interaction alerts (53%) and perform dosing calculations (47%). respondents also highlighted the need for technical support (58%) [table 3]. tables 4 and 5 show the relationship between the overall median scores in each of the questionnaire dim ensions and selected sociodemographic characteristics. the median functionality score of physicians who had received medical education abroad was significantly higher than that of those who had been educated in kuwait (2.4 versus 2.2; p = 0.015). physicians who had received computer courses at medical school had a significantly higher median benefits score compared to those who did not (2.8 versus 2.7; p = 0.026). median functionality scores were also significantly higher among physicians who were aware of e-prescription systems (2.4 versus 2.1; p = 0.039) and who understood how to use them (2.4 versus 2; p = 0.008). median scores for the satisfaction and knowledge dimensions varied according to use of e-prescribing systems; users had significantly higher satisfaction (2.5 versus 2.4; p = 0.039) and knowl edge (3 versus 2.8; p = 0.017) scores compared to nonusers. all four dimensions of the questionnaire were significantly related with each other (p ≤0.001), with spearman’s rank correlation coefficients ranging from 0.177–0.350 [table 6]. discussion the current study assessed perceptions of e-prescribing among physicians in primary healthcare centres in kuwait. as physicians are the primary end-users of such systems, they are in the best position to identify factors that affect successful adoption and implementation of the system.21 the majority of physicians in the present study had positive perceptions of e-prescribing, part icularly with regards to time-savings, ease of use, accessibility and increased healthcare quality, productivity and efficiency. in particular, most physicians anticipated that e-prescribing would result in improvements in prescription accuracy, data confidentiality and patient satisfaction and help to reduce prescription errors. the findings of the present study are in line with those of previous research. in a study in singapore, tan et al. reported that most doctors were satisfied with specific functions of e-prescribing systems such as the ability to review prescription histories, receive drug inter action alerts and create prescriptions and e-prescription processing and system speed.22 a swedish study noted that physicians were satisfied with the clear display of patient information on such systems.23 thomas et al. found that physicians using an ambulatory e-prescribing system in the usa were optimistic about improved work flow, efficiency, cost-savings and patient communication.24 other studies have also reported perceived improve ments in patient safety, care quality, efficiency, productivity and communication with pharmacies.1,9–11,23,25,26 despite mostly positive perceptions, more than half of the physicians in the current study indicated that e-prescribing systems should have better functionality, such as the ability to add electronic signatures, receive medication interaction alerts and perform dosing calcul ations. cohen et al. highlighted a desire for e-prescribing technology to incorporate electronic signatures among physicians in south africa, while savage et al. revealed similar issues regarding allergy and interaction alerts and dosing calculations among staff at a district general hospital in the uk.27,28 in addition, a major area of con cern in the present study was ensuring adequate technical support in the workplace for system maintenance and to overcome technical problems. these results are consistent with the findings of other studies regarding the need for greater technical and organisational support for the successful implementation and maintenance of e-prescribing systems.1,3 jawhari et al. also emphasised the need for on-site technical support.29 the main limitation of the current study was that the sample was not representative of all primary health care physicians in kuwait; furthermore, as the questionnaire data were self-reported, the findings may be subject to bias. conclusion this study found that physicians’ perceptions of e-pres cribing systems in kuwaiti primary healthcare centres were mostly positive, particularly with regards to improve ments in time-savings, efficiency, quality of patient care and safety. these results support the continued adoption and use of e-prescribing systems in kuwait. however, several deficiencies were identified regarding the func tionality of e-prescribing systems and the lack of techn ical support and maintenance. improvements in these areas may maximise the effective adoption and use of such systems. table 6: spearman’s rank correlations between dimensions in a survey assessing perceptions of electronic prescribing systems among phys icians in primary healthcare centres in kuwait (n = 306) dimension knowledge functionality benefits r p value r p value r p value functionality 0.326 <0.001 benefits 0.350 <0.001 0.538 <0.001 satisfaction 0.177 0.001 0.241 <0.001 0.254 <0.001 physicians’ perceptions of electronic prescribing with electronic medical records in kuwaiti primary healthcare centres e482 | squ medical journal, november 2018, volume 18, issue 4 a c k n o w l e d g e m e n t s the authors would like to thank all of the physicians who participated in this study as well as the directors of the primary healthcare centres for facilitating and supporting the data collection process. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. gagnon mp, nsangou ér, payne-gagnon j, grenier s, sicotte c. barriers and facilitators to implementing electronic prescription: a systematic review of user groups’ perceptions. j am med inform assoc 2014; 21:535–41. https://doi.org/10.1136/ amiajnl-2013-002203. 2. ehealth initiative foundation. a clinician’s guide to electronic prescribing. from: www.citizenshealthinitiative.org/sites/citize nshealthinitiative.org/files/media/reports/clinicians_guide_ to_e-prescribing_final_100708.pdf accessed: sep 2018. 3. grossman jm, cross da, boukus er, cohen gr. transmitting and processing electronic prescriptions: experiences of physician practices and pharmacies. j am med inform assoc 2012; 19:353–9. https://doi.org/10.1136/amiajnl-2011-000515. 4. abramson el, barrón y, quaresimo j, kaushal r. electronic prescribing within an electronic health record reduces ambulatory prescribing errors. jt comm j qual patient saf 2011; 37:470–8. https://doi.org/10.1016/s1553-7250(11)37060-2. 5. cresswell k, coleman j, slee a, williams r, sheikh a. invest igating and learning lessons from early experiences of implem enting eprescribing systems into nhs hospitals: a questionnaire study. plos one 2013; 8:e53369. https://doi.org/10.1371/jour nal.pone.0053369. 6. pirmohamed m, james s, meakin s, green c, scott ak, walley tj, et al. adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. bmj 2004; 329:15–19. https://doi.org/10.1136/bmj.329.7456.15. 7. schneeweiss s, göttler m, hasford j, swoboda w, hippius m, hoffmann ak, et al. first results from an intensified monitoring system to estimate drug related hospital admissions. br j clin pharmacol 2001; 52:196–200. https://doi.org/10.1046/j.03065251.2001.01425.x. 8. eslami s, abu-hanna a, de keizer nf. evaluation of outpatient computerized physician medication order entry systems: a systematic review. j am med inform assoc 2007; 14:400–6. https://doi.org/10.1197/jamia.m2238. 9. grossman jm, gerland a, reed mc, fahlman c. physicians’ experiences using commercial e-prescribing systems. health aff (millwood) 2007; 26:w393–404. https://doi.org/10.1377/hlt haff.26.3.w393. 10. salmon jw, jiang r. e-prescribing: history, issues, and potentials. online j public health inform 2012; 4:4304. https://doi.org/ 10.5210/ojphi.v4i3.4304. 11. samadbeik m, ahmadi m, sadoughi f, garavand a. a comparative review of electronic prescription systems: lessons learned from developed countries. j res pharm pract 2017; 6:3–11. https://doi.org/10.4103/2279-042x.200993. 12. van der meijden mj, tange hj, troost j, hasman a. determinants of success of inpatient clinical information systems: a literature review. j am med inform assoc 2003; 10:235–43. https://doi.org/10.1197/jamia.m1094. 13. aarts j, doorewaard h, berg m. understanding implementation: the case of a computerized physician order entry system in a large dutch university medical center. j am med inform assoc 2004; 11:207–16. https://doi.org/10.1197/jamia.m1372. 14. al-azmi sf, al-enezi n, chowdhury ri. users’ attitudes to an electronic medical record system and its correlates: a multivariate analysis. health inf manag 2009; 38:33–40. https://doi. org/10.1177/183335830903800205. 15. ammenwerth e, mansmann u, iller c, eichstädter r. factors affecting and affected by user acceptance of computer-based nursing documentation: results of a two-year study. j am med inform assoc 2003; 10:69–84. https://doi.org/10.1197/jamia. m1118. 16. greenberg md, ridgely ms, bell ds. electronic prescribing and hipaa privacy regulation. inquiry 2004-2005; 41:461–8. https://doi.org/10.5034/inquiryjrnl_41.4.461. 17. sicotte c, taylor l, tamblyn r. predicting the use of electronic prescribing among early adopters in primary care. can fam physician 2013; 59:e312–21. 18. regional health systems observatory, world health organization. health system profile: kuwait. from: apps.who.int/ medicinedocs/documents/s17297e/s17297e.pdf accessed: sep 2018. 19. buabbas a. investigation of the adoption of telemedicine technology in the kuwaiti health system: strategy and policy of impl ementation for overseas referral patients. phd thesis, 2013, brunel university, london, uk. 20. akbar aa. patient information system for national health care: an intranet internet-based model for the state of kuwait. phd thesis, 2003, university of leeds, leeds, uk. 21. tamblyn r, huang a, kawasumi y, bartlett g, grad r, jacques a, et al. the development and evaluation of an integrated electronic prescribing and drug management system for primary care. j am med inform assoc 2006; 13:148–59. https://doi.org/10.1 197/jamia.m1887. 22. tan ws, phang js, tan lk. evaluating user satisfaction with an electronic prescription system in a primary care group. ann acad med singapore 2009; 38:494–7. 23. hellström l, waern k, montelius e, astrand b, rydberg t, petersson g. physicians’ attitudes towards eprescribing: evaluation of a swedish full-scale implementation. bmc med inform decis mak 2009; 9:37. https://doi.org/10.1186/1472-6947-9-37. 24. thomas cp, kim m, mcdonald a, kreiner p, kelleher sj jr, blackman mb, et al. prescribers’ expectations and barriers to electronic prescribing of controlled substances. j am med inform assoc 2011; 19:375–81. https://doi.org/10.1136/ami ajnl-2011-000209. 25. johnson kb, lehmann cu; council on clinical information technology of the american academy of pediatrics. electronic prescribing in pediatrics: toward safer and more effective medic ation management. pediatrics 2013; 131: e1350–6. https://doi. org/10.1542/peds.2013-0193. 26. abramson el, patel v, pfoh er, kaushal r. how physician perspectives on e-prescribing evolve over time: a case study following the transition between ehrs in an outpatient clinic. appl clin inform 2016; 7:994–1006. https://doi.org/10.4338/ aci-2016-04-ra-0069. 27. cohen jf, bancilhon jm, jones m. south african physicians’ acceptance of e-prescribing technology: an empirical test of a modified utaut model. s afr comput j 2013; 50:43–54. https://doi.org/10.18489/sacj.v50i1.175. 28. savage i, cornford t, klecun e, barber n, clifford s, franklin bd. medication errors with electronic prescribing (ep): two views of the same picture. bmc health serv res 2010; 10:135. https:// doi.org/10.1186/1472-6963-10-135. 29. jawhari b, keenan l, zakus d, ludwick d, isaac a, saleh a, et al. barriers and facilitators to electronic medical record (emr) use in an urban slum. int j med inform 2016; 94:246–54. https://doi.org/10.1016/j.ijmedinf.2016.07.015. squ med j, december 2010, vol. 10, iss. 3, pp. 306-309, epub. 14th nov 10 invited article submitted 15th aug 10 revision req. 8th sept 10, revision recd. 21st sept 10 accepted 25th sept 10 obesity is an epidemic disease in oman and something needs to be done about it,” according to dr. mostafa waly of sultan qaboos university's department of food & nutrition, he observes that about half the men and women of oman are obese or overweight, with the highest prevalence being 71% in dhofar, oman’s southernmost region.1 he also notes that there has been a significant concomitant increase in chronic non-communicable diseases (cncds) in oman in the last few years.1 cncds include cardiovascular conditions (mainly heart disease and stroke), some cancers, chronic respiratory conditions and type 2 diabetes. the situation with regards to cncds is serious in the whole arabian gulf region and some of the countries may actually be worse off than oman. according to figures a few years ago about 64% of men and 70% of women in saudi arabia are obese, as are 79% of women in bahrain. diabetes affects around 18% of adults in oman, but close to 24% in saudi arabia.2,3 the rest of the world is also suffering from an ever-worsening epidemic of cncds, which dr. margaret chan, the directorgeneral of the world health organization (who) calls “…one of the world’s fastest growing and most alarming health problems.”4 why are cncds such an alarming problem worldwide? because they affect people of all ages (although the prevalence is higher with advancing age), nationalities and classes and cause the greatest global share of death and disability, accounting for around 60% of all deaths worldwide. some 80% of chronic diseases deaths occur in lowand middleincome countries (lmics). they account for 44% of premature deaths worldwide.5 the number of deaths from these disease is double the number of deaths that result from all infectious diseases (including hiv/aids, tuberculosis and malaria), maternal and perinatal conditions, and nutritional deficiencies combined. over the coming decades, the burden from cncds is projected to rise particularly fast in lmics. without concerted action some 388 million people worldwide will die of one or more cncds in the next 10 years.5 cncds also have a huge negative economic impact. in 2006, it was estimated that over the following decade, china, india and the united kingdom were projected to lose more than $558 billion, $237 billion and $33 billion, respectively, in national income as a result of heart disease, stroke and diabetes, partly as a result of reduced economic productivity.6 it is likely that the negative economic impact for the gulf region and other arab countries will be considerable. so what accounts for this dramatic increase? some of the factors include longer average lifespans, tobacco use, decreasing physical activity, poor nutrition, and the harmful use of alcohol. urbanisation makes the situation worse through various mechanisms, including air pollution, reduced opportunities for physical activity and dalla lana school of public health sciences and department of surgery, university of toronto, canada; mclaughlin-rotman centre for global health, university health network and university of toronto, canada; global alliance for chronic diseases. email: a.daar@utoronto.ca ƒè€r◊÷<çëç„i<ìëö^ä÷]<4∆<ìfl⁄àπ]<ö]ü⁄˘] ìnëçu<ìèπ^¬<l]öå^f⁄  editorialeditorial chronic non-communicable diseases as a threat for all recent global initiatives abdallah s daar abdallah s daar editorial | 307 dietary changes. fortunately, cncds are largely preventable.7 up to 80% of premature deaths from heart disease, stroke and diabetes can be averted with known behavioural and pharmaceutical interventions. yet, until now, the prevention of cncds has not been a major priority in most countries in the world, and especially so in lmics. in sub-saharan africa it is understandable that governments, donors and research-funding agencies have channelled most resources into infectious diseases such as hiv and malaria. the focus in much of the rest of the world has been on treatment rather than prevention. in oman and the rest of the gulf, most health care expenditure is now on treating and managing the consequences of cncds. in 2003, a study identified the grand challenges in cncds, building on previous experience with the bill and melinda gates foundation’s grand challenges in global health initiative.8,9 a grand challenge in this context was defined as, “a specific critical barrier that if removed would help to solve an important health problem.” daar et al. used the delphi structured consensus building methodology with a study panel of 155 geographically and culturally diverse stakeholders from 50 countries. they identified 20 grand challenges grouped under six goals, and proposed 39 potential research ideas. the six goals are: 1) raise public awareness; 2) enhance economic, legal and environmental policies; 3) modify risk factors; 4) engage business and community; 5) mitigate health impacts of poverty and urbanisation, and 6) reorient health systems.10 these goals may seem simple, but in fact they are very difficult to achieve at scale. for example, it seems simple to prevent and treat cardiovascular disease in an individual: eat healthy foods, increase physical activity, do not smoke at all, do not drink alcohol excessively, and seek health care regularly. however, a report from the institute of medicine notes, “the reality is much more complex. behavior change is difficult, individual choices are influenced by broader social and environmental factors, and many people do not have the resources or access to seek appropriate health care.”11 our nature paper had among its co-authors a number of directors of major national research funding agencies, such as the us national institutes of health’s (nih) national heart, lung and blood institute (nhlbi), the uk medical research council, and the canadian institutes of health research.10 in the paper, we identified the need for coordinated efforts by governments, the who, the world bank and regional development banks, philanthropic foundations, research donor agencies, and most relevant here, major national health research funding agencies. less than two years after the publication of the grand challenges paper, six major national research funding agencies got together in seattle to launch the global alliance for chronic diseases (gacd).12,13 the initial six national funding agency members were the canadian institutes of health research; the nih (represented by nhlbi and fogarty international centre, later joined by national institute for mental health); the medical research council (united kingdom); the australian health and medical research council; the chinese academy of medical sciences, and the indian medical research council (which is awaiting signature of the memorandum of understanding). the south african medial research council joined later, and other agencies may join this year at our board meeting in beijing on 17 october 2010. i look forward to the day when arab countries will join the alliance. qatar has shown some interest already. the gacd is the first such alliance with a specific focus on funding implementation research14 in cncds in lmics and under-served and low income populations of high income countries. it will support collaborative, coordinated research at global scale on low-cost interventions and on capacity building for research and health care delivery, in the process identifying common approaches to develop the evidence base to guide policy. in november 2009, the gacd identified its initial three specific priorities for research funding on a global scale: hypertension, which leads to stroke and in china, for example, is the largest cause of death in adults; reducing tobacco use, (smoking, if unchecked, will kill 1 billion people in the 21st century); and reducing indoor pollution caused by crude cooking stoves, which kills about 1.5 million people every year in lmics.15 other priorities for funding will be identified later. the first request for proposals, to fund implementation research in hypertension, is being developed now and will be announced at gacd’s beijing meeting. the gacd will pursue synergies through such joint initiatives, chronic non-communicable diseases as a threat for all recent global initiatives 308 | squ medical journal, december 2010, volume 10, issue 3 balancing concerns for prevention, treatment, and care; and between knowledge generation and knowledge translation into health policies and interventions that will save large numbers of lives. the who's division of chronic diseases and mental health is headed by dr. ala alwan, assistant director-general of who, estimates that it is possible to achieve a 2% annual reduction in cncd death rates worldwide over the next 10 years. if we achieve this with concerted action, we can avert at least 36 million premature deaths in the next decade. some 17 million of these prevented deaths would be among people under the age of 70.5 the who itself is, of course, taking cncds very seriously. it is a member of the board of the gacd. its plan of action on cncds, which was endorsed in 2008 at the 61st world health assembly, has 6 major objectives: 1) raise the priority accorded to cncd; 2) establish and strengthen national policies and plans for prevention and control; 3) promote interventions to reduce the main shared modifiable risk factors; 4) promote research for prevention and control; 5) promote partnerships, and 6) monitor cncds and their determinants and evaluate progress.16 it has developed a global strategy on diet, physical activity and health; passed a new resolution on ‘marketing of foods and nonalcoholic beverages to children’; is working on a global strategy to reduce the harmful use of alcohol, and has created ncdnet, the non-communicable diseases network.17 as the institute of medicine report notes there remains a “profound mismatch” between the compelling evidence documenting the health and economic burden of cardiovascular diseases (and by extension, other cncds) and the lack of concrete steps to increase investment and implement…prevention and disease management efforts in developing countries.” the gacd, whose members account for more than 80% of health and biomedical research funds in the world, hopes to help fill this gap. the nature paper on grand challenges in chronic non-communicable diseases identified the first goal as raising public awareness.10 the first grand challenge in that goal is to “raise the political priority of non-communicable diseases.” this is where we should start. the investment needed is in prevention. the lives of millions of people are at risk, and although the populations of the gulf countries are not huge, they do have very high levels of obesity and of chronic diseases such as diabetes, and the impact on gulf societies in the long run is likely to be severe. the questions to ponder are therefore as follows: is prevention of chronic noncommunicable diseases a high enough priority for gulf politicians? what can the health/medical community do to make it the highest priority? references 1. joseph a. non-communicable diseases become more prevalent. muscat daily 29 march, 2010. 2. skyler js, ed. diabetes atlas. 2nd ed. brussels: international diabetes federation, 2003. 3. nishtar s. lessons in tackling chronic diseases. bmj 2006; 333:820. 4. chan m. agreements at world health assembly: a gift to public health. closing remarks at 63rd world health assembly. geneva, switzerland, 21 may 2010. from: http://www.who.int/dg/speeches/2010/ w h a _ c l o s i n g _ 2 0 1 0 1 8 0 5 2 1 / e n / i n d e x . h t m l accessed: aug 2010. 5. world health organization. preventing chronic diseases: a vital investment. (who, geneva, 2005). f r o m : h t t p : / / w h q l i b d o c . w h o . i n t / p u b l i c a t i o n s / 2 0 0 5 / 9 2 4 1 5 6 3 0 0 1 _ e n g . p d f accessed: aug 2010. 6. suhrcke m, nugent ra, stuckler d, rocco l. chronic disease: an economic perspective. london: oxford health alliance, 2006. 7. jamison dt, breman jg, measham ar, alleyne g, claeson m, eds. priorities in health. washington dc: world bank, 2006. from: http://www.dcp2.org accessed: aug 2010. 8. varmus h, klausner r, zerhouni e, acharya t, daar as, singer pa. public health. grand challenges in global health. science 2003; 302:398–9. 9. grand challenges in global health. from www. grandchallenges.org accessed: aug 2010. 10. daar as, singer pa, persad dl, pramming sk, matthews dr, beaglehole r, et al. grand challenges in chronic non-communicable diseases. nature 2007; 450:494–6. 11. institute of medicine, us national academies of science. promoting cardiovascular health in the developing world: a critical challenge to achieve global health. march 2010. from: http://www.iom. edu/reports/2010/promoting-cardiovascularhe a l th in th ed e v elo p in g-wo rld acr i ti c a l c h a l l e n g e t o a c h i e v e g l o b a l h e a l t h . a s p x accessed: aug 2010. 12. daar as, nabel eg, pramming sk, anderson w, beaudet a, liu d, et al. the global alliance for chronic abdallah s daar editorial | 309 diseases. science 2009; 324:1642. 13. global alliance for chronic diseases. from: www. ga-cd.org accessed: aug 2010. 14. madon t, hofman kj, kupfer l, glass ri. public health. implement sci 2007; 318:1728–9. 15. six of the world’s foremost health research agencies form alliance to curb humanity’s most fatal diseases: top agencies ally to set common priorities to reduce rising toll of “chronic non-communicable diseases. from: http://www.nhlbi.nih.gov/about/globalhealth/ pdf/alliance.pdf accessed: aug 2010. 16. who. plan of action on non-communicable diseases. f r o m : h t t p : / / w h q l i b d o c . w h o . i n t / p u b l i c a t i o n s / 2 0 0 9 / 9 7 8 9 2 4 1 5 9 7 4 1 8 _ e n g . p d f accessed: aug 2010. 17. ncdnet, the non-communicable diseases network. fr o m : h t t p : / / w w w. w h o . i n t / n c d n e t / a b o u t / e n / accessed: aug 2010. squ med j, november 2011, vol. 11, iss. 4, pp. 477-484, epub. 25th oct 11 submitted 6th mar 11 revision req. 13th jun 11, revision recd. 13th jul 11 accepted 31st aug 11 directorate general of health services, dakhilya region, nizwa, oman. *corresponding author email: ss.alhinai@gmail.com السياحة الطبية للخارج حتدي جديد للنظام الصحي يف ُعمان:جتربة املنطقة الداخلية �ضالح بن �ضيف الهنائي، اأحمد بن �ضعيد البو�ضعيدي، اإبراهيم بن هلل البو�ضعيدي ونفقات، م�ضاكل من ذلك يتبع ما مع ال�ضلطنة خارج يف طبية م�ضورة عن للبحث النا�س تدفع التي الأ�ضباب معرفة الهدف: امللخ�ص: وتو�ضيح اأنواِع امل�ضاكِل الطبية والوجهات املف�ضلة والقناعة باملعاجلة يف اخلارج. الهدف الثانوي لهذه الدرا�ضة هو اإعطاء نبذة لأ�ضحاب القرار يف نظاِم الرعاية ال�ضحية عن َكيفية التعامل مع هذه الظاهرة مبا يلبي احتياجات املجتمع. الطريقة: مت توزيع ا�ضتبيان على 45 من املر�ضى الذين �ضافروا للعلج خارج ال�ضلطنة موؤخرا اأو باملقابلة الهاتفية. النتائج: مت ا�ضتلم 40 ا�ضتبيانا، 68% من امل�ضاركني كانوا من الذكور. كانت اأمرا�س العظام من اأكرث الأمرا�س التي مت علجها باخلارج، وكانت تايلند الوجهة املف�ضلة َتليها الهند )50 % و30 % على التوايل(. �ضافر 85َ% من املر�ضى للخارج للمعاجلة فقط، بينما �ضافر 10% منهم للمعاجلة وال�ضياحة معا، و 2.5% كانوا اأ�ضحاء ا�ضت�ضارة طلب دون للخارج مبا�رسة �ضافروا بالدرا�ضة امل�ضاركني اأن 15% من املده�س من الطبية. الفحو�ضات لإجراء �ضافروا ولكنهم طبية داخل ال�ضلطنة. 38.2% من الذين متت معاينتهم يف ال�ضلطنة مل يكن هناك ت�ضخي�س حمدد، و38.2% اأخذوا علجا لكنه مل يكن فعال. ح�ضل 73% من امل�ضاركني يف العينة على معلومات من الأ�ضدقاء عن العلج باخلارج، وكانت مكاتب ال�ضياحة الطبية وال�ضبكة الدولية اأقل امل�ضادر ا�ضتخداما. ح�ضلت م�ضاعفات بعد العلج يف اخلارج عند 15% من املر�ضى.اخلال�صة: ينبغي تعميم احلقائق املختلفة حول العلج يف اخلارج يف املجتمع، وهذا ي�ضتوجب جهودا اأكرب يف تعزيز ال�ضحة العامة والتثقيف ال�ضحي. مفتاح الكلمات: ُعمان، ال�ضياحة الطبية، نظام الرعاية ال�ضحية. abstract: objectives: this study aimed to understand why people seek medical advice abroad given the trouble and expense this entails. the types of medical problems for which treatment abroad was sought, preferred destinations and satisfaction with the treatment were explored. a secondary aim was to give feedback to stakeholders in the health care system on how to handle this issue and meet the needs of the community. methods: 45 patients who had recently travelled abroad for treatment were asked to complete a questionnaire or were interviewed by telephone. results: 40 questionnaires were received. 68% of the respondents were male. orthopaedic diseases were the most common conditions leading patients to seek treatment abroad. thailand was the most popular destination followed by india (50% and 30% respectively). 85% of respondents went abroad for treatment only, 10% for treatment and tourism and 2.5% were healthy, but travelled abroad for a checkup. interestingly, 15% of the participants went abroad without first seeking medical care locally. out of those initially treated in oman, 38.2% had no specific diagnosis and 38.2% had received treatment, but it was not effective. 73% of respondents obtained information on treatment abroad from a friend. the internet and medical tourism offices were the least used sources of information. 15% of the patients experienced complications after their treatment abroad. conclusion: various facts about medical treatment abroad need to be disseminated to the public. this will necessitate greater effort in public health promotion and education. keywords: oman; medical tourism; health care system. medical tourism abroad a new challenge to oman’s health system al dakhilya region experience *saleh s. al-hinai, ahmed s. al-busaidi, ibrahim h. al-busaidi clinical & basic research advances in knowledge 1. medical tourism abroad is a growing phenomenon that needs to be addressed carefully by health care authorities in oman. 2 public misconceptions about the standards of treatment abroad need to be addressed by extensive health education. applications to patient care 1. patients interested in going abroad for medical treatment need to be handled prudently by their treating physician. 2 patients who insist on going abroad for a second opinion need to be appropriately guided and provided with all the relevant clinical data and evidence based medical information. medical tourism abroad a new challenge to oman’s health system the al dakhilya region experience 478 | squ medical journal, november 2011, volume 11, issue 4 in a globalising world, health care is no longer confined within national borders. medical tourism is a new term used to describe the practice of seeking medical care abroad for nonemergency conditions. there is not yet an agreed international term for a person who travels abroad to seek medical treatment. some experts label such patients “health tourists” or “medical tourists”. however, these terms suggests that travel abroad is for pleasure, which is at odds with the anxiety and pain often involved in seeking medical treatment. therefore some prefer to refer to “medical travellers” even though the person might decide to combine his/her medical treatment abroad with tourism. globalisation has prompted countries to evaluate their position on trade in health services.1-5 the full extent of this trend is yet unknown, as data are sparse and anecdotal due to the absence of an internationally agreed definition and of a common methodology for data collection. this means that the limited statistics on medical tourism are often not comparable across countries; however, the available observations suggest that a substantial number of patients do travel to other countries for health care. for example, it is reported that malaysia received 360,000 foreign patients from the association of southeast asian nations (asean) region in 2007.6 according to a study by the world health organization’s (who) regional office for the eastern mediterranean, each year jordan treats more than 120,000 non-jordanian patients, generating an estimated us$ 1 billion in annual revenue.7 regarding the number of residents from the usa travelling abroad for health services, a study by deloitte consulting estimated that 750,000 americans travelled abroad for health services in 2007 and that this number would increase to 1.6 million by 2012.8 a study by the consulting firm, mckinsey, estimated that the number of us residents travelling abroad for medical care was estimated to range between 5,000 and 750,000 depending on the definition of medical travel.9 in oman, there is a national committee for treatment abroad which decides on the eligibility of candidate patients. the number of people it sent for treatment abroad was only 20 per 100,000 of the population in 2010 (so approximately 610 persons), down from about 59 per 100,000 in 1977 (information provided in email by the moh’s department of treatment abroad). the decline in numbers reflects the diminishing importance of treatment abroad following the development of health services in oman. the total expenditure on treatment abroad by the ministry of health (moh) in oman in 2003 was us$ 2,563,171. patients are sent to the uk (london), india and germany.10 it was out of the scope of this study to measure the magnitude of medical tourism in oman or even in dakhilya region due to unavailability of statistics. if this trend continues, experts are convinced that it will have major implications for public health systems around the globe. despite the growing importance of medical travel, we still have little empirical evidence about its impact on public health, especially on health systems.1 the medical community in developed countries has started to recognise medical tourism as a real phenomenon that impacts the profession, practitioners and patients. peer-reviewed medical and health journals began publishing papers on this topic in 2006.11 the medical tourism marketplace consists of a growing number of countries competing for patients by offering a wide variety of medical, surgical, and dental services. some of the medical tourism companies hook patients up with a hospital and surgeon, arrange for their family doctors to send records and consult with the surgeons overseas, make travel arrangements and book hospital admissions.12 they are many motivators for seeking treatment abroad such as: 1) increased access to information about foreign health providers through the new developments in information technology; 2) lower international transportation costs; 3) reduced language barriers due to globalisation; 4) treatments unavailable in the home country for legal, cultural or other reasons such as injections of stem cells; 5) long waiting lists for certain procedures (uk and canada),1 and 6) inappropriate health insurance coverage (usa).12,13 however, researchers also found some barriers to medical tourism like the financial cost, fear of the unfamiliar and lack of confidence in foreign health care systems, discouragement by family doctors or treating physicians, and feeling too ill to travel.14 customers of medical tourism companies can purchase anything from cosmetic procedures and diagnostic examinations to kidney transplants, in vitro fertilisation, cancer therapies, and orthopaedic procedures. the cost of medical tourism packages saleh s. al-hinai, ahmed s. al-busaidi, ibrahim h. al-busaidi clinical and basic research | 479 varies greatly. the prices depend on the types of procedures, where patients travel, how long they intend to stay, and whether they choose postoperative accommodation in budget hotels or luxury resorts.15 medical travel has also raised several ethical issues. this is more evident when there are differential health policies in a particular country, i.e. one for the citizens as a public service and another standard for foreigners coming in as paying clients. informed consent is a key ethical and legal issue as medical tourism companies are obliged to explain to patients the risks and benefits of medical procedures abroad.8 the potential exacerbation of health inequities in destination and source countries and the disruption of continuity of care for patients are other ethical concerns. the international conference on ethical issues in medical tourism (icemt) raised three key points: 1) medical tourism has the potential for crossor inter-disciplinary research; 2) medical tourism research must engage with empirical research from a variety of disciplines, and 3) ethical analyses of medical tourism must incorporate both individual and population-level perspectives.16 many countries, especially in the far east, invest in this emerging industry in order to build a modern medical infrastructure that will attract foreigners and will create a new source of income while improving the medical services provided to the local community.17 to respond to the growth in medical travel, many countries have set guidelines and accreditation tools to regulate its quality. examples are the joint commission (formerly the joint commission on accreditation of health care organizations) which initiated the joint commission international (jci) to accredit hospitals worldwide,18 and the standards framework for regulating the medical tourism industry and statement on medical and surgical tourism.19,20 these tools address a number of concerns about this new industry and some of the safety and quality issues that patients may encounter if they seek health care services abroad. the objectives of this study are thus threefold: first, to provide an overview of the main reasons and trends of patients travelling across borders from the dakhilya region of oman and their preferred destinations; second, to analyse the satisfaction rating of local treatment compared with that received abroad. third, it aims to present the main challenges and areas for improvement for the health system and public health stakeholders in oman as regards medical tourism. methods the study was conducted in al dakhilya region (in north central oman) between march 2009 and august 2010. a questionnaire about medical tourism was developed after a literature review and discussion with colleagues in the directorate general of health services, dakhilya region. the questionnaire was composed of two sections. section one collected demographic and other data (including age, sex, place of residence, date of diagnosis in oman, date of treatment abroad and the country where treatment abroad took place). section two had questions on the reasons for treatment abroad, its costs, quality and the outcome of the treatment and finally which part of the body needed treatment. the questionnaire was distributed to all those who travelled abroad for health care during above period. the subjects, who were mainly employees and all from the dakhilya region, were enrolled in the study when they came to the department of health affairs in the directorate general of health services in nizwa for countersignature of their sick leave permission from their places of work in order to travel abroad for treatment. verbal consent was taken from participants for participation in the study and they were assured that refusal would not lead to any adverse consequences. most of the subjects were given the questionnaire for completion. a few were interviewed by telephone when the person who came to obtain the sick leave countersignature was not the patient. the omani national treatment abroad committee pays the expenses of treatment of those patients sent by the government. those going by themselves are not reimbursed. those who were sent abroad for treatment by the government were excluded from this study because it was not their decision to travel abroad for treatment, therefore their answers as to reasons for travel, destinations and satisfaction would be biased. the data were analysed using the statistical package for the social sciences (spss, chicago, il, usa, version 16). the chi square statistical test was used and the p value set at < 0.05. the study protocol medical tourism abroad a new challenge to oman’s health system the al dakhilya region experience 480 | squ medical journal, november 2011, volume 11, issue 4 was approved by the medical research and ethics committee of the directorate general of health services, al dakhilya region. results out of 45 forms distributed, 40 forms were completed, returned and analysed (response rate 89%). all were completed by omanis. using descriptive analysis, the mean age of the study population was 38 years. the highest percentage of respondents was in the age group 31–40 years (31%). more males went abroad for treatment (67.5%) than females (32.5%). a total of 50% of the participants went to thailand for treatment followed by india (30.0%), iran (10.0%), bahrain (7.5%) and united arab emirates (uae) 2.5%. as to the distribution of clients according to their reason of travel, 85% of the participants travelled abroad to get treatment only; 10% for both treatment and tourism; 2.5% for a check-up, and another 2.5% for other reasons. about 85% of the study sample was treated in oman before going abroad for treatment; thus, 15% went straight abroad for treatment without seeking treatment locally. the results of treatment of those treated inside oman first are shown in figure 1a. a total of 38.2% of the participants did not receive a specific diagnosis in oman, and also 38.2% of the participants received treatment, but they did not find it beneficial. more than 70% of the participants in the study got information about health institutions abroad from their friends and 18.9% from their family [figure 1b]. the highest percentage of respondents went abroad for treatment for orthopaedic diseases followed by neurological and then ophthalmological disease [table 1]. using univariate analysis, those people aged 30–40 years had the most orthopaedic diseases (41.7%) followed by those aged 41–50 years (33.3%). neurological diseases were also more prevalent in both age groups 31-40 and 41-50 years old compared to other age groups. eye diseases were apparently more prevalent among people over 50 years old; however, due to the small sample size, the association between age and type of diseases (p = 0.494) was not statistically significant. male subjects went for treatment abroad mainly for orthopaedic diseases (28%), neurological diseases (28%) and gastroenterological diseases (24%). females went for treatment abroad for orthopaedic diseases (38.5%), eye diseases (38.5%) and neurological diseases (15.4%). the association between type of disease and sex (p = 0.116) was, however, not statistically significant. about one third of the participants stayed abroad for one week for treatment while 25% of the participants stayed 1–2 weeks. those participants who travelled for orthopaedic, gastroenterological and neurological diseases preferred going to thailand while those participants who sought treatment for eye diseases preferred to go to iran; participants who sought treatment for cardiac figure 1a: distribution of subjects according to result of treatment inside oman. figure 1b: distribution of subjects according to source of information about health institutions outside oman. table 1: distribution of subjects according to type of disease type of disease percentage orthopaediatric 31.6 neurological 23.7 ophthalmological 18.4 gastroenterological 15.8 cardiac 7.9 physiotherapy treatment 2.6 saleh s. al-hinai, ahmed s. al-busaidi, ibrahim h. al-busaidi clinical and basic research | 481 diseases preferred to go to india. the association between type of diseases and country (p = 0.051) was, however, not statistically significant. concerning cost, more than 60% of the participants spent less than 2,000 omani rials (c. us $ 5,200) for treatment abroad while 38% of the participants in the study spent more than 2,000 omani rials [figure 2]. a total of 45% of the participants who went to thailand spent more than 2,000 omani rials and 41.7% of the participants who went to india also spent more than 2,000 omani rials whereas 75% of the participants who went to iran spent 1,000–1,500 omani rials. the association between the cost of treatment and the country of treatement (p = 0.249) was, however, not statistically significant. we found that the percentage of satisfaction about treatment abroad was 100% in all countries except india where it was 83.3% giving an overall satisfactory percentage of 95%. there was no association between satisfaction with treatment and country (p = 0.296). a total of 15% of the participants developed some complications related to the treatment. these complications include pain, allergy, swelling and high blood pressure. half of the participants had follow-up in governmental health institutions after coming back from abroad with 55% of them getting better [figure 3]. visits to bahrain produced the highest percentage of treatment complications (33.3%) followed by india (16.7%) and thailand (15%). the association between treatment complications and country (p = 0.685) was, however, not statistically significant. discussion the sample size of this study was relatively small due to the difficulty of enrolling in the study those who travelled abroad for treatment because of the unavailability of a database. nevertheless it revealed some interesting findings. men travelled more than women probably since they are able to travel alone, while women, following islamic and traditional customs, usually need a male companion. the overall mean age was 38 years which means that people tend to seek medical care abroad while they are young. due to low medical care costs in south asian countries, india and thailand were the most popular destinations for treatment abroad. this is contrary to a study of saudi patients who travelled abroad for renal transplantation where the majority of transplant tourists obtained their kidneys in pakistan (49%) followed by the philippines (28%), egypt (11%), and the united states (3.2%).21 although the majority of patients went for treatment only, it is interesting that some of them (10%) went for tourism as well. the explanation could be explained that they initially decide to go for tourism and then decide to obtain a medical check-up at the same time. this decision could also be influenced by the long delays and waiting lists at home. a study on reproductive health tourism in the united arab emirates (uae) found that another reason for travel is privacy; this is a concern in an environment where both infertility and in vivo fertilisation are still stigmatised.22 one of the interesting findings in our study is that 15% of the participants did not even seek any medical care locally, but rather travelled abroad directly although their illness could have been figure 2: distribution of subjects according to cost of treatment abroad in omani rials (ro) (1 ro = c. us $ 2.6). 0% 20% 15.0 % 5.0% 15.0 % 55.0% 10.0% 40% 60% 80% 100% treatment of disease no complication complication present disease got better other no . o f t es ts x 1 00 0 figure 3: distribution of subjects according to evaluation by omani government doctors after return to oman. medical tourism abroad a new challenge to oman’s health system the al dakhilya region experience 482 | squ medical journal, november 2011, volume 11, issue 4 managed locally. the reasons for such trend was not clear from this study so further studies may be necessary in future in order to explore this issue specifically. although dissatisfaction with local treatment was thought to be a major reason for seeking treatment abroad, this study showed only 5.9% of the participants were dissatisfied with local treatment. concerning their source of information on treatment abroad, the internet, newspapers and medical tourism offices were the least used sources (2.7% each); these are all available in oman, but their low usage would indicate that people still intend to use traditional methods (such as word of mouth) as their source of information. although one may think that medical care abroad is cheap, overall costs are high. one third of participants in this study paid more than 2,000 omani rials (c. us $ 5,200) for their treatment. this may give an insight into how much people may be ready to spend on their health. a case report from bahrain showed that the prescription of 19 drugs, many of equivocal benefit, at a monthly estimated cost of us $ 615 imposed a substantial economic burden on the patient and led to poor adherence due to the confusing drug regimen.23 while it is thought that treatment abroad does not lead to complications, this study revealed that 15% of the participants indeed suffered some complications. this percentage may also be an underestimation since people may prefer not to report problems so as not to be blamed for seeking medical care outside their country. in addition, some complications do not manifest immediately; however, the subjects in this study responded to the questionnaire within days or at a maximum 2 weeks after their return from treatment abroad. alghamdi et al. in 2010 showed that the group of ‘transplant tourists’ had a significantly higher rate of acute rejection within the first year compared with those who underwent local transplantation (27.9% versus 9.9%, p = 0.005). also, compared with local transplantation, transplant tourists had a higher rate of cytomegalovirus (cmv) infections (15.1% versus 5.6%, p = 0.05) and hepatitis c seroconversion (7.5% versus 0%, p = 0.02).21 in 2011, al khaja reported on a bahrani patient who experienced adverse effects due to the polypharmacy prescribed abroad; these included nausea, vomiting, gastric pain, flatulence, severe constipation, tiredness, palpitation, nervousness and dizziness which compromised the patient’s quality of life and resulted in poor medication compliance.23 the most popular specialty for which people sought medical care abroad in this study was orthopaedics. this could be explained by the chronic nature of such diseases, its high prevalence, especially among the elderly, and the scarcity of specialist clinics in each health institution or region of oman. the limitations of this study included scarcity of data and statistics on patients who travelled abroad for treatment; this resulted in a small sample size. a further limitation is the shortage of scientific literature about medical tourism in arab and arabian gulf countries. further studies in these various countries, individually or as multicentre studies, are required to obtain a clearer picture of the treatment abroad trend. conclusion this study has shown that it is very difficult to obtain data on patients who travel abroad for treatment. this therefore necessitates the establishment of national registries and databases. many facts regarding medical tourism should be made clear to the community (e.g. treatment abroad can have some complications, is costly and that consultation with a local doctor is necessary prior travel). modern technological methods for accessing information sources should also be advocated (i.e. internet). health education about the treatment of chronic diseases should be intensified so that people can decide whether there is chance for their illness to get cured abroad or not. specifically, two different approaches can be used to respond to the issues which this study raises in oman about medical treatment abroad: the public health sector approach and the community approach. first, the omani public health authorities (the moh and its sister institutions) need to pay more attention to this trend by establishing a national database and registry of treatment abroad which should be regular audited. second, omani authorities, in conjunction with those in the destination countries, should 1) set standards as a framework for regulating the medical tourism saleh s. al-hinai, ahmed s. al-busaidi, ibrahim h. al-busaidi clinical and basic research | 483 industry and encourage other countries to do so; 2) accredit medical tourism companies and then regularly review their accreditation; 3) mandate medical tourism companies to contribute to funds to protect clients from financial losses and to compensate them in case of complications or medical errors.1,5,12 scientific conferences and workshops organised with other gulf cooperation council (gcc) countries should also be encouraged in order to empower researchers and scientists to understand this phenomenon in our immediate region. as to the community approach, the aim would be to raise awareness through the various media among all age groups in the community about medical tourism and its implication for individuals, families, communities and countries. since it was shown clearly by our study that data and statistics about medical tourists are limited and difficult to trace, people should be requested to report to their primary health care institution on their return for recording and follow-up. patients planning on medical tourism should know that they need to consult their local doctors first, use modern technologies (e.g. the internet for browsing destinations options and offers), and be aware that complications can occur in treatment abroad. this awareness raising and education would be better undertaken as a multidisciplinary effort by various ministries, agencies and non-governmental organisations (ngos). c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. helble m. the movement of patients across borders: challenges and opportunities for public health. bull world health organ 2011; 89:68–72. 2. crooks va, kingsbury p, snyder j, johnston r. what is known about the patient’s experience of medical tourism? a scoping review. bmc health serv res 2010; 10:266. 3. johnston r, crooks va, snyder j, kingsbury p. what is known about the effects of medical tourism in destination and departure countries? a scoping review. int j equity health 2010; 9:24. 4. martinez alvarez m, chanda r, smith rd. the potential for bi-lateral agreements in medical tourism: a qualitative study of stakeholder perspectives from the uk and india. global health 2011; 7:11. 5. snyder j, dharamsi s, crooks va. fly-by medical care: conceptualizing the global and local social responsibilities of medical tourists and physician voluntourists. global health 2011; 7:6. 6. whittaker a. pleasure and pain: medical travel in asia. glob public health 2008; 3:271–90. 7. trade in health service and gats. world health organization, regional office for eastern mediterranean. from: http://gis.emro.who.int/ healthsystemobservatory/pdf/trade%20and%20 health%20services/jordan.pdf. accessed: jul 2011. 8. medical tourism consumers in search of value. deloitte center for health solutions. fro m : http : / / w w w. d el o i tte . co m / a s s e t s / d co m unitedstates/local%20assets/documents/us_chs_ medicaltourismstudy(3).pdf. accessed: jun 2011. 9. ehrbeck t, guevara c, mango pd. mapping the market for medical travel. the mckinsey quarterly, may 2008. from: https://www.mckinseyquarterly. c o m / m a p p i n g _ t h e _ m a r k e t _ f o r _ t r a v e l _ 2 1 3 4 . accessed: jul 2011. 10. suleiman bj. trade in health services and gats in the sultanate of oman. from: http://www.searo. who.int/linkfiles/publications_sultanate_oman. pdf. accessed: jul 2011. 11. horowitz md, rosensweig ja, jones ca. medical tourism: globalization of the healthcare marketplace. med gen med 2007; 9:33. 12. eggertson l. wait-list weary canadians seek treatment abroad. cmaj 2006; 174:1247. 13. bouvier pa. medical tourism: a new kind of traveler. rev med suisse 2008; 4:1196, 1198–201. 14. johnston r, crooks va, adams k, snyder j, kingsbury p. an industry perspective on canadian patients’ involvement in medical tourism: implications for public health. bmc public health 2011; 11:416. 15. turner l. medical tourism: family medicine and international health-related travel. can fam physician 2007; 53:1639–41, 1646–8. 16. snyder j, crooks v, turner l. issues and challenges in research on the ethics of medical tourism: reflections from a conference. j bioeth inq 2011; 8:3–6. 17. rotem a, toker a, mor-yossef s. medical tourism: changing a world trend into a national resource. harefuah 2009; 148:30–3, 88. 18. york d. medical tourism: the trend toward outsourcing medical procedures to foreign countries. j contin educ health prof 2008; 28:99–102. 19. turner lg. quality in health care and globalization of health services: accreditation and regulatory oversight of medical tourism companies. int j qual health care 201; 23:1–7. 20. unti ja. medical and surgical tourism: the new medical tourism abroad a new challenge to oman’s health system the al dakhilya region experience 484 | squ medical journal, november 2011, volume 11, issue 4 world of health care globalization and what it means for the practicing surgeon. bull am coll surg 2009; 94:18–25. 21. alghamdi sa, nabi zg, alkhafaji dm, askandrani sa, abdelsalam ms, shukri mm, et al. transplant tourism outcome: a single center experience. j transplant 2010; 90:184–8. 22. inhorn mc, shrivastav p. globalization and reproductive tourism in the united arab emirates. asia pac j public health 2010; 22:s68–74. 23. al khaja ka, sequeira rp, damanhori ah. polypharmacy associated with medical tourism: a critique on drug therapy. int j clin pharm 2011; 33:61–5. 1department of emergency medicine, khoula hospital, muscat, oman; 2division of plastic & reconstructive surgery, university of toronto, toronto, ontario, canada; 3ear, nose & throat residency programme, oman medical specialty board, muscat, oman; 4emergency medicine royal college residency training programme, mcgill university, montreal, quebec, canada *corresponding author e-mail: drsultanalshaqsi@gmail.com نتائج حاالت الرضوح املتعدد يف حوادث املرور يف مستشفى ثالثي عمان هل مثة فرق بني حضور جراحي الرضوح وحضور غريهم من اجلراحني؟ عمار الك�سمريي، �سلطان ال�سق�سي، ندى املرهوبي، حممود ح�سن abstract: objectives: trauma surgeons are essential in hospital-based trauma care systems. however, there are limited data regarding the impact of their presence on the outcome of multi-trauma patients. this study aimed to assess the outcomes of multi-trauma road traffic crash (rtc) cases attended by trauma surgeons versus those attended by non-trauma surgeons at a tertiary hospital in oman. methods: this retrospective study was conducted in december 2015. a previously published cohort of 821 multi-trauma rtc patients admitted between january and december 2011 to the sultan qaboos university hospital, muscat, oman, were reviewed for demographic, injury and hospitalisation data. in-hospital mortality constituted the main outcome, with admission to the intensive care unit, operative management, intubation and length of stay constituting secondary outcomes. results: a total of 821 multi-trauma rtc cases were identified; of these, 60 (7.3%) were attended by trauma surgeons. there was no significant difference in mortality between the two groups (p = 0.35). however, patients attended by trauma surgeons were significantly more likely to be intubated, admitted to the icu and undergo operative interventions (p <0.01 each). the average length of hospital stay in both groups was similar (2.6 versus 2.8 days; p = 0.81). conclusion: no difference in mortality was observed between multi-trauma rtc patients attended by trauma surgeons in comparison to those cared for by non-trauma surgeons at a tertiary centre in oman. keywords: multiple trauma; resuscitation; patient outcome assessment; surgeons; trauma centers; oman. امللخ�ص: الهدف: يعد وجود جراحي الر�سح اأمرا الزما يف امل�ست�سفيات التي بها اأنظمة رعاية للر�سوح. غري اأنه ال تتوفر معلومات كافية عن مدى تاأثري وجودهم على نتائج املر�سي امل�سابني بر�سوح متعددة. وتهدف هذه الدرا�سة لتقومي نتائج حوادث املرور على الطرق التي يقوم عليها جراحو الر�سوح مقارنة مع تلك التي يقوم عليها غريهم من اجلراحني يف م�ست�سفى ثالثي عمان. الطريقة: اأجريت هذه الدرا�سة 821 حلاالت واال�ست�سفاء واالإ�سابة بالدميغرافيا اخلا�سة املخزنة املعلومات مراجعة ومتت 2015م، عام من دي�سمرب يف االإ�ستعادية مري�سا اأدخلوا مل�ست�سفى جامعة ال�سلطان قابو�س يف م�سقط عمان بني يناير ودي�سمرب 2011م. وكانت الوفاة يف امل�ست�سفى هي النتيجة الرئي�سة، اأما النتائج الثانوية فكانت هي االإدخال يف العناية املركزة، والعالج اجلراحي، والتنبيب، ومدة البقاء بامل�ست�سفى. النتائج: بلغ عدد امل�سابني بر�سوح متعددة يف حوادث املرور على الطرق يف فرتة الدرا�سة 821 مري�سا، قام على رعاية 60 منهم )%7.3( جراحو ر�سح. ومل يكن هنالك فرق اإح�سائي معتد )معنوي( يف معدل الوفاة بني هذه املجموعة وغريها )p = 0.35(. اإال اأن معدل املر�سى الذين قام على رعايتهم جراحو الر�سح كانوا اأكرث تنبيبا واإدخاال للعناية املركزة وخ�سوعا للتدخالت اجلراحية من غريهم )p <0.01 يف كل حالة(. ومل يكن هنالك فرق اإح�سائي معنوي يف فرتة البقاء يف امل�ست�سفى بني املجموعتني )2.6 يوما يف مقابل 2.8 يوما، p = 0.81(. اخلال�صة: مل يكن هنالك فرق اح�سائي معنوي يف معدل الوفاة عند امل�سابني الذين قام على رعايتهم جراحو الر�سح مقارنة بامل�سابني الذي قام على رعايتهم جراحون اآخرون يف م�ست�سفى رعاية ثالثية بعمان. الكلمات املفتاحية: ر�سوح متعدد؛ اإنعا�س؛ تقومي نتائج املر�سى؛ اجلراحون؛ مراكز الر�سح؛ عمان. outcomes of multi-trauma road traffic crashes at a tertiary hospital in oman does attendance by trauma surgeons versus non-trauma surgeons make a difference? ammar al-kashmiri,1 *sultan z. al-shaqsi,2 nada al-marhoobi,3 mahmood hasan4 clinical & basic research sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e196–201, epub. 20 jun 17 submitted 25 jan 17 revision req. 27 feb 17; revision recd. 13 mar 17 accepted 19 mar 17 doi: 10.18295/squmj.2016.17.02.010 advances in knowledge in oman, multi-trauma road traffic crash (rtc) cases attended by non-trauma surgeons were found to have similar outcomes to those cared for by trauma surgeons. application to patient care many of the multi-trauma rtc cases in the current study were attended by non-trauma surgeons. as such, non-trauma surgeons in oman should be trained in the management and resuscitation of multi-trauma patients in order to strengthen overall trauma care services in the country. ammar al-kashmiri, sultan z. al-shaqsi, nada al-marhoobi and mahmood hasan clinical and basic research | e197 trauma injuries represent a significant global burden, particularly in middleand lowincome countries; the world health organization (who) has estimated that approximately five million people die every year from injuries, most often due to road traffic crashes (rtcs), violence or burns.1 the physical effects of such injuries can be classified as either immediate, secondary (i.e. within hours of the event) or delayed (i.e. long-term complications). most trauma-related deaths occur either at the scene of the injury or en route to or within hours of arrival at a healthcare facility.1 therefore, pre-hospital and initial hospital-based trauma systems focus on reducing the immediate effects of injuries on mortality and morbidity by promptly providing essential life-saving trauma interventions, such as securing a patient’s airway, maintaining adequate ventilation and controlling bleeding.1 the who has advocated for the establishment of trauma care systems globally in order to mitigate the mortality and morbidity of trauma injuries.2 moreover, the american college of surgeons recommend that trauma surgeons be present upon the initial arrival of a seriously injured patient to the emergency department.3 oman has one of the highest rates of rtcs globally; in 2015, there were approximately 6,279 rtcs and this type of accident was the direct cause of 675 deaths and 3,624 injuries.4 moreover, the rtcrelated fatality rate in 2013 was 30.4 per 100,000 people annually compared to the global yearly average of 18 per 100,000 people.5 an increase in car ownership as a result of rapid modernisation and the development of new roads and highways due to urbanisation processes have contributed to a dramatic increase in rtcs.6–8 other complex behavioural issues related to modernisation, such as increased use of mobile phones while driving, may also be partially responsible for the high rate of rtcs in oman.6,9 in some cases, traffic enforcement and legal authorities have failed to keep up with rapid modernisation, resulting in more lenient and less than optimal law enforcement. the trauma system in oman consists of a pre-hospital emergency system and the emergency medical services (ems) run by the public authority of civil defence and ambulances.10,11 hospitals in oman vary in size and resources, ranging from rural health centres staffed by junior non-specialist doctors to tertiary hospitals with qualified trauma and non-trauma surgeons. the sultan qaboos university hospital (squh) in muscat is the only national tertiary hospital in the country which has board-certified trauma surgeons with training in trauma and critical and acute care surgeries, excluding emergency craniotomies.10,11 at squh, the emergency department receives an average of 900 trauma patients annually.11 trauma teams consist of a team leader (either a trauma or non-trauma surgeon), an anaesthetist, an emergency physician, residents in emergency or general surgery and allied health personnel. however, while some of the trauma teams are led by board-certified trauma surgeons, others are led by non-trauma surgeons for whom the scope of emergency procedures is limited to abdominal damage control. it is therefore not clear whether the presence of board-certified trauma surgeons affects the outcome of injured patients. this study aimed to assess differences in outcomes among multitrauma patients injured in rtcs who were attended by board-certified trauma surgeons compared to those attended by non-trauma surgeons. methods this retrospective study took place in december 2015 and utilised the same cohort as that of a previously published study.11 the electronic medical records of all rtc multi-trauma patients admitted to the emergency department of squh between january and december 2011 were reviewed. data for all cases were collected, including the demographic characteristics of the patient and whether they were attended by a board-certified trauma surgeon or a non-trauma surgeon.11 additionally, information regarding patient outcome, length of hospital stay and injury details, severity and management was recorded.11 the primary outcome was in-hospital mortality, with secondary outcomes constituting of admission to the intensive care unit (icu), surgical interventions and length of hospital stay. data were analysed using the statistical package for the social sciences (spss), version 22.1 (ibm corp., armonk, new york, usa). differences between variables were initially determined using a univariate analysis. for continuous variables, a student’s t-test or mann-whitney u test was used whereas a yates’ chi-squared test or fisher’s exact test was used for categorical variables, as appropriate.12 a p value of <0.05 was considered statistically significant. a general linear multivariate regression analysis was performed to determine if the primary and secondary outcomes were the same between the two groups, after controlling for variables with potential confounding effects, such as age, gender, ethnicity, time of injury, admissions over the weekend, triage status, injury severity score (iss) and the presence of a head injury. this study received ethical approval from the ethics committee of the ministry of health in oman. outcomes of multi-trauma road traffic crashes at a tertiary hospital in oman does attendance by trauma surgeons versus non-trauma surgeons make a difference? e198 | squ medical journal, may 2017, volume 17, issue 2 results a total of 821 multi-trauma rtc cases were admitted during the study period.11 of these, 60 (7.3%) were attended by trauma surgeons and 761 (92.7%) were attended by non-trauma surgeons. the average age of patients attended by trauma surgeons was similar to that of patients attended by non-trauma surgeons; however, significantly more of the trauma patients attended by trauma surgeons were male compared to those attended by other surgeons (85.0% versus 65.8%; p = 0.01). a similar proportion of patients in both groups were of omani ethnicity. almost onethird of the patients in both groups were admitted to the hospital during weekends and approximately twothirds were transported to the hospital by the ems. patients admitted between 8 a.m. and 3 p.m. were significantly more likely to be attended by trauma surgeons (35.0% versus 25.4%; p = 0.04) while those admitted between 4 p.m. and 11 p.m. were significantly more likely to be seen by non-trauma surgeons (51.5% versus 38.3%; p = 0.03). in terms of triage status, significantly more patients in the ‘resuscitation’ (16.7% versus 8.3%) and ‘emergency’ (33.3% versus 9.6%) triage categories were attended by trauma surgeons (p <0.01) [table 1]. the majority of cases in both groups had an iss of 0–15. however, 26.7% of cases attended by trauma surgeons had head injuries compared to 8.7% of cases attended by non-trauma surgeons (p <0.01). nevertheless, when patients with severe head injuries were compared using the abbreviated injury score (ais) for injuries of >3 ais severity, there was still no difference in outcome between the two groups. after controlling for potential confounders in the regression analysis, no significant differences were noted with regards to in-hospital mortality between patients attended by trauma surgeons and those attended by non-trauma surgeons (p = 0.35), even when stratified by head trauma ais or iss scores (p = 0.42 and 0.50, respectively). in addition, no significant difference was observed with regards to the length of stay between the two groups (2.8 versus 2.6 days; p = 0.81) however, patients attended by trauma surgeons were significantly more likely to be intubated (relative risk [rr]: 13.3; confidence interval [ci]: 7.76–22.7; p <0.01), admitted to the icu (rr: 7.2; ci: 4.16–12.62; p <0.01) and undergo surgical interventions (rr: 3.5; ci: 2.64–5.48) [table 2]. discussion the burden of trauma in oman has been steadily rising over the last few decades, thus highlighting the need for a well-established trauma system.6,11 a well-resourced trauma system is known to improve mortality rates.13–17 however, the trauma system in oman has not kept pace with modernisation and rapid population growth in the country. furthermore, a non-holistic approach has led to a lack of integration of trauma care services within the existing healthcare system; for example, as the pre-hospital trauma care system has developed faster than existing hospital systems, there can be a decline in care once the patient is transferred to a medical facility. at present, squh is the only facility in the country with qualified trauma surgeons who have undergone structured training. however, within established hospital trauma systems, it remains to be seen whether all trauma cases require table 1: demographic and injury characteristics of multitrauma road traffic crash cases admitted to the sultan qaboos university hospital, muscat, oman (n = 821) characteristic n (%) p value patients attended by trauma surgeons (n = 60) patients attended by non-trauma surgeons (n = 761) mean age in years (range) 29.8 (1–67) 27.6 (2–79) 0.20 male gender 51 (85.0) 521 (68.5) 0.01 omani ethnicity 40 (66.7) 495 (65.0) 0.20 admitted during the weekend 19 (31.7) 220 (28.9) 0.05 transported to hospital by ems 40 (66.7) 508 (66.8) 0.60 time of arrival to ed 12 a.m. to 7 a.m. 16 (26.7) 176 (23.1) 0.05 8 a.m. to 3 p.m. 21 (35.0) 193 (25.4) 0.04 4 p.m. to 11 p.m. 23 (38.3) 392 (51.5) 0.03 triage category <0.01 urgent 30 (50.0) 625 (82.1) emergency 20 (33.3) 73 (9.6) resuscitation 10 (16.7) 63 (8.3) iss 0.12 0–15 53 (88.3) 665 (87.4) 16–30 6 (10.0) 43 (5.7) 31–75 1 (1.7) 53 (7.0) presence of a head injury 16 (26.7) 66 (8.7) <0.01 ems = emergency medical services; ed = emergency department; iss = injury severity score. ammar al-kashmiri, sultan z. al-shaqsi, nada al-marhoobi and mahmood hasan clinical and basic research | e199 a trauma surgeon. in settings where a trauma system is still in its infancy, such as oman, determining whether this factor affects outcomes can potentially guide policy-makers in the hiring of additional human resources, if necessary, and to anticipate training requirements. in the current study, the outcomes of multitrauma rtc patients attended by trauma surgeons were compared with those of patients cared for by non-trauma surgeons at squh. the primary practice of the non-trauma surgeons was elective general surgery and subspecialties other than trauma; however, they were all certified in the advanced trauma life support® (american college of surgeons, chicago, illinois, usa) training course and were aware of the written resuscitative protocols for trauma care set by the hospital’s trauma committee. in addition, all nontrauma surgeons were included within the trauma case schedule and had a similar amount of exposure to trauma patients. no criteria currently exist at squh to decide which trauma patients should be attended by trauma surgeons; the presence of a trauma surgeon is instead determined by their call schedule, which covers a minimum of two days a week. the findings of the present study indicated that multi-trauma rtc patients attended by trauma surgeons at squh had similar mortality rates to those cared for by non-trauma surgeons. in addition, the severity of injuries was similar between the two groups. these findings would suggest that—in hospitals with established trauma systems—trauma patients may not always require a trauma surgeon, as this factor did not play a significant role in improving patient outcomes. however, an interesting finding of the present study was that trauma patients attended by trauma surgeons were significantly more likely to undergo surgical interventions than those attended by non-trauma surgeons. this finding is probably a reflection of the confidence of trauma surgeons in operative trauma management compared to a potentially more conservative approach among non trauma surgeons. the findings of the present study are in line with some of those reported in the literature. a recent study from a rural trauma centre in the usa similarly found no difference in the mortality rate of trauma patients attended by trauma surgeons versus those attended by other surgeons.18 podnos et al. also reported no difference in mortality among 1,427 patients at a level i trauma centre cared for either by trauma specialists or general surgeons.19 however, other researchers have obtained different results; haut et al. reported significantly better outcomes among patients with severe head injuries treated by full-time trauma surgeons compared to those cared for by parttime trauma surgeons.14 in the present study, analysis of the outcomes of patients with head injuries did not indicate statistically significant differences. this finding may have been the result of grouping together all types of head injuries, including moderate head table 2: outcomes of multi-trauma road traffic crash cases admitted to the sultan qaboos university hospital, muscat, oman (n = 821) outcome n (%) rr (ci) p value patients attended by trauma surgeons (n = 60) patients attended by non-trauma surgeons (n = 761) mortality 2 (3.3) 49 (6.4) 0.5 (0.13–2.10) 0.35 head injury ais >3 1 (1.7) 24 (3.2) 0.2 (0.03–1.12) 0.42 iss >15 1 (1.7) 40 (5.3) 0.2 (0.02–1.02) 0.50 intubation 22 (37) 21 (2.8) 13.3 (7.76–22.7) <0.01 head injury ais >3 10 (46) 1 (0.6) 76.6 (82.3–41.2) <0.01 no tbi 12 (54) 20 (94) 0.7 (1.3–0.34) 0.56 icu admission 16 (27) 28 (3.7) 7.2 (4.16–12.62) <0.01 head injury ais >3 3 (15.8) 3 (1.2) 13.2 (17.3–4.9) <0.01 no tbi 13 (84.2) 25 (98.8) 0.9 (1.9–0.43) 0.34 surgical interventions 25 (41.7) 88 (11.8) 3.5 (2.64–5.48) <0.01 transferred from hospital 4 (6.7) 49 (6.4) 1.1 (0.39–2.77) 0.94 mean los in days (range) 2.8 ± 5.4 (1–75) 2.6 ± 5.5 (1–83) 0.81 rr = relative risk; ci = confidence interval; ais = abbreviated injury score; iss = injury severity score; tbi = traumatic brain injury; icu = intensive care unit; los = length of stay. outcomes of multi-trauma road traffic crashes at a tertiary hospital in oman does attendance by trauma surgeons versus non-trauma surgeons make a difference? e200 | squ medical journal, may 2017, volume 17, issue 2 injuries. in addition, no significant results were found when stratifying patients by iss category. employing full-time surgeons dedicated exclusively to trauma surgery and surgical critical care, such as those employed in the setting described by haut et al., is not yet feasible in oman.14 currently, there are no centres in oman busy enough to support a surgical practice dedicated exclusively to trauma care; this could account for the differences in findings reported by this study. moreover, it may be that the volume of multi-trauma patients seen by non-trauma surgeons at squh allows them sufficient opportunities to improve their skills to the level of that of specialised trauma surgeons. indeed, smith et al. have demonstrated an inverse relationship between patient volume and mortality rates at trauma centres in the usa.20 konvolinka et al. also affirmed that increased surgeon experience with seriously injured patients was associated with improved outcomes while haut et al. reported that surgeons with vastly different levels of training could safely provide trauma care and obtain equivalent patient outcomes.15,21 based on these findings, it seems that more emphasis should be placed on building a cohesive trauma system rather than focusing on capacitybuilding individual components within the system. as such, all components in a hospital trauma system require equal development to assure that a satisfactory level of trauma care is provided, including institutional policies governing clinical and operational processes, round-the-clock availability of a structured trauma team, a dedicated trauma admitting unit and adequate training and qualification standards for healthcare providers involved in trauma care and the provision of essential equipment and services. education and the application of evidence-based protocols and guide lines should also be prioritised among non-trauma surgeons in oman. another important component is the expansion of the available pool of trauma surgeons; however, the extent to which this is needed remains debatable. nevertheless, trauma surgeons may act as advocates for better trauma care at the national level. the current study has several limitations which may have affected the results. first, the study design was retrospective and the cohort was from a single institution. second, the glasgow coma scale of the patients at admission was not assessed, thus precluding further analysis of patients with severe head injuries. this limitation was minimised as much as possible by stratifying outcomes based on ais categorisation; nevertheless, patients with head injuries may still have significantly improved outcomes when cared for by trauma surgeons. third, the low rate of penetrating trauma injuries in the present study population may have resulted in a less defined outcome difference between the two groups. as such, it is possible that a more significant difference would have been evident had the study population been larger and included more severe trauma cases. a multicentre study is recommended for more accurate results. finally, this study focused primarily on mortality and did not investigate morbidity, for which the presence of an attending trauma surgeon may potentially affect patient outcomes. conclusion no significant difference was noted in the mortality rates of multi-trauma rtc cases attended by trauma surgeons compared to those attended by non-trauma surgeons. these findings indicate that addressing only one component of a trauma system (i.e. the presence of trauma surgeons) is not sufficient to achieve better patient outcomes. as such, better outcomes for trauma patients in oman may potentially be achievable by developing all components of a trauma system to ensure that it is both effective and cohesive. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. prehospital trauma care systems. from: whqlibdoc.who.int/publications/2005/924159294x.pdf accessed: mar 2017. 2. toroyan t. global status report on road safety. inj prev 2009; 15:286. doi: 10.1136/ip.2009.023697. 3. american college of surgeons committee on trauma. resources for optimal care of the injured patient: 2014. from: www.facs.org/~/media/files/quality%20programs/trauma/ vrcresources.ashx accessed: mar 2017. 4. times of oman. road accidents drop but fatalities rise in oman. from: www.timesofoman.com/article/101115/oman/ oman-road-accident-rates-down-but-expat-deaths-up-by-16per-cent accessed: mar 2017. 5. world health organization. global status report on road safety 2013: reporting a decade of action. from: www.who. int/violence_injury_prevention/road_safety_status/2013/en/ accessed: mar 2017. 6. al-reesi h, ganguly ss, al-adawi s, laflamme l, hasselberg m, al-maniri a. economic growth, motorization, and road traffic injuries in the sultanate of oman, 1985-2009. traffic inj prev 2013; 14:322–8. doi: 10.1080/15389588.2012.694088. 7. al-kharusi w. update on road traffic crashes: progress in the middle east. clin orthop relat res 2008; 466:2457–64. doi: 10.1007/s11999-008-0439-5. 8. peterson je. oman’s diverse society: southern oman. middle east j 2004; 58:254–69. doi: 10.3751/58.2.15. https://doi.org/10.1136/ip.2009.023697 https://doi.org/10.1080/15389588.2012.694088 https://doi.org/10.1007/s11999-008-0439-5 https://doi.org/10.3751/58.2.15 ammar al-kashmiri, sultan z. al-shaqsi, nada al-marhoobi and mahmood hasan clinical and basic research | e201 9. belwal r, belwal s. mobile phone usage behavior of university students in oman. in: international conference on new trends in information and service science proceedings, 2009. pp. 954–62. doi: 10.1109/niss.2009.65. 10. al-shaqsi sz. ems in the sultanate of oman. resuscitation 2009; 80:740–2. doi: 10.1016/j.resuscitation.2009.04.011. 11. al-shaqsi s, al-kashmiri a, al-hajri h, al-harthy a. emergency medical services versus private transport of trauma patients in the sultanate of oman: a retrospective audit at the sultan qaboos university hospital. emerg med j 2014; 31:754–7. doi: 10.1136/emermed-2013-202779. 12. daly le, bourke gj. interpretation and uses of medical statistics, 5th ed. hoboken, new jersey, usa: wiley-blackwell, 2000. pp. 202–67. 13. mains c, scarborough k, bar-or r, hawkes a, huber j, bourg p, et al. staff commitment to trauma care improves mortality and length of stay at a level i trauma center. j trauma 2009; 66:1315–20. doi: 10.1097/ta.0b013e31819d96d8. 14. haut er, chang dc, efron dt, cornwell ee 3rd. injured patients have lower mortality when treated by “full-time” trauma surgeons vs. surgeons who cover trauma “part-time”. j trauma 2006; 61:272–8. doi: 10.1097/01.ta.0000222939.51147.1c. 15. haut er, chang dc, hayanga aj, efron dt, haider ah, cornwell ee 3rd. surgeonand system-based influences on trauma mortality. arch surg 2009; 144:759–64. doi: 10.1001/ archsurg.2009.100. 16. papa l, langland-orban b, kallenborn c, tepas jj 3rd, lottenberg l, celso b, et al. assessing effectiveness of a mature trauma system: association of trauma center presence with lower injury mortality rate. j trauma 2006; 61:261–6. doi: 10.1097/01.ta.0000221789.53864.ba. 17. margulies dr, cryer hg, mcarthur dl, lee ss, bongard fs, fleming aw. patient volume per surgeon does not predict survival in adult level i trauma centers. j trauma 2001; 50:597–601. 18. louras n, fortune j, osler t, hyman n. nontrauma surgeons can safely take call at an academic, rural level i trauma center. am j surg 2016; 211:129–32. doi: 10.1016/j.amjsurg.2015.05.020. 19. podnos yd, wilson se, williams ra. effect of surgical panel composition on patient outcome at a level i trauma center. arch surg 1998; 133:847–54. doi: 10.1001/archsurg.133.8.847. 20. smith rf, frateschi l, sloan ep, campbell l, krieg r, edwards lc, et al. the impact of volume on outcome in seriously injured trauma patients: two years’ experience of the chicago trauma system. j trauma 1990; 30:1066–75. 21. konvolinka cw, copes ws, sacco wj. institution and persurgeon volume versus survival outcome in pennsylvania’s trauma centers. am j surg 1995; 170:333–40. doi: 10.1016/ s0002-9610(99)80299-2. https://doi.org/10.1109/niss.2009.65 https://doi.org/10.1016/j.resuscitation.2009.04.011 https://doi.org/10.1136/emermed-2013-202779 https://doi.org/10.1097/ta.0b013e31819d96d8 https://doi.org/10.1097/01.ta.0000222939.51147.1c https://doi.org/10.1001/archsurg.2009.100 https://doi.org/10.1001/archsurg.2009.100 https://doi.org/10.1097/01.ta.0000221789.53864.ba https://doi.org/10.1016/j.amjsurg.2015.05.020 https://doi.org/10.1001/archsurg.133.8.847 https://doi.org/10.1016/s0002-9610%2899%2980299-2 https://doi.org/10.1016/s0002-9610%2899%2980299-2 department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com معدل انتشار وحمصالت ونتائج تصوير الشرايني ما بعد السكتة القلبية خارج املستشفى جتربة مركز واحد يف عمان سونيل ندار، حممد جمتىب، حفيظ اهلادي، حممد أطهر صادق، عادل الريامي، ميهار علي، حامت اللوايت abstract: objectives: out-of-hospital cardiac arrests (ohcas) are a leading cause of death worldwide. however, data regarding the management and outcomes of affected patients are lacking in the middle east. the current study aimed to present the angiographic findings and outcomes of patients presenting with ohca in muscat, oman. methods: this retrospective study took place between january 2012 and december 2016 at the sultan qaboos university hospital (squh), muscat, oman. all adult patients who presented following an ohca to the emergency department of squh during the study period were included. demographic and clinical data were collected from electronic medical records. results: a total of 216 patients were included in the study. the majority (63.9%) presented after having collapsed, while 22.3% presented with chest pains. asystole was the most frequent initial cardiac rhythm (62.5%), with only 10% having ventricular tachycardia/fibrillation. very few patients (1.4%) had received cardiopulmonary resuscitation (cpr) prior to presentation. in total, 85 patients (39.4%) returned to spontaneous circulation (rsc); of these, post-rsc electrocardiography revealed an st-segment elevation in 41.2% and normal findings in 23.5%. there were 63 patients who underwent coronary angiography, with 28 requiring stenting. overall, 13% of patients survived and were discharged, although three survivors suffered permanent hypoxic brain damage. conclusion: the overall survival rate of patients who had experienced an ohca was low. education programmes should focus on the benefits of immediate cpr for individuals experiencing an ohca, with more opportunities for cpr training to be made available to the general public in oman. keywords: out-of-hospital cardiac arrest; cardiopulmonary resuscitation; patient outcome assessment; survival rate; coronary angiography; oman. امللخ�ص: الهدف: تعترب ال�شكتات القلبية خارج امل�شت�شفى ال�شبب الرئي�شي للوفيات حول العامل. مع ذالك يفتقر ال�رضق الو�شط اىل املعلومات خارج القلب �شكتة ملر�شى ال�رضايني ق�شطرة نتائج ح�شيلة عر�ض اىل الدرا�شة هذه تهدف املرتتبة. والنتائج احلالة اإدارة تخ�ض التي امل�شت�شفى يف م�شقط عمانل. الطريقة: اأجريت هذه الدرا�شةالأ�شرتجاعية يف الفرتة بني يناير 2012 ودي�شمرب 2016 يف م�شت�شفى جامعة الدرا�شة خالل امل�شت�شفى خارج قلبية �شكتة لهم حدثت اللذين البالغني املر�شى جميع الدرا�شة �شملت عمان. مب�شقط، قابو�ض ال�شلطان الألكرتوين الت�شجيل نظام من الدميوغرافية املعلومات جميع حت�شيل مت قابو�ض. ال�شلطان جامعة م�شت�شفى طوارئ اىل اح�شارهم ومت بامل�شت�شفى. النتائج: مت ر�شد معلومات عن 216 حالة خالل فرتة الدرا�شة، اأح�رض معظمهم )%63.9( اإىل امل�شت�شفى بعد ال�شقوط وفقدان الوعي، بينما مثل %22.3 منهم باأمل يف ال�شدر. �شّكل توقف النقبا�ض يف التخطيط الويل للقلب ن�شبة )%62.5( من املر�شى بينما حدث ت�شارع اأو رجفان بطيني يف %10 منهم فقط. مت عمل النعا�ض القلبي الرئوي قبيل الإح�شار للم�شت�شفى يف قلة قليلة من املر�شى )1.4%(. عاد النب�ض تلقائيا يف جمموع 85 مري�ض )%39.4(. بني التخطيط القلبي بعد الفاقة اأن %41.2 لديهم ارتفاع يف st-segment بينما كان التخطيط طبيعيا يف %23.5. مت عمل ق�شطرة �رضايني ل 63 حالة منها 28 حالة احتاجت اىل زرع دعامات . ب�شورة اإجمالية جنا %13 من املر�شى ومت ترخي�شهم ولكن ثالثة ممن جنو عانو من �رضر دماغي ب�شبب نق�ض الك�شجني. اخلال�صة: لوحظ انخفا�ض �شديد يف جمموع ن�شبة الناجني من ال�شكتات القلبية خارج امل�شت�شفى. يجب اأـن تركز برامج الوعي ال�شحي على فوائد النعا�ض القلبي الرئوي الفوري ملر�شى ال�شكتات القلبية خارج امل�شت�شفى مع توفري فر�ض كثرية لتدريب العامة من النا�ض على النعا�ض القلبي الرئوي يف عمان. الكلمات املفتاحية: ال�شكتات القلبية خارج امل�شت�شفى؛ النعا�ض القلبي الرئوي؛ تقييم ما يوؤول اليه املري�ض؛ معدل النجاة؛ ق�شطرة القلب؛ عمان. epidemiology, outcomes and coronary angiography findings of patients following out-of-hospital cardiac arrest a single-centre experience from oman *sunil k. nadar, mohammed mujtaba, hafidh al-hadi, muhammed sadiq, adil al-riyami, mehar ali, hatim al-lawati clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e155–160, epub. 9 sep 18 submitted 10 dec 17 revisions req. 17 jan & 18 feb 18; revisions recd. 7 & 24 feb 18 accepted 1 mar 18 doi: 10.18295/squmj.2018.18.02.006 advances in knowledge to the best of the authors’ knowledge, this study is the first to investigate the outcomes of patients following an out-of-hospital cardiac arrest (ohca) in oman. epidemiology, outcomes and coronary angiography findings of patients following out-of-hospital cardiac arrest a single-centre experience from oman e156 | squ medical journal, may 2018, volume 18, issue 2 out-of-hospital cardiac arrest (ohca) carries a very poor prognosis and is a leading cause of death worldwide.1,2 the annual incidence is between 36–81 events per 100,000 individuals, with most cases occurring at home and only 20% occurring in public places.3–5 survival rates vary from less than 10% in england and scotland to over 20% in holland and norway.2,6,7 many factors have been identified as contributing to the survival of ohca patients, with the early initiation of first aid or cardiopulmonary resuscitation (cpr) being one of the most important.8 this form of prehospital management, known as the “chain of survival”, has become increasingly popular in western countries.9 previous research shows that more than 70% of patients who are resuscitated following an ohca have significant coronary artery disease, although this might not always be the cause of the cardiac arrest.10 current guidelines and consensus statements recommend that immediate coronary angiography be performed for resuscitated ohca patients in whom post-resuscitation electrocardiography (ecg) shows an st-segment elevation, while early coronary angiography is indicated for patients with unexplained ohca without an st-segment elevation.11,12 unfortunately, very little research is available concerning the incidence of ohca and the outcomes of affected patients in middle eastern countries such as oman. in 2017, the population of muscat, the capital city of oman, was reported to be approximately 1,475,000.13 based on this, the annual incidence of ohca in the omani population is estimated to be between 516–780 cases per year.4,5 the current study aimed to describe the epidemiological patterns of patients presenting to a tertiary care centre in oman following an ohca event. in addition, the survival rate and demographic and angiographic features of resuscitated ohca patients were assessed. methods this retrospective study was conducted at the sultan qaboos university hospital (squh), muscat, oman, between january 2012 and december 2016 and included all adult patients presenting during this period to the emergency department of squh following an ohca. only individuals over 18 years old who had experienced a cardiac arrest requiring cpr at home, in the community or en route to the hospital (i.e. either in an ambulance or another vehicle) were included in the study. patients for whom there was a clear cause for cardiac arrest (e.g. drowning, a drug overdose or motor vehicle crash) and those with a chronic terminal illness (i.e. cancer or a debilitating stroke) were excluded. in addition, patients who were declared dead on arrival (doa) were not included in the analysis, as emergency department physicians would have deemed such patients irresuscitable due to their physical condition or delay in presentation. eligible patients were identified from the squh emergency department log book and pertinent data collected from the patients’ electronic medical records. in all ohca cases, an early invasive strategy was initiated as per the recommendations of international guidelines, in which resuscitated ohca patients with no obvious cause for the cardiac arrest were scheduled for an immediate or early coronary angiography, depending on their ecg results.11,12 subsequently, the identification of a ‘culprit’ lesion or vessel requiring stenting was determined by either the presence of total occlusion or a tight stenosis with a hazy appearance and/or flow of thrombolysis in cases with type 2 myocardial infarctions. statistical analyses were performed using the statistical package for the social science (spss), version 21.0 (ibm corp., armonk, new york, usa). a p value of <0.05 was considered statistically significant. all categorical variables were described as frequencies and percentages. means and standard deviations were used to present continuous normally-distributed variables, while variables which were not normally distributed were presented as medians and interquartile ranges. a chi-squared test was used to compare categorical variables and a student’s t-test was used to compare mean age. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec #1156). results a total of 216 adult patients presented to squh following an ohca during the study period. of these, 150 (69.4%) were male and 66 (30.6%) were despite early intervention, patients were found to have a poor survival rate following an ohca. moreover, a low rate of bystander cardiopulmonary resuscitation (cpr) was observed. application to patient care the findings of the current study indicate that the omani public should be educated about the importance of bystander cpr and early medical attention in ohca cases. sunil k. nadar, mohammed mujtaba, hafidh al-hadi, muhammed sadiq, adil al-riyami, mehar ali and hatim al-lawati clinical and basic research | e157 female. the mean age was 55 ± 17 years old. the vast majority of patients (98.6%) were brought to the hospital by a relative or friend, with only three patients (1.4%) transferred by the emergency medical services (ems). most patients (63.7%) had collapsed, while the remaining patients presented with chest pain (22.3%) or breathlessness (14%). the initial cardiac rhythm for most patients was asystole (63.4%), while 54 (25%) had pulseless electrical activity, 23 (10.6%) had ventricular tachycardia/fibrillation (vt/vf) and two patients (0.9%) had a heart blockage. the overall survival rate was 13% [table 1]. of the 28 surviving patients, three had permanent hypoxic brain injuries and were transferred to long-term rehabilitation units. the other patients were discharged within 10 days with no neurological deficits. prior to their arrival at the hospital, none of the patients had received cpr from bystanders, although the three patients transferred by the ems had had cpr administered by the paramedics. all patients subsequently received cpr immediately upon arrival at the hospital. following the administration of in-hospital cpr, 85 patients (39.4%) returned to spontaneous circulation (rsc). among this subset, 25 patients (29.4%) had normal post-rsc ecg findings, while 35 (41.2%) had an st-segment elevation, 14 (16.5%) had a left bundle branch block, 10 (11.8%) had a right bundle branch block and one (1.2%) had an stsegment depression. overall, 22 patients (25.9%) were deemed unfit for an immediate coronary angiography; of these, 17 (77.3%) experienced a further cardiac arrest and died, while three (13.6%) and two (9.1%) patients were diagnosed with strokes and pulmonary emboli, respectively. the remaining 63 patients (74.1%) were taken for either an immediate or urgent coronary angiography, which revealed significant coronary lesions (i.e. >70% luminal stenosis) in 42 patients (66.7%), of which only 28 (66.7%) required stenting. most of the patients who required stenting had an stsegment elevation (60.7%) [table 2]. no correlation was found between survival and stenting of the coronary artery, the location of the lesion or the number of vessels involved. however, the survival rate was significantly poorer among patients with triple-vessel disease in comparison to those with double-vessel disease, single-vessel disease or normal coronary arteries (7.1% versus 40%, 50% and 45%, respectively; p = 0.05). in addition, patients in whom table 1: demographic and clinical characteristics of patients presenting following an out-of-hospital cardiac arrest to the sultan qaboos university hospital, muscat, oman (n = 216) characteristic n (%) mean age in years 55 ± 17 gender male 150 (69.4) female 66 (30.6) method of arrival private car 213 (98.6) ems 3 (1.4) risk factors* diabetes 73 (33.8) htn 87 (40.3) history of ihd 28 (13) unknown 67 (31) presentation collapsed 137 (63.7) chest pain 49 (22.7) breathlessness 30 (14) initial cardiac rhythm asystole 137 (63.4) pea 54 (25) vt/vf 23 (10.6) heart blockage 2 (0.9) patient outcome survived 28 (13) died 188 (87) ems = emergency medical services; htn = hypertension; ihd = ischae mic heart disease; pea = pulseless electrical activity; vt/vf = ventricular tachycardia/fibrillation. *percentages do not add up to 100% as some patients may have had several risk factors. table 2: angiographic findings of resuscitated* patients presenting following an out-of-hospital cardiac arrest to the sultan qaboos university hospital, muscat, oman (n = 85) ecg findings n (%) total significant disease (n = 42) stented (n = 28) normal 25 (29.4) 7 (16.7) 5 (17.9) st-segment elevation 35 (41.2) 24 (57.1) 17 (60.7) rb bb 10 (11.8) 4 (9.5) 2 (7.1) lb bb 14 (22.4) 7 (16.7) 4 (14.3) st-segment depression 1 (1.2) 0 (0) 0 (0) ecg = electrocardiography; rb = right bundle; bb = branch block; lb = left bundle. *after returning to spontaneous circulation. epidemiology, outcomes and coronary angiography findings of patients following out-of-hospital cardiac arrest a single-centre experience from oman e158 | squ medical journal, may 2018, volume 18, issue 2 an intra-aortic balloon pump (iabp) was deployed were significantly less likely to survive (12.5% versus 43.4%; p = 0.02). in contrast, survival was significantly greater among cases in which cpr was initiated more rapidly (p <0.01) and for a shorter duration of time (p <0.01) [table 3]. in terms of their initial cardiac rhythm, survival was lowest among patients with asystole (1.5%) and highest among those with a heart blockage (50%) followed by vt/vf (34.8%) [table 4]. according to their ecg findings, patients with a left bundle branch block more frequently survived (61.5%) in contrast to those with normal ecg findings (20%) or an st-segment depression (0%) [table 5]. discussion despite reported variations in the international literature, ohca is consistently associated with poor survival.2,6,7,14 in the usa, more than 300,000 deaths annually are attributed to an ohca, whilst this accounts for approximately 28,000 deaths per year in the uk.15,16 in the current study, the survival rate for patients presenting to squh following an ohca was very low (13%). nevertheless, it is likely that this percentage is an overestimation, as it does not include table 3: factors affecting outcomes among resuscitated* patients presenting following an out-of-hospital cardiac arrest to the sultan qaboos university hospital, muscat, oman (n = 85) variable n (%) p value survived (n = 28) died (n = 57) cpr median time before-hand in minutes (iqr) 10 (0–30) 30 (20–40) <0.01 median duration in minutes (iqr) 12 (6–20) 20 (15–30) <0.01 blood investigations mean serum potassium in meq/l ± sd 4.5 ± 1.1 3.9 ± 1.7 0.09 median abg ph (iqr) 7.1 (6.9–7.2) 6.9 (6.7–7.0) 0.02 median serum creatinine in mg/dl (iqr) 81 (67–128) 99 (66–170) 0.43 catheterisation 0.21† yes 23 (37.1) 39 (62.9) no 5 (21.7) 18 (78.3) significant disease 0.41† yes 14 (33.3) 28 (66.7) no 9 (42.9) 12 (57.1) vessel involved 0.12† lad artery 10 (29.4) 24 (70.6) circumflex artery 5 (23.8) 16 (76.2) rca 5 (22.7) 17 (77.3) number of vessels involved 0.05 0 9 (45) 11 (55) 1 9 (50) 9 (50) 2 4 (40) 6 (60) 3 1 (7.1) 13 (92.9) intracoronary stenting 0.38† yes 10 (35.7) 18 (64.3) no 13 (37.1) 22 (62.9) iabp 0.02 yes 2 (12.5) 14 (87.5) no 23 (43.4) 30 (56.6) tpw 0.16 yes 2 (16.7) 10 (83.3) no 23 (40.4) 34 (59.6) cpr = cardiopulmonary resuscitation; iqr = interquartile range; sd = standard deviation; abg = arterial blood gas; lad = left anterior descending; rca = right coronary artery; iabp = intra-aortic balloon pump; tpw = temporary pacing wire. *after returning to spontaneous circulation. †calculated using a chi-squared test. table 4: outcomes of patients presenting following an out-of-hospital cardiac arrest to the sultan qaboos university hospital, muscat, oman, according to initial cardiac rhythm (n = 216) cardiac rhythm n (%) total survived died pea 54 (25) 17 (31.5) 37 (68.5) asystole 137 (63.4) 2 (1.5) 135 (98.5) vt/vf 23 (10.6) 8 (34.8) 15 (65.2) heart blockage 2 (0.9) 1 (50) 1 (50) pea = pulseless electrical activity; vt = ventricular tachycardia; vf = ventricular fibrillation. table 5: outcomes of resuscitated* patients presenting following an out-of-hospital cardiac arrest to the sultan qaboos university hospital, muscat, oman, according to electrocardiography findings (n = 85) ecg findings n (%) total survived died normal 25 (29.4) 5 (20) 20 (80) st-segment elevation 35 (41.2) 11 (31.4) 24 (68.6) rb bb 10 (11.8) 4 (40) 6 (60) lb bb 14 (16.5) 8 (61.5) 6 (46.2) st-segment depression 1 (1.2) 0 (0) 1 (100) ecg = electrocardiography; rb = right bundle; bb = branch block; lb = left bundle. *after returning to spontaneous circulation. sunil k. nadar, mohammed mujtaba, hafidh al-hadi, muhammed sadiq, adil al-riyami, mehar ali and hatim al-lawati clinical and basic research | e159 patients who were declared doa. as with other research, the majority of such doa cases were found at home rather than in a public place.3 as this often means that the cardiac arrest was not witnessed, death is more probable due to delays in seeking medical assistance. in amsterdam, waalewijn et al. demonstrated the benefits of bystander cpr in improving outcomes among ohca patients.7 in western countries such as the uk, usa and sweden, rates of bystander cpr are relatively high, ranging from 30–50%.15,17,18 this high level of bystander participation is primarily due to public education efforts involving mass media campaigns and cpr training programmes.19 in the current study, apart from those who were transferred to the hospital by ambulance, none of the patients received bystander cpr or first aid prior to presentation. a previous survey from saudi arabia demonstrated a low level of interest in and knowledge of cpr among university students.20 improving health education and conducting awareness campaigns regarding the benefits and methods of performing cpr are recommended to address this issue in the omani community. furthermore, ensuring the availability of automated electrical defibrillators in public places should be encouraged as these may be of benefit in certain situations.14,21 in oman, there is a well-established ems system in place with fully trained and equipped paramedics who can administer cpr if required.22 moreover, most people in oman live in the governorate of muscat, a region with excellent ems coverage.13,22 nevertheless, in the majority of cases in the current study, family members brought collapsed patients directly to the hospital by private car rather than initiating cpr on site or contacting the ems. clearly, utilisation of the ems system is low in oman, as in other gulf countries.23 unfortunately, delays in initiating cpr were found to significantly affect survival in the present study. therefore, reliance on individual family members to bring patients to hospital rather than the ems system is potentially one of the biggest barriers to improving outcomes of patients with ohca in the region, as this causes delays in timely medical attention or resuscitation efforts. in accordance with previous research, patients in the current study who presented with asystole had the worst prognosis.1 however, stenting was not found to significantly improve survival; this is in contrast to findings reported by dumas et al.24 perhaps the reason for this surprising finding was due to the delay in initiating cpr for most patients in the present sample; this would likely affect the overall prognosis, regardless of whether the patients received a stent or not. similarly, there was no significant difference in survival according to the coronary artery affected, although patients with triple-vessel disease survived less frequently. the use of an iabp was significantly associated with poor survival; however, this could be due to selection bias, as patients who were haemodynamically unstable would have had an iabp inserted. as per international guidelines, all resuscitated patients at squh who have experienced a cardiac arrest undergo coronary angiography, with those who have an st-segment elevation identified via postresuscitation ecg undergoing immediate coronary angiography.11,12 these patients were found to require more stents than any other group of patients in the current study. in contrast, patients without an stsegment elevation receive coronary angiography only after other investigations have been performed, including a blood workup, a computed tomography (ct) scan of the brain and a ct pulmonary angiography to rule out a pulmonary embolism. in the present study, only 28 of the 63 patients who received coronary angiography were found to have a lesion that required stenting. overall, the neurological outcomes of the patients who survived were relatively good, as there were only three patients with severe residual hypoxic brain injuries. however, it is possible that those with severe brain injuries did not survive to discharge. this study is subject to several limitations. due to the retrospective design of the study, missing or erroneous documentation might have compromised the quality of the data collected. the results of blood investigations were not available for the majority of patients, particularly those who could not be resuscitated. furthermore, neither patients who were declared doa nor those who had experienced ohcas but were not resuscitated or brought to the hospital were included in the study. another limitation was the fact that most patients were brought to the hospital by their relatives or friends; hence, the period of time reported between the cardiac arrest and patient presentation and the subsequent administration of cpr was most likely an approximation. finally, as this study was based on a single centre experience, the sample size was relatively small and the results may not reflect the true incidence and outcomes of ohca in oman. conclusion patients presenting to squh following an ohca were found to have a high mortality rate, most likely contributed to by delays in the initiation of cpr efforts. epidemiology, outcomes and coronary angiography findings of patients following out-of-hospital cardiac arrest a single-centre experience from oman e160 | squ medical journal, may 2018, volume 18, issue 2 furthermore, the rate of bystander cpr was very low. it is therefore necessary that greater efforts be made to improve public awareness of the benefits of cpr and provide cpr training opportunities to members of the omani community. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. de vreede-swagemakers jj, gorgels ap, dubois-arbouw wi, van ree jw, daemen mj, houben lg, et al. out-of-hospital cardiac arrest in the 1990’s: a population-based study in the maastricht area on incidence, characteristics and survival. j am coll cardiol 1997; 30:1500–5. doi: 10.1016/s0735-1097 (97)00355-0. 2. roger vl, go as, lloyd-jones dm, benjamin ej, berry jd, borden wb, et al. executive summary: heart disease and stroke statistics 2012 update: a report from the american heart association. circulation 2012; 125:188–97. doi: 10.1161/ cir.0b013e3182456d46. 3. becker l, eisenberg m, fahrenbruch c, cobb l. public locations of cardiac arrest: implications for public access defibrillation. circulation 1998; 97:2106–9. doi: 10.1161/01.cir.97.21.2106. 4. atwood c, eisenberg ms, herlitz j, rea td. incidence of emstreated out-of-hospital cardiac arrest in europe. resuscitation 2005; 67:75–80. doi: 10.1016/j.resuscitation.2005.03.021. 5. hawkes c, booth s, ji c, brace-mcdonnell sj, whittington a, mapstone j, et al. epidemiology and outcomes from outof-hospital cardiac arrests in england. resuscitation 2017; 110:133–40. doi: 10.1016/j.resuscitation.2016.10.030. 6. lindner tw, søreide e, nilsen ob, torunn mw, lossius hm. good outcome in every fourth resuscitation attempt is achievable: an utstein template report from the stavanger region. resuscitation 2011; 82:1508–13. doi: 10.1016/j.resuscit ation.2011.06.016. 7. waalewijn ra, tijssen jg, koster rw. bystander initiated actions in out-of-hospital cardiopulmonary resuscitation: results from the amsterdam resuscitation study (arre-sust). resuscitation2001; 50:273–9. doi: 10.1016/s0300-9572(01)00354-9. 8. wissenberg m, lippert fk, folke f, weeke p, hansen cm, christensen ef, et al. association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest. jama 2013; 310:1377–84. doi: 10.1001/jama.2013.278483. 9. hazinski mf, nolan jp, billi je, böttiger bw, bossaert l, de caen ar, et al. part 1: executive summary 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. circulation 2010; 122:s250–75. doi: 10.1161/circulationa ha.110.970897. 10. spaulding cm, joly lm, rosenberg a, monchi m, weber sn, dhainaut jf, et al. immediate coronary angiography in survivors of out-of-hospital cardiac arrest. n engl j med 1997; 336:1629–33. doi: 10.1056/nejm199706053362302. 11. ibanez b, james s, agewall s, antunes mj, bucciarelli-ducci c, bueno h, et al. 2017 esc guidelines for the management of acute myocardial infarction in patients presenting with stsegment elevation: the task force for the management of acute myocardial infarction in patients presenting with st-segment elevation of the european society of cardiology (esc). eur heart j 2018; 39:119–77. doi: 10.1093/eurheartj/ehx393. 12. noc m, fajadet j, lassen jf, kala p, maccarthy p, olivecrona gk, et al. invasive coronary treatment strategies for out-of-hospital cardiac arrest: a consensus statement from the european association for percutaneous cardiovascular interventions (eapci)/stent for life (sfl) groups. eurointervention 2014; 10:31–7. doi: 10.4244/eijv10i1a7. 13. national centre for statistics & information. population: total population, muscat, omani. from: https://data.gov.om/ompo p2016/population?indicator=1000140&region=1000020muscat&nationality=1000010-omani accessed: feb 2018. 14. murakami y, iwami t, kitamura t, nishiyama c, nishiuchi t, hayashi y, et al. outcomes of out-of-hospital cardiac arrest by public location in the public-access defibrillation era. j am heart assoc 2014; 3:e000533. doi: 10.1161/jaha.113.000533. 15. nichol g, thomas e, callaway cw, hedges j, powell jl, aufderheide tp, et al. regional variation in out-of-hospital cardiac arrest incidence and outcome. jama 2008; 300:1423–31. doi: 10.1001/jama.300.12.1423. 16. perkins gd, brace-mcdonnell sj; ohcao project group. the uk out of hospital cardiac arrest outcome (ohcao) project. bmj open 2015; 5:e008736. doi: 10.1136/bmjopen-20 15-008736. 17. perkins gd, lockey as, de belder ma, moore f, weissberg p, gray h. national initiatives to improve outcomes from out-ofhospital cardiac arrest in england. emerg med j 2016; 33:448–51. doi: 10.1136/emermed-2015-204847. 18. hasselqvist-ax i, riva g, herlitz j, rosenqvist m, hollenberg j, nordberg p, et al. early cardiopulmonary resuscitation in outof-hospital cardiac arrest. n engl j med 2015; 372:2307–15. doi: 10.1056/nejmoa1405796. 19. abella bs, aufderheide tp, eigel b, hickey rw, longstreth wt jr, nadkarni v, et al. reducing barriers for implementation of bystander-initiated cardiopulmonary resuscitation: a scientific statement from the american heart association for health care providers, policymakers, and community leaders regarding the effectiveness of cardiopulmonary resuscitation. circulation 2008; 117:704–9. doi: 10.1161/circulationaha.107.188486. 20. al-mohaissen ma. knowledge and attitudes towards basic life support among health students at a saudi women’s university. sultan qaboos univ med j 2017; 17:e59–65. doi: 10.18295/ squmj.2016.17.01.011. 21. bækgaard js, viereck s, møller tp, ersbøll ak, lippert f, folke f. the effects of public access defibrillation on survival after out-of-hospital cardiac arrest: a systematic review of observational studies. circulation 2017; 136:954–65. doi: 10.11 61/circulationaha.117.029067. 22. al-shaqsi sz. ems in the sultanate of oman. resuscitation 2009; 80:740–2. doi: 10.1016/j.resuscitation.2009.04.011. 23. alhabib kf, sulaiman k, al suwaidi j, almahmeed w, alsheikh-ali aa, amin h, et al. patient and system-related delays of emergency medical services use in acute st-elevation myocardial infarction: results from the third gulf registry of acute coronary events (gulf race-3ps). plos one 2016; 11:e0147385. doi: 10.1371/journal.pone.0147385. 24. dumas f, bougouin w, geri g, lamhaut l, rosencher j, pène f, et al. emergency percutaneous coronary intervention in postcardiac arrest patients without st-segment elevation pattern: insights from the procat ii registry. jacc cardiovasc interv 2016; 9:1011–18. doi: 10.1016/j.jcin.2016.02.001. https://doi.org/10.1016/s0735-1097%2897%2900355-0 https://doi.org/10.1016/s0735-1097%2897%2900355-0 https://doi.org/10.1161/cir.0b013e3182456d46 https://doi.org/10.1161/cir.0b013e3182456d46 https://doi.org/10.1161/01.cir.97.21.2106 https://doi.org/10.1016/j.resuscitation.2005.03.021 https://doi.org/10.1016/j.resuscitation.2016.10.030 https://doi.org/10.1016/j.resuscitation.2011.06.016 https://doi.org/10.1016/j.resuscitation.2011.06.016 https://doi.org/10.1016/s0300-9572%2801%2900354-9 https://doi.org/10.1001/jama.2013.278483 https://doi.org/10.1161/circulationaha.110.970897 https://doi.org/10.1161/circulationaha.110.970897 https://doi.org/10.1056/nejm199706053362302 https://doi.org/10.1093/eurheartj/ehx393 https://doi.org/10.4244/eijv10i1a7 https://doi.org/10.1161/jaha.113.000533 https://doi.org/10.1001/jama.300.12.1423 https://doi.org/10.1136/bmjopen-2015-008736 https://doi.org/10.1136/bmjopen-2015-008736 https://doi.org/10.1136/emermed-2015-204847 https://doi.org/10.1056/nejmoa1405796 https://doi.org/10.1161/circulationaha.107.188486 https://doi.org/10.18295/squmj.2016.17.01.011 https://doi.org/10.18295/squmj.2016.17.01.011 https://doi.org/10.1161/circulationaha.117.029067 https://doi.org/10.1161/circulationaha.117.029067 https://doi.org/10.1016/j.resuscitation.2009.04.011 https://doi.org/10.1371/journal.pone.0147385 https://doi.org/10.1016/j.jcin.2016.02.001 to the editor, the letter to the editor by ken foster "afghanistan and oman: personal reflections on a profound contrast" published in the april 2010 issue of squmj1 presents an interesting review of some differences between oman and afghanistan in relation to the two countries’ health care systems highlighting political stability, availability of finances, and the quality of decision making as enabling factors in favour of oman. indeed, dr foster's letter has provided also a well articulated discussion of a number of questions that are related to the culture of health professions' training in both oman and afghanistan. hearing of a large majority of female medical students enrolled in the private medical school in sohar, oman,1 ken foster really raised the concern regarding "who gets into medical schools?" blaming society much more than the higher education system itself. actually, this provides a good opportunity to reveal the whole picture for squmj readers. data of 2008 from ministry of health (moh), which is the main provider of health services in oman,2 showed that 59.6% of the ministry's omani manpower forces were females.3 indeed women outnumbered men in all medical and health categories [table 1], with the exception of medical specialists/consultants whose numbers were more or less equal (208 males and 203 females).3 in 2008/09, the number of enrolled and graduated female students (bachelor’s degree level) in governmental, private medical/health sciences universities and colleges in oman and abroad, and in basic and post-basic diploma studies in moh training institutes also outnumbered male students with the exception of students studying medicine (bachelor’s degree) at sultan qaboos university [table 2].3,4 the same bias towards the female side was also true as regards medical residents of oman medical specialty board (omsb) sponsored by moh [table 2].3,4 this very clear "feminisation" of the medical/health sciences professions in oman has reversed the male dominance of past years. worldwide, a similar picture also exists. back in the 1970s, only 10% of american doctors were women compared to one-third of the physician workforce today. in medical schools, they make up half the class.5 foster1 and others6,7 assume that female medical doctors are more likely to work part-time in order to have a family, leading to staffing problems. even those who disagree with that opinion acknowledge that women doctors in the u.s. work less—47 hours per week on average, versus 53 for men. they also see about 10% fewer patients.5 women are also less likely to take part in training or research,7 and are far more likely to choose specialties where they have "set" hours.6 to some extent, that is true in the case of oman. because working full-time is the routine for moh doctors, 2008 statistics revealed an under-representation of female residents in specialties such as medicine, surgery, accident & emergency, anaesthesia and ear, nose & throat surgery,3 the ones that usually require being on-call most of the time. the problem is clearer in the nursing profession where more than 88% of omani nurses working in moh health institutes are females [table 1]. the omanisation ratio in the profession is increasing year on year, reaching 90% in some regions squ med j, august 2010, vol. 10, iss. 2, pp. 272-275, epub. 19th jun 10 received: 04th may 10 أفغانستان وُعمان انطباعات شخصية الختالفات عميقة موؤن�س ال�ش�شتاوي re: afghanistan and oman personal reflections on a profound contrast moeness alshishtawy letter to editor moeness alshishtawy letter to editor | 273 with an average of 66% in 2009.8 omani nurses prefer to work in institutions located near to their homes and tend to take more time off early in their careers. within a year or two of entering practice, married nurses usually take several maternity and morbidity leaves. subsequently, they often ask for more flexible hours, or morning only work, so other staff (mostly expatriate females who have left their families in their original countries) has to cover up the slack often creating bitterness and resentment. these circumstances threaten the delivery of highquality care for moh clients. others, including myself, look at the picture more positively. dr mckinstry,7 researcher at the university of edinburgh, noticed that, like in oman, women are willing to take on "family friendly" specialties shunned by male doctors, such as primary care, pediatrics, and very recently obstetrics.3 another defender, professor jane dacre, at the university college london,7 said: "there is quite a developing evidence base that female doctors are not inferior to male doctors, but in fact are doing better in terms of getting into medical school and in their exams". she added: "rather than worrying about having too many female doctors, there should be more focus on ensuring equal opportunities for medics throughout their careers". like these experts, i think that society and the higher education system should not shoulder the blame. although the recent rise in female medical/health sciences students and graduates is worrying, oman should continue choosing the best candidates regardless of gender. however, flexible hours, on-site child care and part-time training/ work options are needed to ensure female staff has equal career opportunities and time for their families. one should not forget that part-time work or a lighter workload also has its advantages. many studies show that doctors who work fewer hours experience less burnout; moreover, a strong association has been proved between long working hours and medical errors.5 another important concern raised by ken foster is about graduate education in the region and the emphasis on content or skill-set transmission to the trainee without adequate attention to the capacity for critical thinking.1 i fully agree to that and assure that critical thinking simply means good thinking. critical thinking skills enable the students to compare, analyze and critique information. especially when the information content of a discipline is huge, it becomes even more vital to spend time to understand and evaluate this information, not just to learn more information. the result of evaluation can range from positive to negative, from acceptance to rejection or anything in-between.9 thus, critical thinking is not necessarily being "critical". to some extent, the word ‘critical’ has a negative implication.10 in fact, a much more appropriate descriptive term to be used instead of "critical thinking", is "evaluative thinking". evaluative thinking is based on reflective thinking that is focused on interpreting, analyzing, and evaluating information, arguments and experiences with a set of reflective attitudes, skills, and abilities to guide thoughts, beliefs and actions.11 using "evaluative thinking", an individual makes a decision or solves the problem of judging what to believe or what to do, but does so in a reflective way. in problem solving situations, students learn to generate ideas (by creativity) and evaluate ideas (by criticality). although creativity occurs first in the process, it's best to begin with a foundation of critical thinking because wise evaluation, in evaluative "critical" thinking, can prevent "creativity plus enthusiasm" from converting questionable ideas into unwise action.9 a third concern raised in foster's letter1 was about the importance for clinical departments in all omani table 1: omani manpower employed by ministry of health in 2008 categories total % female doctors (general practitioners) 623 61.5 doctors (specialists/consultants) 411 49.4 dentists 100 55.0 pharmacists 120 75.8 nurses 6,014 88.3 physiotherapists 101 60.4 radiographers 316 60.8 laboratory technicians 618 70.7 assistant pharmacists/dispensers 583 66.7 dental technicians 195 55.9 dieticians 127 81.1 health educators 134 99.3 teachers/tutors in moh training institutes 87 71.3 medical orderlies 2482 67.5 re: afghanistan and oman personal reflections on a profound contrast 274 | squ medical journal, august 2010, volume 10, issue 2 health institutions throughout the country to rely on "medline" searches to get answers to clinically relevant questions. ken foster is quite right to highlight the gap between research-based best clinical practice and what doctors actually do. traditionally, the medical profession has behaved as if the dissemination of research findings in peer-reviewed journals would eliminate this gap. however, according to grimshaw et al.,12 physicians typically have less than one hour per week to read and have not necessary been trained to appraise published research. physicians interested in improving their practice also encounter organisational, peer group, and individual barriers in addition to information overload and patient expectations. web-based information has had a significant impact on biomedicine by dramatically improving ease of distribution and access. the success of web-based information arises from ease of use, platform independent client-server software, wide availability of inexpensive web-based information browser applications, and its support of distributed hypertext and multimedia. ongoing innovative encryption-based technologies also facilitate the creation of secure wide-area access to clinical information systems. the information obtained should help physicians rein in inappropriate costs. healy adds another powerful benefit that will accrue to population research itself: computerized information on individuals that can be compiled, searched, shared, and analysed. however, she emphasizes the responsibility of the physician under oath to protect confidentiality and so assure medical privacy.13 moeness alshishtawy directorate general of planning ministry of health, muscat, sultanate of oman email: drmoness@gmail.com table 2: medicine/health sciences training and education activities, oman 2008 activities total (omanis) % female students studying medicine (bachelor’s degree) sultan qaboos university in 2008/09* 353 45.0 students studying nursing (bachelor's degree) sultan qaboos university in 2008/09* 291 59.0 sultan qaboos university graduates (bachelor’s degree in medicine) in 2008/09* 108 62.0 sultan qaboos university graduates (bachelor’s degree in nursing) in 2008/09* 42 76.0 students studying (bachelor’s degree) in private universities & colleges in oman 2008/09*: oman medical college 141 72.3 oman dental college 13 76.9 graduates (bachelor’s degree) from private universities & colleges in oman 2007/08*: oman medical college (medicine) 9 88.9 oman medical college (pharmacology) 4 75.0 students studying medicine (bachelor’s degree) in universities abroad in 2008/09* 74 56.8 residents (doctors) sponsored by moh and registered with oman medical specialty board (omsb) # 276 59.8 students enrolled in basic diploma education at moh training institutes# 2,107 70.6 graduates from basic diploma at moh training institutes# 658 75.8 students enrolled in post-basic diploma in moh training institutes# 185 90.8 legend: * = reference 4; #= reference 3; moh= ministry of health moeness alshishtawy letter to editor | 275 references 1. foster k. afghanistan and oman: personal reflections on a profound contrast. squ med j 2010; 10:144–7. 2. alshishtawy mm. four decades of progress: evolution of the health system in oman. squ med j 2010; 10:12–22 3. ministry of health. annual health report 2008. muscat: ministry of health, oman, 2009. 4. ministry of national economy. statistical year book 2009. issue 37. muscat: ministry of national economy, oman, 2009. 5. arnst c. are there too many women doctors? bloomberg businessweek, health care april 17, 2008. from http:// www.businessweek.com/magazine/content/08_17/b4081104183847.htm accessed may 2010. 6. mirror.co.uk. from http://www.mirror.co.uk/news/top-stories/2009/06/03/warning-of-female-docs-taking-over115875-21410572/ accessed may 2010. 7. bbc news. rise in women doctors 'worrying'. 3 april 2008. from http://news.bbc.co.uk/1/hi/health/7329082.stm accessed may 2010. 8. ministry of health. monitoring and evaluation annual report 2009, domain thirty: human resources development and omanization in the health field, directorate of monitoring and evaluation, directorate general of planning. muscat: ministry of health, oman, 2010. 9. rusbult c. critical thinking skills in education and life, 2001. from http://www.asa3.org/asa/education/think/ critical.htm accessed may 2010. 10. worldwide centre for organisational development, critical thinking, 2008. from http://talentspotters.org/ downloads/critical-thinking.pdf accessed may 2010. 11. kenedy ra. successful critical thinking strategies. york university, toronto, faculty of arts, department of sociology. from http://www.yorku.ca/yulearn/universityskills/presentation_criticalthinking2.pdf accessed may 2010. 12. grimshaw jm, eccles mp, walker ae, thomas re. changing physicians' behavior: what works and thoughts on getting more things to work. j contin educ health prof 2002; 22:237–43. 13. healy b. how technology is changing the medical profession? clinical practice guidelines, electronic medical records, and population science are revolutionary, 2009, all business. from http://www.allbusiness.com/medicinehealth/diseases-disorders-obesity/12439874-1.html accessed may 2010. departments of 1urology and 2radiology, sohar hospital, sohar, oman; 3oman medical college, sohar, oman *corresponding author’s e-mail: mmelawdy@gmail.com حالة حلصوات احلالب البوىل القالبية نوع نادر من احلصوات والىت يتغاضى عنها أحيانا حممد حممد العو�شي، �شامر احللوجي، يا�رص عبد الرازق، عبري را�شد ال�شناين، �شلطان املزروعي abstract: matrix stones are a rare form of urinary calculi with a low mineral content. we report a 63-year-old female patient who presented to the sohar hospital, sohar, oman, in 2018 with unexplained left flank pain and constipation. she had a history of chronic renal failure (crf) and had previously undergone haemodialysis (hd). non-contrast computed tomography (ct) did not show any renal or urinary stones. however, a left-sided ureteroscopy revealed a yellow-coloured stone that was soft in consistency occupying the proximal 5 cm section of the ureter. many attempts at forceps extraction were required for complete clearance. a global quantitative composition analysis revealed the extracted stone to be composed entirely of protein-matrix material. matrix stones require a high index of suspicion as they are sometimes radiolucent and cannot be visualised on ct scans. risk factors include being female and a history of urinary tract infections, crf and hd. keywords: urolithiasis; ureteral calculi; diagnostic imaging; ureteroscopy; case report; oman. امللخ�ص: احل�شى القالبية هي �شكل نادر من احل�شيات البولية ذات املحتوى املعدين املنخف�س. هذا تقرير عن حالة مري�شة تبلغ من العمر 63 عاًما م�شابة بف�شل كلوي مزمن تعالج بالغ�شيل الكلوى و ح�رصت املري�شة يف يناير عام 2018 ايل م�شت�شفى �شحار، غمان، ب�شكوى من األم مزمنة يف اخلا�رصه وام�شاك. مل ُتظهرالأ�شعاعات الت�شوريه و الأ�شعه املقطعيه اي وجود للح�شى لذالك مت اجراء منظار يف احلالب الأي�رص والذي اأو�شح وجود ح�شى ذات لون اأ�شفر ناعم طولها 5 �شنتيميرت. اأجريت اأكرث من حماولة باملنظار لأ�شتخراج كل احل�شيات. اأو�شحت حتاليل احل�شى احتوائها كليا على الربوتني. يتتطلب احل�شى الذي يحتوي على الربوتني الكثري من الفحو�شات لكى يتم ت�شخي�شه لنه يف بع�س الأحيان تكون من النوع ال�شفاف الذي ل ميكن اأن يرى بالأ�شعة الت�شويرية ول املقطعية. هذا النوع من احل�شى اأكرث فى ال�شيدات عنه فى الرجال ومن م�شبباته التهابات املجارى البولية والف�شل الكلوي. الكلمات املفتاحية: حت�شي بويل؛ ح�شوات احلالب البوىل؛ الت�شوير الت�شخي�شي؛ منظار احلالب؛ تقرير احلالة؛ عمان. a case of pure matrix ureteral stone a rare type of urinary calculi that may be overlooked *mohamed m. elawdy,1 samer el-halwagy,1 yasser a. razek,2 abeer r. alsenani,3 sultan almazroui3 case report sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e557–559, epub. 28 mar 19 submitted 20 jun 18 revisions req. 29 jul & 9 sep 18; revisions recd. 13 aug & 12 sep 18 accepted 27 sep 18 doi: 10.18295/squmj.2018.18.04.024 matrix stones are a rare form of urinary calculi, with most reported cases related to renal stones and few cases of ureteral stones.1,2 matrix stones are formed within the renal collecting system and are composed of soft mucoproteinaceous material.3 in normal calcareous calculi, protein usually accounts for no more than 2.5% of the dry weight of the stone; how ever, in matrix calculi, it accounts for between 42–84%.4 pure matrix stones consist solely of protein and are therefore completely radiolucent and cannot be visualised, even on computed tomography (ct); as such, there is a risk of such stones being missed.1–3 this case report describes a patient with a pure matrix ureteral stone which was initially overlooked, resulting in a delay in diagnosis and management. such cases may help to increase awareness of this rare form of urinary calculi among urologists and radiologists. case report a 63-year-old female patient presented to the emergency department of the sohar hospital, sohar, oman, in 2018 with left-sided abdominal pain, dyspepsia and constipation. she had a medical history of ischaemic heart disease as well as chronic renal failure (crf), for which she had undergone haemodialysis (hd). a physical examination revealed left costovertebral angle tenderness and mild abdominal distension. routine laboratory investigations revealed a low haemoglobin (hb) level of 9 g/dl, likely due to the crf and hd. a urine analysis revealed elevated levels of red blood cells (rbcs) and white blood cells (wbcs) at >60 cells/high power field, indicative of a urinary tract infection (uti). in addition, a urine culture was positive for escherichia coli. ultrasonography (us) revealed that both kidneys were small, with increased cortical echogenicity and loss of corticomedullary differentiation. a ct scan showed moderate left-sided hydroureteronephrosis down to the level of the pelvic ureter, with no stones visible and perirenal and periureteral fat stranding [figure 1]. as such, the patient was treated conservatively. however, five days later, she presented to another hospital where she underwent a left-sided ureteroscopy (urs) and the insertion of a double-j ureteral stent. two weeks later, the patient presented once again to sohar hospital due to persistent pain. at this time, an a case of pure matrix ureteral stone a rare type of urinary calculi that may be overlooked e558 | squ medical journal, november 2018, volume 18, issue 4 discussion overall, matrix stones are more common in female patients; rowley et al. reported that seven out of nine patients in a cases series were female.2 this may be explained by the higher frequency of utis among women, another risk factor for matrix stone formation; in rowley et al.’s cases series, all nine patients had utis, while shah et al. reported that 80% of 17 patients with matrix calculi had pyuria.2,5 in the present case, the patient was female and had a uti, as determined by elevated levels of rbcs and wbcs in her urine and a positive e. coli culture. glomerular diseases and crf may also predispose patients to matrix stone formation due to higher protein content in the urine.6–8 based on chemical analysis and transmission and scanning electron microscopy, bommer et al. reported that de novo stones in seven patients undergoing hd were composed of an amorphous organic matrix consisting predominantly of protein.7 the current patient similarly had a history of crf and hd, with the extracted stone found to be composed entirely of protein. flank pain is one of the most frequent complaints of patients with matrix stones.1,5 as this type of stone is soft in consistency, it can be moulded into the shape of the renal pelvis or the ureter, resulting in complete obstruction. in a series of five patients, bani-hani et al. reported that four presented with flank pain and one with acute renal failure.1 similarly, the current case initially presented with left-sided abdominal pain which persisted until the stone was removed. non-contrast ct is the gold-standard modality for the diagnosis of urinary stones.9 however, as a result of their low mineral content, matrix stones are sometimes not visualised during imaging. this is because most matrix stones are radiolucent on plain x-rays and do not have a typical acoustic shadow on us; moreover, they often appear as filling defects on intravenous and abdominal x-ray showed that most of the left double-j ureteral stent had descended into the urinary bladder. a cystoscopy and left-sided urs was performed, during which the double-j stent was removed and insertion of a left guidewire was attempted; however, this failed as the wire could not be inserted past the level of the midureter. this was due to the presence of a long yellowcoloured stone located in the proximal 5 cm section of the ureter. the stone itself was soft, malleable and viscous in consistency. after many trials, the stone was eventually removed by forceps and the ureteroscope could be freely navigated to the kidney. after extraction, the fragments of the stone appeared black and elongated [figure 2]. a global quantitative comp osition analysis revealed the stone to be composed of 100% protein-matrix material. in terms of management, an open-tip ureteral tube was left in for 48 hours before the patient was discharged. at a two-week follow-up visit, she reported a significant reduction in pain. a urine analysis revealed no abnormalities, except for slight levels of rbcs and wbcs. figure 1: non-contrast computed tomography scans of the abdomen of a 63-year-old female patient with unexplained left flank pain and constipation showing moderate hydroureteronephrosis (arrows), but no visible stones at the level of the distal obstruction (arrowhead). figure 2: gross photograph of elongated black fragments of an extracted ureteral matrix stone found to be composed entirely of protein. mohamed m. elawdy, samer el-halwagy, yasser a. razek, abeer r. alsenani and sultan almazroui case report | e559 references 1. bani-hani ah, segura jw, leroy aj. urinary matrix calculi: our experience at a single institution. j urol 2005; 173:120−3. https://doi.org/10.1097/01.ju.0000145868.18824.25. 2. rowley mw, faerber gj, wolf js jr. the university of michigan experience with percutaneous nephrostolithotomy for urinary matrix calculi. urology 2008; 72:61−4. https://doi.org/10.1016/ j.urology.2007.12.080. 3. canales bk, anderson l, higgins l, frethem c, ressler a, kim iw, et al. proteomic analysis of a matrix stone: a case report. urol res 2009; 37:323−9. https://doi.org/10.1007/s00240-009-0213-5. 4. boyce wh, king js jr. crystal-matrix interrelations in calculi. j urol 1959; 81:351−65. https://doi.org/10.1016/s0022-5347 (17)66024-5. 5. shah hn, kharodawala s, sodha hs, khandkar aa, hegde ss, bansal mb. the management of renal matrix calculi: a singlecentre experience over 5 years. bju int 2009; 103:810−14. https://doi.org/10.1111/j.1464-410x.2008.08065.x. 6. branten aj, assmann kj, koene ra. matrix stones and acquired renal cysts in a non-dialysed patient with chronic renal failure. nephrol dial transplant 1995; 10:123−5. https://doi.org/10.1093/ oxfordjournals.ndt.a090828. 7. bommer j, ritz e, tschöpe w, waldherr r, gebhardt m. urinary matrix calculi consisting of microfibrillar protein in patients on maintenance hemodialysis. kidney int 1979; 16:722−8. https://doi.org/10.1038/ki.1979.188. 8. chan ch, el-hakim a, andonian s. renal matrix stone managed by ureteroscopic holmium laser lithotripsy. can j urol 2010; 17:5127−30. 9. worster a, preyra i, weaver b, haines t. the accuracy of non contrast helical computed tomography versus intravenous pyelo graphy in the diagnosis of suspected acute urolithiasis: a meta analysis. ann emerg med 2002; 40:280−6. https://doi.org/10.10 67/mem.2002.126170. 10. stoller ml, gupta m, bolton d, irby pb 3rd. clinical correlates of the gross, radiographic, and histologic features of urinary matrix calculi. j endourol 1994; 8:335−40. https://doi.org/10. 1089/end.1994.8.335. 11. beltrami p, ruggera l, guttilla a, iannetti a, zattoni f, gigli f, et al. the endourological treatment of renal matrix stones. urol int 2014; 93:394−8. https://doi.org/10.1159/000357624. retro-grade pyelography.2,9 on ct scans, they may look like an egg-shaped mass because the centre of the stone is of soft tissue density with a thin outer rim of calcification.1,9 accordingly, the appearance of a filling defect in a patient with normal renal function and no allergies to contrast agents may indicate the presence of a radiolucent stone. nevertheless, this diagnosis may be overlooked in those with impaired renal function. as such, a high index of suspicion should be maintained in the presence of any gas in the renal pelvis or unexplained hydro nephrosis, particularly among patients with unexplained flank pain.1,2,8 in doubtful cases, retrograde pyelography and diagnostic urs should be performed to confirm the diagnosis. treatment options for matrix stones are similar to that for calcareous stones, but with some unique differences. as matrix stones are usually large in size, they are very difficult to pass spontaneously; moreover, there is no effective option to dissolve them due to their low mineral content.10 furthermore, as matrix stones are usually radiolucent, accurate localisation for extra corporeal shock wave lithotripsy (eswl) is problematic. beltrami et al. reported that eswl was used as adjuvant therapy in only one case in a series of nine patients; percutaneous nephrolithotomy (pcnl) was the primary method of treatment for six cases, with urs utilised in the remaining three cases.11 among the five cases reported by bani-hani et al., one was treated by pyelonephrolithotomy, three by pcnl and one by urs.1 laser therapy may also be utilised in the management of matrix stones.8 in the current case, the patient was treated with urs, during which the stone could be removed by forceps extraction alone; however, due to its soft consistency, many attempts were required to ensure complete clearance. conclusion although rare, matrix or protein ureteral stones require a high index of suspicion for diagnosis as they are often completely radiolucent and cannot be visualised on ct scans. female patients and those with utis and a history of crf and hd are at higher risk of matrix stone formation. in most cases, matrix stones can be treated by forceps extraction alone during urs. squ med j, april 2010, vol. 10, iss. 1, pp. 12-22, epub. 17th apr 10 submitted 27th jan 10 revision req. 22nd feb 10, revision recd. 24th feb 10 accepted 24th feb the contemporary history of health care in oman dates back to 1970 when the reign of his majesty sultan qaboos commenced. in just about 40 years, the omani renaissance has brought prosperity, social and economic progress to all the people of oman with health being a primary concern.1 health care up to 1970 was scarce and limited. before 1958, oman had two hospitals; one was opened in 1935 by the american arabian mission and was named the knox memorial hospital while the other was established in 1948. the latter received partial financing from the sultan at the time and was staffed and administered by the british consulate.2 people had to travel up to four days just to reach a hospital, where hundreds of patients would already be waiting in line to see one of the few (expatriate) doctors.3 at that time, only 13 physicians served the entire nation, implying a physician-population ratio of 1 per 50,000. morbidity and mortality rates were very high. one out of every eight infants born alive died before reaching their first birthday, and one out of every five died before reaching the age of 5 years. out of every three people in the population, one had an episode of malaria, and out of every thousand persons, thirty were reported to be infected with trachoma, eight with pulmonary tuberculosis and six with hepatitis. the average life expectancy was only 49.3 years in 1970.4 in the early 1970s, there were no laws or regulatory systems to define how institutions should function, their principles and goals, or the rights and duties of employees. actually, the codification of government began only in the mid-1970.5 a royal decree was issued on 22nd of august 1970 to establish the ministry of health (moh) in oman.6 directorate general of planning, ministry of health, muscat, oman e-mail: drmoness@gmail.com أربعة عقود من التقدم تطور النظام الصحي يف سلطنة ُعمان م�ؤن�س م�شطفى ال�ش�شتاوي يف البالد جناح كبري حد اإىل حتقيقه على �شاعد والذي ال�شحة، يف ومهما �رسيعا تقدما ت�شهد ُعمان و�شلطنة عام 1970م، منذ امللخ�ص: ت�شييد بنية حتتية حديثة لتقدمي الرعاية ال�شحية. تعر�س هذه املقالة جتربة �شلطنة ُعمان يف جمال التنمية ال�شحية، وحُتلل النظام برمته، وُت�شلط ال�ش�ء على نقاط الق�ة فيه، كما حتدد الع�امل التي ميكن اأن ُيعزى اإليها جناح ُعمان يف هذا املجال. عالوة على ذلك، تناق�س املقالة اخلدمات وج�دة ال�شحية، الرعاية تقدمي ونظام ال�شحي، املجال يف العاملة والق�ى ، ُعمان يف ال�شحية الرعاية نفقات مت�يل بالتف�شيل ال�شحية وغريها من الق�شايا. كما تتناول املقالة اأي�شا هيكلية النظام ال�شحي، وال�شيا�شة ال�شحية والتخطيط يف �شلطنة ُعمان. ميكن ا�شتخدام هذا التحليل كم�شدر للمعل�مات للدرا�شات امل�شتقبلية وعملية تط�ير النظام ال�شحي يف �شلطنة ُعمان. مفتاح الكلمات: نظام �شحي، تخطيط �شحي، نتائج �شحية، ُعمان. abstract: since 1970, oman has witnessed rapid and significant improvements in health made possible largely because of the country’s success in building a state-of-the-art health care infrastructure. this paper presents oman’s experience in health development, analyses the whole system, highlights its strengths and delineates the factors to which oman’s success could be attributed. furthermore, health care financing and expenditures, health care workforce, the delivery system, quality and other issues are discussed in detail. the paper intends also to study thoroughly the organisation of oman’s health system and discuss health policy, and planning in oman. this analysis could serve as a source of information for future investigation and development of the health system in oman. keywords: health system; health planning; health outcomes; oman. special contribution four decades of progress evolution of the health system in oman moeness m alshishtawy moeness m alshishtawy special contribution | 13 the ministry was responsible for the organisation and development of the national health service, and spent 534,282 omani rials (usd 1,387,620) on health service development projects.3 in july 1975, the royal decree #26/75 introduced laws to regulate the administration. it set out the council of ministers and other government bodies with powers and responsibilities, in tandem with the first civil service law in the royal decree #27/75, which outlined civil servants’ rights and duties.5 since then, the moh has been able to build from scratch a modern national system that offers all omani citisens universally accessible health services free of charge. such developments were only possible through proper health planning.6 health planning in oman since its establishment in 1971, the moh faced great challenges to build the national health system and improve the health of the people of oman. therefore, the moh developed five-year health development plans to achieve its goals, the first of which started in 1976.7 since then, seven five-year health development plans have been implemented. health planning in oman has passed through three phases. the first phase stretched from 1976 to 1990. during this period, three five-year plans were implemented. they were mainly investment plans that aimed at building health infrastructure. the second phase covered 1991 until the end of 2005. during this period, the fourth, fifth and sixth five-year plans for health development were implemented. at the beginning of this period, a planning agency was established and health services were decentralised by establishing 10 health regions. local health administrations were set up at the wilayat (district) level. that period of development showed an increase in the numbers of health centres and hospitals. it also witnessed the start of a number of preventive programmes, each one of them addressing a priority health or healthrelated problem(s).8, 9,10 with the beginning of the seventh 5-year plan that started in 2006, the new phase of strategic planning started in the country.11 in the seventh five-year health development plan, and in the light of the identified objectives and strategic directions for health development in oman (2006–2010), a number of priorities in different fields were defined. following the prioritisation of important issues and problems, a framework for the seventh five-year plan for health development (2006–2010) was developed, through a consultative process, including ten proposed visions and the goals arising from these visions. the current seventh five-year health development plan (2006–2010) was developed at various levels and is monitored by outcome and performance indicators.11 the seventh plan (2006–2010) has targeted the further development of the health services infrastructure, primary care and early prevention of diseases, and community involvement through health education promotion. this focus is an effort to face the challenges of the demographic, economic and social changes that have brought with them new epidemiological trends.6 national health policy oman’s health policy is committed explicitly to the global health for all (hfa) strategy, and accordingly, has laid down in broad terms the national strategy to achieve hfa based on primary health care (phc).12 in this context, national health policy rests on several basic principles, which govern health development in oman:13 1. provision of comprehensive health services based on primary health care with its four components (curative, preventive, promotive and rehabilitative). 2. equity in the distribution of health services among different population groups according to their health needs (with due consideration of the special needs of marginal and poor people, isolated villages, women, children, elderly and accessibility to health facilities). 3. community involvement in planning and implementation of its health care aimed at developing community self-reliance for sustainable health development. 4. inter-sectoral cooperation with other healthrelated sectors to ensure a positive impact on community health.11 in order to ensure accelerated health development the government adopted several well thought out strategies to implement its health policy. first, the government declared health not only as a four decades of progress evolution of the health system in oman 14 | squ medical journal, april 2010, volume 10, issue 1 fundamental right of the citizen, but also committed itself to the provision of public health services for free.14 the government viewed this investment not only in the context of its contribution to provide financial protection against the cost of ill-health, but also because of the pivotal role of health development in economic and social development.15 second, priority was given to the construction of a basic health infrastructure that would be universally accessible to the whole population. today government local health services reach 100% of urban families and 90% of rural families.16 health services are also provided, through mobile teams, to people living in very isolated areas. third, with insufficient manpower, the moh worked on a twopronged human resource policy: importing health professionals from neighbouring countries of the middle east and south asia to meet the immediate need of the health system and, at the same time, developing its own indigenous human resources to achieve self-reliance in the long term.17 fourth, from the early seventies, the moh launched a series of vertical programmes targeted at the priority health problems based on their magnitude, prevalence and intensity as well as their associated burden of diseases.18 as an example, the rapid decline of malaria from 32,000 cases in 1990 to a few hundred per annum today (and these mostly imported)19 illustrates the success of oman’s health care strategy. health financing in oman oman finances its health system largely through the government budget, very limited cost sharing, limited private payments for private sector expatriates through an “employer mandate”, and very small contributions from automobile accident insurance and social security taxes on private sector employees to cover work-related injuries. oman spends just 2.4% of gross domestic product (gdp) on health [table 1].19 governmental spending on health accounts for about 82.5% of total health expenditure. the government provides 93% of hospitals and about 97.3% of hospital beds. public health services employ 77.2% of the doctors in the sultanate, 91.6% of nurses [table 2] and 85% of other paramedics.20 however, the private sector contribution in the health field has increased fairly rapidly over the last few decades as evidenced by the increasing numbers of private hospitals, clinics and pharmacies.4 the moh is the main provider of health services in the country; currently moh expenditure comprise 3.8% of total government expenditure.4 the moh’s spending amounts to 80% of public sector spending, 47% of which is spent on inpatient care. the ministry provides comprehensive coverage to all omani citizens and expatriates working for the public sector and requires the annual purchase of a “health card” (for 1 omani riyal = us$ 2.6) and a small co-payment for each facility visit (0.2 omani riyals = us$ 0.50). the other public sector providers offer similar treatment benefits with very limited cost-sharing by those eligible to receive benefits. the moh does provide coverage for treatment abroad, and funds treatment for around 350-400 individuals a year.21 private spending is almost evenly split between employer-provided and out-of-pocket spending at 9% and 9.6% of total spending respectively. types of services offered by the private sector vary: 2% for the most expensive services which are inpatients services, 59% for dental services, 51% for drugs and 19% for outpatient services.20 table 1: health expenditure indicators in oman indicators (reference year 2007) gross domestic product (gdp) per capita in us$ 15,229 total expenditure on health per capita in us$ 373 government expenditure on health per capita in us$ 308 total expenditure on health as % of gdp 2.4 general government expenditure on health (gghe) as % of total health expenditure (the) 82.5 out-of-pocket expenditure as % of the 10.2 general government expenditure on health as % of total government expenditure 5.2 ministry of health budget as % of government budget 4.6 source: world health organization. oman country profile.19 moeness m alshishtawy special contribution | 15 health system in oman the sultanate of oman has entrusted the moh with the responsibility of stewardship and coordination of the health sector, apart from being the principal health care provider. the moh develops health policies, strategies and health programmes and plans for the sector and also bears the preventive, curative, and rehabilitative care workload.14 services provided by the moh are supplemented by other government hospitals/clinics including the armed forces medical services (afms), royal oman police medical services (ropms), petroleum development oman medical services (pdoms) and the sultan qaboos university hospital (squh). while the squ hospital serves mainly as a teaching hospital and provides tertiary care, the other public care providers cater mainly to their own employees and their families. the private hospitals and clinics, licensed by moh through its directorate of private health establishments, and supervised by the respective regional directorates, play an increasingly important role in providing health care in oman.4 thus, policies decided by government are necessarily implemented to the full since there is no real alternative to the state health care system. the moh owns alone 49 hospitals (84.5% of the total), with 84.1% of hospital bed capacity in oman. four of these hospitals act as national referral hospitals, and 10 are regional hospitals providing tertiary plus secondary health care services (the last are also provided through 5 wilayat hospitals). in addition, moh operates a network of 30 local hospitals and 167 health centers that provide phc services.4 table 2 presents the currently available information on the existing health infrastructure and human resources by provider. the government has laid special emphasis on the role of private sector in the field of health care industry. it views the involvement of this sector as a contribution towards alleviating the increasing burden on the public health system, and creates an atmosphere of competition between public and private health sectors, thus improving the quality of health care provided in the country. thus, the government has formulated a number of strategies to encourage the private sector to invest in health. the government gives financial support to the private health care sector through a law that treats them on an equal basis with those who invest in industry. they are given the same advantages and the same grants. in addition, the moh provides the private sector with all the technical support they need to start their hospitals or clinics. moreover, the moh has privatised most of its support services in hospitals and health institutions, thus enabling the private sector to play an important role even for the table 2: health infrastructure and human resources in oman (2008) provider hospitals hospital beds health centers & extended health centers clinics physicians nurses ministry of health 49 4,605 167 0 3,620 9,277 sultan qaboos university hospital 1 410* 1 0 329 833* royal omani police 1 50 0 3 34 101 medical services of diwan of royal court 0 0 0 1 18 46 ministry of defense** 3 260 0 31 petroleum development of oman 0 0 0 9 11 36 private sector 4 148 0 766 1,182 941 total 58 5,473 168 810 5,194 11,233 * data updated from: ministry of national economy, statistical year book 2009, issue 37, 2009 * *complete information currently unavailable. note: there are in addition 364 private pharmacies. source: ministry of health statistics.4 four decades of progress evolution of the health system in oman 16 | squ medical journal, april 2010, volume 10, issue 1 market segment of omani nationals, governmentemployed staff, and their families who are generally eligible for free health care to the extent that this is feasible. the pharmaceutical sector and a large part of the dentistry services are almost exclusively left for the private sector to cover. the government provides soft loans (and free or subsidised sites in some cases) to private entrepreneurs desirous of setting up clinics/hospitals. ministry of health also extends other technical support to private establishments in numerous ways.21,22 organisation and management oman has a relatively small population of 2.9 million inhabitants4 who are scattered over large areas of sparsely populated settlements, many with 1,000 or fewer inhabitants.23 the moh has made every effort to make health services easily accessible. more than 98% of the population19 now has access to primary health care services and the remaining 2% is served through mobile teams.6 the institutional organisation of the moh is relatively centralised with three under-secretaries responsible for administrative/financial affairs, health services and planning reporting directly to the minister.24 the moh has, however, pursued a decentralisation process since 1990. a directorate general of health services was established in each of the ten health regions (now eleven). delegation of responsibilities, financial and administrative as well as decision-making was gradually devolved to health regions. decentralisation has also been in effect at the wilayat (district) level since 1993.7 this approach to decentralisation has allowed the moh to delegate necessary authorities and responsibilities to regional and wilayat levels. this has encouraged local initiatives and enabled local planning, and budget control.18 furthermore, the wilayat health level, matching as it does the administrative level of local government, has a pivotal role in addressing determinants of health. it provides the ideal platform for inter-sectoral collaboration on a broader health agenda where the determinants of health need to be addressed by a multiplicity of agencies and the wider community. the wilayat health committees, established in 1999 in all wilayats and chaired by the wali (local governor) provide, in principle, the main forum for supporting the multi-sectoral and community-based activities of the moh and inducting community support group volunteers, whose main orientation is towards health education table 3: coverage and primary health care service indicators in oman indicators % reference year + population with access to local health services, total 98 2008 + population with access to local health services, urban 100 2008 + population with access to local health services, rural 95 2008 + antenatal care coverage 99 2007 + births attended by skilled health personnel 99 2007 + population with sustainable access to improved water source 75 2003 + population with access to improved sanitation 89 2003 one year-old immunised in 2008 with + bcg anti tuberculosis vaccine 99.9 2008* + dpt3 diphtheria, pertussis (whooping cough) and tetanus vaccine 99.2 2008* + opv3 polio vaccine 99.9 2008* + measles/mmr1 (mcv1) measles mumps and rubella vaccine 99.9 2008* + hbv3 hepatitis vaccine 99.2 2008* legend: * = data updated from moh statistics4 source: world health organization. oman country profile.19 moeness m alshishtawy special contribution | 17 in the community.25 several community-based initiatives such as the healthy wilayat project, healthy lifestyle project, healthy city and healthy village projects were recently implemented in order to help increase the awareness of the respective communities about environmental and health problems, and thus create active community involvement and ownership for health actions.11 recently, a number of regional referral hospitals and major wilayat hospitals were made autonomous and now are run, administratively and financially, by hospital management boards with a reasonable degree of decision-making authority.7 plans to monitor performance of the autonomous hospitals are being developed. it is expected that the hospital autonomy initiative will ensure better and more costeffective services in the future than ever before. health workforce in the early years of the omani renaissance, oman imported its health workforce from other countries in large numbers, as its educational infrastructure was inadequate. it adopted that policy in order to accelerate health services development and fulfill the aspirations of the people of oman. his majesty sultan qaboos has advocated omanisation as a national strategy for self-reliance, in order to sustain the social and economic development achieved in the country. the government attaches significant importance to human resources development as a strategy for achieving effective health services development.11 nevertheless, the issue of human resources for health (hrh) is complex in oman as health workforce development strategies are governed by a multiplicity of stakeholders from within the moh itself, but also from outside the ministry. health professional associations and councils have only recently started to form, though with limited influence so far on manpower planning, management and development.26 of the 5,194 physicians now working in the health institutions, there are 1,323 omanis representing a 25% omanisation level.4 physicians are trained by the sultan qaboos university college of medicine and health sciences, the private sector oman medical college, and to a small extent by universities abroad. sultan qaboos university has increased its intake to the md program to meet the increased need for graduate physicians and to promote the omanisation of this category. in order to encourage medical education, the moh permits the use of its sohar regional hospital as a teaching hospital for the oman medical college. the moh, in collaboration with sultan qaboos university, is sponsoring the oman medical specialty board to train physicians in a number of specialties.27 the availability of local training in nursing and other paramedical professions has significantly contributed to omanisation levels. in 1975, there were only 450 nurses working in oman, mostly expatriates. by the end of 2008, there were a total of 11,233 nurses, 56% of them were omanis.4 by the same date, training institutes had also graduated a total of 9,031 health professionals from different specialties (including the basic diploma nursing); among these were 543 laboratory technicians, 376 radiographers, 133 physiotherapists and 622 assistant pharmacists. these graduates have contributed to omanisation levels of 49% for laboratory technicians, and 56% for the last three categories.4 table 4: health status indicators in oman indicators (reference year 2008) total life expectancy at birth (years) 71.6 newborns with low birth weight (%) 9.2 perinatal mortality rate (per 1,000 total births)* 13.8 neonatal mortality rate (per 1,000 total births)** 6.4 infant mortality rate (per 1,000 live births) 9.0 under five mortality rate (per 1,000 live births) 11.7 maternal mortality ratio (per 10,000 live births) 16.7 * calculated as the number of stillborn infants of 24 compeleted weeks or more plus the number of deaths occurring under 7 days of life divided by the number of stillborn infants of 24 weeks or more gestation plus all liveborn infants in the same year **calculated as the number of children dying under 28 days of age divided by the number of live births that year. source: data updated from moh statistics4 four decades of progress evolution of the health system in oman 18 | squ medical journal, april 2010, volume 10, issue 1 health care delivery generally, the organisation of health care delivery in oman is based on a primary health care (phc) approach, with clearly delineated referral pathways between 3 levels of care: primary, secondary and tertiary. the moh is now operating 167 health centers of which 74 have maternity beds and 21 are extended health centres. these health centres provide preventive, curative and promotive primary health care to the community. in addition, the extended health centres were established to provide specialty care in certain disciplines.4 local hospitals, also, provide phc services.19 the phc system is based on the wilayat, or district, the unit of local administration that is the closest to the community. the central role of community health work to a primary health care approach was placed firmly on the international health agenda by world health organization member states in the declaration of alma-ata in 1978.28 secondary health care is provided through regional (mostly autonomous) and sub-regional (wilayat) hospitals. tertiary care is provided through four national referral hospitals each specialising in a few fields. the moh also extends the services of mobile medical teams to about 2% of the population living in remote mountainous areas.19 over the years, there has been a growing trend in the utilization of health services (phc in particular). during 2008, patient visits to outpatient clinics in moh institutions were about 11 million with an average of 3.9 visits per individual per year.4 about 253 thousand patients were discharged from moh hospitals, the average number of inpatients per day being 2,513. the average occupancy rate for all moh hospitals is 54.9%, indicating significant excess capacity.4 concerns for quality assurance and equity in health care availability, have dictated the ministry’s health development plans and infrastructure development. thus, the issue of quality moved high on the agenda of the moh and was introduced in phc in 2001, and then to hospitals as well. the omani quality assurance and improvement programme aims to institutionalise quality in health care institutions with the ultimate goal of providing the highest quality standards of care and thus achieving user satisfaction.29 health outcomes oman is one of the few countries worldwide that has achieved a dramatic transformation in its health status over a remarkably short span of time. oman’s current health indicators compare well with those of many developed countries with a remarkable control of pregnancy related mortality and morbidities, preventable diseases of childhood and other communicable diseases of public health relevance.22 this is evident from the changes in the various health indicators. currently, the country’s health status indices show an average life expectancy of 71.6 years for males and females at birth. this has been achieved despite a relatively high fertility rate and the consequent large proportion of the population under age 15 years (35.19%).4 on the other hand, four indices for population coverage with basic health services are among the highest in the world. these include over 99% coverage rate for major vaccines, 99.2% antenatal care coverage (at least one visit during pregnancy), 98.6% of all deliveries taking place in hospitals 4, and 98% of the population now have access to primary health care services [table 3].19 oman has also moved from a position amongst the countries in the region with the highest childhood mortality in 1970s, to be amongst the best performers and has even caught up with countries with a much earlier start in development and wealth [table 4]. in less than 40 years, infant mortality rate has dropped to less than one tenth of its former level (9.0 per 1,000 live births in 2008, down from 118 in 1972), and the under-five mortality rate has dropped by a staggering 94% (11.7 per 1,000 live births in 2008, down from 181 in 1972).4 such patterns reflects one of the fastest declines in under-five mortality ever recorded globally.30 this means that oman has been successful in utilising all its available resources in order to achieve a satisfactory health status of the population. these dramatic declines in mortality indicators were mainly because of achievements in reducing communicable diseases. childhood diseases were highly prevalent during the 1970s; 103 cases of acute poliomyelitis, 102 cases of tetanus, and 43 cases of diphtheria were reported in 1975. today no single case of poliomyelitis has been reported since 1993. the last case of diphtheria was reported moeness m alshishtawy special contribution | 19 in 1992 and only one case of tetanus neonatorum has been reported since 1991. the number of cases of measles, mumps and pertussis reported was very high in 1975: more than 16,000 cases of measles, 14,000 cases of mumps and 13,000 cases of pertussis; these dropped in 2008 to 6, 995 and 58 respectively. other communicable diseases have seen a similar reduction. there were 6,162 cases of pulmonary tuberculosis diagnosed clinically in 1975 compared to only 217 cases in 2007. about 5,000 cases of hepatitis and 24,000 of trachoma were reported in 1975 compared to only 772 and 72 cases respectively in 2008. malaria, one of the most prevalent diseases in the past, is coming close to eradication. only 965 cases of malaria were confirmed during 2008 compared to 32,720 during 1990. there were also 144 cases of leprosy and 39 cases of filariasis reported in 1975. leprosy today is no longer a public health problem as the incidence is less than 1 per 100,000 of the population and no cases of filariasis have been reported.4 international recognition oman’s remarkable achievements in health developments during the recent past are well recognised and widely acclaimed both regionally and internationally. the country has been recognised for achieving record-breaking gains in population health status and health infrastructural development.31 in respect of its achievements, oman has received the following international recognitions and appreciations in the last two decades: 1. according to the united nations international children’s emergency fund (unicef) progress of nations 1993 report, oman’s 65% decline in its child mortality rate in the 1980s was the second highest in the world, and the highest in the middle east and north africa (mena) region.32 2. in 1993, and according to the previous report, oman’s 97% measles immunisation rate was the highest in the mena region, and one of the best five in the world. oman was among the 12 countries which achieved and exceeded the decade goal of vaccinating 90% of children against measles by the year 2000.32 3. the progress of nations report, issued in 1997 by unicef, acknowledged the omani achievements in child health and ranked oman among the leading countries in the middle east, africa and even the whole world in controlling childhood diseases such as poliomyelitis, diphtheria and tetanus neonatorurm.33 4. according to the human development report 1997, oman was the first in the world for its impressive achievements in under-5 mortality reduction and 99% immunisation coverage of infants, which led also to a marked reduction table 5: top 10 countries in the world according to health system performance performance on health level (dale) overall performance rank member states rank member states 1 oman 1 france 2 malta 2 italy 3 italy 3 san marino 4 france 4 andorra 5 san marino 5 malta 6 spain 6 singapore 7 andorra 7 spain 8 jamaica 8 oman 9 japan 9 austria 10 saudi arabia 10 japan source: who. world health report 2000: health systems: improving performance.31 four decades of progress evolution of the health system in oman 20 | squ medical journal, april 2010, volume 10, issue 1 in childhood morbidity. the report stated that oman was a pioneer in the field of human development.18 5. in a study done by harvard university and commissioned jointly by the government of oman, unicef and the who regional office for the eastern mediterranean region, health sector achievements in oman were analysed and considered as a model to demonstrate health developments.1 6. in an analysis of health systems undertaken by the world health organization (who) in 2000, oman’s health system ranked first among all who member states (191 countries) for its health financing efficiency. it was also ranked 8th using a composite index measuring performance of the health system, attainment of health goals, responsiveness to users and the fairness of its financing [table 5].31 7. the world bank report on the sultanate of oman in 2001, cost effectiveness review of the health sector, praised the health system in oman and stated that it spent less money in percent of gross domestic product (gdp) “public and private” compared with countries at a similar income level. per capita total health expenditure was well below that found in countries with similar income levels.22 it thus appears that oman’s investments in health have been both effective and efficient.22 8. the latest who report in 2008 acknowledged oman’s performance in the last four decades and commended it exclusively as an example of success in investing consistently in a national health service and sustaining that investment over time.28 conclusion recent and ongoing efforts of the moh guided by the national health policy have achieved impressive progress in the health status of omani citizens as evidenced by high level health indicators that are comparable to those of developed countries. the attainment of what can be seen as a population health transition has taken place within a relatively short period of time and has been achieved at a comparatively modest cost.31 to learn from the experience, oman’s success could be attributed to the following factors. it is believed that strong political commitment and national investment in the primary health care approach are the basis for the effective and efficient omani health system. this was demonstrated not only in the assurance given by the government about free provision of health services to the people of oman, but also in the keen interest that the head of the government, his majesty sultan qaboos, has demonstrated towards health development. this is evidenced during his majesty the sultan’s annual tours in various regions of oman during which he meets his people, and personally advocates for health even touching upon such sensitive issues as birth spacing. historically, health transitions on a similar scale to that of oman were widely attributed as much to the improvement of non-health conditions as to those related to the health system, for example, the level of income, education, transport, women’s empowerment and access to information. however, the role of the health sector and the health delivery system in speeding health transition has been significantly boosted by advances such as potent technologies (i.e. vaccines), effective medicines, and the feasibility of wider coverage of populations by these and other far-reaching public health interventions.12 it is interesting to note that with the possible exception of hospital delivery care, almost all of these interventions are provided as ambulatory deliverables at the phc outlets in oman.12 furthermore, the effectiveness of phc delivery was considerably consolidated by decentralisation and adoption of the wilayat phc health system. the strategy brought the phc system closer to the community and led to a number of communitybased initiatives spearheaded and supported by wilayat health committees and community support groups.12 oman laid great emphasis, right from the start, on sound planning supported by an efficient health information system. proper planning at all levels fostered successful linkage between health goals and main functions of oman’s national health system. the omani health sector also benefited from others’ experiences by drawing on regional and international experiences in other countries, including the effective technical cooperation with international organisations such as unicef, who moeness m alshishtawy special contribution | 21 and the world bank. thus, the country was able to develop programmes, the designs of which had already been tested successfully elsewhere. in conclusion, oman has achieved remarkable improvements in health indicators, including a rapid decline in communicable diseases during the past four decades. increased expenditure on health has resulted in improved indicators of health services, health manpower development and health care. planning has helped the government, policymakers, health care providers and all other stakeholders focus and work towards the set goals and objectives and work communally to achieve them. references 1. hill gh, muyeed az, al-lawati ja. the mortality and health transition in oman: patterns and processes: a study commissioned by the government of oman, unicef oman office, and the who regional office for the eastern mediterranean, december 2000. 2. allen ch, rigsbee wl. oman under qaboos: from coup to constitution 1970-1996. portland, or: frank cass, 2000. 3. smith r. oman: leaping across the centuries. bmj 1988; 297: 540–4. 4. ministry of health. annual health report 1975, 2008. muscat: ministry of health, oman, 1976, 2009. 5. united nations international children’s fund (unicef) and ministry of national economy. situation analysis of children and women in oman. muscat: unicef, 2006. 6. ministry of health (oman). development of health services and health care. from http://www.moh. gov.om/nh_menu.php?fnm=reports/devofhelt.htm accessed november 2009. 7. ai bulushi hs, west jr dj. health system reforms and community involvement in oman. j health sci manage public health, 2006; 7:16–28. 8. gadalla f. outlines of the health development programmes of the fourth five-year plan (1991– 1995). muscat: ministry of health, oman, 1993. 9. ministry of health. the fifth five-year plan for health development (1996–2000). muscat: ministry of health, oman, 1996. 10. ministry of health. the sixth five-year plan for health development (2001–2005). muscat: ministry of health, oman, 2001. 11. ministry of health. the seventh five-year plan for health development (2006–2010). muscat: ministry of health, oman, 2006. from http://www.moh.gov. om/fiveyearplan/english/part%2001.pdf accessed november 2009. 12. abdel rahim im. review of primary health care delivery in oman and strategic directives for the future. unpublished report presented to the ministry of health, oman, march 2003. 13. ministry of health, oman. about the ministry: health policy statement. from http://www.moh. gov.om/nv_menu.php?fnm=p olic y/statement . php&sp=1 accessed november 2009. 14. ministry of health, oman. ministry of health mission. from http://www.moh.gov.om/nv_menu. php?fnm=mission/mission.php&sp=1 accessed november 2009. 15. world health organization. macroeconomics and health: investing in health for economic development: report of the commission on macroeconomics and health. geneva: who, 2001. 16. world health organization. demographic, social and health indicators for countries of the eastern mediterranean. cairo: who, regional office for the eastern mediterranean, who-em/hst/206/e, 2008. 17. ministry of health, oman. human resources development review. from http://www.moh.gov. om/nv_menu.php?fnm=hr/hrdeview.htm &sp=1 accessed november 2009. 18. ministry of health (oman). primary health care in the sultanate of oman. from http://www.moh. gov.om/nh_menu.php?fnm=reports/prihelt.htm accessed november 2009. 19. world health organization. oman country profile. from http://www.emro.who.int/emrinfo/index. asp?ctry=oma accessed november 2009. 20. ministry of health. health information system review and assessment, directorate of information and statistics, directorate general of planning. muscat: ministry of health, oman, april 2008. 21. the world bank. sultanate of oman: enhancing revenues for health services: issues and options. washington: the world bank, human development sector, middle east and north africa region, march 2006. 22. the world bank. sultanate of oman: cost effectiveness review of the health sector, main report. washington: the world bank, human development sector, middle east and north africa region, march 2001. 23. ministry of national economy. results of oman 2003 general census. muscat: ministry of national economy, oman, 2004. 24. ministry of health (oman). organization of the ministry of health. from http://www.moh.gov. om/nh_menu.php?fnm=organisation/org_moh. php&sp=1.htm accessed november 2009. 25. alshishtawy mm. health is a right and duty: the experience of health committees in oman. muscat: ministry of health, oman, 2002. four decades of progress evolution of the health system in oman 22 | squ medical journal, april 2010, volume 10, issue 1 26. ministry of health. oman national hrh observatory lead document: human resources for health in the sultanate of oman. muscat: ministry of health, oman, 2008. 27. college of medicine & sultan qaboos university hospital. annual report 2007–2008. muscat: sultan qaboos university, 2009. 28. world health organization. the world health report 2008: primary health care: now more than ever. geneva: who, 2008. 29. ministry of health. the comprehensive manual of quality assurance standards in primary health care. muscat: ministry of health, oman, 2005. 30. hill ag, chen lc. oman’s leap to good health: a summary of rapid health transition in the sultanate of oman. muscat: world health organization, 1996. 31. world health organization. world health report 2000: health systems: improving performance. geneva: who, 2000. 32. united nations international children’s emergency fund (unicef). progress of nations 1993. muscat: unicef, 1993. 33. united nations international children’s emergency fund (unicef). progress of nations 1997. muscat: unicef, 1997. tuberous sclerosis complex (tsc) is anautosomally inherited multisystem neuro-cutaneous disorder with variable expression. it is characterised by various features, including benign tumours in the brain and other vital organs—such as the heart, eyes, kidneys, skin and lungs—and dermatological features such as hypomelanotic macules and shagreen patches.1 according to the 2012 international tuberous sclerosis complex consensus statements, a diagnosis of tsc is either clinical, based on the presence of a specific combination of major and minor features, or genetic, determined by mutations in the tuberous sclerosis (tsc) 1 or tsc2 genes.2 while a relationship between autism spectrum disorder (asd) and tsc has been hypothesised previously, confirmation of a link between these conditions required more validated diagnostic tools for asd. an accurate assessment of the relationship between these two disorders is now possible with the availability of standardised criteria for asd diagnosis, such as those published in the diagnostic and statistical manual of mental disorders (dsm-v), the revised autism diagnostic interview™ (wps, torrance, california, usa) and the autism diagnostic observation schedule™ (wps).3 the estimated prevalence rate of autism in tsc patients is departments of 1child health and 2genetics, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: watfa.almamari@gmail.com حدوث اضطراب طيف التوحد واضطراب التصلب الدرين يف وقت واحد يف ثالثة أطفال تقارير حاالت ومراجعة األدبيات اآمنة الفطي�شية, اأحمد اإدري�س, عبري ال�ش�يغ, وطفة �شعيد املعمرية abstract: tuberous sclerosis complex (tsc) is a multisystem neurocutaneous disorder inherited in an autosomal dominant manner and characterised by benign tumours in the brain and other vital organs such as the heart, eyes, kidneys, skin and lungs. links between autism spectrum disorder (asd) and tsc have been postulated for many decades, with tsc considered to be one of the main syndromic causes of asd; however, precise confirmation of a relationship between these two disorders required validated diagnostic tools. fortunately, accurate evaluation of this relationship is now possible with standardised criteria for asd diagnosis. we report three children who presented to the sultan qaboos university hospital, muscat, oman, between 2014 and 2015 with asd and tsc. these cases demonstrate the spectrum of neuropsychiatric involvement in tsc and highlight the importance of screening children with tsc for asd features in order to encourage the early enrolment of these children in educational and rehabilitation programmes. keywords: autism spectrum disorder; tuberous sclerosis; case report; oman. امللخ�ص: الت�شلب الدرين هو ا�شطراب ع�شبي جلدي متعدد يت�شم ب�شفة وراثية �ش�ئدة ويتميز بوجود اأورام حميدة يف عدة اأع�ش�ء حيوية ك�لدم�غ والقلب والعني والكلى واجللد والرئتني. وبحث احتم�ل وجود ا�شطراب طيف التوحد وا�شطراب الت�شلب الدرين منذ عقود طويلة, اإذ يعترب ا�شطراب الت�شلب الدرين اأحد اأهم املتالزم�ت امل�شببة لطيف التوحد. وعلى الرغم من ذلك ف�إن الت�أكيد الدقيق بني هذين ال�شطراب�ت يتطلب ويحت�ج اإىل التحقق من �شحة اأدوات الت�شخي�س. وحل�شن احلظ ف�إن التقييم والت�شخي�س الدقيق ملعرفة العالقة بني هذين ال�شطرابني ج�معة م�شت�شفى يف عالجه� مت ح�لت ثالث التقرير هذا ويتن�ول التوحد. لطيف للت�شخي�س دقيقة مع�يري وجود ب�شبب ممكن� اأ�شبح الع�شبية العرا�س طيف احل�لت هذه تربز ال�شطرابني. به�ذين م�ش�بة و2015 2014 ع�مي بني م� عم�ن م�شقط, ق�بو�س, ال�شلط�ن لإحل�قهم ال�شطراب�ت هذه من يع�نون الذين لالأطف�ل املبكر الفح�س و�رسورة اأهمية على وتوؤكد الدرين ب�لت�شلب املرتبطة والنف�شية مبكرا يف الربامج التعليمية والت�أهيلية اخل��شة. الكلمات املفتاحية: ا�شطراب طيف التوحد؛ الت�شلب الدرين؛ تقرير ح�لة؛ عم�ن. coexistence of autism spectrum disorders among three children with tuberous sclerosis complex case reports and review of literature amna al-futaisi,1 ahmed idris,1 abeer al-sayegh,2 *watfa s. al-mamari1 case report sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e520–524, epub. 30 nov 16 submitted 13 jan 16 revisions req. 16 mar & 27 jul 16; revisions recd. 24 apr & 3 nov 16 accepted 7 nov 16 doi: 10.18295/squmj.2016.16.04.022 amna al-futaisi, ahmed idris, abeer al-sayegh and watfa s. al-mamari case report | e521 approximately 50%, a similar rate to that of other neurological comorbidities, such as epilepsy (84.5%) and intellectual disability (44%).4–6 however, despite this high prevalence rate, few studies have assessed the severity of autism among patients with tsc. this report describes three children with both asd and tsc, illustrating the coexistence of these disorders. case one a 5-year-old girl presented to the developmental paediatrics clinic of the sultan qaboos university hospital (squh), muscat, oman, in 2014 with major speech and language delays. she demonstrated challenging behaviours typical of asd, including impulsiveness and hyperactivity. she was described by her parents as a very quiet infant who rarely cried, even during vaccinations. when she was approximately one year old, the patient was noted to show poor response to her name and rarely make eye contact. by 18 months of age, there were reported delays in sitting, walking, speech and language. she could crawl by 18 months and walk without support by 20 months of age. when she was four years old, the patient experienced one febrile seizure but had since had no further seizures. her father had a seizure disorder along with adenoma sebaceum. he was evaluated by brain computed tomography (ct); however, the findings were reportedly normal. a clinical examination revealed a hyperactive child who could not speak clearly and who demonstrated a poor response to verbal commands. her head circumference was below the third centile for her age. she had a shagreen patch on her lower back extending to the left side which measured 8 x 5 cm and three hypopigmented macules (two on her lower limbs and one on her back). her neurological and systemic examinations were normal. a comprehensive developmental assessment indicated that she fulfilled the dsm-v diagnostic criteria for asd.7 genetic testing showed that there was a deletion of exon 37 of the tsc2 gene, confirming the diagnosis of tsc. the patient was enrolled in a rehabilitation centre for children with special needs and several of her challenging behaviours improved without the need for medical therapy. case two a 5-year-old boy presented to the developmental paediatrics clinic at squh in 2014 due to concerns related to his language, communication and social milestones. at 19 months old, he was noted to have delayed speech, poor eye contact, poor response to his name, many repetitive play behaviours and restricted interests. he had attention problems and could not remain focused on specific tasks. there were no other reported health issues. a skin examination revealed three hyperpigmented spots and three hypomelanotic macules, with the rest of examination being otherwise normal. a developmental evaluation showed significant deficits in social interaction and communication in addition to significant behaviours and interests typical of asd. he also fulfilled the dsm-v diagnostic criteria for asd.7 magnetic resonance imaging (mri) of the brain showed nodular heterotopias and tubers adjacent to the right lateral ventricle [figure 1]. the clinical and mri findings confirmed the diagnosis of tsc. however, genetic testing revealed no mutations, deletions or duplications in the tsc1 and tsc2 genes. his mother was noted to have one major and one minor feature of tsc—angiofibromata and dental pits, respectively—which suggested that she also had tsc. furthermore, two maternal cousins had had learning problems, with one also having a psychiatric disorder. the patient received treatment at a specialised rehabilitation centre for children with special needs, with notable improvement in his development and behaviours. case three a 1-year-old female infant presented to the developmental paediatrics clinic at squh in 2015 for a seizure disorder which had initially manifested at three months of age. on examination, she was found to have five hypomelanotic macules measuring 0.5 x 1.5 cm. figure 1: t2-weighted magnetic resonance fluidattenuated inversion recovery sequence transverse image showing an isointense nodular lesion in the right periventricular region (arrow) of a 5-year-old boy with autism spectrum disorder and tuberous sclerosis complex. coexistence of autism spectrum disorders among three children with tuberous sclerosis complex case reports and review of literature e522 | squ medical journal, november 2016, volume 16, issue 4 patient was prescribed levetiracetam and clonazepam for her seizures, which resulted in reasonable control. a summary of the clinical features, radiological findings and family history of each case is shown in table 1. unfortunately, it was difficult to ascertain a correlation between mri findings and the severity of autistic features in each patient due to limited resources. discussion the clinical presentation of tsc can be variable and challenging. the three patients in the current report highlight the importance of thoroughly evaluating patients with features of asd in order not to miss other potential causes of these disorders, such as tsc. patients may present to different specialties which can delay diagnosis; for example, two of the patients in the present report were diagnosed with tsc after being evaluated at a paediatric developmental centre. all three patients in the current report fulfilled the clinical diagnostic criteria for both tsc and asd; two patients had tubers and subependymal brain nodules along with major dermatological features of tsc, while the third patient was found to have a mutation in the tsc2 gene. although the genetic testing of one patient did not show any mutations, deletions or duplications in the tsc1 and tsc2 genes, a lack of genetic confirmation has been reported an mri brain scan demonstrated multiple cortical and subcortical tubers and subependymal nodules [figure 2], confirming a clinical diagnosis of tsc. her family history was significant for seizure disorders, asd, intellectual disabilities and similar skin findings. both the developmental history interview and clinical observations of the patient revealed significant deficits in social interaction and communication in addition to typical asd behaviours and interests. she fulfilled the dsm-v diagnostic criteria for asd.7 the figure 2: t2-weighted magnetic resonance fluidattenuated inversion recovery sequence transverse image showing ill-defined hyperintense lesions in the cortical-subcortical right parietal region (arrows) of a 1-year-old female infant with autism spectrum disorder and tuberous sclerosis complex. table 1: clinical features and radiological findings of three patients with autism spectrum disorder and tuberous sclerosis complex case 1 case 2 case 3 age in years at presentation 5 5 1 gender female male female clinical features •asd •history of one febrile seizure •three hypomelanotic macules on the back and lower limbs •shagreen patch on the back •asd •three hyperpigmented spots •three hypomelanotic macules •asd •seizure disorder •five hypomelanotic macules on the back and lower limbs radiological findings •normal echocardiograph •brain mri showed nodular heterotopias and tubers in the right lateral ventricle •echocardiograph showed two rhabdomyomas in the heart •brain mri showed multiple small cortical, subcortical and subependymal hamartomas family history •seizure disorder in the father •angiofibromata, multiple hypomelanotic macules and shagreen patches in the father and one of his sisters •multiple family members affected with seizure disorders, skin findings and intellectual disability on the father’s side •dental pits and angiofibromata in the mother •two maternal cousins had learning problems and one had a psychiatric disorder •multiple hypopigmented lesions in the mother •history of epilepsy, mental retardation and hypopigmented lesions in four maternal uncles and aunts asd = autism spectrum disorder; mri = magnetic resonance imaging. amna al-futaisi, ahmed idris, abeer al-sayegh and watfa s. al-mamari case report | e523 in approximately 10% of patients with a confirmed clinical diagnosis of tsc.2 all three patients fulfilled the dsm-v diagnostic criteria for asd.7 a wide range of neuropsychiatric disorders have been observed in patients with tsc, with an estimated lifetime prevalence of approximately 90%.8,9 the assoc iation of tsc with asd has been documented in various studies; one study reported that 1–4% of autistic patients may have tsc while another indicated that the rate of autism among tsc patients could be as high as 36%.10,11 the coexistence of tsc and asd seems to be underestimated worldwide, mostly due to the under-reporting of both of these conditions. there is currently a worldwide initiative to introduce a tsc-associated neuropsychiatric disorders (tand) checklist to help evaluate tsc patients.8 the findings of an international tuberous sclerosis registry shows that, even in expert tsc centres, patients are often inadequately examined for asd and tand features.12 hopefully, the exponentially increasing amount of research being conducted on neuropsychiatric comorbidities associated with tsc will lead to an improvement in tand detection rates and, eventually, individualised treatment and rehabilitation plans for affected patients.13 the pathophysiological mechanisms leading to neurological manifestations in tsc patients include disorganised cell growth and motility, altered axon outgrowth, abnormal synapse formation and impaired myelination, leading to disorganisation of the central nervous system architecture and neuronal connectivity.14–16 three proteins (tsc1, tsc2 and tre2-bub2-cdc16 domain family member 7) form a complex which acts as a guanosine triphosphate phosphohydrolase (gtp)-activating protein. muta tions in the tsc1 or tsc2 genes result in accumulation of the gtp-bound protein which stimulates mammalian target of rapamycin (mtor).17 designed transgenic models of tsc have been used to enhance understanding of asd; homozygous knock-out mice with tsc1 and tsc2 mutations displayed an autistic-like phenotype with social impairment, restrictive behaviours and abnormal vocalisations.18,19 heterozygous tsc1 or tsc2 knock-out mice have also shown cognitive and social deficits, even in the absence of gross neuropathological changes.18,19 neuropsychiatric manifestations of tsc are among the most difficult to manage for patients, parents and caregivers, as management is often multidisciplinary and requires multiple interventions directed towards rehabilitation.20,21 recent research has changed the outlook for patients with tsc and associated manifestations. molecular-targeted treatments using mtor inhibitors such as rapamycin and everolimus are promising interventions, aimed at relieving cognitive and neurodevelopmental features of tsc.22 in addition to its antiproliferative and immunosuppressive properties, rapamycin inhibits mtor, reversing the process that occurs due to tsc1 and tsc2 mutations. three clinical trials are currently exploring the use of everolimus for patients with neurocognitive manifestations of tsc.22 vigilant assessment of asd in patients with tsc is essential. additionally, new advances in diagnostic and screening tools available for assessing tand in asd patients with tsc should lead to the mandatory screening of tsc patients for associated features.8 it is imperative that paediatricians carry out detailed examinations of children with asd in order to identify any associated disorders and provide an accurate recurrence risk assessment for other family members.23 moreover, children with tsc should undergo screening for features of asd; early interventions in the form of rehabilitation or therapy are recommended to improve the outcomes for and the quality of life of asd patients with tsc and reduce the burden of this disease on affected families and society as a whole. conclusion the current report highlights the spectrum of neuro-psychiatric involvement in tsc by describing three children with both asd and tsc. it is of vital importance that children with tsc be screened for coexisting asd features in order to encourage the rapid implementation of educational and rehabilitation measures. references 1. curatolo p, bombardieri r, jozwiak s. tuberous sclerosis. lancet 2008; 372:657–68. doi: 10.1016/s0140-6736(08)61279-9. 2. northrup h, krueger da; international tuberous sclerosis complex consensus group. tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus confer ence. pediatr neurol 2013; 49:243–54. doi: 10.1016/j.pediatr neurol.2013.08.001. 3. de bildt a, sytema s, ketelaars c, kraijer d, mulder e, volkmar f, et al. interrelationship between autism diagnostic observation schedule-generic (ados-g), autism diagnostic interview-revised (adi-r), and the diagnostic and statistical manual of mental disorders (dsm-iv-tr) classification in children and adolescents with mental retarda tion. j autism dev disord 2004; 34:129–37. doi: 10.1023/b:jad d.0000022604.22374.5f. 4. kong sw, sahin m, collins cd, wertz mh, campbell mg, leech jd, et al. divergent dysregulation of gene expression in murine models of fragile x syndrome and tuberous sclerosis. mol autism 2014; 5:16. doi: 10.1186/2040-2392-5-16. coexistence of autism spectrum disorders among three children with tuberous sclerosis complex case reports and review of literature e524 | squ medical journal, november 2016, volume 16, issue 4 15. sundberg m, sahin m. cerebellar development and autism spectrum disorder in tuberous sclerosis complex. j child neurol 2015; 30:1954–62. doi: 10.1177/0883073815600870. 16. hampson dr, blatt gj. autism spectrum disorders and neuropathology of the cerebellum. front neurosci 2015; 9:420. doi: 10.3389/fnins.2015.00420. 17. switon k, kotulska k, janusz-kaminska a, zmorzynska j, jaworski j. tuberous sclerosis complex: from molecular biology to novel therapeutic approaches. iubmb life 2016. doi: 10.1002/iub.1579. 18. reith rm, mckenna j, wu h, hashmi ss, cho sh, dash pk, et al. loss of tsc2 in purkinje cells is associated with autisticlike behavior in a mouse model of tuberous sclerosis complex. neurobiol dis 2013; 51:93–103. doi: 10.1016/j.nbd.2012.10.014. 19. ehninger d, han s, shilyansky c, zhou y, li w, kwiatkowski dj, et al. reversal of learning deficits in a tsc2+/mouse model of tuberous sclerosis. nat med 2008; 14:843–8. doi: 10.1038/ nm1788. 20. chung tk, lynch er, fiser cj, nelson da, agricola k, tudor c, et al. psychiatric comorbidity and treatment response in patients with tuberous sclerosis complex. ann clin psychiatry 2011; 23:263–9. 21. krueger da, northrup h; international tuberous sclerosis complex consensus group. tuberous sclerosis complex surveillance and management: recommendations of the 2012 international tuberous sclerosis complex consensus conference. pediatr neurol 2013; 49:255–65. doi: 10.1016/j. pediatrneurol.2013.08.002. 22. tsai pt, hull c, chu y, greene-colozzi e, sadowski ar, leech jm, et al. autistic-like behaviour and cerebellar dysfunction in purkinje cell tsc1 mutant mice. nature 2012; 488:647–51. doi: 10.1038/nature11310. 23. johnson cp, myers sm; american academy of pediatrics council on children with disabilities. identification and evaluation of children with autism spectrum disorders. pediatrics 2007; 120:1183–215. doi: 10.1542/peds.2007-2361. 5. jeste ss, sahin m, bolton p, ploubidis gb, humphrey a. characterization of autism in young children with tuberous sclerosis complex. j child neurol 2008; 23:520–5. doi: 10.1177/ 0883073807309788. 6. joinson c, o’callaghan fj, osborne jp, martyn c, harris t, bolton pf. learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. psychol med 2003; 33:335–44. doi: 10.1017/s00332917020 07092. 7. american psychiatric association. diagnostic and statistical manual of mental disorders, 5th ed. arlington, virginia, usa: american psychiatric publishing, 2013. doi: 10.1176/appi. books.9780890425596. 8. de vries pj, whittemore vh, leclezio l, byars aw, dunn d, ess kc, et al. tuberous sclerosis associated neuropsychiatric disorders (tand) and the tand checklist. pediatr neurol 2015; 52:25–35. doi: 10.1016/j.pediatrneurol.2014.10.004. 9. vignoli a, la briola f, peron a, turner k, vannicola c saccani m, et al. autism spectrum disorder in tuberous sclerosis complex: searching for risk markers. orphanet j rare dis 2015; 10:154. doi: 10.1186/s13023-015-0371-1. 10. wiznitzer m. autism and tuberous sclerosis. j child neurol 2004; 19:675–9. doi: 10.1177/08830738040190090701. 11. ronald a, hoekstra ra. autism spectrum disorders and autistic traits: a decade of new twin studies. am j med genet b neuropsychiatr genet 2011; 156b:255–74. doi: 10.1002/ ajmg.b.31159. 12. kingswood jc, bruzzi p, curatolo p, de vries pj, fladrowski c, hertzberg c, et al. tosca: first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. orphanet j rare dis 2014; 9:182. doi: 10.1186/s13023-014-0182-9. 13. leclezio l, de vries pj. advances in the treatment of tuberous sclerosis complex. curr opin psychiatry 2015; 28:113–20. doi: 10.1097/yco.0000000000000136. 14. crino pb. evolving neurobiology of tuberous sclerosis complex. acta neuropathol 2013; 125:317–32. doi: 10.1007/s00401-0131085-x. 1neurovascular research laboratory, massachusetts general hospital, boston, massachusetts, usa; 2division of neurosurgery, department of surgery, pastor hospital, bam university of medical sciences, bam, iran; 3neurosurgical service, beth israel deaconess medical center, boston, massachusetts, usa *corresponding author’s e-mail: rmotiei@bidmc.harvard.edu وزمة منطبعة عند مريض مصاب بانفتاق قرصي قطين تقرير حالة عن ترابط غري معتاد هوما �صادقيان و روزبه مطيعى لنجرودى abstract: oedema refers to the excessive accumulation of fluid within intercellular tissues as a result of disequilibrium between the capillary hydrostatic and oncotic pressure gradients. lumbar disc herniation (ldh) commonly causes lower back pain and radicular leg pain. we report a 57-year-old female who presented to the neurosurgery clinic of the bam university of medical sciences, bam, iran, in 2015 with pain and pitting oedema in the bilateral lower extremities. magnetic resonance imaging confirmed a diagnosis of ldh of the l3–l4 and l4–l5 vertebrae. the patient subsequently underwent a bilateral laminotomy and foraminotomy of the involved vertebrae to relieve her pain. following the surgery, there was a complete resolution of the ldh-related symptoms as well as the oedema. although ldh has never before been associated with oedema, it may nevertheless cause lower limb oedema in exceptional and rare cases, as highlighted in this patient. keywords: intervertebral disc disease; lumbar vertebrae; lower extremities; edema; diskectomy; case report; iran. امللخ�ص: الوزمة هي تراكم مفرط لل�صوائل يف داخل خاليا الأن�صجة نتيجة لختالل التوازن يف مدروجات ال�صغط الهيدرو�صتاتيكي ال�صعري �صنة 57 عمرها لمراأة حالة عن تقرير وهذا القدم. يف جذريا واأملا الظهر يف اأملا القطني القر�صي النفتاق وي�صبب اجلرمي. وال�صغط ح�رشت لعيادة اجلراحة الع�صبية بكلية الطب يف جامعة بام باإيران يف عام 2015، ت�صكو من اأمل ووزمة منطبعة يف الأطراف ال�صفلية ثنائية اجلانب. واأكد الت�صوير بالرنني املغناطي�صي اأن ت�صخي�ض احلالة هو انفتاق قر�صي قطني يف الفقرات القطنية 4–3 و 5–4. واأجريت للمري�صة ع الثقبة للفقرات املتاأثرة لوقف الأمل. واختفت عقب العملية كل الأعرا�ض التي عملية قطع ثنائية اجلانب لل�صحيفة الفقرية، وعملية لَب�صْ القر�صي بالنفتاق مرتبط كعر�ض اأبدا تعرف مل الوزمة اأن من الرغم وعلى املنطبعة. الوزمة ومعها القطني، القر�صي النفتاق �صببها القطني، اإل اأن هذا النفتاق قد ي�صبب ورما يف الطرف ال�صفلي يف حالت ا�صتثنائية ونادرة، كما هو يف حالة املري�صة املذكورة. الكلمات املفتاحية: مر�ض القر�ض بني الفقرتني؛ الفقرات القطنية؛ الأطراف ال�صفلى؛ وزمة؛ ا�صتئ�صال القر�ض؛ تقرير حالة؛ اإيران. pitting oedema in a patient with lumbar disc herniation case report of an unusual association homa sadeghian1 and *rouzbeh motiei-langroudi2,3 sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e464–467, epub. 10 jan 18 submitted 27 apr 17 revision req. 5 sep 17; revision recd. 13 sep 17 accepted 5 oct 17 case report doi: 10.18295/squmj.2017.17.04.015 recover with conservative therapy.3 although ldh commonly causes pain in the lower back and radicular leg (i.e. radicular chronic pain [rcp]), it has never before been reported in association with oedema of the lower extremities. this case report describes a patient with ldh and bilateral pitting oedema in the lower extremities. following a diskectomy, both the ldh-related pain and oedema resolved rapidly. to the best of the authors’ knowledge, this is the first reported case of lower limb pitting oedema which was completely resolved following the successful surgical treatment of ldh. case report a 57-year-old female patient presented to the neurosurgery clinic of the bam university of medical sciences, bam, iran, in 2015 with complaints of pain in oedema is a state of excessive fluid accumulation within intercellular tissues as a result of disequilibrium between hydrostatic and oncotic pressure gradients across the capillary.1 in the extremities, it may be either unilateral or bilateral and acute or chronic, with potential differences in the underlying mechanisms for each type. bilateral chronic oedema can be caused by congestive heart failure, chronic renal or hepatic disease, hypoor hyperthyroidism, malabsorption and protein-calorie malnutrition, obstructive sleep apnoea, pulmonary hypertension, lymphoedema, pregnancy, a premenstrual state, immobility or the use of certain medications.1 lumbar disc herniation (ldh) is a common musculoskeletal condition that affects up to 40% of adults at some point during their life.2 it generally follows a favourable course and the majority of patients homa sadeghian and rouzbeh motiei-langroudi case report | e465 the bilateral lower extremities of one year’s duration. the patient described the pain as shooting down her anterior and lateral legs to her feet and halluces; she also mentioned that the pain was of greater severity on the right side. the distribution of the pain was compatible with rcp. in addition, the patient had persistent pitting oedema in both legs, which had appeared at the same time as the pain had begun and had continued over the course of the preceding year. the patient denied any previous history of lower back or leg pain or any spinal issues before the onset of the symptoms. she had undergone a total hysterectomy and chemotherapy with carboplatin and paclitaxel for a uterine carcinoma three years beforehand. there was no reported history of trauma. between episodes of pain, the patient was very active as a result of her work as a police lieutenant which did not allow extended leave; as such, she had never undertaken complete bed rest for more than two days at a time during the previous year. prior to presentation, the patient had received two courses of a four-week-long conservative therapy regimen for her pain, including physical and medical therapy, the latter of which had consisted of a combination of two or three medications at a time, including acetaminophen, ibuprofen, naproxen, intramuscular methylprednisolone injections (40 mg once weekly for four weeks) and gabapentin. the methylprednisolone was prescribed only once for a total of four doses. nevertheless, the patient’s symptoms persisted despite the treatment. upon presentation, the patient’s body mass index was normal. a general examination showed bilateral oedema of the calves and feet. the swelling was symmetrical, non-tender, without notable changes in skin colour and with pitting upon pressure which resolved in under a minute. a neurological examination was unremarkable, including motor force, light touch and deep tendon reflex testing. colour doppler ultrasonography of the lower extremities showed no evidence of acute or chronic deep vein thrombosis, venous insufficiency or varicosity. however, an echocardiograph revealed grade 1 left ventricular diastolic dysfunction, trivial aortic insufficiency (ai) and mild mitral regurgitation (mr). all laboratory test results were within normal limits, including a complete blood count; serum electrolyte tests (including sodium, potassium, calcium and phosphorus levels); blood urea nitrogen, creatinine, albumin and total protein levels; thyroid and liver function tests (including aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase levels); prothrombin and partial thromboplastin times; international norm alised ratio; creatine phosphokinase (cpk), lactate dehydrogenase and aldolase levels; erythrocyte sedimentation rate; c-reactive protein levels; a 24-hour urinary analysis (including creatinine and protein levels); and rheumatological tests (including rheumatoid factor, anti-cyclic citrullinated peptide, antinuclear antibody and anti-double stranded dna). magnetic resonance imaging (mri) showed broad-based disc protrusion of the l3–l4 and l4–l5 vertebrae with evidence of bilateral l4 and l5 foraminal stenosis [figure 1]. the protrusion of the l3–l4 and l4–l5 vertebrae was more severe on the right side. the decision was made to perform a diskectomy. the patient was informed that the purpose of the surgery was to relieve her rcp and not the pitting oedema. she underwent a bilateral l3–l4 and l4–l5 laminotomy and l4 and l5 foraminotomy via a midline incision. postoperatively, subcutaneous heparin was administered as a thromboembolism prophylactic measure. she also received acetaminophen, gabapentin, diazepam and two doses of cefazolin during the postoperative period. within one hour of the surgery, there was no evidence of rcp or any neurological complications. she was allowed out of bed on the first postoperative day and undertook a few short walks within the hospital room. a substantial decrease in oedema was also noted that same morning before she got out of bed. a postoperative mri scan revealed that the foraminal stenosis had completely resolved. the patient was discharged from the hospital on the second postoperative day with a four-week prescription for ibuprofen (400 mg), nortriptyline (10 mg) and gabapentin (100 mg) three times a day. the oedema had completely subsided within one week of the surgery. at subsequent one-month and one-year follow-up visits, there were no further complaints of rcp, no surgery-related complications and no evidence of recurrence of the oedema. figure 1: preoperative magnetic resonance imaging of a 57-year-old female with radicular chronic pain and pitting oedema in the bilateral lower extremities showing disc protrusion of the (a) l3–l4 and (b) l4–l5 vertebrae with foraminal stenosis. pitting oedema in a patient with lumbar disc herniation case report of an unusual association e466 | squ medical journal, november 2017, volume 17, issue 4 to be expected in cases of right-sided and congestive heart failure, these elements were not present in the current case.1 moreover, the patient was symptomfree during her daily activities and while asleep, excluding a causative role for the mild ai and mr noted during echocardiography. ultrasonography findings and laboratory results also excluded deep vein thrombosis, venous insufficiency and other known causes of oedema. the patient’s medical history and use of prior medications were also reviewed in the current case. she had had a uterine carcinoma three years prior to the onset of her symptoms; accordingly, microvasculature changes in the pelvic floor could have caused the oedema.11 however, her medical records indicated that the carcinoma was not locally extensive and had been cured following a hysterectomy and adjuvant therapy. she had also received carboplatin and paclitaxel before her hysterectomy and had more recently been prescribed nsaids and corticosteroid injections for her ldh-related symptoms. however, these medications were ruled out as possible causative factors as they all had been prescribed intermittently whereas the oedema had remained consistent. furthermore, carboplatin and paclitaxel are not common causes of oedema; in addition, these chemotherapy agents were administered two years before the oedema had initially presented.1 while the patient had been prescribed nsaids, gabapentin and corticosteroids, the drugs had been administered only after the oedema had already presented; moreover, several were also prescribed after the ldh surgery, once the oedema had subsided. ultimately, the oedema in the present case began to resolve soon after the successful ldh surgery, thus excluding prior medications and diseases as potential causes. another factor to consider is that lower limb oedema usually forms in patients with intervertebral disc herniation who restrain their daily activities; indeed, increased bed rest has been associated with some degree of lower limb oedema.12 however, due to her occupational responsibilities, the patient in the present case remained active without long periods of bed rest. this cause can also be excluded by the timing of the resolution of oedema, which had started to subsist by the first postoperative day when the patient had not yet resumed her normal daily activities. although ldh has never before been considered responsible for causing oedema, the current case report shows that it may exceptionally cause lower limb oedema. however, as this is a single case, a causal or anatomical relation between ldh and lower limb pitting oedema cannot be proposed at this stage. moreover, the underlying mechanism by which ldh discussion extravascular water content follows a formula for equilibrium generally known as the starling equation, with any disequilibrium potentially resulting in acute or chronic tissue oedema.1,4 medications that can cause oedema include antidepressants (especially mono amine oxidase inhibitors and trazodone), antihypertensives (e.g. β-adrenergic blockers, calcium channel blockers, clonidine, hydralazine, methyldopa and minoxidil), corticosteroids, hormones (e.g. androgen, oestrogen, progesterone and testosterone), chemotherapy agents (e.g. cytosine arabinoside and mithramycin), immunosuppressives (e.g. cyclophos phamide and cyclosporine), cytokines (e.g. granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-α and interleukin-2 and -4), antiviral drugs (e.g. acyclovir) and non-steroidal anti-inflammatory drugs (nsaids).1,5 although obstructions in the venous or lymphatic drainage pathways, like in cases of deep vein thrombosis or pelvic tumours, may lead to oedema formation, this mostly occurs in a unilateral and localised manner.1 theoretically, ldh never interferes with the starling equation.1,4 moreover, an association has never been reported with lower limb oedema, although there are some reports of ldh cases presenting with swollen calves.6–9 khan et al. reported a patient with a swollen calf who was diagnosed with ldh of the l5–s1 intervertebral disc after deep vein thrombosis and a local tumour were ruled out; electromyography and a muscle biopsy indicated inflammatory myopathy, suggesting a diagnosis of radiculopathy/calf hypertrophy syndrome.6 a similar case attributed to radiculopathy/calf hypertrophy syndrome has also been described.7 gross et al. reported unilateral calf swelling associated with symptomatic ldh of the l5–s1 vertebrae in which increased cpk levels and muscle biopsy findings were in accordance with s1 radiculopathy-associated inflammatory myopathy/ myositis.8 this condition has also been reported with l5 radiculopathy.9 yet, there were essential differences in the current case which eliminated similar diagnoses. first, levels of cpk, lactate dehydrogenase and the more muscle-specific aldolase were all normal. second, the swelling was clearly due to oedema as it was bilateral, non-tender and pitting whereas myopathy and myositis-related swelling is usually unilateral and always non-pitting.10 an evaluation was undertaken to determine the cause of the oedema in the present case. although the patient had left-sided heart failure, ai and mr, all of these features were mild and could not have caused pitting oedema of the limbs. while limb oedema is homa sadeghian and rouzbeh motiei-langroudi case report | e467 may cause pitting oedema is unclear. further cases need to be reported and comprehensive studies undertaken to elucidate the exact association between these two conditions and to determine a pathophysiological explanation. until then, the existence of oedema and ldh in a single patient should be considered and treated as separate conditions. moreover, all known underlying causes of oedema should be evaluated thoroughly, with ldh considered only if all other causes are excluded. conclusion this case report indicates that ldh and foraminal stenosis may cause pitting oedema of the lower extremities in exceptional cases. however, all other known aetiologies of lower limb oedema should be excluded first prior to confirming the diagnosis. references 1. trayes kp, studdiford js, pickle s, tully as. edema: diagnosis and management. am fam physician 2013; 88:102–10. 2. frymoyer jw. lumbar disk disease: epidemiology. instr course lect 1992; 41:217–23. 3. motiei-langroudi r, sadeghian h, seddighi as. clinical and magnetic resonance imaging factors which may predict the need for surgery in lumbar disc herniation. asian spine j 2014; 8:446–52. doi: 10.4184/asj.2014.8.4.446. 4. starling eh. on the absorption of fluids from the connective tissue spaces. j physiol 1896; 19:312–26. doi: 10.1113/jphysiol. 1896.sp000596. 5. volke v, matjus s. unilateral pitting edema of the leg as a manifestation of graves’ disease: a case report. j med case rep 2012; 6:258. doi: 10.1186/1752-1947-6-258. 6. khan sy, hilton-jones d, rigby sp. a swollen calf. lancet 2005; 365:1662. doi: 10.1016/s0140-6736(05)66517-8. 7. dorrell w. another swollen calf. lancet 2005; 366:27. doi: 10. 1016/s0140-6736(05)66822-5. 8. gross r, degive c, dernis e, plat m, dubourg o, puéchal x. focal myositis of the calf following s1 radiculopathy. semin arthritis rheum 2008; 38:20–7. doi: 10.1016/j.semarthrit.2007 .09.004. 9. kottlors m, mueller k, kirschner j, glocker fx. muscle hypertrophy of the lower leg caused by l5 radiculopathy. joint bone spine 2009; 76:562–4. doi: 10.1016/j.jbspin.2009.01.009. 10. chawla j. stepwise approach to myopathy in systemic disease. front neurol 2011; 2:49. doi: 10.3389/fneur.2011.00049. 11. greven km, paunesku t. radiation complications of the pelvis. in: small w, woloschak ge, eds. radiation toxicity: a practical guide. boston, usa: springer, 2008. pp. 125–53. 12. suehiro k, morikage n, murakami m, yamashita o, ueda k, samura m, et al. a study of leg edema in immobile patients. circ j 2014; 78:1733–9. doi: 10.1253/circj.cj-13-1599. https://doi.org/10.4184/asj.2014.8.4.446 https://doi.org/10.1113/jphysiol.1896.sp000596 https://doi.org/10.1113/jphysiol.1896.sp000596 https://doi.org/10.1186/1752-1947-6-258 https://doi.org/10.1016/s0140-6736%2805%2966517-8 https://doi.org/10.1016/s0140-6736%2805%2966822-5 https://doi.org/10.1016/s0140-6736%2805%2966822-5 https://doi.org/10.1016/j.semarthrit.2007.09.004 https://doi.org/10.1016/j.semarthrit.2007.09.004 https://doi.org/10.1016/j.jbspin.2009.01.009 https://doi.org/10.3389/fneur.2011.00049 https://doi.org/10.1253/circj.cj-13-1599 departments of 1pathology and 2obstetrics & gynaecology, employees state insurance corporation medical college & hospital, faridabad, haryana, india *corresponding author’s e-mail: varsha.chauhan3@gmail.com سرطان اخلاليا الصغرية يف الغدد الصم العصبية من عنق الرحم تشابه ورم عنق الرحم الليفي تقرير حالة نادرة موكتا بوجاين، كانيكا �سينغ، فار�سا ت�سوهان، رينا ت�ساوال، را�سمي اأهوجا abstract: primary neuroendocrine tumours of the cervix are extremely rare, with an incidence of only 0.5–1%; as such, these entities can present a clinical and diagnostic challenge. small-cell neuroendocrine carcinomas of the cervix are highly aggressive tumours that have a tendency to metastasise. we report a 44-year-old woman who presented to the gynaecology clinic of the employees state insurance corporation medical college & hospital, faridabad, india, in 2016 with menorrhagia. based on a clinical examination, she was provisionally diagnosed with a cervical fibroid. however, a biopsy revealed features of a small-cell neuroendocrine carcinoma of the cervix which was subsequently confirmed via immunohistochemistry. an accurate diagnosis of a neuroendocrine carcinoma is vital as it forms the basis for treatment decisions as well as informing predictions for long-term survival. keywords: neuroendocrine tumors; small cell carcinoma; cervix; menorrhagia; fibroid tumor; case report; india. امللخ�ص: تعترب اأورام الغدد ال�سم الع�سبية االأولية من عنق الرحم نادرة للغاية مع ن�سبة حدوث �سنوية تعادل فقط %1-0.5. وعلى هذا النحو، ميكن لهذه االأورام اأن متثل حتديا �رصيريا وت�سخي�سيا. و لدى �رصطان اخلاليا ال�سغرية من هذه االأورام ميول عدوانية للغاية و�رصعة يف انت�سار الثانويات. هذا تقرير حالة عن امراأة تبلغ من العمر 44 عاما قدمت اإىل عيادة اأمرا�ض الن�ساء يف م�ست�سفى كلية التاأمني احلكومي الطبي، فريد اباد، الهند، يف عام 2016 لوجود غزارة يف الطمث. وا�ستنادا اإىل الفح�ض ال�رصيري، مت ت�سخي�سها ب�سكل موؤقت على اأنها حالة الرحم. عنق يف الع�سبية ال�سم للغدد ال�سغرية اخلاليا ل�رصطان مالمح وجود اخلزعة حتليل ك�سف ذلك، ومع الرحم. عنق يف ليفي ورم مت تاأكيد الت�سخي�ض يف وقت الحق عن طريق الكيمياء الن�سيجية املناعية. يعترب الت�سخي�ض الدقيق ل�رصطان اخلاليا ال�سغرية الغدد ال�سم الع�سبية اأمر حيوي الأنه ي�سكل االأ�سا�ض لقرارات العالج وكذلك اإبالغ تنبوؤات احلياة على املدى الطويل. الكلمات املفتاحية: اأورام الغدد ال�سم الع�سبية؛ �رصطان اخلاليا ال�سغرية؛ عنق الرحم؛ غزارة الطمث؛ ورم ليفي؛ تقرير حالة؛ الهند. small-cell neuroendocrine carcinoma of the cervix masquerading as a cervical fibroid report of a rare entity mukta pujani,1 kanika singh,1 *varsha chauhan,1 raina chawla,2 rashmi ahuja2 case report sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e100–103, epub. 4 apr 18 submitted 14 aug 17 revision req. 7 nov 17; revision recd. 11 dec 17 accepted 21 dec 17 doi: 10.18295/squmj.2018.18.01.017 primary neuroendocrine tumours (nets) of the female genital tract are extremely rare; among these, only 0.5–1% are cervical.1 a small cell neuroendocrine carcinoma (snec) of the cervix is a poorly differentiated and highly aggressive tumour with a high metastatic propensity.2 on account of its dismal prognosis, an early diagnosis of this entity is crucial in order to differentiate it from other small cell tumours of the cervix.3 although histopathology remains the mainstay of diagnosis, immunohistochemistry (ihc) also plays a crucial role to both confirm the diagnosis as well as ascertain the primary site of origin of the tumour.2,3 case report a 44-year-old woman presented to the gynaecology clinic of the employees state insurance corporation medical college & hospital, faridabad, india, in 2016 with a six-month history of menorrhagia. she had had four children and her last birth had taken place 15 years previously. a speculum examination revealed a globular well-defined mass of approximately 4 cm which was projecting from the posterior wall of the cervix. upon physical contact, the mass did not bleed and did not appear ulcerative or fungating. an ultrasound indicated a 3.6 cm hypoechoic area in the upper part of the cervical canal, just below the internal orifice of the cervix uteri. during examination under anaesthesia, a 4 x 3 cm well-defined mass was seen in the posterior wall of the cervix and was provisionally diagnosed as a fibroid. a cervical biopsy was performed. microscopic sections showed strips of stratified squamous epithelium, of which a few showed dysplasia. the underlying tissues exhibited sheets of tumour cells with erythromukta pujani, kanika singh, varsha chauhan, raina chawla and rashmi ahuja case report | e101 ated, hypermetabolic lesion involving the cervix and lower uterine segment, with likely invasion of the vaginal vault and parametrial extension. the mass appeared to invade the urinary bladder and rectum. multiple hypermetabolic hypodense lesions were present on both lobes of the liver, suggestive of metastasis [figure 3]. the patient was diagnosed with a stage iva snec of the cervix. she subsequently underwent six cycles of chemotherapy, including cisplatin and etoposide. a follow-up pet/ct scan suggested a partial response to treatment, with a residual metabolically-active primary malignant endocervical lesion as well as metastatic left external iliac lymph node and bilobar hepatic parenchymal lesions. there was no evidence of any other new lesions. discussion on account of their rarity, primary nets pose a clinical and diagnostic challenge.1,2 moreover, an accurate diagnosis is vital as it forms the basis for treatment decisions as well as for predicting long-term survival. according to the latest who classifications, cervical neuroendocrine carcinomas are classified, similarly to gastroenteropancreatic neuroendocrine carcinomas, into grade 1, grade 2 or grade 3 nets and into largecell or small-cell variants.4,5 in general, snecs most commonly occur in the cervix, with patients ranging cyte rosetting in many places [figure 1a]. the tumour cells were small and round, with a high nuclear-cytoplasmic ratio and stippled chromatin [figure 1b]. the mitotic rate was very high at >10 mitoses/10 high power fields (hpfs). the surrounding stroma showed a dense inflammatory infiltrate and many areas of haemorrhage and necrosis. these histopathological features were consistent with a diagnosis of a snec of the cervix. this was confirmed by an ihc panel revealing strong positivity for synaptophysin, chromogranin, pan cytokeratin and p16 [figure 2]. neuronspecific enolase (nse) was focally positive while stains for cluster of differentiation (cd)56 and thyroid transcription factor (ttf)-1 were negative. magnetic resonance imaging showed a large ill defined mass in the posterior wall of the cervix, indent ing the cervical canal anteriorly. fluorine-18-fluorodeoxyglucose positron emission tomography (pet)/computed tomography (ct) scans revealed a large, lobul figure 1: haematoxylin and eosin stains at (a) x100 magnification showing sheets of tumour cells displaying erythrocyte rosetting and (b) at x400 magnification showing small round tumour cells with a high nuclearcytoplasmic ratio and stippled chromatin. figure 3: serial fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography scans of a 44-year-old woman with a suspected cervical fibroid showing a large lobulated hypermetabolic mass involving the cervix and lower uterine segment. the mass is seen to invade the urinary bladder and rectum with multiple hypermetabolic hypodense lesions in both lobes of the liver. figure 2: immunohistochemistry photomicrographs showing strong positivity for (a) p16 at x400 magnification, (b) chromogranin at x100 magnification, (c) synap tophysin at x100 magnification and (d) pan cytokeratin at x100 magnification. small-cell neuroendocrine carcinoma of the cervix masquerading as a cervical fibroid report of a rare entity e102 | squ medical journal, february 2018, volume 18, issue 1 differentiated carcinomas.2 due to the rarity of snecs of the cervix, it is important to exclude metastasis from the lung.3 as cervical fibroids can present clinically as a carcinoma or prolapse, cervical carcinomas can sometimes be mistaken for fibroids, as in the present case.9,10 seo et al. described a 46-year-old woman with metastatic breast cancer spreading to the cervix which initially appeared as a large cervical fibroid on sonography and was only diagnosed after treatment of the primary tumour.11 this may lead to grave consequences since fibroids are benign lesions which can be cured via surgical excision while carcin omas usually require a multimodal approach involving surgery, chemotherapy or radiotherapy, with prognosis dependent on the type and stage of the tumour. as such, the radiographical evaluation of suspected nets should include ct or pet/ct scans.12 various combined chemotherapy regimens have improved the median survival rate among patients with small-cell bronchogenic carcinomas and are now being used to treat snecs of the cervix.13 hoskins et al. reported the successful treatment of a stage ia–ivb cervical small-cell carcinoma using chemoradiation with etoposide and cisplatin.14 notably, such regimens are generally preferred over those containing vincristine, adriamycin and cyclophosphamide as they are less toxic. surgical resection is usually undertaken for limited-stage neuroendocrine carcinomas. the use of platinum with or without etoposide has also been observed to improve survival in snec cases.14 an advanced stage, tumour size, the presence of lymph node metastasis, pure small-cell histology and smoking are associated with worse clinical outcomes for patients with snecs.15 conclusion neuroendocrine carcinomas of the cervix, particularly small-cell variants, present a clinical and diagnostic challenge due to their rarity. although histopathology remains the gold standard for diagnosing neuroendocrine carcinomas, ihc is usually required to confirm the diagnosis as well as to inform treatment decisions and provide prognostic information. this case highlights that the clinical presentation of snecs can, on rare occasions, be mistaken with that of a cervical fibroid. references 1. chen j, macdonald ok, gaffney dk. incidence, mortality, and prognostic factors of small cell carcinoma of the cervix. obstet gynecol 2008; 111:1394–402. doi: 10.1097/aog.0b013e31817 3570b. in age from 22–87 years old and usually presenting with vaginal bleeding. occasionally, patients may present with manifestations of paraneoplastic syndromes like syndrome of inappropriate anti-diuretic hormone secre tion or cushing’s disease.2,3 microscopically, the tumour cells of well-differentiated nets are characteristically arranged in organoid, solid, nested, trabecular, insular or mixed patterns.2 cells are typically small with a high nuclearcytoplasmic ratio, round-to-oval nuclei, nuclear moulding and salt-and-pepper chromatin, with scant-to moderate eosinophilic cytoplasm. however, poorly differentiated neuroendocrine carcinomas—including both smalland large-cell types—have high mitotic activity (>10 mitoses/10 hpfs), necrosis and are highgrade malignancies.2 human papillomavirus (hpv) infections have been associated with 90% of cases of snec of the cervix, with hpv type 18 most commonly implicated.6 small-cell variants are also characterised by lymphovascular invasion. small foci of squamous and/or glandular differentiation can be seen, but usually account for less than 5–10% of the total volume of the tumour.2 although histopathology remains the gold standard for diagnosing neuroendocrine carcinomas in most cases, ihc is usually required to establish the neuroendocrinological nature of the tumour, confirm the diagnosis and provide prognostic information.4 in the current case, the typical morphological features of a neuroendocrine carcinoma were evident on histopathology sections, with ihc playing a supplementary role. the ihc panel for a neuroendocrine carcinoma includes nse, chromogranin, synaptophysin, cd56 and synaptic vesicle protein 2.2,4 as not all markers are specific, an integrated ihc panel of three to four markers should be used; of these, chromogranin, synap tophysin and cd56 are most commonly applied.7,8 in a large series of 45 patients, ganesan et al. found synaptophysin to be the most specific and sensitive marker of neuroendocrine differentiation.3 in addition, nets usually express pan cytokeratin, as in the present case.2 various ihc markers may also help to ascertain the primary site of an net, for example ttf-1 (the thyroid and lungs), insulin gene enhancer protein-1 and insulin promoter factor 1 (the pancreas) and caudal type homeobox 2 and villin (the gastrointestinal tract).2 however, ttf-1 may also be positive in neuroendocrine carcinomas of cervical origin.3 although no specific marker is documented for nets of the female genital tract, p16 positivity is commonly found, as in the present case.2 the differential diagnosis of small-blue-cell cervical tumours include basaloid squamous cell carcinomas, embryonal rhabdomyosarcomas, lymphomas and un https://doi.org/10.1097/aog.0b013e318173570b https://doi.org/10.1097/aog.0b013e318173570b mukta pujani, kanika singh, varsha chauhan, raina chawla and rashmi ahuja case report | e103 10. sharma p, swaroop n, kumari k, nagrath a. a case of giant cervical fibroid polyp prolapsed outside introitus in menopausal women: presenting as diagnostic dilemma. j south asian fed menopause soc 2016; 4:47–9. doi: 10.5005/jp-journals 10032-1084. 11. seo sy, shin jy, ji yi. metastatic uterine cancer looking as cervical fibroid in recurrent breast cancer woman: a case report. obstet gynecol sci 2017; 60:481–4. doi: 10.4568/ogs.2017.60. 5.481. 12. baum rp, swietasczyk c, prasad v. fdg-pet/ct in lung cancer: an update. front radiat ther oncol 2010; 42:15–45. doi: 10.1159/000262458. 13. nasu k, hirakawa t, okamoto m, nishida m, kyoshima c, matsumoto h, et al. advanced small cell carcinoma of the uterine cervix treated by neoadjuvant chemotherapy with irinotecan and cisplatin followed by radical surgery. rare tumors 2011; 3:e6. doi: 10.4081/rt.2011.e6. 14. hoskins pj, swenerton kd, pike ja, lim p, aquino-parsons c, wong f, et al. small-cell carcinoma of the cervix: fourteen years of experience at a single institution using a combined-modality regimen of involved-field irradiation and platinum-based com-bination chemotherapy. j clin oncol 2003; 21:3495–501. doi: 10.1200/jco.2003.01.501. 15. gardner gj, reidy-lagunes d, gehrig pa. neuroendocrine tumors of the gynecologic tract: a society of gynecologic onco logy (sgo) clinical document. gynecol oncol 2011; 122:190–8. doi: 10.1016/j.ygyno.2011.04.011. 2. kefeli m, usubütün a. an update of neuroendocrine tumors of the female reproductive system. turk patoloji derg 2015; 31:s128–44. doi: 10.5146/tjpath.2015.01320. 3. ganesan r, hirschowitz l, dawson p, askew s, pearmain p, jones pw, et al. neuroendocrine carcinoma of the cervix: review of a series of cases and correlation with outcome. int j surg pathol 2016; 24:490–6. doi: 10.1177/1066896916643385. 4. kurman rj, carcangiu ml, herrington cs, young rh, eds. who classification of tumours of female reproductive organs, 4th ed. lyon, france: iarc press, 2014. 5. bosman ft, carneiro f, hruban rh, theise nd, eds. who classification of tumours of the digestive system, 4th ed. lyon, france: iarc press, 2010. 6. stoler mh, mills se, gersell dj, walker an. small-cell neuroendocrine carcinoma of the cervix: a human papillomavirus type 18-associated cancer. am j surg pathol 1991; 15:28–32. doi: 10.1097/00000478-199101000-00003. 7. chu p, weiss l. tumors of the endocrine system. in: modern immunohistochemistry, 2nd ed. cambridge, uk: cambridge university press, 2014. pp. 96–132. 8. delellis ra. the neuroendocrine system and its tumors: an overview. am j clin pathol 2001; 115:s5–16. doi: 10.1309/7gr5l7yw-3g78-ldj6. 9. harrison ao. prolapsed giant cervical fibroid polyp mimicking procidentia: aftermath of traditional therapy for fibroids a case report and review of the literature. open sci j clin med 2014; 2:15–18. https://doi.org/10.5005/jp-journals-10032-1084 https://doi.org/10.5005/jp-journals-10032-1084 https://doi.org/10.4568/ogs.2017.60.5.481 https://doi.org/10.4568/ogs.2017.60.5.481 https://doi.org/10.1159/000262458 https://doi.org/10.4081/rt.2011.e6 https://doi.org/10.1200/jco.2003.01.501 https://doi.org/10.1016/j.ygyno.2011.04.011 https://doi.org/10.5146/tjpath.2015.01320 https://doi.org/10.1177/1066896916643385 https://doi.org/10.1097/00000478-199101000-00003 https://doi.org/10.1309/7gr5-l7yw-3g78-ldj6 https://doi.org/10.1309/7gr5-l7yw-3g78-ldj6 squ med j, april 2010, vol. 10, iss. 1, pp. 114-119, epub. 17th apr 10 submitted 5th june 09 revision req. 23rd nov 09, revision recd. 15th dec 09 accepted 27th dec 09 in general, diagnostic cardiac catheterisation is recommended whenever it is clinically important to define the presence or severity of a suspected cardiac lesion that cannot be adequately evaluated by other non-invasive techniques. most of the indications for cardiac catheterisations can be collectively classified into management of patients under the following categories: valvular heart disease;1 chronic heart failure;2 acute myocardial infarction (ami);3 percutaneous coronary intervention (pci),4 and coronary artery bypass surgery (cabg).5 cardiac catheterisation is a relatively safe procedure, but has a well defined risk of morbidity and mortality. in an analysis of 59,792 patients who underwent cardiac catheterisation and coronary angiography, the following were recognised complications (percentage of risk in brackets): mortality (0.11%), myocardial infarction (0.05%), cerebrovascular accidents (0.07%), arrhythmias (0.38%), vascular cardiology unit, department of medicine, sultan qaboos university hospital, muscat, oman *to whom all correspondence should be addressed: halhadi@hotmail.com اإِلْحصاُر احلَُزمِيي األيسر الدائم َعديُم األَْعراض املضاِعف لقسطرة القلب األيسر التشخيصية حافظ الهادي ومن�ش�ر �شالم اخلال�صة: ي�شف هذا التقرير حالة خ�شعت لق�شطرة قلب اأي�رس ت�شخي�شية عادية )ت�ش�ير االأوعية التاجية وال�رسيان االأبهر والبطني االأي�رس( يف م�شت�شفى جامعة ال�شلطان قاب��س – ُعمان، والذي تبعه م�شاعفات متثلت بح�ش�ل اإح�شار ُحَزمِيي اأي�رس دائم ل�حظ عر�شيا عند االنتهاء من مبا�رسة الق�شطرة بعد عليه اأجريت التي الطارئة الفح��شات كل وبعدها. الق�شطرة خالل اجلانبية االأعرا�س من خال املري�س كان الق�شطرة. والتي �شملت فح�س دم عادي، والقيا�س املتكرر لكل من تروب�نني القلب وتخطيط القلب واأ�شعة ال�شدر ال�شينية وتخطيط �شدى القلب الطاريء كانت كلها طبيعية و مل تظهر اأي م�شبب لهذه امل�شاعفات. اأظهرت فح��شات الق�شطرة اأن املري�س يعاين من اأمرا�س يف اثنني من �رسايني القلب و َقَل�س ال�شمام املرتايل. بعد ثمانية اأيام خ�شع املري�س لعملية زراعة ال�رسيان التاجي وتبديل ال�شمام املرتايل وكانت العملية ناجحة بدون م�شاعفات. على حد علمنا هذا التقرير ه� االأول من ن�عه الذي ي�شف حدوث هذا الن�ع من امل�شاعفات بعد ق�شطرة عادية. مت مراجعة االأدبيات الطبية املتعلقة بن�شبة حدوث مثل هذه امل�شاعفات واأهميته ودالالته. مفتاح الكلمات: االإِْح�شاُر احُلَزمِيي االأي�رس، ت�ش�ير االأوعية التاجية، ت�ش�ير ال�رسيان االأبهر، ت�ش�ير البطني االأي�رس، ق�شطرة القلب االأي�رس، ق�شطرة القلب الن�شخي�شية، تقرير حالة، ُعمان. abstract: this case report describes a routine diagnostic left heart catheterisation (coronary angiography, aortography and left ventriculography) procedure at sultan qaboos university hospital, oman, which was complicated by the development of new asymptomatic, but permanent, left bundle branch block that was observed incidentally towards the end of the procedure. the patient was completely asymptomatic and haemodynamically stable throughout the procedure and afterwards. urgent investigations, immediately after the procedure, including routine blood, serial cardiac troponin i, serial electrocardiograms, chest x-ray, and urgent echocardiography were normal and failed to show any possible causation of the lbbb. the results of left heart catheterisation showed two vessel coronary artery disease and severe mitral valve regurgitation. after eight days, the patient went on to have coronary artery bypass surgery and mitral valve replacement surgery both of which were successful. to the best of our knowledge, this is the first case report to describe the occurrence of permanent lbbb after left heart catheterisation. this report describes the case and reviews the literature for the incidence and implications of such a complication. keywords: lbbb; left bundle branch block; coronary angiography; aortography; left ventriculography; left heart catheterisation; diagnostic heart catheterisation; case report; oman asymptomatic permanent left bundle branch block (lbbb) complicating diagnostic left heart catheterisation hafidh al-hadi*, mansour sallam case report hafidh al-hadi and mansour sallam case report | 115 complications (0.43%), contrast reactions (0.37%), haemodynamic complications (0.26%), perforation of heart chambers (0.03%), other complications, in general, diagnostic cardiac catheterisation is recommended whenever it is clinically important to define the presence or severity of a suspected cardiac lesion that cannot be adequately evaluated by other non-invasive techniques. most of the indications for cardiac catheterisations can be collectively classified into management of patients under the following categories: valvular heart disease;1 chronic heart failure;2 acute myocardial infarction (ami);3 percutaneous coronary intervention (pci),4 and coronary artery bypass surgery (cabg).5 cardiac catheterisation is a relatively safe procedure, but has a well defined risk of morbidity and mortality. in an analysis of 59,792 patients who underwent cardiac catheterisation and coronary angiography, the following were recognised complications (percentage of risk in brackets): mortality (0.11%), myocardial infarction (0.05%), cerebrovascular accidents (0.07%), arrhythmias (0.38%), vascular complications (0.43%), contrast reactions (0.37%), haemodynamic complications (0.26%), perforation of heart chambers (0.03%), other complications, including renal failure, heart failure and vasovagal reactions (0.26%).6 the overall risks of cardiac catheterisation are less than 2%. arrhythmias most commonly encountered during cardiac catheterisations include frequent ventricular ectopic beats, short runs of ventricular or supraventricular tachycardia, bradycardia, heart block, asystole, atrial fibrillation and, rarely, ventricular fibrillation with sudden cardiac death. these arrhythmic figure 1: the initial ecg taken one day prior to the cardiac catheterisation procedure. figure 2: the ecg of the patient taken immediately after left heart catheterisation procedure. it shows a typical left bundle branch block pattern that was not present on the initial ecg [figure 1]. asymptomatic permanent left bundle branch block (lbbb) complicating diagnostic left heart catheterisation 116 | squ medical journal, april 2010, volume 10, issue 1 complications are more common with right heart catheterisation, patients with left main stem (lms) coronary artery disease (cad), patients with low ejection fraction (ef) < 30%, and patients with high new york heart association (nyha) class iv. this report describes the case and reviews the literature on the incidence, significance and the implication of this complication during cardiac catheterisation procedures. case report a 67 year-old man, on regular treatment for hypertension (htn) for the previous six years, presented at sultan qaboos university hospital, oman. he had had a history of shortness of breath (sob) on exertion for the previous few years, but this had recently worsened. the echocardiogram showed a mitral valve prolapse (mvp) with severe mitral regurgitation. he was referred for work-up for mitral valve surgery. he was on the following medications: aspirin 81 mg once a day, ranitidine 150 mg twice a day, bisoprolol 2.5 mg once a day, and simvastatin 20 mg at night. the patient had an appearance of good health. heart auscultation revealed a normal first sound, a faint second sound and a pansystolic murmur at the apical region radiating to the axilla. the lungs were clear and the rest of the examination was unremarkable. initial investigations, including total blood count, urea and electrolytes, coagulation profile, lipids, electrocardiogram (ecg), routine chest x-ray, hepatitis b screening and human immunodeficiency virus (hiv) screening were all normal. figure 1 shows the baseline ecg of this patient on admission. it shows a normal sinus rhythm, left atrial abnormalities, rsr1 pattern in frontal leads, and a qt interval that was at the upper limit of normal. the left heart catheterisation procedure was explained and consent was obtained. the procedure was done through the right femoral artery using the seldinger technique. coronary angiography was done using 6f, jl4 and jr4 diagnostic catheters. this required multiple small injections of contrast (5−8ml) by hand at high speed and acquisition of coronary images in different projections. an aortogram was done using a pigtail catheter. thirty-five millilitres of contrast were injected at a rate of 15 ml per second using a power injector. left ventriculography was done after crossing the aortic valve using a j-shaped guide wire followed by the pigtail catheter. twenty-five millilitres were injected at 10 ml per second using a power injector. these investigations revealed the following results: the coronary angiography showed two vessels with cad disease; the first diagonal revealing 75% long stenosis proximally and 75% stenosis distally. the posterior descending artery had 75% stenosis proximally. the rest of the vessels were normal. ventriculography showed good left ventricular (lv) systolic function, severe mitral regurgitation (mr) grade iv, mildly dilated lv and grossly dilated left atrium. there was no significant aortic pressure gradient across the aortic valve. the aortogram showed no aortic root dilatation and mild grade i aortic regurgitation. overall the patient had severe mr and two vessels with cad disease. towards the end of the procedure, it was noticed incidentally on the monitored ecg that the sinus rhythm had changed to an lbbb pattern. the patient heart rate was 75 beats per minutes and was completely asymptomatic and haemodynamically stable, and the catheterisation procedure had no figure 3a : a standard j-shaped tip diagnostic guide wire that is commonly used during left heart catheterisation procedures. figure 3b : a standard 6 french “pigtail” diagnostic catheter. hafidh al-hadi and mansour sallam case report | 117 complications. after sheath removal, the patient was moved back to the ward. the patient had no chest pain or sob. his vital signs were all normal. the physical examination was also entirely normal. a repeat ecg showed a widening of the qrs complex typical for an lbbb pattern [figure 2]. a chest x-ray was similar to the previous one with a normal appearance of pulmonary vasculature, no pleural effusion, and no signs of lung oedema or consolidation. an urgent bed-side echocardiogram revealed: 1) lv: upper limit of normal internal dimensions, no regional wall motion abnormality, excellent systolic function, and a normal relaxation pattern, and an intact septum; 2) mitral valve: thickened, fibrosed and calcified with a significant prolapse of the posterior leaflet with severe mr; 3) aortic valve: mild aortic stenosis (as) with trivial aortic regurgitation (ar); 4) tricuspid valve: normal with trivial tricuspid regurgitation (tr) with estimated pulmonary artery pressure of 20 mm hg; 5) thickened pericardium with no effusion; 6) no intracardiac masses or thrombi noted. serum cardiac troponin i (ctni) was 0.03 µg/l four hours after the procedure and, when repeated next day, was again 0.03 µg/l (normal ≤ 0.03 µg/l). as the patient was asymptomatic and clinically and haemodynamically stable, the investigations did not reveal any specific cause for this new lbbb (normal troponins and echocardiographic findings); he was therefore treated conservatively. he was allowed to proceed with surgery during the index admission. a cabg (one vein graft) with mitral valve replacement (mvr) (tissue bioprosthetic valve) was carried out successfully 8 days after the cardiac catheterisation. the postoperative course was only complicated by transient atrial fibrillation (that eventually reverted to sinus rhythm after a short course of amiodarone and an on-demand pacemaker), and abdominal pain (a computed tomography (ct) scan of the abdomen showed no major pathologies). the patient was discharged home in a stable condition 12 days after surgery. the pre-discharge ecg still showed a lbbb. discussion the appearance of transient lbbb in the setting of cardiac catheterisation (and specifically during left ventriculography) is a well known, although very uncommon complication.7 in the pivotal article of bourassa m and noble j, in which 5.250 coronary arteriographies were reviewed, the incidence of lbbb was 0.17%. however, lbbb in all the above cases subsided either spontaneously or responded rapidly to appropriate drug therapy.8 an iatrogenic left bundle branch block is a rare complication of left ventricular catheterisation and coronary arteriography because unlike the branches of the right bundle, which pass superficially within the thinwalled right ventricle, the left bundle is a fan-like structure that radiates from the left interventricular septum through the thicker-walled left ventricle. this structure results in relatively greater protection of the left bundles from focal mechanical injury. in contrast to catheters frequently used in the right ventricle, left heart catheters such as “pigtails” are usually spatially located in the left ventricle so that the interventricular septum is spared mechanical contact.9 we have reviewed the available literature, but did not find anything on this topic. a permanent lbbb complication as a result of diagnostic cardiac catheterisation has, to the best of our knowledge, not been reported before. our case was admitted for a routine procedure. the patient was not classified into high risk category for the development of arrhythmias. these categories include patients with left main stem (lms) lesions, heart failure and recent acute coronary syndrome (acs) events.2 he had no renal or liver dysfunction, and the basic electrolytes (potassium, calcium, and magnesium) were normal. none of the medications he received were known to be associated with the development of this complication. the guide wire used was j wire, which means it has a j-shaped soft curve at the terminal end. this protects against left ventricular wall trauma or puncture. this type of guide wire rarely causes trauma to the aorta or lv wall [figure 3a]. other guide wires for example straight-tip guide wires which are sometimes used (but not in this case) to cross heavily calcified stenotic aortic valves, may sometimes cause lv wall trauma or perforation or lms dissection if they are manipulated aggressively. performing a left ventriculogram or an aortogram requires the injection of a large volume of contrast solution using a powered injector at high speed into the lv and aorta respectively through a pigtail catheter that has a hole at one end and many small side holes to allow the contrast to leak out [figure asymptomatic permanent left bundle branch block (lbbb) complicating diagnostic left heart catheterisation 118 | squ medical journal, april 2010, volume 10, issue 1 3b]. the end of the catheter is placed near (but not in contact with) the apex and away from the free wall. this is very important to avoid the powered injection jet being injected directly into the wall of the lv. inadvertent injection of contrast solution into the free wall of the lv under high pressure may lead to free wall rupture or perforation with subsequent cardiac tamponade or free septal wall rupture with free left to right shunt. the presence of many side holes in the pigtail catheter is a very important safeguard to reduce the force of the jet by allowing the contrast to leak side ways if the end hole were inadvertently placed in direct contact with the wall. this lbbb complication appeared during heart catheterisation suggesting a direct contribution of the latter to its development. the exact cause(s) of the lbbb in this case is not known, but could be due to one of the following several possible mechanisms: 1) during coronary angiography or aortography, it is possible that a small amount of foreign body material (air, thrombus, coronary plaque, cholesterol or calcium) may have embolised distally and blocked the blood supply to the left bundle branch or some of its fibres; 2) it is possible that manipulation of either the guide wire or the pig-tail might have produced a minimal, localised, septal contusion (without any troponin elevation or pathologic findings in the echo study) leading to lbbb onset; 3) the powered injection of contrast medium into the left ventricle may have caused trauma to the septum or left ventricle and the left bundle branch or one of its distal branches. the overall findings suggests that the trauma to the heart (if any) may have been non-mechanical (as per the echocardiogram) and most probably was very slight, because there was no subsequent significant ctni rise in the serum. lbbb is rare in normal individuals and is most commonly seen in patients with cad; however, as many as 12% of patients with lbbb have no demonstrable heart disease.10 even among patients without overt heart diseases, lbbb is associated with a higher than normal risks of cardiovascular events and all cause mortality.11 it is associated with high grade atrioventricular (av) block and sudden cardiac death.12 the abnormal ventricular activation pattern of lbbb induces an abnormal systolic function with reduced ejection fraction and stoke volumes and abnormal diastolic function.13 it carries a more serious prognosis than right bundle branch block, but neither form requires specific treatment. conclusion this case report describes the development of a de novo permanent lbbb after a left heart catheterisation procedure. we have reviewed the literature and, to the best of our knowledge, this has not been described before. we have offered several possible hypotheses to explain the association between left heart catheterisation and the development of lbbb. it is difficult to predict the long-term prognosis of such a complication in this patient. in general, lbbb, whatever the cause, has a poor prognosis and carries significant morbidity and mortality risks. it remains to be seen whether these risks also apply to the specific case described in this report. a c k n o w l e d g m e n t s we would like to thank the patient and all the nursing staff in the catheterisation laboratory and in ward two purple of sultan qaboos university hospital, oman, who were involved in the management of this case. references 1. bonow ro, carabello ba, chatterjee k, deleon ac, faxon dp, freed md, et al. acc/aha 2006 guidelines for the management of patients with valvular heart diseases. j am coll cardiol 2006; 48:e1. 2. hunt sa, abraham wt, chin mh, feldman am, francis gs, ganiats tg, et al. acc/aha 2005 guideline update for the diagnosis and management of patients with chronic heart failure in the adult. circulation 2005; 112:e154. 3. antman em, anbe dt, armstrong pw, bates er, green la, hand m, et al. acc/aha guidelines for the management of patient with stelevation myocardial infarction. circulation 2004; 110:e82. 4. smith sc jr, feldman te, hirshfeld jw jr, jacobs ak, kern mj, king sb 3rd, et al. acc/aha/scai 2005 guideline update for percutaneous coronary intervention. circulation 2006; 113:e166. 5. eagle ka, guyton ra, davidoff r, edwards fh, ewy ga, gardner tj, et al. acc/aha 2004 guidelines update for coronary artery bypass graft surgery. circulation 2004; 110:e340. hafidh al-hadi and mansour sallam case report | 119 6. scanlon pj, faxon dp, audet am, carabello b, dehmer gj, eagle ka, et al. acc/aha guidelines for coronary angiography: a report of the american college of cardiology/ american heart association task force on practice guidelines (committee on coronary angiography). j am coll cardiol 1999; 33:1760. 7. shimamoto t, nakata y, sumiyoshi m, ogura s, takaya j, sakurai h, et al. transient left bundle branch block induced by left-sided cardiac catheterization in patients without pre-existing conduction abnormalities. jpn circ j 1998; 62:146−9. 8. bourassa mg, noble j. complication rate of coronary arteriography. a review of 5250 cases studied by a percutaneous femoral technique. circulation 1976; 53:106−14. 9. gilchrist i, cameron a. catheterization and cardiovascular diagnosis 1988; 15:229−32. 10. jain ac, mehta mc. etiologies of left bundle branch block and correlation to hemodynamic and angiographic findings. am heart j 2003; 91:1375. 11. miller wl, ballman kv, hodge do, rodenheffer rj, hammill sc, et al. risk factor implications of incidentally discovered uncomplicated left bundle branch block. mayo clin proc 2005; 80:1585. 12. eriksson p, wilhelmson l, rosengren a. bundlebranch block in middle-aged men: risk of complications and death over 28 years. eur heart j 2005; 26:2300. 13. turner ms, bleasdale ra, vinereanu d, mumford ce, paul v, fraser ag, et al. electrical and mechanical components of dyssynchrony in heart failure patients with normal qrs duration and left bundle branch block. circulation 2004; 109:2544. 1department of radiology, hull royal infirmary, hull, uk; 2department of gastroenterology, hull & east yorkshire hospitals national health service trust, hull, uk *corresponding author’s e-mail: drphilipsgm@yahoo.com السدة الصمغية الرئوي مضاعفة غري عادية بعد العالج التصلييب باملنظار لدوايل املعدة فيليب�ض جورج مايكل، جورجو�ض اأنطونياد�ض، اأنكا �شتايكو، �شاهد �شيدات abstract: a pulmonary glue embolism is an unusual but potentially life-threatening complication following the treatment of variceal bleeding, especially in patients with large varices requiring large volumes of sclerosant. other contributory factors include the rate of injection and ratio of the constituent components of the sclerosant (i.e. n-butylcyanoacrylate and lipiodol). this condition may be associated with a delayed onset of respiratory compromise. therefore, a high degree of clinical suspicion is essential in patients with unexplained cardiorespiratory decline during or following endoscopic sclerotherapy. we report a 65-year-old man who was admitted to the hull royal infirmary, hull, uk, in 2017 with haematemesis and melaena. he subsequently developed acute respiratory distress syndrome secondary to a glue embolism following emergency sclerotherapy for bleeding gastric varices. the aetiology of the embolism was likely a combination of the large size of the gastric varices and the large volume of cyanoacrylate needed. after an endoscopy, the patient underwent transjugular intrahepatic portosystemic shunting twice to control the bleeding, after which he recovered satisfactorily. keywords: gastric varices; pulmonary embolism; sclerotherapy; n-butyl-cyanoacrylate; lipiodol; case report; united kingdom. امللخ�ص: ال�شدة ال�شمغية الرئوية هو م�شاعفة غري عادي و قد تكون مميتة بعد عالج نزيف الدوايل، خا�شة عند املر�شى الذين يعانون من دوايل كبرية تتطلب كميات كبرية من املت�شلب. وت�شمل العوامل امل�شاهمة الأخرى حلدوث ال�شدة معدل احلقن ون�شبة املكونات املكونة للمادة املت�شلبة )اأي-ن-بيوتيل-�شيانواأكريليت واللييودولول(. قد ترتبطا هذه احلالة بحدوث ق�شور متاأخر يف التنّف�ض ولذلك، فاإن درجة عالية من الريبة ال�رضيرية اأمر �رضوري للت�شخي�ض املبكر وبخا�شة يف يف املر�شى الذين يحدث لهم هبوط غري مربرة يف وظائف اجلهاز التنف�شي و القلب اأثناء اأو بعد العالج الت�شليبي باملنظار. هذا تقرير حالة لرجل يبلغ من العمر 65 عاًما مت اإدخاله اإىل م�شت�شفى هال امللكي، هال، اململكة املتحدة، يف عام 2017 ب�شبب القيء وا�شوداد لون الرباز. ويف وقت لحق تطورت حالتة مع حدوث متالزمة ال�شائقة التنف�شية احلادة الثانوية نتيجة لل�شدة الرئوية بعد العالج الت�شلبي الطارئ باملنظار لأيقاف نزيف دوايل املعدة. كان امل�شببات املر�شية املحتملة لالن�شداد هي مزيج من احلجم الكبري للدوايل املعدية واحلجم الكبري من مادة ال�شيانوكريالت امل�شتحدمة. بعد اإجراء املنظار والعالج ، ظل املري�ض بدون اأعرا�ض خالل فرتة متابعة ملدة �شتة اأ�شهر. الكلمات املفتاحية: دوايل املعدة؛ ال�شدة الرئوية؛ العالج الت�شليبي؛ اأي-ن-بيوتيل-�شيانواأكريليت؛ اللييودولول؛ تقرير حالة؛ اململكة املتحدة. pulmonary glue embolism an unusual complication following endoscopic sclerotherapy for gastric varices *philips g. michael,1 georgios antoniades,1 anca staicu,2 shahid seedat1 case report sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e231–235, epub. 9 sep 18 submitted 4 dec 17 revision req. 11 jan 18; revision recd. 29 jan 18 accepted 18 feb 18 doi: 10.18295/squmj.2018.18.02.020 although rare, pulmonary glue emboli are potentially life-threatening complications which can arise following endoscopic sclerotherapy for the treatment of variceal bleeding.1 large volumes, the rate of injection and the ratio of components (i.e. the proportion of n-butyl-cyanoacrylate to lipiodol) of the sclerosant are thought to contribute to the condition.1,2 pulmonary glue emboli may be associated with delayed-onset respiratory compromise and may be overlooked in asymptomatic or mildly symptomatic patients.1,2 this case report describes a patient who developed acute respiratory distress synd rome due to a pulmonary glue embolism following endoscopic sclerotherapy. this article highlights the variable clinical spectrum, complex pathophysiology and risk factors of this condition. case report a 65-year-old man was admitted to the accident & emergency department of the hull royal infirmary, hull, uk, in 2017 with a two-day history of coffeecoloured vomiting and melaena. he was known to have child-pugh class c liver cirrhosis secondary to alcoholic liver disease, type 2 diabetes mellitus and hypertension. upon admission, the patient was hypotensive, tachycardic, icteric and encephalopathic. a physical examination revealed a distended abdomen due to ascites and moderate splenomegaly. a thoracic examination was unremarkable and no significant abnormalities were identified on a chest radiograph. laboratory tests revealed haemoglobin levels of 6 g/l, white cell count of 14.9 x 109/l, a prolonged propulmonary glue embolism an unusual complication following endoscopic sclerotherapy for gastric varices e232 | squ medical journal, may 2018, volume 18, issue 2 an emergency upper gastrointestinal endoscopy revealed a large fundal gastric varix with active bleeding and the stomach was filled with blood. endoscopic sclerotherapy of the varix was carried out using a solution of 4 ml of n-butyl-cyanoacrylate and 8 ml of lipiodol. immediately after the procedure, the patient was haemodynamically stable with an oxygen saturation of 98%. however, on the following day, the patient developed tachycardia and became febrile with a temperature of 39 °c. his oxygen saturation proportion had dropped to 90% and his fraction of inspired oxygen requirements increased from 0.4 to 0.8. fine crepitations were audible throughout the chest area. another chest radiograph revealed diffuse infiltrates in both lungs, thought to be due to aspiration pneumonia [figure 1]. a computed tomography (ct) scan revealed diffuse ground glass opacities in both lungs along with consolidation throughout both lower lobes. hyperdense linear structures were observed within the lumen and branches of the pulmonary arteries, along with similar tubular larger volume hyperdense structures within the gastric fundal varices [figure 2]. these findings were consistent with multiple pulmonary glue emboli from the injected sclerosant, with parenchymal changes suggesting acute respiratory distress syndrome. retrospectively, a review of the initial chest radiograph indicated the presence of subtle radiopaque densities, corresponding with glue particles. the patient was subsequently intubated, vent ilated and treated conservatively with intravenous diuretics. broad-spectrum antibiotics were also prescribed empirically to prevent spontaneous bacterial peritonitis and to treat the aspiration pneumonia. five days after the initial ct scan, repeat scans of the chest, abdomen and pelvis were performed due to further variceal bleeding; these showed that the glue emboli had persisted [figure 3]. the patient subsequently required a transjugular intrahepatic portosystemic shunt to control the haemorrhage. thrombin time of 18 seconds, albumin levels of 19 g/l, bilirubin levels of 46 µmol/l, alkaline phosphatase levels of 300 µ/l, alanine transaminase levels of 194 µ/l, urea levels of 6.4 mmol/l and creatinine levels of 55 µmol/l. after being transfused with six units of packed red blood cells along with fresh frozen plasma and cryoprecipitate, the patient was transferred to the intensive care unit and prescribed terlipressin, antibiotics and standard treatment for variceal bleeding. figure 1: chest radiograph of a 65-year-old man following endoscopic sclerotherapy for the treatment of gastric varices showing diffuse infiltrates. note the subtle radioopaque densities which were identified retrospectively to correlate with glue particles. figure 2: axial computed tomography scan of a 65-year-old man following endoscopic sclerotherapy for the treatment of gastric varices demonstrating bilateral lower lobe consolidation and hyperdense linear structures within the lumen and branches of the pulmonary arteries. figure 3: repeat computed tomography (ct) scans of a 65-year-old man in the (a) axial and (b) coronal views showing persistent hyperdense glue emboli following endoscopic sclerotherapy for the treatment of gastric varices. philips g. michael, georgios antoniades, anca staicu and shahid seedat case report | e233 cases of oesophageal rather than cardiac or gastric varices.10–12 the development of high-flow shunts such as the cardiotuberositarian vein can also carry clots or embolic material from injected varices to the pulmonary circulatory system.13,14 in a previous study, marion-audibert et al. injected a mixture of 3 ml of lipiodol and cyanoacrylate into the right cardiac cavity of a pig via a swan-ganz catheter in the intrapulmonary artery; subsequently, the authors noted an immediate dramatic rise in pulmonary artery pressure, along with an associated drop in cardiac output.10 simultaneously, transoesophageal echocardiography demon strated a sudden dilation of the right cavities of the heart, followed by right-sided heart failure that quickly progressed to global heart failure, ventricular fibrillation and cardiac arrest, at which point the animal died.10 in this case, death occurred as a result of the pulmonary glue embolism and was not secondary to chemical acute respiratory distress syndrome. a histological analysis also confirmed that the pulmonary embolism was due to the mechanical occlusion of the pulmonary arteries and not the secondary activation of coagulation.10 the precise incidence of glue migration following variceal embolisation is not known, since chest imaging is not routinely performed for patients with mild post-procedural hypoxaemia. in a review article, saraswat et al. concluded that the risk of embolisation is between 0.5–4.3%.15 another review of 753 cases by cheng et al. identified distant embolisation in five patients (0.7%), of which one embolism was pulmonary, one was cerebral and three were splenic.16 according to alexander et al., the volume of glue used, rate of injection and size of the gastric varices being treated contribute to the risk of embolisation; in particular, large-sized varices with high blood flow rates frequently associated with gastrorenal shunts have a higher risk of pulmonary embolism.11 similarly, hwang et al. observed that injecting volumes of cyano acrylate glue over 4.2 ml resulted in an increased risk of pulmonary embolism.12 altering the composition of the glue by varying the ratio of lipiodol to cyanoacrylate has been explored as a useful strategy to decrease the risk of embolisation.9,10 irisawa et al. found that diluting the cyanoacrylate solution to less than 40% increased the likelihood of such migration; the researchers suggested that a concentration of at least 62.5% be used in treating gastric fundal varices larger than 12 mm in diameter.17 however, it remains difficult to prevent some migration of the glue beyond the bleeding varix. pulmonary glue emboli can cause an extremely wide spectrum of clinical presentations, ranging from over the next two days, the patient’s oxygen requirements gradually decreased. a repeat chest radio graph indicated the resolution of the pulmonary parenchymal changes. the patient was subsequently weaned off ventilation and extubated. a repeat endoscopy immediately before discharge revealed ulceration from the sclerotherapy procedure, but no further active bleeding. the patient required two further transjugular intrahepatic portosystemic shunt procedures to control the haemorrhage, after which he had an uneventful recovery and remained asymptomatic over the following six months. discussion sclerotherapy of gastric fundal varices is the treatment of choice for patients with portal hypertension associated with hepatic cirrhosis who present with acute uncontrolled gastric variceal bleeding.2,3 alternative interventions—such as band ligation or transjugular intrahepatic portosystemic shunting—may be considered for the treatment of bleeding from gastro-oeso phageal varices.1,2 according to international recomm endations, an injection of glue is the most costeffective option for cases of uncontrolled gastric variceal bleeding.3–5 the glue consists of a mixture of n-butyl-cyanoacrylate, which is an aqueous solution, and lipiodol, which is an oil-based agent. n-butylcyanoacrylate causes almost instant haemostasis by undergoing rapid polymerisation when it comes into contact with blood, while the role of lipiodol is to delay the polymerisation process, thus reducing the likelihood of glue particles adhering to the endoscope or needle. nevertheless, there is a risk of distal embolisation and potentially devastating complications.6,7 the blood supply of gastric varices is usually derived from the short gastric and gastroepiploic veins that drain into the left renal vein via a large gastrorenal shunt. migrating glue particles often follow a complex pathway, travelling from the gastric varices through the gastrorenal and splenorenal veins to the inferior vena cava, right side of the heart and into the pulmonary circulatory system.8–10 thus, in most cases, the lungs filter glue emboli; however, among patients with atrial septal defects, patent foramina ovalia or arteriovenous pulmonary shunts, the embolisation of glue particles into systemic circulation may occur, with the glue particles potentially becoming lodged within the cerebral, splenic or coronary arteries with catastrophic consequences.11 alternatively, glue emboli can migrate via the superior vena cava and the azygos vein; however, this more commonly occurs in pulmonary glue embolism an unusual complication following endoscopic sclerotherapy for gastric varices e234 | squ medical journal, may 2018, volume 18, issue 2 3. scottish intercollegiate guidelines network. management of acute upper and lower gastrointestinal bleeding: a national clinical guideline. from: www.sign.ac.uk/assets/sign105.pdf accessed: jan 2018. 4. de franchis r; baveno v faculty. revising consensus in portal hypertension: report of the baveno v consensus workshop on methodology of diagnosis and therapy in portal hypertension. j hepatol 2010; 53:762–8. doi: 10.1016/j.jhep.2010.06.004. 5. national institute for health and clinical excellence. acute upper gastrointestinal bleeding: management. from: www. spg.pt/wp-content/uploads/2015/11/2012-nice-ugib.pdf accessed: jan 2018. 6. singer ad, fananapazir g, maufa f, narra s, ascher s. pulmonary embolism following 2-octyl-cyanoacrylate/lipiodol injection for obliteration of gastric varices: an imaging perspec tive. j radiol case rep 2012; 6:17–22. doi: 10.3941/jrcr.v6i2.845. 7. kazi s, spanger m, lubel j. education and imaging: gastrointestinal pulmonary embolism of cyanoacrylate glue following endoscopic injection of gastric varices. j gastroenterol hepa tol 2012; 27:1874. doi: 10.1111/jgh.12002. 8. hamad n, stephens j, maskell gf, hussaini sh, dalton hr. case report: thromboembolic and septic complications of migrated cyanoacrylate injected for bleeding gastric varices. br j radiol 2008; 81:e263–5. doi: 10.1259/bjr/30231294. 9. ashraf p, haqqi sa, shaikh h, wakani aj. glue embolism: a rare cause of pulmonary embolism. j coll physicians surg pak 2011; 21:574–6. doi: 09.2011/jcpsp.574576. 10. marion-audibert am, schoeffler m, wallet f, duperret s, mabrut jy, bancel b, et al. acute fatal pulmonary embolism during cyanoacrylate injection in gastric varices. gastroenterol clin biol 2008; 32:926–30. doi: 10.1016/j.gcb.2008.07.009. 11. alexander s, korman mg, sievert w. cyanoacrylate in the treatment of gastric varices complicated by multiple pulmonary emboli. intern med j 2006; 36:462–5. doi: 10.1111/j.1445-5994. 2006.01086.x. 12. hwang ss, kim hh, park sh, kim se, jung ji, ahn by, et al. n-butyl-2-cyanoacrylate pulmonary embolism after endoscopic injection sclerotherapy for gastric variceal bleeding. j comput assist tomogr 2001; 25:16–22. 13. wind p, alves a, chevallier jm, gillot c, sales jp, sauvanet a, et al. anatomy of spontaneous splenorenal and gastrorenal venous anastomoses: review of the literature. surg radiol anat 1998; 20:129–34. doi: 10.1007/s00276-998-0129-8. 14. kull e, hernandez m, richer jp, borderie c, silvain c, beauchant m. [severe pulmonary embolism after obturation of gastric varices with a butyl-cyanoacrylate and lipiodol combination]. gastroenterol clin biol 1999; 23:1095–6. 15. saraswat va, verma a. gluing gastric varices in 2012: lessons learnt over 25 years. j clin exp hepatol 2012; 2:55–69. doi: 10.1016/s0973-6883(12)60088-7. 16. cheng lf, wang zq, li cz, lin w, yeo ae, jin b. low incidence of complications from endoscopic gastric variceal obturation with butyl cyanoacrylate. clin gastroenterol hepatol 2010; 8:760–6. doi: 10.1016/j.cgh.2010.05.019. 17. irisawa a, obara k, sato y, saito a, orikasa h, ohira h, et al. adherence of cyanoacrylate which leaked from gastric varices to the left renal vein during endoscopic injection sclerotherapy: a histopathologic study. endoscopy 2000; 32:804–6. doi: 10.10 55/s-2000-7702. 18. chew jr, balan a, griffiths w, herre j. delayed onset pulmonary glue emboli in a ventilated patient: a rare complication following endoscopic cyanoacrylate injection for gastric variceal haemorrhage. bmj case rep 2014; 2014:bcr2014206461. doi: 10.1136/bcr-2014-206461. 19. al-hillawi l, wong t, tritto g, berry pa. pitfalls in histoacryl glue injection therapy for oesophageal, gastric and ectopic varices: a review. world j gastrointest surg 2016; 8:729–34. doi: 10.4240/wjgs.v8.i11.729. asymptomatic patients to those with dyspnoea, pleuritic chest pain, coughing, tachycardia, hypoxia and cardiorespiratory arrest or sudden death.7,9–11,18 in symptomatic patients, it is important to note that the timing of the onset of respiratory symptoms is highly variable, ranging from a few minutes to hours after the cyanoacrylate injection.12,18 a chest radiograph or non-contrast ct scan usually helps to establish the diagnosis.19–21 however, the presence of hyperdense cyanoacrylate glue emboli may be masked by the intravenous contrast medium in ct pulmonary angiography, potentially resulting in a misdiagnosis. it has been observed that imaging findings do not correlate well with the clinical condition of patients and that the radiographic features of glue emboli can persist despite evidence of clinical improvement.20,21 the management of patients with pulmonary glue emboli is mainly supportive and there is usually no need for thrombolysis or anticoagulative measures. for most symptomatic patients who survive, the embolic consequences and clinical symptoms of the condition seem to resolve with time, although the precise mechanism by which this occurs is not yet fully understood.11–14 apart from pulmonary emboli, other adverse effects of a glue injection include splenic infarctions, thrombosis of the portal and splenic veins and persistent sepsis due to the embolism.18 more commonly, complications associated with cyanoacrylate injections include transient pain, fever, incomplete obliteration of the varix and tissue necrosis around the injection site leading to deep ulceration, early rebleeding and occasional perforation.8 conclusion a pulmonary glue embolism should be suspected among patients who develop acute respiratory distress syndrome following endoscopic sclerotherapy. in the current case, the cause of the pulmonary glue embolism was likely a combination of the large size of the gastric varices and the large volume of cyanoacrylate needed to treat them. references 1. de freitas ribeiro bn, sobral de magalhães oliveira al, marchiori e. acute pulmonary embolism following endoscopic glue injection for sclerotherapy. arch bronconeumol 2016; 52:333. doi: 10.1016/j.arbr.2015.05.016. 2. mahadeva s, bellamy mc, kessel d, davies mh, millson ce. cost-effectiveness of n-butyl-2-cyanoacrylate (histoacryl) glue injections versus transjugular intrahepatic portosystemic shunt in the management of acute gastric variceal bleeding. am j gastroenterol 2003; 98:2688–93. doi: 10.1111/j.1572-02 41.2003.08769.x. https://doi.org/10.1016/j.jhep.2010.06.004 https://doi.org/10.3941/jrcr.v6i2.845 https://doi.org/10.1111/jgh.12002 https://doi.org/10.1259/bjr/30231294 https://doi.org/09.2011/jcpsp.574576 https://doi.org/10.1016/j.gcb.2008.07.009 https://doi.org/10.1111/j.1445-5994.2006.01086.x https://doi.org/10.1111/j.1445-5994.2006.01086.x https://doi.org/10.1007/s00276-998-0129-8 https://doi.org/10.1016/s0973-6883%2812%2960088-7 https://doi.org/10.1016/j.cgh.2010.05.019 https://doi.org/10.1055/s-2000-7702 https://doi.org/10.1055/s-2000-7702 https://doi.org/10.1136/bcr-2014-206461 https://doi.org/10.4240/wjgs.v8.i11.729 https://doi.org/10.1016/j.arbr.2015.05.016 https://doi.org/10.1111/j.1572-0241.2003.08769.x https://doi.org/10.1111/j.1572-0241.2003.08769.x philips g. michael, georgios antoniades, anca staicu and shahid seedat case report | e235 21. de luca d, piastra m, pietrini d, rollo m, conti g. “glue lung”: pulmonary micro-embolism caused by the glue used during interventional radiology. arch dis child 2008; 93:263. doi: 10.1136/adc.2007.134445. 20. prytuła a, veereman-wauters g, duval el. pulmonary embo lism due to injection of histoacryl and lipiodol during endoscopic sclerotherapy of fundic varices. acta gastroenterol belg 2008; 71:387–9. https://doi.org/10.1136/adc.2007.134445 1department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2internal medicine residency programme, oman medical specialty board, muscat, oman; 3department of medicine, armed forces hospital, muscat, oman; 4department of statistics & health information, sultan qaboos university hospital, muscat, oman; 5department of biostatics, christian medical college & hospital, vellore, tamil nadu, india *corresponding author’s e-mails: saidalbusafi@gmail.com and busafis@squ.edu.om خصائص ومعدل انتشار التهاب الكبد الوبائي املزمن ج مبركز رعاية ثالثية يف عمان �صعيد البو�صايف، حليمة ال�صعيلية، هبة عمر، هيفا الزهيبية، جي�صيالن، خالد النعماين abstract: objectives: chronic hepatitis c (chc) is a leading cause of liver cirrhosis and hepatocellular carcinoma (hcc) worldwide. however, there is a lack of data regarding the epidemiology of chc in oman. this study aimed to describe the clinicopathological characteristics and outcomes of chc-infected patients at a tertiary care hospital in oman. methods: this retrospective descriptive hospital-based study included all chc-infected patients who presented to the sultan qaboos university hospital (squh) in muscat, oman, between january 2010 and december 2015. the baseline demographic, clinical, laboratory and radiological data of the patients were analysed. results: a total of 603 chc-infected patients were identified during the study period; of these, 65.8% were male and the mean age was 44.8 ± 16.5 years. the main risk factors associated with chc infection were intravenous drug abuse (23.9%) and a history of blood transfusions (20.7%). the most prevalent virus genotypes were 1 and 3 (44.0% and 35.1%, respectively). upon initial presentation, 33.0% of the cohort had liver cirrhosis; of these, 48.7% had decompensated cirrhosis and 23.1% had hccs. liver transplantation was only performed for 7.5% of the cirrhosis patients, mostly as a curative treatment for hcc. conclusion: the implementation of national policies to prevent hepatitis c transmission and encourage the early screening of at-risk patients is recommended to reduce the burden and consequences of this disease in oman. keywords: chronic hepatitis c; hepatocellular carcinoma; liver cirrhosis; infectious disease transmission; genotypes; oman. بيانات توجد العامل.ل اأنحاء جميع يف الكبد و�رشطان لتليف رئي�صيا �صببا ج املزمن الوبائي الكبد التهاب يزال ل الهدف: امللخ�ص: متاحة عن التهاب الكبد الوبائي املزمن ج يف عمان. هدفت هذه الدرا�صة اإىل و�صف اخل�صائ�ض املر�صية ونتائج املر�صى يف م�صت�صفى ومتابعتهم تقييمهم مت الذين ج املزمن الوبائي الكبد التهاب مر�صى جلميع م�صتعر�صة درا�صة هذه الطريقة: عمان. يف ثالثية رعاية وال�رشيرية الدميوغرافية البيانات وحتليل جمع مت .2015 دي�صمرب اإىل 2010 يناير من الفرتة يف قابو�ض ال�صلطان جامعة م�صت�صفى يف واملخربية والإ�صعاعية للمر�صى. النتائج: مت جمع بيانات 603 من املر�صى العمانيني امل�صابني بالفريو�ض الكبدي الوبائي ج املزمن. كان متو�صط اعمارهم 44.8 ± 16.5 �صنة وكانت ن�صبة الذكور منهم هي %65.8. وكانت العوامل الرئي�صية ل�صابة بالفريو�ض ج هي تعاطي املخدرات عن طريق الوريد ومثلت ن�صبة )%23.9( من املر�صى يليه وجود تاريخ مر�صي لنقل الدم من �صخ�ض لخر بن�صبة )%20.7(. وكان منط الفريو�ض اجليني الأكرث انت�صارا هو النمط 1 ثم النمط and 44.0%( 3 %35.1، على التوايل(. وجد تليف الكبد يف %33.0 من املر�صى، وعانى %48.7 منهم من عالمات الف�صل الكبدي بينما اأظهر %23.1 عالمات �رشطان الكبد. اأجريت عملية زرع الكبد يف %7.5 من مر�صى تليف الكبد ومع�صمهم كعالج ل�رشطان الكبد. اخلال�صة: هناك حاجة ما�صة اإىل تطبيق �صيا�صات وطنية منا�صبة للوقاية من انتقال التهاب الكبد الوبائي ج، والفح�ض املبكر للمر�صى املعر�صني خلطر الأ�صابة بالفريو�ض يف عمان للحد من عبء املر�ض وعواقبه. الكلمات املفتاحية: التهاب الكبد الوبائي املزمن ج؛ الأمناط اجلينية؛ �رشطان الكبد؛ تليف الكبد؛ اإنتقال العدوى؛ عمان. epidemiology of chronic hepatitis c infections at a tertiary care centre in oman *said a. al-busafi,1 halima al-shuaili,2 heba omar,3 haifa al-zuhaibi,1 l. jeyaseelan,4,5 khalid al-naamani3 clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e404–410, epub. 10 jan 18 submitted 13 jun 17 revision req. 30 jul 17; revision recd. 26 aug 17 accepted 28 sep 17 doi: 10.18295/squmj.2017.17.04.005 advances in knowledge to the best of the authors’ knowledge, the current study is the first to describe the clinical characteristics, risk factors, genotypes and outcomes of chronic hepatitis c (chc)-infected patients in oman. in the current study, chc-infected patients who were diagnosed based on existing evidence of liver disease had a higher prevalence of cirrhosis and hepatocellular carcinoma compared to patients who were diagnosed as a result of routine screening. application to patient care the results of this study emphasise the importance of implementing national policies for preventing the transmission of the hepatitis c virus in oman. early screening of at-risk patients and prompt management will help to reduce the burden of this disease. said a. al-busafi, halima al-shuaili, heba omar, haifa al-zuhaibi, l. jeyaseelan and khalid al-naamani clinical and basic research | e405 currently, the hepatitis c virus (hcv) infects approximately 177–185 million indivi-duals worldwide.1 chronic hepatitis c (chc) infection is a gradual progressive disease characterised by persistent hepatic inflammation. it leads to the development of cirrhosis in approximately 20–30% of patients over 15–25 years; of those with cirrhosis, 1% subsequently develop hepatocellular carcinoma (hcc) every year.1,2 with the recent development of oral direct-acting antiviral agents, the elimination of hcv within the next 15–20 years is predicted.1 unfortunately, liver cirrhosis and hcc rates are nevertheless expected to continue rising among hcvinfected patients as many cases remain undiagnosed and risk factors go unrecognised.3,4 screening programmes to enhance the early detection of infected patients and improve prevention strategies have been proven to reduce hcv-associated morbidity and mortality.5 most patients with acute hcv infections remain asymptomatic; as such, progression to a chronic subclinical infection is very common. usually, liver cirrhosis and other hcv-related complications occur approximately 20–30 years following hcv exposure.6 in the absence of proper hcv screening, infected patients frequently present at a late stage with multiple complications.5–7 the presence of comorbidities like alcoholic liver disease, viral coinfection with hiv or hepatitis b and the presence of insulin resistance can further accelerate disease progression.8–11 in oman, there are currently no national programmes in effect to promote public awareness, enhance early diagnosis or enable prompt management of chc cases. in 1991, hcv testing was first introduced at the sultan qaboos university hospital (squh), a tertiary referral hospital in muscat, oman.12 the estimated prevalence of anti-hcv-antibodies in oman has been reported as 1% among healthy blood donors, 41% among thalassaemic patients undergoing regular blood transfusions and 26.5% among patients on haemodialysis.12,13 however, more studies are needed to provide necessary information regarding hcv infection rates to policy-makers and health planners in oman. this study therefore aimed to identify the clinical characteristics, risk factors and major clinical outcomes of chc-infected patients at a tertiary care centre in oman. methods this retrospective descriptive hospital-based study was conducted at squh and included all patients with chc infections presenting between january 2010 and december 2015. all chc infections were diagnosed based on positive anti-hcv antibody and hcv ribonucleic acid polymerase chain reaction test results. patients were diagnosed with liver cirrhosis based on the presence of cirrhotic changes on an abdominal ultrasound scan, liver stiffness measurements of >12.5 kpa using a fibroscan® elastography device (echosens™, paris, france) within 12 months of inclusion in the study, a fibrosis-4 score of >3.25 or histopathological findings. patients with acute hcv infections, incomplete records or those who were lost to follow-up were excluded from the study. the final sample was estimated to be representative of the national population. information regarding the demographic and clinical characteristics, risk factors for hcv transmission, histological/radiological data and outcomes of the patients were subsequently collected from electronic hospital records. data were analysed using the statistical package for the social sciences (spss), version 17.0 (ibm corp., armonk, new york, usa). results were expressed as numbers and percentages for categorical variables and as means and standard deviations for continuous table 1: sociodemographic characteristics of chronic hepatitis c-infected patients at the sultan qaboos university hospital, muscat, oman (n = 603) variable n (%) age in years <50 370 (61.4) ≥50 233 (38.6) mean ± sd 44.8 ± 16.5 gender male 397 (65.8) female 206 (34.2) bmi in kg/m2* <29.8 416 (79.5) >29.9 107 (20.5) mean ± sd 25.9 ± 8.1 place of residence muscat 311 (51.6) al-batinah 102 (16.9) other 190 (31.5) abroad 34 (5.6) risky behaviour alcohol consumption 103 (17.1) smoking 68 (11.3) sd = standard deviation; bmi = body mass index. *total dataset for this variable was 523 as 80 patients with ascites were excluded. epidemiology of chronic hepatitis c infections at a tertiary care centre in oman e406 | squ medical journal, november 2017, volume 17, issue 4 variables. the relationships between genotype distrib ution and age, place of residence and mode of transmission were examined using a chi-squared test. all statistical analyses were based on two-sided hypothesis tests with a significance level set at p <0.050. this study was approved by the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #844). results a total of 603 patients with confirmed chc infections presented to squh during the study period. the mean age of the patients was 44.8 ± 16.5 years (range: 5–90 years old) and the majority were male (65.8%). excluding 80 patients with ascites, 20.5% of the sample were classified as obese with a body mass index of >29.9 kg/m2. alcohol consumption and smoking were reported by 103 (17.1%) and 68 (11.3%) patients, resp ectively [table 1]. out of 569 patients with available data, 392 (68.9%) had identifiable hcv risk factors. the most commonly identified risk factors were intravenous drug abuse (23.9%) followed by blood transfusions (20.7%), most of which had been performed before 1991. other risk factors included a history of surgery (5.1%), a family history of infection (7.2%), haemodialysis (4.2%) and organ grafting (2.1%) [figure 1]. overall, routine hcv testing was performed for 290 patients (48.1%) based on standard indications, including for patients undergoing frequent blood transfusions and screening prior to invasive procedures or blood donations and as part of pre-employment conditions. of the screened patients, 46 (15.9%) and 11 (3.8%) had liver cirrhosis and hcc, respectively. on the other hand, 258 cases (42.8%) were diagnosed based on various liver disease-related findings (e.g. elevated liver enzymes, acute hepatitis or acute variceal bleeding). within that subgroup, a higher proportion of patients with liver cirrhosis or hcc were identified (47.3% and 12.4%, respectively) [figure 2]. the vast majority of patients (84.4%) were asymptomatic at the time of initial presentation. for symptomatic patients, dyspepsia (62.8%), fatigue (60.6%), abdominal pain (58.5%) and jaundice (26.6%) were the predominant symptoms reported. a total of 55.6% of the patients had low viral loads. most patients had at least one comorbidity, including hypertension (21.6%), diabetes (20.7%), anaemia (19.2%), renal impairment (13.6%) or cardiac conditions (13.1%). co infections with chronic hepatitis b or hiv was reported in 39.0% and 2.0% of patients, respectively. [table 2]. the most prevalent hcv genotype was genotype 1 (44.0%) followed by genotypes 3 (35.1%), 4 (15.0%), 2 (3.7%) and mixed (2.2%). for intravenous drug abusers, the most common genotype was 3 (53.0%) followed by figure 1: risk factors for hepatitis c virus infection among chronic hepatitis c-infected patients at the sultan qaboos university hospital, muscat, oman (n = 569).‡ iv = intravenous. *of these transfusions, 13.0% were performed before 1991. †including extramarital relationships (1.7%), sharp needle stick injuries (0.5%) and tattooing (0.4%). ‡total dataset for this variable was 569 as 34 patients were excluded due to missing data. figure 2: prevalence of liver cirrhosis and hepatocellular carcinoma among chronic hepatitis c-infected patients diagnosed as a result of (a) routine screening (n = 290) and (b) as a result of existing evidence of liver disease (n = 258) at the sultan qaboos university hospital, muscat, oman (n = 548)*. hcc = hepatocellular carcinoma. *total dataset for this variable was 548 as 55 patients were excluded due to missing data. said a. al-busafi, halima al-shuaili, heba omar, haifa al-zuhaibi, l. jeyaseelan and khalid al-naamani clinical and basic research | e407 1 (40.9%). among those with a history of blood trans fusions, genotype 1 was the most prevalent (59.1%) followed by 3 (20.9%). there were significant associations between genotype distribution and age, place of residence and mode of transmission (p <0.050 each) [table 3]. a total of 199 patients (33.0%) had liver cirrhosis upon initial presentation. of these, 97 (48.7%) had one or more features suggestive of hepatic decompensation, including portal hypertension, ascites, hypersplenism, hepatic encephalopathy, hepatorenal syndrome or hepatic hydrothorax. a total of 61 patients with liver cirrhosis (30.7%) were diagnosed with hcc; among these cases, 27 (44.3%) had advanced hcc beyond the milan criteria for liver transplantation.14 only 15 cirrhosis patients (7.5%) underwent liver transplantation, for which the most common indication was as therapeutic management for early-stage hcc (n = 8; 53.3%) [figure 3]. discussion controlling hcv infections is of critical importance to prevent chc progression and the subsequent development of decompensated cirrhosis and hcc. however, the asymptomatic nature of most chc cases clearly limits this objective.15,16 moreover, oman has no community-based screening programme to target its high-risk population. to the best of the authors’ knowledge, the current study is the first to report the clinical characteristics and outcomes of chc-infected patients in oman. overall, the findings indicated that most patients resided in the highly-populated muscat and al-batinah governorates. similar results have been reported in western countries, with a greater prevalence of hcv in high-population compared to low-population communities, possibly due to the table 2: baseline clinical characteristics among chronic hepatitis c-infected patients at the sultan qaboos university hospital, muscat, oman (n = 603) characteristics n (%) symptoms*† dyspepsia 59 (62.8) fatigue 57 (60.6) abdominal pain 55 (58.5) jaundice 25 (26.6) nausea and vomiting 21 (22.3) viral load in iu/ml <800,000 335 (55.6) ≥800,000 268 (44.4) comorbidities† htn 130 (21.6) dm 125 (20.7) anaemia‡ 116 (19.2) renal impairment 82 (13.6) cardiac conditions 79 (13.1) dyslipidaemia 67 (11.1) psychological disorders 45 (7.5) autoimmune diseases 42 (7.0) sickle cell disease 40 (6.6) malignancies 35 (5.8)§ neutropaenia¶ 33 (5.5) thalassaemia major 25 (4.1) haemophilia 5 (0.8) coinfections hepatitis b// 213 (39.0) hiv** 10 (2.0) htn = hypertension; dm = diabetes mellitus. *total dataset for this variable was 94 as 509 asymptomatic patients were excluded. †percentages for these variables add up to more than 100% as some patients may have reported multiple symptoms/ comorbidities. ‡defined as a haemoglobin level of <10 mg/dl. §of these, six cases had lymphoma. ¶defined as an absolute neutrophil count of <1,000. //out of 546 patients who underwent hepatitis b core antibody testing. **out of 494 patients who underwent hiv testing. table 3: genotype distribution according to age, residence and mode of transmission among chronic hepatitis c-infected patients at the sultan qaboos university hospital, muscat, oman (n = 539)* variable total genotype, n (%) p value 1 3 other younger age† 318 151 (47.5) 117 (36.8) 50 (15.7) 0.002 place of residence muscat 268 111 (41.4) 113 (42.2) 44 (16.4) <0.001 al-batinah 93 45 (48.4) 30 (32.3) 18 (19.4) other 145 75 (51.7) 40 (27.6) 30 (20.7) abroad 27 6 (22.2) 6 (22.2) 15 (55.6) mode of transmission iv drug abuse 115 47 (40.9) 61 (53.0) 7 (6.1) <0.001 blood transfusions 115 68 (59.1) 24 (20.9) 23 (20.0) iv = intravenous. *total dataset for this variable was 539 as 64 patients were excluded due to missing genotype data. †age of <50 years old. epidemiology of chronic hepatitis c infections at a tertiary care centre in oman e408 | squ medical journal, november 2017, volume 17, issue 4 increased availability of illegal drugs.17 however, it is also possible that some patients living in other governorates in oman were referred to other hospitals apart from squh during the study period. globally, the distribution of hcv genotypes differs according to epidemiological variations, including differences in modes of transmission and ethnic and temporal factors.16 however, there is a paucity of data regarding the distribution of hcv genotypes in oman. al-naamani et al. previously reported the genotype distribution of 33 multi-transfused β-thalassaemia omani patients to be 55%, 27%, 9% and 9% for genotypes 1, 4, 2 and 3, respectively.12 however, in the current study, genotype 1 was most prevalent (44.0%), followed by genotypes 3 (35.1%), 4 (15.0%), 2 (3.7%) and mixed (2.2%). this discrepancy in findings could be due to the fact that al-naamani et al.’s study focused purely on a subset of multi-transfused thalassaemic patients; these patients were most likely infected from transfused blood imported to oman before 1991, when hcv screening first began.12 the prevalence of genotype 1 over other genotypes in the current study was similar to reports from other middle eastern countries like the united arab emirates (uae; 49.2%), turkey (95.6%), iran (56.2%) and bahrain (37%).18–21 however, other studies from saudi arabia, yemen and iraq found that genotype 4 was most frequent.22–24 in the current study, alcohol and tobacco use were relatively uncommon. nevertheless, alcohol consumption and smoking are well-known risk factors for disease progression to liver cirrhosis and hcc among chc patients.25 moreover, alcohol intake may be associated with other risky behaviours; as such, this factor should be considered a potential target for hcv screening.26 almost half of the patients in the current cohort were first diagnosed with chc based on existing evidence of liver disease, such as elevated liver enzymes, deranged liver function or imaging findings. moreover, this subgroup of patients had a much higher prevalence of cirrhosis and hcc compared to asymptomatic patients who were diagnosed as a result of routine screening. this finding emphasises the importance of early hcv screening and diagnosis in high-risk populations; indeed, this may be especially effective in improving clinical outcomes coupled with the newfound availability of highly effective antiviral regimens.27 nearly a quarter of the chc patients in the present study were infected as a result of intravenous drug abuse; of these, the majority had genotypes 3 and 1. a similarly high prevalence of genotypes 3 and 1 has been reported among intravenous drug users in france and the uae.18,28 blood transfusions were the second most common mode of hcv transmission in the current study, with genotypes 1 followed by 3 being most prevalent among affected individuals. in contrast, shahraki et al. found that genotype 3a (40%) was most prevalent among transfused thalassaemic patients in iran, followed by genotype 1b (25%).29 critically, the findings of the current study indicate that blood transfusion is still a possible risk factor for hcv transmission in oman despite the routine screening of transfused blood. this may be potentially due to the use of serological testing instead of advanced screening techniques such as nucleic acid amplification.30 a history of surgery is another risk factor for hcv infection due to the role that contaminated surgical equipment can play in the transmission of blood-borne figure 3: diagram showing the clinical outcomes* of chronic hepatitis c-infected patients presenting to the sultan qaboos university hospital, muscat, oman (n = 603). hcc = hepatocellular carcinoma; htn = hypertension; hrs = hepatorenal syndrome; sbp = spontaneous bacterial peritonitis. *percentages for some outcomes add up to more than 100% as some patients may have reported multiple outcomes. said a. al-busafi, halima al-shuaili, heba omar, haifa al-zuhaibi, l. jeyaseelan and khalid al-naamani clinical and basic research | e409 diseases. the incidence of surgery-associated hcv infections caused by breaches in infection control practices have been previously reported in the usa.31 in the current study, many of the surgeries reported by chc patients were performed before routine hcv screening was initiated prior to invasive surgeries. in addition, many of the surgeries were carried out abroad; as such, adherence to blood-borne pathogen screening protocols at such institutions was unknown. therefore, public awareness of the importance of presurgical hcv screening should be increased in oman; in addition, local infection control policies and procedures at governmental hospitals should be reviewed to ensure that surgical equipment is adequately disinfected. approximately one-third of the patients in the present study did not report any risk factors for hcv, which is similar to other findings reported in the literature.32 this suggests the presence of other unidentified modes of hcv transmission in oman, such as traditional healers, body piercings, barber shops and professional pedicures/manicures. another important finding was that many hcv-infected patients in the current study also had advanced liver disease, including decompensated cirrhosis and hcc; moreover, many of the hcc cases were beyond the milan transplantation criteria.14 this prevalence of advanced hcv-related complications upon presentation is high in comparison to other research.27 further studies are therefore needed to assess risk factors for cirrhosis and hcv-related outcomes among omani patients. the current study also showed a low rate of liver transplantation amongst chc-infected patients with decompensated cirrhosis. since oman does not have a liver transplant service, candidates are usually sent abroad for the procedure as long as they can find a willing and compatible living adult donor. the generalisability of the results of the current study was limited by the retrospective nature of the study and the fact that participants were selected from a single tertiary health care facility. conclusion in the current study, major risk factors for hcv transmission included intravenous drug abuse and blood transfusions, with genotypes 1 and 3 being most frequent. moreover, patients diagnosed with chc via routine screening had lower morbidity compared to patients who were only diagnosed as a result of existing signs of liver disease. therefore, the implementation of national policies to prevent hcv transmission and encourage the early screening of at-risk individuals and prompt management of hcv cases is highly recommended. in addition, more studies are needed to understand the prevalence of and risk factors for poor hcv-related outcomes in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. petruzziello a, marigliano s, loquercio g, cozzolino a, cacciapuoti c. global epidemiology of hepatitis c virus infection: an up-date of the distribution and circulation of hepatitis c virus genotypes. world j gastroenterol 2016; 22:7824–40. doi: 10.3748/wjg.v22.i34.7824. 2. alberti a, chemello l, benvegnù l. natural history of hepatitis c. j hepatol 1999; 31:17–24. doi: 10.1016/s01688278(99)80369-9. 3. kanwal f, hoang t, kramer jr, asch sm, goetz mb, zeringue a, et al. increasing prevalence of hcc and cirrhosis in patients with chronic hepatitis c virus infection. gastroenterology 2011; 140:1182–8. doi: 10.1053/j.gastro.2010. 12.032. 4. bandiera s, billie bian c, hoshida y, baumert tf, zeisel mb. chronic hepatitis c virus infection and pathogenesis of hepatocellular carcinoma. curr opin virol 2016; 20:99–105. doi: 10.1016/j.coviro.2016.09.010. 5. coffin po, reynolds a. ending hepatitis c in the united states: the role of screening. hepat med 2014; 6:79–87. doi: 10.2147/ hmer.s40940. 6. denniston mm, jiles rb, drobeniuc j, klevens rm, ward jw, mcquillan gm, et al. chronic hepatitis c virus infection in the united states, national health and nutrition examination survey 2003 to 2010. ann intern med 2014; 160:293–300. doi: 10.7326/m13-1133. 7. talaat n, yapali s, fontana rj, conjeevaram hs, lok as. changes in characteristics of hepatitis c patients seen in a liver centre in the united states during the last decade. j viral hepat 2015; 22:481–8. doi: 10.1111/jvh.12343. 8. sulkowski ms, thomas dl. hepatitis c in the hiv-infected person. ann intern med 2003; 138:197–207. doi: 10.7326/00034819-138-3-200302040-00012. 9. verucchi g, calza l, manfredi r, chiodo f. human immunodeficiency virus and hepatitis c virus coinfection: epidemiology, natural history, therapeutic options and clinical management. infection 2004; 32:33–46. doi: 10.1007/s15010004-3063-7. 10. elgouhari hm, zein co, hanouneh i, feldstein ae, zein nn. diabetes mellitus is associated with impaired response to antiviral therapy in chronic hepatitis c infection. dig dis sci 2009; 54:2699–705. doi: 10.1007/s10620-008-0683-2. 11. caccamo g, saffioti f, raimondo g. hepatitis b virus and hepatitis c virus dual infection. world j gastroenterol 2014; 20:14559–67. doi: 10.3748/wjg.v20.i40.14559. 12. al-naamani k, al-zakwani i, al-sinani s, wasim f, daar s. prevalence of hepatitis c among multi-transfused thalassaemic patients in oman: single centre experience. sultan qaboos univ med j 2015; 15:e46–51. 13. al-dhahry sh, aghanashinikar pn, al-hasani mk, buhl mr, daar as. antibodies to hepatitis c virus in omani patients with renal disease. transplant proc 1992; 24:1938–9. https://doi.org/10.3748/wjg.v22.i34.7824 https://doi.org/10.1016/s0168-8278%2899%2980369-9 https://doi.org/10.1016/s0168-8278%2899%2980369-9 https://doi.org/10.1053/j.gastro.2010.12.032 https://doi.org/10.1053/j.gastro.2010.12.032 https://doi.org/10.1016/j.coviro.2016.09.010 https://doi.org/10.2147/hmer.s40940 https://doi.org/10.2147/hmer.s40940 https://doi.org/10.7326/m13-1133 https://doi.org/10.1111/jvh.12343 https://doi.org/10.7326/0003-4819-138-3-200302040-00012 https://doi.org/10.7326/0003-4819-138-3-200302040-00012 https://doi.org/10.1007/s15010-004-3063-7 https://doi.org/10.1007/s15010-004-3063-7 https://doi.org/10.1007/s10620-008-0683-2 https://doi.org/10.3748/wjg.v20.i40.14559 epidemiology of chronic hepatitis c infections at a tertiary care centre in oman e410 | squ medical journal, november 2017, volume 17, issue 4 14. mazzaferro v, regalia e, doci r, andreola s, pulvirenti a, bozzetti f, et al. liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. n engl j med 1996; 334:693–9. doi: 10.1056/nejm199603143341104. 15. liang tj, rehermann b, seeff lb, hoofnagle jh. pathogenesis, natural history, treatment, and prevention of hepatitis c. ann intern med 2000; 132:296–305. doi: 10.7326/0003-4819-132-4200002150-00008. 16. hajarizadeh b, grebely j, dore gj. case definitions for acute hepatitis c virus infection: a systematic review. j hepatol 2012; 57:1349–60. doi: 10.1016/j.jhep.2012.07.007. 17. ruta s, cernescu c. injecting drug use: a vector for the introduction of new hepatitis c virus genotypes. world j gastroenterol 2015; 21:10811–23. doi: 10.3748/wjg.v21.i38. 10811. 18. abro ah, al-dabal l, younis nj. distribution of hepatitis c virus genotypes in dubai, united arab emirates. j pak med assoc 2010; 60:987–90. 19. bozdayi am, aslan n, bozdayi g, türkyilmaz ar, sengezer t, wend u, et al. molecular epidemiology of hepatitis b, c and d viruses in turkish patients. arch virol 2004; 149:2115–29. doi: 10.1007/s00705-004-0363-2. 20. jahanbakhsh sefidi f, keyvani h, monavari sh, alavian sm, fakhim s, bokharaei-salim f. distribution of hepatitis c virus genotypes in iranian chronic infected patients. hepat mon 2013; 13:e7991. doi: 10.5812/hepatmon.7991. 21. ghaderi-zefrehi h, gholami-fesharaki m, sharafi h, sadeghi f, alavian sm. the distribution of hepatitis c virus genotypes in middle eastern countries: a systematic review and meta-analysis. hepat mon 2016; 16:e40357. doi: 10.5812/ hepatmon.40357. 22. shobokshi oa, serebour fe, skakni l, al-saffy yh, ahdal mn. hepatitis c genotypes and subtypes in saudi arabia. j med virol 1999; 58:44–8. doi: 10.1002/(sici)1096-9071(199905)58: 1<44::aid-jmv6>3.0.co;2-u. 23. ohno t, mizokami m, saleh mg, orito e, ohba ki, wu rr, et al. usefulness and limitation of phylogenetic analysis for hepatitis c virus core region: application to isolates from egyptian and yemeni patients. arch virol 1996; 141:1101–13. 24. al-kubaisy wa, al-naib kt, habib m. seroprevalence of hepatitis c virus specific antibodies among iraqi children with thalassaemia. east mediterr health j 2006; 12:204–10. 25. di costanzo gg, de luca m, tritto g, lampasi f, addario l, lanza ag, et al. effect of alcohol, cigarette smoking, and diabetes on occurrence of hepatocellular carcinoma in patients with transfusion-acquired hepatitis c virus infection who develop cirrhosis. eur j gastroenterol hepatol 2008; 20:674–9. doi: 10.1097/meg.0b013e3282f762e1. 26. abdo aa, sanai fm, al-faleh fz. epidemiology of viral hepatitis in saudi arabia: are we off the hook? saudi j gastroenterol 2012; 18:349–57. doi: 10.4103/1319-3767.103425. 27. konerman ma, yapali s, lok as. systematic review: identifying patients with chronic hepatitis c in need of early treatment and intensive monitoring predictors and predictive models of disease progression. aliment pharmacol ther 2014; 40:863–79. doi: 10.1111/apt.12921. 28. pawlotsky jm, tsakiris l, roudot-thoraval f, pellet c, stuyver l, duval j, et al. relationship between hepatitis c virus genotypes and sources of infection in patients with chronic hepatitis c. j infect dis 1995; 171:1607–10. doi: 10.1093/infdis/171.6.1607. 29. shahraki t, shahraki m, moghaddam es, najafi m, bahari a. determination of hepatitis c genotypes and the viral titer distribution in children and adolescents with major thalassemia. iranian j pediatr 2010; 20:75–81. 30. marwaha n, sachdev s. current testing strategies for hepatitis c virus infection in blood donors and the way forward. world j gastroenterol 2014; 20:2948–54. doi: 10.3748/wjg.v20.i11.2948. 31. perz jf, grytdal s, beck s, fireteanu am, poissant t, rizzo e, et al. case-control study of hepatitis b and hepatitis c in older adults: do healthcare exposures contribute to burden of new infections? hepatology 2013; 57:917–24. doi: 10.1002/ hep.25688. 32. karmochkine m, carrat f, dos santos o, cacoub p, raguin g. a case-control study of risk factors for hepatitis c infection in patients with unexplained routes of infection. j viral hepat 2006; 13:775–82. doi: 10.1111/j.1365-2893.2006.00742.x. https://doi.org/10.1056/nejm199603143341104 https://doi.org/10.7326/0003-4819-132-4-200002150-00008 https://doi.org/10.7326/0003-4819-132-4-200002150-00008 https://doi.org/10.1016/j.jhep.2012.07.007 https://doi.org/10.3748/wjg.v21.i38.10811 https://doi.org/10.3748/wjg.v21.i38.10811 https://doi.org/10.1007/s00705-004-0363-2 https://doi.org/10.5812/hepatmon.7991 https://doi.org/10.5812/hepatmon.40357 https://doi.org/10.5812/hepatmon.40357 https://doi.org/10.1002/%28sici%291096-9071%28199905%2958:1%3c44::aid-jmv6%3e3.0.co%3b2-u https://doi.org/10.1002/%28sici%291096-9071%28199905%2958:1%3c44::aid-jmv6%3e3.0.co%3b2-u https://doi.org/10.1097/meg.0b013e3282f762e1 https://doi.org/10.4103/1319-3767.103425 https://doi.org/10.1111/apt.12921 https://doi.org/10.1093/infdis/171.6.1607 https://doi.org/10.3748/wjg.v20.i11.2948 https://doi.org/10.1002/hep.25688 https://doi.org/10.1002/hep.25688 https://doi.org/10.1111/j.1365-2893.2006.00742.x dengue fever (df) is a potentially life-threatening vector-borne tropical disease caused by a single-stranded positive-sense ribonucleic acid virus belonging to the flaviviridae family. outbreaks have increased in severity over the past few years, especially in developing countries in south asia.1,2 the world health organization (who) estimates that approximately 2.5 billion individuals are susceptible to df and a 100 million are infected every year.3 while df is a self-limiting illness in the majority of patients, about 0.5% of patients develop a complicated course requiring specialised therapy.3 a total of 20,000 deaths are reported annually worldwide due to complications associated with severe df.3 according to the who eastern mediterranean regional office, there have been 16,580 confirmed cases of df and 257 deaths due to the disease in pakistan alone since 2010.4 there have been several preventable df deaths in pakistan, such as those in the dengue outbreak of 2011.5 as such, optimal management and treatment of df and dengue shock syndrome presents a challenge for healthcare professionals. involvement of the cardiovascular system (cvs) with decreased cardiac indices and performance has been observed among patients with this disease.6 in addition, other cardiac abnormalities, such as supraventricular tachycardia and atrioventricular conduction defects, have also been noted.1 although isolated myocarditis has previously been reported in association with the disease, it is still rare.6 this case report presents a child with worsening df signs and symptoms associated with myocarditis. management with fluid therapy and inotropic support resulted in a favourable outcome. the patient eventually had a spontaneous recovery and normalisation of ejection fraction (ef) and cardiac parameters. 1medical college and 2department of pediatrics & child health, aga khan university, karachi, pakistan *corresponding author e-mail: faizanzahid91@hotmail.com جتلي غري معتاد حلمي الدنك حالة طفل مصاب بالتهاب عضل القلب معاذ اأ�شلم، منرة عبد العليم، حممد فيزان زاهد، اأر�شلوز جميلة رحمن abstract: dengue fever (df) is an acute febrile illness that follows a self-limiting course. however, some patients suffer from complications, including myocarditis, due to the involvement of other organs. a child presented at the aga khan university hospital in karachi, pakistan, in june 2013 with a high-grade fever, malaise and epigastric pain radiating to the chest. positive df antigen and immunoglobulin m assays confirmed the diagnosis of df. persistent bradycardia with low blood pressure led to further cardiac investigations which showed a decreased ejection fraction and raised serum cardiac enzymes, indicating myocardial damage. with supportive care and use of inotropes, the spontaneous normalisation of cardiac enzyme levels and ejection fraction was observed. the child was discharged five days after admission. this case highlights the importance of identifying myocarditis in df patients suffering from cardiac symptoms that are not explained by other potential aetiologies. awareness, early suspicion and supportive care are essential to ensure favourable outcomes. keywords: dengue fever; myocarditis; complications; child; case report; pakistan. امللخ�ص: حّمى الدنك علة حّمىح�دة حمددة ذاتي�. غري اأن بع�ص املر�شى به� قد يع�نون من م�ش�عف�ت ت�شيب اأع�ش�ء اأخرى مثل الته�ب ع�شلة القلب. مت ت�شجيل ح�لة طفل يف م�شت�شفى اأغ� خ�ن يف ب�ك�شت�ن يف يونيو 2013م م�ش�ب بحمى مرتفعة وتوعك وفتور واأمل فوق مع املزمن القلب بطء الدنك. حمى ت�شخي�ص m املن�عي والغلوبولني الدنك حمى مل�شت�شد االإيج�بية واأكدت�لنت�ئج لل�شدر. ميتد املعدة انخف��ص �شغط الدم ا�شتدعت ملزيد من التح�ليل، ووجد اأن هن�لك نق�ص يف الك�رض القذيف وارتف�ع ن�ش�ط انزمي�ت القلب، مم� يدل على �رضر بع�شل القلب. ومت عن طريق العالج الداعم وا�شتخدام االأدوية املقوية للتقل�ص الع�شلي اإع�دة ن�ش�ط انزمي�ت القلب والك�رض القذيف اإىل املعدل الطبيعي. ومت تخريج املري�ص من امل�شت�شفى بعد خم�شة اأي�م بعد دخوله اإليه�. وت�شري هذه احل�لة الأهمية التعرف على الته�ب الع�شل عند امل�ش�بني بحمى الدنك الذين يع�نون من اأعرا�ص قلبية ال ميكن تف�شريه� اأو عزوه� الأ�شب�ب حمتملة اأخرى. ويعتمد احل�شول على اأف�شل النت�ئج على الوعي، وال�شك الب�كر والعالج الداعم. مفتاح الكلمات: حمى الدنك؛ الته�ب ع�شل القلب؛ امل�ش�عف�ت؛ طفل؛ ت�شجيل ح�لة؛ الب�ك�شت�ن. unusual presentation of dengue fever a child with acute myocarditis moaz aslam,1 numra a. aleem,1 *mohammad f. zahid,1 arshalooz j. rahman2 sultan qaboos university med j, february 2016, vol. 16, iss. 1, pp. e101–104, epub. 2 feb 16 submitted 16 may 15 revisions req. 15 jul & 24 aug 15; revisions recd. 11 aug & 24 aug 15 accepted 2 sep 15 doi: 10.18295/squmj.2016.16.01.019 case report unusual presentation of dengue fever a child with acute myocarditis e102 | squ medical journal, february 2016, volume 16, issue 1 case report a 12-year-old girl presented to the emergency department of the aga khan university hospital, karachi, pakistan, in june 2013 with a five-day history of high-grade fever associated with lethargy, fatigue, malaise and vomiting. she also complained of palpitations and persistent epigastric pain radiat ing to the chest. her past medical history was unremarkable, revealing a developmentally normal child with up-to-date immunisations and no history of significant medical illnesses, hospitalisation or congenital abnormalities. on general physical examination, the child was irritable and had a temperature of 38.9 ºc. she was tachypnoeic with a respiratory rate of 30 breaths per minute; otherwise, the remainder of her respiratory examination was normal. a cardiovascular and precordium assessment revealed no audible murmurs or other cardiac abnormalities. bradycardia (minimum of 50 beats per minute [bpm]) accompanied by intermittent tachycardia (maximum of 112 bpm) and low blood pressure (90/65 mmhg) were noted. the heart monitor showed a sinus rhythm during both bradycardia and tachycardia. the patient did not have a rash and her systemic examination was unremarkable. a complete blood count showed leukopenia (white cell count: 3.2 x 109/l) and thrombocytopaenia (platelet count: 106 x 109/l). the patient’s electrolytes were within normal limits; however, her erythrocyte sedimentation rate was raised (42 mm/hour). the patient was admitted to the inpatient ward and prescribed intravenous fluid replacement with paracetamol to relieve the fever. empiric intravenous ceftriaxone was started for a possible enteric fever. further work-up revealed normal serum amylase levels (52 u/l), making pancreatitis unlikely. a typhidot test and peripheral smear for malarial parasites were both negative. liver function tests showed elevated alanine aminotransferase and aspartate aminotransferase levels of 49 u/l and 153 u/l, respectively. the patient’s symptoms and a reverse ratio of liver function tests suggested a viral fever as a likely possibility. the platelia dengue ns1 antigen (bio-rad laboratories inc., california, usa) and immunoglobulin m (igm) assays came back positive, which established the diagnosis of df. ceftriaxone was discontinued and serial platelet counts continued to show a persistent decline with a minimum count of 25 x 109/l during the following 48 hours. subsequently, the patient defervesced and her lethargy improved; however, her bradycardia continued (range: 45–50 bpm) with low blood pressure (95/65 mmhg). prolonged causes of bradycardia and hypotension were explored with a 12-lead electrocardiography with postural changes. the findings demonstrated a prolonged r-r interval with no changes in the p-r and q-t intervals, s-t segment or q-r-s abnormalities, indicating sinus bradycardia. a bedside echocardiogram showed global hypokinesia and a decreased ef of 52%. there was no evidence of pericarditis or pericardial effusion. a creatine phosphokinase-mb test was elevated (455 iu/l). a clinical diagnosis of myocarditis, most likely due to the dengue virus, was made. although a myocardial biopsy was advised to establish the diagnosis, the procedure was not performed due to the financial constraints of the patient’s family. the patient was prescribed inotropic support with dopamine to improve her cardiac output and maintain normal blood pressure. management was focused on the symptomatic treatment of df with serial monitoring of platelet counts. on the fourth day of hospital admission, the patient’s platelet count, heart rate and blood pressure had stabilised at 56 x 109/l, 55–65 bpm and 115/78 mmhg, respectively. a limited follow-up echocardiographic assessment was performed which showed ef normalisation at 62%. she was kept under observation for the following 24 hours. the patient was discharged from the hospital after being prescribed paracetamol and omeprazole with instructions to attend weekly followup appointments as an outpatient. discussion dengue is a non-specific febrile illness, presenting most commonly as either df or the more severe dengue shock syndrome.1,7 heart involvement and cardiac abnormalities in association with df have previously been reported in the literature, although they are rare complications.1,8–11 the clinical manifestations of heart involvement in df greatly differ—patients can be completely asymptomatic, have very mild symptomatology or can suffer from severe myocardial damage leading to ventricular failure, global hypokinesia and cardiogenic shock.3,12–15 the incidence of cardiac involvement greatly varies. following the dengue outbreak of 1996 in india, agarwal et al. reported that only one of 206 patients infected with df showed evidence of cardiac involvement upon cvs examination.16 in a more recent outbreak of df in india, 9% of patients showed evidence of myocarditis during the course of their illness.17 during a df outbreak in southern taiwan in 2006, only one of 107 patients with df had a course complicated by acute myocarditis.1 similarly, kabra et al. reported cardiac involvement in 16.7% of 54 paediatric df patients.9 in contrast, other studies have moaz aslam, numra a. aleem, mohammad f. zahid and arshalooz j. rahman case report | e103 associated with other viral illnesses.22 direct damage by the virus may be another mechanism of injury, as is seen in myocarditis caused by other viruses.3 in the present case, based on the unremarkable medical history and up-to-date immunisations, it was concluded that the dengue virus was the most likely cause of the myocarditis. unfortunately, due to the lack of a biopsy and histopathological examination of the cardiac tissue, the complete characterisation of dengue myocarditis was not possible. another aspect to be explored is the genetic susceptibility to developing specific symptoms of dengue infections in local populations, due to different leukocyte antigens and single nucleotide polymorphisms. the effect of myocarditis is not only limited to the mechanical functioning of the heart but may also involve electrical conduction. cardiac rhythm abnormalities have been observed in cases of dengue myocarditis. these include but are not limited to atrial fibrillation, s-t segment abnormalities, low q-r-s amplitude, sinus bradycardia, first-degree atrioventricular block, premature atrial contractions and premature ventricular contractions.8,23 such conduction defects, which are asymptomatic and selflimiting in the vast majority of patients, can potentially evolve into fatal cardiac arrhythmias.8 hypotension and decreased cardiac function during the course of df could be attributable to capillary leakage and intravascular volume depletion, leading to haemodynamic instability in these patients.18 the latter seemed to be unlikely in the current patient, given the fact that she had persistent hypotension which was non-responsive to fluid resuscitation and required inotropic support with dopamine to maintain adequate blood pressure. in such cases, fluid management may need to be reassessed if haemodynamic stability is not achieved with conservative management and fluid resuscitation to avoid volume overload and prolonged tissue hypoperfusion. children require very specific volumes for fluid resuscitation/therapy and are prone to volume overload states such as pulmonary oedema or superimposed infections.3,11 in such circumstances it is necessary to heighten the index of suspicion by reporting to physicians cases with myocarditis as an underlying cause, allowing them to change their approach rather than pursuing vigorous fluid therapy which might be detrimental to the child.3,11 steroids may arguably act as adjuvants to standard therapy due to their anti-inflammatory properties; nevertheless, their role and efficacy has not been established due to a lack of evidence.7 the role of cardiac imaging, especially cardiac magnetic resonance imaging, also needs to be assessed in conjunction with electrocardiographical shown a staggering incidence of cardiac involvement in cases of dengue. wali et al. reported the incidence of cardiac involvement to be 70% in a series of 17 patients.11 in addition, following the dengue outbreak of sri lanka in 2005, cardiac dysfunction was reported to be the dominant abnormality (80%) among patients.6 this disparity in the proportion of cardiac abnormalities likely arises due to the fact that df is a spectrum disease which can present with atypical manifestations, haemorrhagic fever or shock syndrome. while tachycardia and a transient decline in cardiac function may vary in intensity, they are present across the spectrum.18 it is important to differentiate tachycardia due to myocardial involvement; reported incidences of 70–80% may be overestimations.6,11 the majority of the patients in the aforementioned studies exhibited diminished cardiac performance, hypotension and reduced ef; however, some did show electrocardiographical changes.6 several other viruses may give rise to myocarditis.3,19,20 although, the possibility of such viruses was not objectively excluded in the present case, other disease processes responsible for high-grade fever and her initial symptoms— particularly enteric fever and malaria—were ruled out. hence the temporal relationship with the febrile illness, positive igm and dengue ns1 antigen tests and the presence of leukopenia with thrombocytopaenia confirmed the dengue virus to be the most likely aetiological agent. recently, isolated df cases with cardiac involvement have been reported. guadalajara-boo et al. reported a 65-year-old woman who developed severe hypotension and circulatory collapse due to dengue myocarditis.14 she required mechanical ventilation and inotropic support with noradrenaline. additional therapy with methylprednisolone and ribavirin resulted in the resolution of the cardiac manifestations and a favourable outcome.14 however, fatal outcomes have also been reported. miranda et al. reported a 37-year-old woman with df who developed fulminant cardiopulmonary failure.3 despite treatment with mechanical ventilation, vasoactive drugs and inotropic support with dopamine and noradrenaline, the patient died of cardiogenic shock.3 immune response to the viral infection and the resulting cascade of inflammatory mediators, such as tumour necrosis factor, chemokines and inflammatory cells, plays a key role in myocardial damage.8,21 in vitro research indicates that the dengue virus raises intracellular calcium in the myocardium, leading to the opening of mitochondrial membrane pores and activation of the intrinsic apoptotic pathway.22 this may be one of the mechanisms that leads to myocardial injury in df patients and myocarditis unusual presentation of dengue fever a child with acute myocarditis e104 | squ medical journal, february 2016, volume 16, issue 1 findings for an effective evaluation, diagnosis and follow-up of such patients.19 this is a potential topic of future research so that the management of such rare manifestations can be systematised, providing a viable algorithm to avoid preventable deaths, particularly among children. cardiac imaging was not performed on the current patient due to financial constraints. conclusion the dengue virus is capable of involving multiple organ systems simultaneously or in isolation. atypical manifestations, such as myocarditis and cardiac dysrhythmias are usually mild or even asymptomatic but can have serious implications on patient outcomes. this case highlights the necessity of awareness, early suspicion and supportive care in achieving a positive outcome for such patients. the role of cardiac imaging needs to be assessed in conjunction with electrocardiographical findings for a clearer evaluation of such cases. references 1. lee ik, lee wh, liu jw, yang kd. acute myocarditis in dengue hemorrhagic fever: a case report and review of cardiac complications in dengue-affected patients. int j infect dis 2010; 14:e919–22. doi: 10.1016/j.ijid.2010.06.011. 2. murray ne, quam mb, wilder-smith a. epidemiology of dengue: past, present and future prospects. clin epidemiol 2013; 5:299–309. doi: 10.2147/clep.s34440. 3. miranda ch, borges mde c, schmidt a, pazin-filho a, rossi ma, ramos sg, et al. a case presentation of a fatal dengue myocarditis showing evidence for dengue virus-induced lesion. eur heart j acute cardiovasc care 2013; 2:127–30. doi: 10.11 77/2048872613475889. 4. world health organization eastern mediterranean regional office. dengue fever: pakistan. from: www.emro.who.int/pak/ programmes/dengue-fever.html accessed: sep 2015 5. rasheed sb, butlin rk, boots m. a review of dengue as an emerging disease in pakistan. public health 2013; 127:11–17. doi: 10.1016/j.puhe.2012.09.006. 6. kularatne sa, pathirage mm, kumarasiri pv, gunasena s, mahindawanse si. cardiac complications of a dengue fever outbreak in sri lanka, 2005. trans r soc trop med hyg 2007; 101:804–8. doi: 10.1016/j.trstmh.2007.02.021. 7. simmons cp, farrar jj, nguyen vv, wills b. dengue. n engl j med 2012; 366:1423–32. doi: 10.1056/nejmra1110265. 8. gulati s, maheshwari a. atypical manifestations of dengue. trop med int health 2007; 12:1087–95. doi: 10.1111/j.13653156.2007.01891.x. 9. kabra sk, jain y, pandey rm, madhulika, singhal t, tripathi p, et al. dengue haemorrhagic fever in children in the 1996 delhi epidemic. trans r soc trop med hyg 1999; 93:294–8. doi: 10.1016/s0035-9203(99)90027-5. 10. waduge r, malavige gn, pradeepan m, wijeyaratne cn, fernando s, seneviratne sl. dengue infections during pregnancy: a case series from sri lanka and review of the literature. j clin virol 2006; 37:27–33. doi: 10.1016/j.jcv.2006.06.002. 11. wali jp, biswas a, chandra s, malhotra a, aggarwal p, handa r, et al. cardiac involvement in dengue haemorrhagic fever. int j cardiol 1998; 64:31–6. doi: 10.1016/s0167-5273 (98)00008-4. 12. lateef a, fisher da, tambyah pa. dengue and relative bradycardia. emerg infect dis 2007; 13:650–1. doi: 10.3201/ eid1304.061212. 13. satarasinghe rl, arultnithy k, amerasena nl, bulugahapitiya u, sahayam dv. asymptomatic myocardial involvement in acute dengue virus infection in a cohort of adult sri lankans admitted to a tertiary referral centre. br j cardiol 2007; 14:171–3. 14. guadalajara-boo jf, ruiz-esparza me, aranda frausto a, soto abraham mv, gaspar-hernández j. histologic and angio graphic imaging of acute shock dengue myocarditis. rev esp cardiol (engl ed) 2014; 67:226–7. doi: 10.1016/j.rec.2013. 09.009. 15. lee ch, teo c, low af. fulminant dengue myocarditis masquerading as acute myocardial infarction. int j cardiol 2009; 136:e69–71. doi: 10.1016/j.ijcard.2008.05.023. 16. agarwal r, kapoor s, nagar r, misra a, tandon r, mathur a, et al. a clinical study of the patients with dengue hemorrhagic fever during the epidemic of 1996 at lucknow, india. southeast asian j trop med public health 1999; 30:735–40. 17. neeraja m, iakshmi v, teja vd, lavanya v, priyanka en, subhada k, et al. unusual and rare manifestations of dengue during a dengue outbreak in a tertiary care hospital in south india. arch virol 2014; 159:1567–73. doi: 10.1007/s00705-0142010-x. 18. yacoub s, wertheim h, simmons cp, screaton g, wills b. cardiovascular manifestations of the emerging dengue pandemic. nat rev cardiol 2014; 11:335–45. doi: 10.1038/ nrcardio.2014.40. 19. olimulder m, van es j, galjee ma. the importance of cardiac mri as a diagnostic tool in viral myocarditis-induced cardiomyopathy. neth heart j 2009; 17:481–6. doi: 10.1007/ bf03086308. 20. bengtsson e, örndahl g. complications of mumps with special reference to the incidence of myocarditis. acta med scand 1954; 149:381–8. doi: 10.1111/j.0954-6820.1954.tb11449.x. 21. shah i. dengue presenting as viral myocarditis. dengue bull 2007; 31:172–3. 22. szalai g, krishnamurthy r, hajnóczky g. apoptosis driven by ip(3)-linked mitochondrial calcium signals. embo j 1999; 18:6349–61. doi: 10.1093/emboj/18.22.6349. 23. khongphatthallayothin a, chotivitayatarakorn p, somchit s, mitprasart a, sakolsattayadorn s, thisyakorn c. morbitz type i second degree av block during recovery from dengue hemorrhagic fever. southeast asian j trop med public health 2000; 31:642–5. http://dx.doi.org/10.1016/j.ijid.2010.06.011 http://dx.doi.org/10.2147/clep.s34440 http://dx.doi.org/10.1177/2048872613475889 http://dx.doi.org/10.1177/2048872613475889 http://dx.doi.org/10.1016/j.puhe.2012.09.006 http://dx.doi.org/10.1016/j.trstmh.2007.02.021 http://dx.doi.org/10.1056/nejmra1110265 http://dx.doi.org/10.1111/j.1365-3156.2007.01891.x http://dx.doi.org/10.1111/j.1365-3156.2007.01891.x http://dx.doi.org/10.1016/s0035-9203%2899%2990027-5 http://dx.doi.org/10.1016/j.jcv.2006.06.002 http://dx.doi.org/10.1016/s0167-5273%2898%2900008-4 http://dx.doi.org/10.1016/s0167-5273%2898%2900008-4 http://dx.doi.org/10.3201/eid1304.061212 http://dx.doi.org/10.3201/eid1304.061212 http://dx.doi.org/10.1016/j.rec.2013.09.009 http://dx.doi.org/10.1016/j.rec.2013.09.009 http://dx.doi.org/10.1016/j.ijcard.2008.05.023 http://dx.doi.org/10.1007/s00705-014-2010-x http://dx.doi.org/10.1007/s00705-014-2010-x http://dx.doi.org/10.1038/nrcardio.2014.40 http://dx.doi.org/10.1038/nrcardio.2014.40 http://dx.doi.org/10.1007/bf03086308 http://dx.doi.org/10.1007/bf03086308 http://dx.doi.org/10.1111/j.0954-6820.1954.tb11449.x http://dx.doi.org/10.1093/emboj/18.22.6349 1department of ear, nose & throat, imam abdulrahman bin faisal university, khobar, saudi arabia; 2department of ear, nose & throat, king fahd university hospital, khobar, saudi arabia; 3department of ear, nose & throat, king abdullah medical city, makkah, saudi arabia; 4royal college of surgeons in ireland, dublin, ireland *corresponding author’s e-mail: dr.rawan212@gmail.com العالقة بني مؤشر اإلعاقة الصوتية ومؤشر أعراض االرجتاع حبث استبياين لعامة الناس واملعلمني غري املشخصني باملرض يف اململكة العربية السعودية روان العنزي، احمد الرحّيم، �شاره بايون�ص، عبدالرحمن الغوينم، حممد البار abstract: objectives: this study aimed to assess potential associations between self-reported symptoms of laryngo pharyngeal reflux (lpr) and voice disorders among two undiagnosed cohorts in saudi arabia. methods: this crosssectional study was conducted from february to april 2017 in khobar, saudi arabia. validated arabic versions of the reflux symptom index (rsi) and 10-item voice handicap index (vhi-10) were distributed to 400 teachers at 13 schools and 300 members of the general population attending an ear, nose and throat clinic in khobar. scores of >13 and >11 on the rsi and vhi-10 indicated a potential subjective diagnosis of lpr and voice disorders, respectively. results: a total of 446 individuals took part in the study, including 260 members of the general population (response rate: 86.7%) and 186 teachers (response rate: 46.5%). the mean age was 32.5 years. in total, 62.2% complained of voice and/or reflux problems, with the remaining 37.8% not reporting/unaware of any problems in this regard. among the teachers, 30.6% and 18.3% had positive rsi and vhi-10 scores, respectively, while 43.1% and 14.6% of the individuals from the general population had positive rsi and vhi-10 scores, respectively. overall, vhi-10 scores were significantly associated with rsi scores (p <0.001). conclusion: a significant association between rsi and vhi-10 scores suggests that there may be an association between lpr and voice disorders. these tools would therefore be a valuable method of monitoring patients; however, they cannot be used to confirm a diagnosis. thus, more detailed studies are needed to confirm this association using a larger sample size. keywords: voice disorders; laryngopharyngeal reflux; hoarseness; diagnostic self evaluation; school teachers; saudi arabia. امل�شاحبة ال�شوتية والتغريات احلنجري البلعومي الرجتاع اأعرا�ص بني املحتملة العالقة لتقيم الدرا�شة هذه تهدف الهدف: امللخ�ص: البحث هذا عمل مت الطريقة: ال�شعودية. العربية باململكة امل�شخ�شة غري واملدر�شني النا�ص عامة بني من امل�شخ�شني غري للمر�شى لها ال�شتبياين ما بني �شهر فرباير اإىل �شهر اأبريل 2017 يف مدينة اخلرب، باململكة العربية ال�شعودية. ومت توزيع الن�شخة العربية ملوؤ�رس اعرا�ص الرجتاع وموؤ�رس الإعاقة ال�شوتية على 400 مدر�ص يف 13 مدر�شة خمتلفة و 300 ن�شخة مت توزيعها على عامة النا�ص يف عيادات الأنف والأذن واحلنجرة يف مدينة اخلرب يف م�شت�شفى امللك فهد اجلامعي، واإذا كانت النتيجة اأكرث من 13 واأكرث من 11 يف موؤ�رس اعرا�ص الرجتاع وموؤ�رس الإعاقة ال�شوتية على التوايل اأن هناك ت�شخي�شا حمتمال لالرجتاع البلعومي احلنجري والتغريات ال�شوتية امل�شاحبة لها. النتائج: كان اجمايل امل�شاركني يف البحث 446 �شخ�شا �شاركوا معنا، 260 �شخ�شا من عامة النا�ص )معدل ال�شتجابة: %86.7( و 186 مدر�شا )معدل ال�شتجابة: %46.5(. وكان متو�شط العمر 32.5 عاما. املجموع الكلي لأعرا�ص الرجتاع البلعومي احلنجري املبلغ عنها من املري�ص نف�شه وعنده دراية عنها والتغريات ال�شوتية هي %62.2، بينما %37.8 مل يبلغ عن هذه الأعرا�ص لو مل يكن مدركا لوجودها. بني املدر�شني كان هناك %30.6 و %18.3 لديهم موؤ�رس اعرا�ص الرجتاع و موؤ�رس الإعاقة ال�شوتية اإيجابي، على التوايل، بينما كان لدى %43.1 و 14.6% من عامة النا�ص موؤ�رس اعرا�ص الرجتاع و موؤ�رس الإعاقة ال�شوتية اإيجابي، على التوايل. اأثبتت املح�شلة النهائية للبحث اأثبتت اأن هناك عالقة وجود ب�شبب p(. اخلال�صة: >0.001( علمي ب�شكل مرتبطني ال�شوتية الإعاقة موؤ�رس و الرجتاع اعرا�ص موؤ�رس بني وطيدة عالقة وترابط علمي ما بني موؤ�رس اأعرا�ص الرجتاع و موؤ�رس الإعاقة ال�شوتية ن�شتطيع اأن ن�شتنتج اأن هنالك عالقة ما بني الرجتاع البلعومي احلنجري و التغريات ال�شوتية. وبالتايل ميكننا اأن ن�شتخدم هذه املوؤ�رسات يف متابعة املر�شى ونرى مدى حت�شنهم مع العالج، ولكن ل ن�شتطيع ا�شتخدامها كاأداة للت�شخي�ص بحد ذاتها ب�شبب العدد القليل من امل�شاركني يف البحث. لذا نن�شح بعمل درا�شات اأخرى باأعداد اأكرب من امل�شاركني. الكلمات املفتاحية: التغريات ال�شوتية؛ الرجتاع البلعومي احلنجري؛ بحة ال�شوت؛ التقييم الت�شخي�شي الذاتي؛ املعلمون؛ اململكة العربية ال�شعودية. association between voice handicap index and reflux symptom index a cross-sectional study of undiagnosed general and teacher cohorts in saudi arabia *rawan alanazi,1 ahmed alrahim,2 sara bayounos,3 abdulrahman al-ghuwainem,4 mohammad h. al-bar2 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e350–354, epub. 19 dec 18 submitted 9 dec 17 revisions req. 21 dec 17, 30 jan & 19 apr 18; revisions recd. 9 jan, 30 mar & 3 may 18 accepted 10 may 18 advances in knowledge to the best of the authors’ knowledge, no previous study has investigated associations between reflux symptom index (rsi) and 10-item voice handicap index (vhi-10) scores in saudi arabia. this study found a significant association between rsi and vhi-10 scores among two undiagnosed cohorts in saudi arabia. doi: 10.18295/squmj.2018.18.03.014 rawan alanazi, ahmed alrahim, sara bayounos, abdulrahman al-ghuwainem and mohammad h. al-bar clinical and basic research | e351 application to patient care the association between rsi and vhi-10 scores may be useful as a monitoring method in the management of laryngopharyngeal reflux and voice disorders. laryngopharyngeal reflux (lpr) is an inflammatory reaction which causes laryngitis and pharyngitis due to the backflow of gastric acid into the larynx and pharynx, as opposed to gastro esophageal reflux which is restricted to the oesophagus.1,2 although both of these commonly associated diseases are attributed to a loose lower oesophageal sphincter, they are considered different diseases and present with different symptoms.2–5 the most common symptoms of lpr are idiopathic hoarseness, chronic coughing, globus pharyngeus, choking episodes and clearing of the throat.3 previous research has not documented the crude incidence of lpr in the general population.5 currently, the reflux symptom index (rsi) is the only tool available to subjectively assess lpr severity.6 the rsi is a self-administered nine-item questionnaire which has been validated and translated into several languages, including arabic.6,7 up to 50% of patients with voice disorders also have lpr.8 the voice handicap index (vhi) is among the most widely used tools worldwide for the measurement of the physical, functional and emotional aspects of voice disorders.9 the original 30-item vhi (vhi-30) has also been validated and translated into arabic.9,10 franic et al. concluded that the vhi-30 is the best scale to obtain the most relevant clinical information in patients with voice disorders.11 furthermore, the vhi-30 can be used to predict the occurrence of voice disorders in nonsymptomatic high-risk populations, such as smokers and professional voice users.12,13 other scales to assess voice disorders have been found to correlate with the vhi-30.14,15 in 2004, a simplified 10-item version of the vhi (vhi-10) was developed; this version was found to be less time-consuming, easier to administer in a clinical setting and statistically more robust than the full scale.16 belafsky et al. administered the rsi and vhi-30 to 25 patients with lpr.6 after a six-month course of proton pump inhibitors (ppis), both scales were readministered; their findings indicated that those with greater improvement in rsi scores were 11 times more likely to have corresponding improvements in vhi-30 scores.6 other research has also indicated clinically significant improvements in both rsi and vhi scores among lpr patients after treatment, thus confirming the usefulness of these indices for the assessment of voice disorders and lpr-related symptoms.17 wang et al. also noted higher vhi scores among subjects with rsi scores of >13 versus those with scores of <13.18 however, to the best of the authors’ knowledge, no studies have yet been published on this topic in saudi arabia. this study therefore aimed to evaluate the potential assoc iation between self-reported symptoms of voice disorders and lpr using the vhi-10 and rsi, respectively, among two cohorts of undiagnosed members of the general population and teachers in saudi arabia. methods this cross-sectional study was conducted between february and april 2017 in khobar, saudi arabia. an arabic-language questionnaire was compiled by a trained healthcare professional, consisting of a set of standard ised data collection sheets to determine sociodemographic and clinical data (i.e. age, gender, occupation, smoking status, health complaints and allergies) as well as validated arabic versions of the vhi-10 and rsi.7,10 the questionnaires were then randomly distributed to two cohorts. the first cohort consisted of 400 teachers working at 13 public and private schools in khobar. the second constituted 300 members of the general population attending the ear, nose & throat clinic of the king fahd university hospital (kfuh). individuals with a history of laryngology surgery, laryngeal cancer and reflux disease or those with a recent history of ppi use were excluded from the study. as per previous research, rsi scores of >13 and vhi-10 scores of >11 were deemed to indicate lpr-related symptoms and voice disorders, respectively.6,19 data were compiled and analysed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). descriptive statistics such as frequencies and percentages were used to summarise data for the vhi and rsi scores among the teacher and general population cohorts. continuous and categorical variables were analysed using the student’s t-test and chi-squared test, respectively. a multiple linear regression analysis was performed to determine significant risk factors for voice disorders among both cohorts. for all statistical analyses, a p value of <0.050 was considered significant. this study was approved by the kfhu institutional review board (#2016-01-147). all participants gave verbal consent after being informed that their participation in the study was entirely voluntary and that all data would be kept confidential. association between voice handicap index and reflux symptom index a cross-sectional study of undiagnosed general and teacher cohorts in saudi arabia e352 | squ medical journal, august 2018, volume 18, issue 3 results a total of 446 participants took part in the study, including 186 teachers (41.7%; response rate: 46.5%) and 260 members of the general population (58.3%; response rate: 86.7%). in total, there were 222 men (49.8%) and 224 women (50.2%). the mean age was 32.5 years old. the prevalence of smoking was slightly higher among the general population compared to the teachers (11.9% versus 7%). overall, 112 members of the general popul ation (43.1%) and 57 teachers (30.6%) had rsi scores of >13, while 38 members of the general population (14.6%) and 34 teachers (18.3%) had vhi-10 scores of >11, respectively [table 1]. in total, 62.2% of participants complained of voice and/or reflux problems, whereas the remaining 37.8% did not report or were unaware of any issues in this regard. a statistically significant association was found between positive vhi-10 and rsi scores (r = 0.597; p <0.001). a univariate regression analysis indicated that positive rsi and vhi-10 scores were significantly associated among teachers (p <0.001). in the multiple linear regression analysis, smoking was significantly associated with positive vhi-10 scores among members of the general population (β = 2.755; p = 0.027). a subgroup analysis showed that this association was not significant among teachers (β = −2.937; p = 0.259). the adjusted analysis also indicated that positive rsi scores were significantly associated with vhi-10 scores among members of the general population (β = 0.361; p <0.001) [table 2]. according to a pairwise comparison, there were statistically significant differences in mean vhi-10 scores according to smoking status (p <0.001) [table 3]. discussion voice disorders are among the most serious occupational hazards for professional voice users. in particular, teachers have a distinctly higher occurrence of voice dis orders in comparison to individuals in other occupations.20,21 martins et al. showed that the prevalence of dysphonia among teachers varies in different regions (20–80%).22 in a study of teachers in iowa, usa, almost 40% reported having to cut back on their teaching load due to voice problems.23 in contrast, roy et al. found table 1: prevalence of self-reported symptoms and risk factors of laryngopharyngeal reflux and voice disorders* among members of the general population and teachers in khobar, saudi arabia (n = 446) symptom/ risk factor n (%)* teachers (n = 186) members of the general population (n = 260) vhi-10 >11 34 (18.3) 38 (14.6) <11 152 (81.7) 222 (85.4) rsi >13 57 (30.6) 112 (43.1) <13 129 (69.4) 148 (56.9) smoking yes 13 (7) 31 (11.9) no 173 (93) 229 (88.1) allergies yes 35 (18.8) 137 (52.7) no 151 (81.2) 123 (47.3) vhi-10 = 10-item voice handicap index; rsi = reflux symptom index. *self-assessed using validated arabic versions of the rsi and vhi-10, respectively.7,10 table 2: multiple linear regression analysis for risk factors of voice disorders* among members of the general population and teachers in khobar, saudi arabia (n = 446) risk factor unadjusted adjusted β p value β p value teachers smoking status −2.937 0.259 allergies 0.064 0.967 rsi score† 0.514 <0.001 members of the general population smoking status 3.795 0.009 2.755 0.027 allergies 0.505 0.610 rsi score† 0.376 <0.001 0.361 <0.001 rsi = reflux symptom index. *as per scores of >11 on a self-assessed validated arabic version of the 10 item voice handicap index.10 †self-assessed using a validated arabic version of the rsi.7 table 3: pairwise comparison of self-reported symptoms of laryngopharyngeal reflux and voice disorders* among members of the general population and teachers in khobar, saudi arabia (n = 446) index mean score ± sd p value† teachers (n = 186) members of the general population (n = 260) nonsmokers (n = 173) smokers (n = 13) nonsmokers (n = 229) smokers (n = 31) rsi 11.6 ± 9.6 10.5 ± 8.6 11.5 ± 10.3 14.4 ± 12.5 0.705 vhi-10 7.5 ± 8.1 4.6 ± 5.6 5.0 ± 6.7 8.7 ± 10.9 <0.001 sd = standard deviation; rsi = reflux symptom index; vhi-10 = 10-item voice handicap index. *self-assessed using validated arabic versions of the rsi and vhi-10, respectively.7,10 †using the kruskal-wallis test. rawan alanazi, ahmed alrahim, sara bayounos, abdulrahman al-ghuwainem and mohammad h. al-bar clinical and basic research | e353 that nearly 30% of a general adult population in iowa and utah, usa, developed a voice disorder during their lifetime, with 7% already suffering from a voice disorder.24 a combination of personal, behavioural and environmental factors may lead to an increased risk of voice disorders in teachers.24,25 identifying and treating voice disorders at an early stage will improve patient outcomes and quality of life in this population.21,26 the pathophysiology of voice disorders in lpr remains unknown, although a recent systematic review suggested that the disease alters the mucosa at the vibr atory margin of the vocal folds due to exposure to acid and pepsin.27 these changes may be related to epithelial cell dehiscence, microtrauma, inflammatory infiltrates, reinke’s space dryness, mucosal drying and epithelial thickening. however, due to the microscopic nature of such changes, many patients with lpr may not be diagnosed using conventional techniques, such as video laryngostroboscopy.27 a recent study conducted in saudi arabia showed that almost 58% of teachers had symptoms of acid reflux.28 in a study of 119 singers, 70 teachers and 111 control subjects, hočevar-boltežar et al. observed that subjective reports of lpr was more common among the singers and teachers.29 another study indicated that lpr were frequent among teachers with dysphonia.30 however, in the current study, there was a similar percentage of subjects with rsi scores of >13 in both the general population and teacher cohorts. according to two studies, lpr was prevalent in 55–79% of patients with hoarseness persisting for more than three months; associations were also observed between rsi and vhi scores.31,32 in comparison to 2,643 volunteers, wang et al. found that 127 patients with dysphonia had greater lpr-related morbidity based on their rsi, reflux finding score (rfs), vhi and short form health survey-36 scores, a physical exam ination and 24-hour ambulatory double ph monitoring.18 in the current study, there was a statistically significant association between rsi and vhi-10 scores in two undiagnosed populations. in addition, there was a strong association with smoking status among members of the general population, although not teachers. this may be because there were fewer smokers among the teachers compared to the general population. limitations of the present study include the subj ective self-reported nature of the assessment tools and the lack of objective clinical and endoscopic evaluations of the larynx and head and neck region to confirm the diagnosis of lpr and voice disorders. for example, the rsi does not cover all symptoms of lpr, including common complaints such as earache, ear pressure and throat pain.6 a more accurate diagnostic evaluation of lpr would therefore include the rfs or assessment of the patient’s ph levels.31,33 furthermore, certain factors—such as allergies, rhinosinusitis, smoking status and laryngeal overuse—can affect both rsi and vhi-10 scores.3,12,17,22,24 the relatively short study period as well as the need for a larger sample size may have also affected the results. the latter issue is particularly concerning given the low response rate among teachers, as previous research has indicated that awareness of vocal hygiene is low in this subset and that 79% of teachers in saudi arabia have never consulted an otolaryngology service.34 other limit ations include the low response rates and difficulties in the interpretation of certain items. conclusion there was a significant association between rsi and vhi-10 scores in the current study, suggesting a potential link between lpr and voice disorders. this may constitute a valuable monitoring method in lpr and voice disorder cases; however, these tools are subjective in nature and thus cannot be used to confirm a diagnosis. therefore, more detailed objective studies are required to confirm the correlation in a larger sample size. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors would like to thank the editors at editage® (cactus communications, mumbai, india) for their help with the english language editing of this article. references 1. ford cn. evaluation and management of laryngopharyngeal reflux. jama 2005; 294:1534–40. doi: 10.1001/jama.294.12.1534. 2. vaezi mf. extraesophageal manifestations of gastroesophageal reflux disease. clin cornerstone 2003; 5:32–8. doi: 10.1016/ s1098-3597(03)90097-4. 3. salihefendic n, zildzic m, cabric e. laryngopharyngeal reflux disease: lprd. med arch 2017; 71:215–18. doi: 10.5455/med arh.2017.71.215-218. 4. sereg-bahar m, jansa r, hocevar-boltezar i. voice disorders and gastroesophageal reflux. logoped phoniatr vocol 2005; 30:120–4. doi: 10.1080/14015430500320182. 5. joniau s, bradshaw a, esterman a, carney as. reflux and laryn gitis: a systematic review. otolaryngol head neck surg 2007; 136:686–92. doi: 10.1016/j.otohns.2006.12.004. 6. belafsky pc, postma gn, koufman ja. validity and reliability of the reflux symptom index (rsi). j voice 2002; 16:274–7. doi: 10.1016/s0892-1997(02)00097-8. 7. farahat m, malki kh, mesallam ta. development of the arabic version of reflux symptom index. j voice 2012; 26:814.e15–19. doi: 10.1016/j.jvoice.2012.03.010. https://doi.org/10.1001/jama.294.12.1534 https://doi.org/10.1016/s1098-3597%2803%2990097-4 https://doi.org/10.1016/s1098-3597%2803%2990097-4 https://doi.org/10.5455/medarh.2017.71.215-218 https://doi.org/10.5455/medarh.2017.71.215-218 https://doi.org/10.1080/14015430500320182 https://doi.org/10.1016/j.otohns.2006.12.004 https://doi.org/10.1016/s0892-1997%2802%2900097-8 https://doi.org/10.1016/j.jvoice.2012.03.010 association between voice handicap index and reflux symptom index a cross-sectional study of undiagnosed general and teacher cohorts in saudi arabia e354 | squ medical journal, august 2018, volume 18, issue 3 8. koufman ja, amin mr, panetti m. prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. otol aryngol head neck surg 2000; 123:385–8. doi: 10.1067/mhn. 2000.109935. 9. jacobson bh, johnson a, grywalski c, silbergleit a, jacobson g, benninger ms, et al. the voice handicap index (vhi): devel opment and validation. am j speech lang pathol 1997; 6:66–70. doi: 10.1044/1058-0360.0603.66. 10. saleem af, natour ys. standardization of the arabic version of the voice handicap index: an investigation of validity and reliability. logoped phoniatr vocol 2010; 35:183–8. doi: 10.3109/ 14015439.2010.490851. 11. franic dm, bramlett re, bothe ac. psychometric evaluation of disease specific quality of life instruments in voice disorders. j voice 2005; 19:300–15. doi: 10.1016/j.jvoice.2004.03.003. 12. tafiadis d, chronopoulos sk, siafaka v, drosos k, kosma ei, toki ei, et al. comparison of voice handicap index scores bet ween female students of speech therapy and other health prof essions. j voice 2017; 31:583–8. doi: 10.1016/j.jvoice.2017.01.013. 13. tafiadis d, kosma ei, chronopoulos sk, papadopoulos a, drosos k, siafaka v, et al. voice handicap index and interpretation of the cutoff points using receiver operating characteristic curve as screening for young adult female smokers. j voice 2018; 32:64–9. doi: 10.1016/j.jvoice.2017.03.009. 14. murry t, medrado r, hogikyan nd, aviv je. the relationship between ratings of voice quality and quality of life measures. j voice 2004; 18:183–92. doi: 10.1016/j.jvoice.2003.11.003. 15. deary ij, wilson ja, carding pn, mackenzie k. voiss: a patient derived voice symptom scale. j psychosom res 2003; 54:483–9. doi: 10.1016/s0022-3999(02)00469-5. 16. rosen ca, lee as, osborne j, zullo t, murry t. development and validation of the voice handicap index-10. laryngoscope 2004; 114:1549–56. doi: 10.1097/00005537-200409000-00009. 17. park jo, shim mr, hwang ys, cho kj, joo yh, cho jh, et al. combination of voice therapy and antireflux therapy rapidly recovers voice-related symptoms in laryngopharyngeal reflux patients. otolaryngol head neck surg 2012; 146:92–7. doi: 10.11 77/0194599811422014. 18. wang y, zhang l, yu l, li j, li j, zhao y, et al. [clinical study of the influence of laryngopharyngeal reflux on quality of life in patients with dysphonia]. zhonghua er bi yan hou tou jing wai ke za zhi 2015; 50:973–7. doi: 10.3760/cma.j.issn.1673 0860.2015.12.002. 19. arffa re, krishna p, gartner-schmidt j, rosen ca. normative values for the voice handicap index-10. j voice 2012; 26:462–5. doi: 10.1016/j.jvoice.2011.04.006. 20. cantor cutiva lc, vogel i, burdorf a. voice disorders in teachers and their associations with work-related factors: a systematic review. j commun disord 2013; 46:143–55. doi: 10.1016/j.jcom dis.2013.01.001. 21. roy n, merrill rm, thibeault s, parsa ra, gray sd, smith em. prevalence of voice disorders in teachers and the general popul ation. j speech lang hear res 2004; 47:281–93. doi: 10.1044/10924388(2004/023). 22. martins rh, pereira er, hidalgo cb, tavares el. voice disorders in teachers: a review. j voice 2014; 28:716–24. doi: 10.1016/j. jvoice.2014.02.008. 23. smith e, kirchner hl, taylor m, hoffman h, lemke jh. voice problems among teachers: differences by gender and teaching characteristics. j voice 1998; 12:328–34. doi: 10.1016/s0892-1997 (98)80022-2. 24. roy n, merrill rm, gray sd, smith em. voice disorders in the general population: prevalence, risk factors, and occupational impact. laryngoscope 2005; 115:1988–95. doi: 10.1097/01.mlg.00 00179174.32345.41. 25. da rocha lm, de lima bach s, do amaral pl, behlau m, de mattos souza ld. risk factors for the incidence of perceived voice disorders in elementary and middle school teachers. j voice 2017; 31:258.e7–12. doi: 10.1016/j.jvoice.2016.05.018. 26. lin fc, chen sh, chen sc, wang ct, kuo yc. correlation bet ween acoustic measurements and self-reported voice disorders among female teachers. j voice 2016; 30:460–5. doi: 10.1016/j. jvoice.2015.05.013. 27. lechien jr, saussez s, harmegnies b, finck c, burns ja. laryngopharyngeal reflux and voice disorders: a multifactorial model of etiology and pathophysiology. j voice 2017; 31:733–52. doi: 10.1016/j.jvoice.2017.03.015. 28. altwigry am, almutairi ms, ahmed m. gastroesophageal reflux disease prevalence among school teachers of saudi arabia and its impact on their daily life activities. int j health sci (qassim) 2017; 11:59–64. 29. hočevar-boltežar i, šereg-bahar m, kravos a, mumović g, mitrović s. is an occupation with vocal load a risk factor for laryngo pharyngeal reflux: a prospective, multicentre, multivariate comp arative study. clin otolaryngol 2012; 37:362–8. doi: 10.1111/coa. 12006. 30. pereira er, tavares el, martins rh. voice disorders in teachers: clinical, videolaryngoscopical, and vocal aspects. j voice 2015; 29:564–71. doi: 10.1016/j.jvoice.2014.09.019. 31. katz po. ambulatory esophageal and hypopharyngeal ph monitoring in patients with hoarseness. am j gastroenterol 1990; 85:38–40. 32. ozturk o, oz f, karakullukcu b, oghan f, guclu e, ada m. hoarseness and laryngopharyngeal reflux: a cause and effect relationship or coincidence? eur arch otorhinolaryngol 2006; 263:935–9. doi: 10.1007/s00405-006-0097-8. 33. feng gj, zhang lh, zhao ll, liu yl. [a pilot study on diagnosing laryngopharyngeal reflux disease by ph monitoring in laryngopharynx]. zhonghua yi xue za zhi 2008; 88:805–8. doi: 10.3321/j.issn:0376-2491.2008.12.004. 34. hamdan al, sibai am, srour zm, sabra oa, deeb ra. voice disorders in teachers: the role of family physicians. saudi med j 2007; 28:422–8. https://doi.org/10.1067/mhn.2000.109935 https://doi.org/10.1067/mhn.2000.109935 https://doi.org/10.1044/1058-0360.0603.66 https://doi.org/10.3109/14015439.2010.490851 https://doi.org/10.3109/14015439.2010.490851 https://doi.org/10.1016/j.jvoice.2004.03.003 https://doi.org/10.1016/j.jvoice.2017.01.013 https://doi.org/10.1016/j.jvoice.2017.03.009 https://doi.org/10.1016/j.jvoice.2003.11.003 https://doi.org/10.1016/s0022-3999%2802%2900469-5 https://doi.org/10.1097/00005537-200409000-00009 https://doi.org/10.1177/0194599811422014 https://doi.org/10.1177/0194599811422014 https://doi.org/10.3760/cma.j.issn.1673-0860.2015.12.002 https://doi.org/10.3760/cma.j.issn.1673-0860.2015.12.002 https://doi.org/10.1016/j.jvoice.2011.04.006 https://doi.org/10.1016/j.jcomdis.2013.01.001 https://doi.org/10.1016/j.jcomdis.2013.01.001 https://doi.org/10.1044/1092-4388%282004/023%29 https://doi.org/10.1044/1092-4388%282004/023%29 https://doi.org/10.1016/j.jvoice.2014.02.008 https://doi.org/10.1016/j.jvoice.2014.02.008 https://doi.org/10.1016/s0892-1997%2898%2980022-2 https://doi.org/10.1016/s0892-1997%2898%2980022-2 https://doi.org/10.1097/01.mlg.0000179174.32345.41 https://doi.org/10.1097/01.mlg.0000179174.32345.41 https://doi.org/10.1016/j.jvoice.2016.05.018 https://doi.org/10.1016/j.jvoice.2015.05.013 https://doi.org/10.1016/j.jvoice.2015.05.013 https://doi.org/10.1016/j.jvoice.2017.03.015 https://doi.org/10.1111/coa.12006 https://doi.org/10.1111/coa.12006 https://doi.org/10.1016/j.jvoice.2014.09.019 https://doi.org/10.1007/s00405-006-0097-8 https://doi.org/10.3321/j.issn:0376-2491.2008.12.004 departments of 1internal medicine and 2radiology, faculty of medicine, university of kufa, najaf, iraq; 3department of radiology, almustansyria university, baghdad, iraq; 4department of clinical pharmacy, najaf health bureau, najaf, iraq *corresponding author e-mail: husseinaf.alnaffakh@uokufa.edu.iq تأثري دليل كتلة اجلسم على تكلس األوعية الدموية وحجم الدهون يف غشاء التامور بني املرضى الذين يوجد لديهم اشتباه مرض الشريان التاجي ح�صني نفاخي، عبد االمري املو�صوي، حيدر قا�صم الوايل، ح�صن النفاخ، رعد توفيق، احمد نفاخي abstract: objectives: this study aimed to assess the effect of body mass index (bmi) on the relationship between pericardial fat volume (pfv), aortic root calcification (arc) and coronary artery calcification (cac) among patients with suspected coronary artery disease (cad). methods: this cross-sectional study took place between january and december 2014 at the kufa university teaching hospital, najaf, iraq. a total of 130 consecutive patients with an intermediate pretest probability of ischaemic heart disease who underwent 64-slice multidetector computed tomography (ct) angiography during the study period were recruited. of these, 111 were included in the study and divided into groups according to bmi. imaging markers were measured on ct angiography. results: a total of 28 patients were obese, while 42 and 41 were overweight and normal weight, respectively. the median pfv, cac and arc was 109 cm3 (interquartile range [iqr]: 52–176 cm3), 0 agatston score (iqr: 0–52 agatston score) and 0 agatston score (iqr: 0–15 agatston score), respectively, in the normal weight group in comparison to 79 cm3 (iqr: 43–138 cm3), 0 agatston score (iqr: 0–54 agatston score) and 0 agatston score (iqr: 0–0 agatston score), respectively, in the obese group. significant correlations were observed between pfv and cac (r2 = 0.22; p = 0.002) and arc and cac (r2 = 0.37; p <0.001) in the normal weight group. however, no significant correlations were observed for obese and overweight patients. conclusion: these findings indicate that bmi may not be an accurate tool for measuring adiposity or assessing subclinical coronary atherosclerosis in patients with suspected cad. keywords: body mass index; obesity; pericardium; coronary vessels; vascular calcification; atherosclerosis; coronary angiography. امللخ�ص: اأهداف: هدفت هذه الدرا�صة اإىل تقييم تاأثري دليل كتلة اجل�صم )bmi( على العالقة بني حجم الدهون يف التامور )pfv( مع تكل�ض .)cad( التاجي ال�رضيان مر�ض ا�صتباه من يعانون الذين املر�صى بني )cac( التاجي ال�رضيان وتكل�ض )arc( االأبهر ال�رضيان جذر منهجية: اأجريت هذه الدرا�صة امل�صحية يف الفرتة ما بني يناير ودي�صمرب 2014م يف امل�صت�صفى التعليمي جلامعة الكوفة يف النجف، العراق، خالل فرتة الدرا�صة مت ح�رض ما جمموعه 130 مري�صًا على التوايل من بني امل�صتبه باإ�صابتهم مبر�ض نق�ض تروية القلب وخ�صعوا للفح�ض 130 جمموع من مري�ض، لكل اإ�صعاعي مقطع 64 وت�صوير )ct( املحو�صب املقطعي الك�صف متعدد الدموية االأوعية ت�صوير جهاز يف مري�صا،ً مت اإدراج 111 منهم يف الدرا�صة وتق�صيمهم اإىل جمموعات وفقًا لدليل كتلة اجل�صم. نتائج: كان هناك 28 مري�صًا يعانون من ال�صمنة و 42 من فرط يف الوزن، بينما كان 41 مري�صًا الباقني ذو وزن طبيعي، بلغ متو�صط حجم الدهون يف التامور وتكل�ض ال�رضيان التاجي و تكل�ض جذر ال�رضيان االأبهر 109 �صم مكعب )مدى املعدل الرباعي من 176–52 �صم مكعب(، نتيجة اأجات�صون 0 )مدى رباعي 52-0(ونتيجة اأجات�صون 0 )مدى رباعي 15–0( على التوايل يف حاالت الوزن الطبيعي، مقارنًة مبعدل متو�صط 79 �صم مكعب )مدى رباعي 138-43 �صم املر�صى جمموعة يف التوايل على النتيجة( من 0–0 رباعي )مدى 0 اأجات�صون ونتيجة )0-54 رباعي )مدى 0 اأجات�صون نتيجة مكعب(، )r2 = 0.22; p = 0.002( ذوي ال�صمنة، لوحظ وجود ارتباط ذو داللة اإح�صائية بني حجم الدهون يف غ�صاء التامور وتكل�ض ال�رضيان التاجي و بني تكل�ض ال�رضيان التاجي وتكل�ض جذر ال�رضيان االأبهر )r2 = 0.37; p >0.001( يف جمموعة املر�صى ذوي الوزن الطبيعي، يف حني مل يالحظ اأي ارتباط ملمو�ض بني هذه املوؤ�رضات يف الذين يعانون من ال�صمنة وفرط الوزن. خامتة: ت�صري هذه النتائج اإىل اأن دليل كتلة اجل�صم قد ال يكون اأداة دقيقة لقيا�ض ال�صمنة اأو تقييم وجود ت�صلب ال�رضايني التاجية حتت ال�رضيري يف املر�صى الذين يعانون من ا�صتباه مر�ض ال�رضيان التاجي. كلمات مفتاحية: دليل كتلة اجل�صم؛ ال�صمنة؛ غ�صاء التامور؛ االوعية التاجية؛ تكل�ض وعائي؛ ت�صلب ع�صيدي؛ ت�صوير االوعية التاجية. impact of body mass index on vascular calcification and pericardial fat volume among patients with suspected coronary artery disease *hussein nafakhi,1 abdulameer al-mosawi,2 hayder elwali,2 hasan al-nafakh,2 raad tawfeq,3 ahmed nafakhi4 clinical & basic research sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e310–316, epub. 19 aug 16 submitted 1 nov 15 revisions req. 3 jan, 4 feb, 24 feb & 14 mar 16; revisions recd. 25 jan, 14 feb, 28 feb & 23 mar 16 accepted 7 apr 16 doi: 10.18295/squmj.2016.16.03.008 advances in knowledge this study examines the role of emerging imaging markers—coronary artery calcification, aortic root calcification and pericardial fat volume (pfv)—in coronary atherosclerosis among patients with different body mass indexes (bmis). the results of this study suggest that bmi does not accurately predict the role and distribution of adipose tissue in patients with cardiovascular disease. hussein nafakhi, abdulameer al-mosawi, hayder elwali, hasan al-nafakh, raad tawfeq and ahmed nafakhi clinical and basic research | e311 over the last few decades, the global prevalence of obesity has increased drama-tically; this is concerning due to the crucial role that obesity plays in metabolic disorders and in increasing the risk of cardiovascular disease.1 several non-invasive measurement-based techniques have been used to define obesity, including body mass index (bmi), waist circumference, waist-to-hip ratio and abdominal wall thickness. however, there is as yet no optimal method for accurately assessing the burden and distribution of adipose tissue believed to be involved in coronary and vascular atherosclerosis.2 as a marker of subclinical coronary atherosclerosis, coronary artery calcification (cac) has an incremental prognostic role which differs to traditional cardiac risk factors and is associated with a higher cardiovascular burden and improved coronary risk stratification.3 research has shown that cac is a more effective predictor of cardiovascular events and assessment of atherosclerosis burden.4 however, little is known regarding the relation of aortic root calcification (arc) to coronary atherosclerosis and obesity. pericardial fat is a local fat deposit that covers 80% of the surface of the heart, with a close anatomical proximity to the epicardial coronary arteries; pericardial fat volume (pfv) is an emerging imaging marker that has been reported to be involved in coronary atherosclerosis.5–8 the main aim of this study was to assess the impact of bmi on emerging radiological markers of coronary atherosclerosis (cac, arc and pfv) in patients with suspected coronary artery disease (cad). methods this cross-sectional study was carried out between january and december 2014 at the cardiology center of the kufa university teaching hospital, najaf, iraq. a total of 130 consecutive iraqi patients with suspected cad based on age, gender and the presence of cardiac symptoms who had undergone 64-slice multi-detector computed tomography (mdct) angiography for assessment of cad during the study period were recruited. the exclusion criteria for a mdct examination included haemodynamic instability, a history of cardiac surgery, iodine-based contrast allergies, renal failure (creatinine levels of ≥1.5 mg/dl), atrial fibrillation or other unstable heart rhythms, an inability to perform breath-holding, the presence of intracardiac devices (e.g. pacemakers), pregnancy or contraindications for the use of β-blockers.6 of those recruited, 19 patients were subsequently disqualified due to poor imaging technique or motion artifacts (n = 8), aortic root anomalies or dissections (n = 2), difficulties in accurate pfv calculation or segmentation of fat (n = 6) or missing data (n = 3). a total of 111 patients were hence included in the study and divided into obese (bmi of ≥30 kg/m2), overweight (bmi of 25–29.9 kg/m2) or normal weight (bmi of <25 kg/m2) groups. non-contrast multidetector computed tomography (ct) was performed on all patients with suspected cad using a sequence scan with a slice thickness of 3 mm. total heart calcium levels were measured according to the agatston method.6 thereafter, 64-slice ct coronary angiography was performed (aquilion™ 64, version 4.51 er 010, toshiba medical systems corp., otawara, japan) according to previously defined methods.9,10 the scan was obtained from the aortic arch to the level of the diaphragm during a single breath-hold. retrospective electrocardiograph (ecg)-gating and ecg-dependent tube current modulation was performed using defined parameters.9 following this, ct images were reconstructed using a smooth kernel (b25f ) with a slice thickness of 0.5 mm (increment of 0.3 mm) and data sets were transferred to a vitreaworkstation™ (vital images inc., minnetonka, minnesota, usa) for image analysis.6 figure 1: multi-detector computed tomography showing the calculation of aortic root calcification. lm = left main artery; rca = right coronary artery; lad = left anterior descending artery; cx = left circumflex coronary artery; pda = posterior descending artery. application to patient care the utilisation of bmi as a measurement of obesity may result in the inaccurate classification of adiposity among patients. as an imaging marker, pfv may be the optimal tool for the assessment of body adiposity. impact of body mass index on vascular calcification and pericardial fat volume among patients with suspected coronary artery disease e312 | squ medical journal, august 2016, volume 16, issue 3 a minimum of three contiguous voxels with a ct density of >130 hounsfield units (hu) was considered to define the cac area. coronary artery stenosis severity was classified visually according to mean lumen diameter as normal, non-obstructed (reduction of <50%) or obstructive (reduction of ≥50% in a single vessel) by comparing the narrowest segment of the lumen diameter with the more proximal or distal normal segment in two orthogonal projections.9 the part of the aorta lying within 3 cm of the caudal aspect of the aortic annulus containing the sinuses of valsalva and the sinotubular junction was defined as the aortic root. according to this definition, total arc was measured using the agatston method [figure 1].3 areas in the aortic root with an attenuation of >130 hu and an area of >1 mm2 were considered to be calcified lesions.3,10 any adipose tissue located within the pericardial sac was considered to denote pericardial fat; this was measured three-dimensionally with a contrast-enhanced phase [figure 2]. the pericardial layer was manually traced and a three-dimensional (3d) image of the heart constructed.9 the pfv was then estimated using a 3d workstation by measuring the total volume of pericardial tissue with a ct density between -250 and -20 hu. all mdct data sets were evaluated by two independent radiologists with more than five years of experience in mdct angiography data analysis.9 significant differences between arc, cac and pfv markers among the bmi groups were analysed. subsequently, the relationships between arc, cac and pfv in each group was analysed. the presence of conventional cardiac risk factors for cad was obtained from each patient at the time of the coronary mdct angiography examination during clinical history-taking. conventional cardiac risk factors included the following: positive family history of early cad occurring before 55 years of age in men and 65 years of age in women; current smoking status and history defined as more than 10 cigarettes per day in the last year; history of hypertension or use of anti-hypertension medications; hyperlipidaemia (total cholesterol ≥200 mg/dl, triglyceride levels ≥150 mg/dl or use of lipid-lowering drugs); history of diabetes mellitus or use of antidiabetic or insulin-lowering drugs; and obesity (bmi of ≥30 kg/m2). patients with two or more of these risk factors apart from obesity were considered to have multiple cad risk factors.3,6 data were analysed using the statistical package for the social sciences (spss), version 13.0 (ibm corp., chicago, illinois, usa). results were presented as interquartile ranges (iqrs) or percentages, as appro priate. categorical data were expressed as frequencies and group comparisons were performed using pearson’s chi-squared test. continuous variables were presented as median values and iqrs and were compared using the student’s t-test, analysis of variance or non-parametric mann-whitney u test, as appropriate. correlations between pfv, arc and cac were examined using pearson’s correlation coefficient or spearman’s rank correlation for nonparametric data. a multiple regression analysis was used to analyse correlations between the dependent variables (cac, pfv and arc) and the independent variable (bmi) after multivariate adjustment for age, gender, hypertension, smoking, diabetes, family history of premature cad and hyperlipidaemia. a p value of <0.050 was considered statistically significant. this study was approved by the ethical committee of the faculty of medicine, university of kufa. informed consent was obtained from all patients included in the study. figure 2 a & b: multi-detector computed tomography showing the measurement of pericardial fat volume (green shading) in the (a) axial and (b) coronal sections of the heart. hussein nafakhi, abdulameer al-mosawi, hayder elwali, hasan al-nafakh, raad tawfeq and ahmed nafakhi clinical and basic research | e313 results of the 111 patients included in the study, 54 were male (49%). the mean age of the total sample was 54.2 ± 10.3 years. according to bmi category, 28 patients were obese (25%), 42 were overweight (38%) and 41 were of normal weight (37%), with mean ages of 51.3 ± 9.5 years, 56.8 ± 10.3 years and 54.7 ± 10.2 years, respectively. median pfv (109 cm3; iqr: 52–176 cm3 versus 97 cm3; iqr: 43–138 cm3) and arc (0 agatston score; iqr: 0–15 agatston score versus 0 agatston score; iqr: 0–0 agatston score) values were highest in the normal weight group and lowest in the obese group, respectively. in comparison, median cac values were highest in the obese group and lowest in the normal weight group (0 agatston score; iqr: 0–54 agatston score versus 0 agatston score; iqr: 0–52 agatston score). in the overweight group, the median pfv, arc and cac scores were 87 cm3 (iqr: 69–130 cm3), 0 agatston score (iqr: 0–2 agatston score) and 0 agatston score (iqr: 0–53 agatston score), respectively. differences in pfv, cac and arc scores among the patient groups were not statistically significant (p = 0.419, 0.871 and 0.631, respectively). additionally, there was no significant difference in the distribution of obstructive coronary stenosis among the groups (p = 0.121). the presence of cad risk factors was also similar among the groups, except that there were more patients with multiple risk factors in the normal weight group compared to the obese and overweight groups (p = 0.032) [table 1]. for the obese patients, no significant correlations were observed between pfv and cac (r2 = 0.01; p = 0.167), obstructive coronary artery stenosis (r2 <0.01; p = 0.338) or arc (r2 = 0.02; p = 0.266). also, arc showed no significant correlation with cac (r2 = 0.04; p = 0.541) or obstructive coronary stenosis (r2 = 0.04; p = 0.335). in the overweight group, no significant correlation was observed between pfv and cac (r2 = 0.03; p = 0.521), obstructive coronary stenosis (r2 <0.01; p = 0.611) or arc (r2 = 0.01; p = 0.745); additionally, arc showed no significant correlation with cac (r2 = 0.03; p = 0.244) or obstructive coronary stenosis (r2 = 0.02; p = 0.322). in the normal weight group, a significant correlation was observed between pfv and cac (r2 = 0.22; p = 0.002) and obstructive coronary stenosis (r2 = 0.18; p = 0.004), table 1: demographic and imaging characteristics and presence of risks factors among patients with suspected coronary artery disease (n = 111) characteristic n (%) p value obese group (n = 28) overweight group (n = 42) normal weight group (n = 41) mean age ± sd 51.3 ± 9.5 56.8 ± 10.3 54.7 ± 10.2 0.217 gender male 9(32) 23 (55) 22 (54) 0.156 female 19 (68) 19 (45) 19 (46) 0.138 cad risk factors hypertension 12 (43) 16 (38) 23 (56) 0.211 smoking 6 (21) 10 (24) 13 (32) 0.510 hyperlipidaemia 5 (18) 6 (14) 6 (15) 0.982 diabetes 2 (7) 3 (7) 3 (7) 0.954 family history of premature cad 5 (18) 2 (5) 4 (10) 0.150 multiple* 4 (14) 10 (24) 17 (41) 0.032 imaging marker scores median cac score (iqr) in agatston 0 (0–54) 0 (0–53) 0 (0–52) 0.832 median arc score (iqr) in agatston 0 (0–0) 0 (0–2) 0 (0–15) 0.632 median pfv (iqr) in cm3 79 (43–138) 87 (69–130) 109 (52–176) 0.419 obstructive coronary stenosis† 5 (18) 9 (21) 7 (17) 0.871 sd = standard deviation; cad = coronary artery disease; cac = coronary artery calcification; iqr = interquartile range; arc = aortic root calcification; pfv = pericardial fat volume. *presence of two or more risk factors in the same patient. †luminal stenosis ≥50%. impact of body mass index on vascular calcification and pericardial fat volume among patients with suspected coronary artery disease e314 | squ medical journal, august 2016, volume 16, issue 3 although there was no significant correlation between pfv and arc (r2 = 0.04; p = 0.113). the correlations between pfv and cac (p = 0.003; confidence interval [ci] = 0.218–1.012) and between pfc and obstructive coronary stenosis (p = 0.03; ci = 6.441–137.517) persisted after multivariate adjustment for age, gender, arc and conventional cad risk factors. furthermore, arc showed a significant correlation with cac (r2 = 0.37; p <0.001) and obstructive coronary stenosis (r2 = 0.23; p = 0.001); these correla tions persisted after multivariate adjustment for age, gender, pfv and conventional cad risk factors (p <0.001; ci = 0.342–0.870 and p = 0.003; ci = 6.742–29.445, respectively). multiple regression analysis was performed to assess the relationship of bmi with cac, arc and pfv in the sample after adjustment for age, gender and conventional cad risk factors [table 2]. no significant correlation was observed between bmi and any of these markers, including pfv [figure 3]. discussion the use of bmi as a method for identifying obesity has several limitations. for example, bmi calculations do not usually take into consideration age, gender, bone structure, muscle mass or the time relationship between obesity and the clinical outcome being measured.7 furthermore, bmi measurements do not differentiate between body weight due to muscle mass and weight due to adipose mass; the latter is now considered a key factor involved in various metabolic and cardiovascular disorders.1 moreover, the relationship between bmi and percentage of adipose tissue is not linear and differs between men and women.7 in recent years, the results of several studies have suggested that obesity as determined by bmi is not necessarily equivalent to poor metabolic health or adverse cardiovascular outcomes; these findings have led to the generation of a new term— metabolically healthy obesity—which refers to obese subjects who satisfy the current definition of obesity without being metabolically unhealthy.11–13 interestingly, ‘u’or ‘j’-shaped associations between bmi and cardiovascular outcomes or mortality have been identified, in which obese patients show better outcomes in terms of cardiovascular morbidity and total mortality compared to patients of a normal weight.1,13 this inverse relationship between bmi and morbidity or mortality rates has been referred to as the “obesity paradox”.1,13 in a meta-analysis of data from 89 studies including 1,300,794 patients, wang et al. reported a ‘j’-shaped relationship between prognosis table 2: multiple regression analysis of imaging markers with body mass index and risk factors among patients with suspected coronary artery disease (n = 111) cad risk factor arc pfv cac rc se p value rc se p value rc se p value bmi 0.59 0.9 0.521 0.04 0.6 0.993 1.63 0.9 0.933 htn 18.82 27.1 0.434 2.21 16.7 0.863 152.21 113.3 0.112 smoking 21.45 30.0 0.453 13.62 18.2 0.423 18.00 29.1 0.500 diabetes 3.14 12.1 0.853 1.21 7.9 0.813 5.22 12.5 0.643 hyperlipidaemia 21.54 33.4 0.514 11.13 20.6 0.552 9.10 32.6 0.752 family history 11.62 43.5 0.723 12.53 26.8 0.612 7.42 42.1 0.825 age 2.83 1.1 0.012 0.34 0.7 0.544 3.62 1.1 0.002 male gender 53.31 25.6 0.031 15.72 15.8 0.311 22.43 25.4 0.362 cad = coronary artery disease; arc = aortic root calcification; pfv = pericardial fat volume; cac = coronary artery calcification; rc = regression coefficient; se = standard error; bmi = body mass index; htn = hypertension. figure 3: non-significant correlation between body mass index and pericardial fat volume among patients with suspected coronary artery disease (n = 111). pfv = pericardial fat volume; bmi = body mass index. hussein nafakhi, abdulameer al-mosawi, hayder elwali, hasan al-nafakh, raad tawfeq and ahmed nafakhi clinical and basic research | e315 and bmi in patients with cad.14 thus, the use of bmi as a measure of obesity may lead to bias in assessing relationships between obesity and cardiovascular health and outcomes.6 an inconsistent and complex relationship between obesity and vascular calcification has been described in the literature. several studies have suggested that obesity is associated with increased cac and calcification of the aorta; however, these studies were performed in relatively young populations or among individuals without known cad or clinically significant coronary disease.15–18 on the other hand, an inverse relationship between vascular calcification and reduced bone density among the elderly has been suggested in more recent studies, whereby low bmi was independently associated with decreased bone mineral density which, in turn, was associated with increased vascular calcification.19,20 rhee et al. compared cac scores assessed by mdct among 24,000 participants with different metabolic health and obesity statuses; cac levels were similar for both non-obese but metabolically unhealthy individuals and metabolically unhealthy obese paticipants.12 this finding suggests that metabolic health is more closely associated with cac than obesity via a complex pathway.12 recently, after studying the ct scans of 276 participants scoring multiple arteries, including the coronary arteries and aorta, takx et al. reported the systemic nature of cardiovascular calcifications, with a weak link between bmi and cardiovascular calcifications among different arterial beds.21 with regards to the relationship between pfv, vascular calcification and obesity, considerable evid ence supports the vital role of pericardial fat accumulation in the coronary atherosclerosis process via the secretion of hormones and cytokines that modulate coronary artery haemostasis.6 the concept of normal weight obesity—defined as a normal bmi and excess body fat percentage—has been recently reported as an important risk factor for cardiovascular disease and metabolic dysregulation; higher amounts of visceral fat even with a normal bmi carry an elevated cardiovascular risk.22,23 kim et al. reported that patients with normal weight obesity have a higher subclinical atherosclerosis incidence than normal weight lean patients due to a higher amount of visceral fat, regardless of other clinical risk factors for atherosclerosis.23 a recent systematic review and meta-analysis of 38 studies examining the relationship between epicardial fat and generalised obesity, central or visceral adipose tissue and the components of metabolic syndrome found a highly significant correlation between epicardial fat and bmi.24 two ct-based studies found that increased cardiac fat was associated with cad in non-obese patients and with metabolic syndrome regardless of bmi status.25,26 additionally, a magnetic resonance imaging-based study reported that cardiac fat deposits were associated with a worse cardiometabolic profile in non-obese persons.27 nevertheless, it is important to note that there is significant heterogeneity between echocardiographybased and ct-based studies in the assessment of cardiac fat deposits, whereby the volumetric quantification of cardiac fat using mdct is highly reproducible compared to more simple measurements of thickness and area using echocardiography. twodimensional echocardiographic measurements may not be accurate enough to assess the 3d-distribution of pericardial fat deposits.28 moreover, the differences in anatomical description (pericardial versus epicardial fat) and discrepancies and ambiguities in the definition and nomenclature of fat deposits around the heart can attenuate the strength of reported associations between cardiac fat deposits and obesity.6 in the present study, significant correlations were observed between arc and pfv with cac in the normal weight group, while arc, cac and pfv showed no significant correlations in the overweight and obese groups. the assessment of different markers of coronary atherosclerosis through an automated (cac and arc) or semi-automated (pfv) scoring system using mdct was a strength of the current study. however, there were several limitations. first, the patients were not randomly selected and only those patients with suspected cad from a single centre were included, potentially resulting in selection bias which may limit generalisation of the results. second, the sample size was relatively small. third, causal relationships between pfv, arc and cac could not be inferred due to the cross-sectional design of the study. fourth, the progression of cac and arc was not assessed; hence, obesity may have been associated with arterial calcification progression. finally, a high bmi at the time of the mdct examination may not necessarily reflect long-term obesity. conclusion in the present study, pfv and arc showed a significant correlation with subclinical coronary atherosclerosis (cac and obstructive coronary stenosis) in normal weight patients. however, no significant correlations were observed for obese and overweight patients. these results suggest that bmi may not be an accurate tool for the measurement of adipose tissue or the assessment of arterial calcification burden among patients with suspected cad. impact of body mass index on vascular calcification and pericardial fat volume among patients with suspected coronary artery disease e316 | squ medical journal, august 2016, volume 16, issue 3 c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bastien m, poirier p, lemieux i, després jp. overview of epidemiology and contribution of obesity to cardiovascular disease. prog cardiovasc dis 2014; 56:369–81. doi: 10.1016/j. pcad.2013.10.016. 2. edston e. a correlation between the weight of visceral adipose tissue and selected anthropometric indices: an autopsy study. clin obes 2013; 3:84–9. doi: 10.1111/cob.12021. 3. nafakhi h, al-nafakh h, al-mosawi a. impact of obesity on aortic root calcification and coronary calcification using multi-detector ct. artery res 2015; 9:27–32. doi: 10.1016/j. artres.2014.12.001. 4. greenland p, labree l, azen sp, doherty tm, detrano rc. coronary artery calcium score combined with framingham score for risk prediction in asymptomatic individuals. jama 2004; 291:210–15. doi: 10.1001/jama.291.2.210. 5. rabkin sw. epicardial fat: properties, function and relationship to obesity. obes rev 2007; 8:253–61. doi: 10.1111/j.1467789x.2006.00293.x. 6. nafakhi h, al-mosawi a, al-nafakh h, tawfeeq n. association of pericardial fat volume with coronary atherosclerotic disease assessed by ct angiography. br j radiol 2014; 87:20130713. doi: 10.1259/bjr.20130713. 7. rothman kj. bmi-related errors in the measurement of obesity. int j obes (lond) 2008; 32:s56–9. doi: 10.1038/ijo.2008.87. 8. spearman jv, renker m, schoepf uj, krazinski aw, herbert tl, de cecco cn, et al. prognostic value of epicardial fat volume measurements by computed tomography: a systematic review of the literature. eur radiol 2015; 25:3372–81. doi: 10.1007/ s00330-015-3765-5. 9. nafakhi h, al-nafakh ha, al-mosawi aa. abo blood group differences relationship with coronary atherosclerotic markers. artery res 2016; 14:36–40. doi: 10.1016/j.artres.2016.03.001. 10. al-nafakh ha, nafakhi h, al-jiboori ma, al-mosawi aa, tawfeq rh. aortic root calcification and cardiac risk factors in patients with coronary calcium score greater than zero using multidetector computed tomography. artery res 2015; 10:27–31. doi: 10.1016/j.artres.2015.02.002. 11. dobson r, burgess mi, sprung vs, irwin a, hamer m, jones j, et al. metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity. int j obes (lond) 2016; 40:153–61. doi: 10.1038/ijo.2015.151. 12. rhee ej, lee mk, kim jd, jeon ws, bae jc, park se, et al. metabolic health is a more important determinant for diabetes development than simple obesity: a 4-year retrospective longitudinal study. plos one 2014; 9:e98369. doi: 10.1371/ journal.pone.0098369. 13. romero-corral a, montori vm, somers vk, korinek j, thomas rj, allison tg, et al. association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. lancet 2006; 368:666–78. doi: 10.1016/s0140-6736(06)69251-9. 14. wang zj, zhou yj, galper bz, gao f, yeh rw, mauri l. association of body mass index with mortality and cardiovascular events for patients with coronary artery disease: a systematic review and meta-analysis. heart 2015; 101:1631–8. doi: 10.1136/heartjnl-2014-307119. 15. kronmal ra, mcclelland rl, detrano r, shea s, lima ja, cushman m, et al. risk factors for the progression of coronary artery calcification in asymptomatic subjects: results from the multi-ethnic study of atherosclerosis (mesa). circulation 2007; 115:2722–30. doi: 10.1161/circu lationaha.106.674143. 16. lee cd, jacobs dr jr, schreiner pj, iribarren c, hankinson a. abdominal obesity and coronary artery calcification in young adults: the coronary artery risk development in young adults (cardia) study. am j clin nutr 2007; 86:48–54. 17. see r, abdullah sm, mcguire dk, khera a, patel mj, lindsey jb, et al. the association of differing measures of overweight and obesity with prevalent atherosclerosis: the dallas heart study. j am coll cardiol 2007; 50:752–9. doi: 10.1016/j. jacc.2007.04.066. 18. siviero-miachon aa, spinola-castro am, de martino lee ml, de castro monteiro cm, de camargo carvalho ac, calixto ar, et al. subcutaneous adipose tissue plays a beneficial effect on subclinical atherosclerosis in young survivors of acute lymphocytic leukemia. vasc health risk manag 2015; 11:479–88. doi: 10.2147/vhrm.s86883. 19. kovacic jc, lee p, baber u, karajgikar r, evrard sm, moreno p, et al. inverse relationship between body mass index and coronary artery calcification in patients with clinically significant coronary lesions. atherosclerosis 2012; 221:176–82. doi: 10.1016/j.atherosclerosis.2011.11.020. 20. dangas gd, maehara a, evrard sm, sartori s, li jr, chirumamilla ap, et al. coronary artery calcification is inversely related to body morphology in patients with significant coronary artery disease: a three-dimensional intravascular ultrasound study. eur heart j cardiovasc imaging 2014; 15:201–9. doi: 10.1093/ehjci/jet139. 21. takx ra, zanen p, leiner t, van der graaf y, de jong pa; smart study group. the interdependence between cardiovascular calcifications in different arterial beds and vascular risk factors in patients at high cardiovascular risk. atherosclerosis 2015; 238:140–6. doi: 10.1016/j.atherosclerosis.2014.11.024. 22. jean n, somers vk, sochor o, medina-inojosa j, llano em, lopez-jimenez f. normal-weight obesity: implications for cardiovascular health. curr atheroscler rep 2014; 16:464. doi: 10.1007/s11883-014-0464-7. 23. kim s, kyung c, park js, lee sp, kim hk, ahn cw, et al. normal-weight obesity is associated with increased risk of subclinical atherosclerosis. cardiovasc diabetol 2015; 14:58. doi: 10.1186/s12933-015-0220-5. 24. rabkin sw. the relationship between epicardial fat and indices of obesity and the metabolic syndrome: a systematic review and meta-analysis. metab syndr relat disord 2014; 12:31–42. doi: 10.1089/met.2013.0107. 25. shah rv, murthy vl, abbasi sa, blankstein r, kwong ry, goldfine ab, et al. visceral adiposity and the risk of metabolic syndrome across body mass index: the mesa study. jacc cardiovasc imaging 2014; 7:1221–35. doi: 10.1016/j. jcmg.2014.07.017. 26. okada k, ohshima s, isobe s, harada k, hirashiki a, funahashi h, et al. epicardial fat volume correlates with severity of coronary artery disease in nonobese patients. j cardiovasc med (hagerstown) 2014; 15:384–90. doi: 10.2459/ jcm.0b013e32836094da. 27. de larochellière e, côté j, gilbert g, bibeau k, ross mk, dion-roy v, et al. visceral/epicardial adiposity in nonobese and apparently healthy young adults: association with the cardiometabolic profile. atherosclerosis 2014; 234:23–9. doi: 10.1016/j.atherosclerosis.2014.01.053. 28. gorter pm, van lindert as, de vos am, meijs mf, van der graaf y, doevendans pa, et al. quantification of epicardial and peri-coronary fat using cardiac computed tomography: reproducibility and relation with obesity and metabolic syndrome in patients suspected of coronary artery disease. atherosclerosis 2008; 197:896–903. doi: 10.1016/j. atherosclerosis.2007.08.016. http://dx.doi.org/10.1016/j.pcad.2013.10.016 http://dx.doi.org/10.1016/j.pcad.2013.10.016 http://dx.doi.org/10.1111/cob.12021 http://dx.doi.org/10.1016/j.artres.2014.12.001 http://dx.doi.org/10.1016/j.artres.2014.12.001 http://dx.doi.org/10.1001/jama.291.2.210 http://dx.doi.org/10.1111/j.1467-789x.2006.00293.x http://dx.doi.org/10.1111/j.1467-789x.2006.00293.x http://dx.doi.org/10.1259/bjr.20130713 http://dx.doi.org/10.1038/ijo.2008.87 http://dx.doi.org/10.1007/s00330-015-3765-5 http://dx.doi.org/10.1007/s00330-015-3765-5 http://dx.doi.org/10.1016/j.artres.2016.03.001 http://dx.doi.org/10.1016/j.artres.2015.02.002 http://dx.doi.org/10.1038/ijo.2015.151 http://dx.doi.org/10.1371/journal.pone.0098369 http://dx.doi.org/10.1371/journal.pone.0098369 http://dx.doi.org/10.1016/s0140-6736%2806%2969251-9 http://dx.doi.org/10.1136/heartjnl-2014-307119 http://dx.doi.org/10.1161/circulationaha.106.674143 http://dx.doi.org/10.1161/circulationaha.106.674143 http://dx.doi.org/10.1016/j.jacc.2007.04.066 http://dx.doi.org/10.1016/j.jacc.2007.04.066 http://dx.doi.org/10.2147/vhrm.s86883 http://dx.doi.org/10.1016/j.atherosclerosis.2011.11.020 http://dx.doi.org/10.1093/ehjci/jet139 http://dx.doi.org/10.1016/j.atherosclerosis.2014.11.024 http://dx.doi.org/10.1007/s11883-014-0464-7 http://dx.doi.org/10.1186/s12933-015-0220-5 http://dx.doi.org/10.1089/met.2013.0107 http://dx.doi.org/10.1016/j.jcmg.2014.07.017 http://dx.doi.org/10.1016/j.jcmg.2014.07.017 http://dx.doi.org/10.2459/jcm.0b013e32836094da http://dx.doi.org/10.2459/jcm.0b013e32836094da http://dx.doi.org/10.1016/j.atherosclerosis.2014.01.053 http://dx.doi.org/10.1016/j.atherosclerosis.2007.08.016 http://dx.doi.org/10.1016/j.atherosclerosis.2007.08.016 1college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of child health, royal hospital, muscat, oman; 3department of orthopedic surgery, armed forces hospital, muscat, oman *corresponding author e-mail: msalazri@hotmail.com التهاب العظم والنقي الُسّلي يف ورك رضيع بسبب لقاح عصوية كامليت–غورين سجل حالة حممد �سليمان العزري، جازل ماناراجن، يعقوب املفرجي abstract: to this day, tuberculosis (tb) continues to pose a significant global health burden. the world health organization’s expanded programme on immunization (epi) recommends the bacille calmette-guérin (bcg) vaccine for infants to protect against the haematogenous spread of primary tb and other more severe types of tb infection. we report an eight-month-old boy who presented to the armed forces hospital, muscat, oman, in 2015 with a one-month history of intermittent fever associated with a limited range of motion in the right hip area. he was up-to-date with his epi vaccinations and had no history of exposure to individuals with tb infections. he was initially treated for bacterial septic arthritis; however, a genexpert tb assay revealed the presence of mycobacterium tuberculosis, bcg strain. to the best of the authors’ knowledge, this is the first documented case from oman of a child with tb hip osteomyelitis due to a bcg vaccination. keywords: tuberculosis; bcg vaccine; vaccination, adverse effects; osteomyelitis; case report; oman. امللخ�ص: ما زال مر�ص ال�سل ي�سكل عبئا �سحيا ثقيال يف كل اأرجاء العامل. واأو�ست منظمة ال�سحة العاملية يف برناجمها املو�سع للتطعيم يّل، واأنواع اإ�سابات ال�سل االأخرى االأ�سد وخامة التي با�ستخدام لقاح ع�سوية كامليت–غورين عند الر�سع حلمايتهم من انت�سار ال�سل االأوَّ تنتقل عن طريق الدم. وهذا ت�سجيل حلالة ر�سيع عمره ثمانية �سهور اأدخل مل�ست�سفى القوات امل�سلحة، م�سقط، عمان، يف عام 2015م. وجاء يف تاريخه املر�سي اأنه كان م�سابا منذ �سهر واحد بحمى متقطعة، مع حركة حمدودة يف منطقة الورك االأمين. وكان �سجل تطعيماته �سد االأمرا�ص مكتمال، ومل ي�سبق له التعر�ص الأ�سخا�ص م�سابني بال�سل من قبل. ومت عالجه يف البدء باعتبار اأن مر�سه هو التهاب املفا�سل ة ع�سوية كامليت–غورين(. وح�سب البكتريي االإنتاين. غري اأن مقاي�سة genexpert لل�سل ك�سفت عن وجود باكترييا املتطفرة ال�سلية )ُذرِّيَّ علمنا هذه هي احلالة االأوىل امل�سجلة يف عمان لطفل م�ساب بالتهاب العظم والنقي نتج عن تطعيم بلقاح ال�سل )ع�سوية كامليت–غورين(. الكلمات املفتاحية: ال�سل؛ لقاح ال�سل )ع�سوية كامليت–غورين(؛االآثار ال�سارة، تلقيح؛ التهاب العظم والنقي؛ �سجل حالة؛ عمان. bacille calmette-guérin vaccine-induced tuberculous hip osteomyelitis in an infant case report *mohammed s. al-azri,1 jazel manarang,2 yaqoub al-mufargi3 case report sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e358–362, epub. 10 oct 17 submitted 14 feb 17 revision req. 26 mar 17; revision recd. 15 may 17 accepted 8 jun 17 doi: 10.18295/squmj.2017.17.03.019 tuberculosis (tb) is an infection caused by the mycobacterium tuberculosis bacteria which most commonly affects the lungs, but can involve virtually any part of the human body.1,2 in 2014, the world health organization (who) reported an incidence of 9.6 million tb cases with over three million deaths, including almost 300,000 children under the age of 15 years.3 the who’s expanded programme of immunization (epi) recommends the bacille calmette-guérin (bcg) vaccine to protect against the haematogenous spread of primary tb infections among infants.4,5 this case report describes the rare occurrence of hip tuberculosis in an eight-monthold omani infant secondary to the bcg vaccination. although rare, complications following vaccinations should be kept under consideration; however, the risks of the bcg vaccine do not outweigh the potential morbidity and mortality of tb infection.3 case report an eight-month-old omani male infant presented to the orthopaedic emergency department of the armed forces hospital (afh), muscat, oman, in 2015 with a one-month history of intermittent fever associated with a limited range of motion (rom) in the right hip area. there was no reported swelling, erythema, history of trauma at the affected site or any other systemic symptoms. he was up-to-date with his epi vaccinations, including the bcg vaccine which he had received during the first week of life. his parents reported no exposure to individuals with similar symptoms; in addition, none of his family members and neighbours had recently suffered from a chronic cough or unexplained weight loss. he had previously been treated at a secondary local hospital for septic arthritis and prescribed intravenous antibiotics (co amoxiclav). the parents had taken their child home mohammed s. al-azri, jazel manarang and yaqoub al-mufargi case report | e359 during the capsulotomy did not grow any organisms. a postoperative hip magnetic resonance imaging (mri) scan revealed residual fluid collection and proximal femur osteomyelitis [figure 3]. nevertheless, the patient was discharged after three weeks with a prescription for oral cefdinir to complete the six-week course of antimicrobial therapy. two weeks following discharge, the patient was seen at the afh outpatient fracture clinic. the mother reported that he cried during movement and when the right hip bore weight. at the follow-up appointment itself, the infant was afebrile but irritable with direct joint tenderness and restricted rom in the affected limb. a follow-up mri scan showed significant fluid collection and the patient underwent a repeat extended right hip arthrotomy with washout and placement of a hip spica cast. on histopathology, section tissue samples showed granulomatous inflammation with fragments of multiple epithelioid cells with langhans-type giant cells surrounded by lymphocytes, a few plasma cells and scattered neutrophils along with congested blood vessels and focal areas of necrosis. based on the patient’s lack of response to the initial antibiotic therapy, acid-fast bacilli (afb) staining, genexpert testing and fungal cultures were performed. tuberculin skin testing was negative. while awaiting the test results, intravenous antibiotic therapy was continued. the genexpert assay revealed the presence of m. tuberculosis, bcg strain. the patient was immediately prescribed quadruple anti-tb treatment consisting of rifampicin, isoniazid, pyrazinamide and ethambutol. the results of a series of immunodeficiency tests were normal. after two weeks, he was discharged in good health. at a four-week follow-up, there was evidence of mild swelling at the surgical site with improving rom. the patient remained clinically stable with good tolerance to the oral medications. a hip ultrasound showed nonprogressive fluid collection which was monitored on a regular basis. he completed two months of quadruple anti-tb therapy before against medical advice and treated him with oral medications; however, he was admitted shortly afterwards to afh due to his worsening symptoms. on admission, a physical examination revealed no discrepancies in limb length, with no apparent swelling nor changes in perfusion. however, evidence of limited rom, especially on flexion and external rotation of the right hip, and tenderness on direct pressure were observed. a blood work-up and complete blood count revealed leukocytosis and increased levels of acute phase reactants. initial radiographs showed reduced hip joint space with fragmentation and collapse of the right femoral head [figure 1]. an ultrasound indicated synovial thickening with septations [figure 2], features consistent with a diagnosis of septic arthritis. subsequently, the patient underwent an emergency right hip arthrotomy. intraoperatively, a capsulotomy yielded purulent material with clumps of necrotic tissue and intravenous ceftriaxone was administered. following the surgery, the patient remained stable with lysis of the febrile episodes. moreover, there was a gradual full recovery of the rom of the affected joint. serial blood counts showed improving acute phase reactant levels and culture studies of samples taken figure 1: hip x-ray of an eight-month-old boy showing reduced hip joint space with fragmentation and collapse of the right femoral head (arrow). figure 2: ultrasonography of the right hip of an eight-monthold boy showing synovial thickening with the presence of septations (arrow). figure 3: sectional magnetic resonance imaging of the right hip of an eight-month-old boy showing residual fluid collection and proximal femur osteomyelitis (arrow) following an arthrotomy. bacille calmette-guérin vaccine-induced tuberculous hip osteomyelitis in an infant case report e360 | squ medical journal, august 2017, volume 17, issue 3 continuing treatment with rifampicin, isoniazid and pyridoxine for one year. discussion the bcg vaccine was developed as an attenuated live vaccine derived from virulent strains of the m. bovis species. the vaccine was launched as part of the epi in 1974 primarily to help reduce the haematogenous spread of tb infections and the development of more severe types of tb infection (e.g. miliary, meningitic and disseminated tb) rather than to prevent primary infection.4,5 in oman, the epi was launched in 1981 and included the bcg vaccine to be given intradermally at birth; since its implementation, the number of tb cases per year have markedly decreased from 928 in 1981 to 213 in 2010.6 before the advent of modern genome analysis techniques, it was difficult to differentiate between virulent mycobacteria and avirulent bcg strains; however, the development of multiplex polymerase chain reaction (pcr) techniques has since provided rapid, sensitive and specific discrimination of bcg vaccine strains.7–11 specifically, pcr technology has identified distinct genomic regions, designated as rd1, rd2 and rd3, which were found to be absent in the vaccine strains, suggesting that the loss of virulence is due to a particular regulatory mutation in the rd1 region.7–9 this genomic region is present in both human and bovine virulent strains, but absent in all bcg vaccines.8 rarely, complications from the bcg vaccination arise among 3.3% of cases and manifest around 6–9 months after inoculation.12 a review by toida et al. reported an incidence of 0.0182 cases per 100,000 bcg vaccinations of dissemination beyond the vaccination site.13 besides lymphadenitis, which is the most common complication, regional or extraregional localised abscesses and osteomyelitis are uncommon but serious complications following the bcg vaccine.5,12,14–17 osteomyelitis can affect any bone in the body and usually occurs at a single site. koyama et al. reported the incidence of bcg-induced osteomyelitis to be 0.2 cases per 100,000 vaccinations.10 a study of czechoslovakian children with bcg-induced osteomyelitis confirmed by mycobacterial culture noted that the symptoms appeared approximately 17 months after vaccination, with the proximal tibia, distal femur and proximal humerus being most commonly affected.18 in a retrospective study, kröger et al. found that the age of onset of children with bcg-induced osteomyelitis varied from 0.25–5.7 years and that the most common sites affected were the metaphyses of the long bones, with the lower extremities more commonly affected than the upper.19 a systematic review similarly revealed involvement of the lower limbs to be most common (55.6%), followed by involvement of the axial skeleton (26.0%), the upper limbs (15.4%) and multiple bones (3%).16 an association with immunosuppression has also been documented.12,16 although the bcg vaccine may be associated with rare complications, the potential morbidity and mortality resulting from a tb infection outweigh them. in tb osteomyelitis, the bacteria may spread to the synovium, the area around the bone or the bone itself, causing swelling, congestion and the formation of granulation tissue; subsequently, the inflammatory process continues, eventually resulting in bone necrosis and destruction.1 in cases of hip osteomyelitis, this can result in deformity, shortening of the limb, swelling, pathological dislocations and even sinus formation depending on the extent of involvement.1,2 the use of mri has been useful in the early detection of pathologies, such as oedema and inflammation, and soft tissue abnormalities in the affected joint.2 table 1 presents a modified classification of hip tb according to disease severity, including synovitis, early arthritis, advanced arthritis and advanced arthritis with subluxation/dislocation.2,20 a number of confirmed bcg-induced osteomyelitis cases have been reported from europe and asia.5,14 however, to the best of the authors’ knowledge, the current patient is believed to be the first confirmed case of bcg-induced tb hip osteomyelitis from oman. table 1: modified clinicoradiological classifications of hip tuberculosis2,20 stage clinical findings radiological features synovitis flexion, abduction and external rotation with apparent lengthening haziness of the articular margins and rarefaction early arthritis flexion, adduction and internal rotation with apparent shortening rarefaction, osteopaenia and bony erosions in the femoral head, acetabulum or both, without reduction in the joint space advanced arthritis flexion, adduction and internal rotation with shortening all of the above plus destruction of the articular surface and reduction in the joint space advanced arthritis with subluxation/ dislocation flexion, adduction and internal rotation with gross shortening gross destruction and reduction of the joint space and a wandering acetabulum mohammed s. al-azri, jazel manarang and yaqoub al-mufargi case report | e361 most childhood tb infections are contracted as a result of exposure to household contacts with the disease, including parents or other caregivers.21 in the current case, there was allegedly no tb exposure; however, a thorough investigation or field visit to the patient’s locale could not be undertaken to rule out this possibility. a diagnosis of tb should be confimed via the demonstration of tubercle bacilli. the time period between a bcg vaccination and the development of a culture-negative relapsing lesion is an important indication for pathological evaluation.12 ultrasound-guided aspiration of the synovial fluid may be performed and specimens should be obtained for histopathology, afb staining, pcr and culture studies. in the present patient, joint aspirates from the right hip were negative for bacterial growth. hengster et al. found that culture yield percentage decreased with time, with 46% of cases having positive cultures in the first 20 weeks of receiving the bcg vaccination compared to 0% after 20 weeks.22 the use of genexpert, a rapid and automated nucleic acid amplification test, confirmed the presence of m. tuberculosis, bcg strain, in the present case. due to the rapid dissemination of tb infections among children, prompt initiation of therapy is warranted. although both surgical and nonsurgical options exist, chemotherapy remains the cornerstone of treatment.1,2 both the centers for disease control and prevention in the usa and the who emphasise the use of short-course multidrug regimens under directly-observed therapy.3 for skeletal tb, the reco mmended duration of treatment is usually 12 months, except for those with spinal disease, for whom 18 months of therapy is advised. in paediatric cases, treatment strategies are primarily focused towards preserving anatomy, joint mobility and growth plates.1,2,20,23 first-line anti-tb agents include isoniazid, rifampicin, streptomycin, pyrazinamide and ethambutol. a failure to respond to these medications may warrant the use of second-line agents including capreomycin, kanamycin, ethionamide, cycloserine, and paraaminosalicylic acid.1,2 a lack of response to first-line therapy may be due to several factors, such as inadequate treatment, lack of compliance, an alternate diagnosis or the presence of resistant organisms. in the current case, the patient underwent an arthrotomy after which his condition seemed to immediately improve. his fever started to lyse and the acute-phase reactants normalised with the continuation of antibiotics. a recent review reported that adequate drainage and thorough debridement can hasten clinical improvement.24 this reduces the bacterial load and removes necrotic tissue, providing a boost to the host’s immune system and a chance for the antibiotics to control the infection.12,24 however, supplemental surgical intervention may be reserved for specific indications, most often to establish the diagnosis or to treat complications of the disease process.2,20 conclusion clinical suspicion of bcg-induced osteomyelitis is warranted in paediatric patients with chronic symptoms of pain, limping, swelling and a limited rom in the extremities. imaging and culture studies may guide the clinician, although tissue biopsies and genetic tests confirm the diagnosis. chemotherapy remains the definitive treatment in such cases. it is important to note that the benefits of the vaccine in terms of reducing tb-related morbidity and mortality overcome the potential risk of bcg-related complications. a c k n o w l e d g e m e n t s a poster of this case report was presented at the 2nd annual congress and medicare exposition on primary care and general pediatrics from 19–20 september 2016 in phoenix, arizona, usa. an abstract of the poster was published in health care: current reviews in 2016 (vol. 4, suppl. 3, p. 65). references 1. spiegel da, singh gk, banskota ak. tuberculosis of the musculoskeletal system. tech orthop 2005; 20:167–78. doi: 10.1097/01.bto.0000167745.24646.dc. 2. saraf sk, tuli sm. tuberculosis of hip: a current concept review. indian j orthop 2015; 49:1–9. doi: 10.4103/00195413.143903. 3. world health organization. global tuberculosis report 2016. from: www.who.int/tb/publications/global_report/en/ accessed: may 2017. 4. hashimoto t. [bcg vaccines for the prevention of tuberculosis in the world]. kekkaku 1997; 72:629–37. 5. lin cj, yang ws, yan jj, liu cc. mycobacterium bovis osteomyelitis as a complication of bacille calmette-guérin (bcg) vaccination: rapid diagnosis with use of dna sequencing analysis a case report. j bone joint surg am 1999; 81:1305–11. doi: 10.2106/00004623-199909000-00012. 6. oman ministry of health. manual on expanded program on immunization, 3rd edition. from: www.cdscoman.org/uploads/ cdscoman/epi_manual.pdf accessed: may 2017. 7. mahairas gg, sabo pj, hickey mj, singh dc, stover ck. molecular analysis of genetic differences between mycobacterium bovis bcg and virulent m. bovis. j bacteriol 1996; 178:1274–82. doi: 10.1128/jb.178.5.1274-1282.1996. 8. talbot ea, williams dl, frothingham r. pcr identification of mycobacterium bovis bcg. j clin microbiol 1997; 35:566–9. https://doi.org/10.1097/01.bto.0000167745.24646.dc https://doi.org/10.4103/0019-5413.143903 https://doi.org/10.4103/0019-5413.143903 https://doi.org/10.2106/00004623-199909000-00012 https://doi.org/10.1128/jb.178.5.1274-1282.1996 bacille calmette-guérin vaccine-induced tuberculous hip osteomyelitis in an infant case report e362 | squ medical journal, august 2017, volume 17, issue 3 17. lin wl, chiu nc, lee ph, huang as, huang fy, chi h, et al. management of bacillus calmette-guérin osteomyelitis/ osteitis in immunocompetent children: a systematic review. vaccine 2015; 33:4391–7. doi: 10.1016/j.vaccine.2015.07.039. 18. marík i, kubát r, filipský j, galliová j. osteitis caused by bcg vaccination. j pediatr orthop 1988; 8:333–7. 19. kröger l, korppi m, brander e, kröger h, wasz-höckert o, backman a, et al. osteitis caused by bacille calmette-guérin vaccination: a retrospective analysis of 222 cases. j infect dis 1995; 172:574–6. doi: 10.1097/01241398-198805000-00015. 20. moon ms, kim ss, lee sr, moon yw, moon jl, moon si. tuberculosis of hip in children: a retrospective analysis. indian j orthop 2012; 46:191–9. doi: 10.4103/0019-5413.93686. 21. adams lv, starke jr. tuberculosis disease in children. from: www.uptodate.com/contents/tuberculosis-disease-in-children accessed: may 2017. 22. hengster p, sölder b, fille m, menardi g. surgical treatment of bacillus calmette guérin lymphadenitis. world j surg 1997; 21:520–3. doi: 10.1007/pl00012279. 23. mohideen ma, rasool mn. tuberculosis of the hip joint region in children. s afr orthop j 2013; 12:38–43. 24. calhoun jh, manring mm, shirliff m. osteomyelitis of the long bones. semin plast surg 2009; 23:59–72. doi: 10.1055/s0029-1214158. 9. kearns am, magee jg, gennery a, steward m, graham c, seiders pr, et al. rapid identification of mycobacterium bovis bcg by the detection of the rd1 deletion using a multiplex pcr technique. int j tuberc lung dis 1999; 3:635–8. 10. koyama a, toida i, nakata s. [osteitis as a complication of bcg vaccination]. kekkaku 2009; 84:125–32. 11. okada m, kobayashi k. [recent progress in mycobacteriology]. kekkaku 2007; 82:783–99. 12. gharehdaghi m, hassani m, ghodsi e, khooei a, moayedpour a. bacille calmette-guérin osteomyelitis. arch bone jt surg 2015; 3:291–5. doi: 10.22038/abjs.2015.4825. 13. toida i, nakata s. [severe adverse reactions after vaccination with japanese bcg vaccine: a review]. kekkaku 2007; 82:809–24. 14. chan pk, ng bk, wong cy. bacille calmette-guérin osteomyelitis of the proximal femur. hong kong med j 2010; 16:223–6. 15. khotaei gt, sedighipour l, fattahi f, pourpak z. osteomyelitis as a late complication of bacille calmette-guérin vaccination. j microbiol immunol infect 2006; 39:169–72. 16. corrales if, cortés ja, mesa ml, zamora g. [sternal osteomyelitis and scrofuloderma due to bcg vaccination]. biomedica 2003; 23:202–7. doi: 10.7705/biomedica.v23i2.1212. https://doi.org/10.1016/j.vaccine.2015.07.039 https://doi.org/10.1097/01241398-198805000-00015 https://doi.org/10.4103/0019-5413.93686 https://doi.org/10.1007/pl00012279 https://doi.org/10.1055/s-0029-1214158 https://doi.org/10.1055/s-0029-1214158 https://doi.org/10.22038/abjs.2015.4825 https://doi.org/10.7705/biomedica.v23i2.1212 book vendors, whether it is amazon.com or outlets in the shopping mall, are stocked with books entertaining us with promises to lose weight or increase our virility and, more relevant to some of us, a quick fix for androgenic alopecia. the preoccupation with selfhelp books pervades all spheres of our lives, and now the fad appears to be encroaching even upon the ivory tower of the academic world. judging from the title of the book, getting research published an a-z of publication strategy by elizabeth wager, a freelance medical writer, editor and trainer, this indeed appears to be just another self-help book hitting the shelves of bookstores, or does it have more to offer? skimming through the pages, one would think that this book should belong to the same series as the popular “for dummies” reference books. however, whoever bothers to read this book, will realize that it is a gold mine of information on the mystery of the publication process. this book, the second edition, is meant to alleviate the common sources of anxiety we may have regarding the publication process and provide a guide to manoeuvring round the numerous pitfalls that occur on the road to publication. yes, there are many books written for that purpose, but what distinguishes this book from other the books, at least among those that i have so far come across, is that it manages to cover all the essential topics while keeping the language both simple and witty. if you are well versed in the process of medical publication, you will find that this book expresses in print your inner thoughts and experiences in a way that you would yourself find hard to explain. inevitably, the book contains much jargon relevant to the publication process, ]öáéfl⁄<‘nù<·á”ë<^⁄çfl¬ <üéfl÷]<ìèrèi]3â]<ª<^è◊÷<ã÷˘]<‡⁄  book review getting research published an a-z of publication strategy author: elizabeth wager publisher: radcliffe, 2nd edition, 2010 isbn: 13: 978-184619-408-5 orders: www.radcliffe-oxford.com squ med j, february 2011, vol. 11, iss. 1, pp. 132-133, epub. 12th feb 11 submitted -3rd jan 10 elizabeth wager book review | 133 but each term is clearly defined and the large majority of them are worthwhile for any aspiring authors to know, for example, ‘lead time’, ‘nitpickers’ and ‘ombudsman’. the book is also up-to-date with all the new terms and concepts emerging due to the increased complexity of the world of publications with its electronic publications and open access journals, leading to terms such as “digital object identifier systems”, “young reviewers” and “zealot reviewers”. another feature of this book, which makes it clear, concise and easy to understand, is its structure. wager has divided her book into two parts. part one is entitled “publication strategy – an overview” and part two the “a-z of publication strategy”. the first part is divided into five chapters and contains a guide to publication strategy, tips on how to grasp the complexity of multi-centre studies and, finally, a cautionary tale exemplified by a mythical figure known as dr. seymour. being a well-known expert in medical publishing with a track record extending for many decades, wager also gives the reader ample opportunities to learn about the pros and cons of working with a medical writer. the second part of her book is encyclopedia-like with relevant topics arranged alphabetically from a to z, as the title of the book would suggest. its coverage ranges from a guide on how to write an abstract, to a word of caution on the processes of publication. this book also touches upon some interesting topics that might raise eyebrows, such as the topic of ‘xenophobia’. this is not a reference to the rise of the right-wing, ideological thugs who are sweeping across the world as recession gets hold of many economies. in medical publication terms, ‘xenophobia’ or ‘geographical bias’ is a furtive activity that insidiously exists in some journals. for example, you send a manuscript from oman and you are rejected simply because you come from a far away land. indeed, there are anecdotal reports of journals that are known to make negative editorial decisions on articles from this region. today, research is becoming more prominent in oman, and sultan qaboos university is getting its own ‘perestroika’ attitude to research culture. the clique of older academics who function as administrative professors are loosening their hold on the system. in the world which we now inhabit, i strongly believe that this book should be considered essential reading for the new members of the evergrowing and ever-changing research body, where the slogan that you either “publish or perish” is being trumpeted loudly. this book would also be an asset to those who are teaching research methodology or running newly established publications. and for those of us who are reaching the end of our career, this book will only rekindle the lament, “i wish i’d known all of this before”. but on a more positive note, i cannot wait to see what more elizabeth wager will have to offer in the third edition! r e v i e w e r samir al-adawi department of behavioural medicine college of medicine & health sciences sultan qaboos university, muscat, oman email: adawi@squ.edu.om getting research published an a z of publication strategy 133 | squ medical journal, february 2011, volume 11, issue 1 squ med j, december 2010, vol. 10, iss. 3, pp. 310-311, epub. 14th nov 10 submitted 24th may 10 revision req. 23rd june 10, revision recd. 27th june 10 accepted 29th june 10 in 1908, the carnegie foundation for the advancement of education in the united states authorised a study and report on the schools of medicine in the united states. abraham flexner (a high school principal) was requested to conduct the study under the direction of the foundation. flexner visited all medical schools in north america, a total of 150 undergraduate and 12 postgraduate schools in the us and 8 undergraduate schools in canada. his report was published in 1910 [figure 1].1 the report changed the face of medical education in that region, and it is justifiable to say that the changes induced by the flexner report are what have made north american medical education the current world gold standard. given the unprecedented status that the report attained in medical education, and the current “flexner centenary”, it is not inappropriate to encourage debate on the current status of medical education and its future direction. in the april issue of squmj, hans karle, president of the world federation for medical education, wrote an article on how to define a medical school.2 in his article, dr. karle reflects on the status of medical education worldwide since the flexner report. he argues that there are some new trends in the international medical education arena that resemble conditions which pertained before the publication of the report. these include the emergence of many “proprietary” medical schools, and the fact that medical education is becoming a trade commodity and the spread of cross-border providers of medical education. in addition, he suggests rational criteria for the foundation of medical schools that include ownership, curricula of the schools and accreditation systems. hans karle’s article is timely. the carnegie foundation has just published a new study by cooke et al. educating physicians: a call for reform of medical school and residency [figure 2].3 this study was conducted between 2005 and 2006 and case-studied, with detailed analysis, both undergraduate and graduate medical education in 11 medical schools and 3 nonuniversity teaching hospitals in the usa. in contrast to the flexner report, the purpose was not to evaluate educational programmes at these institutions but, rather, to learn from their innovations and challenges.4 it is not the intention of this author to excerpt or abstract from the flexner report or the new study by cooke et al., nor to discuss the issues these publications raised. as a matter of fact, this is not required. both publications are succinctly and clearly presented by irby et al.4 however, a number of points that were discussed in this respect are worthy of being reiterated. undoubtedly, flexner’s critique of the mediocre quality, inadequate curricula/facilities, the profit motive of many schools and teachers, and the nonscientific approach in preparing doctors, acted as the fuel which made the changes he recommended a reality.5 adopting his critical approach and the principles he laid down is an invaluable strategy for providing and maintaining good quality medical education in any school of medicine. conceptually, the flexner report contained no new educational ideas that were unknown to the medical educators of his time.6 the report's significance was in portraying the discussion on medical education as a discussion on “public” education. the extraordinary development in medical education that took place after the report would not have occurred without this “public” catalyst.6 at present, involving the “public” in medical education has transpired, though by a different route. department of pharmacology & clinical pharmacy, college of medicine & health sciences, sultan qaboos university, muscat, oman email: tanira@squ.edu.om <9�÷]<<‹è◊√j÷]<öávjë<<ôü}_<ïü⁄  editorialeditorial medical education is on the move once more musbah o tanira musbah o tanira editorial | 311 nowadays, medical schools have an increasing obligation towards society and stakeholders whose credence could influence future medical education. involvement of the “public” in all forms of education, including medical education, represented by accreditation and ranking agencies, is gaining more perceptible authority. these agencies hold education providers accountable to the public in more ways than one. indeed, accreditation agencies ‘dictate’, with varying degrees, how medical schools should perform and manage their affairs and even how they should design their curricula in accordance with pre-established standards.6 the standards candidly relate undergraduate education to postgraduate training. the same notion is emphasised in the title of the cooke et al. report.3 hence, it is inescapable that undergraduate medical education and postgraduate training should be closely linked. the principles that were advocated by the flexner report created new developments which made medical education more challenging. the introduction of new student-centered educational strategies instigated a partial departure from the apprenticeship model. as a result, the contact between the teacher and the student was reduced. in return, the level of mastery of skills and the professionalism of students was affected. involving clinicians in research compromised, to a certain degree, the importance of patient care and teaching.4 these developments, inter alia, evolved in the face of a vast growth in the knowledge base and ever increasing public expectations of health care delivery. however, although these developments made medical education more complex, they probably paved the way for innovation in medical education and led to the introduction of new educational concepts and strategies as well as new learning modalities. in conclusion, the flexner report put medical education on the move with the principles it laid down. not only that, flexner’s critical analysis of the condition of medical education prior to the report was the essence which made the impact of his report on medical education as immense and perpetual as it was. consequently, with the adoption of these principles, no one strategy in medical education would last for all the time; ‘new’ ideas will always need to be ‘renewed’ to make ‘pristine’ ones, and ‘novel’ ideas will always evolve. for a medical school that is aspiring to be respected in the international arena, a vision of scientific rigour and educational excellence should be the driving force for its mission to prepare graduates that will make future high quality physicians. for the most part, the changes that have been witnessed since the flexner report impacted on the 'form' of medical education with the aim of fulfilling its 'purpose' viz. to prepare competent doctors who can safely practice contemporary medicine and maintain a high level of professionalism. amidst all the inevitable changes, we should hold fast to the purpose and never be carried away by the form. references 1. flexner a. medical education in the united states and canada. a report to the carnegie foundation for the advancement of teaching. boston, 1910. from: http://www.carnegiefoundation.org/ sites/default/files/elibrary/carnegie_flexner_report.pdf accessed: may 2010. 2. karle h. how do we define a medical school? reflections on the occasion of the centennial of the flexner report. squ med j 2010; 10:160–8. 3. cooke m, irby dm, o'brien bc, shulman ls. educating physicians: a call for reform of medical school and residency. san francisco ca: jossey-bass, 2010. 4. irby dm, cooke m, o'brien bc. calls for reform of medical education by the carnegie foundation for the advancement of teaching: 1910 and 2010. acad med 2010; 85:220–7. 5. cooke m, irby dm, sullivan w, ludmere km. american medical education 100 years after the flexner report. n engl j med 2006; 355:1339–44. 6. ludmerer km. understanding the flexner report. acad med 2010; 85:193–6. 7. quality assurance task force, world federation for medical education. wfme global standards for quality improvement in medical education. university of copenhagen, denmark, 2007. from: http://www.wfme. org. accessed: may 2010. figure 1: front page of flexner's report 1910 figure 2: cover page of the new carnegie foundation report on medical education, 2010 1department of surgery, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2post-internship programme, directorate general of health services, ministry of health, muscat, oman; 3otolaryngology residency programme, oman medical specialty board, muscat, oman; 4department of ear, nose & throat, christian medical college, vellore, tamil nadu, india *corresponding author’s e-mail: ajoymathew@gmail.com حساسية األنف وعالقتها حبساسية الغذاء مؤشرات للبحث يف املستقبل را�سد العربي، اأ�سداف �سالح العامري، زينة الذهلي، اجوي ماثيو فارغي�ض abstract: allergic rhinitis is a ubiquitous type of allergic reaction which results in significant costs to affected patients and their families. although allergic rhinitis can coexist with other atopic conditions, the role of food aller gies in the development of allergic rhinitis has not been well studied. this article explores relevant literature on this subject in order to identify gaps in the available body of knowledge and elucidate scope for further research. keywords: allergic reactions; respiratory hypersensitivity; allergic rhinitis; food allergies; allergens. امللخ�ص: تعترب ح�سا�سية االنف نوع من احل�سا�سية وا�سعة االأنت�سار والتي ينتج عنها الكثري من التكاليف املادية وال�سحية على املري�ض امل�ساب وعائلته. بالرغم من اأن ح�سا�سية االأنف ميكن اأن تكون م�ساحبة الأنواع اأخرى من حاالت التاأتب، اإال اأنه مل تتم درا�سة دور ح�سا�سية ذات املن�سورة املقاالت يف البحث اىل العلمية الورقة هذه تهدف االن. اىل كافية ب�سورة االأنف ح�سا�سية حلدوث موؤدي ك�سبب الغذاء البحوث من للمزيد املجال وفتح املعرفية الفجوة وحتديد حاليا املتاحة املعلومات على التعرف بغر�ض املو�سوع بنف�ض ال�سلة والدرا�سات امل�ستقبلية. الكلمات املفتاحية: التفاعل التح�س�سي؛ فرط احل�سا�سية الرئوي؛ احل�سا�سية االأنفية؛ ح�سا�سية الغذاء؛ املواد املثرية للح�سا�سية. allergic rhinitis in relation to food allergies pointers to future research rashid al-abri,1 asdaf s. al-amri,2 zaina al-dhahli,3 *ajoy m. varghese1,4 sounding board sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e30–33, epub. 4 apr 18 submitted 6 sep 17 revisions req. 16 oct & 7 dec 17; revisions recd. 12 nov 17 & 8 jan 18 accepted 18 jan 18 doi: 10.18295/squmj.2018.18.01.005 allergic rhinitis is one of the most common diseases worldwide and usually persists throughout the lifetime of the affected patient. although allergic rhinitis is not associated with significant morbidity or mortality, the burden and cost of this disease are substantial.1 this condition is not only associated with impaired quality of sleep and cognitive function but is also a significant contributor to reduced work performance and increased school absenteeism, with resulting indirect costs greater than those incurred by asthma.2 although allergic rhinitis is an organ-specific disorder, it frequently coexists with other allergic manifestations like asthma and eczema. the presence of rhinitis is a significant risk factor for asthma and the coexistence of rhinitis is associated with poor asthma control.3 similarly, allergic rhinitis is the most common concomitant allergic disease associated with eczema.4 one suggested mechanism to explain the connec tion between common atopic disorders such as eczema, asthma and allergic rhinitis is atopic march, which proposes that the allergic disease progresses from atopic dermatitis to asthma and, subsequently, to allergic rhinitis.5 pols et al. observed that the prevalence of the coexistence of all three atopic diseases was 9.8 times higher than that which would be expected by chance; moreover, the relative risk for the occurrence of asthma and eczema in patients with allergic rhinitis was 6.20 (95% confidence interval: 5.30–7.27).6 similarly, the link between food allergies, asthma and eczema has been well-studied.7,8 however, the same cannot be said of the relationship between food allergies and allergic rhinitis. this article explores the available body of knowledge on food allergies and allergic rhinitis in order to elucidate potential pointers for future research. pathogenesis of food allergies adverse food reactions encompass all abnormal clinical responses to the ingestion of food and can result from either an intolerance or allergy [figure 1].9 the former refers to an adverse reaction to an inherent property of the food item (i.e. toxic contamination) and is beyond the scope of this article. in contrast, a food allergy is an abnormal immunological response which may or may not be mediated by immunoglobulin e (ige).9 when the gastrointestinal barrier breaks down—either due to increased permeability, as in infants, or due to an inflamm atory process—sensitisation to the allergenic antigens occurs. occasionally, sensitisation can occur via the respiratory tract or skin, bypassing the gastrointestinal rashid al-abri, asdaf s. al-amri, zaina al-dhahli and ajoy m. varghese sounding board | e31 barrier, as with oral allergy syndrome or pollen allergy syndrome.9 food sensitisation is considered an important risk factor for developing respiratory allergies. in the classic ige-mediated pathway, which occurs among individuals who have been exposed to the aller gen and have had an initial immune response, subsequent exposure to the allergen triggers ige-mediated degranulation of mast cells and basophils, resulting in allergic symptoms.10–12 on the other hand, non-ige mediated food allergies, such as food protein-induced enterocolitis syndrome, food protein-induced proctocolitis and food protein enteropathy, are less common and are usually due to a chronic inflammation of the gas trointestinal tract; such conditions are mediated through allergen-specific t cells or eosinophils and primarily affect the gastrointestinal rather than respiratory tract.13 allergic rhinitis is more frequently associated with a secondary rather than a primary food allergy. a secondary food allergy, also known as pollen food syndrome, involves cross-reactivity in patients with pollen allergies who develop allergic symptoms to certain types of food; it is a mild food allergy and has been associated with polyvalent airborne allergens.4,14 although no specific genes have been identified, food allergies are at least in part genetically determined, with various studies confirming patterns of familial inheritance.15,16 polymorphisms in up to nine genes have been associated with the incidence or severity of food allergies, including the cd14, forkhead box p3, signal transducer and activator of transcription 6, serine protease inhibitor kazal type 5 and interleukin 10 genes.17 however, most of these findings need to be replicated in other populations. links between food allergies and several human leuko cyte antigen (hla) genotypes have also been found, with significant associations reported between hla class ii dr β-1 (hla-drb1), dq β-1 and dp β-1 gene polymorphisms and peanut allergies as well as between the hla-drb1*07 allele and apple allergies.17 the recent increase in the prevalence of allergic disease has been attributed to either an increase in exposure to aller gens among genetically predisposed individuals or via a heritable epigenetic mechanism from events that occurred while the baby was in utero.18 this is an exciting area for further research. the coexistence of various allergic symptoms in the same individual cannot be explained by chance. one concept that explains this is the previously descr ibed allergic march hypothesis, which suggests a progression of symptoms from eczema and food allergies to asthma and allergic rhinitis; the later presentation of allergic rhinitis in relation to food allergies supports this concept.2 using bayesian machine learning methods figure 1: classification of various food-related adverse reactions. ige = immunoglobulin e; fpies = food protein-induced enterocolitis syndrome. reproduced with permission from cianferoni a, spergel jm. food allergy: review, classification and diagnosis.9 allergic rhinitis in relation to food allergies pointers to future research e32 | squ medical journal, february 2018, volume 18, issue 1 on two large cohorts, belgrave et al. suggested that this is only one of several mechanisms and concluded that heterogeneous patterns exist, with different manifestations sometimes existing independently.19 a few studies have suggested that patients with food allergies have an increased risk of developing respiratory allergies; however, these studies were relatively small and relied primarily on self-reported data.7,20 of the major food allergens, peanut, milk and egg allergies significantly predispose individuals to the development of both allergic rhinitis and asthma. additionally, patients with multiple food allergies are at increased risk of developing allergic rhinitis and asthma as compared to patients with a single food allergy.21 further research on the causal relationship between food allergies and allergic rhinitis may shed more light on this topic. allergic rhinitis and food allergies in children children may be affected by different or co-existing allergic and atopic manifestations. although allergic rhinitis affects about a third of the population, the greatest frequency of the condition is found in children and adolescents.22 the coexistence of primary food allergies and allergic rhinitis in children has been studied in a few cohort studies. in a prospective longitudinal birth cohort study in sweden, goksör et al. concluded that 40% of children with food allergies in infancy had allergic rhinitis by the time they were eight years old.23 the onset of the food allergy was found to precede the onset of allergic rhinitis, with 47% of the children initially developing the food allergies within one year of birth while only 7.9% of children with allergic rhinitis developed the condition before two years of age; the mean age of onset of the food allergies was one year and two months, which was much earlier than the mean age at diagnosis of the allergic rhinitis at four years and nine months.23 although an early food allergy appears to be the strongest predictor of subsequent allergic disease, allergic march is only one of several postulated causal mechanisms. the increased prevalence of allergic rhinitis in older children may be explained by their increased sensitisation to airborne allergens once they reach school age. in a retrospective cohort study of paediatric patients with established food allergies, hill et al. found that 35% went on to develop allergic rhinitis.21 additionally, the food allergens most likely to cause allergic rhinitis were peanuts, milk and eggs (odds ratios: 2.59, 1.46 and 1.8, respectively).22 in a study of french schoolchildren, pénard-morand et al. concluded that self-reported food allergies, food sensitisation and skin prick-tested food allergies were all significantly positively associated with allergic rhinitis; moreover, these associations persisted even when the food allergy did not result in any respiratory symptoms (p <0.001).24 allergic rhinitis and food allergies in adults true food allergies occur at a rate of 0.1–1% in adults.25,26 al-rabia suggested that the peak prevalence was between 21–40 years of age, after which it decreased.27 however, the available literature regarding adult allergies is limited in comparison to that of paediatric allergies. among adults, the prevalence of food allergies varies according to culture and population. in a retro spective analysis of in vitro enzyme-linked immunosorbent assay results, sahin-yilmaz et al. found that the most common food allergens associated with allergic rhinitis among adults in the usa were peanuts (23.4%) and shrimp (22.2%), whereas allergies to milk (13.2%) were much less frequent.28 this seems to indicate that while children tend to outgrow most common food allergies, others like peanut and crustacean allergies persist into adulthood. among the allergens tested, peanuts had a 100% specificity and 100% positive predictive value in diagnosing food allergies with low sensitivity (26.7%) and a negative predictive value (48.8%).28 kumar et al. identified positive skin prick tests to one or more foods among 29.3% of indian adult and adolescents with asthma and allergic rhinitis.29 in contrast, rice (6.2%) and black gram legumes (5.9%) were the most common allergens, while peanuts and soybean allergens were less frequent (2–3%).29 moreover, citrus fruits and chocolate have been reported to be the primary food allergens in the mediterranean region and russia, while nuts, apples, pears and kiwifruit allergens are most common in denmark and sweden.30 additional research is therefore needed to identify the prevalence of specific allergens in other populations. conclusion the development of allergic disease is complex and not well understood. various manifestations can coexist based on individual susceptibility and exposure to different environmental factors. early food allergies appear to be the strongest predictor of subsequent allergic disease. in terms of natural history, allergic march is a credible theory, particularly as allergic rhinitis usually presents later than food allergies. however, additional studies are needed to understand the relation between food allergies and allergic rhinitis. exciting areas for future research include the role of genetics and epirashid al-abri, asdaf s. al-amri, zaina al-dhahli and ajoy m. varghese sounding board | e33 genetics, the identification of specific food allergens that cause allergic rhinitis and the prevalence of various allergens in different regions of the world. references 1. zuberbier t, lötvall j, simoens s, subramanian sv, church mk. economic burden of inadequate management of allergic diseases in the european union: a ga(2) len review. allergy 2014; 69:1275–9. doi: 10.1111/all.12470. 2. camelo-nunes ic, solé d. allergic rhinitis: indicators of quality of life. j bras pneumol 2010; 36:124–33. doi: 10.1590/ s1806-37132010000100017. 3. de groot ep, nijkamp a, duiverman ej, brand pl. allergic rhinitis is associated with poor asthma control in children with asthma. thorax 2012; 67:582–7. doi: 10.1136/thoraxjnl 2011-201168. 4. cingi c, gevaert p, mösges r, rondon c, hox v, rudenko m, et al. multi-morbidities of allergic rhinitis in adults: european academy of allergy and clinical immunology task force report. clin transl allergy 2017; 7:17. doi: 10.1186/s13601-017 0153-z. 5. sun hl, yeh cj, ku ms, lue kh. coexistence of allergic diseases: patterns and frequencies. allergy asthma proc 2012; 33:e1–4. doi: 10.2500/aap.2012.33.3506. 6. pols dh, wartna jb, van alphen ei, moed h, rasenberg n, bindels pj, et al. interrelationships between atopic disorders in children: a meta-analysis based on isaac questionnaires. plos one 2015; 10:e0131869. doi: 10.1371/journal.pone.0131869. 7. liu ah, jaramillo r, sicherer sh, wood ra, bock sa, burks aw, et al. national prevalence and risk factors for food allergy and relationship to asthma: results from the national health and nutrition examination survey 2005-2006. j allergy clin immunol 2010; 126:798–806.e13. doi: 10.1016/j.jaci.2010.07.026. 8. saunes m, øien t, dotterud c, romundstad pr, storrø o, holmen tl, et al. early eczema and the risk of childhood asthma: a prospective, population-based study. bmc pediatr 2012; 12:168. doi: 10.1186/1471-2431-12-168. 9. cianferoni a, spergel jm. food allergy: review, classification and diagnosis. allergol int 2009; 58:457–66. doi: 10.2332/aller golint.09-rai-0138. 10. yu w, freeland dm, nadeau kc. food allergy: immune mechanisms, diagnosis and immunotherapy. nat rev immunol 2016; 16:751–65. doi: 10.1038/nri.2016.111. 11. sicherer sh, sampson ha. food allergy: recent advances in pathophysiology and treatment. annu rev med 2009; 60:261–77. doi: 10.1146/annurev.med.60.042407.205711. 12. lee la, burks aw. food allergies: prevalence, molecular charac terization, and treatment/prevention strategies. annu rev nutr 2006; 26:539–65. doi: 10.1146/annurev.nutr.26.061505.111211. 13. nowak-wegrzyn a, katz y, mehr ss, koletzko s. non-igemediated gastrointestinal food allergy. j allergy clin immunol 2015; 135:1114–24. doi: 10.1016/j.jaci.2015.03.025. 14. czarnecka-operacz m, jenerowicz d, silny w. oral allergy syndrome in patients with airborne pollen allergy treated with specific immunotherapy. acta dermatovenerol croat 2008; 16:19–24. 15. tsai hj, kumar r, pongracic j, liu x, story r, yu y, et al. familial aggregation of food allergy and sensitization to food allergens: a family-based study. clin exp allergy 2009; 39:101–9. doi: 10.1111/j.1365-2222.2008.03111.x. 16. hourihane jo, dean tp, warner jo. peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. bmj 1996; 313:518–21. doi: 10.1136/bmj.313.7056.518. 17. hong x, tsai hj, wang x. genetics of food allergy. curr opin pediatr 2009; 21:770–6. doi: 10.1097/mop.0b013e32833252dc. 18. national academies of sciences, engineering, and medicine. potential genetic and environmental determinants of food allergy risk and possible prevention strategies. in: finding a path to safety in food allergy: assessment of global burden, causes, prevention, management, and public policy. washington d.c., usa: national academies of sciences, engineering, and medicine, 2017. pp. 139–226. 19. belgrave dc, granell r, simpson a, guiver j, bishop c, buchan i, et al. developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies. plos med 2014; 11:e1001748. doi: 10.1371/journal.pmed.1001748. 20. friedlander jl, sheehan wj, baxi sn, kopel ls, gaffin jm, ozonoff a, et al. food allergy and increased asthma morbidity in a school-based inner-city asthma study. j allergy clin immunol pract 2013; 1:479–84. doi: 10.1016/j.jaip.2013.06.007. 21. hill da, grundmeier rw, ram g, spergel jm. the epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study. bmc pediatr 2016; 16:133. doi: 10.1186/s12887-016-0673-z. 22. sih t, mion o. allergic rhinitis in the child and associated comorbidities. pediatr allergy immunol 2010: 21:e107–13. doi: 10.1111/j.1399-3038.2009.00933.x. 23. goksör e, loid p, alm b, åberg n, wennergren g. the allergic march comprises the coexistence of related patterns of allergic disease not just the progressive development of one disease. acta pediatrica 2016; 105:1472–9. doi: 10.1111/apa.13515. 24. pénard-morand c, raherison c, kopferschmitt c, caillaud d, lavaud f, charpin d, et al. prevalence of food allergy and its relationship to asthma and allergic rhinitis in school chil dren. allergy 2005; 60:1165–71. doi: 10.1111/j.1398-9995.2005. 00860.x. 25. boye ji. food allergies in developing and emerging economies: need for comprehensive data on prevalence rates. clin transl allergy 2012, 2:25. doi: 10.1186/2045-7022-2-25. 26. turnbull jl, adams hn, gorard da. review article: the diagnosis and management of food allergy and food intolerances. aliment pharmacol ther 2015; 41:3–25. doi: 10.1111/ apt.12984. 27. al-rabia mw. food-induced immunoglobulin e-mediated allergic rhinitis. j microsc ultrastruct 2016; 4:69–75. doi: 10.10 16/j.jmau.2015.11.004. 28. sahin-yilmaz a, nocon cc, corey jp. immunoglobulin e-mediated food allergies among adults with allergic rhinitis. otolaryngol head neck surg 2010; 143:379–85. doi: 10.1016/j. otohns.2010.04.271. 29. kumar r, kumari d, srivastava p, khare v, fakhr h, arora n, et al. identification of ige-mediated food allergy and aller gens in older children and adults with asthma and allergic rhinitis. indian j chest dis allied sci 2010; 52:217–24. 30. eriksson ne, möller c, werner s, magnusson j, bengtsson u, zolubas m. self-reported food hypersensitivity in sweden, denmark, estonia, lithuania, and russia. j investig allergol clin immunol 2004; 14:70–9. https://doi.org/10.1111/all.12470 https://doi.org/10.1590/s1806-37132010000100017 https://doi.org/10.1590/s1806-37132010000100017 https://doi.org/10.1136/thoraxjnl-2011-201168 https://doi.org/10.1136/thoraxjnl-2011-201168 https://doi.org/10.1186/s13601-017-0153-z https://doi.org/10.1186/s13601-017-0153-z https://doi.org/10.2500/aap.2012.33.3506 https://doi.org/10.1371/journal.pone.0131869 https://doi.org/10.1016/j.jaci.2010.07.026 https://doi.org/10.1186/1471-2431-12-168 https://doi.org/10.2332/allergolint.09-rai-0138 https://doi.org/10.2332/allergolint.09-rai-0138 https://doi.org/10.1038/nri.2016.111 https://doi.org/10.1146/annurev.med.60.042407.205711 https://doi.org/10.1146/annurev.nutr.26.061505.111211 https://doi.org/10.1016/j.jaci.2015.03.025 https://doi.org/10.1111/j.1365-2222.2008.03111.x https://doi.org/10.1136/bmj.313.7056.518 https://doi.org/10.1097/mop.0b013e32833252dc https://doi.org/10.1371/journal.pmed.1001748 https://doi.org/10.1016/j.jaip.2013.06.007 https://doi.org/10.1186/s12887-016-0673-z https://doi.org/10.1111/j.1399-3038.2009.00933.x https://doi.org/10.1111/apa.13515 https://doi.org/10.1111/j.1398-9995.2005.00860.x https://doi.org/10.1111/j.1398-9995.2005.00860.x https://doi.org/10.1186/2045-7022-2-25 https://doi.org/10.1111/apt.12984 https://doi.org/10.1111/apt.12984 https://doi.org/10.1016/j.jmau.2015.11.004 https://doi.org/10.1016/j.jmau.2015.11.004 https://doi.org/10.1016/j.otohns.2010.04.271 https://doi.org/10.1016/j.otohns.2010.04.271 sir, i must at the outset congratulate the author for the interesting article that appeared in your december edition in the sounding board section: the trend to seek a second opinion abroad amongst cancer patients in oman: challenges and opportunities. this article outlined the possible negative consequences in terms of outcomes for cancer patients which can arise if they seek a second opinion abroad. these can be due to travel delays, inappropriate treatment, etc.1 i agree with the author’s view that the problem should be studied further in order to arrive at solutions. a simple questionnaire given to the patients going abroad or returning from their treatment could easily help us understand their reasons and concerns. accordingly, solutions could be implemented and the outcome of these observed. although most of the possible motives and probable solutions have been discussed, i am writing to add a few more thoughts from a surgeon’s perspective. health care seeking behaviour is strongly influenced by family values and recommendations, and the family plays a central role in the decision making of omanis.2 having noted this, when it comes to a cancer, many of our patients are not made aware of their diagnosis on request of their family members. a typical omani family is large and well-knit. no single member wants to make a decision especially when it comes to cancer surgery. they do not want to be responsible should something go wrong. in addition, family members would like to enable the patient to obtain the best treatment, which they think is abroad. the ordinary omani is under the impression that in oman they would be operated upon by trainees. they are also not confident of the skills of omani doctors trained abroad. while the author has noted that a second opinion is desirable in some less common cancers, this is true even for surgical oncology. surgical skill being directly proportional to the volume, it is appropriate for demanding operations like surgery for oropharyngeal and oesophageal malignancy be performed at specialised high volume oncology centres. while awaiting a well-designed study to identify the problem fully and arrive at solutions, we should strive to establish a good rapport with the patient and his family. the dialogue should be simple and sincere. this would improve the patient’s trust and confidence in local health providers. centres liaising with high volume oncology hospitals should be opened where patients can seek another opinion for a nominal fee. with improved technology, facilities like telemedicine can allow the transfer of large data x-ray and pathological investigations. these can be of immense value and decrease the delay in the treatment. in a community where word of mouth is a popular means of dissemination of information, i believe the well-placed affluent section of the community should set a trend by seeking treatment at home rather than travelling abroad. additionally, we can setup a social networking platform on the internet. satisfied patients who had their treatment in oman can not only express their experiences, but also address the concerns of patients who are awaiting their treatment. this would eliminate any bias which the patients may have regarding the treatment offered by the care providers. squ med j, august 2010, vol. 10, iss. 2, pp. 276-277, epub. 19th jun 10 received: 13th mar 10 نزعة احلصول على رأي ثان من اخلارج يف عالج مرضى السرطان يف عمان: حتديات وفرص براديب كوبرا re: the trend to seek a second opinion abroad among cancer patients in oman challenges and opportunities pradeep chopra letter to editor pradeep chopra letter to editor | 277 pradeep chopra department of surgery, sultan qaboos university hospital, muscat, oman. email:chopradeep@gmail.com references 1. burney ia. the trend to seek a second opinion abroad amongst cancer patients in oman: challenges and opportunities. squ med j 2009: 9:260–3. 2. al mandhari a, al adawi s, al zakwani i, al shafee m, eloul l. relatives’ advice and health care-seeking behaviour in oman. squ med j 2009; 9:264–71. author’s response i thank dr chopra for his letter, and expressing a surgeon’s perspective. he has raised the issue of surgical volumes, and suggested that the demanding operations should be done at specialised high volume centres. i agree, and would like to add that for several cancers, high volume surgeons are regarded as independent prognostic factors in terms of outcome of those cancers. however, the process of reaching appropriate centres is the core issue, which formed the basis of my article.1 patients and families travelling abroad without seeking a specialist opinion at home, may and do travel to centres which are not necessarily high volume centres, or centres of excellence, for that particular type of cancer. the hospitals selected by the patients and families through geographical proximity, travel planners, front offices, or word of mouth, are likely to be at best as well equipped as the best hospital in the home country. furthermore, the delay in travel arrangements and discomfort of travel with an advanced cancer, my even reduce the chances of a favorable outcome. dr chopra suggests that the usual decision makers, the family members, do not want to take the responsibility for the outcomes of surgery, and think that the best treatment is available ‘abroad’, and hence the reason for travel. he further suggests the notion that many people think that the patients would be operated upon by trainees, or by doctors who are not very skillful. while many of these factors may urge the family members to take their beloveds to centres where presumably only very skillful surgeons would operate, and where ‘a cure is available’, all these reasons for travel remain speculative. studied systematically, many of the fears and anxieties could be allayed by proper communication and counselling. i agree with dr chopra that telemedicine facilities should be used for speedy transfer of data to centres of excellence to seek a second opinion, if needed, and this would prevent delays in commencing the treatment. this was also suggested earlier; however, this facility in many instances could be utilised by the oncologist/oncological surgeon on behalf of the patient, but only if the opinion was sought in the home country first. this is certainly an option worth considering. ikram burney department of medicine & health sciences, sultan qaboos university hospital, muscat, oman. email: ikramburney@hotmail.com references 1. burney i a. the trend to seek a second opinion abroad amongst cancer patients in oman: challenges and opportunities. squ med j 9:260-3. أدوار وأداء مدريب القيادة املهنية يف تعليم السائق املبتدئ زولهادي حممد جاوي، بابا ديرو�ص، اأحمد اأزاد اأبو را�سد، حممد حفظي حممد عي�سى، عزمي اأوانغ abstract: this review article aimed to analyse existing literature regarding the roles and performance of professional driving instructors (pdis) in novice driver education (de). a systematic classification scheme was adopted to analyse identified articles to determine the study context of pdis in novice de, the competency level of pdis in relation to experienced and learner drivers and the contributions of pdis to the novice driver learning process. a total of 14 original research articles were identified, with no systematic reviews or meta-analyses available. overall, all of the articles were found to be inadequate in providing an in-depth understanding of the roles and performance of pdis in novice de. there is an urgent need to improve current understanding of the roles of pdis in novice de and to work towards an internationally recognised pdi management approach. keywords: public health systems research; safety; accident prevention; automobile driving; automobile driver examination. امللخ�ص: هدف هذه املقالة هو مراجعة و حتليل االأدبيات املوجودة فيما يتعلق باأدوار واأداء مدربي القيادة املهنية يف تعليم ال�سائق املبتدئ. واعتمدت خطة ت�سنيف منهجية لتحليل املقاالت املحددة ملحتوى الدرا�سة وم�ستوى كفاءات مدربي القيادة املهنية فيما يتعلق بال�سائقني من ذوي اخلربة و املتعلم املبتدئ وم�ساهماتها يف عملية التعلم لل�سائق املبتدئ. وقد مت حتديد ما جمموعه 14 مقاال بحثيا اأ�سليا، من دون وجود اأي ا�ستعرا�سات منهجية اأو حتليالت تلوية. وعلى وجه العموم، تبني اأن جميع البحوث املتاحه غري كافية يف توفري فهم متعمق الأدوار واأداء مدربي القيادة املهنية يف عملية التعلم لل�سائق املبتدئ. هناك حاجة ملحة لتح�سني الفهم احلايل الأدوار مدربي القيادة املهنية يف عملية التعلم لل�سائق املبتدئ مما ي�ستوجب العمل على نهج معرتف به دوليا الإدارة املدربني. الكلمات املفتاحية: بحوث نظم ال�سحة العامة؛ ال�سالمة؛ الوقاية من احلوادث؛ قيادة ال�سيارات؛ فح�ص �سائق ال�سيارات. the roles and performance of professional driving instructors in novice driver education *zulhaidi m. jawi,1 baba m. deros,2 ahmad a. a. rashid,1 mohd h. m. isa,1 azmi awang3 review sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e277–285, epub. 10 oct 17 submitted 2 mar 17 revisions req. 11 apr & 31 may 17; revisions recd. 8 may & 19 jun 17 accepted 6 jul 17 doi: 10.18295/squmj.2017.17.03.004 driving is an instrumental activity of daily living; however, it can be extremely dangerous as even a minor mistake can result in complicated and life-threatening injuries or death.1,2 according to the world health organisation, the number of global road traffic fatalities exceeded one million in recent years, with another 20–50 million people either injured or incapacitated due to road traffic accidents.2 in particular, young and novice drivers constitute the highest proportion of road traffic accident victims.2,3 in acknowledgement of this problem, the united nations has instituted a decade of action for road safety framework, with the aim of reducing worldwide road traffic fatalities by 2020.2,4,5 this framework highlights graduated driver licensing (gdl) as an activity that strengthens the process of licensing road users, reflecting the importance of maintaining procedures to ensure that only effective drivers enter the road system.2,6 the pre-licence learning-to-drive phase is important for new drivers to overcome issues associated with inexperience, gain exposure to road traffic rules, train their basic manoeuvring and vehicle handling skills and learn to recognise hazards.7 in gdl, for example, additional curfew restrictions can also address immaturity issues in novice drivers and serve to eliminate external influences which can lead to road traffic accidents.6 every country has a different set of regulations for driver licensing, at either the national or regional level, as well as its own unique philosophy and approach to driving.7,8 for example, differences exist in the minimum age permitted to start the licensing process; the training approach (including the number of required training hours and final assessment type); and various restrictions prior to full licensing.7,9 the gdl licensing process is divided into learner, intermediate/provisional and full license stages.6 in the first stage, learner drivers (lds) must obtain practical driving experience in a low-risk environment with guidance from a more experienced driver.6 in the intermediate stage, lds are subject to restrictions on nighttime driving, driving with passengers and alcohol 1department of vehicle safety & biomechanics, malaysian institute of road safety research, kajang, selangor, malaysia; 2centre for automotive research, faculty of engineering & built environment, universiti kebangsaan malaysia, bangi, selangor, malaysia; 3road transport department, akademi pengangkutan jalan malaysia, melaka, malaysia *corresponding author e-mail: zulhaidi@miros.gov.my the roles and performance of professional driving instructors in novice driver education e278 | squ medical journal, august 2017, volume 17, issue 3 consumption. only after passing these two stages do lds progress to full licensure.6 in countries that do not utilise a gdl system, these first two phases are usually combined, resulting in only pre-and full license stages; lds usually need to complete offand on-road training activities, including classroom lessons, theory tests and on-track and on-road driving sessions before undergoing a practical driving test. in malaysia, for example, the pre-licensing phase is similar to the gdl system with a two-year probationary status for new drivers; however, malaysia neither refers to these two years as a gdl period nor follows the stricter gdl scheme implemented by other countries such as new zealand, australia, the usa or canada.6,10 within the pre-licensing stage, the training process can either be informal or formal.11 with the formal approach, candidate drivers study a standardised driving curriculum and complete a certain number of training hours before taking a final test. these activities are usually handled by commercial driving schools with the involvement of professional driving instructors (pdis) who work within an approved or accredited legislative scope of the government usually in a business or occupational framework (i.e. a driving school or institute).10 in contrast, the informal approach acknowledges the eligibility of parents, family members or other adults to act as driving trainers—as any method adopted to ensure the ability of lds to drive and pass the test is considered valid—even though such instructors may be outside of the established driver education (de) system. these so-called lay instructors are sometimes referred to as private instructors or supervisors.12,13 they normally conduct informal training to help novice drivers meet the required number of supervised driving hours as part of a supervised behind-the-wheel practice scheme. for many novice drivers, the use of lay instructors is more affordable than enrolling in a commercial driving school.13 regardless of the system on which it is based, novice de should focus on three elements: the goals of the education, the educational content and the process/test.14 previous researchers have studied the goals for de and their application in a licensing system.15,16 however, the approach to de instruction is as critical as its content and assessment; central to the delivery of de content is the pdi, sometimes also referred to as a de instructor or approved driving instructor.17,18 additionally, pdis may be involved in the post-licensing stage, for example when drivers wish to upgrade their license class so as to operate heavy (i.e. lorries), recreational (i.e. all-terrain vehicles) or public transport (i.e. buses and taxis) vehicles. qualified pdis may also offer advanced courses that emphasise valueadded driving skills such as driving in hazardous or emergency situations, nocturnal or eco-driving and off-roading, occupational specialist training to drive hearses and limousines or introductory lessons to new crash avoidance or advanced braking technologies. other post-licensing driver trainers include driving instructors either fully or partially in the service of private or government institutions (such as ambulatory services in hospitals) or occupational therapist driver assessors/certified driver rehabilitation specialists for patients recovering from certain illnesses.1,19 figure 1 provides an overview of the various personnel involved in both preand post-licensure de and training. the roles and performance of the pdi in the novice de environment are particularly important since the pdi remains with the ld from their first figure 1: overview of the roles of various personnel, particularly professional driving instructors, in both preand postlicensure driver education. zulhaidi m. jawi, baba m. deros, ahmad a. a. rashid, mohd h. m. isa and azmi awang review | e279 lesson until the final assessment, which usually takes the form of a practical driving test. while previous research has examined the responsibility involved in training novice drivers, few studies have focused on the specific contributions of pdis. this review therefore aimed to analyse existing literature regarding the roles and performance of pdis in novice de. methods this review was performed in january 2017. the search strategy comprised an initial background search of google scholar (google, googleplex, mountain view, california, usa) followed by an investigation of systematic reviews/meta-analyses and original research articles included in scholarly databases [figure 2]. in the initial background search, there were 22,500 results for the keywords “driver training”, 19,400 for “driver education”, 9,360 for “driver licensing”, 4,570 for “driving instructor” and 320 for “driver instructor”. however, the majority of these articles were related to medical fields, including studies of occupational therapist driver assessors or associations between driving and illnesses such as dementia; stroke; parkinson’s disease; visual impairment; neurological conditions; orthopaedic issues; sleep problems; attention deficit hyperactivity disorder (adhd); autism spectrum disorder (asd); down’s syndrome; and the effect of drugs, medications and alcohol.20–28 the subject population was often composed of older drivers, with the articles focusing on their fitness to drive. critically, even if pdis were involved in some articles, they were not the main subjects but were instead contributors, for instance in upholding the research design or its validity and reliability.29 therefore, these articles were excluded from the final analysis. subsequently, the second and third steps of the review methodology involved searching scholarly databases for systematic reviews/meta-analyses and original research articles. all searches were performed using the keywords “driving instructor” and “driver instructor” and were limited to accessible databases such as sciencedirect (elsevier, amsterdam, the netherlands), medline® (national library of medicine, bethesda, maryland, usa), the cochrane library (cochrane, london, england, uk), inderscience publishers (geneva, switzerland), the wiley online library (john wiley & sons inc., hoboken, new jersey, usa), taylor & francis online (milton park, oxfordshire, uk) and emerald ejournals (emerald group publishing, bingley, west yorkshire, uk). the researchers’ expert knowledge of the subject of de contributed extensively to building the search mechanism and strategy; for example, as most articles on de and driver licensing originate from the usa, australia and europe, searches were often focused on publications originating from these regions.6,8,9 for original research articles, a systematic classification scheme was adopted based on previous research published by lage et al. and hachicha et al. and adapted by other researchers, including oviedotrespalacios et al.30–32 accordingly, each original research article was examined using a systematic classification scheme to determine (1) the article’s context with regards to pdis in novice de, including figure 2: diagram illustrating the search strategy used to identify literature related to the roles and performance of professional driving instructors in novice driver education. pdi = professional driving instructor; de = driver education. the roles and performance of professional driving instructors in novice driver education e280 | squ medical journal, august 2017, volume 17, issue 3 the research methodology, type of analysis and the pdi’s position of involvement in the study; (2) the competency of pdis in comparison to other experienced or lds; and (3) the contribution of pdis to the learning process (i.e. the influence of the pdi on the novice driver’s performance). in order to ensure quality, the scope of the review included only articles published between 1990–2016 in peer-reviewed journals. grey literature was not considered suitable for analysis, although it was used to gain insights into the topic. unlike medical research articles, which normally have extensive, descriptive titles that highlight the health issues covered, articles related to pdi at the novice driver level were found to have less explicit titles which required close scrutiny of the abstract, keywords and main text of the articles. results and discussion neither systematic reviews nor meta-analyses relating to pdis at the novice de level were found during the literature research, indicating a scarcity of research on this topic. however, a total of 14 original research articles were identified from 10 countries, including sweden, the netherlands, latvia, france, spain, switzerland, the uk, norway, finland and australia.16,17,27,33–43 the most common data collection tools were questionnaires and interviews. other table 1: literature review of original research articles related to the roles and performance of professional driving instructors in novice driver education16,17,27,33–43 author and year of study methods pdi position in study n type of results pdi sample ld sample almberg et al.27 (2017)* interviews and questionnaires secondary sample† 9 33 lds with adhd or asd quantitative and qualitative roelofs et al.35 (2015) psychometric analyses from an examination database sample 4,741 prospective pdis quantitative austers et al.38 (2015) questionnaires comparative sample 32 400 eds (152 in study 1 and 248 in study 2) quantitative boccara et al.41 (2015) longitudinal analyses dyadic sample 4 pdi-ld dyads quantitative molina et al.16 (2014) interviews sample 676 quantitative de stefani et al.43 (2014) video-recording corpus noncomparative sample 2 7 qualitative arnau-sabatés et al.36 (2012) questionnaires sample 177 future pdis quantitative passmore et al.17 (2011) interviews sample 15 qualitative boccara et al.34 (2011)‡ questionnaires secondary sample† 38 150 quantitative boccara et al.33 (2011)‡ questionnaires comparative sample 38 149 quantitative rismark et al.42 (2007) interviews and observation noncomparative sample 51 191 qualitative lajunen et al.37 (2003) questionnaires comparative sample 47 applicant pdis 54 quantitative treffner et al.39 (2002) instrumented cars comparative sample 4 9 eds (5 in study 1 and 4 in study 2) quantitative katila et al.40 (1996) questionnaires comparative sample 108 382 quantitative pdi = professional driving instructor; ld = learner driver; adhd = attention deficit hyperactivity disorder; asd = autism spectrum disorder; eds = experienced drivers. *first published online in july 2015. †the researchers collected data on/from pdis but placed very little emphasis on the results or discussions of the pdi sample as compared to the ld sample. ‡the same samples were discussed in two separate articles. zulhaidi m. jawi, baba m. deros, ahmad a. a. rashid, mohd h. m. isa and azmi awang review | e281 methods included psychometric and longitudinal analyses, a video-recording corpus, instrumented cars and observation. a total of 5,904 pdis were involved, of which 939 were already qualified while the remaining 4,965 were classified as prospective, future or applicant pdis. additionally, a total of 1,230 learner or experienced drivers were involved, of which 33 had adhd or asd.27 it should be noted that the pdi and ld samples mentioned by boccara et al. were discussed in two separate articles.33,34 in total, 10 of the studies reported quantitative results, three reported qualitative results and one reported results using both approaches [table 1].16,17,27,33–43 a review of the original research articles revealed seven ways of classifying the roles of pdis within the study: as secondary samples in relation to lds; as samples of future/applicant/prospective pdis; as samples of future/applicant/prospective pdis in comparison to lds; as specific samples; as samples compared with experienced or lds; as non-comparative samples; and as dyadic samples (i.e. including both pdis and lds in pairs).16,17,27,33–43 the roles of pdis were deemed non-primary in almberg et al.’s and one of boccara et al.’s studies.27,34 moreover, roelofs et al., arnau-sabatés et al. and lajunen et al. each focused on factors outside the table 2: literature review of original research articles placing less emphasis on professional driving instructors’ roles and performance in novice driver education27,34–37 author and year of study objective of study type of pdi sample results/discussion conclusion almberg et al.27 (2017)* to investigate the facilitators/barriers to de among lds with asd or adhd from the perceptive of both lds and their pdis secondary sample† • lds with asd required twice the number of driving lessons and more on-road tests than those with adhd; translating theory to practice and adapting to ‘new’ driving circumstances were the most common difficulties for lds with asd. • lds with adhd had to repeat written tests more often than those with asd and found theoretical concepts challenging. for lds with asd and adhd, the licensure training process was a stressful experience boccara et al.34 (2011) to examine lds’ selfassessment of their driving capabilities during de training secondary sample† • while men tended to assess themselves more positively, no substantial gender difference was observed at various training stages. • lds’ self-ratings correlated negatively with the number of selfestimated driving hours but did not differ significantly with pdi estimates. lds’ self-assessments were more positive in the initial stage of driver training as compared to later self-assessments roelofs et al.35 (2015) to evaluate the reliability, validity and fairness of different versions of theoretical tests for prospective pdis specific sample of prospective pdis • psychometric analyses showed that the theory tests resulted in reliable and fair decisions regarding pdi certification. • the predictive validity for pdi certification was low for theory tests in the final assessment. follow-up studies should focus on determining whether improved pdi examinations will produce safer drivers arnau-sabatés et al.36 (2012) to analyse the relationship between emotional abilities and drivers’ self-reported risky attitudes specific sample of prospective pdis • risky attitudes correlated negatively with emotional abilities. • adaptability and interpersonal abilities were described based on the global risk attitude index. • the propensity to take risks was influenced by stress management and interpersonal components. • emotional abilities had the weakest relationship with alcohol and drug use. emotional abilities were important to lessen risky driving behaviours and should be stressed in prevention programmes lajunen et al.37 (2003) to investigate the effects of socially desirable response tendencies on selfreports of driving in public and private environments comparative samples of applicant pdis and lds • aberrant behaviours were reported less frequently in public as compared to private settings. • socially desirable response biases were somewhat decreased in dbq responses. self-reports of driver behaviour were fairly reliable and free from socially desirable response bias pdi = professional driving instructor; de = driver education; ld = learner driver; asd = autism spectrum disorder; adhd = attention deficit hyperactivity disorder; dbq = driver behaviour questionnaire. *first published online in july 2015. †the researchers collected data on/from pdis but placed very little emphasis on the results or discussions of the pdi sample as compared to the ld sample. the roles and performance of professional driving instructors in novice driver education e282 | squ medical journal, august 2017, volume 17, issue 3 table 3: literature review of original research articles placing more emphasis on professional driving instructors’ roles and performance in novice driver education16,17,33,38–43 author and year of study objective of study type of pdi sample results/discussion conclusion molina et al.16 (2014) to analyse the implementation of a driver training curriculum using the gde framework as reference specific sample • a two-factor solution was found to match the first dimension of the gde framework; however, there was no factor differentiation in the second dimension. • the curriculum emphasised knowledge and skills related to operative and tactical aspects of driving; however, less importance was placed on risk prevention and self-evaluation skills at the strategic and personal levels of driving behaviour. potential weaknesses were identified in the curriculum as per the gde framework; these potential flaws may be overcome by the proper application of instructional methods and teaching tools to correct ld training passmore et al.17 (2011) to explore the experiences of qualified driving instructors (i.e. adis or pdis) in using coaching as a method for novice de specific sample • seven themes were identified: understanding the nature of coaching; building an integrated approach; developing new skills; accepting responsibility for learning; helping learners to change their attitudes; performance; and achieving wider adoption of coaching within the industry. coaching has a role to play in de austers et al.38 (2015) study 1: to study the judgement of eds and pdis in predicting road accidents based on traffic rule violations comparative sample with eds • there were no differences in ratings of traffic rules by violators and non-violators. • however, there were rating differences between pdis and violators (i.e. violators rated speeding as being a less important factor leading to accidents, whereas driving in reverse and u-turn rules were deemed more important). • pdis were slightly better than eds in predicting accidents based on violations. pdis and eds did not differ significantly in their assessments of ‘unwritten’ traffic rules or judgements that particular traffic rules can facilitate road safety study 2: to explore eds’ and pdis’ assessments of ‘unwritten’ driving rules to explain safe versus risky driving comparative sample with eds • there were some differences in judgments regarding ‘unwritten’ driving rules (i.e. pdis tended to view driving behaviour negatively). • no significant differences were detected between pdis and eds in judging ‘unwritten’ traffic rules, although some of the judgments were interesting (i.e. participants reported that signalling another driver about a police post facilitated road safety). boccara et al.33 (2011) to examine the development of lds’ self-assessments compared to pdi assessments of ld performance comparative sample with lds • ld self-assessments and pdi ratings increased positively in relation to all aspects of the assessment scale as the training progressed. • the lds’ and pdis’ ratings did not differ significantly between each of the three tested driving situations. • similar results were observed between male and female lds at each stage of training. • lds’ overestimation of their driving skills was mainly observed during step one, less so during steps two and three and never during step four. lds accurately assessed their driving skills as the training course progressed treffner et al.39 (2002) study 1: to examine whether deceleration and braking control were augmented by sensitivity to perceptual variable tau based on ttc comparative sample with eds • as hypothesised based on lee’s prediction, braking was initiated at a ttc of 5 seconds and tau-dot was maintained at approximately 0.5, irrespective of skill level.44 training programmes should concentrate on increasing driver stability as a foundation to enhancing driver control while driving, thereby improving road safety study 2:to measure supposed differences in driving behaviour between eds and pdis during a set of normal driving manoeuvres comparative sample with eds • pdis had different cornering paths and emergency braking strategies; their ability to perform a high-speed swerve and perform effectively in the recovery task was higher as compared to eds. • pdis applied greater bracing forces using the door and console and greater footrest forces during emergency braking as compared to eds. • pdis more frequently braced themselves to counter g-forces when driving, indicating an active stabilisation strategy that boosted both postural stability and overall stability and consistency. zulhaidi m. jawi, baba m. deros, ahmad a. a. rashid, mohd h. m. isa and azmi awang review | e283 scope of the systematic classification scheme (i.e. the validity of theoretical assessments for pdis as well as emotional abilities related to self-reported risky driving behaviours and the effects of socially desirable response bias on self-reported driving behaviours).35–37 nonetheless, despite their lack of emphasis on the roles of pdis in novice de, these studies provided useful insights into novice de, including the importance of psychological factors on driving behaviours and selfassessment [table 2].27,34–37 table 3 summarises the remaining six original research articles which placed more emphasis on the role of pdis in novice de, in which pdi samples were either analysed as a specific sample or compared to experienced or ld samples in terms of driving behaviours or knowledge.16,17,33,38–40 austers et al. found that pdis and eds did not differ in their judgement of ‘unwritten’ traffic rules, with pdis only slightly better than lds in predicting traffic violations as causes of accidents.38 moreover, treffner et al. reported that pdis performed better than experienced drivers during a variety of everyday driving manoeuvres, particularly with regards to the application of braking and bracing strategies.39 while studies by boccara et al. and katila et al. were generally focused on the learning process rather than determining the comparative performance of pdis, the findings of these studies nevertheless suggested that there were skill-specific performance differences between pdis and lds; in other words, these two groups were equally competent in certain skills but not others.33,40 one potential explanation for this variation is that while some skills can be taught in katila et al.40 (1996) to compare the views of pdis and lds on skid training courses and why these special training courses have failed to get people to drive more safely on slippery roads comparative sample with lds • in all of the studied countries (denmark, finland, norway and sweden), pdis’ and lds’ assessments of skid training courses were the same. • upon completion of the training course by lds, manoeuvring skills were deemed more important than anticipating skills even though the purpose of the training course was to improve anticipating skills. • the training courses may have given lds the impression that manoeuvring skills were more vital than anticipating skills. manoeuvring exercises increased lds’ selfconfidence and may have influenced lds to underestimate associated risks of skidding, causing them to drive at higher speeds on slippery roads de stefani et al.43 (2014) to study how pdis direct lds to perform salient driving actions noncomparative sample • two types of instructions were frequent during training: navigational and car control/ traffic check instructions. • instructions were frequently given non-verbally and were highly effective in producing immediate execution. • the coordination of time, space, talk and action during driving lessons was complex as lds were required to continuously monitor events and actions both inside and outside of the car. instructional sequences both influence and are influenced by language and social interactions rismark et al.42 (2007) to observe pdi-ld interactions during on-road practice and determine how pdis can use dialogue as an effective learning tool in de noncomparative sample • during on-road practice, pdi-ld dialogues created a shared understanding of the full road traffic situation. • different approaches by pdis led to intersubjectivity of occurring traffic situations in qualitatively different ways. • pdis practiced both clarifying and elaborative processes to inculcate responsible driving. • the merging of the roles of ‘teacher’ and ‘learner’ laid a foundation for subsequent scaffolding processes during on-road practice. further knowledge is still needed to truly determine what makes de effective in terms of driving behaviours and accident risks boccara et al.41 (2015) to comprehend the scaffolding activity of pdis during driving lessons in urban traffic dyadic sample with lds • pdis used integrative approaches in the form of ‘cutting’ and ‘decoupling’ during the learning process as opposed to the step-bystep method suggested in the curriculum. • the pdis transferred responsibility for driving components to lds in the following order: (1) technical manoeuvres; 2) situation identification; and (3) focusing on other road users. • lds’ driving autonomy and efficiency increased as training progressed; however, their execution of basic tasks in complex situations remained uncertain at the end of the training and pdis remained dominant with regards to navigational tasks. by the end of training, lds did not independently perform navigational tasks, with pdi navigation interventions increasing as training progressed; in effect, pdis did not completely uncouple the decision-making process pdi = professional driving instructor; gde = goals for driver education; ld = learner driver; adi = approved driving instructor; de = driver education; ed = experienced driver; ttc = time-to-contact. the roles and performance of professional driving instructors in novice driver education e284 | squ medical journal, august 2017, volume 17, issue 3 classroom settings, others cannot. for instance, while lds can learn traffic laws and regulations from books and the internet, learning to perceive road hazards generally comes only with driving practice, of which pdis have much more hands-on experience. in terms of assessing the contributions of pdis to the learning process, passmore et al. provided a qualitative assessment of pdis’ perspectives of coaching novice des.17 out of the seven themes which emerged from the analysis, several indicated that pdis did not overly contribute to novice de, particularly in stressing learner’s acceptance of responsibility for their learning or helping learners to change their attitudes.17 another study by boccara et al. on the pdi-ld training process suggested that pdis contributed to ld learning even though sometimes the instruction was not delivered according to recommended methods in the curriculum.41 the three remaining studies did not fall under the scope of the systematic classification scheme. for example, molina et al.’s study focused on the delivery of de curricula based on the goals for driver education framework, while rismark et al. and de stefani et al. addressed language use during driving instruction and social interactions in de.16,42,43 in general, the findings of the literature review reaffirm that very little research has been published internationally with regard to pdi; moreover, the research available is highly dispersed and covers a wide range of subtopics.16 more exploration is needed to enrich academic understanding of pdis’ roles and performance and help road safety practitioners reshape or enhance novice de programmes. in addition, such research would enable related government agencies to implement best practices and correctly position pdis in the national de training system. this may eventually lead to the development of an internationally recognised pdi management approach and assessment system. conclusion this review aimed to assess existing literature on the roles and performance of pdis in novice de. overall, the existing literature was insufficient to provide an in-depth understanding of the influential role of pdis in de. furthermore, with regards to the competency and contribution to the novice driver learning process on the part of the pdi, most identified articles were very diverse and covered many different subtopics. further research would contribute to a more developed understanding of the role and performance of pdis; the results of such studies would be useful for future interventions, which might include the implementation of an internationally recognised pdi management approach as well as critical requirements for pdi certifications. a c k n o w l e d g e m e n t s the authors greatly appreciate the feedback provided by the anonymous reviewers and editors as part of the peer-review and submission process. references 1. unsworth c, harries p, davies m. using social judgment theory method to examine how experienced occupational therapy driver assessors use information to make fitness-to-drive reco mmendations. br j occup ther 2015; 78:109–20. doi: 10.1177/ 0308022614562396. 2. world health organization. global status report on road safety 2015. from: www.who.int/violence_injury_prevention/road_ safety_status/2015/en/ accessed: jun 2017. 3. scott-parker b, watson b, king mj. understanding the psychosocial factors influencing the risky behaviour of young drivers. transp res part f traffic psychol behav 2009; 12:470–82. doi: 10.1016/j.trf.2009.08.003. 4. al-lamki l. life loss and disability from traffic accidents: it is imperative we all act now. sultan qaboos univ med j 2010; 10:1–5. 5. united nations road safety collaboration. global plan for the decade of action for road safety 2011-2020. from: www.who. int/roadsafety/decade_of_action/plan/en/ accessed: jun 2017. 6. bates lj, allen s, armstrong k, watson b, king mj, davey j. graduated driver licensing: an international review. sultan qaboos univ med j 2014; 14:e432–41. 7. curry ae, garcia-españa jf, winston fk, ginsburg k, durbin dr. variation in teen driver education by state requirements and sociodemographics. pediatrics 2012; 129:453–57. doi: 10.1542/ peds.2011-2303. 8. mayhew dr. driver education and graduated licensing in north america: past, present, and future. j safety res 2007; 38:229–35. doi: 10.1016/j.jsr.2007.03.001. 9. al-matawah ja. an investigation of driver attitudes towards road safety in kuwait. phd thesis, 2008, university of southampton, southampton, uk. 10. jawi zm, deros b m, osman mr, awang a. a systemic overview on driver training and driver licensing system in malaysia. proceedings conference asean road safety 2015; 185–91. 11. tronsmoen t. differences between formal and informal practical driver training as experienced by the learners themselves. transp res part f traffic psychol behav 2011; 14:176–88. doi: 10. 1016/j.trf.2010.11.009. 12. gregersen np. systematic cooperation between driving schools and parents in driver education: an experiment. accid anal prev 1994; 26:453–61. doi: 10.1016/0001-4575(94)90036-1. 13. jacobsohn l, garcía-españa jf, durbin dr, erkoboni d, winston fk. adult-supervised practice driving for adolescent learners: the current state and directions for interventions. j safety res 2012; 43:21–8. doi: 10.1016/j.jsr.2011.10.008. 14. nyberg a, gregersen np, wiklund m. practicing in relation to the outcome of the driving test. accid anal prev 2007; 39:159–68. doi: 10.1016/j.aap.2006.06.015. 15. hatakka m, keskinen e, gregersen np, glad a, hernetkoski k. from control of the vehicle to personal self-control: broadening the perspectives to driver education. transp res part f traffic psychol behav 2002; 5:201–155. doi: 10.1016/s1369-8478(02) 00018-9. https://doi.org/10.1177/0308022614562396 https://doi.org/10.1177/0308022614562396 https://doi.org/10.1016/j.trf.2009.08.003 https://doi.org/10.1542/peds.2011-2303 https://doi.org/10.1542/peds.2011-2303 https://doi.org/10.1016/j.jsr.2007.03.001 https://doi.org/10.1016/j.trf.2010.11.009 https://doi.org/10.1016/j.trf.2010.11.009 https://doi.org/10.1016/0001-4575%2894%2990036-1 https://doi.org/10.1016/j.jsr.2011.10.008 https://doi.org/10.1016/j.aap.2006.06.015 https://doi.org/10.1016/s1369-8478%2802%2900018-9 https://doi.org/10.1016/s1369-8478%2802%2900018-9 zulhaidi m. jawi, baba m. deros, ahmad a. a. rashid, mohd h. m. isa and azmi awang review | e285 16. molina jg, garcía-ros r, keskinen e. implementation of the driver training curriculum in spain: an analysis based on the goals for driver education (gde) framework. transp res part f traffic psychol behav 2014; 26:28–37. doi: 10.1016/j.trf. 2014.06.005. 17. passmore j, mortimer l. the experience of using coaching as a learning technique in learner driver development: an ipa study of adult learning. int coach psychol rev 2011; 6:33–45. 18. zakrajsek js, shope jt, greenspan ai, wang j, bingham cr, simons-morton bg. effectiveness of a brief parent-directed teen driver safety intervention (checkpoints) delivered by driver education instructors. j adolesc health 2013; 53:27–33. doi: 10.1016/j.jadohealth.2012.12.010. 19. classen s, krasniuk s, knott m, alvarez l, monahan m, morrow s, et al. interrater reliability of western university’s on-road assessment. can j occup ther 2016; 83:317–25. doi: 10.1177/0008417416663228. 20. ott br, festa ek, amick mm, grace j, davis jd, heindel wc. computerized maze navigation and on-road performance by drivers with dementia. j geriatr psychiatry neurol 2008; 21:18–25. doi: 10.1177/0891988707311031. 21. aslaksen pm, ørbo m, elvestad r, schäfer c, anke a. prediction of on-road driving ability after traumatic brain injury and stroke. eur j neurol 2013; 20:1227–33. doi: 10.1111/ene. 12172. 22. wood jm, worringham c, kerr g, mallon k, silburn p. quantitative assessment of driving performance in parkinson’s disease. j neurol neurosurg psychiatry 2005; 76:176–80. doi: 10.1136/ jnnp.2004.047118. 23. kübler tc, kasneci e, rosenstiel w, heister m, aehling k, nagel k, et al. driving with glaucoma: task performance and gaze move ments. optom vis sci 2015; 92:1037–46. doi: 10.1097/opx.000 0000000000702. 24. fox gk, bashford gm, caust sl. identifying safe versus unsafe drivers following brain impairment: the coorabel programme. disabil rehabil 1992; 14:140–5. doi: 10.3109/09638289209165850. 25. kalamaras ma, rando a, pitchford dg. driving plastered: who does it, is it safe and what to tell patients. anz j surg 2006; 76:439–41. doi: 10.1111/j.1445-2197.2006.03762.x. 26. akerstedt t, hallvig d, anund a, fors c, schwarz j, kecklund g. having to stop driving at night because of dangerous sleepiness: awareness, physiology and behaviour. j sleep res 2013; 22:380–8. doi: 10.1111/jsr.12042. 27. almberg m, selander h, falkmer m, vaz s, ciccarelli m, falkmer t. experiences of facilitators or barriers in driving education from learner and novice drivers with adhd or asd and their driving instructors. dev neurorehabil 2017; 20:59–67. doi: 10.3109/17518423.2015.1058299. 28. lamers ct, ramaekers jg. visual search and urban driving under the influence of marijuana and alcohol. hum psychopharmacol 2001; 16:393–401. doi: 10.1002/hup.307. 29. taylor je, deane fp, podd jv. driving fear and driving skills: comparison between fearful and control samples using standardised on-road assessment. behav res ther 2007; 45:805–18. doi: 10.1016/j.brat.2006.07.007. 30. lage m jr, filho mg. variations of the kanban system: literature review and classification. int j prod econ 2010; 125:13–21. doi: 10.1016/j.ijpe.2010.01.009. 31. hachicha w, ghorbel a. a survey of control-chart patternrecognition literature (1991–2010) based on a new conceptual classification scheme. comput ind eng 2012; 63:204–22. doi: 10.10 16/j.cie.2012.03.002. 32. oviedo-trespalacios o, haque mm, king m, washington s. understanding the impacts of mobile phone distraction on driving performance: a systematic review. transp res part c emerg technol 2016; 72:360–80. doi: 10.1016/j.trc.2016.10.006. 33. boccara v, delhomme p, vidal-gomel c, rogalski j. development of student drivers’ self-assessment accuracy during french driver training: self-assessments compared to instructors’ assess ments in three risky driving situations. accid anal prev 2011; 43:1488–96. doi: 10.1016/j.aap.2011.02.029. 34. boccara v, delhomme p, vidal-gomel c, rogalski j. time course of driving-skill self-assessments during french driver training. accid anal prev 2011; 43:241–6. doi: 10.1016/j.aap.2010.08.016. 35. roelofs ec, bolsinova m, verschoor a, vissers ja. development and evaluation of a competence-based exam for prospective driving instructors. j traffic transp eng 2015; 3:147–57. doi: 10. 17265/2328-2142/2015.03.003. 36. arnau-sabatés l, sala-roca j, jariot-garcia m. emotional abilities as predictors of risky driving behavior among a cohort of middle aged drivers. accid anal prev 2012; 45:818–25. doi: 10.1016/j.aap.2011.07.021. 37. lajunen t, summala h. can we trust self-reports of driving? effects of impression management on driver behaviour questionnaire responses. transp res part f traffic psychol behav 2003; 6:97–107. doi: 10.1016/s1369-8478(03)00008-1. 38. austers i, reņģe v, šķilters j. driving instructors are not much better (at least sometimes) in explaining driving safety than ordinary drivers. mediterr j soc sci 2015; 6:416–23. doi: 10.5901/mjss.2015.v6n2s1p416. 39. treffner p, barrett r, petersen a. stability and skill in driving. hum mov sci 2002; 21:749–84. doi: 10.1016/s0167-9457(02) 00168-9. 40. katila a, keskinen e, hatakka m. conflicting goals of skid training. accid anal prev 1996; 28:785–9. doi: 10.1016/s00014575(96)00045-0. 41. boccara v, vidal-gomel c, rogalski j, delhomme p. a longit udinal study of driving instructor guidance from an activityoriented perspective. appl ergon 2015; 46:21–9. doi: 10.1016/j. apergo.2014.06.001. 42. rismark m, sølvberg am. effective dialogues in driver education. accid anal prev 2007; 39:600–5. doi: 10.1016/j.aap.2006.10.008. 43. de stefani e, gazin ad. instructional sequences in driving lessons: mobile participants and the temporal and sequential organization of actions. j pragmat 2014; 65:63–79. doi: 10.1016 /j.pragma.2013.08.020. 44. lee dn. a theory of visual control of braking based on information about time-to-collision. percept 1976; 5:437–59. https://doi.org/10.1016/j.trf.2014.06.005 https://doi.org/10.1016/j.trf.2014.06.005 https://doi.org/10.1016/j.jadohealth.2012.12.010 https://doi.org/10.1177/0008417416663228 https://doi.org/10.1177/0891988707311031 https://doi.org/10.1111/ene.12172 https://doi.org/10.1111/ene.12172 https://doi.org/10.1136/jnnp.2004.047118 https://doi.org/10.1136/jnnp.2004.047118 https://doi.org/10.1097/opx.0000000000000702 https://doi.org/10.1097/opx.0000000000000702 https://doi.org/10.3109/09638289209165850 https://doi.org/10.1111/j.1445-2197.2006.03762.x https://doi.org/10.1111/jsr.12042 https://doi.org/10.3109/17518423.2015.1058299 https://doi.org/10.1002/hup.307 https://doi.org/10.1016/j.brat.2006.07.007 https://doi.org/10.1016/j.ijpe.2010.01.009 https://doi.org/10.1016/j.cie.2012.03.002 https://doi.org/10.1016/j.cie.2012.03.002 https://doi.org/10.1016/j.trc.2016.10.006 https://doi.org/10.1016/j.aap.2011.02.029 https://doi.org/10.1016/j.aap.2010.08.016 https://doi.org/10.17265/2328-2142/2015.03.003 https://doi.org/10.17265/2328-2142/2015.03.003 https://doi.org/10.1016/j.aap.2011.07.021 https://doi.org/10.1016/s1369-8478%2803%2900008-1 https://doi.org/10.5901/mjss.2015.v6n2s1p416 https://doi.org/10.1016/s0167-9457%2802%2900168-9 https://doi.org/10.1016/s0167-9457%2802%2900168-9 https://doi.org/10.1016/s0001-4575%2896%2900045-0 https://doi.org/10.1016/s0001-4575%2896%2900045-0 https://doi.org/10.1016/j.apergo.2014.06.001 https://doi.org/10.1016/j.apergo.2014.06.001 https://doi.org/10.1016/j.aap.2006.10.008 https://doi.org/10.1016/j.pragma.2013.08.020 https://doi.org/10.1016/j.pragma.2013.08.020 department of obstetrics & gynaecology, kasturba medical college, manipal university, mangalore, karnataka, india *corresponding author e-mail: pralhadkushtagi@hotmail.com املقاومة الشريانية يف أواخر األشهر الثالثة األوىل من احلمل باعتباره مؤشرا الحقا على ارتفاع ضغط الدم املرتبط باحلمل براله�د كو�شت�جي و انو�ش� اإمي�ين abstract: objectives: this study aimed to examine the association between indicators of arterial resistance occurring late in the first trimester and the subsequent development of pregnancy-related hypertension. methods: this study took place between may 2014 and august 2015 and included 329 consecutive women with singleton pregnancies attending the antenatal clinics of a medical college in karnataka, india, during this period. pulse pressure (pp) and uterine artery doppler parameters were recorded between 11–14 gestational weeks. consequently, women were followed-up until after delivery for subsequent hypertension. results: hypertension occurred more frequently if pp was high (17.6% versus 14.4% of pregnancies without high pp; p = 0.713), if a diastolic notch (dn) was present (15.1% versus 12.8% of pregnancies with an absent dn; p = 0.612) and if the resistive index (ri) was raised (22.2% versus 14.3% of pregnancies without raised ri; p = 0.366). a raised pulsatility index (pi) was significantly associated with hypertension (p = 0.013). the risk of hypertension was approximately seven-fold higher if two or more arterial resistance indicators were used, except with a present dn plus a raised ri or a present dn plus high pp. all arterial resistance indicators showed negative predictability (>85.6%) and good specificity (≥95.0%), except for the presence of a dn. a population-specific cut-off pi value of 1.72 had high negative predictability (92.8%) and good sensitivity (70.8%) and specificity (65.1%). conclusion: raised pi in the late first trimester was a significant predictor of hypertension later in pregnancy. a combination of arterial resistance indicators may enhance prediction of subsequent hypertension. keywords: vascular resistance; pulse pressure; uterine artery; doppler ultrasonography; pregnancy-induced hypertension; india. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل فح�س العالقة بني عدد من موؤ�رسات املق�ومة ال�رسي�نية التي حتدث يف وقت مت�أخر يف الأ�شهر الثالثة الأوىل من احلمل وارتب�طه� بحدوث ارتف�ع �شغط الدم لحق�. الطريقة: اأجريت هذه الدرا�شة يف الفرتة م� بني م�يو 2014 واأغ�شط�س 2015, و�شملت 329 امراأة ح�مل يف طفل مفرد من الالتي ح�رسن عي�دات م� قبل الولدة يف كلية الطب يف ولية ك�رن�ت�ك�, الهند, على التوايل خالل هذه الفرتة. مت قي��س �شغط النب�س و عمل دوبلر املوج�ت فوق ال�شوتية على ال�رسي�ن الرحمي بني 14-11 اأ�شبوع من احلمل. وبعد ذلك, متت مت�بعة هوؤلء الن�ش�ء ايل بعد الولدة لرتقب حدوث ارتف�ع �شغط الدم لحق�. النتائج: مت ر�شد حدوث ارتف�ع يف �شغط الدم ب�شكل متكرر اإذا ك�ن �شغط النب�س مرتفع� )%17.6 مق�بل %14.4 من ح�لت احلمل ؛ p = 0.713(, اإذا ك�ن هن�ك ارتف�ع يف ال�شق النب�ش�طي )%15.1 مق�بل %12.8 من ح�لت احلمل؛ p = 0.612( اأواإذا مت رفع موؤ�رس املق�ومة ri )%22.2 مق�بل %14.3 من ح�لت احلمل؛ 0.366 = p(. ك�نت هن�ك عالقة ذات دللة اح�ش�ئية بني ارتف�ع موؤ�رس النب�س )pi( وارتف�ع �شغط الدم )p = 0.013(. وك�ن مع�مل خطورة ارتف�ع �شغط الدم حوايل �شبعة اأ�شع�ف اأعلى اإذا مت ا�شتخدام اثنني اأو اأكرث من موؤ�رسات مق�ومة ال�رسايني, اإل مع وجود ال�شق الأنب�ش�طي ب�لإ�ش�فة اإىل ارتف�ع موؤ�رس املق�ومة ri اأو ارتف�ع �شغط النب�س. اأظهرت جميع موؤ�رسات املق�ومة ال�رسي�نية تنبوؤا �شلبي� )%85.6>( ودرجة جيدة تنبوؤا حدود 1.72 يف ب�ل�شك�ن اخل��شة النب�س موؤ�رس قطع لقيمة وك�ن انب�ش�طي. �شق وجود يف ال اخل�شو�شية )95.0%≤(, مع�مل من pi ع�يل ال�شلبية )%92.8( وقيمتي ح�ش��شية وخ�شو�شية جيدتني )%70.8( و علي الرتتيب )%65.1(. اخلال�صة: اأظهر اأرتف�ع موؤ�رس النب�س يف اأواخر الأ�شهر الثالثة الأوىل ارتب�ط� كبريا مع ارتف�ع �شغط الدم يف وقت لحق من احلمل. وجود عدد من موؤ�رسات مق�ومة ال�رسايني قد يوؤدي اإىل تعزيز التنبوؤ ب�رتف�ع �شغط الدم يف احلمل لحق�. الكلمات املفتاحية: مق�ومة الأوعية الدموية؛ �شغط النب�س؛ ال�رسي�ن الرحمي؛ دوبلر املوج�ت فوق ال�شوتية؛ ارتف�ع �شغط الدم الن�جم عن احلمل؛ الهند. arterial resistance in late first trimester as a predictor of subsequent pregnancy-related hypertension *pralhad kushtagi and anoosha emani clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e451–457, epub. 30 nov 16 submitted 21 apr 16 revision req. 12 jun 16; revision recd. 5 jul 16 accepted 31 jul 16 doi: 10.18295/squmj.2016.16.04.008 advances in knowledge among the studied cohort, a raised uterine artery pulsatility index (pi) in the late first trimester was significantly associated with the development of hypertension later in pregnancy. moreover, the risk of subsequently developing hypertension was approximately seven-fold higher if two or more arterial resistance indicators in the late first trimester were used in combination, except with certain combinations of indicators. arterial resistance in late first trimester as a predictor of subsequent pregnancy-related hypertension e452 | squ medical journal, november 2016, volume 16, issue 4 during pregnancy, the development of hypertension after 20 gestational weeks is associated with significant maternal and fetal morbidity and mortality.1 along with sepsis and haemorrhage, it is one of the three main causes of maternal mortality; nearly 15% of deaths are directly due to hypertensive disorders.2 as early detection is therefore critical, tests to predict pregnancy-related hypertension have been developed using the following indicators: placental perfusion and vascular resistance (e.g. ‘roll-over’ and cold pressor tests and uterine artery doppler evaluations); placental products (e.g. proangiogenic and antiangiogenic proteins, human chorionic gonadotropin, placental protein 13 and inhibin a measurements); renal dysfunction (e.g. fractional urate clearance and microalbuminuria tests); and endothelial dysfunction (e.g. fibronectin, pand l-selectin and vascular cell adhesion molecule 1 assessments).3 unfortunately, these investigations and even proteomic and metabolomic tests have all failed individually to provide a reliable means of predicting pregnancy-related hypertension.3 this may be because most of these tests are carried out after 16 gestational weeks, whereas pregnancy-related hypertension by definition manifests after 20 gestational weeks; this would suggest that the disease pathology occurs beforehand, perhaps even during the first trimester of pregnancy.4 vasospasm is central to the pathology of pregnancy-related hypertension and affects multiple organ systems, including uteroplacental circulation. as such, analysing arterial compliance is thought to be helpful in predicting pregnancy-related hypertension.5 arterial compliance in systemic circulation can be measured via pulse pressure (pp), while compliance in uteroplacental circulation can be gauged using uterine artery doppler flow studies. previous research has shown that a 1 mmhg rise in pp during early pregnancy could be associated with a 6% increase in the risk of developing pre-eclampsia.6 similarly, a study evaluating the uterine artery pulsatility index (pi) demonstrated that there is a greater decrease in uterine artery pi between 11–14 gestational weeks and 21–25 gestational weeks in pregnancies with a normal outcome compared to those with preeclampsia.7 the present study aimed to examine the potential association between arterial resistance indicators in the late first trimester, including pp and uterine artery doppler flow velocimetry indices, and the occurrence of hypertension later in pregnancy. methods this study took place between may 2014 and august 2015 at a medical college in southern karnataka, india. the inclusion criteria included consecutive women who were between 11–14 gestational weeks with singleton pregnancies attending antenatal units attached to the medical college during the study period. women with a prior history of pregnancyrelated hypertension, those currently taking drugs likely to interfere with vasculature or circulation (e.g. β-mimetics, aspirin, heparin, vasodilators, smooth muscle relaxants, antioxidants or calcium) and known cases of vascular disease, autoimmune disorders, essential hypertension, renal disease, diabetes mellitus or antiphospholipid syndrome were excluded from the study. the necessary sample size was calculated based on a known incidence of 15% for hypertensive disorders of pregnancy, in order to provide a 95% confidence interval (ci) and with 80% power, according to the following formula:8 where z is the level of confidence (95%), p is the expected prevalence (15%) and d is the desired precision (3–5%). these calculations resulted in a required sample size of 384. of the 8,043 deliveries by women who underwent antenatal care at the selected antenatal clinics during the study period, pregnancyrelated hypertension was present in 1,190 cases (14.8%). there were 504 women who met the inclusion criteria; however, 33 (6.5%) either miscarried or delivered before 32 gestational weeks and 142 (28.2%) did not deliver at the hospital. therefore, a total of 329 women (65.3%) were included in the final analysis. at the time of recruitment, each participant’s blood pressure (bp) was taken after a 20-minute resting period. the bp measurements were taken from the brachial artery of the non-dominant arm while sitting, application to patient care the findings of the current study indicate that selected indicators of arterial resistance in the late first trimester—including pulse pressure (pp) calculated from routinely recorded blood pressure measurements during regular healthcare visits and uterine artery pi determined via doppler ultrasonography during nuchal translucency screening—can be used to predict the development of hypertension later in pregnancy. however, population-specific reference values for arterial resistance indicators are needed in order to more reliably predict the development of pregnancy-related hypertension among specific patient groups. n = z2p(1-p)/d2 pralhad kushtagi and anoosha emani clinical and basic research | e453 using a calibrated mercury sphygmomanometer and a cuff with a length of 1.5 times that of the upper arm circumference.9 the pp was calculated as the difference between systolic and diastolic recordings or the first and fifth korotkoff sounds.10 as there was no standard reference range available for pp, 100 non-pregnant healthy women between 15–40 years old were recruited among postgraduates, interns, medical students, nursing students and staff nurses at the antenatal units for the purposes of recording their bp. from their bp measurements, the mean pp ± standard deviation of this group was calculated to be 38.33 ± 6.44 mmhg. therefore, for the pregnant women, pp was considered low if it was less than two standard deviations below this mean (i.e. 25.5 mmhg) and high if it was more than two standard deviations above this value (i.e. 51.0 mmhg). transabdominal obstetric ultrasound scans were performed using a hd7 xe ultrasound system (philips healthcare, bothell, washington, usa) or a voluson e10 ultrasound system (ge healthcare, bangalore, karnataka, india) equipped with a 3.5-mhz curvilinear transducer. the uterine arteries on each side were localised at the level of the internal opening of the cervix by colour-flow mapping. pulsed wave doppler ultrasonography was performed with the sampling gate set at 2 mm to cover the whole vessel. the angle of insonation was maintained at <50°. the pi and resistive index (ri) and the mean values of the right and left uterine arteries were calculated. for the purposes of the study, the reference upper limit for the indices was based on previously reported 95th centile values of 2.35 and 0.85 for pi and ri, respectively.11,12 the presence or absence of a diastolic notch (dn) on both sides was also noted. to determine the development of hypertension later in pregnancy, the women were followed-up until delivery with routine assessment of bp values at each antenatal visit. additionally, a final bp measurement for each woman was taken post-delivery just before they were discharged from the hospital. a diagnosis of hypertension was made when bp measurements taken after 20 gestational weeks exceeded 140 mmhg systolic and/or 90 mmhg diastolic on two different occasions and at least four hours apart, with diastolic pressure defined as korotkoff phase v.13 throughout the duration of the study, bp and doppler measurements were made by different investigators using standard protocols.14,15 the investigators were not involved in the diagnosis or management of any of the women. pulsed wave doppler ultrasound measurements were not revealed to the obstetricians in charge of patient management. relative risk (rr) was calculated to determine the probability of participants developing hypertension with the presence of an arterial resistance indicator (high pp, raised pi and ri or the presence of a dn), both alone and in various combinations. sensitivity, specificity and positive and negative predictive values were calculated for individual doppler parameters. a receiver-operating curve was plotted for pi and ri to determine cut-off values for this study population. the statistical package for the social science (spss), version 15.0 (ibm corp., chicago, illinois, usa) was used for data analysis. a p value of <0.050 was considered significant. this study was evaluated by the departmental and scientific committees of kasturba medical college, manipal university, mangalore, karnataka, and received approval from the institutional ethics committee (iec kmc mlr #04-14/98). all women gave written consent before participating in the study. results a total of 329 women were included in the study with a mean age of 24.6 ± 4.2 years. there were 59 women (17.9%) under 20 years old, 144 between 21–25 years old (43.8%), 100 (30.4%) between 26–30 years old and 26 (7.9%) over 30 years old. of all the women studied, 208 (63.2%) were primigravidae. pregnancy-related hypertension was noted in 48 women (14.6%); of these, 33 women (68.8%) were diagnosed during a prenatal check after 32 gestational weeks, while six (12.5%) were diagnosed between 28–32 gestational weeks. a total of 15 women (31.3%) were diagnosed while in labour during admission to the hospital; however, their bp reverted to normal within 48 hours of delivery. there were 38 babies (11.6%) born weighing less than 2.5 kg. with regards to arterial resistance indicators, 17 women (5.2%) had high pp, 251 (76.3%) had a dn present, five (1.5%) had a raised pi and nine (2.7%) had a raised ri. hypertension was more likely to occur with high pp (17.6% versus 14.4% of pregnancies without high pp; p = 0.713). similarly, hypertension was more frequent with the presence of a dn (15.1% versus 12.8% without a dn; p = 0.612) and with a raised ri (22.2% versus 14.3% without raised ri; p = 0.366). there was a significant association between raised pi and the development of hypertension (80.0% versus 13.6% without raised pi; p = 0.013) [table 1]. pi was found to have positive and negative likelihood ratios of 20.7 and 0.9, respectively. a combination of different arterial resistance indicators were tested in order to find an accurate predictor of pregnancy-related hypertension. women arterial resistance in late first trimester as a predictor of subsequent pregnancy-related hypertension e454 | squ medical journal, november 2016, volume 16, issue 4 with any combination of at least two indicators had an approximately seven-fold higher risk of developing hypertension than those without these indicators. however, this did not include two combinations—the presence of dn and a raised ri or the presence of dn and high pp—which resulted in a rr of 1.99 and 2.20, respectively. on its own, raised ri did not appear to be a predictor of hypertension (rr = 1.55; 95% ci: 0.44–5.40); however, it augmented rr values for pp table 1: associations between arterial resistance indicators and pregnancy-related hypertension among pregnant women between 11–14 gestational weeks attending antenatal units in karnataka, india (n = 329) indicator total, n (%) hypertensive patients n (%) p value pulse pressure high* 17 (5.2) 3 (17.6) 0.713 not high 312 (94.8) 45 (14.4) diastolic notch present 251 (76.3) 38 (15.1) 0.612 absent 78 (23.7) 10 (12.8) pulsatility index raised† 5 (1.5) 4 (80.0) 0.013 not raised 324 (98.5) 44 (13.6) resistive index raised‡ 9 (2.7) 2 (22.2) 0.366 not raised 320 (97.3) 46 (14.4) *pulse pressure of ≥51.0 mmhg. †pulsatility index of ≥2.35.11 ‡resistive index of ≥0.85.12 table 2: relative risk of pregnancy-related hypertension according to arterial resistance indicators alone or in combination among pregnant women between 11–14 gestational weeks attending antenatal units in karnataka, india (n = 329) indicator total, n (%) hypertensive patients n (%) rr (95% ci) pp high* 17 (5.2) 3 (17.6) 1.22 (0.42–3.33) not high 312 (94.8) 45 (14.4) dn present 251 (76.3) 38 (15.1) 1.17 (0.61–2.25) absent 78 (23.7) 10 (12.8) pi raised† 5 (1.5) 4 (80.0) 5.90 (3.51–9.88) not raised 324 (98.5) 44 (13.6) ri raised‡ 9 (2.7) 2 (22.2) 1.55 (0.44–5.40) not raised 320 (97.3) 46 (14.4) pi + ri abnormal 2 (0.6) 2 (100.0) 7.10 (5.43–9.29) normal 327 (99.4) 46 (14.1) pi + dn abnormal 4 (1.2) 4 (100.0) 7.30 (5.61–9.72) normal 325 (98.8) 44 (13.5) pi + pp abnormal 1 (0.3) 1 (100.0) 6.90 (5.35–9.09) normal 328 (99.7) 47 (14.3) pi + ri + dn abnormal 2 (0.6) 2 (100.0) 7.10 (5.43–9.29) normal 327 (99.4) 46 (14.1) pi + ri + pp abnormal 1 (0.3) 1 (100.0) 6.90 (5.35–9.09) normal 328 (99.7) 47 (14.3) pi + dn + pp abnormal 1 (0.3) 1 (100.0) 6.90 (5.35–9.09) normal 328 (99.7) 47 (14.3) ri + pp abnormal 1 (0.3) 1 (100.0) 6.90 (5.35–9.09) normal 328 (99.7) 47 (14.3) ri + dn abnormal 7 (2.1) 2 (28.6) 1.99 (0.6–6.65) normal 322 (97.9) 46 (14.3) dn + pp abnormal 13 (4.0) 4 (30.8) 2.20 (0.93–5.22) normal 316 (96.0) 44 (13.9) ri + pp + dn abnormal 1 (0.3) 1 (100.0) 6.90 (5.35–9.09) normal 328 (99.7) 47 (14.3) pi + ri + dn + pp abnormal 1 (0.3) 1 (100.0) 6.90 (5.35–9.09) normal 328 (99.7) 47 (14.3) rr = relative risk; ci = confidence interval; pi = pulsatility index; ri = resistive index; dn = diastolic notch; pp = pulse pressure. *pulse pressure of ≥51.0 mmhg. †pulsatility index of ≥2.35.11 ‡resistive index of ≥0.85.12 pralhad kushtagi and anoosha emani clinical and basic research | e455 (rr = 6.90; 95% ci: 5.35–9.09 in combination versus rr = 1.22; 95% ci: 0.42–3.33 alone) and, to some extent, for pi as well (rr = 7.10; 95% ci: 5.43–9.29 in combination versus rr = 5.90; 95% ci: 3.51–9.88 alone). the presence of a dn alone did not help with risk identification (rr = 1.17; 95% ci: 0.61–2.25); however, in certain combinations with other indicators, the rr increased (6.9–7.3) [table 2]. in terms of validation of the indicators as predictors of pregnancy-related hypertension, only the presence of a dn showed good sensitivity (79.2%); the negative predictive value of this indicator was also high (87.2%), although specificity (24.2%) and positive predictive value (15.1%) were very poor. raised pi, which had shown an association with hypertension, failed to be a sensitive marker (8.3%); however, it had good specificity (99.6%), a positive predictive value of 80.0% and a negative predictive value of 86.4%. as indicators, both ri and pp demonstrated poor sensitivity (4.2% and 6.3%, respectively), but had high specificity (97.5% and 95.0%, respectively) and negative predictive values (85.6% each) [table 3]. in order to find specific reference levels for the study population, a receiver-operating curve was applied to the data. a cut-off value of 1.72 was obtained for pi, with increased sensitivity (8.3% versus 70.8%) and without a substantial decrease in specificity (99.6% versus 65.1%). [table 4]. it was not possible to derive a population-specific cut-off value for ri. discussion in the current study, the incidence of pregnancyrelated hypertension (14.6%) mirrored the incidence noted in previous years at the same facility, based on an analysis of unpublished statistics. alarmingly, this rate was almost 2.1-times higher than the global estimate (6–8%) published by the national high blood pressure education program working group.16 however, of the women with hypertension in the present study, almost a third were diagnosed during labour; it is possible that the rise in bp observed in these women was temporary since pregnancy endothelin-1 concentrations significantly increase during labour, especially with a vaginal delivery.17,18 therefore, if these cases were to be excluded, the incidence would fall to 10.0% (n = 33), which is comparable to previously published hospital-based incidence/prevalence rates.19 it should also be noted that most classifications of pregnancyrelated hypertension exclude pressure recordings taken during labour.20 in general, pp is considered a surrogate measurement of vascular compliance.21 thadhani et al. reported significantly higher pp values at 7–15 gestational weeks among women who subsequently developed pre-eclampsia.6 this finding is similar to that of the present study, which found that women with high pp values at 11–14 gestational weeks more frequently developed hypertension later during their pregnancy. increased turbulence, resistance to flow and the presence of a dn have also been associated with the subsequent development of pregnancyrelated hypertension.22 in the present study, there was a marginally higher occurrence of pregnancy-related hypertension among patients with a dn; moreover, while the presence of a dn alone did not help with risk identification, its presence in combination with high pp or a raised pi increased the likelihood of hypertension occurring. this indicator demonstrated good sensitivity and negative predictive value, indicating that the absence of a dn late in the first table 3: validation measures of arterial resistance indicators as predictors of pregnancy-related hypertension validation measure indicator pi ri dn pp sensitivity, % 8.3 4.2 79.2 6.3 specificity, % 99.6 97.5 24.2 95.0 ppv, % 80.0 22.2 15.1 17.6 npv, % 86.4 85.6 87.2 85.6 pi = pulsatility index; ri = resistive index; dn = diastolic notch; pp = pulse pressure; ppv = positive predictive value; npv = negative predictive value. table 4: comparison of reference and population-specific pulsatility index cut-off values to predict pregnancyrelated hypertension among pregnant women between 11–14 gestational weeks attending antenatal units in karnataka, india (n = 329) validation measure cut-off value 2.35* 1.72 htn no htn htn no htn positive tests 4 1 34 98 negative tests 44 280 14 183 sensitivity, % 8.3 70.8 specificity, % 99.6 65.1 ppv, % 80.0 25.8 npv, % 86.4 92.8 htn = hypertension; ppv = positive predictive value; npv = negative predictive value. *reference value sourced from martin m, bindra r, curcio p, cisero s, nicolaides kh. screening for pre-eclampsia and fetal growth restriction by uterine artery doppler at 11–14 weeks of gestation.11 arterial resistance in late first trimester as a predictor of subsequent pregnancy-related hypertension e456 | squ medical journal, november 2016, volume 16, issue 4 trimester reduced the likelihood of subsequent pregnancy-related hypertension. on its own, raised ri was also not useful as a predictor of hypertension, yet the risk of hypertension increased when this indicator was combined with pp and, to some extent, pi. raised pi was significantly associated with hypertension in the current study. these findings are in agreement with those of plasencia et al., in which a steep decrease in uterine artery pi between 11–13.6 and 21–24.6 gestational weeks was noted among normal pregnancies in comparison to those which developed pre-eclampsia.7 in a previous study, the researchers concluded that maternal variables together with uterine artery pi in the first trimester provided a sensitive predictor of pre-eclampsia, especially of severe early-onset disease.23 similarly, martin et al. found that screening for pre-eclampsia at 11–14 gestational weeks with uterine artery doppler parameters allowed the identification of a high proportion of severe pre-eclampsia and/or fetal growth restriction cases.11 nevertheless, although the findings from this study agree with earlier studies in part, the authors of the current study believe that the effect of uterine artery impedance is not uniform. due to their low predictive value, sciscione et al. do not recommend uterine artery doppler testing in either highor low-risk pregnancies.24 as this screening technique is not standardised or universally used, the criteria for abnormal values have yet to be determined.25 there was wide variation in the findings of the current study when different cut-off values for pulse wave analysis were used; this was thought to be mainly attributable to the use of cut-off values for pi and ri sourced from previous studies.11,12 indeed, calculations of cut-off values in the current study indicated that these were lower for the studied indian population than the reference values for other populations.11,12 therefore, the results of the current study would be more comparable if the cut-off values had been specific to the study population. the current study is subject to a few limitations. first, the findings are based on a small number of observations and the study included women who developed hypertension during labour and late in their pregnancies. second, there were possible interobserver variations in the recording of bp and doppler flow measurements; however, it was not possible to have a single person record all of the measurements. moreover, inter-observer variations were believed to be minimal as the antenatal care facilities attended by the patients follow a checklist for recording bp and doppler ultrasonography was performed by consultant radiologist-sonologists following a uniform protocol with computer-generated doppler flow values. third, there were very few cases with abnormal doppler flow values at the end of the study, especially when combinations of pp, dn, pi and ri were used. this drawback could be overcome in future studies involving a greater number of cases. in contrast, the strengths of this study include the development of a cut-off pi value for a local indian population. furthermore, there is an urgent need for a reliable and early indicator of pregnancy-related hypertension. currently, there are no accepted tests for predicting the occurrence of hypertension during pregnancy. a simple, non-invasive and inexpensive test—such as pp as one of the indicators of arterial resistance—may be of great help to primary care physicians at remote facilities in order to prioritise care, make early referrals and provide appropriate counselling for pregnant women. conclusion uterine artery pi in the late first trimester was significantly associated with the subsequent development of hypertension later in pregnancy. additionally, the use of a combination of arterial resistance indicators increased prediction of the subsequent development of hypertension. the authors suggest that future studies develop population-specific reference cut-off values for pi and ri. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. poon lc, kametas na, maiz n, akolekar r, nicolaides kh. first-trimester prediction of hypertensive disorders in pregnancy. hypertension 2009; 53:812–18. doi: 10.1161/hype rtensionaha.108.127977. 2. say l, chou d, gemmill a, tunçalp ö, moller ab, daniels j, et al. global causes of maternal death: a who systematic analysis. lancet glob health 2014; 2:e323–33. doi: 10.1016/ s2214-109x(14)70227-x. 3. levine rj, lindheimer md. first trimester prediction of early preeclampsia: a possibility at last! hypertension 2009; 53:747–8. doi: 10.1161/hypertensionaha.109.129379. 4. kaufmann p, black s, huppertz b. endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. biol reprod 2003; 69:1–7. doi: 10.1095/biolreprod.102.014977. 5. poppas a, shroff sg, korcarz ce, hibbard ju, berger ds, pralhad kushtagi and anoosha emani clinical and basic research | e457 lindheimer md, et al. serial assessment of the cardiovascular system in normal pregnancy: role of arterial compliance and pulsatile arterial load. circulation 1997; 95:2407–15. doi: 10.1161/01.cir.95.10.2407. 6. thadhani r, ecker jl, kettyle e, sandler l, frigoletto fd. pulse pressure and risk of preeclampsia: a prospective study. obstet gynecol 2001; 97:515–20. doi: 10.1097/00006250-20010400000007. 7. plasencia w, maiz n, poon l, yu c, nicolaides kh. uterine artery doppler at 11 + 0 to 13 + 6 weeks and 21 + 0 to 24 + 6 weeks in the prediction of pre-eclampsia. ultrasound obstet gynecol 2008; 32:138–46. doi: 10.1002/uog.5402. 8. pourhoseingholi ma, vahedi m, rahimzadeh m. sample size calculation in medical studies. gastroenterol hepatol bed bench 2013; 6:14–17. 9. redman cw, jacobson sl, russell r. hypertension in pregnancy. in: powrie ro, greene me, camann w, eds. de swiet’s medical disorders in obstetric practice, 5th ed. hoboken, new jersey, usa: wiley-blackwell, 2010. pp. 153–81. doi: 10.1002/9781444323016.ch6. 10. glynn m, drake w, eds. hutchison’s clinical methods: an integrated approach to clinical practice, 23rd ed. philadelphia, pennsylvania, usa: saunders ltd., 2012. p. 174. 11. martin m, bindra r, curcio p, cisero s, nicolaides kh. screening for pre-eclampsia and fetal growth restriction by uterine artery doppler at 11-14 weeks of gestation. ultrasound obstet gynecol 2001; 18:583–6. doi: 10.1046/j.0960-7692. 2001.00594.x. 12. carbillon l. first trimester uterine artery doppler for the prediction of preeclampsia and foetal growth restriction. j matern fetal neonatal med 2012; 25:877–83. doi: 10.3109/14 767058.2011.601364. 13. brown ma, lindheimer md, de swiet m, van assche a, moutquin jm. the classification and diagnosis of the hypertensive disorders of pregnancy: statement from the international society for the study of hypertension in pregnancy (isshp). hypertens pregnancy 2001; 20:9–14. doi: 10.3109/10641950109152635. 14. pickering tg, hall je, appel lj, falkner be, graves j, hill mn, et al. recommendations for blood pressure measurement in humans and experimental animals: part 1 blood pressure measurement in humans: a statement for professionals from the subcommittee of professional and public education of the american heart association council on high blood pressure research. circulation 2005; 111:697–716. doi: 10.1161/01. cir.0000154900.76284.f6. 15. bhide a, acharya g, bilardo cm, brezinka c, cafici d, hernandez-andrade e, et al. isuog practice guidelines: use of doppler ultrasonography in obstetrics. ultrasound obstet gynecol 2013; 41:233–9. doi: 10.1002/uog.12371. 16. national high blood pressure education program working group. national high blood pressure education program working group report on high blood pressure in pregnancy. am j obstet gynecol 1990; 163:1691–712. doi: 10.1016/00029378(90)90653-o. 17. usuki s, saitoh t, sawamura t, suzuki n, shigemitsu s, yanagisawa m, et al. increased maternal plasma concentration of endothelin-1 during labor pain or on delivery and the existence of a large amount of endothelin-1 in amniotic fluid. gynecol endocrinol 1990; 4:85–97. doi: 10.3109/09513599009012325. 18. nisell h, hemsén a, lunell no, wolff k, lundberg mj. maternal and fetal levels of a novel polypeptide, endothelin: evidence for release during pregnancy and delivery. gynecol obstet invest 1990; 30:129–32. doi: 10.1159/000293236. 19. prakash j, pandey lk, singh ak, kar b. hypertension in pregnancy: hospital based study. j assoc physicians india 2006; 54:273–8. doi: 10.4103/0970-0218.164403. 20. davey da, macgillivray i. the classification and definition of the hypertensive disorders of pregnancy. am j obstet gynecol 1988; 158:892–8. doi: 10.1016/0002-9378(88)90090-7. 21. domanski mj, davis br, pfeffer ma, kastantin m, mitchell gf. isolated systolic hypertension: prognostic information provided by pulse pressure. hypertension 1999; 34:375–80. doi: 10.1161/01.hyp.34.3.375. 22. zeeman gg, mcintire dd, twickler dm. maternal and fetal artery doppler findings in women with chronic hypertension who subsequently develop superimposed preeclampsia. j matern fetal neonatal med 2003; 14:318–23. doi: 10.1080/713606710. 23. plasencia w, maiz n, bonino s, kaihura c, nicolaides kh. uterine artery doppler at 11 + 0 to 13 + 6 weeks in the prediction of pre-eclampsia. ultrasound obstet gynecol 2007; 30:742–9. doi: 10.1002/uog.5157. 24. sciscione ac, hayes ej; society for maternal-fetal medicine. uterine artery doppler flow studies in obstetric practice. am j obstet gynecol 2009; 201:121–6. doi: 10.1016/j.ajog.20 09.03.027. 25. cunningham gf, leveno kj, bloom sl, spong cy, dashe js, hoffman bl, et al. williams obstetrics, 24th ed. new york, usa: mcgraw-hill education, 2014. pp. 1358. doi: 10.1111/ tog.12015. a 28 year-old woman presented to the ophthalmology clinic at the armed forces hospital, muscat, oman, with severe pain, redness, photophobia and decrease in visual acuity of her left eye of 1 day’s duration. she gave a history of a pterygium excision with intraoperative topical mitomycin-c application (0.1 mg/ml for 5 minutes ) in the same eye two years before. there was no other systemic or local disease. she underwent a detailed ophthalmic and systemic evaluation and laboratory examination. the best corrected visual acuity in her right eye was -0.25sph/-0.50cyl /90 = 6/6 and in the left eye -0.25sph/-1cyl 140 = 6/12. her left eye showed conjunctival and ciliary congestion. there was a linear ulcer on the cornea about 2 mm from the nasal limbus with a scar immediately temporal to it. there was no surrounding infiltration, but the nasal 4–5mm of cornea was thin between 6 and 11 o’clock [figures 1a and 1b] the adjacent sclera was normal. the intraocular pressure and fundus of both the eyes was normal. scrapings and swabs from the ulcer base were sent for microbiological evaluation. the left eye was treated with prophylactic antibiotic drops and artificial tears. the ulcer responded to treatment in a period of 4 weeks, leaving a thin nasal cornea with peripheral limbal vascularisation [figure 2]. pterygium is an epithelial hyperplasia accompanied by a fibrovascular growth originating at the corneo-conjunctival junction, from where the modified limbic cells migrate and surpass squ med j, may 2011, vol. 11, iss. 2, pp. 286-287, epub. 15th may 11 submitted 27th jul 10 revision req. 3rd oct 10, revision recd. 13th oct 10 accepted 3rd nov 10 1department of ophthalmology, armed forces hospital, oman; 2department of ophthalmology, al ahli eye research center, doha, qatar. *corresponding author email: shenoyvs@omantel.net.om ]êå<ÿ^€√jâ]<ç√e<ü}`jπ]<ìèfiüœ÷]<h^„j÷]ê<–œüi< ïüàø÷]<ìu]üq<ªdíâe<∞äë^⁄ájë^π]<  late corneal thinning and keratitis following mitomycin-c use in pterygium surgery *radha shenoy,1 alexander a bialasiewicz,2 badar al-barwani1 interesting medical image figure 1a: left eye – corneal ulcer 2mm from the nasal limbus. figure 1b: left eye – corneal scar temporal to ulcer. radha shenoy, alexander a bialasiewicz and badar al-barwani interesting medical image | 287 the cornea. it is an active process associated with cell growth, remodelling of the connective tissue, angiogenesis and inflammation, triggered by ultraviolet irradiation. different investigators have recently emphasised the importance of the limbus and its stem cells in the pathogenesis of the pterygium.1,2 surgery as a treatment for pterygium has been known since 1,000 b.c and has been directed towards excision, prevention of recurrence, and restoration of ocular surface integrity. the recurrence rate has, in the past, been estimated as high as 30–70%, despite adoption of different evolutionary techniques.1,2,3 although irradiation therapy and antimetabolite use have diminished the recurrence rate to 5–12%, complications like secondary glaucoma, cataracts, uveitis, corneal perforation, scleritis, scleral necrosis and secondary endophthalmitis can occur.1-5 mitomycin, isolated from streptomyces caespitosus, is an extremely toxic, non cell-specific alkylating antibiotic with antineoplastic properties that selectively inhibits the synthesis of deoxyribonucleic acid (dna), ribonucleinc acid (rna) and protein, and prevents cellular division.1-3 the dna damage mimics that of ionising radiation and has a radiomimetic effect. the drug has been used in the eye since 1963 for its anti-fibroblast proliferating action, in pterygium and glaucoma surgeries and recently in refractive procedures, both for the management of certain complications and to improve vision after surgery.1-5 however, in susceptible individuals, it causes keratocyte depletion leading to delayed wound healing, irrespective of the technique of application.1-5 complications occur either immediately after surgery, or up to 20 years later, and are related to drug concentration, contact time and predisposing ocular factors, highlighting the fact that such patients need long term follow-up.3,4,5 references 1. netto mv, mohan rr, sinha s, sharma a, gupta pc, wilson se. effect of prophylactic and therapeutic mitomycin-c on corneal apoptosis, cellular proliferation, haze and long-term keratocyte density in rabbits. j refract surg 2006; 22:562−74. 2.. detorakis, et, spandidos, da. pathogenetic mechanisms and treatment options for ophthalmic pterygium: trends and perspectives (review). int j mol med 2009; 23:439−47. 3. wan norliza wm, raihan is, azwa ja, ibrahim m. scleral melting 16 years after pterygium excision with topical mitomycin c adjuvant therapy. cont lens anterior eye 2006; 29:165–7. 4. gupta v, saxena t. comparison of single-drop mitomycin c regime with other mitomycin c regimes in pterygium surgery. ind j ophthalmol 2003; 51:59−65. 5. khong jj, muecke j. complications of mitomycin c therapy in 100 eyes with ocular surface neoplasia. br j ophthalmol 2006; 90:819−22. figure 2: left eye – 4 weeks after treatment showing no corneal stain/ healed ulcer. squ med j, december 2010, vol. 10, iss. 3, pp. 401-404, epub. 14th nov 10 submitted 3rd april 10 revision req. 20th june 10, revision recd. 6th aug 10 accepted 11th aug in the past, the impact of cessation or poor compliance with chelation therapy was not easily assessable except by serum ferritin levels. these have ultimately been found to be relatively unreliable with respect to demonstrating the degree of iron load in the heart and liver.1,2 liver biopsies, though valuable, were traumatic and had low patient acceptance. with the advent of magnetic resonance imaging (mri) techniques (t2*), such assessments are more easily accessible although expensive.3 the patient described here was followed prospectively before and after the 1department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of medicine, sultan qaboos university hospital, muscat, oman; 3department of hematology/oncology, children’s hospital of los angeles, usa *corresponding author email: shahina@squ.edu.om <h^í⁄<òëü⁄<çfl¬<çf”÷]ê<g◊œ÷]<ª<çëçv◊÷<<ƒëüâ<ÿ耆 çëç£]<<ìe¯}<]êå<<‰÷ê^fli<›ç¬<çfl¬<^è€èâ˜^n÷]<öü≤     500  19.5 48.8   14.5 12.7 3820 95   28.5 27.5     abstract: iron loading in patients with transfusion dependent thalassaemia is considered to occur primarily in the liver and, once the liver becomes saturated, other organs begin loading. we report here a splenectomised male patient who was treated for hepatitis c virus infection. prior to starting antiviral therapy, his serum ferritin was maintained below 500 ng/ml with deferiprone monotherapy; cardiac t2* by magnetic resonance imaging was 48.8ms and hepatic t2* was 19.5ms. after twelve months of antiviral treatment during which time he was very poorly compliant with his deferoxamine chelation therapy, his ferritin had risen to 3820 ng/ml and cardiac and hepatic t2* findings were 12.7 ms and 14.5 ms respectively, indicating increased iron loading in both organs, but particularly in the heart. fifteen months after recommencing combination chelation, his ferritin was 95 ng/ml and cardiac and hepatic t2* were 27.5 and 28.4ms respectively, indicating complete clearance of iron load in both organs. this case demonstrates that iron overload can develop rapidly and in some cases there is relatively rapid iron loading in the heart as compared to the liver. keywords: thalassaemia major; iron overload; deferiprone; deferoxamine; chelation therapy; magnetic resonance imaging; case report; oman rapid iron loading in heart and liver in a patient with transfusion dependent thalassaemia after brief poor compliance with iron chelation therapy *shahina daar,1 saeed ahmed,2 vasili berdoukas3 case report rapid iron loading in heart and liver in a patient with transfusion dependent thalassaemia after brief poor compliance with iron chelation therapy 402 | squ medical journal, december 2010, volume 10, issue 3 period during which he was on interferon therapy which precluded the use of deferiprone. this demonstrates the impact of poor compliance with chelation therapy for a relatively short period of 12 months. case report this patient, with transfusion dependent thalassaemia, was born in 1974. he commenced regular blood transfusion at 22 months of age and regular deferoxamine iron chelation therapy at the late age of 19 years, when his ferritin was 4869 ng/ml. by 2001, aged 27, his ferritin was 3755 ng/ml. with the availability of the oral chelator deferiprone, and information that combination therapy with deferiprone and deferoxamine was resulting in at least an additive effect with respect to iron excretion,4 he commenced combination therapy in august 2001. the regime was as follows: deferiprone orally at 75 mg/kg/day in three doses and deferoxamine at 40 mg/kg infusion for 5 days of the week. he was always very compliant with his oral chelator and was able to manage 2 days per week of desferoxamine infusions. he did not show any cardiac complications and glucose and thyroid metabolism were normal. gonadal function was normal until the age of 30, at which time he required testosterone replacement. by may 2005, his ferritin was 540 ng/ml, the deferoxamine was stopped and he continued on deferiprone monotherapy. on the basis of being hepatitis c virus (hcv) polymerase chain reaction (pcr) positive with persistently elevated hepatic enzymes (alanine aminotransferase 50-85 iu/l, aspartate aminotransferase 80-115 u/l) and his liver biopsy showing chronic hepatitis with moderate activity and stage 5 fibrosis, he commenced interferon and ribavirin treatment in september 2007. he had an excellent response with viral load falling from >500,000 iu/ml to below detectable limits within 9 weeks of commencing treatment. at the start of hcv therapy his ferritin level was 335 ng/ ml. as interferon can cause neutropaenia, and as deferiprone can also cause both neutropaenia and agranulocytosis, the deferiprone was stopped, and he continued on deferoxamine treatment alone. he was poorly compliant with this treatment and his ferritin gradually rose to a peak of 3820 ng/ml at the end of his hcv therapy. the effect of his poor compliance was compounded by increased transfusion requirements over the period of hcv therapy (increase of 40 mls/kg/year packed red cells). table 1 shows the liver and cardiac t2* before starting interferon, during the treatment, soon after ceasing combination therapy and after recommencing it, the last reading being 15 months after completing hcv therapy. studies have shown that patients who have a cardiac t2* result of <10 ms are at high risk for cardiac disease due to iron overload, and that those whose t2* is above 20 ms are in the ‘normal’ range.3,5 our patient’s cardiac t2* fell from well within the normal range to just above the high risk cut-off in a relatively short period of time [table 1 and figure 1]. he had no cardiac symptoms and his echocardiogram was normal. his liver iron load, as assessed by mri, also increased during this period 0 500 1000 1500 2000 2500 3000 3500 4000 4500 s fe rr iti n (n g/ m l) 0 5 10 15 20 25 30 35 40 45 50 ca rd ia c t2 * (m s) s ferritin cardiac t2* 20 start of hcv treatment cardiac t2* sep 2006 48.8ms completion of hcv treatment. restart combined chelation months 32.5ms 12.7ms 0 40 figure 1: changes in serum ferritin and cardiac t2* before starting interferon therapy and the subsequent course shahina daar, saeed ahmed and vasili berdoukas case report | 403 from completely normal to the upper limit of mild iron loading after 12 months. his most recent study 2 years after recommencing combination therapy shows complete removal of iron in the liver and normalisation of cardiac t2* at 27.5ms. figure 1 shows serial values of cardiac t2* and ferritin levels over the period before, during, and after hcv therapy, it is important to note that the t2* of both the liver and heart started reducing within two months of ceasing chelation therapy. the most striking feature of his results was that the cardiac t2* fell from absolutely normal to a level that was a cause for concern. this was associated with his hepatic iron load reaching the upper limit of mild iron loading. in the past, such levels of iron loading in the liver were considered safe, but it has now been shown that in many patients liver iron does not correlate to cardiac iron.3,6 discussion this case report demonstrates the rapid iron loading that occurred in one patient after the cessation of effective iron chelation therapy and failure to comply with deferoxamine infusion. a case of a pregnant woman showing increased rapid loading after completely ceased chelation therapy for 12 months has been reported.7 however, unlike that patient, whose cardiac iron status remained the same, our patient had a greater rate of iron loading in his heart than in his liver. noetzli et al. have shown that in many patients cardiac iron loading and unloading lags behind liver iron. 8 our patient, however, is similar to the small number of patients in that study who loaded more rapidly in their hearts than in their livers. he also demonstrated a rapid reversal of cardiac iron which is also different to the results of the above study. it would seem that differential iron loading may be very different from one patient to another, hence the need for mri monitoring, particularly during phases of inadequate iron chelation. the differences in relative rate of uptake of iron in various organs in different patients have not yet been adequately explained. it may be that viral infections such as hepatitis play a role, but larger studies are needed to evaluate this. patients should be properly counselled prior to any therapy that may compromise their chelation even though this may be short term. the use of deferoxamine is standard therapy, but compliance is a problem. as the oral chelator deferasirox rarely causes neutropaenia, it may be the chelator of choice in these patients, provided there is no contraindication to its use. as in the case with rapid loading during pregnancy,7 it is also likely that the free iron that results from the iron overload may be very avidly taken up in the liver and may be taken up even more quickly in the heart. another interesting point in this patient is that he has recently reversed his hypogonadism. in april 2009, eight months after restarting combination chelation, he was azoospermic. however, he was able to cease hormone replacement therapy in june 2009, and in october 2009 his sperm count was 76 million/ml, with 10% abnormal forms and 90% motility. these encouraging outcomes are similar to those recently published in which a reversal of hypogonadism was associated with very low ferritin levels. 9 our patient had very low ferritin levels from july 2009 to march 2010 and this was associated with the marked improvement in the sperm count. table 1: serum ferritin and t2* readings before, during, and after interferon therapy date serum ferritin ng/ml t2* heart (ms) t2* liver (ms) lic mg/gdw sept 2006 309 48.8 19.5 1.5 aug 2007 335 nov 2007 2,366 32.5 8.6 3.2 jul 2008 3,820 nov 2008 1,792 12.7 4.5 6.8 jul 2009 162 18.8 16.5 1.4 oct 2009 95 27.5 28.4 0.4 legend: lic = liver iron concentration rapid iron loading in heart and liver in a patient with transfusion dependent thalassaemia after brief poor compliance with iron chelation therapy 404 | squ medical journal, december 2010, volume 10, issue 3 it is very likely that such low ferritin levels are essential to achieve such improvements. conclusion in all transfusion dependent patients, cessation or change to possibly less acceptable chelation therapy may result in rapid iron overload of the heart over a relatively short period of time. patients and physicians should be aware of this risk in order to encourage patients to maintain consistent chelation therapy. c o n f l i c t o f i n t e r e s t shahina daar has received funding for clinical studies from novartis inc. and been a speaker for apopharma inc. as well as attending key opinion leader meetings sponsored by apopharma inc. vasili berdoukas is a consultant for apopharma inc. and has a confidentiality agreement with novartis inc. with respect to the development of deferasirox. saaed ahmed has no conflicts of interest to declare. references 1. aessopos a, fragodimitri c, karabatsos f, hatziliami a, yousef j, giakoumis a et al. cardiac magnetic resonance imaging r2* assessments and analysis of historical parameters in patients with transfusiondependent thalassemia. haematologica 2007; 92:131–2. 2. tanner ma, galanello r, dessi c, westwood ma, smith gc, nair sv, et al. myocardial iron loading in patients with thalassemia major on deferoxamine chelation. j cardiovasc magn reson 2006; 8:543–7. 3. anderson lj, holden s, davis b, prescott e, charrier cc, bunce nh, et al. cardiovascular t2-star (t2*) magnetic resonance for the early diagnosis of myocardial iron overload. eur heart j 2001; 22:2171– 9. 4. wonke b, wright c, hoffbrand av. combined therapy with deferiprone and desferrioxamine. br j haematol 1998; 103:361–4. 5. kirk p, roughton m, porter jb, walker jm, tanner ma, patel j, et al. cardiac t2* magnetic resonance for prediction of cardiac complications in thalassaemia major. circulation 2009; 120:1961–8. 6. daar s, pathare av, zadjali sa, jain r, pennell dj. t2* cardiovascular magnetic resonance in the management of thalassaemia patients in oman. haematologica 2009; 94:140–1. 7. farmaki k, gotsis e, tzoumari i, berdoukas v. rapid iron loading in a pregnant woman with transfusiondependent thalassemia after brief cessation of iron chelation therapy. eur j haematol 2008; 81:157–9. 8. noetzli lj, carson sm, nord as, coates td, wood jc. longitudinal analysis of heart and liver iron in thalassemia major. blood 2008; 112:2973–8. 9. farmaki k, tzoumari i, pappa c, chouliaras g, berdoukas v. normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. br j haematol 2010; 148:466–75. clinical & basic research squ med j, february 2012, vol. 12, iss. 1, pp. 62-68, epub. 7th feb 12. submitted 19th jun 11 revision req. 29th oct 11, revision recd. 13th nov 11 accepted 30th nov 11 1ophthalmology department, school of medicine, king faisal university, al-hassa, saudi arabia; 2ophthalmology department, al jabr eye & ear hospital, ministry of health, al-hassa, saudi arabia; 3eye & ear health care, ministry of health, muscat, oman. corresponding author e-mail: rajiv.khandekar@gmail.com حجم وأسباب اإلعاقة البصرية املعتدلة واحلادة بني طالب معهد النور للمكفوفني يف األحساء باململكة العربية السعودية جمموعة حاالت فهد الودعاين، راجيف خانديكار، منرية احل�سني، اأحمد اخلواجة، حممد خان، رمزي ال�سليمان تهدف هذه الدرا�سة لتقدير حجم واأ�سباب الإعاقة الب�رصية )�سعف الب�رص ال�سديد، و�سعف الب�رص املعتدل( بني طالب امللخ�ص: الهدف: معهد النور للمكفوفني يف الإح�ساء، اململكة العربية ال�سعودية يف عام 2006 م. الطريقة: مت فح�س حدة الإب�سار على 122 عينا لعّينة بلغ عددها 61 طالبا )27 فتى و 34 فتاة(، حيث تراوحت الإعاقة الب�رصية املتو�سطة بني >6/18 اإىل 6/60، والإعاقة الب�رصية ال�سديدة من >6/60 اإىل 3/60. قام اأطباء العيون بفح�س الغرفة الأمامية واخللفية للعني، ومت حتليل نتائج الفحو�سات للو�سول اإىل الت�سخي�س النهائي. مت ت�سنيف النتائج على ثالث جماميع: "ميكن الوقاية منها"، " ميكن عالجها"، و"غري قابلة للعالج". كذلك مت ا�ستعرا�س الرعاية املتوفرة لالإعاقة الب�رصية. النتائج: بلغت حدة الإب�سار ≤ 18/6 يف 12 عينا )%9.8( من عينة الدرا�سة، و>3/60 يف 82 عينا )23%(. وكان ال�سعف الب�رصي �سديدا اإىل متو�سطا يف 82 عينا )%67.2(. وجدت حالت ال�سطرابات ال�سبكية الوراثية يف 68 عينا )55.7%(. ولو اأن الأخطاء الإنك�سارية وجدت يف 112 عينا )%91.8(، اإل اأّن 9 طالب عانوا من اأخطاء اإنك�سارية معزولة. كان داء الَزَرق اخللقي م�ساعدات و�سف مت .)7.4%( 9 عيون يف الب�رص �سعف اخَللقي ال�ساد �سّبب بينما ،)13.1%( 16 عينا يف الب�رص �سعف عن م�سئول لالإب�سار لهوؤلء الطالب. اخلال�صة: اأثبتت الدرا�سة احلالية اأّن مر�س ال�سبكية هو ال�سبب الرئي�سي ل�سعف الإب�سار ال�سديد واملتو�سط. هناك حالت متعددة من طالب معهد النور للمكفوفني قابلة لل�سفاء. اإعادة تاأهيل �سعاف الب�رص تكون خمتلفة عن تلك التي تقدم للمكفوفني ب�سكل تام. مفتاح الكلمات: عمى، �سعف الب�رص، اأطفال، اإعادة تاأهيل، اململكة العربية ال�سعودية. abstract: objectives: this study aimed to estimate the magnitude and causes of low vision disability (severe visual impairment [svi] and moderate visual impairment [mvi]) among students at al-noor institute for the blind (nib) in al-hassa, saudi arabia in 2006. methods: an optometrist conducted refraction of 122 eyes of the 61 students (27 boys and 34 girls) with mvi (vision <6/18 to 6/60) and svi (vision <6/60 to 3/60). ophthalmologists examined the anterior and posterior segments, and analysed the outcomes of additional investigations to finalise the diagnosis. the results were categorised as ‘preventable’, ‘treatable’ and ‘not amenable to treatment’. the low vision care was also reviewed. results: in 12 (9.8%) eyes, visual acuity was ≥6/18 and in 28 (23%) eyes, it was <3/60. mvi and svi were found in 82 eyes (67.2%). hereditary retinal disorders were found in 68 (55.7%) eyes. although refractive errors were found in 112 (91.8%) eyes, isolated refractive error was found in only 9 students. congenital glaucoma and cataract were responsible for visual impairment in 16 (13.1%) and 9 (7.4%) eyes. these students were prescribed optical and non-optical low vision aids. conclusion: retinal disease was the main cause of svi and mvi in our series. some students at al-noor institute for the blind have curable low vision conditions. rehabilitation of low vision disability should be different from that offered to the absolutely blind. keywords: blindness; low vision; children, rehabilitation; saudi arabia. magnitude and causes of low vision disability (moderate and severe visual impairment) among students of al-noor institute for the blind in al-hassa, saudi arabia a case series fahad al-wadani1,2 *rajiv khandekar,3 muneera a. al-hussain,2 ahmed a. alkhawaja,2 mohammed sarfaraz khan,2 ramzy a alsulaiman2 fahad al-wadani, rajiv khandekar, muneera a. al-hussain, ahmed a. alkhawaja, mohammed sarfaraz khan, ramzy a alsulaiman clinical and basic research | 63 as the study of community-based prevalence of childhood blindness needs a large sample, researchers have studied the anatomical and aetiological causes of blindness among students of schools for the blind.1-3 a large number of children with low vision also study in these schools, either due to lack of facilities for low vision care, or to lack of awareness regarding integrated education for those with low vision disability. often these children are only assessed at the time of admission and not subsequently revaluated. hence the progress of their eye condition often goes unnoticed and even those whose sight could be improve are deprived of the advances in management; hence, periodic eye examination of all students is recommended.4 in saudi arabia, visual acuity and refraction services are given to all students through the ministry of education (moed).5 the schools for the visually challenged are also governed by the moed. in al-hassa region of saudi arabia, there are two such schools (one for male and other for female children). we conducted a study to estimate the rate of low vision disability and causes of severe visual impairment (svi) and moderate visual impairment (mvi) among these students. we accordingly recommended policies to improve their eye care. methods the ethical committee of al-jabr eye and ear hospital at al-hassa gave permission to undertake this study. this ‘case series’ type of study was conducted from june to december 2006. of the 120 saudi students attending the male and female schools for the blind, which make up the al-noor institute for the blind in al-hassa, saudi arabia, 61 students with either mvi or svi were included in the present study. the remaining 59 students with absolute blindness (no light perception) were excluded from our study. the eye examination was conducted in two phases. in phase i, a team of an optometrist and an ophthalmologist examined the subjects at the eye department of al-jabr eye and ear hospital. the optometrist noted the best corrected visual acuity (bcva) using snellen’s distant vision chart, held at a three metre distance. we performed dynamic refraction and then added correction in the trial frame; a 100% contrast chart for this purpose. if the student could not identify symbols in the top line in the chart held at a three metre distance, we repeated the test at 1.5 meter distance from the chart. refraction was performed using 0.5% tropicamide eye drops. the presenting and best corrected visual acuity of each eye was noted. the anterior segment of eye was examined using slit-lamp biomicroscope (topcon, japan). the posterior segment was evaluated using an indirect ophthalmoscope (keeler, uk) and +20 d fundus lens (volk, germany). cover test, ocular motility and visual field (confrontation method) were performed for most of the students as their vision allowed. mvi was defined as bcva of 6/18 to 6/60. svi was defined as bcva of <6/60 to 3/60.6 those who were advised to have further investigations, treatment and rehabilitation were evaluated in phase ii of the study at king khaled eye specialist hospital in riyadh. there, further special ophthalmic and neurologic evaluation and investigations were conducted as advised by the paediatric ophthalmologist. advances in knowledge 1. a large number of students at in al-noor institute for the blind in al-hassa, saudi arabia, suffer from low vision disability and need rehabilitation which should be different from that offered to those with absolute blindness. 2. posterior segment pathologies that could not be treated constituted 75% of children, with moderate and severe visual impairment. (mvi and svi) 3. refractive error as a single condition was noted in only nine (15%) children. even after correction of refractive error, these children had low vision and hence rehabilitation was needed. 4. comprehensive visual function assessment of children with svi and mvi is essential for proper low vision care. application to patient care 1. a total of 75% of the children with mvi and svi at al-noor institute for the blind in al-hassa, saudi arabia had posterior segment pathologies. 2. it is important to carry out comprehensive and periodic visual function assessment of students with mvi and svi at schools for the blind. 3. rehabilitation of children with low vision disability should differ from that for children with absolute blindness (no light perception). magnitude and causes of low vision disability (moderate and severe visual impairment) among students of al-noor institute for the blind in al-hassa, saudi arabia a case series 64 | squ medical journal, february 2012, volume 12, issue 1 they included computed tomography (ct) and magnetic resonance imaging (mri) scanning, electroretinography (erg), and electrooculography (eog). the classification of causes of childhood blindness was per the recommendation of the world health organization (who) expert group.7 both the anatomic site of the principal cause of visual impairment (vi), and the disease causing vi were used to classify the causes in our study. the data was collected on a pre-tested form and was then entered into a spreadsheet (microsoft excel). frequency and percentage proportions were calculated for qualitative variables. for quantitative variables, we calculated the mean and the standard deviation. students with eye conditions that were amenable to treatment were offered free treatment. those in need of rehabilitation were provided with low vision aids and training by experts. the outcomes of the study were discussed with the health and education authorities of the region to improve the quality of life of children with mvi and svi. results our series had 61 students and their 122 eyes. there were 27 (44.2%) male and 34 (55.8%) female students. the mean age of the students was 13.59 years (standard deviation 3.97 years). a history of consanguinity was found among parents of 53 students (87%). in 12 (9.8%) eyes, the bcva was ≥6/18 and in 28 (23%) eyes, it was <3/60. mvi and svi were found in 82 eyes (67.2%). the causes of visual impairment are given in table 1. the retina was the main anatomical site of pathologies responsible for visual disabilities. hereditary retinal disorders were the cause of low vision in 68 (58%) eyes. retinitis pigmentosa was found in 30 (44.1%) eyes. other causes included hereditary vitreoretinal degenerations; stargardt’s disease and cone-rod dystrophy—each of these were found in 8 eyes (11.7%); chorioretinal degenerations in 6 (8.8%) eyes; congenital hypoplastic macula in 4 (5.9%) eyes, and foveal hypoplasia in 4 (5.9%) eyes. refractive errors were found in 112 (91.8%) of the total 122 eyes; however, it was the single identifiable cause of the visual impairment in only 17 (14%) eyes. the refractive errors of hyperopia, myopia and astigmatism were found in 54 (44.2%) eyes, 55 (45%) eyes and 3 (2.5%) eyes respectively. we could not determine the type of refractive error in 10 (8%) of eyes. most of these cases had an associated pathology responsible for the low vision. table 1: causes of visual impairment (vision <6/18 to 3/60) causes eyes % hereditary retinal disorders 68 55.7 congenital glaucoma 16 13.1 cataract and uncorrected aphakia 9 7.4 primary optic atrophy 6 4.9 subluxated lens 3 2.5 aniridia 2 1.6 other * 19 15.6 undetermined 2 1.6 refractive error 112 91.8 note: * other includes: ptosis, retinal detachment, phthsis bulbi, cryptophthalmos and corneal scars table 2: low vision aids and care given to children with moderate and severe visual impairment low vision aid number of children % magnifiers 38 62.3 telescopes 27 44.3 filters 6 9.8 non-optical low vision devices (felt tip pen, writing frame, table lamp, cap with eye shade) 52 85.2 close circuit television (cctv) 10 16.4 continuation with same spectacles 6 9.8 prescribed change in spectacle power 3 4.9 counselling to children and parents 61 100 figure 1: distribution of children with visual impairment by type of intervention fahad al-wadani, rajiv khandekar, muneera a. al-hussain, ahmed a. alkhawaja, mohammed sarfaraz khan, ramzy a alsulaiman clinical and basic research | 65 hyperopia of ≥+4.00 d was detected in two eyes (1.6%); myopia of ≥-5.00 d was noted in eight (6.5%) eyes, while in seven (5.7%) eyes anisometropia of ≥3.00 d sph or ≥1.50 d astigmatism were present. seven students (11.47%) had bilateral ptosis with a variable degree of amblyopia in the eye with more severe ptosis. all these 7 children were close relatives. they were referred to paediatric ophthalmologists for further care. two underwent surgery while the others refused surgery as the visual prognosis was poor. isolated refractive error (9 students) and ptosis (7 students) were considered as potentially avoidable causes of visual impairment. those with eye conditions ‘not amenable to treatment at present’, and having mvi or svi, were grouped as cases that needed separate low vision care [figure 1]. the details of low vision care provided to the children with mvi and svi are given in table 2. low vision aids (optical and non-optical) seem to be useful for children with residual vision. two out of 6 children who were advised to have corrective surgery underwent ptosis surgery. the others, when offered a guardedly optimistic prognosis, opted not to undergo an operation. we compared the rate table 3: rate and causes of severe visual impairment (svi) among children at school for the blind in different studies author country year student nos. rate (%) of svi causes of visual impairment remark reference kasmann-klenner b, et al. germany 1998 105 optic atrophy 18%, albinism 12%, rop 11% svi + blind 24 decarlo dk, et al. usa 1999 123 26.2 optic nerve 31%, optic atrophy 24.1%, glaucoma 8%, lens 14% svi + blind 23 kocur i, et al. czech republic 2001 229 21 retina 54%, optic nerve 15%, globe 11%, lens 9%, rop 42% svi + blind 22 titiyal js, et al. india 2003 703 3.1 globe 27%, cornea 22%, lens 11%, retina 15% svi + blind 21 mirdehghan s, et al. iran 2005 362 81 retinal diseases 51% low vision 3 liu b, et al. china 2007 177 8.5 rop 38%, retina 12%, lens 4%, globe 3%, cornea 3% svi + blind 17 haddad m, et al. brazil 2007 3,210 toxoplasma 21%, retinal dystrophy 12%, rop 12% visually impaired children 18 muhit ma, et al. bangladesh 2007 1,935 lens 33%, cornea 27%, globe 13% svi + blind 19 gogate p, et al. india 2009 891 3 anomalies 36%, cornea 15%, retina 20%, lens 11% svi + blind 20 kanaskar i, et al. nepal 2009 285 7.4 cornea 36%, retina 20%, globe 13%, lens 13% svi + blind 2 khandekar r, et al. oman 2010 47 28 not ascertained svi + blind 4 present study saudi arabia 2011 61 67 retinal 66%, glaucoma 13%, lens 7% svi + blind magnitude and causes of low vision disability (moderate and severe visual impairment) among students of al-noor institute for the blind in al-hassa, saudi arabia a case series 66 | squ medical journal, february 2012, volume 12, issue 1 of svi and causes documented in the literature to compare our study outcomes with these studies and the results are shown in table 3. the magnitude and causes of visual impairment among students of the al-noor institute for the blind in the al-hassa province of saudi arabia matched the pattern found in other gulf cooperation council countries and in industrialised countries. discussion this is the first study to focus on visually impaired children enrolled in schools for the blind in the al-hassa region of saudi arabia. previous studies in other parts of saudi arabia covered both blind and low vision children.8–11 we have noted that the disabled students with a useful residual vision can be provided with low vision aids to improve their quality of life. zamzam et al. in kuwait and al alawi et al. in bahrain also noted that the majority of the partially sighted children were given the same educational programme as their normal peers in ordinary schools.12,13 low vision students must not be trained along with the blind. an integrated educational approach for these children within the routine educational system is recommended.14 our study suggests that genetic and hereditary diseases are significant causes of childhood visual impairment in the al-hassa region. this matched with the changing trends, from nutritional and infectious causes, to non-curable causes, contributing to visual disabilities in children of saudi arabia as noted by tabara et al. and worldwide by gogate et al.15,16 it was challenging to compare our study outcomes to the findings of other researchers as most other studies conducted in schools for the blind, in developing as well as industrialised countries, had grouped blind and svi students together. in developing countries, blindness and svi were due to avoidable causes like poor nutrition and lack of timely treatment.2,17–21 by comparison, in industrialised countries, they were mainly due to retinal, optic nerve diseases and birth defects.22–24 a study in iran showed an unusually high rate (81%) of svi among children studying in schools for the blind and suggested that half of these cases were due to retinal diseases.3 the consanguinity rate in the saudi population has been documented to be as high as 56%.25 our subjects had a consanguinity rate of 87%. as the former study was community-based and the present one is focusing on parents with at least one child with visual impairment (mainly due to hereditary causes) the difference in consanguinity rate is logical. genetic counselling and explanation of the risk of birth defects among offspring of closely related parents is recommended.26 in our study, the focus was on visual acuity for distance and the correction of refractive error. assessment of visual functions like contrast sensitivity, near vision, colour vision, glare, and field of vision was not carried out. more detailed assessment of visual functions for all children with sensory disability is recommended in the future.27 more than 10% of the eyes in our series had visual impairment due to congenital glaucoma. trained primary physicians can easily detect this early on. referring the patient to a paediatric ophthalmologist would confirm the diagnosis and lead to initiation of treatment at an earlier stage which would minimise visual disability.28 congenital cataract and aphakia contributed to the cause of visual impairment in 6.2% of those children reviewed at a tertiary eye centre in saudi arabia.29 in our study, 7.4% of eyes had cataract or aphakia related visual impairment. in spite of benefiting from free rehabilitative services, the study sample is less likely to be the representative of low vision children of the alhassa region of saudi arabia. many students with visual disabilities could have double or multiple disabilities and hence might not be attending a school for the blind. further studies to include all children with visual disabilities are suggested. although a large number of children in our series had a refractive error, many of them could not attain corrected vision due to the presence of co-morbidities. as children with high myopia experienced magnification after removing spectacles, they did not accept the use of spectacles. thus care should be taken when prescribing visual aids to children with mvi or mvi with other comorbidities. in our study, we noted that 50% of the students had mvi or svi. there are almost three million children worldwide who have the potential to benefit from low vision care,30 yet many are rehabilitated along with the blind. children with mvi or svi must be trained separately from the absolutely blind children. once they are proficient fahad al-wadani, rajiv khandekar, muneera a. al-hussain, ahmed a. alkhawaja, mohammed sarfaraz khan, ramzy a alsulaiman clinical and basic research | 67 in using low vision aids, they could be integrated into schools for sighted children.31 conclusion retinal diseases were the main cause of svi and mvi in our series. children at the al-noor institute for the blind have low vision disabilities. the method of rehabilitating children whose svi or mvi are due to causes for which there is no treatment should be different from that used for rehabilitating absolutely blind children. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest. a c k n o w l e d g m e n t s we thank the administrators and staff of the alnoor institute for the blind in al-hassa region and the al jabr eye and ear hospital for their support for this study. we also appreciate the cooperation of the students and their parents. references 1. muhit m, gilbert c. a review of the epidemiology and control of childhood blindness. trop doct 2003; 33:197-201. 2. kansakar i, thapa hb, salma kc, ganguly s, kandel rp, rajasekaran s. causes of vision impairment and assessment of need for low vision services for students of blind schools in nepal. kathmandu univ med j (kumj) 2009; 7:44-9. 3. mirdehghan sa, dehghan mh, mohammadpour m, heidari k, khosravi m. causes of severe visual impairment and blindness in schools for visually handicapped children in iran. br j ophthalmol 2005; 89:612-4. 4. khandekar r, shah r, shah m, al harby s, vora u, al balouchi f. ocular status and functional adaptation of visually challenged children of a special school in oman. oman j ophthalmol 2011; 4:17-20. 5. who country representative. eye health through school health. presentation at workshop on integration of eye health into primary health care. world health organization emr, dubai, feb 2011. 6. dandona l, dandona r. revision of visual impairment definitions in the international statistical classification of diseases. bmc med 2006; 4:7. 7. gilbert ce, foster a, negrel ad, thylefors b. childhood blindness: a new form of recording causes of vision loss in children. bull world health org 1993; 71:485-9. 8. tabbara kf, elsheikh hf, shawaf ss. pattern of childhood blindness at a referral center in saudi arabia. ann saudi med 2005; 25:18-21. 9. tabbara kf. childhood blindness in saudi arabia. saudi j ophthalmol 2004; 18:13-16. 10. alrajhi aa, awad a, badeeb o. causes of blindness in students attending schools for the blind in saudi arabia. saudi j ophthalmol 2003; 17:276-80. 11. badr ia, qureshi ih. cause of blindness in the eastern province blind schools. saudi med j 1983; 4:331-8. 12. zamzam am, alrabiha sm. causes of blindness at the al-noor institute for the visually handicapped in kuwait. saudi j ophthalmol 1998; 12:1-8. 13. alalawi e, ahmed aa. causes of visual disability at the al-noor institute for the visually impaired in bahrain. saudi j ophthalmol 1998; 12:101-6. 14. wilkinson me, stewart iw, trantham cs. iowa's pediatric low-vision services. optometry. 2000; 71:40-8. 15. tabbara kf, badr ia. changing pattern of childhood blindness in saudi arabia. br j ophthalmol 1985; 69:312-5. 16. gogate p, deshpande m, sudrik s, taras s, kishore h, gilbert c. changing pattern of childhood blindness in maharashtra, india. br j ophthalmol 2007; 91: 8-12. 17. liu b, huang w, he m, zheng y. an investigation on the causes of blindness and low vision of students in blind school in guangzhou. yan ke xue bao 2007; 23:117-20. 18. haddad ma, sei m, sampaio mw, kara-josé n. causes of visual impairment in children: a study of 3,210 cases. j pediatr ophthalmol strabismus 2007; 44:232-40. 19. muhit ma, shah sp, gilbert ce, foster a. causes of severe visual impairment and blindness in bangladesh: a study of 1935 children. br j ophthalmol 2007; 91:1000-4. 20. gogate p, kishore h, dole k, shetty j, gilbert c, ranade s, et al. the pattern of childhood blindness in karnataka, south india. ophthalmic epidemiol 2009; 16:212-17. 21. titiyal js, pal n, murthy gv, gupta sk, tandon r, vajpayee rb, et al. causes and temporal trends of blindness and severe visual impairment in children in schools for the blind in north india. br j ophthalmol 2003; 87:941-5. 22. kocur i, kuchynka p, rodny s, barakova d, schwartz ec. causes of severe visual impairment and blindness in children attending schools for the visually handicapped in the czech republic. br j ophthalmol 2001; 85:1149-52. 23. decarlo dk, nowakowski r. causes of visual impairment among students at the alabama school for the blind. j am optom assoc. 1999; 70:647-52. magnitude and causes of low vision disability (moderate and severe visual impairment) among students of al-noor institute for the blind in al-hassa, saudi arabia a case series 68 | squ medical journal, february 2012, volume 12, issue 1 24. kasmann-kellner b, hille k, pfau b, ruprecht kw. eye and general illnesses in the public school for blind and visually handicapped students in saarland. developments in the last 20 years. ophthalmologe 1998; 95:51-4. 25. el mouzan mi, al salloum aa, al herbish as, qurachi mm, al omar aa. consanguinity and major genetic disorders in saudi children: a community-based cross-sectional study. ann saudi med 2008; 28:169-73. 26. khandekar r, jaffer y. incidence and determinants of birth defects and enzyme deficiencies among live births in oman: a review of the 2005 national register. sultan qaboos univ med j 2010; 10:23-30. 27. vora u, khandekar r, natrajan s, alhadrami k. refractive error and visual functions in children with special needs compared with the first grade school students in oman. middle east afr j ophthalmol 2010; 17:297-302. 28. walton ds, katsavounidou g. newborn primary congenital glaucoma: 2005 update. j pediatr ophthalmol strabismus 2005; 42:333-41. 29. tabbara kf, elsheikh hf, shawaf ss. pattern of childhood blindness at a referral center in saudi arabia. ann saudi med 2005; 25:18-21. 30. gilbert ce, ellwein lb. refractive error study in children study group. prevalence and causes of functional low vision in school-age children: results from standardized population surveys in asia, africa, and latin america. invest ophthalmol vis sci 2008; 49:877-81. 31. moller ma. working with visually impaired children and their families. pediatr clin north am 1993; 40:881-90. department of biotechnology, universidade federal da paraíba, joao pessoa, brazil *corresponding author e-mail: valdir@cca.ufpb.br اختالفات اجلنسني يف تغري معدل سرعة القلب عند األشخاص الذين يقومون بانتظام بتمارين مقاومة مالحظات أولية ايلني �سونايل فيالر رميالهو، ا�ستفام لوي�س �سوزا-االأ�سغر، مار�سني ماقنيناي، فالدير اأ.براقا abstract: objectives: frequency-domain analysis of heart rate variability (hrv) is an effective tool to evaluate autonomic balance. this study aimed to investigate gender differences in hrv among individuals undergoing regular resistance training. methods: this preliminary cross-sectional study was conducted from april to september 2016 in joão pessoa, paraíba, brazil. the low-frequency (lf), high-frequency (hf) and lf/hf ratio components of hrv spectral analysis were analysed among 22 men and 27 women undergoing regular resistance training. results: among the male participants, the lf component was significantly increased compared to females in both the supine (1,171 ± 192 versus 545 ± 74 ms2; p = 0.0067) and upright (1,824 ± 260 versus 738 ± 133; p = 0.0011) positions. the lf/hf ratio was also significantly increased in both positions among male participants (p <0.0500 each). conclusion: these preliminary data suggest a possible gender difference in the hrv of individuals undergoing resistance training. keywords: sympathetic nervous system; balance; gender; exercise; resistance training; brazil. امللخ�ص: الهدف: يعد حتليل تردد تغري معدل �رشعة القلب اأداة فعالة لتقومي التوازن امل�ستقل )االأتونومي(. وهدفت هذه الدرا�سة لبحث تاأثري النوع )اجلن�س( يف تغري معدل �رشعة القلب. الطريقة: اأجريت هذه الدرا�سة املقطعية يف جوا بي�ساو بالربازيل ما بني اأبريل و�سبتمرب من عام 2016. ومت حتليل نتائج قيا�س مكونات طيف تغري معدل �رشعة القلب التي ت�سمل الرتدد املنخف�س، والرتدد الَعايل، والن�سبة بينهما، وذلك عند 22 رجال و27 امراأة �ساركوا جميعا بانتظام يف متارين مقاومة. النتائج: وجد اأن الرتدد املنخف�س عند الرجال كان يفوق ب�سورة p = 0.0011( والوقوف امل�ستقيم )74 ± 545 مقابل 192 ± 171,1 ms2; p = 0.0067( معنوية اح�سائيا ما عند الن�ساء يف و�سعي اال�ستلقاء ;133 ± 738 مقابل 260 ± 1,824( وكانت ن�سبة الرتدد املنخف�س للرتدد العايل اأكرب عند الرجال ب�سورة معنوية اإح�سائيا يف الو�سعني )p <0.0500 لكل حالة(. اخلال�صة: ت�سري هذه املالحظات االأولية اإىل اأن هنالك فروقا معنوية إح�سائيا بني اجلن�سني يف معدل �رشعة القلب عند االأ�سخا�س الذين يقومون بانتظام بتمارين مقاومة. الكلمات املفتاحية: اجلهاز الع�سبي الودي؛ التوازن؛ النوع )اجلن�س(؛ التمارين؛ تدريبات املقاومة؛ الربازيل. gender differences in heart rate variability among individuals undergoing regular resistance training preliminary observations ellen s. v. ramalho, estevam l. souza-junior, marciane magnani, *valdir a. braga brief communication sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e209–212, epub. 20 jun 17 submitted 21 nov 16 revision req. 26 dec 16; revision recd. 30 dec 16 accepted 19 jan 17 doi: 10.18295/squmj.2016.17.02.012 modulation of an individual’s heart rate by the autonomic nervous system can be evaluated using frequency-domain methods to calculate sympathetic and parasympathetic components of heart rate variability (hrv) and sympathovagal balance.1 the high-frequency (hf) component of hrv is a measure of the vagalmediated parasympathetic influence on heart rate, whereas the low-frequency (lf) component is thought to be either a parameter that includes both sympathetic and vagal influences or a marker of sympathetic modulation, especially when expressed in normalised units. the lf/hf ratio is an indicator of sympathovagal balance.1 sympathovagal abnorma lities are associated with cardiovascular risk factors, including hypertension, obesity and diabetes.2 furthermore, increased body weight has been associated with increased sympathetic and parasympathetic activity which can intensify high blood pressure states.3 regular physical activity reduces blood pressure and resting heart rate while improving autonomic function, with aerobic exercise associated with a greater reduction in blood pressure than resistance training.4,5 a recent cross-sectional study on hrv among professional football players demonstrated a shift in their autonomic balance towards relative gender differences in heart rate variability among individuals undergoing regular resistance training preliminary observations e210 | squ medical journal, may 2017, volume 17, issue 2 sympathetic dominance due to reduced vagal activity.6 however, few studies have sought to determine sympathetic and parasympathetic variations among men and women undergoing resistance training. this study therefore aimed to evaluate the lf, hf and lf/ hf ratio components of cardiac autonomic function among men and women undergoing a regular resistance training routine. the hypothesis was that there would be a gender difference in hrv, based on the well-documented physiological differences in autonomic balance between men and women.7 methods this preliminary cross-sectional study was conducted from april to september 2016 in joão pessoa, paraíba, brazil. a total of 49 healthy adults who regularly underwent resistance training three to five times per week for a minimum of three consecutive months at the formula gym in joão pessoa were recruited to participate in the study. the exclusion criteria precluded individuals with sinus arrhythmia, those who smoked and/or drank alcohol and those with pre-existing diseases, such as diabetes or arterial hypertension. a portuguese-language questionnaire was designed to elicit information from the subjects, including their sleep timings, social routine, alcohol consumption, levels of physical activity, use of drugs that could affect the cardiovascular system and any medical or family history of pre-existing diseases. subsequently, all eligible participants had their height and weight measured. body fat was determined according to the seven-site skinfold method for both men and women.8 additionally, their waist to-hip ratio was measured as another index of obesity.9 fasting blood glucose was determined with a blood glucose monitoring system (onetouch select® plus, lifescan, high wycombe, uk) as described by setford et al.10 heart rate was measured using a ring-type pulse oximeter (advantage™ 2200 fingertip pulse oximeter, american diagnostic corp., hauppage, new york, usa). systolic blood pressure (sbp) and diastolic blood pressure (dbp) were determined using a standard sphygmomanometer in three different positions (supine, sitting and upright). mean blood pressure was calculated using the below formula: for each participant, hrv was measured 24 hours after the exercise session using a chest-based heart rate monitor designed for assessing autonomic function (intellewave inc., nassau county, new york, usa). the participant’s skin was cleaned with a 70% alcohol solution and an electrode belt was strapped around their chest. the participant was then instructed to lie down in a supine position without moving while hrv was recorded for three minutes. subsequently, the participants were instructed to stand up while hrv was recorded for a further three minutes. spectral analysis of the heartbeat-to-heartbeat intervals (i.e. rr intervals) was performed using nerve-express software, version 6.0 (intellewave inc.). the autoregressive spectral model was then applied to the selected segments and spectral power was calculated in the high-frequency (0.15–0.40 hz) and low-frequency (0.0–0.15 hz) bands. the lf/hf ratio was calculated using an excel spreadsheet, version 2013 (microsoft inc., redmond, washington, usa). data were expressed as means ± standard deviation. a student’s t-test was used to compare results between men and women with statistical significance defined at p <0.0500. the software used for the analysis was graphpad prism, version 6.0 (graphpad software inc., la jolla, california, usa). this study was approved by the ethics committee of the center for health sciences, federal university of paraiba (protocol #1.633.962). all procedures were conducted in accordance with the principles of the declaration of helsinki. all subjects provided informed consent before participating in the study. table 1: demographic, glycaemic and cardiovascular variables of healthy adults undergoing resistance training in joão pessoa, paraíba, brazil (n = 49) variable mean ± sd male (n = 22) female (n = 27) age in years 30.9 ± 1.8 32.3 ± 1.6 weight in kg 76.5 ± 2.7 61.3 ± 1.4 body fat in % 16.8 ± 1.1 22.7 ± 0.8 waist-to-hip ratio 0.80 ± 0.02 0.72 ± 0.01 blood glucose in mg/dl* 91.0 ± 2.5 84.0 ± 1.4 sbp in mmhg* 119.1 ± 3.7 108.1 ± 2.3 dbp in mmhg* 77.7 ± 3.2 72.6 ± 2.5 mbp in mmhg* 91.5 ± 3.3 84.4 ± 2.3 heart rate in bpm* 89.9 ± 1.8 85.8 ± 1.3 sd = standard deviation; sbp = systolic blood pressure; dbp = diastolic blood pressure; mbp = mean blood pressure. *no significant differences between men and woman. mean blood pressure = dbp + (1/3[sbp dbp]) ellen s. v. ramalho, estevam l. souza-junior, marciane magnani and valdir a. braga brief communication | e211 results a total of 22 men (44.9%) and 27 women (55.1%) took part in the study. there was no significant difference in age between the male and female participants (range: 18–50 years). body fat and waist-to-hip values were within normal ranges for both genders.9,11 blood pressure, heart rate and glycaemic measurements indicated that all participants were normotensive and euglycemic [table 1]. the lf component of hrv was significantly higher among men in comparison to women in both the supine (1,171 ± 192 versus 545 ± 74 ms2; p = 0.0067) and upright (1,824 ± 260 versus 738 ± 133 ms2; p = 0.0011) positions. moreover, the lf/hf ratio was also significantly increased among men in comparison to women in the supine (4.08 ± 0.30 versus 1.56 ± 0.06; p = 0.0417) and upright (3.34 ± 0.32 versus 2.16 ± 0.21; p = 0.0281) positions. however, there was no significant difference in the hf component of hrv among men and women in the supine (862 ± 237 versus 466 ± 108 ms2; p = 0.4480) and upright (802 ± 286 versus 461 ± 98 ms2; p = 0.6936) positions [figure 1]. discussion resistance training promotes strength gain as well as resistance and hypertrophy in the skeletal muscles.5 in a recent review, kingsley et al. reported that resistance training appeared to have no effect on resting hrv among healthy young adults, but may instead have hrv benefits during recovery from exercise.12 however, different types of training produced different outcomes.12 few studies have sought to identify gender differences in autonomic function among healthy individuals who regularly undergo resistance training. the present study investigated a sample of healthy adults undertaking a regular resistance training routine, which is a typical routine for most gym-goers. under experimental conditions without any interventions, the lf component and lf/hf ratio 24 hours after the exercise session were found to be significantly increased in men compared to women. the findings of the current study indicate that healthy men who take part in resistance training have increased cardiac sympathetic activity and sympathovagal balance in comparison to women. this is significant as hrv in response to exercise provides valuable insight into autonomic cardiovascular modulation; as such, an increase in sympathetic drive and sympathovagal balance among men could indicate an increased risk of cardiovascular disease.3 heffernan et al. similarly found that a single session of resistance training increased the lf/hf ratio among a group of young healthy men.13 the increase of both the lf component and lf/hf ratio in men supports the hypothesis that the physiology of autonomic balance regulation is fundamentally different in figure 1: box plots showing mean components of heart rate variability (hrv) among healthy men and women undergoing regular resistance training in joão pessoa, paraíba, brazil (n = 49). a: low-frequency (lf) component of hrv in the supine position. b: high-frequency (hf) component of hrv in the supine position. c: the lf/hf ratio in the supine position. d: lf component of hrv in the upright position. e: hf component of hrv in the upright position. f: the lf/hf ratio in the upright position. gender differences in heart rate variability among individuals undergoing regular resistance training preliminary observations e212 | squ medical journal, may 2017, volume 17, issue 2 young men and women.7 in a study on hypotension and haemodynamics following resistance exercise, queiroz et al. concluded that, although there were no gender variations in post-exercise hypotension, haemodynamic determinants differed between genders, including decreased cardiac output among men and decreased systemic vascular resistance in women.14 another study evaluating hrv among elderly subjects found that cardiac sympathetic modulation and heart rate remained elevated for a long period of time after a single session of strength training.15 it is important to highlight certain limitations of this preliminary cross-sectional study. first, the effect of resistance training on the sympathetic drive and sympathovagal balance was analysed over a limited period of time. as such, it is unknown whether the observed gender differences will continue to manifest in the same way if the individuals participate in a more long-term sustained resistance training regimen. second, further investigation is needed to determine whether the observed gender differences definitively represent an index of increased risk for cardiovascular disease among men. conclusion the preliminary observations of the current study suggest possible gender differences in hrv among healthy subjects who engage in regular resistance training, potentially indicating increased cardiovascular risk among men. however, further studies are needed to determine whether such gender differences are influenced by the duration and intensity of the exercise undertaken and whether these differences will exacerbate or normalise over time. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this preliminary study was funded by the brazilian national council for scientific and technological development (grants #472133/2013-6 and #304772/ 2014-3). references 1. task force of the european society of cardiology and the north american society of pacing and electrophysiology. heart rate variability: standards of measurement, physiological interpretation and clinical use. circulation 1996; 93:1043–65. doi: 10.1161/01.cir.93.5.1043. 2. grassi g. assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. hypertension 2009; 54:690–7. doi: 10.1161/hypertension aha.108.119883. 3. esler m. sympathetic nervous system moves toward center stage in cardiovascular medicine: from thomas willis to resistant hypertension. hypertension 2014; 63:e25–32. doi: 10.1161/hypertensionaha.113.02439. 4. brooks jh, ferro a. the physician’s role in prescribing physical activity for the prevention and treatment of essential hypertension. jrsm cardiovasc dis 2012; 31:1–9. doi: 10.1258/ cvd.2012.012012. 5. brito lc, queiroz ac, forjaz cl. influence of population and exercise protocol characteristics on hemodynamic determinants of post-aerobic exercise hypotension. braz j med biol res 2014; 47:626–36. doi: 10.1590/1414-431x20143832. 6. botek m, krejčí j, mckune aj, klimešová i. somatic, endurance performance and heart rate variability profiles of professional soccer players grouped according to age. j hum kinet 2016; 54:65–74. doi: 10.1515/hukin-2016-0035. 7. hart ec, charkoudian n, wallin bg, curry tb, eisenach jh, joyner mj. sex differences in sympathetic neuralhemodynamic balance: implications for human blood pressure regulation. hypertension 2009; 53:571–6. doi: 10.1161/ hypertensionaha.108.126391. 8. jackson as, pollock ml, ward a. generalized equations for predicting body density of women. med sci sports exerc 1980; 12:175–82. doi: 10.1249/00005768-198023000-00009. 9. world health organization. waist circumference and waist-hip ratio: report of a who expert consultation. from: http://apps. who.int/iris/bitstream/10665/44583/1/9789241501491_eng. pdf accessed: dec 2016. 10. setford s, smith a, mccoll d, grady m, koria k, cameron h. evaluation of the performance of the onetouch select plus blood glucose test system against iso 15197:2013. expert rev med devices 2015; 12:771–81. doi: 10.1586/17434440.2015.1102049. 11. gallagher d, heymsfield sb, heo m, jebb sa, murgatroyd pr, sakamoto y. healthy percentage body fat ranges: an approach for developing guidelines based on body mass index. am j clin nutr 2000; 72:694–701. 12. kingsley jd, figueroa a. acute and training effects of resistance exercise on heart rate variability. clin physiol funct imaging 2016; 36:179–87. doi: 10.1111/cpf.12223. 13. heffernan ks, kelly ee, collier sr, fernhall b. cardiac autonomic modulation during recovery from acute endurance versus resistance exercise. eur j cardiovasc prev rehabil 2006; 13:80–6. doi: 10.1097/01.hjr.0000197470.74070.46. 14. queiroz ac, rezk cc, teixeira l, tinucci t, mion d, forjaz cl. gender influence on post-resistance exercise hypotension and hemodynamics. int j sports med 2013; 34:939–44. doi: 10.1055/s-0033-1337948. 15. queiroz ac, kanegusuku h, chehuen mr, costa la, wallerstein lf, dias da silva vj, et al. cardiac work remains high after strength exercise in elderly. int j sports med 2013; 34:391–7. doi: 10.1055/s-0032-1323779. https://doi.org/10.1161/01.cir.93.5.1043 https://doi.org/10.1161/hypertensionaha.108.119883 https://doi.org/10.1161/hypertensionaha.108.119883 https://doi.org/10.1161/hypertensionaha.113.02439 https://doi.org/10.1258/cvd.2012.012012 https://doi.org/10.1258/cvd.2012.012012 https://doi.org/10.1590/1414-431x20143832 https://doi.org/10.1515/hukin-2016-0035 https://doi.org/10.1161/hypertensionaha.108.126391 https://doi.org/10.1161/hypertensionaha.108.126391 https://doi.org/10.1249/00005768-198023000-00009 https://doi.org/10.1586/17434440.2015.1102049 https://doi.org/10.1111/cpf.12223 https://doi.org/10.1097/01.hjr.0000197470.74070.46 https://doi.org/10.1055/s-0033-1337948 https://doi.org/10.1055/s-0032-1323779 department of fundamentals and administration, college of nursing, sultan qaboos university, muscat, oman *corresponding author’s e-mails: mickaelj@squ.edu.om; mickaelantoinejoseph@gmail.com ِعظاُم الرُُّسغ والرُُّصغ يف جسم اإلنسان فن اإلستذكار ابللغة العربية ميكائيل جوزيف و جان�سرياين ناتاراجان abstract: memorising human anatomy structures remains a challenge for nursing students. educators endeavour to make human anatomy interesting and easy to memorise. various instructional approaches can be used to help students enhance their memory. mnemonics, for example, are well-established educational strategies that have proven useful in the encoding, retention and retrieval of anatomical terms. the carpal and tarsal bones are some of the anatomical structures that prove challenging to nursing students’ study of anatomy. although available online to students, most of the accessible mnemonics are in english and non-native english-speaking students (students who are native arabic-speakers) might find them difficult to understand. therefore, we have created two simple arabic mnemonics that can simplify the memorisation of the carpal and tarsal bones. we believe that arabic mnemonics effectively enhance memorisation by linking the new learning material to familiar information. keywords: learning; memory; anatomy; nursing; carpal bones; tarsal bones; oman. ممتعا الب�رشي الت�رشيح علم جعل اإىل املعلمون ي�سعى التمري�ض. لطالب حتدًيا ميثل الب�رشي الت�رشيح تركيبات حفظ يزال ال امللخ�ص: و�سهل احلفظ. ميكن ا�ستخدام مناهج تعليمية خمتلفة مل�ساعدة الطالب على تعزيز ذاكرتهم. فن اال�ستذكارعلى �سبيل املثال هو ا�سرتاتيجيات الرتكيبات بع�ض هي غ والرُّ�سُ الرُّ�ُسغ ِعظاُم وا�سرتجاعها. وا�ستبقائها الت�رشيحية امل�سطلحات ترميز يف فائدتها را�سخة اأثبتت تعليمية الت�رشيحية التي ًتثل حتديا لطالب التمري�ض يف درا�ستهم لعلم الت�رشيح. على الرغم من توافر و�سائل اال�ستذكار عرب االإنرتنت للطالب اإال اأن معظم امُلتاح منها متوفر باللغة االإجنليزية مما ي�سكل �سعوبة يف فهمها لدى الطالب غري الناطقني باللغة االإجنليزية )الطالب الذين غ. نحن يتحدثون اللغة العربية(. لذلك قمنا باإن�ساء رمزين خمت�رشين ب�سيطني باللغة العربية ميكنهما تب�سيط ا�ستذكار ِعظاُم الرُّ�ُسغ والرُّ�سُ نعتقد اأن فن اال�ستذكار باللغة العربية يعزز احلفظ ب�سكل فعال من خالل ربط املواد التعليمية اجلديدة باملعلومات املاألوفة.. غ؛ �سلطنة ُعمان. الكلمات املفتاحية: التعلم؛ ذاكرة؛ علم الت�رشيح؛ التمري�ض؛ ِعظاُم الرُّ�ُسغ؛ ِعظاُم الرُّ�سُ the carpal and tarsal bones of the human body arabic mnemonics *mickaël a. joseph and jansirani natarajan technical note sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e223–226, epub. 28 jun 20 submitted 24 dec 19 revision req. 16 feb 20; revision recd. 15 mar 20 accepted 25 mar 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.014 as nursing instructors, we must equipour students with the necessary competencies to meet the challenges of 21st century health care. worldwide, leading nursing educators agree that an understanding of anatomy and physiology (a&p) is critical to ensuring good nursing practice.1,2 however, it is well documented that nursing students struggle with a&p because they find it arduous to memorise huge numbers of anatomical terminology.1 over the years, as gray’s anatomy (the most extensive and detailed book on anatomy) grew to over 1,500 pages, educators have tried to find different strategies and apply new technologies to facilitate the teaching of anatomy.3,4 both students and educators have managed to abbreviate anatomical structures into mnemonics, which are systems used to facilitate easy and effective retention of information.5 as previous students ourselves, mnemonics helped us immensely in retaining anatomical terms and recalling them more easily at a later time. mnemonics are a great teaching strategy which has shown to increase memorisation of human anatomy.6 in nursing education, a previous study has shown the effectiveness of mnemonics in facilitating the memorisation of an “introduction to nursing” course.7 koksal et al. used mnemonics to help students remember basic knowledge about the healthcare system.7 results have shown that nursing students who studied with mnemonics performed better in a retention test than the control group who did not employ the aforementioned technique. through mnemonics, associations are created between new, unknown information and old information that have already been mastered.8 by acting on working memory, these mnemonics lower the introduced cognitive load and enhance the attainment and encoding of new information. mnemonics use familiar words to form a cue that can be better encoded into memory. by using these familiar cues, the load is minimised while allowing an enhancement of the long-term memory.9 https://creativecommons.org/licenses/by-nd/4.0/ the carpal and tarsal bones of the human body arabic mnemonics e224 | squ medical journal, may 2020, volume 20, issue 2 different forms of mnemonic strategies such as acronyms and acrostics have made it easier to remember new information by making it more familiar and meaningful.10 acronyms are words in which each letter stands for a piece of information to be remembered. for example, “rice” is an acronym that is used for a sprained ankle treatment where “r” stands for rest, “i” for ice, “c” for compression and “e” for elevation.9 on the other hand, an acrostic is a sentence where the first letter of each word plays the role of a cue for the information to be recalled. an anatomical acrostic was used by larson to memorise the bones of the orbit: “many friendly zebras enjoy lazy summer picnics” was used, where the acrostic represents the maxillary, frontal, zygomatic, ethmoid, lacrimal, sphenoid and palatine bones, respectively.11 other acrostics have been used to remember the branches of the facial nerve. for instance, the sentence “to zanzibar by motor car” helped students to recall the order of the nerves correctly as temporal, zygomatic, buccal, mandibular and cervical.9 a vast amount of mnemonic examples are readily available with a quick internet search. however, all these mnemonics are in english and sometimes contain complicated words which increase the difficulty for non-native english students. undergraduate nursing students need to be knowledgeable about the skeletal system. in fact, one of the first systems that is taught at sultan qaboos university in a&p is the skeletal system. learning the names of the bones of the human body is particularly important since students need this information to be able to find these landmarks when assessing patients. students must memorise the 206 bones of the human body, a task which have often perturbed nursing students. traditionally, the names of the bones of the human body are taught to undergraduates by means of didactic lectures. teaching these names can be challenging for many educators. consider the carpal and tarsal bones, students need to learn the names of the eight carpal and the seven tarsal bones in order. these short bones can be difficult to distinguish from one another due to their similarities in size and shape.12 using didactic lectures to teach the names of these bones often fail to engage students and, consequently, many students feel overwhelmed. therefore, the use of mnemonics can provide a better and more engaging way of learning. methodology: creating arabic mnemonics a handful of mnemonics addressing the order of carpal and tarsal bones have been published online, yet none are in arabic. furthermore, mnemonics cannot be translated. therefore, we have composed arabic mnemonics that could be used by nursing and other arabic-speaking healthcare students to enhance the memorisation of the names of these bones. the wrist has eight bones, arranged in two rows: scaphoid, lunate, triquetrum, pisiform, trapezium, trapezoid, capitate and hamate [figure 1a]. these bones can be learned by the arabic mnemonic: .[table 1]سامل له تسعة بقرات أتكل مترا كيف هذا؟ the tarsal bones are found in the ankle and include the calcaneus, talus, navicular, medial, intermediate and lateral cuneiform and cuboid [figure 1b]. the bones can be learned by the arabic mnemonic: .[table 2]كسر اتمر انفذة منزهلم، إهنا لفعلٌة كبرية figure 1: illustration of the carpal and tarsal bones of the human body. a: the eight carpal bones of the left hand (anterior view) with the respective arabic mnemonics. b: the seven tarsal bones of the right foot (dorsal view) with the respective arabic mnemonics. drawn by amjad majid hamed alnaabi (nursing student at college of nursing, sultan qaboos university, muscat, oman) and digitised by raitha masoud alhinai (bachelor of graphic design, graduate of the college of applied sciences, ibri, oman). mickaël a. joseph and jansirani natarajan technical note | e225 discussion students and educators can find a plethora of mnemonics on online databases. however, the majority of these mnemonics are in english, which is unfortunate for nonnative english-speaking students.14 therefore, there is a need for creating arabic mnemonics to make the recollection process easier for these students. it is imperative to stress the limitations of these tools. mnemonics are useful merely for memorisation; they are not strategies for understanding, application or analysis.10 they encourage surface learning rather than developing in-depth learning. some nursing educators might abstain from teaching mnemonics because of their perception that this method is a lazy way to study. some even believe that using mnemonics for patient-care might damage the humanistic approach by condensing patients’ symptoms into a 'laundry list'.9 in addition, various mnemonics use humour to increase retention and some teachers decline their use, describing them as unprofessional or even uncivil.14 it is worth mentioning that students can find mnemonics everywhere and it is likely that they are using them without the educators’ knowledge. therefore, it would be appropriate for teachers to be aware of the mnemonics their students are using and to check these learning aids for mistakes. when considering the benefits of mnemonic strategies, it is necessary to mention that many experiments show the beneficial effect of these aids on facilitating learning and memory of students.15 although the benefits of mnemonics use have been documented in many research articles, it must be considered that mnemonics do not address all levels of bloom’s taxonomy and cannot cover all courses’ objectives.5–7 therefore, these memory tools should not be considered as the only study aid needed for learning anatomy. however, we believe that mnemonics could allow students to establish a baseknowledge that could be developed and built upon. furthermore, they allow students to memorise the table 2: acrostic mnemonics in arabic to help remember the tarsal bones from proximal to distal english acrostic arabic mnemonics calcaneus كسر talus اتمر navicular انفذة medial cuneiform منزهلم intermediate cuneiform إهنا lateral cuneiform لفعلٌة cuboid كبرية table 3: the nomenclature of the carpal and tarsal bones with the respective arabic terminology bones meaning arabic terminology carpal bones scaphoid boat-shaped العظم القاريب lunate crescent-shaped العظم اهِلاليل triquetrum three-sided العظم ُثالثي األركان )املثّلثي( pisiform pea-shaped العظم احِلّمصي trapezium irregular four-sided العظم املرُبّعي trapezoid four-sided العظم املنحريف capitate head-shaped العظم الكبري hamate hooked العظم الُكاليب tarsal bones calcaneus heel عظم العقب talus ankle bone عظم القعب navicular boat-shaped العظم الزورقي cuneiform bones wedge-shaped العظام السفينية cuboid cube-shaped العظم النردي table 1: acrostic mnemonics in arabic to help students remember the carpal bones from lateral to medial for the proximal and distal row english acrostic arabic mnemonics scaphoid سامل lunate له triquetrum تسعة pisiform بقرات trapezium أتكل trapezoid مترا capitate كيف hamate هذا the carpal and tarsal bones of the human body arabic mnemonics e226 | squ medical journal, may 2020, volume 20, issue 2 information quickly, leaving more time for higherorder learning. whenever students show difficulties in memorising lists of information, mnemonic devices constitute a powerful tool in the array of instructional resources and strategies. it is worth noting that not only mnemonics can facilitate the learning of the carpal and tarsal bones. knowledge of the terminology used for the nomenclature of these bones can also be helpful. carpal and tarsal bones’ names reflect their shape which can be additionally useful for learning and identification. the english name of each carpal and tarsal bone is derived from either latin or greek. for example, the scaphoid name stems from the greek word skaphidion meaning “a small ship”. due to its boat-like shape it is commonly referred to as the “boat bone” in arabic the lunate was named for its resemblance .(العظم القاريب) to a crescent, which is derived from the latin word luna. in arabic, it is known as the crescent bone اهِلاليل) 16,17 therefore, understanding.[table 3] (العظم the terminology might help in recognising the morphological characters of the carpal and tarsal bones. finally, in-depth analysis should be carried out in the future to test whether these arabic mnemonics will improve students’ learning and enhance their recollection of the names of bones. in addition, students’ perception of the use of arabic mnemonics should be investigated. the observation in the classroom, however, indicated that students enjoyed the use of these tools. the two created mnemonics were found to be helpful in teaching the anatomy of carpal and tarsal bones. the students can now use a simple aidemémoire to simplify the memorisation of these bones. we encourage our students to create their own arabic mnemonics. we also encourage the readers to publish more of these tools to help our non-native englishspeaking students to improve their retention. references 1. johnston an. anatomy for nurses: providing students with the best learning experience. nurse educ pract 2010; 10:222–6. https://doi.org/10.1016/j.nepr.2009.11.009. 2. clifton i, mckillup sc. why such success? nursing students show consistently high satisfaction with bioscience courses at a regional university. aust j adv nurs 2016; 33:21. 3. vázquez r, riesco jm, juanes ja, blanco e, rubio m, carretero j. educational strategies applied to the teaching of anatomy. the evolution of resources. eur j anat 2020; 11:31–43. 4. brennan p, standring s, wiseman s. gray's surgical anatomy e-book. 1st ed. amsterdam, netherlands: elsevier, 2019. 5. yeoh mp. musical mnemonics to facilitate learning of trans cription of rna. lsm 2014; 9:24–34. 6. mcdeavitt jt, king kc, mcdeavitt kr. learning brain stem anatomy: a mnemonic device. pm r 2014; 6:963–6. https://doi.org/10.1016/j.pmrj.2014.03.013. 7. koksal o, sunbul am, ozturk ye, ozata m. the impact of mnemonic devices on attainment and recall in basic knowledge acquisition in nursing education. mije 2013; 3:265–78. 8. mastropieri ma, sweda j, scruggs te. putting mnemonic strategies to work in an inclusive classroom. learn disabil res pract 2000; 15:69–74. 9. caplan jp, stern ta. mnemonics in a mnutshell: 32 aids to psychiatric diagnosis. curr psychiatr 2008; 7:27–33. 10. bakken jp, simpson cg. mnemonic strategies: success for the young-adult learner. hral 2011; 7:79. 11. larson mf. mnemonic: bones of the orbit. hosp physician. [letter to the editor] september 1999. 12. smart ts. carpals and tarsals of mule deer, black bear and human: an osteology guide for the archaeologist. phd thesis, 2009, western washington university, washington, usa. pp. 6. 13. villanueva t. medical mnemonics. from: www.medicalmne monics.com accessed: mar 2020. 14. larson e. criticism of mnemonic device. am j psychiatry 1990; 147:963–4. 15. scruggs te, mastropieri ma, berkeley sl, marshak l. mne monic strategies: evidence-based practice and practice-based evidence. interv sch clin 2010; 46:79–86. https://doi.org/10.11 77/1053451210374985. 16. drake r, vogl aw, mitchell aw. gray’s anatomy for students. 3rd ed. amsterdam, netherlands: elsevier, 2015. pp. 634–7. 17. drake r, vogl aw, mitchell aw. gray’s anatomy for students in arabic [translated by medical students from damascus university under supervision of dr bian al-sayed, md]. 3rd ed. amsterdam, netherlands: elsevier, 2015. pp 634–7. https://doi.org/10.1016/j.nepr.2009.11.009 https://doi.org/10.1016/j.pmrj.2014.03.013 https://doi.org/10.1177/1053451210374985 https://doi.org/10.1177/1053451210374985 squ med j, february 2011, vol. 11, iss. 1, pp. 5-28, epub. 12th feb 11 invited article submitted 4th aug 10 revision req. 5th oct 10, revision recd. 25th oct 10 accepted 8th nov 10 glia-derived neoplasms of the brain (gliomas) of the histological grade 3 (anaplastic astrocytoma, anaplastic oligoastrocytoma, and anaplastic oligodendroglioma) and grade 4 (glioblastoma multiforme, [gbm]) according to the morphologybased classification of the world health organization (who),1 represent different stages of the same fatal neoplastic disease of the central nervous system (cns). who grade 3 and 4 gliomas are also known as malignant gliomas and are the most frequent intrinsic brain tumours in adults.2 according to the us central brain tumour registry, the annual rate of primary tumours of the cns is department of neurosurgery, klinikum augsburg, d-86156 augsburg, germany. *corresponding author email: nikolai.rainov@klinikum-augsburg.de oèf§]< �í �œ� e �å<›ö̌á̌÷<9ëürj÷]<t¯√◊÷<îüëüä÷]<öá�j÷]                  abstract: advances in medical and surgical treatments in the last two to three decades have resulted in quantum leaps in the overall survival of patients with many types of non-central nervous system (cns) malignant disease, while survival of patients with malignant gliomas (who grades 3 and 4) has only moderately improved. surgical resection, external fractionated radiotherapy and oral chemotherapy, during and after irradiation, remain the pillars of malignant glioma therapy and have shown significant benefits. however, numerous clinical trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not achieved a noteworthy extension of survival, or only with considerable deterioration in patients’ quality of life. significant attention was focussed in the last decades on the cell biology and molecular genetics of gliomas. improved understanding of the fundamental features of tumour cells has resulted in the introduction and increasing clinical use of local therapies, which employ spatially defined delivery methods and tumour-selective agents specifically designed to be used in the environment of a glioma-invaded brain. this review summarises the key findings of some of the most recent and important clinical studies of locally administered novel treatments for malignant glioma. several such therapies have shown considerable anti-tumour activity and a favourable profile of local and systemic side effects. these include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection enhanced delivery, and intraand peritumourally injected genetically modified viruses conferring glioma-selective toxicity. areas of possible improvement of these therapies and essential future developments are also outlined. keywords: astrocytoma; convection-enhanced delivery; glioma; immunotoxin; virus review clinical development of experimental therapies for malignant glioma *nikolai g rainov and volkmar heidecke clinical development of experimental therapies for malignant glioma 6 | squ medical journal, february 2011, volume 11, issue 1 14.1 per 100,000 persons, of which more than 36% are malignant gliomas.3,4 malignant gliomas typically arise in the lobar white matter or in the deep grey matter of the brain and are characterised by diffusely infiltrating growth.2,5 these gliomas consist of highly proliferative and exceptionally migratory tumour cells with a variety of acquired genetic alterations which make them extremely resistant to antiproliferative therapies.6,7,8 there is no clear demarcation of tumour from normal surrounding brain tissue to allow the surgeon to completely remove a glioma. neuroradiological imaging such as computed tomography (ct) or magnetic resonance imaging (mri) can only visualise areas with a high percentage of tumour cells and strong neoangiogenesis, but not those with a low density of invading glioma cells and neoplastic capillaries.9 gliomas expand both by mitotic activity of tumour cells and by migration of these cells away from the initial tumour mass and into the surrounding brain.10 it is now generally accepted that widespread migration of glioma cells is a very early feature of these tumours, and by the time of clinical manifestation and histological diagnosis cells have spread throughout the cns and are located beyond the extent of any feasible surgical resection.11,12 there is evidence to suggest that the density of infiltrating malignant cells decreases according to the distance from the initial tumour mass, and there is a tendency of tumour cells to migrate along defined anatomical structures such as white matter tracts.5,13 supporting the notion that malignancy declines with distance from the main tumour, the fact is well known that most malignant gliomas will recur within a few centimetres of the walls of the resection cavity or the visible tumour mass, respectively.6,10,14 simple diffusion of cells could potentially explain this observation. on the other hand, recent insights in glioma cell biology suggest that more malignant and actively proliferating cells might be less migratory and less invasive, while less malignant cells may tend to invade more remote areas of the brain which surround the tumour mass.10,15 survival of patients with malignant glioma has remained essentially the same in the last three decades, despite a quantum leap in medical and surgical technology and major advancements in understanding the natural history and biology of the disease, and the molecular genetics of glioma cells.11,16 median survival time for malignant gliomas varies according to different studies, but is generally agreed to be 18–20 months for anaplastic astrocytomas and 8–14 months for gbm.2,3,11 there are no curative treatments for malignant glioma at present and no treatment able to prevent tumour progression or recurrence. even the most radical surgical resection is unable to cure a malignant glioma, although it may significantly prolong survival and improve quality of life.6,12,14,17 the current standard therapy of newly diagnosed malignant gliomas consists of surgery, preferably a gross total resection of contrastenhancing areas, subsequent fractionated external radiotherapy up to a total dose of 60 gy, and concomitant and adjuvant chemotherapy in who grade 4 tumours, with various combinations of these three approaches.6,8,16,18 the use of chemotherapy, in addition to surgery and radiation, was considered somewhat controversial until recent studies demonstrated significantly improved outcome for patients with previously untreated gbm receiving radiotherapy plus concomitant and adjuvant chemotherapy after surgery.18 however, in all clinical studies, significant improvements in overall survival are demonstrated mostly in selected subpopulations of patients with somewhat better prognostic factors, such as a higher karnofsky performance status (kps), younger age, specific molecular markers, complete surgical resection of tumour, and others.4,11,12,16-18 perhaps the most prominent feature, which renders malignant glioma a preferred target for tumour selective drugs and local treatments, is the unique combination of high mitotic activity of tumour cells against the background of the mostly post-mitotic environment of the adult brain.9,10 in addition, malignant gliomas do not metastasise systemically, but are extremely aggressive in their local environment within the closed compartment of the cns. multidrug and radiation resistance genes are upregulated in primary and recurrent glioma and allow tumour cells to escape the toxicity of the standard treatment modalities and to continue growing even during radioor chemotherapy.6,10,16 distinct biological features common in malignant gliomas, but unusual in normal brain tissue, have been the subject of many research studies. differential expression of specific proteins nikolai g rainov and volkmar heidecke review | 7 and clinically relevant approaches to local intracerebral therapy of malignant gliomas. all of these are currently employed in an adjuvant setting, in addition to the above mentioned and well established standard modalities of surgery and fractionated external radiotherapy with chemotherapy, and not as their replacements. we will focus mostly on therapeutic approaches that have demonstrated safety, feasibility, and potential anti-tumour efficacy in previous and ongoing clinical studies. i n t e r s t i t i a l c h e m o t h e r a p y w i t h b i o d e g r a d a b l e p o ly m e r wa f e r s (g l i a d e l ) sustained and controlled local delivery of therapeutic agents to a brain glioma is one of the recent strategies for increasing toxicity to tumour cells while reducing systemic side effects. gliadel (mci pharma inc., bloomington, mn, usa) wafers were developed as a means for controlled release of a chemotherapeutic agent from biodegradable polymer wafers to the surroundings of surgically resected malignant glioma.21,22 their efficacy was investigated in several preclinical and clinical studies.23-26 gliadel wafers are currently approved for use in patients with primary and recurrent glioblastoma as an adjunct to standard treatment modalities. clinical studies investigating local intracerebral in malignant glioma versus the normal brain and aberrant activation of signal transduction cascades in tumours seems to provide an opportunity for selective molecular targeting of tumour cells despite the molecularly targeted agents being given mostly systemically, thus associated with less toxicity to the patient and with a higher rate of tumour cell killing.6,8,10,16 all these features make gliomas a model disease for the design and testing of novel treatments with tumour-selective toxicity and a local rather than systemic mode of administration. several novel approaches have been introduced into clinical practice in a continuous effort to improve the outcome of malignant glioma. in general, such approaches can be categorised as systemic or local, the latter being intratumoural, peritumoural, intracerebral, or combined.19,20 novel systemic approaches demonstrating potential in early clinical studies are chemotherapy drugs with molecular selectivity mechanisms (such as receptor tyrosine kinase inhibitors), and active (e.g. dendritic cells) or passive (e.g. antibodies) immunotherapies. novel local intracranial approaches include intracerebral delivery of standard chemotherapy drugs (interstitial chemotherapy) by slow release polymers, recombinant targeted toxins administered by convection enhanced delivery (ced), or genetically modified viruses with molecular selectivity for glioma cells.20,21 this review will summarise the most recent figure 1: handling and implantation of gliadel® wafers during brain tumour surgery. a: a single wafer is removed from the sterile aluminium foil protective packaging. b: all 8 gliadel® wafers belonging to a complete pack are removed from the packaging and prepared for intracerebral implantation. c: gliadel® wafers lining the wall of a glioblastoma (gbm) resection cavity. note that the relatively small tumour resection cavity can only accommodate 5 wafers. slight overlapping of wafers is acceptable. d: implanted wafers are covered with oxidised cellulose (surgicel®, ethicon, hamburg, germany) to prevent dislocation and intracavitary movement. clinical development of experimental therapies for malignant glioma 8 | squ medical journal, february 2011, volume 11, issue 1 delivery of the well-known and frequently used chemotherapy drug, 1,3-bis-(2-chloroethyl)-1nitrosourea (bcnu or carmustine) began in the early 1990s.23 bcnu was initially chosen due to proven efficacy against glioma cell lines. for local delivery of bcnu, biodegradable polymer wafers were used so as to deliver the drug to the tumour resection cavity in a controlled-release fashion over time, which should circumvent the short in vivo halflife of the drug, increase the local concentration of bcnu reaching glioma-invaded areas of normal brain, and avoid the concomitant toxicities of systemic drug application.21,22 polymer (prolifeprosan 20) wafers containing 3.85% (w/w) bcnu, which are also known by the brand name gliadel, are currently the only type of interstitial chemotherapy wafers licensed by u.s. and european agencies for treatment of de novo and recurrent malignant gliomas [figure 1, a and b]. wafers are placed directly into the resection cavity of a malignant glioma at the end of surgical resection of the tumour [figure 1, b and c].22 this may result in local bcnu levels approximately 100-fold of those obtained with systemic delivery.27 gliadel wafers have been shown to release bcnu in vivo over a period of approximately 5 days. when in continuous contact with interstitial fluid, wafers have been shown to degrade completely over a period of 6–8 weeks. polymer degradation products are excreted as expired co2 or through the urine. bcnu degradation products are also excreted primarily through the urine.21,27 no direct pharmacokinetic measurements have been made in humans after the implantation of gliadel wafers; however, drug distribution and clearance have been extensively studied in rodents and primates. in addition, degradation of the polymer matrix, the release kinetics of bcnu, and drug and polymer metabolism have been studied both in vitro and in vivo.27 pharmacokinetic studies have demonstrated the capability of gliadel wafers to deliver high (mm) concentrations of bcnu within a few millimetres of the polymer implant and with a limited penetration distance. the limited interstitial spread of the drug is presumably due to the high transcapillary permeability of this lipophilic molecule.22 however, convective flow in the existing peritumoural oedema may augment diffusion.27,28 in 1991, brem et al. established a significant survival advantage of gliadel wafers over placebo in patients with recurrent malignant glioma.23 they conducted a randomised, placebo-controlled, prospective phase 3 clinical study to evaluate the effectiveness of gliadel wafers. their multicentre study enrolled 222 patients with recurrent malignant brain tumours requiring re-operation. cases were randomly assigned to surgically implanted wafers with or without bcnu. median survival of the 110 patients who received gliadel wafers was 31 weeks compared with 23 weeks for the 112 patients who received placebo wafers (p = 0.006). among gbm patients, 6-month survival in the treated group was 50% greater than in the placebo group. there were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically.23,24 a phase 1 trial was carried out in patients with newly diagnosed gbm.28 twenty-two mostly elderly patients (mean age 60 years) with newly diagnosed malignant glioma (21 with gbm) were treated with gliadel wafers. postoperatively, all patients received standard radiation therapy, but no additional chemotherapy in the first 6 months. the neurotoxicity of this regimen was equivalent to that occurring in other series of patients undergoing craniotomy and radiation. no significant bone marrow suppression occurred and there were no wound infections. median survival of the whole group was 42 weeks, 8 patients survived 1 year, and 4 patients survived more than 18 months. the authors concluded that interstitial chemotherapy with gliadel wafers with subsequent radiation appears to be safe as an initial therapy for malignant glioma.28 in 2004, kleinberg et al. described, in a retrospective review, the clinical course, toxicity, and pathologic findings after gliadel wafer implantation for newly diagnosed malignant glioma.29 fortyfive consecutive patients, most of them with gbm, received gliadel wafer implants followed by radiotherapy and were available for follow-up. postoperative infection, or the need for reoperation within 30 days was uncommon after gliadel wafer placement. full-dose external radiotherapy was well tolerated after gliadel implantation; however, 13 patients developed neurological symptoms during radiotherapy, but responded to medication (dexamethasone and/or anticonvulsants). fifteen of these 45 patients underwent re-operation or biopsy for a new local contrast-enhancing lesion. in 5 of these, histological analysis revealed necrosis or nikolai g rainov and volkmar heidecke review | 9 patients (p = 0.017), with a hazard ratio of 0.73 (p = 0.018), representing a significant risk reduction of 27%. this survival advantage was maintained at 1, 2, and 3 years and was statistically significant (p = 0.01) at 3 years. two of the 207 gbm patients remained alive at the end of the follow-up period, both in the gliadel group. the authors concluded that malignant glioma patients treated with gliadel at the time of initial surgery in combination with radiation therapy demonstrated a continuous and significant survival advantage at 2 and 3 years follow-up compared with placebo patients.26 additional studies were aimed at increasing the clinical effects of gliadel treatment using different strategies. olivi et al. treated 44 adult patients with surgery and implantation of bcnu wafers.31 six patients per dose level were studied using wafers with 6.5%, 10%, 14.5%, 20%, and 28% bcnu (weight/weight). toxicity was assessed one month after wafer implantation. no dose-limiting toxicity was identified at the 6.5%, 10%, or 14.5% dose levels, although delayed wound healing, seizures, and brain oedema were noted. at the 20% dose, these side effects seemed more prominent, and 6 additional patients were treated at this dose and tolerated treatment well. three of 4 patients receiving 28% bcnu wafers developed severe brain oedema and seizures. nine additional patients received 20% wafers, confirming this as the maximum tolerated dose (mtd). maximum bcnu plasma concen trations with the 20% wafers were 27 ng/ml. overall median survival of the patients was 12 months. the authors concluded that 20% bcnu wafers are relatively well tolerated and result in minimal systemic bcnu exposure.31 additional studies are however needed to establish the efficacy of high-dose bcnu wafers and a possible significant extension of survival due to the increased concentration of bcnu. beginning in 2004, concomitant temozolomide (tmz) during fractionated brain irradiation (stupp protocol) became the standard of care at most neurooncology centres in europe and the usa.18 patients with newly diagnosed gbm and gliadel implantation received therefore concomitant tmz and irradiation radiochemotherapy); however, it remained unstudied whether combining gliadel and radiochemotherapy is safe or further improves survival in such patients. in 2010, mcgirt et al. reviewed retrospectively the initial experience with post-treatment scars without active tumour. median survival was 12.8 months for all gbm patients.29 to corroborate the evidence from early clinical trials, a randomised controlled trial planned to include 100 cases was carried out in patients undergoing surgery for newly diagnosed gliomas, but was terminated prematurely after enrolment of 32 patients because the gliadel implants became unavailable.30 the median overall survival time was 58.1 weeks for the active treatment group versus 39.9 weeks for the placebo group (p = 0.012). at the end of the study, 6 patients were still alive, 5 of whom belonged to the active treatment group. results were, however, not corrected for the early termination and thus a possible bias may have been introduced in the statistical evaluation.30 westphal et al. reported the results of a further multicentre phase 3 study investigating gliadel wafer treatment in 240 patients with newly diagnosed gbm.25 patients were randomised to receive either bcnu or placebo wafers at the time of primary surgical resection. all patients were given identical standard treatment consisting of surgical resection followed by fractionated external radiation. exclusion criteria were recurrent tumour, prior brain radiotherapy, and multifocal disease. the primary clinical endpoint was overall survival. median survival in the intent-to-treat (itt) population was 13.9 months for the gliadel-treated group, and 11.6 months for the placebo-treated group, with a 29% reduction in the risk of death in the treatment group. time to decline in kps and clinical parameters (e.g. vital signs, level of consciousness, neurological status), were also significantly improved in the treatment group compared to the placebo group. the adverse events (ae) were comparable for the two groups, except for cerebrospinal fluid (csf) leak (5% in the gliadel group versus 0.8% in the placebo group) and intracranial hypertension (9.1% in the gliadel group versus 1.7% in the placebo group). this study is the largest clinical investigation of gliadel activity to date.25 in a later study, the authors reported the longterm follow-up results of the above patient group regarding survival benefits at 2 and 3 years after gliadel implantation.26 of the 59 patients available for long-term follow-up, 11 were alive at 56 months; 9 having received gliadel and 2 placebo wafers. the median survival of patients treated with gliadel was 13.8 months versus 11.6 months in placebo-treated clinical development of experimental therapies for malignant glioma 10 | squ medical journal, february 2011, volume 11, issue 1 application. most importantly, there is only a modest short-term clinical benefit in most patients, while long-term survival is prolonged in a small subset of malignant glioma patients only. the side effects of gliadel are not negligible, and the high cost of treatment is an important issue, at least in most european union (eu) countries. in the future, local release wafers will need to be optimised for increased anti-tumour activity, either by increasing the concentration and improving the release kinetics of well-known agents such as bcnu, or by employing novel agents with a more potent anti-tumour effect, e.g. mitoxantrone or il-2.34 combinations of local release wafers with standard adjuvant therapies such as radiochemotherapy or single-drug oral chemotherapy (e.g. with tmz) may become a standard of care if more reliable clinical evidence is presented for increased survival and unchanged morbidity with these combinations.33 targeted toxins (immunotoxins) targeted toxins represent a new class of anticancer agents providing high specificity for tumour cells selectively overexpressing some surface proteins.35,36 currently used toxins are recombinant polypeptide molecules consisting gliadel and radiochemotherapy in gbm patients.32 thirty-three patients were treated with the combined modalities and the median survival in the group was 20.7 months, with a 2-year survival rate of 36%. sixmonth morbidity included surgical site infection in 1 case (3%), perioperative seizures in 2 cases (6%), deep-vein thrombus in 1 (3%), pulmonary embolism in 3 (9%), and cerebral oedema requiring intravenous dexamethasone administration in 1 case (3%). myelosuppression required premature termination of tmz in 7 patients (21%): (thrombocytopenia in 5, neutropenia in 2 cases). in patients < 70 years of age, gliadel and radiochemotherapy were independently associated with improved median survival (21.3 versus 12.4 months, p = 0.005). moreover, the combined modalities were not associated with an increase in postoperative morbidity in comparison with gliadel or radiation only. the authors concluded that radiochemotherapy can be safely administered to patients receiving gliadel wafers after resection of newly diagnosed gbm.32,33 conclusions and future developments gliadel ® therapy despite the convenience and relative simplicity of use of intraoperatively placed gliadel wafers, there are some factors limiting their widespread clinical figure 2: schematic and 3d-ribbon representations of the structure of the recombinant fusion toxin il13-pe38 (il13pe38qqr). a derivative of the native pseudomonas exotoxin a (pe), pe38qqr, in which domain ia (amino acids 1 to 252) has been completely deleted and domain ib (amino acids 365 to 380) has been partially deleted; lysine residues at positions 590 and 606 have been replaced by glutamine, and at position 613 by arginine, and it has been fused to the carboxy terminus of the human il-13 to produce the fusion toxin il13-pe38qqr (il13-pe38). nikolai g rainov and volkmar heidecke review | 11 of these toxins reaching phase 3 trials.43 il4-pe (nbi-3001) this chimeric recombinant fusion protein (also known as nbi-3001, neurocrine inc., s. diego, ca) is composed of circularly permuted interleukin-4 (il-4) and a truncated form of p. aeruginosa exotoxin (pe) a.44 pe is a 66 kd protein with three domains: ia/ib, ii, and iii. when domain ia is removed, the resulting molecule (termed pe-40) retains its translocation function and elongation factor 2 (ef-2) inhibition properties, but is unable to bind to and kill human cells.35 domain ii is the site of proteolytic cleavage and is responsible for catalysing translocation of the toxin into the cytosol. domain iii, located at the c-terminus, possesses adp-ribosylation activity which in turn leads to inactivation of ef-2 and to cell death. in the genetically engineered pe molecule pe38kdel, amino acids (aa) 253–364 were linked to aa 381–608, which in turn were fused to kdel (an endoplasmic reticulum retaining sequence) at position 609–612. to improve the binding of il-4 toxin to the il-4 receptor (il4-r), a circularly permuted form of il-4 was fused to the toxin. this new agent was termed il-4(38-37)-pe38kdel, or il4-pe.45,46 il4-pe was found to have a 16-fold higher affinity for binding to gbm cell lines than the native pe toxin, and was 3–30-fold more toxic of a tumour-selective ligand coupled to a highly potent peptide toxin, which is truncated to abolish native toxicity.37 the most frequently used and best researched ligands bind to tumour-associated molecules with receptor signalling properties, such as epidermal growth factor receptor (egfr), transferrin receptor (tfr), interleukin-13 receptor (il-13r), or interleukin-4 receptor (il-4r).38 the toxin part of the molecule in all clinically used toxins is a polypeptide derived from bacteria (corynebacterium diphtheriae, pseudomonas aeruginosa), which has been modified by deleting the native targeting and internalisation chains of the polypeptide and replacing them with one of the above ligands [figure 2].39,40 the mechanism of action of targeted toxins may have important advantages over that of radiation and classic chemotherapeutic agents. toxins are effective against radiation-resistant hypoxic tumour cells and far more potent than any chemotherapy drug. one single molecule of toxin is sufficient to cause tumour cell death independent of any malignancy-associated genetic alterations and/or mutations [figure 3].37 multidrug resistance and apoptosis resistance are therefore not an issue with toxins; after receptor binding and internalisation, no tumour cell is able to survive the toxin part of the molecule.38,41,42 a few targeted toxins have advanced from the laboratory to the stage of phase i and ii clinical studies, with two figure 3: schematic representation of the mode of action of the recombinant fusion toxin il13-pe38 (il13-pe38qqr). il-13 receptor (il-13r-ß2 subunit) is a tumour-specific protein in human malignant glioma cells. immune cells, endothelial cells and normal glia and neurons express none or very low amounts of il-13r. il13-pe38 is highly selective and potent in killing human glioblastoma multiforme cells by binding to il-13r, but does not kill normal cells, which are il-13r-negative. clinical development of experimental therapies for malignant glioma 12 | squ medical journal, february 2011, volume 11, issue 1 a multicentre, randomised, open-label phase 2 study with il4-pe was carried out in patients with recurrent gbm to investigate continuous intratumoural infusion of the toxin followed by surgical resection of the tumour. the study was designed to evaluate the efficacy of il4-pe, with a secondary objective to evaluate the safety and tolerability of the toxin.52 in the toxin group, patients received an intratumoural infusion of toxin at total doses of up to 90 µg and underwent surgical resection of the tumour between 2 and 7 days after the end of toxin infusion. patients in the control group underwent tumour resection without prior toxin treatment. a total of 30 adult patients with unilateral, unifocal tumours with a volume <100 ml and a kps ≤60 were enrolled. recruitment was completed in 2003, but no final published results of the study are available yet.52 there are currently no phase 3 protocols using il4-pe. tp-38 tp-38 (teva pharmaceuticals, formerly ivax inc., miami, fl, usa) is a recombinant chimeric protein composed of transforming growth factor α (tgf-α), an epidermal growth factor receptor (egfr) ligand, and the genetically engineered form of pe described above (see il4-pe). the 170-180 kd transmembrane glycoprotein, epidermal growth factor (egf) receptor, is one of four members of the erbb family of receptor tyrosine kinases, which consist of an extracellular domain that can bind ligands, a transmembrane domain and an intracellular tyrosine kinase domain.53 binding of a ligand (egf or tgf-α) to egfr causes receptor dimerisation leading to tyrosine kinase activation.54 the resultant receptor autophosphorylation initiates signal-transduction cascades involved in cell proliferation and survival.53 after ligand binding, the whole receptor-ligand complex undergoes endocytosis and is translocated to the lysosomes, where the ligand dissociates from the receptor.55 human malignant gliomas and many other malignant tumours that metastasise to the brain express egfr, and this is commonly associated with amplification and/or mutation of the egfr gene during neoplastic transformation.54 amplification and high expression of egfr in gliomas may drive tumour growth and proliferation to a significant degree.55 by contrast, egfr is expressed at very low levels, or is undetectable on normal human glial cells to gbm cells.42,47 il-4 is a pleiotropic cytokine composed of 4 α-helices which is primarily produced by th2-type t lymphocytes. whereas normal cns cells such as endothelial cells, microglia, or astrocytes express low levels of il4-r, malignant glioma cells express high levels of this receptor on their surface.44,48 in one series, 16 of 21 surgical samples were determined to express high numbers of il4-r.36 in another series, all of the 25 tested surgical specimens of high-grade gliomas expressed il4-r. in contrast, no detectable il-4r was expressed in a normal brain as determined by immunohistochemistry.49 cell culture studies and animal models have confirmed that il4-pe is highly cytotoxic to glioma cells.50 il4-pe has a 16-fold higher affinity for binding to gbm cell lines than the native pe toxin and is 3–30-fold more toxic to gbm cells.47,48 whereas normal cns cells such as endothelial cells, microglia, or astrocytes express low levels of il-4r, malignant glioma cells do express high levels of this receptor on their surface.42 a recent study demonstrated that 15 of 18 gbm and 12 other brain tumour samples were moderately to intensely positive for il-4r. in contrast, no detectable il-4r was expressed in a normal brain as determined by immunohistochemistry.44 weber et al. carried out an open-label, doseescalation trial of intratumoural administration of il4-pe in patients with recurrent malignant glioma.51 a total of 31 adult patients were enrolled, 25 with gbm and 6 with anaplastic astrocytoma. patients were assigned to one of 4 groups receiving different doses of toxin in different volumes of infusate. the toxin was administered by ced via an external pump connected to stereotactically placed catheters. the overall median survival for the whole group of who grade 3 and 4 tumours was 8.2 months, with a median survival of 5.8 months for gbm patients. six months survival was 52% and 48%, respectively. drug-related grade 3 or 4 cns toxicity was seen in all groups in a total of 39% of all patients, and in 22% of patients at the mtd of 6 µg/ml in 40 ml. treatment-related ae were limited to the cns. no deaths were attributable to treatment. no drugrelated systemic toxicity was apparent in any patient. gadolinium-enhanced mri of the brain in some of the treated patients showed areas of decreased signal intensity within the tumour consistent with toxinmediated tumour necrosis.51 nikolai g rainov and volkmar heidecke review | 13 infusion rate was 200 µl/h per catheter. each catheter delivered 13.4 ml over 67 h. the total volume infused was approximately 40 ml, and the total dose of tp-38 infused was 2 μg (50 ng/ml) or 4 μg (100 ng/ml). one patient had a complete response 48 weeks after infusion, and another showed a partial response stable over 60 weeks. twenty-four patients remained stable. post-infusion mri scans in most patients showed unspecific treatmentrelated changes such as halo contrast enhancement around the infusion sites, which made assessment of response rather difficult. these changes usually resolved by 20 weeks post-treatment. there were no grade 3 and 4 toxicities related to tp-38, and all adverse effects of the treatment were reversible.58 a phase 3 clinical protocol employing tp-38 seems to be in development, but no further details are currently known. il13-pe38 il13-pe38 (il13-pe38qqr, also known as cintredekin besudotox, (neopharm inc., lake forest, il, usa) is a recombinant chimeric toxin consisting of human il-13 fused to the mutated form of pe mentioned above [figure 2]. the t-helper cell 2-derived immunoregulatory cytokine interleukin-13 (il-13) inhibits the production of inflammatory cytokines in monocytes. the cell surface receptor for il-13 (il-13r) is expressed on many human cancer cells, including glioblastoma, aids-associated kaposi’s sarcoma, ovarian carcinoma, renal cell carcinoma, but also fibroblast cell lines.59 the il-13r structure varies according to cell type, existing in three different forms known as type i, type ii and type iii.60 subunit structure studies of the il-13r complex in primary brain tumour cells established the il13rα2 subunit as a tumour-specific protein.59 immune cells, endothelial cells and normal glia and neurons generally express none or very low amounts of il-13r.39 il13-pe38 was found to be highly selective and potent in killing human glioma cells in culture. the activity of il13-pe38 is mediated via il-13r, as its cytoxicity is blocked by exposing cell lines to a 10– to 100-fold excess of human il-13.61 furthermore, il-13r-negative cell lines or cell lines expressing low numbers of il-13r, including human bone marrow-derived cells and pha-activated t-cells, are not susceptible to il13-pe38 mediated cytotoxicity and neurons thus suggesting a potential therapeutic window. the ratio of egfr expression in glioma versus normal control brain specimens has been shown to be as high as 300-fold.56 animal studies with tp-38 have been carried out in rodent and primate models. in tumour bearing mice, a total dose of 0.1 µg tp-38 at a concentration of 5 µg/ml was found to be safe and efficacious in prolonging survival. the mtd of intracerebral tp-38 in normal rats was 0.666 µg at a toxin concentration of 33.3 µg/ml. in non-human primates, it was demonstrated that an intracerebral bolus dose of 2 µg tp-38 at a concentration of 10 µg/ml is safe.50 sampson et al. investigated tp-38 in a phase 1 clinical trial.57 the primary objective of the study was to define mtd and dose limiting toxicity of tp-38 delivered by ced in patients with recurrent malignant glioma. a secondary objective was to detect the efficacy of the toxin. twenty patients were enrolled in the study and doses were escalated from 25 to 100 ng/ml. tp-38 was infused by two stereotactically placed catheters at a flow rate of 0.4 ml/h for each catheter. a total volume of 40 ml was infused. tp-38 was tolerated well, and an mtd was not established. non-specific toxicity was not found at any of the dose levels. the toxicity encountered was solely neurologic and mostly related either to infusion volume, recurrent tumour, or stereotactic catheter placement, but not directly to tp-38. fifteen of the patients in this study died from progressive disease. when the study closed, 4 further patients had not had a recurrence of tumour and were 55, 56, 69, and 116 weeks from the time of tp-38 therapy. overall median survival after tp-38 for all patients was 23 weeks, whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. overall, 3 of 15 patients with residual disease at the time of therapy have demonstrated radiographic responses.57 a multicentre randomised open-label phase 2 study was conducted in adult patients with recurrent gbm.58 patients were randomised to two dose levels of tp-38, 50 ng/ml or 100 ng/ml, and toxin was administered by ced via stereotactically placed catheters. patients did not have to undergo tumour resection prior to treatment. the end points of the study were time to progression, progression-free survival, and overall survival. three catheters were stereotactically placed in investigator-determined locations within the enhancing tumour area. the clinical development of experimental therapies for malignant glioma 14 | squ medical journal, february 2011, volume 11, issue 1 were placed into the brain adjacent to the tumour resection cavity and on days 10 to 14, il13-pe38 was given at 750 µl/h for 96 h at a fixed dose of 0.25 µg/ml (total dose 18 µg). in stage 2, intratumoural infusion was omitted and patients underwent resection of the tumour followed by a 96-h peritumoural infusion of il13-pe38 at 0.5 µg/ml and 1.0 µg/ml. in stage 3, the duration of peritumoural infusion was increased from 5 to 7 days at a fixed dose of 0.5 µg/ml. tumour necrosis up to 2.5 cm from the catheter tip was demonstrated radiologically in at least 5 patients with preoperative intratumoural toxin infusion. tumour specimens from at least two patients after intratumoural injection of 0.5 µg/ml il13-pe38 toxin revealed regional necrosis in an ovoid zone extending 1 to 2 cm from the catheter tip. peritumoural post-resection mtd was defined as 0.5 µg/ml. similar aes occurred across all cohorts, most being neurological. the most frequent ae were headache (53%), hemiparesis (27%), sensory disturbance (20%), fatigue (17%), aphasia (13%), facial paresis (13%), abnormal gait (13%), convulsions (10%), hypaesthesia (10%) and lymphopenia (10%). prolonged individual patient survival has been observed after peritumoural therapy at concentrations of 0.25 µg/ml (total dose 18 µg) and above.39,66,67 a further multicentre phase 1/2 study investigated il13-pe38 in adult recurrent supratentorial malignant glioma with confirmed radiographic evidence of recurrent or progressive tumour. the primary objective of the phase 1 portion of the study was to determine the optimum duration of infusion and drug concentration of il13-pe38 delivered by ced via 1 or 2 intratumoural catheters prior to surgical resection of the tumour.64,67 the phase 2 objective was to determine the proportion of patients surviving at 6 months. in phase 1, cohorts of 3-6 patients received a fixed drug concentration (0.5 µg/ml) with escalating duration of infusion (4–7 days) to determine mtd based on duration. after determining maximum duration, the drug concentration was escalated from 1.0 to 4.0 µg/ml in cohorts of 3–6 patients to determine a mtd based on concentration. tumour necrosis was assessed 6 to 13 days after the end of infusion, at the time of tumour resection. there were no severe drug-related ae in the 10 treated patients. five patients experienced ae grade 2–3. the most frequent ae were headache (70%), hemiparesis [figure 3].62 the significant antitumour activity of il13pe38 was observed in animal models of human glioma, with intratumoural injection proving more efficacious than intravenous (i.v.) or intraperitoneal (i.p.) administration. in nude mice with intracerebral glioma, the mtd of il13-pe38 was 4 µg when delivered by bolus injection, and 10 µg when delivered by ced.39 several phase 1 and 2 studies have been initiated to investigate il13-pe38 as an antitumour agent for the treatment of patients with recurrent malignant glioma. in a phase 1/2 study, il13-pe38 was infused intratumourally in adult patients with recurrent malignant glioma (including anaplastic oligoastrocytoma) to determine the mtd of the drug.63 patients received two il13-pe38 infusions at 8-week intervals via two stereotactically placed intratumoural catheters at a constant infusion rate. one aim of the study was to determine mtd and toxicity of il13-pe38 administered by ced via intratumoural catheters at 200 µl/h/catheter for 96 h (total 38.4 ml), in two courses 8 weeks apart. escalation was planned through 9 levels ranging from 0.125 to 12.0 µg/ml (total dose 4.8 to 460.8 µg) in cohorts of 3 patients per level. cohorts of 3 patients received 0.5, 1.0, 2.0 and 4.0 µg/ml. concentrations of up to 2.0 µg/ml were safe and well tolerated. the ae reported across all dose ranges were mild and mainly neurological. the most frequent drug-related ae were headache (24%), hemiparesis (24%), brain oedema (14%), aphasia (10%), and ataxia (10%). in the phase 1 portion of the study, two histopathological and two radiographic responses were observed, with progression-free survival ranging from 3 to 88 weeks and overall survival of 147 weeks. no results have been published yet for the phase 2 portion of this study.63 another phase 1 study investigated il13-pe38 in adult supratentorial malignant glioma. in this four-stage study, the primary objectives were to determine effective dose of il13-pe38 either prior to or post-resection of the tumour.64,65 in stage one, after biopsy and intratumoural catheter placement on day 1, il13-pe38 was administered for 48 h at 400 µl/h on days 2 to 4 at escalating doses ranging from 0.25 to 2 µg/ml. the tumour was resected on day 8 and tissue was evaluated for necrosis adjacent to the catheter. following resection, 2 or 3 catheters nikolai g rainov and volkmar heidecke review | 15 pulmonary embolism was higher in the toxin arm (8% versus 1%, p = 0.014). this was the first randomised phase 3 evaluation of an agent administered via ced and the first with an active control group in gbm patients. there was no survival difference between il13-pe38 toxin administered via ced and gliadel wafers placed at the time of surgery. drug distribution was not assessed, but may be crucial for evaluating future ced-based therapeutics.43,68 transmid-107 (tf-crm107) transmidtm (known as transmid-107, tfcrm107, or ksb-311; ks biomedix holdings plc, uk, now xenova group plc, uk, and celtic pharmaceutical holdings pl, bermuda) is a thioether conjugate of human transferrin (tf ) with a truncated natural mutant form of diphtheria toxin (dt) known as crm-107, which lacks receptor binding.69 native dt is produced by the bacterium c. diphtheriae and is composed of two disulphidelinked subunits. the a subunit catalyses adpribosylation of ef-2, thereby stopping protein synthesis and killing the cell. the b subunit has two functions: binding to cell-surface receptors and translocation of the a subunit into the cytosol.70 in the natural mutant form of dt, designated crm107, two point mutations (phenylalanine at positions 390 and 525 of the dt sequence) reduce the binding 8,000-fold and its toxicity 10,000-fold, compared to native dt.71 however, conjugation of crm-107 by thioether linkage to various new binding moieties was able to reconstitute the full toxicity of the mutant.72 by linking crm-107 with tf, a receptor-ligand complex was created that is rapidly internalised to an environment that facilitates toxin translocation.70 the tf receptor (tfr) is a transmembrane glycoprotein that mediates cellular uptake of iron. tfr are overexpressed on rapidly dividing cells, such as hematopoietic and neoplastic cells, including glioma cells.72 tfr in normal brains are sparse and their expression is largely restricted to the luminal surface of brain capillaries.73 it is this relative difference in the density of tfr that transmidtm uses to generate differential toxicity to highly tfr expressing neoplastic cells, while sparing low expressing normal brain cells.74 lowdensity background expression of the respective (40%), seizures (40%), oedema (40%) and aphasia (30%). progression-free survival ranged from 6 to 30 weeks and overall survival from 10 to 30 weeks.39,64 in all of the above studies, intratumoural infusion of il13-pe38, with or without tumour resection in patients with recurrent or progressing malignant glioma, seemed to be well tolerated and did not result in any grade 3 and 4 ae, or in any ae in peripheral organs such as the liver, kidney and lungs. neurological ae during and after toxin infusion were, however, encountered in a significant proportion of the treated patients. these included brain oedema, meningitis, seizures, headache, and symptoms of increased intracranial pressure. all these ae were temporary and mostly controllable by administration of steroids. in general, il13-pe38 doses (0.5–2 µg/ml) showing biological activity (e.g. necrosis on mri scans) in tumours were below the threshold of widespread neurotoxicity (4–12 µg/ml). selecting of patients without incipient mass effect in the brain (due to tumour size and/ or peritumoural oedema) seemed a particularly important factor for avoiding serious unwanted side effects. some prolonged survival was observed in this selected population of patients.39,66,67 a multicentre phase 3 randomised, open label, active control, parallel assignment efficacy study (precise) was carried out in order to determine whether overall survival duration, safety, and quality of life were improved for patients treated with il13pe38 compared to patients treated with gliadel wafers following surgical tumour removal in the treatment of first recurrence of gbm after initial surgery and external beam radiation therapy.43,68 patients were randomised 2:1 to receive il13-pe38 or gliadel. the il13-pe38 toxin (0.5 µg/ml, total flow rate 0.75 ml/h) was administered over 96 hours via 2-4 intraparenchymal catheters placed after tumour resection. the primary endpoint was overall survival from the time of randomisation. secondary and tertiary endpoints were safety and health-related quality-of-life assessments. from march 2004 to december 2005, 296 patients were enrolled at 52 centres. median survival was 36.4 weeks (9.1 months) for the toxin group and 35.3 weeks (8.8 months) for the gliadel group (p = 0.476). for the efficacy evaluable population, the median survival was 45.3 weeks (11.3 months) for toxin and 39.8 weeks (10 months) for gliadel (p = 0.310). the ae profile was similar in both arms, except that clinical development of experimental therapies for malignant glioma 16 | squ medical journal, february 2011, volume 11, issue 1 first treatment. tumour response appeared to be concentration and dose dependent. median survival after treatment in the responder group was 74 weeks, with 3 of the responders still alive at 102–142 weeks after the first treatment. nonresponders survived a median of 36 weeks. intratumoural infusions of transmidtm with total volumes of 5–180 ml were well tolerated. there were no treatment related deaths or lifethreatening or irreversible toxicity. in this first clinical trial, the relationship between dose, drug concentration, and sustained neurotoxicity established a mtd of 26.8 µg (40 ml at 0.67µg/ ml). the trial results indicated that therapy with transmidtm can reduce the size of malignant brain tumours refractory to conventional therapy without producing severe neurologic or systemic toxicity.78 an open-label, single-arm, multicentre phase 2 study investigated intratumoural ced infusion of transmid in recurrent or progressive malignant glioma in adults.69 the primary study objective was evaluation of efficacy and safety of transmidtm, and the primary endpoint was a 50% reduction in tumour volume (measured by mri) within 12 months after the second treatment. patients received transmidtm (0.67 µg/ml) at an escalating rate up to 200 µl/h per catheter for 4–5 days, until a total volume of 40 ml was delivered. forty-four patients were enrolled in total and all received at least one transmidtm infusion. of the 34 patients evaluable for analysis, there were a total of 5 complete responders and 7 partial responders (total of 35% response), which was a statistically significant result. median survival time for all 44 patients was 37 weeks. infusions of transmidtm within this clinical protocol resulted in symptomatic progressive brain oedema in 8 of 44 patients (14%). the results of this phase 2 clinical trial have confirmed the safety and tumour response data of the phase 1 trial.69 a multicentre randomised, open label, active control, parallel assignment, safety and efficacy phase 3 study (ksb311r/ciii/001 trial) was launched in 2004 in order to compare transmidtm with the best standard treatment available for patients with progressive and/or recurrent nonresectable gbm.79,80 best standard treatment involved a chemotherapeutic regimen considered to be the best standard of care at the respective target receptor in normal tissue remains, however, a major concern with transmidtm (and with all other targeted toxin based therapies). transmidtm has been thoroughly evaluated in cell culture75 and in vivo. the efficacy of locally administered transmidtm against human glioma in nude mice was demonstrated by laske et al. in 1994.76 these authors studied transmidtm compared to 454a12-rra, and administered toxins intratumourally in a subcutaneous model. repeated intratumoural injections of 10 µg transmidtm, or 10 µg 454a12-rra, were compared to equimolar doses of the untargeted native toxin crm-107, 454a12 antibody, rra, and phosphatebuffered saline. transmidtm administration resulted in almost complete tumour regression (>95%), without evidence of recurrence by day 30. unconjugated toxin components (crm-107, 454a12, or rra) caused significant, but less potent tumour growth inhibition than the conjugated toxin.76 in a more recent study in 2002, engebraaten et al. compared the efficacy of transmidtm with that of pe conjugated with the 425.3 antibody directed against egfr.77 mice with subcutaneous gliomas or rats with intracranial gliomas received different doses (1-10 µg) of transmidtm, or 425.3-pe, injected intratumourally in established tumours. both toxins showed significant antitumour effects in subcutaneous tumours, but only 425.3-pe was effective in intracranial gliomas in rats. intracerebral transmidtm was toxic in doses above 10 ng, while intracerebral 425.3-pe was tolerated up to a dose of 4 µg per animal. the authors concluded that both toxins have promising efficacy in brain tumour models, but that 425.3-pe is better tolerated and has a more specific activity at higher doses.77 in 1997, laske et al. treated 18 patients with recurrent malignant glioma with intratumoural high flow interstitial microinfusion of transmidtm in a dose-escalating single arm phase 1 clinical trial.78 the drug was infused at a maximum flow rate of 4-10 µl/min at a toxin concentration of 0.1 µg/ml. nine of the 15 evaluable patients responded to treatment by at least 50% reduction in tumour volume on mri, including 2 complete responses. reduction in tumour volume occurred no earlier than 1 month after completion of the first toxin infusion. in 4 patients, the response was not maximal until 6–14 months after the nikolai g rainov and volkmar heidecke review | 17 distribution of the large molecules of immunotoxin in the microenvironment of the tumour and/or brain, as well as non-specific associated toxicity to glial and neuronal cells.19 with the introduction of mri-based functional imaging and 3d volumetric techniques in routine clinical practice, it will be possible to determine quantitatively brain tumour volumes and the volume of infusate in the tumour and normal brain.81,82 diffusion tensor imaging (dti) is a new mri imaging technique sensitive to directional movements of water molecules induced by tissue barriers.83 ced makes use of the extracellular space of the brain as a natural pathway for the widespread distribution of agents infused in an aqueous solution, and therefore dti could be used for imaging of ced delivery without the need for contrast agents. further key developments in mr imaging and mr-related computer software as well as infusion catheter design and computerised simulation and delivery modelling within the brain may provide much needed new resources to be combined with the biologically targeted toxins.19 further improvements in the molecular diagnostics of malignant glioma with genetic profiling of individual patients and tumours should allow for selection of subgroups of cases with high expression of the target receptor, who are most likely to benefit from the administration of a targeted immunotoxin. clinical protocols have explored several points of presumed significance, such as the use institution, and consisting of either nitrosoureas, platinum compounds, temozolomide, procarbazine, or pcv (procarbazine, ccnu [lomustine], vincristine). the primary endpoint of the study was overall survival time. adult patients eligible for enrolment into this trial had to be diagnosed with histologically confirmed gbm and had to have undergone conventional treatment, including surgery (biopsy or debulking) and/or radiation therapy and/or chemotherapy. patients were required to have a recurrent and/or progressive tumour ≥1.0 cm and ≤4.0 cm in diameter.79,80 the trial was however prematurely terminated in 2007 after an interim conditional power analysis showed that it was extremely unlikely that transmidtm would meet the trial criteria for efficacy.80 no data from this clinical trial has yet been published. conclusions and future developments immunotoxins targeted toxins have shown considerable promise in phase 1 and 2 clinical trials with recurrent malignant gliomas. there are however some major obstacles that need to be overcome before targeted toxins may enter the mainstream of brain tumour therapies. the most important of them are the heterogeneity of target receptor expression in malignant glioma cells, the non-uniform and poorly predictable figure 4a: schematic diagrams of virus vectors. schematic representation of a wild type retrovirus (rv) and a rv vector with the corresponding packaging cell line (vpc). wild type rv has a double-stranded rna genome which is converted to dna by viral reverse transcriptase and then integrated into the host genome at non-specific sites. the genetically modified rv vector genome contains the cis-acting elements required for replication (long terminal repeats ltr, packaging sequence ψ), but lacks the viral genes (capsid core proteins gag, reverse transcriptase, integrase and protease pol, and the envelope antigens env), which are replaced by up to 8 kb of foreign coding sequences (transgene cassette, e.g. cdna encoding hsv-tk). a selectable marker (e.g. neomycin resistance gene neo) allows for antibiotic selection of cells expressing the rv vector. in order that rv vectors replicate, it is necessary to provide the missing viral genes in trans, e.g. expressed within a genetically engineered rv vpc. vpc are most frequently of murine fibroblast origin. separation of the packaging function from the genetic material to be transferred ensures that a replication incompetent rv is generated and makes rv vectors biologically safe. clinical development of experimental therapies for malignant glioma 18 | squ medical journal, february 2011, volume 11, issue 1 as oncolytic viruses.85 most of the viruses employed in clinical trials are derived from a retrovirus (rv), adenovirus (av), or herpes simplex virus type 1 (hsv1) [figure 4a and b]. other viruses, such as the newcastle disease virus (ndv) or reovirus, have been also employed in clinical trials, but to a much lesser extent.19,20,86-88 the effects of virus-mediated local therapy of malignant gliomas have been investigated only since the 1990s. the initially favoured and best explored gene therapy approach included the use of a replication-disabled, genetically modified virus vector capable of insertion of a toxicity-inducing gene into tumour cells.89-91 most frequently, the inserted gene (transgene) rendered the infected tumour cells and their clonal progeny differentially sensitive to treatment with a pro-drug.91,92 the gene/vector system most widely utilised in initial clinical trials was the hsv thymidine kinase (hsvtk) gene transferred by a replication-incompetent rv vector which was released in situ by fibroblastderived virus-producing cells (vpc) [figure 5].93 the most severe limitation of clinical gene therapy with non-replicating viruses was, however, their inability to achieve sufficiently high levels of gene expression in sufficiently large numbers of target tumour cells to result in a clinical benefit.19,94,95a modified approach was therefore introduced in order to improve anti-tumour toxicity and virus distribution within the tumour mass and the surrounding normal brain. it employed conditionally replicating oncolytic viruses with a lytic life cycle instead of their non-replicating of different numbers of catheters, positioning of catheters, surgical resection of the tumour before or after toxin infusion, and single versus repeated infusion, but there is no clear answer to any of these questions. it remains unknown whether there are benefits from combining targeted toxins with chemotherapy and/or with fractionated external radiation. protocols have investigated patients with recurrent or progressing gbm, and the role of targeted toxin infusion in newly diagnosed malignant glioma remains to be determined. evidence of prolonged survival and late local recurrences in treated glioma patients has raised the question of periodically repeated application of toxin for extended control of local recurrence and progression. the randomised clinical trials were able to provide some answers as to the efficacy of the studied toxins and clinical protocols; however, more clinical research is needed to address the above mentioned global issues. g e n e t i c a l ly m o d i f i e d v i r u s e s wild type viruses have been long known for their capability to destroy malignant tumour cells upon infection and intracellular replication. genetic engineering of some of these viruses was, however, only recently done in an attempt to improve their utility as targeted gene transfer anti-cancer agents.84 recombinant and usually non-replicating viruses transferring to tumour cells genes with toxicityinducing intracellular effects are known as virus vectors, while replicating viruses with a lytic life cycle selectively destroying tumour cells are known figure 4b: schematic representation of the genome of a wild type adenovirus (av) and recombinant av vectors. the wild type av genome is flanked by the inverted terminal repeats (itr) and divided into e1a, e1b, e2, e3, and e4 regions, whose genes are expressed in a defined temporal sequence. it contains 36 kb of double-stranded dna, of which several regions can be deleted to accommodate up to 10 kb of foreign dna (e.g. insertion of a therapeutic transgene cassette in the e1 region, deletion of e3 region). replication-deficient av vectors are generated by placing the av genome in a plasmid and replacing e1 with a transgene (e.g. hsv-tk), then transfecting the plasmid into a packaging cell line (vpc) that provides e1 functions in trans. nikolai g rainov and volkmar heidecke review | 19 the same method and rv-vpc preparation, shand et al. treated 48 patients with recurrent gbm in a phase 1/2 study.105 the authors of both reports independently concluded that rv-vpc injections were safe. gene therapy in both trials resulted in a prolonged delay of recurrence in individual cases. izquierdo et al. conducted phase 1 studies in 7 patients with recurrent gbm. five patients received a single intratumoural rv-vpc injection and 2 patients intraoperative rv-vpc injections, later followed by repeated rv-vpc applications into the tumour resection cavity.106,107 in 2003, prados et al. treated 30 patients in a phase 1/2 study with recurrent gbm by repeated direct injection of rvvpc, initially immediately after tumour resection in the walls of the resection cavity, and a week later via an intracavitary catheter.108 fifty per cent of the patients experienced serious side effects possibly related to rv-vpc therapy. the median survival of all patients in the treatment group was 8.4 months. puumalainen et al. showed low tumour transduction efficiency with a rv-vpc construct carrying the marker gene lacz.109 the same study also evaluated av-mediated marker gene transfer and found much higher transduction rates in some counterparts.96-100 n o n-r e p l i c at i n g r e t r o v i r u s starting in the late 1990s, several clinical studies were published which investigated the use of rv-mediated hsv-tk gene transfer delivered by intratumoural injections of vpc and followed by systemic administration of ganciclovir (gcv).89,90,91,101 the earliest phase 1/2 clinical study was published by ram et al. in 1997.93 these authors investigated, in 15 patients with recurrent malignant glioma, the tolerability and efficacy of rv-producing vpc (rv-vpc) delivered by a single stereotactic intratumoural injection. treatment resulted in anti-tumour activity in 4 patients with relatively small tumours. one patient with gbm had a complete response with a recurrence-free survival of 50 months.93 the limited efficiency of histologically demonstrated rv-mediated gene transfer suggested the presence of a bystander effect conferring toxicity to non-transduced tumour cells.102,103 in 1998, klatzmann et al. treated 12 patients with recurrent gbm in a phase 1/2 study by local injections of rv-vpc into the margins of the tumour cavity after tumour debulking.104 using figure 5: schematic representation of the mode of action of recombinant retrovirus (rv) vector-mediated suicide gene therapy in patients with malignant glioma. up to 20 ml of a suspension of viable rv-producing cells (vpc) carrying the transgene coding for herpes simplex virus (hsv) thymidine kinase (hsv-tk) are manually injected into the walls of the tumour resection cavity at the end of the surgical removal of a human glioblastoma multiforme (gbm). rv vectors, which have been genetically engineered to become replication-deficient, are produced in high titres by the implanted vpc. gbm cells are highly mitotic and, after infection by rv, are able to produce most rv proteins, including hsvtk. this enzyme converts the low-toxicity prodrug ganciclovir (gcv) into highly toxic metabolites, which block dna replication during mitosis and render the tumour cells apoptotic. after repeated i.v. application of gcv to patients, all cells expressing hsv-tk are killed, including vpc. cells not expressing hsv-tk may also be killed by the so-called “bystander effect” transfer of toxic gcv metabolites from hsv-tk-expressing to hsv-tk-negative cells by direct cellular contact. up to 10 non-expressing cells may be killed by one hsv-tk-expressing cells in cell culture. clinical development of experimental therapies for malignant glioma 20 | squ medical journal, february 2011, volume 11, issue 1 the median survival of all patients was 10 months, while 5 patients were alive at 1 year and 1 patient at 3 years after therapy.111 germano et al. carried out a dose-escalating phase 1 study in 11 patients with recurrent gbm.112 av-hsv-tk doses of 2.5x1011-9x1011 virus particles were administered intraoperatively to the walls of the resection cavity immediately after tumour resection. the median survival of treated patients was 59 weeks. no major toxicities occurred, and the few serious aes were not related to av administration.112 smitt et al. conducted another phase 1 dose escalation study in 14 patients with recurrent malignant glioma.113 patients received 4.6x108-4.6x1011 virus particles injected manually in the walls of the tumour resection cavity at the end of tumour removal. median overall survival was 4 months, however 4 patients survived for longer than 1 year following therapy. the treatment was safe and well tolerated. 113 some groups were able to report significantly better clinical outcomes using the av-hsv-tk approach. sandmair et al. enrolled 21 patients with primary or recurrent malignant glioma in a comparative phase 1/2 study employing hsv-tk gene transfer by rv-vpc or by av and comparing these with a third group receiving av carrying only a marker gene, lacz.114 the mean survival in the av-hsv-tk group was significantly longer (15 months) than that of the other groups with mean survival of 7.4 months for rv-vpc and 8.3 months for av-lacz. no serious ae were reported in any of the groups. building on these promising results, immonen et al. conducted a randomised prospective phase 2 study to evaluate further the efficacy and safety of av-hsv-tk in patients with primary or recurrent malignant glioma.115 seventeen of the 36 patients received intraoperative injections of av-hsvtk (3x1010 pfu) into the walls of the surgically created resection cavity followed by gcv (5 mg/ kg twice daily for 14 days), and 19 patients had tumour surgery without av injections. standard radiotherapy was carried out in all patients with previously untreated tumours. the mean survival of patients in the av-hsv-tk group was significantly longer (70.6 weeks) than in the control group (39.0 weeks) (p = 0.0095). an additional post hoc subgroup analysis excluding patients with anaplastic astrocytoma showed that there still was areas of the tumours. harsh et al. performed a gene-marking and neuropathological study in 5 patients with recurrent gbm who received multiple stereotactically guided intratumoural injections of rv-vpc during a single surgical session.94 this study showed an extremely low gene transduction efficiency of the rv-vpc used. finally, a large prospective randomised multicentre phase 3 clinical trial was carried out to allow definitive evaluation of rv-vpc treatment in patients with newly diagnosed gbm.101a total of 248 patients with previously untreated gbm were randomised to two groups and treated using either standard surgical resection and radiotherapy (n = 124) or standard therapy plus adjuvant rv-vpc injected in the walls of the resection cavity at tumour surgery (n = 124). systemic administration of gcv (5 mg/kg i.v. twice daily) was started two weeks after surgery and continued for another 2 weeks. somewhat surprisingly, this study found no significant difference in the progression-free, median, or 12-month survival of both the standard and the gene-therapy groups, although the approach was proven exceptionally safe. based on the results of this trial, local therapy of malignant glioma with rv-vpc expressing hsv-tk has been largely abandoned.101 n o n-r e p l i c at i n g a d e n o v i r u s studies with av vectors were conducted and published, mostly in the late 1990s. trask et al. conducted a phase 1 study of av-hsv-tk in 12 patients with recurrent malignant glioma.110 a single stereotactic intratumoural injection was used to deliver av doses of 2x109-2x1012 pfu. adequate safety was reported with all doses except the highest, which caused significant cns toxicity. median survival in this study was only 4 months, however 3 patients showed long-term survival of 2 years or longer, which was interpreted as evidence for some local tumour control. judy and eck treated 13 patients with primary or recurrent malignant gliomas in a modified phase 1 study.111 twelve patients received stereotactic intratumoural avhsv-tk injections and a week later underwent tumour mass resection with additional av injections in the walls of the resection cavity. total virus doses of 2x108-2x1011 pfu were used. transient side effects, such as increased intracranial pressure (icp), were noted only at the highest dose level. nikolai g rainov and volkmar heidecke review | 21 an acceptable safety profile.116 the results of the study have not been published yet, and final data still need to be provided. preliminary information in the public space however states that the trial may be statistically underpowered and that cerepro® has failed to show sufficient primary endpoint efficacy.117 o n c o ly t i c v i r u s e s genetically modified and conditionally replicating av and hsv have been the most frequently used viruses in early clinical studies with oncolytic viruses.87,89,97,99 four phase 1 trials in recurrent malignant glioma have used intracerebrally inoculated g207 a conditionally replicating hsv with defects in both icp6 and icp34.5 genes, which has demonstrated anti-tumour efficacy in preclinical studies in glioma.89,118,119 markert et al. in 2000 carried out a dose escalation study treating 21 patients with recurrent malignant glioma using stereotactic intratumoural injections of g207 (up to 3x109 pfu total dose).89 mri studies and neuropathological analysis suggested some anti-tumour activity of the treatment. the best responding 4 patients survived for a mean of 12.8 months, while the rest of the group had a mean survival of 6.2 months after therapy. most importantly, this early trial showed that inoculation of a genetically engineered oncolytic hsv virus in the human brain is safe, despite the concerns about possible encephalitis well known from its wild type counterpart.89 rampling et al. (2000) conducted a first phase 1 dose escalation study using another selectively replicating hsv mutant with disrupted icp34.5 genes known as hsv1716.120 nine patients with recurrent malignant glioma received stereotactic intratumoural injections of hsv1716 up to a dose of 1x105 pfu. four patients were alive for 14–24 months after virus injection. no signs of encephalitis or major neurological side effects were noted.120 papanastassiou et al. (2002) used intratumoural injections of hsv1716 (1x105 pfu) in another phase 1 study in 12 patients with malignant glioma.87 the authors were able to demonstrate replication of virus in tumours resected 4–9 days after the hsv1716 injection. no toxicity was apparent. additional data from the above studies were published separately and suggested intratumoural persistence and replication a significant survival benefit in gbm patients (55.3 versus 37.0 weeks, p = 0.0214). the treatment was well tolerated and showed no major side effects.115 a phase 3 randomised and standard carecontrolled multicentre pivotal trial (also known as study 904) using the above av-hsv-tk vector115 designated as sitimagene ceradenovec (cerepro®, arc therapeutics ltd., london, uk) has been carried out in patients with newly diagnosed malignant glioma.116 patients were randomised to either standard care plus cerepro® or standard care alone. standard care was surgery and radiotherapy or surgery and radiotherapy followed by temozolomide, resulting in 4 treatment groups. this allowed comparison of the efficacy of cerepro® and temozolomide in the same trial without denying patients the best possible standard care. the primary endpoint was survival, defined as time to death or re-intervention.116 the overall primary endpoint analysis in the itt population (n = 236) compared cerepro® with and without tmz against controls with and without tmz. it showed a 42 day improvement in median survival (310 days versus 268 days) in the two groups receiving cerepro®. the improvement over standard care reached statistical significance (p < 0.032). at the primary endpoint, the group with cerepro® and tmz showed an improvement of 68% in median survival time compared with standard care (surgery and radiotherapy) controls (350 days versus 208 days). against the same controls, treatment with cerepro® alone showed an improved median survival trend approaching 50%, similar to those given treatment with tmz alone after standard care (300 days and 307 days, respectively versus 208 days with standard care). improvements in the combined cerepro® and tmz treatment group (n = 58) and tmz alone group (n = 76) were significant (p <0.05). in the cerepro® alone treatment group (n = 61), the effect was not statistically significant (p < 0.065). of the total 53 patients still to report an event, only 7 are in the surgery and radiotherapy control group and thus confidence intervals and statistical significance levels in all treatment groups might be expected to improve with time. whilst increases were observed in hemiparesis, aphasia and pyrexia following therapy, the serious ae reports for cerepro® were in line with those in the previous studies, indicating that the virus has clinical development of experimental therapies for malignant glioma 22 | squ medical journal, february 2011, volume 11, issue 1 manual injection of virus into tumours or tumourinvaded surrounding brain, as well as intrinsic barriers to intraand peritumoural spread in a glioma-harbouring brain, such as cysts, fibrotic membranes, and tumour necrosis.84,97 therapy with oncolytic viruses seems to hold more promise in the few early clinical trials than the therapy with non-replicating virus vectors, although both approaches were already proven to be safe and lacking major side effects.96-99, 119,122,126 however, further major advancements in virus designs, application modalities, and understanding of the interactions of the host immune system with the virus are clearly needed before oncolytic virus therapy of malignant brain tumours may enter routine clinical use. final conclusions and future developments of drug delivery modalities to brain tumours the therapeutic success of any tumour-targeting and locally delivered agent will depend not only on its ability to kill tumour cells selectively, but to a high degree also on the delivery mode and distribution throughout a tumour and the surrounding normal brain tissue.19,84 diffusion of particles (e.g. viruses) or large molecules (e.g. recombinant toxins) in tissue is a rather inefficient way of distribution and will depend not only on the concentration of the compound, but also on its size, molecular weight, polarity, and its avidity for the target receptor.40,92,127 to circumvent this limitation, distribution of agents by ced, a much more efficient and fast mode for interstitial delivery by high-flow infusion, has been studied in several animal models.100,127 local delivery of targeted toxins by ced seems to be the best approach to circumvent the limitations of the blood-brain barrier (bbb) and to increase therapeutic efficacy by high local concentrations of drug. all clinical trials with targeted toxins have adopted ced as the delivery mode of choice.19 virus particles can also be delivered by ced, although this modality has been studied mainly in animal experiments,20,84,127,128 while all human clinical trials carried out so far have employed bolus injections of virus or carrier suspensions.91,94,101,124 intratumoural stereotactically guided injections can provide adequate virus delivery only to spatially of hsv1716, allowing the virus to kill tumour cells over extended periods of time. analysis of tumour explants showed viral replication for up to 9 days after initial injection, and the amount of recovered virus exceeded the input dose in some tumour samples. in addition, 1 patient was free of tumour progression at nearly 3 years, and 2 patients were alive and stable after almost 4 years.121 harrow et al. (2004) followed 12 patients with newly diagnosed or recurrent malignant glioma treated in a previous study.122 three long-time survivors with gbm were clinically stable at 15–22 months following surgery and virus injection. no long-term toxicity was reported.122 onyx-015, a naturally occurring av mutant with deletion in the viral e1b gene, has been previously used in clinical trials for head and neck cancer and gastro-intestinal tract malignancies.97,123,124 the first multicentre phase 1 study using onyx-015 in patients with recurrent malignant glioma was published by chiocca et al. in 2004.124 twenty-four patients received intraoperative doses of onyx-015 (1x107-1x1010 pfu) injected manually in the walls of the surgical cavity immediately after tumour resection. the median survival time for all patients was 6.2 months. no definitive anti-tumour effect could be demonstrated, however none of the patients, at any virus dose, experienced serious ae and there was no dose-limiting neurological toxicity.124 conclusions and future developments genetically modified viruses the clinical efficacy of local therapy for malignant glioma with non-replicating viruses has been so far rather disappointing, possibly with the exception of the studies with av-hsv-tk.115,116 no clinical studies using non-replicating virus vectors are currently enrolling patients. encouraging anti-tumour activity has been demonstrated in the some of the studies in malignant glioma treated with local injections of oncolytic av and hsv.97-99,122 systemic chemotherapy has been found to potentiate the anti-tumour effect of virus mediated oncolysis in other cancer types.123,125 factors likely to be an issue with any type of oncolytic virus are the physical limitations of nikolai g rainov and volkmar heidecke review | 23 epidemiology, and end results; and national cancer data base. neurooncol 1999; 1:205–11. 5. swanson kr, alvord ec jr, murray jd. virtual brain tumours (gliomas) enhance the reality of medical imaging and highlight inadequacies of current therapy. br j cancer 2002; 86:14–8. 6. burton ec, prados md. malignant gliomas. curr treat options oncol 2000; 1:459–68. 7. janus tj, kyritsis ap, forman ad, levin va. biology and treatment of gliomas. ann oncol 1992; 3:423– 33. 8. salcman m. malignant glioma management. neurosurg clin n am 1990; 1:49–63. 9. schiffer d, cavalla p, dutto a, borsotti l. cell proliferation and invasion in malignant gliomas. anticancer res 1997; 17:61–9. 10. guha a, mukherjee j. advances in the biology of astrocytomas. curr opin neurol 2004; 17:655–62. 11. mitchell p, ellison dw, mendelow ad. surgery for malignant gliomas: mechanistic reasoning and slippery statistics. lancet neurol 2005; 4:413–22. 12. whittle ir. surgery for gliomas. curr opin neurol 2002; 5:663–9. 13. giese a, westphal m. treatment of malignant glioma: a problem beyond the margins of resection. j cancer res clin oncol 2001; 127:217–25. 14. hess cf, schaaf jc, kortmann rd, schabet m, bamberg m. malignant glioma: patterns of failure following individually tailored limited volume irradiation. radiother oncol 1994; 30:146–9. 15. giese a, bjerkvig r, berens me, westphal m. cost of migration: invasion of malignant gliomas and implications for treatment. j clin oncol 2003; 21:1624–36. 16. deangelis lm. brain tumors. n engl j med 2001; 344:114–23. 17 schiff d, shaffrey me. role of resection for newly diagnosed malignant gliomas. expert rev anticancer ther 2003; 3:621–30. 18 stupp r, mason wp, van den bent mj, weller m, fisher b, taphoorn mj, et al. radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. n engl j med 2005; 352:987–96. 19. chiocca ea, broaddus wc, gillies gt, visted t, lamfers ml. neurosurgical delivery of chemotherapeutics, targeted toxins, genetic and viral therapies in neuro-oncology. j neurooncol 2004; 69:101–17. 20. rainov ng, kramm cm. vector delivery methods and targeting strategies for gene therapy of brain tumors. curr gene ther 2001; 1:367–83. 21. brem h, gabikian p. biodegradable polymer implants to treat brain tumors. j control release 2001; 74:63– 7. limited areas of tumour, since the number of injection sites is limited for practical reasons by tumour size, length of surgery and increasing risk of haemorrhage.94 direct intratumoural injections into the walls of the tumour resection cavity, although they can be performed under direct visual control and with multiple virus depots close to each other, have the same basic limitations as stereotactic procedures.93,101 moreover, the depth of injection is limited to 10–15 mm from the visible resection border, which seems to be insufficient to reach tumour cells migrating away from the main mass.101 ced has been shown to improve significantly virus distribution in and around experimental brain tumours.127 virus particles may be efficiently delivered by ced over large areas of tumour and surrounding brain and achieve widespread distribution and much larger coverage than with bolus injections.92,127,128 since a large amount of clinical experience has become available in the clinical trials employing ced of targeted toxins, it seems a logical step that clinical protocols with ced of viruses should be implemented in future. such trials may be able to combine the biological advantages of oncolytic viruses with the spatial distribution affordable by ced. c o n f l i c t o f i n t e r e s t ngr has received research grants from neurocrine inc. (san diego, ca) and ivax inc. (miami, fl). the authors have no financial interests in any of the biotechnology companies mentioned in the review. references 1. kleihues p, cavenee wk. pathology and genetics of tumours of the nervous system. lyon: iarc press, 2000. 2. ohgaki h, kleihues p. population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. j neuropathol exp neurol 2005; 64:479–89. 3. davis fg, freels s, grutsch j, barlas s, brem s. survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on surveillance, epidemiology, and end results (seer) data, 1973– 1991. j neurosurg 1998; 88:1–10. 4. davis fg, mccarthy bj, berger ms. centralized databases available for describing primary brain tumor incidence, survival, and treatment: central brain tumor registry of the united states; surveillance, clinical development of experimental therapies for malignant glioma 24 | squ medical journal, february 2011, volume 11, issue 1 2009; 110:583–8. 34. rhines ld, sampath p, dimeco f, lawson hc, tyler bm, hanes j, et al. local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma. neurosurgery 2003; 52:872–80. 35. pastan i, chaudhary vk, fitzgerald dj. recombinant toxins as novel therapeutic agents. annu rev biochem 1992; 61:331–54. 36. pastan i, fitzgerald d. recombinant toxins for cancer treatment. science 1992; 254:1173–7. 37. hall wa, fodstad o. immunotoxins and central nervous system neoplasia. j neurosurg 1992; 76:1– 12. 38. reiter y. recombinant immunotoxins in targeted cancer cell therapy. adv cancer res 2001; 81:93–124. 39. husain sr, puri rk. interleukin-13 receptor-directed cytotoxin for malignant glioma therapy: from bench to bedside. j neurooncol 2003; 65:37–48. 40. rustamzadeh e, low wc, vallera da, hall wa. immunotoxin therapy for cns tumor. j neurooncol 2003; 64:101–16. 41. gottstein c, winkler u, bohlen h, diehl v, engert a. immunotoxins: is there a clinical value? ann oncol 5 suppl 1994; 1:97–103. 42. puri rk, siegel jp. interleukin-4 and cancer therapy. cancer invest 1993; 11:473–86. 43. the precise trial: study of il13-pe38qqr compared to gliadel wafer in patients with recurrent glioblastoma multiforme. from: http:// clinicaltrials.gov, study identifier nct00076986. accessed: july 2010. 44. puri rk, leland p, kreitman rj, pastan i. human neurological cancer cells express interleukin-4 (il4) receptors which are targets for the toxic effects of il4-pseudomonas exotoxin chimeric protein. int j cancer 1994; 58:574–81. 45. kreitman rj, puri pk, pastan i. a circularly permuted recombinant interleukin 4 toxin with increased activity. proc natl acad sci usa 1994; 91:6889–93. 46. kreitman rj, puri rk, pastan i. increased antitumor activity of a circularly permuted il-4-toxin in mice with il-4 receptor bearing human carcinoma. cancer res 1995; 55:3357–63. 47. frankel ae, kreitman rj, sausville ea. targeted toxins. clin cancer res 2000; 6:326–34. 48. puri rk, hoon ds, leland p, snoy p, rand rw, pastan i, et al. preclinical development of a recombinant toxin containing circularly permuted interleukin 4 and truncated pseudomonas exotoxin for therapy of malignant astrocytoma. cancer res 1996; 56:5631– 7. 49. joshi bh, leland p, asher a, prayson ra, varricchio f, puri rk. in situ expression of interleukin-4 22. gallia gl, brem s, brem h. local treatment of malignant brain tumors using implantable chemotherapeutic polymers. j natl compr canc netw 2005; 3:721–8. 23. brem h, mahaley ms jr, vick na, black kl, schold sc jr, burger pc, et al. interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. j neurosurg 1991; 74:441–6. 24. brem h, piantadosi s, burger pc, walker m, selker r, vick na, et al. placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. the polymer brain tumor treatment group. lancet 1995; 345:1008–12. 25. westphal m, hilt dc, bortey e, delavault p, olivares r, warnke pc, et al. a phase 3 trial of local chemotherapy with biodegradable carmustine (bcnu) wafers (gliadel wafers) in patients with primary malignant glioma. neurooncol 2003; 5:79– 88. 26. westphal m, ram z, riddle v, hilt d, bortey e. gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. acta neurochir 2006; 148:269–75. 27. fleming ab, saltzman wm. pharmacokinetics of the carmustine implant. clin pharmacokinet 2002; 41:403–19. 28. brem h, ewend mg, piantadosi s, greenhoot j, burger pc, sisti m. the safety of interstitial chemotherapy with bcnu-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase i trial. j neurooncol 1995; 26:111–23. 29. kleinberg lr, weingart j, burger p, carson k, grossman sa, li k, et al. clinical course and pathologic findings after gliadel and radiotherapy for newly diagnosed malignant glioma: implications for patient management. cancer invest 2004; 22:1–9. 30. valtonen s, timonen u, toivanen p, kalimo h, kivipelto l, heiskanen o, et al. interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. neurosurgery 1997; 41:44–8. 31. olivi a, grossman sa, tatter s, barker f, judy k, olsen j, et al. dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a new approaches to brain tumor therapy cns consortium trial. j clin oncol 2003; 21:1845–9. 32. mcgirt mj, brem h. carmustine wafers (gliadel) plus concomitant temozolomide therapy after resection of malignant astrocytoma: growing evidence for safety and efficacy. ann surg oncol 2010; 17:1729–31. 33. mcgirt mj, than kd, weingart jd, chaichana kl, attenello fj, olivi a, et al. gliadel (bcnu) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. j neurosurg nikolai g rainov and volkmar heidecke review | 25 of head and neck: differential sensitivity to chimeric fusion proteins comprised of interleukin-13 and a mutated form of pseudomonas exotoxin. clin cancer res 2002; 8:1948–56. 61. debinski w, obiri ni, powers sk, pastan i, puri rk. human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. clin cancer res 1995; 1:1253–8. 62. puri rk, leland p, obiri ni, husain sr, kreitman rj, haas gp, et al. targeting of interleukin-13 receptor on human renal cell carcinoma cells by a recombinant chimeric protein composed of interleukin-13 and a truncated form of pseudomonas exotoxin a (pe38qqr). blood 1996; 87:4333–9. 63. weingart j, strauss lc, grossman sa. phase i/ ii study: intratumoral infusion of il13-pe38qqr cytotoxin for recurrent supratentorial malignant glioma. neurooncol 2002; 4:379. 64. kunwar s. convection enhanced delivery of il13pe38qqr for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. acta neurochir suppl 2003; 88:105–11. 65. kunwar s, prados m, chang s, berger ms, lang ff, piepmeier jm, et al. peritumoral convectionenhanced delivery of il13-pe38qqr in patients with recurrent malignant glioma phase i interim results. neurooncol 2003; 5:4. 66. chang sm. neuroradiographic changes following convection-enhanced delivery (ced) of the conjugated toxin il13-pe38qqr following resection of recurrent malignant glioma. neurooncol 2003; 5:4. 67. prados md, lang ff, stauss lc, fleming ck, aldape k, kunwar s, et al. intratumoral and intracerebral microinfusion of il13-pe38qqr cytotoxin: phase i/ii study of pre-and post-resection infusions in recurrent resectable maliganant glioma. proc am soc clin oncol 2002; 21:2087. 68. kunwar s, chang s, westphal m, vogelbaum m, sampson j, barnett g, et al. phase iii randomized trial of ced of il13-pe38qqr vs. gliadel wafers for recurrent glioblastoma. neuro oncol 2010; 12:871– 81. 69. weaver m, laske dw. transferrin receptor ligandtargeted toxin conjugate (tf-crm107) for therapy of malignant gliomas. j neurooncol 2003; 65:3–13. 70. johnson vg, wilson d, greenfield l, youle rj. the role of the diphtheria toxin receptor in cytosol translocation. j biol chem 1988; 263:1295–300. 71. greenfield l, johnson vg, youle rj. mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity. science 1987; 238:536–9. 72. recht l, torres co, smith tw, raso v, griffin tw. receptors in human brain tumors and cytotoxicity of a recombinant interleukin-4 (il-4) cytotoxin in primary glioblastoma cell cultures. cancer res 2001; 61:8058–61. 50. husain sr, behari n, kreitman rj, pastan i, puri rk. complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy. cancer res 1998; 58:3649–53. 51. weber f, asher a, bucholz r, berger m, prados m, chang s, et al. safety, tolerability, and tumor response of il4-pseudomonas exotoxin (nbi-3001) in patients with recurrent malignant glioma. j neurooncol 2003; 64:125–37. 52. nbi-3001 followed by surgery in treating patients with recurrent glioblastoma multiforme. from: http://clinicaltrials.gov, study identifier nct00014677. accessed: july 2010. 53. hunter t. the epidermal growth factor receptor gene and its product. nature 1984; 311:414–6. 54. wong aj, bigner sh, bigner dd, kinzler kw, hamilton sr, vogelstein b. increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. proc natl acad sci usa 1987; 84:6899–903. 55. humphrey pa, wong aj, vogelstein b, friedman hs, werner mh, bigner dd, et al. amplification and expression of the epidermal growth factor receptor gene in human glioma xenographs. cancer res 1988; 48:2231–8. 56. liberman ta, nusbaum hr, razon n, kris r, lax i, soreq h, et al. amplification, enhanced expression, and possible rearrangement of egf receptor gene in primary human brain tumors of glial origin. nature 1985; 313:144–7. 57. sampson jh, akabani g, archer ge, bigner dd, berger ms, friedman ah, et al. progress report of a phase i study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (tgf)-alpha and a mutated form of the pseudomonas exotoxin termed pe-38 (tp-38) for the treatment of malignant brain tumors. j neurooncol 2003; 65:27–35. 58. weber f. preliminary results of a phase ii study of tp38 immunotoxin delivered via convection-enhanced delivery to patients with recurrent glioblastoma multiforme: report of the tp-38 study group. ann meeting german soc neurosurg. from: http://www. egms.de/en/meetings/dgnc2005/ 05dgnc0094.htm. accessed: july 2010. 59. joshi bh, plautz ge, puri rk. interleukin-13 receptor alpha chain: a novel tumor-associated transmembrane protein in primary explants of human malignant gliomas. cancer res 2000; 60:1168–72. 60. joshi bh, kawakami k, leland p, puri rk. heterogeneity in interleukin-13 receptor expression and subunit structure in squamous cell carcinoma clinical development of experimental therapies for malignant glioma 26 | squ medical journal, february 2011, volume 11, issue 1 retrovirus therapy of tumors with activated ras pathway. science 1998; 282:1332–4. 87. papanastassiou v, rampling r, fraser m, petty r, hadley d, nicoll j, et al. the potential for efficacy of the modified (icp 34.5-) herpes simplex virus hsv1716 following intratumoural injection into human malignant glioma: a proof of principle study. gene ther 2002; 9:398–406. 88. rainov ng, kramm cm, aboody-guterman k, chase m, ueki k, louis dn, et al. retrovirusmediated gene therapy of experimental brain neoplasms using the herpes simplex virus-thymidine kinase/ganciclovir paradigm. cancer gene ther 1996; 3:99–106. 89. markert jm, medlock md, rabkin sd, gillespie gy, todo t, hunter wd, et al. conditionally replicating herpes simplex virus mutant, g207 for the treatment of malignant glioma: results of a phase i trial. gene ther 2000; 7:867–74. 90. oldfield eh, ram z, culver kw, blaese rm, devroom hl, anderson wf, et al. gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. hum gene ther 1993; 4:39– 69. 91. rainov ng, ren h. gene therapy for human malignant brain tumors. cancer j 2003; 9:180–8. 92. muldoon ll, kroll ra, pagel ma, romangoldstein s, fiamengo sa, neuwelt ea. delivery of therapeutic genes to brain and intracerebral tumors. in: chiocca ea, breakefield xo, eds. gene therapy for neurological disorders and brain tumors. boston: humana press, 1997. pp. 128–39. 93. ram z, culver kw, oshiro em, viola jj, devroom hl, otto e, et al. therapy of malignant brain tumors by intratumoral implantation of retroviral vectorproducing cells. nat med 1997; 3:1354–61. 94. harsh gr, deisboeck ts, louis dn, hilton j, colvin m, silver js, et al. thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a genemarking and neuropathological study. neurosurgery 2000; 92:804–11. 95. ram z, barnett g, vogelbaum m, constantini s, lillehei k, sherman j, et al. pre-operative infusion of il13-pe38qqr cytotoxin by convection-enhanced delivery (ced) in recurrent malignant glioma: a phase i/ii study. proc am soc clin oncol 2003; 22:403. 96. andreansky s, soroceanu l, flotte er, chou j, markert jm, gillespie gy, et al. evaluation of genetically engineered herpes simplex viruses as oncolytic agents for human malignant brain tumors. cancer res 1997; 57:1502–9. 97. chiocca ea. oncolytic viruses. nat cancer rev 2002; 2:938–51. 98. dirven c, van beusechem v, lamfers m, grill j, gerritsen wr, vandertop wp. oncolytic transferrin receptor in normal and neoplastic brain tissue: implications for brain tumor immunotherapy. j neurosurg 1990; 72:941–5. 73. jefferies wa, brandon mr, hunt sv, williams af, gatter kc, mason dy. transferrin receptor on endothelium of brain capillaries. nature 1984; 312:162–3. 74. johnson vg, wrobel c, wilson d, zovickian j, greenfield l, oldfield eh. et al. improved tumorspecific immunotoxins in the treatment of cns and leptomeningeal neoplasia. j neurosurg 1989; 70:240–8. 75. hall wa, godal a, juell s, fodstad o. in vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme. j neurosurg 1992; 76:838–44. 76. laske dw, ilercil o, akbasak a, youle rj, oldfield eh. efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice. j neurosurg 1994; 80:520–6. 77. engebraaten o, hjortland go, juell s, hirschberg h, fodstad o. intratumoral immunotoxin treatment of human malignant brain tumors in immunodeficient animals. int j cancer 2002; 97:846–52. 78. laske dw, youle rj, oldfield eh. tumor regression with regional distribution of the targeted toxin tfcrm107 in patients with malignant brain tumors. nat med 1997; 3:1362–8. 79. study of therapy with transmid™ compared to best standard of care in patients with glioblastoma multiforme. from: http://clinicaltrials.gov, study identifier nct00083447, see also nct00088400 and nct00087230. accessed: july 2010. 80. celtic pharma terminates transmid trial ksb311r/ c i i i / 0 0 1 . fr o m : http : / / w w w. d r u g s . co m / n e w s / celtic-pharma-terminates-transmid-trial-ksb311rciii-001-5246.html. accessed: july 2010. 81. briellmann rs, pell gs, wellard rm, mitchell la, abbott df, jackson gd. mr imaging of epilepsy: state of the art at 1.5 t and potential of 3 t. epileptic disord 2003; 5:3–20. 82. tummala rp, chu rm, liu h, truwit cl, hall wa. application of diffusion tensor imaging to magneticresonance-guided brain tumor resection. ped neurosurg 2003; 39:39–43. 83. cruz junior lc, sorensen ag. diffusion tensor magnetic resonance imaging of brain tumors. neurosurg clin n am 2005; 16:115–34. 84. zlokovic bv, apuzzo ml. cellular and molecular neurosurgery: pathways from concept to reality part ii: vector systems and delivery methodologies for gene therapy of the central nervous system. neurosurgery 1997; 40:805–13. 85. pulkkanen kj, yla-herttuala s. gene therapy for malignant glioma: current clinical status. mol ther 2005; 12:585–98. 86. coffey mc, strong je, forsyth pa, lee pw. nikolai g rainov and volkmar heidecke review | 27 hd, wyde pr, goodman jc. et al. phase i study of adenoviral delivery of the hsv-tk gene and ganciclovir administration in patients with current malignant brain tumors. mol ther 2000; 1:195–203. 111. judy kd, eck sl. the use of suicide gene therapy for the treatment of malignancies of the brain. in: lattime ec, stanton lc, eds. gene therapy of cancer. san diego, ca: academic press, 2002. pp. 505–12. 112. germano im, fable j, gultekin sh, silvers a. adenovirus/herpes simplex–thymidine kinase/ ganciclovir complex: preliminary results of a phase i trial in patients with recurrent malignant gliomas. j neurooncol 2003; 65:279–89. 113. smitt ps, driesse m, wolbers j, kros m, avezaat c. treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. mol ther 2003; 7:851–8. 114. sandmair am, loimas s, puranen p, immonen a, kossila m, puranen m, et al. thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. hum gene ther 2000; 11:2197–205. 115. immonen a, vapalahti m, tyynela k, hurskainen h, sandmair a, vanninen r, et al. advhsv-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. mol ther 2004; 10:967–72. 116. preliminary cerepro® phase iii results meet primary endpoint secondary endpoints yet to be established with 45% of patients still alive. from: http://www.dggt.de/docs/cereprophase.pdf. accessed: july 2010. 117. mitchell p. ark’s gene therapy stumbles at the finish line. nat biotech 2010; 28:183–4. 118. mineta t, rabkin sd, yazaki t, hunter wd, martuza rl. attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. nat med 1995; 1:938–43. 119. markert jm, parker jn, gillespie gy, whitley rj. genetically engineered human herpes simplex virus in the treatment of brain tumours. herpes 2001; 8:17–22. 120. rampling r, cruickshank g, papanastassiou v, nicoll j, hadley d, brennan d, et al. toxicity evaluation of replication-competent herpes simplex virus (icp 34.5 null mutant 1716) in patients with recurrent malignant glioma. gene ther 2000; 7:859–66. 121. harland j, papanastassiou v, brown sm. hsv1716 persistence in primary human glioma cells in vitro. gene ther 2002; 9:1194–8. 122. harrow s, papanastassiou v, harland j, mabbs r, petty r, fraser m, et al. hsv1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. gene ther 2004; 11:1648–58. 123. khuri fr, nemunaitis j, ganly i, arseneau j, tannock if, romel l, et al. a controlled trial of intratumoral adenoviruses for treatment of brain tumours. expert opin biol ther 2002; 2:943–52. 99. heise c, kirn dh. replication-selective adenoviruses as oncolytic agents. j clin invest 2000; 105:847–51. 100. baxter lt, jain rk. transport of fluid and macromolecules in tumors i. role of interstitial pressure and convection. microvasc res 1989; 37:77–102. 101. rainov ng. a phase iii clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. hum gene ther 2000; 11:2389–401. 102. freeman sm, abboud cn, whartenby ka, packman ch, koeplin ds, moolten fl, et al. the “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. cancer res 1993; 53:5274–83. 103. moolten fl. tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. cancer res 1986; 46:5276–81. 104. klatzmann d, valery ca, bensimon g, marro b, boyer o, mokhtari k, et al. a phase i/ii study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma. hum gene ther 1998; 9:2595–604. 105. shand n, weber f, mariani l, bernstein m, gianellaborradori a, long z, et al. a phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. hum gene ther 1999; 10:2325–35. 106. izquierdo m, cortes ml, martin v, de felipe p, izquierdo jm, pérez-higueras a, et al. gene therapy in brain tumours: implications of the size of glioblastoma on its curability. acta neurochir suppl 19097; 68:111–7. 107. izquierdo m, martin v, de felipe p, izquierdo jm, pérez-higueras a, cortés ml, et al. human malignant brain tumor response to herpes simplex thymidine kinase (hsvtk)/ganciclovir gene therapy. gene ther 1996; 3:491–5. 108. prados md, mcdermott m, chang sm, wilson cb, fick j, culver kw, et al. treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vectorproducer cells followed by intravenous ganciclovir administration: a phase i/ii multi-institutional trial. j neurooncol 2003; 65:269–78. 109. puumalainen a, vapalahti m, agrawal rs, kossila m, laukkanen j, lehtolainen p, et al. ß-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. hum gene ther 1998; 9:1769–74. 110. trask tw, trask rp, aguilar-cordova e, shine clinical development of experimental therapies for malignant glioma 28 | squ medical journal, february 2011, volume 11, issue 1 126. jiang h, gomez-manzano c, lang ff, alemany r, fueyo j. oncolytic adenovirus: preclinical and clinical studies in patients with human malignant gliomas. curr gene ther 2009; 9:422–7. 127. bankiewicz ks, eberling jl, kohutnicka m, jagust w, pivirotto p, bringas j, et al. convection-enhanced delivery of aav vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. exp neurol 2000; 164:2–14. 128. nilaver g, muldoon ll, kroll ra, pagel ma, breakefield xo, davidson bl, et al. delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption. proc natl acad sci usa 1995; 92:9829– 33. onyx-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. nat med 2000; 6:879–85. 124. chiocca ea, abbed km, tatter s, louis dn, hochberg fh, barker f, et al. a phase i open-label, dose-escalation, multi-institutional trial of injection with an e1b-attenuated adenovirus, onyx-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. mol ther 2004; 10:958–66. 125. nemunaitis j, khuri f, ganly i, arseneau j, posner m, vokes e, et al. phase ii trial of intratumoral administration of onyx-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. j clin oncol 2001; 19:289–98. department of obstetrics & gynaecology, university of ilorin teaching hospital, ilorin, kwara state, nigeria *corresponding author’s e-mail: munirijaiya@yahoo.com جتربة عشوائية الستخدام دواء امليزوبروستول بالفم مقارنة بإجراء الشفط اخلوائي اليدوي لعالج اإلجهاض غري املكتمل يف مستشفى ثالثي املستوى يف نيجرييا كيهيند فيمي اإيبيمي، منريالدين اأديرمي اإيجايا، كيكيلومو تيميلول اأدي�سينا abstract: objectives: this study aimed to compare the efficacy of oral misoprostol with manual vacuum aspir ation (mva) in first trimester incomplete abortions. methods: this randomised controlled trial study was conducted at the university of ilorin teaching hospital, ilorin, nigeria between april 2014 and november 2015. pregnant women who presented with clinical features of incomplete abortion at a gestational age of 13 weeks or less were included. patients who had profuse vaginal bleeding, an intrauterine device in situ, signs of pelvic infections or who were younger than 18 years old and had no accompanying adults to give informed consent were excluded. a total of 200 participants were randomly and equally allocated to either the mva or misoprostol treatment group. the treatment group were given 600 µg of misoprostol orally. the primary outcome measure was complete uterine evac uation, while secondary outcome measures included the need for additional surgical evacuation for failed treatment, adverse effects/complications, acceptability of and satisfaction with the treatment. results: both misoprostol and mva had high complete evacuation rates, yet mva was significantly higher (99% versus 83%, relative risk [rr]: 0.84, confidence interval [ci]: 0.766–0.918; p <0.001). significantly more women in the misoprostol group required additional mva for failed treatment than in the mva treatment group (17% versus 1%, rr: 16.67, ci: 2.260–12.279; p <0.001). no significant difference was found between the misoprostol and mva treatment groups in terms of satisfaction (92.7% versus 89.8%, rr: 1.04, ci: 0.946–1.127; p = 0.473). conclusion: treatments with misoprostol and mva had high complete uterine evacuation rates, as well as high rates of acceptability and satisfaction. however, mva had a significantly higher complete evacuation rate than misoprostol. keywords: misoprostol; abortion techniques; first trimester; incomplete abortion; nigeria. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل مقارنة فعالية دواء امليزوبرو�ستول الذي يتناول عن طريق الفم مع اجراء ال�سفط اخلوائي اليدوي لعالج الإجها�ض غري املكتمل خالل فرتة احلمل الأوىل. الطريقة: اأجريت جتربة مقارنة ع�سوائية الإنتقاء يف م�ست�سفى جامعة اإيلورين التعليمي، يف نيجرييا يف الفرتة ما بني اإبريل 2014 ونوفمرب 2015، �سملت الدرا�سة ن�ساءاً حوامل يحملن اأعرا�ض �رسيرية لإجها�ض غري مكتمل يف عمر احلمل املبكر اأي 13 اأ�سبوًعا اأو اأقل، مت تخ�سي�ض ما جمموعه 200 م�ساركة اخرتن ب�سكل ع�سوائي ووزعن اإما ملجموعة العالج باإجراء ال�سفط اليدوي اأو عن طريق اإعطاء دواء امليزوبرو�ستول، اأعطيت جمموعة العالج الدوائي 600 ميكروغرام من امليزوبرو�ستول عن طريق الفم، كان مقيا�ض النتيجة الأويل هو الإخالء الكامل للرحم بعد العالج، يف حني ت�سمنت مقايي�ض النتائج الثانوية احلاجة اإىل اإخالء جراحي اإ�سايف للعالج الأويل الغري ناجح والآثار اأو امل�ساعفات، كما مت درا�سة قبول العالج ون�سبة الر�سا. النتائج: كان لكل من دواء امليزوبرو�ستول واإجراء ال�سفط اخلوائي اليدوي معدلت اإخالء رحم تامة بن�سب عالية، لكن الن�سبة كان اأعلى بكثري يف الإجراء اليدوي، اأي بن�سبة )%83 لالإجراء اليدوي مقابل %99 للدواء، ]ci[ ،0.84 = ]rr[ = 0.766–0.918؛ p >0.001(. احتاج عدد اأكرب بكثري من الن�ساء يف جمموعة امليزوبرو�ستول اإىل عالج اإ�سايف بنف�ض الإجراء ب�سبب عدم جناح العالج الأويل مقارنة مع جمموعة عالج جمموعة عالج ال�سفط اليدوي )بن�سبة %17 مقابل %1، ci ،16.67 = rr = 2.260–12.279؛ p >0.001( مل يكن هناك فرق كبري بني جمموعات العالج بدواء امليزوبرو�ستول وال�سفط اليدوي من من حيث معدل الر�سا )%92.7 مقابل ci ،1.04 = rr ،89.9% = 0.946–1.127؛ p = 0.473(. اخلال�صة: كان العالج بدواء امليزوبرو�ستول والـعالج باإجراء ال�سفط اخلوائي اليدوي فاعاًل لإجالء للرحم بالكامل ومعدلت القبول والر�سا، مع ذلك كان معدل الإخالء الكامل اأعلى ب�سكل وا�سح يف جمموعة ال�سفط اليدوي من جمموعة دواء امليزوبرو�ستول. الكلمات املفتاحية: امليزوبرو�ستول؛ طرق الإجها�ض؛ ف�سل احلمل الأول؛ اإجها�ض غري مكتمل؛ نيجرييا. randomised trial of oral misoprostol versus manual vacuum aspiration for the treatment of incomplete abortion at a nigerian tertiary hospital kehinde f. ibiyemi, *munir’deen a. ijaiya, kikelomo t. adesina sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e38–43, epub. 30 may 19 submitted 27 aug 18 revision req. 30 sep 18; revision recd. 1 nov 18 accepted 19 nov 18 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge misoprostol and manual vacuum aspiration (mva) had high complete evacuation rates in first trimester incomplete abortion treatment. mva had a significantly higher complete evacuation rate than misoprostol. there was a high satisfaction rate in both the misoprostol and mva treatment groups. https://doi.org/10.18295/squmj.2019.19.01.008 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ kehinde f. ibiyemi, munir’deen a. ijaiya and kikelomo t. adesina clinical and basic research | e39 complications arising from spontaneous and unsafe induced abortions have been recognised worldwide as a major public health concern and are one of the leading reasons women seek emergency care.1 a 2014 world health organization systematic ana lysis estimated that 7.9% of all maternal deaths are due to abortion; however, this figure is lower than the previous estimate of 13%.2 unsafe abortions are prevalent in countries with limited resources, where abortion laws are restrictive and/or access to safe abortion services is difficult.2 in sub-saharan africa, access to post-abortion care (pac) services, especially treatment of incomplete preg nancy terminations, is a priority.3 a major advancement in pac services has been the use of manual vacuum aspiration (mva) for uterine evacuation when uterine size is consistent with or ≤12 weeks of gestation.4 how ever, research has shown that there is insufficient use, inadequate access to and low availability of uterine evacuation services in nigeria.5 medical treatment of incomplete abortion with misoprostol is an effective alternative to mva or sharp curettage.6–10 most studies comparing mva with miso prostol have shown that the former is more effective, but both have a high success rate.11,12 however, weeks et al.’s study contradicts this; 600 µg of oral misoprostol was found to be more effective than mva (96.3% versus 91.5%, respectively).13 misoprostol is cheap, safe, heat stable, easy to store and requires no surgical skills to admin ister, making it attractive for use in sub-saharan africa.1,7,14 misoprostol use for incomplete abortions could decrease the burden on healthcare facilities and skilled surgical providers while also reducing the need for surgical equip ment, supplies, anaesthesia and cutting costs to health care systems worldwide.6 these features make misoprostol an important alternative to mva in pac. at the univ ersity of ilorin teaching hospital, ilorin, nigeria, mva was the traditional treatment for first trimester incom plete miscarriage. this study aimed to compare the out comes of oral misoprostol with mva in first trimester incomplete abortion treatment at the university of ilorin teaching hospital in nigeria. methods this randomised controlled trial was done at the gynaecological emergency ward and gynaecology outpatient clinic of the department of obstetrics and gynaecology at the university of ilorin teaching hospital, between april 2014 and november 2015 (trial code: pactr201803003087264). the subjects were pregnant women who had pres ented at the gynaecological emergency ward with clin ical features of incomplete abortion at a gestational age of ≤13 weeks. gestational age was calculated from the patient’s last menstrual period to the time of miscarr iage. incomplete abortion was defined as past or present history of vaginal bleeding during index pregnancy, open cervical os, history of passing tissue and/or positive urinary pregnancy test with evidence of substantial debris in the uterus on transvaginal ultrasound. patients with profuse vaginal bleeding, an intrauterine device in situ or signs of pelvic infections or younger than 18-years-old and had no accompanying adults to provide informed consent were excluded. the participants were equally allocated to either the mva or misoprostol treatment group by computer generated random numbers using the stat trek© random number generator.15 the misoprostol group was labelled as treatment one and mva was labelled treatment two. the upper limit of random numbers input into the stat trek© random number generator was 200 (reflecting the sample size), with a minimum value of one and a maximum of two, representing the two groups; it allowed for duplicate entries. thereafter, a statistician created a table of 200 entries and labelled each entry with either number one or two. participants’ assigned number one were allocated to the misoprostol group and those assigned number two were part of the mva group. a tag was attached to each patient’s folder to indi cate the assigned treatment group for easy subsequent identification and follow-up. the participants, resear chers and data analysers therefore were not blinded to the allocation. from the calculated sample size using a power of 80%, each group in the study consisted of 100 subjects giving a total of 200 subjects, including a 10% attrition rate. appropriate corrections were affected after the research instrument was pretested. following the treatment, all patients were observed in-hospital for six hours before being discharged. participants allocated to the misoprostol group were given 50 ml of water with 600 µg of oral misoprostol. participants allocated to the mva group under went the procedure (ipas, chapel hill, north carolina, usa) after intramuscular administration of 60 µg of pentazocine and 0.5 mg of ergometrine. the authors or research team resident doctors performed the proced ures in an emergency ward operating theatre. application to patient care healthcare providers can prescribe misoprostol as a good alternative to mva for treatment of first trimester incomplete abortion in limited resource countries in order to improve post-abortion care service availability and accessibility. randomised trial of oral misoprostol versus manual vacuum aspiration for the treatment of incomplete abortion at a nigerian tertiary hospital e40 | squ medical journal, february 2019, volume 19, issue 1 this study employed a verbal rating scale translated into yoruba that was applicable for the study participants to assess the severity of abdominal pain (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, 4 = excru ciating pain). women were not routinely given analgesics based on the unit protocol for pain management. participants were observed for six hours—foll owing misoprostol administration or the mva proced ure—before being discharged from the hospital. during this observation period, any products of conception at the cervical os were removed during speculum exam ination. patients were also monitored for side effects of misoprostol, including vaginal bleeding, headache, skin rash, abdominal pain, pyrexia (temperature ≥37.5°c), chills, nausea, vomiting, headache, diarrhoea and comp lications of mva such as uterine perforation. vaginal bleeding was visually assessed based on patients’ reports as either absent, mild, moderate or severe. during the observation period, an interviewer administered a quest ionnaire to the participants in both groups to assess adverse effects, pain and blood loss. adverse effects were treated according to standard pain management prot ocols. prior to discharge, the participants were given the names and contact details of the researchers and research assistants in case of complications or if they wanted more information about their treatment. packed cell volume was estimated one week before and after treatment in each group. follow-up appointments at the gynaecological clinic were scheduled for one-week post-procedure for women in both groups to confirm their abortion status or in case of complications. all women underwent ultra sound assessment irrespective of their symptoms and clinical findings. transvaginal ultrasound was used for further assessment due to its sensitivity. the same team of radiologists performed the ultrasound investigations at diagnosis and follow-up. transvaginal ultrasound findings of an anteroposterior diameter of >1.5 cm was regarded as significant debris. in this study, treatment failure was defined as inc omplete uterine evacuation warranting additional mva based on persistent vaginal bleeding and/or ultrasound findings indicating significant debris. in such a situation, a sample was sent for histological evaluation. at the oneweek post-treatment follow-up, all participants were asked a series of questions on the treatment’s adverse effects, acceptability and their satisfaction. data were analysed using statistical package for the social sciences (spss), version 21.0 (ibm, corp., armonk, new york, usa). the primary outcome measure was complete uterine evacuation, while secondary outcome measures included the need for additional surgical evac uation, adverse drug effects/surgical complications and satisfaction with treatment. levels of statistical significance were tested via a chi-square test, a mann-whitney u test, student’s t-test and by calculating relative risk (rr) with a 95% confidence interval (ci) applied as appropriate. a value of p <0.05 was considered statistically significant. the ethical committee of the university of ilorin teaching hospital approved the study (erc pan/2014/ 01/1264). participants gave informed consent and their data were treated confidentially. the participants did not bear any service costs and no incentive was provided in any form. results a total of 238 subjects were screened for eligibility, of which 200 subjects satisfied the inclusion criteria and subsequently 100 participants were allocated to each group in the study. in total, 38 subjects were excluded from the study because of excessive vaginal bleeding (n = 23) or refusal to participate (n = 15). in the miso prostol group, four patients made unscheduled visits to the hospital 3–4 days after treatment due to bleeding per vaginam and therefore were assigned to the treatment failure category. two mva patients were lost to follow-up and were therefore excluded from the analysis [figure 1]. the baseline demographic and reproductive variables were similar in both groups [table 1]. mean gestational age at miscarriage for the misoprostol and mva groups figure 1: flow of participants through the enrolment, allocation, follow-up and analysis stages of the study. mva = manual vacuum aspiration. kehinde f. ibiyemi, munir’deen a. ijaiya and kikelomo t. adesina clinical and basic research | e41 were 8.13 ± 1.45 and 8.17 ± 1.14 weeks, respectively (p = 0.832). the misoprostol and mva groups had high com plete evacuation rates; however, mva had a significantly higher rate (83% versus 99%, rr: 0.84, ci: 0.766–0.918; p <0.001). mva had a significantly higher complete evacuation rate than misoprostol in the 8–10 weeks’ gestational age group [table 2]. significantly more participants in the misoprostol group required additional mva for treatment failure than in the mva group (17% versus 1%, rr: 16.67, ci: 2.260–12.279; p <0.001) [table 3]. of the 17 (17%) participants in the misoprostol group who required add itional treatment, eight (47.1%) participants had products of conception in the debris sample. significantly higher proportions of participants in the mva group experienced moderate to severe abdominal pain than in the misoprostol group (99% versus 33.3%, rr: 0.34, ci: 0.254–0.447; p <0.001). however, more participants in the misoprostol group had moderate to severe vaginal bleeding than in the mva group (29.2% versus 12.2%, rr: 2.30, ci: 1.346–4.590; p <0.001). pyrexia was the most common adverse effect (40.6%) in the misoprostol group, followed by nausea (12.5%), chills (7.3%) and vomiting (6.3%); in the mva group, nausea (7.1%) and vomiting (4.1%) were the most common adverse effects. both misoprostol and mva groups had high satisfaction rates (92.7% versus 89.8%, rr: 1.04, ci: 0.946–1.127; p = 0.473). most participants in both groups expressed the desire to choose the respective method again and would recommend that method to their friends [table 3]. discussion in the current study, the complete uterine evacuation rate was high in both the misoprostol and mva groups, with mva having a significantly higher success rate (83% versus 99%; p <0.001). this finding is in agreement with other studies in burkina faso, tanzania, ghana, finland and ecuador.10–12,14,16 the success rate of 600 µg oral misoprostol in this study was comparable with findings from varying dosages and routes of administration of misoprostol used in other studies.8,17,18 similarly, a recent cochrane database systematic review that compared different routes of administration of misoprostol with mva showed no clear evidence to suggest that one regimen was superior to another.19 contrary to this and table 1: characteristics of patients who had been given oral misoprostol and/or manual vacuum aspiration in first trim ester incomplete abortions at the university of ilorin teaching hospital, ilorin, nigeria (n = 200) characteristic n (%) p value* misoprostol mva total age group in years ≤19 5 (5) 0 (0) 5 (2.5) 0.074 20–24 21 (21) 12 (12) 33 (16.5) 0.117 25–29 38 (38) 44 (44) 82 (41) 0.508 30–34 23 (23) 32 (32) 55 (27.5) 0.225 ≥35 13 (13) 12 (12) 25 (12.5) 0.842 mean ± sd 28.38 ± 5.51 28.44 ± 3.31 0.93† occupation housewife 9 (9) 3 (3) 12 (6) 0.083 student 9 (9) 5 (5) 14 (7) 0.285 employed 76 (76) 84 (84) 160 (80) 0.527 unemployed 6 (6) 8 (8) 14 (7) 0.593 educational status primary education 3 (3) 2 (2) 5 (2.5) 0.655‡ secondary education 9 (9) 6 (6) 15 (7.5) 0.438 post-secondary education 7 (7) 9 (9) 16 (8) 0.617 post-graduate education 81 (81) 83 (83) 164 (82) 0.876 marital status married 91 (91) 94 (94) 185 (92.5) 0.825 single 5 (5) 3 (3) 8 (4) 0.480 unwed partnership 4 (4) 3 (3) 7 (3.5) 0.706 estimated gestational age in weeks 5–7 36 (36) 32 (32) 68 (34) 0.628 8–10 62 (62) 68 (68) 130 (65) 0.599 11–13 2 (2) 0 (0) 2 (1) 0.157 mva =manual vacuum aspiration; sd = standard deviation. *using chi-square test. †using independent samples t-test. ‡yates correction. table 2: primary outcome measures of first trimester incomplete abortions using oral misoprostol and manual vacuum aspiration (n = 200) outcome n (%) rr (95% ci) p value misoprostol group (n = 100) mva group (n = 98)* complete evacuation 83 (83) 97 (99) 0.84 (0.766–0.918) <0.001 gestational age compared against complete evacuation in weeks 5–7 31/36 (86.1) 30/31 (96.8) 1.01 (0.667–1.538) 0.953 8–10 51/62 (82.3) 67/67 (100) 0.75 (0.590–0.943) 0.013 11–13 1/2 (50) 0/0 (0) 0.321 rr = relative risk; ci = confidence interval; mva = manual vacuum aspiration. *two women were lost to follow-up in the mva group and were not included. randomised trial of oral misoprostol versus manual vacuum aspiration for the treatment of incomplete abortion at a nigerian tertiary hospital e42 | squ medical journal, february 2019, volume 19, issue 1 other findings, weeks et al.’s study in uganda found a slightly higher success rate among the misoprostol group than the mva group, although the difference was not statistically significant (96.3% versus 91.5%; p = 0.43).13 this study shows that mva is more effective than misoprostol in treatment of incomplete abortion in the 8–10 week gestational age group. however, treatment outcomes of mva and misoprostol depended on providers’ skills and quality of the misoprostol. the higher failure rate and need for mva in this study could be due to the use of transvaginal ultrasono graphy to assess complete emptiness of the uterine cavity as opposed to abdominal ultrasonography and clinical assessment used for post-intervention evaluation in other studies.10,11,20 however, transvaginal ultrasonography is more sensitive than abdominal ultrasonography and clinical assessment.21 this study, as has been observed in another study, demonstrated higher cases of pyrexia, nausea and chills among the misoprostol versus the mva group.19 these symptoms are common side effects of misoprostol, with pyrexia being the most common side effect as a result of the drug’s action (prostaglandin e1 analogue) on the central thermoregulatory centre.22 mva was identified as more painful than misoprostol, which is in agreement with shwekerela et al. and bique et al.’s studies but in contrast with niinimäki et al.’s findings.10,12,23 miso prostol causes uterine cramping and bleeding during expulsion of the remaining products of conception; however, these side effects are transient and tolerable. as in other studies, the current participants indic ated high satisfaction with both misoprostol and mva.9,11,16 this finding was contrary to a study by shwekerela et al., where the misoprostol group had a significantly higher percentage of participant satisfaction than the mva group (75% versus 55%; p = 0.001).10 a comparably high percentage of participants in both groups in this study expressed a desire to recommend their treatment method to a friend and would use the same approach again, which is in-line with the findings of dao et al.11 in contrast, shwekerela et al.’s study determined that a significantly higher proportion of participants in the misoprostol group would recommend the treatment to a friend than in the mva group (95% versus 75%; p <0.001).10 niinimäki et al.’s study found that fewer participants in the miso prostol group expressed a desire to choose the same treat ment method in the future because of pain.12 limitations of this study included the subjective visual estimation of vaginal bleeding and the small sample size; hence, it was difficult to assess the significance of some outcomes that were of low occurrence. table 3: secondary outcome measures of first trimester inc omplete abortions using oral misoprostol and manual vacuum aspiration (n = 200) outcome n (%) rr (95% ci) p value misoprostol group (n = 100) mva group (n = 98) required an additional mva 17 (17) 1 (1) 16.67 (2.260–12.279) <0.001 total participants* 96 (100) 98 (100) moderate-to severe abdominal pain 32 (33.3) 97 (99) 0.34 (0.254–0.447) <0.001 moderate-tosevere vaginal bleeding 28 (29.2) 12 (12.2) 2.30 (1.346–4.590) <0.001 adverse effects/complications chills 7 (7.3) 0 (0) 0.006 headache 3 (3.1) 2 (2) 1.55 (0.262–8.962) 0.490 nausea 12 (12.5) 7 (7.1) 1.76 (0.720–4.256) 0.155 vomiting 6 (6.3) 4 (4.1) 1.54 (0.446–5.257) 0.466 diarrhoea 2 (2.1) 0 (0) 0.244 rash 1 (1) 0 (0) 0.495 pyrexia 39 (40.6) 0 (0) <0.001 uterine perforation 0 (0) 0 (0) acceptability of method satisfied with the method 89 (92.7) 88 (89.8) 1.04 (0.946–1.127) 0.473 simple, quick and successful were the best features 83 (86.5) 90 (91.8) 0.94 (0.853–1.039) 0.228 good counselling/care were the best features 60 (62.5) 80 (81.6) 0.77 (0.639–0.918) 0.003 pain was the worst feature 5 (5.2) 29 (29.6) 0.18 (0.071–0.436) <0.001 vaginal bleeding was the worst feature 11 (11.5) 9 (9.2) 1.25 (0.542–2.875) 0.602 would choose same method again 90 (93.8) 88 (89.8) 1.04 (0.960–1.136) 0.317 would recommend chosen method to friend 89 (92.7) 88 (89.8) 1.03 (0.946–1.127) 0.473 rr = relative risk; ci = confidence interval; mva = manual vacuum aspiration. *four women in the misoprostol group who made an unscheduled visit and two women lost to follow-up in the mva group were not included. kehinde f. ibiyemi, munir’deen a. ijaiya and kikelomo t. adesina clinical and basic research | e43 conclusion both misoprostol and mva had high rates of satisfac tion and complete uterine evacuation, which could ulti mately reduce maternal death from abortion. however, mva had a significantly higher complete evacuation rate than misoprostol. misoprostol is cheap, readily available and does not require any surgical equipment or expertise. therefore, healthcare providers should be encouraged to prescribe misoprostol for treatment of first trimester incomplete miscarriage as a form of task-shifting in limited resource countries and to improve the availability and accessibility of pac services. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. american college of obstetricians and gynecologist. acog committee opinion no. 427: misoprostol for postabortion care. obstet gynecol 2009; 113:465–8. https://doi.org/10.1097/aog.0b 013e31819930f9. 2. say l, chou d, gemmill a, tunçalp ö, moller ab, daniels j, et al. global causes of maternal death: a who systematic analysis. lancet glob health 2014; 2:e323–33. https://doi.org/10.1016/ s2214-109x(14)70227-x. 3. adefuye po, sule-odu ao, olatunji ao, lamina ma, oladapo ot. maternal deaths from induced abortions. trop j obstet gynaecol 2003; 20:101–4. https://doi.org/10.4314/tjog.v20i2.14410. 4. world health organization. safe abortion: technical and policy guidance for health systems. from: apps.who.int/iris/bitstream/ handle/10665/70914/9789241548434_eng.pdf?sequence=1 accessed: nov 2018. 5. etuk sj, ebong if, okonofua fe. knowledge, attitude and practice of private medical practitioners in calabar towards post-abortion care. afr j reprod health 2003; 7:55–64. https://doi.org/10.2307/ 3583289. 6. blum j, winikoff b, gemzell-danielsson k, ho pc, schiavon r, weeks a. treatment of incomplete abortion and miscarriage with misoprostol. int j gynecol obstet 2007; 99:s186– 9. https://doi.org/10. 1016/j.ijgo.2007.09.009. 7. ambusaidi q, zutshi a. effectiveness of misoprostol for induction of first-trimester miscarriages: experience at a single tertiary care centre in oman. sultan qaboos univ med j 2015; 15:e534–8. https://doi.org/10.18295/squmj.2015.15.04.016. 8. dabash r, ramadan mc, darwish e, hassanein n, blum j, winikoff b. a randomized controlled trail of 400-μg sublingual misoprostol versus manual vacuum aspiration for the treatment of incomplete abortion in two egyptian hospitals. int j gynaecol obstet 2010; 111:131–5. https://doi.org/10.1016/j.ijgo.2010.06.021. 9. taylor j, diop a, blum j, dolo o, winikoff b. oral misoprostol as an alternative to surgical management for incomplete abortion in ghana. int j gynaecol obstet 2011; 112:40–4. https://doi.org/10. 1016/j.ijgo.2010.08.022. 10. shwekerela b, kalumuna r, kipingili r, mashaka n, westheimer e, clark w, et al. misoprostol for treatment of incomplete abortion at the regional hospital level: results from tanzania. bjog 2007; 114:1363–7. https://doi.org/10.1111/j.1471-0528.2007.01469.x. 11. dao b, blum j, thieba b, raghavan s, ouedraego m, lankoande j, et al. is misoprostol a safe, effective and acceptable alternative to manual vacuum aspiration for postabortion care? results from a randomised trial in burkina faso, west africa. bjog 2007; 114:1368–75. https://doi.org/10.1111/j.1471-0528.2007.01468.x. 12. niinimäki m, jouppila p, martikainen h, talvensaari-mattila a. a randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage. fertil steril 2006; 86:367–72. https://doi.org/10.1016/j.fertnstert.2005.12.072. 13. weeks a, alia g, blum j, winikoff b, ekwaru p, durocher j, et al. a randomized trial of misoprostol compared with manual vacuum aspiration for incomplete abortion. obstetgynecol 2005; 106:540–7. https://doi.org/10.1097/01.aog.0000173799.82687.dc. 14. fawole ao, diop a, adeyanju ao, aremu ot, winikoff b. miso prostol as first-line treatment for incomplete abortion at a secondary-level health facility in nigeria. int j gynaecol obstet 2012; 119:170–3. https://doi.org/10.1016/j.ijgo.2012.06.012. 15. stat trek. random number generator. from: www.stattrek.com/ statistics/random-number-generator.aspx accessed: nov 2018. 16. montesinos r, durocher j, león w, arellano m, peña m, pinto e, et al. oral misoprostol for the management of incomplete abortion in ecuador. int j gynaecol obstet 2011; 115:135–9. https://doi. org/10.1016/j.ijgo.2011.06.015. 17. diop a, raghavan s, rakotovao jp, comendant r, blumenthal pd, winikoff b. two routes of administration for misoprostol in the treatment of incomplete abortion: a randomized clinical trial. contraception 2009; 79:456–62. https://doi.org/10.1016/j.contra ception.2008.11.016. 18. shochet t, diop a, gaye a, nayama m, sall ab, bukola f, et al. sublingual misoprostol versus standard surgical care for treatment of incomplete abortion in five sub-saharan african countries. bmc pregnancy childbirth 2012; 12:127. https://doi.org/10.11 86/1471-2393-12-127. 19. kim c, barnard s, neilson jp, hickey m, vazquez jc, dou l. medical treatments for incomplete miscarriage. cochrane data base syst rev 2017; 1:cd007223. https://doi.org/10.1002/146 51858.cd007223. 20. blandine t, ouattara az, coral a, hassane c, clotaire h, dao b, et al. sublingual [corrected] misoprostol as first-line care for incomplete abortion in burkina faso. int j gynaecol obstet 2012; 119:166–9. https://doi.org/10.1016/j.ijgo.2012.05.036. 21. dipi rm, amin ms, islam mn, khan na, chaiti mm, hossain mm. comparison of transabdominal and transvaginal sonography in the evaluation of uterine mass with histological correlation. mymensingh med j 2013; 22:69–74. 22. elati a, weeks a. risk of fever after misoprostol for the prev ention of postpartum hemorrhage: a meta-analysis. obstet gynecol 2012; 120:1140–8. 23. bique c, ustá m, debora b, chong e, westheimer e, winikoff b. comparison of misoprostol and manual vacuum aspiration for the treatment of incomplete abortion. int j gynaecol obstet 2007; 98:222–6. https://doi.org/10.1016/j.ijgo.2007.05.003. https://doi.org/10.1097/aog.0b013e31819930f9 https://doi.org/10.1097/aog.0b013e31819930f9 https://doi.org/10.1016/s2214-109x%2814%2970227-x https://doi.org/10.1016/s2214-109x%2814%2970227-x https://doi.org/10.4314/tjog.v20i2.14410 https://doi.org/10.2307/3583289 https://doi.org/10.2307/3583289 https://doi.org/10.2307/3583289 https://doi.org/10.2307/3583289 https://doi.org/10.18295/squmj.2015.15.04.016 https://doi.org/10.1016/j.ijgo.2010.06.021 https://doi.org/10.1016/j.ijgo.2010.08.022 https://doi.org/10.1016/j.ijgo.2010.08.022 https://doi.org/10.1111/j.1471-0528.2007.01469.x https://doi.org/10.1111/j.1471-0528.2007.01468.x https://doi.org/10.1016/j.fertnstert.2005.12.072 https://doi.org/10.1097/01.aog.0000173799.82687.dc https://doi.org/10.1016/j.ijgo.2012.06.012 https://doi.org/10.1016/j.ijgo.2011.06.015 https://doi.org/10.1016/j.ijgo.2011.06.015 https://doi.org/10.1016/j.contraception.2008.11.016 https://doi.org/10.1016/j.contraception.2008.11.016 https://doi.org/10.1186/1471-2393-12-127 https://doi.org/10.1186/1471-2393-12-127 https://doi.org/10.1002/14651858.cd007223 https://doi.org/10.1002/14651858.cd007223 https://doi.org/10.1016/j.ijgo.2012.05.036 https://doi.org/10.1016/j.ijgo.2007.05.003 املؤمتر الدويل الثاين للتمريض تطوير مستقبل التمريض التكنولوجيا واالبتكار والتعاون جامعة ال�شلطان قابو�ص، م�شقط، 4-6 فرباير 2018 2nd international nursing conference transforming nursing future technology, innovation and collaboration sultan qaboos university, muscat, oman, 4–6 february 2018 online conference abstracts oral presentations professionalism through reflection: a mixed-methods study *jayasree radhamaniamma,1 jogindravati gupta,2 pity koul3 1salalah nursing institute, salalah, oman; 2sri guru harkrishan sahib school of nursing, mohali, punjab, india; 3department of nursing, school of health sciences, indira gandhi national open university, new delhi, india. *corresponding author’s e-mail: jayasreebibi@gmail.com objectives: reflective practice can help nursing students to become professional nurses. this study was conducted to understand the formation of professional identity through reflective practice from the point of view of bachelor of science in nursing (bsn) students at a nursing college in kerala, india. methods: a mixed-methods sequential explanatory design was used. in the quantitative phase, the experimental group were taught about reflective practice and maintained weekly reflective journals for 14 weeks. clinical performance was then evaluated for both the experimental and control groups. in the second phase, focus group interviews were conducted to gain insight into the students’ experiences. results: there was significant improvement in the performance of selected clinical competencies in the experimental group (p <0.05). this was supported by the focus group interviews and themes generated during content analysis. conclusion: reflective practice can be implemented to help bsn students to develop their identities as professional nurses. students’ perception of the educational environment in saudi arabia maxie martis,1 hanm a. a. oommen,1 talal t. al-shalwi,2 *mesheil b. m. al-alyani,2 shreemathi s. mayya3 1college of nursing and 2department of emergency medical services, college of applied medical sciences, king khalid university, khamis mushayt, saudi arabia; 3department of biostatistics, manipal university, manipal, karnataka, india. *corresponding author’s e-mail: alalyani@gmail.com objectives: the educational environment influences learning and the behaviour of learners and is a manifestation of the curriculum. the provision and assessment of a quality learning environment is one of the responsibilities of an educational institution and may form part of their continuous quality improvement initiatives. methods: this cross-sectional descriptive study was undertaken in the assir region of saudi arabia. a total of 384 students in medical, nursing, dental and allied health sciences undergraduate programmes were recruited using stratified random sampling. their perceptions of the educational environment were assessed using the dundee ready education environment measure. results: the mean scores of the participants were analysed, with additional data collection in progress. conclusion: this presentation highlights learners’ perceptions of the educational environment within saudi arabia in light of similar studies. such data may provide useful information on the strengths and limitations of the current educational atmosphere in saudi arabia. development and validation of an emotional reaction scale for stroke survivors *asha sasikumar,1 thomas iype,2 g. mini1 departments of 1medical surgical nursing and 2neurology, government medical college, thiruvananthapuram, kerala, india. *corresponding author’s e-mail: ashask2003@yahoo.com objectives: this study aimed to develop and validate a new emotional reaction scale for stroke survivors using a mixed-methods approach. methods: in-depth interviews with stroke survivors, nurses, spouses and doctors and focus group discussions with three caregiver groups were conducted to identify the emotional outcome domains. the items were reviewed by experts and the 30-item tool was tested on a sample of 75 participants. content validity, convergent validity with the hospital anxiety and depression scale and construct validity using factor analysis were then examined. results: the identified domains were anger, hostility, paranoia, inferiority, anxiety and depression. the total number of items was reduced to 15 after review. cronbach’s α values for test-retest reliability, interobserver reliability and internal consistency were >0.80. a principal component analysis yielded a factor loading of >0.35 and a total variance of >60%. the tool demonstrated satisfactory convergent validity (p <0.001). conclusion: the final tool had 12 items. mothers’ satisfaction with postpartum care based on the bruce model at urban health centres in mashhad, iran somayyeh o. ghadikolaee1 and *khadigeh mirzaiinajmabai2 departments of 1reproductive health and 2midwifery, faculty of nursing & midwifery, mashhad university of medical sciences, mashhad, razavi khorasan province, iran. *corresponding author’s e-mail: mirzaiikh@mums.ac.ir objectives: this study aimed to investigate mothers’ satisfaction with postpartum care at urban health centres in mashhad, iran, in 2013. methods: a total of 500 individuals who were receiving postpartum care for the second or third time at 19 health centres in mashhad were recruited using a multistage sampling technique. a questionnaire to assess their satisfaction with postpartum care was sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e414–424, epub. 19 dec 18 doi: 10.18295/squmj.2018.18.03.031 online conference abstracts | e415 sultan qaboos university, muscat, oman, 4–6 february 2018 developed based on the bruce model. results: the mean satisfaction score was 198/60 ± 27/43, indicating that the participants were very or fairly satisfied with their postpartum care. the highest satisfaction scores were noted in the aspects of education and counselling and the lowest was in the aspect of follow-up care. there was a significant relationship between demographic variables and satisfaction scores (p <0.05). conclusion: investigating maternal satisfaction with postpartum care is an important step towards improving the overall quality of healthcare services. effectiveness of the “predict, explain, observe, explain” model in academic achievement and the development of creative thinking skills among general nursing diploma students in oman jamal m. al-manasrah oman specialized nursing institute, muscat, oman. e-mail: jamal195@yahoo.com objectives: this study aimed to investigate the effectiveness of the “predict, explain, observe, explain” (peoe) model in terms of academic achievement and the development of creative thinking skills among general nursing diploma students. methods: the study involved a pre-post design and two classes of second-year students (n = 45) at the oman nursing institute, muscat, oman. each class was randomly assigned to either the experimental group in which students were taught according to the peoe model (n = 22) or the control group in which students were taught using traditional methods (n = 23). outcomes were measured using the academic achievement test and the verbal torrance test of creative thinking form a. results: there was a significant difference in academic achievement and creative thinking skills between the two groups, in favour of the experimental group (p = 0.05). conclusion: use of the peoe model is recommended when teaching different nursing courses. home-delivered education in cancer pain management *irene b. kizza and joshua k. muliira department of adult health & critical care, college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: irene.kizza@squ.edu.om objectives: this study aimed to determine the influence of home-delivered education on the pain management knowledge and selfefficacy of family caregivers (fcgs) of adult cancer patients (acps) in uganda. methods: a one-group pre-post-test design was used. the study included 54 fcgs with low knowledge and self-efficacy who had provided pain management assistance to acps for at least one month. an at-home intervention was delivered, consisting of two 45–60 minute one-on-one educational sessions using a booklet, as well as follow-up visits by peer-support volunteers at 4, 8 and 12 weeks. knowledge and self-efficacy were measured using the family pain questionnaire and caregiver pain management self-efficacy scale, respectively. results: the preand post-intervention mean scores yielded significant differences in knowledge and self-efficacy scores (p <0.001 each). conclusion: the home-based educational and peer support intervention significantly increased the fcgs’ knowledge and self-efficacy regarding acp pain management. impact of an innovative versus traditional approach to teaching paediatric clinical practica to male nursing students at the oman nursing institute: randomised controlled study salem al-touby,1 samia s. al-sabari,1 *omar al-omar,1 jocelyn p. gensoli,1 mohammed shamnad,1 vanaja muniswamy,2 s. sunil,1 percy e. monteiro3 1oman nursing institute, muscat, oman; 2institute of health sciences, muscat, oman; 3ministry of health, muscat, oman. *corresponding author’s e-mail: omaralomari3@gmail.com objectives: this study aimed to assess the impact of an innovative approach to teaching a paediatric nursing clinical practicum. methods: available third-year male general diploma nursing students (n = 19) were randomly assigned to either the control group (n = 10) or experimental group (n = 9). students in the experimental group underwent their practicum in innovative care settings (i.e. health centres, schools, emergency/outpatient departments, paediatric intensive care units, etc.), while those in the control group had theirs in traditional settings (i.e. general paediatric wards). each student then completed a validated semi-structured questionnaire. results: the control group less frequently reported providing care confidently in the general wards (33% versus 56%). furthermore, 89% of students in the experimental group agreed that innovative paediatric settings increased their confidence as future paediatric nurses. conclusion: partnerships with healthcare teams and community members may provide opportunities for male nursing students to undergo more innovative childcare practica. development and validation of a cross-cultural adjustment tool for overseas filipino nurses in the middle east mara g. d. ruiz sur nursing institute, sur, oman. e-mail: maragerbabeoman@gmail.com objectives: this study aimed to develop a tool to measure the cross-cultural adjustment of overseas filipino nurses based in the middle east. methods: this sequential exploratory mixed-methods study collected qualitative data first, followed by quantitative data. using colaizzi’s descriptive phenomenology method, three themes were identified: the preparation process, coping strategies and the changes and challenges faced by overseas filipino nurses. subsequently, the instrument was developed in four phases: item generation and scale construction; validity testing; piloting; and evaluation of psychometric properties. results: a 68-item tool was developed. the scalelevel content-validity index was 0.88 and the cronbach’s α value was 0.936. an exploratory factor analysis using the varimax rotation method set at 0.30 with kaiser normalisation resulted in a three-factor structure: (1) cross-cultural sensitivity and encounters, (2) crosscultural knowledge and (3) support and cross-cultural challenges. conclusion: cross-cultural adjustment can be reliably measured using the developed tool. e416 | squ medical journal, august 2018, volume 18, issue 3 2nd international nursing conference transforming nursing future technology, innovation and collaboration the effectiveness of an innovative teaching method on family health assessment among bachelor nursing students in selected nursing colleges srinivasan gandhi tripurasundari college of nursing, agartala, tripura, india. e-mail: srinivasangandhi@yahoo.com objectives: alternative/innovative teaching methods such as computer-aided instruction, problem-based learning and programmed instruction allow students to grow through their experiences. this study aimed to evaluate the effectiveness of an innovative teaching method among bachelor of science students in selected nursing colleges. methods: a quasi-experimental nonequivalent experimental and control group design was used. the sample consisted of 193 second-year nursing students selected by purposive sampling. a questionnaire was used to collect the data. the experimental and control groups were taught using team-based learning and lecture methods, respectively. results: according to the pre-test results, 7.3% of the experimental group had poor knowledge compared to 10.3% of the control group. the post-test mean knowledge scores of the experimental and control groups increased from 57.6% to 62.8% and 58% to 59%, respectively. the mean difference between the groups was statistically significant (t = 3.988; p <0.001). conclusion: team-based learning is an effective method of teaching family health assessment. the effect of an educational intervention on self-efficacy and adherence to healthy behaviours among women with gestational diabetes iman al-hashmi department of maternal & child health, college of nursing, sultan qaboos university, muscat, oman. e-mail: eiman@squ.edu.om objectives: this study aimed to evaluate the effect of an educational intervention on self-efficacy and adherence to healthy behaviours among women with gestational diabetes mellitus (gdm). methods: this study involved a two-group pre-post comparative experimental design. a random sampling technique was used to recruit 90 participants who were randomised to a control or intervention group. the control group (n = 45) received standard prenatal care while the intervention group (n = 45) received an additional health education session and biweekly text messages for four weeks. different strategies were used to encourage women to maintain recommended healthy behaviours. results: there was a significant improvement in the post-test self-efficacy scores of the intervention group compared to the control group (t(88) = -2.99; p <0.001). however, improved self-efficacy was not a significant predictor for improved adherence to healthy behaviours (b = 0.01; se = 0.01; p = 0.08). conclusion: the intervention significantly improved self-efficacy scores among women with gdm. reflective journaling: an innovative strategy beyond clinical learning divya k. yesodharan department of community & mental health, college of nursing, sultan qaboos university, muscat, oman. e-mail: divyaky@squ.edu.om objectives: reflective journaling is a strategy which can be used by the students to voice their views on a day-to-day basis during their clinical placement. this study aimed to explore the perceptions of nursing students on reflective journaling as a strategy beyond clinical learning. methods: a pilot study using a descriptive survey approach was conducted among 40 mental health nursing students at a nursing college in india. the unstructured written feedback of the students at the end of their clinical experience was then used to explore their perceptions of reflective journaling. results: on the whole, the students perceived that reflective journals enhanced their personal, professional and clinical learning. conclusion: the results of this study reinforce the notion that journalling is an effective method of teaching and learning in nursing education. predictive modelling of risk factors for clinical deterioration among adult inpatients in acute care settings in oman *g. al-hasani,1 khaled al-omari,2 huda al-noumani2 2department of adult health & critical care, 1college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: s40736@student.squ.edu.om objectives: the identification of factors which contribute to patient risk during hospitalisation can help in the prevention of clinical deterioration. this study aimed to identify risk factors associated with clinical deterioration and build a predictive model. methods: this retrospective case-control study analysed 1,000 adult patients managed by critical care outreach teams (ccots) at two tertiary hospitals between february 2016 and february 2017. a similar number of adult patients admitted during the same period who did not require ccot management constituted the control group. descriptive, univariable and multivariable regression analyses were conducted to identify predictors for ccot management. results: approximately 49% of cases necessitating ccot management could be predicted by a combination of variables; of these, gender, admitting diagnosis, access to healthcare and modified early warning score (mews) were significant predictors (p ≤0.006 each). conclusion: gender, admitting diagnosis, access to healthcare and mews are significant predictors for ccot management and clinical deterioration during hospitalisation. physicians’ and nurses’ awareness and perception of patients’ rights within ministry of health institutions in oman *a. n. al-saadi,1 s. b. a. slimane,2 r. a. al-shibli,3 f. y. al-jabri4 1directorate of planning & studies, al buraimi hospital, buraimi, oman; 2directorate of nursing affairs, ministry of health, muscat, oman; 3department of nursing, sohar hospital, sohar, oman; 4department of nursing, al-nahdha hospital, muscat, oman. *corresponding author’s e-mail: challenger.777@hotmail.com objectives: in oman, healthcare is considered a fundamental right and is delivered free-of-charge to the local population. this study aimed to determine awareness of and adherence to patients’ rights among physicians and nurses. methods: a cross-sectional survey was conducted using a self-reported questionnaire. nurses (n = 685) and physicians (n = 528) working at 23 ministry of health institutions were recruited by proportional stratified random sampling. results: the majority (87%) were aware of the importance of patients’ rights; however, there was low adherence (63.81%) in actual practice. nationality (p = 0.0021), role (p = 0.0244) and institutional level (p = 0.0338) were significantly associated with awareness of and adherence to patients’ rights. conclusion: awareness of the importance of patients’ rights is high among nurses and physicians in oman; however, greater adherence to these rights should be promoted. nonomani staff more often perceived and adhered to patients’ rights in comparison to omani staff. online conference abstracts | e417 sultan qaboos university, muscat, oman, 4–6 february 2018 a cross-country comparative study on evidence-based practice competence among student nurses *leodoro j. labrague,1 denise mcenroe-petitte,2 melba s. d’souza,3 olaide b. edet,4 latha venkatesan,5 helen s. j. cecily,6 julia e. ibebuike,7 joseph u. al-mazan,6 majid al-amri,6 dennis c. fronda,1 arcalyd r. cayaban,1 ephraim c. mirafuentes,3 asma al-yahyaei1 departments of 1fundamentals & administration and 3adult health & critical care, college of nursing, sultan qaboos university, muscat, oman; 2department of nursing, kent state university, kent, ohio, usa; 4department of nursing science, university of calabar, calabar, nigeria; 5apollo college of nursing, chennai, tamil nadu, india; 6department of nursing, college of applied medical sciences, majmaah university, al-majma’ah, saudi arabia; 7department of nursing science, faculty of health sciences, imo state university, owerri, nigeria. *corresponding author’s e-mail: leodoroj@squ.edu.om objectives: this study aimed to compare evidence-based practice (ebp) competence among student nurses in four countries to examine barriers to ebp implementation. methods: a descriptive cross-sectional comparative design was used. convenience samples (n = 1,383) were recruited from india, saudi arabia, nigeria and oman. data were collected using the evidence-based practice competence questionnaire (ebp-coq) and the barriers scale between january 2016 and august 2017. results: nursing students from all four countries reported moderate-to-high ebp competence; however, significant differences were noted between countries in terms of mean ebp-coq subscale scores (i.e. knowledge, skills and attitudes). identified barriers to ebp implementation included: having no authority to change patient care policies; delayed publication of evidence; and lack of time in clinical settings to implement evidence. conclusion: these findings emphasise the need for multifaceted and culturally-tailored approaches to teaching ebp to nursing students in order to enhance ebp competence and, ultimately, patient care. impact of an innovative and collaborative structured teaching programme for cardiac patients on knowledge of lifestyle modifications to maintain a healthy heart: a quasi-experimental study at the royal hospital, muscat, oman *vanaja muniswamy1 and tahira al-zedjali2 1oman nursing institute, muscat, oman; 2department of nursing, royal hospital, muscat, oman. *corresponding author’s e-mail: mvanaja306@gmail.com objectives: cardiovascular diseases (cvds) account for 33% of all noncommunicable diseases in oman. this study aimed to compare preand post-test knowledge scores regarding lifestyle modifications (lsms) for maintaining a healthy heart among cardiac patients following the administration of a structured teaching programme (stp). methods: a total of 70 patients from an intermediate cardiac care unit were selected by non-probability purposive sampling. the patients participated in a structured interview and took part in an interactive individualised stp. results: prior to the stp, the majority of participants lacked high levels of knowledge pertaining to lsms. the mean preand post-test knowledge scores were 50.5% and 76.5%, respectively, with an increase of 26.1%. this difference was statistically significant (t = 18.65; p <0.05). conclusion: an stp implemented by advanced practice nurses can aid in the prevention of modifiable risk factors of cvd progression. effect of cognitive behavioural therapy on diet adherence among individuals undergoing haemodialysis *blessy p. valsaraj1 and shripathy m. bhat2 1department of community & mental health, college of nursing, sultan qaboos university, muscat, oman; 2department of psychiatry, manipal university, manipal, india. *corresponding author’s e-mail: blessy.v@squ.edu.om objectives: chronic renal failure patients often display poor adherence to dietary regimens, thus leading to increased mortality. this study aimed to determine the effect of cognitive behavioural therapy (cbt) on diet adherence among haemodialysis patients. methods: this randomised controlled trial involved 33 patients in the experimental group and 34 patients in the control group. all participants were selected via computerised block randomisation from a tertiary care hospital in south karnataka, india. a diet adherence scale and dietary guide were developed in collaboration with nephrologists, dialysis technicians and dietetics and nutrition experts. each member of the experimental and control groups underwent 10 sessions of either cbt or non-directed counselling, respectively. results: diet adherence as a result of cbt in the experimental group (from 138.45 at baseline to 198.82 at three months and 199.64 at six months) was greater than that of the control group (f = 1.464; p =0.001). conclusion: cbt seems to be a cost-effective intervention in promoting diet adherence among individuals undergoing haemodialysis. nursing quality clinical rounds: the road towards continuous quality improvement parvathi mudaliar, *huda al-awaisi, shinoona al-harthi department of nursing, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: hudas@squ.edu.om objectives: this study aimed to explore the effectiveness of nursing quality clinical rounds by comparing the rate of compliance with quality standards between 2016 and 2017. methods: a prospective comparative study was conducted in inpatient areas at sultan qaboos university hospital (squh), muscat, oman. an objective tool was developed based on the required organisational practices of accreditation canada international and squh policies. the tool consisted of 10 key clinical and administrative areas. data were collected during visits to different squh units by two senior nurses. a total of 21 inpatient wards/units were involved in the study. results: there was significant improvement in certain indicators, including adherence to the call bell and patient fall and pressure ulcer prevention standards. conclusion: these findings indicate that implementing nursing quality clinical rounds improves staff compliance to quality standards. such initiatives can be adopted by clinical nursing staff to take ownership in improving compliance to such standards. work-related stress and psychosomatic complaints among omani nurses a. m. al-mayahi1 and *cherry a. ballad2 2school of nursing, 1college of pharmacy & nursing, university of nizwa, nizwa, oman. *corresponding author’s e-mail: cherryann@unizwa.edu.om objectives: stress contributes to health problems among nurses and decreases efficiency. this study aimed to examine work-related stress and psychosomatic complaints among omani nurses. methods: a descriptive correlational design and non-proportionate quota sampling was used to recruit 100 omani nurses from rustaq hospital, rustaq, oman. data were collected using a self-administered e418 | squ medical journal, august 2018, volume 18, issue 3 2nd international nursing conference transforming nursing future technology, innovation and collaboration questionnaire adapted from the nursing stress scale. results: most respondents were female (73%), 26–30 years old (38%), diploma holders (72%) and had 5–10 years’ nursing experience (42%). respondents reported moderate stress levels (mean score: 2.98). nurses who were ≤25 years, female, diploma holders, had <5 years’ work experience and who were working in intensive/special care units had higher stress levels. the most common psychosomatic complaints were headaches (83%), back/spine pain (81%), fatigue (69%), tiredness (62%) and difficulty sleeping (61%). conclusion: healthcare institutions should encourage therapeutic communication, professional mentoring and supportive work environments to help nurses cope with work-related stress. emergency triage nurse-led application of the ottawa ankle rules: effect on pain and satisfaction with emergency care at selected hospitals in oman *f. al-abri,1 joshua k. muliira,2 huda al-awaisi3 2department of adult health & critical care, 1college of nursing, sultan qaboos university; 3department of nursing, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: s70236@student.squ.edu.om objectives: this study aimed to examine the effectiveness of the application of the ottawa ankle rules by emergency triage nurses in improving pain upon discharge and satisfaction with care among ankle injury patients. methods: a quasi-experimental design was used to collect data from 96 adult patients presenting to the emergency department with acute ankle injury. the intervention group (n = 46) received nurse-led triage assessment and radiographical tests as per the ottawa ankle rules while the nonequivalent control group (n = 50) received usual care. results: there was no significant difference in pain upon discharge (t = 1.74; p = 0.86) between the control and intervention groups. however, there was a significant difference in terms of satisfaction with care (t = 5.60; p <0.01). conclusion: implementing the ottawa ankle rules had no effect on pain but significantly increased satisfaction with emergency care among ankle injury patients. patients’ and nurses’ perceptions of post-coronary artery bypass graft learning needs in two cardiac centres in oman *a. al-maskari1 and huda al-noumani2 2department of adult health & critical care, 1college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: s53199@student.squ.edu.om objectives: in oman, education regarding self-care after a coronary artery bypass graft (cabg) may be given to the patient by nurses. this study aimed to examine differences between patients’ and nurses’ perceptions of the learning needs of post-cabg patients. methods: a cross-sectional descriptive design was used. a sample of nurses and patients with cabg (n = 180) were recruited from two tertiary hospitals in muscat, oman. data were collected using the cardiac patients learning needs inventory questionnaire. results: patients reported needing more education regarding the cardiac unit, chest and leg wound care and complications (mean scores: 14.7 ± 1.72, 14.7 ± 1.72 and 14.4 ± 1.3, respectively). nurses perceived that information related to chest and leg wound care, the cardiac unit and complications (mean scores: 14.6 ± 0.96, 14.3 ± 1.17 and 14.3 ± 1.36, respectively) were the most important learning needs. conclusion: this study emphasises the significance of assessing post-cabg patients’ learning needs and the role of nurses in fulfilling these learning needs prior to discharge. compliance with integrated management of childhood illness standards: a comparative study fannah a. al-araimi ministry of health, muscat, oman. e-mail: falfannah@gmail.com objectives: this study aimed to compare compliance with the world health organization’s integrated management of childhood illness (imci) standards at health centres in two regions of oman. methods: a cross-sectional comparative design was used and data were collected from five health centres. caregiver compliance with imci standards was assessed in terms of medical professionals’ advice, the correct prescription of oral antibiotics and cough syrup in non-emergency cases, standard health practices and the availability of essential medical supplies at the healthcare centres. results: the number of follow-up visits were reduced by 15% at imci-compliant healthcare centres. furthermore, there was a 20% reduction in the unnecessary prescription of both oral antibiotics and cough syrup at imci-compliant healthcare centres. finally, there was a 90% improvement in standard healthcare practices at imci-compliant health centres. conclusion: the imci-compliant healthcare centres demonstrated superior healthcare practices compared to non-imcicompliant centres. simulation to improve caregivers’ home safety practices *g. renu1 and anice george2 2department of child health nursing, 1manipal college of nursing, manipal university, manipal, india. *corresponding author’s e-mail: renugeethalayam@gmail.com objectives: paediatric injuries are among the least recognised public health issues in the world. this study aimed to evaluate the effectiveness of simulation in improving caregivers’ home safety practices. methods: the study took place in 30 out of 108 villages in an indian taluk district, of which 15 villages constituted the experimental group and 15 the control group. a sample of 300 caregivers from these villages were randomly selected. face validity was taken into account and the simulation environment was finalised for use in the study. interventions were conducted in each village separately. home safety practices were assessed using a home safety practice scale. results: there was a statistically significant difference in observed home safety practices for falls (f(3,447) = 262.24; p = 0.001; ηp2 = 0.638). conclusion: the results proved that simulation is an effective intervention in improving caregivers’ home safety practices and reducing paediatric injuries. online conference abstracts | e419 sultan qaboos university, muscat, oman, 4–6 february 2018 outcomes of simulation among novice nursing students *suja karkada,1 jayanthi radhakrishnan,1 jansi natarajan,1 gerald a. matua,1 sujatha shanmugasundaram2 1department of fundamentals & administration, college of nursing, sultan qaboos university, muscat, oman; 2school of nursing, fresno state university, fresno, california, usa. *corresponding author’s e-mail: karkada@squ.edu.om objectives: simulation provides a positive learning environment and guarantees patient safety during clinical teaching. this study was conducted to evaluate students’ satisfaction and self-confidence after simulation and to assess the effect of an intervention on their competency with nasogastric tube feeding. methods: this quasi-experimental study included a sample of 69 students, of which 35 received an intervention with simulation and 34 constituted the control group and were taught using case scenarios. results: there was a positive statistically significance difference in the satisfaction and self-confidence scores of students in the intervention group (p = 0.002). however, there was a significant improvement in the mean competency scores of both groups, indicating that both simulation and teaching using case scenarios were effective in improving student competency with nasogastric tube feeding (p = 0.001). conclusion: these findings support the use of both simulation and case scenario teaching techniques to improve competency among novice students. factors associated with nurse absenteeism in al-dakhiliyah governorate, oman: a cross-sectional study z. r. al-abri,1 ibrahim s. al-busaidi,2 k. a. al-rawahi,3 mohammed s. al-tobi,4 m. r. platel,5 *jonas u. dupo,6 m. al-yaroubi7 1department of school & university health, directorate of primary health care and 4directorate of nursing affairs, ministry of health, al-dakhiliyah governorate, oman; 2department of general medicine, christchurch hospital, christchurch, new zealand; 3samail hospital, samail, oman; 5northern navajo medical center, shiprock, new mexico, usa; 6department of nursing, nizwa polyclinic, nizwa, oman; 7regional research committee, al-dakhiliyah governorate, oman.*corresponding author’s e-mail: dupojonasdg@gmail.com objectives: the incidence of absenteeism in al-dakhiliyah governorate, oman, has gradually increased in recent years. this study aimed to examine factors associated with absenteeism among nurses in al-dakhiliyah governorate. methods: a descriptive crosssectional design was employed. a stratified random sampling technique was used to recruit omani and non-omani nurses working night duty in six hospitals and two primary care centres. all participants were invited to complete a survey. results: a total of 248 nurses completed the questionnaire; of these, most were omani (61.1%), female (86.6%), married (86.6%) and holders of a nursing diploma (69.4%). perceived factors leading to absenteeism included a lack of family support, personal health problems, family emergencies and unforeseen circumstances. enjoying nursing as a profession, institutional support/motivation and appreciation of nurses by patients were reported as factors that could reduce absenteeism. conclusion: these findings can be utilised to modify existing policies pertaining to absenteeism and develop new strategies to prevent nurse absenteeism. job satisfaction among staff nurses in the eastern province of saudi arabia jessica colquhoun department of nursing administration, king fahad specialist hospital, dammam, saudi arabia. e-mail: jessica.colquhoun@kfsh.med.sa objectives: this study aimed to identify factors related to job satisfaction among nurses at an acute care hospital in eastern saudi arabia. methods: a descriptive design was used to determine job satisfaction among saudi-trained and foreign-trained nurses. results: the relationship between job satisfaction and balancing family and work interaction opportunities and professional opportunities was significant. a factor analysis also revealed that motivation, professional development, leadership style and interpersonal relations were important to nurses. saudi nurses raised an important concern unique to the nature of work in saudi arabia as an area for improvement. conclusion: studying such factors will help identify areas for improvement so as to meet future nurses’ satisfaction goals. prevalence of delayed umbilical cord clamping practices *girija madhavanprabhakaran,1 lani a. wittmann,2 vaidyanathan gowri,3 tamima al-dughaishi,4 deepa thomas1 1department of maternal & child health, college of nursing and 3department of obstetrics & gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2women's health research institute, b.c. women’s hospital & health centre, vancouver, british columbia, canada; 4department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: girija@squ.edu.om objectives: this study aimed to explore the umbilical cord clamping practices of maternity care providers in oman. methods: a descriptive survey was undertaken among 175 maternity care providers using questionnaires. results: the respondents reported varied cord clamping practices. most maternity care providers clamped the cord within one minute of birth (70–72.6%) and defined early cord clamping timing as ≤1 minute for both term and preterm newborns (87.4–89.6%). only 10% and 15% reported delayed cord clamping practices for normally-delivered preterm and term newborns, respectively. the most commonly reported benefits of delayed cord clamping were physiological transitioning, increased iron storage and reduced anaemia, while polycythaemia and jaundice were identified as the greatest risks. conclusion: the low prevalence of delayed cord clamping practices—as recommended by recent evidence and guidelines—necessitates further research. there is a need for clear policies at the national level to promote evidence-based practices related to cord clamping. cardiac learning needs of post-myocardial infarction patients in oman *r. al-mamari,1 eilean r. lazarus,2 joshua k. muliira2 2department of adult health & critical care, 1college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: s40475@student.squ.edu.om objectives: myocardial infarction (mi) is a common cardiovascular condition; in oman, the estimated prevalence of mi is 0.0034%. this study aimed to assess cardiac learning needs among post-mi patients in oman. methods: a descriptive cross-sectional design was used. the learning needs of 180 omani post-mi patients at the royal hospital and sultan qaboos university hospital, muscat, oman, were assessed using the arabic cardiac learning needs inventory. results: the majority had high cardiac learning needs (70%). the average total learning need score was 177.4 ± 20.1. the greatest learning needs were in the medication (81.1%), diet (78.9%), anatomy/ physiology (76.6%), risk factors (76.1%) and psychological factors (72.7%) categories. there were significant differences in physical activity learning needs according to gender (p = 0.015) and income level (p <0.001), as well as in physical activity learning needs (p <0.001) and total cardiac learning needs (p = 0.017) according to marital status. conclusion: post-mi patients have critical learning needs related to disease management and prevention. e420 | squ medical journal, august 2018, volume 18, issue 3 2nd international nursing conference transforming nursing future technology, innovation and collaboration effectiveness of implementing the emergency severity index triage system in a secondary healthcare centre in oman *a. k. al-hasni1 and omar m. al-rawajfah2 2department of adult health & critical care, 1college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: s70241@student.squ.edu.om objectives: this study aimed to assess the effectiveness of the emergency severity index (esi) triage system at a secondary healthcare centre in oman in terms of waiting time, length of stay (los), patient satisfaction and patient safety. methods: a pre-post quasiexperimental design was used. convenience samples of 187 patients before and 102 patients after implementing the esi system were included. data were collected from electronic medical records and using the brief emergency department patient satisfaction scale. results: following implementation, mean time from registration to triage (p = 0.002) and los (p = 0.65) were reduced, while patient satisfaction score increased (p = 0.64). regarding triage level decisions, inter-rater agreement showed improved accuracy (p <0.001) compared to pre-implementation (p = 0.005). conclusion: although the results from the current study are from a single setting, they demonstrate that the esi system can decrease waiting time and los and increase patient satisfaction in the emergency department. exploring nursing students’ learning outcomes from clinical experiences *jahara hayundini,1 zainab al-azri,2 arwa a. obeidat,1 asma al-yyaei1 departments of 1fundamentals & administration and 2maternal & child health, college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: hayudini@squ.edu.om objectives: clinical education forms a core component of nursing practice. however, the gap between theory and practice is a global problem. this study aimed to explore the perceptions of omani students regarding their clinical learning outcomes. methods: a convenience sample of 37 fourthand fifth-year students from sultan qaboos university, muscat, oman, volunteered to participate in the study. six focus groups of 7–8 students each were held to obtain students’ views regarding their clinical learning outcomes. subsequently, a content analysis of transcribed responses was performed with coding and categorisation as per qualitative data analysis methods. results: four major themes emerged during the focus group sessions: nursing skills, clinical time, relationships and the alignment of nursing courses in the curriculum. conclusion: this study supports a reform in clinical training so as to develop more innovative and learner-centred approaches. male nursing students’ perceptions of child health nursing practica at the oman nursing institute: a qualitative study salem al-touby,1 vanaja muniswamy,2 samia s. al-sabari,1 *omar al-omar,1 jocelyn p. gensoli,1 mohammed shamnad,1 s. sunil,1 percy e. monteiro3 1oman nursing institute, muscat, oman; 2institute of health sciences, muscat, oman; 3ministry of health, muscat, oman. corresponding author’s e-mail: omaralomari3@gmail.com objectives: clinical practica can influence students’ perceptions of the nursing profession. this study aimed to assess omani male nursing students’ perceptions of paediatric practica. methods: a descriptive phenomenological approach was undertaken to answer the following research questions: (1) what are the perceptions of male nursing students regarding providing paediatric care; (2) what are facilitating factors/barriers to paediatric nursing; and (3) what are innovative approaches that can strengthen such practica. data were gathered during focus group interviews with all third-year male nursing students (n = 19) at the oman nursing institute, muscat, oman, undergoing child health practica. results: a thematic analysis of the discussions yielded the following four themes: perceptions; sociocultural and communication barriers; facilitators of care; and strengthening clinical experience. students perceived that fear, anxiety and a lack of confidence were barriers, while the need for collaborative support with cultural adaptation was evident. conclusion: innovative approaches to strengthen clinical placements for omani male nursing students are necessary. poster presentations does student self-evaluation enhance the learning outcomes of nursing students? suthan pandarakutty department of nursing, university of buraimi, buraimi, oman. e-mail: suthan0912@gmail.com objectives: the aim of this systematic review was to assess the impact of self-evaluation on learning outcomes among nursing students. methods: a systematic literature search was conducted using the medline® database (national library of medicine, bethesda, maryland, usa). articles were initially compared in terms of title or abstract and those relevant to the subject of this review were retrieved in full-text format. a critical appraisal was performed to assess the impact of self-evaluation on learning outcomes among nursing students. results: a total of 12 articles were identified. many of these demonstrated that self-assessment contributes to mastery goal orientation, higher self-efficacy, greater intrinsic motivation, higher academic performance, improved student behaviour, increased awareness of one’s own learning and improved problem-solving skills. conclusion: student self-assessment appears to be key to reflective practice and a good predictor of learning outcomes. predictors of academic learning outcomes among diploma nursing graduates: towards programme intervention *glenn f. valdez, maryam farhan, zakiya doloolat department of nursing, salalah nursing institute, salalah, oman. *corresponding author’s e-mail: glennfordvaldez@yahoo.com objectives: this study aims to identify the degree that the learning outcomes of graduated nursing students are associated with nonacademic and academic factors as predictors. methods: a correlational prospective design was used and a sample of 161 diploma nursing graduates obtained using consecutive sampling. an analysis was undertaken of the students’ academic profile, marks and demographic characteristics. learning success was measured according to the passing marks of the students at the end of their threeyear diploma programme. results: most of the students were female and resided in rural areas. overall, the graduating class of 2015 online conference abstracts | e421 sultan qaboos university, muscat, oman, 4–6 february 2018 had the lowest success rate (38.5%). there was a correlation between overall grade point average (gpa) and age (kendall’ tau p = 0.523). second-year gpa was a significant predictor of learning success (spearman’s rho p = 0.534) among the class of 2013–2015. conclusion: these findings may aid in future nursing programme interventions. effectiveness of a hybrid problem-based learning method among nursing students at the oman nursing institute lakshmi renganathan oman nursing institute, muscat, oman. e-mail: lakshmi6911@gmail.com objectives: problem-based learning (pbl) is an increasingly popular teaching technique in nursing education and enhances critical thinking, decision-making, communication and problem-solving skills. this study aimed to determine the effectiveness of a hybrid pbl method and satisfaction among nursing students at the oman nursing institute, muscat, oman. methods: a quasi-experimental onegroup post-test design was used among second-year (n = 28) and third-year (n = 31) general nursing diploma students. a hybrid pbl method was used to teach paediatric nursing care for children with different conditions. results: there was a significant improvement in the knowledge scores of both groups. however, the performance of the second-year students was better than that of the third-year students. conclusion: pbl is an innovative and student-friendly method which can effectively improve the academic scores of nursing students. problem identification web: a novel learning strategy anitha thanka department of adult health & critical care, college of nursing, sultan qaboos university, muscat, oman. e-mail: thanka@squ.edu.om objectives: this review paper aimed to identify a meaningful learning model for novice nursing students. methods: two research databases—cumulative index of nursing and allied health® (ebsco information services, ipswich, massachusetts, usa) and sciencedirect™ (elsevier, amsterdam, the netherlands)—were searched using the following keywords: “meaningful learning”, “nursing process” and “novice nursing students”. all articles published between 2014–2017 were included in the analysis. results: a total of 12 articles were identified. the themes from these articles were used to develop a diagrammatic representation model consisting of five concentric circles, called the problem identification (pi) web. the innermost circle consists of the patient name and medical diagnosis. the second circle portrays the patient’s complaints and any abnormal physical examination findings. abnormal diagnostic characteristics are displayed in the third circle and therapeutic modalities are depicted in the fourth circle. the fifth circle shows the final diagnosis. conclusion: the pi web model may help student nurses to focus on important information to be prioritised during diagnosis. teaching the ‘net generation’: an integrative review of barriers to e-learning among nursing faculty susan achora department of adult health & critical care, college of nursing, sultan qaboos university, muscat, oman. e-mail: susana@squ.edu.om objectives: information technology (it) continues to transform the nursing education landscape, with e-learning offering opportunities for easily accessible student-centred teaching and learning. however, not all nursing faculty members embrace e-learning. this review aimed to explore barriers to implementing e-learning among nursing faculty. methods: an integrative review and narrative analysis was conducted. the medline® (national library of medicine, bethesda, maryland, usa), embase™ (elsevier, amsterdam, the netherlands), cinahl® (ebsco information services, ipswich, massachusetts, usa), psycinfo® (american psychological association, washington d.c., usa) and web of science™ (clarivate analytics, philadelphia, pennsylvania, usa) databases were searched for english-language primary research studies published between 2000–2018 focusing on e-learning and related barriers. results: a total of 10 articles were identified with three main themes: use of it; nurse educator pedagogical issues; and institutional issues. most studies utilised cross-sectional designs (i.e. weak levels of evidence). conclusion: the integration of e-learning into nursing education is hampered by a number of barriers that require intervention. simulation in psychiatric nursing: an integrative review *ghada k. al-mukhaini and r. s. falatah department of community & mental health nursing, college of nursing, king saud university, riyadh, saudi arabia. *corresponding author’s e-mail: galmukhaini@ksu.edu.sa objectives: although the use of simulation in nursing education has been proven to improve students’ self-confidence and skill acquisition, simulation remains highly underutilised in psychiatric nursing courses. this review aimed to determine the learning outcomes associated with the use of different simulation techniques in preand post-graduate psychiatric nursing courses. methods: whittemore and knafl’s integrative review method was applied. the keywords “simulation” and “psychiatric nursing” were used to search the cinahl® (ebsco information services, ipswich, massachusetts, usa), psycinfo® (american psychological association, washington d.c., usa) and medline® (national library of medicine, bethesda, maryland, usa) databases. results: a total of 25 articles were identified. the majority of the studies associated simulation with positive educational outcomes and recognised it be an effective and safe teaching method. however, most studies used convenience sampling techniques which might limit the generalisability of their results. conclusion: the benefits of simulation in psychiatric nursing education requires further investigation. development and validation of information, education and communication materials for improving awareness of teenage pregnancy magnolia m. gallardo-ninobla oman nursing institute, muscat, oman. e-mail: maggienin6969@gmail.com objectives: this study aimed to explore, develop and validate an educational video to improve awareness of and attitudes towards teenage pregnancy among high school students and their mothers in a rural community. methods: this study utilised a quasiexperimental design. a video regarding teenage pregnancy was conceptualised, designed, piloted, evaluated and validated using the e422 | squ medical journal, august 2018, volume 18, issue 3 2nd international nursing conference transforming nursing future technology, innovation and collaboration theory of planned behaviour/reasoned action. a total of 180 female students and 96 mothers were recruited and assigned to control and experimental groups. a video, scripted in tagalog, and entitled “dalawang larawan ni maria (two faces of maria)” was shown to the experimental group. results: the post-test scores of students (mean score: −0.90; t = −6.48) and mothers (mean score: −1.20; t = −6.60; p <0.01) revealed a significant difference in level of awareness between the control and experimental groups. however, there was no significant difference in attitude. conclusion: the video intervention improved awareness of teenage pregnancy among high school students and their mothers. beyond the bedside: crisis-driven nursing intervention miriam o. kanti department of community & extension services, college of nursing, western mindanao state university, zamboanga city, philippines. e-mail: miriamkanti01@yahoo.com objectives: as the largest group of healthcare providers, nurses can contribute to reducing the effects of conflict through policy, research and skill training in different phases of disaster risk reduction and mitigation. this study aimed to document the challenges faced by nurses working in areas where armed incursions may occur. methods: an interpretive phenomenology design was implemented. focus group discussions were used to explore the experiences of nurses working at conflict evacuation sites and satellite hospitals during the armed zamboanga siege in 2013. colaizzi’s analytic method was utilised to determine themes. results: the discussions focused on the nurses’ lack of preparedness to deal with violence, extremism and terrorism. conclusion: these results show a need for nurses to evolve from individual bedside patient carers to healthcare practitioners that can respond and adapt to ever-changing environments and potential disasters. barriers to and facilitators of research utilisation among nurses latha naidu, samiya al-busaidi, ali al-shukaili, *huda al-awaisi department of nursing, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: hudas@squ.edu.om objectives: this study aimed to explore nurses’ perception regarding the barriers to and facilitators of research utilisation at an academic hospital in oman. methods: data were collected via a descriptive survey using the previously validated barriers and facilitator scales. a convenience sample of 60 nurses from different units of the hospital was recruited randomly. results: most nurses (63%) reported being aware of new research and 56% were willing to change their current practices or try new ideas. however, 45% identified a lack of authority to change patient care procedures to be the main barrier to research utilisation; moreover, 46% were unsure how to identify indicators of research quality, potentially signifying a lack of knowledge of research methodology. conclusion: despite its small sample size, this study provides important information regarding nurses’ perceptions of research facilitators and barriers. kangaroo care and its effect on vital signs among low-birth-weight preterm babies: the importance of collaboration between nurses and mothers *sharon adonay, b. jiji, betty justine department of nursing, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: pedres_bamci@yahoo.com objectives: this study was conducted to evaluate the effectiveness of implementing kangaroo maternal care on the vital signs of lowbirth-weight preterm babies. methods: an interventional clinical trial was conducted in a neonatal unit using a convenience sample of 20 medically stable infants of 25–35 gestational weeks weighing <1,500 g. all mothers agreed to participate in the study and provide kangaroo care. a standardised checklist was used by nurses to record the infants’ temperatures, oxygen blood saturation and blood pressure before and after attachment. heart rate and respiratory rate were monitored continuously with neonatal electrodes. results: there was a significant decrease in the infants’ respiratory rate and increase in temperature and oxygen blood saturation following kangaroo care. conclusion: despite the cultural limitations of this study and the small sample size, the results indicate that kangaroo care results in positive outcomes. however, maternal collaboration is vital during implementation. clinical practices of nursing staff in emergency departments regarding oral and axilla body temperature measurements: an observational study *kalyani wilson, davis enriquez, joanne guevara, rasha al-hudar department of nursing, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: knreddywilson29@gmail.com objectives: this study aimed to determine the current clinical practices of staff nurses working in an emergency department (ed) in the measurement of oral and axilla body temperatures. methods: an observational study was conducted using a convenience sample of 60 ed staff nurses. a standardised tool sourced from the royal marsden hospital manual of clinical procedures was utilised to assess the nurses’ practices while checking the body temperature of stable adult patients. results: overall, 56.96% and 56.66% of nurses failed to explain the procedure to the patients when taking oral and axilla temperatures, respectively. in addition, a large number (63.33%) failed to place the probe in the proper position when taking the patient’s oral temperature. conclusion: these findings indicate that greater emphasis should be placed on standard practices for checking oral and axilla body temperature among nurses. proposal for smart phone applications for nurse interns to be ‘smart’ nurses *vidhya kaleeswaran, a. al-nasri, r. al-hakmani department of administration, directorate of nursing affairs, ministry of health, south sharqiyah governorate, oman. *corresponding author’s e-mail: vidhyasivaram@gmail.com objectives: this study will aim to develop and evaluate the effectiveness of a smart phone-based application in increasing nursing interns’ knowledge, skills and confidence when providing care. methods: a randomised trial using a pre-post-test design will be conducted among nursing interns at jalan bani bu ali hospital and sur hospital, south sharqiyah governorate, oman. a playway® smart phone-based application (playway sa, hornówek, poland) will be developed using a learning scenario/video and administered to the experimental group, while the control group will receive one-time lecture-based education. the application will focus on ministry of health mandatory training courses, including electrocardiography, intravenous therapy and basic life support. results: the online conference abstracts | e423 sultan qaboos university, muscat, oman, 4–6 february 2018 learning outcomes of the nursing interns will be evaluated. data analyses will be performed using descriptive and inferential statistics. conclusion: smart phone-based education may be an effective learning method in nursing education to enhance student interest in learning. proposal for integrating virtual reality simulation in the undergraduate nursing curriculum in oman a. al-nasri and *vidhya kaleeswaran department of administration, directorate of nursing affairs, south sharqiyah governorate, oman. *corresponding author’s e-mail: vidhyasivaram@gmail.com objectives: although different types of simulation are widely used in undergraduate nursing curricula worldwide, virtual learning models have not yet been integrated into the undergraduate nursing curriculum in oman. this study will aim to implement virtual simulation modalities in the undergraduate nursing curriculum in oman. methods: the project proposes to pilot-test virtual scenarios focusing on medication administration on nursing students at one of the ministry of health nursing institutes in oman. avatars will be created on the second life® three-dimensional virtual reality platform (linden lab inc., san francisco, california, usa) and will interact with students. in addition, students will also be able to control the avatars themselves. results: preand post-test analyses will be conducted to evaluate the effectiveness of the virtual reality scenario-based learning approach among the nursing students. conclusion: virtual reality simulation scenarios may prove to enhance students’ learning and interest in nursing theory and practical skills. quality of life, stress and coping strategies among wives of alcohol-dependent patients admitted to selected hospitals in udupi district, india tessy t. jose, *asha k. nayak, yesodharan renjulal, k. g. anjali department of psychiatric nursing, manipal academy of higher education, manipal, karnataka, india. *corresponding author’s e-mail: asha.np@manipal.edu objectives: alcoholism affects both the alcohol-dependent individual and their spouse. this study aimed to determine the quality of life (qol), stress and coping strategies of the wives of alcohol-dependent individuals. methods: a descriptive design was used to collect data from a tertiary care hospital in udupi district, india. a sample of 60 women with alcohol-dependent spouses were recruited. the coping scale and abbreviated world health organization quality of life scale were used. results: the majority of the participants reported moderate (60%) or severe (26.67%) stress. there were moderate negative correlations between stress and the physical (r = −0.524; p <0.001), psychological (r = −0.527; p <0.001), social (r = −0.460; p <0.001) and environmental (r = −0.480; p <0.001) domains of qol. conclusion: there is a need for continuous support from families, communities and healthcare professionals towards the spouses of those affected by alcohol abuse. benefits of nonpharmacological interventions during labour: a systematic review *sushmitha r. karkada,1 parvati bhat,2 shashikala k. bhat,2 anice george,3 judith a. noronha,1 baby k. nayak3 departments of 1obstetrical & gynaecological nursing and 3child health nursing, manipal college of nursing, manipal, karnataka, india; 2department of obstetrics & gynaecology, melaka manipal medical college, manipal, karnataka, india. *corresponding author’s e-mail: sushmithrk@gmail.com objectives: a variety of nonpharmacological methods are available to relieve labour pain. the aim of this systematic review was to appraise common nonpharmacological interventions during labour in reducing maternal and neonatal discomfort. methods: a search was conducted in the medline® (national library of medicine, bethesda, maryland, usa) and proquest® (proquest llc, ann arbor, michigan, usa) databases. data were extracted from full-text articles by one individual and reviewed by a second individual. a third individual was contacted whenever there was a discrepancy. results: a total of 12 relevant studies were identified, of which 11 were randomised control trials. a variety of nonpharmacological interventions were described, including prenatal yoga, progressive muscle relaxation, acupressure, massage (both perineal and lumbar), warm showers/cold therapy, foot reflexology and use of a birthing ball. conclusion: the use of nonpharmacological interventions during pregnancy or labour can help to enhance maternal wellbeing, thereby reducing maternal and neonatal complications. comparative study on training and development at two tertiary hospitals in muscat, oman yousuf al-khamisi medical engineering research centre, university of bradford, bradford, uk. e-mail: yusufsquh@gmail.com objectives: the aim of this study was to assess and compare nurses’ perceptions regarding training and development at two tertiary hospitals in muscat, oman. it also sought to identify the methods of training and development used at both hospitals and employee satisfaction. methods: a questionnaire designed to measure three dimensions, including demographic data and training and development opportunities, was utilised. the scale was tested for validity and reliability. results: a total of 185 respondents from both hospitals completed the survey. nurses in both hospitals responded positively regarding opportunities for development in general. the majority of respondents at each hospital agreed that they have opportunities to improve their knowledge-based competencies. overall, 92% of respondents from both hospitals agreed that they were equipped with adequate skills to deal with the demands of their workplace. conclusion: there was little difference in the training opportunities provided to omani and non-omani nurses. adoption of evidence-based practice in nursing education: concept analysis mohammed al-maskari department of adult health nursing, ibra nursing institute, ibra, oman. e-mail: mohammed.almaskari20@gmail.com in order to provide high-quality nursing care, many countries have adopted the use of evidence-based practice (ebp) in their healthcare systems. however, a lack of resources and essential knowledge for ebp can cause difficulties in adopting ebp in clinical practice. walker and avant’s method of concept analysis was used to help produce a consistent operational definition so that the ebp concept has e424 | squ medical journal, august 2018, volume 18, issue 3 2nd international nursing conference transforming nursing future technology, innovation and collaboration validity in the practice of nursing. this can aid in exploring what is known regarding the adoption of ebp for application in an academic context in nursing education. the attributes, antecedents, consequences and referents for ebp adoption are discussed and a definition of adoption formulated using the attributes of this concept analysis. the role of socratic questioning in improving critical thinking skills among nursing students *vijayalakshmi g. nair1 and shanthi ramasubramaniam2 1school of nursing, college of pharmacy & nursing, university of nizwa, nizwa, oman; 2independent researcher & consultant, united arab emirates. *corresponding author’s e-mail: vijiharshu_2003@yahoo.co.in nursing students and educators should understand socratic pedagogy and its role in facilitating critical and creative thinking skills and clinical reasoning. there are six types of socratic questions: reflection, induction, deduction, analysis, challenging assumptions and evaluation of data/information to guide decision-making. nurse educators should move away from emphasising critical thinking and instead focus on thinking in multiple ways. nurse educators can help students to improve their critical thinking skills using the socratic questioning method during interactive dialogues. this will help students to identify problems and clarify misconceptions. mutualism: a method of clinical teaching joy k. kamanyire department of adult health & critical care, college of nursing, sultan qaboos university, muscat, oman. e-mail: joyk@squ.edu.om registered nurses sometimes study alongside direct-entry students during the completion of their bachelor of science in nursing (bsn) degree. however, teaching mixed groups of students can be challenging. mutualism involves the voluntary collaboration of two different types of students as part of a mutual learning relationship during the final clinical course of the bsn programme. the two types of students are assigned to the same clinical preceptor, have the same clinical shifts and observe and review each other’s clinical competencies. this allows them to overcome challenges in interpersonal communication and differences in age, knowledge and clinical exposure and results in increased knowledge, patient care abilities and independent learning skills. ear, nose & throat clinic, policlinico santa maria alle scotte, siena, italy *corresponding author’s e-mail: mariacarla.spinosi@gmail.com قيلة حنجرية غائرة حدوث حالة غري اعتيادية يف مريضة عمرها 91 عاما ماريا سبنويس، كيارا ميزيدميي، جونفاين مون�سياتي، ديزديرو باسايل abstract: while internal laryngoceles rarely cause major clinical complaints, they may lead to airway obstruction and require emergency intervention on rare occasions. we report a 91-year-old patient who was referred to the ear, nose & throat clinic of the policlinico santa maria alle scotte, siena, italy, in 2017 due to recurrent episodes of severe dyspnoea. a flexible nasopharyngolaryngoscopic examination revealed an internal laryngocele of approximately 1.5 cm in diameter that moved up and down the glottic plane, occasionally invading the subglottic space during inspiration and impeding airflow. this caused cyanosis and dyspnoea so severe that an emergency tracheotomy was considered. luckily, after considerable effort, the patient was able to cough, causing the mass to move above the vocal plane and allowing normal breathing. the laryngocele was subsequently removed via laryngomicrosurgery. although the incidence of internal laryngoceles is quite rare, physicians should consider this potentially life-threatening condition among patients with dyspnoea. keywords: laryngocele; dyspnea; laryngoscopy; otolaryngology; case report; italy. امللخ�ص: قلما حتدث القيلة احلنجرية الغائرة �سكاوى رئي�سة عند املر�سى، ولكنها قد تف�سي اإىل ان�سداد يف م�سالك الهواء يتطلب تدخال عاجال يف اأحيان نادرة. ونعر�ض هنا حلالة مري�سة عمرها 91 عاما ُحولت لعيادة االأذن واالأنف واحلنجرة يف م�ست�سفى �سانتا ماريا اللي بوا�سطة املري�سة فح�ض ومت املم�ض. النف�ض �سيق من راجعة نوبات حدوث ب�سبب 2017م عام يف باإيطاليا �سيينا مدينة يف ا�سكوتي، منظار االأنف والبلعوم واحلنجرة، حيث تبني وجود قيلة حنجرية قطرها 1.5 �سم تتحرك اأعلى واأ�سفل م�ستوى املزمار، ويف بع�ض االأحيان تدخل اإىل الفراغ املوجود حتت املزمار يف اأثناء عملية ال�سهيق، وتعيق مرور الهواء. وت�سبب ذلك يف حدوث ُزراق و�سيق نف�ض مم�ض لدرجة جعلتنا نفكر يف عمل فغر اإ�سعايف للرغامي. ولكن متكنت املري�سة بعد بذل جمهود كبري من ال�سعال، مما جعل الكتلة تتحرك اأعلى م�ستوى احلبال ال�سوتية، وجعل املري�سة تتنف�ض ب�سورة طبيعية. ومت الحقا اإزالة القيلة احلنجرية بجراحة حنجرية جمهرية. وعلى الرغم من ندرة حدوث القيلة احلنجرية الغائرة، اإال اأنه ينبغي على االأطباء اأن ي�سعوا يف اعتبارهم احتمال حدوث مثل هذه احلالة التي قد تهدد احلياة عند الر�سى امل�سابني ب�سيق التنف�ض. الكلمات املفتاحية: قيلة حنجرية؛ �سيق التنف�ض؛ َتْنظرُي احَلْنَجَرة؛ طب االأنف واالأذن واحلنجرة؛ عر�ض حالة؛ اإيطاليا. internal laryngocele unusual onset in a 91-year-old female patient *maria c. spinosi, chiara mezzedimi, giovanni monciatti, desiderio passali case report sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e104–106, epub. 4 apr 18 submitted 16 sep 17 revision req. 16 nov 17; revision recd. 12 dec 17 accepted 7 jan 18 doi: 10.18295/squmj.2018.18.01.018 a laryngocele is a relatively rare benign dilatation of the laryngeal saccule arising in the region of the laryngeal ventr icle; the sac contains air and maintains open communication with the laryngeal lumen.1 it occurs in approximately one in 2.5 million cases per year and is usually found in males during the sixth decade of life. although the exact aetiopathogenesis of laryngoceles has yet to be explained, both congenital and acquired factors are involved.2 laryngoceles can be either internal, external or combined, according to their site; internal laryngoceles are confined to the larynx and do not pierce the thyrohyoid membrane. when the neck of the laryngocele is obstructed, it can fill with mucus and become a laryngomucocele that, if infected, transforms into a laryngopyocele. while this occurs rarely, this severe condition can present with acute airway obstruction and sepsis and may be fatal.3 while most laryngoceles are asymptomatic, symptoms can vary according to the type of laryngocele. external laryngoceles usually present as a neck mass that can mimic a neck abscess, lymphadenopathy and saccular, branchial or thyroglossal cysts.2 internal laryngoceles may cause coughing, hoarseness, a sore throat, dysphonia, dysphagia, stridor and even airway obstruction.4,5 the valsalva manoeuvre accentuates the mass, while palpation reduces its volume. among patients with mixed laryngoceles, the symptoms can be severe, particularly dyspnoea due to the passage of air from the external to the internal component of the laryngocele following compression of the external mass.2 such symptoms may have severe consequences, especially in fragile or elderly patients who often suffer from other comorbidities that may delay diagnosis or complicate management. maria c. spinosi, chiara mezzedimi, giovanni monciatti and desiderio passali case report | e105 fortunately, after considerable effort, the patient was able to cough, causing the mass to move above the vocal plane and allowing normal breathing to resume [figure 1b]. after obtaining informed consent, the patient was immediately scheduled for surgery. utilising fiberoptic intubation, the anaesthetist was able to secure the air way without breaking the mass. a microdirect laryngoscopy revealed a roundish mass with a peduncle originating from the anterior third of the ventricle (i.e. the inferior third of the false vocal fold). along with its base, the mass was completely removed and, upon opening, extruded serous-mucous material. the peduncle region was inspected, but no macroscopic passage connecting it to the ventricle was detected. a histological examination of the specimen revealed that the neoformation had respiratory epithelium compatible with a diagnosis of a laryngocele. no nasogastric feeding tube or tracheotomy was required. the postoperative recovery period was uneventful and a fiberoptic insp ection revealed normal healing of the region. two days later, the patient was discharged without any complications, after which she was sent to the cardiovascular unit for examination of the aneurysm. follow-up appointments at one week, one month and three months showed no recurrence of the laryngocele or the development of any other laryngeal anomalies. discussion certain acquired or environmental factors have been implicated in the aetiopathogenesis of laryngoceles, including as an occupational hazard among wind instrument players or glass blowers and associations with neoplasms of the larynx and atmospheric pressure changes during air travel.1,6 in turn, congenital laryngoceles have been reported to cause newborn respiratory distress that may lead to death.7 in this particular case, the cause of the laryngocele could not be determined. the age of the patient prevented any stressful activity and there was no history of any previous episodes of acute dyspnoea, dysphagia or a sore throat. in addition, the patient did not smoke and there was no evidence of a laryngeal carcinoma. internal laryngoceles may cause severe symptoms, with particularly serious consequences in fragile or elderly patients, as in the present case. in fact, even though laryngocele surgeries are usually elective, the current patient required urgent management due to the extreme severity of her dyspnoea, for which an emergency tracheotomy was considered.8 imaging is essential for the diagnosis of a laryngocele. overall, ct scans are the most effective method to determine the type, location and extent of the laryngocele and case report a 91-year-old woman was referred to the ear, nose & throat (ent) clinic of the policlinico santa maria alle scotte, siena, italy, in 2017 due to complaints of dyspnoea and asthaenia. the previous day, she had been admitted to the casualty department due to sudden dyspnoea which had begun a few hours previously. she had spent 12 hours in the casualty department where she had been diagnosed and treated for a reactivation of known chronic obstructive pulmonary disease. in addition, she reported having an aortic aneurysm. while the patient was cooperative, she was not completely reliable due to slight age-related memory impairment and her poor education level. her relatives could not be contacted and, in light of her suspected impaired anamnesis, it was not possible to confirm when the symptoms had begun. electrocardiography findings and the patient’s c-reactive protein levels, erythrocyte sedimentation rate and troponin levels were within normal range, while a complete blood count showed 9.93 x 109/l white blood cells with 8.48 x 103 neutrophils (85.4%). following several episodes of severe inspiratory dyspnoea and desaturation which resolved spontaneously but kept recurring at progressively shorter intervals, the patient was referred to the ent clinic. at referral, she was in a state of eupnoea, but complained of extreme fatigue, mild dysphonia and mild dysphagia. at first, the ent examination seemed normal; however, during a flexible nasopharyngolaryngoscopic exam ination, a roundish enlargement of the right false vocal fold was observed, while the ipsilateral true vocal fold could not be visualised. the roundish mass had a diameter of approximately 1.5 cm and its mucosal surface was smooth. a computed tomography (ct) scan of the neck was scheduled. before this could be performed, it was noticed that the mass moved up and down the glottic plane, occasionally invading the subglottic space during inspiration and impeding airflow [figure 1a]. this caused cyanosis and dyspnoea so severe that an emergency tracheotomy was considered. figure 1: laryngeal endoscopic photographs of a 91-yearold female patient with recurrent severe dyspnoea show ing a laryngocele (a) descending into the trachea and (b) having moved above the vocal folds after coughing. internal laryngocele unusual onset in a 91-year-old female patient e106 | squ medical journal, february 2018, volume 18, issue 1 for treatment planning in conjunction with a laryngoscopy and/or laryngostroboscopy.9 due to its widespread availability, ct is the most popular modality for general laryngeal imaging, whereas magnetic resonance imaging is used as a problem-solving tool and ultrasonography can be helpful in the assessment of a laryn geal lesion.9 however, ct is the most accurate radiological method of defining spatial relationships between the laryngocele, laryngeal structures and extralaryngeal tissues as well as excluding carcinomas during the differential diagnosis.10,11 in the current case, a ct scan was not performed prior to surgery due to the patient’s extreme dyspnoea and age-related fragility. while surgery is considered the treatment of choice for laryngocele cases, the approach essentially depends on the size of the lesion.4,12 small internal laryngoceles should be excised endoscopically with a carbon dioxide laser or by laryngomicrosurgery using an oral approach under general anaesthesia, since a minimally invasive approach allows for a safer surgery and quicker recovery, as in the current case.13,14 large internal, external or mixed laryngoceles should be treated either via an external surgery (i.e. a laryngofissure or lateral thyroidotomy) or a combined approach.2,8 recently, transoral robotic surgery has been reported to reduce morbidity and preserve the glottic space and vocal function, even for combined laryngoceles extending deep within the neck.15 moreover, this type of surgery has been found to be superior to classical methods in terms of safety, technical feasibility and curative effectiveness, in part because of the absence of skin incisions.16 unfortunately, the robotic equipment necessary for such surgeries is not yet available in every hospital. in general, the success of surgical procedures in laryngocele cases depends upon the accurate delineation of the neck of the sac within the ventricle and the correct identification of the dissection plane between the sac and surrounding tissue; the latter factor may be challenging, especially in emer gency cases.14 conclusion although the surgical treatment of laryngoceles is usually elective, patients may nevertheless require emergency interventions such as a tracheotomy. in rare cases, the internal part of the laryngocele may cause rapid and complete airway obstruction with potentially fatal consequences. although the incidence of internal laryn goceles is relatively rare, physicians should include this condition in the differential diagnosis of upper airway problems. references 1. prasad kc, vijayalakshmi s, prasad sc. laryngoceles: presentations and management. indian j otolaryngol head neck surg 2008; 60:303−8. doi: 10.1007/s12070-008-0108-8. 2. oukessou y, abada rl, roubal m, mahtar m. laryngocele: an unusual presentation. eur ann otorhinolaryngol head neck dis 2015; 132:177−8. doi: 10.1016/j.anorl.2015.03.002. 3. byard rw, gilbert jd. lethal laryngopyocele. j forensic sci 2015; 60:518−20. doi: 10.1111/1556-4029.12676. 4. prasad n, singh m, nagori r, singh s. laryngopyocele: presenting with pressure symptom. int j appl basic med res 2015; 5:228−30. doi: 10.4103/2229-516x.165375. 5. topal k, kilic k, sakat ms, altaş e, üçüncü h. laryngocele causing airway obstruction: a unique case report. west indian med j 2016. epub ahead of print. doi: 10.7727/wimj.2015.340. 6. butskiy o, anderson dw. upper airway obstruction due to a change in altitude: first report in fifty years. j otolaryngol head neck surg 2016; 45:9. doi: 10.1186/s40463-016-0121-y. 7. taskinlar h, vayisoglu y, avlan d, polat a, nayci a. congenital laryngomucocele: a rare cause of airway obstruction in a newborn. j craniofac surg 2015; 26:e238−40. doi: 10.1097/scs. 0000000000001543. 8. zelenik k, stanikova l, smatanova k, cerny m, kominek p. treatment of laryngoceles: what is the progress over the last two decades? biomed res int 2014; 2014:819453. doi: 10.11 55/2014/819453. 9. swain sk, chandra mallik k, mishra s, chandra sahu m. laryngocele: experience at a tertiary care hospital of eastern india. j voice 2015; 29:512−16. doi: 10.1016/j.jvoice.2014.09.013. 10. storck c, buitrago-tellez c. multidetector computed tomo graphy in nonmalignant laryngeal disease. curr opin otolaryngol head neck surg 2012; 20:443−9. doi: 10.1097/moo. 0b013e328359f358. 11. töro k, kardos m, dunay g. fatal asphyxia due to laryngomucocele. forensic sci int 2009; 190:e1−4. doi: 10.1016/j.fors ciint.2009.05.002. 12. mobashir mk, basha wm, mohamed ae, hassaan m, anany am. laryngoceles: concepts of diagnosis and management. ear nose throat j 2017; 96:133−8. 13. kusunoki t, wada r, homma h, kidokoro y, yanai a, ikeda k. two cases of the laryngeal cystic lesions. clin pract 2016; 6:822. doi: 10.4081/cp.2016.822. 14. fox r, ramdoo k, tatla t. endoscopic co2 laser excision of a ruptured laryngocele: a novel ‘blue-dye’ technique to assist dissection and avoid recurrent laryngeal nerve injury. clin otolaryngol 2017; 42:957−8. doi: 10.1111/coa.12503. 15. ciabatti pg, burali g, d’ascanio l. transoral robotic surgery for large mixed laryngocoele. j laryngol otol 2013; 127:435−7. doi: 10.1017/s0022215113000236. 16. kayhan ft, güneş s, koç ak, yiğider ap, kaya kh. management of laryngoceles by transoral robotic approach. j craniofac surg 2016; 27:981−5. doi: 10.1097/scs.0000000000002641. https://doi.org/10.1007/s12070-008-0108-8 https://doi.org/10.1016/j.anorl.2015.03.002 https://doi.org/10.1111/1556-4029.12676 https://doi.org/10.4103/2229-516x.165375 https://doi.org/10.7727/wimj.2015.340 https://doi.org/10.1186/s40463-016-0121-y https://doi.org/10.1097/scs.0000000000001543 https://doi.org/10.1097/scs.0000000000001543 https://doi.org/10.1155/2014/819453 https://doi.org/10.1155/2014/819453 https://doi.org/10.1016/j.jvoice.2014.09.013 https://doi.org/10.1097/moo.0b013e328359f358 https://doi.org/10.1097/moo.0b013e328359f358 https://doi.org/10.1016/j.forsciint.2009.05.002 https://doi.org/10.1016/j.forsciint.2009.05.002 https://doi.org/10.4081/cp.2016.822 https://doi.org/10.1111/coa.12503 https://doi.org/10.1017/s0022215113000236 https://doi.org/10.1097/scs.0000000000002641 departments of 1pulmonary medicine, 2radiodiagnosis and 3pathology & laboratory medicine, all india institute of medical sciences, bhopal, india *corresponding author’s e-mail: khuranaalkesh@gmail.com تكون احلصّيات الدقيقة يف حويصالت الرئة اهلوائية حالة نادرة غالباً ما ُيطَأ يف تشخيصها األكي�ض كورانا، راجي�ض ماليك، جيتندرا �شارما، اأوجوال كورانا، ديبتي جو�شي، ابي�شيك جويال abstract: pulmonary alveolar microlithiasis (pam) is an uncommon entity which can pose a diagnostic challenge. we report a 45-year-old female who was referred to the all india institute of medical sciences, bhopal, india, in 2017 with a two-year history of progressively worsening dyspnoea and dry coughing. she had been previously diagnosed with pulmonary tuberculosis elsewhere and prescribed antitubercular therapy; however, there was little improvement in her symptoms. following referral, the patient was diagnosed with pam based on high-resolution computed tomography findings and the abundance of lamellar microliths in a bronchoalveolar lavage sample. she was subsequently managed symptomatically and enrolled in a rehabilitation programme. keywords: calcinosis; pulmonary alveolar microlithiasis; pulmonary tuberculosis; misdiagnosis; case report; india. حتدًيا الغالب يف متثل والتي �شائعة الغري املر�شية احلالت من الهوائية الرئة حوي�شالت يف الدقيقة احل�شّيات تكون يعترب امللخ�ص: للعلوم الهند عموم معهد اإىل اأحيلت عاًما 45 العمر من بالغة امراأة عن عبارة هي والتي احلالت هذه اأحد ت�شجيل هنا يتم ت�شخي�شًيا، الطبية يف مدينة بوبال يف الهند يف عام 2017 وهي تعاين منذ �شنتني من تدهور تدريجي يف �شيق التنف�ض و�شعال جاف، مت ت�شخي�ض ن الأعرا�ض طفيفًا، بعد معاينة املراأة �شابقًا يف مكان اآخر مبر�ض ال�شل الرئوي وو�شف لها اآنذاك العالج امل�شاد لل�شل، ولكن كان حت�شُّ املري�شة، مت ت�شخي�شها بالإ�شابة باحل�شّيات الدقيقة يف حوي�شالت الرئة الهوائية بناءاً على ما اأظهرته نتائج الت�شوير املقطعي عايل الدقة والك�شف عن وجود ح�شّيات دقيقة بوفرة يف عينة اإفرازات الق�شبات الهوائية، متَّ عالج املراأة عن طريق تخفيف الأعرا�ض واإدخالها يف برنامج اإعادة تاأهيل. الكلمات املفتاحية: التكلُّ�ض؛ تكون احل�شّيات الدقيقة يف حوي�شالت الرئة الهوائية؛ ال�شل الرئوي؛ خطاأ الت�شخي�ض الطبي؛ تقرير حالة؛ الهند. pulmonary alveolar microlithiasis a commonly misdiagnosed rare entity *alkesh khurana,1 rajesh malik,2 jitendra sharma,2 ujjawal khurana,3 deepti joshi,3 abhishek goyal1 sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e236–238, epub. 9 sep 18 submitted 3 jan 18 revision req. 30 jan 18; revision recd. 5 feb 18 accepted 18 feb 18 case report doi: 10.18295/squmj.2018.18.02.021 pulmonary alveolar microlithiasis (pam)is a rare pathological entity not commonly encountered in routine clinical practice.1 affected patients are often initially misdiagnosed and may undergo unnecessary treatment, such as antitubercular therapy in tuberculosis-endemic countries.2 as such, clinicians, radiologists and pathologists should be made aware of this entity so as to ensure a correct diagnosis. case report a 45-year-old female was referred to the outpatient pulmonology department of the all india institute of medical sciences, bhopal, india, in 2017 with progressively worsening dyspnoea and dry coughing over the past two years. there was no history of fever, anorexia or weight loss. she had previously undergone chest radiography at other centres and been diagnosed with pulmonary tuberculosis, for which she was prescribed antitubercular therapy. however, as there was very little improvement in her symptoms, she was sub sequently referred to the all india institute of medical sciences. at referral, a chest x-ray of the patient showed a bilateral dense micronodular pattern with fine reticulation predominantly at the bases, with a ‘sandstorm’-like appearance [figure 1]. similar findings were noted in serial radiographs from the previous year. her total leukocyte count was 9,000/mm3, with a differential cell count of 56% neutrophils, 39% lympho cytes, 4% monocytes and 1% eosinophils. her haemoglobin levels were 13.1 g/dl and there was no history of haemoptysis since the onset of the illness. other investi gations, namely serum electrolytes (i.e. sodium, potassium, calcium, phosphorus and magnesium), renal function and liver function tests, were all within normal limits. pulse oximetry indicated an oxygen saturation of 94% in room air. pulmonary function tests yielded a classical restrictive pattern with a normal forced expiratory volume (fev1)/forced vital capacity (fvc) ratio and reduced fev1 and fvc measurements (percent predicted values of 101%, 49% and 49%, respectively). an electrocardiogram and two-dimensional echocardiograph were essentially normal, with alkesh khurana, rajesh malik, jitendra sharma,ujjawal khurana, deepti joshi and abhishek goyal case report | e237 mildly elevated pulmonary artery pressure and no evidence of valvular heart disease. a high-resolution computed tomography (ct) scan revealed extensive dense interlobular and intralobular septal thickening of the parenchymal window and dense microcalcification with a predominantly subpleural and peri bronchial distribution, suggestive of pulmonary alveolar microlithiasis [figure 2]. the next day, the patient underwent flexible bron choscopy. bronchoalveolar lavage (bal) smears showed microliths, alveolar macrophages, ciliated columnar epithelial cells and multinucleate macrophage giant cells [figure 3]. according to a differential cell count, the bal sample consisted predominantly of alveolar macro phages (91%). the microliths were spherical lamellate refractile fragile bodies which were predominantly extracellular and varied from 100–120 µm in size. there were between 2–12 nuclei in the multinucleate giant cells. a transbronchial lung biopsy (tblb) showed sheets of foamy macrophages containing periodic acid-schiff (pas)-positive material in the subepithelium; however, no microliths were visible. the patient was subsequently diagnosed with pam. since a lung transplant was not feasible, she was managed symptomatically and enrolled in a rehabilitation programme. her family was also screened for the disease using chest x-rays; however, no other cases were identified. discussion pam is a rare disease characterised by the widespread accumulation of minute calculi known as microliths in the lung parenchyma.1 the most likely aetiopathogenesis of the disease is a mutation in the solute carrier family 34 member 2 (slc34a2) gene, which leads to the ineffective uptake of phosphate from the alveoli and, therefore, the accumulation of calcium phosphate crystals.3 in the most comprehensive review of this entity to date, castellana et al. analysed 1,022 pam cases reported worldwide and noted that the disease had a slight male preponderance and most patients were in their second or third decade of life.1 a total of 80 patients were of indian origin. a positive family history was reported in 37% of cases.1 in the current case, the patient was an indian female in her fifth decade of life and had no family history of pam or a similar illness. a diagnosis of pam usually depends on the identification of various radiological and histopathological features. in particular, the radiographical appear ance of the patient’s lungs corresponds to the increasing severity of the disease.4 during the first stage, the radio figure 1: chest x-ray of a 45-year-old female showing a bilateral dense micronodular pattern with fine reticulation. figure 2: computed tomography of the (a) lung window of a 45-year-old female showing diffuse dense interlobular and intralobular septal thickening with patchy ground glass opacities and (b) the mediastinal window showing diffuse microcalcification in both lungs with a subpleural and peribronchial distribution. pleural and pericardial calcification (arrows) is also present. figure 3: a: wright giemsa stain at x400 magnification showing spherical concentrically lamellate refractile micro liths*. b: papanicolaou stain of a bronchoalveolar lavage sample at x400 magnification showing a microlith (arrowhead), alveolar macrophage (black arrow) and ciliated columnar epithelial cell (white arrow). *the fine focusing of these bodies makes the background cells appear out of focus. pulmonary alveolar microlithiasis a commonly misdiagnosed rare entity e238 | squ medical journal, may 2018, volume 18, issue 2 conclusion despite its rarity, there is a need to increase the index of suspicion of pam among clinicians, radiologists and pathologists in order to avoid misdiagnosis and unnecessary treatment. this case emphasises the combined role of high-resolution ct and bal analysis in the diagnosis, thus avoiding the need for invasive procedures such as an open lung biopsy. references 1. castellana g, castellana g, gentile m, castellana r, resta o. pulmonary alveolar microlithiasis: review of the 1022 cases reported worldwide. eur respir rev 2015; 24:607−20. doi: 10.11 83/16000617.0036-2015. 2. govindaraj v, manju r, jaganathan v, udupa a, hariprasad v, saka v. pulmonary alveolar microlithiasis: a case report. int j sci study 2015; 3:212−15. doi: 10.17354/ijss/2015/190. 3. corut a, senyigit a, ugur sa, altin s, ozcelik u, calisir h, et al. mutations in slc34a2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. am j hum genet 2006; 79:650−6. doi: 10.1086/508263. 4. castellana g, castellana r, fanelli c, lamorgese v, florio c. [pulmonary alveolar microlithiasis: clinical and radiological course of three cases according to conventional radiology and hrct a hypothesis for radiological classification]. radiol med 2003; 106:160−8. 5. martínez-girón r, martínez-torre s, tamargo-peláez ml, lópez-cabanilles md, torre-bayón c. calcareous concretions and psammoma bodies in sputum smears: do these similar structures have different clinical significance? diagn cytopathol 2014; 42:759−65. doi: 10.1002/dc.23120. 6. jönsson ål, simonsen u, hilberg o, bendstrup e. pulmonary alveolar microlithiasis: two case reports and review of the literature. eur respir rev 2012; 21:249−56. doi: 10.1183/09059 180.00009411. 7. monabati a, ghayumi ma, kumar pv. familial pulmonary alveolar microlithiasis diagnosed by bronchoalveolar lavage: a case report. acta cytol 2007; 51:80−2. doi: 10.1159/000325688. 8. casoni gl, cordeiro cr jr, tomassetti s, romagnoli m, chilosi m, cancellieri a, et al. the role of transbronchial biopsy in the diagnosis of diffuse parenchymal lung diseases: pro. rev port pneumol 2012; 18:57−60. doi: 10.1016/j.rppneu.2011.05.003. 9. mariotta s, ricci a, papale m, de clementi f, sposato b, guidi l, et al. pulmonary alveolar microlithiasis: report on 576 cases published in the literature. sarcoidosis vasc diffuse lung dis 2004; 21:173−81. 10. prakash ub, barham ss, rosenow ec 3rd, brown ml, payne ws. pulmonary alveolar microlithiasis: a review including ultrastructural and pulmonary function studies. mayo clin proc 1983; 58:290−300. 11. kashyap s, mohapatra pr. pulmonary alveolar microlithiasis. lung india 2013; 30:143−7. doi: 10.4103/0970-2113.110424. 12. kanat f, teke t, imecik o. pulmonary alveolar microlithiasis with epididymal and periurethral calcifications causing obstruc tive azospermia. int j tuberc lung dis 2004; 8:1275. 13. jackson kb, modry dl, halenar j, l’abbe j, winton tl, lien dc. single lung transplantation for pulmonary alveolar microlithiasis. j heart lung transplant 2001; 20:226. doi: 10.1016/s1053 2498(00)00500-3. logical findings are precalcific, although this is identified very rarely. in the second stage, the lungs have a typical ‘sandy’ appearance, with scattered microliths and a delineated cardiac border.4 the density of the microliths then increases to obscure the cardiac borders in the third phase, before involving the pleura in the fourth phase, as noted in the current case.4 despite these typical radiological features, it is not uncommon for patients to be misdiagnosed with tuberculosis, as in the present case, particularly in endemic areas.2 despite this, the coexistence of tuberculosis and pam is rare.1 other diseases associated with a miliary dissem ination include sarcoidosis, pneumoconiosis, haemosiderosis, amyloidosis and mycosis. however, while the radiological appearance of calcifications are more intense in pam cases, the symptoms of these other differential diagnoses are usually more severe.1 in order to confirm the diagnosis, a lung biopsy is required to demonstrate the presence of characteristic pas-positive concentric calcareous lamellae around a central nucleus.1 the microliths should be differentiated from psammoma bodies, indicative of a malignant condition; these are similar in structure but occur as part of the epithelial cell group or as small tissue fragments.5 while the analysis of bal samples is often inconclusive, the cytological findings in the current case were very characteristic of pam, demonstrating both microliths and multinucleate giant cells.6,7 however, the presence of microliths in the bal fluid rather than in the tblb specimen was unusual, particularly as the latter technique is usually more sensitive for diffuse lung disease.8 this may have been because of the blind nature of the technique. in general, less than 50% of pam cases have positive tblb findings.9 however, pulmonary function tests may have a support ive role by revealing a restrictive pattern, as seen in the present case.10 once diagnosed, the course of the illness is variable and can either remain stable or become progressively worse, resulting in cor pulmonale.11 however, since the onset is insidious and the clinical course is generally quite slow, it can be difficult to definitively establish the onset of the disease. furthermore, since the slc34a2 gene is expressed in certain extrapulmonary tissues—including the testicles, kidneys, pancreas, intestines, breasts, ovaries, liver and prostate—some patients may also have extrapulmonary symptoms, such as infertility, azoospermia, haematuria and gallstones.11,12 currently, no medical or genetic therapy is yet available, with chelating agents and therapeutic lung lavage reported to be ineffective.10 to date, lung transplantation is the only accepted treatment, with survival up to 15 years reported without recurrence.13 https://doi.org/10.1183/16000617.0036-2015 https://doi.org/10.1183/16000617.0036-2015 https://doi.org/10.17354/ijss/2015/190 https://doi.org/10.1086/508263 https://doi.org/10.1002/dc.23120 https://doi.org/10.1183/09059180.00009411 https://doi.org/10.1183/09059180.00009411 https://doi.org/10.1159/000325688 https://doi.org/10.1016/j.rppneu.2011.05.003 https://doi.org/10.4103/0970-2113.110424 https://doi.org/10.1016/s1053-2498%2800%2900500-3 https://doi.org/10.1016/s1053-2498%2800%2900500-3 patient safety has emerged as an important theme in clinical practice and research priority, as well as in modern undergraduate and postgraduate medical and nursing curricula. over the past few years, an increasing awareness on the part of health care consumers, the demand for safe care, the documented high rate of medical errors, along with legal, economic and ethical demands on the health care system, have resulted in the issue of patient safety being included in all quality assurance systems. sultan qaboos university hospital (squh) has achieved iso 9000:2001 certification and has embarked on the journey to accreditation by the joint commission international (jci). patient safety symposia have been held in the past at squh. selected abstracts from the 4th patient safety symposium are reproduced below. infection control: a patient safety issue abdullah balkhair, squh, muscat, sultanate of oman.email: balkhair@squ.edu.om hospital-acquired infections have long been considered the greatest risk the hospital environment poses to patients. these infections are considered by many to be the most common type of adverse event in health care; they are certainly by far the most common complication affecting hospitalised patients. between 5 and 10% of patients admitted to acute-care hospitals acquire one or more infections. these infections result in significant morbidity and mortality and are of considerable economic burden to any health care system. recently, the agency for healthcare research and quality released a report that reviewed the evidence in favor of 79 patient-safety practices, of which 22 (28%) are involved in infection control. five of the eleven practices that were judged worthy of widespread implementation involved infection control, further illustrating the common ground shared by these two disciplines. infection prevention and control in hospital-settings are critical components of patient safety. modern patient safety practices can enhance the field of infection-control and the patient-safety movement can also learn much from the traditions of infection-control in hospitals. the concept of patientsafety in the practice of hospital infection prevention and control has resulted in new approaches in the practice of hospital-based infection-control programmes. the premise that “many hospital-acquired infections are inevitable; although some can be prevented” has become “each hospital-acquired infection is potentially preventable unless proven otherwise”. infection-control could also benefit by adopting several approaches (such as root-cause analysis) advocated by patient-safety adherents. however, it is not practical (or even useful) to perform a root-cause analysis of every hospital-acquired infection. infections that cause substantial harm or are implicated as a cause of death should be reviewed and, when preventable causes are suspected, a root-cause analysis should be considered to identify those factors in the system or processes of care that contributed to the errors. in turn, applying infection control based practices could enhance patient safety. such practices include instituting evidence-based intervention programmes, and relying on skilled professionals to promote ongoing improvements in care amongst others. clinical triggers (also called “signals” or “alerts”) are elements drawn from patients’ electronic medical records that suggest ongoing or potential adverse events, including infections. continuous, real-time scanning of such records facilitates cost-effective surveillance and active interventions aimed at preventing or ameliorating adverse events, including infections. these practices are now being widely adopted by infection-control programmes in many hospitals worldwide. the importance of the patient-safety movement in revitalising hospital infection-control programmes is evident. health care acquired infections as indicator of infection control seif salem al-abri, royal hospital, muscat, sultanate of oman. email: salabri@gmail.com health care professionals and facilities should be accountable to patients for strict adherence to key evidence-based infection prevention recommendations, and they should also be accountable for reducing rates of infections. ‘getting to zero’ is a concept that was introduced by the quality-improvement community and was avidly embraced by most stakeholders. this means that the aim of abstracts squ med j, december 2009, vol. 9, iss. 3, pp. 362-368, epub. 19th dec 2009 املؤمتر الرابع لسالمة املريض هدف واحد و مسؤوليات مشرتكة مستشفى جامعة السلطان قابوس، سلطنة ُعمان 2-4 فبراير 2009 4th symposium on patient safety one aim with shared responsibilities sultan qaboos university hospital, sultanate of oman 2nd 4th february 2009 abstracts 2nd 4th february 2009 abstracts | 363 eliminating hospital-acquired infections (hais) is believed to be attainable, and, therefore, all hais are preventable. furthermore, this supports the claim that all hais must be the fault of someone. ‘getting to zero’ has now been translated into ‘zero tolerance’ for hais and for any practices leading to hais. there are some infection prevention programmes which have almost succeeded in eliminating hais altogether. the strategies that these successful programmes adopted to eliminate hais are: 1) they set their goal at zero (for bsi, vap, ssi, and mrsa); 2) strong leadership, physician support and departmental champions were engaged; 3) the “bundle” approach to evidence-based prevention measures for all patients at risk from hais was used by all; 4) real-time root cause analysis was performed even when only one infection occurred; 5) hais were personalised with the information given concerned with the people involved rather than rates; 6) data management was reliable and shared routinely with front line staff; 7) they communicated persistently with key staff and the leadership team; 8) teamwork was made a priority and team success was celebrated; 9) the value of infection-prevention was marketed to executive leadership. by setting up partnerships between patients, families and health care teams and researchers, educators, standardsand law-makers, industrialists and innovators, reliable systems that prevent hais can be established. we must continue to negotiate effectively to get the resources needed to prevent hais, and then we can ‘pay it forward’. this presentation covers the role of infection-control and prevention programmes in patient safety and examines the elements needed to eliminate/reduce the risk of hais in our health-care facilities. risk management in health care rashid al abri, squh, muscat, sultanate of oman. email: ralabri@hotmail.com the term “risk management” usually refers to self-protective activities aimed to prevent real or potential threats of financial loss due to accident, injury or medical malpractice. it provides strategies, techniques and an approach to recognising and confronting any threat faced by an organisation in fulfilling its mission. the gold standard method of risk management is risk assessment. a risk assessment is simply a careful examination of what, in your workplace, could cause harm to people, so that you can weigh up whether you have taken enough precautions to prevent harm befalling others. there are two principles which should always be borne in mind when approaching a risk assessment: 1) to structure the assessment to ensure that all relevant hazards and risks are addressed; and 2) when a risk is identified, to begin assessment from first principles by asking whether the risk can be eliminated entirely. there is a five steps approach to risk assessment: 1) identifying hazards and those at risk: looking for those things in the workplace that have the potential to cause harm, and identifying those workers who may be exposed to the hazards; 2) evaluating and prioritising risks: estimating the existing risks (the severity and probability of harm) and prioritising them; 3) deciding on preventive action: identifying the appropriate measures to eliminate or control the risks; 4) taking action: putting in place the preventive and protective measures through a prioritisation plan; 5) monitoring and reviewing: the assessment should be reviewed regularly to ensure that it remains current. in conclusion, risk management is a retrospective strategy in managing risks. it is part of the quality assurance process that requires change and deciding which changes needed to be studied. medication errors ibrahim al-zakwani, squh, muscat, sultanate of oman. email: ial_zakwani@yahoo.com medication errors are one of the public health concerns associated with significant morbidity and mortality. the cost burden in both human and economic terms is immense. the aim of this presentation is to outline the various causes of medication errors. the five most common causes include incomplete patient information, unavailable drug information, miscommunication of prescription orders, environmental factors, and labelling and packaging problems. information about patients’ diagnoses and allergies are very important to determine that the prescribed drugs are correct and that there are no contraindications. furthermore, information about other medications patients are already taking is essential to avoid duplicating prescriptions and to prevent adverse drug interactions. miscommunication of prescription orders is one of the most important and frequently encountered causes of medication error in practice. examples include poor handwriting, look-alike names, sound-alike names, misuse of decimal points and zeroes, inappropriate abbreviations, dose miscalculations, incorrect drug administration and ambiguous or incomplete orders. environmental factors and distractions include noise or interruptions, transcription errors, multitasking, fatigue, poor lighting, stocking and storage problems. factors that patients themselves bring to the situation may lead to medication error. an example would be a lack of education on the part of the patient. factors that reduce the occurrence of these errors are also discussed. creating a patient-safety culture: an squh initiative of measuring to improve yasmeen s. al hatmi, salim al tamemi, moosa al kindi, squh, muscat, sultanate of oman. email: yza4me2@yahoo.ca introduction: patient safety has emerged as an important research priority in health care. the world health organization (who) addressed this challenge by launching the world alliance for patient safety in october 2004. this alliance aimed to reduce the number of preventable illnesses, injuries and deaths experienced by patients in health care. many hospitals worldwide are implementing patient safety programmes, systems and activities with the cooperation and compliance of the staff. equally important is the involvement of the patient. sultan qaboos university hospital (squh) is an iso certified organisation (re-certified may 2008) on the journey toward hospital accreditation. this requires comprehensive compliance to international standards developed by and for health care professionals from many parts of the world. objectives: this presentation will discuss the jci guidelines and look at the squh patient safety improvement strategy based on data trends at squh for the period january 2006 to december 2008. in addition, it will explore the innovative quality activities aimed at developing a patient safety culture at this hospital as part of our compliance with international standards in patient safety and quality care. the purpose of this presentation is to share some squh experiences and raise awareness about the importance of improving the quality and safety of health care. methods: as an initial step, squh identified all hospital staff 4th symposium on patient safety one aim with shared responsibilities 364 | squ medical journal, december 2009, volume 9, issue 3 whose roles link with patient care directly or indirectly, and who considered themselves as eligible to participate in the initial awareness campaign and follow through with the improvement strategy initiated by the squh patient safety team. understanding the status of patient safety through gathered information and aggregated data is an important first step towards achieving safer care, giving the hospital the full perspective and an accurate tool for identifying where problems exist and furthermore, enabling the monitoring and tracking of improvements in the patient care provided. therefore, as part of the aim at squh to create a patient safety culture, a baseline was formed by examining the issues raised from numerous audits and walkabouts conducted in the hospital between 2006 and 2008. these included quality audits, health and safety audits, risk assessments, incidence reporting, quality rounds, infection control team rounds and a hospital-wide patient safety gap analysis. these findings were classified to highlight the trends in patient safety, or rather, the events or near-misses which have occurred and considered dangerous to the patient. a squh patient safety team has recently been formed to plan the strategies necessary for improvement in the hospital. patients safety training materials developed, best practices in patients' safety web-database recio miguel, spain objectives: the main objective of this programme is to improve professionals’ knowledge of, skills in and attitudes towards risk management. for this reason, an on-line training course in risk management (rmc) and patient safety (ps) improvement was designed which included an electronic platform of the teaching programme (tp). this platform was developed using all the tools necessary to enable participants to know their progress at any point, and to communicate effectively with their tutors. methodology: the tp of the spanish patient safety strategy uses a multi-faceted methodology to promote a national patient safety culture. the rmc includes theoretical content on risk management processes as well as practical risk management tools. implementation is facilitated by the provision of templates and clear formats. this 120 hour course is aimed at managers and clinical professionals who are grouped in teams of 3-4 to develop a final ps improvement project for their working area. the participants use the methodology and tools covered in the course. a freely available database was designed to analyse the projects. reports could be produced by using a variety of filters. an analysis has been done with the data so far retrieved to identify which are the most important risks and what the most efficient actions are to manage and prevent each. results: in the period 2005-2008, nine rmc editions were completed with the participation of 480 health professionals from 18 spanish health regions. there were also 120 participants from seven latin-american countries. the most valued aspects of the course were: satisfaction with the clarity of the materials and the effective communication with the tutorial team. the most recurrent health areas were identified as emergency, the hospital as a whole and surgery. education, patient information and attention, surgical complications, and intensive care were the most recurrent ps topics. a database has been developed that summarises the use of risk management tools. as a result of the analysis, a ‘good practices’ report has been generated. five sessions of the course are planned in 2009, including the first english edition. technology and confidentiality c. deborah packiajothi and anitha nesathanka, college of nursing, squ, muscat, oman. email: bamri@squ.edu.om technology has been a boon both to the nursing community and patient care. however, its use in the health care system should never compromise patient care and patient safety. nursing professionals need to understand their responsibilities in relation to the use of technology both within and outside the setting of their practice. some situations raise issues related to the conduct of professionals outside the practice setting. the main issues are confidentiality, privacy, consent, nurse-patient relationships and professional conduct. as self-regulating professionals, registered nurses are expected to maintain confidentiality and to uphold the profession by demonstrating honesty, integrity and respect. nurses have a high level of public trust and are expected to maintain high standards of professional conduct. this may have an impact on the profession itself as conduct outside the practice setting may affect public perceptions of the nursing profession. if nurses do not handle information carefully and with professional judgment, they may disclose confidential information about their patients. listed are some of the ways technology-use may pose a threat to patient confidentiality: 1) by sharing information about clients on the website “myspace”. it is not appropriate for professionals to share client information unless it is with other members of the health care team, and for the sole purpose of providing care for which the client has given consent. even though a client’s name may not be shared directly, there can be identifying features that could make the client recognisable to someone browsing this particular website. withholding the client’s name is not sufficient to maintain confidentiality. nurses must safeguard information learned in the context of the professional relationship and ensure that if it is shared outside the health care team, it is only done so with the patient’s consent when legally required or when failure to disclose would cause significant harm (according to the canadian nurses association); 2) by nurses blogging on websites. nurses sometimes share their frustrations about self, workplace, over-capacity and workload through blogging. these frustrations are often shared as s/he feels that it is her obligation to do so as a registered nurse. it is important to note that expressing thoughts and feelings through a public domain such as this is akin to talking on the corridor where anyone can eavesdrop on what is being said. instead, nurses’ concerns about their workplace or client safety need to be expressed using an appropriate channel of communication; 3) by nurses having patients as e-mail friends. it is not appropriate for nurses to relate to their clients in an informal way as the nurse-patient relationship is developed within a certain context which requires nurses to make a clear distinction between the professional and personal relationships. it is the nurse’s responsibility to initiate, maintain and terminate the professional relationship in an appropriate manner; 4) by photographing clients using phone cameras. photographs contain confidential information which belongs to the client. prior consent is therefore needed from the client for any sharing of photographs between members of the health care team. they should only be used to enhance patient care. obtaining and sharing confidential client information without consent for purposes unrelated to health care is a breach of patient confidentiality. 2nd 4th february 2009 abstracts | 365 evidence based practice: use of ventilator bundle to prevent ventilator associated pneumonia in nizwa hospital (oman). sangeet narang, nizwa hospital, nizwa, oman. email: nizwahosptal@hotmail.com objectives: to determine the impact of “ventilator bundle” in the prevention of ventilator associated pneumonia (vap) and other outcome variables in patients admitted to our adult intensive care unit (aicu). preventing nosocomial infections is a very important aspect in improving patient safety. implementing "ventilator bundle" has shown to reduce the incidence of vap. encouraged by this fact, we at nizwa hospital have implemented this bundle in our aicu. methods: all the adult medical and surgical patients who were intubated and ventilated in our aicu from january to september in the years 2005 and 2006 were included in this study. patients who expired within 24 hrs of admission, were transferred to tertiary care unit within 48hrs, were diagnosed with pulmonary embolism or had gastrointestinal bleed prior to admission were excluded from this study. the concept of “ ventilator bundle’ was introduced after educating the nursing staff, respiratory therapists and the medical personnel through group discussions and presentations during infection control and staff development symposia. “ventilator bundle” is a package of evidence-based interventions that include: 1) elevation of the patient’s head of bed to 30-45 degrees; 2) daily sedation vacation and daily assessment of readiness for extubation; 3) peptic ulcer prophylaxis, and 4) deep vein thrombosis (dvt) prophylaxis. demographic data was collected from the computer database. vap was diagnosed when it met the (clinical, non-invasive) diagnostic criteria. the incidence of vap was calculated separately amongst the medical and surgical patients. results: introducing the concept of “ventilator bundle” reduced the incidence of vap by 24.2% in the surgical patients and by 12% in the medical group. it also significantly reduced the incidence of upper gastrointestinal bleeding. the mean age of patients who developed vap in 2006 was significantly higher in both the medical and the surgical groups. the length of stay decreased significantly in the surgical group, while it increased in the medical group. in those patients who developed vap, the mean duration of ventilation was reduced by 29.1% in the medical group and by 55.12% in the surgical group. in patients who did not develop vap, a decrease of 9.9% in the mean duration of ventilation was seen in the surgical group, but increased by 14.2% in the medical group. conclusion: introducing the concept of “ventilator bundle” helped us to reduce the incidence of vap as well as the incidence of upper gastrointestinal bleeding. it reduced the mean duration of ventilation in both the medical and surgical patients who developed vap. the effect of decreasing the length of stay was seen amongst the surgical patients only. audit of medication practices in maternity wards at sultan qaboos hospital, salalah veena paliwal, neersha sharma, sultan qaboos hospital, salalah, oman. email: sq-md@moh.gov.om objectives: to audit medication practice in patients admitted to maternity wards to find out medication errors with the aim of decreasing or eliminating medication errors according to their category for better care and patient safety. methods: sultan qaboos hospital is a secondary cum tertiary hospital with 100 inpatient beds for obstetrics and gynaecology (80-90 % bed occupancy rate) and a delivery rate of 4,500 babies per annum. this study was done on a daily basis over a period of one year from november 2007 to october 2008. data were collected from medication charts, staff and doctors reports, patient complaints, pharmacy complaints and any adverse events. in order to audit prescription documentation, 500 randomly collected prescription sheets were studied over a period of 6 months (january to june 2008). the standard used accorded with ministry of health policy. results: our hospital uses handwritten records and medicines are prescribed using a standard yellow sheet. errors were categorised into 3 types: prescription errors, made mainly by doctors; dispensing errors made by pharmacy staff; and end-user errors made by patients. prescription errors: from a total of 500 prescription sheets reviewed, 42% of cases revealed a problem in legibility of hand writing. in 80% of cases, medicine names were not written in block letters. there was confusion in the name of the drug, in administration (oral or injectable) and in duration. dosage was frequently under prescribed because many of our patients are obese. iv fluids were often written collectively and the duration was frequently not stated. incomplete details concerning medication on the discharge summary lead to errors. dispensing errors: a combination of a lack of experience of new staff and bad hand writing on the part of many doctors often has unfortunate consequences. the following errors were noted: wrong medication; medicines not given on time; not stopping medication as advised; drugs left unattended at a patient’s bedside; unavailability of medicine due to lack of stock and doctors not being informed to indicate a substitute; interchange of drug sheets, wrong stickers etc. some of these errors were due to staff shortages, others to unnecessary drugs left on trolleys. user errors: these occurred when patients had their own beliefs about pregnancy; patients did not take their medication on time; medications were thrown away; the over-use of drugs, especially analgesics; refusing medicines during ramadan (which affects care during pregnancy especially for diabetic and hypertensive patients leading to repeated admissions and unnecessary interventions); incorrect or inadequate information given to patient at the time of discharge. conclusion: medication errors are few in oman, but not uncommon. they also tend to be under reported. appropriate knowledge and experience, good hand writing, the taking of proper safety precautions (such as the cross-checking of records and medicine) could prevent a number of medication errors. protocols and guidelines should be followed especially in emergency situations. supervision of new staff should be mandatory. for good patient compliance, health education regarding disease and medication is most important. transfusion medicine and patient safety prassana n kumar, oman medical college, sohar, oman. email: sohar@omc.edu.om introduction: safe transfusion therapy depends upon an interconnected series of processes that begin with the donor and end with the patient. blood safety is concerned with the safety of the component which is the primary responsibility of the blood bank. transfusion safety focuses on the overall process that results in the delivery of transfusion therapy to the patient and includes blood 4th symposium on patient safety one aim with shared responsibilities 366 | squ medical journal, december 2009, volume 9, issue 3 safety. objectives: this presentation addresses the important points in the transfusion process that are potentially unsafe: the collection of patient samples, the medical decision to transfuse and the administration of blood components at the bedside. it will also deal with some solutions to current problems in hospital transfusion safety like newer technologies, computerised blood utilisation reviews and nanotechnology. methodology: patient sample collection: errors in this first step can lead to an acute haemolytic transfusion reaction due to abo incompatibility. acute haemolysis continues to be an important cause of morbidity and mortality. although the majority of abo errors occur at the time of blood administration, a significant percentage occurs at the time of specimen collection. mislabeling of specimens: this accounts for a very high percentage of high-severity events which have a potential for patient harm. the mislabelling could be a minor one misspelled name, truncated name or number, or a major one, also known as wbit (wrong blood in tube), in which the error is an unlabelled specimen or an ab/rh not matching the blood bank record. attention to the prevention of such errors represents an area where quality improvement efforts could have a major impact in improving transfusion safety. decision to transfuse: like decisions associated with commonly prescribed antibiotics, it is quite often seen that many transfusion decisions are incorrect. transfusion is associated with potential risks to the patient; hence, prescribers of transfusions must be aware of the clinical setting where their use is appropriate. there must be adequate justification for a transfusion and local hospital transfusion committees can play a vital role in overseeing transfusion practices to ensure optimal use of blood/component therapy. bedside administration of blood: the serious hazards of transfusion (shot) programme documents that mistransfusion is the most common serious hazard of transfusion. a hospital must have in place patient safeguards to prevent mistransfusion. a variety of technologies exist that can be used to improve transfusion safety: bar codes, machine-readable patient identification bracelets and radio-frequency chips. conclusion: this presentation will also deal with solutions to current problems in hospital transfusion safety. it is important that hospitals form professional groups whose responsibility would be to set performance standards in key areas of the transfusion process. newer technologies designed to improve patient safety should be explored. simulation-based teaching enhances patient safety girija k m, college of nursing, squ, muscat, oman. email: girija@squ.edu.om background & objectives: quality and safety education in health care has changed practice expectations. quality and safety education can ensure safe and competent health professionals. the three guiding steps to patient safety are developing safety lessons, learning and sharing safety lessons and implementing solutions to prevent harm (npsa 2004, npsa 2005). the ‘quality and safety education for nurses’ project team recommended the use of simulation-based teaching to enhance patient safety on a systems level. simulation develops a more relaxed relationship between student and teacher, and makes the student feel more valued and confident (alinier, 2003). both teachers and students believe that simulation makes it easier for students to transfer skills and helps to reduce the gap between theory and practice. methods: quasi experimental one group post test design. population: squ students who were registered for maternal health nursing in autumn 2008. sample: 39 students (11 male, 28 female). tools: objective structured clinical examination (osce), a questionnaire and an observation checklist. all students were exposed to three weeks of skill laboratory training. this was followed by an osce, and then they were given three weeks of clinical posting. at the end of the third week of their posting, their safety practices in caring for newborns were observed. questionnaires were distributed to get feedback on how skill laboratory training had helped them to gain confidence and to practice safety while caring for newborns. results: the average osce score was 85%. knowledge about patient safety in the care of newborns was tested by multiple choice questions and the average score was 83%. skill laboratory training helped them to develop skills in safety issues. 75% of students expressed confidence in handling newborns at the end of their first week of posting. this increased to 95% by the end of the posting. 88% could correctly distinguish and identify different newborns reducing the risk of error in assessment and documentation. overall, skill laboratory training enabled the students to transfer learning better, to organise care and to master the skills that eventually ensure patient safety. using a check list, the observation of students in the clinical area found 98% of students cared for newborns safely especially in areas of injury and fall prevention as well as universal precautions. conclusion: simulation-based teaching prepares students to practice safely and effectively to the extent that safety can be assured. skill laboratory training offers alternative methods of assessment such as osce, sparing the need for patients to be at risk. simulation-based teaching is highly beneficial in the nursing curriculum especially in the training of novices, and in areas where it may be culturally and ethically inappropriate to practice on patients, such as male students practising in the maternity ward. a novel method to improve knowledge, attitude and practice of hand washing among staff in the clinical setting hind ali, aisha khalfan, nadia hamed, john idikula, ibri regional hospital, ibri, oman. email: dghsibri@gto.net.om introduction: hand washing and hand hygiene are important in preventing nosocomial infection in hospital settings. compliance to proper hand washing technique is vital. method: a study was conducted using a self-administered questionnaire to determine the knowledge, attitude and practice of hand washing in the inpatient care setting of ibri regional hospital. results: the main findings were as follows: 171 staff participated in the study with representation from all wards, icu, special care baby unit etc. the average length in practice among participating nurses was 8.17 years (sd = 3.8). in the 5 questions pertaining to the practice of hand washing, a score of only 84% was obtained on self-reporting of hand washing practice. a score of 91.7% was obtained relating to their knowledge of hand washing. in response to the factors that led to poor adherence to hand washing, 84% reported lack of adequate staff, 54% reported unsuitable location of wash basin, 78% reported skin irritation due to frequent washing and 32% reported that the hand washing procedure was lengthy. intervention: in order to improve attitudes towards hand washing and to encourage better practice thereof, we conducted a caption contest and prizes were offered for the best entries among various categories of staff. 72 captions were received indicating a high level of interest. caricature pictures based on the interesting captions were prepared. these were laminated and put up in different wards as a reminder. staff who participated were delighted to see their own captions on display in various wards. the 2nd 4th february 2009 abstracts | 367 follow-up indicated significant improvement in the attitude and practice of hand washing by hospital staff. conclusion: attitude and practice of hand washing can be improved through motivation, involvement and incentives. nosocomial infections in a tertiary hospital: a one-yearsurveillance at squh abdullah balkhair, mansoor al jabri, al raya rashdi, squh, oman. email: balkhair@squ.edu.om introduction: the nosocomial infection rate in patients in any hospital is an indicator of the quality and safety of care. the development of a surveillance process to monitor the rate is an essential step in identifying local problems and priorities, and in evaluating the effectiveness of infection control activity. in august 2006, the infection control programme at sultan qaboos university hospital (squh) launched a hospital-wide, targeted surveillance for nosocomial infections. objectives: the main aim was to reduce nosocomial infection rates. methods: all patients admitted to squh between august 1 and december 31 2006 and the corresponding period in 2007 were observed for the development of nosocomial infections during hospitalisation. prospective identification of nosocomial infections using microbiology reports was carried out daily and this was the primary basis for the diagnosis of nosocomial infections. daily reports from the infection control link nurses in each ward were also used to identify patients with nosocomial infections. electronic patient records were examined when in doubt as to the presence of colonisation or true infection. a monthly report addressing overall infection (attack) rates, clinical unit infection rate, site of infection and isolated pathogens was produced and circulated amongst all wards. results: a total of 6,984 patients were admitted during the first period (2006) and nosocomial infections were noted on 243 occasions from 135 patients. the attack rate of nosocomial infection during this period was 19.3/1000 patients and 1.8 infections per patient with nosocomial infection. during the corresponding period in 2007, a total of 7,744 patients were admitted and nosocomial infections were noted on 169 occasions from 105 patients. the attack rate of nosocomial infection during this period was 13.6/1000 patients and 1.6 infections per patient with nosocomial infection. blood stream infections (bsi) were the leading site of nosocomial infections during both periods. of the total infections noted, 43% were bsi, 20% were pneumonia, 20% were urinary tract infections (uti), 11% were surgical site infections (ssi) and 6% were infections in other sites. the gram-negative bacilli were the primary pathogens accounting for 70% of the pathogens isolated. staphylococcus epidermidis and staphylococcus aureus were the predominant gram-positive isolates. candida species were the only fungal pathogens seen and accounted for 8% of pathogens isolated. conclusion: there was a significant drop in the number of nosocomial infections at squh from 19.3/1000 patients to 13.6/1000 hospitalised patients (a rate reduction of 29%). this was attributed mainly to the feedback and dissemination of surveillance results to the clinical staff, as well as the improvement in hand hygiene practices. nosocomial infections cannot be totally eradicated, but they can be reduced. this study will form the basis for more in-depth studies on the details of the multiple aspects and problems of nosocomial infections. nurses knowledge of decontamination and identification of training requirements fatma neilson, squh, muscat, oman. email: don-nrs@squ.edu.om introduction: in the uk, the national audit office estimated that in 2005 1 in 9 inpatients acquired an infection while in hospital resulting in 5,000 deaths and an estimated cost of 1 billion pounds. improved standards of cleanliness and reduced infection risks have since halved the rates of methicillin resistant staphylococcus aureus (mrsa). as part of this process, many reusable items have been replaced with single-use items, but such items are only now being considered in oman. inadequate decontamination of reusable items contributes to health care associated infections (hcais), patient mortality and morbidity. manufacturer’s guidelines do not always explain the principles of disinfection and sterilisation, and the practical application of these is poorly understood and often not seen as important by nursing staff. objectives: the aim was to establish the degree of nurses’ knowledge about decontamination procedures and to identify training requirements. methods: in this pilot study, a supervised questionnaire was administered to an opportunistic sample of 24 intensive care nurses working in a 16 bedded icu in a tertiary university hospital in oman. the questionnaire covered processes commonly carried out by nurses in this area. results and conclusion: the results are being used to inform the contents of a short training programme and a repeat questionnaire. compliance with key performance indicators will be used to evaluate the course outcomes. squh takes on joint commission international patient safety goals yasmeen s. al hatmi, salim al tememi, ahmed al barwani, squh, muscat, oman. email: yza4me2@yahoo.ca introduction: as an important step towards improving patient safety at sultan qaboos university hospital (squh), the hospital made the decision to follow the joint commission international (jci) international patient safety goals and produce a poster to raise awareness about them. objectives: the purpose of the poster was to introduce some of the most common types of adverse events: incorrectly identifying patients, health-care-acquired infections and confusion in communication between caregivers. the focus was on improving patient safety. the goals were designed to provide clear priorities and offer solutions for improvement that could be implemented in a practical and cost-effective manner in any health care organisation regardless of size or location. methods: this poster introduced the six international patient safety goals and described the importance of each one and how it applied to different areas of the hospital. goal 1: identifying patients correctly. this goal helps to identify the individual as the correct person for whom treatment is intended and to match the care to that person. goal 2: improving effective communication. ineffective communication is the root cause of all adverse events. it is the most frequently identified cause of adverse events such as wrong-site surgery, medication errors, delay in treatment, and ventilator events. goal 3: improving the safety of high alert medications. preventing tragic deaths and serious injuries from the mistaken use, incorrect storage and dispensing of medications as well as errors in dosage calculation of high alert medications, such as concentrated electrolytes and multiple concentrations. goal 4: eliminating wrong-site, wrong-patient, wrong4th symposium on patient safety one aim with shared responsibilities 368 | squ medical journal, december 2009, volume 9, issue 3 procedure surgery. common causes of these avoidable adverse events include issues such as breakdowns in communication and lack of verification checklists in the operating room. goal 5: reducing the risk of health care-acquired infections. these standards focus on reducing the risk of infections and recognising that knowledge and hand hygiene are the most effective ways to reduce the spread of infections such as catheter associated urinary tract infection, blood stream infections (usually associated with intravascular devices) and pneumonia (often associated with mechanical ventilation). other frequent types of infections are surgical site infections, and skin and soft tissue infections. goal 6: reducing the risk of patient harm resulting from falls. by thoroughly assessing and reassessing a patient’s risk, the hospital can include fall prevention as part of the process of planning and providing care. moreover, hospitals can take action to prevent potential falls from occurring. conclusion: frequently asked questions about international patient safety goals are included for a better understanding of implementation and compliance, with reference to joint commission international patient safety and joint commission resources. over the past three decades, the field of cardiovascular intervention has strikingly expanded in terms of technique, technology and information. it has gained sound acceptance owing to both its short and long-term proven benefits. consequently, the interventionalist should be aware about these procedures in a tactile, cognitive and clinical sense. the authors’ philosophy in writing this book is to discuss the potential clinical benefits of interventional versus surgical modalities for adult cardiovascular disease patients who require either percutaneous or surgical interventional procedures. this textbook has 64 chapters covering a wide range of topics related to cardiovascular and extracardiac interventional techniques. they are organised into five sections: 1) septal defects and valvular heart disease; 2) coronary interventions; 3) aortic coarctation, aneurysms and dissections; 4) carotid and cerebral artery interventions, and 5) renal and peripheral arterial interventions. in general, the chosen topics are well written, with easily understood subtitles. the selected coloured as well as black and white photos and images are lucid with self-explanatory legends. each chapter has an extensive bibliography to support the review of the materials presented thus making the book attractive to readers. the data presented provides the latest scientific information in techniques and technology as well as new surgical alternatives. the chapters on chronic total occlusions and bifurcation lesions show that interventional cardiology can be a very sophisticated art when fully supported by new and refined technology. the main strength of this book, as compared to others in the same field, lies in the sections on the application of new technologies like optical coherence tomography (oct), the increasing role of magnetic resonance imaging (mri) in cardiology, as well as new procedures such as transcatheter aortic valve implantation (tavi). in my opinion, most interventional cardiologists will find all ìëüëüä÷]<ìâö^€π]<ª<íò^¬á÷]<9◊œ÷]<ÿ}çj÷]  book review cardiovascular interventions in clinical practice authors: jürgen haase, hans-joachim schäfers, horst sievert, ron waksman. publisher: wiley-blackwell, 1st edition, 2010 isbn: 978-1-4051-8277-5 orders: www.wiley.com/wiley-blackwell squ med j, february 2011, vol. 11, iss. 1, pp. 134-135, epub. 12th feb 11 submitted 6th dec 10 chapters worth reading, either to refresh their basic knowledge or to refine techniques. training and hands-on experience are the fundamental foundation for the interventionalist and no single text can displace this. there are some topics that i found missing in this otherwise valuable book. first, vascular access approaches, the first and most crucial step in any percutaneous technique. second, the difficulties associated with each procedure and tips and tricks to overcome these. third, given that complications related to interventional procedures were gruentzig's (the father of interventional cardiology) greatest concern. i think the editors did not give the prevention and management of complications the central role that they should merit. this book describes the recent advances in the field of cardiovascular intervention. the intended audiences, according to the authors, include students, residents, general practitioners, cardiologists, neurologists and surgeons. i believe that the book is not suitable for students, general practitioners or even for cardiology residents in their early clinical practice. despite these few negative points, a text book like cardiovascular interventions in clinical practice can advance the knowledge of an experienced interventionalist performing percutaneous coronary and peripheral interventions as well as being of interest to cardiac surgeons. the editors, authors, and publisher must be congratulated on delivering a first edition of such high quality. personally, i consider this book to be a tremendous addition to the library of cardiologists, cardiosurgeons and radiologists interested in intervention. r e v i e w e r mansour sallam department of medicine sultan qaboos university hospital, muscat, oman, and al-azhar university, cairo, egypt. email: mansoursallam@yahoo.com. jürgen haase, hans-joachim schäfers, horst sievert and ron waks book review | 135 clinical & basic research squ med j, may 2011, vol. 11, iss. 2, pp. 215-220, epub. 15th may 11 submitted 12th jul 10 revision req. 28th sept 10, revision recd. 9th nov 10 accepted 15th dec 10 <›ç÷]<ö^ñèe]<öüπ<ª]ü«¢]<ƒëááj÷]ê<;⁄à÷]<óvflπ] <d—]ü√÷]e<ïüíf÷]<ª<ì÷áà�÷]<ì◊uü⁄<ª<d^è€è“áè◊÷]e 2009<óju<2004<‡⁄     14 0 2009 2004   21 181 200639 31  5p 0.81    5   :مفتاح الكلمات abstract: objectives: this study aimed to assess the incidence and trend of childhood leukaemia in basrah. methods: this was a hospital-based cancer registry study carried out at the pediatric oncology ward, maternity & children’s hospital and other institutes in basrah, iraq. all children with leukaemia, aged 0 to 14 years diagnosed and registered in basrah from january 2004 to december 2009 were included in the study. their records were retrieved and studied. the pattern of childhood leukaemia by year of diagnosis, age at diagnosis, morphological subtypes, and geographical distribution was analysed. rates of childhood leukaemia over time were calculated for six years using standard linear regression. results: the total number of cases of childhood leukaemia was 181. the number of cases ranged from 21 in year 1, to 31 in the final year reaching a peak of 39 in 2006. leukaemia rates did not change over the study period (test for trend was not significant, p = 0.81). the trend line shows a shift towards younger children (less than 5 years). the commonest types of leukaemia were acute lymphoblastic leukaemia (all), then acute myeloid leukaemia (aml) and finally chronic myeloid leukaemia (cml). conclusion: annual rates of childhood leukaemia in basrah were similar to those in other countries with a trend towards younger children. this raises the question about the effect of environmental catastrophes in the alteration of some specific rates of childhood leukaemia, rather than the overall incidence rate. there is a need for further epidemiological studies to understand the aetiology of childhood leukaemia in basrah. keywords: childhood leukemia; incidence; time trend; cancer registry study; basrah; iraq clinical & basic research time trends and geographical distribution of childhood leukaemia in basrah, iraq, from 2004 to 2009 *laith a alrudainy,1 jenan g hassan,2 hussam m salih,2 mohammed k abbas,2 athar as majeed2 clinical & basic research 1department of community medicine, college of medicine, university of basrah, iraq; 2basrah maternity and children hospital, basrah, iraq. *corresponding author email: alrudainy_laith@yahoo.com advances in knowledge 1. this article is based on one of many studies by the basrah cancer research group and looks at the time trends and geographical distribution of childhood leukaemia in basrah. laith a alrudainy,jenan g hassan,hussam m salih, mohammed k abbas and athar as majeed clinical and basic research | 215 leukaemia is the most common childhood cancer, accounting for 25% to 35% of the incidence of all childhood cancer among most populations.1,2 the commonest type of childhood leukaemia is acute lymphoblastic leukaemia (all), which occurs in approximately 80% of leukaemia cases, followed by acute myeloid leukaemia (aml) and chronic myeloid leukaemia (cml), and a few in other categories.3 the incidence of childhood leukaemia is higher in resource rich countries, ranging from 4.0 to 4.4 per 100,000 per year,4 and lower in less-income countries5 although these variations may reflect a lack of registrations of cancer in low-income countries.6 studies from different parts of the world have indicated an increase in recent decades in the incidence of childhood leukaemia in some countries,7,8 while rates have stayed largely stable in the usa and nordic countries.9,10 in most countries, the incidence of childhood leukaemia is higher among boys than girls.11,12 although the aetiology of most childhood leukaemias is unknown,13 several factors have been associated with the disease, including socioeconomic status,14,15 environmental exposures including ionising radiation and benzene,16 infectious agents,17 and parental exposure risk factors.18,19 basrah is iraq’s second largest city and its main port. it is located along the shatt al-arab waterway, approximately 545 km southeast of baghdad and adjacent to iran and kuwait. basrah is composed of a flat alluvial plain formed by the combined flood plains and deltas of the tigris, euphrates, and shatt al-arab rivers. the area surrounding basrah has substantial petroleum resources with many oil wells. basrah has been exposed to massive environmental pollution as a consequence of military conflicts and lack of an efficient protective policy from 1980 to 2003. previous research work and growing impressions among physicians and lay people suggest that childhood leukaemia has increased in basrah since the second gulf war.20,21,22 however, these suggestions were criticised for being inadequate proof of a real increase in the risk of childhood leukaemia because of incomplete case registration and/or inaccurate population denominators before 2003. in order to study the subject properly, the basrah cancer research group (bcrg) was established in 2004. bcrg initiated a project to improve registration, identify risk factors, and improve care. this group has achieved good results in registration of cancer, including childhood leukaemia.23 the purpose of this study was to assess the rates and trends of childhood leukaemia in basrah, iraq, from 2004 to 2009. the data reported here can be used for comparison with past figures or future findings. methods the basrah governorate is divided into five areas congruent to the health sectors established by the basrah health authorities: city centre, south basrah, west basrah north basrah and east basrah (see map, figure 4). information related to the population of basrah was based on data available from basrah health authorities, electronic lists and the statistical office in basrah. the authors depended on the information from ration cards to assess the size of the population in basrah. the ration card system was established from the 1990s to provide basic foodstuffs to iraqi people during 2. although the rates of leukaemia in children aged 0 to 14 years did not change over the 6 year period (possibly because of incomplete cancer registration), the rates were much higher than in other western and eastern countries. this may be due to exposure to environmental leukemogens. 3. another finding is the shift of the incidence of leukaemia in recent years towards children under 5 years. 4. the highest average rate of childhood leukaemia is in west and east basrah, two regions exposed to great environmental pollution during recent decades. application to patient care 1. the results of our study are useful for determining the extent of childhood leukaemia in basrah in recent years. 2. comparison of the incidence rates in population groups that differ in exposures permits one to estimate the effect of exposure to a hypothesised factor of interest. 3. the extent of the time trend and geographical distribution of childhood leukaemia will help in future planning of health care services, drug supplies, and other preventive measures for patients and the general population. time trends and geographical distribution of childhood leukaemia in basrah from 2004 to 2009 216 | squ medical journal, may 2011, volume 11, issue 2 the economic sanctions after the 1991 gulf war. it is therefore the best way to assess the basrah population's size under the prevailing circumstances, because the iraqi government monitors it carefully for economic reasons. it is renewed annually to take into account migration, death, and births in the population. in comparison with other parts of iraq, the population in basrah is more stable and, due to a stable political and economic environment migration is not an important issue. this hospital-based cancer registry study was based on all new cases of childhood leukaemia which were registered at the pediatric oncology ward of the basrah maternity & children’s hospital and other institutes, e.g. the main oncology centre in basrah, the cancer regisration section at the department of pathology, college of medicine university of basrah, and data from some specialist doctors who keep their own collection of cancer cases as part of their routine clinical work. the research protocol was approved by the scientific committee in the department of community medicine, college of medicine, university of basrah, in december 2009. the permission of the directorate of health in basrah was obtained prior to the research implementation. in basrah, all childhood leukaemia cases are referred to the pediatric oncology ward in basrah’s maternity & children’s hospital, which is responsible for the treatment and registration of all childhood malignancies in southern iraq. many of the children are treated outside iraq, but they are diagnosed and registered in basrah before travelling. diagnosis was based on the histopathology of the bone marrow and complete blood counts. two haematologists agreed on all diagnoses, and no changes in diagnostic techniques occurred over the study period. standard criteria are used to diagnose leukaemia, which for the purpose of this analysis have been divided into acute lymphoblastic leukaemia (all), acute myeloblastic leukaemia (aml), chronic myeloid leukaemia (cml), and chronic lymphocytic leukaemia. cases identified by various sources were entered first on excel spreadsheets in most centres, or identified from their original documents and entered by bcrg on excel. then, all the excel files were merged, matched and checked for any duplications. all analyses were carried out with the statistical package for the social sciences (spss) programme (version 15.0). some of the figures were constructed using excel 2007. incidence data were reported for each year by dividing the incidence by the population (aged 0–14 years) for each year, then multiplying by 100,000. to assess whether the increase in leukaemia rates over time was statistically significant, we calculated rates for the six years 2004–2009 and used standard linear regression to test whether the slope of the line between each year average rates was different from 0. this method is similar to that used by linet et al. in their study of the changes in leukaemia rates in the usa.24 age standardised incidence was derived using the world standard population by the direct method.25 results there were 181 cases of leukaemia in children aged 0–14 years registered in basrah during the six years 2004 to 2009. this represented 46.2 % of the total percentage of cancers among children in basrah. the number of cases ranged from 21 cases in the first year to 31 cases in the final year and reached a peak of 39 cases in 2006 [table 1]. leukaemia rates in children aged 0 to 14 years did not change over the 6 year period (ratio of 2008–2009 rate to 2004–2005 rate = 0.96; 95% confidence interval = 0.96 – 1.01). by using the parameter estimate from the regression model of untransformed values, it was found that leukaemia rates decreased by 0.123 per 100,000 during the 6 table 1: leukaemia rates for children aged 0 to 14 years in basrah, iraq, from 2004 to 2009. year no. of leukaemia casesa populationb rate per 100,000 population 2004 21 777,709 2.70 2005 32 837,293 3.82 2006 39 866,896 4.49 2007 27 946,377 2.85 2008 31 971,929 3.18 2009 31 998,171 3.10 note: the data were collected from the cancer registry at the pediatric oncology ward in basrah maternity & children’s hospital. legend: a = cases of acute lymphoblastic leukaemia, acute myeloid leukaemia, and chronic myeloid leukaemia. b = population aged from 0 to 14 years. laith a alrudainy,jenan g hassan,hussam m salih, mohammed k abbas and athar as majeed clinical and basic research | 217 year period: beta (b) = 0.123; standard error (se) = 0.17); the test for trend was not significant, with p = 0.81. we were satisfied that presentation of rates in figure 1 was a robust finding of no change in childhood leukaemia in basrah over the period of our study. the total reported cases during the years 2004– 2009 shows that leukaemia was more frequent in boys (59.8%) than in girls (40.2%), with a male to female ratio of 149:100. the total leukaemia rate among boys was 3.63 per 100,000 during the years 2004–2005 and 4.18 per 100,000 for 2008–2009. for girls, the rates were 3.03 during the earlier period and 2.07 during the most recent two year period (data not shown). the trend line in figure 2 shows the shift of the incidence of leukaemia in recent years towards younger children (below 5 years of age). in the 2004–2005 period, children ages 0 through 4 had overall annual leukaemia rates of 3.04 per 100,000, compared with 3.46 for children aged 10 to 14 years. in the 2008–2009 period, children aged 0 to 4 years had an annual rate of 4.36 per 100,000, compared with 1.73 for children aged 10 to 14 years. different trends in incidence were observed for all, aml, and cml from 2004 to 2009 [figure 3]. in the period 2004–2005, there were 40 cases of all, 8 cases of aml, and 6 cases of cml. these case number reflect rates of 2.47 per 100,000 children for all, 0.49 for aml, 0.37 for cml. during the period 2008–2009, the case counts and rates were 50 for all, 9 for aml, and 3 for cml, reflecting rates of 2.53, 0.45, and 0.15 per 100,000, respectively (data not shown). the rates of childhood leukaemia in each region of basrah over the five years are shown in figure 4. the highest rate was found in west basrah (4.01/100,000), followed by east basrah (3.88/100,000), north basrah (3.69/100,000), south basrah (3.58/100,000), and basrah city centre (2.77/100,000) respectively. discussion the aim of this study was to describe rates and changes in childhood leukaemia for the population of basrah, iraq, in recent years. data for this study were taken from the cancer registry of the pediatric oncology word of the maternal & children’s hospital in cooperation with the college of medicine of the university of basrah and the bcrg. basrah is confronted with a range of environmental problems, some of which can be directly linked with the effects of recent military conflicts. others have been triggered by internal iraqi policies and actions, and were exacerbated by factors such as the impact of economic sanctions.26 during the 2003 gulf war, there were reports of oil wells having been deliberately set on fire in the rumeila oilfield in basrah, while a thick haze of dark smoke could be seen from kuwait city the following day. the broad categories of contaminants are volatile hydrocarbons, hydrogen sulphide, and naturally occurring radioactivity. since the aromatic hydrocarbons (like benzene), which are known to be leukaemogenic, are the most volatile of hydrocarbons, exposure even at low levels can be very harmful.27 also, in gulf wars of 1991 and 2003, the us figure 1: leukaemia rates and 95% confidence intervals among children aged 0 to 14 in basrah, iraq, from 2004 to 2009 0 1 2 3 4 5 2004-2005 2008-20092006-2007 year of diganosis 0-4 yrs 10-14 yrs r a te p e r 1 0 0 0 0 0 figure 2: the rates of childhood leukaemia in basrah, iraq, according to the age and year of diagnosis. time trends and geographical distribution of childhood leukaemia in basrah from 2004 to 2009 218 | squ medical journal, may 2011, volume 11, issue 2 and uk governments acknowledged that known depleted uranium munitions were used in iraq. many tons of this radioactive substance was targeted at the basrah governorate.28 our data show that the rates of leukaemia in children aged 0 to 14 years did not change over the 6 year period. this finding is inconsistent with hagopian et al. study which reported that the average annual incidence of childhood leukaemia in basrah has raisen substantially.22 in the hagopian et al. study, the average annual rates of childhood leukaemia were measured by dividing the incidence by the population (aged 0–14 years) for each year, then multiplying by 100,000. the incidence included all new cases of childhood leukaemia that were diagnosed and treated in basrah (included cases from basrah and those who came from other provinces in southern iraq) and divided by the estimated size of the population from basrah province only; this led to an increase in the average annual rate to about 12 per 100,000. also, the change in the trend of childhood leukaemia in hagopian et al. study might be attributed to the underestimation of cancer cases, because of incomplete cancer registration prior to 2003 in basrah.23 in the present study, leukaemias make up about 46% of paediatric cancers in basrah, whereas international percentages ranged from 27% of paediatric cancers in the united states, 30% in ireland and france, 33% in germany, 35% in shanghai, china, and india.29–34 the high percentage of leukaemia in the present study may reflect the underestimation of other types of paediatric cancer, or it may be suggest a relatively higher risk of leukaemias in basrah reflecting an exposure to certain risk factors, like the exposure to environmental leukemogens. another finding in the present study is the shift of the incidence of leukaemia in recent years towards younger children (below 5 years of age). our results are similar to those from the united states and great britain,35 where the peak occurs between the age of 2–5 years, but the peak is less marked in less developed countries.36,37 this observation may also be attributed to the effect of environmental pollution and/or the changes in the life style of the population in basrah in recent years compared to the west. the highest average rate of childhood leukaemia is present in west and east basrah. these two regions were exposed to great environmental pollution during recent decades. west basrah was exposed to many environmental carcinogens in the wars of 1991 and 2003 such as depleted uranium and aromatic hydrocarbons. east basrah was also affected by environmental pollution as a result of the military conflict in the period from 1980 to 1988, during the iraq-iran war. on the other hand, our data show that the average annual rate of all types of childhood leukaemia (per 100,000 children aged 0 – 14) did not noticeably rise in basrah during the six years under review. also, the rates of childhood leukaemia subtypes (all, aml, and cml) were not elevated. because all was by far the commonest type, the trends in the rates of all leukaemias combined should mostly reflect trends in the incidence of all. figure 3: the rates of acute lymphoblastic leukaemia (all), acute myeloid leukaemia (aml), and chronic myeloid leukaemia (cml) from 2004 to 2009 figure 4: average rates per 100,000 of childhood leukaemia in different areas of basrah, 2004 – 2009: 1) basrah city centre, 2) south basrah, 3) west basrah, 4) north basrah, 5) east basrah. laith a alrudainy,jenan g hassan,hussam m salih, mohammed k abbas and athar as majeed clinical and basic research | 219 conclusion although we observed no temporal increase in the incidence rates for childhood leukaemia during the 6 year period from 2004 to 2009, there is shift in the incidence of leukaemia in recent years towards younger children and there is an increase in the percentage of childhood leukaemia in comparison with other studies worldwide. this result raises the question about the effect of environmental pollution on the specific characteristics of childhood leukaemia rather than on the overall incidence rate. it is known that the basrah region was exposed to environmental insults including the known leukemogen benzene 27 and pyrophoric depleted uranium, 21,28 but also, and still ongoing, undifferentiated water and air pollution; however, no data are available on the doses to which the leukaemia patients in our study were exposed. there is a need for further epidemiological studies to understand the effect of environmental pollution on the pattern of childhood leukaemia in basrah. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g m e n t s the authors would like to thank professor hans peer wagner, professor of paediatric haematology and oncology (university of bern, switzerland) for valuable discussions and for checking the manuscript. we express our appreciation to all the members of bcrg for their continuous effort in updating and improving the data collected. references 1. parkin dm, stiller ca, draper gj, bieber ca. the international incidence of childhood cancer. int j cancer 1988; 42:511−20. 2. pui ch, schrappe m, ribeiro rc, niemeyer cm. childhood and adolescent lymphoid and myeloid leukemia. hematology 2004:118–145. 3. linet ms, devesa s, morgan gj. the leukemias. in: schottenfeld d, joseph f, fraumeni j, eds. cancer epidemiology and prevention. oxford: oxford university press; 2006:841–871. 4. parkin dm. cancer incidence in five continents. geneva: world health organization, international agency for research on cancer, international association of cancer registries, 2005. 5. freedman ls, edwards bk, rise lag, young jl. cancer incidence in four member countries (cyprus, egypt, israel, and jordan) of the middle east cancer consortium (mecc) compared with us seer. national cancer institute. from: .http://seer. cancer.gov/publications/mecc/mecc_monograph. pdf accessed: april 2007. 6. howard sc, metzger ml, wilimas ja, pui ch, robison ll, ribeiro rc. childhood cancer epidemiology in low-income countries. cancer 2008; 112:461−472. 7. hrusak o, trka j, zuna j, polouckova a, kalina t, stary j. acute lymphoblastic leukemia incidence during socioeconomic transition: selective increase in children from 1 to 4 years. leukemia 2002; 16:720−5. 8. mcnally rjq, eden tob. an infectious etiology for childhood leukemia: a review of the evidence. br j haematol 2004; 127:243−63. 9. linet ms, ries la, smith ma, tarone re, devesa ss. cancer surveillance series: recent trends in childhood cancer incidence and mortality in the united states. j natl cancer inst 1999; 91:1051− 8. 10. hjalgrim ll, rostgaard k, schmiegelow k, söderhäll s, kolmannskog s, vettenranta k, et al. ageand sex-specific incidence of childhood leukemia by immunophenotype in the nordic countries. j natl cancer inst 2003; 95:1539−44. 11. mcnally rj, rowland d, roman e, cartwright ra. age and sex distributions of hematological malignancies in the u.k. hematol oncol 1997; 15:173−189. 12. pearce ms, parker l. childhood cancer registrations in the developing world: still more boys than girls. int j cancer 2001; 91:402−6. 13. thompson jr, gerald pf, willoughby ml, armstrong bk. maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. lancet 2001; 358:1935−40. 14. borugian mj, spinelli jj, mezei g, wilkins r, abanto z, mcbride ml. childhood leukemia and socioeconomic status in canada. epidemiology 2005; 16:526−31. 15. raaschou-nielsen o, obel j, dalton s, tjønneland a, hansen j. socioeconomic status and risk of childhood leukaemia in denmark. scand j public health 2004; 32:279–86. 16. belson m, kingsley b, holmes a. risk factors for acute leukemia in children: a review. environ health perspect 2007; 115:138−45. 17. infante-rivard c, olson e, jacques l, ayotte p. drinking water contaminants and childhood leukemia. epidemiology 2001; 12:13−19. 18. fear nt, simpson j, roman e. childhood cancer and social contact: the role of paternal occupation (united kingdom). cancer causes control 2005; 16:1091−7. time trends and geographical distribution of childhood leukaemia in basrah from 2004 to 2009 220 | squ medical journal, may 2011, volume 11, issue 2 19. perez-saldivar ml, ortega-alvarez mc, fajardogutierrez a, bernaldez-rios r, del campomartinez l, medina-sanson a. father’s occupational exposure to carcinogenic agents and childhood acute leukemia: a new method to assess exposure (a casecontrol study). bmc cancer 2008; 8:7. 20. ciment j. iraq blames gulf war bombing for increase in child cancers. bmj 1998; 317:1612−15. 21. yacoub aah, al-sadoon io, hassan gg, al-hemadi m. incidence and pattern of malignant disease among children in basrah with specific reference to leukemia during the period 1990 – 1998. med j basrah univ 1999; 17:27−34. 22. hagopian a, lafta r, hassan j, davis s, mirick d, takaro t. trends in childhood leukemia in basrah, iraq, 1993–2007. am j public health from: http:// a j p h . a p h a p u b l i c a t i o n s . o r g / c g i / d o i / 1 0 . 2 1 0 5 / ajph.2009.164236 accessed: feb 2010. 23. basrah cancer research group. cancer in basrah 2005-2008. basrah: dar alkutub for press & publication, university of basrah, 2009. pp. 34. 24. linet ms, ries la, smith ma, tarone re, devesa ss. cancer surveillance series: recent trends in childhood cancer incidence and mortality in the united states. j natl cancer inst 1999; 91:1051–58. 25. boyle p, parkin dm. statistical methods for registries. in: jensen om, parkin dm, maclennan r, muir cs, skeet rg, eds. cancer registration, principles and methods. lyon: iarc, 1991. p.26. 26. united nations environment programme. desk study on the environment in iraq from: www.unep. org/pdf/iraq accessed: feb 2010. 27. environment in iraq. unep progress report, un, geneva, 2003. from: http://postconflict.unep.ch/ publications/iraq_pr.pdf accessed: feb 2010. 28. dyer o. who suppressed evidence on effects of depleted uranium; expert says. bmj 2006; 333:990. 29. linabery am, ross ja. trends in childhood cancer incidence in the us (1992–2004). cancer 2008; 112:416−32. 30. stack m, walsh pm, comber h, ryan ca, o’lorcain p. childhood cancer in ireland: a population-based study. arch dis child 2007; 92:890−7. 31. desandes e, clavel j, berger c, bernard jl, blouin p, de lumley l, et al. cancer incidence among children in france, 1990–1999. pediatr blood cancer 2004; 43: 749−57. 32. spix c, eletr d, blettner m, kaatsch p. temporal trends in the incidence rate of childhood cancer in germany 1987–2004. int j cancer 2008; 122:1859−67. 33. bao pp, zheng y, wang cf, gu k, jin f, lu w. time trends and characteristics of childhood cancer among children age 0–14 in shanghai. pediatr blood cancer 2009; 53:13−16. 34. swaminathan r, rama r, shanta v. childhood cancers in chennai, india, 1990-2001: incidence and survival. int j cancer 2008; 122:2607−11. 35. margolin jf, steuber cp, poplack dg. acute lymphoblastic leukemia. in: pizzo pa, poplack dg, eds. principles and practice of pediatric oncology. philadelphia: lippincott williams & wilkins. 15th ed. 2006. pp. 538–90. 36. stiller ca, parkin dm. geographic and ethnic variations in the incidence of childhood cancer. br med bull 1996; 52:682−703. 37. plesko i, somogyi j, dimitrova e, kramaroki. descriptive epidemiology of childhood malignancy in slovakia. neoplasm 1989; 36:233−43. 1department of anaesthesiology, resuscitation & pain therapeutics, hospital general universitario de ciudad real, ciudad real, spain; departments of 2surgical services and 3anaesthesiology, resuscitation & pain therapeutics, consorcio hospital general universitario de valencia, valencia, spain; 4department of anaesthesiology, resuscitation & pain therapeutics, hospital sant joan de déu, barcelona, spain *corresponding author’s e-mail: errando013@gmail.com التسكني بالراميفنتانيل الوريدي ملريضة يف مرحلة الوالدة مصابة بالنوع 1 من الورم الليفي العصيب و العامل اخلامس لطفرة ليدن خو�صيه لو�ض جالفيز، كارلو�ض لو�ض اإراندو، �صيلفيا �صريانو، مارجا مارتن-اآيو�صو، خو�صيه ميجيول فالفريدي-مانتيكون abstract: type i neurofibromatosis is characterised by altered skin pigmentation and the growth of benign tumours, particularly along the peripheral nerves and central nervous system. we report a 36-year-old primigravida woman in labour who was admitted to the obstetric suite of the hospital sant joan de déu, barcelona, spain, in 2007 with hypothyroidism, type i neurofibromatosis and a factor v leiden mutation. due to a lack of cranial and spinal imaging data, an epidural was not indicated; instead, continuous intravenous remifentanil analgaesia was administered. the remifentanil infusion was self-titrated by the patient using a visual analogue scale, with the dosage ranging from 0.01 to 0.25 μg/kg/minute. due to rotational dystocia, kjelland-type forceps were used during the delivery. after birth, the infant was found to have apgar scores of 9 and 10, with no maternal or neonatal adverse effects observed. although still controversial, remifentanil may be a successful alternative for analgaesia in similar cases; however, the specific risks and benefits for each patient should be considered prior to administration. keywords: obstetrical analgesia; drug contraindications; type 1 neurofibromatosis; factor v deficiency; case report; spain. امللخ�ص: يتميز النوع 1 للورم الليفي الع�صبي بتغري يف ت�صبغ اجللد ومنو الأورام احلميدة خا�صة على طول الأع�صاب املحيطية والنظام الع�صبي املركزي. نعر�ض هنا حالة ملراأة حامل للمرة الأوىل عمرها 63 عاما يف حالة ولدة مت تنوميها بجناح الولدة يف م�صت�صفى �صانت لطفرة اخلام�ض العامل و الع�صبي الليفي للورم 1 والنوع الدرقية بق�صور م�صابة وهي 2007 عام يف اأ�صبانيا بر�صلونة، ديو، دي جون ليدن. ب�صبب عدم توفر معلومات الأ�صعة الدماغية والنخاعية، مل يكن بالإمكان اأ�صتخدام تخدير فوق اجلافية ولذلك مت اإعطاء جرعة وريدية متوا�صلة من تخدير الراميفنتانيل. مت معايرة ت�رشيب الراميفنتانيل عن طريق املري�صة نف�صها باإ�صتخدام مقيا�ض التنظري الب�رشي بجرعة ترتاوح من 0.01 اإىل 0.25 ملغ/كلغ/دقيقة. ب�صبب ع�رش الولدة الدوراين مت اإ�صتخدام ملقط كيالند عند الولدة. بعد الولدة، �صجل الر�صيع 9 و 10 نقاط ح�صب مقيا�ض اأبجر، بدون وجود اأي اآثار �صائرة اأمومية اأو وليدية تذكر. على الرغم من وجود اإختالفات، قد يكون الراميفنتانيل بديل ناجح للت�صكني يف حالت مماثلة. ومع ذلك؛ ينبغي النظر يف املخاطر والفوائد املحددة لكل مري�ض قبل الإ�صتخدام. الكلمات املفتاحية: ت�صكني توليدي؛ موانع اأ�صتعمال الدواء؛ النوع 1 للورم الليفي الع�صبي؛ عوز العامل اخلام�ض؛ تقرير حالة؛ اأ�صبانيا. intravenous remifentanil analgaesia for an obstetric patient with type i neurofibromatosis and a factor v leiden mutation josé l. gálvez,1 *carlos l. errando,2,3 silvia serrano,4 marga martín-ayuso,1 josé m. valverde-mantecón1 sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e468–471, epub. 10 jan 18 submitted 10 apr 17 revision req. 11 may 17; revision recd. 9 jun 17 accepted 6 jul 17 case report doi: 10.18295/squmj.2017.17.04.016 the concurrence of multiple genetically unrelated inherited diseases is rare and complicates analgaesic or anaesthetic management. type i neurofibromatosis (nf)—also known as von recklinghausen’s disease—is an autosomal dominant disease caused by a mutation in the nf1 gene on chromosome 17; it has a prevalence of 1 in 2,500–3,500 live births and accounts for 80% of all nf cases.1,2 approximately half of all type i nf cases are inherited, while the rest are de novo mutations.2 the classical features of type 1 nf include benign tumours of the peripheral nerves (i.e. neurofibromas), pigmented milky-brown skin lesions, freckles in unexposed areas such as the armpits and iris hamartomas (i.e. lisch nodules).3 while most patients are usually asymptomatic, these features can result in compressive radicu lopathies or neuropathies. notably, the clinical presentation is quite variable even between affected members of the same family.2 type i nf can be associated with first-trimester miscarriages and obstetric patients often require a caesarean section delivery due to complications such as pelvic neurofibromas, pelvic bone abnormalities and kyphoscoliosis.3 adults with type i nf can develop multiple cutaneous and subcutaneous neurofibromas which increase in number and size throughout their life.3 plexiform neurofibromas can cause deformities, pain and functional problems and may sometimes become malignant. osteopaenia, osteoporosis, bone overgrowth, short stature, macrocephalia, scoliosis, josé l. gálvez, carlos l. errando, silvia serrano, marga martín-ayuso and josé m. valverde-mantecón case report | e469 skeletal dysplasia (particularly of the sphenoid bone and vertebral wing) or pseudoarthrosis may also be present.3 other alterations include arterial hypertension, vasculopathy, intracranial tumours, malignant peripheral nerve sheath tumours and, occasionally, seizures or hydrocephalus. cognitive deficits and learning difficulties commonly occur in 30–45% of adults with nf, along with an increased risk of cancer.3 most inherited hypercoagulable disorders are due to deficiencies of proteins c or s and antithrombin iii, which occur in 15% of venous thrombosis cases.4 from a pathophysiological point of view, factor v leiden (fvl) is the most common causative factor in this group of diseases.4 a fvl defect results from a mutation in the g1691a gene that encodes clotting factor v, which is inherited as an autosomal dominant trait; this leaves factor v resistant to inactivation by factor v-activated protein c.4,5 in the normal population, up to 3–5% of people carry the fvl mutation.6 pregnant women suffering from this deficiency appear to have an increased rate of spontaneous recurrent fetal loss.5 to the best of the authors’ knowledge, no relationship between fvl deficiency and nf has yet been reported in the literature. moreover, the occurrence of these conditions during pregnancy makes analgaesic management challenging during delivery. this report describes a pregnant woman who presented with both of these conditions and in need of analgaesia during labour. case report a 36-year-old primigravida woman at 39 gestational weeks and five days was admitted to the obstetric suite of the hospital sant joan de déu, barcelona, spain, in 2007 for the induction of labour. she weighed 84 kg and her height was 162 cm. her fetus was of low weight. she was known to have hypothyroidism, type i nf and a fvl mutation. these diseases were under medical control both before and during her pregnancy, with the hypothyroidism treated with levothyroxine. during the last trimester of her pregnancy, she had been prescribed 3,500 u of bemiparin per day; she had been advised to discontinue use 12 hours prior to delivery and/or the epidural puncture and to subsequently resume taking the drug 24–48 hours postpartum, provided there were no haemorrhagic complications. childbirth was induced using vaginal dinoprostone. after 24 hours, dilatation of the cervix was still unfavourable with a bishop’s score of <6. as such, oxytocin perfusion was initiated. a few hours later, amniorrhexis was performed and the patient requested analgaesia. her coagulation profile showed a thromboplastin time of 12.6 seconds, 98% prothrombin activity, an activated partial thromboplastin time of 26.2 seconds, fibrinogen levels of 465 mg/dl and an international normalised ratio of 0.92. a clinical evaluation indicated that she had neurofibromas covering the entire surface of her back. due to the lack of recent skull, central nervous system or spine imaging, neuraxial analgaesia could not be administered and alternative techniques for labour analgaesia were considered. subsequently, a remifentanil infusion was agreed upon with the patient’s consent. the potential adverse effects and complications of the drug were explained to the patient and a visual analogue scale (vas) was used to continuously evaluate her pain. during dilatation, the patient’s blood pressure was monitored non-invasively every 10 minutes while her heart rate and pulse oximetry peripheral arterial oxygen saturation were monitored continuously. the fetal heart rate and uterine tone were also continuously recorded. a total of 150 mg of ranitidine was administered via an intravenous injection, along with 2 l/minute of oxygen through nasal prongs. the patient was instructed on how to use and control the remifentanil infusion herself; however, the midwife and/or the anaesthesiologist assisted her with the infusion pump whenever necessary. the infusion was initiated at a rate of 0.01 μg/kg/minute with the maximum limit set at 0.25 μg/kg/minute. the patient’s vas scores increased from 0–3 to 4–5 by the time she was fully dilated towards the end of the labour, with the remifentanil infusion rate modified upon demand. the delivery was performed using kjelland-type forceps due to rotational dystocia and an episiotomy was performed with local anaesthetic infiltration. after 395 minutes of labour, a male neonate weighing 3,120 g was born. his apgar scores were 9 and 10 at one and five minutes, respectively. cord blood tests were within the normal range and no haemodynamic alterations in the patient were observed, other than transient sinus tachycardia during the delivery. discussion remifentanil is an ultrashort-acting synthetic opioid with a short duration of action and no cumulative effects; its peak effect usually occurs 1–2 minutes after administration.7,8 it also has a very short half-life of approximately three minutes, independent of hepatic or renal function.8 an infusion rate of 0.1 μg/kg/minute preserves spontaneous breathing among patients who are awake.9 however, arterial hypotension, muscle stiffness, nausea and vomiting, chills, bradycardia, apnoea and respiratory depression have been reported intravenous remifentanil analgaesia for an obstetric patient with type i neurofibromatosis and a factor v leiden mutation e470 | squ medical journal, november 2017, volume 17, issue 4 effect hydrocephalus or suggestive imaging findings have a minimal risk of herniation following a dural puncture.17 the parturient women at most risk include those who present with lesions that compress the brain tissue and cause midline deviation, either with or without obstruction of the cerebrospinal fluid flow.17 as such, cranial or neuraxial computed tomography or magnetic resonance imaging is highly recommended for pregnant women with both type i nf and fvl deficiency.12,17 in addition, it is also crucial to provide such patients with a comprehensive explanation of the associated risks and benefits of each analgaesic option. conclusion the concurrence of rare diseases—such as type i nf and fvl deficiency—can complicate the management of analgaesia during labour, particularly with regards to standard neuraxial approaches. in the current case, the use of a usually contraindicated alternative, remifentanil, was successful; however, neuraxial analgaesia might also have been a feasible option, had recent imaging studies of the patient been available. references 1. vallejo mc. anaesthesia recommendations for patients suffering from neurofibromatosis type 2. from: www.orpha. net/data/patho/pro/en/nf2_en.pdf accessed: jun 2017. 2. friedman jm, riccardi vm. clinical epidemiological features. in: friedman jm, gutmann dh, maccollin m, riccardi vm, eds. neurofibromatosis: phenotype, natural history, and pathogenesis, 3rd ed. baltimore, maryland, usa: johns hopkins university press, 1999. pp. 29–86. 3. online mendelian inheritance in man (omim). entry #162200: neurofibromatosis, type i. from: http://omim.org/ entry/162200 accessed jun 2017. 4. bande bd, bande sb, mohite s. the hypercoagulable states in anaesthesia and critical care. indian j anaesth 2014; 58:665–71. doi: 10.4103/0019-5049.144682. 5. online mendelian inheritance in man (omim). entry #612309: coagulation factor v. from: http://omim.org/entry/612309 accessed: jun 2017. 6. leff j, shore-lesserson l, fischer gw. hematologic diseases. in: fleisher la, ed. anesthesia and uncommon diseases, 6th ed. philadelphia, pennsylvania, usa: saunders, 2012. pp. 350–68. 7. blair jm, dobson gt, hill da, mccracken gr, fee jp. patient controlled analgesia for labour: a comparison of remifentanil with pethidine. anaesthesia 2005; 60:22–7. doi: 10.1111/j.13652044.2004.03975.x. 8. volmanen p, sarvela j, akural ei, raudaskoski t, korttila k, alahuhta s. intravenous remifentanil vs. epidural levobupivacaine with fentanyl for pain relief in early labour: a randomised, controlled, double-blinded study. acta anaes thesiol scand 2008; 52:249–55. doi: 10.1111/j.1399-6576.2007. 01509.x. 9. ohashi y, baghirzada l, sumikura h, balki m. remifentanil for labor analgesia: a comprehensive review. j anesth 2016; 30:1020–30. doi: 10.1007/s00540-016-2233-y. as side-effects.7–10 tolerance and hyperalgaesia have also been described.7,8 the concurrence of type i nf and fvl deficiency in a pregnant patient is an unusual challenge both from an obstetric point of view and in relation to the choice of analgaesia. although the use of remifentanil is gradually becoming more common among obstetric patients, it is still a subject of some debate.7–10 moreover, remifentanil infusions are rarely reported among obstetric patients with comorbidities. in cases similar to the one described in this report, intramuscular or intravenous analgaesia with opiates (i.e. meperidine) or inhaled nitrous oxide are usually considered instead.10 however, previous research indicates that remifentanil is more effective than either of these options.7 in a multicentre study of pregnant women with fvl deficiency, martinelli et al. noted a significant increase in the prevalence of venous thrombosis both during and after pregnancy.11 although, anticoagulation with low-molecular-weight heparin (lmwh) would have permitted neuraxial analgaesia in the current case, the dose-response time frame in a patient with coexisting type i nf is still unclear.4,11,12 harnett et al. have previously described the successful use of epidural analgaesia and lmwh in a pregnant woman with fvl deficiency.13 however, neuraxial imaging prior to invasive procedures is recommended for patients with type i nf and coexisting hereditary neuropathies, such as charcot-marie-tooth disease.14 since this was unavailable in the present case, the anaesthesiologists decided to forego neuraxial tech niques despite the patient’s normal creatinine clearance rate. the occurrence of neurofibromas at the puncture site for the administration of anaesthesia or analgaesia can make the technical procedure either difficult or impossible. an epidural haematoma following a dural puncture has been reported in a parturient woman with nf.15 spinal tumours have also been reported in 40% of patients with type i nf, even among asymptomatic cases; most of these tumours were lateral to the intervertebral foramen and would therefore have been at risk of trauma during a neuraxial puncture, especially if they had spread towards the midline.16 another possible complication following a dural puncture is rapid decompression, particularly among patients with intracranial tumours; this could cause spinal cord injury or death as a result of the increased intracranial pressure.17 moreover, regional neuraxial anaesthesia is usually contraindicated for patients with neurological symptoms. nevertheless, even intracranial space-occupying lesions do not always cause an increase in intracranial pressure; for example, individuals with no mass https://doi.org/10.4103/0019-5049.144682 https://doi.org/10.1111/j.1365-2044.2004.03975.x https://doi.org/10.1111/j.1365-2044.2004.03975.x https://doi.org/10.1111/j.1399-6576.2007.01509.x https://doi.org/10.1111/j.1399-6576.2007.01509.x https://doi.org/10.1007/s00540-016-2233-y josé l. gálvez, carlos l. errando, silvia serrano, marga martín-ayuso and josé m. valverde-mantecón case report | e471 10. kranke p, girard t, lavand’homme p, melber a, jokinen j, muellenbach rm, et al. must we press on until a young mother dies? remifentanil patient controlled analgesia in labour may not be suited as a “poor man’s epidural”. bmc pregnancy childbirth 2013; 13:139. doi: 10.1186/1471-2393-13-139. 11. martinelli i, legnani c, bucciarelli p, grandone e, de stefano v, mannucci pm. risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. thromb haemost 2001; 86:800–3. 12. katz d, beilin y. disorders of coagulation in pregnancy. br j anaesth 2015; 115:ii75–88. doi: 10.1093/bja/aev374. 13. harnett mj, walsh me, mcelrath tf, tsen lc. the use of central neuraxial techniques in parturients with factor v leiden mutation. anesth analg 2005; 101:1821–3. doi: 10.1213/01. ane.0000184135.00502.3e. 14. kapur s, kumar s, eagland k. anesthetic management of a parturient with neurofibromatosis 1 and charcot-marie tooth disease. j clin anesth 2007; 19:405–6. doi: 10.1016/j. jclinane.2007.03.001. 15. esler md, durbridge j, kirby s. epidural haematoma after dural puncture in a parturient with neurofibromatosis. br j anaesth 2001; 87:932–4. doi: 10.1093/bja/87.6.932. 16. thakkar sd, feigen u, mautner vf. spinal tumours in neurofibromatosis type 1: an mri study of frequency, multiplicity and variety. neuroradiology 1999; 41:625–9. doi: 10.1007/s002340050814. 17. leffert lr, schwamm lh. neuraxial anesthesia in parturients with intracranial pathology: a comprehensive review and reassessment of risk. anesthesiology 2013; 3:703–18. doi: 10. 1097/aln.0b013e31829374c2. https://doi.org/10.1186/1471-2393-13-139 https://doi.org/10.1093/bja/aev374 https://doi.org/10.1213/01.ane.0000184135.00502.3e https://doi.org/10.1213/01.ane.0000184135.00502.3e https://doi.org/10.1016/j.jclinane.2007.03.001 https://doi.org/10.1016/j.jclinane.2007.03.001 https://doi.org/10.1093/bja/87.6.932 https://doi.org/10.1007/s002340050814 https://doi.org/10.1097/aln.0b013e31829374c2 https://doi.org/10.1097/aln.0b013e31829374c2 departments of 1child health and 2microbiology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: tamemi@squ.edu.om أمناط التحسس للمواد الغذائية لدى مرضى عمانيني لديهم مظاهر احلساسية �شامل التميمي، �شفيق الرحمن ن�شيم، منرية طفيل الرحمن، حممود الكندي، جليلة ال�شكيلية abstract: objectives: this study aimed to evaluate the relationship between food allergen sensitisation patterns and allergic manifestations in omani patients and highlight the importance of specific immunoglobulin e (ige) testing. methods: this retrospective study included all patients referred due to allergic manifestations to the sultan qaboos university hospital (squh), muscat, oman, from november 2012 to november 2016. specific ige blood testing was performed to determine sensitisation to common foods known to cause allergic reactions. results: a total of 164 patients were referred to squh over the study period, with 35.4% presenting with one allergic manifestation, 48.8% with 2–3 and 15.9% presenting with more than three manifestations. there was a family history of allergies in 70.7% of patients. eosinophil counts and total and specific ige levels were elevated in 18.9%, 54.9% and 73.2% of patients, respectively. patients demonstrated sensitisation to cow milk (47.6%), wheat (41.5%), chicken eggs (34.8%), mixed tree nuts (34.1%), lentils (33.5%), peanuts (32.9%), soy (32.3%), shrimp (23.2%) and fish (15.2%). overall, 19.5% were sensitised to a single allergen, 14% were sensitised to 2–3 and 39.6% were sensitised to more than three allergens. almost one-third (29.3%) of patients suffered from food-induced anaphylaxis, of which 85.4% were prescribed self-injectable adrenaline. conclusion: to the best of the authors’ knowledge, this study is the first to describe food allergen sensitisation patterns among omani patients with allergic manifestations. in conjunction with clinical symptoms, the correct interpretation of specific ige levels is important to diagnose food allergies and make safe decisions about reintroducing foods. keywords: hypersensitivity; food allergies; anaphylaxis; urticaria; atopic dermatitis; asthma; immunoglobulin e; oman. امللخ�ص: الهدف: تهدف هذه الدرا�شة اإىل تقييم العالقة بني اأمناط التح�ش�س املواد الغذائية وظهور اأعرا�س احل�شا�شية لدى مر�شى عمانيني احل�شا�شية مظاهر ب�شبب املحولني املر�شى جميع ال�شتعادية الدرا�شة هذه �شملت الطريقة: .e املناعي الغلوبولني اختبار اأهمية واإبراز مل�شت�شفى جامعة ال�شلطان قابو�س، م�شقط، ُعمان، من نوفمرب 2012 اإىل نوفمرب 2016. مت اإجراء اختبارات الدم املحددة للغلوبولني املناعي e لتحديد ح�شا�شية الأطعمة ال�شائعة واملعروفة بالت�شبب يف احل�شا�شية. النتائج: مت اإحالة ما جمموعه 164 مري�شا اإىل م�شت�شفى جامعة ال�شلطان قابو�س خالل فرتة الدرا�شة، مع %35.4 لديهم ظهور واحد من مظاهر احل�شا�شية، %48.8 مع 3-2 و %15.9 مع اأكرث من ثالثة مظاهر. كان هناك تاريخ عائلي من احل�شا�شية يف %70.7 من املر�شى. كان معدل التعداد اليوزيني وجمموع الغلوبولني املناعي الكلي مرتفع عند %18.9، %54.9 و %73.2 من املر�شى على التوايل. اأظهر املر�شى التح�ش�س حلليب البقر )%47.6(، والقمح )%41.5(، وبي�س الدجاج )%34.8(، وخليط جوز ال�شجر )%34.1(، والعد�س )%33.5(، والفول ال�شوداين )%32.9(، وفول ال�شويا )%32.3(، والروبيان )23.2%( 39.6% و 2-3 اإىل متح�ش�شني 14% للح�شا�شية، واحد مل�شبب بح�شا�شية م�شابني 19.5% هناك كان عام، ب�شكل .)15.2%( الأ�شماك و متح�ش�شني لثالثة م�شببات للح�شا�شية. ما يقرب من ثلث )%29.3( من املر�شى يعانون من التاأق ب�شبب الغذاء، بحيث مت و�شف الأدرينالني القابل للحقن الذاتي ملجموعة %85.4 من املر�شى. اخلال�صة: ح�شب اأف�شل معرفة للباحثني، فاإن هذه الدرا�شة هي الأوىل التي ت�شف اأمناط التح�ش�س للمواد الغذائية بني املر�شى العمانيني الذين لديهممظاهر احل�شا�شية. بالقرتان مع الأعرا�س ال�رصيرية، فاإن التف�شري ال�شحيح للم�شتويات املحددة للغلوبولني املناعي e مهم لت�شخي�س احل�شا�شية الغذائية واتخاذ قرارات اآمنة ب�شاأن اإعادة تقدمي الأطعمة. الكلمات املفتاحية: فرط احل�شا�شية؛ ح�شا�شية الطعام؛ تاأق؛ ال�رصى؛ التهاب اجللد التاأتبي؛ الربو؛ الغلوبولني املناعي e؛ عمان. food allergen sensitisation patterns in omani patients with allergic manifestations *salem al-tamemi,1 shafiq-ur-rehman naseem,1 munira tufail-alrahman,2 mahmood al-kindi,2 jalila alshekaili2 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e483–488, epub. 28 mar 19 submitted 23 may 18 revision req. 19 jul 18; revision recd. 16 sep 18 accepted 4 oct 18 doi: 10.18295/squmj.2018.18.04.009 advances in knowledge the current study provides baseline information on food allergen sensitisation patterns and their relationship with different allergic manifestations among omani patients. application to patient care the current study highlights the importance of specific immunoglobulin e testing as an integral part of food allergy evaluations, in conjunction with clinical symptoms. these findings may help treating physicians in the management of omani patients with allergies in order to reduce the risk of anaphylaxis. food allergen sensitisation patterns in omani patients with allergic manifestations e484 | squ medical journal, november 2018, volume 18, issue 4 allergic diseases constitute a group of hypersensitivity disorders resulting in clinical symptoms involving different organs, such as the skin (i.e. urticaria and angioedema), respiratory system (i.e. coughing, wheezing and breathing difficulties), gastro intestinal system (i.e. vomiting, diarrhoea and abdominal pain) and cardiovascular system (i.e. flushing, tachycardia and syncope).1 the most severe form of allergic reaction is anaphylaxis, which can be life-threatening.2 the under lying mechanism of immediate or type i hypersensitivity is primarily due to the formation of specific immuno globulin e (ige) molecules against a particular allergen, usually a peptide or protein. upon subsequent exposure, the crosslinking of ige receptors on mast cells triggers the activation and release of mediators responsible for the symptoms, primarily histamine, leukotrienes, prosta glandins and tryptase.3,4 food is a common cause of allergic symptoms, although the exact prevalence of food allergies varies in different countries due to differences in dietary habits. generally, studies in developed countries report food allergy rates of 8% and 4% among children and adults, respectively.5,6 common trigger foods include cow milk, eggs, soy, wheat, fish, seafood, peanuts and tree nuts among children and fish, seafood, peanuts and tree nuts among adults.7,8 for most patients, the diagnosis is made based on clinical symptoms; however, an in vivo skin prick test may be necessary. more recently, diagnoses have been achieved by measuring in vitro levels of igespecific antibodies in the blood sera.4,9 both in vivoand in vitro-specific ige testing are very sensitive, with high false-positive rates; however, both forms of testing have an excellent negative pred ictive value, which helps in excluding allergies, especially in doubtful cases.9 parents or physicians often suspect food after an allergic manifestation and patients are advised to avoid foods that are considered allergenic prior to a proper evaluation by a specialist. double-blind placebo-controlled food challenges are the gold-standard diagnostic tool for food allergies and are usually used in research centres; however, such testing is timeconsuming and often requires special precautions.10,11 to the best of the authors’ knowledge, local food allergen sensitisation patterns have not been previously studied in oman. as such, this study aimed to evaluate the relationship between food allergen sensitisation patterns and allergic manifestations in omani patients. in addition, the importance of specific ige testing is highlighted. methods this retrospective study included all patients referred to the allergy clinic of the sultan qaboos university hospital (squh), muscat, oman, between november 2012 and november 2016. for each patient, a routine history was taken and a physical examination was cond ucted. a diagnosis of an allergic manifestation was made based on clinical symptoms of anaphylaxis, acute or chronic urticaria/angioedema, eczema/dermatitis, angio edema without urticaria, asthma, rhinitis or vomiting/ diarrhoea. as part of their diagnostic work-up, patients under went blood investigations to determine their eosinophil count and total and specific ige levels for common food triggers (i.e. cow milk, chicken eggs, fish, soy, wheat, shrimp, peanuts, lentils and mixed tree nuts). total and specific ige levels were measured using the immunocap® phadia® 100 immunoassay analyser (thermo fi sher scientific, waltham, massachusetts, usa), as per the manufacturer’s instructions. assays were calibrated to the 75/502 ige standard of the world health organization.12 reference cut-off values were established at <165 and <0.35 kiu/l for normal total and specific ige levels, respectively. eosinophil counts of >0.8 × 109/l were considered raised. the coefficient of variation between runs was <10%. allergic symptoms were correlated with any obvious food triggers based on information received from the patients or their parents/caregivers. in addition, the patients were questioned regarding the consumption of other common allergenic food triggers. other inform ation, such as demographic characteristics, a family history of allergies and age at the onset of symptoms, was retrieved from the patients’ electronic medical records. patients with allergic manifestations who had ingested common food triggers and reported no symptoms or signs of sensitisation on exposure to those foods were not tested and were excluded from the study. all patients were given medical advice based on available clinical information at post-investigation follow-up visits. symptomatic treatment was provided in cases of dermatitis, asthma, rhinitis or chronic urticaria. in cases of anaphylaxis, patients were prescribed self-injectable adrenaline and trained on its use.13,14 analysis of the data was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). frequencies and percentages were calculated using simple functions. statistical differences were measured using pearson’s chi-squared test. differences were considered significant at p <0.05. this study was approved by the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #1648). salem al-tamemi, shafiq-ur-rehman naseem, munira tufail-alrahman, mahmood al-kindi and jalila alshekaili clinical and basic research | e485 results a total of 164 new patients were referred to squh during the study period because of suspected food all ergies. of these, 53 (32.3%) were female and 111 (67.7%) were male. at referral, 92.5% of patients were <18 years old, with a mean age at presentation of 5.8 years old (range: one month–53 years). the mean age at onset of symptoms was 3.3 years old (range: one week–48 years). the mean interval between onset of symptoms and diagnosis was 30.5 months. allergies presented as a single manifestation in 58 patients (35.4%), while 2–3 manifestations were present in 80 patients (48.8%) and more than three manifestations occurred in 26 patients (15.9%). there was a family history of allergies in 116 patients (70.7%). allergies most commonly manifested as eczema/ dermatitis (65.9%) and acute urticaria/angioedema (58.5%), followed by anaphylaxis (29.3%), asthma (25%), vomiting/diarrhoea (18.9%), rhinitis (12.2%), chronic urticaria/angioedema (3.7%) and angioedema without urticaria (1.8%). in total, 48 (29.3%) patients received a diagnosis of food-induced anaphylaxis. of these, seven (14.6%) had normal levels of total ige but positive specific ige levels and one (2.1%) had normal levels of both total and specific ige. most patients with anaphylaxis (85.4%) were prescribed self-injectable adrenaline. eosinophil counts ranged from 0–8.3 × 109/l with a mean of 0.6 × 109/l. in total, 18.9% of patients had raised eosinophil counts. total ige levels were elevated in 90 patients (54.9%). the mean total ige level was 1,567.9 kiu/l, with a maximum level of 34,522.4 kiu/l. specific ige levels were positive in 120 patients (73.2%), occurring in response to cow milk in 78 patients (47.6%; mean = 4.8 kiu/l), wheat in 68 patients (41.5%; mean = 5.1 kiu/l), chicken eggs in 57 patients (34.8%; mean = 4.4 kiu/l), mixed tree nuts in 56 patients (34.1%), lentils in 55 patients (33.5%; mean = 6.4 kiu/l), peanuts in 54 patients (32.9%; mean = 3.7 kiu/l), soy in 53 patients (32.3%; mean = 2.5 kiu/l), shrimp in 38 patients (23.2%; mean = 4.1 kiu/l) and fish in 25 patients (15.2%; mean = 0.6 kiu/l). table 1 illustrates the frequency of sensitisation to common food triggers according to allergic manifestation. normal total ige levels were observed in 67 patients (40.9%), of which 35 (52.2%) had positive specific ige levels. overall, 21.3% of patients had pos itive specific ige levels and normal total ige levels. sensit isation to a single allergen was present in 19.5% of patients, sensitisation to 2–3 allergens in 14% and sensitisation to more than three allergens in 39.6%. the remaining 26.8% were not sensitive to any allergens. figure 1 presents monosensitisation and polysensitisation rates according to allergic manifestation. discussion food allergies represent a management challenge for the affected patient, their parents and/or caregivers and the healthcare provider. however, a thorough patient history, physical examination and diagnostic testing can table 1: frequency of raised eosinophil counts and total immunoglobulin e levels and sensitisation to common food triggers among omani patients according to allergic manifestation (n = 164) sensitivity allergic manifestation, n (%) eczema/ dermatitis (n = 108) acute urticaria/ angioedema (n = 96) anaphylaxis (n = 48) asthma (n = 41) vomiting/ diarrhoea (n = 31) rhinitis (n = 20) chronic urticaria/ angioedema (n = 6) angioedema without urticaria (n = 3) raised ec 25 (23.1) 18 (18.8)* 12 (25) 10 (24.4) 6 (19.4) 3 (15) 1 (16.7) 0 (0)* raised total ige level 62 (57.4) 60 (62.5)* 38 (79.2)* 30 (73.2)* 13 (41.9) 18 (90)* 4 (66.7) 0 (0)* cow milk 53 (49.1) 50 (52.1) 23 (47.9) 15 (36.6) 19 (61.3) 5 (25) 2 (33.3) 2 (66.7) chicken eggs 46 (42.6)* 39 (40.6) 21 (43.8) 16 (39) 9 (29) 5 (25) 1 (16.7) 1 (33.3) fish 20 (18.5) 17 (17.7) 15 (31.3)* 9 (22) 4 (12.9) 3 (15) 2 (33.3) 0 (0) lentils 44 (40.7)* 36 (37.5) 23 (47.9)* 20 (48.8)* 8 (25.8) 10 (50)* 2 (33.3) 1 (33.3) peanuts 41 (38)* 38 (39.6) 26 (54.2)* 17 (41.5) 9 (29) 7 (35) 2 (33.3) 1 (33.3) shrimp 27 (25) 25 (26) 19 (39.6)* 16 (39)* 5 (16.1) 10 (50)* 2 (33.3) 0 (0) soy 40 (37)* 36 (37.5) 25 (52.1)* 21 (51.2)* 9 (29) 9 (45)* 2 (33.3) 1 (33.3) wheat 53 (49.1)* 44 (45.8) 32 (66.7)* 25 (61)* 11 (35.5) 9 (45) 2 (33.3) 1 (33.3) mixed tree nuts 44 (40.7)* 41 (42.7)* 26 (54.2)* 19 (46.3) 12 (38.7) 8 (40) 0 (0) 0 (0)* ec = eosinophil count; ige = immunoglobulin e. *significant at p <0.05 according to a pearson’s chi-squared test. food allergen sensitisation patterns in omani patients with allergic manifestations e486 | squ medical journal, november 2018, volume 18, issue 4 help in managing the condition and minimising the risk of complications. after diagnosis, food allergies should be treated with strict avoidance of the identified allergenic foods. patients and/or their parents or caregivers should be educated about possible allergen sources, taught to check the labels of processed foods and cautioned to be careful about eating in restaurants to minimise the risk of cross-contamination and accidental exposure. in cases of anaphylaxis, patients should be prescribed self-injectable adrenaline and trained on its use in case of accidental exposure.13,14 however, while adrenaline can be a life-saving measure, delays in administration or the presence of other comorbidities such as uncontr olled asthma may be fatal.15–18 to the best of the authors’ knowledge, this study is the first to describe food allergen sensitisation patterns in omani patients with allergic manifestations. the true prevalence of food allergies in oman is unknown; how ever, recent data indicate that the prevalence of allergic manifestations such as asthma, rhinitis and eczema in schoolchildren is increasing.19,20 moreover, given changing sociodemographic patterns and dietary habits in the gulf region, it is expected that allergies will continue to have a significant impact on the national healthcare system.21 in the current study, the majority of patients had atopic manifestations and most had a family history of allergies and elevated total ige levels; these factors may explain the high rate of positive specific ige reactions to common food triggers. moreover, the majority of patients presented with 2–3 allergic manifestations; this finding is to be expected in light of the natural progression of allergic diseases—known as atopic march—which starts in early infancy with a single allergy and progresses over time to other allergies.22–24 however, the mean period of time between onset of symptoms and diagnosis was approximately two years, indicating that there is a need to enhance awareness of food allergies and promote early referral services in oman. varying rates of monosensitisation and polysensitisation have been reported in the international literature depending on the baseline characteristics of the studied population.25 in the present study, the rate of monosensitisation (positive specific ige levels to one allergen) was 19.5%, with 14% of patients positive for 2–3 allergens. polysensitisation (i.e. a reaction to more than three aller gens) was seen in 39.6% of patients, manifesting mostly as atopic dermatitis. however, not all positive sensitising allergens are responsible for clinical symptoms. in such cases, the predictive value of specific ige levels is useful in conjunction with clinical symptoms to confirm an allergy diagnosis. in addition, specific ige testing can help allergists to determine the correct time to reintroduce certain allergenic foods. both skin prick and specific ige tests are very sensitive with excellent negative predictive values.26–28 published specific ige cut-off values reflect a high probability of patients reacting to certain foods, such as cow milk, chicken eggs and peanuts.29–31 the role of specific ige to food allergens has been well established in acute urticaria/angioedema, anaphylaxis, atopic dermatitis and, to some extent, gastrointestinal allergies such as eosinophilic oesophagitis; however, its role in respiratory allergic manifestations such as asthma and rhinitis is probably marginal.32,33 while patients with clinical allergic manifestations do have positive specific ige results to food allergens, they may also have other manifestations or allergies which might account for the results. in the presence of normal total ige levels, certain patients may also display positive specific ige reactions to certain foods, as was the case for 21.3% of patients in the current study. this finding may be accompanied by clinical allergic manifestations; for example, 14.6% of anaphylactic figure 1: monosensitisation and polysensitisation rates in omani patients according to allergic manifestation (n = 164). salem al-tamemi, shafiq-ur-rehman naseem, munira tufail-alrahman, mahmood al-kindi and jalila alshekaili clinical and basic research | e487 patients had normal total ige levels, yet high specific ige levels. this finding emphasises the importance of searching for specific allergens in the presence of normal total ige levels and consistent allergic manifestations. prior to commencing school, most children outgrow food allergies such as those to cow milk, chicken eggs and wheat.34,35 in fact, parents may sometimes continue feeding common food triggers to allergic children if the resulting reaction is mild or not anaphylactic. a double-blind oral food challenge is considered the gold standard for diagnosing food allergies; however, such an approach may not necessarily be applied to all patients as it is time-consuming and logistically difficult to safely perform.10,11,32 based on earlier studies, prof essional recommendations for primary allergy prevention involve introducing a weaning diet at 4–6 months of age and delaying the introduction of certain allergenic foods such as eggs, fish and peanuts until children reach 12, 24 and 36 months of age, respectively.36–38 recent evidence, however, does not support restriction of these foods beyond four months of age.39 conclusion this study determined sensitisation rates to common food triggers by measuring specific ige levels in omani patients with different clinical allergic manifestations. the results were in line with previous research in other populations. further studies would be helpful for health care policy makers, especially with regards to reducing allergy-related mortality rates due to food-induced anaphylaxis and other causes. preventative measures would help to minimise comorbidities and reduce the economic burden of allergies on the omani healthcare system. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. galli sj, tsai m, piliponsky am. the development of allergic inflammation. nature 2008; 454:445–54. https://doi.org/10.10 38/nature07204. 2. sampson ha, muñoz-furlong a, bock sa, schmitt c, bass r, chowdhury ba, et al. symposium on the definition and man agement of anaphylaxis: summary report. j allergy clin imm unol 2005; 115:584–91. https://doi.org/10.1016/j.jaci.2005.01.009. 3. berin mc. pathogenesis of ige-mediated food allergy. clin exp allergy 2015; 45:1483–96. https://doi.org/10.1111/cea.12598. 4. stanworth dr. the discovery of ige. allergy 1993; 48:67–71. https://doi.org/10.1111/j.1398-9995.1993.tb00687.x. 5. savage j, johns cb. food allergy: epidemiology and natural history. immunol allergy clin north am 2015; 35:45–59. https://doi. org/10.1016/j.iac.2014.09.004. 6. verrill l, bruns r, luccioli s. prevalence of self-reported food allergy in u.s. adults: 2001, 2006, and 2010. allergy asthma proc 2015; 36:458–67. https://doi.org/10.2500/aap.2015.36.3895. 7. peters rl, koplin jj, gurrin lc, dharmage sc, wake m, ponsonby al, et al. the prevalence of food allergy and other allergic diseases in early childhood in a population-based study: healthnuts age 4-year follow-up. j allergy clin immunol 2017; 140:145–53.e8. https://doi.org/10.1016/j.jaci.2017.02.019. 8. venter c, patil v, grundy j, glasbey g, twiselton r, arshad sh, et al. prevalence and cumulative incidence of food hyper-sensitivity in the first 10 years of life. pediatr allergy immunol 2016; 27:452–8. https://doi.org/10.1111/pai.12564. 9. lifschitz c, szajewska h. cow’s milk allergy: evidence-based diagnosis and management for the practitioner. eur j pediatr 2015; 174:141–50. https://doi.org/10.1007/s00431-014-2422-3. 10. sampson ha, gerth van wijk r, bindslev-jensen c, sicherer s, teuber ss, burks aw, et al. standardizing double-blind, placebo-controlled oral food challenges: american academy of allergy, asthma & immunology-european academy of allergy and clinical immunology practall consensus report. j allergy clin immunol 2012; 130:1260–74. https://doi.org/10. 1016/j.jaci.2012.10.017. 11. rancé f, deschildre a, villard-truc f, gomez sa, paty e, santos c, et al. oral food challenge in children: an expert review. eur ann allergy clin immunol 2009; 41:35–49. 12. seagroatt v, anderson sg. the second international reference preparation for human serum immunoglobulin e and the first british standard for human serum immunoglobulin e. j biol stand 1981; 9:431–7. https://doi.org/10.1016/s0092-1157(81) 80034-0. 13. sicherer sh, simons fe. epinephrine for first-aid management of anaphylaxis. pediatrics 2017; 139:e20164006. https://doi. org/10.1542/peds.2016-4006. 14. sicherer sh, forman ja, noone sa. use assessment of selfadministered epinephrine among food-allergic children and ped iatricians. pediatrics 2000; 105:359–62. https://doi.org/10.1542/ peds.105.2.359. 15. turner pj, jerschow e, umasunthar t, lin r, campbell de, boyle rj. fatal anaphylaxis: mortality rate and risk factors. j allergy clin immunol pract 2017; 5:1169–78. https://doi.org/ 10.1016/j.jaip.2017.06.031. 16. jerschow e, lin ry, scaperotti mm, mcginn ap. fatal anaphylaxis in the united states, 1999-2010: temporal patterns and demgraphic associations. j allergy clin immunol 2014; 134:1318–28.e7. https://doi.org/10.1016/j.jaci.2014.08.018. 17. umasunthar t, leonardi-bee j, hodes m, turner pj, gore c, habibi p, et al. incidence of fatal food anaphylaxis in people with food allergy: a systematic review and meta-analysis. clin exp allergy 2013; 43:1333–41. https://doi.org/10.1111/cea.12211. 18. pumphrey rs, gowland mh. further fatal allergic reactions to food in the united kingdom, 1999-2006. j allergy clin immunol 2007; 119:1018–19. https://doi.org/10.1016/j.jaci.2007.01.021. 19. al-rawas oa, al-riyami bm, al-maniri aa, al-riyami aa. trends in asthma prevalence and severity in omani schoolchildren: comparison between isaac phases i and iii. respir ology 2008; 13:670–3. https://doi.org/10.1111/j.1440-1843.2 008.01313.x. 20. al-tamemi sh, al-shidhani an, al-abri rk, jothi b, al-rawas oa, al-riyami bm. the pattern of sensitisation to inhalant allergens in omani patients with asthma, allergic rhinitis and rhinoconjunctivitis. sultan qaboos univ med j 2008; 8:319–24. 21. musaiger a. change in dietary habits, lifestyle and trend in diseases in the gcc countries. bahrain med bull 1998; 20:87–90. food allergen sensitisation patterns in omani patients with allergic manifestations e488 | squ medical journal, november 2018, volume 18, issue 4 22. williams hc, strachan dp. the natural history of childhood eczema: observations from the british 1958 birth cohort study. br j dermatol 1998; 139:834–9. https://doi.org/10.1046/j.13 65-2133.1998.02509.x. 23. allen kj, dharmage sc. the role of food allergy in the atopic march. clin exp allergy 2010; 40:1439–41. https://doi.org/10.11 11/j.1365-2222.2010.03605.x. 24. martin pe, matheson mc, gurrin l, burgess ja, osborne n, lowe aj, et al. childhood eczema and rhinitis predict atopic but not nonatopic adult asthma: a prospective cohort study over 4 decades. j allergy clin immunol 2011; 127:1473–9.e1. https://doi.org/10.1016/j.jaci.2011.02.041. 25. kim ny, kim gr, kim jh, baek jh, yoon jw, jee hm, et al. food allergen sensitization in young children with typical signs and symptoms of immediate-type food allergies: a comparison between monosensitized and polysensitized children. korean j pediatr 2015; 58:330–5. https://doi.org/10.3345/kjp.2015.5 8.9.330. 26. ahlstedt s. understanding the usefulness of specific ige blood tests in allergy. clin exp allergy 2002; 32:11–16. https://doi. org/10.1046/j.0022-0477.2001.01289.x. 27. griffiths rl, el-shanawany t, jolles sr, selwood c, heaps ag, carne em, et al. comparison of the performance of skin prick, immunocap, and isac tests in the diagnosis of patients with allergy. int arch allergy immunol 2017; 172:215–23. https://doi.org/10.1159/000464326. 28. chokshi ny, sicherer sh. interpreting ige sensitization tests in food allergy. expert rev clin immunol 2016; 12:389–403. https://doi.org/10.1586/1744666x.2016.1124761. 29. sampson ha, ho dg. relationship between food-specific ige concentrations and the risk of positive food challenges in children and adolescents. j allergy clin immunol 1997; 100:444–51. https://doi.org/10.1016/s0091-6749(97)70133-7. 30. shek lp, soderstrom l, ahlstedt s, beyer k, sampson ha. determination of food specific ige levels over time can predict the development of tolerance in cow’s milk and hen’s egg allergy. j allergy clin immunol 2004; 114:387–91. https://doi. org/10.1016/j.jaci.2004.04.032. 31. beyer k, ellman-grunther l, järvinen km, wood ra, hourihane j, sampson ha. measurement of peptide-specific ige as an additional tool in identifying patients with clinical reactivity to peanuts. j allergy clin immunol 2003; 112:202–7. https://doi. org/10.1067/mai.2003.1621. 32. onorato j, merland n, terral c, michel fb, bousquet j. placebo controlled double-blind food challenge in asthma. j allergy clin immunol 1986; 78:1139–46. https://doi.org/10.1016/0091-6749 (86)90263-0. 33. hill da, dudley jw, spergel jm. the prevalence of eosinophilic esophagitis in pediatric patients with ige-mediated food allergy. j allergy clin immunol pract 2017; 5:369–75. https://doi.org/ 10.1016/j.jaip.2016.11.020. 34. sicherer sh, wood ra, vickery bp, jones sm, liu ah, fleischer dm, et al. the natural history of egg allergy in an observational cohort. j allergy clin immunol 2014; 133:492–9. https://doi. org/10.1016/j.jaci.2013.12.1041. 35. wood ra, sicherer sh, vickery bp, jones sm, liu ah, fleischer dm, et al. the natural history of milk allergy in an observational cohort. j allergy clin immunol 2013; 131:805–12. https://doi. org/10.1016/j.jaci.2012.10.060. 36. zeiger rs, heller s, mellon mh, forsythe ab, o’connor rd, hamburger rn, et al. effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. j allergy clin immunol 1989; 84:72–89. https://doi.org/10.1016/0091-6749(89)90181-4. 37. zeiger rs. food allergen avoidance in the prevention of food allergy in infants and children. pediatrics 2003; 111:1662–71. 38. fergusson dm, horwood lj, shannon ft. early solid feeding and recurrent childhood eczema: a 10-year longitudinal study. pediatrics 1990; 86:541–6. 39. sausenthaler s, heinrich j, koletzko s; giniplus and lisaplus study groups. early diet and the risk of allergy: what can we learn from the prospective birth cohort studies giniplus and lisaplus? am j clin nutr 2011; 94:2012s–17s. https://doi. org/10.3945/ajcn.110.001180. department of radiology, armed forces hospital, muscat, oman *corresponding author e-mail: drphilipsgm@yahoo.com حالة غري معتادة ألم الدم داخل القحف مت تشخيصها خطًأ كالتهاب سحايا قاعدي متمركز فيليب�ص جورج مايكل، راكي�ص ملهاري جاخمانديكار، عمران خان ميمون، طاهرة ال�سعدية، �سعيد االأغربي، ماجد املقيمي، م�سباح الدين اأن�ساري، اأحمد ال�سماخي، عا�سفة اأحمد unusual case of an intracranial aneurysm misdiagnosed as focal basal meningitis *philips g. michael, rakesh m. jamkhandikar, imran k. memon, tahra al-saadi, said al-aghbari, majed al-muqaimi, misbahuddin ansari, ahmed al-shamakhi, asifa ahmad a 67-year-old diabetic male patient pres-ented to the accident & emergency department of the armed forces hospital, muscat, oman, in 2016 with a headache, low-grade intermittent fever and progressive confusion with decreased sensorium of two weeks’ duration. the patient had a past history of malignant otitis externa along with right-sided mastoiditis for which he had undergone a cortical mastoidectomy and debridement seven months previously. he had subsequently developed right-sided facial palsy immediately after the surgery. the patient also disclosed a recent history of admission to a local secondary hospital, at which time a computed tomography (ct) scan of the brain was reportedly unremarkable. an unsuccessful lumbar puncture was attempted and, shortly afterwards, the patient had left the previous hospital against medical advice at the behest of his relatives and sought admission to the armed forces hospital. unfortunately, no detailed documentation, prior medical reports or imaging scans were available since the patient had been discharged without following the proper referral procedures. at admission, the patient was clinically afebrile upon examination; however, there was evidence of neck rigidity for which a contrast-enhanced ct scan of the brain was requested to rule out meningitis. the ct scan showed postoperative changes of right-sided otomastoiditis with chronic osteomyelitis. apart from this, there was an irregular curvilinear and nodular area of abnormal enhancement on the right side of the prepontine and suprasellar cistern extending to the pituitary fossa which was deemed indicative of focal interesting medical image sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e363–365, epub. 10 oct 17 submitted 13 nov 16 revision req. 12 jan 17; revision recd. 19 feb 17 accepted 9 mar 17 figure 1: initial (a) preand (b) post-contrast axial computed tomography scans of the brain of a 67-year-old male patient showing an irregular curvilinear and nodular area of abnormal enhancement on the right side of the prepontine and suprasellar cistern extending to the pituitary fossa (arrows). this was initially diagnosed as focal basal meningitis. doi: 10.18295/squmj.2017.17.03.020 unusual case of an intracranial aneurysm misdiagnosed as focal basal meningitis e364 | squ medical journal, august 2017, volume 17, issue 3 comment despite significant improvements in imaging technology, diagnostic radiological errors can still occur due to poor imaging techniques or failure of perception, lack of knowledge or misjudgment on the part of the radiologist.1 as such, both diagnostic radiologists and referring physicians should be aware of potential sources of error when interpreting imaging scans. errors in which an abnormality is detected on imaging but its true pathological nature and significance are not recognised are classified as cognitive errors; these include false-positive cases as well as the inaccurate classification of abnormal findings.1 erroneous conclusions drawn from improper clinical information, a paucity of knowledge or the consideration of only a restricted number of differential diagnoses have been previously implicated in misdiagnoses.1 in the current case, although the abnormality was correctly identified on the initial ct scan, it was falsely attributed to focal basal meningitis rather than a ruptured aneurysm; this represents a rare instance of cognitive error. in hindsight, magnetic resonance imaging (mri) might have helped to detect the haemorrhage and ensured that the correct diagnosis was made at an earlier stage. however, the patient’s condition was not stable enough for an emergency mri at presentation; moreover, the armed forced hospital did not have mri-compatible monitoring devices for such patients at the time. in addition, the patient’s previous history of otitis externa, mastoiditis and surgery as well as the clinical suspicion of meningitis for which the scan was requested may also have played a role in misleading the radiologist, resulting in an erroneous diagnosis. when interpreting imaging findings, care must be taken so as not to become overdependent on the patient’s medical history basal meningitis [figure 1]. in view of these findings, a repeat lumbar puncture was planned; however, the patient’s relatives were initially unwilling to consent to the procedure. as such, the lumbar puncture was delayed by 24 hours and, when attempted, was traumatic and unsuccessful. subsequently, the patient was prescribed intravenous antibiotics but failed to improve. in view of the lack of response to treatment and the patient’s impaired renal function, repeat noncontrast ct imaging of the brain was performed 48 hours after the initial scan. this demonstrated minimal intraventricular haemorrhage in the dependent part of both lateral ventricles, with a developing area of infarction in the region of the right middle cerebral artery (mca) [figure 2]. apart from this, there were no significant changes in comparison to the initial ct scan. over the next three days, the patient’s condition further deteriorated and he was transferred to the intensive care unit where he required intubation and ventilation. five days after admission, another follow-up contrast-enhanced ct scan demonstrated a leaking aneurysm arising from the right mca with subarachnoid and intraventricular haemorrhage [figure 3]. upon review of the initial ct images, it was revealed that the abnormality initially considered to indicate focal basal meningitis was actually an mca aneurysm. as there were no neurosurgical and vascular interventional departments available at the armed forces hospital, an urgent consultation was sought with neurosurgical and interventional neuroradiology experts at a nearby institution; unfortunately, the patient could not be immediately referred as his condition was very unstable and he died the following day. figure 2: a follow-up non-contrast axial computed tomography scan of the brain of a 67-year-old male patient initially diagnosed with focal basal meningitis showing intra ventricular haemorrhage in the dependent part of both lateral ventricles (white arrows), with a developing hypodense area of infarction in the region of the right middle cerebral artery (black arrow). figure 3: a final axial post-contrast computed tomography image of the brain of a 67-year-old male patient initially diagnosed with focal basal meningitis showing a leaking aneurysm in the right middle cerebral artery (arrow). philips g. michael, rakesh m. jamkhandikar, imran k. memon, tahra al-saadi, said al-aghbari, majed al-muqaimi, misbahuddin ansari, ahmed al-shamakhi and asifa ahmad interesting medical image | e365 and clinical information as this could be a source of potential bias. it is vital that radiologists resist the temptation to fit imaging findings with the clinical diagnosis. malatt et al. identified several factors contributing to false-negative interpretations of emergency head ct scans, including inadequate or inaccurate clinical information, failure to compare recent images with those from prior scans, use of improper windowing and leveling settings and lack of use of multiplanar reconstruction technology to provide various anatomical views.2 lawson et al. also reported that excessive reliance on previous experience, the inclination to find and/or exaggerate supporting evidence to favour a specific diagnosis while neglecting or failing to obtain opposing evidence and the penchant to make a diagnosis without sufficient testing could all contribute to bias and result in an erroneous diagnosis.3 it is therefore essential to keep an open mind and consider relevant alternative diagnoses when interpreting a specific imaging finding. intravenous contrast ct imaging and optimal contrast bolus timing may also play a crucial role in establishing the diagnosis of an intracranial aneurysm.4 in the present case, the final ct scan was in the angiographic (i.e. arterial) phase and unequivocally established the presence of an mca aneurysm. however, the initial post-contrast ct scan was not performed in the angiographic phase; it is therefore possible that, had the initial images been obtained in the optimal arterial phase, the correct diagnosis could have been established earlier. taheri et al. have previously highlighted unusual configurations and presentations of intracranial aneurysms which may mimic neoplastic lesions or an infectious process and therefore be misdiagnosed on imaging.5 references 1. bahrami s, yim cm. quality initiatives: blind spots at brain imaging. radiographics 2009; 29:1877−96. doi: 10.1148/rg.2 97095123. 2. malatt c, zawaideh m, chao c, hesselink jr, lee rr, chen jy. head computed tomography in the emergency department: a collection of easily missed findings that are lifethreatening or life-changing. j emerg med 2014; 47:646−59. doi: 10.1016/j.jemermed.2014.06.042. 3. lawson ae, daniel es. inferences of clinical diagnostic reasoning and diagnostic error. j biomed inform 2011; 44:402−12. doi: 10.1016/j.jbi.2010.01.003. 4. yoon nk, mcnally s, taussky p, park ms. imaging of cerebral aneurysms: a clinical perspective. neurovasc imaging 2016; 2:6−13. doi: 10.1186/s40809-016-0016-3. 5. taheri sm, haghighatkhah hr, noori m. uncommon patterns of intracranial aneurysms: a pictorial essay. iran j radiol 2009; 6:237−46. https://doi.org/10.1148/rg.297095123 https://doi.org/10.1148/rg.297095123 https://doi.org/10.1016/j.jemermed.2014.06.042 https://doi.org/10.1016/j.jbi.2010.01.003 https://doi.org/10.1186/s40809-016-0016-3 squ med j, april 2010, vol. 10, iss. 1, pp. 120-125, epub. 17th apr 10 submitted 26th sept 09 revision req. 23rd nov 09, revision recd. 9th dec 09 accepted 21st dec 09 ever since the beginning of aviation in 1904, rapid strides have been made in the development of aircraft performance. this has imposed severe stress on the human operator whose physiology has remained unchanged. development of life support systems such as sophisticated oxygen systems, escape systems, flying clothing and cockpit layout and instrumentation have helped man to cope with the increasing stress. and yet there are occasions when, under a given set of circumstances, various factors interact to produce an untoward incident called an accident. in military aviation, an aircraft accident is defined as: “an occurrence, not directly caused by enemy action, involving one or more aircraft, which happens during the operation of any one of these aircraft, and which results in injury to one or persons, or damage to aircraft or property."1 a variety of reasons such as technical failure and inclement weather conditions may have a role to play, but it is has been generally accepted that in as many as 70–80% of aircraft accidents, various levels of human operator error are likely to be a contributory cause.2 an analysis of fatal aircraft accidents in the indian air force indicated that 68% were caused by “pilot error”.3 department of physiology, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: mohand@squ.edu.om خطأ االنسان تقرير حالتني من حوادث الطريان احلربي احتمال آليات فشل اإلنسان م�هان ديك�شيت اخلال�صة: من املفترض أن أخطاء الطيار أو عجزه وضعف أدائه أثناء الطيران رمبا يكون العامل املسبب حلوادث الطيران في (%70-80) من حوادث الطيران. ندرج هنا حادثتي طيران مميتتني رمبا كانتا بسبب أحد العاملني املذكورين. احلالة األولى تصف قرار خاطىء لطيار حربي الستعمال كرسيه في حالة القذف من الطائرة سببت الوفاة. مت افتراض آلية احلادث القاتل وذلك من خالل إصابات جسم الطيار والتدقيق في مالبسه وكرسي القذف. أما احلالة الثانية فهي تصف سلسلة من األحداث التي انتهت بعجز الطيار أثناء تنفيذ مناورة عادية، مما أدى إلى حادث مميت. قمنا مبناقشة العوامل البيئية التي رمبا سببت فشال في اآلليات الفسيولوجية للطيار مما أدى إلى احلادث. أخطاء الطيران، في القدرة، شل اجلاذبية، بسبب الوعي فقدان الطيران، مالبس اصابة، القذف، مقعد حيِّزّي، تََوهاٌن الطيران، حوادث الكلمات: مفتاح الطيار. abstract: it has been postulated that pilot error or in-flight incapacitation may be the main contributory factors to 70–80% of aircraft accidents. two fatal aircraft accidents are presented in which either of the above possibilities may have played a role. the first case report describes an erroneous decision by a fighter pilot to use a seat position adjustment of the ejection seat leading to fatal injuries when he had to eject from his aircraft. injuries to the body of the pilot, and observations on the state of his flying clothing and the ejection seat were used to postulate the mechanism of fatal injury and establish the cause of the accident. the second case report describes the sequence of events which culminated in the incapacitation of a fighter pilot while executing a routine manouevre. this resulted in a fatal air crash. possible contributions of environmental factors which may have resulted in failure of his physiological mechanisms are discussed. keywords: aviation accident; spatial disorientation; ejection seat; injury; flying clothing; gravity-induced loss of consciousness; incapacitation, in-flight; pilot error. to err is human case reports of two military aircraft accidents possible mechanisms of human failure mohan b dikshit case report mohan b dikshit case report | 121 a flow chart has been constructed to outline various reasons which may induce pilot error [figure 1]. the final outcome may be precipitated because of pilot incapacitation or an error of judgment and possibly caused by a combination of circumstances. this case report attempts to highlight human frailty which may have led to fatal outcomes in two accidents involving indian air force aircraft and aircrew. these incidents have been chosen as they had occurred in the early 1970s, and hence do not compromise military intelligence. where ever possible, an attempt has been made to use the findings at autopsy to explain the possible reasons for a fatal outcome to the pilot involved. case report one the pilot of a sukhoi 7 b supersonic fighter bomber (flying officer v) was seen to eject from the aircraft at low level. the army rescue patrol found the pilot dead. no obvious injury was noticed. the flying clothing of the pilot, including the oxygen mask and the protective helmet were apparently intact, as was the parachute to which he was still attached. the ejection seat was recovered from some distance from the site where he was found. the body was evacuated to a forward dressing station where it was examined by an army medical officer (mo). he noted that there was a large contusion on the forehead, and an extensive pulpy swelling which he described as a possible haematoma on the back of the head. he disposed of the body as per operational orders, but had the ejection seat and the flying clothing sent to the pilot’s airbase. there the items were examined by the flight surgeon. he noticed that the protective helmet had a dent in the front area which would have been covering the forehead. the area of impact had some debris which could be matched with the front, lower margin of the aircraft cockpit canopy. the back of the helmet was also dented. this dent was impacted with the leather debris from the head rest of the ejection seat. the findings indicated that the forehead of the pilot was struck by the rear end of the canopy, which in turn had smashed the back of the head in to the head rest of the ejection seat. when this possibility was correlated to the findings of an abrasion and pulpy swelling noted by the mo in the field, it was concluded that the probable cause of death was severe head injury. discussion the sukhoi 7b fighter aircraft was equipped with an ejection seat which could be used in three positions: low, medium and high. pilots with high sitting heights (sitting height is the vertical distance between the base of the spine while sitting erect on a hard surface, and the top of the head) were advised to use either the medium or the low position depending on their “eye datum” line which was marked in the cockpit. if a pilot had to eject from the aeroplane, the canopy of the aircraft would slide backwards over the pilot’s head and leave the aircraft at its rear end. if the pilot sat in a position which was too high for him, there was the strong possibility that the leading lower border of the canopy would strike his forehead as it slid over him. the pilot, flying officer v, had a high sitting height and had been advised to fly in the low seat position. the possibility of his head being fouled by a i r c r a f t a c c i d e n t physcial incapacitation (partial or compelete) physiological stresses & failure of life support systems psychological stresses error of judgement attitude training figure 1: possible algorithm for occurrence of an aircraft accident which may be caused by pilot error/incapacitation. to err is human case reports of two military aircraft accidents: possible mechanisms of human failure 122 | squ medical journal, april 2010, volume 10, issue 1 the canopy while ejecting had been demonstrated to him; however, he had chosen to use the high seat position because he found the bomb sight and the front gun sight easier to operate in the high position. given this information, the possible sequence of events may be reconstructed. the pilot was flying as per his practice in the “high” position which was inappropriate for him. when he initiated ejection (once initiated, the ejection sequence, which occurs in less than a second, can not be arrested) the canopy which weighed approximately 60kg, was jettisoned by the explosive charge, developing extremely high kinetic energy. it slid backwards along the cockpit, and as it was about to leave the aircraft from the rear of the cockpit its leading edge struck a hammer blow on the forehead of the pilot. this accounted for the dent seen on the frontal region of the helmet which had taken the shape of the lower ridge of the canopy. the impact jolted the pilot’s head backward striking the head rest of the ejection seat so denting the back of the helmet covering the occipital region. both the impacts, which probably occurred in about 200-300msecs, were enough to produce a fatal head injury as noted by the army doctor in the battle zone. conclusion the correlation of head injury of the pilot to the various marks on his helmet was strong enough evidence to prove that he had fouled the canopy fatally as he tried to eject from the aircraft. as per the classical definition,1 this incident may not be classified as an accident as it happened indirectly as a result of enemy action during operations. nevertheless, such an event was inevitable when the pilot chose to fly in a position which would compromise his flight safety. if he had chosen the prescribed seat position, he would probably have made an uneventful escape from his aircraft. it was thus the attitudinal error [figure 1] of the pilot which led to this uncalled for incident. no other failure on the part of the pilot was responsible for the event. it is for this reason that it has been classified as an accident. case report two two sukhoi 7b fighter aircraft were detailed to undertake a low level high speed navigation sortie (flight). the aim of the mission was to familiarise the newly posted flight commander of the squadron, who had a considerable amount of recent flying experience on hawker hunter fighter aircraft, with the sukhoi aircraft. the flight was led by no 1. pilot who, though junior in rank to his flight commander, was experienced on the sukhoi and had been flying in the area for about two years. the flight commander was no. 2 in the formation [figure 2]. the sortie progressed as planned until the last part of the exercise. in this, the aircraft were to simulate a dummy attack on an imagined target. both aircraft, with no. 1 in the lead, were to “pull up “ rapidly from their flight altitude of about 100 meters above ground level to about 2 km, dive towards the imagined target, and then pull gradually out of the dive and resume the low level course. in flying terminology, this is known as a loop followed by a dummy dive [figure 2]. accordingly, the section leader (no. 1) initiated the manoeuvre into which both the aircraft entered. a few seconds later no. 2 crashed fatally into the ground. discussion both pilots had been declared medically fit to fly by the squadron flight surgeon during the routine preflight medical examination. the sequence of events as per an eye witness account of the lead pilot was as follows. the aircraft were airborne at around 0800 hours on a warm april day, and set course for the designated flying area as per the pre-flight briefing. towards the end of the mission, no. 1 “pulled up” to go into ground attack mode as shown in figure 2. he completed his manoeuvre and when he was on the descent he saw his no. 2 also reach the top of the loop. however, after that the lead pilot noticed that the no. 2 aircraft seemed to be out of control and started to “fall out of the sky”. he called the pilot, but got no response. within 15-20 seconds, he saw the aircraft hit the ground on its belly and burst into flames. the pilot had made no attempt to eject. no. 1 also stated that just before the aircraft finally hit the ground, he may have heard some sort of a grunt on his radio transmitter. he reported the accident to the air traffic control and returned to base. the rescue team found the crashed aircraft had landed on its belly and was almost completely burnt. the cockpit had been destroyed. the pilot mohan b dikshit case report | 123 had also almost burnt to ashes, and only a few of his remains could be identified. his flying clothing was burnt, and the helmet had melted. the aircraft had not exploded. there was no evidence to indicate aircraft malfunction and this was corroborated later by a technical investigation. body parts/tissue were not available for a postmortem examination. during a loop manoeuvre, the pilot experiences effects of +gz (positive acceleration) which drives the blood column towards the lower part of the body thus reducing perfusion to the brain. autonomic reflex activity is brought in to play to restore the brain circulation. this reaction takes between 5-7 seconds to be established in a normal individual.4 the reflex response may found to be wanting in a number of circumstances such as heat stress, hypoxia, medication with centrally acting drugs, use of antihypertensives, and consumption of alcohol.5 the response may also be affected adversely by the magnitude and the rate of application of the +gz force. the contribution of circadian rhythm effects contributing to the pilot’s incapacitation is ruled out as the flight was launched in the morning as per the routine operations schedule. the pilot had not been flying late into the preceding night. hence he had not altered his routine circadian rhythm. there was no history to suggest that he had indulged in any other activity that may have altered their night-day physiologic cycle. in fact, it has been suggested that cardiovascular reflex activity may be functioning at its peak during the morning hours.6 hence the scheduling of the flight in the morning should have enhanced his performance. in the manoeuvre undertaken [figure 2], the magnitude of the stress is usually about +5gz, and is considered within tolerable limits for a trained fighter pilot. the rate of application may vary, but pilots usually control it to less than 1 gz/sec in a planned manoeuvre as undertaken in this case. the manoeuvre was successful until no. 2 had almost reached the peak of the loop, a point at which the maximal +gz stress is felt. for unexplained reasons, it may be presumed that the pilot then suffered a gravity-induced loss of consciousness (g-loc) which incapacitated him. the aircraft in question was not equipped with an in-flight data recorder (the so-called black box). hence it was not possible to establish whether the pilot had inadvertently applied a +gz force in excess of the usual tolerable limits. from the available documents, it appears that he had not been grounded at any time in his career, nor was he taking any medications; however, consumption of unprescribed medications, such as no. 1 no. 2 impact top of the loop approximately +5gz figure 2: the construction of the flight profile which may have led to the fatal crash because of possible pilot incapacitation due to a gravity-induced loss of consciousness (g-loc). note the figure is not mathematically accurate. to err is human case reports of two military aircraft accidents: possible mechanisms of human failure 124 | squ medical journal, april 2010, volume 10, issue 1 antihistamines, or tranquilisers, cannot be ruled out. such medications are known to affect tolerance to + gz stress.5 he was reported to have put on the anti-g suit before getting into the cockpit. it may be argued that for unknown reasons, he did not connect the suit to the aircraft system, and hence did not get the protection against the gz force which the g-suit offers. this in turn may have led to the g loc. april mornings in the north of india are often quite warm. the ambient temperature at the time of the sortie was around 27o–28oc. during high speed low level flight, aerodynamic friction is known to increase the cockpit temperature by about 8–10 c.7,8 therefore at the time of the manoeuvre, the cockpit temperature may have been around 36–38 c, and would have been so for about 20–25 minutes before the episode. whole body heating causes vasodilatation with sweating as a heat dissipating mechanism. it is possible that no. 2 reacted to the increase in cockpit temperature with these mechanisms, and the mild dehydration and peripheral vasodilatation aggravated the adverse effects of +gz stress and induced the g loc. there are two phases of g loc: 1) the stage of complete incapacitation which lasts for about 12– 16 seconds. this is followed by a period of mental confusion and partial incapacitation during which consciousness is partly regained, but the pilot is incapable of performing useful tasks. this phase may last or another 12–15 seconds.9,10,11 therefore, after suffering a g loc, a pilot is not in control of the aircraft for as long as 25–30 seconds. in the case under discussion, no. 1 had estimated that 15–20 seconds had elapsed from the time he noticed that no. 2 was not in control to the time he crashed. the possible grunt he heard before impact may have been the sounds made in the cockpit by the partially conscious no. 2. given the time frame of recovery from g loc, this may have happened before any perceivable recovery had occurred. it may be presumed then that, at time of impact, no. 2 had just about regained partial consciousness and he died because of the crash impact and the post crash fire. if the episode had occurred at a much higher altitude, the pilot might have been able to regain control of his aircraft. in-flight spatial disorientation (sd) has been associated with partial or total pilot incapacitation resulting in an accident.1,3 in the case under discussion, the weather at the time of flight was clear, devoid of clouds, or poor visibility which are often the contributing factors to sd. the manouevre performed by the pilot was not one which would have caused stimulation of more than one set of semicircular canals or the otoliths to generate conflicting vestibular sensations which might have progressed to sd.12 the pilot was fit to fly on the day of the accident, and there was no reason to suspect the presence of vestibular pathology. this rules out the occurrence of in-flight disorientation as a cause of the fatal accident. conclusion on the basis of circumstantial evidence, it is postulated that the accident occurred because the pilot had become incapacitated during the flight. there is a strong likelihood that this happened because his physiological mechanisms failed to sustain brain perfusion when he went in to a loop manoueuvre. references 1. fryer di. accident statistics. in: gillies ja, ed. text book of aviation physiology. oxford: pergamon press, 1965. pp. 1139–42. 2. shappell sa, wiegmann da. human factors analysis and classification analysis of aviation accidents: a north american comparison. internat soc air safety investigators (australia), 2004. pp. 1–8. 3. umesh kumar bk, malik h. analysis of fatal human error accidents in the indian air force. indian j aerospace med 2003; 47:30–6. 4. howard p. the physiology of positive acceleration. in: gillies ja, ed. text book of aviation physiology. oxford: pergamon press, 1965. pp. 551–687. 5. dikshit mb. cardiovascular reflex assessment for aerospace applications. in: manchanda sk, selvamurthy w, mohan kumar v, eds. advances in physiological sciences (proceedings 2nd congress asian & oceanic physiological societies, new delhi), 1990. pp. 263–71. 6. patrick jm, dikshit mb, fentem p, mcdonald i. human orthostatic reflexes after taking temazepam at night. br j clin pharmacol 1987; 24:799–807. 7. dikshit mb. heat problems in high speed low level flight. aviat med 1980; 24:31–6. 8. nunnley sa, james gr. cockpit thermal conditions and crew skin temperature measured in flight. aviat space & environ med 1977; 48:44. mohan b dikshit case report | 125 9. tripp dl, warm js, matthews g, chiu p, werchan p, deaton je. positive g z acceleration loss of consciousness: time course of performance deficits with repeated experience human factors. j hum factors & ergonom soc 2006; 48:109–20. 10. whinnery je, burton rr, boll pa, eddy dr. characterization of resulting incapacitation following unexpected + gz-induced loss of consciousness. aviat space & environ med. 1987; 58:631–6. 11. whinnery je, whinnery am. acceleration induced loss of consciousness. arch neurol 1990; 47:764–76. 12. benson aj. spatial disorientation in flight. in: gillies ja, ed. text book of aviation physiology. oxford: pergamon press, 1965. pp. 1086–129. squ med j, august 2010, vol. 10, iss. 2, pp. 160-168, epub. 19th jun 10 submitted: 8th april 10 reviewed internally & externally accepted: 19th may 10 in 2010, the international medical education constituency can celebrate the centennial of the flexner report medical education in the united states and canada a report to the carnegie foundation for the advancement of teaching.1 the reason to recall this important document is not only its tremendous influence on medical education all over the world at that time, but also because a revisit might inspire the identification of solutions to the problems of medical education in our own time, which by their nature and scale may be indicating a return to “preflexnerian” conditions. the process of globalisation of medicine and medical education, manifested by the increasing migration of medical doctors and the growth of cross-border education providers as prominent indicators, has raised a wave of concern about how to safeguard the quality of medical schools. the debate emphasises the need for adequate criteria for what we expect from and require of medical schools/colleges/universities and their educational programmes. in response to these challenges, it is the aim of this paper to outline the obstacles to the achievement of high quality medical education and to discuss what should be seen as fundamental principles for establishment of medical schools in the 21st century. office of the world federation for medical education (wfme), panum institute, faculty of health sciences, university of copenhagen, denmark. email: wfme@wfme.org كيف لنا أن نَُعّرف كلية الطب؟ انطباعات مبناسبة الذكرى املئوية لتقرير فلكسنر هان�س كارل امللخ�ص: مع مرور قرن لن�رش تقرير فلك�شرن عن التعليم الطبي يف اأمريكا ال�شمالية الذي كان مبثابة ثورة يف منهجية تدريب الأطباء يف كافة اأنحاء العامل ، اآن الأوان ملراجعة ودرا�شة هذه الوثيقة امل�شهورة وحتليل عالمات واأعرا�س ما ي�شتجد الآن من عودة اإىل اأو�شاع ما قبل فلك�شرن. فاإن ، املادي الربح هدفها والتي املا�شية العقود خالل الرديئة النوعية ذات ال�شغرية التعليمية واملوؤ�ش�شات الكليات وانت�شار ازدياد فمع التعليم الطبي اأ�شبح مهددا ويف و�شع حرج . ولهذا املو�شوع اهتمام عاملي وا�شع مع وجود هجرة متزايدة لالأطباء . لهذا ال�شبب فاإن هناك حاجة ما�شة ملناق�شة ما يجب اأن تكون عليه املعايري املقبولة واملطالب الأ�شا�شية لإن�شاء مدار�س طب حديثة . مفتاح الكلمات: مدار�س ، طب ، تعليم ، طبي ، طالب جامعي، خ�شخ�شة، العوملة ، نوعية. abstract: a century after the flexner report on medical education in north america, which revolutionised the training of medical doctors all over the world, it is time to revisit this famous document and analyse symptoms and signs of a return to pre-flexnerian conditions. with the ongoing mushroom growth over the last decades of small, proprietary educational institutions of low quality and driven by for-profit purposes, medical education is in a threatened position. this trend is of general international interest because of the increasing migration of medical doctors. there is a need for discussion of what should be the rational criteria and basic requirements for establishing new medical schools. keywords: schools, medical; education, medical, undergraduate; privatization; globalization; quality. special contribution how do we define a medical school? reflections on the occasion of the centennial of the flexner report hans karle hans karle special contribution | 161 essentials of the flexner influence on medical education abraham flexner was born 1859 within a family of german heritage in kentucky, us, and graduated as a teacher from johns hopkins university at the age 19. he founded a private school in his home city in kentucky, but became engaged in the study of medical education. he was inspired by the european university tradition as it had particularly developed in germany and which had great influence on the teaching principles used at johns hopkins university. in the beginning of the 20th century, the existing 155 medical schools in north america showed great variance with respect to curricular principles, and some small “proprietary” schools, owned by one or a few doctors and operated on a for-profit basis, had no affiliation to a university or a college. entrance requirements were low, and a medical degree was typically awarded after a few months-long didactic course of lectures; laboratory training, dissections and clinical work were not necessarily part of the study. the regulations and requirements set by their authorities were minimal or nearly non-existent. there had been increasing awareness of these problems in the late 19th century; reforms were seen in some institutions such as the harvard medical school, and the medical school at johns hopkins university, established in 1893, became a model in the country. in 1904, the american medical association established a council on medical education whose objective was to restructure medical education in the country. in 1908, the council asked the carnegie foundation for the advancement of teaching to undertake a survey of american medical education, and abraham flexner was called to conduct the study. flexner visited all 155 medical schools and prepared his revolutionary report, which was a milestone in medical education in the us. it also had great influence on the education and training of doctors in europe and other parts of the world, and is probably the most influential key debate document on medical education ever produced. the main recommendations in the report of 1910 dealt with the following issues: a) admission of students: rigorous entrance requirements to a medical school were set up; at minimum, a high school diploma and at least two years of college or university study, primarily with focus on basic sciences (biology, chemistry and physics), should be required; b) scientific method: flexner emphasised the need for adherence to scientific principles and evidence-based medicine. the scientific method of critical thinking and problem solving should be the key for physicians to manage clinical problems; c) teaching staff: the faculty should be of adequate number, and the qualifications of teachers, including their engagement in research, should be evaluated carefully; d) resources: sufficient resources were needed, and medical schools should be associated with universities; e) clinical training facilities: clinical training should be ensured and clerkships controlled directly by the medical school; f ) research attainment: medical education should have a close relation to medical research, and exposure to laboratory work should be part of the training programme; g) length of the medical education programme: the duration of the curriculum should be four years, divided into two years of basic science teaching followed by two years of clinical instruction; h) medical pedagogy: flexner underlined the value of small classes, personal attention, hands-on teaching and learning by doing, and thereby heralded the pedagogical innovations seen much later in the century. these basic requirements are still the fundamental model for the graduate curriculum for medicine used in the us and increasingly in other countries. flexner recommended that proprietary medical schools should either be closed or incorporated into existing universities, and his report eventually led to closure of more than 50% of medical schools in the us. the logical consequence of the report was the introduction of the principle of review and accreditation of medical schools, which has been in operation in the us since 1942, when the american medical association (ama) and the association of american medical colleges (aamc) jointly formed the liaison committee on medical education (lcme).2 flexner became involved in development of other parts of higher education. as an influential member of the staff of the rockefeller foundation he channelled huge funds to medical schools. later he became director of the institute for advanced studies at princeton university, us, and was instrumental in recruiting albert einstein to this how do we define a medical school? reflections on the occasion of the centennial of the flexner report 162 | squ medical journal, august 2010, volume 10, issue 2 institution in 1933. return to pre-flexnerian conditions? the 20th century saw a constantly growing number of medical schools in the world, explained not only by increases in population and wealth, as expressed by rises in gross national product (gnp) in many countries, but also by the increasing priority of health issues in connection with the development of medical sciences and services. another factor was the foundation of national schools in former colonies as a consequence of the decolonisation process after the second world war. later in the century, the need for more doctors increased due to a changed gender pattern of, and stronger workload regulations for, the medical profession. concomitantly with the quantitative changes, a number of other trends were seen in the structure and organisational conditions of medical education. most prominent has been the reintroduction of a proprietary for-profit concept and increased privatisation of higher education institutions, which have transformed higher education, including medical education, into a trade commodity, sometimes even systematised to provide doctors for bulk export. finally, in many countries medical education has been dissociated from national medical manpower planning and to a high extent steered by cross-border providers. some of the new trends resemble conditions before the publication of the flexner report, and need more detailed comments. n u m b e r a n d s i z e o f m e d i c a l s c h o o l s fair quality statistical information about numbers of medical schools in the world has been available from the middle of the 20th century with the appearance of the world health organization’s (who) directory of medical schools; the first edition was published in 19533 and the seventh in 2000.4 from about 1953 to about 2000, the number of medical schools included increased from 566 to 1,642 or 2.9 times. in the same period, the world population increased from approximately 2.5 billion to approximately 6 billion or 2.4 times. over the years, up-dating of information in subsequent editions of the directory showed that the values presented in the database underestimated the real number of schools by about 5%. the rate of increase in the number of schools over the last 50 years of the 20th century showed a slightly rising trend with about 20 new schools per year in the first half of the period compared with about 25 new schools per year in the second half. a register of medical schools produced by the international institute for medical education (iime),5 established by the china medical board of new york, showed 1,829 medical schools in 171 countries of the world in 2006; this database is not being updated. in 2009, the international medical education database (imed),6 produced by the foundation for the advancement of international medical education and research (faimer), had 2,161 registered medical schools in 160 countries, but the database has the weakness that schools are sometimes registered more than once. when the who database of 2000 with updates to 2007 was transferred and established as a new database (the avicenna directory of medical schools)7 in copenhagen in march 2008 (see later), the number of medical schools was 1,750. after that, further updating had, by february 2010, resulted in a total number of registered medical schools of 1,850 in 165 countries added to the database, and new schools are being added at an increasing rate. obviously, there is a need for better statistical information about the number of medical schools/ colleges/universities, which are providing a basic or undergraduate medical education programme as a basis for obtaining a licence as a medical doctor. a fair estimate of the global situation, one hundred years after the flexner report, would be that approximately 2,000 medical schools are educating 1 million doctors per year, and feeding a total medical doctor population of approximately 6 million serving the global population of now 6.2 billion. the increase in the number of medical schools has not necessarily resulted in a proportional increase in educational capacity. data from the avicenna directories indicate a tendency towards the establishment of smaller institutions, sometimes with very low admission figures (5–50 students per year). on the other hand, the number of admissions per year has probably increased in many schools, at least in some countries. the estimated number of graduates per medical school varies around hans karle special contribution | 163 the world: relatively low values of around 40–100 per annum in sub-saharan africa with many new schools; increasing values of between 100–150 in canada, japan, the us, parts of south asia, the middle east and australia/new zealand; about 200– 250 in east asia and the pacific region; and high values with averages about 330 and 510 in western and eastern europe (central and eastern europe/ commonwealth of independent state countries) respectively.8 some western european universities (e.g. in austria, belgium, denmark, germany, spain and the uk) have a student intake of more than 500 per year, and intakes of 1,000–1,500 per year are seen in some institutions in, for instance, china, egypt, russia and south america. there is no general consensus about the optimal number of medical schools in relation to the size of population, and figures for school/population ratio vary greatly. globally, the average number of medical schools per million inhabitants is 0.30, but with clear regional differences: 0.15 in africa, 0.22 in asia, 0.54 in europe, and about 0.60 in north and south america.9 some countries show extreme deviation from this pattern; in africa, some big countries like eritrea and somalia have no medical school and malawi and zambia, both with more than 10 million people, have only one school each. some small, but rich, countries like iceland and malta have a medical school for a population of less than half a million people. completely out of proportion to the size of the population, high medical school/population ratios are found in countries in the caribbean region; the overall value is 1.42,10 but the most extreme example is seen in montserrat with 2 schools and a population of 10–20,000; this illustrates the mercantile trend in medical education discussed below. p r i vat i s at i o n, f o r-p r o f i t p u r p o s e s a n d r o l e a s t r a d e c o m m o d i t y a clear indicator of a return to a situation akin to the time before the flexner report is the reappearance of private proprietary medical schools in an increasing number of countries. there are driving forces other than the societal need for medical doctors behind the establishment of a new medical school. in addition to population developments in terms of size and geographical distribution, or any need for specific affiliations due to ethnic, linguistic or religious factors, the explanations for the foundation of new medical schools are often political and personal ambitions and pressures, increasingly motivated by business purposes. this is simply an expression of a general trend, which has turned higher education into a trade commodity being regulated internationally more by trade organisations than by health and education authorities. the difference between public and private is not always sharp. in some countries, private schools are still under strong governmental regulation, and some private schools obtain major official grants; on the other hand, some public schools are dependent on financial support from private sources such as companies or funding agencies. it is important to distinguish between privatisation and for-profit purposes. some of the best medical schools in some countries have traditionally been established as a private enterprise. there is high variation in the trend of privatisation in different parts of the world.11 in india and the us, about 50% of all medical schools has a private basis. in japan, more than 35% are private. privatisation is also prominent in the caribbean region, the gulf cooperation council countries, malaysia, pakistan, the philippines and in the oceanic region, whereas it is still a rarity in africa, canada and europe. also in china, the government has full control. a special example of the trade in medical education is that at least one country (cuba) has deliberately expanded its medical education system for the export of medical doctors to south america, africa and eastern europe in exchange for other commodities like oil. c r o s s-b o r d e r p r o v i d e r s a n d d i s s o c i at i o n f r o m n at i o n a l m a n p o w e r p l a n n i n g in close relationship to privatisation we also find a trend of cross-border provision of basic medical education. the so-called “offshore medical schools” model is increasingly contributing to the production of medical doctors. some countries have always been dependent on the influx of doctors from abroad to cover their own medical manpower requirements. this is the problem behind the highly problematic brain drain phenomenon. but, in addition to doctors with a foreign nationality, we now see a systematic how do we define a medical school? reflections on the occasion of the centennial of the flexner report 164 | squ medical journal, august 2010, volume 10, issue 2 recruitment to the profession of nationals with a diploma in medical education from institutions outside the country. the best example is the us, in which about 25% of the medical profession is international medical graduates (img), a majority of them with a us national background. this “off shore medical school” model is probably most prominent in the caribbean region which has dozens of medical education programmes, mainly for us nationals, based on a combination of education in the basic medical sciences in a medical school in the caribbean region and clinical training arrangements somewhere in the us. the owners and the administrations of the schools are frequently located in the us. ironically, the us is thus again becoming dependent on proprietary schools, very many of them being of doubtful quality, as in the time of the criticism made by flexner, but now located in other countries. the resulting situation could be described thus: that due to flexner’s influence, such high requirements were set for the establishment of a medical school that society could not afford the development of an educational capacity sufficient to cover all national needs, but, instead, society indirectly accepted lower quality education institutions. another aspect of cross-border education of doctors is that some of the well established and most prestigious medical schools in the world, especially located in us, uk and australia, now, for business reasons, build satellite schools in other countries, e.g. in the middle east or asia. problems with the present definition of medical schools the questions related to the numbers and size of medical schools, the increasing privatisation of educational institutions and the cross-border provision of medical education have a number of implications for the quality of basic medical education. the problems are to some extent interconnected. decisions to create medical schools without any connection to the national needs for doctors are problematic and might lead to either undersupply or overproduction of doctors. fulfilment of national medical doctor manpower needs based on the assumption of either attracting foreign doctors or on any kind of systematic cross-border education model is also difficult to justify and might sometimes be unethical. in many countries, there has not been sufficient focus on the acceptable size of a medical school. there are potential problems with very big schools due to the risk of weak teacher/student interaction (of course again depending on the organisation of the school), less use of interactive student instruction methods, which may be too expensive, and insufficient capacity for clinical training. on the other hand, small schools can also create problems due to the ineffective use of limited resources, from low governmental support and/or low income from tuition fees, difficulties in the recruitment of qualified teachers, weak or non-existing research attainment, programme deficiencies as a result of missing medical disciplines, or sub-standard educational facilities and equipment. data collection, made by the new avicenna directory of medical schools7 show examples of educational institutions applying for inclusion in the directory that have only a handful of students and teachers, some of whom might even have associations to other schools as well. it could be argued that such institutions should not be called medical schools. the complex situation of privatisation and crossborder provision of medical schools implies specific risk factors. some private enterprises, for instance established by religious or otherwise charitable organisations, have undoubtedly been valuable in supporting profitable management conditions and adequate access to resources; such schools might also provide valuable competition for the public schools and so assist in keeping quality high. however, in order to conduct a profitable business, introduction of this concept of privatisation mainly leads to the risk of low quality education. privatisation has furthermore been a great financial burden on the student population, creating high levels of study debt and steering recruitment of students by favouring wealthy, but often less suitable students with lower intellectual or ethical capacities; it can also have a negative impact on the functioning of health care systems by not allowing access to the medical profession by underrepresented minority groups. furthermore, it is a fact, that education programmes of private medical schools more often have insufficient capacity of clinical training settings hans karle special contribution | 165 and very often no research background. in 2005, following a joint collaboration process by the organisation for economic co-operation and development (oecd) and the united nations educational, scientific and cultural organization (unesco), guidelines for quality provision in cross-border higher education12,13 were launched as an educational response to the general agreement on trade in services (gats) for crossborder education. the guidelines give an overview of the problems and important recommendations to the issue of cross-border higher education. rational criteria for the foundation of medical schools in the 21 st century a complete or merely comprehensive coverage of all elements relevant for the definition of a medical school is outside the scope of this discussion. it is not the intention here to deal with factors such as physical facilities and other resources necessary for an effective and quality based medical school programme, and only some general aspects of what should be the prerequisite and background for establishment of a medical school – as was the case in the flexner report – will be discussed. o w n e r s h i p, a c c r e d i tat i o n s y s t e m s a n d r e g i s t r at i o n although it would be totally unrealistic, and also unnecessary, to prevent medical schools being founded as private enterprises, the shift in the quantitative balance between public and private institutions over the last decades is alarming, and governmental authorities must demonstrate a greater interest in higher education, including the education and training of medical doctors. also, regulatory authorities, including accreditation agencies, should have a stronger influence. presently, systems for proper accreditation or other types of recognition of medical schools are not sufficiently established in all countries; approximately one third of countries with medical schools do not have any quality assurance system. the concept of accreditation is not accepted everywhere and the term used around the world covers a variety of principles and practical methods. the greatest problem is that national systems for recognition do not always cover all existing schools and very often exempt private institutions. in the future, legislation should ensure that private medical schools undergo the same controls as public schools using the same criteria and procedures for recognition. the criteria for establishment of a medical school should look at the methods and means of recruitment and admission of students, and also consider the amount of tuition fees acceptable in order to ensure a balanced mix of students to cover societal needs and an adequate spectrum of medical manpower expertise. in recognising a medical school, it should be a prerequisite that the school admits nationals as well as foreign students, and that graduates of the school are formally allowed to seek a licence to practise as medical doctors in the country. sometimes, new schools are seen as good tax-earners for the country, even when the quality of the product is not considered sufficiently high to allow practising in the country. the global standards for the improvement of basic medical education, developed in 2003 by the world federation for medical education (wfme) and broadly adopted internationally, offer a template for the formulation of national specifications when setting standards;14 according to information available, these standards have now contributed to reforms in up to half of the world’s medical schools. also regarding accreditation of basic medical education institutions and programmes, guidelines were established jointly by the world health organisation (who) and wfme in 2005 to improve medical education.15 proper accreditation of medical schools has some limitations and weaknesses. it is a complicated and expensive process both in terms of consumption of academic time and in direct costs. the process is also endangered by critical factors such as the following risks: 1) insufficient independence of accreditation councils in relationship to governments and providers of education; 2) assessors who lack the necessary objectivity and proficiency; 3) political pressure from outside and conflicts of interests; 4) problems with reliability of the information provided by the institutions and with selectivity in choice of demonstrations during site visits. therefore, some countries prefer alternative means of quality assurance built on elements such as the procedures used in the selection of students; entrance how do we define a medical school? reflections on the occasion of the centennial of the flexner report 166 | squ medical journal, august 2010, volume 10, issue 2 examinations; centrally regulated curricula, and national board examinations, etc. there is a clear need for the promotion of internationally accepted quality assurance methods and recognition of medical schools and for easier access to obtain adequate information about medical schools. one step will be the new avicenna directory of medical schools,7 established in 2007 according to an agreement between the who, the university of copenhagen (faculty of health sciences) and the wfme. the directory has replaced the who world directory of medical schools, and will provide more comprehensive information on schools and their programmes and be updated regularly. such a register will allow a kind of international meta-recognition of medical schools and will help regulatory agencies, responsible for the licensing of doctors, in evaluating the educational background of foreign medical doctors. it will also allow research on medical education in relationship to demographic data. n u m b e r a n d s i z e o f m e d i c a l s c h o o l s the relevant number of medical schools in a country, and the appropriate size of schools in terms of student admission and the annual number of graduates must be considered when governments are planning or recognising a new medical school. the motives behind the initiative and how quality will be measured must be considered. the optimal number of schools in a specific country will depend not only on population size and the status of the health care system, but also on population density and need for coverage of rural as well as urban areas, and also the need for special ethnic and religious affiliations. there might therefore be reasons for deviations from a general consensus on the optimal value, which could be estimated to be around one medical school per 1.5–2 million inhabitants. small countries wanting to have their own medical training would of course need special conditions. above, examples were given about the main problems related to small medical schools. again, it can be difficult to define the optimal size of a medical school measured by the number of students or graduates, but a fair estimate would be 200–300 graduates per year within an acceptable range of 50–500. p r o g r a m m e a n d i n s t r u c t i o n a l m e t h o d s a medical school is an educational institution providing a complete or full programme leading to a basic medical qualification, that is, a qualification that permits the holder to obtain a licence to practise as a medical doctor or physician. the educational programme of a modern medical school must demonstrate its foundation on evidence-based “westernised” medicine and scientific principles. deviation from this can in some cases be accepted; an example is osteopathic schools in the us, which are recognised by health authorities as a basis for the achievement of a licence to practice as a medical doctor, whereas graduates in osteopathic medicine in many other countries are normally not eligible to function as medical practitioners. also, schools of unorthodox, traditional or alternative medicine in china, for example, can be accepted when close curricular similarities with normal medical schools are ensured. however, the programme of the majority of schools providing unorthodox medicine will not be compatible with the function of a medical doctor. programmes of schools having a strong religious affiliation must in principle be carefully scrutinised before recognition, as they might provide programmes with obvious deficiencies or aberrant views. special programmes of medical schools, such as a paediatric track, can not automatically lead to authorisation to practise as a medical doctor. in planning and reviewing its educational programme, the medical school must demonstrate social responsiveness — probably a more fair and valid expression than the “social accountability”, so often used by critics of medical schools — i.e. the awareness of and willingness to adapt to societal needs and expectations. regarding requirements for clinical training settings, restriction to the use of wards in tertiary university hospitals alone should not be accepted in the future, since health care activities relevant for the training of new doctors are more and more moving to other types of institutions and to ambulatory care facilities. clinical training, which should comprise not less than 50% of the total programme, must include exposure to a broad spectrum of clinical experiences, including secondary and district hospitals, health care centres, general practice, etc. emphasis should also be put on ambulatory health hans karle special contribution | 167 care activities. the involvement of the full spectrum of the health care system in the educational process will require effective collaboration between the schools and their partners in the health sector and thorough supervision of decentralised functions by the faculties. with respect to instructional methods, it should be recalled that the development in medical education pedagogic methodology over the last decades has brought many innovations, but not proved the significant superiority of any specific method. organisation of the education process and choice of methods should thus allow considerable flexibility, taking into account tradition, academic experience, resources, etc. however, it must be ensured that teaching and learning is studentcentred with adequate student-activating elements. the student group must also have influence on the programme. the numbers of teachers and teacher/student ratios must be held within standards for modern medical education with some flexibility depending on the pedagogic methods in use, and the staff group must together be able to cover all relevant disciplines at a sufficiently high academic and scientific level. r e s e a r c h at ta i n m e n t a n d u n i v e r s i t y a f f i l i at i o n the flexner report showed a strong commitment to the adherence of medical education to scientific principles, underlining the need for laboratories, research and evidence-based medicine. a consequence of this was the increase in resources needed for the establishment and maintenance of medical schools, which became an unaffordable requirement in many countries, especially in the poorer parts of the world, throughout the 20th century. the result was that many new medical schools have no research background for their education programme, whereas the older, wellestablished schools conduct research-based education, meaning that teachers also are competent and active in medical research and developments, so that students are directly exposed to and even directly engaged in research projects. again the situation varies around the world. in europe, according to the requirements for basic medical training enumerated in the directive on the recognition of professional qualifications,16 graduates from medical schools must have “adequate knowledge of the sciences on which medicine is based and good understanding of the scientific methods including the principles of measuring biological functions, the evaluation of scientifically established facts and the analysis of data.” the wfme global standards in basic medical education14 underline, that “the medical school must have a policy that fosters the relationship between research and education.” as a goal for quality development of the programme, it is added “that interaction between research and education activities should be reflected in the curriculum and influence current teaching, and should encourage and prepare students to engagements in medical research and development.” for europe, the last recommendation is considered a basic standard.17 there are reasons to believe that research related competencies will increasingly be sought as a foundation for medical practice, and therefore research attainment should be a basic requirement for a medical school in the 21st century. this might potentially be part of a reform process of the health care sector, which would gradually diminish the number of medical doctors required with competencies in science and research, by transferring elementary health care activities to other cadres of health workers functioning under the supervision of physicians.18 as a consequence of the need for research attainment, medical schools should normally be part of or otherwise affiliated to a university. concluding remarks the carnegie foundation for the advancement of teaching, which helped transformation of medical education one hundred years ago, will in 2010 issue a new report on medical education,19 that will deal with standardisation of learning outcomes, promotion of multiple forms of integration and also focus on formation of the professional identity of physicians. nevertheless, a revisit to the flexner report should be an obligation for medical schools and authorities with responsibility for medical education. this should not only be seen as a respectful homage to one of the most significant reformers of the discipline of medical education, but also as an inspiration to conduct analysis and necessary reforms of medical schools. how do we define a medical school? reflections on the occasion of the centennial of the flexner report 168 | squ medical journal, august 2010, volume 10, issue 2 although, there has been criticism and misunderstanding of flexner and his goals20 — for instance a postulation of not taking into account the importance of the doctor-patient relationship or in stimulating a non-flexible and overcrowded curriculum — there are good reasons to investigate if medical schools comply adequately with the original recommendations of flexner, especially when plans for a new medical school are being discussed. in this process, governmental authorities should reconsider the situation of very small and inadequate educational institutions and the criteria in use to allow private initiatives in founding medical schools. references 1. flexner a. medical education in the united states and canada: a report to the carnegie foundation for the advancement of teaching. bulletin no 4. new york: carnegie foundation, 1910. 2. kassebaum dg. origin of the lcme, the aamcama partnership for accreditation. acad med 1992; 67:85–7. 3. world health organization. world directory of medical schools, 1st ed. geneva: who, 1953. 4. world health organization. world directory of medical schools, 7th ed. geneva: who, 2000. 5. institute for international medical education. database of medical schools, 2006. iime. from http://www.iime.org/database accessed march 2010. 6. foundation for advancement of international medical education and research. faimer. 2005. international medical education directory (imed). from http://imed.ecfmg.org accessed march 2010. 7. avicenna directories. copenhagen. from http:// avicenna.ku.dk accessed march 2010. 8. eckhert nl. the global pipeline: too narrow, too wide or just right. med educ 2002; 36:606–13. 9. boulet j, bede c, mckinley d, norcini j. an overview of the world´s medical schools. med teacher 2007; 29:20–6. 10. van zanten m, parkins lm, karle h, hallock ja. accreditation of undergraduate medical education in the caribbean: report on the accreditation authority for education in medicine and other health professions. acad med 2009; 84:1–5. 11. shehnaz si. privatisation of medical education: viewpoints with a global perspective. squ med j 2010; 10:6–11. 12. organisation for economic co-operation and development. guidelines for quality provision in cross-border higher education. paris: oecd, 2005. 13. united nations educational, scientific and cultural organization. guidelines for quality provision in cross-border higher education. paris: unesco, 2005. 14. world federation for medical education. basic medical education. wfme global standards for quality improvement. copenhagen: wfme, 2003. from http://www.wfme.org. accessed march 2010. 15. world health organization/world federation for medical education. accreditation guidelines for basic medical education, geneva/copenhagen 2005. from http://www.wfme.org accessed march 2010. 16. european union. eu directive 2005/36/ec of 7 september 2005 on the recognition of professional qualifications. brussels 2005. from http://www. europa.eu.int/comm./internal market/qualifications/ future en.htm accessed march 2010. 17. quality assurance task force, the thematic network on medical education in europe (medine). wfme global standards for quality improvement in medical education. european specifications. copenhagen: wfme 2007. from http://www.wfme. org accessed march 2010. 18. gordon d, lindgren s. the global role of the doctor in health care. world medical & health policy j 2010. from http://www.psocommons.org/wmhp. accessed may 2010. 19. irby dm, cooke m, o´brien bc. call for reform of medical education by the carnegie foundation for the advancement of teaching: 1910 and 2010. acad med 2010; 85:220–7. 20. ludmerer km. commentary: understanding the flexner report. acad med 2010; 85:193–6. 1department of maternal, child & family health, hashemite university, zarqa, jordan; 2department of maternal child health, jordan university of science & technology, irbid, jordan *corresponding author’s e-mail: mohammada_m@hu.edu.jo مواقف األطفال الغري مصابني بالربو جتاه أقراهنم املصابني باملرض تأثري التفاعل مع بالربو األقارب واألقران حممد املطلق و نهايه ال�شياب abstract: objectives: this study aimed to examine non-asthmatic children’s acceptance of and attitudes towards their asthmatic peers in jordan. methods: this descriptive cross-sectional study was conducted between september 2015 and january 2016 among 1,812 non-asthmatic children aged 9–13 years old at 10 schools in zarqa, jordan. arabic versions of the peers attitude towards children with asthma scale and the asthma knowledge test for children were used to assess attitudes towards children with asthma and asthma-related knowledge, respectively. results: a total of 1,586 children participated in the study (response rate: 87.5%). of these, 158 (10%) and 399 (25.2%) children reported a family history of asthma or knew at least one person with asthma, respectively. although 50.3% stated that they would sit next to such children in the classroom, only 34.9% reported that they would be friends with an asthmatic child. however, 73.1% of the non-asthmatic children believed that asthmatic children were not pretending to be ill and 61.4% believed that such children were not ill due to their own carelessness. female non-asthmatic children (p <0.001), those with a family history of asthma (p = 0.004) and those who knew other individuals with asthma (p <0.001) had significantly more positive attitudes towards and acceptance of their asthmatic peers. in addition, age was significantly related to attitude scores (p <0.001). however, there was no correlation between asthma-related knowledge and the children’s attitudes towards peers with asthma (p = 0.611). conclusion: previous interactions with asthmatic family members or peers were found to significantly influence non-asthmatic children’s attitudes towards their asthmatic peers. keywords: asthma; children; attitudes; knowledge; jordan. يف امل�شابني نظرائهم جتاه بالربو امل�شابني غري الأطفال وموافقة قبول مدى على التعرف اإىل الدرا�شة هذه هدفت الهدف: امللخ�ص: الأردن. الطريقة: اأجريت هذه الدرا�شة الو�شفية امل�شتعر�شة بني �شبتمرب 2015 ويناير 2016 على 1,812 من الأطفال غري امل�شابني بالربو الذين ترتاوح اأعمارهم بني 13-9 �شنة يف 10 مدار�ض يف الزرقاء، الأردن. مت ا�شتخدام الإ�شدارالعربي من مقيا�ض اجتاه النظراء من الأطفال حول اأقرانهم الذين يعانون من الربو واختبار مدى معرفتهم مبر�ض الربو لتقييم مواقف الغري م�شابني جتاه الأطفال الذين يعانون من من 158 اأبلغ هوؤلء، بني من .)87.5% ال�شتجابة: )معدل الدرا�شة يف طفل 1,586 �شارك النتائج: بالربو. املتعلقة املعرفة ومدى الربو ا واحًدا على الأقل م�شاًبا بالربو، على التوايل. وعلى الرغم الأطفال )%10( و 399 )%25.2( عن تاريخ عائلي للربو اأو كانوا يعرفون �شخ�شً من اأن %50.3 ذكروا اأنهم �شيجل�شون بجانب هوؤلء الأطفال يف الف�شل، اأفاد %34.9 منهم فقط اأنهم قد ي�شادقوا طفال م�شابا بالربو. ومع ذلك، يعتقد %73.1 من الأطفال غري امل�شابني بالربو اأن الأطفال امل�شابني بالربو ل يتظاهرون باأنهم مر�شى و %61.4 يعتقدون اأن هوؤلء الأطفال لي�شوا مر�شى ب�شبب اإهمالهم. كان لدى الإناث اللواتي ل يعانني من الربو )p >0.001(، واللواتي لديهن تاريخ عائلي من الربو امل�شابني اأقرانهم قبول جتاه اإيجابية اأكرث مواقف )p >0.001( الربو من يعانون اآخرين ا اأ�شخا�شً يعرفون الذين واأولئك )p = 0.004( بالربو. بالإ�شافة اإىل ذلك، كان العمر مرتبطا ب�شكل كبري مع درجات قبول الأطفال امل�شابني بالربو )p >0.001(. ومع ذلك، مل يكن هناك التفاعالت اأن وجد p(. اخلال�صة: = 0.611( الربو من يعانون الذين اأقرانهم جتاه الأطفال ومواقف بالربو املتعلقة املعرفة بني ارتباط ال�شابقة مع اأفراد من العائلة م�شابني بالربو اأو الأقران توؤثر ب�شكل كبري على مواقف الأطفال غري امل�شابني بالربو جتاه اأقرانهم امل�شابني. الكلمات املفتاحية: الربو؛ الأطفال؛ الجتاهات؛ املعرفه؛ الأردن. attitudes of non-asthmatic children towards their asthmatic peers influence of interactions with asthmatic relatives and peers *mohammad al-motlaq1 and nihaya al-sheyab2 clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e161–166, epub. 9 sep 18 submitted 10 aug 17 revisions req. 20 nov & 31 dec 17; revisions recd. 6 dec 17 & 4 jan 18 accepted 18 jan 18 advances in knowledge in the current study, female non-asthmatic children, those with a family history of asthma and those who knew someone with asthma had significantly more positive attitudes towards their asthmatic peers in zarqa, jordan. application to patient care healthcare providers in jordan should promote positive attitudes towards children with asthma in clinical practice. doi: 10.18295/squmj.2018.18.02.007 childhood asthma is a long-term respi-ratory disease which impacts both physical and emotional wellbeing, often affecting the patient’s daily quality of life (qol). 1,2 previous studies have indicated that children with chronic illnesses often suffer from reduced academic performance attitudes of non-asthmatic children towards their asthmatic peers influence of interactions with asthmatic relatives and peers e162 | squ medical journal, may 2018, volume 18, issue 2 due to disease-associated exacerbations, absenteeism and stress.3,4 moreover, children with illnesses are often less accepted or engaged with by their peers.5–8 for children with asthma, qol may be affected by social acceptance or rejection by their peers in light of the stigma associated with the disease.3,9 in general, graetz et al. found that children with asthma who were more frequently hospitalised were less preferred as playmates by other children and perceived to be more sensitive and isolated.5 another study demonstrated that symptomatic evidence of a disease negatively influenced some children’s perceptions of and responses towards their sick peers.10 unfortunately, social rejection and negative attitudes often have an unfavourable impact on the wellbeing of the ill child.6,11–13 the role of peer support in facilitating psychosocial adjustment among children has proven beneficial in improving resilience and well being.8 therefore, direct contact between healthy and ill children is highly advised in order to effectively improve the attitudes of the former towards the latter.7,11,14,15 previous research has indicated that greater asthma-related knowledge and being female positively affect children’s attitudes towards their asthmatic peers.11,16 such research is important in order to identify appropriate interventions to improve asthma-related attitudes in schools and the wider community. specifically, it is important to study whether having a family history of asthma or knowing others (i.e. a friend, peer or relative) with asthma positively contributes to children’s acceptance of or attitudes towards their diseased peers. in jordan, the prevalence of asthma is comparable to that of other developed countries.17 however, this may be due to underdiagnosis of the condition; a review from the middle east indicated a noticeable increase in the prevalence and burden of asthma due to increased public and professional awareness of the disease.18 frequent asthma-related triggering factors include respiratory tract infections, exercise, dust and parental smoking.17,19 nevertheless, there are few asthma health education and promotion programmes targeting children and adolescents in jordan.19 this study aimed primarily to examine the association between attitudes towards peers with asthma among non-asthmatic children and having a family history of asthma or knowing someone with asthma. based on the outcomes of studies evaluating perceptions of physical disability, it was hypothesised that interactions with family members or peers with asthma would positively influence acceptance of and attitudes towards asthmatic peers among nonasthmatic children.14,15 the second aim of the study was to investigate the relationship between non-asthmatic children’s levels of asthma-related knowledge and their attitudes towards their asthmatic peers. finally, the third aim was to determine asthma-related knowledge and attitudes among children without asthma. methods this descriptive cross-sectional study was conducted between september 2015 and january 2016 at 10 schools in the second educational district of zarqa, jordan. these schools included nine governmental schools and one private school and were recruited from a list of 100 schools in zarqa, including 29 male-only schools, 23 female-only schools and 48 coeducational schools. a simple random sampling technique was subsequently used to select one class of children from each grade between grades 4–7 at the selected schools. overall, 1,812 non-asthmatic children aged 9–13 years old were invited to participate in the study. three questionnaire tools were utilised to gather data from the participants. demographic information was elicited using a four-item questionnaire, including age, gender, the presence of a family history of asthma and pre-existing relations with individuals with asthma. subsequently, the 10-item peers attitude towards children with asthma (paca) scale was used to measure attitudes towards (items 3, 4, 5, 7, 8 and 10) and acceptance of (items 1, 2, 6 and 9) children with asthma on two subscales.11 the children responded to each item with yes/no responses, with a score of one given to a positive response and zero to a negative response. after reverse scoring negatively-worded items, the scores were summed up to provide a total overall score, in which higher overall scores indicated more positive attitudes towards children with asthma. finally, the 22-item asthma knowledge test for children was used to assess the children’s general knowledge about asthma, including its triggers, symptoms, treatment and management.20 this questionnaire consisted of 21 true/false items and one item asking the child to list three symptoms of asthma. one point was awarded for each correct answer or symptom listed, for a maximum of 24 points. correct responses to each item were summed to provide a total score. all of the questionnaires were translated into arabic and pilot-tested for comprehension and clarity among a group of children with similar characteristics to that of the study sample. the final questionnaires were distributed among selected classes with the aid of classroom teachers. when necessary, the teachers also helped the children to read and complete the forms. a total of 81 students who self-reported an asthma diagnosis were excluded from the analysis. mohammad al-motlaq and nihaya al-sheyab clinical and basic research | e163 not mind if their asthmatic peers used their inhalers in class [table 1]. with regards to asthma-related knowledge levels, the percentage of correct responses to each item ranged widely from 15.2–79.4% [table 2]. overall, 74.1% of the children gave correct responses to six items, while 49.3% provided correct responses to 15 items. overall, female students (t[1,566] = -4.3; p <0.001), those with a family history of asthma (t[1,566] = 2.9; p <0.004) and those with prior knowledge of someone with asthma (t[1,566] = -7.6; p <0.001) had significantly more positive attitudes towards their asthmatic peers [table 3]. age was also significantly positively correlated to attitude scores (r = 0.14; p <0.001). however, there was no correlation between levels of asthma knowledge and attitudes towards asthmatic peers (r = 0.01; p = 0.611). discussion the current study aimed to explore the possibility that interactions with asthmatic family members or peers would have a positive influence on the acceptance of and attitudes of non-asthmatic children towards their data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). descriptive statistics were used to illustrate the characteristics and attitude scores of the sample. in addition, a correlation coefficient test was used to examine the relationship between asthma-related knowledge and attitude scores. a p value of ≤0.050 was considered statistically significant. in order to identify the effect of a family history of asthma and previous relations with other asthmatic individuals on the children’s attitudes, a multiple regression analysis was performed using all factors associated with attitude scores as independent variables. however, this technique was not successful due to the violation of multiple regression assumptions (i.e. multicollinearity). instead, a student’s t-test and analysis of variance were performed, with a bonferroni adjustment made to the alpha value (p <0.001). ethical approval to conduct this study was obtained from the hashemite university institutional review board (#2015/2014/2/3) and the ministry of education in jordan (#2/7/1/8221). in addition, the appropriate authorities at each school gave permission for the study to be conducted. parental informed consent was obtained for each of the children prior to their participation in the study. results a total of 1,586 non-asthmatic children participated in the study (response rate: 87.5%). of these, 659 (41.6%) were male and 927 (58.4%) were female. a family history of asthma was reported by 158 children (10%), while 399 (25.2%) stated that they knew at least one person with asthma. the mean total paca score was 4.97 ± 2.11 out of 10, with mean total scores for the acceptance and attitudes subscales being 1.73 ± 1.10 out of 4 and 3.24 ± 1.47 out of 6, respectively. total knowledge scores ranged from 0–21, with a mean score of 11.5 ± 3.09 out of 24. in terms of attitudes towards and acceptance of asthmatic children, the percentage of positive responses ranged from 30.1–59.9% for positivelyworded items and 26.9–56.9% for negatively-worded items. while 73.1% of students in the current study believed that children with asthma do not pretend to be sick and 61.4% believed that asthmatic children were ill due to factors other than carelessness, only 34.9% reported that they would be happy to accept children with asthma as their friends. in addition, only 30.1% believed that such children could participate in sports, while just over half (50.3%) did not mind sitting next to them. however, despite these generally negative attitudes, most children (59.9%) stated that they did table 1: attitudes towards children with asthma* among non-asthmatic children in jordan (n = 1,586) item positive responses, n (%)† positively-worded items 1. i am happy to be the friend of a child with asthma 542 (34.9) 3. children with asthma usually do well at school 734 (47.8) 6. it is acceptable for a child with asthma to use their puffer (inhaler) in class 927 (59.9) 9. children with asthma can participate in all school activities such as sports and games 463 (30.1) negatively-worded items 2. i do not like sitting next to a child with asthma 775 (49.7) 4. children with asthma often have a bad temper 750 (48.5) 5. children with asthma are shy about their disease 721 (46.8) 7. children with asthma get sick because they are careless 595 (38.6) 8. children with asthma often pretend to be sick 414 (26.9) 10. children with asthma get more attention from the teachers than other children 878 (56.9) *assessed using an arabic version of the 10-item peers attitude towards children with asthma scale.11 †percentages are not calcul-ated out of the total sample due to missing data for certain items. attitudes of non-asthmatic children towards their asthmatic peers influence of interactions with asthmatic relatives and peers e164 | squ medical journal, may 2018, volume 18, issue 2 asthmatic peers. however, compared to other studies from developed countries which revealed more positive attitudes and higher levels of asthma-related awareness, the current study revealed that nonasthmatic jordanian children held mostly negative attitudes towards their asthmatic peers and had low levels of asthma-related knowledge.11–13,21,22 in the present study, the majority of asthma knowledge-related items were answered incorrectly by most non-asthmatic children. this lack of knowledge extended across all aspects of the disease, including its causes, symptoms, treatment and management. a previous study conducted in northern jordan similarly reported low levels of asthma-related knowledge among adolescents in contrast to studies from the usa.19,23,24 additionally, the findings of the current study indicated a negative attitude trend extending across all components of the scale. moreover, high knowledge scores did not necessarily correlate with more positive attitudes. this is in contrast to a previous study of australian children which found that higher knowledge scores correlated positively with attitude scores.11 this variation in findings may be attributable to differences in the average knowledge scores between the two samples, particularly as the australian children had higher total scores than children in the current sample.11 this finding suggests that attitudes should be measured while controlling for knowledge scores, particularly when assessing potential influences such as a family history of asthma or knowing others with asthma. table 3: factors influencing attitudes towards children with asthma* among non-asthmatic children in jordan (n = 1,568)† factor n mean attitude score p value‡ gender male 644 4.7 ± 1.9 <0.001 female 924 5.2 ± 2.2 family history of asthma present 149 5.5 ± 2.2 0.004 absent 1,419 4.9 ± 2.1 prior knowledge of someone with asthma present 399 5.7 ± 2.1 <0.001 absent 1,169 4.7 ± 2.0 df = degrees of freedom. *assessed using an arabic version of the 22-item asthma knowledge test for children.20 †the total number of children who completed both the knowledge and attitude questionnaires. ‡a p value of ≤0.001 was considered significant after a bonferroni adjustment was made to the alpha value. table 2: asthma-related knowledge* among non-asthmatic children in jordan (n = 1,586) item correct responses, n (%)† 1. lots of children have asthma 770 (48.6) 2. children with asthma can play with other children 619 (39.1) 3. people with asthma can drink milk and eat yoghurt 1,214 (76.6) 4. having the flu (influenza) can cause an asthma attack 930 (58.7) 5. smoking is acceptable for people with asthma 241 (15.2) 6. people with asthma become addicted to their medication 967 (61) 7. if you do not have asthma now, you will never get it 582 (36.7) 8. an asthma attack is caused by hypersensitiv ity and inflammation in the airways of the lungs 1,216 (76.7) 9. most children with asthma are smaller than other children 561 (35.4) 10. asthma can be spread from person to person 693 (43.7) 11. if one child in a family has asthma, then their brothers and sisters will have asthma too 391 (24.7) 12. people with asthma can die if they are not treated 1,237 (78) 13. medicines that keep asthma from happening should be taken every day 1,175 (74.1) 14. a puffer (inhaler) should be used when a person has an asthma attack 965 (60.9) 15. having pet birds is acceptable for people with asthma 320 (20.2) 16. asthma attacks happen more frequently at night 1,057 (66.7) 17. it is acceptable for people with asthma to swim and play sports 532 (33.6) 18. asthma medicines can hurt the heart 697 (44) 19. rest is needed to stop an asthma attack 1,187 (74.9) 20. when asthma is controlled, all medicines can be stopped 781 (49.3) 21. with the right treatment, a child with asthma can live a normal life 1,259 (79.4) 22. can you list three signs of asthma? no correct symptoms 248 (16.6) one correct symptom 441 (28.3) two correct symptoms 487 (31.2) three correct symptoms 363 (23.9) *assessed using an arabic version of the 22-item asthma knowledge test for children.20 †percentages are not calculated out of the total sample due to missing data for certain items. mohammad al-motlaq and nihaya al-sheyab clinical and basic research | e165 a previous study found that a family history of asthma and prior knowledge of others with asthma were not significantly related to attitudes towards asthmatic peers among non-asthmatic australian children.11 this finding was attributed to the high level of acceptance of asthmatic peers among their studied sample. in contrast, both of these factors along with being female were found to positively contribute to total attitude scores in the current study. the low level of acceptance of asthmatic peers noted in the present study underlines the importance of social interactions between non-asthmatic and asthmatic children so as to foster positive attitudes and acceptance among the former group towards the latter.12 children with asthma have reported feelings of anxiety and embarrassment about their illness which affected their attitudes towards self-treatment.25 it is therefore important to change social perceptions of chronic illnesses in order to foster a positive attitude towards affected patients.6,10,16 healthcare providers in jordan should therefore seek to educate children regarding childhood asthma as well as promote positive attitudes towards asthmatic children among their non-asthmatic peers. the current study was limited by its crosssectional nature which does not imply a causal relationship; an interventional case-control study might have produced more valid results. in addition, a longitudinal rather than descriptive design would have contributed to the strength of the findings. however, this could not be achieved due to feasibility-related constraints such as lack of time and funds. another limitation of the study was the reliance on selfreported data potentially subject to reporting bias. in addition, this study was conducted in only one region of jordan; as such, the results cannot be generalised on a national level. conclusion the results of this study indicated low levels of asthmarelated knowledge and generally negative attitudes towards asthmatic peers among non-asthmatic students in zarqa, jordan. gender, age, a family history of asthma and prior knowledge of someone with asthma positively influenced attitudes towards asthmatic peers. therefore, additional interactions bet ween non-asthmatic and asthmatic children may be helpful in improving children’s attitudes towards their asthmatic peers. healthcare professionals should encourage positive interactions between nonasthmatic and asthmatic children in order to improve the knowledge and attitudes of non-asthmatic children towards their asthmatic peers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded with the aid of a grant from the ministry of higher education & scientific research support fund in jordan (grant #mph/1/10/2013). references 1. von mutius e. the burden of childhood asthma. arch dis child 2000; 82:ii2–5. doi: 10.1136/adc.82.suppl_2.ii2. 2. woolcock aj, bastiampillai sa, marks gb, keena va. the burden of asthma in australia. med j aust 2001; 175:141–5. 3. annett rd, bender bg, duhamel tr, lapidus j. factors influencing parent reports on quality of life for children with asthma. j asthma 2003; 40:577–87. doi: 10.1081/jas-120019030. 4. celano mp, geller rj. learning, school performance, and children with asthma: how much at risk? j learn disabil 1993; 26:23–32. doi: 10.1177/002221949302600103. 5. graetz b, shute r. assessment of peer relationships in children with asthma. j pediatr psychol 1995; 20:205–16. doi: 10.1093/ jpepsy/20.2.205. 6. link bg, phelan jc. conceptualizing stigma. annu rev sociol 2001; 27:363–85. doi: 10.1146/annurev.soc.27.1.363. 7. jorm af, wright a. influences on young people’s stigmatising attitudes towards peers with mental disorders: national survey of young australians and their parents. br j psychiatry 2008; 192:144–9. doi: 10.1192/bjp.bp.107.039404. 8. olsson ca, boyce mf, toumbourou jw, sawyer sm. the role of peer support in facilitating psychosocial adjustment to chronic illness in adolescence. clin child psychol psychiatry 2005; 10:78–87. doi: 10.1177/1359104505048793. 9. asano m, sugiura t, miura k, torii s, ishiguro a. reliability and validity of the self-report quality of life questionnaire for japanese school-aged children with asthma (jsca-qol v.3). allergol int 2006; 55:59–65. doi: 10.2332/allergolint.55.59. 10. guite jw, walker ls, smith ca, garber j. children’s perceptions of peers with somatic symptoms: the impact of gender, stress, and illness. j pediatr psychol 2000; 25:125–35. doi: 10.1093/jpepsy/25.3.125. 11. al-motlaq ma, sellick k. i don’t mind: children’s attitude towards their peers with asthma in primary schools. child aust 2014; 39:125–30. doi: 10.1017/cha.2014.10. 12. gibson pg, henry rl, vimpani gv, halliday j. asthma knowledge, attitudes, and quality of life in adolescents. arch dis child 1995; 73:321–6. doi: 10.1136/adc.73.4.321. 13. shaw sf, marshak hh, dyjack dt, neish cm. effects of a classroom-based asthma education curriculum on asthma knowledge, attitudes, self-efficacy, quality of life, and self-management behaviors among adolescents. am j health educ 2005; 36:140–7. doi: 10.1080/19325037.2005.10608175. 14. longoria l, marini i. perceptions of children’s attitudes towards peers with a severe physical disability. j rehab 2006; 72:19–25. 15. vignes c, godeau e, sentenac m, coley n, navarro f, grandjean h, et al. determinants of students’ attitudes towards peers with disabilities. dev med child neurol 2009; 51:473–9. doi: 10.1111/j.1469-8749.2009.03283.x. 16. brook u, kishon y. knowledge and attitude of healthy high school students toward bronchial asthma and asthmatic pupils. chest 1993; 103:455–7. doi: 10.1378/chest.103.2.455. https://doi.org/10.1136/adc.82.suppl_2.ii2 https://doi.org/10.1081/jas-120019030 https://doi.org/10.1177/002221949302600103 https://doi.org/10.1093/jpepsy/20.2.205 https://doi.org/10.1093/jpepsy/20.2.205 https://doi.org/10.1146/annurev.soc.27.1.363 https://doi.org/10.1192/bjp.bp.107.039404 https://doi.org/10.1177/1359104505048793 https://doi.org/10.2332/allergolint.55.59 https://doi.org/10.1093/jpepsy/25.3.125 https://doi.org/10.1017/cha.2014.10 https://doi.org/10.1136/adc.73.4.321 https://doi.org/10.1080/19325037.2005.10608175 https://doi.org/10.1111/j.1469-8749.2009.03283.x https://doi.org/10.1378/chest.103.2.455 attitudes of non-asthmatic children towards their asthmatic peers influence of interactions with asthmatic relatives and peers e166 | squ medical journal, may 2018, volume 18, issue 2 17. abu-ekteish f, otoom s, shehabi i. prevalence of asthma in jordan: comparison between bedouins and urban schoolchildren using the international study of asthma and allergies in childhood phase iii protocol. allergy asthma proc 2009; 30:181–5. doi: 10.2500/aap.2009.30.3208. 18. al-motlaq m. prevalence and factors affecting childhood asthma in the middle east: a literature review. middle east j nurs 2009; 3:11–16. 19. al-sheyab n, gallagher r, crisp j, shah s. peer-led education for adolescents with asthma in jordan: a cluster-randomized controlled trial. pediatrics 2012; 129:e106–12. doi: 10.1542/peds. 2011-0346. 20. al-motlaq m, sellick k. development and validation of an asthma knowledge test for children 8–10 years of age. child care health dev 2011; 37:123–8. doi: 10.1111/j.13652214.2010.01133.x. 21. hayes se, huang ky, evans d, bruzzese jm. minors’ attitudes towards peers with asthma: a developmental study. j asthma 2013; 50:90–6. doi: 10.3109/02770903.2012.743153. 22. roberts ca, geryk ll, sage aj, sleath bl, tate df, carpenter dm. adolescent, caregiver, and friend preferences for integrating social support and communication features into an asthma self-management app. j asthma 2016; 53:948–54. doi: 10.3109/ 02770903.2016.1171339. 23. haver hl, stieb e. abstract a14/238: improving children’s knowledge of asthma triggers. paediatr respir rev 2006; 7:s279. doi: 10.1016/j.prrv.2006.04.040. 24. cohen r, franco k, motlow f, reznik m, ozuah po. perceptions and attitudes of adolescents with asthma. j asthma 2003; 40:207–11. doi: 10.1081/jas-120017992. 25. bruzzese jm, fisher ph, lemp n, warner cm. asthma and social anxiety in adolescents. j pediatr 2009; 155:398–403. doi: 10.1016/j.jpeds.2009.04.004. https://doi.org/10.2500/aap.2009.30.3208 https://doi.org/10.1542/peds.2011-0346 https://doi.org/10.1542/peds.2011-0346 https://doi.org/10.1111/j.1365-2214.2010.01133.x https://doi.org/10.1111/j.1365-2214.2010.01133.x https://doi.org/10.3109/02770903.2012.743153 https://doi.org/10.3109/02770903.2016.1171339 https://doi.org/10.3109/02770903.2016.1171339 https://doi.org/10.1016/j.prrv.2006.04.040 https://doi.org/10.1081/jas-120017992 https://doi.org/10.1016/j.jpeds.2009.04.004 clinical & basic research squ med j, november 2011, vol. 11, iss. 4, pp. 485-491, epub. 25th oct 11 submitted 10th may 11 revision req. 19th jul 11, revision recd. 25th jul 11 accepted 9th sep 11 1department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 2al khoud health center, ministry of health, oman. *corresponding author email: rkindi@squ.edu.om and alrahma23@gmail.com معدل انتشار وتأثري عسر الطمث لدى الطالبات الُعمانيات يف املدارس الثانوية رحمة الكندية وعنربين البلو�ضية امللخ�ص: الهدف: حتديد معدل انت�ضار ع�رس الطمث و تاأثريه و العلج امل�ضتخدم لدى الطالبات الُعمانيات يف املدار�س الثانوية. الطريقة: اأجريت هذه الدرا�ضة املقطعية يف �ضهر مايو 2010 على 404 طالبة من مدر�ضتني من املدار�س الثانوية العامة يف منطقة م�ضقط، ومت جمع البيانات من خلل ا�ضتبيان ذاتي ي�ضمل معلومات عن اخل�ضائ�س الدميوغرافية، ومعدل انت�ضار ع�رس الطمث، و�ضدته، واأثره، والعلج امل�ضتخدم. النتائج: دلت النتائج على معاناة 94% ) 380 طالبة( من امل�ضاركات من ع�رس الطمث. كان ع�رس الطمث خفيفا لدى %27 )104 طالبة( ، بينما كان متو�ضط ال�ضدة لدى 41% )155 طالبة(، و�ضديدا لدى 32% )121 طالبة(. وكان ع�رس الطمث �ضببا يف ق�ضور يف الأن�ضطة الريا�ضية )81%(، وقلة الرتكيز يف ال�ضف )75%(، وتقييد يف اأداء الواجبات املنزلية )59%(، والتغيب عن املدر�ضة )%45(، وق�ضور يف الأن�ضطة الجتماعية )25%(، وانخفا�س الأداء الأكادميي )8%( لدى الطالبات امل�ضابات. التم�س 3% فقط )10 طالبات( طلب امل�ضورة الطبية، بينما كان العلج ذاتيا يف 21% )80 طالبة(، والأكرثية منهن مل يحركن �ضاكنا 55% )210 طالبة(. كانت مل .)%3 )12 طالبة، امليفيناميك وحم�س )%8 )29 طالبة، ايبوبروفني ،)%16 )60 طالبة، البارا�ضيتامول هي امل�ضتخدمة الأدوية يكن هناك اأي ارتباط معتد بني ع�رس الطمث و اخل�ضائ�س الدميوغرافية وخ�ضائ�س الدورة ال�ضهرية. اخلال�صة: رغم انت�ضار ع�رس الطمث بني الطالبات العمانيات يف املدار�س الثانوية اإل اأنه مل يلق العلج اللزم. الآلم امل�ضاحبة لع�رس الطمث ميكن اأن تكون �ضديدة ومعيقة ولذلك ينبغي على الأطباء اأن يكونوا على ا�ضتعداد ملناق�ضة هذا بحرية اأكرب مع طالبات املدار�س. بالإ�ضافة اإىل ذلك هناك حاجة للتثقيف بخ�ضو�س ع�رس الطمث وخيارات العلج للتقليل من اأثره على الأن�ضطة املدر�ضية والريا�ضية والجتماعية واليومية. مفتاح الكلمات: ع�رس الطمث، اآلم احلي�س، معدل انت�ضار، تاأثري، الفتيات املراهقات، املدر�ضة الثانوية، الطلب، ُعمان. abstract: objectives: the objectives of this study were to determine the prevalence of dysmenorrhoea in omani high schoolgirls, its impact and the treatment used. methods: a cross-sectional survey was carried out in may 2010 on 404 girls from two public high schools in the muscat region. data were collected by self-administered questionnaire including information on demographics, prevalence of dysmenorrhoea, severity, its impact, and the treatment used. results: overall, 94% (n = 380) of the participants had dysmenorrhoea. it was mild in 27% (n = 104), moderate in 41% (n = 155), and severe in 32% (n = 121). dysmenorrhoea was the cause of limited sports activities in 81%, decreased class concentration in 75%, restricted homework in 59%, school absenteeism in 45%, limited social activities in 25%, and decreased academic performance in 8% of the affected students. only 3% (n = 10) had consulted a physician; 21% (n = 80) self-medicated, and 55% (n = 210) took no action. the commonest drugs used were paracetamol (n = 60, 16%), ibuprofen (n = 29, 8%) and mefenemic acid (n = 12, 3%). there was no statistically significant correlation between dysmenorrhoea, demographics and menstrual characteristics. conclusion: dysmenorrhoea is a prevalent and yet undertreated menstrual disorder among omani adolescent schoolgirls. the pain suffered can be severe and disabling. doctors should therefore be prepared to discuss this more freely with schoolgirls. in addition, there is a need for education regarding dysmenorrhoea and treatment options to minimise the impact on school, sports, social and daily activities. keywords: dysmenorrhoea; painful menstruation; prevalence; impact; adolescent girls; high school; students; oman. prevalence and impact of dysmenorrhoea among omani high school students *rahma al-kindi1 and anbarin al-bulushi2 advances in knowledge 1. this study is the first in arabian gulf countries to explore the prevalence of dysmenorrhoea in adolescent girls in high school. 2. this study has shown both a high prevalence of dysmenorrhoea and its huge impact on schoolgirls both academically and socially. however, adolescent schoolgirls seem reluctant to seek medical help for this problem. 3. this study will improve awareness among health care providers and allow them to be more sensitive to issues related to the management prevalence and impact of dysmenorrhoea among omani high school students 486 | squ medical journal, november 2011, volume 11, issue 4 dysmenorrhoea, or painful menstruation, is defined as painful cramps that begin a few hours before the onset of bleeding and may persist for hours or days. dysmenorrhoea may be either primary, when there is no identifiable cause, or secondary to organic pelvic diseases. primary dysmenorrhoea occurs typically between 17 and 22 years of age while secondary dysmenorrhoea is more common in older women. dysmenorrhoea is commonly associated with systemic symptoms like lower back pain, nausea, vomiting, diarrhoea, fatigue and headache. the cause of primary dysmenorrhoea has yet to be established. it has been attributed to uterine contractions with ischaemia and production of prostaglandin. based on the patient’s history, it is important to differentiate between dysmenorrhoea and premenstrual syndrome (pms). pms starts before the menstrual cycle and stops shortly after menstrual flow begins. the symptoms associated with pms are more likely to be abdominal bloating and breast heaviness rather than lower abdominal cramps.1 dysmenorrhoea is a common gynaecological complaint among adolescents and young adults. the prevalence rates reported for dysmenorrhoea vary widely across studies due to the differences in measurement methods. prevalence rates have been reported to be as high as 93%2 and as low as 16%.3 in the middle east, the prevalence of dysmenorrhoea in egypt has been estimated to be 75%.4 many adolescents consider dysmenorrhoea to be a normal part of the menstrual cycle and thus fail to report their pain to their physicians. the consequences of untreated primary dysmenorrhoea range from school absenteeism5-8 to disruption of relationships with family and friends.8,9 the risk factors reported in the literature for dysmenorrhoea are: age <20, nulliparity, higher/ upper socioeconomic status, heavy menses, attempts to lose weight, physical activity, smoking, disruption of social networks, depression and anxiety;10 however, studies have been quite heterogeneous in terms of association. although dysmenorrhoea is an important public health problem, there has, to our knowledge, not been any data published from oman. in order to lay the groundwork for such an undertaking, studies are needed to establish the prevalence of dysmenorrhoea in adolescent omani girls. the bulk of the population in oman is in the adolescent age group.11 therefore, this study aims to quantify the prevalence of dysmenorrhoea in adolescent schoolgirls and its impact on school performance as well as the treatments used. an integral part of the present study is to ascertain the associated risk factors among adolescent schoolgirls with dysmenorrhoea. methods a cross-sectional survey was carried out in two female public high schools, namely al hail alawamir and omama bint alaas, in may 2010. the two schools were randomly selected out of four high schools in the al seeb area of the muscat region. like most of the high schools in the muscat region, each school has around 1,500 students in 50 classes of grades 11 and 12, the students’ ages ranging from 15 to 23. in each school, 4 classes from each grade were randomly selected. a total of 16 classes were studied. the survey was conducted during school hours and included a total of 404 students. a pre-tested and structured questionnaire was developed by the authors based on a pilot study and thorough review of relevant literature addressing of dysmenorrhoea. 4. this study can encourage further research to identify and determine the associated risk factors of dysmenorrhoea. 5. the results of this study could be used for better understanding of the epidemiology of dysmenorrhoea and its effect on public health. application to patient care 1. the information that dysmenorrhoea is a common menstrual disorder among adolescent schoolgirls needs to be disseminated to the public and health professionals by: a) educating health professionals about dysmenorrhoea, its severity and impact on adolescent schoolgirls; b) encouraging doctors to screen routinely for dysmenorrhoea among adolescent schoolgirls and offer treatment if necessary, and c) encouraging adolescent schoolgirls to consult their physicians for dysmenorrhoea. 2. there is a need for health education measures in this area to prevent unnecessary suffering and interruption in the adolescent's education. the introduction in the school curriculum of culture-specific education regarding menstrual disorders and the use of appropriate medication is recommended for effective relief of dysmenorrhoea. rahma al-kindi and anbarin al-bulushi clinical and basic research | 487 the prevalence and severity of dysmenorrhoea, the impact of dysmenorrhoea on daily activities and the prevailing management strategies.2-10 the participants were briefed on the objectives of the study and the definition of dysmenorrhoea was explained as any lower abdominal pain or discomfort associated with the menstrual period. the degree of pain was categorised by a multidimensional scoring system as mild, moderate and severe based on pain, limitation of activities and medications taken.12 mild pain was defined as “painful menstruation that seldom inhibits normal activity and analgesics are seldom required”; moderate pain as “painful menstruation that affects daily activities and analgesics are required and give relief ”; severe pain as “painful menstruation that clearly inhibits daily activities and the pain is not totally relieved by analgesics”.12 the amount of bleeding was defined depending on the number of pads used per day as little (<4 pads per day), moderate (5–10 pads per day) and heavy (2 pads at a time).13 information was gathered on the students' age, grade, residency, and family history of dysmenorrhoea. questions related to menstruation elucidated their age at menarche, regularity of the cycle, length and duration of the cycle, amount of bleeding (little, moderate or heavy), pain during menstruation, severity of the pain (mild, moderate or severe), associated symptoms, premenstrual symptoms, their impact on daily activities and absenteeism from school, and treatment taken, if any. the weight and height of the participants was measured by the researchers and/or trained research assistants. the cut-off points for body mass index (bmi) were based on recommendations by the world health organization’s (who) expert committee on physical status.14 data was collected using a self-administered questionnaire. the researchers and/or research assistants were available on site to assist the students in completing the questionnaire which took 20 to 30 minutes. students who had not yet experienced the menarche, or had gynaecological diseases, had had abdominal or pelvic surgery, or refused to give consent, were excluded from the analysis. the participation was therefore on a voluntarily basis with written consent being taken before initiating the data collection. anonymity and confidentiality was assured and emphasised. ethical approval for the study was granted by the medical research and ethics committee of sultan qaboos university, college of medicine and health sciences in 2010. permission to distribute the questionnaires in schools was obtained from the directorate general of muscat region, ministry of education. stata software (statacorp lp, texas, usa, version 10) was used for data entry and analysis. frequencies and percentages were computed for discrete variables and the mean and standard deviation were computed for continuous variables. the pearson’s χ2 tests (or fisher’s exact tests for cells less than 5) were used as appropriate to test the association between dysmenorrhoea and the studied variables. the 5% level of significance was taken to test the significance of the obtained results. results this study included a total of 404 omani students; 200 (49.5%) were from al hail al awamir school and 204 (50.5%) were from omama bint alaas school. nearly two thirds of participants (n = 259, 64%) were in grade 12 and one third (n = 145, 36%) were in grade 11. their ages ranged from 15 to 23 years, with a mean of 17.50 (±0.98) years. the vast majority of students were originally from the muscat region (n = 344, 85%). nearly half of the participants (n = 212, 52%) were of normal weight; 90 (22%) were underweight and 102 (25%) were overweight and/or obese. the age at menarche ranged from 9 to 17 years. the mean age at menarche was 13.00 (±1.31) years. the sociodemographic data and characteristics of the menstrual cycle are given in table 1. regular cycles were reported by 59% (n = 237) of the students; a cycle duration of 21 to 35 days was reported by 89% (n = 359); menstrual duration of 2 to 7 days was reported by 88% (n = 354), and little to moderate flow was reported by 95% (n = 382). the overall prevalence of dysmenorrhoea was 94% (n = 380). of the participants with dysmenorrhoea, the pain experienced was reported as mild by 27% (n = 104); moderate by 41% (n = 155), and severe by 32% (n = 121). there was no statistically significant correlation between dysmenorrhoea and the following: age at menarche, regularity of the cycle, length and duration of the cycle, reported amount of flow, bmi, and family history of dysmenorrhoea at (p = >0.05) [table 1]. all the participants with dysmenorrhoea prevalence and impact of dysmenorrhoea among omani high school students 488 | squ medical journal, november 2011, volume 11, issue 4 reported some associated symptoms. the most frequently reported symptoms were backache (n = 302, 79%), stomach cramps (n = 266, 70%) and mood changes (n = 260, 68%). table 2 shows the most commonly reported symptoms associated with dysmenorrhoea. a total of 39% percent of the table 1: factors associated with dysmenorrhoea characteristics total frequency (n = 404) presence of dysmenorrhoea p value yes n = 380 (94.06%) no n = 24 (5.94%) age, n (%) 15–17 203 (50) 192 (51) 11 (46) 0.656 18–23 201 (50) 188 (49) 13 (54) school, n (%) 1 200 (50) 190 (50) 10 (42) 0.428 2 204 (50) 190 (50) 14 (58) grade, n (%) 11 145 (36) 139 (37) 6 (25) 0.251 12 259 (64) 241 (63) 18 (75) body mass index (bmi), n (%) underweight <18.50 90 (22) 83 (22) 7 (29) 0.684average weight 18.50– 24.99 212 (52) 201 (53) 11 (46) overweight/obesity ≥25.00 102 (25) 96 (25) 6 (25) menarche, n (%) <13 132 (33) 124 (33) 8 (33) 1.00013–14 231 (57) 217 (57) 14 (58) >14 41 (10) 39 (10) 2 (8) regularity, n (%) yes 237 (59) 226 (59) 11 (46) 0.188 duration of bleeding (days), n (%) 2–7 days 354 (88) 334 (88) 20 (83) 0.510 8–14 days 50 (12) 46 (12) 4 (17) length of cycle (days), n (%) <21 days 21 (5) 21 (6) 0 (0) 0.721–35 days 359 (89) 336 (88) 23 (96) >35 days 24 (6) 23 (6) 1 (4) amount of blood flow/cycle, n (%) little (1–4 pads/day) 253 (63) 234 (62) 19 (79) 0.077 moderate (5–10 pads/ day) 129 (32) 126 (33) 3 (13) heavy (2 pads at a time) 22 (5) 20 (5) 2 (8) family history of dysmenorrhoea, n (%) yes 338 (84) 317 (83) 21 (88) 0.428 rahma al-kindi and anbarin al-bulushi clinical and basic research | 489 participants (n = 147) suffered from some form of pms, of which the majority reported backache (n = 103, 27%) and/or irritability (n = 90, 24%). the other symptoms reported were loss of appetite (n = 74, 19%), gastrointestinal symptoms (n = 68, 18%), abdominal bloating (n = 63, 17%), headache (n = 56, 15%), breast heaviness (n = 50, 13%) and skin changes (n = 19, 5%). over two thirds of the participants (n = 276, 73%) had not sought treatment for their pain, with only 3% (n = 10) having consulted a physician. the majority of participants with dysmenorrhoea (n = 300, 79%) did not take any medications. paracetamol (n = 60, 16%), ibuprofen (n = 29, 8%) and mefenamic acid (n = 12, 3%) were the most commonly used analgesics. others reported using complementary and alternative medicine in the form of herbs (n = 47, 12%) and a heating pad (n = 45, 12%). almost all the participants with dysmenorrhoea (n = 377, 99%) reported that the pain adversely affected their daily activities. among the participants, 308 (81%) limited their sports activities, 285 (75%) reported decreased concentration in the classroom, and 226 (59%) complained of a diminished ability to do homework. there were 170 (45%) students who endorsed the idea that dysmenorrhoea made them miss classes, 94 (25%) reported a limitation of social activities and 32 (8%) had experienced decreased academic performance. discussion this study provides new information not previously available from oman, or even from the neighbouring arab/islamic countries of the gulf, on the prevalence, impact and treatment of dysmenorrhoea in adolescent high schoolgirls. this study found the prevalence of dysmenorrhoea in girls in high school to be 94% of the cohort surveyed. estimates of the prevalence of dysmenorrhoea range between 16%3 and 93%.2 the rate of dysmenorrhoea revealed by the present study is comparable to the 90–93% reported from usa,15 iran,16 and canada,2 but it is higher than the rates reported from egypt,4 nigeria,6 turkey8 and india17 that ranged between 25–80%. the wide variation in these estimates may be attributed to the use of differently selected groups of subjects12,18 and the absence of a universally accepted definition of dysmenorrhoea and system for grading its severity.15,19another reason for the variation could be due to ethnic and sociocultural factors. differences among ethnic groups have been reported in western20 as well as asian communities;5 however, it remained unclear whether the variation was related to biological or cultural factors.5 of this study population, 32% reported having severe dysmenorrhoea which is twice the prevalence reported in a similar study in egypt.4 more than two third of the participants (73%) described their pain as moderate to severe. this indicates that although dysmenorrhoea may be a furtive illness, its prevalence is high and therefore has an implication on the quality of life and public health. some studies have shown a link between dysmenorrhoea and several risk factors including early menarche, irregular or long cycles and heavy menses.12,18 however, this study did not find any significant association between dysmenorrhoea and age at menarche, regularity of the cycle, length and duration of the cycle, amount of flow, bmi, or family history of dysmenorrhoea. this could be due to the small sample size, a very homogenous group and the fact that pain is experienced subjectively and therefore difficult to measure. it remained unclear if the high prevalence of dysmenorrhoea among omani high schoolgirls in our study is related to biological or cultural factors, and further studies are needed to explore these issues. dysmenorrhoea is known to be associated with table 2: percentage of participants with dysmenorrhoea who suffer from associated symptoms (more than one symptom per person) symptoms participants with associated symptoms (n = 380) n % backache 302 79.5 stomach cramps 266 70.0 mood change 260 68.4 myalgia 227 59.7 fatigue 194 51.1 nausea 157 41.3 headache 139 36.6 dizziness 100 26.3 diarrhea 92 24.2 vomiting 61 16.1 edema 19 5.0 prevalence and impact of dysmenorrhoea among omani high school students 490 | squ medical journal, november 2011, volume 11, issue 4 a wide variety of physical symptoms. backache and stomach cramps were the two most common reported symptoms in our study, and similar to findings elsewhere in the literature.3,4,21 on the other hand, pms is also known to be associated with a wide variety of symptoms like abdominal bloating and breast heaviness. the distinction between the two may not have been clear to the participants thus leading to over-reporting of dysmenorrhoea. the results clearly showed that dysmenorrhoea adversely affected the students’ daily activities. dysmenorrhoea had an adverse effect on school performance reflected in low concentration during classes, difficulties in accomplishing homework and school absenteeism. it also limited participation in sports and social activities. this is consistent across different cultures, supporting an underlying biological origin of dysmenorrhoea. despite the considerable impact of dysmenorrhoea, both academically and socially, only 3% of the participants with dysmenorrhoea had consulted a doctor about it. this is consistent with other findings that most adolescents with dysmenorrhoea do not consult a health care provider.4,22-24 we found that 21% (n = 80) of the participants self-medicated by drugs like paracetamol, ibuprofen and mefenemic acid. the low rates of self-treatment and physician consultation rates may be due to the sensitive nature of dysmenorrhoea among adolescent girls, conservative social values and cultural beliefs, and the reluctance of young unmarried girls to consult a physician, particularly a male physician. we also found that more than half of the participants did nothing to alleviate their pain. likewise, studies in egypt,4 nigeria,6 turkey8 and india17 reported that more than half of the adolescents studied did not seek treatment for dysmenorrhoea. this may suggest that there is a significant lack of awareness and knowledge among adolescent girls regarding treatment for dysmenorrhoea.25 our study did not investigate barriers to seeking medical attention for dysmenorrhoea; nevertheless, the participants’ responses indicated that many girls accept dysmenorrhoea as a normal aspect of the menstrual cycle and believe that it cannot be treated. these ideas likely provided the rationale for not seeking medical treatment. improving the girls’ knowledge about dysmenorrhoea could therefore positively influence their healthcare-seeking behaviour. health promotion in the primary health care setting or at school may be an efficient way of achieving this. there are several limitations to the current study. although girls with potential causes of secondary dysmenorrhoea were excluded from the study sample, it was not possible to discriminate between primary and secondary dysmenorrhoea in this study population. in addition, despite the fact that the definition of dysmenorrhoea was explained before the questionnaires were completed, some of the responses may reflect general experience rather than specific menstrual discomfort. the selfreporting nature of this study may have resulted in recall bias and over-reporting of the condition. besides, it is possible that some of the participants completed their questionnaires with peers, which may have biased their responses. finally, this study was conducted in only two schools of muscat region; the results may therefore not be generalisable to other regions or to the entire country. conclusion this study unequivocally suggests a high prevalence of dysmenorrhoea among omani girls in high school indicating that it is a significant health problem needing attention. young girls are unlikely to discuss dysmenorrhoea with their family physician, or seek painkillers available over the counter. they seem to accept dysmenorrhoea and its consequences as part of the physiological process of the transition between adolescence and adulthood. this reflects a shortage of information about primary dysmenorrhoea targeted at female adolescents. health education on issues related to reproductive health should be incorporated early enough in the school curriculum to prepare girls for menstruation and inform them about available treatment options in case they experience dysmenorrhoea. a number of professionals can play a crucial role in educating young people especially family physicians and school personnel. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g m e n t s the authors acknowledge with thanks the participation of the omani ministry of education, rahma al-kindi and anbarin al-bulushi clinical and basic research | 491 the school teaching staff and the students who facilitated the implementation of this study. grateful thanks are also extended to the medical students who assisted in data collection: ms aisha al-huraizi, ms hagar al-mazroui, ms huda razvi, and ms iman al-rashdi. references 1. hacker nf, gambone jc, hobel cj. hacker and moore's essentials of obstetrics and gynecology. 5th ed. philadelphia, pa: saunders/elsevier, 2010. pp. 256–7. 2. campbell ma, mcgrath pj. non-pharmacologic strategies used by adolescents for the management of menstrual discomfort. clin j pain 1999; 15:313–20. 3. ohde s, tokuda y, takahashi o, yanai h, hinohara s, fukui t. dysmenorrhea among japanese women. int j gynaecol obstet 2008; 100:13–17. 4. el-gilany ah, badawi k, el-fedawy s. epidemiology of dysmenorrhoea among adolescent students in mansoura, egypt. east mediterr health j 2005; 11:155–63. 5. wong lp, khoo em. dysmenorrhea in a multiethnic population of adolescent asian girls. int j gynaecol obstet 2010; 108:139–42. 6. nwankwo to, aniebue uu, aniebue pn. menstrual disorders in adolescent school girls in enugu, nigeria. j pediatr adolesc gynecol 2010; 23:358–63. 7. ortiz mi, rangel-flores e, carrillo-alarcón lc, veras-godoy ha. prevalence and impact of primary dysmenorrhea among mexican high school students. int j gynaecol obstet 2009; 107:240–3. 8. eryilmaz g, ozdemir f, pasinlioglu t. dysmenorrhea prevalence among adolescents in eastern turkey: its effect on school performance and relationships with family and friends. j pediatr adolesc gynecol 2010; 23:267–72. 9. titilayo a, agunbiade om, banjo o, lawani a. menstrual discomfort and its influence on daily academic activities and psychosocial relationship among undergraduate female students in nigeria. tanzan j health res 2009; 11:181–8. 10. harlow sd, park m. a longitudinal study of risk factors for the occurrence, duration and severity of menstrual cramps in a cohort of college women. br j obstet gynaecol 1996; 103:1134–42. 11. oman census 2010. ministry of national economy – sultanate of oman. from: www.omancensus. net/new/images/stories/docs/2010_preliminary_ results.pdf accessed: may 2011. 12. andersch b, milsom i. an epidemiologic study of young women with dysmenorrhoea. am j obstet gynecol 1982; 144:655–60. 13. higham jm, o'brien pm, shaw rw. assessment of menstrual blood loss using a pictorial chart. br j obstet gynaecol 1990; 97:734–9. 14. world health organization. global database on body mass index. from: www.apps.who.int/bmi/ index.jsp?intropage=intro_3.html accessed: may 2011. 15. jamieson dj, steege jf. the prevalence of dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome in primary care practices. obstet gynecol 1996; 87:55–8. 16. tavallaee m, joffres mr, corber sj, bayanzadeh m, rad mm. the prevalence of menstrual pain and associated risk factors among iranian women. j obstet gynaecol res 2011; 37:442–51. 17. agrawal ak, agrawal a. a study of dysmenorrhea during menstruation in adolescent girls. indian j community med 2010; 35:59–164. 18. sundell g, milsom i, andersch b. factors influencing the prevalence and severity of dysmenorrhoea in young women. br j obstet gynaecol 1990; 97:588– 94. 19. shapiro ss. treatment of dysmenorrhoea and premenstrual syndrome with nonsteroidal antiinflammatory drugs. drugs 1988; 36:475–90. 20. harlow sd, campbell b. ethnic differences in the duration and amount of menstrual bleeding duration during the postmenarcheal period. am j epidemiol 1996; 144:980–8. 21. tangchai k, titapant v, boriboonhirunsarn d. dysmenorrhea in thai adolescents: prevalence, impact and knowledge of treatment. j med assoc thai 2004; 87:69–73. 22. davis ar, westhoff cl. primary dysmenorrhea in adolescent girls and treatment with oral contraceptives. j pediatr adolesc gynecol 2001; 14:3–8. 23. banikarim c, chacko mr, kelder sh. prevalence and impact of dysmenorrhea on hispanic female adolescents. arch pediatr adolesc med 2000; 154:1226–9. 24. agrawal a, venkat a. questionnaire study on menstrual disorders in adolescent girls in singapore. j pediatr adolesc gynecol 2009; 22:365–71. 25. johnson j. level of knowledge among adolescent girls regarding effective treatment for dysmenorrhea. j adolesc health care 1988; 9:398–402. to the editor i read the article detailing the tragic death of flying officer v with interest.1 the cause of death was given as the result of his head striking parts of the aircraft upon ejection, and the author is to be commended for such a detailed analysis. troubling, however, is the conclusion in the article: “nevertheless, such an event was inevitable when the pilot chose to fly in a position which would compromise his flight safety. if he had chosen the prescribed seat position, he would probably have made an uneventful escape from his aircraft. it was thus the attitudinal error…of the pilot which led to this uncalled for incident.” the question is: why did the pilot elect to sit in a position that he knew “would compromise his flight safety”? the answer is given a few paragraphs earlier: “he had chosen to use the high seat position because he found the bomb sight and the front gun sight easier to operate in the high position.” this is key. using the bomb site and the front gun site properly and easily are essential requirements and duties of a fighter-bomber pilot. in other words, the pilot had a choice: he could either fly in a position that was safer for him, but then he would not be able to perform his duty properly, or he could fly in a dangerous position, but do his duty. he chose the latter. as if his work were not dangerous enough, he knowingly increased the risk to his own life so that he could perform the duty that was expected of him. while the conclusion to the article is not inaccurate, i feel that it does not go far enough. it should also state that the pilot had been put into the unenviable position of having to increase the risk to his own life in order to perform his work, and he chose to sacrifice his life. he compensated for an aircraft design flaw with courage beyond the call of duty. it also leaves one wondering whether or not changes to the design of the aircraft were made after his death, and how many other fighter-bomber pilots are currently making the same unenviable choice. ken masters medical education unit, college of medicine & health sciences, sultan qaboos university, muscat, oman email: kmasters@ithealthed.com squ med j, august 2010, vol. 10, iss. 2, pp. 278-279, epub. 19th jun 10 submitted: 26th apr 10 ان ختطيء -من طبيعة البشر تقرير حالتني من حوادث الطريان احلربي إحتمال آليات فشل اإلنسان كني ما�شرت�س re: to err is human: case report of two military aircraft accidents possible mechanisms of human failure ken masters letter to editor ken masters letter to editor | 279 reference 1. dikshit, b. to err is human case reports of two military aircraft accidents: possible mechanisms of human failure. squ med j 2010; 10:120–5. author’s response i read with great interest the very erudite comments offered by dr ken masters on my article to err is human: case report of two military aircraft accidents and thank him for the same.1 i do wish however to clarify a slight misconception he seems to have developed. the unfortunate pilot was aware of the risk he ran by using a seat position in which he perceived he could operate the gun and bomb sight more efficiently while doing ground attack using front guns and dive bombing. there was no problem of seat height in air to air gunnery. in all probability, he resorted to the use of a mental mechanism of denial where in he convinced himself that he would not be injured during ejection, if it so happened, while using the higher seat position. alternatively, he could have jettisoned the canopy first, and then ejected. many other pilots also felt that they could not operate the front gun and bomb sights efficiently during ground attack in their prescribed seat positions, but accepted the operational limitation. anecdotally, there were no reports to suggest that the front gun strafing and dive bombing scores on the firing range of pilots who stuck to their prescribed seat positions were any worse than the occasional pilot who selected his own position in order to overcome this perceived deficiency. it was thus a perception which the ill fated pilot had developed that made him use the wrong seat position. to take the explanation further: according to the aircraft manufacturer’s specifications, the seat positions in sukhoi 7 b (also known as the s 22) were allotted as per the sitting height of the pilot. in the correct position, the pilots “eye datum line” was expected to coincide with a similar line marked on the ejection seat bulk head. once this happened, the front gun and bomb sights could be operated suitably. pilots were therefore carefully allotted their given seat positions. the aircraft cockpit and ejection seat design was tailored to suit the anthropometric data of russian pilots. it was accepted therefore that some indian air force pilots would not fit in to the requisite scheme of things. minor readjustments had to be made by the use of specially designed seat cushions in order to ensure that the eye datum lines were correctly aligned. it is to be appreciated that aircraft designs can not be changed once the aircraft is put into operational service. it is also reiterated that this accident was the only one of its kind in the indian airforce (iaf) where the fatal injuries suffered were attributed to flying in a faulty seat position. perhaps it would not have occurred if human frailty had not won the day. the findings of this accident were publicised amongst pilots of the sukhoi so as to caution them against flying in a wrong seat position. suffice to say that such an accident was not reported again. this class of aircraft was later withdrawn after rendering many years of yeoman service to the iaf. mohan b dikshit dept of physiology college of medicine & health sultan qaboos university muscat, sultanate of oman email: mohand@squ.edu.om reference 1. dikshit, b. to err is human case reports of two military aircraft accidents: possible mechanisms of human failure. squ med j 2010; 10:120–5. to the editor, i read your editorial on “evaluation tools in postgraduate medical education do we need “made in oman” tools?”1 with interest and felt that the issue of formative versus summative assessment needed to be clarified before conclusions could be made about which and how assessment tools should be used. the terms “formative” and “summative” define the purpose of assessment and not the tools of that assessment. formative assessment is used for diagnosis and remediation, while summative assessment is used for promotion and certification. the tools being used can be the same for both assessments; there are no tools that are specific for formative while others are for summative assessment. for example, an multiple choice question based test can be used in either a formative or a summative fashion. ideally, all assessments should have a formative component even if used in a summative manner. the purpose of the formative component is to provide feedback to students on their strengths and weaknesses. the practice of using certain assessment methods for summative purposes stems from the reliability of the scores obtained from these methods; hence, their use in making important decisions about student progression as they alone can reliably ensure the fulfillment of the teaching mission of the medical school. several very appealing assessment methods, especially in postgraduate medical education, are now emerging, but, despite their high face value, their cost effectiveness, educational impact, and use in undergraduate medical education needs to be carefully assessed before their use can be advocated. the resource intensity of these methods might very well be the factor that limits their use to very few medical schools as mentioned in your editorial. what one can advocate, however, is research into the evaluation of these assessment methods which is exactly what the document of “assessment policy, regulations, & guidelines” of the college of medicine & health sciences at sultan qaboos university does.2 the policy not only affirms that assessment should be used in both formative and summative manner, but also goes further to recommend that assessment methods used should be evidence-based and, where evidence is lacking, best-practiced methods should be used and evaluated. feedback, a major component of formative assessment, is also highlighted very well in this policy document which emphasizes that it should be given to students in a timely manner. the assessment tools listed in the policy document have, when used correctly, demonstrated validity and reliability. tools such as checklists and rating scales are the basis of most workplace-based assessments such as the mini-clinical evaluation exercises, 360° assessment, direct observation of procedural skills, etc. can be used in any manner desired, formative or summative. nadia al wardy head, medical education unit college of medicine & health sciences sultan qaboos university email: naiwardi@squ.edu.om squ med j, august 2010, vol. 10, iss. 2, pp. 280-281, epub. 19th jun 10 submitted: 18th apr 10 أدوات التقييم للدراسة الطبية التخصصية هل حنتاج إىل أدوات “صنع يف ُعمان”؟ نادية الوردي re: evaluation tools in postgraduate medical education–do we need “made in oman” tools? nadia al wardy letter to editor nadia al wardy letter to editor | 281 references 1. lamki l, lamki n. evaluation tools in postgraduate medical education-do we need “made in oman” tools? squ med j 2009; 9:219-23. 2. college of medicine & health sciences, squ assessment policy, regulations, & guidelines. 1st ed. 2009. from http://www.squ.edu.om/medicine-health/tabid/1638/default.aspx accessed april 2010. authors’ response we thank dr. al wardy for her interest in our editorial. the purpose of the editorial was to stimulate discussion on the subject and we are glad it did, because this is a very important subject to all medical educationalists, undergraduate even more than postgraduate as pointed out by dr. al wardy. we agree with dr. al wardy that the terms summative and formative refer more to how the tool is used rather than the actual type of tool, but what we were pointing out in the editorial is that some tools are intrinsically more formative than others. indeed all tools can be used for both purposes. we also agree with dr. al wardy that the summative purpose of the assessment tools in the “assessment policy, regulations, & guidelines” of the college of medicine & health sciences at sultan qaboos university stems from the reliability of these tools in ensuring the fulfillment of the teaching mission of the medical school – and hence our comment in the editorial about those tools. we congratulate the college of medicine & health sciences at sultan qaboos university for the two major steps forward they have taken recently in producing the new avant-garde curriculum and impressive set of assessment tools in the new “assessment policy, regulations, & guidelines”. congratulations to you and the medical education unit, and keep up the great work. lamk al-lamki neela al-lamki editor-in-chief co-author squ medical journal oman medical specialty board email: mjournal @squ.edu.om email: n_lamki@yahoo.com this is an images of the hands of a 23 year-old omani girl who presented to the family medicine clinic of sultan qaboos university hospital, oman, with complaints of bilateral wrist pain for the previous four weeks [figure 1]. the pain was aggravated by activities especially those requiring weight lifting. the history revealed no other joint involvement, no previous trauma, fever, morning stiffness, or weight loss. on examination, she was of average height and weight. her wrist examination showed mild tenderness and swelling over the lateral aspect of her wrists proximal to the second metacarpal base, especially in her left wrist. in addition, her left fourth metacarpal was relatively shorter than rest of her metacarpals. however, the range of movements at the wrist and the metacarpophalangeal joints were full, but were associated with pain at the extremes of movement. the diagnosis after x-ray was congenital fusion of carpal bones. fusion or synostosis of various carpal bones is possible in different combinations. it can either be a part of a syndrome or can occur as an isolated anomaly.2 the term ‘fusion’ can be considered as a misnomer as it is not truly a fusion of carpal bones, rather it is an absence of joint cavitation, squ med j, december 2010, vol. 10, iss. 3, pp. 405-406, epub. 14th nov 10 submitted 27th march 10 revision req. 22nd june 10, revision recd. 23rd june 10 accepted 29th june 10 department of family medicine & public health, sultan qaboos university hospital, muscat, oman. *corresponding author email: nafisa77@squ.edu.om <ªüvflπ]<<‹ø√÷]ê<í√eüπ]<‹ø√÷]<∞e<íœ◊§̌]<t^⁄çfi˜]  congenital fusion of the trapezium and trapezoid *nafisa samir and abdulaziz al-mahrezi interesting medical image figure 1: x-ray of both hands, posterior-anterior view. the upper arrow shows the short left fourth metacarpal while the lower arrows show bilateral fusion of the trapezium and trapezoid. congenital fusion of the trapezium and trapezoid 406 | squ medical journal, december 2010, volume 10, issue 3 and chondrification of the joint interzone. this leads to the phenomenon of carpal synostosis which becomes apparent only after the bones ossify. carpal fusions occur as normal variations in about 0.1% of the population. lunate-triquetral fusion is the most common fusion anomaly of the carpus.2 this bone anomaly is mostly bilateral, but more common on the left side when unilaterally present.3 among the various population groups studied, the highest incidence is seen in people of african descent with a with a higher female to male ratio (2:1) and a strong familial tendency. carpal coalition is usually asymptomatic and often discovered incidentally. there have been reports of symptomatic pisohamate coalition, scapholunate triquetral coalition, and scaphoid trapezium synchondrosis.1,2,5 the loss of movement between the fused bones leads to a compensatory increase in motion at surrounding joints. this predisposes the person to recurrent sprains causing pain, especially under stressful conditions. occasionally, this may also result in an overgrowth of bone called carpal bossing.1,2 increased demand on the joint, especially in high activity level people like sportsmen, may lead to progressive stress loading and early degenerative arthritis or pseudoarthrosis. generally, isolated carpal fusions involve two bones of the same row, while the syndrome-associated fusions, such as ellis van creveld syndrome, osteochondritis dissecans, foetal alcohol syndrome, symphalangia, diastrophic dwarfism, gonadal dysgenesis, and poland syndrome, are quite often multiple.1,2 acquired fusion can occur secondary to arthritis, trauma or as a result of surgery for joint stabilisation.2 radiological findings may vary in appearance and fusion may present as partial or complete union of the carpal bone or there may be narrowing of the joint space without adjacent sclerosis or osteophytosis.2 for asymptomatic cases, treatment is rarely required. symptomatic treatment might be needed for the minority of patients who present with symptoms. references 1. terrence jjj. congenital fusion of the trapezium and trapezoid. rom j morphol embryol 2008; 49:417–9. 2. singh p, tuli a, choudhry r, mangal a. intercarpal fusion – a review. j anat soc india 2003; 52:183–8. 3. cockshott wp. carpal fusion. am j roentgenol radium ther nucl med 1963; 89:1260–71. 4. resnick d, niwayama g. diagnosis of bone and joint disorders, 2nd ed. philadelphia: wb saunders co., 1988. pp. 3560–1. 5. knezevich s, gottesman m. symptomatic scapholunatotriquetral carpal coalition with fusion of the capitatometacarpal joint: report of a case. clin orthop relat res 1990; 251:153–6. 6. simmons bp, mckenzie wd. symptomatic carpal coalition. j hand surg 1985; 10:190–3. 7. chouhdry r, tuli a, chimmalgi m, anand m. os capitate trapezoid: a case report. surg radiol anat 1998; 20:373–5. 8. friedman t, reed m, elliott am. the carpal fusion in poland syndrome. skeletal radiol 2009; 38:585–91. sir, the editorial article by lamk al-lamki “un millennium development goals and oman: kudos to oman on its 40th national day” published in the december 2010 issue of squmj1 depicts comprehensively how oman has fared in relation to the millennium development goals (mdg’s) benchmarks. indeed, allamki’s article has also provided a well articulated discussion of oman’s development and progress in the health field in the last 40 years that has exceeded all expectations. there is no doubt that oman has made impressive gains in achieving health-related targets and evidence for that was carefully provided in the article. in this regard, i would like to comment on three important points that were especially mentioned in that article. the first point is related to the problem of undernourished children in oman. as mentioned in allamki’s article, the first national survey that was carried out in oman to assess the rate of protein energy malnutrition (pem) was conducted in 1999, and it was found that 17.9% of children below five years of age were underweight.2 following that, another study on the risk factors associated with pem was conducted in three regions in oman in 2004. this study indicated that the most important risk factors of pem among young infants and children were related to feeding practices such as bottle feeding, improper hygiene and lack of nutrition awareness among mothers.3 as a result of these studies, a national programme for combating pem was implemented through primary health care institutions and community-based activities. a national pem reporting and monitoring system was also established and integrated into the ministry of health’s regular statistics. through this system, the pem incidence among children who attend the ministry of health facilities is reported on a monthly basis and feeding patterns of children are being accessed and reported. in 2008, the second national protein energy malnutrition survey was conducted to monitor the trend in pem, and assess whether it still persisted as a public health problem or not, in order to guide efforts to eliminate pem in future years. now comes the good news: the recently published survey results showed that 8.6% of children below five years of age were underweight.4 this figure is less than half of that reported in 1999 which means a great success has been achieved in the battle against pem in oman. my second point relates to the future health challenges in oman that were very well identified in the article. it is quite clear that, if health improvement is to have its full impact on reducing poverty as per mdg1, there is a need to address the growing burden of non-communicable diseases that are leading to a “double burden” of ill-health in oman. unfortunately, these diseases are not included among the millennium development goals, targets, or indicators; nonetheless, we should not forget them. also, we should not forget the “nutrition transition” change process whereby people in oman began to adopt the unhealthy eating habits common in richer countries and then suffer the ensuing health consequences. further, we should not forget the need for universal access to reproductive and sexual health services as well as the impact of globalisation on the worldwide spread of infectious diseases. moreover, as a means of improving the quality of life of the people, oman needs continuing investment in the fight against road squ med j, may 2011, vol. 11, iss. 2, pp. 288-289, epub. 15th may 11 submitted 27th feb 11 ïçvjπ]<‹⁄˙÷<ìèà÷˘]<ìè€flj÷]<õ]ç‚_<<<vó◊¬<åö ;õá÷]<çè√◊÷<∞√eö˘]<ôü“ñ÷]<ª<·�̂ €√÷<ç.] re: un millennium development goals and oman kudos to oman on its 40th national day letter to editor moeness m. alshishtawy letter to editor | 289 traffic accidents, tobacco and drug addiction. success in these battles depends on effective health awareness interventions throughout peoples’ lives. this can only be achieved by extensive cooperation with local civil society organisations, mainstream and traditional media, religious and traditional leaders, and the communities themselves. in other words, oman needs strategies that deliver interventions to hard-to-reach populations, strategies that build social and grassroots support, and strategies that enhance accountability. unless urgent investments are made in the omani health system, the current rates of progress towards the mdgs will not be sufficient to meet the currently prevalent health problems in oman. the third and last point is my support of prof. al-lamki in his emphasis on health advocacy to educate the people of oman about improving their health and that of their families. as prof. al-lamki stated in his article, all health professionals, and not just the ministry of health alone, have a major responsibility to act as advocates for public health at all levels. i suggest, besides the current efforts, that health advocacy should be carried out using mass and multi-media and community mobilisation. through such vehicles, health advocacy may be carried out within an institution or through public social societies, patients’ associations and even through the private sector. this is very important because advocacy is the only way to enable individuals to take more responsibility and control for the decisions that affect their health and to lessen their dependency on the public health system. moeness moustafa alshishtawy office of h.e. the undersecretary of planning ministry of health, muscat, oman email: drmoness@gmail.com references 1. al-lamki l. un millennium development goals and oman: kudos to oman on its 40th national day, squ med j 2010; 10:301–5. 2. alasfoor d, al sayed mk, al qasmi am, malankar p, sheth m, prakash n. protein energy malnutrition among pre-school children in oman: results of a national survey. east mediterr health j 2007; 13:146–54. 3. alasfoor d, traissac p, gartner a, delpeuch f. determinants of persistent underweight among 6-35 month old children after huge economic and health services improvements in oman; j health popul nutr 2007; 25:359–69. 4. department of nutrition, directorate general of health affairs, ministry of health. second national survey on protein energy malnutrition among infants and young children in oman 2008 – preliminary results. muscat: ministry of health, 2011. squ med j, august 2011, vol. 11, iss. 3, pp. 343-348, epub. 15th aug 11 submitted 14th feb 11 revision req. 16th may 11, revision recd. 29th may 11 accepted 8th jun 11 diabetes has become one of the largest burdens on health care systems worldwide. with the alarming global increase in people who are overweight and obese, the diabetes problem will be magnified. india, china and the usa had the highest number of people with diabetes in 2000 (31.7 million, 20.8 million and 17.7 million, respectively). the numbers are expected to increase by 2030 to 7.9 million, 42.3 million and 30.3 million, respectively. the numbers in north and south america and africa as a whole are expected to double between 2000 and 2030 while in asia and australia combined the numbers are expected to rise in the same period at an even faster rate (from 82.7 to 190.5 million).1 obesity has reached epidemic proportions globally, with more than 1 billion adults overweight at least 300 million of them clinically obese—and it is a major contributor to the global burden of chronic disease and disability.2,3 in children the trend is almost the same 4,5 and a previous study in oman showed a doubling of cases of overweight grade 10 students between 2004 and 2008.6 currently type 2 diabetes affects obese children even before puberty. approximately 85% of people with diabetes are type 2 diabetics, and the majority is obese or overweight. it was also noted that the new emerging markets with high yearly economic growth had the highest number of diabetics. if current trends continue, by 2025 india and the middle east region will be the most affected areas in the world.2,3 in the arabian gulf countries, we are facing a huge challenge with a similar increase in the prevalence of diabetes [table 1].7, 1 a national survey in the united arab emirates (uae) conducted jointly by the world health organization (who) and the uae ministry of health between 1998 and 2000 reported that 19.6% of the population had diabetes, while among uae citizens (as opposed to expatriates) it was 24%. the uae currently has the second highest rate of diabetes in the world.8 in oman, the prevalence is not very different. in 2000, the age-adjusted prevalence of diabetes among omanis aged 30–64 years reached 16.1% compared department of child health, sultan qaboos university hospital, muscat, oman. corresponding author email: hawa34@hotmail.com ·^€ �¬<ìfl�◊â<ª<îü”ä÷]<óïü⁄<ìë^¬ö ÿá◊£]ê<l^œá√π]        :مفتاح الكلمات abstract: diabetes has become one of the most challenging chronic diseases with its prevalence increasing in most countries worldwide. the arabian gulf countries face a similar increasing prevalence of diabetes. diabetes care requires not only the support of the health authorities, but the contribution of all the sectors of the community and requires good financial support. in oman, there are many factors which affect the care of diabetes. in this article, these factors are addressed and recommended solutions discussed. keywords: diabetes care; oman; obstacles; solutions sounding board diabetes care in oman obstacles and solutions saif alyaarubi diabetes care in oman obstacles and solutions 344 | squ medical journal, august 2011, volume 11, issue 3 with 12.2% in 1991.9 the estimated economic cost of diabetes in 2007 in usa was $174 billion for a population of over 311 million.10 the cost is divided between the direct medical costs of $116 billion and indirect costs, (such as lost workdays, restricted activity, and disability due to diabetes) of $58 billion.10 by contrast, with a total population of only around 4 million, the uae spent $436 million (1.6 billion dirhams) on diabetes related treatments in 2007.8 diabetes treatment and its complications will soon consume most of its national health care budget. in a recent study involving six health centres from the muscat region, only 2.4% of diabetic patients achieved international recognised goals for all 6 diabetes factors (hba1c <7%; bp <-130/80 mmhg; total cholesterol <5.2 mmol/l; low-density lipoproteins cholesterol (ldl) <3.3 mmol/l; highdensity lipoproteins cholesterol (hdl) >1.1-<1.68 mmo/l, and triglyceride (tgd) <1.8 mmol/l.11 there are many factors which affect diabetes care in oman and result in poor diabetes control. the link between the poor control of diabetes and the higher risk of microvascular and macrovascular complications is well established. the work done by the uk prospective diabetes study (ukpds) and the diabetes control and complications trial (dcct) is the landmark study in this field.12,13 major obstacles affecting diabetes care in oman h e a lt h c a r e s y s t e m o r g a n i s at i o n diabetes is considered as a model for chronic disease management. in order to cope with diabetes, the omani health care system will not only need the implementation of evidence-based clinical practice, but also a reframing of the existing community health care system. this is because the current health care policies and delivery system do not fully support the management of diabetes. the health care system in oman is based on the primary health care system and all patients with diabetes are followed up at this level, leaving the complicated cases to secondary or tertiary hospital care. not all the primary health care facilities have diabetologists so most of these patients are looked after by nonspecialised primary health care physicians. health centres are not equipped with facilities for the early detection of the complications of diabetes as most of these tests are done in tertiary care facilities. this may therefore affect the quality of diabetic care. another issue is the initiation of the insulin policy which only allows tertiary hospitals and certain health centres to prescribe insulin therapy. chronic disease management should be framed within the context of the chronic care model (ccm). the non-adoption of this model will result in disorganisation of care and wastage of resources. the uk, australia, new zealand and canada have taken the lead in adopting models of chronic care.15‒19 in the gulf countries, some efforts are being made in the right direction for diabetes care, e.g. the recently established national committees and campaigns to raise awareness about diabetes and the standards of its care. f i n a n c i a l r e s o u r c e s f o r d i a b e t e s c a r e prescribing medications is not the most important factor in diabetes control. monitoring blood glucose levels is associated with much better control and hence less complications as supported by the dcct and ukpds studies.12,13 some of the benefits of glucose monitoring at home are that it: 1) helps to monitor immediate and daily levels of control; 2) detects hypoglycaemia; 3) assists in the safe management of hyperglycaemia, and 4) has educational value in assessing blood glucose (bg), responses to insulin, food and exercise. however, glucose strips for home testing are not provided free by the health care system. unfortunately, many patients have a low incomes and the cost of glucose strips is approximately omani rials (or) 15 to 50 (= us $39 to 130) per patient per month. moreover, newer modalities of treatment and monitoring are also not supported by the health care system e.g. insulin pens, insulin pumps and continuous glucose monitoring systems, etc. h u m a n p r o f e s s i o n a l r e s o u r c e s there is a severe shortage of medical professionals worldwide and fierce competition between various countries to recruit them. oman is not an exception and the numbers of certified physicians in the field are inadequate compared to the number of diabetic patients. according to the 2009 annual report of the omani ministry of health, there are only 18 certified diabetologists in the whole of oman.20 saif alyaarubi sounding board | 345 moreover, other health professionals specialised the field of diabetes are even more scarce, e.g. diabetic education nurses, social workers, psychiatrists, podiatrists and dietitians. the population of oman is distributed over a wide geographic area and reaching diabetics in their communities is difficult and very expensive. t r e at m e n t p r o t o c o l s the adoption of internationally accepted treatment protocols is fundamental in the treatment of diabetic patients. the current protocol followed in oman has not been updated since 2003. there is also a general tendency to delay the initiation of insulin treatment. moreover, the practice of limiting the initiation of insulin and the adjustment of doses to certain specialised clinics and to tertiary hospitals has led to the poor management and non-compliance of patients. the lack of adherence to the international diabetes guidelines is reflected in the large percentage of diabetic patients not achieving internationally accepted glycated haemoglobin targets.11 ava i l a b i l i t y o f m e d i c at i o n s diabetes is a chronic disease with fatal complications. in the last 50 years, there have been tremendous improvements in the type of insulin and the oral hypoglycaemic agents available for treating diabetics. new insulin analogues have appeared in the market and new insulin regimens have been introduced in the guidelines. new oral hypoglycaemic agents have also been recently discovered. the unavailability of these medications in oman and the use of generic medications have left the physicians with very few alternatives to upgrade the treatment to achieve better control. however, there is no evidence so far to prove that the new medications are more effective and the generic medications are less potent. l a b o r at o r y s u p p o r t most omani diabetic patients have associated hypertension and obesity (metabolic syndrome). in these patients, the hba1c, lipid profile, renal functions, liver function tests and albumin creatinine ratio have to be monitored very closely on a regular basis. hba1c and lipid profile tests are not done in primary health centres on a regular basis and the samples are sent to the nearest tertiary hospital for testing which delays the results and consequently the follow-up of the treatment. d i a b e t e s h e a lt h c a r e t e a m diabetes needs a multidisciplinary approach for effective care of diabetics. the team should consist of a specialist/family physician, a diabetes educator, a dietitian, a social worker, a podiatrist and a psychiatrist. this team should have a proper and effective communication network within the health care system and the community. most of the time, this team approach does not exist because of lack of human resources or unavailability of the services. as a result, the patients mostly see only the treating physician. pat i e n t a n d s o c i e t y c o n t r i b u t i o n s a n d r e s p o n s i b i l i t i e s oman is similar to the other gulf countries in its rapidly changing patterns of behaviour, a table 1: actual & projected numbers of diabetics in selected countries of the world health organization’s eastern mediterranean region country total numbers in 2000 % population in 2000 projected numbers in 2030 united arab emirates 350,000 7.78 684,000 bahrain 37,000 5.96 99,000 qatar 38,000 4.67 88,000 oman 113,000 4.40 343,000 lebanon 146,000 4.08 378,000 kuwait 104,000 3.87 319,000 pakistan 5,217,000 3.73 13,853,000 saudi arabia 890,000 3.62 2,523,000 egypt 2,623,000 3.54 6,726,000 jordan 195,000 3.42 680,000 syria 627,000 3.29 2,313,000 iran 2,103,000 3.02 6,421,000 iraq 668,000 2.32 2,009,000 afghanistan 468,000 1.57 1,403,000 yemen 327,000 1.56 1,286,000 libya 88,000 1.50 245,000 sudan 447,000 1.23 1,277,000 diabetes care in oman obstacles and solutions 346 | squ medical journal, august 2011, volume 11, issue 3 consequence of the oil business and industrial boom. our ancestors used to wake up early, have a good breakfast and burn plenty of calories during the day. later, they would have an early dinner and a good night’s sleep. now we tend to get up late, have little or no breakfast, a lunch with heavy carbohydrate content and late dinner. a sedentary lifestyle and lack of exercise is becoming the trend.21 junk food in oman is relatively cheap and widely available. in 2004, the ministry of health studied the food habits of school children in oman. they found that 95% of schools sold chips, 79% cheese sandwiches, 78% biscuits and 57% cakes.6 these changes in eating behaviour and attitudes towards food and exercise have disturbed body metabolism and resulted in an energy imbalance with more energy being stored and less energy consumed. the best example of food habits that affect diabetes control is the heavy lunch with high carbohydrate content that leads to a high excursion of blood glucose levels lasting until dinner time and carrying on to overnight. the usual twice daily insulin will not cover the lunch glucose excursion and patient should either be given short acting insulin or decrease their carbohydrate content at lunch time. patients also tend not to follow the dietary advice strictly and do not comply with medications. noncompliance may be a problem although evidence from oman is lacking; this is maybe partly related to poor patient education and low communication skills in health professionals. it is very difficult for the treating physician to adjust the medications and upgrade the treatment if the patients are noncompliant. o m a n d i a b e t e s a s s o c i at i o n the oman diabetes association has been active in the last few years specifically in terms of patient advocacy. the association actively participates in fund raising activities for diabetic patients and in providing continuous medical education for professionals. the association also organises activities on the world day of diabetes each year. however, a lot of effort is required from the community to assist the association both administratively and financially. solutions in the following sections some solutions are recommended which may benefit diabetes care in oman. h e a lt h c a r e s y s t e m o r g a n i s at i o n the chronic care model is based on the who’s innovative care for chronic conditions framework.22,23 this framework recognises the need to expand the delivery of health care from acute care to a system that includes prevention and advanced management. it includes six interrelated components that are the key to improving care: 1) community resources and policy; 2) health system organisation of health care; 3) self-management support; 4) delivery system design; 5) decision support, and 6) clinical information system.24,25 the adoption of such a system by health care authorities in oman is a key element in the success of diabetes care. the success of diabetic care depends also on 5 basic key components:22,24 1) identification of patients with diabetes; 2) accurate diabetes registry; 3) systematic recall process; 4) clinical flow sheets, and 5) diabetes focus groups/group visits. f i n a n c i a l s u p p o r t f o r d i a b e t e s c a r e all diabetic patients in oman should be provided with free glucose meter strips as part of the treatment package. insulin pumps should also be subsidised at least for type 1 diabetic patients. h u m a n p r o f e s s i o n a l r e s o u r c e s the health care system should attract diabetologists and other medical professionals from abroad by offering them contracts with reasonable salaries, allowances and incentives comparable to other arabian gulf countries. omani medical residents should be encouraged to join diabetes fellowship programmes for training. continuous medical education programmes should be held throughout the country for nurses and dietitians on a regular basis. all regional hospitals should have a complete diabetes team consisting of qualified diabetologists/ family physicians, diabetes educators, podiatrists, dietitians, psychiatrists and social workers. t r e at m e n t p r o t o c o l s the treating physicians should be up-to-date on the latest diabetes treatment guidelines and should strictly follow the international recommendations. saif alyaarubi sounding board | 347 continuous medical education should be provided regularly to all members of the diabetic care team in all the regions. the omani health care organisation should ensure that all the necessary policies and arrangements are in place and that the international guidelines are accessible and easy to implement. ava i l a b i l i t y o f m e d i c at i o n s brand name oral hypoglycaemic agents should be widely available. new agents should be introduced to the protocols. insulin analogs, with their new delivery devices, should also be accessible to all patients in oman. a system of providing insulin pumps with patients bearing only part of the cost should established for qualifying patients. l a b o r at o r y s u p p o r t the treating physicians in local health centers and regional hospitals should be able to order all the necessary investigations for the treatment of diabetes and its comorbidities and receive the results rapidly. pat i e n t a n d s o c i e t y c o n t r i b u t i o n s a n d r e s p o n s i b i l i t i e s patients should follow the medical and the dietary advice strictly, take their medications, check their glucose daily and keep a log book in a responsible manner. a sedentary life style must be avoided; patients should be more active and exercise daily for a minimum of 30 minutes. the weather in oman has been always been hot; however, this did not preclude previous generations from being physically active. a good alternative is indoor gyms which are available at a reasonable cost. diabetes education should be carried out not only by the medical team, but also by the mass media. d i a b e t e s h e a lt h c a r e t e a m diabetes educators and physicians should have the responsibility of teaching patients about their chronic disease and diabetes control. understanding the basic concepts of glycated haemoglobin, dietary control, carbohydrate counting and multiple daily injections is crucial for better control. type 1 diabetic patients should be introduced to the concept of carbohydrate counting and offered multiple daily injections (or continuous subcutaneous insulin infusion) of long-acting insulin as basal insulin, as well as fast or shortacting insulin to cover glucose from meals. this will not only improve their glycaemic control, but also give them flexibility in their daily routine. finally, coordinated efforts between health care authorities, physicians, diabetic health teams, patients, the community and the media are needed to optimise diabetic care in oman. the first step forward in this direction, is the opening of a national diabetes centre in oman which should be the organising and coordinating body for diabetic care in the country conclusion diabetes is a chronic disease and its care requires a lot of effort. in oman, there are many obstacles that affect optimum diabetes care, linked to various factors including the health care system, financial resources, lack of professional human resources, inadequate laboratory support and availability of medications. organised efforts by health care policy makers should be made as soon as possible to improve the current disorganised practice. application of the current who chronic care model is of key importance. contributions from various sectors of society and the cooperation of patients are important additional factors in successful diabetes care. with the expected increase in the number of diabetics in oman, it is highly recommended to conduct further prospective research. references 1. global prevalence of diabetes: estimates for the year 2000 and projections for 2030. diabet care 2004; 27:1047‒53. 2. obesity and overweight. from: www.who.int/hpr/ nph/docs/gs_obesity.pdf accessed: sep 2010. 3. diabetes facts. international diabetes federation. from: http://www.idf.org/ accessed: may 2011. 4. ogden c, carroll m, curtin l, lamb m, flegal k. prevalence of high body mass index in children and adolescents, 2007-2008. jama 2010; 303:242–9. 5. twenty years of environment and health in europe: trends and gaps. from: www.euro.who.int/__data/ assets/pdf_file/0013/103513/fs_parmaopening.pdf accessed: dec 2010. 6. ministry of health oman. annual health report 2008. from: http://www.moh.gov.om/stat/2008/ index.htm. accessed: may 2011. 7. world health organization diabetes program, diabetes care in oman obstacles and solutions 348 | squ medical journal, august 2011, volume 11, issue 3 country and regional data. from http://www.who. int/diabetes/facts/world_figures/en/index2.html accessed: jan 2011. 8. diabetes cost the uae millions in 2007. from: www. arabianbusiness.com/diabetes-costs-uae-millionsin-2007-85671.html. accessed: sep 2011. 9. al-lawati ja, al-riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. 10. diabetes research and statistics. from: www. c d c . g o v / d i a b e t e s / c o n s u m e r / r e s e a r c h . h t m . accessed: sep 2010. 11. almundhri a, al-zakwani i, el shafie o, al shafaee m, woodhouse n. quality of diabetes care: a crosssectional observational study in oman. squ med j 2009; 9:32–6. 12. diabetes control and complications trial (dcct) research group. the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. n eng j med 1993; 329:977–86. 13. uk prospective diabetes study (ukpds) group. effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (ukpds34 ). lancet 1998; 352:854–65. 14. uk prospective diabetes study (ukpds) group. intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (ukpds 33). lancet 1998; 352:837–53. 15. wong j, gilber j, kilburn l. seeking program sustainability in chronic disease management: the ontario experience. toronto, ontario: the change foundation, 2004. from: www.changefoundation. com accessed: feb 2011. 16. battersby mw. health reform through coordinated care: sa health plus. bmj 2005; 330:662–5. 17. wellingham j, tracey j, rea h, gribben b. the development and implementation of the chronic care management programme in counties manukau. n z med j 2003; 116:u327. 18. chronic care model. government of british columbia. from: www.healthservices.gov.bc.ca/ cdm. accessed: feb 2011. 19. barr vj, robinson s, marin-link b, underhill l, dotts a, ravensdale d, et al. the expanded chronic care model: an integration of concepts and strategies from population health promotion and the chronic care model. hosp q 2003; 7:73–82. 20. ministry of health, oman. annual health report 2009. from: www.moh.gov.om/stat/2009/index.htm accessed: jan 2011. 21. sridhar gr. eat, drink and live merry? intl j diabetes dev countries 2011; 31:1–3. 22. organization of diabetes care. from: www.diabetes. ca/for-professionals/cpg/ooc/. accessed: sep 2010. 23. innovative care for chronic conditions: building blocks for action. from: www.who.int/ diabetesactiononline/about/icccglobalreport.pdf accessed: sep 2008. 24. bodenheimer t, wagner eh, grumbach k. improving primary care for patients with chronic illness. jama 2002; 288:1775–9. 25. optimizing diabetes care: a systematic approach. f r o m : w w w. d i a b e t e s . c a / g e ti n v o l v e d / n e w s / optimizing-diabetes-care-a-systematic-approach/ accessed: sep 2010. squ med j, december 2009, vol. 9, iss. 3, pp. 231-246, epub. 19th dec 2009 submitted 2nd nov 08. reformat recd. 4th april 09. revision req. 19th aug 09 revision recd. 9th sept 09 accepted 12th oct 09 acute myocardial infarction (ami) is the leading cause of death in developed countries;1 however, in-hospital mortality from this cause has been declining over the last three decades.2 this reduction in mortality coincides with the improvement in health and living standards and with new treatments like thrombolysis and new interventions like percutaneous coronary intervention (pci) and coronary artery bypass grafting (cabg). secondary and primary prevention strategies have contributed significantly and the age-adjusted mortality is expected to continue to decline with further improvements in treatments, better uptake of primary and secondary prevention strategies and also with further improvement in our ability to recognise this challenging disease very early in its course. the success of treatment rests on: 1) identification of patients in the very early stages of ami; 2) implementation of treatment to recanalise the occluded artery; 3) access to early defibrillation and 4) admission to properly monitored coronary care or intensive care units (ccu or icu) for the 1cardiology unit, department of medicine, sultan qaboos university hospital, muscat, sultanate of oman; 2the university of edinburgh, cardiovascular research unit. the royal infirmary of edinburgh, scotland *to whom correspondence should be addressed: halhadi@hotmail.com استخدام العالمات القلبية الواصمة يف التشخيص والعالج املبكر للمرضى الذين يعانون من املتالزمة القلبية احلادة حفيظ الهادي، كيث فوكس الطبية. الرعاية طلب على املريض يجبر الذي حدوثا األكثر السبب يكون ما غالبا أنه من الرغم على نوعية غير شكوى الصدر ألم يعد امللخص: مجموعة صغيرة من هؤالء املرضى يعانون من املتالزمة القلبية احلادة. نظام التشخيص املتبع حاليا واملبني على التاريخ السريري وتخطيط القلب غير كافي، وقد يؤدي في بعض األحيان إلى التشخيص اخلاطئ وإدخال املرضى إلى األقسام غير املناسبة، أو أن يتلقوا رعاية أو أدوية أو فحوًصا غير مناسبة. وفي بعض املرضى يتأخر التشخيص وهذا يؤدي إلى تأخير إعطاء األدوية الضرورية أو حتى عدم إعطائها. قليل من املرضى الذين يعانون من املتالزمة القلبية احلادة قد يتم إخراجهم من الطوارئ خطأ، مما قد يترتب عليه أخطار صحية وقانونية. كما أن نظام التشخيص هذا قد يؤدي أيضا إلى إدخال عدد كبير من املرضى الذين ال يعانون من أمراض قلبية إلى املستشفى بدون داع. ميكن تطوير النظام احلالي لتشخيص وعالج املرضى الذين يعانون من آالم الصدر بشكل العالمات يتناول املقال احلادة. هذا القلبية اجللطة عن جدا املبكر للكشف املتسلسلة الواصمة القلبية العالمات فحص نظام إدخال طريق عن كبير كاينيز كرياتني فاعلية)، و (كتلة والدماغ العضلة كاينيز كرياتني كاينيز، كرياتني مثل القلب عضلة تلف لتشخيص حاليا املتوفرة الواصمة القلبية العضلة والدماغ (مثلي)، البروتني الرابط حلمض القلب الدهني، مايوجلوبني، تروبنني القلب (ت) وتروبنني القلب ( أ). مفتاح الكلمات: العالمات القلبية الواصمة، املتالزمة القلبية احلادة، جلطة قلبية حادة، ألم الصدر. abstract: chest pain is a non-specific complaint and is the most frequent reason for patients seeking urgent medical attention. a small group of these patients will have acute coronary syndromes (acs). the current diagnostic and triage systems based on clinical history and electrocardiograms are insufficient. they may result in some of these patients being misdiagnosed and being admitted to the wrong units or receiving inappropriate care, treatment and investigations. in some patients, the diagnosis is delayed resulting in the late administration (or no administration) of essential early treatment. a few patients with acs may be inadvertently discharged from the emergency department leading to serious health and legal implications. these systems also result in the unnecessary admission of a substantial number of patients without acs. the triage and management of patients with chest pain can be considerably improved by implementation of serial cardiac markers testing that can identify acs in the very early stages of presentation. this review article will discuss the currently available markers of myocardial damage such as creatine kinase (ck), creatine kinase muscle and brain (ck-mb) (mass and activity), ck-mb isoforms, heart-type fatty acid-binding protein, myoglobin, cardiac troponin t, and cardiac troponin i. keywords: cardiac markers; acute coronary syndromes; acs; acute myocardial infarction; ami; non-st elevation myocardial infarction; nstemi; chest pain. review cardiac markers in the early diagnosis and management of patients with acute coronary syndrome *hafidh a al-hadi,1 keith a fox2 cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 232 | squ medical journal, december 2009, volume 9, issue 3 detection and treatment of complications. the diagnosis of ami was previously based on the criteria set by the world health organization (who) and had to include two of the following: 1) typical history of prolonged ischaemic chest pain; 2) presence of typical acute ischaemic changes on the admission electrocardiograms (ecg); 3) typical rise and fall of cardiac enzymes in blood.3 this old definition has recently been changed with the publication of a new definition of myocardial infarction by the joint european society of cardiology/american college of cardiology (esc/ acc) committee, which redefines myocardial infarction (mi) according to cardiac markers as follows: 1) an increase in cardiac troponin ctni, ctnt exceeding the decision limit (99th percentile of the value for a reference control group) on at least one occasion; 2) an increase in creatine kinase muscle and brain (ck-mb), preferably ck-mb mass exceeding the decision limit (99th percentile of the value for a reference control group) on at least two occasions with a rise and fall pattern, or greater than twice the upper limit of the reference range on one occasion. within this definition, acute coronary syndromes (acs) are classified into st and non-st elevation. st elevation acs is further classified into q-wave and non q-wave mi. non-st elevation mi (with cardiac marker elevation) is also classified into q-wave and non q-wave mi. non-st elevation acs without cardiac markers elevations is called unstable angina.4 the very early diagnosis of ami can be a challenging task for many physicians in an emergency department. when a typical history is present, it helps to orient the clinician to the right diagnosis, but its absence by no means rules it out. this is often the case in a significant proportion of patients in whom the history is either atypical or absent. diabetic, hypertensive, and elderly patients often have silent ami. in these cases ami may go unnoticed or may produce atypical symptoms such as hypotension, breathlessness, syncope, or arrhythmias.5 the ecg is an important tool for detecting ami, but it lacks sensitivity and as many as 30-50% of patients may initially present with normal or non-diagnostic ecg.6 the ecg has an overall diagnostic sensitivity for ami of 70-81%;7 however, when changes typical of ami are present on the admission ecg (st elevation and new q-wave) they are highly specific and have a very high positive predictive value for the diagnosis of ami. cardiac markers are formidable tools for the diagnosis of ami.8 characteristic features of biochemical markers of myocardial injury the ideal characteristics of a marker of myocardial injury are: 1) it should be abundant in the myocardium and not present in other tissues. this gives it a high specificity for the myocardium and reduces the rate of false positive results; 2) it should have a high concentration in the myocardium and a low or undetectable concentration in the blood in the absence of disease. this gives it a high sensitivity so that the release of only a small amount can be readily detected thereby reducing the rate of false negatives; 3) it should be released completely and quickly when myocardial damage occurs. this will allow its utilisation for the early detection and quantification of injury; 4) it should persist in the circulation to give a convenient diagnostic window, but not so long as to prevent the detection of complications such as early re-infarction, and 5) the assay must have a high analytical sensitivity and specificity and a short turn around time, so that results could be obtained fast enough to influence the decision-making process regarding patients’ triage and management. biochemical markers and early detection of acute myocardial infarction cardiac markers play an important role in the detection of ami when the patient’s history and ecg are non-diagnostic or equivocal.9 diagnosing ami early (i.e. within 6 hours after symptom onset) is difficult, because some time must elapse after symptom onset for markers to exceed values above the reference range. the diagnosis of ami based only on one single value at presentation or soon after admission is unreliable, and serial sampling is the most effective method. the sensitivity and specificity of cardiac markers for the early diagnosis of ami is influenced by several factors such as: 1. time of presentation: early presentation after symptom onset is likely to show a relatively hafidh a al-hadi and keith a fox review | 233 increased sensitivity for markers like myoglobin, which is released very early in the course of ami, and less sensitivity for markers like ck-mb or ctni, which are released slightly later. a delayed presentation is likely to have the opposite effect. therefore, the onset of symptoms should be used as the reference point when commenting on the sensitivity and specificity of the markers for the early diagnosis of ami rather than criteria such as time of presentation, and time of admission.10 2. size of infarct: cardiac markers are released in proportion to the volume of myocardium in jeopardy, the bigger the infarct the greater the quantity of cardiac markers released. this will lead to improved sensitivity compared to small infarcts where a limited release of markers may be close to the threshold for detection.11 3. selection criteria and prior probability of acute myocardial infarction: selecting certain group(s) of patients for the study with a high possibility of ami, such as those admitted to the ccu, can also influence sensitivity of a marker. 4. treatment: treatment can have an influence on the sensitivity of the marker. for example, patients who have been successfully thrombolysed show a greater and earlier peak of some of the markers compared to those who were not successfully reperfused.12 5. diagnostic threshold: the selection of an appropriate diagnostic threshold requires careful consideration of concentrations seen in the normal and disease free population and those seen in diseased populations. there is always a continuous balance between the sensitivity and specificity of any marker. if the cut-off concentration used is low, the sensitivity is improved at the expense of specificity unless the marker is 100% cardiac specific, and only present in diseased populations.13 6. kinetic factors: kinetic factors like the molecular size of the marker, the biological compartment of the marker (i.e. whether it exchanges freely in the cytoplasm or is attached to structural elements within the cell), the volume of distribution, and whether the marker is released directly into the blood or cleared by the lymphatic system can all influence plasma concentration. markers that have a low molecular weight, lie free in the cytoplasm, and are released directly into the circulation show better early sensitivity compared with larger molecules that are attached to structural elements and/or cleared slowly by the lymphatic system.14 it is not surprising therefore that different studies report differing results for sensitivity and specificity for the various cardiac markers for the early diagnosis of ami. the variations in the reported results will predominantly be influenced by the above factors. this review article will discuss the currently available markers of myocardial damage like creatine kinase (ck), ck muscle and brain (mb) (mass and activity), ck-mb isoforms, heart-type fatty acid-binding protein (h-fabp), myoglobin, cardiac troponin t (ctnt) and ctni. the discussion will focus in particular on the suitability of these markers as tools for: 1) the early diagnosis of mi within 6 hours; 2) their ability to detect myocardial damage during ischaemic episodes in patients with non-st elevation mi or undergoing cardiac intervention like pci or surgery; 3) their ability to guide further treatments i.e. antiplatelets, antithrombotics, coronary interventions, etc; 4) their ability to detect reperfusion and re-infarction; 5) their specificity and limitations and 6) future directions with these markers. for the sake of clarity, unstable angina with elevated cardiac markers quoted in various references in the literature will be used synonymously with non-st elevation mi using the recent new definition of acute coronary syndromes referred to above.4 creatine kinase creatine kinase is an enzyme composed of two subunits, m and/or b. three different pairs of these units combine to give rise to three different isoenzymes, ck-bb, ck-mb and ck-mm. ckbb is the brain isoenzyme and is present in large quantity in the brain and many internal organs. ckmb is the heart specific isoenzyme and has been the gold standard method for the diagnosis of ami in many laboratories. it exists in large quantity in heart muscle, but is not totally cardiac specific and exists also in skeletal muscles and other tissues. cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 234 | squ medical journal, december 2009, volume 9, issue 3 about 15-40% of the total ck activity of heart muscle is due to ck-mb, the rest is largely due to the ck-mm isoenzyme. ck-mm is the skeletal muscle isoenzyme. it has the highest distribution in skeletal muscles. the three isoenzymes are present in varying concentrations in the smooth muscle of the colon, ileum, stomach, and urinary bladder.15 the reference range for ck is approximately 80-200 iu/l for men and 60-140 iu/l for women. this is the result of the normal turnover of this enzyme in skeletal muscles, and it is influenced by factors like muscle mass and physical work. c r e at i n e k i n a s e a n d a c u t e m y o c a r d i a l i n fa r c t i o n creatine kinase was introduced in 1965 as a biochemical marker for myocardial damage and it is one of the oldest markers in this field.16 it has a clinical sensitivity for the diagnosis of ami of 90%. unfortunately, this is not matched by high specificity. it is released within 12 hours after symptom onset of ami, peaks in serum at 24-36 hours, and returns to normal in 48-72 hours. as a result of these release kinetics, measurement of total ck is not suitable for the early diagnosis (within 6 hours) of ami. ck as a marker is also unsuitable for the detection of myocardial damage that may occur in patients presenting with non-st elevation mi, or in patients undergoing pci or surgery. as mentioned earlier, a marker that is suitable for the early diagnosis of ami, and the detection of small injuries to the heart should have: a high cytoplasmic (cell) to vascular (plasma) ratio, very low or undetectable normal plasma concentration and total cardiac specificity. ck does not fulfil these criteria since it has a moderate cytoplasmic to vascular ratio of 60,000:1; a high reference range up to 200 iu/l, and is widely distributed in the body. to improve on the cardiac specificity of ck for the diagnosis of ami, it was recommended to measure both total ck and ck-mb (the cardiac specific isoenzyme of ck). a ck-mb to ck ratio of > 6% is reported to be specific for myocardial injury, whereas a ratio of < 6% is consistent with skeletal muscle damage or non-cardiac causes. in some clinical settings, a ck-mb test is not requested unless the total ck activity is elevated. the use of total ck as a screening test before ordering ck-mb could miss some patients with ami and should be used with caution. there are cases of ami without elevation of total ck concentration, but the total ck-mb fraction and the ck-mb to ck ratio in these patients is diagnostic for ami. this is likely to happen in situations when there is a small mi in a small sized person with a low muscle bulk, and a low baseline value of total ck. the normal reference range of ck is very broad and these patients could release small amounts of the enzyme, insufficient to raise the concentration above the reference range. if this possibility is not borne in mind, the diagnosis could be missed when ck is used. unless the baseline total ck is known in a patient presenting with highly suspicious diagnosis of ischaemia, a low total ck should not exclude the diagnosis nor should it preclude requests for ck-mb.10 l i m i tat i o n s a n d f u t u r e d i r e c t i o n o f c r e at i n e k i n a s e m e a s u r e m e n t the ck enzyme is widely distributed and there are various causes of elevated total ck in the absence of myocardial injury.17 haemolysis leads to the release of the adenylate kinase enzyme, which interferes with the assay and causes false elevation of total ck activity. various forms of skeletal muscle injury can lead to increased ck activity including strenuous exercise, intramuscular injection, rhabdomyolysis, burns, and trauma. chronic muscle diseases like polymyositis, dermatomyositis, and myopathy can all lead to increased concentrations of ck. total ck activity is a very sensitive indicator of injury to skeletal muscles. drugs like cocaine and alcohol can also raise ck concentrations to abnormal values, presumably due to the associated myopathy that can occur with the use of these drugs. neurological conditions like myasthenia gravis also elevate total ck activity. other miscellaneous conditions including pregnancy, hypothermia, and sepsis can increase total ck concentrations.18 in many of these situations, the activity of ck-mb is also increased, giving a ratio of ck-mb to ck that remains below the 6% cut-off point required to differentiate between skeletal muscle injury and cardiac muscle injury.19 measurement of ck is a relatively cheap assay that is widely available. for this reason, total ck measurement will probably continue to be used as a marker for myocardial injury especially in situations such as: 1) absence of ctni, ctnt, and ck-mb assays; 2) patients with unequivocal ecg diagnosis of mi where a non-specific marker such as ck can be used to confirm the diagnosis, monitor hafidh a al-hadi and keith a fox review | 235 the progress of the patient in hospital and to gauge infarct size. creatine kinase muscle brain isoenzyme the ck-mb isoenzyme has been considered as the gold standard for the diagnosis of ami. it is the isoenzyme of ck specific for heart muscle. it is measured in serum or plasma by one of two methods: 1) ck-mb activity: this measures the total activity of the enzyme in serum/plasma by methods like electrophoresis, column chromatography, immunoinhibition or immunoprecipitation. the results are reported as iu/l. these methods are non-specific, measure only active enzymes, and have a low analytical sensitivity (5 iu/l); 2) ckmb mass: this measures the protein mass in serum/ plasma using specific antibodies against the m, b or mb subunits. the results are reported in ng/ml or µg/l. these assays are highly specific and have a high analytical sensitivity (0.3ng/ml) and can measure both active and inactive enzymes. the reference ranges using various methods have been reported to be 8-16 iu/l for ck-mb activity, and 5-10 ng/ml (µg/l) for ck-mb mass.10 c r e at i n e k i n a s e-m b a c t i v i t y v e r s u s c r e at i n e k i n a s e-m b m a s s different groups have reported that measurement of ck-mb using mass is better than that measuring ck-mb activity.20 the recent guidelines for the redefinition of ami recommend the use of ck-mb mass as opposed to ck-mb activity.4 the problems inherent in measuring activity are: 1. the enzyme may become deactivated by experimental manipulations leading to a low value or underestimation. this is likely to happen in the low range of ck-mb activity such as in patients with small ami or with minor myocardial damage. in an extreme situation, a false negative result could result in the missed diagnosis of ami. unlike ck-mb activity assays, ck-mb mass assays measure both active and inactive enzyme. 2. in haemolysed blood samples, interference from adenylate kinase, an enzyme released from red blood cells which catalyses the same reaction as ck-mb, could result in false positive results. this problem is irrelevant with mass assays because the antibodies are specific for the ck-mb and the presence of adenylate kinase has no effect on the assay.17 3. creatine kinase-mb measurement using mass has better early sensitivity for the diagnosis of st elevation ami. it has also been reported to be more sensitive in detecting small injuries to the myocardium that occur in patients with non-st elevation acs.21 4. the presence of ck-bb, macro ck type 1, or macro ck type 2 in high concentrations could interfere with the result and lead to false elevation of ck-mb when activity measurement is used. these interferences have no such effects when mass assays are used because the antibodies are specific for ck-mb and do not cross-react with these compounds.22 c r e at i n e k i n a s e-m b a n d s t e l e vat i o n m y o c a r d i a l i n fa r c t i o n creatine kinase mb follows the same release kinetics as ck and has a sensitivity and specificity for the diagnosis of ami of more than 90%. this sensitivity and specificity changes with the time of presentation after symptom onset. measurement of ck-mb activity is most reliable in the 12-24 hours period after symptom onset.23 a negative result earlier than 12 hours from the start of symptoms is too early to rule out ami, and a negative result after 24 hours may be too late. studies comparing the utilisation of these assays for the early diagnosis of ami have shown that ck-mb mass reaches the cut-off point in serum several hours before ck-mb activity and have claimed its superiority within 4-8 hours after symptom onset.21 the ckmb mass assay has been shown to be sensitive for the diagnosis of ami even in situations where the ecg is equivocal and can increase the number of diagnoses made within the time scale required for the administration of reperfusion treatment.24 c r e at i n e k i n a s e-m b a n d n o n-s t e l e vat i o n m i creatine kinase mb activity tends to be normal in patients with non-st elevation mi, whereas ck-mb mass is increased in a proportion of these patients. this observation has been substantiated by different groups.25 a study by seo et al. in 1993 cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 236 | squ medical journal, december 2009, volume 9, issue 3 compared ck-mb mass versus ck-mb activity and concluded that ck-mb mass is more sensitive when ck-mb concentration is in the low range.26 this is important especially in cases of myocardial injury in non-st elevation mi, following complicated pci, and in radiofrequency ablation of arrhythmias when the amount of ck-mb released can be small. sensitive ck-mb mass assays can detect prolonged ischaemia in non-st elevation mi and have been used for risk stratification in these patients. one small study has shown a very high death rate (64%) during four years follow-up in patients who were admitted to the ccu with chest pain, positive ckmb mass, and non-diagnostic ecg changes of st elevation mi.27 several investigators have also studied the release of ck-mb mass following pci.28 they demonstrated that ck-mb mass is a sensitive indicator of myocardial injury following pci. one study reported that 40% of patients showed evidence of myocardial damage following pci using both ck-mb mass and ctnt.29 l i m i tat i o n s a n d f u t u r e d i r e c t i o n o f c r e at i n e k i n a s e-m b a s s ay s creatine kinase mb measurement is not totally specific for mi and there are various causes for elevated ck-mb concentrations other than ami.17 cardiac pathologies like congestive cardiac failure and arrhythmia lead to elevated ck-mb concentration. severe skeletal muscle damage e.g. acute muscle trauma, skeletal muscle disorders like myositis, polymyositis, chronic inflammatory and degenerative muscle disorders can lead to ck-mb elevation. in these situations, the ck-mb to ck ratio or cardiac troponins can be used to differentiate cardiac and non-cardiac pathologies.30 measurement of ck-mb is a widely accepted assay that is both sensitive and relatively specific for the detection of ami. however, ck-mb (activity or mass) is not sufficiently sensitive in the first 6 hours after symptom onset for the early diagnosis of ami.4 c r e at i n e k i n a s e m u s c l e b r a i n i s o f o r m s (s u b f o r m s) creatine kinase mb isoforms are variants of the ckmb isoenzyme, which result from post-synthetic modification of the m subunit. they were discovered by weavers in 1972.31 after ischaemic damage to the heart, the ck-mb isoenzyme is released from the damaged heart muscle into the blood. this isoenzyme is converted into other forms by the action of the plasma enzyme carboxypeptidase n (cpn) according to the following reaction: 32 ck-mb2 (tissue form)  cpn (-lysine)  ckmb1 (plasma form) in this reaction, the cpn enzyme removes one lysine amino acid from the m subunit of the released ck-mb2 to produce ck-mb1. ck-mb2 and ckmb1 exist in equilibrium (1:1 ratio) in the serum of normal healthy people. therefore, measurement of total ck-mb at any point in time is equivalent to 50% ck-mb2 and 50% ck-mb1. most assays that measure ck-mb use a relatively high upper limit of reference range (10ng/ml, 14 iu/l). humans differ in their background level of ck-mb and some people may express normal concentrations as low as 1-2 iu/l (or ng/ml). therefore, in the event of myocardial injury, it will require a several-fold increase in the marker before it exceeds the upper limit of the reference range. ck-mb, being a relatively large molecule, may take even longer to reach the circulation and become important diagnostically. when myocardial injury occurs, there is a sudden release and rise of the tissue isoforms, i.e. ck-mb2 compared to the plasma form ck-mb1, leading to a rise in the ratio of ck-mb2 to ck-mb1. by using ck-mb isoforms effectively each patient acts as his own control, and a release of only a small amount of the marker is required to raise the ratio much earlier to a significant level. the requirement for the diagnosis of ami is two-fold: 1) increase of ck-mb2 > 2.6 iu/l and 2) increase of ck-mb2 to ck-mb1 ratio > 1.7. c r e at i n e k i n a s e-m b i s o f o r m s a n d a c u t e m y o c a r d i a l i n fa r c t i o n creatine kinase mb isoforms are reported to be released within 1 hour after symptom onset and peak at 4 hours. evidence of ami can be detected as early as 1-2 hours post-infarction, several hours before total ck-mb reaches diagnostic level.33 these release kinetics make ck-mb isoforms potential markers for the early diagnosis of ami. the sensitivity and specificity of ck-mb2 to ckmb1 ratio for the diagnosis of ami was reported to be 92% and 95% respectively within 6 hours of infarction.34 during this time interval, total ck-mb hafidh a al-hadi and keith a fox review | 237 mass or activity would just be approaching the upper limit of the reference range. one study reported a sensitivity and specificity of 95.7% and 93.9% respectively with a high positive predictive value and a high negative predictive value within 6 hours of infarction. a total of 114 out of 118 patients with ami were identified using ck-mb isoforms within 6 hours. the sensitivity and specificity of conventional ck-mb during this time interval was 48% and 94% respectively.35 seventeen patients who were discharged from the emergency department fulfilled the criteria for the diagnosis of ami using ck-mb isoforms (missed diagnosis). the test was also positive in patients with hypothyroidism and rhabdomyolysis.35 these findings were also substantiated by other studies.36 some investigators however, have questioned the value of ck-mb isoforms for the early diagnosis of ami. a study by laurino et al. in 1996 showed no difference between ck-mb isoforms and conventional ck-mb isoenzyme at 6 hours after symptom onset.37 another study by bhayana et al., using comparison between ck-mb mass, ckmm3 to ck-mm1 ratio, and ck-mb2 to ck-mb1 ratio found no significant advantage of isoforms over ck-mb mass for the diagnosis of ami within 6 hours.38 l i m i tat i o n s o f c r e at i n e k i n a s em b i s o f o r m s a s s ay s there are still unresolved issues surrounding the use of ck-mb isoforms for the early diagnosis of mi. there is still some concern regarding the stability of these isoforms in serum/plasma after their release from damaged tissues.39 there are also some reports of possible variations in the activity of the cpn enzyme among humans.40 this may have a profound effect on the use of the isoforms as markers for the early diagnosis of ami and could lead to false positive or false negative results.39 the other drawback is that the use of isoforms does not obviate the need to analyse total ck and the relative index of ck-mb to total ck to exclude false positive results.41 myoglobin myoglobin is a small heme protein (17 k da) that functions in oxygen binding and transport. it stores oxygen in red muscles (skeletal and cardiac) and, under conditions of severe oxygen deprivation, it releases the oxygen to be used by muscle mitochondria for synthesis of adenosine triphosphate (atp). the myoglobin content of heart muscle is reported to be 2.5mg/g wet weight of tissue and the skeletal muscle content is 4.0mg/g wet weight of tissue.42 myoglobin constitutes 2% of the total cytosolic protein content of cardiac muscle. the reference range of serum myoglobin is about 20-80ng/ml. males have higher levels than females because they have bigger body size and muscle bulk. m y o g l o b i n a n d a c u t e m y o c a r d i a l i n fa r c t i o n myoglobin is one of the best available early markers of ami within 3 hours after symptom onset. the relationship between ami and high myoglobin levels was first reported in 1975.43 myoglobin starts to increase in blood within 2 hours after symptom onset of ami, peaks at 6-9 hours, and returns to normal within 24 hours. in a study by bhayana in 1994, myoglobin was found to be superior to ckmb mass and tnt for ruling out ami within the period of 3-6 hours after symptom onset.44 this early release feature of myoglobin is attributed to its small size and localisation within the cytosol of the cell. several investigators have confirmed a significant role for myoglobin in the early diagnosis of ami, the most promising role being in the early exclusion of ami in patients presenting within 6 hours after symptoms onset.45 within this period, the overall diagnostic sensitivity and specificity ranged from 77-97% and 90-97.9% respectively. the variation in sensitivity depends mostly on the time of presentation after symptom onset and drops considerably with very early (< 2 hours) or late presentation (> 15 hours) to the hospital.11 a consistently negative result within this time interval has such a high negative predictive value for ruling out ami that confident decisions regarding patients’ management can be based on it. however, a positive result should be used with caution, as there are many situations that could give rise to myoglobin elevation in the absence of ami.46 l i m i tat i o n s o f m y o g l o b i n m e a s u r e m e n t myoglobin is a non-specific marker protein for myocardial injury. serum myoglobin is raised in cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 238 | squ medical journal, december 2009, volume 9, issue 3 skeletal muscle damage including intramuscular injection, exhaustive exercise, muscle trauma, direct current shock cardioversion, and also in patients and carriers of genetic muscle disease. severe renal disease leads to failure of clearance of myoglobin from the circulation. the concentration tends to rise and the circulation time is prolonged in these patients. although these factors interfere with the specificity of the test, in clinical practice most of them could be ruled out by careful attention to history taking and simple blood tests. the specificity is increased when myoglobin measurement is combined with other diagnostic methods like ecg or more specific cardiac markers like ck-mb, ctnt, or ctni.47 m y o g l o b i n a n d t h e d e t e c t i o n o f r e p e r f u s i o n ideally, all ami patients should be treated with intravenous thrombolytic treatment or pci. the success of thrombolytic treatment in establishing reperfusion is reported to be 50-80% depending on the thrombolytic agent.48 establishment of reperfusion after the initiation of thrombolytic treatment is important to clinicians in terms of treatment and prognostic implications. coronary angiography is the most definitive method to assess the success of thrombolytic treatment, but this procedure is invasive, carries morbidity and mortality risks, requires a catheterisation laboratory team, and is not widely available. biochemical markers like myoglobin (among others) offer an alternative non-invasive, safe and potentially sensitive method for the detection of reperfusion. this can be done by monitoring the changes in serum concentration immediately before and 60 or 90 minutes after initiation of thrombolysis. patients who successfully reperfuse their occluded artery show a higher and early concentration peak of the biochemical marker compared to those who fail to reperfuse.49 patients with uncomplicated mi who reperfuse achieve a peak value of myoglobin at 1 hour, whereas those who fail to reperfuse reach peak value about 5 hours later.50 a two-fold increase in myoglobin concentrations within 60 minutes compared to the base line pre-thrombolysis value is associated with 95% predictive accuracy for the detection of reperfusion.51 the existence of “no-reflow” is an important indicator of impaired reperfusion and functional recovery. thus a patent artery does not invariably indicate tissue reperfusion. accurate markers of tissue reperfusion are required. the combination of serial 12-lead ecg, clinical features, and serial cardiac markers testing offer a practical alternative to coronary angiography for assessment of reperfusion status. heart-type (h-fabp) fatty acid-binding protein heart-type fatty acid binding protein (h-fabp) is a small (15 kda) soluble non-enzyme protein. it is composed of 132 amino acids. it is one of the most abundant proteins in the heart and comprises 5-15% of the total cytosolic protein pool in the aqueous cytoplasm. it was introduced by glatz et al. in 1988 as a potential novel biochemical marker for the early diagnosis of ami;52 this was soon confirmed in other studies.53-54 under normal conditions, h-fabp is not present in plasma or interstitial fluid, but is released into the blood upon cardiac cellular injury. the cytoplasmic to vascular concentration of h-fabp is of the order of 200,000:1.55 the plasma or serum concentration of h-fabp under normal conditions is < 5µg/l. this makes the plasma estimation of h-fabp a suitable indicator for the early detection and quantification of myocardial tissue injury. h-fa b p a n d a c u t e m y o c a r d i a l i n fa r c t i o n heart-type fabp is released into plasma within 2 hours after symptom onset and is reported to peak at about 4-6 hours and to return to normal base line level in 20 hours.55 within the period of 30210 minutes after symptom onset, h-fabp has > 80% sensitivity for the diagnosis of ami.56 within the interval of 0-6 hours after symptom onset, the other cardiac markers such as ck, ck-mb (mass or activity), i ctni and ctnt will only be starting to accumulate in the plasma, and their sensitivity has been reported to be around 64%.57 a rise in serum and urine h-fabp concentration above reference values is seen in patients presenting with ami as early as 1.5 hours after symptom onset. serial measurements of h-fabp in the first 24 hours after onset of symptoms may be potentially useful for: the diagnosis of ami; to identify patients who need early reperfusion treatment; to identify patients who reperfuse their infarct related artery; to detect hafidh a al-hadi and keith a fox review | 239 re-infarction if it occurs early and for estimation of infarct size.58 however, some of the more recent studies have questioned the value of these early markers (h-fabp and myoglobin) when compared with specific markers like ctni.59-60 l i m i tat i o n s a n d f u t u r e d i r e c t i o n s o f h-fa b p m e a s u r e m e n t s heart-type fabp exists in high concentrations in the heart only. however, this protein is not totally cardiac specific and occurs in other tissues although in much lower concentrations.57 it is present in skeletal muscles in concentrations varying between 0.05-0.2 mg/g wet weight of tissue, depending on the muscle fibre type studied.61 it has also been reported in very low concentrations in tissues like the kidney, aorta, testes, mammary glands, placenta, brain, adrenal glands, adipose tissue, and stomach.57 heart-type fabp is secreted by the kidney and circulates for a longer time (> 25 hours) after ami in the presence of renal failure. gorski et al. reported that h-fabp and myoglobin concentrations were both significantly elevated in patients with renal failure. the concentrations of these markers were not affected by dialysis.62 we have also shown that the efficiency of h-fabp for the diagnosis of ami is severely limited in patients with renal failure.63 skeletal muscle damage during the course of ami, e.g. intramuscular injections, electric cardioversion and traumatic cardiopulmonary resuscitation, may result in the leakage of h-fabp and this could interfere with the results of the assays.64 diagnosis of ami in these groups of patients using h-fabp alone can be difficult. h-fabp is increased in the plasma of healthy volunteers after strenuous exercise.65 surgery (both cardiac and non-cardiac) causes elevation of h-fabp concentration. h-fa b p a n d m y o g l o b i n myoglobin and h-fabp share many key features: 1) low molecular weight proteins (17 and 15kda, respectively); 2) abundant concentrations in the cytosol of myocardial cells; 3) substrate for mitochondrial oxidation (oxygen and fatty acids, respectively and 4) both are released within 2 hours after symptom onset, peak early (6 hours) and return to normal baseline concentration within 24 hours. both proteins are present in the heart and skeletal muscle in different concentrations. the concentration of myoglobin in heart and skeletal muscle is 2.5 and 4.0mg/g wet weight of tissue, respectively. the h-fabp concentration in heart and skeletal muscle is 0.5 and 0.05-0.2 mg/g wet weight of tissue, respectively. the myoglobin content of skeletal muscle is twice that of the heart. the h-fabp content of skeletal muscle is only 10-50% of that of the heart. the normal plasma concentration of h-fabp (< 5µg/l) is 10 to 15-fold lower than that of myoglobin (30-80µg/l). h-fabp is therefore more cardio-specific than myoglobin. the normal ratio of myoglobin: h-fabp in the myocardium is about 1:5, whereas the ratio in skeletal muscle is in the order of 21:70 (depending on muscle type).66 the main disadvantage of myoglobin and h-fabp as early markers of myocardial injury is their lack of total specificity due to their presence in skeletal muscle. because both proteins are released into plasma after injury at about the same time and in a ratio similar to the protein’s concentration in the tissue of origin, the measurement of the myoglobin: h-fabp ratio could be a useful index for discrimination between cardiac and skeletal muscle damage. a myoglobin: h-fabp ratio that is around 1:5 is considered to be specific for the heart and a ratio that is between 21:70 is more specific to skeletal muscle damage.64 the ratio has been reported by some investigators to increase the diagnostic specificity for the diagnosis of ami more than relying on either marker alone. however, the use of this ratio should not be a rigid criterion as overlaps do occur. some investigators did not support additional value over the measurement of h-fabp alone.64,67 cardiac troponins the troponin complex is found on the thin filament (actin) of all types of striated muscle (fast, slow, and cardiac). its function is to regulate calcium dependent contraction of muscles. there are three types of troponins: tnt, tni and tnc. they are designated with a letter that refers to the function of the troponin protein; tnc binds calcium; tni inhibits the action of the enzyme actomyosin adenosine triphosphatase; tnt binds to tropomyosin.68 they are called isoforms and have a pre-fix to indicate the muscle type they are in e.g. ctnt, stnt, ftnt stand for cardiac muscle, slow twitch skeletal muscle, and fast twitch skeletal muscle tnt respectively. cardiac tnt has more tissue distribution and more free cytoplasmic cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 240 | squ medical journal, december 2009, volume 9, issue 3 concentration and is released as a complex with the other cardiac troponin t-i-c. cardiac tni is released more in the binary form (troponin i-c complex).69 each troponin protein within these muscles has a different molecular weight, different amino acids, and an amino acid sequence unique to that muscle type. the different isoforms of tnt and tni share between 40-55% of amino acid sequence homology.70 c a r d i a c t r o p o n i n t a n d a c u t e m y o c a r d i a l i n fa r c t i o n cardiac-tnt (34 kda) was first introduced in 1989 as a marker for ami.71 the upper limit for ctnt has been reported as < 0.1µg/l, but concentrations between 0.03-0.1µg/l may also have significance as markers of an adverse outcome.72 cardiac-tnt appears in the serum within 12 hours after symptom onset in patients with ami. it shows similar release kinetics to ck-mb and ctni, and thus does not provide an earlier detection for ami than ckmb or ctni within the first 6 hours after symptom onset.73 once in the circulation, it persists for a long time (2-3 weeks) after symptom onset. the halflife of ctnt in circulation is 120 minutes and this long diagnostic window is thought to be due to the continuous release of the marker from myocardial cells after necrosis, and not due to slow clearance from the circulation.74 the clinical sensitivity of ctnt for the diagnosis of ami approaches 100% at about 12 hours after symptom onset and remains elevated at 100% for at least 4 days.74 u n s ta b l e a n g i n a a n d i n c r e a s e d c a r d i a c t r o p o n i n t (n o n-s t e l e vat i o n m i) unstable angina/non-st elevation mi carries significant morbidity and mortality risks and early detection and treatment are essential to minimise complications.75 cardiac-tnt has been shown to be elevated in patients with non-st elevation mi and the magnitude of elevation can be used for diagnostic purposes, risk stratification, and for selection of appropriate patient groups for treatment. elevated ctnt in patients with non-st elevation mi is associated with poor prognosis.76 the increase correlates well with the severity of coronary artery lesions determined by angiography.77 in one important study, the prognostic value of ctnt was assessed in 967 patients with unstable angina. it was found that the group that had elevated concentrations of ctnt had an increased risk of cardiac events and the higher the ctnt the more frequent the complications. patients were followedup for 6 months for cardiac complications. the risk of further ami and death was 4.3% in patients with ctnt less than 0.06µg/l and 16.1% for those with ctnt equal or greater than 0.18µg/l.78 in another study by stubbs et al., 62 non-st elevation mi patients were followed-up for about three years after their admission with ctnt concentration greater or equal to 0.2 ng/ml. the incidence of complications in this group was very high: cardiac death (12 patients), coronary revascularisation (22 patients), death and non-fatal ami (18 patients).79 cardiac-tnt measurement can help select the appropriate patients for treatment with antithrombotics. treatment of non-st elevation mi patients with thrombolytic therapy had not been found to be useful.80 however, treatment of non-st elevation mi with antiplatelet and antithrombotic drugs like aspirin, clopidogrel, low molecular weight heparin (lmwh) and glycoprotein iib/iiia (gp iib/iiia) receptor antagonist was associated with 30% reduction in the incidence of mortality and ami.81 those patients with ctnt < 0.1 ng/ ml fared equally well whether they were treated by lmwh, deltaparin or a placebo (4.7 versus 5.7% x 40 day mortality respectively). however, patients with ctnt greater than or equal to 0.1ng/ ml had reduced ami and mortality if they received deltaparin rather than a placebo (7.4 versus 14.2% respectively).82s p e c i f i c i t y o f c a r d i a c t r o p o n i n t a s s ay s elevated ctnt concentration has been reported in a significant numbers of patients with chronic renal failure. these levels do not seem to be affected by haemodialysis, with elevations persisting after treatment.83 in chronic kidney disease patients on haemodialysis without acute coronary syndrome, ctni was reported to have better sensitivity and specificity for the diagnosis of ami compared with ctnt, but positive ctnt was associated with increased all cause mortality during follow up.84-85 vigorous exercise, e.g. marathon runners; rhabdomyolysis; inflammatory muscle disease, e.g. polymyositis and dermatomyositis, and degenerative muscle disease, e.g. duchenne/becker hafidh a al-hadi and keith a fox review | 241 muscular dystrophy, have been reported to show elevated concentrations of ctnt.86 high ctnt and ctni concentrations have been reported in critically ill patients who had not been diagnosed with comorbid ami.87 blunt trauma to the chest, closed heart massage, external defibrillation is also reported to result in elevation of ctnt.88 elevations have also been reported in cases of myocarditis and drug induced cardiac toxicity.89,90 elevated troponin levels (i and t) occur in some patients with acute pulmonary embolism and this elevation has been associated with a high risk of short-term death and an adverse outcome events.91 the advantage of the ctnt immunoassay is that currently it is marketed by one source only hence there are well-established standards in terms of reference range, detection limits, and clinical cut-off concentrations. there is however, a slightly higher rate of positive results with ctnt assays in some patients with chronic renal failure and acute or chronic muscle disease.86,92 c a r d i a c t r o p o n i n i a n d a c u t e m y o c a r d i a l i n fa r c t i o n cardiac-tni (24 kda) is reported to have a unique segment containing 31 amino acids that makes it different to either stni or ftni (19 kda). during foetal development both stni and ctni are expressed in the myocardium; however, at birth, the ctni remains as the only isoform present in the human myocardium.93 cardiac-tni has not been shown to be expressed in any type of skeletal muscle during either development or disease stimuli.94 this makes ctni 100% specific for the myocardial tissue and an excellent marker for the detection of myocardial injury in serum. cardiactni was first reported as a biochemical marker of myocardial injury in 1992 and has since been shown to be a very sensitive and specific marker for the diagnosis of ami. it has similar release kinetics to ck-mb and to ctnt and does not provide an earlier detection for ami within the first 6 hours after symptom onset.95 cardiac-tni peaks between 1236 hours after onset of ami and remains elevated for 3-7 days after ami. the half-life of ctni is < 2 hours and the prolonged diagnostic window is due to the continuous release of this marker from the myofibril. c a r d i a c t r o p o n i n i a n d n o n-s t e l e vat i o n m i cardiac-tni is cardiac specific and its concentration in normal and disease free populations is undetectable or very low. this makes it a suitable marker for the detection of myocardial injury in patients with non-st elevation mi as well as other situations where myocardial injury is expected, but the amount released could be small, e.g. following pci.96 many studies have also shown ctni to have prognostic value in patients with non-st elevation mi similar to that of ctnt. those patients showing higher levels at admission have more complications increased mortality and ami on subsequent follow-up.97 the prognostic risk in these patients is significantly altered if early intervention (pharmacological and invasive) is undertaken in these patients compared to conservative treatment. s p e c i f i c i t y o f c a r d i a c t r o p o n i n i a s s ay s cardiac-tni was not found in patients who underwent uncomplicated angioplasty.98 in patients with chest trauma, cocaine associated chest pain, and hypothyroidism where ck and ck-mb were elevated, ctni was able to distinguish true myocardial injury from cases with false elevation. in marathon runners, more than 80% of samples were positive for ck-mb and in all of these samples ctni was negative. cardiac-tni was found to be significantly elevated (43%) in patients with bacteraemia.99 the main problem with ctni is that there are several commercial assays available, and each assay differs with respect to reference range, detection limit, and medical decision cut-off limits. thus, there is a lack of standardisation of methodology for ctni assays. however, ctni has been reported to show slightly better specificity in situations where there is severe skeletal muscle injury and renal failure.84,85 s p e c i f i c i t y o f c a r d i a c t r o p o n i n s f o l l o w i n g s u r g e r y cardiac-tni was not elevated in patients who underwent non-cardiac surgery, but was raised in patients undergoing cabg due to surgical injury of the myocardium. cardiac-tni or ctnt may be the preferred markers of choice to detect myocardial injury in patients who undergo non-cardiac surgery. in the situation of non-cardiac surgery, ctni (or ctnt), being specific to the myocardium, will also cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 242 | squ medical journal, december 2009, volume 9, issue 3 help to distinguish elevation of ck-mb due to skeletal muscle damage alone from elevation due to myocardial injury.100 conclusion the markers that are well suited for the early diagnosis of ami within the time interval 0-6 hours after symptom onset are myoglobin, h-fabp and ck-mb isoforms. although all have been shown to be excellent sensitive early markers, there are still significant issues concerning its specificity. h-fabp is more cardio-specific than myoglobin and the use of h-fabp as a marker for the early diagnosis of ami seems preferable. ck-mb mass measurement is suitable in the 6-24 hours interval; ck-mb based on activity measurement is more sensitive in the 12-24 hours interval, and the other cardiac markers like total ck, ctnt, and ctni are most reliable after 12 hours from symptom onset. the prolonged diagnostic window of cardiac troponins of several days that is highly sensitive and specific obviates the needs for less specific markers with long diagnostic window like aspertate aminotransferase (alt) and ck. decision-making regarding triage and treatment of patients should not be based on a single measurement of cardiac markers alone because of the time delay required for the marker to exceed the upper limit of reference range. based on the recent recommendations by the esc/ acc, ctni and ctnt are the best markers for the confirmation of ami. ck-mb (preferably mass) is the second best marker in the absence of troponins assays. patients who present with acute chest pain suspicious of acs are best managed within specifically designated units that have rapid access to specific equipment (ecg, echocardiogram) and facilities (point of care instruments to measure cardiac markers), and with appropriate staffing. acute chest pain units attached to emergency departments can accommodate patients for 12 hours, so that appropriate investigations can be carried out quickly after presentation in order to identify patients with evolving infarction who are at increased risk. a serial combination testing of a sensitive early marker (e.g. h-fabp, myoglobin or ck-mb isoforms) and one of the cardiac specific troponins (ctnt or ctni) offers the best approach. two serial testings within a minimum of 12 hours (e.g. at 0 hour, 4-6 hours, or at 12 hours) after symptom onset provide reliable sensitivity and specificity for detecting ischaemia and evolving infarction within the time interval required for the implementation of reperfusion therapy. this 12 hour strategy also identifies patients at low-risk for acute ischaemic events. references 1. sans s, kesteloot h, kromhout d. the burden of cardiovascular disease mortality in europe. task force of the european society of cardiology on cardiovascular mortality and morbidity statistics in europe. eur heart j 1997; 18:1231-48. 2. ericsson cg, lindvall b, olsson g. trends in coronary care. a retrospective study of patients with myocardial infarction treated in coronary care units. acta med scand 1988; 224:507-13. 3. nomenclature and criteria for diagnosis of ischemic heart disease. report of the joint international society and federation of cardiology/world health organization task force on standardization of clinical nomenclature. circulation 1979; 59:607-9. 4. alpert js, thygesen k. myocardial infarction redefined a consensus document of the joint european society of cardiology/american college of cardiology committee for the redefinition of myocardial infarction. eur heart j 2000; 21:1502-13. 5. cohn pf. silent myocardial ischemia. ann intern med 1989; 109:312-17. 6. gibler wb, lewis lm, erb re, makens pk, kaplan bc, vaughan rh, et al. early detection of acute myocardial infarction in patients presenting with chest pain and nondiagnostic ecg’s: serial ck-mb sampling in the emergency department. ann emerg med 1990; 19:1359-66. 7. stark me, vacek jl. the initial electrocardiogram during admission for myocardial infarction. use as a predictor of clinical course and facility utilization. arch intern med 1987; 147:843-6. 8. adams je 3rd, abendschein dr, jaffe as. biochemical markers of myocardial injury. is mb creatine kinase the choice for the 1990s? circulation 1993; 88:75063. 9. hedges jr, rouan gw, toltzis r, goldstein-wayne b, stein ea. use of cardiac enzymes identifies patients with acute myocardial infarction otherwise unrecognized in the emergency department. ann emerg med 1987; 16:248-52. 10. van blerk m, maes v, huyghens l, derde mp, meert r, gorus fk. analytical and clinical evaluation of creatine kinase mb mass assay by imx: comparison with mb isoenzyme activity and serum myoglobin for early diagnosis of myocardial infarction. clin chem 1992; 38:2380-6. hafidh a al-hadi and keith a fox review | 243 11. de winter rj, koster rw, sturk a, sanders gt. value of myoglobin, troponin t, and ck-mb mass in ruling out an acute myocardial infarction in the emergency room. circulation 1995; 92:3401-7. 12. apple fs, henry td, berger cr, landt ya. early monitoring of serum cardiac troponin i for assessment of coronary reperfusion following thrombolytic therapy. am j clin pathol 1996; 105:6-10. 13. henderson ar, bhayana v. a modest proposal for the consistent presentations of roc plots in clinical chemistry. clin chem 1995; 41:1205-6. 14. wu ahb. introduction to coronary artery disease (cad) and biochemical markers. in: wu ahb, ed. cardiac markers. totowa, nj: human press inc 1998. pp. 3-20. 15. perryman mb, strauss aw, buettner tl, roberts r. molecular heterogeneity of creatine kinase isoenzymes. biochim biophys acta 1983; 747:28490. 16. duma rj, seigel al. serum creatine phosphokinase in acute myocardial infarction. arch intern med 1965; 115:443-51. 17. pierce gf, jaffe as. increased creatine kinase mb in the absence of acute myocardial infarction. clin chem 1986; 32:2044-51. 18. wu ahb. creatine kinase, isoenzymes, and variants in: wu ahb, ed. cardiac markers. totowa, nj: humana press inc, 1998. pp.113-20. 19. sasse ea, madiedo g, kopenski w. evaluation of abbott imx: ck-mb immunoassay. clin chem 1990; 36:1858-9. 20. delanghe jr, de mol am, de buyzere ml, de scheerder ik, weime rj. mass concentration and activity concentration of creatine kinase isoenzyme mb compared in serum after acute myocardial infarction. clin chem 1990; 36:149-53. 21. bakker aj, gorgels jp, van vlies b, haagen fd, smits r. the mass concentrations of serum troponin t and creatine kinase-mb are elevated before creatine kinase and creatine kinase-mb activities in acute myocardial infarction. eur j clin chem 1993; 31:71524. 22. venta r, geijo sa, sanchez ac, bao cg, bartolome la, casares g, et al. iga-ck-bb complex with ckmb electrophoretic mobility can lead to erroneous diagnosis of acute myocardial infarction. clin chem 1989; 35:2003-8. 23. irvin rg, cobb fr, roe cr. acute myocardial infarction and mb creatine phosphokinase. relationship between onset of symptoms of infarction and appearance and disappearance of enzyme. arch intern med 1980; 140:329-34. 24. gibler wb, young gp, hedges jr, lewis lm, smith ms, carleton sc, et al. acute myocardial infarction in chest pain patients with nondiagnostic ecgs: serial ck-mb sampling in the emergency department. the emergency medicine cardiac research group. ann emerg med 1992; 21:504-12. 25. ravkilde j, hansen ab, horder m, jorgensen pj, thygesen k. risk stratification in suspected acute myocardial infarction based on a sensitive immunoassay for serum creatine kinase isoenzyme mb. a 2.5 year follow-up study in 156 consecutive patients. cardiology 1992; 80:143-51. 26. seo h, miyazaki s, furuno t. creatine kinase-mb protein mass is a better indicator for the assessment of acute myocardial infarction in the lower range of creatine kinase level. jpn heart j 1993; 34:717-27. 27. pettersson t, ohlsson o, tryding n. increased ck-mb (mass concentration) in patients without traditional evidence of acute myocardial infarction. a risk indicator of coronary death. eur heart j 1992; 13:1387-92. 28. ravkilde j, nissen h, mickley h, andersen pe, thayssen p, horder m. cardiac troponin-t and ck-mb mass release after visually successful percutaneous transluminal coronary angioplasty in stable angina pectoris. am heart j 1994; 127:13-20. 29. abbas sa, glazier jj, wu ah, dupont c, green sf, pearsall la, et al. factors associated with the release of cardiac troponin t following percutaneous transluminal coronary angioplasty. clin cardiol 1996; 19:782-86. 30. sasse ea, madiedo g, kopenski w. evaluation of abbott imx: ck-mb immunoassay. clin chem 1990; 36:1858-9. 31. wevers ra, delsing m, klein gebbink ja, soons jb. post-synthetic changes in creatine kinase isoenzymes (ec 2.7.3.2). clin chim acta 1978; 86:323-7. 32. hendriks d, soons j, scharpe s, wevers r, van sande m, holmquist b. identification of the carboxypeptidase responsible for the post-synthetic modification of creatine kinase in human serum. clin chim acta 1988; 172:253-60. 33. hossein-nia m, kallis p, brown pa, chester mr, kaski jc, murday aj, et al. creatine kinase mb isoforms: sensitive markers of ischemic myocardial disease. clin chem 1994; 40:1265-71. 34. puleo pr, guadagno pa, roberts r, scheel mv, marian aj, churchill d, et al. early diagnosis of acute myocardial infarction based on assay for subforms of creatine kinase-mb. circulation 1990; 82:759-64. 35. puleo pr, meyer d, wathen c, tawa cb, wheeler s, hamburg rj, et al. use of a rapid assay of subforms of creatine kinase-mb to diagnose or rule out acute myocardial infarction. n engl j med 1994; 331:561-6. 36. zimmerman j, fromm r, meyer d, boudreaux a, wun cc, smalling r, et al. diagnostic marker cooperative study for the diagnosis of myocardial infarction. circulation 1999; 99:1671-7. 37. laurino jp, bender ew, kessimian n, chang j, pelletier t, usategui m. comparative sensitivities and specificities of mass measurements of ck-mb2, ckcardiac markers in the early diagnosis and management of patients with acute coronary syndrome 244 | squ medical journal, december 2009, volume 9, issue 3 mb, and myoglobin for diagnosing acute myocardial infarction. clin chem 1996; 42:1454-9. 38. bhayana v, cohoe s, leung fy, jablonsky g, henderson ar. diagnostic evaluation of creatine kinase-2 mass and creatine kinase-3 and -2 isoform ratios in early diagnosis of acute myocardial infarction. clin chem 1993; 39:488-95. 39. davies j, reynolds t, penney md. creatine kinase isoforms: investigation of inhibitors of in vitro degradation and establishment of a reference range. ann clin biochem 1992; 29:202-5. 40. schweisfurth h, pickert e, gramer e, reiners c. alterations of carboxypeptidases n activities in patients with thyroid dysfunction. clin biochem 1987; 20:43-6. 41. wu ah, wang xm, gornet tg, ordonez-llanos j. creatine kinase mb isoforms in patients with skeletal muscle injury: ramifications for early detection of acute myocardial infarction. clin chem 1992; 38:2396-400. 42. van nieuwenhoven fa, kleine ah, wodzig kw, hermens wt, kragten ha, maessen jg, et al. discrimination between myocardium and skeletal muscle injury by assessment of the plasma ratio of myoglobin over fatty acid-binding protein. circulation 1995; 92:2848-54. 43. kagen l, scheidt s, roberts l, porter a, paul h. myoglobinemia following acute myocardial infarction. am j med 1975; 58:177-82. 44. bhayana v, cohoe s, pellar tg, jablonsky g, henderson ar. combination (multiple) testing for myocardial infarction using myoglobin, creatine kinase-2 (mass), and troponin t. clin biochem 1994; 27:395-406. 45. vaidya hc. myoglobin: an early biochemical marker for the diagnosis of acute myocardial infarction. j clin immunoassay 1994; 17:35-9. 46. varki ap, roby ds, watts h, zatuchni. serum myoglobin in acute myocardial infarction: a clinical study and review of the literature. am heart j 1978; 96:680-8. 47. collins r, tucker j. myoglobin and ck-mb for the diagnosis of acute myocardial infarction in emergency room patients. clin chem 1991; 37:978. 48. anderson hv, willerson jt. thrombolysis in acute myocardial infarction. n engl j med 1993; 329:703-9. 49. ishii j, nomura m, ando t, hasegawa h, kimura m, kurokawa h, et al. early detection of successful coronary reperfusion based on serum myoglobin concentration; comparison with serum creatine kinase isoenzyme mb activity. am heart j 1994; 128:641-8. 50. zabel m, honloser sh, koster w, prinz m, kasper w, just h. analysis of creatine kinase, ck-mb, myoglobin and troponin t time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. circulation 1993; 87:1542-50. 51. miyata m, abe s, arima s, nomoto k, kawataki m, ueno m, et al. rapid diagnosis of coronary reperfusion by measurement of myoglobin level every 15 min in acute myocardial infarction. j am coll cardiol 1994; 23:1009-15. 52. glatz jf, van bilsen m, paulussen rj, veerkamp jh, van der vusse gj, reneman rs, et al. release of fatty acid-binding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox. biochim biophys acta 1988; 961:148-52. 53. ishii j, wang jh, naruse h, taga s, kinoshita m, kurokawa h, et al. serum concentrations of myoglobin vs human heart-type cytoplasmic fatty acid-binding protein in early detection of acute myocardial infarction. clin chem 1997; 43:1372-8. 54. alhadi ha, fox ka. do we need additional markers of myocyte necrosis: the potential value of heart fatty acid-binding protein. qjm 2004; 97:187-98. 55. glatz jf, van der vusse gj, maessen jg, van dieijenvisser mp, hermens wt. fatty acid-binding protein as marker of muscle injury: experimental finding and clinical application. acta anaesthesiol scand suppl 1997; 111:292-4. 56. kleine ah, glatz jf, van nieuwenhoven fa, van der vusse gj. release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. mol cell biochem 1992; 116:155-62. 57. bakker aj, koelemay mj, gorgels jp, van vlies b, smits r, tijssen jg, et al. failure of new biochemical markers to exclude acute myocardial infarction at admission. lancet 1993; 342:1220-2. 58. colli a, jossa m, pomar jl, mestres ca, gharli t. heart fatty acid binding proteins in diagnosis of myocardial infarction: where do we stand now? cardiology 2007; 108:4-10. 59. alansari se, croal bl. diagnostic value of heart fatty acid binding protein and myoglobin in patients admitted with chest pain. ann clin biochem 2004; 41:391-6. 60. iiva t, lund j, poreta p, mustonen h, voipio-pulkki lm, eriksson s, et al. early markers of myocardial injury: ctni is enough. clinica chimica acta 2009; 400:82-5. 61. crisman ts, claffey kp, saouaf r, hanspal j, brecher p. measurement of rat heart fatty acid-binding protein by elisa. tissue distribution, developmental changes and subcellular distribution. j mol cell cardiol 1987; 19:23-31. 62. gorski j, hermens wt, borawski j, mysliwiec m, glatz jf. increased fatty acid-binding protein concentration in plasma of patients with chronic renal failure. clin chem 1997; 43:193-5. 63. alhadi ha, william b, fox ka. serum level of heart fatty acid binding protein in patients with chronic renal failure. squ med j 2009; 9:311-13. hafidh a al-hadi and keith a fox review | 245 64. van nieuwenhoven fa, kleine ah, wodzig kw, hermens wt, kragten ha, maessenn jg et al. discrimination between myocardium and skeletal muscle injury by assessment of the plasma ratio of myoglobin over fatty acid-binding protein. circulation 1995; 92:2848-54. 65. sorichter s, mair j, kollar a, pelsers mm, puschendorf b, glatz jf. early assessment of exercise induced skeletal muscle injury using plasma fatty acid binding protein. br j sports med 1998; 32:121-4. 66. glatz jf, van der vusse gj, maessen jg, van dieijenvisser mp, hermens wt. fatty acid-binding protein as marker of muscle injury: experimental finding and clinical application. acta anaesthesiol scand suppl 1997; 111:292-4. 67. ishii j, wang jh, naruse h, taga s, kinoshita m, kurokawa h et al. serum concentrations of myoglobin vs human heart-type cytoplasmic fatty acid-binding protein in early detection of acute myocardial infarction. clin chem 1997; 43:1372-8. 68. greaser ml, gergely j. purification and properties of the components from troponin. j biol chem 1973; 248:2125-33. 69. wu ah, feng yj. biochemical differences between ctnt and ctni and their significance for diagnosis of acute coronary syndromes. eur heart j 1999; 19 suppl: n25-n29. 70. dhoot gk, frearson n, perry sv. polymorphic forms of troponin t and troponin c and their localization in striated muscle cell types. exp cell res 1979; 122:339-50. 71. katus ha, remppis a, looser s, hallermeier k, scheffold t, kubler w. enzyme linked immuno assay of cardiac troponin t for the detection of acute myocardial infarction in patients. j mol cell cardiol 1989; 21:1349-53. 72. muller-bardorff m, hallermayer k, schroder a, ebert c, borgya a, gerhardt w, et al. improved troponin t elisa specific for cardiac troponin t isoform: assay development and analytical and clinical validation. clin chem 1997; 43:458-66. 73. gerhardt w, ljungdahl l, herbert a. troponin t and ck-mb (mass) in early diagnosis of ischemic myocardial injury. the helsingborg study, 1992. clin biochem 1993; 26:231-40. 74. wu ah, valdes r jr, apple fs, gornet t, stone ma, mayfield-stokes s, et al. cardiac troponin-t immunoassay for diagnosis of acute myocardial infarction. clin chem 1994; 40:900-7. 75. hugenholtz pg. unstable angina revisited once more. eur heart j 1986; 7:1010-15. 76. ohman em, armstrong pw, christenson rh, granger cb, katus ha, hamm cw et al. cardiac troponin t levels for risk stratification in acute myocardial ischemia. gusto iia investigators. n engl j med 1996; 335:1333-41. 77. jurlander b, farhi er, banas jj jr, keany cm, balu d, grande p, et al. coronary angiographic findings and troponin t in patients with unstable angina pectoris. am j cardiol 2000; 85:810-14. 78. lindahl b, venge p, wallentin l. relation between troponin t and the risk of subsequent cardiac events in unstable coronary artery disease. the frisc study group. circulation 1996; 93:1651-7. 79. stubbs p, collinson p, moseley d, greenwood t, noble m. prospective study of the role of cardiac troponin t in patients admitted with unstable angina. bmj 1996; 13:262-4. 80. schreiber tl, rizik d, white c, sharma gv, cowlev m, macina g, et al. randomized trials of thrombolysis versus heparin in unstable angina. circulation 1992; 86:1407-14. 81. fox ka. acute coronary syndromes: presentationclinical spectrum and management. heart 2000; 84:93-100. 82. lindahl b, venge p, wallentin l. troponin t identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic treatment. fragmin in unstable coronary artery disease (frisc) study group. j am coll cardiol 1997; 29:43-8. 83. li d, jialal i, keffer j. greater frequency of increased cardiac troponin t than increased cardiac troponin i in patients with chronic renal failure. clin chem 1996; 42:114-15. 84. needham dm, shufelt ka, tomlinson g, scholey jw, newton ge. troponin i and t levels in renal failure patients without acute coronary syndrome: a systematic review of the literature. can j cardiol 2004; 20:1212-18. 85. khan na, hemmelgarn br, tonell m, thompson cr, levin a. prognostic value of troponin t and i among asymptomatic patients with end-stage renal disease: a meta-analysis. circulation 2005; 112:308896. 86. kobayashi s, tanaka m, tamura n, hashimoto h, hirose s. serum cardiac troponin t in polymyositis/ dermatomyositis. lancet 1992; 340:726. 87. guest tm, ramanathan av, tuteur pg, schechtman kb, ladenson jh, jaffe as. myocardial injury in critically ill patients: a frequently unrecognized complication. jama 1995; 273:1945-9. 88. grubb nr, fox ka, cawood p. resuscitation from out-of-hospital cardiac arrest: implications for cardiac enzyme estimation. resuscitation 1996; 33:35-41. 89. lauer b, niederau c, kuhl u, schannwell m, pauschinger m, strauer be, et al. cardiac troponin t in patients with clinically suspected myocarditis. j am coll cardiol 1997; 30:1354-9. 90. herman eh, lipshultz se, rifai n, zhang j, papoian t, yu zx, et al. use of cardiac troponin t levels as an indicator of doxorubicin-induced cardiotoxicity. cancer res 1998; 58:195-7. cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 246 | squ medical journal, december 2009, volume 9, issue 3 91. becattini c, vedovati mc, agnelli g. prognostic value of troponin in acute pulmonary embolism: a meta-analysis. circulation 2007; 116:427-33. 92. agezew y. elevated serum cardiac troponin in nonacute coronary syndrome. clin cardiol 2009; 32:1520. 93. sasse s, brand nj, kyprianou p, dhoot gk, wade r, arai m, et al. troponin i gene expression during human cardiac development and in end-stage heart failure. circ res 1993; 72:932-8. 94. bodor gs, porterfield d, voss em, smith s, apple fs. cardiac troponin-i is not expressed in adult human skeletal muscle tissue. clin chem 1995; 41:1710-15. 95. adams je 3rd, schechtman kb, landt y, ladenson jh, jaffe as. comparable detection of acute myocardial infarction by creatine kinase mb isoenzyme and cardiac troponin i. clin chem 1994; 40:1291-5. 96. genser n, mair j, talasz h, puschendorf b, puschendorf b, calzolari c, et al. cardiac troponin i to diagnose percutaneous transluminal coronary angioplasty-related myocardial injury. clin chim acta 1997; 265:207-17. 97. galvani m, ottani f, ferrini d, ladenson jh, destro a, baccos d, et al. prognostic influence of elevated values of cardiac troponin i in patients with unstable angina. circulation 1997; 95:2053-9. 98. hunt ac, chow sl, shiu mf, chilton dc, cummins b, cummins p. release of creatine kinase-mb and cardiac specific troponin-i following percutaneous transluminal coronary angioplasty. eur heart j 1991; 12:690-4. 99. kalla c, raveh d, algur n, rudensky b, yinnon am, ballan j. incidence and significance of a positive troponin test in bacteremic patients without acute coronary syndrome. am j med 2008; 121:909-15. 100. adams je 3rd, sicard ga, allen bt, bridwell kh, lenke lg, davilla-roman vg, et al. diagnosis of perioperative myocardial infarction with measurement of cardiac troponin i. n engl j med 1994; 330:670-4. التهوية غري الباضعة وعالج قنيات األنف ذات التدفق العايل لألطفال املصابني بالفشل التنفسي احلاد استعراض عام خلود �شعيد املخينية و جنوى مرهون الرحبية abstract: noninvasive ventilation (niv) refers to the use of techniques to deliver artificial respiration to the lungs without the need for endotracheal intubation. as niv has proven beneficial in comparison to invasive mechanical ventilation, it has become the optimal modality for initial respiratory support among children in respiratory distress. high-flow nasal cannulae (hfnc) therapy is a relatively new niv modality and is used for similar indications. this review discusses the usefulness and applications of conventional niv in comparison to hfnc. keywords: noninvasive ventilation; nasal cannulae; endotracheal intubation; mechanical ventilation; children. امللخ�ص: التهوية غري البا�شعة ت�شري اإىل ا�شتخدام تقنيات لتوفري التنف�ص ال�شطناعي للرئتني دون احلاجة اىل التهوية امليكانيكية. مبا اأن تقنية التهوية غري البا�شعة اأثبتت فائدتها باملقارنة مع التهوية امليكانيكية البا�شعة، فقد اأ�شبحت الطريقة املثلى للدعم التنف�شي الأويل لالأطفال الذين يعانون من �شيق التنف�ص. يعترب عالج القنيات الأنفية ذات التدفق العايل من الطرق اجلديدة ن�شبيًا للتهوية غري عالج مع باملقارنة التقليدية البا�شعة غري التهوية واإ�شتخدامات فوائد املراجعة هذه تناق�ص مماثلة. لتطبيقات وي�شتخدم البا�شعة القنيات الأنفية ذات التدفق العايل. الكلمات املفتاحية: التهوية غري البا�شعة؛ قنيات اأنفية؛ تنبيب الرغامى؛ التهوية امليكانيكية؛ الأطفال. noninvasive ventilation and high-flow nasal cannulae therapy for children with acute respiratory failure an overview *khaloud s. al-mukhaini and najwa m. al-rahbi review sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e278–285, epub. 19 dec 18 submitted 5 feb 18 revisions req. 28 mar & 27 may 18; revisions recd. 1 may & 9 jun 18 accepted 21 jun 18 department of child health, royal hospital, muscat, oman *corresponding author’s e-mail: kholoud_saeed@hotmail.com doi: 10.18295/squmj.2018.18.03.003 the use of noninvasive devices in the treatment of acute respiratory distress has inc-reased in paediatric care over the last decade.1 noninvasive ventilation (niv) includes the use of an interface to support breathing, thus avoiding invasive procedures like endotracheal intubation.2 techniques for niv include continuous positive airway pressure (cpap), bilevel positive airway pressure (bpap) and, more recently, high-flow nasal cannulae (hfnc).1,3 this article discusses conventional niv in comparison with hfnc therapy. conventional noninvasive ventilation various adult and paediatric studies have demonstrated the advantages of conventional niv modalities, such as reducing the need for invasive mechanical ventilation and, therefore, its associated complications.2,4–6 in an adult randomised controlled trial (rct), antonelli et al. found that niv resulted in a reduced risk of pneumonia and sinusitis; moreover, pulmonary gas exchange resulted in similar effects to invasive mech anical ventilation within the first hour of treatment.2 yañez et al. reported similar findings among 50 children with respiratory failure, in which the niv group demonstrated significant improvement following gas exchange within the first hour as well as a reduced need for intubation.4 in other studies, niv use has reduced the length of intensive care unit (icu) stay.5,6 furthermore, niv has economic advantages over conventional mechanical ventilation, as most children undergoing invasive mechanical ventilation require icu admission and additional interventions, thereby increasing the overall cost of treatment.7 over time, niv has become the first line of treatment for paediatric respiratory distress in many countries.1,5,8 moreover, in view of the advantages of this modality, its khaloud s. al-mukhaini and najwa m. al-rahbi review | e279 use has been adopted not only in specialised paediatric icus but also in general emergency departments, transport teams and general wards, although trained staff and proper equipment are still necessary.9 m e c h a n i s m o f a c t i o n cpap involves the use of continuous distending pressure applied to the airway at a constant level.10,11 on the other hand, bpap delivers two different types of pressure during inspiration and expiration, respectively.11 both cpap and expiratory positive airway pressure during bpap allow for the relief of upper airway obstruction and lung recruitment resulting in enhanced gas exchange, thereby reducing ventilation-perfusion mismatching and improving oxygenation and carbon dioxide (co2) clearance.10,11 in addition, bpap devices have the option of a backup rate to ensure a minimum respiratory rate is maintained in cases where respiratory effort is inadequate. essouri et al. reported the physiological effects of niv in children presenting with acute respiratory failure; the study showed that children receiving niv had signif icantly improved work of breathing (wob) as well as blood gas results and inspiratory muscle effort.12 additionally, oesophageal and diaphragmatic pressure-time products dropped with niv treatment, while measured tidal volume and minute ventilation increased.12 c l i n i c a l i n d i c at i o n s a n d a p p l i c at i o n s for infants and children presenting with acute respiratory distress and secondary respiratory failure, niv is the first line of treatment to improve gas exchange, avoid invasive ventilation and prevent extubation failure. ganu et al. reported an annual 2.8% increase in niv use among bronchiolitis patients over a nine-year period, with an annual 1.9% drop in the rate of invasive ventilation.5 both wolfler et al. and essouri et al. have reported similar declines in the rate of invasive mechanical ventilation corresponding to an increase in niv use.8,13 different success rates with niv use have been reported for various clinical diseases. essouri et al. and abadesso et al. reported overall success rates of 77% and 77.5%, respectively, among paediatric patients receiving niv for different causes of respiratory distress.13,14 however, children admitted with acute respiratory distress syndrome (ards) has less favourable outcomes compared to those admitted with pneumonia, sickle cell disease presenting with acute chest syndrome and immunocompromised patients presenting with acute respiratory failure.13 in two other studies of infants treated for bronchiolitis, the niv success rate was 81–83%.5,15 children with asthma also reportedly respond well to niv treatment, with improvements in wob and asthma severity scores.16 in addition, niv is also indicated in the prevention of postextubation respiratory failure, either pro phylactically for children at high risk of extubation failure or to treat those with postextubation respiratory distress or failure. in a recent study, the niv success rate was higher when utilised prophylactically in comp arison to its use as a rescue treatment.17 in addition, niv resulted in an overall success rate of 85% in the postextubation period among children receiving treatment after open heart surgery.18 children with underlying malignancies who present with acute respiratory failure are also candidates for niv. however, careful patient selection is required as therapy usually fails for cases with a more severe clinical course, signif icant pulmonary disease or haemodynamic instability.19 the niv success rate among children with ards and substantial acute lung injuries is between 30–50%.20 therefore, it is highly advised that children with ards are closely monitored when niv is initiated so that any deterioration in their respiratory state can be immediately addressed. furthermore, niv is recommended early during the ards disease process in order to avoid muscle fatigue from the increase in wob and to improve gas exchange.20 table 1 provides a summary of selected studies investigating niv use in children.4,8,14,19 i n t e r fa c e c h o i c e a wide range of interfaces are available for niv therapy, including helmets, full-face masks, oronasal masks, nasal masks and nasal cannulae. for children, the choice of interface plays an important role in affecting their niv tolerance. in general, most interfaces are effective in reducing wob and improving gas exchange.21 an ideal niv interface is one that is comfortable, does not cause claustrophobia, has minimal leakage and results in the least patient-ventilator asynchrony. nasal masks are generally better tolerated and have less dead space than other types of interfaces. in addition, children are often better able to communicate and thus more comfortable. however, the use of nasal masks is limited in children due to air leaking through the mouth.22,23 in contrast, full-face or oronasal masks result in minimal leakage and ventilator patient asynchrony, although patients can experience intolerance and discomfort.24 differences in leakage, side-effects and asynchrony with different niv interfaces are not well described in the literature. the british thoracic society recommends having different sizes and types of niv interfaces available to ensure treatment success.25 m o n i t o r i n g a n d p r e d i c t i n g r e s p o n d e r s although niv use is primarily advised for children with respiratory distress, it is also recommended to differnoninvasive ventilation and high-flow nasal cannulae therapy for children with acute respiratory failure an overview e280 | squ medical journal, august 2018, volume 18, issue 3 entiate those who respond to treatment from non-resp onders so as to avoid delaying intubation, if necessary, thus worsening patient outcomes.20 specific predictors of niv failure include worsening vital signs (e.g. respiratory rate and heart rate) following niv treatment, the presence of isolated respiratory disease versus multiple organ dysfunction and the oxygen saturation (spo2)/ fraction of inspired oxygen (fio2) ratio. 26–30 the spo2/fio2 ratio is used as a clinical indicator for hypoxaemia, with a lower ratio indicating greater severity.26 children with more severe disease upon admission are at increased risk of niv failure.27 physiological parameters before treatment have also been linked to treatment failure, with responders showing improved respiratory rates, heart rates and blood gas results.28 in particular, response to niv therapy is demonstrated by improved respiratory rates one hour after treatment, with continued improvement in subse quent hours.29 likewise, responders’ heart rates have shown improvement 2–6 hours following the intervention.30 in contrast, a higher fio2 requirement and lower spo2/fio2 ratio within one hour of treatment has been associated with treatment failure.26–28,30 finally, children with underlying respiratory disease alone are less likely to fail niv treatment compared to children with other comorbidities, such as underlying malignancies.27,29 high-flow nasal cannulae hfnc therapy delivers a humidified oxygen and gas mixture heated to approximately 34 °c, allowing higher air flow rates exceeding 2 l/minute.3,31,32 these features enable the delivery of air flow equal to or greater than the inspiratory flow of a spontaneously breathing patient.31 hfnc also has the ability to generate distending pressure.3,31 over the last decade, the use of hfnc has increased among neonates, infants, children and adults for various clinical indications.31–33 long et al. showed that, in a paediatric population presenting with respiratory failure, hfnc had a success rate of 61% when initiated in the emergency department.34 m e c h a n i s m o f a c t i o n hfnc works via different mechanisms to improve oxy genation and ventilation and reduce wob. moreover, hfnc reduces nasopharyngeal dead space due to the effect of the high flow on nasopharyngeal oxygen-depleted gas, leading to co2 clearance. 3 hfnc improves oxygenation as it provides higher fio2 compared to conventional oxygen therapy. additionally, as the gas flow is humidified and warmed, this modality improves lung compliance, reduces airway resistance and aids in secretion clearance.3,31 depending on the patient’s weight, the hfnc flow and the size of the nasal cannulae compared to the nares, hfnc is associated with the generation of positive end-expiratory pressure (peep).35 the amount of generated peep is also affected by the degree of leakage via the mouth.35,36 an early study of preterm babies suggested that hfnc can generate positive distending pressure similar to that of cpap and therefore treat apnoea of prematurity.37 in a neonate, a flow rate of 3–5 l/minute is equivalent to cpap at 6 cm of water (h2o), with effective distending pressure. 35,38 moreover, during hfnc, inspiratory pressure remains positive throughout the breathing cycle. milési et al. measured oesophageal pressures at different flow rates, with a pharyngeal pressure of 0.2 cm of h2o at 1 l/minute increasing to 4 cm of h2o at 6–7 l/minute. 39 overall, table 1: summary of selected studies evaluating the use of noninvasive ventilation in children4,8,14,19 author and year of study study design and period mode of niv patients clinical results yañez et al.4 (2008) prospective rct (2005) bpap 50 children admitted to the picu with respiratory distress • the rate of intubation in the niv group was 28% compared to 60% in the control group wolfler et al.8 (2015) national multicentre observational retrospective study (2011–2012) cpap and bpap 7,100 children admitted to the picu with respiratory failure • the use of niv increased from 11.6% in 2006 to 14.3% in 2011 and 18.2% in 2012 abadesso et al.14 (2012) observational prospective study (2006–2010) cpap and bpap 151 children with respiratory distress • the overall niv success rate was 77.5% pancera et al.19 (2008) observational retrospective study (1997–2005) bpap 239 children admitted to the picu with underlying malignancies and presenting with respiratory failure • the overall niv success rate was 74% • predictors of niv failure included cardiovascular dysfunction and a tiss of >40 points niv = noninvasive ventilation; rct = randomised controlled trial; bpap = bilevel positive airway pressure; picu = paediatric intensive care unit; cpap = continuous positive airway pressure; tiss = therapeutic intervention scoring system. khaloud s. al-mukhaini and najwa m. al-rahbi review | e281 no universal equivalence exists between pressure and flow rate; therefore, close monitoring of the patient remains a necessity. c l i n i c a l i n d i c at i o n s a n d a p p l i c at i o n s the use of hfnc has broad indications, including different causes of respiratory distress. overall, hfnc is most commonly used among children with bronchiol itis and pneumonia.40 frat et al. found that the use of hfnc in hypoxic respiratory failure reduced the intubation rate to 38%, leading to a greater number of ventilation-free days in an icu.41 roca et al. showed that hfnc reduced the need for mechanical ventilation among patients with respiratory failure post-lung transplant.42 kawaguchi et al. conducted a retrospective study evaluating intubation rates in a group of children presenting with respiratory distress.43 this study showed reduced intubation rates among children receiving hfnc in comparison to those who did not receive hfnc (38% versus 63%), with more ventilator-free days in the former group. however, no differences were observed in terms of mortality rate or paediatric icu (picu) length of stay.43 in a cochrane review evaluating the effectiveness of hfnc among children with bronchiolitis, a single pilot study with 19 participants was identified comparing hfnc with oxygen delivery via a headbox; however, there was insufficient evidence to determine the effectiveness of hfnc for treating bronchiolitis.44 nevertheless, a recent multicentre rct comparing the outcomes of infants with bronchiolitis treated with low-flow oxygen or hfnc showed that there was a reduced need for escalation of care among the group receiving hfnc.45 in addition, schlapbach et al. evaluated the safety of hfnc while transporting ill children between hospitals.46 the majority of these children had respiratory conditions requiring admission to a picu, of which 77% were diagnosed with bronchiolitis. overall, the intubation rate decreased from 49% to 35% (p <0.001), with none of the hfnc patients requiring intubation, developing pneumothorax or going into cardiac arrest.46 two other studies similarly noted a reduction in intubation rates among infants admitted with bronchiolitis following the intro duction of hfnc in picus (37% versus 7% and 23% versus 9%, respectively).47,48 various studies investigating hfnc use in children and adults are presented in table 2.41,45,49–52 in spain, two rcts involving seven adult icus were conducted to assess the effect of using hfnc in the postextubation period on the incidence of reintubation and respiratory failure in highand low-risk patients, respectively.49,50 in the first trial, high-risk patients who passed spontaneous breathing trials randomly received either hfnc or conventional niv while, in the second trial, low-risk patients randomly received either hfnc or conventional oxygen therapy.49,50 table 2: summary of selected studies evaluating the use of high-flow nasal cannulae in children and adults41,45,49–52 author and year of study study design and period patients clinical results frat et al.41 (2015) randomised multicentre open-label trial (2011–2013) 310 adult patients with acute hypoxaemic respiratory failure with a pao2/fio2 ratio of <300 mmhg • the rate of intubation in the hfnc group was 38% compared to 50% in the niv group and 47% in the standard oxygen therapy group franklin et al.45 (2018) multicentre rct (2013–2016) infants below 12 months with bronchiolitis • the need to escalate care was higher in the group receiving low-flow oxygen therapy compared to the hfnc group hernández et al.49 (2016) multicentre randomised clinical trial (2012–2014) 604 critically-ill adult patients admitted to the icu who were at high risk of extubation with respiratory failure • hfnc was not inferior to niv in preventing extubation failure and post-extubation respiratory failure among high-risk patients hernández et al.50 (2016) multicentre randomised clinical trial (2012–2014) 527 critically-ill adult patients admitted to the icu who were at low risk of reintubation • hfnc was superior to conventional oxygen therapy in preventing reintubation among low-risk patients pedersen et al.51 (2017) retrospective study (2013–2015) 49 infants with severe bronchiolitis • when compared to hfnc, cpap was more effective in reducing respiratory distress • overall, 55% of infants being treated with hfnc had to switch treatment to cpap milési et al.52 (2017) multicentre rct (2014–2015) 142 infants admitted to picus with moderateto-severe bronchiolitis • nasal cpap is more effective than hfnc in initial supportive treatment for infants with moderate-to-severe bronchiolitis pao2 = partial pressure of arterial oxygen; fio2 = fraction of inspired oxygen; hfnc = high-flow nasal cannulae; niv = noninvasive ventilation; rct = randomised controlled trial; icu = intensive care unit; cpap = continuous positive airway pressure; picus = paediatric intensive care units. noninvasive ventilation and high-flow nasal cannulae therapy for children with acute respiratory failure an overview e282 | squ medical journal, august 2018, volume 18, issue 3 no difference was found between the two modalities in terms of preventing reintubation or postextubation respiratory failure among high-risk patients.49 however, in low-risk patients, hfnc was superior to conventional oxygen therapy in reducing the risk of reintubation within a 72-hour period.50 a d va n ta g e s a n d l i m i tat i o n s for infants, hfnc therapy is well tolerated, therefore reducing the need for sedation. furthermore, the humidified oxygen improves secretion clearance.3 among adults, hfnc minimises mouth dryness and is generally perceived to be more comfortable.53 spentzas et al. assessed the comfort of 46 children with respiratory distress at 60–90 minutes and 8–12 hours following hfnc therapy and found that comfort significantly improved following hfnc use.40 generally, hfnc use has been demonstrated to be safe with few reported complications. in 2005, there was an outbreak of ralstonia mannitolilytica infections due to contaminated hfnc devices (vapotherm inc., exeter, new hampshire, usa), which were subsequently withdrawn from the market.54 in addition, three cases of serious air leak syndrome have been reported.33 nevertheless, the over-all risk of air leak syndrome with hfnc is no higher than that of low-flow oxygen.45 m o n i t o r i n g a n d p r e d i c t i n g r e s p o n d e r s as with niv, certain clinical features can predict the response to hfnc therapy. for example, children with improved respiratory distress and heart rates are likely to be responders to hfnc therapy.55 moreover, fio2 requirements and illness severity are predictors of response to treatment. accordingly, children with high spo2/fio2 ratios—indicating milder forms of lung injuries—and those with lower respiratory rates are likely to respond to therapy.35 roca et al. conducted a four-year multicentre prospective observational cohort study to assess possible predictors of hfnc failure, in which the respiratory rate oxygenation (rox) index (i.e. the ratio of pulse oximetry/fio2 to respiratory rate) was used to assess therapy success.56 at a cut-off value of ≥4.88, the rox index 12 hours after the initiation of hfnc therapy yielded a sensitivity of 70% and specificity of 72.4% in predicting successful treatment for patients with pneumonia.56 clinical indicators for hfnc therapy failure include a lack of improvement in oxygenation, thoraco abdominal asynchrony and the presence of haemodynamic and neurological impairment.42,57,58 according to oto et al., a drop in heart or respiratory rate and improvement in the mean dyspnoea score 30 minutes and 12 hours after the initiation of hfnc are indicative of successful treatment.55 in a cohort of 113 infants with bronchiolitis undergoing hfnc therapy, abboud et al. observed that a higher paediatric risk of mortality score—which indicates illness severity upon admission to the icu—as well as an elevated co2 level before treatment were predictors of treatment failure.59 the study also emphasised that non-improvement in wob was noted among the non-responders.59 comparison of therapies early studies have shown that the effectiveness of hfnc is similar to cpap, with comparable effects on wob, oxygenation and gas exchange.37,60 the advantages of the hfnc system include the easy setup and increase in the child’s comfort.34,40 in general, hfnc therapy is safe and associated complications, as described earlier, are uncommon. likewise, niv treatment is safe, with dry eyes, dry mouth, claustrophobia and pressure effects on the areas of the face covered by the mask being the most common complications.22 recently, several studies have assessed clinical out comes among children receiving cpap and hfnc therapy. pedersen et al. reviewed clinical outcomes among a historical cohort of 49 infants admitted with severe bronchiolitis and treated with cpap or hfnc.51 in both groups, respiratory rate declined with treatment; however, improvements in respiratory distress were faster with cpap treatment. moreover, in 55% of children, the mode of treatment was changed from hfnc to cpap due to an increase in respiratory distress.51 additionally, a multicentre rct evaluated the clinical outcomes of infants presenting with mod erate-to-severe bronchiolitis, comparing cpap treatment at a peep level of 7 cm of h2o to hfnc therapy at a rate of 2 l/minute/kg.52 only 5.7% of the infants required intubation, with the rest managed using either hfnc or cpap. interestingly, 31% of the cpap group failed initial respiratory support compared to 50.7% of the hfnc group.52 the most common reason for failure in the cpap group was discomfort, while the hfnc group failed due to an increase in respiratory distress. in both groups, there was a crossover of treatment in cases of failure or intolerance to the initial support modality.52 an observational study by pilar et al. investigated the outcomes of children with asthma who were treated with hfnc or niv.61 the study showed no failure in the niv group, while respiratory support had to be changed to niv among 40% of children in the hfnc group, thus showing that cpap was associated with a more rapid improvement in respiratory distress.61 collectively speaking, while cpap and hfnc were both associated with improvement in respiratory khaloud s. al-mukhaini and najwa m. al-rahbi review | e283 distress, cpap was superior in treating children with significant respiratory distress. on the other hand, hfnc was associated with improved tolerance in comparison to niv.52 therefore, hfnc can be used to treat children presenting with milder or less severe forms of respiratory distress and in cases where patient discomfort is a concern. conclusion globally, niv treatment has become the first line of respiratory support for children and is safe and effective in the treatment of various causes of respiratory distress. however, healthcare practitioners should be aware of the various indicators or predictors of niv failure in order to avoid unwanted complications assoc iated with delayed invasive ventilation. hfnc therapy is a promising niv modality of respiratory support and is indicated for milder forms of respiratory distress. greater use of niv may reduce the number of referrals to icus as well as prevent complications resulting from invasive mechanical ventilation. references 1. ducharme-crevier l, essouri s, emeriaud g. noninvasive vent ilation in pediatric intensive care: from a promising to an established therapy, but for whom, when, why, and how? pediatr crit care med 2015; 16:481–2. doi: 10.1097/pcc.00000 00000000390. 2. antonelli m, conti g, rocco m, bufi m, de blasi ra, vivino g, et al. a comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. n engl j med 1998; 339:429–35. doi: 10.1056/ nejm199808133390703. 3. milési c, boubal m, jacquot a, baleine j, durand s, odena mp, et al. high-flow nasal cannula: recommendations for daily prac tice in pediatrics. ann intensive care 2014; 4:29. doi: 10.1186/ s13613-014-0029-5. 4. yañez lj, yunge m, emilfork m, lapadula m, alcántara a, fernández c, et al. a prospective, randomized, controlled trial of noninvasive ventilation in pediatric acute respiratory failure. pediatr crit care med 2008; 9:484–9. doi: 10.1097/pcc.0b013 e318184989f. 5. ganu ss, gautam a, wilkins b, egan j. increase in use of non-invasive ventilation for infants with severe bronchiolitis is associated with decline in intubation rates over a decade. intensive care med 2012; 38:1177–83. doi: 10.1007/s00134-0 12-2566-4. 6. keenan sp, sinuff t, cook dj, hill ns. does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? a systemic review. crit care med 2004; 32:2516–23. doi: 10.1097/01.ccm.0000148011.51681.e2. 7. essouri s, laurent m, chevret l, durand p, ecochard e, gajdos v, et al. improved clinical and economic outcomes in severe bronchiolitis with pre-emptive ncpap ventilator strategy. intensive care med 2014; 40:84–91. doi: 10.1007/s00134-013-3129-z. 8. wolfler a, calderini e, iannella e, conti g, biban p, dolcini a, et al. evolution of noninvasive mechanical ventilation use: a cohort study among italian picus. pediatr crit care med 2015; 16:418–27. doi: 10.1097/pcc.0000000000000387. 9. davies jd, gentile ma. what does it take to have a successful noninvasive ventilation program? respir care 2009; 54:53–61. 10. morley cj, davis pg. continuous positive airway pressure: scientific and clinical rationale. curr opin pediatr 2008; 20:119–24. doi: 10.1097/mop.0b013e3282f63953. 11. shaffer th, alapati d, greenspan js, wolfson mr. neonatal non-invasive respiratory support: physiological implications. pediatr pulmonol 2012; 47:837–47. doi: 10.1002/ppul.22610. 12. essouri s, durand p, chevret l, haas v, perot c, clement a, et al. physiological effects of noninvasive positive ventilation during acute moderate hypercapnic respiratory insufficiency in children. intensive care med 2008; 34:2248–55. doi: 10.1007/ s00134-008-1202-9. 13. essouri s, chevret l, durand p, haas v, fauroux b, devictor d. noninvasive positive pressure ventilation: five years of experience in a pediatric intensive care unit. pediatr crit care med 2006; 7:329–34. doi: 10.1097/01.pcc.0000225089.21176.0b. 14. abadesso c, nunes p, silvestre c, matias e, loureiro h, almeida h. non-invasive ventilation in acute respiratory failure in children. pediatr rep 2012; 4:e16. doi: 10.4081/pr.2012.e16. 15. javouhey e, barats a, richard n, stamm d, floret d. noninvasive ventilation as primary ventilatory support for infants with severe bronchiolitis. intensive care med 2008; 34:1608–14. doi: 10.1007/s00134-008-1150-4. 16. mayordomo-colunga j, medina a, rey c, concha a, menéndez s, arcos ml, et al. non-invasive ventilation in pediatric status asth maticus: a prospective observational study. pediatr pulmonol 2011; 46:949–55. doi: 10.1002/ppul.21466. 17. mayordomo-colunga j, medina a, rey c, concha a, menéndez s, los arcos m, et al. non invasive ventilation after extubation in paediatric patients: a preliminary study. bmc pediatr 2010; 10:29. doi: 10.1186/1471-2431-10-29. 18. fernández lafever s, toledo b, leiva m, padrón m, balseiro m, carrillo a, et al. non-invasive mechanical ventilation after heart surgery in children. bmc pulm med 2016; 16:167. doi: 10.1186/ s12890-016-0334-x. 19. pancera cf, hayashi m, fregnani jh, negri em, deheinzelin d, de camargo b. noninvasive ventilation in immunocompromised pediatric patients: eight years of experience in a pediatric oncology intensive care unit. j pediatr hematol oncol 2008; 30:533–8. doi: 10.1097/mph.0b013e3181754198. 20. pediatric acute lung injury consensus conference group. pediatric acute respiratory distress syndrome: consensus rec ommendations from the pediatric acute lung injury consensus conference. pediatr crit care med 2015; 16:428–39. doi: 10.1097/ pcc.0000000000000350. 21. fraticelli at, lellouche f, l’her e, taillé s, mancebo j, brochard l. physiological effects of different interfaces during noninvasive ventilation for acute respiratory failure. crit care med 2009; 37:939–45. doi: 10.1097/ccm.0b013e31819b575f. 22. pravinkumar se. a face that matters in distress: interface selection for acute noninvasive ventilation. crit care med 2009; 37:344–6. doi: 10.1097/ccm.0b013e318193050f. 23. argent ac. noninvasive ventilator support: the details lies in the interface. respir care 2015; 60:1708–10. doi: 10.4187/ respcare.04492. 24. chidini g, calderini e, cesana bm, gandini c, prandi e, pelosi p. noninvasive continuous positive airway pressure in acute respiratory failure: helmet versus facial mask. pediatrics 2010; 126;e330–6. doi: 10.1542/peds.2009-3357. 25. british thoracic society standards of care committee. noninvasive ventilation in acute respiratory failure. thorax 2002; 57:192–211. doi: 10.1136/thorax.57.3.192. 26. mayordomo-colunga j, pons m, lópez y, josé solana m, rey c, martinez-camblor p, et al. predicting non-invasive ventilation failure in children from the spo2/fio2 (sf) ratio. intensive care med 2013; 39:1095–103. doi: 10.1007/s00134-013-2880-5. https://doi.org/10.1097/pcc.0000000000000390 https://doi.org/10.1097/pcc.0000000000000390 https://doi.org/10.1056/nejm199808133390703 https://doi.org/10.1056/nejm199808133390703 https://doi.org/10.1186/s13613-014-0029-5 https://doi.org/10.1186/s13613-014-0029-5 https://doi.org/10.1097/pcc.0b013e318184989f https://doi.org/10.1097/pcc.0b013e318184989f https://doi.org/10.1007/s00134-012-2566-4 https://doi.org/10.1007/s00134-012-2566-4 https://doi.org/10.1097/01.ccm.0000148011.51681.e2 https://doi.org/10.1007/s00134-013-3129-z https://doi.org/10.1097/pcc.0000000000000387 https://doi.org/10.1097/mop.0b013e3282f63953 https://doi.org/10.1002/ppul.22610 https://doi.org/10.1007/s00134-008-1202-9 https://doi.org/10.1007/s00134-008-1202-9 https://doi.org/10.1097/01.pcc.0000225089.21176.0b https://doi.org/10.4081/pr.2012.e16 https://doi.org/10.1007/s00134-008-1150-4 https://doi.org/10.1002/ppul.21466 https://doi.org/10.1186/1471-2431-10-29 https://doi.org/10.1186/s12890-016-0334-x https://doi.org/10.1186/s12890-016-0334-x https://doi.org/10.1097/mph.0b013e3181754198 https://doi.org/10.1097/pcc.0000000000000350 https://doi.org/10.1097/pcc.0000000000000350 https://doi.org/10.1097/ccm.0b013e31819b575f https://doi.org/10.1097/ccm.0b013e318193050f https://doi.org/10.4187/respcare.04492 https://doi.org/10.4187/respcare.04492 https://doi.org/10.1542/peds.2009-3357 https://doi.org/10.1136/thorax.57.3.192 https://doi.org/10.1007/s00134-013-2880-5 noninvasive ventilation and high-flow nasal cannulae therapy for children with acute respiratory failure an overview e284 | squ medical journal, august 2018, volume 18, issue 3 27. james cs, hallewell cp, james dp, wade a, mok qq. predicting the success of non-invasive ventilation in preventing intubation and re-intubation in the paediatric intensive care unit. intensive care med 2011; 37:1994–2001. doi: 10.1007/s 00134-011-2386-y. 28. bernet v, hug mi, frey b. predictive factors for the success of noninvasive mask ventilation in infants and children with acute respiratory failure. pediatr crit care med 2005; 6:660–4. doi: 10.1097/01.pcc.0000170612.16938.f6. 29. mayordomo-colunga j, medina a, rey c, díaz jj, concha a, los arcos m, et al. predictive factors of non invasive ventilation failure in critically ill children: a prospective epidemiological study. intensive care med 2009; 35:527–36. doi: 10.1007/s00 134-008-1346-7. 30. muñoz-bonet ji, flor-macián em, brines j, roselló-millet pm, cruz llopis m, lópez-prats jl, et al. predictive factors for the outcome of noninvasive ventilation in pediatric acute respiratory failure. pediatr crit care med 2010; 11:675–80. doi: 10.10 97/pcc.0b013e3181d8e303. 31. lee jh, rehder kj, williford l, cheifetz im, turner da. use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of the literature. intensive care med 2013; 39:247–57. doi: 10.1007/s00134-012-2743-5. 32. frat jp, coudroy r, marjanovic n, thille aw. high-flow nasal oxygen therapy and noninvasive ventilation in the management of acute hypoxemic respiratory failure. ann transl med 2017; 5:297. doi: 10.21037/atm.2017.06.52. 33. hegde s, prodhan p. serious air leak syndrome complicating high-flow nasal cannula therapy: a report of 3 cases. pediatrics 2013; 131:e939–44. doi: 10.1542/peds.2011-3767. 34. long e, babl fe, duke t. is there a role for humidified heated high-flow nasal cannula therapy in paediatric emergency departments? emerg med j 2016; 33:386–9. doi: 10.1136/ emermed-2015-204914. 35. dysart k, miller tl, wolfson mr, shaffer th. research in high flow therapy: mechanisms of action. respir med 2009; 103:1400–5. doi: 10.1016/j.rmed.2009.04.007. 36. sivieri em, gerdes js, abbasi s. effect of hfnc flow rate, cannula size, and nares diameter on generated airway pressures: an in vitro study. pediatr pulmonol 2013; 48:506–14. doi: 10.1002/ ppul.22636. 37. sreenan c, lemke rp, hudson-mason a, osiovich h. highflow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive air way pressure. pediatrics 2001; 107:1081–3. doi: 10.1542/peds. 107.5.1081. 38. mikalsen ib, davis p, øymar k. high flow nasal cannula in children: a literature review. scand j trauma resusc emerg med 2016; 24:93. doi: 10.1186/s13049-016-0278-4. 39. milési c, baleine j, matecki s, durand s, combes c, novais ar, et al. is treatment with a high flow nasal cannula effective in acute viral bronchiolitis? a physiologic study. intensive care med 2013; 39:1088–94. doi: 10.1007/s00134-013-2879-y. 40. spentzas t, minarik m, patters ab, vinson b, stidham g. child ren with respiratory distress treated with high-flow nasal cannula. j intensive care med 2009; 24:323–8. doi: 10.1177/088506660 9340622. 41. frat jp, thille aw, mercat a, girault c, ragot s, perbet s, et al. high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. n eng j med 2015; 372:2185–6. doi: 10.1056/ nejmoa1503326. 42. roca o, de acilu mg, caralt b, sacanell j, masclans jr; icu collaborators. humidified high flow nasal cannula supportive therapy improves outcomes in lung transplant recipients readmitted to the intensive care unit because of acute respiratory failure. transplantation 2015; 99:1092–8. doi: 10.1097/tp. 0000000000000460. 43. kawaguchi a, yasui y, decaen a, garros d. the clinical impact of heated humidified high-flow nasal cannula on pediatric respiratory distress. pediatr crit care med 2017; 18:112–19. doi: 10.10 97/pcc.0000000000000985. 44. beggs s, wong zh, kaul s, ogden kj, walters ja. high-flow nasal cannula therapy for infants with bronchiolitis. cochrane database syst rev 2014; 1:cd009609. doi: 10.1002/14651858. cd009609.pub2. 45. franklin d, babl fe, schlapbach lj, oakley e, craig s, neutze j, et al. a randomized trial of high-flow oxygen therapy in infants with bronchiolitis. n engl j med 2018; 378:1121–31. doi: 10.10 56/nejmoa1714855. 46. schlapbach lj, schaefer j, brady am, mayfield s, schibler a. high-flow nasal cannula (hfnc) support in interhospital trans port of critically ill children. intensive care med 2014; 40:592–9. doi: 10.1007/s00134-014-3226-7. 47. schibler a, pham tm, dunster kr, foster k, barlow a, gibbons k, et al. reduced intubation rates for infants after introduction of high-flow nasal prong oxygen delivery. intensive care med 2011; 37:847–52. doi: 10.1007/s00134-011-2177-5. 48. mckiernan c, chua lc, visintainer pf, allen h. high flow nasal cannulae therapy in infants with bronchiolitis. j pediatr 2010; 156:634–8. doi: 10.1016/j.jpeds.2009.10.039. 49. hernández g, vaquero c, colinas l, cuena r, gonzález p, canabal a, et al. effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial. jama 2016; 316:1565–74. doi: 10.1001/jama.2016.14194. 50. hernández g, vaquero c, gonzález p, subira c, frutos-vivar f, rialp g, et al. effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: a randomized clinical trial. jama 2016; 315:1354–61. doi: 10.1001/jama.2016.2711. 51. pedersen mb, vahlkvist s. comparison of cpap and hfnc in management of bronchiolitis in infants and young children. children (basel) 2017; 4:e28. doi: 10.3390/children4040028. 52. milési c, essouri s, pouyau r, liet jm, afanetti m, portefaix a, et al. high flow nasal cannula (hfnc) versus nasal continuous positive airway pressure (ncpap) for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized controlled trial (tramontane study). intensive care med 2017; 43:209–16. doi: 10.1007/s001 34-016-4617-8. 53. roca o, riera j, torres f, masclans jr. high-flow oxygen therapy in acute respiratory failure. respir care 2010; 55:408–13. 54. kubicka zj, limauro j, darnall ra. heated, humidified high flow nasal cannula therapy: yet another way to deliver continuous positive airway pressure? pediatrics 2008; 121:82–8. doi: 10.1542/ peds.2007-0957. 55. oto a, erdoğan s, boşnak m. oxygen therapy via high flow nasal cannula in pediatric intensive care unit. turk j pediatr 2016; 58:377–82. doi: 10.24953/turkjped.2016.04.005. 56. roca o, messika j, caralt b, garcía-de-acilu m, sztrymf b, ricard jd, et al. predicting success of high-flow nasal cannula in pneumonia patients with hypoxemic respiratory failure: the utility of the rox index. j crit care 2016; 35:200–5. doi: 10.10 16/j.jcrc.2016.05.022. 57. sztrymf b, messika j, bertrand f, hurel d, leon r, dreyfuss d, et al. beneficial effects of humidified high flow nasal oxygen in critical care patients: a prospective pilot study. intensive care med 2011; 37:1780–6. doi: 10.1007/s00134-011-2354-6. 58. rello j, pérez m, roca o, poulakou g, souto j, laborda c, et al. high-flow nasal therapy in adults with severe acute respiratory infection: a cohort study in patients with 2009 influenza a/h1n1v. j crit care 2012; 27:434–9. doi: 10.1016/j.jcrc.2012.04.006. https://doi.org/10.1007/s00134-011-2386-y https://doi.org/10.1007/s00134-011-2386-y https://doi.org/10.1097/01.pcc.0000170612.16938.f6 https://doi.org/10.1007/s00134-008-1346-7 https://doi.org/10.1007/s00134-008-1346-7 https://doi.org/10.1097/pcc.0b013e3181d8e303 https://doi.org/10.1097/pcc.0b013e3181d8e303 https://doi.org/10.1007/s00134-012-2743-5 https://doi.org/10.21037/atm.2017.06.52 https://doi.org/10.1542/peds.2011-3767 https://doi.org/10.1136/emermed-2015-204914 https://doi.org/10.1136/emermed-2015-204914 https://doi.org/10.1016/j.rmed.2009.04.007 https://doi.org/10.1002/ppul.22636 https://doi.org/10.1002/ppul.22636 https://doi.org/10.1542/peds.107.5.1081 https://doi.org/10.1542/peds.107.5.1081 https://doi.org/10.1186/s13049-016-0278-4 https://doi.org/10.1007/s00134-013-2879-y https://doi.org/10.1177/0885066609340622 https://doi.org/10.1177/0885066609340622 https://doi.org/10.1056/nejmoa1503326 https://doi.org/10.1056/nejmoa1503326 https://doi.org/10.1097/tp.0000000000000460 https://doi.org/10.1097/tp.0000000000000460 https://doi.org/10.1097/pcc.0000000000000985 https://doi.org/10.1097/pcc.0000000000000985 https://doi.org/10.1002/14651858.cd009609.pub2 https://doi.org/10.1002/14651858.cd009609.pub2 https://doi.org/10.1056/nejmoa1714855 https://doi.org/10.1056/nejmoa1714855 https://doi.org/10.1007/s00134-014-3226-7 https://doi.org/10.1007/s00134-011-2177-5 https://doi.org/10.1016/j.jpeds.2009.10.039 https://doi.org/10.1001/jama.2016.14194 https://doi.org/10.1001/jama.2016.2711 https://doi.org/10.3390/children4040028 https://doi.org/10.1007/s00134-016-4617-8 https://doi.org/10.1007/s00134-016-4617-8 https://doi.org/10.1542/peds.2007-0957 https://doi.org/10.1542/peds.2007-0957 https://doi.org/10.24953/turkjped.2016.04.005 https://doi.org/10.1016/j.jcrc.2016.05.022 https://doi.org/10.1016/j.jcrc.2016.05.022 https://doi.org/10.1007/s00134-011-2354-6 https://doi.org/10.1016/j.jcrc.2012.04.006 khaloud s. al-mukhaini and najwa m. al-rahbi review | e285 59. abboud pa, roth pj, skiles cl, stolfi a, rowin me. predictors of failure in infants with viral bronchiolitis treated with highflow, high-humidity nasal cannula therapy*. pediatr crit care med 2012; 13:e343–9. doi: 10.1097/pcc.0b013e31825b546f. 60. de klerk a. humidified high-flow nasal cannula: is it the new and improved cpap? adv neonatal care 2008; 8:98–106. doi: 10.1097/01.anc.0000317258.53330.18. 61. pilar j, modesto i alapont v, lopez-femandez ym, lopezmacias o, garcia-urabayen d, amores-hernandez i. high-flow nasal cannula therapy versus non-invasive ventilation in children with severe acute asthma exacerbation: an observational cohort study. med intensiva 2017; 41:418–24. doi: 10.1016/j.medine.20 17.01.001. https://doi.org/10.1097/pcc.0b013e31825b546f https://doi.org/10.1097/01.anc.0000317258.53330.18 https://doi.org/10.1016/j.medine.2017.01.001 https://doi.org/10.1016/j.medine.2017.01.001 1department of public health & policy, university of liverpool, liverpool, uk; 2department of child health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: ahmed30411@gmail.com تفسري مؤشرات منو املواليد يف عمان هل يتم بالشكل الصحيح؟ رمي عبد الرحيم، اأحمد بابكر اإدري�ض، اأ�صد الرحمن، حممد عبد اللطيف، نايجل فلر abstract: objectives: this study aimed to compare reference anthropometric measures of omani neonates with the international standard growth charts of the world health organization (who) in order to determine the appropriateness of these growth charts to assess the growth of omani neonates. methods: this cross-sectional study included all healthy full-term omani neonates born between november 2014 and november 2015 at the sultan qaboos university hospital, muscat, oman. birth weight, length and head circumference measurements were identified and compared to those of the 2006 who growth charts. results: a total of 2,766 full-term neonates were included in the study, of which 1,401 (50.7%) were male and 1,365 (49.3%) were female. mean birth weights for omani males and females were 3.16 ± 0.39 kg and 3.06 ± 0.38 kg, respectively; these were significantly lower than the who standard measurements (p <0.001). similarly, the mean head circumferences of omani males and females (33.8 ± 1.27 cm and 33.3 ± 1.26 cm, respectively) were significantly lower than those reported in the who growth charts (p <0.001). in contrast, mean lengths for omani males and females (52.0 ± 2.62 cm and 51.4 ± 2.64 cm, respectively) were significantly higher than the who standard measurements (p <0.001). conclusion: the who growth charts might not be appropriate for use with omani neonates; possible alternatives should therefore be considered, such as national growth charts based on local data. keywords: anthropometry; growth charts; neonates; world health organization; oman. امللخ�ص: الهدف: تهدف هذه الدرا�صة ملقارنة القيا�صات املرجعية لنمو املواليد العمانيني بالر�صوم البيانية القيا�صية ال�صادرة عن منظمة املواليد جميع ت�صم م�صتعر�صة درا�صة هذه الطريقة: العمانيني. املواليد منو لتقييم الر�صوم تلك منا�صبة مدى لتحديد العاملية ال�صحة الأ�صحاء مكتملي النمو والذين ولدوا يف الفرتة ما بني نوفمرب 2014 و ونوفمرب 2015 يف م�صت�صفى جامعة ال�صلطان قابو�ض، م�صقط، عمان. ال�صحة ملنظمة القيا�صية البيانية الر�صوم على لها املقابلة بالقيم قورنت ثم ومن الراأ�ض وحميط والطول، الولدة، عند الوزن حتديد مت العاملية لعام 2006. النتائج: �صملت الدرا�صة 2,766 مولودا كامل النمو، وكان 1,401 )%50.7( منهم ذكورا و 1,365 )%49.3( منهم اإناثا. وكان متو�صط الوزن عند الولدة للذكور والإناث ي�صاوي 0.39 ± 3.16 كجم و 0.38 ± 3.06 كجم، على التوايل؛ وكانت هذه القيم اأقل ب�صكل �صم و كبري من القيم القيا�صية ملنظمة ال�صحة العاملية )p >0.001(. وباملثل، كان متو�صط حميط الراأ�ض للذكور والإناث )1.27 ± 33.8 1.26 ± 33.3 �صم، على التوايل( اأقل ب�صكل كبري من القيم القيا�صية ملنظمة ال�صحة العاملية )p >0.001(. وعلى العك�ض من ذلك، كانت قيم متو�صط الطول للذكور والإناث )2.62 ± 52.0 �صم و 2.64 ± 51.4 �صم، على التوايل( اأعلى ب�صكل كبري من القيم القيا�صية ملنظمة ال�صحة العاملية )p >0.001(. اخلال�صة: قد ل تكون الر�صوم البيانية القيا�صية ملنظمة ال�صحة العاملية مالئمة لتقييم منو املواليد العمانيني، وعليه ينبغي النظر يف البدائل املمكنة، كر�صوم بيانية وطنية مبنية على بيانات حملية. الكلمات املفتاحية: القيا�صات الب�رشية؛ الر�صوم البيانية للنمو؛ املواليد؛ منظمة ال�صحة العاملية؛ عمان. interpreting neonatal growth parameters in oman are we doing it right? reem m. abdulrahim,1 *ahmed b. idris,2 asad ur-rahman,2 mohamed abdellatif,2 nigel fuller1 clinical & basic research sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e411–417, epub. 10 jan 18 submitted 17 jul 17 revision req. 7 sep 17; revision recd. 10 oct 17 accepted 26 oct 17 advances in knowledge the results of this study revealed that full-term omani neonates have significantly lower birth weights and head circumferences and greater lengths than the international standards reported in the world health organization (who) 2006 growth charts. application to patient care this study provides preliminary evidence that the who standard growth charts might not be the best tool to assess the growth of fullterm omani neonates, indicating potential gaps in the interpretation of anthropometric measurements. based on these findings, clinicians are advised to balance the use of international growth charts with a degree of well-informed clinical judgment in order to help reduce unnecessary clinic visits, investigations, costs and parental anxiety. doi: 10.18295/squmj.2017.17.04.006 anthropometry is the quantitative assessment of an individual’s physical dimensions which, in combination with age and gender, can subsequently be used to assess growth status.1 neonatal anthropometric measurements—such as birth weight, height and head circumference—are considered rapid, reliable and feasible indicators of fetal intrauterine and postnatal growth, as well as interpreting neonatal growth parameters in oman are we doing it right? e412 | squ medical journal, november 2017, volume 17, issue 4 predictors of potential shortand long-term health complications.2 in turn, any significant deviation from normal anthropometric values may be associated with increased perinatal morbidity and mortality.3 in combination with gestational age, birth weight helps to group newborns into small for gestational age (sga), appropriate for gestational age and large for gestational age (lga) categories, according to a normal distribution curve for weight in which the 10th and 90th percentiles mark infants as either sga or lga, respectively.4 neonates who are sga are subject to extensive clinical interventions and investigations and are likely to have congenital abnormalities, while lga newborns are prone to a wide range of neo natal complications such as respiratory distress, hypo glycaemia and polycythaemia.3,5 additionally, head circumference values below the third percentile (i.e. microcephaly) might indicate serious genetic or acquired health problems.6 two types of growth charts are regularly used to assess neonatal anthropometric measurements. while reference charts merely describe the growth patterns of a certain population, standard charts apply strict inclusion and exclusion criteria to determine the optimal growth of children in favourable socioeconomic and health conditions.7 internationally, the most widely used growth charts are the standard charts developed by the world health organization (who) which describe growth in optimal conditions.8 these charts were developed as a result of the multicentre growth reference study (mgrs) in which six countries participated, including oman.9 currently, oman has no specific national growth charts and the 2006 who standard charts have been adopted to assess the growth of omani neonates.10 however, marked variation in the interpretation of child growth measurements can occur depending on the growth chart used.11 the potential misclassification of healthy children as having growth abnormalities has critical public health implications, particularly in terms of the burden on future healthcare management. therefore, this study aimed to identify reference anthropometric measurements among omani neonates and compare these to the who international standards in order to determine the appropriateness of the who growth charts within the omani population. methods this retrospective cross-sectional study included all healthy full-term omani neonates born at the sultan qaboos university hospital (squh) in muscat, oman, between november 2014 and november 2015. only those neonates of omani nationality between 37–42 gestational weeks and born from singleton pregnancies were included. cases with significant maternal or neonatal illness were excluded. neonatal characteristics and anthropometric measurements, including gender, birth weight, length and head circumference, were obtained from the electronic hospital information system. gestational age was calculated according to dates of the mother’s last menstrual period and delivery. birth weight was measured using digital scales to a precision level of 0.001 kg. a regular measuring tape was used to measure length to a 0.1 cm precision level. head circumference to the nearest 0.1 cm was calculated using flexible non-stretchable tape. in terms of sample size, the who expert committee recommends including at least 200 individuals in each age and gender group in order to construct reference growth curves with sufficiently precise estimates.12 however, no standard approach exists to establish precision for each percentile. therefore, the omani reference data were taken from a single time point with precise estimates of weight, length and head circumference. a minimum of 200 male and 200 female neonates were considered sufficient to establish precision at the 10th and 90th percentiles within 0.1 of a standard deviation (sd), with the range between the 3rd and 97th percentiles considered to be four sds.13 the mean values and sds for birth weight, length and head circumference measurements were calculated for males and females separately. moreover, anthropometric measurements for the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentiles were also calculated. subsequently, the mean values and percentiles of the omani sample were compared to the standard measurements and percentiles reported in the 2006 who standard growth charts.14 data were analysed using the statistical package for the social sciences (spss) software, version 21.0 (ibm corp., armonk, new york, usa). mean values were compared using a student’s t-test calculator (graphpad software inc., la jolla, california, usa). percentiles were compared graphically by plotting the data points in a word document, version 2016 (microsoft inc., redmond, washington, usa). a p value of <0.050 was considered statistically significant. ethical approval for this study was obtained from the medical ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #1163). reem m. abdulrahim, ahmed b. idris, asad ur-rahman, mohamed abdellatif and nigel fuller clinical and basic research | e413 results a total of 4,867 neonates were born at squh during the study period. following application of the inclusion/exclusion criteria, there were 2,766 eligible mother-neonate pairs [figure 1]. while missing values were reported in the birth weight (0.4%), length (0.5%) and head circumference (0.5%) categories, the total percentage of missing data was considered acceptable at <5%.15 of the 2,766 neonates, 1,401 (50.7%) were male and 1,365 (49.3%) were female. table 1 shows the percentile values for birth weight, length and head circumference according to gender. for the male neonates, mean birth weight, length and head circumference values were 3.16 ± 0.39 kg, 52.0 ± 2.62 cm and 33.8 ± 1.27 cm, respectively. the same measurements for females were 3.06 ± 0.38 kg, 51.4 ± 2.64 cm and 33.3 ± 1.26 cm, respectively. both omani male and female neonates had significantly lower mean birth weights and head circumferences when compared to data from the standard who charts (3.30 ± 0.40 kg and 3.20 ± 0.40 kg, respectively, and 34.5 ± 1.20 cm and 33.9 ± 1.10 cm, respectively; p <0.001 each). in contrast, the mean length of omani male and female neonates was significantly higher than that indicated in the who charts (49.9 ± 1.89 cm figure 1: diagram showing the application of inclusion and exclusion criteria to determine the final sample used in the current study. squh = sultan qaboos university hospital. *including a variety of illnesses such as diabetes, hypertension, anaemia, asthma, bleeding disorders, infectious diseases and thyroid, renal, autoimmune, neurological and psychiatric problems. table 1: percentile values for birth weight, length and head circumference measurements among omani neonates born at the sultan qaboos university hospital, muscat, oman (n = 2,766) measurement percentile 3rd 10th 25th 50th 75th 90th 97th birth weight in kg males 2.47 2.69 2.89 3.14 3.41 3.68 3.95 females 2.36 2.56 2.79 3.07 3.31 3.55 3.77 length in cm males 48.0 49.0 51.0 52.0 54.0 55.0 56.0 females 47.0 49.0 50.0 52.0 53.0 54.0 56.0 head circumference in cm males 31.5 32.0 33.0 34.0 34.5 35.5 36.0 females 31.0 32.0 32.5 33.0 34.0 35.0 36.0 table 2: comparison of mean birth weight, length and head circumference measurements among omani neonates born at the sultan qaboos university hospital, muscat, oman (n = 2,766) with the 2006 world health organization standard growth charts14 measurement omani sample who standards 95% ci p value n mean ± sd se n mean ± sd se birth weight in kg males 1,401 3.16 ± 0.39 0.01 890 3.30 ± 0.40 0.01 0.107–0.173 <0.001 females 1,365 3.06 ± 0.38 0.01 838 3.20 ± 0.40 0.01 0.107–0.173 <0.001 length in cm males 1,401 52.0 ± 2.62 0.07 893 49.9 ± 1.89 0.06 1.901–2.298 <0.001 females 1,365 51.4 ± 2.64 0.07 842 49.1 ± 1.89 0.06 2.094–2.505 <0.001 head circumference in cm males 1,401 33.8 ± 1.27 0.03 890 34.5 ± 1.20 0.04 0.595–0.804 <0.001 females 1,365 33.3 ± 1.26 0.03 838 33.9 ± 1.10 0.04 0.496–0.703 <0.001 sd = standard deviation; se = standard error; who = world health organization; ci = confidence interval. interpreting neonatal growth parameters in oman are we doing it right? e414 | squ medical journal, november 2017, volume 17, issue 4 and 49.1 ± 1.89 cm; p <0.001) [table 2]. graphic representations of observed differences between the mean values for birth weight, length and head circumference are shown in figures 2–4. discussion the results of the current study raise concerns regarding the appropriateness of the who growth charts to assess the growth of omani neonates. according to the who, their charts are prescriptive, indicating that any difference between chart values and those observed in a given population is due to a deviation from normal growth within that population.16 the underlying theory behind this assumption is that 90% of genetic variations are attributable to differences between people from the same continent, while only 10% are attributable to differences across continents, thus justifying the international generalisability of results from studies such as the mgrs.9,17 nevertheless, some researchers have warned of the dangers of misinterpretations resulting from the 90/10% genetic variation figure 2: comparison of birth weight percentiles for (a) males and (b) females among omani neonates (dotted lines) born at the sultan qaboos university hospital, muscat, oman (n = 2,766) with the 2006 world health organization standard growth charts (continuous lines).14 reproduced and modified from the world health organization (public domain). figure 3: comparison of length percentiles for (a) males and (b) females among omani neonates (dotted lines) born at the sultan qaboos university hospital, muscat, oman (n = 2,766) with the 2006 world health organization standard growth charts (continuous lines).14 reproduced and modified from the world health organization (public domain). figure 4: comparison of head circumference percentiles for (a) males and (b) females among omani neonates (dotted lines) born at the sultan qaboos university hospital, muscat, oman (n = 2,766) with the 2006 world health organization standard growth charts (continuous lines).14 reproduced and modified from the world health organization (public domain). reem m. abdulrahim, ahmed b. idris, asad ur-rahman, mohamed abdellatif and nigel fuller clinical and basic research | e415 rule, stating that such analyses are based on certain randomly selected common alleles, thus making general assertions about genetic variation difficult to verify.18 there is existing evidence that inhabitants of the eastern mediterranean region have lower anthropometric measurements compared to international growth charts, while european individuals tend to have similar or even greater anthropometric measurements.19–23 in fact, an analysis of the data from each of the six mgrs sites in isolation indicates that oman and india had the lowest mean values for neonatal birth weight, length and head circumference in comparison to the other sites.9 as an example to showcase the variability of these measurements, mean values for birth weight, length and head circumference were 3.2 ± 0.4 kg, 49.2 ± 1.7 cm and 33.4 ± 1.0 cm, respectively, among omani neonates compared to 3.6 ± 0.5 kg, 50.4 ± 1.9 cm and 34.9 ± 1.2 cm, respectively, among norwegian neonates.9 according to the findings of the current study, differences in neonatal birth weight, length and head circumference were consistent across all percentile values, indicating an overestimation of growth insufficiency in the birth weight and head circumference categories and an underestimation of overgrowth in the length category. for example, 8.9% of the omani sample in the current study would be deemed to be sga using the who charts in comparison to only 3.3% when using a normal distribution curve. furthermore, according to the who chart, 10.4% of the omani sample had microcephaly compared to 2.5% when the sample’s normal distribution curve was applied. hence, utilisation of the who growth charts would potentially result in 201 and 220 neonates being misclassified as sga and microcephalic, respectively. such discrepancies can lead to the unnecessary expenditure of health resources and undue parental anxiety.24 when babies are diagnosed as being sga or having intrauterine growth restriction, a number of investigations are needed, including viral screening and serial ultrasound measurements.25 in addition, sophisticated investigations such as brain imaging and genetic testing are necessary for infants with microcephaly.6 according to internal financial sources at squh, the 421 aforementioned potential misdiagnoses would result in unnecessary interventions costing approximately usd $250,000–300,000. inconsistencies were noted in the length results compared to birth weight and head circumference findings in the current study. this can perhaps be attributed to the inaccuracy of the measurement instrument, as a measuring tape was used instead of a proper length board or infantometer, as per the who recommendations.26 the accuracy of tape measurement is questionable, with differences between tape and length board measuring techniques reaching up to 2.23 cm.27 this potential inaccuracy may have caused bias in the recorded length values, minimising the validity of the results.28 on the other hand, the findings of the present study may perhaps reflect accurate length measurements among omani neonates. another who study conducted to assess length/height disparities among the six mgrs sites found that, despite the homogeneity of the study sample, oman accounted for the majority of the negative height variances, with more positive values obtained once this site was excluded.29 the authors stated that this negative difference was attributable to short parental stature as a result of suboptimal economic conditions which would require several generations to improve.29 based on this supposition, it might be assumed that neonatal height has improved due to the country’s recent economic development, given that the gross domestic product has dramatically risen from usd $42.08 billion in 2007 to usd $81.03 billion in 2014.30 however, this assumption might not hold because this change should also have been reflected in improved birth weight and head circumference measurements as well. this study was based on data collected from a single centre, which potentially constitutes a major limitation. however, it is important to note that over 50% of the omani population live in the regions of muscat and al-batinah, both of which are served by squh.31 therefore, it is likely that the sample was nevertheless nationally representative. in addition, like all studies based on retrospective or secondary data, information about potential confounding variables may have been missed, such as socioeconomic class and smoking. such factors must be considered in future studies, although smoking is unlikely to have influenced the present results as its prevalence among adult omani females is very low (0.5%).32 future well-designed prospective studies with more rigorous methodologies are recommended in order to address the limitations of the present study and determine the need for national growth charts based on local reference data. alternatively, researchers in gulf cooperation council (gcc) countries are advised to collaborate in order to determine whether a unified gcc growth chart may be possible. as individuals from gcc countries have similar ethnicities, social norms, cultures and economies, future research may unveil potential similarities in child growth patterns within the region. finally, proper length assessment tools are needed at squh in order to establish a wellstructured anthropometric training protocol to ensure interpreting neonatal growth parameters in oman are we doing it right? e416 | squ medical journal, november 2017, volume 17, issue 4 the application of who recommendations.26 to this end, onsite reminder materials, regular assessments of staff competency and regular assessments of instrument accuracy and measurement reliability are also needed. conclusion from the findings of the current study, it appears that the standard 2006 who growth charts might not accurately reflect growth patterns among omani neonates. it is possible that such growth differences may continue into childhood, which will require further assessment of the appropriateness of childhood growth assessment tools. meanwhile, in the absence of an oman-specific neonatal growth assessment tool, clinicians are advised to account for potential discrepancies when using international growth assessment standards and to combine chart usage with well-informed clinical judgment. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. united nations children’s fund. section 3: measuring undernutrition in individuals. from: www.unicef.org/nutrition/ training/list.html accessed: oct 2017. 2. pereira-da-silva l. neonatal anthropometry: a tool to evaluate the nutritional status and predict early and late risks. in: preedy vr, ed. handbook of anthropometry: physical measures of human form in health and disease. new york, usa: springer, 2012. pp. 1079–104. 3. royal college of obstetricians and gynaecologists. greentop guideline no. 31: the investigation and management of the smallfor-gestational-age fetus. from: www.rcog.org.uk/globalassets/ documents/guidelines/gtg_31.pdf accessed: oct 2017. 4. cogill b. anthropometric indicators measurement guide. from: www.fantaproject.org/sites/default/files/resources/anth ropometry-2003-eng.pdf accessed: oct 2017. 5. mandy gt. large for gestational age newborn. from: www. uptodate.com/contents/large-for-gestational-age-newborn accessed: oct 2017. 6. woods g. microcephaly: a clinical genetics approach. from: w w w.upto date.com/content s/mic ro ce phaly -a-clinic algenetics-approach accessed: oct 2017. 7. zorlu g. new who child growth standards catch on. bull world health organ 2011; 89:250–1. doi: 10.2471/blt.11. 040411. 8. world health organization. the who child growth standards. from: www.who.int/childgrowth/en/ accessed: oct 2017. 9. who multicentre growth reference study group. enrolment and baseline characteristics in the who multicentre growth reference study. acta paediatr suppl 2006; 450:7–15. doi: 10. 1111/j.1651-2227.2006.tb02371.x. 10. oman ministry of health. new child growth standards: 2006 (world health organization). from: www.cdscoman.org/ uploads/cdscoman/newsletter%2015-3.pdf accessed: oct 2017. 11. rolland-cachera mf, péneau s. assessment of growth: variations according to references and growth parameters used. am j clin nutr 2011; 94:1794s–8s. doi: 10.3945/ajcn. 110.000703. 12. world health organization. physical status: the use and interpretation of anthropometry report of a who expert committee. world health organ tech rep ser 1995; 854:1–452. 13. altman dg, ohuma eo; international fetal and newborn growth consortium for the 21st century. statistical considerations for the development of prescriptive fetal and newborn growth standards in the intergrowth-21st project. bjog 2013; 120:71–6. doi: 10.1111/1471-0528.12031. 14. espejo mr. who child growth standards: methods and development. j r stat soc ser a stat soc 2007; 170:512. doi: 10.1111/j.1467-985x.2007.00473_18.x. 15. schafer jl. multiple imputation: a primer. stat methods med res 1999; 8:3–15. doi: 10.1177/096228029900800102. 16. de onis m, garza c, victora cg, onyango aw, frongillo ea, martines j. the who multicentre growth reference study: planning, study design, and methodology. food nutr bull 2004; 25:s15–26. doi: 10.1177/15648265040251s103. 17. jorde lb, wooding sp. genetic variation, classification and ‘race’. nat genet 2004; 36:s28–33. doi: 10.1038/ng1435. 18. risch n, burchard e, ziv e, tang h. categorization of humans in biomedical research: genes, race and disease. genome biol 2002; 3:2007.1. doi: 10.1186/gb-2002-3-7-comment2007. 19. el mouzan mi, al herbish as, al salloum aa, foster pj, al omar aa, qurachi mm, et al. comparison of the 2005 growth charts for saudi children and adolescents to the 2000 cdc growth charts. ann saudi med 2008; 28:334–40. doi: 10. 5144/0256-4947.2008.334. 20. alshimmiri mm, al-saleh ea, alsaeid k, hammoud ms, al-harmi ja. birthweight percentiles by gestational age in kuwait. arch gynecol obstet 2004; 269:111–16. doi: 10.1007/ s00404-002-0434-0. 21. payande a, tabesh h, shakeri mt, saki a, safarian m. growth curves of preschool children in the northeast of iran: a population-based study using quantile regression approach. glob j health sci 2013; 5:9–15. doi: 10.5539/gjhs.v5n3p9. 22. scherdel p, botton j, rolland-cachera mf, léger j, pelé f, ancel py, et al. should the who growth charts be used in france? plos one 2015; 10:e0120806. doi: 10.1371/journal. pone.0120806. 23. tinggaard j, aksglaede l, sørensen k, mouritsen a, wohlfahrtveje c, hagen cp, et al. the 2014 danish references from birth to 20 years for height, weight and body mass index. acta paediatr 2014; 103:214–24. doi: 10.1111/apa.12468. 24. so hk, nelson ea, sung ry, ng pc. implications of using world health organization growth reference (2007) for identifying growth problems in hong kong children aged 6 to 18 years. hong kong med j 2011; 17:174–9. 25. lausman a, kingdom j; maternal fetal medicine committee. intrauterine growth restriction: screening, diagnosis, and management. j obstet gynaecol can 2013; 35:741–8. doi: 10. 1016/s1701-2163(15)30865-3. 26. world health organization. training course on child growth assessment: who child growth standards module b: measuring a child’s growth. from: www.who.int/childgrowth/ training/module_b_measuring_growth.pdf accessed: oct 2017. 27. corkins mr, lewis p, cruse w, gupta s, fitzgerald j. accuracy of infant admission lengths. pediatrics 2002; 109:1108–11. doi: 10.1542/peds.109.6.1108. https://doi.org/10.2471/blt.11.040411 https://doi.org/10.2471/blt.11.040411 https://doi.org/10.1111/j.1651-2227.2006.tb02371.x https://doi.org/10.1111/j.1651-2227.2006.tb02371.x https://doi.org/10.3945/ajcn.110.000703 https://doi.org/10.3945/ajcn.110.000703 https://doi.org/10.1111/1471-0528.12031 https://doi.org/10.1111/j.1467-985x.2007.00473_18.x https://doi.org/10.1177/096228029900800102 https://doi.org/10.1177/15648265040251s103 https://doi.org/10.1038/ng1435 https://doi.org/10.1186/gb-2002-3-7-comment2007 https://doi.org/10.5144/0256-4947.2008.334 https://doi.org/10.5144/0256-4947.2008.334 https://doi.org/10.1007/s00404-002-0434-0 https://doi.org/10.1007/s00404-002-0434-0 https://doi.org/10.5539/gjhs.v5n3p9 https://doi.org/10.1371/journal.pone.0120806 https://doi.org/10.1371/journal.pone.0120806 https://doi.org/10.1111/apa.12468 https://doi.org/10.1016/s1701-2163%2815%2930865-3 https://doi.org/10.1016/s1701-2163%2815%2930865-3 https://doi.org/10.1542/peds.109.6.1108 reem m. abdulrahim, ahmed b. idris, asad ur-rahman, mohamed abdellatif and nigel fuller clinical and basic research | e417 28. ulijaszek sj, kerr da. anthropometric measurement error and the assessment of nutritional status. br j nutr 1999; 82:165–77. doi: 10.1017/s0007114599001348. 29. who multicentre growth reference study group. assessment of differences in linear growth among populations in the who multicentre growth reference study. acta paediatr suppl 2006; 450:56–65. doi: 10.1111/j.1651-2227.2006.tb02376.x. 30. trading economics. oman gdp: 1960-2017. from: www. tradingeconomics.com/oman/gdp accessed: oct 2017. 31. world health organization. country cooperation strategy for who and oman 2010-2015. from: http://apps.who.int/iris/ bitstream/10665/113221/1/ccs_oman_2010_en_14485.pdf accessed: oct 2017. 32. al riyami aa, afifi m. smoking in oman: prevalence and characteristics of smokers. east mediterr health j 2004; 10:600–9. https://doi.org/10.1017/s0007114599001348 https://doi.org/10.1111/j.1651-2227.2006.tb02376.x 1dental research center, faculty of dentistry, 3research center for molecular medicine, faculty of medicine, and 4modeling of noncommunicable diseases research center, school of public health, hamadan university of medical sciences, hamadan, iran; 2department of oral medicine, school of dentistry, university of medical sciences, tabriz, iran *corresponding author e-mails: fatahmadim@yahoo.com and f.ahmadi@umsha.ac.ir مقارنة بني درجة احلموضة اللعابية وكفاءة معادلة احلموضة والفوسفاتاز القلوية يف املدخنني وغري املدخنني األصحاء دراسة جمموعة استعادية فاطمة اأحمدي-متمايل، باري�صا فل�صفي، حممد تقي جودارزي، جالل پورالعجل abstract: objectives: saliva contains alkaline phosphatase (alp)—a key intracellular enzyme related to destructive processes and cellular damage—and has buffering capacity (bc) against acids due to the presence of bicarbonate and phosphate ions. smoking may have deleterious effects on the oral environment due to ph changes which can affect alp activity. this study aimed to evaluate the salivary ph, bc and alp activity of male smokers and healthy non-smokers. methods: this retrospective cohort study took place between august 2012 and december 2013. a total of 251 healthy male non-smokers and 259 male smokers from hamadan, iran, were selected. unstimulated whole saliva was collected from each participant and ph and bc were determined using a ph meter. salivary enzymes were measured by spectrophotometric assay. results: mean salivary ph (7.42 ± 0.48 and 7.52 ± 0.43, respectively; p = 0.018) and bc (3.41 ± 0.54 and 4.17 ± 0.71; p = 0.001) was significantly lower in smokers compared to non-smokers. mean alp levels were 49.58 ± 23.33 iu/l among smokers and 55.11 ± 27.85 iu/l among non-smokers (p = 0.015). conclusion: significantly lower ph, bc and alp levels were observed among smokers in comparison to a healthy control group. these salivary alterations could potentially be utilised as biochemical markers for the evaluation of oral tissue function and side-effects among smokers. further longitudinal studies are recommended to evaluate the effects of smoking on salivary components. keywords: saliva; alkaline phosphatase; acids; buffers; smoking. امللخ�ص: اأهداف: يحتوي اللعاب على الفو�صفاتيز القلوي)alp(، وهو اإنزمي اأ�صا�صي خلوي مرتبط بتلف اخلاليا والعمليات احليوية ال�صارة. يعادل alp االأحما�ض ب�صبب وجود اأيونات البيكربونات والفو�صفات. قد يكون للتدخني اآثار �صارة على بيئة الفم نتيجة لتغريات درجة احلمو�صة التي ميكن اأن توؤثر على ن�صاط alp. هدفت هذه الدرا�صة اإىل تقييم درجة احلمو�صة اللعابية، وكفاءة معادلة االأحما�ض، ون�صاط alp يف املدخنني وغري املدخنني من الذكور االأ�صحاء. منهجية: هذه درا�صة ا�صتعادية اأجريت يف الفرتة ما بني اأغ�صط�ض 2012 ودي�صمرب 2013. مت اإختيار 251 من غري املدخنني و 259 من املدخنني الذكور من همدان، اإيران. مت جمع اللعاب الكامل الغري حمفز من كل م�صارك ومت حتديد درجة احلمو�صة و وكفاءة معادلة االأحما�ض با�صتخدام جهاز مقيا�ض درجة احلمو�صة. مت قيا�ض االإنزميات اللعابية بوا�صطة الفح�ض االأحما�ض معادلة وكفاءة )7.42 ± 0.48 و 7.52 ± 0.43, التوايل ;على p = 0.018( اللعابي الهيدروجيني الرقم معدل الطيفي. نتائج: )p = 0.001 ;0.71 ± 4.17 و 0.54 ± 3.41( كانتا اأقل ذات بداللة اإح�صائية لدى املدخنني مقارنة بغري املدخنني. كان معدل م�صتويات alp: 23.33 ± 49.58 وحدة دولية/لرت للمدخنني و 27.85 ± 55.11 وحدة دولية/لرت لغري املدخنني )p = 0.015(. خامتة: وجد انخفا�ض من مدخنة. الغري املراقبة جمموعة مع باملقارنة املدخنني بني alp وم�صتويات االأحما�ض معادلة وكفاءة احلمو�صة، لدرجة ملحوظ املحتمل اأن ت�صتخدم هذه التغريات اللعابية كعالمات كيميائية حيوية لتقييم وظيفة االأن�صجة الفموية واالآثار اجلانبية للتدخني. ين�صح م�صتقبال باإجراء درا�صات طولية لتقييم اآثار التدخني على املكونات اللعابية. كلمات مفتاحية: اللعاب؛ الفو�صفاتيز القلوي؛ االأحما�ض؛ معادل احلمو�صة؛ التدخني. comparison of salivary ph, buffering capacity and alkaline phosphatase in smokers and healthy non-smokers retrospective cohort study *fatemeh ahmadi-motamayel,1 parisa falsafi,2 mohammad t. goodarzi,3 jalal poorolajal4 clinical & basic research advances in knowledge smoking was found to significantly alter salivary ph and buffering capacity (bc), which can have many dangerous and deleterious effects on the oral mucosa. application to patient care this study found significantly lower ph, bc and alkaline phosphatase levels among smokers. these changes could potentially be used as biochemical markers to evaluate oral tissue function among smokers. dental and medical practitioners should make patients aware of the effect of smoking on salivary components. the findings of this study could be used by healthcare workers to encourage patients to take part in smoking cessation programmes. sultan qaboos university med j, august 2016, vol. 16, iss. 3, pp. e317–321, epub. 19 aug 16 submitted 21 feb 16 revision req. 6 apr 16; revision recd. 27 apr 16 accepted 26 may 16 doi: 10.18295/squmj.2016.16.03.009 comparison of salivary ph, buffering capacity and alkaline phosphatase in smokers and healthy non-smokers retrospective cohort study e318 | squ medical journal, august 2016, volume 16, issue 3 saliva is an oral fluid secreted from major and minor salivary glands for the primary purposes of digestion, lubrication and the protection of tooth integrity.1,2 overall, saliva is composed of 99% water and 1% organic and inorganic molecules.1 important components of saliva include electrolytes such as bicarbonate, calcium, fluoride and phosphate; enzymes such as α-amylase, invertase and mucins; immunoglobulins (igs) including iga, igg and igm; lipids including neutral lipids, glycolipids and phospholipids; non-igs such as histidine-rich proteins, lactoferrin and lysozyme; and proteins such as peroxidase, proline-rich proteins, agglutinins and statherin.1 alkaline phosphatase (alp) is an intracellular enzyme present in the saliva and most tissues, organs and bones, including the epithelial, inflammatory cells, bacterial organisms and mineralising tissue cells.3–5 the enzyme is related to cell injury and death. alp most commonly correlates with bone metabolism and is present in the osteoblast cell membrane and polymorphonuclear leukocyte granules.3 destructive processes in the alveolar bone can lead to increased alp activity.4,5 a key factor in enzyme functionality is ph, with the optimum ph for alp activity being ≈ 7.4.6 therefore, the maximum enzyme activity of alp is related to the ph and concentration of phosphate esters existing in cells.6 normal salivary ph values range from 7.4–7.6, depending on salivary calcium and phosphate concentrations.1,7,8 due to the presence of bicarbonate/carbonate ions and, to a lesser extent, phosphate ions and proteins, saliva has a buffering capacity (bc) and can neutralise acids produced in the oral cavity or ingested.9,10 oral health and integrity, demineralisation-remineralisation balance and dilution and antimicrobial activity are important to maintain good salivary bc.11 high salivary ph and bc have been found to lead to better oral health outcomes and a lower incidence of dental caries.12 bagherian et al. reported lower ph and bc values among children without caries.13 in contrast, another study indicated lower resting salivary ph values among individuals with dental caries.14 however, changes in ph can also result in pathological changes to the teeth and oral cavity.10 cigarette smoke contains harmful components such as pyridine alkaloids, aromatic hydrocarbons and combustion gases; these can lead to the development of various life-threatening diseases.15,16 moreover, smoking has many side-effects which manifest in the oral mucosa, including delays in wound healing, periodontitis and premalignant and malignant oral lesions.16 due to the deleterious effects of smoking on the oral mucosa, associated salivary changes and the limited number of studies in this field, the aim of this study was to evaluate the salivary ph, bc and alp activity of male smokers and healthy non-smokers in hamadan, iran. methods this retrospective cohort study took place between august 2012 and december 2013 and included 251 male non-smokers and 259 male smokers. participants in the smoking group were selected from smokers patients attending routine dental examinations at the oral medicine department of the hamadan dental school who had been smoking at minimum of five cigarettes a day for at least five years. the control group included healthy non-smokers who attended routine dental examinations at the oral medicine department of the hamadan dental school during the study period. new smokers and individuals with systemic diseases, a history of alcohol and tobacco consumption and/or drug treatment were excluded from the study. on the basis of a previous study assessing salivary enzymes and total antioxidant capacity among smokers and non-smokers, the ideal sample size was determined to be 258 for each group with a total sample size of 516 at a 95% significance level and with 90% statistical power.17 prior to saliva collection, all participants were requested to avoid any oral stimuli for at least 90 minutes beforehand and smokers were asked to refrain from smoking for one hour. unstimulated whole saliva was then collected according to a previously described method.18 a total of 5 ml of spat unstimulated saliva was collected from each participant in a sterile falcon tube. the specimens were immediately centrifuged (1,000 g for 10 minutes) at 4 °c. squamous cells and cell debris were removed and the supernatant was isolated. saliva samples were immediately frozen at -80 °c until the sample collection period was complete. after this, the ph of each saliva sample was determined using a ph meter (hanna instruments inc., ann arbor, michigan, usa).13 the salivary bc was then evaluated by the addition of 1 ml of 0.1 n of hydrochloric acid to 1 ml of saliva. the bc was calculated according to changes in ph and ranked via the ericsson method as high (ph >5.5), moderate (ph 4.5–5.5) or low (ph <4.5).19 salivary alp levels were determined using a spectrophotometric assay kit (pars azmoon inc., tehran, iran) by the addition of a p-nitrophenyl phosphate solution. the production of p-nitrophenol in the saliva was evaluated by measuring absorbance at 450 nm on a spectrophotometer. data were analysed using an independent t-test and mann-whitney u test at the 0.050 significance level by fatemeh ahmadi-motamayel, parisa falsafi, mohammad t. goodarzi and jalal poorolajal clinical and basic research | e319 stata® data analysis and statistical software, version 12 (statacorp lp, college station, texas, usa). all values were reported as means ± standard deviation. this study protocol was approved by the ethics committee of the hamadan university of medical sciences & health (#16/35/4749). written informed consent was obtained from all participants after the aims of the study had been explained. results overall, participants in both groups ranged in age from 20–50 years old. the mean age was 27.76 ± 6.54 years and 30.98 ± 7.80 years for the smoker and control groups, respectively [table 1]. smokers had significantly lower salivary ph in comparison to nonsmokers (7.42 ± 0.48 versus 7.52 ± 0.43, respectively; p = 0.018). mean levels of salivary bc were also significantly lower among smokers compared to nonsmokers (3.41 ± 0.54 versus 4.17 ± 0.71, respectively; p = 0.001). additionally, mean alp levels were significantly lower among smokers in comparison to non-smokers (49.58 ± 23.33 iu/l versus 55.11 ± 27.85 iu/l, respectively; p = 0.015). however, the latter difference was not significant according to the mannwhitney u analysis (p = 0.064) [table 2]. discussion the composition of saliva can act as a biomarker for the diagnosis of certain systemic diseases, determination of exposure to harmful substances and general assessment of health and disease status.2 since the second half of the twentieth century, saliva has been used diagnostically; in terms of biological testing, saliva has many advantages over serum, including easily accessible non-invasive sample collection. as such, saliva can play an important role in the early detection and monitoring of drug use.20 furthermore, various studies have shown that altered salivary ph, bc and alp levels are associated with the formation or development of dental caries, gingivitis, periodontitis, human immunodeficiency virus (hiv) infection, diabetes, orthodontic tooth movements, cancer, abdominal inflammatory diseases and the early onset of menopause.3,4,12,13,21–29 in the current study, salivary ph was lower among smokers in comparison to non-smokers; although the mean values found seem to reflect a minimal difference between the two groups (7.42 versus 7.52, respectively), even very small alterations in ph can influence salivary enzyme activity.6 additionally, bc was significant lower among smokers in the current study. in previous research, salivary ph and bc values were reportedly lower among hiv-positive patients; this reduction correlated with an increase in the degree of immunosupression.24 salivary ph has also been reported to be lower and bc higher in postmenopausal women.21 age may also have an effect on bc; in one study, bc was found to be higher among the elderly.22 however, no significant differences in ph and bc were noted among individuals with different stages of periodontal disease.22 in the current study, alp activity levels were significantly lower in the smoker group than the control group, which may indicate the effect of smoking on salivary enzymes. the lower alp levels observed among table 1: age profile of male smokers and healthy nonsmokers in hamadan, iran (n = 510) n (%) p value smokers (n = 259) non-smokers (n = 251) age in years 20–30 188 (72.6) 128 (51) 0.00131–40 53 (20.5) 83 (33.1) 41–50 18 (6.9) 40 (15.9) mean ± sd 27.76 ± 6.54 30.98 ± 7.80 sd = standard deviation. table 2: salivary ph, buffering capacity and alkaline phosphatase levels among male smokers and healthy nonsmokers in hamadan, iran (n = 510) variable mean ± sd (95% ci) mean difference ± se (95% ci) p value smokers (n = 259) non-smokers (n = 251) independent t-test mann-whitney u ph 7.42 ± 0.48 (0.48–7.37) 7.52 ± 0.43 (0.43–7.47) 0.10 ± 0.04 (0.02–0.17) 0.018 bc 3.41 ± 0.54 (3.34–3.47) 4.17 ± 0.71 (4.08–4.26) 0.77 ± 0.06 (0.65–0.87) 0.001 alp in iu/l 49.58 ± 23.33 (46.72–52.43) 55.11 ± 27.85 (51.65–58.57) 5.54 ± 2.27 (1.07–10.00) 0.015 0.064 sd = standard deviation; ci = confidence interval; se = standard error; bc = buffering capacity; alp = alkaline phosphatase. comparison of salivary ph, buffering capacity and alkaline phosphatase in smokers and healthy non-smokers retrospective cohort study e320 | squ medical journal, august 2016, volume 16, issue 3 smokers may be explained by hyperkeratinisation of the oral and gingival mucosa, which could prevent the release of alp in the saliva. in addition, these changes could also be due to the wide age range of participants in the current study. in contrast to the findings of the current study, some researchers have shown higher alp levels in smokers.30,31 another study found that smoking had no effect on alp activity.28 kibayashi et al. noted significantly lower levels of salivary alp and albumin in current smokers compared to noncurrent smokers; smoking was therefore considered a risk factor for periodontitis and a potential biomarker for the disease.23 higher salivary alp levels have also been found among individuals with periodontal disease, pancreatitis and appendicitis, with treatment of the disease resulting in lowered enzyme levels.3,4,29 therefore, non-invasive assessment of alp levels may be useful in the diagnosis and prognosis of periodontal tissue function and treatment monitoring of abdominal inflammatory diseases.3,29 smoking has been found to cause periodontal disease and bone destruction.32 however, in the current study, smokers with periodontal disease were not included and specific side-effects of smoking on the oral mucosa were not evaluated. further longitudinal studies among smokers with and without oral manifestations in comparison with a healthy control group in different ageand gender-matched populations are necessary to evaluate the effects of smoking on salivary components and oral conditions. conclusion in the current study, salivary alp activity levels, ph and bc were significantly decreased among smokers in comparison to non-smokers. these findings are probably due to the deleterious effect of smoking on the oral environment, including saliva. salivary changes in smokers may therefore be potential biochemical markers of the functional condition of the oral tissues, which could consequently help in the diagnosis of various conditions and the evaluation of the effect of smoking on oral and dental health. further longitudinal studies should be carried out to understand the true effects of smoking on saliva and its components. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. ahmadi motamayel f, davoodi p, dalband m, hendi s. saliva as a mirror of the body health. avicenna j dent res 2010; 1:1–15. 2. schipper rg, silletti e, vingerhoeds mh. saliva as research material: biochemical, physicochemical and practical aspects. arch oral biol 2007; 52:1114–35. doi: 10.1016/j. archoralbio.2007.06.009. 3. dabra s, china k, kaushik a. salivary enzymes as diagnostic markers for detection of gingival/periodontal disease and their correlation with the severity of the disease. j indian soc periodontol 2012; 16:358–64. doi: 10.4103/0972-124x.100911. 4. dabra s, singh p. evaluating the levels of salivary alkaline and acid phosphatase activities as biochemical markers for periodontal disease: a case series. dent res j (isfahan) 2012; 9:41–5. doi: 10.4103/1735-3327.92942. 5. yoshie h, tai h, kobayashi t, oda-gou e, nomura y, numabe y, et al. salivary enzyme levels after scaling and interleukin-1 genotypes in japanese patients with chronic periodontitis. j periodontol 2007; 78:498–503. doi: 10.1902/ jop.2007.060216. 6. warnes tw. alkaline phosphatase. gut 1972; 13:926–37. doi: 10.1136/gut.13.11.926. 7. dawes c. what is the critical ph and why does a tooth dissolve in acid? j can dent assoc 2003; 69:722–4. 8. owlia f, akhavan karbassi m, ahadian h, kazemeiny k. comparison of salivary ph in diabetic patients referring to diabetes center of shahid sadoughi university of medical sciences with non-diabetic controls. j shahid sadoughi univ med sci 2012; 20:82–9. 9. bardow a, moe d, nyvad b, nauntofte b. the buffer capacity and buffer systems of human whole saliva measured without loss of co2. arch oral biol 2000; 45:1–12. doi: 10.1016/s00039969(99)00119-3. 10. cheaib z, lussi a. role of amylase, mucin, iga and albumin on salivary protein buffering capacity: a pilot study. j biosci 2013; 38:259–65. doi: 10.1007/s12038-013-9311-1. 11. dodds mw, johnson da, yeh ck. health benefits of saliva: a review. j dent 2005; 33:223–33. doi: 10.1016/j.jdent.2004.10.009. 12. kaur a, kwatra ks, kamboj p. evaluation of non-microbial salivary caries activity parameters and salivary biochemical indicators in predicting dental caries. j indian soc pedod prev dent 2012; 30:212–17. doi: 10.4103/0970-4388.105013. 13. bagherian a, asadikaram g. comparison of some salivary characteristics between children with and without early childhood caries. indian j dent res 2012; 23:628–32. doi: 10.41 03/0970-9290.107380. 14. farsi n. dental caries in relation to salivary factors in saudi population groups. j contemp dent pract 2008; 9:16–23. 15. saggu tk, masthan km, dudanakar mp, nisa su, patil s. evaluation of salivary antioxidant enzymes among smokers and nonsmokers. world j dent 2012; 3:18–21. doi: 10.5005/jpjournals-10015-1121. 16. bakhtiari s, bigom taheri j, bakhshi m, mortazavi h, shah hoseini a, vahid dastjerdi e, et al. effect of vitamin c on salivary total antioxidant capacity in smokers. iran j pharm res 2012; 11:1045–9. 17. buduneli n, kardeşler l, işik h, willis cs 3rd, hawkins si, kinane df, et al. effects of smoking and gingival inflammation on salivary antioxidant capacity. j clin periodontol 2006; 33:159–64. doi: 10.1111/j.1600-051x.2006.00892.x. 18. navazesh m. methods for collecting saliva. ann n y acad sci 1993; 694:72–7. doi: 10.1111/j.1749-6632.1993.tb18343.x. http://dx.doi.org/10.1016/j.archoralbio.2007.06.009 http://dx.doi.org/10.1016/j.archoralbio.2007.06.009 http://dx.doi.org/10.4103/0972-124x.100911 http://dx.doi.org/10.4103/1735-3327.92942 http://dx.doi.org/10.1902/jop.2007.060216 http://dx.doi.org/10.1902/jop.2007.060216 http://dx.doi.org/10.1136/gut.13.11.926 http://dx.doi.org/10.1016/s0003-9969%2899%2900119-3 http://dx.doi.org/10.1016/s0003-9969%2899%2900119-3 http://dx.doi.org/10.1007/s12038-013-9311-1 http://dx.doi.org/10.1016/j.jdent.2004.10.009 http://dx.doi.org/10.4103/0970-4388.105013 http://dx.doi.org/10.4103/0970-9290.107380 http://dx.doi.org/10.4103/0970-9290.107380 http://dx.doi.org/10.5005/jp-journals-10015-1121 http://dx.doi.org/10.5005/jp-journals-10015-1121 http://dx.doi.org/10.1111/j.1600-051x.2006.00892.x http://dx.doi.org/10.1111/j.1749-6632.1993.tb18343.x fatemeh ahmadi-motamayel, parisa falsafi, mohammad t. goodarzi and jalal poorolajal clinical and basic research | e321 19. tulunoglu o, demirtas s, tulunoglu i. total antioxidant levels of saliva in children related to caries, age, and gender. int j paediatr dent 2006; 16:186–91. doi: 10.1111/j.1365263x.2006.00733.x. 20. pink r, simek j, vondrakova j, faber e, michl p, pazdera j, et al. saliva as a diagnostic medium. biomed pap med fac univ palacky olomouc czech repub 2009; 153:103–10. doi: 10. 5507/bp.2009.017. 21. mahesh dr, komali g, jayanthi k, dinesh d, saikavitha tv, dinesh p. evaluation of salivary flow rate, ph and buffer in pre, post & post menopausal women on hrt. j clin diagn res 2014; 8:233–6. doi: 10.7860/jcdr/2014/8158.4067. 22. shaila m, pai gp, shetty p. salivary protein concentration, flow rate, buffer capacity and ph estimation: a comparative study among young and elderly subjects, both normal and with gingivitis and periodontitis. j indian soc periodontol 2013; 17:42–6. doi: 10.4103/0972-124x.107473. 23. kibayashi m, tanaka m, nishida n, kuboniwa m, kataoka k, nagata h, et al. longitudinal study of the association between smoking as a periodontitis risk and salivary biomarkers related to periodontitis. j periodontol 2007; 78:859–67. doi: 10.1902/ jop.2007.060292. 24. hegde m, malhotra a, hegde n. salivary ph and buffering capacity in early and late human immunodeficiency virus infection. dent res j (isfahan) 2013; 10:772–6. 25. cutando a, lópez-valverde a, gómez-de-diego r, ariassantiago s, de vicente-jiménez j. effect of gingival application of melatonin on alkaline and acid phosphatase, osteopontin and osteocalcin in patients with diabetes and periodontal disease. med oral patol oral cir bucal 2013; 18:e657–63. doi: 10.4317/ medoral.18832. 26. flórez-moreno ga, marín-restrepo lm, isaza-guzmán dm, tobón-arroyave si. screening for salivary levels of deoxypyridinoline and bone-specific alkaline phosphatase during orthodontic tooth movement: a pilot study. eur j orthod 2013; 35:361–8. doi: 10.1093/ejo/cjr138. 27. guerra rn, oliveira-junior jj, mouchrek-filho jc, liberio sa, lima mv, paim db, et al. salivary evaluation of pediatric patients with cancer, before and after antineoplasic treatment. j oral pathol med 2012; 41:527–32. doi: 10.1111/j.1600-0714. 2012.01165.x. 28. nagler rm, klein i, reznick az. [the interaction between saliva and cigarette smoke and its devastating biological effects as related to oral cancer]. harefuah 2001; 140:614–18. 29. sukhareva ae, bulakh na, ermolaeva tn, nikolaeva aa. [alkaline phosphatase in mixed saliva in abdominal inflammatory diseases and gestoses]. klin lab diagn 2011; 6:16–18. 30. ketabi m, mesripour m, rafiei e. the comparison of gcf and salivary level of alp in smokers, non-smokers with periodontitis and in healthy subjects. j res dent sci 2015; 11:236–41. 31. abdul ameer lr, ali bg. effects of light smoking on salivary levels of alkaline phosphatase and osteocalcin in chronic periodontitis patients. j baghdad coll dent 2015; 27:110–14. doi: 10.12816/0015305. 32. kubota m, yanagita m, mori k, hasegawa s, yamashita m, yamada s, et al. the effects of cigarette smoke condensate and nicotine on periodontal tissue in a periodontitis model mouse. plos one 2016; 11:e0155594. doi: 10.1371/journal. pone.0155594. http://dx.doi.org/10.1111/j.1365-263x.2006.00733.x http://dx.doi.org/10.1111/j.1365-263x.2006.00733.x http://dx.doi.org/10.5507/bp.2009.017 http://dx.doi.org/10.5507/bp.2009.017 http://dx.doi.org/10.7860/jcdr/2014/8158.4067 http://dx.doi.org/10.4103/0972-124x.107473 http://dx.doi.org/10.1902/jop.2007.060292 http://dx.doi.org/10.1902/jop.2007.060292 http://dx.doi.org/10.4317/medoral.18832 http://dx.doi.org/10.4317/medoral.18832 http://dx.doi.org/10.1093/ejo/cjr138 http://dx.doi.org/10.1111/j.1600-0714.2012.01165.x http://dx.doi.org/10.1111/j.1600-0714.2012.01165.x http://dx.doi.org/10.12816/0015305 http://dx.doi.org/10.1371/journal.pone.0155594 http://dx.doi.org/10.1371/journal.pone.0155594 clinical & basic research squ med j, april 2010, vol. 10, iss. 1, pp. 23-30, epub. 17th apr 10 submitted 21st oct 2009 revision req. 12th dec 09, revision recd. 21st jan 10 accepted 16th feb 10 1eye & ear health care, department of non-communicable diseases control, directorate general of health affairs, ministry of health, oman; 2department of maternal & child health care, ministry of health, oman to whom correspondence should be addressed. email: rajshpp@omantel.net.om حدوث وحتديد العيوب اخِللِْقيّة وقصور اإلنزيم لدى املواليد األحياء يف سلطنة ُعمان مراجعة السجل الوطين لعام 2005م راجيف خانديكار، يا�شمني جعفر ال�رقة هذه اخِلْلِقّية. الت�ش�هات حاالت ت�شجيل ببدء الطف�لة رعاية بربنامج ممثلة 2003 عام يف ال�شحة وزارة �رسعت الهدف: امللخ�ص: عام 2005م. بال�شجل وامل�شجلة ُعمان ب�شلطنة االأحياء امل�اليد بني اخِلْلِقّية الت�ش�هات ذوي االأطفال لدى ااِلْخِتطار َع�اِمِل مقدار ت�شتعر�س الطريقة: قام االأطباء املخت�ش�ن بطب االأطفال وطب حديثي ال�الدة بفح�س االأطفال ذوي العي�ب اخِلْلِقّية الذين مت ت�شجيلهم والتبليغ عنهم اإما اأثناء فح�شهم عند ال�الدة اأو يف خالل ال�شنة االأوىل من العمر اأثناء ترددهم للعيادات.مت اإجراء الفح��شات ال�رسيرية واملختربية والت�ش�ير . قبل الفح��شات مت كتابة التفا�شيل ال�شخ�شية، ن�ع الت�ش�هات اخِلْلِقيّة باالإ�شافة اإىل ا�شتخدام الت�شنيف الدويل َ�اِتيِّ ال�شعاعي والَتْخطيط الَت�شْ لالأمرا�س icd-10 ( 10 ( مع َع�اِمِل اِْخِتطار خمتارة. مت ح�شاب معدالت االإ�شابة بالن�شبة املئ�ية.النتيجة: كان معدل االإ�شابة ال�شن�ية يف �شلطنة ُعمان %2.53 )فرتة ثقة 95 : 2.68-2.38 (. كان لدى الذك�ر اِْخِتطار اأعلى بالت�ش�هات اخللقية من االإناث. )اْخِتطاٌر ِن�ْشِبّي = 2.0 (. التباين املناطقي كان معتدا اإح�شائيا اأي�شا ) مربع كاي = 363 (. كان معدل االإ�شابة بفقر الدم نتيجة ا�شطرابات االإنزميات %1.4. اأما ت�ش�هات اجلهاز الب�يل-التنا�شلي واليدين والقدمني ومتالزمة داون فكانت مُتّثل العي�ب الت�رسيحية الرئي�شية. كان الزواج لدي االأقارب )اْخِتطاٌر ِن�ْشِبّي = 0.85( وانخفا�س ال�زن عند ال�الدة ) )اْخِتطاٌر ِن�ْشِبّي = 0.28 ( مرتبطني �شلبيا مع الت�ش�هات اخِلْلِقّية. كان االْخِتطاٌر الِن�ْشِبّي )1.89( واالأم. االأب من كل عمر ارتباطا.بني جند مل اأطفالهن. عند عالية اخِلْلِقّية الت�ش�هات اأن تبني حيث اأ�شب�عا 37< يلدن الل�اتي االأمهات لدى اخلال�صة: يعترب ال�شجل ال�طني للت�ش�هات اخِلْلِقّية اأداة هامة للتقييم. اإن َع�اِمِل ااِلْخِتطار الناجتة عن الع�امل ال�راثية واملكت�شبة ميكن اأن ت�ؤثر على معدل العي�ب اخِلْلِقّية ون�عيتها يف �شلطنة ُعمان. مفتاح الكلمات: الت�ش�هات اخِللقية، العي�ب اخِللقية، �شلطنة ُعمان. abstract: objectives: in 2003, the omani ministry of health child health care program initiated a national birth defects (bd) register. this paper reviews the magnitude and risk factors of birth defects in children born and registered in 2005 using data from the bd register. methods: pediatricians and neonatologists examined children with bds found either during screening at birth or when attending clinics in their first year of their life. clinical examination, laboratory, sonographic and radiological investigations were carried out. a pre-tested form was used to note personal details, type of birth defect including international classification of diseases-10 (icd-10) codes of bd and selected risk factors. the incidence rates per 100 live births were calculated. results: the annual incidence of bd in oman was 2.53% (95% ci 2.38–2.68). males had a significantly higher risk of bd than females (relative risk (rr) = 2.0). the regional variation of bd was also significant (χ 2 = 363). the incidence of anaemia due to enzyme disorders was 1.4%. bd of urogenital organs, hands and feet and down’s syndrome were the main types of anatomical defects. consanguinity among parents (rr = 0.85) and low birth weight (rr = 0.28) was negatively associated to birth defects. mothers giving birth at gestational age of <37 weeks (rr = 1.89) had a higher risk of having children with bd. maternal and paternal age were not associated to bd. conclusion: the national register for bd is an important evaluation tool. both genetic and acquired risk factors seem to affect bd rates and types in oman. keywords: birth defects; congenital anomalies; oman. incidence and determinants of birth defects and enzyme deficiencies among live births in oman a review of the 2005 national register *rajiv khandekar,1 yasmin jaffer2 clinical & basic research incidence and determinants of birth defects and enzyme deficiencies among live births in oman a review of the 2005 national register 24 | squ medical journal, april 2010, volume 10, issue 1 the united nation’s millennium developmental goal-4 to reduce child mortality by two-thirds from 1990 levels by 2015 will not be met unless the mortality from birth defects and preterm birth is recognised and addressed.1 worldwide, the prevalence rates of all genetic birth defects combined range from a high of 82/1,000 live births in low-income regions to a low of 39.7/1,000 live births in highincome regions.2 countries like oman, which has undergone rapid socioeconomic development, are currently undergoing epidemiological transition. communicable disease rates are declining, but chronic and non-communicable diseases are on the rise.3 the magnitude of genetic disorders is high in omani children and it is likely to increase unless known risk factors like consanguinity, better survival of preterm babies due to improved child health care, and limited acceptance of therapeutic abortions are addressed.4 the maternal and child health care program as well as the programme for controlling genetic disorders in oman has recognised this health problem and included it in 6th five year health plan.5 a national bd register was started in 2003 with bd defined as physical abnormalities or enzyme deficiency, mainly glucose-6-phosphate dehydrogenase deficiency (g6pd). paediatricians provide the information for the register and its programme managers improved its quality of register in the initial years. the authors analysed the national bd register for 2005 to estimate the incidence of bds for live births and their epidemiological determinants. on this basis, public health related recommendations were proposed. methods this was a review of the national bd register. the ethical and research committee of the ministry of health gave permission for the study. paediatricians and neonatologists at ten regional hospitals were our study investigators. all babies born in the year 2005 in oman were our total study population. children with bds, found either during screening at birth or when attending clinics in their first year of their life, were our specific study population. those identified with anatomical deformities were registered after detailed clinical examination. blood tests were performed for children suspected to suffer from genetic blood disorders. children with bds also underwent radiological and sonographic evaluation to identify any other anomalies in addition to the principal defect. personal information like date of birth, sex, area of residence, tribe, mother’s age at birth, father’s age, order of birth, birth weight, gestational age on birth, status of child in the first year of life (alive or dead), medical history and degree of consanguinity among parents were noted on a standardised pre-tested form. the principal bd as per the international classification of diseases-10 (icd-10) code was also noted. all the children with down’s syndrome had their condition confirmed by laboratory tests. the children were managed by paediatric services either in regional hospitals or with the help of a paediatric surgeon advances in knowledge 1. this review provides a profile of infants with birth defects (bd) as reported in the oman bd register 2. the incidence of different bd in relation to live births for 2005. 3. down’s syndrome and anomalies of extremities were common in oman. 4. to meet international standards, the register should include bds of aborted fetuses. 5. the current methodology of including enzyme deficiencies as bds, although important for oman, is not as per the international database on bd. 6. incidence of bd in oman in this study could be underestimated. application to patient care 1. countries experiencing a significant decline in the infant mortality rate due to less communicable and nutrition-related diseases still have to face the burden of genetic and birth defect related problems in infants. 2. knowledge of the magnitude of the bd problem, the profile of birth defects and risk factors will enable the child health care programme of a country improve its implementation and planning. 3. the prevalence of bds in oman in 2005 was 2.53% (95% ci 2.38–2.68). males, children with low birth weight, and residents of specific regions were significantly associated with bds in children. 4. a well maintained national bd register is an important tool for global and national efforts to address this problem. rajiv khandekar and yasmin jaffer clinical and basic research | 25 at tertiary hospitals. if treatment was possible, but facilities were not available within the country, the child’s treatment, in a reputed centre abroad, was paid for by the omani government. the bd register was initiated in the year 2002. the first year was the pilot phase to strengthen the registration system. from 2003, a national data collection system was implemented by the national health information management system (hims). the department of mother and child health (mch) of the ministry of health (moh) liaised with regions to monitor and follow the registration of children with bd. neonatologists and other specialists like paediatric ophthalmologists, ear, nose and throat surgeons, cardiologists, etc, in regional and wilayat (district) moh hospitals reported information on bd. the attending physician of the institution where such a child was first reported was labelled as the reporting person. as information in the register was based on identity of the parent health institution, duplications were avoided. the national supervisor for mch followed through with the attending physicians to ensure the completion of all relevant information in the bd register. the data on live births, children with low birth weights (< 2.5 kg) and the proportion of twin births, to determine plurality, was provided by the department of health information and statistics.6 the proportion of preterm babies in general population was 9.4% in a study in saudi arabia.7 we took it as reference for calculating preterm babies in the cohort of live births in 2005 in oman. the regional health information officers computed the data from the pre-tested forms by using epi info™ 6 software (center for disease control, usa).the statistician of the oman ministry of health’s (moh) maternal & child health care (mch) department compiled the national register. after ensuring completion of information, univariate analysis was carried out using the parametric method and the statistical package for social studies (spss, version 12). frequencies and incidence of bds nationally and of regional subgroups were calculated per 100 live births. the risk of bd was compared to the children born without bd in 2005 in oman by calculating relative risk, 95% confidence intervals (ci) and p values (set at (< 0.05). the identities of children with bd and their parents were de-linked from information on risk factors of bd and only the principal investigator had access to this information. the results of this study were shared with regional paediatricians and the staff of the programme for the control of genetic diseases. policies for strengthening the bd register and the care of children with bd were then proposed to the members of the national mother and child health care committee. results the bd register of oman had 1,393 children registered in 2005. of them, 1,065 (76.5%) children were born in 2005. fifty-seven (4.02%) children with bd died in the first year of life. the characteristics of children with bd were compared to all the omani children born in 2005 [table 1]. five children with bd had undetermined gender on clinical examination. the incidence of bds was calculated for different epidemiological variables. live births were used as the denominator to calculate the incidence of bd. data on the birth cohort, number of children with bd, incidence per 100 live births, the relative risk, their 95% ci and the p values are given in table 2. the incidence of bd in oman during 2005 table 1: characteristics of the children born in 2005 and children with birth defects in oman children born in 2005 children with birth defects # % # % gender male female undetermined missing 21,264 20,801 50.6 49.4 582 288 5 190 54.6 27.0 0.5 17.8 region muscat dhofar dhakhiliya north sharqiya south sharqiya north batinah south batinah dhahira musandam al wusta 9,861 4,115 5,727 3,466 4,088 6,856 3,778 3,578 436 160 23.4 9.8 13.6 8.2 9.7 16.3 9.0 8.5 1.0 0.4 184 66 338 40 105 190 78 41 21 2 17.3 6.2 31.7 3.8 9.9 17.8 7.3 3.8 2.0 0.2 total 42,065 100 1,065 100 incidence and determinants of birth defects and enzyme deficiencies among live births in oman a review of the 2005 national register 26 | squ medical journal, april 2010, volume 10, issue 1 was 2.53 per 100 live births and was significantly higher in boys compared to girls. (rr = 1.98 (95% ci 1.72–2.27), p = <0.001). the regional variation of reporting bd in children was significant. the dhakhiliya region had significantly higher bd rates (5.90 per 100 live births; 95% ci 5.29–6.51), whereas the north sharqiya and dhahira regions had lower incidences of bd (1.15/100 live births). the types of bds as per the icd-10 codes with incidence per 100 live births are given in table 3. of the 1,065 children with bd, 589 (55.3%) had anaemia due to g6pd enzyme disorders. deformities of hands and feet were noted in 106 children with an incidence of 0.25 per 100 live births. the rate of bds was compared among the different subgroups of children born in 2005; the frequencies, relative risks, 95% ci and p values are given in table 4. we did not find a significant association between maternal age at birth and the presence of bd. the information on other variables was missing for nearly half of the participants. discussion this is the first attempt at national level in oman to review the profile of children with bd. the infant mortality rate (imr) in oman of 10.28/1,000 live births is now mainly due to non-communicable diseases. the high rate of hospital deliveries in oman, together with a nearly 100% immunisation rate of children against infectious diseases (including rubella) as well as free access to high standard, regional neonatal and child health care services have resulted in a marked decline in deaths due to avoidable conditions.8 unfortunately, risk factors for genetic disorders such as the high rate of diabetes in women,9 consanguineous marriage practices, 10 limited therapeutic abortions and mothers of older age are still present in oman. in such a situation, knowledge of the incidence of bds and their risk factors is crucial in order to formulate future prevention and intervention policies. in 2005, the overall incidence of bd in oman was 2.53% (95% ci 2.38–2.68), but a study in one of the regions of oman showed a bd prevalence of 2.46%.11 the rate in oman was more than that reported in iran (1.01%),12 kuwait (1.25%)13 bangladesh (2.3%)14 and the uae (0.79%).15 it is worth noting that, in spite of variations in all these studies, the populations were all of muslim religion. apart from bangladesh, the other study areas were in middle eastern countries, where the health services are accessible and of a high standard. therapeutic abortion is also not widely accepted in these countries. despite the similarities among these countries the differences in the rates cannot be explained. perhaps the high incidence of diabetes in the >20 population in oman and diabetes in mothers being a known risk factor of bd, could be a logical explanation for the higher incidence of bd in our study.16,17,18 further studies of specific bds in oman are recommended to explain the reason for the higher incidence of bd in oman compared to neighbouring countries. however, oman has the following factors which militate against the higher incidence of bds found in this study: 1) only 0.5% prevalence of smoking among females;19 2) a religious taboo on the consumption of alcohol and controls on its availability; 3) low incidence of malnourishment and folic acid provision to females during antenatal period points at a lower risk of central nervous system congenital malformation;20 4) universal immunisation against rubella,21 and 5) controlled prescription of medicines with teratogenic properties. the incidence of bd was significantly higher in males compared to females in our study. this was also reported in iran and in a study by cui et table 2: incidence of birth defect (bd) per 100 live births in oman in 2005. variant live births no. with bd % of bd 95% ci gender* male female 21,264 20,801 799 390 2.74 1.38 2.52–2.96 1.23–1.54 region** muscat dhofar dhakhiliya n. sharqiya s. sharqiya n. batinah s. batinah dhahira musundam wousta 9,861 4,115 5,727 3,466 4,088 6,856 3,778 3,578 436 160 184 66 339 40 105 190 78 41 21 2 1.87 1.60 5.90 1.15 2.57 2.77 2.06 1.15 4.82 1.25 1.60–2.13 1.22–1.99 5.29–6.51 0.80–1.51 2.08–3.05 2.38–3.16 1.61–2.52 0.80–1.49 2.81–6.83 -0.47 -2.97 legend: rr = relative risk; *validity: rr = 1.98, 95% ci = 1.72 – 2.27, p value = <0.001; **validity: χ 2 = 363, 95% ci : df =8, p value = <0.001 rajiv khandekar and yasmin jaffer clinical and basic research | 27 al.12, 22 a study of opposite sex twins suggested that males had a 29% higher risk of bd compared to their sisters.23 a study with a large sample showed that a higher percentage of males was noted with obstructive cardiac defects while females were more likely to have all types of neural tube defects.24 folic acid supplementation and high take-up rates of antenatal care in oman may have resulted in a lower incidence of neural tube defects and less females with bd of these types. the regional variation in bd was marked in oman. different tribes in different regions could explain this variation. regional variation was noted in the prevalence of congenital heart defects in a study done in saudi arabia.20 a maternal age of more than 25 years was associated with bds in the united arab emirates.15 in our study also, younger mothers had children with bd. in contrast, mothers of >35 years of age had a significantly higher risk of having children with autism and heart defects bd.25, 26 in another study in oman, older aged mothers had a significant risk of giving birth to children with down’s syndrome.27 we cannot explain the reason for this negative association in the present study. we did not include stillborn and naturally aborted preterm infants when calculating the incidence and risk factor in our study. multi-system genetic disorders could be higher in the group that died prematurely. perhaps this could be the reason of the observed nonassociation in our study. the influence of paternal age (>35 years) was associated with a higher incidence of down’s syndrome.28 factors related to the father’s occupation also have been attributed to incidence of bd.29 in our study, we did not find such an association. information on the father’s age was missing for 29 children and these fathers are more likely to be in the >45 years age group. if we review the risk of bd on this assumption, then paternal age was a significant risk factor for bd in oman. low birth weight and preterm babies are known risk factors for bd.13, 15, 30 surprisingly, low birth weight was negatively associated to bd in our study. the non-inclusion of stillbirths with bd might be the reason for such an association. the risk of bd has been noted in twin and multiple pregnancies especially those arising from artificial reproductive techniques.31 since there was no information on weight and plurality for a large number of children in our cohort, the association of bd with birth weight and plurality should be viewed with caution. given the fact that there were only seven pairs of twin children, we did not calculate the risk of bd to plurality. it should be noted that bd could be the reason for preterm deliveries and low birth weight of infants. consanguinity has been documented as a risk factor for many congenital anomalies.32, 33 however, in our study, it was not found to be a risk factor for bd. since we excluded still births and aborted fetuses, we may have found less multi-syndromic congenital anomalies with a strong genetic link. in addition, small and close-knit communities, such as the kabila tribe in oman, could have a long history of consanguinity; however, given better education table 3: birth defect (bd) by type in oman in 2005 (42,065 live births in 2005) children with bd incidence of bd 95% confidence interval type of bd anaemia due to enzyme disorders deformities of hand & feet urogenital anomalies anomalies of skull & spine anomalies of heart & great vessels down’s syndrome musculoskeletal anomalies cleft palate/lip anomalies of alimentary canal malformations of eye & ear respiratory anomalies other 589 106 80 41 41 32 23 21 21 19 6 86 1.40 0.25 0.19 0.10 0.10 0.08 0.05 0.05 0.05 0.05 0.01 0.20 1.29–1.51 0.20–0.30 0.15–0.23 0.07–0.13 0.07–0.13 0.05–0.10 0.03–0.08 0.03–0.07 0.03–0.07 0.02–0.07 0.00–0.03 0.16–0.25 oman 1,065 2.53 2.38–2.68 incidence and determinants of birth defects and enzyme deficiencies among live births in oman a review of the 2005 national register 28 | squ medical journal, april 2010, volume 10, issue 1 in the younger generation, consanguinity, a known risk factor for bd, may now be less than in the past. migration to urban areas and the growth of the nuclear family has also been postulated to dilute the role of consanguinity and that could be the reason for the observed association of consanguinity with bd in our study. 34 anaemia due to g6pd enzyme disorders was the main reported bd in oman. this agreed with earlier observations in oman.35, 36 there were a significant number of bds of the urogenital system, down’s syndrome children and deformities of the hands and feet in our study. further studies with a larger sample of these bds are recommended. the surveillance for bd in different countries as reported by international center for birth defect surveillance and research (icbdsr) suggested that rate of down’s syndrome in our study matched that of cuba and italy. however, it was lower than usa, canada and france.37 inclusion of bd among aborted fetuses in other countries could be the reason for the higher rate compared to our study. in these countries, the registration included bd among aborted fetus and paid special attention to factors during pregnancy associated to bd. in oman, the bd register included genetic blood disorders and excluded aborted fetuses therefore comparison of rates should be done with great caution. as this study was a retrospective register review, loss of data or incomplete data was an inherent limitation. in spite of communicating with regional programme managers to complete the register as well as using indirect indicators from other sources like the child health registers at primary health institutions and records of infant deaths at regional hospitals, we still had missing information that could have introduced bias into our study especially while reviewing the association of risk factors to bd. our study suggested that the incidence of bd in surviving infants was high. the maternal and child health program should emphasise the table 4: risk factors for birth defects (bd) risk factor live births children with bd rr 95% confidence interval p value mother’s age < 35 years ≥ 35 years missing 36,122 5,929 874 128 13 0.89 0.77– .07 0.25 father’s age < 45 years ≥ 45 years missing 37,981 4,084 1,217 147 29 1.11 0.95–1.29 0.19 history of consanguinity in parents yes no 23,683 18,382 555 510 0.85 0.75–0.96 0.007 birth weight < 2.5 kg ≥ 2.5 kg missing 3,470 38,595 114 350 601 0.28 0.23–0.35 < 0.0001 gestational age at birth < 37 weeks ≥ 37 weeks missing 3,954 38,111 77 371 617 1.98 1.55–2.53 < 0.001 plurality single birth multiple births missing 41,689 376 457 7 601 1.70 0.81–3.56 0.20 rajiv khandekar and yasmin jaffer clinical and basic research | 29 need for improved quality of registration in order to ensure complete records. both genetic and acquired factors seem to interact and result in a high incidence of bd in oman. the health services at regional level should be well equipped to identify and manage children with bd. some of the children with bd, even after successful management, will need long term follow-up and rehabilitation. hence prevention, care and rehabilitation should be an integral component of the bd control programme. further studies of important bds and their risk factors would enable the programme to formulate a preventive and rehabilitative approach for each of them. a c k n o w l e d g e m e n t s we would like to thank mr hamoud s al-gabri, health information officer and ms flor deliza of the ministry of health’s maternal and child health program for their help in interpreting the data related to maternal and child health care linked to the national register for bd in oman. we also acknowledge the contribution of health professionals in regions especially the paediatricians and neonatologists who examined the children with bds. we thank dr. anna rajab of the genetics unit at the royal hospital, muscat, oman, for advice in writing part of the discussion section. the cooperation and commitment of parents and relatives of children with bd are highly appreciated. the preliminary results of this study were presented in 1st national conference of birth defects held in muscat, oman, in 2007. references 1. martines j, paul vk, bhutta za, koblinsky m, soucat a, walker n, et al. neonatal survival: a call for action. lancet 2005; 365:1189–97. 2. christianson a, howeson cp, modell b. executive summary, global report on birth defects. white plains, new york: march of dimes birth defects foundation, 2006. pp. 2–8. 3. yusuf s, reddy s, ounpuu s, anand s. global burden of cardiovascular diseases: part i: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. circulation 2001; 104:2746–53. 4. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:1–20. 5. ministry of health, sultanate of oman. birth defect domain in 7th five year health plan. muscat: international printing press. pp. 197–204, 6. ministry of health, sultanate of oman. annual health report year 2005, muscat: ministry of health. pp: 8/11–8/15. 7. arafa ma, alkhouly a, youssef me. influence of inter-pregnancy interval on preterm delivery. paediatr perinat epidemiol 2004; 18:248–52. 8. sulaiman aj, al-riyami a, farid s, ebrahim gj. oman family health survey 1995. j trop pediatr 2001; 47:1–33. 9. sawardekar kp. profile of major congenital malformations at nizwa hospital, oman: 10-year review. j paediatr child health 2005; 41:323–30. 10. golalipour mj, ahmadpour-kacho m, vakili ma. congenital malformations at a referral hospital in gorgan, islamic republic of iran. east mediterr health j 2005; 11:707–15. 11. madi sa, al-naggar rl, al-awadi sa, bastaki la. profile of major congenital malformations in neonates in al-jahra region of kuwait. east mediterr health j 2005; 11:700–6. 12. khanum s, noor k, kawser ca. studies on congenital abnormalities and related risk factors. mymensingh med j 2004; 13:177–80. 13. cui w, ma cx, tang y, chang v, rao pv, ariet m, et al. sex differences in birth defects: a study of opposite-sex twins. birth defects res a clin mol teratol 2005; 73:876–80. 14. sharpe pb, chan a, haan ea, hiller je. maternal diabetes and congenital anomalies in south australia 1986-2000: a population-based cohort study. birth defects res a clin mol teratol 2005; 73:605–11. 15. al-lawati ja, mohammed aj. diabetes in oman: comparison of 1997american diabetes association classification of diabetes mellitus with 1985 who classification. ann saudi med 2000; 20:12–5. 16. al riyami aa, afifi m. smoking in oman: prevalence and characteristics of smokers. east mediterr health j 2004; 10:600–9. 17. gao lj, zhao zt, li d, jiang bf, hao fr. a casecontrol study on the risk factors of central nervous system congenital malformations. zhonghua liu xing bing xue za zhi 2004; 25:794–8. 18. cutts ft, robertson se, diaz-ortega jl, samuel r. control of rubella and congenital rubella syndrome (crs) in developing countries, part 1: burden of disease from crs. bull world health organ 1997; 75:55–68. 19. al hosani h, salah m, abu-zeid h, farag hm, saade d. the national congenital anomalies register in the united arab emirates. east mediterr health j 2005; 11:690–9. 20. lisi a, botto ld, rittler m, castilla e, bianca s, bianchi f, et al. sex and congenital malformations: an incidence and determinants of birth defects and enzyme deficiencies among live births in oman a review of the 2005 national register 30 | squ medical journal, april 2010, volume 10, issue 1 international perspective. am j med genet a 2005; 134:49–57. 21. greer w, sandridge al, al-menieir m, al rowais a. geographical distribution of congenital heart defects in saudi arabia. ann saudi med 2005; 25:63–9. 22. maimburg rd, vaeth m. perinatal risk factors and infantile autism. acta psychiatr scand 2006; 114:257–64. 23. reefhuis j, honein ma. maternal age and nonchromosomal birth defects, atlanta, 1968-2000: teenager or thirty-something, who is at risk? birth defects res a clin mol teratol 2004; 70:572–9. 24. rajab a, neitzel h, näthe j, goud m, al-harrasi s, khandekar r, et al. down syndrome in oman. epidemiol molecul studies (in press) 25. chia se, shi lm, chan oy, chew sk, foong bh. a population-based study on the association between parental occupations and some common birth defects in singapore (1994-1998). j occup environ med 2004; 46:916–23. 26. salt a, d’amore a, ahluwalia j, seward a, kaptoge s, halliday s, et al. outcome at 2 years for very low birth weight infants in a geographical population: risk factors, cost, and impact of congenital anomalies. early hum dev 2006; 82:125–33. 27. hellmann o, bentov y. congenital malformations in children born after ivf. harefuah 2005; 144:852–8, 910. 28. ramegowda s, ramachandra nb. parental consanguinity increases congenital heart diseases in south india. ann hum biol 2006; 33:519–28. 29. donbak l. consanguinity in kahramanmaras city, turkey, and its medical impact. saudi med j 2004; 25:1991–4. 30. bittles ah. endogamy, consanguinity and community genetics. j genet 2002; 81:91–8. 31. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 32. rajab ag, patton ma, modell b. study of hemoglobinopathies in oman through a national register. saudi med j 2000; 21:1168–72. 33. rajab a, patton m. a study of consanguinity in the sultanate of oman. annals of hum biology 2000; 3:321-326. 34. mathew m, machado l, al-ghabshi r, al-haddabi r. fetal macrosomia. risk factor and outcome. saudi med j 2005 jan; 26:96-100. 35. mathew m, saquib s, rizvi sg. polyhydramnios. risk factors and outcome. saudi med j 2008 feb; 29:256-60. 36. ghosh s, feingold e, dey sk. etiology of down syndrome: evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. am j med genet a 2009; 149:1415–20. 37. international center on birth defects and research (icbdsr). table 6 in collaborative research projects. in: annual report for 2007 with data for 2005. icbdsr, rome: italy, 2007. p. 13. from http://www. icbdsr.org/filebank/documents/ar2005/report2007. pdf accessed january 2010. departments of 1dermatology and 2radiology & diagnostic imaging, hospital general universitario de ciudad real, ciudad real, spain *corresponding author’s e-mail: mgarciaa73@yahoo.es املعلومات األولية عن تثخن الفروة حالة مرضية تصيب فروة الرأس حتدث يف عدد من األمراض مونيكا قار�شيا-اأربا، مقيول فلوري�س-تريي، لو�شيا قونزل�س-روي�س، من�رصات فرانكو-منوز، مانولو-كالفو-قار�شيال primary essential cutis verticis gyrata a scalp condition that may appear in various disorders *mónica garcía-arpa,1 miguel a. flores-terry,1 lucía gonzález-ruiz,1 monserrat franco-muñoz,1 manolo calvo-garcía2 a 35-year-old male patient of bolivian origin was referred to the dermatology department of the hospital general de ciudad real, ciudad real, spain, in 2017 with intense scalp pruritus and nodules of one year’s duration. a physical exam ination revealed skin redundancy with deep cerebri form folds and wrinkles in the scalp consistent with a diagnosis of cutis verticis gyrata (cvg) [figure 1]. there was no reported family history of similar scalp conditions or any evidence of intellectual disabilities or neurological, psychiatric or ophthalmological manifestations. the rest of the physical examination revealed no other abnormalities, including digital clubbing. in order to exclude secondary disorders, a cutaneous biopsy and various complementary examinations were performed. this included a complete blood count, biochemistry testing, electrophoresis and urine analysis and testing for immunoglobulins, serum thyroid-stimulating hormone, free thyroxine, growth hormone, insulin-like growth factor 1, insulin and insulin resistance index. in addition, the patient underwent serological screening for the hepatitis virus, hiv and syphilis, as well as karyo typing, hand x-raying and an ophthalmological examination. there was no evidence of any abnormalities. magnetic resonance imaging (mri) with volume-rend ering revealed subcutaneous thickening of the scalp [figure 2]. intracranial abnormalities were ruled out by axial mri [figure 3]. given the benign nature of the condition, the patient was discharged and localised hygiene practices were recommended. comment overall, cvg cases are classified into primary and sec ondary forms; primary cvg cases are sometimes further subclassified as either non-essential (i.e. those with assoc iated neurological, psychiatric and ophthalmological manifestations) or essential (i.e. those without abnorm alities or secondary disorders).1–3 primary essential interesting medical image sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e560–562, epub. 28 mar 19 submitted 6 jun 18 revision req. 10 jul 18; revision recd. 31 jul 18 accepted 30 aug 18 figure 1: photographs of the scalp of a 35-year-old male patient with intense scalp pruritus and nodules showing skin redundancy and deep symmetrical cerebriform folds in the frontoparietal, vertex and occipital areas, typical of cutis verticis gyrata. doi: 10.18295/squmj.2018.18.04.025 mónica garcía-arpa, miguel a. flores-terry, lucía gonzález-ruiz, monserrat franco-muñoz and manolo calvo-garcía interesting medical image | e561 cvg is a rare disorder of unknown aetiology which is five times more frequent in men.4 most cases are sporadic, although hereditary cases have been described.2 the prevalence of cvg is unknown in most south american countries, including bolivia; however, a colombian study indicated the prevalence of cvg to be 5.9% among institutionalised patients.5 primary essential cvg usually presents in puberty as symmetric scalp folds extending from the vertex to the occiput which cannot be flattened by traction or pressure.1–3 typically, the folds resemble the brain cortex and extend anteroposteriorly, although they may also occur in a horizontal direction in the occipital region. biopsies of the folds show normal skin histopathology.1,3 on mri, cvg has a typical appearance due to the thickening of the skin and subcutaneous tissues, especially with three-dimensional volume rendering.2 primary essential cvg must be differentiated from secondary cvg. the latter type can manifest in areas other than the scalp and has been associated with different conditions, such as acromegaly and pachydermoperiostosis.6,7 furthermore, cvg has been described among patients receiving external-beam whole-brain radiotherapy, vemurafenib and anabolic steroids.8,9 primary essential cvg may also be associated with certain genetic disorders, like fragile x syndrome.10 other cond itions that may present with cvg include endocrine diseases (i.e. thyroid disease and diabetes mellitus), intracranial and benign scalp tumours, intracerebral aneurysms, internal malignancy, hiv-related lipodystrophy, inflammatory dermatoses and direct cutaneous infiltration in the setting of malignant haematological disease.1,2 in the present case, the patient had a normal karyotype and did not present with any features of other disorders. apart from the cutaneous scalp lesions, the physical examination was normal. furthermore, the patient had no medical or family history of genetic diseases; as such, he was diagnosed with primary essential cvg. as the condition is benign, only symptomatic treatment is necessary.2 careful local hygiene is some times recommended in order to avoid secretions, unplea sant odours and pruritus. surgical treatment is only necessary for aesthetic reasons and ranges from simple excision to tissue expansion and skin grafts, depending on the size and location of the lesions.2 references 1. yang jj, sano dt, martins sr, tebcherani aj, sanchez ap. primary essential cutis verticis gyrata: case report. an bras dermatol 2014; 89:326−8. https://doi.org/10.1590/abd1806-48 41.20142949. 2. tucci a, pezzani l, scuvera g, ronzoni l, scola e, esposito s, et al. is cutis verticis gyrata-intellectual disability syndrome an underdiagnosed condition? a case report and review of 62 cases. am j med genet a 2017; 173:638−46. https://doi.org/10. 1002/ajmg.a.38054. 3. zeljko-penavić j, šimić d, jurišić k, gunarić a. cutis verticis gyrata: a case report. acta dermatovenerol croat 2016; 24:140−3. 4. akesson ho. cutis verticis gyrata and mental deficiency in sweden: ii genetic aspects. acta med scand 1965; 177:459−64. figure 2: volume-rendering magnetic resonance imaging of the scalp of a 35-year-old male patient showing typical features of cutis verticis gyrata. figure 3: axial magnetic resonance imaging scan of the brain of a 35-year-old male patient showing no evidence of intracranial abnormalities. primary essential cutis verticis gyrata a scalp condition that may appear in various disorders e562 | squ medical journal, november 2018, volume 18, issue 4 5. fernando hernández j, espejo jiménez lm, correa díaz rl, de la espriella r. cutis verticis gyrata in adult male institutionalized population in colombia: case series. acta neurol colomb 2015; 31:404−11. https://doi.org/10.22379/2422402259. 6. yerawar c, bandgar t, lila a, shah ns. acromegaly presenting as cutis verticis gyrata. qjm 2016; 109:423. https://doi.org/10. 1093/qjmed/hcw020. 7. sandoval ar, flores-robles bj, llanos jc, porres s, dardón jd, harrison rm. cutis verticis gyrata as a clinical manifestation of touraine-solente-golé syndrome (pachydermoperiostosis). bmj case rep 2013; 2013:bcr2013010047. https://doi.org/10. 1136/bcr-2013-010047. 8. harding jj, barker ca, carvajal rd, wolchok jd, chapman pb, lacouture me. cutis verticis gyrata in association with vemurafenib and whole-brain radiotherapy. j clin oncol 2014; 32:e54−6. https://doi.org/10.1200/jco.2013.49.3528. 9. sommer a, gambichler t, altmeyer p, kreuter a. a case of cutis verticis gyrata, induced by misuse of anabolic substances? clin exp dermatol 2005; 31:129–156. https://doi.org/10.1111/ j.1365-2230.2005.01911.x. 10. schepis c, palazzo r, cannavo sp, ragusa rm, barletta c, spina e. prevalence of primary cutis verticis gyrata in a psychiatric population: association with chromosomal fragile sites. acta derm venereol 1990; 70:483−6. medical disorders in pregnancy may cause complications and have adverse affects on the mother, foetus and the newborn. the physiological changes that occur during pregnancy may aggravate a maternal disease process thus increasing maternal morbidity and mortality rates. it is essential that all who care for pregnant women have insight into medical disorders and the way that these are influenced by pregnancy. adequate knowledge of these medical disorders helps and guides the obstetricians in managing complicated pregnancies. several text books on medical disorders and pregnancy have been published. one of the foremost books in this field, medical disorders in obstetric practice, was first published by professor michael de swiet more than 35 years ago. it was one of the first international text books to focus exclusively on providing expert guidance to obstetricians, medical specialists and anesthesiologists for the care of medical illness during pregnancy. the goal of this book is to provide obstetricians with information in instances in which an optimal medical consultant may be lacking. this fifth edition has been entirely revised, co-written and co-edited by an expert team of practising clinicians from all over the world, including a high risk obstetrician, a medical subspecialist and an obstetric anesthesiologist when required. the team approach provides a broad interdisciplinary practical perspective to the care of medical illness in pregnancy that addresses the entire period from preconception to postpartum follow-up. the current edition’s 50 chapters cover a wide variety of diseases in pregnancy, divided by different body systems. for example, the first five chapters deal with pulmonary, haematological, coronary and thromboemobolic diseases in pregnancy as well as thrombophilia and pregnancy. an entirely new section has been added to the fifth edition. this provides brief, practical, and evidence-based advice from highly experienced clinicians about the proper investigation and safe management of dkëáâ<îåeÿ<ìèf�÷]<l^e]ü�ï˜] ïå˜á÷]<gõ<ìâö^∫<ª<  book review de swiet’s medical disorders in obstetric practice editors: raymond o. powrie, michael f. greene and william camann publisher: wiley-blackwell, 5th edition, 2010 isbn: 978-1-405-1484-74 orders: www.wiley.com/wiley-blackwell squ med j, february 2011, vol. 11, iss. 1, pp. 136-137, epub. 12th feb 11 submitted 28th aug 10 raymond o. powrie, michael f. greene and william camann book review | 137137 | squ medical journal, february 2011, volume 11, issue 1 the most common medical problems in pregnancy. topics covered include syncope, palpitations, headaches and abnormal liver function tests. additional chapters have also been added on a wide range of topics including cancer, critical care, obesity, advanced maternal age and prescribing in pregnancy and lactation. this edition makes much greater use of tables, algorithms, text boxes and figures to summarise and illustrate key points for busy clinicians. a special section of each major chapter now addresses issues related to the provision of anaesthesia care to obstetric patients. almost all chapters include details that cover the needs of an obstetrician. however, the chapter on prescribing in pregnancy has limited details on medications and risks to pregnancy compared to their risks with lactation, a subject that is addressed well in the appendix section. overall, this book is a useful resource for general and high risk obstetricians. it covers many aspects of medical diseases and problems in pregnancy. i would definitely use this book as a reference and i do recommend it to others. r e v i e w e r nihal al-riyami department of obstetrics & gynaecology sultan qaboos university hospital, muscat, oman email: drriyami@hotmail.com squ med j, december 2010, vol. 10, iss. 3, pp. 312-317, epub. 14th nov 10 invited article submitted 17th april 10 revision req. 20th june 10, revision recd. 6th july 10 accepted 13th july 10 the hepatitis c virus (hcv) is a worldwide public health problem affecting an estimated 200 million individuals. there are approximately 3–4 million new cases of hcv infection each year. hcv is a serious infectious problem in the middle east with egypt having the highest prevalence of hcv infection and oman being in the intermediate category.1,2 hcv is a flavivirus comprising 6 genotypes with numerous subtypes. genotype 1 is the most prevalent in europe and north america and the most difficult to treat. genotypes 2 and 3 appear to be more prevalent in the far east. of the other genotypes, genotype 4 is common in africa and the middle east, whereas genotypes 5 and 6 are predominant in south africa and south-east asia, respectively.3-5 only 10% 40% of acute hcv-infected individuals can be cured by spontaneous viral clearance and 60% 90% of infected individuals develop chronic infection.6 there is a very slight chance of clearing the virus spontaneously in chronic hcv carriers (0.5% 0.74%); however, the majority of patients with chronic hepatitis c infection will not clear the infection without treatment. progression of liver diseases usually takes decades and up to 20% of those infected may develop complications including cirrhosis, liver failure, or hepatocellular carcinoma.7 end-stage liver disease, due to infection with hcv, currently represents the major indication for liver transplantation, and the virus universally recurs after transplantation. acute hcv infection is characterised by a delay of 6–8 weeks in the induction of adaptive immunity. this is despite active viral replication; this therefore suggests the failure of innate immunity to contain viral replication and the presence of a blockade in the cross-talk between innate and adaptive department of microbiology & immunology, faculty of medicine, montreal university; montreal, quebec, canada; and montreal university hospital research center (cr-chum), st-luc hospital, montreal, quebec, canada. email: elias_a_said@yahoo.fr t<i<çf”÷]<h^„j÷]<öüπ<<ïçëçq<t¯¬<l^èü]3â˜<ìq^£] –èœç÷]<îá◊§]<9ëü÷]<îêáfl÷]<ò€£]<õ]ç„jâ]        abstract: infection with the hepatitis c virus (hcv) is a worldwide problem. patients with chronic hcv infection who are non-responders to standard therapy represent a growing population within the hcv epidemic. novel, more efficient and tolerable therapies are urgently needed. this review discusses the recent results showing that targeting mir-122, a micro-ribonucleic acid (microrna) that enhances hcv replication, is a new anti-hcv therapy with a high barrier to resistance. keywords: hepatitis c virus; micrornas; interferon; liver; infection; therapy. review the need for new anti-hepatitis c virus therapeutic strategies targeting the cellular micro-ribonucleic acids? elias a said elias a said review | 313 immunity. cd8+ (cluster of differentiation 8) and cd4+ (cluster of differentiation 4) hcvspecific t-cell responses are essential to prevent viral persistence8,9 and it has been demonstrated that infections that progress to chronicity are characterised by a limited immune response either in frequency, magnitude or the number of effector functions that can be detected.10 unfortunately, the mechanisms underlying the inefficient priming of hcv-specific t-cells in infections with chronic evolution are poorly understood. in this review we will discuss how targeting microrna-122 (mir-122), which enhances hcv replication with specific oligonucleotidic sequences, can be a new anti-hcv therapy with a high barrier to resistance. the efficacy of current anti-hcv treatments there is currently no effective anti-hcv vaccine available. the use of interferon-α (ifn-α) for treatment was based on the fact that this cytokine is an important element of the innate antiviral immune response; however, success with the ifnbased therapy was modest. treatment with ifn-α induced a quick decrease of hcv ribonucleic acid (rna) levels in the serum, and the longterm responses were characterised by a sustained absence of hcv rna from the serum and liver, and resolution of the chronic infection. the use of ribavirin and pegylated (peg-) ifn-α, where ifn-α was linked to polyethylene glycol (peg) in order to increase the half-life of ifn, significantly increased the proportion of patients achieving sustained antiviral response (svr).6,7 long-term studies have shown that svr indicates clearance of the virus and cure of the disease. unfortunately, although antihcv therapy combining peg-ifn-α with ribavirin has significantly improved, it leads to sustained clearance in only about 50% of patients and the treatment is frequently associated with severe side effects.6,7 multiple factors can modulate the response to therapy, i.e. viral genotype and patient characteristics. rates of svr range from 42% 46% in patients with genotype 1. in contrast, svr rates for patients with genotypes 2 and 3 are 76 80% and the clearance can be reached with a shorter course of therapy and lower doses of ribavirin. the host determinants of therapy are still not well known. certain patient populations hardly respond to treatment. a transient response with relapse occurs in 10 25% of patients. non-response to treatment occurs in about one-third of chronic hcv-infected patients. these patients never reach clearance, although viral loads might fall at some stage in treatment.6,7 however, treatment in the acute phase of the infection is accompanied by a high rate of response where ifn-α therapy reduces the chronicity rate to 10% or lower. nonetheless, nonresponders among the hcv-infected represent a growing population within the hcv epidemic. the majority of these patients is frequently labelled as “difficult to treat”. they are infected with genotype 1 and have a high viral load and advanced fibrosis or cirrhosis. the best therapy available has been unsuccessful in inducing a virologic response in these patients. clarification of the reasons of nonresponse to ifn-α therapy is a main challenge to research on hcv. the mechanism of how ifn-α inhibits hcv replication remains poorly understood. it has been reported that ifn-α has potent antiviral activity, but does not act directly on the virus or the replication complex. instead, it acts by inducing ifn-stimulated genes (isgs), which establish a non-virus-specific antiviral state within the cell.7 recently, microarray analyses were performed on liver biopsies taken before therapy from a cohort of hcv-infected patients treated with peg-ifn-α and ribavirin. the results showed that patients who were subsequently identified as non-responders had higher baseline expression of isgs than responders to therapy (and those who relapsed); the latter resembled healthy controls more closely. interestingly, peg-ifn-α did not induce the expression of isgs to levels higher than those observed at the pre-treatment stage in the non-responders.7 these findings suggest that non-responders have an up-regulated and largely ineffective ifn response. coincidentally, chimpanzees with chronic hcv infection have high expression levels of isgs; however, neither type-1 nor type-2 ifns are induced during the infection.11,12 although ifn-α could induce isgs expression in healthy chimpanzees, those chronically infected do not respond to ifn treatment and thus appear to be an extreme representative of nonresponders in human hcv-infected patients. this makes chimpanzees an ideal model for the study of non-responsiveness to ifn-α therapy and the need for new anti-hepatitis c virus therapeutic strategies targeting the cellular micro-ribonucleic acids? 314 | squ medical journal, december 2010, volume 10, issue 3 therapy (cart).17-19 therapies that target essential host functions for hcv may provide a high barrier to resistance and, thus, could present an effective approach for the development of new hcv antiviral drugs. sequestrating cellular micrornas is a promising strategy new hope can be given by targeting cellular micrornas that are implicated in the hcv life cycle. micrornas are a class of small non-coding rna molecules that function through posttranscriptional regulation of gene expression. those small rnas are important in development and disease.20 therefore, they represent a potential new class of targets for therapeutic intervention. microrna 122 (mir-122) is specifically expressed in the liver, where it constitutes 70% of the total microrna population.21 three mir-122 binding sites in the hcv genome have been reported: one is located in 3’ non-coding region (ncr) of the hcv genome and its function remains unknown; the other two binding sites are closely located in the 5’ ncr and separated by a highly conserved 14-nucleotides sequence.21 those sequences are highly conserved among the six hcv genotypes. mir-122 binds to sequences in the 5’ ncr of hcv rna, i.e. s1 and s2, resulting in the up-regulation of viral rna levels [figure 1].22 interaction of mir122 with the hcv genome is essential for the accumulation of viral rna in the cultured liver cells and all target sites are required for modulation of hcv rna abundance. although treatment with ifn has been shown to decrease mir-122 levels, no correlation between mir-122 levels in the liver and the viral load was observed upon treatment with ifn.23,24 however, lower levels of mir-122 were observed in non-responders.24 of note, the cd56+ t-cells were shown to inhibit hcv replication by decreasing mir-122 expression. whether this effect is due to the up-regulation of type-i ifn expression by hepatocytes remains to be clarified.25 rna oligonucleotides with exact complementarity to mir-122 have been shown to sequester mir-122 leading to significant decrease in hcv rna accumulation [figure 1]. this observation underscored mir-122 as a potential therapeutic target for the treatment of for the development of novel antiviral agents. overall, although ifn therapy has considerably improved, 50% of the infected individuals with chronic disease do not achieve sustained clearance of hcv. recent studies suggest that the duration of the treatment with peg-ifn plus ribavirin therapy must be determined in each patient according to the on-treatment virological response, i.e. the viral load at 4 weeks and the genotype.13 currently, there are no approved treatment options available for patients who have failed to respond to previous treatments. novel, more efficient and tolerable therapies are urgently needed. a greater understanding of the viral life cycle has led to an increase in the number of possible targets for antiviral intervention. it has resulted in the development of several agents that target specific stages of the life cycle. potential processes for viral inhibition include virus entry into the host cell, proteolytic processing, rna replication and the assembly and release of the new viral particles. those agents include protease inhibitors, i.e., biln 2061 (the trials were stopped due to severe side effects in the animal model); proceprevi sch 503034 and telaprevir (both tested in phase ii); polymerase inhibitors (i.e., valopicitabine, bilb 1941– the trials were stopped due to gastrointestinal-related side effects); immune modulators (i.e., ana 975 for tlr7) and host factor inhibitors (i.e., nim-811 for cyclophilin b). a very recent study showed the potential clinical antihcv effect of bms-790052, an inhibitor of ns5a, which is an hcv protein with no known enzymatic function.14 a list of other trials, including two other forms of ifn (albuferon [albumin ifn]) and locteron (a newly developed controlled-release formulation of lemna-derived free (unpegylated) recombinant interferon-α2b), can be found on the website of the hiv and hepatitis treatment advocates, inc.15 however, the generation and selection of resistant variants can allow the virus to escape the antiviral pressure exerted by treatment. indeed, mutations in both the polymerase and protease enzymes have already been identified.16 the hiv infection model suggests that the combination of different anti-viral therapies might decrease hcv chances to develop escape mutations; however recent studies on hivinfected patients demonstrated the emergence of drug resistance during receipt of combined therapy and described a relatively common virological failure by 8 years of combination antiretroviral elias a said review | 315 hcv infection. locked nucleic acid (lna) technology20 has been introduced into the development of an efficient approach for mir122 targeting in vivo and high-affinity lnamodified dna oligonucleotides (lna anti-mirs) complementary to mir-122 were developed.26 lna-modified nucleosides are a class of nucleic acid analogues in which the ribose ring is “locked” by a methylene bridge connecting the 2’-o atom and the 4’-c atom. by “locking” the molecule with the methylene bridge, the lnamodified nucleosides are constrained in the ideal conformation for watson-crick binding.20 when incorporated into a dna oligonucleotide, lna therefore enhances the speed of the pairing with a complementary nucleotide strand and increases the stability of the resulting duplex. phosphorothioate modifications have been shown to provide good pharmacokinetic and tissue uptake properties in antisense oligonucleotides along with protection against nucleases. moreover, it has been reported that specific mir-122 silencing in vivo using a lna-modified phosphorothioate oligonucleotide (spc3649) complementary to the 5’-end of mir-122 leads to long-lasting decrease of serum cholesterol in mice and african green monkeys, which make it possible to inhibit the mir-122 function in vivo. thus, it was tempting to investigate the potential of mir-122 antagonism as a new anti-hcv therapy. the potential role of spc3649 as a new antihcv treatment was tested in chronically hcvinfected chimpanzees.26 treatment with high doses of spc3649 induced a decrease of 2.3 log10 in hcv rna levels in the liver of the animals. these results showed that mir-122 is essential for accumulation of hcv rna in vivo. moreover, the absence of viral resistance to therapy during treatment with spc3649 has been demonstrated. this lack of viral resistance to spc3649 is in striking contrast to what has been observed with direct acting antiviral drugs in hcv-infected chimpanzees. within two days of treatment with a non-nucleoside polymerase inhibitor, 67% of the hcv clones already possessed known resistance mutations, with 10% of the clones figure 1: the binding of mir-122 to hepatitis c virus (hcv) genome and its inhibition by spc3649. the attachment of mir-122 to target sites, s1 and s2, in the 5’utr of hcv ribonucleic acid (rna) induces an increase in the amount of viral rna and thus viral replication. the locked nucleic acid (lna)-anti-mir-122, spc3649, binds to mir-122 and prevents its interaction with hcv rna, which inhibits the replication of hcv. the need for new anti-hepatitis c virus therapeutic strategies targeting the cellular micro-ribonucleic acids? 316 | squ medical journal, december 2010, volume 10, issue 3 currently being explored and could decrease hcv replication.27 of note, two other micrornas, mir199a and mir-196, were identified as possible targets for anti-hcv therapy as, in contrast to mir122, the overexpression of these two molecules leads to the inhibition of hcv replication in the replicon system in vitro.28,29 however, the effect of these molecules should be validated on real hcv infection in vitro prior to testing them in the animal model and then in clinical trials. conclusion many therapeutic strategies against hcv infection are available, such as the combination of peg-ifn and ribavirin. however, the failure of these therapies, because of viral escape or the non-response of many patients to these therapies, makes the use of lna-modified phosphorothioate oligonucleotide (spc3649), which blocks mir-122, a very potent anti-hcv treatment with no side effects or escape mutations. references 1. hoofnagle jh. course and outcome of hepatitis c. hepatology 2002; 36:s21–9. 2. hepatitis c. geneva: world health organization, 2002. pp. 1–69 (who/cds/csr/lyo/2003) from: http://www.who.int/csr/disease/hepatitis/hepc.pdf. accessed: march 2010. 3. gish rg, lau jyn. hepatitis c virus: eight years old. viral hep rev 1997; 3:17–37. 4. maertens g, stuyver l. genotypes and genetic variation of hepatitis c virus. in: harrison tj, zuckerman aj, eds. the molecular medicine of viral hepatitis. hoboken, nj: wiley, 1997. pp. 183–233. 5. mcomish f, yap pl, dow bc, follett ea, seed c, keller aj, et al. geographical distribution of hepatitis c virus genotypes in blood donors: an international collaborative survey. j clin microbiol 1994; 32:884–92. 6. manns mp, mchutchison jg, gordon sc, rustgi vk, shiffman m, reindollar r, et al. peg-interferon alfa2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis c: a randomised trial. lancet 2001; 358:958–65. 7. sarasin-filipowicz m, oakeley ej, duong fh, christen v, terracciano l, filipowicz w, et al. interferon signaling and treatment outcome in chronic hepatitis c. proc natl acad sci usa 2008; 105:7034–9. 8. dustin lb, rice cm. flying under the radar: the having two resistance mutations, which triggered a rapid rebound in viraemia.26 the reduction in viraemia upon treatment with spc3649 was clearly associated with a down-regulation of most ifn-regulated genes (irgs) in chimpanzees. this correlated with serum levels of the chemokine ip10 (cxcl10), a highly induced irg during hcv infections.26 these data show that the endogenous ifn pathway in the liver is rapidly normalised in response to inhibition of hcv rna accumulation even when therapy does not completely eradicate detectable viral rna. thus, the treatment with spc3649 results in the normalisation of irg levels suggesting that this therapy could be used to convert the ifn non-responders, described above, to responders by reducing the viral load. to assess the safety of the treatment with spc3649, complete blood counts, blood chemistries, coagulation markers, urinalysis, and complement activation were determined throughout the study, as were lymphocyte subsets, circulating cytokine-chemokine profiles and additional safety parameters. no spc3649-related abnormalities were observed for any of the measurements.26 alanine aminotransferase (alt) was reduced to normal levels, likely due to reduction in the viral load, and was again elevated at the end of the followup period when viraemia returned to baseline. histological examinations of the baseline liver biopsies revealed hcv-specific changes including mild hepatocellular swelling with disruption of hepatocellular sinuses and cords. improved liver histology was observed after treatment at week 19, indicating a response to prolonged suppression of viraemia and normalisation of the ifn pathway.26 indeed, none of the treated chimpanzees achieved svr, thus a longer course, higher dose and optimisation of the delivery methods should be considered. however, these results show the feasibility and safety of the prolonged administration of an lna oligonucleotide drug that antagonises the function of a specific microrna in a highly relevant disease model and pave the way for new anti-hcv treatments that are greatly needed. although targeting mir-122 had no major side effects, modulating other micrornas might have non-desirable impacts as they might inhibit or enhance one or more cell functions rendering the therapeutic molecule toxic. other molecules targeting mir-122 are elias a said review | 317 19. lihana rw, khamadi sa, lubano k, lwembe r, kiptoo mk, lagat n, et al. hiv type 1 subtype diversity and drug resistance among hiv type 1-infected kenyan patients initiating antiretroviral therapy. aids res hum retroviruses 2009; 25:1211–7. 20. fluiter k, mook or, baas f. the therapeutic potential of lna-modified sirnas: reduction of offtarget effects by chemical modification of the sirna sequence. methods mol biol 2009; 487:189–03. 21. niepmann m. activation of hepatitis c virus translation by a liver-specific microrna. cell cycle 2009; 8:1473–7. 22. jangra rk, yi m, lemon sm. regulation of hepatitis c virus translation and infectious virus production by the microrna mir-122. j virol 2010; 84:6615– 25. 23. pedersen im, cheng g, wieland s, volinia s, croce cm, chisari fv, et al. interferon modulation of cellular micrornas as an antiviral mechanism. nature 2007; 449; 919–22. 24. sarasin-filipowicz m, krol j, markiewicz i, heim mh, filipowicz w. decreased levels of microrna mir-122 in individuals with hepatitis c responding poorly to interferon therapy. nat med 2009; 15:31–3. 25. ye l, wang x, wang s, wang y, song l, hou w, et al. cd56+ t cells inhibit hepatitis c virus replication in human hepatocytes. hepatology 2009; 49:753–62. 26. lanford re, hildebrandt-eriksen es, petri a, persson r, lindow m, munk me, et al. therapeutic silencing of microrna-122 in primates with chronic hepatitis c virus infection. science 2010; 327:198–201. 27. young dd, connelly cm, grohmann c, deiters a. small molecule modifiers of microrna mir122 function for the treatment of hepatitis c virus infection and hepatocellular carcinoma. j am chem soc 2010; 132:7976–81. 28. hou w, tian q, zheng j, bonkovsky hl. microrna196 represses bach1 protein and hepatitis c virus gene expression in human hepatoma cells expressing hepatitis c viral proteins. hepatology 2010; 51:1494– 504. 29. murakami y, aly hh, tajima a, inoue i, shimotohno k. regulation of the hepatitis c virus genome replication by mir-199a. j hepatol 2009; 50:453–60. immunobiology of hepatitis c. annu rev immunol 2007; 25:71–99. 9. shoukry nh, cawthon ag, walker cm. cellmediated immunity and the outcome of hepatitis c virus infection. annu rev microbiol 2004; 58:391– 424 . 10. gruener nh, lechner f, jung mc, diepolder h, gerlach t, lauer g, et al. sustained dysfunction of antiviral cd8+ t lymphocytes after infection with hepatitis c virus. j virol 2001; 75:5550–8. 11. bigger cb, guerra b, brasky km, hubbard g, beard mr, luxon ba, et al. intrahepatic gene expression during chronic hepatitis c virus infection in chimpanzees. j virol 2004; 78:13779–92. 12. lanford re, guerra b, bigger cb, lee h, chavez d, brasky km. lack of response to exogenous interferonalpha in the liver of chimpanzees chronically infected with hepatitis c virus. hepatology 2007; 46:999–1008. 13. zeuzem s, poordad f. pegylated-interferon plus ribavirin therapy in the treatment of chc: individualization of treatment duration according to on-treatment virologic response. curr med res opin 2010; 26:1733–43. 14. gao m, nettles re, belema m, snyder lb, nguyen vn, fridell ra, et al. chemical genetics strategy identifies an hcv ns5a inhibitor with a potent clinical effect. nature 2010; 465:96–100. 15. hcv experimental treatments hiv and hepatitis treatment advocates, inc. from: http://www. hivandhepatitis.com/hep_c/hepc_news_alter.html. accessed: sept 2010. 16. kieffer tl, kwong ad, picchio gr. viral resistance to specifically targeted antiviral therapies for hepatitis c (stat-cs). j antimicrob chemother 2010; 65:202– 12. 17. uk collaborative group on hiv drug resistance. long-term probability of detecting drug-resistant hiv in treatment-naive patients initiating combination antiretroviral therapy. clin infect dis 2010; 50:1286–7. 18. gupta r, hill a, sawyer aw, pillay d. emergence of drug resistance in hiv type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials. clin infect dis 2008; 47:712–22. department of obstetrics, gynecology & oncology, medical university of warsaw, warsaw, poland *corresponding author e-mail: drnabilabdalla@yahoo.com ورم دموي حتت السلوي مرتبط بوالدة خالية من األحداث نبيل عبد اهلل، روبرت بيوركوا�سكي، باأول �ستانريوي�سكي، كريز�ستوف �سيندو�سكر�سي، لودزمريز �ساويكي subamniotic haematoma associated with an uneventful labour *nabil abdalla, robert piorkowski, pawel stanirowski, krzysztof cendrowski, wlodzimierz sawicki a 34-year-old caucasian multiparous woman (gravida 3, para 1) in labour was admitted to the department of obstetrics, gynecology & oncology, medical university of warsaw, poland, in 2016 at 40 gestational weeks and three days. her pregnancy had been uneventful, aside from the development of gestational diabetes, which was controlled by dietary changes. an ultrasonogram showed a fundal placenta with no abnormalities. the membranes ruptured spontaneously 50 minutes after admission. the first and second stages of labour lasted for 9 hours and 40 minutes, respectively. cardiotocography monitoring did not show any abnormalities. the fetal head was delivered in the occiput posterior position. the infant’s apgar scores were 9, 9 and 10 at the first, third and fifth minutes, respectively. at birth, the baby weighed 4,280 g. active management of the third stage of labour was undertaken and the placenta was delivered 5 minutes later by controlled cord traction. the placenta measured 19 x 18 cm. a macroscopic inspection showed a subamniotic haematoma measuring 15 x 8 x 7 cm located between the amnion and chorionic plate [figure 1a]. after rupturing the haematoma, a pale area of 6 x 5 cm in size could be observed at the base of the haematoma [figure 1b]. the umbilical cord had three blood vessels. a microscopic histopathological examination showed an ischaemic infarction in the observed pale area. no other abnormalities were noted in the placenta, amniotic membranes or umbilical cord. the first three days of the puerperal period were uneventful. the results of a maternal full blood count on the second day following delivery indicated a haemoglobin level of 10.6 g/dl and red blood cell (rbc) count of 3.64 x 106/µl. an echocardiogram and cranial and abdominal ultrasounds of the neonate were normal. on the third day, the blood tests showed a haemoglobin level of 16.7 g/dl and rbc count of 4.78 x 106/µl. both the mother and baby were subsequently discharged in good condition later that day. figure 1: photographs showing (a) a subamniotic haematoma (arrow) and (b) an ischaemic infarction (arrow) in the placenta of a 34-year-old caucasian multiparous woman following an uneventful labour at 40 gestational weeks. interesting medical image sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e366–367, epub. 10 oct 17 submitted 6 feb 17 revision req. 27 feb 17; revision recd. 30 mar 17 accepted 12 apr 17 doi: 10.18295/squmj.2017.17.03.021 coincidental, as a placental infarction that results from the arrest of maternal intervillous blood flow from the uteroplacental spinal arteries cannot be related to the rupture of a chorionic vessel.2 as such, the placenta in the present case was sent for histopathological examination to assess the solid mass of the placenta and to exclude rare placental neoplasms, such as a chorioangioma.4 placental infarctions may also be related to gestational diabetes.5 references 1. loi k, tan kt. massive pre-placental and subchorionic haematoma. singapore med j 2006; 47:1084–6. 2. deans a, jauniaux e. prenatal diagnosis and outcome of subamniotic hematomas. ultrasound obstet gynecol 1998; 11:319–23. doi: 10.1046/j.1469-0705.1998.11050319.x. 3. van den bosch t, van schoubroeck d, cornelis a, dubin m. prenatal diagnosis of a subamniotic hematoma. fetal diagn ther 2000; 15:32–5. doi: 10.1159/000020971. 4. abdalla n, bachanek m, trojanowski s, cendrowski k, sawicki w. placental tumor (chorioangioma) as a cause of polyhydramnios: a case report. int j womens health 2014; 6:955–9. doi: 10.2147/ijwh.s72178. 5. salge ak, rocha km, xavier rm, ramalho ws, rocha él, guimarães jv, et al. macroscopic placental changes associated with fetal and maternal events in diabetes mellitus. clinics (sao paulo) 2012; 67:1203–8. doi: 10.6061/clinics/2012(10)13. comment placental haematomas can be anatomically classified into three main types: subchorionic, retroplacental and subamniotic.1 the origin of blood in retroplacental and subchorionic haematomas is maternal. however, subamniotic placental haematomas are rare and result from the rupture of chorionic vessels near the umbilical cord insertion; most of these types of haematomas are discovered after birth and result from excessive traction of the umbilical cord.1,2 however, some may occur during pregnancy, with van den bosch et al. previously reporting an antenatal subamniotic haematoma diagnosed at 34 gestational weeks and associated with an uneventful pregnancy and labour.3 in the current case, the precise moment of formation of the haematoma could not be established. it may have developed during labour or due to excessive traction of the umbilical cord. however, as the bleeding arose from the allantochorionic vessels and surprisingly had no effect on the fetus and the course of labour was uneventful, this may suggest that the haematoma was formed during the third stage of labour. the presence of both a placental infarction and subamniotic haematoma is rather nabil abdalla, robert piorkowski, pawel stanirowski, krzysztof cendrowski and wlodzimierz sawicki interesting medical image | 367 https://doi.org/10.1046/j.1469-0705.1998.11050319.x https://doi.org/10.1159/000020971 https://doi.org/10.2147/ijwh.s72178 https://doi.org/10.6061/clinics/2012%2810%2913 as in many countries, the public health-care system in oman strives to maintain high-quality services despite rising costs.1 between 1970 and 2017, healthcare services in the country have witnessed remarkable improvements, resulting in an increase in the life expectancy of omanis from 49 to 75 years and a drop in the infant mortality rate from 120 to 9 cases per 1,000 live births.2 notably, the world health organization ranked the health system in oman to be the eighth best in the world in 2000.3 the omani government provides universal health coverage, ensuring free access to omani citizens and subsidised services for expatriates; however, this makes the system vulnerable to unnecessary waste and results in avoidable operational costs. between 2000 and 2010, healthcare expenditures constituted approximately 3% of the gross domestic pro duct; in 2016, this was equivalent to about $3.4 billion usd allocated mainly to the ministry of health, which handles almost 80% of all healthcare expenditures.4 in 2017, the omani government reduced overall healthcare expenditures by 47% to $1.6 billion usd.5 nevertheless, it has been projected that healthcare expenditures in oman will continue to rise at an annual rate of 12.9%, with total healthcare expenditures reaching $4.3 billion usd by 2020.6 as in other gulf cooperation council (gcc) countries, securing and maintaining sufficient financial support for healthcare expenditures in oman can be challenging due to fluctuations in crude oil prices. as a result, there is an urgent need to adopt sustainable cost-reducing operational models, thereby reducing costs without compromising the quality of healthcare services. one particular model is the adoption of lean man agement (lm), a system that originated in the japanese automobile industry and focuses on value-creating pro cesses.7,8 in the healthcare sector, an lm approach is based on five important principles.9 the first is ident ifying value in patient care-related activities. the second is creating a value stream map (vsm) of the entire patient care process from entrance to discharge so as to identify which parts are necessary and which are wasteful.9 the third is creating flow to ensure that discrete activities within the process are aligned and standardised based on best practices. the fourth is establishing a pull system, whereby each activity is a product of the prior step.9 finally, the fifth principle is seeking perfection in a cycle of continuous quality improvement. there is a growing body of research regarding the applications and potential benefits of lm principles in healthcare; however, much of this research is sourced from hospitals in developed countries, with very limited research in other contexts.10 in particular, a recent review of the literature found that there was limited research on this topic being conducted in the gcc region.11 in oman, al farsi et al. recommended that lean improvement pilot projects be undertaken so as to guide the development of a national strategy for implementing lm principles in the healthcare sector.7 in the august 2018 issue of squmj, al-balushi et al. published a study describing the implementation of lm principles in the radiation oncology department of a tertiary hospital in muscat, oman.12 the study aimed to streamline workflow and reduce waste in response to a transition that had occurred following the decomm issioning of a treatment machine. various lm concepts were introduced via continuing medical education act ivities and a vsm was created to outline the chain of processes followed in the department.12 the vsm indic ated that only six out of 13 steps were value-adding; accordingly, several waste-reduction strategies were introduced. the authors concluded that the application of lm principles improved workflow, reduced waste and enhanced patient and staff satisfaction.12 the findings of such pilot studies are promising and indicate the successful implementation of lm principles in one omani setting. however, in terms of the readiness of the entire healthcare system, there are seven readiness factors which need to be taken into account in order to ensure the successful launch of lm in healthcare in 1department of family medicine & public health, college of medicine & health sciences and 2department of operations management & business statistics, college of economics & political science, sultan qaboos university, muscat, oman *corresponding author’s e-mail: ymfarsi@squ.edu.om كن رشيقا، واسعى حنو مزيد من الرشاقة تطبيق "إدارة اللني" يف الرعاية الصحية العمانية يحي حممد الفار�شي و �شاهد حممود البلو�شي editorial go lean, get leaner the application of lean management in omani healthcare *yahya m. al-farsi1 and shahid m. al-balushi2 sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e431–432, epub. 28 mar 19 submitted 17 jan 19 revision req. 11 feb 19; revision recd. 19 feb 19 accepted 21 feb 19 doi: 10.18295/squmj.2018.18.04.001 go lean, get leaner the application of lean management in omani healthcare e432 | squ medical journal, november 2018, volume 18, issue 4 oman.11 these factors are: (1) leadership support; (2) the identification of lm principles in a strategic agenda; (3) an understanding of the concept of value and specific customer groups in healthcare; (4) having a complete end-to-end view of the entire process; (5) the training and involvement of personnel; (6) the implementation of measurement and reward systems; and (7) matching of demand and capacity levels.11 maijala et al. found that the characteristics of leadership and management associated with the successful adoption of lm thinking in healthcare were mainly conceptualised as skills and capabilities, such as making changes occur, being empow ered, communicating, facilitating and organisational success.13 nevertheless, it is also important to evaluate the results of such studies in view of the limitations associated with lm implementation. despite the success concluded by al-balushi et al., there may be challenges in sustaining these improvements in the long term.12 for example, the main motivation for implementing lm principles in this case was to overcome an antic ipated yet temporary disruption in workflow. however, the lm model aims to completely transform an organisation’s thinking, ultimately leading to holistic and funda mental changes in behaviour and culture over time in a continuous cycle of waste reduction and quality impr ovement.9,14 in the usa, shortell et al. found that there were wide variations in terms of the degree of lm implem entation in hospitals and that lm concepts took time to gain traction; moreover, they found that the length of time performing lm activities was positively associated with implementation progress and resulted in a positive impact on performance.15 furthermore, it is possible that the successes rep orted by pilot studies such as that of al-balushi et al. might not be reproducible or sustainable.12 mazzocato et al. reported that research on the sustainability of lm principles in healthcare is limited, with primary studies often lacking appropriate or explicit concepts, designs, analysis and outcome measures necessary to produce valid and generalisable results that ensure reproducibility and sustainability.16 for example, in al-balushi et al.’s study, no survey was conducted to assess patient and staff satisfaction regarding the application of lm principles.12 in addition, no statistical or objective analysis was performed to quantitatively assess the timeliness of treatment delivery. in conclusion, lm appears to be a strategy which has the potential to cause a transformational shift in the efficiency of the healthcare setup in oman; moreover, existing research shows that the omani healthcare sector has most of the readiness factors necessary for the success ful implementation of lm principles.7,11,13 nevertheless, it is important to take into consideration the holistic and long-term scope of the lm model, as well as the limitations associated with the application of lm principles in healthcare settings. references 1. al-riyami a. health vision 2050 oman: a committed step towards reforms. oman med j 2012; 27:190–1. https://doi.org/10.5001/ omj.2012.43. 2. oman ministry of health. annual reports. from: www.moh. gov.om/en/web/statistics/annual-reports accessed: feb 2018. 3. world health organization. the world health report 2000: health systems improving performance. from: www.who.int/ whr/2000/en/ accessed: feb 2019. 4. oman national centre for statistics and information. statistical year book 2017. from: www.ncsi.gov.om/elibrary/libr arycontentdoc/bar_statistical%20year%20book%202017_ c2111831-e13a-4075-bf7b-c4b5516e1028.pdf accessed: feb 2019. 5. oxford business group. oman’s health care system increasingly ready to meet the population’s needs. from: https://oxfordbusine ssgroup.com/overview/rise-growing-population-finds-healthcare-system-ready-meet-its-needs accessed: feb 2019. 6. alpen capital. alpen capital forecasts steady growth for the gcc healthcare industry. from: www.alpencapital.com/news/ 2018/2018-march-26.html accessed: feb 2019. 7. al farsi y, al abri r, al hajri a, al balushi s. the need for lean thinking in the omani health care sector. oman med j 2014; 29:248–9. https://doi.org/10.5001/omj.2014.66. 8. liker jk. the toyota way: 14 management principles from the world’s greatest manufacturer, 1st ed. new york, usa: mcgraw-hill, 2004. pp. 67–330. 9. graban m. lean hospitals: improving quality, patient safety, and employee engagement, 2nd ed. new york, usa: productivity press, 2011. pp. 1–16. 10. henrique db, filho mg. a systematic literature review of empirical research in lean and six sigma in healthcare. total qual manag bus excell 2018. https://doi.org/10.1080/1478336 3.2018.1429259. 11. al-balushi s, sohal as, singh pj, al-hajri a, al-farsi ym, al-abri r. readiness factors for lean implementation in healthcare settings: a literature review. j health organ manag 2014; 28:135–53. https://doi.org/10.1108/jhom-04-2013-0083. 12. al-balushi mm, al-mandhari z. implementing lean management techniques at a radiation oncology department. sultan qaboos univ med j 2018; 18:e362–6. https://doi.org/10.18295/ squmj.2018.18.03.016. 13. maijala r, eloranta s, reunanen t, ikonen ts. successful impl ementation of lean as a managerial principle in health care: a conceptual analysis from systematic literature review. int j tech nol assess health care 2018; 34:134–46. https://doi.org/10.10 17/s0266462318000193. 14. smith g, poteat-godwin a, harrison lm, randolph gd. applying lean principles and kaizen rapid improvement events in public health practice. j public health manag pract 2012; 18:52–4. https://doi.org/10.1097/phh.0b013e31823f57c0. 15. shortell sm, blodgett jc, rundall tg, kralovec p. use of lean and related transformational performance improvement systems in hospitals in the united states: results from a national survey. jt comm j qual patient saf 2018; 44:574–82. https://doi.org/ 10.1016/j.jcjq.2018.03.002. 16. mazzocato p, holden rj, brommels m, aronsson h, bäckman u, elg m, et al. how does lean work in emergency care? a case study of a lean-inspired intervention at the astrid lindgren children’s hospital, stockholm, sweden. bmc health serv res 2012; 12:28. https://doi.org/10.1186/1472-6963-12-28. 290 | squ medical journal, may 2011, volume 11, issue 2 sir, i would like to congratulate you on your a timely editorial in the february issue of squmj1 which has strangely coincided with a clinical review by davies et al. recently published in the british medical journal.2 according to davies et al., an estimated 30% of imaging may be unnecessary. some of the most relevant issues have been brought by prof. lamki including the massive increase in the number of procedures performed, and the need to educate both physicians and patients. the arguments in favour of imaging are growing as it is non-invasive compared to surgical procedures and thus increases patient satisfaction, etc. medical imaging and nuclear medicine is also the most sought after specialty in oman, india and even western countries for postgraduate studies. this development is at the expense of bedside clinical examination which is becoming a forgotten art at the expense of technology and high radiation exposure. we do not hear any more of mcburney and murphy in morning meetings, but only that (computed tomography) ct abdomen ruled out appendicitis and so on. this wake-up call is necessary not only for oman, but also for the rest of the world, as the risks of radiation exposure are underestimated by both patients and physicians. vaidyanathan gowri department of obstetrics & gynaecology college of medicine & health sciences sultan qaboos university, muscat, oman email: gowri@squ.edu.om references 1. al lamki l. radiation exposure from medical imaging a wake up call for oman. squ med j 2011; 11:1-4. 2. davies he, wathen cg, gleeson fv. the risks of radiation exposure related to diagnostic imaging and how to minimise them bmj 2011; 342:d947 doi: 10.1136/bmj.d947 cite this as: bmj 2011; 342:d947. squ med j, may 2011, vol. 11, iss. 2, pp. 290, epub. 15th may 11 received 12th mar 11 <≈^√ç˛÷<öü√j÷]<vó◊¬<åö 9�÷]<üëáíj÷]<‡⁄ =·^€�√÷<ö]ñfic<åüq re: radiation exposure from medical imaging a wake-up call for oman! letter to editor 1department of obstetrics & gynaecology, indian naval hospital ship asvini, mumbai, india; 2department of clinical microbiology & infectious diseases, army college of medical sciences & base hospital, new delhi, india *corresponding author’s e-mail: titan_afmc@yahoo.com نتائج التوليد والوالدة عند احلجاج احلوامل من اهلند خربة ثالث سنوات يف بعثة احلج اهلندية الطبية �شازيا خان و اإنعام داني�ص خان abstract: objectives: the hajj, an annual mass gathering of muslim pilgrims, is known for its high morbidity and mortality rates. however, pregnant women sometimes participate in this pilgrimage, despite guidelines that discourage such an undertaking due to potential fetomaternal complications. this study aimed to evaluate fetomat ernal outcomes among pregnant indian hajj pilgrims. methods: this prospective cross-sectional study was conducted at two indian hajj medical mission (ihmm)-affiliated secondary care hospitals in saudi arabia during the hajj periods of august–october 2015 and 2016 and july–september 2017. all female indian pilgrims of reproductive age who underwent pregnancy screening at secondary care ihmm hospitals during this period were included in the study. definitive obstetric care was provided at the makkah maternity & child hospital. data regarding the pilgrims’ obstetric characteristics, antenatal complications, management and fetomaternal outcomes were evaluated. results: a total of 114 pregnant indian pilgrims were identified during the study period. the most common antenatal complications were respiratory tract infections (51.75%), followed by iron deficiency anaemia (17.54%), hyperemesis gravidarum (14.04%), hypothyroidism (9.65%) and gestational diabetes mellitus (5.26%). there were 20 vaginal deliveries (17.54%), two caesarean sections (1.75%) and 32 abortions (28.07%). the cumulative three-year birth rate was 24.60 per 1,000 females. conclusion: during hajj, pregnant pilgrims have a high risk of abortion, respiratory tract infections and various antenatal, perinatal and neonatal complications which may go unreported or untreated. women should therefore be educated regarding the risk of adverse fetomaternal outcomes which may occur while undertaking a hajj pilgrimage during pregnancy. keywords: travel medicine; muslims; pregnancy outcomes; miscarriage; respiratory infections; saudi arabia. امللخ�ص: الهدف: احلج، وهو جتمع جماعي �شنوي للحجاج امل�شلمني، ومعروف مبعدلت مرا�شة ووفيات عالية. ومع ذلك، ت�شارك الن�شاء احلوامل اأحيانا يف هذا املو�شم على الرغم من املبادئ التوجيهية التي تثبط مثل هذه امل�شاركات ب�شبب امل�شاعفات الأمومية اجلنينية. تهدف هذه الدرا�شة اإىل تقييم النتائج الأمومية اجلنينية بني احلجاج احلوامل من الهند. الطريقة: اأجريت هذه الدرا�شة الإ�شتباقية امل�شتعر�شة يف اأثنني من م�شت�شفيات رعاية ثانوية للحّج الطبي يف اململكة العربية ال�شعودية خالل فرتات احلج من اأغ�شط�ص-اأكتوبر 2015 و 2016 ويوليو-�شبتمرب 2017. �شملت هذة الدرا�شة جميع احلجاج الن�شاء من الهند يف �شن الأجناب والالآتي خ�شعن لفح�ص احلمل يف م�شت�شفيات الرعاية الثانوية التابعة لبعثة احلج الهندية. مت توفري الرعاية التوليدية النهائية يف م�شت�شفى مكة للولدة والأطفال. مت تقييم املعطيات من 114 حتديد مت النتائج: اجلنينية. الأمومية والنتائج والإدارة للولدة ال�شابقة وامل�شاعفات التوليدية احلجاج بخ�شائ�ص املتعلقة احلجاج الهنود احلوامل خالل فرتة الدرا�شة. كانت اأكرث م�شاعفات ما قبل الولدة �شيوعا هي التهابات اجلهاز التنف�شي )%51.75( يليها فقر الدم ب�شبب نق�ص احلديد )%17.54(، تقيء احلمل املفرط )%14.04(، ق�شور الغدة الدرقية )%9.65( و�شكري احلمل )%5.26(. كان هناك 20 حالة ولدة مهبلية )%17.54(، وحالتان لولدة قي�شريية )%1.75( و 32 حالة اإجها�ص )%28.07(. وبلغ معدل الولدة الرتاكمي ملدة ثالث �شنوات 24.60 لكل 1,000 امراأة. اخلال�صة: اأثناء احلج، يكون احلجاج احلوامل اأكرث عر�شة لالإجها�ص، والتهابات اجلهاز التنف�شي وم�شاعفات ما قبل الولدة والفرتة املحيطة بالولدة وم�شاعفات التوليد والتي قد ل يتم الإبالغ عنها اأو عدم عالجها. لذلك يجب اأن يتم تعليم الن�شاء فيما يتعلق بخطر النتائج املعاك�شة الأمومية اجلنينية والتي قد حتدث للحوامل اأثناء اأداء فري�شة احلج. الكلمات املفتاحية: طب ال�شفر؛ امل�شلمني؛ نتائج احلمل؛ اإجها�ص؛ التهابات اجلهاز التنف�شي؛ اململكة العربية ال�شعودية. obstetric and neonatal outcomes of pregnant indian pilgrims a three-year experience at the indian hajj medical mission shazia khan1 and *inam d. khan2 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e355–361, epub. 19 dec 18 submitted 21 jan 18 revisions req. 18 feb & 18 mar 18; revisions recd. 28 feb & 19 mar 18 accepted 12 apr 18 doi: 10.18295/squmj.2018.18.03.015 advances in knowledge this prospective study is the first of its kind to evaluate fetomaternal outcomes among pregnant indian hajj pilgrims. the cumulative three-year birth rate was 24.60 per 1,000 women. the most common antenatal complications were respiratory infections, followed by iron deficiency anaemia. there was also a high incidence of abortions and other adverse pregnancy and neonatal outcomes. application to patient care mass gatherings increase the transmissibility of respiratory pathogens. in addition, local healthcare systems may not be able to detect antenatal complications during hajj or may experience transport difficulties due to crowded conditions, potentially leading to neonatal morbidity and mortality. pregnant women considering undertaking hajj pilgrimage should be educated regarding such risks. obstetric and neonatal outcomes of pregnant indian pilgrims a three-year experience at the indian hajj medical mission e356 | squ medical journal, august 2018, volume 18, issue 3 the hajj is an annual muslim pilgrimage of more than 2.3 million people from all over the world.1 hajj forms one of the five pillars of islam and is obligatory for all able-bodied men and women of requisite means.2 muslims consider hajj to be the most important pilgrimage for spiritual enlight enment during their lifetime. however, the pilgrimage involves physically demanding rituals which take place over approximately 45 days in the desert climate of saudi arabia, sometimes without adequate nourishment, hyd ration or sufficient rest.2 furthermore, hajj is associated with high rates of morbidity and mortality due to various factors, including old age, chronic diseases, infectious disease outbreaks, accidents and disasters, all of which require appropriate surveillance and emergency response systems.3–5 mass gathering medicine is challenging due to the increased transmission of communicable diseases, limited healthcare accessibility, the often overwhelming number of patients and difficulties in evacuating patients during emergencies. healthcare during hajj is also affected by pilgrim diversity and vulnerability, despite yearly efforts to augment resources and enhance preparedness.6–8 while the holy quran does not prohibit performing hajj during pregnancy and air travel during this time is considered safe, the governments of several countries actively discourage women from undertaking hajj while pregnant.9–12 nevertheless, pregnant women regularly undertake this arduous journey, sometimes in the belief that giving birth in the holy cities of makkah or medina will confer spiritual benefit. such pregnancies are often not declared and remain largely undetected prior to departure for hajj.10 the indian hajj medical mission (ihmm) caters to pregnant indian women during their pilgrimage before transferring them to saudi arabian state-sponsored hosp itals for appropriate fetomaternal care.7,8 the ihmm comprises a multi-tier network of medical outreach teams, mobile medical task forces, primary care clinics, tent clinics and two secondary care hospitals with 30–40 beds each. in addition, the ihmm has referral and evacuation capabilities in makkah, medina and jeddah.7,8 to the best of the authors’ knowledge, no data have yet been reported in the literature regarding pregnancy and neonatal outcomes during hajj or in comparable mass gathering settings. this study therefore aimed to evaluate the obstetric and neonatal outcomes of pregnant indian hajj pilgrims over a three-year period from 2015–2017. methods this prospective cross-sectional study was conducted at two ihmm-affiliated secondary care hospitals in saudi arabia during the hajj seasons of august–october 2015 and 2016 and july–september 2017. all female indian pilgrims between 15–45 years old with amenorr hoea who were seen at secondary care ihmm hospitals during the study period underwent pregnancy screening under the supervision of obstetricians and gynaecologists. all pregnant patients identified during hajj as well as those who had registered their pregnancies in indian hospitals prior to their arrival in saudi arabia were included in the study as part of a convenience inclusive sampling strategy. patients who attended the hospitals for follow-up appointments for preand post pregnancy events or those who had conditions unrelated to pregnancy were excluded. all pregnant patients either presented to the secondary care hospitals directly or after referral from ihmm-affiliated clinics or mobile task forces. subsequently, a prenatal nursing assessment was performed to determine gravidity, parity and the number of prev ious abortions or living offspring. at their first visit to the secondary care hospital, the pregnancy was registered under the supervision of an ihmm-affiliated obstetrician and gynaecologist. a basic work-up was performed to confirm the pregnancy, including height, weight and blood pressure measurements, a complete blood count and random blood glucose and urine pregnancy tests. all results were processed in the secondary care hospital laboratory under the supervision of a pathologist or microbiologist. for high-risk pregnancies, patients were referred to the makkah maternity & children hospital for an antenatal work-up that included blood grouping, rhesus typing, a coagulation profile and screening for hiv, hepatitis b and c, syphilis, toxoplasmosis, rubella, cyto megalovirus and herpes simplex virus (i.e. torch screening), followed by ultrasonography and routine follow-up. potential exposure to pilgrims from developing or underprivileged countries mandates detailed screening for infectious diseases, including torch screening, which would otherwise not be routinely recommended.13 in addition, patients requiring fetal monitoring, perinatal care and neonatal intensive care, those in labour and obstetric emergency cases were also transferred to the makkah maternity & children hospital. however, all patients were followed up by ihmm-affiliated doctors throughout their entire stay in saudi arabia and, when necessary, were transferred to india under medical supervision. data were analysed using microsoft excel, version 2010 (microsoft inc., redmond, washington, usa). various clinicodemographic characteristics, including diagnosis, management, the presence of antenatal compl ications and fetomaternal outcomes, were compiled and compared with previous years for analysis. the results were expressed as descriptive statistics, including frequ encies, percentages and 95% confidence intervals. shazia khan and inam d. khan clinical and basic research | e357 ethical approval for this study was provided by the ihmm. written informed consent was obtained from all participants prior to their inclusion in the study. results overall, there were 450,000 indian pilgrims seen at ihmm-affiliated secondary care hospitals between 2015–2017, including 89,400 female pilgrims of reprod uctive age (19.87%). of these, 114 (0.13%) were pregnant. the pregnancy was identified by urine test for the first time in 22 women (19.3%). a total of 101 women (88.6%) had planned pregnancies, although these were not declared to the hajj medical authorities prior to beginning the pilgrimage. of these, nine women (8.91%) were unaware of their pregnancy prior to their arrival in saudi arabia. a total of 39 women (38.61%) had received routine antenatal care in india. among 23 women (20.18%) who were in the early stages of pregnancy, nine (39.13%) had had an antenatal appointment in india after conception and 14 (60.87%) were unaware of the date of their last menstrual period. there were four patients (3.51%) with twin pregnancies. the cumulative threeyear birth rate was 24.60 per 1,000 women [table 1]. all of the women had received oral poliomyelitis, combined seasonal influenza and influenza a subtype h1n1 and meningococcal (serogroups a, c, y and w-135) vaccines prior to their arrival in saudi arabia. respiratory tract infections were the most common antenatal complication (51.75%), followed by iron deficiency anaemia (17.54%), hyperemesis gravidarum (14.04%), hypothyroidism (9.65%) and gestational diabetes mellitus (gdm; 5.26%) [table 2]. there were no reported cases of calf pain or deep vein thrombosis. all respiratory infections were treated empirically with antimicrobials as specific bacterial, fungal and viral cultures and immunological and molecular diagnostic procedures were unavailable. in addition, affected women were regularly monitored to avoid the transmission of suspected cases of h1n1 or middle east respiratory syndrome (mers). none of the women with respiratory infections required intensive care table 1: obstetric characteristics of pregnant indian pilgrims undertaking hajj pilgrimage between 2015–2017 (n = 114) characteristic n (%) 95% ci* 2015 (n = 38) 2016 (n = 32) 2017 (n = 44) total gravidity primigravidae 10 (26.32) 9 (28.13) 11 (25) 30 (26.32) 18.72–35.55 multigravidae 28 (73.68) 23 (71.88) 33 (75) 84 (73.68) 64.45–81.28 type of pregnancy single 37 (97.37) 31 (96.88) 42 (95.45) 110 (96.49) 90.73–98.87 twin 1 (2.63) 1 (3.13) 2 (4.55) 4 (3.51) 1.13–9.27 birth rate per 1,000 females 42.85 13.60 18.75 24.60 ci = confidence interval. *of the cumulative percentage. table 2: antenatal complications of pregnant indian pilgrims undertaking hajj pilgrimage between 2015–2017 (n = 114) complication* n (%) 95% ci† 2015 (n = 38) 2016 (n = 32) 2017 (n = 44) total rtis 19 (50) 18 (56.25) 22 (50) 59 (51.75) 42.24–61.14 iron deficiency anaemia‡ 6 (15.79) 8 (25) 6 (13.64) 20 (17.54) 11.29–26.03 hyperemesis gravidarum 4 (10.53) 5 (15.63) 7 (15.91) 16 (14.04) 8.49–22.09 hypothyroidism 2 (5.26) 5 (15.63) 4 (9.09) 11 (9.65) 5.15–16.98 gdm 2 (5.26) 3 (9.38) 1 (2.27) 6 (5.26) 2.16–11.57 oligohydramnios 1 (2.63) 0 (0) 1 (2.27) 2 (1.75) 0.30–6.81 severe pe 0 (0) 0 (0) 1 (2.27) 1 (0.88) 0.05–5.51 ci = confidence interval; rtis = respiratory tract infections; gdm = gestational diabetes mellitus; pe = pre-eclampsia. *percentages do not add up to 100% as some women may have had more than one complication. †of the cumulative percentage. ‡defined as a haemoglobin level of <10.5 g/dl. obstetric and neonatal outcomes of pregnant indian pilgrims a three-year experience at the indian hajj medical mission e358 | squ medical journal, august 2018, volume 18, issue 3 or mechanical ventilation. cases of iron deficiency anaemia received haematinic supplements, while those with hyperemesis gravidarum were admitted to hospital for supportive care and received intravenous (iv) fluids and antiemetics. patients with gdm were prescribed 500 mg of metformin three times daily to ensure good glycaemic control and those with hypothyroidism were treated with thyroxine. the most common adverse early pregnancy outcomes were missed (23.68%) or threatened (8.77%) abortions. there were 20 vaginal deliveries (17.54%) and two caesarean deliveries (1.75%) [table 3]. there were no instrumental deliveries. four of the women with threatened abortions were admitted for progesterone support and bed rest, while the remaining six patients were managed conservatively. of the 32 missed and table 4: neonatal outcomes of births among pregnant indian pilgrims undertaking hajj pilgrimage between 2015– 2017 (n = 22) outcome* n (%) 95% ci† 2015 (n = 12) 2016 (n = 4) 2017 (n = 6) total alive and well 10 (83.33) 4 (100) 5 (83.33) 19 (86.36) 0.64–0.96 low birth weight‡ 2 (16.67) 0 (0) 2 (33.33) 4 (18.18) 0.06–0.41 low apgar score§ 2 (16.67) 0 (0) 1 (16.67) 3 (13.64) 0.03–0.36 neonatal resuscitation 2 (16.67) 0 (0) 1 (16.67) 3 (13.64) 0.03–0.36 admission to nicu 2 (16.67) 0 (0) 1 (16.67) 3 (13.64) 0.03–0.36 preterm¶ 2 (16.67)\\ 0 (0) 1 (16.67) 3 (13.64) 0.03–0.36 fetal distress/birth asphyxia 2 (16.67) 0 (0) 1 (16.67) 3 (13.64) 0.03–0.36 rds 1 (8.33) 0 (0) 0 (0) 1 (4.55) 0.24–0.25 jaundice 1 (8.33) 0 (0) 0 (0) 1 (4.55) 0.24–0.25 stillborn 0 (0) 0 (0) 1 (16.67) 1 (4.55) 0.24–0.25 ci = confidence interval; nicu = neonatal intensive care unit; rds = respiratory distress syndrome. *percentages do not add up to 100% as some neonates may have fallen into more than one category. †of the cumulative percentage. ‡defined as <2,500 g. §defined as <5 at 10 minutes. ¶defined as <37 gestational weeks. \\two preterm babies were born as a result of preterm labour occurring in a twin pregnancy. table 3: pregnancy outcomes of pregnant indian pilgrims undertaking hajj pilgrimage between 2015–2017 (n = 114) outcome* n (%) 95% ci† 2015 (n = 38) 2016 (n = 32) 2017 (n = 44) total early pregnancy missed abortion 9 (23.68) 6 (18.75) 12 (27.27) 27 (23.68) 16.44–32.73 threatened abortion 4 (10.53) 2 (6.25) 4 (9.09) 10 (8.77) 4.52–15.93 inevitable abortion 2 (5.26) 0 (0) 3 (6.82) 5 (4.39) 1.63–10.44 ectopic pregnancy 0 (0) 0 (0) 1 (2.27) 1 (0.88) 0.05–5.51 single fetal demise 0 (0) 0 (0) 1 (2.27) 1 (0.88) 0.05–5.51 term pregnancy vaginal delivery 11 (28.95) 4 (12.5) 5 (11.36) 20 (17.54) 11.29–26.03 caesarean delivery 1 (2.63) 0 (0) 1 (2.27) 2 (1.75) 0.3–6.81 preterm birth 1 (2.63) 0 (0) 1 (2.27) 2 (1.75) 0.3–6.81 premature labour 1 (2.63) 0 (0) 1 (2.27) 2 (1.75) 0.3–6.81 iufd/stillbirth 0 (0) 0 (0) 1 (2.27) 1 (0.88) 0.05–5.51 ci = confidence interval; iufd = intrauterine fetal demise. *percentages do not add up to 100% as some women may have fallen into more than one category. †of the cumulative percentage. shazia khan and inam d. khan clinical and basic research | e359 inevitable abortions, the spontaneous expulsion of products of conception was confirmed by ultrasonography in 28 cases (87.5%), whereas the remaining four patients (12.5%) underwent outpatient dilation and evacuation procedures. one patient with an ectopic pregnancy underwent a laparoscopic salpingectomy at the makkah maternity & child hospital. among the four patients with twin pregnancies, one experienced the demise of a single fetus at 29 gestational weeks, although an examination four weeks earlier had indicated that both fetuses were viable. this patient was closely monitored for coagulopathy disorders until she returned to india. another pregnancy ended in intrauterine fetal demise at 29 gest ational weeks due to ultrasonography-confirmed oligo hydramnios, intrauterine growth restriction and skeletal and skull defects. this patient went into spontaneous premature labour and subsequently required postnatal inpatient care. there were a total of 22 births (19.3%) during the study period. the male-to-female ratio was 1.4:1. neonatal outcomes were good in 19 cases (86.36%). however, there were three cases (13.64%) of birth asphyxia [table 4]. in one of these cases, the mother was multigravida and presented with imminent eclampsia, high blood pressure (190/160 mmhg), albuminuria, headache, visual disturbances and epigastric discomfort. a magnesium sulphate infusion was administered, along with steroids. subsequently, the patient was transferred to the makkah maternity & child hospital for an immediate caesarean section at 34 gestational weeks. the preterm neonate had perinatal asphyxia and seizures, requiring a six-day stay in the neonatal intensive care unit and phenobarbital and ventilator support. he was later readmitted with neonatal sepsis and administered iv antimicrobials. discussion the saudi arabian ministry of health has published succinct guidelines for pregnant pilgrims recommending that such women postpone pilgrimage due to the risk of infection, heat stroke and dehydration.14,15 the hajj committee of india has similarly prohibited hajj pilgrimages for pregnant women over four gestational months, cautioning that pregnant pilgrims may potentially be deboarded from hajj flights.11 however, many pregnant women are likely to covertly attempt hajj pilgrimage, perhaps for religious or financial reasons. in saudi arabia, maternal and child healthcare is sponsored for foreign hajj pilgrims, which may tempt those who reside in countries where adequate obstetric and neonatal care is not accessible or affordable. the overcrowding of people from diverse geographical backgrounds in mass gathering settings—in which population density may reach up to 9 indiv iduals/m2—can increase the transmissibility of certain respiratory pathogens, such as ebola virus, mers, h1n1, multidrug-resistant tuberculosis and polymicrobial infections, against which many people do not have pre-existing immunity.16 moreover, if an out break occurs during hajj, there is high risk of the global spread of pathogens and continuing risk once affected individuals return to their countries of residence. although most viral pathogens cause limited morbidity in healthy adults, they can pose significant risks to both mother and fetus during pregnancy.17,18 cardiorespiratory compromise can adversely affect maternal haemodynamic stability, thereby affecting fetal nourishment.19 in addition, viruses which are transmitted trans placentally can cause fetal viraemia, leading to multiorgan infections.20 this is particularly worrying as the detection of such infections is limited in mass gathering settings.21 furthermore, the clinical presentation of certain respiratory infections may be non-specific, especially in cases of seasonal influenza and h1n1, thus increasing the burden of laboratory testing. during hajj, the saudi arabian healthcare system has limited resources at its disposal, particularly when it comes to the sophisticated molecular tests required for the diagnosis and identification of novel respiratory pathogens.21–23 while there are operational stringencies in place for the isolation of suspected cases of infection, there are no approved anti viral drugs for treating novel respiratory pathogens—the teratogenic effects of which would need to be assessed in any case—nor available guidelines for their specific monitoring, prognosis or follow-up.21 moreover, hospitalisation can further increase the transmission of respiratory pathogens.24 unfortunately, sociolinguistic and ethnocultural differences are barriers to proposed measures aiming to help prevent the transmission of respiratory infections among hajj pilgrims. it is possible that the adverse outcomes observed in the present study are attributable to the strenuous physical demands of hajj. pilgrims routinely perform physically demanding religious rituals including tawaf (circumambulating the kaaba) and sa’i (a religious ritual involving walking for long distances) along with trips to mina, muzdalifah and arafat, often without eating or drinking properly or getting sufficient rest. pregnancy can negatively affect the physiological status of the mother due to the increasing demands of the growing fetus. physical exhaustion can lead to contractions of the lower abdomen, backaches, physical injuries and physiological compromise.25 however, there is an incrobstetric and neonatal outcomes of pregnant indian pilgrims a three-year experience at the indian hajj medical mission e360 | squ medical journal, august 2018, volume 18, issue 3 easing body of evidence that women who participate in sustained and vigorous physical activity in the first and second trimester, such as high-performance sports and endurance training, have successful fetomaternal outcomes.25–27 nevertheless, pregnant pilgrims run the risk of the spontaneous onset of labour during hajj rituals, resulting in unattended delivery. furthermore, other complications like anaemia, pre-eclampsia, gdm and hypothyroidism can have adverse fetomaternal outcomes. such compl ications require on-site antenatal management which may not be readily accessible; moreover, transportation to other facilities may not be possible due to overcrowding.7,8 generally, pregnant women who travel for extended periods of time are likely to miss out on opportunities for breast feeding counselling, family planning, neonatal care and antenatal surveillance to detect gynaecological comorbidities. it is recommended that women with high-risk pregnancies, a history of preterm labour, recurrent pregn ancy losses, gdm, chronic hypertension, pre-eclampsia, heart disease and those in the third trimester postpone hajj pilgrimage. if determined to proceed, pregnant women should consult an obstetrician prior to embarking on hajj and travel with sufficient medications for the entire pilgrimage. in addition, they should do their best to avoid crowds, wear comfortable clothes and shoes and maintain proper nutrition, hydration, rest and exercise.28 adverse symptoms like bleeding, abdominal contractions, headaches and watery vaginal discharge should be immediately reported. moreover, pregnant women should avoid excessive physical effort during hajj rituals and take advantage of allowances, such as using a wheelchair during tawaf and sa’i. patients should also declare known pregnancies or their intention to conceive during hajj to the saudi arabian medical authorities, thereby enabling the adequate provision of antenatal care. such efforts should be further promulgated by medical missions in various countries. conclusion women who perform hajj pilgrimages while pregnant have a high risk of abortion, respiratory infections and various antenatal and neonatal complications which may go untreated. practitioners should therefore educate patients of these risks and advise them to postpone the pilgrimage until after the pregnancy. conflict of interest the authors declare no conflicts of interest. funding no funding was received for this study. references 1. general authority for statistics, kingdom of saudi arabia. num ber of domestic and foreign pilgrims during hajj. from: www. stats.gov.sa/en/28 accessed: mar 2018. 2. gatrad ar, sheikh a. hajj: journey of a lifetime. bmj 2005; 330:133–7. doi: 10.1136/bmj.330.7483.133. 3. al-jasser fs, kabbash ia, almazroa ma, memish za. patterns of diseases and preventive measures among domestic hajjis from central, saudi arabia. saudi med j 2012; 33:879–86. 4. shafi s, memish za, gatrad ar, sheikh a. hajj 2006: communicable disease and other health risks and current official guid ance for pilgrims. euro surveill 2005; 10:e051215.2. doi: 10.2807/ esw.10.50.02857-en. 5. ahmed qa, arabi ym, memish za. health risks at the hajj. lancet 2006; 367:1008–15. doi: 10.1016/s0140-6736(06)68429-8. 6. memish za, stephens gm, steffen r, ahmed qa. emergence of medicine for mass gatherings: lessons from the hajj. lancet infect dis 2012; 12:56–65. doi: 10.1016/s1473-3099(11)70337-1. 7. khan id, khan sa, asima b, hussaini sb, zakiuddin m, faisal fa. morbidity and mortality amongst indian hajj pilgrims: a 3 year experience of indian hajj medical mission in mass-gathering medicine. j infect public health 2018; 11:165–70. doi: 10.10 16/j.jiph.2017.06.004. 8. khan id, khan s, khan ma, mustafa ms, kidwai ms, khan sa, et al. indian medical mission at hajj-2016: mass-gathering med icine perspectives, challenges, and opportunities in a mission posture. int j travel med glob health 2017; 5:94–101. doi: 10.15 171/ijtmgh.2017.20. 9. american college of obstetricians and gynecologists. air travel during pregnancy. from: www.acog.org/clinical-guidance-and publications/committee-opinions/committee-on-obstetricpractice/air-travel-during-pregnancy accessed: mar 2018. 10. uae national. pregnant women should not perform haj, uae mission warns. from: www.thenational.ae/uae/pregnantwomen-should-not-perform-haj-uae-mission-warns-1.378701 accessed: apr 2018. 11. times of india. pregnant women barred from haj. from: https:// timesofindia.indiatimes.com/india/pregnant-women-barredfrom-haj/articleshow/51735066.cms accessed: mar 2018. 12. doha news. saudi: no hajj, umrah visas for pregnant, elderly this year due to mers concerns. from: https://dohanews.co/ s au d i n o h aj j u m r a h v i s a s fo rp re g n a ntel d e r l y th i s / accessed: mar 2018. 13. federation of obstetricians and gynaecologists of india. screening and management of torch in pregnancy. from: w w w. fo g s i . o rg / w p co nte nt / u p l o a d s / 2 0 1 5 / 1 1 / s mtp . p d f accessed: mar 2018. 14. saudi arabia ministry of health. health guidelines: woman and child. from: www.moh.gov.sa/en/hajj/healthguidelines/ pages/womanandchild.aspx accessed: mar 2018. 15. embassy of the kingdom of saudi arabia. consular and travel services: hajj requirements. from: www.saudiembassy.net/hajjrequirements accessed: mar 2018. 16. jindal ak, pandya k, khan id. antimicrobial resistance: a public health challenge. med j armed forces india 2015; 71:178–81. doi: 10.1016/j.mjafi.2014.04.011. 17. khan id, gupta rm, sen s, rajmohan ks, jindal ak, makkar a, et al. emerging antimicrobial resistance and evolving healthcare: dangerous crossroads for the community and the military. j arch mil med 2017; 5:e12097. doi: 10.5812/jamm.12097. 18. new zealand ministry of health. travelling for hajj or umrah. from: www.health.govt.nz/your-health/healthy-living/travellin g/travelling-hajj-or-umrah accessed: mar 2018. 19. soma-pillay p, nelson-piercy c, tolppanen h, mebazaa a. physiological changes in pregnancy. cardiovasc j afr 2016; 27:89–94. doi: 10.5830/cvja-2016-021. https://doi.org/10.1136/bmj.330.7483.133 https://doi.org/10.2807/esw.10.50.02857-en https://doi.org/10.2807/esw.10.50.02857-en https://doi.org/10.1016/s0140-6736%2806%2968429-8 https://doi.org/10.1016/s1473-3099%2811%2970337-1 https://doi.org/10.1016/j.jiph.2017.06.004 https://doi.org/10.1016/j.jiph.2017.06.004 https://doi.org/10.15171/ijtmgh.2017.20 https://doi.org/10.15171/ijtmgh.2017.20 https://doi.org/10.1016/j.mjafi.2014.04.011 https://doi.org/10.5812/jamm.12097 https://doi.org/10.5830/cvja-2016-021 shazia khan and inam d. khan clinical and basic research | e361 20. straface g, selmin a, zanardo v, de santis m, ercoli a, scambia g. herpes simplex virus infection in pregnancy. infect dis obstet gynecol 2012; 2012:385697. doi: 10.1155/2012/385697. 21. khan id, asima b, khan sa. operations throughput as a determinant of golden-hour in mass-gathering medicine. int j medicine med res 2017; 3:52–9. doi: 10.11603/ijmmr.2413 6077.2017.1.7804. 22. khan id, gupta n, rangan nm, singh r, sharma ak, khurana a, et al. evaluation of pre and post analytical variables in clinical microbiology services in multidisciplinary icu of a medical college and tertiary care hospital. j basic clin med 2016; 5:2–4. 23. khan id, sahni ak, bharadwaj r, lall m, jindal ak, sashindran vk. emerging organisms in a tertiary healthcare set up. med j armed forces india 2014; 70:120–8. doi: 10.1016/j.mjafi.2013.09.005. 24. khan id, basu a, kiran s, trivedi s, pandit p, chattoraj a. device associated healthcare-associated infections (da-hai) and the caveat of multiresistance in a multidisciplinary intensive care unit. med j armed forces india 2017; 73:222–31. doi: 10.1016/j. mjafi.2016.10.008. 25. nascimento sl, surita fg, cecatti jg. physical exercise during pregnancy: a systematic review. curr opin obstet gynecol 2012; 24:387–94. doi: 10.1097/gco.0b013e328359f131. 26. wolfe la, weissgerber tl. clinical physiology of exercise in pregnancy: a literature review. j obstet gynaecol can 2003; 25:473–83. doi: 10.1016/s1701-2163(16)30309-7. 27. martínez-pascual b, alvarez-harris s, fernández-de-las-peñas c, palacios-ceña d. pregnancy in spanish elite sportswomen: a qualitative study. women health 2017; 57:741–55. doi: 10.1080/ 03630242.2016.1202883. 28. khan id, hussaini sb, khan s, ahmad fm, faisal fa, salim ma, et al. emergency response of indian hajj medical mission to heat illness among indian pilgrims in tent-clinics at mina and arafat during hajj, 2016. int j travel med glob health 2017; 5:135–9. doi: 10.15171/ijtmgh.2017.26. https://doi.org/10.1155/2012/385697 https://doi.org/10.11603/ijmmr.2413-6077.2017.1.7804 https://doi.org/10.11603/ijmmr.2413-6077.2017.1.7804 https://doi.org/10.1016/j.mjafi.2013.09.005 https://doi.org/10.1016/j.mjafi.2016.10.008 https://doi.org/10.1016/j.mjafi.2016.10.008 https://doi.org/10.1097/gco.0b013e328359f131 https://doi.org/10.1016/s1701-2163%2816%2930309-7 https://doi.org/10.1080/03630242.2016.1202883 https://doi.org/10.1080/03630242.2016.1202883 https://doi.org/10.15171/ijtmgh.2017.26 to the editor, i read your editorial on “evaluation tools in postgraduate medical education do we need “made in oman” tools?”1 with interest and felt that the issue of formative versus summative assessment needed to be clarified before conclusions could be made about which and how assessment tools should be used. the terms “formative” and “summative” define the purpose of assessment and not the tools of that assessment. formative assessment is used for diagnosis and remediation, while summative assessment is used for promotion and certification. the tools being used can be the same for both assessments; there are no tools that are specific for formative while others are for summative assessment. for example, an multiple choice question based test can be used in either a formative or a summative fashion. ideally, all assessments should have a formative component even if used in a summative manner. the purpose of the formative component is to provide feedback to students on their strengths and weaknesses. the practice of using certain assessment methods for summative purposes stems from the reliability of the scores obtained from these methods; hence, their use in making important decisions about student progression as they alone can reliably ensure the fulfillment of the teaching mission of the medical school. several very appealing assessment methods, especially in postgraduate medical education, are now emerging, but, despite their high face value, their cost effectiveness, educational impact, and use in undergraduate medical education needs to be carefully assessed before their use can be advocated. the resource intensity of these methods might very well be the factor that limits their use to very few medical schools as mentioned in your editorial. what one can advocate, however, is research into the evaluation of these assessment methods which is exactly what the document of “assessment policy, regulations, & guidelines” of the college of medicine & health sciences at sultan qaboos university does.2 the policy not only affirms that assessment should be used in both formative and summative manner, but also goes further to recommend that assessment methods used should be evidence-based and, where evidence is lacking, best-practiced methods should be used and evaluated. feedback, a major component of formative assessment, is also highlighted very well in this policy document which emphasizes that it should be given to students in a timely manner. the assessment tools listed in the policy document have, when used correctly, demonstrated validity and reliability. tools such as checklists and rating scales are the basis of most workplace-based assessments such as the mini-clinical evaluation exercises, 360° assessment, direct observation of procedural skills, etc. can be used in any manner desired, formative or summative. nadia al wardy head, medical education unit college of medicine & health sciences sultan qaboos university email: naiwardi@squ.edu.om squ med j, august 2010, vol. 10, iss. 2, pp. 280-281, epub. 19th jun 10 submitted: 18th apr 10 أدوات التقييم للدراسة الطبية التخصصية هل حنتاج إىل أدوات “صنع يف ُعمان”؟ نادية الوردي re: evaluation tools in postgraduate medical education–do we need “made in oman” tools? nadia al wardy letter to editor nadia al wardy letter to editor | 281 references 1. lamki l, lamki n. evaluation tools in postgraduate medical education-do we need “made in oman” tools? squ med j 2009; 9:219-23. 2. college of medicine & health sciences, squ assessment policy, regulations, & guidelines. 1st ed. 2009. from http://www.squ.edu.om/medicine-health/tabid/1638/default.aspx accessed april 2010. authors’ response we thank dr. al wardy for her interest in our editorial. the purpose of the editorial was to stimulate discussion on the subject and we are glad it did, because this is a very important subject to all medical educationalists, undergraduate even more than postgraduate as pointed out by dr. al wardy. we agree with dr. al wardy that the terms summative and formative refer more to how the tool is used rather than the actual type of tool, but what we were pointing out in the editorial is that some tools are intrinsically more formative than others. indeed all tools can be used for both purposes. we also agree with dr. al wardy that the summative purpose of the assessment tools in the “assessment policy, regulations, & guidelines” of the college of medicine & health sciences at sultan qaboos university stems from the reliability of these tools in ensuring the fulfillment of the teaching mission of the medical school – and hence our comment in the editorial about those tools. we congratulate the college of medicine & health sciences at sultan qaboos university for the two major steps forward they have taken recently in producing the new avant-garde curriculum and impressive set of assessment tools in the new “assessment policy, regulations, & guidelines”. congratulations to you and the medical education unit, and keep up the great work. lamk al-lamki neela al-lamki editor-in-chief co-author squ medical journal oman medical specialty board email: mjournal @squ.edu.om email: n_lamki@yahoo.com squ med j, april 2010, vol. 10, iss. 1, pp. 126-128, epub. 17th apr 10 submitted 11th may 2009 revision req. 26th aug. 09. revision recd. 15th sept. 09 accepted 14th oct 09 a stylet is an essential airway adjunct, frequently used to facilitate endotracheal intubation. there have been several case reports of the shearing of the tip of a stylet.1-4. we report a case of broken piece of metallic stylet which remained initially unnoticed in an endotracheal tube. case report a 58 year-old male patient with a fractured neck of the femur was scheduled for hemiarthoplasty. he was classified as a grade ii american society of anaesthesiologists (asa ii) patient. he was a known case of insulin dependent diabetes. preoperatively, the physical examination and relevant investigations were found to be within normal limits. the patient was premedicated with midazolam 7.5 mg orally one hour prior to anaesthesia. following induction of the anaesthesia and adequate neuromuscular relaxation, laryngoscopy and intubation were attempted by a senior anaesthetist. the first attempt was unsuccessful as the larynx was noted to be very anterior. the second attempt at tracheal intubation aided by a sheathed metallic stylet was successful. the trachea was intubated with an endotracheal tube size 8.0 mm. immediately after intubation the chest was auscultated. air entry was noted to be equal bilaterally and there were no adventitious sounds. peak airway pressure and oxygen saturation were well maintained between 1820 cm h2o and 97–99% respectively. about 15 minutes later, while patient was being painted and draped, the anaesthesia staff nurse brought to the notice of the attending anaesthetist that part of stylet was missing. immediately department of anesthesia & icu, khoula hospital, national trauma centre, muscat, sultanate of oman *to whom correspondence should be addressed. e-mail: nassn@omantel.net.om قطعة مكسورة غري ُمالحظة يف األنبوب الرغامي من ِ مرود معدني ُمغلَّف تقرير حالة براديب �شارما، را�شد خان، ناري�س ك�ل امللخ�ص: ندرج هنا حالة مري�س عمره 58 �شنة كانت قد اأجريت له عملية لعالج ك�رس يف عنق عظم الفخذ. متت عمل الَتْنبيب الرغامي مب�شاعدة مرود، لكن بعد 15 دقيقة اأعيد اإىل اأخ�شائي التخدير واأخرب اأن قطعة من املرود انك�رست وبقيت يف االأنب�ب الرغامي، مع العلم اأنه ال ي�جد ِبيّة. مت بنجاح �شحب قطعة املرود ب�ا�شطة ملقط دليل قبل هذا ب�ج�د ج�شم غريب �ش�اء كان داخل االأنب�ب الرغامي اأو ال�شجرة الُرغاِميةٌّ الَق�شَ ك��رس. مفتاح الكلمات: ِمرود مك�ش�ر، ان�شداد االأنب�ب الرغامي، ج�شم غريب، تقرير حالة. abstract: we report a 58-years old patient, who underwent surgery for a fracture to the neck of the femur. tracheal intubation was performed with the aid of a stylet; however, 15 minutes later, it was brought to the notice of the attending anesthesiologist that a broken piece of stylet had been left inside the lumen of the endotracheal tube. prior to this, there was no evidence of a foreign body in the endotracheal tube or tracheobronchial tree. the broken piece of stylet was successfully retrieved with the help of a kocher’s forceps. keywords: broken stylet; endotracheal tube obstruction; foreign body; case report; oman. an unnoticed broken sheathed metallic stylet in an endotracheal tube a case report pradeep k sharma, rashid m khan, *naresh kaul case report pradeep k sharma, rashid m khan and naresh kaul case report | 127 laryngoscopy was done and something could be visualised above the vocal cord inside the lumen of the endotracheal tube. the surgeon was informed of the incident and requested not to proceed further, till the diagnosis of broken stylet could be confirmed and remediable measures taken. the radiographer was asked to perform a c-arm (x-ray image intensifier) screening of the head and neck region. during screening a radio opaque shadow could be visualised around the glottic region. immediately after confirmation of the foreign body, a kocher’s forceps was introduced in the oropharynx and the endotracheal tube was firmly grasped just above the vocal cord. the endotracheal tube was now gently pulled out along with the broken stylet in-situ. the sheared portion of the stylet measured 13.2 cm [figure 1]. the trachea was now re-intubated with the help of a new sheathed metallic stylet. after confirmation of correct the placement of endotracheal tube, the surgeon was allowed to proceed. the surgery lasted for about 90 minutes and the intra-operative period remained uneventful. after completion of surgery, the residual neuromuscular blockade was reversed and the endotracheal tube removed. the postoperative period was uneventful. discussion there are occasional reports in the literature regarding broken stylets, especially unsheathed metallic stylets. despite this fact, this type of stylet is still being used in third world countries, may be because of cost constraints or ignorance. in many places anaesthetists have abandoned the use of stylet and are pre-shaping the endotracheal tube by immersing it in ice cold water.5 in the present case, we used a sheathed metallic stylet, but our anaesthesia staff nurse did not notice that its sheath had been damaged. the shearing off of a tip can occur in both metallic and plastic covered stylets, especially when removal of the stylet from an endotracheal tube is difficult.6 however, in our case, we did not encounter any difficulty in removing the stylet. these patients usually show some chest signs or a change in ventilatory parameters which mimics a partial endotracheal tube obstruction, or increasing resistance to flow, or bronchospasm. surprisingly, our case remained asymptomatic. this could have been because the broken stylet may not have occupied enough of the internal diameter of the endotracheal tube to produce respiratory signs or increased airway resistance. had it not been for the vigilance of the anaesthesia staff nurse, the event could have gone unnoticed until it progressed into the trachea with signs and symptoms of a foreign figure 1: the broken stylet with sheath measuring 13.2 cm. an unnoticed broken sheathed metallic stylet in an endotracheal tube a case report 128 | squ medical journal, april 2010, volume 10, issue 1 body in the tracheobronchial tree or, rarely, until tracheal extubation. conclusion in conclusion, it is strongly recommended that a routine, regular check of equipment be performed to avoid such mishaps. if the removal of the stylet proves difficult, the attending anaesthetist should immediately examine the stylet to note if any portion of it has been damaged, broken or shorn off into the endotracheal tube or tracheobronchial tree. references 1. sharma ml, bhardwaj n, chari p. broken metal intubating stylet. anaesth intens care, 1994; 22:624. 2. martin p, campbell am. tracheal intubation: a complication. anaesthesia 1992; 47:75. 3. zmyslowski wp, kam d, simpson gt. an unusual case of endotracheal obstruction. anesthesiology 1989; 70:883. 4. sharma a, jain v, mitra jk, prabhakar h. a rare case of endotracheal tube obstruction: a broken stylet going unnoticed. m e j anesth 2008; 19:909. 5. kubota y, toyoda y, kuborota h. shaping tracheal tubes. anaesthesia 1987; 42:896. 6. rabb mf, larson sm, greger jr. an unusual case of partial ett obstruction. anesthesiology 1998; 88:548. squ med j, april 2010, vol. 10, iss. 1, pp. 156-159, epub. 19th jun 10 submitted: 1st jun 10 reviewed internally accepted: 2nd jun 10 "how weary, stale, flat and unprofitable, seem to me all the uses of this world!" shakespeare: hamlet (act 1, scene 2) in this issue of the medical journal, dr. al-dabal and her colleagues publish a comparative study of perceived stress among female medical and non-medical university students in saudi arabia.1 they investigated the difference between medical and non-medical students with respect to the prevalence and causes of stress, as well as mental and physical changes in their health. they report a statistically higher incidence of stress among the medical students compared to those in another faculty (48.6% of 319, versus 38.7% of 297) and a higher incidence of mental health problems, anxiety and depression amongst the medical students. of possible special relevance to oman is the finding of more underlying social problems among the medical students. while these findings may be disputed by some studies in the literature, it is by far in agreement with the majority of studies on factors affecting medical students and, in the final analysis, the medical profession. it is of significance that dr. al-dabal’s team recommends that there should be a student support committee, implying that such a committee does not exist at the university in dammam, saudi arabia. such support services are essential in an educational setting. as will become apparent in the ensuing paragraph, academic stress among tomorrow’s doctors is likely to be common in this part of the world. there is also reason to suggest that academic stress may be further compounded by some social issues that are peculiar to the region. such issues need to be addressed. stress, depression and a dim view of the world around you is not an affliction limited to shakespeare’s characters or confined only to medical students, but also affects young doctors in specialty training as well as practising physicians. stress is possibly even more widespread later in the professional life than during the student years. dr. al-dabal’s study indeed adds to the suspicion that the roots of high stress in the medical profession are in the medical school. a large national survey of 2,584 physicians in canada, reported by richardsen et al.2, showed that both male and female physicians experienced high levels of occupational stress associated with lower levels of satisfaction with their medical practice. this study also showed that there was a sex difference in specific variables that predicted stress and satisfaction at their job. in another study by caplan,3 examining the presence of depression among physicians found that 27% of the sampled physicians scored in the clinical range in the indices of depression. general practitioners were more likely to be depressed than managers in the hospital setting that caplan studied. general practitioners were also significantly more likely to display suicidal tendencies than consultants in the hospital setting (15% versus 5%). more than half of those questioned showed debilitating forms of anxiety disorders. they concluded that the levels of stress, anxiety and depression in senior doctors in the national health service were high, and perhaps, higher than generally expected. editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, oman email: mjournal@squ.edu.om الضغط النفسي يف مهنة الطب وجذوره من كليات الطب ملك اللمكي editorial stress in the medical profession and its roots in medical school lamk al-lamki lamk al-lamki editorial | 157 in another study reported by khuwaja et al.,4 conducted in a teaching hospital in karachi, pakistan, 68% of the doctors were not satisfied with their jobs and workload. female doctors had significantly lower satisfaction with their workload. overall, in that study, about half of the doctors endorsed the view that their jobs were marked with high to very high levels of stress and distress. thus, the authors concluded that majority of doctors working at the teaching hospitals in karachi had not only poor job satisfaction in their profession, but they also had high levels of job stress and its consequences. the literature is replete with the view that higher levels of anxiety, depression and the general consequences of stress for medical professionals, compared to the general population, is the norm rather than the exception. such a dire situation has been associated with a higher incidence of suicide compared to the rest of the population.5–9 the world health organization (who) estimates that stress-related disorders will be one of the leading causes of disability by the year 2020. “stress” has been defined as the consequence of events that are perceived as endangering one’s physical or emotional wellbeing.10 indeed, stress clearly has endangered the physical and emotional well being of physicians as discussed above, from an increased incidence of anxiety and depression to an increased incidence of suicide. the problem is compounded, of course, in medicine because doctors are a privileged group of people who can self-medicate with very little or no questions asked from the society or its members. self-medication can lead to chemical addiction of all sorts, from the intake of just marijuana and khat (a stimulant drug derived from a shrub, catha edulis, that is native to east africa and southern arabia), to “crack” and intravenous heroine. when i reviewed the literature on the subject of stress and its consequences in the medical profession, both on physicians in practice and students in medical schools, there was remarkable similarity between the two categories thus suggesting factors that might contribute to the prevailing problem. dahlin et al. have shown that first year students in medical school indicate experiencing the highest degree of pressure from their medical training.11 they also compared medical to other students and found that medical students had higher depression rates than the general student population. they also incidentally found that women students have higher rates of depression than men, and that the women reported higher levels of stress. it is, however, very difficult to ascertain the root of stress among medical students. firth studied 318 medical students and found higher stress levels amongst them than in other groups in the general population.12 in this qualitative study, he found four events likely to be associated with academic stress. these included talking to psychiatric patients, effects on personal life, presenting cases, and dealing with death and suffering. relationships with consultants raised the strongest negative feelings, students finding this particularly stressful. clearly, most of these are peculiar to medical students and not generally found in the lives of other students. there are other sources of stress among students, prevalent in oman and in some other eastern cultures whereby students are pressurised by their family and community to go into medicine and “be a doctor”. unfortunately, some of these students are not interested in studying medicine, but cannot say no or resist family pressure to any extent. naturally, these students are more likely to have problems with their studies, which in turn can have negative repercussions on their emotional well being. the academic pressures of a complex syllabus and long hours of study may further deplete their enthusiasm for their prospective career. with respect to gender difference among medical students, the evidence is mixed. there are, however, more publications which indicate that women are more stressed.13,14 on the other hand, amr et al. have shown no overall significant difference in perceived stress according to gender;15 however, this study did show some differences: a higher incidence of depression in females; less relationship problems with teachers, and less substance abuse among women. the question now is how do we cope with such a predicament? clearly, we have to accept that there is a temporal relationship between adverse experiences during student days and later professional burnout. it is well known that adverse experiences whether in medical school, or later on as a full-fledged physician, are likely to dent much needed productivity, increase the amount of sick leave, and lead to early retirement with all its attendant social and economic effects. there is stress in the medical profession and its roots in medical school 158 | squ medical journal, april 2010, volume 10, issue 1 empirical evidence to suggest that the majority of prospective medical students are likely to be “type a” personalities, a temperament known to be prone to stress because it is characterised by a poor ability to relax, coupled with a tendency to be extremely competitive and achievement oriented. therefore, there is an urgent need to reverse such a trend, however, this may be difficult since it can be hypothesised that the medical profession attracts people with particular temperaments that are prone to succumb to the ill-effect of stress. the sources of stress are plentiful as discussed above, including the sense of helplessness in the face of certain incurable disorders like cancer and the trauma of dealing with death and despair. therefore, more effort should be put into helping medical personnel cope with this predicament. mosely et al.16 have shown that students who employed coping efforts characterised by ‘engagement strategies’, suffered from fewer depressive symptoms, suggesting that training in these types of strategies may be a useful intervention to lessen the negative consequences of stress. this has also been reported by shanua et al. who showed that participation in an eight-week medication-based stress reduction intervention effectively reduced anxiety and depression and increased scores on overall empathy levels for medical and pre-medical students.17 there is no study that has documented stress in medical students or the medical profession in oman. if the global trend exists in oman, the question then becomes how can we reduce stress among our own medical students? here are some of the possible panaceas to contemplate. the first one is to consider geography and social variables. we now have two medical schools in muscat, one public and the other private. perhaps, it would be pertinent to design a comparative study that compares the effect of private and public education at that level, as well as gender, and compare these students with non-medical students at sultan qaboos university and private colleges. comparing the levels of stress between omani medical students studying in oman and those studying abroad may shed light on socialcultural variables that may contribute to high stress among students. there are, however, some factors that are perhaps specific to oman that may impact students particularly, and medical students in particular. these are the social factors. many students studying in muscat are expected to go to their villages and visit their families almost every weekend and this can be a major source of stress and interfere with their academic performance. trying to be an effective medical student, while having no opportunity to study over the weekend, is obviously a great source of anxiety for some students. in addition to this, for those students whose families are located in muscat, there are other pressures on students such as the obligation to attend family weddings and the need for their presence during family illnesses and deaths. all of these can mean that students are required to juggle so many issues that these are likely to ‘rob’ the time required to perform adequately in their medical studies. perhaps a possible answer to dealing with this source of stress in oman would be to establish two public medical schools, one here in muscat and possibly another campus, or a separate public medical school, in an area very distant from the students’ homes such as in the city of salalah in the southernmost dhofar region. a provocative thought would be to suggest that each of these medical schools (and likewise in the future perhaps elsewhere too) take students from outside their own region, within a certain radius. thus, students will be far from their homes (much like students who go abroad to study), and therefore cannot readily go to their home town over a weekend or spend an evening there. like the students who study abroad, these students would thus be free to a great extent from the social pressures that contribute to stress and its consequences. as evidence for the potential benefits from this arrangement, we know that omani students and postgraduate trainees abroad excel and in fact are doing very well even when compared to the local students in those countries. it is clear that the time has come for a comprehensive cross-sectional study in oman, preferably conducted at sultan qaboos university, with the inclusion of the private medical colleges, to evaluate the factors that cause stress among our medical students. squ medical journal (squmj) welcomes the opportunity to review such articles for publication. references 1. al-dabal bk, koura mr, rasheed p, al-sowielem l, makki sm. a comparative study of perceived stress lamk al-lamki editorial | 159 among female medical and non-medical university students in dammam, saudi arabia. squ med j 2010; 10:231-40. 2. richardsen am, burke rj. occupational stress and job satisfaction among physicians: sex differences. soc sci med 1991; 33:1179–87. doi: 10.1016/02779536(91)90234-4. 3. caplan rp. stress, anxiety, and depression in hospital consultants, general practitioners, and senior health service managers. bmj 1994; 309:1261–3. from http:// www.bmj.com/cgi/content/abstract/309/6964/1261 accessed may 2010. 4. khuwaja ak, qureshi r, andrades m, fatmi z, khuwaja nk. comparison of job satisfaction and stress among male and female doctors in teaching hospitals of karachi. j ayub med coll abbottabad 2004; 16:23–7. from http://www.ncbi.nlm.nih.gov/ pubmed/15125175 accessed may 2010. 5. phipps l. stress among doctors and nurses in the emergency department of a general hospital. editorial. cmaj 1988; 139: 375–6. from http:// www.ncbi.nlm.nih.gov/pmc/articles/pmc1268150/ accessed may 2010. 6. hale r, hudson l. the tavistock study of young doctors: report of the pilot phase. br j hosp med 1992; 47:452–64. 7. firth-cozens j, greenhalgh j. doctors’ perceptions of the links between stress and lowered clinical care. soc sci med 1997; 44:1017–22. 8. editorial. doctors, their well-being, and their stress: it’s time to be proactive about stress – and prevent it. bmj 2003; 326:670–1. 9. tattersall aj, bennett p, pugh s. stress and coping in hospital doctors. stress and health 1999; 15:109–13. from http://www.ingentaconnect.com/content/jws/ smi/1999/00000015/00000002/art00793 accessed may 2010. 10. selye h. the stress of life. new york: mcgraw-hill, 1978. 11. dahlin m, joneborg n, runeson b. stress and depression among medical students: a cross-sectional study. med educ 2005; 39:594–604. 12. firth j. levels and sources of stress in medical students. br med j (clin res ed) 1986; 292:1177– 80. doi:10.1136/bmj.292.6529.1177. from http:// www.bmj.com/cgi/content/abstract/292/6529/1177 accessed may 2010. 13. bernstein j, carmel s. gender differences over time in medical school stressors, anxiety, and the sense of coherence. sex roles 1991; 24:335–44. doi: 10.1007/ bf00288306. from http://www.springerlink.com/ content/k3327683u3246501/ accessed may 2010. 14. clark ej. gender differences in relationships and stress of medical and law. j med educ 1986; 61:32-40. from http://www.ncbi.nlm.nih.gov/pubmed/3941420 accessed may 2010. 15. amr m, el gilany ah, el-hawary a. does gender predict medical students’ stress in mansoura, egypt? from http://www.med-ed-online.net/index. php/meo/article/viewfile/4481/4661 accessed may 2010. 16. mosley th jr, perrin sg, neral sm, dubbert pm, grothues ca, pinto b. stress, coping, and well-being among third-year medical students. acad med 1994; 69:765–7. 17. shapiro sl, schwartz ge, bonner g. effects of mindfulness-based stress reduction on medical and premedical students. j behav med 1998; 21:581–99. doi: 10.1023 / a: 1018700829825. from http:// www.springerlink.com/content/rv62q98671062146/ accessed may 2010 1department of forensic toxicology, legal medicine research center, legal medicine organization, tehran, iran; 2department of anaesthesiology & critical care, tehran university of medical sciences, tehran, iran *corresponding author e-mail: akhgari1349@yahoo.com التمييز بني تعاطي املخدرات والعالج الدوائي تقرير حالة عن وفاة ذات صلة باستعمال جرعة زائدة لعقار الرتانيلسيربومني مرمي اخجري، فرزانه جوكار، اف�سار اعتمادي اآالآقا، على قا�سمى abstract: tranylcypromine is an effective antidepressant from the class of monoamine oxidase inhibitors and is structurally related to amphetamine. however, reports differ regarding the potential metabolism of tranylcypromine to amphetamine and methamphetamine within the human body. we report a 25-year-old woman with severe depression who died due to a fatal tranylcypromine overdose in 2016. she had been prescribed tranylcypromine one day previously and had no history of previous suicide attempts or substance abuse. the body was transferred to a forensic medicine department in tehran, iran for the autopsy. a urine sample was positive for tranylcypromine, amphetamine and methamphetamine using gas chromatography/mass spectrometry after derivatisation with heptafluorobutyric acid. as amphetamines were present in the urine sample, it was assumed that the tranylcypromine had been converted to amphetamines metabolically. as such, it is possible that the legitimate use of certain prescription drugs may complicate the interpretation of test results for illegal drugs. keywords: tranylcypromine; amphetamine; metabolism; forensic toxicology; substance abuse detection; case report; iran. امللخ�ص: عقار الرتانيل�سيربومني امل�ساد لالكتئاب هو من فئة مثبطات مونو اأمني اأوك�سيديز و ي�سابه هيكليا االأمفتامني. توجد تقارير خمتلفة لعملية اأي�س الرتانيل �سيربومني اثناء حتويله اإىل اأمفيتامني و ميثا مفيتامني. هذا تقرير عن اإمراأة يبلغ عمرها 25 عاما كانت تعاين من االكتئاب ال�سديد توفت ب�سبب تناول جرعة زائدة مميتة من عقار الرتانيل �سيربومني عام 2016م. مت و�سف عقار الرتانيل �سيربومني لها قبل وفاتها بيوم واحد. اأظهر التاريخ املر�سي لها عدم وجود �سابقة انتحار اأو ادمان املخدرات. مت نقل اجلثمان اإىل ق�سم الطب ال�رشعي يف طهران-اإيران بغر�س الت�رشيح. بعد ا�ستقاق عينة البول مت الك�سف عن وجود الرتانيل �سيربومني، ميثا مفيتامني و االأميفتامني با�ستخدام طريقة الكروماتوجرايف الغازي/التحليل الطيفي. وقد افرت�س اأن االأمفيتامني ناجت عن اأي�س عقار الرتانيل �سيربومني. بناء على هذا فاأن ا�ستعمال بع�س االأدوية املرخ�سة قد ي�سبب م�ساكل يف تاأويل نتائج فح�س العقاقري املمنوعة. الكلمات املفتاحية: ترانيل �سيربومني؛ اأمفيتامني؛ اأي�س؛ علم ال�سموم ال�رشعي؛ التعرف على ادمان املواد؛ تقرير حالة؛ اإيران. discrimination between drug abuse and medical therapy case report of a tranylcypromine overdose-related fatality *maryam akhgari,1 farzaneh jokar,1 afshar etemadi-aleagha,2 ali ghasemi2 case report sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e213–217, epub. 20 jun 17 submitted 22 dec 16 revision req. 5 feb 17; revision recd. 23 feb 17 accepted 9 mar 17 doi: 10.18295/squmj.2016.17.02.013 contribution of amphetamine to the pharmacological response should not be underestimated.5 reliable laboratory methods of detecting drugs such as tranylcypromine and amphetamine-type stimulants have been previously validated using various parameters, such as selectivity, linearity, accuracy and precision, limits of detection, limits of quantitation and recovery.6,7 most countries legally restrict the recreational use of amphetamines and categorise this class of drugs under controlled substances.8 despite this, the use of amphetaminetype stimulants has become increasingly popular, particularly among young people;7 it is therefore important to accurately interpret any forensic toxicology results in both living and deceased patients. in addition, physicians should be aware of the possibility tranylcypromine is an irreversible non-selective monoamine oxidase inhibitor often prescribed as an antidepressant.1,2 tranylcypromine is a well-known structural analogue of amphetamine to which a cyclopropyl ring is fused; however, there is some evidence that suggests the cyclopropyl ring undergoes metabolic cleavage to form three metabolites: amphetamine, 1-amino-2phenylpropane and 1-amino-3-phenylpropane.1,3 this metabolic formation of amphetamine is responsible for the therapeutic effects of tranylcypromine as well as those that occur following withdrawal.1–4 a therapeutic dose of tranylcypromine constitutes 30 mg per day, usually given in divided doses. while this amount of the drug is unlikely to produce a marked degree of amphetamine-like central activity, the discrimination between drug abuse and medical therapy case report of a tranylcypromine overdose-related fatality e214 | squ medical journal, may 2017, volume 17, issue 2 were analysed quantitatively to detect ethanol and methanol via headspace gas chromatography using the 6890n network gas chromatograph (agilent technologies inc.) equipped with a flame ionisation detector. a spectrophotometer (series 9000, cecil instruments, peterborough, uk) was used to analyse carboxyhaemoglobin levels. amphetamine and methamphetamine levels in the urine sample were analysed using the derivatisation reagent heptafluorobutyric acid (hfba).6,7 a total of 1 ml of urine was centrifuged for five minutes at 9,000 rpm and the supernatant was separated. the sample was alkalinised by adding 0.5 m of potassium hydroxide and the ph was adjusted to 11–12. amphetamine and methamphetamine were extracted by adding 3 ml of n-hexane and shaking the sample for 20 minutes before immersing it in a freezing bath to separate the organic compounds. a freezing bath was used instead of more common methods, such as a separatory funnel, because of the low volume of urine in the sample, which made it more difficult to distinguish between aqueous and organic phases. in order to avoid losing volatile analytes such as amphetamine and methamphetamine, a small amount of hydrochloric acid (hcl) was added before the evaporation stage as a keeper solvent.9 a total of 100 μl of methanol and hcl (at a ratio of 99:1 v/v) was added to the medium and the solvent was completely evaporated under a gentle stream of nitrogen. the extract was reconstituted with 100 μl of n-heptane and vortexed for one minute. for derivatisation, 25 μl of hfba was added and the mixture was vortexed for three minutes. the excess hfba was deactivated by adding 500 μl of sodium bicarbonate and vortexing the mixture for one minute. the mixture was again placed in a freezing bath and the organic layer was separated for gcms analysis. instrument control and data acquisition was performed using chemstation software, version g2070ba (agilent technologies inc.) with a 5-ms capillary column at a length of 30 m, internal diameter of 0.25 mm and film thickness of 0.25 mm. gas chromatographic conditions were set as follows. helium of 99.99% purity was used as a carrier gas with a constant flow rate of 1.5 ml per minute. the inlet temperature was set at 250 °c and a volume of 1 ml was used for the splitless injection. the column temperature was set at 90 °c for one minute and then increased at a rate of 20 °c per minute to 280 °c for five minutes. mass source and quadrupole temperatures were fixed at 230 °c and 150 °c, respectively. the ion source was operated by electron impact at 70 ev in selected ion monitoring and full-scan mode with a scan range of that certain therapeutic prescription drugs—such as tranylcypromine—may be metabolised to illegal drugs like amphetamines in humans. this report describes a case of a fatal overdose involving tranyl cypromine, wherein tranylcypromine, methamphetamine and amphetamine were detected postmortem. case report a 25-year-old woman was found dead in her bed in tehran, iran, in 2016. she had last been seen alive five hours previously. she had a history of severe depression, but there was no record of any prior suicide attempts. in addition, her relatives reported that she had no history of substance abuse. one day before her death, she had been prescribed tranylcypromine by her psychiatrist, to be taken twice a day. upon investigation of the scene of death, the police found a bottle of 100 tablets containing 10 mg of tranylcypromine each beside her bed, of which 19 tablets appeared to be missing. the corpse was subsequently transferred to the department of forensic medicine at the legal medicine organization in tehran for an autopsy in order to determine the cause of death. the autopsy revealed no external injuries to the body. the woman weighed 60 kg and her height was 163 cm. the internal organs were normal in size and shape. the stomach contained approximately 300 ml of fluid and some digested food. under the supervision of a forensic specialist, biological specimens were collected, including liver, stomach content, vitreous humour, blood and bile samples. solid tissue, such as that of the liver, was minced and homogenised with two parts of distilled water. liquid-liquid extraction with chloroform and isopropanol (at 80:20 volume/volume percent [v/v]) was used to prepare the biological matrices before analysis. extraction products were subsequently analysed via thin-layer chromatography, high-performance liquid chromatography (hplc) and gas chromatography/mass spectrometry (gcms). thin-layer chromatography was performed with 20 x 20 cm pre-coated aluminium sheets of 0.25 mm silica gel layer thickness with an ultraviolet fluorescent indicator (alugram® xtra sil g sil uv254, macherey-nagel gmbh, düren, germany) whereas hplc was performed with a diode array detector using a eurospher ii 100-5 c18 column of 250 mm x 4.6 mm at 5 μm particle size and 100 å pore size (knauer, berlin, germany) with a pump (smartline 1000, knauer). gcms was performed using the 7890a gas chromatograph and 5975c mass selective detector (agilent technologies inc., santa clara, california, usa). blood and vitreous humour samples maryam akhgari, farzaneh jokar, afshar etemadi-aleagha and ali ghasemi case report | e215 figure 1: chromatogram of amphetamine, methamphetamine and tranylcypromine derivatised with heptafluorobutyric acid as detected in the urine of a 25-year-old woman who died due to a fatal tranylcypromine overdose. hfb = heptafluorobutyric acid. figure 2: mass spectra graphs of (a) amphetamine, (b) methamphetamine and (c) tranylcypromine derivatised with heptafluorobutyric acid as detected in the urine of a 25-year-old woman who died due to a fatal tranylcypromine overdose. 40–500 m/z. the toxicological results of the urine sample were negative for all drugs except for tranylcypromine, amphetamine and methamphetamine [figures 1 and 2]. tranylcypromine was also detected in the stomach contents. discussion among humans, severe intoxication can occur if the maximum daily dose of 60 mg of tranylcypromine is exceeded.1 tranylcypromine-related deaths can be attributed to either an overdose due to misuse of the drug by the patient or to a hypertensive crisis leading to a cerebrovascular accident as a result of a therapeutic dose.10 although tranylcypromine has been commercially available for many years, little is yet known of its metabolic pathway. baker et al. reported finding nacetylcysteine and ringhydroxylated metabolites in the brain of a rat following the administration of tranylcypromine.11 however, there are conflicting reports as to whether tranylcypromine is metabolised to amphetamine and methamphetamine.3,4,8,12,13 in the current case, tranylcypromine was detected in combination with amphetamine and methamphetamine in the urine sample of a fatal overdose case. one possible explanation for the presence of amphetamines in such postmortem specimens is the biotransformation of tranylcypromine to amphetamine and methamphetamine within the human body. crifasi et al. similarly reported the presence of metabolic products, such as amphetamine and methamphetamine, in the body of a tranylcypromine overdose case.14 youdim et al. also detected amphetamine in the plasma of a patient who had overdosed on tranylcypromine.4 however, sherry et al. found no amphetamines in biological samples obtained from both rats and discrimination between drug abuse and medical therapy case report of a tranylcypromine overdose-related fatality e216 | squ medical journal, may 2017, volume 17, issue 2 in iran, it was not possible to publish a case series on this topic. conclusion the present report described a fatal tranylcypromine overdose case in which methamphetamine and amphetamine were found in the urine samples of a young woman with no history of substance abuse. in this case, it is conceivable that the tranylcypromine underwent a metabolic opening of the cyclopropyl ring to produce amphetamine and meth amphetamine. however, further investigation is needed to determine the exact metabolic pathway of tranylcypromine in the human body. this would provide valuable evidence when interpreting forensic toxicology results so as to ascertain whether the presence of methamphetamine and amphetamine indicate the legitimate use of a prescription drug or, alternatively, illegal substance abuse. references 1. gahr m, schönfeldt-lecuona c, kölle ma, freudenmann rw. intoxications with the monoamine oxidase inhibitor tranylcypromine: an analysis of fatal and non-fatal events. eur neuropsychopharmacol 2013; 23:1364–72. doi: 10.1016/j.euro neuro.2013.05.009. 2. fišar z. drugs related to monoamine oxidase activity. prog neuropsychopharmacol biol psychiatry 2016; 69:112–24. doi: 10.1016/j.pnpbp.2016.02.012. 3. sherry rl, rauw g, mckenna kf, paetsch pr, coutts rt, baker gb. failure to detect amphetamine or 1-amino-3phenylpropane in humans or rats receiving the mao inhibitor tranylcypromine. j affect disord 2000; 61:23–9. doi: 10.1016/ s0165-0327(99)00188-3. 4. youdim mb, aronson jk, blau k, green ar, grahame-smith dg. tranylcypromine ('parnate') overdose: measurement of tranylcypromine concentrations and mao inhibitory activity and identification of amphetamines in plasma. psychol med 1979; 9:377–82. doi: 10.1017/s0033291700030890. 5. gentil v, alevizos b, felix-gentil m, lader m. single-dose effects of tranylcypromine on psychophysiological measures in normals. br j clin pharmacol 1978; 5:536–8. doi: 10.1111/ j.1365-2125.1978.tb01672.x. 6. peters ft, drummer oh, musshoff f. validation of new methods. forensic sci int 2007; 165:216–24. doi: 10.1016/j. forsciint.2006.05.021. 7. bahmanabadi l, akhgari m, jokar f, sadeghi hb. quantitative determination of methamphetamine in oral fluid by liquid-liquid extraction and gas chromatography/mass spectrometry. hum exp toxicol 2017; 36:195–202. doi: 10.1177/0960327116638728. 8. berman sm, kuczenski r, mccracken jt, london ed. potential adverse effects of amphetamine treatment on brain and behavior: a review. mol psychiatry 2009; 14:123–42. doi: 10.1038/mp.2008.90. 9. telepchak mj, chaney g, august tf. drug methods for the toxicology lab. in: forensic and clinical applications of solid phase extraction. totowa, new jersey, usa: humana press, 2004. p. 169–244. humans following tranylcypromine administration.3 other studies have also not detected amphetamine or methamphetamine in the biological samples of tranylcypromine overdose cases.15,16 according to yonemitsu et al., amphetamine and methamphetamine can be identified as metabolic products following a tranylcypromine overdose as these metabolites produce symptoms of poisoning; however, with therapeutic doses of tranylcypromine, amphetamine and methamphetamine cannot be detected.10 in another study, 5 mg/kg of tranylcypromine-14c was injected into animals in which approximately 4% of the injected drug was excreted unchanged and 12% was excreted as hippuric acid; in contrast, when amphetamine was injected, these values changed to 15% and 2%, respectively.12 as such, the authors concluded that the opening of the cyclopropyl ring in tranylcypromine did not involve the formation of amphetamine.12 ragab et al. noted that tranylcypromine is relatively stable on exposure to ultraviolet light and that only small amounts of degradation products can be detected using reversed-phase hplc; the authors concluded that the cyclopropyl ring opens in both acidic and alkaline conditions and that the degradation products have different chemical structures from amphetamine and methamphetamine.17 one possible explanation for the discrepancies in the findings of the aforementioned studies may be individual variations in drug metabolism among patients. for example, ethnic variations in cytochrome p450 isoenzymes have resulted in differing levels of metabolic activity, clinical responses and drug interactions.18,19 furthermore, variations in drug metabolism between individuals may also be the reason for contradictory results when biological samples are analysed to detect a parent drug and its metabolites.20 additionally, the pharmacokinetic characteristics of certain drugs may be altered in an overdose situation.19,21 therefore, a number of confounding variables can influence the interpretation of postmortem forensic toxicology results. as such, details of a specific case can be crucial to forensic toxicologists, particularly when interpreting analytical toxicology results and seeking to determine the source of the drugs found. as there are conflicting data regarding the production of amphetamine and methamphetamine in tranylcypromine overdose cases, further studies among larger samples are needed to confirm the in vivo biotransformation of tranylcypromine to amphetamine and methamphetamine. unfortunately, in the current case, due to the limited number of tranylcypromine overdose-related fatalities https://doi.org/10.1016/j.euroneuro.2013.05.009 https://doi.org/10.1016/j.euroneuro.2013.05.009 https://doi.org/10.1016/j.pnpbp.2016.02.012 https://doi.org/10.1016/s0165-0327%2899%2900188-3 https://doi.org/10.1016/s0165-0327%2899%2900188-3 https://doi.org/10.1017/s0033291700030890 https://doi.org/10.1111/j.1365-2125.1978.tb01672.x https://doi.org/10.1111/j.1365-2125.1978.tb01672.x https://doi.org/10.1016/j.forsciint.2006.05.021 https://doi.org/10.1016/j.forsciint.2006.05.021 https://doi.org/10.1177/0960327116638728 https://doi.org/10.1038/mp.2008.90 maryam akhgari, farzaneh jokar, afshar etemadi-aleagha and ali ghasemi case report | e217 10. yonemitsu k, pounder dj. postmortem changes in blood tranylcypromine concentration: competing redistribution and degradation effects. forensic sci int 1993; 59:177–84. doi: 10.1016/0379-0738(93)90157-6. 11. baker gb, coutts rt, greenshaw aj. neurochemical and metabolic aspects of antidepressants: an overview. j psychiatry neurosci 2000; 25:481–96. 12. alleva jj. metabolism of tranyleypromine-c14 and dl amphetamine-c14 in the rat. j med chem 1963; 6:621–4. doi: 10.1021/ jm00342a001. 13. baker gb, urichuk lj, mckenna kf, kennedy sh. metabolism of monoamine oxidase inhibitors. cell mol neurobiol 1999; 19:411–26. doi: 10.1023/a:1006901900106. 14. crifasi j, long c. the gcms analysis of tranylcypromine (parnate) in a suspected overdose. forensic sci int 1997; 86:103–8. doi: 10.1016/s0379-0738(97)02126-9. 15. youdim mb, paykel es, eds. monoamine oxidase inhibitors: the state of the art. london, uk: john wiley & sons ltd., 1981. pp. 63–76. 16. spahn-langguth h, hahn g, mutschler e, möhrke w, langguth p. enantiospecific high-performance liquid chromato graphic assay with fluorescence detection for the monoamine oxidase inhibitor tranylcypromine and its applicability in pharmacokinetic studies. j chromatogr 1992; 584:229–37. doi: 10.1016/0378-4347(92)80580-j. 17. ragab gh, saleh hm, el-henawee mm, elsayed of. validated, ultra high efficiency rp-hplc and stability indicating method for determination of tranylcypromines sulphate in bulk and in tablet dosage forms. j app pharm sci 2016; 6:064–71. doi: 10.7324/japs.2016.60209. 18. gogtay nj, mali nb, iyer k, kadam pp, sridharan k, shrimal d et al. evaluation of cytochrome p450 2d6 phenotyping in healthy adult western indians. indian j pharmacol 2014; 46:266–9. doi: 10.4103/0253-7613.132154. 19. zanger um, schwab m. cytochrome p450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. pharmacol ther 2013; 138:103–41. doi: 10.1016/j.pharmthera.2012.12.007. 20. tracy ts, chaudhry as, prasad b, thummel ke, schuetz eg, zhong xb, et al. interindividual variability in cytochrome p450-mediated drug metabolism. drug metab dispos 2016; 44:343–51. doi: 10.1124/dmd.115.067900. 21. sue yj, shannon m. pharmacokinetics of drugs in overdose. clin pharmacokinet 1992; 23:93–105. doi: 10.2165/00003088199223020-00003. https://doi.org/10.1016/0379-0738%2893%2990157-6 https://doi.org/10.1021/jm00342a001 https://doi.org/10.1021/jm00342a001 https://doi.org/10.1023/a:1006901900106 https://doi.org/10.1016/s0379-0738%2897%2902126-9 https://doi.org/10.1016/0378-4347%2892%2980580-j https://doi.org/10.7324/japs.2016.60209 https://doi.org/10.4103/0253-7613.132154 https://doi.org/10.1016/j.pharmthera.2012.12.007 https://doi.org/10.1124/dmd.115.067900 https://doi.org/10.2165/00003088-199223020-00003 https://doi.org/10.2165/00003088-199223020-00003 squ med j, december 2010, vol. 10, iss. 3, pp. 407-408, epub. 14th nov 10 submitted 31st aug 10 revision req. 11th sept 10, revision recd. 4th oct 10 accepted 4th oct 10 leaning nauseous against the wall as the room swam round me, i wondered how much longer i could live like this – unable to work or do normal tasks. what hope had my children with a father so strangely disabled? supported by the government in 1991 to study aircraft engineering, a bright future was opening before me. after successfully completing my course, i began work in 1996 as a technician on royal air force of oman (rafo) helicopters and was especially excited to test the aircraft in flight with the pilots. in 2004, i had the privilege to be sent to the uk for a helicopter maintenance course. as we landed in london, i suddenly felt dizzy and was sick, having to rest on the plane before disembarking. the doctors over there gave me hydrochlorothiazide tablets (dyazide, maxzide). i had no further problems either during the 6 months course or on return to oman in 2005. in both 2006 and 2007, i had two similar events to the one at the airport in london, but more serious: a feeling of pressure in my body, sweating, extreme dizziness, vomiting, and severe pain in my ears. each ‘attack’ lasted 30 to 60 minutes. as i was then working for rafo in salalah, i was cared for by their medical centre. routine tests did not reveal any abnormalities. accordingly, the attacks were attributed to stress and fatigue as i was often working 7am to midnight on new aircraft. my work pressure further increased in 2007 when i began a bsc. mechanical engineering course at dhofar university. i would study at the university from 8–12, work 1–7pm and then study late into the night or even early morning. this may have further aggravated my problem. in 2008, the attacks became more frequent and much more severe lasting for 2–3 days each time. i was admitted to sultan qaboos hospital in salalah for 4 days, but although no evident abnormality was noted, i was given indefinite sick leave as i was no longer fit to work. during this period, i began feeling down and started to lose hope for my future. i could no longer study or do the work i loved and feared for my family’s future. my condition rendered even self-care difficult; for example i had to sit like a small child to take a shower. transferred to muscat, the air force hospital's ent department found i had severe hearing loss in my left ear, the nerve from my left cochlea being dysfunctional. this was attributed to working in the high noise environment of helicopter maintenance. i was referred to sultan qaboos university hospital (squh) in muscat for magnetic resonance imaging (mri) and an audiogram which led to the same diagnosis of noise related hearing loss; however, the doctors were perplexed by my symptoms. subsequent results of more advanced electrocochleography and electronystagmography tests conducted at a private clinic suggested that i suffered from ménières disease, a disorder of the inner ear which often manifests as pain in both ears, tinnitus, vertigo and nausea. with a clear diagnosis of ménières, the doctors proposed possible treatment. i could undergo decompression or an injection to reduce the fluid in my inner ear and maybe also have an royal air force of oman, salalah, oman email: abuomar634@hotmail.com ç �qê<<‹m<<≈^ï<ÿ⁄_ 4èflè⁄<öü⁄<ƒ⁄<í¬]üë  patient's viewpoint hope lost and found my struggle with ménières disease khamis al-naamani hope lost and found my struggle with ménières disease 408 | squ medical journal, december 2010, volume 10, issue 3 operation, but this could mean i would lose the hearing in my right ear as well. the squh consultant suggested that before undergoing any of this risky treatment, it would be good to try gentler self-care and he suggested i explore the various ménières disease websites.1-8 the diagnosis and this suggestion were a turning point in my struggle both with the disease and with the constant anxiety that i felt. the websites had lots of information about the disease and forums where sufferers from many parts of the world could share their experiences. i began to put into practice the some of the suggestions i gathered from the websites. for a start, i gave up my studies. then i radically changed my diet: less rice, no red meat, no oil, no added sugar or salt and lots of salads, vegetables and fruit. i walked 2–3 km a day or ran 1–2 km and ensured i had a minimum of 8 hours sleep. this regime, together with a new medicine, betaserc (betahistine dihydrochloride), significantly reduced my symptoms to the surprise of my ent specialists. from mid 2009, with their agreement, i began to reduce the medication gradually over 3 months from 3 tablets a day to none. i had the occasional attack, but only lasting 1–2 minutes and these had completely ceased by january 2010. another key part of my treatment, suggested by an american ‘web friend’ was to restore my self-confidence and prepare myself for an eventual return to work by undertaking some social activity. i spent a rewarding 3 months as volunteer teaching english to 25 children. it was an excellent way to forget my own problems as i interacted with these poor children. in early 2010, i went to see the rafo director of engineering to ask to return to work. i am now employed as a teacher at rafo’s technical training school in salalah teaching 3–4 courses per year to new aircraft technicians using dummy aircraft. what is my conclusion from my 6 years experience with ménières disease? i think it’s important to be your own physician to educate yourself and to learn from the experience of others in order to get well. i am trying to educate others in oman about the disease and would like to create a website in arabic. my ent specialists call on me to advise other sufferers and i was recently very pleased to help someone in the ministry of defense to recover from the disease. i now have hope for a bright future for me and my family. references 1. ménières disease. from: www.sehha.com/diseases/ ent/meniere1.htm accessed: 2009. 2. ménières disease. from: www.menieresinfo.com/ start.html accessed: 2009. 3. ménières disease. from: www.menieres.org/ accessed: 2009. 4. ménières disease. from: www.sehha.com/diseases/ ent/meniere.htm accessed: 2009. 5. ménières disease. from: www.entnet.org/ h e a l t h i n f o r m a t i o n / m e n i e r e s d i s e a s e . c f m accessed: 2009. 6. ménières disease. from: www.menieres.org/forum/ index.php?action=chat accessed: 2009. 7. ménières disease. from: www.dizziness-andbalance.com/disorders/menieres/menieres.html accessed: 2009. 8. ménières disease. from: www.earsurgery.org/ site/pages/conditions/menieres-syndrome.php accessed: 2009. 1department of medicine, sultan qaboos university hospital, muscat, oman; 2medicine residency programme, oman medical specialty board, muscat, oman *corresponding author’s e-mail: kowhassan@gmail.com االلتهاب الرئوي الناتج عن امليكوبالزما الرئوية مع تدهور يف االنصباب اجلنيب بالرغم من العالج املناسب مبضادات امليكروبات تقرير حالة كوثر سلمان حسن و غالب اخلضوري abstract: mycoplasma pneumoniae is a common cause of community-acquired pneumonia. as m. pneumoniae pneumonia is usually a mild and self-limiting disease, complications such as pleural effusion occur only rarely. we report a 22-year-old woman who presented to the emergency medicine department of the sultan qaboos university hospital, muscat, oman, in 2017 with an eight-day history of fever associated with coughing, chills and rigors. she was diagnosed with m. pneumoniae pneumonia, but subsequently developed pleural effusion which worsened despite treatment with appropriate antimicrobials. the pleural effusion required drainage, which revealed that it was of the more severe exudative type. following drainage, the patient improved dramatically. she was discharged and advised to continue taking antibiotics. keywords: mycoplasma pneumoniae; bacterial pneumonia; pleural effusion; antimicrobial agents; drainage; case report; oman. امللخ�ص: امليكوبالزما الرئوية هي �شبب �شائع لاللتهاب الرئوي املكت�شب يف املجتمع. مبا اأن اللتهاب الرئوي الناجت عن امليكوبالزما الرئوية هوعادة مر�ض خفيف وحمدود ذاتيًا، فاإن امل�شاعفات مثل الن�شباب اجلنبي ل حتدث اإل نادراً. نعر�ض هنا حالة امراأة تبلغ من العمر 22 عامًا مت اإدخالها اإىل ق�شم طب الطوارئ يف م�شت�شفى جامعة ال�شلطان قابو�ض، م�شقط، ُعمان، يف عام 2017 مع تاريخ مر�شي من احلمى املرتبط بال�شعال والق�شعريرة وق�شوة ملدة ثمانية اأيام. مت ت�شخي�ض اإ�شابتها بالتهاب رئوي ناجت عن امليكوبالزما الرئوية، ولكن تفريغ اإىل اجلنبي الن�شباب احتاج املنا�شبة. امليكروبات مب�شادات العالج من بالرغم �شاء الذي اجلنبي الن�شباب اإىل تطور ذلك بعد والذي ك�شف على اأنه كان من نوع ن�شحي �شديد. بعد التفريغ، حت�شن و�شع املري�شة ب�شكل كبري. ومت ترخي�شها ون�شحت مبوا�شلة تناول امل�شادات احليوية. الكلمات املفتاحية: امليكوبالزما الرئوية؛ اللتهاب الرئوي البكتريي؛ الن�شباب اجلنبي؛ م�شادات اجلراثيم؛ تفريغ؛ تقرير حالة؛ عمان. mycoplasma pneumoniae pneumonia with worsening pleural effusion despite treatment with appropriate antimicrobials case report *kowthar s. hassan1 and ghalib al-khadouri2 sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e239–242, epub. 9 sep 18 submitted 27 nov 17 revision req. 3 jan 18; revision recd. 29 jan 18 accepted 22 feb 18 case report doi: 10.18295/squmj.2018.18.02.022 mycoplasma pneumoniae are extremely small self-replicating free-living bacteria which can cause upper respiratory tract infections, including pharyngitis, sinusitis, ear pain, rhinorrhoea and pneumonia.1,2 m. pneumoniae pneu monia is described as atypical and accounts for 1–29% of community-acquired pneumonia cases.2 the causative bacteria can be transmitted through aerosols as well as in settings which promote close physical contact, such as homes, schools, military barracks and dormitories.3 the post-exposure incubation period is between two to three weeks and infections are more prevalent among children and young adults.4 common risk factors include age (i.e. younger children or older adults), immune status (i.e. immunocompromised individuals with hiv or those undergoing chemotherapy or taking steroids), smoking and pre-existing lung disease.5 classic symptoms of m. pneumoniae infection include fever, cough and the production of sputum; in most cases, the disease is self-limiting and results in a good prognosis.6 however, m. pneumoniae pneumonia can be life-threatening, resulting in respiratory failure or acute respiratory distress syndrome in certain cases.7 however, pulmonary complications such as parapneumonic effusion are rare and occur mainly in children and adolescents; most cases are unilateral, low-volume and resolve with appropriate antimicrobial therapy.8–10 m. pneumoniae pneumonia can be diagnosed by serology using an enzyme immunoassay. an acute infection is indicated by the detection of immunoglobulin (ig) a and/or igm, with a single titre of mycoplasma pneumoniae pneumonia with worsening pleural effusion despite treatment with appropriate antimicrobials case report e240 | squ medical journal, may 2018, volume 18, issue 2 igm greater than 1:64 or a four-fold rise in the igg titre.11,12 polymerase chain reaction (pcr) analysis can also be used to detect m. pneumoniae in clinical samples of sputum and those of nasopharyngeal and throat swabs. however, microbial testing is not usually performed for outpatients with community-acquired pneumonia because empirical treatment is almost always successful.13 this case report describes a patient with pneumonia who was not initially tested for m. pneumoniae. the patient deteriorated and developed severe pleural effusion, despite the administration of appropriate antimicrobials, necessitating drainage. case report a 22-year-old woman presented to the emergency medicine department of the sultan qaboos university hospital (squh), muscat, oman, in 2017 with an eight-day history of fever associated with coughing, chills and rigors. although her coughing was initially dry, she had begun producing yellow-green sputum on day five and developed shortness of breath on day seven. the patient reported having recently undertaken a trip one week prior with her classmates, some of whom had also developed coughs. she was known to have the sickle cell trait and vitamin b12 deficiency and was taking weekly cyanocobalamin injections. upon initial examination, the patient appeared ill, dehydrated, febrile and tachycardic. her temperature was 40.3 ºc, her heart rate was 134 beats per minute and her respiratory rate was 18 breaths per minute. pulse oximetry indicated an oxygen saturation of 97% in room air. auscultation of the chest revealed reduced breath sounds in the right base. the results of initial and serial laboratory investigations are shown in table 1. a chest x-ray showed consolidation of the right middle and lower lobes, with right-sided pleural effusion and partial lower lobe collapse [figure 1a]. subsequently, the patient was diagnosed clinically with communityacquired pneumonia. while awaiting the results of a respiratory viral screening panel and sputum culture, she was prescribed 2 g of ceftriaxone once daily and 500 mg of intravenous azithromycin and 75 mg of oseltamivir twice daily. however, the respiratory viral panel results were negative and the oseltamivir was discontinued. three days later, the culture results of the sputum sample showed only upper respiratory commensals. two days after admission, the condition of the patient deteriorated. she was breathless at rest with a respiratory rate of 40 breaths per minute. her heart rate had decreased to 120 beats per minute and she frequently vomited after episodes of coughing. a chest examination revealed absent breath sounds and table 1: serial blood results of the current case investigation day 0 day 2 day 3 day 6 hb level in g/dl 11.9 10.9 12.6 11.1 wcc x 109/l 6.9 7.0 8.7 anc x 109/l 6.9 5.7 5.8 lp level x 109/l 0.7 0.7 1.6 pc x 109/l 142 157 208 sodium level in mmol/l 134 137 140 potassium level in mmol/l 3.9 3.6 4.0 urea level in mmol/l 1.5 1.4 1.2 creatinine level in µmol/l 59 48 59 anion gap in mmol/l 19 16 14 bicarbonate level in mmol/l 17 19 20 alt level in u/l 136 33 ast level in u/l 118 36 bilirubin level in µmol/l 6 5 hb = haemoglobin; wcc = white cell count; anc = absolute neutrophil count; lp = lipoprotein; pc = platelet count; alt = alanine aminotransferase; ast = aspartate transferase. figure 1: chest x-rays of a 22-year-old female patient with mycoplasma pneumoniae pneumonia on (a) the day of admission and (b) two days later, showing worsening pleural effusion (arrow). kowthar s. hassan and ghalib al-khadouri case report | e241 stony dullness involving the middle and lower chest. a repeat chest x-ray confirmed that the right-sided pleural effusion had worsened [figure 1b]. accordingly, a drainage procedure was performed, during which 2 l of exudative fluid consisting predominantly of lymphocytes (80%) was drained via a pigtail catheter over a 24-hour period. in view of her worsening condition, a nasopharyngeal aspirate sample was sent for serological and pcr testing. the pcr test results were positive for m. pneumoniae, while the serology was positive for iga, igm and igg. as the serology test was qualitative, exact titres were not available. treatment was continued with intravenous azithromycin for five days, after which the patient was discharged and advised to take moxifloxacin for six more days. she made a remarkable improvement and a chest x-ray four weeks later showed the complete resolution of the pneumonic patch and pleural effusion. discussion narita et al. described two types of m. pneumoniaerelated pleural effusion with varying degrees of severity.14 the first is characterised by a benign transient chest disease, is most probably reactive as evidence of the m. pneumoniae genome is usually undetectable and has lower but still abnormal concentrations of interleukin (il)-18 and il-8. the second involves more persistent disease, contains m. pneumoniae dna and has significantly higher il-18 and il-8 concentrations.14 it is possible that the presence of m. pneumoniae dna elicits a stronger immunological reaction, thus causing greater lung damage and higher concentrations of il-8 and il-18. in addition, two major strains of m. pneumoniae clinical isolates have been reported to differ in adhesin gene sequence.15 of these, type 2 is more virulent, causing respiratory epithelial destruction, and has a more robust biofilm, presumably conferring increased resistance to host defence mechanisms and antimicrobial penetration.15 in the current case, although the patient was not tested, it is likely that she had the more severe type with biofilm formation, especially as she did not improve following antimicrobial treatment. drainage of the pleural effusion might have disrupted these biofilms, thereby aiding the recovery process. thrombocytosis can occur as a feature of m. pneumoniae infection and probably represents an acute phase response, while thrombocytopenia is unusual.16 another study found that children with severe m. pneumoniae pneumonia had prolonged fevers, higher c-reactive protein levels and lower lymphocyte and white cell counts (wccs).17 the patients with segmental/lobar pneumonia were usually older and had a longer fever duration and lower wcc and lymphocyte counts compared with those with broncho pneumonia.17 m. pneumoniae infections have also been associated with acute chest syndrome and haemolytic anaemia in patients with sickle cell anaemia.18 in the current case, the patient did not have haemolytic anaemia but did have the sickle cell trait. however, no particular association has been reported within this group in terms of the severity of the infection. the diagnosis of an m. pneumoniae infection can be difficult. the gram staining of sputum samples is not feasible to identify mycoplasma bacterium due to the absence of a cell wall; moreover, a sputum culture is time-consuming because of the slow growth rate of the pathogen in vitro.1 enzyme-linked immunoassaybased serology is the technique most frequently used to diagnose m. pneumoniae infections, although it can be confusing to interpret. unfortunately, igm antibodies can persist for months in some patients, thereby not necessarily indicating an acute infection, while others do not demonstrate an igm response at all in cases of acute infection or reinfection.19,20 moreover, while iga is reported to be more sensitive than igm in diagnosing acute infections in adults, yamazaki et al. reported a lower sensitivity in young children.21,22 therefore, the diagnosis of an m. pneumoniae infection relies on determining a four-fold increase in igg titres taken two to four weeks apart.23 spuesens et al. reported no obvious differences between pcr positivity rates in the throat swabs of individuals with suspected cases of m. pneumoniae infections and those of healthy subjects.24 this suggests that m. pneumoniae may colonise the upper airway without necessarily inducing disease. in the current case, the diagnosis of an m. pneumoniae infection was established by the iga, igm, igg and pcr results of a nasopharyngeal swab. furthermore, the patient’s positive response to azithromycin treatment following drainage of the pleural fluid supports this diagnosis. at squh, hospitalised patients with pneumonia are not routinely tested for m. pneumoniae; therefore, the current patient was tested only after she had deteriorated clinically. nevertheless, the bacterial diagnosis of admitted cases of pneumonia is important, as patients with m. pneumoniae pneumonia require greater infection control measures for the duration of their illness, such as droplet isolation precaution measures.25 although physicians tend to empirically treat patients requiring admission for atypical pneumonia, testing for m. pneumoniae pneumonia might also allow for the better management of pleural effusion cases, should further intervention be required beyond antimicrobial therapy.13 mycoplasma pneumoniae pneumonia with worsening pleural effusion despite treatment with appropriate antimicrobials case report e242 | squ medical journal, may 2018, volume 18, issue 2 conclusion m. pneumoniae is a common cause of communityacquired pneumonia. patients requiring hospital ad mission should be tested for the presence of this bacteria, especially if they have pleural effusion. a c k n o w l e d g e m e n t s the authors wish to acknowledge dr. hatem l. farhan and dr. abdul h. al-hashim who were involved in the care of this patient. references 1. holzman rs, simberkoff ms. mycoplasma pneumoniae and atypical pneumonia. in: bennett je, dolin r, blaser mj, eds. mandell, douglas, and bennett’s principles and practice of infectious diseases, 8th ed. philadelphia, pennsylvania, usa: saunders, 2014. pp. 2183–9. 2. blasi f. atypical pathogens and respiratory tract infections. eur respir j 2004; 24:171–81. doi: 10.1183/09031936.04.00135703. 3. waites kb, talkington df. mycoplasma pneumoniae and its role as a human pathogen. clin microbiol rev 2004; 17:697–728. doi: 10.1128/cmr.17.4.697-728.2004. 4. dorigo-zetsma jw, wilbrink b, van der nat h, bartelds ai, heijnen ml, dankert j. results of molecular detection of mycoplasma pneumoniae among patients with acute respiratory infection and in their household contacts reveals children as human reservoirs. j infect dis 2001; 183:675–8. doi: 10.1086/318529. 5. klement e, talkington df, wasserzug o, kayouf r, davidovitch n, dumke r, et al. identification of risk factors for infection in an outbreak of mycoplasma pneumoniae respiratory tract disease. clin infect dis 2006; 43:1239–45. doi: 10.1086/508458. 6. clyde wa jr. clinical overview of typical mycoplasma pneumoniae infections. clin infect dis 1993; 17:s32–6. 7. fraley ds, ruben fl, donnelly ej. respiratory failure secondary to mycoplasma pneumoniae infection. south med j 1979; 72:437–40. 8. chiou cc, liu yc, lin hh, hsieh ks. mycoplasma pneumoniae infection complicated by lung abscess, pleural effusion, thrombocytopenia and disseminated intravascular coagulation. pediatr infect dis j 1997; 16:327–9. 9. jayantha uk. study on pleural effusions due to mycoplasma pneumoniae infection. sri lanka j child health 2009; 34:5–6. doi: 10.4038/sljch.v34i1.562. 10. john sd, ramanathan j, swischuk le. spectrum of clinica and radiographic findings in pediatric mycoplasma pneumonia. radiographics 2001; 21:121–31. doi: 10.1148/radiographics.21. 1.g01ja10121. 11. jacobs e. serological diagnosis of mycoplasma pneumoniae infections: a critical review of current procedures. clin infect dis 1993; 17:s79–82. doi: 10.1093/clinids/17.supplement_1.s79. 12. räty r, rönkkö e, kleemola m. sample type is crucial to the diagnosis of mycoplasma pneumoniae pneumonia by pcr. j med microbiol 2005; 54:287–91. doi: 10.1099/jmm.0.45888-0. 13. kaysin a, viera aj. community-acquired pneumonia in adults: diagnosis and management. am family physician 2016; 94:698–706. 14. narita m, tanaka h. two distinct patterns of pleural effusions caused by mycoplasma pneumoniae infection. pediatr infect dis j 2004; 23:1069. doi: 10.1097/01.inf.0000143655.11695.99. 15. simmons wl, daubenspeck jm, osborne jd, balish mf, waites kb, dybvig k. type 1 and type 2 strains of mycoplasma pneumoniae form different biofilms. microbiology 2013; 159:737–47. doi: 10.1099/mic.0.064782-0. 16. marrie tj. mycoplasma pneumoniae pneumonia requiring hospitalization, with emphasis on infection in the elderly. arch intern med 1993; 153:488–94. doi: 10.1001/archinte.19 93.00410040054008. 17. youn ys, lee ky, hwang jy, rhim jw, kang jh, lee js, et al. difference of clinical features in childhood mycoplasma pneumoniae pneumonia. bmc pediatr 2010; 10:48. doi: 10.1 186/1471-2431-10-48. 18. neumayr l, lennette l, kelly d, earles a, embury s, groncy p, et al. mycoplasma disease and acute chest syndrome in sickle cell disease. pediatrics 2003; 112:87–95. 19. thacker wl, talkington df. analysis of complement fixation and commercial enzyme immunoassays for detection of anti bodies to mycoplasma pneumoniae in human serum. clin diagn lab immunol 2000; 7:778–80. doi: 10.1128/cdli.7.5.778-780.2000. 20. sillis m. the limitations of igm assays in the serological diagnosis of mycoplasma pneumoniae infections. j med microbiol 1990; 33:253–8. doi: 10.1099/00222615-33-4-253. 21. granström m, holme t, sjögren am, ortqvist a, kalin m. the role of iga determination by elisa in the early serodiagnosis of mycoplasma pneumoniae infection, in relation to igg and mu-capture igm methods. j med microbiol 1994; 40:288–92. doi: 10.1099/00222615-40-4-288. 22. yamazaki t, narita m, sasaki n, kenri t, arakawa y, sasaki t. comparison of pcr for sputum samples obtained by induced cough and serological tests for diagnosis of mycoplasma pneumoniae infection in children. clin vaccine immunol 2006; 13:708–10. doi: 10.1128/cvi.00413-05. 23. gavranich jb, chang ab. antibiotics for community acquired lower respiratory tract infections (lrti) secondary to mycoplasma pneumoniae in children. cochrane database syst rev 2005; 20:cd004875. doi: 10.1002/14651858.cd004875.pub2. 24. spuesens eb, fraaij pl, visser eg, hoogenboezem t, hop wc, van adrichem ln, et al. carriage of mycoplasma pneumoniae in the upper respiratory tract of symptomatic and asymptomatic children: an observational study. plos med 2013; 10:e1001444. doi: 10.1371/journal.pmed.1001444. 25. siegel jd, rhinehart e, jackson m, chiarello l; health care infection control practices advisory committee. 2007 guideline for isolation precautions: preventing transmission of infectious agents in health care settings. am j infect control 2007; 35:s65–164. doi: 10.1016/j.ajic.2007.10.007. https://doi.org/10.1183/09031936.04.00135703 https://doi.org/10.1128/cmr.17.4.697-728.2004 https://doi.org/10.1086/318529 https://doi.org/10.1086/508458 https://doi.org/10.4038/sljch.v34i1.562 https://doi.org/10.1148/radiographics.21.1.g01ja10121 https://doi.org/10.1148/radiographics.21.1.g01ja10121 https://doi.org/10.1093/clinids/17.supplement_1.s79 https://doi.org/10.1099/jmm.0.45888-0 https://doi.org/10.1097/01.inf.0000143655.11695.99 https://doi.org/10.1099/mic.0.064782-0 https://doi.org/10.1001/archinte.1993.00410040054008 https://doi.org/10.1001/archinte.1993.00410040054008 https://doi.org/10.1186/1471-2431-10-48 https://doi.org/10.1186/1471-2431-10-48 https://doi.org/10.1128/cdli.7.5.778-780.2000 https://doi.org/10.1099/00222615-33-4-253 https://doi.org/10.1099/00222615-40-4-288 https://doi.org/10.1128/cvi.00413-05 https://doi.org/10.1002/14651858.cd004875.pub2 https://doi.org/10.1371/journal.pmed.1001444 https://doi.org/10.1016/j.ajic.2007.10.007 departments of 1obstetrics & gynaecology, 2minimally invasive surgery and 3reproductive medicine & infertility, faculty of medicine, hashemite university, zarqa, jordan; 4department of obstetrics & gynaecology, jordan healthcare centre, amman, jordan *corresponding author’s e-mail: iabumahfouz@gmail.com حالة نادرة من الناسور شرجي-مهبلي بسبب اجلماع اجلنسي بالرتاضي فداء الع�سلي، رامي كيالين، فرا�ض ر�سود، اإ�سماعيل اأبو حمفوظ abstract: rectovaginal fistulae after sexual intercourse are rare. we report a healthy recently married 21-year-old woman who presented to the jordan healthcare centre, amman, jordan in 2014 with a five-week history of passing flatus and stool from the vagina. six weeks prior, she had sustained a rectovaginal injury during initial consensual sexual intercourse, leading to the development of a distal rectovaginal fistula. a successful transvaginal repair was performed nine weeks after presentation which resulted in the complete resolution of her symptoms. keywords: rectovaginal fistula; sexual intercourse; dyspareunia; case report; jordan. امللخ�ص: ن�سوء نا�سور �رصجي-مهبلي بعد اجلماع حالة نادرة. نعر�ض هنا حالة اإمراأة متزوجة عمرها 21 عاما وب�سحة جيدة قدمت اإىل املركز ااالأردين للرعاية ال�سحية، عمان، االأردن يف عام 2014 وتعاين منذ خم�سة اأ�سابيع من مترير غازات بطنية و براز من املهبل. قبل �ستة اأ�سابيع، كانت قد تاأثرت باإ�سابة للم�ستقيم املهبلي اأثناء اجلماع اجلن�سي االأول الذي مت برتا�سي الزوجني. هذا اأدى اإىل ن�سوء نا�سور �رصجي-مهبلي قا�سي. مت بنجاح عالج واإ�سالح املهبل بعد ت�سعة اأ�سابيع من قدوم احلالة مما اأدى اإىل زوال جميع اأعرا�سها. الكلمات املفتاحية: نا�سور �رصجي-مهبلي؛ اجلماع اجلن�سي؛ ع�رص اجلماع؛ تقرير حالة؛ االأردن. a rare case of rectovaginal fistula due to consensual sexual intercourse fida al-asali,1 rami kilani,2 firas rshoud,3 *ismaiel a. mahfouz4 sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e107–109, epub. 4 apr 18 submitted 1 aug 17 revisions req. 10 oct & 23 nov 17; revisions recd. 29 oct & 3 dec 17 accepted 7 dec 17 case report doi: 10.18295/squmj.2018.18.01.019 mild genital injuries during consensual sexual intercourse are not uncommon and are usually associated with minor bleeding; abasiattai et al. reported that genital injuries related to sexual intercourse accounted for 0.7 out of 1,000 gynaecological emergencies in calabar, nigeria.1 worldwide, the most common causes of rectovaginal fistulae (rvf) are obstetric, followed by cervical cancer, radiation injuries, inflammatory bowel disease, operative gynaecological trauma and rectal cancer.2 however, the development of rvf after sexual intercourse is rare, with only 91 cases related to both consensual sexual intercourse and rape reported between 1991 and 1997 at the addis ababa fistula hospital in ethiopia.3 case report a healthy 21 year-old woman presented to the gynae cology clinic of the jordan healthcare centre, amman, jordan in 2014 with a five-week history of passing flatus and stool from the vagina. she had gotten married six weeks prior to presentation and had had sexual intercourse twice on her wedding night. during the first act, she noted mild pain and vaginal bleeding; however, the second time, penetration of the vagina was difficult and much more painful. this second act of penetration was immediately followed by heavy vaginal bleeding. the following day, she consulted her gynaecologist and a vaginal examination showed a distal posterior vaginal wall laceration. she was reassured and prescribed oral antibiotics. however, the patient began to notice the passage of flatus and stool from the vagina one week later. she therefore sought a second opinion from another gynaecologist. at this time, the vaginal examination showed an rvf measur ing around 2.5 cm. both the gynaecologist and a general surgeon advised conservative management, including oral antibiotics, stool softeners and perineal care. subsequently, the patient presented to the jordan healthcare centre six weeks after the incident. she described little improvement in her symptoms and felt that the condition was seriously affecting her psychological wellbeing. an examination showed a scarred deficient perineum measuring 1.5 cm, with right lateral vaginal wall scar tissue at the 8 o’clock position. the opening of the fistula was clearly visualised in the distal posterior vaginal wall, traversing in a longitudinal direction and measuring approximately 0.5 x 2 cm. the distal edge of the rvf was around 0.5 cm proximal to the hymenal ring and the vaginal skin surrounding the tract was inflamed. a rectal examination showed a 2 cm distal fistula, with good anal sphincter tone. unfortunately, it was not possible to objectively evaluate the anal sphincter due to the lack of endoanal a rare case of rectovaginal fistula due to consensual sexual intercourse e108 | squ medical journal, february 2018, volume 18, issue 1 ultrasonography equipment. the skin surrounding the fistula tract was infected. following a detailed consultation, the patient req uested that the rvf be surgically repaired as soon as possible, despite medical advice to continue conservative management for another few weeks. nevertheless, she agreed to take oral antibiotics to treat the infection and to continue taking stool softeners. at a follow-up visit two weeks later, the infection was found to have resolved. the planned transvaginal repair was sched uled a week later and the patient underwent preoperative bowel preparation. intraoperatively, the posterior vaginal wall and perineal skin were incised, the vaginal wall was reflected, the rvf was isolated and the edges of the tract were excised. using fine delayedabsorbable sutures, the rectum was closed, followed by a two-layer closure of the endopelvic fascia. the perineum was then reconstructed and the vaginal skin closed. the following morning, the patient was discharged and prescribed a two-week regimen of stool softeners and oral antibiotics. she attended follow-up appointments every two weeks for a total of eight weeks. nine weeks after the surgery, a vaginal and rectal examination showed that the rvf had healed and the patient was able to resume sexual intercourse. she reported no dyspareunia or recurrence of the fistula-related symptoms. she subsequently became pregnant twice, with the first pregnancy occurring six months after the repair. she delivered both babies by elective caesarean section at 39 gestational weeks. discussion risk factors for developing an rvf after sexual intercourse include young patient age, rough coitus, the first act of penetrative sexual intercourse, penovaginal disproportion and intercourse during the puer perium period.4 in the current case report, the patient was believed to have sustained a traumatic rectovaginal injury during her first act of sexual intercourse. as well as rupturing the hymen, this likely caused a laceration in the distal part of the posterior vaginal wall which subsequently acted as a weak entry point for the penis to pass through the vaginal wall during the second act of intercourse, thus resulting in the rvf. this may have been compounded by particularly hard thrusts on the part of an over-eager husband and the contracture of the patient’s pelvic muscles in response to the pain. considering its presentation shortly after the initial act of intercourse, direct rectovaginal trauma was deemed the most probable cause of rvf in this patient; however, vascular injury and infection may also have been contributing factors. in the current case, the traumatic rvf was an isolated injury and was easily diagnosed on a clin ical basis, with no need for any further specific invest igations. however, various other diagnostic modalities may be useful in evaluating patients with suspected fistulae, such as a colonoscopy, barium enema, computed tomography or magnetic resonance imaging.5 an anorectal ultrasound scan can also be used to check the integrity of the anal sphincter. if diagnosed early, traumatic rvf should be treated surgically.5 however, infected fistulae or those of infective origin require initial medical care. conservative management includes perineal care, the drainage of any abscesses, antibiotic therapy to treat the infection and stool softeners to regulate bowel function.5 if a fistula has not healed completely after 6–12 weeks of conservative treatment, then surgical repair should be considered.6 the surgical repair of an rvf may be performed either locally (i.e. transrectal or transvaginal repairs) or transabdominally.5 prior to surgery, mechanical bowel preparation and intravenous antibiotics are essential. currently, the vast majority of fistulae are repaired without the need for a preoperative colostomy.5 when considering local repair, either transanal advancement flaps or transvaginal repairs are used. transabdominal repairs are generally used for high fistulae resulting from inflammatory bowel disease, cancer or radiotherapy.5 the simplest abdominal approach involves division and closure of the fistula without bowel resection; however, the latter may be necessary in cases of radiation damage or cancer. a simple faecal diversion with an ileostomy or colostomy may be necessary in patients with high operative risk or individuals who do not have a long life expectancy.5 while the patient in the present case presented early to a healthcare facility, the diagnosis was unfortunately delayed due to an in complete clinical evaluation. it is possible that a thorough examination would have helped ensure earlier diagnosis and treatment. there are limited reports about reproductive performance and managing delivery among pregnant women following the successful repair of a genital fistula. in 1974, aimakhu reported that 20% of women with obstetric traumatic vesicovaginal fistulae who had had a successful repair went on to have a term pregnancy.6 while several researchers have indic ated that the optimal mode of delivery after the successful repair of an obstetric fistula is an elective caesarean section, the evidence for this approach is limited.7,8 however, among women with successfullyrepaired obstetric fistulae who were allowed to deliver vaginally, 55% had their fistulae opened during delivery.9 in the current case, the patient became pregnant twice and successfully delivered both times via elective caesarean section. fida al-asali, rami kilani, firas rshoud and ismaiel a. mahfouz case report | e109 3. ekwempu cc. fistulae. in: agboola a, ed. textbook of obstetrics & gynaecology for medical students. ibadan, nigeria: heinemann educational books, 1988. pp. 46–59. 4. amenu d. rectovaginal fistula in a newly-married woman. gynecol obstet (sunnyvale) 2015; 5:296. doi: 10.4172/21610932.1000296. 5. vogel jd, johnson ek, morris am, paquette im, saclarides tj, feingold dl, et al. clinical practice guideline for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula. dis colon rectum 2016; 59:1117–33. doi: 10.1097/dcr.000000 0000000733. 6. aimakhu ve. reproductive functions after the repair of obs-tetric vesicovaginal fistulae. fertil steril 1974; 25:586–91. doi: 10.1016/s0015-0282(16)40514-5. 7. browning a, menber b. women with obstetric fistula in ethiopia: a 6-month follow up after surgical treatment. bjog 2008; 115:1564–9. doi: 10.1111/j.1471-0528.2008.01900.x. 8. browning a. pregnancy following obstetric fistula repair, the management of delivery. bjog 2009; 116:1265–7. doi: 10.11 11/j.1471-0528.2009.02182.x. 9. emembolu j. the obstetric fistula: factors associated with improved pregnancy outcome after a successful repair. int j gynaecol obstet 1992; 39:205–12. doi: 10.1016/0020-7292(92) 90658-6. conclusion female genital injuries after consensual sexual intercourse are rare. however, if serious, such injuries can have a negative impact on a woman’s health and quality of life. in cases of traumatic rvf, a thorough and timely physical examination may help avoid any unnecessary delays in treatment. a c k n o w l e d g e m e n t s the authors would like to thank mr. salem a. mahfouz for his contributions in the preparation of this manuscript for publication. references 1. abasiattai am, etuk sj, bassey ea, asuquo ee. vaginal injuries during coitus in calabar: a 10-year review. niger postgrad med j 2005; 12:140–4. 2. abu gazala m, wexner sd. management of rectovaginal fistulas and patient outcome. expert rev gastroenterol hepatol 2017; 11:461–71. doi: 10.1080/17474124.2017.1296355. https://doi.org/10.4172/2161-0932.1000296 https://doi.org/10.4172/2161-0932.1000296 https://doi.org/10.1097/dcr.0000000000000733 https://doi.org/10.1097/dcr.0000000000000733 https://doi.org/10.1016/s0015-0282%2816%2940514-5 https://doi.org/10.1111/j.1471-0528.2008.01900.x https://doi.org/10.1111/j.1471-0528.2009.02182.x https://doi.org/10.1111/j.1471-0528.2009.02182.x https://doi.org/10.1016/0020-7292%2892%2990658-6 https://doi.org/10.1016/0020-7292%2892%2990658-6 https://doi.org/10.1080/17474124.2017.1296355 1department of child health, oman medical specialty board, muscat, oman; 2department of child health and 3radiology and molecular imaging, sultan qaboos university hospital, muscat, oman; 4department of child health, sultan qaboos university, muscat, oman *corresponding author’s e-mail: amnaf@squ.edu.om ضحك بشكل غري الئق لدى مريض مصاب بورم عاِب ِوطاِئي فار�س الكلباين، َفراز اأحمد، عالء املنزالوي، اآمنة الفطي�سية inappropriate laughter in a patient with hypothalamic hamartoma faris al kalbani,1 faraz ahmad,2 alaa elmanzalawy,3 *amna al futaisi4 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e231–233, epub. 28 jun 20 submitted 25 nov 19 revision req. 7 jan 20; revision recd. 27 jan 20 accepted 1 mar 20 a two-year and seven-month-old boy presented to the emergency department at sultan qaboos university hospital, muscat, oman, in 2019, with a two-day history of uprolling of eyeballs, unresponsiveness and drooling of saliva lasting for seconds. there was no abnormal limb movement or loss of tone. the episodes were followed by a postictal state that lasted 30 minutes. there were no triggers for the episodes, such as fever or intercurrent illness. the patient was born at term gestation to a consanguineous marriage. antenatal, birth and family history were unremarkable. his developmental milestones were appropriate for his age and his immunisation was up-to-date. a sleep electro encephalogram (eeg) showed abnormal interictal generalised epileptiform discharges with no associated clinical accompaniment. there were bilateral occipital epileptiform discharges with slowing over the left this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.016 interesting medical image figure 1: sagittal t1-weighted magnetic resonance images (mris) of the brain of a two-year and seven-month-old boy before (a) and after (b) intravenous gadolinium contrast administration. they show a mass (asterisk) arising from the both above and below the floor of the third ventricle (red arrows). accordingly, this mass has both vertical and horizontal planes of attachment to the floor of the third ventricle classifying it radiologically as delalande type iii. it occupies most of the suprasellar and interpeduncular cisterns. it compresses the optic chiasm (white arrows) and pituitary stalk (white arrowhead) anteriorly. coronal (c) and axial (d) t2-weighted mris show the mass having a heterogenous hyperintense signal. it is seen stretching the optic tracts bilaterally (yellow arrows) in (d). https://creativecommons.org/licenses/by-nd/4.0/ inappropriate laughter in a patient with hypothalamic hamartoma e232 | squ medical journal, may 2020, volume 20, issue 2 posterior head region. in view of some lateralising features on eeg, mri of the brain was done within three weeks of initial presentation, which revealed features of a hypothalamic hamartoma (hh; figures 1 and 2). formal visual field assessment was not possible due to the patient’s young age. however, no visual symptoms were observed and endocrine workup was normal. initial seizure control was achieved with levetiracetam reaching a dose of 40 mg/kg/day. two months later, he developed multiple, sudden onset, unprovoked and uncontrollable laughing episodes that were occurring for no obvious reasons, suggestive of gelastic seizures. postictally, he was immediately back to his baseline with no tiredness or sleepiness. repeated routine eeg did not capture the events and showed no clear epileptiform abnormality except bilateral posterior slowing with left temporal dominance. long-term video eeg was not performed. the episodes of gelastic seizures were difficult to control and required the administration of topiramate (6 mg/ kg/day) as well as a short course of phenytoin (6 mg/ kg/day) to control a cluster of focal seizures. currently, he is on two anti-epileptic medications (levetiracetam and topiramate). eight months later during follow-up, the father of the child reported mild hyperactivity. there was no evidence of neuroregression. during the write-up of this article, the patient was awaiting formal assessment with the developmental and behavioural paediatric team. although he was not yet seizure-free, the episodes were reasonably controlled with 1–2 brief daily episodes of eyelid twitching and occasional gelastic seizures once in 1–2 weeks. the parents were offered the option of surgical intervention, but decided against it. comment as a rare developmental malformation, hh can display diverse clinical manifestations. it may present with intractable seizures, central precocious puberty and cognitive and neuropsychiatric disturbances. seizures associated with hh can be of variable types and include focal seizures with impaired awareness, generalised tonic-clonic seizures, epileptic spasms, atonic, tonic, focal seizures with retained awareness and the hallmark gelastic seizures.1 based on the radiological features, the hh of the current patient was classified as delalande type iii.2 the patient initially presented with focal seizure with impaired awareness and later developed gelastic seizures, which are a unique type of seizures that are usually seen in early childhood. gelastic seizures are characterised by frequent brief attacks of inappropriate laughter.3 the eeg during a gelastic seizure is usually normal or may show non-specific abnormalities, which may contribute to the difficulty in establishing the diagnosis when gelastic seizures are the sole presentation. the seizures in hh are thought to be due to either the intrinsic epileptogenicity of the hamartoma itself or contributed by the extensive epileptogenic networks and possible kindling-like relationship between the hh and the cortex.4,5 this epileptogenic spread could possibly explain the eeg findings in the current patient. most patients with epilepsy secondary to hh develop an associated mood disorder, behavioural issues and/or cognitive delay. a significant proportion of patients with hh and epilepsy may present with central precocious puberty. however, growth hormone deficiency, hypothyroidism and adrenal insufficiency are rare. although diabetes insipidus is not seen in non-operated hh, it is frequently seen postoperatively.6 treatment of hh-associated epilepsy is chall enging and complete seizure freedom with antiseizure medications is rarely achieved. behavioural and learning difficulties as well as cognitive delay lead to an overall developmental impairment contributing to the increased morbidity associated with hh. treatment strategies in such cases of progressive encephalopathy associated with hh should be based on multidisciplinary care, including neurologists, figure 2: magnetic resonance imaging (mri) of the brain of a two-year and seven-month-old boy showing a hypothalamic (tuber cinereum) hamartoma (asterisk). it shows (a & b) hyperintense signal on fluid-attenuated inversion recovery and t2 mris. axial diffusionweighted mri (c) and apparent diffusion coefficient map (d) images showing no evidence of diffusion restriction in this lesion. faris al kalbani, faraz ahmad, alaa elmanzalawy and amna al futaisi interesting medical image | e233 neuropsychologists and neurosurgeons. therapeutic options include anti-seizure medications, ketogenic diet therapy and vagal nerve stimulation. neurosurgical options include microsurgical resection, endoscopic disconnection, stereotactic laser ablation therapy, gamma knife surgery and laser interstitial thermal therapies. although surgical intervention remains the best treatment option for achieving seizure control in drug refractory cases, it is associated with a high risk of postoperative long-term endocrine dysfunction, especially with disconnection surgeries. newer surgical techniques—including stereotactic radiofrequency thermo-coagulation, gamma knife surgery and laser interstitial thermal therapies—are reported to have better outcomes, though long-term follow-up of such patients is needed to monitor the neurodevelopmental and endocrine functions.7 therefore, multidisciplinary care with regular follow up and monitoring is recommended in such cases to make timely decisions based on individual case progress and evolution.8 references 1. parvizi j, le s, foster bl, bourgeois b, riviello jj, prenger e, et al. gelastic epilepsy and hypothalamic hamartomas: neuro anatomical analysis of brain lesions in 100 patients. brain 2011; 134:2960–8. https://doi.org/10.1093/brain/awr235. 2. delalande o, fohlen m. disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification. neurol med chir (tokyo) 2003; 43:61–68. https://doi.org/10.2176/nmc.43.61. 3. shahar e, kramer u, mahajnah m, lerman-sagie t, goez r, gross v, et al. pediatric-onset gelastic seizures: clinical data and outcome. pediatr neurol 2007; 37:29–34. https://doi.org/10.10 16/j.pediatrneurol.2007.03.003. 4. wu j, gao m, shen jx, qiu sf, kerrigan jf. mechanisms of intrinsic epileptogenesis in human gelastic seizures with hypo thalamic hamartoma. cns neurosci ther 2015; 21:104–11. https://doi.org/10.1111/cns.12348. 5. scholly j, staack am, kahane p, scavarda d, régis j, hirsch e, et al. hypothalamic hamartoma: epileptogenesis beyond the lesion? epilepsia 2017; 58:32–40. https://doi.org/10.1111/epi.13755. 6. harrison vs, oatman o, kerrigan jf. hypothalamic hamartoma with epilepsy: review of endocrine comorbidity. epilepsia 2017; 58:50–59. https://doi.org/10.1111/epi.13756. 7. arocho-quinones ev, koop j, lew sm. improvement of hypothalamic hamartoma-related psychiatric disorder after stereotactic laser ablation: case report and review of literature. world neurosurg 2019; 122:680–3. https://doi.org/10.1016/j. wneu.2018.11.166. 8. helen cross j, spoudeas h. medical management and anti epileptic drugs in hypothalamic hamartoma. epilepsia 2017; 58:16–21. https://doi.org/10.1111/epi.13758. https://doi.org/10.1093/brain/awr235 https://doi.org/10.2176/nmc.43.61 https://doi.org/10.1016/j.pediatrneurol.2007.03.003 https://doi.org/10.1016/j.pediatrneurol.2007.03.003 https://doi.org/10.1111/cns.12348 https://doi.org/10.1111/epi.13755 https://doi.org/10.1111/epi.13756 https://doi.org/10.1016/j.wneu.2018.11.166 https://doi.org/10.1016/j.wneu.2018.11.166 https://doi.org/10.1111/epi.13758 squ med j, august 2010, vol. 10, iss. 2, pp. 215-220, epub. 19th jun 10 submitted: 17th feb 10 revision req. 25th april 10, revision recd. 15th may 10 accepted: 26th may 10 األهمية التشخيصية إلجراء فحص الغدة الدرقية املخربي يف عيادة الطلبة جبامعة السلطان قابوس وجدواها من ناحية الفعالية والكلفة مراجعة منحنيات استعادية كوثر الشفيع، أصيلة الشقصية، بدريه املروقية، هادية اللواتية، سمير العدوي، محمد الشافعي، شيام جنجولي املحددة وغري املحددة لالأعرا�س والفعالية الكلفة ناحية من وجدواه املخربي الدرقية الغدة فح�س اأهمية مدى معرفة الهدف: امللخ�ص: لأمرا�س الغدة الدرقية لطلبة اجلامعة الطريقة: درا�شة ا�شتعادية للملفات اأجريت يف عيادة الطلبة بجامعة ال�شلطان قابو�س يف عمان �شملت كل املر�شى )319 مري�شا( من اجلن�شني اأجري لهم الفح�س املذكور لعامي 2008-2007 ومت جتميع كافة البيانات املتعلقة بفح�س الغدة الدرقية املخربي من نتائج واأعرا�س وت�شخي�س نهائي من ملفات املر�شى. النتائج: لوحظ اأن اأكرث الأعرا�س �شيوعا والتي كانت �شببا لطلب الفح�س هي عدم انتظام الدورة ال�شهرية )82 مري�شا(، الإعياء)49 مري�شا(، اخلفقان )39 مري�شا( وتغري الوزن )22 مري�شا( وتغري ال�شعر )20 مري�شا( وال�شعور باحلرارة والربودة )18 مري�شا( والإ�شهال والإم�شاك )13 مري�شا( وتورم الرقبة )13 مري�شا(. وقد �شخ�س معظم املر�شى ت�شخي�س ي�شجل مل بينما والقلق، الكتئاب من يعانون مري�شا ووجد 11 مري�شا(. 42( الدم وفقر مري�شا( 51( املباي�س تكي�س مبتالزمة حمدد لإجمايل 193 مري�شا. اأما الذين �شخ�شوا باأمرا�س الغدة الدرقية )ق�شور الدرقية اأو فرط اإفراز الدرق ال�رشيري ودون ال�رشيري واأورام .)p<0.05( فبلغ عددهم 22 مري�شا فقط، ت�شكل ن�شبة الناث %7.1 مقارنة ب %2.1 من الذكور وهي ذات دللة اإح�شائية معتدة )الغدة �شكلت اأمرا�س الغدة الدرقية %61.5 من الذين عانوا من ورم الرقبة، %7.7 من الذين عانوا من اخلفقان، %4.1 من الذين عانوا من الإعياء و %1.2 من املري�شات اللواتي عانني من عدم انتظام الدورة. كانت كلفة الفحو�شات 20 دولرا اأمريكيا. اخلال�صة: من ال�رشوري اإجراء فح�س الغدة الدرقية املخربي للمر�شى الذين يعانون من اأورام الرقبة، وتاأجيل اإجرائه للمر�شى الذين يعانون من اخلفقان والإعياء امل�شتمر موؤقتًا حلني التاأكد من خلوهم من فقر الدم.، وعدم اإجرائه للمري�شات اللواتي يعانني من عدم انتظام الدورة فقط دون وجود اأية اأعرا�س اأخرى لعدم وجود عالقة بني ذلك ال�شطراب وفح�س الدرقية املخربي. مفتاح الكلمات: فحوصات وظيفة الغدة الدرقية، مرض الدرقية ، الكلفة والفعالية ، عمان. abstract: objectives: to assess the significance of requesting thyroid function tests (tft) and their cost effectiveness for specific and non-specific symptoms of thyroid disease in a specific population in oman. methods: a retrospective chart review study was conducted in the student clinic at sultan qaboos university in oman in the year 2007–2008. it included all patients (n = 319) of both sexes for whom tfts were requested. the patients’ main complaints and the final diagnoses were collected from their medical records. results: the most common presentations for which tfts were requested were irregular periods (n = 82); fatiguability (n = 49), palpitations (n = 39); weight changes (n = 22); hair changes (n= 20); sensation of heat and cold (n= 18); diarrhoea and constipation (n = 13), and neck swelling (n = 13).the most common diagnoses reached in relation to these complaints were polycystic ovarian syndrome (n = 51); iron deficiency anaemia (n = 42); anxiety and depression (n = 11); thyroid disease (n = 18), and no specific diagnosis (n = 193). the percentage of thyroid diseases among females (7.1%) compared to males (1.2%) was statistically significant (p <0.05). thyroid disease accounted for 61.5% of those patient with neck swelling, 7.7% of those with palpitations, 4.1% of those with fatigue, 3% of those with other complaints, and 1.2% of those with irregular periods. the cost of the tests was around 20,000 us dollars. conclusion: tft is necessary for those presenting with neck swelling, but restraint should be used in administering the test for those complaining of palpitations or fatigue. additionally, irregular periods have little link with tft abnormality. keywords: thyroid function tests; retrospective study; cost-effective; student clinic; oman. the diagnostic yield of thyroid function tests and their cost-effectiveness in the student clinic at sultan qaboos university retrospective chart review *kawther el shafie,1 asila al-shaqsi,2 badriya al-mahrouqi,2 hadia al lawati,2 shyam s ganguly,2 samir al adawi4 and mohammed al shafaee3 clinical & basic research 1department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 2ministry of health, muscat, oman; departments of 3family medicine & public health, 4behavioral medicine, college of medicine and health sciences, sultan qaboos university, muscat, oman *corresponding author email: kawther@squ.edu.om the diagnostic yield of thyroid function tests and their cost-effectiveness in the student clinic at sultan qaboos university retrospective chart review 216 | squ medical journal, august 2010, volume 10, issue 2 thyroid diseases are common, non-specific, clinical consequences of many medical, neurological and psychiatric conditions and tend to affect women disproportionately. disorders of the thyroid gland include clinical and subclinical hyperthyroidism, hypothyroidism, goiter and thyroid cancer.1 thyroid dysfunction can be diagnosed accurately and is amenable to treatment. due to the wide range of specific and non-specific symptoms of thyroid diseases, thyroid function tests (tft) are among the most frequently prescribed laboratory procedures.2 because of their relative low cost and widespread availability, tft are often considered to be a standard work-up procedure.3 recently, there has been much criticism of this trend since such screening may not be as reliable as clinical impression. in some professionals’ opinion, tft procedures are seldom essential as a first-level measurement.4,5 since the results from clinical laboratories help clinicians to determine diagnoses and monitor responses to therapy, inappropriate use of laboratory tests can lead to poor case management, unnecessary increases in the cost of patient management, and may even result in adverse medical outcomes.6 the skyrocketing costs incurred by wide usage of tft is an additional consequence which is often overlooked. beckett and toft have reported that in the uk there were approximately 10 million requests for tft each year, the cost of which has been estimated at £30 million (c. 16 million or).7 a number of guidelines have emerged suggesting more prudent ordering of tft.8 to our knowledge, no such studies have been performed on the pattern of routine assessment of thyroid function in the arab/islamic part of the world. in order to fill this gap in the literature, this paper aims to examine the pattern of thyroid function test requests for specific and non-specific symptoms at the student clinic at sultan qaboos university (squ) in the sultanate of oman. oman, is an arab/islamic country situated in the southeastern corner of the arabian peninsula, which has experienced a dramatic development of its health care infrastructure in the past few decades. postnatal coverage in oman is the highest among arab nations.9 in recent estimates, malnutrition and infectious diseases appear to be on the wane as many eradication and immunisation programs are being implemented throughout the country. there have been no studies in oman to investigate the prevalence of thyroid diseases, but it has been indicated that the prevalence may be inflated due to the cultural practice of consanguineous marriages.10,11 anecdotal evidence suggests that rather than relying on clinical impression clinicians tend to employ tft routinely as an integral part of the work-up procedure. in our experience at the squ student clinic, thyroid function tests are frequently requested for a wide range of complaints including palpitations, irregular periods, fatiguability and non-specific symptoms such as chest pain and headache. there have been no studies on the pattern of routine assessment of thyroid functions. one of the implicit benefits of such studies is to audit the quality of services and to enhance good medical practice in the country. given this background, the present study aims to investigate the factors that contribute to requesting the use of tft among university students in oman, the utility of the test and its cost effectiveness. methods a retrospective chart review was carried out at the squ student clinic in the sultanate of oman. this clinic serves the student population of this national university with an enrollment of more than advances in knowledge 1. some thyroid function tests administered in the student clinic at sultan qaboos university for both specific and non-specific symptoms of thyroid diseases were unnecessary. 2. most of the symptoms for which these tests were requested proved to be either due to anaemia, or menstrual irregularities. application to patient care 1. thyroid function tests should be requested at the student clinic for students who have an enlarged thyroid gland with or without associated thyroid symptoms. 2. it is advisable to exclude anaemia for students who present with fatiguability before requesting this test. 3. it is not advisable to administer this test to students who present with irregular periods because dysfunctional uterine bleeding and polycystic ovarian disease are common in this age group. kawther el shafie, asila al-shaqsi, badriya al-mahrouqi, hadia al lawati, shyam s ganguly, samir al adawi and mohammed al-shafaee clinical and basic research | 217 14,000 students. it is staffed by physicians from the department of family medicine and public health in the college of medicine and health sciences. squ is the only national university and the student population comes from all parts of the country and all social classes. the study was carried out between january 2007 and january 2008. the clinic caters to the health needs of approximately 14,000 students at both undergraduate and graduate levels. the total number of consultations during this period was 18,000. the average number of visits per day was around 70 students. the sample size of the study was 319 students (240 females and 79 males) with no known thyroid disease. it involved every student between 18 and 30 years of age of both sexes who visited the student clinic during this period and for whom tfts were requested. this included thyroid stimulating hormone (tsh), free thyroxin (free t4) and triodothyronine (free t3). four of these patients were excluded from the study because they had a pre-existing thyroid disease. the information was gathered from electronic medical records with the help of the squ hospital information systems department. the patients’ demographic data, the main presenting complaint for which the tfts was requested, as well as the results of these tests and the different diagnoses reached were noted. the cost of requesting these tests was also calculated. patients who had already been diagnosed with thyroid diseases were excluded from the study. the consultation in the clinic was carried out by final year residents in family medicine and the study was approved by the medical ethics and research committee of the college of medicine & health sciences, sultan qaboos university, muscat, oman. results table 1 shows the number of patients for each main presenting complaint and their percentages in relation to the total number of patients in the study. their complaints were either specific thyroid disease complaints such as weight changes (n = 22); hair changes (n = 20); diarrhoea and constipation (n = 13); heat and cold intolerance (n =18), or nonspecific complaints such as chronic headache (n =3); chronic chest pain (n = 4), or simply seeking a general check-up (n = 6). when the two gender groups were compared for complaints including fatiguability, palpitations, and neck swelling, it was observed that the rate of complaints among females was significantly higher as compared to males (p < 0.01). table 2 represents the number of patients for each diagnosis reached and its percentage in relation to the total number of patients in the study. the most common diagnosis in patients for whom tft was done was polycystic ovarian disease (n = 51), followed by anaemia (n = 42). when the two gender groups were compared for the various diagnoses reached such as anaemia, thyroid disease, psychiatric problems, and others, it was observed that the potentially anaemic patients included 40 females and only 2 males. thyroid problems (whether hypothyroidism, hyperthyroidism, subclinical hypoand hyperthyroidism or thyroid table 1: the number of patients for each main presenting complaint and their percentages, squ student clinic complaints no. of patients male female total irregular periods -----82 (34.7%) 82 (25.7%) fatiguability 7 (2.2%) 42 (17.7%) 49 (15.4%) palpitations 11 (3.4%) 28 (11.8%) 39 (12.2%) neck swelling 1 (0.3%) 12 (5.0%) 13 (4.1%) other complaints 60 (18.8%) 76 (30.5%) 132 (42.0%) total 79 (100%) 236 (100%) 315 (100%) table 2: the percentages of each diagnosis among the student clinic at sultan qaboos university diagnosis no. of patients (percentage) male female total polycystic ovarian syndrome -----51(21.5%) 51 (16.0%) anaemia 2 (2.5%) 40 (16.8%) 42 (13.3%) thyroid disease 1 (1.2%) 17 (7.1%) 18 (5.7%) anxiety and depression 5 (6.3%) 6 (2.5%) 11 (3.4%) other diagnosis 71 (89.8%) 122 (51.4%) 193 (61.2%) total 79 (100%) 237 (100%) 315 (100%) the diagnostic yield of thyroid function tests and their cost-effectiveness in the student clinic at sultan qaboos university retrospective chart review 218 | squ medical journal, august 2010, volume 10, issue 2 nodules) were diagnosed in 18 out of 315 students, of whom 17 were females and only one was a male. eleven patients were found to be suffering either from psychiatric distress, anxiety or depression. six of these were females and five were males. there was no specific diagnosis given for 193 students (122 females and 71 males) due to either lack of follow-up or documentation. the percentage of thyroid diseases among the females was 7.1% as compared to males 1.2%. this difference was found to be statistically significant (p < 0.05). table 3 shows the number of patients in each diagnosis reached for each specific complaint the cost of the tfts which were requested for the studied group during the 12 month period was estimated to be around 20,000 us dollars (c. 7,660 or). since only 6% of the tests administered had positive results, the unnecessary expenditure for tfts amounted to 18,800 us dollars during the period of the study. discussion this, to our knowledge, is the first study in the arab/islamic part of the world to examine the trajectory between case-finding strategies for thyroid dysfunction as a first-level measurement, the viability of such prescribed laboratory procedures and the cost entailed in administering tfts. on the whole, the present study has demonstrated that there is a temporal relationship between first-level measurement and eventual diagnosis. there was also a discrepancy between initial diagnosis and subsequent diagnosis confirmed by using tft. with a few exceptions, the results of the tft were not remarkable. it is worthwhile noting that most of the cases could have been diagnosed by clinical impression only. the present findings are similar to the results of an italian study by roti et al.12 who reported that there was one abnormal tft for every fourteen patients tested in their sample population. in a longitudinal study in france, toubert et al.2 reported that, while there was an increase in ‘rate of appropriate ordering’ of tft, actual appropriateness remained low. the incidence of inappropriate ordering has a direct bearing on cost. one plausible implication of this finding is that judicial ordering appears to be essential. proper history taking, starting with simple and cheaper basic investigations such as haemoglobin to exclude common problems such as anaemia, which appears table 3: the frequency of diagnosis in relation to the main presenting complaints of the the student clinic at sultan qaboos university complaints diagnosis no. of patients total male female total irregular period polycystic ovarian syndrome -----45 (54.9%) 45(54.9%) 82 anaemia -----2 (2.4%) 2 (2.4%) thyroid disease -----1 (1.2%) 1 (1.2%) psychiatry -----0 (0.0%) 0 (0.0%) other diagnosis -----34 (41.5%) 34 (41.5%) fatiguability polycystic ovarian syndrome -----2 (4.1%) 2 (4.1%) 49 anaemia 1 (2.0%) 16 (32.7%) 17(34.7%) thyroid disease -----2 (4.1%) 2 (4.1%) psychiatry -----1 (2.0%) 1 (2.0%) other diagnosis 6 (12.2%) 21 (42.9%) 27 (55.1%) palpitation polycystic ovarian syndrome -----0 (0.0%) 0 (0.0%) 39 anaemia -----14 (35.9%) 14 (35.9%) thyroid disease -----3 (7.7%) 3 (7.7%) psychiatry 4 (10.3%) 2 (5.1%) 6 (15.4%) other diagnosis 7 (17.9%) 9 (23.1%) 16(41.0%) kawther el shafie, asila al-shaqsi, badriya al-mahrouqi, hadia al lawati, shyam s ganguly, samir al adawi and mohammed al-shafaee clinical and basic research | 219 to be common in the present cohort, would be the most appropriate approach. paula et al.13 have recommended ordering tft for all patients who present with irregular periods before diagnosing them with polycystic ovarian syndrome; however, since our study is confined to a certain age group, where ovarian dysfunction and polycystic ovarian syndrome are common,14 this recommendation may not apply within the present context. the main symptom for which tft was ordered during the period of this study was irregular periods. although irregular periods are one of the known symptoms of thyroid diseases,15 only a few students who presented with irregular periods were found to have thyroid problems. there are several explanations for this. first, the majority of the sample population in this study was female. second, most of the females in this group were in adolescence or early adulthood where irregular periods are a common occurrence.16 it was found that some students who presented with irregular periods were diagnosed with polycystic ovarian syndrome. presentations of extremely irregular periods need more evaluation in regard to common differential diagnoses such as ovulation dysfunction and polycystic ovarian disease.14 the other common reasons for ordering tft in this study group were distress symptoms reported by the patient such as fatiguability and palpitations. these complaints were predominantly made by females. as in the case of irregular periods, the diagnosis of thyroid disease accounts for a small number of patients who presented with these symptoms, while most of them were found to have anaemia. although tft was one of the recommended tests for patients who present with fatiguability,17 according to the results of our study and for cost effectiveness, it is advisable to exclude anaemia for this age group before requesting a tft. on the other hand, from the present study, it appears that ordering tft for any patient who presents with a neck swelling is appropriate, since most of our patients who presented with neck swelling were females and the majority of them were diagnosed with thyroid diseases. this suggests tft should be a basic constituent of any thyroid diagnostic work-up. this idea is consistent with thomas et al.18 who have suggested that a swelling in the neck is a strong indicator of thyroid dysfunction. it is worthwhile to note that very few patients were found to have thyroid diseases in the large category of patients with other complaints, although tft was advised for some of these patients who presented with specific complaints of thyroid diseases,21 such as constipation19 and hair changes.20 this study suggests that such requests were overall unnecessary because these thyroid diagnostic work-ups were predominately negative. this led to the issue of cost. previous studies, mostly from europe,12,22,23,24,25 suggested that cost for a first-level measurement in clinical diagnosis still constitutes a large proportion of the public health budget. moreover, the cost for thyroid function testing can be reduced by ordering tsh only, as ft4 and ft3 add little information in such circumstances. viera concluded that requesting tsh alone is generally adequate, limiting administration of ft4 tests to those with abnormal tsh.24 wastage could be minimised by contemplating strategies to optimise diagnostic tools without loss of efficiency. the cost of tfts at our student clinic amounted to 20,000 us dollars (c. 7,660 or). if other diagnostic tools had been used in advance of administering tft, the total necessary expenditure could have been limited to 2,000 dollars. the limitation of this study is that it includes only the patients’ main presenting complaints and excludes other associated complaints which may also be related to thyroid disease. clinical diagnosis of thyroid dysfunction is based on multiple symptoms rather than on a single symptom, as well as the presence of risk factors for thyroid dysfunction and physical signs. therefore, the diagnostic yield of thyroid function testing could be improved which has direct bearing on costeffectiveness. we recommend including these factors in future studies in order to shed light on such important confounding variables. the second obvious limitation is that there were a substantial number of subjects who were not given a specific diagnosis. because the study was retrospective, some of the required information was missing and follow-up was not performed in some cases. last but not least, the results of this study may not be fully generalisable because the study’s cohort consisted of university students. a prospective study, with a wider population would be essential to circumvent this limitation. the diagnostic yield of thyroid function tests and their cost-effectiveness in the student clinic at sultan qaboos university retrospective chart review 220 | squ medical journal, august 2010, volume 10, issue 2 conclusion despite the aforementioned limitations due to the type of the study, one theme emerges in light of the available literature and present data. judicial use of thyroid diagnostic work-ups would be essential in this particular age group, as it contains many individuals who commonly present with specific and non-specific complaints that have little relation to the presence of thyroid diseases. it is advisable to request tft for all students who present with thyroid swelling and to eliminate the possibility of anaemia for those who present with palpitations or fatiguability before requesting this test. it is not advisable to administer tft to students who present exclusively with irregular periods without associated thyroid symptoms, or for students who present with non-specific complaints of thyroid diseases. education can be an effective tool for modifying clinicians’ testing patterns by introducing simple clinical guidelines. references 1. vanderpump mpj, tunbridge wmg, french jm, appleton d, bates f, clark j, et al. the incidence of thyroid disorders in the community; a twenty-year follow up of the whickham survey. clin endocrinol 1995; 43:55–68. 2. toubert me, chevret s, cassinat b, schlageter mh, beressi jp, rain jd. from guidelines to hospital practice: reducing inappropriate ordering of thyroid hormone and antibody tests. eur j endocrinol 2000; 142:605–10. 3. gibbons v, lillis s, conaglen jv, lawrenson r. do general practitioners use thyroid stimulating hormone assay for opportunistic screening? n z med j 2009; 122:25–30. 4. stockigt j. assessment of thyroid function: towards an integrated laboratory clinical approach. clin biochem rev 2003; 24:109–22. 5. stockigt jr. guidelines for diagnosis and monitoring of thyroid disease: nonthyroidal illness. clin chem 1996; 42:188–92. 6. ladenson pw, singer pa, ain kb, bagchi n, bigos st, levy e, et al. american thyroid association guidelines for detection of thyroid dysfunction. arch int med 2000; 160:1573–5. 7. beckett gj, toft ad. first-line thyroid function tests – tsh alone is not enough. clin endocrinol 2003; 58:20– 21. 8. demers lm, spencer ca, eds. laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. thyroid 2003; 13:32– 43. 9. world health organization. demographic, social and health indicators for countries of the eastern mediterranean. cairo: who, regional office for the eastern mediterranean, who-em/hst/206/e, 2008. 10. al shaikh ha, bappal b, nair r, al khusaiby s. a retrospective hospital-based study on congenital hypothyroidism in the sultanate of oman. j trop pediatr 2003; 49:245–7. 11. ordookhani a, mirmiran p, moharamzadeh m, hedayati m, azizi f. a high prevalence of consanguineous and severe congenital hypothyroidism in an iranian population. j pediatr endocrinol metab 2004; 17:1201–9. 12. roti e, gardini e, magotti mg, pilla s, minelli r, salvi m, et al. are thyroid function tests too frequently and inappropriately requested? j endocrinol invest 1990; 22:184–90. 13. paula j, hillard a, deitch hr. menstrual disorders in the college age female. pediatr clin n am 2005; 52:172– 197. 14. gupta m, duckitt k. irregular periods. womens health med 2005; 2:5–9. 15. kasper dl, brauwald e, fauci as, hauser sl, longo dl, jameson jl. harrison’s principles of internal medicine. 16th ed. new york: mcgraw-hill company, 2005 pp. 2104–26. 16. cowan bd, morrison jc. management of abnormal genital bleeding in girls and women. new engl j med 1991; 324:1710–15. 17. burke a cunha. chronic fatigue syndrome: differential diagnosis workup: an update. ann rev med 1998; 49:1– 13. 18. thomas we. thyroid swelling – a protocol for management. jr soc med 1998; 91:21–7. 19. rao ss, ozturk r, laine l. clinical utility of diagnostic tests for constipation in adults: a systemic review. am j gastroentrol 2005; 100:1605–15. 20. sathyapalan t, atkin sl. investigating hirsutism: rational testing. br med j 2009; 338: b912. doi: 10.1136/bmj. b912. 21. spiller r, aziz q, creed f, emmanuel a, houghton l, hungin p, et al. clinical services committee of the british society of gastroenterology. gut 2007; 56:1770– 98. 22. rodríguez espinosa j. use of thyroid function tests in public clinical laboratories of catalonia. quimica clinica 2002; 21:254–61. 23. benitez aj, calvo m. results and cost determination of thyrotropin for screening of functional thyroid pathology. quimica clinica 2006; 25:19–23. 24. viera aj. thyroid function testing in outpatients: are both sensitive thyrotropin (stsh) and free thyroxine (ft4) necessary? fam med 2003; 35:408–10. 25. wong et. improving laboratory testing: can we get physicians to focus on outcome? clin chem 1995; 41:1241–7. رد: سرطان خلية بالزما الدم األويل تقرير حالة ومراجعة األدبيات re: primary plasma cell leukaemia case report and review of the literature dear editor, i read with interest the recent case report by singh et al. published in the august 2018 issue of squmj, in which the authors describe a 69-year-old male patient with rectal bleeding associated with pallor, dyspnoea and chest pain.1 laboratory tests showed microcytic hypochromic anaemia, leukocytosis, low platelets and a high erythrocyte sedim entation rate. elevated levels of urea, creatinine, uric acid, immunoglobulin d, kappa light chains and β2-microglobulins were also detected, while abdominal, thoracic and skeletal imaging did not show any abnormalities.1 a bone marrow aspirate revealed 61% atypical plasma cells. subsequently, a diagnosis of primary plasma cell leukaemia (pcl) was confirmed and bortezomib-based chemotherapy was administered, resulting in a good response.1 myeloma cells can travel to the peripheral blood if expression of the cell adhesion molecule cluster of differentiation (cd)56 decreases.2,3 along with cd19, cd20 and cd23 positivity, this phenomenon is often observed among patients with primary pcl, while the positive expression of cd28 and interleukin-6 are considered important in secondary cases.2,3 leukocytosis, high levels of lactate dehydrogenase and β2-microglobulins and the presence of bone lesions can help to differentiate primary pcl from myeloma.4 singh et al. therefore highlighted the need for consensus guidelines in primary healthcare for the purposes of early diagnosis and prompt and adequate treatment.1 other case reports have also emphasised the diagnostic pitfalls associated with unsuspected cases of myeloma, rib plasmacytoma, multiple myeloma and secondary pcl.4–6 these cases may help to enhance suspicion of plasma cell malignant disorders among primary healthcare workers. dos santos et al. reported a 53-year-old female patient with multiple myeloma and secondary pcl; the patient had 25% plasma cells in a bone marrow aspirate and positive expressions of lambda light chains, cd56 and cd20 as well as 23% circulating peripheral blood plasma cells.4 she had high levels of urea and creatinine and was hypercalcaemic and anaemic. an x-ray showed radiolucent speckled areas in the humeral diaphysis with no evidence of organomegaly or lymphadenopathy.4 a diagnosis of leukaemia was made, based on the presence of >2,000/mm3 circulating plasma cells, some of which were dysplastic. subsequently, the patient demonstrated significant clinical improvement following treatment with dexamethasone, cyclophosphamide, thalidomide, cisplatin, doxorubicin and etoposide.4 another case report described a 65-year-old female patient who was diagnosed with rib plasmacytoma, overt immunoglobulin (ig)-a-producing multiple myeloma and hyperviscosity syndrome.5 she had a history of dyspnoea and a mental disorder and subsequently developed chronic renal failure, respiratory disturbance and heart failure. bio-chemistry tests showed elevated urea, creatinine and calcium levels and β2-microglobulins; in addition, she was anaemic and her iga and kappa light chain levels were 8,917 mg/dl (normal range: 153–359 mg/dl) and 2,990 mg/dl (normal range: 625–1,668 mg/dl), respectively.5 the presence of >50% plasma cells with basophilic cytoplasm, eccentric nuclei and large nucleoli in a bone marrow biopsy established the diagnosis of multiple myeloma. the patient was treated with dexamethasone and underwent plasmapheresis without improvement.5 finally, dos santos et al. reported a 64-year-old male patient who presented with dizziness, fatigue, dyspnoea, lumbar pain and high levels of calcium, urea and creatinine.6 multiple osteolytic lesions were detected in the cranium and lumbar spine, in addition to a monoclonal peak in the gamma region and high levels of igg. a bone marrow aspirate revealed >40% plasma cells.6 the patient was eventually diagnosed with multiple myeloma at a late stage, due partly to a history of activities resulting in overload on the axial skeleton because of his profession as a construction foreman, as well as nonsteroidal anti-inflammatory drug abuse. he underwent chemotherapy which resulted in an unsatisfactory response.6 vitorino m. dos santos1,2 1department of internal medicine, armed forces hospital, cruzeiro novo, brazil; 2medical division, catholic university of brasilia, cruzeiro novo, brazil e-mail: vitorinomodesto@gmail.com letter to the editor sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e563–564, epub. 28 mar 19 submitted 14 jan 19 accepted 7 feb 19 doi: 10.18295/squmj.2018.18.04.026 re: primary plasma cell leukaemia case report and review of the literature e564 | squ medical journal, november 2018, volume 18, issue 4 references 1. singh s, rath a, yadav s. primary plasma cell leukaemia: case report and review of the literature. sultan qaboos univ med j 2018; 18:e397–401. https://doi.org/10.18295/squmj.2018.18.03.024. 2. fernández de larrea c, kyle ra, durie bg, ludwig h, usmani s, vesole dh, et al. plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the international myeloma working group. leukemia 2013; 27:780–91. https://doi.org/10.1038/leu.2012.336. 3. pellat-deceunynck c, barillé s, jego g, puthier d, robillard n, pineau d, et al. the absence of cd56 (ncam) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma. leukemia 1998; 12:1977–82. 4. dos santos vm, melim sp, de faria ps, passini vv, duarte ml, casasanta ra. multiple myeloma and secondary plasma cell leukemia. rom j morphol embryol 2016; 57:837–9. 5. santos vm, brito ef, paz bc, leal ct. rib plasmacytoma and iga multiple myeloma with hyperviscosity syndrome. arch iran med 2012; 15:517–19. https://doi.org/012158/aim.0015. 6. dos santos vm, de castro ra, marques hv jr, de paula fh. unsuspected multiple myeloma: a growing challenge. braz med 2007; 44:138–41. response from the authors dear reader, thank you for your letter highlighting similar cases of unsuspected multiple myeloma and primary or secondary plasma cell leukaemia (pcl).1–3 there are certain points upon which we wish to elaborate. firstly, as mentioned in the original publication by singh et al., a decrease in the expression of cluster of differentiation (cd)56 is a reliable marker of pcl.4 however, in the 40–50% of cases wherein cd56 is not expressed, diagnostic difficulties ensue.5 secondly, flow cytometry has proven to be a valuable adjunct in diagnosing myeloma and/or pcl.6 this method should therefore be paired with bone marrow and peripheral blood flow cytometry for the detection of circulating plasma cells by using cd markers such as cd27, cd28, cd117, cd200, cd229 and cd81. specifically, the expression of myc, cyclin d1 and p53 in bone marrow biopsies can differentiate between different types of pcl, as cyclin d1 is exclusive to primary pcl, while the other two markers are seen in both forms.7 thirdly, we wish to caution against the interchangeable usage of the terms dysplastic and anaplastic.2 *sarika singh, ashutosh rath, surekha yadav department of pathology, maulana azad medical college, new delhi, india e-mail: sarikasingh97b@gmail.com references 1. dos santos vm, melim sp, de faria ps, passini vv, duarte ml, casasanta ra. multiple myeloma and secondary plasma cell leukemia. rom j morphol embryol 2016; 57:837–9. 2. santos vm, brito ef, paz bc, leal ct. rib plasmacytoma and iga multiple myeloma with hyperviscosity syndrome. arch iran med 2012; 15:517–19. https://doi.org/012158/aim.0015. 3. dos santos vm, de castro ra, marques hv jr, de paula fh. unsuspected multiple myeloma: a growing challenge. braz med 2007; 44:138–41. 4. singh s, rath a, yadav s. primary plasma cell leukaemia: case report and review of the literature. sultan qaboos univ med j 2018; 18:e397–401. https://doi.org/10.18295/squmj.2018.18.03.024. 5. mckenna rw, kyle ra, kuehl wm, grogan tm, harris nl, coupland rw. plasma cell neoplasms. in: swerdlow sh, campo e, harris nl, jaffe es, pileri sa, stein h, et al., eds. who classification of tumours of haematopoietic and lymphoid tissues, 4th ed. lyon, france: international agency for research on cancer, 2008. pp. 200–13. 6. tembhare pr, ghogale s, tauro w, badrinath y, deshpande n, kedia s, et al. evaluation of cd229 as a new alternative plasma cell gating marker in the flow cytometric immunophenotyping of monoclonal gammopathies. cytometry b clin cytom 2018; 94:509–19. https://doi. org/10.1002/cyto.b.21619. 7. jelinek t, kryukov f, rihova l, hajek r. plasma cell leukemia: from biology to treatment. eur j haematol 2015; 95:16–26. https://doi. org/10.1111/ejh.12533. departments of 1dentistry & ophthalmology, 2pathological anatomy, 3medical biotechnology and 4ear, nose & throat, university of siena, siena, italy *corresponding author’s e-mail: mailarticoli@libero.it ساركوما عضلية ملساء عند شابة تقرير حالة واستعراض لألدب العلمي ما�صيمو فيفانيو، �صليليا مرياكو، جودو لوريزيني، جينارو بالدينو، �صريينا كوكا abstract: leiomyosarcoma (lms) is a rare mesenchymal malignancy, of which 3–10% of cases occur in the head and neck region. we report a 22-year-old woman who was referred to the university hospital of siena, italy, in 2016 with an ostensibly benign asymptomatic lump on the mandibular gingiva. the lesion grew rapidly, causing otalgia in the right ear. an excisional biopsy was performed and primary lms was diagnosed histologically. subsequently, the patient underwent radical re-excision of the perilesional mucosa, a partial bone resection and the extraction of four teeth. no recurrences or metastases were detectable at a 20-month follow-up. this report discusses the differential diagnosis of lms with regards to other benign and malignant lesions and reviews the recent literature on primary and secondary oral lms. due to its innocuous clinical features—including its asymptomatic nature and presentation at a young age—this aggressive malignancy can go undetected; therefore, an early histopathological diagnosis is crucial. keywords: leiomyosarcoma; soft tissue neoplasms; gingival neoplasms; smooth muscle tumors; otalgia; immunohistochemistry; case report; italy. امللخ�ص: تعد ال�صاركوما الع�صلية املل�صاء �رشطانة نادرة يف اللحمة املتو�صطة، حتدث نحو %10-3 من حالتها يف منطقتي الراأ�ض والعنق. ونعر�ض هنا حالة امراأة عمرها 22 �صنة مت حتولها مل�صت�صفى �صينا اجلامعي يف �صينا باإيطاليا عام 2016، فيما بدا اأنه ورم حميد عدمي التو�صيل بعدها مت ا�صتئ�صالية، خزعة اأخذ ومت اليمنى. الأذن يف اأملا حمدثة ب�رشعة الآفة تلك ومنت ال�صفلي. الفك لثة يف الأعرا�ض لت�صخي�ض الإ�صابة بال�صاركوما الع�صلية املل�صاء بالفح�ض املجهري الهي�صتوباثلوجي. وبعد ذلك عمل للمري�صة اإعادة ا�صتئ�صال للغ�صاء املخاطي املحيط بالآفة، وقطع جزئي للعظم، وخلع اأربعة اأ�صنان. ومت تتبع احلالة ملدة 20 �صهرا، ومل يثبت يف غ�صون تلك املدة حدوث الأخرى، واحلميدة اخلبيثة والآفات املل�صاء الع�صلية ال�صاركوما بني التفريقي الت�صخي�ض التقرير هذا يف ونناق�ض نقائل. اأو نك�صات اأي ون�صتعر�ض ما ورد حديثا يف الأدب العلمي املتعلق بال�صاركوما الفموية الع�صلية املل�صاء الأولية والثانوية. وقد ل تتم مالحظة هذا الآفة ال�صديدة اخلبث ب�صبب طبيعة اأعرا�صها ال�رشيرة احلميدة ظاهريا، التي ت�صمل عدم وجود اأعرا�ض لها، وحدوثها يف عمر باكر. لذا فالفح�ض الهي�صتوباثلوجي يعد من اأهم و�صائل ت�صخي�ض مثل هذه احلالت. الكلمات املفتاحية: ال�صاركوما الع�صلية املل�صاء؛ �رشطانات الأن�صجة الرخوة؛ �رشطانات اللثة؛ �رشطانات الع�صالت املل�صاء؛ اأمل الأذن ؛ الكيمياء الهي�صتولوجية املناعية؛ تقرير حالة؛ اإيطاليا. gingival leiomyosarcoma in a young woman case report and literature review massimo viviano,1 clelia miracco,2 guido lorenzini,3 gennaro baldino,2 *serena cocca4 case report sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e472–476, epub. 10 jan 18 submitted 15 aug 17 revisions req. 25 sep & 7 nov 17; revisions recd. 23 oct & 16 nov 17 accepted 23 nov 17 doi: 10.18295/squmj.2017.17.04.017 constituting 6–7% of all soft tissue sarcomas, leiomyosarcoma (lms) is a malig-nant tumour of mesenchymal origin which occurs very rarely in the oral cavity, with only 3–10% of cases arising in the head and neck region.1,2 oral lms arises primarily in the bones and soft tissue and is reported predominantly among adult patients, without any significant gender predominance.3 the aetiology of this entity remains uncertain, with suggested causes including trauma, oestrogen stimulation, ionising radiation and epstein-barr virus infections.3–5 the sarcoma has an aggressive growth pattern and a high rate of recurrence due to its dissemination in the bloodstream.5 the presenting signs of oral lms are generally nonspecific and the similarity of this entity to certain benign lesions typically delays its diagnosis. this report presents a case of oral lms in a young patient which was rapidly diagnosed and resulted in a positive outcome. as the patient was disease-free following radical surgical excision, further surgery, chemotherapy or radiation therapy was avoided. case report a 22-year-old caucasian woman was referred to the department of dentistry at the university hospital of siena, italy, in 2016 with otalgia in the right ear and an asymptomatic swelling on the lower right lingual gingiva, which she had initially noticed approximately one month beforehand. the patient’s medical history indicated that she was in good health and was not currently taking any medication. an examination of the massimo viviano, clelia miracco, guido lorenzini, gennaro baldino and serena cocca case report | e473 antibiotics consisting of 1g of amoxicillin and clavulanic acid twice daily. the excised mass was fixed in buffered formalin. a histopathological examination showed an unencapsulated tumour with pushing margins and an absence of infiltrative growth patterns. the lesion consisted of bundles of spindle cells intersecting at right angles, with well-defined brightly eosinophilic cytoplasm, cigar-shaped pleomorphic nuclei and occasional paranuclear vacuoles [figure 3a]. there were a few microfoci of coagulative necrosis and 13–1510 mitoses in a high-power field at x400 magnification (corres ponding to about 1 mm2) [figure 3b]. immunohistochemistry was performed on 3-μm-thick sections using the benchmark ultra® automated staining system (ventana medical systems inc., roche diagnostics, monza, italy). the ultraview universal dab detection kit® (ventana medical systems inc.) was used with horseradish peroxidase multimer chromogen diaminobenzidine in order to stain positive structures brown. the neoplastic cells were positive for smooth muscle markers, including h-caldesmon (clone e89), hhf35, myosin, smooth muscle actin (clone 1a4) and smooth muscle myosin monoclonal antibody-1 [figures 3c and d]. the ki-67 labelling index (clone mib-1) was approximately 30–40%. all other tested antibodies were negative, including activin receptorlike kinase, cluster of differentiation (cd)34, c-kit, desmin, dog1, oestrogen receptors, pankeratin, prog esterone receptors, skeletal muscle actin and s100 oral cavity revealed a hard, non-painful, reddish-pink, non-haemorrhagic gingival swelling around the first lower right molar (i.e. tooth number 46) [figure 1a]. the rest of the ear, nose and throat examination was normal. an orthopantomogram and periapical x-ray of tooth number 46 appeared normal [figures 1b and c]. an excisional biopsy was subsequently performed under local anaesthesia, with the excised lesion measuring 1.5 x 1.2 cm [figure 2]. following the surgery, the patient was prescribed a six-day course of figure 1: a: intraoral photograph of a 22-year-old woman with an asymptomatic gingival lesion. b: preoperative orthopantomogram of the lesion showing no abnormalities. c: preoperative periapical x-ray of the mandibular right molar which also appears normal. figure 3: a: haematoxylin and eosin stain (h&e) at x100 magnification showing a leiomyosarcoma composed of perpendicularly oriented fascicles of spindle cells. b: h&e stain at x200 magnification showing deep eosinophilic cytoplasm and elongated blunt-ended nuclei with mitoses (arrows). c and d: immunohistochemistry chromogen diaminobenzidine stains at x200 magnification showing diffuse cytoplasmic positivity for smooth muscle actin antibodies and h-caldesmon, respectively. figure 2: intraoral photographs of a 22-year-old woman undergoing an excisional biopsy of an asymptomatic gingival lesion in which (a) the lesion was radically resected under local anaesthesia, leaving (b) the apparently healthy teeth, gingiva and alveolar bone intact. gingival leiomyosarcoma in a young woman case report and literature review e474 | squ medical journal, november 2017, volume 17, issue 4 discussion smooth muscle tumours rarely develop in the head and neck region; however, if present, they occur mainly in the walls of blood vessels, the erector pili musculature of the skin, the circumvallate papillae of the tongue and in the myoepithelial cells of the salivary glands.7 soft tissue lms can be divided into retroperitoneal/ intra-abdominal, cutaneous/subcutaneous and vascular subgroups, with distinct clinical and biological differ ences despite their similar histology.8 the most common intraoral site for lms appears to be the tongue, usually as a result of metastasis from a primary tumour in the uterus, gastrointestinal tract or retroperitoneum.7,9 oral lms may also involve the jaw bones, cheek, gingiva, floor of the mouth, mandible, soft or hard palate and lips. these tumours present with a wide range of clinical features, including painless or painful smooth rubbery firm masses with or without ulceration, tooth mobility, epistaxis, nasal obstruction, otalgia and a variety of other symptoms depending on the site of the lesion.2–5,8,10 clinically, oral lms is often confused with other benign and malignant lesions. with regards to the current patient, the clinical and macroscopic features of the case ostensibly mimicked a benign lesion. this was further compounded by the young age of the patient and the well-circumscribed growth of the swelling. among benign tumours, the most problematic entity to exclude during the differential diagnosis is a leiomyoma, as well-differentiated lms may show similar microscopic features, including a ‘pushing’ growth pattern; as a result, the absence of mitoses is the major differentiating factor.10 in the present case, mitoses were clearly observed, along with other features of malignancy including nuclear atypia and necrosis. due to the insidious clinical presentation of lms, histopathological analysis is critical to exclude other benign lesions such as fibromas, haemangiomas, neurofibromas, schwannomas and peripheral giant cell granulomas. the rapid growth of a lesion in a young patient and certain histological features may also suggest nodular fasciitis, although this is rare in the orofacial area and is usually characterised by selflimiting growth, mitotic activity and focal infiltration.11 microscopically, a solitary fibrous tumour was also excluded in the current case as this entity is rarely reported in the oral cavity.10 other malignancies with spindle cell morphology include squamous cell carcinomas, gastrointestinal stromal tumours, fibrosarcomas, myofibroblastic sarcomas, melanomas, rhab domyosarcomas and spindle cell myoepithelial carcinomas.11–17 in particular, myofibroblastic sarcomas and rhabdomyosarcomas also affect younger individuals, proteins. the final diagnosis was of a well-differentiated grade i lms.6 as a result of this diagnosis, further surgery was deemed necessary. preoperatively, a contrast computed tomography (ct) scan showed thickening of the soft tissue adjacent to the inferior right hemimandibular surface, without bone or neck lymph node involvement. a metastatic work-up was negative, including ct imaging of the chest, abdomen and pelvis and a bone scan. a gynaecological examination and transvaginal ultrasound was also normal. however, an magnetic resonance imaging (mri) scan showed increased mucosal impregnation near teeth number 46 and 47. subsequently, under general anaesthesia an excision of the perilesional mucosa, a partial bone resection sparing the lingual and mandibular nerves and the extraction of teeth number 45–48 was performed [figure 4a]. postoperatively, the patient was prescribed antibiotics (1 g of ceftriaxone per day) along with an anti-discolouration mouthwash containing 0.2% chlorhexidine and hyaluronic acid. the patient was discharged two days later with no complications. every three months, she attended follow-up appointments wherein mri and chest and abdominal ultrasounds were performed. a wholebody ct scan was also undertaken six months after the surgery, with positron-emission tomography/ct performed at 12 months. at the time of writing, 20 months after the radical surgery, there were no signs of local recurrence or metastasis and the patient appeared healthy [figure 4b]. figure 4: intraoral photographs of a 22-year-old woman (a) immediately after radical surgical bone resection and the extraction of teeth number 45–48 and (b) 20 months later with no evidence of recurrence of the leiomyosarcoma. massimo viviano, clelia miracco, guido lorenzini, gennaro baldino and serena cocca case report | e475 with the former showing local destructive growth.13,16 squamous cell carcinomas and their rarer spindle cell variants, sarcomatoid carcinomas, are the most frequent overall and spindle cell malignancies in the oral cavity, respectively.10,11,17 as such, all other malignant lesions with a spindle cell morphology were excluded in the present case due to their rare occurrence at this site. moreover, the morphological features of the lesion—including the fascicles of spindle-shaped cells with abundant eosinophilic cytoplasm, blunt ended cigar-shaped nuclei, high mitotic rate and pleomorphism—were consistent with a diagnosis of lms; this was also supported by the immunohistochemical results of an extensive panel of antibodies.8,18 while metastasis from primary lms arising in another site could not be excluded histologically, a high percentage of uterine lms express oestrogen and/or progesterone receptors, which were negative in this case.19 table 1 summarises the main differential diagnoses of lms and their various histopathological features.1–17 besides early diagnosis, the prognosis of oral lms patients depends on the tumour grade, size, site and treatment.20–22 currently, there are no standard criteria for therapy, although the complete excision of the tumour with wide surgical margins is recommended.7,23,24 the five-year survival rate among patients with primary oral lms is 55%, with bone involvement and metastasis significantly associated with poorer prognosis.24 lung and cervical lymph node metastases frequently occur, with the regional lymph nodes affected in >15% of oral lms cases.4 distant metastases, mostly in the lungs, occur in approximately 39% of patients with oral lms; in addition, lms lesions arising in the uterus, gastrointestinal tract and retroperitoneum sometimes metastasise to the lungs, brain, bone and oral cavity.4,25 as such, preoperative staging of the whole body is mandatory. in the present case, the regional lymph nodes were free and systemic tests did not reveal any metastasis; hence, no adjuvant therapy was given. however, regular follow-up is essential to rapidly detect recurrence. conclusion smooth muscle tumours of the oral cavity are exceedingly rare. a diagnosis of oral lms should be established histologically and supported by immunohistochemical analysis using specific markers. in certain cases, such as the one presented here, early table 1: differential histopathological diagnoses of leiomyosarcoma1–17 differential diagnosis histopathological features fibroma • usually abundant fibrous stroma • immunonegative for h-caldesmon head and neck leiomyoma • no mitoses lobular capillary haemangioma/ pyogenic granuloma • proliferation of capillary vessels neurofibroma/ schwannoma • absence of perpendicularly oriented fascicles of spindle cells • pointed rather than blunt-ended nuclei • immunopositive for s100 proteins and other neural markers • immunonegative for muscle markers nodular fasciitis • absence of perpendicularly oriented fascicles of spindle cells • blunt-ended hyperchromatic nuclei and paranuclear vacuoles peripheral giant cell granuloma • patternless proliferation of mononuclear cells with multinucleated giant cells • immunopositive for macrophage and osteoclast markers • a vascular background with haemorrhagic material solitary fibrous tumour • storiform pattern • ovoid to spindle cd34-positive fibroblasts • in a collagenous stroma, with stellate to ‘stag-horn’-shaped vessels gastrointestinal stromal tumour • immunopositive for c-kit, cd34 and dog1 fibrosarcoma • fascicles of uniform spindle cells • tapered nuclei intersecting in a ‘herringbone’-like pattern melanoma • variably pigmented and haphazardly arranged cells, either epithelioid or spindle-shaped • immunopositive for s100 proteins and other melanocytic markers • immunonegative for smooth muscle markers myofibroblastic sarcoma • fibromatosis-like features • negative for smm and h-caldesmon rhabdomyosarcoma • immunopositive for skeletal muscle markers • immunonegative for smooth muscle markers spindle cell/ sarcomatoid carcinoma • organised fascicular pattern • usually immunopositive for cytokeratins • immunonegative for smooth muscle markers cd = cluster of differentiation; smm = smooth muscle myosin. gingival leiomyosarcoma in a young woman case report and literature review e476 | squ medical journal, november 2017, volume 17, issue 4 13. demarosi f, bay a, moneghini l, carrassi a. low-grade myofibroblastic sarcoma of the oral cavity. oral surg oral med oral pathol oral radiol endod 2009; 108:248–54. doi: 10.1016/j.tripleo.2009.03.031. 14. perez-montiel md, plaza ja, dominguez-malagon h, suster s. differential expression of smooth muscle myosin, smooth muscle actin, h-caldesmon, and calponin in the diagnosis of myofibroblastic and smooth muscle lesions of skin and soft tissue. am j dermatopathol 2006; 28:105–11. doi: 10.1097/01. dad.0000200009.02939.cc. 15. warszawik-hendzel o, słowińska m, olszewska m, rudnicka l. melanoma of the oral cavity: pathogenesis, dermoscopy, clinical features, staging and management. j dermatol case rep 2014; 8:60–6. doi: 10.3315/jdcr.2014.1175. 16. tandon a, sethi k, pratap sa. oral rhabdomyosarcoma: a review. j clin exp dent 2012; 4:e302–8. doi: 10.4317/jced.50926. 17. kane sv, bagwan in, shet t, bavi p, d’cruz a. spindle cell myoepithelial carcinoma of the oral cavity: a report of two cases. oral oncol extra 2006; 42:66–9. doi: 10.1016/j. ooe.2005.09.002. 18. rodini co, pontes fs, pontes ha, santos ps, magalhães mg, pinto ds jr. oral leiomyosarcomas: report of two cases with immunohistochemical profile. oral surg oral med oral pathol oral radiol endod 2007; 104:e50–5. doi: 10.1016/j. tripleo.2007.05.005. 19. hensley ml, barrette ba, baumann k, gaffney d, hamilton al, kim jw, et al. gynecologic cancer intergroup (gcig) consensus review: uterine and ovarian leiomyosarcomas. int j gynecol cancer 2014; 24:s61–6. doi: 10.1097/igc.000000000 0000261. 20. suárez-alén f, otero-rey e, peñamaría-mallón m, garcíagarcía a, blanco-carrión a. oral leiomyosarcoma: the importance of early diagnosis. gerodontology 2015; 32:314–17. doi: 10.1111/ger.12126. 21. de bree r, van der waal i, de bree e, leemans cr. management of adult soft tissue sarcomas of the head and neck. oral oncol 2010; 46:786–90. doi: 10.1016/j.oraloncology.2010.09.001. 22. gupta r, astekar m, dandriyal r, manjunath bs. leiomyosarcoma of maxilla: a case report with review of literature. j exp ther oncol 2015; 11:147–53. 23. akcam t, oysul k, birkent h, gerek m, yetiser s. leiomyosarcoma of the head and neck: report of two cases and review of the literature. auris nasus larynx 2005; 32:209–12. doi: 10.1016/j.anl.2005.01.012. 24. ethunandan m, stokes c, higgins b, spedding a, way c, brennan p. primary oral leiomyosarcoma: a clinico-pathologic study and analysis of prognostic factors. int j oral maxillofac surg 2007; 36:409–16. doi: 10.1016/j.ijom.2006.12.015. 25. kaziro gs. metastatic uterine leiomyosarcoma to the tongue: report of case. j oral surg 1981; 39:128–9. radical excision constitutes the treatment of choice. critically, lms should be considered in the differential diagnosis of oral masses as early diagnosis and aggressive treatment are essential to ensure a good prognosis and patient survival. lifelong periodical follow-up is also recommended. references 1. zanakis sn, lyris v, kyriakou s, agrogiannis g, korkolopoulou p. primary leiomyosarcoma of the mandibular gingiva. glob j cancer ther 2016; 2:1–4. 2. al-bayaty h, balkaran rl. spindle cell carcinoma of the mandible: clinicopathological and immunohistochemical characteristics. j oral biol craniofac res 2016; 6:160–3. doi: 10.1016/j.jobcr.2015.08.009. 3. vilos ga, rapidis ad, lagogiannis gd, apostolidis c. leiomyosarcomas of the oral tissues: clinicopathologic analysis of 50 cases. j oral maxillofac surg 2005; 63:1461–77. doi: 10.1016/j.joms.2005.06.018. 4. schenberg me, slootweg pj, koole r. leiomyosarcomas of the oral cavity: report of four cases and review of the literature. j craniomaxillofac surg 1993; 21:342–7. doi: 10.1016/s10105182(05)80495-0. 5. yan b, li y, pan j, xia h, li lj. primary oral leiomyosarcoma: a retrospective clinical analysis of 20 cases. oral dis 2010; 16:198–203. doi: 10.1111/j.1601-0825.2009.01635.x. 6. neuville a, chibon f, coindre jm. grading of soft tissue sarcomas: from histological to molecular assessment. pathology 2014; 46:113–20. doi: 10.1097/pat.0000000000000048. 7. amarapala h, tilakaratne wm. leiomyosarcoma of the oral cavity: report of seven cases and review of literature. oral oncol extra 2006; 42:14–17. doi: 10.1016/j.ooe.2005.08.001. 8. weiss sw, goldblum jr. enzinger and weiss’s soft tissue tumors, 5th ed. missouri, usa: mosby, 2008. pp. 545–64. 9. xiao w, mohseny ab, hogendoorn pc, cleton-jansen am. mesenchymal stem cell transformation and sarcoma genesis. clin sarcoma res 2013; 3:10. doi: 10.1186/2045-3329-3-10. 10. international agency for research on cancer. who classification of head and neck tumours, 4th ed. geneva, switzerland: who, 2017. pp. 35–47. 11. regezi ja, sciubba jj, jordan rc. oral pathology: clinical pathologic correlations, 7th ed. philadelphia, pennsylvania, usa: saunders, 2016. pp. 161–71. 12. friedrich re, zustin j. late metastasis of gastrointestinal stromal tumour to the oral cavity. anticancer res 2010; 30:4283–8. https://doi.org/10.1016/j.tripleo.2009.03.031 https://doi.org/10.1097/01.dad.0000200009.02939.cc https://doi.org/10.1097/01.dad.0000200009.02939.cc https://doi.org/10.3315/jdcr.2014.1175 https://doi.org/10.4317/jced.50926 https://doi.org/10.1016/j.ooe.2005.09.002 https://doi.org/10.1016/j.ooe.2005.09.002 https://doi.org/10.1016/j.tripleo.2007.05.005 https://doi.org/10.1016/j.tripleo.2007.05.005 https://doi.org/10.1097/igc.0000000000000261 https://doi.org/10.1097/igc.0000000000000261 https://doi.org/10.1111/ger.12126 https://doi.org/10.1016/j.oraloncology.2010.09.001 https://doi.org/10.1016/j.anl.2005.01.012 https://doi.org/10.1016/j.ijom.2006.12.015 https://doi.org/10.1016/j.jobcr.2015.08.009 https://doi.org/10.1016/j.joms.2005.06.018 https://doi.org/10.1016/s1010-5182%2805%2980495-0 https://doi.org/10.1016/s1010-5182%2805%2980495-0 https://doi.org/10.1111/j.1601-0825.2009.01635.x https://doi.org/10.1097/pat.0000000000000048 https://doi.org/10.1016/j.ooe.2005.08.001 https://doi.org/10.1186/2045-3329-3-10 it has been well established that many illnesses, disabilities and distress are influenced by psychosocial factors.1 these psychosocial factors are central to the predisposition, onset, course, and out come of illnesses.2 thus, biopsychosocial factors are of major importance in designing intervention and manage ment plans. according to sirri et al., “when patient behav iors differ from those expected or recommended by phys icians, the greater this discrepancy, the less likely the course of the disease will be predicted solely by bio med ical factors” (p. 74).3 however, social and cultural factors appear to be marginalised when applying informed con sent in traditional societies around the world where factors underpinning cultural beliefs or practices and social behav iour might be different to what is often taught in medical schools. in this issue of squmj, al-balushi raised interesting points on the hegemony of modern medicine in the midst of a pluralistic world.4 specifically, al-balushi has observed that in a traditional society, it is the male members of a family rather than the female patients themselves who took the lead on issues pertinent to the doctor-patient relationship. from a bioethical persepective, this conduct undermines the patient’s inalienable right to personal autonomy. such occurrence has been previously observed in many traditional societies.5–7 this contradictory practice of bioethics in traditio nal societies owes its origin to how medical science has spread in different parts of the world without being cul turally sensitive. modern medicine, sometimes known as ‘cosmopolitan medicine’ or simply biomedicine, often tends to have its true identity hidden. when one examines the underlying bioethical outlook, one cannot escape observing that it is shrouded with a western philosoph ical view. the western bioethical approach is taken as an article of faith.8 such a stance appears to have set forth what has been previously observed by al-balushi.4 it is well-known that western medicine with its reliance on experimentation and empiricism has triumphed over many epidemics that have caused the deaths of millions.9 the global impact of the development of antibiotics and vaccinations, without which the world would have looked very different than what it is today, can also not be ignored. on a superficial level, it appears that western medicine has transcended geographical, cultural and linguistic groups. therefore, it is safe to assume that western med icine is accepted in all corners of the world. however, such acceptance appears to be limited to its curative ability and there is a concern regarding its applicability in medical policy, practice and professionalism. the uni versal applicability of western bioethical approaches, including issues pertinent to confidentiality, determin ation of death, doctor-patient relationship and the topic of present scrutiny, informed consent.10 informed consent refers to the process of obtaining the permission of a patient before proceeding with health care intervention.10 in essence, informed consent requires the treatment team to enlighten the patient about the nature of the treatment, risks and benefits and alter native treatments, if any. once informed, patients have the choice to agree or disagree with the suggested inter vention. informed consent is, therefore, a voluntary agree ment. the principle of informed consent is based on the undeniable right to personal autonomy, self-determin ation, self-governance or ‘self-mastery’.10 according to the internet encyclopedia of philosophy, “autonomy is an individual’s capacity for self-determin ation or self-governance”.11 this stems from western philo sophies such as those expounded by kant.12 the proponent of personal autonomy in bioethics has stated that it is the only way to safeguard us against mistakes of the past.10 this view was consolidated further in 2005 during the 33rd session of the general conference of the united nations educational, scientific and cultural organization when the universal declaration on bioethics and human rights was adopted.13 there are many situations where informed consent is legally waived. for example, it is waived if the patient lacks decision-making capacity, has 1department of child health and 2behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: munasa@squ.edu.om املوافقة املستنرية يف اجملتمعات ذات األخالقيات املختلفة من ’الذات‘ منى ال�سعدون و �سمري العدوي informed consent in societies with different ethos of ‘selfhood’ *muna al-saadoon1 and samir al-adawi2 editorial sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e1–3, epub. 30 may 19 submitted 5 apr 19 revision req. 7 apr 19; revision recd. 9 may 19 accepted 12 may 19 https://doi.org/10.18295/squmj.2019.19.01.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ informed consent in societies with different ethos of ‘selfhood’ e2 | squ medical journal, february 2019, volume 19, issue 1 depressive symptoms, suicidal intent, in an emergency or in a life-threatening situation. in the absence of such circumstances, failure to obtain informed consent prior to medical intervention could lead to legal action. while informed consent has been developed with good intent, sometimes, when applied in non-western societies, it may be deemed as being ethnocentric or simply insensitive to the ‘norm’ in traditional societies. this editorial examined some of the constraining factors including cross-cultural variations in the role of ‘the sick’, selfhood and the doctor patient relationship. cross-cultural variations in the sick role blind enforcement of the western view on self-mastery is opposed to what has been observed as the societal view of the sick role or illness behaviour. sigerist observed that societies tend to assign a specific role or social status to ‘sick’ people.14 parsons indicated that being sick entails that the afflicted person enter a new role.15 accordingly, the sick person is not only marked by a physical ailment, but acquires a new social role that is intimately tied to his/her state of health. one of the main aspects of the sick person’s new role is to be alleviated from their assigned premorbid role since his/ her well-being has been compromised. thus, a sick person is deemed incapable of taking care of themselves and as a result, the family ‘takes over’ the responsibility of their welfare.16 in most cases, the family willingly commits to take responsibility for the afflicted individual even if this would entail temp orarily seizing his/her personal autonomy. these studies suggest that some communities around the world are likely to revoke the personal autonomy of the sick.14–16 such societal practices would invariably be at odds with western bioethics stance on self-mastery. cross-cultural variations in selfhood some societies may not prescribe to the ethos of personal autonomy. in a collective society, such as oman, indiv idual identity is infused with the collective identity of the society; thus, from birth to death, an individual is ushered into the collective mindset. selfhood, as defined in western psychology, is generally not tailored to different sociocultural values—such as that of a collective society.17 therefore, it is not surprising that constant observation by the family infringes on personal autonomy of the afflicted family member. there are impressionistic and anecdotal reports that the family does not allow the patient to be informed of his/her diagnosis.16 conseq uently, the family finds it incomprehensible that a health care professional demands from the sick to decide for themselves and sign consent forms. when viewed through the lens of western biomedical ethics, such an under taking clearly denigrates the much cherished autonomy of the sick person. cross-cultural variations in the doctor-patient relationship the central tenet of informed consent is to promote shared decision-making.10 this ensures that the patients remain informed which in turn would permit them to play an active role in the intervention process and have the liberty to agree or disagree. although shared decision making may theoretically be desirable, in reality, patient expectations have been documented to vary across diff erent societies. in some non-western societies, the phy sician is perceived as hakim or ‘the wise’.18 the concept of hakim suggests that doctors are the experts and, therefore, the patients are expected to surrender all their self-determination or self-governance. hence, in such societies, the doctor-patient relationship befits emanuel and emanuel’s paternalistic model.19 in this model, the doctor decides what is best based solely on medical inform ation and the doctor’s judgment, where he/she acts as a guardian and determines from his/her perspective what is best for the patient. there is an indication that omanis tend to prefer a doctor who takes on this paternalistic role rather than a person who simply acts as a provider of technical expertise.20 within such a socio-cultural setting, it is not surprising that the patient may not want to indulge in any discussions on informed consent. conclusion in order to ensure that current medical practice does not suffer from past mistakes, many bioethical principles have emerged to safeguard the doctor-patient relationship and intervention process. existing bioethics owe their origins to western philosophical principles of respect for persons, with a strong emphasis on individual autonomy. the centrality of individual autonomy has pervaded modern medical practice worldwide; yet their entrance into non-western communities, as in the case of inf ormed consent, appears to be out of sync with the local understanding of self-determination or self-governance in societies in transition. therefore, cultural relativism and adaptability should be the goal when employing bio ethical principles in traditional societies around the world, where such concepts of self-determination, self-govern ance or self-mastery are different. muna al-saadoon and samir al-adawi editorial | e3 references 1. al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos univ med j 2006; 6:3–9. 2. engel gl. the need for a new medical model: a challenge for biomedicine. science 1977; 196:129–36. 3. sirri l, fava ga, sonino n. the unifying concept of illness behavior. psychother psychosom 2013; 82:74–81. https://doi.org/10.1159/ 000343508. 4. al-balushi, a. female patients and informed consent: oman’s cultural background. sultan qaboos univ med j. sultan qaboos univ med j 2019; 19:e11–14. https://doi.org/10.18295/ squmj.2019.19.01.003. 5. bhutta za. beyond informed consent. bull world health organ 2004; 82:771–7. 6. rosenthal j, bannister k, berlin b, berlin e, brush s, field l, et al. politics, culture, and governance in the development of prior informed consent in indigenous communities. current anthropology 2006; 47:119–42. https://doi.org/10.1086/497670. 7. lloyd ce, johnson mr, mughal s, sturt ja, collins gs, roy t, et al. securing recruitment and obtaining informed consent in minority ethnic groups in the uk. bmc health serv res 2008; 8:68. https://doi.org/10.1186/1472-6963-8-68. 8. waller bn, repko ra. informed consent: good medicine, dangerous side effects. camb q healthc ethics 2008; 17:66–74. https://doi.org/10.1017/s0963180108080079. 9. mckeown t. the role of medicine: dream, mirage, or nemesis? new jersey, usa: princeton university press, 2014. 10. lo b. resoliving ethical dilemma: guide for clinicians, 5th ed. new york, usa: wolters kluwer, 2013. 11. internet encyclopedia of philosophy. autonomy. from: https:// www.iep.utm.edu/autonomy/ accessed: may 2019. 12. bird g. kant's theory of knowledge: an outline of one central argument in the ‘critique of pure reason’. new york, usa: routledge, 2016. 13. united nations educational, scientific and cultural organization (unesco). report of the international bioethics committee of unesco (ibc) on consent. paris, france: unesco. shs/ est/cib08-09/2008/1. 14. sigerist h. the special position of the sick. in: roemer mi, henry e, eds. sigerist on the sociology of medicine. new york, usa: md publications, 1929. pp. 9–22. 15. parsons t. the social system. new york, usa: the free press, 1951. 16. silbermann m. cancer care in countries and societies in transi tion: individualized care in focus. cham, switzerland: springer; 2016. 17. vignoles vl, owe e, becker m, smith pb, easterbrook mj, brown r, et al. beyond the ‘east–west’ dichotomy: global variation in cultural models of selfhood. j exp psychol gen 2016; 145:966–1000. https://doi.org/10.1037/xge0000175. 18. chamsi-pasha h, albar ma. doctor-patient relationship. islamic perspective. saudi med j 2016; 37:121–6. https://doi.org/10.15 537/smj.2016.2.13602. 19. emanuel ej, emanuel ll. four models of the physician-patient relationship. jama 1992; 267:2221–6. https://doi.org/10.1001/ jama.1992.03480160079038. 20. norrish mi. disclosure of medical errors in oman: public preferences and perceptions of current practice. sultan qaboos univ med j 2015; 15:e283–7. https://doi.org/10.1159/000343508 https://doi.org/10.1159/000343508 https://doi.org/10.18295/squmj.2019.19.01.003 https://doi.org/10.18295/squmj.2019.19.01.003 https://doi.org/10.1086/497670 https://doi.org/10.1186/1472-6963-8-68 https://doi.org/10.1017/s0963180108080079 https://doi.org/10.1037/xge0000175 https://doi.org/10.15537/smj.2016.2.13602 https://doi.org/10.15537/smj.2016.2.13602 https://doi.org/10.1001/jama.1992.03480160079038 https://doi.org/10.1001/jama.1992.03480160079038 departments of 1anaesthesia & intensive care unit and 2orthopaedics, khoula hospital, muscat, oman; 3department of community medicine, mansoura university, mansoura, egypt *corresponding author e-mail: nilay.chatt@gmail.com مقارنة فغر الرغامى املبكر واملتأخر عند املصابني بإصابات يف احلبل النخاعي العنقي العلوي والسفلي اأكرم حنني جرج�س, فينوجوب�ل مينون, نيالم �شورى, نيالى �ش�ت�رجى, اأميل عط� اهلل, م�جد يو�شف �شعد, �شريين ال�ش�عر abstract: objectives: this study aimed to evaluate the effects of early versus late tracheostomies among patients with cervical spinal cord injuries (cscis). methods: this retrospective study included 69 adult csci patients who underwent bedside percutaneous tracheostomies at the intensive care unit of khoula hospital, muscat, oman, between january 2011 and october 2015. the tracheostomy was considered early if the procedure took place within one week of the csci. the impact of an early tracheostomy on patient outcomes was analysed in terms of duration of mechanical ventilation and intensive care unit (icu) stay among patients with high (c1–c2 vertebrae) and low (c3–c7 vertebrae) cscis. ventilator dependence, bradycardia episodes and surgical intervention outcomes were also examined. results: patients with a high csci who underwent an early tracheostomy spent significantly fewer days on mechanical ventilation compared to those who underwent a late tracheostomy (9.3 ± 7.2 days versus 13.7 ± 3.2 days; p = 0.041). low csci patients who received an early tracheostomy also experienced significantly fewer days on mechanical ventilation compared to those undergoing a late tracheostomy (12.1 ± 10.4 days versus 25.2 ± 17.7 days; p = 0.035). moreover, icu mortality was significantly lower for high csci patients who underwent an early tracheostomy (p = 0.015). however, there was no association between length of icu stay and either type of csci or timing of the tracheostomy procedure. conclusion: an early tracheostomy is beneficial in reducing the duration of mechanical ventilation among patients with cscis, irrespective of the level of injury. keywords: spinal cord injuries; tracheostomy; treatment outcome; mechanical ventilation; intensive care unit. امللخ�ص: الهدف: تهدف هذه الدرا�شة اإىل تقييم اأثر اإجراء عملية فغر الرغ�مى فى وقت مبكر يف مق�بل اإجراوؤه� فى وقت مت�أخر للمر�شى امل�ش�بني ب�إ�ش�ب�ت يف الفقرات العنقية العلي� وال�شفلى من احلبل النخ�عي. الطريقة: اأجريت هذه الدرا�شة ال�شتع�دية على ملف�ت 69 مري�ش� املركزة العن�ية ق�شم فى لهم �رسيرى رغ�مى فغر عمل مت والذين النخ�عي, احلبل من العنقية الفقرات اإ�ش�ب�ت من يع�نون ك�نوا ب�لغ� مب�شت�شفى خولة مب�شقط فى الفرتة م� بني ين�ير 2011م اكتوبر 2015م. واعتربت عملية فغر الرغ�مي مبكرة فى ح�ل مت اإجراوؤه� فى غ�شون اأ�شبوع واحد من ت�ريخ ا�ش�بة الفقرات العنقية. ولقد مت اأي�ش� تقييم تقييم اأثر اإجراء فغر الرغ�مى مبكرا على نت�ئج العالج من خالل حتديد مدة احل�جة اإىل تنف�س �شن�عى, ومدة البق�ء فى العن�ية املركزة, والعتم�د على جه�ز التنف�س ال�شن�عى, ونوب�ت انخف��س عدد �رسب�ت القلب, مع تقييم نت�ئج التدخل اجلراحي ملثل هذه احل�لت. وقد مت تق�شيم املر�شى اإىل فئتني: املر�شى من ذوي الإ�ش�ب�ت العلي� )الفقرات ح�جة مدة اأن ثبت وال�ش�بعة(. النتائج: الث�لثة بني م� العنقية )الفقرات ال�شفلى الإ�ش�ب�ت ذوي من واملر�شى والث�نية(, الأوىل العنقية املر�شى من ذوي الإ�ش�ب�ت العلي� اإىل التنف�س ال�شن�عي عند اإجراء عملية فغر الرغ�مى لهم فى وقت مبكر اأقل فى عدد الأي�م مق�رنة مع الذين مت عمل نف�س العملية لهم ولكن فى وقت مت�أخر )7.2 ± 9.3 يوم� يف مق�بل 3.2 ± 13.7 يوم�؛ p = 0.041( وك�نت النت�ئج مم�ثلة لتلك .)p = 0.035 التي مت احل�شول عليه� يف ح�لت اإ�ش�ب�ت فقرات احلبل النخ�عي ال�شفلى )10.4 ± 12.1 يوم� يف مق�بل 17.7 ± 25.2 يوم�؛ ا�شتنتجن� كذلك اأن معدل الوفي�ت ب�لعن�ية املركزة يف اأو�ش�ط مر�شى الإ�ش�ب�ت العلي� ك�ن اأقل مم� ك�ن م�شجال عند مر�شى الإ�ش�ب�ت �شواء املبكر الرغ�مى فغر بني و املركزة العن�ية فى البق�ء مدة بني ارتب�ط هن�ك يكن مل اأخرى ن�حية من ولكن .)p = 0.015( ال�شفلى لالإ�ش�ب�ت العلي� اأو ال�شفلى. اخلال�صة: اإجراء اإجراء فغر الرغ�مى فى وقت مبكر يفيد مر�شى اإ�ش�ب�ت الفقرات العنقية من احلبل النخ�عي بغ�س النظر عن م�شتوى الإ�ش�بة علي� اأم �شفلى, وذلك من ن�حية تقلي�س عدد الأي�م التي يحت�ج فيه� املري�س اإىل تنف�س �شن�عى. الكلمات املفتاحية: اإ�ش�ب�ت احلبل النخ�عي؛ فغر الرغ�مى؛ نت�ئج العالج؛ التنف�س ال�شن�عى؛ وحدة العن�ية املركز. early versus late tracheostomy for patients with high and low cervical spinal cord injuries akram h. guirgis,1 venugopal k. menon,2 neelam suri,1 *nilay chatterjee,1 emil attallah,1 maged y. saad,1 shereen elshaer3 advances in knowledge the current study sought to determine the ideal timing of a tracheostomy and its impact on patient outcomes, which is a subject of substantial controversy. an early tracheostomy was found to significantly reduce the duration of mechanical ventilation in patients with both high and low cervical spinal cord injuries (cscis). high csci patients had significantly lower mortality when undergoing an early tracheostomy compared to those receiving a late tracheostomy; however, this trend was not observed for patients with low cscis. clinical & basic research sultan qaboos university med j, november 2016, vol. 16, iss. 4, pp. e458–463, epub. 30 nov 16 submitted 20 may 16 revision req. 13 jul 16; revision recd. 8 aug 16 accepted 25 aug 16 doi: 10.18295/squmj.2016.16.04.009 akram h. guirgis, venugopal k. menon, neelam suri, nilay chatterjee, emil attallah, maged y. saad and shereen elshaer clinical and basic research | e459 tracheostomies are among the most commonly performed procedures in the intensive care unit (icu).1 the intervention is designed to improve mechanical ventilatory support by decreasing dead space, enabling trachea-bronchial clearance and avoiding the sequelae of prolonged orotracheal intubation. hence, a tracheostomy facilitates early weaning from mechanical ventilation, shortens the length of time that patients must remain under sedation and reduces associated complications.2 however, a tracheostomy is an invasive procedure and, although rare, can cause tracheal stenosis or other complications.3 patients with cervical spinal cord injuries (cscis) have a high incidence (40–70%) of respiratory complications, such as atelectasis and pneumonia.4 fractures to the upper cervical spine (c1–c2 vertebrae) are considered high injuries, while fractures to the rest of the cervical spine are classified as low injuries.5,6 in patients with a csci, a neurological injury at or above the c4 vertebrae and haematoma-like changes in the spinal cord revealed via magnetic resonance imaging predict the need for an early tracheostomy.7 although tracheostomies play a vital role in the airway management of csci patients, the ideal timing of the procedure remains a subject of substantial debate.8 long-term dependence on mechanical ventilation is common in patients with high cscis.9 the conventional practice is to perform a tracheostomy if the anticipated duration of mechanical ventilation exceeds two weeks.10 in 1989, plummer et al. stated that patients requiring mechanical ventilation for up to 10 days should be endotracheally intubated, whereas a tracheostomy was favoured when the predicted course of mechanical ventilation was greater than 21 days.11 however, evidence for this practice is limited and a defined pathway for the airway management of csci patients does not exist.10,12 the broad consensus among published studies is that an early tracheostomy is associated with fewer days in the icu and a shorter duration of mechanical ventilation, although there are divergent findings regarding the impact of this procedure on rates of pneumonia or mortality.13–15 this study aimed to assess the impact of an early versus late tracheostomy among patients with high (c1–c2) and low (c3–c7) cscis. to the best of the authors’ knowledge, this study is the first to compare early and late tracheostomies among patients with high and low cscis. methods this retrospective study included 69 adult patients with cscis who underwent a bedside percutaneous tracheostomy in the icu of khoula hospital, muscat, oman, between january 2011 and october 2015. only patients aged between 18–60 years old with an anticipated period of mechanical ventilation of >14 days and an initial acute physiology and chronic health evaluation ii score of >25 were included. the exclusion criteria consisted of patients with an anatomical deformity of the neck, those who had had an earlier tracheostomy and those with active coagulopathy (defined as a platelet count <50,000/cc, an activated partial thromboplastin or prothrombin time >1.5 or bleeding time more than twice the normal range) or a soft tissue infection of the neck. in addition, patients with fraction of inspired oxygen requirements of >0.7 or a positive end-expiratory pressure of >12 were excluded. a tracheostomy was considered early if it was performed within seven days of injury; when performed from day eight onwards, it was considered a late tracheostomy. the level of csci was classified as high when the injury involved the first or second cervical vertebrae (c1–c2 vertebrae) and low if the injury involved the rest of the cervical spine (c3–c7 vertebrae). an injury severity score (iss) of >30 and a sepsis-related organ failure assessment score of >11 was considered severe. the primary objective of the study was to evaluate the impact of an early versus late tracheostomy on outcomes in terms of duration of mechanical ventilation and icu stay. in addition, the impact in terms of ventilator dependence, bradycardia episodes and surgical intervention outcomes was analysed. the effects of an early tracheostomy were compared with those of a late tracheostomy separately for both high and low csci patients. in addition, the impact of an early tracheostomy was compared between high and low csci patients. the statistical package for the social sciences (spss), version 16.0 (ibm corp., chicago, illinois, usa) was used for data analysis. data were expressed as means and standard deviations or as numbers and percentages. non-parametric data were compared using pearson’s chi-squared or fisher’s exact tests, as applicable. continuous variables were compared using student’s t-test. a p value of <0.050 was considered statistically significant. application to patient care the findings of this study indicate that patients with high cscis should undergo an early tracheostomy within seven days of injury in order to reduce duration of mechanical ventilation and its sequelae. patients with low cscis need to be evaluated on an individual basis regarding the decision to proceed with an early tracheostomy. early versus late tracheostomy for patients with high and low cervical spinal cord injuries e460 | squ medical journal, november 2016, volume 16, issue 4 the protocol of this study was approved by the institutional ethical committee of khoula hospital. informed consent was obtained from each patient or their surrogate decision-maker before the tracheostomy was performed. results of the 69 csci patients who underwent bedside percutaneous tracheostomies during the study period, 45 (65.2%) had high cscis and 24 (34.8%) had low cscis. the demographic and clinical characteristics of these patients were comparable [table 1]. during the course of their stay in the icu, the following complications were observed: pneumonia (n = 11; 15.9%), dependency on inotropes (n = 8; 11.6%), sepsis (n = 6; 8.7%), ventilator-associated pneumonia (n = 4; 5.8%), gastrointestinal haemorrhage (n = 3; 4.8%), severe bradycardia (n = 3; 4.8%), respiratory arrest (n = 3; 4.8%), abdominal compartment syndrome (n = 1; 1.4%) and abdominal haemorrhage (n = 1; 1.4%). among patients with high cscis, the duration of mechanical ventilation was significantly reduced for those who had received an early tracheostomy compared to those who had undergone a late tracheostomy (9.3 ± 7.2 days versus 13.7 ± 3.2 days; p = 0.041). however, no significant difference was found in terms of length of icu stay between these groups (p = 0.982). high csci patients undergoing an early tracheostomy demonstrated significantly lower mortality compared to those with late tracheostomy (6.3% versus 38.5%; p = 0.015) [table 2]. the duration of mechanical ventilation was also significantly reduced for patients with low cscis who had undergone an early tracheostomy compared to those with low cscis who had undergone a late tracheostomy (12.1 ± 10.4 days versus 25.2 ± 17.7 days; p = 0.035); however, patients with low csci undergoing an early tracheostomy did not have a significantly reduced mortality rate (15.8% versus 20.0%; p = 0.999) [table 3]. in comparing the impact of an early tracheostomy between high and low csci patients, high csci patients had a reduced icu stay (19.1 ± 32.7 days versus 23.4 ± 27.8 days) and duration of mechanical ventilation (9.3 ± 7.2 days versus 12.1 ± 10.4 days); table 1: comparison of characteristics of patients with cervical spinal cord injuries undergoing tracheostomies according to level of injury (n = 69) characteristic n (%) p value high csci (n = 45) low csci (n = 24) mean age in years ± sd 32.4 ± 8.5 33.7 ± 7.8 0.532 male-to-female ratio 34:11 20:4 0.550 mean icu stay in days ± sd 20.8 ± 7.4 22.3 ± 5.5 0.383 mean mechanical ventilation duration in days ± sd 10.8 ± 7.9 15.3 ± 13.4 0.089 deaths 7 (15.6) 4 (16.7) 0.945 ventilator dependence 2 (4.4) 4 (16.7) 0.417 severe cord trauma 5 (11.1) 9 (37.5) 0.041* bradycardia 3 (6.7) 5 (20.8) 0.116 severe sofa score 26 (57.8) 15 (62.5) 0.799 severe iss 29 (64.4) 15 (62.5) 0.872 associated severe head injury 1 (2.2) 2 (8.3) 0.546 early tracheostomy 32 (71.1) 19 (79.2) 0.571 late tracheostomy 13 (28.9) 5 (20.8) 0.571 csci = cervical spinal cord injury; sd = standard deviation; icu = intensive care unit; sofa = sequential organ failure assessment score; iss = injury severity score. *significant at p <0.050. table 2: comparison of characteristics of patients with high cervical spinal cord injuries undergoing tracheostomies according to type of tracheostomy (n = 45) characteristic n (%) p value early tracheostomy (n = 32) late tracheostomy (n = 13) mean age in years ± sd 31.7 ± 8.3 35.9 ± 9.2 0.257 male-to-female ratio 24:8 10:3 0.999 mean icu stay in days ± sd 19.1 ± 32.7 18.2 ± 5.2 0.982 mean mechanical ventilation duration in days ± sd 9.3 ± 7.2 13.7 ± 3.2 0.041* deaths 2 (6.3) 5 (38.5) 0.015* ventilator dependence 2 (6.3) 0 (0.0) 0.579 severe cord trauma 3 (9.4) 2 (15.4) 0.617 bradycardia 1 (3.1) 2 (15.4) 0.196 severe sofa score 19 (59.4) 7 (53.8) 0.751 severe iss 23 (71.9) 6 (46.2) 0.168 associated severe head injury 1 (3.1) 0 (0.0) 0.999 sd = standard deviation; icu = intensive care unit; sofa = sequential organ failure assessment score; iss = injury severity score. *significant at p <0.050. akram h. guirgis, venugopal k. menon, neelam suri, nilay chatterjee, emil attallah, maged y. saad and shereen elshaer clinical and basic research | e461 however, these associations were not significant (p = 0.568 and 0.114, respectively) [table 4]. no significant differences were observed in bradycardia incidence or ventilator dependence between patients undergoing early tracheostomies compared to those receiving late tracheostomies, irrespective of the anatomical level of injury. surgical intervention also had no impact on duration of mechanical ventilation or icu stay, regardless of the level of injury. discussion patients with a csci have a substantial risk of developing respiratory compromise, particularly those with a high or complete spinal cord injury.16 this study evaluated the effect of an early tracheostomy on patients with cscis; the results demonstrated the benefit of an early tracheostomy in terms of reduced duration of mechanical ventilation, irrespective of the anatomical level of the csci. however, length of icu stay, ventilator dependence and bradycardia incidence were not significantly affected by the timing of the intervention. in the icu, a practical decision regarding the optimal timing of a tracheostomy in csci patients is often based on the perceived risk-to-benefit ratio and the clinical indications of the procedure. an early tracheostomy has been reported to lower complication rates, particularly tracheal granulomas and stenosis.14 in a systematic review, griffiths et al. found that an early tracheostomy significantly reduced the duration of mechanical ventilation and the length of stay in the icu; however, there was no impact on mortality or the incidence of pneumonia.17 in comparison, rumbak et al. reported that a tracheostomy performed within 48 hours of injury significantly decreased rates of mortality and pneumonia as well as the duration of mechanical ventilation and icu stay.13 a meta-analysis by dunham et al. indicated that an early tracheostomy resulted in patients with severe head injuries being more rapidly weaned off of mechanical ventilation, although survival rates did not change.18 de leyn et al. demonstrated that a tracheostomy performed within seven days of the injury shortened the duration of mechanical ventilation and icu stay in adult trauma table 3: comparison of characteristics of patients with low cervical spinal cord injuries undergoing tracheostomies according to type of tracheostomy (n = 24) characteristic n (%) p value early tracheostomy (n = 19) late tracheostomy (n = 5) mean age in years ± sd 32.7 ± 7.8 35.8 ± 7 0.414 male-to-female ratio 16:3 4:1 0.999 mean icu stay in days ± sd 23.4 ± 27.8 33.6 ± 31.8 0.479 mean mechanical ventilation duration in days ± sd 12.1 ± 10.4 25.2 ± 17.7 0.035* deaths 3 (15.8) 1 (20.0) 0.999 ventilator dependence 3 (15.8) 1 (20.0) 0.999 severe cord trauma 7 (36.8) 2 (40.0) 0.999 bradycardia 4 (21.1) 1 (20.0) 0.999 severe sofa score 12 (63.2) 3 (60.0) 0.999 severe iss 11 (57.9) 4 (80.0) 0.614 associated severe head injury 2 (10.5) 0 (0.0) 0.999 sd = standard deviation; icu = intensive care unit; sofa = sequential organ failure assessment score; iss = injury severity score. *significant at p <0.050. table 4: comparison of characteristics of patients with cervical spinal cord injuries undergoing early tracheostomies according to level of injury (n = 51) characteristic n (%) p value high csci (n = 32) low csci (n = 19) mean age in years ± sd 31.7 ± 8.3 32.7 ± 7.8 0.611 male-to-female ratio 24:8 16:3 0.504 mean icu stay in days ± sd 19.1 ± 32.7 23.4 ± 27.8 0.568 mean mechanical ventilation duration in days ± sd 9.3 ± 7.2 12.1 ± 10.4 0.114 deaths 3 (9.4) 3 (15.8) 0.348 ventilator dependence 2 (6.3) 3 (15.8) 0.348 severe cord trauma 3 (9.4) 7 (36.8) 0.027* bradycardia 1 (3.1) 4 (21.1) 0.057 severe sofa score 19 (59.4) 12 (63.2) 0.999 severe iss 23 (71.9) 11 (57.9) 0.365 associated severe head injury 1 (3.1) 2 (10.5) 0.547 csci = cervical spinal cord injury; sd = standard deviation; icu = intensive care unit; sofa = sequential organ failure assessment score; iss = injury severity score. *significant at p <0.050. early versus late tracheostomy for patients with high and low cervical spinal cord injuries e462 | squ medical journal, november 2016, volume 16, issue 4 victims.19 in another meta-analysis of early versus late tracheostomies, liu et al. reported that the former significantly decreased icu stays but did not influence mortality; similar results were presented by jeon et al.15,20 leelapattana et al. also found that an early tracheostomy resulted in fewer days on mechanical ventilation and a shorter hospital stay.21 a high csci is invariably associated with respiratory compromise and higher mortality.22 in a retrospective analysis of 178 patients, harrop et al. found that all patients with grade a injuries as classified by the american spinal injury association at the c2 and c3 vertebrae needed tracheostomies, whereas no patients with c8 injuries required the procedure.8 according to a nationwide study of finnish patients with fatal cervical spine injuries between 1987 and 2010, the majority of high csci patients who were <60 years old died within 24 hours of injury.6 the present study found that a tracheostomy performed within seven days of injury in csci patients resulted in significantly reduced duration of mechanical ventilation regardless of the anatomical level of injury. although the current study did not show an overall reduction in the length of icu stay following an early tracheostomy, patients with a low csci stayed for a longer length of time in the icu on average. an early tracheostomy significantly reduced mortality rates among patients with high cscis, although this trend was not observed for the low csci group; as a result, an early tracheostomy is recommended for patients with high cscis although patients with low cscis should be evaluated on a case-by-case basis. tracheostomies offer numerous advantages over endotracheal intubation, such as reduced airway resistance, improved pulmonary hygiene and diminished work of breathing, thereby enabling easier and earlier weaning from mechanical ventilation.23,24 a fenestrated tracheostomy also allows for phonation, enabling the patient to communicate vocally; this has been shown to improve both medical and psychological outcomes among patients with neurological injuries.25,26 factors which can influence the decision to perform a tracheostomy in csci patients include the presence of a complete csci, the anatomical level of injury, the patient’s glasgow coma scale score and iss and the presence of an associated thoracic injury.27 a bedside percutaneous tracheostomy is currently the standard procedure for patients requiring mechanical ventilation.28 in low cscis (c5–t1 vertebra), a catastrophic loss of airway control often negates the benefits of treatment.29 hassid et al. affirmed that an immediate thorough evaluation for respiratory failure is necessary among low csci patients, regardless of the severity of the injury; they recommended early intubation in these patients and found that half of incomplete csci patients would eventually require a tracheostomy.29 this retrospective study had several limitations. the analysis focused on a moderate number of patients from a single centre with a limited follow-up period; therefore, the impact of an early tracheostomy on long-term mortality or survival benefits could not be assessed. the total length of hospital stay was also not considered. moreover, the impact of operator skill in performing the tracheostomy may have affected outcomes. future studies should be prospective in nature and include a higher number of patients from different centres, more rigorous inclusion and exclusion criteria and a longer follow-up period in order to determine the replicability of the findings observed in the present study. conclusion a tracheostomy performed within seven days of injury significantly reduced the duration of mechanical ventilation among csci patients, irrespective of the anatomical level of injury. however, there was no association between length of icu stay and either the timing of the tracheostomy or level of injury, although patients with a low csci spent a longer time in the icu on average. mortality was significantly lower among high csci patients who underwent an early tracheostomy, although this was not the case for patients with low cscis. based on these findings, it is recommended that all patients with high cscis be considered for an early tracheostomy, while those with a low csci should be evaluated on an individual basis. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s this study was previously presented as a poster abstract at the european society of intensive care medicine lives 2016 conference in milan, italy, on 1–5 october 2016. an abstract of the poster was published in intensive care medicine experimental in 2016 (vol. 4, iss. s1, p. a307). akram h. guirgis, venugopal k. menon, neelam suri, nilay chatterjee, emil attallah, maged y. saad and shereen elshaer clinical and basic research | e463 references 1. rana s, pendem s, pogodzinski ms, hubmayr rd, gajic o. tracheostomy in critically ill patients. mayo clin proc 2005; 80:1632–8. doi: 10.4065/80.12.1632. 2. jaeger jm, littlewood ka, durbin cg jr. the role of tracheostomy in weaning from mechanical ventilation. respir care 2002; 47:469–80. 3. dempsey ga, morton b, hammell c, williams lt, tudur smith c, jones t. long-term outcome following tracheostomy in critical care: a systematic review. crit care med 2016; 44:617–28. doi: 10.1097/ccm.0000000000001382. 4. jackson ab, groomes te. incidence of respiratory complications following spinal cord injury. arch phys med rehabil 1994; 75:270–5. doi: 10.1016/0003-9993(94)90027-2. 5. herkowitz hn, garfin sr, eismont fj, bell gr, balderston ra. rothman-simeone: the spine, 6th ed. philadelphia, pennsylvania, usa: saunders , 2011. pp. 1307–32. 6. thesleff t, niskakangas t, luoto tm, öhman j, ronkainen a. fatal cervical spine injuries: a finnish nationwide registerbased epidemiologic study on data from 1987 to 2010. spine j 2016; 16:918–26. doi: 10.1016/j.spinee.2015.11.054. 7. tanaka j, yugue i, shiba k, maeyama a, naito m. a study of risk factors for tracheostomy in patients with a cervical spinal cord injury. spine (phila pa 1976) 2016; 41:764–71. doi: 10.1097/brs.0000000000001317. 8. harrop js, sharan ad, scheid eh jr, vaccaro ar, przybylski gj. tracheostomy placement in patients with complete cervical spinal cord injuries: american spinal injury association grade a. j neurosurg 2004; 100:20–3. doi: 10.3171/spi.2004. 100.1.0020. 9. como jj, sutton er, mccunn m, dutton rp, johnson sb, aarabi b, et al. characterizing the need for mechanical ventilation following cervical spinal cord injury with neurologic deficit. j trauma 2005; 59:912–16. doi: 10.1097/01. ta.0000187660.03742.a6. 10. mcwhorter aj. tracheotomy: timing and techniques. curr opin otolaryngol head neck surg 2003; 11:473–9. doi: 10.1097 /00020840-200312000-00012. 11. plummer al, gracey dr. consensus conference on artificial airways in patients receiving mechanical ventilation. chest 1989; 96:178–80. doi: 10.1378/chest.96.1.178. 12. littlewood k, durbin cg jr. evidenced-based airway management. respir care 2001; 46:1392–405. 13. rumbak mj, newton m, truncale t, schwartz sw, adams jw, hazard pb. a prospective, randomized, study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal intubation (delayed tracheotomy) in critically ill medical patients. crit care med 2004; 32:1689–94. doi: 10.1097/01.ccm.0000134835.05161.b6. 14. romero j, vari a, gambarrutta c, oliviero a. tracheostomy timing in traumatic spinal cord injury. eur spine j 2009; 18:1452–7. doi: 10.1007/s00586-009-1097-3. 15. liu cc, livingstone d, dixon e, dort jc. early versus late tracheostomy: a systematic review and meta-analysis. otolaryngol head neck surg 2015; 152:219–27. doi: 10.1177 /0194599814561606. 16. aarabi b, harrop js, tator ch, alexander m, dettori jr, grossman rg, et al. predictors of pulmonary complications in blunt traumatic spinal cord injury. j neurosurg spine 2012; 17:38–45. doi: 10.3171/2012.4.aospine1295. 17. griffiths j, barber vs, morgan l, young jd. systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. bmj 2005; 330:1243. doi: 10.1136/bmj.38467.485671.e0. 18. dunham cm, ransom kj. assessment of early tracheostomy in trauma patients: a systematic review and meta-analysis. am surg 2006; 72:276–81. 19. de leyn p, bedert l, delcroix m, depuydt p, lauwers g, sokolov y, et al. tracheotomy: clinical review and guidelines. eur j cardiothorac surg 2007; 32:412–21. doi: 10.1016/j.ejcts. 2007.05.018. 20. jeon yt, hwang jw, lim yj, lee sy, woo ki, park hp. effect of tracheostomy timing on clinical outcome in neurosurgical patients: early versus late tracheostomy. j neurosurg anesthesiol 2014; 26:22–6. doi: 10.1097/ana.0b013e31829770a0. 21. leelapattana p, fleming jc, gurr kr, bailey si, parry n, bailey cs. predicting the need for tracheostomy in patients with cervical spinal cord injury. j trauma acute care surg 2012; 73:880–4. doi: 10.1097/ta.0b013e318251fb34. 22. shao j, zhu w, chen x, jia l, song d, zhou x, et al. factors associated with early mortality after cervical spinal cord injury. j spinal cord med 2011; 34:555–62. doi: 10.1179 /2045772311y.0000000024. 23. davis k jr, campbell rs, johannigman ja, valente jf, branson rd. changes in respiratory mechanics after tracheostomy. arch surg 1999; 134:59–62. doi: 10.1001/archsurg.134.1.59. 24. diehl jl, el atrous s, touchard d, lemaire f, brochard l. changes in the work of breathing induced by tracheotomy in ventilator-dependent patients. am j respir crit care med 1999; 159:383–8. doi: 10.1164/ajrccm.159.2.9707046. 25. lanza dc, parnes sm, koltai pj, fortune jb. early complications of airway management in head-injured patients. laryngoscope 1990; 100:958–61. doi: 10.1288/00005537-199009000-00009. 26. boyd sw, benzel ec. the role of early tracheotomy in the management of the neurosurgical patient. laryngoscope 1992; 102:559–62. doi: 10.1288/00005537-199205000-00015. 27. jones ts, burlew cc, johnson jl, jones e, kornblith lz, biffl wl, et al. predictors of the necessity for early tracheostomy in patients with acute cervical spinal cord injury: a 15-year experience. am j surg 2015; 209:363–8. doi: 10.1016/j. amjsurg.2014.07.016. 28. kornblith lz, burlew cc, moore ee, haenel jb, kashuk jl, biffl wl, et al. one thousand bedside percutaneous tracheostomies in the surgical intensive care unit: time to change the gold standard. j am coll surg 2011; 212:163–70. doi: 10.1016/j.jamcollsurg.2010.09.024. 29. hassid vj, schinco ma, tepas jj, griffen mm, murphy tl, frykberg er, et al. definitive establishment of airway control is critical for optimal outcome in lower cervical spinal cord injury. j trauma 2008; 65:1328–32. doi: 10.1097/ ta.0b013e31818d07e4. أول ملف للجينات اخللوية للمرضى العمانيني املصابني مبتالزمة خلل النسج النقوي مقارنة مع بيانات من اسيا وافريقيا وامريكا الشمالية واجلنوبية اأ�سانديرا موثابا اأوداياكومار، جنالء فواز، اأنيل باثاري، �ساكيلة اأ�رصف، حممد احلنيني، خليل الفار�سي، �سالم الكندي، مرت�سى اخلابوري abstract: clonal cytogenetic abnormalities have been reported among 30–80% of patients with myelodysplastic syndromes (mds); however, 20–70% of patients with mds show a normal karyotype that may nevertheless harbour a cryptic genetic alteration. earlier reports have suggested that the distribution of specific chromosomal aberrations varies among western and asian countries, with geographical and ethnic differences in the frequency of specific chromosomal aberrations. this article compared the cytogenetic data of 36 adult omani patients with mds to previously reported data from other populations. differences were noted between the percentages of clonal aberrations and the median age of omani subjects at presentation in comparison to individuals of different ethnicities and from various geographical locations. to the best of the authors’ knowledge, this is the first report to describe the cytogenetic data of patients with mds from oman. keywords: cytogenetic abnormalities; chromosomal aberrations; myelodysplastic syndromes; population heterogeneity; ethnic groups; oman. امللخ�ص: توجد تقاريرعن ت�سوهات للجينات اخللوية بني %80-30 من املر�سى الذين يعانون من متالزمات خلل التن�سج النقوي ومع ذلك فاأن، %70-20 من املر�سى الذين يعانون من هذه املتالزمة تظهر لديهم النمط النووي العادي الذي قد يوؤوي تغيري وراثي خفي. وقد اأ�سارت تقارير �سابقة اإىل اأن هناك توزيع كرومو�سومي �ساذ حمدد يتفاوت بني البلدان الغربية واالآ�سيوية، مع وجود اختالفات جغرافية وعرقية يف تواتر االنحرافات ال�سبغية املحددة. وقد قارنت هذه املقالة بيانات الوراثة اخللوية ل 36 مري�سا عمانيا بالغني يعانون من متالزمة خلل الن�سج النقوي اإىل بيانات �سبق االإبالغ عنها من �سعوب اأخرى. وقد لوحظت فروق بني ن�سب االنحرافات الن�سيلية والعمر الو�سيط للمواطنني العمانيني عند بداية املر�ص مقارنة باأفراد من خمتلف االأعراق ومن خمتلف املناطق اجلغرافية. اإىل حد علم املوؤلفني، هذا هو اأول تقرير لو�سف البيانات اخللوية اجلينية للمر�سى الذين يعانون من متالزمة خلل الن�سج النقوي من عمان. جماعات ال�سكاين؛ التجان�ص عدم النقوي؛ التن�سج خلل متالزمات الكرومو�سومات؛ �سذوذ املن�ساأ؛ خلوية ت�سوهات املفتاحية: الكلمات عرقية؛ عمان. first cytogenetic profile of omani patients with de novo myelodysplastic syndromes comparison with data from asia, africa, europe and north and south america *achandira m. udayakumar,1,2 nagla fawaz,3 anil pathare,4 shakila asraf,4 mohammed al-huneini,4 khalil al-farsi,4 salam al-kindi,3 murtadha al-khabouri4 special contribution sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e286–292, epub. 10 oct 17 submitted 6 oct 16 revisions req. 1 dec 16, 4 jan & 14 mar 17; revisions recd. 17 dec 16, 25 feb & 19 mar 17 accepted 6 apr 17 departments of 1genetics and 3haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of malignancy cytogenetics & molecular pathology, hammersmith hospital, imperial college healthcare national health service trust, london, uk; 4department of haematology, sultan qaboos university hospital, muscat, oman *corresponding author e-mail: uday.achandira@gmail.com doi: 10.18295/squmj.2017.17.03.005 myelodysplastic syndromes (mds) area group of clonal haematopoietic stem cell diseases characterised by cytopaenia, dysplasia in one or more of the major myeloid cell lines, ineffective haematopoiesis and an increased risk of developing acute myeloid leukaemia (aml).1 cytogenetic and molecular abnormalities are key elements in the diagnosis of mds. clonal chromosomal abnormalities in mds have been observed in 30–80% of patients, depending on the subtype and whether it is de novo or mutageninduced.2,3 for the other 20–70% of mds patients with normal karyotypes, there is substantial evidence for the presence of submicroscopic alterations—such as point mutations, microdeletions, microamplifications, epi genetic changes or copy number neutral loss of information—which may form the genetic basis of the disease.4–6 the percentage of clonal abnormalities in the literature varies between 23–78%.7–9 over time, mds has been increasingly recognised as a cause of bone marrow failure; however, the precise incidence of de novo mds is unknown.10 jacobs et al. have suggested that the distribution of specific chromosomal aberrations in mds varies between western and asian countries.11 another report also indicated geographical and ethnic differences in the frequency of specific chromosomal aberrations.12 the incidence of chromosomal abnormalities achandira m. udayakumar, nagla fawaz, anil pathare, shakila asraf, mohammed al-huneini, khalil al-farsi, salam al-kindi and murtadha al-khabouri special contribution | e287 in indian population has been reported to vary from 37.5–88%.13 in addition, the frequency of chromosomal abnormalities varies between 37–50% in china, thailand, hong kong and japan.13,14 complex aberrations have been more frequently observed in indian patients as compared to those from other asian countries.13 as such, ethnic and/or geographical differences could be heterogeneous and contribute to clinical, cytogenetic or molecular events leading to mds. available reports on the incidence of mds mostly originate from european countries, although major studies have been conducted in japan.15–22 to the best of the authors’ knowledge, this is the first report detailing the cytogenetic profile of omani patients with mds. in order to analyse ethno-geographical differences in the pathogenesis of mds, the current article aimed to compare the cytogenetic findings of omani patients with de novo mds with available data from europe, north and south america, africa and other asian countries. methods data were collected from all patients with mds presenting between 2006–2013 to the department of haematology at the sultan qaboos university hospital (squh), a tertiary care centre in muscat, oman. a diagnosis of mds was made as per the criteria of the world health organization (who).23 patients who did not fulfill the who criteria were excluded. all eligible subjects subsequently had their peripheral blood count recorded. in addition, bone marrow samples were obtained prior to the initiation of any therapy. cytogenetic analysis of the bone marrow samples was performed using gtg banding, with karyotypes reported according to the international system for human cytogenomic nomenclature.24 at least 20 metaphases were karyotyped and analysed from 24and 48-hour bone marrow cultures. clonal table 1: characteristics of omani patients with myelodysplastic syndromes presenting to the sultan qaboos university hospital, muscat, oman (n = 36) characteristic n (%) gender male 18 (50.0) female 18 (50.0) age in years mean/median (range) 63/65 (16–86) >60 23 (63.9) <60 13 (36.1) peripheral blood count median haemoglobin in g/dl (range) 8.7 (6.2–14.9) median anc in x109/l (range) 1.3 (0.1–31.5) median platelet count in x109/l (range) 77 (5–591) cytopaenia none 1 (2.8) single lineage 7 (19.4) bilineage 15 (41.7) trilineage 13 (36.1) bone marrow blast in % <5 27 (75.0) 5–10 5 (13.9) >10 4 (11.1) therapy supportive only 29 (80.6) chemotherapy 1 (2.8) bone marrow transplantation 2 (5.6) hydroxyuraea 2 (5.6) azacitidine 2 (5.6) chelation 0 (0.0) mds subtype* ra 8 (22.2)† rars 3 (8.3) rcmd 11 (30.6) raeb 6 (16.7) mds-u 8 (22.2) aml transformation yes 7 (19.4) no 29 (80.6) mortality yes 9 (25.0) no 27 (75.0) anc = absolute neutrophil count; mds = myelodysplastic syndromes; ra = refractory anaemia; rars = refractory anaemia with ringed sideroblasts; rcmd = refractory cytopaenia with multilineage dysplasia; raeb = refractory anaemia with excess blasts; u = unclassified; aml = acute myeloid leukaemia. *defined as per the criteria of the world health organization.23 †including one case of mds associated with an isolated del(5q) abnormality. first cytogenetic profile of omani patients with de novo myelodysplastic syndromes comparison with data from asia, africa, europe and north and south america e288 | squ medical journal, august 2017, volume 17, issue 3 abnormalities were defined as two or more cells with the same whole chromosome gain/chromosome rearrangement or three or more cells with the same chromosome loss. a complex karyotype was defined as three or more cytogenetic abnormalities. ethical approval for this research was received from the research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #896). table 2: age/gender distribution across subtypes of omani patients with myelodysplastic syndromes presenting to the sultan qaboos university hospital, muscat, oman (n = 36) mds subtype* n (%) total age in years gender 0–20 21–40 41–60 >60 male female ra 8 (22.2) 0 (0.0) 0 (0.0) 2 (5.4) 6 (16.7) 3 (8.3) 5 (13.9) rars 3 (8.3) 0 (0.0) 0 (0.0) 1 (2.8) 2 (5.6) 3 (8.3) 0 (0.0) rcmd 11 (30.6) 0 (0.0) 1 (2.7) 4 (11.1) 6 (16.7) 5 (13.9) 6 (16.7) raeb 6 (16.7) 1 (2.8) 0 (0.0) 2 (5.6) 3 (8.3) 3 (8.3) 3 (8.3) mds-u 8 (22.2) 0 (0.0) 1 (2.7) 1 (2.8) 6 (16.7) 4 (11.1) 4 (11.1) total 36 (100.0) 1 (2.8) 2 (5.6) 10 (27.8) 23 (63.9) 18 (50.0) 18 (50.0) mds = myelodysplastic syndromes; ra = refractory anaemia; rars = refractory anaemia with ringed sideroblasts; rcmd = refractory cytopaenia with multilineage dysplasia; raeb = refractory anaemia with excess blasts; u = unclassified. *defined as per the criteria of the world health organization.23 table 3: cytogenetic prognosis of omani patients with myelodysplastic syndromes presenting to the sultan qaboos university hospital, muscat, oman (n = 36) cytogenetic prognosis* cytogenetic abnormality n (%) total† mds subtype ra rars rcmd raeb mds-u‡ very good -y 1 (2.8) 1 (2.8) good normal 23 (63.9) 6 (16.7) 2 (5.6) 8 (22.2) 4 (11.1) 3 (8.3) del(5q) 1 (2.8) 1 (2.7) del(12p) 0 (0.0) del(20q) 0 (0.0) intermediate (all single/double abnormalities) del(7q) 0 (0.0) +8 2 (5.6) 1 (2.8) 1 (2.8) 1 (2.8) i(17)(q10) 1 (2.8) 1 (2.8) +19 0 (0.0) +21 1 (2.8) 1 (2.8) poor (including double abnormalities) inv(3) 0 (0.0) t(3q) 0 (0.0) del(3q) 0 (0.0) very poor complex 1 (2.8) 1 (2.8) mds = myelodysplastic syndromes; ra = refractory anaemia; rars = refractory anaemia with ringed sideroblasts; rcmd = refractory cytopaenia with multilineage dysplasia; raeb = refractory anaemia with excess blasts; u = unclassified. *as per the revised international prognostic scoring system.25 †the total dataset does not add up to 36 as some patients may have had more than one abnormality. ‡including two cases of mds-u with a del(18p) abnormality and one other abnormality. achandira m. udayakumar, nagla fawaz, anil pathare, shakila asraf, mohammed al-huneini, khalil al-farsi, salam al-kindi and murtadha al-khabouri special contribution | e289 cytogenetic and patient data from oman a total of 36 omani patients with mds were successfully karyotyped. of these, eight patients had refractory anaemia (ra; 22.2%), three had ra with ringed siderolasts (8.3%), 11 had refractory cytopaenia with multilineage dysplasia (30.6%), six had ra with excess blasts (16.7%) and eight had unclassified mds (22.2%). one of the patients with ra with ringed siderolasts had mds associated with an isolated del(5q) abnormality. cytopaenia with bilineage was observed in 15 patients (41.7%), while cytopaenia with trilineage was seen in 13 patients (36.1%). most of the patients (75.0%) had <5% bone marrow blasts. a total of 29 patients received supportive therapy only (80.6%). seven patients had aml transformation (19.4%). the mortality rate was 25.0%. there was an equal number of male and female patients and the majority of the patients were over 60 years old (63.9%) [table 1]. the median follow-up period was 28 months (range: 3–70 months). table 2 shows the distribution of mds subtypes according to age and gender. overall, 26 patients (72.2%) had normal karyotypes which indicated a good prognosis according to the revised international prognostic scoring system (ipss-r) [table 3].25 one patient had a normal variant and another had a non-clonal abnormality. eight patients had abnormal karyotypes (22.2%), of which two patients had clones which had trisomy 8 and one patient each had trisomy 21, a del(5)(q15q31) abnormality, a del(11)(q23) abnormality, an i(17)(q10) abnormality, a del(18)(p11) abnormality and an absent y chromosome [table 4]. six of these eight patients also showed normal clones along with abnormal clones. comparison of omani data with other populations the characteristics of omani patients with mds were compared to those previously reported from other populations [table 5].3,7,11,13,15,16,22,26–33 the median age of patients with mds in oman (65 years old) was lower than that reported from europe (65–74 years old) but was higher compared to other asian countries (50–60 years old).10,13,15,17,19–22,26,28,31 the median age of the patients in tunisia was 60 years old.22 brazilian patients had the youngest median age (29 years old).27 among omani patients, the male-to-female ratio was 1:1, which was in accordance with a sample from thailand and close to ratios reported from brazil (1.2:1) and germany (1.3:1);3,26,27 however, this finding was contrary to many other asian countries and certain european, north american and african countries in which males outnumbered females.7,11,13,15,22,28,30,31 further research is needed to determine a possible cause for this gender difference between populations. the majority of omani patients showed normal karyotypes (62.2%) and were believed to have a good prognosis according to ipss-r classifications.25 only published data on the frequency of abnormal karyotypes from japan (23.9%) and china (37.1%) were close to the data from oman.16,28 chromosomal abnormalities such as i(17q), trisomy 21 and the absence of the y chromosome were seen in one each of the omani patients (2.8% each). studies from germany, japan and argentina also reported patients with loss of the y chromosome (7.0%, 1.1% and 2.7%, respectively);3,15,29 however, this abnormality was not observed among patients from thailand, switzerland or brazil.7,26,27 similarly, trisomy 21 was not observed table 4: abnormal karyotypes among omani patients with myelodysplastic syndromes presenting to the sultan qaboos university hospital, muscat, oman (n = 36) patient age/gender mds subtype* karyotype survival in months 1 69/m mds-u 45,x,-y[17]/46,xy[3] 18 2 67/f mds-u 46,xx,del(18)(p11)[20] 5 3 67/f raeb 46,xx,add(1)(q42) del(13)(q31)[13]/46,xx[7] 16 4 78/f rcud 47,xx,+21[17]/46,xx[1] 4 5 68/f mds-u 47,xx,+8[9]/46,xx[11] 7 6 64/f ra 46,xx,del(5)(q15q31),del(11)(q23)[8]/46,xx[6] 5 7 58/f raeb 51,xx,+1,+8,+10,+i(11)(q10),+13[18] 3 8 67/m mds-u 46,xy,i(17)(q10)[4]/46,xy[27] 15 mds = myelodysplastic syndromes; m = male; u = unclassified; f = female; raeb = refractory anaemia with excess blasts; rcud = refractory cytopaenia with unilineage dysplasia; ra = refractory anaemia. *defined as per the criteria of the world health organization.23 first cytogenetic profile of omani patients with de novo myelodysplastic syndromes comparison with data from asia, africa, europe and north and south america e290 | squ medical journal, august 2017, volume 17, issue 3 ta bl e 5: l it er at ur e re vi ew a nd c om pa ri so n of th e cy to ge ne ti c m ar ke r pr ofi le s of p at ie nt s w it h m ye lo dy sp la st ic s yn dr om es 3, 7, 11 ,1 3, 15 ,1 6, 22 ,2 6– 33 r eg io n a fr ic a n a so ut h a m er ic a e ur op e a si a c ou nt ry tu ni si a u sa a rg en ti na b ra zi l g er m an y it al y sp ai n sw it ze rl an d in di a c hi na k or ea ta iw an th ai la nd ja pa n o m an a ut ho r a nd y ea r o f st ud y to ta l s ub je ct s 22 4 49 51 8 93 2, 12 4 49 1 96 8 10 9 52 12 8 14 9 68 11 7 83 8 36 m ed ia n ag e in y ea rs 60 62 69 29 66 65 70 69 § 55 50 53 59 56 60 65 m al eto -f em al e ra ti o 1. 4: 1 1. 3: 1 1. 4: 1 1. 2: 1 1. 3: 1 1. 5: 1 1. 3: 1 1. 5: 1 1. 7: 1 1. 6: 1 1. 9: 1 1. 9: 1 1. 1 1. 7: 1 1: 1 o ve ra ll 11 4 (5 0. 9) 19 (3 8. 8) 22 2 (4 2. 9) 64 (6 8. 8) 1, 08 0 (5 0. 8) 29 4 (5 9. 9) 45 4 (4 6. 9) 61 (5 6. 0) 31 (5 9. 6) 42 (3 2. 8) 34 (5 0. 0) 15 (1 2. 8) 20 0 (2 3. 9) ¶ 8 (2 2. 2) de l5 q/ -5 30 (1 3. 4) 3 (6 .1 ) 19 (3 .7 )* (1 2. 5) † 71 (1 1. 9) ‡ 43 (8 .8 ) 55 (5 .7 ) 37 (3 3. 9) 13 (2 5. 0) 6 (4 .7 ) 5 (7 .4 ) 3 (2 .6 ) 8 (1 .0 )¶ 1 (2 .8 ) de l7 q/ -7 17 (7 .6 ) 2 (4 .0 ) 15 (2 .9 )* (1 4. 1) † 44 6 (2 0. 9) 33 (6 .7 ) 43 (4 .4 ) 16 (1 4. 7) 10 (1 9. 2) 2 (1 .6 ) 11 (1 6. 2) 4 (3 .4 ) 9 (1 .1 )¶ t ri so m y 8 7 (3 .1 ) 5 (1 0. 2) 26 (5 .0 )* (9 .4 )† 33 9 (1 6. 0) 22 (4 .5 ) 56 (5 .8 ) 16 (1 4. 7) 6 (1 1. 5) 8 (6 .3 ) 7 (1 0. 3) 4 (3 .4 ) 15 (1 .8 )¶ 3 (8 .3 ) de l(2 0q ) 7 (3 .1 ) 3 (6 .1 ) 14 (2 .7 )* (7 .8 )† 19 (0 .9 ) 15 (3 .1 ) 13 (1 .3 ) 14 (1 2. 8) 6 (1 1. 5) 1 (0 .8 ) 3 (4 .4 ) 1 (0 .9 ) 16 (1 .9 )¶ i(1 7q ) 2 (0 .9 ) 10 (1 .0 ) 1 (1 .9 ) 1 (2 .8 ) t ri so m y 21 1 (0 .4 ) 1 (0 .2 )* (7 .8 )† 8 (0 .8 ) 1 (2 .8 ) -y 1 (0 .4 ) 14 (2 .7 )* 14 8 (7 .0 ) 5 (1 .0 ) 17 (1 .8 ) 1 (1 .9 ) 1 (0 .8 ) 9 (1 .1 )¶ 1 (2 .8 ) a m l tr an sf or m at io n, n (% ) 11 (2 2. 4) 11 1 (2 1. 4) 13 2 (2 6. 9) 21 8 (2 2. 5) 10 (1 9. 2) 50 (3 9. 1) 25 (1 6. 8) 20 (2 9. 4) 29 (2 4. 8) 7 (1 9. 4) n a = n or th a m er ic a; a m l = ac ut e m ye lo id le uk ae m ia . *f ra gm en t o f a nt ib od y su bt yp ecl as sifi ed p op ul at io n. † p er ce nt ag es o ut o f t he to ta l n um be r o f m d s ca se s w ith a bn or m al k ar yo ty pe s. n o ex ac t v al ue s w er e p ro vi de d in th e o ri gi na l p ub lic at io n. ‡ 5 qsy nd ro m e a s p er th e w or ld h ea lth o rg an iz at io n cl as sifi ca tio ns (a va ila bl e i n 59 5 pa tie nt s) .23 § m ea n ag e. ¶ d at a fo r t he se c at eg or ie s s ou rc ed fr om : s hi m iz u h , m at su sh ita y , a ok i k , n om ur a t, y os hi da y , m iz og uc hi h . p re va le nc e o f t he m ye lo dy sp la st ic sy nd ro m es in ja pa n. 16 w patients with abnormal karyotypes, n (%) gmid ène e t al. 22 (200 8) jacob s et al .11 (19 86) belli e t al. 29 (2012 ) borgo novo et al. 27 (200 5) haase et al. 3 (2005 ) bernasc oni et al .32 (2007 ) solé et a l.33 (2005 ) parlier et al.7 (1994 ) dakshinam urthy et al. 13 (2005) zhao et al.2 8 (2002) lee et a l.31 (1999 ) tien et al .30 (1994) oguma et al. 15 (1995) present res earch intragumto rnchai et a l.26 (1998) achandira m. udayakumar, nagla fawaz, anil pathare, shakila asraf, mohammed al-huneini, khalil al-farsi, salam al-kindi and murtadha al-khabouri special contribution | e291 in thailand or india.13,26 the usa had the lowest percentage of aml transformation (2.8%), followed by korea (16.8%) and oman (19.4%).31 the overall percentage of abnormal karyotypes was lower among omanis compared to other populations (22.2% versus 23.9–68.8%), although this may be due to the low number of patients included in the omani sample.3,7,11,13,15,16,22,26–33 the highest percentage of patients with abnormal karyotypes was reported from brazil.27 the frequency of cytogenetic abnormalities according to mds subtype was found to be different among omani patients when compared to other populations, with most omani patients having normal karyotypes and thus a good prognosis.3,7,11,13,15,16,22,26–33 the current research sought to compare the cytogenetic characteristics of omani patients with mds to those reported among other geographic/ ethnic populations. a review of the literature revealed that this dataset constitutes the first report from an ethnic omani population. however, verification of the findings of this research is needed with a larger sample. as the native omani population is relatively small, numbering approximately 2.35 million in 2015, the number of patients with mds presenting to squh was hence limited and the sample size too small to draw statistically significant conclusions.34 as such, it is recommended that the sample size be increased in future studies. socioeconomic characteristics and access to the healthcare system may also contribute to mds awareness and detection rates within a given population. the referral of suspected patients from rural healthcare centres to tertiary hospitals for cytogenetic testing could also increase the detection/confirmation of mds markers for better characterisation. conclusion to the best of the authors’ knowledge, this report is the first from an omani population detailing the cytogenetic characteristics of patients with mds. these data may serve as a basis for further research in oman and a comparison with other populations. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this research. references 1. greenberg pl. implications of pathogenetic and prognostic features for management of myelodysplastic syndromes. lancet 2001; 357:1059–60. doi: 10.1016/s0140-6736(00)04306-3. 2. pedersen-bjergaard j, philip p, larsen so, andersson m, daugaard g, ersbøll j, et al. therapy-related myelodysplasia and acute myeloid leukemia: cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the copenhagen series. leukemia 1993; 7:1975–86. 3. haase d, steidl c, schanz j, schabla r, pfeilstöcker m, nösslinger t, et al. correlation of cytogenetic findings with morphology, clinical course and prognosis in 2124 patients with mds. blood 2005; 106:787. 4. boultwood j, wainscoat js. gene silencing by dna methylation in haematological malignancies. br j haematol 2007; 138:3–11. doi: 10.1111/j.1365-2141.2007.06604.x. 5. mohamedali a, gäken j, twine na, ingram w, westwood n, lea nc, et al. prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in lowrisk myelodysplastic syndromes. blood 2007; 110:3365–75. doi: 10.1182/blood-2007-03-079673. 6. bejar r, stevenson k, abdel-waheb o, galili n, nilsson b, garcia-manero g, et al. clinical effect of point mutations in myelodysplastic syndromes. n engl j med 2011; 364:2496–506. doi: 10.1056/nejmoa1013343. 7. parlier v, van melle g, beris p, schmidt pm, tobler a, haller e, et al. hematologic, clinical, and cytogenetic analysis in 109 patients with primary myelodysplastic syndrome: prognostic significance of morphology and chromosome findings. cancer genet cytogenet 1994; 78:219–31. doi: 10.1016/0165-4608(94) 90094-9. 8. pfeilstöcker m, reisner r, nösslinger t, grüner h, nowotny h, tüchler h, et al. cross-validation of prognostic scores in myelodysplastic syndromes on 386 patients from a single institution confirms importance of cytogenetics. br j haematol 1999; 106:455–63. doi: 10.1046/j.1365-2141.1999.01559.x. 9. solé f, espinet b, sanz gf, cervera j, calasanz mj, luño e, et al. incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes: grupo cooperativo español de citogenética hematológica. br j hematol 2000; 108:346–56. doi: 10.1046/j.1365-2141.2000.01868.x. 10. aul c, gattermann n, heyll a, germing u, derigs g, schneider w. primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposal for an improved scoring system. leukemia 1992; 6:52–9. 11. jacobs rh, cornbleet ma, vardiman jw, larson ra, le beau mm, rowley jd. prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. blood 1986; 67:1765–72. 12. mitelman f. geographic heterogeneity of chromosome aberrations in hematologic disorders. cancer genet cytogenet 1986; 20:203–8. 13. dakshinamurthy ag, novitzky n, bharadwaj r, prakhya bm. cytogenetic analysis of 52 indian patients with de novo myelodysplastic syndromes: a comparative analysis of results with reports from asia. ann hematol 2005; 84:298–303. doi: 10. 1007/s00277-004-0997-x. 14. chan lc, kwong yl, liu hw, chan tk, todd d, ching lm. cytogenetic analysis of hematologic malignancies in hong kong: a study of 98 cases. cancer genet cytogenet 1992; 62:154–9. doi: 10.1016/0165-4608(92)90255-7. https://doi.org/10.1016/s0140-6736%2800%2904306-3 https://doi.org/10.1111/j.1365-2141.2007.06604.x https://doi.org/10.1182/blood-2007-03-079673 https://doi.org/10.1056/nejmoa1013343 https://doi.org/10.1016/0165-4608%2894%2990094-9 https://doi.org/10.1016/0165-4608%2894%2990094-9 https://doi.org/10.1046/j.1365-2141.1999.01559.x https://doi.org/10.1046/j.1365-2141.2000.01868.x https://doi.org/10.1007/s00277-004-0997-x https://doi.org/10.1007/s00277-004-0997-x https://doi.org/10.1016/0165-4608%2892%2990255-7 first cytogenetic profile of omani patients with de novo myelodysplastic syndromes comparison with data from asia, africa, europe and north and south america e292 | squ medical journal, august 2017, volume 17, issue 3 15. oguma s, yoshida y, uchino h, maekawa t, nomura t, mizoguchi h. clinical characteristics of japanese patients with primary myelodysplastic syndromes: a co-operative study based on 838 cases anemia study group of the ministry of health and welfare. leuk res 1995; 19:219–25. doi: 10.1016/0145-2126 (94)00135-w. 16. shimizu h, matsushita y, aoki k, nomura t, yoshida y, mizoguchi h. prevalence of the myelodysplastic syndromes in japan. int j hematol 1995; 61:17–22. 17. toyama k, ohyashiki k, yoshida y, abe t, asanso s, hirai h, et al. clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in japan. leukemia 1993; 7:499–508. 18. yoshida y, oguma s, uchino h, maekawa t. clinical features and prognosis of refractory myelodysplastic anemias: a japanese cooperative study. nihon ketsueki gakkai zasshi 1987; 50:37–50. 19. juneja sk, imber m, jouault h, scoazec jy, sigaux f, sultan c. hematological features of primary myelodysplastic syndromes (pmds) at initial presentation: a study of 118 cases. j clin pathol 1983; 36:1129–35. 20. goasguen je, garand r, bizet m, bremond jl, gardais j, callat mp, et al. prognostic factors of myelodysplastic syndromes: a simpli fied 3-d scoring system. leuk res 1990; 14:255–62. doi: 10.1016/ 0145-2126(90)90133-t. 21. cunningham i, maccallum sj, nicholls md, byth k, hewson jw, arnold b, et al. the myelodysplastic syndromes: an analysis of prognostic factors in 226 cases from a single institution. br j haematol 1995; 90:602–6. doi: 10.1111/j.1365-2141.1995. tb05590.x. 22. gmidène a, sennana h, fenaux p, laatiri a, zarrouk m, bouaziz h, et al. cytogenetic abnormalities in tunisian de novo myelodysplastic syndrome: a comparison with other populations. leuk res 2008; 32:1824–9. doi: 10.1016/j.leukres. 2008.05.002. 23. the international agency for research on cancer; swerdlow sh, campo e, harris nl, jaffe es, pileri sa, et al. who classification of tumours of haematopoietic and lymphoid tissue (iarc who classification of tumours), 4th ed. geneva, switzerland: world health organization, 2008. 24. mcgowan-jordan j, simons a, schmid m, eds. an international system for human cytogenomic nomenclature: iscn 2016. basel, switzerland: karger, 2016. 25. greenberg pl, tuechler h, schanz j, sanz g, garcia-manero g, solé f, et al. revised international prognostic scoring system for myelodysplastic syndromes. blood 2012; 120:2454–65. doi: 10. 1182/blood-2012-03-420489. 26. intragumtornchai t, prayoonwiwat w, swasdikul d, suwanwela n, chaimongkol b, jootar s, et al. myelodysplastic syndromes in thailand: a retrospective pathologic and clinical analysis of 117 cases. leuk res 1998; 22:453–60. doi: 10.1016/s0145-2126 (98)00022-8. 27. borgonovo t, ribeiro em, cornélio da, schmid-braz at, jamur vr, wuicik l, et al. cytogenetic study of brazilian patients with myelodysplastic syndrome (mds). genet mol biol 2005; 28:654–60. doi: 10.1590/s1415-47572005000500002. 28. zhao wl, xu l, wu w, yan h, tang w, hu j, et al. the myelodysplastic syndromes: analysis of prognostic factor and comparison of prognostic systems in 128 chinese patients from a single institution. hematol j 2002; 3:137–44. doi: 10.1038/ sj.thj.6200173. 29. belli cb, bestach y, correa wa, sakamoto f, flores mg, basquiera al, et al. prognostic relevance of cytogenetic systems in myelodysplastic syndromes. leuk lymphoma 2012; 53:1640–2. doi: 10.31 09/10428194.2012.661053. 30. tien hf, wang ch, chuang sm, chow jm, lee fy, liu mc, et al. cytogenetic studies, ras mutation, and clinical characteristics in primary myelodysplastic syndromes: a study on 68 chinese patients in taiwan. cancer genet cytogenet 1994; 74:40–9. 31. lee jj, kim hj, chung ij, kim js, sohn sk, kim bs, et al. comparisons of prognostic scoring systems for myelodysplastic syndromes: a korean multicenter study. leuk res 1999; 23:425–32. doi: 10.1016/s0145-2126(99)00032-6. 32. bernasconi p, klersy c, boni m, cavigliano pm, calatroni s, giardini i, et al. world health organization classification in combination with cytogenetic markers improves the prognostic stratification of patients with de novo primary myelodysplastic syn dromes. br j haematol 2007; 137:193–205. doi: 10.1111/j.13652141.2007.06537.x. 33. solé f, luño e, sanzo c, espinet b, sanz gf, cervera j, et al. identification of novel cytogenetic markers with prognostic significance in a series of 968 patients with primary myelodysplastic syndromes. haematologica 2005; 90:1168–78. 34. national centre for statistics and information. population clock. from: www.ncsi.gov.om/pages/ncsi.aspx accessed: mar 2017. https://doi.org/10.1016/0145-2126%2894%2900135-w https://doi.org/10.1016/0145-2126%2894%2900135-w https://doi.org/10.1016/0145-2126%2890%2990133-t https://doi.org/10.1016/0145-2126%2890%2990133-t https://doi.org/10.1111/j.1365-2141.1995.tb05590.x https://doi.org/10.1111/j.1365-2141.1995.tb05590.x https://doi.org/10.1016/j.leukres.2008.05.002 https://doi.org/10.1016/j.leukres.2008.05.002 https://doi.org/10.1182/blood-2012-03-420489 https://doi.org/10.1182/blood-2012-03-420489 https://doi.org/10.1016/s0145-2126%2898%2900022-8 https://doi.org/10.1016/s0145-2126%2898%2900022-8 https://doi.org/10.1590/s1415-47572005000500002 https://doi.org/10.1038/sj.thj.6200173 https://doi.org/10.1038/sj.thj.6200173 https://doi.org/10.3109/10428194.2012.661053 https://doi.org/10.3109/10428194.2012.661053 https://doi.org/10.1016/s0145-2126%2899%2900032-6 https://doi.org/10.1111/j.1365-2141.2007.06537.x https://doi.org/10.1111/j.1365-2141.2007.06537.x woman-centered care in pregnancy and childbirth provides lay women as well as professionals, obstetricians, midwives and general care physicians with valuable information on the normal process of pregnancy and childbirth. the text incorporates dozens of clinical vignettes (patient stories) describing how a varied group of clinicians approach the specifics of woman-centered care. they work with many women from a variety of social, cultural, and economic situations who face both normal situations and challenges from the inception of their pregnancies onwards. the authors justify their title, woman-centered care as a necessary reaction, first, to technology centered care where the pressure of modern technology which forces institutions to use more machines to reduce labour costs. second, the title is also in reaction to physician controlled care in pregnancy and child birth and their preoccupation with malpractice suits leading to a leap in interventions. for those clinicians who were trained without all these gadgets and trends these are understandably good arguments. family-centered care is another approach to labour and delivery which happens to a large extent in asian and middle eastern countries, but is not possible for women who are single, lesbian, or drug users etc, in a western population. in familycentered care, men can exert emotional control over the lives of women and children and one of the examples being a husband denying a woman an epidural anesthaesia for pain relief. the authors also present how care is becoming fetal-centered with the advancing technology of ultrasound and fetal monitoring in labour and how fetocentric care can obscure the needs of the pregnant woman. this book is written to promote the practice of maternity care in the context of the womanwhere she comes from, where her partner comes from and ïå˜á÷]ê<ÿ€£]<^flm_<<ï_üπ]<ó◊¬<ïà”iüπ]<ìë^fl√÷]  book review woman-centered care in pregnancy and childbirth editors: sara g. shields and lucy m. candib publisher: radcliffe publishing, oxford & new york, 2010 isbn: 978-184619-1619-9 orders: www.radcliffe-oxford.com squ med j, may 2011, vol. 11, iss. 2, pp. 291-292, epub. 15th may 11 submitted 9th feb 11 woman-centered care in pregnancy and childbirth 292 | squ medical journal, may 2011, volume 11, issue 2 how the baby fits into that context. there are a lot of case vignettes and narratives that makes the book interesting to read. the authors have divided the book into seven sections. part one addresses the magnitude of the problem. other six chapters detail the normal process of pregnancy and its problems, women experiencing miscarriage, fetal anomalies, preterm labour, cesarean sections, etc. there are also chapters on the cultural issues that arise when caring for immigrant women, on prevention and health promotion and on the importance of woman centeredness in family planning and contraception. the final chapter focuses on team work and wise stewardship of resources and the worldwide increase in cesarean sections and the efforts to reverse it. the goal of the authors is to combine practical, woman-centered, evidence-based perspectives that trainees and fully-fledged clinicians can apply in clinical practice in order to strengthen the healing relationship, make it easier to provide good pregnancy and child birth care and lead to women’s self empowerment. on the whole, this book is a very interesting read for patients, physicians and anyone interested in the care of women without the overuse of technology. it is a heavy volume to carry, but nevertheless worth reading. r e v i e w e r s rahma al-mabslai department of obstetrics & gynaecology sultan qaboos university hospital, muscat, oman vaidyanathan gowri department of obstetrics & gynaecology college of medicine & health sciences sultan qaboos university, muscat, oman squ med j, february 2011, vol. 11, iss. 1, pp. 29-37, epub. 12th feb 11 invited article submitted 19th aug 10 revision req. 5th oct 10, revision recd. 2nd nov 10 accepted 10th nov 10 deterrence theory the importance of improving road safety within motorised countries is reflected in the wide array of countermeasures that are presently being employed to reduce the prevalence of engaging in unsafe driving behaviours, e.g., law enforcement, media campaigns, rehabilitation and education, etc. many of these countermeasures utilise deterrence theory as this theory is central to criminology and criminal justice policy.1,2,3 in regards to deterrence, the classical deterrence theory remains the mostly widely understood model, and it proposes that individuals will avoid offending behaviour(s) if they fear the perceived consequences of the act.3,4 two 18th century utilitarian philosophers, bentham and beccaria, are regarded as the founders of this theory which makes implicit assumptions regarding human behaviour. these are, namely, that law breaking is inversely related to the certainty, severity centre for accident research and road safety, institute of health and biological innovation, queensland university of technology, australia. *corresponding author email: j.davey@qut.edu.au <ÿ¯}<‡⁄<—ü�÷]<ì⁄¯â<∞ä† ≈åü÷]<ó◊¬<ìèflf⁄<l]öå^f⁄ páù<ì√q]ü⁄<           :مفتاح الكلمات abstract: the efficacy of road safety countermeasures to deter motorists from engaging in illegal behaviours is extremely important when considering the personal and economic impact of road accidents on the community. in many countries, deterrence theory has remained a cornerstone of criminology and criminal justice policy, particularly within the field of road safety, as policy makers and enforcement agencies attempt to increase perceptions regarding the certainty, severity and swiftness of sanctions for those who engage in illegal motoring behaviours. using the australian experience (particularly the tremendous amount of research into drink driving), the current paper reviews the principles underpinning deterrence theory, the utilisation of the approach within some contemporary road safety initiatives (e.g., random breath testing) as well as highlighting some methods to enhance a deterrent effect. the paper also provides direction for future deterrence-based research, in particular, considering the powerful impact of non-legal sanctions, punishment avoidance as well as creating culturally embedded behavioural change. keywords: deterrence; road safety countermeasures; sanctions; non-legal sanctions improving road safety through deterrence-based initiatives a review of research *jeremy d davey and james e freeman review improving road safety through deterrence-based initiatives a review of research 30 | squ medical journal, february 2011, volume 11, issue 1 review | 30 and swiftness of punishment.5 this means that legal threats are most effective when possible offenders perceive a high likelihood of apprehension, and believe that the impending punishment will be both severe and swift.3 certainty of apprehension within the classic deterrence doctrine, a number of researchers have asserted that the most powerful deterrent effects on offending behaviour are produced by the perceived threat of the certainty of apprehension.3,4,6,7 certainty in the present context refers to the perceived likelihood that an offender will be arrested and punished for their criminal act. in order for the “fear of punishment” to be effective, individuals must believe that the likelihood of apprehension for breaking the law is relatively high.3 evaluations regarding the certainty of apprehension have been extensively reviewed for a variety of different criminal acts (e.g., robbery, violent crimes, shop lifting, drug abuse), with a considerable body of research demonstrating a significant, although weak, negative relationship between certainty of arrest and crime rates.4,8,9,10,11,12 that is, individuals who perceive the chances of arrest as high are more deterred from committing an offence than individuals who believe that they are unlikely to be apprehended.3 as a result, road safety operations that increase the perceptions of apprehension certainty for engaging in illegal behaviours are likely to have a positive effect on deterring offenders.13 severity of sanctions the perceived severity of legal sanctions has also been considered to be extremely important when examining the deterrent effects of legal penalties on offending behaviour(s).4 the classic deterrence doctrine proposes that individuals will be reluctant to commit an offence if they consider that the penalty for such an offence is severe.4 not only have the deterrent effects of perceived severity of punishment not received the same level of attention as that of certainty,14,15 but also the results within the literature are conflicting. a considerable body of early research demonstrated a weak negative relationship between perceived severity of sanctions and a range of illegal behaviours.11,12,14,16,17 that is, as perceptual severity increases, the likelihood of an individual committing that offence decreases;4 however, an opposing body of research demonstrates that perceptions regarding the severity of penalties do not have the salient deterrent impact that was once assumed.3,6,11,15,17 in fact, some researchers have reported a counter-intuitive relationship, with crime rates actually increasing with increases in the severity of the penalty.10,12,18,19 nevertheless, it may be suggested that the greatest deterrent impact in regards to severity of sanctions will be found among those who have never committed an offence, rather than habitual offenders.3 swiftness of sanctions the third aspect of the classic deterrence doctrine refers to the deterrent effect of celerity, as it is proposed that the application of punishments for illegal behaviour will be most salient when they are administered soon after the criminal act.3 this belief has direct links to models of learning and experimental psychology (e.g., conditioning), as it has been demonstrated that the time between stimulus and response is vital in regards to learning new behaviours.7 likewise, it is recognised that for road safety, the swiftness of impending penalties is an important aspect for achieving deterrence.3,20 however, despite the link between the speed of the response and learned behaviour, the effects of the celerity of legal sanctions is by far the least studied of the three major deterrent mechanisms in the classic deterrence doctrine.2,7 this is partly because penalties are rarely applied swiftly in the criminal justice system.2 specific versus general deterrence while there are many different variations of deterrence, in the broadest sense there are two deterrence processes commonly known as specific and general deterrence.3,4 specific deterrence is most commonly understood to be the process whereby an individual who has been apprehended and punished for a criminal act refrains from further offending behaviour for fear of incurring additional punishment.3,21 in contrast, general deterrence jeremy d davey and james e freeman review | 31 cultural behaviours such as drink driving. in regards to the latter, arguably one of the best known examples of general deterrence working effectively is through the implementation of random breath testing (rbt). rbt was introduced into australia in the 1980s and involves police officers randomly stopping motorists and analysing their breath samples, via a hand held device, to determine if they have consumed more alcohol than is legally permitted in order to operate a motor vehicle. while a number of factors have contributed to the reduction of drink driving in australia over the past 30 years, studies evaluating the effectiveness of rbt have revealed this countermeasure to be one of the primary reasons why alcohol-related crashes have reduced in australia.30,31 for example, a review of rbt in queensland found that the introduction of the programme was associated with an 18% reduction in alcohol-related driver and rider fatalities.32 the general deterrent effect is achieved (in part) by the queensland police service (qps) conducting the equivalent of one (preliminary) breath test for every licensed driver per year. in the financial years 2001–2002 and 2002–2003, the qps conducted over 2.6 million preliminary breath tests.33,34 this currently represents the highest rate of breath testing by any police jurisdiction in australia,35 and demonstrates a high level of commitment by the qps to the rbt program as well as to promote a general deterrent effect. this commitment to high testing levels has required high levels of resources including extra manpower, officer hours and equipment, to maintain. the qps has also implemented improvements to rbt operations through the acquisition of state of the art breath testing equipment, booze buses (e.g., mobile testing units) and the implementation of coordinated intelligence efforts in relation to crash and offender hot spots.33,34 although the apprehension of drink driving offenders is important, it has been argued that the main purpose of rbt is to deter the general driving population from drink driving.3 this also remains a central aim of other road safety initiatives, such as visible speed cameras on the side of the road to deter motorists from breaking the speed limit. again in regards to drink driving (or other similar behaviours) the ideal general deterrence-based operation is one that is highly visible, sustained and widespread.3,28 however, these features should occurs when an individual refrains from engaging in a criminal behaviour as a result of observing others being punished for the offending behaviour or they are warned of the impending penalties for committing an offence such as through media campaigns.3,4 in regards to specific deterrence, the application of legal sanctions following a conviction for an offence such as drink driving or speeding has a number of purposes including punishment, reform, retribution and possibly incapacitation.22 however, a primary goal of the sanctioning process is to deter offenders from repeating the same crime in the future, and thus, the penalty should be perceived as certain, severe and swift.3,22 attempts to deter motoring offenders through the application of legal sanctions form a core component of current sentencing practices,2,23 and a growing body of research has demonstrated that sanctions have the capacity to reduce the likelihood of re-offending among a range of motoring groups for a range of offences including speeding,24,25 unlicensed driving,26,27 drink driving,3,28 etc. in regards to general deterrence, a considerable body of evidence suggests that the threat of apprehension and subsequent legal sanctions, especially when supported by well-publicised media campaigns, can produce a deterrent effect, even if short, on offending behaviour.3,7,29 more specifically, campaigns to reinforce the consequences of an aberrant behaviour (such as drink driving in the australian context), or increasing the perceived severity or certainty of penalties (as well as apprehension) have produced a beneficial effect on crashes and serious injury rates15 as well as actual perceptions of arrest certainty.3,29 random breath testing as an example of targeting cultural change in general, research has demonstrated that the utilisation of deterrence-based initiatives can create lasting attitudinal and behaviour change in regards to aberrant driving behaviours, such as speeding and drink driving. in fact, within australia, deterrence-based countermeasures have been demonstrated to have the potential to create attitudinal and behavioural change even among established, entrenched and previously accepted improving road safety through deterrence-based initiatives a review of research 32 | squ medical journal, february 2011, volume 11, issue 1 remain central to all road safety countermeasures that aim to deter offending behaviours. in regards to rbt, it is also a communication tool, influencing community perceptions of the social unacceptability of drink driving. for example, the aim is not only to target the specific behaviour, but also the cultural climate in which that behaviour occurs and is supported. community surveys conducted over the years have shown that since the introduction of rbt, there has been an increase in the number of people who disapprove of drink driving.36 as a result, deterrence-based initiatives have the potential to create lasting cultural and attitudinal change in behaviours that were once supported (or tolerated) within the community. for example, in regards to drink driving, while the behaviour was historically accepted for many decades in australia, research has consistently demonstrated changes in community perceptions regarding the offence. illustrating this, an earlier study by the australian transport safety bureau37 found that 54% of australians believe that drink driving is a major cause of crashes. the same study also found that 97% of australians support random breath testing enforcement by police. in addition to rbt, a number of australian states have commenced, using a similar method, to analyse randomly the oral fluid of motorists to determine if they have recently consumed illicit substances such as cannabis and amphetamines. preliminary research is beginning to demonstrate that randomly testing motorists can also produce a general deterrent effect, although the practice should be complemented with a wide spread media campaign to increase the overall deterrent effect, e.g., increase motorists’ perceptions regarding the wide spread use of the technique as well as the increased likelihood of being detected. taken together, a foundation of deterrence theory focuses on modifying road safety behaviour, and it can also be applied within a range of road safety concerns such as speeding, unlicensed driving, etc. as well as setting the agenda for cultural change. within australia, the tremendous amount of knowledge that has been obtained from focusing on deterring the drinking driver is now being re-directed towards other unsafe driving behaviours such as those mentioned above and which are more common in the gulf states. extending deterrence theory: non-legal sanctions despite the prominence of the deterrence doctrine within road safety initiatives, a number of additional theories that focus on social, developmental, environmental and biological factors have been developed in an attempt to understand a range of criminal activities. as a result, a number of models have stemmed from, and expanded the scope of, the classic deterrence doctrine. one significant direction of theoretical change has been to commence examining the deterrent effect that non-legal sanctions have on decisions to commit an offence, e.g., social control theory. this endeavour has resulted in an increase in the number of factors proposed to influence criminal behaviour, e.g., social disapproval, feelings of guilt, fear of physical injury. one of the reasons for this expansion was criticisms that traditional deterrence models did not account for the large array of nonlegal factors that may influence an individuals’ decision regarding committing an offence, as it is recognised that penalties are not applied within a social vacuum.38,39,40 in fact, researchers have argued that road safety offences occur within a social context, and that there are a plethora of additional attitudinal and behavioural factors (e.g., morality, peer pressure, etc) that may produce a stronger impact on offending behaviour(s) than traditional legal sanctions.3,39 as a result, a number of additional models have been developed that focus on rational choice and prospect theories, and thus suggest that both legal and non-legal sanctions affect a person’s decision to commit an unsafe driving behaviour. this reorientation has resulted in an increase in the number of factors proposed to influence offending behaviour, such as peer/social sanctions, fear of being injured, moral attachment to the norm, and moral obligations to the law. as a result, such additional factors have now influenced associated educational campaigns designed to increase motorists’ attitudes regarding the importance of road safety. while a complete review of the many non-legal factors proposed to influence criminal and “at-risk” behaviour is beyond the scope of the current paper, some factors are briefly discussed below and may be relevant to societies with high jeremy d davey and james e freeman review | 33 avoidance; c) indirect (vicarious) experience of punishment; and d) indirect (vicarious) experience with punishment avoidance. the model suggests that both general and specific deterrence have the potential to influence an individual’s decision to commit an illegal behaviour, and are thus compatible with contemporary learning theories through the acknowledgement that both experiential and vicarious experiences have a direct effect on learning and decision making.46 the model highlights the fact that the experience of punishment is not the only important factor to achieve deterrence, but also recognises that the process of punishment avoidance is likely to influence further offending behaviours.47 preliminary research has suggested the model has considerable potential to shed light on why some individuals are not deterred by the threat of legal sanctions, particularly in regards to the problem of personally avoiding detection and punishment and/ or observing others achieve similar outcomes. for example, preliminary research has demonstrated punishment avoidance to be negatively associated with perceptions of arrest certainty, and positively associated with illegal drug use in high school students.47 these findings highlight the need to implement road safety initiatives that maximise the probability of apprehending individuals who violate road rules. directions for future research and theoretical limitations despite the tremendous amount of research that has focused on the mechanisms and processes of deterrence over the past 30 years, researchers admit that the precise circumstances under which sanctions (or the threat of sanctions) are likely to influence or change a person’s behaviour are still not known.2,48 one limitation within the deterrence literature is the lack of research that has examined convicted offenders,6 particularly repeat offenders, and why they seem immune or impervious to the threat of legal sanctions.44 specifically, research has yet to determine whether repeat offenders consider penalties to be “certain, severe and swift”, or why a considerable proportion continue to drink and drive despite incurring increasingly severe sanctions.3,15 another major limitation within the deterrence field is that the vast majority of deterrence research degrees of social pressure such as those in the gulf area. one non-legal sanction that has consistently been proposed to influence motorists’ driving behaviours has been the threat of injuring oneself or another motorist.3,41 this deterrent factor forms a central component of many road safety advertising campaigns that promotes the serious negative health consequences that may result from an offence such as drink driving, e.g., crashes and fatalities. a second non-legal sanction that has been hypothesised to affect criminal behaviour is moral commitment to the norm, such as whether individuals are willing to break the law. more broadly, both moral commitment to the norm and respect for the law have been identified as having an effect on the prevalence of criminal activities.3,10,42,43 as a result, increasing individuals’ awareness of social norms (such as not drink driving) has considerable merit to influence subsequent driving behaviours. another non-legal factor involves the threat of social stigma resulting from informal sanctions. given that deterrence is a psychological process that takes place within a larger social context of human activity,3 it has been hypothesised that social and cultural norms affect the prevalence of offending behaviours in a community.4,7,40 a considerable body of research has demonstrated that informal sanctions such as social disapproval or fear of social stigma produce a significant deterrent effect on a number of illegal acts such as shoplifting, violent behaviour, etc.4,15,17,41 in fact, some researchers have reported that the threat of informal sanctions produces a greater deterrent effect on offending behaviour than the threat of formal legal sanctions.12,44,45 as a result, the negative effect of social sanctions are also increasingly being included in campaigns designed to improve road safety. another prominent direction of theoretical development in regards to deterrence has been to consider the effect of avoiding punishment and exposure to others avoiding punishment, which has been proposed to have a major influence on subsequent offending behaviour. in 1993, stafford and warr proposed a reconceptualised model of deterrence that incorporates four categories of experiences that have been suggested to affect the deterrent process: a) direct experience of punishment; b) direct experience of punishment improving road safety through deterrence-based initiatives a review of research 34 | squ medical journal, february 2011, volume 11, issue 1 has focused on college students and the general public.16 more specifically, current understanding regarding the mechanics of deterrence initiatives is heavily skewed towards programmes of research that have focused predominantly on younger populations. thus, less is currently known about the general deterrent impact of possible future legal punishment on wider motoring populations’ actual offending behaviours. in part, this limitation stems from the difficulties associated with determining casual directions, eliminating competing explanations,3 and examining large groups of motorists’ self-reported attitudes and offending behaviours. what is commonly understood is that deterrence processes are generally unstable and fluctuate over time,3 which suggests that individuals’ perceptions of sanctions, and the impact that such sanctions have on their behaviours, are likely to change. therefore, one of the primary concerns with deterrence theory is that deterrence is considered to be unstable and can change over time.3 there thus remains a continual need to investigate and refine the deterrent impact of current countermeasures on the motoring population. increasing deterrent effects the various principles incorporated within deterrence theory have together been proven to increase road safety in a number of motorised countries (e.g., united states, canada, australia, etc.) and within a range of areas including speeding, unlicensed driving, drink driving, and drug driving. however, in order to maximise the greatest deterrent effect, it appears that policy makers and enforcement agencies need to maintain a balance between both the general and specific deterrent aspects of the theory. for example, in regards to speeding enforcement, the overall efficiency of the programme could be optimised by maintaining (and increasing over time) the high level of speed cameras and mobile operations as well as increasing the number of drivers detected. importantly, in order to create and maintain a deterrent effect, policing operations should be highly visible, sustained and widespread.3,35 this ensures that all motorists, whether newly licensed or experienced, perceive a constant high risk of apprehension. if drivers do not regularly observe policing operations, they may become undeterred which may be then reinforced by successfully engaging in offending behaviours that remain undetected, e.g., punishment avoidance. stemming from this, the effectiveness of any deterrence-based enforcement practice is heavily dependent upon increasing motorists’ perceptions regarding the risk of being apprehended for an offence, e.g., general deterrence. as a result, there is a need to utilise a variety of public education strategies to ensure motorists are aware of current efforts to apprehend offenders. one proven method is to conduct regular publicity campaigns that highlight sustained efforts to detect offenders through a variety of mediums including television advertising, radio, brochures, posters, etc. in general, research has begun to demonstrate that well-executed mass media campaigns (that are widely implemented, targeted and persuasive rather than fear eliciting) have the potential to reduce offending behaviours and/or culturally-embedded unsafe behaviours.49,50,51 in summary, deterrence remains unstable and requires high levels of police resources and commitment in order to maintain it. as highlighted previously, it should also be noted that our current understanding of the mechanisms of deterrence is based heavily on studies that have focused on younger populations. in fact, the bulk of published deterrence-based studies are from a small number of highly industrialised countries (e.g., united states, canada, australia, etc), and thus deterrent forces are likely to fluctuate with the surrounding environment. in fact, it should be acknowledged that environmental modifications have the potential to create a greater level of behavioural change in some countries than deterrence-based initiatives.52 nevertheless, in order to ‘maximise’ deterrent effects, enforcement operations should consider utilising targeted and intelligence-led enforcement methods to increase the likelihood of identifying and apprehending motorists engaging illegal behaviours. in regards to speeding, this might involve commencing mobile operations at high risk times in high risk locations where people are most likely to speed. this could be complemented with the use of crash and apprehension data which highlights where and when crashes or previous arrests have occurred. however, there are other enforcement methods jeremy d davey and james e freeman review | 35 3. homel j. policing and punishing the drinking driver. a study of specific and general deterrence. new york: springer-verlag, 1988. 4. von hirsch a, bottoms a, burney e, wikstrom p. criminal deterrence and sentence severity: an analysis of recent research. oregon: hart publishing, 1999. 5. taxman s, piquero a. on preventing drunk driving recidivism: an examination of rehabilitation and punishment approaches. j crim justice 1998; 26:129–43. 6. decker s, wright r, logie r. perceptual deterrence among active residential burglars: a research note. criminol 1993; 31:135–47. 7. nagin, s, pogarsky g. integrating celerity, impulsivity, and extralegal sanction threats into a model of general deterrence: theory and evidence. criminol 2001; 39:865–89. 8. grasmick hg, jacobs d, mccollom cb. social class and social control: an application of deterrence theory. soc forces 1983; 62:359–74. 9. richards p, tittle cr. socioeconomic status and perceptions of personal arrest probabilities. criminol 1982; 20:329–46. 10. silberman m. toward a theory of criminal deterrence. am sociol rev 1976; 41:442–61. 11. teevan jj. subjective perception of deterrence (continued). j res crime & delinq1976; 13:155–64. 12. tittle cr. evaluating the deterrent effects of criminal sanctions. in: klein mw, teilmann ks, eds. handbook of criminal justice evaluation. beverly hills: sage publications, 1980. 13. watson b, freeman j. perceptions and experiences of random breath testing in queensland and the selfreported deterrent impact on drunk driving. traffic injury prevent 2007; 8:11–19. 14. grasmick hg, bryjak gj. the deterrent effect of perceived severity of punishment. soc forces 1980; 59:471–91. 15. ross hl. deterring the drinking driver. legal policy and social control. lexington, ma: lexington books, 1982. 16. klepper s, nagin d. the deterrent effect of perceived certainty and severity of punishment revisited. criminol 1989; 27:721–46. 17. paternoster r, iovanni l. the deterrent effect of perceived severity: a reexamination. soc forces 1986; 64:751–77. 18. mann re, vingilis er, gavin d, adlaf e, anglin l. sentence severity and the drinking driver: relationship with traffic safety outcome. accident anal & prevent 1991; 23:483–91. 19. meier rf, johnson wt. deterrence as social control: the legal and extralegal production of conformity. am sociol rev 1977; 42:292–304. that have resulted in increased detection rates including the use of covert operations comprised of unmarked cars and plain-clothes police.53 this approach may prove particularly useful in rural areas and the greatest effects may be achieved through a mixture of overt and covert enforcement methods. however, it is noted that any deterrence-based method employed in isolation does not offer a panacea for the problem of road accidents and fatalities, and thus researchers and policy makers also need to look beyond such principles to identify other methods both to increase motorists’ awareness of the importance of safe motoring as well as to create lasting behavioural change. in fact, there are a number of initiatives that are likely either to complement the general deterrent effect of law enforcement operations (e.g., use of publicity, media advocacy, changing community norms), or improve the management of convicted offenders, e.g., rehabilitation, licence actions, vehicle sanctions. therefore, it is important that deterrentbased approaches are not considered in isolation, but rather, form part of a multi-modal approach (including education) to improve road safety and change entrenched “at-risk” driving behaviours. more generally, and when attempting to alter behaviour, there are two main pathways to ensure compliance: 1) the extrinsic pathway governed by systems and rules with rewards and punishments, and 2) the intrinsic pathway that establishes voluntary compliance via individual commitment to safety. while deterrence theory may be argued to be one of the key ingredients to improve road safety, it is noted that an excessive amount of extrinsic motivation in the form of policies and regulations may actual trigger further issues by reducing the intrinsic motivation of drivers to perform safety behaviours. as a result, establishing intrinsic commitment to road safety throughout the community can only assist in achieving more sustainable and reliable behavioural change. references 1. andenaes j. punishment and deterrence. ann arbor: the university of michigan press, 1974. 2. babor t, caetano r, casswell s, edwards g, giesbrecht n, graham k, et al. alcohol: no ordinary commodity. research and public policy. oxford: oxford university press, 2003. improving road safety through deterrence-based initiatives a review of research 36 | squ medical journal, february 2011, volume 11, issue 1 20. mcarthur dl, kraus jf. the specific deterrence of administrative per se laws in reducing drunk driving recidivism. am j prev med 1999; 16:68–75. 21. watson b. the effectiveness of drink driving licence actions, remedial programs and vehicle-based sanctions. proceedings of the 19th arrb research conference. melbourne: australian road research board, 1998. 22. freeman j, liossis p, schonfeld c, sheehan m, siskind v, watson b. the self-reported impact of legal and non-legal sanctions on a group of recidivist drink drivers. transport res part f: traffic psychol & behav 2006; 9:53–64. 23. smith k. a qualitative study of deterrence and deviance in a group of recidivist drink drivers. unpublished masters manuscript. university of canberra, australia, 2003. 24. elvik r, christensen p. the deterrent effect of increasing fixed penalties for traffic offences: the norwegian experience. j safety res 2007; 38:689– 95. 25. glendon a, cernecca l. young drivers’ responses to anti-speeding and anti-drink-driving messages. transport res part f: traffic psychol & behav 2003; 6:197–216. 26. siskind v. does license disqualification reduce reoffence rates? accident anal & prevent 1996; 28:519–24. 27. voas rb, tippetts as, lange je. evaluation of a method for reducing unlicensed driving: the washington and oregon license plate sticker laws. accident anal & prevent 1997; 29:627–34. 28. watson b, hart s, freeman j, tay r, davey j, madden j, et al. review of random breath testing (rbt) in queensland. queensland: queensland university of technology, 2005. 29. grosvenor d, toomey tl, wagenaar ac. deterrence and the adolescent drinking driver. j safety res 1999; 30:187–91. 30. henstridge j, homel r, mackay, p. the long-term effects of random breath testing in four australian states: a time series analysis (cr 162). canberra, australia: federal office of road safety, 1997. 31. harrison w, newman s, baldock m, mclean j. issues in developing better practice in enforcement targeting drink driving. draft contract report for austroads. melbourne, australia: monash university accident research centre, 2003. 32. watson b, fraine g, mitchell l. enhancing the effectiveness of rbt in queensland. prevention of alcohol related road crashes: social and legal approaches conference, brisbane, australia. griffith university and queensland transport, 1994. 33. queensland police service annual report 2001– 2002. queensland government. from: http://www. police.qld.gov.au/pr/services/reports/01_02/index. shtml accessed: sept 2003. 34. queensland police service annual report 2002– 2003. queensland government. from: http://www. police.qld.gov.au/pr/services/reports/02_03/index. shtml accessed: sept 2003. 35. kolesnik p. queensland police service random breath testing targets issues paper. brisbane: queensland police service, 2002. 36. mitchell-taverner p. community attitudes to road safety: community attitudes survey wave 11 (cr 180). canberra, australia: federal office of road safety, 1998. 37. australian transport safety bureau (atsb). road fatalities australia: 2000 statistical summary. canberra, australia: atsb, 2001. 38. anderson ls, chiricos tg, waldo gp. formal and informal sanctions: a comparison of deterrent effects. soc probs 1977; 25:103–14. 39. berger d, snortum j. a structural model of drinking and driving: alcohol consumption, social norms, and moral commitments. criminol 1986; 24:139–53. 40. sherman lw. defiance, deterrence, and irrelevance: a theory of the criminal sanction. j res crime & delinq 1993; 30:445–73. 41. baum s. self-reported drink driving and deterrence. austr & nz j criminol 1999; 32:247–61. 42. brown s. associations between peer attitudes and behaviour, random breath testing experience and drink driving in a population-representative sample of south australians. from: http://www.druglibrary. org/schaffer/misc/driving/s6p4.htm. accessed: may 2002. 43. piquero ar, tibbetts s. specifying the direct and indirect effects of low self-control and situational factors in offenders’ decision making: toward a more complete model of rational offending. justice quart 1996; 13:481–510. 44. beirness dj, mayhew dr, simpson hm. dwi repeat offenders: a review and synthesis of the literature. canada: health canada, 1997. 45. snortum r. deterrence of alcohol-impaired driving: an effect in search of a cause. in: laurence md, snortum r, zimring fe, eds. the social control of drinking and driving. chicago: university of chicago press, 1988. pp.189–226. 46. stafford mc, warr m. a reconceptualisation of general and specific deterrence. j res crime & delinq 1993; 30:123–35. 47. paternoster r, piquero a. reconceptualizing deterrence: an empirical test of personal and vicarious experiences. j res crime & delinq 1995; 32:251–86. 48. piquero ar, pogarsky g. beyond stafford and warr’s reconceptualization of deterrence: personal and vicarious experiences, impulsivity, and offending behavior. j res crime & delinq 2002; 39:153–86. 49. elder rw, shults ra, sleet da, nichols jl, jeremy d davey and james e freeman review | 37 messages. accident anal & prevent 2010; 42:459–67. 52. world health organisation. global status report on road safety: time for action. geneva: who, department of violence and injury prevention, 2009. 53. healy d, wylie b. evolving drink driving enforcement strategies and public education in regional victoria. in: proceedings road safety research, policing, education conference, 16-17 november, wellington, new zealand. new zealand: land transport safety authority and new zealand police, 1998, vol. 2, pp. 70–3. thompson rs, rajab w. effectiveness of mass media campaigns for reducing drinking and driving and alcohol-involved crashes. am j prev med 2004; 27:57–65. 50. lewis i, watson b, white k, tay, r. promoting public health messages: should we move beyond fear-evoking appeals in road safety? qual health res 2007; 17:61–74. 51. lewis i, watson b, white, k. response efficacy: the key to minimizing rejection and maximizing acceptance of emotion-based anti-speeding sir, i am responding to professor lamki’s editorial in your august 2010 issue.1 the article discusses the roots of stress among medical students, dealing especially with omani medical students and their social backgrounds. he elucidates some social aspects and obligations that may impose more stress upon omani students than those elsewhere in the world. professor lamki’s suggestion that certain social obligations in our part of the world impose extra stress and interfere with students’ academic performance may, in my opinion, not be absolutely valid. obligations such as going back home over weekends, attending weddings, exchanging family visits, etc. are well engrained in our society and the fabric of our family structure. i would like to challenge his assumption given my position as assistant dean, where i have first line contact with students, listening to their aches and pains and their academic and social problems. i personally believe that having family support is one of the most important factors for a student’s academic excellence. in my experience, it is those students who live away from their families that are the ones who struggle most. in general, whether we like it or not, we live in a society where the family is a tight knit and interdependence is the core of our culture, unlike western society where individualism is the essence. this is the essential and most important difference between eastern and western cultures although things may change with time of course, as societies change. professor lamki’s idea of having two medical schools far apart from each other and having students exchanged so that they are not living in the vicinity of their families may be a westernised view and may work in other parts of world, but not in oman. i may refer also to my own personal experience as a medical student. i left home at the age of 17 and went to a medical school away from my home country. my success in secondary education was mainly due to the support and warmth that i had from my family. tertiary education was traumatic, not in the sense of studying and making it academically, but in the sense of having a dramatic change from the protected living in the warmth and backup of the family to a socially exposed environment where i was left on my own, so to speak, to find my own way. it did have its advantages, as i found out later on in my life, but it did not help me personally during my tertiary education. although frompersonal experience, i have no doubt that it reflects on the lives of many other students in this part of the world. in short, having medical students away from their families may not be the answer to palliating stress. on the contrary, probably family is the one significant support that our students need most. omar habbal office of the dean college of medicine & health sciences sultan qaboos university, muscat, oman email: habbal@squ.edu.om references 1. al-lamki l. stress in the medical profession and its roots in medical school. squ med j 2010; 10:156–9. squ med j, december 2010, vol. 10, iss. 3, pp. 409, epub. 14th nov 10 received 5th sep 10 <‡⁄<âöêñqê<g�÷]<ìfl„⁄<ª<íäàfl÷]<º«ñ÷]<v±c<ïö^çc g�÷]<l^è◊“  re: stress in the medical profession and its roots in medical school omar al-habbal letter to editor letter to editor | 409 clinical & basic research squ med j, february 2012, vol. 12, iss. 1, pp. 69-76, epub. 7th feb 12. submitted 6th aug 11 revision req. 10th oct 11, revision recd. 2nd nov 11 accepted 16th nov 11 1department of physical education, college of education, sultan qaboos university, muscat, oman; 2department of food science & nutrition department, sultan qaboos university, muscat, oman; 3department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman. corresponding author e-mail: hakilani@squ.edu.om اجتاه السمنة و زيادة الوزن عند طالب املرحلة اجلامعية بسلطنة ُعمان دراسة مقطعية ها�سم الكيالين، م�سطفى وايل، رندا يو�سف الطالب بني الوزن وزيادة ال�سمنة مع البدين والن�ساط الكلية الدهون كمية و اجل�سم كتلة من�َسب بني العالقة درا�سة الهدف: امللخ�ص: العمانيني. الطريقة: درا�سة مقطعية �سملت 202 طالبا ُعمانيا )101 ذكرا و 101 اأنثى( من جامعة ال�سلطان قابو�س. مت جتميع النتائج جهاز با�ستخدام البدين الن�ساط ومعدل الكلية الدهون وكمية الوزن قيا�س مت كما البحث ا�ستبيان با�ستخدام ال�سخ�سية املقابلة اأثناء الوزن ناق�سو الآتية: املجاميع اإىل اجل�سم كتلة من�سب ح�سب العّينة تق�سيم مت النتائج: الطول. لقيا�س ُمَقيَّ�س �رصيط وا�سُتخدم التانيتا، البحث عينة تق�سيم مت كما .)1.49%( ال�سمنة واأ�سحاب )26.73%( الوزن وزائدو )69.31%( الطبيعي الوزن واأ�سحاب )2.48%( تبعًا لكمية الدهون الكلّية اإىل املجموعة ذي الكمية القليلة )26.73%( و املجموعة ذوي الكمية العالية )%26.73( واملجموعة ذوي الكمية العالية جداً )22.28%(. مل جند عالقة معتّدة اإح�سائيا بني كمية الدهون القليلة ومتو�سط عدد �ساعات ممار�سة الريا�سة الأ�سبوعي )متغري الدللة =0.728 – فرتة الثقة %95 = 0.448 1.119( ومعدل الن�ساط البدين )متغري الدللة =0.728 فرتة الثقة 95% = 0.562-0.944( ، بينما وجدت عالقة معتّدة اإح�سائيا بني كاًل من كمية الدهون العالية والعالية جداً باملقارنة جمموعة الأ�سحاء الطالب فئة بني مرتفعًا فكان الغذائية املعرفة م�ستوى اأما .)1.20 ± 6.73( الأ�سبوعي الريا�سة ممار�سة �ساعات متو�سط كان حيث ذي املرتفع الغذائي املعريف امل�ستوى يكن ومل جداً. والعالية والعالية، القليلة الدهون كمية ذوي الطالب مبجموعة مقارنة الأ�سحاء دللة اإح�سائية معتّدة بالن�سبة ملجموعة الطالب ذوي كمية الدهون القليلة )متغري الدللة =0.986 فرتة الثقة 95% بني 0.958 و 1.015( وهذا ينطبق اأي�سا على اأ�سحاب كمية الدهون العالية والعالية جداً )متغري الدللة = 0.984 – فرتة الثقة 95% بني 0.961 و 1.008(. اخلال�صة: م�ستوى الدهون البدين العايل والعايل جداً كان منت�رصاً بني الطالب ذوي النمط احلياتي الذي يّت�سم بقلة الن�ساط البدين، لذلك نو�سي بتبني برامج لزيادة املعرفة الغذائية والن�ساط البدين ملكافحة م�سكلة زيادة الوزن وال�سمنة بني الطالب يف املرحلة اجلامعية مفتاح الكلمات: ال�سمنة، الن�ساط البدين، منط احلياة. abstract: objectives: body mass index (bmi), total body fat (tbf), and physical activity in relation to obesity and overweight prevalence among omani students were studied. methods: a cross-sectional study of 202 omani students (101 males and 101 females) from sultan qaboos university (squ) was carried out. data were collected by interview using a structured questionnaire. weight, tbf and physical activity score (pas) were measured using tanita scales, and height measured using a standardised measuring tape. results: subjects were classified based on bmi as: underweight (2.48%), normal weight (69.31%), overweight (26.73%) and obese (1.49%). according to tbf, 32.67% of students had low body fat scores (bfs), 26.73% high bfs and 22.28% very high bfs. low bfs was insignificantly less likely with the increase in the mean hours of weekly exercising, (odds ratio [or] = 0.708; 95% confidence interval [ci] = 0.448, 1.119) and the pas (or = 0.728; 95% ci= 0.562, 0.944). among high and very high bfs students, the mean hours of weekly exercising (6.73±1.20) and physical activity scores (7.51±1.67) were higher than those of healthy students. nutrition knowledge was higher among healthy students compared to low bfs, and high and very high bfs subjects. higher nutrition knowledge was associated with a non-significant lower risk of low bfs (or = 0.986; 95% ci = 0.958, 1.015), high and very high bfs (or = 0.984; 95% ci = 0.961, 1.008). conclusion: high and very high bfs were prevalent among subjects with sedentary lifestyles. nutritional and physical activity interventions should be introduced to combat the problem of overweight students. keywords: obesity; physical activity; lifestyle; students; oman. trends of obesity and overweight among college students in oman a cross sectional study *hashim al-kilani,1 mostafa waly,2 randa yousef3 trends of obesity and overweight among college students in oman a cross sectional study 70 | squ medical journal, february 2012, volume 12, issue 1 advances in knowledge 1. information gained through this study on the prevalence of overweight, and obesity among in the student population at sultan qaboos university can help in predicting related diseases in middle and old age. 2. nutrition knowledge was generally very poor (below 60%) among the studied population regardless of body weight or body fat. application to patient care 1. in order to maintain a quality life style, students need to follow a regular physical activity regime and be aware of good nutrition. 2. students with poor malnutrition and a sedentary lifestyle may develop increasingly unhealthy habits which may lead to them having higher disease risk factors. 3. using the information from this study, weight reduction can be achieved through a programme to monitor body composition and fitness levels. 4. the knowledge obtained from this study can encourage young people to initiate an active life style early in their lives thus preventing the onset of hypokinetic diseases. the prevalence of obesity and overweight among adults has drastically increased during the past decade. anthropometric indices such as body mass index (bmi) and total body fat (tbf) analyses are used widely for assessing the physical wellbeing of adults. worldwide, obesity and sedentary lifestyles have been involved in the aetiology of many noncommunicable diseases (ncds) among adults.1-3 recent reports suggested that there was a direct relationship between adolescent fatness and increased risk of cardiovascular diseases.4,5 healthrelated fitness parameters were more dependent on the anthropometrical parameters in obese than in control adolescents.5 cardiovascular disease is the leading cause of mortality among adults, and a systematic analysis of population health data revealed that, among the nine risk factors of heart attacks and strokes, six risk factors are modifiable, while three are non-modifiable risk factors; these include increasing age, male gender and family history of cardiovascular disease (cvd).6,7 the six modifiable risk factors that are the focus of current research for primary prevention are 1) increased blood cholesterol; 2) increased blood pressure (hypertension); 3) cigarette smoking; 4) lack of regular physical exercise; 5) type 2 diabetes, and 6) obesity. according to the world health organization and the american college of sports medicine, the most important risk factors of ncds in arab countries are high blood pressure; high blood cholesterol level; inadequate intake of fruit and vegetables; overweight or obesity; physical inactivity, and smoking. five of these risks are closely related to improper diet and physical inactivity.8-10 primary prevention of ncds among adolescents can be achieved through early screening for associated risk factors, and health education on the various risks of obesity and a sedentary lifestyle. this study was conducted to: 1) determine the body mass index (bmi), tbf and physical activity score (pas) of a sample of college aged students and so assess the prevalence of underweight, overweight and obesity; 2) evaluate the physical activity of all study participants, and 4) determine the relationship between the study participants’ body composition (the relative amounts of various components in the body, such as percentage of body fat) and their general nutritional knowledge. methods a cross-sectional survey was conducted on the sultan qaboos university (squ) campus during the period august 2010 to june 2011. enrollment in the study was on voluntary basis and it included 202 students (101 male and 101 female) from five colleges at squ. the inclusion criteria were to be healthy subjects who were free of any endocrine disorders or any chronic diseases. the research data were collected by means of a questionnaire. the questionnaire form was composed of two sections: general and anthropometric information, and nutrition knowledge questions. ethics committee approval for conducting the study was obtained from office of the advisor for academic affairs at sultan qaboos university. the study questionnaire was designed to collect sociodemographic data and general nutritional knowledge as determined by 10 multiple-choice questions, each with three possible answers. the questionnaire was pre-tested in a pilot study hashim al-kilani, mostafa waly, randa yousef clinical and basic research | 71 on a sample of 20 students to assure its validity, reliability and reproducibility before conducting the study. examples of the questions asked to assess the nutritional knowledge were: a) what type of dietary fibre is helpful in lowering blood cholesterol level? b) what are good sources of vitamin b12? c) what are the nutrients that raise low density lipoprotein (ldl)-cholesterol levels? d) what is the highest source of energy? for all study participants, the study questionnaire was completed during a personal interview with one of the researchers. after questionnaire completion, the weight (recorded to the nearest 0.5 kg); tbf percentage (ranges for women aged 20-39: <20% = underfat; 21-33% = healthy; 34-38% = overfat, and 39-46% = obese; ranges for men aged 20-39: <8% = underfat; 8-20% = healthy; 21-25% = overfat and 26-46% = obese) and pas (on a scale of 1 [resting] to 9 [very active]) of each participant were determined using the tanita body fat scale analyzer 300a (tanita corp., tokyo, japan). height was measured to the nearest 0.5 cm using a standardised tape measure. the bmi for every subject was calculated as weight in kilograms divided by height in metres squared (kg/m2) and categorised as normal (bmi = 18–25) or overweight (bmi >25) [figures 1 and 2]. data analysis was done using the statistical package for social sciences (spss-pc, version 17, ibm, chicago, illinois, usa). the scores on nutritional knowledge were computed as the percentage of correct responses to the set of questions (ranging from 0% to 100%). univariate logistic regression analysis was used to calculate the odds ratio (or) and associated confidence interval (ci). the significance of the results was judged at the 5% level and p = <0.05 was considered significant. results this study included 202 students (101 male and 101 female) from five colleges at sultan qaboos university whose mean age was 21.22±1.37 years. the mean percentage scores of enrolled students in nutrition knowledge were 56.46±13.50; ranging from a minimum of 25% to a maximum of 85%. all students reported exercising weekly; 38.61% reported exercising 4 to 6 hours a week, and 30.69% reported exercising 7 to 9 hours a week. the pas of 44.06% of the students ranged from 7 to 9. based on bmi, more than two thirds of enrolled students were of normal weight (69.31%), 26.73% were overweight while obese students constituted only 1.49% of the sample. in contrast, based on percentage of body fat only, one third was healthy (32.67 %) with normal body fat scores (bfs), while almost half of them had high (26.73%) or very high bfs (22.28%). table 2 portrays the determinants of overweight and obesity. the enrolled students were classified into three categories including normal weight (n = 140), underweight (n = 5), overweight and obese (n = 57). overweight or obesity were encountered among 77.78% of male students and 27.78% of female students. the risk of overweight and obesity was 3.8 times higher among male students (or = 3.843; 95% ci = 1.950, 7.572). the mean age of overweight and obese students (21.07+0.90 years) was slightly lower than that of students with normal weight (21.22+1.79 years). the risk of overweight and obesity was lower with the increase in age yet insignificant (or= 0.885; 95% ci = 0.669, 1.171). there was no relation in respect to excess risk of low, high or very high bfs with the type of college attended. the percentage of students who were figure 1: numbers and percentage of underweight, normal, overweight and obese students based on body mass index classification. figure 2: numbers and percentage of underweight, normal, overweight and obese students based on total body fat classification. trends of obesity and overweight among college students in oman a cross sectional study 72 | squ medical journal, february 2012, volume 12, issue 1 overweight and obese was the lowest (12.96%) among those who scored 70% to 85% on the nutrition knowledge questionnaire. relative to this category of students, the risk of overweight and obesity was higher among those who had lower scores on nutrition knowledge, yet it was not statistically significant. the majority of overweight and obese students was exercising for more than 3 hours a week and had a physical activity scores ranging from 4 to 9. among overweight and obese students, the odds of exercising for 4 to 6 hours a week was 2.939 (95% ci = 1.255, 6.884) and the odds of exercising for 7 to 9 hours a week was 2.788 (95% ci = 1.152, 6.749). among this group, the odds of physical activity scores of 4 to 6 was 4.5 (or = 4.545; 95% ci = 1.431, 14.438) and increased to 5.8 for physical activity scores of 7 to 9 (or = 5.893; 95% ci = 1.934, 17.955). as illustrated in tables 3 and 4, the study subjects were classified as healthy (normal bfs) (n = 66, 32.67%), low bfs (n = 37, 18.32%) and high or very high bfs (n = 99, 49.2%). the majority of female students (90.91%) were healthy. all underweight students were female and 95.96% of male students had either high or very high bfs. the risk of high or very high bfs was 237.5 times among male students relative to female students (or = 237.5; 95% ci= 64.35, 876.51). increase in students’ age was associated with an insignificantly higher risk low bfs (or = 1.198; 95% ci= 0.848, 1.692) as well as high or very high bfs (or = 1.045; 95% ci = 0.791, 1.380). there was no relation in respect to excess risk of low, high or very high bfs with the type of college attended. the mean percentage of score on nutrition knowledge was slightly higher among healthy students (58.33±13.93) compared to those who had low bfs (56.78±13.64) as well as those who had high or very high bfs (55.53±12.88). higher nutritional knowledge was associated with an insignificantly lower risk of having a low bfs (or= 0.986; 95% ci = 0.958, 1.015) as well as having a high or very high bfs (or = 0.984; 95% ci = 0.961, 1.008). the mean hours of weekly exercising were slightly higher among healthy students (3.65±1.19) relative to those with low bfs (3.41±0.67). among the latter, the physical activity score (3.66±1.52) was lower than that of healthy students (4.26±1.87). the likelihood of a low bfs was insignificantly lower with the increase in the mean hours of weekly exercising (or = 0.708; 95% ci = 0.448, 1.119) and the physical activity scores (or = 0.728; 95% ci = 0.562, 0.944). table 1: description of students enrolled in the study characteristic no. % gender male 101 50.00 female 101 50.00 age (years) 18–20 49 24.26 21–23 145 71.78 24–25 8 3.96 squ college: medicine 40 19.80 agriculture 40 19.80 education 44 21.78 engineering 38 18.81 nursing 40 19.80 nutritional knowledge 25–30 21 10.40 40–54 69 34.16 55–69 76 37.62 70–85 36 17.82 exercises (hours/week) 2–3 62 30.69 4–6 78 38.61 7–9 62 30.69 physical activity score 1–3 49 24.26 4–6 64 31.68 7–9 89 44.06 body mass index underweight (<18) 5 2.48 normalweight (18-25) 140 69.31 overweight (>25) 54 26.73 obese (>40) 3 1.49 body fat scores underweight 37 18.32 healthy 66 32.67 overweight 54 26.73 obese 45 22.28 hashim al-kilani, mostafa waly, randa yousef clinical and basic research | 73 among students with a a high or very high bfs, the mean hours of weekly exercising (6.73±1.20) and physical activity scores (7.51±1.67) were higher than those of healthy students. relative to healthy students, students with a high or very high bfs were 4.6 times more likely to exercise (or= 4.641; 95% ci = 3.034, 7.101) and their physical activity scores were 2.3 times higher (or = 2.311; 95% ci = 1.828, 2.922). on the nutritional knowledge scale, the mean scores of female students (57.04±14.031) were slightly higher than those of male students (55.87±12.983) yet not statistically significant (t = 0.614, p = 0.540). on the other hand, the mean physical activity score of male students (7.75±1.081) was significantly higher than that of female students (3.60±1.670) where t = 20.925, p = 0.000. also, male students spent significantly more time exercising weekly (6.84±1.037) than female students (3.36±0.701) where t = 27.986, p = 0.000. discussion in our study, the whole population was similar in their eating/dietary habits as well as in residential status, thus eliminating the dietary factor table 2: determinants of overweight and obesity based on body mass index characteristic normal weight (n = 140) overweight/obese (n = 57) or 95% confidence interval no. % no. % gender male 59 42.14 42 77.78 3.843 1.950, 7.572 female 81 57.86 15 27.78 squ college agriculture 31 22.14 8 14.81 1 medicine 27 19.29 12 22.22 0.680 0.240, 1.929 education 25 17.86 16 29.63 1.172 0.443, 3.096 engineering 28 20.00 10 18.52 1.687 0.662, 4.301 nursing 29 20.71 11 20.37 0.942 0.346, 2.563 nutritional knowledge 25–39 13 9.29 6 11.11 1.912 0.536, 6.819 40–54 48 34.29 20 37.04 1.726 0.650, 4.583 55–69 50 35.71 24 44.44 1.989 0.763, 5184 70–85 29 20.71 7 12.96 1 exercises (hours/week) 2–3 49 35.00 9 16.67 1 4– 6 50 35.71 27 50.00 2.939 1.255, 6.884 7–9 41 29.29 21 38.89 2.788 1.152, 6.749 physical activity score 1–3 40 28.57 4 7.41 1 4–6 44 31.43 20 37.04 4.545 1.431, 14.438 7–9 56 40.00 33 61.11 5.893 1.934, 17.955 age (years) x ± s 21.22+1.79 21.07+0.90 0.885 0.669, 1.171 min–max 18–25 19–23 trends of obesity and overweight among college students in oman a cross sectional study 74 | squ medical journal, february 2012, volume 12, issue 1 contribution in the aetiology of overweight and obesity. nutrition knowledge was generally very poor (below 60%) among the studied population regardless of body weight or body fat. there was a gender variation in pas and number of hours spent in exercising every week; males spent more hours exercising, due to cultural norms such as males having more access to fitness clubs and outdoors physical activities than their female peers. the rate of pas and number of hours of exercising per week were higher in overweight and obese subjects, perhaps because of the need they expressed to lose weight as observed during the interview session. bmi is not the perfect measure for assessing overweight and obesity for all population groups,11 body fat percentage being a better indicator for classifying the prevalence of overweight and obesity.12,13 in our study, the majority of female students were healthy, while male students scored higher in overweight and obesity than female students, which is consistent with recent reports from other arab countries.14,15 in the 2008 yahia, et al. study on lebanese students, the prevalence of overweight and obesity was more common among male students compared to females (37.5% and 12.5% versus 13.6% and 3.2%, respectively).14 the lower rate of obesity among female students might be because of their desire to be slimmer due to their concern with body image during adolescence.16 a recent study conducted in kuwait of 787 students (48% males and 52% females) reported that 354 students were physically inactive, and that obesity was more prevalent in males (13%) than in females (10.5%).17 it seems that in the gulf table 3: determinants of percentage of body fat characteristic healthy (n = 66) underweight (n = 37) or 95% ci overweight/ obese(n = 99) or 95% ci no. % no. % gender male 6 9.09 0 0.00 95 95.96 237.500 64.353, 876.512 female 60 90.91 37 100.00 4 4.04 college agriculture 14 21.21 7 18.92 1 19 19.19 1 medicine 11 16.67 8 21.62 1.455 0.402, 5.260 21 21.21 1.407 0.515, 3.840 education 14 21.21 7 18.92 1 0.277, 3.608 23 23.23 1.211 0.464, 3.156 engineering 12 18.18 8 21.62 1.333 0.373, 4.768 18 18.18 1.105 0.405, 3.020 nursing 15 22.73 7 18.92 0.933 0.261, 3.343 18 18.18 0.884 0.334, 2.339 age (years) x ± s 21.11±1.14 21.38±1.13 1.198 0.848, 1.692 21.16±1.12 1.045 0.791, 1.380 min–max 18–25 20–25 18–24 nutritional knowledge (%) x ± s 58.33±13.93 56.78±13.64 0.986 0.958, 1.015 55.53±12.88 0.984 0.961, 1.008 min–max 30–85 36–81 33–84 exercise (hours/week) x ± s 3.65±1.19 3.41±0.67 0.708 0.448, 1.119 6.73±1.20 4.641 3.034, 7.101 min–max 2-8 2-5 3-9 physical activity score x ± s 4.26±1.87 3.66±1.52 0.728 0.562, 0.944 7.51±1.67 2.311 1.828, 2.922 min–max 1-9 1-8 1-9 legend: or = odds ratio; ci = confidence interval hashim al-kilani, mostafa waly, randa yousef clinical and basic research | 75 countries societal perceptions encourage females to be slimmer. this assumption was supported by the fact that all 5 underweight students were female as compared to male in this studied sample. obviously, pictures of movie stars and models in fashion magazines and mass media have a strong impact on girls’ body shape and image perception.16 in addition, the results of general nutritional information for females support their desire for health and good body composition. anecdotal evidence seems to indicate that female university students in this region see the shape and weight of fashion models as the ideal body shape and figure to attain in order to get married early after graduation, especially in oman. contrary to this finding, a research study in the south of brazil studied a group of 738 public university students (59.2% males) with regards to their physical activity participation and weight gain. they found that female and overweight students were less involved in physical activity, and the prevalence of inadequate physical activity participation was 30.8%.18 cultural differences may affect societal perceptions towards lifestyle and body image and genders on the one hand, while, on the other hand, overweight students are usually less active due to their lower physical fitness. physical inactivity, disordered eating perceptions, and disordered eating behaviour are associated with increased rates of overweight and obesity.19,20 identification of these risk factors in obese youths may increase the understanding of weight loss barriers and facilitate the treatment of adolescent obesity. eating and physical activity behaviours appear to be determined by a complex interplay between motivation and self-regulatory skills as well as the unique social and physical environment of college life.21 moreover, there appear to be gender differences in how these determinants impact behaviour.22 in this study, female responses were different to those of males as shown in table 4. although this study has some limitations and may be subject to bias given the small sample size, its findings are consistent with the general trends of an increasing prevalence of obesity, decreasing engagement in physical activity, the emergence of numerous resultant health risks and the great cost of obesity necessitating heightened efforts toward controlling and reducing this trend. increased physical activity among college students would be helpful in preventing overweight and obesity and their resulting chronic diseases such as type 2 diabetes mellitus, coronary heart disease, stroke, osteoporosis, some forms of cancer, and gall bladder disease. behavioural modifications, dietary intervention studies, and health education to promote the benefits of being physically active should be instituted to increase the practice of sports and other physical activities in order to control and decrease obesity-related morbidity and mortality. conclusion physical inactivity and lack of basic nutritional knowledge about healthy foods and energy dense foods were the main factors associated with overweight and obesity among the study participants. overweight and obesity, if not managed, will be involved in the aetiology of noncommunicable diseases among this high risk group of the omani population. there is a need to adopt nutritional and physical activity awareness strategies and intervention programmes on the squ campus to combat the problem of overweight among its students. table 4: gender differences in nutritional knowledge, physical activity score and exercise knowledge and physical activity male (n = 101) female (n = 101) t-test p value x s x s nutritional knowledge (% of correct answers) 55.87 12.983 57.04 14.031 0.614 0.540 physical activity score (tanita) 7.75 1.081 3.60 1.670 20.925 0.000 physical activity (hours/week) 6.84 1.037 3.36 0.701 27.986 0.000 trends of obesity and overweight among college students in oman a cross sectional study 76 | squ medical journal, february 2012, volume 12, issue 1 c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest and state that no funding was received for this work. a c k n o w l e d g e m e n t the authors are deeply appreciative of the dedicated efforts by ms. obaida al-hashmi for the data collection of this study. references 1. manson je, skerrett pj, greenland p, vanitallie tb. the escalating pandemics of obesity and sedentary lifestyle: a call to action for clinicians. arch intern med 2004; 164:249-58. 2. world health organization. obesity: controlling the global epidemic, 2003, updated 2006. from: https:// apps.who.int/nut/obs.htm. accessed: july 2011. 3. huang kc, lin wy, lee lt, chen cy, lo h, hsia hh, et al. four anthropometric indices and cardiovascular risk factors in taiwan. int j obes relat metab disord 2002; 26:1060-8. 4. eisenmann jc, wickel ee, welk gj, blair sn. relationship between adolescent fitness and fatness and cardiovascular disease risk factors in adulthood: the aerobics center longitudinal study (acls). am heart j 2005; 149:46-53. 5. jürimäe t, jürimäe j. anthropometric and healthrelated fitness characteristics in middle-aged obese women. coll antropol 1998; 22:97-106. 6. lopez a, mathers c, ezzati m, jamison d, murray c. global and regional burden of disease and risk factors, systematic analysis of population health data. lancet 2001; 360:1747-57. 7. mokdad ah, ford es, bowman ba, dietz wh, vinicor f, bales vs, marks js. prevalence of obesity, diabetes, and obesity-related health risk factors, jama 2003; 289:76-9. 8. acsm/aha recommendations: physical activity and public health: updated recommendation for adults from the american college of sports medicine and the american heart association. circulation 2007; 116:1081–93. epub 1 aug 2007. doi:10.1161/circulationaha.107.185649 9. al-hazzaa hm, musaiger ao, arab teens lifestyle study research group. physical activity patterns and eating habits of adolescents living in major arab cities: the arab teens lifestyle study. saudi med j 2010; 31:210-11. 10. musaiger a, al hazzaa a, al-qahtani a, elati j, ramadan j, aboulella n, et al. strategy to combat obesity and to promote physical activity in arab countries. diabetes metab syndr obes 2011; 4:89– 97. 11. kilani h, abu eisheh a, optimum anthropometric criterion for ideal body composition. sultan qaboos univ med j 2010; 10:74–9. 12. kilani h. physiology of physical effort. amman: haneen publisher, 2006. pp. 360–90. 13. osman yf, muscati sk, ganguly ss, khan m, alsharji b. progression of obesity among seeb children in oman. a preliminary study. saudi med j 2004; 25:2038-40. 14. yahia n, achkar a, abdallah a, rizk s. eating habits and obesity among lebanese university students. nutr j 2008; 7:32. 15. musaiger ao, lloyd ol, al neyadi sm, bener ab. lifestyle factors associated with obesity among male university students in the united arab emirates. nutr food sci 2003; 33:145-7. 16. field ae, cheung l, wolf am, herzog db, gortmaker sl, colditz ga. exposure to the mass media and weight concerns among girls. pediatrics 1999; 103:e36. 17. al-isa an, campbell j, desapriya e, wijesinghe n. social and health factors associated with physical activity among kuwaiti college students. j obes 2011; 2011:512363. epub 27 apr 2011. doi: 10.1155/2011/512363. 18. silva da, petroski el. factors associated with the degree of participation in physical activities among students of a public university in the south of brazil. cien saude colet 2011; 16:4087-94. 19. nelson tf, gortmaker sl, subramanian sv, cheung l, wechsler h. disparities in overweight and obesity among us college students. am j health behav 2007; 31:363-73. 20. yang gh, ma jm, liu n, chen ap. study on diet, physical activities and body mass index in chinese population in 2002. zhonghua liu xing bing xue za zhi 2005; 6:246-51. 21. desai mn, miller wc, staples b, bravender t. risk factors associated with overweight and obesity in college students. j am coll health 2008; 57:109-14. 22. lacaille lj, dauner kn, krambeer rj, pedersen j. psychosocial and environmental determinants of eating behaviors, physical activity, and weight change among college students: a qualitative analysis. j am coll health 2011; 59:531-8. departments of 1ear, nose & throat, 2dentistry & ophthalmology and 3medical biotechnology, university hospital of siena, siena, italy *corresponding author e-mail: mailarticoli@libero.it الرتابط بني عسر البلع وسوء اإلطباق يف متالزمة ريت دراسة أولية �شريينا كوكا، ما�شيمو فيفيانو، مي�شيل لوجلي�شي، �شتيفانو باريني، جيوفاين مون�شياتي، اإيالريا اإينو�شنتي باغانيللي، والرت ليفي، كيارا ميزيدميي abstract: objectives: rett syndrome (rs) is a severe neurological developmental disorder characterised by stereotypical hand movements, epileptic seizures, craniofacial dysmorphism and digestive dysfunction. this study aimed to examine the correlation between the severity of malocclusion and dysphagia in patients with rs. methods: this preliminary study was conducted at the ear, nose & throat clinic of the university hospital of siena, siena, italy, from january 2014 to december 2017. a total of 56 patients with rs were examined and grouped according to the severity of dysphagia (absent, mild, moderate or severe) and malocclusion (<2 mm, 2–3 mm, 3–4 mm or >4 mm). results: all of the patients were female and the mean age was 11.3 years. eight (14.3%) patients had mild, 18 (32.1%) had moderate and 30 (53.6%) had severe dysphagia. four (7.1%) patients had <2 mm occlusion, 10 (17.9%) had 2–3 mm occlusion, 26 (46.4%) had 3–4 mm occlusion and 16 (28.6%) had >4 mm occlusion. mild dysphagia was observed in 100% and 40% of patients with <2 and 2–3 mm malocclusion, respectively, while moderate dysphagia was present in 60% and 38.5% of patients with 2–3 and 3–4 mm malocclusion, respectively. severe dysphagia was observed in 28.6% and 87.5% of patients with 3–4 and >4 mm malocclusion, respectively. there was a significant correlation between dysphagia and malocclusion severity (p <0.001). conclusion: a higher degree of malocclusion was associated with more severe dysphagia among a cohort of patients with rs. keywords: x-linked mental retardation; rett syndrome; dysphagia; malocclusion; feeding and eating disorders of childhood. امللخ�ص: الهدف: متالزمة ريت هي ا�شطراب منو ع�شبي حاد يتميز بحركات يد منطية ونوبات من �رصع وت�شوهات القحف والوجه وخلل الطريقة: ريت. متالزمة مر�شى عند البلع وع�رص الإطباق �شوء �شدة بني الإرتباط عالقة فح�س اإىل الدرا�شة هذه تهدف اله�شمي. الأداء دي�شمرب اإىل يناير 2014 من اإيطاليا، �شيينا، �شيينا، جامعة م�شت�شفى يف واحلنجرة والأنف الأذن عيادة يف الأولية الدرا�شة هذه اأجريت 2017. مت فح�س ما جمموعه 56 مري�شا من متالزمة ريت ومت جتميعهم وفقا ل�شدة ع�رص البلع )غري موجود، ب�شيط، متو�شط، اأو �شديد( و �شوء الإطباق )2< ملم، 3-2 ملم، 4-3 ملم و 4> ملم(. النتائج: جميع املر�شى كانوا من الإناث وكان متو�شط العمر 11.3 �شنة. كان ثمانية من )7.1%( اأربعة �شديد. بلع ع�رص لديهم )53.6%( 30 و متو�شط ع�رص لديهم )32.1%( 18 ب�شيط، بع�رص م�شابني املر�شى من )14.3%( املر�شى كان لديهم اإطباق 2> ملم، 10 )%17.9( لديهم اإطباق 3-2 ملم، 26 )%46.4( كان لديهم اإطباق 4-3 ملم و 16 )%28.6( لديهم اإطباق 4> ملم. لوحظ وجود ع�رص البلع الب�شيط يف %100 و %40 من املر�شى الذين يعانون من �شوء الإطباق 2< و 3-2 ملم، على التوايل، يف حني اأن ع�رص البلع املتو�شط كان موجود يف %60 و %38.5 من املر�شى الذين يعانون من 3-2 و 4-3 ملم �شوء الإطباق، على التوايل. ولوحظ ع�رص البلع ال�شديد يف %28.6 و %87.5 من املر�شى مع 4-3 و 4> ملم �شوء الإطباق، على التوايل. كانت هناك عالقة اإرتباط ملحوظة بني ع�رص البلع و�شدة �شوء الإطباق )p >0.001(. اخلال�صة: درجة اأعلى من �شوء الإطباق كانت مرتابطة مع ع�رص البلع الأكرث �شدة بني عينة املر�شى امل�شابني مبتالزمة ريت. الكلمات املفتاحية: التخلف العقلي املرتبط بـاجلن�س؛ متالزمة ريت؛ ع�رص البلع؛ �شوء الإطباق؛ التغذية وا�شطراب الأكل عند الأطفال. correlation between dysphagia and malocclusion in rett syndrome a preliminary study serena cocca,1 massimo viviano,2 michele loglisci,1 stefano parrini,3 giovanni monciatti,1 ilaria i. paganelli,1 walter livi,1 *chiara mezzedimi1 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e489–493, epub. 28 mar 19 submitted 20 may 18 revision req. 26 jun 18; revision recd. 7 aug 18 accepted 30 aug 18 advances in knowledge the findings of this study indicate that a high degree of malocclusion is associated with more severe dysphagia in patients with rett syndrome. application to patient care correcting malocclusion may improve the oral preparatory phase of swallowing, thereby enabling patients with feeding and eating disorders to have a natural diet. this reduces the risk of ab ingestis pneumonia and offers a recourse to percutaneous endoscopic gastrostomy, thus improving the patient’s quality of life. doi: 10.18295/squmj.2018.18.04.010 correlation between dysphagia and malocclusion in rett syndrome a preliminary study e490 | squ medical journal, november 2018, volume 18, issue 4 rett syndrome (rs) is a rare neurological disorder which occurs in approximately one in 10,000 live births and develops almost exclusively among females due to an x-linked dominant mutation.1,2 first described by andreas rett in 1966, rs is the second most common cause of mental retard ation in females after down’s syndrome.1,3 classical rs, the most common form, is characterised by a mutation in the methyl-cpg-binding protein 2 gene.4 the diagnosis is mostly based on clinical characteristics, clinical course and genetic/molecular testing.1,2 in addition, other atyp ical forms of rs may present with different symptoms and/or mutations.4,5 the disease is characterised by abnormal hand movements, epileptic seizures, craniofacial dysmorphism and digestive system problems.1 affected patients appear to develop normally until two years of age, at which point they begin to manifest motor and speech disabilities. in addition, the syndrome can present with autism, ataxia and intermittent hypoventilation.1 the condition subsequently stabilises and patients can live to adulthood. hagberg defined four stages of classical rs: (1) early-onset stagnation marked by delayed developmental milestones; (2) developmental regression with a loss of acquired skills/communication and signs of mental retardation; (3) apparent walking difficulties and slow neuromotor regression; and (4) late motor deterioration resulting in complete wheelchair dependency, weight loss and skeletal deformities.6 patients with rs often have feeding and digestive problems aggravated by poor bolus preparation/propulsion, respiratory anomalies, ineffective tongue move ments, incomplete chewing and head and neck dysmor phism (e.g. advancement of the maxilla, neuromuscular insufficiency and back deformities).6–12 dental anomalies are also common, such as open bite due to the absence of vertical overlap/contact between the anterior maxillary and mandibular teeth and malocclusion resulting from unfavourable growth patterns and incorrect mandibular positioning associated with exacerbated open-mouth breathing and tongue thrusting habits [figure 1].7,13,14 bruxism is also a typical feature, although it is not pathog nomonic. the current study aimed to evaluate oral and dental characteristics in a series of patients with rs in order to determine a correlation between the severity of malocclusion and dysphagia. methods this preliminary study was conducted at the ear, nose & throat (ent) clinic of the university hospital of siena, siena, italy, from january 2014 to december 2017. a total of 56 patients with classical rs admitted to the ent clinic were randomly enrolled in the study. various clinical examinations were conducted during hospitalisation, including history-taking, body weight and height measurements as well as laryngological, ent, speech and dental evaluations. patients were also monitored during mealtimes and underwent evaluations by a speech therapist. in addition, detailed feeding histories were taken from parents/caregivers during interviews. the same speech therapist evaluated all of the patients so as to ensure reliable results. the perioral tissue, oral mucosa and tongue of each patient was assessed by a dentist. as part of the laryngological evaluation, the patients underwent a partial fiberoptic endoscopic evaluation of the pharynx and larynx during and after the act of swallowing for the detection of uncontrolled bolus, piecemeal deglutition, premature loss of liquid, vallecular and pyriform sinus residue, aspiration and absence of cough reflex. however, due to poor patient compliance, only a partial endoscopic assessment of swallowing could be performed to establish the severity of dysphagia. the endoscopic evaluation was performed without anaes thesia while the patient was at rest after being fed 2–3 spoons of a semi-liquid bolus of water gel. all patients were classified according to dysphagia severity. mild dysphagia was defined as slight coughing while eating, oral leakage/drooling, no choking, no vocal fold alterations, good laryngeal sensitivity and minimal stagnation of secretions in the pyriform sinuses.7,13 mode rate dysphagia was indicated by delayed pharyngeal clearance of vallecular and pyriform sinus secretions, abundant coughing after eating, slow laryngeal sphincter function and a high risk of aspiration. finally, severe dysphagia was defined as an absence of coughing, ineffective pharyngeal clearance, permanent post-swallow residue, premature loss of liquid or uncontrolled bolus, poor deglutitive airway protection and a very high risk of aspiration.7,13 patients with normal swallowing were deemed not to have any dysphagia. figure 1: photographs of a 14-year-old girl with rett syndrome showing typical dental features of (a) maxillary advancement and (b) maxillary protrusion, resulting in (c) misalignment of the maxillary and mandibular teeth (i.e. malocclusion). serena cocca, massimo viviano, michele loglisci, stefano parrini, giovanni monciatti, ilaria i. paganelli, walter livi and chiara mezzedimi clinical and basic research | e491 occlusion was categorised using angle’s classification according to the relationship between the mesiobuccal cusp of the maxillary first molar and the mesio buccal groove of the mandibular first molar.15 class i was defined as the alignment of the mesiobuccal cusp of the maxillary first molar with the mesiobuccal groove of the mandibular first molar (i.e. neutral or normal occlusion). class ii was indicated in cases wherein the mesiobuccal groove of the lower first molar aligned posteriorly to the mesiobuccal cusp of the maxillary first molar (i.e. distocclusion).15 depending on the position of the anterior teeth, patients with class ii occlusion were subdivided into either division one (proclined upper incisors) or two (lingually inclined upper central incisors possibly overlapped by the upper later incisors). for class iii occlusion, the mesiobuccal groove of the mandibular first molar aligned anteriorly to the mesio buccal cusp of the maxillary first molar (i.e. mesiocclusion).15 malocclusion severity was assessed in terms of the distance between the mesiobuccal cusp of the maxillary first molar and mesiobuccal groove of the mandibular first molar in the sagittal plane (<2 mm, 2–3 mm, 3–4 mm or >4 mm). data were analysed by linear regression using graph pad software (graphpad software inc., la jolla, california, usa). a p value of <0.001 was considered stat istically significant. this study was approved by the local ethics committee of the tuscany region area vasta sud est (#22.1.14). both parents or legal guardians of each patient provided informed written consent for their participation in the study. results all 56 patients were female. the mean age was 11.3 years (range: 8–17 years old) and the patients resided in the southern (59%), central (22%) and northern (19%) regions of italy. all cases showed an early arrest in growth associated with body weight below the lower limit of their peers (<28 and <36 kg for 8–10 and 11–17-year-olds, respectively). in total, 39 (69.6%) patients were taking anti-epileptic medications. all of the patients had some form of dysphagia, with eight (14.3%) patients with mild, 18 (32.1%) with moderate and 30 (53.6%) with severe dysphagia. reduced lip consistency and uncontrolled tongue movements hindered chewing and bolus preparation, making feeding slow. swallowing dysfunction and upper gastrointestinal motility disorders were associated with other anomalies, including gastroesophageal reflux disease (60.7%) and a history of recurrent bronchitis (85.7%), aspiration (14.3%) and ab ingestis pneumonia requiring percutaneous endoscopic gastrostomy (peg; 3.6%). open bite was identified in 50 (89.3%) patients [table 1]. all of the patients had angle’s class ii malocclusion. four (7.1%) patients had <2 mm malocclusion, 10 (17.9%) had 2–3 mm malocclusion, 26 (46.4%) had 3–4 mm malocclusion and 16 (28.6%) had >4 mm malocclusion. overall, all patients with <2 mm malocclusion and 40% of patients with 2–3 mm malocclusion had mild dysphagia, while 60% and 38.5% of patients with 2–3 and 3–4 mm malocclusion, respectively, had moderate dysphagia. severe dysphagia was observed table 1: oral and dental characteristics of patients with rett syndrome admitted to the university hospital of siena, siena, italy (n = 56) characteristic n (%) open bite 50 (89.3) open-mouth breathing 46 (82.1) drooling 52 (92.9) reduced lip continence 56 (100) bruxism 48 (85.7) involuntary tongue movements 46 (82.1) poor lateralisation of the tongue 52 (92.9) table 2: severity of malocclusion and dysphagia among patients with rett syndrome admitted to the university hospital of siena, siena, italy (n = 56) dysphagia severity malocclusion severity*, n (%) <2 mm (n = 4) 2–3 mm (n = 10) 3–4 mm (n = 26) >4 mm (n = 16) mild 4 (100) 4 (40) 0 (0) 0 (0) moderate 0 (0) 6 (60) 10 (38.5) 2 (12.5) severe 0 (0) 0 (0) 16 (28.6) 14 (87.5) *defined as the distance between the mesiobuccal cusp of the maxillary first molar and mesiobuccal groove of the mandibular first molar in the sagittal plane. figure 2: severity of malocclusion and dysphagia among patients with rett syndrome admitted to the university hospital of siena, siena, italy (n = 56). *defined as the distance between the mesiobuccal cusp of the maxillary first molar and mesiobuccal groove of the mandibular first molar in the sagittal plane. correlation between dysphagia and malocclusion in rett syndrome a preliminary study e492 | squ medical journal, november 2018, volume 18, issue 4 in 28.6% and 87.5% of patients with 3–4 and >4 mm malocclusion, respectively [table 2 and figure 2]. acc ording to a linear regression analysis, there was a statistically significant correlation between dysphagia and malocclusion severity (p <0.001) [figure 3]. discussion swallowing is a complex biological process, with the oral preparatory and propulsive stages closely linked to events in the pharyngeal phase.7,13,16–18 the oral phase begins when the tongue pushes the bolus up and posteriorly towards the oropharynx. the propulsive action of the tongue is the result of the centr ipetal movement of the central groove of the tongue with the tip pressed against the hard palate and the sides of the tongue contacting the oral phase of the upper dental arch. the process lasts less than a second and involves closing the lips to prevent the bolus falling laterally. the jaw is normally kept closed by the action of the temporal, masseter, internal pterygoid and external pterygoid muscles. since the tongues of rs patients tend to move repetitively up and down without creating enough comp ression against the palate to push the bolus into the pharynx, the palate has a poor glossopharyngeal seal resulting in the escape of liquids from the mouth into the pharynx (i.e. pharyngeal spillover and the premature fall of bolus). an incorrect tongue position and irregular tongue movements inevitably aggravate maxillary protrusion. advancement of the maxilla makes it difficult to move the tongue towards the oropharynx, resulting in the lateral leakage of food. this condition is often aggravated by lip incontinence due to hypotonia of the orbicularis muscles. all patients with rs have structural and functional abnormalities that impair the oral phase, such as reduced lip continence, drooling, open-mouth breathing, involuntary tongue movements, open bite, growth defects of the maxilla, incorrect mandibular positioning and neurogenic scoliosis with double curve deformation.6–9 molina-garcía et al. found that anterior open bite, ogival palate, bruxism, open-mouth breathing and tongue thrusting were common in patients with rs.19 fuertes-gonzález et al. reported diurnal bruxism to be the most frequent oral habit of patients with rs, followed by stereotypical tongue movements and open mouth breathing.14 despite a decreased incidence of caries compared to the control group, rs patients also had greater periodontal alterations and an increased prevalence of drooling, dental wear, high-arched palates and anterior open bite.14 in addition, rs patients often demonstrate digit sucking and orofacial motor functional disorders; in the early stages of the disease, these charact eristics can give rise to malocclusions such as anterior open bite and a high-arched palate.20 to the best of the authors’ knowledge, this prelim inary study is the first to show a significant association between malocclusion and dysphagia severity in patients with rs. although there are many causes of dysphagia in patients with rs, malocclusion is an obvious imped iment to the oral phase of physiological swallowing. in the current study, a higher degree of malocclusion was found to be associated with more severe dysphagia, with an increase in the degree of misalignment of the maxillary and mandibular teeth corresponding to a more severe degree of dysphagia. presumably, correcting the malocclusion could potentially reduce the severity of dysphagia and promote a normal diet, delaying the risk of ab ingestis pneumonia and peg, thus improving the patient’s quality of life. unfortunately, initiating such corrective measures for patients with rs is complex and often logistically difficult due to postural requirements and lack of patient cooperation during radiological procedures. should future techniques allow x-rays to be taken in different positions, it might be possible to undertake appropriate interventions to correct malocclusion and tongue position in patients with rs. however, it is important to reiterate that malocclusion is only one possible cause of dysphagia in rs; therefore, the correction of malocclusion alone may not completely eliminate dysphagia in rs patients. it is therefore recommended that further research be undertaken to evaluate malocclusion in a larger sample of rs patients. conclusion this preliminary study showed a significant correlation between malocclusion and dysphagia in patients with rs, with a higher degree of malocclusion associated with figure 3: chart showing a statistically significant correlation (p <0.001) between dysphagia and malocclusion severity among patients with rett syndrome admitted to the university hospital of siena, siena, italy (n = 56). serena cocca, massimo viviano, michele loglisci, stefano parrini, giovanni monciatti, ilaria i. paganelli, walter livi and chiara mezzedimi clinical and basic research | e493 more severe dysphagia. based on these findings, it can be postulated that correction of the malocclusion would result in improvements in the oral preparatory phase of swallowing and, therefore, in dysphagia severity. this would promote a normal diet, delaying the risk of ab ingestis pneumonia, ultimately improving the patient’s quality of life. however, it is important to note that malocclusion is only one possible cause of dysphagia in rs and therefore such corrective measures may prove insufficient to treat affected patients. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. moser sj, weber p, lütschg j. rett syndrome: clinical and electrophysiologic aspects. pediatr neurol 2007; 36:95–100. https://doi.org/10.1016/j.pediatrneurol.2006.10.003. 2. laurvick cl, de klerk n, bower c, christodoulou j, ravine d, ellaway c, et al. rett syndrome in australia: a review of the epidemiology. j pediatr 2006; 148:347–52. https://doi.org/10. 1016/j.jpeds.2005.10.037. 3. rett a. [on a unusual brain atrophy syndrome in hyperammonemia in childhood]. wien med wochenschr 1966; 116:723–6. 4. ip jpk, mellios n, sur m. rett syndrome: insights into genetic, molecular and circuit mechanisms. nat rev neurosci 2018; 19:368–82. https://doi.org/10.1038/s41583-018-0006-3. 5. neul jl, kaufmann we, glaze dg, christodoulou j, clarke aj, bahi-buisson n, et al. rett syndrome: revised diagnostic criteria and nomenclature. ann neurol 2010; 68:944–50. https://doi.org/ 10.1002/ana.22124. 6. hagberg b. clinical manifestations and stages of rett syndrome. ment retard dev disabil res rev 2002; 8:61–5. https://doi.org/ 10.1002/mrdd.10020. 7. mezzedimi c, livi w, de felice c, cocca s. dysphagia in rett syndrome: a descriptive study. ann otol rhinol laryngol 2017; 126:640–5. https://doi.org/10.1177/0003489417723033. 8. viviano m, hayek j, lorenzini g, viviano f, vinci d, batoni l, et al. odontosomatologic anomalies associated with rett syndrome in 216 patients. int j clin dent 2012; 5:357–61. 9. peak j, eveson jw, scully c. oral manifestation of rett’s syndrome. br dent j 1992; 172:248–9. https://doi.org/10.1038/sj.bd j.4807837. 10. hennessy mj, haas rh. the orthopedic management of rett syndrome. j child neurol 1988; 3:s43–7. https://doi.org/10.117 7/0883073888003001s09. 11. lotan m, merrick j, carmeli e. managing scoliosis in a young child with rett syndrome: a case study. scientificworldjournal 2005; 5:264–73. https://doi.org/10.1100/tsw.2005.33. 12. reilly s, cass h. growth and nutrition in rett syndrome. disabil rehabil 2001; 23:118–28. https://doi.org/10.1080/0963 8280150504199. 13. schindler o, ruoppolo g, schindler a. [swallowing], 2nd ed. torino, italy: omega edizioni, 2011. pp. 349–75. 14. fuertes-gonzález mc, silvestre fj. oral health in a group of patients with rett syndrome in the regions of valencia and murcia (spain): a case-control study. med oral patol oral circ bucal 2014; 19:e598–604. https://doi.org/10.4317/medor al.19743. 15. angle eh. treatment of malocclusion of the teeth and fractures of the maxillae: angle’s system, 6th ed. philadelphia, pennsylvania, usa: andesite press, 1900. pp. 248–56. 16. baikie g, ravikumara m, downs j, naseem n, wong k, percy a, et al. gastrointestinal dysmotility in rett syndrome. j pediatr gastroenterol nutr 2014; 58:237–44. https://doi.org/10.1097/ mpg.0000000000000200. 17. lotan m, zysman l. the digestive system and nutritional consi derations for individuals with rett syndrome. scientificworldjournal 2006; 6:1737–49. https://doi.org/10.1100/tsw.2006.264. 18. aldallal sm, alkathemi mm, haj wh, aldallal nm. dental health in sickle cell disease. j med ther 2017; 1:1–4. https://doi. org/10.15761/jmt.1000105. 19. molina-garcía a, castellanos-cosano l, machuca-portillo g, posada-de la paz m. impact of rare diseases in oral health. med oral patol oral circ bucal 2016; 21:e587–94. https://doi. org/10.4317/medoral.20972. 20. fuertes-gonzález mc, silvestre fj, almerich-silla jm. oral findings in rett syndrome: a systematic review of the dental literature. med oral patol oral circ bucal 2011; 16:e37–41. https://doi.org/10.4317/medoral.16.e37. division of endocrinology, david geffen school of medicine, university of california los angeles, los angeles, california, usa *corresponding author’s e-mail: runyu@mednet.ucla.edu جهام عظمي يورميي جني �شيم و رن يو uremic leontiasis ossea jien shim and *run yu a 23-year-old female patient presented to the ronald reagan university of california los angeles medical center, los angeles, california, in 2016 with a two-month history of progressive swelling and pain of the upper and lower jaws and palate, drooling, lisping and difficulty chewing and swallowing. she had undergone a bilateral nephrectomy due to a bilateral wilms’ tumour 22 years prior at 14 months of age. she then received haemodialysis until she was six years old, at which time she received a kidney transplant. however, the transplanted kidney failed due to medication noncompliance and she subsequently resumed haemodialysis at the age of 16 years. she had secondary hyperparathyroidism and was noncompliant with medications to control the disorder. she also had congestive heart failure and cryptogenic organising pneumonia requiring home oxygen therapy. she had no family history of hyperparathyroidism. a physical examination revealed maxillary and mandibular swelling, tenderness and wide interdental spacing. before haemodialysis, the patient’s parathyroid hormone level was >1,700 pg/ml (normal range: 11–51 pg/ml), total calcium level was 10.3 mg/dl (normal range: 8.6–10.3 mg/dl), ionised calcium level was 1.09 mmol/l (normal range: 1.09–1.29 mmol/l), phosphorus level was 7.3 mg/dl (normal range: interesting medical image sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e243–244, epub. 9 sep 18 submitted 31 jan 18 revision req. 7 mar 18; revision recd. 11 mar 18 accepted 25 mar 18 figure 1: three-dimensional reconstructions of the (a) facial features and (b) bones of a 23-year-old female with uremic leontiasis ossea based on non-contrast sinus computed tomography of the (c) mandible and (d) maxilla. doi: 10.18295/squmj.2018.18.02.023 uremic leontiasis ossea e244 | squ medical journal, may 2018, volume 18, issue 2 the term ulo is derived from the appearance of the facial deformity due to bony overgrowth around the oral cavity which resembles the face of a lion. radiographically, ulo manifests as hypertrophy and hyperostosis of the facial bones and calvaria, especially the maxilla and mandible, and diffuse mixed sclerotic and lytic changes best illustrated by non-contrast ct.2–5 the reason as to why the facial bones and calvaria are selectively affected in ulo cases is not clear. in the current case, the affected patient had all of the typical clinical, laboratory and radiographical features of ulo. if left untreated, patients with ulo may develop severe disfigurement, dysphagia, speech impairment, respiratory distress and blindness.2–4 the management of ulo cases should focus on controlling secondary or tertiary hyperparathyroidism, either with medication or surgically with a parathyroidectomy.3 unfortunately, surgical resection was not feasible in the current case and the patient did not adhere to prescribed medical therapy. as such, there was no evidence of clinical improvement at a one-month follow-up appointment. references 1. zangeneh f, clarke bl, hurley dl, watts nb, miller pd. chronic kidney disease-mineral and bone disorders (ckdmbds): what the endocrinologist needs to know. endocr pract 2014; 20:500–16. doi: 10.4158/ep12291.ra. 2. lee vs, webb ms jr, martinez s, mckay cp, leight gs jr. uremic leontiasis ossea: “bighead” disease in humans? radiologic, clinical, and pathologic features. radiology 1996; 199:233–40. doi: 10.1148/radiology.199.1.8633151. 3. bakathir aa, margasahayam mv, al-ismaily mi. maxillary hyperplasia and hyperostosis cranialis: a rare manifestation of renal osteodystrophy in a patient with hyperparathyroidism secondary to chronic renal failure. saudi med j 2008; 29:1815–18. 4. stoopler et, aloyouny a, greenberg ms. uremic leontiasis ossea. am j med sci 2017; 354:527. doi: 10.1016/j.amjms.2017. 07.004. 5. abdel razek aa. computed tomography and magnetic resonance imaging of maxillofacial lesions in renal osteodystrophy. j craniofac surg 2014; 25:1354–7. doi: 10.1097/scs.00 00000000000819. 2.3–4.4 mg/dl), 25-hydroxyvitamin d level was 16 ng/ml (normal range: 20–50 ng/ml) and serum alkaline phosphatase level was 1,610 u/l (normal range: 37–113 u/l). three-dimensional reconstructions and axial non-contrast sinus computed tomography (ct) scans showed deformities of the mouth and nose, gross expansion of the mandible, maxilla and calvaria, overbite and overjet, diffuse mixed sclerotic and lytic changes to all visualised osseous structures and regions of focal lytic expansion in the mandible and maxilla [figure 1]. subsequently, the patient was diagnosed with uremic leontiasis ossea (ulo). due to her significant cardiopulmonary comorbidities and high perioperative risk, a parathyroidectomy was not possible. the patient was advised to resume medical therapy with cinacalcet, calcitriol and sevelamer. however, one month later, the patient was found to be only intermittently compliant with these medications and did not exhibit significant clinical improvement. comment chronic kidney disease-associated mineral and bone disorders (ckd-mbds), previously termed renal osteo dystrophy, include hormonal abnormalities such as secondary hyperparathyroidism, deranged bone turnover and mineralisation and extraskeletal calcification.1 also known as maxillary hyperplasia and hyperostosis cranialis, ulo is the rarest and most severe form of ckd-mbds; it usually occurs in young adults with longstanding chronic renal failure and poorly controlled secondary or tertiary hyperparathyroidism, as in the current case.2–4 while the specific pathogenesis of ulo is unknown, deranged bone turnover and mineralisation caused by poorly controlled secondary hyperparathyroidism is likely a key feature.2 https://doi.org/10.4158/ep12291.ra https://doi.org/10.1148/radiology.199.1.8633151 https://doi.org/10.1016/j.amjms.2017.07.004 https://doi.org/10.1016/j.amjms.2017.07.004 https://doi.org/10.1097/scs.0000000000000819 https://doi.org/10.1097/scs.0000000000000819 the backbone of all scientific endeavours is either to employ a ‘bottom-up’ or a ‘top-down’ approach to understand our natural world. the bottom-up approach is basically reductionist in outlook. the obvious candidates in this category include genomics and other molecular sciences. on the other hand, the top-down approach perceives content from the whole rather than from individual parts. in psychology, for example, topdown thinking holds the view that our habits are shaped by forces of socialisation and environmental factors. bottom-up and top-down approaches represent diametrically opposing paradigms in the history of sciences; however, the wind of change is imminent. as if heeding the poem by t.s. eliot, “we shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time”, the bottomup and top-down approaches are on the verge of reconciliation. in fact, with the birth of genetic counselling, it is becoming evident that these two seemingly opposing approaches, divided for so long by ‘isms’ and ‘schisms’, are in fact two sides of the same coin. forget eugenics where social control was meant to reduce the number of ‘defective people’ in order to achieve the goals of vanity. the marketeering practice of using genetic information to discriminate against some people seeking medical insurance and employment is something that has little affinity with ممارسة اإلرشاد الوراثي مفاهيم ومهارات حديثة املحررون: بوين لوروي ، باتري�شيا ماكارثي فيت�س ، ديانا بارتيلز . مراجعة �شمري العدوي book review genetic counseling practice advanced concepts and skills authors: bonnie s. leroy, patricia mccarthy veach, dianne m. bartels publisher: wiley-blackwell, 2010 isbn: 978-0-470-18355-7 orders: www.wiley.com/wiley-blackwell squ med j, august 2010, vol. 10, iss. 2, pp. , epub. submitted genetic counseling practice advanced concepts and skills 196 | squ medical journal, august 2010, volume 10, issue 2 the modern approach to genetic counselling. the new kid on the block mandates itself to dispense a dose of humanity. the central tenet of genetic counselling is to draw on evidence-based options in order to mitigate some of the vagaries of inherited diseases. the field prides itself on being in the vanguard in dispensing health education for people who have potential, or already evident, inherited disorders. this field has wide scope, including breaking the news to those who have been diagnosed with inherited diseases, providing family planning advice or charting out a meaningful existence for those who are prone to inherited diseases. the inner workings of genetic counselling have received little attention despite its indispensable role in an age where the pendulum of science has swung towards genetic determinism. despite its short but rapid growth, this field has yet to have its own ‘classic read’. genetic counseling practice: advanced concepts and skills fulfils this role. the volume represents the synthesis of current knowledge and practice in the field of genetics as it applies to human diseases and its consequences in the social context. editors bonnie s. leroy, patricia mccarthy veach and dianne m. bartels have invited a group of genetic counselor writers to synthesize fresh approaches to genetic counselling. the resultant volume has 15 chapters with 18 authors, mainly from north america and minnesota in particular. the contributors have expertise in various fields including biology, genetics, nursing, psychology, public health and social work. inclusion of perspectives from diverse disciplines gives testimony to the fact that genomic medicine has many repercussions and so requires a multidisciplinary effort. in many publications with multiple authors, repetitions are often inevitable. this volume has managed to avoid such pitfalls. proffered as an introduction to the field, the volume indeed lives up to expectations. the authors have laboured to include practical activities or scenarios to further consolidate the application of the concepts presented. the volume is not written on a ‘mickey mouse’ simplistic level, but the concepts presented can be grasped by anyone curious about the subject. there are many references that could be used for situations outside the industrialised countries of the west. two chapters entitled ‘client cultural and individual characteristics’ and ‘honoring diversity: cultural competence in genetic counseling' bear witness to cross-cultural coverage. such inclusions give strength to this book. in developing countries like oman, genetic disorders are increasingly being recognised. one hypothesis is that such conditions are likely to be rife because of the cultural practice of consanguinity. if indeed culture contributes to the magnitude of inherited disorders, health education would be the best method to mitigate a rising tide of genetic disorders, since gene therapy has yet to find entrance into widespread clinical application. in addition to being inescapably social, genetic counselling generally embraces a pluralistic approach. the volume has a chapter entitled ‘developmentally based approaches for counseling children and adolescents’ and ‘genetic counseling for women with intellectual disabilities’. these chapters represent another interesting facet of the work in accommodating even those who are often marginalised by society. as should be expected, genetic counsellors are the sole ‘breakers of bad news’ and must daily confront stark ethical questions. the coverage in this volume also leaves room for genetic counsellors to introspect. the chapters entitled ‘counter-transference: making the unconscious conscious’ and ‘genetic counselors: caring mindfully for ourselves’ help inoculate genetic counsellors against events that could lead to occupational burnout. additional tips for professional development are featured in a chapter entitled ‘professional development: reflective genetic counseling practice’ and ‘mobilizing genetic counselor leadership skills’ genetic counselors are purveyors of technical services relevant to genomic medicine. the purveyors of genomic medicine, on one hand, and the victims of inherited disease, on the other hand, are required to form a dyadic relationship. such a relationship requires a genetic counsellor to be well versed in interpersonal and communication skills something akin to the skills needed in doctor-patient relationships in general medical settings. this book has vividly and succinctly captured such themes. however, on the less positive side, in tackling such bonnie s. leroy, patricia mccarthy veach, and dianne m. bartels book review | 197 a complex issue, the authors of this volume have laboriously tried to revamp psychological concepts that are largely considered a relic of the past in modern mainstream psychological literature. for example, “grief work” was viewed as inevitable for people who are digesting bad news; however, although grief has been shown to be a universal phenomenon, it is often expressed in a sociocultural context. the concept of “grief work”, as tackled on this volume, appears to rely on the predominantly western-centric perspective on human nature which has been largely discredited in the field of thanatology. similarly, statements such as ‘making the unconscious conscious’ make the reader wonder whether freud’s vienna is being resurrected in minnesota. what has been disappointedly overlooked in this volume is the acknowledgment that issues pertinent to genetic counselling are inescapably social in nature. rather consider genetic counsellors as a modern day ‘priests of the psyche’, it would be more appropriate to assign them the role of ‘anthrotherapists’. from this perspective, genetic counsellors could be correctly seen as purveyors of technical expertise that requiring them to liaise between with social structures and genomic medicine. in a nutshell, their role would be to mediate between the bottom-up knowledge of genomic medicine and the top-down social forces that foster perceptions and attitudes towards and knowledge of inherited diseases. who should read this volume? as the mantra of the time is genetic determinism, literally everyone could benefit from this book. for genetic counsellors, this volume would be a valuable textbook for their shelf. for all other caregivers, this volume will open up new horizons in the appreciation of the much heralded communication skills and essential dynamism relevant for the doctor-patient relationship. it would be heartening if the publisher of this volume soon contemplated a second edition. maybe this time inclusions should not just be limited to minnesota. r e v i e w e r samir al-adawi department of behavioural medicine, college of medicine & health sciences, s ultan qaboos university, muscat, oman email: adawi@squ.edu.om 1department of general surgery, faculty of medicine, alexandria university, alexandria, egypt; 2cheeloo college of medicine, shandong university, jinan, shandong, china; 3department of surgical oncology, oncology center, king faisal specialist hospital & research center, riyadh, saudi arabia *corresponding author’s e-mail: aazzam70@yahoo.com إزالة أنبوب أنفي-معدي مشتبك مع مفاغرة املريء من نوع roux-en-y عن طريق اخلطأ بعد استئصال كلي ملعدة مصابة بالسرطان تقرير حالة واستعراض املنشورات السابقة اأمين زكي عزام، كرمي اأمين عزام، طارق اأمني abstract: nasogastric tubes (ngts) are important for feeding, stenting and decompression after gastrointestinal surgeries, particularly in the upper gastrointestinal tract. resistance in the removal of a ngt is a rare surgical complication and may be due to a knot in the tube or a stitch anchoring the tube to an anastomosis. we report a 41-year-old male patient who was admitted to the king faisal specialist hospital & research center, riyadh, saudi arabia, in 2015 with stomach cancer. he underwent a radical total gastrectomy with a roux-en-y oesopha gojejunostomy. one week after the surgery, removal of the ngt was attempted; however, this was very difficult and the proximal end of the tube was cut off as a temporary measure. six weeks later, an upper gastrointestinal tract endoscopy revealed that the distal end of the ngt had been accidentally stitched to the roux-en-y oesophagojejunostomy. the stitch was removed and the rest of the ngt was successfully extracted using a snare. keywords: enteral nutrition; gastrointestinal intubation; roux-en-y anastomosis; gastrectomy; case report; saudi arabia. امللخ�ص: اأنابيب املعدة االأنفية مهمة للتغذية وتفتيح اأو اإزالة ال�سغط على املنطقة اجلراحية يف قناة اله�سم، باالأخ�ض يف اجلزء العلوي للجهاز اله�سمي، لكن مقاومة هذه االأنابيب لالإزالة تعترب من امل�ساعفات اجلراحية النادرة احلدوث التي قد يكون املت�سبب فيها هو عقدة يف االأنبوب اأو غرزة ت�سبك االأنبوب باملفاغرة، نعر�ض هنا حالة عن مري�ض يبلغ من العمر 41 عامًا مت اإدخاله اإىل م�ست�سفى امللك في�سل التخ�س�سي ومركز االأبحاث يف الريا�ض باململكة العربية ال�سعودية يف عام 2015 وكان م�سابًا ب�رصطان املعدة، خ�سع لعملية ا�ستئ�سال املعدة الكلي ومفاغرة املريء مع ال�سائم بطريقة roux-en-y، بعد اأ�سبوع واحد من اجلراحة، مت حماولة اإزالة اأنبوب املعدة االأنفي، مع اله�سمي للجهاز منظارعلوي عمل مت اأ�سابيع �ستة بعد اأنه اإال موؤقت، كتدبري جراحيًا االأنبوب طرف نهاية قطع قرر ال�سعوبة، من �َسْيٍء فاكت�سف اأن طرف االأنبوب البعيد قد مت خياطته عن طريق اخلطاأ مع الفاغرة، فتمت اإزالة الغرزة وا�ستئ�سال بقية االأنبوب العالق بنجاح با�ستخدام اأداة انتزاع جراحي )�ِسنار(. الكلمات املفتاحية: التغذية املعوية؛ التنبيب املعدي؛ مفاغرة roux-en-y؛ ا�ستئ�سال املعدة؛ تقرير حالة؛ اململكة العربية ال�سعودية. removal of nasogastric tube accidentally stitched to roux-en-y oesophagojejunostomy following a radical gastrectomy for stomach cancer case report and review of the literature *ayman z. azzam,1,3 kareem a. azzam,2 tarek amin3 sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e110–111, epub. 4 apr 18 submitted 2 nov 17 revision req. 24 dec 17; revision recd. 30 dec 17 accepted 18 jan 18 case report doi: 10.18295/squmj.2018.18.01.020 case report a 41-year-old male patient was admitted to the king faisal specialist hospital & research center, riyadh, saudi arabia, in 2015 with stomach cancer. he subsequently underwent a radical total gastrectomy with a roux-en-y oesophagojejunostomy, intraoperative radiation and hyperthermic intraperitoneal chemo therapy. immediately following the procedure, the patient was extubated and sent to the intensive care unit in a satisfactory condition. during the postoperative period, oral feeding was discontinued for one week and the patient was fed via ngt. clinical laboratory tests the placement of a nasogastric tube (ngt)for feeding, stenting and gastric decomp-ression is common after major surgeries—esp ecially gastrointestinal surgeries with critical anast omoses, such as a radical total gastrectomy and rouxen-y oesophagojejunostomy—and rarely results in complications.1,2 the accidental stitching of an ngt to a gastrointestinal anastomosis is an infrequent surgical complication.3–5 this report describes the successful removal of an ngt which had been accidentally stitched to an anastomosis in a patient with stomach cancer after a radical total gastrectomy and roux-en-y oesophagojejunostomy. ayman z. azzam, kareem a. azzam and tarek amin case report | e111 were performed on a daily basis. one week after the surgery, a contrast meal was administered, which showed that the anastomosis was widely patent with no evidence of leakage or obstruction. the decision was made to remove the ngt so that the patient could begin a clear liquid diet. however, the ngt was very resistant and could not be removed by conventional means. an upper gastrointestinal tract (ugit) endoscopy was not considered an option so early due to the risk of rupturing the anastomosis. surgical exploration was also not a viable choice so as to avoid a prolonged hospital stay and any delay in initiating a postoperative chemotherapy regimen. after an otolaryngology consultation, the removal of the ngt was attempted under general anaesthesia. the patient was intubated and a mouth gag was used to open the patient’s mouth in order to examine the oral cavity. the nasal cavity and the nasopharynx were examined via surgical telescope and the ngt was found to be freely mobile. an upper rigid oesophagoscopy was also performed, but the cause of the difficulty in removing the ngt could not be identified. accordingly, the proximal portion of the ngt relative to the nose was cut off, leaving behind the distal portion for later removal once the patient had completely recovered. the patient tolerated the procedure well with no complications. a second contrast meal administered the following day showed no evidence of leakage, enabling the patient to start a liquid-based diet and undergo postoperative chemotherapy treatment. six weeks later, an ugit endoscopy was done and revealed that the distal end of the ngt had been accidentally fixed with a single stitch to the roux-en-y oesophagojejunostomy. subsequently, the stitch was cut and the remaining portion of the ngt was removed using an endoscopic snare. soon after, the patient was discharged in good condition. discussion unexpected complications can arise during the insertion or removal of an ngt. following gastric surgery, such as a radical gastrectomy, a mechanically stuck ngt can be indicative of a stitch anchoring the tube. the accidental iatrogenic suturing of an ngt is a rare complication but may nevertheless occur, especially if the ngt passes through an anastomosis.3–5 this serious complication is difficult to manage due to its rarity; moreover, little information is available in the literature to provide guidance for physicians when dealing with such complications.6 any attempt to forcibly remove the ngt should be avoided as this may lead to serious complications, including dehiscence of the anastomosis, perforation of the gut and profuse bleeding.7 in the current case, removing as much of the prox imal end of the ngt as possible was beneficial as it enabled the patient to continue eating, decreased his hospital stay and permitted the early initiation of postoperative chemotherapy, while allowing sufficient time for the anastomosis to heal. in addition, an ugit endoscopy was deemed the investigation of choice as it allows for the complete assessment and diagnosis of the problem as well as the relatively safe removal of the ngt. however, an endoscopy may itself cause dehiscence of the anastomosis, especially if performed at an early postoperative stage when the anastomosis has not yet completely healed.8 as such, this procedure should be delayed for at least two weeks after the surgery, based on the wound healing process and the strength of the suture material.5 conclusion difficulty in the removal of an ngt following gastric surgery involving a roux-en-y oesophagojejunostomy may be due to the presence of a stitch anchoring the tube to the anastomosis, as in the present case. initially, partial removal of the proximal end of the ngt is recommended to allow sufficient time for the anastomosis to heal; subsequently, the distal end of the tube can be removed at a later date via ugit endoscopy. references 1. akbaba s, kayaalp c, savkilioglu m. nasogastric decompression after total gastrectomy. hepatogastroenterology 2004; 51:1881–5. 2. santhanam v, margarson m. removal of self-knotted nasogastric tube: technical note. int j oral maxillofac surg 2008; 37:384–5. doi: 10.1016/j.ijom.2007.11.020. 3. urschel jd, stockburger hj. endoscopic extraction of an entrapped nasogastric tube. am surg 1990; 56:730–2. 4. reissman p, udassin r, goldin e, durst al. management of an inadvertently sutured nasogastric tube after nissen fundoplication. gastrointest endosc 1994; 40:260–1. doi: 10.1016/ s0016-5107(94)70191-1. 5. chen cn, lee wj, cheng tj, chang kj. endoscopic removal of nasogastric tube sutured unintentionally to gastrojejunostomy. surg laparosc endosc 1997; 7:359–60. 6. hirwa kd, toshniwal n. knotted nasogastric tube in the posterior nasopharynx: a case report. qatar med j 2016; 2016:11. doi: 10.5339/qmj.2016.11. 7. mahmood a, joseph e, robinson rb, akhras j, mckany m, gordon w. the role of endoscopy in nasogastric tube removal following esophageal surgery: a case report. int j surg 2007; 5:342–4. doi: 10.1016/j.ijsu.2007.04.020. 8. asge standards of practice committee; ben-menachem t, decker ga, early ds, evans j, fanelli rd, et al. adverse events of upper gi endoscopy. gastrointest endosc 2012; 76:707–18. doi: 10.1016/j.gie.2012.03.252. https://doi.org/10.1016/j.ijom.2007.11.020 https://doi.org/10.1016/s0016-5107%2894%2970191-1 https://doi.org/10.1016/s0016-5107%2894%2970191-1 https://doi.org/10.5339/qmj.2016.11 https://doi.org/10.1016/j.ijsu.2007.04.020 https://doi.org/10.1016/j.gie.2012.03.252 department of hand surgery, khoula hospital, muscat, oman *corresponding author’s e-mail: doctrahul@yahoo.co.in إعادة زراعة تسعة أصابع يف مريض تقرير حالة ر�هول كري�صنارو باتيل، جوبال مالهوتر�، �رصينيفا�صان فينوغوبال، عماد �صالح، عبد �لفتاح رم�صان abstract: amputation of multiple fingers of both hands is a rare and serious injury. we report a case of a 41-yearold male patient who presented to khoula hospital, muscat, oman, in 2015 with the amputation of nine fingers due to a workplace injury. with two teams working in tandem, all the amputated fingers were re-attached. a total of seven fingers survived and the patient regained reasonable functionality of his hands. to the best of the authors’ knowledge, this is the first case of several finger amputations in oman. keywords: fingers; traumatic amputation; crush injuries; replantation; case report; oman. امللخ�ص: برت �الأ�صابع �ملتعددة بكلتا �ليدين هو �إ�صابة نادرة وخطرية. هذ� تقرير عن حالة مري�س يبلغ من �لعمر 41 عاًما قدم �إىل م�صت�صفى خولة، م�صقط، ُعمان، يف عام 2015 ببرت ت�صعة �أ�صابع ب�صبب �إ�صابة يف مكان �لعمل. قام فريقني من �جلر�حني يعملون جنبا �إىل جنب بعمل �إعادة ربط كل �الأ�صابع �ملبتورة. جنا ما جمموعه �صبعة �أ�صابع و��صتعاد �ملري�س عمل يديه �لوظيفي بدرجة مقبولة. ح�صب علم �ملوؤلفني، هذه هي �حلالة �الأوىل لبرت �الأ�صابع يف عمان. الكلمات املفتاحية: �أ�صابع؛ برت نتيجة �أ�صابة؛ �إ�صابات �صحق؛ �إعادة زرع؛ تقرير حالة؛ عمان. replantation of nine fingers in a patient a case report *rahul k. patil, gopal malhotra, srinivasan venugopal, emad salah, abdelfattah ramadan sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e248–252, epub. 5 nov 19 submitted 11 feb 19 revision req. 16 apr 19; revision recd. 29 may 19 accepted 19 jun 19 case report a 41-year-old male patient presented to khoula hospital, muscat, oman, in 2015 with nine amputated fingers. while operating a paper cutting machine, eight of the patient’s fingers were amputated through the proximal phalanges, while the right thumb was amputated through the distal phalanx [figure 1]. the parts were well preserved and were reasonably clean cut. the patient was haemody namically unstable with a blood pressure of 90/60 mmhg, most likely due to bleeding from the amputation sites. further assessment ruled out any associated injury. the bleeding was controlled with pressure dressing and hand elevation and the patient was adequately returned to a normal haemodynamic state. appropriate consent was obtained once the patient was stabilised. the total ischaemia time when the patient was received at the hospital was approximately two hours and 30 minutes. x-ray images of the hands with amputated parts are shown in figure 2. the amputated parts were transferred to the operation theatre to facilitate exploration of the structures while the patient was being prepared for replantation surgery. two separate teams began microscopic dissection of the amputated fingers. the procedure involved debr idement and exploration through mid-lateral incisions for identification of the tendons, nerves and vessels of indications for replantation have evolved since the possibility of replantation of an amputated finger became a reality in the late nineteenth century.1 thumb, distal digital amputations, amputations in children and proximal amputations such as through the hand and distal forearm are currently considered indications for replantation.2 in addition, multi-finger amputation is an indication for replantation, although the incidence of such injuries is relatively low.3 the overall function of the hand improves following replant ation of these parts and outweighs the risk associated with the stiffness of the replanted parts.4 single finger amputations with crush or avulsion type injuries and amputations proximal to the insertion of the superficialis tendon are relative contraindications for replantation. these fingers are unlikely to function well following replantation and may compromise the overall hand function.3 multi-finger replantation is challenging even for experienced microsurgeons. it is time consuming and involves extensive planning. the access incisions and sequence of repair of structures requires careful appraisal depending upon the ischaemia time. amputation of nine fingers in a single patient is quite rare; we report the first case of a nine-finger replantation in oman. the proc edure and functional outcome is presented three years after the replantation surgery. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.012 case report https://creativecommons.org/licenses/by-nd/4.0/ rahul k. patil, gopal malhotra, srinivasan venugopal, emad salah and abdelfattah ramadan case report | e249 the amputated parts. adequate length of these structures was exposed for later repair and replantation. the bone of each amputated finger was prepared by passing 1.2 mm kirschner wires in a retrograde manner through the distal parts for later skeletal stabilisation. the patient was put under general anaesthesia and his hands were prepared for the procedure which was performed on both hands simultaneously. through mid-lateral incisions on the radial and ulnar side of the stumps of each finger, the structures including bone, tendons, vessels and nerves were identified and prepared. healthy vessels were found at the bases of all fingers distal to the bifurcation of common digital vessels. proximal phalanges were adequately shortened in each of the finger stumps to achieve primary soft tissue closure without tension. the amputated fingers were then aligned with the stumps and the prefixed wires were driven into the proximal stumps to achieve skeletal stabilisation. the flexor digitorum profundus tendons in all fingers were repaired. repair of the radial and ulnar digital nerves followed the tendon repair with 9-0 nylon sutures. after appropriate preparation, the radial and ulnar digital arteries for each finger were repaired. following the repair of the arteries, 5,000 international units of intravenous heparin was administered and the arterial clamps were released. extensor tendon repair was done on the dorsal aspect of the fingers and two dorsal subcutaneous veins were repaired for each of the involved fingers. the right thumb pulp was defattened and replaced by a full thickness graft. after the initial two and a half hours to reach the hospital (cold ischaemia time), there was further delay of six hours (warm ischaemia time) until the arterial clamps were released. the entire procedure took approximately 14 hours to complete. the fingers perfused immediately following replantation. there was a significant amount of blood loss during the latter part of the operation, possibly due to the heparin injection given when the arterial clamps were released. the wounds continued to ooze postoperatively and the patient was monitored in the intensive care unit (icu) for the following 48 hours where he received a total of eight units of blood transfusion including the intraoperative and postoperative period. his coagulation parameters were monitored throughout this period. all the fingers were perfusing well until the fourth postoperative day, when the ring and little fingers on the right hand gradually became congested. by the time the patient had to leave the country, the perfusion of these two fingers was doubtful. the patient was subsequently treated at a medical college hospital in india, where the little and ring figure 1: photograph of multiple finger amputations of a 41-year-old male patient following a workplace injury showing the amputations on the (a) left hand and (b) right hand. figure 2: x-ray images of multi-finger amputations on the (a) left and (b) right hand of a 41-year-old male patient showing the levels of amputation through the proximal phalanges. figure 3: photographs of both hands of a 41-year-old male patient showing (a) the palmar aspect and (b) the dorsal aspect three years after the replantation surgery. replantation of nine fingers in a patient a case report e250 | squ medical journal, august 2019, volume 19, issue 3 fingers of the right hand were terminalised. the left index finger developed a similar congestion followed by skin loss over the volar aspect of the middle phalanx. however, debridement and skin grafts were done to cover the exposed area. follow-up was done with the same institute in india and all his wounds have healed well [figure 3]. he had reasonable functionality of his hands and was able to manage daily tasks [figure 4]. additionally, he began working four months following the replantation procedure and was engaged in a meaningful job and was able to support himself and his family during the writing of this report. three years following the surgery, he was satisfied with the outcome of the procedure. his activities of daily living (adl) score was 6/6 and instrumental adl score was 8/8. overall, he was able to perform all activities reasonably well, with an average total active motion (tam) for the replanted fingers of approximately 120 degrees. he has good protective sensations with an average static 2 point discrimination of 8–9 mm at the fingertips. his range of movement can be improved by tenolysis and arthrolysis, as was suggested to him from time to time. however, the patient refused further interventions as he was the sole source of financial support for his family. discussion the field of microsurgery and replantation has been expanding in recent years. with advances in magnif ication, instrumentation, sutures and growing experience, more distal amputations are being attempted. while the replantation success rates are improving in some regions, trends in the usa suggest otherwise.6–8 there has been a steady decline in replantation attempts due to the fact that fingertip amputations are no longer considered indications for replantation at many centres.8 although, some asian studies have reported excellent results following replantation for zone 1 amputations, the technical and decision-making aspects of finger replantation are still being discussed.8–12 bilateral multi-finger amputations are fortunately rare and only a few cases have been reported.13–15 ischaemia time is a major concern when dealing with cases of multi-finger amputation.16 there should be good communication between the referring team and the receiving team with an emphasis on appropriate preservation of amputated parts, resuscitation of the patient and immediate transfer, which at times may require transport by air. the initial assessment at the receiving centre should be completed by the most experienced team member and should include assessment of the tissue injury both clinically and radiologically. the parts that are functionally important such as the thumb or those that have the best chance of recovery (i.e. minimally crushed fingers and injuries away from joints) should be given priority. if a digit that has a vital function (such as the thumb) is severely damaged, the team should consider replacing it with one of the available amputated fingers with minimal trauma.2,17,18 there are two ways to approach a multi-finger replantation where the fingers have been amputated at a similar level and have a similar amount of tissue damage, as is in the present case. first, a “digit by digit” replantation approach can be taken where each finger is reattached one at a time. this approach saves some critical ischaemia time and possibly avoids some blood loss; however, a negative aspect of this approach is that the repaired finger is handled and manipulated repeatedly. surgeons using this approach must decide the sequence as per the functional importance of a digit and the extent of damage. second, a “structure by structure” approach can be used where the surgeon stabilises all fingers followed by repairing the flexor tendons, nerves and then the arteries. following repair of the volar structures, the hand is turned and the dorsal structures such as the vein and extensor tendons are repaired. this method saves time and avoids manipulation of the digits after replantation, however, it increases ischaemia time as figure 4: photographs of both hands of a 41-year-old male patient three years after the replantation surgery showing the functionality of his hands. rahul k. patil, gopal malhotra, srinivasan venugopal, emad salah and abdelfattah ramadan case report | e251 all fingers are exposed to warm ischaemia until the revascularisation is complete; there is also the possib ility of increased blood loss.1,19 bilateral multi-finger amputation is a rare injury and fortunately adequate resources were available for a simultaneous bilateral surgery. in the current case, a “structure by structure” method was chosen as the patient presented soon after the injury. however, the patient had a significant amount of blood loss which could have been prevented by replanting fewer digits at functionally important positions as a ‘damage control measure’; this would have also reduced the total surgical time. repairing veins before arteries also could have reduced the blood loss that later resulted in haemo dynamic instability and an icu stay. the patient’s bleeding tendency was possibly multifactorial as it may have been caused by the multiple wounds, hypothermia and the lengthy surgery along with multiple blood transfusions. the decline in the perfusion of the fingers, after the fourth post operative day, may have been due to the patient’s coagulation abnormalities and frequent manipulations to change the soaked dressings which may have contributed to the delayed blockage of veins causing congestion and non-survival of two fingers on the right hand. the functional outcome should be the main criteria for assessing the results of a replantation, not the survival of the fingers. although the current patient returned to almost normal activity levels and was satisfied with the outcome, the range of motion at the interphalangeal (ip) joints was restricted (average tam: 120 degrees). the axial kirschner wires immob ilising the ip joints, which was used to achieve quick and stable fixation, may have contributed to the stiffness. additionally, the patient’s inability to attend the physio therapy clinics and unwillingness for further inter ventions are also possible causes of residual stiffness. while attempting salvage procedures following such injuries, patients’ expectations should be ascert ained. the possible functional outcome and the timeframe for recovery should be clearly discussed with the patient. in addition, it is essential that an informed consent be obtained before proceeding with any proc edure to avoid any liability.19 conclusion multi-finger amputation is an important indication for replantation as salvaged fingers can contribute towards improving the overall hand function. close observ ation of patients’ vitals and coagulation parameters is important during the intraand postoperative periods. multiple teams of trained surgeons with experience in digital level replantation should be available to help overcome fatigue and improve overall efficiency and success of the procedure, which would ultimately improve the outcome for the patient. a c k n o w l e d g e m e n t the authors would like to acknowledge dr j. satish kumar, senior consultant at the sri ramachandra medical college, chennai, india, for following-up the patient, recording the necessary clinical data and providing his feedback. references 1. pederson wc. replantation. plast reconstr surg 2001; 107:823–47. https://doi.org/10.1097/00006534-200103000-00027. 2. chim h, maricevich ma, carlsen bt, moran sl, salgado cj, wei fc, et al. challenges in replantation of complex amput ations. semin plast surg 2013; 27:182–9. https://doi.org/10.1 055/s-0033-1360585. 3. salah mm, khalid kn. replantation of multiple digits and hand amputations: four case reports. cases j 2008; 1:266. https://doi. org/10.1186/1757-1626-1-266. 4. baek sm, kim ss. ten-digit and nine-digit replantation (4 cases). br j plast surg 1992; 45:407–12. https://doi.org/10.1016/00071226(92)90202-9. 5. chung kc, alderman ak. replantation of the upper extremity: indications and outcomes. j hand surg am 2002; 2:78–94. https://doi.org/10.1053/jssh.2002.33319. 6. kwon gd, ahn bm, lee js, park yg, ha yc. clinical outcomes of a simultaneous replantation technique for amputations of four or five digits. microsurgery 2016; 36:225–9. https://doi.org/10.1 002/micr.30009. 7. woo sh, cheon hj, kim yw, kang dh, nam hj. delayed and suspended replantation for complete amputation of digits and hands. j hand surg am 2015; 40:883–9. https://doi.org/10.10 16/j.jhsa.2015.01.006. 8. reavey pl, stranix jt, muresan h, soares m, thanik v. disappearing digits: analysis of national trends in amputation and replantation in the united states. plast reconstr surg 2018; 141:e857–67. https://doi.org/10.1097/prs.0000000000004368. 9. hattori y, doi k, ikeda k, estrella ep. a retrospective study of functional outcomes after successful replantation versus amputation closure for single fingertip amputations. j hand surg am 2006; 31:811–18. https://doi.org/10.1016/j.jhsa.20 06.02.020. 10. sebastin sj, chung kc. a systematic review of the outcomes of replantation of distal digital amputation. plast reconstr surg 2011; 128:723–37. https://doi.org/10.1097/prs.0b013e3182 21dc83. 11. chiu hy. [indications and contraindications of digital replant ation]. j formos med assoc 1992; 91:s214–21. 12. barbary s, dap f, dautel g. finger replantation: surgical technique and indications. chir main 2013; 32:363–72. https://doi.org/10.1016/j.main.2013.04.012. 13. baek sm, kim ss. ten-digit and nine-digit replantation (4 cases). br j plast surg 1992; 45:407–12. https://doi.org/10.1016/00071226(92)90202-9. https://doi.org/10.1097/00006534-200103000-00027 https://doi.org/10.1055/s-0033-1360585 https://doi.org/10.1055/s-0033-1360585 https://doi.org/10.1186/1757-1626-1-266 https://doi.org/10.1186/1757-1626-1-266 https://doi.org/10.1016/0007-1226%2892%2990202-9 https://doi.org/10.1016/0007-1226%2892%2990202-9 https://doi.org/10.1053/jssh.2002.33319 https://doi.org/10.1002/micr.30009 https://doi.org/10.1002/micr.30009 https://doi.org/10.1016/j.jhsa.2015.01.006 https://doi.org/10.1016/j.jhsa.2015.01.006 https://doi.org/10.1097/prs.0000000000004368 https://doi.org/10.1016/j.jhsa.2006.02.020 https://doi.org/10.1016/j.jhsa.2006.02.020 https://doi.org/10.1097/prs.0b013e318221dc83 https://doi.org/10.1097/prs.0b013e318221dc83 https://doi.org/10.1016/j.main.2013.04.012 https://doi.org/10.1016/0007-1226%2892%2990202-9 https://doi.org/10.1016/0007-1226%2892%2990202-9 replantation of nine fingers in a patient a case report e252 | squ medical journal, august 2019, volume 19, issue 3 14. kim wk, lee jm, lim jh. eight cases of nine-digit and ten-digit replantations. plast reconstr surg 1996; 98:477–84. https://doi. org/10.1097/00006534-199609000-00018. 15. kantarci u, cepel s, buldu h. successful replantation in tendigit amputation. acta orthop traumatol turc 2010; 44:76–8. https://doi.org/10.3944/aott.2010.2109. 16. zumiotti a, ferreira mc. replantation of digits: factors influencing survival and functional results. microsurgery 1994; 15:18–21. https://doi.org/10.1002/micr.1920150107. 17. zenn mr, scott l. chapter 15 multiple-digit replantations. in: weinzweig n, weinzweig j, eds. the mutilated hand. amsterdam, netherlands: elsevier, 2005; pp. 217–24. 18. koul ar, patil rk. thumb reconstruction. in: textbook of plastic, reconstructive, and aesthetic surgery: volume ii: hand and upper extremity. delhi, india: thieme, 2017. pp. 457–92. 19. tang jb, wang zt, chen j, wong j. a global view of digital replantation and revascularization. clin plast surg 2017; 44:189–209. https://doi.org/10.1016/j.cps.2016.11.003. https://doi.org/10.1097/00006534-199609000-00018 https://doi.org/10.1097/00006534-199609000-00018 https://doi.org/10.3944/aott.2010.2109 https://doi.org/10.1002/micr.1920150107 https://doi.org/10.1016/j.cps.2016.11.003 1department of endocrinology & internal medicine, king fahad central hospital, jizan, saudi arabia; 2department of family & community medicine, college of medicine, najran university, najran, saudi arabia *corresponding author e-mail: awadresearch17@gmail.com تشخيص متأخر للنوع الثاين من مرض نقص إنزمي α-5-ريدوكتاس، لفتاة مراهقة مصابة بانقطاع الطمث األويل تقرير حالة عبد الرحمن اأحمد حمادي، عايل عمر يحيى، عو�س حممد القحطاين abstract: deficiency of the 5-α-reductase enzyme has been found to affect male sexual development. we report an 18-year-old patient who was referred to an endocrinology clinic in jizan, saudi arabia, in april 2014 with primary amenorrhoea, virilisation and a lack of secondary sex characteristics. as female external genitalia were present at birth, she had been raised as a female. magnetic resonance imaging revealed no uterine or ovarian tissue in the pelvis and the presence of a scrotal sac. she was diagnosed with 5-α-reductase type 2 deficiency, a 46,xy disorder of sexual development. typically, affected males have pseudovaginal perineoscrotal hypospadias and ambiguous genitalia at birth. individuals who have been raised as female manifest characteristics of virilisation at puberty, including deepening of the vocal tone, phallus enlargement, scrotal hyperpigmentation and increased muscle mass. keywords: 46, xy disorders of sex development; testosterone 5-alpha-reductase; dihydrotestosterone; hypospadias; puberty; case report; saudi arabia. مت عاما 18 العمر من تبلغ مري�سة عن حالة �سجلنا للذكور. اجلن�سي التطور على يوؤثر α-5-ريدوكتا�س اإنزمي نق�س اأن وجد امللخ�ص: اإحالتها اإىل عيادة الغدد ال�سماء يف جازان باململكة العربية ال�سعودية، يف اأبريل 2014 مع انقطاع الطمث االأويل، والرتجل، وعدم وجود يكت�سف مل كاأنثى. ن�ساأت فقد الوالدة، عند لها حا�رشة كانت لالإناث اخلارجية التنا�سلية االأع�ساء اأن ومبا ثانوية. جن�سية خ�سائ�س الت�سوير بالرنني املغناطي�سي اأي ن�سيج للرحم اأو املبي�س يف احلو�س، وتبني وجود كي�س ال�سفن. ومت ت�سخي�سها باأنها م�سابة بالنوع الثاين من مر�س نق�س اإنزمي α-5-ريدوكتا�س، xy،46 وهو ا�سطراب يف النمو اجلن�سي. عادة ما يكون لدى الذكور املت�رشرين مهبل كاذب �سن يف الرتجل �سفات كاإناث تن�سئتهم متت الذين االأفراد ويظهر وا�سحة. غري تنا�سلية واأع�ساء ال�سفن، كي�س يف البول جمرى وفتحة البلوغ، مبا يف ذلك خ�سونة ال�سوت، وت�سخم الع�سو الذكري، وفرط ت�سبغ ال�سفن وزيادة كتلة الع�سالت. الكلمات املفتاحية: xy،46 ا�سطرابات النمو اجلن�سية؛ الت�ستو�ستريون 5-األفا-ريدوكتا�س؛ ديهدروت�ستو�سرتون؛ فتحة جمرى البول يف كي�س ال�سفن؛ بلوغ؛ تقرير حالة؛ اململكة العربية ال�سعودية. late diagnosis of 5-α-reductase type 2 deficiency in an adolescent girl with primary amenorrhoea case report abdul-rahman a. hummadi,1 ayel o. yahya,1 *awad m. al-qahtani2 sultan qaboos university med j, may 2017, vol. 17, iss. 2, pp. e218–220, epub. 20 jun 17 submitted 23 oct 16 revision req. 14 nov 16; revision recd. 11 dec 16 accepted 15 jan 17 case report doi: 10.18295/squmj.2016.17.02.014 case report an 18-year-old patient was referred to an endocrine clinic in jizan, saudi arabia, in april 2014 with primary amenorrhoea, virilisation and a lack of secondary sex characteristics. as female external genitalia were present at birth, she had been raised as female. the patient reported vocal changes over the course of two years, which made her voice sound deeper and harsher. additionally, over the previous year, she had experienced unusually thick hair growth on her upper and lower limbs as well as the axillary and inguinal regions. her previous developmental history was normal. there was no history of consanguinity on the part of the parents. the 5-α-reductase enzyme, also known as 3-oxo-5α-steroid 4-dehydrogenase, converts testosterone to the more physiologically active dihydrotestosterone (dht).1 a deficiency of 5-α reductase results in a rare autosomal recessive 46,xy disorder of sexual development caused by mutations in the steroid 5-α-reductase 2 (srd5a2) gene located on chromosome 2p23.1,2 most affected individuals have female external genitalia present at birth and are raised as female; however, a few patients are adequately masculinised by childbirth and are raised as male.2,3 due to its rarity, the prevalence of 5-α-reductase type 2 deficiency in the general population is unknown.4 abdul-rahman a. hummadi, ayel o. yahya and awad m. al-qahtani case report | e219 on physical examination, the patient communicated well, appeared to be comfortable and was not in any emotional distress. her height was 162 cm, she weighed 68 kg and her body mass index was 25.9 kg/m2. hair was present on the extensor surfaces of her forearms and legs. breast development corresponded to tanner stage i, while pubic hair growth was categ orised as tanner stage iii. further physical examination revealed pseudovaginal perineoscrotal hypospadias and a blind vaginal pouch. the scrotal skin was rugose and pigmented with the right gonad palpable in the inguinal ligament. the left gonad was 3.2 cm and located in the labioscrotal pouch, while the phallus was 3 cm in length. the results of a hormonal assay are shown in table 1. magnetic resonance imaging of the pelvis revealed no uterine or ovarian tissue. a scrotal sac was apparent and contained the left testis which measured 33 x 24 x 23 mm and was of normal shape and signal intensity [figure 1a]. the undescended right testis was located in the right inguinal canal measuring 31 x 24 x 20 mm and was also of normal shape and signal intensity [figure 1b]. the urinary bladder, urethra and seminal vesicles appeared normal. no prostatic tissue was identified. a final diagnosis was made of a 46,xy disorder of sexual development due to 5-α-reductase type 2 deficiency. after extensive counselling with the patient and her parents, the patient decided to undergo gender reassignment to become male. discussion at birth, clinical symptoms of 5-α-reductase type 2 deficiency range from the appearance of female external genitalia to a nearly complete male phenotype; however, most patients who present with ambiguous genitalia are usually diagnosed in early infancy.5 the current case describes the late diagnosis of 5-α-reductase type 2 deficiency in an 18-year-old female patient presenting with primary amenorrhoea and characteristics of virilisation. young children with 5-α-reductase type 2 deficiency can either escape diagnosis or be misdiagnosed as having partial or complete androgen insensitivity syndrome.6 since biochemical findings can be misleading, molecular testing is mandatory to identify the underlying cause of a disorder of sexual development.6,7 however, measurement of the basal serum concentration and the testosterone/dht ratio after puberty is usually sufficient for an accurate figure 1: magnetic resonance imaging (mri) of the pelvis of an 18-year-old female patient with primary amenorrhoea, virilisation and a lack of secondary sex characteristics showing (a) no uterine or ovarian tissue and the presence of a scrotal sac (asterisk) containing a left testis of normal shape and signal intensity (arrow) and (b) an undescended right testis (arrow) in the right inguinal canal of normal shape and signal intensity. table 1: hormonal assay results of an 18-year-old female patient with primary amenorrhoea, virilisation and a lack of secondary sex characteristics hormone result normal range males females fsh in miu/ml 6 2–12 2–12 lh in miu/ml 7 2–12 2–12 cortisol in µg/dl 7.2 5.1–19.9 5.1–19.9 estradiol in pg/ml 42.22 7.6–40.9 12.5–163.5 t in ng/dl 572 200–1,080 10–70 dht in ng/dl 8 29–76 22–380 dhea in μg/dl 126 22–640 22–380 ae in ng/dl 127 ≤250 ≤250 t/dht ratio 67.8 8–16 8–16 17-ohp in ng/ml 0.8 0.1–1.4 0.1–2.9 fsh = follicle-stimulating hormone; lh = luteinising hormone; t = testosterone; dht = dihydrotestosterone; dhea = dehydroepiandrosterone; ae = androstenedione; ohp = hydroxyprogestrone. late diagnosis of 5-α-reductase type 2 deficiency in an adolescent girl with primary amenorrhoea case report e220 | squ medical journal, may 2017, volume 17, issue 2 references 1. fratianni cm, imperato-mcginley j. the syndrome of 5[alpha]reductase deficiency. endocrinologist 1994; 4:302–14. 2. genetics home reference. 5-alpha reductase deficiency. from: https://ghr.nlm.nih.gov/condition/5-alpha-reductase-defi ciency accessed: dec 2016. 3. hekimsoy z, hatipoglu o, öz d, alarslan p, özmen b. 5-alpha reductase type 2 deficiency: a case report. endocr abstr 2012; 29:p418. 4. wilson jd, griffin je, russell dw. steroid 5 alpha-reductase 2 deficiency. endocr rev 1993; 14:577–93. doi: 10.1210/er.14. 5.577. 5. bertelloni s, scaramuzzo rt, parrini d, baldinotti f, tumini s, ghirri p. early diagnosis of 5alpha-reductase deficiency in newborns. sex dev 2007; 1:147–51. doi: 10.1159/000102103. 6. walter kn, kienzle fb, frankenschmidt a, hiort o, wudy sa, van der werf-grohmann n, et al. difficulties in diagnosis and treatment of 5alpha-reductase type 2 deficiency in a newborn with 46,xy dsd. horm res paediatr 2010; 74:67–71. doi: 10.1159/000313372. 7. skordis n, neocleous v, kyriakou a, efstathiou e, sertedaki a, philibert p, et al. the ivs1-2a>g mutation in the srd5a2 gene predominates in cypriot patients with 5α reductase deficiency. j endocrinol invest 2010; 33:810–14. doi: 10.3275/7079. 8. maleki n, kalantar hormozi m, iranparvar alamdari m, tavosi z. 5-alpha-reductase 2 deficiency in a woman with primary amenorrhea. case rep endocrinol 2013; 2013:631060. doi: 10.1155/2013/631060. 9. mendonca bb, inacio m, costa em, arnhold ij, silva fa, nicolau w, et al. male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency: diagnosis, psychological evaluation, and management. medicine (baltimore) 1996; 75:64–76. doi: 10.1097/00005792-199603000-00003. 10. imperato-mcginley j, guerrero l, gautier t, peterson re. steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. science 1974; 186:1213–15. doi: 10.1126/science.186.4170.1213. 11. sinnecker gh, hiort o, dibbelt l, albers n, dörr hg, hauss h, et al. phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. am j med genet 1996; 63:223–30. doi: 10.1002/(sici)1096-8628(19960 503)63:1<223::aid-ajmg39>3.0.co;2-o. 12. conte fa, grumbach mm. abnormalities of sexual determination and differentiation. in: greenspan fs, gardner dg. basic & clinical endocrinology, 7th ed. new york, usa: mcgraw-hill medical, 2003. pp. 564–607. diagnosis of 5-α-reductase type 2 deficiency.8 in the present case, the diagnosis of 5-α-reductase 2 type 2 deficiency was based on the patient’s clinical presentation and a hormonal assay which revealed an abnormally elevated testosterone/dht ratio of >60. nevertheless, karyotyping and molecular studies are recommended to confirm a homozygous mutation of the srd5a2 gene; unfortunately, this could not be performed in the current case.4,7 many 46,xy individuals raised as females will experience psychological difficulties during puberty, which results in most affected patients choosing to undergo gender reassignment to become male, as in the present case.9–11 in such cases, either dht or highdose testosterone therapy should be initiated so as to increase the size of the phallus. for patients diagnosed after infancy and whose gender identity is definitively female, a genitoplasty, prophylactic orchiectomy and oestrogen substitution therapy are recommended.12 conclusion although rare, 5-α-reductase type 2 deficiency should be suspected among female patients presenting with pubertal virilisation and primary amenorrhoea. early recognition of this condition is critical to avoid psychological distress on the part of the patient, particularly after puberty. molecular analysis of the srd5a2 gene should be performed to confirm the diagnosis. https://doi.org/10.1210/er.14.5.577 https://doi.org/10.1210/er.14.5.577 https://doi.org/10.1159/000102103 https://doi.org/10.1159/000313372 https://doi.org/10.3275/7079 https://doi.org/10.1155/2013/631060 https://doi.org/10.1097/00005792-199603000-00003 https://doi.org/10.1126/science.186.4170.1213 https://doi.org/10.1002/%28sici%291096-8628%2819960503%2963:1%3c223::aid-ajmg39%3e3.0.co%3b2-o https://doi.org/10.1002/%28sici%291096-8628%2819960503%2963:1%3c223::aid-ajmg39%3e3.0.co%3b2-o squ med j, august 2011, vol. 11, iss. 3, pp. 349-356, epub. 15th aug 11 submitted 4th dec 10 revision req. 11th apr 11, revision recd. 10th may 11 accepted 8th jun 11 1ministry of health, south batinah region, oman; 2ministry of health, dakhliyah region, oman; 3ministry of health, north sharqiah region, oman; ministry of health, oman; 4department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, oman. *corresponding author email: zakiya95@hotmail.com <ìë^¬ü÷]<l^äâˆ⁄<ª<ºfñ�flπ]<4∆<›ç÷]<º«ï<≈^àiö]<ö^éjfi]<ôç⁄ ·^€ �¬<ìfl�◊â<hgèä÷]<ìë˜ê<ª<ìè÷ê˘]         18≤ 41150%   3459 p < 0.05  39%   95%  p≤ 0.0016.4%44 34 95%   58%p 0.02 18.5% 47%24%   56.3% 58.2%  60%      :مفتاح الكلمات abstract: objectives: this study aimed to estimate the prevalence of uncontrolled hypertension (htn) among omani hypertensive patients, on treatment and under primary health care (phc) follow-up in al seeb wilayat, oman. socio-demographic and clinical factors were explored for possible influence on blood pressure (bp) control. methods: based on an assumption of 50% prevalence of uncontrolled htn, a retrospective data collection was conducted on the last three follow-up visits of 411 randomly selected omani adults (≥18 years) from 3,459 hypertensive patients. adequate bp control was defined using criteria from 7th report of the joint national committee on prevention detection evaluation & treatment of high blood pressure (jnc-7). a p value of <0.05 and odds ratios with 95% confidence interval were used to assess for association. results: the targets for adequate bp control were achieved in 39% of the studied patients (95% confidence interval [ci]: 34–44%). lower bp control was found among hypertensives with diabetes (6.4%, p = <0.001) and renal disease (18.5%, p = 0.02); those with cardiovascular disease (cvd) showed relatively better control (58%). age and gender had no impact on bp control. most patients were only on one (24%) or two (47%) antihypertensive medications, the most frequently used being β-blockers (58.2%) and diuretics (56.3%). conclusion: htn is not adequately controlled in over 60% of treated patients; the presence of co-morbidity and less than aggressive treatment are significant contributors. improving the quality of htn care is a priority; effective efforts should be undertaken to improve bp control. keywords: hypertension; primary care; oman prevalence of uncontrolled hypertension in primary care settings in al seeb wilayat, oman rashid al-saadi,1 sulaiman al-shukaili,2 suleiman al-mahrazi,3 *zakiya al-busaidi4 clinical & basic research prevalence of uncontrolled hypertension in primary care settings in al seeb wilayat, oman 350 | squ medical journal, august 2011, volume 11, issue 3 advances in knowledge 1. control of hypertension (htn) among omani adult hypertensive patients on treatment was significantly suboptimal. 2. hypertensive patients who were obese, diabetic or had renal disease were at higher risk for uncontrolled htn. 3. it is likely that the treatment of most hypertensive patients was inadequate and should have been more aggressive. 4. it seems that our primary care physicians have insufficient knowledge and experience in treating htn to achieve international targets. applications to patient care 1. improving the quality of htn care in primary health care settings is a priority and effective efforts need to be undertaken in this regard. 2. hypertensive patient who are also obese or diabetic should be targeted for a greater attention to blood pressure control. 3. primary care physicians should be encouraged to become familiar with updated evidence-based htn management guidelines. hypertension (htn) is a major medical problem affecting more than 1 billion individuals worldwide.1 it is sufficiently common to represent a public health concern in oman as well. according to preliminary data from the world health survey is 2008 (currently in press), the community prevalence of htn in the country was estimated to be 40% and a further 17% of the population had pre-htn.2 three quarters of this hypertensive population were found to be unaware of their htn. solid data on the number of hypertensive patients under follow-up at different health facilities is limited. across the globe, it is well established that high blood pressure (bp) is a leading modifiable risk factor for cardiovascular disease, cerebrovascular disease, heart failure and renal disease.3,4 reviewed literature has shown a consistent, strong relationship between higher levels of both systolic and diastolic bp, as well as mortality from these diseases.5 generally, the higher the bp, the greater is the risk. cohort studies and randomised clinical trials have shown that the risks from raised htn can be partially reversed if an optimal bp control is achieved.6,7 htn has been considered to be a common reason for patients to be seen by primary care physicians.8 it is generally accepted that well organised healthcare can improve the outcome in hypertensive patients,9 and clinical trials have clearly demonstra ted that adequate bp control can be achieved in most patients.10,11 still, uncontrolled htn is a challenge for primary health care (phc) services all over the world. the direct reasons for this global epidemic of uncontrolled htn are not well understood, but it seems that the barriers for adequate control of htn are complex and arise from a combination of factors related to patients, physicians and health systems.12 studies have shown the influence of socio-demographic factors, such as age, gender and co-morbidity, on htn control was variable with contradictory findings.13‒16 similar findings have been shown for the influence on bp of the number of antihypertensive medications taken by patients. the prevalence of uncontrolled htn in oman and possible associated factors have not been adequately studied to date. only a single small study was conducted between 1998 and 2002 in a tertiary hospital setting and it showed that bp control was 35% for omani hypertensive patients examined, versus 53% for non-omani.17 the current study aims to obtain an insight into the prevalence of uncontrolled htn among omani hypertensive patients on treatment and follow-up at the phc settings in an urban town in oman. furthermore, certain socio-demographic and clinical factors will be explored for their possible influence on bp control. methods the study was conducted using a retrospective data collection of hypertensive patients seen in the six phc centres serving al-seeb wilayat, an urban area belonging to the muscat governorate of oman. al-seeb is the most populated wilayat (district) in oman with more than 225,000 residents.18 a total of 3,459 patients were registered as hypertensive patients and were under-follow up at htn clinics in these six phc centres by 1 june 2009. a hypertensive patient usually attends the clinic every one to three months for follow-up and on monthly basis for a repeat prescription. the sample size based on the assumption of a 50% prevalence of uncontrolled bp, α = 0.05, and permissible error of 5% on either side of the estimate to be around 400. to account for the inclusion criteria, a total of 500 patients were then selected rashid al-saadi, sulaiman al-shukaili, suleiman al-mahrazi, zakiya al-busaidi clinical and basic research | 351 randomly using computer-generated numbers. all adult omani hypertensive patients aged ≥18 years, who had made at least three previous phc visits and had been on antihypertensive medications for at least 6 months, were included. newly diagnosed individuals, those having less than three previous bp readings and those without any follow-up in the previous 6 months were excluded from the study. despite being at risk of inadequate bp control, hypertensive patients who were not on pharmacotherapy were also excluded as the majority of them were found to be either newly diagnosed, or not on the expected regular followup. a total of 411 patients (82.2%) met the inclusion criteria. figure 1 summarises the selection process of the patients in the study. the following information was collected from the electronic records of the patients’ last three visits: age, gender, duration of follow-up, three most recent bp readings, presence of co-existing diseases, current smoking status, body mass index (bmi), prescribed regular medications, frequency of attendance at the outpatient clinic (in the last 6 months) and presence or absence of care continuity. the traditional definition of 'continuity of care' is the patient's experience of a “continuous caring relationship' with an identified health care professional”.19 in this study continuity of care was defined as any included patient having been seen by same physician in the last three visits. uncontrolled htn was defined based on guidelines from 7th report of the joint national committee on prevention detection evaluation & treatment of high blood pressure (jnc-7) as a bp of >140/90 mm hg or >130 mmhg systolic and >80 mmhg diastolic with coexisting diabetes or renal disease.1 uncontrolled htn was based on the average of the collected three bp readings and it could be either uncontrolled in systolic, diastolic or both. data were entered by authors 1 and 3, then analysed by author 2 using the statistical package for social sciences (spss, ibm, usa, version 17.0). the chi-squire test was used to evaluate the association between qualitative variables (uncontrolled htn and different independent variables). a p value of 0.05 or less was considered statistically significant. in addition, variables with a p value of less than 0.25 were included in a multivariate logistic regression model. odds ratios (or) with a 95% confidence interval for those variables was then estimated. ethical approval was obtained from the regional research and ethics committee, directorate general of health services, governorate of muscat. results data on a total of 411 subjects who met the inclusion criteria were analysed. the mean length of followup in the same clinic for the studied population was 5 ± 2 years. their mean age ± standard deviation (sd) was 57 ± 12 years, and 68% (n = 281) were females. only 39% (n = 160; 95% confidence interval [ci]: 34–44%) had a mean bp up to the goal. table 1 describes the demographic and clinical characteristics of the patients with controlled and uncontrolled htn. it can be observed that the age and gender of the subjects had no impact on bp control. smoking was a measurable problem as 8% (n = 34) of subjects were documented as smokers; total hypertensive patients in seeb wilayat (n = 3459) representative sample (n = 500) eligible (n = 411) not eligible (n = 89) more than 3 visits age >18 on antihypertensive medications for > 6 months omani on medication less than 3 visits age <18 on antihypertensive medications for < 6months non-omani not on medication no follow-up in last 6 months figure 1: selection of patients in the study. prevalence of uncontrolled hypertension in primary care settings in al seeb wilayat, oman 352 | squ medical journal, august 2011, volume 11, issue 3 however, they were equally divided between the controlled and uncontrolled groups (p = 0.59). around 23% of hypertensive patients in this study were diabetic; 47% were dyslipidemic; 9% had cardiovascular disease (cvd), and 6.5% were labelled as having kidney disease. the presence of diabetes mellitus or chronic kidney disease was associated with significantly poorer bp control, as more than 93% (n = 88/94) and 81% (n = 22/27) of these patients respectively had uncontrolled htn. the presence of cvd, however, was associated with relatively better bp control, as 58% of hypertensive patients with cvd achieved their bp targets. the presence of dyslipidemia failed to show any association with the control of htn. in addition, 74% (n = 305) of the total subjects were overweight (27%) or obese (47%). of those who were obese, 69% failed to achieve their bp targets (p = 0.02). being overweight was not a determinant of htn control status, nor was normal weight. only 29 individuals (7%) of the total 411 analysed subjects experienced continuity of care in relation to their htn management and follow-up. the statistical analysis did not show any association between continuity of care and htn control (p = 0.89). of 276 individuals with a history of nonadherence to scheduled htn clinic follow-up appointments, 72% had inadequate bp control. a total of 100 subjects (24%) were on a single anti-hypertensive medication, 193 subjects (47%) were on two medications, 96 subjects (23%) were on three medications, and only 18 subjects (4%) were on more than three anti-hypertensive drugs [table 2]. those on monotherapy were more likely to attain their bp control than those on two or more drugs (49% versus 37.8 and 31.3% respectively; p = 0.043). the most commonly prescribed antihypertensive agents were β-blockers and diuretics, 58% and 56% respectively. the class of antihypertensive agent had no influence on htn control among those patients on monotherapy. table 1: demographic and clinical characteristics of the study stratified by blood pressure (bp) goal attainment as per the 7th report of the joint national committee on prevention detection evaluation & treatment of high blood pressure (jnc-7) recommendations blood pressure goal as per jnc-7 p value no (n = 251, 61.1%) yes (n = 160, 38.9%) demographic data (n, % unless indicated otherwise) age, mean ± sd, in years 56.40 ± 12.17 57.43 ± 11.87 0.393 female gender 173 (68.9) 108 (67.5) 0.762 male gender 78 (31.1) 52 (32.5) 0.762 smoking status 21 (8.3) 13 (8.1) 0.593 clinical data (n, % unless indicated otherwise) dyslipidemia 101(40) 70 (44) 0.570 cvd 15 (6) 21 (13) 0.477 diabetes mellitus 88 (35.0) 6 (4.0) 0.001 stroke 5 (2.0) 6 (2.4) 0.416 nephropathy 22 (8.8) 5 (3.1) 0.024 retinopathy 1(0.4) 0 (0) 0.389 thyroid disease 9 (3.6) 8 (5) 0.703 asthma 11(4.4) 11 (6.9) 0.469 normal bmi overweight obese 55 (22) 43 (26.9) 0.02160 (24) 53 (33) 133 (53) 59 (36.8) length of followup in the same clinic (mean ± sd) 4.95 ± 2.18 5.01 ± 2.17 0.620 non-adherence to scheduled follow-up appointments 200 (80) 76 (48) 0.696 continuity of care 17 (7) 12 (8) 0.892 legend: sd = standard deviation; cvd = cardiovascular disease; bmi = body mass index; bp control was defined as casual bp of <140 (systolic) and <90 mmhg (diastolic) and <130 (systolic) and <80 mmhg (diastolic) for diabetic patients as per the jnc-7. table 2: patient and health care related factors and pharmaceutical characteristics of the study stratified by blood pressure (bp) goal attainment as per the 7th report of the joint national committee on prevention detection evaluation & treatment of high blood pressure recommendations blood pressure goal as per jnc7 p value no (n = 251 (61.1%) yes (n = 160 (38.9%) level of antihypertensive therapy mono therapy 51 (20%) 49 (30%) 0.043 dual therapy 113 (45%) 80 (50%) triple therapy 61 (24%) 35 (22%) more than three medications 10 (4%) 8 (5%) rashid al-saadi, sulaiman al-shukaili, suleiman al-mahrazi, zakiya al-busaidi clinical and basic research | 353 discussion inadequate control of htn appears to be a significantly prevalent problem challenging the phc system in oman, as is the case globally. in this practice-based study, the majority (61%) of hypertensive patients failed to reach the targeted bp goals. this can potentially make a significant impact on the morbidity and mortality associated with cardiovascular disease, stroke and other htn-related diseases. almost 20% of the national total hospital deaths in adults aged ≥45 yrs are collectively due to htn-related diseases (ischaemic heart disease 9.7%, cerebrovascular disease 6.8%, and heart failure 3.1%), while direct hypertensive diseases are estimated to account for 3.6% of total deaths.20 inadequate control of htn not only has significant consequences in terms of patient morbidity and mortality, but also in terms of health care costs.21 the high prevalence of uncontrolled htn suggests that a substantial number of cardiovascular events can be prevented by improving bp control. using data from the third national health & nutrition examination survey (nhanes iii), wong et al. estimated that control of htn to levels recommended by the jnc could prevent 19–56% of coronary heart disease events in men and 31–57% of coronary heart disease events in women, depending on the bp achieved.22 the level of htn control found in our study (39%) was similar to that reported in a smaller hospital-based study conducted 8 years earlier in oman (41%).17 the situation of htn control in the arabian gulf region is no better. reports from saudi arabia and bahrain showed a control rate of 25% and 16.5% respectively.23,24 globally, htn control rates vary from one country to another, from as low as 5.4% in korea to as high as 58% in barbados, with a worldwide average of around 30%,9 which clearly demonstrates the worldwide difficulty in achieving satisfactory bp control. as shown in table 1, only half of those 24% who were on a single antihypertensive medication achieved their bp targets. research has demonstrated that bp targets will be reached in only 40–50% of patients taking any single antihypertensive agent.25 the htn management and control guideline by jnc-71 has recommended that most patients with htn will require two or more antihypertensive medications to achieve goal bp (<140/90 mmhg, or <130/80 mmhg for patients with diabetes or chronic kidney disease). several previous studies26,27 have shown that primary care physicians may not be managing htn aggressively enough, and the majority was satisfied with the existing bp values. on the other hand and despite the fact that three quarters of our patients were on two or more antihypertensive medications (the majority taking two drugs), the control of htn in this group was relatively worse than in those taking a single drug. similar findings were reported in a neighbouring country.23 these findings contradict what is concluded by major clinical trials that effective bp control is better achieved with two or more antihypertensive drugs for most patients.28‒30 the association between bp control and level of management is not so self-evident. patient characteristics may contribute a significant influence. our patients who were on monotherapy were likely to have been diagnosed more recently and have less complications and co-morbidities, be younger in age and more involved in their care, and hence probably complied better with the recommended lifestyle adjustments. the current study has also shown that diabetes, dyslipidemia and obesity were common comorbidities among hypertensive patients. the relatively low prevalence (23%) of diabetes among the study population is likely not a representative figure of diabetics with co-existing htn. this is due to the fact that in those phc centres involved in the study most diabetic patients with htn were seen and followed-up in the diabetic clinic rather than in the htn clinic. it is well accepted that patients who have both diabetes and htn are at a greater risk for cardiovascular events compared to non-diabetic hypertensive patients.31 despite this, research by abbott et al. has shown poor bp control in diabetic patients with only 11% of the diabetic patients treated for htn reported as having achieved the systolic bp goal of <130 mmhg.32 a similar percentage was found in a national study where the bp control in diabetics was (10%).17 our study demonstrated remarkably poor control of htn among hypertensive patients with diabetes mellitus (6%, p = 0.001) as well as those with renal insufficiency (18%, p = 0.02). these findings could prevalence of uncontrolled hypertension in primary care settings in al seeb wilayat, oman 354 | squ medical journal, august 2011, volume 11, issue 3 be related to the strict definition of controlled bp in diabetic and kidney disease patients (i.e. <130/80 mmhg) used in this study. it is likely that such a target might not yet be fully employed or accepted in routine practice. in this study, cvd was found to be relatively associated with better bp control. such a positive effect was observed by other studies as well.15,33 the mechanism of this effect is not clear, but it might be a result of improved compliance in these patients or more aggressive treatment by a specialist rather than by a phc physician. another potentially important observation was the relationship between poor bp control and the presence of obesity (p = 0.02), in addition to the high prevalence of obesity (47%) among the studied population. these remarkable figures make it necessary for the health care providers in phc settings to be aware of the importance of emphasising the treatment of obesity as part of the management of htn, if better htn control is to be achieved. although this study failed to show any statistically significant association between the control of htn and continuity of care (as defined in this study), the importance of this aspect in the long term management of chronic diseases like htn is beyond doubt. the absence of such an aspect from the care provided for hypertensive patients in all phc centres in this study was a significant defect which needs to be addressed. several limitations of this study deserve mention. as this is a retrospective study, no information was available on how bp was measured and recorded which might question the accuracy of the bp readings obtained. the absence of some data from patients' electronic records could also have affected the findings and their ability to be generalised. a possible bias in this study is related to hypertensive patients who were also diabetics and whose htn was followed-up in the diabetic clinic; they were thus not registered as hypertensive and so not included in the study. another possible bias might also arise from the exclusion of hypertensive patients who were not on anti-hypertensive medication. however, such biases, if true, could contribute to further supporting our findings of poor htn control since the excluded group could be expected to have even worse bp control. this study was conducted in phc centres where family physicians were available, which is not the case in other phc centres in rural parts of oman. this limits the generalisation of the results to the whole of oman. the lack of a global assessment of cardiovascular risk for each patient was another limitation. conclusion the present study concluded that htn is not adequately controlled in over 60% of treated patients, and that is explained by different factors including co-existing conditions like diabetes and obesity, as well as insufficient pharmacological treatment in many patients. moreover, it seems that our primary care physicians have little training and experience in treating to target, as we have observed with the results of hypertensive patients with diabetes and renal disease. improving the quality of htn care is a priority and effective efforts need to be taken in order to improve bp control among hypertensive patients. clinical experience affords sufficient reason not to delay aggressive treatment in patients with uncontrolled htn. obese patients and diabetics should be targeted for even greater attention to bp control. any effort to decrease any degree of bp which is above the normal range is beneficial. further improvements in htn control will require changes in physician behaviour which should be associated with more awareness of and familiarity with updated evidence-based practice guidelines. further research is needed to explore in depth different underlying factors influencing the appropriate htn control. a c k n o w l e d g e m e n t the authors also would like to thank dr. abdullah al-muniri for his generous help with the statistical part of the study. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. chobanian av, bakris gl, black hr, cushman wc, green le, izzo jl, et al. the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. jama 2003; 289:2560–72. rashid al-saadi, sulaiman al-shukaili, suleiman al-mahrazi, zakiya al-busaidi clinical and basic research | 355 2. preliminary data from world health survey. 2008. used with permission from non-communicable disease department, ministry of health, oman, 2010. (in press). 3. berrios x, kopnen t, huiguang t, khaltaev n, puska p, nissinen a. distribution and prevalence of major risk factors of non-communicable diseases in selected countries: who inter-health program. bull world health organ 1997; 75:99–108. 4. us department of health and human services. screening for hypertension: the guide to clinical preventive services: task force. 2nd ed. 1996. pp. 39‒53. 5. al-rukban mo, al-sughair am, al-bader bo, altolaihi ba. management of hypertensive patients in primary health care setting, auditing the practice, saudi arabia. saudi med j 2007; 28:85–90. 6. konzem sl, devore vs, bauer dw. controlling hypertension in patients with diabetes. am fam physician 2002; 66:1209–14. 7. padwal r, straus se, mcalister fa. cardiovascular risk factors and their effects on the decision to treat hypertension: evidence based review. bmj 2001; 322:977–80. 8. bernard db, townsend rr, sylvestri mf. health and disease management: what is it and where is it going? what is the role of health and disease management in hypertension? am j hypertens 1998; 11:103–11. 9. kearney pm, whelton m, reynolds k, whelton pk, he j. worldwide prevalence of hypertension: a systematic review. j hypertens 2004; 22:11–19. 10. cushman wc, ford ce, cutler ja, marqolis kl, davis br, grimm rh, et al. success and predictors of blood pressure control in diverse north american settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (allhat). j clin hypertens 2002; 4:393–404. 11. black hr, elliott wj, neaton jd, grandits g, grambsch p, grimm rh jr, et al. baseline characteristics and elderly blood pressure control in the convince trial. hypertension 2001; 37:12–8. 12. düsing r. overcoming barriers to effective blood pressure control in patients with hypertension. curr med res opin 2006; 22:1545–53. 13. avanzini f, alli c, colombo f, tognoni g. control of hypertension in italy: results of the study on antihypertensive treatment in general practice (stap). g ital cardiol 1998; 28:760–6. 14. inkster m. organizational factors in relation to control of blood pressure: an observational study. j gen pract 2005; 55:931–7. 15. deqli esposti e, di martino m, sturani a, russo p, dradi c, falcinelli s, et al. risk factors for uncontrolled hypertension in italy. j hum hypertens 2004; 18:207–13. 16. llisterri caro jl, rodríguez roca gc, alonso moreno fj, lou arnol s, divisón garrote ja, santos rodríguez ja, et al. blood pressure control in spanish hypertensive patients in primary health care centers. prescap 2002 study. med clin (barc) 2004; 122:165–71. 17. almahrezi a, al-zakwani i, al-aamri a, al-khaldi s, al-zadjali n, al-hatali m, et al. control and management of hypertension at a university health centre in oman. squ med j 2006:179–84. 18. oman census 2003 report. muscat: oman census administration, ministry of national economy, 2004. 19. gulliford m, naithani s, morgan m. what is 'continuity of care'? j health serv res policy 2006; 11:248–50. 20. department of health information & statistics, directorate general of planning, ministry of health, oman annual health report 2009. muscat: ministry of health, 2010. 21. kalantan ka, mohamed ag, al-taweel aa, abdulghani hm. hypertension among attendants of primary health care centers in al-qassim region, saudi arabia. saudi med j 2001; 22:960–3. 22. wong nd, thakral g, franklin ss, l'italien gj, jacobs mj, whyte jl, et al. preventing heart disease by controlling hypertension: impact of hypertensive subtype, stage, age, and sex. am heart j 2003; 145:888–95. 23. al-rukban mo, al-sughair am, al-bader bo, altolaihi ba. management of hypertensive patients in primary health care setting: auditing the practice. saudi med j 2007; 28:85–90. 24. al khaja ka, sequeira rp, damanhori ah. treatment of hypertension in bahrain. ann pharmacother 2003; 37:1511–17. 25. materson bj, reda dj, cushman wc. department of veterans affairs cooperative study group on antihypertensive agents. department of veterans affairs single-drug therapy of hypertension study. revised figures and new data. am j hypertens 1995; 8:189–92. 26. oliveria sa, lapuerta p, mccarthy bd, l’italien gi, berlowitz dr, asch sm. physician-related barriers to the effective management of uncontrolled hypertension. arch intern med 2002; 162:413–20. 27. sever ps. blood pressure control for the hypertensive patient: what can we do better? am j hypertens 1997; 10:128–30. 28. fox jc, leight k, sutradhar sc, demopoulos la, gleim gw, lewin aj, et al. the jnc-7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy. j clin hypertens (greenwich) 2004; 6:437–442. 29. jamerson k, bakris gl, dahlof b, pitt b, velazquez e, gupte j, et al. exceptional early blood pressure prevalence of uncontrolled hypertension in primary care settings in al seeb wilayat, oman 356 | squ medical journal, august 2011, volume 11, issue 3 control rates: the accomplish trial. blood press 2007; 16:80–86. 30. neutel jm, smith dh, weber ma, schofield l, purkayastha d, gatlin m. efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the systolic evaluation of lotrel efficacy and comparative therapies (select) study. j clin hypertens 2005; 7:641–6. 31. casiglia e, zanette g, mazza a, donadon v, donada c, pizziol a, et al. cardiovascular mortality in noninsulin dependent diabetes mellitus. a controlled study among 683 diabetics and 683 ageand sexmatched normal subjects. eur j epidemiol 2000; 16:677–84. 32. abbott k, basta e, bakris gl. blood pressure control and nephroprotection in diabetes. j clin pharmacol 2004; 44:431–8. 33. knight el, bohn rl, wang ps, glynn rj, mogun h, avorn j. predictors of uncontrolled hypertension in ambulatory patients. hypertension 2001; 38:809–14. 1department of psychiatry, king saud university, riyadh, saudi arabia; 2college of medicine, al-imam university, riyadh, saudi arabia; 3college of medicine, taibah university, madinah, saudi arabia; 4department of psychiatry, faculty of medicine, kuwait university, kuwait; 5department of psychiatry, faculty of medicine, university of toronto, toronto, ontario, canada *corresponding author’s e-mail: malarabi@ksu.edu.sa الرتمجة العربية و تصديق مقياس هاميلتون لإلكتئاب ذي السبعة عناصر يف شرحيتني من اجملتمع اأحمد الهادي، حممد العرابي، عبدالعزيز ال�شمراين، راأفت �شقدار، حممد ال�شويدان، روجر ماكنتاير abstract: objectives: depression is a common mental disorder, the severity of which is frequently assessed via interview-based clinical scales such as the 7-item hamilton depression rating scale (hamd-7). the current study aimed to translate and examine the validity of an arabic version of the hamd-7 scale. methods: this study took place between february and march 2016 in the psychiatry department of king saud university, riyadh, saudi arabia. the hamd-7 scale was translated into arabic using forward and backward translation methods. a total of 153 arabic speakers were recruited to test the translated scale, including 57 medical students and 96 members of the general public. the arabic version of the hamd-7 scale was completed by trained investigators during face-toface interviews with the participants. in order to assess convergent validity, participants also completed an arabic version of the self-assessed patient health questionnaire-9 (phq-9) scale. subsequently, the test-retest reliability of the translated hamd-7 scale was evaluated two weeks later during a second interview. results: overall, hamd7 scores were positively correlated with phq-9 scores (r = 0.633–0.749). moreover, the translated hamd-7 scale proved to be reliable in terms of test-retest reliability (intra-class correlation coefficient: 0.807; p <0.001). with regards to internal consistency, the cronbach’s α values ranged between 0.607–0.756. conclusion: the arabic hamd-7 scale was found to be reliable and valid among two samples of arabic speakers in saudi arabia. however, further research among arab-speaking patients diagnosed with depression is needed in order to establish its usefulness in assessing the severity of depressive symptoms. keywords: psychiatry; depression; psychometrics; validity and reliability; translation; questionnaire design; saudi arabia. امللخ�ص: االهدف: يعد الإكتئاب من الإ�شطرابات النف�شية ال�شائعة الذي يتم تقدير �شدة اأعرا�شه با�شتخدام مقايي�ض �رضيرية مثل مقيا�ض هاميلتون لالإكتئاب املحتوي على �شبعة عنا�رض، تهدف هذه الدرا�شة لرتجمة املقيا�ض للغة العربية والتاأكد من م�شداقيته ودقته. الطريقة: مت اإجراء هذه الدرا�شة يف كلية الطبق�شم الطب النف�شي بجامعة امللك �شعود بالريا�ض يف اململكة العربية ال�شعودية يف الفرتة املمتدة من �شهر فرباير اإىل �شهر مار�ض 2016، ومتت ترجمة مقيا�ض هاميلتون لالإكتئاب ذي ال�شبعة عنا�رض اإىل اللغة العربية ومن ثم اإعادة ترجمته للغة الأ�شل للتاأكد من �شحة الرتجمة، بعد ذلك قام باحثون مت تدريبهم بتجربة املقيا�ض املرتجم من خالل مقابالت �شخ�شية وجهًا لوجه مع 153 م�شاركًا متحدثًا باللغة العربية منهم 57 طالبًا من كلية الطب الب�رضي و 96 متحدثًا من عامة النا�ض، قام امل�شاركون اأي�شًا بتعبئة الن�شخة املرتجمة للعربية وامل�شدقة من ا�شتبيان �شحة املري�ض-ن�شخة-9 وذلك بهدف التحقق من م�شداقية ترجمة مقيا�ض هاميلتون، بعد ذلك مت اإعادة تقييم مقيا�ض هاميلتون املرتجم للعربية من خالل مقابالت �شخ�شية اأخرى انعقدت بعد اأ�شبوعني من املقابلة الأوىل. عنا�رض ال�شبع ذي لالإكتئاب هاميلتون مقيا�ض ونتائج املري�ض-9 �شحة ا�شتبيان نتائج بني طرديًا تنا�شبًا عام ب�شكل وجد النتائج: )معامل التنا�شب: 0.749–0.633(. كما مت اإثبات موثوقية املقيا�ض عندما متت اإعادة جتربته على امل�شاركني )معامل الرتباط: 0.807؛ p >0.001(، واأظهر التحليل الإح�شائي اأن معامل الإن�شجام الداخلي chronbach’s α كان يرتاوح ما بني 0.756–0.607. اخلال�صة: كانت على املرتجمة الن�شخة جتربة متت عندما موثوقية و م�شداقية ذات ال�شبعة العنا�رض ذي لالإكتئاب هاميلتون ملقيا�ض العربية الرتجمة عينتني من املتحدثني باللغة العربية يف اململكة العربية ال�شعودية، لكن ي�شتلزم اإجراء املزيد من الأبحاث لتجربة املقيا�ض املرتجم على املر�شى امل�شخ�شني بالإكتئاب واملتحدثني باللغة العربية لإثبات فاعلية املقيا�ض يف تقدير �شدة اأعرا�ض الإكتئاب. الكلمات املفتاحية: الطب النف�شي؛ اإكتئاب؛ قيا�ض العمليات النف�شية؛ م�شداقية وموثوقية؛ ترجمة؛ ت�شميم ا�شتبيان؛ اململكة العربية ال�شعودية. arabic translation, validation and cultural adaptation of the 7-item hamilton depression rating scale in two community samples ahmad n. alhadi,1 *mohammed a. alarabi,1 abdulaziz t. alshomrani,2 raafat m. shuqdar,3 mohammad t. alsuwaidan,4 roger s. mcintyre5 clinical & basic research sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e167–172, epub. 9 sep 18 submitted 7 nov 17 revision req. 19 dec 17; revision recd. 16 jan 18 accepted 18 feb 18 advances in knowledge to the best of the authors’ knowledge, this study is the first to translate the 7-item hamilton depression rating scale (hamd-7) into arabic using forward and backward translation methods. doi: 10.18295/squmj.2018.18.02.008 arabic translation, validation and cultural adaptation of the 7-item hamilton depression rating scale in two community samples e168 | squ medical journal, may 2018, volume 18, issue 2 depression is a frequent problem in thegeneral population and the most common mental health condition among patients seen at primary care facilities.1,2 moreover, it is currently the leading cause of disability and premature death among those aged 18–43 years old.3 however, unlike many other chronic medical disorders, there are currently no clinically relevant biological markers for depression, meaning that the assessment of depressive symptoms depends on standardised rating tools. patient-administered self-assessment screening tools are a quick and reliable option in the initial assessment of depression or for treatment monitoring purposes. such scales frequently used in clinical practice and research include the beck depression inventory (bdi), patient health questionnaire-9 (phq-9), center for epidemiologic studies depression (ces-d) scale and the zung self-rating depression scale.4–9 the hamilton depression rating scale (hamd) is one of the most widely used scales to objectively rate depression severity worldwide.10–12 the original scale contains 17 items, of which four do not contribute to the final score and instead provide additional clinical information. the other items are scored on a 3–5 point scale, with the final score indicative of the severity of the patient’s depression.10 since its development in 1960, structured interview guides, self-report forms and computerised versions of the scale have been created in an effort to standardise administration of the tool and improve the reliability and validity of individual items.10,12,13 researchers have also attempted to shorten the scale while preserving its psychometric properties; accordingly, a 7-item version was developed in 2003 to estimate depression severity based on criteria in the fourth edition of the diagnostic and statistical manual of mental disorders.14 the 7-item hamd (hamd-7) scale utilises the same scoring system as the original version, but can also be used to evaluate treatment efficacy by distinguishing between a clinical response to treatment and full symptomatic remission. mcintyre et al. reported that the hamd-7 scale takes significantly less time to complete than the original version, while offering the same level of accuracy.11 overall, the hamd-7 scale focuses on a subset of symptoms covered in the original ham-d (i.e. depressed mood, feelings of guilt, interest, pleasure and level of activity, psychological anxiety, somatic anxiety, energy level and suicidality) and differs from other depression rating scales like the bdi or the ces-d by omitting various indicators of depression, such as altered sleep patterns and changes in appetite.4,8,14 in contrast, the 6-item version of the hamd scale has shown good psychometric properties and has been translated into several languages, including arabic.15–19 however, this version does not score for suicidality, which may limit its clinical usefulness. moreover, a review of the literature did not reveal any other brief validated structured arabic-language interview-based scale to measure depression severity and response to treatment in clinical settings. therefore, this study aimed to translate the hamd-7 scale into arabic and determine the validity and reliability of the final arabic version. methods this study took place between february and march 2016 in the psychiatry department of king saud university, riyadh, saudi arabia. a multi-step process was undertaken to translate the hamd-7 scale into arabic and validate it in an arab population. the original english-language version of the hamd-7 scale was translated using established forwards and backwards translation methods.14,20,21 first, two independent translators each translated the englishlanguage version of the scale into arabic. a committee of arabic-speaking researchers then compared these translations both with each other and with the original english version in order to create a first draft. next, the two independent translators translated the draft back into english and the committee again compared both back-translated versions together and with the first draft to ensure the accuracy of the content. a second draft was then created and examined to resolve any ambiguities. the second draft, along with the original english-language version of the hamd-7 scale, was submitted to five mental health experts to check face validity, with minor modifications made based on their feedback. the final arabic version of the scale was deemed to reflect an accurate translation of the items in the original hamd-7 scale.14 a pilot study was subsequently conducted among 10 healthy bilingual adults (six males and four females) to assess the results of this study indicate that the translated scale had acceptable reliability and convergent validity among two samples of arabic-speaking participants in saudi arabia. application to patient care the validated arabic version of the hamd-7 scale may be a potentially useful psychiatric tool for the assessment of depression among arabic-speaking patients, due to its brevity and focus on major aspects of depressive disorders. ahmad n. alhadi, mohammed a. alarabi, abdulaziz t. alshomrani, raafat m. shuqdar, mohammad t. alsuwaidan and roger s. mcintyre clinical and basic research | e169 the clarity of the items in the final arabic version of the hamd-7 scale, estimate the time required for the interview and carry out a preliminary investigation of the psychometric properties of the scale. the results indicated that the arabic hamd-7 scale was timeefficient, taking approximately 4 minutes to administer. moreover, feedback from the participants in the pilot study refined the translation of the sixth item in that “energy level” was instead translated to “activity level” due to the latter term being more comprehensible in arabic. a total of 153 arabic-speaking participants were recruited to complete the arabic hamd-7 scale in two separate samples. the first sample (n = 57) was selected randomly using online randomisation software (research randomizer, version 4.0, wesleyan university, middletown, connecticut, usa) from a list of fourth-year medical students at king saud university. the second sample (n = 96) was recruited as a convenience sample from members of the gen eral arabic-speaking population at two public parks in riyadh. the inclusion criteria encompassed individuals with arabic literacy and no pronounced cognitive deficits. the sample size was calculated using a subject-to-item ratio with at least 10 subjects per item, resulting in a total required sample size of 70 participants.20 each participant was interviewed by trained investigators who administered the arabic hamd-7 scale while following a structured interview guide.13 in order to measure the test-retest reliability of the scale, the translated hamd-7 scale was administered to each subject twice, including once at enrolment (day one) and then again two weeks after the initial interview (day 14). each participant was assigned a code number so that their scores in the first and second interviews could be paired for analysis. subjects also completed an arabic version of the selfadministered phq-9 during the first interview so as to establish convergent validity.5 the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa), was used to carry out the analysis of the data. due to the skewed distribution of the scale scores, spearman’s rank correlation coefficient with a twotailed test of significance was used to test agreement between the arabic hamd-7 and phq-9 scores and establish convergent validity. internal consistency of the arabic hamd-7 scale was deemed satisfactory at a cronbach’s α value of >0.600.22 the test-retest reliability was quantified using intra-class correlation coefficient (icc) values for absolute agreement. a p value of <0.050 was deemed statistically significant. ethical approval for this study was granted by the king saud university institutional review board prior to data collection (#e-15-1691). each participant provided written informed consent before being included in the study. the identity of each participant was codified for the purposes of anonymity and no incentives or rewards were given for participation. results a total of 153 arabic-speaking individuals took part in the study, including 57 medical students and 96 members of the general public [figure 1]. among the first sample, 38 were female (66.7%) and 19 were male (33.3%). the mean age was 22.12 ± 0.44 years old figure 1: diagram showing the protocol of the study and total number of participants at each stage. the first sample consisted of randomly selected fourth-year medical students from king saud university, riyadh, saudi arabia, while the second sample was recruited via convenience sampling from two public parks in riyadh. an arabic version of the 7-item hamilton depression rating scale was completed for each participant during two face-to-face interviews held two weeks apart.14 the participants also filled out the self-assessed patient health questionnaire-9 during the initial interview.5 hamd-7 = 7-item hamilton depression rating ; phq-9 = patient health questionnaire-9. arabic translation, validation and cultural adaptation of the 7-item hamilton depression rating scale in two community samples e170 | squ medical journal, may 2018, volume 18, issue 2 (range: 21–23 years). the second sample consisted of 74 female (77.1%) and 22 male (22.9%) members of the general public. the mean age was 27.42 ± 8.28 years old (range: 19–63 years). among the first sample, mean hamd-7 scores were 4.3 ± 2.9 (range: 0–16) and 3.5 ± 3.4 (range: 0–13) at days one and 14, respectively. the mean phq-9 score was 5.3 ± 4.3 (range: 0–17). among the second sample, the initial mean hamd-7 score was 4.2 ± 3.5 (range: 0–16), while the mean score two weeks later was 3.2 ± 3.4 (range: 0–13). the mean phq-9 score was 6.3 ± 4.3 (range: 0–20). for both samples combined, the mean hamd-7 scores were 4.2 ± 3.3 and 3.6 ± 3.4 at days one and 14, respectively, while the mean phq-9 score was 5.7 ± 4.3 [table 1]. in general, female participants had higher hamd-7 scores, with a mean difference of 1.83 at day one and 1.54 at day 14 (p <0.010 each). the phq-9 scores differed as well, with females scoring an average of 1.5 points higher than males (p = 0.920). the internal consistency of the arabic hamd-7 scale was acceptable among both the first and second samples during the initial interview (cronbach’s α: 0.607 and 0.660, respectively) and two weeks later (cronbach’s α: 0.756 and 0.719, respectively). moreover, the internal consistency remained acceptable after the scores of both samples were combined (cronbach’s α: 0.641 and 0.728, respectively). furthermore, the testretest reliability of the translated scale was maintained among both samples, with icc values of 0.836 for the first sample and 0.793 for the second sample [table 2]. for convergent validity, the initial scores of the arabic hamd-7 scale were significantly positively correlated with scores from the phq-9 for both samples (r = 0.668 and 0.749, respectively; p <0.001 each). the second hamd-7 scores also correlated with the initial phq-9 scores for both samples (r = 0.714 and 0.648; p <0.001 each) [table 3]. in terms of individual items on the arabic hamd-7 scale, the lowest measure of inter-item correlation was between the suicidality and psychological anxiety items (0.046), while the highest was between the energy level and somatic anxiety items (0.428) [table 4]. in addition, an analysis of the psychometric properties of the individual items revealed that the internal consistency of the translated scale did not improve with the deletion of any of the seven items [table 5]. all of the individual items of the hamd-7 scale correlated positively with the phq-9 scores (p <0.050). discussion this study aimed to validate an arabic version of the hamd-7 scale to ensure conceptual and performance equivalence with the original scale.14 during the interviews, the participants noted that they found the individual items in the scale easy to understand; however, in the event of any ambiguity, the interviewer provided additional clarification, as recommended in the structured interview guide for the original hamd table 1: mean scores of arabic versions of the 7-item hamilton depression rating scale14 and patient health questionnaire-95 among two samples in riyadh, saudi arabia (n = 153) scale total first sample (n = 57) second sample (n = 96) day one mean ± sd 4.2 ± 3.3 4.3 ± 2.9 4.2 ± 3.5 median (iqr) 4 (6–2) day 14 mean ± sd 3.6 ± 3.4 3.5 ± 3.4 3.2 ± 3.4 median (iqr) 3 (6–1) mean ± sd 5.7 ± 4.3 6.3 ± 4.3 5.3 ± 4.3 median (iqr) 5 (8–2) hamd-7 = 7-item hamilton depression rating; phq-9 = patient health questionnaire-9; sd = standard deviation; iqr = interquartile range. h a m d -7 sc or e ph q -9 sc or e table 2: internal consistency and test-retest reliability of an arabic version of the 7-item hamilton depression rating scale14 among two samples in riyadh, saudi arabia (n = 153) cronbach’s α icc* day one day 14 first sample (n = 57) 0.607 0.756 0.836 second sample (n = 96) 0.660 0.719 0.793 total 0.641 0.728 0.807 icc = intraclass correlation coefficient. *tested for absolute agreement table 3: convergent validity between arabic versions of the 7-item hamilton depression rating scale14 and patient health questionnaire-95 among two samples in riyadh, saudi arabia (n = 153) rho p value* day one day 14 first sample (n = 57) 0.668 0.714 <0.001 second sample (n = 96) 0.749 0.648 <0.001 total 0.717 0.633 <0.001 hamd-7 = 7-item hamilton depression rating scale; phq = patient health questionnaire. *calculated using spearman’s rank correlation coefficient with a twotailed test of significance. ahmad n. alhadi, mohammed a. alarabi, abdulaziz t. alshomrani, raafat m. shuqdar, mohammad t. alsuwaidan and roger s. mcintyre clinical and basic research | e171 scale.13 the average time taken to complete the arabic hamd-7 scale was approximately 4 minutes, although administration of the scale in a clinical setting may take more or less time depending on whether the scale is incorporated as part of a psychiatric interview. in the present study, neither the mean hamd-7 nor phq-9 scores of the two samples differed significantly. females, however, scored higher than males; this finding may be a reflection of the higher incidence of depressive disorders in the female population.1 in addition, subjects of the first student sample scored slightly higher in the first interview, possibly because the students had undertaken an examination very shortly beforehand. overall, the current study found that the arabic hamd-7 scale had acceptable internal consistency, with cronbach’s α values ranging between 0.607—0.756.22 however, this does not rule out the possibility that the scale measures a different, albeit related, construct to depression. moreover, these values likely do not represent a true measure of the internal consistency of the scale as both samples consisted of individuals without clinically-diagnosed depression. hence, in order to more accurately measure internal consistency, the scale should be tested among a sample of depressed patients. the present study also revealed good convergent validity between the arabic hamd-7 and phq-9 scales. this indicates that, despite the different depressive symptoms included in each scale, both the hamd-7 and phq-9 scales measure similar constructs, with all items of the hamd-7 scale correlating with the phq-9 scores. finally, an analysis of the test-retest reliability of the arabic hamd-7 scale showed that the test was reliable over a 14-day period, despite being administered at different times and by different investigators. the current study was subject to certain limitations. due to difficulties in testing the newly translated scale on patients diagnosed with depression, two community samples of college students and members of the general population, respectively, were utilised. this limits the generalisability of the results, especially as the hamd-7 scale is not intended to be a diagnostic tool, but instead a measure of the severity of certain depressive symptoms among patients already diagnosed with clinical depression.14 further studies are therefore recommended to fully explore the psychometric properties of the arabic version of the scale by testing it on patients diagnosed with clinical depression. in addition, future research should table 5: psychometric properties of items in an arabic version of the 7-item hamilton depression rating scale14 among two samples in riyadh, saudi arabia (n = 153) item scale mean* scale variance* itc cronbach’s α* depressed mood 3.14 6.848 0.517 0.541 feelings of guilt 3.75 8.941 0.307 0.618 interest, pleasure and level of activity 3.76 8.316 0.365 0.601 psychological anxiety 3.28 7.901 0.322 0.620 somatic anxiety 3.49 8.173 0.310 0.621 energy level 3.80 8.939 0.452 0.590 suicidality 4.08 9.757 0.277 0.629 itc = item-total correlation. *after elimination of the item in question from the scale. table 4: inter-item correlation matrix of an arabic version of the 7-item hamilton depression rating scale14 among two samples in riyadh, saudi arabia (n = 153) group a group b depressed mood feelings of guilt interest, pleasure and level of activity psychological anxiety somatic anxiety energy level suicidality depressed mood 1.000 feelings of guilt 0.274 1.000 interest, pleasure and level of activity 0.349 0.183 1.000 psychological anxiety 0.328 0.245 0.164 1.000 somatic anxiety 0.247 0.064 0.164 0.095 1.000 energy level 0.268 0.173 0.270 0.228 0.428 1.000 suicidality 0.284 0.136 0.155 0.046 0.213 0.152 1.000 arabic translation, validation and cultural adaptation of the 7-item hamilton depression rating scale in two community samples e172 | squ medical journal, may 2018, volume 18, issue 2 be conducted to determine the efficacy of the arabic hamd-7 scale in assessing the response to treatment with antidepressants. conclusion in this study, an arabic version of the interview-based hamd-7 scale was validated among two communitybased samples of arabic speakers in riyadh. the scale showed good convergent validity when compared to a previously validated arabic version of the selfreported phq-9 scale. in addition, it also showed acceptable test-retest reliability over a period of two weeks, even when the scale was completed by different interviewers. overall, the translated arabic hamd-7 scale may be a potentially useful clinical tool for clinicians and researchers seeking to assess depression severity among arab patients. however, further research is required to assess the validity of the scale among patients diagnosed with depression. a c k n o w l e d g e m e n t s the authors acknowledge the efforts of abdulrahman bahhari, amani al-rafie, bodoor al-enazi, dalal al-roais, haifa al-katheri, hannin khurmi, manal al-anzi, mohamad al-dkheel, nujud al-otaibi, omar al-bader, rawand al-otaibi, reem al-shehri, reemah al-aifan, sara al-bakr and sultan al-otaibi, whose work as trained interviewers was indispensable in the data collection process. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this research was financially supported by the sabic psychological health research and applications chair of king saud university. references 1. world health organization. depression and other common mental disorders: global health estimates. from: http://apps. who.int/iris/bitstream/10665/254610/1/who-msd-mer2017.2-eng.pdf accessed: jan 2018. 2. roca m, gili m, garcia-garcia m, salva j, vives m, garcia campayo j, et al. prevalence and comorbidity of common mental disorders in primary care. j affect disord 2009; 119:52–8. doi: 10.1016/j.jad.2009.03.014. 3. murray cj, lopez ad. alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. lancet 1997; 349:1498–504. doi: 10.1016/s0140-6736(96) 07492-2. 4. beck at, steer ra, brown gk. manual for the beck depression inventory-ii. san antonio, texas, usa: psychological corp., 1996. pp. 1–82. 5. kroenke k, spitzer rl, williams jb. the phq-9: validity of a brief depression severity measure. j gen intern med 2001; 16:606–13. doi: 10.1046/j.1525-1497.2001.016009606.x. 6. spitzer rl, kroenke k, williams jb. validation and utility of a self-report version of prime-md: the phq primary care study. jama 1999; 282:1737–44. doi: 10.1001/jama.282.18.1737. 7. gilbody s, richards d, brealey s, hewitt c. screening for dep ression in medical settings with the patient health questionnaire (phq): a diagnostic meta-analysis. j gen intern med 2007; 22:1596–602. doi: 10.1007/s11606-007-0333-y. 8. radloff ls. the ces-d scale: a self-report depression scale for research in the general population. appl psychol meas 1977; 1:385–401. doi: 10.1177/014662167700100306. 9. zung ww. a self-rating depression scale. arch gen psychiatry 1965; 12:63–70. doi: 10.1001/archpsyc.1965.01720310065008. 10. hamilton m. a rating scale for depression. j neurol neurosurg psychiatry 1960; 23:56–62. doi: 10.1136/jnnp.23.1.56. 11. mcintyre rs, konarski jz, mancini da, fulton ka, parikh sv, grigoriadis s, et al. measuring the severity of depression and remission in primary care: validation of the hamd-7 scale. cmaj 2005; 173:1327–34. doi: 10.1503/cmaj.050786. 12. williams jb. standardizing the hamilton depression rating scale: past, present, and future. eur arch psychiatry clin neurosci 2001; 251:ii6–12. doi: 10.1007/bf03035120. 13. williams jb. a structured interview guide for the hamilton depression rating scale. arch gen psychiatry 1988; 45:742–7. doi: 10.1001/archpsyc.1988.01800320058007. 14. mcintyre r, fulton ka, bakish d, jordan j, kennedy sh. the ham-d 7: a brief depression scale to distinguish antidepressant response from symptomatic remission. prim psychiatry 2003; 10:39–42. 15. bech p, gram lf, dein e, jacobson o, vitger j, bolwing tg. quantitative rating of depressive states. acta psychiatr scand 1975; 51:161–70. doi: 10.1111/j.1600-0447.1975.tb00002.x. 16. lecrubier y, bech p. the ham d(6) is more homogenous and as sensitive as the ham d(17). eur psychiatry 2007; 22:252–5. doi: 10.1016/j.eurpsy.2007.01.1218. 17. lee cp, liu cy, hung ci. psychometric evaluation of a 6-item chinese version of the hamilton depression rating scale: mokken scaling and item analysis. asia pac psychiatry 2017; 9:e12287. doi: 10.1111/appy.12287. 18. bachner yg, o’rourke n, goldfracht m, bech p, ayalon l. psychometric properties of responses by clinicians and older adults to a 6-item hebrew version of the hamilton depression rating scale (ham-d6). bmc psychiatry 2013; 13:2. doi: 10.11 86/1471-244x-13-2. 19. bachner yg. psychometric properties of responses to an arab ic version of the hamilton depression rating scale (ham d6). j am psychiatr nurses assoc 2016; 22:27–30. doi: 10.117 7/1078390316629959. 20. sousa vd, rojjanasrirat w. translation, adaptation and validation of instruments or scales for use in cross-cultural health care research: a clear and user-friendly guideline. j eval clin pract 2011; 17:268–74. doi: 10.1111/j.1365-2753.2010.01434.x. 21. world health organization. management of substance abuse: process of translation and adaptation of instruments. from: www.who.int/substance_abuse/research_tools/translation/en/ accessed: jan 2018. 22. loewenthal km. an introduction to psychological tests and scales, 2nd ed. hove: psychology press, 2001. pp. 53–76. https://doi.org/10.1016/j.jad.2009.03.014 https://doi.org/10.1016/s0140-6736%2896%2907492-2 https://doi.org/10.1016/s0140-6736%2896%2907492-2 https://doi.org/10.1046/j.1525-1497.2001.016009606.x https://doi.org/10.1001/jama.282.18.1737 https://doi.org/10.1007/s11606-007-0333-y https://doi.org/10.1177/014662167700100306 https://doi.org/10.1001/archpsyc.1965.01720310065008 https://doi.org/10.1136/jnnp.23.1.56 https://doi.org/10.1503/cmaj.050786 https://doi.org/10.1007/bf03035120 https://doi.org/10.1001/archpsyc.1988.01800320058007 https://doi.org/10.1111/j.1600-0447.1975.tb00002.x https://doi.org/10.1016/j.eurpsy.2007.01.1218 https://doi.org/10.1111/appy.12287 https://doi.org/10.1186/1471-244x-13-2 https://doi.org/10.1186/1471-244x-13-2 https://doi.org/10.1177/1078390316629959 https://doi.org/10.1177/1078390316629959 https://doi.org/10.1111/j.1365-2753.2010.01434.x 1department of haematology, sultan qaboos university hospital, muscat, oman; departments of 2obstetrics & gynaecology and 3haematology & transfusion medicine, royal hospital, muscat, oman; 4department of studies & research, oman medical specialty board, muscat, oman; 5department of blood bank services, ministry of health, muscat, oman *corresponding author’s e-mail: mouzaalsalmani@gmail.com نقل الدم للجنني يف داخل الرحم دراسة وصفية لتجربة األربعة سنوات األوىل يف سلطنة عمان اأروى زكريا الريامي، موزة ال�سلماين، �سربية الها�سمي، �سباح املحروقي، علي املرهوبي، �سمية الهنائي، �سيف احلو�سني، �ساثية مورثي بان�سات�سارام، زينب الفنا العرميي abstract: objectives: haemolytic disease of the fetus and newborn (hdfn) causes hydrops fetalis. the successful treatment of hdfn has been reported with intrauterine blood transfusion (iut). this study aimed to describe the initial experience with iut procedures in oman. methods: this retrospective observational study took place at the royal hospital and sultan qaboos university hospital blood bank, muscat, oman, and included all women who underwent iut procedures in oman between march 2012 and march 2016. gestational and neonatal outcomes were assessed, including complications, morbidity, neurodevelopmental sequelae and mortality. results: a total of 28 iut procedures for 13 fetuses carried by 11 women were performed. gestational age at the time of referral ranged from 13–30 weeks, while the median gestational age at first iut procedure was 26 weeks (range: 19–30 weeks). indications for the procedure included hdfn caused by anti-d (n = 6), a combination of anti-d and anti-c (n = 4), anti-k (n = 1) and anti-jsb (n = 1) antibodies and nonimmune hydrops fetalis due to a congenital parvovirus infection (n = 1). median fetal haemoglobin levels at the beginning and end of the procedure were 4.6 g/dl and 12.8 g/dl, respectively. most procedures were transplacental intravascular transfusions through the placental umbilical cord root (71.4%), followed by transamniotic intravascular transfusions (14.3%). the overall survival rate was 61.5%, with five deaths; of these, four were intrauterine and one was an early neonatal death due to non-resolved hydrops and severe cardiac dysfunction. conclusion: as a relatively novel obstetric procedure in oman, iut seems to result in a favourable outcome for hydropic fetuses. keywords: fetus; hydrops fetalis; anemia; intrauterine blood transfusion; fetal death; oman. امللخ�ص: الهدف: مر�ض انحالل الدم لدى االأجنة وحديثي الوالدة ي�سبب حالة جتمع لل�سائل اجلنيني، وتوؤ�رص التقارير ال�سابقة عن عالج ناجح لهذا املر�ض با�ستخدام تقنية نقل الدم داخل الرحم، هدفت الدرا�سة احلالية اإىل و�سف التجربة االأولية الإ�ستخدام هذه الطريقة يف عمان. الطريقة: اأجريت هذه الدرا�سة االإ�ستعادية يف امل�ست�سفى ال�سلطاين وبنك الدم يف م�ست�سفى جامعة ال�سلطان قابو�ض يف م�سقط، عمان، و�سملت الدرا�سة جميع الن�ساء اللواتي خ�سعن لعملية نقل الدم داخل الرحم يف عمان بني �سهر مار�ض 2012 ومار�ض 2016. مت خالل الدرا�سة الوفيات. ر�سد اإىل اإ�سافة الع�سبي، النمو على التاأثري وتوابع الالحقة، امل�ساعفات ذلك وت�سّمن الوالدة، بعد وما احلمل نتائج تقييم النتائج: مت اإجراء 28 عملية نقل دم داخل الرحم، ل 13 جنني الأحد ع�رص اأم حامل، تراوح عمر احلمل يف وقت التحويل بني 30–13 اأ�سبوعًا، يف حني اأن متو�سط عمر اجلنني يف اأول عملية نقل دم كان 26 اأ�سبوعًا )املدى: 30–19 اأ�سبوعًا(، �سملت م�ستدعيات عمل هذا االإجراء اجلراحي وجود مر�ض انحالل الدم اجلنيني اأو حلديثي الوالدة الناجت عن اأج�سام مناعة م�سادة من نوع م�ساد d )عدد احلاالت = 6(، ومزيج من م�ساد d وم�ساد c )عدد احلاالت = 4(، اأو م�ساد k )عدد احلاالت = 1( وم�ساد jsb )عدد احلاالت = 1(، وكذلك الناجت عن جتمع ال�سائل اجلنيني الغري مناعي، ب�سبب اإلتهاب فريو�ض احلميات ال�سغرية اخللقي )عدد احلاالت = 1(. كان متو�سط م�ستوى الهيموجلوبني اجلنيني يف بداية ونهاية االإجراء 4.6 غرام/دي�سيلرت و 12.8 غرام/دي�سيلرت، على التوايل، وكانت معظم اإجراءات نقل الدم خالل امل�سيمة عرب االأوعية الدموية من خالل جذر احلبل ال�رصي امل�سيمي )%71.4(، تليها نقل داخل االأوعية خالل ال�سائل ال�سلوي )%14.3(، بلغ معدل البقاء على قيد احلياة %61.5، مع خم�ض حاالت وفاة؛ اأربعة منهم داخل الرحم، وواحد منهم حديث الوالدة وكانت الوفاة يف وقت مبكر بعد عدم اال�ستجابة لعالج جتمع ال�سائل اجلنيني وكذلك وجود خلل وظائفي يف القلب. اخلال�صة: ميكن اعتبار اإجراء عملية نقل دم داخل الرحم املت�سخدمة حديثًا يف �سلطنة عمان، اإجراء ي�ساعد على احل�سول على نتائج مف�سلة لالأجنة امل�سابني بحالة التجمع املائي اجلنيني. الكلمات املفتاحية: اجلنني؛ جتمع ال�سائل اجلنيني؛ فقر دم؛ نقل الدم داخل الرحم؛ وفاة اجلنني؛ عمان. intrauterine fetal blood transfusion descriptive study of the first four years’ experience in oman arwa z. al-riyami,1 *mouza al-salmani,2 sabria n. al-hashami,3 sabah al-mahrooqi,1 ali al-marhoobi,1 sumaiya al-hinai,1 saif al-hosni,1 sathiya m. panchatcharam,4 zainab a. al-arimi5 clinical & basic research sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e34–42, epub. 4 apr 18 submitted 9 sep 17 revisions req. 24 oct & 14 dec 17; revisions recd. 21 nov & 20 dec 17 accepted 21 dec 17 advances in knowledge intrauterine blood transfusion (iut) is a new addition to obstetric management in oman. this study found that the outcomes of this procedure in oman were comparable to reported rates from pioneer studies in the literature. in oman, the commonest indication for an iut was anti-d haemolytic disease of the fetus and the newborn. doi: 10.18295/squmj.2018.18.01.006 arwa z. al-riyami, mouza al-salmani, sabria n. al-hashami, sabah al-mahrooqi, ali al-marhoobi, sumaiya al-hinai, saif al-hosni, sathiya m. panchatcharam and zainab a. al-arimi clinical and basic research | e35 haemolytic disease of the fetus and newborn (hdfn) is caused by maternal allo-antibodies that actively cross the placenta to the fetal circulatory system during gestation and destroy fetal erythroid cells.1 as a result, fetal anaemia, hydrops fetalis and intrauterine fetal death (iufd) may occur. currently, the prevention and treatment of hdfn is successful in most modern obstetric practices worldwide. the primary prevention of hdfn includes the antenatal and postnatal administration of anti-d immunoglobulin for rhesus (rh) d-negative mothers, while secondary prevention is achieved via antenatal screening for red blood cell (rbc) antibodies.2 one of the greatest breakthroughs in fetal medicine was the introduction of percutaneous intraperitoneal transfusions in the 1960s.3 this was followed by intra vascular intrauterine blood transfusions (iuts), in which intravascular transfusions are performed using an ultra sound-guided needle inserted into the umbilical vein.4–6 the treatment of fetal anaemia using iut has been associated with survival rates that exceed 90% in specialised centres.7–9 the main indication for an iut is fetal anaemia due to rbc alloimmunisation, but the procedure is also considered in any fetal disease with severe anaemia, including parvovirus b19 infections and massive fetomaternal haemorrhage.10 nonetheless, the blood components needed for the iut procedure must adhere to existing guidelines and recommendations.11 the procedure is not free from risks, including a 1–2% rate of fetal loss.11–13 prior to 2012, cases necessitating iut in oman were referred abroad due to a lack of certified fetal medicine specialists and necessary support services in the country. in march 2012, the first iut procedure in oman was performed on a patient with hdfn due to anti-d antibodies, thanks to collaboration between the fetal medicine unit of the department of obstetrics & gynaecology at the royal hospital and the sultan qaboos university hospital (squh) blood bank in muscat, oman. this study aimed to describe the first four years’ experience with iut procedures in oman, including indications for iut and the gestational and neonatal outcomes of the procedures. to the best of the authors’ knowledge, this is the first descriptive study of iut procedures in oman. methods this retrospective observational study was conducted at the royal hospital and squh blood bank and included all women who underwent iut in oman between march 2012 and march 2016. data were collected from the patients’ records, including indications for the procedure, gestational age (including at the time of referral, at each iut and at delivery), the number of procedures performed per pregnancy and the development of any procedureor non-procedurerelated complications, such as fetal bradycardia requir ing an emergency caesarean section (cs), cord haema tomas, intrauterine death within one week of the procedure, intrauterine infections, premature rupture of the membranes (prom) or spontaneous preterm labour before 32 gestational weeks.14 perinatal and neonatal mortality and morbidity and the development of postnatal neurodevelopmental sequelae was also determined. at presentation, the patients’ obstetric history was determined and fetal middle cerebral artery peak systolic velocity (mca-psv) was measured. in addition, blood group was determined and viral and anti body screening was performed. subsequently, a decision was made as to whether an iut procedure was needed and, if so, the volume of rbc units required. fetal doppler mca-psv measurements were used to determine the optimal timing of the first and second iuts.15 cordocentesis was planned if the fetus had mca-psv values of ≥1.5 multiples of the median and/or signs of hydrops fetalis were detected via ultrasonography.16 the transfusion was then performed if pre-iut blood samples confirmed fetal anaemia. decisions on subsequent iuts were made after predicting the likelihood of continuing fetal anaemia, indicated by an expected haemoglobin (hb) decrease of 0.3 g/dl per day from post-transfusion hb measurements following the second iut procedure.17 once the decision to perform an iut was made, a search for suitable blood donors was initiated. all blood donors selected were regular donors at the squh blood bank or the department of blood bank services at the ministry of health (moh) in oman. selected donors fulfilled standard donor selection criteria and application to patient care as per the findings of this study, obstetricians in oman need to prevent anti-d alloimmunisation by ensuring that anti-d prophylaxis is administered to rhesus-negative mothers. moreover, obstetricians need to be made aware of the availability of iut facilities in the country to facilitate the early referral of high risk cases before hydrops fetalis develops. intrauterine fetal blood transfusion descriptive study of the first four years’ experience in oman e36 | squ medical journal, february 2018, volume 18, issue 1 completed their fellowship training abroad. each patient was given 5 mg of diazepam and intravenous prophylactic antibiotics prior to the procedure. in addition, antenatal steroids were administered to patient ≥25 gestational weeks, in case an emergency cs was necessary. accordingly, all iut procedures were per formed in close proximity to an operating theatre. for the transfusion, a 20or 22-gauge spinal needle was used while the patient was under local analgaesia. prior to the transfusion, 1 ml of fetal blood was tested to assess baseline hct proportion, complete blood count and reticulocyte count. if fetal anaemia was confirmed, the transfusion was performed at a rate of 5 ml/minute, with close fetal monitoring and targeting to raise the fetal hct proportion to 45–50%, except in cases of hydrops fetalis. in hydropic fetuses, an exchange transfusion was performed. alternatively, half of the estimated volume was transfused to avoid volume overload, followed by assessment of the fetus. a second procedure was planned 24–48 hours later so as to reach the target hct proportion. the volume of the processed rbc units to be transfused was calculated as follows:20 where fpbv is the fetoplacental blood volume in ml, th is the target hct proportion, ih is the initial fetal hct proportion and htb is the hct proportion of the transfused rbc unit. the fetoplacental blood volume was calculated from the ultrasound estimate of fetal weight (uefw) in g according to the following formula:20 immediately following the free return of blood, the fetus was paralysed using 0.3 mg/kg of pancuronium to reduce the risk of a catastrophic wharton’s jelly haematoma or dislodgement of the needle.21 the umbilical vein at the site of the cord root into the placenta was targeted for the transfusion. a transplacental route was used for cases with an anterior placenta, while a transamniotic route was used in cases with a posterior placenta. an intracardiac route was chosen in cases in which it was technically difficult to reach the site where the umbilical cord connected to the placenta. none of the procedures were performed via an intrahepatic route or a free loop of the umbilical cord. once the transfusion was complete, post-transfusion hb level and hct proportion was checked. all patients >28 gestational weeks were monitored with fetal heart rate tracing for one hour following the procedure. intervals between the procedures were determined based on weekly mca-psv doppler assessments and had to have made a minimum of one previous donation negative for all serological markers within two years of the planned iut. all potential donors were tested for the sickle cell trait, hiv-1 and -2, hepatitis c virus, hepatitis b virus (including surface antigen and anti core antibodies) and syphilis. all rbc units used were of blood group o, rhd-negative, sickle-negative, negative for the corresponding antigens of the implicated hdfn-causing maternal antibodies and crossmatch compatible with the maternal sera.11 in addition, the donors were matched to the maternal rh (c, c, e and e) and kell (k) phenotype whenever possible. donated whole blood was collected in a citrate phosphate dextrose anticoagulant solution and process ed at the squh blood bank based on a written protocol. none of the processed rbc units were suspended in a saline, adenine, glucose and mannitol additive solution. prior to storage, processed rbc units were leukoreduced to a residual white blood cell (wbc) count of <5 x 106/l. the rbc units were then haemoconcentrated by centrifugation in order to reach a haematocrit (hct) proportion of 70–85%.18 a saline wash was used for the processed rbc units of one previously reported patient with hdfn due to the presence of anti-jsb antibodies; in this case, the mother had donated blood while pregnant due to the low likelihood of finding a suitable donor.19 all rbc units were quality-checked for final volume measurements, hct proportion and residual wbc counts. after testing to determine the abo blood group, the donor samples were additionally screened for rh (c, c, e and e) and k antigens, the sickle cell trait and glucose 6-phosphate dehydrogenase deficiency. the rbc units were irradiated using a cesium-based irradiation method to a minimum target dose of 25 grays, as per existing recommendations.11 an irradiation tag was attached to each unit to ensure the target dose of irradiation was delivered (radtag® irradiation indicator, radtag technologies, edmonton, alberta, canada). finally, the rbc units were labelled before being issued. the volume of prepared rbc units for each patient was determined according to the obstetrician’s orders. all components used in the iut procedures were fresh, having been issued within 24 hours of donation from the squh or moh blood banks. a multidisciplinary team supervised all blood component and transfusion aspects of the iut procedures, including two haematopathologists and a haematologist with expertise in transfusion medicine. all iut procedures were performed by a fetal therapist at the fetal medicine unit in the royal hospital using a prespecified protocol under aseptic conditions and employing continuous ultrasound guidance. the fetal therapist who performed the procedure had rbc volume = (fpbv × th ih) fpbv = 1.046 + uefw × 0.14 htb arwa z. al-riyami, mouza al-salmani, sabria n. al-hashami, sabah al-mahrooqi, ali al-marhoobi, sumaiya al-hinai, saif al-hosni, sathiya m. panchatcharam and zainab a. al-arimi clinical and basic research | e37 according to the expected decline in hb level, as des cribed above.17,22 a repeat iut procedure was arranged if any signs of fetal anaemia developed, particularly for fetuses with features of hydrops fetalis at referral. the last procedure was generally performed at 34 gestational weeks, with delivery planned at >35 gestational weeks. in cases where the fetus had received an intraperitoneal transfusion, delivery was planned at 32–34 gestational weeks. data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). descriptive statistics were calculated for continuous variables, including means, medians, standard deviations and ranges. percentages were computed for frequency variables. nonparametric statistical methods were employed. the correlation between gestational age at time of delivery and the number of iut procedures performed was tested using spearman’s correlation coefficient. a chi-squared test was used to assess the difference in outcome measures between fetuses delivered at <30 gestational weeks and those delivered at ≥30 gestational weeks. a p value of <0.05 was considered statistically significant. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine and health sciences at sultan qaboos university (mrec #1382) and the centre of studies & research at the moh (#23/2017). in all cases, the iut procedure was explained to the patient and informed consent was obtained prior to the transfusion. results the demographic characteristics of the cases and details of the iut procedures are shown in table 1. during the four-year study period, 28 iuts were performed for 13 fetuses carried by 11 women. the mean maternal age was 30.25 ± 3.40 years. over half of the women had a gestational history of fetal anaemia causing iufd. all cases had features of fetal anaemia at the time of presentation, while hydrops fetalis was present in 10 fetuses. the median gestational age at referral was 20 gestational weeks. nine pregnancies presented with fetal anaemia at ≤22 gestational weeks, six of which were hydropic at presentation necessitating urgent transfusion. all fetuses with alloimmune-induced hdfn had very high antibody titre levels. the most common cause of immune hdfn was anti-d alloimmunisation (n = 6). four patients had multiple antibodies (anti-d and anti-c) and only one fetus was affected by the anti-k alloantibody. there was one case of non-immune hydrops fetalis due to a parvovirus b19 infection diagnosed via maternal screening. median table 1: characteristics of intrauterine transfusions performed in oman over a four-year period (n = 28)* characteristic n maternal history previous hdfn 10 previous iufd 6 fetal presentation hydrops fetalis 10 fetal anaemia 13 median gestational weeks in weeks (range) at time of referral 20 (13–30) at first iut 26 (18–30) at live delivery 32 (28–36) maternal blood group o+ 2 o5 a+ 1 a1 b4 maternal antibodies detected† anti-d 6 anti-d and anti-c 4 anti-k 1 anti-jsb 1 none 1 antibody titre 1:128 1 1:512 1 1:1,024 2 1:2,048 4 >1:2,048 1 np 2‡ initial iut approach transplacental intravascular§ 10 intracardiac 2 intraperitoneal 1 mean hb level in g/dl ± sd baseline 5.2 ± 2.7 post-iut 12.5 ± 3.8¶ post-delivery 10.4 ± 2.9 hdfn = haemolytic disease of the fetus and newborn; iufd = intrauterine fetal death; iut = intrauterine transfusion; k = kell; np = not performed; hb = haemoglobin; sd = standard deviation. *a total of 28 iuts were performed for 13 fetuses carried by 11 women. †at time of referral. ‡including one case with anti-k antibodies and one with non-immune hdfn due to a parvovirus infection. §through the placental umbilical cord root. ¶statistically significant increase in comparison to mean baseline hb levels (p <0.01). intrauterine fetal blood transfusion descriptive study of the first four years’ experience in oman e38 | squ medical journal, february 2018, volume 18, issue 1 baseline fetal hb levels prior to the first iut procedure were 3.5 g/dl (range: 1.5–8.0 g/dl). a median of two iut procedures were required per patient (range: 1–4 procedures). there was a statistically significant difference between mean fetal hb levels before and after the iut procedure (5.16 ± 2.74 g/dl versus 12.48 ± 3.76 g/dl, respectively; p <0.01). the median gestational age at first iut was 26 weeks. of the nine pregnancies presenting with fetal anaemia at ≤22 gestational weeks, six cases were hydropic and were transfused at ≤22 gestational weeks, while the other cases presented at ≥25 gestational weeks. of the 28 procedures, 20 were transplacental intravascular transfusions, four were transamniotic intravascular, three were intracardiac and one was intraperitoneal. six procedures required an exchange transfusion at the beginning of the procedure due to severe fetal anaemia. none of the patients received intravenous immunoglobulin or underwent therapeutic plasma exchange prior to the iut procedures. the overall survival rate was 61.5%, with eight neonates surviving, including all of the non-hydropic fetuses and half of the hydropic fetuses. all four patients with multiple antibodies survived. four of the cases of anti-d immune hdfn survived. there were five deaths, including four iufd cases and one early neonatal death. one of the iufds occurred due to severe hydrops fetalis in a fetus transfused at ≤22 gestational weeks. of the iufd cases, 80% died at <30 gestational weeks. the median gestational age at the time of delivery for live fetuses was 32 gestational weeks. there was a statistically significant difference in survival rates between fetuses born at <30 gestational weeks and those born at ≥30 gestational weeks (p = 0.03). a weak correlation was also noted between gestational age at delivery and the number of iut procedures performed; however, this difference was not statistically significant (r = 0.4; p = 0.18). four cases were delivered by emergency cs. of these, one was indicated due to a procedure-related cord haematoma at 29 gestational weeks and another was indicated due to abnormal cardiotocography measurements at 30 gestational weeks. the third patient had had four previous css with focal placenta accreta in which part of the placenta attached abnormally to the myometrium and went into preterm labour. the fourth patient experienced preterm prom leading to antepartum haemorrhage and resulting in early neonatal death. no procedure-related complications were noted in the latter three cases. the median gestational age at the time of delivery of the alive fetuses was 32 weeks (range: 28–36 weeks). of the eight surviving fetuses, six were born at or before 32 gestational weeks. overall, mean fetal hb levels at birth were 10.4 ± 2.9 g/dl. all eight surviving babies were followed up by paediatricians and received phototherapy, with 87.5% requiring a top-up and/or exchange transfusion post-delivery. two neonates suffered from neurodevelopmental delay in the early neonatal period, which resolved in one case. during the study period, one patient underwent iut procedures during three separate pregnancies, with successful outcomes in two cases. the overall complication rate was 21%. details of the complications and outcomes of the iut procedures are shown in table 2. discussion to the best of the authors’ knowledge, this is the first descriptive study of iut outcomes in oman. other countries have similarly reported their experiences with iut procedures.2,9,13,14,23–26 despite the low number of cases, the overall mortality and complication rates observed in the current study were comp arable to those of initially reported rates in other research available in the literature, which range from 75% when hydrops fetalis is present at the start of treatment to over 90% for non-hydropic fetuses.27 overall, the fetal loss rate due to the procedure is 1–2%.12,13 the mortality rate appears to be higher at gestational ages of <22 weeks (5.6%), due to the technical difficulties encountered when the procedure is performed very early in gestation.13 the presence of hydrops fetalis is a major contributor to adverse outcomes. the rate of fetal death at <20 gestational weeks is higher (5.6%).13,28 in the current study, the majority of deaths occurred among fetuses of <30 gestational weeks. this outcome is to be expected given the higher rate of prematurityrelated complications in this group. many rbc antibodies have been implicated in immune hdfn. most cases of severe fetal anaemia requiring in utero treatment are caused by anti-d, anti-c or anti-k antibodies.29,30 anti-d alloimmunisation is known to be associated with severe hdfn.23 despite ongoing efforts to prevent anti-d alloimmunisation, it remains the most common cause of hdfn.2,9,13,14,23,24,31,32 this is consistent with the findings of the current study, in which anti-d antibodies were the most common cause of fetal anaemia necessitating iut. this is especially concerning given the anti-d immunoglobulin policy in oman. al-dughaishi et al. previously reported the rate of anti-d alloimmunisation in one institution in oman to be 10%.33 fetal anaemia due to anti-k alloimmunisation generally develops earlier in gestation, regardless of the antibody titre level, due to the additional effect of anti-k antibodies in suppressing the erythroid precursors that express k antigens.34 in the current study, there was one case arwa z. al-riyami, mouza al-salmani, sabria n. al-hashami, sabah al-mahrooqi, ali al-marhoobi, sumaiya al-hinai, saif al-hosni, sathiya m. panchatcharam and zainab a. al-arimi clinical and basic research | e39 ta bl e 2: c ha ra ct er is ti cs a nd fe ta l c om pl ic at io ns a nd o ut co m es a m on g w om en w it h co m pl ic at io ns a nd fe ta l d ea th s af te r un de rg oi ng in tr au te ri ne tr an sf us io ns p er fo rm ed in o m an o ve r a fo ur -y ea r pe ri od (n = 1 1) b as el in e a t fi rs t iu t a t ti m e of c om pl ic at io n o ut co m es c au se o f h d fn (t it re ) m at er na l h is to ry g a in w ee ks h b le ve l in g /d l pr es en ce of h f iu t ap pr oa ch g a in w ee ks n um be r of iu ts c om pl ic at io n pr en at al / de liv er y po st na ta l fo llo w -u p 1 an tid (1 :1 02 4) g 6/ p3 /a 2; 2 pr ev io us l sc s 26 3. 7 n o t pi 30 3 a bn or m al c t g m ea su re m en ts w ith in 24 h ou rs o f t he iu t em er ge nc y ls c s r eq ui re d t u t a nd ph t h ea lth y at fo ur y ea rs po st -d el iv er y 2 an tijs b (1 :1 28 ) g 2/ p0 ; 2 pr ev io us iu fd s du e to h f 22 1. 5 ye s t pi 29 4 c or d ha em at om a le ad in g to in te rr up tio n of th e iu t em er ge nc y ls c s r eq ui re d t u t a nd ph t h ea lth y an d un de rg oi ng pt a t f ou r ye ar s po st de liv er y 3 an tid (> 1: 2, 04 8) g 4/ p4 ; 4 pr ev io us l sc s w ith a p† 30 5. 0 ye s t pi 30 1 pr et er m la bo ur b y ls c s du e to p re vi ou s ls c s hi st or y em er ge nc y ls c s r eq ui re d t u t a nd ph t ; n eo na te h ad ea rl y n d se qu el ae th at r es ol ve d up on fo llo w -u p h ea lth y at th re e ye ar s po st -d el iv er y 4 an tid (1 :2 ,0 48 ) g 7/ p4 /a 2; 3 pr ev io us l sc s‡ 19 ye s ip 19 1 iu fd d ue to s ev er e in iti al h f an d d c ca rd ia c st at us iu fd 5 an tid (1 :1 ,0 24 ) g 3/ p3 ; 1 pr ev io us em er ge nc y ls c s du e to f a § 25 3. 0 ye s ic 25 1 c ar di ac ta m po na de iu fd 9 n on im m un e h f du e to b 19 g 0/ p0 20 5. 0 ye s t pi 20 1 iu fd d ue to s ev er e in iti al h f an d d c ca rd ia c st at us iu fd 10 an tid g 2/ p2 ; 1 pr ev io us l sc s du e to h f¶ 22 2. 2 ye s t pi 22 2 iu fd d ue to s ev er e h f an d d c c ar di ac s ta tu s iu fd 11 an tik g 6/ p5 ; 1 pr ev io us iu fd w ith h f 29 3. 9 ye s t pi 31 3 pp r o m d ue to p h d // em er ge nc y ls c s n eo na ta l d ea th d ue to s ev er e ca rd ia c dy sf un ct io n/ / iu t = in tr au te ri ne tr an sfu sio n; h d fn = h ae m ol yt ic d is ea se o f t he fe tu s a nd n ew bo rn ; g a = g es ta tio na l a ge ; h b = ha em og lo bi n; h f = hy dr op s f et al is ; g = g ra vi da ; p = p ar a; a = a bo rt us ; l sc s = lo w -s eg m en t c ae sa re an se ct io n; t pi = tr an spl ac en ta l i nt ra va sc ul ar ; c t g = c ar di ot oc og ra ph y; t u t = to pup tr an sfu sio n; p h t = p ho to th er ap y; p t = p hy sio th er ap y; a p = ab no rm al p la ce nt at io n; n d = n eu ro de ve lo pm en ta l; ip = in tr ape ri to ne al ; d c = d ec om pe ns at ed ; iu fd = in tr au te ri ne fe ta l d ea th ; f a = fe ta l a na em ia ; i c = in tr ac ar di ac ; b 19 = p ar vo vi ru s b 19 ; k = k el l; pp ro m = p re te rm p re m at ur e r up tu re o f t he m em br an e; p h d = p ol yh yd ra m ni os . *a to ta l o f 2 8 iu ts w er e p er fo rm ed fo r 1 3 fe tu se s c ar ri ed b y 11 w om en . † o f t he se , t hr ee n eo na te s r eq ui re d ph t a nd o ne h ad a n iu t. ‡ o f t he se , o ne p re gn an cy w as a ffe ct ed b y se ve re f a , w ith th e f et us su rv iv in g f ol lo w in g i u t. § pr et er m de liv er y at 3 2 ge st at io na l w ee ks . ¶ p re te rm d el iv er y. // a t 3 2 ge st at io na l w ee ks . intrauterine fetal blood transfusion descriptive study of the first four years’ experience in oman e40 | squ medical journal, february 2018, volume 18, issue 1 of anti-k-induced hdfn and hydrops fetalis in which the mother had a past history of iufd due to severe hydrops fetalis; unfortunately, despite three iut attempts, the neonate died due to severe cardiac dysfunction. specialised blood bank facilities are needed in oman for the detection and monitoring of clinically significant antibodies in such cases. in cases with detectable antibodies, prenatal monitoring of maternal antibody titres and fetal mcapsv doppler ultrasonography assessments can help to plan fetal blood sampling and iut procedures. in general, mca-psv values correlate well with fetal hb levels as a function of gestational age. the quick response of the fetal cerebral arteries to hypoxaemia—which can be determined by measuring the peak velocity of systolic blood flow using doppler ultrasonography—is an ideal indicator of fetal anaemia.16 therefore, mcapsv measurements in fetuses at risk of anaemia due to maternal rbc alloimmunisation provide an accurate and non-invasive means of determining the severity of the anaemia, enabling the early referral of at-risk patients to specialised centres for monitoring and/or management. the frequency of iut procedures is determined clinically based on fetal status; in general, the interval between procedures is 2–3 weeks.10 mca-psv measure ments may be less accurate for the assessment of already transfused fetuses because the association between hb levels and blood velocity is weaker in such cases. therefore, reassessment of the need for subsequent iuts is based on the estimated fetal hb decrease following the initial transfusion. a previous study estimated a 1–2% decline in hct proportion per day after an iut procedure.35 therefore, in patients receiving multiple previous iut transfusions, decisions on the timing of subsequent iuts is made by estimating the hb decrease in comparison to post-transfusion hb levels after the second transfusion; the assumption is that the rate of decrease will be 0.3 g/dl per day.17 that being said, the decision to repeat the iut procedure should be made on an individual case-by-case basis, as an earlier procedure might be indicated if the fetus shows signs of anaemia. the high rate of hydrops fetalis in the present study may reflect the late referral of patients from other centres; this supposition is also supported by the high antibody titres noted in many cases at the time of presentation. the presence of hydrops fetalis is a major contributor to adverse post-iut outcomes and worsens the rate of survival.27,28,36 unfortunately, a comparison of survival in the current study with that reported in the existing literature was hindered by the small size of the current sample as well as the comparatively higher rate of hydrops fetalis at the time of patient referral which negatively affected the overall post-procedure survival rate.27,28,36 a recent study by zwiers et al. reported improved post-iut survival at a national referral centre in new zealand since the procedure was pioneered in 1998; this was explained by reduced severity of the disease at referral, lower rates of hydrops fetalis at presentation and increased hb levels at the time of the first iut.23 these findings support the recommendation that high-risk pregnancies be followed up in a tertiary care centre between 15–20 gestational weeks.24 overall, the complication and fetal loss rates in the current study were comparable to rates reported by other pioneer studies (0.9–4.9%).9,37 procedure-related fetal distress in iut cases is usually due to either local cord complications or excessive bleeding followed by exsanguination.13 differ ent approaches are utilised in transfusing fetuses and prognosis can be predicted based on the presence of hydrops fetalis.32 transfusion via a free loop of the umbilical cord is technically difficult and such an approach has been associated with increased complication rates; hence, this was not attempted in the present study.9,13,23,24,31 early gestational age at first transfusion is another significant risk factor for procedurerelated complications, especially as performing iuts at ≤22 gestational weeks is particularly challenging; moreover, even if the procedure is successful, many premature fetuses cannot tolerate the transfusion and therefore die in utero.9,32 fetal distress during the procedure remains one of the most critical iud compl ications as this may result in preterm delivery or fetal death.14 in the current study, only one fetus died in utero when transfused at ≤22 gestational weeks. emergency cs deliveries are usually indicated due to cord complications or exsanguination following needle removal/displacement; the perinatal mortality rate for this type of delivery is estimated at 1.4–2%.13,27,38 in most countries, the critical antibody titre cutoff value used for fetal monitoring is 1:16, although this can vary from 1:8 to 1:32.12,31 however, all cases of immune-induced hdfn in the current study presented with antibody titres exceeding this limit, highlighting the need for a nationwide programme for the early recognition and referral of high-risk pregnancies in oman. such a programme would be strengthened by the development of existing blood bank services to enhance the prompt detection of fetal antibodies and assessment of titres. moreover, there is a need to assess compliance with existing policies regarding the antenatal and postnatal administration of anti-d immunoprophylaxis. finally, a larger study is required to enable a comparison of omani iut outcomes with those reported elsewhere. arwa z. al-riyami, mouza al-salmani, sabria n. al-hashami, sabah al-mahrooqi, ali al-marhoobi, sumaiya al-hinai, saif al-hosni, sathiya m. panchatcharam and zainab a. al-arimi clinical and basic research | e41 conclusion this study presents the first four years’ experience with iut as a life-saving pioneer procedure in oman. overall, this procedure appears safe and effective when carried out by a multidisciplinary team of individuals with extensive training and experience. however, access to a high-quality blood bank is necessary to ensure the availability of the required blood components, among other specialised services. nationwide procedures for the monitoring, referral and follow-up of high-risk hdfn cases are recommended. patients should be referred before the development of hydrops fetalis as this compromises postiut fetal survival. in the present study, the most frequent indication for iut was due to anti-d hdfn; accordingly, compliance with existing antenatal and postnatal anti-d prophylaxis policies should be enforced to prevent anti-d alloimmunisation. a c k n o w l e d g e m e n t s a poster of the preliminary version of this study was presented at the 27th regional congress of the international society of blood transfusion on 17–21 june 2017 in copenhagen, denmark. an abstract of this poster presentation was subsequently published in vox sanguinis in june 2017, volume 112, issue s1, pp. 249–50. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. de haas m, thurik ff, koelewijn jm, van der schoot ce. haemolytic disease of the fetus and newborn. vox sang 2015; 109:99–113. doi: 10.1111/vox.12265. 2. sainio s, nupponen i, kuosmanen m, aitokallio-tallberg a, ekholm e, halmesmäki e, et al. diagnosis and treatment of severe hemolytic disease of the fetus and newborn: a 10-year nationwide retrospective study. acta obstet gynecol scand 2015; 94:383–90. doi: 10.1111/aogs.12590. 3. liley aw. intrauterine transfusion of foetus in haemolytic disease. br med j 1963; 2:1107–9. doi: 10.1136/bmj.2.5365.1107. 4. rodeck ch, kemp jr, holman ca, whitmore dn, karnicki j, austin ma. direct intravascular fetal blood transfusion by fetoscopy in severe rhesus isoimmunisation. lancet 1981; 1:625–7. doi: 10.1016/s0140-6736(81)91549-x. 5. bang j, bock je, trolle d. ultrasound-guided fetal intravenous transfusion for severe rhesus haemolytic disease. br med j (clin res ed) 1982; 284:373–4. doi: 10.1136/bmj.284.6313.373. 6. daffos f, capella-pavlovsky m, forestier f. a new procedure for fetal blood sampling in utero: preliminary results of fiftythree cases. am j obstet gynecol 1983; 146:985–7. doi: 10.10 16/0002-9378(83)90982-1. 7. lindenburg it, van kamp il, oepkes d. intrauterine blood transfusion: current indications and associated risks. fetal diagn ther 2014; 36:263–71. doi: 10.1159/000362812. 8. van kamp il, klumper fj, meerman rh, oepkes d, scherjon sa, kanhai hh. treatment of fetal anemia due to red-cell allo immunization with intrauterine transfusions in the netherlands, 1988-1999. acta obstet gynecol scand 2004; 83:731–7. doi: 10.1111/j.0001-6349.2004.00394.x. 9. tiblad e, kublickas m, ajne g, bui th, ek s, karlsson a, et al. procedure-related complications and perinatal outcome after intrauterine transfusions in red cell alloimmunization in stockholm. fetal diagn ther 2011; 30:266–73. doi: 10.1159/00 0328683. 10. oepkes d, adama van scheltema p. intrauterine fetal trans fusions in the management of fetal anemia and fetal thrombocytopenia. semin fetal neonatal med 2007; 12:432–8. doi: 10.1016/j.siny.2007.06.007. 11. gibson be, todd a, roberts i, pamphilon d, rodeck c, boltonmaggs p, et al. transfusion guidelines for neonates and older children. br j haematol 2004; 124:433–53. doi: 10.1111/j.13652141.2004.04815.x. 12. moise kj jr. management of rhesus alloimmunization in preg nancy. obstet gynecol 2008; 112:164–76. doi: 10.1097/aog. 0b013e31817d453c. 13. van kamp il, klumper fj, oepkes d, meerman rh, scherjon sa, vandenbussche fp, et al. complications of intrauterine intravascular transfusion for fetal anemia due to maternal red-cell alloimmunization. am j obstet gynecol 2005; 192:171–7. doi: 10.1016/j.ajog.2004.06.063. 14. deka d, dadhwal v, sharma ak, shende u, agarwal s, agarwal r, et al. perinatal survival and procedure-related complications after intrauterine transfusion for red cell alloimmunization. arch gynecol obstet 2016; 293:967–73. doi: 10.1007/s00404015-3915-7. 15. society for maternal-fetal medicine (smfm); mari g, norton me, stone j, berghella v, sciscione ac, et al. society for maternal-fetal medicine (smfm) clinical guideline #8: the fetus at risk for anemia diagnosis and management. am j obstet gynecol 2015; 212:697–710. doi: 10.1016/j.aj og.2015.01.059. 16. mari g, deter rl, carpenter rl, rahman f, zimmerman r, moise kj jr, et al. noninvasive diagnosis by doppler ultra sonography of fetal anemia due to maternal red-cell alloimmunization: collaborative group for doppler assessment of the blood velocity in anemic fetuses. n engl j med 2000; 342:9–14. doi: 10.1056/nejm200001063420102. 17. scheier m, hernandez-andrade e, fonseca eb, nicolaides kh. prediction of severe fetal anemia in red blood cell alloimmunization after previous intrauterine transfusions. am j obstet gynecol 2006; 195:1550–6. doi: 10.1016/j.ajog.2006. 03.060. 18. transfusion task force. amendments and corrections to the ‘transfusion guidelines for neonates and older children’; and to the ‘guidelines for the use of fresh frozen plasma, cryoprecipitate and cryosupernatant’. br j haematol 2007; 136:514–16. doi: 10.1111/j.1365-2141.2006.06451.x. 19. al riyami az, al salmani m, al hashami s, al mahrooqi s, al hinai s, al balushi h, et al. successful management of severe hemolytic disease of the fetus due to anti-jsb using intrauterine transfusions with serial maternal blood donations: a case report and a review of the literature. transfusion 2014; 54:238–43. doi: 10.1111/trf.12331. 20. fisk nm, moise kj jr. fetal therapy: invasive and transplacental. cambridge, uk: cambridge university press, 1997. pp. 141–63. 21. james d, steer pj, weiner cp, gonik b, crowther ca, robson sc, eds. high risk pregnancy: management options, 3rd ed. philadelphia, pennsylvania, usa: saunders, 2010. pp. 209-28. https://doi.org/10.1111/vox.12265 https://doi.org/10.1111/aogs.12590 https://doi.org/10.1136/bmj.2.5365.1107 https://doi.org/10.1016/s0140-6736%2881%2991549-x https://doi.org/10.1136/bmj.284.6313.373 https://doi.org/10.1016/0002-9378%2883%2990982-1 https://doi.org/10.1016/0002-9378%2883%2990982-1 https://doi.org/10.1159/000362812 https://doi.org/10.1111/j.0001-6349.2004.00394.x https://doi.org/10.1159/000328683 https://doi.org/10.1159/000328683 https://doi.org/10.1016/j.siny.2007.06.007 https://doi.org/10.1111/j.1365-2141.2004.04815.x https://doi.org/10.1111/j.1365-2141.2004.04815.x https://doi.org/10.1097/aog.0b013e31817d453c https://doi.org/10.1097/aog.0b013e31817d453c https://doi.org/10.1016/j.ajog.2004.06.063 https://doi.org/10.1007/s00404-015-3915-7 https://doi.org/10.1007/s00404-015-3915-7 https://doi.org/10.1016/j.ajog.2015.01.059 https://doi.org/10.1016/j.ajog.2015.01.059 https://doi.org/10.1056/nejm200001063420102 https://doi.org/10.1016/j.ajog.2006.03.060 https://doi.org/10.1016/j.ajog.2006.03.060 https://doi.org/10.1111/j.1365-2141.2006.06451.x https://doi.org/10.1111/trf.12331 intrauterine fetal blood transfusion descriptive study of the first four years’ experience in oman e42 | squ medical journal, february 2018, volume 18, issue 1 22. detti l, oz u, guney i, ferguson je, bahado-singh ro, mari g, et al. doppler ultrasound velocimetry for timing the second intrauterine transfusion in fetuses with anemia from red cell alloimmunization. am j obstet gynecol 2001; 185:1048–51. doi: 10.1067/mob.2001.118161. 23. zwiers c, lindenburg itm, klumper fj, de haas m, oepkes d, van kamp il. complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures. ultrasound obstet gynecol 2017; 50:180–6. doi: 10.1002/uog.17319. 24. deka d, dadhwal v, sharma ak, shende u, agarwal s, agarwal r, et al. perinatal survival and procedure-related com plications after intrauterine transfusion for red cell alloimmunization. arch gynecol obstet 2016; 293:967–73. doi: 10.1007/ s00404-015-3915-7. 25. pasman sa, claes l, lewi l, van schoubroeck d, debeer a, emonds m, et al. intrauterine transfusion for fetal anemia due to red blood cell alloimmunization: 14 years experience in leuven. facts views vis obgyn 2015; 7:129–36. 26. klumper fj, van kamp il, vandenbussche fp, meerman rh, oepkes d, scherjon sa, et al. benefits and risks of fetal red cell transfusion after 32 weeks gestation. eur j obstet gynecol reprod biol 2000; 92:91–6. doi: 10.1016/s0301-2115(00)004 30-9. 27. schumacher b, moise kj jr. fetal transfusion for red blood cell alloimmunization in pregnancy. obstet gynecol 1996; 88:137–50. doi: 10.1016/0029-7844(96)00113-5. 28. lindenburg it, van kamp il, van zwet ew, middeldorp jm, klumper fj, oepkes d. increased perinatal loss after intrauterine transfusion for alloimmune anaemia before 20 weeks of gestation. bjog 2013; 120:847–52. doi: 10.1111/1471-0528. 12063. 29. moise kj. red blood cell alloimmunization in pregnancy. semin hematol 2005; 42:169–78. doi: 10.1053/j.seminhematol. 2005.04.007. 30. zwiers c, van kamp i, oepkes d, lopriore e. intrauterine transfusion and non-invasive treatment options for hemolytic disease of the fetus and newborn: review on current management and outcome. expert rev hematol 2017; 10:337–44. doi: 10.1080/17474086.2017.1305265. 31. van dijk ba, dooren mc, overbeeke ma. red cell antibodies in pregnancy: there is no ‘critical titre’. transfus med 1995; 5:199–202. doi: 10.1111/j.1365-3148.1995.tb00228.x. 32. yinon y, visser j, kelly en, windrim r, amsalem h, seaward pg, et al. early intrauterine transfusion in severe red blood cell alloimmunization. ultrasound obstet gynecol 2010; 36:601–6. doi: 10.1002/uog.7696. 33. al-dughaishi t, al harrasi y, al-duhli m, al-rubkhi i, al-riyami n, al riyami a, et al. red cell alloimmunization to rhesus antigen among pregnant women attending a tertiary care hospital in oman. oman med j 2016; 31:77–80. doi: 10.5001/omj.2016.15. 34. vaughan ji, warwick r, letsky e, nicolini u, rodeck ch, fisk nm. erythropoietic suppression in fetal anemia because of kell alloimmunization. am j obstet gynecol 1994; 171:247–52. doi: 10.1016/0002-9378(94)90477-4. 35. macgregor sn, socol ml, pielet bw, sholl js, silver rk. prediction of hematocrit decline after intravascular fetal trans fusion. am j obstet gynecol 1989; 161:1491–3. doi: 10.1016/ 0002-9378(89)90910-1. 36. van kamp il, klumper fj, bakkum rs, oepkes d, meerman rh, scherjon sa, et al. the severity of immune fetal hydrops is predictive of fetal outcome after intrauterine treatment. am j obstet gynecol 2001; 185:668–73. doi: 10.1067/mob.2001. 116690. 37. johnstone-ayliffe c, prior t, ong c, regan f, kumar s. early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia. acta obstet gynecol scand 2012; 91:458–62. doi: 10.1111/j.1600-0412.2011.01353.x. 38. brennand j, cameron a. fetal anaemia: diagnosis and management. best pract res clin obstet gynaecol 2008; 22:15–29. doi: 10.1016/j.bpobgyn.2007.08.005. https://doi.org/10.1067/mob.2001.118161 https://doi.org/10.1002/uog.17319 https://doi.org/10.1007/s00404-015-3915-7 https://doi.org/10.1007/s00404-015-3915-7 https://doi.org/10.1016/s0301-2115%2800%2900430-9 https://doi.org/10.1016/s0301-2115%2800%2900430-9 https://doi.org/10.1016/0029-7844%2896%2900113-5 https://doi.org/10.1111/1471-0528.12063 https://doi.org/10.1111/1471-0528.12063 https://doi.org/10.1053/j.seminhematol.2005.04.007 https://doi.org/10.1053/j.seminhematol.2005.04.007 https://doi.org/10.1080/17474086.2017.1305265 https://doi.org/10.1111/j.1365-3148.1995.tb00228.x https://doi.org/10.1002/uog.7696 https://doi.org/10.5001/omj.2016.15 https://doi.org/10.1016/0002-9378%2894%2990477-4 https://doi.org/10.1016/0002-9378%2889%2990910-1 https://doi.org/10.1016/0002-9378%2889%2990910-1 https://doi.org/10.1067/mob.2001.116690 https://doi.org/10.1067/mob.2001.116690 https://doi.org/10.1111/j.1600-0412.2011.01353.x https://doi.org/10.1016/j.bpobgyn.2007.08.005 1department of emergency medicine, faculty of medicine & dentistry and 2school of public health, university of alberta, edmonton, alberta, canada; 3department of continuing professional development, oman medical specialty board, muscat, oman *corresponding author’s e-mail: jbreton@ualberta.ca تدريس دور املناصر الصحي تأمالت يف ورشيت عمل تعاونيتني للتدريب على دور املناصر الصحي عرب الثقافات للمتدربني واملدربني الطبيني يف عمان جي�شيكا بريتون، لوي�ص هيوجو فران�شي�شكوتي، يو�شف الو�شاحي abstract: in march 2014, medical educators from canada and oman collaborated to shape the foundation of health advocacy training in oman. using existing research and innovative tools, two workshops were developed, representing the first formalised approach to health advocacy for medical trainees in oman. the development and application of the workshops highlighted many unique challenges and opportunities in advocacy training. this article summarises the process of developing and implementing the workshops as well as feedback from the participants and short-term consequences. furthermore, this article seeks to explore the complexities of designing a cross-cultural curriculum. in particular, it reflects on how the role of health advocate may be perceived differently in various cultural and societal settings. understanding and adapting to these influences is paramount to creating a successful health advocacy curriculum that is relevant to learners and responsive to the communities in which they work. keywords: patient advocacy; medical education; social determinants of health; health promotion; problem-based learning; cross-cultural comparison; canada; oman. امللخ�ص: حدث تعاون يف مار�ص من عام 2014 بني خرباء التعليم الطبي يف كندا وعمان لإر�شاء قاعدة للتدريب على التَّْب�ِشرْيُ ال�شحي يف ة حَّ عمان. ومت با�شتخدام اأبحاث معا�رسة واأدوات مبتكرة ا�شتحداث ور�شتا عمل للمتدربني الطبيني مثلتا اأول نهج ر�شمي للتَّْب�ِشرْيُ بال�شِّ يف عمان. وقد اأف�شى ا�شتحداث وتطبيق الور�شتني اإىل التعرف على حتديات وفر�ص فريدة. ويلخ�ص هذا املقال العملية التي مت اتباعها يف ا�شتحداث تطبيق الور�شتني، وكذلك التغذية الراجعة من ِقَبل امل�شاركني فيهما، ونتائجهما ق�شرية الأجل. وعالوة على ذلك، يهدف هذا املقال ل�شتق�شاء تعقيدات ت�شميم منهج م�شرتك بني ثقافات خمتلفة. ويعك�ص املقال ب�شورة خا�شة كيف ُينظر لدور املب�رس ال�شحي ب�شور ناجح منهج لتاأ�شي�ص و�رسوريا مهما اأمرا معها والتكيف التاأثريات تلك فهم وُيعد املختلفة، واملجتمعية الثقافية الو�شاط يف خمتلفة ة يكون وثيق ال�شلة باملتعلمني، وملبيا حلاجات املجتمع التي يطبق فيها. حَّ للتَّْب�ِشرْيُ بال�شِّ عرب املقارنات امل�شكالت؛ حل على القائم التعلم ال�شحة؛ تعزيز لل�شحة؛ الجتماعية املحددات الطبي؛ التعليم املر�شى؛ منا�رسة املفتاحية: الكلمات الثقافات؛ كندا؛ عمان. teaching the role of health advocate reflections on two cross-cultural collaborative advocacy workshops for medical trainees and instructors in oman *jessica breton,1 louis h. francescutti,2 yousef al-weshahi3 special contribution sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e286–290, epub. 19 dec 18 submitted 9 apr 18 revision req. 31 may 18; revision recd. 29 jun 18 accepted 19 jul 18 doi: 10.18295/squmj.2018.18.03.004 health advocacy is a fundamental skill for physicians. doctors have the potential to make a significant impact on policies and pract ices that affect societal wellbeing; indeed, it can be argued that doctors have a duty to act as advocates, especially in circumstances involving vulnerable populations or inequity.1 several medical organisations worldwide have identified health advocacy to be an essential component within all levels of medical training. for example, the royal college of physicians and surgeons of canada designates ‘health advocate’ as one of the seven core roles of a physician within the canmeds framework.2 however, it is only recently that most major medical schools have started to provide formal advocacy training and, as a result, the evidence for how to teach advocacy and what to include in an advocacy curriculum is still in its infancy. one of the major challenges in teaching advocacy is that it includes a skill set so broad and nuanced that it can be difficult to objectively quantify or evaluate.3 this article highlights some of the successes and challenges of developing two advocacy workshops for medical residents and instructors in oman. these work shops were the first formalised exposure to advocacy teaching for most participants. furthermore, the workshops involved the collaborative efforts of instructors from both canada and oman, creating a unique opport unity for cross-cultural learning as well as challenges in ensuring the relevance and applicability of the content to both settings. jessica breton, louis h. francescutti and yousef al-weshahi special contribution | e287 programme setting oman is located on the southeast coast of the arabian peninsula. in 2010, the united nations ranked oman as the most improved country in the world in terms of development over the preceding 40 years.4 additionally, oman is categorised as a high-income economy and ranks as the 45th most peaceful country worldwide. life expectancy at birth was estimated to be 76.1 years in 2010.4 the healthcare system is government-operated and health services are free for nationals and all expatriate government employees. in 2001, oman’s healthcare system was ranked eighth by the world health organization.5 major challenges include chronic lifestyle diseases (i.e. diabetes and obesity), mental illnesses, geriatric medicine, traffic-related injuries, the health of foreign workers and equitable access to healthcare services.6 oman medical specialty board the oman medical specialty board (omsb) is a govern mental organisation founded in 2006 to oversee the training of specialist physicians.7 currently, there are approximately 600 medical residents in 18 different programmes, supervised by approximately 600 teachers of varying backgrounds. the omsb provides training programmes modelled on the core competencies of a physician as identified by the canmeds framework.2 most of these programmes are delivered as one-day workshops in collaboration with local and international experts. limited follow-up in the form of a post-workshop evaluation is routinely completed. longer term follow-up and more integrated training programmes are not yet commonplace. workshop design and implementation two four-hour workshops were held in muscat, oman, in march 2014. the first was titled ‘resident-as-health advocate’ and included 148 medical residents in their fourth and fifth years of training. similarly, a parallel ‘teaching and evaluating health advocacy’ workshop was conducted involving 57 instructors. the workshops took place in a single morning or afternoon session. the materials for both workshops were distributed in printed format with links to websites and articles for further reading. the workshops were led by two physicians. the first was an emergency medicine physician with a post graduate doctoral degree in medical education who also served as a resource consultant for healthcare regulation and medical education issues in oman. the other was an emergency physician who had advocated for injury control over the past 30 years and taught advocacy methodology and skills to students at the university of alberta, edmonton, alberta, canada. in addition, the latter physician was an international consultant and speaker on topics relating to safety culture, injury and wellness. r e s i d e n t w o r k s h o p basic components of advocacy during the ‘resident-as-health advocate’ workshop, a significant amount of time was devoted to establishing a common framework and language for advocacy work. participants were provided with definitions and examples of advocacy. during the workshop itself, participants were given the opportunity to brainstorm different ways physicians could act as advocates. the canmeds comp etencies for the health advocate role provided the main backbone for outlining what is expected and included within health advocacy.2 these competencies were prov ided in printed format for the participants and reviewed during the workshop. the next topic introduced was social determinants of health. understanding and identifying these determinants is critical to health advocacy work. as such, a significant proportion of the workshop was spent solidifying these concepts using printed handouts, illust rative examples and discussions. the examples focused on diseases of particular relevance to oman, especially chronic diseases and injury prevention, so that participants would learn to look beyond the immediate contr ibutors of ill health and bring abstract concepts to life.8 in particular, one powerful exercise describing two different heart attack case studies gave participants the chance to reflect on how subtle differences in socioeconomic factors and access to healthcare resources can bring about radically different outcomes for patients who otherwise share similar physiological and demographic characteristics. advocacy spectrum following this, the participants were introduced to the many ways in which advocacy can be integrated into medical practice at the individual, institutional, community and societal/governmental levels, with examples discussed for each level. by presenting advocacy on a spectrum, participants were encouraged to make the connection between their work with patients and the broader context of issues facing their community. it also solidified the notion that not all physicians need to be community leaders or high-profile advocates. instead, it gave equal importance to the many different styles of advocacy that exist. teaching the role of health advocate reflections on two cross-cultural collaborative advocacy workshops for medical trainees and instructors in oman e288 | squ medical journal, august 2018, volume 18, issue 3 in addition, the spectrum exercise exposed partic ipants to differing outlets for advocacy that might be more appropriate to the setting of oman. in particular, there may be perceived or actual barriers to more outwardly active forms of advocacy due to the country’s unique political and societal circumstances. many omani physicians may not feel comfortable taking a public advocacy role, especially with regards to controversial issues or projects that challenge certain societal norms. such advocacy projects therefore require careful planning and implementation in order to mediate a conducive atmosphere for advocacy and change. a step-by-step approach the final exercise in the workshop involved developing an advocacy project. using a step-by-step approach adapted from the canadian public health association guide to advocacy, participants went through the proc esses of recognising problems, developing position state ments/goals, identifying opportunities/risks, mapping stakeholders, choosing an advocacy approach, developing key messages, creating an action plan and evaluating the project.9 the benefit of such a step-by-step approach means that large complicated tasks become easier to understand, particularly for novice advocates. participants were divided into small groups to discuss a health problem relevant to oman, such as enforcing child car seats, substance misuse in schoolaged children, childcare facilities at workplaces or sports injuries among young athletes. they were then given approximately one hour to collaborate and create a hypothetical advocacy project using a step-by-step guide and special advocacy worksheet. subsequently, each group presented their ideas to the rest of the participants, giving them the opportunity to practise their presentation and communication skills. the workshop then concluded with a review of the materials discussed, answering any questions and a brainstorming session to explore future directions and opportunities for participants to integrate advocacy skills into practice. i n s t r u c t o r w o r k s h o p the parallel workshop for instructors was tailored specif ically to staff and teachers. it aimed to demonstrate how the role of health advocate could be integrated into a curriculum and how this role should be taught and evaluated. the structure of the workshop was similar to that given to the medical residents in that it began by providing basic information regarding advocacy and social determinants of health, as well as guidance on how to run an advocacy project. thereafter, the canmeds health advocate competencies were explored in more detail, with discussions on how to teach and evaluate each one.2 various examples of successes in advocacy training at other medical schools and residency programmes were also highlighted. finally, participants reviewed evidence for various methods of successfully teaching and evaluating health advocacy.1–3 workshop feedback all participants completed anonymous written evaluation forms immediately following the workshops. information from these evaluation forms were used to improve teaching methods and materials for future workshops. they also provided some early insights into how advocacy teaching was perceived by the participants. for most participants, the workshops constituted their first exposure to the concept of health advocacy. a total of 93% and 89% of the medical residents and instructors, respectively, felt that the workshop met their expectations. both the medical residents and teachers also felt that the workshop met the stated objectives (94% and 98%, respectively) and was relevant to their educational needs (93% and 91%, respectively). in the comments section of the evaluation form, participants of both workshops shared an appreciation for the importance of advocacy work in medicine, with many listing possible advocacy issues to tackle in the future. some participants also reported a strong sense of duty to become better advocates for their communities and patients. an informal follow-up within a month of the workshops indicated that two participants had taken on their own advocacy projects. in the first case, a faculty member had initiated a mobile phone-free driving campaign. in the second case, a medical resident had encountered a patient with suspected carbon monoxide poisoning due to poor ventilation in an industrial kitchen; the resident had then used skills and knowledge gained from the workshop to write a letter to the appropriate authorities to try to improve working conditions at this location. discussion many institutions have sought to integrate advocacy teaching into their curricula in unique ways.10–14 at the university of toronto, ontario, canada, emergency medicine staff conduct an annual health advocacy day, bringing in guest speakers and conducting training sessions.10 medical students at the university of alberta can participate in a one-to-one longitudinal mentorship programme with a local leader in health advocacy.12 several residency programmes in north america now also include a mandatory advocacy project to be compl eted during training as well as fellowship training progr ammes for physician advocacy.11 jessica breton, louis h. francescutti and yousef al-weshahi special contribution | e289 the advocacy workshops described in this article utilised a novel teaching approach specifically tailored to learners and teachers in oman. however, it is important to distinguish between advocacy workshops and an actual advocacy curriculum. this workshop provided a basic set of tools for learning advocacy; nevertheless, ongoing opportunities are required for advocacy practice and reflection to be integrated within residency programmes. the authors therefore hope that these workshops will be the springboard for such a curriculum in oman. the eventual goal is that oman will develop a self-led and sustained advocacy programme that reflects and is relevant to the unique cultural and political climate of the country [table 1]. teaching the fundamentals of advocacy over the course of a four-hour workshop was an ambitious project. while some participants had previous experience with this topic, many did not. this variability in exposure also created challenges in ensuring that the workshop was engaging and useful to all participants. additionally, while single-day workshops were logistically easier to organise, they are not an ideal format for effective learning. a series of shorter lectures or sessions separated by several weeks might allow participants time and space to process the information and integrate skills into practice. moreover, previous research supports the notion that it is better to introduce key issues like social determinants of health prior to residency training.15 belkowitz et al. highlighted promising results from a longitudinal advocacy training intervention whereby medical students were given opportunities to partner with community agencies and put their advocacy skills into practice; this approach was associated with greater acquisition of advocacy skills and knowledge compared to students who did not participate in the intervention.16 in the current project, it was vital to ensure that the workshops reflected the needs and realities of omani society. during the course of the workshops, it became clear that many of the north american constructs surrounding the role of health advocate did not easily translate to the omani cultural setting. although the workshops were designed and led by both canadian and omani physicians, most of the research and inform ation used was from north american sources due to the lack of literature showcasing advocacy training from a middle eastern perspective. the researchers attempted to overcome this limitation by creating examples and engineering discussions relevant to issues within oman. however, there were still major gaps in ensuring that the workshop was relevant and accessible to all participants. nevertheless, as omani faculty members are trained to teach and evaluate advocacy, it is hoped that they will be able to adapt the materials and concepts to better fit the needs of the community. learning to adjust to unique setting-specific factors is pivotal to the success of an advocacy programme. this unique cross-cultural teaching experience provided an opportunity to reflect on how advocacy is a culturally-bound skill that means different things in various social settings. in addition, the workshops reinforced the idea that advocacy cannot be taught in rigid or overly prescriptive ways. instead, the role of a health advocate needs to be flexible and responsive to individual physicians or learners, the communities in which they work and the advocacy issues they face. finally, advocacy training cannot be limited to a single workshop or printed handout. the most meaningful forms of learning advocacy occur outside the classroom, over time and practice.17 in retrospect, it would have been valuable to conduct a validated survey of participants with a prepost design to assess changes in advocacy-related attitudes, knowledge and skills after the workshops. the workshop evaluation forms focused on gathering useful feedback for improvement rather than a rigorous or quantifiable assessment of learning impact. furthermore, the long-term effect and retention of the workshop materials was not measured. while informal reports of two participants taking on advocacy projects after the workshop are promising, such findings are anecdotal and further research is required to identify correlations between workshop sessions and measureable changes in advocacy-related attitudes, knowledge and skills. conclusion this article describes the development and evaluation of two advocacy workshops for medical residents and table 1: practice points for health advocacy training in oman practice points • health advocacy is one of the core roles of a physician and training in advocacy skills should be formally integrated across all levels of the medical curriculum. • social determinants of health form the backbone of effective health advocacy. • students should be given the opportunity to explore the wide spectrum of advocacy work, from the individual to community/governmental levels. • teachers and staff physicians should be prepared to model, explore and evaluate many forms of advocacy with medical trainees. • advocacy encompasses a wide range of skills and practices shaped by the cultural and political context in which they are employed. related training should therefore take into account the unique social, cultural and political characteristics of oman. teaching the role of health advocate reflections on two cross-cultural collaborative advocacy workshops for medical trainees and instructors in oman e290 | squ medical journal, august 2018, volume 18, issue 3 instructors in oman. this was the first formal approach to advocacy training of its kind in oman and the experience of designing and presenting the workshops highlights opportunities and challenges to teaching health advocacy in oman. medical educators must continue to push for innovative curricula that provide the framework for integrating these skills into all levels of medical training. a c k n o w l e d g e m e n t s all procedures described in this article conformed to local ethical and institutional guidelines as well as to those in the revised declaration of helsinki. c o n f l i c t s o f i n t e r e s t dr jessica breton declares no conflicts of interest. dr louis h. francescutti received an honorarium from the omsb to develop and teach the advocacy workshops described in this article and to cover travel and accommodation expenses. dr yousef al-weshahi was working as a part-time visiting faculty member for the omsb and also received an honorarium for leading the workshops. references 1. dharamsi s, osei-twum j, shroff f, mu l, woollard r. the health advocate role: preparing future physicians for socially responsive practice. univ b c fac res publ 2010. doi: 10.14288/1.0074591. 2. royal college of physicians and surgeons of canada. canmeds framework. from: www.royalcollege.ca/rcsite/canmeds/canme ds-framework-e accessed: jun 2018. 3. flynn l, verma s. fundamental components of a curriculum for residents in health advocacy. med teach 2008; 30:e178–83. doi: 10.1080/01421590802139757. 4. united nations development programme. human development report 2010. from: http://hdr.undp.org/en/content/humandevelopment-report-2010 accessed: jun 2018. 5. world health organization. world health report 2010. from: www.who.int/whr/2010/en/ accessed: jun 2018. 6. al dhawi aa, west dj jr, spinelli rj, gompf ta. the challenge of sustaining health care in oman. health care manag (frederick) 2007; 26:19–30. 7. oman medical specialty board. about us. from: www.omsb. org/#omsb-about-us accessed: jun 2018. 8. marmot m. social determinants of health inequalities. lancet 2005; 365:1099–104. doi: 10.1016/s0140-6736(05)71146-6. 9. canadian public health association. leadership in public health: an advocacy guide for public health associations. ottawa, ontario, canada: canadian public health association, 2009. 10. lalani a. introduction of a health advocacy module into an emer gency medicine curriculum. from: www.royalcollege.ca/rcsite/ documents/canmeds/canmeds-lalani-emergency-curricu lum-e.pdf accessed: jun 2018. 11. raza d. advocating for the advocate. can fam physician 2011; 57:1353. 12. hewko a. leading the way into advocacy: mentoring program gives students the ability to get involved early. from: www.med. ualberta.ca/news/2013/december/hal accessed: jun 2018. 13. canadian federation of medical students. day of action. from: www.cfms.org/what-we-do/advocacy/lobby-day.html accessed: jun 2018. 14. university of alberta faculty of medicine & dentistry. medical students’ association: political advocacy. from: www.ualberta. ca/medicine/programs/medical-students-association/clubsand-initiatives/political-advocacy accessed: jun 2018. 15. maeshiro r, johnson i, koo d, parboosingh j, carney jk, gesundheit n, et al. medical education for a healthier population: reflections on the flexner report from a public health pers pective. acad med 2010; 85:211–19. doi: 10.1097/acm.0b013 e3181c885d8. 16. belkowitz j, sanders lm, zhang c, agarwal g, lichtstein d, mechaber aj, et al. teaching health advocacy to medical students: a comparison study. j public health manag pract 2014; 20:e10–19. doi: 10.1097/phh.0000000000000031. 17. luft lm. the essential role of physician as advocate: how and why we pass it on. can med educ j 2017; 8:e109–16. https://doi.org/10.14288/1.0074591 https://doi.org/10.1080/01421590802139757 https://doi.org/10.1016/s0140-6736%2805%2971146-6 https://doi.org/10.1097/acm.0b013e3181c885d8 https://doi.org/10.1097/acm.0b013e3181c885d8 https://doi.org/10.1097/phh.0000000000000031 squ med j, may 2011, vol. 11, iss. 2, pp. 221-229, epub. 15th may 11 submitted 9th aug 10 revision req. 28th sept 10, revision recd. 6th nov 10 accepted 15th dec 10 departments of 1physiology, 3medicine, sultan qaboos university hospital, muscat, oman; departments of 2physiology; 4family medicine & community health, 5medicine , college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: deepali@squ.edu.om <ó◊¬ê<íäàflj÷]<á^„¢]<º«ï<ó◊¬<›^ë^fi]2÷]<ãàfli<ö^ma <‡⁄<·áfi^√ë<‡ëñ÷]<óïü€◊÷<퀄f� π]<î �åá÷]<·á]áj÷] ∞è√èf�÷]<‡⁄<‹‚4∆<ê<‡⁄àπ]<ãàflj÷]<–èï      ² 5.5 ± 21.9 43.91 ± 20.56 ² 3.2 ± 25.4  14.6 ± 43.5    ± 7.2 2.4 ± 5.4 p < 0.031.2      :مفتاح الكلمات abstract: objectives: the objective of this study was to compare the effects of pranayam breathing on respiratory muscle strength measured as maximum expiratory and inspiratory pressures (mep and mip) and relevant spirometry parameters in patients with chronic obstructive pulmonary disease (copd) and in control subjects, and on the sympatho-vagal balance in both the groups. methods: the research was performed in the clinical physiology department, sultan qaboos university hospital, oman. eleven patients (mean age 43.91 ± 20.56 yr; mean bmi 21.9 ± 5.5 kg/m2) and 6 controls (43.5 ± 14.6yr; 25.4 ± 3.2 kg/m2) learnt and practised pranayam. their respiratory and cardiovascular parameters were recorded. their respiratory “well being” was noted as a visual analogue score (vas). the respiratory parameters were expressed as a percentage change of predicted values. results: patients’ respiratory parameters were significantly lower than those of controls. patients’ maximum respiratory pressures did not improve after pranayam; however, they showed significant improvement in vas 5.4 ± 2.4 to 7.2 ± 1.2 (p < 0.03). controls showed significant increase in mip after pranayam exercises. there were no changes in other spirometry indices. controls showed significant increase in their systolic blood pressure and stroke index after exercise. the vago-sympathetic balance shifted towards sympathetic in both patients and controls after exercise. conclusion: the improvement in mip in controls indicated the positive effect of pranayam exercise; however, it may not be an adequately stressful exercise to produce changes in the respiratory parameters of copd patients. the increase in vas in patients suggested improvement in respiratory distress and quality of life. keywords: copd; pranayam exercise; autonomic nervous system; respiratory pressures; vas effects of pranayam breathing on respiratory pressures and sympathovagal balance of patients with chronic airflow limitation and in control subjects *deepali s jaju,1 mohan b dikshit,2 jothi balaji,1 jyoji george,3 syed rizvi,4 omar al-rawas5 clinical & basic research effects of pranayam breathing on respiratory pressures and sympathovagal balance of patients with chronic airflow limitation and in normal subjects 222 | squ medical journal, may 2011, volume 11, issue 2 by definition, chronic obstructive pulmonary disease (copd) is “a state that is characterised by the presence of airflow limitation which is not fully reversible. the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. copd is a preventable and treatable disease with significant extrapulmonary effects that may contribute to its severity in individual patients. the chronic airflow limitation characteristic of copd is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema). the relative contribution of these may vary from person to person”.1,2 copd has also been associated with inspiratory and expiratory muscle weakness which may contribute to the sensation of dyspnea.3-5 respiratory muscle weakness was confirmed by the low maximal inspiratory (mip) and expiratory (mep) pressures generated by patients with copd.6 enhancing respiratory muscle strength with physical training has been found to have some success in alleviating the respiratory distress of such patients.7,8 most of this training involved breathing against pressure loads or endurance training.9 respiratory muscle training in patients of copd decreased the sense of dyspnea during exercise and improved tolerance to exercise, but the effect on mep and mip was contradictory.10,11 the intense training may have caused distress to the already compromised patients. a respiratory manoeuvre which does not accentuate the respiratory distress of copd patients, but at the same time improves respiratory muscle strength and spirometry parameters while allaying the sense of dyspnea and fatigue, would be a more acceptable proposition. sub-clinical cardiovascular autonomic neuropathy has been known to occur in patients of copd12 even in the early stages of the disease.13 the basic pathophysiology involved is likely to be chronic hypoxia as autonomic modulation could be brought about by supplemental oxygen breathing.14 patients with chronic airflow limitation are thus under a constant physiological stress which needs to be alleviated if their quality of life is to be improved. pranayam is a non-distressing, slow, yogic breathing exercise which modifies autonomic functions in control subjects.15 others have used it with varying success as an adjunct to existing therapy for copd patients.16-18 however, respiratory pressures were not measured in any of the studies involving pranayam. we hypothesised that pranayam breathing exercises might lead to clinical provement with positive changes in mip and mep as well as readjustments of the vagosympathetic balance of the cardiovascular system. this study aimed to examine this hypothesis and compare their respiratory, haemodynamic and autonomic parameters with control subjects who also undertook pranayam breathing exercises. methods eleven patients (7 males; 4 female; mean ± standard deviation (sd): age 43.9 + 20.6 yr; body mass index (bmi) 21.9 + 5.52 kg/m2) and 6 control subjects (6 males; 2 female; 43.5 + 14.6yr, bmi 25.4 + 3.2 kg/ m2) volunteered for the study which was approved by the ethical committee of the college of medicine & health sciences at sultan qaboos university (squ). written consent was obtained from all participants. inclusion criteria for patients were: 1) registered as patients of copd/chronic airflow limitation with the respiratory clinic at squ hospital; 2) forced expiratory volume 1 sec (fev1) < 60% of predicted, and forced expiratory flow (fef) of 25–75% at < 40% predicted. none of the selected patients suffered from diabetes mellitus, hypertension or congestive cardiac failure. they continued with their prescribed treatment, if any, advances in knowledge 1. this paper contributes to advancing understanding of the haemodynamic and autonomic reflex responses to pranayam exercise in chronic obstructive pulmonary disease (copd) /chronic airflow limitation patients. application to patient care 1. regular pranayam breathing exercise may improve the respiratory distress and quality of life of patients having copd/ chronic airflow limitation. 2. regular pranayam breathing exercise may improve the inspiratory muscle strength in control subjects. deepali s jaju, mohan b dikshit, jothi balaji, george jyoji, syed rizvi and omar al-rawas clinical and basic research | 223 throughout the experiment. the control subjects were volunteers from among departmental staff. the patients and the control subjects were asked to follow the breathing sequence as per pal et al.13 as follows; close one nostril with the thumb; inhale slowly over a count of 6 seconds; at the end of the inhalation, close both the nostrils; count to 6; open the second nostril and exhale slowly over a count of 6 seconds; inhale with the same nostril slowly over 6 seconds; this constituted a single sequence. this was to be repeated for 30 minutes each day for at least 5 days a week for 3 months. spirometry indices were measured using medgraphics (elite dx, usa) which was calibrated daily at the start of the day, and zero flow of the pneumotach was confirmed prior to testing. all measurements were performed by one/two trained technologists, and measurements were made using standard procedures.19 minimum and maximum respiratory pressures (mip, mep)20 were measured as described in the american thoracic society/european respiratory society statement.21 to elaborate, for the measurement of the mep, after connecting to the pneumotach, the subjects breathed normally at tidal volume for six breaths. following this, s/he inspired maximally to total lung capacity (tlc). at this point, the shutter of the body box was occluded, and the patient breathed out using maximal force which could be sustained for at least 3 seconds against the closed shutter. at least three to four satisfactory attempts were recorded, and the best effort was included for the analysis. for recording the mip, the patient/subject started the manoeuvre at the end of a maximal expiration to residual volume (rv), and inhaled maximally against the closed shutter. follow-up lung function testing was done after three months practice of pranayam breathing. most studies also have this time sequence in assessing effects of respiratory training in copd patients.22 the vas (visual analogue score) for respiratory well being (scale 0–10) was recorded at the first visit and after 3 months of breathing exercise. haemodynamic and autonomic measurements were taken as follows. beat-to-beat haemodynamic and autonomic parameters were obtained noninvasively at rest using task force monitor (tfm) (cnsystems, graz, austria). haemodynamic measurements of heart rate and r-r interval were acquired with a 6-lead electrocardiogram. beatto-beat blood pressure (bp), systolic and diastolic, (sbp and dbp) was measured with the vascular unloading technique using finger cuffs. beat-tobeat bp was automatically counterchecked and corrected every minute by the oscillometric bp measurements recorded from the contralateral upper arm.23 impedance cardiography measurements were also taken. derived haemodynamic parameters were computed from continuous bp and heart rate (hr) and the impedance signal.23 the latter was acquired from a small constant sinusoidal alternating current passing through the thorax between an electrode placed around the neck and another placed at the lower end of the sternum. the voltage between the electrodes is proportional to the thorax impedance. left ventricular ejection time (lvet), the time between points ‘b’ and ‘x’ (opening and closure of aortic valve, respectively) of the impedance signal, was considered in further calculations of haemodynamic parameters using the standard kubisek’s formula. the haemodynamic parameters calculated and indexed for body surface area were stroke index (si), cardiac index (ci) and total peripheral resistance index (tpr, tpri). autonomic measurements were made as follows. an adaptive autoregressive model (aar) was used to compute online beat-to-beat time varying spectral analysis of the heart rate variability (hrv) in the frequency domain. very low frequency (vlf 0.01-0.05 hz band); low frequency (lf 0.050.17 hz band), and high frequency (hf 0.17-0.5 hz band) were calculated in absolute values (ms2) and in normalised units: low frequency (lfnu) and high frequency (hfnu).23,24 there is a general agreement that hf, hfnu reflect the parasympathetic or vagal activity, and lf, lfnu reflect the sympathetic modulation of the sinoatrial node and vasomotion.25 the change in status of the sympatho-vagal balance was indicated by the lf/hf ratio.25 all experiments were done in the morning at a comfortable room temperature of 27 0c. an informed consent was obtained after explaining the procedure. all subjects underwent the same protocol. after spirometry and respiratory pressure measurements, subjects were connected to the tfm with electrodes. they were made to rest supine on a comfortable bed in a quiet room. beat-tobeat recordings of haemodynamic and autonomic parameters were obtained at rest for 10 mins. all effects of pranayam breathing on respiratory pressures and sympathovagal balance of patients with chronic airflow limitation and in normal subjects 224 | squ medical journal, may 2011, volume 11, issue 2 subjects were asked to mark on the vas scale. the same protocol was repeated on subsequent visits. compliance of pranayam breathing was confirmed verbally on each revisit. all subjects confirmed that they had carried out the exercise as instructed. descriptive and comparative analyses were performed using the statistical package for the social sciences (spss, version 13.0). parametric data were expressed as means + sd. a probability value of <0.05 was considered statistically significant. beat-to-beat measurements obtained with tfm were averaged for time periods of 10 mins of rest. the unpaired two tailed student’s ‘t’ test was used to compare anthropometric measurements, baseline haemodynamic and autonomic parameters and respiratory pressures and spirometry indices between the 2 groups (control and patients). the paired 't’ test was used to compare these cardiovascular and respiratory parameters before and after pranayam exercise separately between control subjects and patients. the difference between baseline and post pranayam values of cardiovascular and respiratory parameters was taken as measure of responses to pranayam exercises. this estimated reactivity was compared between control subjects and patients using the wilcoxon rank test for non-parametric samples. results anthropometric and baseline cardiovascular and respiratory parameters for control subjects and patients are given in table 1. both groups were comparable for age and bmi. the vas was significantly lower in the patients (p = 0.03). there were no differences in haemodynamic and autonomic parameters between two groups [table 1]. all respiratory pressures and spirometry indices were within normal physiological range in control subjects and were significantly lower in patients [table 1]. this confirmed the impaired pulmonary table 1: baseline haemodynamic and autonomic parameters, respiratory pressures and spirometry indices in control subjects and patients value (standard deviation) anthropometric, haemodynamic and autonomic parameters respiratory pressures and spirometry indices controls n = 6 patients n = 11 p controls n = 6 patients n = 11 p age 43.5 (14.5) 43.9 (20.5) ns mep 153.5 (32.4) 98.5 (27.1) 0.001 bmi 25.4 (3.2) 21.9 (5.4) ns pcmep 79.5 (18.6) 60.8 (16.3) 0.05 vas 7.0 (2.1) 5.4 (2.3) 0.03 mip 113.5 (34.1) 65.4 (37.7) 0.02 hr 72.0 (13.6) 78.6 (13.4) ns pcmip 106.0 (21.3) 57.8 (26.5) 0.0001 sbp 108.8 (15.5) 112.3 (14.5) ns fvc 4.0 (1.3) 2.4 (0.8) 0.01 dbp 78.6 (9.3) 74.5 (7.3) ns pcfvc 95.8 (9.5) 73.2 (10.5) 0.0001 si 47.4 (12.9) 47.4 (7.5) 0.05 fev1 3.1 (0.9) 1.5 (0.7) 0.01 tpri 2218.5 (639.2) 1885.4 (431.5) ns pcfev1 90.5 (5.8) 58.2 (12.6) 0.001 lfnu 56.8 (13.7) 41.5 (26.1) ns fev1/fvc 78.6 (5.7) 63.8 (12.3) 0.001 hfnu 43.1 (13.7) 60.3 (23.2) ns pc fev1/fvc 98.3 (6.3) 80.2 (15.0) 0.001 vlf 102.3 (102.7) 113.6 (117.8) ns fef25-75% 2.75 (0.8) 0.9 (0.4) 0.0001 lf/hf 1.5 (0.9) 1.1 (0.9) ns pcfef25-75% 68.1 (12.3) 25.5 (12.4) 0.0001 psd 731.0 (103.6) 677.4 (313.4) ns pefr 9.0 (1.3) 4.4 (1.4) 0.0001 pcpefrc 112.7 (14.5) 61.4 (15.5)c 0.0001 legend: age (years); bmi = body mass index (kg/m2); vas = visual analogue score; hr = heart rate (bpm); sbp = systolic blood pressure (bp) (mmhg ); dbp = diastolic bp (mmhg ); si = stroke index (ml/m2); tpri = total peripheral resistance index (dyne*s*m2/cm2); lfnu = low frequency normalized units (%); hfnu = high frequency normalized units (%); vlf = very low frequency (ms2); lf/hf = sympatho-vagal balance; psd = power spectral density (ms3); mep = maximum expiratory pressure (cmh2o ); pcmep = % predicted of mep (cmh2o); mip = maximum inspiratory pressure (cmh2o); pcmip = % predicted of mip (cmh2o ); fvc = forced vital capacity (l); pcfvc = % predicted of fvc; fev1 = forced expiratory volume 1 sec (l); pcfev1 = % predicted of fev1; fev1/fvc = ratio of fev1 to fvc (%); pcfev1/fvc = % predicted of fev1/fvc (%); fef25-75% = forced expiratory flow 25-75% (l/sec); pcfef25-75% = % predicted of fef25-75%; pefr = peak expiratory flow rate (l/sec); pcpefr = % predicted of pefr (l/sec); ns = not significant, p >0.05. deepali s jaju, mohan b dikshit, jothi balaji, george jyoji, syed rizvi and omar al-rawas clinical and basic research | 225 functions in patients. responses of cardiovascular and respiratory parameters and vas to pranayam exercise are given in table 2 for the control subjects and in table 3 for the patients. the comparison of cardiovascular and respiratory responses to pranayam exercises between control subjects and patients are given in table 4. in the control subjects, there was a significant increase in sbp (p = 0.01) and si (p = 0.05) after pranayam exercise [table 2]. there was also an increase in sympathetic parameters (lfnu and lf/hf) after pranayam exercise; however, the difference was not significant. the mep and mip both increased in response to pranayam exercise; however, the difference was significant only for mip (p = 0.03). there was no difference in other respiratory pressures and indices in response to pranayam exercise. patients showed significant improvement in vas (p = 0.04) after pranayam exercise [table 3]. paradoxically, they did not show a significant change in cardiovascular parameters, respiratory pressures and indices in response to the pranayam exercise [table 3]. there were no differences in cardiovascular responses to pranayam exercises between control subjects and patients [table 4]. amongst respiratory pressures, the control subjects showed a significant increase in percent predicted mip (pcmip; control subjects 24.7 ± 18.3 versus patients 0.9 ± 19.5; p = 0.03) compared with patients. there were no differences in the responses of other respiratory pressures and indices between control subjects and patients [table 4]. in patients, the measure of respiratory well being, vas, showed a significant increase in response to pranayam exercise (control subjects 0.5 ± 1.5 versus patients 1.8 ± 1.2; p = 0.05). discussion the major findings of this study were, first, that pranayam exercise produced significant increase table 2: differences in visual analogue score (vas), haemodynamic and autonomic parameters, respiratory pressures and spirometry indices in control subjects before and after pranayam exercise value (standard deviation) vas, haemodynamic and autonomic parameters respiratory pressures and spirometry indices controls before pranayam n = 6 after pranayam n = 6 p before pranayam n = 6 after pranayam n = 6 p vas 7.0 (2.1) 7.5 (2.2) ns mep 153.5 (32.4) 170.3 (27.5) ns hr 72.0 (13.6) 72.2 (12.8) ns pcmep 79.5 (18.6) 84.7 (4.9) ns sbp 108.8 (15.5) 118.2 (6.9) 0.01 mip 113.5 (34.1) 134.7 (35.6) 0.03 dbp 78.6 (9.3) 78.5 (5.7) ns pcmip 106.0 (21.3) 123.7 (19.5) ns si 47.4 (12.9) 52.5 (22.4) 0.05 fvc 4.0 (1.3) 3.9 (1.0) ns tpri 2218.5 (639.2) 2330.0 (419.8) ns pcfvc 95.8 (9.5) 93.2 (10.0) ns lfnu 56.8 (13.7) 66.6 (3.6) ns fev1 3.1 (0.9) 3.1 (0.7) ns hfnu 43.1 (13.7) 33.4 (3.6) ns pcfev1 90.5 (5.8) 90.4 (4.3) ns vlf 102.3 (102.7) 116.3 (138.2) ns fev1/fvc 78.6 (5.7) 77.5 (6.4) ns lf/hf 1.5 (0.9) 1.7 (0.6) ns pcfev1/fvc 98.3 (6.3) 97.5 (6.7) ns psd 731.0 (103.6) 393.3 (90.8) ns fef25-75% 2.75 (0.8) 2.6 (0.8) ns pcfef25-75% 68.1 (12.3) 64.0 (11.9) ns pefr 9.0 (1.3) 8.8 (1.2) ns pcpefr 112.7 (14.5) 106.0 (13.0) ns legend: vas = visual analogue score; hr = heart rate (bpm); sbp = systolic blood pressure (bp) (mmhg ); dbp = diastolic bp (mmhg ); si = stroke index (ml/m2); tpri = total peripheral resistance index (dyne*s*m2/cm2); lfnu = low frequency normalized units (%); hfnu = high frequency normalized units (%); vlf very low frequency (ms2); lf/hf = sympatho-vagal balance; psd = power spectral density (ms3); mep = maximum expiratory pressure (cmh2o); pcmep = % predicted of mep (cmh2o ); mip = maximum inspiratory pressure (cmh2o); pcmip = % predicted of mip (cmh2o ); fvc = forced vital capacity (l); pcfvc = % predicted of fvc; fev1 = forced expiratory volume 1 sec (l); pcfev1 = % predicted of fev1; fev1/fvc = ratio of fev1 to fvc (%); pcfev1/fvc = % predicted of fev1/fvc (%); fef25-75% = forced expiratory flow 25-75% (l/sec); pcfef25-75% = % predicted of fef25-75%; pefr = peak expiratory flow rate (l/sec); pcpefr = % predicted of pefr (l/sec); ns = not significant, p >0.05. effects of pranayam breathing on respiratory pressures and sympathovagal balance of patients with chronic airflow limitation and in normal subjects 226 | squ medical journal, may 2011, volume 11, issue 2 only in the mip of control subjects; second, in patients, there were no significant changes in cardiovascular parameters, respiratory pressures and indices in response to the pranayam exercise; and third, patients showed significant improvement in the score of respiratory well-being in response to the pranayam exercise. the impaired respiratory muscle function in copd patients leading to exertional dyspnoea is well established.22 we hypothesised that pranayam, a non-distressing slow yogic breathing exercise, may train respiratory muscles and improve their performance. however, our study showed significant increase in mip only in control subjects and not in patients. inspiratory muscles of respiration are an important factor contributing to exertional dyspnoea. the improvement in mip in control subjects suggested that pranayam worked positively for them. it is possible that pranayam was not a sufficiently stressful breathing exercise to produce the change in patients. however, the significant increase in vas in our study group indicated that the pranayam exercise improved the respiratory distress and quality of life. the positive outcome from the respiratory muscle training depends upon the overload principle applied to the training22 which includes increase in frequency, duration and intensity of the training. the respiratory muscle training would be of benefit to patients if respiratory muscle function is a major limiting factor during performance of the training. reid suggested that an exercise training programme should be tailored to an individual patient’s needs and abilities.22 rigorous aerobic exercise has not consistently produced benefit on mip and mep values. gemeniz et al. showed that maximally intense aerobic exercise significantly improved mep and mip and decreased dyspnoea at rest.9 in copd patients, however, de lucas ramos et al. found that progressive maximal exercise tolerance decreased the sense of dyspnoea, but had no effect on respiratory pressures.11 cooper et al. showed that the buteyko breathing technique (a device that mimics paranayama) attenuated the symptoms and reduced bronchodilator use, but table 3: differences in visual analogue score (vas), haemodynamic and autonomic parameters, respiratory pressures and spirometry indices in patients before and after pranayam exercise vas, haemodynamic and autonomic parameters respiratory pressures and spirometry indices patients before pranayam n = 11 after pranayam n = 11 p before pranayam n = 11 after pranayam n = 11 p vas 5.4 (2.3) 7.2 (1.2) 0.04 mep 98.5 (27.1) 99.7 (17.4) ns hr 78.6 (13.4) 74.4 (10.60 ns pcmep 60.8 (16.3) 61.4 (17.3) ns sbp 112.3 (14.5) 112.2 (15.7) ns mip 65.4 (37.7) 66.6 (37.8) ns dbp 74.5 (7.3) 70.8 (11.6) ns pcmip 57.8 (26.5) 59.0 (27.1) ns si 47.4 (7.5) 47.2 (6.8) ns fvc 2.4 (0.8) 2.6 (0.7) ns tpri 1885.4 (431.5) 1853.7 (400.7) ns pcfvc 73.2 (10.5) 76.9 (12.2) ns lfnu 41.5 (26.1) 47.6 (24.9) ns fev1 1.5 (0.7) 1.7 (0.4) ns hfnu 60.3 (23.2) 51.8 (24.9) ns pcfev1 58.2 (12.6) 57.13.6) ns vlf 113.6 (117.8) 132.4 (128.0) ns fev1/fvc 63.8 (12.3) 66.0 (8.4) ns lf/hf 1.1 (0.9) 1.6 (1.4) ns pc fev1/fvc 80.2 (15.0) 82.1 (9.1) ns psd 677.4 (313.4) 865.0 (516.4) ns fef25-75% 0.9 (0.4) 0.9 (0.2) ns ns pcfef25-75% 25.5 (12.4) 26.2 (8.1) ns ns pefr 4.4 (1.4) 4.7 (1.1) ns pcpefr 61.4 (15.5) 65.0 (10.0) ns legend: vas = visual analogue score; hr = heart rate (bpm); sbp = systolic blood pressure (bp) (mmhg ); dbp = diastolic bp (mmhg ); si = stroke index (ml/m2); tpri = total peripheral resistance index (dyne*s*m2/cm2; lfnu = low frequency normalized units (%); hfnu = high frequency normalized units (%); vlf = very low frequency (ms2); lf/hf = sympatho-vagal balance; psd = power spectral density (ms3); mep = maximum expiratory pressure (cmh2o); pcmep = % predicted of mep (cmh2o); mip = maximum inspiratory pressure (cmh2o); pcmip = % predicted of mip (cmh2o) ); fvc = forced vital capacity (l); pcfvc = % predicted of fvc; fev1 = forced expiratory volume 1 sec (l); pcfev1 = % predicted of fev1; fev1/fvc = ratio of fev1 to fvc (%); pcfev1/fvc = % predicted of fev1/fvc (%); fef25-75% = forced expiratory flow 25-75% (l/sec); pcfef25-75% = % predicted of fef25-75%; pefr = peak expiratory flow rate (l/sec); pcpefr = % predicted of pefr (l/sec); ns = not significant, p>0.05. deepali s jaju, mohan b dikshit, jothi balaji, george jyoji, syed rizvi and omar al-rawas clinical and basic research | 227 it did not change lung functions.26 yoga therapy which included asanas (body postures) and timed pranayam breathing improved the tolerance of copd patients for the 6 minute walk test.27 however, donesky-cuenco et al. did not study the effect of yogic therapy on respiratory parameters. a recent meta-analysis of respiratory muscle training in chronic air flow limitation suggested that there is little evidence of clinically important benefits of respiratory muscle training in patients with chronic air flow limitation. the meta-analysis also suggested that benefit may result if resistance exercises are conducted in a fashion that ensures the adequate generation of mouth pressures.28 the inspiratory muscle training schedule which improves mip is 15–50 min exercise/ day 5 days a week for 1–6 months.3,10,22 although the schedule of the training offered in our study was adequate, the type, intensity and duration of exercise were probably not adequate to produce beneficial changes in copd patients. our subjects were asked to follow the schedule at home. the reliability of compliance from patients thus remains questionable. conducting the exercises in controlled environment could have provided better results. most studies involving respiratory muscle strength were conducted in copd patients who had a fev1/fvc ratio of 50% or less. in comparison, our patients were less compromised (fev1/fvc ratio 63.8% ± 12.3). it is possible that patients with more severe limitation may have responded more positively to the exercise. our study did not find any significant differences between resting haemodynamic and autonomic parameters between patients and control subjects. the autonomic dysfunction was documented in copd patients using interventions that excite cardiovascular reflexes like valsalva manoeuvre, 30:15 ratio, handgrip or postural challenge.12,13,29-31 few studies correlated the autonomic dysfunction with hypoxaemia and severity of the disease in these patients.12,13,29 camillo et al. associated autonomic dysfunction not with severity of disease, but with a lower level table 4: comparison of responses of visual analogue score (vas), haemodynamic and autonomic parameters, respiratory pressures and spirometry indices before and after pranayam exercise between control and patients vas, haemodynamic and autonomic parameterscontrols respiratory pressures and spirometry indices controls controls n = 6 patients n = 11 p controls n = 6 patients n = 11 p vas 0.5 (1.5) 1.8 (1.2) 0.05 mep 7.5 (24.8) 0.2 (13.3) ns hr 3.5 (3.7) -1.1 (14.1) ns pcmep 4.0 (13.4) 1.2 (7.2) ns sbp 9.8 (3.8) 1.3 (2.3) ns mip 25.0 (13.2) 0.1 (19.5) ns dbp 3.5 (6.6) -2.7 (12.5) ns pcmip 24.7 (18.3) 0.9 (15.5) 0.03 si 3.4 (8.30 -0.2 (5.1) ns fvc 0.0 (0.01) 0.1 (0.20 0.04 tpri 112.8 (445.0) -31.6 (593.8) ns pcfvc -0.5 (0.6) 4.0 (8.6) ns lfnu 10.3 (14.7) 9.9 (22.7) ns fev1 -0.02 (0.04) 0.2 (0.4) ns hfnu -10.4 (14.6) -12.7 (21.7) ns pcfev1 -0.8 (1.3) 3.0 (7.6) ns vlf 14.0 (51.0) 18.8 (90.4) ns fev1/fvc -0.3 (1.3) 0.4 (6.5) ns lf/hf 0.3 (0.9) 0.7 (1.7) ns pc fev1/fvc -0.3 (1.7) 0.6 (7.9) ns psd -337.7 (650.4) 187.8 (462.6) ns fef25-75% -0.05 (1.1) -0.02 (0.3) ns pcfef25-75% -1.5 (3.8) 1.3 (9.1) ns pefr -0.3 (0.5) 0.3 (0.7) ns pcpefr -3.3 (4.9) 3.0 (8.6) ns legend: vas = visual analogue score; hr = heart rate (bpm); sbp = systolic blood pressure (bp) (mmhg ); dbp = diastolic bp (mmhg ); si = stroke index (ml/m2); tpri = total peripheral resistance index (dyne*s*m2/cm2); lfnu = low frequency normalized units (%); hfnu = high frequency normalized units (%); vlf = very low frequency (ms2); lf/hf = sympatho-vagal balance; psd = power spectral density (ms3); mep = maximum expiratory pressure (cmh2o); pcmep = % predicted of mep (cmh2o); mip = maximum inspiratory pressure (cmh2o); pcmip = % predicted of mip (cmh2o) ); fvc = forced vital capacity (l); pcfvc = % predicted of fvc; fev1 = forced expiratory volume 1 sec (l); pcfev1 = % predicted of fev1; fev1/fvc = ratio of fev1 to fvc (%); pcfev1/fvc = % predicted of fev1/fvc (%); fef25-75% = forced expiratory flow 25-75% (l/sec); pcfef25-75% = % predicted of fef25-75%; pefr = peak expiratory flow rate (l/sec); pcpefr % predicted of pefr (l/sec); ns = not significant, p>0.05. effects of pranayam breathing on respiratory pressures and sympathovagal balance of patients with chronic airflow limitation and in normal subjects 228 | squ medical journal, may 2011, volume 11, issue 2 of physical activity in daily life along with poor health-related quality of life, functional status and respiratory and peripheral muscle force.30 correction of hypoxaemia may not have any effect on improvement of autonomic functions,12,29 but the 6 weeks aerobic exercise training significantly improved the submaximal performance in the 6 minute walk test and it was associated with increased parasympathetic activity.31 our study investigated the autonomic activity at rest and not during the cardiovascular challenges. the similar autonomic functions in patients and control subjects could be attributed to normal resting oxygen saturation in them (po2: control subjects: 99.0 ± 1.1; patients: 97.0 ± 1.3%). pranayam exercise is known to activate the parasympathetic limb of the autonomic nervous system.15 although non-significant, we found that pranayam exercise activated the sympathetic limb of the autonomic nervous system in both control subjects and patients. the improvement in quality of symptoms as indicated by vas could be attributed to the correction of autonomic balance. in this study, we compared the effect of pranayam breathing in copd patients and control subjects by investigating both improvement in respiratory muscle strength and also the relief of stress. the small sample size posed a limitation in drawing conclusions. in the future, a well organised clinical trial with adequate sample size and strict supervision of the breathing exercises may give a better understanding of the usefulness of pranayam breathing exercise for these patients. conclusion our study did not show significant alterations in the autonomic studies or in the pulmonary functions status of copd/ chronic airflow limitation patients. the improvement in mip in control subjects indicated the positive effect of pranayam. although pranayam was not an adequately stressful breathing exercise to produce the change in copd patients, it improved the respiratory distress and quality of life as indicated by the significant increase in vas in patients. it was also interesting to note the shift of the autonomic balance towards sympathetic which may suggest that this could be a better coping mechanism induced by pranayam breathing. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g e m e n t s this project (rs/06/041) was funded by the college of medicine & health sciences, sultan qaboos university, muscat, oman. we sincerely acknowledge the help of ms. adila al-touqui, superintendent, department of clinical physiology, sultan qaboos university hospital, oman for the arabic translation. references 1. american thoracic society statement: occupational contribution to the burden of airway disease. am j respir crit care med 2003; 167:787−97. 2. global initiative for chronic obstructive lung disease 2005. global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2009. medical communications resources, inc. from: www.goldcopd.org accessed: oct 2010. 3. larson jl, covey mk, corbridge s. inspiratory muscle strength in chronic obstructive pulmonary disease. aacn clin issue 2002; 13:320−32. 4. newall c, stockley ra, hill sl. exercise training and inspiratory muscle training in patients with bronchiectasis. thorax 2005; 60:943−8. 5. ramirez-sarmiento a, orzocxo-levi m, barreiro e, ferrer a, broquetas j, geas j. expiratory muscle endurance in chronic obstructive pulmonary disease. thorax 2002; 57:132−6. 6. brunetto a, alves l. comparing peak and sustained values of maximum respiratory pressures in healthy subjects and chronic pulmonary disease patients. j pnuemologica 2003; 29:1−9. 7. sturdy g, hillman d, green d, jenkins s, cecins n, eastwood p. feasibility of high intensity interval based respiratory muscle training in copd. chest 2003; 123:142−50. 8. covey mk, larson jl, wirtz se, berry jk, pogue nj, alex cg, et al. high intensity inspiratory muscle training in patients with chronic obstructive pulmonary disease and severely reduced function. j cardiopulmonary rehabil 2001; 21:231−40. 9. gimenez m, servera e, vergara p, bach jr, polu jm. endurance training in patients with chronic obstructive pulmonary disease: a comparison of high versus moderate intensity. arch phys med rehabil 2000; 81:102−9. 10. guyatt g, keller j, singer j, halcrow s, newhouse m. controlled trial of respiratory muscle training in chronic airflow obstruction. thorax 1992; 47: deepali s jaju, mohan b dikshit, jothi balaji, george jyoji, syed rizvi and omar al-rawas clinical and basic research | 229 598−602. 11. de lucas ramos p, rodriguez gonzalez-moro jm, garcia de pedro j, santacruz siminiani a, tatay marti e, cubillo marcos jm. training of inspiratory muscles in chronic obstructive lung disease. its impact on functional changes and exercise tolerance. arch broncopneumol 1998; 34:64−70. 12. stewart ag, waterhouse jc, howard p. cardiovascular autonomic nerve function in patients with hypoxaemic chronic obstructive pulmonary disease. eur respir j 1991; 4:1207−14. 13. chhabra sk, de s. cardiovascular autonomic neuropathy in chronic obstructive pulmonary disease. respir med 2005; 99:126−33. 14. bartels mn, jelic s, gonzalez jm, kim w, de meersman re. reproducibility of heart rate and blood pressure variability in patients with chronic obstructive pulmonary disease. clin auton res 2004; 14:194−6. 15. pal gk, velkumary s, madanmohan. effect of short term practice of breathing exercises on autonomic functions in normal human volunteers. indian j med res 2004; 120:115−21. 16. behera d. yoga therapy in chronic bronchitis. j assoc physicians india 1998; 46:207−8. 17. tandon mk. adjunct to treatment with yoga in chronic severe airway obstruction. thorax 1978; 33:514−17. 18. katiyar sk, bihari s. role of pranayam in rehabilitation of copd patients a randomized controlled study. indian j allergy, asthma, immunol 2006; 20:98−104. 19. quanjer ph. standardized lung function testing. report working party. standardization of lung function tests. european community for coal and steel. bull europ physiopathol respir 1983; 19:1−82. 20. black lf, hyatt re. maximal respiratory pressures: normal values and relationship to age and sex. american review respir dis 1969; 99:696−702. 21. ats/ers statement on respiratory muscle testing. am j respir crit care med 2002; 166:518 −624. 22. reid wd, samrai b. respiratory muscle training for patients with chronic obstructive pulmonary disease. phys ther 1995; 75:996–1005. 23. skrabal f. syncope, falls and cobalamin deficiency in the old population. clin auton res 2004; 14:60−6. 24. gratze g, rudnicki r, urban w, mayer h, schlögl a, skrabal f. hemodynamic and autonomic changes induced by ironman: prediction of competition time by blood pressure variability. j appl physiol 2005; 99:1728−35. 25. task force of the european society of cardiology and the north american society of pacing and electrophysiology. standards of measurement, physiological interpretation, and clinical use. circulation 1996; 93:1043−65. 26. cooper s, oborne j, newton s, harrison v, thompson coon j, lewis s, et al. effect of two breathing exercises (buteyko and paranayama) in asthma: a randomized controlled trial. thorax 2003; 58:649-50. 27. donesky-cuenco d, nguyen hq, paul s, carrierikohlman v. yoga therapy decreases dyspnea-related distress and improves functional performance in people with chronic obstructive pulmonary disease: a pilot study. j altern complement med 2009; 15: 225−34. 28. smith k, cook d, guyatt gh, madhavan j, oxman ad. respiratory muscle training in chronic airflow limitation: a meta-analysis. am rev respir dis 1992; 145:533−9. 29. hjalmarsen a, aasebø u, aleksandersen g, jorde r. cardiovascular responses to tests for autonomic dysfunction in patients with chronic obstructive pulmonary disease with and without continuous long-term oxygen therapy. j auton nerv syst 1996; 60:169−74. 30. camillo ca, pitta f, possani hv, barbosa mv, marques ds, cavalheri v, et al. heart rate variability and disease characteristics in patients with copd. lung 2008; 186:393-401. 31. borghi-silva a, arena r, castello v, simões rp, martins le, catai am, et al. aerobic exercise training improves autonomic nervous control in patients with copd. respir med 2009; 103:1503−10. squ med j, december 2009, vol. 9, iss. 3, pp. 311-314, epub. 19th dec 2009 submitted 30th june 2008, reformat recd. 25th oct 2008 revision req. 12th nov 08, revision recd. 21st mar 09 accepted 10th may 09 heart-type fatty acid bindingprotein (h-fabp) was introduced in 1988 as a potential novel biochemical marker for the early diagnosis of acute myocardial infarction (ami).1 this was soon confirmed by many other studies.2-7 under normal conditions, h-fabp is not present in plasma or interstitial fluid, but is released into the blood upon cardiac cellular injury. the h-fabp is released into plasma within 2 hours after symptom onset and is reported to peak at about 4-6 hours and to return to normal base line level in 20 hours. within the period of 30-210 minutes after symptom onset, h-fabp has > 80% sensitivity for the diagnosis of ami.4-5 within the interval of 0-6 hours after symptom onset, the other cardiac markers such as creatine kinase (ck), ck-muscle and brain (mb) (mass or activity), cardiac troponin i (ctni) and cardiac troponin t (ctnt) will only be starting to accumulate in the plasma, and their sensitivity has been reported to be around 64%.8 the exact route(s) of excretion of h-fabp from the circulation is not fully understood. as suggested by previous studies, the kidney may be the major route of excretion of h-fabp from circulation.4,6,9 the effect of disease states and in particular kidney disease on the renal handling of h-fabp has not yet been fully evaluated. the aim of this study was to compare the effect of renal failure on the level of h-fabp and ctnt concentrations. 1department of medicine, sultan qaboos university hospital, muscat, sultanate of oman; 2department of medical sciences, faculty of medicine, edinburgh university, uk; 3university of edinburgh, cardiovascular research unit, royal infirmary of edinburgh, uk *to whom correspondance whould be addresses. email: gunnbc@gmail.com قياس معدل بروتني محض القلب الدهين الرابط يف مصل املرضى الذين يعانون من الفشل الكلوي حفيظ الهادي، برنت ويليام، كيث فوكس امللخص: الهدف: اكتشف جالتز بروتني حمض القلب الدهني الرابط عام 1988 كأحد العالمات الكيميائية احليوية املبكرة الدالة على وجود جلطة قلبية. غير إن تأثير أمراض الكلى على هذا البروتني لم يتم دراسته بشكل واف حتى اآلن. هذه الدراسة تقارن تأثير الفشل الكلوي على تركيز بروتني حمض القلب الدهني الرابط الدراسة على مجموعة مكونة من 16 مريضا يعانون من فشل كلوي مزمن (ست نساء وعشرة رجال) تتراوح و تروبونني القلب (ت) في الدم. الطريقة: اشتملت أعمارهم بني 30 70 سنة، ويتلقون عالج غسيل كلى بشكل دوري. النتائج: معدل اليوريا و الكرياتنني في هذه اجملموعة هو 19 ± 9.6 مليمول / لتر و 531.3 ± 231.2 مليمول / لتر على التوالي. كان بروتني حمض القلب الدهني الرابط مرتفعا عند كل املرضى( 81 ± 53.3) مايكروجرام / لتر. وكذلك كان تروبونني القلب (ت) مرتفعا بأكثر من 0.1 مايكروجرام / لتر في ثمانية مرضى) %50 ( ، و أكثر من 0.2 مايكروجرام / لتر في خمسة مرضى) %31(، و أكثر من 0.3 مايكروجرام / لتر في مريض واحد ) %6(. اخلالصة: هذه الدراسة تشير إلى إن قدرة بروتني حمض القلب الدهني الرابط و تروبونني القلب (ت) على تشخيص اجللطة القلبية في وجود فشل كلوي محدود. مفتاح الكلمات: بروتني حمض القلب الدهني الرابط، تروبونني القلب (ت)، فشل كلوي. abstract: objectives: heart-type fatty acid binding-protein (h-fabp) has been reported to be a potential novel biochemical marker for the early diagnosis of acute myocardial infarction (ami). the effect of kidney diseases on the renal handling of h-fabp has not yet been fully evaluated. the aim of this study was to compare the effect of renal failure on the level of h-fabp and cardiac troponin (ctnt) concentrations. methods: the study population was a small group of 16 patients with renal failure (6 females, 10 males aged 30-70 years) on routine regular haemodialysis or peritoneal dialysis. results: the mean ±sd of serum urea and creatinine concentration in this group of patients was 19 ±9.6 mmol/l and 531.3 ±231.2 mmol/l respectively. h-fabp was increased in all 16 patients (81 ±53.3µg/l). the ctnt was increased ≥ 0.1µg/l in 8 patients (50%), ≥ 0.2µg/l in 5 patients (31.3%), and ≥ 0.3µg/l in 1 patient (6%). conclusion: the diagnostic efficiency of h-fabp and ctnt for the diagnosis of ami in the presence of renal failure may be limited and such patients may have high levels even in the absence of ami. keywords: heart-type fatty acid-binding protein; cardiac troponin t; renal failure. serum level of heart-type fatty acid-binding protein in patients with chronic renal failure hafidh a al-hadi,1 *brent william,2 keith a fox3 brief communication serum level of heart-type fatty acid-binding protein in patients with chronic renal failure 312 | squ medical journal, december 2009, volume 9, issue 3 methods the study population consisted of a small group of 16 patients with renal failure (6 females, 10 males, aged between 30-70 years) without evidence of acute coronary syndromes. these patients were on routine regular haemodialysis or peritoneal dialysis, and were recruited from the renal unit at the royal infirmary of edinburgh, u.k. these patients had a range of diseases that were commonly seen in the renal unit including chronic glomerulonephritis (3 patients), interstitial nephritis (3 patients), adult dominant polycystic kidney disease (2 patients), hypertensive and diabetic nephropathy (8 patients). peripheral blood samples were collected in white starstedt monovette vacutainer tubes by venepuncture. the blood samples (5mls) were taken through a peripheral line (intravascular access). the extracted samples were allowed to clot at room temperature for 1 hour and then centrifuged at 4°c, and the resulting serum was divided into small aliquots and frozen at -70°c until analysis. the h-fabp was analysed by an enzyme linked immunosorbent assay method using commercially available assays (hycult, cambridge). the analytical sensitivity of h-fabp, presented as mean ±2sd, was 0.206 ±0.047g/l.10 the ctnt was analysed on elecsys 2010 using commercial assays (roche, germany). ethical approval was obtained from the local ethical committee and an informed consent was obtained from each patient before beginning the study. the study complies with the declaration of helsinki. results the reference ranges quoted by the manufacturer for ctnt (< 0.01µg/l) and h-fabp (< 5µg/l) assays were validated by assaying the normal ranges of 20 healthy blood donors samples (healthy blood donor controls: 10 males and 10 females, mean age sd = 63.8 ±8.01 years (median = 65 years [range 53-75 years]). the mean ±sd concentrations of ctnt and h-fabp were 0.011 ±0.002µg/l, and 6.86 ±2.21 µg/l respectively. the coefficients of variation (cvs) of the assays were always < 10%. the serum urea and creatinine concentration in this group of patients was 19 ±9.6 mmol/l and 531.3 ±231.2 µmol/l respectively. h-fabp was increased in all 16 patients (mean = 81 ±53.3µg/l [range 24173µg/l]). the ctnt was increased ≥0.1µg/l in 8 patients (50%), ≥ 0.2µg/l in 5 patients (31.3%), and ≥ 0.3µg/l in 1 patient (6%). in the remaining 8 patients, ctnt was 0.069 ±0.023µg/l (range 0.0210.087µg/l). there were no correlations between the concentration of either urea or creatinine and the concentration of h-fabp and ctnt. there was a positive correlation between the concentrations of ctnt and h-fabp (r = 0.569, p < 0.02). discussion h-fabp is a small (15 kda) soluble non-enzyme protein. it is composed of 132 amino acids. it is one of the most abundant proteins in the heart and comprises 5-15% of the total cytosolic protein pool in the aqueous cytoplasm. h-fabp exists in high concentrations in the heart only. however, this protein is not totally cardiac specific and occurs in other tissues although in much lesser concentrations.11 it is present in skeletal muscles in concentrations varying between 0.05-0.2mg/g wet weight of tissue, depending on the muscle fibre type studied.2 it has also been reported in very low concentrations in tissues like the kidney, aorta, testes, mammary glands, placenta, brain, adrenal glands, adipose tissue, and stomach.11 preliminary but promising applications of these proteins have been demonstrated for liver rejection, viability selection of kidneys from non-heart-beating donors (nhbd), inflammatory and ischaemic bowel disease, traumatic brain injury and in the prevention of muscle injury in trained athletes.12 the cytoplasmic to vascular concentration of h-fabp is of the order of 200,000:1. the plasma or serum concentration of h-fabp under normal conditions is < 5µg/l.1 this makes the plasma estimation of h-fabp a suitable indicator for the early detection and quantification of myocardial tissue injury. a rise in serum and urine h-fabp concentrations above normal values is seen in patients presenting with ami as early as 1.5 hours after symptom onset.6 studies in animals have also shown decreased myocardial tissue content and rising plasma and urine concentrations of h-fabp very early after coronary artery ligation.9 some of the more recent studies have questioned the value of these early markers (h-fabp and myoglobin) when compared with specific markers like ctni.13 the reason for elevated h-fabp in our study of patients with chronic kidney disease (ckd) on hafidh a al-hadi, brent william, and keith a fox brief communication | 313 regular dialysis is not clearly understood. these patients did not have any evidence of myocardial injury clinically (neither by history nor by electrocardiogram criteria). this may simply be due to lack of clearance by the diseased kidneys, because h-fabp is totally cleared by the kidneys. uraemic cardiomyopathy is a recognised complication of ckd and it may be possible that some of the leakage of h-fabp could reflect sub-clinical myocardial injury. the release of h-fabp may be from other tissues containing this protein which are affected by ckd or by drugs used in management e.g. brain or bowel. h-fabp circulates for a longer time (> 25 hours) after ami in the presence of renal failure.4 gorski et al. reported that h-fabp and myoglobin concentrations were both significantly elevated in patients with renal failure. the concentrations of these markers were not affected by dialysis. in addition, the myoglobin to h-fabp ratio in this group was similar to the ratio found in patients with myocardial infarction.14 the ctnt (34 kda) was first introduced in 1989 as a marker for ami. the upper limit for ctnt has been reported as < 0.1µg/l, but concentrations between 0.03-0.1µg/l may also have significance as markers of an adverse outcome.15 this marker appears in the serum within 12 hours after symptom onset in patients with ami. elevated ctnt in patients with unstable angina is associated with poor prognosis.16 the increase correlates well with the severity of coronary artery lesions as determined by angiography. the ctnt marker is a sensitive and specific marker of myocardial injury. however, elevated ctnt concentrations have been reported in a significant numbers of patients with chronic renal failure. these levels do not seem to be affected by haemodialysis, with elevations persisting after treatment.17-18 nadheem et al. have shown that ctnt had lower sensitivity and specificity for the diagnosis of ami compared with ctni in patients with ckd on dialysis. they also demonstrated that increased ctnt was associated with all causes mortality during two years follow-up.19 a significant numbers of patients in our study had elevated ctnt concentrations. these elevated levels may be due to a combination of slow clearance and/or uraemic cardiomyopathy. in a separate study, we used the following concentrations to define the presence of ami: h-fabp ≥ 12.5µg/l (sensitivity = 91.4%, specificity = 86%); ctnt ≥ 0.1µg/l (sensitivity = 76.4%, specificity = 99%). these cut-off concentrations for the diagnosis of ami were based on receiver operating characteristices (roc) analysis between patients with ami (n = 45 patients) and patients without ami (stable angina, atypical angina, normal controls, n = 70 patients).20 based on these cut-off values, all 16 patients would meet the criteria for the diagnosis of ami if we used h-fabp concentrations. also significant numbers (8 patients, 50%) had raised values ≥ 0.1µg/l. conclusion this study indicates that the efficiency of h-fabp for the diagnosis of ami in the presence of renal failure is limited. the presence of renal failure may also interfere with the specificity of ctnt for the detection of myocardial injury. this interference should be borne in mind when interpreting the result of these two markers in patients with acute coronary syndromes in the presence of renal impairment. acknowledgments the research was funded by a grant from the cardiovascular research unit at the university of edinburgh. references 1. glatz jf, van bilsen m, paulussen rj, veerkamp jh, van der vusse gj, reneman rs, et al. release of fatty acid-binding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox. biochim biophys acta 1988; 961:148-52. 2. yoshimoto k, tanaka t, somiya k, tsuji r, okamoto f, kawamura k, et al. human heart-type cytoplasmic fatty acid-binding protein as an indicator of acute myocardial infarction. heart vessels 1995; 10:304-9. 3. colli a, jossa m, pomar jl, mestres ca, gharli t. heart fatty acid binding proteins in diagnosis of myocardial infarction: where do we stand now? cardiology 2007; 108:4-10. 4. kleine ah, glatz jf, van nieuwenhoven fa, van der vusse gj. release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. mol cell biochem 1992; 116:155-62. 5. abe s, okino h, lee s, toda h, miyata m, nomoto k, et al. human heart fatty acid-binding protein. a sensitive and specific marker of coronary reperfusion. circulation 1991; 84:ii-291. 6. tanaka t, hirota y, sohmiya k, nishimura s, kawamura k. serum and urinary human heart fatty serum level of heart-type fatty acid-binding protein in patients with chronic renal failure 314 | squ medical journal, december 2009, volume 9, issue 3 acid-binding protein in acute myocardial infarction. clin biochem 1991; 24:195-201. 7. alhadi ha, fox ka. do we need additional markers of myocyte necrosis: the potential value of heart fatty acid-binding protein. qjm 2004; 97:187-98. 8. bakkeraj, koelemay mj, gorgels jp, van vlies b, smits r, tijssen jg, et al. failure of new biochemical markers to exclude acute myocardial infarction at admission. lancet 1993; 342:1220-2. 9. volders pg, vork mm, glatz jf, smits jf. fatty acidbinding proteinuria diagnoses myocardial infarction in the rat. mol cell biochem 1993; 123:185-90. 10. hycult biotechnology b.v. hbt human h-fabp elisa test kit product information manual, 1999. 11. bass nm, manning ja. tissue expression of three structurally different fatty acid binding proteins from rat heart muscle, liver, and intestine. biochem biophys res comm 1986; 137:929-35. 12. pelsers mm, hermmens wt, glatz jf. fatty acidbinding proteins as plasma markers of tissue injury. clin chim acta 2005; 352:15-35. 13. alansari se, croal bl. diagnostic value of heart fatty acid binding protein and myoglobin in patients admitted with chest pain. ann clin biochem 2004; 41:391-6. 14. gorski j, hermens wt, borawski j, mysliwiec m, glatz jf. increased fatty acid-binding protein concentration in plasma of patients with chronic renal failure. clin chem 1997; 43:193-5. 15. hamm cw, ravkilde j, gerhardt w, jorgensen p, peheim e, liungdahl l, et al. the prognostic value of serum troponin t in unstable angina. n engl j med 1992; 327:146-50. 16. ohman em, armstrong pw, christenson rh, granger cb, katus ha, hamm cw, et al. cardiac troponin t levels for risk stratification in acute myocardial ischemia. gusto iia investigators. n engl j med 1996; 335:1333-41. 17. haller c, stevanovich a, katus ha. are cardiac troponins reliable serodiagnositic markers of cardiac ischemia in end-stage renal disease? nephrol dial transplant 1996; 11:941-4. 18. li d, jialal i, keffer j. greater frequency of increased cardiac troponin t than increased cardiac troponin i in patients with chronic renal failure. clin chem 1996; 42:114-5. 19. needham dm, shufelt ka, tomlinson g, scholey jw, newton ge. troponin i and t levels in renal failure patients without acute coronary syndrome: a systematic review of the literature. can j cardiol 2004; 20:1212-8. 20. alhadi ha, fox ka. heart fatty acid binding protein in the early diagnosis of acute myocardial infarction: the potential for influencing patient management. eur heart j 2009 (submitted for publication). squ med j, august 2010, vol. 10, iss. 2, pp. 169-179, epub. 19th jun 10 submitted: 27th jan 10 revision req. 17th feb 10, revision recd. 28th feb 10 accepted: 2nd mar 10 contrary to some students’ beliefs, medical and health sciences education is not aimed at educating students to pass their exams, but rather at educating students to become practising health professionals and critical life-long learners. most importantly, we are educating students so that they can deliver highquality health care to their patients. medical informatics in medical education is the component of student training concerned with equipping health professionals to deal with the impact of the information age in the provision of health care. health care professionals interested in medical informatics and its technology may combine their work in health care with their exploration of an ever-changing technology. this fascination with the technology, however, carries a danger; we may become so enthralled by the technology that we lose focus of its purpose. as coiera noted more than 10 years ago, medical informatics is “as much about computers as cardiology is about stethoscopes”.1 in this light, the focus of medical informatics is not on the technology, but on its use in the delivery of quality health care to patients. a crucial part of medical informatics in health care deals with the use of information technology in the sourcing and transmission of medical and other information between doctor and patient. there is a conventional view that the role of the health professional in medical information transfer is to have the medical knowledge (obtained from education, experience and a wide range of credible sources) to sift and sort the information and present it to the patient. ideally, the information should be presented in a manner that makes it understandable to the patient, respecting their language and other needs.2 where procedures are required, consent that is truly informed can then be given.3 although informed consent is considered important, implicit 1ithealthed, austria; 2centre for educational technology, university of cape town, south africa; 3department of medicine, university of cape town, south africa *corresponding author email: kmasters@ithealthed.com "وجدته يف الشبكة العنكبوتية الدولية" اإلستعداد للمريض اإللكرتوني يف عمان كني ما�شرتز، ديك جنامبي، جيل تود امللخ�ص: يف ع�رش الإعالم تتغري �شبل التوا�شل بني الطبيب واملري�س . وبا�شتخدام نظرية ايفرييت روجرز لنت�شار الخرتاعات ، تدر�س هذه الورقة انت�شار ال�شبكة العنكبوتية الدولية يف عمان ، وبعد ذلك ناأخذ باحل�شبان ظهور املري�س الإلكرتوين . مت و�شف املري�س اللكرتوين ب�شيء من التف�شيل . يف نهاية الورقة ن�شف اخلطوات التي ميكن اتخاذها عند تعليم طلبة كليات الطب يف عمان من اأجل اأن يكونوا مهيئني للمر�شى الإلكرتونيني . مفتاح الكلمات : التعليم الطبي ، عمان ، ن�رش الخرتاعات ، ال�شبكة العنكبوتية الدولية ، عالقات املري�س – الطبيب ، التوا�شل . abstract: in the information age, the communication patterns between doctor and patient are changing. using everett rogers’ theory of diffusion of innovations, this paper begins by examining the diffusion of the internet in the world and in oman. it then considers the emergence of e-patients. the characteristics of e-patients are described in some detail. the paper ends by describing steps that should be taken when teaching medical students in oman so that they can be prepared for e-patients. keywords: medical education; oman; innovation diffusion; internet; world wide web; physician-patient relationships; communication special contribution “i found it on the internet” preparing for the e-patient in oman *ken masters,1 dick ng’ambi,2 gail todd3 “i found it on the internet” preparing for the e-patient in oman 170 | squ medical journal, august 2010, volume 10, issue 2 in much of the writing on informed consent is that the doctor informs and the patient consents. even where this has been viewed as too paternalistic an attitude, the arguments for listening to the patient stop short of actually obtaining medical information from the patient. the philosophy is that the “physician brings research information about available treatments and their benefits and risks; the patient brings personal information about her or his illness, lifestyle, and values”.3 if the patient armed with medical literature is considered, it is under the heading of the “difficult patient”.4 this picture of medical information transfer is not accurate in the information age, and is daily becoming less so; health professionals who practice in this way will need to recognise that the role of information transfer is changing as a new kind of patient has arrived. s/he is called the “e-patient,” and is sitting in consulting rooms right now. many more will be in the consulting rooms of our students when they become doctors. to understand better the phenomenon of the e-patient and the implications for oman, this paper begins by examining the adoption of the internet over the past decades viewed against the backdrop of everett rogers’ theory of diffusion of innovations, and with particular reference to internet usage in oman. the paper will then describe the concept of the e-patient, examining some of the characteristics of the e-patient. finally, the paper will discuss the implications of the information age for the training of medical students in oman. adoption of an innovation over time – rogers’ diffusion of innovations future trends of any innovation, such as the internet, can be better understood by viewing current and past growth in the context of everett rogers’ theory of diffusion of innovations (doi).5 in doi theory, rogers considers the demographic characteristics that encourage the diffusion (i.e. adoption) of an innovation throughout a population. in relation to the new innovation, doi classifies the population of potential adopters into “adopter categories,” and each classification contains a percentage of the population. these adopter categories are: 1) innovators (2.5%); 2) early adopters (13.5%); 3) early majority (34%); 4) late majority (34%); and 5) laggards (16%). rogers shows this as a standard distribution curve as depicted in figure 1. although several demographic characteristics play a role in determining the composition of the adopter categories, perhaps the most important is literacy and level of education, especially when they are associated with a corresponding increase in socio-economic status.5 an increased literacy and education level is associated with an increased rate of innovation adoption. the doi theory also shows the accumulation of new adopters over time, as indicated in figure 2. figure 2 shows a familiar s-curve. at some point in the adoption process, a ‘critical mass’ is reached. critical mass is the stage of diffusion where enough of the population have accepted the innovation for the adoption to become self-sustaining. the critical mass point is not identical for each innovation, innovators early adopters 13.5% early majority 34% late majority 34% laggards 16%2.5% x-2sd x-sd x x+sd figure 1: everett rogers’ adopter categories in a population, based on the time in which the population adopts an innovation ken masters, dick ng’ambi, gail todd special contribution | 171 although it appears to occur at approximately 10–25% of usage. before critical mass, efforts at diffusion and development of the innovation are aimed at the early adopters and innovators who also serve as role models for the others. at the point of critical mass, the innovation is no longer seen as innovative, and is close to the norm with the benefits being observable. the innovation is then in a ‘take-off ’ stage, and usage of the innovation spreads across the population. diffusion of innovations and the adoption of the internet bearing in mind the descriptions given in doi, we can now examine the growth of internet usage across the world. the rapid growth in internet usage is illustrated in figure 3, which shows the increase in the number of internet hosts since 1981.6 of particular note in this chart is the change that occurred in the mid-1990s, when the impact of the world wide web was felt. there has been a corresponding growth in the number of internet users from 361 million in 2000 to 1.7 billion in 2009.7 a breakdown of those figures by region, is shown in table 1.7 for the purposes of this paper, we should take note of the 48 million people in the middle east, which, apart from oceania/australia, is the smallest group. these figures can be standardised as a percentage of the population in each region [table 2]. shown as a percentage, some 24% of the population in the middle east uses the internet. at a deeper level, the percentage for oman is statistically significantly lower than the rest of the middle east (p < 00.1), at approximately 13.7%, or 469, 000 people.8 this percentage is a conservative estimate, and is based on an estimated 2009 oman population of 3.42 million;8 other estimates put the 2009 oman population at 2.85 million,9 which would mean that internet penetration is approximately 16.5%, statistically significantly lower than the rest of the middle east. to guard against over-inflation, we shall use the conservative estimate of 13.7%. although the number of internet users in oman is relative low, figure 4 shows usage figures over time,8,10,11 and indicates that growth is proceeding at a rapid pace. more importantly, oman’s figure of 13.7% innovators later adopters take-off pe rc en ta ge o f a do pt io n time 0 10 20 30 40 50 60 70 80 90 100 ealier adopters figure 2: diffusion process: accumulating new adopters table 1: number of internet users in the world by geographic region, in descending order of magnitude, in 2009 region number (millions) asia 704.2 europe 402.4 north america 251.7 latin america / caribbean 175.8 africa 65.9 middle east 48.0 oceania / australia 20.8 total 1,668.9 table 2: percentage of the population that are internet users in the world by geographic region, in descending order of magnitude, in 2009 region total % north america 73.9 oceania / australia 60.1 europe 50.1 latin america / caribbean 30.0 middle east 23.7 asia 18.5 africa 6.7 “i found it on the internet” preparing for the e-patient in oman 172 | squ medical journal, august 2010, volume 10, issue 2 internet usage places its usage in the late stage of rogers’ “early adopters” [figures 1 and 2]. with doi indicating that ‘critical mass’ is in the region of 10–25%, and figure 4 indicating that growth shows no sign of decreasing in the short term, there is strong argument to support the contention that oman’s ‘critical mass’ either has been reached or will be reached within the next few years. it is reasonable to expect that oman is into the takeoff phase of internet adoption [figure 2], and that internet adoption is about to increase at a more rapid rate. this expectation is further supported by doi’s argument associating levels of education and adoption of an innovation, and the fact that, since the 1970s, oman has introduced widespread education programmes aimed and improving the overall educational levels of all citizens. the emergence and characteristics of the ‘e-patient’ in the context of internet usage and oman’s expected future growth, we examine the concept of the ‘e-patient.’ the term ‘e-patient’ is constructed from the familiar ‘e-‘ that is now part of e-mail, e-learning, e-banking, etc, and refers to the patient who uses the internet as a health resource.12 before we can prepare our students (and current doctors) to function in the work environment in which their patients are e-patients, it is necessary to look at the typical characteristics of e-patients. e-pat i e n t s s e a r c h i n t e r n e t f o r h e a lt h i n f o r m at i o n the most important characteristic of e-patients is that they look on the internet for information regarding their health. this should not come as a surprise, as it was foreseen by tim berners-lee,13 the architect of the world wide web. the numbers of e-patients seeking health information around the world is unknown. figure 5, however, shows the number of americans who used the internet to look for health-related information from 2001 to 2007,1417 usually because of a “specific disease or medical problem”.15,18 these figures represent as much as 80% of american internet users,15 and is a marked increase from estimates of 55% in 2000.18 on any given day, more than 8 million americans search for health-related information on the internet.15 the reasons for e-patients’ seeking information from the internet are wide-ranging, including dissatisfaction with their health care providers’ level of information, needing more confidence when talking to their doctor, or wanting to reassure themselves of the information that their doctor has given them.18,19 patients are frequently motivated by the fact that access to the information is convenient, that they can get more information from the internet than from other sources, and that they can get it anonymously.18 0 81 82 83 84 85 86 87 88 89 90 91 92 93 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 100 200 300 400 500 600 700 800 in te rn te h os ts m illi on s year figure 3: number of world internet hosts, 1981 – july 2009 ken masters, dick ng’ambi, gail todd special contribution | 173 e-pat i e n t s m a k e d e c i s i o n s b a s e d o n i n t e r n e t i n f o r m at i o n a second characteristic of e-patients is that they may make important decisions based on that information. in one study of those who sought health information on the internet, as many as 70% made decisions about their health care based on what they found on the internet. comforting to health professionals is that some 50% made the decision to ask a doctor new questions or get a second opinion.15,18 i m pa c t o n pat i e n t d o c t o r r e l at i o n s h i p it is at the point of contact between patient and doctor that the greatest impact of e-patients is noticeable; e-patients are being encouraged by changes in the patient-doctor relationship, and are, in turn, impacting on the patient-doctor relationship. to understand the impact on this relationship, one needs to consider the changing nature of health care delivery from a doctor-centred approach to an increasingly patient-centred approach in which the patient is viewed as a partner in the delivery of health care. informed consent is no longer the gold standard, but rather an assumption, and the patient is increasingly taking a more active role in the management of the health care process.3,20-23 within this context, as e-patients becomes less reliant on doctors as the sole source of information, they will utilise the internet as an alternative source of information. in addition to their using that information to make decisions, e-patients will bring that information with them into the consultation. earlier, reference was made to a conventional view of the doctor gathering information, sorting it and then presenting it to the patient in a manner in which it can be understood. it was also argued that this view is out-dated. international figures indicate that as many as 80–90% of doctors are reporting that some patients are bringing internet material into the consulting room,24 although the percentage of patients who do this is low. doctors need to be prepared for better-informed patients while also being prepared to correct incorrect information.25 some recent works, while not explicitly addressing the issue, are arguing that a doctor must “encourage patients who have knowledge about their condition to use this when they are making decisions about their care”.2 the impact on the patient-doctor relationship is varied, but significant, and doctors’ reactions to this phenomenon are mixed. first, doctors fear that a patient with loads of information for discussion is a potential threat to one of their most valuable resources: time. second, there are fears of confrontations with over-aggressive and misinformed patients, which would threaten to worsen the patient-doctor relationship.19 conversely, many doctors report a richer experience in the consultation, and an improvement in the patientdoctor relationship.12,14,19, 26 in addition, while there are certainly dangers of patients’ seeking such information, there are many reports of patients receiving better information from the internet than from their doctors, and even saving lives by 2000 0 50,000 100,000 150,000 200,000 250,000 300,000 350,000 400,000 450,000 500,000 2001 2002 2003 2004 2005 2006 2007 2008 2009 us er s year figure 4: number of internet users in oman, 2000–2009 “i found it on the internet” preparing for the e-patient in oman 174 | squ medical journal, august 2010, volume 10, issue 2 following internet advice.14,18,26,27 although patients bringing this information to the consulting room may be problematic, a worse scenario occurs when patients find this information, but do not tell their doctors. one study18 found that as many as 65% of patients who find information on the internet do not discuss it with their doctors. while some of this is due to the fact that they are searching on behalf of someone else,18 frequently, they are keeping their own information to themselves because of negative feedback from their doctors. in many cases, if they have a choice, they move to another doctor.15 preventing this scenario is discussed later in this paper. e-pat i e n t f o u n d i n a l l d e m o g r a p h i c g r o u p s while differences in the percentages of e-patients across demographic groups exist, a point of consistency is that all population groups, whether viewed by age, gender, race or education level, are increasingly accessing the internet; over the past 10 years, they have increased their use of the internet for seeking health information.15,17,18 differences by gender exist, and there is some indication that women tend to seek for health information more than men do; part of the reason might be that women are more likely than men to be looking for health information for children.18 of particular importance is the use of the internet by the youngest population groups. global figures on internet usage are difficult to obtain for patients aged below 18, but those that do exist indicate that the usage for people aged 10–18 is among the highest of the age groups in general.28-33 some 93% of americans aged 12–17 are online,29 and other current figures indicate that, “with few exceptions, children (aged 5-14) and youth (aged 15-24) are much more likely to use computers and the internet than the general population”.28 some studies indicate that these groups also search more for health information,34,35 although this is not always the case.18 while these figure have an impact for paediatricians and other doctors working with younger patients, many information seekers (as many as 30–50%) search for medical information on behalf of others, and this is likely to be case with youth searching for information on behalf of their elders.12,14,15,17,18 this emphasises that it is not only paediatricians who need to note the use of the internet; all ages will have access to it. this concentration of internet usage by younger age groups is of particular significance to oman, given oman’s population statistics, showing that some 43% of oman’s total population is below the age of 15 years.36 e-pat i e n t s e m p l o y r a n g e o f i n t e r n e t i n f o r m at i o n the internet is not a single and uniform mass, and the sources of information are wide. in some instances, patient sources will be the same as many of the doctors’, beginning with reputable medical journals, and including the many new online, openaccess journals. while the quality of the material may be high, a problem is that many lay-people are not equipped to access and understand the information in a seeming confusion of methods, protocols, contradictory trials, or information that is outdated or inappropriate or masked by impenetrable medical jargon.15 there is also the problem of dubious information. 2000 0 20 40 60 80 100 120 140 2001 2002 2003 2004 2005 2006 2007 2008 2009 us er s (m ill io ns ) year figure 5: usa internet users seeking health information online 2001–2009 ken masters, dick ng’ambi, gail todd special contribution | 175 most e-patients start their search with a general search engine,15,37 and may not have access to reputable and current journals. as much of the information on the internet is uncontrolled, it may be wrong or dangerous, and patients do not usually verify the validity of sources; in one study, as few as 25% of e-patients checked information such as the source and date of the material they found.15 in addition, some of the material may be commercially motivated, although there is an indication that many e-patients are quick to recognise this, and generally shy away from these sites.14 studies have indicated a correlation between doctors recommending sites and the number of patients bringing material to them.38-40 while recommending sites will lead to an increase in patients bringing information into the consultation, at least the doctor will have some control over the information, and will also be aware of the influences on the patients’ thinking. e-pat i e n t u s e i n t e r n e t d i s c u s s i o n g r o u p s patients connect with other patients around the world who may be suffering from similar conditions and form electronic online support groups, social networks, or virtual communities. there is little suggestion that these groups are harmful, and several studies have found them to be useful to patients, especially those patients suffering from rare conditions, and where health professionals are scarce.19,26,27,41 in these discussion forums, patients are not only consumers of information, but also producers, with most of the information being produced by patients or lay-people working with patients. these e-patients also supply valuable research material, but the use of such material needs to be carefully guided by ethics.42 e-pat i e n t s e m a i l d o c t o r s e-patients will discover a doctor’s email address and will use it. while some topics, such as the cancellation of an appointment, or requesting information about a foreign destination, may seem innocuous, enquiries about symptoms, new conditions, are not as easily discussed over email, and the impact on the patient-doctor relationship is a concern – as much as it was a concern when the telephone first started to be used by patients.12 a large number (as much as 70%) of physicians report using email with patients, although the number of patients is usually few (less than 5%24), and this low figure corresponds with studies of patients.18 email with patients raises many issues, including doctors missing facial cues, privacy and security (both in the doctor’s office and in the patient’s home), imposition (patients’ expecting quick responses), time, re-imbursement, and the doctors not being prepared to discuss some things in an email.43-45 simultaneously, however, email offers the patient and the health professional the flexibility of asynchronous communication, the opportunity to reflect and give carefully-constructed questions and answers, further references to further resources, and also saves time on telephone calls.19,24,44,46-48 e-pat i e n t wa n t a c c e s s t o m e d i c a l r e c o r d s there are several debates about electronic medical records (emrs), including the complexity of systems and costs. one crucial area is the degree to which patients have access to and ownership of their health records. the european union’s data directive (effective from 1998) enables all patients to have direct access to their own emrs.49 other regions will have laws (which may be changing) regarding patients’ access to emrs, and doctors need to be aware of these. e-pat i e n t s l i k e e l e c t r o n i c d e v i c e s more patients are becoming comfortable with using electronic devices at home (for activities such as testing blood-glucose and blood-pressure levels), and recording these online for health personnel to access, rather than patients’ coming into the hospital or clinic. the long term benefits of complex systems, however, are not always clear-cut.50 e-pat i e n t s r at e s d o c t o r the last characteristic of e-patients is one that many may not have considered. because doctors have used the internet, they have ‘digital footprints.’ they may have a webpage, may have published in journals that have the articles online, may have a presence in facebook,51 twitter, discussion lists and groups, or any number of other sites. much of this information is available to their patients who can look it up, and find out more about their doctors than their doctors may know about them. one study in 2000,18 found that 9% of e-patients looked for information about “i found it on the internet” preparing for the e-patient in oman 176 | squ medical journal, august 2010, volume 10, issue 2 specific doctors, hospitals or medicines. by 2006, a similar study found that 29% of e-patients had looked for information about specific doctors or hospitals.15 not only can e-patients find information about their doctors, e-patients can contribute information about their doctors. there are hundreds of “rate your doctor” websites, and many of the ratings and comments can be posted anonymously by patients. examples of these sites include ratemds. com (http://www.ratemds.com/), ratemymd.ca (http://www.ratemymd.ca/), drscore (http://www. drscore.com/), and vitals (http://www.vitals.com/). while these sites may be fruitful to the doctor (for advertising purposes), the potential for abuse by patients is obvious, but perhaps less obvious is the potential for abuse by competing doctors or others. preparing today’s students for e-patients thus far, this paper has established e-patients as a reality, and has described their characteristics. the question now remains – what can we do in oman to prepare current medical students as they train to become practising professionals? we begin with an attitude change. we need to recognise that there is another side to the information age to which our students must be exposed. we need to continue to teach students how to use the range of office, communication, learning, statistical, referencing and medical computer packages, and many other applications deemed important. medical informatics, however, is not a distraction or just for the fascinated, or a separate convenience bolted on to students’ courses, to be forgotten once they are practicing professionals. just as their training in anatomy, physiology, chemistry, pharmacology, pathology, etc. all have a bearing on their interaction with their patients, so too, what they have learnt about medical informatics will impact on their interaction with, and health care delivery to, patients. with this in mind, we need to acknowledge the existence of e-patients, and train our students to cope with this phenomenon. the e-patient numbers cited in this paper are from a few places in the world only, chiefly the usa. while these serve as useful guides, it is difficult to make hard decisions for oman based on these figures. as a result, oman will need to conduct similar studies of patients and health professionals, regarding e-patients in oman. although internet usage is comparatively low, doi predicts that we stand on a cusp, and to delay such a study will result in challenges to our doctors that will threaten to compromise the delivery of health care in oman. among other things, we need to know the number of e-patients, the demographics, and the patterns of usage. in the meantime, we can prepare our students for what they will encounter when they are practising doctors. in this section, we revisit the characteristics discussed in the previous section (sometimes combining more than one where appropriate), and suggest strategies for meeting the new situation created by the e-patient. as far as looking for health information on the internet is concerned, students should be taught how to: 1. elicit from patients their methods of finding information, and whether or not they use the internet; 2. search for, identify and select sites appropriate to their patients’ conditions and situations, and guide their patients to those sites; 3. use standards and other tools, such as health on the net at http://www.hon.ch/honcode/, that can help them to help their patients; 4. explain, or point patients to explanations of research methodologies to allow patients to navigate through some of the seeming contradictions and complexities; 5. be open to new sites found by patients, and to advise patients on assessing some types of information, practising basic strategies like looking for the source. a good starting point is the credible system;52 6. encourage their patients to involve themselves in the decision-making process, but deal with the inevitable problems of self-diagnosis; some of these suggestions will require extra work, and the doctor will need to judge the necessity of the short-term demand on time against perceived long-term benefits. this will depend mostly on the doctor’s situation and the nature of the patients; regarding the impact of internet use on the patientdoctor relationship, students need to be: 1. alerted to the role that the internet will play in their patients’ lives; ken masters, dick ng’ambi, gail todd special contribution | 177 2. aware of the positive and negative impact that the use of the internet by patients may have on their relationship with them; 3. aware of, and avoid, the risks (including of patients’ moving to other doctors) of dismissing the internet as a source of patient information; 4. taught methods to deal with the situations where they feel they are arguing against the whole internet; 5. students need to be aware that, although internet usage may be greater by younger and more literate patients, doctors cannot make assumptions about patients’ internet usage or contact with internet information based solely demographic indicators. patients will have access to the internet by proxy. with respect to internet medical discussion groups, students need to be: 1. aware of the existence and value of discussion group sites, both to their own patients, and to understanding perceptions and problems of the conditions in general. these are valuable for both patients and for health care research sources, but suitability and ethical issues must be understood; 2. coached in the possibilities and methods of contributing to these sites, where they can share their medical expertise. to prepare for the possibility of email correspondence with their patients, students need to be 1. aware of the reality of patient-provider electronic communication, and how to set boundaries, limits and expectations so that the value of such communication can be experienced without compromising the delivery of health care; 2. trained in written communication with patients; 3. trained to deal with issues of online security, privacy and liability; 4. trained how to advise patients (even if in the form of a short advice sheet) about issues of security and privacy. to meet the issue of patients wanting to view and update their emrs, students need to be aware of the laws governing patients’ access to their emrs and the situation in which, in effect, the patient is looking over their shoulder as they write the medical record. doctors’ reports and comments need to be adjusted to this situation. in particular, short-hand notations, off the cuff writings, or information that may have been kept confidential between health care professionals may now be known to the patient. students also need to be taught how to coach patients on the best and most appropriate use of electronic health devices, including when not to use them. given that e-patients may search for and rate doctors via the internet, students need to be: 1. guarded about personal information, especially information about their behaviour during student days, that they place online; 2. aware that too much perfectly appropriate information may tempt patients to cross the boundary from professional to personal relationships; 3. prepared to browse for such rating sites, and take corrective action if they deem it necessary; 4. aware that becoming the best doctor possible, should always be their guiding principle, and, in the current era of e-patients, the doctor’s best defence. conclusion this paper has situated its argument in the context of a changing approach to doctor-patient communication, and the diffusion of the internet, with particular reference to the diffusion of the internet in oman. using everett rogers’ theory of diffusion of innovations, we have argued that diffusion of the internet in oman is set to increase dramatically within the next few years. these developments have been viewed in the light of the emergence of e-patients. the characteristics of e-patients have been described, with reference to international studies. both theory and international studies have pointed to a need to prepare current medical students in oman to deal with e-patients, and this paper has outlined some strategies that should “i found it on the internet” preparing for the e-patient in oman 178 | squ medical journal, august 2010, volume 10, issue 2 be followed when training medical students to practice in oman. it is our belief that a programme addressing these should be implemented as soon as is possible, so that future doctors in oman can be better prepared to utilise all aspects of the information age to deliver high quality health care to their patients. acknowledgements much of the information in this paper was presented to the sultan qaboos university college of medicine and health sciences on 25th october 2009. we are indebted to the college for the opportunity to give the presentation. portions of this work have been taken from one of the author’s (km) unpublished phd dissertation. references 1. coiera e. guide to medical informatics, the internet, and telemedicine. london: chapman & hall medical, 1997. 2. general medical council (uk). good medical practice. london: general medical council, 2006. 3. charles ca, whelan t, gafni a, willan a, farell s. shared treatment decision making: what does it mean to physicians? j clin oncol 2003; 21:932–6. 4. godolphin w, towle a, mckendry r. challenges in family practice related to informed and shared decision-making: a survey of preceptors of medical students. cmaj 2001; 165:434–5. 5. rogers e. diffusion of innovations. 5th ed. new york: free press, 2003. 6. internet host count history number of internet hosts. from https://www.isc.org/solutions/survey/ history. accessed october 2009. 7. world internet users and population stats. from http://w w w.internetworldstats .com/stats .htm. accessed october 2009. 8. internet usage in the middle east. from http:// www.internetworldstats.com/stats5.htm. accessed october 2009. 9. world population prospects: the 2008 revision, highlights (tables 1.1.–a.20). from http://www. un.org/esa/population/publications/wpp2008/ wpp2008_text_tables.pdf. accessed october 2009. 10. itu. world telecommunication ict development report. geneva, switzerland: international telecommunications union, 2006. 11. itu. world information society report: beyond wsis. geneva: itu, 2007. 12. forkner-dunn j. internet-based patient self-care: the next generation of health care delivery. j med internet res 2003; 5:e8 13. berners-lee t, hendler j, lassila o. the semantic web. scientific american 2001; 28:29–37. 14. fox s. vital decisions. washington, dc: pew internet & american life project: health information online, 17 may, 2005. 15. fox s. online health search 2006. washington, dc: pew internet & american life project: health information online, 29 october, 2006. 16. horrigan j, rainie l. counting on the internet. washington, dc: pew internet and american life project, 2002. 17. tu ht, chen gr. striking jump in consumers seeking health care information. washington, dc: health system change, 2008. 18. fox s, horrigan j, lenhart a, spooner t, burke m, lewis o, et al. the online health care revolution: how the web helps americans take better care of themselves. washington, dc: the pew internet & american life project, 2000. 19. eysenbach g. the impact of the internet on cancer outcomes. ca a cancer j clin 2003; 53:356–71. 20. godolphin w. the role of risk communication in shared decision making: first, let's get to choices. bmj 2003; 327:692–3. 21. gottlieb k, sylvester i, eby d. transforming your practice: what matters most. fam pract manag 2008; 15:32–8. 22. hellenthal n, ellison l. how patients make treatment choices. nat clin pract urol 2008; 5:426–33. 23. simmons l, baker nj, schaefer j, miller d, anders s. activation of patients for successful self-management. j ambul care manage 2009; 32:16–23. 24. masters k. for what purpose and reasons do doctors use the internet: a systematic review. int j med informatics 2008; 77:5–16. 25. fope ii task force. the future of pediatric education ii: organizing pediatric education to meet the needs of infants, children, adolescents, and young adults in the 21st century. pediatrics 2000; 105:163–212. 26. ferguson t. god bless my cml support group: an interview with gabe. the ferguson report 2002. from www.fergusonreport.com/articles/fr00803. htm accessed october 2009. 27. the ferguson report. from www.fergusonreport. com/articles/fr039905.htm. accessed october 2009. 28. itu. use of information and communication technology by the world's children and youth. geneva: international telecommunication union, 2008. 29. jones s, fox s. generations online in 2009. washington, dc: pew internet and american life project, 2009. ken masters, dick ng’ambi, gail todd special contribution | 179 30. schau t. internet use: here, there and everywhere. occup outlook q 2000; 1:41–7. 31. silver c. internet use among older canadians. ottawa, on: statistics canada, august, 2001. 32. u.s. department of commerce. falling through the net: towards digital inclusion, washington dc: u.s. department of commerce, october 2000. 33. victory nj, cooper kb. a nation online: how americans are expanding their use of the internet. washington dc: us department of commerce, 2002. 34. lewis t. seeking health information on the internet: lifestyle choice or bad attack of cyberchondria? media cult & soc 2006; 28:521–39. 35. välimäki m, nenonen h, koivunen m, suhonen r. patients' perceptions of internet usage and their opportunity to obtain health information. med inform internet med 2007; 32:305-14. 36. the world factbook. from http://www.cia.gov/ librar y/publications/the-world-factbook/geos/ mu.html. accessed october 2009. 37. eysenbach g, köhler c. how do consumers search for and appraise health information on the world wide web? qualitative study using focus groups, usability tests, and in-depth interviews. bmj 2002; 324:573–7. 38. masters k. the diffusion of the internet amongst south african primary care doctors: an activity systems view (unpublished phd dissertation) university of cape town, south africa, 2009. 39. mccaw b, mcglade k, mcelnay j. the impact of the internet on the practice of general practitioners and community pharmacists in northern ireland. inform prim care 2007; 15:231-7. 40. podichetty v, booher j, whitfield m, biscup r. assessment of internet use and effects among healthcare professionals: a cross sectional survey. postgrad med j 2006; 82:274–9. 41. eysenbach g, powell j, engesakis m, rizo c, stern a. health related virtual communities and electronic support groups: systematic review of the effects of online peer to peer interactions. bmj 2004; 328:1166–71. 42. eysenbach g, till je. ethical issues in qualitative research on internet communities. bmj 2001; 323:1103–5. 43. anand s, feldman m, geller d, bisbee a, bauchner h. a content analysis of e-mail communication between primary care providers and parents. pediatrics 2005; 115:1283–5. 44. leong sl, gingrich d, lewis, peter r, mauger d, george jh. enhancing doctor-patient communication using email: a pilot study. j am board fam pract 2005; 18:180–8. 45. tattersall mh, butow pn, brown je, thompson jf. improving doctors’ letters. med j aust 2002; 177(9): 516-20. 46. coiera e, tombs v. communication behaviours in a hospital setting: an observational study. bmj 1998; 316:673–6. 47. rosen p, kwoh c. patient-physician e-mail: an opportunity to transform pediatric health care delivery. pediatrics 2007; 120:701–6. 48. stone j. communication between physicians and patients in the era of e-medicine. n engl j med 2007; 356:2451–5. 49. eysenbach g. consumer health informatics. brit med j 2000; 320:1713–6. 50. moreno l, shapiro r, dale sb, foster l, chen a. final report to congress on the informatics for diabetes education and telemedicine (ideatel) demonstration, phase i and ii. princeton, nj: mathematica policy research, 2008. 51. jain sh. practicing medicine in the age of facebook. n engl j med 2009; 361:649–51 52. eysenbach g. infodemiology: the epidemiology of (mis)information. am j med 2002; 113:763–5. squ med j, april 2010, vol. 10, iss. 1, pp. 129-132, epub. 17th apr 10 submitted 7th aug 09 revision req. 6th oct 09, revision recd. 4th nov & 29th dec 09 accepted 6th jan 10 the reconstruction of an eye socket presents a series of complex problems. the interdependence of the elements of the orbit is such that change in one element will automatically affect the function and structure of each of the other elements, and thus the integrity of the whole. therefore the surgical approach should provide a soft tissue bed for movements and aesthetics in order for the prosthesis to have a natural appearance. this case report describes the timely intervention of a prosthodontist resulting in a prosthesis which prevented contraction and prolapse of the contents of the eye ball and ensured its satisfactory appearance. case report a male patient aged 35 years was referred to the department of prosthodontics and implantology, government dental college and research institute, bangalore, india, with a missing right eye. the patient had had a major road traffic accident one year previously, following which he had undergone emergency surgical treatment at a local hospital. the initial treatment was the enucleation of the right eye as it was badly ruptured with no visual potential. the tears in the upper and lower eyelid of the right eye were also repaired. the initial management of the injury was unsatisfactory as the socket was left with disrupted tissues and suture. a year later, the examination of the patient revealed a right anopthalmic socket with severe loss department of prosthodontics and implantology, government dental college and research institute, victoria hospital, fort, bangalore, india *to whom correspondence should be addressed. email: drkhare22@yahoo.co.in طريقة جراحية بديلية مشرتكة لعالج ناجح حَلَجاج جمدوع تقرير حالة د ر بريثفرياج، �ش�ميت خار، اأني�س ج�بتا، د ب �رسوثي را للمري�س ورمبا يرتك خيارات قليلة الأخ�شائي العي�ن، خا�شة اإذا امللخ�ص: ت�ش�ه ال�جه نتيجة فقدان العني ب�شبب ح�ادث املرور قد يك�ن ُمدِمّ ما كانت احلالة ملحة وت�شت�جب ال�رسعة. يف تقرير هذه احلالة التي اأ�شيبت بحادث مرور عنيف نتج عنه متزق �شديد يف ال�شنخ. متطلبات ِتْقنِّيُّ ِبيٌَّة. �شنعت القطعة البديلة بحيث �شمنت �شالمة و�شكل املحجر. نِّيَّة فيما يتعلق ب�شكل ال�شنخ دلت اأخ�شائي العي�ن لعمل جراحة َراأْ الِبْدِليَّاِت ال�شِّ مفتاح الكلمات: َحَجاج، ِبْدَلٌة َعيِنيَّة ، ف�شع العني، اإجراءات جراحية راأبية جتميلية، تقرير حالة، الهند. abstract: facial disfigurement through the loss of an eye due to a road traffic accident can be devastating for the patient and may leave few options for an ophthalmologist, especially if the situation demands urgency. in the present case report, the patient had a major accident, which resulted in the severe disruption of the socket. the requirements of the prosthodontist regarding the morphology of the socket guided the ophthalmologist to undertake reconstructive surgery. the prosthesis was then fabricated such that both its longevity and the morphology of the socket were safe guarded. keywords: eye socket; ocular prosthesis; eye enucleation; cosmetic reconstructive surgical procedures; case report; india. a combined surgical and prosthetic approach for the successful management of a mutilated eye socket a case report d r prithviraj, *sumit khare, anish gupta, d p shruthi case report a combined surgical and prosthetic approach for the successful management of a mutilated eye socket a case report 130 | squ medical journal, april 2010, volume 10, issue 1 of contour, depressed and with scarred tissues. the contour of the upper eyelid was lost as the medial end of the eye lid was sutured near the supraorbital rim. as it had remained like this for about a year, this had resulted in the formation of a notch at the medial end of the socket. the lower eye lid was shrunken with medial fornix contracture leading to a shortening of the lower fornix. a fibrous band running from the medial margin of lower lid to the bulbar conjunctiva was also seen. there was a nasoethmoidal fracture on the right side which resulted in the distance of the nasion from right medial canthus having increased to almost double that of the left eye (traumatic telecanthus) [figure 1]. cosmetic rehabilitation surgery was performed. in the upper eyelid, the notch was removed by releasing the lateral portion that was adherent to the supraorbital rim. the edges were freshened and the medial end was reapproximated to the medial canthus. in the lower lid, the fibrous band was released and fornix reconstruction stitches were placed from the inferior fornix to the skin over the intraorbital rim. the healed socket was found suitable to support the prosthesis [figure 2] so then the prosthetic rehabilitation procedure could begin. according to allen and webster’s “modified impression method”,1 an impression was made using a stock ocular tray along with syringe filled with irreversible hydrocolloid. in the first appointment, an iris button was selected according to the size of iris of other eye. the selected iris button was preliminarily painted under natural light,2 to match the basic colour and tint of the other eye. the impression was poured with irreversible hydrocolloid into a small tumbler. on setting, it was cut to remove the impression, leaving the mould space behind. the mould space was filled with a combination of molten inlay wax and carving wax in order to have sufficient rigidity for carving and handling. the poured wax was then removed and smoothened carefully for a trial to verify its fit and support of the soft tissue for bulge in the depressed socket. after the contour and retention were assured, the movements of the wax template in the socket were matched with that of the other eye. therefore, an aluminium button (to simulate the movement of the iris) with an outward projection or stent was secured to the centre of the external surface of the wax template in order to help to assess the movement easily). the patient was instructed to gaze in different directions and then the movement of the aluminium button was matched with the other iris. following this, the wax template and attached aluminium button were invested. after dewaxing, the aluminium button was replaced with a pre-painted iris button in the mold space. acrylization was completed with white acrylic. the processed eye shell was removed, trimmed and tried on the patient. at this stage, the support, fit and movements were checked. later, final scleral painting was carried out. to give the effect of blood vessels small red fibers were incorporated [figure 3]. during the painting, patient was asked to remain calm to keep the sympathetic reflexes down in order to avoid redness and watering of the other eye. subsequently the shell was trimmed about 1-2 mm on the external surface and then packed with transparent acrylic to give a natural appearance. later it was removed, trimmed, finished and polished. finally, it was tried on the patient and was figure 1: pre operative figure 2: post operative prithviraj, sumit khare, anish gupta and dp shruthi case report | 131 found to support the surrounding natural tissue with acceptable aesthetics [figure 4]. due to persisting traumatic telecanthus, the distance from the medial end of the prosthesis to the nasion appeared to be more than the distance from the medial canthus of other eye to the nasion. to mask this asymmetry, it was decided that the patient should wear spectacles of same power for both the eyes. this camouflage provided an enhanced natural appearance [figure 5]. discussion in a long standing case like this where suture has been present for around a year, the soft tissue anatomy changes considerably. the postoperative changes as described by iverson and vistness result in superior sulcus depression, pseudoptosis of the upper eyelid and ptosis of the lower eyelid.3 this further leads to a backward shift of the entire muscle cone and a downward and forward shift of the orbital fat. frequently, patients report to the prosthodontist after surgery is over when little can be done to improve the anatomy of the existing socket. a socket that is not treated bearing the requirements of the prosthodontist in mind may result in an ill-fitting prosthesis. on the other hand, if the prosthesis is not well designed it eventually alters the size, shape and surface of the conjunctival sac. thus the maxillofacial prosthodontist plays an important role in the surgery and subsequent fabrication of an aesthetically acceptable ocular prosthesis in order to restore facial symmetry and a normal appearance for an anophthalmic patient.4 the fabrication of an ocular prosthesis is arguably the most difficult of the three single-site facial prostheses, including the nasal and auricular prosthesis. the difficulty arises because the ocular prosthesis must correctly match the other eye in size and contour, and should be positioned exactly in a 3-dimensional space to simulate the correct gaze and interlid opening.5 the movement of the prosthesis in harmony with other eye is the most realistic aspect of an ocular prosthesis. close adaptation to the tissue beds uses the full potential of the prosthesis to produce movement.6 thus it is critical to ensure that the soft tissue of the eye socket is handled to support the prosthesis fabricated by prothodontist. conclusion this case report shows how a carefully constructed ocular prosthesis can markedly improve the facial appearance of an anophthalmic patient. figure 3: sclera and iris painted figure 5: final prosthesis figure 4: use of spectacles to camouflage the traumatic telecanthus a combined surgical and prosthetic approach for the successful management of a mutilated eye socket a case report 132 | squ medical journal, april 2010, volume 10, issue 1 references 1. allen l, webster he. modified impression method of artificial eye fitting. am j ophthalmol 1969; 67:189. 2. philip b. the fitting and fabrication of a custom resin artificial eye. j prosthet dent 1977; 38:532–38. 3. iverson re, vistness lm, siegl rj. correction of enophthalmos in the anophthalmic orbit. plast reconstr surg 1973; 51:545–54. 4. artopoulou i, montgomery pc, wesley pj, lemon jc. digital imaging in the fabrication of occular prosthesis. j prosthet dent 2006; 95:327–30. 5. maureen s, casey md, alberico r, litwin a, ng shaaf. hyperostosis in an orbital defect with craniofacial implants and open-field magnets: a clinical report. j prosthet dent 2007; 97:196–9. 6. cain r j. custom ocular prosthesis. j prosthet dent 1982; 48:690–4. measles was thought to be almost eradicated, however, recent reports from around the world are proving otherwise. in 2018, the world health organization (who) received reports of approximately 229,000 cases of measles; this represents an increase of approximately 35% compared to 2017.1,2 according to the united nations international children's emergency fund (unicef), 98 countries have reported a rise in measles cases in 2018. the countries that had the highest increase in the number of measles cases were philippines, yemen, sudan, thailand, ukraine, france, brazil, venezuela, serbia and madagascar.1,2 in oman, no cases of measles have been reported in 2018, which reflects a significant drop since a measles outbreak in 2016–2017.3 however, measles should be constantly monitored worldwide as, for example, brazil declared the eradication of measles in 2017 yet had 10,262 cases in 2018.2 measles is a very contagious disease that can be transmitted via aerosol particles or through contact with infected throat and nasal secretions. the disease can effectively spread in a travel-related manner especially in under-vaccinated populations.4 when exposed to the virus, individuals who are not immunised against measles have an approximately 90% chance of infection and each infected person can infect 9–18 other individuals in a susceptible population.4 before the introduction of the anti-measles vaccine in 1963, the disease caused 2–3 million deaths per year worldwide, with a significant drop to <90,000 deaths per year in 2016. however, 2018 witnessed the death of 136,000 individuals due to measles, which constituted a 51% increase.2,4 several factors might have led to the current out breaks of measles. these include wars and conflicts, unavailability of healthcare, lack of health education and the hesitancy to be vaccinated.2 the challenge of eradi cating measles is related to human factors rather than issues associated with the microorganisms themselves. measles can be completely prevented using existing vaccination. two doses of the live-attenuated measles vaccine provides 97% protection, which classifies them as potent vaccines.4 the side-effects of the measles vaccine are minor, particularly when compared to the protection that the vaccine offers.4 aside from medical contraindications—such as immunosuppression, preg nancy, among others—there is no valid scientific reason not to be vaccinated.5 refusing vaccination is often related to incorrect beliefs regarding its safety. there is a wide spread misconception that vaccination for measles has the potential to trigger the development of autism spectrum disorder.6 such ‘fake news’ has been spread easily by the anti-vaccination movement, especially through social media and plays an important role in making people hesitant to be vaccinated.2,4,7 vaccin ation hesitancy is among the top threats to global health according to the who.2,4,7 the relation between antivaccine campaigns and measles outbreaks suggests that the rate of other infectious diseases, that can also be prevented by vaccination, may increase as well.2 what are the solutions? awareness and vaccination constitute an efficient arsenal to fight measles. physicians, healthcare providers and educational institutions should discuss the importance of vaccinations and encourage the public to get vaccinated. such healthcare providers can disseminate knowledge about the benefits of vaccin ation and clarify false information about its alleged detri mental effect. the public should be informed that the risk vaccination entails is similar to the side-effects of commonly utilised medications. it is highly advised to take the vaccine when the benefits are vital and out weigh the potential risks. the measles vaccination led to an approximately 96.5% decrease in the number of measles-related deaths around the world.2,4 for example, the number of measles related deaths in brazil was estimated to be approximately 900 deaths per year before the introduction of vaccination department of microbiology and immunology, college of medicine and health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: elias.said@gmail.com ارتفاع معدل اإلصابة مبرض احلصبة أمهية التطعيم اليا�س �شعيد و حممد البلو�شي measles on the rise the importance of vaccination *elias a. said and mohamed s. al-balushi editorial sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e89–90, epub. 8 sep 19 submitted 6 may 19 revision req. 17 jun 19; revision recd. 27 jun 19 accepted 30 jun 19 https://doi.org/10.18295/squmj.2019.19.02.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ measles on the rise the importance of vaccination e90 | squ medical journal, may 2019, volume 19, issue 2 campaigns, which consequently reduced this number by 98%.8,9 an approximate 53% decrease in the per centage of children who have received the second dose of a measles vaccine preceded the surge in the number of measles cases in 2018.10 social media companies should take measures to limit the spread of false anti vaccination information and legislators and goverments should take action to avoid the spread of such information. assessing the level of hesitancy to be vaccinated in a community will help establish strategic plans, potentially based on target groups, to deal with this hesitancy. access to vaccinations should be available to all as vaccination is the most effective tool to eliminate the spread of measles. in addition, vaccination campaigns should be encouraged when necessary. a significant drop in the number of reported measles cases was observed after an anti-measles vaccination campaign in 2017 in oman.3,11 healthcare providers, educational institutions, social media companies, legislators and governments should collaborate on strategies to spread knowledge about the benefits of vaccination, block false anti-vaccine information and establish successful vaccination campaigns. references 1. world health organization. measles and rubella surveillance data. from: https://www.who.int/immunization/monitoring_ surveillance/burden/vpd/surveillance_type/active/measles_ monthlydata/en/ accessed: jun 2019. 2. cousins s. measles: a global resurgence. lancet infect dis 2019; 19:362–3. https://doi.org/10.1016/s1473-3099(19)30129-x. 3. world health organization. measles monthly bulletin 2019. from: https://www.who.int/immunization/monitoring_surveil l a n ce / b u r d e n / v p d / s u r v e i l l a n ce _ t y p e / a c t i v e / m e a s l e s _ monthlydata/en/. accessed: jun 2019. 4. paules ci, marston hd, fauci as. measles in 2019 going back ward. n engl j med 2019; 380:2185–7. https://doi.org/10.1056/ nejmp1905099. 5. centers for disease control and prevention. routine measles, mumps, and rubella vaccination. from: https://www.cdc.gov/vac cines/vpd/mmr/hcp/recommendations.html accessed: jun 2019. 6. hviid a, hansen jv, frisch m, melbye m. measles, mumps, rubella vaccination and autism: a nationwide cohort study. ann intern med 2019; 170:513–20. https://doi.org/10.7326/m 18-2101. 7. shao c, ciampaglia gl, varol o, yang kc, flammini a, menczer f. the spread of low-credibility content by social bots. nat commun 2018; 9:4787. https://doi.org/10.1038/s41467-018-06930-7. 8. pan american health organization. measles elimination in the americas. from: https://www.paho.org/hq/index.php?option= com_content&view=article&id=12526:measles-eliminationin-the-americas&itemid=40721&lang=en accessed: jun 2019. 9. pannuti cs, moraes jc, souza va, camargo mc, hidalgo nt. measles antibody prevalence after mass immunization in são paulo, brazil. bull world health organ 1991; 69:557–60. 10. world health organization. who and unicef estimates of immunization coverage: 2018 revision. from: https://www.who. int/immunization/monitoring_sur veillance/data/bra.pdf. accessed: jun 2019. 11. ministry of health. national measles immunization campaign, 10-16 september 2017. from: https://www.moh.gov.om/en/ /---499 accessed: jun 2019. https://doi.org/10.1016/s1473-3099%2819%2930129-x https://doi.org/10.1056/nejmp1905099 https://doi.org/10.1056/nejmp1905099 https://doi.org/10.7326/m18-2101 https://doi.org/10.7326/m18-2101 https://doi.org/10.1038/s41467-018-06930-7 department of radiation oncology, royal hospital, muscat, oman *corresponding author’s e-mail: sanjoor123@gmail.com تطبيق تقنيات إدارة لني يف قسم طب األورام اإلشعاعي م�شطفى حممود البلو�شي و زاهد املنذري abstract: objectives: lean management (lm) principles were first developed by a japanese manufacturing company to maximise value and minimise waste in the automotive industry. however, these principles can also be applied in the healthcare sector. this study aimed to illustrate the process of implementing lm principles in a radiation oncology department to streamline workflow and identify and reduce waste. methods: this study took place in the department of radiation oncology, royal hospital, muscat, oman, in december 2016. a value stream map (vsm) was created for the chain of processes followed in the department. a waste analysis was conducted to determine which processes did not add value for the patient or healthcare provider. results: based on the vsm analysis, only six out of 13 steps were found to be of value. necessary and unnecessary non-value-adding activities were identified. sources of waste included parking and registration. in addition, variabilities in workload were noted. conclusion: overall, lm principles improve workflow, reduce waste and enhance patient and staff satisfaction. in the current study, the application of lm principles helped to improve value in a radiation oncology department. keywords: health services administration; healthcare quality assurance; total quality management; organization and administration; efficiency; oman. �شناعة يف الهدر وتقليل القيمة من قدر اأق�شى لتحقيق يابانية ت�شنيع �رسكة قبل من تطويرها مت لني اإدارة مبادئ الهدف: امللخ�ص: ا يف قطاع الرعاية ال�شحية، تهدف هذه الدرا�شة اإىل تو�شيح عملية تطبيق مبادئ اإدارة ال�شيارات، وبالإمكان تطبيق هذه املبادئ اأي�شً لني يف ق�شم طب الأورام الإ�شعاعي لتي�شري تدفق العمل وحتديد الهدر وتقليله. الطريقة: اأجريت هذه الدرا�شة يف ق�شم طب الأورام الإ�شعاعي بامل�شت�شفى ال�شلطاين يف م�شقط، ُعمان، وذلك خالل �شهر دي�شمرب 2016، مت اإن�شاء خريطة تدفق القيمة ل�شل�شلة العمليات املتبعة يف الق�شم، مت بعدها مت اإجراء حتليل للهدر لتحديد العمليات التي مل تكن لها اأي قيمة اإ�شافية �شواءاً للمري�ص اأو للموظف ال�شحي. النتائج: ا�شتناداً اإىل حتليل خريطة تدفق القيمة، مت العثور على �شتة خطوات فقط من اأ�شل 13 خطوة والتي كانت ذات قيمة. مت كذلك حتديد الأن�شطة ال�رسورية وغري ال�رسورية التي مل تكن لها اأي قيمة م�شافة، �شملت م�شادر الهدر مواقف ال�شيارات وعمليات الت�شجيل، بالإ�شافة اإىل ذلك، لوحظت تفاوت يف اأعباء العمل. اخلال�صة: ب�شكل عام، تعمل مبادئ اإدارة لني على حت�شني �شري العمل وتقليل الهدر اإ�شافة اإىل تعزيز مدى الر�شا لدى املر�شى واملوظفني، وقد �شاعد تطبيق مبادئ اإدارة لني على تعزيز القيمة يف ق�شم طب الأورام الإ�شعاعي. الكلمات املفتاحية: اإدارة اخلدمات ال�شحية؛ �شمان جودة الرعاية ال�شحية؛ اإدارة اجلودة ال�شاملة؛ التنظيم والإدارة؛ جناعة؛ عمان. implementing lean management techniques at a radiation oncology department *mustafa m. al-balushi and zahid al-mandhari clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e362–366, epub. 19 dec 18 submitted 3 feb 18 revision req. 22 mar 18; revision recd. 14 apr 18 accepted 10 may 18 doi: 10.18295/squmj.2018.18.03.016 advances in knowledge this study delineates the steps involved to apply lean management principles at a radiation oncology department in order to streamline work flow and reduce waste. application to patient care in the healthcare sector, lean management principles can help to increase patient satisfaction by increasing value (e.g. timely treatment delivery, reduced waiting time, etc.) and reducing wasteful activities and processes. lean management (lm) principles were first developed to improve production and increase customer satisfaction in the automotive industry by the toyota company (toyota motor corp, aichi prefecture, japan).1 since then, lm principles have been widely applied in various sectors with trem endous success, including in healthcare delivery.2–4 the aim of lm tools and techniques is to organise processes, leading to increased value which manifests as increased customer satisfaction and the elimination of waste.5,6 however, lm principles are not designed as a set of regulations and rules to be applied at a certain stage; instead, the aim is the continuous improvement of existing processes.7 one specific lm tool is the creation of a value stream map (vsm). this technique involves the identification of the chain of processes involved in the creation and distribution of a product or a service, thus helping personnel to detect inefficiencies, work load variability or non-value-adding (nva) activities that lead to increased mustafa m. al-balushi and zahid al-mandhari clinical and basic research | e363 waste.8−10 it is an integral instrument used in lm interv entions to assist in delineating the steps which would help an organisation to reach its goals. however, a vsm is quite different from other flowcharts in that it incorp orates both materials and information.9 in healthcare, lm is defined as “an organization’s cultural commitment to applying the scientific method to designing, performing and continuously improving the work delivered by teams of people, leading to measurably better value for patients and other stakeholders”.11 the focus is on the movement of the patient through the system, rather than individual interactions between patients and healthcare providers.12 in healthcare facilities, lm techniques have been documented to reduce costs, errors and time wastage as well as improve patient and staff satisfaction.7,9 moreover, one hospital in the usa reported that lm techniques resulted in the timely initiation of 99% of its operations, while another managed to reduce inpatient total care costs by 25% and improve patient satisfaction by almost 100%.11 prior to the delivery of radiotherapy treatment, multiple important steps must be completed; however, any initial setbacks or wastage is reflected in subsequent steps, resulting in treatment delays and decreased patient satisfaction. the royal hospital is a tertiary care centre in muscat, oman, and is the only centre in the country to offer radiotherapy. in december 2016, one of the hospital’s two radiotherapy treatment units was shut down while a new radiotherapy machine was being commissioned. this resulted in a greater patient load at the remaining unit, thereby obligating staff to work harder to ensure that there were no unnecessary delays in treatment. based on previous research, lm implementation was deemed an appropriate measure to help enable a smoother transition during this period.9,11 this study was therefore undertaken to delineate the process of implementing lm principles to improve workflow and identify and eliminate sources of waste in the context of radiotherapy treatment. methods this study was conducted in the department of radiation oncology at the royal hospital in december 2016. a value stream map (vsm) was developed to document all the steps being undertaken prior to the patient receiv ing treatment. subsequently, the vsm was analysed using the ‘3mus’ tool to detect muda (activities with no value), mura (unbalanced workload) and muri (the overburdening of staff and processes). of the activities which were designated nva, the researchers sought to determine whether these were nonessential or necessary as well as those which constituted sources of waste. finally, heijunka, another lm tool, was utilised to level workload. other lm tools were either not applicable to the department or it would have been too early to implement them. for the purposes of the study, value was defined as achieving patient satisfaction through the timely delivery of treatment. sources of waste were identified in eight categories, consisting of transportation, inventory, motion, waiting, overproduction, overprocessing, defects and intellect/skills [table 1].6 prior to the implementation of lm principles, all personnel affiliated with the department participated in a series of continuing medical education activities to introduce underlying lm concepts and how to implement these principles effectively. the vsm was constructed using conceptdraw office software, version 11 (computer systems odessa, odessa, ukraine). radiation oncologists, medical phys icists, dosimetrists, radiotherapy technologists and oncol ogy nurses all helped in formulating and editing the vsm. the vsm started from the moment the patient first arrived at the hospital’s parking lot for their first clinical appointment and ended with the conclusion of treatment. this study was approved by the centre of studies & research at the ministry of health in oman (src #4/2018). informed consent was not deemed necessary as there were no direct encounters with patients. further more, no information was obtained from electronic patient records during the course of this study. results a vsm was constructed to delineate the steps involved in the provision of radiotherapy treatment at the royal hospital [figure 1]. after analysing the vsm, six out table 1: categories of waste according to lean management principles4 category definition transportation unnecessary transportation of a product through a system inventory unnecessary storage of a product motion non-productive motion that adds no value to the patient or healthcare provider waiting unnecessary waiting for the next event/ step in the process overproduction overproduction of supplies overprocessing overprocessing in which more value than necessary is added to the product defects defects in equipment/processes intellect/skills steps/actions which do not utilise the full intellectual capacity or skills of the employees implementing lean management techniques at a radiation oncology department e364 | squ medical journal, august 2018, volume 18, issue 3 of 13 steps were deemed value-adding. these constituted the patient’s first visit to the outpatient department, simulation, re-simulation, treatment, the actual radiotherapy sessions and the conclusion of treatment. steps which did not add value, but which did not involve the patient’s presence at the hospital, included importing, contouring and planning. parking and registration were waste generating steps that were deemed necessary nva activities [table 2]. parking was deemed a source of waste in the waiting category. however, no intervention to reduce parkingrelated waste was possible as the designated parking lot for radiotherapy patients was also being utilised by other hospital visitors; furthermore, any intervention table 2: procedural steps and their value for the chain of processes followed at the department of radiation oncology at the royal hospital, muscat, oman step details role value 1 parking time spent by the patient to secure a parking space patient waste-generating/ necessary nva 2 registration time taken for the patient to register at the hospital patient waste-generating/ necessary nva 3 opd time spent during the first visit to determine indication for and doses of radiation physician value-adding 4 simulation duration of radiotherapy simulation radiotherapist value-adding 5 importing duration of importing simulation images to the medical physics department medical physicist necessary nva 6 contouring determining target planning volumes physician necessary nva 7 planning calculating patient dosage medical physicist necessary nva 8 re-simulation duration of radiotherapy re-simulation radiotherapist value-adding 9 treatment inclusive of steps 10 to 13 value-adding 10 parking time spent by the patient to secure a parking space patient waste-generating/ necessary nva 11 registration time taken for the patient to register at the hospital patient waste-generating/ necessary nva 12 radiotherapy duration of radiotherapy sessions radiotherapist value-adding 13 conclusion final radiotherapy session, including provision of a treatment summary physician value-adding nva = no-value-adding ; opd = outpatient department. figure 1: value stream map for the chain of processes followed at the department of radiation oncology at the royal hospital, muscat, oman. opd = outpatient department. mustafa m. al-balushi and zahid al-mandhari clinical and basic research | e365 required approval by the hospital administration. regist ration was also identified as a source of waste in the transportation, waiting and overproduction categories. in order to register, the patients had to go to the main hospital building and wait alongside outpatients attending other departments. additionally, the patients had to bring separate appointment slips at every visit for the duration of their treatment, which usually spanned a few weeks. this was solved by introducing a registration desk in the department itself and providing patients with appointment charts that included the dates of each appointment. the simulation step was also identified to constitute a potential source of intellectual waste. this was because of variations in patient load; on some days, the radiation oncologists sent a large number of patients for simulation while, on other days, there were no patients at all. this problem was solved by abandoning the ‘push’ system of appointments and implementing a ‘pull’ system instead. this involved picking a treatment start date slot in the clinic, with the simulation technicians authorised to create simulation appointment slots. furthermore, medical physicists were encouraged to prioritise cases based on a thorough discussion with the concerned physician, instead of on a ‘first come, first served’ basis. finally, a two-shift system was introduced in order to reduce the intellect waste caused by having an excessive number of employees working at the same time. discussion during the study period, the department of radiation oncology at the royal hospital was undergoing a period of transition as one of two treatment machines was being decommissioned to facilitate the commission and installation of a new one. this transition created a great deal of stress within the department, with staff anticipating severe treatment delays and patient dissatisfaction. hence, the current study was conducted to implement lm principles so as to improve efficiency and reduce unnecessary waste, thereby enhancing workflow and, ultimately, ensuring the delivery of treatment in a timely manner.9,11 prior to the application of lm techniques, the dep artment utilised a ‘push’ system to book appointments for simulation. the radiation oncologist, as the individual who first saw the patient and decided to administer radiation therapy, would book the patient in for simul ation, thus ‘pushing’ the patient through the system. during times when multiple cases presented simultaneously, all of the patients would be sent for simulation at the same time, placing unnecessary pressure on the simulation staff to finish each case as soon as possible so as not to delay treatment. however, on other days, the radiation oncologist would not send any patients for simulation and the staff would not have any work to do, leading to intellectual waste. this practice resulted in mura (an unbalanced workload) as well as muri (over pressuring of staff ). the simulation step itself was there fore seen as a muda (source of waste); this can also be extrapolated to subsequent steps in the treatment chain. in contrast, a ‘pull’ approach was a simple solution wherein the physician could decide on a treatment start date based on available treatment slots. the term ‘pull’ indicates that, as all other steps were initiated after the prescribed start date, every event in the chain of events was ‘pulled’ towards that date. this new appointment system ensured that treatment slots were not available during a particular period if a pre-set number of patients was exceeded, ensuring that patient load would not exceed staff capacity at any stage. the workload therefore became completely predictable, with the fluctuations previously observed in the number of patients greatly reduced. hence, heijunka (levelling of the workload) was achieved, eliminating mura and muri. several interventions helped to reduce waste in the transportation, inventory and intellectual/skills categ ories. these involved the introduction of a registration desk in the treatment unit, eliminating the need for patients to go to the registration desk at the entrance of the hospital and then return to the radiotherapy treat ment unit, as well as the provision of an appointment chart, which helped reduce the overuse of registration slips. additionally, a two-shift system was introduced in order to reduce intellect waste caused by having more employees than required during working hours due to the presence of only one treatment unit. finally, cases were prioritised according to those who needed to undergo treatment first rather than on a ‘first come, first served’ basis. currently, three more lm-related projects have been initiated at the royal hospital to improve the efficiency of radiotherapy delivery and sustain current improvements. the authors hope that the results of this study inspire other healthcare researchers to seek solutions to waste and escalating costs of care by applying lm principles. however, it should be noted that lm principles are not temporary solutions to address acute issues arising in a department. fundamentally, lm involves a long-term cultural shift that needs to be adopted by all personnel in a particular setting in order to be effective and produce positive results.1,6 overall, lm interventions should form part of a continuous cycle of quality improvement with no set endpoint. the current study was subject to certain limitations. first, a survey to assess patients and staff satisfaction was not conducted; this would have been a valuable tool to assess the increase in value and reduction in waste implementing lean management techniques at a radiation oncology department e366 | squ medical journal, august 2018, volume 18, issue 3 as a result of applying lm principles. additionally, the survey could have highlighted areas of staff overwork potentially arising as a result of introducing lm inter ventions. second, the data were not statistically analysed in terms of the timeliness of treatment delivery, which is the ultimate goal. further observational studies are therefore needed to evaluate the effect of implementing the abovementioned techniques. the department of radiation oncology is currently working on integrating lm principles within the electronic hospital software. this will allow personnel to record the exact time taken to complete each step of the treatment delivery process. conclusion applying lm principles is a promising technique to identify sources of waste and streamline workflow in healthcare delivery. although not all sources of waste were completely eliminated in the current study, they were reduced following the implementation of lm principles; in addition, these principles also enabled a smoother transition process from two treatment units to a single one by improving workflow and workload predictability. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. liker jk. the toyota way: 14 management principles from the world’s greatest manufacturer, 1st ed. new york, usa: mcgraw-hill, 2004. pp. 67–330. 2. teichgräber uk, de bucourt m. applying value stream mapping techniques to eliminate non-value-added waste for the procurement of endovascular stents. eur j radiol 2012; 81:e47–52. doi: 10.1016/j.ejrad.2010.12.045. 3. kim cs, spahlinger da, kin jm, billi je. lean health care: what can hospitals learn from a world-class automaker? j hosp med 2006; 1:191–9. doi: 10.1002/jhm.68. 4. institute for healthcare improvement. going lean in health care. from: www.ihi.org/resources/pages/ihiwhitepapers/go ingleaninhealthcare.aspx accessed: apr 2018. 5. nowak m, pfaff h, karbach u. does value stream mapping affect the structure, process, and outcome quality in care facilities? a systematic review. syst rev 2017; 6:170. doi: 10.1186/ s13643-017-0563-y. 6. simon rw, canacari eg. a practical guide to applying lean tools and management principles to health care improvement projects. aorn j 2012; 95:85–100. doi: 10.1016/j.aorn.2011.05.021. 7. moen r, norman c. evolution of the pdca cycle. from: www. i d e m p l o y e e . i d . t u e . n l / g . w. m . r a u t e r b e r g / l e c t u r e n o t e s / d g000%20dr p-r/reference s/mo en-nor man-2009.p df accessed: apr 2018. 8. rath f. tools for developing a quality management program: proactive tools (process mapping, value stream mapping, fault tree analysis, and failure mode and effects analysis). int j radiat oncol biol phys 2008; 71:s187–90. doi: 10.1016/j.ijrobp.2007. 07.2385. 9. ramaswamy r, rothschild c, alabi f, wachira e, muigai f, pearson n. using value stream mapping to improve quality of care in low-resource facility settings. int j qual health care 2017; 29:961–5. doi: 10.1093/intqhc/mzx142. 10. gellad zf, day te. what is value stream mapping, and how can it help my practice? am j gastroenterol 2016; 111:447–8. doi: 10.1038/ajg.2016.38. 11. toussaint js, berry ll. the promise of lean in health care. mayo clin proc 2013; 88:74–82. doi: 10.1016/j.mayocp.2012.07.025. 12. joosten t, bongers i, janssen r. application of lean thinking to health care: issues and observations. int j qual health care 2009; 21:341–7. doi: 10.1093/intqhc/mzp036. https://doi.org/10.1016/j.ejrad.2010.12.045 https://doi.org/10.1002/jhm.68 https://doi.org/10.1186/s13643-017-0563-y https://doi.org/10.1186/s13643-017-0563-y https://doi.org/10.1016/j.aorn.2011.05.021 https://doi.org/10.1016/j.ijrobp.2007.07.2385 https://doi.org/10.1016/j.ijrobp.2007.07.2385 https://doi.org/10.1093/intqhc/mzx142 https://doi.org/10.1038/ajg.2016.38 https://doi.org/10.1016/j.mayocp.2012.07.025 https://doi.org/10.1093/intqhc/mzp036 the worth of a book is to be measured by what you can carry away from it james bryce “life would be much simpler for general practitioners (gps) if patients presented with a diagnosis. unfortunately, patients present with symptoms that are frequently vague, sometimes multiple and often obscure” is an often repeated statement in the book. it is this situation which first prompted the authors to write this book which has become so popular that it is already in its fourth edition. there is a gap between how medicine is taught and practised. the focus in teaching on the biomechanical model together with the current advances in technology are replacing the crucial tasks of history taking and examination with more and more investigations. the importance of symptoms in making decisions about diagnosis is being whittled away. this book is a pleasure to read because of its contents and the way they are presented, each symptom described in brief and to the point sections of bulleted points. it helps to make sense of 100 or so symptoms with which patients commonly present to the family physician (fp). it is written by two gps in uk and primarily targeted at gps at all levels of training and experience, as a source of rapid reference. each chapter in the book addresses a symptom under the headings of: gp overview, differential diagnosis (further subdivided into common, occasional and rare), ready reckoner, possible investigations (categorised into likely, possible and small print), top tips and red flags. each symptom chapter could be reviewed in less than five minutes. to test this book, we tried it out in a real life situation. a 37 year-old lady presented to a fp with a history of three episodes of dizziness since that morning; they were self limiting and lasted for about 3–5 minutes each. she was worried because she had been operated on for coarctation of the aorta 12 years ago, had then had angioplasty 6 years later and an ablation done last year. she was being followed up by the cardiologist. on examination she was apparently healthy, not distressed, öü√÷]<áö^   book review symptom sorter authors: keith hopcroft and vincent forte publishers: radcliffe publishing, 4th edition, 2010 isbn: 13:978 1 84619 4535 orders: www.radcliffe-oxford.com squ med j, may 2011, vol. 11, iss. 2, pp. 293-294, epub. 15th may 11 submitted 16th feb 11 symptom sorter 294 | squ medical journal, may 2011, volume 11, issue 2 haemodynamically stable with a pulse of 68, regular, normal volume and blood pressure of 130/70 mmhg. the systemic exam was non-contributory. the fp was faced with the challenge of a familiar symptom in an unfamiliar territory. referring to the book, i found a chapter on dizziness and had a quick glance at the list of differential diagnosis to identify possible reasons such as viral illnesses, postural hypotension and arrhythmias. a review of the section on red flags excluded any urgent condition. the patient was discharged with advice to follow up after three days or sooner, and that if the symptoms worsened she should go to the emergency department. the above example demonstrates the usefulness of this book and justifies the “highly commended” recommendation by the british medical association book awards in both 2004 (2nd edition) and 2008 (3rd edition). what i would like to see in the future edition of this book is, first, that it be available in electronic format and, second, that it would give the likelihood ratios of various symptoms so that it becomes a more ‘evidence-based’ book. in summary, this is a book worth having available at the point of care for health professionals, including doctors, nurses, undergraduates and postgraduates, to help them make sense of common symptoms. with the help of the authors’ opinions in combination with our own experience we should then, as health care professionals, be able to make better clinical decisions. r e v i e w e r kamlesh bhargava department of family medicine & public health sultan qaboos university hospital, muscat, oman email: drkamlesh@gmail.com department of general surgery, kasturba medical college, manipal academy of higher education, manipal, india *corresponding author’s e-mail: gabyrodricks@gmail.com الورم احلبييب القيحي والتشوه الشرياين غابرييل رودريغز، باالجي جايا�شانكار، كري�شنا جانومبايل pyogenic granuloma and arteriovenous malformation *gabriel rodrigues, balaji jayasankar, krishna k. r. janumpalli a 44-year-old male patient presented to the kasturba medical college hospital, manipal, india, in 2018 with a two-month history of a repeatedly bleeding, non-healing nodule over the tip of his left thumb following minor trauma with a sharp object during his work as a barber. he had been treated on an outpatient basis at various clinics without success. evaluation revealed a nodular growth of 0.5 × 0.5 cm over the distal phalanx of his left thumb [figure 1a]. the nodule continued to bleed and required a continuous pressure dressing to control the flow. on occlusion of the left radial artery, the bleeding temporarily receded. with a clinical diagnosis of a post-traumatic arteriovenous (av) malformation, a computed tomography angiogram of the left upper limb revealed an av fistula at the site of the distal phalanx of the left thumb with feeding vessels from the left radial artery [figure 1b]. the lesion was excised and haemostasis was achieved [figure 2a]. histopathology revealed lobulated proliferation of capillary sized vessels, inflammatory cells in a loose and oedematous stroma with findings indicative of a pyogenic granuloma (pg) [figure 2b]. comment pg is often regarded as a hyperplastic process and is known to grow in response to trauma, hormonal factors and usually presents with pouting granulation tissue. however, histologically they are lobular capillary haemangiomas.1 clinically, they mimic lesions such as vascular malformations, haemangiomas, amelanotic melanomas (amm), dermal nevi and basal cell carci nomas.2,3 these lesions should be histopathologically distinguished from each other, especially as amm accounts for a small proportion of all melanomas and poses a risk of delayed diagnosis and poor prognosis. an interesting variant of pg or lobular capillary haemangioma involving the hand is the intravenous pg which develops within the lumen of the vein. however, in this variant the classical lobular pattern may not be as pronounced as in their extravascular counterparts.1 treatment modalities vary and range from topical application of 1% propranolol to laser coagulation and surgical excision depending on the site and location.4 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e168–169, epub. 8 sep 19 submitted 26 jan 18 revision req. 26 feb 19; revision recd. 7 mar 19 accepted 4 apr 19 figure 1: a: photograph of the distal phalanx of the left thumb of a 44-year-old male patient showing a noduloulcerative lesion. b: computed tomography angiogram showing a tumour blush (arrow). this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.017 interesting medical image https://creativecommons.org/licenses/by-nd/4.0/ gabriel rodrigues, balaji jayasankar and krishna k. r. janumpalli interesting medical image | e169 av fistulas following a low velocity penetrating injury is well known and the associated clinical signs could be misleading, which might not indicate a clear diagnosis.4 despite the various treatment modalities described for av fistula (e.g. ligation of feeders, embolisation and injection of sclerosing agents), an early surgical excision is recommended to alleviate local and systemic complications.3,5 this case highlights that both these conditions may mimic each other especially in small wounds following a trauma. it is prudent to differentiate between a relatively benign pg versus its sinistral counterpart, an av fistula. references 1. pantanowitz l, duke wh. intravascular lesions of the hand. diagn pathol 2008; 3:24. https://doi.org/10.1186/1746-1596-3-24. 2. baroni a, piccolo v. images in clinical medicine. red melanoma. n engl j med 2013; 368:1536. https://doi.org/10.1056/nejmic m1207155. 3. colletti g, valassina d, bertossi d, melchiorre f, vercellio g, brusati r. contemporary management of vascular malforma tions. j oral maxillofac surg 2014; 72:510–28. https://doi.org/10.1 016/j.joms.2013.08.008. 4. longhurst wd, khachemoune a. an unknown mass: the differential diagnosis of digit tumors. int j dermatol 2015; 54:1214–25. https://doi.org/10.1111/ijd.12980. 5. wollina u, langner d, frança k, gianfaldoni s, lotti t, tchernev g. pyogenic granuloma a common benign vascular tumor with variable clinical presentation: new findings and treatment options. open access maced j med sci 2017; 5:423–6. https://doi.org/10.3889/oamjms.2017.111. figure 2: a: photograph of the excised specimen from the left thumb of a 44-year-old male patient. b: haematoxylin and eosin stain at x40 magnification showing lobulated proliferation of capillary sized vessels and inflammatory cells in a loose and oedematous stroma. https://doi.org/10.1186/1746-1596-3-24 https://doi.org/10.1056/nejmicm1207155 https://doi.org/10.1056/nejmicm1207155 https://doi.org/10.1016/j.joms.2013.08.008 https://doi.org/10.1016/j.joms.2013.08.008 https://doi.org/10.1111/ijd.12980 https://doi.org/10.3889/oamjms.2017.111 squ med j, december 2010, vol. 10, iss. 3, pp. 318-325, epub. 14th nov 10 invited article submitted 3rd may 10 revision req. 1st june 10, revision recd. 23rd july 10 accepted 27th july 10 communication skills – why? being clinically active in general practice and psychiatry in the 1970s and 80s, we noticed, as did many colleagues, that conditions were changing for physicians. a new wave of patient expectations and complaints began, and there were fewer manpower hours, but more patients. physicians began to complain about too much work (increasingly many doctors lost their motivation and basic curiosity). many were at risk of burning out. a lot of the patient complaints were due to insufficient communication skills in the health care system. on the positive side, patients defended their right to become collaborators with their doctor rather than just subordinate customers. health care information had become readily available in newspapers and magazines and on the internet leading to doctors being challenged by well informed patients. a growing awareness of compliance and life style issues arose. the need for a patient focused health care culture and rehabilitation outcomes became apparent. this was supported by research and development on consultation models.1,2 we participated in some of this research world federation for medical education, faculty of health sciences, the panum institute, university of copenhagen, copenhagen, denmark *corresponding author email: wfme@sund.ku.dk <<›^√÷]<g�÷^e<<ïö^éjâ˜]<ìè◊€¬<ª<ÿë]áj÷]<l]ö^„⁄<üëá�i     1992 2000      15   abstract: medical curriculum revisions all over the world in the last 20 years have increased the number of teaching hours in communication skills. this article describes a concrete communication skills teaching programme focused on general practice. since the spring of 1992, more than 2,000 physicians from denmark, sweden and finland have attended courses within this programme in kalymnos, greece. the training mainly takes place in groups of 8 doctors and 1 supervisor. the skills training is based on video feedback using the window supervision method described here. we have identified several classical pitfalls for the doctor which this training programme seeks to address. we have also defined the 9 steps in an effective consultation process, which are given the acronym practical. the major issue is to discriminate between the patient’s, the doctor’s and the shared part of the communication process. in our experience, this model shortens the consultation time to c. 15 minutes as doctors collaborate with their patients and build up an agreed agenda in order to deal effectively with the main problems of the patients. keywords: general practice; communication; skills special contributionspecial contribution developing communication skills for the general practice consultation process *jørgen nystrup, jan-helge larsen, ole risør jørgen nystrup, jan-helge larsen and ole risør special contribution | 319 and developed a new model for conducting consultation in general practice.3,4,5 with this model, we wanted to offer general practitioners a set of tools and skills to become more efficient communicators and more satisfied doctors. we launched the consultation training courses in kalymnos, greece, in the spring of 1992 with, so far, close to 2,000 physicians from denmark, sweden and finland having attended them. communication in the medical curriculum curriculum revisions all over the world in the last 20 years have increased the number of teaching hours in communication. the importance of communication is emphasised in lectures and small group teaching as well as in skills laboratories with simulated patients. this all has the purpose of improving the doctor-patient collaboration and relationship which is not an option, but a necessity.6 a well-known international programme of teaching communication skills in the medical curriculum is published by juliet draper and co-workers.7,8 doctor ong and partners have written a review of the literature on doctor-patient communication.9 in addition to the factors mentioned above, there are some classical reasons for making sure that future doctors do have sufficient competence as communicators. first, history taking is a crucial task for any physician and an essential part of it is building up a trusting relationship with the patient without which collaboration and compliance with the patient is not attainable. special communication skills are required to deliver so-called 'bad news' – poor prognosis! – but even sound instructions, explanations and reassurance require skillful communication. stressful working loads or single exhausting experiences require debriefing or supervision implying new communication challenges. medical education must be life-long and communication skills should be continuously trained and refined. specific challenges in the consultation based on our courses we can delineate several classical pitfalls for the doctor: 1. patients with a long list of complaints. requires skills to prioritise and collaborate with the patient. 2. the worried patient. requires skills to phrase the worries and to console or inform rationally. 3. new problems on the way out of the consultation room. need to start all over. the agenda for the consultation has not been set. 4. the angry patient. requires acceptance and containing functions. 5. the patient with low self esteem. requires praise and respect, focus on resources. 6. the patient seeking prolonged sickness certificate. may be promised some prolongation before discussion of alternatives and long term solutions. 7. the patient asking for superfluous expensive investigations (magnetic resonance (mr) or positron emission tomography (pet) scans, etc.). the motives for the wishes must be thoroughly understood before any decision is taken. 8. the patient in need of life style changes. how much information is needed at the outset? 9. the doctor feeling hurt by the patient. analyse the counter transference feelings. 10. patient asking for more drugs. check the consumption well before deciding on continued prescription. 11. gifts – expensive or clearly personalised gifts must not be accepted. gifts from the doctor should be exceptional. the kalymnos courses the kalymnos courses have been run spring and autumn since 1992. they have been conducted in danish, swedish, and english. the setting is 3-hour scheduled learning in the morning and 3-hour scheduled learning in the evening. the afternoon, from 12 noon to 5 pm is free for recreation – an important dimension of the course. the general practitioners participating in the courses have been of different types from the very experienced needing new inspiration to very young doctors needing basic skills. in groups of 8, the learning process is built on mutual respect and eagerness to developing communication skills for the general practice consultation process 320 | squ medical journal, december 2010, volume 10, issue 3 learn from each other.10 the exercises concerning social networks and life scripts aim to develop personal resources within the individual doctor enabling him or her to integrate personal challenges into the professional role as a physician.11 the outcome of the course can easily be detected in terms of a high degree of self confidence and personal enlightenment by the end of the week. t h e l e a r n i n g f r a m e w o r k i s: • limited plenary sessions • small group sessions with videotaped role plays • small group sessions with videotaped real consultations (brought from home) • video replay with supervision • training in supervision with various techniques • exercise in uncovering own social network • life script exercise the phases of effective consultations the core of the communication skills training is based on the 9 steps shown in table 1.5 t h e pat i e n t’s pa r t 1. p r i o r patients usually prepare themselves before seeking a doctor. although many patients and doctors like to start the consultation with the present complaints, it pays off to start more openly tracing the events more generally prior to the consultation. this also includes self treatment, information from the internet, advices from family and friends and it may even include consultations with other doctors. in any case, the patient will have a history before visiting the present doctor. the patient should have the opportunity to reveal his history. information from this phase can help the doctor to avoid suggesting remedies already tried by the patient. the patients’ preparation also includes questions to themselves like: what is happening? why this? why me? why now? what can i do? who might be able to help me?12 2. r e l at i o n s h i p when the doctor asks the patient to tell his story, the relationship is beginning to develop. this phase includes more than “hello! how do you do?” and it stretches throughout the consultation process. a positive relationship is fundamental for trust and confidence in the doctor, and necessary for constructive collaboration and compliance. the most important technique for obtaining a positive relationship with the patient is reassurance and attentive listening by the doctor. another important technique is to give permission to the patient for having his or her complaints, and to be the person they are. many patients fear that they are not interesting for the doctor. they might even feel shame. 3. a n x i e t i e s (c o n c e r n s a n d e x p e c tat i o n s) through our courses we have learned that the key to managing the consultation is embedded in the phase we call anxieties: clarifying ideas, concerns and expectations on behalf of the patient, and revealing the reflections of the patient.1 if this part of the consultation is not fully completed, it is not possible to work out a valid and prioritised agenda for the consultation. this might result in the classical remark from the patient with his hand on the door handle on his way out: “oh, what i really came to see you for was…!” the patient, like the doctor, has his or her model of the world which includes a model of the illness. examples of such models are: destiny, biological, environmental, and psychological. it is very useful for the doctor to know which model the patient is employing most in the present situation. 13 asking for the patient’s concerns reinforces the respectful relationship and may give the patient a deep sense of relief that the doctor is interested in such feelings. the patients often have their very concrete expectations about the consultation varying from reassurance, explanation of symptoms to expensive laboratory investigations, extended sick leave or prescription of addictive drugs. instead of waiting for or maybe fearing these jørgen nystrup, jan-helge larsen and ole risør special contribution | 321 demands, the doctor should encourage these expectations to be put into words early in the consultation in order to plan and make the right decision later on in the consultation. to summarise this phase, a norwegian doctor has suggested five key questions.14 1. why do you want to see me today? 2. what are your own thoughts on the situation? 3. what are your own thoughts on the reason for the problem? 4. what are you particularly worried about? 5. what do you want me to help you with? so far, the consultation has focused on the premises of the patient. we call this phase the patient’s part of the consultation. this distinction between the patient’s and the doctor’s part is crucial to learn and practice because if the doctor interrupts the patient, he or she will eventually distract the patient. this can make the patient forget what s/he needs to tell the doctor, leading to confusion and waste of time for both of them. t h e d o c t o r’s pa r t 4. c o m m o n u n d e r s ta n d i n g first the agenda of the consultation should be settled. this should be initiated by the doctor through testing their common understanding. the doctor summarises what he or she has heard, and how different complaints and wishes should be prioritised in the present consultation. the summary should be phrased as the doctor’s temporary understanding and preferably contain both emotional (affective) and factual (cognitive) statements. the doctor is seeking the informed consent of the patient. 5. t r a n s l at i o n the doctor now continues with traditional physician communication. he asks questions to circumscribe the symptoms. when did it all start? where is the pain most severe? is there any fever? etc. in this phase, the doctor will conduct a physical examination and he may order some laboratory investigations. in this way, the doctor translates the verbal and physical findings, giving an explanation to the patient and maybe a diagnosis, prescription, referral, treatment etc. t h e c o m m o n pa r t 6. i n t e r ac t i o n the doctor’s suggestions might be challenged by the patient, requiring further interaction with negotiations in respect of aetiology, treatment modalities, and further investigations. the doctor may try to change the terms of reference of the patient or present a choice of possibilities. the more the patient agrees to the plan, the more compliance is likely. 7. c o n v e rt i n g i n s i g h t in order to strengthen compliance further the doctor might invite a discussion on the obstacles and facilitators to solving the table 1: practical model for doctor-patient communication (9 steps) p rior to the consultation (feelings, thoughts and actions) r elationship (permission) the patient’s part a nxieties (ideas, concerns, and expectations both affective and cognitive) c ommon understanding (summarise, check of health beliefs) t ranslating (verbal, physical examination into a diagnosis) the doctor’s part i nteraction (common understanding, change of frame of reference, doctor’s or patient’s choice) c onverting insight into action (impede, promote) a greement check (safety netting, prolonging) the common part l et’s try it (ok feelings on both sides, housekeeping) developing communication skills for the general practice consultation process 322 | squ medical journal, december 2010, volume 10, issue 3 problem. this also can be named converting insight into action. 8. ag r e e m e n t c h e c k in order to finish the consultation an agreement check is advisable. can we conclude, that we agree so and so? do we need a safety net in terms of a follow-up consultation? this can be necessary also for the doctor to verify his judgment or simply to quality assure his or her work. 9 . l e t ’s t ry i t bye, bye… before starting the next consultation, housekeeping is necessary for the doctor. it might be some fresh air, a cup of tea or coffee – or a brief interaction with another staff member in the workplace. the doctor’s screen should be erased before the next patient comes in. the important lesson is to remember the three main phases: the patient’s part, the doctor’s part, and the common part. all nine phases might seem for some doctors to be too structured. some will even think that they will not have sufficient time in a normal consultation. our experience, which has been shared with numerous colleagues, is that on the contrary this model shortens the consultation time through collaboration with the patient and building up an agreed agenda (avoiding superfluous questions on the doctor’s part and a list of patient complaints that the doctor should deal with successively). it is our goal to be able to conduct most consultations within 15 minutes and in that time to be able to deal effectively with the main problems of the patient. the window supervision method lectures and texts are not enough to master the 9 phases of the consultation. it requires various skills to manage the different phases. so the main focus in the course is learning these skills through role play, video feedback of role play and video recordings of real life situations brought from the doctor’s home consultations. the video feedback must be supervised. we prefer a supervision method invented by coles and modified by larsen, risør, and nystrup.15,16,17 this supervision has a rigid, structured schedule, which must be followed sequentially. for this reason, we call the method the window supervision method, since one window (schedule) must be dealt with before the next one should be opened [table 2]. the method thus defines a set of rules which make the participants secure, and it conveys a supervision culture that prevents self-criticism which is a common defense. supervision amongst peers easily creates competition and arguments, both scientific and attitudinal. such arguments will very often hurt someone in the group, and such arguments will most often create a barrier for learning. for this reason no free discussion is allowed. by building up trust and confidence, the supervision reaches a stage where brainstorming is allowed. the objective of the supervision is to enhance the doctor’s skills in communicating and dealing with their patients. the supervision takes place in groups with 8 doctors and 1 supervisor. the next section describes how the model works. t h e c o n t r a c t in order to emphasise ownership of the process on the part of the supervisee, we first of all ask the supervisee to state what s/he wants from the colleagues. this is called a contract. sometimes it is difficult for the supervisee doctor to formulate this in advance. it can facilitate the process to view the videotape first. in this way, the doctor might present his case and provide more information than contained on the videotape. f e e l i n g s o n t h e pa r t o f t h e s u p e r v i s e e many different – and often contradictory – feelings arise in the doctor during a consultation. in this window, the supervisor is particularly interested in the feelings towards the patient. such counter transference feelings are often the reason why the doctor may feel poisoned after the consultation. a successful supervision should be able to detoxify the supervisee. typical negative counter transference feelings are: helplessness, meaninglessness, pain, loneliness, anger, grief and fear of illness or death. positive counter transference feelings can be sympathy, pity, compassion, engagement to help. some of the feelings are real feelings created by the situation (the personality and the illness); however, surprisingly, many are countertransference feelings originating from something that happened in the jørgen nystrup, jan-helge larsen and ole risør special contribution | 323 doctor’s past. it is not constructive in the supervision process to spend time on the real origination. this might be relevant in psychotherapy. what interests us is how different kinds of feelings will influence the consultation and how the feelings of the patient are transmitted and reflected in the doctor. in this way, the feelings of the doctor can become a diagnostic tool for how the patient feels. in many instances, when starting to learn this new method, the supervisee will begin by being self-critical. the supervisor might clarify the nature of these feelings as originating from the doctor him or herself, and in this way guide the detection of feelings towards the patient. also the supervisor might need to emphasise that supervision is not a type of competition. the aim is not to find the right solution to the problem, but rather to find different and alternative solutions. first of all the aim is to be open for learning. f e e l i n g s o n t h e pa r t o f c o l l e a g u e s now the colleagues are invited to open their window. what are their feelings if they have identified with the supervisee? this often runs quite smoothly. additional feelings arise – often unexpected ones. this illustrates for the group and for the supervisee that no single feeling is sought for, and different – even negative – feelings toward the patient can be a reality in a consultation. this often creates an atmosphere of permission and a group dynamic of understanding, sharing and respecting differences in attitudes and personalities. the supervisor might join the process by sharing his or her own feelings towards the patient. p r a i s e t o m y s e l f many colleagues wonder about the relevance of all the positive comments. they are ready for constructive criticism, they often say. our experience tells us, that this is not so. the supervisee first needs to be assured of his or her competence. something must be put in the bank account before it is meaningful to draw from it. so this window encourages the supervisee to describe what he or she managed well in the consultation giving as many concrete instances as possible. the group is not allowed to argue or dispute the descriptions. p r a i s e f r o m m y c o l l e a g u e s now the colleagues are asked to point out what they detected (through the videotape) as working well in the consultation. the supervisor might join in this session. and the supervisor might summarise the content of these two windows making sure that the supervisee accepts the positive points. c o n s t r u c t i v e c r i t i c i s m in this window, the supervisee is asked (after viewing the videotape) what he or she thinks could have been done differently, and maybe what s/he would want to do differently another time. no discussion or arguments is allowed from the group. b r a i n s t o r m in order to avoid the tendency for the supervisee table 2: window supervision process what do i want the colleagues help with? ...................................................................................................................................... physician colleagues 1. feelings of the supervisee 2. feelings of the colleagues which feelings does the patient evoke in me? if i place myself in the physician’s situation which feelings does the patient evoke in me? 3. praise to myself 4. praise from my colleagues i think … worked well it worked well when you …. 5. constructive criticism 6. brainstorm i wish i had done … in that way if it had been me, i might have done …. 7. take home messages for the supervisee 8. take home messages for the colleagues what i take home is …. as for me, i take home ….. 9. feelings of supervisee 10. feelings of the colleagues now i am feeling ….. now i am feeling ….. developing communication skills for the general practice consultation process 324 | squ medical journal, december 2010, volume 10, issue 3 to defend him or herself, the supervisor might instruct the supervisee to turn his back to the group – and just listen and reflect on what ideas from the brainstorming process could be useful for the kind of doctor the supervisee is. now the group starts brainstorming: “if i had been in the same situation, may be i would have tried this or that. and maybe i also would have been able to…. if i had had a real lucky day, then…….” the supervisor does not need to summarise this. he might join the session. and he might encourage creativity. also he might permit discussion amongst the colleagues at this point. it is, however, important to underline that one right solution, in terms of a group consensus, is not what is being sought. on the contrary, a variety of different constructive approaches are welcomed. ta k e h o m e m e s s a g e s f o r t h e s u p e r v i s e e this window serves the purpose that the supervisee might reflect on alternative ways of conducting the consultation. what of the many suggestions would be relevant for him or her – and what should be given priority? the supervisor gives permission to neglect or discard what has been said by the group. but it is all right to ask if something was interesting for the supervisee and draw attention to the helpful resources. ta k e h o m e m e s s a g e s f o r t h e c o l l e a g u e s now it is time to elucidate the learning in the group in a wider context. this is done, by asking each individual member, what he or she has learned and would like to implement at home. f e e l i n g s o f t h e s u p e r v i s e e in order to check the process, the supervisor asks about the feelings of the supervisee at this point. this is both about the feelings of having gone through the supervision process, and if the feelings towards the patient, as stated in the first window, have changed particularly whether the negative countertransference feelings have diminished or vanished. if not, it might be necessary to start the supervision all over again. f e e l i n g s o f t h e c o l l e a g u e s exactly the same two questions are put to each of the colleagues. it is important to check whether somebody has been hurt by the group process. this very rarely occurs if the rigid structured schedule is adhered to. another safety measure is time. don’t rush through this exercise. it normally requires 1–1 ½ hours. conclusion some patients are experienced as a burden by their doctor who experiences heartbeat, sweat and anxiety before consultations. this is often the case with psychosomatic patients waiting to tell their doctor that their symptoms have worsened since the last consultation. with empathy and consultation skill tools, the doctors are encouraged to meet the patients on a deeper emotional and psychosocial level. our experience from these supervision courses is that, after the course, doctors no longer feel burdened by their patients. the patients have been taken seriously and therefore have received the help they sought. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. pendleton d, schofield t, tate p, havelock p. the consultation. oxford: oxford university press, 1984. 2. neighbour r. the inner consultation. london: mtp press ltd., 1987. 3. lassen lc. connections between the quality of consultations and patient compliance in general practice. fam pract 1991; 8:154–60. 4. larsen r-h, risør o. konsultationsprocessen i almen praksis. månedsskr prakt lægegern 1994; 72:319–30. 5. larsen j-h, risør o, putnam s. practical: a step-by-step model for conducting the consultation in general practice. family practice 1997; 14:295– 301. 6. meryn s. improving doctor-patient communication. not an option, but a necessity. bmj 1998; 316:1922– 30. 7. kurtz s, silverman j, draper j. teaching and learning communication skills in medicine. 2nd ed. oxford: radcliffe publishing, 2005. 8. silverman j, kurtz s, draper j. skills for jørgen nystrup, jan-helge larsen and ole risør special contribution | 325 communicating with patients. 2nd ed. oxford: radcliffe publishing, 2005. 9. ong lm, de haes jc, hoos am, lammes fb. doctor-patient communication. a review of the literature. soc sci med 1995; 40:903–18. 10. roger cr. freedom to learn. columbus, ohio: charles e. merrill publishing co., 1969. 11. golding mm, golding rl. changing lives through redecision therapy. new york: brunner/mazel, 1979. 12. hellman cg. disease versus illness in general practice. j r coll gen pract 1981; 31:548–52. 13. larsen j-h. the consultation as a mutual process of recognition. european general practice research workshop (egprw), budapest, hungary. 24–27 may 1990. 14. malterud k. key questions – a strategy for modifying clinical communication. scand j prim health care 1994; 12:121–7. 15. coles c. self assessment and medical audit: an educational approach. bmj 1989; 299:807–8. 16. larsen j-h, risør o, nystrup j. gruppe-supervision af video. månedskr prakt lægegern 1997; 75:163– 76. 17. larsen j-h, nystrup j, risør o, hedberg c. group supervision using the window method. mededuc. submitted august 2010. squ med j, february 2011, vol. 11, iss. 1, pp. 138-145, epub. 12th feb 11 ‘fi2äç4‚<öüπ<ìnëç£]<ìè€◊√÷]<l^⁄á◊√π] ·^€ �¬<håáe^œ<·^�◊ä÷]<ì√⁄^q<óàéjä⁄ 25 أكتوبر 2010 hirschsprung’s disease scientific update sultan qaboos university hospital 25th october 2010 abstracts hirschsprung disease (hscr) is a developmental disorder of the enteric nervous system, characterised by an absence of ganglion cells in the distal colon resulting in a functional obstruction.1 although this condition was described by ruysch in 1691 and popularised by hirschsprung in 1886, swenson in 1949 described the first consistent definitive procedure for hscr. early diagnosis of hscr is important to prevent failure to thrive, enetrocolitis, colonic perforation and dilatation of distal gut, which not only affects the type and number of surgical procedures, but also helps to prevent post-surgical morbidity. patients need to be monitored closely after surgery for years after surgical treatment of hscr. with early diagnosis and timely treatment, most children with hscr will not have long-term adverse effects and can live normally. our observation has been that there is paucity of the knowledge about hscr in our region. this observation has been based on the late referral of children with chronic constipation from primary health care teams to tertiary hospitals in oman. the diagnosis of hscr has been a dilemma due to many constraints. the management has been hampered both by local beliefs and by inadequate community and parental education about the impact of delaying surgical treatment in these children. the result is poor outcome with or without surgical intervention and hence the cycle goes on. to address this complex socio-medical issue, we organised this educational session for general doctors, nurses and specialists, who are involved in care of children, to highlight the necessity of early referral, diagnosis and the management. currently, approximately 90% of patients with hscr are diagnosed in the newborn period.2 hscr should be considered in any newborn, who fails to pass meconium within 24–48 hours after birth, or in any child with a history of chronic constipation since birth. other symptoms include bowel obstruction with bilious vomiting, abdominal distention, poor feeding, failure to thrive and poor weight gain as shown in figure 1 below. the exact worldwide frequency of hscr is unknown, but reported occurrence is approximately 1:1500– 1:7000 newborns.3,4 hscr occur more often in males; however, long-segment disease is common introduction to the update and to hirschsprung’s disease dr. prakash mandhan division of paediatric surgery, department of surgery, sultan qaboos university hospital, muscat, oman figure 1: hirschsprung’s disease patient with abdominal distension and visible bowel loops. abstracts | 139 in females. hscr is uncommon in premature infants. approximately 20% of infants will have one or more associated abnormalities involving the neurological, cardiovascular, urological, or gastrointestinal systems.5 children may present with diarrhoea caused by enterocolitis, which is related to stasis and bacterial overgrowth. this may progress to colonic perforation, causing life-threatening sepsis.6 plain abdominal radiographs may show distended bowel loops with a paucity of air in the rectum. a barium enema will demonstrate a narrowed distal colon with proximal dilation, a classic finding of hscr, [figure 2]. another positive radiographic finding of hscr is the retention of barium for longer than 24 hours after the barium enema has been performed. anorectal manometry, which detects the relaxation reflex of the internal sphincter after distension of the rectal lumen and this normal inhibitory reflex is thought to be absent in patients with hscr, is not commonly used for hscr due false positive results and other limitations.7 the gold standard to diagnose hscr is rectal biopsy. the current practice is to perform a bedside simple suction rectal biopsy in the newborn to obtain tissue for histologic examination by a special device [figure 3]. on histology, both the myenteric (auerbach) plexus and the submucosal (meissner) plexus are absent from the muscular layer of the bowel wall and hypertrophied nerve trunks enhanced with acetylcholinesterase stain are also observed throughout the lamina propria and muscularis propria. once the diagnosis is confirmed, the treatment is to remove the poorly functioning aganglionic bowel [figure 4] and to create an anastomosis to the distal rectum with the healthy innervated bowel (with or without an initial diversion). a number of definitive procedures have been used, all of which have demonstrated excellent results in experienced hands. the three most commonly performed surgeries are the swenson, duhamel, and soave endorectal pull-through procedures. recently, the transanal pull-through in which no intra-abdominal dissection is performed has also been popular.8,9 another addition to the surgical armamentarium is the laparoscopic approach to the surgical treatment of hscr,10 where the transition figure 2: barium enema of hirschsprung’s disease patient showing narrow rectosigmoid with proximally dilated bowel. the drawing is a demonstration of the radiological findings. figure 3: suction rectal biopsy procedure for patients with suspected hirschsprung’s disease. figure 4: operative findings in a hirschsprung's disease patient showing hugely dilated distal gut proximal to the aganglionic segment of bowel. sultan qaboos university hospital 25th october 2010 hirschsprung’s disease scientific update 140 | squ medical journal, february 2011, volume 11, issue 1 zone is first identified laparoscopically, and then the mobilised rectum is brought down through the anus. short-term outcomes for both, transanal and laparoscopic approaches have been similar to open single stage approaches with the benefits of minimal analgesia and shortened hospital stays.8,11,12 postoperatively, although patients may encounter one or more problems such as anastomotic leak, anastomotic stricture, intestinal obstruction, pelvic abscess, wound infection, chronic constipation, incontinence and enterocolitis, the long-term follow-up studies have shown that greater than 90% of children experience significant improvement and will do relatively well.8,11,12 patients with an associated syndrome have been found to have poorer outcomes.13,14 the future of children with hscr is looking promising. the possibility of stem cell transplantation into the aganglionic gut and the reactivation of dormant stem cells in the gut to regenerate the enteric nervous system are being actively investigated.15 experiments have demonstrated that neural crest stem cells (ncsc) are present, even in the adult gut, and are capable of proliferation and differentiation. in addition, researchers have been able to inject neural crest stem cells and later identify them in the native rectum. whether or not injected stem cells or reactivated native progenitor cells will have the capability to recreate a functional enteric nervous system remains to be elucidated. s p e c i a l c o n c e r n s total colonic aganglionosis is a more severe form of hscr in which the entire colon and even some of the small intestine is aganglionic. these children have increased morbidity and mortality.16,17 ultrashort-segment hscr is characterised by a few centimeters of aganglionic bowel in the rectum, adjacent to the anus. recognizing this condition can be very difficult. these patients are not typically diagnosed until they are older and most patients can be satisfactorily treated with a surgical myomectomy, which involves resecting a longitudinal strip of the posterior muscular wall of the rectum. references 1. heanue ta, pachnis v. enteric nervous system development and hirschsprung's disease: advances in genetic and stem cell studies. nat rev neurosci 2007; 8:466–79. 2. vorobyov gi, achkasov si, biryukov om, clinical features diagnostics and treatment of hirschsprung's disease in adults. colorectal dis 2009. aug 5. epub ahead of print. 3. meza-valencia be, de lorimier aj, person da. hirschsprung disease in the u.s. associated pacific islands: more common than expected. hawaii med j 2005; 64:96–8, 100–1. 4. russell mb, russell ca, niebuhr e. an epidemiological study of hirschsprung's disease and additional anomalies. acta paediatr 1994; 83:68–71. 5. ryan et, ecker jl, christakis na, folkmann j. hirschsprung's disease: associated abnormalities and demography. j pediatr surg, 1992; 27:76–81. 6. teitelbaum dh, caniano da, qualman sj, the pathophysiology of hirschsprung's-associated enterocolitis: importance of histologic correlates. j pediatr surg 1989; 24:1271–7. 7. pensabene l, youssef nn, griffiths jm, di lorenzo c. colonic manometry in children with defecatory disorders: role in diagnosis and management. am j gastroenterol, 2003; 98:1052–7. 8. de la torre l,ortega a. transanal versus open endorectal pull-through for hirschsprung's disease. j pediatr surg 2000; 35:1630–2. 9. langer jc. repeat pull-through surgery for complicated hirschsprung's disease: indications, techniques, and results. j pediatr surg 1999; 34:1136–41. 10. georgeson ke, cohen rd, hebra a, jona jz, powell dm, rothenberg ss, et al. primary laparoscopic-assisted endorectal colon pull-through for hirschsprung's disease: a new gold standard. ann surg 1999; 229:678–82; discussion 682–3. 11. langer j, durrant ac, de la torre l, teitelbaum dh, minkes rk, caty mg, et al. one-stage transanal soave pullthrough for hirschsprung disease: a multicenter experience with 141 children. ann surg 2003; 238:569–83;discussion 583–5 12. langer jc, seifert m, minkes rk. one-stage soave pullthrough for hirschsprung's disease: a comparison of the transanal and open approaches. j pediatr surg 2000; 35:820–2. 13. caniano da, teitelbaum dh, qualman sj. management of hirschsprung's disease in children with trisomy 21. am j surg 1990;159:402–4. 14. hackam dj, reblock k, barksdale em, redlinger r, lynch j, gaines ba. the influence of down's syndrome on the management and outcome of children with hirschsprung's disease. j pediatr surg 2003; 38:946–9. 15. thapar n. new frontiers in the treatment of hirschsprung disease. j pediatr gastroenterol nutr 2009; 48:s92–4. 16. bickler sw, harrison mw, campbell tj, campbell jr. long-segment hirschsprung's disease. arch surg 1992; 127:1047–50; discussion 1050–1. 17. ikeda k, goto s. total colonic aganglionosis with or without small bowel involvement: an analysis of 137 patients. j pediatr surg 1986; 21:319–22. sultan qaboos university hospital 25th october 2010 abstracts | 141 what is hirschsprung disease – a surgeon’s perspective dr. madhvan nayer department of paediatric surgery, royal hospital, muscat, oman hirschsprung’s disease (hscr) is a common cause of intestinal obstruction that affects 1:1500 to 1:5000 live births. it is more common in male children. it usually presents in the newborn period as intestinal obstruction or in older children as constipation and abdominal distention. hscr occurs due to the absence of ganglion cells in the muscle wall at muscle and submucosa levels, hence causing a failure of relaxation of the circular muscle and internal sphincter, leading to functional constipation. it occurs in the rectosigmoid in 85% of cases; however, hscr may be more extensive and may extend into the entire colon (total colonic hscr). the diagnosis of hscr is made by demonstration of absence of ganglion cells in the submucosa or in muscle layer of the intestine. a plain x-ray of the abdomen will show a distended bowel with no gas shadows in the pelvis. when a barium enema is done, it will delineate a dilated proximal colon and a very narrow “corkscrew” rectum. rectal biopsy is performed after bowel decompression and the specimen is then subjected to a histopathological examination by the usual staining technology (haematoxylin and eosin) or enzymehistochemistry methods that demonstrate an abundance of acetyl cholinesterase (ach) in the nerve bundles. once diagnosis is confirmed, either a one-stage procedure involving resection of the aganglionic bowel and restoring continuity or a multi-stage procedure (colostomy, pull-through and reversal of stoma) is carried out. in patients who have failed to achieve good decompression of the proximal bowel or in whom there is refractory enterocolitis, a preliminary diverting colostomy is mandatory. there are quite a few techniques to perform definitive (pullthrough) procedure in hscr and the recent development is minimal invasive surgery. irrespective of the type of surgery technique, the outcome is promising and fairly good long term results are achieved in over 85% cases. constipation and/or occasional soiling have been noted in about 15% of children in the post-operative period. one of the most serious early complications is anastomotic leak and intestinal obstruction and the most serious late complication is enterocolitis. enterocolitis in hscr can be serious and life threatening, hence it is addressed very aggressively and has been seen more often in patients who have had enterocolitis prior to definitive treatment or those in whom there has been persistent obstruction. it is possible to do re-surgery in patients who have had inadequate results or in those whose colon becomes much dilated due to inadequate post-operative bowel management. the role of parents, patient and community nurses in ensuring good regular evacuation cannot be overemphasised. medical aspects of hirschsprung’s disease dr. siham al-sinani departement of child health,sultan qaboos university hospital, muscat, oman this paper includes a brief introduction about the history of hirschsprung disease (hscr), as well as an introduction to its pathogenesis and epidemiology as described in the literature. the typical clinical manifestation of hscr might not be evident in all patients, which poses major difficulties in diagnosing children with atypical features of hscr and therefore delays its treatment. criteria for the diagnosis of hscr in different age groups is discussed with proposal of an algorithm for patients with delayed passage of meconium according to their accessibility to medical care and opportunities for close follow-up in the omani health system. the different presentations of hscr are explained and studies of differences between children with idiopathic constipation and children with constipation secondary to hscr. these studies did not show major differences in the clinical features based only on constipation, once again making it even more difficult to identifying hscr based solely on clinical features without further investigations. the only exception is a child with constipation with no other organic features, normal natal history, normal growth with normal physical examination and normal rectal examination. to most pediatricians, this presentation is not commonly seen in oman. very few children with a history of constipation, who are referred to us at the pediatric gastroenterology unit of child health department at sultan qaboos university hospital, have this negative history and physical examination. studies comparing diagnostic investigations commonly used for hscr have revealed significant differences in the sensitivity and specificity of such investigations. suction rectal biopsy (srb) and anorectal manometry (arm) (when the expertise is available) have the highest sensitivity and specificity. srb and arm are therefore preferred over contrast studies if hscr is to be ruled out with greater certainty. hscr is not a disorder seen in children only. different age groups (including adults) can have hscr, with interesting studies comparing the initial presentation, different pathogenesis and outcome in older patients compared to children. case reports describe adults with long standing constipation to have catastrophic complications with enterocolitis and gut perforation found on postmortem examination. adults with long standing constipation should be investigated for hscr. hirschsprung's associated enterocolitis (haec) is a known major complication of hscr. the discussion covers it definition, pathogenesis, when to suspect it and how to diagnose and treat it as a pediatrician (and not a surgeon). appropriate and timely medical intervention avoids morbidity and mortality from haec. hirschsprung’s disease and syndromes dr. adila al-kindy department of child health, sultan qaboos university hospital, muscat, oman hirschsprung’s disease (hscr) is an important genetic cause of functional intestinal obstruction. about 20% of hscr cases have another congenital anomaly either isolated or part of a syndrome (mainly monogenic mendelian inherited). hscr is a congenital malformation of the hindgut, a neurocristopathy, resulting from failure of migration of the neural crest cells that form the enteric nervous system between 5–12 wks gestation. neurocristopathies are a group of diverse disorders resulting from defective growth, differentiation, and migration of the neural crest cells. neural crest is a multipotent embryonic structure that gives rise to neuronal, endocrine and hirschsprung’s disease scientific update 142 | squ medical journal, february 2011, volume 11, issue 1 paraendocrine craniofacial, conotruncal heart and pigmentary tissues.here we present a few examples of syndromic hscr. hscr is frequently associated with syndromic neurocristopathy disorders such as shah-waardenburg syndromes (ws4), a clinically and genetically heterogeneous disorder characterised by pigmentary anomalies of the hair, skin and iris and sensorineural deafness and a long segment hscr.ws4 is caused by homozygous mutations in ednrb (ar) or heterozygous sox10 mutations (ad). another example of a neurocristopathy disorder is haddad syndrome defined by an association of hscr and congenital central hypoventilation syndrome due to phox2b gene. most cases are sporadic and few are dominantly inherited. screening for other neurocristopathy tumours such as neuroblastoma may be indicated. the syndromic hscr, commonly associated with dysmorphism, is the mowat-wilson syndrome, associated with hscr in 60% of cases. these patients have a characteristic facial gestalt with multiple congenital anomalies and severe mental retardation. it is caused by heterozygous de novo deletions encompassing the zeb2 or truncating mutations. hscr is also frequently associated with a wide spectrum of additional isolated anomalies such as hypospadia, limb abnormalities, cardiac atrial septal defect (asd) and ventricular septal defect (vsd). all hscr patients should be carefully evaluated for additional anomalies. embryological and molecular mechanisms of hindgut and enteric nervous system development dr. prakash mandhan department of surgery, sultan qaboos university hospital, muscat, oman hirschsprung disease (hscr) and anorectal malformations result from alterations in hindgut development. progress in the understanding of the genetic basis of hscr and other anorectal malformations has been made by the application of the findings from genetic and chemical animal models of altered hindgut and neuromuscular development. several genes have been shown to be important for the hindgut and enteric nervous system development and work is going on to identify genetic alterations and interactions that may explain the variable phenotypes of hscr and arms. we used ethylenethiourea (etu) rat model in our lab to study the embryological and molecular mechanisms of hindgut and enteric nervous system development. our experiments have shown that the downregulation of shh, bmp4 and hox genes in developing hindgut of etu-exposed fetal rats. when the immunohistochemical studies of the neurons and glia that comprise the enteric nervous system (ens) (the intrinsic innervations of the gut) were performed, we found that there was marked reduction in the immunoreactivity of nse, vip and sp in the hindgut of experimental foetuses as compared with the controls. our observations are that the expression of shh and its target genes in etu-exposed fetal rats is downregulated and intramural nerves, stained by vip and sp-100 antisera, were decreased in various phenotypes of hindgut developmental derivatives. the embryological and cellular mechanisms of hindgut development in etu-exposed fetal rats will be presented as well as similar work done in other laboratories. current molecular biological understanding of hirschsprung’s disease dr. david croaker department of paediatric surgery, canberra hospital, australia people have appreciated the hereditary contribution to hirschsprung's (hscr) disease at least since the 1960s. at about the same time, the association with down syndrome was noted. since then, particularly in the last 20 years, a number of karyotype abnormalities have been observed on a number of chromosomes. the observation of an interstitial deletion on chromosome 10 about 20 years ago was an important clue to the identification of the first and most important gene responsible for hirschsprung's disease-ret. at the same time gene screening for mutations in this gene never identified more than a minority of patients with significant sequence changes in the coding region. it became apparent that hscr risk was determined by the sum of a number of risk alleles, as well as, more rarely, by mutations of large effect in ret and also other genes, such as the endothelin b receptor gene. there are about a dozen relatively important genes, and perhaps many dozens more less important genes, contributing to hscr. some of these genes are associated with particular and recognisable phenotypes, such as the so-called mowat-wilson syndrome described by us. other gene mutations carry implications that are not necessarily immediately obvious: some mutations in phox2b for instance carry a risk of neuroblastoma. particular mutations in ret are responsible for multiple endocrine neoplasia type 2 (men2) cancer syndromes. it is of interest that a long-term follow-up in scandinavia has picked up a higher rate of medullary thyroid cancer in adult survivors of hirschsprung's disease. although i do not believe that gene therapy will even be possible in the majority of cases, gene screening for known multi-case families is certainly possible, and may be useful, particularly as the cost of sequencing comes down. in particular, mutation screening would be of some use if it detects that minority of patients who may be at risk for malignancy, or other as yet undiscovered late effects. we already screen ret for several of the known men associated mutations in hirschsprung's patients on occasion. at present, we are studying the lethal spotting rat, a hirschsprung's disease model with a mutation in the endothelin b receptor gene, and a phenotype like the shahwaardenburg syndrome in humans. this animal suggests clues as to where our attention should be directed in further human studies and follow-up. anorectal manometry in hirschsprung's disease dr. tawfiq al-lawati division of gastroenterology, department of paediatrics, royal hospital, muscat, oman hirschsprung's disease (hscr) is a common intestinal anomaly that presents mainly in the neonatal age. the diagnosis may prove difficult in patients with no classical symptoms. the gold standard of diagnosis remains rectal biopsy. anorectal manometry (arm) sultan qaboos university hospital 25th october 2010 abstracts | 143 relies on absence of recto-anal inhibitory reflex. the test is infrequently done due to the absence of standardised reference ranges and high false negative rates. however, recent studies in neonates have shown reliable results. arm is being further developed and might have wider diagnostic use in the future. arm has an important role in assessing postsurgical patients with hscr to determine the integrity of the anal sphincter. arm has helped in planning the management of patients with both constipation and incontinence post surgery. radiological findings of hirschsprung’s disease dr. dilip sankhla department of radiology & molecular imaging, sultan qaboos university hospital, muscat, oman radiology in hscr is paramount as it helps the clinicians to make the diagnosis as well as to evaluate postoperative morbidity. this presentation addresses the following. 1) imaging protocol: plain radiography; single-supine view; two views frontal and left lateral decubitus or upright or crosstable view; contrast enema; 2) contrast media: water soluble contrast enema or barium enema; 3) preparation and technique; 4) imaging findings: radiography multiple dilated bowel loops and paucity of air in rectum; contrast enema recto-sigmoid ratio <1; presence of narrowed zone (transition zone); fasciculation or saw tooth appearance of mucosa of involved colon; delayed emptying of contrast media from colon; thickened ulcerated colon if associated with enterocolitis; normal study in early weeks; 5) classification criteria: short segment 70–80% cases; long segment 15–25% cases; total colonic 1–4% cases; ultra short segment rare; 6) differential diagnosis: meconium plug syndrome; meconium ileus; immature colon; ileal atresia; colonic atresia. pathological findings in hirschsprung’s disease dr. indira praseeda nair department of pathology, royal hospital, muscat, oman hirschsprung’s disease (hscr) is a group of disorders characterised by a lack of propulsive peristalsis in the distal colon resulting from an absence of ganglion cells in the wall (submucosal and myenteric). an increase in adrenergic and cholinergic nerves is associated in the aganglionic segment. colonic smooth muscle relaxation is also deficient due to the disturbed function of vasoactive intestinal polypeptide and nitrous oxide mediated inhibitory nerves. the hscr can be of short or long segment type, total bowel aganglionosis, ultra-short segment hscr and zonal aganglionosis. diagnostic work up requires a full-thickness rectal biopsy specimen for haematoxylin and eosin staining and various special stainings. inadequate tissue samples and low rectal biopsy are major pitfalls for histopathology. pathologic diagnosis includes pre-operative and intra-operative biopsies. the presence of ganglion cells in rectal or colonic biopsy rules out the possibility of hscr. multiple serial sections need to be examined before a definitive diagnosis of hscr can be rendered. the special stainings such as acetylecholinestrase staining, calretinin immunostaining and rapid intra-operative immunoperoxidase staining for synaptophysin have been found to diagnose hscr much faster and more accurately. in hirschsprung associated enterocolitis (haec), microscopic examination reveals cryptitis, crypt abscesses, mucosal necrosis and transmural necrotising inflammation and perforation. the co-existence of neuronal intestinal dysplasia (nid) above the aganglionic segment of hscr can complicate the interpretation of intra-operative biopsies specimen for hscr. the diagnosis of intestinal motility disorders remains a challenge for both clinicians and pathologists. difficulties in hirschsprung’s disease pathology dr. ritu lakhtakia department of pathology, college of medicine & health sciences, sultan qaboos university, muscat, oman hirschsprung’s disease is characterised histopathologically by demonstrating aganglionosis in the meissner (submucosal) and/or auerbach (myenteric) plexuses of the rectum, depending on whether the specimen is mucosal or full thickness. equally important for patient management is establishing the presence of ganglion cells in the proximal functional colonic segment at the anastomotic site after surgical resection of the aganglionic segment. factors that render histopathologic diagnosis difficult in both these settings include: site (sampling: operator dependant) and type of biopsy (rectal suction vs. full thickness); type of histopathologic processing (frozen vs. paraffin); nature of disease (classical vs. ultrashort segment vs. total colonic aganglionosis); abnormal appearance of ganglion cells or poor development (neonates) and their look-alikes; availability and standardisation of adjunctive techniques (histochemistry and immunohistochemistry); differential diagnosis like functional constipation, hypoganglionosis, intestinal neuronal dysplasia, pseudohscr and, lastly, familiarity with morphologic patterns (observer dependant). false positive and false negative diagnosis based on these factors impact clinico-pathologic correlation thus affecting patient management. current surgical management of hirschsprung’s disease dr. adel ismail department of paediatric surgery, hamad medical corporation, doha, qatar hirschpsrung’s disease is a common cause of intestinal obstruction in children and requires surgical intervention, where the surgeon removes the aganglionic part of distal gut and restores the continuity. the surgical treatment of this condition has gone through various stages of the development. initial surgical management was multi-stage, where the surgeon would create a colostomy to relieve the hirschsprung’s disease scientific update 144 | squ medical journal, february 2011, volume 11, issue 1 obstruction, later resect the aganglionic bowel and do a pull-through procedure and finally the reversal of stoma. this traditional approach has changed and progressed to an entirely transanal pull-through procedure, where the entire operation is performed without laparotomy. this paper presents a brief review of the various surgical procedures used for the treatment of hscr and the impact of the transanal procedure on the management hscr in various age groups. long term outcome of hirschprung’s disease – oman experience dr. m. jaffer sajwani and dr. lalith wijesinghe department of pediatric surgery, royal hospital, muscat, oman the surgical management of hirshcsprung’s disease (hscr) has progressed, over the last few decades, from a 2–3 staged procedure to a primary operation. in the past decade, definitive surgery for the hscr has been performed using minimally invasive techniques. we have been operating on hscr children for the last 25 years and here share our recent experience. in the period 2001–2009, we operated on 85 children with hscr and have been able to collect follow-up clinical data regarding functional outcomes for 79 children. follow-ups were divided into the type of pull-through, age at time of procedure and length of the last follow-up. follow-up periods ranged from 1 month to 8 years. we employed different operative procedures for hscr: duhamel in 50, soave in 23, swenson in 2 and the transanal procedure in 10 children. post-operative complications included enterocolitis (10%) and bowel obstruction secondary to post-op adhesions (10%). there was no mortality. post-operatively, constipation was observed more in children who underwent the duhamel procedure, when compared with other groups. functional outcomes were not significantly different among the various operative techniques. long term outcome of hirschsprung’s disease – dubai experience dr. a. r. mustafawi department of paediatric surgery, al-wasal hospital, dubai, united arab emirates over the last hundred years, different surgical techniques have been used for definite correction of hirschsprung’s disease (hscr) in multi-stage procedures. now the transanal endorectal pull-through has become the standard surgical procedure fro hscr. since march 2004, our protocol for hscr is to proceed for single stage transanal pullthrough in the same anaesthesia session after rectal biopsy frozen sections have proved hscr positive. during the period 2004 to date, 68 patients have been diagnosed with hscr and all except 7 patients have been treated by single stage endorectal pull-through. we share our results and the follow-up of these patients. we believe that our protocol for hscr is a real single-stage transanal pull-through as it avoids two general anaesthesias, is cost-effective and facilitates a shorter stay in hospital with no more colostomies and associated morbidities. long term outcome of hirschsprung’s disease – qatar experience dr. adel ismail department of paediatric surgery, hamad medical corporation, doha, qatar we have been managing children with hirschsprunt’s disease (hscr) in qatar for many years and here i share our experience both of the modes of presentation and the outcomes of children with hscr in the last 10 years. we have reviewed our experience of the different surgical techniques used for the care of these patients and draw attention to the impact of the transanal approach on the management of this condition. during these 10 years, we had 39 children diagnosed with hscr. seven children were managed by traditional 3-staged surgical procedure; three of them had total colonic aganglionsis. the remaining 32 children had one-stage pullthrough, either assisted by laparoscopy or mini-laparotomy or the entirely transanal approach. postoperative complications included enterocolitis (12.8%), stricture (7.6%), soiling (2.5%) and constipation (28%). the mean hospital stay was 12, 5 and 3 days for the staged procedure, one stage assisted procedure and transanal procedures respectively. one child died. long term outcome of hirschsprung’s disease – canberra experience dr. david croaker department of paediatric surgery, canberra hospital, australia looked at over the last 40 years, we can see that survival from hirschsprung's disease has improved from about 70% in the 1960s, to close to 100% now. not only has survival improved, but the mean age at diagnosis has also improved, and plateaued about 20 years ago. i will discuss results first presented during my ph.d. more than 10 years ago, then some results presented more recently after we started regularly to use laparoscopic assisted transanal pull-throughs, and give a roundup of my impression of the literature of the last few years. generally speaking, functional results after pull-through are not quite as good as the older generation of surgeons liked to believe. there is a substantial incidence of at least some degree of soiling and constipation. survival, however, has improved and modern laparoscopic surgery means that patients are subjected to much less surgical trauma and fewer operations with less time in hospital. i want to stress that long-term follow-up does not only include the functional results for defecation and continence, but also should include an assessment of general quality of life, psychological well-being, and the possibility of an increased risk of associated illnesses as foreshadowed in my talk on the genetics of hirschsprung's disease. we do not know how our patients will do as they enter middle and old age. this knowledge requires decades of follow-up. well-constructed studies of this sort are difficult to achieve, and there are few sultan qaboos university hospital 25th october 2010 abstracts | 145145 | squ medical journal, february 2011, volume 11, issue 1 of them in the literature. hirschsprung's enterocolitis is still a poorly understood problem, and a source of much of our remaining postoperative morbidity. it may very well be multifactorial, and it has been suggested that hirschsprung's disease patients may have immune deficits, altered motility and functional obstruction, or simply technical anastomotic problems giving them low-grade obstruction. all of these factors may then singly or in combination result in enterocolitis. although in most cases the attacks decrease with age, while in some patients there are persistent problems. i will discuss several ideas concerning this entity. several authors and research groups are investigating the possibility of stem cell rescue in the animal model. the development of the enteric nervous system is complex and guided by signals that are ordered in both space and time. it remains to be seen whether injected neuroblasts will be able to order themselves in a functionally useful way. if this sort of therapy is possible, it would make bowel resection and anastomosis a thing of the past. despite the promise of the new genetic technologies, in practice progress at present is more evolutionary than revolutionary and good results continue to depend on attention to all the details of care. lipoleiomyomas account for approximately 0.03–0.2% of all uterine leiomyomas and are comprised of a mixture of variable amounts of mature adipocytes and smooth muscle cells.1–3 lipoleiomyomas typically occur in older post-menopausal women, whereas leiomyomas occur mostly in women of reproductive age and usually regress after menopause.2,3 the most common location of a lipoleiomyoma is the uterus, while other reported sites include the cervix, ovaries and, on occasion, the retroperitoneum.2–4 however, lipoleiomyomas on the broad ligament—a peritoneal fold that connects the uterus to the pelvis—are extremely uncommon, with only seven cases reported in the literature to date.2,5–10 broad ligament lipoleiomyomas are difficult to diagnose preoperatively upon radiology and may be mistaken for an ovarian carcinoma.11 however, it is important to distinguish between these entities as broad ligament lipoleiomyomas can be treated conservatively with a lumpectomy.6 this report describes two cases of broad ligament lipoleiomyoma in which both patients were initially diagnosed with a solid malignant adnexal mass. case one a 15-year-old girl was admitted to the lok nayak jai prakash hospital (lnjph), new delhi, india, in 2016 with lower abdominal discomfort and an abdominal mass of three months’ duration. the patient’s past medical history was insignificant. she had first undergone menarche at the age of 12 years. a physical examination revealed a hard movable mass in the lower abdomen of a size similar to a pregnancy of 20 gestational weeks. there was no evidence of lymphadenopathy or organomegaly. magnetic resonance imaging (mri) showed a well-defined, large, solid, cystic abdominopelvic mass measuring 26 x 26 x 14.5 cm. the mass was abutting the posterior wall of the urinary bladder, uterus, anterior wall of the rectum and the retroperitoneal structures, displacing the uterus and reaching up to the lower margin of the liver [figure 1]. laboratory tests revealed raised levels of serum thyroid-stimulating hormone (14.74 µiu/ml) and total triiodothyronine (t3; 60 ng/dl), although her thyroxine (5.42 µg/dl) and free t3 (2.2 ng/dl) levels were normal. based on these clinical and radiological features, the patient was diagnosed with an ovarian tumour. departments of 1pathology and 2obstetrics & gynaecology, maulana azad medical college, new delhi, india *corresponding author’s e-mail: dr.surekhay@gmail.com األورام الشحمية العضلية يف الرباط العريض للرحم حاالتني غريبتني متنكرتني كما سرطان املبيض �صوريكا ياداف، بركا ماهي�صواري، ني�صانت �صاجار، فارونا ماليا، نيتا كورانا، �صاجنيتا جوبتا abstract: lipoleiomyomas are an extremely rare form of uterine leiomyoma; moreover, the occurrence of this type of tumour on the broad ligament is even rarer. we report two cases of broad ligament lipoleiomyomas in 15and 38-year-old female patients who presented to the lok nayak jai prakash hospital in new delhi, india, between 2016 and 2017. in both cases, the preoperative diagnosis was of a solid ovarian malignancy. most broad ligament tumours are mistaken for ovarian masses as they are difficult to diagnose radiologically. keywords: ovarian neoplasms; leiomyoma; broad ligament; thyroid hormones; hypothyroidism; case report; india. امللخ�ص: الأورام ال�صحمية الع�صلية هي �صكل نادر للغاية من الورم الع�صلي الأمل�ض للرحم. وعالوة على ذلك، فاإن حدوث هذا النوع من الورم على الرباط العري�ض هو اأكرث ندرة. هذا تقرير عن حالتني م�صابتني بالأورام ال�صحمية الع�صلية يف الرباط العري�ض كانت اأعمارهم 15 و 38 عاما قدما اإىل م�صت�صفى لوك ناياك جاي براكا�ض يف نيودلهي، الهند، بني عامي 2016 و 2017. يف كلتا احلالتني، كان الت�صخي�ض قبل اجلراحة هو �رشطان املبي�ض ال�صلب. يخطئ الت�صخي�ض الإ�صعاعي يف معظم اأورام الرباط العري�ض للرحم على اأنه �رشطان املبي�ض. الكلمات املفتاحية: اأورام املبي�ض؛ الورم الع�صلي الأمل�ض؛ الرباط العري�ض؛ هرمونات الغدة الدرقية؛ ق�صور الغدة الدرقية؛ تقرير حالة؛ الهند. broad ligament lipoleiomyoma masses two curious cases masquerading as ovarian carcinomas *surekha yadav,1 barkha maheswari,1 nishant sagar,1 varuna mallya,1 nita khurana,1 sangeeta gupta2 case report sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e477–480, epub. 10 jan 18 submitted 4 may 17 revisions req. 15 jun & 6 jul 17; revisions recd. 19 jun & 11 jul 17 accepted 19 jul 17 doi: 10.18295/squmj.2017.17.04.018 broad ligament lipoleiomyoma masses two curious cases masquerading as ovarian carcinomas e478 | squ medical journal, november 2017, volume 17, issue 4 an exploratory laparotomy revealed a tumour of 26 cm in size protruding out of the abdominal cavity. there was no connection between the tumour and the left ovary; instead, it was attached to the left lateral aspect of the uterus. upon gross examination, the tumour was smooth, homogenous and greyish-white [figure 2a]. the lump was excised and a specimen was sent for frozen section analysis. microscopically, interlacing bundles of benign spindle-shaped cells with intermingled fat cells were observed [figure 2b]. the randomly distributed fat cells were mature and there was no evidence of lipoblasts, mitosis, necrosis or angiomatosis. there was no cytological atypia in the spindle cells or adipocytes. on immunohistochemistry, the tumour cells were positive for smooth muscle actin (sma) but negative for human melanoma black (hmb)-45. the patient was diagnosed with a broad ligament lipoleiomyoma and subsequently underwent conservative surgery to fully excise the mass. one week later, her thyroid hormone profile had returned to normal. at a six-month follow-up appointment, the patient appeared to be healthy with no evidence of disease recurrence. case two a 38-year old gravida 2, para 2 female presented to lnjph in 2017 with an uncomfortable abdominal mass which had been increasing in size over the previous year. she had never experienced any menstrual irregularities and there were no significant events in her past medical or surgical history. a physical examination revealed a left-sided abdominopelvic mass without evidence of lymphadenopathy or organomegaly. routine tests, including serum tumour markers, were within normal limits. an mri scan showed a large left-sided heterogeneously enhancing abdominopelvic mass with figure 2: a: gross image of an excised lesion from a 15-year-old female, showing a well-circumscribed greyish soft mass with a smooth external surface. b: haematoxylin and eosin stain at x400 magnification showing mature smooth muscle cells and intermingled mature adipose tissue (arrow). figure 1: magnetic resonance imaging scan of a 15-year-old female showing a heterogeneously enhancing solid-cystic pelvic mass (arrow). figure 3: a: gross photograph of an excised lesion from a 38-year old female, showing a homogenous greyish mass with focal areas of central fat (arrow). b: haematoxylin and eosin stain at x400 magnification showing interlacing bundles of benign spindle-shaped cells with intermingled fat cells (arrow). surekha yadav, barkha maheswari, nishant sagar, varuna mallya, nita khurana and sangeeta gupta case report | e479 adenopathy) and malignant (malignant teratoma and liposarcoma) lesions.6 a brief summary of reported cases of broad ligament lipoleiomyoma is shown in table 1.2,5–10 to the best of the authors’ knowledge, the 15-year-old girl described in the first case of this report appears to be the youngest known patient to develop a broad ligament lipoleiomyoma. among lipoleiomyomas, distribution of the adipocytic component can vary widely from being uniformly spread throughout the tumour to a more focal concentration in small areas; as such, there is no defined cut-off percentage of adipocytes to confirm the diagnosis. in terms of appearance, those tumours containing few microscopic foci of adipocytes tend to resemble regular leiomyomas with large amounts of adipocytic components usually indicated by a yellowish appearance and a lobulated cut surface.2 radiologically, the diagnosis of a lipoleiomyoma is challenging as these masses often resemble an ovarian tumour.9,11 the lobules of mature fat in a lipoleiomyoma intermingle with wisps of smooth muscles, which can be misleading and resemble the atypical hyperchromatic spindle cells of a well-differentiated liposarcoma. therefore, the accurate diagnosis of this entity depends on the correct identification of the benign smooth muscle cells.7 several hypotheses have been proposed to explain the origin of uterine lipoleiomyomas, including lipomatous metaplasia, metaplasia in the pluripotent lobulated margins measuring 30 x 25 x 15 cm. the left adnexa was not visualised separately. a provisional diagnosis of a malignant ovarian tumour was made. accordingly, the patient underwent a total abdominal hysterectomy with a bilateral salpingo-oophorectomy. during the surgery, the tumour was observed to be separate from the left ovary and attached to the left broad ligament. there was no evidence of lymphadenopathy and all other organs appeared to be healthy. on gross examination, the tumour measured 30 cm in its greatest dimension and was homogenous and greyish-coloured, with focal yellow areas [figure 3a]. microscopically, the tumour showed features of a benign spindle cell lesion [figure 3b]. immunohistochemistry was once again positive for sma but negative for hmb-45. the final diagnosis was of a broad ligament lipoleiomyoma. the patient appeared healthy at a three-month follow-up appointment. discussion lipomatous tumours of the uterus are divided into three groups: pure lipomas composed of mature adipose tissue, lipoleiomyomas composed of a mixture of smooth muscle cells and mature adipose tissue and malignant liposarcomas.2 the differential diagnosis of pelvic lipoleiomyomas includes both benign (i.e. teratomas, benign pelvic lipomas, non-teratomatous lipomatous ovarian tumours and lipoblastic lymphtable 1: literature review of cases of broad ligament lipoleiomyoma2,5–10 author and year of case report patient age in years symptoms tumour size in cm clinical diagnosis treatment associated disease wang et al.2 (2006) 54* 4.6* mishra et al.5 (2016) 45 abdominal pain 17 ovarian tumour tah and bso none bajaj et al.6 (2000) 63 abdominal pain 20 ovarian tumour myomectomy none cinel et al.7 (2002) 68 54 swelling abdominal pain 40 8 ovarian neoplasm ovarian cyst tah and bso tah and bso none none fernández et al.8 (1989) ovarian tumour salman et al.9 (2010) 54 abdominal pain 8 solid ovarian malignancy tah and bso none kim et al.10 (2012) 56 abdominal discomfort 15 mature cystic teratoma tah and bso dm present cases (2017) 15 38 abdominal discomfort abdominal discomfort 26 30 ovarian tumour malignant ovarian tumour myomectomy tah and bso hypothyroidism none tah = total abdominal hysterectomy; bso = bilateral salpingo-oophorectomy; dm = diabetes mellitus. *mean. broad ligament lipoleiomyoma masses two curious cases masquerading as ovarian carcinomas e480 | squ medical journal, november 2017, volume 17, issue 4 mesenchymal cells or the perivascular extension of fat along the blood vessels with a complex histogenesis according to immunohistochemical studies.2,7,11 renal angiomyolipoma-like vascular proliferation has also been reported in a case of lipoleiomyoma.5 however, neither of the present cases exhibited cellular atypia nor vascular proliferation; furthermore, the tumour cells were immunonegative for hmb-45. patients with uterine lipoleiomyomas may also present with associated metabolic disorders like hyperlipidaemia, diabetes mellitus or hypothyroidism, like the younger patient described in this report.10–12 the cause of metabolic disturbances among older patients with lipoleiomyomas is generally assumed to be due to altered lipid metabolism; however, the precise reason for this alteration is still unknown.10 conclusion the diagnosis of a lipoleiomyoma can be challenging as their appearance upon imaging resembles that of a liposarcoma. due to their solid nature, lipoleiomyomas may necessitate surgical intervention to relieve associated symptoms and rule out ovarian malignancy. patients may also have underlying hormonal disturbances which normalise after surgery; as a result, regular follow-up appointments should be undertaken. references 1. prieto a, crespo c, pardo a, docal i, calzada j, alonso p. uterine lipoleiomyomas: us and ct findings. abdom imaging 2000; 25:655–7. doi: 10.1007/s002610000052. 2. wang x, kumar d, seidman jd. uterine lipoleiomyomas: a clinicopathologic study of 50 cases. int j gynecol pathol 2006; 25:239–42. doi: 10.1097/01.pgp.0000192273.66931.29. 3. aung t, goto m, nomoto m, kitajima s, douchi t, yoshinaga m, et al. uterine lipoleiomyoma: a histopathological review of 17 cases. pathol int 2004; 54:751–8. doi: 10.1111/ j.1440-1827.2004.01748.x. 4. mira jl. lipoleiomyoma of the ovary: report of a case and review of the english literature. int j gynecol pathol 1991; 10:198–202. doi: 10.1097/00004347-199104000-00008. 5. mishra ss, saha a, mishra p, jena sk. lipoleiomyoma of the left broad ligament with dermoid cyst in ipsilateral ovary and synchronous multiple benign lesions of female genital tract: an unusual association. indian j pathol microbiol 2016; 59:355–8. doi: 10.4103/0377-4929.188117. 6. bajaj p, kumar g, agarwal k. lipoleiomyoma of broad ligament: a case report. indian j pathol microbiol 2000; 43:457–8. 7. cinel l, düşmez d, nabaei sh, taner d, pata o. two intraligamentary lipomatous tumors with immunohistochemical features. acta obstet gynecol scand 2002; 81:786–7. doi: 10.1034/j.1600-0412.2002.810818.x. 8. fernández fa, val-bernal f, garijo-ayensa f. mixed lipomas of the uterus and the broad ligament. appl pathol 1989; 7:70–1. 9. salman mc, atak z, usubutun a, yuce k. lipoleiomyoma of broad ligament mimicking ovarian cancer in a postmenopausal patient: case report and literature review. j gynecol oncol 2010; 21:62–4. doi: 10.3802/jgo.2010.21.1.62. 10. kim hk, kim jh, hong sy, choi ys, oh hk, lee ts. a uterine lipoleiomyoma of the broad ligament mimicking an ovarian tumor. korean j obstet gynecol 2012; 55:787–90. doi: 10.5468/ kjog.2012.55.10.787. 11. aizenstein r, wilbur ac, aizenstein s. ct and mri of uterine lipoleiomyoma. gynecol oncol 1990; 40:274–6. doi: 10.10 16/0090-8258(90)90291-r. 12. lin kc, sheu bc, huang sc. lipoleiomyoma of the uterus. int j gynaecol obstet 1999; 67:47–9. doi: 10.1016/s0020-7292 (99)00094-6. https://doi.org/10.1007/s002610000052 https://doi.org/10.1097/01.pgp.0000192273.66931.29 https://doi.org/10.1111/j.1440-1827.2004.01748.x https://doi.org/10.1111/j.1440-1827.2004.01748.x https://doi.org/10.1097/00004347-199104000-00008 https://doi.org/10.4103/0377-4929.188117 https://doi.org/10.1034/j.1600-0412.2002.810818.x https://doi.org/10.3802/jgo.2010.21.1.62 https://doi.org/10.5468/kjog.2012.55.10.787 https://doi.org/10.5468/kjog.2012.55.10.787 https://doi.org/10.1016/0090-8258%2890%2990291-r https://doi.org/10.1016/0090-8258%2890%2990291-r https://doi.org/10.1016/s0020-7292%2899%2900094-6 https://doi.org/10.1016/s0020-7292%2899%2900094-6 مؤمتر اإلنعاش القليب والبحث العلمي 2018 قسم طب الطوارئ جبامعة السلطان قابوس، اجلمعية العمانية لطب الطوارئ، واألكادميية األمريكية لطب الطوارئ، 2–1أبريل 2018 resuscitation & research conference 2018 sultan qaboos university department of emergency medicine, oman society of emergency medicine and american academy of emergency medicine, 1–2 april 2018 conference abstracts poster presentations scorpion sting management practices in omani tertiary care emergency departments: a retrospective study and survey *suad al-abri,1 munira al-rumhi,1 ghaitha al-mahrouqi,1 ali s. shakir2 1department of emergency medicine, sultan qaboos university hospital, muscat, oman; 2department of emergency care, nmc specialty hospital, muscat, oman. *corresponding author’s e-mail: ghammari2011@gmail.com objectives: this study aimed to review scorpion sting (ss) management practices in omani tertiary care emergency departments. methods: this retrospective study included all emergency ss cases at three tertiary hospitals in muscat, oman, between march 2016 and july 2017. in addition, emergency physicians were surveyed to determine common ss management practices. results: there were 128 ss cases. localised pain was observed in 97.7% of patients, swelling in 14.8% and localised redness in 7%. some patients (13.3%) had systemic symptoms, with tachycardia being most common. bedside clotting tests were ordered for 11.7% of patients. the most common form of treatment was local anaesthesia (54.7%). none of the patients received antivenom. the survey was completed by 80 emergency physicians with experience in ss management. analgaesia was the main form of management (88.8%), followed by local anaesthesia (81.3%). most doctors (80%) believed that local anaesthesia was the most effective form of treatment. only 32.5% reported that they would order a bedside clotting test, of which 69.2% were junior doctors. conclusion: analgaesia was the main form of management, followed by local anaesthesia. few doctors ordered bedside clotting tests. comparison between the analgaesic effects of nefopam versus tramadol for postoperative pain following a laparoscopic cholecystectomy ridha m. al-kaabi department of pain management & intensive care unit, al safeer hospital, karbala, iraq. e-mail: x5uae2003@yahoo.com objectives: pain is a common postoperative complication depending on the type, technique and duration of the surgery. this study aimed to evaluate the effect of nefopam versus tramadol as analgaesics among post-laparoscopic cholecystectomy patients. methods: this prospective cross-sectional study was conducted between january and april 2017 at al safeer hospital, karbala, iraq. a total of 61 elective laparoscopic cholecystectomy patients were divided into two groups. the first group (n = 29) received 1 mg/kg of tramadol while the second group (n = 32) received 20 mg of nefopam intravenously. both groups received 1 g of acetaminophen. all patients were observed over the following 24 hours and monitored for pain at zero, one, two, four, eight and 16 hours. results: the first group demonstrated more postoperative pain as compared to the second group, often requiring rescue doses of tramadol. in contrast, rescue doses of nefopam were not required in the second group. conclusion: a single dose of nefopam is more effective than tramadol for postoperative pain following a laparoscopic cholecystectomy. chest trauma cases in a tertiary hospital: aetiology, patterns, management approaches and correlations with poor sequelae *omar al-mutair, waseem hajjar, nawaf al-dosari, majed al-tulian, abdul r. al-fahadi, abdul r. al-boqami king saud university hospital, riyadh, saudi arabia. *corresponding author’s e-mail: omar_sa94@hormail.com objectives: this study aimed to determine patterns of chest trauma and associated factors related to poor outcomes in a tertiary hospital. methods: this retrospective cross-sectional study was conducted from january 2010 to december 2016 at the king saud university hospital, riyadh, saudi arabia. results: a total of 235 chest trauma cases were reviewed. the mean age was 32.4 ± 14.5 years and 87.7% were male. the most common causes of chest trauma were blunt trauma (95.7%) and traffic crashes (87.2%). fractured ribs were most common (63.8%), followed by lung contusions (59.1%), pneumothorax (57%) and haemothorax (34.5%). many patients had extrathoracic injuries (81.3%). overall, 55.3% of patients were intubated and ventilated and 48.9% underwent chest tube insertion. emergency thoracotomies were performed in 8.1%, either due to haemothorax or laceration of the lungs. poor outcomes were significantly correlated with length of hospital stay, intubation, extrathoracic injuries, blood transfusions, chest tube insertion, lung contusions, tracheostomies and flail chest (p <0.050 each). conclusion: most chest trauma cases were due to blunt trauma and road traffic crashes. various factors were significantly correlated with poor outcomes, such as intubation, chest tube insertion and the presence of lung contusions. sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e565–567, epub. 28 mar 19 doi: 10.18295/squmj.2018.18.04.027 e566 | squ medical journal, november 2018, volume 18, issue 4 resuscitation & research conference 2018 transoral endoscopic thyroidectomy vestibular approach: the first 10 cases in iraq sadiq g. kadem department of surgery, al-shiffa general hospial, basrah, iraq. e-mail: sadiqalsaidi222@yahoo.com objectives: a transoral endoscopic thyroidectomy vestibular approach (toetva) is a novel noninvasive type of endoscopic surgery using a natural orifice. this study aimed to review the first 10 toetva cases reported in iraq. methods: this prospective study included all 10 toetva procedures performed in iraq from august to december 2017. results: all of the procedures were performed using three laparoscopic ports inserted at the oral vestibule. of the 10 cases, one had bilateral benign thyroid pathology, while the others had rightsided benign thyroid pathology. all of the patients were female, 24–40 years old and had body mass indexes between 20–26 kg/m2. the patient with bilateral benign thyroid pathology underwent a near-total thyroidectomy, while the others underwent lobectomies. the duration of operating time ranged from 90–150 minutes, drain removal from 20–24 hours (with 15–25 ml of fluid drained) and hospital stay from 33–47 hours. the final histopathological results were benign in all cases. only one complication was recorded, with a patient developing mild cervical emphysema which resolved within 24 hours. there were no deaths and none of the cases required an open thyroidectomy. conclusion: a toetva is a safe and feasible procedure; however, it requires longer operating times compared to a conventional open thyroidectomy. paediatric cardiopulmonary resuscitation: comparison between emergency department and inpatient settings at a tertiary academic hospital in oman *shilpa ramachandran,1 ali s. shakir,1 niranjan lal,1 sathiya m. panchatcharam,2 marwan al-raisi,1 suad al-abri1 1department of emergency medicine, sultan qaboos university hospital, muscat, oman; 2emergency medicine residency programme, oman medical specialty board, muscat, oman. *corresponding author’s e-mail: shilpar2010@hotmail.com objectives: this study aimed to compare paediatric cardiopulmonary resuscitation (cpr) cases seen in emergency department (ed) and inpatient settings. methods: this retrospective cohort study took place at the sultan qaboos university hospital, muscat, oman, and included all paediatric cpr cases occurring between january 2012 and august 2017. results: a total of 83 paediatric cpr cases were reviewed, of which 57.8% were male. in total, 67.5% were inpatients and 32.5% were ed cases. cpr was initiated due to either respiratory arrest (73.5%) or cardiac arrest (26.5%). almost half of the patients (49.3%) were under one year old. bradycardia with hypoperfusion was the predominant cause of arrest (65.1%), followed by asystole (31.3%). overall, 51.9% of ed patients were previously healthy, while 78% of inpatients had a history of chronic disease. only 9.6% of patients survived to discharge. among cases of brain death/mortality, 87.5% were ed cases and 92.6% were inpatients. although 24-hour (18.5%) and one-year (11.1%) survival rates were higher among ed cases, this difference was not significant. conclusion: paediatric cpr was most commonly performed due to respiratory arrest. most arrests were due to bradycardia with hypoperfusion. very few patients survived to discharge. despite significant differences in clinical variables, cpr outcomes in ed and inpatient settings were similar. perceptions of nursing managers regarding the nursing working environment at the sultan qaboos university hospital salimah a. al mamari1 and *huda al-awaisi2 1directorate of nursing, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: hudas@squ.edu.om objectives: nursing is a physically demanding profession with long working hours and heavy workloads; moreover, in some regions there may be a lack of funds for necessary training and development. such working conditions can be attributed to poor management practices and may negatively affect nurses’ job satisfaction, performance and patient outcomes. this study aimed to identify perceptions of the nursing work environment at a tertiary hospital. methods: this cross-sectional study was conducted at the sultan qaboos university hospital (squh), muscat, oman. questionnaires were distributed to nursing managers/administrators. the questionnaire surveyed various dimensions of a working environment, including organisational support, leadership, managerial practices, communication, professionalism, interpersonal relationships, resources, autonomy and workload. results: nursing leaders/managers had very high perceptions of leadership ability and autonomy at squh. however, other factors, especially professional development, workload and resource availability, were identified as requiring further improvement. conclusion: an action plan is recommended to help nursing leaders/managers at squh to enhance the nursing working environment. further research is recommended to assess the nursing work environment from the perspective of staff nurses. healthcare workers’ attitudes towards individuals with malingering phenomenon at the department of behavioural medicine, sultan qaboos university hospital ibtisam s. al-zakwani department of behavioural medicine, sultan qaboos university, muscat, oman. e-mail: malaklovehazza@gmail.com objectives: malingering phenomenon (mp) is the fabrication of illness symptoms for various motives, such as avoiding school/work, obtaining drugs or to attract sympathy. this study aimed to establish healthcare providers’ attitudes towards individuals with mp. methods: this cross-sectional study was conducted in the department of behavioural medicine, sultan qaboos university hospital, muscat, oman. an existing tool to assess attitudes towards patients with borderline personality disorder was modified to assess attitudes towards mp. results: a total of 40 healthcare workers participated in the study. most (89%) believed that emotional/psychological problems were contributing factors in mp development, with few (18.9%) believing that socioeconomic status played a role. females reported greater difficulty dealing with malingerers than males (82.6% versus 64%); however, there was little difference between doctors and nurses (70% versus 68.7%). when dealing with malingerers, females reported feeling more helpless and often manipulated compared to males (17.3% versus 7% and 26% versus 7%, respectively). additionally, more males than females believed that malingerers could be cured (92.8% versus 43.4%). however, males more often felt provoked by malingering behaviour compared to females (28% versus 21%). conclusion: female healthcare workers had greater difficulty tolerating malingerers and felt more helpless when dealing with them, often losing their temper. although male healthcare workers felt more provoked by malingering behaviour, they felt less discomfort/ annoyance compared to their female colleagues. abstracts | e567 sultan qaboos university department of emergency medicine, oman society of emergency medicine and american academy of emergency medicine, 1–2 april 2018 tracheal tear in a child with a bicycle handlebar injury: a complex resuscitation scenario niranjan l. jeswani and *muhammad f. khilji department of emergency medicine, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: faisalkhilji@yahoo.com we report an 11-year-old male who presented to the emergency department of the sultan qaboos university hospital, muscat, oman, with swelling and pain after a bicycle handlebar injury to the left side of the neck. an initial examination was unremarkable; however, a secondary examination revealed oedema in both supraclavicular areas, although more so on the left side of the neck. the swellings were soft upon palpation, with evidence of crepitus. subsequently, there was a progressive increase in the right-sided oedema, resulting in dyspnoea and hoarseness. in light of imminent airway compromise, the patient was intubated using a portable videolaryngoscope. a chest radiograph revealed left apical pneumothorax and pneumomediastinum. computed tomography showed a large bilateral pneumomediastinum with extensive surgical emphysema over the anterior chest wall, neck and the left side of the face. a bronchoscopy revealed a small longitudinal tear in the posterior membranous wall at the mid-tracheal level. the patient was managed conservatively, kept intubated for seven days and was discharged after an uneventful recovery. headscarf pin in the right main bronchus: habits need to be changed qazi z. ullah and *muhammad f. khilji department of emergency medicine, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: faisalkhilji@yahoo.com we report a 25-year-old female who presented at the emergency medicine department of the sultan qaboos university hospital, muscat, oman, after having accidentally inhaled a headscarf pin. a chest radiograph showed a metal pin lodged in the right main bronchus of the lung. the pin was immediately removed via fiberoptic bronchoscopy. the patient was discharged the next day, after an uneventful overnight stay in the hospital. emergency balloon atrial septotomy *khalid a. khalid and abdulhadi h. al-kabbi ibn albitar cardiac center, baghdad, iraq. *corresponding author’s e-mail: kak983@yahoo.com a balloon atrial septotomy (bas) is a technique for dilating atrial septal defects without the need for a thoracotomy or general anaesthesia. we report a 4-day-old neonate who was referred to the ibn albitar cardiac center, baghdad, iraq, with d-transposition of the great arteries and an atrial septal aneurysm (asa). the asa had a small shunt across it. there were no ventricular septal defects or patent ductus arteriosus. upon examination, the patient was deeply cyanosed and in respiratory distress. an emergency bas procedure was performed, in which a 6fr rashkind balloon catheter was introduced from the right femoral vein, advanced through the right atrium and, subsequently, into the left atrium. the balloon was inflated with 2–3 ml of diluted contrast medium (20:80%). fluoroscopy and echocardiography were used to position the balloon. the inflated balloon was then rapidly passed into the right atrium where it immediately deflated. this process was repeated three times until peripheral capillary oxygen saturation had increased from 58% to 81%, with equalisation of pressure between the atria and free flapping of the ostium primum on echocardiography. sir, i have read with interest the articles, study of perceived stress among female medical and non-medical university students in dammam, saudi arabia, by dabal et al.1 and the accompanying editorial by al-lamki.2 i would like to congratulate the authors for their scholarship and for highlighting this issue empirically. the study authors have compared levels of stress among medical students using certain defined parameters. the study suggested that medical students appear to have a greater propensity towards academic stress, than their counterpart nonmedical students.1 studies from different parts of the world, including from the arabian gulf are congruent with such a view.3,4 however, compared to other studies, the present finding of a 48.6% rate of academic stress appear to be bewilderingly high considering that, due to cultural patterning, there is a low tendency in such a population to admit to emotional distress.5 the ensuing paragraphs ponder about some of the methodological and conceptual factors that could contribute to what could amount to a spurious rate of academic stress. first, the high incidence could be partly explained due the phenomena know as ‘hypochondriasis of medical students’. medical students are likely to perceive themselves as distressed partly because they are familiar with many of the ill-effects of stress from their medical education. these are the people who are exposed to such concepts and terminologies routinely in their medical education. relevant to this, there is a lot of hype, in the media as well as in the medical profession, that medical schools are ‘hard’. this, of course, is likely to create the climate of a self-fulfilling prophecy. this, in turn, may lead to the dire consequence of endorsing stress that is not really there. second, the contribution of one’s personality to academic stress has often been overlooked in current discussion on academic stress. it is well known that certain personality types are prone to stress and in this context, it is the so called ‘type-a personality’.6 there is empirical evidence to suggest that medical professions tends to attract people with ‘type-a’ personalities, known to be marked by competitiveness, machiavellianism and envy as well as characterised by the cardinal temperaments that are prone to ‘burnout’, or in the present context, to suffering from academic stress. equally, there is an indication that medical teachers are not spared from having such a disposition. this echoes the dictum, ‘birds of a feather flock together”. third, another point of contention that has been overlooked in this study is the particular role of the medical teacher in this region. gulf countries tend to attract medical teachers from different parts of the world, but predominantly from other developing countries. such medical teachers, ambitious as they may be to distinguish themselves in an international setting, are known to have come here because they are unable to thrive elsewhere in competitive academic medicine. such ‘substandard’ teachers, it could be speculated here, are likely to be ill-equipped to provide an effective learning environment for their students. one salient squ med j, december 2010, vol. 10, iss. 3, pp. 410-411, epub. 14th nov 10 received 9th sep 10 <ìè◊“<l^f÷^õ<^„„q]ái<:÷]<<ìèäàfl÷]<<ωá«ñ÷]<∞e<ìfiö^œ€◊÷<<ìâ]öå ìëåá√ä÷]<ìèeü√÷]<ì”◊€π]<ª<<›^⁄ç÷^e<<ìèfõ<4∆<ìè◊“<l^f÷^õê<g�÷]  re: comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia sarah s. h. al-adawi letter to editor sarah s. h. al-adawi letter to editor | 411 and ostensible victim of such a situation is the quality of medical education. the reverse side of this coin is the creation of stressed-out medical students. fourth, a possible cause of the high rate of academic stress among the reported medical student cohort may reflect the ‘united nations’ of medical teachers in the region and a tendency towards ‘lost in translation’. in general, multi-culturalism and pluralism are often considered to be important ingredients in academic culture; however, there may be a downside to such an environment: the issue of language. students often complain that they have attended a lecture given by medical teacher whose accent was rendered the content unintelligible to them. medicine is taught in english, the well meaning intention being that english is the language of science and technology, but the burden of learning or trying rapidly to improve on language skills in the midst of a challenging medical curriculum can further deplete student enthusiasm for life and learning. the situation is further affected by the mode of school education in the region which is often by ‘rote’ learning.7 effective ‘rote learners’ may have excelled in secondary school to gain entrance into medical school, but it remains to be seen how such a learning strategy fares in medical school. therefore, the discrepancy in learning styles between secondary school and university, compounded by the characteristics of the medical teachers, may contribute to the high propensity towards academic stress. the aforementioned methodological and conceptual constraints need to be considered in future research so that evidence-based prevention and intervention can be contemplated in order to mitigate intransigent and debilitating academic stress, something well known to dent one’s social, health and occupational competency. sarah s. h. al-adawi department of behavioral medicine, college of medicine & health sciences, sultan qaboos university email: sara93916@hotmail.com references 1. al-dabal bk, koura mr, rasheed p, al-sowielem l, makki sm. a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia. squ med j 2010; 10:231–40. 2. al-lamki l. stress in the medical profession and its roots in medical school. squ med j 2010; 10:156–9. 3. ahmed i, banu h, al-fageer r, al-suwaidi r. cognitive emotions: depression and anxiety in medical students and staff. j crit care 2009; 24:e1–7. 4. al-saleh sa, al-madi em, al-angari ns, al-shehri ha, shukri mm. survey of perceived stress-inducing problems among dental students, saudi arabia. saudi dent j 2010; 22:83–8. 5. dwairy m. foundations of psychosocial dynamic personality theory of collective people. clin psychol rev 2002; 22:343–60. 6. aziz a, vallejo d. an exploratory study of the facets of type a personality and scores on the machiavellian behavior (mach-b) scale. psychol rep 2007; 101:555 –60. 7. gillett mpt, bayoumi, ra. teaching gulf medical students about chemical solutions by means of problem-solving laboratory practicals. biochem educ 1998; 26:126–9. department of dermatology, school of medicine, university of california san diego, la jolla, california, usa author’s e-mail: mitehead@gmail.com حديبة دارون فيليب كوهني darwin’s tubercle philip r. cohen a healthy 47-year-old man presented to the dermatology office of the university of california san diego, la jolla, california, usa, in 2017 for a complete examination of his skin. on the posterior-superior helix of his left ear, an asymptomatic firm elastotic triangular prominence of skin-covered cartilage was observed, measuring 10 x 10 x 22 mm [figures 1a and b]. in addition, there was a cutaneous pit in the left preauricular area [figure 1c]. a similar yet less pronounced helical tubercle was also present on his right ear. the patient had no family history of auditory or renal impairment. comment darwin’s tubercle is a benign and unique helical feature that often appears as a solitary peculiarity on the ear but can also present bilaterally on both ears.1 while the condition requires no additional evaluation or treatment, surgical treatment—consisting of a full thickness excision of the skin and the prominent cartilage underneath—may be considered in order to address cosmetic concerns. in addition to darwin’s tubercle, other peculiarities of the helix include pointy ear, satyr ear and stahl’s ear deformity.1,2 although darwin’s tubercle usually occurs alone, it has been associated with accessory tragus, congenital absence of the helix and weathering nodules.1,2 isolated preauricular pits are a congenital anomaly with an incidence of 5–10 cases per 1,000 newborns.3 according to recent research, hearing tests or a urin alysis are not recommended for patients with preauricular pits unless the individual has an associated syndrome or a family history of auditory or renal impairment.3,4 therefore, the current patient did not require any additional evaluation or treatment of his preauricular pit. darwin’s tubercles contribute to the individuality of human ears and may have applications in the fields of personal identification or forensic sciences.1 the presence of darwin’s tubercle has not been associated with any significant adverse clinical consequences or systemic anomalies, including chondrodermatitis or hearing and urinary anomalies. the concurrent presence of darwin’s tubercle and a preauricular pit of the ipsilateral ear, such as that observed in the present case, may represent a coincidental occurrence rather than an association between the two conditions. interesting medical image sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e112–113, epub. 4 apr 18 submitted 22 oct 17 revision req. 21 nov 17; revision recd. 26 nov 17 accepted 30 nov 17 figure 1: photographs of the left ear of a 47-year-old man showing (a) a darwin’s tubercle presenting as (b) a prominence of the posterior-superior helix (arrows). in addition, (c) a preauricular pit (asterisk) was observed. doi: 10.18295/squmj.2018.18.01.021 philip r. cohen interesting medical image | e113 3. firat y, sireci s, yakinci c, akarçay m, karakaş hm, firat ak, et al. isolated preauricular pits and tags: is it necessary to investigate renal abnormalities and hearing impairment? eur arch otorhinolaryngol 2008; 265:1057−60. doi: 10.1007/s004 05-008-0595-y. 4. kugelman a, hadad b, ben-david j, podoshin l, borochowitz z, bader d. preauricular tags and pits in the newborn: the role of hearing tests. acta paediatr 1997; 86:170−2. doi: 10.1111/ j.1651-2227.1997.tb08860.x. references 1. loh ty, cohen pr. darwin’s tubercle: review of a unique congenital anomaly. dermatol ther (heidelb) 2016; 6:143−9. doi: 10.1007/s13555-016-0109-6. 2. lykoudis eg, seretis k, spyropoulou ga. a 6-year experience in flat helix correction with a simple procedure. arch facial plast surg 2011; 13:168−72. doi: 10.1001/archfacial.2011.31. https://doi.org/10.1007/s00405-008-0595-y https://doi.org/10.1007/s00405-008-0595-y https://doi.org/10.1111/j.1651-2227.1997.tb08860.x https://doi.org/10.1111/j.1651-2227.1997.tb08860.x https://doi.org/10.1007/s13555-016-0109-6 https://doi.org/10.1001/archfacial.2011.31 squ med j, december 2009, vol. 9, iss. 3, pp. 247-256, epub. 19th dec 2009 submitted 20th jan 09 revision req. 19th aug 09, revision recd. 27th sept 09 accepted 12th oct 09 children are not miniature adults so there are differences between childhood and adult onset uveitis. special considerations and modifications are required in our approach to dealing with childhood uveitis. the most common aetiologies, the disease presentation, clinical course and outcome are quite different in children compared to adults. in general, idiopathic uveitis is the most common cause of uveitis; however, the most common identifiable cause of uveitis in adults and children varies. in adults, the most common identifiable cause of uveitis is hla-b27 associated spondyloarthropathy, while in children the most common identifiable cause is juvenile idiopathic arthritis. similarly, the clinical presentation is quite different between the two. in adults, the most common presentation of uveitis is an acutely painful red eye, while in children it is chronic, bilateral persistent uveitis and can be completely asymptomatic; therefore, the diagnosis of uveitis is often delayed in children because it goes unrecognised or misdiagnosed. another major difference between children and adults is that the prognosis of uveitis is usually worse in children, with up to 35% of children experiencing complications such as posterior synechiae, cataract, band keratopathy, glaucoma and visual impairment. similarly, even when complications, such as glaucoma, develop secondary to uveitis in both adults and children, they tend to be more severe in children than in adults.1 another special consideration in children with chronic uveitis, which adds to the diagnostic and therapeutic challenges, is the unique clinical presentations of the disease in children, such as leukocoria, strabismus, or difficulty with routine activities at home or at school. similarly, children have unique complications due to uveitis that are not seen in adults, such as the risk of developing amylopia and strabismus. another challenge in children is the difficulty of routine examination. complete examination is essential department of child health, sultan qaboos university hospital, muscat, sultanate of oman email: reemabd@hotmail.com حتديات الِْتهاب الِعَنِبيَّة يف الطفولة رمي عبدواني هو املعدي غير املزمن الِعَنِبيَّة اللِْتهاُب انتشارا األكثر السبب البصر. سالمة يهدد أن ميكن لكنه نادر مرض املزمن الِعَنِبيَّة الِْتهاُب امللخص: ذلك إن إذ هنا، سنناقشه ما وهذا الِعَنِبيَّة الِْتهاُب يصاحبها أن ميكن الطفولة في اجلسم أجهزة أمراض السبب. بعض معروف غير االلتهاب يستحق عناية خاصة. الفروقات الفريدة في األطفال مت توضيحها مع اعتبارات هامة في التحديات التي حتصل في التشخيص والعالج. بينما تبقى الستيرويدات القشرية الدعامة األساسية في العالج األولي، لكن هناك عدد كبير من العوامل الكابتة للمناعة استعملت مع جناحات متفاوتة. مت مراجعة دور بعض العوامل مثل امليثوتركسيت والسايكلوسبورين وبعض العوامل احليوية اجلديدة مثل ايتانسيبت وانفليكسيماب واديلموماب. ميكن احلصول على نتائج ناجحة بواسطة العالج بالعوامل الكابتة للمناعة عندما تعطى في بداية املرض، ولو أن القضية بحاجة إلى دراسات سريرية ملعرفة وحتديد فعالية هذه اإلستراتيجية. مفتاح الكلمات: الِْتهاُب الِعَنِبيَّة، العالج. abstract: chronic uveitis is a rare, but potentially sight-threatening disease. the most common cause of chronic non-infectious uveitis is “idiopathic uveitis”. however, some systemic diseases are associated with chronic uveitis in children and are discussed. chronic uveitis merits special consideration in children. the unique differences in children are highlighted with special consideration for the diagnostic and therapeutic challenges encountered in their management. while corticosteroids remain the mainstay of initial therapy, a wide range of immunosuppressive agents have been used with variable success. the role of immonomodulatory agents such as methotrexate, cyclosproin and some of the new biologic agents such as etanecept, infliximab, adalimumab are reviewed. successful outcomes may be achieved with appropriate immunosuppressant therapy when given early in the disease, although clinical trials are required to define the true efficacy of this strategy. keywords: uveitis; treatment review challenges of childhood uveitis reem abdwani challenges of childhood uveitis 248 | squ medical journal, december 2009, volume 9, issue 3 and often requires examination under anaesthesia. additionally, children are more vulnerable than adults and have different sides effects to systemic therapy such as corticosteroid-induced growth retardation in prepubescent children and an increased tendency for corticosteroids to induce ocular hypertension and cataracts.2 definition and classification of uveitis uveitis is inflammation of the uvea, the middle coat of the eye that is sandwiched between the sclera and retina. the ophthalmologist is uniquely placed to observe directly the amount of inflammation and measure the eye’s ability to function (visual acuity and visual field). clinically, the patient could present with pain, redness, headache, photophobia and change in vision. however, the patient can also be entirely asymptomatic in cases of chronic uveitis. uveitis is classified according to different categories. the classification of uveitis can be based on anatomical location as recommended by the international uveitis study group (iusg).1 anterior uveitis refers to inflammation of the anterior chamber including iritis, iridocyclitis, and anterior cyclitis. intermediate uveitis involves the vitreous including pars planitis, posterior cyclitis and hyalitis, while posterior retinitis involves the retina and choroids including choroiditis, chorioretinitis and neuroretinitis. the term panuveitis describes a uveitis that involves the anterior chamber, the retina and the choroids. uveitis can also be classified as acute, recurrent or chronic based on the onset and duration of inflammation. in addition, uveitis can be classified as either infectious or non-infectious in aetiology and by the presence or absence of any systemic disease. epidemiology uveitis commonly affects young adults; however, it occurs in all age groups from children to the elderly. in general, uveitis is an uncommon disease with an annual incidence of 17-52/100,000 population.2,3 in children, uveitis is rare with an annual incidence of 4-7/100,000 children/year.4,5 children constitute 5-10% of all cases of uveitis seen in many tertiary centres,6 but more recently a higher percentage (33%) of childhood uveitis has been reported.7 a recent study of the prevalence of uveitis in an urban population in south india, found evidence of either past or active uveitis in 1 out of 140 people in the population, suggesting that the prevalence of uveitis may be of higher magnitude in developing than in developed nations.8 aetiology of uveitis there is a wide range of differential diagnoses in uveitis. the role of the physician is to make sure that the patient does not have an infectious cause of uveitis before considering a systemic non-infectious cause. table 1 lists bacterial, viral, spirochetal, fungal and parasitic causes of uveitis. in children, it is also very important to rule out masquerading syndromes that may mimic uveitis such as malignancies, leukaemia, lymphoma or neuroblastoma. once infectious and masquerading syndromes have been excluded, one can then consider non-infectious systemic conditions [table 2]. however, the most common cause of uveitis in both adults and children still remains “idiopathic uveitis”.3 given the diversity of differential diagnoses, there table 1: infectious causes of uveitis bacterial viral fungal parasitic tuberculosis cytomegalovirus aspergillosis toxocariasis atypical mycobacteria epstein-barr blastomycosis toxoplasmosis brucellosis herpes simplex candidiasis pneumocystis carinii syphilis herpes zoster coccidioidomycosis lyme disease herpes zoster cryptococosis cat scratch disease mumps histoplasmosis rubeola hiv reem abdwani review | 249 is no recommended routine battery of investigations for the work-up of uveitis. the most helpful test in raising the diagnostic probability is a proper history and physical examination. in children, the history is often limited; therefore, information obtained from parents is valuable. similarly, examination may be difficult due to poor cooperation from the child and subtle ocular findings so examination under anesthaesia may be necessary to complete the assessment. appropriate investigations need to be tailored to individual cases, depending upon the history and physical examination findings, in order to support the clinical suspicion. systemic inflammatory non-infectious causes of uveitis uveitis can occur as a manifestation in many systemic diseases [table 2]. some of these systemic diseases occurring in the paediatric age group will be discussed. j u v e n i l e i d i o pat h i c a r t h r i t i s (j i a) jia is defined as chronic arthritis of unknown aetiology occurring before the age of 16 years and lasting at least six weeks. the international league against rheumatism (ilar) classification of jia includes seven subtypes:systemic onset jia, oligoarticular jia, polyarticular rheumatoid factor (rf) positive and negative jia, enthesitis-related arthritis, juvenile psoriatric arthritis and unclassified jia.9 the uveitis affecting children with jia is predominantly bilateral chronic anterior, nongranulomatous uveitis. it is important to note that, although the disease can cause macular oedema as a complication, the presence of features of posterior uveitis (choroidal infiltrate, retinitis, retinal vasculaitis) is not consistent with the diagnosis of jia associated uveitis; if found, an alternative diagnosis should be considered. jia associated uveitis is especially common in young girls who have oligoarticular jia, present with early disease onset and are anti-nuclear antibody (ana) seropositive.10 in patients with oligoarticular jia, uveitis is observed in 16-40% of cases, while in rf negative polyarticular jia, uveitis is observed in 5-24% of cases and in 2-23% of patients with psoriatic arthritis; however, uveitis is uncommon in rf positive polyarticular jia and in systemic onset jia.11-14 uveitis precedes arthritis in 10% of cases; however, most children develop uveitis within 4 to 7 years of the onset of arthritis, although the risk is never entirely absent.15 the onset is often entirely asymptomatic in chronic uveitis; therefore, early detection by slit lamp examination should be performed at the time of diagnosis in every child with uveitis and repeated at regular intervals as suggested by the american academy of pediatrics [table 3].16 b e h ç e t’s d i s e a s e behçet’s disease (bd) is a multisystem inflammatory disorder characterised by a triad of recurrent oral ulcers, genital ulcers and uveitis; but many systems may be involved including the skin, joints, central nervous system and gastrointestinal tract, with vascular inflammation predisposing to thrombosis as a prominent feature. in asian and middle eastern populations, in whom the disease is most prevalent, hla-b51 is a marker for bd. ocular involvement occurs in 30-61% of children with bd.17-19 it is typically bilaterally episodic, involves the entire uveal tract (panuveitis), and may not resolve completely between episodes. hypopyon, table 2: systemic inflammatory non-infectious causes of uveitis chronic inflammatory diseases juvenile idiopathic arthritis reactive arthritis ulcerative colitis crohn’s disease systemic connective tissue diseases systemic lupus erythematosus sjögren’s syndrome systemic vasculitis behçet’s disease sarcoidosis wegener’s granulomatosis polyarteritis nodosa kawasaki disease relapsing polychondritis others tubulointerstitial nephritis uveitis syndrome blau syndrome vogt-koyanagi-harada syndrome challenges of childhood uveitis 250 | squ medical journal, december 2009, volume 9, issue 3 a severe anterior uveitis with purulent material in the anterior chamber, is characteristically seen in patients with behçet’s disease. other ocular involvement includes retinal vasculitis and optic neuritis. in bd uveitis there is high frequency of blindness in untreated patients. s a r c o i d o s i s sarcoidosis is a multisystem disorder characterised pathologically by the presence of noncaseating granulomas in the involved organs. two subsets of paediatric sarcoidosis are identified. the 8-15 year old group develops disease similar to adults, characterised by pulmonary reticular opacities, and hilar lymphadenopathy with skin, joint or eye involvement. younger children, however, are characterised by a triad of skin rash, arthritis and uveitis without apparent lung involvement or lymphadenopathy. uveitis may be more common in early onset disease than in the later onset disease. in children in the 8-15 year old group, 32% had ocular disease,20 while in the early onset sarcoidosis 77% of children had ocular disease.21 ocular involvement in sarcoidosis, unlike jia, can involve all segments of the eye including anterior uveitis, posterior uveitis, retinal vasculitis and kerato-conjunctivitis. in addition, extraocular orbital tissue involvement can occur, affecting the lacrimal glands, extraocular muscles and optic nerve sheath, and may present as a soft tissue orbital mass. anterior uveitis is the most common paediatric ocular involvement in sarcoidosis.22 b l a u s y n d r o m e blau syndrome (bs) is a multisystem granulomatous disease. bs and early onset sarcoidosis are now believed to belong to the same disease spectrum. bs represents a familial autosomal dominant form while early onset sarcoidosis represents a sporadic form. it is characterised by inflammation of the skin, eye and joints, with a typical onset before 5 years. both bs and early onset sarcoidosis are associated with mutations in the gene encoding nod2/card15 located on chromosome 16.23 diagnosis may be confirmed through skin, synovial or conjunctival biopsy as well as by genetic testing. t u b u l o i n t e r s t i t i a l n e p h r i t i s a n d u v e i t i s s y n d r o m e tubulointerstitial nephritis and uveitis syndrome (tinu) is a rare oculo-inflammatory disease which is comprised of acute idiopathic tubulointerstitial nephritis and uveitis. tinu may be associated with other systemic findings including fever, weight loss, fatigue, malaise, anorexia, arthralgia, myalgia and headache. uveitis is predominantly anterior although posterior uveitis can occur. uveitis is typically bilateral, although unilateral or alternating uveitis has been observed. tinu occurs in all age spectrums, but most commonly in adolescent females with favorable prognosis.24 nephritis tends to be self-limiting, whereas uveitis tends to relapse and recurrences tend to be more severe than the initial uveitis. therefore, routine careful ophthalmologic examinations are required to prevent secondary ocular complications. v o g t-k o ya n a g i-h a r a d a s y n d r o m e vogt-koyanagi-harada (vkh) syndrome is a rare systemic disease involving various melanocytecontaining organs. this syndrome is characterised by bilateral granulomatous panuveitis associated table 3: guidelines for ophthalmologic screening in juvenile idiopathic arthritis (jia) jia sub-type age < 7 years at onset age >7 years at onset oligoarticular jia + ana ana h m m m polyarticular jia + ana ana h m m m systemic jia l l legend: ana = anti-nuclear antibody; h = high risk (ophthalmologic exam every 3 months); m = medium risk (ophthalmologic exam every 6 months); l = low risk (ophthalmologic exam every 12 months) reem abdwani review | 251 with a variety of extra-ocular manifestations including central nervous system, auditory and integumentary system involvement. vkh syndrome is an immune-mediated disease. the mechanism of the disease is thought to be a t helper cell mediated autoimmune attack of melanocytes in the skin, uvea, central nervous system and inner ear. the american uveitis society has recommended that at least three of the following four criteria be met to confirm the diagnosis of vkh syndrome: 1) bilateral iridocyclitis; 2) posterior uveitis; 3) cerebrospinal fluid (csf) pleocytosis or evidence of tinnitus, dysacusis, headache or meningismus, or cranial nerve involvement and 4) cutaneous findings of vitiligo, alopecia, or poliosis. vkh associated uveitis tends to be more aggressive in children than in adults.25 local treatment of uveitis treatment of uveitis in children is challenging. the outcome of uveitis is often poor with up to 35% of children with uveitis left with vision loss as a result of complications.6 there are a number of reasons that lead to the poor outcome of uveitis in children including: 1) delay in diagnosis, as the majority of paediatric patients are practically asymptomatic; 2) a more severe and aggressive course than in adults; 3) poor compliance with therapy. another reason that makes effective treatment challenging is that there are only limited numbers of randomised controlled clinical trials that can guide therapy in paediatric uveitis based on evidence-based practice. most of the paediatric literature in the treatment of systemic diseases associated with uveitis is based on small retrospective case series. treatment with immunosuppressive agents should be initiated once infectious and masquerading causes have been excluded and in conjunction with a paediatric rheumatologist who has experience in prescribing and in monitoring for drug toxicity. treatment is often initiated by an ophthalmologist once the diagnosis of uveitis is made. regardless of the cause, initial treatment of anterior uveitis begins with corticosteroids eye drops that effectively penetrate the cornea and have a highly potent anti-inflammatory effect. prednisolone actetate 1% is often the drug of choice. frequency of administration, which could be up to hourly administration, depends on the intensity of the inflammatory reaction; however, frequency is tapered once the inflammation improves. careful and frequent review is necessary to avoid excessive use of topical steroids which increases the risk of medication-related side-effects including glaucoma, cataract and increased susceptibility to eye infections, including reactivation of latent herpetic infections. similarly, early withdrawal of topical corticosteroids may lead to rebound ocular inflammation. in addition to topical corticosteroids, a topical mydriatic agent such as 1% cyclopentolate is often initiated in the treatment of uveitis. this gives rapid relief of pain that may be caused by uveal smooth muscle spasm and may prevent the formation of synechia. periocular injections of steroids can be considered in patients with intermediate and posterior uveitis to achieve rapid quiescence of inflammation as part of the shortterm management to prevent disease exacerbation. following local treatment for uveitis (corticosteroids and mydriatic agents) therapy should be escalated in the following circumstances: 1) the uveitis is refractory to treatment with topical steroids; 2) the requirement of unacceptably high doses of steroids for a prolonged period to control uveitis; 3) the development of unacceptable side-effects. in these situations, the introduction of immunosuppressive agents is warranted. the current trend is for earlier and more aggressive use of immunosuppressive agents. the traditional approach of waiting until vision drops or complications develop before beginning immunmodulatory therapy is no longer considered appropriate. systemic treatment of uveitis s y s t e m i c c o r t i c o s t e r o i d s glucocorticoids (oral/parenteral route) are the most potent anti-inflammatory agents. the dose of steroids needed to control inflammation varies according to extent of uveitis. it may be as low as 2-4mg/day and as high as requiring pulses of methylprednisolone 30mg/kg/day. glucocorticoids are very effective in achieving a very rapid control over inflammation; however, their side-effects make them our foe. some of these include cushing’s syndrome, growth suppression, osteoporosis, challenges of childhood uveitis 252 | squ medical journal, december 2009, volume 9, issue 3 avascular necrosis, hypertension, myopathy, increased risk of infection, glucose intolerance and adrenal crisis. due to the severity of potential sideeffects of glucocorticoids, other immunosuppressive agents have been used for the treatment of uveitis. m e t h o t r e x at e methotrexate is one of the most commonly used immunosuppressive agents due to its low cost and well-known safety profile. its once weekly dose enables increased compliance. the general recommended dose for methotrexate in the paediatric age group is 10-25 mg/m² given orally or parenterally. it is generally well-tolerated; however, some of the most encountered side-effects include gastrointestinal toxicity in the form of nausea, vomiting and abdominal pain. switching the route of administration of the drug from the oral to the parenteral route as well as folic acid supplementation may help overcome the gastrointestinal toxicity. other side-effects include mucositis, increased risk of opportunistic infections, haematologic toxicity (pancytopenia), hepatic toxicity and interstitial pneumonitis. concern about methotrexate’s teratogenic effect is considered in the later stages of life. recommended routine laboratory monitoring for methotrexate toxicity includes complete blood count and liver function tests at 4-6 weekly intervals. some of the main reasons for the elevated liver enzymes on routine screening are the drawing of blood within two days of taking the medication or the presence of an intercurrent viral illness. generally speaking, liver enzymes normalise with a decrease in the methotrexate dose or transient discontinuation. a number of studies have demonstrated the effective use of methotrexate in the treatment of paediatric uveitis due to a variety of systemic inflammatory conditions.26-29 heiligenhaus et al. treated 35 patients with jia with methotrexate for an associated anterior uveitis.26 a total of 71% of patients were able to achieve remission with methotrexate alone, while 20% of patients required the addition of another immunosuppressive agent to achieve quiescence of uveitis. shetty et al. successfully used methotrexate in the treatment of uveitis associated with sarcoidosis in two children.27 soheilian et al. treated ten patients with paediatric vhk-associated panuveitis with oral prednisolone with methotrexate being added for six refractory patients. in all the eyes of these patients, inflammation decreased and vision was preserved or improved.28 similarly, methotrexate has been found to be effective in the treatment of tinu syndrome.29 c y c l o s p o r i n e cyclosporine (csa) is a fungal analogue that inhibits t-cell activity by inhibiting the translocation of a family of transcription factors leading to reduced transcriptional activation of several cytokines including il-2 il-3, il-4, g-csf, and interferongamma. the usual dose for csa for the treatment of uveitis is 3-5mg/kg. some of the common side effects of csa include impaired renal function, hypertension, hepatic toxicity, gum hyperplasia and hypertrichosis. another serious complication includes neurotoxicity in the form of headaches, parasthaesia and seizures. concomitant use of non-steroidal antiinflammatory drugs may exacerbate these toxic effects. it is important to monitor closely for renal toxicity that can occur at the initiation of therapy. the recommendation is to monitor for drug toxicity by monitoring blood pressure and carrying out a renal function test biweekly at the start of the treatment and then on a monthly basis. a rise in serum creatinine of 30%, despite being in the normal reference creatinine range, is considered to be significant and merits dose reduction. complete blood count and liver function tests should be monitored on a monthly basis as well. there are many controversial studies in the literature on the efficacy of csa in the treatment of chronic uveitis in children. kilmartin et al. used low dose csa in the treatment of refractory noninfectious uveitis in 14 patients (n = 25 eyes) for a mean duration of 20.9 months (range 3.5-88.3 months). in their cohort of patients, visual acuity improved or was maintained in 92% of eyes and the binocular indirect ophthalmoscopy (bio) score improved in 75% of eyes, indicating that csa is safe and effective in the treatment of refractory non-infectious uveitis in childhood.30 however, the results of both walton et al. and tappeiner et al. did not support the effective use of csa in the treatment of chronic uveitis in children.31,32 walton et al. treated 15 children with chronic uveitis using higher doses of csa in combination with prednisolone. after 4 years of treatment, 4 patients discontinued reem abdwani review | 253 medication as they were in remission, 2 patients discontinued medication due to treatment failure or side-effects and 9 patients continued to be on csa with ongoing median vitreous inflammation of 0.5. tappeiner et al. used low dose csa in 82 children with jia associated chronic uveitis. when csa was used as a monotherapy, the uveitis became inactive in 24% of cases. however, when csa was used in combination with other immunosuppressive agents for the treatment of uveitis, inactivity occurred in 48.6% (p = 0.037). pre-existing cystoid macular oedema did not resolve under csa treatment in any of the patients. csa was discontinued in 11% of cases due to systemic side-effects. tappeiner et al. concluded that csa has limited value in the treatment of jia associated uveitis. there are other immunosuppressive agents like azathioprin, mycophenolate mofetil and cyclophosphomide that are used in other types of paediatric inflammatory disease and have been used in the treatment of uveitis in children. however, there is scant published data on the use of these agents in the paediatric literature. b i o l o g i c a g e n t s biologic agents have successfully been introduced in the treatment of many autoimmune conditions including uveitis. tumour necrosis factor (tnf) alpha is persistently elevated in the aqueous humour and in the peripheral blood in patients with chronic uveitis.33 this cytokine is thought to participate actively in the pathogenesis of the inflammatory process in uveitis; however, its role is still unclear. there are three different types of anti-tnf antagonists which include etanercept, infliximab, and adalimumab. one has to be aware of the problems associated with the use of these agents, some of which include an increased risk of developing opportunistic infections, malignancy and demyelinating diseases.34 etanercept, a soluble tnf receptor, is a fusion protein made up of two recombinant p75-soluble receptors fused with the fc fragment from human igg. the fc fragment is added to prolong its halflife. it is administered subcutaneously at a dose of 0.4mg/kg twice weekly. no spectacular successes have been reported in the literature on the use of etanercept in the treatment of uveitis. smith et al. reported a worsening of anterior uveitis and the development of a new onset of scleritis in patients, even though the systemic inflammatory disease was brought under control.35 similarly, foster et al. found no difference in the relapse rate and the final visual acuity in a randomised double-blinded placebo controlled trial using etanercept in the treatment of chronic uveitis in 20 children.36 although reiff et al. notice marked significant improvement of uveitis within 3 months in 10 children with jia associated uveitis, on follow-up only 4 patients had a sustained response.37 infliximab is a chimeric monoclonocal antibody; the term “chimeric” refers to the use of both murine and human components in the drug. it blocks the action of the pro-inflammatory tnf alpha by binding to it and preventing it from signalling the receptors on the surface of cells. the results have been more promising with infliximab than with etanercept. saurenmann et al. treated 21 children with chronic uveitis with the anti-tnf agents etanercept (n = 11) and infliximab (n = 13) resulting in 24 treatment courses.38 the response to etanercept treatment was good in 27%, moderate in 27% and poor in 45% of the patients, whereas the response to infliximab treatment was good in 38%, moderate in 54% and poor in 8% of patients. the difference in the percentage of patients with a moderate or good response was statistically significant (p = 0.0481). a lower rate of complications was observed in the infliximab-treated group. similarly, galor et al. performed a retrospective analysis on 22 patients treated with anti-tnf therapy, comparing the effectiveness of etanercept versus infliximab in the treatment of ocular inflammation.39 they reported a statistically significant difference in the reduction of the inflammation recurrence rate, topical steroid use and treatment response in patients treated with infliximab compared to those treated with etanercept. whilst there was an initial response in patients treated with etanercept, all eventually required a change in medication to control inflammation. adalimumab is a fully human monoclonal antibody that binds to tnfα, preventing it from activating tnf receptors and therefore down regulates inflammatory reactions. the results in the literature on the treatment of chronic uveitis in children with adalimumab have been encouraging even in patients who are non-responsive to other anti-tnf agents. biester et al. described an improvement of uveitis in 88% of the patients challenges of childhood uveitis 254 | squ medical journal, december 2009, volume 9, issue 3 when their response was based on the number of relapses.40 vazquez-cobian et al. showed improved activity in 81% of the eyes.41 in another retrospective observational study of 20 patients with jia associated chronic uveitis treated with adalimumab, 35% of patients showed improved ocular inflammation especially in patients who were younger and had shorter disease duration.42 differences in patient characteristics and response criteria may explain the lower rate of favorable outcomes in the last study compared with previous studies. there is also favorable evidence that supports switching biologic agents when there is loss of initial clinical response to one biological agent (infliximab or adalimumab). switching biologic agents can restore control of intraocular inflammation. in addition, switching helps to control systemic symptoms and allows ease of administration.43 daclizumab is a recombinant humanised immunoglobulin g monoclocal antibody that acts as an il-2 receptor antagonist. il-2 receptors are expressed on activated t-cell surfaces during inflammation, antagonising the receptor and preventing t-cell proliferation and differentiation. in a recent open-label prospective study, 6 patients with jia associated uveitis were treated with high dose intravenous daclizumab for 52 weeks. four of the 6 participants achieved two-step reduction in anterior chamber cells according to the standardization of uveitis nomenclature working group grading scheme for anterior chamber cells 12 weeks into the study and met the primary efficacy endpoint. one additional patient responded to reinduction, whereas one patient failed reinduction and was considered an ocular treatment failure.44 in the literature on adults, daclizumab appears to be relatively well tolerated and may be promising in the treatment of ocular inflammatory disorders.45,46 interferon (alpha) is a cytokine that disrupts viral replication, prevents tumour growth, acts against tolerance inducers of autoimmune disease and has an antiproliferative and apoptotic effect on t-cells. in inflammatory eye disease, interferon (alpha) has been mainly used in the treatment of uveitis associated with behçet’s disease.47,48 in the paediatric literature, there is one report of its use in children with uveitis: a retrospective study of 7 children with corticodependent uveitis of behcet’s disease who were treated with interferon (alpha). a remarkable corticosparing effect with remission maintenance was achieved in five out of seven patients. the remission was sustained in four of the five patients even after interferon was discontinued in three of them. the other patient relapsed 1.5 yrs after the discontinuation of interferon. two patients faced early severe adverse events: thrombosis and major depression.49 other biologic therapies that are used in the treatment of rheumatic diseases are rituximab (anti-b cell therapy), and alemtuzumab, a humanised monoclonal antibody that acts against the pan-lymphocyte antigen cd52, anti-interleukin 6 antibodies and anti-cytotoxic t-lymphocyte associated antigens (ctla-4). the use of these agents in the treatment of ocular inflammatory conditions is still being explored. besides medical treatment, surgery has a prominent role in the management of complications secondary to chronic uveitis such as cataract, glaucoma, and vitroretinal problems. surgical interventions are complicated and beyond the scope of this review. conclusion there are many diagnostic and therapeutic challenges that we need to overcome when dealing with children with chronic uveitis. a close relationship should be fostered between paediatricians, paediatric rheumatologists and ophthalmologists for the effective monitoring of these patients who have multiple medical, surgical and refractive needs. the longer the uveitis is under treated, the worse seem to be the complications in frequency and severity. given the relatively poor prognosis, early and aggressive treatment with immunosuppressive agents and, in more severe cases, biologic agents is advocated. experience in treating adult uveitis cannot necessarily be extrapolated to paediatric uveitis. given the rarity of the disease, multi-centred randomised controlled trials are required to determine the long term efficacy, safety and optimal dosing of various therapeutic agents in children. references 1. kanski jj, shun-shin ga. systemic uveitis syndromes in childhood: an analysis of 340 cases. ophthalmology 1984;91:1247 2. emmett t, cuuningham jr. uveitis in children. reem abdwani review | 255 occular immunology and inflammation. 2000; 8:25261. 3. bloch-michel e, nussenblatt rb. international uveitis study group recommendations for the evaluation of intraocular inflammatory disease. am j ophthalmol 1987; 103:234-5. 4. darrell rw, wagener hp, kurland lt. epidemiology of uveitis: incidence and prevalence in a small urban community. arch ophthalmol 1962; 68:502-14. 5. gritz dc, wong ig. incidence and prevalence of uveitis in northern california; the northern california epidemiology of uveitis study. ophthalmol 2004; 111:491-500. 6. edelsten c, reddy ma, stanford mr, graham em. visual loss associated with pediatric uveitis in english primary and referral centers. am j ophthal 2003; 135:676-80. 7. paivonsalo-hietanen t, tuominen j, saari km. uveitis in children: population-based study in finland. acta ophthalmol scand 2000; 78:84-8. 8. pivetti-pezzi p. uveitis in children. eur j ophthalmol 1996; 6:293-8. 9. benezra d, cohen e, maftzir g. uveitis in children and adolescents. br j ophthalmol 2005; 89:444-8. 10. dandona l, dandona r, john rk, mccarty ca, rao gn. population based assessment of uveitis in an urban population in southern india. br j ophthalmol 2000; 84:706-9. 11. petty re, southwood tr, baum j. revision of the proposed classification criteria for juvenile idiopathic arthritis: durban 1997. j rheumatol 1998; 25:1991-4. 12. chylack lt jr. the ocular manifestations of juvenile rheumatoid arthritis. arthritis rheum 1997; 20:21723. 13. packham jc, hall ma. long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. rheumatology 2002; 41:1428-1435. 14. kanski jj. screening for uveitis in juvenile chronic arthritis. br j ophthalmol 1989; 73:225-8. 15. minden k, niewerth m, listing j, biedermann t, bollow m, schontube m, et al. long-term outcome in patients with juvenile idiopathic arthritis. arthritis rheum 2002; 46:2392-401. 16. saurenmann rk, levin av, feldman bm, rose jb, laxer rm, schneider r, et al. prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long term follow-up study. arthritis rheum 2007; 56:647-57. 17. grassi a, corona f, casellato a, carnelli v, bardare m. prevalence and outcome of juvenile idiopathic arthritis-associated uveitis and relation to articular disease. j rheumatology 2007; 24:1139-45. 18. american academy of pediatrics section on rheumatology and section on ophthalmology. guidelines for ophthalmologic examinations in children with juvenile rheumatoid arthritis. pediatrics 1993; 92:295-6. 19. bahabri sa, al-mazyed a, al-balaa s, el-ramahi l, al-dalaan a. juvenile behçet disease in arab children. clin exp rheumatol 1996; 14:331-5. 20. pivetti-pezzi p, accorinti m, abdulazaiz ma, la cava m, torella m, riso d. behçet’s disease in children. jpn j ophthalmom 1995; 39:309-14. 21. koné-paut i, yurdakul s, bahabri sa, shafae n, ozen s, özdogan h, et al. clinical features of behçet’s disease in children: an international collaborative study of 86 cases. j pediatr 1998; 132:721-5. 22. kendug el. the clinical picture of sarcoidosis in children: a review. pediatrics 1974; 54:289-92. 23. khan ja, hoover dl, giangiacomo j, singsen bh. orbital and childhood sarcoidosis. j pediatr ophthalmol strabismus 1986; 23:190-4. 24. hafner r, vogel p. sarcoidosis of early onset. a challenge for the pediatric rheumatologist. clin exp rheumatol 1993; 11:685-91. 25. miceli-richard c, lesage s, rybojad m, prieur am, manouvrier-hanu s, häfner r, et al. card15 mutations in blau syndrome. nature genet 2001; 29:19-20. 26. manderville jt, levinson rd, holland gn. the tubulointerstitial nephritis and uveitis syndrome. surb ophthalmol 2001; 46:195-08. 27. tabbara kf, chavis ps, freemann wr. vogtkoyanagi-harada syndrome in children compared to adults. acta ophthalmo scand 1998; 76:723-6. 28. heiligenhaus a, mingels a, heinz c, ganser g. methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication. eur j ophthalmol 2007; 17:743-8. 29. shetty ak, zganjar be, ellis gs jr, ludwig ih, gedalia a. low dose methotrexate in the treatment of severe juvenile rheumatoid arthritis and sarcoid iritis. j pediatric opthalmol strabismus 1999; 36:125-8. 30. soheilian m, aletaha m, yazdani s, dehghan mh, peyman ga. management of pediatric vogtkoyanagi-harada (vkh)-associated panuveitis. ocul immunol inflamm 2006; 14:91-8. 31. gion n, stavrou p, foster cs. immunomodulatory therapy for chronic tubulointerstitial nephritisassociated uveitis. am j ophthalmol 2000; 129:764-8. 32. kilmartin dj, forrester jv, dick ad. cyclosporin a therapy in refractory non-infectious childhood uveitis. br j ophthalmol 1998; 82:737-42. 33. walton rc, nussenblatt rb, whitcup sm. cyclosporine therapy for severe sight-threatening uveitis in children and adolescents. opthalmology 1998; 105:2028-34. challenges of childhood uveitis 256 | squ medical journal, december 2009, volume 9, issue 3 34. tappeiner c, roesel m, heinz c, michels h, ganser g, heiligenhaus a. limited value of cyclosporine a for the treatment of patients with uveitis associated with juvenile idiopathic arthritis. eye 2009; 23:1192-8. 35. lacomba ms, martin cm, galera jm, vidal ag, estevez ec, chamond rr, et al. aqueous humor and serum tumor necrosis factor ∞ in clinical uveitis. ophthalmic res 2001; 33:251-5. 36. leombruno jp, einarson tr, keystone ec. the safety of anti-tumor necrosis factor treatments in rheumatoid arthritis: meta and exposure adjusted pooled analyses of serious adverse events. ann rheum dis 2009; 68:1136-45. 37. smith jr, levinson rd, holland gn, jabs da, robinson mr, whitcup sm, et al. differential efficacy of tumour necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. arthritis rheum 2001; 45:252-7. 38. foster cs, tufail f, waheed nk, chu d, miserocchi e, baltatzis s, et al. efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. arch ophthalmol 2003; 121:437-40. 39. reiff a, takei s, sadeghi s, stout a, shaham b, bernstein b, et al. etanercept therapy in children with treatment-resistant uveitis. arthritis rheum 2001; 44:1411-15. 40. saurenmann rk, levin a, rose j, parker s, rabinovitch t, tyrrell p, et al. tumour necrosis factor inhibitors in the treatment of childhood uveitis. rheumatology 2006; 45:982-9. 41. galor a, perez vl, hammel jp, lowder cy. differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. ophthalmology 2006; 113:2317-23. 42. biester s, deuter c, michels h, haefner r, kuemmerle-deschner j, doycheva d, et al. adalimumab in the therapy of uveitis in childhood. br j ophthalmol 2007; 91:319-24. 43. vazquez-cobian lb, flynn t, lehman tj. adalimumab therapy for childhood uveitis. j pediatr 2006; 149:572-5. 44. tynjälä p, kotaniemi k, lindahl p, latva k, aalto k, honkanen v, et al. adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. rheumatology 2008; 47:339-44. 45. dhingra n, morgan j, dick ad. switching biologic agents for uveitis. eye 2009; 23:1868-70. 46. sen hn, levy-clarke g, faia lj, li z, yeh s, barron ks, et al. high-dose daclizumab for the treatment of juvenile idiopathic arthritis-associated active anterior uveitis. am j ophthalmol 2009 aug 5 [e-pub ahead of print]. 47. bhat p, castañeda-cervantes ra, doctor pp, foster cs. intravenous daclizumab for recalcitrant ocular inflammatory disease. graefes arch clin exp ophthalmol 2009; 247:687-92. 48. nussenblatt rb, peterson js, foster cs, rao na, see rf, letko e, et al. initial evaluation of subcutaneous daclizumab treatments for noninfectious uveitis: a multicenter noncomparative interventional case series. ophthalmology 2005; 112:764-70. 49. gueudry j, wechsler b, terrada c, gendron g, cassoux n, fardeau c, et al. long-term efficacy and safety of low-dose interferon alpha2a therapy in severe uveitis associated with behçet’s disease. am j ophthalmol 2008; 146:837-44. 50. kotter i, zierhut m, eckstein ak, vonthein r, ness t, gunaydin i, et al. human recombinant interferon alpha-2a for the treatment of behçet’s disease with sight-threatening posterior or panuveitis. br j ophthalmol 2003; 87:423-31. 51. guillaume-czitrom s, berger c, pajot c, bodaghi b, wechsler b, kone-paut i. efficacy and safety of interferon-alpha in the treatment of corticodependent uveitis of paediatric behçet’s disease. rheumatology (oxford) 2007; 46:1570-3. departments of 1maternal & child health and 3food science & nutrition, sultan qaboos university, muscat, oman; 2school of nursing, university of north carolina at chapel hill, chapel hill, usa *corresponding author’s e-mail: basma84@squ.edu.om أمناط احلياة احملددة للسمنة بني األطفال العمانيني با�صمة اليزيدية، ديان بريي، جيمي كرانديل، م�صطفى وايل abstract: objectives: this study aimed to examine the relationship between body mass index (bmi) z-scores and lifestyle-related factors including nutrition, physical activity, screen time and time spent sleeping in 6–10-year-old omani children. methods: this cross-sectional study included mother-child dyads that were recruited from five provinces in oman. children’s bmi measurements and questionnaires on nutrition intake, physical activity, screen time and time spent sleeping and a single-day dietary recall were collected. results: a total of 197 dyads were included in this study. the children's mean age was 7.7 ± 1.6 years and 53% were female. in this study, 17.4% of the children were classified as overweight or obese. no significant relationship was found between the children's bmi z-scores and nutrition intake, moderate-tovigorous physical activity time or screen time (p ≥0.05). increased time spent sleeping at night was positively associated with childhood obesity (p <0.05). conclusion: the relationship between obesity and caloric intake, physical activity and screen time among children younger than 10 years seems to be moderated by certain factors that need to be investigated. qualitative studies and questionnaires that are culturally sensitive are therefore needed. keywords: children; pediatric obesity; diet, food, and nutrition; physical activity; screen time; sleep; oman. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل اختبار العالقة بني الدرجات املعيارية ملوؤ�رش كتلة اجل�صم والعوامل املتعلقة بنمط احلياة مبا يف ذلك التغذية والن�صاط البدين ومدة اجللو�س اأمام ال�صا�صة والوقت الذي يتم ق�صاوؤه يف النوم عند الأطفال العمانيون يف عمر 10-6 �صنوات. الطريقة: ت�صمنت هذه الدرا�صة املقطعية ثنائيات من اأم وطفل من خم�س واليات يف �صلطنة ُعمان. مت جمع قيا�صات موؤ�رش كتلة اجل�صم لالأطفال وا�صتبيانات حول التغذية والن�صاط البدين ومدة اجللو�س اأمام ال�صا�صة والوقت الذي يق�صيه الطفل يف النوم وا�صرتجاع النظام الغذائي للطفل ليوم واحد. النتائج: مت ت�صمني ما جمموعه 197 ثنائي يف هذه الدرا�صة. كان متو�صط عمر الأطفال 1.6 ± 7.7 �صنة وكانت ن�صبة الإناث 53%. مت ت�صنيف %17.4 من الأطفال على اأنهم يعانون من زيادة الوزن اأو ال�صمنة يف هذه الدرا�صة. مل يتم العثور على عالقة ذات دللة اإح�صائية بني .)p ≤0.05( الدرجات املعيارية ملوؤ�رش كتلة ج�صم الأطفال وتناول الغذاء اأو مدة الن�صاط البدين املعتدل اإىل القوي اأو مدة اجللو�س اأمام ال�صا�صة ارتبطت الزيادة يف الوقت الذي يتم ق�صاوؤه يف النوم لياًل ارتباطا اإيجابيًا ب�صمنة الأطفال )p >0.05(. اخلال�صة: يبدو اأن العالقة بني ال�صمنة وتناول ال�صعرات احلرارية والن�صاط البدين ومدة اجللو�س اأمام ال�صا�صة بني الأطفال الذين تقل اأعمارهم عن 10 �صنوات تتاأثر ببع�س العوامل الأخرى التي حتتاج اإىل درا�صة. ولذلك، هناك حاجة اإىل بحوث نوعية وا�صتبيانات تراعي العتبارات الثقافية. الكلمات املفتاحية: اأطفال؛ �صمنة الأطفال؛ النظام الغذائي والغذاء والتغذية؛ ن�صاط بدين؛ وقت اأمام ال�صا�صة؛ نوم؛ ُعمان. lifestyle-related determinants of obesity among omani children *basma al yazeedi,1 diane c. berry,2 jamie crandell,2 mostafa waly3 clinical & basic research sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e279–286, epub. 5 oct 20 submitted 2 sep 19 revisions req. 29 oct, 25 dec 19 & 29 jan 20 revisions recd. 26 nov 19, 9 jan & 10 feb 20 accepted 12 feb 20 https://doi.org/10.18295/squmj.2020.20.03.006 advances in knowledge the relationships between obesity and caloric intake, time spent in moderate-to-vigorous physical activity and screen time among children younger than 10 years old are generally statistically weak, probably due to moderating factors. in oman, childhood obesity is associated with increased time spent sleeping. this study is the first to examine lifestyle-related determinants of obesity among omani children aged 6–10 years. application to patient care children should have regular health check-ups which include weight and height measurements. awareness of healthy nutrition intake needs to be emphasised for children and their families. a movement towards preventing and treating obesity among children needs to be initiated in oman. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. childhood obesity is a global public health concern. the worldwide prevalence of childhood obesity doubled from 1980–2013.1 in oman from 2012–2018, the rate of overweight and obesity increased from 3.5% to 4.2% among children in the first grade (i.e. 6–7 years), from 12.8% to 15% among children in the seventh grade (i.e. 12–13 years) and from 12.5% to 16.7% among children in the tenth grade (i.e. 15–16 years).2,3 in 2016, 32.3% of omani children aged 5–19 years old were overweight.4 childhood obesity increases children’s risk of developing prediabetes, type two diabetes and cardiovascular disease later in life.5 children with obesity are also vulnerable to peer neglect and https://creativecommons.org/licenses/by-nd/4.0/ lifestyle-related determinants of obesity among omani children e280 | squ medical journal, august 2020, volume 20, issue 3 rejection, attention-deficit hyperactivity disorder, anxiety and depression.6,7 obesity is a complex health problem; it has genetic attributes that are influenced by environmental factors.8 these environmental factors contributing to obesity are partly explained by the imbalance between energy intake and energy expenditure.9 when there is high energy intake and low energy expenditure, the resultant extra energy is stored in the body as adipose tissue.10 in oman, research of childhood obesity is limited. a recent study found that 9–10-year-old omani children with obesity had generally but not significantly (p >0.05) lower physical fitness levels compared to their non-obese counterparts.11 no other study from oman was found upon a search of the literature. it is well reported, nevertheless, that children with obesity have higher energy intake, lower physical activity levels and higher sedentary time (e.g. screen time) when compared to non-obese children.12,13 findings from gulf cooperation council (gcc) countries, excluding oman, contain inconsistent findings in regards to the association between childhood obesity and nutrition, physical activity and screen time.14 uncertainty persists about the influence of nutrition and physical activity patterns on childhood obesity, particularly in oman. middle childhood (i.e. 6–10 years) is an excellent age to deliver obesity-related programmes. healthy behaviours learned during middle childhood have more potential to support sustainable changes.15 prior to health promotion programmes, it is essential to understand the contributing factors to the obesity problem. therefore, this study aimed to examine the relationship between bmi z-scores and nutrition, physical activity, screen time and time spent sleeping in 6–10-year-old children in oman. methods using a cross-sectional research design, data were collected from december 11, 2017, to january 24, 2018. participants consisted of mother-child dyads and were recruited on a volunteer basis from five public schools, seven non-governmental community centres and six home visits in five omani provinces (al-seeb, bowsher, bidbid, nizwa and ibra). mothers who were omani, aged 18 years or older and possessed the ability to speak, read and write in arabic were included. omani children who were between 6–10 years old, had no chronic illness that restricted nutrition or physical activity and had no sibling(s) in the study were included. based on similar factors’ correlation findings from other studies’, calculations generated from the g-power programme resulted in a required minimum sample size for children-mother dyads of 193. this calculation resulted in an 80% power to detect a correlation as small as r = 0.2 or a cohen's d of 0.41. invitation messages were distributed to mothers through whatsapp messenger (facebook. inc., mountain view, california, usa) and letters were distributed to mothers via their children at school. trained and supervised research assistants collected all data. children’s anthropometric measurements were taken and mothers completed an arabiclanguage questionnaire for their children regarding nutrition, physical activity, screen time and time spent sleeping. in addition, a single-day dietary recall for children was collected. children’s weights were measured using a seca 877 class iii scale (seca gmbh & co. kg, hamburg, germany) to the nearest 0.1 kg. height was measured with a seca 213 portable stadiometer (seca gmbh & co. kg) to the nearest 0.1 cm. both height and weight were measured twice and averaged. the children’s bmi z-scores were calculated by computer and organised according to the world health organization growth charts for children aged 5–19 years: severely thin was defined as a z-score of less than −3, thin was defined as a z-score between −3 to −2, normal growth was defined as a z-score between −2 to 1, overweight was defined as a z-score between 1 to 2 and obese was defined as a z-score of greater than 2.16 the mothers completed a questionnaire adapted from the fish feeding study (ffs).17 the ffs questionnaire was developed in arabic by a team of researchers from the department of food science and nutrition, college of agricultural and marine sciences, sultan qaboos university, muscat, oman and tested for content validity, reliability (83%) and reproducibility among 100 omani children age 6–10 years old (unpublished data). for this study, the ffs questionnaire was modified slightly: four items related to fish and salt intake were removed and one item relating to the number of hours slept per day was added. permission to modify the tool was obtained from its developers. mothers were also asked about their children’s frequency of consumption of 22 different foods. the answer options were "daily", "weekly", "monthly", "occasionally" or "never". for the analysis, those options were categorised into “more frequent”, representing daily or weekly, and “less frequent” reflecting monthly, occasionally or never. physical activity was examined by asking about the frequency and duration of nine different moderate-to-vigorous physical activities (mvpa) the child completed in a week (e.g. riding basma al yazeedi, diane c. berry, jamie crandell and mostafa waly clinical and basic research | e281 a bicycle, jumping rope, etc.). mothers were also asked about the frequency and duration of their children’s activities involving screen time during a week, including watching television or videos, playing video games and using computers. questions about mvpa and screen time involved either ‘‘yes’’ or ‘‘no’’ answers as well as how many times per week the child engaged in the activity and the duration in minutes of each activity. sleep was examined by asking mothers about their child’s number of night-time sleep hours over a 24-hour period. the mothers could choose ‘‘less than nine hours’’, ‘‘nine to eleven hours’’ or ‘‘more than eleven hours,’’ which were based on the usa’s national sleep foundation’s categories for the number of nighttime sleep hours for children aged 6–11 years.18 for single-day dietary recall, the researchers used the automated self-administered 24-hour (asa24) dietary assessment tool (2016) developed by the united states national cancer institute which includes detailed questions about food preparation and portion sizes.19 the asa24 has adequate face validity for estimates of energy, nutrients and different food groups consumed.19 a previous study showed that 80% of items consumed were correctly reported in the asa24.20 bilingual english/arabic research assistants with backgrounds in nutrition science conducted the interviews with the children’s mothers.21 this approach addressed challenges related to english language proficiency and internet access.22 univariate analysis was used to examine each of the study variables by looking at descriptive statistics including mean ± standard deviation, range for continuous variables and frequency tables for categorical/dichotomous variables. several statistical tests including correlation, independent t-test, chi-square test, multiple linear regression and binary logistic regression were used to analyse the relationships between the study variables. multiple linear regression was used to predict the children’s bmi z-scores from a single-day nutrition intake. to avoid collinearity, three separate models were built. the children’s bmi z-scores were calculated based on energy intake, macronutrients (i.e. protein, fat, carbohydrates) and main food groups (i.e. grains, fruits, vegetables, protein and dairy) controlling for age and gender. additionally, a logistic regression model was run with the children’s weight status as table 1: omani children’s body mass index z-score means for frequency of consumption of soft and sugary drinks, addition of fat or butter, moderate-to-vigorous physical activity, screen time and time spent sleeping (n = 197) variable n* mean bmi z-score ± sd p value frequency of soft drink and sugary drink consumption 0.01 daily or weekly 104 −0.45 ± 1.37 monthly, occasionally or never 91 0.08 ± 1.51 frequency of addition of fat/butter 0.02 daily or weekly 131 −0.38 ± 1.48 monthly, occasionally or never 59 0.15 ± 1.41 mvpa in minutes /day 0.99 ≤60 76 −0.22 ± 1.46 <60 108 −0.22 ± 1.52 screen time in minutes /day 0.99 ≤120 156 −0.21 ± 1.50 >120 30 −0.22 ± 1.51 time spent sleeping at night in hours/day 0.12 <9 49 −0.50 ± 1.39 ≤9 147 −0.12 ± 1.49 bmi = body mass index; sd = standard deviation; mvpa = moderateto-vigorous physical activity. * the number of participants in each variable add up to 195, 190, 184, 186 and 196, respectively, instead of 197 for each variable, due to missing data. table 2: omani children’s weight status and frequency of cons umption of soft and sugary drinks, moderate-to-vigorous phys ical activity, screen time and time spent sleeping (n = 197) variable n (%)* chisquare test p value normal or underweight overweight or obese frequency of soft drink and sugary drink consumption 3.772 0.052 daily or weekly 91 (87.5) 13 (12.5) monthly, occasionally or never 70 (77) 21 (23) mvpa in minutes /day 0.02 0.89 ≤60 62 (81.6) 14 (18.4) <60 89 (82.4) 19 (17.6) screen time in minutes/day 0.07 0.79 ≤120 128 (82.1) 28 (17.9) >120 24 (80) 6 (20) time spent sleeping at night in hours/day 3.843 0.052† <9 45 (91.8) 4 (8.2) ≤9 117 (79.6) 30 (20.4) mvpa = moderate-to-vigorous physical activity *the number of participants in each variable add up to 195, 184, 186 and 196, respectively, instead of 197 for each variable, due to missing data. †using fisher’s exact test due to small cell count. lifestyle-related determinants of obesity among omani children e282 | squ medical journal, august 2020, volume 20, issue 3 the outcome and single-day nutrition intake as the predictor. three models were built based on energy, macronutrients and main food groups consumed. multiple linear regression was also used to predict the children’s bmi z-scores from the 22 foods on the ffs. also, binary logistic regression was run with the children’s weight status as an outcome, and the 22 foods’ frequency of intake as predictors. additionally, multiple linear regression was used to predict the children’s bmi z-scores from mvpa time, screen time and time spent sleeping as well as after controlling for age and gender. statistical package for the social sciences (spss), version 25 (ibm, corp., armonk, new york, usa) was used for the statistical tests. a p value of <0.05 was considered statistically significant. approval for this study was obtained from the institutional review board at the university of north carolina at chapel hill (irb study number 17-2785) and the research ethical committee at the technical office for research and development at the ministry of education (moe) in oman. the risks and benefits of participating in this study were explained in arabic to the mothers and children and all questions were answered before the mothers were asked to give consent for their and their child’s participation or the children were asked to assent to their own participation. results a total of 197 dyads were included in the final study analyses. of the 204 dyads who consented to participate, four dyads were not eligible according to the inclusion criteria and the electronic questionnaire data for three other dyads were categorised as lost, most likely due to incomplete submission. the mean age of the children was 7.7 ± 1.6 years and the majority of the children were female (53%). a total of 17.4% of the children were classified as overweight or obese and 5.6% were classified as thin or severely thin. children’s energy intake ranged from 613–3,736 kcal/day (mean = 1,770 ± 563.5 kcal/day), while their mean protein and carbohydrate intakes were 65.0 ± 26.6 and 250.2 ± 87.0 g/day, respectively. the children’s mean daily fat intake was 58.6 ± 23.7 g and their mean grain intake was 7.6 ± 3.9 ounces/day. the study demonstrated that 81% of the children consumed refined grains daily and only 35% of the children consumed whole grains daily. the mean daily intake of fruit was 1.4 ± 1.2 cups, while the mean intake of vegetables was 1.5 ± 1.1 cups per day. the majority of children (80%) consumed dairy daily and 60% of children consumed fast food either rarely or never. nearly half of the children (46.4%) consumed soft or sugary drinks rarely or never. for the single-day dietary recall, 92.4% of mothers reported that it was the usual pattern of their children’s daily dietary intake. children’s mean daily mvpa was 61.4 ± 63.7 minutes. children’s mean daily screen time was 63.0 ± 68.6 minutes per day and the majority of the children (75%) complied with the national sleep foundation table 3: coefficient-based model of physical activity pattern predictors on omani children’s weight status variable* unstandardised β se p value exp(b) 95% ci for exp(b) lower upper mvpa time −0.00 0.00 0.26 0.996 0.99 1.00 screen time −0.00 0.00 0.21 1.00 0.998 1.01 sleep time −1.19 0.58 0.04 0.31 0.10 0.94 se = standard error; ci = confidence interval; mvpa = moderate-to-vigorous physical activity. *weight status reference group was constituted of children identified as overweight or obese. mvpa time and screen time were continuous variables. the sleep time reference group was constituted of children achieving less than nine hours of sleep a night. table 4: coefficient-based models of single-day nutrition intake predictors on omani children’s body mass index z-scores model* unstandardised β se p value energy in kcal −1.04 × 10−5 0.00 0.96 macronutrients protein in g 0.01 0.01 0.17 fat in g 0.00 0.01 0.85 carbohydrates in g −0.00 0.00 0.27 food groups grains in oz 0.03 0.03 0.37 fruits in cup −0.03 0.09 0.72 vegetables in cup 0.08 0.10 0.41 protein-based foods in oz 0.03 0.04 0.49 dairy in cup 0.03 0.11 0.76 se = standard error; kcal = kilocalories; g = grams; oz = ounces. *separate models were run for energy, macronutrients (i.e. protein, fat and carbohydrates) and food groups (i.e. grains, fruits, vegetables, protein based foods and dairy); children’s ages and genders were statistically controlled. basma al yazeedi, diane c. berry, jamie crandell and mostafa waly clinical and basic research | e283 recommendations of at least nine hours of sleep per night for those aged 6–11 years. the children’s bmi z-scores were not significantly correlated with the single-day intake of total energy, protein, total fat, carbohydrate, grains, fruits, vegetables, protein food or dairy (r = -0.04–0.08; p ≤0.05 each) [no table for correlation analysis]. with regression analysis, no significant predictor of bmi z-scores was found (p ≤0.05) [table 4]. no significant nutrition intake predictor was found for the children’s weight status either (p ≤0.05 each) [table 5]. the mean bmi z-scores for the children reported to consume soft drinks or sugary drinks more frequently were significantly (p = 0.01) lower compared to children who were reported to consume soft or sugary drinks less frequently [table 1]. likewise, the mean bmi z-scores among the children who had fat or butter added to their food more frequently were significantly (p = 0.02) lower than the mean bmi z-scores of the children who had fat or butter added less frequently [table 1]. the relationships between each of the other 20 food types and children’s bmi z-scores and weight status were found not to be significant. multiple linear regression showed that none of the 22 items was a significant predictor of the children’s bmi z-scores or weight status (p ≤0.05). the children’s bmi z-scores were not significantly associated with time spent engaged in mvpa (r = −0.04; p ≤0.05). similarly, the mean bmi z-score was not significantly different between the children reported to engage in mvpa for 60 minutes or more per day compared to the children reported to engage in mvpa less than 60 minutes per day [table 1]. a chisquare test analysis indicated no significant association between mvpa (stated as a dichotomous variable) and children’s weight status [table 2]. the children’s bmi z-scores were not significantly associated with daily screen time (r = 0.06; p ≤0.05) irrespective of duration [table 1]. no significant associations were detected between screen time and weight status [table 2]. mean bmi z-scores were not significantly different between children reported to sleep less than nine hours per night compared to children reported to sleep nine hours or more per night [table 1]. children’s weight status was also not significantly associated with the time spent sleeping (p = 0.52) [table 2]. multiple linear regression indicated that mvpa time, screen time and time spent sleeping were not significant predictors of children’s bmi z-scores [table 6]. however, binary logistic regression (with the children’s weight status as an outcome) suggested that sleeping less than nine hours per night was table 5: coefficient-based models of single day nutrition intake predictors on omani children’s weight status model* unstandardised β se p value exp(b) 95% ci for exp(b) lower upper energy in kcal 0.00 0.00 0.29 1.00 0.999 1.00 macronutrients protein in g −0.00 0.01 0.72 0.997 0.98 1.01 fat in g 0.01 0.01 0.50 1.01 0.99 1.03 carbohydrates in g −0.00 0.00 0.19 0.996 0.99 1.00 food groups grains in oz −0.02 0.05 0.76 0.98 0.89 1.09 fruits in cup 0.05 0.15 0.75 1.05 0.78 1.42 vegetables in cup 0.16 0.17 0.33 1.18 0.85 1.62 protein-based foods in oz −0.03 0.07 0.71 0.97 0.85 1.12 dairy in cup −0.10 0.21 0.65 0.91 0.61 1.37 se = standard error; ci = confidence interval; kcal = kilocalories; g = grams; oz = ounces. *weight status reference group was overweight or obesity; separate models were run for energy, macronutrients (i.e. protein, fat, carbohydrates) and food groups (i.e. grains, fruits, vegetables, protein-based foods and dairy); children’s age and gender were statistically controlled. table 6: coefficient-based models of physical activity pattern predictors on omani children’s body mass index z-scores variable* unstandardised β se p value mvpa time −0.00 0.00 0.43 screen time 0.00 0.00 0.22 sleep time 0.39 0.27 0.15 se = standard error; mvpa = moderate-to-vigorous physical activity. *the outcome was considered body mass index z-score; mvpa time and screen time were considered continuous variables; the sleep reference group had at least nine hours sleep each night. lifestyle-related determinants of obesity among omani children e284 | squ medical journal, august 2020, volume 20, issue 3 significantly associated with decreased odds of being overweight or obese (p = 0.04) [table 3]. discussion the study aimed to assess the relationship between bmi zscores and nutrition, physical activity, screen time and time spent sleeping in omani children. analyses suggest no significant relationship between total energy or macronutrient intake and children’s bmi z-scores. in a previous study, an increase in total energy intake was linked to an increase in body weight.12 the relationship between energy intake and overweight and obesity, however, relies in part on energy expenditure.9 this relationship may explain why researchers in a previous study reported no significant association between energy intake and body composition while others found that energy and carbohydrate intake were significantly (p <0.05) associated with children’s bmi.23,24 the current study also found that total grain intake per day and whole grain or other grain-intake frequency had no significant relationship with bmi z-scores. different influences of whole grains and refined grains on obesity have been documented previously in the literature.25–27 whole-grain intake was found to be inversely related to bmi and obesity among children 6–18 years old (p <0.05) according to a large study conducted in the usa.25 another study found that reducing white bread consumption versus reducing whole-grain bread consumption was associated with a lower increase in weight.26 however, another study showed similar findings to the current study, indicating no significant relationship between total grain intake and obesity in children.27 fast food intake has also been linked to obesity.12 however, in the current study, fast food intake was low, most likely because the children were too young to eat outside of their homes with friends.28 this behaviour might explain the lack of a significant relationship between the frequency of fast food intake and the children’s bmi z-scores in the current study. further research is needed to clarify the nature of homeprepared food and its relationship to obesity, especially because societal changes in the gcc countries imply that home-prepared food is becoming more calorie dense. in the present study, mean bmi z-scores were significantly (p <0.05) higher among children who had fat or butter added to their food less frequently (i.e. monthly, occasionally or never) compared to children who had fat or butter added to their food more frequently (i.e. daily or weekly). however, during data collection, mothers revealed that they preferred to use homemade or natural fat (e.g. ghee) extracted from milk. previous research has shown that trans-fatty acids are linked to obesity, in contrast to natural fats which have not been found to have such an association.29 a systematic literature review found no supporting evidence indicating a significant relationship between dairy fat or high-fat dairy foods and obesity.30 interestingly, the current study showed that mean bmi z-scores were higher among children who were reported to consume soft drinks or sugary drinks less frequently compared to those who consumed them more frequently. the frequency of soft drink or sugary drink intake, however, was not a significant predictor of children’s weight status in this study. similar findings have been reported in other gcc countries. one study reported a significant negative relationship between soft drinks or sugary drinks and childhood obesity, while another reported no significant relationship.31,32 in oman, sugary drink portion sizes are usually small (6–8 ounces), which could partly explain its non-significant relationship with obesity; especially in light of the fact that acceptable juice intake for children older than seven years is eight ounces a day.33 children who consume sugary drinks as a daily snack may get full easily and eat less or skip main meals that are more calorie dense. it is important to note that the data collected were subjective and reported by mothers who may not necessarily be aware of all items consumed by their children throughout the day, including soft drinks or sugary drinks. further investigation is needed to clarify the risk of consuming soft drinks and sugary drinks on obesity in oman. in this study, mvpa time was not significantly associated with children’s bmi z-scores. one study from the gcc supports these findings, documenting no significant (p >0.05) relationship between physical activity and bmi.32 however, another study conducted in the gcc suggested that low levels of physical activity were associated with childhood obesity.31 participants in the current study demonstrated an acceptable daily level of mvpa as children’s mean daily mvpa was 61.4 ± 63.7 minutes. nevertheless, objective measurement tools such as accelerometers should be considered in future research. this study found that screen time was not significantly associated with children’s bmi z-scores. similarly, no significant relationship between screen time and childhood obesity has been reported in other gcc-based studies.31,34 however, a gcc-based study reported that mean bmi was significantly (p <0.05) higher among children and adolescents engaged in more than two hours of screen time per day compared to those engaging in less than an hour basma al yazeedi, diane c. berry, jamie crandell and mostafa waly clinical and basic research | e285 per day.35 in the current study, the majority of children had healthy screen time behaviour (i.e. less than two hours of screen time per day), which may indicate that the relationship between screen time and childhood obesity is moderated by age or other environmental factors. in this study, sleeping at least nine hours per night was significantly associated with increased odds of children becoming overweight or obese. in general, short sleep duration in children has been linked to obesity.36 other mechanisms, including dietary intake, time of eating and obesogenic dietary behaviours have been linked to sleep and obesity.35 these mechanisms need to be investigated from a cultural perspective to further understand the relationship between sleep and obesity among omani children. the nutrition intake and physical activity measures used in this study were unable to establish a statistically positive relationship to childhood obesity in omani children. it is worth noting that genetic factors play a role in the relationship between environmental factors and obesity.37 a strong positive relationship (p = 0.001) between maternal bmi and childhood obesity has been reported in oman.38 children who did not inherit the obesity-associated genes may practice unhealthy nutritional behaviours yet have a normal body weight. this study was subject to certain limitations. the study was cross-sectional with a relatively small sample size that was selected using convenience sampling from urban and suburban communities, which limits the generalisability of the study’s findings. also, child nutrition and physical activity pattern instruments provided only subjective data as these data were selfreported by mothers, which could have added bias. due to feasibility issues, dietary recall reporting was limited to a single day of data collection. a question at the end of the dietary recall interview, however, asked mothers whether the child’s nutrition intake of that day was usual, more than usual or less than usual. the majority of mothers (92.4%) answered that the intake was as usual. conclusion this study demonstrated that childhood obesity is a complex health problem that needs to be examined at different levels. this study provides primary data that can be used for future childhood obesity research in oman. future research in oman can be directed toward designing culturally tailored assessment tools to better capture significantly associative factors. investing in school-based health programmes would promote general child health and control childhood obesity in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. ng m, fleming t, robinson m, thomson b, graetz n, margono c, et al. global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the global burden of disease study 2013. lancet 2014; 384:766–81. https://doi.org/10.1016/s01406736(14)60460-8. 2. ministry of health, oman. 2012 oman health annual report chapter eight health domains. from: www.moh.gov.om/ documents/274609/275098/ch08y12.pdf/1156f97d-e9e340f3-84ec-a9004c264c11 accessed: feb 2020. 3. ministry of health, oman. 2018 oman health annual report chapter eight health domains. from: www.moh.gov.om/docu ments/274609/3563447/%d8%a7%d9%84%d9%81%d8%b5% d9%84+%d8%a7%d9%84%d8%ab%d8%a7%d9%85%d9%86 /383080f3-a72e-5c05-fd09-c7b5fb2c985b accessed: feb 2020. 4. world health organization. nlis country profile: oman. from: https://apps.who.int/nutrition/landscape/report.aspx?iso =omn&rid=1620&gobutton=go accessed: feb 2020. 5. kelsey mm, zaepfel a, bjornstad p, nadeau kj. age-related consequences of childhood obesity. gerontology 2014; 60:222-8. https://doi.org/10.1159/000356023. 6. harrist aw, swindle tm, hubbs-tait l, topham gl, shriver lh, page mc. the social and emotional lives of overweight, obese, and severely obese children. child dev 2016; 87:1564–80. https://doi.org/10.1111/cdev.12548. 7. pulgarón er. childhood obesity: a review of increased risk for physical and psychological comorbidities. clin ther 2013; 35:a18–32. https://doi.org/10.1016/j.clinthera.2012.12.014. 8. brockmann ga, arends d, heise s, dogan a. systems genetics of obesity. methods mol biol 2017; 1488:481–97. https://doi. org/10.1007/978-1-4939-6427-7_23. 9. hill jo, wyatt hr, peters jc. energy balance and obesity. circulation 2012; 126:126–32. https://doi.org/10.1161/circul ationaha.111.087213. 10. cuthbertson dj, steele t, wilding jp, halford jc, harrold ja, hamer m, et al. what have human experimental overfeeding studies taught us about adipose tissue expansion and suscept ibility to obesiaty and metabolic complications? int j obes (lond) 2017; 41:853–65. https://doi.org/10.1038/ijo.2017.4. 11. delextrat a, hayes ld, al ghannami ss, min y, hussein i, al oufi h, et al. physical fitness characteristics of omani primary school children according to body mass index. j sports med phys fitness 2019; 59:440–8. https://doi.org/10.23736/ s0022-4707.18.08136-7. 12. kuźbicka k, rachoń d. bad eating habits as the main cause of obesity among children. pediatr ednocrinol diabetes metab 2013; 19:106–10. 13. hills ap, andersen lb, byrne nm. physical activity and obesity in children. br j sports med 2011; 45:866–70. https://doi. org/10.1136/bjsports-2011-090199. https://doi.org/10.1016/s0140-6736%2814%2960460-8 https://doi.org/10.1016/s0140-6736%2814%2960460-8 https://doi.org/10.1159/000356023 https://doi.org/10.1111/cdev.12548 https://doi.org/10.1016/j.clinthera.2012.12.014 https://doi.org/10.1007/978-1-4939-6427-7_23 https://doi.org/10.1007/978-1-4939-6427-7_23 https://doi.org/10.1161/circulationaha.111.087213 https://doi.org/10.1161/circulationaha.111.087213 https://doi.org/10.1038/ijo.2017.4 https://doi.org/10.23736/s0022-4707.18.08136-7 https://doi.org/10.23736/s0022-4707.18.08136-7 https://doi.org/10.1136/bjsports-2011-090199 https://doi.org/10.1136/bjsports-2011-090199 lifestyle-related determinants of obesity among omani children e286 | squ medical journal, august 2020, volume 20, issue 3 14. al yazeedi b, berry dc. childhood overweight and obesity is increasing in gulf cooperation council countries: a review of the literature. j transcult nurs 2019; 30:603–15. https://doi. org/10.1177/1043659619829528. 15. huston ac, ripke mn, eds. developmental contexts in middle childhood: bridges to adolescence and adulthood. cambriedge, uk: cambridge university press, 2006. 16. de onis m, onyango aw, borghi e, siyam a, nishida c, siekmann j. development of a who growth reference for school-aged children and adolescents. bull world health organ 2007; 85:660–7. https://doi.org/10.2471/blt.07.043497. 17. al-ghannami ss, sedlak e, hussein is, min y, al-shmmkhi sm, al-oufi hs, et al. lipid-soluble nutrient status of healthy omani school children before and after intervention with oily fish meal or re-esterified triacylglycerol fish oil. nutrition 2016; 32:73–8. https://doi.org/10.1016/j.nut.2015.07.014. 18. national sleep foundation. children and sleep. from: www. sleepfoundation.org/articles/children-and-sleep accessed: feb 2020. 19. subar af, kirkpatrick si, mittl b, zimmerman tp, thompson fe, bingley c, et al. the automated self-administered 24-hour dietary recall (asa24): a resource for researchers, clinicians, and educators from the national cancer institute. j acad nutr diet 2012; 112:1134–7. https://doi.org/10.1016/j.jand.2012.04.016. 20. kirkpatrick si, subar af, douglass d, zimmerman tp, thompson fe, kahle ll, et al. performance of the automated self-administered 24-hour recall relative to a measure of true intakes and to an interviewer-administered 24-h recall. am j clin nutr 2014; 100:233–40. https://doi.org/10.3945/ ajcn.114.083238. 21. zoellner j, anderson j, gould sm. comparative validation of a bilingual interactive multimedia dietary assessment tool. j am diet assoc 2005; 105:1206–14. https://doi.org/10.1016/j. jada.2005.05.011. 22. kirkpatrick si, gilsing am, hobin e, solbak nm, wallace a, haines j, et al. lessons from studies to evaluate an online 24-hour recall for use with children and adults in canada. nutrients 2017; 9:100. https://doi.org/10.3390/nu9020100. 23. fogel a, mccrickerd k, fries lr, goh at, quah pl, chan mj, et al. eating in the absence of hunger: stability over time and associations with eating behaviours and body composition in children. physiol behav 2018; 192:82–9. https://doi.org/10.10 16/j.physbeh.2018.03.033. 24. papandreou d, makedou k, zormpa a, karampola m, ioannou a, hitoglou-makedou a. are dietary intakes related to obesity in children? open access maced j med sci 2016; 4:194–9. https:// doi.org/10.3889/oamjms.2016.045. 25. albertson am, reicks m, joshi n, gugger ck. whole grain consumption trends and associations with body weight measures in the united states: results from the cross sectional national health and nutrition examination survey 2001-2012. nutr j 2016; 15:8. https://doi.org/10.1186/s12937-016-0126-4. 26. serra-majem l, bautista-castaño i. relationship between bread and obesity. br j nutr 2015; 113:s29–35. https://doi.org/10.10 17/s0007114514003249. 27. torres r, santos e, orraca l, elias a, palacios c. diet quality, social determinants, and weight status in puerto rican children aged 12 years. j acad nutr diet 2014; 114:1230–5. https://doi. org/10.1016/j.jand.2014.01.011. 28. burke sj, mccarthy sn, o'neill jl, hannon em, kiely m, flynn a, et al. an examination of the influence of eating location on the diets of irish children. public health nutr 2007; 10:599–607. https://doi.org/10.1017/s1368980007258379. 29. thompson ak, minihane am, williams cm. trans fatty acids and weight gain. int j obes (lond) 2011; 35:315–24. https://doi. org/10.1038/ijo.2010.141. 30. kratz m, baars t, guyenet s. the relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease. eur j nutr 2013; 52:1–24. https://doi.org/10.1007/ s00394-012-0418-1. 31. musaiger ao, al-roomi k, bader z. social, dietary and lifestyle factors associated with obesity among bahraini adolescents. appetite 2014; 73:197–204. https://doi.org/10.1016/j.appet.20 13.11.002. 32. al-haifi ar, al-fayez ma, al-athari bi, al-ajmi fa, allafi ar, al-hazzaa hm, et al. relative contribution of physical activity, sedentary behaviors, and dietary habits to the prevalence of obesity among kuwaiti adolescents. food nutr bull 2013; 34:6–13. https://doi.org/10.1177/156482651303400102. 33. heyman mb, abrams sa, section on gastroenterology h, nutrition, committee on n. fruit juice in infants, children, and adolescents: current recommendations. pediatrics. 2017;139(6). 34. al-muhaimeed aa, dandash k, ismail ms, saquib n. prev alence and correlates of overweight status among saudi school children. ann saudi med 2015; 35:275–81. https://doi.org/10.51 44/0256-4947.2015.275. 35. alghadir ah, gabr sa, iqbal za. television watching, diet and body mass index of school children in saudi arabia. pediatr int 2016; 58:290–4. https://doi.org/10.1111/ped.12834. 36. miller al, lumeng jc, lebourgeois mk. sleep patterns and obesity in childhood. curr opin endocrinol diabetes obes 2015; 22:41–7. https://doi.org/10.1097/med.0000000000000125. 37. qi q, kilpeläinen to, downer mk, tanaka t, smith ce, sluijs i, et al. fto genetic variants, dietary intake and body mass index: insights from 177,330 individuals. hum mol genet 2014; 23:6961–72. https://doi.org/10.1093/hmg/ddu411. 38. alyazeedi b, berry dc, crandell j. the influence of the family on childhood obesity in oman. from: https://stti.confex.com/ stti/congrs19/webprogram/paper97814.html accessed: feb 2020. https://doi.org/10.1177/1043659619829528 https://doi.org/10.1177/1043659619829528 https://doi.org/10.2471/blt.07.043497 https://doi.org/10.1016/j.nut.2015.07.014 https://doi.org/10.1016/j.jand.2012.04.016 https://doi.org/10.3945/ajcn.114.083238 https://doi.org/10.3945/ajcn.114.083238 https://doi.org/10.1016/j.jada.2005.05.011 https://doi.org/10.1016/j.jada.2005.05.011 https://doi.org/10.3390/nu9020100 https://doi.org/10.1016/j.physbeh.2018.03.033 https://doi.org/10.1016/j.physbeh.2018.03.033 https://doi.org/10.3889/oamjms.2016.045 https://doi.org/10.3889/oamjms.2016.045 https://doi.org/10.1186/s12937-016-0126-4 https://doi.org/10.1017/s0007114514003249 https://doi.org/10.1017/s0007114514003249 https://doi.org/10.1016/j.jand.2014.01.011 https://doi.org/10.1016/j.jand.2014.01.011 https://doi.org/10.1017/s1368980007258379 https://doi.org/10.1038/ijo.2010.141 https://doi.org/10.1038/ijo.2010.141 https://doi.org/10.1007/s00394-012-0418-1 https://doi.org/10.1007/s00394-012-0418-1 https://doi.org/10.1016/j.appet.2013.11.002 https://doi.org/10.1016/j.appet.2013.11.002 https://doi.org/10.1177/156482651303400102 https://doi.org/10.5144/0256-4947.2015.275 https://doi.org/10.5144/0256-4947.2015.275 https://doi.org/10.1111/ped.12834 https://doi.org/10.1097/med.0000000000000125 https://doi.org/10.1093/hmg/ddu411 1department of family medicine, ministry of health, muscat, oman; 2department of family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asmaa_9988@hotmail.com التأثري النفسي لإلحالة لفحص الثدي باألشعة لسرطان الثدي بني النساء يف حمافظة مسقط دراسة مستعرضة نوف مبارك �لعلوي، نبيلة �لبلو�صي، �أ�صماء علي �ل�صلماين abstract: objectives: breast cancer constitutes the majority of diagnosed cancers in oman’s females, accounting for 19.2%, which prompted the introduction of a breast cancer screening programme into the omani healthcare system. there are rising international concerns about the effectiveness of mammography as a screening tool and its psychological impact. the current study aimed to determine the social, emotional and physical dysfunction caused by the waiting time from the day of scheduling the appointment until the day of screening and explore associated risk factors. methods: this cross-sectional study was conducted between march and december 2017 at khoula hospital, muscat, oman, using a two-part self-administered questionnaire. part one of the questionnaire collected clinical and demographic data. part two consisted of the psychological consequences questionnaire (pcq) and focused on psychological consequences, measuring the effect of mammographic screening on emotional, physical and social functions. results: a total of 300 women aged ≥40 years old participated in this study (response rate: 100%). results revealed that there was a minimal negative psychological impact from screening using mammograms. all pcq domains were significantly impacted for participants who reported a family history of cancer (p = 0.007). the social score was significantly higher among women between 40–50 years old (p = 0.008). scores of emotional and social functions were significantly affected by participants’ employment status; employed women were more affected than those who were not (p = 0.043 and 0.012, respectively). however, women’s levels of literacy did not affect any of the domains. conclusion: the psychosocial impact of the waiting period between scheduling and undergoing mammography screening was minimal in the current sample. future research should evaluate the psychosocial impact on patients at different recall times. keywords: breast cancer; mammography; psychological factors; depression; anxiety; oman. امللخ�ص: الهدف: ي�صكل �رصطان �لثدي �لن�صبة �الأعلى من �ل�رصطانات �مل�صخ�صة يف ن�صاء ُعمان بن�صبة تعادل %19.2، مما �دى �إىل �إدر�ج بر�مج �لفح�س �ملبكر للثدي يف نظام �لرعاية �ل�صحية �لعماين. هناك خماوف عاملية متز�يدة ب�صاأن فعالية �لت�صوير �ل�صعاعي للثدي كاأد�ة فح�س وتاأثريه �لنف�صي. �لدر��صة �حلالية تهدف ملعرفة مدى �لتاأثر �لعاطفي و�جل�صدي و�لعجز �لبدين الذي ينتج من طول �نتظار �ملوعد من يوم حتديده وحتى يوم �لفح�س. كما تهدف �لدر��صة �إىل �كت�صاف عو�مل �خلطر �ملرتبطة. الطريقة: �أجريت هذه �لدر��صة �مل�صتعر�صة بني �صهر مار�س ودي�صمرب من عام 2017 يف م�صت�صفى خولة مبحافظة م�صقط، �صلطنة عمان، با�صتخد�م ��صتبيان ذ�تي يتكون من جزئني. �جلزء �الأول من �ال�صتبيان ت�صمن �لبيانات �ل�رصيرية و�لدميغر�فية. �أما �جلزء �لثاين فقد ت�صمن ��صتبيان �لعو�قب �لنف�صية وركز على �لعو�قب �لنف�صية، وقيا�س تاأثري �لفح�س �ل�صعاعي للثدي على النواحي �لعاطفية و�جل�صدية و�الجتماعية. النتائج: �صاركت 300 �مر�أة ترت�وح �أعمارهن بني 40 سنة وأكرث يف هذه �لدر��صة )معدل �ال�صتجابة: %100(. ك�صفت �لنتائج �أن �لتاأثري �لنف�صي �ل�صلبي من �لفح�س با�صتخد�م ت�صوير �لثدي باالأ�صعة قليل جد�. كما بينت �لنتائج تاأثر جميع جماالت ��صتبيان �لعو�قب �لنف�صية ب�صكل كبري للم�صاركات �لالتي �أبلغن عن تاريخ عائلي ملر�س �ل�رصطان )p = 0.007(. كانت النواحي �الجتماعية �أعلى تاأثر� يف �لن�صاء بني عمر 40-50 �صنة )p = 0.008(. تاأثرتالنواحي �لعاطفية و�الجتماعية ب�صكل كبري باحلالة �ملهنية للم�صرتكات؛ وكانت �لن�صاء �لعامالت �أكرث تاأثر� من �لالتيال يعملن )p = 0.043 و p =0.012، على �لتو�يل(. كما �أو�صحت �لدر��صة �أن �مل�صتوى �لتعليمي للمر�أة لي�س له تاأثري على �أي من �ملجاالت �لثالث. اخلال�صة: كان �لتاأثري �لنف�صي و�الجتماعي لفرتة �النتظار حتى وقت �خل�صوع لفح�س ت�صوير �لثدي �صئياًل يف �لعينة �حلالية. ين�صح بعمل �أبحاث م�صتقبلية لتقيم �لتاأثري �لنف�صي-�الجتماعي للمر�صى يف حال ��صتدعائهم الإعادة �لفح�س. الكلمات املفتاحية: �رصطان �لثدي؛ �لت�صوير �ل�صعاعي للثدي؛ عو�مل نف�صية؛ كاآبة؛ قلق؛ عمان. the psychological impact of referral for mammography screening for breast cancer among women in muscat governorate a cross-sectional study nouf m. al-alawi,1 nabila al-balushi,1 *asma a. al salmani2 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e225–229, epub. 5 nov 19 submitted 17 dec 18 revisions req. 29 jan, 19 mar & 7 apr 19; revisions recd. 25 feb, 31 mar & 18 apr 19 accepted 5 may 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.008 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ the psychological impact of referral for mammography screening for breast cancer among women in muscat governorate a cross-sectional study e226 | squ medical journal, august 2019, volume 19, issue 3 breast cancer is a major concern as it caused 410,000 deaths annually and is the leading cause of death due to cancer in women.1 el saghir et al. conducted a literature and registry analysis in the american university of beirut medical centre, beirut, lebanon, and estimated that breast cancer represents 13–35% of all female cancers in the arab world.2 in addition, they found that women younger than 50 years old account for almost 50% of breast cancer patients in the arab world, with a median age of 49–52 years compared to 63 years in more industrialised nations.2 in 2011, the gulf centre for cancer control reported that breast cancer accounted for 23.5% of all cancers among women.3 in oman, breast cancer constitutes the majority of cancers in women, accounting for 19.2% of cases; 53.5% of these breast cancers occur in women under the age of 50.4 the highest incidence of breast cancer recorded in muscat, oman, was in 2008, at 15.6 cases per 100,000 women.5 recently, mammography screening for breast cancer has been a subject of debate and international concern due to adverse pre-screening and post-screening effects reported in different trials.6–8 however, the level of anxiety felt by women waiting for breast cancer screening appointments has been shown to vary, reflecting patients’ varying levels of concern about breast cancer screening.9 the degree of pre-screening anxiety corresponds to the extent of the procedure’s invasiveness as shown in a study comparing physiological impact and demographic variability in women awaiting three different medical procedures, including mammo graphy.10 these studies also showed that the time and place of baseline assessment should be considered before drawing any conclusions about the psychological effect of breast screening, as participants are not a homogeneous entity.9,10 in 2016, oman’s ministry of health (moh) initiated breast cancer screening via mammography for the early detection of breast cancer. the most recent moh guidelines recommend a programme of breast cancer screening in all low-risk omani women that are ≥40 years old, which is to be repeated every two years in case of normal results. the current study aimed to evaluate the psychological impact on women waiting for mammography screening after being referred for the procedure by their primary healthcare institution and associated risk factors. methods this cross-sectional study was conducted between march and november 2017 at the radiology department of khoula hospital, muscat, oman, which is one of the main secondary healthcare centres in oman. the waiting time for mammography screening for eligible women ranged from 3–4 months according to the availability of appointments. the participants in this study were undergoing their first mammographic screening. patients were recruited directly from the radiology department while waiting for their mammography appointment and included all female patients referred by their primary healthcare provider for mammo graphy screening regardless of the waiting time since referral. patients who were ≥40 years of age and able to understand and complete the self-administered questionnaire were included. women who were preg nant, not competent to give consent, attending for a follow-up screening, had a history of breast cancer, a psychological condition or were diagnosed with depr ession were excluded. the study used a two-part self-administered quest ionnaire. part one collected clinical and demographic data including age, marital status, educational level and employment status. the clinical data included information about personal or family history of breast cancer. part two was the psychological consequences questionnaire (pcq), which is a reliable and valid measure of the effect of the mammographic screening on an individual's emotional, physical and social function. it includes 12 items and three domains, with five items measuring emotional dysfunction, four items measuring physical dysfunction and three items meas uring social dysfunction. the ratings for the symptoms within each of the domains were added to give a score, indicating the level of dysfunction in that domain with a higher score indicating greater dysfunction. the pcq advances in knowledge the psychological effects of the waiting period between the day of referral and mammography screening were minimal. application to patient care the psychological impact of mammography screening suggests that patients with family history of cancer and those employed experience some degree of stress during the time between scheduling the examination and undergoing the screening. employed women with a family history of cancer or aged 40–50 years may require counselling and/or referral to a psychologist prior to mammography screening to mitigate the psychological impact of the pre-screening waiting period. nouf m. al-alawi, nabila al-balushi and asma a. al salmani clinical and basic research | e227 has been previously utilised for psychological screening in both preand post-mammography screening periods.11 however, since the pcq had not been previously available in arabic, the investigators had to translate and validate it for this study. for linguistic validation, the arabic version was translated back into english to determine the equivalence of the concepts in the questionnaire. the arabic version was piloted in a different hospital with 20 participants for cultural validation, including the appropriateness of the wording and potential misinterpretations; few amendments were required. the participants were asked to complete the quest ionnaire and the pcq while waiting for their mammo gram in the waiting area of the radiology department. any queries were answered by the investigators. for illit erate women, the questionnaire was completed by the investigators, who verbally asked the women the questions. descriptive statistics were computed for sociodemographic characteristics and all items in the questionnaire. the mean and standard deviation (sd) were reported for continuous variables, while freq uencies and percentages were reported for categorical variables. the association of the independent variables with the outcome variables was estimated using the kruskal-wallis and mann-whitney-u tests. the twotailed significance level was set at p ≤0.05. all statistical analyses were carried out using statistical package for the social sciences (spss), version 25.0 (ibm corp., armonk, new york, usa). the research protocol was approved by the research ethics committee of khoula hospital. verbal consent was obtained from all participants after providing a full explanation of the study. results a total of 300 women aged ≥40 years participated in this study (response rate: 100%). a total of 196 participants (65.3%) were between 40–50 years of age, while 77 women (25.7%) were between 51–60 years of age. most participants were omani (91%) and had graduated from university (35%). the remainder had graduated from secondary school (23%), were illiterate (22.3%) or could read and write but had not completed secondary school (19.7%). the majority of participants were married (79.3%) and unemployed (64.7%). a total of 77 women (25.7%) reported having a history of cancer in their family [table 1]. a total of 212 women (70.7%) reported not having any social dysfunction in response to waiting for mammography screening, while 187 (62.3%) and 171 (57%) reported not having any physical or emotional dysfunction, respectively. only 21 (7%), 13 (4.3%) and 12 (4%) women reported dysfunction "quite a lot of the time" in the emotional, physical and social domains, respectively. one-third of the participants reported “rarely” or “some of the time” for emotional (36.3%) and physical (32.7%) dysfunction, while only a quarter reported the same for social dysfunction (25.6%) [figure 1]. the results showed that social dysfunction was significantly higher in respondents between 40–50 table 1: characteristics of women who underwent mammography screening at khoula hospital, muscat, oman (n = 300) characteristic n (%) age in years 40–50 196 (65.3) 51–60 77 (25.7) >60 27 (9) nationality omani 273 (91) non-omani 27 (9) region of residence muscat 288 (96) north batinah 6 (2.1) south batinah 2 (0.7) south sharqiah 2 (0.7) dakhiliah 2 (0.7) literacy level university graduate 105 (35) secondary school graduate 69 (23) illiterate 67 (22.3) literate* 59 (19.7) marital status married 238 (79.3) widowed 32 (10.7) single 16 (5.3) divorced 14 (4.7) employment status employed 106 (35.3) unemployed 194 (64.7) family history of cancer yes 77 (25.7) no 223 (74.3) *did not complete secondary school. the psychological impact of referral for mammography screening for breast cancer among women in muscat governorate a cross-sectional study e228 | squ medical journal, august 2019, volume 19, issue 3 years of age (p = 0.008). literacy levels did not have a significant effect on any of the pcq domains. emotional and social scores were significantly affected by participants’ employment status; women who were employed were significantly more affected than those who were unemployed (p = 0.043 and 0.012, respectively). marital status did not have a significant effect on any of the pcq domains, perhaps due to the fact that most participants (79.3%) were married. interestingly, participants who reported a history of cancer in their family had significantly higher scores in all three domains of the pcq (p = 0.047, 0.008 and 0.007 for emotional, physical and social scores, respectively) [table 2]. discussion undergoing any health-related screening exposes the patient to the possibility of an unintended adverse effect, most commonly increased anxiety.12,13 the negative psychological impact of waiting for mammography screening was found to be minimal in the current sample. the percentage of women reporting dysfunction in their emotional, physical or social well-being “quite a lot of the time”, as measured by the pcq, was less than 7%. this finding is similar to other studies which found low levels of anxiety.9,14 this might be explained by either the fact that women in the current study received good counselling at the time of referral or that mammography screening is a minimally invasive procedure.10 the present results confirmed that age has a negative effect on participants’ social scores, which were significantly higher in those aged 40–50 years (p = 0.008). this finding might be due to the fact that younger women are more aware of disease con sequences and treatments available.15 several other studies table 2: psychological consequences questionnaire results showing the affected psychological functions as expressed through the characteristics of women who underwent mammography screening at khoula hospital, muscat, oman (n = 300) characteristic mean emotional score ± sd p value* mean physical score ± sd p value* mean social score ± sd p value* age in years 40–50 3.93 ± 4.16 0.189 2.72 ± 3.10 0.182 1.69 ± 2.24 0.008 51–60 3.32 ± 3.50 2.29 ± 2.84 0.94 ± 1.67 >60 2.38 ± 3.26 1.61 ± 2.41 0.61 ± 1.16 educational level illiterate 3.09 ± 3.60 0.553 2.33 ± 2.95 0.106 1.06 ± 1.78 0.405 literate† 4.34 ± 4.42 3.10 ± 3.34 1.86 ± 2.48 secondary school 3.58 ± 3.89 2.94 ± 3.14 1.41 ± 1.95 university graduate 3.73 ± 3.83 1.98 ± 2.58 1.28 ± 1.98 employment status employed 4.17 ± 4.11 0.043 2.40 ± 2.89 0.637 1.67 ± 2.23 0.012 unemployed 3.26 ± 3.76 2.42 ± 2.96 1.13 ± 1.88 family history of cancer yes 1.67 ± 2.23 0.047 1.67 ± 2.23 0.008 1.67 ± 2.23 0.007 no 1.13 ± 1.88 1.13 ± 1.88 1.13 ± 1.88 sd = standard deviation. *using kruskal-wallis and mann-whitney-u tests. †did not complete secondary school. figure 1: the psychological impact of the waiting time from the day of referral to mammography screening in women at khoula hospital, muscat, oman (n = 300). nouf m. al-alawi, nabila al-balushi and asma a. al salmani clinical and basic research | e229 have also shown an inverse relationship between age and psychological outcomes.16 having a family history of cancer is associated with a significant psychological impact for screening for any type of cancer.17 in the current study, all three pcq domains were significantly influenced in the participants who reported a history of familial cancer. similarly, taylor et al. found a positive correlation between the perceived risk and a family history of cancer in men screened for prostate carcinoma and that these men had a particularly high level of psychological distress.17 in a study by fujiwara et al., the level of education of participants with serious psy chological distress significantly increased their willingness to participate in cancer screening.16 however, in the current study, education level of the participants had no significant effect on the pcq results. conclusion the current study found that the waiting time between the day of referral and the day of the mammography screening had only minimal impact on the social, emotional and physical well-being of the participants. further research is required in this field and future studies should include patients undergoing other screening tests. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. ferlay j, héry c, autier p, sankaranarayanan r. global burden of breast cancer. in: li ci, ed. breast cancer epidemiology. new york, usa: springer, 2010. pp 1–19. 2. el saghir ns, khalil mk, eid t, el kinge ar, charafeddine m, geara f, et al.trends in epidemiology and management of breast cancer in developing arab countries: a literature and registry analysis. int j surg 2007; 5:225–33. https://doi.org/10.1016/j. ijsu.2006.06.015. 3. gulf center for cancer control and prevention. ten-year cancer incidence among nationals of the gcc states 1998–2007. from: www.moh.gov.bh/content/files/publications/gcc%20 cancer%20incidence%202011.pdf accessed: apr 2019. 4. mehdi i, monem ea, al bahrani bj, al kharusi s, nada am, al lawati j, et al. age at diagnosis of female breast cancer in oman: issues and implications. south asian j cancer 2014; 3:101–6. https://doi.org/10.4103/2278-330x.130442. 5. renganathan l, ramasubramaniam s, al-touby s, seshan v, al-balushi a, al-amri w, et al. what do omani women know about breast cancer symptoms? oman med j 2014; 29:408–13. https://doi.org/10.5001/omj.2014.110. 6. miller ab, wall c, baines cj, sun p, to t, narod sa. twenty five year follow-up for breast cancer incidence and mortality of the canadian national breast screening study: randomised screening trial. bmj 2014; 348:g366. https://doi.org/10.1136/ bmj.g366. 7. bleyer a, welch hg. effect of three decades of screening mammography on breast-cancer incidence. n engl j med 2012; 367:1998–2005. https://doi.org/10.1056/nejmoa1206809. 8. bond m, pavey t, welch k, cooper c, garside r, dean s, et al. systematic review of the psychological consequences of falsepositive screening mammograms. health technol assess 2013; 17:1–170, v–vi. https://doi.org/10.3310/hta17130. 9. swanson v, mcintosh ib, power kg, dobson h. the psychological effects of breast screening in terms of patients’ perceived health anxieties. br j clin pract 1996; 50:129–35. 10. weller a, hener t. invasiveness of medical procedures and state anxiety in women. behav med 1993; 19:60–5. https://doi.org/10.1 080/08964289.1993.9937566. 11. rijnsburger aj, essink-bot ml, van as e, cockburn j, de koning hj. measuring psychological consequences of screening: adaptation of the psychological consequences questionnaire into dutch. qual life res 2006;15:933–40. https://doi.org/10.1007/s11136005-5093-8. 12. leggatt v, mackay j, marteau tm, yates jr. the psychological impact of a cancer family history questionnaire completed in general practice. j med genet 2000; 37:470–2. https://doi.org/10.1 136/jmg.37.6.470. 13. croyle rt. psychosocial effects of screening for disease prevention and detection. new york, usa: oxford university press, 1995. p. 218. 14. bull ar, campbell mj. assessment of the psychological impact of a breast screening programme. br j radiol 1991; 64:510–15. https://doi.org/10.1259/0007-1285-64-762-510. 15. løken k, steine s, laerum e. mammography: influence of departmental practice and women’s characteristics on patient satisfaction: comparison of six departments in norway. qual health care 1998; 7:136–41. https://doi.org/10.1136/qshc.7.3.136. 16. fujiwara m, inagaki m, nakaya n, fujimori m, higuchi y, kakeda k, et al. association between serious psychological distress and nonparticipation in cancer screening and the modifying effect of socioeconomic status: analysis of anonymized data from a national cross-sectional survey in japan. cancer 2018; 124:555–62. https://doi.org/10.1002/cncr.31086. 17. taylor kl, diplacido j, redd wh, faccenda k, greer l, perlmutter a. demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. cancer 1999; 85:1305–12. https://doi.org/10.1002/(sici)10970142(19990315)85:6<1305::aid-cncr13>3.0.co;2-i. https://doi.org/10.1016/j.ijsu.2006.06.015 https://doi.org/10.1016/j.ijsu.2006.06.015 https://doi.org/10.4103/2278-330x.130442 https://doi.org/10.5001/omj.2014.110 https://doi.org/10.1136/bmj.g366 https://doi.org/10.1136/bmj.g366 https://doi.org/10.1056/nejmoa1206809 https://doi.org/10.3310/hta17130 https://doi.org/10.1080/08964289.1993.9937566 https://doi.org/10.1080/08964289.1993.9937566 https://doi.org/10.1007/s11136-005-5093-8 https://doi.org/10.1007/s11136-005-5093-8 https://doi.org/10.1136/jmg.37.6.470 https://doi.org/10.1136/jmg.37.6.470 https://doi.org/10.1259/0007-1285-64-762-510 https://doi.org/10.1136/qshc.7.3.136 https://doi.org/10.1002/cncr.31086 https://doi.org/10.1002/%28sici%291097-0142%2819990315%2985:6%3c1305::aid-cncr13%3e3.0.co%3b2-i https://doi.org/10.1002/%28sici%291097-0142%2819990315%2985:6%3c1305::aid-cncr13%3e3.0.co%3b2-i this is one of the best books that i have read. it consists of 48 chapters, each one discussing a common scenario where a patient can be difficult. when you read this book you start recalling memories of almost the same situations you went through yourself. you will realise after reading the book that it would have been much more useful if you had read this book before graduation from medical school. you would then have been more skilled in handling similar situations from the start of your career. the way this book is organised makes it very attractive to read. each chapter starts with a problem, illustrated by a dialogue between the doctor and the patient, representing day to day phrases and responses in clinical practice. then the authors give the principles for handling the situation, followed by procedures for applying them. next, they talk about the pitfalls to avoid and finally end with a pearl of wisdom for that particular scenario. this is usually the message that you need to take from the chapter. after each chapter, the authors provided references to selected readings for those who are interested to read more in depth about that scenario. the language of the book is simple and easily understood. the book also contains several illustrative photographs that show the gestures and position of patient responses. the physical structure of the book is very handy and it can be easily carried in your pocket. it is very hard to say much that is negative about this book, but since it was published by people who are living and practicing at united states, they have used scenarios common in their culture. these might not be applicable for people with major differences in culture, attitudes and beliefs. however, this is not the case in most of the chapters and you can easily skip a chapter if you feel the scenario is not related to your practice. i highly recommend this book to all practising physicians and medical students and it is a good الدليل امليداني ملقابلة املرضى الصعبني املوؤلفون: فريدريك بالت وجيوفري جوردون book review field guide to the difficult patient interview authors: frederic w. platt & geoffrey h. gordon publisher: lippincott williams and wilkins, 2nd edition, 2004 isbn: 0-7817-4774-0 orders: http://www.lww.com/product/?978-0-7817-4774-5 squ med j, august 2010, vol. 10, iss. 2, pp. 285-286, epub. 19th jun 10 submitted: 6th mar 10 field guide to the difficult patient interview 286 | squ medical journal, april 2010, volume 10, issue 1 choice for faculty who teaches communication skills for health care providers. r e v i e w e r ahmed s al-busaidi department of family medicine & public health, sultan qaboos university hospital, muscat, oman email: aalbusaidi@hotmail.com clinical & basic research squ med j, april 2010, vol. 10, iss. 1, pp. 31-40, epub. 17th apr 10 submitted 26th sept 09 revision req. 24th nov 09, revision recd. 22nd dec 09 accepted 23rd jan 10 َمْصدوِقيَّة الواصمات القلبية كمؤّشرات تشخيصية وحمّددات ملآل املضاعفات أثناء القسطرة العالجية عرب اجللد حفيظ الهادي، كيث ف�ك�س امللخ�ص: الهدف: تقدير القيمة الت�شخي�شية وحتديد املاآل لربوتني حم�س القلب الدهني الرابط اأثناء الق�شطرة العالجية املختارة عرب اجللد ومقارنته بال�ا�شمات القلبية املعيارية الطريقة: اأجريت درا�شة ا�شتباقية على 80 حالة متعاقبة اأدخلت امل�شت�شفى الإجراء ق�شطرة خمتارة عالجية عرب اجللد. مت درا�شة تركيز ال�ا�شمات القلبية: تروب�نني القلب )ت(، تروب�نني القلب )اآي(، كتلة كاينيز الكرياتينني )م ب(، ماي�جل�بني، و حم�س القلب الدهني الرابط قبل الق�شطرة وبعدها ب�شاعة، و�شاعتني واأربع �شاعات و�شت ع�رسة �شاعة واأربع وع�رسين �شاعة. ارتفاع تركيز ال�ا�شمات القلبية كان مرتبطا مبتغريات دمي�غرافية واأخرى تتعلق بالعملية والت�ش�ير ال�شعاعي لالأوعية.. مت متابعة املر�شى ملدة 20 – 26 �شهرا. النتيجة: بروتني حم�س القلب الدهني الرابط كان االأ�رسع ارتفاعا و ذلك بعد �شاعتني فقط من الق�شطرة، وكان االأن�شب للت�شخي�س املبكر للجلطة القلبية للفرتة من 1 – 3 �شاعات بعد راأب ال�عاء. ارتفعت ال�ا�شمات االأخرى بالن�شب التالية: تروب�نني القلب )اآي( )%46.25(، ماي�جل�بني )%17.5(، بروتني حم�س القلب الدهني الرابط )%13.3(، كتلة كاينيز الكرياتني )م.ب( )%11.25(، و تروب�نني القلب )ت( )%7.5(. كان تروب�نني القلب )اآي( ،)p >0.02( االأكرث ح�شا�شية لت�شخي�س كل امل�شاعفات و كان االأف�شل بني ال�ا�شمات االأخرى. ارتبط ارتفاع ال�ا�شمات القلبية مع تقدم العمر وامل�شاعفات ،)p < 0.019( الدعامات وا�شتخدام ،)p > 0.003( القلب تخطيط يف الرتوية نق�س تغريات مع احلادة ال�شدرية واالآالم الكربى مثل الت�شليخ الرئي�شي )p > 0.004(، وان�شداد ال�عاء امل�ؤقت )p >0.022(، والدعامات العاطلة )p > 0.003(، وعند حدوث اجللطة القلبية )p > 0.042(. ارتفاع ال�ا�شمات القلبية كان مرتافقا مع انخفا�س معدل البقاء بدون م�شاعفات )16.92( �شهرا مقارنة ب )20.67( �شهرا) p > 0.03(. اخلال�صة: قد يك�ن با�شتطاعة بروتني حم�س القلب الدهني الرابط الت�شخي�س املبكر للجلطة القلبية بعد �شاعة من حدوثها )اأو بعدها(. تروب�نني القلب )اآي( ه� االأكرث قدرة على ت�شخي�س امل�شاعفات الرئي�شية اأثناء الق�شطرة العالجية. نن�شح باأن يتم قيا�س تروب�نني القلب )اآي( بعد كل ق�شطرة عالجية بفرتة )16 24 �شاعة(. مفتاح الكلمات: الق�شطرة العالجية، اجللطة القلبية، حم�س القلب الدهني الرابط، ال�ا�شمات القلبية، تروب�نني القلب. abstract: objectives: the aim of this study was to assess the diagnostic and prognostic value of heart-type fatty acid-binding protein (h-fabp) in elective percutaneous coronary intervention (pci) and compare it with standard cardiac markers. methods: a prospective evaluation was done of 80 consecutive patients admitted for elective pci. serum cardiac troponin t (ctnt), cardiac troponin i (ctni), creatine kinase-mb (ck-mb mass), myoglobin, and h-fabp were determined pre-angioplasty and 1, 2, 4, and 16–24 hrs post-angioplasty. elevated cardiac markers were correlated with demographic, angiographic and procedural variables. patients were followed up for 20–26 months. results: h-fabp peaked early at 2 hours and was useful for the early detection of evolving ami within 1–3 hours after angioplasty. cardiac-tni, myoglobin, h-fabp, ck-mb mass, and ctnt concentrations were elevated in 46.25%, 17.5%, 13.3%, 11.25%, and 7.5% respectively. cardiac-tni was the most sensitive marker for detecting all complications and was superior to all other markers. elevated cardiac markers were correlated with old age (p < 0.02); chest pain ± ecg changes of ischaemia (p < 0.003); use of stents (p < 0.019) and major complications such as major dissection (p < 0.004); transient vessel closure (p < 0.022); bail out stent (p < 0.003), and ami (p < 0.042). elevated cardiac markers were associated with a reduction of event-free survival (16.92 versus 20.67 months, p < 0.03). conclusion: heart-type-fabp measurements at 1 hour (or thereafter) post-pci may offer an early chance of detecting evolving ami; ctni was the most sensitive marker for the detection of major complications in patients undergoing pci. measurements of ctni 16–24 hours post-pci should be part of the routine management of patients following elective pci. keywords: percutaneous coronary intervention; pci; acute coronary syndrome; heart-type fatty acid-binding protein; cardiac markers; cardiac troponins; complications. validity of cardiac markers as diagnostic and prognostic indicators of complications in patients undergoing percutaneous coronary intervention *hafidh a alhadi1 and keith a a fox2 clinical & basic research 1department of medicine, sultan qaboos university hospital, muscat, oman; 2university of edinburgh cardiovascular research unit, royal infirmary of edinburgh, uk to whom correspondence should be addressed. e-mail: halhadi@hotmail.com validity of cardiac markers as diagnostic and prognostic indicators of complications in patients undergoing percutaneous coronary intervention 32 | squ medical journal, april 2010, volume 10, issue 1 percutaneous coronary intervention (pci) is widely used in the treatment of many patients with stable angina, unstable angina (ua), recurrent angina after coronary artery bypass grafting (cabg), and acute myocardial infarction (ami).1-3 pci is, in general, a safe procedure; however, occasionally complications occur, including ami (3–5%),1-2 emergency cabg (3–7%),4 and death (0.9%).5 these events are usually caused by extensive arterial dissection, intracoronary thrombosis, or both, with resultant vessel occlusion. acute closure occurs in 2–8% of patients undergoing pci.6 in 75% of patients with abrupt closure, it occurs within minutes, in the other 25% it usually occurs within 24 hours.7 ultrasound imaging has shown that dissection of the arterial wall is detected in 50– 80% of patients who have undergone successful pci.8 other complications of pci include coronary vessel rupture or injury, re-stenosis, arrhythmias, coronary artery spasm/elastic recoil, and embolism.9 side branch occlusion occurs in 5% of side branches that are adjacent to a dilated coronary stenosis.10 uncomplicated angioplasty is not associated with any significant release of cardiac markers;11 however, more sensitive cardiac markers have increased the numbers of patients diagnosed with myocardial injury after pci. these infarclets have been associated with increased risk of future complications.12-14 minor increases of creatine kinase-muscle and brain (ck-mb) after an apparently successful coronary intervention have been reported in 11.5–26% of cases, and have been associated with an increased risk of cardiac death and ami during follow-up.12,15 serum cardiac troponin i (ctni) and cardiac troponin t (ctnt) elevations have been detected in 13–44% of patients undergoing pci.14,16-17 an increased ctnt concentration post-pci has been correlated with a higher incidence of complex lesion morphology during angioplasty.18 heart-type fatty acid-binding protein (h-fabp) has been found to be a useful early marker for the detection of myocardial injury.19 the value of h-fabp as an early marker for the identification of myocardial damage during pci has not yet been studied. the aims of the study were to examine the relation between elevations of cardiac markers postpci and complication rates during and after pci and to determine whether elevated cardiac markers post-pci are related to demographic, angiographic or procedural variables. methods the study population consisted of a consecutive series of 80 patients recruited from the cardiology unit at the royal infirmary of edinburgh over an eight month period in 2002. ethical approval for the study was obtained from the local ethical committee and written informed consent was obtained from each patient. thereafter, five serial blood samples were collected from each patient at 0 hour (base line concentration, pre-angioplasty) and at 1 hour, 2 hours, 4 hours and 16–24 hours after angioplasty. the study group consisted of patients who were referred for elective angioplasty for both stable angina pectoris and ua. patients who had a nonelective angioplasty (e.g. rescue angioplasty, primary angioplasty, salvage angioplasty, or emergency angioplasty) were excluded from this study. patients were categorised into two main groups according to the presence (ctni positive) or absence (ctni negative) of elevated ctni concentrations ≥ 0.18 µg/l. the two groups were compared with respect to demographic, angiographic and procedural advances in knowledge 1. this article highlights the fact that the release of cardiac markers after percutaneous coronary intervention (pci) is not uncommon and is associated with increased rate of future complications and reduction of event-free survival. 2. this article is the first of its kind to study the value of h-fabp in patients undergoing pci and to evaluate its role in the diagnosis and prognosis of complications during and after pci. 3. this study provided a standardised setting to compare and contrast the ability of the different cardiac markers available in clinical use today to detect myocardial damage post pci. application to patient care 1. this study will help health care professionals select the most appropriate early test for the diagnosis of suspected ami in patients with acute chest pain post pci. 2. this article recommends the introduction into clinical practice of routine measurements of ctni after all elective pci procedures. this will guide the estimation of myocardial damage, which is sometimes not obvious clinically, and may guide further management with antiplatelet therapy. hafidh a alhadi and keih a a fox clinical and basic research | 33 variables, and the frequency of complications during pci and the in-hospital period. patients were followed-up for 20–26 months after discharge from hospital and the numbers of cardiac events in each group were compared. angiographic success was defined according to the european society of cardiology task force guideline on angioplasty as < 20% residual diameter stenosis and thrombolysis in myocardial infarction (timi) 3 flow.20 clinical success was defined as angiographic success without in-hospital complications (death, ami, emergency cabg, or ischaemia driven repeat pci). cardiac-tni, ck-mb mass, and myoglobin were analysed on a stratus cs analyser machine (dade behring, germany), using commercially available test materials. the coefficients of variations for ctni were 6.8%, and 6.7% at concentration range 0.24–0.36µg/l, and 4.6–6.9 µg/l respectively. heart-type-fabp was analysed by an enzyme linked immunosorbent assay method using commercially available assays (hycult, table 1: demographic and angiographic data of patients with and without elevated serum cardiac troponin i (ctni). continuous variables are presented as mean ± sd and categorical variables are presented as percentages (in brackets). demographic data ctni positive group (n = 37) ctni negative group (n = 43) p value age (yrs ± sd) 64.35 ± 9.22 59.1 ± 7.47 0.02 male female 26 (70) 11 (30) 33 (77) 10 (23) ns ns type of preceding angina stable angina unstable angina atypical angina 19 (51) 14 (38) 4 (11) 26 (43) 17 (40) ns ns risk factors smoking diabetes mellitus hypercholestrolaemia hypertension family history of ihd 24 (65) 3 (8) 27 (73) 18 (49) 16 (43) 27 (63) 8 (19) 37 (86) 14 (33) 23 (53) ns ns ns ns ns previous cardiac events previous pci previous cabg previous ami 10 (27) 4 (11) 15 (41) 16 (37) 3 (7) 14 (33) ns ns ns angiographic data ctni positive group (n = 37) ctni negative group (n = 43) p value type of cad single vessel cad multiple vessel cad 6 (16) 31 (84) 14 (33) 29 (67) ns ns anatomic site of pci lad lcx rca vein grafts 27 (73) 11 (30) 6 (16) 1 (3) 29 (67) 14 (32) 4 (9) 3 (7) ns ns ns ns multiple vessel pci 5 (14) 6 (14) ns left ventricular ef (% ± sd) 62 ± 12 65 ± 14 ns clinical success) 27 (73) 41 (95) 0.013 angiographic success 30 (81) 41 (95) 0.04 legend: ctni = cardiac troponin i; p = probability value; ihd = ischaemic heart disease; pci = percutaneous coronary intervention; cabg = coronary artery bypass grafting ; ami = acute myocardial infarction; cad = coronary artery disease; lad = left anterior descending artery; lcx = left circumflex artery; rca = right coronary artery; ef = ejection fraction; validity of cardiac markers as diagnostic and prognostic indicators of complications in patients undergoing percutaneous coronary intervention 34 | squ medical journal, april 2010, volume 10, issue 1 cambridge, uk). the analytical sensitivity of h-fabp mean ± 2sd was 0.206 ± 0.047 µg/l. cardiac-tnt was analysed on elecsys 2010 using commercial assays (roche, germany). the reference ranges quoted by the manufacturer for ck-mb mass, ctni, myoglobin, ctnt, and h-fabp assays were validated by assaying the reference ranges of 20 healthy blood donors samples (10 males and 10 females, mean age ±sd = 63.8 ±8.01, range 53–75 years, median = 65 years). the mean ± sd concentrations of these markers were ck-mb mass =1.52 ± 0.8 µg/l, ctni = 0.015 ± 0.006 µg/l, myoglobin = 41.5 ± 13.3 µg/l, ctnt = 0.011 ± 0.002 µg/l, and h-fabp = 6.86 ± 2.21 µg/l. the optimal cut-off concentrations of cardiac markers were based on receiver operating characteristic (roc) curve analysis between patients with and without complications after pci, and also considerations of cardiac markers concentrations in the normal healthy blood donor group, the control group, and the basal or pre-angioplasty concentrations. the following cut-off concentrations were used to indicate myocardial injury following angioplasty (ctni ≥ 0.18 µg/l; ctnt ≥ 0.1 µg/l; ck-mb mass ≥ 5 µg/l; myoglobin ≥ 95 µg/l, and h-fabp ≥ 16 µg/l). all these cut-off concentrations were associated with statistically significant areas under the curve (p < 0.0005). statistical analyses were performed using the statistical package for social sciences (spsstm, pittsburgh, statistical software, version 12). continuous variables were presented as mean ± sd. comparisons between ctni positive and negative groups demographic, angiographic and procedural variables were conducted by the mann-whitney u test for continuous variables and chi-square or fisher’s exact test for categorical variables. comparison of the mean concentrations of serial cardiac markers changes at 0 hour (before angioplasty) and at 1, 2, 4, and 16–24 hours after angioplasty was conducted by the friedman test. significance was defined as a p value ≤ 0.05. the rate of event-free survival was estimated from the kaplan-meier survival method and was compared with the log rank test. results the study group included 21 females (26%) and 59 males (74%). the mean age of the group was 61.1 ± 7.5 years. the control group (who had an angiography procedure alone without angioplasty) consisted of 12 patients, 5 females and 7 males with a mean age 61.9 ± 8.7 years. there were no significant releases of any of the cardiac markers in the control group (data not shown). this provides evidence that excludes diagnostic procedure as the cause of cardiac trauma and supports angioplasty as the primary cause of cardiac markers release. cardiac-tni was the most frequent abnormal marker and was therefore chosen for comparison in this study. in 37 out of 80 patients (46.25%), the ctni concentration was ≥ 0.18 µg/l. an increase in ctni concentration (> 0.06– ≤ 0.17 µg/l) was observed in 22 patients (27.5%). the area under the curve (auc) for ctni was greater than that for other markers. myoglobin was increased in 14 (17.5%) patients, h-fabp in 13.3%, and ck-mb mass in 11.25%. in all cases where ck-mb mass, ctnt, h-fabp or myoglobin were elevated, ctni was also elevated. 0 20 40 60 80 100 0hr 1hr 2hr 4hr 16-24hrs time (hours) c o n ce n tr at io n ( u g /m l) ckmbmass ctni ctnt myoglobin h-fabp legend: ck-mb = creatine kinase-muscle and brain mass; ctni = serum cardiac troponin i; ctnt = serum cardiac troponin t; hfabp = hearttype fatty acid-binding protein figure 1: serum cardiac markers before (0 hour), and at 1, 2, 4, and 16–24 hours after pci in ctni positive group. data are presented as mean ± sd hafidh a alhadi and keih a a fox clinical and basic research | 35 as compared with ctni, ctnt was increased above the cut-off concentration in only 6 (7.5%) patients, and five of them had significant complications. cardiac-tnt was elevated to concentrations between 0.01–0.06 µg/l in 36 patients, and between ≥ 0.06 – < 0.1 µg/l in 4 patients. the complications reported in these two groups were in 10 and 3 patients respectively. all 6 patients with ctnt > 0.1 µg/l and the 13 patients in the last two groups had ctni ≥ 0.18 µg/l. in the ctni negative group (43 patients, 53.75%), no increase in ctnt or ck-mb mass above the cut-off concentration was observed. myoglobin was elevated in two patients, and h-fabp (concentration = 21 µg/l) in one table 2: procedural variables in patients with and without elevated cardiac troponin i (ctni). continuous variables are presented as mean ± sd and categorical variables are presented as percentages (in brackets). procedure data ctni positive group (n = 37) ctni negative group (n = 43) p value chest pain ± ecg changes of ischaemia 19 (51.4) 6 (13.9) 0.004 procedure information number of lesions dilated (per patient) number of vessels dilated (per patient) balloon diameter (mm) total number of balloon inflation (n) total time of balloon inflation (minutes) maximum inflation time (seconds) maximum inflation pressure (pa) total duration of procedure (minutes) 46 (1.24) 41 (1.11) 3.3 ± 0.56 6.4 ± 4.6 3.77 ± 4.18 50.12 ± 26 11.21 ± 3.34 56.9 ± 38.3 41 (1.24) 40 (1.21) 3.12 ± 0.45 4.81 ± 2.8 3.41 ± 2.86 55.24 ± 24.34 10.45 ± 3.56 42.31 ± 19.2 ns ns ns ns ns ns ns ns major complications during pci major dissection side branch occlusion transient vessel occlusion major technical failure bail out stent 10 (27) 5 (13.5) 7 (19) 1 (3) 7 (19) 1 (2) 2 (5) 1 (2) 0 (0) 0 (0) 0.004 ns 0.022 ns 0.003 minor complications during pci minor dissection coronary spasm/ elastic recoil minor technical failure 8 (21.6) 2 (5.4) 1 (3) 7 (16) 5 (12) 2 (5) ns ns ns post-procedural complications (24h) ami angina with re-catheterisation angina without re-catheterisation emergency cabg. 3 (8) 5 (13.5) 1 (3) 0 (0) 0 (0) 1 (2) 2 (5) 0 (0) 0.042 ns ns total number of stents 42 32 0.019 reason for stenting stent for dissection stent for sub-optimal result elective stent bail out stent 15 (40.5) 12 (32.4) 3 (8) 7 (19) 8 (17) 15 (35) 6 (14) 0 (0) 0.05 ns ns 0.003 use of ivus during pci 6 (16) 1 (2) 0.045 post-procedural treatment ticlopidine clopidogrel abciximab + ticlopidine abciximab + clopidogrel 11 (30) 8 (22) 3 (8) 3 (8) 20 (47) 7 (16) 2 (5) 1 (2) ns ns ns ns legend: ctni = cardiac troponin i; p = probability value; ecg = electrocardiogram; ns = not significant; mm = millimetre; pa = pascal; pci = percutaneous coronary intervention; ami = acute myocardial infarction; cabg = coronary artery bypass grafting validity of cardiac markers as diagnostic and prognostic indicators of complications in patients undergoing percutaneous coronary intervention 36 | squ medical journal, april 2010, volume 10, issue 1 patient. the release patterns of cardiac markers in the ctni positive group are shown in figure 1. the peak concentrations of h-fabp, myoglobin, ctni, ctnt, and ck-mb mass were achieved at 2 hrs, 4–16 hrs, 16–24 hrs, 16–24 hrs, and 16–24 hrs respectively. eighteen patients had an increase in ctni concentration alone. eight patients had some complications during pci, whereas in 6 patients no specific complications were reported. however, in these patients the angioplasty was described as technically difficult and prolonged or the lesion was complex, and three patients had failure of stent deployment, sudden drop of blood pressure after sheath removal, and limb ischaemia post-procedure. two patients in this group had total occlusion of the vessels and two had ostial lesions. in four patients with ctni elevations (range 0.18–0.65 µg/l), no specific complications were reported to explain this rise. the use of newer and potent antiplatelets treatment after pci was liberal in this group of patients. fifty-five patients (68%) received a combination of ticlopidine and/or clopidogrel and/or abciximab antiplatelets after stenting. the demographic and angiographic data of the ctni positive and negative groups are shown in table 1. patients in the ctni positive group were older (p < 0.02). clinical and angiographic successes were reported more frequently in the ctni negative group (95% versus 73%, p < 0.013), and (95% versus 81%, p < 0.04) respectively. table 2 illustrates the procedural variables. there was a significant increase of the following in the ctni positive group: chest pain ± ischaemic ecg changes during pci (51.4% versus 13.9%, p < 0.004); numbers of stents used (42 versus 32, p < 0.019); and use of intravascular ultrasound during pci (16% versus 2%, p < 0.045). there was no difference between the groups related to the total duration of pci, the total numbers of balloon inflations per procedure, the number of lesions treated, balloon size, inflation time and pressure, or the antiplatelet regimes after pci. the frequency and types of complications reported during and after pci were significantly increased in the ctni positive group. out of the 37 patients in this group, 23 (62%) had complications compared to only 14 out of the 43 patients (32.5%) in the ctni negative group (p < 0.03). these complications included one or a combination of the following: major dissection (27%, p < 0.004); transient vessel occlusion (19%, p < 0.022); bail out table 3. cardiac events during follow up for ≥ 20 months. except where otherwise indicated, numbers in brackets indicate percentages. events ctni (+) group (n = 37) ctni (-) group (n = 43) p value angina control post-procedure worse better unchanged 10 (27) 20 (54) 7 (19) 10 (23) 30 (70) 2 (5) ns ns ns cardiac event(s) during follow-up admitted with angina admitted with ua admitted with ami admitted with heart failure target vessel revascularisation non-target vessel revascularisation referred for cabg death 5 (14) 5 (14) 1 (3) 1 (3) 6 (16) 5 (14) 3 (8) 1 (3) 3 (7) 2 (5) 0 0 7 (16) 4 (9) 3 (7) 2 (5) ns ns ns ns ns ns total no. with uncontrolled angina 17 (46) 12 (28) ns total no. of patients with events 17 (46) 12 (28) ns total no. of events per group 29 (78) 21 (48) ns average duration of follow-up (months) 22.6 ± 1.5 23 ± 1.2 ns patients lost to follow-up 0 1 legend: ctni = cardiac troponin i; p = probability value; ns = not significant; ua = unstable angina; ami = acute myocardial infarction; cabg = coronary artery bypass grafting. hafidh a alhadi and keih a a fox clinical and basic research | 37 stents (19%, p < 0.003); ami (8%, p < 0.042); side branch occlusion (sbo) (13.5%, p = ns); major technical failure of equipment during angioplasty (3%, p = ns); angina requiring re-catheterisation (13.5%, p = ns); and minor dissection (21.6%, p = ns). forty-two stents were used in this group compared to 32 stents in the ctni negative group. the increased frequency of stents in this group was mostly to treat dissections (40.5% versus 17%, p = 0.05). thirteen stents (31%) were used mostly on a bail-out basis to treat major dissection ± acute vessel closure. the use of stents for sub-optimal angioplasty results was slightly more in the ctni negative group (49% versus 40.4%). three patients developed ami after pci (1 q wave and 2 non-q wave ami). the concentrations of cardiac markers in these patients were significantly elevated. h-fabp was the first marker to appear in significant concentrations after ami. peak concentrations of h-fabp, myoglobin, ck-mb mass and troponins occurred at 2 hours, 4 hours, 16–24 hours, and 16–24 hours respectively after angioplasty. the release patterns of cardiac markers were similar to the release patterns seen in figure 1. h-fabp reached diagnostic concentrations for ami 1–2 hours post-angioplasty. the diagnosis of ami based on myoglobin, ck-mb mass, and troponins was established at 2–4, 4–16, and 4–16 hours respectively. five patients had sbo during angioplasty. in 3 patients, this complication followed an extensive dissection. out of the 5 patients, two developed ami, two had considerable chest discomfort and st segment depression ± t wave inversion, and in one patient the sbo was asymptomatic. cardiactni concentration was elevated in all patients. the mean ctni increase in these three groups was 14.7 µg/l, 1.73 µg/l, and 0.18 µg/l respectively. creatine kinase-mb mass, and myoglobin were increased in three patients, whereas h-fabp and ctnt were increased in two patients only. in the ctni negative group, two patients had asymptomatic sbo, but there was no increase in cardiac markers in any of them. forty-three patients had ctni < 0.18 µg/l. fourteen patients (32.5%) in this group developed complications during pci; however, the frequency and severity of complications in this group were considerably lower than the ctni positive group. these complications included one patient with major dissection, two patients with transient sbo, and one patient with transient vessel closure. the types of complications reported in the remaining 10 patients were minor dissections, coronary spasm, elastic recoil, and minor technical problems. after discharge, clinical follow-up was possible in 79 out of 80 patients (98.75%). the mean followup period was 22.3 ± 1.7 months (range 20–26 months). the incidence of adverse clinical events is summarised in table 3. patients who had ctni elevation post-pci had a non-significant higher incidence of complications (angina pectoris, ua, and non-target vessel revascularisation). the total number of clinical events per group in the ctni positive and ctni negative group was 29/37 (78%) versus 21/43 (48%) respectively, p = ns. three time to first event (months) 2724211815129630 c um s ur vi va l 1.2 1.0 0.8 0.6 0.4 0.2 0.0 ctni--censored ctni+ ctnictni+-censored legend: ctni = cardiac troponin i figure 2: kaplan-meier event-free survival analysis for the two groups of patients with cardiac troponin i (ctni +) and without (ctni -) elevations during angioplasty. validity of cardiac markers as diagnostic and prognostic indicators of complications in patients undergoing percutaneous coronary intervention 38 | squ medical journal, april 2010, volume 10, issue 1 patients who were included in the ctni negative group had several adverse clinical events during follow-up (worsening of their angina, target and non-target vessel pci, and cabg), despite uneventful pci. their ctni concentration was between 0.08–0.11 µg/l. surprisingly, ctnt was highly predictive of the need for cabg on long-term follow-up. fifty per cent of patients with elevated ctnt after pci were referred for cabg compared to only 4% of patients with normal ctnt after pci (p < 0.004). there were no other statistical differences between the ctnt positive and negative groups when other cardiac events were compared between the two groups. the time-dependent effect of post-procedural ctni elevation on late clinical outcome was assessed using the kaplan-meier survival analysis. there was a significant decrease in event-free survival with more recurrent angina, myocardial infarction, repeat pci, and cabg in the group of patients who had ctni elevations during angioplasty [figure 2]. the mean event-free survival for the group with ctni elevation and those without ctni elevation was 16.92 months (standard error (se) = 1.66, 95% confidence interval (ci) = 13.67–20.18, median = 23 months) versus 20.67 months (se = 1.64, 95% ci = 17.46–23.88, median = 27 months) respectively (p < 0.03). eventfree survival was also decreased in ctnt and h-fabp positive groups. there were no event-free survival differences when ck-mb mass or myoglobin positive and negative groups were compared. discussion the frequency of ctni increases post-pci in patients with complications was much higher than that seen with myoglobin, ck-mb mass, h-fabp, and ctnt. cardiac-tni was the most useful marker for the detection and quantification of pci related complications. this reflects the superior sensitivity of ctni for the detection of small releases of myocardial proteins after pci. heart-type-fabp was the earliest marker that could detect evolving ami postpci within 1–2 hours and the concentration had returned to normal within 16–24 hours. h-fabp may be a potential early marker that can help select patients with chest pain, in the early post-pci period, for early investigations to ascertain the diagnosis of ami. there were different rises of concentrations of ctni and other markers and different symptoms in the various subgroups of patients with sbo. these differences may be related to the size of the side branch vessel, the extent of collaterals, and the duration of the occlusion. the occurrence of asymptomatic sbo, and also the absence of the rise of concentration of cardiac markers following documented sbo has been reported by others.10,13 cardiac markers were also increased in the groups that had more stents and intravascular ultrasound investigations. cardiac marker concentrations are elevated in some patients after pci procedures involving stenting.21 however, this increase indirectly reflects more complications, for example dissection in this group. it is not clear whether the use of intravascular ultrasound during pci contributes to myocardial injury or merely reflects underlying complications. cardiac-tni was increased in a small numbers of patients who had no complications reported during pci. this may be due to: 1) the formation of small thrombi at the angioplasty site that may subsequently embolise to small distal arteries leading to small areas of focal necrosis; 2) the inability of contrast angiography to detect complications (indeed, intravascular ultrasound has been shown to be much more sensitive for the detection of coronary dissection after pci compared with contrast angiography: 83% versus 27%;8 3) the variability of observers reporting complications and 4) mechanical trauma to the heart caused by guide wires manipulations within the coronary arteries. in our study, we found no apparent explanations for ctni increases in 27% of patients, which was comparable to data published by garbarz et al. who reported a 34% increase in ctni concentrations in their study, which was not accounted for by complications during pci.22 the increases in ctni, ctnt, ck-mb mass in the group with sbo was in agreement with genser et al., who reported an increase in these markers in patients with sbo even when this complication was asymptomatic.13 the total frequency of ctni rise (46.25%) in this study was slightly higher than that reported elsewhere in the literature. this could be explained by the use of ctni sensitive assays with a relatively low cut-off concentration (≥ 0.18 µg/l) to indicate myocardial injury post-pci. the frequency of ck-mb mass elevation in our study (11.25%) was lower than that reported previously (15–26%). this could be related to differences in assay methods used. kugelmass et al. reported elevated ck-mb in 11.5% of patients following elective pci, with no clinical sequels over hafidh a alhadi and keih a a fox clinical and basic research | 39 two years follow-up.15 however, in a small subset with a greater elevation of ck-mb, there was a trend towards decreased late survival compared to patients without ck-mb elevation. they also reported common ck-mb elevation after coronary stenting.15 an increased frequency of cardiac events on longterm follow-up (angina, pci, cabg) was noticed in some patients who had very small increases of ctni concentration (0.08–0.1 µg/l), which suggests that even small increases of ctni may have a significant prognostic value and may reflect more diffuse or extensive cad. long-term complications in patients with elevated cardiac markers post-pci have been suggested by abdelmeguid et al. who reported more frequent and more serious complications (e.g. death and ami).12 these differences could be related to several factors. first, the follow-up period in our study was relatively short compared to the study by abdelmeguid (3–5 years, in some patients up to 8.5 years). second, the use of stents was more frequent in the group of patients with elevated cardiac markers concentrations, which may alter the short-term risk of further progression to more serious complications.23 third, the use of newer and more potent antiplatelets regimes (clopidogrel, abciximab) was also high in our study. the clinical benefit of these antiplatelets compounds in reducing the progression to ami and death in patients with myocardial injury is well-established.24 despite the fact that there were no statistically significant differences between the numbers of events, there was still a significant difference with respect to event-free survival between groups with and without elevations of these markers after angioplasty. increases in ctnt after pci had been described previously.17,21 ravkilde et al. found moderate increases in ck-mb mass in 6 of 23 patients (26%) undergoing visually successful pci, whereas only 3 (13%) showed ctnt elevation.17 in this study, the percentage of positive ctnt results after pci was only 7.5% using a third generation ctnt assay that was very sensitive (< 0.01 µg/l) and specific. some of the previous studies used a lower cut-off concentrations e.g. ≥ 0.04 µg/l or ≥ 0.06 µg/l, to indicate the presence of myocardial injury postpci.18,25 increased ctnt ≥ 0.06 µg/l has also been found to be associated with increased risk of death and ami (10.5%) compared to ctnt ≤ 0.06 µg/l.25 based on roc curve analysis, a cut-off concentration of ctnt ≥ 0.06 µg/l was slightly more sensitive and equally specific to ctnt ≥ 0.1 µg/l for the detection of complications. depending on whether the cut-off concentration used was ≥ 0.1 µg/l or ≥ 0.06 µg/l, the frequency of abnormal ctnt elevations was 7.5% and 12.5 % respectively. despite the low sensitivity of ctnt, the specificity and positive predictive value for the detection of complications was very high. event-free survival of patients with elevated ctnt concentrations was significantly lower than those without ctnt elevations after angioplasty. cardiactnt was also associated with increased risk of cabg on long-term follow-up thus validating the prognostic significance of ctnt elevations post-pci. measurements of cardiac markers post-pci will be a useful adjunct to angioplasty and will help detect patients with subtle myocardial damage and may guide further management. twelve patients (32%) with elevated ctni in our study did not receive any form of antiplatelets (other than aspirin) during or after pci. the ctni concentrations range in these patients were 0.18–2.12 µg/l. eight out of these 12 patients had worsening of their angina or further cardiac events during follow-up. conclusion heart-type-fabp measurements at 1 hour (or thereafter) post-pci in patients with suspected complications may offer the best early chance of detecting evolving ami. cardiac-tni has emerged as the most sensitive marker for the detection of major complications in patients undergoing pci. it offers a reliable detection of myocardial damage that is sometime not obvious by visual assessment alone. the adjunctive measurements of cardiac markers post-pci could help identify certain groups with elevated cardiac markers concentrations that might benefit from long-term treatment with newer antiplatelets therapy. measurements of ctni 16–24 hours post-pci should be part of the work-up management of patients following elective pci. conflict of interest the authors report no conflict of interest. references 1. parisi af, folland ed, hartigan p. a comparison of angioplasty with medical therapy in the treatment of validity of cardiac markers as diagnostic and prognostic indicators of complications in patients undergoing percutaneous coronary intervention 40 | squ medical journal, april 2010, volume 10, issue 1 single-vessel coronary artery disease. veterans affairs acme investigators. n engl j med 1992; 326:10–16. 2. myler rk, shaw re, stertzer sh, bashour tt, ryan c, hecht hs, et al. unstable angina and coronary angioplasty. circulation 1990; 82:ii88–ii95. 3. grines cl, browne kf, marco j, rothbaum d, stone gw, o’keefe j, et al. a comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. the primary angioplasty in myocardial infarction study group. n engl j med 1993; 328:673–9. 4. talley jd, weintraub ws, roubin gs, douglas js jr, anderson hv, jones el, et al. failed elective percutaneous transluminal coronary angioplasty requiring coronary artery bypass surgery: in-hospital and late clinical outcome at 5 years. circulation 1990; 82:1203–13. 5. dorros g, cowley mj, janke l, kelsey sf, mullin sm, van raden m. in-hospital mortality rate in the national heart, lung, and blood institute percutaneous transluminal coronary angioplasty registry. am j cardiol 1984; 53:17c–21c. 6. sinclair in, mccabe ch, sipperly me, baim ds. predictors, therapeutic options and long-term outcome of abrupt reclosure. am j cardiol 1988; 61:61g–66g. 7. lincoff am, popma jj, ellis sg , hacker ja, topol ej. abrupt vessel closure complicating coronary angioplasty: clinical, angiographic and therapeutic profile. j am coll cardiol 1992; 19:926–35. 8. potkin bn, keren g, mintz gs , douek pc, pichard ad, satler lf, et al. arterial responses to balloon coronary angioplasty: an intravascular study. j am coll cardiol 1992; 20:942–51. 9. landau c, lange ra, hillis ld. percutaneous transluminal coronary angioplasty. n engl j med 1994; 330:981–93. 10. meier b, gruentzig ar, king sb 3rd, douglas js jr, hollman j, ischinger t, et al. risk of side branch occlusion during coronary angioplasty. am j cardiol 1984; 53:10–14. 11. genser n, mair j, friedrich g, talasz h, moes n, mühlberger v, et al. uncomplicated successful percutaneous transluminal coronary angioplasty does not affect cardiac troponin t plasma concentration. am j cardiol 1996; 78:127–8. 12. abdelmeguid ae, topol ej, whitlow pl, sapp sk, ellis sg. significance of mild transient release of creatine kinase-mb fraction after percutaneous coronary intervention. circulation 1996; 94:1528–36. 13. genser n, mair j, talasz h , puschendorf b, calzolari c, larue c, et al. cardiac troponin i to diagnose percutaneous transluminal coronary angioplastyrelated myocardial injury. clin chim acta 1997; 265:207–17. 14. johansen o, brekke m, stromme jh, valen v, seljeflot i, skjaeggestad o, et al. myocardial damage during percutaneous transluminal coronary angioplasty as evidenced by troponin t measurements. eur heart j 1998; 19:112–17. 15. kugelmass ad, cohen dj, moscucci m, piana rn, senerchia c, kuntz re, et al. elevation of the creatine kinase myocardial isoform following otherwise successful directional coronary atherectomy and stenting. am j cardiol 1994; 74:748–54. 16. la vecchia l, bedogni f, finocchi g, mezzena g, martini m, sartori m, et al. troponin t, troponin i and creatine kinase-mb mass after elective coronary stenting. coron artery dis 1996; 7:535–40. 17. ravkilde j, nissen h, mickley h, andersen pe, thayssen p, hørder m. cardiac troponin t and ckmb mass release after visually successful percutaneous transluminal angioplasty in stable angina pectoris. am heart j 1994; 127:13–20. 18. abbas sa, glazier jj, wu ah , dupont c, green sf, pearsall la, et al. factors associated with the release of cardiac troponin t following percutaneous transluminal coronary angioplasty. clin cardiol 1996; 19:782–6. 19. alhadi ha, fox ka. do we need additional markers of myocyte necrosis: the potential value of heart fatty acid-binding protein. qjm 2004; 97:187–98. 20. silber s, albertsson p, avilés ff, camici pg, colombo a, et al. guidelines for percutaneous coronary intervention: the task force for percutaneous coronary intervention of the european society of cardiology. eur heart j 2005; 26:804–7. 21. la vecchia l, bedogni f, finocchi g, mezzena g, martini m, sartori m, et al. troponin t, troponin i and ck-mb (mass) in the detection of peri-procedural myocardial damage after coronary angioplasty. cardiologia 1997; 42:405–13. 22. garbarz e, iung b, lefevre g, makita y, farah b, michaud p, et al. frequency and prognostic value of cardiac troponin i elevation after coronary stenting. am j cardiol 1999; 84:515–18. 23. serruys pw, van hout b, bonnier h, legrand v, garcia e, macaya c, et al. randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (benestent ii). lancet 1998; 352:673–81. 24. chan aw, moliterno dj, berger pb, stone gw, dibattiste pm, yakubov sl, et al. triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival; results from the do tirofiban and reopro give similar efficacy outcome trial (target). j am coll cardiol 2003; 42:1188–95. 25. lindahl b, venge p, wallentin l. relation between troponin t and the risk of subsequent cardiac events in unstable coronary artery disease. the frisc study group. circulation 1996; 93:1651–7. departments of 1pulmonary medicine, 2cardiothoracic & vascular surgery, 3general surgery and 4pathology & laboratory medicine, all india institute of medical sciences, bhopal, madhya pradesh, india *corresponding author’s e-mail: khuranaalkesh@gmail.com أنتباذ صدري بطاين رمحي يظهر مع أسرتواح الصدر املوهي ثنائي اجلانب فر�شا في�شوناث، األكي�ض كورانا، اأبي�شيك جويال، يوجي�ض نيواريا، ماهيندرا براتاب �شينج، هيمالتا بانوار، جارينا جويل thoracic endometriosis presenting with bilateral hydropneumothorax varsha viswanath,1 *alkesh khurana,1 abhishek goyal,1 yogesh niwariya,2 mahendra p. singh,3 hemlata panwar,4 garima goel4 a 36-year-old woman was admitted to the all india institute of medical sciences, bhopal, madhya pradesh, india, in 2018 with complaints of breathlessness upon exertion and a dry cough of one week’s duration. she had been previously diagnosed with recurrent right-sided hydropneumo thorax and one episode of left-sided hydropneumothorax over the course of the past two years; at these times, she was treated with an intercostal drain (icd), antibiotics and analgaesics. serosanguinous aspiration revealed lymphocytic and exudative pleural effusion and her adenosine deaminase levels were below normal. a polymerase chain reaction-based assay for mycobacterium tuberculosis was negative. a detailed medical history indicated a clear correlation between the patient’s symptoms and her menstrual cycle. upon admission, a chest x-ray showed right-sided hydropneumothorax and minimal pleural effusion and an air pocket on the left side [figure 1a]. computed tomography of the thorax confirmed these findings [figure 1b]. an icd was inserted in the right lung and the patient underwent pleurocentesis to relieve the air pocket in the left lung. a pleural fluid analysis yielded similar results to those of prior investigations. an echocardiograph and ultrasonogram of the abdomen were normal and tests revealed no indication of collagen vascular disease. the patient underwent video-assisted thoracoscopic surgery in the right pleural cavity, combined with a thoracotomy on the left side due to intercostal narrowing. marked adhesions and haemorr hagic spots were observed [figure 2], which were success fully treated using adhesiolysis. multiple biopsies of the pleural surface revealed the presence of endometrial gland fragments, confirming a diagnosis of thoracic endometriosis [figure 3]. a pleurodesis procedure using povidone-iodine was performed on both sides of the lungs. the patient made an uneventful recovery and was prescribed danazol and gonadotropin-releasing hormone analogues to suppress ovulation. there was no evidence of recurrence at a six-month follow-up appointment. interesting medical image sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e245–246, epub. 9 sep 18 submitted 25 feb 18 revision req. 10 apr 18; revision recd. 25 apr 18 accepted 10 may 18 figure 1: a: chest x-ray of a 36-year-old woman with menstruation-associated coughing and breathlessness showing right-sided hydropneumothorax (arrow) and left pleural effusion (arrowhead). b: chest computed tomography showing right-sided hydropneumothorax treated with an intercostal drain in situ (arrow) and left pleural effusion with a small air pocket (arrowhead). doi: 10.18295/squmj.2018.18.02.024 thoracic endometriosis presenting with bilateral hydropneumothorax e246 | squ medical journal, may 2018, volume 18, issue 2 while right-sided pneumothorax is seen in the majority of cases of thoracic endometriosis, bilateral involvement is extremely rare.4 to the best of the authors’ knowledge, this is the first reported case of thoracic endometriosis presenting with bilateral hydro pneumothorax. in addition, the presence of seroanguinous pleural effusion along with pneumothorax and thoracic endometriosis is very rare.5 various theories have been suggested to elucidate the pathophysiology of thoracic endometriosis, including the metaplastic transformation of cells lining the pleural cavity, vascular embolisation and peripheral implantation of endometrial tissue or retrograde menst ruation.1 the latter theory explains the right-sided predilection of the disease whereby endometrial tissue from the pelvis travels up the right paracolic gutter into the right subphrenic space. diagnosis of the condition relies heavily upon clinical suspicion, based on the synchronisation of symptoms with the patient’s menstrual cycle, and histological confirmation.1,6 thera peutic options include hormonal suppression or ovarian ablation.1 a c k n o w l e d g e m e n t s the authors wish to acknowledge dr. ashish khanna, staff physician of the anesthesiology institute, cleveland clinic, ohio, usa, for his help in proofreading and editing this manuscript. references 1. honoré gm. extrapelvic endometriosis. clin obstet gynecol 1999; 42:699–711. 2. joseph j, sahn sa. thoracic endometriosis syndrome: new observations from an analysis of 110 cases. am j med 1996; 100:164–70. doi: 10.1016/s0002-9343(97)89454-5. 3. alifano m, roth t, broët sc, schussler o, magdeleinat p, regnard jf. catamenial pneumothorax: a prospective study. chest 2003; 124:1004–8. doi: 10.1378/chest.124.3.1004. 4. marjański t, sowa k1, czapla a1, rzyman w. catamenial pneumothorax: a review of the literature. kardiochir torakochirurgia pol 2016; 13:117–21. doi: 10.5114/kitp.2016.61044. 5. mehta aa, gupta a, venkitakrishnan r. a case of young woman with recurrent right pleural effusion. lung india 2015; 32:648–50. doi: 10.4103/0970-2113.168097. 6. ziedalski tm, sankaranarayanan v, chitkara rk. thoracic endometriosis: a case report and literature review. j thorac cardiovasc surg 2004; 127:1513–14. doi: 10.1016/j.jtcvs.2003. 12.016. comment endometriosis refers to the growth of endometrial tissue outside of the uterus and almost always occurs in women of reproductive age.1 in patients with thoracic endometriosis, classical symptoms consist of catamenial pneumothorax, catamenial haemothorax, catamenial haemoptysis or lung nodules, with pneumothorax and haemothorax occurring in 73% and 14% of cases, respectively.2 pneumothorax can occur due to a spontaneous rupture of blebs, alveolar rupture caused by prostaglandin-induced bronchial constriction or an air leak following endometrial sloughing.3 figure 2: thoracoscopic photograph of the pleural cavity of a 36-year-old woman with menstruation-associated coughing and breathlessness showing dense adhesions and haemorrhagic spots (arrow) on the parietal pleural surface. figure 3: haematoxylin and eosin stain at x100 magnification showing an intravascular endometrial gland frag ment (arrow) in the interalveolar septa, indicative of thoracic endometriosis. https://doi.org/10.1016/s0002-9343%2897%2989454-5 https://doi.org/10.1378/chest.124.3.1004 https://doi.org/10.5114/kitp.2016.61044 https://doi.org/10.4103/0970-2113.168097 https://doi.org/10.1016/j.jtcvs.2003.12.016 https://doi.org/10.1016/j.jtcvs.2003.12.016 as all contributors to this journal know, writing is hard work and effective scientific writing, in particular, requires knowledge, effort, discipline and experience. most of us find putting all this together rather difficult, hence the ongoing demand for workshops and short courses at sultan qaboos university on writing academic and scientific papers. the fact that most scientific writing must be done in english, whereas most staff at squ are not native english speakers, adds to the challenges. everyone who can identify with these statements will find this little book useful it is clear, practical and to the point. tim albert has structured it as a short course consisting of several self-exercises. these exercises take the reader through a simple set of steps that develop a procedure for effective writing. the emphasis throughout is on brevity and clarity and the need to have a structured approached to writing. it is not a lesson in english. he points out that writing papers is primarily a craft that can be learnt, and not an art. albert starts by recognising that most of us find writing difficult and health workers, like everyone else, may often experience ‘writer’s block’. the various reasons for this are listed and the reader is guided to identify those impediments relevant to them. it is shown that some of these blocks to writing are just excuses and that most can easily be easily overcome! the need to write from the perspective of the target audience is emphasised, i.e. to write to or for the intended reader. bearing this in mind, albert provides exercises to define or identify the five key elements that need to be clear in the mind of an author who wants to write a good paper: the central message to be conveyed, the target market, the desired length and format of the article, relevant deadlines, and the pay-off or desired end result. identifying all these issues defines the brief of the writer. a technique for sorting all the information that must go into a paper into a logical structure is to summarise the content in a diagram known as a spidergram. this enables the writer to collate their thoughts and information, group them in a structured way, and visualise the complete layout of the paper. for a scientific paper that is to be published in a journal, for example, the four elements that revolve around the central message are the introduction (why), methods (how), results (what was found) and discussion (what does it mean), each with subsections. i believe most scientific writers will find this simple spidergram a very useful tool. when it comes to putting together the paper, emphasis is placed on the importance of paragraph structure and content. simple rules are provided with methods to accomplish this and how this may vary for different kinds of article targeting different audiences. the various stages of drafting are covered and the main elements of self-editing are placed in two categories: macro-editing and micro-editing. اُكتب بفعالية مساق سريع للعاملني املشغولني يف قطاع الصحة املؤلف: تيم البيرت book review write effectively a quick course for busy health workers author: tim albert publisher: radcliffe publishing, oxford, 1st edition, 2008 isbn: 13: 9781846191350 orders: www.radcliffe-oxford.com squ med j, december 2009, vol. 9, iss. 3, pp. 357-358, epub. 19th dec 2009 submitted 1st september 09 write effectively a quick course for busy health workers 358 | squ medical journal, december 2009, volume 9, issue 3 macro-editing involves checking paragraph flows and the tone of the article to ensure that it is logical and appropriate. a useful method for checking the tone is provided by the so-called gunning fog test, which involves quantifying the average length of sentences and the use of excessively long words by using a simple index; high scores indicate writing that is complex and unwieldy. micro-editing is the tedious, but important process of reviewing all the details, attention to which is essential to make a polished manuscript. this includes checking: facts for accuracy, accidental omissions, grammar, spelling, punctuation, style and references. layout, format and design are also important issues touched on, with examples. feedback and review by family, friends, colleagues, bosses and/or others before final submission is essential, but needs to be balanced in order to be constructive and helpful. the differences between appropriate and inappropriate, good and bad reviews, how to deal with them, and when to ignore them, accept them or otherwise, are touched on. although feedback is necessary before a manuscript is submitted for formal review, not all feedback is useful. it can, if inappropriate or not handled properly, be destructive. the book ends with a series of 16 appendices of useful, often humorous information and quotations. this book is not a course in english, but rather a set of techniques in the method of writing. nevertheless, several useful tips on english use do emerge and the appendices cover many common english errors. write effectively is an easy read and can be skimmed through in an hour or so. working through the exercises will take longer, but is recommended for anyone having difficulty in writing. if you regularly experience ‘writer’s block’ you will find this a useful manual and a worthwhile addition to your bookshelf. i plan to incorporate several elements and exercises from tim albert’s book into the workshops on writing scientific papers which the deanship of postgraduate studies offers to squ staff and postgraduate students. in particular, i will recommend to colleagues the spidergram method for sorting information and the gunning fog test for assessing the tone of their writing. r e v i e w e r anton mclachlan deanship of postgraduate studies sultan qaboos university, muscat, sultanate of oman. email: anton.m@squ.edu.om e170 | squ medical journal, may 2019, volume 19, issue 2 رد: املرضى اإلناث واملوافقة املستنرية اخللفية الثقافية لعمان re: female patients and informed consent oman’s cultural background dear editor, i read with great interest the recent sounding board article by al balushi in the february 2019 issue of squmj.1 the author raised the important issue of informed consent and ensuring that patients understand consent. however, i take issue with the following point: “moreover, the informed consent document should be written in the language used most commonly in the country or region. if a patient cannot read or understand the language, a translation should be provided by professional medical translators.”1 although the reasoning for this is understandable, the implication of this statement is that the consent form should be in one language only and that translators should provide different language versions when needed. given the shortage of suitable translators at any one time, this would result in various problems and delays; in oman, there are at least three languages in which informed consent forms should be readily available. in addition to the author’s other suggestions, i would like to add that electronic language tools can be used to test consent form language level. while these types of tools are not fool-proof, they can add an extra layer of support. for english, the flesch-kincaid tool that is available by default in microsoft word (microsoft corp., redmond, washington, usa) and the gunning-fog tool that is available online can be used. for arabic, the automatic arabic readability index or general language tools, such as the coleman-liau index and the lasbarhetsindex and rix are possible options.2–5 furthermore, physicians should ensure that a patient has understood the informed consent by requesting an explanation. the author does emphasise the need to ensure understanding, but does not provide much guidance on how this can be done. having a good informed consent form and asking the patient if they understand the information provided to them is a good start; however, this is not a valid way of gauging understanding. if it were, there would not be examinations for students. for example, students would simply have to answer “do you understand cardiology?” with a “yes” to be awarded an a grade. as a result, understanding is gauged by the use of an examination. while a patient cannot be given an examination, physicians could do the following: after the consent form is given and all explanations are provided, the patient is asked a simple question “please explain it back to me.” while a patient should not be expected to use all the correct medical terminology, their originally-constructed explanation, which should not be merely parroting phrases the physician used, should rapidly determine whether the patient has understood and is truly informed. ken masters medical education & informatics unit, college of medicine & health sciences, sultan qaboos university, muscat, oman e-mail: itmeded@gmail.com references 1. al balushi aa. female patients and informed consent: oman’s cultural background. sultan qaboos univ med j 2019; 19:e11–14. https://doi.org/10.18295/squmj.2019.19.01.003. 2. al-tamimi ak, jaradat m, aljarrah n, ghanim s. aari: automatic arabic readability index. int arab j inf technol 2014; 11:370–8. 3. coleman m, liau tl. a computer readability formula designed for machine scoring. j appl psychol 1975; 60:283–4. https://doi.org/10.1037/ h0076540. 4. anderson j. analysing the readability of english and non-english texts in the classroom with lix. from: https://files.eric.ed.gov/fulltext/ ed207022.pdf accessed: jul 2019. 5. anderson j. lix and rix: variations on a little-known readability index. j read 1983; 26:490–6. sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e170, epub. 8 sep 19 submitted 16 jul 19 accepted 25 jul 19 https://doi.org/10.18295/squmj.2019.19.02.018 letter to the editor this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.003 https://doi.org/10.1037/h0076540 https://doi.org/10.1037/h0076540 https://creativecommons.org/licenses/by-nd/4.0/ dr. robin l. bennett has extensive experience in the field of medical genetics and is certified as a genetic counsellor by the american board of medical genetics and the american board of genetic counseling. she currently serves as the senior genetic counsellor and co-director of the genetic medicine clinic in the division of medical genetics, department of medicine, at the university of washington. such extensive expertise has allowed dr. bennett to provide the scientific and clinical communities with two editions of the volume entitled: “the practical guide to the genetic family history”. in comparison to the first edition, the second one provides an updated version compiling the most recent tools and strategies to assess family pedigrees in order ultimately to provide diagnoses, evaluate risk, and counsel patients. the innovative aspect of this second edition lies not only in guiding health care professionals on how to record a medical family history and establish the family pedigree, but also provides clear explanations of why each piece of information collected is invaluable. this book is a valuable resource which outlines the appropriate methods for taking and recording a patient's family medical history, allowing the primary care physician to be more accurate in diagnosing conditions with potential genetic origin. dr. bennett presents genetic screening forms outlining directed questions, pedigree nomenclature, and common strategies, thus providing readers with the basic knowledge in human genetics needed to diagnose inherited disorders and further identify patients with familial disease susceptibility. in addition to providing essential tools that will aid the primary care physician in diagnosing ím]öá÷]<í◊ò^√÷]<�ëö`j◊÷<í◊€√÷]<ÿè÷ç÷]  book reviewbook review a practical guide to the genetic family history author: robin l bennett publisher: wiley-blackwell, 2nd edition, 2010 isbn: 978-0-470-04072-0 orders: www.wiley.com/wiley-blackwell squ med j, december 2010, vol. 10, iss. 3, pp. 412-413, epub. 14th nov 10 submitted 3rd nov 10 robin l bennett book review | 413 conditions with inherited genetic components, the book outlines the various criteria that will help in determining patterns of inheritance; calculating risk of disease; referring the patients for genetic counseling; informing and educating patients about the disease; managing the disease, and recommending the patients for genetic laboratory testing. as an expert in genetic counselling, dr. bennett also provides specific clues in her book that will help the wide range of readers to deal with the psychological, cultural, and ethical issues that arise when taking family history and breaking news to patients. this is an essential aspect of the book because genetic counselling relies strongly on the environment of the patient, and the health practitioner needs to be familiarised with the patient’s cultural and social environment. in fact, genetic counselling in the arab world requires specific knowledge about the community and its culture. in summary, using clinical examples based on hypothetical families, this second edition presents the most up to date methods and strategies for establishing a family pedigree, including: 1) questionnaires to use when preparing a detailed medical family history for a specific disease; 2) sharing information and education of patients and families during genetic counselling; 3) identification of individuals with increased risk based on analysis of family pedigrees and 4) ethical issues and special considerations related to adoptions or gamete donors…, etc. in conclusion, this book is an invaluable resource which will enable clinical geneticists, counsellors, primary care and specialist physicians, as well as nurses, medical social workers, and physician assistants to take full advantage of the information and strategies provided. this will enable them to prepare and establish a family pedigree as a primary tool for making a genetic risk assessment and providing counselling for patients and their families. r e v i e w e r allal ouhtit department of genetics college of medicine & health sciences sultan qaboos university, muscat, oman email: aouhtit@squ.edu.om squ med j, august 2010, vol. 10, iss. 2, pp. 221-226, epub. 19th jun 10 submitted: 13th jan 10 revision req. 29th mar 10, revision recd. 4th april 10 accepted: 14th april 2010 1department of life sciences, university of calicut, calicut, kerala, india; 2institute of cardiology, banglore, india; 3department of biochemistry, al arab medical university, benghazi, libya *corresponding author email: dhastagir@yahoo.ca مرض الكبد الدهين غري الكحولي هل هو عامل اختطار ملرض الشريان التاجي؟ دراسة أولية جملموعة من سكان اهلند مانوبرايا ثريوفاجندر، �شاهني خان ، دا�شتاجري �رشيف امللخص: الهدف: حتديد وجود مرض الكبد الدهني غير الكحولي عند مرضى الشريان التاجي . الطريقة: مت اختيار 149 مريضا أحيلوا إلى معهد القلب في منطقة باجنلور بالهند، في الفترة ما بني يناير 2007 إلى يونيو 2009، ومت تشخيصهم بإصابتهم مبرض الشريان التاجي . أربعة مرضى لم يشاركوا في الدراسة. مت أخذ عينات دم وريدي من املرضى املشاركني ومن عينة ضابطة (100 شخصا) من الذين ترددوا ألداء الفحص الطبي الدوري .متوافقة أعمارهم والبروتني (i) البالزمينوجني منشط ملثبط املناعية املقايسة وإنزمي األمني ناقالت أنزميات شامال الكبد لوظائف روتيني فحص عمل مت املرضى. كذلك مع الدهني الكبد مرض وجود حتديد مت املصل في االالنني أمني ناقلة أنزمي مستوى وقياس َدى الصَّ طيطحُ تَخنْ (ألفا) .وباستخدام الورم نخر (ج) وعامل املتفاعل غير الكحولي عند مرضى الشريان التاجي. النتائج: وجد لدى مرضى الشريان التاجي الذين يعانون من مرض الكبد الدهني غير الكحولي مستويات مرتفعة املقايسة إنزمي (ألفا) وكذلك الورم نخر عامل مستويات الضابطة. كانت العينة مبستويات (aic) مقارنة مبستوى طفيف ارتفاع مع الكبد أنزميات من املناعية ملثبط منشط البالزمينوجني (i) أعلى لدى مرضى الشريان التاجي والكبد الدهني غير الكحولي مقارنة مبستويات العينة الضابطة بدرجة معتدة إحصائيا (p<0.1,p<0.05) في كل من املرضى اإلناث والذكور.كان مستوى البروتني املتفاعل (ج) (p<0.01 في املموعتني) وكذلك حمض اليوريك أعلى في املموعتني من املرضى (p<0.05,p<0.01 في املرضى الذكور واإلناث على التوالي). كما كانت مستويات االديبونكتني منخفضة بشكل كبير في املرضى ملثبط املناعية املقايسة إنزمي من كل مستوى التوالي). اخلالصة: زيادة على واإلناث الذكور املرضى مقارنة بالعينة الضابطة (p<0.05, p<0.001 في منشط البالزمينوجني (i) وعامل نخر الورم (ألفا) في املصل عكس حالة االستعداد لاللتهاب في هؤالء املرضى والذي قد يكون بسبب وجود مرض الكبد الدهني غير الكحولي، وهذا قد يساهم بشكل إضافي في نشوء أمراض القلب واألوعية الدموية. مفتاح الكلمات: مرض الكبد الدهني غير الكحولي، اديبو نكتني، مقاومة األنسولني، متالزمة االيض، مرض الشريان التاجي . abstract: objectives: the objective of this study was to identify the presence of non-alcoholic fatty liver disease (nafld) in patients with coronary artery disease (cad). methods: 149 patients were selected, who had been referred to the institute of cardiology, banglore, india, between january 2007 and june 2009 and diagnosed with cad. four patients did not participate in the study. venous blood samples were taken from these cases, and agematched healthy controls who came for a master health check-up (n = 100). all were subjected to routine liver function tests including serum transaminases, enzyme immunoassays for plasminogen activator inhibitor i (pai-i), c reactive protein (crp), and tumour necrosis factor-alpha (tnf-α). using ultrasonography and serum alanine aminotransferase (alt) levels, the presence of nafld in cad patients was reported. results: cad patients with nafld had significantly higher liver enzymes and marginally higher a1c levels compared to control subjects. levels of tnf-α and pai-i were higher in cad patients with nafld compared to both female and male controls (p <0.1 and p <0.05). levels of crp (p <0.01 in both groups) and uric acid were increased in both group of patients (p <0.05 and p <0.01 in male and female patients, respectively). levels of adiponectin were significantly reduced in the patients compared to the controls (p <0.05 and p <0.001) in male and female patients respectively. conclusion: the increased serum levels of pai-i and tnf-α reflected the proinflammatory status in these cad patients which may be due to the presence of nafld. this could contribute additively to the development of cardiovascular events (cvd). keywords: non-alcoholic fatty liver disease; adiponectin; insulin resistance; metabolic syndrome; coronary artery disease. non-alcoholic fatty liver disease (nafld) is it an emerging risk factor for coronary artery disease? preliminary study in a local indian population manopriya thiruvagounder,1 shaheen khan,2 *dhastagir s sheriff3 clinical & basic research non-alcoholic fatty liver disease (nafld) is it an emerging risk factor for coronary artery disease a preliminary study in a local indian population 222 | squ medical journal, august 2010, volume 10, issue 2 metabolic syndrome is frequently associated with a hypercoagulable condition, in that the coagulation system is switched towards a prothrombotic state, involving increased plasmatic coagulation, reduced fibrinolysis, decreased endothelial thromboresistance and predominantly platelet hyperactivity.1-6 all of these abnormalities in the coagulation and fibrinolytic systems may contribute to the development of cardiovascular complications in patients with metabolic syndrome. now, there is growing evidence that non-alcoholic fatty liver disease (nafld), a hepatic manifestation of the metabolic syndrome,7-8 is strongly associated with a systemic proinflammatory/procoagulant state, independently of shared cardiometabolic risk factors. recently, we have shown that in non-alcoholic steatohepatitis (nash) patients there is an increase in the levels of acute inflammatory markers, including c-reactive protein (crp).9 there is evidence from another study that nash is not simply a marker of the prothrombotic state in the metabolic syndrome, but is directly involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic/ inflamed liver.10 therefore, the present study was undertaken to evaluate the levels of plasminogen activator inhibitor-i (pai-i), tumour necrosis factor-α (tnf-α), along with crp in nafld patients in a local population in india. methods the patients for the present study were among those referred between january 2007 and june 2009 to the institute of cardiology, banglore, india. a total of 149 patients with coronary artery disease (cad) and nafld and 124 age-matched healthy control subjects who came for a master health check-up (n = 124) were selected for the present study. the presence of nafld in cad cases was identified by serum alanine transaminase levels, serum aspartate aminotransferase/serum alanine aminotransferase (ast/alt) ratio <1 and ultrasonographic findings. these cases were subjected to the following analyses. venous blood was drawn in the morning after an overnight fast. plasma liver function tests and other biochemical blood measurements were determined by standard laboratory procedures including enzyme immunoassays for pai-i and tnf-α. all participants had negative serology for hepatitis b or c. levels of low density lipoprotein (ldl) cholesterol was calculated by friedwald’s equation. hba1c (a1c) was measured by a highperformance liquid chromatography analyser (ha8140, menarini diagnostics, florence, italy); the upper limit of normal for the laboratory was 5.9%. the respective intraand inter-assay coefficients of variation (cvs) for the assays were: fasting plasma glucose (fpg) 1.4 and 2.0%; total cholesterol (tc) 1.2% and 2.1%; triglyceride (tg) 1.5% and 3.6%; hdl-c 2.8% and 3.5%; pai-i 2.5% and 6.5%; tnfalpha 3.5% and 6.65%; hba1c 1.9% and 2.1%. the bmi was calculated by dividing weight in kilogrammes by height in metres squared. waist advances in knowledge 1. this study clarifies and contributes to the hypothesis that non-alcoholic fatty liver disease (nafld) could be a risk factor for coronary artery disease (cad). 2. the release of proinflammatory markers like tumour necrosis factor alpha (tnf-alpha) and plasminogen activator inhibitori (pi-i) may be causative factors that may initiate or contribute to the precipitation of coronary vascular events. 3. the study confirms this supposition reflected by the increased serum levels of serum tnf-alpha and pai-i in cad patients with nafld. 4. the study points out that every region and race must have their physical as well as biochemical parameters standardised for early detection and prevention of obesity related disorders application to patient care 1. the study indicates that it would be prudent to look for markers other than lipid or diabetic profiles in patients with marked visceral obesity susceptible to coronary artery disease. 2. it is shown that in india the prevalence of diabetes is very high due to obesity. it is known that a body mass index (bmi) of >25 is considered to be high for the indian population, but considered normal for western populations. therefore, it is necessary to have a standardised record of bmi for all populations. 3. it may be helpful to estimate serum aminotransferases to identify the presence of nafld in obese patients along with impaired glucose tolerance and hypertriglyceridemia (excluding other causes of fatty liver disease). manopriya thiruvagounder, shaheen khan, dhastagir s sheriff clinical and basic research | 223 circumference was measured in a standing position at the level of the umbilicus. blood pressure was assessed with a standard mercury manometer. metabolic syndrome was defined according to criteria proposed by the national cholesterol education program adult treatment panel iii (atp iii).11 hepatic ultrasound scanning was performed in all participants by a trained operator who was blind to all clinical and laboratory characteristics of participants, using an acuson 128-xp/10 scanner with a 3.5-mhz linear transducer. hepatic steatosis was diagnosed by characteristic echo patterns, according to conventional criteria, i.e. evidence of diffuse hyperechogenicity of liver relative to kidneys, ultrasound beam attenuation, and poor visualisation of intrahepatic structures.12-14 repeated measurements (that were performed on a subgroup of 100 patients) on the same subjects gave intra and inter observer coefficients of variation within 5%.9 the ethics review committee of the institute of cardiology, banglore, india approved the study project. data are presented as the means ± standard devitaion (sd) or frequencies. skewed variables (serum triglyceride and liver enzyme levels) were logarithmically transformed to improve normality before analysis. statistical analyses included the unpaired t test and the χ2 test with yates’ correction for continuity (for categorical variables). results the clinical and biochemical characteristics of participants are shown in table 1 for male and table 2 for female subjects respectively. because of the study design, case and control subjects were almost identical in terms of gender and age. the cad patients with nafld had significantly higher liver enzymes and marginally higher a1c levels compared to control subjects. the proportion using antihypertensive drugs was higher among case subjects (~72 versus ~58%), whereas the proportion taking lipid-lowering or antiplatelet drugs was essentially similar in both male and female groups (~35 and ~50%, respectively). cad patients with nafld were older (p < 0.001), had higher liver enzymes (p < 0.001), and some tended to have a longer duration of diabetes (5.5 ± 2.5 years duration, p = 0.064). gender, smoking status, ldl cholesterol, a1c, and diabetes treatment did not differ between the groups (not shown). the levels of tnf-α and pai-i were higher in cad patients with nafld compared to normal control subjects (p <0.1 and p <0.05) in both female and male patients. the levels of crp and uric acid were increased in both groups of patients (p <0.05 table 1: basic characteristics of males with nafld normal (n = 63) cad patients with nafld (n = 69) p age (years) 47.7 ± 3.6 48.1 ± 14.6 0.982 weight kg 66.1 ± 7.8 79 ± 11.9 <0.0001 bmi (kg/m2) 22.7 ± 2.4 27.8 ± 3.4 <0.0001 waist-to-hip ratio (cm/cm), 0.87 ± 0.04 0.94 ± 0.04 <0.0001 body fat mass (kg) 12.5 ± 3.4 21.3 ± 6.3 <0.0001 systolic blood pressure (mmhg) 113.6 ± 13.4 127.9 ± 16.2 <0.0001 diastolic blood pressure (mmhg) 69.6 ± 11.4 78.8 ± 11.8 0.002 triglyceride (mg/dl) 123.6 ± 63.9 181.8 ± 92.1 0.004 hdl cholesterol (mg/dl) 47.1 ± 9.1 41.0 ± 7.9 0.005 homa 1.49 ± 0.71 3.04 ± 1.6 <0.0001 uric acid (mg/dl) 5.6 ± 1.2 7.4 ± 1.7 0.05 alt (iu/i) 20.7 ± 9.3 42.9 ± 29.1 , <0.0001 ast (iu/i) 19.7 ± 4.3 28.4 ± 14.2 <0.001 ast/alt ratio >1 <1 crp (mg/l) 3.72 ± 2.11 8.48 ± 2.75 <0.01 pai-i ng% 3.6 ± 1.2 7.9 ± 2.3 <0.01 tnfα pg/ ml% 6.66 ± 0.26 8.92 ± 0.44 <0.05 adiponectin (ug/ml) 6.2 ± 3.4 4.5 ± 2.8 <0.05 legend: nafld = non-alcoholic fatty liver disease; cad = coronary artery disease; bmi = body mass index; hdl = high density lipoproteins; homa = homeostasis model assessment; ast = serum aspartate aminotransferase; alt = serum alanine aminotransferase; crp = c reactive protein; pai-i =plasminogen activator inhibitor i; tnf-α = tumor necrosis factor-alpha. non-alcoholic fatty liver disease (nafld) is it an emerging risk factor for coronary artery disease a preliminary study in a local indian population 224 | squ medical journal, august 2010, volume 10, issue 2 and p <0.01 in male and female patients, respectively). the levels of adiponectin were significantly reduced in the patients compared to the control subjects (p <0.05 and p <0.001 in male and female patients respectively.) discussion the biological mechanisms by which nafld could contribute to accelerated atherosclerosis are still poorly known. previous data suggest that the relationship between nafld and increased risk of cad is mostly reflected by hypertension and dyslipidemia.8,15,16 in this study, cad patients with nafld show an increase in proinflammatory markers tnf-α, crp and pai-i which may have additively contributed to future cardiovascular disease (cvd) events. this may be independent of metabolic syndrome and classic risk factors.10,11 conversely, several studies have consistently documented that insulin resistance predicts the incidence of cvd events10,11 and plays a pivotal role in the development of poor clinical outcomes in nafld patients.12-14 thus, nafld in its more advanced forms might act as a stimulus for further increased whole-body insulin resistance and dyslipidemia, leading to accelerated atherosclerosis. this hypothesis is also partly validated by recent prospective studies demonstrating that raised liver enzymes independently predict the development of type 2 diabetes and other metabolic syndrome features.8,10,18 another possible atherogenic mechanism linking nafld and increased cvd risk is represented by increased oxidative stress and subclinical inflammation, which are thought to be causal factors in the progression from simple steatosis to more advanced forms of nafld.1,12,24 reactive oxygen species derived from steatosis-stimulated fatty acid oxidation, attendant hepatocyte injury and cytokine release, and the ensuing proinflammatory milieu are likely to perpetuate the liver damage of nafld and add further atherogenic stimuli to the already high oxidative/ proinflammatory status that is closely related to the metabolic syndrome.8,10 in the present study, significant associations of nafld with impaired fibrinolytic activity were evidenced by increased levels of pai-i and elevated plasma c-reactive protein; these associations were independent of age, bmi, blood pressure, lipids, and insulin resistance.20 decreased plasma levels of adiponectin, which is an adipose-secreted cytokine with antiatherogenic properties,21 may represent another possible mechanism linking nafld and cvd risk. it is shown that hypoadiponectinemia is closely correlated to nafld in obese individuals, independent of insulin resistance and other metabolic syndrome variables.22 finally, accumulating evidence also exists that nafld table 2: basic characteristics of females with nafld normal (n = 61) cad patients with nafld (n = 76) p age (years) 47.1 ± 11.5 55.6 ± 8.5 weight kg 55.8 ± 6.4 67.2 ± 8.9 <0.0001 bmi (kg/m2) 22.6 ± 2.5 27.1 ± 2.9 <0.0001 waist-to-hip ratio (cm/cm), 0.87 ± 0.05 0.94 ± 0.05 <0.0001 body fat mass (kg) 16.3 ± 4.3 23.7 ± 4.3 <0.0001 systolic blood pressure (mmhg) 116.8 ± 16.7 124.7 ± 13.6 0.0008 diastolic blood pressure (mmhg) 71.5 ± 11.6 76.7 ± 10.4 0.015 triglyceride (mg/dl) 98.7 ± 53.7 150.0 ± 73.2 <0.0001 hdl cholesterol (mg/dl) 57.2 ± 11.4 47.8 ± 9.0 <0.0001 homa 1.46 ± 0.8 2.56 ± 1.1 <0.0001 uric acid (mg/ dl) 4.55 ± 2.40 7.55 ± 2055 <0.001 alt (iu/i) 16.6 ± 6.8 68.0 ± 19.7 <0.0001 ast (iu/i) 20.0 ± 5.9 45.0 ± 10.7 <0.001 ast/alt ratio <1 crp (mg/l) 3.22 ± 1.11 7.80 ± 2.75 <0.01 pai – i ng% 3.80 ± 1.2 6.90+2.3 <0.01 tnfα pg/ml% 6.86+0.26 8.92+0.44 <0.05 adiponectin (ug/ml 10.6 ± 4.8 7.2 ± 3.5 <0.0001 legend: nafld = non-alcoholic fatty liver disease; cad = coronary artery disease; bmi = body mass index; hdl = high density lipoproteins; homa = homeostasis model assessment; ast = serum aspartate aminotransferase; alt = serum alanine aminotransferase; crp = c reactive protein; pai-i = plasminogen activator inhibitor i; tnf-α = tumor necrosis factor-alpha. manopriya thiruvagounder, shaheen khan, dhastagir s sheriff clinical and basic research | 225 could be linked to accelerated atherogenesis through the presence of abnormal lipoprotein metabolism. in nafld, hepatic apolipoprotein b-100 synthesis, a rate-determining step in hepatic very-low-density lipoprotein (vldl) formation and in hepatocyte lipid export, is markedly reduced, and postprandial apolipoprotein b-100 responses are flat and strikingly dissociated from the concomitant increases of postprandial triglycerides.23,24 disturbances of vldl assembly are an important factor in the natural history of nafld and can also result in increased levels of atherogenic triglyceride and cholesterol-rich remnant particles.1,10,11 small dense ldl particles, which are thought to be more atherogenic,8,10 could also be increased in nafld patients. however, detailed compositional lipoprotein studies should be performed in patients with nafld to prove this contention. the diagnosis of nafld was based on ultrasonography and exclusion of known aetiologic factors of chronic liver disease and serum transaminases levels. indeed, it has been reported that the presence of >33% fat on liver biopsy is optimal for ultrasound detection of steatosis, although ultrasonography is not completely sensitive, particularly when hepatic fat infiltration is <33%.26 currently, it will be worthwhile to study whether improving nafld will ultimately prevent the development of cvd. however, it is notable that interventions that are known to be effective in preventing cvd among type 2 diabetic patients, including weight reduction and treatment with insulin-sensitising oral antidiabetic agents, may also improve nafld.1,8,14 the fact that the study was done on a representative sample of cad patients with low reported alcohol intake and with no exposure to hepatotoxic chemical or viral agents, and that a liver ultrasound for the diagnosis of nafld was performed on all participants, could enhance the validity of the present findings. conclusion in conclusion, the present study was done on proven cad patients with nafld to show the presence of nafld in cad patients. the increased levels of tnf-α, pai-i coupled with reduced adiponectin levels in cad patients with nafld, along with dyslipidemia, establishes the fact that nafld could be an additive risk factor for abnormal coronary vascular events. it is to be noted that the average age of cad with nafld patients was below fifty years in the males and above fifty years in the females.27 the lowered levels of adiponectin along with an increase in tnfalpha may be aggravating insulin resistance in these patients. further studies are being carried out with more patients to understand the possible link of nafld to atherogenic mechanisms. references 1. franchini m, targher g, montagnana m, lippi g. the metabolic syndrome and the risk of arterial and venous thrombosis. thromb res 2008; 122:727–35. 2. trost s, pratley r, sobel b. impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes. curr diab rep 2006; 6:47–54. 3. hivert mf, sullivan lm, shrader p, fox cs, nathan dm, d'agostino rb sr, et al. the association of tumor necrosis factor α receptor 2 and tumor necrosis factor α with insulin resistance and the influence of adipose tissue biomarkers in humans. metabolism 2010; 59:540–6. 4. palomo i, alarcon m, moore-carrasco r, argiles jm. hemostasis alterations in metabolic syndrome. int j mol med 2006; 18:969–74. 5. mina a, favaloro ej, koutts j. hemostatic dysfunction associated with endocrine disorders as a major risk factor and cause of human morbidity and mortality: a comprehensive meta-review. semin thromb hemost 2009; 35:798–809. 6. alessi mc, juhan-vague i. metabolic syndrome, haemostasis and thrombosis. thromb haemost 2008; 99:995–1000. 7. després jp, lemieux i, bergeron j, pibarot p, mathieu p, larose e, et al. abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. arterioscler thromb vasc biol 2008; 28:1039–49. 8. targher g. non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens. diabet med 2007; 24:1–6. 9. priya mt, sheriff ds. a preliminary study of inflammatory markers in non-alcoholic steatohepatitis patients. libyan j med 2010; 5:5071. 10. targher g, chonchol m, miele l, zoppini g, pichiri i, muggeo m. nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome. semin thromb hemost 2009; 35:277–87. non-alcoholic fatty liver disease (nafld) is it an emerging risk factor for coronary artery disease a preliminary study in a local indian population 226 | squ medical journal, august 2010, volume 10, issue 2 11. third report of the national cholesterol education program (ncep) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii). final report. circulation 2002; 106:3143–421. 12. diamant m, nieuwland r, pablo rf, sturk a, smit jw, radder jk. elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. circulation 2002; 106:2442–7. 13. cornier ma, dabelea d, hernandez tl, lindstrom rc, steig aj, stob nr, et al. the metabolic syndrome. endocr rev 2008; 29:777–822. 14. weisberg sp, mccann d, desai m, rosenbaum m, leibel rl, ferrante aw. obesity is associated with macrophage accumulation in adipose tissue. j clin invest 2003; 112:1796–808. 15. bonetti po, lerman lo, lerman a. endothelial dysfunction: a marker of atherosclerotic risk. arterioscler thromb vasc biol 2003; 23:168–75. 16. kim ja, montagnani m, koh kk, quon mj. reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. circulation 2006; 113:1888–904. 17. shoelson se, lee j, goldfine ab. inflammation and insulin resistance. j clin invest 2006; 116:1793–801. 18. targher g, bertolini l, rodella s, lippi g, franchini m, zoppini g, et al. nash predicts plasma inflammatory biomarkers independently of visceral fat in men. obesity 2008; 16:1394–9. 19. aubert h, frere c, aillaud mf, morange pe, juhanvague i, alessi mc. weak and non-independent association between plasma tafi antigen levels and the insulin resistance syndrome. j thromb haemost 2003; 1:791–7. 20. kopp cw, kopp hp, steiner s, kriwanek s, krzyzanowska k, bartok a, et al. weight loss reduces tissue factor in morbidly obese patients. obes res 2003; 11:950–6. 21. mills jd, mansfield mw, grant pj. factor xiiicirculating levels and the val34leu polymorphism in the healthy male relatives of patients with severe coronary artery disease. thromb haemost 2002; 87:409–14. 22. targher g, bonadonna rc, alberiche m, zenere mb, muggeo m, bonora e. relationship between soluble adhesion molecules and insulin sensitivity in type 2 diabetic individuals. role of adipose tissue. diabetes care 2001; 24:1961–6. 23. chan dc, watts gf, sengkhee d, wong aty, ooi emm, hugh p, et al. nonalcoholic fatty liver disease as the transducer of hepatic oversecretion of very low density lipoprotein – apolipoprotein b100 in obesity. clinical and population studies. arterio thromb vas biol 2010; 30:1043–50. 24. morange pe, renucci jf, charles ma, aillaud mf, giraud f, grimaux m, et al. plasma levels of free and total tfpi, relationship with cardiovascular risk actors and endothelial cell markers. thromb haemost 2001; 85:999–1003. 25. marchesini g, bugianesi e, forlani g, cerrelli f, lenzi m, manini r, et al. nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. hepatology 2003; 37:917–23. 26. bonora e, targher g, formentini g, calcaterra f, lombardi s, marini f, et al. the metabolic syndrome is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the verona diabetes complications study. diabet med 2004; 21:52–8. as implied by the title, the book is aimed at medical students and practising doctors, and focuses on their communication with patients. chapter titles include: how doctors talk to patients and why, different types of patient, ways of looking at the consultation and useful strategies and skills. generally, the book is an easy read. as it is not aimed at communication studies’ students or practitioners, it contains very little reference to communication theory. the author draws primarily on experience (his own and others) and uses these examples to illustrate concepts. some of the more valuable aspects include: • balancing the patients’ concerns and perceptions with those of the doctor. in several instances, the author sketches situations, and illustrates how differences between concerns and perceptions have a negative impact on health care delivery. the author then offers solutions to the problem. • history taking. the author considers the standard model of history taking as “victorian, patronising and, in most hands, communicatively disastrous,” and provides other approaches to achieve the desired result. • listening, especially active listening, and avoiding the too-quick reaction of “putting communication into a straightjacket in order to maximise pattern recognition.” • the weaknesses of reliance on patient pamphlets and handouts, and the related confusion of information diffusion and effective communication. • considerations of language. the author deals with problems of jargon, and also considers other, more common vocabulary misconceptions (such as the use of the word “risk”), that impact negatively on patient-doctor communication. i do, however, have some criticisms of the book. i would like to see: • a brief chapter summary at the end of each chapter, although there is an overall summary of the text at the end. • a far greater acknowledgment of the impact of 21st century technology in patientdoctor communication. although there are references to the internet, there are several missed opportunities for guidance on the more problematic areas. for example, the chapter entitled useful strategies and skills ends with a discussion of telephonic communication, but does not mention the use gèf�÷]<ÿë]ái<gèj“  book review the doctor’s communication handbook author: peter tate publisher: radcliffe publishing, oxford & new york, 6th edition, 2010 isbn: 978-1-84619-392-7 squ med j, may 2011, vol. 11, iss. 2, pp. 295-296, epub. 15th may 11 submitted 16th feb 11 the doctor’s communication handbook 296 | squ medical journal, may 2011, volume 11, issue 2 of email, text messaging, and other new forms of communication currently facing doctors. in addition, while reference is made to patients accessing information on the internet, the model is still firmly that there are two experts: “one on medical matters and the other on their own mind and body.” medical communication is still viewed a one-way flow from doctor to patient. • at least one chapter devoted to communication between doctors, or a change in book title. the title of the book does not mention patients, but the book is focused on communication between doctors and patients. overall, the doctor’s communication handbook is a useful text for medical students and practising doctors. r e v i e w e r ken masters medical education unit college of medicine & health sciences sultan qaboos university, muscat, oman email: kmasters@ithealthed.com a 43 year-old woman presented with increasing menorrhagia, pelvic pressure, and pain. an ultrasound of the pelvis showed multiple small uterine fibroids with a dominant intramural fibroid measuring 5cm in diameter and a 3cm left ovarian cyst with a solid component and normal doppler. the cancer antigen 125 (ca 125) was 32 iu/ml. her her menstrual cycle was regular with menorrhagia. there was no history of oral contraceptive use. she was para 2, with unremarkable past medical, surgical and family history. the endometrial biopsy was consistent squ med j, december 2009, vol. 9, iss. 3, pp. 315-318, epub. 19th dec 2009 submitted 27th jan 2009 revision req. 30th june 09, revision recd. 3rd july 09 accepted 24th aug 09 department of obstetrics and gynecology, mcgill university, quebec, canada *to whom correspondence should be addressed. email: ayman.altalib@gmail.com ُوراٌم َعَضِليٌّ أَمْلَس صفاقي منتشر مع صفات سرطانية عند تنظري البطن تقرير حالة أمين الطالب، عبدالرحمن الفارسي، جيرالد ستانيمير امللساء العضالت خاليا من أساسا وتتكون الصفاق حتت احلميدة العقيدات بتكاثر يتميز نادر مرض الصفاقي األَْملَس الَعَضلِيٌّ الُوراٌم امللخص: احلميدة، والتي حتاكي السرطان الصفاقي بالعني اجملردة . هذا وصف حلالة امرأة عمرها 43 عاما كانت تشكو من غزارة الطمث مع ضغط وآالم في احلوض. أظهرت املوجات فوق الصوتية ملنطقة احلوض وجود أورام ليفية رحمية وكيس مبيضي. كان من املقرر أن يجرى لها استئصال الرحم مع الُبوِق واملَِبْيض األيسر لتخفيف األعراض. شوهدت صورة سرطان صفاقي عند التنظير ومت أخذ خزعات متعددة أثناءه وأحيلت املريضة إلى فريق األورام النسائية. أجريت اجلراحة النهائية وكان التشريح املرضي النهائي متسقا مع الُوراٌم الَعَضلِيٌّ األَْملَس الصفاقي بدون وجود دالئل سرطانية. لم تعطى الهرمونات البديلة بعد اجلراحة. ولو أن شكل الُوراٌم الَعَضلِيٌّ األَْملَس الصفاقي بالعني اجملردة يشبه السرطان ، لكن عادة ما يتبع مساق حميد بعد اجلراحة . راجعنا األدبيات الطبية املنشورة مبختلف املصادر باستعمال مفاتيح الكلمات ملعرفة العالج احلالي للورام الَعَضلِيٌّ األَْملَس الصفاقي واختطار حتوله إلى ورم خبيث. يعتبر تشخيص الُوراٌم الَعَضلِيٌّ األَْملَس الصفاقي حتد، ولو أن حتوله إلى مرض خبيث نادر لكنه ميكن أن يحصل، خاصة ان الهرمونات تلعب دورا مهما في إِْمراض الُوراٌم الَعَضلِيٌّ األَْملَس الصفاقي ، ولهذا يجب متابعة املرضى بعد اجلراحة بعناية إذا كانوا يعاجلون بالهرمونات البديلة، ألن هذه األورام ميكن أن تنمو من جديد وتسبب أعراضا، أو تتحول إلى أورام خبيثة. مفتاح الكلمات: الُوراٌم الَعَضلِيٌّ األَْملَس الصفاقي، السرطان الصفاقي، التحول السرطاني، تقرير حالة. abstract: leiomyomatosis peritonealis disseminata (lpd), also known as diffuse peritoneal leiomyomatosis, is a rare disease characterised by subperitoneal proliferation of benign nodules mainly composed of benign smooth muscle cells, macroscopically mimicking peritoneal carcinomatosis. we report a 43 year-old woman who presented with menorrhagia, pelvic pressure and pain. ultrasound of the pelvis showed uterine fibroids and an ovarian cyst. she was scheduled to have a laparoscopic hysterectomy and left salpingo-oophorectomy for symptomatic relief. a picture of carcinomatosis was seen on laparoscopy so multiple biopsies were taken and the patient was referred to the gynaecological oncology team. definitive surgery was performed and final pathology was consistent with lpd with no evidence of malignancy. no hormone replacement therapy was offered after surgery. macroscopically, lpd has features of malignancy; it usually pursues a benign course. to review current management of lpd and the risk of malignant transformation, we conducted a search in medline, embase, and the cochrane database of systematic reviews using the keywords: leiomyomatosis peritonealis disseminata, management and malignant transformation. lpd is a diagnostic challenge. although rare, malignant transformation can occur since hormones play an important role in the pathogenesis of lpd, following surgery, patients should be followed carefully if they are on hormone replacement as these tumours could re-grow and cause symptoms or transform to malignancy. keywords: leiomyomatosis peritonealis disseminata; peritoneal carcinomatosis; malignant transformation; case report leiomyomatosis peritonealis disseminata with features of carcinomatosis on laparoscopy a case report *ayman al-talib, abdul r al-farsi and gerald stanimir case report leiomyomatosis peritonealis disseminata with features of carcinomatosis on laparoscopy a case report and review of the literature 316 | squ medical journal, december 2009, volume 9, issue 3 with a proliferative phase endometrium. she was scheduled to undergo a laparoscopic hysterectomy and left salpingo-oophorectomy for symptomatic relief. laparoscopy revealed a uterus enlarged with fibroids, and the left ovary contained a 3cm cyst with a smooth surface. the omentum was vascular and thick, covered by numerous nodules of variable sizes ranging from 2mm to 1cm. these nodules were also found in the posterior cul-de-sac and under the diaphragm. because disseminated malignancy was suspected, biopsies were taken from the peritoneal and omental lesions. definitive surgery was postponed to a later date and the patient was transferred to the gynaecological oncology team. the histopathologic examination was consistent with leiomyomatosis peritonealis disseminata (lpd) [figure 1]. a computed tomography scan was suggestive of peritoneal nodules. no ascites, no pulmonary or hepatic nodules were seen; there were no enlarged retroperitoneal lymph nodes. the patient subsequently underwent total abdominal hysterectomy (tah), bilateral salpingooopherectomy (bso), omentectomy and excision of all grossly visible peritoneal lesions [figure 2]. final histological examination confirmed the diagnosis of lpd, uterine fibroids, and dermoid cyst in the left ovary. estrogen receptors (er) were positive and progestin receptors (pr) were negative in the nodules. discussion lpd was first described in 1952 by willson and peale1 and was identified as a pathological entity in 1965 by taubert et al.2 the aetiology of lpd is unknown, but it is thought to originate from metaplasia of submesothelial, multi-potential mesenchymal cells.3 an association with high levels of exogenous and endogenous female gonadal steroids, e.g. in pregnancy and prolonged exposure to oral contraceptive agents, has been found indicating that estrogen and progestins do play an important role in the pathogenesis of lpd.4 both ers and prs have been described in tumour cells.5 although lpd is most common in females of reproductive age, cases have been reported in postmenopausal women. 6-9 recently, familial clustering of lpd has been reported, proposing an autosomal-dominant model with varying degrees of penetrance.10 lpd has also been reported in men 11, 12 and in association with currarino syndrome.13 patients usually present with nonspecific abdominal problems, such as abdominal discomfort or pain, rectal or vaginal bleeding or a mass in the lower abdomen as in our case. the condition presents a multiple, firm, round, white-to-gray nodules ranging in diameter from 0·5 cm to 10 cm lining the peritoneal surface. the cut surface resembles uterine leiomyoma with firm, white and whorled architecture.14 microscopically, the round nodules of lpd consist of mature fusiform smooth muscle cells. these cells are arranged in interdigitating fascicles. often the nodules lack mitotic figures or the mitotic index (mi) is less than 3/10 high power field (hpf). cellular atypia, nuclear polymorphy, hyperchromasia, and tumour cell necrosis are absent in lpd while a leiomyosarcoma has a higher mi and shows nuclear atypia, tumour necrosis, and infiltrative growth into adjacent structures/organs. immunohistological staining is typical of smooth muscle tumours with expression for vimentin, desmin, smooth muscle actin, and muscle-specific actin.15 some rare cases of malignant transformation in patients suffering from lpd have been reported and the incidence is unknown. results presented in the literature are conflicting as to whether malignant transformation is related to estrogen stimulation or not, the majority of cases having no association with hormonal stimulation.16-20 in a review of 103 case reports, beckers described six cases with malignant leiomyosarcoma diagnosed shortly after the diagnosis of lpd was made.3, 21 surprisingly, none of these patients had been exposed to exogenous estrogen and none had uterine leiomyomas. beckers hypothesised that lpd without exogenous or increased endogenous estrogen exposure, and without expression of er and pr in the lpd figure 1: multiple small nodules of mature smooth muscle surrounded by omental fat ayman al-talib, abdul r al-farsi and gerald stanimir case report | 317 nodules, may represent a different entity carrying a higher risk of malignant transformation and so will need a more aggressive approach. imaging studies have not been of great help for the diagnosis of lpd. ultrasound, computed tomography or magnetic resonance imaging can show the soft tissue masses along the subperitoneal surface and mesentery that resemble peritoneal carcinomatosis, but biopsy is essential for histopathologic diagnosis. due to the high vascularity of these tumours, biopsies taken by laparoscopy need to be done with great care to ensure proper haemostasis, and furthermore to allow assessment of the extent of lpd and to exclude other diagnoses.10 the therapy of this benign disease remains controversial and, so far, there are no firm guidelines in the literature with regard to the management of these patients. in women with reproductive desire, many authors advocate a conservative approach. reducing exposure to estrogen is often sufficient to cause regression of lpd.22 regression of lpd was reported with hormonal therapy using gonadotropin-releasing hormone (gnrh) agonists,23 megestrol acetate,24 and danazol.25 a tah with unilateral or bso is only recommended for symptomatic relief in patients who have completed their families or for postmenopausal patients. recurrence of lpd has been reported even after a radical surgical approach. conclusion lpd is a rare disease that clinically mimics peritoneal carcinomatosis on presentation. diagnosis of lpd should be based on histopathological examination and imaging studies have a limited role in this regard. due to the association of this rare disease with hormonal stimulation and the fact that there are no solid data to support the safety of hormone replacement therapy following tah and bso, patients should be followed carefully after surgery if they are on hormone replacement. this is because these tumors, though benign, could re-grow and cause symptoms or transform to malignancy. although this clinical entity was described in the 1950s, there are as yet no firm guidelines for the management of these cases. references 1. willson jr, peale ar. multiple peritoneal leiomyomas associated with a granulosa-cell tumor of the ovary. am j obstet gynecol 1952; 64:204-8. 2. taubert hd, wissner se, haskins al. leiomyomatosis peritonealis disseminata; an unusual complication of genital leiomyomata. obstet gynecol 1965; 25:561-74. 3. heinig j, neff a, cirkel u, klockenbusch w. recurrent leiomyomatosis peritonealis disseminata after hysterectomy and bilateral salpingo-oophorectomy during combined hormone replacement therapy. eur j obstet gynecol reprod biol 2003; 111:216-8. 4. goldberg mf, hurt wg, frable wj. leiomyomatosis peritonealis disseminata. report of a case and review of the literature. obstet gynecol 1977; 49:46-52. 5. ruscalleda n, eixarch e, pages m, carmona f, sanchez m, ayuso jr et al. leiomyomatosis peritonealis disseminata. eur radiol 2006;16:287982. 6. kokcu a, alvur y, baris ys, kuskonmaz i. leiomyomatosis peritonealis disseminata. acta obstet gynecol scand 1994; 73:81-3. 7. mansour f, darai e, felgeres a, meicler p, pinet c, colau jc. la léiomyomatose péritonéale disséminée: à propos d’un cas. rev fr gynecol obstet 1992; 87:431-3. 8. rajab k, aradi a, datta b. postmenopausal leimyomatosis peritonealis disseminata. int j gynaecol obstet 2000; 68:271-2. 9. nguyen gk. disseminated leiomyomatosis peritonealis: report of a case in a postmenopausal woman. can j surg 1993; 36:46-8. 10. halama n, grauling-halama s, daboul i. familial clustering of leiomyomatosis peritonealis disseminata: an unknown genetic syndrome? bmc gastroenterol 2005; 5:33. figure 2: vascular omentum with multiple nodules leiomyomatosis peritonealis disseminata with features of carcinomatosis on laparoscopy a case report and review of the literature 318 | squ medical journal, december 2009, volume 9, issue 3 11. yamaguchi t, imamura y, yamamoto t, fukuda m. leiomyomatosis peritonealis disseminata with malignant change in a man. pathol int 2003; 53:17985. 12. lausen i, jensen oj, andersen e, lindahl f. disseminated peritoneal leiomyomatosis with malignant change, in a male. virchows archiv 1990; 417:173-5. 13. nappi c, sardo a, mandato v, bifulco g, merello e, savanelli a et al. leiomyomatosis peritonealis disseminata in association with currarino syndrome? bmc cancer 2006; 6:127. 14. karuppaswamy j, tapp a. leiomyomatosis peritonealis disseminata-is a different approach needed? j obstet gynaecol 2002; 22: 446-7. 15. bucher m, pusztaszeri m, bouzourene h. leiomyomatosis peritonealis disseminata: immunohistochemical profile and origin. ann pathol 2006; 26:207-10. 16. fulcher as, szucs ra. leiomyomatosis peritonealis disseminata complicated by sarcomatous transformation and ovarian torsion: presentation of two cases and review of the literature. abdom imaging 1998; 23:640-4. 17. raspagliesi f, quattrone p, grosso g, cobellis l, di re e. malignant degeneration in leiomyomatosis peritonealis disseminata. gynecol oncol 1996; 61:272-4. 18. morizaki a, hayashi h, ishikawa m. leiomyomatosis peritonealis disseminata with malignant transformation. int j gynaecol obstet 1999; 66:43-5. 19. akkersdijk gj, flu pk, giard rw, van lent m, wallenburg hc. malignant leiomyomatosis peritonealis disseminata. am j obstet gynecol 1990; 163:591-3. 20. rubin sc, wheeler je, mikuta jj. malignant leiomyomatosis peritonealis disseminata. obstet gynecol 1986; 68:126-30. 21. bekkers rl, willemsen wn, schijf cp, massuger lf, bulten j, merkus jm. leiomyomatosis peritonealis disseminata: does malignant transformation occur? a literature review. gynecol oncol 1999; 75:158-63. 22. butnor kj, burchette jl, robboy sj. progesterone receptor activity in leiomyomatosis peritonealis disseminata. int j gynecol pathol 1999; 18:259-64. 23. hales ha, peterson cm, jones kp, quinn jd. leiomyomatosis peritonealis disseminata treated with a gonadotropin-releasing hormone agonist. a case report. am j obstet gynecol 1992; 167:515-6. 24. parente jt, levy j, chinea f, espinosa b, brescia mj. adjuvant surgical and hormonal treatment of leiomyomatosis peritonealis disseminata. a case report. j reprod med 1995; 40:468-70. 25. buckshee k, verma a, karak ak. leiomyomatosis peritonealis disseminata. int j gynaecol obstet 1998; 61:191-2. departments of 1microbiology & immunology and 2haematology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: jalila@squ.edu.om حتديد املستوى املرجعي لألجسام املناعية املضادة )نوع g( للرشاشيات أسبرييغيلوس فوميغاتوس بني السكان البالغني العمانيني منرية الرحمن، حممود الكندي، اإبراهيم كوتي، اإبراهيم الكلباين، جليلة ال�سكيلي abstract: objectives: the presence of abnormally high levels of aspergillus fumigatus-specific immunoglobulin (ig) g antibodies can serve as a diagnostic criterion for severe conditions like allergic bronchopulmonary and chronic pulmonary aspergillosis. this study aimed to determine a reference range of a. fumigatus-specific igg levels within a healthy adult omani population. methods: this study took place during november 2015 at the sultan qaboos university hospital, muscat, oman. the sera of 125 healthy omani blood donors were tested for a. fumigatusspecific igg levels using an automated fluorescence enzyme immunoassay. results: initially, the data were not normally distributed; however, log transformation and the exclusion of four outliers resulted in an acceptable gaussian distribution. the reference range was 2.0–68.7 mga/l at the 2.5 th and 97.5th percentiles, respectively, with 90% confidence intervals of 2.0–3.0 mga/l and 48.0–76.0 mga/l, respectively. conclusion: the a. fumigatusspecific igg reference range within a healthy adult omani population was comparable to those reported in other populations. keywords: aspergillus fumigatus; allergic bronchopulmonary aspergillosis; pulmonary aspergillosis; immunoglobulin g; reference range; oman. يعترب احلالتني كلتي ويف فطري. اإلتهاب اأو ح�سا�سية اإحداث خالل من لالإن�سان خمتلفة اأمرا�ض الر�سا�سيات ت�سبب الهدف: امللخ�ص: الق�سبي الر�سا�سيات داء لت�سخي�ض الرئي�سة الركائز اأحد فوميغاتو�ض للر�سا�سيات )g )نوع امل�سادة املناعية االأج�سام م�ستوى حتديد الرئوي التح�س�سي اأو داء الر�سا�سيات الرئوي املزمن. وال يوجد حاليا معدل مرجعي �سواء اأكان حمليا اأو اإقليميا ميكن ا�ستخدامه لدعم هذه فوميغاتو�ض. للر�سا�سيات )g )نوع امل�سادة املناعية االأج�سام مل�ستوى املرجعي امل�ستوى حتديد اإىل الدرا�سة هذه هدفت الت�سخي�سات. الطريقة: اأجريت هذه الدرا�سة خالل �سهر نوفمرب2015 يف م�ست�سفى جامعة ال�سلطان قابو�ض، م�سقط، �سلطنة عمان اىلمت فح�ض جمموعة من العينات ماأخوذة من االأ�سحاء العمانيني املتربعني بالدم والبالغ عددهم 125 وذلك با�ستخدام نظام اإميونوكاب من فاديا اأوب�ساال، )g )نوع امل�سادة املناعية االأج�سام مل�ستوى االأولية القيا�سات تتبع مل النتائج: العلمية(. في�رص احلرارية با�سم االآن )املعروفة ال�سويد للر�سا�سيات فوميغاتو�ض منحنى املعدل الطبيعي مما تتطلب تطبيق التحويل اللوغاريثمي على البيانات والذى اأدى بدوره اإىل احل�سول على توزيع طبيعي ومقبول للبيانات. ومن ثم مت ح�ساب امل�ستوى املرجعي لالأج�سام املناعية امل�سادة )نوع g( للر�سا�سيات فوميغاتو�ض 97.5th وات�سح انها ترتاوح بني 2.0 مليغرام/لرت و 68.7 مليغرام/لرت بفوا�سل ثقة %90 ترتاوح 2.5th و با�ستخدام طريقة الن�سب املئوية )g )نوع امل�سادة املناعية لالأج�سام املرجعي امل�ستوى اخلال�صة: التوايل. على مليغرام/لرت 48.0–76.0 و مليغرام/لرت 2.0–3.0 بني للر�سا�سيات فوميغاتو�ض للبالغني االأ�سحاء العمانيني م�سابه ملا مت ر�سده يف جمتمعات اخرى. الكلمات املفتاحية: الر�سا�سيات فوميغاتو�ض؛ داء الر�سا�سيات الق�سبي الرئوي التح�س�سي؛ داء الر�سا�سيات الرئوي املزمن؛ امل�ستوى املرجعي؛ عمان. determination of an aspergillus fumigatus-specific immunoglobulin g reference range in an adult omani population munira al-rahman,1 mahmood al kindi,1 ibrahim kutty,1 ibrahim al-kalbani,2 *jalila alshekaili1 clinical & basic research sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e43–46, epub. 4 apr 18 submitted 3 oct 17 revision req. 5 nov 17; revision recd. 26 nov 17 accepted 14 dec 17 doi: 10.18295/squmj.2018.18.01.007 advances in knowledge to the best of the authors’ knowledge, this study is the first in oman and the arabian gulf region to evaluate the reference range of aspergillus fumigatus-specific immunoglobulin g (igg) levels in a local population. application to patient care the findings of the current study may guide clinicians in establishing diagnoses of allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis at the sultan qaboos university hospital, muscat, oman. the aspergillus genus is an extremely abundant type of airborne fungi constantly inhaled by humans which, for the most part, does not cause significant illness; however, individuals with pre-existing lung pathologies or weak ened immune systems can develop aspergillus-related diseases known as aspergillosis.1 most cases of asper gillosis are caused by a. fumigatus (80%), although other species can also cause infection, such as a. flavus, a. terreus and a. niger.1–3 aspergillosis caused by determination of an aspergillus fumigatus-specific immunoglobulin g reference range in an adult omani population e44 | squ medical journal, february 2018, volume 18, issue 1 a. fumigatus presents with either allergies—including allergic aspergillus sinusitis and allergic bronchopulmonary aspergillosis (abpa)—or infections, such as local aspergillomas affecting the lungs and sinuses, necrotising chronic pulmonary aspergillosis (cpa) and systemic invasive aspergillosis.4–6 usually, abpa or cpa is diagnosed following assessment of the patient’s medical history for risk factors, a physical examination, radiological imaging and laboratory investigations. to this end, elevated levels of a. fumigatus-specific immunoglobulin (ig) g antibodies are considered the main clinical criterion to support the diagnosis.4 however, there is currently no published reference range of anti-a. fumigatus-specific igg levels for healthy adult populations in arab countries. there fore, the aim of this study was to establish a reference range for a. fumigatus-specific igg antibodies in an omani population. hopefully, this reference range will guide clinicians in oman when establishing diagnoses of abpa and cpa. methods this study took place in november 2015 at the sultan qaboos university hospital (squh) in muscat, oman. samples of sera were collected from 125 healthy adult donors attending the squh blood bank during the study period. only healthy adult donors without any previous history of lung disease or asthma and no prior significant exposure to birds were included. four out liers were excluded from the initial sample; however, the final sample of 121 subjects complied with the minimum sample size recommended by the clinical and laboratory standards institute (clsi) for establish ing a reference range.7–9 a total of 5–10 ml of blood was obtained from each subject. the sera were immediately separated and stored at -80 °c until analysis. specific igg antibodies against a. fumigatus were determined using an auto mated fluorescence enzyme immunoassay (immunocap® system, thermo fisher scientific inc., phadia ab, uppsala, sweden), as per the manufacturer’s instructions. the assay was performed by an experienced senior biomedical scientist in the immunology laboratory of squh. results were expressed as milligrams of aspergillus-specific igg antibodies per litre (mga/l). all reagents were received from the same lot number and each run included internal quality control samples. the interassay coefficient of variation between runs for the quality control samples was <10%, as per the manufacturer’s instructions. data were analysed using the medcalc® statistical software package, version 16.4.3 (medcalc software, ostend, belgium). a non-parametric percentile method following the clsi guidelines was used on log-transformed data to establish the reference range at a 90% confidence interval (ci).8,9 the level of statistical significance was set at p <0.050. ethical approval for this study was obtained from the research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #1220-a). all subjects gave informed written consent prior to their participation in the study. results the median age of the subjects was 24 years (range: 18–52 years old). most of the donors were male, with a female-to-male ratio of 1:9.3. initially, a frequency histogram and quantile-quantile plot to assess the distri bution of the collected data indicated that the data were not normally distributed [figure 1]. this finding was further supported by the results of a d’agostinopearson test (p <0.001). accordingly, the data were log-transformed for subsequent analysis. however, the data were still not normally distributed [figure 2]. a tukey’s test identified four outliers, the exclusion of which resulted in the normal gaussian distribution of the log-transformed data of the remaining 121 samples [figure 3]. the reference range of a. fumigatus-specific figure 1: a: relative frequency histogram of aspergillus fumigatus-specific immunoglobulin g (igg) antibodies in the sera of healthy omani blood donors (n = 125). b: quantile-quantile plot of results obtained for a. fumigatus-specific igg antibodies in the sera of healthy omani blood donors (n = 125). igg = immunoglobulin g. munira al-rahman, mahmood al kindi, ibrahim kutty, ibrahim al-kalbani and jalila alshekaili clinical and basic research | e45 igg for these 121 samples was 2.0–76.0 mga/l, with a geo metric mean of 10.9 mga/l and median of 11.0 mga/l. the 2.5th percentile was 2.0 mga/l with a 90% ci of 2.0–3.0 mga/l and the 97.5 th percentile was 68.7 mga/l with a 90% ci of 48.0–76.0 mga/l. discussion although uncommon, both abpa and cpa are serious diseases that can affect immunocompetent patients with underlying lung pathologies. the former is a severe allergic and inflammatory condition that predominantly affects patients with asthma or cystic fibrosis and presents with fever, cough, shortness of breath, wheezing and haemoptysis; moreover, patients become sensitised to a. fumigatus, causing significant morbidity and mortality.10 immunological mechanisms in abpa that result in pathology are mainly type i immediate and type iii immune complex hypersensitivity reactions mediated by ige and igg antibodies, respectively.4 the primary treatment for abpa is oral corticosteroids to control the inflammatory process, while anti-fungals are used only as an adjuvant therapy in order to reduce the fungal load.9 in contrast, cpa is a chronic lung infection that can progress to pulmonary fibrosis and loss of lung function; the disease presents with constitutional and respiratory symptoms including weight loss, fatigue, shortness of breath and haemoptysis.10 in general, cpa affects immunocompetent patients with pre existing lung conditions as opposed to invasive aspergillosis, which usually occurs in immunocompromised patients.11 underlying lung comorbidities which may predispose a patient to cpa include chronic obstructive pulmonary disease, pre-existing pulmonary cavitary tuberculosis, fibrotic sarcoidosis and abpa. in some cases, cpa can manifest as a simple aspergilloma, chronic cavitary pulmonary aspergillosis, chronic fibro sing pulmonary aspergillosis, subacute invasive asper gillosis and aspergillosis nodules.11,12 for most patients, cpa is treated with antifungal agents and surgery. however, interferon-γ has been recently proposed as an adjuvant therapy.4 in the current study, the reference range of a. fumigatus-specific igg levels among a sample of healthy adult omani blood donors was found to be 2.0–68.7 mga/l using the percentile method. this reference range was comparable to other published ranges figure 2: a: relative frequency histogram of log-transformed aspergillus fumigatus-specific immunoglobulin g (igg) antibodies in the sera of healthy omani blood donors (n = 125). b: quantile-quantile plot of log-transformed data for a. fumigatus-specific igg antibodies in the sera of healthy omani blood donors (n = 125). igg = immunoglobulin g. figure 3: a: relative frequency histogram of log-transformed aspergillus fumigatus-specific immunoglobulin g (igg) antibodies in the sera of healthy omani blood donors (n = 121). b: quantile-quantile plot of log-transformed data for a. fumigatus-specific igg antibodies in the sera of healthy omani blood donors (n = 121). igg = immunoglobulin g. determination of an aspergillus fumigatus-specific immunoglobulin g reference range in an adult omani population e46 | squ medical journal, february 2018, volume 18, issue 1 and can potentially be used in conjunction with other parameters to diagnose patients suspected of having abpa or cpa. utilising the same immunoassay as that of the current study, watkins et al. found the reference range of a. fumigatus-specific igg levels to be 2.79–66.45 mga/l in a group of 122 healthy adults in south africa.13 the same method and assay technology was used to detect an a. fumigatus-specific igg range of 2.01–70.10 mga/l in a group of 42 healthy individuals in belgium.14 an enzyme-linked immuno sorbent assay yielded similar results when assessing a. fumigatus igg levels among 100 healthy finnish children between 7–13 years old to the 95th percentile (67.8–68.3 mg/l); in addition, the researchers observed that a. fumigatus-specific igg concentrations increased with age to reach a plateau at 6–7 years old, although the concentrations were not affected by gender.15 agarwal et al. compared 67 patients with abpa to 32 asthmatic controls in india; using a receiver operated characteristic curve, the researchers determined the ideal cut-off value for a. fumigatus-specific igg to be 26.9 mga/l. 16 however, it is important to note that the controls in this study were a small cohort of diseased rather than healthy individuals.16 to the best of the authors’ knowledge, this study is the first in the arabian gulf region to derive a reference range for a. fumigatus-specific igg levels in a cohort of healthy donors. in addition, the sample size was adequate in comparison to other studies and complied with clsi recommendations.8,9,17 nevertheless, this study was limited in that patients with abpa or cpa were not included. such patients should there fore be included in future research so as to validate the reference range determined. in addition, due to a lack of female patients within the cohort, no differences in a. fumigatus-specific igg levels were noted between genders. conclusion in summary, a. fumigatus-specific igg levels are an important diagnostic parameter for patients with abpa or cpa. in the current study, the reference range of a. fumigatus-specific igg levels in healthy omani donors was found to be 2.0–68.7 mga/l at the 2.5 th and 97.5th percentiles, respectively. this reference range was comparable to other published ranges reported from different populations worldwide. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. barnes pd, marr ka. aspergillosis: spectrum of disease, diagnosis, and treatment. infect dis clin north am 2006; 20:545–61. doi: 10.1016/j.idc.2006.06.001. 2. greenberger pa. allergic bronchopulmonary aspergillosis. j allergy clin immunol 2002; 110:685–92. doi: 10.1067/mai.20 02.130179. 3. nierman wc, pain a, anderson mj, wortman jr, kim hs, arroyo j, et al. genomic sequence of the pathogenic and allergenic filamentous fungus aspergillus fumigatus. nature 2005; 438:1151–6. doi: 10.1038/nature04332. 4. patterson kc, strek me. diagnosis and treatment of pulmonary aspergillosis syndromes. chest 2014; 146:1358–68. doi: 10.13 78/chest.14-0917. 5. agarwal r, sehgal is, dhooria s, aggarwal an. developments in the diagnosis and treatment of allergic bronchopulmonary aspergillosis. expert rev respir med 2016; 10:1317–34. doi: 10.10 80/17476348.2016.1249853. 6. denning dw, cadranel j, beigelman-aubry c, ader f, chakrabarti a, blot s, et al. chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and manage ment. eur respir j 2016; 47:45–68. doi: 10.1183/13993003.005 83-2015. 7. hyltoft petersen p, rustad p. prerequisites for establishing common reference intervals. scand j clin lab invest 2004; 64:285–92. doi: 10.1080/00365510410006298. 8. horn ps, pesce aj. reference intervals: an update. clin chim acta 2003; 334:5–23. doi: 10.1016/s0009-8981(03)00133-5. 9. clinical and laboratory standards institute. ep28: defining, establishing, and verifying reference intervals in the clinical laboratory, 3rd ed. from: https://clsi.org/standards/products/ method-evaluation/documents/ep28/ accessed: nov 2017. 10. shah a, panjabi c. allergic bronchopulmonary aspergillosis: a perplexing clinical entity. allergy asthma immunol res 2016; 8:282–97. doi: 10.4168/aair.2016.8.4.282. 11. patterson tf, thompson gr 3rd, denning dw, fishman ja, hadley s, herbrecht r, et al. practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america. clin infect dis 2016; 63:e1–60. doi: 10.1093/cid/ciw326. 12. hayes ge, novak-frazer l. chronic pulmonary aspergillosis: where are we? and where are we going? j fungi (basel) 2016; 2:18. doi: 10.3390/jof2020018. 13. watkins ml, benjamin rl, kotzé e, hawarden d. reference range for specific igg antibodies to aspergillus fumigatus in the south african adult population. curr allergy clin immunol 2012; 25:212–14. 14. van hoeyveld e, dupont l, bossuyt x. quantification of igg antibodies to aspergillus fumigatus and pigeon antigens by immu nocap technology: an alternative to the precipitation technique? clin chem 2006; 52:1785–93. doi: 10.1373/clinchem.2006.067546. 15. korppi m, laitinen s, taskinen t, reiman m, nevalainen a, husman t. mold-specific immunoglobulin g antibodies in a child population. pediatr allergy immunol 2003; 14:371–7. doi: 10.10 34/j.1399-3038.2003.00059.x. 16. agarwal r, dua d, choudhary h, aggarwal an, sehgal is, dhooria s, et al. role of aspergillus fumigatus-specific igg in diagnosis and monitoring treatment response in allergic bron chopulmonary aspergillosis. mycoses 2017; 60:33–9. doi: 10.11 11/myc.12541. 17. hyltoft petersen p, rustad p. prerequisites for establishing common reference intervals. scand j clin lab invest 2004; 64:285–92. doi: 10.1080/00365510410006298. https://doi.org/10.1016/j.idc.2006.06.001 https://doi.org/10.1067/mai.2002.130179 https://doi.org/10.1067/mai.2002.130179 https://doi.org/10.1038/nature04332 https://doi.org/10.1378/chest.14-0917 https://doi.org/10.1378/chest.14-0917 https://doi.org/10.1080/17476348.2016.1249853 https://doi.org/10.1080/17476348.2016.1249853 https://doi.org/10.1183/13993003.00583-2015 https://doi.org/10.1183/13993003.00583-2015 https://doi.org/10.1080/00365510410006298 https://doi.org/10.1016/s0009-8981%2803%2900133-5 https://doi.org/10.4168/aair.2016.8.4.282 https://doi.org/10.1093/cid/ciw326 https://doi.org/10.3390/jof2020018 https://doi.org/10.1373/clinchem.2006.067546 https://doi.org/10.1034/j.1399-3038.2003.00059.x https://doi.org/10.1034/j.1399-3038.2003.00059.x https://doi.org/10.1111/myc.12541 https://doi.org/10.1111/myc.12541 https://doi.org/10.1080/00365510410006298 1pharmaceutical sciences research center, hemoglobinopathy institute and 2department of toxicology & pharmacology, faculty of pharmacy, mazandaran university of medical sciences, sari, iran; 3razi drug research center and 4department of toxicology & pharmacology, school of pharmacy, international campus, iran university of medical sciences, tehran, iran *corresponding author e-mail: shetab.v@iums.ac.ir اإلضافة للسيستني يعيد تنشيط أنزمي کولينسرتاز البشري اليت يثبطها مبيد احلشرات العضوية الفوسفاتية الديكلوروفوس حميد ر�سا حممدى، جعفر جليليان، حممد يحيى كرميي، �سيد �ستاب بو�سهرى abstract: objectives: organophosphate (op) pesticides inhibit both red blood cell (rbc) and plasma cholinesterases (ches). oximes, especially pralidoxime (2-pam), are widely used as antidotes to treat op poisoning. in addition, n-acetylcysteine (nac) is sometimes used as an adjuvant antidote. the current study aimed to assess the feasibility of using nac as a single therapeutic agent for op poisoning in comparison to in vitro 2-pam. methods: this study was carried out at the razi drug research center of iran university of medical sciences, tehran, iran, between april and september 2014. a total of 22 healthy human subjects were recruited and 8 ml citrated blood samples were drawn from each subject. dichlorvos-inhibited blood samples were separately exposed to low and high doses (final concentrations of 300 and 600 μmol.l-1, respectively) of 2-pam, nac and cysteine. plasma and rbcs were then separated by centrifugation and their che activity was measured using spectrophotometry. results: although cysteine—and not nac—increased the che activity of both plasma and rbcs over those of dichlorvos, it did not increase them over those of a high dose of 2-pam. conclusion: these results suggest that the direct reactions of 2-pam and cysteine with dichlorvos and the reactivation of phosphorylated ches occurr via an associative stepwise addition-elimination process. high therapeutic blood concentrations of cysteine are needed for the elevation of che activity in plasma and rbcs; however, both this agent and nac may still be effective in the reactivation of plasma and rbc ches. keywords: organophosphate poisoning; antidotes; cysteine; n-acetylcysteine; pralidoxime compounds; cholinesterases. امللخ�ص: الهدف: مبيدات الفو�سفات الع�سوي هي مواد من �سنع االإن�سان وهي تثبط انزمي الكولين�سرتاز يف كل من خاليا الدم احلمراء )كرات الفو�سفات مببيدات الت�سمم لعالج كرتياق �سائعة، ب�سورة الرباليدوك�سيم خ�سو�سا و االأوك�سيمات، وت�ستخدم البالزما. و احلمراء( الدم الع�سوي. وباالأ�سافة ايل ذلك فقد ت�ستخدم مادة ال ن-اأ�سيتيل �سي�ستني يف بع�ص االأحيان كرتياق م�ساعد. هدفت هذه الدرا�سة اأيل تقييم جدوى اأ�ستخدام مادة ال ن-اأ�سيتيل �سي�ستني كعامل عالجي احدي للت�سمم مببيدات الفو�سفات الع�سوي ومقارنتها مع مادة الرباليدوك�سيم يف املخترب. الطريقة: اأجريت هذه الدرا�سة يف مركز الرازي لبحوث املخدرات، جامعة ايران للعلوم الطبية، طهران، اإيران، بني اأبريل و�سبتمرب 2014. يف هذه الدرا�سة مت �سحب ثمانية ميلى ليرت عينات دم معالج مبادة ال�سيرتات من 22 �سخ�سا �سليما. مت تعري�ص عينات الدم املثبطة مبادة الديكلوروفو�ص ب�سكل منف�سل جلرعات منخف�سة ثم مرتفعة من الرباليدوك�سيم و ال ن-اأ�سيتيل �سي�ستني وال�سي�ستني )برتكيزات نهائية مقدارها 300 ميكروموالر 600 ميكروموالر علي التوايل(. بعد ذلك مت ف�سل البالزما وكرات الدم احلمراء من العينات بوا�سطة الطرد املركزي تالها القيا�ص الطيفي لن�ساط اأنزمي الكولين�سرتاز بهم. النتائج: اأظهرت النتائج اأنه على الرغم من ال�سي�ستني )ولي�ص ال ن-اأ�سيتيل �سي�ستني ( اأدى ايل زيادة كبرية يف ن�ساط انزمي الكولين�سرتاز يف كل من البالزما وكرات الدم احلمراء تغلبت على تثبيط مادة الديكلوروفو�ص، ولكنها لي�ست بنف�ص الن�سبة التي حتدثها تلك اجلرعة العالية من الرباليدوك�سيم. اخلال�صة: ت�سري نتائج الدرا�سة احلالية ايل اأن التفاعالت املبا�رصة بني كل من الرباليدوك�سيم وال�سي�ستني مع مادة الديكلوروفو�ص توؤدي اأيل تن�سيط انزمي الكولين�سرتاز املف�سفر، بطريقة ت�ساعدية تعتمد على االأ�سافة واحلذف. وبالرغم من احلاجة اأيل وجود تركيزات عالية من ال�سي�ستني يف الدم لكي تزيد من ن�ساط انزمي الكولين�سرتاز اال ان هذه املاده ومادة ال ن-اأ�سيتيل �سي�ستني قد يكون لهما دور فعال يف اعادة تن�سيط انزمي الكولين�سرتاز يف كل من البالزما وكرات الدم احلمراء. الكلمات املفتاحية: الت�سمم مبركبات الفو�سفات الع�سوي؛ ترياق؛ ال�سي�ستني؛ ن-اأ�سيتيل �سي�ستني؛ مركبات الرباليدوك�سيم؛ انزمي الكولين�سرتاز. in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases hamidreza mohammadi,1,2 jafar jalilian,2 mohammad y. karimi,3 *seyed v. shetab-boushehri3,4 clinical & basic research sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e293–300, epub. 10 oct 17 submitted 26 mar 17 revisions req. 1 may & 8 jun 17; revisions recd. 19 may & 9 jun 17 accepted 18 jun 17 doi: 10.18295/squmj.2017.17.03.006 advances in knowledge the results of the present study showed that, although high concentrations of cysteine increased dichlorvos-inhibited acetyland pseudocholinesterase activities, this agent was less efficient than pralidoxime in the reactivation of human cholinesterases. in addition, the study illustrated that cysteine directly reacts with and inactivates dichlorvos at low plasma concentrations, while it replaces serine in the dichlorvos-cholinesterase complex at a very high plasma concentration and regenerates inhibited cholinesterases as well as having a direct reaction with dichlorvos. in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases e294 | squ medical journal, august 2017, volume 17, issue 3 organophosphate (op) pesticides are manmade phosphoric acid esters that inhibit and inactivate both true (i.e. acetylcholin esterase [ache]) and pseudo(i.e. butyrylcholinesterase [buche]) cholinesterases (ches) by a nucleophilic reaction in which the associative two-step additionelimination reaction with the serine hydroxyl group at their active sites results in phosphorylated and inactivated enzymes.1,2 ache is primarily found in nervous tissue and erythrocytes; erythrocytic che activity more accurately reflects nervous tissue ache activity than buche, which is primarily produced in the liver and appears in plasma, with its activity varying with a number of disorders including liver disease.3,4 the irreversible inactivation of ches by the dealkylation of the op moiety of the op-che complex is known as ageing, in which the phosphorusoxygen bond of the op-che complex strengthens.5 after ageing occurs, even oximes are ineffective in reactivating the enzyme, and the only means of restoring che activity is via the lengthy process of synthesizing a new ache enzyme.2 at present, two main antidotes exist for the treatment of op poisoning: atropine and oximes, particularly pralidoxime (2-pam) in the latter group.2 however, oximes are not always useful in the management of op poisoning.6–8 moreover, the phosphorylated oxime complex is a strong inhibitor of ches and oximes themselves can inhibit aches.9 thus, the introduction of new, more efficient and less toxic antidotes to op poisoning seems necessary. n-acetylcysteine (nac) is a prodrug of cysteine and a mucolytic agent with potent antioxidant and free radical scavenging properties; it is currently used to treat acetaminophen poisoning and as an adjuvant antidote for op poisoning.10,11 other medical uses of nac include the treatment of radiocontrastinduced nephropathy, cyclophosphamide-induced haemorrhagic cystitis and a number of psychiatric disorders.12–14 furthermore, nac has significant anti viral activity against the influenza a viruses.15 the present study aimed to assess the feasibility of cysteine administration as a single therapeutic agent for the reactivation of both ache and buche in comparison with in vitro 2-pam administration. methods this study was carried out at the razi drug research center, iran university of medical sciences, tehran, iran, between april and september 2014. a total of 22 healthy human subjects were recruited to participate in the study. each participant was requested to complete a questionnaire to determine their health status, use of medications, occupational history and exposure to pesticides. subjects with a history of diabetes mellitus, hypertension, liver disease, anaemia, malnutrition, cancer or other chronic illnesses and those who smoked cigarettes, used alcohol or drugs or had a history of radiotherapy were excluded from the study. the following chemicals and solutions were purchased: 5,5'-dithiobis(2-nitrobenzoic acid) (dtnb), n-acetylcysteine, cysteine, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride and tripotassium citrate monohydrate (merck kgaa, darmstadt, germany); quinidine sulfate dihydrate, acetylthiocholine iodide and s-butyrylthiocholine iodide (sigma-aldrich corp., st. louis, missouri, usa); dichlorvos of 98% weight/weight purity (gyah corp., karaj, iran); and 2-pam methylsulfate (laboratoires serb, paris, france). stock solutions of dichlorvos, 2-pam, nac and l-cysteine were each separately prepared in a 0.9% weight/volume (w/v) solution of sodium chloride in distilled water (i.e. normal saline) to produce final concentrations of 21.0 μg.ml-1 (95 μmol.l-1), 14.9 mg.ml-1 (60 mmol.l-1), 9.80 mg.ml-1 (60 mmol.l-1) and 7.27 mg.ml-1 (60 mmol.l-1). all stock solutions were stored in the dark at 4 °c. an 8-ml blood sample was obtained from each subject and immediately citrated with a 3.8% w/v tripotassium citrate solution to prevent clot formation.16 each sample was then divided into 1 ml aliquots. the first aliquot was considered as a control and placed in a water bath at 37 °c for 80 minutes. the second aliquot was exposed to dichlorvos at a final concentration of 0.95 μmol.l-1 in a 37 °c water bath for 80 minutes.17 the remaining aliquots were exposed to dichlorvos at a final concentration of 0.95 μmol.l-1 in a water bath at 37 °c for 20 minutes, followed by these findings indicate that the effectiveness of cysteine in dichlorvos-induced poisoning depends on both dichlorvos and cysteine plasma concentrations. application to patient care according to the findings of this study, the efficacy of cysteine in the treatment of cases of organophosphate poisoning may depend on maintaining high therapeutic concentrations of cysteine. hamidreza mohammadi, jafar jalilian, mohammad y. karimi and seyed v. shetab-boushehri clinical and basic research | e295 exposure to low and high concentrations of 2-pam, l-cysteine and nac separately in a water bath at 37 °c for 60 minutes. in total, 10 μl of the dichlorvos, 2-pam, nac and cysteine solutions were added to 1 ml of blood to produce final concentrations of 0.21 μg.ml-1 (0.95 μmol.l-1), 149 μg.ml-1 (600 μmol.l-1), 98 μg.ml-1 (600 μmol.l-1) and 72.7 μg.ml-1 (600 μmol.l-1), representing the high doses of the drugs. an additional 5 μl of the 2-pam, nac and l-cysteine solutions were added to 1 ml of blood to produce final concentrations of 74.5 μg.ml-1 (300 μmol.l-1), 49 μg.ml-1 (300 μmol.l-1) and 36.3 μg.ml-1 (300 μmol.l-1), representing the low doses of the drugs. the plasma and red blood cells (rbcs) of each blood sample were then separated by centrifugation at 5,000 revolutions per minute for 10 minutes. each plasma sample was diluted 100 times with distilled water and the diluted sample was used to determine buche activity. each volume of the rbc sample was first washed three times with three volumes of normal saline and then haemolyzed and diluted 60 times with distilled water to sufficiently dilute thiol-containing (i.e. cysteine and nac) and oxime-containing (i.e. 2-pam) compounds and prevent reactions with dtnb. the haemolyzed diluted sample (haemolysate) was used to determine ache activity. ellman’s kinetic method was used to determine the buche and ache activities of diluted samples at 410 and 440 nm, respectively.18 in order to measure buche activity, 50 μl of the diluted plasma sample was added to 150 μl of a reagent containing 0.423 mmol.l-1 of dtnb in 0.1 mol.l-1 of a phosphate buffer with a ph of 7.6 as well as 50 μl of substrate (10 mmol.l-1 of butyrylthiocholine iodide in distilled water) in each well of a 48-well plate and marked as a test well. all components of the test well were included in five blank wells, except for the sample which was replaced by an equivolume of normal saline. initial and final absorbances of the test and blank wells were then recorded at 410 nm over a 5-minute period. test well absorbances were subtracted from the average absorbance of the blank wells and divided by 0.0216 as the product of the time period and the molar attenuation coefficient of the 5-thio-2-nitrobenzoate anion at 410 nm (0.0136 l.μmol-1.cm-1) and light path length (0.318 cm) and multiplied by the dilution factor (100 x 5 = 500). subsequently, ache activity was measured using 10 μl of the haemolysate sample added to 300 μl of a reagent containing 0.27 mmol.l-1 of dtnb and 20 μmol.l-1 of quinidine sulfate in 0.1 mol.l-1 of a phosphate buffer at a ph of 7.6 and preincubated for 5 minutes at 37 °c. this procedure was followed by the addition of 10 μl of substrate (100 mmol.l-1 of acetylthiocholine iodide in distilled water) in each well of a 48-well plate and marked as a test well. as before, five blank wells contained all components of the test well, except for the sample, which was replaced by an equivolume of normal saline. the initial and final absorbances of the test and blank wells were recorded during a 5-minute period at 440 nm. the absorbances of the test wells were subtracted from the average absorbance of the blank wells and divided by 0.023 as the product of the time period and the molar attenuation coefficient of the 5-thio-2-nitrobenzoate anion at 440 nm (0.01434 l.μmol-1.cm-1) and light path length (0.32 cm) and multiplied by the dilution factor (60 x 32 = 1,920). the visible absorbances of samples were measured using a multi-mode microplate reader (synergy™ ht microplate reader, biotek instruments inc., winooski, vermont, usa). all buche and ache activities were expressed in units per l (u.l-1). the activity of each sample was divided by that of the respective control (normalisation) and represented as a percentage. a one sample t-test was used to analyse the statistical differences between the percentages of buche and ache activities in the dichlorvos and control groups, for which the latter was deemed to have 100% che activity. differences between percentages of buche and ache activities in the experimental groups were analysed using a one-way analysis of variance test followed by a scheffe post-hoc test. the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa) was used for all statistical analyses. a p value of <0.050 was considered statistically significant. graphs were produced using sigmaplot software, version 12.0 (systat software inc., san jose, california, usa). this study was approved by the ethics committee of the mazandaran university of medical sciences, sari, mazandaran, iran (#1072). all procedures were performed in accordance with the ethical standards of the revised declaration of helsinki of 2008. all participants signed an informed consent form before being included in the study. results dichlorvos significantly reduced buche activity in comparison to the control group (37.8% ± 2.5%; p <0.010). both low and high doses of 2-pam (55.0% ± 3.5% and 72.0% ± 3.4%, respectively) significantly increased buche activity in comparison to the dichlorvos group (p <0.010 and <0.001, respectively). low concentrations of nac and cysteine (38.8% ± 2.0% and 35.5% ± 2.7%, respectively) did not significantly in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases e296 | squ medical journal, august 2017, volume 17, issue 3 increase buche activity over dichlorvos (p >0.050 each). a high dose of nac (37.5% ± 1.7%) also did not significantly increase buche activity in comparison to dichlorvos (p >0.050). however, a high concentration of cysteine (53.8% ± 3.9%) significantly increased buche activity over that of dichlorvos (p <0.010). a high concentration of 2-pam significantly increased buche activity in comparison to a low concentration (p <0.010). moreover, a low dose of 2-pam significantly increased buche activity in comparison to a low dose of cysteine (p <0.010) [figure 1]. ache activity was significantly reduced in the dichlorvos group compared to the control group (60.0% ± 2.5%; p <0.010), although to a lesser extent than for buche activity. both low and high doses of 2-pam (81.9% ± 2.4% and 94.6% ± 2.8%, respectively) significantly increased ache activity over that of dichlorvos (p <0.010 each). low and high concentrations of nac (63.0% ± 2.0% and 67.1% ± 4.7%, respectively) did not significantly increase ache activity in comparison to dichlorvos (p >0.050 each). low and high concentrations of cysteine (75.0% ± 3.3% and 88.7% ± 3.4%, respectively) significantly increased ache activity compared to the dichlorvos group (p <0.010 and <0.010, respectively). there was no significant difference between low and high concentrations of 2-pam or low concentrations of 2-pam and cysteine in terms of ache activity (p >0.050 each). there was also no significant difference between high concentrations of 2-pam and cysteine with regards to ache activity. however, a high dose of 2-pam significantly increased ache activity over that of a low cysteine dose (p <0.010) [figure 2]. discussion previous research has indicated that nac replenishes glutathione storage and has antioxidant and free radical scavenging properties.19 it is a prodrug which is enzymatically metabolised (i.e. deacetylated) by the liver into its active metabolite cysteine and serves as a cysteine donor.20 the thiol group of cysteine is reactive toward xenobiotics and seems to be responsible for its beneficial effects in poisoning cases.21 in the present study, the reactivation effect of equimolar concentrations of 2-pam, nac and cysteine on dichlorvos-induced buche and ache inhibition was investigated. the results demonstrated that dichlorvos inhibited buche activity to a greater degree than ache activity; this finding is in agreement with a statement by jafari et al. indicating that ache is less sensitive to ops than buche.22 ríos et al. have previously shown that while 2-pam concentrations as low as 66 μmol.l-1 are sufficient to prevent deaths in most in vivo cases of op poisoning, concentrations of up to 700 μmol.l-1 are much more effective.23 in the present study, samples were treated with both low (300 μmol.l-1) and high (600 μmol.l-1) concentrations of 2-pam in order to compare che reactivation effects; the results showed that a high concentration of 2-pam increased buche but not ache activity in comparison to a low concentration. these findings confirm that che reactivation in op poisoning is dependent on the plasma concentrations of 2-pam.23 the concentrations of 2-pam, nac and cysteine in the current study were selected based on their therapeutic plasma concentrations in humans.23,24 the figure 1: chart showing mean plasma cholinesterase activity in different experimental groups as a measure of human cholinesterase reactivation in the treatment of organophosphide poisoning (n = 22). the dichlorvos group was compared with the control group while all other groups were compared with the dichlorvos group. che = cholinesterase; ddvp = dichlorvos; 2-pam = pralidoxime; nac = n-acetylcysteine. *statistically significant difference in comparison to the control group (p <0.010). †statistically significant difference in comparison to the dichlorvos group (p <0.010). ‡statistically significant difference in comparison to a low dose of cysteine (p <0.010). §statistically significant difference in comparison to a low dose of 2-pam (p <0.010). figure 2: chart showing mean red blood cell cholinesterase activity in different experimental groups as a measure of human cholinesterase reactivation in the treatment of organophosphide poisoning (n = 22). the dichlorvos group was compared with the control group while all other groups were compared with the dichlorvos group. rbc = red blood cell; che = cholinesterase; ddvp = dichlorvos; 2-pam = pralidoxime; nac = n-acetylcysteine. *statistically significant difference in comparison to the control group (p <0.010). †statistically significant difference in comparison to the dichlorvos group (p <0.010). ‡statistically significant difference in comparison to a low dose of cysteine (p <0.010). hamidreza mohammadi, jafar jalilian, mohammad y. karimi and seyed v. shetab-boushehri clinical and basic research | e297 standard intravenous regimen of nac—150 mg/kg-1 for 15 minutes followed by 50 mg/kg-1 for four hours and 100 mg/kg-1 over the next 16 hours—produces initial nac plasma concentrations ranging from 304–875 μg.ml-1.24 concentrations subsequently fall rapidly and reach a relatively constant level of approximately 35 μg.ml-1 after 12 hours until the infusion is stopped.24 in comparison to dichlorvos, concentrations of nac in the present study did not significantly increase buche and ache activities; however, both buche and ache activities significantly increased with concen trations of cysteine. this finding indicates that cysteine, the active metabolite of nac, is responsible for the reactivation of ches. the absence of a metabolising organ—the liver—in the present in vitro study may explain why nac did not elevate buche and ache activities in comparison to cysteine.20 thus, in clinical situations in which liver function is normal, nac treatment may still be effective. the results of the present work indicate that therapeutic plasma concentrations of cysteine (or, potentially, nac) for the treatment of op poisoning strongly depends on op plasma concentrations. the pka of nucleophiles has been shown to play an important role in their reaction with ops, in that more basic nucleophiles with higher pka values show a lower reactivity.2,25 the pka values of the 2-pam oxime and cysteine thiol groups are 7.8 and 8.3, respectively, which reflect a favourable range.2,26 in addition, according to the henderson-hasselbalch equation, the 2-pam oxime and cysteine thiol groups are 28.48% and 11.18% ionised at a ph of 7.4, respectively.2 thus, it is expected that, in addition to 2-pam, cysteine could also react with the op-che complex and displace op with a nucleophilic attack, resulting in the reactivation of ches. with a pka of 9.5, nac is less reactive to nucleophiles than cysteine.27 for a nucleophilic attack of the cysteine thiol group to the phosphorus-oxygen bond of the op-che complex, the phosphorus-oxygen bond between the serine hydroxyl oxygen atom from che and the phosphorous atom of op should be cleaved and a phosphorus-sulfur bond formed between the cysteine thiol sulfur atom and the phosphorus atom of op. cysteine is a weak nucleophile and the phosphorus-sulfur bond is much weaker than a phosphorus-oxygen bond and therefore easier to break; however, the concentration of the reactants, namely cysteine and op, seems to play a critical role in this reaction.28,29 on the basis of collision theory, a higher concentration of reactants increases the probability of effective collisions, consequently resulting in the formation of a product.30 however, to be effective, collisions should occur in a particular molecular orientation. in the present study, concentrations of dichlorvos and cysteine were 0.95 μmol.l-1 and 300 μmol.l-1 (low dose) and 600 μmol.l-1 (high dose), respectively. in clinical cases of op poisoning, the plasma concentration of op is very high due to the high intake.31 thus, large amounts of nac and even 2-pam should be administered intravenously to be effective. some researchers have reported that although intravenous nac reduced hospitalisation time among oppoisoned individuals, it unfortunately did not increase che activity.11 one explanation for this outcome may be related to the low plasma concentration of nac in comparison to the high plasma concentration of op. another explanation may be related to the direct reaction of nac—or, more accurately, cysteine-with ops which results in more polar and may be more excretable product.2 a similar result has been observed with the administration of 2-pam to op-poisoned individuals, in that che reactivation seems to depend on the plasma concentrations of 2-pam and op, with high concentrations of 2-pam necessary for the adequate reactivation of op-inhibited human rbc ches.23 this phenomenon explains why oximes are not always useful in the management of op poisoning.6–8 figure 3 illustrates the proposed mechanism of nucleophilic attack of 2-pam and cysteine to dichlorvos, in which the reactions of 2-pam and cysteine with dichlorvos proceed through an associative stepwise addition-elimination mechanism.2 in both of these reactions, the 2,2-dichlorovinylate anion (as a leaving group) is separated from a pentacoordinate phosphorene intermediate and leaves a polar product which seems to be more excretable than dichlorvos. the 2,2-dichlorovinylate anion then gains a hydrogen ion and is converted to 2,2-dichlorovinyl alcohol which in turn undergoes a spontaneous rearrangement and is converted to dichloroacetaldehyde, a metabolite of dichlorvos.2 one of the detoxification mechanisms of nac in acetaminophen poisoning is its direct reaction with n-acetyl-p-benzoquinone imine, the toxic meta bolite of acetaminophen.19 thus, nac may still act as an antidote in op poisoning due to its direct reaction and neutralisation properties. on this basis, figure 4 depicts another proposed mechanism for the reactivation of op-inhibited ches by 2-pam and cysteine wherein the reactions of 2-pam and cysteine with op-inhibited ches also proceed via an associative stepwise addition-elimination process. similarly, the serine anion of che as a leaving group is separated from a pentacoordinate phosphorane intermediate in both of these reactions. the pka of the leaving group has also been shown to play an important role in the reaction of nucleophiles, as more acidic leaving groups with low pka values are in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases e298 | squ medical journal, august 2017, volume 17, issue 3 figure 3: diagram showing a proposed nucleophilic mechanism for the reaction of (a) pralidoxime and (b) n-acetylcysteine with dichlorvos. ch3/h3c = methyl group; n = nitrogen; oh = hydroxide; h = hydrogen; cl = chlorine; o = oxygen; p = phosphorus; ddvp = dichlorvos; nh2 = amine group; s = sulfur. figure 3a reproduced with permission from shetab-boushehri sv, shetab-boushehri sf, abdollahi m. possible role of mg2+ ion in the reaction of organophosphate (dichlorvos) with serine.2 figure 4: diagram showing a proposed nucleophilic mechanism for the reaction of (a) pralidoxime and (b) n-acetylcysteine with the dichlorvos-cholinesterase complex. for simplification, only the serine moiety of cholinesterase is shown. ch3/h3c = methyl group; n = nitrogen; oh = hydroxide; h = hydrogen; o = oxygen; nh2 = amine group; p = phosphorus; op = organophosphate; s = sulfur; hn = amine; sh = thiol; h2o = water. hamidreza mohammadi, jafar jalilian, mohammad y. karimi and seyed v. shetab-boushehri clinical and basic research | e299 more easily separated from ops.25 this could explain why certain ops more rapidly age ches in comparison to others.5 in the current study, the displacement of serine as a leaving group with a pka of 13.0 by 2-pam and cysteine as nucleophiles with pkas of 7.8 and 8.3, respectively, seems thermodynamically unfavourable;2,26 nevertheless, clinical evidence as well as the results of the present study show that although 2-pam has a lower pka than serine, it displaces the serine moiety in the op-che complex which results in reactivated ches.3,4,8,9 cysteine, although a weaker nucleophile, seems to follow this mechanism but at much higher plasma concentrations. as in the case of direct reactions of 2-pam and cysteine with dichlorvos, the displacement of the serine moiety of the op-ache complex by 2-pam and cysteine seems to be dose-dependent. although cysteine is a weak nucleophile, the current study demonstrates that it nevertheless displaces the serine moiety in the opche complex at high concentrations. the authors suggest the administration of a maximum tolerable intravenous dose of nac for the treatment of op poisoning; however, extensive animal studies are needed to confirm this suggestion and nac should be considered a supportive antidote until the safety and efficacy of this approach is approved. considering its potential for metabolising into cysteine, nac could be an alternative therapeutic agent in op poisoning. a comparative animal study on the beneficial effects of nac and cysteine on the reactivation of ches in op poisoning is therefore proposed for future research. conclusion the results of the present study suggest that the direct reactions of 2-pam and cysteine with dichlorvos, and the subsequent reactivation of phosphorylated ches, proceed through an associative stepwise addition-elimination process. in addition, the findings indicate that cysteine directly reacts with ops at low concentrations while, at very high concentrations, it replaces serine in the pentacoordinate intermediate and regenerates inhibited ches as well as directly reacting with dichlorvos. moreover, it is possible that higher doses of nac in a clinical context may also have the same effect; however, further studies are required to confirm this theory. a c k n o w l e d g e m e n t s the authors thank the gyah corporation for providing the purified dichlorvos used in the present study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded with the aid of a grant from the mazandaran university of medical sciences (grant #1072). references 1. kirby aj, mora jr, nome f. new light on phosphate transfer from triesters. biochim biophys acta 2013; 1834:454–63. doi: 10. 1016/j.bbapap.2012.04.010. 2. shetab-boushehri sv, shetab-boushehri sf, abdollahi m. possible role of mg2+ ion in the reaction of organophosphate (dichlorvos) with serine. j med hypotheses ideas 2012; 6:53–7. doi: 10.1016/j.jmhi.2012.05.001. 3. sidhu g, jandial s, khubchandani a. a study of erythrocyte cholinesterase in comparison with serum cholinesterase activity in organophosphorous poisoning patients. int j res med 2014; 3:77–9. 4. santarpia l, grandone i, contaldo f, pasanisi f. butyrylcholinesterase as a prognostic marker: a review of the literature. j cachexia sarcopenia muscle 2013; 4:31–9. doi: 10.1007/s13539 012-0083-5. 5. sirin gs, zhang y. how is acetylcholinesterase phosphonylated by soman? an ab initio qm/mm molecular dynamics study. j phys chem a 2014; 118:9132–9. doi: 10.1021/jp502712d. 6. rahimi r, nikfar s, abdollahi m. increased morbidity and mortality in acute human organophosphate-poisoned patients treated by oximes: a meta-analysis of clinical trials. hum exp toxicol 2006; 25:157–62. doi: 10.1191/0960327106ht602oa. 7. abdollahi m, behmanesh y, akhgari m. the effects of oximes in the assay of acetylcholinesterase activity in lysed erythrocytes in vitro. acta med iran 1997; 35:45–8. 8. nurulain sm. efficacious oxime for organophosphorus poisoning: a minireview. trop j pharm res 2011; 10:341–9. doi: 10.4314/tjpr. v10i3.10. 9. johnson mk, jacobsen d, meredith tj, eyer p, heath aj, ligtenstein da, et al. evaluation of antidotes for poisoning by organophosphorus pesticides. emergen med australas 2000; 12:22–37. doi: 10.1046/j.1442-2026.2000.00087.x. 10. prescott l. oral or intravenous n-acetylcysteine for acetaminophen poisoning? ann emerg med 2005; 45:409–13. doi: 10.1016 /j.annemergmed.2004.09.028. 11. shadnia s, ashrafivand s, mostafalou s, abdollahi m. n-acetylcysteine a novel treatment for acute human organophosphate poisoning. int j pharmacol 2011; 7:732–5. doi: 10.3923/ijp.2011. 732.735. 12. liu r, nair d, ix j, moore dh, bent s. n-acetylcysteine for the prevention of contrast-induced nephropathy: a systematic review and meta-analysis. j gen intern med 2005; 20:193–200. doi: 10.1111/j.1525-1497.2005.30323.x. 13. palma pc, villaça júnior cj, netto júnior nr. n-acetylcysteine in the prevention of cyclophosphamide induced haemorrhagic cystitis. int surg 1986; 71:36–7. 14. berk m, malhi gs, gray lj, dean om. the promise of n-acetylcysteine in neuropsychiatry. trends pharmacol sci 2013; 34:167–77. doi: 10.1016/j.tips.2013.01.001. 15. geiler j, michaelis m, naczk p, leutz a, langer k, doerr hw, et al. n-acetyl-l-cysteine (nac) inhibits virus replication and expression of pro-inflammatory molecules in a549 cells infected with highly pathogenic h5n1 influenza a virus. biochem pharmacol 2010; 79:413–20. doi: 10.1016/j.bcp.2009.08.025. https://doi.org/10.1016/j.bbapap.2012.04.010 https://doi.org/10.1016/j.bbapap.2012.04.010 https://doi.org/10.1016/j.jmhi.2012.05.001 https://doi.org/10.1007/s13539-012-0083-5 https://doi.org/10.1007/s13539-012-0083-5 https://doi.org/10.1021/jp502712d https://doi.org/10.1191/0960327106ht602oa https://doi.org/10.4314/tjpr.v10i3.10 https://doi.org/10.4314/tjpr.v10i3.10 https://doi.org/10.1046/j.1442-2026.2000.00087.x https://doi.org/10.1016/j.annemergmed.2004.09.028 https://doi.org/10.1016/j.annemergmed.2004.09.028 https://doi.org/10.3923/ijp.2011.732.735 https://doi.org/10.3923/ijp.2011.732.735 https://doi.org/10.1111/j.1525-1497.2005.30323.x https://doi.org/10.1016/j.tips.2013.01.001 https://doi.org/10.1016/j.bcp.2009.08.025 in vitro cysteine reactivates organophosphate insecticide dichlorvos-inhibited human cholinesterases e300 | squ medical journal, august 2017, volume 17, issue 3 16. young ds, bermes ew. specimen collection and processing: sources of biological variation. in: burtis ca, ashwood er, eds. tietz textbook of clinical chemistry, 3rd ed. philadelphia, pennsylvania, usa: saunders, 1999. pp. 42–72. 17. lotti m, johnson mk. neurotoxicity of organophosphorus pesticides: predictions can be based on in vitro studies with hen and human enzymes. arch toxicol 1978; 41:215–21. doi: 10.10 07/bf00354093. 18. ellman gl, courtney kd, andres v jr, featherstone rm. a new and rapid colorimetric determination of acetylcholinesterase activity. biochem pharmacol 1961; 7:88–95. doi: 10.1016/00062952(61)90145-9. 19. asevedo e, mendes ac, berk m, brietzke e. systematic review of n-acetylcysteine in the treatment of addictions. rev bras psiquiatr 2014; 36:168–75. doi: 10.1590/1516-4446-2013-1244. 20. cacciatore i, cornacchia c, pinnen f, mollica a, di stefano a. prodrug approach for increasing cellular glutathione levels. molecules 2010; 15:1242–64. doi: 10.3390/molecules15031242. 21. heidari r, babaei h, roshangar l, eghbal ma. effects of enzyme induction and/or glutathione depletion on methimazole-induced hepatotoxicity in mice and the protective role of n-acetylcysteine. adv pharm bull 2014; 4:21–8. doi: 10.5681/apb.2014.004. 22. jafari m, pourheidari g. the reactivation effect of pralidoxime in human blood on parathion and paraoxon-induced cholinesterase inhibition. daru 2006; 14:37–43. 23. ríos jc, repetto g, galleguillos i, jos a, peso ad, repetto m. high concentrations of pralidoxime are needed for the adequate reactivation of human erythrocyte acetylcholinesterase inhibited by dimethoate in vitro. toxicol in vitro 2005; 19:893–7. doi: 10.1016/j.tiv.2005.06.024. 24. prescott lf, donovan jw, jarvie dr, proudfoot at. the disposition and kinetics of intravenous n-acetylcysteine in patients with paracetamol overdosage. eur j clin pharmacol 1989; 37:501–6. doi: 10.1007/bf00558131. 25. lassila jk, zalatan jg, herschlag d. biological phosphoryl transfer reactions: understanding mechanism and catalysis. annu rev biochem 2011; 80:669–702. doi: 10.1146/annurev-bio chem-060409-092741. 26. kennelly pj, rodwell vw. amino acids & peptides. in: rodwell vw, bender da, botham km, kennelly pj, weil pa. harper’s illustrated biochemistry, 30th ed. new york, usa: mcgraw-hill, 2015. pp. 15–24. 27. moffat ac, osselton md, widdop b, eds. clarke’s analysis of drugs and poisons, 4th ed. london, uk: pharmaceutical press, 2011. p. 823. 28. iyer s, hengge ac. the effects of sulfur substitution for the nucleophile and bridging oxygen atoms in reactions of hydroxy alkyl phosphate esters. j org chem 2008; 73:4819–29. doi: 10.1021 /jo8002198. 29. haynes wm. crc handbook of chemistry and physics, 95th ed. boca raton, florida, usa: crc press, 2014. pp. 9–69. 30. silberberg m. principles of general chemistry, 2nd ed. new york, usa: mcgraw-hill, 2009. p. 529. 31. futagami k, otsubo k, nakao y, aoyama t, iimori e, urakami s, et al. acute organophosphate poisoning after disulfoton ingestion. j toxicol clin toxicol 1995; 33:151–5. doi: 10.3109/155636595 09000465. https://doi.org/10.1007/bf00354093 https://doi.org/10.1007/bf00354093 https://doi.org/10.1016/0006-2952%2861%2990145-9 https://doi.org/10.1016/0006-2952%2861%2990145-9 https://doi.org/10.1590/1516-4446-2013-1244 https://doi.org/10.3390/molecules15031242 https://doi.org/10.5681/apb.2014.004 https://doi.org/10.1016/j.tiv.2005.06.024 https://doi.org/10.1007/bf00558131 https://doi.org/10.1146/annurev-biochem-060409-092741 https://doi.org/10.1146/annurev-biochem-060409-092741 https://doi.org/10.1021/jo8002198 https://doi.org/10.1021/jo8002198 https://doi.org/10.3109/15563659509000465 https://doi.org/10.3109/15563659509000465 1department of psychology & counselling, faculty of human development, sultan idris education university, tanjung malim, malaysia; 2department of psychological medicine, university malaysia sarawak, sarawak, malaysia; 3department of community medicine, universiti sains malaysia, kelantan, malaysia; 4department of cardiology, institut jantung negara, kuala lumpur, malaysia; 5department of cardiology, universiti kebangsaan malaysia medical centre, kuala lumpur, malaysia *corresponding author’s e-mails: norfirdous@fpm.upsi.edu.my and norfirdous.m@gmail.com التطوير والتحقق من صحة استبيان نوعية احلياة عرب الثقافات اخلاص بالفشل القليب نور فردو�س حممد، �شيتي رودزه غزايل، نور عزواين يعقوب، اإيزيا عزان عبدالرحيم، اأوتيه م�شكون abstract: objectives: heart failure (hf) is a common clinical syndrome with an enormous impact on prognosis and lifestyle. accordingly, rehabilitation measures need to be patient-specific and consider various sociocultural factors so as to improve the patient’s quality of life (qol). this study aimed to develop and validate a hf-specific qol (hfqol) questionnaire within a multicultural setting. methods: this study took place at the national heart institute and universiti kebangsaan malaysia medical centre, kuala lumpur, malaysia, between march 2013 and march 2014. a self-administered 75-item hfqol questionnaire was designed and administrated to 164 multi-ethnic malaysian hf patients. exploratory factor analysis was performed to assess the instrument’s construct validity. cronbach’s alpha coefficients were used to determine internal consistency. results: a total of 33 out of 75 items were retained in the final tool. the hfqol questionnaire had three common factors—psychological, physical-social and spiritual wellbeing—resulting in a cumulative percentage of total variance of 44.3%. the factor loading ranges were 0.450–0.718 for psychological wellbeing (12 items), 0.394–0.740 for physical-social wellbeing (14 items) and 0.449–0.727 for spiritual wellbeing (seven items). the overall cronbach’s alpha coefficient of the questionnaire was 0.82, with coefficients of 0.86, 0.88 and 0.79 for the psychological, physical-social and spiritual wellbeing subdomains, respectively. conclusion: the hfqol questionnaire was found to be a valid and reliable measure of qol among malaysian hf patients from various ethnic groups. such tools may facilitate cardiac care management planning among multi-ethnic patients with hf. keywords: heart failure; quality of life; culturally competent care; ethnic groups; questionnaire design; reliability and validity; malaysia. تكون اأن يجب ذلك، على وبناًء احلياة. واأمناط التكهن على هائل تاأثري ذات �شائعة �رصيرية متالزمة هو القلب ف�شل الهدف: امللخ�ص: تدابري التاأهيل حمددة للمر�شى واأن تراعي العديد من العوامل الجتماعية والثقافية لتح�شني نوعية حياة املري�س. تهدف هذه الدرا�شة معهد يف الدرا�شة هذه اأجريت الطريقة: الثقافات. متعددة بيئة يف القلب لف�شل احلياة نوعية ا�شتبيان �شحة من والتحقق تطوير اإىل مت .2014 ومار�س 2013 مار�س بني ما الفرتة يف ماليزيا، لمبور، كوال ماليزيا، كيباجن�شان جلامعة الطبي واملركز الوطني القلب ت�شميم ا�شتبيان نوعية احلياة لف�شل القلب ذو 75 عن�رًصا باإدارة ذاتية وتوزيعه على 164 مري�شا متعدي الأعراق م�شابني بف�شل القلب. النتائج: الداخلي. الت�شاق لتحديد كرونباخ األفا معامالت ا�شتخدام مت ال�شالحية. اأدوات لتقييم ال�شتق�شائية العوامل حتليل اإجراء مت م�شرتكةعوامل ثالثة القلب لف�شل احلياة نوعية ل�شتبيان كان النهائية. الأداة يف عن�رصا 75 اأ�شل من 33 جمموعه مبا الحتفاظ مت النف�شية والبدنية-الجتماعية والرفاهية الروحية، مما اأدى اإىل ن�شبة تراكمية من التباين الكلي من %44.3. كانت نطاقات حتميل العوامل 0.718-0.450 للرفاهية النف�شية )12 عن�رص(، 0.740-0.394 للرفاهية البدنية-الجتماعية )14 عن�رص( و 0.727-0.449 للرفاهية الروحية )�شبعة عنا�رص(. بلغ معامل األفا كرونباخ الإجمايل لال�شتبيان 0.82، مع معامالت بلغت 0.86، 0.88 و 0.79 بالن�شبة للنطاقات الفرعية م�شداقية ذو التوايل. اخلال�صة: يعترب ا�شتبيان نوعية احلياة لف�شل القلب مقيا�س والبدنية-الجتماعية والرفاهية الروحية على النف�شية وموثوق لنوعية احلياة بني مر�شى ف�شل القلب من خمتلف املجموعات العرقية. ميكن ملثل هذه الأدوات اأن ت�شهل تخطيط اإدارة الرعاية القلبية بني املر�شى متعددي الأعراق امل�شابني بف�شل القلب. الكلمات املفتاحية: ف�شل القلب؛ نوعية احلياة؛ ثقافة الرعاية املتخ�ش�شة؛ فئات عرقية؛ ت�شميم ال�شتبيان؛ املوثوقية وامل�شداقية؛ ماليزيا. development and validation of a cross-cultural heart failure-specific quality of life questionnaire *nor f. mohamed,1 siti r. ghazali,2 nor a. yaacob,3 aizai a. a. rahim,4 oteh maskon5 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e494–500, epub. 28 mar 19 submitted 2 apr 18 revision req. 28 may 18; revision recd. 12 jul 18 accepted 2 aug 18 advances in knowledge this study provides a valid and reliable heart failure (hf)-specific questionnaire to measure quality of life (qol) in a multi-ethnic population. application to patient care the hf-specific qol questionnaire can be used to assess the qol of malaysian hf patients, regardless of ethnic, cultural or religious background. such instruments facilitate patient-specific management by prioritising items with a lower qol domain, enhancing the effectiveness of care as well as patient satisfaction. doi: 10.18295/squmj.2018.18.04.011 nor f. mohamed, siti r. ghazali, nor a. yaacob, aizai a. a. rahim and oteh maskon clinical and basic research | e495 the number of heart failure (hf) patients worldwide is increasing, with the condition affecting an estimated 26 million people globally.1 in southeast asia, the population is growing, with the majority younger than 65 years old; however, rapid epid emiological transition has led to high rates of premature death from noncommunicable diseases, particularly cardiovascular disease.2 southeast asians also have a high prevalence of hf risk factors, including hypertension, tobacco smoking, physical inactivity, overweight/obesity and raised blood glucose levels. moreover, southeast asian patients with hf tend to be younger and have more severe clinical features, with higher rates of mechanical ventilation and longer hospital stays compared to those in developed countries.2 in malaysia, ischaemic heart disease is a major cause of death, with the condition contributing to 13.2% of all deaths in 2016.3 unfortunately, as malaysia has an ageing population, the prevalence and burden of hf is expected to increase in the future.4 among patients with hf, quality of life (qol) is not only affected by the physical symptoms of illness but also by a myriad of social, emotional, sexual and mental factors.5 in particular, patients may suffer from significant psychological distress due to changes in functional level, work status and family relationships.5 as such, the treatment goal in hf is not only to enhance survival rates, but to improve the patient’s qol (i.e. meaningful survival).6,7 however, most existing qol measures for hf patients are based on expert opinions, with only a limited number based on actual patient exp eriences.8–11 dunderdale et al. opined that qol measures based on expert opinions rather than on patients’ perc eptions might demonstrate lower accuracy and usefulness in real-life settings.10 furthermore, qol may vary in the context of the patient’s unique culture and value systems and in relation to their specific goals, expectations, standards and con cerns.6 yusuf et al. recommended that cultural and ethnic differences be taken into consideration when designing qol tools, especially in view of the collectivist nature of southeast asian communities.12 recently, efforts have been made to maintain cultural sensitivity when developing qol measures.13 this study therefore aimed to develop and validate a hf-specific qol (hfqol) questionnaire within a multi-ethnic setting in malaysia. methods this study was conducted at the national heart institute (ijn) and universiti kebangsaan malaysia medical centre (ukmmc), kuala lumpur, malaysia between march 2013 and march 2014. a preliminary version of the hfqol questionnaire was developed based on qualitative findings from in-depth interviews conducted with 19 hf patients. during the interviews, the questions focused on the patients’ experiences during hf and the recovery stage; interview guides were developed based on a literature review and feedback from experts in cardiology management. qualitative data from the inter views were then analysed to identify themes for the quest ionnaire constructs.14 the preliminary constructs were physical wellbeing (i.e. restrictions in physical function), social wellbeing (i.e. dependency on social support net works), psychological wellbeing (i.e. the grieving process and negative emotions regarding adapting to the cond ition) and spiritual wellbeing (i.e. a personal or religious belief system). subsequently, the content of the preliminary hfqol questionnaire was reviewed by seven experienced prof essionals, including four cardiologists and three cardiac unit nurses, all of whom had experience managing hf patients of various ethnicities. each reviewer was asked to rate the relevance of each item for the purposes of the tool from 1–10. they were also asked to evaluate each item’s agreement with the identified constructs, which resulted in the rephrasing of some items. the final version of the hfqol questionnaire was administered in either malay or english, according to the respondent’s preference, and consisted of 75 items scored on a four-point likert scale, with specific definitions tailored to each item [table 1].15 all of the reviewers rated the final version of the questionnaire to be relevant and adequate to measure the qol of hf patients. a pilot study of 35 hf patients confirmed the appropriateness of the questionnaire from a patient’s point of view. the questionnaire could be completed by the respondents either individually or with assistance from the researchers in 20 minutes. a minimum sample of 210 patients was deemed necessary based on the sample size calculations, where in the construct with the highest number of variables (35 variables) was multiplied by five at 80% power.16 due to the limited number of patients with hf, a convenience sampling technique was employed to recruit participants. all respondents were either inor outpatients at the ijn and ukmmc and had hf as identified by cardiologists based on the criteria of reduced left ventricular function (ejection fraction of ≤45%).17 patients from all three major ethnic groups in malaysia were eligible to participate in the study; however, only those able to communicate in either malay or english were included. patients were assessed by cardiologists for hf severity according to the classifications of the new york heart association (nyha), with class i indicating no hf symptoms and no limitations in ordinary physical activity, class ii indicating mild hf symptoms and slight limitations during ordinary activity, class iii development and validation of a cross-cultural heart failure-specific quality of life questionnaire e496 | squ medical journal, november 2018, volume 18, issue 4 indicating significant limitations in activity due to hf symptoms and class iv indicating severe limitations and hf symptoms which persist even at rest.18 all quantitative data were analysed using the statistical package for the social sciences (spss), version 19.0 (ibm corp., armonk, new york, usa). item-level descriptions were performed to explore the distribution of responses. an exploratory factor analysis (efa) was performed to assess construct validity using a principal component analysis with varimax rotation. the kaiser meyer-olkin (kmo) measure of sampling adequacy and bartlett’s test of sphericity was used to assess the adequacy of the sample size for the efa.19 scree plots and eigen values of >1 were used to guide the number of factors, along with the construct of four domains.20 a correlation coefficient of ≥0.3 with a p value of ≤0.050 was considered statistically significant. following the efa, a reliability analysis was done to assess internal consistency utilising cronbach’s alpha coefficient for each identified factor, with a coefficient of >0.70 considered acceptable.21,22 the protocols of this study were approved by the ijn ethics committee (#ijnec/03/2011) and ukmmc ethics committee (#ff-390-2011). informed consent was obtained from all patients following screening by a cardiologist to determine their fitness to participate in the study. results a total of 164 hf patients participated in the study, with a mean age of 61 years. the majority of patients were malay (64%), male (68.3%) and married (81.1%). many participants were unemployed (37.2%) and had not been educated past secondary school level (77.4%). in terms of religious beliefs, the majority were muslims (65.9%), followed by buddhists (16.5%), hindus (12.2%), christians (4.3%) and atheists (1.2%). more than half of the respondents had a family history of heart disease (52.4%) and were currently non-smokers (90.8%). most patients were categorised as having nyha classes i or ii hf (92.1%), with only two patients (1.2%) having class iv hf [table 2]. the kmo measure was 0.81, with significant spheri city (p = 0.001), thus indicating that the sample size was suitable for the efa. in total, 42 items were elimin ated from the hfqol questionnaire based on poor communality, inter-item correlations and factor loading. the rotated component matrix of the remaining 33 items was loaded into three rather than four common factors, due to the combination of the physical and social wellbeing constructs into a single subdomain. the first common factor, psychological wellbeing, consisted of 12 items with a factor loading range of 0.450–0.718. the second common factor was physical-social wellbeing table 1: example of items in each construct in a cross-cultural heart failure-specific quality of life questionnaire item likert score 1 2 3 4 psychological wellbeing i feel sad whenever thinking about my health condition almost every day of the week at least 4–6 days per week at least 1–3 days per week never i feel depressed whenever thinking about my health condition almost every day of the week at least 4–6 days per week at least 1–3 days per week never physical wellbeing ease of breathing difficult even without performing any activity difficult even when performing simple activities easy when performing simple activities easy when performing any activity ability to walk impossible even with assistance impossible without assistance possible without assistance, but with limitations possible without assistance or limitations social wellbeing interactions with family members or friends very distant distant the same as before strengthened support from family members not supportive less supportive than before more supportive than before very supportive spiritual wellbeing level of spiritual beliefs when having heart problems none reduced the same as before strengthened involvement in spiritual activities (e.g. prayer, meditation, etc.) none reduced the same as before strengthened nor f. mohamed, siti r. ghazali, nor a. yaacob, aizai a. a. rahim and oteh maskon clinical and basic research | e497 table 2: sociodemographic and clinical characteristics of multi-ethnic malaysian patients with heart failure (n = 164) characteristic n (%) gender male 112 (68.3) female 52 (31.7) ethnicity malay 105 (64) chinese 33 (20.1) indian 26 (15.9) religion muslim 108 (65.9) buddhist 27 (16.5) hindu 20 (12.2) christian 7 (4.3) atheist 2 (1.2) marital status single 31 (18.9) married 133 (81.1) education level none 12 (7.3) primary school 51 (31.1) secondary school 64 (39) diploma/college/university 37 (22.6) employment status employed 57 (34.8) unemployed 61 (37.2) retired 46 (28) smoking status non-smoker 104 (63.4) ex-smoker 45 (27.4) current smoker 15 (9.1) family history of heart disease yes 86 (52.4) no 78 (47.6) nyha class i 67 (40.9) ii 84 (51.2) iii 11 (6.7) iv 2 (1.2) nyha = new york heart association. table 3: factor loading* of items in a cross-cultural heart failurespecific quality of life questionnaire item factor loading psychological wellbeing 1. i feel sad whenever i think about my health condition 0.718 2. i feel anxious whenever i think about my health condition 0.702 3. i feel pressured whenever i think about my health condition 0.695 4. i worry whenever i think about my health condition 0.692 5. i feel depressed whenever i think about my health condition 0.660 6. my mind is troubled whenever i think about my health condition 0.630 7. i easily feel frustrated 0.619 8. i feel something is not right with my physical abilities 0.605 9. i feel inferior 0.548 10. i blame myself for the effects of my past lifestyle choices 0.485 11. i feel angry whenever i think about my physical weaknesses 0.480 12. i often cry 0.450 physical-social wellbeing 13. ability to climb up stairs 0.740 14. my family responsibilities have increased 0.672 15. ability to walk 0.654 16. ability to bend down 0.647 17. the effects of my heart problem on my health 0.621 18. interactions with family members or friends 0.587 19. ease of breathing 0.565 20. level of tiredness 0.555 21. quality of sleep 0.538 22. ability to perform simple exercises 0.516 23. i feel less energetic than i have in the past 0.504 24. my heart problem causes a burden 0.493 25. my recent lifestyle is far better than before 0.481 26. appetite 0.394 spiritual wellbeing 27. involvement in spirituality is important to me 0.727 28. my spirituality is helpful in facing my heart problem 0.725 29. level of spiritual beliefs when having heart problems 0.673 30. during disasters, i increase my level of worship/prayer 0.603 31. the concept of life and death is decided by god 0.542 32. involvement in spiritual activities feels peaceful 0.476 33. during disasters, i believe god protects me from danger 0.449 *using principal axis factoring in which all items with a factor loading of >0.2 were removed from the table. development and validation of a cross-cultural heart failure-specific quality of life questionnaire e498 | squ medical journal, november 2018, volume 18, issue 4 and consisted of 14 items with a factor loading range of 0.394–0.740. lastly, the third common factor, spiritual wellbeing, consisted of seven items with a factor loading range of 0.449–0.727 [table 3]. the cumulative percentage of total variance explained by the three common factors was adequate at 44.3%, with a factor-structure coefficient of 39%. in terms of internal consistency, the first two factors (psychological and physical-social wellbeing) had cron bach’s alpha coefficients of >0.80, whereas factor three (spiritual wellbeing) had a value of 0.79. the overall cronbach’s alpha coefficient for the hfqol instrument was 0.82 [table 4]. discussion the current study aimed to design and validate a hfqol questionnaire in a multi-ethnic population in malaysia. the preliminary version of the questionnaire was designed based on the qualitative findings of in-depth interviews conducted with hf patients which sought to determine their perspectives on qol. the four constructs identified from these interviews included physical wellbeing (i.e. restricted functionality), social wellbeing (i.e. dependency on social support), psychological wellbeing (i.e. the emotional processes involved in adapting to their illness) and spiritual wellbeing (i.e. religious belief systems). the overall hfqol and each of its three subdomains were found to be a reliable measure of qol among malaysian hf patients, regardless of differences in ethnicity, social background or religious beliefs. in the current study, the physical and social well being constructs were later grouped into a single sub domain; this may reflect the idea that physical restrictions are closely related to dependency on social support. moreover, certain physical disabilities can be observed by others, thus affecting how a patient is treated and how that individual interacts in society.23 in malaysia, there is a strong culture of collectivism; as such, patients rely heavily on their family and caregivers for support.24 therefore, malaysian hf patients who receive social support may perceive themselves to have a better qol and improved self-care behaviours.25 on the other hand, negative perceptions of physical-social interactions may lead to negative psychological responses.26 psychological wellbeing remained a separate sub domain in the final hfqol questionnaire, thus highlighting the importance of the psychological impact of hf in determining the qol of affected patients. patients with hf may suffer negative psychological effects such as sadness, depression, anger and anxiety—all of which were established in the qualitative phase of the current study—due to functional disability, rehospitalisation and daily variations in symptoms, such as dyspnoea and the need for oxygen therapy.7 among other factors, the presence of a close protective individual may strengthen the patient’s coping skills, leading to fewer psychological problems.14,27 similarly, spiritual wellbeing also remained a separate subdomain in the final hfqol questionnaire. this finding is interesting as it indicates that the participants considered spirituality to be a significant part of qol, despite the multi-ethnic nature of the sample and consequent variations in social norms or religious beliefs. spiritual peace has been shown to be closely related to mortality risk in hf patients; moreover, reduced spirit uality has been associated with decreased psychological and physical wellbeing, thus indirectly contributing to less favourable outcomes as a whole.28 according to previous research, spiritual factors related to religious beliefs and practices have enabled patients with adv anced hf to cope positively with the disease, improving their psychological wellbeing.29–31 this study was subject to certain limitations. first, as the patients were recruited from a tertiary referral hospital, the sample may not be representative of the entire hf population in malaysia. however, the high proportion of malay patients included in the current study is reflective of the overall demographic structure of the national population.32 the larger number of male patients also conforms to previous research indicating that heart disease is more prevalent in males.33 second, most of the patients had less severe forms of hf as it was deemed unethical to ask severely ill patients to answer research questions that might remind them of their disabilities. this limitation also serves to explain the smaller than ideal sample size. further research is therefore needed to assess the sensitivity of the hfqol instrument for patients with different stages of hf. third, the expert panel strongly recommended that two additional items—sexual relationships and interest in having a life partner—be incl uded in the questionnaire; however, these items were excluded as these concepts did not arise during the interviews. this may be due to general reluctance to discuss such topics or conservative cultural or social norms. alternatively, this may reflect perceptions that table 4: internal consistency of a cross-cultural heart failure-specific quality of life questionnaire subdomain number of items cronbach’s alpha coefficient psychological wellbeing 12 0.86 physical-social wellbeing 14 0.88 spiritual wellbeing 7 0.79 total 33 0.82 nor f. mohamed, siti r. ghazali, nor a. yaacob, aizai a. a. rahim and oteh maskon clinical and basic research | e499 such factors are not important aspects of qol for those suffering from hf, especially for those with more severe disease. nevertheless, these factors should not be ignored in a care management plan. conclusion the hfqol questionnaire is a valid and reliable tool for measuring qol among multi-ethnic malaysian hf patients. such tools may help cardiac and rehabilitation teams to develop patient-specific management plans. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the malaysian ministry of higher learning (rags #2013-0012-105-72). references 1. ambrosy ap, fonarow gc, butler j, chioncel o, greene sj, vaduganathan m, et al. the global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. j am coll cardiol 2014; 63:1123–33. https://doi.org/10.1016/j.jacc.2013.11.053. 2. lam cs. heart failure in southeast asia: facts and numbers. esc heart fail 2015; 2:46–9. https://doi.org/10.1002/ehf2.12036. 3. department of statistics malaysia. press release: statistics on causes of death, malaysia, 2017. from: www.dosm.gov.my/v 1 / i n d e x . p h p ? r = c o l u m n / p d f p r e v & i d = y 3 p sy u i 2 vj u 0 zzrhzu1kcvfmmthgut09 accessed jul 2018. 4. rajadurai j, chew d, samion h, pasamanickam k, yusoff mr, mohammad nm, et al. malaysian cpg for heart failure. asean heart j 2014; 22:66–72. https://doi.org/10.7603/s40602-014-0012-2. 5. cully ja, jimenez de, ledoux ta, deswal a. recognition and treatment of depression and anxiety symptoms in heart failure. prim care companion j clin psychiatry 2009; 11:103–9. https://doi.org/10.4088/pcc.08m00700. 6. adebayo so, olunuga to, durodola a, ogah os. quality of life in heart failure: a review. niger j cardiol 2017; 14:1–8. https://doi.org/10.4103/0189-7969.201914. 7. nieminen ms, dickstein k, fonseca c, serrano jm, parissis j, fedele f, et al. the patient perspective: quality of life in advanced heart failure with frequent hospitalisations. int j cardiol 2015; 191:256–64. https://doi.org/10.1016/j.ijcard.2015.04.235. 8. rector ts, cohn jn. assessment of patient outcome with the minnesota living with heart failure questionnaire: reliability and validity during a randomized, double-blind, placebo-cont rolled trial of pimobendan pimobendan multicenter research group. am heart j 1992; 124:1017–25. https://doi.org/10.1016 /0002-8703(92)90986-6. 9. green cp, porter cb, bresnahan dr, spertus ja. development and evaluation of the kansas city cardiomyopathy questionnaire: a new health status measure for heart failure. j am coll cardiol 2000; 35:1245–55. https://doi.org/10.1016/s0735-1097 (00)00531-3. 10. dunderdale k, thompson dr, miles jn, beer sf, furze g. quality-of-life measurement in chronic heart failure: do we take account of the patient perspective? eur j heart fail 2005; 7:572–82. https://doi.org/10.1016/j.ejheart.2004.06.006. 11. dunderdale k, thompson dr, beer sf, furze g, miles jn. devel opment and validation of a patient-centered health-related quality-of-life measure: the chronic heart failure assessment tool. j cardiovasc nurs 2008; 23:364–70. https://doi.org/10.1097/01. jcn.0000317439.82704.e8. 12. yusuf s, reddy s, ounpuu s, anand s. global burden of card iovascular diseases: part ii variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. circulation 2001; 104:2855–64. https://doi.org/10.11 61/hc4701.099488. 13. lua pl, salek s, finlay i. the malay mcgill quality of life questionnaire (mmqol): adaptation and validation. selangor, malaysia: university publication center, 2006. pp. 5–7. 14. mohamed nf, azan a, lebar o, shaharom mh, peterson rf. family support, positive thinking and spirituality correlates on psychologically distressed heart failure patients. procedia soc behav sci 2014; 127:484–8. https://doi.org/10.1016/j. sbspro.2014.03.295. 15. jackson cj, furnham a. designing and analysing questionnaires and surveys: a manual for health professionals and administrators. london, uk: whurr publishers, 2000. pp. 137–80. 16. gorsuch rl. exploratory factor analysis: its role in item analysis. j pers assess 1997; 68:532–60. https://doi.org/10.1207/s15327 752jpa6803_5. 17. ministry of health malaysia. management of heart failure: 3rd edition clinical practice guideline 2014. from: www.acadmed. org.my/view_file.cfm?fileid=684 accessed: jul 2018. 18. american heart association. classes of heart failure. from: www.heart.org/en/health-topics/heart-failure/what-is-heartfailure/classes-of-heart-failure accessed: jul 2018. 19. worthington rl, whittaker ta. scale development research: a content analysis and recommendations for best practices. couns psychol 2006; 34:806–38. https://doi.org/10.1177/0011 000006288127. 20. fayers pm, hand dj. factor analysis, causal indicators and quality of life. qual life res 1997; 6:139–50. 21. costello ab, osborne jw. best practices in exploratory factor analysis: four recommendations for getting the most from your analysis. pract assess res eval 2005; 10:1–9. 22. bland jm, altman dg. cronbach’s alpha. bmj 1997; 314:572. https://doi.org/10.1136/bmj.314.7080.572. 23. siegrist j, junge a. conceptual and methodological problems in research on the quality of life in clinical medicine. soc sci med 1989; 29:463–8. https://doi.org/10.1016/0277-9536(89)90295-5. 24. yasin s, chan ck, reidpath dd, allotey p. contextualizing chronicity: a perspective from malaysia. global health 2012; 8:4. https://doi.org/10.1186/1744-8603-8-4. 25. gallagher r, luttik ml, jaarsma t. social support and self-care in heart failure. j cardiovasc nurs 2011; 26:439–45. https://doi. org/10.1097/jcn.0b013e31820984e1. 26. rector ts. a conceptual model of quality of life in relation to heart failure. j card fail 2005; 11:173–6. https://doi. org/10.1016/j.cardfail.2004.09.002. 27. jaarsma t, johansson p, agren s, strömberg a. quality of life and symptoms of depression in advanced heart failure patients and their partners. curr opin support palliat care 2010; 4:233–7. https://doi.org/10.1097/spc.0b013e328340744d. 28. park cl, aldwin cm, choun s, george l, suresh dp, bliss d. spiritual peace predicts 5-year mortality in congestive heart failure patients. health psychol 2016; 35:203–10. https://doi. org/10.1037/hea0000271. 29. dunn ks, horgas al. the prevalence of prayer as a spiritual self-care modality in elders. j holist nurs 2000; 18:337–51. https://doi.org/10.1177/089801010001800405. development and validation of a cross-cultural heart failure-specific quality of life questionnaire e500 | squ medical journal, november 2018, volume 18, issue 4 30. westlake c, dracup k. role of spirituality in adjustment of patients with advanced heart failure. prog cardiovasc nurs 2001; 16:119–25. https://doi.org/10.1111/j.0889-7204.2001.00592.x. 31. bekelman db, dy sm, becker dm, wittstein is, hendricks de, yamashita te, et al. spiritual well-being and depression in patients with heart failure. j gen intern med 2007; 22:470–7. https://doi.org/10.1007/s11606-006-0044-9. 32. liu jh, lawrence b, ward c, abraham s. social representations of history in malaysia and singapore: on the relationship between national and ethnic identity. asian j soc psychol 2002; 5:3–20. https://doi.org/10.1111/1467-839x.00091. 33. savarese g, lund lh. global public health burden of heart failure. card fail rev 2017; 3:7–11. https://doi.org/10.15420/ cfr.2016:25:2. squ med j, february 2011, vol. 11, iss. 1, pp. 38-44, epub. 12th feb 11 invited article submitted 15th aug 10 revision req. 28th sept 10, revision recd. 30th oct 10 accepted 6th nov 10 advances in medicine and health care are influenced by technological achievements, information technology and evolving new knowledge and discoveries. these, in turn, change the way in which we practise and provide health care. the changes not only influence the practice within the various medical specialities, but they also influence the way those specialities interact with each other. the latter can not be more obvious than in supporting clinical services such as radiology and pathology. reasons for changing trends and rising challenges within pathology in addition to the changes outlined above, pathology practice has also been faced with its own changes. these have both necessitated considering new trends and also raised challenges in the way the service is delivered. among these are: 1) increased demand for pathology services;1 in diagnostic surgical pathology this has not only been in order to deal with the increased number of biopsies, but also to comply with guidelines for cancer case reporting2,3 and with the various recommendations of specimen handling and additional testing;4 2) the need to improve turnaround time as a critical element in clinical management;5 3) the need to comply with the statutory requirements of the various laboratory accreditation and quality assurance regulatory bodies; 4) the rising trend of subspecialisation within the clinical specialities;6 5) the introduction of the principle of multidisciplinary team meetings for the management of cancer patients;7 6) the decline in the number of autopsies; 7) the explosion in the number of rapidly evolving new techniques, and 8) advances in information technology and digital imaging.8,9 department of laboratory medicine & pathology, hamad medical corporation, doha, qatar. *corresponding author email: h.kamel@btinternet.com ö]ü⁄˘]<‹◊¬<ìâö^∫<ª<l^ëçvj÷]ê<l^‚^ü˜] l]öêüïê<l]ö^è}        مفتاح الكلمات: علم األمراض، التخصص، اجتماعات فريق متعدد التخصصات، تشريح اجلثة، مقاطع مجمدة، علم اخلاليا. abstract: the way we provide healthcare is influenced by ongoing experiences, increased knowledge, new discoveries and scientific as well as technological advances. the rapid pace of important developments that have taken place in recent years have significantly influenced our choices of the ways we provide our health service. like other medical specialties, pathology and its practice have had to respond to the rising needs and challenges within the health service in general and those facing the speciality in particular. this article addresses some of the challenges, particularly those which are unique to pathology. it discusses the choices that are available to different pathology departments depending on their individual circumstances. keywords: pathology; specialisation; multidisciplinary team meetings; autopsy; frozen sections; cytology special contribution trends and challenges in pathology practice choices and necessities hassan mh kamel for these reasons, it was inevitable that the various aspects of the pathology service would need to respond to these challenges and to change the way that they deliver their services. some of those challenges and the choices of solutions are discussed here as follows: subspecialisation in the diagnostic surgical pathology service and cytology; frozen sections; the autopsy; multidisciplinary team meetings; ancillary techniques; the pathology report and some other administrative duties. however, first, a brief reference to the pathology service users and their contribution in shaping the service is warranted. pathology service users any changes to the pathology service should ultimately take into consideration the needs of the service users. it is appropriate, therefore, to highlight first who are the main users of pathology services and how they contribute to the changing trends and the challenges that face the specialty. the main users of the pathology service include surgeons, oncologists, gynaecologists, hospital physicians, radiologists, general practitioners, students and various research groups. surgical specialties, including gynaecology, continue to be the major service users of the histopathology service and therefore remain the main drivers of the changes to service delivery and provision. it was the move of general surgery into various surgical subspecialties6 that originally drove the histopathology service to follow suit. as surgical techniques and approaches develop and progress, the histopathology service should be able to adapt and respond to rising needs and demands. this requires close interaction and better sustained communications between the pathologists and their various surgical colleagues. equally, newly developed techniques and new knowledge within the various subspecialties of pathology need to be communicated to our surgical colleagues to explain how these new developments can contribute to the management and care of patients. radiologists are not strictly speaking service users, but they are increasingly providers of pathology material on behalf of other service users. in recent decades, they have contributed to important changes that happened within histopathology. on the one hand, advanced imaging techniques have improved significantly the accuracy of premortem diagnosis thus significantly decreasing the need for hospital autopsies and contributing to the decline in autopsy numbers. on the other hand, the accessibility by modern radiological techniques to various sites in the body and the provision of cytology or biopsy material from previously difficult 10,11 or inaccessible locations has contributed to: 1) increasing the number of biopsies and consequently the pathologist’s workload; 2) better accuracy and adequacy of sampling of the targeted lesion; 3) understanding and unravelling of new pathological entities, and 4) better pathological staging of cancer cases and improved clinicopathological correlation. the contribution of our oncologist colleagues in influencing the way we report cancer cases should also not be underestimated. they contributed significantly to the present format of cancer management and were instrumental in the establishment of multidisciplinary team meetings. their input on the required contents in synoptic reporting and in minimal data sets as well as checklists and guidelines2,3 can not be overestimated. the diagnostic surgical pathology service in recent years, one of the most important developments that has changed the diagnostic surgical pathology service is the move towards subspecialisation in departments where the pathologists used to provide a general diagnostic service. this means that each pathologist now provides services only within one or very few subspecialties. for example, some pathologists report only on breast pathology, others specialise in gastrointestinal (gi) pathology or soft tissue diseases etc. pathology subspecialisation has existed for a long time in some subspecialties such as paediatrics and neuropathology, but it has only recently spread into all other subspecialties, particularly within large teaching departments and big referral centres. subspecialisation in pathology was seen as the natural response to the move to subspecialisation in surgery and as a solution to the problem of increasing workload, whether due to increased numbers of biopsies or the increased reporting requirements for various cancer and non-cancer hassan mh kamel special contribution | 39 trends and challenges in pathology practice choices and necessities 40 | squ medical journal, february 2011, volume 11, issue 1 cases.12 it also seemed a natural progression in response to the overwhelming increase in our knowledge in the past three decades. overall, and if it can be afforded, the advantages of subspecialisation outweigh those of the general diagnostic service. the acknowledged benefits and advantages of subspecialisation include: 1) increased experience and skill of the pathologists at interpreting challenging cases within their own subspecialties, thus allowing timely and accurate diagnosis; 2) maximising clinical efficiency through enhanced team work and communications with the corresponding subspecialised clinical services; 3) optimisation of teaching; 4) promotion of research efforts in the various subspecialty areas, and 5) creation of an environment in which research can be successfully planned and performed. however, subspecialisation has its demanding requirements and it can not be applied in all pathology laboratories. the main disadvantages include: 1) decreased staffing flexibility in comparison to laboratories which provide a wider general service; 2) increased operational overheads with every subspecialty operating as if it were a separate unit; 3) difficulties in measuring the equity of workload between staff of different subspecialty teams;13,14,15 4) difficulties in evaluating the efficiency of the pathologists’ work due to weights and indicators varying from one subspecialty to another,13,14,15 and 5) the need for more staffing which remains the biggest factor hindering the wider development of subspecialisation. subspecialisation: choice or necessity? subspecialisation remains largely a choice that is dictated by a variety of factors including the laboratory setting (service versus academic), specimen volume and specimen composition as well as level of staffing. for example, subspecialisation cannot be afforded by departments that are staffed by less than six consultant pathologists. also, if they have a low number of biopsies or range of materials, the significant increase in costs and staff cannot be justified. on the other hand, subspecialisation should be seen ultimately as a necessity for large academic and teaching departments with heavy workloads. in this case, it will accommodate and improve research and optimise teaching obligations, in addition to the other benefits of subspecialisation. the fate of cytology in subspecialised pathology departments prior to the subspecialisation trend, cytology often constituted an independent department or a separate unit, within the pathology department while in a small department it was regarded as part of the general diagnostic service. as histopathology moved to subspecialisation, some institutions opted to integrating the various cytological specimens into the corresponding or appropriate subspecialty histopathology teams; for example, breast fine needle aspiration (fna) was allocated to the breast team and so on. cervical cytology was dealt as a separate issue in places where there were large screening programmes. other places continued to have an independent cytology service that did not integrate into the subspecialty teams. there are reasons that favour integrating cytology specimens into the corresponding histopathology subspecialty: 1) it allows the correlation of the histological and cytological findings, thus resulting in more accurate diagnoses and better patient care; 2) it increases experience and improves skill; 3) it enhances team work with the corresponding subspecialised clinical services, and 4) it optimises teaching and promotes research. equally, there are arguments against the need for such integration which call for cytology to remain independent. these include: 1) existing cytopathologists who are experienced across the whole of the cytology spectrum. with subspecialisation, a major part of their expertise would become redundant, lost or underutilised; 2) unlike histopathology specimens, there could be difficulties in assigning and allocating some materials: e.g. should ascetic fluid go to the gi team or to the gynaecology team? 3) the heavy cytology burden in some subspecialties in comparison to others, e.g. breast versus gi, and 4) the nature and amount of material where there are cervical cytology screening programmes. the reasons for and against integration of cytology seem to be equally strong. it therefore seems logical, for the time being at least, that the choice should depend on the circumstances of each establishment. hassan mh kamel special contribution | 41 intraoperative consultation/diagnosis (frozen sections) most pathologists accept that the frozen section procedure is an important and difficult procedure that requires experience, knowledge, the ability to make quick decisions under pressure and good judgement. it is often needed in order to confirm the extent of disease, the nature of a pathological process, the resection margins and the nature of a tissue, such as parathyroid. the procedure has its obvious limitations which are mainly time, sampling error, lack of consultation, lack of special stains/studies, inconsistency in the quality of the sections and the type of artefacts particularly ice crystal artefacts. changing trends in the practice of pathology have significantly contributed to the decline, relative or absolute, in the frequency of the pathologists' exposure to frozen section materials. the main trends responsible for this are subspecialisation and the availability of radiologically guided biopsies. the former have resulted in the number of available frozen sections being thinly distributed among a large number of trainee pathologists. the latter means that materials that were in the past only accessible through frozen sections became less dependent on this procedure. in either case, the result is that the frozen section procedure has become even more challenging for the less experienced pathologist. the problem is often further compounded by the requesting clinicians being unfamiliar with the difficulties and limitations of the procedure, when it comes to particular pathological processes such as follicular lesions of the thyroid.16 in today's practice, therefore, preand intraoperative consultation and communication between surgeons and pathologists are a necessity while the decision to have a frozen section for intraoperative diagnosis should ultimately be the surgeon's choice and decision. the autopsy the availability of an autopsy service is a necessity both within the health and forensic services. the reasons for this include cases of unexplained, or suspected wrongful deaths in the case of forensic service. in the health service, autopsy is required in cases of death with no premortem diagnosis and for the purpose of auditing and correlating premortem diagnoses with those of the autopsy findings. various factors have contributed in the last three decades to the dramatic worldwide decline in the number of autopsies.17,18 these relate generally to the increasing public reluctance to give consent for an autopsy, exacerbated by the publicity given to certain infamous episodes. in addition and unfortunately, autopsy practice does not appeal nowadays to the majority of pathologists. they consider it disruptive to other increasing duties and a source of distraction for staff employed to meet the clinical needs of live patients. the decline has also been accelerated by advanced imaging and other diagnostic techniques that have significantly improved premortem diagnosis.the unpopularity and decline of the autopsy has confronted the specialty with the challenge of providing adequate training and experience for trainee pathologists. there is a consensus that autopsy training is a necessity since, as outlined above, the autopsy service is a necessity. however, while it is essential to have proper autopsy training, it is not essential that all trainees in pathology should have such training. making autopsy training an “elective” subspecialty19 will ensure that only genuinely interested trainees are able to get the proper experience from the declining pool of autopsies. furthermore, centralisation of the service may be the solution in order to maximise the experience and exposure of those trainees to a larger number and wider spectrum of autopsy cases, improve the standard of service and cope with the problem of the declining number of pathologists interested in this particular subspecialty. it has also been suggested that the rigid rules and regulations that determine which cases should be considered for hospital autopsies need to be relaxed. instead, requests for autopsy needs to be decided on a case by case basis and could include the few cases where the relatives of the deceased request an autopsy, even when it is deemed unnecessary by the treating physicians. multidisciplinary team meetings (mdts) to many pathologists, mdts are looked upon as the “best thing” that happened to the speciality in recent times. through participation in clinical trends and challenges in pathology practice choices and necessities 42 | squ medical journal, february 2011, volume 11, issue 1 decision making, pathologists gain improved job satisfaction and have sense of being appreciated. mdts have increased awareness among other health professions of the speciality of pathology and its important role in the management of cancer patients. they have also improved communication with our service users and other health professions leading to more accurate, meaningful and informative pathology results.20,10 for many, it is also regarded as part of continual professional development so that although it is a time consuming duty it is often welcomed.21 mdts are undoubtedly here to stay as they have proven to be immensely useful both to the patients and to all parties involved in management and care of cancer patients.20,21,22 as mdts are a relatively recent innovation, they need to be formally regulated to ascertain who should attend, the meeting venue, the technology and equipment required and the decision making method. mdts should also be recognised as a significant component in the pathologist’s duties and job plan.21 old and new ancillary techniques special stains, enzyme histochemistry, virtual slide telepathology, confocal light microscopy, immunohistochemistry, flow cytometry, electron microscopy (with its various modalities including transmission electron microscopy [tem] , scanning electron microscopy [sem], scanning transmission electron microscopy [stem], low voltage electron microscopy [lvem], reflective electron microscopy [rem]) and molecular pathology techniques are some of the techniques that pathologists utilise in their various activities and roles whether for diagnosis, prognosis, teaching and/or research. ancillary techniques, including those which are new or technologically and scientifically highly advanced, are the means to achieve specific aims, be it for the diagnostic service or for research. in the drive for excellence, the focus on the aims can get distracted by the intriguing means to the point that the means become aims in themselves. we need always to remember to choose and apply techniques that answer our questions and address our needs rather than searching for irrelevant questions in order to adopt fascinating and attractive, yet irrelevant, new techniques. in the recent past, several exciting and promising techniques did not match expectations. others eventually occupied an important, yet significantly smaller, role than that which was originally expected. one example, more than two decades ago, was when silver staining for nucleolar organising regions was seen a promising tool as a proliferation marker; this topic generated an enormous number of publications.23,24 a second example is electron microscopy in the 1970s and 1980s which was seen as the "ultimate" means for identifying tumour differentiation,25,26 yet it has now largely been replaced by immunohistochemistry. on the other hand, it still makes an essential and major contribution to specific topics mainly in kidney and neuromuscular diseases. we should also remember that the pace of technological advance far exceeds our ability to adopt or implement all newly emerging techniques. before adopting them, we need to identify the problems they can address while recognising our limitations. otherwise new technologies can have an adverse impact on our basic and essential functions. we should also seek opportunities in global collaboration as rapid email and transport communications make our world increasingly smaller. the pathology report naturally perhaps, choices are limited when it comes to the style of the pathology report. for a long time, free text and summary style reports constituted the majority of pathology reports. they still remain the norm for reporting many nonneoplastic diseases. in the last two decades, with the increase in information requirements,27 synoptic reports have become fashionable particularly in reporting cancer cases. a mixture of both free text and synoptic style reports are also adopted by some, but they are often tedious and time consuming to compose. digital images have also found their way into the pathology report in many centres worldwide, but their value and contribution is often questioned. there is an overwhelming case for adopting a standardised synoptic report style especially for cancer cases. their contents and designs are based on recommendations and guidelines issues hassan mh kamel special contribution | 43 by international professional bodies.2,3 most are simple and thorough in their contents, having the advantages of consistency, uniformity and being quicker to produce while avoiding oversight and typographic errors. they are also appealing to the service users who seem to recommend them. there does not seem to be a case against the synoptic report style. as such, it is reasonable to say that they should be regarded as a necessity for reporting cancer cases and at least a good choice for the reporting of non-neoplastic diseases. other duties that influence today's pathology practice the pathologists’ growing administrative duties have increased their work load and responsibilities in addition to the clinical duties referred to above. the former include the requirements to comply with various regulatory bodies for both the medical and non-medical aspects of the provision of the pathology laboratory service. issues such as accreditation; external and internal quality assurances;28 continuing professional development activities; various performance indicators including appraisal and job planning; continuous internal and external audit activities and revalidation and participation in clinical governance activities are just some of the essential tasks expected of medical professionals nowadays. regardless of whether we like them or not, believe in them or not, we have to carry them out. they are necessary because: 1) they justify our confidence in our practice; 2) they justify the confidence of our service users and managers; 3) they safeguard the standard of our practice, and 4) they ensure continuous pathology service improvement. conclusion maintaining the momentum of pathology service improvements finally, facing and responding to the challenges, as well as to the changing trends, are strategies through which pathology service improvements continue and are ensured. certain approaches are fundamental within any organisation to maintain the momentum of ongoing improvement. these include: 1) effective communication, the significance of which cannot be overstated. this entails communication at all levels be it within the department, with other pathology departments and institutions or with service users and managers; 2) the strong support of service users and managers in order for the service to continue to thrive and improve; 3) taking radical decisions, if deemed necessary for improvements, for example, centralisation of some aspects of the service which could concentrate expertise and reduce costs; 4) participation in regulatory bodies and schemes; 5) continuous adaptation to and adoption of useful new technology and procedures, and 6) exploration of opportunities for collaboration. no organisation, regardless of its size, can survive in isolation with today’s rapidly changing pace of technological and medical advances. references 1. gopal rao g, crook m, tillyer ml. pathology tests: is the time for demand management ripe at last? j clin pathol 2003; 56:243–8. doi:10.1136/jcp.56.4.243 2. datasets for the reporting of common cancers. from: http://w w w.rcpath.org/index .asp?pageid=154. accessed: july 2010. 3. the college of american pathologists (cap) cancer protocols and checklists. updated july 15, 2010. from: http://www.cap.org/apps/cap.portal?_ nfpb=true&_pagelabel=reference. accessed: july 2010 4. hewitt sm, lewis fa, cao y, conrad rc, cronin m, danenberg kd, et al. tissue handling and specimen preparation in surgical pathology: issues concerning the recovery of nucleic acids from formalin-fixed, paraffin-embedded tissue. arch pathol lab med 2008; 132:1929–35. 5. ribé a, ribalta t, lledó r, torras g, miguel a, asenjo ma, et al. evaluation of turnaround times as a component of quality assurance in surgical pathology. int j qual health care 1998; 10:241–5. 6. wan-yee lau j. generalization versus subspecialization in surgery. ann coll surg hong kong 2001; 5:151–5. 7. ruhstaller t, roe h, thürlimann b, nicholl jj. the multidisciplinary meeting: an indispensable aid to communication between different specialities. eur j cancer 2006; 42:2459–62. 8. wienert s, beil m, saeger k, hufnagl p, schrader t. integration and acceleration of virtual microscopy as the key to successful implementation into the routine diagnostic process. diagn pathol 2009; 4:3. doi:10.1186/1746-1596-4. 9. kane b, luz s, menezes g, hollywood dp. trends and challenges in pathology practice choices and necessities 44 | squ medical journal, february 2011, volume 11, issue 1 enabling change in healthcare structures through teleconferencing. proceedings 18th ieee international symposium on computer-based medical systems. los alamitos, ca: ieee computer society 2005; pp. 76–81. from: http://ieeexplore. ieee.org/xpl/freeabs_all.jsp?arnumber=1467671. accessed: 2005. 10. ribeiro a, pereira d, escalón mp, goodman m, byrne ge jr. eus-guided biopsy for the diagnosis and classification of lymphoma. gastrointest endosc 2010; 71:851–5. 11. storch i, jorda m, thurer r, raez l, rocha-lima c, vernon s, et al. advantage of eus trucut biopsy combined with fine-needle aspiration without immediate on-site cytopathologic examination. gastrointest endosc 2006; 64:505–11. 12. black-schaffer ws, young rh, harris nl. sub specialization of surgical pathology at the massachusetts general hospital. am j clin path 1996; 106:s33–42. 13. guidelines on staffing and workload for histopathology and cytopathology departments royal college of pathologists (uk), 2005. fr o m : h t t p : / / w w w. r c p a t h . o r g / r e s o u r c e s / p d f / guidehistocytoworkload0605.pdf. accessed: july 2010. 14. maung rta. what is the best indicator to determine anatomic pathology workload? am j clin pathol 2005; 123:45–55. 15. horne gj, barber df, bruecks ak, maung rta, trotter mj. workload measurement in subspecialty dermatopathology j clin pathol 2009; 62:435–8. doi:10.1136/jcp.2008.061150 16. wong z, muthu c. role of intraoperative frozen section in the management of thyroid nodules. anz journal of surgery 2004; 74:1052–5. 17. loughrey mb, mccluggage wg, toner pg. the declining autopsy rate and clinicians' attitudes. ulster med j 2000; 69:83–9. 18. ayoub t, chow j. the conventional autopsy in modern medicine. j r soc med 2008; 101:177–81. 19. cross ss, bull ad. is the informational content of histopathological reports increasing? j clin pathol 1992; 45:179–80. 20. yap rl, chan dy, fradin j, jarrett tw. intraoperative ultrasound guided retroperitoneal laparoscopic renal biopsy in the morbidly obese patient. j urol 2000; 163:1197–8. 21. kane b, luz s, o'brian ds, mcdermott r. multidisciplinary team meetings and their impact on workflow in radiology and pathology departments. bmc medicine 2007; 5:15. doi:10.1186/1741-70155-15 22. fleissig a, jenkins v, catt s, fallowfield l. multidisciplinary teams in cancer care: are they effective in the uk? lancet oncol 2006; 7:935–43. 23. egan mj, crocker j. nucleolar organiser regions in pathology. br j cancer 1992; 65:1–7. 24. rowlands dc. nucleolar organising regions in cervical intraepithelial neoplasia. j clin pathol 1988; 41:1200–02. 25. dar au, hird pm, wagner be, underwood jc. relative usefulness of electron microscopy and immunocytochemistry in tumour diagnosis: 10 years of retrospective analysis. j clin pathol 1992; 45:693– 6. 26. fisher c, ramsay a d, griffiths m, mcdougall j. an assessment of the value of electron microscopy in tumour diagnosis. j clin pathol 1985; 38:403–8. 27. valenstein pn. formatting pathology reports: applying four design principles to improve communication and patient safety. arch pathol lab med 2008; 132:84–94. 28. quality assurance in histopathology and cytopathology reporting practice. from: http://www. rcpath.org/resources/pdf/g082_qahistoreporting_ feb09.pdf. accessed: 2009. cost-effectiveness of wound care a concept analysis *koukab a. al-gharibi,1 sajana sharstha,2 maria a. al-faras2 sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e433–439, epub. 28 mar 19 submitted 29 apr 18 revision req. 13 jun 18; revision recd. 9 jul 18 accepted 2 aug 18 1college of nursing, sultan qaboos university, muscat, oman; 2college of nursing & health professions, valparaiso university, valparaiso, indiana, usa *corresponding author’s e-mail: kawkab@squ.edu.om doi: 10.18295/squmj.2018.18.04.002 chronic or difficult-to-he al skin wounds—such as diabetic leg ulcers, burns or pressure ulcers—impose an economic burden on the affected patient and healthcare system due to the increased costs associated with wound care, such as additional hospital/clinic visits, dressing changes, nursing care and hospital stays.1,2 unfortunately, due to the increasing ageing population worldwide and the high prevalence of chronic diseases among the elderly, it is estimated that the number of patients with chronic wounds will continue to rise.3 in addition, the growing prevalence of antibiotic resistance and comorbidities such as diabetes mellitus, obesity, venous hypertension and peripheral vascular disease also increases the cost of wound care.2,4 moreover, optimal wound care often requires changes in practice, including the implementation of advanced technologies.5–8 this review aimed to analyse the concept of cost-effectiveness in wound care in terms of the financial impact of wound care on patients, medical staff and healthcare institutions. these findings may serve as a guide to future researchers studying the benefits of cost-saving wound care measures. methods the concept of cost-effectiveness was analysed using walker and avant’s method.9 a literature search for articles related to cost-effectiveness was performed of the cumulative index to nursing and allied health literature® (ebsco information services, ipswich, massachusetts, usa), medline® (national library of medicine, bethesda, maryland, usa) and nursing & allied health® (proquest llc, ann arbor, michigan, review فعالية التكلفة يف العناية باجلروح حتليل املفهوم كوكب عبداهلل الغريبي، �شاجانا �شريا�شثا، ماريا ارورا الفرا�س abstract: this review aimed to analyse the concept of cost-effectiveness within the context of chronic wound care using walker and avant’s approach. the cumulative index to nursing and allied health literature® (ebsco information services, ipswich, massachusetts, usa), medline® (national library of medicine, bethesda, mary land, usa) and nursing & allied health® (proquest llc, ann arbor, michigan, usa) databases were searched using a combination of keywords. a total of 18 peer-reviewed articles were identified. in wound care, defining attributes for the concept of cost-effectiveness encompassed treatments which were both effective and economical. four antecedents were identified, including the type of wound, care setting, type of dressing and patient-related characteristics. the consequences of cost-effective wound care were patient prognosis, quality of life, the economic burden on the patient and healthcare system and cost-savings. these findings will hopefully help to standardise cost-effectiveness terminology among nursing professionals in various healthcare settings. keywords: cost effectiveness; wounds and injuries; healthcare costs; nursing; concept formation. امللخ�ص: هدفت هذه املراجعة إىل حتليل مفهوم الفعالية من حيث التكلفة يف سياق الرعاية الصحية للجروح املزمنة باستخدام طريقة "ووكر" و "أفانت"، مت البحث يف قواعد البيانات باستخدام جمموعة من الكلمات الرئيسية يف حمركات البحث مثل املؤشر الرتاكمي للمنشورات العلمية املتعلقة بالتمريض واملهن الوطنية )املكتبة medline® و األمريكية( املتحدة الواليات يف ماساتشوستس ايبسويتش، املعلومات، خلدمات ،ebsco( املساندة® الصحية للطب، بيثيسدا ، مرييالند يف الواليات املتحدة األمريكية( والتمريض و املهن الصحية املساندة® )proquest llc، آن اربور، ميتشجني يف الواليات املتحدة األمريكية(. وقد مت حتديد 18 جمموعة من البحوث العلمية يف جمال العناية باجلروح، ويف هذه الدراسة مت تعريف السمات ملفهوم فعالية التكلفةواليت تشمل العالجات اليت كانت فعالة واقتصادية يف الوقت نفسه، ومت حتديد أربع ميزات سابقة، وهي نوع اجلرح، وإعدادات الرعاية، ونوع التضميد ومسات متعلقة باملريض، كانت النتائج املرتتبة على رعاية اجلروح فعالة من حيث التكلفة تشمل االستجابة للعالج، ونوعية احلياة، والعبء االقتصادي على املريض ونظام الرعاية الصحية والرتشيد يف التكاليف املستخدمة. تسعى نتائج هذه الدراسة إىل أن تساعد يف توحيد مصطلحات فعالية التكلفة بني املتخصصني يف التمريض يف خمتلف إعدادات الرعاية الصحية. الكلمات املفتاحية: الفعالية من حيث التكلفة؛ اجلروح واإلصابات؛ تكلفة الرعاية الصحية؛ التمريض؛ تشكيل مفهوم. cost-effectiveness of wound care a concept analysis e434 | squ medical journal, november 2018, volume 18, issue 4 usa) databases. subsequently, the search was narrowed down using more specific keywords either alone or in combination, including “cost-effectiveness”, “economical”, “profitable”, “cheap”, “cost-saving”, “cost-analysis”, “nursing”, “wound care”, “wound management”, “dressing change” and “wound dressing”. however, the term “cost-effectiveness” was consistently used throughout the search process in order to maintain the focus of the analysis. finally, all scholarly english-language articles published between 2011–2016 were identified in order to gather recent research findings related to cost-effectiveness in nursing. initially, 64,618 articles were identified using the term “cost-effectiveness” and related keywords; this was subsequently narrowed down to 17,445 articles with the inclusion of the term “nursing” and 2,175 articles when combined with wound care-related keywords. however, 1,771 articles were excluded as they did not meet the inclusion criteria with regards to the year or language of publication or because they were not published in scholarly peer-reviewed journals. although the term “cost analysis” was interchangeably used with “costeffectiveness” in some articles, such results were excluded to maintain the focus on cost-effectiveness. articles with general information, commentaries, speeches/lectures, biographies and instructional materials/guidelines were also excluded. finally, the remaining 32 articles were screened to ensure their relevance to cost-effectiveness in wound care, resulting in 18 articles which were included in the final analysis [table 1].1,2,5–8,10–21 use of concept in nursing literature, the concept of cost-effectiveness was used mainly in relation to the cost and frequency of wound dressing changes, the duration of wound healing, the size of the wound and the use of other treatments or medications. wound dressing results in both direct healthcare costs (encompassing both hospital and nursing costs), the cost of the actual dressing itself and the costs associated with applying the dressing or treating any systemic infections. direct healthcare costs include the salaries of the nurses, various hospital costs, the time needed for the nurses to care for the patients, the time and costs related to home visits, if necessary, as well as visits to the primary care provider and follow-up visits.6,13–16 in addition, the rate of wound healing also has an effect on costs in relation to the size and duration of the wound as it progresses.11 moreover, the use of other medications and treatments also contributes to the total cost of wound care, such as analgaesics, anxiolytic medications and topical/systemic antibiotics to treat underlying infections and prevent downstream interventions.7,10,17 defining attributes attributes denote the key characteristics of the concept being analysed.9 overall, two defining attributes—effect iveness and economy—were identified for the concept of cost-effectiveness in wound care. for the first attribute, it is imperative that treatment modalities are effective, as evidenced via rapid wound healing and a decrease in wound size. for the second, the total cost of wound care, including both direct and indirect healthcare costs, should not be more expensive than comparable treatments available on the market while still meeting treatment needs. the concept of cost-effectiveness is sometimes conflated with cost-saving, cost comparisons, cost analyses, cost-benefit ratios or being cost-conscious. however, these terms should not be used interchangeably. in the researchers’ opinion, cost-saving is a consequence of cost-effective measures rather than a synonym of costeffectiveness. for example, even if a particular wound care product is cost-saving, it cannot be considered cost-effective if the treatment outcome is suboptimal. furthermore, if a wound is not treated properly to begin with, various complications might arise requiring further treatment or surgical interventions such as wound debridement. e f f e c t i v e n e s s rapid healing is a hallmark of effective treatment. several studies reported faster wound healing times and smaller wound sizes with the use of newer, more cost-effective wound dressing technologies.5,7,12 jemec et al. found that the use of silver dressings resulted in wound closure occurring approximately three weeks earlier among patients with chronic leg ulcers compared to those treated with non-silver dressings.19 although the initial cost of silver dressings was higher than that of non-silver dressings during the first four weeks of treatment, the average total treatment cost per patient was lower due to the shorter healing time.19 hämmerle et al. also found that patients with venous leg ulcers treated with octenidine gel had significantly faster healing rates and decreased wound sizes compared to those treated with modern wound dressings.11 brown et al. compared treatment costs in relation to healing rates and changes in wound size among paediatric burn victims.1 wounds treated with single-use negative pressure wound therapy (npwt) resulted in a marked decrease in wound size, with an average reduction in size of 21% per week. as such, the expense of npwt was offset by the reduction in wound size, as this form of treatment resulted in wound healing occurring after two weeks compared koukab a. al-gharibi, sajana sharstha and maria a. al-faras review | e435 ta bl e 1: c on ce pt a na ly si s of c os teff ec ti ve ne ss in w ou nd c ar e1 ,2 ,5 – 8, 10 – 21 a ut ho r an d ye ar o f pu bl ic at io n t yp e of a rt ic le t re at m en t t yp e of w ou n d fi n di n gs p os si bl e at tr ib ut es a nt ho ny 6 ( 20 15 ) m et aan al ys is n pw t v ar io us • n pw t r eq ui re s a sh or te r tr ea tm en t d ur at io n an d fe w er d re ss in g ch an ge s. • n pw t is e ffe ct iv e in d iff er en t s et tin gs . • c os t o f t re at m en t • sa fe ty o f t re at m en t • effi ci en cy o f t re at m en t • si ze o f w ou nd • d ur at io n of tr ea tm en t a ug us tin e t a l.7 (2 01 6) c om pa ra tiv e st ud y h yd ro ac tiv e dr es si ng c on ta in in g a na no -o lig os ac ch ar id e fa ct or ve rs us a n eu tr al fo am d re ss in g v as cu la r le g ul ce rs • th e hy dr oa ct iv e dr es si ng w as m or e eff ec tiv e in r ed uc in g th e w ou nd a re a co m pa re d to th e ne ut ra l f oa m d re ss in g. • effi ci en cy o f t re at m en t • ty pe o f d re ss in g • si ze o f w ou nd br ow n et a l.1 (2 01 5) r c t n on ph ar m ac ol og ic al d it t o in te rv en tio n ve rs us s ta nd ar d w ou nd c ar e pa ed ia tr ic b ur ns • o n av er ag e, th e d it t o in te rv en tio n re su lte d in lo w er d ir ec t h ea lth ca re co st s, d ir ec t n on -h ea lth ca re c os ts a nd o ve ra ll co st s pe r ch ild . • w ou nd s tr ea te d w ith th e d it t o in te rv en tio n re -e pi th el ia lis ed a n av er ag e of th re e da ys fa st er . • c os t o f t re at m en t • effi ci en cy o f t re at m en t • ty pe o f t re at m en t • r at e of w ou nd c lo su re br ow ni ng 10 (2 01 4) r ev ie w v ar io us v ar io us • th e to ta l c os t o f t re at m en t i s de pe nd en t o n th e co st o f s pe ci al is ed m ed ic al st aff a nd th e nu m be r of d re ss in g ch an ge s re qu ir ed p er w ee k. • th e co st o f t re at m en t f or in fe ct io n is d ep en de nt o n th e nu m be r of tr ea tm en ts r eq ui re d an d th e ne ed fo r su rg ic al d eb ri de m en t. • c os t o f t re at m en t • d ur at io n of tr ea tm en t • n um be r of d re ss in g ch an ge s • o cc ur re nc e of c om pl ic at io ns b ut ch er e t a l.1 3 ( 20 14 ) r ev ie w v ar io us c hr on ic w ou nd s • th e to ta l c os t o f c ar e de pe nd s on th e fr eq ue nc y of in te rv en tio ns a nd dr es si ng c ha ng es a nd c os ts a ss oc ia te d w ith s ta ff tim e an d re so ur ce s. • o th er c os ts in cl ud e di sp os ab le it em s su ch a s dr es si ng p ac ks , p ai n re lie f m ea su re s, in pa tie nt /o ut pa tie nt h os pi ta l c os ts a nd n ur si ng ti m e. • ph ar m ac eu tic al in te rv en tio ns s uc h as a na lg ae si cs a nd a nx io ly tic m ed ic at io ns al so c on tr ib ut e to c os ts . • c os t o f t re at m en t • d ur at io n of tr ea tm en t • n um be r of d re ss in g ch an ge s c ar te r2 (2 01 4) r ev ie w v ar io us c hr on ic w ou nd s • o ne s tu dy o f d ia be tic fo ot u lc er s de m on st ra te d th at ig c in c on ju nc tio n w ith op tim al fo ot c ar e w as m or e co st -e ffe ct iv e co m pa re d to s ta nd ar d ca re . • c os t o f t re at m en t • c os t o f p re ve nt at iv e ca re ev an s1 7 ( 20 14 ) r ev ie w v ar io us v ar io us • so ft s ili co ne w ou nd c on ta ct d re ss in gs h av e a w id e ra ng e of w ou nd c ar e ap pl ic at io ns . • su ch d re ss in gs a re m or e co st -e ffe ct iv e in a c om m un ity s et tin g as o ne s in gl e pr od uc t c an b e us ed fo r a va ri et y of d iff er en t t yp es o f w ou nd s. • r at e of h ea lin g • eff ec tiv en es s of tr ea tm en t • v er sa til ity o f t re at m en t g ill ig an e t a l.2 0 (2 01 5) r et ro sp ec tiv e st ud y b ec ap le rm in g el p lu s g w c v er su s g w c a lo ne d ia be tic fo ot u lc er s • b ec ap le rm in g el p lu s g w c r es ul te d in b et te r ou tc om es a t l ow er c os ts co m pa re d to g w c a lo ne . • d ur at io n of tr ea tm en t • r at e of w ou nd c lo su re • c os t o f t re at m en t h äm m er le e t a l.1 1 (2 01 4) r c t o ct en id in eba se d w ou nd g el ve rs us m od er n dr es si ng s c hr on ic v en ou s le g ul ce rs • o ct en id in e ge l r es ul te d in a g re at er r ed uc tio n in w ou nd s iz e an d fa st er he al in g ra te s co m pa re d to m od er n dr es si ng s. • th e ov er al l c os t o f t re at m en t w ith o ct en id in e ge l w as lo w er . • c os t o f t re at m en t • sa fe ty o f t re at m en t • effi ca cy o f t re at m en t • si ze o f w ou nd • in ci de nc e of lo ca l i nf ec tio ns • r at e of h ea lin g (g ra nu la tio n tis su e an d bi ob ur de n) cost-effectiveness of wound care a concept analysis e436 | squ medical journal, november 2018, volume 18, issue 4 ta bl e 1 (c on td .): c on ce pt a na ly si s of c os teff ec ti ve ne ss in w ou nd c ar e1 ,2 ,5 – 8, 10 – 21 a ut ho r an d ye ar o f pu bl ic at io n t yp e of a rt ic le t re at m en t t yp e of w ou n d fi n di n gs p os si bl e at tr ib ut es h am pt on 5 ( 20 15 ) c oh or t s tu dy n pw t v er su s st an da rd c ar e h ar dto -h ea l l eg ul ce rs o r pr es su re ul ce rs • th e av er ag e w ee kl y re du ct io n in w ou nd s iz e w as 2 1% w ith n pw t. • a lth ou gh th e w ee kl y co st o f n pw t w as e xp en si ve , t he to ta l c os t w as lo w er co m pa re d to s ta nd ar d ca re d ue to th e sh or te ne d tr ea tm en t d ur at io n. • r at e of h ea lin g • si ze o f w ou nd • c os t o f t re at m en t • d ur at io n of tr ea tm en t je m ec e t a l.1 9 ( 20 14 ) c om pa ra tiv e st ud y si lv er d re ss in gs v er su s no nsi lv er dr es si ng s h ar dto -h ea l ch ro ni c ve no us le g ul ce rs • pa tie nt s tr ea te d w ith s ilv er d re ss in gs h ad fa st er r at es o f w ou nd c lo su re co m pa re d to th os e tr ea te d w ith n on -s ilv er d re ss in gs . • si lv er d re ss in g tr ea tm en t r es ul te d in a c os tsa vi ng o f £ 14 1. 57 c om pa re d to no nsi lv er d re ss in gs . • r at e of h ea lin g • c os t o f t re at m en t li m a et a l.1 4 ( 20 16 ) d es cr ip tiv e st ud y v ar io us pr es su re u lc er s • h yd ro co llo id d re ss in gs w er e th e m os t c os teff ec tiv e ty pe o f d re ss in g. • r at e of h ea lin g • ty pe o f t re at m en t • c os t o f t re at m en t • d ur at io n of tr ea tm en t m au no ur y et a l.2 1 (2 01 5) r c t a nt im ic ro bi al c hl or he xi di ne gl uc on at eco nt ai ni ng se cu re m en t d re ss in gs v er su s no nan tim ic ro bi al tr an sp ar en t dr es si ng s ic u v en ou s/ ar te ri al c at he te r in se rt io n si te s • th e ch lo rh ex id in e dr es si ng w as b et te r in te rm s of in fe ct io n pr ev en tio n co m pa re d to th e no nan tim ic ro bi al d re ss in g. • c os t o f t re at m en t • eff ec tiv en es s of tr ea tm en t • r at e of h ea lin g • c os t o f t re at m en t • d ur at io n of tr ea tm en t • in ci de nc e of in fe ct io n o th m an 18 (2 01 2) r ev ie w n pw t c hr on ic w ou nd s • n pw t r ed uc es th e co st o f c hr on ic w ou nd c ar e m an ag em en t a nd in cr ea se s q o l du e to fa st er w ou nd h ea lin g ra te s. • c os t o f t re at m en t • d ur at io n of tr ea tm en t • r at e of h ea lin g ph am e t a l.1 5 ( 20 12 ) r c t 4l b ve rs us s sb c om pr es si on te ch ni qu es v en ou s le g ul ce rs • b ot h 4l b an d ss b co m pr es si on te ch ni qu es w er e eff ec tiv e an d ha d co m pa ra bl e co st -e ffe ct iv en es s w he n us ed b y tr ai ne d re gi st er ed n ur se s. • r at e of h ea lin g • eff ec tiv en es s of tr ea tm en t • c os t o f t re at m en t • d ur at io n of tr ea tm en t si bb al d et a l.8 (2 01 5) c m e ar tic le / va lid at io n st ud y n on co nt ac t i nf ra re d sk in th er m om et er s pa tie nt s at h ig h ri sk o f d ev el op in g di ab et ic fo ot u lc er s • n on co nt ac t i nf ra re d sk in th er m om et er s w er e ea sy to u se a nd a va ila bl e at a co ns id er ab ly lo w er c os t c om pa re d to c on ta ct in fr ar ed th er m om et er s. • d ue to it s ea se o f u se a nd a va ila bi lit y, th is to ol c ou ld b e us ed o n a da ily b as is at h om e. • c os t o f t re at m en t • eff ec tiv en es s of tr ea tm en t • c os t o f p re ve nt at iv e ca re • eff ec tiv en es s of p re ve nt at iv e ca re t ri cc o et a l.1 2 ( 20 15 ) r ev ie w v ar io us c om pl ex w ou nd in te rv en tio ns c hr on ic h ar dto he al w ou nd s an d pr es su re u lc er s • a to ta l o f 2 2 co m pl ex w ou nd in te rv en tio ns w er e id en tifi ed to b e eff ec tiv e an d le ss e xp en si ve c om pa re d to o th er m et ho ds . • r at e of h ea lin g • c os t o f t re at m en t • ty pe o f t re at m en t • d ur at io n of tr ea tm en t w hi tlo ck e t a l.1 6 (2 01 4) c ro ss -s ec tio na l st ud y v ar io us c hr on ic w ou nd s an d ul ce rs • o nl y ha lf of th e ge ne ra l p ra ct iti on er s’ tim e w as c ov er ed b y pa tie nt b ill in g. • in m os t c as es , t he to ta l c os t w as g re at er th an th e to ta l i nc om e, r es ul tin g in a ne t l os s to th e pr ac tic e. • c os t o f t re at m en t n pw t = n eg at iv e p re ss ur e w ou nd th er ap y; r c t = ra nd om is ed co nt ro lle d tr ia l; d it t o = co m pu te ri se d m ul tim od al p ro ce du ra l p re pa ra tio n an d di st ra ct io n; ig c = in te ns iv e g ly ca em ic co nt ro l; g w c = g oo d w ou nd c ar e; ic u = in te ns iv e ca re u ni t; q o l = qu al ity o f l ife ; 4 lb = fo ur -l ay er b an da ge ; s sb = sh or tst re tc h ba nd ag e; c m e = co nt in ui ng m ed ic al e du ca tio n. koukab a. al-gharibi, sajana sharstha and maria a. al-faras review | e437 to an average of 3.2 weeks of treatment with standard care.1 similar findings were reported in a recent meta-analysis; although the initial cost of npwt was higher during treatment, the overall cost was reduced due to the lower costs incurred for personnel-related expenses and the shorter duration of treatment.6 augustin et al. explored the cost-effectiveness of treating vascular leg ulcers using urgostart® (urgo ltd., loughborough, uk), a hydroactive dressing containing a nano-oligosaccharide factor, and urgocell contact® (urgo ltd.), a neutral foam dressing.7 according to an economic model, the hydroactive dressing was less expensive than the neutral foam dressing after eight weeks of treatment (usd $849.86 versus $1,335.51). in addition, the hydroactive dressing resulted in a ≥40% reduction in wound size, with greater healing observed over a shorter treatment period.7 gilligan et al. investigated the expected cost of treatment per week and the number of weeks needed for wound closure using becaplermin gel and good wound care (gwc) versus gwc alone among patients with diabetic foot ulcers.20 as with npwt, although treatment with becaplermin gel and gwc was initially more expensive compared to gwc alone, the former treatment method resulted in accelerated wound closure and lowered the risk of amputation, thus reducing overall long-term costs.20 e c o n o m y a treatment is considered cost-effective only if it is economical in terms of both time and money. as mentioned earlier, the duration of treatment is often directly linked with costs as the shorter the duration of treatment, the less expensive the total costs of treatment.11,19 however, apart from increasing the rate of wound healing, a treatment may also be economical in that it reduces the number of wound dressing changes needed or decreases the time required to apply the dressing. in a cohort study, both the frequency of dressing changes and the time required to change dressings was reduced using npwt in comparison to standard treatment.5 m o d e l c a s e a 60-year-old man developed a diabetic foot ulcer after wearing a new pair of shoes for one week. he had initially been diagnosed with diabetes mellitus five years previously. the surface area of the wound was 10 cm2 at baseline prior to starting treatment. after six months of standard wound care, the surface area of the wound had decreased to 7 cm2. the cost of each standard dressing was usd $24, with the dressing changed every other day. as a result, the total cost of treatment was usd $3,456 over a six-month period. subsequently, the patient’s primary care provider advised changing treatment methods from standard dressings to becaplermin gel due to poor wound healing. after three months, the wound size had decreased to 3 cm2. the becaplermin gel dressing was re-applied three times a week at a cost of usd $30 each time. in total, the cost over three months of treatment was usd $1,040. this case highlights the two defining attributes of cost-effectiveness.9 treatment with becaplermin dressing gel was more effective compared to standard wound care, as evidenced by the rapid wound healing and the greater decrease in wound size over a shorter period of time (a 4 cm2 decrease over three months versus a 3 cm2 decrease over six months). moreover, although the cost per dressing change of becaplermin gel was higher than standard wound care, it was more economical in the long term (usd $1,040 versus usd $3,456). antecedents antecedents refer to the factors, events or incidents that must arise or be present prior to the occurrence of the concept.9 four antecedents were identified in the concept of cost-effectiveness in wound care, including the type of wound, the setting at which the wound care takes place, the type of dressing/treatment used and patient-related characteristics. in terms of wound type, injuries and wounds may be classified as either acute or chronic (e.g. pressure ulcers, venous/arterial leg ulcers, diabetic ulcers and burns). this will therefore have an impact on duration of care and treatment costs. generally, chronic wounds are more expensive and difficult to treat than acute wounds.2,6 however, certain treatments for acute wounds might be less costeffective, particularly when used only for short periods of time.5 wound care can take place in a variety of settings which will affect cost of treatment, such as in a hospital, outpatient department, home-care facility or an ambulatory clinic. for instance, the cost of treatment might be higher in a hospital setting in contrast to an outpatient setting.8 the type of dressing or treatment utilised will also have an impact on cost-effectiveness. common treatments include beca plermin gel, infrared thermometry, bandages, hydro active/neutral foam dressings, antimicrobial dressings and npwt.5,7,8,20,21 finally, certain patient-related characteristics will affect care costs, such as age and the presence of comorbidities such as diabetes mellitus or other conditions affecting health such as decreased immunity or immobility.2–4 cost-effectiveness of wound care a concept analysis e438 | squ medical journal, november 2018, volume 18, issue 4 consequences consequences are the events or outcomes that arise as a result of the occurrence of the concept.9 in terms of the concept of cost-effectiveness in wound care, four consequences were identified: patient prognosis, economic burden, quality of life (qol) and cost-savings. as cost-effective wound dressings result in more rapid wound healing and reduce the risk of complications such as infection, the prognosis of the patient is improved.10 additionally, as costeffective treatments are more affordable and result in desired outcomes within shorter periods of time, the economic burden of wound care on the part of the patients and, ultimately, the healthcare system is reduced. moreover, the patient’s qol is significantly improved as a result of the more rapid recovery and reduced costs associated with the use of cost-effective treatments.18 finally, there are obvious cost-savings that come with the use of wound dressings which are cost-effective. empirical referents empirical referents indicate actual factors or events that, by virtue of their presence, demonstrate the occurrence of the concept.9 the empirical referents for the concept analysis of cost-effectiveness in wound care were divided into observable referents and measurable referents. observable referents are factors associated with wound healing, such as photographs which showcase observable changes in wound healing after the application of dressings.11 measurable referents include measuring the size of the wound throughout its progression and estimating the total cost of wound dressings. the following formulae may be used to calculate wound size:11 where r is the radius of the wound, l is the length of the wound and wmin and wmax are the minimum and maximum widths of the wound, respectively. equation 1 is used mainly to calculate the size of circular wounds, while equation 2 is used for wounds of other shapes. implications clinicians and managers should have a better understanding of the effect that clinical decisionmaking has on financial budgets and how the concept of cost-effectiveness can benefit various stakeholders, including both patients and healthcare facilities. as a result, clinicians should consider ways to reduce costs of care while maintaining optimal clinical outcomes. this will allow nurses and clinicians to support patients and their families in choosing effective treatments with a reduced economic burden and fewer financial constraints. conclusion nurses and clinicians should promote cost-effectiveness in wound care in terms of both efficacy and economy, by considering healing rates and patient prognosis while maintaining low treatment costs in light of the duration of treatment. further research is recommended to investigate nurses’ perceptions of cost-effective wound care. references 1. brown nj, david m, cuttle l, kimble rm, rodger s, higashi h. cost-effectiveness of a nonpharmacological intervention in pediatric burn care. value health 2015; 18:631–7. https://doi. org/10.1016/j.jval.2015.04.011. 2. carter mj. economic evaluations of guideline-based or strategic interventions for the prevention or treatment of chronic wounds. appl health econ health policy 2014; 12:373–89. https://doi.org/10.1007/s40258-014-0094-9. 3. gist s, tio-matos i, falzgraf s, cameron s, beebe m. wound care in the geriatric client. clin interv aging 2009; 4:269–87. https://doi.org/10.2147/cia.s4726. 4. sen ck, gordillo gm, roy s, kirsner r, lambert l, hunt tk, et al. human skin wounds: a major and snowballing threat to public health and the economy. wound repair regen 2009; 17:763–71. https://doi.org/10.1111/j.1524-475x.2009.00543.x. 5. hampton j. providing cost-effective treatment of hard-toheal wounds in the community through use of npwt. br j community nurs 2015; 20:s116–20. https://doi.org/10.12968/ bjcn.2015.20.sup6.s14. 6. anthony h. efficiency and cost effectiveness of negative pressure wound therapy. nurs stand 2015; 30:64–70. https:// doi.org/10.7748/ns.30.8.64.s50. 7. augustin m, herberger k, kroeger k, muenter kc, goepel l, rychlik r. cost-effectiveness of treating vascular leg ulcers with urgostart(®) and urgocell(®) contact. int wound j 2016; 13:82–7. https://doi.org/10.1111/iwj.12238. 8. sibbald rg, mufti a, armstrong dg. infrared skin thermometry: an underutilized cost-effective tool for routine wound care practice and patient high-risk diabetic foot selfmonitoring. adv skin wound care 2015; 28:37–44. https://doi. org/10.1097/01.asw.0000458991.58947.6b. 9. walker lo, avant kc. strategies for theory construction in nursing, 5th ed. london, uk: pearson, 2010. pp. 160–8. 10. browning p. the cost-effectiveness of wound dressings. br j healthc manag 2014; 20:462–6. https://doi.org/10.12968/ bjhc.2014.20.10.462. 11. hämmerle g, strohal r. efficacy and cost-effectiveness of octenidine wound gel in the treatment of chronic venous leg ulcers in comparison to modern wound dressings. int wound j 2016; 13:182–8. https://doi.org/10.1111/iwj.12250. mean wound area = l × (wmin + wmax) 2 [equation 2] wound area = r2 × π [equation 1] koukab a. al-gharibi, sajana sharstha and maria a. al-faras review | e439 12. tricco ac, cogo e, isaranuwatchai w, khan pa, sanmugalingham g, antony j, et al. a systematic review of cost-effectiveness analyses of complex wound interventions reveals optimal treatments for specific wound types. bmc med 2015; 13:90. https://doi.org/10.1186/s12916-015-0326-3. 13. butcher m, white r. factors affecting cost-effectiveness in wound care decision making. nurs stand 2014; 28:51–8. https://doi.org/10.7748/ns2014.04.28.35.51.e7671. 14. lima af, castilho v, baptista cm, rogenski nm, rogenski ke. direct cost of dressings for pressure ulcers in hospitalized patients. rev bras enferm 2016; 69:290–7. https://doi. org/10.1590/0034-7167.2016690212i. 15. pham b, harrison mb, chen mh, carley me; canadian bandaging trial group. cost-effectiveness of compression technologies for evidence-informed leg ulcer care: results from the canadian bandaging trial. bmc health serv res 2012; 12:346. https://doi.org/10.1186/1472-6963-12-346. 16. whitlock e, morcom j, spurling g, janamian t, ryan s. wound care costs in general practice: a cross-sectional study. aust fam physician 2014; 43:143–6. 17. evans j. a solution to cost-effective wound management in the community. j community nurs 2014; 28:46–51. 18. othman d. negative pressure wound therapy literature review of efficacy, cost effectiveness, and impact on patients’ quality of life in chronic wound management and its implementation in the united kingdom. plast surg int 2012; 2012:374398. https://doi. org/10.1155/2012/374398. 19. jemec gb, kerihuel jc, ousey k, lauemøller sl, leaper dj. cost-effective use of silver dressings for the treatment of hardto-heal chronic venous leg ulcers. plos one 2014; 9:e100582. https://doi.org/10.1371/journal.pone.0100582. 20. gilligan am, waycaster cr, motley ta. cost-effectiveness of becaplermin gel on wound healing of diabetic foot ulcers. wound repair regen 2015; 23:353–60. https://doi.org/10.1111/ wrr.12285. 21. maunoury f, motrunich a, palka-santini m, bernatchez sf, ruckly s, timsit jf. cost-effectiveness analysis of a transparent antimicrobial dressing for managing central venous and arterial catheters in intensive care units. plos one 2015; 10:e0130439. https://doi.org/10.1371/journal.pone.0130439. squ med j, august 2011, vol. 11, iss. 3, pp. 357-362, epub. 15th aug 11 submitted 24th apr 11 revision req. 29th may 11, revision recd. 4th jun 11 accepted 12th jun 11 1department of biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman; departments of 2medicine and 3child health, sultan qaboos university hospital, muscat, oman. *corresponding author email: bayoumi@squ.edu.om ì÷áúäπ]<í‚<≈^�œjâ˜]<ƒœá⁄<ª<ïçëçq<ìèm]öê<ïüàõ ìèfi^€ �¬<ïüâ_<ª<·áä◊ëê<öü⁄<‡¬<      46 atp7b c28662a>g chtm6 exon 13  exons 1213 and 14cdna    atp7b exon 13  atp7b  atp7b:مفتاح الكلمات abstract: objectives: the objective of this study was to characterise wilson's disease (wd) [omim 277900] genetically and test for allelic variants in the copper transport gene (atpase, cu++ transporting, beta polypeptide, atp7b) responsible for the disease in an omani family. methods: three index patients from an omani family had been previously diagnosed with wd. all three patients suffered neurological symptoms and signs. forty-six relatives in the family were screened for wd. eleven more individuals were positive, but asymptomatic. results: thirteen non-disease-causing allelic gene variants, described previously, were identified in the atp7b gene from 46 family members. a putative novel disease-causing splice-site variant (c.2866-2a>g), which has not been reported previously, was detected in this family. it is located upstream of exon 13 which encodes part of transmembrane copper channel (ch/tm6). reverse transcription polymerase chain reaction was used to amplify a complementary dna (cdna) fragment containing exons 12, 13 and 14. exon 13 was entirely skipped from the transcript which probably would result in a defective atp7b protein. conclusion: a new atp7b splice-site allelic variant, found among the 14 wd patients segregated with the disease in a recessive manner, suggests it is a disease-causing variant. keywords: wilson disease; atp7b; copper; allelic variant; splice site; mutation; oman a novel splice-site allelic variant is responsible for wilson disease in an omani family mohammed al-tobi,1 masoud kashoob,2 surendranath joshi,3 *riad bayoumi1 clinical & basic research advances in knowledge 1. this is the first time that the molecular genetic cause of wilson disease is revealed in an omani family. it adds to the body of knowledge of pathophysiology and genetic heterogeneity of the disease. application to patient care 1. a new omani-specific molecular diagnostic test could be developed to confirm diagnosis of wilson disease and screen asymptomatic family members for prevention and early treatment. a novel splice-site allelic variant is responsible for wilson disease in an omani family 358 | squ medical journal, august 2011, volume 11, issue 3 wilson disease (wd, omim 277900) 1 is an autosomal recessive disorder of copper metabolism resulting from allelic variants of the atpase, cu++ transporting, beta polypeptide (atp7b) gene on chromosome 13q14.3. the gene is 78,826 bp long, with 21 exons coding for a copper transporting atpase.2,3 in wd, there is failure of copper excretion from the liver and defective incorporation of copper into ceruloplasmin by the atp7b (ec 3.6.3.4). the disease typically manifests at any age from 5 to 50 years with hepatic or neurologic symptoms, alone or in combination, and occasionally with psychiatric, haematological or rheumatological problems.4 the disorder usually manifests early as chronic liver disease and/or later as neurologic impairment due to the toxic accumulation of copper in several tissues, principally the liver and the brain.5 kayserfleischer (kf) rings result from copper deposition in descemet’s membrane of the cornea and reflect a high degree of copper storage in the body. wd has been described in every region of the world and its incidence is estimated at 30 per million worldwide.4 it is more common (1 in 3,000–10,000) in communities where consanguineous marriages are prevalent such as the druze, yemenite and iranian jews and palestinians.6 wd is lethal if left untreated. analysis of disease-causing allelic variants reveals enormous molecular heterogeneity consisting of a small number of frequent variants that are population specific, as well as a much greater number of rare individual alleles. to date, more than 300 different variants have been characterised in wd patients from varying ethnic origins.3,7-19 the majority are missense variants, with splicesite variants accounting for 10% only.14,15 here we describe wd in an extended highly consanguineous omani family, with a possible novel splice-site disease-causing allelic variant. methods one omani family of asian origin, referred to previously,20 was included in the study. three patients from the family were previously diagnosed at sultan qaboos university hospital using standard tests for wd and are under continuous treatment now. a total of 46 siblings, parents or relatives from the family were examined. several standard tests were used to screen for wd: serum ceruloplasmin, penicillamine challenge test and kayser-fleischer ring (kf ring). eleven more family members tested positive for wd, but were all asymptomatic. fifty dna samples were obtained from medical students exhibiting no clinical disease or aliment, to be used as controls. ethical clearance for the study was obtained from the ethics committee of the college of medicine & health sciences, sultan qaboos university. all individuals gave their consent for inclusion in the study. dna was extracted from whole blood using the standard procedure of phenol-chloroform method. all 21 exons of the atp7b gene with a flanking region from the introns, the 5’utr, 3’utr and the promoter region were amplified using primers specified previously,5 with minor modifications. gene variant detection was performed by direct sequencing using the abi3100 dna sequencer (applied biosystems, usa). the sequencing result for each sample was aligned with the reference sequence retrieved from the national center for biotechnology information (ncbi) genome website (nc_000013.10).2 alignments were processed using three software programmes: bioedit, (2007, ibisbiosciences, carlsbad, ca, usa), chromaspro (version 15, technelysium pty ltd., brisbane, australia), and lasergene (2010, dnastar inc., madison, usa). fresh blood samples were collected from two wd patients and one normal control. ribonucleic acid (rna) was extracted using abi prismtm 6100 nucleic acid prep station (applied biosystems, usa). reverse transcription of dna was performed using the high capacity complementary dna (cdna) archive kit (applied biosystems, usa). a cdna fragment containing exons 12, 13 and 14 was amplified using forward primer: 5’agctggctgaccggttta3’ and reverse primer: 5’caaggggtgttcactgctg3’ giving a product size of 470bp in normal controls. the size of the fragment (470bp) is smaller than the total size of exons 12, 13 and 14 (514bp) because of the inward positioning of the primers. agarose gel electrophoresis was used to separate cdna fragments obtained from wd patients and normal control. mohammed al-tobi, masoud kashoob, surendranath joshi, riad bayoumi clinical and basic research | 359 results all 21 exons were sequenced in each of the 46 individuals in the family. overall, 14 variants were detected in the atp7b gene [table 1]; 13 of them were identified as disease non-causing polymorphisms. there was one in the promoter region, two in the untranslated region (5’utr), six in the coding region, one in a splice site and four in intronic regions. the 13 known variants were previously recorded in the wd snp database16 and the ncbi/dbsnp.19 most are substitution polymorphisms while there is only one insertion. only one of the detected variants (c.28662a>g),21 at genomic location 52,520,615 ( ncbi, nc_000013.10),19 was suspected as a cause of wd. it is located at -2 of the splice acceptor site of intron 12. the splice acceptor dinucleotide ag has been replaced by gg upstream of exon 13. it was genotyped in all wd patients, all relatives of patients and in fifty normal controls. it was found in 3 patients with wd and 11 asymptomatic individuals within the family who tested positive for the disease, but not in the normal controls. the c.2866-2a>g variant segregated in a recessive manner with the disease in all 14 individuals who were all homozygous for the allelic variant [figure 1]. this variant has not been documented in the wd-human gene mutation (hgmd)-ncbi databases,16-19 nor cited in any publication on wd; therefore, it was necessary to confirm as a disease-causing variant, using reverse transcription polymerase chain reaction (rt-pcr). rna was extracted from two patients and one normal control. a cdna fragment containing exons 12, 13 and 14 was amplified. agarose gel electrophoresis showed that the cdna pcr product of wd patients is 275 bp compared to 470 bp in normal control [figure 2]. upon sequencing this amplified region, it was found that the entire exon-13 (195 bp) was skipped in wd patients [figure 3]. the atp7b protein will probably, therefore, be non-functional. discussion allelic variants of the atp7b gene causing wd can be common or specific for certain ethnic groups. one of the aims of this study was to examine whether omani wd patients harbour common table 1: all identified allelic variants of the atpase, cu++ transporting, beta polypeptide, (atp7b) gene found in a large extended consanguineous family with wilson disease (wd) in oman location polymorphism# snp id@ type promoter -521t>c rs9563084 substitution 5’utr -119 ins cgccg rs28362531 insertion 5’utr -75c>a rs2277448 substitution exon 2 1216t>g rs1801243 non-synonymous exon 3 1366g>c rs1801244 non-synonymous intron 3 1544-53a>c rs2147363 substitution intron 9 2448-25g>a rs10870860 rs9526811 substitution exon 10 2485a>g rs1061472 non-synonymous exon 12 2855g>a rs732774 non-synonymous intron 12 2866-90g>t rs2296246 substitution intron 12 c.2866-2a>g* splicing exon 13 3045g>a rs1801248 synonymous exon 16 3419t>c rs1801249 non-synonymous intron 18 3903+6c>t rs2282057 substitution note: # numbering is in reference to first translation site @ numbers in the snp database for wilson disease (ncbi / dbsnp) * suggested disease causing mutation. a novel splice-site allelic variant is responsible for wilson disease in an omani family 360 | squ medical journal, august 2011, volume 11, issue 3 or specific variants. a novel splice-site diseasecausing allelic variant (c.2866-2a>g) was found in 14 individuals who belonged to an omani large consanguineous family of asian origin. in the c.2866-2a>g variant, the normal allele a has been substituted by g at -2 position of the consensus sequence of the acceptor splice-site in intron 12, upstream of exon 13 (ttcagaac>ttcggaac). it appears that the highly conserved splice acceptor ag dinucleotide has been replaced by gg, resulting in complete skipping of the downstream exon 13. to confirm figure 1: exon-13 sequence showing the novel c.2866-2a>g variant in a wilson disease affected individual, one parent and a normal control. figure 2: polymerase chain reaction (pcr) of exons 12, 13 and 14 where m = marker (50 bp); n = control sample; p1 and p2 are wilson disease (wd) patients. the amplified cdna fragment of wd patient is smaller (275 bp) than that of normal control (470 bp). mohammed al-tobi, masoud kashoob, surendranath joshi, riad bayoumi clinical and basic research | 361 the variation, transcript analysis using rt-pcr was performed. transcripts from wd patients showed complete deletion of exon 13. a similar novel splice-site disease-causing variant in -6 position at the intron/exon junction (ivs12-6g>a) has been reported previously.14 exon 13 encodes part of the transmembrane copper channel (ch/tm6) which is essential for copper transport. it is probable, therefore, that the c.2866-2a>g mutation would result in a defective protein. further analysis of the 3 patients and 11 positive, but asymptomatic, relatives showed that all 14 individuals were homozygous for the c.2866-2a>g variant. the disease appears to segregate with the allelic variant in a recessive manner. this new allelic variant is not documented in the ncbi/hgmd database;17 therefore, it seems to be the most probable novel variation causing wd, specific to this omani family. however, the study has been limited by the paucity of reports on wd in oman. very few patients have been recorded previously. it is also essential that further molecular functional studies be done, to firmly establish the pathogenicity of the described mutation, which at present is not feasible in oman. conclusion a novel splice-site variant of the atp7b gene that segregated with wilson disease in a recessive manner in an omani family, strongly suggests it is the disease causing mutation. a c k n o w l e d g e m e n t s this work is part of the m.sc. thesis of mr. mohammed al-tobi. we thank the graduate college, sultan qaboos university, muscat for its support. we also thank mrs. taruna dutt for typing the manuscript. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. omim catalogue number. from: www.ncbi.nlm.nih. gov/sites/entrez?db=omim. accessed: may 2011. 2. national center for biotechnology information (ncbi) genome website: atp7b, atpase. from: www.ncbi.nlmnih.gov/gene/540. accessed: may 2011. 3. thomas gr, forbes jr, roberts ea, walshe jm, cox dw. the wilson disease gene: spectrum of mutations and their consequences. nat genet 1995; 9:210–17. 4. cox dw, robert e. in: pagon ra, bird td, dolan figure 3: the complementary dna (cdna) sequence of the junction of exon 12-13 in normal individuals and junction 12-14 in a wilson disease patient, where exon 13 has been entirely skipped. a novel splice-site allelic variant is responsible for wilson disease in an omani family 362 | squ medical journal, august 2011, volume 11, issue 3 cr, stephens k, eds. genereviews. seattle, wa: university of washington, seattle, 1993-1999, updated 2006. 5. vrabelova s, letocha o, borsky m, kozak l. mutation analysis of the atp7b gene and genotype/ phenotype correlation in 227 patients with wilson disease. mol genet metab 2005; 86:277–85. 6. kalinsky h, funes a, zeldin a, pel-or y, korostishevsky m, gershoni-baruch r, et al. novel atp7b mutations causing wilson disease in several israeli ethnic groups. hum mutat 1998; 11:145–51. 7. thomas gr, roberts ea, walshe jm, cox dw. haplotypes and mutations in wilson disease. am j hum genet 1995; 56:1315–19. 8. figus a, angius a, loudianos g, bertini c, dessi v, loi a, et al. molecular pathology and haplotype analysis of wilson disease in mediterranean populations. am j hum genet 1995; 57:1318– 24. 9. waldenstrom e, lagerkvist a, oahlman t, westermark k, landegren u. efficient detection of mutations in wilson disease by manifold sequencing. genomics 1996; 37:303–9. 10. loudianos g, dessi v, lovicu m, angius a, nurchi a, sturniolo gc, et al. further delineation of the molecular pathology of wilson disease in the mediterranean population. hum mutat 1998; 12:89– 94. 11. nanji ms, nguyen vt, kawasoe jh, inuik k, endo f, nakajima t, et al. haplotype and mutation analysis in japanese patients with wilson disease. am j hum genet 1997; 60:1423–29. 12. kim ek, yoo oj, song ky, yoo hw, choi sy, cho sw, et al. identification of three novel mutations and a high frequency of the arg778leu mutation in korean patients with wilson disease. hum mutat 1998; 11:275–78. 13. shah ab, chernov i, zhang ht, ross bm, das k, lutsenko s, et al. identification and analysis of mutations in the wilson disease gene (atp7b): population frequencies, genotype-phenotype correlation, and functional analyses. am j hum genet 1997; 61:317–28. 14. loudianos g, lovicu m, dessi v, tzetis m, kanavakis e, zancan l, et al. abnormal mrna splicing resulting from consensus sequence splicing mutations of atp7b. hum mutat 2002; 20:260–6. 15. lovicu m, lepori mb, incollu s, dessi v, zappu a, iorio r, et al. rna analysis of consensus sequence splicing mutations: implications for diagnosis of wilson disease. genet test mol biomarkers 2009; 13:185–91. 16. wilson disease mutation database. from: www. w i l s o n d i s e a s e . m e d . u a l b e r t a . c a / d at ab a s e . a s p . accessed: may 2011. 17. human gene mutation database. from: http:// www.hgmd.cf.ac.uk. accessed: may 2011. 18. human genome variation databse: from www. hgvs.org/dblist/ccent.html. accessed: may 2011. 19. national center for biotechnology information (ncbi) snp database. from: http://www.ncbi.nlm. nih.gov/sites/entrez?db=snp. accessed: may 2011. 20. joshi sn, hashim j, venugopalan p. pattern of inborn errors of metabolism in an omani population of the arabian peninsula. ann trop paed 2002; 22:93–6. 21. hugo gene nomenclature committee. from: http://www.genenames.org/index.html. accessed: may 2011. departments of 1surgery, 2haematology and 3oncology, hamad medical corporation, doha, qatar *corresponding author’s e-mails: alismc2051@gmail.com and ali_2051@hotmail.com ورم سرطاىن )كارسينويد( باألمعاء الوسطى يظهر كمشتبه أورام ثانوية مبحجر العني �أمين عبد �حلفيظ، �صيد حممد على، �صلوى حممد �صيد�حمد، �أ�صما �حل�صن، نهلة حممد مو�صى �لنجار abstract: although metastasis of carcinoid tumours of the intestine is rare, it has been reported in several organs, mainly in the lungs, the liver and less commonly in the orbits. we report a 50-year-old male patient who presented at hamad general hospital, doha, qatar, in 2016 with central abdominal pain, distention, nausea and vomiting for the previous four days. the patient had unilateral right-sided exophthalmos for two years prior to presentation. following an abdominal computed tomography (ct) scan and an ultrasound guided biopsy, the patient was diagnosed with extensive multi-focal metastatic carcinoid tumour of the small bowel and mesentery; histopathology confirmed the diagnosis. subsequently, the patient underwent a laparotomy and small bowel resection and was administered somatostatin therapy. one week postoperatively, the patient developed an acute increase in his right eye exophthalmos. ct, magnetic resonance imaging and scintigraphy scans revealed an orbital metastatic lesion, which probably originated from the previously diagnosed carcinoid tumour. the orbital metastasis was treated with somatostatin therapy and the patient was lost to follow-up when he left the country. keywords: carcinoid tumor; orbital neoplasm; metastasis; exophthalmos; scintigraphy; case report; qatar. امللخ�ص: بالرغم من ندرة �الأور�م �لثانوية �لتي تنتج من �الأور�م �ل�رصطانية )كار�صينويد( �لتي ت�صيب �الأمعاء �لو�صطى �إال �ن هذه �الأور�م قد تتو�جد فى �لعديد من �ع�صاء �جل�صم، وب�صورة رئي�صية فى �لرئتني و �لكبد لكنها �قل �صيوعا فى حمجر �لعني. هذ� تقرير عن مري�س عمره 50 عام ح�رص �ىل م�صت�صفى حمد �لعام، فى �لدوحة،قطر، فى عام 2016 يعانى من �الم و �إنتفاخ بالبطن،غثيان و قئ ملدة �أربعة �يام. عانى �أ�صعة باإ�صتخد�م موجهة عينة �أخذ و �لبطن على مقطعية �أ�صعة �جر�ء بعد �صنتني. ملدة �ليمنى بالعني �حادى جحوظ من �أي�صا �ملري�س �ملوجات �لفوق �صوتية ،مت �أكت�صاف ورم �رصطانى )كار�صينويد( متعدد �لبوؤر و ممتد على نطاق و��صع، فى �الأمعاء�لدقيقة و �أغ�صية �مل�صاريقا عملية �إجر�ء مت ذلك بعد للعينة. �لن�صيجي �لت�رصيح بنتيجة �لت�صخي�س تاأكد قد و بالكبد، ثانوية باأور�م م�صطحب و �المعاء تغلف �لتي �إ�صتك�صاف جر�حى للبطن و �إ�صتئ�صال جزء من �الأمعاء �لدقيقة. تطورت حالة �ملري�س بعد �لعملية باأ�صبوع و ��صبح يعانى من زيادة حادة فى جحوظ �لعني �ليمنى .�ثبتت �الأ�صعة �ملقطعية على �لعني و �أ�صعة �لرنني �ملغنطي�صي على �لعني و �أ�صعة �مل�صح �لذري باملو�د �مل�صعة �ن �ملري�س يعانى من �أور�م ثانوية مبحجر �لعني �ليمنى ناجتة من �لورم �ل�رصطانى )كار�صينويد( �ملذكور �صابقا. مت معاجلة �الأور�م �لثانوية مبحجر �لعني مبادة �ل�صوماتو�صتاتني و لكن �ملري�س مل ي�صتكمل �ملتابعة �الإكلينيكية النه ترك �لدولة. قطر. حالة؛ تقرير �لذري؛ �مل�صح �أ�صعة �لعني؛ جحوظ ثانوية؛ �أور�م �لعني؛ مبحجر ورم �رصطانى؛ ورم املفتاحية: الكلمات mid-gut carcinoid tumour presenting as suspected orbital metastasis ayman a. hafiz,1 *syed m. ali,1 salwa m. sidahmed,1 asma al-hassan,2,3 nahla m. m. el-naggar3 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e253–256, epub. 5 nov 19 submitted 2 apr 19 revision req. 30 may 19; revision recd. 23 jun 19 accepted 18 jul 19 carcinoid tumours are neuroendocrine tumours (net) originating mainly from primitive stem cells of the gut, yet they can occur in the lungs, thymus, mediastinum, bronchus, liver, pancreas, ovaries, prostate and kidneys.1–3 while originally thought to be of a low grade, metastases are reported in 50–75% of patients.1 the most common locations for gastrointestinal (gi) carcinoids to metastasise are the lymph nodes, liver and bone.2–4 ocular metastasis is a rare finding. carcinoid tumours that have orbital metastases can be difficult to diagnose and differentiate from primary eye malig nancies or metastatic lesions from other malignancies such as lymphoma, breast or gi tract adenocarcinomas and malignant melanoma.5 detection of such lesions can be obtained either by general diagnostic imaging, like computed tomography (ct) and magnetic resonance imaging (mri), or the more specific diethylene triamine penta-acetic acid (dtpa)-labelled octreotide analogue scintigraphy and histopathological examination.1 prognosis is generally favourable with treatment options including surgery, external beam radiation, chemotherapy and octreotide and somatostatin analogues. this case report describes an orbital metastasis that originated from a carcinoid tumour of the small bowel and mesentery. case report a 50-year-old male patient presented at hamad general hospital, doha, qatar, in 2016 with a history of central abdominal pain, distention, nausea and vomiting for the previous four days. he had no history of flushing, diarrhoea or shortness of breath. the this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.013 case report https://creativecommons.org/licenses/by-nd/4.0/ mid-gut carcinoid tumour presenting as suspected orbital metastasis e254 | squ medical journal, august 2019, volume 19, issue 3 a metastatic well-differentiated net with possible gi tract primary involvement. the mitotic count was <2/10 cells per high power field and the ki-67 index was 1%. the 5-hydroxyindoleacetic acid levels in a 24-hour urine sample were 250 µmol (normal level: <47 µmol/24-hour urine sample). subsequently, the patient was diagnosed with metastatic carcinoid tumour of the small bowel and mesentery. the case was discussed at a gi cancer multidisciplinary team meeting and it was decided that the tumour would be debulked followed by somatostatin therapy with or without chemotherapy. the patient underwent an exploratory laparotomy which revealed multiple lesions of various sizes involving the jejunum and proximal ileum; the small bowel mesentery had two large lesions encasing the superior mesenteric artery and a large nodule in the greater omentum. in addition, multiple small nodules were seen on the small bowel serosa and parietal peritoneum and palpable bi-lobar liver lesions [figure 2]. segmental small bowel resection from proximal jejunum to mid-ileum was carried out with avoidance of debulking the mesenteric and retroperitoneal lesions to maintain blood supply to the bowels. histopathology of the small intestine showed multifocal well-differentiated net/carcinoid tumour histological grade 1 and a mitotic count of <2/10 cells per high power field invading through the muscle into the serosa with lymphovascular and perineural invasion. the mesenteric/radial margin was positive for patient had normal bowel movements and no history of jaundice, fatigue or rectal bleeding. he had unilateral right-sided exophthalmos for two years. although the patient sought medical advice for the exophthalmos, he did not receive a diagnosis or treatment. there was neither decline of vision nor history of headaches suggestive of raised intracranial pressure. the patient was mildly dehydrated, yet not distressed, and had normal vital signs. no cervical/ axillary/inguinal lymphadenopathy was detected. the abdomen was not distended; however, mild tenderness in the periumbilical region without guarding and a palpable mass in the epigastric region was observed. the mass was firm, partially mobile and measured 10 × 10 cm. the patient’s white cell count was 14 × 103/µl (normal range: 4–7 × 103 cells/µl), his haemoglobin level was 15.1 g/dl (normal range: 12–16 g/dl) and all other biochemical tests were normal. abdominal ct scan showed an ill-defined enhancing soft tissue mass in the left upper quadrant of the abdomen arising from the jejunal loops with an exophytic mesenteric soft tissue component causing obstruction of the jejunum along with significant retroperitoneal and mesenteric lymphadenopathy and multiple hyper-vascular liver lesions [figure 1]. no metastatic lesions were seen in the thorax. a metastatic intestinal lesion was suspected as the patient had incomplete/partial small bowel obstruction. an ultrasound guided biopsy from the liver lesion showed figure 1: computed tomography scan of a 50-year-old male patient showing (a) a mass in the mesentery of the small intestine (red arrow) and (b) a lesion in the liver (white arrow). figure 2: operative photographs of an exploratory laparotomy of a 50-year-old male patient showing (a) a nodule in the mesentery of the small intestine and (b) multiple nodules in the greater omentum. ayman a. hafiz, syed m. ali, salwa m. sidahmed, asma al-hassan and nahla m. m. el-naggar case report | e255 presence of the tumour. the pathological staging was pt4 and immunohistochemical stains were positive for synaptophysin and chromogranin, whereas ki-67 was at 2% positivity in the tumour cells. the mesentery towards the tumour site was positive for the presence of the carcinoma. the omentum showed multifocal metastatic net/carcinoid tumour presence with the largest nodule measuring 3.5 cm. the patient had an uneventful postoperative course, however, on the seventh postoperative day he developed an acute increase in the right eye exoph thalmos with deterioration of vision and severe conjunc tival and periorbital oedema. treatment was initiated with tobramycin and dexamethasone, lubricant eye drops and oral prednisone. an orbital ct scan showed a lobular mass in the inferior aspect of the right orbit measuring 3.1 × 2.6 cm; it was not separate from the inferior rectus muscle. an mri scan showed a heterogeneous intense postcontrast, central breakdown and bright t1/t2 areas likely representing a haemorrhage within the mass. the lesion was causing proptosis of the right globe and displacement of the optic nerve and superior oblique muscle superiorly [figure 3]. the acute ocular symptoms were attributed to a haemorrhage inside the orbital tumour, which was suspected to be a metastasis from the carcinoid tumour. the patient’s symptoms improved significantly with topical eye drops and steroid treatment. dtpa-labelled octreotide analogue scintigraphy showed somatostatin-rich neuroendocrine metastasis from the previously diagnosed carcinoid tumour. these lesions were seen in the liver, central abdomen, chest and right orbit [figure 4]. the patient was treated in the department of oncology with octreotide and was lost to follow-up as he left the country. discussion orbital metastasis is rarely seen and can be associated with lymphoma, carcinoma of the breast or gi tract, melanoma or other secondary orbital tumours.4,6,7 carcinoid tumour is a rare entity and the prevalence of orbital and uveal involvement is approximately 2.2%.1 metastatic spread of carcinoid tumours results in a poor 5-year survival rate of <50% compared to 70% survival without metastasis.1,3 in a case series of 13 patients with orbital metastasis, the reported 5-year survival rate was 72% and the 10-year survival rate was 38%.8 ocular metastasis can be suspected when the patient has a previous history of carcinoid tumour, evid ence of systemic metastasis and/or clinical symptoms of carcinoid syndrome. the most common presenting symptoms include diplopia (48%), pain (42%) and visual loss (30%), while the most frequent clinical signs include proptosis (63%), strabismus (62%) and visual loss (41%).9 while ultrasound and ct scans can help with the diagnosis, mri scans are considered the gold standard for diagnosing orbital metastasis.1 furthermore, accu rate localisation of primary and/or metastatic carcinoid tumours is obtained using scintigraphy with i-123 metaiodobenzylguanidine and 111in-dtpa pente treotide.1,10 imaging with these modalities provides a sensitivity of 72–87% whereas specificity may vary.11,12 however, histopathology should be used to confirm the diagnosis. although a biopsy of the orbital lesion was considered gold standard for the definitive diagnosis of the lesion, das et al. recently refuted this modality and suggested that in the presence of classic radiologic findings, history of mid-gut carcinoid tumour and other metastasis, treatment can be started without a figure 3: magnetic resonance imaging scan of the head of a 50-year-old male patient showing a mass in the right orbit (arrow). figure 4: diethylenetriamine penta-acetic acid-labelled octreotide analogue scintigraphy of a 50-year-old male patient showing right orbital uptake (arrow). mid-gut carcinoid tumour presenting as suspected orbital metastasis e256 | squ medical journal, august 2019, volume 19, issue 3 3. modlin im, sandor a. an analysis of 8305 cases of carcinoid tumors. cancer 1997; 79:813–29. https://doi.org/10.1002/(si ci)1097-0142(19970215)79:4<813::aid-cncr19>3.0.co;2-2. 4. harbour jw, de potter p, shields cl, shields ja. uveal meta stasis from carcinoid tumor. clinical observations in nine cases. ophthalmology 1994; 101:1084–90. https://doi.org/10.1016/s0 161-6420(94)38030-4. 5. peixoto rda, lim hj, cheung wy. neuroendocrine tumor metastatic to the orbit treated with radiotherapy. world j gastrointest oncol 2013; 5:177–80. https://doi.org/10.4251/ wjgo.v5.i8.177. 6. dobson r, vinjamuri s, hsuan j, banks m, terlizzo m, weishmann h, et al. treatment of orbital metastases from a primary midgut neuroendocrine tumor with peptide-receptor radiolabeled therapy using 177 lutetium-dotatate. j clin oncol 2013; 31:e272–5. https://doi.org/10.1200/jco.2012.45.8612. 7. shinder r, al-zubidi n, esmaeli b. survey of orbital tumors at a comprehensive cancer center in the united states. head neck 2011; 33:610–14. https://doi.org/10.1002/hed.21498. 8. mehta js, abou-rayyah y, rose ge. orbital carcinoid metastases. ophthalmology 2006; 113:466–72. https://doi.org/10.1016/j. ophtha.2005.10.051. 9. valenzuela aa, archibald cw, fleming b, ong l, o’donnell b, crompton jj, et al. orbital metastasis: clinical features, manage ment and outcome. orbit 2009; 28:153–9. https://doi.org/10.10 80/01676830902897470. 10. meunier b, le cloirec j, dazord l, leveque j, lesimple t, tas p, et al. per operative localization of a carcinoid tumour of the breast using indium-111 pentetreotide and a nuclear surgical probe. eur j nucl med 1995; 22:281–3. https://doi.org/10.1007/ bf01081525. 11. carnaille b, nocaudie m, pattou f, huglo d, deveaux m, marchandise x, et al. scintiscans and carcinoid tumors. surgery 1994; 116:1118–21. 12. hoefnagel ca. metaiodobenzylguanidine and somatostatin in oncology: role in the management of neural crest tumours. eur j nucl med 1994; 21:561–81. https://doi.org/10.1007/bf 00173045. 13. das s, pineda g, goff l, sobel r, berlin j, fisher g. the eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience. cancer imaging 2018; 18:47. https://doi.org/10.1186/s40644-018-0181-5. 14. bardenstein ds, char dh, jones c, crawford jb, miller tr, riekhof ft. metastatic ciliary body carcinoid tumor. arch ophthalmol 1990; 108:1590–4. https://doi.org/10.1001/archo pht.1990.01070130092038. 15. rush ja, waller rr, campbell rj. orbital carcinoid tumor metastatic from the colon. am j ophthalmol 1980; 89:636–40. https://doi.org/10.1016/0002-9394(80)90279-2. 16. fan jt, ortiz rg, buettner h. regression of choroidal metastases from a bronchial carcinoid tumor after chemotherapy with cisplatin and etoposide. am j ophthalmol 1994; 117:111–13. https://doi.org/10.1016/s0002-9394(14)73026-0. 17. gragoudas es, carroll jm. multiple choroidal metastasis from bronchial carcinoid treated with photocoagulation and proton beam irradiation. am j ophthalmol 1979; 87:299–304. https:// doi.org/10.1016/0002-9394(79)90067-9. 18. makis w, mccann k, mcewan aj. orbital metastases of neuroendocrine tumors treated with 177lu-dotatate prrt or 131i-mibg therapies. clin nuc med 2016; 41:137–41. https://doi.org/10.1097/rlu.0000000000001008. biopsy.9,13 orbital biopsy was not done in the current patient. radiation and/or chemotherapy are the mainstay of treatment, although surgical excision has also been described in the largest series by mehta et al. of 13 patients with orbital metastasis.8 external beam radiation is a useful and non-invasive treatment modality that has been used in selected cases, particularly for single and symptomatic lesions.14,15 somatostatin analogues (i.e. radio-labelled octreo tide) have been widely used to locate primary and metastatic carcinoid tumours and identify individuals who may be eligible for targeted therapy. these radio pharmaceuticals can be used for treating disseminated lesions in various locations especially orbital lesions, as in the current case, and the dose can be repeated if required. fan et al. reported that chemotherapy can result in regression of choroidal metastasis, while gragoudas and carroll mentioned complete response of choroidal metastasis with xenon arc photocoagulation from a bronchial carcinoid tumour.16,17 in addition, marked symptomatic improvement and stabilisation of the disease process can be achieved by combining chemotherapy with external beam radiation.1 recently, the food and drug administration approved peptide radionucleotide receptor therapy (prrt) using 177lutentium (lu)-dotatate as systemic cytoreduc tive and cytostatic treatment modality for mid-gut carcinoid tumours. it involves 177lu, a beta-emitting radionuclide, as the targeted radiation by conjugating with somatostatin receptor analogue. many reports have documented the symptom relief and stable radiographic findings after 177lu-dotatate prrt treatment, particularly in orbital metastasis.6,13,18 conclusion orbital metastasis originating from a carcinoid tumour is rare yet may compromise patients’ quality of life. therefore, early detection and treatment are needed to prevent incapacitating visual loss. a multidisciplinary team approach is required for optimal treatment and patient outcome. references 1. isidori am, kaltsas g, frajese v, kola b, whitelocke ra, plowman pn, et al. ocular metastases secondary to carcinoid tumors: the utility of imaging with [(123)i]meta-iodobenzyl guanidine and [(111)in]dtpa pentetreotide. j clin endocrinol metab 2002; 87:1627–33. https://doi.org/10.1210/jc.87.4.1627. 2. godwin jd 2nd. carcinoid tumors. an analysis of 2,837 cases. cancer 1975; 36:560–9. https://doi.org/10.1002/1097-0142(197 508)36:2<560::aid-cncr2820360235>3.0.co;2-4. https://doi.org/10.1002/%28sici%291097-0142%2819970215%2979:4%3c813::aid-cncr19%3e3.0.co%3b2-2 https://doi.org/10.1002/%28sici%291097-0142%2819970215%2979:4%3c813::aid-cncr19%3e3.0.co%3b2-2 https://doi.org/10.1016/s0161-6420%2894%2938030-4 https://doi.org/10.1016/s0161-6420%2894%2938030-4 https://doi.org/10.4251/wjgo.v5.i8.177 https://doi.org/10.4251/wjgo.v5.i8.177 https://doi.org/10.1200/jco.2012.45.8612 https://doi.org/10.1002/hed.21498 https://doi.org/10.1016/j.ophtha.2005.10.051 https://doi.org/10.1016/j.ophtha.2005.10.051 https://doi.org/10.1080/01676830902897470 https://doi.org/10.1080/01676830902897470 https://doi.org/10.1007/bf01081525 https://doi.org/10.1007/bf01081525 https://doi.org/10.1007/bf00173045 https://doi.org/10.1007/bf00173045 https://doi.org/10.1186/s40644-018-0181-5 https://doi.org/10.1001/archopht.1990.01070130092038 https://doi.org/10.1001/archopht.1990.01070130092038 https://doi.org/10.1016/0002-9394%2880%2990279-2 https://doi.org/10.1016/s0002-9394%2814%2973026-0 https://doi.org/10.1016/0002-9394%2879%2990067-9 https://doi.org/10.1016/0002-9394%2879%2990067-9 https://doi.org/10.1097/rlu.0000000000001008 https://doi.org/10.1210/jc.87.4.1627 https://doi.org/10.1002/1097-0142%28197508%2936:2%3c560::aid-cncr2820360235%3e3.0.co%3b2-4 https://doi.org/10.1002/1097-0142%28197508%2936:2%3c560::aid-cncr2820360235%3e3.0.co%3b2-4 squ med j, may 2011, vol. 11, iss. 2, pp. 230-235, epub. 15th may 11 submitted 27th nov 10 revision req. 2nd feb 11, revision recd. 17th feb 10 accepted 2nd mar 10 department of cardiology, college of medicine, king khaled university, abha, saudi arabia. *corresponding author email: aassiri@yahoo.com <g◊œ÷]<öáíœ<óïüπ<ìèq¯√÷]ê<ìëüëüä÷]<ì◊“^é÷] ín÷^m<óàéjä⁄<±c<‹7^}åc<#<‡ëñ÷] dìëåá√ä÷]<ìèeü√÷]<ì”◊€π]e<4ä¬<ìœ�fl⁄<ª<    300  2009 31 2007 1 %68.713.7 ± 67.4 %33.3%38.3     %13%9.7%61.3 17 ± %33%98.7%48.3 %28.3%51.6   %68.3 2     %33     :مفتاح الكلمات abstract: objectives: this study aimed to investigate the clinical and therapeutic profiles of heart failure (hf) cases admitted to aseer central hospital (ach), saudi arabia. methods: a retrospective cohort of 300 consecutive patients admitted with the diagnosis of hf to ach from 1 june 2007 to 31 may 2009 were included in the study. data on demographic variables, aetiologic factors, risk factors, and therapeutic profiles of patients with hf were collected and analysed. results: the patients’ mean age was 67.4 ± 13.7 years and 68.7% of them were male. the commonest aetiologies for hf were ischaemic heart disease (ihd) and hypertension in 38.3% and 33.3% of patients, respectively. a total of 61.3% of patients were diabetics. other risk factors for hf included renal failure in 9.7%, atrial fibrillation in 13%, and anaemia in 48.3% of patients. echocardiography was performed in 98.7% of cases: the average ejection fraction (ef) was 33% ± 17. angiotensin converting enzyme inhibitors (acei) or angiotensin 2 receptor blockers were used in 68.3% of cases, β-blockers in 51.6% of cases and digoxin in 28.3% of cases. conclusion: the major causes of hf in our study were ihd and hypertension. diabetes and anaemia were common risk factors. the cohort constituted an intermediate hf risk group (ejection fraction (ef) 33%). important therapeutic agents like angiotensin converting enzyme inhibitor i, β-blockers and digoxin were underutilised. fostering such therapy in practice will lead to a better outcome in the management of hf patients. anaemia was a significant risk factor in our hf patients and should be managed properly. keywords: heart failure; therapeutics; saudi arabia clinical and therapeutic profiles of heart failure patients admitted to a tertiary hospital, aseer region, saudi arabia abdullah s assiri clinical & basic research advances in knowledge 1. this study provides information on the pattern and aetiology of heart failure in saudi arabia and the pattern of risk factors for heart failure in saudi population. 2. it highlights the underutilisation of important drug therapies in heart failure for saudi patients. abdullah s assiri clinical and basic research | 231 heart failure (hf) is defined as a complex syndrome resulting from inability of the heart to meet peripheral tissues metabolic demands at a normal filling pressure.1 it is a common final pathway of many chronic disorders namely hypertension, diabetes, and ischaemic heart disease (ihd).2 the global prevalence of heart failure varies from 2.3% to 3.9% per annum.3-5annually, an estimated 23 million people have heart failure worldwide and 2 million new cases are diagnosed each year. due to therapeutic improvement in the treatment of acute myocardial infarction and hypertension and improved survival, the incidence of heart failure has increased and become a real public health issue.2,6-7 it is characterised by decreased quality of life with high morbidity and mortality. the hf mortality rate is approximately 25% within one year of initial diagnosis.3-5,8 the aetiology of hf varies from different reports around the world, but ischaemic heart disease, hypertension, rheumatic heart disease and to a lesser extent cardiomyopathy and anaemia are the leading causes of hf. ischaemic heart disease is becoming a major leading cause of heart failure in developed countries, where more than two thirds of hf cases are due to ihd.9,10 despite clear evidence of the beneficial effect of certain therapeutic agents like angiotensin converting enzyme inhibitors (acei,) β-blockers and k-sparing diuretics on survival, these agents continue to be underutilised globally.11 the aseer region (population 1,200,000) is located in the southwest of saudi arabia covering an area of more than 80,000 km2. the region extends from the high mountains of sarawat (with an altitude of 3,200 m above the sea level) to the red sea. health services delivery in aseer region is provided by a network of 244 primary health care centers, 16 referral hospitals and one tertiary hospital, aseer central hospital (ach). ach, with 500 beds, is run by the ministry of health and the college of medicine of king khalid university (kku), abha. we aimed in this study to analyse the demographic data, clinical and therapeutic profiles of patients admitted with the diagnosis of heart failure to aseer central hospital (ach) and to find out how close we were to the recommended international standards of management of heart failure. methods a retrospective cohort of all consecutive patients admitted to aseer central hospital (ach) with the diagnosis of heart failure according to medical records, during the two-year period 1 june 2007 to 31 may 2009, were included in this study. approval of the local medical ethical committee was obtained. demographic data, underlying aetiologies, risk factors for heart failure (diabetes, hypertension, anaemia, atrial fibrillation and renal failure), echocardiographic features and ejection fraction (ef) values were collected. conventionally patients with ef < 30% were labelled as having severe left ventricular dysfunction, 30–44 % as moderate left ventricular dysfunction, and 45–54% as mild left ventricular dysfunction.12 records on all medications used conventionally for treatment of heart failure were collected. the main angiotensin converting enzyme (ace) inhibitor agent used was captopril, and the target recommended dose was considered to be one 50 mg tablet taken three times a day, with any lower dose considered to be below the target dose.13 the main β-blocker agent used was carvedilol and the target recommended dose was considered to be one 25 mg tablet taken twice daily, with any lower dose considered to be below the target dose.14 data were analysed using the statistical package for the social sciences (spss) software package (version 15.0). frequency, percentage, mean, standard deviation and median were used to present the data. application to the patient care 1. this study highlights the need to improve the use of proven important drug therapies for heart failure. 2. physicians should recognise and address the problem of drug underutilisation in heart failure management. 3. the study also provides information on important risk factors for heart failure development and how to improve their prevention. clinical and therapeutic profiles of heart failure patients admitted to a tertiary hospital, aseer region, saudi arabia 232 | squ medical journal, may 2011, volume 11, issue 2 results the present study included 300 patients with the diagnosis of heart failure. the age ranged from 26 to 101 years with an average 67.4 ± 13.7 years. a total of 206 patients (68.7%) were male. the commonest aetiology for heart failure was ihd in 38.5% of cases followed by hypertension in 33.3 % of cases. other aetiologies included dilated cardiomyopathy in 10% and valvular heart disease in 3% of patients. the commonest risk factors were diabetes in 61.3%, hypertension in 59% and anaemia in 48.3% of patients. other risk factors were atrial fibrillation in 13% and renal failure in 9.7% of patients. table 1 shows the demographic and clinical characteristics of heart failure patients in aseer region, saudi arabia. echocardiography was performed in 98.75% of patients and the average ef was 33% ± 17 for the study group. our patients lay in the moderate left ventricular dysfunction group. table 2 shows the distribution of heart failure patients according to their ejection fraction values. table 3 shows the frequency of types of treatment used in hf patients in the study cohort. the use of acei or angiotensin 2 receptor blockers (a2rb) was reported in 68.3% of patients, and among patients on acei, the majority (91.85%) were on lower than the target dose, thus only 8.15 % of patients were on the recommended target dose. captopril was the main acei agent used in this cohort. the rate of use of β-blockers in our study was 51.6%. among those patients prescribed this treatment, 82% were on lower than the target dose, thus only 18% were on the recommended target dose. carvedilol was the main β-blocker agent used in this cohort. other heart failure medications used were digoxin for 28.3% of patients; loop diuretics for 87%; k-sparing diuretics for 45.3%; vasodilator therapy (hydralazine or calcium channel blockers) for 13%; warfarin for 16%, and amiodarone for 1.3%. discussion the literature on clinical and therapeutic profiles of heart failure patients in saudi arabia is scarce. this makes it difficult to plan policies for the prevention and management of heart failure in saudi arabia. the only study in neighbouring countries was the omani study which included 1,164 patients with symptomatic heart failure and showed a prevalence of heart failure in an arab population to be 5.17/1,000 population.15 in our series, the mean age was 67.4 years which is similar to the framingham series of a western population, where the most susceptible age for the onset of hf was 60 years and older.16 in our cohort, more than two thirds of patients were older than 60 years. ihd and hypertension were the commonest aetiology of heart failure in our series, this concurs with similar findings both the framingham16 and the omani study.15 among risk factors for heart failure, we found the incidence of diabetes in our group to be high (61.3%); this data corroborates well with al-nozha’s findings of a high prevalence of diabetes in saudi society.17 an important relevant finding in our study table 1: demographic and clinical characteristics of heart failure patients in aseer region, saudi arabia demographic/clinical characteristic no ( % ) age, ( mean ± sd) 67.4 ± 13.7 ≥ 60 years, no (%) 228 (76%) male gender 206 (68.7%) aetiology ischaemic cardiomyopathy hypertensive heart disease dilated cardiomyopathy valvular heart disease 115 (38.3%) 100 (33.3%) 30 (10%) 9 (3%) risk factors diabetes hypertension anaemia atrial fibrillation renal failure 184 (61.3%) 177 (59%) 145 (48.3%) 39 (13%) 29 (9.7%) table 2: distribution of heart failure patients by ejection fraction value type of lvd no (%) mild lvd (ef 45-54%) 29 (9.7%) moderate lvd (ef 30-44%) 83 (27.7%) severe lvd (ef < 30%) 141 (47%) normal (ef ≥ 55%) 43 (14.3%) echocardiography was not done 4 (1.3%) legend: lvd = left ventricular dysfunction; ef = ejection fraction abdullah s assiri clinical and basic research | 233 is the high prevalence of anaemia (defined as haemoglobin level less than 12 gm/dl in females and less than 13 gm/dl in males according to the who definition).18 in our series, anaemia was detected in 48.3% of patients with heart failure. evidence from previous studies showed that anaemia is a long term predictor of poor prognosis in patients with severe heart failure.19 this group of patients requires special attention as correcting their anaemia will improve their clinical and haemodynamic status. the reasons for this relatively high prevalence of anaemia in our cohort could be due to different factors among them the fact that the assir region is considered to be one of the major pockets of sickle cell genes in saudi arabia.20 other important risk factors for heart failure include atrial fibrillation and renal failure which we found in our series (13% and 9.7% respectively); similar incidences of these two disorders were reported in other studies.7 these disorders were found to contribute to a high need of hospitalisation for elderly patients with heart failure.21,22 the rate of echocardiography performance was adequate in our series where the vast majority of heart failure patients (98.7%) underwent echocardiographic assessment. the majority of our patients were in the moderate risk group according to the ef value categorisation. in large trials, acei was clearly found to improve survival, functional capacity and to reduce the need for hospitalisation when given to heart failure patients.23-25 despite these studies, the drugs are underutilised and, when used, the optimal dose is not achieved.24-28 in the current study, only 68.3% of heart failure patients were prescribed acei, and the majority of them were not on the recommended target dose. in contrast to this finding, in the usa acei is used in 89% of patients with heart failure.29 this low rate of use in our cohort can be due to several factors: 1) lack of awareness of the important role of acei in improving mortality in hf patients; 2) inappropriate broadening of the scope of the contraindications by clinicians; 3) lack of adherence to the recommended guidelines; 4) patient’s poor compliance with medications, or the economic cost of prescribing multiple medications to heart failure patients. similar findings regarding the underutilisation of ace inhibitors in heart failure patients was observed in other studies and multiple factors were found to contribute to such a practice; among these were the older age of patients, the presence of renal dysfunction, the presence of only diastolic dysfunction, and the substandard quality of care given to heart failure patients.30 β-blockers were found to reduce mortality and frequency of hospital admissions when given to patients with heart failure.14,31-32 the meta analysis of 21 trials showed that β-blockers improve left ventricular ejection fraction by 25%.33 in our study, we found only 51.6% of hf patients were prescribed β-blockers, and the majority of those were not on the recommended target dose. the same reasons postulated for acei underutilisation can be applied to the underutilisation of β-blockers. digoxin was found to decrease the need for admissions, but did not reduce mortality when given to patients with heart failure.34-36 digoxin was used in only 28.3% of our cohort which is lower than the rate reported in the usa (50%).29 this low rate in our series could be due to clinicians giving more priority to drugs that reduce mortality only and less importance to drugs that only improve morbidity. the use of oral anticoagulation warfarin in hf patients, especially those with severe left ventricular dysfunction, was found to reduce stroke, sudden death, and myocardial infarction.37 in large hf trials like solvd (study of left ventricular dysfunction), oral anticoagulation warfarin was used in 12% of patients.38 in our series, it was used in 16% of patients which is close to the international figure. amiodarone was found to reduce arrhythmia, table 3: frequency of types of drugs used in treatment of heart failure patients drugs no (%) loop diuretics 261 (87%) acei (angiotensin converting enzyme inhibitor) or a2rb (angiotensin 2 receptor blockers) 205 (68.33%) β-blockers 155 (51.7%) k-sparing diuretics 136 (45.3%) nitrates 91 (30.3%) digoxin 85 (28.3%) warfarin 48 (16%) hydralazine 21 (7%) amplodipine 18 (6%) amiodarone 4 (1.3%) clinical and therapeutic profiles of heart failure patients admitted to a tertiary hospital, aseer region, saudi arabia 234 | squ medical journal, may 2011, volume 11, issue 2 but not mortality, in hf patients.39 the rate of amiodarone use in large hf trials was 14.4%.38 which is clearly higher than our rate of 1.3%. the reason for such a discrepancy is not obvious. the observed underutilisation of different evidence-based therapeutic agents for the treatment of heart failure patients in our cohort was also reported in other larger studies such as the euro heart survey on heart failure.40 conclusion in conclusion, we believe that this study shed some light on the clinical and the therapeutic profile of hf patients treated in the tertiary hospital in aseer region, saudi arabia. it has shown that ihd and hypertension were the leading causes of hf in this cohort. diabetes is a highly prevalent risk factor and anaemia is a significant problem in our hf patients and should be corrected. furthermore, this study showed underutilisation of the important treatment modalities used for hf, mainly acei, β-blockers and digoxin, and when used, the doses were not optimal. awareness of this data will contribute to improvement in management of hf patients and encourage clinicians to adhere to the recommended guidelines for hf management. this study also calls for an urgent need to establish a national registry for heart failure in saudi arabia in order to evaluate the economic burden of such a common medical disorder and therefore plan a better health care system. c o n f l i c t o f i n t e r e s t the author reported no conflict interest. a c k n o w l e d g m e n t s the author would like to thank the following colleagues from the college of medicine, abha, saudi arabia for their assistance with this paper: dr ahmed a. mahfouz, professor of epidemiology, department of family & community medicine for statistical consultation and dr. awad ahmed el-mekki, department of medicine for english language revision. references 1. hunt sa, baker dw, chin mh, konstam m, dracup k, baker d, et al. report of the acc/aha guidelines for the evaluation and management of chronic heart failure in the adult. circulation 2001; 104:2996. 2. neto jmr. a dimensão do problema da insuficiência cardíaca do brasil e do mundo (dimension of the problem of heart failure in brazil and the world). rev soc esp 2004; 14:1−7. 3. mckee pa, castelli wp, mcnamara pm, kannel wb. the natural history of congestive heart failure: the framingham study. n engl j med 1971; 285:1441−6. 4. mcmurray jjv, stewart s. epidemiology, aetiology, and prognosis of heart failure. heart 2000; 83:596− 602. 5. mosterd a, hoes aw, de bruyne mc, deckers jw, linker dt, hofman a, et al. prevalence of heart failure and left ventricular dysfunction in the general population. eur heart j 1999; 20:447−55. 6. sociedade brasileira de cardiologia. ii diretrizes da sociedade brasileira de cardiologia para o diagnóstico e tratamento da insuficiência cardíaca (brazilian society of cardiology. ii guidelines of the brazilian society of cardiology for the diagnosis and treatment of heart failure). arq bras cardiol 1999; 72:4−30. 7. barretto acp, nobre mcr, wajngarten m, canesin mf, ballas d, serro-azul jb. insuficiência cardíaca em grande hospital terciário de são paulo (heart failure in large tertiary hospital in são paulo). arq bras cardiol 1998; 71:15−20. 8. mcmurray j, mcdonagh t, morrison ce, dargie hj. trends in hospitalization for heart failure in scotland 1980-1990. eur heart j 1993; 14:1158−62. 9. sutton gc. epidemiologic aspects of heart failure. am heart j 1990; 120:1538−40. 10. cowie mr. annotated references in epidemiology. eur j heart failure 1999; 1:101−7. 11. lenzen mj, boersma e, reimer wj, balk ah, komajda m, swedberg k, et al. under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the euro heart survey on heart failure. eur heart j 2005; 26:2706−13. 12. roberto ml, michelle b, richard bd, frank af, elyse f, patricia ap, et al. recommendations for chamber quantification: a report from the american society of echocardiography’s guidelines. j am soc echocardiogr 2005; 18:1440−1463. 13. pitt b, segal r, martinez fa, meurers g, cowley aj, thomas i, et al. randomized trial of losartan versus captopril in patients over 65 with heart failure (evaluation of losartan in the elderly study, elite). lancet 1997; 349:747−52. 14. packer m, fowler mb, roecker eb, coats aj, katus ha, krum h, et al. for the carvedilol prospective randomized cumulative survival (copernicus) study group. effect of carvedilol on the morbidity of abdullah s assiri clinical and basic research | 235 patients with severe chronic heart failure results of the carvedilol prospective randomized cumulative survival (copernicus) study. circulation 2002; 106:2194. 15. agarwala ak, venugopalana p, de bonob d. prevalence and aetiology of heart ailure in an arab population. eur j heart fail 2001; 3:301−305. 16. ho kkl, pinsky jl, kannel wb, levy d. the epidemiology of heart failure: the framingham study. j am coll cardiol 1993; 22:6−13. 17. al-nozha mm, al-maatouq ma, al-mazrou yy, al-harthi ss, arafah mr, khalil mz, et al. diabetes mellitus in saudi arabia. saudi med j 2004; 25:1603−10. 18. world health organization. worldwide prevalence of anaemia 1993–2005. geneva: world health organization, 2008. from: http://whqlibdoc.who. int/publications/2008/9789241596657_eng .pdf. accessed: march 2009. 19. bacal f, freitas jr af. o que acrescentar após inibidor da enzima conversora da angiotensina, betabloqueador e espironolactona na insuficiência cardíaca sintomática? (what happens after adding angiotensin converting enzyme inhibitor, betablockers and spironolactone in symptomatic heart failure?) rev soc esp 2008; 18:16−22. 20. el hazmi maf. hemoglobin disorder: pattern for thalassemia and haemoglobinopathies in saudi arabia. acta haematol 1982; 68:43−51. 21. freiberger l, heinisch rh, bernardi a. estudo de internações por cardiopatias em um hospital general (study of hospitalizations for heart disease in a general hospital). acm arq catarin med 2004; 33:25−30. 22. coelho fac, moutinho mae, miranda va, tavares lr, rachid m, rosa mlg, et al. associação da síndrome metabólica e seus componentes na insuficiência cardiac encaminhada da atenção primária (association of metabolic syndrome and its components in heart failure referred from primary). arq bras cardiol 2007; 89:42−51. 23. lechat p. prevention of heart failure progression: current approaches. eur heart j 1998; 19:12−8. 24. consensus trial study group: effects of enalapril on mortality in severe congestive heart failure results of the cooperative north scandinavian enalapril survival group (consensus). n engl j med 1987; 316:1429−35. 25. greenberg b, quinones ma, koilpillai c, limacher m, shindler d, benedict c, et al. effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. results of the solvd echocardiography substudy. circulation 1995; 91:2573−81. 26. cody rj. management of refractory heart failure. am j cardiol 1992; 4:141g−9g. 27. pitt b. use of “xapril” in patients with chronic heart failure: a paradigm of epitaph for our times? circulation 1994; 90:1550−1. 28. gheorghiade m, bonow ro. chronic heart failure in the us: a manifestation of coronary artery disease. circulation 1998; 97:282−9. 29. rich mw, brooks k, luther p. temporal trends in pharmacotherapy for congestive heart failure at an academic medical center: 1990-1995. am heart j 1998; 135:367−72. 30. philbin ef. factors determining angiotensinconverting enzyme inhibitor underutilization in heart failure in a community setting. clin cardiol 1998; 21:103−8. 31. waagstein f, bristow mr, swedberg k, camerini f, fowler mb, silver ma, gilbert em, et al. beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. lancet 1993; 342:1441−6. 32. cibis investigators and committees. a randomized trial of beta-blockade in heart failure: the cardiac insufficiency bisoprolol study (cibis). circulation; 1994; 90:1765− 73. 33. leizorovicz a, lechat p, cucherat m, bugnard f. bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies cibis and cibis ii. cardiac insufficiency bisoprolol study. am heart j 2002; 143:301−7. 34. the digitalis investigation group. the effect of digoxin on mortality and morbidity in patients with heart failure. n engl j med 1997; 336:525−33. 35. packer m, gheorghiade m, young jb, costantini pj, adams kf, cody rj, et al. withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. n engl j med 1993; 329:1−7. 36. uretsky bf, young jb, shahidi fe. randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the proved trial. j am coll cardiol 1993; 22:955−62. 37. dries dl, domanski mj, waclawiw ma, gersh bj. effect of antithrombotic therapy on risk of sudden coronary death in patients with congestive heart failure. am j cardiol 1997; 79:909−13. 38. the solvd investigators: effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. n engl j med 1991; 325:293−302. 39. nul dr, doval hc, grancelli ho, varini sd, soifer s, perrone sv, et al. on behalf of the gesica-gema investigators. heart rate is a marker of amiodarone mortality reduction in severe heart failure. j am coll cardiol 1997; 29:1199−205. 40. drechsler k, dietz r, klein h, wollert kc, storp d, molling j, et al. euro heart failure survey. medical treatment not in line with current guidelines. z kardiol 2005 : 94:510−5. squ med j, february 2012, vol. 12, iss. 1, pp. 77-85, epub. 7th feb 12. submitted 3rd may 11 revision req. 1st jun 11, revision recd. 23rd jul 11 accepted 27th aug 11 departments of 1pharmacology and 3biochemistry, gulf medical university, ajman, united arab emirates; 2research division, gulf medical university, ajman, united arab emirates. *corresponding author e-mail: shehnazilyas@yahoo.com آراء أعضاء هيئة التدريس والطالب لتجربة تغيري املنهاج الدراسي لكلية الطب بدولة اإلمارات العربية املتحدة �سيـد �ساهيناز، جيدافن �رصيدهاران، كادايام جوماثي امللخ�ص: الهدف: يف عام 2008 قامت جامعة اخلليج الطبية بدولة الإمارات العربية املتحدة بتغيري نظام التدري�س فيها، فاأ�سبح املنهاج متداخال ومعتمدا على درا�سة اأجهزة اجل�سم كوحدة متكاملة بدًل من املنهاج القدمي املعتمد على درا�سة املواد الدرا�سية بطريقة منف�سلة. تهدف هذه الدرا�سة اإىل مقارنة مدى تقّبل اأع�ساء هيئة التدري�س والطالب للمنهاج اجلديد. الطريقــة: مت جمع املعطيات من اأع�ساء هيئة التدري�س وطالب الطب يف ال�سنة الثانية حول املنهاج اجلديد با�ستخدام مقيا�س دندي اجلاهز للبيئة التعليمية، وجرى حتليل املعطيات اإح�سائيا بوا�سطة برنامج التحليالت التنبوؤية، الإ�سدار 18، وكذلك ا�ستخدمنا برنامج حم�سلة رتبة ولكوك�سن للعالمات العامة واخلا�سة، بينما ا�ستخدمنا فح�س )ز( للن�سب. النتائج: وجدنا عدم وجود فرق اإح�سائي معتّد بني تقّبل اأع�ساء هيئة التدري�س )200/135( والطالب وقدرة فر�س من زاد قد اجلديد املنهاج باأن التدري�س هيئة اأع�ساء لدى اإح�سا�س وجود مع اجلديد، املتداخل للمنهاج )200/139( الطالب على التعلم الإيجابي كما تبني ذلك من "اإدراك الطالب للتعلم". وظهر اأّن هناك اتفاقا بني اأع�ساء هيئة التدري�س والطالب مفاده اأّن اأع�ساء هيئة التدري�س يت�سورون اأن هناك حاجة اأكرث اإىل زيادة التغذية الراجعة للطالب وزيادة الرتكيز على التعلم على املدى الطويل. اخلال�صة: اأظهرت الدرا�سة اأن كال من اأع�ساء الهيئة التدري�سية والطالب لديهم اإدراك مماثل حول جتارب الطالب يف املنهاج اجلديد، ومن املجالت التي كانت ت�ستلزم تدابري عالجية هي حاجة اأع�ساء هيئة التدري�س لتعلم تقنيات التغذية الراجعة البّناءة والرتكيز على التعّلم على املدى الطويل يف املناهج اجلديدة. مفتاح الكلمات: املنهاج، التعليم الطبي الأويل، طالب الطب، هيئة التدري�س الطبي، اإدراك. abstract: objectives: in 2008, the gulf medical college in the united arab emirates underwent a curricular change from a discipline-based to an organ-system-based integrated curriculum. in this context, this study aimed to compare the faculty and students’ perceptions of the student experiences with the new curriculum. methods: data were collected from faculty and second-year students in the integrated curriculum using the dundee ready education environment measure (dreem). data collected were transferred to predictive analytics software, version 18. global and domain scores were assessed with the wilcoxon rank-sum test. percentage agreement, disagreement and uncertainty were assessed by the z-test for proportion. results: there were no significant differences between the total dreem scores of faculty (139/200) and students (135/200). the faculty perceived that the students were experiencing significantly more positive learning as indicated by the domain score of “students' perceptions of learning”. proportions of agreement between faculty and students showed that more faculty members than students perceived the need for increased feedback to students and a greater emphasis on long term learning. conclusion: the study showed that the faculty and students had similar perceptions about the student experiences in the integrated curriculum. areas necessitating remedial measures were the need for faculty to learn constructive feedback techniques and an emphasis on long term learning in the new curriculum. keywords: curriculum; undergraduate medical education; medical students; medical faculty; perception. faculty and students’ perceptions of student experiences in a medical school undergoing curricular transition in the united arab emirates *syed i shehnaz,1 jayadevan sreedharan,2 kadayam g gomathi3 clinical & basic research advances in knowledge 1. this is the first study in gulf cooperation council countries comparing perceptions of students and faculty regarding student experiences in an integrated medical curriculum. faculty and students’ perceptions of student experiences in a medical school undergoing curricular transition in the united arab emirates 78 | squ medical journal, february 2012, volume 12, issue 1 the educational environment of a medical school has considerable bearing on students’ learning, academic progress, and well-being.1-3 a conducive educational environment will result in positive learning outcomes.1 the connection between the learning environment and the curriculum is robust. the “curriculum's most significant manifestation and conceptualization is the environment, educational and organizational, which embraces everything that is happening in the medical school”.1 following in-depth reviews in 2008 of the existing curriculum at the gulf medical college, in ajman, united arab emirates (uae), which revealed major weaknesses, a major curricular change was introduced from a traditional disciplinebased curriculum to a modular, organ-systembased integrated curriculum with elements of problem-based learning (pbl). the new curriculum accentuates student-centered learning with more interactive teaching/learning sessions such as small group learning, computer-aided learning, case-based learning and pbl. the language of instruction remains english as in the previous curriculum. the first year involves an introduction to medical sciences beginning with courses like cells, molecules and genes and then moving on to more in-depth courses such as tissues and organs; embryogenesis and life cycle; metabolism and nutrition, and internal and external environment. courses like language and communication skills and psychosocial sciences introduce the students to various aspects of the delicate doctor-patient relationship. the next two years are dedicated to the integrated study of organ systems. the final two years are the clinical clerkship phase which is followed by a one-year compulsory rotating internship. students’ perceptions of the educational environment have been explored in depth,4-7 but the same attention has not been paid to teachers’ perceptions. faculty perceptions of the educational environment will have a strong bearing on the learning environment of the students.1 as the learning environment is an important determinant of the behaviour of both students and teachers, a comparative study of the perceptions of the teaching faculty and the students will enable the development of guidelines to improve the quality of the educational environment in any institution. such a study would also help ascertain whether the faculty perceptions of student experiences in the new integrated curriculum actually align with those of the students. subsequently, these findings will probably reveal the strengths and weaknesses of a newly introduced curriculum with the findings contributing to the ultimate aim of refining it. the aim of this study was to compare the faculty members’ and students’ perceptions of the student experiences after one year of study in the newly introduced organ-system based integrated curriculum at the gulf medical college, ajman, uae. methods the dreem questionnaire, which has universal face validity4,7 and high reliability,6,8 has been used to assess the learning environment as perceived by students.4-7 this questionnaire has identified the perceived weaknesses of a new curriculum3 and has been used to compare the educational environment in two different curricula.7,9 in a uk medical school, a modified version of the dreem inventory10 was used to compare the perceptions of teachers and students. the dreem inventory comprises 50 items divided into 5 domains which are 1) students' perceptions of learning (spl) 12 items (max. score 48); 2) students' perceptions of teachers (spt) 11 items (max. score 44); 3) students' academic selfperceptions (sap) 8 items (max. score 32); 4) students' perceptions of atmosphere (spa) 12 items (max. score 48); 5) students' social self-perceptions 2. perceptional differences highlighted by this study give insights into the differences between the intended curriculum and that which is actually implemented. 3. constructive feedback techniques and more emphasis on long-term learning were areas identified as requiring remedial intervention. application to the patient care 1. the insights gained from this study into student and faculty perceptions of student experiences should help in the design of better curricular strategies to maximise the learning of future physicians. it should ultimately improve the quality of health care which they will subsequently deliver. syed i shehnaz, jayadevan sreedharan, kadayam g gomathi clinical and basic research | 79 (ssp) 7 items (max. score 28). the total score for all domains is 200. each item is scored from 0–4 with 4 = strongly agree; 3 = agree; 2 = unsure; 1= disagree; 0 = strongly disagree. nine negative items are scored in reverse for analysis. the dreem questionnaire was pilot tested on a sample of our students and faculty. following the pilot study, descriptive phrases were added to some items of the questionnaire for better understanding. as the dreem questionnaire was originally developed to give only the students’ perceptions of the educational environment. the faculty dreem questionnaire was modified in our study to assess the perceptions of the faculty about the student experiences in our institution. (i feel comfortable in class socially was modified to the students feel comfortable in class socially). the questionnaire was administered to 44 second year students in the integrated curriculum at the gulf medical college at the beginning of the 2009 academic year. brief explanations of the objectives and the method of filling out the questionnaire were given. the 28 faculty members of the gulf medical college, teaching in the integrated curriculum of the bachelor of medicine, bachelor of surgery (mbbs) programme, were given details of the objectives. they were informed that their perceptions should be about the students’ experiences in the previous academic year. they were encouraged to answer items regarding students’ personal views of the environment (e.g. students have good friends in this school), or which were outside the context in which the staff dealt with the students (e.g. teachers are patient with the hospital patients) as “unsure”. voluntary participation was stressed for both the sample groups. the dreem questionnaire was answered anonymously by both students and faculty. the study was approved by the ethics review committee of the institution. data were analysed using the statistical package predictive analytics software (version 18, ibm, illinois, chicago, usa). the mean global scores and domain scores were expressed as mean ± standard deviation (sd). the comparison of scores was done using the wilcoxon rank-sum test. a p value of less than 0.05 was considered statistically significant. we also analysed the domain scores based on the interpretation suggested by mc aleer and roff.11 as there were items in the dreem questionnaire on the personal views of the students, we anticipated a large number of “unsure” responses by the faculty.” hence, to weed out the actual differences between the student and faculty responses, the responses to each individual item of the questionnaire were classified into three categories: ‘agreement’ (strongly agree/agree), ‘disagreement’ (strongly disagree/disagree) and ‘unsure’ (unsure); they were compared using the z-test for proportion with a significance level of 0.05. results the response rate for the faculty was 93% and all students present in the class on the day of the survey responded (93% of all second year students). the characteristics of the sample are given in table 1. the total dreem scores for the faculty and the students table 1. demographics of the study sample variable faculty students gender male 10 (36%) 17 (39%) female 18 (64%) 27 (61%) age (yrs) (mean ± standard deviation) male 49.4±8.7 yrs 20.6±2.2 yrs female 44.4±9.0 yrs 19.5±1.7 yrs teaching experience (yrs) ≤10 yrs 9 (32%) 11–36 yrs 19 (68%) department preclinical 23 (82%) clinical 5 (18%) table 2: mean ± standard deviation dundee ready education environment measure (dreem) domain scores (% of maximum score) for faculty and students domain faculty student students’ perception of learning (spl) 36.89±4.34 (76.9%)* 33.36±5.21 (69.5%) students’ perception of teachers (spt) 31.68±4.60 (72%) 29.98±5.08 (68%) students’ academic selfperception (sap) 21.25±3.34 (66.4%) 22.41±4.13 (70%) students’ perceptions of atmosphere (spa) 32.57±4.80 (67.9 %) 31.45±7.17 (65.5%) students’ social selfperceptions (ssp) 16.57±2.86 (59.2%) 18.20±4.66 (65%) total dreem score for the group 138.96±15.51 (69.5%) 135.4±22.1 (67.7%) *p = <0.001 faculty and students’ perceptions of student experiences in a medical school undergoing curricular transition in the united arab emirates 80 | squ medical journal, february 2012, volume 12, issue 1 was 139/200 and 135/200 respectively. the mean domain scores obtained by faculty and students are shown in table 2. the domain scores of students' perceptions of teachers in the range 23–33 revealed that both the groups perceived “moving in the right direction” for the teachers; scores between 17–24 for students' academic self-perceptions showed “feeling more on the positive side” for the academic self-perception; scores between 25–36 for students' perceptions of atmosphere indicated “a more positive atmosphere” and scores between 15–21 for students' social self-perceptions suggested “not too bad” for the social self-perceptions. as the domain score of students' perceptions of learning for faculty was 36.8, they perceived “teaching highly thought of ” while the students perceived “a more positive approach” for the learning (students' perceptions of learning score of 33.4). the mean domain score for this domain (spl) was significantly higher for the faculty as compared to the students (p < 0.001). the faculty identified perception of learning as the domain with the highest mean score, whereas the students gave the highest scores to the domains perception of learning and academic self-perceptions. both groups gave the lowest mean scores to the domain social self-perceptions. there was consensus between the faculty and students with respect to percentage agreement, disagreement and uncertainty. on comparison of percentage agreement, the faculty tended to agree significantly more than the students for two items: #47 long term learning is given importance over short term learning, and #29 the teachers are good at providing feedback to students. on the other hand, the students tended to agree significantly more than the faculty for 9 items: #6 the teachers are patient with the hospital patients; #18 the teachers have good communication skills with hospital patients; #10 the students are confident about passing this year; #26 the students’ last year’s work has been a good preparation for this year’s work; #31 the students have learned a lot about empathy in this profession; #11 the atmosphere is relaxed during the hospital ward teaching; #15 the students have good friends in this school; #19 the students’ social life is good, and #46 the students’ accommodation is pleasant [tables 3 & 4]. analysis of percentage uncertainty identified two items for which faculty were significantly unsure as compared to the students: #11 the atmosphere is relaxed during the hospital ward teaching and #46 the student’s accommodation is pleasant. discussion the educational environment is the soul and spirit of the medical curriculum.1 the success of an effective curriculum depends on a positive educational environment. a curricular modification will customarily affect the educational environment. hence, we anticipated a positive change in the learning environment of our institution due to a shift to a more student-centered curriculum. for curricular change to be a successful, the commitment of the faculty must be ensured. faculty perceptions of the changed educational environment could not be assessed due to the lack of an appropriate instrument, so we dealt with this problem by modifying the dreem questionnaire and using it to assess the perceptions of the faculty about student experiences in our school. the same instrument was used to investigate whether the views of the faculty and students were univocal with respect to the student experiences in the new integrated curriculum. we had an acceptable response rate of 93% for both the faculty and students. we found that the total dreem mean scores of our faculty (139/200) and students (135/200) were lower than that found by miles and leinster10 (144/200 for staff and 141/200 for students). the results of the present study show that both the faculty and students had positive perceptions of the student experiences in the educational environment, which is similar to that reported by miles and leinster.10 these higher scores can be ascribed to the student-centered curricular change which is fully endorsed both by the faculty and the students. the faculty in our study perceived that the students were experiencing significantly more positive learning as indicated by the domain score of students' perceptions of learning. proportions of agreement between faculty and students showed that more faculty members than students thought there was increased feedback to students and a greater emphasis on long term learning. “curriculum generates and establishes environment”.1 as the curriculum forms an integral part of the educational environment, we used it as a proxy for comparison between syed i shehnaz, jayadevan sreedharan, kadayam g gomathi clinical and basic research | 81 faculty and student perceptions of the educational environment. we therefore looked at studies dealing with faculty and student perceptions of the curriculum. we found a plethora of studies detailing student perceptions of integrated medical curricula, but studies focusing on faculty perceptions and comparing faculty and student perceptions were sparse. many previous studies12-14 have shown teachers’ views on revised, integrated, problembased medical curricula to be positive, with the students in the new curriculum being perceived as faring better in many respects, including taking self-directed learning initiatives, gaining problemsolving and interpersonal skills, and improved clinical performance in patient care. our study, which showed a positive effect on faculty members' attitudes to students’ experiences and (indirectly) to the curriculum, is similar to that reported by table 3 : items with significant differences between faculty and students items agreement disagreement uncertainity faculty and student dreem faculty number (%) student number (%) faculty number (%) student number (%) faculty number (%) ) student number (%) students' perceptions of learning (spl) long term learning is given importance over short term learning 26 (92.9%) 32 (72.7%)# 0 5 (11.4%) 2 (7.1%) 7 (15.9%) students' perceptions of teachers (spt) the teachers are patient with the hospital patients 13 (46.4%) 38 (86.4%)* 0 3 (6.8%) 15 (53.6%) 3 (6.8%) the teachers have good communication skills with hospital patients 15 (53.6%) 38 (86.4%)* 0 5 (11.4%) 13 (46.4%) 1 (2.3%) the teachers are good at providing feedback to students 22 (78.6%) 20 (45.5%) 3 (10.7%) 14 (31.8%) 3 (10.7%) 10 (22.7%) students perceptions of atmosphere (spa) the atmosphere is relaxed during the hospital ward teaching 6 (21.4%) 35 (79.5%)* 1 (3.6%) 6 (13.6%) 21 (75.0%) 3 (6.8%)# faculty dreem student dreem students academic self perception (sap) the students are confident about passing this year i am confident about my passing this year 11 (39.3%) 33 (75%)# 5 (17.9%) 1 (2.3%) 12 (42.9%) 10 (22.7%) the students’ last year’s work has been a good preparation for this year’s work. last year work has been a good preparation for this year’s work. 15 (53.6%) 39 (88.6%)* 2 (7.1%) 2 (4.5%) 11 (39.3%) 3 (6.8%) the students have learned a lot about empathy in this profession in my profession, i have learned a lot about empathy 15 (53.6%) 38 (86.4%)* 0 5 (11.4%) 13 (46.4%) 1 (2.3%) students social self-perceptions (ssp) the students have good friends in this school i have good friends in this school 18 (64.3%) 40 (90.9%) # 0 1 (2.3%) 10 (35.7%) 3 (6.8%) the students’ social life is good my social life is good 10 (35.7%) 36 (81.8%)* 2 (7.1%) 6 (13.6%) 16 (57.1%) 2 (4.5%) the students’ accommodation is pleasant my accommodation is pleasant 2 (7.1%) 36 (81.8%) # 4 (14.3%) 6 (13.6%) 22 (78.6%) 2 (4.5%)# note: *p = <0.01; #p = <0.05 faculty and students’ perceptions of student experiences in a medical school undergoing curricular transition in the united arab emirates 82 | squ medical journal, february 2012, volume 12, issue 1 table 4 : examples of items without significant differences between faculty and students items agreement disagreement uncertainty faculty (student) dreem faculty no. (%) student no. (%) faculty no. (%) student no. (%) faculty no. (%) student no. (%) students' perceptions of learning (spl) the students(i am)are encouraged to participate in class 25 (89.3) 39 (88.6) 1 (3.6) 2 (4.5) 2 (7.1) 3 (6.8) the teaching is often stimulating 24 (85.7) 38 (86.4) -5 (11.4) 4 (14.3) 1 (2.3) the teaching is “student centered” 24 (85.7) 35 (79.5) 2 (7.1) 2 (4.5) 2 (7.1) 7 (15.9) the teaching is sufficiently concerned to develop the student’s (my) competence 24 (85.7) 38 (86.4) -2 (4.5) 4 (14.3) 4 (9.1) the teaching overemphasizes factual learning 6 (21.4) 23 (52.3) 18 (64) 16 (36.4) 4 (14.3) 5 (11.4) the students are (i am) clear about l.o. of the course 25 (89.3) 31 (70.5) 1 (3.6) 4 (9.1) 2 (7.1) 9 (20.5) the teaching is too teacher-centered 5 (17.9) 5 (11.4) 20 (71) 24 (54.5) 3 (10.7) 15 (34.1) students' perceptions of teachers (spt) the teachers are knowledgeable 25 (89.3) 42 (95.5) 1 (2.3) 3 (10.7) 1 (2.3) the teachers ridicule the students 5 (11.4) 25 (89.3) 34 (77.3) 3 (10.7) 5 (11.4) the teachers are authoritarian 3 (10.7) 11 (25.0) 15 (53.6) 25 (56.8) 10 (35.7) 8 (18.2) the teachers provide constructive criticism 24 (85.7) 32 (72.7) 1 (3.6) 4 (9.1) 3 (10.7) 8 (18.2) the teachers get angry in class 3 (10.7) 7 (15.9) 17 (60.7) 29 (65.9) 8 (28.6) 8 (18.2) teachers are well prepared for classes 22 (78.6) 35 (79.5) 2 (7.1) 2 (4.5) 4 (14.3) 7 (15.9) the students irritate the teachers 3 (10.7) 11 (25.0) 18 (64.3) 21 (47.7) 7 (25.0) 12 (27.3) students academic self perception (sap) learning strategies which worked for the students (me) before continue to work 13 (46.4) 26 (59.1) 7 (25) 6 (13.6) 8 (28.6) 12 (27) the students are (i am) able to memorize all they (i) need 9 (32.1) 19 (43.2) 7 (25.0) 14 (31.8) 12 (42.9) 11 (25.0) the students’ (my )problem solving skills are being well developed here 27 (96.4) 35 (79.5) -3 (6.8) 1 (3.6) 6 (13.6) much of what students (i) have to learn seems relevant for a career in medicine 26 (92.9) 41 (93.2) -1 (2.3) 2 (7.1) 2 (4.5) students perceptions of atmosphere (spa) cheating is a problem in this school 6 (21.4) 16 (36.4) 12 (42.9) 15 (34.1) 10 (35.7) 13 (29.5) the atmosphere is relaxed during lectures 23 (82.1) 33 (75.0) -5 (11.4) 5 (17.9) 6 (13.6) there are opportunities for students (me) to develop interpersonal skills 23 (82.1) 33 (75.0) 1 (3.6) 8 (18.2) 4 (14.3) 3 (6.8) the atmosphere is relaxed during seminars/tutorial 22 (78.6) 39 (88.6) 2 (7.1) 5 (11.4) 4 (14.3) the students (i) find the experience disappointing 4 (14.3) 11 (25.0) 14 (50.0) 19 (43.2) 10 (35.7) 14 (31.8) the students are (i am) able to concentrate well 20 (71.4) 34 (77.3) 2 (7.1) 8 (18.2) 6 (21.4) 2 (4.5) the enjoyment outweighs stress of studying medicine 12 (42.9) 21 (47.7) 7 (25.0) 12 (27.3) 9 (32.1) 11 (25.0) the students’(i) feel able to ask question they (i )want 26 (92.9) 36 (81.8) -3 (6.8) 2 (7.1) 5 (11.4) students social self-perceptions (ssp) there is a good support system for students who get stressed 18 (64.3) 20 (45.5) 5 (17.9) 13 (29.5) 5 (17.9) 11 (25.0) the students are (i am) too tired to enjoy the course 10(35.7) 15(34.1) 10(35.7) 22(50.0) 8 (28.6) 7(15.9) the students are (i am) rarely bored in the course 16(57.1) 19(43.2) 6(21.4) 19(43.2) 6(21.4) 6(13.6) the students (i) seldom feel lonely 14(50.0) 29(65.9) 3(10.7) 11(25.0) 11(39.3) 4(9.1) syed i shehnaz, jayadevan sreedharan, kadayam g gomathi clinical and basic research | 83 tavanaiepour et al. where they concluded that a hybrid curriculum had almost as great a positive effect as did the pbl curriculum.15 in two other studies, the students’ and faculty’s opinions about pbl were found to be closely aligned and positive.16,17 brynhildsen et al. found that students and teachers highly appreciated horizontal and vertical integration.18 our findings appear to be consistent with the above studies. enduring and successful curricular change necessitates the support of all the stakeholders.19 factors found to be positively associated with successful innovation are 1) participating students’ acceptance, feedback and enthusiasm for the change; 2) a cooperative environment, characterised by collaborative problem solving, harmony, effective communication and skillful conflict resolution; 3) involvement of different disciplines or departments in the planning and implementation of curricular innovation; 4) ensuring faculty involvement (through orientations, problem-solving teams, committees) so as to strengthen their collective ownership of the project and deepen their commitment to seeing the innovation through to completion; 5) frequent, timely, substantive and effective communication among participants to promote understanding of the goals; 6) faculty comprehension of the theoretical underpinnings of the desired innovati on and the required training in the skills to implement it; 7) formative evaluation (through focus groups and student feedback) to locate difficulties and solve problems thus fostering a cooperative climate, and renewing ‘‘ownership’’ of the project and 8) stable positive leadership with leaders who effectively communicate and promote the organisation’s shared vision for curricular change.20 all these factors were an essential component of the curricular change in our institution and may have contributed to most faculty and students finding the experiences of the students in the new curriculum favourable. this study, in fact, contributed to the evaluation process of our curricular change. the higher mean scores in the domain students' perception of learning by both groups reflects the positive response to our student-centered curriculum which emphasises long term learning and problem solving skills. low scores in the domain social self-perceptions by the faculty does not reveal perceptions of weaknesses, but suggests staff ’s unfamiliarity with these aspects of the students’ experience. we had in fact mentioned that the faculty was advised to select “unsure” when the statements dealt with social self-perceptions and other unfamiliar aspects. however, the low student scores for the domain social self-perceptions reveal this to be an area of weakness necessitating rectification. this had already been identified in another study conducted in our institution where the insufficient support system for stressed students, the tiredness of students and the tediousness of the course emerged as areas of concern.9 we were aware that the dreem was not designed to investigate other stakeholders’ opinions on how the students experience their educational climate. consequently, we compared the percentage of agreement, disagreement and uncertainty rather than analysing subscale and item mean scores so as to provide a clearer view of staff and student perceptions of the students’ experience. comparison of percentage agreement (faculty and students who agreed/strongly agreed) identified two areas where the staff significantly believed that students would have a more positive perception than the students actually did. these two items were: long-term learning is given importance over short term learning and the teachers are good at providing feedback to students. students in pbl curricula tend to use a more in-depth approach of learning and have a greater intrinsic interest in learning and this may foster longterm knowledge retention.21,22 as students’ learning approaches are affected by their perceptions of the learning environment, any changes in learning environment will invariably alter their learning approach.23,24 though our new curriculum had incorporated features to enhance a deep approach to learning (clearly written learning objectives, assessment methods aligned to the learning objectives, student-centered teaching)25 apparently these were not sufficient to influence the students and thus faculty and students perceptions’ were not in consensus. effective feedback is a renowned catalyst for effective learning, especially for average or poor performers. feedback should be given in a way that “helps the recipient to listen to it, receive it constructively, reflect on it, and consider how to take action as a result”.26 however, often there is a mismatch between student expectations and faculty feedback practices,27,28 as also perceived in our study. faculty and students’ perceptions of student experiences in a medical school undergoing curricular transition in the united arab emirates 84 | squ medical journal, february 2012, volume 12, issue 1 the rest of the items with which the students tended to agree significantly more compared to the faculty were mainly items with which the predominantly basic sciences staff were unfamiliar, e.g. the teachers are patient with the hospital patients; or unsure as these concerned the personal views of the students, for example, the students are confident about passing this year; the students have learned a lot about empathy in the profession; the students have good friends in this school; the students’ social life is good; similarly, the two items about which the faculty were significantly unsure compared to the students, the atmosphere is relaxed during the hospital ward teaching; the student’s accommodation is pleasant, also dealt with areas involving personal views of the students. the comparison of student and faculty perceptions revealed the need for certain interventions to improve our curriculum. constructive and effective feedback techniques should be reinforced through faculty development programmes so as to influence attitudes as well as skills. formative feedback should be task oriented, simple, timely, provided by the appropriate person, in a friendly non-threatening climate and involve praise alongside constructive criticism and corrective advice.26,28,29 however, as student satisfaction ratings are not an accurate indicator of the quality of feedback, improved performance should instead be the gauge.27 avoidance of curriculum overload, clearly written objectives, teaching practices promoting conceptual change, assessments which emphasise understanding and application should be adopted to enhance long term learning.25 our study provides preliminary data about the faculty perceptions’ of the student experiences in the new curriculum. we are aware that our study was restricted to one school and our sample size was small. consequently, it may be premature to come to concrete conclusions, or to generalise the results to other schools. the method we have used is subjective and dependent on students’ and teachers' recollections of students’ experiences from the previous year; however, these perceptions will inevitably have some relation to actual faculty and student behaviour. future structured qualitative studies can also deal with the limitations of these questionnaire-based data.30 another limitation is that the instrument used was not intended to evaluate staff opinions about the students’ experience with the educational environment. we dealt with this limitation by analysing the data slightly differently so as to extract valuable differences between the staff and student opinions of the student experiences. while all attempts had been made to ensure validity of the questionnaire, we are aware that a modification of the instrument may have had an effect on the validity. conclusion the desired outcomes of excellent student behaviour, achievement, satisfaction and success have a proven connection to positive perceptions of the educational environment. moreover, continuous assessments are important for the sustainability of the curriculum. student and faculty perceptions are essential as they have direct impact on teaching and learning, and the development and well-being of the students.1 in addition, these different perspectives will shed light on alternative focus points in the improvement of the new curriculum. although the modified dreem questionnaire identified that both the students and the faculty perceived that the new organ system-based integrated curriculum provided a good educational environment, they also had differing perceptions regarding effective feedback and the emphasis on long term learning. therefore, the remedial measures identified were that faculty should learn constructive feedback techniques, and a greater emphasis should be placed on long term learning in the new curriculum. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g m e n t the authors would like to thank dr. gamini premadasa for his suggestions in editing this article. references 1. genn jm. amee medical education guide no.23 (part 1): curriculum, environment, climate, quality and change in medical education—a unifying perspective. med teach 2001; 23:337–44. 2. roff s, mcaleer s, ifere os, bhattacharya s. a global diagnostic tool for measuring educational environment: comparing nigeria and nepal. med teach 2001; 23:378–82. syed i shehnaz, jayadevan sreedharan, kadayam g gomathi clinical and basic research | 85 3. till h. identifying the perceived weaknesses of a new curriculum by means of the dundee ready education environment measure (dreem) inventory. med teach 2004; 26:39–45. 4. bassaw b, roff s, mcaleer s, roopnarinesingh s, de lisle j, teelucksingh s, et al. students’ perspectives of the educational environment, faculty of medical sciences, trinidad. med teach 2003; 25:522–6. 5. jiffry mtm, mcaleer s, fernandoo s, marasinghe rb. using the dreem questionnaire to gather baseline information on an evolving medical school in sri lanka. med teach 2005; 27:348–52. 6. mayya s, roff s. students’ perceptions of educational environment: a comparison of academic achievers and under-achievers at kasturba medical college, india. educ health (abingdon) 2004; 17:280–91. 7. alhazimi a, zaini r, alhyiani a, hassan n, gunaid a, ponnamperuma g, et al. educational environment in traditional and innovative medical schools: a study in four undergraduate medical schools. educ health (abingdon) 2004; 17:192–203. 8. riquelme a, oporto m, oporto j, méndez j, viviani p, salech f, et al. measuring students' perceptions of the educational climate of the new curriculum at the pontificia universidad católica de chile: performance of the spanish translation of the dundee ready education environment measure (dreem). educ health (abingdon) 2009; 22:112. 9. shehnaz si, sreedharan j. students' perceptions of educational environment in a medical school experiencing curricular transition in united arab emirates. med teach 2011; 33:e37–42. 10. miles s, leinster sj. comparing staff and student perceptions of the student experience at a new medical school. med teach 2009; 31:539–46. 11. mcaleer s, roff s. a practical guide to using the dundee ready education environment measure (dreem). in: genn jm, ed. amee education guide no. 23 (part 3): curriculum, environment, climate, quality and change in medical education: a unifying perspective. dundee: association for medical education in europe, 2001. pp. 29–33. 12. lam tp, khoo us, chan ys, cheng yh, lam kf. the first batch of graduates of a new medical curriculum in asia: how their teachers see them. med teach 2004; 38:980–6. 13. vernon dta. attitudes and opinions of faculty tutors about problem-based learning. acad med 1995; 70:216–23. 14. vernon dta, hosokawa mc. faculty attitudes and opinions about problem-based learning. acad med 1996; 71:1233–8. 15. tavanaiepour d, schwartz pl, loten eg. faculty opinions about a revised pre-clinical curriculum. med educ 2002; 36:299–302. 16. musal b, taskiran c, kelson a. opinions of tutors and students about the effectiveness of pbl in dokuz eylul university school of medicine. med educ online 2003; 8:16. from: http://www.med-ed-online. org. accessed: jun 2011. 17. khoo he, chhem rk, gwee mc, balasubramaniam p. introduction of problem-based learning in a traditional medical curriculum in singapore students' and tutors' perspectives. ann acad med singapore 2001; 30:371–4. 18. brynhildsen j, dahle lo, fallsberg mb, rundquist i, hammar m. attitudes among students and teachers on vertical integration between clinical medicine and basic science within a problem based undergraduate medical curriculum. med teach 2002; 24:286–8 19. watson rt, suter e, romrell lj, harman em, rooks lg, neims ah. moving a graveyard: how one school prepared the way for continuous curriculum renewal. acad med 1998; 73:948–55. 20. bland cj, starnaman s, wersal l, mooreheadrosenberg l, zonia s, henry r. curricular change in medical schools: how to succeed. acad med 2000; 75:575–94. 21. norman gr, schmidt hg. the psychological basis of problem-based learning: a review of the evidence. acad med 1992; 67:557–65. 22. beers gw, bowden s. the effect of teaching method on long-term knowledge retention. j nurs educ 2005; 44:511–4. 23. newble di, clarke rm. the approaches to learning of students in a traditional and in an innovative problem-based medical school. med educ 1986; 20:267–73. 24. lizzio a, wilson k, simons r. university students’ perceptions of the learning environment and academic outcomes: implications for theory and practice. stud high educ 2002; 27:27–52. 25. reid wa, duvall e, evans p. can we influence medical students' approaches to learning? med teach 2005; 27:401–7. 26. henderson p, ferguson-smith ac, johnson mh. developing essential professional skills: a framework for teaching and learning about feedback. bmc med educ 2005; 5:11. 27. boehler ml, rogers da, schwind cj, mayforth r, quin j, williams rg, et al. an investigation of medical student reactions to feedback: a randomised controlled trial. med educ 2006; 40:746–9. 28. perera j, lee n, win k, perera j, wijesuriya l. formative feedback to students: the mismatch between faculty perceptions and student expectations. med teach 2008; 30:395–9. 29. nicol dj, macfarlane-dick d. formative assessment and self regulated learning: a model and seven principles of good feedback practice. stud high educ 2006; 31:199–218. 30. seabrook m. clinical students’ initial reports of the educational climate in a single medical school. med educ 2004; 38:659–69. departments of 1pharmacy, 2dermatology and 3pathology, complejo hospitalario de granada, granada, spain *corresponding author’s e-mail: b.cancela.diez@gmail.com حالة َطَفِحيَّة َمَذِحّية ثـَنـَْيِويّة سببها دواء اموكسيسيللني باربرا كان�صيال-دياز، ديفيد اوبز-ديلقادو، هوزي انريو�ض-فريناندز، ريكاردو رويز-فيالفريدي abstract: we report a 50-year-old male patient who presented to the dermatological outpatient clinic at the hospital universitario san cecilio, granada, spain, in 2017 with symmetrical inguinal eruption and eruption on the dorsum of both feet four hours after the intake of amoxicillin. physical examination showed confluent non-palpable purpuric macules covering the dorsum of both feet and medial malleolus, giving rise to dusky erythema in some areas. only oral antihistamines were prescribed and cutaneous exanthema resolved within three weeks. symmetric drug-related intertriginous and flexural exanthema (sdrife) is a sub-type of systemic allergic contact dermatitis, where previous sensitisation can only be demonstrated in up to 50% of patients by skin patch testing. therefore, a provocation test was performed with amoxicillin without prior skin patch testing. as drug provocation produced the same reaction, the patient was diagnosed with sdrife. a parvovirus b19 infection was ruled out by negative serology. sdrife is challenging to distinguish from other skin rashes with similar features and distribution; it is important to be aware of these characteristics and their possible causes. keywords: exanthema; amoxicillin; drug allergy; drug eruption; groin; feet; case report; spain. اجلامعي �صي�صيلو �صان م�صت�صفى يف اخلارجية اجللد اأمرا�ض عيادة اإىل جاء عمره من اخلم�صني يف مري�ض حالة هنا ن�صجل امللخ�ص: تناول على �صاعات اأربع بعد القدمني ظهر يف جلدي طفح مع ُمَتناِظر اأُْرِبّي جلدي طفح من ي�صكو وهو 2017م عام اإ�صبانيا بغرناطة، داكن ُحمامي م�صببة الأن�صي، والكعب القدمني ظهر تغطي جم�صو�صة غري متمادية فرفرية بقع البدين الك�صف اأظهر اموك�صي�صيلني. دواء اللون يف بع�ض املوا�صع. اختفى الطفح الظاهر يف غ�صون ثالثة اأ�صابيع، ومل يو�صف للمري�ض �صوى دواء واحد م�صاد للهي�صتامني. يعد الطفح اجللدي الأُْرِبّي امُلَتناِظر الذي ي�صببه تناول بع�ض الأدوية نوعا فرعيا من التهاب اجللد التما�ّصي الأََرِجّي امَلْجموِعّي ميكن اأن يظهر رِّ�ض بدواء اموك�صي�صيلني قبل عمل بالتح�صي�ض ال�صابق يف نحو %50 من املر�صى عن طريق اختبار اللطخة اجللدي. لذا مت عمل اختبار حُمَ اختبار اللطخة اجللدي. و�صبب َحْر�ض الدواء نف�ض التفاعل. لذا مت ت�صخي�ض حالة هذا املري�ض على اأنها طفح جلدي اأْرِبّي ُمَتناِظر �صببه تناول دواء. ومت ا�صتبعاد الإ�صابة بفريو�ض بارو ب19 ك�صبب لهذا املر�ض عن طريق ال�صريولوجي ال�صالبة. ي�صعب ت�صخي�ض الطفح اجللدي الأُْرِبّي امُلَتناِظر الذي ي�صببه تناول بع�ض الأدوية وتفريقه عن اأنواع الطفح اجللدي الأخرى التي لها نف�ض ال�صفات والتوزيع. لذا فمن املهم اإدراك خوا�ض ذلك املر�ض واأ�صبابه املمكنة. الكلمات املفتاحية: َطَفِحيَّة؛ اموك�صي�صيلني؛ اأرجية الدواء؛ طفح جلدي؛ اأقدام؛ الأربية؛ تقرير حالة؛ اإ�صبانيا. a case of intertriginous and flexural exanthema caused by amoxicillin *bárbara cancela-díez,1 david lópez-delgado,2 josé aneiros-fernandez,3 ricardo ruiz-villaverde2 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e369–371, epub. 22 dec 19 submitted 29 jan 19 revisions req. 2 may, 26 jun & 25 jul 19; revisions recd. 22 may, 8 jul & 1 aug 19 accepted 17 sep 19 baboon syndrome (bs) is a systemic contact dermatitis which occurs after systemic exposure to an allergen in previously sensitised individuals. it was first described by andersen et al. and subsequently, häusermann et al. proposed the term “symmetric drug related intertriginous and flexural exanthema” (sdrife) as bs may be considered a derogatory term.1,2 case report a 50-year-old male patient presented to the dermatological outpatient clinic at the hospital universitario san cecilio, granada, spain, in 2017 complaining of symmetrical inguinal eruption that was subsequently followed by a similar rash on the dorsum of both feet. symptoms appeared four hours after the intake of amoxicillin for a respiratory infection (500 mg every eight hours for three days). the patient had a history of allergies to penicillin and codeine, yet no provocation test had previously been performed. in addition, the patient had swyer-jamesmacleod syndrome, hepatomegaly and hypertension. he did not smoke or drink alcoholic beverages. there was no history of other drug use except enalapril for hypertension. physical examination showed confluent non-palpable purpuric macules covering the dorsum of both the feet and medial malleolus, giving rise to dusky erythema in some areas [figure 1]. ill-defined erythema with no obvious purpura was found in the groin [figure 2]. blood cell count, coagulation profile, renal and liver function tests were all within normal range. the patient did not show systemic signs or symptoms. parvovirus b19 had been negative in this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.014 case report https://creativecommons.org/licenses/by-nd/4.0/ a case of intertriginous and flexural exanthema caused by amoxicillin e370 | squ medical journal, november 2019, volume 19, issue 4 serology. subsequently, the patient was admitted to hospital for clinical observation. amoxicillin was stopped and bilastine (20 mg/day) was prescribed for 20 days. the cutaneous exanthema resolved within three weeks. after resolution of the rash, with the patient's consent, a provocation test was performed with one dose of amoxicillin 500 mg without prior skin patch testing. the result of the provocation test was positive as the patient developed the same eruptions at the same locations within 48 hours; therefore, the patient was diagnosed with sdrife by amoxicillin. discussion sdrife is defined by the following criteria: (1) systemic exposure to a drug for the first time or repeatedly; (2) symmetrically distributed well-demarcated erythema in the gluteal/perianal area and/or v-shaped erythema in the inguinal/perigenital area; (3) at least one other intertriginous or bending area being affected; and (4) absence of systemic signs and symptoms.2 differential diagnosis includes inflammatory dermatological cond itions such as allergic contact dermatitis, irritant contact dermatitis and inverse psoriasis, and infectious entities such as mainly intertrigo and tinea cruris.3 it is also important to exclude a parvovirus b19 infection, as this may present clinically with a wide variety of dermatological features, including the same flexural erythema of sdrife. in the current patient, papular–purpuric gloves and socks syndrome was also considered, but his hands were not affected.4 several cases of sdrife after exposure to amox icillin have been previously reported.3,5–7 however, sdrife has also been associated with other drugs such as rivastigmine, risperidone, valaciclovir and chemotherapeutics agents among others.3,8 more recently, sdrife has been associated with pristi namycin, secnidazol, nefopam and mefenamic acid.9,10 skin lesions are frequently distributed on the gluteal and intertriginous areas. the current case showed lesions on the upper thighs near the groin, but not in other traditional areas (such as the buttocks). in addition, lesions appeared on the dorsal feet, which has not been reported previously. the skin lesions mostly reported for sdrife are maculopapular erythema or plaques. however, one case with petechial eruptions and oral mucosal involvement has been previously reported.11 similarly, the current patient presented with non-palpable purpura in the dorsum of the feet and ankles in addition to ill-defined erythema on the groin; these are very unusual findings in sdrife. the onset of the eruption can range from hours to two days after the systemic administration of the medication.3 the current patient’s symptoms developed within four hours. a biopsy was not performed as the histopathology in sdrife shows non-specific features. typically, a superficial perivascular infiltrate of mononuclear cells is observed and may include some neutrophils and eosinophils.9 it is important to be aware, that previous sensitisation can only be demonstrated in up to 50% of patients by skin patch testing.12 figure 1: photograph of the feet of a 50-year-old male patient showing non-palpable purpuric erythema on the dorsum of both feet. figure 2: photograph of the groin of a 50-year-old male patient showing ill-defined erythema in the inguinal area. bárbara cancela-díez, david lópez-delgado, josé aneiros-fernandez and ricardo ruiz-villaverde case report | e371 conclusion sdrife is a cutaneous adverse drug reaction, with distinct characteristic distribution and presentation of the rash. for clinicians, it is important to recognize and distinguish a hypersensitivity reaction from other dermatoses in order to prevent future accidental reexposures. as shown in the current case, the atypical distribution of the lesions should be taken into account in order to provide a correct differential diagnosis. references 1. andersen ke, hjorth n, menné t. the baboon syndrome: systemically-induced allergic contact dermatitis. contact dermatitis 1984; 10: 97–100. https://doi.org/10.1111/j.1600-05 36.1984.tb00343.x. 2. häusermann p, harr t, bircher aj. baboon syndrome resulting from systemic drugs: is there strife between sdrife and allergic contact dermatitis syndrome? contact dermatitis 2004; 51:297–310. https://doi.org/10.1111/j.0105-1873.2004.00445.x. 3. winnicki m, shear nh. a systematic approach to systemic contact dermatitis and symmetric drug-related intertriginous and flexural exanthema (sdrife): a closer look at these cond itions and an approach to intertriginous eruptions. am j clin dermatol 2011; 12:171–80. https://doi.org/10.2165/11539080000000000-00000. 4. vargas-díez e, buezo gf, aragües m, daudén e, de ory f. papular-purpuric gloves-and-socks syndrome. int j dermatol 1996; 35:626–32. https://doi.org/10.1111/j.1365-4362.1996.tb03686.x. 5. handisurya a, stingl g, wöhrl s. sdrife (baboon syndome) induced by penicillin. clin exp dermatol 2009; 34:355–7. https://doi.org/10.1111/j.1365-2230.2008.02911.x. 6. dogru m, ozmen s, ginis t, duman h, bostanci i. symmetrical drug-related intertriginous and flexural exanthema (baboon syndrome) induced by amoxicillin-clavulanate. pediatr der matol 2012; 29:770–1. https://doi.org/10.1111/j.1525-1470.20 11.01577.x. 7. kick g, przybilla b. delayed prick test reaction identifies amoxicillin as elicitor of baboon syndrome. contact dermatitis 2000; 43:366–7. 8. powers r, gordon r, roberts k, kovach r. symmetrical drugrelated intertriginous and flexural exanthema secondary to topical 5-fluorouracil. cutis 2012; 89:225–8. 9. nespoulous l, matei i, charissoux a, bédane c, assikar s. symmetrical drug-related intertriginous and flexural exanthema (sdrife) associated with pristinamycin, secnidazole, and nefopam, with a review of the literature. contact dermatitis 2018; 79:378–80. https://doi.org/10.1111/cod.13084. 10. weiss d, kinaciyan t. symmetrical drug-related intertriginous and flexural exanthema (sdrife) induced by mefenamic acid. jaad case rep 2018; 5:89–90. https://doi.org/10.1016/j.jdxcr.20 18.10.015. 11. karadag as, ozlu e, akdeniz n, uzuncakmak tk, turkoglu z, ozkanli s, et al. oral mucosal involvement and petechial lesions: a sdrife case with unusual findings. cutan ocul toxicol 2016; 35:157–9. https://doi.org/10.3109/15569527.201 5.1067227. 12. harbaoui s, litaiem n. symmetrical drug-related intertriginous and flexural exanthema (sdrife). from: https://www.ncbi. nlm.nih.gov/books/nbk539750/ accessed: aug 2019. https://doi.org/10.1111/j.1600-0536.1984.tb00343.x https://doi.org/10.1111/j.1600-0536.1984.tb00343.x https://doi.org/10.1111/j.0105-1873.2004.00445.x https://doi.org/10.2165/11539080-000000000-00000 https://doi.org/10.2165/11539080-000000000-00000 https://doi.org/10.1111/j.1365-4362.1996.tb03686.x https://doi.org/10.1111/j.1365-2230.2008.02911.x https://doi.org/10.1111/j.1525-1470.2011.01577.x https://doi.org/10.1111/j.1525-1470.2011.01577.x https://doi.org/10.1111/cod.13084 https://doi.org/10.1016/j.jdcr.2018.10.015 https://doi.org/10.1016/j.jdcr.2018.10.015 https://doi.org/10.3109/15569527.2015.1067227 https://doi.org/10.3109/15569527.2015.1067227 1department of medical oncology, regional cancer centre, thiruvananthapuram, kerala, india; 2department of internal medicine, government medical college, thiruvananthapuram, kerala, india; 3department of anaesthesia, sree gokulam medical college & research institute, thiruvananthapuram, kerala, india *corresponding author’s e-mail: rakulnambiar@yahoo.com املتالزمة القلبية–الصوتية سبب نادر من أسباب حبة الصوت عند مريض له تاريخ مرضي بالسل الرئوي راكول نامبيار، ديي دالو�ض، اأجنايل �رشيكمار abstract: hoarseness is a common clinical condition with underlying causes which can vary from reversible and benign to life-threatening and malignant. cardiovocal syndrome may cause hoarseness secondary to left recurrent laryngeal nerve palsy when the recurrent laryngeal nerve is mechanically affected due to enlarged cardiovascular structures. we report a 28-year-old male who presented to the government medical college, thiruvananthapuram, india, in 2013 with hoarseness. he had undergone irregular treatment for pulmonary tuberculosis (tb) two years previously. fiber-optic laryngoscopy indicated left vocal cord palsy and a computed tomography scan of the chest revealed features of pulmonary hypertension with extensive enlargement of the pulmonary arteries. an echocardiogram confirmed severe pulmonary arterial hypertension with severe tricuspid regurgitation. he was diagnosed with left recurrent laryngeal palsy secondary to cardiovocal syndrome. although reports exist of recurrent laryngeal palsy in tb, this case appears to be the first to report cardiovocal syndrome in a patient treated for pulmonary tb. keywords: hoarseness; pulmonary tuberculosis; vocal cord paralysis; cor pulmonale; pulmonary hypertension; case report; india. امللخ�ص: بحة ال�صوت هي حالة �رشيرة �صائعة خمتلفة الأ�صباب، وميكن اأن تكون حالت رجوعية وحميدة، وميكن اأن تكون مهددة للحياة وخبيثة. وميكن اأن ت�صبب املتالزمة القلبية–ال�صوتية ُبّحة يف ال�صوت كنتيجة ثانوية ل�صلل الع�صب احلنجري الأي�رش الراجع، نتيجة لإ�صابة ذلك الع�صب ب�صبب ميكانيكي نتيجة لت�صخم بنيات اجلهاز القلبي الوعائي. ونعر�ض هنا حالة مري�ض يف 28 من العمر، اأح�رش مل�صت�صفى الكلية الطبية احلكومية مبدينة تيدوواندابروم يف الهند يف عام 2013 ب�صبب بحة يف �صوته. وكان الرجل يتلقى عالجات غري منتظمة من مر�ض ال�صل الرئوي قبل عامني. واأثبت الفح�ض بوا�صطة منظار احلنجرة الب�رشي الليفي وجود �صلل يف احلبال ال�صوتية واأو�صح الت�صوير املقطعي املحو�صب ل�صدر املري�ض عالمات تدل على وجود ارتفاع يف �صغط الدم الرئوي، وت�صخم كبري يف ال�رشايني الرئوية. واأكد خمطط �صلل اأنها على احلالة ت�صخي�ض ومت ال�رُشف. الثالثي بقل�ض م�صحوبا الرئوي، ال�رشيان دم �صغط يف وخيم ارتفاع وجود القلب �صدى الع�صب ل�صلل حالت عن من�صورة تقارير وجود من الرغم وعلى القلبية–ال�صوتية. للمتالزمة نتيجة الراجع الأي�رش احلنجري الع�صب يف احلنجري الراجع عند مر�صى ال�صل، فيبدو اأن هذه هي احلالة الأوىل عن املتالزمة القلبية–ال�صوتية يف مري�ض تعالج من ال�صل الرئوي. الكلمات املفتاحية: بحة ال�صوت؛ ال�صل الرئوي؛ �صلل احلبال ال�صوتية؛ قلب–رئوي؛ ارتفاع �صغط الدم الرئوي؛ تقرير حالة؛ الهند. cardiovocal syndrome a rare cause of hoarseness in a patient with a history of pulmonary tuberculosis *rakul nambiar,1 dae dalus,2 anjali srikumar3 case report sultan qaboos university med j, november 2017, vol. 17, iss. 4, pp. e481–483, epub. 10 jan 18 submitted 9 apr 17 revisions req. 14 jun & 12 jul 17; revisions recd. 14 jun & 16 jul 17 accepted 3 aug 17 doi: 10.18295/squmj.2017.17.04.019 case report a 28-year-old male was admitted to the government medical college, thiruvananthapuram, india, in 2013 with hoarseness persisting for three months. he also complained of a history of dyspnoea both upon moderate exertion during the last year and at rest over the past two days. he did not report any symptoms of coughing, haemoptysis, difficulty in swallowing, paroxysmal nocturnal dyspnoea, rheumatic fever or previous surgical interventions or trauma to the head and neck region. two years previously, he had been diagnosed with open pulmonary tb and was prescribed a regimen of antitubercular therapy including isoniazid, rifampicin, pyrazinamide and among patients with tuberculosis (tb), hoarseness can occur either due to the tuberculous inflammation of the vocal cord (i.e. tuberculous laryngitis) or recurrent laryngeal nerve palsy as a result of acute lymphadenopathy, caseating granulomatous inflammation or late complications of chronic fibrosis.1,2 this report describes a 28-year-old male with cardiovocal syndrome who presented with hoarseness and a history of non-compliant treatment for pulmonary tb. to the best of the authors’ knowledge, although there are previous reports of recurrent laryngeal palsy in patients with tb, cardiovocal syndrome has never been before reported with pulmonary tb.3 cardiovocal syndrome a rare cause of hoarseness in a patient with a history of pulmonary tuberculosis e482 | squ medical journal, november 2017, volume 17, issue 4 the mitral valve apparatus was normal and there was no sign of aortic dilatation. a ct pulmonary angiogram ruled out a pulmonary embolism; however, arterial blood gas analysis showed hypoxaemia with hypercapnia. a diagnosis of pulmonary hypertension group iii was made according to the classifications of the world health organization.4 as such, the patient was treated with oxygen administration, bronchodilators, a low-salt diet, diuretics (furosemide) and calcium channel blockers (diltiazem). while the symptoms of breathlessness gradually improved over the course of the following week, there was no improvement in the hoarseness. supplemental oxygen therapy was considered; however, this was not pursued due to financial constraints. the patient was discharged after two weeks of admission and was unfortunately lost to further follow-up. discussion also known as ortner’s syndrome, cardiovocal syndrome was first described in 1897 among three patients with severe mitral stenosis, wherein it was postulated that left atrial dilatation can cause left recurrent laryngeal nerve palsy due to the compression of the nerve against the aorta.5 during autopsies, fetterolf et al. found that the normal distance between the aorta and pulmonary artery in the aortic window was 4 mm; as such, compression of the recurrent laryngeal nerve between these structures can cause palsy.6 other causes of hoarseness in cardiac disorders include lymphadenitis in the aortic window, pressure from the left bronchus, right ventricular hypertrophy, pulmonary artery atherosclerosis, the anatomical posi tion of the ligamentum arteriosum, a dilated pulmonary artery, mitral regurgitation, atrial myxoma or a left ventricular aneurysm.7 ethambutol. however, due to patient noncompliance, the treatment was discontinued after two months and was only resumed five months later. at this point, the patient completed the treatment regimen and was found to be sputum smear-negative for tb. upon examination, the patient was emaciated and had bilateral pitting pedal oedema, elevated jugular venous pressure, palpable second heart sounds with a loud pulmonary component, loud right ventricular third heart sounds and a pansystolic murmur with inspiratory increase in the tricuspid area. he also exhibited features of volume loss of the right lung, including drooping shoulders and narrowing of the intercostal spaces with rib crowding on the right side of his chest. voluntary and reflex movements of the soft palate were present and a neurological examination was essentially normal. the results of repeat sputum acid-fast bacilli stains and culture tests were negative. fiber-optic laryngoscopy confirmed left vocal cord palsy. a chest x-ray showed extensive fibrosis of the right lung with a mediastinal shift to the right and increased aeration of the left lung due to compensating emphysema [figure 1]. a computed tomography (ct) scan of the chest showed signs of pulmonary arterial hypertension, including extensive dilatation of the central pulmonary artery at 32 mm, abrupt tapering of the peripheral pulmonary vessels, right ventricular hypertrophy and right atrial enlargement [figure 2]. there was no evidence of any other mediastinal pathology. the left recurrent laryngeal nerve palsy was caused by the compression of the nerve between the aorta and dilated pulmonary artery. an echocardiogram indicated severe pulmonary arterial hypertension with severe tricuspid regurgitation causing gross dilatation of the right atrium, right ventricle and pulmonary artery (tricuspid annular plane systolic excursion: 14 mm; right ventricular systolic pressure: 55 mmhg). figure 1: chest x-ray of a 28-year-old male with hoarseness showing extensive fibrosis of the right lung (arrow) with a mediastinal shift to the right and hyperinflation of the left lung. figure 2: computed tomography scan of the chest of a 28-year-old male with hoarseness showing extensive central pulmonary artery dilatation (arrow), a mediastinal shift to the right and increased volume in the left lung. rakul nambiar, dae dalus and anjali srikumar case report | e483 the left vagus nerve gives rise to the left recurrent laryngeal nerve at the level of the aortic arch. the recurrent laryngeal nerve then curves around the aorta on the outer side of the ligamentum arteriosum and ascends in the groove between the trachea and the oesophagus. this thoracic course makes the recurrent laryngeal nerve vulnerable to injury and it has been suggested that compression of the nerve between the dilated pulmonary artery and the aorta occurs among almost all patients with cardiovascular disease.7 in the current case, the left recurrent laryngeal nerve palsy was due to the compression of the nerve between the dilated pulmonary artery and thoracic aorta, in which the dilated pulmonary artery was secondary to pulmonary hypertension. initially, the suspected cause of the recurrent laryngeal nerve palsy was a mediastinal lymph node; however, this was ruled out by the chest ct scan. interestingly, pulmonary tb has not yet been included as a cause for the development of pulmonary hypertension in the existing western literature. in contrast, it is not unusual to find patients in india who have been treated for pulmonary tb to present with features of right heart failure; according to a recent study, the prevalence of cor pulmonale among indian patients with pulmonary tb was 11%.8 pulmonary hypertension in tb can be caused by the destruction of the vascular bed due to parenchymal abnormalities, endarteritis or vasculitis leading to the reduced crosssectional area of the pulmonary vasculature.9 it has been suggested that recurrent secondary respiratory tract infections also play an important role in the pathogenesis of pulmonary hypertension in previously treated pulmonary tb patients.10 commonly, such patients present with dyspnoea to a degree disproportionate to that indicated radiologically or with desaturation present even upon mild exertion. in rare instances, the presentation can also include overt heart failure with pedal oedema, raised jugular venous pressure and tender hepatomegaly.11 this is consistent with that seen in the current case, whereby the patient presented with features of right heart failure. among former tb patients presenting with worsening dyspnoea, the management and diagnosis can be challenging as such cases can be misdiagnosed as a tb relapse. the correct diagnosis and timely management of pulmonary tb can prevent future complications, such as those observed in the patient described in the present case report. although the patient had previously received antitubercular therapy, his initial noncompliance with the treatment may have led to further lung damage and resulted in the subsequent development of pulmonary hypertension two years later. conclusion clinicians should be aware of cardiovocal syndrome as a cause of left recurrent laryngeal nerve palsy, particularly among patients with a history of tb who may also be at risk of developing pulmonary hypertension. although reports exist of recurrent laryngeal palsy in tb cases, cardiovocal syndrome has never before been reported among patients with pulmo nary tb. references 1. rafay ma. tuberculous lymphadenopathy of superior mediastinum causing vocal cord paralysis. ann thorac surg 2000; 70:2142–3. doi: 10.1016/s0003-4975(00)01193-0. 2. springford lr, ramdoo k, nair d, taghi a. hoarse voice: a rare presentation of tuberculosis lymphadenitis. bmj case rep 2016; 2016. doi: 10.1136/bcr-2016-216022. 3. rajasekaran v, srividhya g. a clinical study on laryngeal manifestations of tuberculosis. int j otorhinolaryngol head neck surg 2017; 3:845–8. doi: 10.18203/issn.2454-5929.ijohns 20173121. 4. simonneau g, gatzoulis ma, adatia i, celermajer d, denton c, ghofrani a, et al. updated clinical classification of pulmonary hypertension. j am coll cardiol 2013; 62:d34–41. doi: 10.1016/j.jacc.2013.10.029. 5. ortner n. [recurrence of mitral stenosis]. wien klin wochenschr 1897; 10:753–5. 6. fetterolf g, norris gw. the anatomical explanation of the paralysis of the left recurrent laryngeal nerve found in certain case of mitral stenosis. am j med sci 1911; 141:637. 7. subramaniam v, herle a, mohammed n, thahir m. ortner’s syndrome: case series and literature review. braz j otorhinolaryngol 2011; 77:559–62. doi: 10.1590/s1808-86942 011000500004. 8. kotresh n, raghavendra, kadappa j. study of prevalence of cor pulmonale in patients with pulmonary tuberculosis with reference to ecg, echocardiographic changes and radiological extent of the disease. int j med res 2016; 1:27–9. 9. fishman ap. state of the art: chronic cor pulmonale. am rev respir dis 1976; 114:775–94. doi: 10.1164/arrd.1976.114.4.775. 10. kapoor sc. cor pulmonale in pulmonary tuberculosis: a preliminary report on 66 patients. indian j tuberc 1959; 6:50–64. 11. ahmed ae, ibrahim as, elshafie sm. pulmonary hypertension in patients with treated pulmonary tuberculosis: analysis of 14 consecutive cases. clin med insights circ respir pulm med 2011; 5:1–5. doi: 10.4137/ccrpm.s6437. https://doi.org/10.1016/s0003-4975%2800%2901193-0 https://doi.org/10.1136/bcr-2016-216022 https://doi.org/10.18203/issn.2454-5929.ijohns20173121 https://doi.org/10.18203/issn.2454-5929.ijohns20173121 https://doi.org/10.1016/j.jacc.2013.10.029 https://doi.org/10.1590/s1808-86942011000500004 https://doi.org/10.1590/s1808-86942011000500004 https://doi.org/10.1164/arrd.1976.114.4.775 https://doi.org/10.4137/ccrpm.s6437 cancer care can be seen as a three-legged stool. whereas, the centre of attention is the patient, care cannot be provided without healthcare providers and caregivers. quality caregiving enhances the patient’s physical and emotional well-being. the informal caregivers in oncologic practice need enhanced support, whether faced with the imminent demise of a cancer patient or in the long-term care of survivors. yet, in cancer care protocols, informal caregivers are often neglected; a compromise of their quality of life is a foregone conclusion.1 for example, a physician whose sibling is wasting away from advanced cancer may express their angst by expressing “she [the cancer patient] is the strong one in the family”. young parents may mask their emotions to hide their distress of seeing their child with neuroblastoma buoyant between cycles of chemotherapy. what do cancer caregivers witness, cope with, buffer and express? a spouse, parent, sibling, partner or close friend may take the first steps to becoming a caregiver when they are present when the diagnosis is given. the impact of this news is, at best, a close second in intensity, to what the patient experiences. one has witnessed both sides of the coin—the patient who receives the diagnosis with equanimity as those close to the patient dissolve in tears or, a family member assuming strength and hope when the patient retreats into shock or denial. caregiver’s involvement in cancer care varies from culture to culture, but also across time in care of the same patient. the caregiving spectrum can range from silent/supportive to paternalistic/decision-maker. as the initial trauma of acceptance of the diagnosis subsides, caregivers begin a journey of frequent hospital visits and witnessing the physical and psychological effects of therapy. many undiscovered attributes of the caregiver can arise: patience, attentiveness, dependability and trustworthiness. a absence from the workplace, lack of attention to daily chores and children’s needs and abandonment of lifestyle activities may become the new norm for the caregiver. there may be simultaneous financial struggle due to mounting medical expenses. in addition, legal ramifications of inheritance, in the event of the patient’s death, become an unspoken dilemma. quality of life, including effect on physical health, spir ituality, psychological distress and social support has recently been reviewed across a range of caregivers.2 the success of advanced oncologic therapy with resultant long-term survival has brought hope to patients and families. cancers are curable or can be treated as chronic diseases. the effort to sustain chronic care giving increasingly affects the caregiver’s personality and physical well-being. as the disease progresses, the caregiver may have to take responsibility for adopting unproven or minimally beneficial and often expensive and confusing secondand third-line options. homecare in the palliative setting may challenge the caregiver by the administration of pain relief or other medications as well as a more intimate observation of deterioration and suffering. the stressful caregiving adult reactions to experiences of dying scale has been used to aid in early identification of caregivers stress level due to dying patients’ critical health events.3 when cancers progress rapidly, attempts at coping with the situation either induce yeoman efforts or prove overwhelming; witnessing a child’s suffering can be part icularly devastating. post-bereavement, caregivers are called cancer survivors and their recovery can manifest in multiple ways: a lifelong phobia of cancer; failure to return to a healthy lifestyle or relationships; continued support to other family members such as children and parents; and/or long-term economic burden. despite the many challenges integral to cancer care, some caregivers may gain a sense of satisfaction in this humanitarian mission; caregiving may enrich 1college of medicine, mohammed bin rashid university of medicine and health sciences, dubai, uae; 2department of medicine, sultan qaboos university hospital, muscat, oman; 3visiting faculty, international center for chemical and biological sciences, karachi university, karachi, pakistan *corresponding author’s e-mail: ikramburney@hotmail.com ملن ال يقرع هلم اجلرس القصة امللحمية غري املرئية ملقدمي رعاية مرضى السرطان ريتو لكتاكيا و اإكرام بريين for whom the bell does not toll the invisible saga of cancer caregivers ritu lakhtakia1 and *ikram burney2,3 editorial sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e275–276, epub. 22 dec 19 submitted 28 aug 19 revision req. 11 nov 19; revision recd. 30 nov 19 accepted 3 dec 19 https://doi.org/10.18295/squmj.2019.19.04.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ for whom the bell does not toll the invisible saga of cancer caregivers e276 | squ medical journal, november 2019, volume 19, issue 4 life and instil pride and a sense of purpose. in some cultures, such as in the east, familial bonds oblige one to provide care to other family members, providing a sense of satisfaction and dutifulness. religious anchors endorse caregiving as a noble means of obeying the commands of god. some caregivers see the opportunity to learn new skills, socialise, make friends and have gone on to champion this cause, such as by creating non-governmental organisations. the emergence of excellence in oncologic therapies on the one hand and holistic cancer care on the other, have been the hallmarks of the fight against cancer. out of necessity, research has focused on the patients and their disease while the multi-nuanced experiences of cancer caregivers remains undiscovered and as a result they may be unprepared and untrained to support their loved ones and protect themselves. psychoeducational interventions have been the predominant approach to caregiver interventions while adaptive flexibility in the format of interventions is recommended.4 further research should be carried out on outpatient cancer care and reinforcement of caregivers’ capacity and well being at all levels of healthcare. misconceptions of cancer caregivers should be addressed via recognition, awareness and supportive inclusion in the cancer care paradigm. in this era of rapidly evolving and expanding technology such as educational websites, internet-based support groups and smartphone applications, a technology-driven inter vention may be helpful in this regard. healthcare professionals and social support mechanisms should unite and support each other to empower silent care givers. references 1 kilic st, oz f. family caregivers’ involvement in caring with cancer and their quality of life. asian pac j cancer prev 2019; 20:1735–41. https://doi.org/10.31557/apjcp.2019.20.6.1735. 2 ochoa cy, buchanan lunsford n, lee smith j. impact of informal cancer caregiving across the cancer experience: a systematic literature review of quality of life. palliat support care 2019; 7:1–21. https://doi.org/10.1017/s1478951519000622. 3 galatsch m, prigerson hg, schnepp w, zu sayn-wittgenstein f, li j. caregiver exposure to critical events and distress in home-based palliative care in germany a cross-sectional study using the stressful caregiving adult reactions to experiences of dying (scared) scale. bmc palliat care 2019; 18:9. https://doi.org/10.1186/s12904-019-0395-8. 4 ferrell b, wittenberg e. a review of family caregiving inter vention trials in oncology. ca cancer j clin 2017; 67:318–25. https://doi.org/10.3322/caac.21396. https://doi.org/10.31557/apjcp.2019.20.6.1735 https://doi.org/10.1017/s1478951519000622 https://doi.org/10.1186/s12904-019-0395-8 https://doi.org/10.3322/caac.21396 clinical & basic research squ med j, august 2010, vol. 10, iss. 2, pp. 227-230, epub. 19th jun 10 submitted: 10th mar 10 revision req. 10th may 10, revision recd. 12th may 10 accepted: 15th may 10 نسبة حدوث إنتان الدم الوليدي املتأخر لدى األطفال اخلدج ذوي الوزن املنخفض بشدة عند الوالدة يف مستشفى من الدرجة الثالثة حتٍد مستمر خــالـد بن مرجــي الفالح امللخ�ص: الهدف: يعد اإنتان الدم الوليدي املتاأخر لدى املواليد ذوي الوزن املنخف�س ب�شدة عند الولدة اأحد الأ�شباب الرئي�شية للمرا�شة والوفيات . هدف الدرا�شة الرئي�شي هو اإيجاد ن�شبة حدوث اإنتان الدم الوليدي املتاأخر عند املواليد اجلدد يف مركزنا ال�شحي من امل�شتوى الثالث على مدى ثالث )3( �شنوات، ثم مقارنتها مع املعايري الدولية. الطريقة: اأجريت هذه الدرا�شة ال�شتعادية حلالت �شابقة يف وحدة العناية املركزة حلديثي طبيعة لتحديد ، دي�شمرب 2008 اإىل يناير 2006 من ال�شعودية، العربية باململكة الريا�س مدينة يف اجلامعي خالد امللك مب�شت�شفى الولدة اجلراثيم وح�شا�شيتها جتاه امل�شادات اجلرثومية وتغري النزعة خالل فرتة الدرا�شة. ت�شمنت الدرا�شة جميع املواليد اخلدج الذين قلت اأوزانهم عند الولدة عن 1250 غرام. النتائج: بلغ اإجمايل عدد املواليد الذين ت�شمنتهم الدرا�شة 273 وليداً. بلغت ن�شبة من اأُخذت منهم عينة واحدة من الدم اأو اأكرث لغر�س زرع الدم بعد اليوم الثاين من ولدتهم )%91.5( )217( وليدا. وكانت ن�شبة من حدث عنده اإنتان الدم مرة واحدة على الأقل %41 . )98/237( معظم احلالت التي حدث عندها اإنتان الدم لأول مرة )%71.4( �شببها ميكروبات اإيجابية اللون يف �شبغة غرام. و ا�شتاأثرت املكورات العنقودية ما ن�شبته %80 من اإجمايل امليكروبات الإيجابية اللون التي ظهرت يف �شبغة غرام ، بينما حازت امُلمر�شات ال�شلبية اللون يف �شبغة غرام على ما ن�شبته %24.5 والفطريات على %4.. اخلال�صة: ما تزال ن�شبة حدوث اإِْنتان الدم الوليدي املتاأخر لدى الأطفال اخلدج ذوي الوزن املنخف�س ب�شدة عند الولدة يف وحدة الرعاية املركزة حلديثي الولدة ثالثيةامل�شتوى ن�شبًة مرتفعة وتتجاوز الن�شب العاملية املبلغ عنها، و تظل امليكروبات الإيجابية اللون يف �شبغة غرام هي امل�شبب الرئي�س حلدوثه. لذلك توجد �رشورة ملحة لتخاذ اإجراءات وقائية جدية لل�شيطرة على الإِْنتان النا�شئ من داخل امل�شت�شفى. مفتاح الكلمات: الأطفال اخلدج ذوي الوزن املنخف�س ب�شدة عند الولدة ، علم الأوبئة ، اإنتان الدم. abstract: objectives: late onset neonatal septicaemia (lons) is one of the major causes of morbidity and mortality in very low birth weight (vlbw) infants. the main objective of this study was to investigate the rate of lons in the neonatal intensive care unit (nicu) of king khalid university hospital (kkuh) in riyadh, saudi arabia over a three year period and compare it to international standards. methods: to determine the incidence of lons, a retrospective study was undertaken and premature infants with a birth weight less than 1250 g were included, giving a total of 273 infants. their bacterial profile and the antimicrobial susceptibility of the isolates were investigated, and the changes in trends over the study period studied. results: 91.5% of included infants (217/237) had 1 or more blood cultures obtained beyond the second day of life. 41% (98/237) of included infants had at least one episode of proven sepsis. the majority (71.4%) of first episode sepsis was caused by gram-positive organisms. coagulase negative staphylococcus accounted for around 80% of all gram-positive infections. gramnegative pathogens accounted for 24.5% of the late onset infections while fungal organisms were responsible for 4%. conclusion: the rate of lons was high and exceeded internationally reported rates in our tertiary care nicu. gram-positive organisms continue to be major causative isolates. high priority should be placed on preventative steps to control nosocomial sepsis. keywords: very low birth weight infants; sepsis; epidemiology incidence of late onset neonatal sepsis in very low birth weight infants in a tertiary hospital an ongoing challenge khalid m alfaleh clinical & basic research neonatal intensive care unit, department of pediatrics, college of medicine, king saud university & king khalid university hospital, riyadh, saudi arabia email: kfaleh@ksu.edu.sa this is a unique book about preventing childhood obesity because contributors from around the world share their knowledge and experience, approaching and analysing the topic from an international perspective rather than the usual narrow national approach. this book also provides the latest evidence-based research, as well as policies and practices in the prevention of childhood obesity. the book is divided into four parts. in part one, the readers are given an overall picture of how the problem needs to be solved. what social and environmental factors drive the increase in childhood obesity? how do social, environment and cultural issues affect the solutions? this section is subdivided into five chapters which familiarise the reader with the context of childhood obesity covering topics such as: the obesity epidemic, the sharp rise of childhood obesity and how most countries of the world are affected by the epidemic. the experience of attempting to scale up the resource to non-communicable diseases in resource poor settings is also covered. the section describes the collective effort by governments, international organisations, the private sector and civil society to prevent childhood obesity. what are the ethical issues when it comes to intervention and programmes aimed at the prevention or treatment of obesity in children? this part of the book concludes by discussing the human rights which are relevant to childhood obesity. it is an excellent introduction to the subsequent chapters of the book and sets out the analytical process which the authors use to tackle the issue. part two commences with an overview which provides the framework for evaluation and alternative study designs in building a useful evidence base. this part of the book outlines the evidence for prevention in multiple settings from the home and family environment to school. it also describes the current evidence and practices in the prevention of childhood obesity in primary health care settings. the current evidence base ÿ^àõ˘]<<ìfl5<ƒfl⁄ ÿ€√÷]ê<<ìâ^èä÷]<hìflèf÷]<  book reviewbook review preventing childhood obesity evidence, policy and practice editors: elizabeth waters, boyd swinburn, jacob seidell, ricardo uauy publisher: wiley-blackwell, bmj books, 2010 isbn: 978-1-4051-5889-3 orders: http://eu.wiley.com squ med j, december 2010, vol. 10, iss. 3, pp. 414-415, epub. 14th nov 10 submitted 21st aug 10 elizabeth waters, boyd swinburn, jacob seidell and ricardo uauy book review | 415 for childhood obesity prevention in primary care is poor and no clear effective approach can be advocated from the literature. it concludes with evidence on the environmental influences on obesity: food and food marketing, physical activity and poverty. many researchers have discussed the effect of rapid economic growth and cultural changes in developing countries on the nutritional status of communities. this part of the book gives the reader a good understanding of the relationship between the rapid growth and urbanisation in developing countries in the coexisting model of undernutrition and obesity and how it affects the prevention of childhood obesity. in part 3, there is an explanation of how new evidence is gathered and applied in the field. the authors have utilised their experience and previous studies to discuss this evidence and how to utilise it in different settings. they also discuss what other factors could hinder the translation of knowledge into practice. it starts with the evaluation of community based obesity interventions. what works at home and in what circumstances and why does it work? marj moodie points out the cost effectiveness of these interventions by using the modelling method. jaap seidell describes the importance of monitoring the childhood obesity epidemic and how this can help in putting actions into effect and evaluating impacts. rebecaa armstrong et al. discuss knowledge translation and exchange. this is a complex process because of the many systems that need to change to reduce the “obesogenic” environment. the last chapter discusses the guidelines on advocacy for childhood prevention and how to implement a successful advocacy campaign. the final section of the book discusses the application of existing evidence to various sectors where policies and practices can be changed. the reader will understand how difficult it is to apply the solutions in the real world, and what tactics are needed as well as how to deal with the political agenda. it starts with defining the role of policy in obesity prevention and how to put these policies onto government agendas around the world. chapters 26 and 27 examine the epode (ensemble prévenons l’obesité des enfants) programme which has the credentials internationally of a programme extending across many communities and several countries. the lessons from this programme, in social marketing for obesity, are discussed in the next chapter. this section also discusses very important practical issues like health promotion in schools with a focus on healthy eating and physical activity and the interventions needed for minorities in developed countries with all the complexity of culture, migration effect, marginalisation and socioeconomic disadvantages which they experience. the last chapter is written by bill dietz a pioneer in obesity research. he explores the lessons learned from the efforts to control tobacco consumption as a potential model for obesity prevention and control by the end of the book, the reader will understand the real threat facing the world in fighting this disease. the problem is complex and the reader might find it difficult initially to follow the different aspects discussed in this book, but later on once he or she has an overall idea, the reader will get a good grasp of it. it would have been useful if more graphs and diagrams had been used to make the book more reader friendly. the book has been written by many authors from around the globe which gives it an international flavour and enriches its scientific content. the book also has a website where updates and resources for the books in this series are available. i recommend the book as a reference tool for professionals working in this field. saif al-yaarubi department of child health sultan qaboos university hospital, muscat, oman email: hawa34@hotmail.com حنو فلسفة وتعليم وحبث وممارسة طبية ذات ثقافة جمتمعية نا�رص بن حماد العزري abstract: medicine is a sociotechnical system wherein culture manifests itself in all its aspects. culture, however, is often intangible and is frequently neglected in formal healthcare education, research and practice. this sounding board article attempts to generate interest in making culture a serious component of healthcare systems at different levels, including its founding philosophical underpinnings, educational systems, research activities and clinical practice. it is recommended that a framework of culture-oriented medical philosophy, education, research and practice be implemented. each component of this framework is briefly discussed in relation to healthcare. culture should be reflected explicitly in healthcare through research activities, medical humanities, cultural competence, communication and ethics. keywords: medicine; medical education; medical philosophy; biomedical research; communication; bioethics; culture; policy making. امللخ�ص: الهدف: الطب نظام اجتماعي تقني تتجلى فيه الثقافة املجتمعية يف كافة جوانبه. ولكن، كثريا ما جند اأن الثقافة املجتمعية اإما اأن تكون غري حم�سو�سة أو غالبا مهم�سة يف اأنظمة التعليم الطبي الر�سمية ويف البحث الطبي واملمار�سة العملية. لذلك، فاإن هذه املقالة ت�سعى لإذكاء الهتمام بجعل الثقافة املجتمعية مكوًنا جاًدا لأنظمة الرعاية ال�سحية على م�ستويات خمتلفة مبا يف ذلك الأ�س�س الفل�سفية التاأ�سي�سية والأنظمة التعليمية واأن�سطة البحث واملمار�سة ال�رصيرية. وبناء على ذلك، فاإنه يو�سى بتنفيذ اإطارعملي يجعل الفل�سفة والتعليم يتعلق فيما باإيجاز الإطار هذا مكونات من مكون كل املجتمعية حيث نوقش الثقافة حمددات �سمن موجهة الطبية واملمار�سة والبحث الإن�سانية والعلوم البحثية الأن�سطة خالل من ال�سحية الرعاية يف وا�سح ب�سكل املجتمعية الثقافة تنعك�س اأن يجب ال�سحية. بالرعاية الطبية والكفاءة الثقافية والتوا�سل والأخالقيات. الكلمات املفتاحية: الطب؛ التعليم الطبي؛ الفل�سفة الطبية؛ البحوث الطبية احليوية ؛ التوا�سل؛ الأخالقيات احليوية؛ الثقافة املجتمعية؛ �سناعة ال�سيا�سات. towards culture-oriented medical philosophy, education, research and practice nasser hammad al-azri sounding board sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e290–295, epub. 21 dec 20 submitted 24 feb 20 revision req. 28 apr 20; revision recd. 5 jun 20 accepted 1 jul 20 https://doi.org/10.18295/squmj.2020.20.04.003 medicine and healthcare form a social system with complex interactions among the various scientific, social, cultural, religious and philosophical backgrounds that form society’s particular worldviews. this paper aims to emphasise the importance of culture in medicine and reiterate the genuine need for reconsidering culture’s role in it. in particular, this paper advocates for culture-oriented medical philosophy, education, research and practice (com-pherp). each component—philosophy, educ ation, research and practice—is discussed in terms of its link to culture and medicine. this paper does not aim to present a detailed account of the topic but rather to assert the need for and spark interest in adopting a greater cultural orientation in the medical field. culture in medicine culture is not easily defined. raymond williams considered the word “culture” to be “one of the two or three most complicated words in the english language”.1 culture involves an amalgamation of factors including personal psychology, perceptions of time and space, proximity to authority and power, dignity and facial recognition, religion, language, uncertainty avoidance, individualism versus collectivism and masculinity versus femininity. trying to combine these factors into a single definition results in varying perspectives. culture is often conceptualised as a way of life that is learned, shared and transmitted by members of a particular group or society.2 there is probably no social activity or behaviour that does not involve culture in some way. while shenkar correctly asserts that “culture does not explain everything,” it is certainly everywhere and in everything and so must be acknowledged in medicine.3 unfortunately, culture’s influence on societal health is often considered distal, diffuse and unspecified; consequently, it is an underestimated determinant of population health, which can have serious implications for medical practice.4 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. department of emergency medicine, ibri hospital, ministry of health, ibri, oman author’s e-mail: dralazri@yahoo.com https://creativecommons.org/licenses/by-nd/4.0/ nasser hammad al-azri sounding board | e291 considering culture in medicine can be highly advantageous and yield positive results by helping aligning healthcare systems with societal as well as the patient’s values. for instance, a national survey on alternative medicine in the united states found that most people who engage in alternative healthcare practices do so because of it is in alignment with their values and beliefs rather than due to a dissatisfaction with biomedicine.5 aligning healthcare systems with patients’ values and worldviews may also improve patient compliance when individuals begin to see their healthcare system as conforming to their needs. consequently, integrating cultural awareness into medicine should lead to safer and more efficient healthcare systems. in contrast, an ignorance of culture’s impact and biases can have serious medical implications.6 miscommunication, noncompliance and discrepancies between patient and practitioner values can limit the benefits of biotechnology and care. such disconnects can lead to inefficient systems that negatively impact patient safety and limit population health improvements. adolf meyer, professor of psychiatry at johns hopkins university, argues that “when the patient and the physician agree on the nature of the problem, the patient gets better”.6 such agreement requires an understanding of the cultures involved. thinking of culture in medicine there are many ways to think about the elements of culture and their relationship to medicine. without a doubt, culture drives medicine because “while medicine benefits from a certain amount of scientific input, culture intervenes at every step of the way”.6 culture might be considered to consist of four dimensions that form the basis for culture-oriented medicine: cultureoriented medical philosophy, culture-oriented medical education, culture-oriented medical research and culture-oriented medical practice. c u lt u r e-o r i e n t e d m e d i c a l p h i l o s o p h y philosophy lays the foundation of knowledge. it elicits worldviews and makes them explicit. practice cannot change without understanding its philosophical underpinnings. education and its practice within any profession is grounded in a particular philosophy. if this philosophy is not explored, there is a risk of importing and applying educational and clinical practices that may not align with societal needs and expectations. such oversights can create a dichotomy and result in wasted resources. medical philosophy is defined as “a field that seeks to explore fundamental issues in theory, research, and practice within the health sciences, particularly metaphysical and epistemological topics”.7 medicine in every society is grounded in a particular worldview. mead asserts “the concepts of health and disease are part of man’s view of the universe and his place within it”.8 in turn, systems can be viewed through a lens that highlights the theoretical as well as practical aspects of everyday life, helping practitioners align their duties with patients’ needs. systems of medical education and practice should be developed with cultural backgrounds in mind and also be able to change and reflect on societal dynamics. healthcare practitioners are rarely taught the philosophical background of medical practice. many might even think such knowledge adds little or no value to medical practice. thus, healthcare systems frequently “mask the physician’s underlying anxiety and relative impotence to deal with the open-ended, frequently insoluble, problems of life, living, and death that are brought to physicians by their expectant patients”.7 this masking and impotence reflect negatively on healthcare as a discipline that must amalgamate its experimental knowledge with patients’ existential enquiries. to bring cultural awareness into medicine, pract itioners must consider the ontological, epistemological and axiological dimensions of medicine, healthcare education and practice. ontological aspects relate to the questions of existence and reality. ontology probes the nature of being human and the social facts of health and illness.9 considering medicine’s epistemological background helps practitioners determine appropriate questions, research methodologies and tools to use and actions to take. axiology focuses on worth in society which relates to bioethical issues.9 studying these philosophical underpinnings should not be considered a purely theoretical exercise but rather a key to developing culturally guided and bioethically acceptable medical education, research and practice. healthcare policy solidifies the concepts of med ical and healthcare philosophy. policy bridges the gap between theoretical philosophical underpinnings and the practical aspects of medical education, research and practice. practically, culture is an important, yet neglected, component in healthcare policy and planning.10 healthcare policymakers need cultural awareness to understand how health and well-being are perceived within a particular society in order to develop more effective and equitable health policies.11 moreover, public trust in healthcare systems reflects cultural dimensions, which in turn affects public towards culture-oriented medical philosophy, education, research and practice e292 | squ medical journal, november 2020, volume 20, issue 4 orientation towards healthy lifestyles, such as a healthy diet.12,13 medical professionals, therefore, must under stand philosophical worldviews and incorporate cultural dimensions in societal healthcare policymaking. c u lt u r e-o r i e n t e d m e d i c a l e d u c at i o n education plays a social role far beyond transference of knowledge and skills from teachers to students. it is the bridge between societal worldviews and a community’s daily practices. medical education transforms cultural values and beliefs about health and illness from theoretical societal worldviews into a platform on which practice can build a strong base. academic medicine carries implicit and explicit worldviews about life, health, illness and the practice of medicine. these worldviews manifest themselves in educational objectives, curricular priorities, teaching methods and training approaches.14 the german society for medical education (gesellschaft für medizinische ausbildung), committee on cultural competence and global health’s position paper advocates for integrating cultural aspects into existing subject curricula.15 minding the philosophical underpinnings of medical education is essential to developing culturally competent medical practices. cultural competence has become a requirement of healthcare professionals’ education and the need for it cannot be denied.16 unfortunately, a disconnect between culture and medical education is not uncommon. in a study of urban medical environments, malone et al. found a significant cultural mismatch between physicians and their residents and medical students, ultimately negatively impacting the programme’s curriculum design and implementation.17 moreover, certain national cultural characteristics can hinder or enhance medical education and innovation.18 considering medical education’s cultural dimensions may guide curricular activities and augment innovation. c u lt u r e-o r i e n t e d m e d i c a l r e s e a r c h science is a social enterprise and research is a tool for exploring social phenomena in society.19 researching cultural aspects of health and illness may boost understanding of these phenomena and help build more efficient and culturally-oriented healthcare systems. culture also is a determinant of research on societal impact.20 the ability to influence culture is the ability to influence conceptions that may affect health behaviour in society.19 technical scientific knowledge may be considered the ‘hardware’ of societal health behaviour. this ‘hardware’, however, does not operate in a vacuum; rather, it needs ‘software’ informed by cultural knowledge. culture alters the physical environment as much as the physical environment transforms culture.21 hardware and software cannot operate in isolation from each other. if research—and the practice that follows it—focuses only on ‘hardware’ and ignores the ‘software’ (or vice versa), it is unlikely to impact society effectively or efficiently. unfortunately, although technical knowledge abounds, the cultural knowledge to implement it is lacking.21 greater investment is needed in researching culture and acculturating research in order to enrich and advance the practice of healthcare research. researching culture includes digging deep to understand relationships between health and illness. by enhancing the ‘software’ informed by cultural knowledge, practitioners would improve their understanding of societal behaviours around health promotion. acculturating research prioritises, designs, conducts, interprets and implements changes through empirical findings which are framed within a cultural paradigm. developing countries generally are so immersed in the technical knowledge (i.e. the ‘hardware’) of applied sciences that the social sciences including cultural studies (i.e. the ‘software’) are mainly considered theoretical exercises. medical research, however, needs to be envisioned as a socio-technical endeavour.22 although incorporating cultural considerations in health systems research is challenging, encouraging culture-oriented, medically applied research which integrates ‘hardware’ and ‘software’ can help achieve a more effective healthcare system.10 c u lt u r e-o r i e n t e d m e d i c a l p r a c t i c e healthcare professionals do not practice value-free techniques and they do not exercise skills that are divorced of culture. assumptions and beliefs frame thinking and guide such value-laden practice. medical practice, however, is just the tip of the values, norms, philosophies and worldviews ‘iceberg’. whether considering scientific knowledge or the art of medical delivery, culture manifests itself in most stages of clinical practice. the extent to which different countries apply scientific knowledge in clinical medicine varies remarkably. payer noted “not only do ways of delivering medical care differ from country to country; so does the medicine that is delivered. the differences are so great that one country’s treatment of choice may be considered malpractice across the border”.6 she added “the same clinical signs may even receive nasser hammad al-azri sounding board | e293 different diagnoses. often, all one must do to acquire a disease is to enter a country where that disease is recognised—leaving the country will either cure the malady or turn it into something else”.6 cultural values and worldviews are often most strongly embodied in bioethics and communication. practical bioethics must be culturally grounded due to its relationship to ethical considerations. the dominant approach in modern biomedical practice is principlism, represented by autonomy, beneficence, nonmaleficence and justice—four principles that carry different meanings across cultures and are not universally applicable.23,24 unfortunately, bioethics principlists rarely consider cultural assumptions and variations, resulting in a lack of cultural perspective around the four principles.25 when applied to cultures with different understandings of these principles, problems can arise. communication, which is central to clinical practice and includes everything that speaks to patients verbally and nonverbally while they are receiving healthcare, is also culturally mediated. communication includes the language used, a person’s tone of voice and body language, the design of the hospital environment and even the signs in the corridors. understanding cultural dimensions may help contextualise comm unication processes and give a better sense of doctor/ patient roles in a clinical encounter.26 unfortunately, there is evidence showing that physicians in training are becoming less empathetic and demonstrate declining communication skills as they progress in their medical education.27,28 efforts to improve technical aspects of healthcare services or patient experiences without improving communication are doomed to failure.29 challenges and limitations culture is like air—it is everywhere—but its presence goes unnoticed until we experience its absence. its intangibility, however, does not negate its existence.4 considering culture in medicine and incorporating it consciously in medical education, research and practice is important but, unfortunately, it is not straightforward. the process of framing culture in relation to medical practice will likely face many challenges and limitations. one major challenge is to bring subconscious cultural assumptions to the surface to think about them consciously. it is particularly true that once immersed within a particular cultural worldview, people tend to neglect other worldviews or consider them irrelevant. payer noted the common ground between french and american medical practices lamenting that “many of the practices i had taken for granted now seemed to be not so much the result of scientific progress but rather outgrowths of american cultural biases that in some cases harmed more than helped our health and wellbeing”.6 another challenge is that culture is commonly considered an ethnic phenomenon. for example, the western/non-western dichotomy is often referred to as a core element in two sets of cultures and their related ethos.30 however, this dichotomy is artificial and oversimplifies differences. the generalisation could even be considered harmful as “it blinds us to real differences within each region”.31 there are as many differences within western communities as there are within non-western communities; likewise, “many comparisons have shown that while doctors within a given country differ somewhat, doctors from different countries differ even more”.6 distinctions in ethos are due less to the western/non-western dichotomy and more to cultural backgrounds and biases. while it might be safe to assume that the closer cultures are in their worldviews, geography and history, the more likely they are to share cultural characteristics, there will still be varying degrees of difference. for example, in examining the differences in saudi arabian, kuwaiti and omani values, robertson et al. found that the three countries share a belief system deeply rooted in islam. each country’s emphasis on the fundamental values they share, however, differs significantly.32 this example shows how generalisations in cultural comparisons can be problematic. the call for com-pherp is not a call for a rigid or limited approach to medical education, research and practice. instead, ahmad noted, “to be of value, either in exploratory or practical terms, ‘culture’ needs to be recognised as a context, itself flexible and contested, interacting with, shaping and shaped by other social and structural contexts of people’s lives”.33 this call recognises the potential that culture offers for medical education, research and practice in particular, and healthcare as a social system in general. it is also worth noting that culture is not an ‘all or none’ phenomenon. rather, it should be incorporated and analysed consciously and critically. some cultural processes can be health hazards in and of themselves.4 this potential threat to health is a good reason to incorporate culture within medical education, research and practice. doing so would allow implicit and taken-for-granted concepts to be made explicit and brought to the surface for discussion, analysis and better understanding. towards culture-oriented medical philosophy, education, research and practice e294 | squ medical journal, november 2020, volume 20, issue 4 the way forward incorporating culture in healthcare is not a theoretical exercise. sociological, anthropological and cultural studies can be utilised to build better healthcare systems. despite its seemingly elusive nature, the concept of culture can be addressed at several levels, and the following practical approach ties research, medical humanities, cultural competence, communication and ethics in this pursuit. interestingly, the way forward in addressing the concept of culture in medicine is also culturally mediated. healthcare practitioners hold varying perspectives on health, illness and life, especially in the current era of strong cultural diversity. medical education and practice, however, generally lack the perspectives offered by medical humanities.34 an understanding of medical humanities is needed as it focuses on interacting with others and understanding the meanings assigned to different situations within the medical context.35 integrating humanities in medical education can help future practitioners develop essential skills of professionalism, communication, self-awareness and reflective practice towards a more holistic approach to their clinical work.36 moreover, the cultural competence movement in healthcare is increasingly recognised at an international level.37 one might assume that healthcare students in their native countries practicing among their compatriots would be culturally competent. in fact, their original concepts of health, well-being and illness change during their medical training when interacting with different cultures of education. in this way, their original conceptualisation of health, well-being and illness is modified.38 consequently, it is essential to re-think how to address health and illness issues from a culturally competent perspective, even for locally-educated healthcare professionals. cultural competence, rather than being limited to selective medical courses, should be inclusive, permeating medical education, research and practice. cultural competence in clinical practice can provide a more holistic approach to patient care. culture manifests itself vividly in communication and ethics—two essential components of medicine. it is surprising, therefore, that a subject so deeply grounded in culture is mostly absent when students are medically trained in a foreign language in medical and allied health schools. medical educators must teach from a cultural perspective, allowing future healthcare providers to apply these perspectives in practice. based on the authors’ experience in teaching bioethics to medical residents and communication to nursing students, the participants’ experiences and comprehension were greatly enhanced when their mother tongue (i.e. arabic) was used with culturally illustrative approaches. once these suggested appr oaches start to permeate medical education, research and practice, culture will become an integrative part of medical practice. miller suggested that “medicine spans the two ends of the [art-science] spectrum: one foot is planted in the physical world, electronic impulses and the muck of the human body; the other is planted in the subjective experiential world of consciousness and conduct”.39 culture offers a chance to appreciate and utilise the subjective world of medicine. therefore, in the bigger picture of health and healthcare in societies, a culture-oriented medical philosophy as well as education, research and practice imbued in culture are needed. conclusion culture is a critical ethereal component of medicine and healthcare. this paper presented a glimpse into com-pherp. these components share individual elements while also presenting an opportunity for cohesive integration. in order to acknowledge culture and its importance, this paper suggests utilising research, medical humanities, cultural competence, communication and ethics to crystallise the concept of culture within medicine and healthcare. if culture is not incorporated and utilised purposefully and consciously, healthcare providers may lose opport unities for enhancing health and bettering healthcare for society. policymakers, educators, researchers and practitioners in healthcare need to address culture as an integrative, core component of all healthcare activities. references 1. williams r. keywords: a vocabulary of culture and society. new york, usa: oxford university press, 2014. p. 87. 2. haralambos m, holborn m. sociology: themes and perspectives. 7th ed. london, uk: harpercollins uk, 2008. p. 663. 3. shenkar o, luo y. international business. 2nd ed. los angeles, usa: sage publications, 2008. 4. eckersley r. is modern western culture a health hazard? int j epidemiol 2006; 35:252–8. https://doi.org/10.1093/ije/dyi235. 5. astin ja. why patients use alternative medicine: results of a national study. jama 1998; 279:1548–53. https://doi.org/10.10 01/jama.279.19.1548. 6. payer l. medicine and culture. new york, usa: henry holt and company, 1996. 7. reiss j, ankeny ra. philosophy of medicine. from: https:// plato.stanford.edu/archives/sum2016/entries/medicine/ accessed: jun 2020. https://doi.org/10.1093/ije/dyi235 https://doi.org/10.1001/jama.279.19.1548 https://doi.org/10.1001/jama.279.19.1548 nasser hammad al-azri sounding board | e295 8. mead m. cultural patterns and technical changes. new york, usa: the new american library, 1955. p. 245. 9. edelheim jr. ontological, epistemological and axiological issues. in: dredge d, airey d, gross mj (eds), the routledge handbook of tourism and hospitality education. london: routledge, 2015. p. 30–42. 10. atkinson s. political cultures, health systems and health policy. soc sci med 2002; 55:113–24. https://doi.org/10.1016/s02779536(01)00213-1. 11. napier da, depladge m, knipper m, lovell r, ponarin e, sanabria e, et al. culture matters: using a cultural contexts of health approach to enhance policy-making. from: www.euro. who.int/__data/assets/pdf_file/0009/334269/14780_worldhealth-organisation_context-of-health_text-aw-web.pdf accessed: jun 2020. 12. van der schee e, braun b, calnan m, schnee m, groenewegen pp. public trust in health care: a comparison of germany, the netherlands, and england and wales. health policy 2007; 81:56–67. https://doi.org/10.1016/j.healthpol.2006.04.004. 13. sun t, horn m, merritt d. impacts of cultural dimensions on healthy diet through public self-consciousness. j consum mark 2009; 26:241–50. https://doi.org/10.1108/07363760910965846. 14. tilburt j, geller g. the importance of worldviews for medical education. acad med 2007; 82:819–22. https://doi.org/10.1097/ acm.0b013e3180d098cc. 15. mews c, schuster s, vajda c, lindtner-rudolph h, schmidt le, bösner s, et al. cultural competence and global health: persp ectives for medical education position paper of the gma committee on cultural competence and global health. gms j med educ 2018; 35:doc28. https://doi.org/10.3205/zma001174. 16. shaya ft, gbarayor cm. the case for cultural competence in health professions education. am j pharm educ 2006; 70:124. https://doi.org/10.5688/aj7006124. 17. malone b, hasan s, sanni a, reilly j. mismatch of cultural dim ensions in an urban medical educational environment. j biomed educ 2013; 617674. https://doi.org/10.1155/2013/617674. 18. jippes m, majoor gd. influence of national culture on the adoption of integrated medical curricula. adv health sci educ theory pract 2011; 16:5–16. https://doi.org/10.1007/s10459010-9236-5. 19. kuruvilla s, mays n, pleasant a, walt g. describing the impact of health research: a research impact framework. bmc health serv res 2006; 6:134. https://doi.org/10.1186/1472-6963-6-134. 20. leroy jl, habicht jp, pelto g, bertozzi sm. current priorities in health research funding and lack of impact on the number of child deaths per year. am j public health 2007; 97:219–23. https://doi.org/10.2105/ajph.2005.083287. 21. graham sa. the sociological approach to epidemiology. am j public health 1974; 64:1046–9. https://doi.org/10.2105/ajph.6 4.11.1046. 22. al-azri nh. do we need a new medical paradigm? oman med j 2012; 27:256–7. https://doi.org/10.5001/omj.2012.60. 23. beauchamp tl, childress jf. principles of biomedical ethics. 7th ed. new york: oxford university press, 2001. 24. ali m. the “bio” in biomedicine: evolution, assumptions, and ethical implications. in: ghaly m, ed. islamic perspectives on the principles of biomedical ethics. london, uk: world scientific publishing, 2016. p. 41–67 25. traphagan jw. rethinking autonomy: a critique of principlism in biomedical ethics. new york, usa: state university of new york press, 2013. p. 31 26. verma a, griffin a, dacre j, elder a. exploring cultural and linguistic influences on clinical communication skills: a qualitative study of international medical graduates. bmc med educ 2016; 16:162. https://doi.org/10.1186/s12909-016-0680-7. 27. woloschuk w, harasym ph, temple w. attitude change during medical school: a cohort study. med educ 2004; 38:522–34. https://doi.org/10.1046/j.1365-2929.2004.01820.x. 28. hojat m, vergare mj, maxwell k, brainard g, herrine sk, isenberg ga, et al. the devil is in the third year: a longitudinal study of erosion of empathy in medical school. acad med 2009; 84:1182–91. https://doi.org/10.1097/acm.0b013e3181b17e55. 29. cosgrove t. the cleveland clinic way: lessons in excellence from one of the world’s leading health care organizations. new york, usa: mcgraw-hill education, 2014. 30. al-saadoon m, al-adawi s. informed consent in societies with different ethos of ‘selfhood’. sultan qaboos univ med j 2019; 19:e1–3. https://doi.org/10.18295/squmj.2019.19.01.001. 31. mead r, andrews tg. international management, 4th ed. west sussex, uk: wiley-blackwell, 2009. p.9. 32. robertson cj, al-khatib ja, al-habib m, lanoue d. beliefs about work in the middle east and the convergence versus divergence of values. j world bus 2001; 36: 223–44. https://doi. org/10.1016/s1090-9516(01)00053-0. 33. ahmad wiu. the trouble with culture. in: kelleher d, hillier s, eds. researching cultural differences in health. london, uk: routledge, 1996. p. 190–219. 34. al-azri nh. sent to explore, conquer and heal: history of the evolution of biomedicine in oman during the 19 century. sultan qaboos univ med j 2011; 11:187–95. 35. malpas p, jowsey t. humanities for medical students: essential to their cultural competence and patient-engaged practices of care. med ed publish 2018. https://doi.org/10.15694/mep.20 18.0000202.1. 36. wald hs, mcfarland j, markovina i. medical humanities in medical education and practice. med teach 2019; 41:492–6. https://doi.org/10.1080/0142159x.2018.1497151. 37. betancourt jr, green ar, carrillo je, ananah-firempong o 2nd. defining cultural competence: a practical framework for addressing racial/ethnic disparities in health and health care. public health rep 2003; 118:293–302. https://doi.org/10.1093/ phr/118.4.293. 38. mcgarvey a, brugha r, conroy rm, clarke e, byrne e. international students’ experience of a western medical school: a mixed methods study exploring the early years in the context of cultural and social adjustment compared to students from the host country. bmc med educ 2015; 15:111. https://doi. org/10.1186/s12909-015-0394-2. 39. mcmanus ic. humanity and the medical humanities. lancet 1995; 346:1143–5. https://doi.org/10.1016/s0140-6736(95)91806-x. https://doi.org/10.1016/s0277-9536%2801%2900213-1 https://doi.org/10.1016/s0277-9536%2801%2900213-1 https://doi.org/10.1016/j.healthpol.2006.04.004 https://doi.org/10.1108/07363760910965846 https://doi.org/10.1097/acm.0b013e3180d098cc https://doi.org/10.1097/acm.0b013e3180d098cc https://doi.org/10.3205/zma001174 https://doi.org/10.5688/aj7006124 https://doi.org/10.1155/2013/617674 https://doi.org/10.1007/s10459-010-9236-5 https://doi.org/10.1007/s10459-010-9236-5 https://doi.org/10.1186/1472-6963-6-134 https://doi.org/10.2105/ajph.2005.083287 https://doi.org/10.2105/ajph.64.11.1046 https://doi.org/10.2105/ajph.64.11.1046 https://doi.org/10.5001/omj.2012.60 https://doi.org/10.1186/s12909-016-0680-7 https://doi.org/10.1046/j.1365-2929.2004.01820.x https://doi.org/10.1097/acm.0b013e3181b17e55 https://doi.org/10.18295/squmj.2019.19.01.001 https://doi.org/10.1016/s1090-9516%2801%2900053-0 https://doi.org/10.1016/s1090-9516%2801%2900053-0 https://doi.org/10.15694/mep.2018.0000202.1 https://doi.org/10.15694/mep.2018.0000202.1 https://doi.org/10.1080/0142159x.2018.1497151 https://doi.org/10.1093/phr/118.4.293 https://doi.org/10.1093/phr/118.4.293 https://doi.org/10.1186/s12909-015-0394-2 https://doi.org/10.1186/s12909-015-0394-2 https://doi.org/10.1016/s0140-6736%2895%2991806-x 2department of pharmaceuticals, 1faculty of pharmacy, university of indonesia, depok, indonesia; 3department of pharmaceutical installation, dharmais cancer hospital, jakarta, indonesia *corresponding author’s e-mails: ratna.sari51@ui.ac.id and wiwi.ratnasaridewi@gmail.com تقييم استخدام املضادات احليوية عند املصابني باإلنتان يف وحدة عناية مركزة دراسة مستعرضة يف مستشفى مرجعي بإندونيسيا راتنا �شاري دووي، ماك�شوم رادجي، رزقا اأندلو�شيا abstract: objectives: this study aimed to evaluate the appropriateness of antibiotic use and factors associated with outcomes among sepsis patients in an intensive care unit (icu). methods: this cross-sectional study was carried out from february to may 2017 and included all adult patients with sepsis or septic shock admitted to the icu of dharmais cancer hospital, jakarta, indonesia. data were collected from the patients’ medical records. results: a total of 60 patients with sepsis or septic shock were admitted to the icu during the study period. the most common source of infection was hospital-acquired pneumonia (61.7%) and the majority had two or more comorbidities (93.3%). there were 115 antibiotic regimens prescribed. overall, 33.3% of patients were prescribed inappropriate types of antibiotics and 51.7% were given an inappropriate dosage. the mortality rate was 68.3%. there was a statistically significant association between patient outcome and inappropriate doses of antibiotics (p = 0.034), although not inappropriate types of antibiotics (p = 0.050). a multivariate analysis indicated that the main factors influencing patient outcome were septic shock and the presence of at least two comorbidities (p <0.050 each). conclusion: inappr opriate doses of antibiotics, a diagnosis of septic shock and the presence of at least two comorbidities were found to significantly increase the mortality rate of sepsis patients admitted to an icu in indonesia. keywords: drug prescription, trends; antibiotics; sepsis; septic shock; intensive care units; indonesia. امللخ�ص: الهدف: هدفت هذه الدرا�شة لتقومي مالئمة ا�شتخدام امل�شادات احليوية، والعوامل املرتبطة بنتائج ذلك عند امل�شابني بالإنتان املر�شى من البالغني كل و�شملت ،2017 عام اأبريل اإىل فرباير من امل�شتعر�شة الدرا�شة هذه اأجريت الطريقة: مركزة. عناية وحدة يف امل�شابني بالإنتان اأو ال�شدمة النتانية الذين اأدخلوا يف وحدة العناية املركزة يف م�شت�شفى دهارميا�ص لعالج لل�رسطان بجاكارتا يف اإندوني�شيا. وجمع املعلومات من �شجالت املر�شى. النتائج: اأُدخل �شتون مري�شا بالإنتان اأو ال�شدمة النتانية للعناية املركزة خالل فرتة الدرا�شة. وكان اأكرب �شبب العدوى هو التهاب الرئة املكت�شب يف امل�شت�شفى )%61.7(، كان غالبهم م�شابا اأي�شا مبر�شني م�شاحبني اأو اأكرث )%93.3(. ومت و�شف 115 من نظم امل�شادات احليوية. ووجد على وجه العموم اأن %33.3 من امل�شادات املو�شوفة للمر�شى كانت غري مالئمة، واأن %51.7 من املر�شى كانوا قد اأُعطيوا امل�شادات بجرعات غري مالئمة. وبلغت ن�شبة الوفيات بني اأولئك املر�شى %68.3. ووجد اأن هنالك عالقة اإح�شائية معتدة بني ما حدث من نتائج عند املر�شى وعدم مالئمة جرعات امل�شادات احليوية )p = 0.034(، ولكن لي�ص بينها وبني مالئمة امل�شادات نف�شها )p = 0.050(. واأو�شح حتليل متعدد املتغريات اأن ال�شبب الرئي�ص ملا حدث للمر�شى كان هو ال�شدمة احليوية، امل�شادات جرعات مالئمة عدم اأن وجد حالة(. اخلال�صة: كل يف p >0.050( الأقل على م�شاحبني مر�شني ووجود النتانية، وت�شخي�ص حدوث �شدمة اإنتانية، مع وجود مر�شني م�شاحبني اأو اأكرث هي ما يزيد ب�شورة يعتد بها من الوفيات عند املر�شى امل�شابني بالإنتان يف ق�شم للعناية املركزة مب�شت�شفى يف اندوني�شيا. الكلمات املفتاحية: و�شفات الأدوية، اجتاهات؛ م�شادات حيوية؛ اإنتان؛ �شدمة اإنتانية؛ وحدة عناية مركزة؛ اإندوني�شيا. evaluation of antibiotic use among sepsis patients in an intensive care unit a cross-sectional study at a referral hospital in indonesia *ratna s. dewi,1 maksum radji,2 rizka andalusia3 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e367–373, epub. 19 dec 18 submitted 20 dec 17 revisions req. 21 feb & 25 apr 18; revisions recd. 31 mar & 9 may 18 accepted 24 may 18 doi: 10.18295/squmj.2018.18.03.017 advances in knowledge this study found that the mortality rate of sepsis patients admitted to an intensive care unit in indonesia was quite high. factors found to significantly influence mortality included inappropriate doses of antibiotics, a diagnosis of septic shock and the presence of at least two comorbidities. application to patient care the results of this study could be used by physicians, pharmacists and other healthcare workers to increase the appropriate use of antibiotics, perhaps by implementing an antibiotic stewardship programme or with the formulation of guidelines for appropriate antibiotic usage based on the source of infection and the patient’s clinical condition. sepsis is a life-threatening condition caused by a dysregulated host response to infection leading to organ dysfunction.1 it is most likely to develop in individuals with a weakened immune system, often because of treatments such as chemotherapy. however, critically-ill patients are also at risk due to the prevalence of drug-resistant bacteria in hospital settings and the need for catheterisation and wound drainage.2 sepsis evaluation of antibiotic use among sepsis patients in an intensive care unit a cross-sectional study at a referral hospital in indonesia e368 | squ medical journal, august 2018, volume 18, issue 3 occurs in approximately 2% of all hospitalised cases and among 6–30% of all patients admitted to intensive care units (icus) in developed countries.3,4 both sepsis and septic shock are leading causes of morbidity and mortality in icus (21% and 28%, respectively).4–6 the management of sepsis or septic shock requires a comprehensive and systematic approach combining the use of appropriate diagnostic measures, the rapid initiation of appropriate empirical antibiotics and the administration of supportive therapy.7 according to internat ional guidelines for the management of sepsis and septic shock, appropriate antimicrobials should be administered within one hour of diagnosis, with the dosage optimised according to standard pharmacokinetic/pharmacodynamic principles.8 in addition, the patient’s location at the time of infection, the source of the infection and the prevalence and susceptibility patterns of common local pathogens should also be factored into the choice of therapy.8,9 in icus, antibiotics are the most common type of medicine and are prescribed approximately 10 times more than in general hospital wards.10 however, inappropriate therapy and delays in prescribing appropriate antibiotics are important factors related to increased morbidity and mortality in sepsis patients.8,11,12 in thailand, there were 229 cases of sepsis reported in 2012, of which 61.6% developed septic shock; the overall mortality rate for patients who were prescribed first-dose inappropriate and appropriate antibiotics was 75% and 68.3%, respectively.13 in a referral hospital in indonesia, there were 126 cases of sepsis admitted between 2011 and 2012; the mortality rate was 81.8% and 66.7%, respectively, for patients prescribed inappropriate types and doses of antibiotics.14 the dharmais cancer hospital is a 364-bed tertiary care hospital in jakarta, indonesia, which also serves as a cancer referral centre. according to a retrospective study, 18.5% of patients admitted to this hospital between 2011 and 2012 had sepsis.9 however, to the best of the authors’ knowledge, no studies have yet evaluated the appropriateness of antibiotic usage for sepsis patients in the hospital’s icu. this study therefore aimed to evaluate the appropriateness of antibiotic use with regards to antibiotic type and dosage and factors associated with patient outcomes among icu patients with sepsis or septic shock admitted to dharmais cancer hospital. methods this cross-sectional study was carried out between february and may 2017 in the icu of dharmais cancer hospital. all adult sepsis or septic shock patients who were receiving antibiotic therapy and were hospitalised in the icu for at least 24 hours during the study period were included. patients with incomplete medical records, those who had subsequent episodes of sepsis/septic shock or who were admitted for less than 24 hours and those who were under 18 years of age were excluded. in addition, patients readmitted to the icu during the study period were not evaluated again. the required sample size was calculated using the following formula:15 ( )21z 2 2d p (1-p) n = α where is 1.96 (at a 95% confidence interval), p is 10% (the expected proportion of sepsis) and d is 0.1 (the relative precision).15,16 therefore, the total sample size required was 35 patients. 1-z α2 table 1: recommended antibiotic regimen in sepsis cases according to source of infection17–20 source of infection recommended antibiotic regimen pulmonary cap • β-lactam (i.e. ceftriaxone, cefotaxime or ampicillin/sulbactam) plus azithromycin • β-lactam (i.e. ceftriaxone, cefotaxime or ampicillin/sulbactam) plus respiratory flouroquinolones (i.e. levofloxacin or moxifloxacin) hap, hcap or vap • antipseudomonal β-lactam (i.e. piperacillin/ tazobactam, cefepime, meropenem, imipenem or doripenem) plus aminoglycosides (i.e. gentamicin, tobramycin or amikacin) or antipseudomonal flouroquinolone (i.e. levofloxacin or ciprofloxacin)* blood stream crbsi • vancomycin or daptomycin† plus antipseudomonal β-lactam (i.e piperacillin/ tazobactam and cefepime) or carbapenem (i.e. meropenem, imipenem or doripenem) with or without an aminoglycoside (i.e. gentamicin, tobramycin or amikacin) urinary urosepsis • third-generation cephalosporin (ceftriaxone or cefotaxime) with or without an aminoglycoside (gentamicin, tobramycin or amikacin) or fluoroquinolone (levofloxacin or ciprofloxacin) urological interventions • antipseudomonal β-lactam (i.e piperacillin/ tazobactam and cefepime) or carbapenem (i.e. meropenem, imipenem or doripenem)‡ unknown unspecified • antipseudomonal β-lactam (i.e piperacillin/ tazobactam and cefepime) or carbapenem (i.e. meropenem, imipenem or doripenem) plus an aminoglycoside or antipseudomonal flouroquinolon (i.e. levofloxacin or ciprofloxacin) plus vancomycin cap = community-acquired pneumonia; hap = hospital-acquired pneumonia; hcap = healthcare-associated pneumonia; vap = ventilator-associated pneumonia; crbsi = catheter-related blood-stream infection. *vancomycin or linezolid can be added if methicillin-resistant staphylococcus aureus is suspected. †if there is a high rate of resistance to vancomycin (minimum inhibitory concentration of ≥2 µg/ml). ‡this regimen is also recommended if there is a risk of multidrug resistance. ratna s. dewi, maksum radji and rizka andalusia clinical and basic research | e369 the diagnosis of sepsis and septic shock were based on international criteria.1 data were collected from the patients’ medical and drug-prescribing records using a predesigned structured form. this included the patients’ demographic characteristics, diagnosis, length of stay (los), sequential organ failure assessment (sofa) score, the presence of co-morbidities (i.e. malignancy, diabetes mellitus, cardiovascular disease, chronic kidney disease, liver disease or respiratory insufficiency), source of infection, ventilator use, causative pathogens, antibi otic usage (i.e. type and dose), the timing of the specimen collection for culture and outcome. in addition, samples of blood, sputum, bronchial rinse and urine were collected for cultures and antimicrobial sensitivity testing. antibiotics were assessed for appropriateness acc ording to type and dosage. local microbial patterns during the period of june to december 2016 in the icu were used to determine antimicrobial susceptibility data.9 the type of antibiotic prescribed during the study period was subsequently deemed appr opriate if it was prescribed empirically according to the local microbial susceptibility data, whereas it was deemed to be inappropriate if it did not reflect the susceptibility data. this assessment was undertaken by the antibiotic stewardship committee of the hospital, consisting of physicians, clinical pharmacists and nurses. additionally, the appropriateness of each type of antibiotic was considered in light of the source of infection, as determined by the attending physician [table 1].17–20 the initial dose of the antibiotic was deemed appropriate after adjustment for the patient’s clinical condition, while unadjusted dos ages were considered inappropriate.21 data were analysed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). the independent variable was the appropriateness of the antibiotics (according to dose and type) and the dependent variable was patient outcome. other variables included age, gender, diagnosis, number of comorbidities, ventilator use and sofa score. differences in the appropriateness of antibiotics based on local microbial patterns were presented as descriptive data, while differences in the appropriateness of antibiotics based on the source of infection and dosage were presented as both descriptive and analytical data. a corr ected chi-squared test was used to determine if the differences were significant. all correlations with a p value of <0.250 were included in a subsequent multivariate analysis. a logistic regression analysis was performed to identify factors influencing patient outcome. a p value of <0.050 was considered statistically significant. ethical approval for this study was obtained from the ethical committee of dharmais cancer hospital (#013/kepk/ii/2017). no patient consent was deemed necessary as permission to review the medical records was granted by the appropriate authorities at dharmais table 2: characteristics of sepsis patients admitted to the intensive care unit of dharmais cancer hospital, jakarta, indonesia (n = 60) characteristic n (%) age in years 18–39 9 (15) 40–59 39 (65) ≥60 12 (20) mean ± sd (range) 51.4 ± 11.7 (24–82) gender male 32 (53.3) female 28 (46.7) diagnosis sepsis 31 (51.7) septic shock 29 (48.3) length of stay in days ≥7 12 (20) <7 48 (80) median ± sd (range) 4.0 ± 4.4 (2–23) ventilation use yes 52 (86.7) no 8 (13.3) sofa score >8 29 (48.3) ≤8 31 (51.7) source of infection hap 37 (61.7) iai 11 (18.3) cap 3 (5) uti 2 (3.3) hcap 1 (1.7) unknown 6 (10) number of comorbidities ≥2 56 (93.3) <2 4 (6.7) type of comorbidity* malignancy 60 (100) respiratory insufficiency 51 (85) cardiovascular disease 20 (33.3) chronic kidney disease 16 (26.7) liver disease 7 (11.7) diabetes mellitus 2 (3.3) sd = standard deviation; sofa = sequential organ failure assessment; hap = hospital-acquired pneumonia; iai = intra-abdominal infection; cap = community-acquired pneumonia; uti = urinary tract infection; hcap = healthcare-associated pneumonia. *percentages do not add up to 100% as some patients may have had more than one comorbidity. evaluation of antibiotic use among sepsis patients in an intensive care unit a cross-sectional study at a referral hospital in indonesia e370 | squ medical journal, august 2018, volume 18, issue 3 cancer hospital. all information obtained during the review of the records was kept confidential and used only for the purposes of this study. results a total of 182 patients were admitted to the icu of dharmais cancer hospital during the study period. of these, 60 adults (33%) were diagnosed with either sepsis (51.7%) or septic shock (48.3%). the mean age of the patients was 51.4 ± 11.7 years (range: 24–82 years old) and 53.3% were male. the median los was 4.0 ± 4.4 days (range: 2–23 days), with 80% staying less than seven days. most patients had a sofa score of ≤8 (51.7%) and used a ventilator (86.7%). the most common source of infection was hospital-acquired pneumonia (hap; 61.7%), followed by intra-abdominal infections (iai; 18.3%). almost all of the patients had two or more comorbidities (93.3%), with the most frequent being malignancy (100%) and respiratory insufficiency (85%) [table 2]. blood, sputum, bronchial rinse and urine samples were available for 49 patients (81.7%). a total of 66 cultures were taken from the samples, of which 44 (66.7%) were positive and 22 (33.3%) were negative. overall, 21 microorganisms were detected in the positive cult ures, the most common being acinetobacter baumannii (15.2%), followed by escherichia coli (6.1%), klebsiella pneumoniae (4.6%) and staphylococcus haemolyticus (4.6%). of the isolates from positive cultures, 41 (93.2%) were known to be susceptible to antibiotics, while the remaining three (6.8%) contained only fungi. in total, 39.3% of the microorganisms were resistant to the anti biotic administered, 28.6% were sensitive to the antibiotic administered, 4.8% had intermediate resistance to the antibiotic administered or required a higher dose and 27.4% were not tested for sensitivity. pseudomonas aeruginosa was the most sensitive to the administered antibiotics (87.5%), while a. baumannii was the most resistant (72.2%). in total, there were 115 different antibiotic regimens, of which eight (7%) constituted definitive therapy and 107 (93%) were empirical. a total of 16 antibiotics were prescribed. meropenem (41.1%) was most frequently prescribed, followed by levofloxacin (20%) and amikacin (11.3%). levofloxacin was prescribed in three of the def initive regimens (37.5%) [figure 1]. the most common antibiotic regimens consisted of meropenem (16% in hap cases, 40% in community-acquired pneumonia (cap) cases, 50% in iai cases and 33.3% in cases wherein the source of infection was unknown), mero penem plus levofloxacin (26% in hap cases, 40% in table 3: correlations between appropriateness of type and dose of antibiotics and outcome among sepsis patients admitted to the intensive care unit of dharmais cancer hospital, jakarta, indonesia (n = 60) variables n (%) p value* total died (n = 41) survived (n = 19) type of antibiotic inappropriate 20 (33.3) 17 (85) 3 (15) 0.050 appropriate 40 (66.7) 24 (60) 16 (40) dose of antibiotic inappropriate 31 (51.7) 25 (80.6) 6 (19.4) 0.034 appropriate 29 (48.3) 16 (55.2) 13 (44.4) *using a chi-squared test. figure 1: distribution of empirical and definitive antibiotic regimens prescribed to sepsis patients admitted to the intensive care unit of dharmais cancer hospital, jakarta, indonesia. *inappropriate according to local microbial patterns/antimicrobial susceptibility data. ratna s. dewi, maksum radji and rizka andalusia clinical and basic research | e371 cap cases and 14.3% in iai cases), cefepime plus amikacin (100% in healthcare-associated pneumonia cases), cefotaxime and ceftriaxone plus levofloxacin (50% each in urinary tract infection cases). overall, 23 patients (38.3%) received one antibiotic, 26 (43.3%) received two antibiotics, four (6.7%) received three antibiotics, five (8.3%) received four antibiotics and two (3.3%) received five antibiotics. a total of 20 patients (33.3%) received inappropriate types of antibiotics according to either local microbial patterns or the source of infection (45.2% and 25%, respectively). inappropriate doses of antibiotics were prescribed to 31 patients (51.7%), with dose adjustments required by 16 patients (26.7%). the mortality rate was 68.3%. there was a statistically significant positive assoc iation between patient outcome and inappropriate doses of antibiotics (p = 0.034), but not inappropriate types of antibiotics (p = 0.050) [table 3]. according to a bivariate analysis, a diagnosis of septic shock, having at least two comorbidities, ventilator use, a sofa score of >8 and the presence of a liver disorder had an effect on mortality (p <0.250 each) [table 4]. a multivariate analysis indicated that a diagnosis of septic shock and the presence of at least two comorbidities were significantly associated with mortality (p <0.050 each) [table 5]. discussion in the current study, sepsis was more common among patients under 60 years old, although the mortality rate was higher among those over 60 years old. in the usa, the risk of sepsis increases with every table 4: correlations between risk factors and outcome among sepsis patients admitted to the intensive care unit of dharmais cancer hospital, jakarta, indonesia (n = 60) risk factor n (%) p value* total died (n = 41) survived (n = 19) age in years ≥60 12 (20) 9 (75) 3 (25) 0.579 <60 48 (80) 32 (66.7) 16 (33.3) gender male 32 (53.3) 23 (71.9) 9 (28.1) 0.528 female 28 (46.7) 18 (64.3) 10 (35.7) diagnosis sepsis 31 (51.7) 15 (48.4) 16 (51.6) 0.001 septic shock 29 (48.3) 26 (89.7) 3 (10.3) ventilator use yes 52 (86.7) 37 (71.2) 15 (28.8) 0.231 no 8 (13.3) 4 (50) 4 (50) sofa score >8 29 (48.3) 25 (86.2) 4 (13.8) 0.004 ≤8 31 (51.7) 16 (51.6) 15 (48.4) number of comorbidities ≥2 56 (93.3) 40 (71.4) 16 (28.6) 0.054 <2 4 (6.7) 1 (25) 3 (75) type of comorbidity malignancy 60 (100) 41 (68.3) 19 (31.7) respiratory insufficiency 51 (85) 36 (70.6) 15 (29.4) 0.371 cardiovascular disease 20 (33.3) 15 (75) 5 (25) 0.432 chronic kidney disease 16 (26.7) 12 (75) 4 (25) 0.503 liver disease 7 (11.7) 7 (100) 0 (0) 0.055 diabetes mellitus 2 (3.3) 2 (100) 0 (0) 0.327 sofa = sequential organ failure assessment. *using a chi-squared test. table 5: multivariate analysis showing correlations bet ween risk factors and outcome of sepsis patients in the intensive care unit of dharmais cancer hospital, jakarta, indonesia (n = 60) factors or (95% ci) p value* step 1 septic shock 0.064 (0.007–0.573) 0.014 presence of liver disease 0.000 0.999 ventilator use 0.485 (0.050–4.706) 0.533 sofa score of >8 0.295 (0.066–1.310) 0.108 ≥2 comorbidities 0.042 (0.002–1.018) 0.051 constant 78.297 0.015 step 2 septic shock 0.063 (0.007–0.561) 0.013 presence of liver disease 0.000 0.999 sofa score of >8 0.294 (0.067–1.290) 0.105 ≥2 comorbidities 0.033 (0.001–0.786) 0.035 constant 51.619 0.018 step 3 septic shock 0.048 (0.006–0.411) 0.006 sofa score of >8 0.251 (0.060–1.053) 0.059 ≥2 comorbidities 0.023 (0.001–0.556) 0.020 constant 71.819 0.012 or = odds ratio; ci = confidence interval; sofa = sequential organ failure assessment. *using a logistic regression test. evaluation of antibiotic use among sepsis patients in an intensive care unit a cross-sectional study at a referral hospital in indonesia e372 | squ medical journal, august 2018, volume 18, issue 3 year of age by 1.5%.22 increased age over 60 years is a predictor of mortality in sepsis, particularly if adequate empirical antibiotic therapy is not initiated.23 in terms of gender, there were slightly more male than female patients in the current study. however, the frequency of sepsis among male patients was higher in a similar study conducted by ferrer et al. (61.9%).24 adrie et al. demonstrated that older men are more vulnerable to sepsis than women.25 another study showed that cross-linked mutations or polymorphisms in female mice resulted in the more dynamic activation, regulation and function of immune cells during the inflammatory process, while male mice only demonstrated a partial response to inflammation.26 unfortunately, the mortality rate of patients with septic shock in icus remains high, despite fluid resusc itation measures, adequate care and the early administration of empirical antibiotics.27 in the current study, a diagnosis of septic shock was significantly associated with mortality, despite septic shock being less common. in a similar study, ogura et al. reported that 45.2% of japanese patients were diagnosed with septic shock, with a significantly higher mortality rate in this group (63.6% versus 37.5%; p <0.010).28 in sepsis, venodilation, fluid transudation from the vesicular space into the tissues, decreased oral intake and increased fluid loss facilitates the occurrence of hypovolaemic events; in septic shock, ventricular dysfunction and arteriolar dilatation contr ibute to the failure of function and organ perfusion.27 hap is one of the most frequent and severe complications observed among patients hospitalised in icus.29 in the current study, hap was the most frequent source of infection. however, katu et al. found cap to be most common among sepsis patients in a referral hospital in indonesia.14 this could be due to differences in the location of the study, the sample and incidence of infections, as well as the extent of each individual patient’s immune response. empirical antibiotic therapy is key in the initial management of sepsis patients. the type of antibiotic to be prescribed is usually determined by an assessment of the potential pathogens responsible for the infection, taking into account local antibiotic susceptibility patterns.30 however, failure to determine the source of infection can potentially lead to the misidentification of pathogens, resulting in the inappropriate selection of antibiotics.8,9 previous research has established that the administration of inappropriate antimicrobials substantially incr eases mortality among sepsis patients.8,11–13 in the current study, a significant association was noted between inappr opriate doses of antibiotics and mortality; however, there was no significant association between inappropriate types of antibiotics and mortality. in contrast, katu et al. found that inappropriate types of antibiotics were significantly associated with mortality.14 this variation in results may again be due to differences in the sample as well as study design, such as the inclusion and exclusion criteria and antibiotic guidelines used. nevertheless, the multivariate analysis in the present study indicated that the most significant factors associated with mort ality were septic shock and the presence of at least two comorbidities; therefore, regardless of the appropriateness of the antibiotics administered, the mortality rate was still high. this is likely due to the critical clinical cond ition of such patients, which is generally poor in light of their admission to the icu. according to international guidelines, it is strongly recommended that appropriate antimicrobial therapy be administered within one hour of recognising cases of sepsis or septic shock.8 however, the exact antibiotic delivery time in the current study could not be assessed as almost all of the patients had received antibiotics prior to their admission to the icu. furthermore, antimicrobial sensitivity testing was not performed for all of the antibiotics administered during the study period due to interdepartmental miscommunication, wherein staff of the microbiology laboratory were unaware of the specific antibiotics being administered to sepsis patients in the icu. additionally, as the antibiotic stew ardship committee was still under development during this time, no uniform reference was available for the selection of antibiotics by hospital staff. finally, microbial cultures could not be performed in 11 cases due to diff iculties collecting samples from these patients. conclusion this study found that inappropriate doses of antibiotics were significantly associated with mortality among sepsis patients in an indonesian icu, although inappropriate types of antibiotics were not. furthermore, a diagnosis of septic shock and the presence of at least two comorb idities were significant risk factors related to mortality. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. singer m, deutschman cs, seymour cw, shankar-hari m, annane d, bauer m, et al. the third international consensus definitions for sepsis and septic shock (sepsis-3). jama 2016; 316:801–10. doi: 10.1001/jama.2016.0287. https://doi.org/10.1001/jama.2016.0287 ratna s. dewi, maksum radji and rizka andalusia clinical and basic research | e373 2. international sepsis forum. promoting a better understanding of sepsis. from: http://internationalsepsisforum.com/wp-cont ent/uploads/2012/02/2003-revsion-sepsis1103.pdf accessed: may 2018. 3. ullah ar, hussain a, ali i, samad a, ali shah st, yousef m, et al. a prospective observational study assessing the outcome of sepsis in intensive care unit of a tertiary care hospital, pesha war. pak j med sci 2016; 32:688–93. doi: 10.12669/pjms.323.9978. 4. fleischmann c, scherag a, adhikari nk, hartog cs, tsaganos t, schlattmann p, et al. assessment of global incidence and mort ality of hospital-treated sepsis: current estimates and limitations. am j respir crit care med 2016; 193:259–72. doi: 10.1164/rccm. 201504-0781oc. 5. ortíz g, dueñas c, rodríguez f, barrera l, de la rosa g, dennis r, et al. epidemiology of sepsis in colombian intensive care units. biomedica 2014; 34:40–7. doi: 10.1590/s0120-41572014000100007. 6. kaukonen km, bailey m, suzuki s, pilcher d, bellomo r. mortality related to severe sepsis and septic shock among critically ill patients in australia and new zealand, 2000-2012. jama 2014; 311:1308–16. doi: 10.1001/jama.2014.2637. 7. bochud py, glauser mp, calandra t; international sepsis forum. antibiotics in sepsis. intensive care med 2001; 27:s33–48. doi: 10.1007/pl00003796. 8. rhodes a, evans le, alhazzani w, levy mm, antonelli m, ferrer r, et al. surviving sepsis campaign: international guidelines for man agement of sepsis and septic shock 2016. intensive care med 2017; 43:304–77. doi: 10.1007/s00134-017-4683-6. 9. yunus l, prihartono na, tobing dl. [primary bloodstream inf ection related to central venous catheter in patient with cancer at dharmais national cancer center year 2011-2012]. m.sc. thesis, 2013, university of indonesia library, depok, indonesia. 10. erbay a, bodur h, akinci e, colpan a. evaluation of antibiotic use in intensive care units of a tertiary care hospital in turkey. j hosp infect 2005; 59:53–61. doi: 10.1016/j.jhin.2004.07.026. 11. kumar a, ellis p, arabi y, roberts d, light b, parrillo je, et al. initiation of inappropriate antimicrobial therapy results in a five fold reduction of survival in human septic shock. chest 2009; 136:1237–48. doi: 10.1378/chest.09-0087. 12. gaieski df, mikkelsen me, band ra, pines jm, massone r, furia ff, et al. impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. crit care med 2010; 38:1045–53. doi: 10.1097/ccm.0b013e3181cc4824. 13. lueangarun s, leelarasamee a. impact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: a retrospective study. interdiscip perspect infect dis 2012; 2012:765205. doi: 10.1155/2012/765205. 14. katu s, suwarto s, pohan ht, abdullah m. [factors that influence the success of empirical antibiotic therapy in patients with severe sepsis and septic shock in the inpatient ward of the hosp ital cipto mangunkusumo]. indones int med j 2015; 2;96–106. doi: 10.7454/jpdi.v2i2.72. 15. lwanga sk, lemeshow s. sample size determination in health studies: a practical manual. geneva, switzerland: world health organization, 1991. pp. 1–26. 16. anggriani y, banun a, erliana. [evaluation of antibiotic usage in hcu and icu wards in dharmais cancer hospital february to march 2012]. j indones pharm sci 2013; 11:182–90. 17. mandell la, wunderink rg, anzueto a, bartlett jg, campbell gd, dean nc, et al. infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults. clin infect dis 2007; 44:s27–72. doi: 10.1086/511159. 18. american thoracic society; infectious diseases society of america. guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneu monia. am j respir crit care med 2005; 171:388–416. doi: 10.11 64/rccm.200405-644st. 19. mermel la, allon m, bouza e, craven de, flynn p, o’grady np, et al. clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the infectious diseases society of america. clin infect dis 2009; 49:1–45. doi: 10.1086/599376. 20. wagenlehner fm, lichtenstern c, rolfes c, mayer k, uhle f, weidner w, et al. diagnosis and management for urosepsis. int j urol 2013; 20:963–70. doi: 10.1111/iju.12200. 21. lacy cf, armstrong ll, goldman mp, leonard ll. drug information handbook 2010–2011: a comprehensive resource for all clinicians and healthcare professionals, 19th ed. hudson, ohio, usa: lexi-comp inc., 2010. 22. martin gs, mannino dm, eaton s, moss m. the epidemiology of sepsis in the united states from 1979 through 2000. n engl j med 2003; 348:1546–54. doi: 10.1056/nejmoa022139. 23. nasa p, juneja d, singh o, dang r, arora v. severe sepsis and its impact on outcome in elderly and very elderly patients admitted in intensive care unit. j intensive care med 2012; 27:179–83. doi: 10.1177/0885066610397116. 24. ferrer r, artigas a, levy mm, blanco j, gonzález-díaz g, garnacho-montero j, et al. improvement in process of care and outcome after a multicenter severe sepsis educational program in spain. jama 2008; 299:2294–303. doi: 10.1001/jama.299.19.2294. 25. adrie c, azoulay e, francais a, clec’h c, darques l, schwebel c, et al. influence of gender on the outcome of severe sepsis: a reappraisal. chest 2007; 132:1786–93. doi: 10.1378/chest.07-0420. 26. chandra r, federici s, németh zh, horváth b, pacher p, haskó g, et al. female x-chromosome mosaicism for nox2 deficiency presents unique inflammatory phenotype and improves outcome in polymicrobial sepsis. j immunol 2011; 186:6465–73. doi: 10.40 49/jimmunol.1100205. 27. daniels r. surviving the first hours in sepsis: getting the basics right (an intensivist’s perspective). j antimicrob chemother 2011; 66:ii11–23. doi: 10.1093/jac/dkq515. 28. ogura h, gando s, saitoh d, takeyama n, kushimoto s, fujishima s, et al. epidemiology of severe sepsis in japanese intensive care units: a prospective multicenter study. j infect chemother 2014; 20:157–62. doi: 10.1016/j.jiac.2013.07.006. 29. imran m, amjad a, haidri fr. frequency of hospital acquired pneumonia and its microbiological etiology in medical intensive care unit. pak j med sci 2016; 32:823–6. doi: 10.12669/pjms. 324.8942. 30. fitousis k, moore lj, hall j, moore fa, pass s. evaluation ofempiric antibiotic use in surgical sepsis. am j surg 2010; 200:776–82. doi: 10.1016/j.amjsurg.2010.09.001. https://doi.org/10.12669/pjms.323.9978 https://doi.org/10.1164/rccm.201504-0781oc https://doi.org/10.1164/rccm.201504-0781oc https://doi.org/10.1590/s0120-41572014000100007 https://doi.org/10.1001/jama.2014.2637 https://doi.org/10.1007/pl00003796 https://doi.org/10.1007/s00134-017-4683-6 https://doi.org/10.1016/j.jhin.2004.07.026 https://doi.org/10.1378/chest.09-0087 https://doi.org/10.1097/ccm.0b013e3181cc4824 https://doi.org/10.1155/2012/765205 https://doi.org/10.7454/jpdi.v2i2.72 https://doi.org/10.1086/511159 https://doi.org/10.1164/rccm.200405-644st https://doi.org/10.1164/rccm.200405-644st https://doi.org/10.1086/599376 https://doi.org/10.1111/iju.12200 https://doi.org/10.1056/nejmoa022139 https://doi.org/10.1177/0885066610397116 https://doi.org/10.1001/jama.299.19.2294 https://doi.org/10.1378/chest.07-0420 https://doi.org/10.4049/jimmunol.1100205 https://doi.org/10.4049/jimmunol.1100205 https://doi.org/10.1093/jac/dkq515 https://doi.org/10.1016/j.jiac.2013.07.006 https://doi.org/10.12669/pjms.324.8942 https://doi.org/10.12669/pjms.324.8942 https://doi.org/10.1016/j.amjsurg.2010.09.001 doi: 10.18295/squmj.2018.18.02.009 مقياس دندي جلاهزية بيئة التعليم دراسة مقارنة استباقية إلدراك طلبة الطب واملتدربني يف عمان جودا بارام�شورا برا�شناث و �شامل خ�شري اإ�شماعيل abstract: objectives: this study aimed to assess perceptions of the educational environment in oman among medical undergraduate students and interns using the dundee ready education environment measure (dreem) tool. methods: this cross-sectional study was conducted between october 2016 and april 2017 at the oman medical college (omc), sohar, oman. a total of 737 medical undergraduate students and interns from the omc and college of medicine & health sciences of sultan qaboos university in muscat, oman, were invited to complete the dreem questionnaire in the form of an online survey. mean overall scores, subscale scores and individual item scores were subsequently compared between undergraduate students and interns. results: a total of 418 undergraduate students and interns completed the survey (response rate: 56.7%). the mean overall dreem score was 130.75 ± 12.69. while interns had higher mean dreem scores than undergraduate students, this difference was not significant (133.00 ± 17.64 versus 128.50 ± 15.53; p = 0.326). the mean score percentages for the perceptions of learning (66.7% versus 58.3%; p = 0.028) and perceptions of teachers (75% versus 68.2%; p = 0.038) subscales were significantly higher among omc interns compared to undergraduate students from the same college. the perceptions of the environment subscale received the lowest mean score percentages among undergraduate students and interns from both colleges. conclusion: overall, medical undergraduate students and interns viewed the educational environment in oman in a positive light. it is possible that undergraduate students’ perceptions of the educational environment may become more favourable as they progress with their medical career and become interns. keywords: medical education; undergraduate medical students; internships; perceptions; oman. دندي مقيا�ض باإ�شتخدام واملتدربني الطب طالب بني عمان يف التعليمية البيئة اإدراك تقييم اإىل الدرا�شة هذه تهدف االهدف: امللخ�ص: جلاهزية بيئة التعليم. الطريقة: مت اإجراء هذه الدرا�شة امل�شتعر�شة بني اأكتوبر 2016 و اأبريل 2017 يف كلية عمان الطبية، �شحار، عمان. متت دعوة جمموع 737 من طالب الطب واملتدربني من كلية عمان الطبية و كلية الطب والعلوم ال�شحية بجامعة ال�شلطان قابو�ض، م�شقط، عمان، للم�شاركة باإكمال اإ�شتبيان مقيا�ض دندي جلاهزية بيئة التعليم عرب م�شح الأنرتنت. متت مقارنة متو�شط اإجمايل الدرجات، درجات الفروع ال�شتجابة )معدل واملتدربني الطب طالب من 418 عدد اأكمل واملتدربني. النتائج: الطب طلبة بني الفردية العنا�رض ودرجات اجلانبية املقيا�ض معدل متو�شط كان حني يف .130.75 التعليم 12.69 ± بيئة جلاهزية دندي ملقيا�ض الإجمالية الدرجات متو�شط كان .)56.7% .)p = 0.326 ،128.50 ± 15.53 اأعلى عند املتدربني باملقارنة بطالب الطب، مل يكن الفارق معتد به اإح�شائيا )17.64 ± 133.00 مقابل املدر�شني لإدراك اجلانبية الفروع متو�شط وكان )p = 0.028 ،58.3% مقابل 66.7%( التعليم اإدراك لنتائج املئوية الن�شبة متو�شط )%75 مقابلp = 0.038 ،68.2%( اأعلى بكثري بني املتدربني من كلية عمان الطبية باملقارنة مع طالب الطب من نف�ض الكلية. كان اأقل كانت اإجمال، الكليتني. اخلال�صة: كال من واملتدربني الطب طالب بني للبيئة اجلانبية الفروع اإدراك يف للنتائج املئوية للن�شبة متو�شط نظرت طالب الطب واملتدربني للبيئة التعليمية يف عمان اإيجابية. من املمكن اأن ي�شبح اإدراك طلبة الطب للبيئة التعليمية اأكرث مالءمة عند تقدمهم املهني وو�شولهم اإىل مرحلة متدرب. الكلمات املفتاحية: التعليم الطبي؛ طالب الطب؛ التدريب الداخلي؛ الإدراك؛ عمان. the dundee ready education environment measure a prospective comparative study of undergraduate medical students’ and interns’ perceptions in oman *gowda p. prashanth and salim k. ismail sultan qaboos university med j, may 2018, vol. 18, iss. 2, pp. e173–181, epub. 9 sep 18 submitted 18 dec 17 revision req. 22 jan 18; revision recd. 21 feb 18 accepted 15 mar 18 department of paediatrics, oman medical college, sohar, oman *corresponding author’s e-mail: prashanth_lucknow@rediffmail.com clinical & basic research advances in knowledge to the best of the authors’ knowledge, this is the first study reporting undergraduate students’ and interns’ perceptions of the medical educational environment in oman. the findings of the study suggest that undergraduate students’ perceptions of their educational environment may become more favourable as they advance to their internship. application to patient care this study serves as an important initial step in identifying strengths and weaknesses in the current medical learning climate of oman. this knowledge may help educational administrators identify underlying factors that hamper medical students’ learning experiences, ultimately improving the overall quality of medical education and clinical care in oman. the dundee ready education environment measure a prospective comparative study of undergraduate medical students’ and interns’ perceptions in oman e174 | squ medical journal, may 2018, volume 18, issue 2 the goal of medical education is to produce graduates with the necessary know-ledge, clinical skills and professional attributes to be successful doctors.1 to a certain extent, a physician’s level of competence in these areas reflects the educational institution they attended and the medical education they received.2 therefore, it is vital to appraise the educational environment in which medical students learn, including the institutional culture, curriculum and learning climate.3 meaningful learning correlates positively with students’ perceptions of their educational environment, as this can influence how, why and what students learn.4,5 while various tools are available to allow medical educators to evaluate students’ perceptions of their educational environments, the 50-item dundee ready education environment measure (dreem) tool is currently most frequently utilised.6–8 the dreem tool is a widely accepted and globally validated instrument for assessing the educational environment in undergraduate medical institutions and has five subscales including perceptions of learning, perceptions of teachers, academic self-perceptions, perceptions of the environment and social self-perceptions.5–7 the internal consistency of the questionnaire has been validated in previous research.9 such tools can help educational administrators identify problem areas at the curricular or institutional level and make necessary changes, resulting in significant improvements in the learning environment and, therefore, student performance. in oman, the ministry of health recognises the importance of developing health education and training programmes so as to ensure a high level of clinical care.10 however, to the best of the authors’ knowledge, no studies to date have analysed medical undergraduates’ and interns’ perceptions of the educ ational environment in oman. as such, this study aimed to assess undergraduate students’ and medical interns’ perceptions of various aspects of the educational environment in oman, including a range of topics directly related to the educational climate and every day learning. in addition, this study aimed to identify specific problem areas for elucidation and improvement. methods this prospective descriptive cross-sectional study took place at the oman medical college (omc) in sohar, oman, between october 2016 and april 2017. students in the clinical phase of the omc medical degree programme (i.e. years 5 and 6) and phase iii of the medical degree programme at the college of medicine & health sciences of sultan qaboos university (squ) in muscat, oman, were eligible to participate in the study. in addition, former medical students who had graduated from either institution during the 2016–2017 academic year and begun internships were also included. as all 737 eligible students and interns at these institutions could be contacted and were given an opportunity to participate in the study, a precisionbased sample size calculation was not performed. the original english-language version of the 50-item dreem tool was incorporated into an online survey using questionpro™ software (questionpro inc., san francisco, california, usa).7 subsequently, a link to the survey was forwarded to the institutional e-mails of all eligible students, with a three-week timeframe to complete the questionnaire. responses to the questionnaire were monitored in real time using the questionpro™ software (questionpro inc.). reminders to complete the survey were sent to previously established whatsapp groups (whatsapp inc., menlo park, california, usa), whenever available, and follow-up e-mails were sent every fifth day. the questionpro inc. online assistance team was consulted to overcome any technical difficulties in the electronic delivery of the questionnaire and data collection. in cases where these issues remained unresolved, printed questionnaires were hand-delivered to the participants. responses to each individual item in the dreem survey were scored on a five-point likert scale from four to zero as either strongly agree, agree, uncertain, disagree or strongly disagree, respectively.7 nine negatively-worded items (items #4, #8, #9, #17, #25, #35, #39, #48 and #50) were reverse scored. in total, figure 1: mean total dundee ready education environment measure scores of medical undergraduate stud ents and interns at the oman medical college and sultan qaboos university, oman (n = 418). squ = sultan qaboos university; omc = oman medical college. gowda p. prashanth and salim k. ismail clinical and basic research | e175 the maximum overall dreem score was 200, indicating an ideal educational environment.7,9 all questionnaires with incomplete data were excluded from the analysis. the overall total scores and those of each subscale were calculated separately for students and interns at each college, with average scores tabulated for each group. agreement or disagreement with individual items was calculated by combining responses in the agree and strongly agree categories and the disagree and strongly disagree categories, respectively.11 the total scores, subscale scores and individual item scores were expressed as means ± standard deviation. the mean scores of undergraduate students and interns were compared using a student’s t-test. the statistical package for the social sciences (spss), version 17.0 (ibm corp., armonk, new york, usa) was used for the data analysis. the level of statistical significance was set at p <0.050. this study received ethical approval from the institutional proposal evaluation committee of the omc. all participants gave informed consent, either via digital acknowledgement during completion of the online survey or by signing a written consent form. the privacy and anonymity of the participants were ensured at all times during the delivery and collection of the questionnaires. results of the 737 medical undergraduate students and interns at omc and squ invited to participate in the study, a total of 418 completed the questionnaire (response rate: 56.7%). of these, there were 326 undergraduate students (response rate: 58%) and 92 interns (response rate: 52.2%). there were significantly higher response rates among the omc undergraduate students (74.3% versus 65%; p = 0.001) and medical interns (47.8% versus 51.7%; p = 0.002) compared to those from squ. the mean overall total dreem score was 130.75 ± 12.69 [figure 1]. while interns had higher mean dreem scores than undergraduate students, this difference was not significant (133.00 ± 17.64 versus 128.50 ± 15.53; p = 0.326). the mean score percentages per subscale (i.e. the percentage out of the total available score per subscale) among medical undergraduate students and interns from both colleges is shown in figure 2 and table 1. according to subscale, the mean score was 30.50 ± 5.90 for perceptions of learning (63.5%), 34.00 ± 5.80 for perceptions of teachers (77.2%), 27.25 ± 3.32 for academic self-perceptions (85.1%), 28.00 ± 6.20 for perceptions of atmosphere (58.3%) and 20.25 ± 5.80 for social self-perceptions (72.3%) items. the mean scores of individual items table 1: mean dundee ready education environment measure subscale scores according to institution among med ical undergraduate students and interns at the oman medical college and sultan qaboos university, oman (n = 418) subscale mean percentage* p value mean percentage* p value omc students (n = 162) omc interns (n = 52) squ students (n = 164) squ interns (n = 40) perceptions of learning 58.3 66.7 0.028 62.5 62.5 0.771 perceptions of teachers 68.2 75 0.038 68.2 72.7 0.585 academic self-perceptions 78.1 75 0.342 84.4 87.5 0.283 perceptions of the environment 50 52.1 0.278 52.1 54.2 0.294 social self-perceptions 64.3 60.7 0.403 71.4 67.9 0.783 omc = oman medical college; squ = sultan qaboos university. *out of the total available score for the subscale. figure 2: mean dundee ready education environment measure scores per subscale among medical undergraduate students and interns at the oman medical college and sultan qaboos university, oman (n = 418). dreem = dundee ready education environment measure. *out of the total available score for the subscale. the dundee ready education environment measure a prospective comparative study of undergraduate medical students’ and interns’ perceptions in oman e176 | squ medical journal, may 2018, volume 18, issue 2 table 2: mean dundee ready education environment measure scores for individual items among medical undergraduate students and interns at the oman medical college and sultan qaboos university, oman (n = 418) item mean score ± sd omc students (n = 162) omc interns (n = 52) squ students (n = 164) squ interns (n = 40) pe rc ep ti on s o f l ea rn in g 1. i am encouraged to participate in class. 3.12 ± 1.05 3.22 ± 1.21 3.02 ± 1.16 3.12 ± 1.03 7. teaching is often stimulating. 3.18 ± 1.22 3.28 ± 1.08 3.28 ± 1.03 3.19 ± 1.06 13. teaching is student-centred. 1.96 ± 0.92 2.06 ± 1.08 2.16 ± 0.86 2.26 ± 1.18 16. the teaching helps to develop my competence. 2.23 ± 1.04 2.13 ± 1.03 2.20 ± 1.12 2.53 ± 1.03 20. the teaching is well focused. 2.63 ± 1.05 2.13 ± 1.12 2.60 ± 0.98 2.58 ± 0.94 21. the teaching helps to develop my confidence. 2.30 ± 1.17 2.28 ± 1.02 2.42 ± 1.04 2.16 ± 0.97 24. the teaching time is put to good use. 1.92 ± 1.07 2.12 ± 0.97 2.92 ± 1.07 3.12 ± 1.07 25. the teaching overemphasises factual learning. 2.98 ± 0.96 3.21 ± 1.12 3.17 ± 1.06 3.08 ± 1.20 38. i am clear about the learning objectives of the course. 3.50 ± 1.12 3.58 ± 1.06 3.82 ± 1.03 3.63 ± 1.14 44. the teaching encourages me to be an active learner. 3.25 ± 0.79 3.55 ± 1.13 3.89 ± 0.96 3.62 ± 0.79 47. long-term learning is emphasised over short-term learning. 2.18 ± 1.21 2.26 ± 0.87 3.18 ± 1.02 3.05 ± 1.01 48. the teaching is too teacher-centred. 1.52 ± 0.87 1.87 ± 1.12 2.11 ± 0.92 2.82 ± 1.02 pe rc ep ti on s o f t ea ch er s 2. the teachers are knowledgeable. 3.11 ± 0.92 3.2 ± 1.01 3.21 ± 1.02 3.11 ± 1.04 6. the teachers are patient with students. 3.23 ± 1.21 3.23 ± 0.92 3.17 ± 1.27 3.2 ± 0.89 8. the teachers make fun of their students. 2.48 ± 1.31 3.08 ± 0.91 2.58 ± 1.21 2.31 ± 0.96 9. the teachers are strict and controlling. 2.43 ± 1.09 3.04 ± 1.21 2.22 ± 1.02 2.52 ± 0.94 18. the teachers appear to have effective communication skills with students. 2.59 ± 1.23 2.43 ± 1.07 2.6 ± 1.72 2.49 ± 0.98 29. the teachers are good at providing feedback to students. 2.29 ± 1.12 2.28 ± 1.21 2.42 ± 1.02 2.26 ± 1.12 32. the teachers provide constructive criticism. 2.21 ± 1.02 2.12 ± 0.92 2.91 ± 1.08 3.03 ± 0.97 37. the teachers give clear examples. 3.03 ± 1.71 3.87 ± 0.97 2.17 ± 1.21 3.1 ± 0.87 39. the teachers get angry in teaching sessions. 3.01 ± 1.36 3.31 ± 1.28 2.42 ± 1.29 3.33 ± 0.86 40. the teachers are well prepared for their classes. 2.95 ± 1.58 3.55 ± 1.22 3.29 ± 0.98 3.62 ± 0.85 49. the students irritate and annoy the teachers. 3.17 ± 1.75 3.22 ± 1.09 3.11 ± 0.92 3.05 ± 0.85 so ci al s el fpe rc ep ti on s 3. there is a good support system for students who get stressed. 1.15 ± 0.67 1.67 ± 0.76 1.92 ± 0.86 1.95 ± 0.96 4. i am too tired to enjoy this course. 2.23 ± 1.08 2.28 ± 0.85 3.28 ± 0.91 3.12 ± 1.03 14. i am rarely bored in this course. 3.96 ± 0.89 3.23 ± 1.04 3.16 ± 0.92 3.29 ± 1.06 15. i have good friends in this school. 3.97 ± 0.85 4.21 ± 1.07 4.22 ± 0.95 4.53 ± 1.06 19. my social life is good. 2.2 ± 0.87 2.13 ± 0.98 2.72 ± 0.87 2.58 ± 0.96 28. i seldom feel lonely. 3.52 ± 0.85 2.28 ± 0.98 3.42 ± 0.92 2.06 ± 0.91 46. my accommodation is pleasant. 1.21 ± 0.77 1.33 ± 0.78 2.01 ± 0.67 1.98 ± 0.62 a ca de m ic s el fpe rc ep ti on s 5. learning strategies which worked for me before continue to work for me now. 1.89 ± 1.02 2.12 ± 0.84 3.02 ± 0.89 3.12 ± 0.93 10. i am confident about passing this year. 3.92 ± 1.04 3.11 ± 1.07 4.12 ± 0.88 4.32 ± 0.96 22. i feel i am being well prepared for my profession. 1.86 ± 0.89 3.21 ± 1.03 2.12 ± 0.99 2.18 ± 0.89 26. last year’s work was good preparation for this year’s work. 4.23 ± 0.94 4.11 ± 0.97 4.24 ± 1.04 4.02 ± 1.02 27. i am able to memorise all i need. 1.54 ± 0.95 1.76 ± 0.88 1.98 ± 0.87 2.01 ± 0.94 31. i have learned a lot about empathy in my profession. 4.87 ± 0.78 4.32 ± 0.81 4.22 ± 0.77 4.18 ± 1.03 41. my problem-solving skills are being well developed. 3.76 ± 1.06 3.12 ± 0.79 4.02 ± 0.95 4.13 ± 0.98 45. much of what i have to learn seems relevant to a career in healthcare. 3.12 ± 0.89 3.01 ± 0.86 3.82 ± 0.96 4.09 ± 0.96 gowda p. prashanth and salim k. ismail clinical and basic research | e177 “more positive”, while the score for the perceptions of teachers subscale suggested “movement in the right direction”. in addition, the mean scores for the academic self-perceptions, perceptions of the environment and social self-perceptions subscales indicated “confident feelings”, “a more positive attitude” and “not too bad”, respectively.7 in terms of percentages of the total available score, the academic self-perceptions subscale had the highest mean score percentage, followed by the perceptions of teachers subscale for all participants, apart from squ undergraduate students. similarly, a study from the united arab emirates (uae) conducted among faculty members found that the perceptions of teachers and perceptions of learning subscales had the highest mean scores, whereas the lowest mean score was noted in the social self-perceptions subscale.20 the psychological wellbeing of medical undergraduate students and interns is of paramount importance in terms of ensuring learning retention and quality healthcare delivery.3 although the mean subscale scores observed in the current study were highly encouraging, an analysis of the mean scores for individual items in the dreem tool indicated a need to improve student accommodation services and recreational facilities. in addition, there was a need to improve the atmosphere in the classroom during teaching, which might be more conducive to students asking questions during class. very few of the students and interns were of the opinion that their medical colleges had a good support system for stressed students, implying that these institutions of the dreem tool are shown in table 2. the percentage of positive, neutral and negative responses for individual items of the dreem tool are shown in table 3. discussion to the best of the authors’ knowledge, this study is the first to report the perceptions of medical undergraduate students and interns regarding the educational environment in oman using the validated dreem tool. overall total dreem scores have been reported to range from 45.0–72.5%.11,12 the overall total dreem score observed in the present study was high and comparable with findings from established international medical schools in the uk, south africa and ireland.1,12,13 however, mean scores reported from medical schools at the university of east anglia and university of birmingham in the uk and the university of lund in sweden were higher.14–16 in contrast, studies of medical schools in korea, germany and spain have reported lower dreem scores.17–19 such varied results could be due to potential differences in the learning preferences and social lives of these diverse student populations. additionally, variations in students’ and interns’ perceptions may also reflect the complex construct of the learning environment at any educational institute. according to standard interpretations of dreem subscale scores, the mean score for the perceptions of learning subscale in the current study was deemed table 2 (contd.): mean dundee ready education environment measure scores for individual items among medical undergraduate students and interns at the oman medical college and sultan qaboos university, oman (n = 418) item mean score ± sd omc students (n = 162) omc interns (n = 52) squ students (n = 164) squ interns (n = 40) pe rc ep ti on s o f t he e nv ir on m en t 11. the atmosphere is relaxed during ward teaching. 3.16 ± 0.96 3.29 ± 1.07 3.02 ± 0.87 3.19 ± 1.12 12. this school is well time-tabled. 1.92 ± 0.95 1.82 ± 0.79 1.95 ± 0.94 2.03 ± 1.19 17. cheating is a problem in this school. 1.22 ± 0.87 1.38 ± 1.08 1.43 ± 1.02 1.52 ± 1.02 23. the atmosphere is relaxed during teaching. 2.83 ± 0.78 2.81 ± 1.04 2.29 ± 0.92 2.23 ± 1.05 30. there are opportunities for me to develop interpersonal skills. 2.08 ± 0.83 2.89 ± 0.77 2.6 ± 0.93 2.58 ± 0.97 33. i feel comfortable in teaching sessions socially. 1.32 ± 0.93 1.54 ± 0.92 1.92 ± 0.88 2.04 ± 0.92 34. the atmosphere is relaxed during tutorials. 2.11 ± 0.78 2.12 ± 0.95 2.32 ± 1.05 2.51 ± 0.82 35. i find the experience disappointing. 1.98 ± 1.03 2.02 ± 0.93 2.38 ± 0.79 2.44 ± 1.02 36. i am able to concentrate well. 1.21 ± 0.82 1.32 ± 0.79 1.23 ± 0.95 1.2 ± 0.84 42. the enjoyment outweighs the stress of the course. 1.82 ± 0.86 1.88 ± 0.82 2.08 ± 0.88 2.11 ± 0.86 43. the atmosphere motivates me as a learner. 1.87 ± 0.89 2.29 ± 1.07 2.11 ± 1.03 2.42 ± 0.86 50. i feel able to ask the questions i want. 3.21 ± 1.02 2.18 ± 0.79 2.03 ± 0.92 2.1 ± 0.97 sd = standard deviation; omc = oman medical college; squ = sultan qaboos university. the dundee ready education environment measure a prospective comparative study of undergraduate medical students’ and interns’ perceptions in oman e178 | squ medical journal, may 2018, volume 18, issue 2 other studies from the middle eastern region have addressed students’ perceptions of the educational environment at various medical colleges [table 4].11,21–33 in general, the scores of medical schools in previous studies from 2004–2010 were much lower compared to those reported from more recent studies.11,21–33 this observation suggests that significant improvements have been made to the learning environments of medical schools in the region. the results of a study from the uae found that the use of an integrated curriculum led to significantly more had inadequate facilities to cope with academic and/ or social life-related stress. therefore, the authors of the current study recommend prioritising the establishment of organised student support systems and psychological counselling centres at both the omc and squ so as to address the issue of stress among undergraduate students and interns. further studies should be conducted to evaluate the effects of stress on academic performance during medical training in oman and elucidate underlying factors that may lead to stressful conditions. table 3: responses to individual items of the dundee ready education environment measure among medical undergraduate students and interns at the oman medical college and sultan qaboos university, oman (n = 418) item percentage of responses undergraduate students (n = 326) interns (n = 92) agree/ strongly agree uncertain disagree/ strongly disagree agree/ strongly agree uncertain disagree/ strongly disagree pe rc ep ti on s o f l ea rn in g 7. teaching is often stimulating. 40.2 30.4 29.4 44.3 25.2 30.5 13. teaching is student-centred. 41.2 29.2 29.6 32.1 28.2 39.7 25. the teaching over emphasises factual learning. 50.3 25.1 24.6 45.3 32.1 22.6 38. i am clear about the learning objectives of the course. 40.2 20.2 39.6 33.8 38.2 28 44. the teaching encourages me to be an active learner. 30.7 40.1 29.2 38.2 31.6 30.2 48. the teaching is too teacher-centred. 33.5 39.2 27.3 39.1 38.1 22.8 pe rc ep ti on s o f t ea ch er s 6. the teachers are patient with patients. 45.3 35.2 19.5 40.7 39.1 20.2 8. the teachers make fun of their students. 35.8 39 25.2 40.1 44.1 15.8 9. the teachers are strict and controlling. 44.5 30.2 25.3 30.6 49.2 20.2 37. the teachers give clear examples. 44.8 29.1 26.1 35.2 39.6 25.2 39. the teachers get angry in teaching sessions. 40.4 33.2 26.4 43.8 32 24.2 so ci al s el fpe rc ep ti on s 3. there is a good support system for students who get stressed. 15.1 20.7 64.2 17.8 19.1 63.1 4. i am too tired to enjoy this course. 35.1 49.3 15.6 30.9 51 18.1 14. i am rarely bored in this course. 43.8 30.9 25.3 35.2 39.6 25.2 19. my social life is good. 30.3 54.1 15.6 32.5 49.2 18.3 28. i seldom feel lonely. 34.3 22.4 43.3 40.7 21.1 38.2 46. my accommodation is pleasant. 27.4 48.4 24.2 43.2 30.6 26.2 a ca de m ic se lfpe rc ep ti on s 10. i am confident about passing this year. 33.4 39.3 27.3 41.7 38.1 20.2 22. i feel i am being well prepared for my profession. 35.2 25.2 39.6 41.6 29.2 29.2 27. i am able to memorise all i need. 22.2 48.2 29.6 26.2 41.3 32.5 pe rc ep ti on s o f t he e nv ir on m en t 11. the atmosphere is relaxed during ward teaching. 40.7 30.8 28.5 40.4 25.2 34.4 17. cheating is a problem in this school. 20.2 30.2 49.6 29.2 32.2 38.6 23. the atmosphere is relaxed during teaching. 31.3 48.3 20.4 35.8 40.9 23.3 33. i feel comfortable in teaching sessions socially. 24.4 38.2 37.4 41.2 28.5 30.3 34. the atmosphere is relaxed during tutorials. 33.5 43.3 23.2 41.4 29.3 29.3 36. i am able to concentrate well. 24.3 39.9 35.8 36.3 38 25.7 42. the enjoyment outweighs the stress of the course. 20.7 29.8 49.5 35.6 25.7 38.7 omc = oman medical college; squ = sultan qaboos university. gowda p. prashanth and salim k. ismail clinical and basic research | e179 independent. in addition, there is some scope for cultural bias with use of this tool.35 other limitations include lack of analysis of the effect of demographic factors such as age, gender and nationality on the overall dreem and subscale scores. however, it should be noted that approximately 80–90% of the sample consisted of omani females; as such, nationality and gender were unlikely to have affected the results. another limitation was the overall lower response rate of interns compared to their undergraduate counterparts; this was due to difficulties in locating interns providing clinical services at different hospitals in oman. additionally, there was a higher response rate among students and interns at omc compared to those from squ; this was probably due to the fact that the study itself was conducted at omc, potentially resulting in greater awareness of the study among the omc-affiliated participants. conclusion overall, the findings of this study suggest that medical undergraduate students and interns at the omc and squ viewed the educational environment in oman in a positive manner. moreover, it is possible positive perceptions compared to a discipline-based curriculum.20 a previous study conducted in ireland reported similar results.12 these findings highlight the importance of curricular reforms in improving the overall learning environment of medical schools. in the current study, interns on the whole had more positive perceptions of the educational environment compared to the undergraduate students. in contrast, investigators from saudi arabia and iran have reported that second-year undergraduate students had higher dreem scores compared to third-year students.25,26 it is possible that curricular differences and the use of heterogeneous samples from different sociocultural backgrounds could result in these varying observations. curriculum planners in oman should heed the feedback of medical students and interns, as their opinions may be valuable in determining potential areas for and methods of improving the learning climate at specific institutions, thus ensuring the students’ and interns’ preparedness for clinical work.34 the findings of the current study are limited by pre-existing constraints and criticisms of the dreem tool, particularly its psychometric properties, as items included in the dreem subscales may not be wholly table 4: literature review of recent studies using the dundee ready education environment measure tool at institutions in the middle east11,21–33 author and year of study institution and setting type of participants mean overall total score karim et al.11 (2015) kuwait university, kuwait undergraduates 108.7 al sheikh25 (2014) university of dammam, dammam, saudi arabia undergraduates 106 alfarsi et al.27 (2014) king saud university, riyadh, saudi arabia undergraduates 118.5 el-sobkey28 (2015) king saud university, riyadh, saudi arabia physiotherapy trainees 135.6 soliman et al.24 (2017) king saud university, riyadh, saudi arabia undergraduates 171.5* al-ayed et al.23 (2008) king saud university, riyadh, saudi arabia undergraduates 89.9 al-hazimi et al.22 (2002) king abdulaziz university, jeddah, saudi arabia undergraduates 102 al-hazimi et al.21 (2002) umm al-qura university, mecca, saudi arabia undergraduates 107 sana’a university, yemen undergraduates 100 shehnaz et al.29 (2012) gulf medical college, ajman, uae teaching faculty 139 undergraduates 135 farahmand et al.30 (2014) imam-khomeini hospital, tehran, iran emergency medicine interns 133.72 imanipour et al.31 (2015) tehran university of medical sciences, tehran, iran nursing or midwifery students 104.39 andalib et al.32 (2015) tehran university of medical sciences children’s medical center, tehran, iran undergraduates 95.8 bakhshialiabad et al.33 (2015) rafsanjan university of medical sciences, rafsanjan, iran undergraduates 113.5 taheri26 (2009) gilan university of medical sciences, gilan, iran basic science students 100.96 clinical students 94.19 uae = united arab emirates. *out of a total score of 250, instead of 200. the dundee ready education environment measure a prospective comparative study of undergraduate medical students’ and interns’ perceptions in oman e180 | squ medical journal, may 2018, volume 18, issue 2 9. swift l, miles s, leinster sj. the analysis and reporting of the dundee ready education environment measure (dreem): some informed guidelines for evaluators. creat educ 2013; 4:340–7. doi: 10.4236/ce.2013.45050. 10. oman ministry of health. organization and health policy of the ministry of health. from: www.moh.gov.om/en/about-moh accessed: feb 2018. 11. karim j, al-halabi b, marwan y, sadeq h, dawas a, al-abdulrazzaq d. the educational environment of the undergraduate medical curriculum at kuwait university. adv med educ pract 2015; 6:297–303. doi: 10.2147/amep.s81729. 12. finn y, avalos g, dunne f. positive changes in the medical educational environment following introduction of a new sys tems-based curriculum: dreem or reality? curricular change and the environment. ir j med sci 2014; 183:253–8. doi: 10. 1007/s11845-013-1000-4. 13. dreyer a, gibbs a, smalley s, mlambo m, pandya h. clinical associate students’ perception of the educational environment at the university of the witwatersrand, johannesburg. afr j prim health care fam med 2015; 7:a778. doi: 10.4102/phcfm. v7i1.778. 14. varma r, tiyagi e, gupta jk. determining the quality of educational climate across multiple undergraduate teaching sites using the dreem inventory. bmc med educ 2005; 5:8. doi: 10. 1186/1472-6920-5-8. 15. edgren g, haffling ac, jakobsson u, mcaleer s, danielsen n. comparing the educational environment (as measured by dre em) at two different stages of curriculum reform. med teach 2010; 32:e233–8. doi: 10.3109/01421591003706282. 16. miles s, leinster sj. medical students’ perceptions of their educational environment: expected versus actual perceptions. med educ 2007; 41:265–72. doi: 10.1111/j.1365-2929.2007.02686.x. 17. park kh, park jh, kim s, rhee ja, kim jh, ahn yj, et al. [students’ perception of the educational environment of medical schools in korea: findings from a nationwide survey]. korean j med educ 2015; 27:117–30. doi: 10.3946/kjme.2015.27.2.117. 18. rotthoff t, ostapczuk ms, de bruin j, decking u, schneider m, ritz-timme s. assessing the learning environment of a faculty: psychometric validation of the german version of the dundee ready education environment measure with students and teachers. med teach 2011; 33:e624–36. doi: 10.3109/0142159x. 2011.610841. 19. palés j, gual a, escanero j, tomás i, rodríguez-de castro f, elorduy m, et al. educational climate perception by preclinical and clinical medical students in five spanish medical schools. int j med educ 2015; 6:65–75. doi: 10.5116/ijme.5557.25f9. 20. shehnaz si, sreedharan j. students’ perceptions of educational environment in a medical school experiencing curricular transition in united arab emirates. med teach 2011; 33:e37–42. doi: 10.3109/0142159x.2011.530312. 21. al-hazimi a, zaini r, al-hyiani a, hassan n, gunaid a, ponnamperuma g, et al. educational environment in traditional and innovative medical schools: a study in four undergraduate medical schools. educ health (abingdon) 2004; 17:192–203. doi: 10.1080/13576280410001711003. 22. al-hazimi a, al-hyiani a, roff s. perceptions of the educational environment of the medical school in king abdul aziz university, saudi arabia. med teach 2004; 26:570–3. doi: 10.10 80/01421590410001711625. 23. al-ayed ih, sheik sa. assessment of the educational environment at the college of medicine of king saud university, riyadh. east mediterr health j 2008; 14:953–9. 24. soliman mm, sattar k, alnassar s, alsaif f, alswat k, alghonaim m, et al. medical students’ perception of the learning environment at king saud university medical college, saudi arabia, using dreem inventory. adv med educ pract 2017; 8:221–7. doi: 10. 2147/amep.s127318. that undergraduate students’ perceptions of the educational environment may become more positive once they graduate and become interns. a c k n o w l e d g e m e n t s this study received ethical approval from omc and was reviewed by the research council (trc) oman. while no individuals from squ were involved in conducting the study, a copy of the questionnaire was sent to administrators at the student section and internship programme office of squ before the squ students’ and interns’ contact details were provided to the researchers. the squ student class representatives were then contacted by omc students. the authors wish to express their sincere gratitude to the student section of squ for their cooperation, as well as the team of omc students led by ms. sara f. tejani for their help in coordinating the data collection process. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded with the aid of a grant from the faculty mentored undergraduate research award program of trc oman (grant #frp/omc/16/012). references 1. dunne f, mcaleer s, roff s. assessment of the undergraduate medical education environment in a large uk medical school. health educ j 2006; 65:149–58. doi: 10.1177/001789690606500205. 2. brown t, williams b, lynch m. the australian dreem: evaluating student perceptions of academic learning environments within eight health science courses. intl j med educ 2011; 2:94–101. doi: 10.5116/ijme.4e66.1b37. 3. general medical council. promoting excellence: standards for medical education and training. from: www.gmc-uk.org/-/ media/documents/promoting-excellence-standards-formedical-education-and-training-0715_pdf-61939165.pdf accessed: feb 2018. 4. mayya s, roff s. students’ perceptions of the educational environment: a comparison of academic achievers and underachievers at kasturba medical college, india. educ health (abingdon) 2004; 17:280–91. doi: 10.1080/13576280400002445. 5. roff s, mcaleer s, ifere os, bhattacharya s. a global diagnostic tool for measuring educational environment: comparing nigeria and nepal. med teach 2001; 23:378–82. doi: 10.1080/01421590 120043080. 6. soemantri d, herrera c, riquelme a. measuring the educational environment in health professions studies: a systematic review. med teach 2010; 32:947–52. doi: 10.3109/01421591003686229. 7. roff s, mcaleer s, harden rm, al-qahtani m, ahmed au, deza h, et al. development and validation of the dundee ready education environment measure (dreem). med teach 1997; 19:295–9. doi: 10.3109/01421599709034208. 8. miles s, swift l, leinster sj. the dundee ready education environment measure (dreem): a review of its adoption and use. med teach 2012; 34:e620–34. doi: 10.3109/0142159x. 2012.668625. https://doi.org/10.4236/ce.2013.45050 https://doi.org/10.2147/amep.s81729 https://doi.org/10.1007/s11845-013-1000-4 https://doi.org/10.1007/s11845-013-1000-4 https://doi.org/10.4102/phcfm.v7i1.778 https://doi.org/10.4102/phcfm.v7i1.778 https://doi.org/10.1186/1472-6920-5-8 https://doi.org/10.1186/1472-6920-5-8 https://doi.org/10.3109/01421591003706282 https://doi.org/10.1111/j.1365-2929.2007.02686.x https://doi.org/10.3946/kjme.2015.27.2.117 https://doi.org/10.3109/0142159x.2011.610841 https://doi.org/10.3109/0142159x.2011.610841 https://doi.org/10.5116/ijme.5557.25f9 https://doi.org/10.3109/0142159x.2011.530312 https://doi.org/10.1080/13576280410001711003 https://doi.org/10.1080/01421590410001711625 https://doi.org/10.1080/01421590410001711625 https://doi.org/10.2147/amep.s127318 https://doi.org/10.2147/amep.s127318 https://doi.org/10.1177/001789690606500205 https://doi.org/10.5116/ijme.4e66.1b37 https://doi.org/10.1080/13576280400002445 https://doi.org/10.1080/01421590120043080 https://doi.org/10.1080/01421590120043080 https://doi.org/10.3109/01421591003686229 https://doi.org/10.3109/01421599709034208 https://doi.org/10.3109/0142159x.2012.668625 https://doi.org/10.3109/0142159x.2012.668625 gowda p. prashanth and salim k. ismail clinical and basic research | e181 25. al sheikh mh. educational environment measurement, how is it affected by educational strategy in a saudi medical school? a multivariate analysis. j taibah univ med sci 2014; 9:115–22. doi: 10.1016/j.jtumed.2013.11.005. 26. taheri m. students’ perceptions of learning environment in guilan university of medical sciences. j med educ 2009; 13:127–33. doi: 10.22037/jme.v13i4.4524. 27. alfaris ea, naeem n, irfan f, qureshi r, van der vleuten c. student centered curricular elements are associated with a healthier educational environment and lower depressive symptoms in medical students. bmc med educ 2014; 14:192. doi: 10. 1186/1472-6920-14-192. 28. el-sobkey sb. effect of a new campus, educational level, and instructional mode on the students’ perceptions of educational environment of physical therapy program, king saud university. pyrex j educ res rev 2015; 1:17–30. 29. shehnaz si, sreedharan j, gomathi kg. faculty and students’ perceptions of student experiences in a medical school undergoing curricular transition in the united arab emirates. sultan qaboos univ med j 2012; 12:77–85. 30. farahmand s, bagheri-hariri s, moghanloo s, basir ghafouri h, saeedi m, afzalimoghadam m, et al. evaluating the quality of the educational environment for medical interns in an emergency department using the dreem inventory. acta med iran 2014; 52:631–7. 31. imanipour m, sadooghiasl a, ghiyasvandian s, haghani h. evaluating the educational environment of a nursing school by using the dreem inventory. glob j health sci 2015; 7:211–16. doi: 10.5539/gjhs.v7n4p211. 32. andalib mm, malekzadeh mm, agharahimi z, daryabeigi m, yaghmaei b, ashrafi mr, et al. evaluation of educational environment for medical students of a tertiary pediatric hospital in tehran, using dreem questionnaire. iran j pediatr 2015; 25:e2362. doi: 10.5812/ijp.2362. 33. bakhshialiabad h, bakhshi m, hassanshahi g. students’ perceptions of the academic learning environment in seven medical sciences courses based on dreem. adv med educ pract 2015; 6:195–203. doi: 10.2147/amep.s60570. 34. al sinawi h, al alawi m, al qubtan a, al lawati j, al habsi a, jose s. perception of preparedness for clinical work among new residents: a cross-sectional study from oman. oman med j 2017; 32:201–6. doi: 10.5001/omj.2017.38. 35. hammond sm, o’rourke m, kelly m, bennett d, o’flynn s. a psychometric appraisal of the dreem. bmc med educ 2012; 12:2. doi: 10.1186/1472-6920-12-2. https://doi.org/10.1016/j.jtumed.2013.11.005 https://doi.org/10.22037/jme.v13i4.4524%09 https://doi.org/10.1186/1472-6920-14-192 https://doi.org/10.1186/1472-6920-14-192 https://doi.org/10.5539/gjhs.v7n4p211 https://doi.org/10.5812/ijp.2362 https://doi.org/10.2147/amep.s60570 https://doi.org/10.5001/omj.2017.38 https://doi.org/10.1186/1472-6920-12-2 squ med j, august 2010, vol. 10, iss. 2, pp. 180-186, epub. 19th jun 10 submitted: 20th feb 10 revision req.25th apr 10, revision recd. 8th may 10 accepted: 9th may 10 somatisation is generally defined as the tendency to experience psychological distress in the form of somatic symptoms and to seek medical help for these symptoms, which may be initiated and/or perpetuated by emotional responses such as anxiety and depression. multiple or unexplained physical symptoms cause substantial disability in patients, excess use of medical services, disappointment for therapists, and frustration for physicians. somatisation is a common problem in primary health care leading to disproportionately heavy demands on health services. patients with somatisation account for about 20% of the work load in general practice.1,2 presenting psychiatric distress with physical symptoms has been recognised as one of the important factors associated with the reduced recognition and treatment of depression in primary health care.3 while their psychiatric distress remains unrecognised and untreated, patients with somatisation undergo long and costly investigations.4 this article aims to review the literature on the development of the concept of somatisation and how this definition is applied, from a cross-cultural perspective. department of family medicine & public health, sultan qaboos university hospital, muscat, oman email: zakiyaq@squ.edu.om مفهوم اضطراب اجلسدنة من منظور ثقافات متعددة زكيه البو�شعيدية لتلك الطبية امل�شاعدة وطلب ج�شدية اأعرا�س هيئة على النف�شية بال�شغوط ال�شعور اىل املري�س نزعة اأنها على اجل�شدنة تعرف امللخ�ص: األعرا�س. وقد تبداأ اأو تت�شاعف هذه الأعرا�س بوجود القلق ااأو الكتئاب. تعترب اجل�شدنة م�شكلة منت�رشة ب�شكل وا�شع خ�شو�شا يف الرعاية ال�شحية الأولية. وتوؤدي هذه امل�شكلة اإىل تعدد زيارات املري�س ملراكز اخلدمات ال�شحية وت�شبب الإحباط للمري�س والطبيب. خالل ال�شنوات وتطبيقاتها با�شتخداماتها يتعلق فيما خ�شو�شا له، الطبية والت�شنيفات وتعريفه اجل�شدنة مب�شطلح مرتبط ر�شى عدم ظهر املا�شية ومالءمتها للمجتمعات غري الغربية. هذه امل�شكلة مرتبطة بتنوع التعاريف، خا�شة الفائدة والكفاية والتطبيق. تهدف هذه الدرا�شة ملراجعة الأدبيات اخلا�شة يف تطور مفهوم اجل�شدنة وكيف يطبق التعريف يف خمتلف املجتمعات. مفتاح الكلمات: ا�شطراب اجل�شدنة، مقارنة بني احل�شارات، الكتاب الت�شخي�شي والح�شائي لالأمرا�س النف�شية، الت�شنيف الإح�شائي الدويل لالأمرا�س، عمان. abstract: somatisation is generally defined as the tendency to experience psychological distress in the form of somatic symptoms and to seek medical help for these symptoms, which may be initiated and/or perpetuated by emotional responses such as anxiety and depression. somatisation has been recognised as a commonly encountered problem, especially in primary health care, contributing to frequent use of medical services and to frustration in both the patient and the doctor. in recent years, there has been a great deal of dissatisfaction with the terminology and classification of somatisation, and the way this definition is applied to non-western cultures. this dilemma pertains to different aspects of the definitions, mainly their usefulness, adequacy and applicability. this article aims to review the literature on the development of the concept of somatisation and how this definition is applied from a cross-cultural aspect. keywords: somatization disorders; cross-cultural comparison; oman; diagnostic and statistical manual of mental disorders; international classification of diseases. review the concept of somatisation a cross-cultural perspective zakiya q al busaidi zakiya q al busaidi review | 181 neurological symptoms.12 these classifications in the dsm-iii and dsmiv have been criticised for being confusing and lacking a satisfactory organising principle. the combination of tightly defined specific categories and large vague non-specific subcategories was described as misleading.8 this method of categorisation has resulted in most of the literature concentrating on rare phenomena and ignoring more common forms of somatisation, especially those presenting to primary health care. studies have shown that in primary health care patients with undifferentiated or not otherwise specified somatoform disorders are far more common than those with a named disorder.13,14 the concept of somatisation presented in the above definitions is based on the assumption that psychological symptoms of depression are more central than somatic symptoms. this assumption has being challenged lately by several studies, including the world health organization international study, in which the findings suggest that somatic symptoms are a core component of the depressive episodes.15 another reason given for the limited acceptance of the present definitions is that the concept has been based on the mind-body dualism characteristic of western medicine. in addition, it implies a causal relationship between psychological distress and its physical manifestation, an approach that is not used in a number of other cultures where the mind-body dichotomy cannot be applied in diagnostic and therapeutic approaches to the patient. the use of the concept in other cultures leads to a problem of translation and communication bearing in mind that the term “somatoform disorders” is difficult to translate into many languages, and that terminology can have important implications for treatment and outcome.14 in arabic, for example, the word soma is translated as jasad, which means body, but there is no word for somatisation in arabic dictionaries. in the medical literature, the arabic term used to indicate somatisation is tajseed. when translated back to english, this word means 'embodiment' or 'embodying'.16,17 in addition, the classifications are not clear with regard to the possibility of these syndromes presenting as primary conditions, or whether they are only linked to psychopathology, i.e. to diagnoses current definitions of somatisation a number of definitions and categories have been proposed for somatisation; among these are the classification of mental and behavioural disorders section of the international classification of diseases (icd) and the diagnostic and statistical manual of mental disorders (dsm). the icd-8 and icd-9 referred to psychic factors contributing to the pathogenesis of physical illnesses without associating them to psychosocial events or calling them psychosomatic.5,6 in the icd-10, somatisation is defined as multiple, recurrent and frequently changing physical symptoms usually present for several years, (at least 2 years) before the patient is referred to a psychiatrist. it is associated with a long complicated history, negative investigations and fruitless operations with the patient’s refusal to accept the advice or reassurance of doctors. marked depression and anxiety are frequently present and may justify specific treatment.7 later, the term “unexplained somatic complaints” was introduced in the primary care version of the icd-10 to describe patients presenting with any physical symptom and frequent medical visits in spite of negative investigations.6 this description is more practical as it has the advantage of having no aetiological implications. in addition, it was proposed to be less intrusive and more acceptable to patients. in spite of this, the term is not without cultural bias and uses negative investigations as an indicator to rule out organic disease.8,9 somatoform disorders were first introduced in the dsm-iii as a category for patients whose presenting symptoms suggest physical illness in the absence of demonstrable organic findings, and lack any known pathophysiological mechanisms. in the dsm-iiir this new category was developed further to include seven disorders: body dysmorphia; conversion; somatisation; somatoform pain; undifferentiated somatoform disorders; somatoform disorders not otherwise specified, and hypochondriasis.10,11 in the dsm-iv, somatisation was defined as a poly-symptomatic disorder that begins before the age of 30 years, extends over a period of years, and is characterised by a combination of pain, gastrointestinal tract, sexual and pseudothe concept of somatisation a cross-cultural perspective 182 | qu medical journal, august 2010, volume 10, issue 2 of anxiety and depression. for example, the criteria defined by goldberg and bridges include psychiatric disorder as a necessity for diagnosing somatisation.1 in their criteria, they argue that a patient with somatisation must seek medical help for the somatic manifestation of psychiatric illness and does not in fact have psychological symptoms. instead, these symptoms are attributed to a physical problem. in the previous definitions, somatisation is viewed as a way of presenting psychopathology. in their current form, these definitions of somatisation reflect the increasing emphasis in psychiatric nosology on creating distinct entities by turning forms of distress into disorders and labelling them.14 however, several authors have called for differentiation between expression of distress, primary somatisation and a formal psychopathologic state.12 in addition, recent studies have suggested that persistent somatic symptoms can occur without there being any conventional psychiatric disorder.9 moreover, some authors prefer not to consider somatisation as a diagnosis, but as a behavioural phenomenon in which there is a disturbance of the sick person role of the patient and the healer role of the doctor.18 for this reason cooper19 suggested that “in future studies, it will be important to examine social and cross-cultural issues by involving medical anthropologists from the start”, as the sick person role is partly determined by cultural factors. as a result of all the controversies mentioned above, a new term, "medically unexplained symptoms", has emerged in recent literature and is becoming widely acceptable. medically unexplained symptoms (mus) are defined as those physical symptoms having little or no basis in underlying organic disease.18 when organic disease exists, the symptoms are inconsistent with or out of proportion to the disease.20 people with mus are not necessarily abnormal. many people exhibit mus, but seldom seek care.20 mus becomes a problem when it leads to frequent health care seeking for feared but nonexistent physical illness.21 the term ‘medically unexplained symptoms’ is useful, over and above somatisation, because it represents a broader concept; has no aetiological implication; includes the full spectrum of severity, and is consistent with the presence of concurrent organic and psychiatric illness causing these symptoms.8 however, the term has been criticised for being based on a negative statement that withholds from the patient a positive explanation for their symptoms. the term implies that the symptom are either organic (medically explained) or medically unexplained which reinforces the mind-body dualism concept. in addition, it covers a very large group of patients since it does not include information about the severity and duration of the symptoms and thus their clinical significance;22 hence, the term still needs to be researched further especially for application in non-western cultures. the dsm and icd are currently being revised. the dsm-v is due to be released in 2013 while the icd-11 release is expected in 2015. the dsm-v workgroup is proposing a series of changes to somatoform disorders. first, the disorders would be grouped together under one term entitled “somatic symptom disorders”, which would include somatoform disorders, factitious disorders, and psychological factors affecting a medical condition. second, because of their many common features, the group is proposing that hypochondriasis, pain disorders, somatisation disorders, and undifferentiated somatoform disorders be grouped together as complex somatic symptom disorders.23,24 the proposed classification has the advantage of shortening the duration of symptoms to six months. moreover, it allows a diagnosis of somatic symptom disorder in addition to a general medical condition, whether the latter is a well-recognised organic disease or a functional somatic syndrome such as irritable bowel syndrome or chronic fatigue syndrome. however, professionals in the field have been voicing concerns that mind-body dualism remains inherent in the proposed criteria. furthermore, the proposals for broadening of the criteria would bring many more patients under a possibly stigmatising mental illness diagnosis.25,26 cross-cultural aspects of somatisation culture is defined as the accumulated beliefs, practices, attitudes, and values shared by a social collective. it is the lens through which a person registers experiences that shape his/ her perceptions, understanding and reactions to events.27 in the perspective of health and illness, zakiya q al busaidi review | 183 attributions and illness behaviour might differ across cultures due to culture-specific characteristics.31,38,39 moreover, epidemiological data has not shown major cross-cultural differences, and community surveys have shown a similar balance between psychological and somatic symptoms in western and non-western countries. in addition, clinical studies have shown that the somatic presentation of depression is common in all cultures.40 recent research on mental disorders in primary care increasingly suggests that somatisation, instead, appears to be the norm in primary care across cultures.15 moreover, while some authors have claimed that less sophisticated subjects are more likely to somatise, others have noted the absence of social and cultural differences between somatisers and psychologisers.41 this evidences suggest that differences cross-culturally and between classes exist at the level of presentation rather than with the experience of somatic symptoms. one of the major studies on the cross-cultural aspects of somatisation is the who collaborative study of psychological problems in general health care to examine the relationship between current somatic symptoms and current psychological distress. the study involved data from 15 participating sites in 14 countries and examined a large number of subjects (5,438) using the general health questionnaire (ghq) and the composite international diagnostic interview.39 the results of the study showed a generally similar pattern of association between physical symptoms and psychological distress among patients from western and non-western countries indicating that cultural factors might not affect the rate of somatisation, but might influence other factors related to it such as subsequent illness behaviour.14 the study found that somatisation is common in many countries, but its frequency depends on how the phenomenon is defined. reports from the arab world show a high incidence of patients complaining of depression and anxiety and a variety of somatic symptoms;42,43,44 however, most of these reports have relied on clinical impressions and psychological scales depending on items eliciting psychological rather than somatic symptoms. generally, there has been little published on somatisation in the arab world. among the culture is recognised to play a fundamental role in defining the states that comprise health and illness, shaping the expression of somatic and psychosocial distress, identifying the aetiological factors believed to be responsible for illness, and shedding light on culturally appropriate help-seeking behaviour and social stigma.27,28 kleinman and good29 state that culture and society shape the meanings and expressions people give to sadness, unhappiness, hopelessness and lack of pleasure. they add that there are dramatic differences in the way different cultures express physical complaints associated with depressive illness. in addition, cultural factors determine which symptoms or signs are normal or abnormal. they act to mould diffuse emotional and physical changes into a pattern which is recognisable to the person suffering from it and to people around him/her.30,31 the presentation of symptoms to the health care system is also affected by culture, as patients are selective regarding what to present to the doctor. they select verbal presentation elements which they believe are relevant and culturally acceptable.32 kleinman,33 in addition to other authors, explains that somatisation as an "idiom of distress" is more common in cultures where stigma is connected with psychiatric problems and the expression of emotional distress is inhibited.33,34,35 other explanations given to support this point of view suggest that patients from non-western cultures are less willing or less able to express emotional distress as they may lack the capacity to label an emotional state.32 this inability to express emotions has been suggested to be due to vocabulary inadequacies in the original languages of these communities. a series of studies by mumford et al.36 support the traditional view mentioned above. according to the authors, many patients presenting to medical outpatient clinics in pakistan complained of unexplained somatic symptoms. another series of studies in china and taiwan by kleinman,37 found that somatisation was the main language of distress and was used to express psychological disorders. the traditional claim that somatisation is more typical of patients from non-western and developing countries is, however, strongly challenged by contrary evidence. there is a growing body of evidence that somatisation is a universal phenomenon. however, the presentation, the concept of somatisation a cross-cultural perspective 184 | qu medical journal, august 2010, volume 10, issue 2 few studies, a screening study using the patient health questionnaire in saudi arabia identified the prevalence of somatisation to be 19.3%.45 on the other hand, a study by el-rufaie et al.46 showed that 48% of a sample of psychiatrically referred arab primary care patients presented with predominantly somatic expressions of mental disorders. this contrasts with 42% who presented with predominantly psychological expressions. this study showed that the patients involved use both psychological as well as somatic language to express their distress. a study assessing the prevalence of somatisation and psychological morbidity in patients presenting to primary health care in oman showed that both somatisation and psychological morbidity are relatively common. the study population equally experienced psychological distress as well as somatic distress.16 these finding challenges the old belief that people in developing countries express their distress mainly somatically. the challenges facing cross-cultural studies researchers studying disorders across cultures face the dilemma of applying the definition of a disorder derived from one culture context to others in which their applicability might be doubtful. this is especially true regarding somatisation because somatisation has often been seen from a number of different perspectives. due to the diverse ways in which the phenomenon is conceptualised, research findings have tended to be conflicting. both diversity and conflicting results are evident as regards the different aspects of the phenomenon presented in the literature. in addition to the diversity of definitions, there is a diversity of settings in which these studies were conducted, as somatisation in community and primary health care patients might differ from that of psychiatric patients. this diversity of definitions and settings makes it difficult to generalise or interpret accurately the results of these studies across different cultures.39 in addition to the differences in the definitions used in various studies, there are differences in the settings of these studies, which make the generalisation of the results rather difficult. although psychological morbidity has been shown to be very high among patients seeking primary health care, it has been suggested that, among psychiatric outpatients, somatisation may represent a more severe and chronic phenomenon. this is in comparison to the rather acute and more selflimiting form that presents in primary health care and in the community;39 however, most studies have focused on patients at the most severe end of the spectrum of the phenomenon. other studies show a difference in the characteristics of somatising patients between those who present to hospital clinics and those presenting to primary health care. cross-cultural studies reveal specific biases in western patterns of causal attribution that are not shared by many other cultures. for example, people in western societies tend to overestimate the importance of the individual and of personality traits, and underestimate the importance of situational factors in making attributions for behaviour. however, this bias is culture-specific, since people in india, china and japan, for example, are more likely to attribute behaviour to situational or contextual factors.47 kirmayer et al.47 explain that one of the reasons for the impression that western patients usually express psychiatric distress in terms of emotional symptoms is related to the fact that most of the research in the past was based largely on tertiary care patients. hence there is a need to differentiate between studies done on community and primary health care patients and those on patients in psychiatric clinics or tertiary care. in addition, most of the studies published on somatisation use quantitative research methods while qualitative research may be more suitable for eliciting patients’ own beliefs and help-seeking behaviour across cultures. conclusion there is a need to reform the present classifications and definitions of somatisation aimed at finding better and more practial nosological solutions that take cultural variety more into account. such reforms have to be based on extensive research on the subject, in addition to literature review of more recent research. adopting a cross-cultural perspective in addressing psychosomatic questions can benefit both basic knowledge and practical health care applications. from the perspective of basic knowledge, attention to cross-cultural zakiya q al busaidi review | 185 12. american psychiatric association. diagnostic and statistical manual of mental disorders. 4th ed. washington dc: american psychiatric association, 1994. 13. lloyd g. somatisation: a psychiatric perspective. j psychosom res 1989; 33:665–9. 14. kirmayer lj, robbins jm. somatoform disorders: personality and the social matrix of somatic distress. j abnorm psychol 1994; 58:481–8. 15. simon ge, gater r, kisely s, piccinelli m. somatic symptoms of distress: an international primary care study. psychosom med 1996; 58:481–8. 16. al-lawati j, al-lawati n, al-siddiqui m, anthony sx, al-naamani a, martin rg, et al. psychological morbidity in primary health care in oman: a preliminary study. squ j sci res: med sci 2000; 2:105–10. 17. baalabki m, baalabki r. al-mawrid dictionary: englisharabic, arabic-english. beirut: dar-el-illm lilmalayin, 1999. 18. escobar ji. transcultural aspects of dissociative and somatoform disorders. psychiatr clin north am 1995; 18:555–69. 19. cooper je. the classification of somatoform disorders in icd-10. new york: springer, 1999. 20. kellner r. hypochondriasis and somatization. jama 1987; 258:2718. 21. verbrugge lm, ascione fj. exploring the iceberg. common symptoms and how people care for them. med care 1987; 25:539. 22. creed f, guthrie e, fink p, henningsen p, rief w, sharpe m, et al. is there a better term than “medically unexplained symptoms” j psychosom res 2009; 68:5–8. 23. proposed dsm-v criteria. from www.dsm5.org. accessed apr 2010. 24. dimsdale j, creed f, and on behalf of the dsm-v workgroup on somatic symptom disorders. the proposed diagnosis of somatic symptom disorders in dsm-v to replace somatoform disorders in dsmiv—a preliminary report. j psychosom res 2009; 66:473–6. 25. the proposed dsm-v revision. from www.dsmwatch. wordpress.com. accessed apr 2010. 26. schroder a, fink p. the proposed diagnosis of somatic symptom disorders in dsm-v: two steps forward and one step backward? j psychosom res 2010; 68:95–100. 27. devins gm. culturally informed psychosomatic research. j psychosom res 1999; 46:519–24. 28. katon w, ries rk, kleinman am. the prevalance of somatization in primary care. compr psychiatry 1984; 25:208–15. 29. kleinman am, good b. introduction: culture and depression. berkeley: university of california press, 1985. questions can help to differentiate fundamental principles from culturally specific ones. moreover, there is a growing awareness of the importance of integrating culturally relevant considerations in medical management and in education and training strategies so as to provide more effective health care.27,38 acknowledgements i would like to thank sultan qaboos university, oman, for granting me a scholarship to study for my phd at the university of nottingham (20012005), on which part of this article is based. i would also like to thank my phd supervisor, dr. margaret oates, for her guidance and support. references 1. bridges rn, goldberg dp. somatic presentation of dsm-iii psychiatric disorders in primary care. j psychosom res 1985; 29:563–9. 2. craig tk, boardman ap, mills k, daly-jones o, darke h. the south london somatisation study. i: longitudinal course and the influence of early life experience. br j psychiatry 1993; 163:579–88. 3. cape j, mcculloch y. patients' reasons for not presenting emotional problems in general practice consultations. br j gen pract 1999; 49:875–9. 4. kirmayer lj, robbins jm, dowrkind m, taffe mj. somatisation and the recognition of depression and anxiety in primary care. am j psychiatry 1993; 150:734– 41. 5. kramer m, sartorius n, jablensky a, gulbinat w. the icd-9 classification of mental disorders: a review of its development and contents. acta psychiatr scand 1979; 59:241–62. 6. sartorious n. classification: an international perspective. psychiatr ann 1976; 6:22–35. 7. the icd-10 classification of mental and behavioural disorders: diagnostic criteria for research. geneva: who, 1992. 8. barsky aj, ettner sl, horsky j, bates dw. resource untilization of patients with hypochondriacal health anxiety and somatization. med care 2001; 39:705. 9. kendler ks. a psychiatric dialogue on the mind-body problem. am j psychiatry 2001; 158:989–1000. 10. diagnostic and statistical manual of mental disorders. 3rd ed. american psychiatric association; washington dc: 1980. 11. diagnostic and statistical manual of mental disorders. 3rd ed, revised. washington dc: american psychiatric association, 1987. the concept of somatisation a cross-cultural perspective 186 | qu medical journal, august 2010, volume 10, issue 2 30. helman c. culture, health and illness. oxford, uk: butterworth-heineman, 1990. 31. kirmayer lj. culture, affect and somatisation. transcult psychiatr res rev 1984; 21:159–88. 32. lipowski zj. somatisation and depression. psychosomatics 1990; 31:13–21. 33. kleinman am. depression, somatisation and the "new cross-cultural psychiatry". soc sci med 1977; 11:3–10. 34. kleinman am. culture and depression. cult med & psychiatr 1978; 2:295–6. 35. mechanic d. social and psychological factors affecting the presentation of bodily complaints. n engl j med 1972; 286:1132–9. 36. mumford db, bavington jt, bhatnagar ks. the bradford somatic inventory: a multi-ethnic inventory of somatic symptoms reported by anxious and depressed patients in britain and the indo-pakistan subcontinent. br j psychiatry 1991; 158:379–86. 37. kleinman am. patients and healers in the context of culture, berkeley: university of california press, 1980. 38. ono y, janca a. rethinking somatoform disorders. j psychosom res 1999; 46:537–9. 39. gureje o, simon ge, ustun tb, goldberg dp. somatisation in cross-cultural perspective: a world health organisation study in primary care. am j psychiatry 1997; 154:989–95. 40. simon ge, vonkorff m, piccinelli m, fullerton c, ormel j. an international study of the relation between somatic symptoms and depression. n engl j med 1999; 341:1329–35. 41. bridges k, goldberg dp, evans b, sharpe t. determinants of somatization in primary care. psychol med 1991; 21:478–83. 42. hamdi ti, al-hasani l, mahmood a, al-hussaini aa. hysteria: a large series in iraq. br j psychiatry 1981; 138:177–8. 43. racy j. somatisation in saudi women: a therapeutic challenge. br j psychiatry 1980; 137:212–6. 44. zaidan z, alwash r, al-hussaini aa, al-jarrah m. psychiatric morbidity in northern jordan: a ten-year review. med sci 2000; 35–40. 45. beker s, al-zaid kh, al-faris e. screening for somatisation and depression in saudi arabia: a validation study. int j psychiatry med 2002; 32:271– 83. 46. el-rufaie oef, al-sabosy mma, bener a, abuzeid mso. somatised mental disorder among primary care arab patients: 1. prevalence and clinical and sociodemographic characteristics. psychosom med 1999; 46:549–55. 47. kirmayer lj, young a, robbins jm. symptom attribution in cultural perspective. can j psychiatry 1994: 39:584–95. squ med j, april 2010, vol. 10, iss. 1, pp. 80-83, epub. 17th apr 10 submitted 2nd sept 09 revision req. 23rd nov 09. revision recd. 9th dec. 09 accepted 6th jan 09 1department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of medicine, sultan qaboos university hospital, muscat, oman; 3school of medicine, university of nottingham, uk *to whom correspondence should be addressed. email: nickwood2@doctors.org.uk ِرّي الباِدِئ ِعنَْد النُّْضج احملدد سريريا عند البالغني كَّ داء السُّ الُعمانيني صغار السن غياب املوّرثات اجلينية الشائعة يف الغرب نيكوالس وودهاوس، أميمة الشفيع، علي املعمري، ناجي هاشم، فاطمة الريامي، ساندي رايبرن ال�شكري مر�س ال�رسيرية خ�شائ�شه ت�شابه الذي ال�شكر بداء امل�شابني ال�شن �شغار املر�شى من متزايدة اأعدادا ن�شنقبل الهدف: امللخ�ص: الباديء عند الن�شج حيث التاريخ االأ�رسي ي�شري اىل تاأثر م�ّرث اأحادي، مع غياب الدليل الذي ي�شري اىل وج�د داء ال�شكري من الن�ع االأول ذي ،1α 4 ، والعامل الكبدي الن�ويα املناعة الذاتية. الهدف من هذه الدرا�شة حتديد م�ش�ؤولية الطفرات ال�راثية الثالثة )العامل الكبدي الن�وي واجلل�ك�كاينيز( االكرث �شي�عا بني املر�شى الغربيني من عدمه عند البالغني الُعمانيني �شغار ال�شن. الطريقة: متت الدرا�شة يف م�شت�شفى جامعة ال�شلطان قاب��س ب�شلطنة ُعمان، حيث مت اختيار ع�رسين مري�شا بالغا من �شغار ال�شن ممن لهم تاريخ اأ�رَسي باحتمالية الت�ريث مب�ّرث واحد بفرتة تقل عن )18( �شهرا، وكان مت��شط االأعمار )25( �شنة مع و�شيط من�شب كتلة اجل�شم )29(. اأجري التحري ل�ج�د م�شادات املناعة الذاتية �شد خاليا البنكريا�س اجلزيرية – ن�ع بو ناِزَعُ الَكْرُب�ك�ِشيل حلام�س اجلل�تاميك وكان �شلبيا. وافق اأربعة ع�رس مري�شا على اإجراء حتري فح�س الدم ال�راثي ومت اإر�شاله ل�حدة الربوفي�ش�ر هاتر�شلي يف كلية الطب بباك�شرت )اململكة املتحدة(، حيث مت فح�س احَلْم�ُس الرِّْيِبيُّ النََّ�ِوي َمْنُزوع االأوك�ِشجني للطفرات اجلينية يف االك�ش�ن )10-1( من انزمي ناِزَعُ الَكْرُب�ك�ِشيل حلام�س اجلل�تاميك واالك�ش�ن )10-2( من م�ّرثات (، الطفرات ال�راثية االأكرث �شي�عا يف اوروبا. النتائج: مل يتم العث�ر على اأي من 4α ( والعامل الكبدي الن�وي ) 1α (العامل الكبدي الن�وي الطفرات ال�راثية املذك�رة يف اأي من املر�شى. اخلال�صة: يف هذه املجم�عه ال�شغرية من املر�شى العمانيني البالغني �شغريي ال�شن الذين تطابق ج مل يتم العث�ر على اأي من الطفرات ال�راثية الثالث االأكرث �شي�عا يف الغرب. وهذا قد يك�ن ناجتا حالتهم ال�رسيرية داء ال�شكري الباِدُئ ِعْنَد النُّ�شْ من وج�د طفرات جديدة يف املر�شى العمانيني اأو اأن ه�ؤالء املر�شى يعان�ن من داء ال�شكري من الن�ع الثاين نتيجة لت�ريث بع�س امل�ّرثات التي ت�شكل خطرا يف اال�شابة املبكرة بداء ال�شكري من الن�ع الثاين الذي يتميز ب�ج�د مقاومة كبرية لالن�ش�لني ناجتة عن ال�شمنة . ج، طفرات، داء ال�شكري العائلي، البالغني ال�شغار، ُعمان. ِريُّ الباِدُئ ِعْنَد النُّ�شْ كَّ مفتاح الكلمات: داء ال�شكري – الن�ع الثاين، داء ال�شُّ abstract: objectives: we are seeing a progressive increase in the number of young patients with clinically defined maturity onset diabetes of the young (mody) having a family history suggestive of a monogenic cause of their disease and no evidence of autoimmune type 1 diabetes mellitus (t1dm). the aim of this study was to determine whether or not mutations in the 3 commonest forms of mody, hepatic nuclear factor 4α (hnf4α), hnf1α and glucokinase (gk), are a cause of diabetes in young omanis. methods: the study was performed at sultan qaboos university hospital (squh), oman. twenty young diabetics with a family history suggestive of monogenic inheritance were identified in less than 18 months; the median age of onset of diabetes was 25 years and the median body mass index (bmi) 29 at presentation. screening for the presence of autoimmune antibodies against pancreatic beta cells islet cell antibody (ica) and glutamic acid decarboxylase (gad) was negative. fourteen of them consented to genetic screening and their blood was sent to prof. a. hattersley’s unit at the peninsular medical school, exeter, uk. there, their dna was screened for known mutations by sequencing exon 1-10 of the gck and exon 2-10 of the hnf1α and hnf4α genes, the three commonest forms of mody in europe. results: surprisingly, none of the patients had any of the tested mody mutations. conclusion: in this small sample of patients with clinically defined mody, mutations of the three most commonly affected genes occurring in caucasians were not observed. either these patients have novel mody mutations or have inherited a high proportion of the type 2 diabetes mellitus (t2dm) susceptibility genes compounded by excessive insulin resistance due to obesity. keywords: diabetes mellitus, type ii; diabetes mellitus, maturity onset; mody; mutations; diabetes, familial; young adults; oman. clinically-defined maturity onset diabetes of the young in omanis absence of the common caucasian gene mutations *nicholas jy woodhouse,1 omayma t elshafie,2 ali s al-mamari,2 nagi hs mohammed,2 fatma al-riyami,2 sandy raeburn3 brief communication nicholas jy woodhouse, omayma t elshafie,ali s al-mamari, nagi hs mohammed,fatma al-riyami and sandy raeburn brief communication | 81 diabetes mellitus (dm), both types i and ii, is common worldwide and now affects more than 5% of all obese adolescents;1-4 however, optimal investigation and management is still unclear. doctors often struggle to provide the best therapy, especially in regions where lifestyle changes in the last one or two generations have contributed to the diabetogenic risk. in oman, as in other countries of the arabian peninsula, type 2 diabetes (t2dm) especially and other complex, multifactorial disorders have reached epidemic levels.5 we are now seeing a progressive increase in the number of young omani diabetics (<25 years) with a family history indicating a monogenic cause of their disease and who have no evidence of type 1 diabetes mellitus (t1dm). these patients have clinically defined maturity onset diabetes of the young (mody), a disorder resulting from mutation in 6 different genes causing deficient insulin secretion. they are often misdiagnosed as t1dm and treated with insulin. however, some patients have mutations in the genes encoding hnf1α or β-cell potassium adenosine triphosphate (k-atp) channels both of which respond well to low dose sylphonylurea (su) therapy. to date, we have identified three such families (not included in the present study) who were able to discontinue insulin and continue on su therapy alone. clearly therefore, mody exists in oman and in this study we have screened an additional 14 patients for common mody mutations. methods twenty young diabetics with a family history suggesting monogenic inheritance [figure 1], and whose antibodies against pancreatic betacells islet cell antibodies (ica) and glutamic acid decarboxylase (gad)) were negative, were identified in less than 18 months. of these 14 patients, whose characteristics are shown in table 1, consented to genetic screening and their blood was sent to the molecular genetics laboratory at the peninsular medical school, exeter, uk. there, their dna was screened for known mutations by sequencing exon 1-10 of the glucokinase gene and exon 2-10 of the hnf1α and hnf4α, the commonest forms of mody in europe6 using the dna abi prism® 3100 genetic analyzer, results and discussion in this small group of young omani diabetics, we expected to find several with known mody mutations, particularly as we have already identified 3 different mody families responsive to su therapy. surprisingly, this was not the case and mutations in the three commonest forms of mody were not observed, although all had family histories suggestive of a monogenic cause of their disease and no evidence of t1dm. how might this be explained? either these patients had novel mody mutations or have inherited one or more of the t2dm susceptibility genes. novel mutations cannot be ruled out as, in a recent and larger danish study, mutations were found in only half the patients with clinically defined mody, as ours.7 interestingly, patients with clinically defined mody in mexico and china8,9 have few of the documented mutations occurring in caucasians which suggests that our omani mody patients may have novel gene mutations as well. however, we suspect that early onset t2dm is more likely, particularly as the median bmi in our study group was 29, an additional factor associated with early onset disease. mody is a familial monogenic form of diabetes with autosomal dominant inheritance and high penetrance of 80–95%. in contrast to type 1 and type 2 diabetes, mody usually develops below 25 years6,10 [figure 2]. currently there are 6 identified gene mutations, three of them, hnf1α, hnf4α and glucokinase, are common and account for >80% of mody cases in europe and north america, while others are rare (hnf1β, insulin promoter factor 1 and neurogenic differentiation factor 1).10 some of the mody patients will not advances in knowledge 1. it would appear that the maturity onset diabetes of the young mutations common in caucasians are rare in oman. application to patient care 1. families with mutations of the beta cells potassium atp channels may be identified and thus the use of insulin avoided clinically-defined maturity onset diabetes of the young in omanis absence of the common caucasian gene mutations 82 | qu medical journal, april 2010, volume 10, issue 1 have a known gene mutation (mody x), but efforts are on going to determine the responsible mutations.10, 11 with young patients, the clinician should distinguish between t1dm (with autoimmune destructions of the beta-cells and insulin dependence), monogenic defects due to the maturity onset of diabetes in the young (mody) and t2dm which is multifactorial.3,12,13 with their early age of onset, patients with single gene disorders such as mody are often misdiagnosed as t1dm and inappropriately treated with insulin.12,14-16 this is unfortunate as patients with glucokinase deficiency (gkd) have few complications and rarely require treatment.13,17 furthermore, patients with transcriptions factor mutations (such as hnf1α and neonatal kir6.2) respond dramatically to sulphonylurea medication.14 recently, we have successfully switched diabetics, from three families, from insulin of many years duration to oral sus. although monogenic dm in the uk is only estimated to occur in 1–2% of the diabetic population (i.e. up to 40,000 patients), in oman the incidence of monogenic disease is probably much higher due to the higher rate of consanguinity. mutagenesis screening is expensive so we are now actively screening candidate patients using a trial of su therapy. screening is carried out in patients aged <30 years who are taking insulin, have a positive family history and no gad or ica antibodies. of the 10 patients studied so far 3 have gratifyingly responded to low dose su therapy. this trial is currently in progress, together with screening of the patients for the t2dm susceptibility genes which are currently known to be associated with t2dm.18-21 references 1. field ll. type 1 diabetes. in: t bishop t, sham p, eds. analysis of multifactorial disease. oxford: bios scientific publishers ltd, 2000. 2. hanson rl, knowler wc. type 2 diabetes mellitus and maturity onset diabetes of the young. in: t bishop t, sham p, eds. analysis of multifactorial disease. oxford: bios scientific publishers ltd, 2000. 3. mccarthy m. approaches to detemining the genetics basis of non-insulin-dependent diabetes mellitus. in: day inm, humphries se, eds. genetics of common diseases: future therapeutic and diagnostic possibilities. oxford: bios scientific publishers ltd, 40s 65 60 31 30 figure 1: pedigree of index omani patient. the numbers indicate the age at diagnosis 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 age at diagnosis type 1 mody type 2 legend: mody = maturity onset diabetes of the young figure 2: age at onset with differnt types of diabetes table 1: details of the 14 patients with a family history suggesting a monogenic cause of their disease. shown is the median and range of age and bmi at diagnosis. four were taking insulin alone and 10 oral hypoglycaemic agents. age at diagnosis/yr median sex bmi therapy gad / ica 20 (12-40) 10 m 29 ins negative 4 f 20-41 oha negative legend: bmi = body mass index; gad = glutamic acid decarboxylase; ica =islet cell antibody; ins = insulin; oha = oral hypoglycaemic agents nicholas jy woodhouse, omayma t elshafie,ali s al-mamari, nagi hs mohammed,fatma al-riyami and sandy raeburn brief communication | 83 1997. 4. pearson er, starkey bj, powell rj, gribble fm, clark pm, hattersley at, et al. genetic cause of hyperglycaemia and response to treatment in diabetes. lancet 2003; 362:1275–81. 5. hassan mo, barwani s, al-yahyaee s, al haddabi s, rizvi s, jaffer a, et al. a family study in oman: large consanguineous, polygamous omani arab pedigrees. a planned model for the study of complex diseases. community genet 2005; 8:56–60. 6. hattersley a, bruining j, shield j, njolstad p, donaghue k. the diagnosis and management of monogenic diabetes in children. pediatr diabetes 2006; 7:352–60. 7. johansen a, ek j, mortensen hb, pedersen o, hansen t. half of clinically defined maturity-onset diabetes of the young patients in denmark do not have mutations in hnf4a, gck, and tcf1. j clin endocrinol metab 2005; 90:4607–14. 8. domínguez-lópez a, miliar-garcía a, segura-kato yx, riba l, esparza-lópez r, ramírez-jiménez s, et al. mutations in mody genes are not common cause of early-onset type 2 diabetes in mexican families. jop 2005; 6:238–45. 9. xu jy, dan qh, chan v, wat nm, tam s, tiu sc, et al. genetic and clinical characteristics of maturityonset diabetes of the young in chinese patients. eur j hum genet 2005; 13:422–7. 10. froguel p, velho g. molecular genetics of maturityonset diabetes of the young. trends endocrinol metab 1999; 10:142–6. 11. fajans ss, bell gi, polonsky ks. molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. n engl j med 2001; 345:971. 12. hattersley at. molecular genetics goes to the diabetes clinic. clinical medicine 2005; 5:476–81. 13. page rc, hattersley at, levy jc, barrow b, patel p, lo d. clinical characteristics of subjects with a missense mutation on glucokinase. diabet med 1995; 12:209–17. 14. hattersley at, ashcroft fm. activating mutations in kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights and new therapy. diabetes 2005; 54:2503–13. 15. pearson er, liddell wg, shepherd m, corrall rj, hattersley at. sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1 alpha gene mutations: evidence for pharmacogenetics in diabetes. diabet med 2000; 17:543-5. 16. shepherd m, hattersley at. i don’t feel like a diabetic anymore”: the impact of stopping insulin in patients with maturity onset diabetes of the young following genetic testing. clin med 2004; 4:144. 17. velho g, blanche h, vaxillaire m, bellanne-chantelot c, pardini vc, timsit j, et al. identification of 14 new glucokinase mutations and description of the clinical profile of 42 mody-2 families. acta diabetol 1997; 40:217–24. 18. florez jc. clinical review: the genetics of type 2 diabetes, a realistic appraisal in 2008. clin endocrinol metab 2008: 93:4633. 19. groop l, lyssenko v. genes and type 2 diabetes mellitus. curr diab rep 2008; 8:192–7. 20. lyssenko v, groop l. genome-wide association study for the type 2 diabetes: clinical applications. curr opin lipidol 2009; 20:87. 21. zeggini e, scott lj, saxena r, voight bf, marchini jl, hu t, et al. meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. nat genet 2008; 40:638–45. faculties of 1nursing and 2medicine and 5center for research in medical sciences, autonomous university of mexico state, toluca, mexico; 3faculty of medicine, universidad de la sabana, chía, colombia; 4coordination of high specialty hospitals, ministry of health, toluca, mexico *corresponding author’s e-mail: mezh_74@yahoo.com العالقة بني َمْنِسب تقييم منوذج االستباب ومستويات األديبونيكنت واللبتني واألنسولني ومنسب كتلة اجلسم املرتبط بتعدد األشكال اجلينية عند املراهقني ماريا دي لو�ص أنجليس مارتينيز-مارتينيز، هوجو منديتا-زيرون، لوي�ص �شيلي�ص، كري�شتيان ليتون-توفار، روكيو توريه-جار�شيا، لورا قوتريز-بليقو، انيدا كاملريو-رومريو، هوزي دي جي�شي�شقارديونو-قار�شيا، ماريا كاملريو-رومريو abstract: objectives: this study aimed to describe correlations between glucose, insulin and adipokine levels and the homeostasis model assessment (homa) index with regards to the presence/absence of fat mass and obesityassociated (fto) rs9939609 and peroxisome proliferator-activated receptor (ppar)-y rs1801282 single nucleotide polymorphisms (snps) as indicators of body mass index in adolescents. methods: this cross-sectional study was conducted between september and december 2016 in toluca, mexico. a total of 71 students between 14–18 years old were included. various anthropometric and laboratory measurements were collected, including lipid profile, glucose, insulin and adipokine levels and homa index. the degree of association between variables was evaluated with regards to the presence/absence of the snps. results: leptin levels were significantly higher among female students (p = 0.001), although adiponectin levels did not differ significantly (p = 0.060). there were significant positive correlations between insulin levels and homa index with fto (r = 0.391; p = 0.007 and r = 0.413; p = 0.005, respectively) and pparγ (r = 0.529; p = 0.007 and r = 0.537; p = 0.007, respectively) snps. leptin showed a significant positive correl ation in the presence of pparγ (r = 0.483; p = 0.007) or in the absence of both snps (r = 0.627; p = 0.039). however, adiponectin was significantly negatively correlated in the presence of fto, either alone (r = −0.333; p = 0.024) or in combination with pparγ (r = −0.616; p = 0.043). conclusion: the presence of fto and/or pparγ snps might be related to a genetic predisposition to metabolic syndrome. keywords: obesity; body mass index; single nucleotide polymorphisms; fat mass and obesity associated protein, human; peroxisome proliferator-activated receptor gamma; adipokines. ال�شتباب منوذج تقييم وَمْن�ِشب والديبونكتني، والأن�شولني اجللوكوز م�شتويات بني العالقات الدرا�شة هذه ت�شف الهدف: امللخ�ص: )fto rs9939609 و pparγ rs1801282( ملعرفة وجود اأو عدم وجود تعدد اأ�شكال النوكليوتيدات املفردة ملورثات كتلة الدهن وال�شمنة بح�شبانها موؤ�رسات لكتلة اجل�شم عند املراهقني. الطريقة: اأجريت هذه الدرا�شة امل�شتعر�شة ما بني �شبتمرب ودي�شمرب عام 2016م يف تولو�شا باملك�شيك، و�شارك فيها 71 طالبا يف عمر ما بني 18–14 عاما. ومت اإجراء عدد من القيا�شات الأنرثوبومرتية واملختربية �شملت م�شتويات الدهون واجللكوز والأن�شولني والأديبونيكنت وَمْن�ِشب تقييم منوذج ال�شتباب. ومت تقييم درجة العالقة بني تلك املتغريات ن�شبة ً اإىل وجود ،)p = 0.001( اأو غياب تعدد يف اأ�شكال النوكليوتيدات املفردة. النتائج: كان م�شتوى تركيز اللبتني اأعلى ب�شورة ُمْعَتدٌّة عند الطالبات الإناث غري اأن م�شتوى الديبونكتني مل يتغري ب�شورة ُمْعَتدٌّة )p = 0.060(. وكانت هنالك عالقات اإيجابية بني م�شتويات الن�شولني وَمْن�ِشب تقييم منوذج ال�شتباب وبني اأ�شكال النوكليوتيدات املفردة ملورثات كتلة الدهن وال�شمنة )r = 0.413; p= 0.005 و r = 0.391; p = 0.007، على التوايل(، و pparγ )r = 0.537; p = 0.007 و r = 0.529; p = 0.007، على التوايل(، وجد هناك عالقة طردية إيجابية لهرمون الليبتني بوجود pparγ (r = 0.483; p = 0.007) اأو يف غياب �شكلي النوكليوتيدات املفردة (p ;r = 0.627 = 0.039). غري اأن م�شتوى الديبونكتني كان .)r = -0.616; p = 0.043( pparγ اأو يف وجود )r = -0.333; p = 0.024( يتنا�شب �شلبيا مع وجود مورثات كتلة الدهن وال�شمنة، اإما مبفرده الوراثي بال�شتعداد عالقة pparγ ل املفردة النوكليوتيدات اأ�شكال و/اأو وال�شمنة الدهن كتلة مورثات لوجود يكون اأن ميكن اخلال�صة: لالإ�شابة باملتالزمة الأي�شية )ال�شتقالبية(. الكلمات املفتاحية: ال�شمنة؛ موؤ�رس كتلة اجل�شم؛ تعدد اأ�شكال النوكليوتيدات املفردة؛ الربوتني املرتبط بكتله الدهن وال�شمنة، اإِْن�شان؛ pparγ؛ الأديبوكاينز. correlation of the homeostasis model assessment index and adiponectin, leptin and insulin levels to body mass index-associated gene polymorphisms in adolescents maría d. martínez-martínez,1 *hugo mendieta-zerón,2 luis celis,3 cristian f. layton-tovar,4 rocío torres-garcía,5 laura e. gutiérrez-pliego,5 eneida camarillo-romero,5 josé d. garduño-garcía,5 maría d. camarillo-romero5 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e291–298, epub. 19 dec 18 submitted 31 jan 18 revision req. 25 feb 18; revision recd. 13 mar 18 accepted 5 apr 18 doi: 10.18295/squmj.2018.18.03.005 advances in knowledge certain single nucleotide polymorphisms (snps) have been associated with obesity and insulin resistance. however, current data are conflicting regarding the roles of the fat mass and obesity-associated (fto) rs9939609 and peroxisome proliferator-activated receptor (ppar)-y rs1801282 snps in this regard. correlation of the homeostasis model assessment index and adiponectin, leptin and insulin levels to body mass index-associated gene polymorphisms in adolescents e292 | squ medical journal, august 2018, volume 18, issue 3 obesity is a multifactorial disease determined by a complex interaction between genetic and environmental factors. previous research has associated an obesogenic phenotype with the presence of specific polymorphisms also linked to the development of insulin resistance, diabetes mellitus and metabolic syndrome.1 moreover, pancreatic function may be altered by mutations that cause changes in the activity or expression of proteins involved in the regul ation of basal energy expenditure; the latter phenomenon is explained in part by the various mechanisms of oxid ative phosphorylation. although the effect of each indiv idual gene or combination of different genetic variants on metabolism and thermogenesis is uncertain, this may explain why certain individuals have a greater tendency to develop metabolic disorders.2 in recent decades, efforts have intensified in the search for single nucleotide polymorphisms (snps) caus ing observed changes in the signalling pathways that regulate metabolic processes, leading to failures in energy homeostasis and predisposing individuals to diabetes and obesity.3 peroxisome proliferator-activated receptors (ppars) are a group of nuclear receptor proteins that function as transcription factors. these receptors are present in different metabolic pathways related to energy homeostasis, in addition to the lipid route. so far, three ppar isoforms have been identified; the pparγ isoform, which is highly expressed in white adipose tissue, is involved in lipid storage and energy dissipation and is recognised to be the master regulator of adipogenesis.4 the fat mass and obesity-associated (fto) gene is comp osed of nine exons on chromosome 16 (16q12.2).5 it was the first gene to be associated with obesity in genomewide association studies.6 frayling et al. observed that adults with the fto rs9939609 snp had a 1.67-fold incr eased risk of obesity and weighed an average of 3–4 kg more than those without this polymorphism.7 in mexico, genomic studies have demonstrated several genetic ancestries for the local population.8 how ever, this implies that there may be discrepancies in the role of some snps in the presence of obesity-related conditions, such as metabolic syndrome. this study aimed to identify correlations between glucose, insulin and adipokine levels and the homeostasis model assessment (homa) index with regards to the presence or absence of fto rs9939609 and ppary rs1801282 snps as indicators of body mass index (bmi) in mexican adolescents. methods this cross-sectional study was conducted from sept ember to december 2016 at the autonomous university of mexico state (uaem) in toluca, mexico. all adolesc ents between 14–18 years old attending the lic. adolfo lópez mateos preparatory school in toluca were invited to participate in the study. the exclusion criteria included a history of smoking, being pregnant or having been diagnosed with a chronic or acute disease. the sample size was calculated as follows:9 where n is the infinite population of available participants (981 adolescents), z is the 95% confidence level (1.96), p is the estimated percentage of the studied poly morphisms in the total population (30%), ε is the margin of error set at 11% with a replacement rate of 9%, n' is the required finite sample size and n is the population size. based on this, the required sample size was set at 68 adolescents. a body composition monitor was used to measure the subjects’ weight (bc-533 innerscan body composition monitor®, tanita corp., tokyo, japan), while a standard stadiometer was used to measure height. bmi was calculated as weight in kg divided by height in m2. according to genderand age-specific world health organization bmi classifications for adolescents, the participants were categorised as either normal, overweight (≥1 standard deviation [sd] of the z score) or obese (≥2 sd of the z score).10 waist and hip circumferences were measured using a fibreglass tape to the nearest 0.1 cm and waist-to-height and waist-to-hip ratios calculated accordingly. blood pressure was checked by auscultation using a sphygmomanometer with an appropriately sized cuff. systolic and diastolic hypertension was determined according to the criteria for high blood pressure in children and adolescents from the national high blood pressure education program working group.11 after a fasting period of 8 hours, 3 ml of venous blood were drawn from participants and collected into bd vacutainer® tubes (becton, dickinson and co., fran klin lakes, new jersey, usa). using enzymatic methods, concentrations of glucose, uric acid, total cholesterol, the current study found that certain adipokines were significantly correlated with fto and pparγ expression. application to patient care determining the presence or absence of fto and ppary snps among adolescents might help in the design and implementation of more intensive obesity prevention strategies in this population. z2 × p(1-p) n z2 × p(1-p) ε2 n n = n’ = ε2 1 + maría d. martínez-martínez, hugo mendieta-zerón, luis celis, cristian f. layton-tovar, rocío torres-garcía, laura e. gutiérrez-pliego, eneida camarillo-romero, josé d. garduño-garcía and maría d. camarillo-romero clinical and basic research | e293 high-density lipoproteins (hdls), low-density lipoproteins (ldls) and triglycerides were determined according to the manufacturer’s instructions for each reagent assay kit (randox laboratories ltd., crumlin, county antrim, uk). the participants’ thyroid profiles were measured by radioimmunoassay, whereas adiponectin, insulin and leptin levels were determined using the 900 series invitrogen® enzyme-linked immunosorbent assay (thermo fisher scientific inc., pittsburgh, pennsylvania, usa). one sample remained frozen at -70 °c until dna extraction. the atherogenic index of plasma (aip) was calcul ated as total cholesterol divided by hdl. the homa index for insulin resistance was calculated as follows:12 where fpi is fasting plasma insulin and fpg is fasting plasma glucose. a diagnosis of metabolic syndrome was based on the criteria of the international diabetes feder ation (idf) and adjusted for age.13 dna extraction was performed using the magna pure lc 2.0 instrument and magna pure lc dna isolation kit 1 (roche diagnostics gmbh, manheim, germany). results were quantified using the n60 nano photometer® (implen gmbh, munich, germany), rep orting the concentration (in μg/ml) and purity (the ratio of the absorbance of 260/280 nm). genotyping was performed by polymerase chain reaction analysis in a life eco® thermal cycler (bioer technology co. ltd., hangzhou, china). the primers and conditions for each polymorphism are listed in table 1.14 oligonucleotides were designed using the primerquest® web tool (integrated dna technologies inc., skokie, illinois, usa) and synthesised at the institute of biotechnology, national autonomous university of mexico, cuernavaca, morelos, mexico. the basic local align ment search tool® (national library of medicine, bethesda, maryland, usa) was used to verify the correct hybridisation. the final products were visualised in 2% agarose gel, stained with ethidium bromide and digitally documented using an ultraviolet transilluminator system (gel logic 212 pro, carestream health, rochester, new york, usa) [figure 1]. sequencing was performed at the national institute of genomic medicine in mexico city to confirm the detection of polymorphisms as per previously described methods.14 statistical analyses were performed using the statistical package for the social sciences (spss), version 19 (ibm inc., armonk, new york, usa). descriptive continuous data were presented as means and sds while qualitative variables were expressed as percentages. either the student’s t-test or mann-whitney u test were used, depending on whether the variables were normally distributed. using pearson’s correlation coeff icient, the degree of association between glucose, insulin and adipokine levels, aip and homa index were eval uated in two different settings, the first being the absence of either snp and the second being the presence of either or both snps. multivariate linear modelling was perf ormed to establish the possible effect of the presence of polymorphisms and gender on lipid profile. a linear regression model weighted by gender was used to determine whether very-low-density lipoprotein (vldl), ldl, hdl and triglyceride levels were predictors of homa index. a linear regression analysis was also used fpi × fpghoma index = 22.5 figure 1: agarose gel electrophoresis image of polymerase chain reaction amplification products showing the presence of a fat mass and obesity-associated (fto) polymorphism. lane one contains the molecular marker, lanes 2–8 contain amplified fto gene dna fragments, lane nine contains the positive control and lane 10 contains the negative control. table 1: primers and polymerase chain reaction conditions for the studied polymorphisms14 polymorphism fto pparγ accession number* ng_012969.1 xm_011533843.2 variant rs9939609 rs1801282 forward primer tggctcttgaatgaatag gattcagaa ccaattcaagcccagtcctttc reverse primer agcctctctaccatcttat gtccaaaca cagtgaaggaatcgctttccg pcr conditions denaturation 10 minutes at 95 °c 15 seconds at 95 °c 30 seconds at 60 °c 30 seconds at 72 °c extension end cycle 5 minutes at 72 °c fto = fat mass and obesity-associated; ppar = peroxisome proliferator-activated receptor; pcr = polymerase chain reaction. *from the national center for biotechnology information database. }× 40 cycles correlation of the homeostasis model assessment index and adiponectin, leptin and insulin levels to body mass index-associated gene polymorphisms in adolescents e294 | squ medical journal, august 2018, volume 18, issue 3 to test bmi as the dependent variable and age as the independent variable according to gender and weighted by the presence of polymorphisms. a p value of ≤0.050 was considered statistically significant. this study was approved by the institutional review board of the medical sciences research center at uaem (#2015/14). all subjects and their parents/guardians provided informed consent prior to participation in the study. all of the study procedures were in line with the ethical standards of the revised declaration of helsinki as well as the mexican standard for the implementation of projects of research for health in humans (#nom-012-ssa3-2012). results a total of 71 adolescents were included in the study, of which 40 (56.3%) were female and 31 (43.7%) were male. the mean age was 15.7 ± 0.7 years and the mean bmi was 24.5 ± 3.8 kg/m2. based on the idf criteria, 21.1% of the subjects had metabolic syndrome.13 nevertheless, 56 adolescents (78.8%) were positive for at least one diagnostic criterion of metabolic syndrome, with high triglyceride levels being most frequently observed (52%). in terms of family history, 14 (19.7%) and 16 (22.5%) adolescents had a mother or father, respectively, with metabolic disease. interesting, 39 adol escents (54.9%) had relatives affected by chronic disease; however, none of these individuals had been diagnosed with hypothyroidism. according to gender, there was a statistically signif icant difference among the participants in terms of weight, height, waist-to-hip ratio and cholesterol, hdl, leptin and uric acid levels (p <0.050 each) [table 2]. age and leptin levels showed a non-parametric distribution. although fto snps were more frequent among females, this difference was not statistically significant (χ2 = 2.4671; p = 0.116). similarly, there was a non-significant increase in pparγ snp frequency among males (χ2 = 1.2884; p = 0.256). there was no difference according to gender in terms of the presence of both snps (χ2 = 0.2819; p = 0.595) [table 3]. according to a linear regression analysis weighted by gender, vldl, hdl, ldl and tri glyceride levels significantly influenced homa index (p ≤0.001). similar results were observed among adolescents with fto or pparγ snps (p = 0.002) as well as those without pparγ polymorphisms (p = 0.035). table 2: anthropometric and laboratory variables according to gender among adolescents in toluca, mexico (n = 71) variable mean ± sd p value total females (n = 40) males (n = 31) age in years 15.7 ± 0.7 15.7 ± 0.7 15.8 ± 0.7 0.525 height in m 1.63 ± 0.09 1.57 ± 0.06 1.70 ± 0.07 ≤0.001 weight in kg 65.8 ± 13.8 59.4 ± 9.6 74.0 ± 14.2 ≤0.001 bmi in kg/m2 24.5 ± 3.8 23.9 ± 3.8 25.3 ± 3.7 0.111 whr 0.86 ± 0.06 0.84 ± 0.0 0.88 ± 0.06 0.006 adiponectin in µg/nl 12.9 ± 4.4 13.8 ± 4.2 11.8 ± 4.4 0.060 glucose in mg/dl 91.9 ± 6.4 90.7 ± 4.9 93.4 ± 7.8 0.079 insulin in iu/ml 14.6 ± 8.3 14.5 ± 8.2 14.8 ± 8.5 0.899 homa index 3.03 ± 1.83 2.96 ± 1.7 3.11 ± 1.92 0.743 cholesterol in mg/dl 168.9 ± 37.9 179.3 ± 40.2 156.0 ± 30.7 0.010 hdl in mg/dl 42.5 ± 10.7 45.7 ± 11.1 38.67 ± 8.9 0.006 leptin in ng/ml 18.0 ± 1.6 23.3 ± 15.7 11.0 ± 14.0 0.001 ldl in mg/dl 107.1 ± 31.8 112.0 ± 34.0 100.9 ± 28.2 0.149 triglycerides in mg/dl 131.8 ± 72.1 131.2 ± 63.3 132.5 ± 82.9 0.939 uric acid in mg/dl 4.4 ± 1.4 3.6 ± 1.0 5.3 ± 1.3 ≤0.001 vldl in mg/dl 19.2 ± 12.2 21.5 ± 12.5 16.3 ± 11.3 0.080 aip 4.0 ± 0.9 4.0 ± 1.0 4.1 ± 0.8 0.743 sd = standard deviation; bmi = body mass index; whr = waist-to-hip ratio; homa = homeostatic model assessment; hdl = high-density lipoprotein; ldl = low-density lipoprotein; vldl = very-low-density lipoprotein; aip = atherogenic index of plasma. maría d. martínez-martínez, hugo mendieta-zerón, luis celis, cristian f. layton-tovar, rocío torres-garcía, laura e. gutiérrez-pliego, eneida camarillo-romero, josé d. garduño-garcía and maría d. camarillo-romero clinical and basic research | e295 overall, the pparγ snp was present in 25 adolescents (35.2%) and the fto snp was present in 46 (64.8%), including 11 cases (15.5%) in which both pparγ and fto snps were present. neither snp was present in 11 individuals (15.5%). insulin levels and homa index were statistically correlated with the presence of fto (p = 0.007 and 0.005, respectively), pparγ (p = 0.007 each) and both snps combined (p = 0.039 and 0.029, respectively). while leptin showed a positive significant correlation in the presence of pparγ (r = 0.483; p = 0.014) and in the absence of either snp (r = 0.627; p = 0.039), adiponectin was significantly negatively correlated with fto, either alone (r = −0.333; p = 0.024) or in combination with pparγ (r = −0.616; p = 0.043) [table 4]. a multivariate linear model showed that the presence of the snps were not determinants of bmi and lipid profile. however, the effect of gender was significant (p <0.050), particularly in the setting of both snps together (p = 0.021) [table 5]. discussion worldwide, various studies of different ethnic populations have shown conflicting results regarding the relationship between body weight and fto and pparγ polymorphisms. for example, the pparγ pro12ala rs1801282 polymorphism has been associated with obesity and insulin resistance among asian indians; however, in a chinese sample, it was reported to be a protective factor against type 2 diabetes and obesity.15,16 huang et al. found that the presence of the rs2282440sdc3t/t genotype alongside the rs1801282 pparγ2 carrier genotype was strongly associated with obesity.17 on the other hand, queiroz et al. found that pparγ rs1801282 conferred a higher risk of altered insulin levels and homa index for insulin resistance among overweight adolescents.18 to some extent, the latter obs ervation is consistent with the results of the present study. a previous study demonstrated that circulating lipids in mexican children modified the association between the pparγ2 rs1801282 genotype and insulin resistance.19 in the current study, significant associations were noted between homa index and the presence of fto or pparγ polymorphisms, taking into account the role of lipids and weighted by gender. in asiatic populations, fto has been associated with an increased risk of obesity and type 2 diabetes.20 saldaña-alvarez et al. found that fto snps made differential contributions to obesity risk, supporting the hypothesis that mechanisms involving these variants are gender-dependent and that these changes may contribute to disease development.21 although the researchers evaluated different fto snps (rs1121980, rs17817449, rs3751812, rs9930506 and rs17817449) to that of the present study (rs9939609), such findings confirm the possibility that gender is a risk table 4: correlations between glucose, insulin and adipokine levels and homeostasis model assessment index with body mass index-related polymorphisms among adolescents in toluca, mexico (n = 71) variable polymorphisms neither fto nor pparγ (n = 11) fto (n = 46)* pparγ (n = 25)* both fto and pparγ (n = 11) r p value r p value r p value r p value glucose 0.303 0.365 0.272 0.070 0.090 0.675 0.292 0.413 insulin 0.600 0.051 0.391 0.007 0.529 0.007 0.627 0.039 homa index 0.600 0.051 0.413 0.005 0.537 0.007 0.685 0.029 leptin 0.627 0.039 0.248 0.096 0.483 0.014 0.221 0.513 adiponectin −0.323 0.332 −0.333 0.024 −0.110 0.599 −0.616 0.043 aip 0.721 0.012 0.463 0.001 0.192 0.368 0.487 0.154 fto = fat mass and obesity-associated; ppar = peroxisome proliferator-activated receptor; homa = homeostasis model assessment; aip = atherogenic index of plasma. *including the 11 adolescents with both polymorphisms. table 3: frequency of body mass index-related polymor phisms according to gender among adolescents in toluca, mexico (n = 71) polymorphism n (%) p value total females (n = 40) males (n = 31) neither fto nor pparγ 11 (15.5) 4 (10) 7 (22.6) 0.146 fto alone 35 (49.3) 23 (57.5) 12 (38.7) 0.116 pparγ alone 14 (19.7) 6 (15) 8 (25.8) 0.256 both fto and pparγ 11 (15.5) 7 (17.5) 4 (12.9) 0.595 fto = fat mass and obesity-associated; ppar = peroxisome proliferator -activated receptor. correlation of the homeostasis model assessment index and adiponectin, leptin and insulin levels to body mass index-associated gene polymorphisms in adolescents e296 | squ medical journal, august 2018, volume 18, issue 3 factor for obesity.17 similarly, these results are supported by those of huđek et al., who found a statistically signif icant positive correlation between frequencies of highrisk fto genotypes in obese women (aa rs9939609, cc rs1421085 and gg rs17817449).22 díaz-anzaldúa et al. reported that differences in mean bmi levels among mexican patients with bipolar disorder were explained by the presence of fto rs8050136 and rs9939609 genotypes.23 another study showed that the locus of the fto gene was significantly associated with increased bmi in indigenous mexican populations.24 muñoz-yáñez et al. found that fto rs9939609 polymorphisms were associated with obesity related traits, including elevated bmi, cholesterol and ldl levels, tricep skinfolds and an increased waist circumference and waist-to-height ratio.25 in the present study, an extremely high percentage of adolescents had fto snps (64.8%). given a population of approximately nine million mexicans aged 15–20 years old, there are an estimated 5,830,200 young people with fto rs9939609 polymorphisms and, therefore, a corresponding risk of obesity.26 such findings are alarming for the local healthcare system. fortunately, despite a genetic predisposition influenced by polymorphisms, obesity is a modifiable condition, even with a positive genetic profile risk score.27 in the predimed-navarra randomised trial, pparγ pro12ala rs1801282 carriers exhibited lower telomere shortening compared to those with the pro/pro genotype after five years of adherence to a mediterraneanstyle diet.28 unfortunately, the molecular effects of a traditional mexican diet have yet to be fully elucidated. in the current study, mean hdl levels were significantly higher among females. however, this may be because the mean level for males was below recomm endations reported for the mexican population.29 in addition, female students also had significantly higher leptin levels. although leptin is a significant predictor of carotid intima media thickness, previous research has confirmed that men suffer from higher cardiovascularrelated mortality compared to women.30,31 such findings undermine the epidemiological evidence for utilising leptin as a prognostic tool for cardiovascular disease in adolescents. as in previous research, females in the current study also demonstrated significantly higher cholesterol levels.32 a strong correlation has been established bet ween cholesterol and visceral adipose tissue as quantified by dual-energy x-ray absorptiometry.33 unfortunately, this technique was not utilised in the present study. finally, the frequency of metabolic disease among the parents of the studied adolescents was lower than exp ected; instead, students’ relatives were found to have a high rate of chronic disease. however, it is unclear whether these individuals had lipid-related abnormalities. it is worth noting that various researchers have recommended lowering bmi cut-off values for overtable 5: multivariate linear model for body mass indexrelated polymorphisms and gender as determinants for body mass index and lipid profile variable statistical test value* f value p value fto pillai’s trace 0.066 1.027 0.401 wilks’ lambda 0.934 1.027 0.401 lawley-hotelling trace 0.071 1.027 0.401 roy’s largest root 0.071 1.027 0.401 pparγ pillai’s trace 0.107 1.738 0.154 wilks’ lambda 0.893 1.738 0.154 lawley-hotelling trace 0.120 1.738 0.154 roy’s largest root 0.120 1.738 0.154 gender pillai’s trace 0.162 2.797 0.034 wilks’ lambda 0.838 2.797 0.034 lawley-hotelling trace 0.193 2.797 0.034 roy’s largest root 0.193 2.797 0.034 fto × pparγ pillai’s trace 0.105 1.697 0.163 wilks’ lambda 0.895 1.697 0.163 lawley-hotelling trace 0.117 1.697 0.163 roy’s largest root 0.117 1.697 0.163 fto × gender pillai’s trace 0.040 0.607 0.659 wilks’ lambda 0.960 0.607 0.659 lawley-hotelling trace 0.042 0.607 0.659 roy’s largest root 0.042 0.607 0.659 pparγ × gender pillai’s trace 0.032 0.477 0.752 wilks’ lambda 0.968 0.477 0.752 lawley-hotelling trace 0.033 0.477 0.752 roy’s largest root 0.033 0.477 0.752 fto × pparγ × gender pillai’s trace 0.178 3.143 0.021 wilks’ lambda 0.822 3.143 0.021 lawley-hotelling trace 0.217 3.143 0.021 roy’s largest root 0.217 3.143 0.021 fto = fat mass and obesity-associated; pparγ = peroxisome proliferator -activated receptor. *the degrees of freedom of hypothesis and error were 4.000 and 58.000, respectively, for each value. maría d. martínez-martínez, hugo mendieta-zerón, luis celis, cristian f. layton-tovar, rocío torres-garcía, laura e. gutiérrez-pliego, eneida camarillo-romero, josé d. garduño-garcía and maría d. camarillo-romero clinical and basic research | e297 weight and obese categories in mexican and asiatic populations.34,35 thus, if a bmi of ≥27 kg/m2 were cons idered to indicate obesity, 31% of the adolescents in the current study would have been considered obese. males were significantly heavier than females; this was accordingly reflected by slight elevations in glucose and insulin levels and homa index. however, these differences were not significant, possibly due to similarities in bmi in both genders. therefore, further studies are recommended including other variables which could influence bmi in adolescents, such as physical activity and dietary habits.36 another limitation of this study was the small sample size; nevertheless, investigations regarding associations between polymorphisms and clinical parameters for metabolic syndrome or obesity can be clinically significant in small samples.37 conclusion the results of this study suggest significant positive correlations between insulin levels and homa index with bmi-related fto rs9939609 and/or pparγ rs180 1282 polymorphisms. future epidemiological studies are recommended to determine the net causative effect of such gene variants so as to halt the development of a pandemic of obesity-related health problems. although the main causes of obesity, diabetes and metabolic syndr ome are lifestyle factors, the role of such polymorphisms could help to explain why some individuals have a greater tendency to develop metabolic disorders and are more resistant to weight control interventions than others. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded with the aid of a grant from the mexican ministry of education (grant #promep/ 2013/ca-186/103105/13/9057). a c k n o w l e d g e m e n t s the preliminary version of this study was submitted as a m.sc. thesis to the uaem in 2016. this version is available on the university website. references 1. kasim nb, huri hz, vethakkan sr, ibrahim l, abdullah bm. genetic polymorphisms associated with overweight and obesity in uncontrolled type 2 diabetes mellitus. biomark med 2016; 10:403–15. doi: 10.2217/bmm-2015-0037. 2. kong x, zhang x, xing x, zhang b, hong j, yang w. the association of type 2 diabetes loci identified in genome-wide association studies with metabolic syndrome and its components in a chinese population with type 2 diabetes. plos one 2015; 10:e0143607. doi: 10.1371/journal.pone.0143607. 3. miranda-lora al, cruz m, aguirre-hernández j, molina-díaz m, gutiérrez j, flores-huerta s, et al. exploring single nucleotide polymorphisms previously related to obesity and metabolic traits in pediatric-onset type 2 diabetes. acta diabetol 2017; 54:653–62. doi: 10.1007/s00592-017-0987-9. 4. ali at, hochfeld we, myburgh r, pepper ms. adipocyte and adipogenesis. eur j cell biol 2013; 92:229–36. doi: 10.1016/j.ejcb. 2013.06.001. 5. speakman jr. the ‘fat mass and obesity related’ (fto) gene: mech anisms of impact on obesity and energy balance. curr obes rep 2015; 4:73–91. doi: 10.1007/s13679-015-0143-1. 6. loos rj, bouchard c. fto: the first gene contributing to common forms of human obesity. obes rev 2008; 9:246–50. doi: 10.1111/ j.1467-789x.2008.00481.x. 7. frayling tm, timpson nj, weedon mn, zeggini e, freathy rm, lindgren cm, et al. a common variant in the fto gene is assoc iated with body mass index and predisposes to childhood and adult obesity. science 2007; 316:889–94. doi: 10.1126/science.1141634. 8. rangel-villalobos h, muñoz-valle jf, gonzález-martín a, gorostiza a, magaña mt, páez-riberos la. genetic admixture, relatedness, and structure patterns among mexican populations revealed by the y-chromosome. am j phys anthropol 2008; 135:448–61. doi: 10.1002/ajpa.20765. 9. camacho-sandoval j. [sample size in clinical studies]. acta med costarric 2008; 50:20–21. 10. de onis m, onyango aw, borghi e, siyam a, nishida c, siekmann j. development of a who growth reference for school -aged children and adolescents. bull world health organ 2007; 85:660–7. doi: 10.2471/blt.07.043497. 11. national high blood pressure education program working group. the fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. pediatrics 2004; 114:555–76. 12. salgado al, carvalho ld, oliveira ac, santos vn, vieira jg, parise er. insulin resistance index (homa-ir) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals. arq gastroenterol 2010; 47:165–9. 13. international diabetes federation. idf consensus definition of metabolic syndrome in children and adolescents. from: www. idf.org/e-library/consensus-statements/61-idf-consensus-defin ition-of-metabolic-syndrome-in-children-and-adolescents accessed: mar 2018. 14. martínez-martínez md. [association between molecular mar kers and obesity in adolescents of the upper level of the uaeméx]. msc thesis, 2016, autonomous university of mexico state, toluca, mexico. 15. bhatt sp, misra a, sharma m, luthra k, guleria r, pandey rm, et al. ala/ala genotype of pro12ala polymorphism in the peroxisome proliferator-activated receptor-γ2 gene is associated with obesity and insulin resistance in asian indians. diabetes technol ther 2012; 14:828–34. doi: 10.1089/dia.2011.0277. 16. wang x, liu j, ouyang y, fang m, gao h, liu l. the association between the pro12ala variant in the pparγ2 gene and type 2 diabetes mellitus and obesity in a chinese population. plos one 2013; 8:e71985. doi: 10.1371/journal.pone.0071985. 17. huang wh, hwang lc, chan hl, lin hy, lin yh. study of seven single-nucleotide polymorphisms identified in east asians for association with obesity in a taiwanese population. bmj open 2016; 6:e011713. doi: 10.1136/bmjopen-2016-011713. 18. queiroz em, cândido ap, castro im, bastos aq, machadocoelho gl, freitas rn. igf2, lepr, pomc, pparg, and ppargc1 gene variants are associated with obesity-related risk phenotypes in brazilian children and adolescents. braz j med biol res 2015; 48:595–602. doi: 10.1590/1414-431x20154155. 19. stryjecki c, peralta-romero j, alyass a, karam-araujo r, suarez f, gomez-zamudio j, et al. association between ppar-γ2 pro12ala genotype and insulin resistance is modified by circulating lipids in mexican children. sci rep 2016; 6:24472. doi: 10.1038/srep24472. https://doi.org/10.2217/bmm-2015-0037 https://doi.org/10.1371/journal.pone.0143607 https://doi.org/10.1007/s00592-017-0987-9 https://doi.org/10.1016/j.ejcb.2013.06.001 https://doi.org/10.1016/j.ejcb.2013.06.001 https://doi.org/10.1007/s13679-015-0143-1 https://doi.org/10.1111/j.1467-789x.2008.00481.x https://doi.org/10.1111/j.1467-789x.2008.00481.x https://doi.org/10.1126/science.1141634 https://doi.org/10.1002/ajpa.20765 https://doi.org/10.2471/blt.07.043497 https://doi.org/10.1089/dia.2011.0277 https://doi.org/10.1371/journal.pone.0071985 https://doi.org/10.1136/bmjopen-2016-011713 https://doi.org/10.1590/1414-431x20154155 https://doi.org/10.1038/srep24472 correlation of the homeostasis model assessment index and adiponectin, leptin and insulin levels to body mass index-associated gene polymorphisms in adolescents e298 | squ medical journal, august 2018, volume 18, issue 3 20. li h, kilpeläinen to, liu c, zhu j, liu y, hu c, et al. association of genetic variation in fto with risk of obesity and type 2 diabetes with data from 96,551 east and south asians. diabetologia 2012; 55:981–95. doi: 10.1007/s00125-011-2370-7. 21. saldaña-alvarez y, salas-martínez mg, garcía-ortiz h, luckie duque a, garcía-cárdenas g, vicenteño-ayala h, et al. gender dependent association of fto polymorphisms with body mass index in mexicans. plos one 2016; 11:e0145984. doi: 10.1371/ journal.pone.0145984. 22. huđek a, škara l, smolkovič b, kazazić s, ravlić s, nanić l, et al. higher prevalence of fto gene risk genotypes aa rs99 39609, cc rs1421085, and gg rs17817449 and saliva containing staphylococcus aureus in obese women in croatia. nutr res 2018; 50:94–103. doi: 10.1016/j.nutres.2017.12.005. 23. díaz-anzaldúa a, ocampo-mendoza y, hernández-lagunas jo, díaz-madrid fa, romo-nava f, juárez-garcía f, et al. differ ences in body mass index according to fat massand obesityassociated (fto) genotype in mexican patients with bipolar disorder. bipolar disord 2015; 17:662–9. doi: 10.1111/bdi.12328. 24. león-mimila p, villamil-ramírez h, villalobos-comparán m, villarreal-molina t, romero-hidalgo s, lópez-contreras b, et al. contribution of common genetic variants to obesity and obesity related traits in mexican children and adults. plos one 2013; 8:e70640. doi: 10.1371/journal.pone.0070640. 25. muñoz-yáñez c, pérez-morales r, moreno-macías h, callerosrincón e, ballesteros g, gonzález ra, et al. polymorphisms fto rs9939609, pparg rs1801282 and adipoq rs4632532 and rs182052 but not lifestyle are associated with obesity relatedtraits in mexican children. genet mol biol 2016; 39:547–53. doi: 10.1590/1678-4685-gmb-2015-0267. 26. national institute of statistics and geography. population. from: www.beta.inegi.org.mx/temas/estructura/ accessed: mar 2018. 27. celis-morales ca, lyall dm, gray sr, steell l, anderson j, iliodromiti s, et al. dietary fat and total energy intake modifies the association of genetic profile risk score on obesity: evidence from 48 170 uk biobank participants. int j obes (lond) 2017; 41:1761–8. doi: 10.1038/ijo.2017.169. 28. garcía-calzón s, martínez-gonzález ma, razquin c, corella d, salas-salvadó j, martínez ja, et al. pro12ala polymorphism of the pparγ2 gene interacts with a mediterranean diet to prevent telomere shortening in the predimed-navarra randomized trial. circ cardiovasc genet 2015; 8:91–9. doi: 10.1161/circ genetics.114.000635. 29. bibiloni md, salas r, de la garza ye, villarreal jz, sureda a, tur ja. serum lipid profile, prevalence of dyslipidaemia, and associated risk factors among northern mexican adolescents. j pediatr gastroenterol nutr 2016; 63:544–9. doi: 10.1097/ mpg.0000000000001325. 30. velarde gp, sherazi s, kraemer df, bravo-jaimes k, butterfield r, amico t, et al. clinical and biochemical markers of cardiovascular structure and function in women with the metabolic syndrome. am j cardiol 2015; 116:1705–10. doi: 10.1016/j.amj card.2015.09.010. 31. bots sh, peters sa, woodward m. sex differences in coronary heart disease and stroke mortality: a global assessment of the effect of ageing between 1980 and 2010. bmj glob health 2017; 2:e000298. doi: 10.1136/bmjgh-2017-000298. 32. lotufo pa, santos rd, sposito ac, bertolami m, rocha-faria j neto, izar mc, et al. self-reported high-cholesterol prevalence in the brazilian population: analysis of the 2013 national health survey. arq bras cardiol 2017; 108:411–16. doi: 10.5935/abc.20170055. 33. miazgowski t, kucharski r, sołtysiak m, taszarek a, miazgowski b, widecka k. visceral fat reference values derived from healthy european men and women aged 20-30 years using ge healthcare dual-energy x-ray absorptiometry. plos one 2017; 12:e0180614. doi: 10.1371/journal.pone.0180614. 34. mexico ministry of health. [norma official mexican nom174-ssa1-1998: for the integral management of obesity]. from: www.salud.gob.mx/unidades/cdi/nom/174ssa18.html accessed: mar 2018. 35. ko gt, chan jc, cockram cs, woo j. prediction of hypertension, diabetes, dyslipidaemia or albuminuria using simple anthropometric indexes in hong kong chinese. int j obes relat metab disord 1999; 23:1136–42. doi: 10.1038/sj.ijo.0801043. 36. liu w, he mz, wang y, wang y, zhou y, wu m, et al. differences in health-related behaviors between middle school, high school, and college students in jiangsu province, china. asia pac j clin nutr 2017; 26:731–7. doi: 10.6133/apjcn.072016.06. 37. saldaña-rivera e, careaga-castilla mj, olvera-cárdenas gd, pérez-soto e, sánchez-monroy v. mitochondrial t16189c poly morphism is associated with metabolic syndrome in the mexican population. dis markers 2018; 2018:3981315. doi: 10.1155/2018/ 3981315. https://doi.org/10.1007/s00125-011-2370-7 https://doi.org/10.1371/journal.pone.0145984 https://doi.org/10.1371/journal.pone.0145984 https://doi.org/10.1016/j.nutres.2017.12.005 https://doi.org/10.1111/bdi.12328 https://doi.org/10.1371/journal.pone.0070640 https://doi.org/10.1590/1678-4685-gmb-2015-0267 https://doi.org/10.1038/ijo.2017.169 https://doi.org/10.1161/circgenetics.114.000635 https://doi.org/10.1161/circgenetics.114.000635 https://doi.org/10.1097/mpg.0000000000001325 https://doi.org/10.1097/mpg.0000000000001325 https://doi.org/10.1016/j.amjcard.2015.09.010 https://doi.org/10.1016/j.amjcard.2015.09.010 https://doi.org/10.1136/bmjgh-2017-000298 https://doi.org/10.5935/abc.20170055 https://doi.org/10.1371/journal.pone.0180614 https://doi.org/10.1038/sj.ijo.0801043 https://doi.org/10.6133/apjcn.072016.06 https://doi.org/10.1155/2018/3981315 https://doi.org/10.1155/2018/3981315 squ med j, december 2009, vol. 9, iss. 3, pp. 257-260, epub. 19th dec 2009 submitted 19th september 09 revision req. 21st oct. 09. revision recd. 24th oct. 09 accepted 25th oct. 09 in the new millennium, the world has seen the emergence of three novel human respiratory viruses: sars virus (a novel corona virus) in 2003, influenza a h5n1 (‘avian flu’) in 2004 and in the past six months, a pandemic caused by a new strain: the influenza a (h1n1) 2009 virus.1 in sharp contrast to the sars and avian influenza a h5n1 viruses which emerged from the asian continent, the influenza a (h1n1) 2009 virus emerged from north america and unlike the sars and avian influenza a h5n1 viruses, which were never reported in oman, the novel influenza a (h1n1) 2009 virus has already been detected here in more than 2,500 patients. influenza viruses by nature are highly unpredictable and unstable.2 they have the unique distinction of having a segmented genome which permits them to re-assort their genetic structure resulting in the evolution of new subtypes. this genetic restructuring occurs regularly in nature and at times provides the virus with the unusual capability to cause widespread disease in immunologically naïve populations and swiftly move across geographical borders to cause pandemics. the 20th century saw three such pandemics; the first (spanish flu) caused by influenza a (h1n1) killing between 20-50 million people.3 the other two pandemics, in 1957 and 1968, were relatively milder, but still killed nearly one million. there are several key epidemiological features that determine the occurrence of a pandemic influenza. according to miller et al.4 who recently analysed the “signature features” of the three previous influenza pandemics (a/h1n1 in 1918, a/h2n2 in 1957 and a/h3n2 in 1968) four important factors emerge as key determinants: 1) occurrence of a shift in the virus subtype; 2) shifts of the highest death rates to younger populations; 3) successive pandemic waves, and 4) higher transmissibility than that of seasonal influenza. while the world was grappling with h5n1 avian flu “which had caused 442 cases and 262 deaths in 15 countries as of september 24th 2009”,5 and while the world was preparing for a pandemic that could emerge, another influenza virus made a dramatic appearance in mexico in march 2009 in the form of a novel h1n1 subtype. many of us were surprised when, instead of h5n1 acquiring mutations necessary for efficient person-to-person transmission, reports emerged from mexico about a novel influenza virus that was killing young people. the novel influenza a (h1n1) virus has the genetic structure resulting from re-assortment of genes from four influenza viruses: north american swine influenza, asia/europe swine influenza, human influenza and avian influenza (non h5). the virus has a unique genetic composition that has never been seen earlier. as a result of this, within a short period of six months the virus had spread to 189 countries, caused more than 414,000 confirmed cases (the number of cases reported actually understates the real number of cases) and at least 5,000 deaths.6 in oman as of the latest update, 2,681 people have been reported as infected with the a (h1n1) virus of which 153 cases required hospitalisation and 24 have died. most cases described during the three influenza pandemics of the 20th century and during seasonal influenza involved transient illness not requiring hospitalisation. most deaths are described in the infection control department and infectious diseases unit, department of medicine, sultan qaboos university hospital, muscat, sultanate of oman email: balkhair@squ.edu.om التصدي لوباء انفلونزا a )h1n1(2009 اجلائح عبد اهلل باخلير special contribution the struggle against pandemic influenza a (h1n1) 2009 abdullah balkhair the struggle against pandemic influenza a (h1n1) 2009 258 | squ medical journal, december 2009, volume 9, issue 3 very young or the elderly or those with underlying disease. the available information also indicates that, unlike seasonal influenza, the current h1n1 pandemic has primarily affected younger adults. this is in contrast to the fact that complications of seasonal influenza affect primarily the elderly or young children. the reported clinical presentation of the novel influenza a (h1n1) infection ranges broadly from mild uncomplicated infection to severe pneumonia that can result in death. the available data show that the clinical features of fever, cough and sore throat are similar to those of seasonal influenza. to date, the case fatality ratios (cfr) attributable to the current h1n1 pandemic has been estimated at around 0.4%, based on surveillance data from mexico and mathematical modelling.7 this cfr is higher than that of average seasonal influenza, but remains of the same order of magnitude. whether this will change is unknown. the who regional office for the eastern mediterranean (emro) reported that 96 of the 14,739 laboratory-confirmed cases as of october 23, 2009 had been fatal.8 most of these deaths were related to respiratory failure resulting from severe pneumonia with multi-focal infiltrates and acute respiratory distress syndrome. unlike most seasonal influenza strains, this pandemic h1n1 2009 strain seems to invade the lower airway and alveoli, not just the upper airways, resulting in more severe illness.9,10 the world’s experience so far tells us that serious illness associated with this virus often manifests as acute lung injury resulting in overwhelming hypoxaemia. advanced life-support technologies for prolonged periods are often required to save lives. there are few data on risk factors, severe cases and deaths associated with the pandemic h1n1 influenza 2009. analysis of available data suggests that the elderly may to some extent be protected from infection. there was underlying disease in at least half of the fatal cases (574 studied). two risk factors seem of particular importance: pregnancy and metabolic condition (including obesity which has not been considered as risk factor in previous pandemics or seasonal influenza).11 the transmission is thought to occur in the same way as seasonal influenza which is mainly person-to-person transmission through coughing or sneezing of people infected with this virus. people may be infected by touching something with influenza viruses on it and then touching their mouth or nose. the recommended procedure for laboratory diagnosis of influenza a (h1n1) 2009 virus infection is real-time reverse-transcriptase polymerase chain reaction (rt-pcr.12 in oman, this facility is only, at present, available at the public health laboratory (phl) muscat, and at sultan qaboos university hospital (squh), muscat. two classes of anti-viral medication are available for the treatment and post-exposure chemoprophylaxis of seasonal human influenza: neuraminidase inhibitors (oseltamivir and zanamivir) and adamantanes (amantadine and rimantadine). however, the novel influenza a (h1n1) 2009 virus is resistant to amantadine and rimantadine, but is sensitive to oseltamivir (tamiflu) and zanamivir (relenza).13 based on experience with other influenza viruses, treatment would be most effective if given within two days of symptom onset. the data show that the virus continues to remain susceptible to oseltamivir and zanamivir. the access to these drugs and their rational use are critical in mitigating the disease as well as prolonging the utility of the drugs by obviating the emergence of resistance. presently, a vigorous development process is underway to develop the pandemic vaccine. it is believed that manufacturers could produce 2.5 billion doses of pandemic vaccine in 12 months following receipt of the production strain and global demand can be met within 2-3 years. however, the supply of vaccine, at least during the first year of the pandemic, will be limited and not easily accessible to the vast majority of people living in developing countries. we must therefore identify vulnerable or at-risk groups as a first step. it is also important to note that no immunisation programme is 100% effective and, if therefore a sufficient number of cases are not prevented, we can expect more young critically ill patients to fill all tertiary-level intensive care beds. it is important to highlight here that fair access to the vaccine against the pandemic novel h1n1 influenza virus is an ethical issue involving justice for all. it is also a prerequisite for the success of the global pandemic strategy to safeguard global health. intensive public education for adopting costeffective non-pharmaceutical interventions can yield substantial results.14 non-pharmaceutical abdullah balkhair special contribution | 259 prevention through repeated hand washing and following cough/sneeze etiquettes can be easily employed at all levels in communities and prevent the spread of the disease. isolation of cases and proper case management, including infection control, are equally important to cut down on the transmission of the disease. national leadership is needed in all countries. a visible independent health care leadership, with executive powers across all jurisdictions and ultimately accountable to the highest office in the country, must be in place. next, local leaders must be identified. all stakeholders should have clear communication with and rapid access to experts. we need leaders at all levels who will work together quickly and collaboratively to solve problems such as moving equipment and personnel from one area of a country to another as required without barriers imposed by licensing and hospital privileges. since 2003 when influenza a (h1n1) 2009 emerged as a potential influenza pandemic, the national authorities in oman have been engaged in strengthening their response efforts with assistance from world health organization. the national influenza pandemic preparedness plan has provided a valuable framework of action and, with minor modifications, was activated to launch an effective response to the current pandemic. the pandemic, however, is far from over, and deaths will unfortunately continue to occur. we should therefore plan for important increases in pandemic h1n1 2009 cases that manifest at the two ends of the spectrum of disease severity. we must not underestimate a foe like pandemic h1n1 2009, especially now. this pandemic has already created chaos in communities worldwide. the virus’s place of origin, the speed of its spread and the severity of the illness in otherwise healthy people could not be anticipated before the initial outbreaks, even by experts. in addition, containment, a first step in the control of an outbreak, has failed. it would be naïve to extrapolate the impact of the 1918 pandemic to the current event because today effective tools are available including drugs, diagnostics and a high level of preparedness in place in many countries including such measures as infection control practices, case management facilities and mass media reach for public awareness and risk communication. advances in technology are now swiftly translatable into tools. while we still hope for the best, we need to act now to deal with the worst that pandemic h1n1 2009 may deliver. doing so will save lives. references 1. ravi v. emergence of novel influenza a h1n1 virus as a pandemic agent. indian j med microbiol 2009; 27:179-81. 2. narain jp, bhatia r. influenza a (h1n1): responding to a pandemic threat. indian j med res 2009; 129:465-7. 3. pandemic influenza preparedness and response: a who guidance document. geneva: world health organization, 2009. p.16. 4. miller ma, viboud c, balinska m, simonsen l. the signature features of influenza pandemicsimplications for policy. n engl j med 2009; 360:2595-8. 5. cumulative number of confirmed human cases of avian influenza a /h5n1 reported to who. from http://www.who.int/csr/disease/avian_influenza/ country/cases_table_2009_09_24/en/index.html. accessed 24 october 2009 6. pandemic (h1n1)2009 update. from: http:// www.who.int/csr/don/2009_10_23/en/index.html. accessed 23 october 2009. 7. fraser c, donnelly ca, cauchemez s, hanage wp, van kerkhove md, hollingsworth td, et al. pandemic potential of a strain of influenza a (h1n1): early findings. science 2009; 324:1557-61. 8. world health organization. influenza a (h1n1) update 71, october 17 2009. from: http://www.who. int/csr/disease/swineflu/updates/en/index.html. accessed 23 october 2009. 9. munster vj, de wit e, van den brand jm, herfst s, schrauwen ej, bestebroer tm, et al. pathogenesis and transmission of swine-origin 2009 a (h1n1) influenza virus in ferrets. science 2009; 325:481-3. 10. maines tr, jayaraman a, belser ja, wadford da, pappas c, zeng h, et al. transmission and pathogenesis of swine-origin 2009 a (h1n1) influenza viruses in ferrets and mice. science 2009; 325:484-7. 11. vaillant l, la ruche g, tarantola a, barboza p; epidemic intelligence team at invs. epidemiology of fatal cases associated with pandemic h1n1 influenza 2009. euro surveill 2009; 14: pii:19309. 12. united states centers for disease control and prevention. interim guidance on specimen collection, processing, and testing for patients with suspected swine-origin influenza a (h1n1) virus infection. from: http://www.cdc.gov/h1n1flu/specimencollection. htm. accessed 15 september 2009. 13. update: drug susceptibility of swine-origin influenza a (h1n1) viruses, april 2009. mmwr morb mortal wkly rep 2009; 58:433-5. 14. bhatia r, narain jp. preventing avian influenza in humans: the role of simple public health interventions. southeast asian j trop med public health 2006; 37:1229-36. squ med j, december 2009, vol. 9, iss. 3, pp. 260-263, epub. 19th dec 2009 submitted 29th sep 2009 revision req. 25th oct 09. revision recd. 26th oct 09 accepted 8th nov 09 a 55 year-old man was diagnosed as having metastatic colon cancer following an endoscopic biopsy at my university hospital in oman, and was referred to a medical oncologist. the patient, together with his son, travelled to an other asian country seeking a ‘second-opinion’. there he was initially treated with a colonic stent, resulting in the perforation of the colon. he underwent emergency resection of the perforated segment, leading to intestinal obstruction. a second surgery was performed to relieve the obstruction, and combination chemotherapy (including the antiangiogenic drug, bevacizumab) was started. during the first course of treatment, the patient developed urinary retention, was catheterised, and then went on to develop haematuria. he returned to oman with severe haematuria, a prescription to continue the combination chemotherapy, and radiographic evidence of a bilateral pulmonary artery embolism. stories like this are not uncommon and are frequently encountered during routine medical practice in general, and in oncology practice in particular. what is not mentioned in the above story is the fact that the duration between the diagnosis of cancer in oman and arriving at the hospital abroad was about 4 weeks, during which time the metastatic disease in the liver had increased considerably and the patient’s performance status had declined. inserting a stent was unnecessary in a non-obstructing bowel, a procedure which ultimately led to two needless surgeries and a further delay in starting standard systemic treatment. the expensive anti-angiogenic drug was contraindicated in a patient with two recent surgeries, and is definitely contra-indicated following a diagnosis of a pulmonary embolism. the patient spent the equivalent of 28,000 omani riyals (us$ 45,000) during his 4 week stay abroad. he regretted the decision made by his family members. what is a second opinion? and why do patients, especially those with a diagnosis of cancer, seek one? what are the challenges that face both patients and health providers when a second opinion is sought? indeed, is the desire to get a second opinion problematic and, if so, can the situation be improved? asking for a second opinion is understandable. when it comes to choice (be it selecting food in a restaurant, buying a car, or purchasing a new house) we all value the opinions of others, and sometimes we may even look for a third or fourth opinion. seeking a second opinion is a way of making choices. however, it is not quite the same when one has received the diagnosis of a cancer. in such a situation, with the likelihood of extensive surgery, chemotherapy and/or radiotherapy, opinions should be sought to see if alternative forms of treatment or cure were available. from the point of view of the department of medicine, sultan qaboos university hospital, muscat, oman email: ikramburney@hotmail.com نزعة احلصول على رأي ثان من اخلارج يف عالج مرضى السرطان يف ُعمان حتديات وفرص اكرام برني sounding board the trend to seek a second opinion abroad amongst cancer patients in oman challenges and opportunities ikram a burney ikram a burney sounding board | 261 oncologist, seeking a second opinion is desirable and, in some cases, obligatory. the vast majority of cases are straightforward, and treatment begins as soon as diagnosis and staging are known. in cases of less common cancers, borderline cases or cancers of unknown primary sites, practising doctors frequently invite a second opinion from their colleagues. seeking a second opinion is a recognised practice in the specialty of oncology. however, the situation described in the above story is something commonly encountered in oncology-related practice in oman: the seeking of a second opinion abroad before any treatment at home in oman. a significant number of patients, especially from small towns, bypass the tertiary care/specialist hospitals available to them in bigger centres and immediately go abroad. once overseas, they may not be provided with a second opinion, but instead are started on the first stage of treatment even when it is uncalled for. patients invariably return home to continue the treatment. although the off-shore clinics are very quick to commence ‘treatment’, valuable time, not to mention savings or borrowed money, is often lost in the making of travel arrangements. the tendency to seek a second opinion abroad can endanger the patient’s health. the clinical condition may not be fully known to the patient and/or his/her family members, and urgent clinical attention is sometimes delayed. any delay in travel arrangements may lead to a progression of the disease; this in turn leads to an increased burden of disease and a decline in performance status, both conditions decreasing the chances of successful treatment and a subsequent cure. a decline in performance status by a single grade is an adverse prognostic factor in almost all cases of cancer, and for some, this decline may occur within just a few weeks. furthermore, the patient’s selection of country or medical centre is often not informed by prior knowledge of expertise, excellence in the field or familiarity with the type of cancer, but rather by geographical proximity, convenience of travel or simply by a verbal recommendation. some patients are known to have arrived at centres in which they have received less than adequate treatment or been the victim of experimental/investigational treatment without their knowledge. in both cases, the chances of any subsequent standard treatment being effective are reduced. sometimes patients end up in good centres where standard treatment is offered or advised for straightforward cases, but there are complications as a result of travel-related delays. additionally, cancer treatment overseas is seldom cheaper. in order to influence the behaviour of persons seeking a second opinion abroad, one needs to study the mechanisms underlying this phenomenon. first, it is important to understand the motives and expectations of the patients. second, in a society where decision-making in health care is often shared, it is important to consider the point of view of all the decision-makers involved. patients do not always make their own decisions. they are often influenced by the care-givers/well-wishers who, in some cases, are the only ones involved in important decisions. although many patients with cancer seek second opinions, there is a dearth of literature on the subject. only a few have looked at the phenomenon, even fewer have tried to assess its incidence and outcomes.1,2 the actual incidence of seeking a second opinion is likely to differ from country to country, and amongst different groups of patients. with an increase in the knowledge of disease and improvements in communication, an increasing number of patients seek second opinions. for example, 56% of more than 1,500 cancer patients in the united states sought a second opinion in a single year.3 the incidence in oman is unknown. it would be useful to know how often a second opinion has impacted upon the course of treatment. in a survey done in holland of 403 patients, the majority with breast cancer, the investigators found that in 84% of cases the advice given was comparable. not everybody had a review of either histological or radiological diagnosis and when this occurred, a major change in treatment was observed in only 3% of patients and a change in prognosis in just 2%.4 who are the people more likely to travel abroad to seek a second opinion before the first? are they the well-informed, the well-read or the wealthy? there is insufficient information on this subject. however, a common observation is that the phenomenon transcends the boundaries of information and financial resources as much as it transcends national boundaries. for example, kangas reported on the behavior of not-so-rich yemeni patients with various diseases seeking biomedical treatment in other countries, and noted that their behaviour did not differ significantly from that of relatively wellthe trend to seek second opinions abroad amongst cancer patients in oman challenges and opportunities 262 | squ medical journal, december 2009, volume 9, issue 3 off saudis.5 in the absence of published data concerning omani patients, the motives for seeking second opinions before the first remain hypothetical. the motives may be intrinsic or extrinsic, or a combination of both.6 intrinsic motives could include: seeking reassurance and more certainty about the diagnosis; seeking a treatment other than the conventional one ‘usually’ offered to cancer patients; the desire to be treated in a different environment perhaps to maintain ‘confidentiality’; or the belief that ‘paying more’ will produce better treatment. extrinsic motives are more varied. these could include: experiences from the patient’s past; doubts about the health care services in the home country; market forces, such as dynamic advertisements by external health care organisations; social and societal pressures; or merely word of mouth information that a ‘cure’ is available elsewhere, and hence borrowing or spending large amounts of money might bring positive results. common extrinsic motivators for seeking a second opinion may not be applicable in the case of omani patients, since a ‘first’ opinion has not yet been sought. these may include: the lack of effective communication by and with the oncologist; dissatisfaction with the primary oncologist; seeking an opinion on a rare cancer; concern about the side-effects of a particular type of treatment; an ambivalent attitude towards the care provided resulting in the need for more information, or the desire to participate in a clinical trial. is there a solution? first of all, the phenomenon needs to be studied, and the motives and expectations of the local population explored. this would provide a wonderful opportunity not only for examining patients’ and families’ motives, but also to investigate the health services offered. a lack of communication between health care providers, a delay in diagnosis (especially at the point of primary care), or simply the unavailability of resources (actual or perceived) may contribute to the need for a second opinion. in cases of the latter, these could be easily rectified by better utilisation of our material resources. on the other hand, if the major motivations are intrinsic (or social), then the solution may lie in sustained and concrete efforts aimed at enhancing public awareness and confidence-building through a process of education and information dissemination. the ultimate winners should and would be the patients and society at large. in conclusion, seeking a second opinion amongst cancer patients in oman poses certain challenges for the health of our patients and provides the health care profession with opportunities to study the problem and to aim for practical solutions. first of all, it must be recognised that seeking a second opinion is not only justified, but also desirable in many situations. oncologists themselves should support patients in their efforts to obtain an opinion. however, seeking a patient-initiated second opinion abroad, especially in the case of cancer management, may have an adverse effect on the outcome of the disease, both because of the delay it causes in diagnosis, and because of the chance of receiving sub-optimal treatment or advice elsewhere. in order to overcome the challenge, there is an urgent need to study patients’ or their decision makers’ motives and expectations. meanwhile, it may help omani patients diagnosed with cancer and their families, who are seeking a cure wherever it may be found, to know that the world health organization (who) has ranked oman as the most efficient ‘health care system in the world in terms of outcomes’.7 furthermore, patients should be advised that second opinions can be easily and quickly sought at little or no cost through fax, email, and telemedicine from places in oman or abroad that are widely perceived to be centres of academic and clinical excellence. this will avoid the need for cancer sufferers to seek opinions from more profitoriented health care centres which may not have the necessary expertise to provide the best advice. references 1. sikora k. second opinion for patients with cancer. br med j 1995; 311:1179-80. 2. macdonald ea. second opinions in oncology: nuisance or opportunity. clin oncol 1997; 9:418-20. 3. hewitt m, breen n, devesa s. cancer prevalence and survivorship issues: analyses of the 1992 national health interview survey. j natl cancer inst 1999; 91:1480-6. 4. meink wa, henzen-logmans sc, bongaerts ah, ooijen bv, rodenburg cj, wiggers th. discrepancy between second and first opinion in surgical oncological patients. eur j surg oncol 2006; 32:10812. 5. kangas b. therapeutic itineraries in a global world: ikram a burney sounding board | 263 yemenis and their search for biomedical treatment abroad. med anthropol 2002; 21:35-78. 6. mellink wam, dulmen amv, wiggers t, spreeuwenberg pmm, eggermont amm, bensing jm. cancer patients seeking a second surgical opinion: results of a study on motives, needs, and expectations. j clin oncol 2003; 8:1492-7. 7. al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? squ med j 2006; 6:3-9. o n l i n e s u b m i s s i o n ! you can now submit your manuscript online on the squmj website www.squ.edu.om/squmj note: please make sure that you register only once for all your manuscripts 1division of plastic surgery, department of surgery, 2college of medicine, imam mohammad ibn saud islamic university, riyadh, saudi arabia; 3division of plastic surgery, department of surgery, college of medicine, king khalid university hospital, king saud university, riyadh, saudi arabia *corresponding author’s e-mail: bindahmash.a@gmail.com املعرفة والسلوك جتاه االنتحال األديب لدى طالب كلية الطب يف السعودية عبداملجيد �صعد الهدلق، عبداملجيد بن دهم�س، فرا�س ال�صومر abstract: objectives: this study aimed to determine attitudes towards and perceptions of plagiarism among medical students in saudi arabia. methods: this cross-sectional, multicentre study was conducted between april and may 2018 and involved medical students enrolled in three medical schools in riyadh, saudi arabia. the previously validated attitude towards plagiarism questionnaire was used to evaluate approval (i.e. a positive attitude) and disapproval of plagiarism (i.e. a negative attitude) among medical students. furthermore, this study evaluated whether attending medical writing courses or courses in medical ethics influenced medical students’ attitudes towards plagiarism. results: a total of 551 students participated in the study (response rate = 73.5%). a significant association was found between mean negative and positive attitude scores and grade point average (gpa; p = 0.004 and 0.007, respectively). students attending medical ethics courses had higher mean negative attitude scores compared to students who did not attend such courses (odds ratio = 2.369, 95% confidence interval: 1.540–3.645; p <0.001). attending medical ethics courses was associated with a significantly more negative attitude towards plagiarism (p <0.001, each). conclusion: the majority of medical students in saudi arabia included in this study indicated a highly negative attitude towards plagiarism. a higher gpa, the authoring of a published manuscript and attending courses in medical ethics were associated with negative attitudes towards plagiarism among medical students. keywords: plagiarism; attitude; cross-sectional study; medicine; medical students; saudi arabia. الطريقة: ال�صعودية.. يف الطب كلية طالب لدى الأدبي النتحال جتاه وال�صلوك املعرفة قيا�س اإىل الدرا�صة هذه هدفت الهدف: امللخ�ص: اأجريت هذه الدرا�صة املقطعية متعددة املراكز يف الفرتة ما بني اأبريل ومايو 2018 و�صمت طالب يف ثالث كليات طب خمتلفة. مت ا�صتخدام ا�صتبيان �صابق يقي�س املعرفة وال�صلوك جتاه النتحال الدبي بالإ�صافة اإىل عالقة ذلك بدرا�صة مواد كالأخالقيات الطبية والكتابة العلمية. النتائج: �صارك يف هذه الدرا�صة عدد 551 طالًبا )معدل ا�صتجابة = %73.5(. وجدت عالقة بني ال�صلوك الراف�س لالنتحال الأدبي وارتفاع لل�صلوك راف�صة اأعلى نتيجة لديهم وجد حيث الطبية الأخالقيات ملادة الدار�صني الطالب بني واأي�صا p = 0.004 الطالب درجات معدل .)p >0.001 ;1.540–3.645 = لالنتحال الأدبي مقارنًة بالطالب الذين مل يدر�صوا مواد مماثلة )ن�صبة احتمالت = 2.369، %95 معامل ثقة مرتفع، معدل على احل�صول اأن النتائج اأظهرت الأدبي. لالنتحال راف�س �صلوك الدرا�صة هذه يف امل�صاركني معظم لدى كان اخلال�صة: امل�صاركة يف ن�رش بحث علمي ودرا�صة مادة الأخالقيات الطبية ت�صاهم يف ارتفاع ال�صلوك الراف�س لالنتحال الأدبي لدى العينة امل�صاركة يف هذه الدرا�صة. الكلمات املفتاحية: النتحال الأدبي؛ درا�صة مقطعية؛ الطب؛ طالب الطب؛ ال�صعودية. plagiarism perceptions and attitudes among medical students in saudi arabia abdulmajeed s. alhadlaq,1 *abdulmajeed bin dahmash,2 feras alshomer3 clinical & basic research sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e77–82, epub. 9 mar 20 submitted 22 may 19 revision req. 2 jul 19; revision recd. 30 jul 19 accepted 13 sep 19 advances in knowledge this study suggested that the majority of medical students had a highly negative attitude towards plagiarism. a higher grade point average, the authoring of a published manuscript and attending courses in medical ethics were associated with negative attitudes towards plagiarism among medical students. application to patient care addressing plagiarism and determining the factors that can decrease its occurrence among medical students can increase future physicians’ awareness of the unacceptability of plagiarism. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.011 plagiarism and cheating are two concepts with overlapping characteristics. plagiarism can be defined as the unauthorised “appropriation of another person’s ideas, processes, results, or words without giving appropriate credit and usually claiming it to be one’s own”.1 others define plagiarism as “a continuum ranging from sloppy paraphrasing to verbatim transcription without crediting sources”.2,3 while others have stated that plagiarism “involves stealing someone else's work and lying about it afterward”.2,4 the difference between plagiarism and cheating is based on the intent of the author; an author could either be negligent, resulting in accidental plagiarism https://creativecommons.org/licenses/by-nd/4.0/ plagiarism perceptions and attitudes among medical students in saudi arabia e78 | squ medical journal, february 2020, volume 20, issue 1 (as seen with in-text citation problems) or acting intentionally, with actions stemming from dishonesty.3,5 nevertheless, students can engage in unintentional cheating and not acknowledge it as academic dishonesty. rennie and crosby reported that 56% of us medical students have plagiarised at least once in their academic careers.6 a croatian cross-sectional study evaluated the attitudes of pharmacy and medical bio chemistry students on the subject of plagiarism and concluded that there was an insufficient level of seriousness and awareness in perceptions of plagiarism, as well as a lack of knowledge about scientific methodology and academic and scientific misconduct.7 similarly, a croatian study on the prevalence of plagiarism in writing essays among 198 second-year medical students found that only 9% of the students did not plagiarise.1 plagiarism is considered dishonest because the plagiariser uses someone else’s ideas and takes credit for them; the plagiariser can advance in their career or be promoted on that basis. such promotions can be a risk to others, especially in the medical field, as someone may be promoted to a position for which they would otherwise not have been qualified. if undetected, plagiarism has a serious negative influence on educational feedback, defeating the purpose of instructional strategies.2,8 in the saudi arabian context, a recent study by kattan et al. concluded that, even though the studied group of postgraduate medical trainees had attended courses in medical writing, were aware of research ethics and/or had published a scientific manuscript before, they were still susceptible to plagiarism. the study recommended increasing awareness among trainees to avoid this issue.9 saudi arabia’s cultural backgrounds, religious beliefs and ethical values may be different from those in western countries. prior to entering medical school in saudi arabia, high school students generally attend islamic-related courses that include topics that condemn and reject cheating while encouraging sincere and honest behaviour. furthermore, most medical colleges in saudi arabia have a core ethics course in their curriculum in addition to clear and strict regulations that prohibit cheating and plagiarism. this study aimed to evaluate the perceptions of and attitude towards plagiarism among undergraduate medical students in saudi arabia by using a validated questionnaire. methods this cross-sectional, online, questionnaire-based study was conducted between april and may 2018 at medical schools in riyadh, saudi arabia. all medical colleges in riyadh (three public and two private schools) were contacted for permission to send the survey to their students through their email lists. of the five colleges that were contacted, three provided consent. the survey was distributed among the three colleges by student volunteers, most of whom were leaders of their batches, who then distributed the survey through the students’ email lists. the estimated student population of the three medical schools at the time of the study was 1,250 and the required sample size, in order to achieve a 95% confidence interval (ci) with a 5% margin of error, was 295. in total, 750 undergraduate medical students were randomly chosen from first to fifth year from the three selected medical schools; 250 students from each university were approached. this sample size was chosen as it was within the researchers’ financial budget. surveymonkey (svmk inc., san mateo, california, usa) was used to gather responses.10 attitudes towards plagiarism were assessed using the previously validated attitude towards plagiarism (atp) questionnaire.11,12 the atp questionnaire is a standard method used to evaluate the attitudes towards plagiarism and has been validated using principal component analysis with a reliability score of >0.70.11 the questionnaire consists of 29 questions divided into three main sections: approval of plagiarism (i.e. positive attitude), disapproval of plagiarism (i.e. negative attitude) and social and normative components that could change a person’s thinking on the issue (i.e. subjective norms). all questions were self-reported and scored on a 1–5 likert scale, with one indicating ‘strongly disagree’ and five indicating ‘strongly agree’. twelve statements self-measured positive attitude, with a score range of 12–60. the scoring system is summarised in table 1. demographic variables and characteristics (i.e. age, academic year, gender and grade point average [gpa]) were assessed. participants were also asked if they had attended any medical writing and/or medical ethics courses or authored a published manuscript. statistical analysis was performed using statistical product and service solutions (spss), version 24 (ibm, corp., armonk, ny, usa). student’s t-test was used to assess associations between the participants’ atp scores and the variables set in the questionnaire. a one-way analysis of variance (anova) was performed using two different approaches: a sum of squares contrast was used to compare the mean scores across atp sections to demographic characteristics with more than two categories (i.e. age, academic year and gpa) and results for various atp sections were summarised using means and standard deviation. in addition, a binary logistic regression test was performed to identify the independent predictors of low positive attitude, high negative attitude and low subjective norm attitudes towards plagiarism. counts and percentages were used to summarise categorical variables as well as abdulmajeed s. alhadlaq, abdulmajeed bin dahmash and feras alshomer clinical and basic research | e79 the attitude towards plagiarism after using the scoring system in table 1. a value of p <0.05 was considered statistically significant ethical approval was obtained from the instit utional review board (irb) of the medical research unit, college of medicine, imam mohammad ibn saud islamic university, riyadh, saudi arabia (irb code: 0037/04/2018-55). informed consent was obtained from the participants through the online questionnaire. participants’ anonymity was maintained by not asking for their names or university identification numbers; participation was entirely voluntary. results a total of 551 students participated in this study (response rate = 73.5%) of which the majority were male (57%). almost half of the participants had a gpa of 4.25–5.0 (47.5%). most respondents (58.8%) had received courses in medical ethics and some (20.7%) had previously authored a published manuscript [table 2]. very few respondents had a high positive attitude towards plagiarism or low negative attitude towards plagiarism (2% each). moreover, few participants (3.4%) had high subjective norms towards plagiarism. however, most students had a moderate score on all three scales (65%, 58.4% and 56.6%, respectively) [table 3]. the mean positive attitude score was 31.34 ± 7.26, the mean negative attitude score was 25.26 ± 4.61 and the mean subjective norm score was 25.16 ± 6.12. all these scores indicate a moderate attitude towards plagiarism. the difference in positive attitude scores was statistically significant between females and males (32.05 ± 7.24 versus 30.8 ± 7.24, respectively; p = 0.046). there was no significant difference in the mean negative attitude or subjective norm scores between males and females. statistical analysis indicated no significant differ ence between age groups in mean attitude scores for all three scales (p >0.05). one-way anova results indicated a statistically significant difference in the mean negative and positive attitude scores across various gpa groups (p = 0.004 and 0.007, respectively). there was no significant differ ence in the mean subjective norm scores across gpas [table 4]. in addition, statistical analysis using oneway anova showed no significant difference for any of the three scales between any of the academic years in mean attitude scores (p >0.05). the mean attitude score across students who had attended medical writing courses compared to students who had not attended medical writing courses was statistically different; a higher mean positive attitude score was found among students who had not attended medical writing courses compared to students who had attended medical writing courses (32.50 ± 6.84 versus 30.33 ± 7.47; p <0.001). the mean negative attitude table 1: scoring system used to evaluate attitudes towards plagiarism of medical students in saudi arabia attitude low moderate high positive attitude 12–28 29–45 46–60 negative attitude 7–16 17–26 27–26 subjective norm 10–23 24–37 38–50 table 2: characteristics and variables of medical students included in a survey to determine attitudes towards plag iarism in saudi arabia (n = 551) characteristic n (%) gender female 237 (43) male 314 (57) academic year first 84 (15.2) second 163 (29.6) third 114 (20.7) fourth 90 (16.3) fifth 100 (18.1) age in years 18–19 43 (7.8) 20–21 192 (34.8) 22–23 191 (34.7) 24–25 92 (16.7) >25 33 (6) gpa <2.75 14 (2.5) 2.75–3.5 80 (14.5) 3.5–4.25 195 (35.4) 4.25–5.0 262 (47.5) have you attended any writing courses? no 256 (46.5) yes 295 (53.5) have you previously attended any courses on ethics? no 227 (41.2) yes 324 (58.8) have you ever authored a published manuscript? no 437 (79.3) yes 114 (20.7) gpa = grade point average. plagiarism perceptions and attitudes among medical students in saudi arabia e80 | squ medical journal, february 2020, volume 20, issue 1 score was higher in students who had attended medical writing courses compared to those who had not (25.66 ± 4.63 versus 24.81 ± 4.65; p = 0.03). the mean subjective norms score was significantly higher in students who had not attended medical writing courses compared to those who had (26.03 ± 5.87 versus 24.41 ± 6.25; p = 0.002). attending medical ethics courses was significantly associated with more negative attitudes towards plagiarism (p <0.001 for all scales). mean positive attitudes and subjective norm scores were higher in individuals who had not attended medical ethics courses compared to those that had (33.37 ± 6.54 versus 29.92 ± 7.41 and 26.86 ± 5.70 versus 23.98 ± 6.14, respectively). mean negative attitude scores were higher in individuals who had attended medical ethics courses compared to those that had not (25.93 ± 4.70 versus 24.32 ± 4.32). respondents who had authored a published manuscript were significantly associated with negative attitudes only (p = 0.02) and the mean negative attitude score was lower in individuals who had previously authored a published manuscript comp ared to those who had not (24.37 ± 4.37 versus 25.50 ± 4.56) [table 5]. attending courses in medical ethics was associated with a low positive attitude (odds ratio [or] = 2.469, 95% ci: 1.570–3.883; p <0.001), high negative attitude (or = 2.369, 95% ci: 1.540–3.645; p <0.001) and low subjective norms towards plagiarism (or = 2.181, 95% ci: 1.426–3.337; p <0.001). having authored a published manuscript was associated with high negative attitudes towards plagiarism (or = 0.577, 95% ci: 0.366–0.911; p = 0.018). gender, age, gpa, academic year and having taken medical writing courses were not significantly associated with high negative attitudes, low positive attitudes or low subjective norms towards plagiarism [table 6]. discussion continuous assessment and education in the medical field represents the essence of learning. medical students in their early years are less familiar with the concept of plagiarism as has been indicated by past studies, and therefore tend to have a more permissive attitude towards plagiarism.13 educating and training students on how to appropriately cite academic literature and research may change the attitude towards plagiarism of students who are starting their medical careers. in a middle eastern study, which aimed to explore academic integrity among medical students, researchers found that plagiarism was considered a minor offense and table 3: scoring of attitudes towards plagiarism among medical students in saudi arabia (n = 551) attitude n (%) low moderate high positive attitude 182 (33) 358 (65) 11 (2) negative attitude 11 (2) 322 (58.4) 218 (39.6) subjective norm 220 (39.9) 312 (56.6) 19 (3.4) table 4: attitude scores towards plagiarism across grade point average groups among medical students in saudi arabia attitude mean ± sd p value <2.75 2.75–3.5 3.51–4.25 4.26–5.0 negative attitude 22.14 ± 4.72 24.94 ± 4.55 24.87 ± 4.72 25.82 ± 4.46 0.004 positive attitude 34.64 ± 8.76 33.63 ± 7.20 31.01 ± 7.15 30.71 ± 7.13 0.007 subjective norm 27.14 ± 8.55 26.38 ± 6.57 25.14 ± 6.03 24.70 ± 5.87 0.107 sd = standard deviation. table 5: attitude scores towards plagiarism based on having attended medical writing courses, medical ethics courses or having authored a published manuscript among medical students in saudi arabia attitude mean ± sd attended a medical writing course attended a medical ethics course authored a published manuscript no yes p value* effect size no yes p value* effect size no yes p value* effect size positive attitude 32.50 ± 6.84 30.33 ± 7.47 <0.001 0.3 33.37 ± 6.54 29.92 ± 7.41 <0.001 0.49 31.64 ± 7.23 30.20 ± 7.28 >0.05 0.198 negative attitude 24.81 ± 4.56 25.66 ± 4.63 0.03 0.299 24.32 ± 4.32 25.93 ± 4.70 <0.001 0.357 25.50 ± 4.56 24.37 ± 4.73 0.02 0.24 subjective norm 26.03 ± 5.87 24.41 ± 6.25 0.002 0.268 26.86 ± 5.70 23.98 ± 6.14 <0.001 0.486 25.32 ± 6.10 24.56 ± 6.20 >0.05 0.12 sd = standard deviation. *using student’s t-test. abdulmajeed s. alhadlaq, abdulmajeed bin dahmash and feras alshomer clinical and basic research | e81 many medical students believed that it was not their responsibility to report it.14 in the present study, the atp questionnaire was used to evaluate the attitudes of medical students towards plagiarism.11 in addition, this study analysed whether gpa influences attitudes of medical students towards plagiarism; results from a one-way anova showed a statistically significant difference in the mean positive and negative attitude scores across gpa groups (p = 0.007 and 0.004, respectively). the impact of gpa on cheating has been previously investigated, although with mixed results.15–17 a study involving saudi arabian medical students showed that students with higher gpas are less likely to be involved in cheating and a study on pharmacy students showed a similar association.15,16 however, hrabak et al. did not find significant differences between gpa scores and academic misconduct.17 interestingly, in the present study, 58.8% of the respondents had attended medical ethics courses and 20.7% had authored a paper prior to the survey. most students had a moderate score for the scales of positive attitude, negative attitude and subjective norms (65%, 58.4% and 56.6%, respectively); this suggests that saudi medical students in this study were aware of plagiarism. however, only 39.6% of the respondents had a high negative attitude towards plagiarism. attending medical ethics courses had a positive impact on students’ attitudes towards plagiarism; those who had not attended medical ethics courses had a significantly higher positive attitude towards plagiarism. this finding is in agreement with the results of brkic et al., who reported that a short lecture focusing on the negative impact of plagiarism contributed to creating awareness among students on types of plagiarism and that plagiarism is a violation of scientific ethics.18 in addition, few participants in the current study had high subjective norms towards plagiarism (3.4%) indicating a low inclination towards plagiarism. attending medical ethics courses was found to be an independent predictor associated with low positive attitudes and high negative attitudes towards plagiarism as well as low subjective norms. these results are in agreement with abdulghani et al.’s study which also found that students with high gpas were less likely to cheat.15 however, the current results were not in line with kattan et al.’s findings, who found no significant correlation between attitudes and attendance in ethics courses but did find that medical trainees who had previously authored scientific publ ications and attended writing courses tended to lean positively towards plagiarism.9 educating students and faculty can help change their attitudes toward and perceptions of plagiarism, but it is also important to have a standard institutional policy against plagiarised content, mandating punish ment for repeat offenders.19,20 the strengths of the present study include its multicentre approach and detailed correlations related to different student characteristics. some of the limitations of the present study include the cross-sectional nature of assessments. the interplay between students’ knowl edge, attitudes and behaviours with regards to a complex subject such as plagiarism is a complicated evaluation to engage with via a survey, which can only be treated as a proxy measure. in addition, there is a possibility of table 6: logistic regression analysis of independent predictors of low positive attitude, high negative attitude and low subjective norms towards plagiarism among medical students in saudi arabia independent predictor low positive attitude (r2 = 0.289) high negative attitude (r2 = 0.255) low subjective norm (r2 = 0.256) or (95% ci) p value or (95% ci) p value or (95% ci) p value gender 0.952 (0.639–1.419) 0.810 1.242 (0.847–1.822) 0.267 1.005 (0.687–1.427) 0.978 age 0.919 (0.726–1.164) 0.485 0.860 (0.684–1.083) 0.201 0.866 (0.689–1.089) 0.218 gpa 1.240 (0.978–1.572) 0.076 1.253 (0.999–1.572) 0.05 1.171 (0.936–1.464) 0.168 academic year 1.052 (0.883–1.252) 0.570 1.078 (0.909–1.278) 0.389 1.029 (0.870–1.218) 0.735 attended a medical writing course 1.126 (0.739–1.715) 0.581 1.003 (0.668–1.508) 0.988 1.287 (0.861–1.922) 0.219 attended a medical ethics course 2.469 (1.570–3.883) <0.001 2.369 (1.540–3.645) <0.001 2.181 (1.426–3.337) <0.001 authored a published manuscript 1.514 (0.973–2.354) 0.066 0.577 (0.366–0.911) 0.018 1.132 (0.732–1.750) 0.576 or = odds ratio; ci = confidence interval; gpa = grade point average. plagiarism perceptions and attitudes among medical students in saudi arabia e82 | squ medical journal, february 2020, volume 20, issue 1 response bias which is a known limitation in surveybased studies. conclusion most medical students in saudi arabia were found to have a negative attitude towards plagiarism. higher gpas, the authoring of a publication and attending courses in medical ethics were associated with negative attitudes towards plagiarism among medical students. to increase the students’ awareness of plagiarism, structured courses related to the practice of plagiarism should be implemented. medical students should be familiar with issues and consequences related to plagiarism. future studies should investigate the content of ethics courses in medical schools and whether different medical schools give equal attention to plagiarism and academic dishonesty in their curricula. a c k n o w l e d g e m e n t the authors would like to express their sincere gratitude to shoog f. alfadheel, fouad a. kanadily, ali m. alshardan, rawan s. aljohany, abdulaziz y. alturki, nawaf a. alosaimi and hani alanazi for their assistance in data collection for this study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bilić-zulle l, frković v, turk t, azman j, petrovecki m. prevalence of plagiarism among medical students. croat med j 2005; 46:126–31. https://doi.org/10.1037/e520942012-037. 2. guraya sy, guraya ss. the confounding factors leading to plagiarism in academic writing and some suggested remedies: a systematic review. j pak med assoc 2017; 67:767–72. 3. yeo s. first-year university science and engineering students’ understanding of plagiarism. high educ res dev 2007; 26:199–216. https://doi.org/10.1080/07294360701310813. 4. ballor jj. plagiarism in a digital age. j mark moral 2014; 17:349–52. 5. james r, mcinnis c, devlin m. assessing learning in australian universities: ideas, strategies and resources for quality in student assessment. melbourne, australia: centre for the study of higher education, 2002. 6. rennie sc, crosby jr. are “tomorrow’s doctors” honest? quest ionnaire study exploring medical students’ attitudes and reported behaviour on academic misconduct. bmj 2001; 322:274–5. https://doi.org/10.1136/bmj.322.7281.274. 7. pupovac v, bilić-zulle l, mavrinac m, petrovecki m. attitudes toward plagiarism among pharmacy and medical biochemistry students – cross-sectional survey study. biochemia medica 2010; 20:307–13. https://doi.org/10.11613/bm.2010.039. 8. austin z, collins d, remillard a, kelcher s, chui s. influence of attitudes toward curriculum on dishonest academic behavior. am j pharm educ 2006; 70:50. https://doi.org/10.5688/aj700350. 9. kattan ae, alshomer f, alhujayri ak, alfaqeeh f, alaska y, alshakrah k. the practice and attitude towards plagiarism among postgraduate trainees in saudi arabia. j health spec 2017; 5:181–4. https://doi.org/10.4103/jhs.jhs_64_17. 10. svmk inc. survey monkey. from: www.surveymonkey.com accessed: jul 2019. 11. mavrinac m, brumini g, bilić-zulle l, petrovecki m. construction and validation of attitudes toward plagiarism questionnaire. croat med j 2010; 51:195–201. https://doi.org/10.3325/cmj.2010.51.195. 12. bazdaric k. plagiarism detection--quality management tool for all scientific journals. croat med j 2012; 53:1–3. https://doi.org/10. 3325/cmj.2012.53.1. 13. shirazi b, jafarey am, moazam f. plagiarism and the medical fraternity: a study of knowledge and attitudes. j pak med assoc 2010; 60:269–73. 14. elzubeir ma, rizk de. exploring perceptions and attitudes of senior medical students and interns to academic integrity. med educ 2003; 37:589–96. https://doi.org/10.1046/j.1365-29 23.2003.01552.x. 15. abdulghani hm, haque s, almusalam ya, alanezi sl, alsulaiman ya, irshad m, et al. self-reported cheating among medical students: an alarming finding in a cross-sectional study from saudi arabia. plos one 2018; 13:e0194963. https://doi.org/10.1371/journal.pone.0194963. 16. hardigan pc. first-and third-year pharmacy students’ attitudes toward cheating behaviors. am j pharm educ 2004; 68:1–5. https://doi.org/10.5688/aj6805110. 17. hrabak m, vujaklija a, vodopivec i, hren d, marusić m, marusić a. academic misconduct among medical students in a post-communist country. med educ 2004; 38:276–85. https://doi.org/10.1111/j.1365-2923.2004.01766.x. 18. brkic s, bogdanovic g, vuckovic-dekic l, gavrilovic d, kezic i. science ethics education: effects of a short lecture on plagiarism on the knowledge of young medical researchers. j buon 2012; 17:570–4. 19. viale ph. avoiding plagiarism in professional writing. j adv pract oncol 2012; 3:134–5. https://doi.org/10.6004/jadpro.2012.3.3.1. 20. sovacool bk. using criminalization and due process to reduce scientific misconduct. am j bioeth 2005; 5:w1–7. https://doi. org/10.1080/15265160500313242. https://doi.org/10.1037/e520942012-037 https://doi.org/10.1080/07294360701310813 https://doi.org/10.1136/bmj.322.7281.274 https://doi.org/10.11613/bm.2010.039 https://doi.org/10.5688/aj700350 https://doi.org/10.4103/jhs.jhs_64_17 https://doi.org/10.3325/cmj.2010.51.195 https://doi.org/10.3325/cmj.2012.53.1 https://doi.org/10.3325/cmj.2012.53.1 https://doi.org/10.1046/j.1365-2923.2003.01552.x https://doi.org/10.1046/j.1365-2923.2003.01552.x https://doi.org/10.1371/journal.pone.0194963 https://doi.org/10.5688/aj6805110 https://doi.org/10.1111/j.1365-2923.2004.01766.x https://doi.org/10.6004/jadpro.2012.3.3.1 https://doi.org/10.1080/15265160500313242 https://doi.org/10.1080/15265160500313242 department of radiology, royal hospital, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com معدل انتشار وأنواع الشذوذ اخللقية للشرايني التاجية املكتشفة باستخدام التصوير املقطعي احملوسب لالوعية الدموية جتربة مركز واحد يف سلطنة عمان را�شد �شيف العمري، فايزة الكندي، �شقر الطائي abstract: objectives: coronary artery anomalies (caas) are uncommon congenital abnormalities with a prev alence ranging from 0.2–2%. caas can be asymptomatic or less commonly present with life-threatening symptoms. this study aimed to investigate the prevalence and spectrum of caas in patients who underwent coronary comp uted tomography angiography (ccta) in oman. methods: this retrospective study was conducted at the national heart centre, muscat, oman between september 2012 and august 2018. all consecutive patients who had undergone ccta were included. results: a total of 4,445 patients were included in this study. of these, 59 patients (1.3%) were diagnosed with caas with a mean age of 52.6 years (range: 12–80 years) and an equal gender distribution. among the patients with caas, the majority (69.5%) had anomalous origins from the opposite or non-coronary sinus. right coronary artery arising from the left coronary sinus was the most common type (33.9%). fewer patients (18.6%) had left circumflex arising from the right coronary sinus (rcs). seven patients (11.9%) had left main arising from the rcs. other caas were in the dual left anterior descending artery (8.5%), high coronary artery take-off (6.8%), single coronary ostia (6.8%) and coronary artery fistula (6.8%). conclusion: the prevalence of caas was 1.3% which is similar to the literature. keywords: coronary vessel anomalies; computed tomography angiography; prevalence; oman. امللخ�ص: الهدف: ال�شذوذ اخللقية لل�رشايني التاجية هي ت�شوهات خلقية نادرة ويرتاوح معدل انت�شارها من %2-0.2. يف كثري من االأحيان تكون ال�شذوذ اخللقية لل�رشايني التاجية بدون اعرا�س ولكن يف حاالت قليلة تكون االعرا�س مهددة للحياة باخلطر. هدفت هذه الدرا�شة اىل معرفة معدل انت�شار واأنواع ال�شذوذ اخللقية لل�رشايني التاجية عند املر�شى الذين خ�شعوا للت�شوير املقطعي املحو�شب لل�رشايني التاجية هذه و�شملت عمان. �شلطنة م�شقط، القلب، وجراحة لطب الوطني املركز يف اال�شتعادية الدرا�شة هذه اجريت الطريقة: عمان. �شلطنة يف الدرا�شة جميع املر�شى الذين خ�شعوا للت�شوير املقطعي املحو�شب لل�رشايني التاجية ما بني �شهر �شبتمرب لعام 2012 و�شهر اأغ�شط�س لعام 2018. النتائج: ت�شمنت هذه الدرا�شة 4,445 مري�شا ومن بني هوؤالء وجد ان 59 مري�شا لديهم �شذوذ خلقية يف ال�رشايني التاجية )1.3%( ال�شذوذ مر�شى من العظمى الغالبية وكانت اجلن�شني. كال بني مت�شاو وبتوزيع عاما( �شنة )املدى: 80-12 اعمارهم 52.6 متو�شط وكان اخللقية لل�رشايني التاجية لديهم من�شاأ �شاذ من اجليب التاجي املقابل اواجليب غري التاجي )%69.5(. وقد مثل من�شاأ ال�رشيان التاجي االأمين من اجليب التاجي االي�رش )%33.9(. وجد عند عدد قليل من املر�شى ان ال�رشيان التاجي املنعطف االي�رش ين�شا من اجليب التاجي االأمين )6.81%(. ووجد عند �شبعة من املر�شى )%11.9( ان ال�رشيان التاجي االي�رش لديهم ين�شاأ من اجليب التاجي االأمين. توزعت بقية حاالت ال�شذوذ اخللقية لل�رشايني التاجية بني ازدواجية ال�رشيان النازل االمامي )%8.5( وارتفاع فتحة ال�رشيان التاجي )%6.8( ووجود فوهة تاجية وحيدة )%6.8( ونا�شور ال�رشيان التاجي )%6.8(. اخلال�صة: معدل انت�شارال�شذوذ اخللقية لل�رشايني التاجية هو %1.3 وهو مماثل ملا هو موجود يف االدبيات الطبية. الكلمات املفتاحية: ت�شوهات االأوعية التاجية؛ الت�شوير املقطعي املحو�شب لالوعية الدموية؛ معدل انت�شار؛ عمان. prevalence and spectrum of coronary anomalies detected on coronary computed tomography angiography a single centre experience in oman *rashid s. al-umairi, faiza al-kindi, saqar al-tai sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e108–113 , epub. 8 sep 19 submitted 1 oct 18 revision req. 26 nov 18; revision recd. 26 dec 18 accepted 28 jan 19 advances in knowledge the findings of this study demonstrate that there is no significant difference in the prevalence and spectrum of coronary artery anomalies (caas) between this study’s population and the rest of the world. application to patient care this study highlights the importance of utilising coronary computed tomography angiography as a robust non-invasive test for evaluating caas. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.005 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ rashid s. al-umairi, faiza al-kindi and saqar al-tai clinical and basic research | e109 coronary artery anomalies (caas) are uncommon congenital abnormalities with a prevalence of 0.2–2% in the general population.1–5 caas encompass a spectrum of anomalies including abnormalities of origin, course, number, structure and termination of the coronary arteries.6 most patients with caas are asymptomatic; however, some caas have been linked to ischaemic heart disease, syncope and sudden cardiac death.7–9 caas are generally detected incidentally on autopsy, conventional coronary angio graphy (cca) or through coronary computed tomo graphy angiography (ccta). although cca is the gold standard for assessing contrary arteries, it is an invasive procedure and has limited ability to demonstrate the anatomy of complex caas. in contrast, ccta is non-invasive and can show complex anatomy.1,2,10 the national heart centre, muscat, oman, is a tertiary cardiac centre which receives referrals from all of oman. this study aimed to assess the prevalence and spectrum of caas in oman’s general population. methods a total of 4,445 consecutive patients who underwent ccta at the national heart centre, from september 2012 to august 2018 were included. the indications for performing ccta were chest pain to exclude coronary artery disease (cad), assessment of coronary artery grafts or stents, cardiomyopathy, evaluation for congenital heart disease, evaluation of syncope and pre-cardiac surgery assessment. patients were excl uding from ccta if they had a history of allergy to iodinated contrast material, impaired renal function defined as an estimated glomerular filtration rate of <45 ml/min/1.73m2, an inability to follow breathing instructions, an uncontrolled heart rate, cardiac arrhythmia and severe coronary calcification on calcium score scan. patients with myocardial bridging (mb) were excluded as some authors considered mb to be a normal variant, whereas others considered it to be an anomaly. in addition, there is a lack of clarity regarding its definition in the literature.11–13 prior to the ccta, participants received an electro cardiogram (ecg) and heart rate and blood pressure were checked. procedure preparation included the oral administration of 25–100 mg of atenolol with a baseline heart rate >70 beats/min in order to lower the heart rate. sublingual nitroglycerine (0.8 mg) was administered to all patients one minute prior to injecting 60–75 ml of contrast followed by 30 ml of saline solution at a rate of 6 ml/second, unless it was contraindicated. the ccta was performed using a dual source 256 slice (2 × 128) scanner (somatom definition flash, siemens ag), a rotation time of 280 minutes and dual source 384 (2 × 192; somatom force, siemens ag, berlin and munich, germany) with a rotation time of 250 minutes. all scans started with a topogram followed by a prospective ecg-gated nonenhanced computed tomography (ct) scan at a 75% r-r interval. subsequently, a contrast-enhanced scan was performed where an ecg-gated prospective or retrospective scan with a slice thickness of 0.6 mm was acquired during breath holding after inspiration. the scan parameters were adjusted automatically or manually to acquire the best quality image with the lowest radiation dose. data from the scanners were sent to separate image processing work stations (syngo.via, siemens ag) and analysed by three cardiothoracic radiologists with three, six and nine years of experience. coronary arteries were assessed for atherosclerotic disease, anom alous origins, courses and terminations. patients with caas were selected and images were again reviewed by a single radiologist before inclusion in the study. the scientific research committee of the royal hospital, muscat, oman approved this study (src#53/ 2018) and waived informed consent. results in the current study, the prevalence rate of patients with caas was 1.3% [table 1]. the baseline clinical characteristics of these patients are shown in table 2. anomalous origin of the coronary artery from the opposite or non-coronary sinus (acaos) was the most common caa. right coronary artery (rca) arising from the left coronary sinus (lcs) was the most common anomaly (33.9%) [figures 1a and b]. the rca arose from the non-coronary sinus (ncs) in two patients (3.4%) [figures 1c and d]. in all patients, the anomalous rca arose from the lcs and then passed between the aortic root and the pulmonary artery taking an interarterial course. one patient underwent deroofing surgery and another patient refused to undergo surgery. the second most common type (18.6%) of acaos was a left circumflex artery (lcx) originating from the right coronary sinus (rcs) or rca with a retro-aortic course. five patients (8.5%) had anomalous origin of the left main coronary artery (lmca) from the rcs and two patients had an interarterial course [figures 2a and b]. one patient underwent a coronary artery bypass surgery and one patient refused surgery. three patients with anomalous lmca from the rcs had a transseptal course [figures 2c and d]. prevalence and spectrum of coronary anomalies detected on coronary computed tomography angiography settings a single centre experience in oman e110 | squ medical journal, may 2019, volume 19, issue 2 table 2: baseline characteristics of omani patients with coro nary artery anomalies who underwent coronary computed tom ography angiography (n = 59) characteristic n (%) mean age in years (range) 52.6 (12–80) male:female ratio 30:29 presenting symptoms typical chest pain 13 (22) atypical chest pain 28 (47.5) syncope 2 (3.4) dyspnoea 12 (20.3) palpitation 9 (15.3) risk factors diabetes 18 (30.5) hypertension 24 (40.7) dyslipidaemia 7 (11.9) underlying cardiac problem dilated cardiomyopathy 5 (8.5) previous myocardial infarction 1 (1.7) figure 1: axial maximal intensity projection via coronary computed tomography angiography imaging (a & c) and three-dimensional volume rendering (b & d) showing (a & b) the right coronary artery (arrow) arising from the left coronary sinus before it courses to the right bet ween the main pulmonary artery and the aorta and showing (c & d) the right coronary artery (arrowhead) arising from the non-coronary sinus. rcs = right coronary sinus; ncs = non-coronary sinus; mpa = main pulmonary artery; lcs = left coronary sinus; la = left atrium; ao = aorta; rvot = right ventricular outflow tract. figure 2: axial maximal intensity projection via coronary computed tomography angiography imaging (a & c) and three-dimensional volume rendering (b & d) showing (a & b) the left main coronary artery (arrow) arising from the right coronary sinus before it courses to the left between the main pulmonary artery and the aorta and showing (c & d) the left main coronary artery (arrow) arising from the right coronary sinus before it courses to the left through the interventricular septum. the right coronary artery is indicated by the arrowhead. rcs = right coronary sinus; mpa = main pulmonary artery; ncs = non coronary sinus; lcs = left coronary sinus; la = left atrium; ao = aorta. table 1: prevalence and spectrum of coronary artery anom alies in omani patients undergoing coronary computed tomo graphy angiography (n = 59) coronary artery anomaly n (%) percentage among total sample (n = 4,445) anomalous origin from opposite or ncs with anomalous course rca arising from the lcs with interarterial course 20 (33.9) 0.450 lcx arising from the rcs or rca with retroaortic course 11 (18.6) 0.250 lmca arising from the rcs with interarterial course 2 (3.4) 0.045 lmca arising from the rcs with transseptal course 3 (5.1) 0.076 lmca arising from the rcs with retroaortic course 2 (3.4) 0.045 rca arising from the ncs 2 (3.4) 0.045 lmca from the ncs 1 (1.7) 0.022 multiple ostia absent left main trunk with lad and lcx originating separately from the aorta 1 (1.7) 0.022 single coronary ostium 4 (6.8) 0.089 high take-off lmca 1 (1.7) 0.045 rca 3 (5.1) 0.076 dual lad anomaly 5 (8.5) 0.110 caf 4 (6.8) 0.089 ncs = non-coronary sinus; rca = right coronary artery; lcs = left coronary sinus; lcx = left circumflex artery; rcs = right coronary sinus; lmca = left main coro nary artery; lad = left anterior descending artery; caf = coronary artery fistula. rashid s. al-umairi, faiza al-kindi and saqar al-tai clinical and basic research | e111 lmca was absent in one patient (1.7%) with the left anterior descending (lad) coronary artery and lcx arising separately from the lcs [figure 3a]. three patients (5.1%) had high take-off rca [figure 3b]. four patients (6.8%) had coronary artery fistulas (cafs) in the forms of a fistula connecting the rca to the main pulmonary artery (mpa) [figure 4], a fistula between the left anterior descending artery (lad) or the mpa, which is a complex fistula that connects the rca, the lad and a bronchial artery. one patient had a complex fistula between the rca, lmca, lad and mpa. discussion caas are part of a spectrum of uncommon coronary artery congenital anomalies.13 in the literature, discrep ancies in the prevalence of caas are largely due to the inclusion or exclusion of mb due to the fact that some authors consider mb as a normal variant, whereas others consider it an anomaly.12,14,15 when mb is excl uded, the prevalence of caas ranges between 0.5–3.1%; however, when mb is included, prevalence increases to 7.9–18.4%.3 in the current study, the prevalence of caas, excluding mb, was 1.3% which falls within the reported range in the literature.3,5,11,16 to the best of the authors’ knowledge, this study is the first to estimate the prevalence and spectrum of caas in the general omani population. cca can be used to detect caas, although it is an invasive procedure and has a risk of complications.17 however, ccta is a non-invasive test that has recently become the gold standard for detecting and characterising caas. ccta can precisely delineate the course of the anomalous artery and provide three-dimensional inform ation about the relation of anomalous to other cardio vascular structures, namely cardiac chambers and major arteries.18–20 caas can be categorised based on the origin, course, number and termination of the coronary arteries.6 in the current study, acaos was the most common caa (69.5%) which was similar to reports from previous studies.7,11,20,21 acaos can be classified into four groups: 1) rca arising from the lcs, 2) lca arising from the rcs, 3) lcx or lad arising from the rcs and 4) lca or rca arising from the ncs.6,22 the course of the anomalous artery can be interarterial between the aorta and the mpa, anterior to the mpa, retroaortic or trans septal through the interventricular septum.5,9,13,16 of these courses, the most clinically significant anomaly is the interarterial course because it is strongly associated with sudden death, particularly in young competitive athletes.23 although not fully understood, the assumed mechanism of ischaemia in an anomalous artery with an interarterial course is that the anomalous artery is squeezed between the aorta and the mpa.11 therefore, patients with an interarterial course should be treated; however, many patients with these anomalies are asymp tomatic. moreover, there are difficulties implicit in routine examinations and clinical testing for these anomalies. in such cases ccta is an important diagnostic tool as it can differentiate between interarterial and transseptal courses with high spatial and temporal resolution.9,16 however, a disadvantage of using ccta is the radiation that accompanies it; however, the new generation of multidetector scanners has much lower radiation comp ared to older generations.24 figure 3: three-dimensional volume-rendered coronary image showing (a) the separate origin of the left anterior descending artery (arrow) and the left circumflex artery (arrowhead) from the left coronary sinus and (b) the anomalous origin from the right coronary artery (arrow head) from the aorta above the sinotubular junction. ao = aorta; rvot = right ventricular outflow tract. figure 4: three-dimensional volume rendered coronary computed tomography angiography image showing a tor tuous vessel (blue arrowhead) arising from the right cor onary artery (white arrowhead). the tortuous vessel passes anterior to the main pulmonary artery and forms a small aneurysm (blue arrow) before it enters the main pulmo nary artery distal to the valve. the left anterior descending artery is marked by the white arrow. ao = aorta; mpa = main pulmonary artery. prevalence and spectrum of coronary anomalies detected on coronary computed tomography angiography settings a single centre experience in oman e112 | squ medical journal, may 2019, volume 19, issue 2 there are three different treatment options for patients with interarterial anomalous arteries: 1) medical treatment, 2) angioplasty and 3) surgical repair.25 in the current study, all 20 patients with anomalous rca from the lcs had an interarterial course. multiple coronary artery ostia is either due to the separate origins of the rca and conus branch from the aorta or the absent lmca with the lcx and lad arising separately from the aorta. the prevalence of the absence of lmca ranges from 0.5–8%.5 in this study’s sample, the prevalence was lower (0.03%) and only one patient had no lmca and separate ostia of the lad and lcx. multiple ostia allow alternative collateral supplies in patients with proximal cad; however, these can cause technical difficulties in cannulation during invasive coronary angiography.11,13,26 a single coronary ostium is an extremely rare congenital anomaly characterised by a single artery arising with a single ostium from the aorta. it is seen in only 0.0024–0.044% of the population.6 patients with a single coronary artery are at increased risk for sudden death if a major coronary branch has an interarterial course between the pulmonary artery and the aorta.27 four of the current patients (6.8%) had single coronary ostia which originated from the rcs. a high take-off caa is a coronary artery which arises from the aortic wall 0.5 cm above the sinotubular junction.6 although this anomaly is benign, it can cause technical difficulties of coronary artery cannulation during conventional angiography. moreover, cardiac surgeons should be aware of this anomaly prior to cardiac surgery to avoid damaging the anomalous artery while cross-clamping the aorta.5,16 in the current study, four patients (6.8%) had high take-off coronary arteries, one patient (1.7%) had high take-off of the lmca and three (5.1%) had high take-off rca. dual lad is a rare congenital anomaly which is defined by the presence of short and long lads which supply the course of the lad.28 it is traditionally classified into four types based on the origin, course and termination of the short and long lads; however, cca has led to recognition of other variants. to date, eleven types of dual lad variants have been identified.29 awareness of dual lad variants is crucial for interpreting cardiac cts in patients with dual lad anomalies and for planning percutaneous and surgical reperfusion strategies. five of the patients (8.5%) in the current study had dual lads. cafs are defined by abnormal communication between a coronary artery and another structure such as a heart chamber, the mpa or the coronary sinus.16,30 small cafs are usually asymptomatic and detected incidentally on echocardiography, coronary arterio graphy or ccta performed for other reasons. however, large cafs can lead to the ‘steal phenomenon’ which can lead to ischaemia due to diminished blood supply to the portion of the myocardium supplied by the involved coronary artery. cafs are seen in 0.05–0.25% of patients undergoing conventional angiography.30 in this study, the prevalence of cafs was 0.089%. this study had some limitations. this was a single centre experience and some important clinical characteristics of the patients included in this study were not documented due to its retrospective nature. in addition, minor caas, including coronary artery ectasia, aneurysm and variant origins of the conus artery were excluded. mb was also excluded due to uncertainty about diagnostic and classification criteria. conclusion the prevalence of caas in oman was similar to reported figures from earlier studies performed worldwide. in oman, anomalous origin of the rca arising from the lcs was the most common type. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. zukić f, miljko m, vegar-zubović s, behmen a, arapović ak. prevalence of coronary artery anomalies detected by coronary ct angiography in canton sarajevo, bosnia and herzegovina. psychiatr danub 2017; 29:830–4. 2. smettei oa, sayed s, abazid rm. the prevalence of coronary artery anomalies in qassim province detected by cardiac computed tomography angiography. j saudi heart assoc 2017; 29:84–9. https://doi.org/10.1016/j.jsha.2016.07.006. 3. sirasapalli cn, christopher j, ravilla v. prevalence and spec trum of coronary artery anomalies in 8021 patients: a single centre study in south india. indian heart j 2018; 70:852–6. https://doi.org/10.1016/j.ihj.2018.01.035. 4. kardos a, babai l, rudas l, gaál t, horváth t, tálosi l, et al. epidemiology of congenital coronary artery anomalies: a coronary arteriography study on a central european population. cathet cardiovasc diagn 1997; 42:270–5. https://doi.org/10.1002/(sici) 1097-0304(199711)42:3<270::aid-ccd8>3.0.co;2-9. 5. graidis c, dimitriadis d, karasavvidis v, dimitriadis g, argyropoulou e, economou f, et al. prevalence and charact eristics of coronary artery anomalies in an adult population undergoing multidetector-row computed tomography for the evaluation of coronary artery disease. bmc cardiovasc disord 2015; 15:112. https://doi.org/10.1186/s12872-015-0098-x. 6. kim sy, seo jb, do kh, heo jn, lee js, song jw, et al. coronary artery anomalies: classification and ecg-gated multi-detector row ct findings with angiographic correlation. radiographics 2006; 26:317–34. https://doi.org/10.1148/rg.262055068. https://doi.org/10.1016/j.jsha.2016.07.006 https://doi.org/10.1016/j.ihj.2018.01.035 https://doi.org/10.1002/%28sici%291097-0304%28199711%2942:3%3c270::aid-ccd8%3e3.0.co%3b2-9 https://doi.org/10.1002/%28sici%291097-0304%28199711%2942:3%3c270::aid-ccd8%3e3.0.co%3b2-9 https://doi.org/10.1186/s12872-015-0098-x https://doi.org/10.1148/rg.262055068 rashid s. al-umairi, faiza al-kindi and saqar al-tai clinical and basic research | e113 7. garg n, tewari s, kapoor a, gupta dk, sinha n. primary congenital anomalies of the coronary arteries: a coronary arter iographic study. int j cardiol 2000; 74:39–46. https://doi.org/10.1 016/s0167-5273(00)00243-6. 8. cox id, bunce n, fluck ds. failed sudden cardiac death in a patient with an anomalous origin of the right coronary artery. circulation 2000; 102:1461–2. https://doi.org/10.1161/01.cir.1 02.12.1461. 9. cheezum mk, ghoshhajra b, bittencourt ms, hulten ea, bhatt a, mousavi n, et al. anomalous origin of the coronary artery arising from the opposite sinus: prevalence and outcomes in patients undergoing coronary cta. eur heart j cardiovasc imaging 2017; 18:224–35. https://doi.org/10.1093/ehjci/jev323. 10. al umairi rs, al kindi f, al busaidi f. anomalous origin of the left coronary artery from the pulmonary artery: the role of multislice computed tomography (msct). oman med j 2016; 31:387–9. https://doi.org/10.5001/omj.2016.77. 11. namgung j, kim ja. the prevalence of coronary anomalies in a single center of korea: origination, course, and termina tion anomalies of aberrant coronary arteries detected by ecggated cardiac mdct. bmc cardiovasc disord 2014; 14:48. https://doi.org/10.1186/1471-2261-14-48. 12. möhlenkamp s, hort w, ge j, erbel r. update on myocardial bridging. circulation 2002; 106:2616–22. https://doi.org/10.11 61/01.cir.0000038420.14867.7a. 13. kim pj, hur g, kim sy, namgung j, hong sw, kim yh, et al. frequency of myocardial bridges and dynamic compression of epicardial coronary arteries: a comparison between computed tomography and invasive coronary angiography. circulation 2009; 119:1408–16. https://doi.org/10.1161/circulationaha.108.788901. 14. leschka s, koepfli p, husmann l, plass a, vachenauer r, gaemperli o, et al. myocardial bridging: depiction rate and mor phology at ct coronary angiography--comparison with con ventional coronary angiography. radiology 2008; 246:754–62. https://doi.org/10.1148/radiol.2463062071. 15. hwang jh, ko sm, roh hg, song mg, shin jk, chee hk, et al. myocardial bridging of the left anterior descending coronary artery: depiction rate and morphologic features by dual-source ct coronary angiography. korean j radiol 2010; 11:514–21. https://doi.org/10.3348/kjr.2010.11.5.514. 16. gräni c, benz dc, schmied c, vontobel j, possner m, clerc of, et al. prevalence and characteristics of coronary artery anom alies detected by coronary computed tomography angiography in 5634 consecutive patients in a single centre in switzerland. swiss med wkly 2016; 146:w14294. https://doi.org/10.4414/ smw.2016.14294. 17. tavakol m, ashraf s, brener sj. risks and complications of coronary angiography: a comprehensive review. glob j health sci 2012; 4:65–93. https://doi.org/10.5539/gjhs.v4n1p65. 18. schmitt r, froehner s, brunn j, wagner m, brunner h, cherevatyy o, et al. congenital anomalies of the coronary arteries: imaging with contrast-enhanced, multidetector computed tomo graphy. eur radiol 2005; 15:1110–21. https://doi.org/10.1007/s0 0330-005-2707-z. 19. john j, miller jh, leslie sj. a case of anomalous coronary art ery origin: the role of computerised tomography. sage open med case rep 2016; 4:2050313x16628729. https://doi.org/10.1 177/2050313x16628729. 20. fujimoto s, kondo t, orihara t, sugiyama j, kondo m, kodama t, et al. prevalence of anomalous origin of coronary artery detec ted by multi-detector computed tomography at one center. j cardiol 2011; 57:69–76. https://doi.org/10.1016/j.jjcc.2010.10.006. 21. xu h, zhu y, zhu x, tang l, xu y. anomalous coronary arte ries: depiction at dual-source computed tomographic coronary angiography. j thorac cardiovasc surg 2012; 143:1286–91 https://doi.org/10.1016/j.jtcvs.2011.11.025. 22. amado j, carvalho m, ferreira w, gago p, gama v, bettencourt n. coronary arteries anomalous aortic origin on a computed tomo graphy angiography population: prevalence, characteristics and clinical impact. int j cardiovasc imaging 2016; 32:983–90. https://doi.org/10.1007/s10554-016-0849-5. 23. basso c, maron bj, corrado d, thiene g. clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. j am coll cardiol 2000; 35:1493–501. https://doi.org/10.1016/s0 735-1097(00)00566-0. 24. sun z, choo gh, ng kh. coronary ct angiography: current status and continuing challenges. br j radiol 2012; 85:495–510. https://doi.org/10.1259/bjr/15296170. 25. wu gr, saini a, ahmed i, finch c. interarterial course of anom alous right coronary artery: pathophysiology, diagnosis, and treat ment. radiol case rep 2017; 12:664–7. https://doi.org/10.1016/ j.radcr.2017.06.006. 26. sohrabi b, habibzadeh a, abbasov e. the incidence and pattern of coronary artery anomalies in the north-west of iran: a coronary arteriographic study. korean circ j 2012; 42:753–60. https://doi.org/10.4070/kcj.2012.42.11.753. 27. said sa, de voogt wg, bulut s, han j, polak p, nijhuis rl, et al. coronary artery disease in congenital single coronary artery in adults: a dutch case series. world j cardiol 2014; 6:196–204. https://doi.org/10.4330/wjc.v6.i4.196. 28. bozlar u, uğurel mş, sarı s, akgün v, örs f, taşar m. prevalence of dual left anterior descending artery variations in ct angiography. diagn interv radiol 2015; 21:34–41. https://doi.org/10.5152/dir.2 014.14275. 29. al-umairi rs, al-kindi fa, al-tai sa. a new variant of dual left anterior descending artery anomaly: type xi. 2018; 18:e386–8. https://doi.org/10.18295/squmj.2018.18.03.021. 30. zenooz na, habibi r, mammen l, finn jp, gilkeson rc. coronary artery fistulas: ct findings. radiographics 2009; 29:781–9. https://doi.org/10.1148/rg.293085120. https://doi.org/10.1016/s0167-5273%2800%2900243-6 https://doi.org/10.1016/s0167-5273%2800%2900243-6 https://doi.org/10.1161/01.cir.102.12.1461 https://doi.org/10.1161/01.cir.102.12.1461 https://doi.org/10.1093/ehjci/jev323 https://doi.org/10.5001/omj.2016.77 https://doi.org/10.1186/1471-2261-14-48 https://doi.org/10.1161/01.cir.0000038420.14867.7a https://doi.org/10.1161/01.cir.0000038420.14867.7a https://doi.org/10.1161/circulationaha.108.788901 https://doi.org/10.1148/radiol.2463062071 https://doi.org/10.3348/kjr.2010.11.5.514 https://doi.org/10.4414/smw.2016.14294 https://doi.org/10.4414/smw.2016.14294 https://doi.org/10.5539/gjhs.v4n1p65 https://doi.org/10.1007/s00330-005-2707-z https://doi.org/10.1007/s00330-005-2707-z https://doi.org/10.1177/2050313x16628729 https://doi.org/10.1177/2050313x16628729 https://doi.org/10.1016/j.jjcc.2010.10.006 https://doi.org/10.1016/j.jtcvs.2011.11.025 https://doi.org/10.1007/s10554-016-0849-5 https://doi.org/10.1016/s0735-1097%2800%2900566-0 https://doi.org/10.1016/s0735-1097%2800%2900566-0 https://doi.org/10.1259/bjr/15296170 https://doi.org/10.1016/j.radcr.2017.06.006 https://doi.org/10.1016/j.radcr.2017.06.006 https://doi.org/10.4070/kcj.2012.42.11.753 https://doi.org/10.4330/wjc.v6.i4.196 https://doi.org/10.5152/dir.2014.14275 https://doi.org/10.5152/dir.2014.14275 https://doi.org/10.18295/squmj.2018.18.03.021 https://doi.org/10.1148/rg.293085120 a narrative synthesis of qualitative studies conducted to assess patient safety culture in hospital settings *hamad alqattan,1 zoe morrison,2 jennifer a. cleland3 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e91–98, epub. 8 sep 19 submitted 11 oct 18 revision req. 9 dec 18; revision recd. 23 dec 18 accepted 10 jan 19 1department of medical education, university of aberdeen, aberdeen, scotland; 2department of human resources & organisational behaviour, university of greenwich, london, uk; 3centre for healthcare education research and innovation (cheri), university of aberdeen, aberdeen, uk *corresponding author’s e-mail: r01haha@abdn.ac.uk in 1999, the institute of medicine’s to err is human highlighted that a considerable number of patients die annually in the usa as a result of avoidable medical errors.1 since this seminal publication, healthcare professionals and leaders have been more alert to the role of human factors in providing safe health care services.1 evidence suggests that organisational patient safety culture (psc) plays a critical role in determining patient safety outcomes such as medication errors, hosp ital-acquired infections and post-operative complications.2 knowledge about the extent to which healthcare prov iders perceive patient safety is an important initial step for improving psc in healthcare organisations.3 psc is an abstract concept and is difficult to measure; there is a need to develop an understanding of healthcare providers’ attitudes and behaviours related to patient safety. furthermore, healthcare providers should use this understanding to form interventions addressing patient safety issues.4 the vast majority of studies examining psc in healthcare organisations have adopted quantitative survey methods such as the hospital survey on patient safety culture (hsopsc), safety attitudes questionnaire and culture of safety survey.5 these tools were designed to evaluate healthcare providers’ perceptions of the diff erent dimensions of psc (e.g. leadership support, non review نبذة وصفية من الدراسات النوعية اليت أجريت لتقييم ثقافة سالمة املرضى يف بيئة املستشفيات حمد القطان، زوي موري�شون، جينيفري كليالند abstract: this review aimed to identify methodological aspects of qualitative studies conducted to assess patient safety culture (psc) in hospital settings. searches of google scholar (google llc, menlo park, california, usa), medline® (national library of medicine, bethesda, maryland, usa), embase (elsevier, amsterdam, netherlands), psycinfo (american psychological association, washington, district of columbia, usa) and web of science (clarivate analytics, philadelphia, pennsylvania, usa) databases were used to identify qualitative articles published between 2000 and 2017 that focused on psc. a total of 22 studies were included in this review and analysis of methodological approaches showed that most researchers adopted purposive sampling, individual interviews, inductive content and thematic analysis. psc was affected by factors related to staffing, communication, nonhuman resources, organisation and patient-related factors. most studies lacked theoretical frameworks. however, many commonalities were found across studies. therefore, it is recommended that future studies adopt a mixed methods approach to gain a better understanding of psc. keywords: patient safety; culture; needs assessment; qualitative research. بيئة يف املر�شى �شالمة ثقافة لتقييم اأجريت التي النوعية للدرا�شات املنهجية اجلوانب حتديد اإىل املراجعة هذه تهدف امللخ�ص: امل�شت�شفيات. وقد اأجريت عملية املراجعة باإ�شتخدام قاعدة البيانات، مثقف البحث من جوجل )جوجل، مينلو بارك، كاليفورنيا، الواليات املتحدة االأمريكية(، ميدالين )املكتبة الوطنية للطب، بيثي�شدا، مرييالند، الواليات املتحدة االأمريكية(، اأم بي�س )اإل�شفري، اأم�شرتدام، هولندا(، كالرفيت، العلوم )حتليالت �شبكة االأمريكية(، املتحدة الواليات كولومبيا، مقاطعة وا�شنطن، االأمريكية، النف�س علم اأنفو )جمعية �شيكو على ركزت والتي 2017 و 2000 عامي بني املن�شورة النوعية املقاالت لتحديد االأمريكية(، املتحدة الواليات بن�شلفانيا، فيالدلفيا، ثقافة �شالمة املر�شى. مت ت�شمني ما جمموعه 22 درا�شة يف هذه املراجعة وحتليل االأ�شاليب املنهجية التي اأظهرت اأن معظم الباحثني اعتمد اأخذ العينات الهادفة، واملقابالت ال�شخ�شية، واملحتوى اال�شتقرائي والتحليل املو�شوعي. تاأثرت ثقافة �شالمة املر�شى بالعوامل املتعلقة باملوظفني والتوا�شل واملوارد غري الب�رشية والتنظيم والعوامل املتعلقة باملري�س. واخلال�شة اأن معظم الدرا�شات كانت تفتقر اإىل االأطر النظرية. ومع ذلك، مت العثور على العديد من القوا�شم امل�شرتكة بني الدرا�شات. لذلك، يو�شى باأن تتبنى الدرا�شات امل�شتقبلية منهج طرق خمتلطة للح�شول على فهم اأف�شل لـثقافة �شالمة املر�شى. الكلمات املفتاحية: �شالمة املر�شى؛ ثقافة؛ تقييم االحتياجات؛ بحث نوعي. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.002 https://creativecommons.org/licenses/by-nd/4.0/ a narrative synthesis of qualitative studies conducted to assess patient safety culture in hospital settings e92 | squ medical journal, may 2019, volume 19, issue 2 punitive response to error, teamwork, job satisfaction, etc.).5 surveys are useful as they are economical, time efficient and allow for direct comparisons across various contexts.6 however, such questionnaires cannot provide an understanding of why certain responses are provided and fail to gather personal stories and experiences related to organisational safety culture.7 qualitative research approaches are typically used to understand attitudes and behaviours and therefore, have a greater potential to document personal experiences, feelings about and opinions of organisational safety culture than responses to pre-determined survey questions.5,8–10 this type of research uses either inductive or deductive reasoning.11 inductive approaches use patterns derived from data related to a particular phenomenon under study to construct theories, while deductive approaches use pre-existing theories in the literature as an analytical tool to gain insight into certain aspects of the data.11 in addition to the presence of different approaches in this field, a wide range of methods can be adopted for qualitative data collection (e.g. surveys, individual inter views and focus group discussions) and analysis (e.g. con tent analysis, thematic analysis and discourse analysis).12 this review aimed to evaluate the methodological aspects of existing qualitative studies which focused on psc in hospital settings. the objective was to provide an overview of study quality and identify gaps in knowledge which could then be addressed in future research. methods in this narrative synthesis of published studies, content analysis was used to describe the most commonly adopted qualitative methods in the included studies, and findings were quantified via frequency counts.13,14 thematic syntheses was used to explain the different factors underpinning patient safety in the included studies.15 the specific research questions for this review were: “what are the most widespread methods used in previous qualitative studies of psc in hospital settings?” and “what commonalities are there, if any, across studies, regarding factors affecting patient safety?”. to address these research questions, independent searches of google scholar (google llc, menlo park, california, usa), medline® (national library of med icine, bethesda, maryland, usa), embase (elsevier, amsterdam, netherlands), psycinfo (american psych ological association, washington, district of columbia, usa) and web of science (clarivate analytics, phila delphia, pennsylvania, usa) databases were conducted to identify studies on psc. to be included in this review, studies had to be: 1) published original articles that focused on healthcare providers’ perception of psc; 2) qualitative or mixed methods studies conducted in hospital settings; 3) published in english; and 4) published from january 2000 to december 2017 to focus on studies conducted between the publication of to err is human in 1999 and december 2017. studies were excluded if they only assessed a subset of psc, they did not have a methods section, they were opinion papers including anecdotal and discussion papers, editorials, letters to the editor, short communications, positions and expert opinion papers or theoretical literature reviews. the following search terms were collectively used when searching the databases: “patient safety culture” or “patient safety climate” or “perception of patient safety” or “safety culture” or “safety climate” or “patient safety and hospital”. abstracts of the identified articles were used to determine relevance of the study based on this review’s inclusion criteria. if a study’s relevance could not be determined from the abstract, the article was read in its entirety. five questions from the critical appraisal skills programme (casp) checklist were used to guide and standardise data extraction from the included articles.16 these questions were selected as they focus on the methodological aspects of qualitative studies such as appropriateness of research design, recruitment strategy, data collection and analysis and clarity of findings. answers to the selected question from the casp were coded and then thematically sorted into tables. sorted data relating to the identified methods were quant ified using microsoft excel, version 2013 (microsoft corporation, redmond, washington, usa). further thematic synthesis was carried out to identify factors affecting patient safety, develop descriptive sub-themes and generate analytical themes.17 results an initial database search revealed 390 articles relevant to psc assessment. duplicates (n = 139) were excluded and abstracts of the remaining 251 titles were used to decide relevance of the study based on the inclusion criteria. a summary of the search process is shown in figure 1. a total of 22 studies carried out between 2006–2017 were included in this review. of these, four studies were conducted in sweden, three studies each were conducted in the usa, china and iran and one study each was conducted in the uk, canada, finland, australia, brazil, uruguay, congo, ethiopia and bhutan. most studies (72.7%) were purely qualitative, while six studies used mixed methods approaches. the majority (81.8%) did not state an epistemological basis or tradition (foundation for the study design). of the four studies hamad alqattan, zoe morrison and jennifer a. cleland review | e93 which did report an epistemological basis, two used case studies, one used dialectic hermeneutics and one used social constructivism. the latter represents an overarching epistemological basis, whereas case studies and dialectic hermeneutics may be more accurately categorised as methods.18 most participants (59.1%) were selected using purposive or criterion sampling. individual face-toface interviews was the most frequent data collection technique (54.5%) followed by focus groups (18.2%). the majority of studies adopted content (50%) or thematic (22.7%) or both (9.1%) approaches to qualit ative data analysis as well as grounded theory, frame work analysis and template analysis (4.5% each). frame work analysis and template analysis are, broadly speaking, sub-branches of thematic approach.19,20 inductive, or data-driven, analysis was the preferred approach (72.7%) where as deductive data analysis using pre-established psc models was used only in six studies [table 1]. models differed in terms of numbers of psc dimensions, ranging from 6–12 dimensions in each model. they also differed by the labels given for each dimension; however, some dimensions shared similar meaning regarding teamwork, communication, leadership and other organisational and environmental characteristics [table 2]. despite being conducted in diverse contexts, many common factors were identified that related to facil itating or compromising patient safety. these factors were related to staffing, communication, non-human resources, organisational factors and patient-related factors. the number of available staff was commonly perceived as a determinant of patient safety.21–31 in general, participants believed that adequate staff numbers would help minimise workload and burnout and would sub sequently help them work more accurately and safely. in addition, staff attitudes were perceived as important. commitment to patient safety and compliance with clinical practice and patient safety standards were thought to play a vital role in determining the level of patient safety in the workplace.23–26,29,31–35 job satisfaction and staff turnover rate were also identified as key determinants of patient safety.25,32 communication factors commonly perceived as determinants of patient safety were teamwork, health care provider-patient relationships, handovers and tran sitions.22–29,32,33,35–37 for example, zhu et al.’s study found that feedback and communication concerning errors were seen as important determinants of patient safety.22 there was widespread agreement among the diff erent studies’ participants that the availability and appro priateness of non-human resources, including policies, procedures, equipment, supplies, the physical environ ment, technology and medical records in healthcare organisations were key factors for providing safe ser vices.21–25,27–35,37–39 study participants emphasised the importance of organisational factors, including staff training and cont inuous education, in improving patient safety.22,25–27,29,34 they also emphasised the role of leadership in creating a permissive and open working atmosphere which facilitates reporting and learning from mistakes.22–24,27,34,38 emphasis was also placed on the role of leadership in mentoring staff toward safe practices.22,25,30,32,37 patient-related factors were less frequently raised in the reviewed studies. however, patient numbers, under lying conditions, awareness of their condition and health literacy were all thought to contribute to patient safety [table 3].29,36,37 discussion theoretically, psc consists of objective aspects, like healthcare providers’ behaviours and practices related to patient safety, and subjective aspects such as their beliefs, values and attitudes about patient safety.40 these subjective aspects cannot be captured by quantitative survey-based methods, which only determine aspects about psc in a healthcare organisation at a particular period.41 qualitative methods can provide a more detailed understanding of psc in healthcare settings; however, this review showed that only a few studies adopted quali tative methods to explore this issue.9 most studies lacked clear conceptual or theoretical frameworks and used relatively direct approaches to data collection and analysis. these studies were carried out in diverse contexts and countries and showed variations between the groups under study. despite these differences, study findings shared commonalities regarding factors facilitating or compromising patient safety—such as figure 1: flow chart of the search process for articles on patient safety culture. a narrative synthesis of qualitative studies conducted to assess patient safety culture in hospital settings e94 | squ medical journal, may 2019, volume 19, issue 2 table 1: summary of the methods adopted in 22 studies on patient safety culture author and year of publication study design tradition sampling data collection technique data saturation form of data data analysis approach analytical model(s) used rathert et al.21 (2006) mixed methods not adopted whole population survey not applicable electronic data not stated not adopted zhu et al.22 (2012) qualitative not adopted purposive or criterion sampling focus group clarified audio records thematic analysis hsopsc framework lui et al.23 (2014) mixed methods not adopted opportunity and purposive sampling interview clarified audio records thematic analysis ssc model and hsopsc framework vaismoradi et al.24 (2014) qualitative not adopted purposive or criterion sampling interview and observation clarified audio records and field notes content analysis not adopted abdi et al.25 (2015) mixed methods case study critical case interview not clarified audio records framework analysis saq framework umpiérrez et al.26 (2015) qualitative dialectic hermeneutic purposive or criterion sampling interview clarified audio records content analysis not adopted wang et al.27 (2017) qualitative not adopted stratified sampling interview clarified audio records grounded theory hsopsc framework wami et al.28 (2016) mixed methods not adopted purposive or criterion sampling interview not clarified audio records content analysis not adopted pazokian et al.29 (2017) qualitative not adopted critical case interview clarified audio records content analysis not adopted tarling et al.30 (2017) mixed methods not adopted convenience sampling focus group not clarified audio records thematic analysis not adopted källberg et al.31 (2017) qualitative not adopted purposive or criterion sampling telephone interview not clarified audio records content analysis not adopted danielsson et al.32 (2014) qualitative not adopted purposive or criterion sampling interview and focus group not clarified audio records content analysis not adopted ridelberg et al.33 (2014) qualitative not adopted purposive or criterion sampling interview not clarified audio records content analysis vincent’s framework kanerva et al.34 (2016) qualitative not adopted purposive or criterion sampling interview not clarified audio records content analysis not adopted labat and sharma35 (2016) qualitative social constructivism purposive or criterion sampling interview not clarified audio records content analysis not adopted bishop and cregan36 (2015) qualitative not adopted purposive or criterion sampling interview not applicable video records thematic analysis not adopted jones37 (2014) qualitative not adopted purposive or criterion sampling focus group not clarified audio records content analysis not adopted dos reis et al.38 (2017) qualitative not adopted purposive or criterion sampling interview not clarified audio records content and thematic analysis not adopted pelzang et al.39 (2017) qualitative not adopted purposive or criterion sampling interview not clarified audio records content and thematic analysis not adopted elder et al.52 (2008) qualitative not adopted convenience sampling focus group not clarified audio records thematic analysis not adopted karlsson et al.53 (2011) qualitative not adopted whole population survey not applicable written data content analysis not adopted allen et al.54 (2010) mixed methods case study critical case interview and document audit not clarified audio records template analysis saq framework hsopsc = hospital survey on patient safety culture; ssc = sammer’s safety culture; saq = safety attitude questionnaire. hamad alqattan, zoe morrison and jennifer a. cleland review | e95 staffing, communication, non-human resources, organi sational factors and patient-related factors. most frontline staff (e.g. doctors, nurses and pharmacists) generally linked patient safety with the availability of appropriate systems and procedures to support patient safety in the workplace. managers embraced more proactive approaches for risk identification and management. this difference is reflected in the findings of surveys on psc conducted in different contexts.42–45 in addition, psc was not uniform across healthcare providers working even in a single hospital.41 evidence suggests that different patient safety subcultures within the same hospital are likely related to individual factors such as diverse healthcare providers that have different national, religious, educational and occupational backgrounds.40 this factor must be consid ered when exploring psc in hospital settings; however, further research is needed to examine this area. as previously mentioned, few studies have used theoretical models or categories offered by popular survey tools to categorise their data (deductive analysis). the benefits of using theoretical models or conceptual frameworks for qualitative data analysis can establish links between different concepts in the data and aid conceptual generalisability by illustrating how findings from one context are transferable to other contexts.12,46,47 theoretical models were adopted in the included studies for two purposes. first, researchers of some studies int ended to develop a context-specific psc survey quest ionnaire based on the psc dimensions of an already established one. for example, both zhu et al. and wang et al. mentioned that the hsopsc was widely used in china to evaluate psc; however, they thought that the psc dimensions of this tool should be indigenised.22,27 therefore, they used the hsopsc model as an analyt ical tool in their qualitative inquiry in order to create a model applicable to the chinese setting.22,27 second, theo retical models were adopted when data could fit in a particular pre-existing theoretical model. for example, ridelberg et al. conducted a qualitative study to identify facilitators and barriers for patient safety in a swedish hospital setting and adopted vincent’s model after data analysis since the data aligned with this model.33 another limitation noted in this review’s studies is that they were highly dependent on interviews and focus groups for data collection. while these techniques are good for exploring individual thoughts, experiences and shared idea, they have been criticised for being subjective—where participants can filter information before sharing it with the researchers. other qualitative approaches, such as an observational approach, may be useful in exploring actions and verbal communication and for gathering useful contextual data.12 for example, vaismoradi et al. used observations to gain a better under standing and interpretation of nursing leadership in medical and surgical wards.24 interestingly, qualitative studies seemed less prevalent in some contexts. for example, no qualitative or mixed methods studies were identified from the gulf corp oration council countries. however, elmontsri et al. reported that the hsopsc survey tool was adopted in 18 studies conducted in different arabic countries from 2005–2015.48 they also found that non-punitive response to errors and communication openness were problematic and impacted negatively on adverse events.48 qualitative approaches would be appropriate to explore the reasons behind these obstacles.49 these findings suggest that the focus of psc research is on the healthcare providers and managers and not table 2: comparison between the characteristics of four safety culture models55–57 characteristic hsopsc model55 saq model55 css model56 vincent’s model57 1 teamwork within units teamwork climate teamwork institutional context 2 teamwork across units perception of management leadership organisational and management factors 3 supervisor/manager expectations and actions promoting safety stress recognition learning work environment 4 management support for patient safety working conditions evidence-based team factors 5 staffing job satisfaction fair culture individual staff factors 6 overall perception of patient safety safety climate patient-centred care task factors 7 organisational learning which continues improvement communication patient characteristics 8 non-punitive response to error 9 handovers and transitions 10 open communication 11 feedback and communication about error 12 frequency of events reported hsopsc = hospital survey on patient safety culture; saq = safety attitudes questionnaire; css = culture of safety survey. a narrative synthesis of qualitative studies conducted to assess patient safety culture in hospital settings e96 | squ medical journal, may 2019, volume 19, issue 2 on the patient. when patients were included in studies, they demanded that healthcare providers create a closer relationship and communicate better; these concerns were not indicated by healthcare providers in the same studies. thus, patients appear to have a different pers pective on psc compared to providers. for example, davis et al.’s study evaluated the reporting of adverse event and medical errors that occurred during hospital stays.50 they found that patients’ (n = 80) reports of medical errors were not found in medical records.50 table 3: factors influencing patient safety culture22,24–33,35–38 categories quotation (speaker) staffing staff number “it is difficult to practice safely and take care of every detail of your work, when you deliver care to many patients.”(nurse)24 staff awareness and commitment to patient safety “i have undertaken education in patient safety. it was a course that i requested when i resigned as manager three years ago because i wanted to know a bit more about it.” (nurse)33 staff competency “the fact is that i just did not know what to do. these things are quite rare in your career.” (nurse)26 job satisfaction “a worker who is not well paid, at times he will say ‘but why i have to spend all my time at work and it doesn’t change anything in my monthly salary?” (provider)35 staff turnover “recently, many registered nurses have left because they have felt that there is too much pressure.” (nurse)32 staff compliance with policies and procedures “we [nurses] are supposed to double-check for high-alert medications, but it is not always done.” (nurse)25 communication teamwork “in my opinion patient safety is improved by teamwork/collaboration between healthcare prof essionals.” (nurse)28 healthcare providerpatient relation ship “i hope doctors or nurses alleviate my anxieties and doubts with their professional answers and psychological support.” (patient)27 handover “the first doctor that had seen vance had gone away for the weekend and we assumed erroneously that a handover had been done, that this doctor would be taking over vance’s care, but he didn’t even know vance was there. there was no handover.” (patient)36 feedback about error “in this unit, we discuss ways to prevent errors from happening again.” (nurse)22 power conflict “you will never be able to manage [the senior nurses].” (nurse)35 non-human resources availability of process and policies supporting patient safety “we have a checklist now and we check every single patient on the ward is safe.” (medical surgical ward group)30 equipment availability “sometimes gloves and syringes which seems simple were not found when we try to give medic ation.” (nurse)28 safety of physical environment “we have a laminated grip flooring. they can still have a fall but it is much better for them.” (medical ward group)30 availability of supporting technology “this computer system that we now have here makes it easier to find information, i think, and that is also part of patient safety.” (nurse)33 appropriateness of medical records “major security problems with complicated electronic health systems.” (doctor)31 organisational factors staff training and continuous education “i just did not know what to do. these things are quite rare in your career, nobody tells you what to do when things go wrong.” (nurse)26 openness “safety things are still seen as a burden, and it is not cool to speak up about them.” (general surgery resident)37 leadership supervision and inpatient safety process engagement “they (supervisors) have just ordered us to follow the protocols, but no one checks on us to see if we are doing so.” (nurse)25 non-punitive response to errors “a person who makes mistakes often is incompetent and should be fired.” (manager)27 staff participation in decision making “you have to listen to the people involved in the process. we have to raise issues and this can only happen if we listen to people who provide direct care.” (nurse)38 competing interest between public health and clinical services “the government usually emphasises the importance of public health in words but not in actions.” (manager)27 patient-related factors patient volume “services where volume is the highest, that is where things will fall through the cracks.” (general surgery resident)37 underlying illness “in my opinion, i have to look at the conditions of all the patients; separate rooms should be consid ered for patients who have the potential to disturb others.” (nurse)29 patient awareness and literacy “now young parents are well educated and usually learn relevant information on the internet before seeking care for their babies.” (provider)27 hamad alqattan, zoe morrison and jennifer a. cleland review | e97 following the example of king and coldham, the current authors tentatively propose that patients should be included in future psc studies to provide a broader perspective on the issue.51 quantitative and qualitative methods seek to address different questions and, therefore, one method cannot be superior to the other. however, a vast body of liter ature highlights the utility of mixed methods research in healthcare. future studies of psc should consider using both qualitative and quantitative approaches simultan eously or sequentially to gain a comprehensive underst anding of psc in a particular healthcare organisation.21,23,25 while narrative synthesis helped to answer the current research questions, it had two limitations. first, only empirical studies written in english were included. relevant data from non-english articles could provide valid input to this narrative synthesis. however, english is common in the scientific field and is nowadays used in the vast majority of published studies. second, the search was limited to electronic databases. literature was not searched by hand and authors were not contacted to seek out unpublished works. although this approach may have limited the number of studies included in this review, yet all included studies have been published in peer-reviewed journals. conclusion this review focused on a relatively small number of studies using qualitative approaches to explore psc in hospital settings. most studies lacked conceptual or theo retical frameworks. despite this finding, there were many commonalities across diverse studies. future studies should adopt a mixed methods approach to help gain knowledge of psc in everyday workplaces. such an approach would improve understanding of staff knowl edge, attitude toward patient safety and help identify strategies to enhance patient safety. references 1. leape ll, berwick dm. five years after to err is human: what have we learned? jama 2005; 293:2384–90. https://doi. org/10.1001/jama.293.19.2384. 2. the health foundation. evidence scan: does improving safety culture affect patient outcomes? from: www.health.org.uk/sit e s/def ault/file s/d o e simprov ingsafe tycultureaffe ctpati entoutcomes.pdf. accessed: dec 2018. 3. martin wf. is your hospital safe? disruptive behavior and work place bullying. hosp top 2008; 86:21–8. https://doi.org/10.320 0/htps.86.3.21-28. 4. talati z, griffin m. patient safety culture and organizational beh aviour: intergrating error, leadership and the working environ ment. in: waterson p, ed. patient safety culture theory, method and application. 1st ed. boca raton, usa: crc press, 2017. pp. 43–6. 5. colla jb, bracken ac, kinney lm, weeks wb. measuring patient safety climate: a review of surveys. qual saf health care 2005; 14:364–6. https://doi.org/10.1136/qshc.2005.014217. 6. nieva vf, sorra j. safety culture assessment: a tool for improving patient safety in healthcare organizations. qual saf health care 2003; 12:ii17–23. https://doi.org/10.1136/qhc.12.suppl_2.ii17. 7. mcleod sa. questionnaire. from: www.simplypsychology.org/ questionnaires.html accessed: dec 2018. 8. cleland j. exploring versus measuring: considering the funda mental differences between qualitative and quantitative research. in: cleland j, durning sj, ed. researching medical education. new jersey, usa: wiley, 2015. pp. 1–14. https://doi.org/10.10 02/9781118838983.ch1. 9. pumar-méndez mj, attree m, wakefield a. methodological aspects in the assessment of safety culture in the hospital setting: a review of the literature. nurse educ today 2014; 34:162–70. https://doi.org/10.1016/j.nedt.2013.08.008. 10. rahman ms. the advantages and disadvantages of using qualitative and quantitative approaches and methods in language “testing and assessment” research: a literature review. j edu learn 2017; 6:102–12. https://doi.org/10.5539/jel.v6n1p102. 11. ormston r, spencer l, barnard m, snape d. the foundations of qualitative research. in: ritchie j, lewis j, nicholls c, ormston r, eds. qualitative research practice. 2nd ed. thousand oaks, california, usa: sage publications ltd, 2014. pp. 1–26. 12. hays dg, singh aa. qualitative inquiry in clinical and educ ational settings. 1st ed. new york, usa: the guilford press, 2011. 13. thomas j, harden a, newman m. synthesis: combining results systematically and appropriately. in: gough d, oliver s, thomas j, eds. an introduction to systematic reviews. thousand oaks, usa: sage publications ltd, 2012. pp. 179–227. 14. mays n, pope c, popay j. systematically reviewing qualitative and quantitative evidence to inform management and policymaking in the health field. j health serv res policy 2005; 1:6–20. https://doi.org/10.1258/1355819054308576. 15. thomas j, harden a. methods for the thematic synthesis of qualitative research in systematic reviews. bmc med res methodol 2008; 8:45. https://doi.org/10.1186/1471-2288-8-45. 16. critical appraisal skills programme. casp checklist. from: casp-uk.net/wp-content/uploads/2018/03/casp-qualitativechecklist-2018_fillable_form.pdf accessed: dec 2018. 17. snilstveit b, oliver s, vojtkova m. narrative approaches to systematic review and synthesis of evidence for international development policy and practice. j dev effect 2012; 4:409–29. https://doi.org/10.1080/19439342.2012.710641. 18. crotty m. the foundations of social research: meaning and perspective in social research. 1st ed. thousand oaks, california, usa: sage publications ltd, 1998. 19. gale nk, heath g, cameron e, rashid s, redwood s. using the framework method for the analysis of qualitative data in multidisciplinary health research. bmc med res methodol 2013; 13:117. https://doi.org/10.1186/1471-2288-13-117. 20. brooks j, mccluskey s, turley e, king n. the utility of template analysis in qualitative psychology research. qual res psychol 2015; 12:202–22. https://doi.org/10.1080/14780887.2014.955224. 21 rathert c, fleig-palmer mm, palmer dk. minimizing medical errors: a qualitative analysis of health care providers' views on improving patient safety. j appl manag entrep 2006; 11:5. 22. zhu j, li l, li y, shi m, lu h, garnick dw, et al. what const itutes patient safety culture in chinese hospitals? int j qual health care 2012; 24:250–7. https://doi.org/10.1093/intqhc/mzs010. 23. liu c, liu w, wang y, zhang z, wang p. patient safety culture in china: a case study in an outpatient setting in beijing. bmj qual saf 2014; 23:556–64. https://doi.org/10.1136/bmjqs-2 013-002172. https://doi.org/10.1001/jama.293.19.2384 https://doi.org/10.1001/jama.293.19.2384 https://doi.org/10.3200/htps.86.3.21-28 https://doi.org/10.3200/htps.86.3.21-28 https://doi.org/10.1136/qshc.2005.014217 https://doi.org/10.1136/qhc.12.suppl_2.ii17 https://doi.org/10.1002/9781118838983.ch1 https://doi.org/10.1002/9781118838983.ch1 https://doi.org/10.1016/j.nedt.2013.08.008 https://doi.org/10.5539/jel.v6n1p102 https://doi.org/10.1258/1355819054308576 https://doi.org/10.1186/1471-2288-8-45 https://doi.org/10.1080/19439342.2012.710641 https://doi.org/10.1186/1471-2288-13-117 https://doi.org/10.1080/14780887.2014.955224 https://doi.org/10.1093/intqhc/mzs010 https://doi.org/10.1136/bmjqs-2013-002172 https://doi.org/10.1136/bmjqs-2013-002172 a narrative synthesis of qualitative studies conducted to assess patient safety culture in hospital settings e98 | squ medical journal, may 2019, volume 19, issue 2 24. vaismoradi m, bondas t, salsali m, jasper m, turunen h. facilitating safe care: a qualitative study of iranian nurse leaders. j nurs manag 2014; 22:106–16. https://doi.org/10.1111/j.13652834.2012.01439.x. 25. abdi z, delgoshaei b, ravaghi h, abbasi m, heyrani a. the culture of patient safety in an iranian intensive care unit. j nurs manag 2015; 23:333–45. https://doi.org/10.1111/jonm.12135. 26. umpiérrez af, fort zf, tomás vc. adverse events in health and nursing care: patient safety from the standpoint of the professional's experience. text context nurs 2015; 24:310–15. https://doi.org/10.1590/0104-07072015000122014. 27. wang y, liu w, shi h, liu c, wang y. measuring patient safety culture in maternal and child health institutions in china: a qualitative study. bmj open 2017; 7:e015458. https://doi.org/10.1 136/bmjopen-2016-015458. 28. wami sd, demssie af, wassie mm, ahmed an. patient safety culture and associated factors: a quantitative and qualitative study of healthcare workers’ view in jimma zone hospitals, south west ethiopia. bmc health serv res 2016; 16:495. https://doi. org/10.1186/s12913-016-1757-z. 29. pazokian m, borhani f. nurses’ perspectives on factors affecting patient safety: a qualitative study. evid based care j 2017; 7:76–81. https://doi.org/10.22038/ebcj.2017.24174.1520. 30. tarling m, jones a, murrells t, mccutcheon h. comparing safety climate for nurses working in operating theatres, critical care and ward areas in the uk: a mixed methods study. bmj open 2017; 7:e016977. https://doi.org/10.1136/bmjopen-2017-0 16977. 31. källberg as, ehrenberg a, florin j, östergren j, göransson ke. physicians' and nurses' perceptions of patient safety risks in the emergency department. int emerg nurs 2017; 33:14–19. https://doi.org/10.1016/j.ienj.2017.01.002. 32. danielsson m, nilsen p, ohrn a, rutberg h, fock j, carlfjord s. patient safety subcultures among registered nurses and nurse assistants in swedish hospital care: a qualitative study. bmc nurs 2014; 13:39. https://doi.org/10.1186/s12912-014-0039-5. 33. ridelberg m, roback k, nilsen p. facilitators and barriers infl uencing patient safety in swedish hospitals: a qualitative study of nurses’ perceptions. bmc nurs 2014; 13:23. https://doi.org/10. 1186/1472-6955-13-23. 34. kanerva a, lammintakanen j, kivinen t. nursing staff 's perc eptions of patient safety in psychiatric inpatient care. perspect psychiatr care 2016; 52:25–31. https://doi.org/10.1111/ppc.12098. 35. labat f, sharma a. qualitative study exploring surgical team members' perception of patient safety in conflict-ridden eastern democratic republic of congo. bmj open 2016; 6:e009379. https://doi.org/10.1136/bmjopen-2015-009379. 36. bishop ac, cregan br. patient safety culture: finding meaning in patient experiences. int j health care qual assur 2015; 28:595–610. https://doi.org/10.1108/ijhcqa-03-2014-0029. 37. jones dl. residents' perspectives on patient safety in university and community teaching hospitals. j grad med educ 2014; 6:603–7. https://doi.org/10.4300/jgme-d-14-00350.1. 38. dos reis gax, hayakawa ly, murassaki acy, matsuda lm, gabriel cs, de oliveira mlf. nurse manager perceptions of patient safety strategy implementation. text context nurs 2017; 26:e00340016. https://doi.org/10.1590/0104-07072017000340016. 39. pelzang r, johnstone m, hutchinson am. culture matters: indigenizing patient safety in bhutan. health policy plan 2017; 32:1042–8. https://doi.org/10.1093/heapol/czx042. 40. guldenmund f. organizational safety culture principles. in: waterson p, ed. patient safety culture: theory, methods and appl ication. 1st ed. boca raton, usa: crc press, 2014. pp. 15–36. 41. lardner r. safety culture application guide. from: http://epsc. be/prism/_/fg1safety_culture_guide.doc accessed: dec 2018. 42. gershon rr, karkashian cd, grosch jw, murphy lr, escamilla cejudo a, flanagan pa, et al. hospital safety climate and its relationship with safe work practices and workplace exposure incidents. am j infect control 2000; 28:211–21. https://doi.org/10.1 067/mic.2000.105288. 43. alharbi w, cleland j, morrison z. assessment of patient safety culture in an adult oncology department in saudi arabia. oman med j 2018; 33:200–8. https://doi.org/10.5001/omj.2018.38. 44. huang ch, wu hh, lee yc. the perceptions of patient safety culture: a difference between physicians and nurses in taiwan. appl nurs res 2018; 40:39–44. https://doi.org/10.1016/j.apnr.2 017.12.010. 45. alqattan h, cleland j, morrison z. an evaluation of patient safety culture in a secondary care setting in kuwait. j taibah univ sci 2018; 13:272–80. https://doi.org/10.1016/j.jtumed.201 8.02.002. 46. davidoff f, dixon-woods m, leviton l, michie s. demystifying theory and its use in improvement. bmj qual saf 2015; 24:228–38. https://doi.org/10.1136/bmjqs-2014-003627. 47. o'donnell ca, mair fs, dowrick c, brún mo, brún t, burns n, et al. supporting the use of theory in cross-country health ser vices research: a participatory qualitative approach using nor malisation process theory as an example. bmj open 2017; 7:e014289. https://doi.org/10.1136/bmjopen-2016-014289. 48. elmontsri m, almashrafi a, banarsee r, majeed a. status of patient safety culture in arab countries: a systematic review. bmj open 2017; 7:e013487. https://doi.org/10.1136/bmjopen-2 016-013487. 49. savin-baden m, major ch. qualitative research: the essential guide to theory and practice. abingdon-on-thames, uk: rout ledge, 2013. 50. davis re, sevdalis n, neale g, massey r, vincent ca. hospital patients' reports of medical errors and undesirable events in their health care. j eval clin pract 2013; 19:875–81. https://doi. org/10.1111/j.1365-2753.2012.01867.x. 51. king e, coldham t. patients and carers can be our service design consultants. from: www.england.nhs.uk/blog/tina-cold ham/ accessed: dec 2018. 52. elder nc, brungs sm, nagy m, kudel i, render ml. intensive care unit nurses' perceptions of safety after a highly specific safety intervention. qual saf health care 2008; 17:25–30. https://doi.org/10.1136/qshc.2006.021949. 53. karlsson g, hedman k, fridlund b. views on patient safety by operations managers in somatic hospital care: a qualitative ana lysis. open j nurs 2011; 1:33–42. https://doi.org/10.4236/ojn.20 11.13005. 54. allen s, chiarella m, homer cs. lessons learned from meas uring safety culture: an australian case study. midwifery 2010; 26:497–503. https://doi.org/10.1016/j.midw.2010.07.002. 55. itoh k, anderson h, milkkelsen k. safety culture dimensions, patient safety outcomes and their correlations. in: waterson p, ed. patient safety culture theory, method and application. boca raton, usa: crc press, 2017. pp. 67–71. 56. sammer ce, lykens k, singh kp, mains da, lackan na. what is patient safety culture? a review of the literature. j nurs scholarsh 2010; 42:156–65. https://doi.org/10.1111/j.1547-506 9.2009.01330.x. 57. vincent c, taylor-adams s, stanhope n. framework for ana lysing risk and safety in clinical medicine. bmj 1998; 316:1154–7. https://doi.org/10.1136/bmj.316.7138.1154. https://doi.org/10.1111/j.1365-2834.2012.01439.x https://doi.org/10.1111/j.1365-2834.2012.01439.x https://doi.org/10.1111/jonm.12135 https://doi.org/10.1590/0104-07072015000122014 https://doi.org/10.1136/bmjopen-2016-015458 https://doi.org/10.1136/bmjopen-2016-015458 https://doi.org/10.1186/s12913-016-1757-z https://doi.org/10.1186/s12913-016-1757-z https://doi.org/10.22038/ebcj.2017.24174.1520 https://doi.org/10.1136/bmjopen-2017-016977 https://doi.org/10.1136/bmjopen-2017-016977 https://doi.org/10.1016/j.ienj.2017.01.002 https://doi.org/10.1186/s12912-014-0039-5 https://doi.org/10.1186/1472-6955-13-23 https://doi.org/10.1186/1472-6955-13-23 https://doi.org/10.1111/ppc.12098 https://doi.org/10.1136/bmjopen-2015-009379 https://doi.org/10.1108/ijhcqa-03-2014-0029 https://doi.org/10.4300/jgme-d-14-00350.1 https://doi.org/10.1590/0104-07072017000340016 https://doi.org/10.1093/heapol/czx042 https://doi.org/10.1067/mic.2000.105288 https://doi.org/10.1067/mic.2000.105288 https://doi.org/10.5001/omj.2018.38 https://doi.org/10.1016/j.apnr.2017.12.010 https://doi.org/10.1016/j.apnr.2017.12.010 https://doi.org/10.1016/j.jtumed.2018.02.002 https://doi.org/10.1016/j.jtumed.2018.02.002 https://doi.org/10.1136/bmjqs-2014-003627 https://doi.org/10.1136/bmjopen-2016-014289 https://doi.org/10.1136/bmjopen-2016-013487 https://doi.org/10.1136/bmjopen-2016-013487 https://doi.org/10.1111/j.1365-2753.2012.01867.x https://doi.org/10.1111/j.1365-2753.2012.01867.x https://doi.org/10.1136/qshc.2006.021949 https://doi.org/10.4236/ojn.2011.13005 https://doi.org/10.4236/ojn.2011.13005 https://doi.org/10.1016/j.midw.2010.07.002 https://doi.org/10.1111/j.1547-5069.2009.01330.x https://doi.org/10.1111/j.1547-5069.2009.01330.x https://doi.org/10.1136/bmj.316.7138.1154 1department of microbiology, royal hospital, muscat, oman; 2department of epidemiology, ministry of health, muscat, oman; 3 department of infectious diseases, royal hospital, muscat, oman; 4central public health laboratory, ministry of health, muscat, oman *corresponding author email: jalila76.mohsin@gmail.com squ med j, december 2010, vol. 10, iss. 3, pp. 326-334, epub. 14th nov 10 submitted 23rd june 10 revision req. 1st aug 10, revision recd. 17th aug 10 accepted 30th aug 10 a<dh1n1e<<<]àfiá◊àfi^e<·áe^íπ]<óïüπ] ·^€�√e<ífi^�◊ä÷]<óàéjäπ]<ª<·êçœüπ]< 2009<2€äëå<±]<áè÷áë<‡⁄<ï3à◊÷<ín÷^m<<ìë^¬ö<óàéjä⁄<ìeüü  ah1n1   ah1n1 131 2009 31 23     %63 %34.4 24  %83%89.3%99.3  %22.9 %75.7%57.3 %64.5%70.8    %75 %95.4%60.6 %88.9%6.9 48  ah1n1   %9.6  ah1n1 abstract: objectives: : the aim of this study was to describe the clinical characteristics, risk factors, laboratory investigations and outcome of hospitalised patients with positive influenza a (h1n1) at the royal hospital in oman. methods: we extracted data from the retrospective medical charts, radiological and laboratory findings of 131 patients who were confirmed as positive for influenza a (h1n1) by real-time reverse-transcriptasepolymerase-chain-reaction from 21 july to 23 december 2009. results: the median age was 24 years with 34.4% in the paediatric age group. most (63%) of hospitalised patients were female. symptoms at presentation included mainly fever (93.9%) and respiratory symptoms (89.3%). 83% of the patients had at least one risk factor and pregnancy was the most common associated condition (22.9%). most of the patients had reduced lymphocytic count (57.3%) and high levels of serum c-reactive protein, aspartate transaminase and lactate dehydrogenase (75.7%, 75% and 70.8% respectively). the majority of the patients (64.5%) had evidence of pneumonia and radiological findings constituted mainly bi-lateral infiltrates (60.6%). antiviral therapy was administered to 95.4% of the patients who mostly received it 48 hours after disease onset. death occurred in 6.9% of patients. out of these, 88.9% required intensive care unit (icu) care and mechanical ventilation. conclusion: influenza a (h1n1) infection mainly affected those of younger age and females. associated medical conditions were common, clinical & basic researchclinical & basic research hospitalised patients with influenza a (h1n1) in the royal hospital, oman experience of a tertiary care hospital, july–december 2009 *jalila al-lawati,1 nada al-tamtami,1 ahmed al-qasmi,2 amina al-jardani,1 saif al-abri,3 sulaiman al busaidy4 jalila al-lawati, nada al-tamimi, ahmed al-qasmi, amina al-jardani, saif al-abri, and sulaiman al busaidy clinical and basic research | 327 advances in knowledge this study adds to the literature on the data on the epidemiological and clinical characteristics of the pandemic influenza a (h1n1) especially in the middle east region. application to patient care information on the clinical spectrum of illness and risk factors for severity among people who were hospitalised at a tertiary hospital in oman will substantially influence the clinical management, infection control policies and future preparedness plans. in spring 2009, the united states centers for disease control and prevention (cdc) reported an occurrence of 2009 influenza a (h1n1) in mexico and california.1,2 it was subsequently reported in virtually all countries.3 the world health organization (who) declared the "first" phase 6 global influenza pandemic of the century on 11 june 2009.4 as of 20 december 2009, more than 208 countries had reported laboratory confirmed cases of pandemic influenza a (h1n1) 2009, including at least 11,516 deaths.4 in oman, as of 2 january 2010, the ministry of health (moh) announced that the total number of confirmed influenza a (h1n1) positive cases was 7,040 with 31 deaths.5 the who update on the 20 december 2009 stated that oman had a declining trends of respiratory disease activity after a peak in november 2009.4 weekly reports on pandemic influenza a (h1n1) from oman are available in the moh website;5 however, descriptive data on hospitalised patients has not so far been published. this study describes the clinical characteristics, risk factors, laboratory investigations and outcome of hospitalised patients, including health care workers, with positive influenza a (h1n1) between 21st july 2009 and 23rd december 2009 at the royal hospital in oman. methods we retrospectively reviewed the medical charts, radiological and laboratory findings of patients who were confirmed as positive for influenza a (h1n1) by real-time reverse-transcriptase-polymerasechain-reaction (rt-pcr). these patients were admitted to the royal hospital (a 625 bed tertiary health care hospital) in muscat, the capital city of oman, between 21 july and 23 december 2009. they were distributed among medicine, paediatric, surgery, obstetrics and gynaecology wards, and the adult, paediatric and neonatal critical care units. the following data were collected: demographic information on age, sex, and nationality; month of onset of illness; community versus hospital acquisition of the illness; duration of onset of illness to hospital admission; clinical features; risk factors for complications from influenza a (h1n1); specific therapy given; the need for intensive care unit admission and/or ventilation; total hospital stay, and outcome. a suspected case was defined as either 1) acute febrile respiratory illness (fever >38oc) with onset within 7 days of close contact with a confirmed case of (h1n1) influenza a virus, or 2) within 7 days of travel to countries where one or more confirmed case of (h1n1) influenza a virus had been reported or 3) residence in a community where there were one or more confirmed cases of (h1n1) influenza a virus. a confirmed case was defined by the positive result of rt-pcr, viral culture or four-fold rise in (h1n1) influenza a virus specific neutralising antibodies.6 associated medical conditions or risk factors for complications from influenza a (h1n1) were defined according to the cdc criteria.7 patients ≥12 years were categorised as adults and those <12 years as children. obesity was included as a risk factor if mentioned in the patients’ medical chart. for time calculations, the day of admission was considered to be hospital day 0. community acquired infection was defined as onset of illness in the community or <48 hours in the hospital, while hospital acquired infection was defined as the onset of illness ≥48 hours in the hospital. with pregnancy being interestingly the commonest risk factor. the infection caused severe illness that required icu admission and led to death in 6.9% of patients. keywords: influenza; a (h1n1); pandemic; oman hospitalised patients with influenza a (h1n1) in oman experience of a tertiary care hospital, july–december 2009 328 | squ medical journal, december 2010, volume 10, issue 3 laboratory tests included the total white cell count with specific lymphocyte count, total bilirubin, aspartate transaminase (ast), lactate dehydrogenase (ldh), creatine kinase (ck), serum creatinine and c-reactive protein (crp). the radiological tests included either a chest x-ray or computed tomography of the chest which might show unilateral, bilateral or lobar findings. routine bacterial cultures of blood, sputum or urine were performed upon clinicians’ requests. data collection and recording was undertaken by two candidates in the study team. the study was approved by the research ethics board of the royal hospital. all tests and procedures were performed at the requests of the physicians in charge of the patients. two nasopharyngeal and two throat swab specimens were collected from each patient at or during admission whenever suspected. rt-pcr (abi® real time pcr) testing was done in accordance with the published guidelines from the cdc.8 data entry forms were designed in epidata software with check files to control for any entry errors. the statistical package for the social sciences (spss) version 12, (spss inc., chicago, il, usa) was used for analysis. frequencies for categorical variables and means and medians for continuous variables were obtained. results a total of 497 cases with suspected influenza a (h1n1) infection were hospitalised between 21 july and 23 december 2009. out of these, 131 were confirmed to be positive and available for analysis. the characteristics and clinical features of patients are presented in table 1. the median age of the patients was 24 years (range 29.2 days–78 years) with the paediatric group accounting for 34.4% of patients. of the total hospitalised patients, 63% were females, and the majority was omani (86.3%). the mean ± standard deviation (sd) duration from onset of illness to hospitalisation was 4.8 ± 4.63 days and the majority of cases were community acquired (93.1%). table 1: characteristics and clinical features of all patients (n = 131) with influenza a (h1n1). data are presented as no. (%) unless specified otherwise characteristic value/no (%) gender female male 83 (63.4%) 48 (36.6%) nationality omani non-omani 113 (86.3%) 18 (13.7%) age in years mean ± sd median (range) age <12 years 25.9 ± 21.1 24 (29.2 days – 78years) 45 (34.4) duration from onset of illness to hospitalisation in days mean ± sd 4.8 ± 4.63 acquisition community hospital 122 (93.1%) 9 (6.9%) symptoms fever respiratory gastointestinal tract any adults (≥12years) children (<12 years) 123 (93.9%) 117 (89.3%) 8 (6.1%) 3 (3.5%) 5 (11.1%) table 2: associated medical conditions in all (n = 131) patients with confirmed influenza a (h1n1) according to their age group. data are presented as no. (%) medical condition <12yr n = 45 ≥12yr n = 86 all patients n =131 asthma or other chronic lung disease 8 (17.8%) 4 (4.7%) 12 (9.2%) obesity 0 7 (8.1%) 7 (5.3%) smoking 0 5 (5.8%) 5 (3.85) diabetes (type 1 or 2) 0 20 (23.3%) 20 (15.3%) central nervous system disorders 2 (4.4%) 10 (11.6%) 12 (9.2%) cardiovascular/ peripheral vascular disease 7 (15.6%) 13 (15.1%) 20 (15.3%) gastrointestinal disease 5 (11.1%) 3 (3.5%) 8 (6.1%) chronic renal failure 3 (6.7%) 8 (9.3%) 11 (8.4%) auto-immune disease 0 4 (4.7%) 4 (3.1%) immune suppression 5 (11.1%) 11 (12.8%) 16 (12.2%) malignancy 5 (11.1%) 1 (1.2%) 6 (4.6%) sickle cell disease 3 (6.7%) 2 (2.3%) 5 (3.8%) pregnancy 0 30 (34.9%) 30 (22.9%) jalila al-lawati, nada al-tamimi, ahmed al-qasmi, amina al-jardani, saif al-abri, and sulaiman al busaidy clinical and basic research | 329 symptoms at presentation mainly included fever (93.9%) and respiratory symptoms (89.3%). diarrhoea or vomiting was found in 6.1%, including 11.1 % of children and 3.5% of adults. table 2 shows the risk factors for complications with influenza a (h1n1). overall, 109 patients (83.2%) had at least one risk factor. pregnancy was the most common condition (n = 30, 22.9%). out of these 30 patients, none was in the first trimester, two were in the second trimester, 25 in the third trimester and three in the first 2 weeks postpartum. six out of the 30 patients with pregnancy had additional co-morbidities including gestational diabetes mellitus, cardiovascular disease, bronchial asthma and immunosuppression. around 15% of patients were diabetic and also had cardiovascular disease and 9.2% of patients had asthma or another chronic lung disease and also had a central nervous system (cns) disorder. asthma or other chronic lung diseases were more common in children (17.8%) and cns disorders were more common in adults (11.6%). interestingly, obesity, diabetes, smoking and auto-immune diseases were not found as risk factors in children. malignancy and sickle cell disease were considerably higher in the paediatric age group. table 3 illustrates the diagnostic findings. all patients were tested for full blood count. the majority had lymphopaenia 75 (57.3%) while 32 (24.4%) had leucocytosis. serum levels of crp, ast and ldh were noticeably high (75.7%, 75% and 70.8% respectively) in the proportion of patients who were tested. of the 110 patients who underwent chest radiography, 71 (64.5%) had evidence of pneumonia of which 60.6% had bilateral infiltrates. only 9 of the 104 patients had positive blood cultures. five of these 9 patients had community onset bacteraemias (less than 48 hours post admission); one was due to streptococcus pneumoniae pneumonia, three had urosepsis due to gram negative organisms and one had salmonella species meningitis (a post road traffic accident patient with skull injury). four patients had hospital onset bacteraemias (more than 48 hours post admission). organisms were hospital acquired gram negative bacteria like multidrug resistant acinetobacter baumannii (one case) and the other (two cases) resistant gram negative bacteria and candida albicans (one case). of the 131 patients, 125 (95.4%) received antiviral therapy (oseltamivir). none received zanamivir or a combination antiviral therapy. among patients who received antiviral therapy, 29.8% received it within 48 hours after onset of illness. a total of 121 (92.3%) patients received antibiotic therapy, and corticosteroids were given for 39 patients (30%) mainly as intravenous administration. the indications of corticosteroids administration were mainly for underlying diseases (asthma, systemic lupus erythematosus (sle), post renal transplant, etc). others received it in the intensive care unit (icu) for indications like septic shock and adult respiratory distress syndrome (ards). the median hospital stay was 6 days (range 1-70 table 3: results of diagnostic tests in all patients (n = 131) with confirmed influenza a (h1n1) diagnostic test abnormal result/ finding no/ total* (%) cut off limit leucocytosis 32 (24.4%) >11.5x109/l (adults) >15.1x109/l (children) leucopaenia 11 (8.4%) <3.6x109/l (adults) <4.9x109/l (children) lymphopaenia 75 (57.3%) <1x109/l (adults) <4x109/l (children) total bilirubin 27/72 (37.5%) 3–17 µmol/l ast 3/4 (75%) 10–45 iu/l ldh 17/24 (70.8%) 95–190 iu/l ck 7/16 (43.7%) 25–270 iu serum creatinine 24/113 (21.2%) 35–70 µmol/l in <15 yr 45–100 in >15 yr males 45–90 in >15 yr females crp 53/70 (75.7%) <5 mg/l chest radiography: any 71/110 (64.5%) n/a lobar 12/71 (16.9%) uni-lateral 16/71 (22.5%) bi-lateral 43/71 (60.6%) *this represents the number of patients with a positive laboratory/ radiology finding divided by the number of patients who underwent that test. legend: ast = aspartate transaminase; ldh = lactate dehydrogenase; ck = creatine kinase; crp = c-reactive protein; n/a = not applicable hospitalised patients with influenza a (h1n1) in oman experience of a tertiary care hospital, july–december 2009 330 | squ medical journal, december 2010, volume 10, issue 3 days) [table 4]. of 131 patients, 112 (85.5%) were discharged. the number of patients who required intensive care was 18 (13.7%) including 5 pregnant patients, while the number of patients who required mechanical ventilation was 14 (10.7%) including 3 pregnant patients. the mean ± sd of duration of intensive care and that of ventilation were 9.2 ± 5.5 days and 9.9 ± 5.9 days respectively. death occurred in 9 out of 131 patients (6.9%). out of the 9 patients who died, 8 (88.9%) required icu care and mechanical ventilation. the median age was 50 (range 24–78) years with the mean ± sd of the time from onset of illness to death being 22.6 ± 12.5 days. there was no sex predilection. all of them (100%) had at least one associated medical condition. pregnancy was not a risk factor, but one of the adult female patients was in the first week postpartum with no known medical risk factors. eight out of the nine patients (88.9%) received oseltamivir more than 48 hours after the onset of illness. patients who were admitted to an icu or died when compared to patients who were not admitted to an icu and survived were older in age (median age 29 years, range 153.3 days – 78 years) and mostly female (73.7%) [table 5]. they were less likely to have had received oseltamivir within 48 hours (15.8%), but were more likely to have received antibiotics (100%) and corticosteroids (68.4%). pregnancy was found in (26.3%) and pneumonia on radiography was found in 89.5% compared to 59.3% in the group of survivors not admitted to the icu. discussion we have described a cohort of 131 patients with confirmed influenza a (h1n1) who were hospitalised at the royal hospital, oman, between 21 july and 23 december 2009. this is the largest series of hospitalised patients with influenza a (h1n1) reported to date in oman. the infection table 4: clinical outcome in all patients (n = 131) with confirmed influenza a (h1n1). data are presented as no. (%) unless specified otherwise. characteristic value/no (%) total hospital stay in days median (range) 6 (1-70 days) icu admissions 18 (13.7%) mechanical ventilation 14 (10.7%) icu durationdays mean ± sd 9.2 ± 5.5 mechanical ventilation durationdays mean (± sd) 9.9 (± 5.9) death outcome 9 (6.9%) icu admissions 8 (88.9%) mechanical ventilation 8 (88.9%) age in years: median (range) 50 (24–78) duration from onset to death in days: mean ± sd 22.6 ± 12.5 legend: sd = standard deviation table 5: characteristics of patients with confirmed influenza a (h1n1) who were admitted to an intensive care unit (icu) or died, and those not admitted to an icu and survived. data are presented as no. (%) unless specified otherwise. characteristic admitted to icu or died (n = 19) not admitted to icu& survived (n = 112) age in years median (range) 29 (153.3 days – 78 years) 24 (29.2 days –70 years) gender female male 14 (73.7%) 5 (26.3%) 69 (61.6%) 43 (38.4%) antiviral treatment ≤48 hours after onset of illness 3 (15.8%) 36 (32.1%) antibiotic treatment 19 (100%) 102 (91.1%) corticosteroid treatment 13 (68.4%) 26 (23.2%) associated medical conditions any pregnancy 16 (84.2%) 5 (26.3%) 92 (82.1%) 25 (22.3%) pneumonia diagnosed by radiography* 17/19 (89.5%) 54/91 (59.3%) organ dysfunction elevated serum creatinine* elevated ast* elevated total bilirubin* elevated ck* 8/8 (100%) 1/1(100%) 9/18 (50%) 5/7 (71.4%) 16/94 (17.0%) 2/3 (66.7%) 18/54 (33.3%) 2/9 (22.2%) *this represents the number of patients with a positive laboratory/ radiology finding divided by the number of patients who underwent that test. legend: ast = aspartate transaminase; ck = creatine kinase; crp = c-reactive protein jalila al-lawati, nada al-tamimi, ahmed al-qasmi, amina al-jardani, saif al-abri, and sulaiman al busaidy clinical and basic research | 331 affected mainly those of younger age and females. associated medical conditions were common in this cohort with pregnancy found to be the commonest risk factor; however, 16.8% of the patients were free of any associated medical conditions. the infection caused severe illness that required icu admission in 13.7% and death in 6.9% of the patients. antiviral therapy was administered to most patients; however, it was commenced more than 48 hours after onset of the disease in the majority of cases. the observation of female susceptibility to develop influenza a (h1n1) in this cohort is striking. this tendency, in general, has not been observed in other influenza case series except in two reports from canada and chile.9,10 the explanation behind this observation could be partly because of the relatively high proportion of pregnant women in this case series and that our hospital is the only tertiary hospital across oman that serves for referral cases of obstetrics and gynaecology. the distribution of cases in this cohort by age is characterised by the predominance of infection in the younger age group. this was similar to the findings observed worldwide10,11 including the first report of the present epidemic12 and previous influenza pandemics.13 possible explanations for this observation include the greater susceptibility of young people to the virus on the basis of serological studies,14,15 and the fact that younger patients are more likely to be tested as they are more symptomatic than older ones.16 in this cohort, the patients experienced symptoms related to influenza a (h1n1) infection over a mean duration of 4.8 days. this time period was comparable to other case series.9,17 fever was the most frequent symptom that was observed in our patients (93.9%). it was the most common presenting symptom reported in most case series18,19 except one report in china17 where fever was less common. the incidence of diarrhoea or vomiting has occasionally been reported in children and in less than 5% of adults during peak periods of seasonal influenza.16 this rate is similar to our results which showed 6% of patients with gastrointestinal symptoms. the prevalence of associated medical conditions in our patients was high (83.2%). published and unpublished data from the cdc showed that 44 to 84% of hospitalised adults with seasonal influenza had an underlying condition.20,21 this high prevalence was also reported in other influenza a (h1n1) series.22,23 pregnancy was interestingly the commonest (22.9%) risk factor in our patients. pregnancy as a risk factor has been noticed in previous influenza pandemics24-26 with a high disease-specific mortality;24 however, the prevalence in pregnancy in our study was higher than those reported by others.22,24 most of our patients (84%) were infected in their third trimester which is similar to the findings in a large series in california which found that 95% of pregnant and postpartum women were infected in the second or third trimester.27 diabetes mellitus (type 1 or 2) and cardiovascular disease were found in 15.3% of our cases, while asthma or other chronic lung diseases and central nervous system disorder occurred in 9.2%. these rates were much lower than those reported in the us and canadian influenza a (h1n1) series.9,23 the most consistent laboratory characteristics were lymphopaenia and leucocytosis. lymphopaenia was reported in patients with influenza a (h1n1) from canada, china and mexico.9,17 most of our patients also had increased serum crp, ast and ldh levels. nine patients in our cohort had bacterial co-infection mostly caused by gram negative bacteria. the low number of positive blood cultures in our series could be due to the fact that patients were mostly admitted as referrals from other hospitals and so would probably have been started empirically on antibiotics for pneumonia. this would have decreased the yield of positive blood cultures when they reached our hospital. the possible explanation for most of the cases of community onset bacteraemia being due to gram negative organisms is that they mainly presented with infections (urosepsis) caused usually by gram negative organisms and that most of them had risk factors for such infections (pregnancy, renal impairment, post skull fracture). the risk factors in hospital acquired bacteraemias due to gram negative organisms were long hospital stay (more than a week), the presence of long lines and mechanical ventilation. during the 1918 pandemic, a large number of deaths were associated with bacterial infection.28 other influenza a (h1n1) series also reported bacterial co-infections;22 however, the impact of concurrent bacterial infection on the severity of illness in our patients was difficult to assess especially because many patients received antibiotics before hospitalisation. hospitalised patients with influenza a (h1n1) in oman experience of a tertiary care hospital, july–december 2009 332 | squ medical journal, december 2010, volume 10, issue 3 a significant proportion of our patients had radiological evidence of pneumonia with the majority having bilateral infiltrates on their chest radiography. the relationship of radiological findings with the cause of pneumonia is not yet established. therefore, patients who are hospitalised with suspected influenza and lung infiltrates should be considered for treatment with both antibiotics and antiviral drugs.29 according to the cdc and who guidelines on the pharmacological management of the influenza virus, hospitalised patients and outpatients who are at high risk of complication should, if possible, receive oseltamivir or zanamivir as soon as symptoms develop.30,31 although the evidence supporting such a recommendation is low, it has been shown that administration of oseltamivir within 48 hours of the onset of symptoms can reduce the duration of viral shedding as measured by real-time rt-pcr assay.17 moreover, observational studies suggest that a reduction in mortality in hospitalised patients with influenza treated with oseltamivir can be achieved even when such therapy is initiated more than 48 hours after the onset of illness.22 a total of 30% of patients in our study received corticosteroids; however, steroids were given both to patients with an underlying disease (post renal transplant, systemic lupus erythematosus, chronic obstructive pulmonary disease, asthma, etc.) and to those who were critically ill in the icu. although the who recommendations state that steroids should be avoided in (h1n1) influenza a, unless indicated for other reasons, the use of low dose steroids has been anecdotally accepted for such patients. moreover, most of our patients in the icu received it for indications like severe sepsis, septic shock or acute respiratory distress syndrome which could justify its use. in our study, the patients who died or were admitted to the icu were less likely to have received oseltamivir within 48 hours as compared to those who survived and were not admitted to the icu (15.3% versus 32.1%). this might support the beneficial effect of early antiviral therapy. moreover, although pregnancy was found to be the main risk factor in our series, pregnant patients were disproportionately admitted to icu or died. death occurred in 6.9% of our patients. out of these, 88.9% required icu care and mechanical ventilation. all patients who died had at least one underlying medical condition. eight out of these nine patients (88.9%) received oseltamivir more than 48 hours after the onset of illness. delayed administration of antiviral therapy and the presence of underlying medical conditions could be seen as the causes that contributed to the mortality in our series. there is compelling evidence from the post mortem studies done on deaths in the 1918-1919 influenza pandemic that bacterial pneumonia had a predominant role in mortality;28 however, most patients in our series had received antibiotics and all of those who were admitted to the icu or died eventually did receive antibiotics. the protective effect of h1n1 vaccine against h1n1 infection and related morbidity and mortality could not be assessed in our study. this was because the h1n1 vaccine did not reach the country until the last week of october 2009 and was only launched in the first week of november 2009. our data collection was over by end of december 2009 by which time the number of vaccinated individuals is assumed to have been low. our study has some limitations. the study included mainly hospitalised patients in one hospital and did not represent patients in the community or those with less severe illness that required admission to a secondary health care facility. also, our study followed up the patients during the study period only which might have resulted in underestimation of the actual mortality rate. finally, this study was retrospective and some data were missing. for example, it was not possible to get the weight and height for many patients to calculate the bmi and also it was not possible to segregate the respiratory symptoms into cough, dyspnoea, etc. conclusion influenza a (h1n1) infection in our setting affected mainly those of younger age and females. associated medical conditions were common and pregnancy was interestingly found to be the commonest risk factor. the infection caused severe illness that required icu admission and death in 6.9% of patients. clinicians should consider influenza, including h1n1 infection, in their differential diagnosis for patients presenting with fever with respiratory or gastrointestinal symptoms. jalila al-lawati, nada al-tamimi, ahmed al-qasmi, amina al-jardani, saif al-abri, and sulaiman al busaidy clinical and basic research | 333 wp, van kerkhove md, hollingsworth td, et al. pandemic potential of a strain of influenza a (h1n1): early findings. science 2009; 324:1557–61. 13. simonsen l, clark mj, schonberger lb, arden nh, cox nj, fukuda k. pandemic versus epidemic influenza mortality: a pattern of changing age distribution. j infect dis 1998; 178:53–60. 14. hancock k, veguilla v, lu x, zohong w, butler en, sun h, et al. cross reactive antibody responses to the 2009 pandemic h1n1 influenza virus. n eng j med 2009; 361:1945–52. 15. centers for disease control and prevention (cdc). serum cross reactivity response to a novel influenza a h1n1 virus after vaccination with seasonal influenza vaccine. mmwr morb mortal wkly rep 2009; 58:521–4. 16. nicholson kg. clinical features of influenza. semin respir infect 1992; 7:26–37. 17. cao b, li xw, mao y, wang j, lu hz, chen ys, et al. clinical features of the initial cases of 2009 pandemic influenza a h1n1 virus infection in china. n eng j med 2009; 361:2507–17. 18. swine influenza a h1n1 infection in two children southern california. mmwr morb mortal wkly rep 2009; 58:400–2. 19. kwong kl, lung d, wong sn, que tl, kwong ns. influenza-related hospitalization in children. j paediatr child health 2009; 45:660–4. 20. walsh ee, cox c, ealsey ar. clinical features of influenza a infection in older hospitalized persons. j am geriatr soc 2002; 50:498–503. 21. neuzil km, maynard c, griffin mr, heagerty p. winter respiratory viruses and health care use: a population based study in the northwest united states. clin infect dis 2003; 37:201–7. 22. jain s, kamimoto l, bramley am, schmitz am, benoit sr, louie j, et al. hospitalised patients with 2009 h1n1 influenza in the unites states. 2009; 361:1935–44. 23. peiris jm, poon llm, guan y. emergence of a novel swine-origin influenza a (s-oiv) h1n1 virus in humans. j clin viro 2009; 45:169–73. 24. jamieson dj, honein ma, rassmusen sa, williams jl, swerdlow dl, biggerstaff ms, et al. h1n1 2009 influenza virus infection during pregnancy in the usa. lancet 2009; 274:451–8. 25. freeman dw, barno a. deaths from asian influenza associated with pregnancy. am j obstet gynecol 1959; 78:1172–5. 26. harris jw. influenza occurring in pregnant women. jama 1919; 72:978–80. 27. louie jk, acosta m, jamieson dj, honein ma. severe 2009 h1n1 influenza in pregnant and postpartum women in california. n engl j med 2010; 362:27– 35. empirical and early treatment with antiviral therapy, especially in pregnant women and other patients with significant underlying conditions should also be considered. future studies are necessary to show the protective effect of h1n1 vaccine as a predictive factor for disease severity and related mortality. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. swine-origin influenza a (h1n1) virus infections in a school new york city. mmwr morb mortal wkly rep 2009; 58:470–2, 2. outbreak of swine-origin influenza a (h1n1) virus infection mexico. mmwr morb mortal wkly rep 2009; 58:467–70. 3. new influenza a (h1n1) infections: global surveillance summary. wkly epidemiol rec 2009; 84:173–9. 4. world health organisation. h1n1 influenza a updates. from: http://www.who.int/mediacentre/ news/en accessed: mar 2010. 5. ministry of health, sultanate of oman. weekly pandemic influenza reports. from: http://www.moh. gov.om/a_h1n1/index.html. accessed: jan 2010. 6. ministry of health, sultanate of oman. national pandemic h1n1 influenza a preparedness plan. from: http://www.moh.gov.om/a_h1n1/index.html accessed: aug 2010. 7. centers for disease control and prevention (cdc). definitions of groups at high risk of influenza complication. from: http://www.cdc.gov/h1n1 flu/ recommendations.htm accessed: jan 2010. 8. centers for disease control and prevention (cdc). protocol of the real time rt-pcr for influenza a (h1n1). from: http://www.cdc.gov/h1n1flu/ diagnosis/ accessed: jan 2010. 9. kumar a, zarychanski r, pinto r, deborah jc, marshall j, lacroix j. critically ill patients with 2009 influenza a (h1n1) infection in canada. j am med assoc 2009; 302:1872–9. 10. torres jp, o’ryan m, herve b, espinoza r, acuna g, manalich j, et al. impact of the novel influenza a (h1n1) during the 2009 autumn-winter season in a large hospital setting in santiago, chile. clin infect dis 2010; 50:860–70. 11. echevarría-zuno s, mejía-aranguré jm, mar-obeso aj, grajales-muñiz c, robles-pérez e, gonzálezleón m, et al. infection and death from influenza a (h1n1) virus in mexico: a retrospective analysis. lancet 2009; 374:2072–9. 12. fraster c, donnelly ca, cauchemez s, hanage hospitalised patients with influenza a (h1n1) in oman experience of a tertiary care hospital, july–december 2009 334 | squ medical journal, december 2010, volume 10, issue 3 28. morens dm, taubenberger jk, fauci as. predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. j infect dis 2008; 198:962–70. 29. harper sa, bradley js, englund ja, file tm, gravenstein s, hyden fg, et al. seasonal influenza in adults and children diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the infectious diseases society of america. clin infect dis 2009; 48:1003–32. 30. centers for disease control (cdc). updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 seasons. atlanta, ga: centers for disease control and prevention. from: http://www.cdc.gov/ h1n1flu/antivirals/ accessed: april 2010. 31. world health organization. who guidelines for pharmacological management of pandemic (h1n1) 2009 influenza and other influenza viruses. geneva: world health organization, 20 august 2009. july 2008.indd abstract uterine cavity occlusion following caesarean section for central placenta praevia culminating in haematometra and thereby amenorrhoea is one of the rarest long term complications of lower segment caesarean section. we report a case of 28 year old primigravida with grade 4 placenta praevia who underwent elective caesarean section at 35 weeks gestation. she presented at nizwa hospital, sultanate of oman, after 7 months with cyclical lower abdominal pain and amenorrhoea. she was treated by hysteroscopic adhesiolysis and an in utero foley’s catheter. she had complete resolution of her condition within 2 months and resumption of menstrual cycles. multiple haemostatic sutures at caesarean section for placenta praevia can be an causative factor for such a complication along with other risk factors like multiple caesarean sections, chorioamniotis etc. recognition of these factors, meticulous surgical technique and appropriate post operative care can effectively prevent it. keywords: placenta previa; adhesions, intrauterine; occlusion; genital tract; case report, oman. occlusion of upper genital tract following lower segment caesarean section for placenta praevia *mini b poothavelil, ilham hamdi, geeta zunjurwad sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 215-218 sultan qaboos university© submitted 20th january 2008 accepted 15th april 2008 department of obstetrics and gynaecology, nizwa hospital , nizwa, sultanate of oman *to whom correspondence should be addressed. email: drminibenny@hotmail.com ةِ عَ طْ القِ رِيَّةُ يْصَ قَ عملية بعد التناسلي اجلهاز من العلوي اجلزء إنسداد لِيَّة فْ السُّ زينجوارد جيتا حمدي، إلهام بوثافيليل، بي ميني وانقطاع الرحم داخل دموي جتمع إلى مركزية والذي يؤدي منزاحة عملية قيصرية ملشيمة إجراء عن الناجت الرحمي التجويف امللخص: يعتبر انسداد ــيمة بها مش 28 عاما األولى عمرها للمرة حامل امرأة حالة هنا ــتعرض نس . ــفلية الس القطعة قيصرية تلي التي املضاعفات املديدة من أندر احليض سلطنة عمان في نزوى مستشفى املريضة راجعت . احلمل من اخلامس والثالثني األسبوع في قيصرية اختيارية لها أجريت الرابعة الدرجة من منزاحة م تَنْظيرُ الرَّحِ طريق عن بإزالتها الرحم داخل االلتصاقات من عوجلت . ــهر أش ــبعة س ملدة انقطاع احليض مع البطن ــفل أس دورية آالم من وهي تعاني اجلراحية اخلياطة تكون أن املمكن من بانتظام. ــهرية الدورة الش إليها وعادت ــهرين ش خالل املريضة ــفيت .ش الرحم داخل بولية ــطرة مع تثبيت قس االختطار عوامل إلى باإلضافة ، املضاعفات لهذه املسببة العوامل أحد ــيمة املنزاحة للمش القيصرية العملية إجراء أثناء إليقاف النزيف ــتعملة املس الدقيق والرعاية اجلراحي اإلجراء املسببة مع العوامل على هذه التعرف إن . أخره إلى لَى. السَّ و َشيماءِ امل والتهاب القيصرية العمليات تعدد األخرى مثل املضاعفات. هذه متنع ميكن أن العملية املالئمة بعد الصحية عمان. ، حالة تقرير ، التناسلي ، اجلهاز إنسداد ، الرحم جتويف داخل ، التصاقات ، املنزاحة الكلمات: املشيمة مفتاح when the placenta is implanted partially or completely over the relative-ly noncontractile lower uterine segment, it is termed placenta praevia.1 in an attempt to achieve haemostasis during caesarean section, a number of innovative techniques have been tried apart from the usual method of oversewing the open bleeding sinuses on the lower segment.2, 3, 4 none of the methods have been known to cause postoperative intrauterine adhesions, haematometra or amenorrhea. in our unique case, there was absence of any other risk factors like previous caesarean section, placenta accreta or percreta, multiparity, post partum endometritis, intra uterine fibroids or polyps. c a s e r e p o r t a 28 year old primigravida woman presented at nizwa hospital, oman, in november 2005 at 32 weeks gestation with type 4 placenta praevia. she was admitted for observation and underwent an elective lower segment caeserean section at 35+ week’s gestation after attaining satisfactory fetal lung maturity. intraoperative findings included a lower segment not well formed with varicosities, the placenta being anterolac a s e r e p o r t m i n i b p o o t h av e l i l , i l h a m h a m d i a n d g e e ta z u n j u r wa d 216 teral and extending posteriorly covering the cervical internal os. multiple haemostatic sutures were made with polyglactin 910 number 0 in the posterior uterine wall in view of the multiple bleeding vessels from the placental bed. a small vertical extension around 1.5cm at the right side of the anterior lower segment was sutured with polyglactin 910 number 0. the internal os was digitally checked. the postoperative period was uneventful and the patient was discharged on the third postoperative day. the patient returned after 7 months to nizwa hospital outpatient department with complaints of cyclical lower abdominal pain and amenorrhoea. detailed ultrasonography revealed a distended uterine cavity with hypoechoic shadows resembling haematometra with biloculated endometrium in between [figure 1]. the patient underwent cervical dilatation and diagnostic hysteroscopy with adhesiolysis. intraoperatively, the cervix was pinpoint dilated gradually with hegars dilator until no. 9 under ultrasound guidance. during the process, flimsy adhesions around the internal os area were broken followed by drainage of the haematometra. hysteroscopy revealed flimsy adhesions around the internal os and the lower uterine cavity, the cavity being filled with dark altered blood [figure 2]. foleys catheter no.16 was introduced into the uterine cavity and the bulb dilated till 10cc to facilitate figure 1: ultrasonography revealing haematometra and intrauterine adhesions figure 2: hysteroscopy under ultrasonographic guidance helped in diagnosis and appropriate management figure 3: post procedure: near complete drainage of the haematometra o c c l u s i o n o f u p p e r g e n i ta l tr a c t f o l l o w i n g l o w e r s e g m e n t c a e s a r e a n s e c t i o n f o r p l a c e n ta p r a e v i a 217 the drainage of the intrauterine blood, the procedure being uneventful [figure 3]. the patient was administered intravenous antibiotics and discharged on the third postoperative day after removal of the intrauterine foley’s catheter. after 2 weeks, she resumed her menstrual cycle with a normal flow of 5 days with minimal dysmenorrhoea. a follow up ultrasonography revealed complete resolution of the haematometra and no evidence of any intrauterine adhesions [figure 4]. the patient was followed up for 10 months after the procedure and found to have continued regular menstrual cycle with normal flow. ultrasonography confirmed no persistent cervical stenosis. d i s c u s s i o n intrauterine adhesions following lower segment caesarean section are one of the rare complications with few case reports available in the literature. our patient was a primigravida with no previous history of uterine surgery, no other antepartum events suggesting chorioamnionitis, no postpartum evidence suggesting endometritis-like fever, uterine tenderness, offensive lochia or absence of lochia. a normal amount of lochia was observed in the postpartum period. she was asymptomatic for approximately 5 to 6 months thereafter. our investigations of the patient led to the diagnosis of intrauterine synchiae and haematometra as result of the multiple hemostatic sutures that were made in the raw surface of the lower segment in an attempt for quick haemostasis. these adhesions were flimsy and could be easily broken during slow gradual dilatation, followed by hysteroscopy. insertion of a foley’s catheter served two purposes: first, easy and complete drainage of the hematometra and second, preventing apposition of the uterine walls and allowing the regeneration of the endometrium. lower segment caesarean section for placenta preavia will eventually lead to bleeding from open sinuses of the relatively noncontractile lower segment that can be catastrophically heavy. such events can be severe in the presence of a morbidly adherent placenta or placenta accreta or percreta. after the delivery of the placenta, the bleeding vessels are oversewn by haemostatic sutures usually polyglactin 910 or daxon. when we are confronted with a patient experiencing placenta praevia with massive haemorrhage in cesarean delivery, haemostasis is first attempted using uterotonic drugs, uterine massage, and intrauterine packing. however, if these manoeuvres fail, a number of surgical techniques to control severe bleeding at cesarean delivery have been proposed, such as uterine artery ligation, hypogastric artery ligation, and uterine compression suturing.5 perhaps these procedures alone or in combination can successfully control the haemorrhage. every obstetrician must be familiar with these simple methods in order to avoid having to perform a hysterectomy and thus preserving the reproductive capability, as well as diminishing the operative morbidity. there are a few other techniques such as the isthmicocervical apposition, an intrauterine balloon or a b-lynch uterine brace suture.6 women with multiple previous cesarean deliveries risk the development of uterine synechiae and ventral fixation of the uterus to the abdominal wall.7 hysteroscopic treatment of infigure 4: postoperative follow-up ultrasound reveals complete resolution of the haematometra and a thin endometrial echo trauterine adhesions is a safe and effective treatment for the restoration of normal menstruation.8 c o n c l u s i o n although rare, the occurrence of intrauterine adhesions and haematometra/pyometra can be a longterm sequel of caesarean section.9 the associated risks factors include placenta praevia, placenta accreta, percreta, chorioamonitis with prolonged rupture of membranes, multiple caesarean sections or a scarred uterus, postpartum endometritis and iatrogenic occlusion of the posterior uterine wall. manual removal of the placenta can contribute significantly to these complications.10 the use of multiple sutures through the uterus is effective to control postpartum hemorrhage, but may lead to uterine synechiae. r e f e r e n c e s 1. badawy sz, orbuch l, khurana kk. secondary amenorrhea with severe intrauterine adhesions and chronic uterine torsion after cesarean section in a teenage girl. j pediatr adolesc gynecol 1998; 11:93-96. 2. ferrazzani s, guariglia l, triunfo s, caforio l, caruso a. successful treatment of post-cesarean hemorrhage related to placenta praevia using an intrauterine balloon. two case reports. fetal diagn ther 2006; 21:277280. 3. li yt, yin cs, chen fm, chao tc. a useful technique for the control of severe cesarean hemorrhage: report of three cases. chang gung med j 2002; 25:548-552. 4. das c, mukherjee p. isthmico cervical apposition suture-an effective method to control pph during caesarean section for placenta praevia. j obstet gynaecol india 2005; 55:322-324. 5. wu hh, yeh gp. uterine cavity synechiae after hemostatic square suturing technique. obstet gynecol 2005; 105:1176-1178. 6. muge h, nese g, adil o. b-lynch uterine compression suture for postpartum haemorrhage due to placenta praevia accrete, aust n z j obstet gynaecol 2005; 45:93-95. 7. mathelier ac. unusual late complications after two previous cesarean deliveries: a case report. int j fertil womens med 2003; 48:70-73. 8. pabuccu r, atay v, orhon e, urman b, ergun a. hysteroscopic treatment of intrauterine adhesions. fertil steril 1997; 68:1141-1143. 9. ochoa m, allaire ad, stitely ml. pyometra after hemostatic square suture technique. obstet gynecol 2002; 99:506-509. 10. golan a, raziel a, pansky m, bukovsky i. manual removal of the placenta its role in intrauterine adhesion formation. int j fertil menopausal stud 1996; 41:450451. m i n i b p o o t h av e l i l , i l h a m h a m d i a n d g e e ta z u n j u r wa d 218 مستوايت الكفاءة الذاتية املتعلقة مبهارات التعلم بني طالب الرعاية الصحية اجلامعيني يف ماليزاي حممد �سعيد نورمال، نورال قمرية هريو ديونو، حممد كامل ت�سي ح�سن abstract: objectives: self-efficacy is an important factor in determining the ability of students to execute tasks or skills needed in the implementation of interprofessional learning (ipl). this study aimed to identify levels of self-efficacy with regards to ipl skills among undergraduate healthcare students and to investigate differences according to gender, programme of study and year of study. methods: this descriptive cross-sectional study was conducted between january and march 2018 at the international islamic university malaysia, kuantan, malaysia. the self-efficacy for interprofessional experiential learning scale was used to evaluate the self-efficacy of 336 students from five faculties including nursing, medicine, dentistry, pharmacy and allied health sciences. results: significant differences in self-efficacy scores for the interprofessional interaction subscale were identified according to programme of study, with pharmacy students scoring significantly lower than allied health students (mean score: 54.1 ± 10.4 versus 57.4 ± 10.1; p = 0.014). in addition, there was a significant difference in self-efficacy scores for the interprofessional interaction subscale according to year of study, with first-year students scoring significantly lower compared to fifth-year students (mean score: 52.8 ± 10.4 versus 59.9 ± 11.9; p = 0.018). no statistically significant differences in self-efficacy scores were identified with regards to gender or for the interprofessional team evaluation and feedback subscale. conclusion: these findings may contribute to the effective implementation of ipl education in healthcare faculties. acknowledging the influence of self-efficacy on the execution of ipl skills is crucial to ensure healthcare students are able to adequately prepare for future interprofessional collaboration in real clinical settings. keywords: self efficacy; intersectoral collaboration; interdisciplinary research; professional competence; learning; undergraduate medical education; malaysia. امللخ�ص: الهدف: تعترب الكفاءة الذاتية عاماًل مهًما يف حتديد قدرة الطالب على تنفيذ املهام اأو املهارات الالزمة يف تنفيذ التعلم بني املهنيني. هدفت هذه الدرا�سة اإىل حتديد م�ستويات الكفاءة الذاتية فيما يتعلق مبهارات التعلم بني املهنيني بني طالب الرعاية ال�سحية اجلامعيني والبحث عن االختالفات وفًقا للجن�س وبرنامج الدرا�سة و�سنة الدرا�سة. الطريقة: اأجريت هذه الدرا�سة املقطعية الو�سفية يف الفرتة ما بني يناير ومار�س 2018 يف اجلامعة االإ�سالمية العاملية ماليزيا، كوانتان، ماليزيا. مت ا�ستخدام مقيا�س الكفاءة الذاتية للتعلم التجريبي بني املهنيني لتقييم الكفاءة الذاتية لـ 336 طالًبا من خم�س كليات، مبا يف ذلك التمري�س والطب وطب االأ�سنان وال�سيدلة والعلوم ال�سحية امل�ساعدة. النتائج: مت حتديد فروق ذات داللة اإح�سائية يف درجات الكفاءة الذاتية للمقيا�س الفرعي للتفاعل بني املهنيني وفًقا لربنامج الدرا�سة، حيث �سجل طالب ال�سيدلة درجات اأقل بكثري من طالب ال�سحة امل�ساعدة )p = 0.014؛ 10.1 ± 57.4 مقابل 10.4 ± 54.1 :متو�سط الدرجة(. باالإ�سافة اإىل ذلك، كان هناك اختالف كبري يف درجات الكفاءة الذاتية للمقيا�س الفرعي للتفاعل بني املهنيني وفًقا ل�سنة الدرا�سة، حيث �سجل طالب ال�سنة االأوىل درجات اأقل بكثري مقارنة بطالب ال�سنة اخلام�سة )p = 0.018؛ 11.9 ± 59.9 مقابل 10.4 ± 58.2 :متو�سط الدرجة(. مل يتم حتديد فروق ذات داللة اإح�سائية يف درجات الكفاءة الذاتية فيما يتعلق باجلن�س اأو للمقيا�س الفرعي لتقييم الفريق بني املهنيني وردود الفعل. اخلال�صة: قد ت�ساهم هذه النتائج يف التنفيذ الفعال للتعليم بني املهنيني يف كليات الرعاية ال�سحية. يعد االعرتاف بتاأثري الكفاءة الذاتية على تنفيذ مهارات التعلم بني املهنيني اأمًرا بالغ االأهمية ل�سمان قدرة طالب الرعاية ال�سحية على اال�ستعداد ب�سكل كاٍف للتعاون املهني امل�ستقبلي يف واقع البيئة ال�رسيرية. الكلمات املفتاحية: الكفاءة الذاتية؛ التعاون بني القطاعات؛ بحث متعدد التخ�س�سات؛ الكفاءة املهنية؛ التعلم؛ التعليم الطبي يف املرحلة اجلامعية االأوىل؛ ماليزيا. self-efficacy levels regarding interprofessional learning skills among undergraduate healthcare students in malaysia mohd s. nurumal,1 nurul q. h. diyono,3 *muhammad k. che hasan2 clinical & basic research sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e374–379, epub. 21 dec 20 submitted 31 oct 19 revisions req. 24 dec 19 & 11 feb 20; revisions recd. 22 jan & 24 feb 20 accepted 7 apr 20 advances in knowledge the current study found that healthcare students studying at a university in malaysia demonstrated moderately-high levels of selfefficacy with regards to interprofessional learning (ipl) skills. however, there was a significant difference in self-efficacy scores according to programme of study, with pharmacy students scoring significantly lower compared to those enrolled in allied health sciences. https://doi.org/10.18295/squmj.2020.20.04.015 departments of 1critical care nursing and 2medical-surgical nursing, faculty of nursing, international islamic university malaysia, kuantan, malaysia 3department of intensive care unit, prince court medical centre, kuala lumpur, malaysia *corresponding author’s e-mail: mkamil@iium.edu.my this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ mohd s. nurumal, nurul q. h. diyono and muhammad k. che hasan clinical and basic research | e375 in modern healthcare, the capacity to deal with complex medical problems is enhanced immeasurably by the sharing of values, knowledge and skills across different specialties.1 to this end, the world health organization utilises the term interprofessional learning (ipl) to describe the skills shown when individuals from different healthcare professions work together in order to provide high-quality care.2 according to the centre for the advancement of interprofessional education, ipl is defined as active learning occasions when “two or more professions learn with, from and about each other to improve collaboration and quality of care”.3 the goal of ipl is to enhance health outcomes via effective interprofessional collaboration, thereby improving the quality of care as well as patient safety.4 self-efficacy refers to an individual’s perceptions of their own competency with regards to the performance of a skill or task.5 the confidence level of an individual regarding their ability to perform can be an important factor affecting the outcomes of the action(s) taken and can influence and modify human behaviour.6 multiple studies have shown that self-efficacy appears to be a substantial contributor to student learning outcomes particularly in undergraduate healthcare ipl education.7–11 all students in health professions are expected to demonstrate high levels of personal efficacy and competency in the skills required for the establishment of an effective learning environment and a constructive learning experience.12 moreover, becoming more confident in certain skills can also empower students to more effectively handle complex and stressful situations, an important quality when treating ailments and managing patients.13 despite the importance of ipl in modern healthcare practice, no structured ipl education has yet been incorporated officially within the undergraduate healthcare curricula in malaysia. thus, this study was conducted to identify levels of self-efficacy regarding ipl skills among a cohort of undergraduate students enrolled in various healthcare-related programmes at a university in malaysia and to investigate potential differences in self-efficacy according to gender, programme of study and year of study. methods this descriptive cross-sectional study took place between january and march 2018 at the international islamic university malaysia (iium), kuantan, malaysia. a convenience sample of undergraduate students aged between 19–25 years was recruited from five healthcare faculties including the medicine, dentistry, pharmacy, nursing and allied health sciences faculties. all students had clinical postings involving personnel outside of their chosen profession. the required sample size was calculated to be 299 out of a total of 1,343 potential participants, assuming that the level of self-efficacy would be 50% and with a 95% confidence interval and a margin of error of 5%. accordingly, a total of 336 undergraduate healthcare students were recruited. levels of self-efficacy were assessed using an english questionnaire which incorporated the 16item self-efficacy for interprofessional experiential learning (seiel) scale.14 this tool was chosen as it is specifically designed to measure students’ perceptions of their ability to execute skills and tasks as they relate to interprofessional practice. the seiel scale consists of two subscales covering interprofessional interaction and interprofessional team evaluation and feedback.14 the former focuses on assessing students’ self-efficacy in skills that enable them to work and communicate effectively with other students from multidisciplinary healthcare programmes, whereas the latter assesses self-efficacy regarding the use of higher-level skills associated with evaluating, understanding and providing feedback on the quality of interprofessional interactions. each subscale consists of eight items scored from 1 to 10, resulting in a total score ranging from 8–80.14 in order to test the validity and reliability of the questionnaire, a pilot study was conducted among 30 second-, thirdand fourth-year nursing students at iium who were subsequently excluded from the main sample. the findings revealed that the tool had excellent internal consistency (cronbach’s alpha: 0.96–0.97). as such, the questionnaire was distributed to the recruited students via class representatives for each of the programmes. the statistical package for the social sciences (spss), version 20 (ibm corp., armonk, new york, usa), was used to analyse the data. descriptive statistics were used to present findings regarding the students’ level of self-efficacy for ipl skills with higher mean seiel scores indicating greater levels of self-efficacy in terms of ipl skills. an independent sample t-test was conducted to compare mean application to patient care overall, ipl is an indirect yet important aspect of patient care, given that modern healthcare treatment and services has become a collaborative endeavour involving healthcare professionals from multiple specialties. as such, ensuring that students attain a high level of self-efficacy in ipl skills will ensure no redundancy of care or information in their future clinical practice. self-efficacy levels regarding interprofessional learning skills among undergraduate healthcare students in malaysia e376 | squ medical journal, november2020, volume 20, issue 4 seiel scores according to gender, while a one-way analysis of variance was computed to compare scores according to programme and year of study. post-hoc comparisons were performed using tukey’s multiple comparison test. results were considered statistically significant at p <0.050. ethical approval for this study was obtained from the kulliyyah of nursing postgraduate research committee (#iium/313/ddaa/20/4/10) as well as the international islamic university malaysia research ethics committee (#iium/504/14/11/2/irec 2018026). all students gave informed consent prior to completing the questionnaire. results the demographic characteristics of the participants are presented in table 1. overall, the undergraduate healthcare students demonstrated moderately high levels of self-efficacy with regards to both the interprofessional interaction (mean score: 57.4 ± 10.1) and interprofessional team evaluation and feedback (mean score: 55.7 ± 9.7) subscales of the seiel tool. no significant differences in self-efficacy were observed according to gender, with male and female students demonstrating comparable overall mean seiel scores (mean overall score: 114.6 ± 18.5 versus 112.4 ± 19.3; p = 0.322). similar findings were noted among male and female participants for the individual subscales of interprofessional interaction (mean score: 58.1 ± 9.8 versus 57.1 ± 10.2; p = 0.383) and interprofessional team evaluation and feedback (mean score: 56.5 ± 9.3 versus 55.3 ± 9.8; p = 0.295) [table 2]. significant differences in self-efficacy were observed with regards to programme of study, with pharmacy students scoring significantly lower than allied health sciences for the interprofessional interaction subscale (mean score: 54.1 ± 10.4 versus 57.4 ± 10.1; p = 0.014) [table 3]. moreover, there was a significant difference according to year of study, with first-year students scoring significantly lower compared to fifth-year students for the interprofessional interaction subscale (mean score: 52.8 ± 10.4 versus 59.9 ± 11.9; p = 0.018) [table 4]. however, neither programme nor year of study had a significant effect on scores for the interprofessional team evaluation and feedback subscale. discussion preparing healthcare students for future collaborative practice in the workplace is essential, particularly as current treatment and management of medical issues usually involves multiple disciplines and professions. as such, all healthcare students need to understand that working together across discipline boundaries is vital.15 previous research suggests that high selfefficacy has positive effects on students’ self-regulation strategies and academic performance in educational settings.16,17 simulation-based learning is a potential teaching method which exposes students to clinical scenarios in which ipl skills can be integrated.18 in addition, students have been shown to demonstrate positive attitudes towards ipl based on feedback from subsequent debriefing sessions.19 this study found that undergraduate healthcare students at a university in malaysia demonstrated a moderately high level of selfefficacy when executing ipl skills. with time, the idea of implementing ipl into the healthcare curriculum is table 1: demographic characteristics of healthcare students at the international islamic university malaysia, kuantan, malaysia (n = 336) characteristic n (%) gender male 99 (29.5) female 237 (70.5) year of study 1 13 (3.9) 2 13 (3.9) 3 128 (38.1) 4 132 (39.3) 5 50 (14.9) programme of study nursing 54 (16.1) medicine 107 (31.8) pharmacy 53 (15.8) dentistry 38 (11.3) allied health sciences 84 (25) table 2: level of self-efficacy in interprofessional learning skills according to gender among healthcare students at the international islamic university malaysia, kuantan, malaysia (n = 336) subscale mean score* ± sd p value male (n = 99) female (n = 237) interprofessional interaction 58.1 ± 9.8 57.1 ± 10.2 0.383 interprofessional team evaluation and feedback 56.5 ± 9.3 55.3 ± 9.8 0.295 overall 114.6 ± 18.5 112.4 ± 19.3 0.322 sd = standard deviation. *assessed using the self-efficacy for interprof essional experiential learning scale.14 mohd s. nurumal, nurul q. h. diyono and muhammad k. che hasan clinical and basic research | e377 gradually being adopted around the globe including in asia.20 in the current study, no significant differences in self-efficacy scores were found according to gender. this finding is in line with those observed by nørgaard et al. during a quasi-experimental study.21 similarly, vuong et al. also reported no significant differences in levels of self-efficacy between students of either gender in terms of academic success.22 interestingly, other studies have published contradictory findings. for instance, a meta-analysis indicated that levels of self-efficacy in language or the arts are usually higher in females, whereas males show greater self-efficacy in mathematics or computer science.23 this difference might be more pronounced for domain-specific selfefficacy as existing research indicates that the strength and direction of gender differences varies with subject and area of interest.16 other factors likely also play a role and should be investigated, including the individual’s interest, willingness to learn and preferred learning style, in order to determine whether these aspects directly or indirectly influence levels of self-efficacy between genders. showing interest and willingness to learn is a major factor contributing to self-efficacy.24 williams et al. reported that neither subscale of the seiel instrument was able to assess a significant difference in the level of self-efficacy between healthcare disciplines.25 in contrast, the current study highlighted an interesting finding in which significant differences in self-efficacy scores for the interprofessional interaction subscale arose according to programme of study, particularly between students of two different programmes (i.e. pharmacy and allied health sciences). these mean scores reflect a small difference which does not necessarily contradict the previous study which found no significant difference with regard to healthcare disciplines.25 however, there is no explanation as to why this happens and larger longitudinal studies are required for further clarification. the authors of the current study speculate that different healthcare curricula may offer unique learning opportunities throughout the course of study which will result in variations in ipl self-efficacy. in addition, other factors may have influenced the outcomes of the present study such as the varying involvement of the students with patient care and differences in terms of degree of interaction with other professions during clinical practice. moreover, it is important to note that students in allied health sciences programmes are frequently exposed to other disciplines namely audiology, optometry, physiotherapy, radiography and dietetics; in addition, these students are often more heavily involved in patient care and actively participate in multidisciplinary interactions and research during their course of study. in contrast, pharmacy students tend to focus primarily table 3: level of self-efficacy in interprofessional learning skills according to programme of study among healthcare students at the international islamic university malaysia, kuantan, malaysia (n = 336) subscale mean score* ± sd p value nursing (n = 54) medicine (n = 107) pharmacy (n = 53) dentistry (n = 38) allied health sciences (n = 84) interprofessional interaction 55.1 ± 10.0 58.5 ± 9.3 54.1 ± 10.4 58.9 ± 9.1 57.4 ± 10.1 0.014† interprofessional team evaluation and feedback 54.6 ± 9.0 56.3 ± 8.3 53.6 ± 9.5 56.8 ± 12.0 56.3 ± 9.3 0.351 overall 109.7 ± 18.5 114.9 ± 17.1 107.7 ± 19.2 115.2 ± 18.9 113.0 ± 19.1 0.075 sd = standard deviation. *assessed using the self-efficacy for interprofessional experiential learning scale.14 †statistically significant at p <0.050. table 4: level of self-efficacy in interprofessional learning skills according to year of study among healthcare students at the international islamic university malaysia, kuantan, malaysia (n = 336) subscale mean score* ± sd p value year 1 (n = 13) year 2 (n = 13) year 3 (n = 128) year 4 (n = 132) year 5 (n = 50) interprofessional interaction 52.8 ± 10.4 53.2 ± 9.6 56.1 ± 9.1 58.5 ± 10.0 59.9 ± 11.9 0.018† interprofessional team evaluation and feedback 51.2 ± 8.8 54.2 ± 9.7 54.9 ± 9.1 56.5 ± 9.5 57.1 ± 11.4 0.204 overall 104.0 ± 18.9 107.9 ± 18.8 110.9 ± 17.3 115.0 ± 18.9 116.9 ± 22.9 0.059 sd = standard deviation. *assessed using the self-efficacy for interprofessional experiential learning scale.14 †statistically significant at p <0.050. self-efficacy levels regarding interprofessional learning skills among undergraduate healthcare students in malaysia e378 | squ medical journal, november2020, volume 20, issue 4 on reviewing and supplying prescribed drugs and may therefore be less involved in actual patient care or have less direct contact with other healthcare professionals. hall stated that each healthcare profession has a different culture, with unique values, beliefs, attitudes, customs and behaviours.26 educational experiences and socialisation processes that take place during training also reinforce the common values and problemsolving approaches of each profession. this increased specialisation may lead to learners becoming further immersed in their own professional group. indirectly, these factors might contribute to differences in the level of self-efficacy in ipl skills observed in students in the current study. year of study was not found to significantly affect levels of self-efficacy for subscale interprofessional team evaluation and feedback of the seiel instrument in the present study. similar results were reported in williams et al.’s study, which showed a non-significant difference in ipl self-efficacy with regards to study year.25 in contrast, other studies have noted that students in their senior years appear to have a higher level of self-efficacy compared to junior students.24,27 increasing maturity on the part of the students could potentially lead to an increase in their levels of selfefficacy, both as a natural result of getting older and as they progress further in their studies. both the knowledge as well as the clinical experience attained during senior years might be a contributory factor to increased self-efficacy.24 other external factors might also exist which have not been highlighted in this research. undergraduate healthcare students, irrespective of their year of study, might have been exposed early to the importance of ipl via indirect discussion as well as during specific courses. in fact, many educators nowadays actively implement teaching and learning strategies that may offer students the opportunity to attain the skills necessary to function effectively as a member of an interprofessional team in real practical settings.28 simulation exercises, for example, are just one of many effective learning strategies to enhance self-confidence and reduce anxiety among healthcare students, particularly when it comes to caring for patients.8,12 a limitation of this study was the inability to generalise findings as the participants consisted solely of students from a single university. as such, larger longitudinal studies involving greater sample sizes are necessary to further explore this phenomenon. other factors such as support, the involvement of peers and the use of simulation in both the academic and clinical performance of healthcare students should also be considered particularly when seeking to determine an individual student’s level of self-efficacy for the entire duration of study. further research is also needed to clarify how self-efficacy relates to clinical learning as this may become a foundation from which to initiate positive changes to healthcare education in the future.29 conclusion this study found that iium undergraduate students from five different healthcare-related programmes exhibited moderately-high levels of self-efficacy with regards to their ipl skills. self-efficacy in the execution of ipl skills is crucial to ensure students can adequately prepare themselves for future interdisciplinary collaboration in real-life clinical settings. ideally, these findings may contribute to the more effective and standardised implementation of ipl skills in healthcare curricula in the future. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. olenick m, allen lr. faculty intent to engage in interprof essional education. j multidiscip healthc 2013; 6:149–61. https://doi.org/10.2147/jmdh.s38499. 2. world health organization. framework for action on interprofessional education and collaborative practice. from: www.who.int/hrh/resources/framework_action/en/ accessed: feb 2020. 3. dahlberg j, falk al, kjellgren k, dahlgren ma. creating a common curriculum for interprofessional learning: strategic development of undergraduate programs in medicine and health. from: www.iced2014.se/proceedings/1514_ abrandt%20dahlgren.pdf accessed: feb 2020. 4. leotsakos a, ardolino a, cheung r, zheng h, barraclough b, walton m. educating future leaders in patient safety. j multidiscip healthc 2014; 7:381–8. https://doi.org/10.2147/ jmdh.s53792. 5. hughes a, galbraith d, white d. perceived competence: a common core for self-efficacy and self-concept? j pers assess 2011; 93:278–89. https://doi.org/10.1080/00223891.2011.559390. 6. bandura a. self-efficacy: toward a unifying theory of behavioral change. psychol rev 1977; 84:191–215. https://doi. org/10.1037//0033-295x.84.2.191. 7. bartimote-aufflick k, bridgeman a, walker r, sharma m, smith l. the study, evaluation, and improvement of university student self-efficacy. stud high educ 2016; 41:1918–42. https:// doi.org/10.1080/03075079.2014.999319. 8. labrague lj, mcenroe-petitte dm, bowling am, nwafor ce, tsaras k. high-fidelity simulation and nursing students’ anxiety and self-confidence: a systematic review. nurs forum 2019; 54:358–68. https://doi.org/10.1111/nuf.12337. https://doi.org/10.2147/jmdh.s38499 https://doi.org/10.2147/jmdh.s53792 https://doi.org/10.2147/jmdh.s53792 https://doi.org/10.1080/00223891.2011.559390 https://doi.org/10.1037//0033-295x.84.2.191 https://doi.org/10.1037//0033-295x.84.2.191 https://doi.org/10.1080/03075079.2014.999319 https://doi.org/10.1080/03075079.2014.999319 https://doi.org/10.1111/nuf.12337 mohd s. nurumal, nurul q. h. diyono and muhammad k. che hasan clinical and basic research | e379 9. baaij a, özok ar, væth m, musaeus p, kirkevang ll. selfefficacy of undergraduate dental students in endodontics within aarhus and amsterdam. int endod j 2019; 53:276 –84. https://doi.org/10.1111/iej.13218. 10. inuwa im. interprofessional education (ipe) activity amongst health sciences students at sultan qaboos university: the time is now! sultan qaboos univ med j 2012; 12:435–41. https://doi. org/10.12816/0003168. 11. brock d, abu-rish e, chiu cr, hammer d, wilson s, vorvick l, et al. interprofessional education in team communication: working together to improve patient safety. postgrad med j 2013; 89:642–51. https://doi.org/10.1136/postgradmedj-2012000952rep. 12. khan ns, shahnaz si, gomathi kg. currently available tools and teaching strategies for the interprofessional education of students in health professions: literature review. sultan qaboos univ med j 2016; 16:e277–85. https://doi.org/10.18295/squ mj.2016.16.03.003. 13. riesen e, morley m, clendinneng d, ogilvie s, murray ma. improving interprofessional competence in undergraduate students using a novel blended learning approach. j interprof care 2012; 26:312–18. https://doi.org/10.3109/13561820.2012.660286. 14. mann k, mcfetridge-durdle j, breau l, clovis j, martinmisener r, matheson t, et al. development of a scale to measure health professions students’ self-efficacy beliefs in interprofessional learning. j interprof care 2012; 26:92–9. https://doi.org/10.3109/13561820.2011.640759. 15. mayo at, ms, woolley aw. teamwork in health care: maximizing collective intelligence via inclusive collaboration and open communication. ama j ethics 2016; 18:933–40. https://doi.org/10.1001/journalofethics.2016.18.9.stas2-1609. 16. schnell k, ringeisen t, raufelder d, rohrmann s. the impact of adolescents’ self-efficacy and self-regulated goal attainment processes on school performance: do gender and test anxiety matter? learn individ differ 2015; 38:90–8. https://doi.org/10.1 016/j.lindif.2014.12.008. 17. williams b, beovich b, ross l, wright c, ilic d. self-efficacy perceptions of interprofessional education and practice in undergraduate healthcare students. j interprof care 2017; 31:335–41. https://doi.org/10.1080/13561820.2017.1286637. 18. alinier g, harwood c, harwood p, montague s, huish e, ruparelia k, et al. immersive clinical simulation in undergrad uate health care interprofessional education: knowledge and perceptions. clin simul nurs 2014; 10:e205–16. https://doi. org/10.1016/j.ecns.2013.12.006. 19. honan l, fahs db, talwalkar js, kayingo g. interprofessional learning: perceptions of first year health students. j nurs educ pract 2015; 5:39–49. https://doi.org/10.5430/jnep.v5n6p39. 20. lestari e, stalmeijer re, widyandana d, scherpbier a. under standing students’ readiness for interprofessional learning in an asian context: a mixed-methods study. bmc med educ 2016; 16:179. https://doi.org/10.1186/s12909-016-0704-3. 21. nørgaard b, draborg e, vestergaard e, odgaard e, jensen dc, sørensen j. interprofessional clinical training improves selfefficacy of health care students. med teach 2013; 35:e1235–42. https://doi.org/10.3109/0142159x.2012.746452. 22. vuong m, brown-welty s, tracz s. the effects of self-efficacy on academic success of first-generation college sophomore students. j coll stud dev 2010; 51:50–64. https://doi.org/1 0.1353/csd.0.0109. 23. huang c. gender differences in academic self-efficacy: a meta-analysis. eur j psychol educ 2013; 28:1–35. https://doi. org/10.1007/s10212-011-0097-y. 24. jones sh. nursing students’ perceptions of working with staff nurses. msn thesis, 2010, montana state university, bozeman, montana, usa. 25. williams b, beovich b, ross l, wright c, ilic d. self-efficacy perceptions of interprofessional education and practice in undergraduate healthcare students. j interprof care 2017; 31:335–41. https://doi.org/10.1080/13561820.2017.1286637. 26. hall p. interprofessional teamwork: professional cultures as barriers. j interprof care 2005; 19:188–96. https://doi.org/10. 1080/13561820500081745. 27. mueller sa, naragon rm, smith rr. the relationship between nursing students’ perceptions of staff nurses’ attitudes towards them and self-efficacy in sophomoreand senior-level nursing students. honours research project, 2016, university of akron, akron, ohio, usa. 28. rossler kl, buelow jr, thompson aw, knofczynski g. effective learning of interprofessional teamwork. nurse educ 2017; 42:67–71. https://doi.org/10.1097/nne.0000000000000313. 29. townsend l, scanlan jm. self-efficacy related to student nurses in the clinical setting: a concept analysis. int j nurs educ scholarsh 2011; 8: 1–15. https://doi.org/10.2202/1548923x.2223. https://doi.org/10.1111/iej.13218 https://doi.org/10.12816/0003168 https://doi.org/10.12816/0003168 https://doi.org/10.1136/postgradmedj-2012-000952rep https://doi.org/10.1136/postgradmedj-2012-000952rep https://doi.org/10.18295/squmj.2016.16.03.003 https://doi.org/10.18295/squmj.2016.16.03.003 https://doi.org/10.3109/13561820.2012.660286 https://doi.org/10.3109/13561820.2011.640759 https://doi.org/10.1001/journalofethics.2016.18.9.stas2-1609 https://doi.org/10.1016/j.lindif.2014.12.008 https://doi.org/10.1016/j.lindif.2014.12.008 https://doi.org/10.1080/13561820.2017.1286637 https://doi.org/10.1016/j.ecns.2013.12.006 https://doi.org/10.1016/j.ecns.2013.12.006 https://doi.org/10.5430/jnep.v5n6p39 https://doi.org/10.1186/s12909-016-0704-3 https://doi.org/10.3109/0142159x.2012.746452 https://doi.org/10.1353/csd.0.0109 https://doi.org/10.1353/csd.0.0109 https://doi.org/10.1007/s10212-011-0097-y https://doi.org/10.1007/s10212-011-0097-y https://doi.org/10.1080/13561820.2017.1286637 https://doi.org/10.1080/13561820500081745 https://doi.org/10.1080/13561820500081745 https://doi.org/10.1097/nne.0000000000000313 https://doi.org/10.2202/1548-923x.2223 https://doi.org/10.2202/1548-923x.2223 this book has a high degree of reader friendliness. it provides a practical and easy-to-follow six-step approach to curriculum development for medical education. it starts with a suitable introduction and an overview of the six steps that highlight the interactive and continuous nature of the approach. the following chapters (2 to 7) describe each of the six steps in detail: problem identification, needs assessment, goals and objectives, educational strategies, implementation, and evaluation. chapter 8 explains the significance of the maintenance, enhancement, and dissemination of a curriculum. appendix a is a highlight because it gives practical examples of the six step approach. appendix b provides the reader with a selected list of published and unpublished resources on funding, faculty development, and already developed curricula. on a more personal level, i chose to read and review this book because i am interested in curriculum design and found it to be a great starting place. i have completed my major paper on curriculum development in a residency program using this approach. the major strength of the book is that the six steps are clearly presented with relevant examples to illustrate important concepts. it is very useful for beginner curriculum developers. summary tables are available which help readers with limited time to get to grips with the comprehensive text. every chapter finishes with conclusions and questions which stimulate critical reflection. these are then followed by helpful general and specific references. there is an evaluation form at end of the book which can be used by the reader to contribute to improvements in future editions. the weakness of this book is that it is mainly focused on education in medicine. incorporating examples 9�÷]<<‹è◊√j◊÷<<s„flπ]<üëá�i <l]á�}<kâ<2¬<ìœëüõ  book reviewbook review curriculum development for medical education a six-step approach authors: david e kern, patricia a thomas, donna m howard, eric b bass publisher: johns hopkins university press, baltimore, maryland, 2nd edition, 2009 isbn: 0-8018-5844-5 orders: http://jhupbooks.press.jhu.edu squ med j, december 2010, vol. 10, iss. 3, pp. 416-417, epub. 14th nov 10 submitted 25th june 10 david e kern, patricia a thomas, donna m howard and eric b bass book review | 417 from other health professions might attract a wider audience. in addition, some of the examples are challenging to understand. finally, it contains only one figure; having more would make it more applicable to readers with visual learning styles. the intended audience includes program directors and other faculty members who are responsible for the educational experiences of students, residents, fellows and clinical practitioners. i recommend this book to all health educators to use as a basic framework to guide them through the curriculum development process. also, it would be useful for all beginner curriculum developers. r e v i e w e r thuraya a al-shidhani department of family and community medicine university of toronto toronto, canada email: shidhanitutu@yahoo.com quercetin a potential treatment for keloids sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e372–373, epub. 22 dec 19 submitted 19 jun 19 revision req. 7 aug 19; revision recd. 14 aug 19 accepted 5 sep 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.015 letter to the editor ُكريسيتني عالج حمتمل للُجَدرات dear editor, plant secondary metabolites are chemically diverse compounds, some of which have been largely exploited as pharmaceuticals, food additives and flavours. flavonoids and other phenolic compounds constitute one of the main classes of secondary metabolites.1,2 as one of the most abundant form of flavonoids, quercetin (3,3’, 4’, 5,7-pentahydroxyflavone) has been receiving much attention owing to its potential antioxidant, anti-allergic, antiinflammatory, anti-cancer, anti-diabetic, anti-microbial and cardio-protective properties.1 keloids are exuberant overgrowths of scar with excessive fibroblast proliferation and matrix deposition, which has the ability to spread beyond the original boundary of the wound.3 despite existence of a wide array of therapies available for keloids, no treatment is yet considered completely effective. corticosteroids, surgical excision, silicone sheeting, cryosurgery, radiotherapy, laser therapy and photodynamic therapy have been extensively applied to treat keloids.4 other promising approaches such as mesenchymal stem cell therapy, fat grafting, electrical stimulation, and deployment of rna interference seem to be beneficial for the treatment of keloids.5 over the past years, studies found compelling evidence that indicate the advantageous properties of quercetin as a potential candidate for adjuvant therapy of keloids.3,4 according to si et al.’s recent study, keloid fibroblasts treated with quercetin showed augmented sensitisation to radiation compared to untreated cells.3 the main mechanism underlying the suppression of radio-resistance by quercetin is down-regulation of hypoxia-inducible factor 1, a prognostic factor used in clinical practice after radiation therapy, through the phosphoinositide 3-kinase/akt pathway.3 an in vitro study by mathangi ramakrishnan et al. revealed a dose-dependent action of quercetin and vitamin d3 on isolated keloid fibroblasts.4 in this context, both agents alone were capable of reducing either collagen i synthesis or b-cell lymphoma 2 gene expression and increasing caspase-3 levels in fibroblast cells, resulting in higher number of apoptotic fibroblasts.4 cho et al. found that quercetin and onion extract diminished the proliferation rate of fibroblasts in a concentratedependent manner by up-regulation of matrix metalloproteinase-1 expression levels in vitro and in vivo.2 however, contrary to expectations, expression levels of type i collagen were not markedly changed. khonkarn et al. attempted to develop a quercetin-incorporated microemulsion-based gel formulation for topical delivery against keloids and concluded that the developed gel may be a promising vehicle for topical drug delivery.6 doersch and newell-rogers found that quercetin diminishes fibrosis at wound sites in quercetin-treated mice by altering cell interactions with the extracellular matrix (ecm) through increasing αvand decreasing β1-integrin expression levels.1 this would enhance cell migration with less ecm requirement to facilitate wound closure. gopalakrishnan et al. showed beneficial properties of 0.1% quercetin ointment in accelerating cutaneous wound healing in rats by increasing the expression levels of vascular endothelial growth factor, transforming growth factor-β1 and interleukin-10 as well as reducing tumour necrosis factor-α levels in rats.7 in addition, quercetintreated rats exhibited less inflammatory cells, more regular collagen deposition and better re-epithelialisation compared to the control group.7 multiple approaches can be propounded to improve therapeutic efficacy of quercetin for ideal skin delivery. the conjugation of quercetin with nanoparticles or fatty acids and designing quercetin-based hydrogels are novel strategies for combating keloids. furthermore, the use of quercetin as an adjuvant therapy with other antikeloid treatments may result in lower keloid recurrence rates. in patients with keloids and hypertrophic scars, onion extract gel which is a rich source of quercetin, has been shown to be beneficial when combined with other therapeutic strategies such as silicone gel sheet and corticosteroids.8,9 in terms of sensitiveness, pain, itching and elevation, intralesional triamcinolone acetonide plus onion extract gel was superior to triamcinolone acetonide alone.8 hosnuter et al.’s comparative prospective study combined onion extract gel and silicone gel sheet, which significantly reduced scar height; the combination was found to be more effective than onion extract gel alone.9 https://creativecommons.org/licenses/by-nd/4.0/ hamideh moravvej, mojtaba memariani and hamed memariani letter to the editor | e373 quercetin can be formulated in different dermatological preparations such as micro-emulsion gels, liposomes and a nanostructured lipid carrier. these formulations can be used topically for both prevention and treatment of keloid scars. overall, the propitious role of quercetin as an immunomodulatory, anti-fibrotic agent will hopefully increase the treatment options available for patients who are afflicted with keloids, hypertrophic scars and wounds. hamideh moravvej, *mojtaba memariani, hamed memariani skin research center, shahid beheshti university of medical sciences, tehran, iran *corresponding author’s e-mail: memaryani@gmail.com references 1. doersch km, newell-rogers mk. the impact of quercetin on wound healing relates to changes in αv and β1 integrin expression. exp biol med (maywood) 2017; 242:1424–31. https://doi.org/10.1177/1535370217712961. 2. cho jw, cho sy, lee sr, lee ks. onion extract and quercetin induce matrix metalloproteinase-1 in vitro and in vivo. int j mol med 2010; 25:347–52. https://doi.org/10.3892/ijmm_00000351. 3. si lb, zhang mz, han q, huang jn, long x, long f, et al. sensitization of keloid fibroblasts by quercetin through the pi3k/akt pathway is dependent on regulation of hif-1α. am j transl res 2018; 10:4223-34. https://doi.org/10.4172/2155-9554.1000409. 4. mathangi ramakrishnan k, babu m, lakshmi madhavi ms. response of keloid fibroblasts to vitamin d3 and quercetin treatment in vitro study. ann burns fire disasters 2015; 28:187–91. 5. lee hj, jang yj. recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids. int j mol sci 2018; 19:e711. https://doi.org/10.3390/ijms19030711. 6. khonkarn r, mankhetkorn s, okonogi s. formulation, optimization, and photostability assessment of microemulsion gel for topical quercetin delivery. lat am j pharm 2017; 36:959–67. 7. gopalakrishnan a, ram m, kumawat s, tandan s, kumar d. quercetin accelerated cutaneous wound healing in rats by increasing levels of vegf and tgf-β1. indian j exp biol 2016; 54:187–95. 8. koc e, arca e, surucu b, kurumlu z. an open, randomized, controlled, comparative study of the combined effect of intralesional triamcinolone acetonide and onion extract gel and intralesional triamcinolone acetonide alone in the treatment of hypertrophic scars and keloids. dermatol surg 2008; 34:1507–14. https://doi.org/10.1111/j.1524-4725.2008.34314.x. 9. hosnuter m, payasli c, isikdemir a, tekerekoglu b. the effects of onion extract on hypertrophic and keloid scars. j wound care 2007; 16:251–4. https://doi.org/10.12968/jowc.2007.16.6.27070. https://doi.org/10.1177/1535370217712961 https://doi.org/10.3892/ijmm_00000351 https://doi.org/10.4172/2155-9554.1000409 https://doi.org/10.3390/ijms19030711 https://doi.org/10.1111/j.1524-4725.2008.34314.x https://doi.org/10.12968/jowc.2007.16.6.27070 squ med j, december 2009, vol. 9, iss. 3, pp. 319-323, epub. 19th dec 2009 submitted 5th jun 09 revision req. 18th sept 09. revision recd. 30th sept 09 accepted 13th oct 09 amiodarone is an iodinated benzofuran derivative widely used in the treatment of a variety of arrhythmias. however, in patients on prolonged treatment with this agent, a variety of thyroid abnormalities are observed primarily resulting from an inhibition of 5 deiodinase activity. the complex effects of this drug on the thyroid range from subclinical abnormalities in thyroid function to overt hypo or hyper function of the thyroid. amiodarone-induced thyrotoxicosis (ait) develops in 3% of patients treated with amiodarone and 10% of those in iodine deficient areas. the different mechanisms leading to development of ait results in two types of thyrotoxicosis labelled as type 1 and type 2. differentiation of the types can be achieved using a combination of clinical, laboratory and radiological means and is important in deciding the appropriate treatment for the patient. case report a 56 year-old male patient presented to the outpatient service of armidale rural referral hospital, australia, with complaints of extreme lethargy, tiredness and a lack of initiative experienced over the preceding three months. in 2001, the patient had been diagnosed as having atrial fibrillation and was on a maintenance dose of amiodarone 200mg daily. clinical examination revealed him to be in atrial fibrillation with a heart rate of 90/minute. there was mild enlargement of the thyroid and minimal exophthalmos. there was no tenderness of the thyroid on palpation. on suspicion of amiodarone-induced thyroid dysfunction, an urgent thyroid function test was done which revealed surprisingly hyperthyroidism. it was decided to admit the patient with a provisional diagnosis of amiodarone-induced thyrotoxicosis for further workup. the patient underwent a full evaluation which armidale rural referral hospital, armidale, nsw 2350, australia * to whom correspondence should be addressed: email: sudheer.ahamed@hnehealth.nsw.gov.au تقرير حالة تسمم درقي ناتج عن العالج بعقار أميودارون حرية تشخيصية وعالجية سدير أحمد ، آبي ماثيو امللخص: عقار أميودارون غني باليود ويستعمل بشكل واسع في عالج اضطراب النظم البطيني ، تََسرُُّع الَقلِْب االنِْتيابِّي فوق البطيني ، الرجفان األذيني والرفرفة. يصاب (%18-14) من املرضى الذين يعاجلون بالدواء املذكور باضطراب واضح بالغدة الدرقية ، على شكل تسمم درقي أو قصور في الغدة الدرقية. هناك نوعني من التسمم الدرقي ، يكون التمييز بينهما صعبا لكنه ضروريا إلجراء العالج املناسب . نصف هنا حالة مريض عمره 56 سنة عولج باألميودارون بسبب الرجفان األذيني لكنه أصيب بتسمم الغدة الدرقية . ناقشنا حتديات التشخيص والعالج ملثل هذه احلاالت. مفتاح الكلمات : أميودارون ، الغدة الدرقية ، التسمم الدرقي ، اضطراب النظم ، نقص الدرقية اخلامل. abstract: amiodarone is an iodine rich agent widely used for the treatment of ventricular arrhythmias, paroxysmal supraventricular tachycardia, atrial fibrillation and flutter. however 14-18% of patients treated with amiodarone develop overt thyroid dysfunction in the form of either amiodarone-induced thyrotoxicosis (ait) or amiodaroneinduced hypothyroidism (aih). two different types of ait have been recognised and designated as type 1 and type 2. distinguishing between the two is often difficult, but necessary for instituting appropriate treatment. we report a case of a 56 year-old male patient who was started on amiodarone for atrial fibrillation and then developed ait. the challenges in the diagnosis and management of these patients are discussed. keywords: amiodarone; thyroid; thyrotoxicosis; apathetic hyperthyroidism; arrhythmias; case report. a case of amiodarone-induced thyrotoxicosis a diagnostic and therapeutic dilemma *sudheer ahamed ps, abe mathew case report a case of amiodarone-induced thyrotoxicosis a diagnostic and therapeutic dilemma 320 | squ medical journal, december 2009, volume 9, issue 3 included a repeat thyroid function test, inflammatory markers, thyroid autoantibodies and radiological evaluation of the thyroid using an ultrasound and nuclear scan study [table 1]. the ultrasound study of the thyroid did not reveal any enlargement of the gland or increased vascularity [figure 1]. the nuclear study showed no uptake in activity consistent with amiodaroneinduced thyroiditis [figure 2]. inflammatory markers were mildly elevated with an erythrocyte sedimentation rate (esr) of 40mm/hour and a c-reactive protein (crp) of 30mg/l. the clinical presentation, laboratory features and radiological evaluation was suggestive of type 2 ait or a mixed picture. after discussion with the endocrinologist, it was decided to start the patient on propylthiouracil (ptu) 100mg three times daily with a plan to add steroids if the thyroid function did not revert to normal. amiodarone was discontinued and the patient started on metoprolol, adopting a rate control strategy for his atrial fibrillation. on follow-up after one month, the patient reported an improvement in his clinical symptoms. however, his thyroid functions continued to be in the toxic range with a thyroid stimulating hormone (tsh) of 0.03 mu/l, free t4 of 44 pmol/l and free t3 4.9 pmol/l. in view of these results, it was decided to start the patient on oral steroids with a dose of 30mg prednisolone per day. ptu was continued at the same dosage. after a further month, the patient reported, during a follow-up visit, that there was a significant reduction in his symptoms. a repeat blood test revealed normalisation of his thyroid functions with a tsh of 1.65mu/l and free t4 of 14 pmol/l. it was decided to taper his ptu to a maintenance dose of 50mg twice daily. steroids were tapered and discontinued over the next week. the final diagnosis was type 2 amiodarone-induced thyrotoxicosis responding to antithyroid drugs and steroids. discussion amiodarone is a benzofuranic acid derivative with a high content of iodine and a structural formula that resembles t4. it is a widely-used anti-arrhythmic drug. the maintenance dose of amiodarone varies from 200 to 600mg per day releasing approximately 7 to 21mg of iodide. considering the daily requirement of iodine to be 150 to 200mcg, amiodarone treatment releases daily a 50 to 100 fold excess of iodine.2 in addition, amiodarone inhibits type 1 5’-deiodinase enzyme activity thereby decreasing the peripheral conversion from t4 to t3. amiodarone is predominantly metabolised by dealkylation into desethylamiodarone (dea) which is known to have anti-arrhythmic properties. a total of 75% of the drug is excreted through the bile and faeces. the elimination half-life of amiodarone is unusually long at an average of 58 days.3 chronic treatment with amiodarone can have several effects on thyroid function. over half of the patients treated with this agent can develop innocent changes in thyroid hormone levels. a total of 14 to 18% of patients treated with amiodarone develop overt thyroid dysfunction.3 this can be in the form of acute transient suppression of thyroid function, hypothyroidism in patients susceptible to the inhibitory effects of a high iodine load or table 1: laboratory values at the time of admission full blood count inflammatory markers thyroid function tests renal function tests thyroid antibodies hb 12.7mg/dl (13-15) esr 40mm/hr tsh 0.06mu/l(0.304.50) blood urea 9 mmol/l (3.6-8.4) anti-thyro globulin negative total count 7900 cells/mm3(4-11000) crp 30 mg/l free t4 67.4 pmol/l (7-17) creatinine 119 mmol/l (60-120) anti-microsomal antibodynegative platelet 280000 cells/ mm3 (1.5-450000) free t3 7.6pmol/l (3.8-6) sodium 140 mmol/l (136-144) anti-thyroid peroxidise antibody negative potassium 3.5 mmol/l (3.5-5) legend: esr = erythrocyte sedimentation rate; crp = c-reactive protein; tsh = thyroid stimulating hormone; sudheer ahamed ps and abe mathew case report | 321 thyrotoxicosis which can be due to two different mechanisms. type 1 ait is seen in patients with preexisting or latent thyroid disorders and is caused by unregulated hormonal synthesis (the jod-basedow phenomenon). type 2 ait occurs in patients who had normal thyroid function and is probably due to an increased release in the hormones from an inflammatory process resulting in thyroiditis.3, 4 differentiation of these two types of ait is often difficult, but important for deciding promptly upon the appropriate therapy. in addition, one often finds a mixed form with features from both types, further compounding differential diagnosis. although the differentiation can be extremely difficult, there are several clinical and laboratory clues which help the clinician in making a distinction. the initial task of the physician is to establish whether the patient had a pre-existing thyroid disorder. clinical examination should focus on looking for signs of thyroid illness such as goitre, exophthalmos or other peripheral signs of thyrotoxicosis, the presence of which would make the probability of type 1 ait more likely. the presence of fever and tenderness over the thyroid gland may indicate ongoing thyroiditis and suggest a type 2 ait picture. it is important to remember that patients with ait may lack the classical signs of thyrotoxicosis because of the cardioinhibitory effects of amiodarone.5 other clinical features of thyrotoxicosis such as weight loss, muscle weakness or irritability can predominate in these patients. our patient presented with features atypical of hyperthyroidism and fitted into the clinical syndrome of apathetic thyrotoxicosis. the apathetic presentation of thyrotoxicosis is not unusual, especially in older persons. in patients with this syndrome, the usual hyperactivity and restlessness of thyroid hyper-function is replaced with apathy and depression. the presence of thyroid autoantibodies such as antimicrosomal antibody or antithyroglobulin antibody may indicate a preexisting autoimmune thyroid disease.6 normal or increased values of radioactive iodine uptake in the nuclear studies indicate type 1 ait whereas in type 2 ait, the uptake is usually reduced or nil.7 inflammatory markers such as esr and crp may be elevated in type 2 ait indicating an ongoing thyroiditis. interleukin-6 (il-6) appears to be a better marker for thyroid gland destruction and is usually elevated in type 2 ait.8 however, falsely low il-6 levels are often encountered in type 2 ait limiting its usefulness. in addition, several preexisting disorders of thyroid such as grave’s disease can give rise to high il-6 levels. at present, the role of interleukin in differentiation of type i and type 2 ait remains unclear. colour flow sonography is another promising radiological modality which can help to distinguish between type 1 and type 2 ait. an increased vascularity of the thyroid gland is often figure 1: doppler ultrasound of the thyroid showing no increased vascularity of the thyroid a case of amiodarone-induced thyrotoxicosis a diagnostic and therapeutic dilemma 322 | squ medical journal, december 2009, volume 9, issue 3 evident in type 1 ait, whereas type 2 ait usually shows absent or uneven patchy parenchymal flow.9 the treatment of ait is often a challenge for the clinician. mild ait can subside spontaneously in approximately 20% of patients.10 it is important to distinguish between the types of ait as the treatment differs for each. it is also often difficult to make a decision about the continuation of amiodarone as many patients will require this drug from the cardiac point of view. however, immediate stoppage of amiodarone should not make a difference as this drug has a very long elimination half life. type 1 ait is often treated with antithyroid agents with a view to reducing the thyroid hormone synthesis. the addition of potassium perchlorate to this regimen helps to achieve a faster euthyroid state by inhibiting iodine uptake by the thyroid.11 type 2 ait is usually treated with a course of glucocorticoids for its anti-inflammatory and membrane stabilising effects. the usual dose required is between 30 and 50mg per day which is tapered over two to three months. another agent which has been tried in the treatment of type 2 ait is lithium carbonate which inhibits the thyroid hormone secretion. a further method of treatment which can be considered is a total thyroidectomy especially in patients who would need to continue amiodarone.12 patients with ait were found to have a high incidence of mortality and morbidity in a study conducted by conen et al.13 very often clinical and laboratory features suggest a mixed mechanism for ait. in such situations, the physician often has to combine both modalities of treatment. our patient had clinical features suggestive of type 1 ait whereas the laboratory and radiological investigations suggested a thyroiditis-like picture. in view of this, we decided to combine antithyroid drugs with corticosteroids resulting in a better outcome for the patient. conclusion this report shows that ait continues to be a diagnostic and therapeutic dilemma for clinicians. however, vigorous efforts to distinguish between the two types of ait are warranted in order to provide optimal treatment. it is important for health care providers, who regularly prescribe amiodarone, to figure 2: radionuclide scan of the thyroid showing no uptake activity sudheer ahamed ps and abe mathew case report | 323 be aware of the consequences on thyroid function in long-term users of this medication. patients who are likely to be on this drug on a long-term basis should have a baseline thyroid examination including thyroid hormone levels and antibodies. repeat thyroid examinations and hormone level tests are recommended every six months or sooner if clinical signs of hypoor hyperthyroidism develop in patients on amiodarone. references 1. martino e, safran m, aghini-lomardi f, rajatanavin r, lenziardi m, fay m, et al. environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. ann internal medicine 1984; 101:28-34. 2. martino e, bartalena l, bogazzi f, braverman le. the effects of amiodarone on thyroid. endocr rev 2001; 22:240-54. 3. rajeswaran c, shelton rj, gilbey sg. management of amiodarone-induced thyrotoxicosis, swiss med wkly 2003; 133:579-85. 4. brennan md, erickson dz, carney ja, bahn rs. nongoitrous (type 1) amiodarone-associated thyrotoxicosis: evidence of follicular disruption in vitro and in vivo; thyroid 1995; 5:177-83. 5. cardenas ga, gustavo ac, cabral jm, jose mc, leslie ca, camilo al. amiodarone-induced thyrotoxicosis: diagnostic and therapeutic strategies. cleve clinic j med 2003; 70:624-31. 6. iudica-souza c, burch hb. amiodarone-induced thyroid dysfunction. endocrinologist 1999; 9:216227. 7. martino e, bartalena l, marriotti s, aghini-lombardi f, ceccarelli c, lippi f, et al. radioactive iodine thyroid uptake in patients with amiodarone-iodineinduced thyroid dysfunction. acta endocrinol 1988; 119:167-73. 8. bartalena l, grasso l , brogioni s, aghini-lombardi f, braverman le, martino e. serum interleukin-6 in amiodarone induced thyrotoxcosis. j clin endocrinol metab 1994; 789:423-7. 9. daniels gh. clinical review 120: amiodarone-i induced thyrotoxicosis. j clin endocrinol metab 2001; 86:3-8. 10. eaton se, euinton ha, newman cm, weetman ap, bennet wm. clinical experience of amiodarone induced thyrotoxicosis over a 3-year period: role of colour-flow doppler sonography. clin endocrinol 2002; 56:33-8. 11. wolff j. perchlorate and thyroid gland: pharmacol rev 1998; 50:89-105. 12. williams m, logerfo p. thyroidectomy using local anaesthesia in critically ill patients with amiodarone induced thyrotoxicosis: a review and description. thyroid 2002; 12:523-5. 13. conen d, melly l, kaufmann c, bilz s, ammann b, schaer b, et al. amiodarone-induced thyrotoxicosis: clinical course and predictors of outcome. j am coll cardiol 2007; 49:2350-5. åáe^œ<·^�◊ä÷]<ì√⁄^q<›çœjπ]<›^√÷]<g�÷]<ü≥ˆ⁄ 20112324 abstracts advanced general medicine conference joint conference of sultan qaboos university and the ministry of health, oman 23rd–24th february 2011 squ med j, may 2011, vol. 11, iss. 2, pp. 297-300, epub. 15th may 11 gastrointestinal endocrinology prof. steve bloom hammersmith hospital, imperial college of london, uk. email s.bloom@imperial.ac.uk. there are two types of endocrine tissue, one gathered in glands – this is classical endocrinology. the other is dispersed endocrine cells spread throughout particular tissues – the diffuse endocrine system. the latter, although less well recognised is the larger and, arguably the more important. hormones are actually even wider than this – hormones being released from many cells not normally thought as endocrine (paracrine and neurocrine). the gut is controlled by both diffuse endocrine cells and non-endocrine cells producing “hormones”. the endocrine cells are mostly in the mucosa and integrate with the submucous neural plexus as well as sensing what has been eaten. from the physicians viewpoint there are two main conditions of interest – gastrointestinal endocrine tumours and dysfunctional regulation of digestion. endocrine tumours are important because they are eminently treatable. our understanding of digestive regulation is less well developed but shows the tight integration of the body as several gut hormones have powerful effects on how we think and behave. treatment of obesity prof. steve bloom hammersmith hospital, imperial college of london, uk. email s.bloom@imperial.ac.uk. the treatment of obesity is easy – eat less food. obesity clinics are frustrating as it is rare for patients to successfully lose weight and they often blame their physician. obviously low calorie, high fibre foods eaten with restraint and plenty of exercise are the key. equally obviously it often doesn’t work. with chronic conditions we need safe medication (eg hypertension, hypercholesterolaemia, chronic lymphatic leukaemia etc are all handled with chronic medication). can we treat obesity with a pill? approaching 130 new obesity treatments have been tested in human trials and only one remains on the market throughout the world – orlistat (xenical, alli), an agent which blocks lipase with such significant gi consequences that only 1% of patients are still taking it at the end of a year. is there no successful approach? bariatric bypass surgery works well, producing lifelong major weight loss, improving physical activity, halving heart disease and halving cancer and often curing diabetes. the increased release of satiety hormones in mainly responsible and we propose to mimic their increase medically. changing classification of neurological diseases prof. alastair compston department of clinical neurosciences, university of cambridge, uk.. email:kd203@medschl.cam.ac.uk. the naming of disease does not stand still. at first merely providing a description of symptoms or the most obvious physical manifestations, nomenclature later adopted the style of the medical eponym or acronym. famous figures were remembered through diseases named after them. many of these designations attracted rival claims for priority in having provided the first account of that disease, but as clinical neurology became more sophisticated and laboratory methods were introduced, the descriptive phenotypes broadened and overlap between apparently different conditions came to be recognised. the beginnings of mechanism-based disease classifications began to emerge. that process has continued with the recognition of a genetic basis for many common disorders, the identification of their environmental triggers, and the characterisation of molecular pathways involved in the pathogenesis of these complex phenotypes. generic principles such as aberrant protein folding, immune-based disorders and the failure of ion-channel activity have changed the classification of neurological disease. this is not just a matter of naming: the future of neurology may be less colourful in terms of hagiography but it will be more realisticand useful in terms of mechanism-based disease classification and therapeutics. neuromyelitis optica advanced general medicine conference joint conference of sultan qaboos university and the ministry of health, oman 298 | squ medical journal, may 2011, volume 11, issue 2 prof. alastair compston department of clinical neurosciences, university of cambridge, uk. email: kd203@medschl.cam.ac.uk. the disease that eugene devic described in 1894 was largely forgotten as knowledge on the aetiology, pathogenesis and phenotype of more common demyelinating diseases flourished in the 20th century. although cases were often misdiagnosed, the distinguishing features of neuromyelitis optica have been increasingly recognised and emphasised over the last 10 years. some patients respond to plasma exchange; antibody and complement deposition are demonstrated in tissue samples; a serum immunoglobulin biomarker for the condition has been described; and aquaporin 4 identified as the target antigen. with improved recognition attention has been drawn to the fact that neuromyelitis optica has a geographical distribution that differs from that of typical multiple sclerosis. this has led to debate on the relationship between these two disorders, the true and the false distinguishing features, and the status of transitional cases. as a result, the phenotype and features of neuromyelitis optica have broadened. now neuromyelitis optica is a disorder of astrocytes with complex secondary pathological effects, originating from autoimmunity against aquaporin 4, in which lesions usually but not exclusively involve the optic nerves and spinal cord, and with treatments directed at reducing antibody production sometimes altering the otherwise poor natural history. non cirrhotic portal hypertension prof. elwyn elias british society of gastroenterology, liver unit, queen elizabeth hospita,uk. email: elwyn.elias@uhb.nhs.uk. portal hypertension is most commonly associated with cirrhosis of the liver. in this lecture we will briefly review the range of other conditions that can similarly lead to bleeding from oesophageal varices, ascites and even hepatic encephalopathy. vascular conditions may interfere with the flow of blood into or its exit from the liver. we will discuss occlusion of the portal vein at extraand intra-hepatic levels, sinusoids and hepatic vein. in addition hepatic problems may induce vascular changes in the pulmonary circulation which have a profound effect on gas exchange and right heart function. intrahepatic cholestasis prof. elwyn elias british society of gastroenterology, liver unit, queen elizabeth hospita,uk. email: elwyn.elias@uhb.nhs.uk. cholestasis may result from purely intrahepatic problems involving hepatocytic function, canalicular secretion, canalicular obstruction and ductular obstruction. intrahepatic cholestasis may be caused by a variety of factors including inherited genetic mutations, metabolic, endocrine, toxic and pharmacological agents. we will review the symptoms and signs of cholestasis as well as approaches to its treatment. oral diseases: systemic disease diagnosis from oral signs prof. farida fortune clinical and diagnostic oral sciences, barts & the london school of medicine and dentistry. email:f.fortune@qmul.ac.uk . most diseases (approximately 95%) can be diagnosed by careful consideration of oral symptoms and signs. these are commonly neglected in the diagnostic hierarchy. the presentation will allow delegates to develop structured methods for examination of the head and neck. it will also give a clinical overview to assist in increasing the diagnostic accuracy within the general medical environment. behcets disease prof. farida fortune clinical and diagnostic oral sciences, barts & the london school of medicine and dentistry. email:f.fortune@qmul.ac.uk. behçet’s syndrome (bs) is an immune related disease which is markedly prevalent in areas surrounding the old silk trading routes in the middle east, including oman ,qatar, and central asia. it is a multi-systemic disease characterised by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. bs is often associated with other major organ involvement, vasculitis and thrombotic activity. uveitis is the main cause of blindness while the central nervous system involvement can lead to stroke or death especially in young people. bs is a debilitating chronic disease which severely affects patients’ quality of life (fortune, 2003, mumcu et al., 2009b). patients most frequently present with recurrent oral ulceration as the initial sign of the disease. because of this observation, it is thought that the oral environment may play a very important role in its etiology and pathogenesis. to date the consensus is that the disease is triggered by a profound inflammatory response to an undefined environmental factor in a genetically susceptible host but as yet the etiology remains poorly understood (lehner, 1999).diagnosis is based on clinical criteria, dependent on the presence of recurrent oral ulcerations, plus any two of recurrent genital ulcerations, ocular or skin lesions, and a positive pathergy test . diagnosis is difficult but once diagnosed treatment options lead to good quality of life. the presentation will discuss issues of specific clinical symptoms and signs associated with diagnostic pathways. and current treatment options.whilst clinical activity is associated with considerable morbidity, specific indicators for onset of disease activity are not known. t cells, neutrophils and inflammatory cytokines and chemokines are all believed to play important roles .recent research associated with disease will be explored. individualisation of cancer care: reality or pipedream? dr. charlie gourley medical oncology, university of edinburgh, uk. email : charlie.gourley@ed.ac.uk. cancer is a complex disease which historically has been largely treated according to the assumed tissue of origin of the tumour. it 23rd–24th february 2011 abstracts | 299 has always been known that cancers from a particular site may vary considerably in their histology and treatments sometimes take account of this. recent research however has demonstrated the considerable molecular heterogeneity of tumours with apparently identical histology. novel treatments are now being developed to target particular molecular or pathway defects and the necessity of individualisation of care is clear in this cases. what is less clear is how we should progress the stratified medicine agenda in tumours with clearly different molecular make-up but without such obvious molecular targets. we will discuss various aspects of individualisation of cancer care; success stories to date, areas of imminent progress, difficult areas where progress is possible, mechanisms to speed up the discovery phase for molecular therapies and how to create molecular tests which are accessible to non-specialist centres. the brca1 and brca2 genes in ovarian cancer: so much more than markers of hereditary risk dr. charlie gourley medical oncology, university of edinburgh, uk. email : charlie.gourley@ed.ac.uk. since the mid-1990s it has been clear that mutations in the brca1 and brca2 genes predispose female carriers to breast, ovarian and other cancers. now we know that germline brca1/2 mutation carriers who develop ovarian cancer have a different disease course to non brca1/2 mutation carriers. they are more likely to: have a serous histology; respond to multiple lines of platinum-based chemotherapy; develop visceral metastases. despite the propensity for visceral metastases their median survival is approximately twice that of comparable non-brca1/2 germline mutation carriers. the recognition of this discrete molecular entity has partly been driven by the development of a new class of anti-cancer agents known as poly (adp-ribose) polymerase (parp) inhibitors. early phase clinical trials have demonstrated exciting efficacy of these agents. as an extension of this, researchers have sought other ovarian cancer patients who have the ‘brcaness’ phenotype without carrying a brca1/2 germline mutation (other mechanisms include somatic mutation, epigenetic inactivation or mutation of other pathway members). there is now preliminary evidence that these patients may also benefit from parp inhibition. the hope is that being able to identify this molecular subtype will allow use of parp inhibitors and improve the outcome for these ovarian cancer patients. lupus: a story of failure and success prof. graham hughes the london lupus centre, london bridge hospital uk. email:graham.hughes@hcaconsultant.co.uk. despite the advances in recognition and treatment of lupus, pitfalls and obstacles persist in the management of this complex disease. examples of ‘failure’ at the individual level include the development of strokes or m.i. in under-treated aps (hughes syndrome) patients, the treatmentresistance of some cases of severe lupus skin disease, the failure at present to protect against congenital heart block. at a more general level, there remains the problem of under-recognition and under treatment on the one hand, with, perversely, overtreatment and iatrogenic cushings on the other. it is also apparent that lupus rivals diabetes in its risk of late atherosclerosic disease and that known risk factors such as high cholesterol and positive apl are inadequately addressed. on the bonus side, the outcome of lupus pregnancy has been drastically improved, and the development of renal failure reduced. new drugs such as mofetil and rituximab are already extensively used and, at last, major pharmaceutical firms are keen on developing new agents for lupus another major ‘advance’ has been the more conservative approach to steroid and cyclophosphamide treatment, and the wider use of milder agents such as hydroxychloroquine. international co-operation in lupus research is good, and developments in lupus are having an impact on many other diseases.perhaps the single most important change in lupus has come from the recognition of the importance of aps. many features such as stroke, migraine, atypical m.s., seizures and m.i., previously ascribed to ‘vasculitis’ and treated with steroids and cyclophosphamide, are recognised as more likely due to aps and treated more appropriately with anti-thrombotic agents. tuesday : a clinician’s tale prof. graham hughes the london lupus centre, london bridge hospital uk. email:graham.hughes@hcaconsultant.co.uk. in 1983, a detailed clinical description of a new syndrome was published. this pro-thrombotic syndrome was initially called the anticardiolipin syndrome and subsequently the antiphospholipid syndrome (aps) or hughes syndrome. almost uniquely, it results in arterial as well as venous thrombosis and is marked by the presence of circulating antiphospholipid antibodies. clinical features are protean, ranging from peripheral deep vein thrombosis (dvt) to involvement of internal organs such as the liver, kidneys and adrenals. likewise arterial thrombosis can result in life-threatening infarction of organs such as the heart. the nervous system is frequently affected, with migraine, memory loss, balance disorders, stroke and atypical multiple sclerosis being prominent. other features include recurrent miscarriage, thrombocytopenia and livedo reticularis. more recent observations have included ischaemic bone fractures, renal and celiac artery stenosis and a possible tendency to accelerated atherosclerosis. the condition is seen in lupus patients, but, significantly, occurs without associated lupus (‘primary’ aps) – indeed increasing clinical recognition of hughes syndrome suggests that this condition will overtake lupus in prevalence. treatment at present is by anticoagulation. the mechanisms for thrombosis are being worked out; it has been suggested that in some situations (e.g., in pregnancy loss), an inflammatory component as well as thrombosis may play a part. pathogenesis and management of osteoporosis prof. stuart h ralston rheumatology, western general hospital university of edinburgh, edinburgh, uk. email: stuart.ralston@ed.ac.uk. advanced general medicine conference joint conference of sultan qaboos university and the ministry of health, oman 300 | squ medical journal, may 2011, volume 11, issue 2 osteoporosis is a common disease characterised by reduced bone mineral density (bmd), and an increased risk of fragility fractures. it has been estimated that about 30% of women and 12% of men will suffer fractures related to the presence of osteoporosis at some point in life. genetic factors play an important role in regulating susceptibility to osteoporosis and account for up to 80% of the variance in peak bone mass. however, many other factors such as diet, exercise, sex hormone deficiency, co-existing diseases and drug treatment such as corticosteroid therapy interact to modulate the risk of developing osteoporosis. although low bone density is a major risk factor for the development of fractures, the majority of fractures occur in patients who do not have osteoporosis, as defined on the basis of low bmd, illustrating the importance of falls as a risk factor for the occurrence of fractures. the most useful tool for assessing patients at risk of osteoporosis is dual energy x-ray absorptiometry (dxa) and individuals with a bmd t-score of -2.5 or less at the spine or hip on dxa examination are considered to have osteoporosis. measurements of bmd are important not only for diagnosis but also in targeting therapies since most of the pharmacological treatments for osteoporosis have undergone clinical trials in patients with osteoporosis as defined by dxa. optimal management of osteoporosis requires a multidisciplinary approach. lifestyle modifications such as increasing dietary calcium and vitamin d intake; taking regular exercise, stopping smoking and limiting alcohol intake to within recommended levels are beneficial in osteoporotic patients and those at risk of the disease. drug treatments for osteoporosis can be divided into two broad groups depending on whether they inhibit osteoclast activity (antiresorptive drugs) or stimulate bone formation (anabolic drugs). the most widely used drugs in the treatment of osteoporosis are bisphosphonates which are antiresorptive. these agents typically reduced the risk of vertebral fractures by about 50% and non vertebral fractures by 25-30%. the most widely used anabolic drug is the 1-34 fragment of parathyroid hormone (teriparatide) which stimulates new bone formation. this agent reduces the risk of vertebral factures by about 65% and non vertebral fractures by 50%. it is particularly effective in corticosteroid induced osteoporosis and seems to be superior to the bisphosphonate alendronic acid in this situation. although the treatments currently available are effective, none are completely effective in preventing fractures emphasising the importance of combining drug treatment for osteoporosis with falls prevention to reduce the risk of fractures. vitamin d metabolism, osteomalacia and rickets prof. stuart h ralston rheumatology, western general hospital university of edinburgh, edinburgh, uk. email: stuart.ralston@ed.ac.uk. osteomalacia is a bone disease characterised by reduced mineralisation of bone, which in most cases is due to vitamin d deficiency. when osteomalacia occurs in the growing skeleton it is known as rickets. muslim women and elderly housebound individuals are at increased risk of osteomalacia, since vitamin d is mostly derived from exposure to sunlight. osteomalacia and rickets occur because of deficiency of the active metabolite of vitamin d (1,25(oh)2d). the most common cause is deficiency of the precursor cholecalciferol which is synthesised in the skin from 7-dehydrocholesterol under the influence of uv light or obtained from the diet. cholecalciferol is converted in the liver to 25(oh)d and then in the kidney to (1,25(oh)2d) which is biologically active. when vitamin deficiency occurs, intestinal calcium absorption is reduced, stimulating production of parathyroid hormone which stimulates bone resorption and promotes renal phosphate wasting resulting in defective mineralisation of bone. osteomalacia and rickets may also occur in patients with renal failure, as the result of drug treatment (bisphosphonates, fluoride, aluminium); inherited defects in vitamin d metabolism (vitamin d resistant rickets); inherited defects in phosphate metabolism (hypophosphataemic rickets) and acquired defects in phosphate metabolism (tumour induced osteomalacia). major advances have been made in understanding the pathophysiology of hypophosphataemic rickets over recent years leading to identification of the phex, dmp1, mepe and fgf23 genes as key regulators of mineralisation and phosphate homeostasis. osteomalacia and rickets due to vitamin d deficiency can be treated with vitamin d supplements whereas active vitamin d metabolites and/or phosphate supplements are required for hypophosphataemic rickets. إستخدام وإدمان اإلنرتنت عند طالب كلية الطب جبامعة القصيم باململكة العربية السعودية حممد ح�شن طه، خالد �شهزاد، اأحمد �شالح العمرو، ماجد وادي abstract: objectives: this study aimed to measure the prevalence of internet use and addiction and determine its association with gender, academic performance and health among medical students. methods: this cross-sectional study was conducted between december 2017 and april 2018 at the college of medicine, qassim university, buraydah, saudi arabia. the validated internet addiction test questionnaire was distributed by simple random methods to medical students (n = 216) in the pre-clinical phase (first-, secondand third-years). a chi-square test was used to determine significant relationships between internet use and addiction and gender, academic performance and health. results: a total of 209 student completed the questionnaire (response rate: 96.8%) and the majority (57.9%) were male. in total, 12.4% were addicted to the internet and 57.9 had the potential to become addicted. females were more frequent internet users than males (p = 0.006). academic performance was affected in 63.1% of students and 71.8% lost sleep due to late-night internet use, which affected their attendance to morning activities. the majority (59.7%) expressed feeling depressed, moody or nervous when they were offline. conclusion: internet addiction among medical students at qassim university was very high, with addiction affecting academic performance and psychological well-being. suitable interventional and preventive measures are needed for proper internet use to protect students’ mental and physical health. keywords: internet; addictive behavior; medical students; universities; academic performance; saudi arabia. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل قيا�س مدى انت�شار ا�شتخدام االإنرتنت وادمانه وحتديد ارتباط ذلك باجلن�س واالأداء االأكادميي وال�شحة بني طالب الطب بجامعة الق�شيم. الطريقة: اأجريت هذه الدرا�شة املقطعية بني دي�شمرب 2017 واأبريل 2018 يف كلية الطب، جامعة الطب كلية طالب على ع�شوائية بطريقة املوثوق االإنرتنت اإدمان اختبار ا�شتبيان توزيع مت ال�شعودية. العربية اململكة بريدة، الق�شيم، وعددهم 216 يف املرحلة ما قبل ال�رشيرية )ال�شنوات االأوىل والثانية والثالثة(. مت ا�شتخدام اختبار مربع كاي لتحديد العالقات ذات الداللة االإح�شائية بني ا�شتخدام االإنرتنت واالإدمان على اإ�شتخدامه وجن�س الطالب واأدائه االأكادميي و�شحته. النتائج: اأكمل 209 طالب اال�شتبيان )معدل اال�شتجابة: %96.8( وكانت الغالبية )%57.9( من الذكور. يف املجموع، كان %12.4 مدمنني على االإنرتنت و %57.9 لديهم القابلية على اأن ي�شبحوا مدمنني. كانت االإناث اأكرث تواتراً من الذكور )p = 0.006( يف ا�شتخدام االنرتنت. تاأثر االأداء االأكادميي يف %63.1 من الطالب وعانى %71.8 من الطالب من قلة النوم ب�شبب اال�شتخدام يف وقت متاأخر من الليل، مما اأثر على ح�شورهم لالأن�شطة ال�شباحية. اأعربت االأغلبية )%59.7( عن �شعورهم باالكتئاب اأو املزاج اأو التوتر اأثناء عدم االت�شال. اخلال�صة: كان اإدمان االإنرتنت بني طالب الطب بجامعة الق�شيم مرتفًعا جًدا، حيث كان لالإدمان تاأثري على االأداء االأكادميي وال�شحة النف�شية. هناك حاجة اإىل تدابري تدخلية ووقائية منا�شبة لال�شتخدام املنا�شب لالإنرتنت حلماية �شحة الطالب العقلية والبدنية. الكلمات املفتاحية: االإنرتنت؛ �شلوك االإدمان؛ طالب الطب؛ اجلامعات؛ االأداء االأكادميي؛ العربية ال�شعودية. internet use and addiction among medical students in qassim university, saudi arabia *mohamed h. taha,1,2 khalid shehzad,3 ahmad s. alamro,2 majed wadi2 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e142–147, epub. 8 sep 19 submitted 10 sep 18 revisions req. 25 oct & 10 jan 19; revisions recd. 11 dec & 20 jan 19 accepted 26 jan 19 advances in knowledge the findings of this study indicate that internet use and addiction among medical students at qassim university, buraydah, saudi arabia, is very high. internet addiction ultimately affects students’ academic performance and psychological well-being. application to patient care this study highlights the effect of internet use and related health issues among medical students at qassim university. students would benefit from decreased internet use to the level of not being addicted, which may also help improve health and academic performance. 1college of medicine & medical education center, university of sharjah, sharjah, united arab emirates; departments of 2medical education and 3anatomy, college of medicine, qassim university, buraydah, saudi arabia *corresponding author’s e-mails: mtaha@sharjah.ac.ae and mohamedhassantaha@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.010 clinical & basic research addiction is defined as a “compulsive need for and use of a habit-forming substance,” characterised by tolerance and well-defined physiological symptoms upon withdrawal; or broadly, “persistent compulsive use of a substance known by the user to be harmful”.1 kandell defined internet addiction https://creativecommons.org/licenses/by-nd/4.0/ mohamed h. taha, khalid shehzad, ahmad s. alamro and majed wadi clinical and basic research | e143 (ia) as “a kind of psychological addiction representing the need to be active on the internet”.2 griffiths described ia as “a kind of technology addiction and a behavioural addiction similar to a gambling habit”.3 problematic use of computers is a growing social issue which has been debated worldwide due to its potentially addictive qualities.4 internet addicts prioritise the internet and can cause severe stress on family, friends, work or the work environment.4 in ia, unmanage able behaviours include compulsive use, a mental pre occupation with being online, lying or hiding the extent of true online behaviour and an inability to control online behaviour; no single behaviour pattern defines ia. as with other addictions, ia provides a “high” feeling and addicts become dependent on that feeling. internet addicts choose temporary gratification rather than seeking normal intimate relationships.5 furthermore, this addiction follows the progressive nature of other addictions: addicts struggle to control their behaviour but remain unsuccessful in their constant failure to do so, their loss of self-esteem grows, pushing them to proceed further into their addictive behaviours and finally, addicts experience a sense of powerlessness.6 evidence suggests that there can be a genetic predis position to addictive behaviours.4–6 ia is highly prevalent, especially among students and teens.7 wieland et al. reported that in 2005 “around nine to fifteen million people in the united states used the internet on a daily basis”.8 furthermore, the rate of internet use has increased 25% every three months. the prevalence rates of problematic internet use is 30% or more in chinese, taiwanese and korean populations. the overall prevalence rates of ia in north america and europe is 1.5–8.2%.9 arab news reported in 2014 that saudis are “wasting” eight hours a day on the internet. rashad faqiha, an expert in human development, stated that “7.6 million saudi users have accounts on facebook, more than 4.8 million use twitter, and more than 1 million are on linkedin. moreover, saudis view youtube videos 290 million times a day”.10 this study aimed to measure the prevalence of internet use and addiction among medical students at qassim university, buraydah, saudi arabia and deter mine associations between internet use and sleep, eating habits, weight changes, exercise habits and academic performance. to the best of the authors’ knowledge, this is the first study to analyse internet use and deter mine the prevalence of ia in this setting. methods this cross-sectional study was conducted at the college of medicine, qassim university from december 2017 to april 2018 using the internet addiction test (iat) questionnaire. the validated iat questionnaire has been utilised in studies in italy, japan, hong kong, kuwait, malaysia and egypt.11–16 the iat questionnaire is a commonly used screening tool that examines uncontrollable internet use.16 for the current study, the questionnaire was adjusted and sociodemographic parameters were added to the context of saudi arabia. a simple random sampling technique was used to collect data. the sample size was calculated using the following formula: where n is the sample size, z is the z statistic for the level of confidence, p is the expected prevalence or proportion (if expected prevalence is 20%, then p = 0.2) and d is the precision (if the precision is 5%, then d = 0.05).17 the sample size calculated was 216 [equation 1], which was confirmed using a sample size calculator.18 the population constituted 443 pre-clinical (in the first-, secondand third-year of the academic phase of training) medical students at qassim university's college of med icine. the questionnaire was distributed to 216 students. the questionnaire was translated by forward and backward translation following recommended guide lines. the original english questionnaire items were included next to the arabic translated items. forward translation into arabic was independently carried out by one bilingual professional translator (native arabic speaker) and one bilingual psychiatrist who was familiar with the related terminology. the translators were asked to use standardised literary arabic. the translations emphasised conceptual and cultural meanings rather than literal translations. the questionnaire comprised 20 questions that examined the symptoms of ia based a five-point likert scale (0 = not applicable, 1 = rarely, 2 = occasionally, 3 = frequently, 4 = often, 5 = always). the severity of ia according to the iat was as follows: 0–30 points is ‘no addiction’; 31–49 points is ‘mild addiction’; 50–79 points is ‘moderate addiction’; and 80–100 points is ‘severe addiction’. sociodemographic data included age, gender, year of study, living situation and body mass index (bmi). two other sections about internet use and health, and internet use and academic performance were added to the original questionnaire. the questionnaire was pretested on 30 students, who were not included in the present study, to ensure that the instructions and items were easily understandable and appropriate for this study. most parts of the questionnaire revealed acceptable cronbach’s alpha values (mean = 0.917) n = z2 × p × [equation 1](1−p) d internet use and addiction among medical students in qassim university, saudi arabia e144 | squ medical journal, may 2019, volume 19, issue 2 ranging between 0.873–0.961, which indicated that both instruments possessed good internal consistency and reliability. data were analysed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). various descriptive statistics were used to calculate frequencies, means and standard deviation. a chi-square test was used to assess asso ciations between internet use and sleep, bmi, eating and exercise habits and academic performance. ethical approval was obtained from the institutional review board and permission to conduct the study was given by the dean of the college of medicine (72/ k/6-2017). informed consent was obtained from all participants and confidentiality was ensured including the right to withdraw participation at any time. results a total of 209 student completed the questionnaire (response rate: 96.8%) and the majority were male (57.9%). most respondents (80.4%) were living with their families [table 1]. the iat showed that 12.4% were addicted to the internet and 57.9% had the potential to become addicted [table 2]. the majority (82.3%) of participants reported at least frequently staying online longer than intended. most participants stated that at least frequently their academic performance was affected (62.2%), they would become defensive or secretive when anyone asked about their online presence (60.7%) and that they lost sleep because of late-night internet use (70.8%), which affected their attendance at morning activities. more than half of the participants (58.9%) at least frequently expressed feeling depressed, moody or nervous when they were offline [table 3]. females indicated using the internet significantly more than males (p = 0.006) and second-year students more than firstor third-year students (p = 0.001). there was a significant difference between the total iat score and neck pain (p = 0.03) and a state of sleeplessness because of staying online (p = 0.006). however, there was no significant difference between total iat score and bmi (p = 0.618), although, there was a statistically significant difference when students were asked if internet use can lead to weight gain or loss (p = 0.002) [table 4]. study respondents also reported health problems including headaches, backache, weight gain, neck pain and other psychological problems as a result of internet use [figure 1]. discussion ia is a psychological issue with potential sociological effects.19 the american psychiatric association incl uded ia as a disorder in its supplement of the diagnostic and statistical manual for mental disorders, fifth edition.20 the current study showed that more than 80% of students at least frequently stayed online longer than intended. this finding is supported by uzun et al.’s study conducted at a turkish university.19 this study showed that 72.8% at least frequently neglected their household chores to spend more time online, which was slightly more than a study conducted at the malaysian school of medicine and more than a study conducted in japan.13,15 the present findings on respondents’ preferences for internet use over inter action with partners, colleagues and friends were inline with findings of studies conducted in kuwait, egypt and india, but was much lower than a study conducted at table 1: characteristics of medical students who completed the internet addiction test questionnaire at qassim univ ersity, buraydah, saudi arabia (n = 209) characteristic n (%) male (n = 121) female (n = 88) total age in years 18–22 82 (67.8) 19 (21.6) 101 (48.3) 23–26 38 (31.4) 67 (76.1) 105 (50.2) >26 1 (0.8) 2 (2.3) 3 (1.4) bmi in kg/m2 <18.5 25 (20.7) 23 (26.1) 48 (23) 18.5–24.9 57 (47.1) 50 (56.8) 107 (51.2) 25–29.9 22 (18.2) 14 (15.9) 36 (17.2) ≥30 17 (14) 1 (1.1) 18 (8.6) academic year of university education first year 46 (38) 23 (26.1) 69 (33) second year 30 (24.8) 38 (43.2) 68 (32.5) third year 45 (37.2) 27 (30.7) 72 (34.4) living/ residence status alone in college accomm odation 20 (16.5) 3 (3.4) 23 (11) with family 86 (71.1) 79 (92.9) 168 (80.4) alone offcampus 13 (10.7) 3 (3.5) 16 (7.7) other 2 (1.7) 0 (0) 2 (1) bmi = body mass index. table 2: distribution of internet addiction test scores among medical students (n = 209) iat score n (%) lower than average 6 (2.9) average user 56 (26.8) possible addict 121 (57.9) addict 26 (12.4) iat =internet addiction test. mohamed h. taha, khalid shehzad, ahmad s. alamro and majed wadi clinical and basic research | e145 table 3: distribution of internet addiction test responses among medical students (n = 209) items n (%) does not apply rarely occasionally frequently often always stay online longer than intended. 6 (2.9) 8 (3.8) 23 (11) 24 (11.5) 50 (23.9) 98 (46.9) neglect household chores to spend more time online. 7 (3.3) 13 (6.2) 37 (17.7) 42 (20.1) 85 (40.7) 25 (12) prefer internet use to interaction with partner/ friends/colleagues. 43 (20.6) 24 (11.5) 25 (12) 64 (30.6) 39 (18.7) 14 (6.7) form new relationships online with fellow internet users. 32 (15.3) 14 (6.7) 34 (16.3) 52 (24.9) 46 (22) 31 (14.8) others complain about the amount of time you spend online. 22 (10.5) 30 (14.4) 49 (23.4) 52 (24.9) 38 (18.2) 18 (8.6) grades or school-work suffer due to the amount of time you spend online. 16 (7.7) 29 (13.9) 38 (18.2) 60 (28.7) 36 (17.2) 30 (14.4) check e-mail before completing other necessary tasks. 20 (9.6) 27 (12.9) 40 (19.1) 56 (26.8) 47 (22.5) 19 (9.1) academic performance/attendance in awake time suffers due to internet use. 18 (8.6) 24 (11.5) 37 (17.7) 64 (30.6) 41 (19.6) 25 (12) become defensive or secretive when anyone asks you about your online presence. 9 (4.3) 36 (17.2) 37 (17.7) 57 (27.3) 49 (23.4) 21 (10) block out disturbing thoughts about your life with soothing thoughts about the internet. 10 (4.8) 26 (12.4) 30 (14.4) 60 (28.7) 44 (21.1) 39 (18.7) find yourself anticipating when you will go online again. 9 (4.3) 19 (9.1) 34 (16.3) 63 (30.1) 41 (19.6) 43 (20.6) fear that life without the internet would be boring, empty and joyless. 8 (3.8) 22 (10.5) 34 (16.3) 56 (26.8) 46 (22) 43 (20.6) snap, yell or act annoyed if someone interrupts you while you are online. 15 (7.2) 33 (15.8) 41 (19.6) 63 (30.1) 35 (16.7) 22 (10.5) lose sleep due to late-night internet use. 11 (5.3) 22 (10.5) 28 (13.4) 59 (28.2) 43 (20.6) 46 (22) feel preoccupied with the internet when offline or fantasize about being online. 19 (9.1) 35 (16.7) 39 (18.7) 52 (24.9) 44 (21.1) 20 (9.6) find yourself saying “just a few more minutes” when online. 14 (6.7) 21 (10) 28 (13.4) 66 (31.6) 43 (20.6) 37 (17.7) try to cut-down the amount of time you spend online and fail. 18 (8.6) 15 (7.2) 34 (16.3) 59 (28.2) 51 (24.4) 32 (15.3) try to hide how long you have been online. 34 (16.3) 31 (14.8) 24 (11.5) 61 (29.2) 35 (16.7) 24 (11.5) choose to spend more time online than going out with others. 19 (9.1) 25 (12) 36 (17.2) 66 (31.6) 36 (17.2) 27 (12.9) feel depressed, moody or nervous when you are offline, which goes away once you are back online. 18 (8.6) 29 (13.9) 39 (18.7) 55 (26.3) 43 (20.6) 25 (12) figure 1: frequency of relationship between internet use and students’ health (n = 209). internet use and addiction among medical students in qassim university, saudi arabia e146 | squ medical journal, may 2019, volume 19, issue 2 an italian high school.12,14,16,21 the development of new relationships with fellow online users in the current study was consistent with other studies in developing and developed countries.22,23 approximately one-quarter of students received complaints about spending too much time online. this finding was lower than in a study conducted in malaysia and oman and much lower than in a study conducted in the usa.9,15,24 in the present study, almost two-thirds of students stated that their academic performance was affected by excessive internet use. many studies have reported the relationship between excessive internet use and diminished academic performance.25 in the present study, one-quarter of students stated that they check their e-mail before completing other necessary tasks. this proportion is much lower than in two studies conducted in italy and the usa.9,12 one-third of students declared that their attendance at class has been affected by excessive internet use. this finding is lower than in other studies conducted in the region and slightly higher than in studies conducted in western countries.14,24,26 aydm and san stated that “self-esteem is an essential determinant of individuals’ behaviours and activities” and determined that there is a robust connection between ia and self-esteem.27 a large number of students (60.7%) in the present study showed defensive or secretive behaviour when anyone asked them about their online presence; these findings were in agreement with other findings in the literature.17,26 the present study also showed that one-third of the students faced some obsessive behaviour related to internet use. these findings are similar to those from a studies conducted in malaysia, france and hong kong.15,28,29 the current study showed that more than 70% of students at least frequently felt that excessive internet use had affected their sleep; this finding is in-line with various studies that found that excessive internet use can lead to sleep disorders, depression and low quality of work and study.30–32 however, the present study has some limitations. the results of this study cannot be generalised as only a small sample of students from one college in saudi arabia were included. furthermore, it was not possible to conclude a cause-and-effect relationship between the factors and ia among students. the iat instrument, although it gives some insight, does not fully differentiate between different types of internet usage in relation to addiction. for example, some of the students may have been using the internet for workor research-related purposes. further research is needed to determine the specific nature of internetbased activities in order to determine the true level of ia in qassim university’s medical students. table 4: comparison between internet addiction test scores of medical students and their characteristics and other variables (n = 209) characteristic n (%) χ2 df p value* iat score less than average average internet user possible addict addict gender male (n = 121) 2 (1.65) 39 (32.23) 72 (59.5) 8 (6.61) 12.557 3 0.006female (n = 88) 4 (4.55) 18 (20.45) 48 (54.55) 18 (20.45) total 6 (2.87) 57 (27.27) 120 (57.42) 26 (12.44) bmi in kg/m2 <18.5 0 (0) 12 (25.53) 27 (57.45) 8 (17.02) 7.181 9 0.618 18.5–24.9 2 (1.89) 32 (30.19) 58 (54.72) 14 (13.21) 25.0–29.9 2 (5.26) 10 (26.32) 24 (63.16) 2 (5.26) ≥30 1 (5.56) 4 (22.22) 11 (61.11) 2 (11.11) academic year of university education first year 8 (11.43) 16 (22.86) 37 (52.86) 9 (12.86) 46.005 12 0.001second year 7 (11.29) 13 (20.97) 29 (46.77) 13 (20.97) third year 5 (6.49) 17 (22.08) 51 (66.23) 4 (5.19) suffering from neck pain because of excessive internet use yes 0 (0) 22 (21.78) 64 (63.37) 15 (14.85) 13.961 6 0.03no 2 (2.82) 22 (30.99) 39 (45.93) 8 (11.27) to some extent 3 (8.11) 15 (40.54) 16 (43.24) 3 (8.11) neglecting adequate sleep to stay online yes 2 (2.41) 13 (15.66) 51 (61.45) 17 (20.48) 17.993 6 0.006no 3 (3.33) 32 (35.56) 46 (51.11) 9 (10) to some extent 0 (0) 14 (38.89) 22 (61.11) 0 (0) internet use has led to weight gain or loss yes 0 (0) 11 (14.67) 51 (68) 13 (17.33) 16.763 7 0.002no 3 (2.88) 32 (30.77) 56 (53.85) 13 (12.5) to some extent 2 (6.67) 15 (50) 13 (43.33) 0 (0) iat = internet addiction test; df = degrees of freedom; bmi = body mass index. *using chi-square test. mohamed h. taha, khalid shehzad, ahmad s. alamro and majed wadi clinical and basic research | e147 conclusion ia is prevalent among medical students at qassim university, showing that 12.4% of medical students are addicted to the internet and 57.9% are at risk of becoming addicted. this study found a relationship between ia and students’ health and their academic performance. suitable interventional and preventive measures are needed to encourage proper internet use to protect students’ physical and mental health. a c k n o w l e d g e m e n t the authors would like to thank all the students who participated in this study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. merriam-webster's dictionary. "addiction". from: https://www. merriam-webster.com/dictionary/addiction accessed: jan 2019. 2. kandell. internet addiction on campus: the vulnerability of college students. cyberpsycho behav 1998; 1:11–17. 3. griffiths m. does internet and computer "addiction" exist? some case study evidence. cyberpsychol behav 2000; 3:211–18. https://doi.org/10.1089/109493100316067. 4. spada mm. an overview of problematic internet use. addictive behav 2014; 1:3–6. 5. young k. internet addiction: symptoms, evaluation and treatment. in: vandecreek l, jackson tl, eds. innovations in clinical practice: a source book. florida, usa: professional resource press, 1999; pp. 351–2. 6. reuter m, montag c. internet addiction: neuroscientific appr oaches and therapeutical interventions. new york, usa: springer international publishing, 2017. https://doi.org/10.1007/978-3319-07242-5. 7. kuss dj, lopez-fernandez o. internet addiction and problematic internet use: a systematic review of clinical research. world j psychiatry 2016; 6:143–76. https://doi.org/10.5498/wjp.v6.i1.143. 8. wieland dm. computer addiction: implications for nursing psychotherapy practice. perspect psychiatr care 2005; 41:153–61. https://doi.org/10.1111/j.1744-6163.2005.00038.x. 9. weinstein a, lejoyeux m. internet addiction or excessive internet use. am j drug alcohol abuse 2010; 36:277–83. https://doi.org/ 10.3109/00952990.2010.491880. 10. arab news. expert: saudis waste eight hours a day on internet. available at http://www.arabnews.com/saudi-arabia/news/680 406 accessed: jan 2019. 11. young k. caught in the net: how to recognize the signs of internet addiction – and a winning strategy for recovery. new york, usa: john wiley & sons, inc., 1998. p. 31. 12. bianchini v, cecilia mr, roncone r, cofini v. prevalence and factors associated with problematic internet use: an italian survey among l’aquila students. riv psichiatr 2017; 52:90–3. https://doi.org/10.1708/2679.27445. 13. sato t. internet addiction among students: prevalence and psycho logical problems in japan. japan med assoc j 2006; 49:279–83. 14. al-menayes jj. dimensions of social media addiction among university students in kuwait. psychol behav sci 2015; 4:23–8. https://doi.org/10.11648/j.pbs.20150401.14. 15. haque m, rahman na, majumder ma, haque sz, kamal zm, islam z, et al. internet use and addiction among medical students of universiti sultan zainal abidin, malaysia. psychol res behav manag 2016; 9:297–307. https://doi.org/10.2147/prbm.s119275. 16. saied sm, elsabagh hm, el-afandy am. internet and facebook addiction among egyptian and malaysian medical students: a com parative study, tanta university, egypt. int j community med public health 2016; 3:1288–97. https://doi.org/10.18203/23946040.ijcmph20161400. 17. srijampana vvgr, endreddy ar, prabhath k, rajana b. prev alence and patterns of internet addiction among medical students. med j dr dy patil univ 2014; 7:709–13. https://doi.org/10.41 03/0975-2870.144851. 18. creative research system. sample size calculator. from: www. surveysystem.com/sscalc.htm accessed: jan 2019. 19. uzun am, unal e, tokel st. exploring internet addiction, academic procrastination and general procrastination among pre-service ict teachers. mevlana int j educ 2014; 189–201. https://doi.org/ 10.13054/mije.14.18.4.1. 20. american psychiatric association. diagnostic and statistical manual of mental disorders, 5th ed. virginia, usa: american psychiatric association, 2013. 21. patil sd, deshmukh js, dagdiya kr. prevalence and pattern of internet addiction among medical students in nagpur, maha rashtra. int j community med public health 2017; 4:2412–16. https://doi.org/10.18203/2394-6040.ijcmph20172833. 22. christakis da, moreno mm, jelenchick l, myaing mt, zhou c. problematic internet usage in us college students: a pilot study. bmc med 2011; 9:77. https://doi.org/10.1186/1741-7015-9-77. 23. frangos cc, frangos cc, sotiropoulos i. a meta-analysis of the reliability of young’s internet addiction test. from: http://www. iaeng.org/publication/wce2012/wce2012_pp368-371.pdf accessed: jan 2019. 24. masters k. social networking addiction among health sciences students in oman. sultan qaboos univ med j 2015; 15:e357–63. 25. samaha m, hawi ns. relationships among smartphone addiction, stress, academic performance, and satisfaction with life. comput human behav 2016; 57:321–5. https://doi.org/10.1016/j.chb.20 15.12.045. 26. whang ls, lee s, chang g. internet over-users’ psychological profiles: a behavior sampling analysis on internet addiction. cyberpsychol behav 2003; 6:143–50. https://doi.org/10.1089/10 9493103321640338. 27. aydm b, san sv. internet addiction among adolescents: the role of self-esteem. procedia soc behav sci 2011; 15:3500–5. https://doi.org/10.1016/j.sbspro.2011.04.325. 28. khazaal y, billieux j, thorens g, khan r, louati y, scarlatti e, et al. french validation of the internet addiction test. cyber psychol behav 2008; 11:703–6. https://doi.org/10.1089/cpb.20 07.0249. 29. fu kw, chan ws, wong pw, yip ps. internet addiction: prev alence, discriminant validity and correlates among adolescents in hong kong. br j psychiatry 2010; 196:486–92. https://doi.org/10.1 192/bjp.bp.109.075002. 30. lack dm. presenteeism revisited. a complete review. aaohn j 2011; 59:77–91. https://doi.org/10.1177/216507991105900205. 31. a’lamelhuda d, dimetry da. the impact of facebook and others social networks usage on academic performance and social life among medical students at khartoum university. int j sci technol res 2014; 3:41–6. 32. mohammadbeigi a, absari r, valizadeh f, saadati m, sharifimoghadam s, ahmadi a, et al. sleep quality in medical students; the impact of over-use of mobile cell-phone and social networks. j res health sci 2016; 16:46–50. https://doi.org/10.1089/109493100316067 https://doi.org/10.1007/978-3-319-07242-5 https://doi.org/10.1007/978-3-319-07242-5 https://doi.org/10.5498/wjp.v6.i1.143 https://doi.org/10.1111/j.1744-6163.2005.00038.x https://doi.org/10.3109/00952990.2010.491880 https://doi.org/10.3109/00952990.2010.491880 https://doi.org/10.1708/2679.27445 https://doi.org/10.11648/j.pbs.20150401.14 https://doi.org/10.2147/prbm.s119275 https://doi.org/10.18203/2394-6040.ijcmph20161400 https://doi.org/10.18203/2394-6040.ijcmph20161400 https://doi.org/10.4103/0975-2870.144851 https://doi.org/10.4103/0975-2870.144851 https://doi.org/10.13054/mije.14.18.4.1 https://doi.org/10.13054/mije.14.18.4.1 https://doi.org/10.18203/2394-6040.ijcmph20172833 https://doi.org/10.1186/1741-7015-9-77 https://doi.org/10.1016/j.chb.2015.12.045 https://doi.org/10.1016/j.chb.2015.12.045 https://doi.org/10.1089/109493103321640338 https://doi.org/10.1089/109493103321640338 https://doi.org/10.1016/j.sbspro.2011.04.325 https://doi.org/10.1089/cpb.2007.0249 https://doi.org/10.1089/cpb.2007.0249 https://doi.org/10.1192/bjp.bp.109.075002 https://doi.org/10.1192/bjp.bp.109.075002 https://doi.org/10.1177/216507991105900205 departments of 1pathology, 2otolaryngology and 3paediatric surgery, chacha nehru bal chikitsalya, delhi, india *corresponding author’s e-mail: singhlavleen04@gmail.com تشوهات منائية كيسية معوية أمامية داخل الفم ثالث حاالت مع مراجعة موجزة لألدبيات �أرتي كاتري، لفلني �صنج، نيها جيان، مامتا �صينجر، �أبهيجت د��س abstract: foregut cystic developmental malformations (fcdm) are a type of rare cystic lesion. the occurrence of fcdm is exceedingly uncommon in the intraoral location. we report three cases of fcdm with intraoral location who presented at chacha nehru bal chikitsalaya, new delhi, india, in 2016, 2017 and 2018 with symptoms of respiratory distress and feeding difficulties. two patients were male and one was female with an age range of 29 days to eight years. the clinical differential diagnosis included mucocele, ranula, dermoid, lymphangioma, teratoma, thyroglossal duct cyst, etc. all patients were treated with simple surgical excision and diagnosed, based on histopathology, with fcdm. these should be considered as differential diagnosis of head and neck midline cystic mass lesions. this case report aimed to discuss differential diagnosis and appropriate terminology for these cystic masses as there is varied and ambiguous nomenclature. keywords: bronchogenic cyst; cyst; congenital abnormalities; oral cavity; case report; india. امللخ�ص: �لت�صوه �لنمائي �لكي�صي �ملعوي �الأمامي هو نوع من �الآفات �لكي�صية �لنادرة. حدوث �لت�صوه �لنمائي �لكي�صي �ملعوي �الأمامي غري �صائع د�خل �لفم. نعر�س تقرير عن ثالث حاالت من �لت�صوه �لنمائي �لكي�صي �ملعوي �الأمامي يف موقع د�خل �لفم مت �لك�صف عنها يف �صا�صا نيهرو بال �صيكت�صاليا، نيودلهي، �لهند، يف 2016، 2017 و 2018 مع �أعر��س �ل�صائقة �لتنف�صية و�صعوبات �لتغذية. كان �ثنان من �ملر�صى من �لذكور وو�حدة من �الإناث وترت�وح �أعمارهم بني 29 يوما �إىل ثماين �صنو�ت. �صمل �لت�صخي�س �لتفريقي �ل�رصيري �صليلة خماطية، كي�س �صفدعي، كي�صة جلد�نية، ورم وعائي ملفي، ورم م�صخي، كي�صة �لقناة �لدرقية �لل�صانية، �إلخ. مت عالج جميع �ملر�صى عن طريق �ال�صتئ�صال �جلر�حي �لب�صيط ومت ت�صخي�صهم هي�صتوباثولوجيا بالت�صوه �لنمائي �لكي�صي �ملعوي �الأمامي. ينبغي �عتبار هذ� �لت�صوه �صمن �لت�صخي�س �لتفريقي الآفات �لكتلة �لكي�صية يف و�صط �لر�أ�س و�لعنق. يهدف هذ� �لتقرير �إىل مناق�صة �لت�صخي�س �لتفريقي و�مل�صطلحات �ملنا�صبة لهذه �الآفات �لكي�صية حيث توجد ت�صميات متنوعة وملتب�صة. الكلمات املفتاحية: كي�صة ق�صبية �ملن�صاأ؛ كي�س؛ �لت�صوهات �خللقية؛ جوف �لفم؛ تقرير حالة؛ �لهند. intraoral foregut cystic developmental malformations three cases with a brief review of literature arti khatri,1 *lavleen singh,1 neha jain,2 mamta sengar,3 abhijit das1 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e257–261, epub. 5 nov 19 submitted 29 jan 19 revision req. 4 mar 19; revision recd. 1 apr 19 accepted 6 may 19 foregut cystic developmental malformations (fcdm) are a type of choristomas containing histologically normal gastroint estinal and respiratory epithelium. these arise due to migration anomalies during fetal life.1 the most common site for fcdm are the chest and abdomen and can occur anywhere along the alimentary tract. however, the oral cavity is one of the rarest locations. most cases present in the neonatal period with a cystic mass lesion in the head and neck, causing difficulty in breathing or deglutition. the common differential diagnosis of paediatric cystic head and neck masses includes dermoid, lymphangioma, venous malformation, haemangioma, teratoma, thyroglossal duct cyst and lymphoepithelial cyst.2 fcdm is an exceedingly rare cause of a midline cystic mass lesion in the head and neck, especially in an intraoral location. fcdm have a risk of malignant transformation such as adenocarcinoma if left untreated.3 we present three cases of intraoral fcdm with one case of anterior involvement of the tongue and two involving the floor of the mouth. these cases highlight the rarity of these developmental lesions and stress the need for uniform nomenclature to establish better communication bet ween histopathologists and surgeons. informed consent was given by the legal guardians of all patients. case one a 29-day-old male infant presented to chacha nehru bal chikitsalaya, new delhi, india, in 2018 with a cystic swelling measuring 3 × 2 cm located in the anterior ventral surface of the tongue causing feeding difficulty [figure 1a]. the swelling was present at birth and gradually increased in size which resulted in posterior displacement of the tongue causing difficulty this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.014 case report https://creativecommons.org/licenses/by-nd/4.0/ intraoral foregut cystic developmental malformations three cases with a brief review of literature e258 | squ medical journal, august 2019, volume 19, issue 3 during feeding. there were no associated anomalies. laboratory tests including complete blood count, liver function tests, renal function tests and coagulation profile were within normal limits. ultrasonography of the floor of mouth showed a cystic swelling measuring 5 × 4 cm in the midline, pushing on the muscles of the floor of the mouth. the cyst was completely resected and tissue was sent for histopathological examination with a provisional diagnosis of a ranula. the patient was discharged one day postoperatively. follow-ups during the next six months were uneventful. on gross inspection, the cyst was well circum scribed measuring a maximum of 3 cm in diameter and containing a mucinous transparent fluid. histo pathological examination revealed a fibromuscular wall partially lined by ciliated pseudostratified columnar epithelium and gastric epithelium. few mucinous glands were seen embedded within the wall. based on these findings, the patient was diagnosed with a lingual fcdm [figure 1b]. case two an eight-month-old female infant presented at chacha nehru bal chikitsalaya in 2017 with swelling in the floor of the mouth with complaints of respiratory distress. on local examination, a non-transilluminant swelling was present in the floor of the mouth extending up to the base of the tongue measuring 3.5 × 2.5 cm [figure 2a]. provisional clinical diagnoses were infected ranula and epidermoid cyst. there were no associated anomalies. the patient did not undergo preoperative radiological investigation and the swelling was excised and sent for histopathological examination. on gross examination, it was a soft, cystic swelling, greyish white in colour with the smooth outer surface. the cut section showed a multiloculated cyst with the presence of turbid fluid. microscopic examination showed a cyst wall with a smooth muscle layer lined by stratified squamous and overlying pseudostratified columnar epithelium [figure 2b]. the surrounding fibro-fatty soft tissue and skeletal muscle showed mild inflammation. subseq uently, the patient was diagnosed with intraoral fcdm. the postoperative follow-up period of one year was uneventful. case three an eight-year-old boy presented to the outpatient department of chacha nehru bal chikitsalaya in 2016 with a small anterior neck swelling. the swelling had been present for one year. on local physical examination, the swelling was firm in consistency and located in the anterior floor of the mouth. it appeared to be an enlarged submental lymph node. a provisional clinical diagnosis of tubercular lymphadenitis was made and fine needle aspiration was attempted but did not yield any diagnostic material. laboratory tests including complete blood count, liver function test, renal function test and coagulation profile were within normal limits. the patient did not undergo any preoperative radiological investigation and the swelling was excised and sent for histopathological examination. on gross examination, it was a single globular cystic soft tissue piece measuring 1 × 0.5 × 0.5 cm. micro scopic examination showed a cyst wall with smooth muscle layer lined by pseudostratified ciliated columnar epithelium. mild chronic inflammation was noted in the surrounding tissue. the final diagnosis of fcdm was based on clinical and histopathological findings. the postoperative follow-up period of one year was uneventful. discussion fcdm are rare congenital choristomas which develop due to aberrant embryogenesis.1,3 they can occur figure 2: a: intraoperative photograph of an eightmonth-old female infant showing cystic swelling in the floor of the mouth. b: haematoxylin and eosin stain of the cystic swelling tissue sample at x100 magnification showing a cyst wall lined by stratified squamous epithelium and a smooth layer beneath it. figure 1: a: intraoperative photograph of a 29-day-old male infant showing cystic swelling in the ventral surface of the anterior tongue. b: haematoxylin and eosin stain of the cystic swelling tissue sample at x100 magnification showing a cyst wall lined with pseudostratified ciliated columnar epithelium (black arrow) and gastric epithelium (red arrow) with a smooth muscle layer beneath. arti khatri, lavleen singh, neha jain, mamta sengar and abhijit das case report | e259 anywhere from the mouth to anus but the most common site for fcdm is the chest and abdomen.3 approximately one-third of total alimentary tract duplication cysts are foregut duplication cysts and the noted incidence of alimentary tract duplication is 1:4500.4 oral cavity fcdm comprises 0.3% of all alimentary tract duplications. in addition, the anterior part of the tongue is one of the rarest sites for fcdm.1 congenital gastric and intestinal cysts of the oral cavity are mostly solitary with a male preponderance. clinical features of the fcdm depend on the location, size and type of epithelial lining. oral fcdm may present with feeding and breathing difficulties or manifest in unexpected ways such as recurrent bleeding.5 these may be complicated by obstruction, perforation or infection with the continued growth of these cystic masses if not surgically removed.6 figure 3: pictures of theories explaining the formation of foregut cystic developmental malformations (fcdm). a: theory one depicts foregut duplication cysts arising from supernumerary lung bud. b: theory two shows the normal canalisation of foregut epithelial plug during intrauterine life which leads to the formation of a normal lumen. disturbed recanalisation may lead to the formation of an abnormal heterotopic rest in relation to the developing gut wall, which may later result in cystic developmental malformations. c: theory three shows that during embryogenesis the developing stomach may become entrapped between lateral lingual swellings explaining the occasional presence of gastric epithelium in oral fcdm. iul = intrauterine life. the first case of fcdm was reported by duncan and daniel in 1942.7 various authors have used different terminologies such as oral cyst with heterotopic gastrointestinal mucosa, congenital gastro intestinal cyst, gastrointestinal duplication cyst, enteric duplication cyst, foregut cyst, epithelial cyst, cyst of foregut origin, cystic duplication, etc.; this creates and adds to the confusion amongst histopathologists and paediatric surgeons regarding its nomenclature. sharma et al. proposed that, as these malformations share their origin from the foregut and are cystic, they should be labelled as fcdm.8 there are various theories of the formation of fcdm. the most widely accepted theory for the formation of fcdm is that during the third week of embryogenesis, foregut division is followed by the formation of diverticula (normal lung bud) from the ventral part of foregut; the intraoral foregut cystic developmental malformations three cases with a brief review of literature e260 | squ medical journal, august 2019, volume 19, issue 3 formation of an additional diverticula (supernumerary lung bud) may occur as a result of aberration in normal embryogenesis. during the fifth and seventh week of embryogenesis, a foregut duplication cyst develops from this supernumerary lung bud which explains the presence of respiratory type epithelium in fcdm [figure 3a].3,8 another theory says that the disturbed recanalisation of the foregut during intrauterine life leads to the development of abnormal foregut rests in relation to the wall of the developing gut, leading to formation of fcdm from these rests. the cyst lining of fcdm depends on the epithelial type of these heterotopic rests [figure 3b].9 when these heterotopic rests are incorporated into a hollow structure such as the gastrointestinal tract it leads to duplication of the muscle layer; these are also known as a duplication cyst. the presence of two layers of smooth muscle indicates an attempt at recapitulating the outer and inner muscle coat of intestine.8 gorlin and jirasek and, later, daley et al. proposed that the entrapment of stomach or stomatodeum between lateral swellings of the tongue during the embryonic period as they close over the tuberculum impar can result in presence of heterotopic gastric mucosa in fcdm [figure 3c].9,10 foregut duplication cyst is frequently associated with vertebral anomalies; veeneklaas proposed that the abnormal persistence of foregut adherence to notochord is responsible for this association.11 fcdm are benign anomalies which need to meet three diagnostic criteria: (1) a smooth muscle layer; (2) covering epithelium derived from the foregut; and (3) attachment to a part of the foregut.4 these cysts may show squamous metaplasia, mucosal ulceration, inflammation and necrosis and therefore pose a diagnostic challenge.3 fcdm should be considered as differential diagnosis of other midline developmental cystic lesions in the head and neck region. the differential diagnosis for midline cystic lesions of the oral cavity include mucocele, dermoid cyst, lymphoepithelial cyst, thyroglossal duct cyst, etc.2,13 the overlapping clinical and radiological features of midline cystic mass lesions in the head and neck necessitates a histopathological confirmation for appropriate management of these lesions.12 mucocele is the most appropriate clinical differential diagnosis for intraoral fcdm as it has similar clinical characteristics and radiological features.13 the management of mucocele includes removal of the fibrous capsule along with the associated minor salivary gland. in addition, on clinical and imaging findings it is difficult to distinguish fcdm from dermoid cysts, thyroglossal duct cysts and lympho epithelial cysts. while simple surgical excision is curative in fcdm, dermoid and lymphoepithelial cysts, a sistrunk operation is required for thyroglossal duct cysts. antenatal ultrasonography can be a useful investigation for antenatal diagnosis of fcdm. if antenatal ultrasonography shows findings suggestive of fcdm ex utero intrapartum management of these lesions should be started to prevent respiratory compromise. in an emergency situation when a child presents with respiratory compromise, the cyst should be aspirated to relieve obstruction with excision of the cyst to be done at a later date.13,14 surgical excision is the treatment of choice as there is an increased risk of malignancy in untreated cases.1,15 conclusion intraoral fcdm commonly presents with difficulty in breathing and deglutition. this should be considered in the differential diagnosis of other developmental midline cystic lesions in the head and neck region. a uniform embryology-based nomenclature of devel opmental anomalies, such as fcdm, should be used to avoid confusion between histopathologists and paediatric surgeons. in addition, antenatal ultrasono graphy may aid in early diagnosis and timely management. references 1. patel p, branstetter bf 4th, myers en. lingual foregut duplic ation in a middle-aged adult. ajnr am j neuroradiol 2011; 32:e40–1. https://doi.org/10.3174/ajnr.a1994. 2. vogl tj, stegler w, ihrler s, ferrera p, grevers g. cystic masses in the floor of the mouth: value of mr imaging in planning surgery. ajr am j roentgenol 1993; 161:183–6. https://doi. org/10.2214/ajr.161.1.8517299. 3. kieran sm, robson cd, nosé v, rahbar r. foregut duplication cysts in the head and neck: presentation, diagnosis, and manage ment. arch otolaryngol head neck surg 2010; 136:778–82. https://doi.org/10.1001/archoto.2010.127. 4. qi bq, beasley sw, williams ak. evidence of a common pathogenesis for foregut duplications and esophageal atresia with tracheo-esophageal fistula. anat rec 2001; 264:93-100. https://doi.org/10.1002/ar.1125. 5. mir r, weitz j, evans j, coren c. oral congenital cystic chorio stomas: a case report. pediatr pathol 1992; 12:835-8. https:// doi.org/10.3109/15513819209024240. 6. burgner dp, carachi r, beattie tj. foregut duplication cyst presenting as neonatal respiratory distress and haemoptysis. thorax 1994; 49:287–8. https://doi.org/10.1136/thx.49.3.287. 7. duncan gw, daniel ra, jr. cystic tumor of the tongue: report of an unusual case. arch surg 1942; 44:164–9. http://doi.org/10.1 001/archsurg.1942.01210190167018. 8. sharma s, nezakatgoo n, sreenivasan p, vanatta j, jabbour n. foregut cystic developmental malformation: new taxonomy and classification--unifying embryopathological concepts. indian j pathol microbiol 2009; 52:461–72. https://doi.org/10.4103/03 77-4929.56119. https://doi.org/10.3174/ajnr.a1994 https://doi.org/10.2214/ajr.161.1.8517299 https://doi.org/10.2214/ajr.161.1.8517299 https://doi.org/10.1001/archoto.2010.127 https://doi.org/10.1002/ar.1125 https://doi.org/10.3109/15513819209024240 https://doi.org/10.3109/15513819209024240 https://doi.org/10.1136/thx.49.3.287 http://doi.org/10.1001/archsurg.1942.01210190167018 http://doi.org/10.1001/archsurg.1942.01210190167018 https://doi.org/10.4103/0377-4929.56119 https://doi.org/10.4103/0377-4929.56119 arti khatri, lavleen singh, neha jain, mamta sengar and abhijit das case report | e261 9. daley td, wysocki gp, lovas gl, smout ms. heterotopic gastric cyst of oral cavity. head neck surg 1984; 7:168–71. https://doi.org/10.1002/hed.2890070212. 10. gorlin rj, jirasek je. oral cysts containing gastric or intestinal mucosa. an unusual embryological accident or heterotopia. arch otolaryngol 1970; 91:594–7. https://doi.org/10.1001/ archotol.1970.00770040824018. 11. veeneklaas gm. pathogenesis of intrathoracic gastrogenic cysts. ama am j dis child 1952; 83:500–7. https://doi.org/10.1001/ archpedi.1952.02040080096010. 12. stocker jt, dehner lp, husain an. stocker & dehner's pediatric pathology. 4th ed. philadelphia, usa: wolters kluwer, 2016. 13. chen mk, gross e, lobe te. perinatal management of enteric duplication cysts of the tongue. am j perinatol 1997; 14:161–3. https://doi.org/10.1055/s-2007-994119. 14. kong k, walker p, cassey j, o’callaghan s. foregut duplication cyst arising in the floor of mouth. int j pediatr otorhinolaryngol 2004; 68:827–30. https://doi.org/10.1016/j.ijporl.2004.01.011. 15. agaimy a, raab b, bonkowsky v, wünsch ph. intestinal-type adenocarcinoma arising in a congenital sublingual teratoid cyst. virchows arch 2007; 450:479–81. https://doi.org/10.1007/s004 28-007-0369-8. https://doi.org/10.1002/hed.2890070212 https://doi.org/10.1001/archotol.1970.00770040824018 https://doi.org/10.1001/archotol.1970.00770040824018 https://doi.org/10.1001/archpedi.1952.02040080096010 https://doi.org/10.1001/archpedi.1952.02040080096010 https://doi.org/10.1055/s-2007-994119 https://doi.org/10.1016/j.ijporl.2004.01.011 https://doi.org/10.1007/s00428-007-0369-8 https://doi.org/10.1007/s00428-007-0369-8 squ med j, april 2010, vol. 10, iss. 1, pp. 41-49, epub. 17th apr 10 submitted 28th june 09 revision req. 24th oct 09, revision recd. 1st nov 09 accepted 3rd jan 10 1department of medicine, sultan qaboos university hospital, muscat, oman; 2university of edinburgh cardiovascular research unit, royal infirmary of edinburgh, uk to whom correspondence should be addressed. e-mail: halhadi@hotmail.com دور الربوتني الرابط للحمض الدهين النوع القليب يف التشخيص املبكّر للجلطة القلبية احلادة امكانية التأثري يف عالج املريض حافظ الهادي وكيث ف�ك�س امللخص: الهدف: دراسة قدرة البروتني الرابط للحمض الدهني – النوع القلبي على التشخيص املبكر للجلطة القلبية عند املرضى الذين يعانون من آالم حادة في الصدر ومقارنتها مع الواصمات القلبية القياسية. الطريقة: أجريت دراسة استباقية ملئة حالة متعاقبة اُدخلوا عن طريق الطوارئ بآآلم صدرية حادة مايوجلوبني، والبروتني الرابط للحمض كتلة كاينيز الكرياتني (م ب)، تروبونني القلب (ت)، كمؤشر لوجود جلطة قلبية. مت قياس تركيز تروبونني القلب ( آ)، الدهني – النوع القلبي مباشرة عند الوصول للطوارئ، وبعد ساعتني و 4 ساعات، وبني 8-10 ساعة، و 16-24 ساعة من وصول املريض. مقياس النتيجة الرئيسية هو قياس أفضل نتيجة للتحسس خالل 6 ساعات من وقوع اآلالم. النتائج: أظهرت النتائج أن ذروة تركيز البروتني الرابط للحمض الدهني – النوع القلبي حصل بعد 8 ساعات من بداية اإلحساس بآالم الصدر، وكان أفضل واصم مبكر على وجود جلطة قلبية مقارنة باآلخرين، حيث حصل على معدل حتسس بنسبة (%79.9 و %98) عند املرضى املصابني بجلطة قلبية حني وصولهم للطوارئ وبعد ساعتني على التوالي. كانت حساسية الواصمات األخرى (تروبونني القلب آ، تروبونني القلب – ت، كتلة كاينيز الكرياتني (م ب)، واملايوجلوبني) أقل من (%62) عند الوصول للطوارئ. القدرة التنبؤية السلبية للبروتني الرابط للحمض الدهني – النوع القلبي (%94) وكانت أيضا أفضل من الواصمات األخرى خالل أول ساعتني من وصول املريض للطوارئ. حصل املايوجلوبني الساعة بني حصلت ت القلب تروبونني ب)، (م الكرياتني كاينيز كتلة –آ، القلب لتروبونني التحسس قمة حتسس. معدل كأعلى الثاني الترتيب �على 4.8 10، و 8-10 على التوالي بعد وصول املريض للطوارئ. اخلالصة: القياس املشترك للبروتني الرابط للحمض الدهني – النوع القلبي و تروبونني القلب – آ، مرتني خالل الساعات الثمان االولى بعد ظهور األعراض ذو حساسية ونوعية كافية للتشخيص املبكر ملعظم املرضى الذين يعانون من جلطة قلبية حادة. وهذا الفحص املشترك يوفر امتيازات أفضل من الفحوص املشتركة لبقية الواصمات األخرى. مفتاح الكلمات: جلطة قلبية حادة، متالزمة تاجية حادة، الربوتني الرابط للحم�س الدهني – الن�ع القلبي ، ال�ا�شمات القلبية. abstract: objectives: the objective of this study was to evaluate the diagnostic value of heart-type fatty acidbinding protein (h-fabp) in patients with acute chest pain and compare it with standard cardiac markers. methods: we undertook a prospective evaluation of 100 consecutive patients admitted with acute chest pain suggestive of acute coronary syndromes (acs). serum cardiac troponin i (ctni), cardiac troponin t (ctnt), creatine kinasemb (ck-mb) mass, myoglobin, and h-fabp were determined at presentation and 2, 4, 8–10, and 16–24 hours after presentation. the main outcome measure was the best sensitivity value within 6 hours after symptom onset. results: h-fabp peak concentration occurred at 8 hours after symptoms onset and was the most sensitive early marker with 79.9% and 98% of patients with ami identified at presentation and 2 hours after presentation respectively. the sensitivity of all other cardiac markers (ck-mb mass, ctni, ctnt, and myoglobin) at presentation was < 62%. the negative predictive value of h-fabp (94%) was also superior to other markers within the first 2 hours of presentation. myoglobin was the second most sensitive early marker at presentation. peak sensitivity of ctni, ck-mb mass, and ctnt were present at 4, 8–10, and 8–10 hours respectively after presentation. conclusion: combined measurement of h-fabp and ctni on two occasions during the first 8 hours after symptom onset was sufficiently sensitive and specific for the early diagnosis of most patients with acute mi and may provide advantages over other cardiac marker combinations. keywords: acute myocardial infarction; acute coronary syndromes; heart-type fatty acid-binding protein; cardiac markers. heart-type fatty acid-binding protein in the early diagnosis of acute myocardial infarction the potential for influencing patient management *hafidh a alhadi1 and keith a a fox2 clinical & basic research heart-type fatty acid-binding protein in the early diagnosis of acute myocardial infarction the potential for influencing patient management 42 | squ medical journal, april 2010, volume 10, issue 1 chest pain is a non-specific complaint and is the most frequent reason for patients to seek urgent medical attention.1 a proportion of these patients will be in the process of evolving acute myocardial infarction (ami) and, of these, about 25% lack the diagnostic features of infarction at presentation despite subsequently evolving q wave infarcts. current diagnostic and triage systems based on clinical history and electrocardiogram (ecg) results lack both sensitivity and specificity. between 2 and 10% of patients with ami may be inadvertently discharged from accident and emergency (a&e) departments leading to serious health and legal consequences. conversely, inappropriate admissions of a large number of patients without acute coronary syndromes (acs) will have substantial cost implications.2 cardiac markers are critical in making the diagnosis of ami but, thus far, their role has mainly been for retrospective confirmation of ami, 12-24 hours after admission. creatine kinase (ck), ck muscle and brain (ck-mb) and troponins lack sufficient precision within the first 6 hours of presentation. myoglobin is an early marker of myocardial injury, but has poor specificity.3 heart-type fatty acid-binding protein (h-fabp) is a novel marker with the potential for the early diagnosis of ami within 6 hours of symptoms onset.4 its sensitivity for the diagnosis of ami is comparable with myoglobin; however, the specificity of h-fabp for myocardial tissue is significantly better than that of myoglobin.5 this early release of h-fabp coupled with relative cardiac tissue specificity are potential advantages that may be valuable for the early diagnosis, triage, and management of patients with ami.6-7 to date, there have been few studies comparing the value of these markers for the early diagnosis of ami.8 the aim of the current study is to compare the value of h-fabp for the early diagnosis of ami with other cardiac markers such as myoglobin, creatine ck-mb mass, serum cardiac troponin i (ctni), and cardiac troponin t (ctnt) in a standardised setting. methods included in the study, over a seven months period in 2002, were 100 consecutive patients with acute chest pain admitted within 6 hours of symptoms onset through the a&e department at the royal infirmary of edinburgh. ethical approval was obtained from the local ethical committee, the lothian health board, edinburgh, uk. informed consent was obtained from each patient before beginning the study. all enrolled patients were evaluated by the a&e department physician. the evaluation included a brief history and physical examination and a recording of a 12-lead ecg. the time of onset of symptoms was carefully recorded for each patient at presentation. five serial blood samples beginning at 0 hour (at presentation), 2 hours, 4 hours, 8–10 hours, and 16–24 hours after presentation and ctni, ctnt, ck-mb mass, myoglobin, and h-fabp were measured at each time interval. all sequential patients were included in this study if they presented within 6 hours after the onset of symptoms, and had prolonged ischaemic chest pain (≥ 10 minutes in duration) suggestive of acs, with or without ecg changes suggestive of ischaemia. patients were excluded from the study if they had: 1) repeated intramuscular injection; 2) cardiac arrest at presentation; 3) recent surgery, coronary artery bypass graft (cabg) or ami (< 1month); 4) any evidence of renal impairment or hypothyroidism. the diagnosis of st elevation myocardial infarction (mi) was based on the revised definition of mi and had to include at least two of the following three findings:9 1) clinical history of prolonged ischaemic chest pain ≥ 30 minutes in advances in knowledge 1. this article broadens our knowledge of the novel marker, heart-type fatty acid binding protein, and its place in the hierarchy system of currently available cardiac markers for the very early diagnosis of acute myocardial infarction in patients who present with acute chest pain. application to patient care 1. the information in this article will help health care professionals, who deal directly with patients with acute coronary syndromes, to understand better the advantages and limitations of the cardiac marker, heart-type fatty acid-binding protein. 2. this article offers some recommendations to clinicians on the best combination of cardiac markers for the early diagnosis of acs and when to use them. hafidh a alhadi and keith a a fox clinical and basic research | 43 table 1: demographic and clinical data of patients in the various study groups. continuous variables are presented as mean ± sd and categorical variables are presented as percentages (in brackets). demographic & clinical data stemi group 1 non-stemi group 2 ua group 3 angina/atypical group 4 p value no. patients 45 14 20 21 age (years) 66.58 ± 11.74 67.36 ± 11.34 67.45 ± 12.31 64.55 ± 9.54 ns male female 29 (64) 16 (36) 9 (64) 5 (36) 16 (80) 4 (20) 12 (57) 9 (43) ns ns time to presentation (hrs) 3.57 ± 2.33 5.3 ± 1.28 5.63 ± 1.17 5.0 ± 1.95 ns previous history angina ua ami cabg pci 6 (13) 6 (13) 1 (2) 6 (13) 10 (22) 9 (64) 3 (21) 6 (43) 5 (36) 4 (29) 10 (50) 3 (15) 10 (50) 2 (10) 2 (10) 15 (71) 4 (19) 8 (38) 5 (23) 3 (14) < 0.05 ns ns ns ns risk factors dm htn smoker ex-smoker high cholesterol fhx of ihd 8 (18) 11 (24) 15 (33.3) 4 (8.7) 31 (69) 10 (22.2) 2 (14) 5 (36) 5 (36) 1 (7) 10 (71) 3 (21) 3 (15) 4 (20) 3 (15) 8 (40) 9 (45) 1 (5) 2 (10) 3 (14) 9 (43) 2 (10) 13 (62) 6 (29) ns ns ns ns ns ns admission hr systolic bp diastolic bp typical chest pain atypical chest pain 72.97 ± 17.14 136.4 ± 25.93 71.83 ± 16.86 34 (76) 11 (24) 75.56 ± 17.99 133.22 ± 34.26 71.44 ± 18.44 13 (93) 1 (7) 66.92 ± 11.18 151.92 ± 17.93 74.92 ± 11.7 17 (85) 3 (15) 77.0 ± 16.35 134.67 ± 10.49 79.0 ± 13.99 13 (62) 8 (38) ns 0.024 ns 0.027 ns ecg changes at admission persistent st elevation transient st elevation st depression ± t wave changes other ecg changes no acute changes old q waves present 39 (87) 6 (13) 3 (21) 9 (64) 1 (7) 1 (7) 1 (7) 2 (10) 14 (74) 1 (5) 2 (10) 5 (25) 1 (5)* 3 (14) 2 (10) 15 (71) 6 (29) ecg changes at admission: persistent st elevation transient st elevation st depression ± t wave changes other ecg changes no acute changes old q waves present 39 (87) 6 (13) 3 (21) 9 (64) 1 (7) 1 (7) 1 (7) 2 (10) 14 (74) 1 (5) 2 (10) 5 (25) 1 (5)* 3 (14) 2 (10) 15 (71) 6 (29) legend: sd = standard deviation; stemi = st elevation myocardial infarction; ua = unstable angina; ami = acute myocardial infarction; cabg = coronary artery bypass grafting ; pci = percutaneous coronary intervention; dm = diabetes mellitus; htn = hypertension; fhx of ihd = family history of ischaemic heart disease; hr = heart rate; bp = blood pressure; st, t, q, = st segment, t wave segment, q wave segment of electrocardiogram (ecg); ns = not significant. heart-type fatty acid-binding protein in the early diagnosis of acute myocardial infarction the potential for influencing patient management 44 | squ medical journal, april 2010, volume 10, issue 1 duration; 2) evolution of typical changes in at least two adjacent leads of the ecg, appearance of st segment elevation > 2 mm 0.08 seconds after j point persisting for at least 24 hours with or without q waves, defined as st elevation mi; 3) a time-dependent rise in concentration of ck-mb or troponins and a subsequent fall. unstable angina was diagnosed when patients had two or more of the following criteria without clear-cut ecg changes of infarction or cardiac markers (troponins or ckmb) elevations diagnostic of ami: 1) ischaemic chest pain ≥ 10 minutes in duration; 2) transient st segment elevation ≥ 1 mm 0.08 seconds after j point less than 30 minutes in duration; 3) transient or persistent st segment depression ≥ 1 mm 0.08 seconds after j point in two adjacent leads; 4) symmetrical or asymmetrical t wave inversion ≥ 1 mm excluding t wave inversion in leads iii, avr, and v1 only. patients were diagnosed as having non st elevation mi if they had one or more of the criteria listed above and in addition, they had evidence of myocardial necrosis as reflected by ck-mb or troponin elevation and a subsequent fall. patients were diagnosed as having atypical or anginal chest pain if they had all the following criteria: 1) typical or atypical presentation of chest pain; 2) none of the above listed ecg changes and 3) no rise in ck-mb or ctni. patients were divided into four main groups for comparison: group 1 included patients with st elevation mi, the ‘stemi group’; group 2 included patients with non st elevation mi, the ‘non-stemi’ group; group 3 included patients with unstable angina (ua), the ‘ua group’; group 4 included a heterogeneous population of patients with mixed medical diagnoses other than the above. patients in group 4 were referred to as ‘atypical/anginal chest pain group’. the selected diagnostic cut-off concentrations were based on receiver operator characteristic (roc) curve analysis [figures 1a and 1b] between patients with mi (stemi and non-stemi groups, n = 59) and controls (atypical/anginal chest pain group, n = 21 and healthy blood donor controls, n = 20). these cut-off concentrations were ck-mb mass ≥ 5 µg/l (sensitivity = 86.3%, specificity = 99%); ctni ≥ 0.18 µg/l (sensitivity = 90.8%, specificity = 99%); ctnt ≥ 0.1 µg/l (sensitivity = 76.4%, specificity = 99%); h-fabp ≥ 12.5 µg/l (sensitivity = 91.4%, specificity = 86%), and myoglobin ≥ 95 µg/l (sensitivity = 81.2%, specificity = 99%). the laboratory analysis of ctni, ck-mb mass, and myoglobin was done on a stratus cs analyser machine (dade behring, germany), using commercially available test materials. the coefficients of variations for ctni were 6.8%, and 6.7% at concentration range 0.24–0.36 µg/l, and 4.6– 6.9 µg/l respectively. h-fabp was analysed by an enzyme linked immunosorbent assay method using commercially available assays (hycult, cambridge, specificity [false positive] 1.00.80.60.40.200.00 se ns iti vi ty [t ru e po si tiv e] 1.00 .80 .60 .40 .20 0.00 a specificity [false positive] 1.0 0.80.60.40.200.0 0 se ns iti vi ty [t ru e po si tiv e] 1.0 0 .80 .60 .40 .20 0.0 0 b figures 1a and b: receiver operator characteristic (roc) curves that were used to derive the cut-off concentrations for a) the various cardiac markers (blue = ck-mb mass concentrations; green = ctni concentrations; red = ctnt concentrations; black = myoglobin concentrations); and b) h-fabp. see text for sensitivity and specificity values. hafidh a alhadi and keith a a fox clinical and basic research | 45 uk). the analytical sensitivity of h-fabp (mean ± 2sd) was 0.206 ± 0.047 µg/l. the coefficient of variation for h-fabp measurements was always < 10%. cardiac-tnt was analysed on elecsys 2010 using commercial assays (roche, germany). the reference ranges quoted by the manufacturer for ck-mb mass, ctni, myoglobin, ctnt, and h-fabp assays were validated by assaying the normal ranges of 20 healthy blood donor samples (10 males and 10 females). the mean ± sd concentrations of these markers were ck-mb mass = 1.52 ± 0.8 µg/l; ctni = 0.015 ± 0.006 µg/l; myoglobin = 41.5 ± 13.3 µg/l; ctnt = 0.011 ± 0.002 µg/l, and h-fabp = 6.86 ± 2.21 µg/l. statistical analyses were performed using the statistical package for social sciences (spsstm, pittsburgh, statistical software, version 12). variables were expressed as mean ± sd. the sensitivity, specificity, positive predictive value (ppv), and negative predictive value (npv) were measured for each marker at each time interval after presentation and compared. chi-square tests were used to explore the group differences with respect to categorical variables. the kruskal–wallis h-test was conducted to compare continuous variables and mean cardiac markers concentrations differences in the four groups. significant results are indicated by probability values less than or equal to 0.05. table 2: sensitivity, specificity, positive predictive value, and negative predictive value of cardiac markers for the early diagnosis of ami within 6 hours after symptoms onset. marker(s) validity indicator 0 hr 2 hrs 4 hrs 8-10 hrs 16-24 hrs ck-mb sensitivity 42 92.2 95.3 95.3 90.6 specificity 93.75 93.75 93.75 93.75 86.7 ppv 96 98.3 98.4 98.4 96.7 npv 29 75 83.3 83.3 81.25 ctni sensitivity 56 95.3 100 100 100 specificity 81.25 87.5 93.75 96.88 100 ppv 92.3 96.8 98.46 99.2 100 npv 31.7 82.35 100 100 100 ctnt sensitivity 32.8 67.2 85.9 96.9 95.3 specificity 93.75 93.75 93.75 93.75 93.75 ppv 95.5 97.7 98.2 98.4 98.4 npv 25.4 41.7 62.5 88.23 83.3 h-fabp sensitivity 79.7 98 95.3 93.75 75 specificity 92.3 .93.3 93.75 87.5 93.3 ppv 98 98.4 98.4 98 98 npv 52 94 83 78 47 myoglobin sensitivity 59.4 87.5 89.1 84.38 68.75 specificity 94 93.75 93.75 93.75 93.75 ppv 97.4 98.24 98.3 98.18 97.8 npv 38.1 65.22 68.2 60 42.8 legend: ck-mb = creatine kinase-muscle & brain; ppv = positive predictive value; npv = negative predictive value; ctni = serum cardiac troponin i; ctnt = serum cardiac troponin t; hfabp = heart-type fatty acid-binding protein heart-type fatty acid-binding protein in the early diagnosis of acute myocardial infarction the potential for influencing patient management 46 | squ medical journal, april 2010, volume 10, issue 1 panel a: patients with st elevation myocardial infarction (stemi) and non-st elevation myocardial infarction (nonstemi) st elevation mi group 0 250 500 750 1000 1250 1500 1750 2000 time (hours) ck-mb ctni myoglobin h-fabp non-st elevation mi group 0 250 500 750 1000 1250 1500 1750 2000 0hr 2hrs 4hrs 8-10hrs 16-24hrs time (hours) c on ce nt ra tio n (u g/ m l) ck-mb ctni myoglobin h-fabp panel b: patients with unstable angina and atypical/anginal pain unstable angina group 0 25 50 75 100 125 150 175 200 0hr 2hrs 4hrs 8-10hrs 16-24hrs time (hours) c on ce nt ra tio n (u g/ m l) ck-mb ctni myoglobin h-fabp atypical/anginal pain group 0 25 50 75 100 125 150 175 200 0hr 2hrs 4hrs 8-10hrs 16-24hrs time (hours) c on ce nt ra tio n (u g/ m l) ck-mb ctni myoglobin h-fabp legend: ck-mb = creatine kinase-muscle & brain; ctni = serum cardiac troponin i; h-fabp = heart-type fatty acid-binding protein figure 2: illustrates the release pattern (time-concentration profile) of the different cardiac markers at each time after presentation in patients in the various study groups. the data for ctnt were omitted from the graph because they were on a different scale, but were similar to those of cardiac troponin i. hafidh a alhadi and keith a a fox clinical and basic research | 47 results out of 100 consecutive patients presenting with acute chest pain, 45 patients (45%) had st elevation mi (group 1), 14 patients (14 %) had non-stemi (group 2), 20 patients (20%) had ua (group 3). the last 21 patients (21%) constituted group 4. the demographic and clinical data of the patients in these four groups is shown in table 1. the study group consisted of 66% males. the mean age, percentage of males/females, the prevalence of risk factors, and the prevalence of previous cardiac disease (cabg, pci) were not significantly different between the groups. the prevalence of previous angina (p < 0.05), systolic blood pressure (p < 0.024) and type of chest pain at presentation (p < 0.027) were statistically different. figure 2 illustrates the release characteristics of cardiac markers in the four groups. for the stemi group, myoglobin and h-fabp were the earliest makers of myocardial injury. the peak concentrations of myoglobin and h-fabp were reached in samples taken 2 hours after presentation (8 hours after symptoms onset). the peak concentrations of ck-mb mass and ctni occurred at 8–10 hours after presentation (14–16 hours after the onset of chest pain). the peak concentrations of ctnt occurred at 16–24 hours after presentation (24–30 hours after onset of symptoms). h-fabp and myoglobin concentrations decreased significantly at 16–24 hours, whereas ck-mb mass, ctni, and ctnt were still present in high concentrations. for the non-stemi group, h-fabp and myoglobin peak concentrations were achieved at 2 hours and the concentrations of these markers had decreased to normal levels at 16– 24 hours after presentation. for ck-mb mass, the peak concentration occurred at 8–10 hours. the maximum increase in ctni and ctnt occurred late at 16–24 hours. the concentrations of ck-mb mass, ctni, and ctnt were still present in significant levels at 16–24 hours. figure 3 is a line chart representation of the sensitivity values of cardiac markers for the diagnosis of mi in the stemi only group, n = 45 patients. h-fabp was the most sensitive marker at presentation (75.5%), and it remained elevated with a sensitivity of 100% for the next 2–8 hours after presentation. h-fabp sensitivity was also superior to other markers within the first two hours of presentation. myoglobin and ck-mb mass sensitivity were similar in the first 2 hours (93%). however, the peak sensitivity of myoglobin (93%) and ck-mb mass (100%) were reached at 2 hours, and 8–10 hours respectively. cardiac-tni reached higher sensitivity (97.7%) earlier (2 hours) than myoglobin, ck-mb mass, and ctnt. the sensitivity of ctnt gradually increased from a low level at presentation (24%) to the highest level (100%) at 8–10 hours after presentation [figure 3]. the overall sensitivity, specificity, ppv, and npv were determined for the whole group (n = 100 patients). table 2 shows the percentages of these values for the different cardiac markers at each time interval after presentation. h-fabp still had the the sensitivity of cardiac markers for the early diagnosis of ami 0 20 40 60 80 100 120 0 hr 2 hrs 4 hrs 8 hrs 16 hrs time after presentation (hours) se ns iti vi ty (% ) ck-mb mass ctni ctnt myoglobin h-fabp legend: ck-mb = creatine kinase-muscle & brain; ctni = serum cardiac troponin i; ctnt = serum cardiac troponin t; h-fabp = heart-type fatty acid-binding protein figure 3: line chart representation of the sensitivity values. each mark represents the percentage sensitivity of the cardiac marker at that time interval heart-type fatty acid-binding protein in the early diagnosis of acute myocardial infarction the potential for influencing patient management 48 | squ medical journal, april 2010, volume 10, issue 1 highest sensitivity at presentation (79.9%). almost all patients (98%) with mi were diagnosed within 2 hours after admission (8 hours after onset of symptoms). the specificity of h-fabp at 2 hours was 93.3%. compared to other markers, h-fabp had the highest npv (94%) at 2 hours. the ppv of h-fabp was also high (98%). myoglobin had the second highest sensitivity at 0 hour (59.4%) rising to 87.5% two hours after presentation. the corresponding specificity, ppv, and npv were 93.75%, 98.24%, and 65.22% respectively. all other cardiac markers had low sensitivities at 0 hr (i.e. at presentation) 32.8%, 42%, 56% for ctnt, ckmb mass and ctni respectively. the npv of cardiac markers was also low at presentation 25%, 29%, 31.7%, 38.1%, 52% for ctnt, ckmb mass, ctni, myoglobin, and h-fabp respectively. most of the cardiac markers had high ppv (92–100%). the performance of ctni was better than ctnt in terms of overall sensitivity, specificity, ppv, and npv. reliable sensitivity, specificity, ppv, and npv by ck-mb mass and ctni were observed at 4 hours after presentation. reliable sensitivity (96.9%), specificity (93.75%), ppv (98.4%), and npv (88.23%) of ctnt were evident at 8–10 hours after presentation. discussion in patients presenting with ami, h-fabp appeared to be a reliable cardiac marker indicator 6 hours after symptom onset, peaked at 8 hours and had decreased significantly towards normal concentrations by 16-24 hours after presentation. these two features of h-fabp, early concentration peak following myocardial injury and rapid return to normal base line concentration, differentiate this marker from the troponins and ck-mb. they suggest the potential of h-fabp for early detection of myocardial injury and early detection of reinfarction. the sensitivities of h-fabp (75.5% and 79.7%) for the detection of ami, observed within the first 6 hours after symptoms onset in this study, was in agreement with some previously published data.5,10 in our study, h-fabp was the most sensitive marker at presentation and within the first two hours after presentation (i.e. 8 hours after symptom onset) and demonstrated the highest npv (94%). this was consistent with other previously published data.11 a study by alansari et al. showed that myoglobin and h-fabp provide little clinical value when measured on admission in patients presenting with chest pain.8 most of the standard cardiac markers in alansari’s study had limited diagnostic value at presentation. the overall npv of all cardiac markers was low < 52% within the first 6 hours after symptom onset. the sensitivity of these markers for the early diagnosis of ami was < 62%. bakker et al. reported low sensitivity (< 64%) and low npv of routine cardiac markers ck-mb mass, ctnt, myoglobin, ck-mb activity, and ck to allow early exclusion of ami.12 this study highlights two important facts: 1) h-fabp was more sensitive than myoglobin and 2) h-fabp had higher npv than myoglobin. high sensitivity is essential for the early ‘rule in’ of patients with ami, and high npv is important for the early ‘rule out’ of ami, since more than 90% of patients who present with acute chest pain to an a&e department do not have ami. this superiority of h-fabp over myoglobin may be attributable to the fact that 1) the myoglobin content of skeletal muscle is twice that of the heart (hence interference from skeletal muscle injury i.e. less specific) whereas the h-fabp content of skeletal muscles is only 10– 50% of that of the heart and 2) the normal plasma concentration of h-fabp (< 5 µg/l) is 10–15 fold lower than that of myoglobin (20–80 µg/l).5 hence, the differing features of myoglobin and h-fabp allow the use of lower, but more discriminate, cutoff concentrations of h-fabp thus improving the sensitivity. the limitation of the enzyme-linked immunosorbent assay (elisa) method, which produces results in around 90 minutes, could be overcome by using the new rapid bed-side h-fabp tests.13 however, as it is solely excreted by the kidney, this cardiac marker has limitations in patients with renal impairment and skeletal muscle injury.14 conclusion the main conclusions of this study are, first, that h-fabp was superior to myoglobin (and other markers) for the early diagnosis of ami within 6 hours after symptom onset. second, the diagnostic window for h-fabp is relatively prolonged (up to 14 hours after symptom onset). this diagnostic window provides sufficient opportunity for the detection of ami and initiation of appropriate therapy. third, ctni, as measured on the stratus cs machine, was highly sensitive supporting its use for hafidh a alhadi and keith a a fox clinical and basic research | 49 the early detection of patients with ami. fourth, measurement of h-fabp and ctni at two intervals during the first 8 hours after symptom onset was sufficiently sensitive and specific for the early diagnosis of most patients with ami. we propose an alternative: that h-fabp should be combined with a specific marker like ctni. the combination of h-fabp and ctni improves specificity for a definitive diagnosis of ami. we also propose that this combination should be tested in a larger-scale study and, if the current findings are confirmed, h-fabp and ctni may constitute the standard combination for early diagnosis of mi. a c k n o w l e d g m e n t s we would like to thank the many patients and nurses who took part in this study. we would also like to thank mrs. jean cunningham for outstanding secretarial assistance. f u n d i n g this study was funded by a separate grant from the cardiovascular research unit, university of edinburgh, and sultan qaboos university. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. british heart foundation statistics database 1999. coronary heart disease statistics. 2002 ed. london: british heart foundation, 2002. 2. puleo pr, meyer d, wathen c, tawa cw, wheeler s, humburg rj, et al. use of a rapid assay of subforms of creatine kinase-mb to diagnose or rule out acute myocardial infarction. n engl j med 1994; 331:561–6. 3. woo j, lacbawan fl, sunheimer r, mccabe jb. is myoglobin useful in the diagnosis of acute myocardial infarction in the emergency department setting? am j clin pathol 1995; 103:725–9. 4. glatz jf, van bilsen m, paulussen rj, veerkamp jh, van der vusse gj, reneman rs. release of fatty acidbinding proteins from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox. biochem biophys acta 1988; 961:148–52. 5. glatz jf, van der vusse gj, simoons ml kragten ja, van dieijen-visser mp, hermens wt. fatty acidbinding protein and the early detection of acute myocardial infarction. clin chim acta 1998; 272:87– 92. 6. alhadi ha, fox ka. do we need additional markers of myocyte necrosis: the potential value of heart-type fatty-acid-binding protein? qjm 2004; 97:187–98. 7. colli a, jossa m, pomar jl, and gherli t. heart fatty acid binding proteins in diagnosis of myocardial infarction: where do we stand now? cardiology 2007; 108:4–10. 8. alnsari se, croal bl. diagnostic value of heart fatty acid binding protein and myoglobin in patients admitted with chest pain. ann clin biochem 2004; 41:391–6. 9. alpert js, thygesen k. myocardial infarction redefined a consensus document of the joint european society of cardiology/american college of cardiology committee for the redefinition of myocardial infarction. eur heart j 2000; 21:1502– 13. 10. ishii j, wang jh, naruse h, taga s, kinoshita m, kurokawa h, et al. serum concentrations of myoglobin vs human heart-type fatty acid-binding protein in early detection of acute myocardial infarction. clin chem 1997; 43:1372–8. 11. ruzgar o, bilge ak, bugra z, umman s, yilmaz e, ozben b, et al. the use of human heart-type fatty acidbinding protein as an early diagnostic biochemical marker of myocardial necrosis in patients with acute coronary syndrome, and its comparison with troponin-t and creatine kinase-myocardial band. heart vessels 2006; 21:309-14. 12. bakker aj, koelemay mj, gorgels jp, van vlies b, smits r, tijssen jg, et al. failure of new biochemical markers to exclude acute myocardial infarction at admission. lancet 1993; 342:1220–3. 13. seino y, ogata k, takano t, ishii j, hishida h, morita h, et al. use of a whole blood rapid panel test for heart-type fatty acid-binding protein in patients with acute chest pain: comparison with rapid troponin t and myoglobin tests. am j med 2003; 115:185-90. 14. alhadi ha, william b, fox ka. serum level of heart fatty acid binding protein in patients with chronic renal failure. squ med j 2009; 9:311-14. 1department of general medicine, christchurch hospital, canterbury district health board, christchurch, new zealand; 2nizwa polyclinic, directorate of nursing, nizwa, oman *corresponding author’s e-mail: ibra.3sk@gmail.com معدل وتنبؤات نشر امللخصات البحثية لألطباء املقيمني اليت قدمت يف االجتماعات العلمية للمجلس الُعماين لالختصاصات الطبية اإبراهيم �شالح البو�شعيدي و جونا�س دوبو abstract: objectives: this study aimed to examine the rate and factors associated with the publication of abstracts presented by residents at oman medical specialty board (omsb) scientific meetings. methods: this retrospective study was performed in february 2018. two previous national omsb scientific meetings at which resident abstracts were presented were identified, having taken place in january 2014 and december 2016, respectively. independent searches of the medline® (national library of medicine, bethesda, maryland, usa) and google scholar (google llc, menlo park, california, usa) databases were conducted to determine subsequent publication of the abstracts. results: a total of 68 resident abstracts were presented, of which most were clinical research (92.6%). residents comprised 36.4% of the authors, of which 73.1% were senior residents. in 64 abstracts (94.1%), a resident was the first author. overall, 15 abstracts (22.1%) resulted in articles published in 11 journals. of these, 12 (80%) represented clinical research and 10 articles (66.7%) were published in medline®-indexed journals. residents were the first authors of eight articles (53.3%). the median time to publication was 19 months. the presence of two or more resident authors per abstract was significantly associated with publication (odds ratio = 5.50, 95% confidence interval = 1.15–26.36; p = 0.03). conclusion: the publication rate of resident abstracts presented at two omsb research meetings was low; however, a higher number of resident authors per abstract significantly increased the likelihood of publication. these findings may influence policymakers to implement measures to support inter-resident collaboration so as to increase research productivity. keywords: biomedical research; graduate medical education; internship and residency; meeting abstracts; publications; oman. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل معرفة امُلَعدَّل والعوامل املتعلقة بن�رص امللَخ�شات الَبْحِثية التي قدمها الأطباء امُلقيمني �شمن حتديد مت .2018 فرباير يف ة ال�ْشِتَعاِديَّ الِدرا�َشة هذه اإجراء مت الطريقة: الطبية. لالخت�شا�شات الُعماين للمجل�س الِعلِمية الجتماعات بحثيه معايري با�شتخدام .2016 و�شبتمرب 2014 يناير يف َعقدها مت والتي الطبية لالخت�شا�شات الُعماين للمجل�س �شابقني اجتماعني موحدة مت البحث يف قواعد البيانات ميدلين® )املكتبة الوطنية للطب، بيثي�شدا، ماريالند، الوليات املتحدة الأمريكية( وجوجل �شكولر )جوجل، مينلو بارك، كاليفورنيا، الوليات املتحدة الأمريكية( لتحديد جميع امللَخ�شات الَبْحِثية التي مت ن�رصها لحقا على هيئة مقالت طبية. النتائج: كان هناك 68 ملخ�شا بحثيا، ُجلها كانت ُبحوثا �رَصيِرّية )%92.6(. �شكل الأطباء املقيمني %36.4 من اإجمايل املوؤلفني، بحثيا. مت حتديد 15 ملخ�شا )94.1%( 64 يف الأول املوؤلف املقيمني الأطباء كان الأخرية. الخت�شا�س �شنوات يف كانوا منهم 73.1% ملخ�شا )%22.1( مت ن�رصها لحقا كمقالت بحثية يف 11 جملة علمية. كان من اإجمايل املن�شورات 12 مقال )%80( كانت ُبحوثا �رَصيِرّية من قاِعدة البيانات ميدلين®. كان الأطباء املقيمني املوؤلف الأول يف ثماين من�شورات بحثية )53.3%(. و 10 مقالٍت )%66.7( ُمدَرَجة �شِ �شمن من اأكرث اأو مقيمني طبيبني وجود اأن علما �شهرا. 19 العلمية املجالت يف كمقالت الَبْحِثية امللَخ�شات لن�رص الوقت متو�شط كان .)p = 0.03 موؤلفي امللخ�س البحثي كان من العوامل املرتبطة بالن�رص ب�شكل كبري )ن�شبة الأرجحية = 5.50، فا�شل الثقة = 26.36-1.15؛ اخلال�صة: كان معدل ن�رص امللَخ�شات الَبْحِثية التي قدمها الأطباء امُلقيمني يف اجتماعني �شابقني للمجل�س الُعماين لالخت�شا�شات الطبية قليال؛ لوحظ اأن ازدياد عدد املوؤلفني من الأطباء املقيمني ارتبط ب�شكل كبري مع معدل الن�رص. عليه وعلى �شوء ما تقدم ذكره، قد توؤثر نتائج هذه الدرا�شة على �شانعي القرار لتطبيق اإجراءات لدعم التعاون البحثي بني الأطباء املقيمني لزيادة الإنتاجية البحثية. الكلمات املفتاحية: البحوث الطبية احليوية؛ التعليم الطبي املتقدم؛ فرتة التخ�ش�س يف الطب؛ ملخ�شات الجتماعات الِعلِمية؛ من�شورات؛ عمان. rate and predictors of publication of resident abstracts presented at oman medical specialty board scientific meetings *ibrahim s. al-busaidi1 and jonas u. dupo2 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e501–506, epub. 28 mar 19 submitted 6 may 18 revision req. 5 jun 18; revision recd. 10 jun 18 accepted 21 jun 18 advances in knowledge to the best of the authors’ knowledge, this is the first study to examine the characteristics, publication rate and factors associated with the successful conversion of resident abstracts to peer-reviewed articles in oman. although the publication rate of resident abstracts in oman was within acceptable international limits for conference abstracts, it was nevertheless considerably lower than reported rates for abstracts presented by trainees at intramural resident research meetings. the successful publication of resident abstracts was significantly higher for abstracts with two or more resident authors. doi: 10.18295/squmj.2018.18.04.012 rate and predictors of publication of resident abstracts presented at oman medical specialty board scientific meetings e502 | squ medical journal, november 2018, volume 18, issue 4 according to the world medical assoc-iation, investigators have an ethical obligation to make the findings of their research available to the public, irrespective of outcome.1 although research findings can be appropriately disseminated via conference presentations, book chapters and technical reports, publication in peer-reviewed journals is widely recog nised as the preferred vehicle for scientific communication.2,3 for this reason, the majority of accepted conference abstracts should ideally be published in refereed journals shortly after presentation, thus ensuring that their findings can influence patient care and inform future research.3 furthermore, converting a conference abstract into a full publication is a marker of the quality of the conference and reflects the value of the published research to the scientific community.2,4 in contrast, a failure to disseminate research findings wastes valuable resources, may negatively affect patient care and results in the unnecessary potential duplication of research.5 established in 2006, the oman medical specialty board (omsb) oversees graduate medical education and training in oman.6 as an accredited national body, the omsb encourages its resident doctors to participate in research by holding workshops and courses on research methods, ethical principles and academic writing. furthermore, successful completion of a research project—from design to the dissemination of research findings (e.g. presentation at conferences/ research meetings or publication in peer-reviewed journals)—is mandatory in certain specialty programmes.6 the omsb also provides its residents with a platform to present their findings and exchange research ideas during annual intramural scientific meetings. previous research has extensively examined the subsequent publication rates of abstracts presented at regional, national and international scientific meetings.3,7 according to fosbøl et al., the publication rates of conference abstracts across medical specialties ranges from 8–81% (median: 47%).7 however, research examining the publication rates of abstracts presented by resident doctors/trainees is sparse.8 moreover, the publication rate of conference abstracts presented by residents in oman is unknown. this study therefore aimed to examine the rate, characteristics and factors associated with the successful publication of abstracts presented by omsb residents at national research meetings. methods this retrospective cohort study examined the subsequent publication of resident abstracts presented at national research meetings in oman. based on a manual search of archived issues of the oman medical journal (omj), the affiliated journal of the omsb, two national intra mural scientific meetings were identified at which residents presented abstracts—the 4th annual research day (ard) and the omsb career and research forum 2016 (crf) held in january 2014 and december 2016, respectively.9–11 subsequently, the medline® (national library of medicine, bethesda, maryland, usa) and google scholar (google llc, menlo park, california, usa) databases were searched in february 2018 for peer-reviewed publications. publications were identified using the residents’ first and last names, with or without keywords based on the title of the presented abstract. for a resident abstract to be considered published, at least one resident had to be a co-author in the corresponding publication and the conclusion of the publication had to match that of the abstract. identification of the publications was based on independent literature searches conducted by two separate researchers, with inter-rater agreement found to be 100% according to cohen’s kappa coefficient. the resident abstracts were reviewed to determine the total number of authors (both resident and nonresident), their genders, resident authorship order (i.e. first author versus co-author), resident level and specialty training programme and the type of research (clinical versus basic science research). for each corresponding publication, various authorand article-related data were collected, including the number of authors and resident authorship order and the year of publication, article citation rate and journal name and impact factor (if) at the time of publication. citation rates were retrieved from the scopus® database (elsevier, amsterdam, netherlands). the journal if was obtained from the web of science™ journal citation reports (clarivate analytics, philadelphia, pennsylvania, usa). all collected data were entered into a predesigned excel spreadsheet, version 2016 (microsoft corp., red mond, washington, usa). the analysis was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). most of the results were presented as descriptive statistics. a direct logistic regression model was used application to patient care failure to disseminate research findings erodes the integrity of the scientific process and may negatively affect patient care. identifying predictors of publication of resident abstracts would help in the greater dissemination of research findings, thus indirectly influencing patient care and informing future research. ibrahim s. al-busaidi and jonas u. dupo clinical and basic research | e503 to examine the impact of certain factors on the likelihood of publication of the abstracts. the model contained four independent variables postulated to be associated with publication, including the type of study (clinical versus basic science research), resident authorship order (first author versus co-author), number of resident authors per abstract (one versus more than one) and the total number of authors per abstract. overall, the model was statistically significant (χ² = 10.24; p = 0.04), indicating that it was able to distinguish which abstracts resulted in a peer-reviewed journal publication. a value of p <0.05 was considered statistically significant. as this study did not involve participants and was focused on publicly available data obtained from open access sources, formal ethical approval was not deemed necessary. results out of 214 abstracts presented at the two national omsb scientific meetings, there were 68 resident abstracts (31.8%). of these, 32 (47.1%) were presented at the ard and 36 (52.9%) at the crf. the vast majority of resident abstracts represented clinical research table 1: characteristics of abstracts presented by residents at two oman medical specialty board meetings in muscat, oman (n = 68) characteristic n (%) meeting presented ard 32 (47.1) crf 36 (52.9) resident authorship order first author 64 (94.1) co-author 4 (5.9) type of research basic science 5 (7.4) clinical 63 (92.6) field of research anaesthesia 6 (8.8) clinical biochemistry 5 (7.4) dermatology 2 (2.9) emergency medicine 2 (2.9) family medicine 5 (7.4) general surgery 2 (2.9) haematology 2 (2.9) histopathology 2 (2.9) internal medicine 6 (8.8) microbiology 1 (1.5) obstetrics and gynaecology 5 (7.4) ophthalmology 6 (8.8) orthopaedics 4 (5.9) otolaryngology, head and neck surgery 5 (7.4) paediatrics 4 (5.9) psychiatry 5 (7.4) radiology 6 (8.8) ard = fourth annual research day; crf = career and research forum. table 2: characteristics of residents presenting abstracts at two oman medical specialty board meetings in muscat, oman (n = 78) characteristic n (%) gender female 43 (55.1) male 35 (44.9) specialty anaesthesia 7 (9.0) biochemistry 5 (6.4) dermatology 2 (2.6) emergency medicine 2 (2.6) family medicine 8 (10.3) general surgery 2 (2.6) haematology 2 (2.6) histopathology 2 (2.6) internal medicine 6 (7.7) microbiology 1 (1.3) obstetrics and gynaecology 5 (6.4) ophthalmology 6 (7.7) orthopaedics 5 (6.4) otolaryngology, head and neck surgery 5 (6.4) paediatrics 7 (9) psychiatry 7 (9) radiology 6 (7.7) residency level 1 4 (5.1) 2 7 (9) 3 10 (12.8) 4 19 (24.4) 5 23 (29.5) 6 15 (19.2) rate and predictors of publication of resident abstracts presented at oman medical specialty board scientific meetings e504 | squ medical journal, november 2018, volume 18, issue 4 (92.6%). there were 214 authors in total, with a median of three authors (range: 1–10 authors per abstract). in total, 78 authors (36.4%) were residents, with a mean of 1.1 resident authors per abstract (range: 1–3 resident authors). a total of 64 abstracts (94.1%) had resident first authors [table 1]. in terms of the characteristics of the residents, most were female (55.1%; p = 0.37) and in level ≥4 of their specialty/postgraduate training (73.1%). family medicine was the most commonly represented specialty (10.3%) [table 2]. by the end of february 2018, a total of 15 resident abstracts had been subsequently published in peerreviewed journals, resulting in an overall publication rate of 22.1%. of the 15 original articles, 12 (80%) represented clinical research and 10 (66.7%) were published in medline®-indexed journals (national library of medicine). there were 80 authors in total, with a median of six authors per article (range: 3–8 authors). residents were first authors in eight articles (53.3%); however, one article did not include one of the residents who had been an author of the corresponding abstract. the median time to publication was 19 months (mean: 20 months), although five articles (33.3%) were published prior to their presentation as abstracts at the meetings [figure 1]. the 15 articles were published in 11 different journals, with the omj being most common (n = 4; 26.7%). information regarding journal if was only available for two journals, which had ifs of 0.34 and 0.70, respectively. at the time of analysis, the articles had a total of 18 citations, with an average of 1.2 citations per article (range: 0–5 citations). six articles (40%) had been cited at least once. according to the logistic regression analysis, the number of resident authors per abstract was the only statistically significant predictor of publication. abstracts authored by two or more resident authors were 5.5-times more likely to be published in peer-reviewed journals (odds ratio = 5.50, 95% confidence interval = 1.15–26.36; p = 0.03). other factors, including the type of research, resident authorship order and the total number of authors per abstract, did not significantly influence publication [table 3]. discussion research is an essential part of postgraduate medical training; exposure to research during residency has been shown to improve critical thinking skills, stimulate interest in academic medicine and result in better clinical performance during residency training.12,13 by presenting their research at biomedical meetings or conferences, residents have the opportunity to critically discuss their findings, exchange research ideas and potentially establish new avenues for collaboration with established investigators. in addition, the process of converting an abstract into a full-text article and submitting it to a peer-reviewed journal offers residents practical experience in data analysis, critical appraisal and academic writing as they navigate the peer-review and publication process.2,14 finally, the entire research experience, from designing a study to the publication of the findings, can be used as a measure of resident competency. to the best of the authors’ knowledge, the current study is the first in oman to explore the characteristics, rate and factors associated with the successful public ation of resident abstracts. unfortunately, the publication rate of resident abstracts in the present cohort was low (22.1%). although this rate falls within the range of reported publication rates of conference abstracts across specialties (8–81%), it is considerably lower than those reported by studies specifically examining the publication rates of abstracts presented by trainees at intramural resident research meetings (40–64%).7,8,15 nevertheless, the relatively high conversion rates reported in these other studies may be partly explained by the fact that the examined cohorts were residents figure 1: time between presentation and publication of articles converted from resident abstracts presented at oman medical speciality board scientific meetings (n = 10)*. *excluding five abstracts which were published prior to their presentation at the meetings. table 3: logistic regression model of predictive factors related to the publication of resident abstracts presented at oman medical speciality board scientific meetings (n = 15) factor or (95% ci) p value number of resident authors per article 5.51 (1.15–26.36) 0.03 resident authorship order 1.03 (0.08–12.68) 0.98 total number of authors per abstract 1.20 (0.86–1.68) 0.29 type of research 0.15 (0.02–1.17) 0.07 or = odds ratio; ci = confidence interval. ibrahim s. al-busaidi and jonas u. dupo clinical and basic research | e505 from two highly sought-after programmes (the division of plastic & reconstructive surgery, university of toronto, toronto, canada, and the department of plastic surgery, johns hopkins hospital, baltimore, maryland, usa).8,15 given the research-intensive nature of these programmes and the high degree of emphasis on research productivity—for example, the department of plastic surgery at johns hopkins hospital includes a mandatory research year as part of their residency programme—it is likely that residents at these institutions are more motivated to publish their research findings.8 susarla et al. also suggested that the residents may have benefitted from experienced mentorship, as publication of resident abstracts was associated with the academic rank of their faculty investigator.8 the low publication rate of resident abstracts in the current study highlights the importance of examining factors which may affect the conversion rate of resident abstracts to full publications. in the present study, the successful publication of resident abstracts was significantly associated with a higher number of resident authors. similarly, yumeen et al. previously reported inter-resident collaboration to be a facilitator of publication.15 collaborating on a joint research project is mutually beneficial for both senior and junior residents, as it can mitigate certain difficulties faced by senior residents (i.e. time constraints due to clinical duties) while allowing junior residents to benefit from the guidance of their more experienced counterparts. furthermore, the preparation of a manuscript for publication in peer-reviewed journals is often technical and time-consuming; thus, such tasks can be shared by multiple residents.14 based on these findings, the authors encourage the implementation of collaborative/joint resident research projects to improve research productivity. in general, over half of the abstracts presented at biomedical conferences go unpublished.7 in a survey of internal medicine residents who had successfully completed a scholarly project, rivera et al. found that time constraints and inadequate research skills were the most frequent barriers to publication.16 in many cases, residents become distracted by their busy clinical schedules and only those interested in academic medicine may be motivated to put additional effort into getting their research published as peer-reviewed articles. other studies have implicated a number of other obstacles to publication, including a lack of research resources (e.g. research assistants or statistical software), inter-author conflicts and poor mentorship (i.e. lack of involvement on the part of the project supervisor).15–17 future studies should explore additional factors that may hinder or facilitate publication of resident abstracts in oman, such as the number of prior publications by resident authors or the senior author/faculty supervisor, a history of formal research training/attainment of a postgraduate research degree, interest in academic medicine as a career, the availability of research resources and the academic rank of the senior author/faculty supervisor.8,15–17 the findings of this study should be considered in the light of certain limitations. first, due to the retrospective nature of the study, the examination of other important factors influencing publication rate of resident abstracts was not possible, such as those mentioned above. second, the sample size may have been insufficient to detect statistically significant differ ences. however, although the omsb office was contacted in order to identify additional resident abstracts, further data could not be obtained. third, the mean period of time between the presentation of the abstracts and the literature search was 1.2 years, which may not have been sufficient for some residents to convert their abstract into a full-text publication. however, previous research has reported that 1.2 years is the mean time between presentation and publication of resident abstr acts.8 it is also possible that some unpublished resident abstracts were part of larger ongoing studies. finally, the overall number of publications may have been under estimated, as abstracts published in journals which are not included in the medline® (national library of medicine) or google scholar (google llc) databases were not included in the study. however, these databases are the largest and most widely used biomedical databases in the world; thus, the number of overlooked articles is likely to have been negligible. conclusion the publication rate of resident abstracts presented at two omsb scientific meetings was low, with only onefifth of resident abstracts subsequently published as full-text articles. a higher number of resident authors per abstract was a significant predictor of successful publication, suggesting that greater emphasis on collab orative research projects may improve resident research productivity. however, future research is recommended to identify other facilitators and barriers to the publication of resident abstracts. conflict of interest the authors declare no conflicts of interest. funding no funding was received for this study. rate and predictors of publication of resident abstracts presented at oman medical specialty board scientific meetings e506 | squ medical journal, november 2018, volume 18, issue 4 references 1. general assembly of the world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. j am coll dent 2014; 81:14–18. 2. al-busaidi is, alamri y. publication rates and characteristics of undergraduate medical theses in new zealand. n z med j 2016; 129:46–51. 3. fosbøl el, fosbøl pl, harrington ra, eapen zj, peterson ed. conversion of cardiovascular conference abstracts to publications. circulation 2012; 126:2819–25. https://doi.org/10.11 61/circulationaha.112.120535. 4. hicks rr. transforming a presentation to a publication: tips for nurse practitioners. j am assoc nurse pract 2015; 27:488–96. https://doi.org/10.1002/2327-6924.12228. 5. chan aw, song f, vickers a, jefferson t, dickersin k, gøtzsche pc, et al. increasing value and reducing waste: addressing in-accessible research. lancet 2014; 383:257–66. https://doi.org/10.1016/s01 40-6736(13)62296-5. 6. oman medical specialty board. about us. from: www.omsb.org/ accessed: jun 2018. 7. scherer rw, langenberg p, von elm e. full publication of results initially presented in abstracts. cochrane database syst rev 2007; 2:mr000005. https://doi.org/10.1002/14651858.mr0000 05.pub3. 8. susarla sm, lopez j, mundinger gs, lifchez sd, redett rj. abstract presentations by residents at an intramural research day: what factors affect publication? j surg educ 2015; 72:566–71. https://doi.org/10.1016/j.jsurg.2015.01.001. 9. oman medical journal. archive 2007-2018. from: www.omjour nal.org/omj_archives.aspx accessed: jun 2018. 10. oman medical specialty board. oman medical specialty board: fourth annual research day. oman med j 2014; 29:148–63. 11. oman medical specialty board. oman medical specialty board career and research forum 2016: abstracts. oman med j 2017; 32:e017. 12. shanmugalingam a, ferreria sg, norman rm, vasudev k. research experience in psychiatry residency programs across canada: current status. can j psychiatry 2014; 59:586–90. https://doi.org/10.1177/070674371405901104. 13. seaburg la, wang at, west cp, reed da, halvorsen aj, engstler g, et al. associations between resident physicians’ publications and clinical performance during residency training. bmc med educ 2016; 16:22. https://doi.org/10.1186/s12909016-0543-2. 14. al-busaidi is. publication and authorship challenges experienced by medical students involved in biomedical research. n z med j 2018; 131:89–91. 15. yumeen s, ho es, wong k, borschel gh. what factors influence resident research publication in the division of plastic surgery? j surg educ 2018; 75:409–16. https://doi.org/10.1016/j. jsurg.2017.07.016. 16. rivera ja, levine rb, wright sm. completing a scholarly project during residency training: perspectives of residents who have been successful. j gen intern med 2005; 20:366–9. https://doi.org/10.1111/j.1525-1497.2005.04157.x. 17. atreya ar, stefan m, friderici jl, kleppel r, fitzgerald j, rothberg mb. characteristics of successful internal medic ine resident research projects: predictors of journal publication versus abstract presentation. acad med 2018; 93:1182–8. https://doi.org/10.1097/acm.0000000000002164. clinical & basic research squ med j, august 2011, vol. 11, iss. 3, pp. 363-368, epub. 15th aug 11 submitted 15th feb 11 revision req. 12th apr 11, revision recd. 15th may 11 accepted 24th may 11 1department of physiology, sultan qaboos university hospital, muscat, oman; departments of 2medicine and 3physiology, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: malabri@squ.edu.om <ãàflj÷]<å]çäfi]<gäfl⁄<ƒ⁄<‰jœ¯¬ê<∞äfl¢]<∞e<õ¯j}˜] ∞èfi^€�√÷]<ª<ü€√÷]ê<‹ä¢]<ì◊j“<gäfl⁄ê<í⁄áfl÷]    4% 2%    608 1042 2006 1995  33.5% 47.9% 15 0.01p < 0.001 p 0.1p < 0.0001p 0.0001p    :مفتاح الكلمات abstract: objectives: obstructive sleep apnoea/hypopnoea syndrome (osahs) is a disorder characterised by repetitive upper airway collapse during sleep in association with daytime sleepiness. it has an estimated prevalence of 2% and 4% among middle-aged women and men respectively. the aim of the study was to look at the association of body mass index (bmi), age and gender and prevalence of osahs in the omani population. methods: polysomnography reports and hospital medical records of all patients who took part in the sleep study at the sleep laboratory of the clinical physiology department, sultan qaboos university hospital, between january 1995 and december 2006, were retrospectively reviewed. data from both sources was gathered and analysed. results: a total of 1,042 sleep studies were conducted with 608 valid studies for analysis. the study showed that the apnoea/ hypopnoea index (ahi) >15 was more prevalent in men compared to women (47.9% versus 33.5%, p = 0.001). there was significant correlation of ahi with bmi (p <0.0001) among men compared to women (p = 0.1); however, age was significantly correlated with ahi among women (p <0.0001), but not with men (p = 0.1). conclusion: the results indicate that there is a gender difference in the prevalence of osahs and obesity is a major risk factor for osahs among omani men whereas age is found to be a risk factor for osahs among women. keywords: sleep; apnoea; age; obesity; oman gender difference in relationship of apnoea/hypopnoea index with body mass index and age in the omani population *mohammed al-abri,1 khamis al-hashmi,1 deepali jaju,1 omar al-rawas,2 bazdawi al-riyami,2 mohammed hassan3 advances in knowledge 1. this is the first study to be conducted in omani population assessing the risk factors of obstructive sleep apnoea/hypopnoea syndrome (osahs) and describing the difference in the prevalence of apnoea/hypopnoea syndrome. 2. the study revealed that there is a major gender difference in the prevalence of osahs between men and women in oman. 3. age is the major determinant among women compared with men. men are more susceptible to osahs at younger age compared to women. application to patient care 1. this article provides evidence-based information for sleep physicians to aid in the diagnosis of osahs. 2. it will also help them to prioritise the need for a sleep study as hospital waiting lists are long. gender difference in relationship of apnoea/hypopnoea index with body mass index and age in the omani population 364 | squ medical journal, august 2011, volume 11, issue 3 obstructive sleep apnoea/hypopnoea syndrome (osahs) is a disorder characterised by repetitive upper airway collapse during sleep associated with arterial oxygen desaturation. this leads to repetitive night awakenings and excessive daytime sleepiness.1 osahs has also been associated with adverse cardiovascular consequences such as hypertension,2 and ischaemic heart disease.3 major aetiological factors, such as obesity, and craniofacial anatomic predisposition, are both genetically and environmentally influenced, and it is therefore pertinent to determine the prevalence of sleep apnoea in different populations.4 it was shown previously by young et al. that the prevalence of osahs was 2% in women and 4% in men in subjects who had an apnoea/hypopnoea index (ahi) of more than 5 and had symptoms.5 ahi is determined by number of apnoeas and hypopnoeas per hour of sleep. duran et al. showed that the prevalence was higher with ahi of more than 5 and no symptoms, but with marginal gender difference between males and females. however, the gender difference became more obvious with higher levels of ahi with higher prevalence among men in all age groups.6 nevertheless, gender differences in osahs prevalence could not be well established due to controversial results.7 obesity is the main risk factor for osahs and more than 80% of osahs patients have a body mass index (bmi) of more than 30 kg/m.2,8 recently, obesity has been found to be a major health problem in the omani population with increasing prevalence in relatively young subjects.9 nevertheless, age also has a major role in increasing the prevalence of osahs.10 to date, there has been scanty documentation of the gender difference in the prevalence of osahs in the omani population. the aim of the study is to evaluate the association of bmi, age, and gender difference with prevalence of osahs in the omani population. methods a retrospective analysis study was conducted among all patients (n = 1,042) listed in the registry of the sleep laboratory of the clinical physiology department, of sultan qaboos university hospital (squh), oman, between january 1995 and december 2006. polysomnography data were retrospectively collected from polysomnography reports. information on demography and related medical disorders, e.g. hypertension, chronic obstructive pulmonary disease (copd), ischaemic heart disease (ihd), hypothyroidism, behavioural disorders and diabetes were collected from hospital medical electronic records and paper files. details of data collection were previously published.11 the study was approved by the ethical committee of the college of medicine & health sciences at sultan qaboos university. weight and height were measured with bare feet and light clothing, using a standard scale (seca, germany) for all patients attending for a sleep study. all the anthropometric measurements were done at the time of the sleep study. weight was recorded to nearest 0.5 kg and height to the nearest centimetre. the bmi was calculated as weight divided by square of height in meters (bmi = weight [kg] / height [m2]). age was verified based on hospital medical records. a sleep study was conducted for all patients. the study consisted of two channels of electroencephalogram (eeg), two electro-oculograms (eog), a chin and legs electromyography (emg) and an electro cardiogram (ecg). respiratory events were monitored by means of an airflow sensor and chest and abdominal movement sensors. snoring was recorded using a microphone. leg movements and sleep position were also monitored using special sensors. oxygen saturation was assessed by pulse oxymetry and the patient was observed with an infra-red camera. the test is supervised by a trained polysmnographer who was also responsible for the manual scoring of the study. polysomnography records were scored manually based on the guidelines of the american academy of sleep medicine.12 an abnormal breathing event during objectively measured sleep was defined according to the commonly used clinical criteria of either a complete cessation of airflow lasting 10 seconds (apnoea) or a discernible reduction in airflow accompanied by a decrease of 4% in oxyhaemoglobin saturation (hypopnoea). the apnoea/hypopnoea index (ahi) was calculated as number of apnoeas and hypopnoeas per hour of sleep. descriptive and comparative analyses were performed using the statistical package for the social sciences (spss®) software (ibm, usa, mohammed al-abri, khamis al-hashmi, deepali jaju, omar al-rawas, bazdawi al-riyami, mohammed hassan clinical and basic research | 365 version 13.0). parametric data were expressed as means + standard deviation (sd). a p value of <0.05 was considered significant. the relationship of ahi with age and bmi was tested using pearson’s bivariate correlations. correlations were estimated separately for men and women. ahi was grouped as ≤15 and >15.1 per hour. age and bmi were categorised as follows: age: <40 years, 41–60 and >60 years; bmi: <24.9, 25–29.9, 30–34.9 and >35 kg/m2. an age of 40 years was chosen based on the distribution of the sample population. the χ2 analysis was used to test the association of ahi with gender and association of co-morbidities with gender in both ahi groups. the first model of binary logistic regression was used to estimate odds of having ahi >15 included gender, age, bmi and other associated co-morbidities like hypertension, copd, asthma, ihd, hypothyroidism, behavioural disorders and diabetes. co-morbidities were removed from the final model as there were no significant associations of ahi with co-morbidities adjusted for age, bmi and gender. finally, age adjusted odds for having ahi >15 with bmi and bmi adjusted odds for having ahi >15 with age were calculated in males and females. the bmi <24.9 kg/m2 and age up to 40 years were taken as a reference control. results the total number of patients reviewed between january 1995 and december 2006 were 1,042. the analysis was conducted on 608 valid sleep study reports for patients of more than 18 years old of age. a total of 374 reports were excluded because of incomplete data and 60 sleep study reports for patients under 18 years of age. the men (n = 405) to women (n = 203) ratio of studied patients was approximately 3:1. women were significantly older than men (women: 45.3 + 12.1 versus men: 39.8 + 13.2 years p = 0.0001) and had higher bmi (36.0 + 8.7 versus 31.8 + 5.5 kg/m2, p = 0.0001). the total number of patients who had ahi >15 was 300 (232 men and 68 women). the prevalence of comorbidities in men and women with ahi <15 and ahi >15 are given in table 1. in men, the prevalence of hypertension, ihd and hypothyroidism was higher in the group with ahi >15 compared with ahi <15. in women, the prevalence of copd/ asthma, ihd, diabetes and hypothyroidism was higher with ahi >15 [table 1]. the ahi <15 group showed a significant gender difference for all comorbidities except ihd, but the group ahi >15 showed a significant gender difference only in copd (p = 0.005), diabetes mellitus (dm) (p = 0.007), and hypothyroidism (p = 0.018) [table 1]. gender was strongly associated with ahi (χ212.1, p = 0.0001, df1). the ahi showed a weak but significant correlation with age (r2: 0.092; p = 0.02) and bmi (r2: 0.121; p = 0.004). however, the gender difference surfaced when ahi was correlated with age and bmi separately in males and females. interestingly, in males, ahi was correlated significantly with bmi (r2: 0.224; p = 0.0001), but not with age (r2: 0.066; p = 0.14). by contrast, ahi in women showed significant correlation with age table 1: prevalence of co-morbidities in males and females with apnoea/hypopnoea index (ahi) <15 or ahi >15/ hour comorbidity males females ahi <15 % ahi >15 % ahi <15 % ahi >15 % chronic obstructive pulmonary disease/ asthma 8.9* 6.0§ 22.4 24.3 hypertension 9.1* 12.9 22.2 22.1 ischaemic heart disease 4.8 5.2 8.1 8.8 diabetes mellitus 5.2* 4.3§ 12.6 14.7 hypothyroidism 0.8* 1.7§ 6.7 8.8 behavioural diseases 10.3* 0.9§ 8.1 2.9 notes: * = p <0.05 for gender difference in co-morbidity in group ahi <15; § = p <0.05 for gender difference in co-morbidity in group ahi >15. gender difference in relationship of apnoea/hypopnoea index with body mass index and age in the omani population 366 | squ medical journal, august 2011, volume 11, issue 3 (r2: 0.295; p = 0.0001) but not with bmi (r2: 0.117; p = 0.13). the age adjusted odds of having ahi >15 for pooled data were significant in all bmi categories, the highest value being for the bmi >35 category, and were significantly dependent on age and gender [table 2]. when estimated separately for gender, men showed significant odds of having ahi >15 for all bmi categories. however, the odds were maximum for category bmi >35 kg/m2 (odds: 6.97, p = 0.0001). on the contrary, in women, having ahi >15 was independent of bmi [table 2]. in pooled data, the bmi adjusted odds of having ahi >15 were significant for bmi (p = 0.0001) and gender (p = 0.006). the gender difference became prominent when bmi adjusted odds were estimated separately for males and females. compared with women aged <40 years, women aged 41–60 had odds of 2.64 (p = 0.025) and women aged >61 had odds of 4.08 (p = 0.01) of having ahi >15. in men, the odds of having ahi >15 were independent of age [table 3]. discussion this study was conducted for the first time in the omani population to understand the relationship between osahs and the two main risk factors, age and obesity. the study was conducted on a clinic-based population sample at sultan qaboos university hospital, oman, and was done as part of the sleep medicine audit in oman.11 the main outcome of analysis was that having ahi >15 is differently related to gender; in men, it is related to bmi and not age, on the contrary, in women, it is related to age and not bmi. the prevalence of osahs of 4% in men and 2% in women estimated by young et al. was based on an ahi score of 5 or higher and moderate to severe daytime hypersomnolence.5 in this study, ahi >15 was implicated as a cut-off point for osahs and the results showed that 49% of the study sample had obstructive sleep apnoea, with higher prevalence among men (57%) compared with women (33%). a limitation of this study is that the study sample was hospital-based and may therefore have selection bias. in addition, daytime sleepiness was not assessed by a validated scale or questionnaire, e.g. the epworth sleepiness scale, which could be a further limitation of this study. however, this study confirmed that there is a gender difference in the association of osahs with age and bmi. ahi correlated significantly with bmi, but not with age, in men. on the contrary, ahi in women showed a significant correlation only with age with a fourfold increase in risk for women older than 60 years of age compared to women under 40 [tables 2 and 3]. these findings could be attributed to the lower levels of sex hormones, especially progesterone, which occurs in post-menopausal women. the association of reduced female sex hormones with an increased probability of obstructive sleep apnoea table 2: age adjusted odds for apnoea/hypopnoea index (ahi) >15 for different categories of body mass index (bmi) in males and females total males females bmi kg/m2 or p or p or p < 24.9 ----25–29.9 1.79 0.10 2.51 0.18 2.58 0.41 30–34.9 2.50 0.011 3.39 0.02 3.10 0.32 > 35 5.03 0.0001 6.97 0.0001 5.51 0.11 age in years 1.05 1.00 0.49 1.00 1.04 0.01 gender 0.32 0.0001 ---legend: or = odds ratio. mohammed al-abri, khamis al-hashmi, deepali jaju, omar al-rawas, bazdawi al-riyami, mohammed hassan clinical and basic research | 367 in women is well documented.13 previous studies found that those women with an ahi >10 had significantly lower levels of 17-oh progesterone, progesterone, and estradiol than those with an ahi less than 10.12 similar results were found by redline et al. who found in a community study that females with osahs were significantly older (p <0.01) than apnoeic male subjects and the majority of those females were postmenopausal.8 however, they found no significant difference in bmi between the two genders.8 furthermore, young et al. found that postmenopausal women had a higher odds ratio of having ahi >15 compared to perimenopausal women (perimenopause: 1.1 [0.5, 2.2] versus postmenopause: 3.5 [1.4, 8.8]).14 our results were in accord with the increasing prevalence of obesity and metabolic syndrome in the omani population. al-lawati et al. found that the prevalence of metabolic syndrome increased with age in both sexes, but the increase was steeper in women.9 furthermore, in the age group 20–29 years, 4.7% of men and 2.8% of women had metabolic syndrome. in the age group 60 years and over, the prevalence was 29.8% and 48.7%, respectively. in durán’s study, a strong association between ahi and age was found in the logistic regression model adjusted to sex and bmi, suggesting that factors other than obesity play a role in the presence of osahs.6 when ahi for men and women were pooled together, there was significant correlation with age and bmi. the results indicated that obesity is the main risk factor for osahs in omani men with increasing risk with higher bmi. similar results were found by young et al. who found that male sex, age and bmi were strongly associated with ahi >15.15 a study by bahammam et al. found that the prevalence of obstructive sleep apnoea among middle-aged saudi women (35–60 years) was 40%.16 however, the population sample was screened using the berlin questionnaire only and found no correlation with age. it was shown in an urban indian population that, when bmi was normal, metabolic syndrome may be the first event, followed by osahs as age increases and eventually it may culminate in syndrome z (osahs and metabolic syndrome together).17 more recently, it was found that metabolic syndrome prevalence, including obesity is associated with increased severity of osahs.18 conclusion our study revealed gender difference in associations of sleep disordered breathing in an omani population. male gender and obesity led to higher risk compared to women in the same age group. however, age is the major predictor for obstructive sleep apnoea among women, with a higher risk of osahs in postmenopausal woman a c k n o w l e d g m e n t the results of this study were previously presented as a poster in the australian sleep meeting, melbourne, australia, in october 2009. c o n f l i c t o f i n t e r e s t s the authors reported no conflict of interest. table 3: body mass index (bmi) adjusted odds ration (or) for apnoea/hypopnoea index (ahi) >15 for different age groups in males and females total males females age years or p or p or p <40 ----41–60 1.31 0.16 1.05 0.83 2.64 0.025 >61 1.89 0.059 1.28 0.58 4.09 0.01 bmi kg/m2 1.07 0.0001 1.07 0.0001 1.04 0.06 gender 0.30 0.006 gender difference in relationship of apnoea/hypopnoea index with body mass index and age in the omani population 368 | squ medical journal, august 2011, volume 11, issue 3 references 1. guilleminault c, tilkian a, dement w. the sleep apnoea syndrome. ann rev med 1976; 27:465–84. 2. peppard p, young t, palta m, skatrud j. prospective study of the association between sleep-disordered breathing and hypertension. n engl j med 2000; 342:1378–84. 3. kuniyoshi fh, pusalavidyasagar s, singh p, somers vk. cardiovascular consequences of obstructive sleep apnoea. indian j med res 2010; 131:196–205. 4. ip ms, lam b, lauder ij, tsang kw, chung kf, mok yw, et al .a community study of sleep-disordered breathing in middle-aged chinese men in hong kong. chest 2001; 119:62–9. 5. young t, finn l. epidemiological insights into the public health burden of sleep disordered breathing: sex differences in survival among sleep clinic patients. thorax 1998; 53:16–19. 6. durán j, esnaola s, rubio r, iztueta a. obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yrs. am j respir crit care med 2001; 163:685–9. 7. redline s, kump k, tishler pv, browner i, ferrette v. gender differences in sleep disordered breathing in a community-based sample. am j respir crit care med 1994; 149:722–6. 8. redline s, tishler pv. the genetics of sleep apnoea. sleep med rev 2000; 4:583–602. 9. al-lawati ja, mohammed aj, al-hinai hq, jousilahti p. prevalence of the metabolic syndrome among omani adults. diabetes care 2003; 26:1781– 5. 10. bixler eo, vgontaz an, ten have t. effect of age on sleep apnea in men: i. prevalence and severity am j respir crit care med 1998; 157:144–8. 11. al-abri ma, al-hashmi km, jaju d, al-rawas oa, al-riyami bm, hassan mo. an audit of the sleep medicine service in oman. saudi med j 2008; 29:1621–4. 12. iber c, ancoli-israel s, chesson a, quan s. the aasm manual for the scoring of sleep and associated events: rules, terminology and technical specifications. westchester: american academy of sleep medicine, 2007. il 45–7. 13. netzer nc, eliasson ah, strohl kp. women with sleep apnoea have lower levels of sex hormones. sleep breath 2003; 7:25–9. 14. young t, finn l, austin d, peterson a. menopausal status and sleep-disordered breathing in the wisconsin sleep cohort study. am j respir crit care med 2003; 167:1181–5. 15. young t, shahar e, nieto fj, redline s, newman ab, gottlieb dj, et al. predictors of sleep-disordered breathing in community-dwelling adults: the sleep heart health study. arch intern med 2002; 16:893– 900. 16. bahammam as, al-rajeh ms, al-ibrahim fs, arafah ma, sharif mm. prevalence of symptoms and risk of sleep apnoea in middle-aged saudi women in primary care. saudi med j 2009; 30:1572–6. 17. sharma sk, sreenivas v. are metabolic syndrome, obstructive sleep apnoea and syndrome z sequential? a hypothesis. indian j med res 2010; 131:455–8. 18. ozol d, turkay c, kasapoglu b, karamanlı h, yıldırım z. relationship between components of metabolic syndrome and polysomnographic findings in obstructive sleep apnoea. metab syndr relat disord 2010. in press. challenges of establishing a de novo consultation-liaison psychiatry service in a tertiary hospital practical considerations and challenges nawal n. al mahyijari1 and *ibrahim m. inuwa2 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e147–150, epub. 28 jun 20 submitted 18 oct 19 revision req. 8 oct 20; revision recd. 12 feb 20 accepted 5 mar 20 1department of medicine, royal hospital, muscat, oman; 2department of basic medical sciences, mohammed bin rashid university of medicine and health sciences, dubai, united arab emirates *corresponding author’s e-mail: ibrahim.inuwa@mbru.ac.ae consultation-liaison psychiatry (clp) has been described as “the guardian of holistic approach to the patient”.1 this emphasises its vital role in the care of patients admitted to any general hospital. other researchers have stated that there is “no health without mental health” and that integrating therapy into the bio-psychosocial model should be the main objective of clp services rather than administration of psychiatric treatment only.2,3 in many situations, health professionals have patients with existing physical comorbidities and/ or mental health disorders.4 in hospitals where there are no clp services, such situations place a heavy economic burden on finite hospital resources and prolong the suffering of affected patients.2 studies have observed that the existence of mental health disorders, even when sub-clinical in patients with a medical illness, could lead to longer hospital stays and worse health outcomes.5–7 establishing de novo clp services has been studied in various parts of the world.3,8–13 for example, de giorgio et al.’s study provides evidence that supports establishing inpatient clp services.3 they found that implementing inpatient clp in medical/surgical/ obstetrics-gynaecology wards with an emphasis on clinimetric approaches (i.e. “the development of instruments to measure multiple constructs with a single index”) rather than psychometric approaches (i.e. the development of “instruments that measure a single construct using multiple items”), especially in a multidisciplinary context and specifically for complex cases, yields holistic health benefits.3,14 the availability of clp services shortens length of hospital stay and facilitates a more coordinated approach when dealing with complex cases.3 as a result, several countries, including some in the gulf region, have started to implement inpatient clp services in general hospitals.11,12 sounding board حتدايت إنشاء خدمة جديدة للطب النفسي للتشاور واإلتصال يف مستشفى مرجعي اثلثي االعتبارات والتحدايت العملية نو�ل �ملحيجري و �إبر�هيم حممد �إنوة abstract: consultation-liaison psychiatry (clp), also known as psychosomatic medicine, is a subspecialty of psychiatry that focuses on the care of patients with mental health disorders and general medical/surgical conditions. integrating clp services facilitates diagnosis and management of patients with complex comorbidities. this article aimed to report the practical considerations and challenges associated with establishing a de novo clp service in a tertiary hospital in the gulf region. this includes discussing the rationale and clinical and educational benefits as well as the resources required for establishing a clp service. keywords: psychiatry; medical education. ا با�سم �لطب �لنف�سي �جل�سدي، هو �لتخ�س�ص �لفرعي للطب �لنف�سي �لذي يركز امللخ�ص: �لطب �لنف�سي للت�ساور و�الت�سال، و�ملعروف �أي�سً على رعاية �ملر�سى �لذين يعانون من ��سطر�بات �ل�سحة �لعقلية و�حلاالت �لطبية و �جلر�حية �لعامة. ي�سهل تكامل خدمات �لطب �لنف�سي �العتبار�ت تو�سيف �إىل �ملقالة هذه تهدف معقدة. م�ساحبة �أمر��ص من يعانون �لذين �ملر�سى و�إد�رة ت�سخي�ص و�الت�سال للت�ساور و�لتحديات �لعملية �ملرتبطة باإن�ساء خدمة �لطب �لنف�سي للت�ساور و�الت�سال يف م�ست�سفى جامعي يف منطقة �خلليج. و ي�سمل هذ� �أي�سا مناق�سة �الأ�سا�ص �ملنطقي و�لفو�ئد �ل�رسيرية و�لتعليمية وكذلك �ملو�رد �لالزمة الإن�ساء هذه �خلدمة. الكلمات املفتاحية: �لطب �لنف�سي؛ �لتعليم �لطبي. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.004 https://creativecommons.org/licenses/by-nd/4.0/ challenges of establishing a de novo consultation-liaison psychiatry service in a tertiary hospital practical considerations and challenges e148 | squ medical journal, may 2020, volume 20, issue 2 inpatient clp services are well developed in many countries around the world including europe and north america where continuous scientific exchanges have a positive impact on education, healthcare practice and, ultimately, patients outcomes.15–17 in oman specif ically, and in the gulf region generally, there are no comprehensive statistics available on overall levels of activity, or resources allocated to clp services in general hospitals. general psychiatrists who can facilitate this clp services are needed in the ministry of health general hospitals. there is an urgent need to focus resources within and between different gulf countries with the aim of developing clp scientific exchange. therefore, the main objective of this article is to discuss the practical considerations and challenges associated with establishing a de novo clp service in a tertiary hospital, including the rationale and clinical and educ ational benefits as well as the resource requirements for establishing such a service. the rationale the prevalence of comorbid mental health disorders among patients in general hospitals is extremely high; a questionnaire-based study revealed nearly one in five patients admitted for acute medical service required psychiatric consultation.9 furthermore, many of these cases are typically undiagnosed and, therefore, not treated.9 the absence of effective intervention may affect patients’ response to medical treatment, quality of life, utilisation of services, length of hospital stays and increase the cost of health care.8,13 improvement in diagnosis and management of mental health conditions in general hospitals can significantly reduce the scale and cost of these problems.9,14 given these epidemiological considerations, there is a need for dedicated and specialised inpatient clp services in general hospitals.9 currently, there is a trend towards emphasising the importance of collaboration among health prof essionals in the treatment of patients with complex comorbidities.9,12 this includes combined medicalmental health consultation and longitudinal care in order to provide integrated and holistic care. therein lies a vital role for clp to help bridge the gap between the physical and mental health needs of patients and reducing mental health stigma.13 therefore, inpatient clp service has numerous advantages in assessing mental health and physical comorbidities accurately and educating clinicians about the impact of symptoms on psychological/physical health and how to manage them.11,13 clinical benefits an important function of clp service is the identif ication of patients that require complex biopsycho social intervention such as patients with delirium, delib erate self-harm, substance abuse and unexplained physical complaints. these patients require an effective inter disciplinary team approach for their care. such patients should be identified upon admission or early during their hospitalisation in order to optimise the coordination and management necessary for their care. importantly, validated tools, such as complexity prediction instrument (compri) and intermed, that are useful in ident ifying the needs of these complex cases either at the time of admission or among the outpatient population should be made available to clp teams.15,18 educational benefits with respect to medical education, there is authoritative evidence-based information that supports integrating inpatient clp into medical and surgical department.8 liaison-psychiatry has been a core-training requirement of residency programmes in certain parts of the world.8,10 medical students who were exposed to clp training had greater knowledge of and a positive attitude towards psychiatry, which might encourage recruitment to the profession.8,10 inpatient clp professionals may play a major role in collaborating with the medical team to provide a strong focus on education and training of various medical/surgical teams. this training could include how to implement basic psychotherapeutic interventions that could facilitate patients’ coping with the stress of medical illness. on a larger community-wide scale, clp services could also perform an important bridge function between general practice and mental healthcare thereby reducing stigma around mental health and improving the training of general practitioners.19 in addition, there are many areas in medicine that lend themselves to developing exciting research questions within the context of clp. educational benefits could include future research on topics such as the phenomenology of somatisation disorders (soma toform disorders in the international classification of diseases-10), interactions of biopsychosocial factors and the effectiveness of clp interventions. resource requirements for establishing a clp service a full-time clp specialist is essential in establishing clear guidelines and in determining what constitutes optimal interventions for a patient in need of complex nawal n. al mahyijari and ibrahim m. inuwa sounding board | e149 care. in addition, psychologists and social workers will greatly contribute to patients’ quality of life and decrease the burden of care of this highly complex patient population. furthermore, a liaison nurse is an essential professional necessary for a well-functioning interdisciplinary clp service.9,11 a liaison nurse provides support to nursing staff in medical/surgical departments inside the hospital and facilitates the organisation of mental health follow-ups on discharge or transfers to psychiatric facilities. finally, it would be necessary to ensure adequate physical resources to support the clp team. a suggested flowchart of how such service could be embedded in the care of patients is illustrated in figure 1. challenges in establishing clp service baseline staffing of clp services in general hospitals have been previously described.20 multiple factors that determine efficient sizing of a clp service include the number of beds, nature of illnesses, availability of on-site trainees and financial constraints. while it is easy to find consensus that clp implementation is important to ensure the adequate diagnosis and treatment of medically ill patients with mental health disorders, the provision of such clp services face a number of challenges. evidence suggests that in hospitals where clp service exists, referral rates are very low.21,22 this may figure 1: suggested flowchart of how a consultation-liaison psychiatry service could be embedded in the care of hospital patients. med = medical; surg = surgical; obgyn = obstetrics and gynaecology; cl = consultation liaison; s. = senior; moca = montreal cognitive assessment; ams = arabic memory screening test; cam = confusion assessment method; mdt = multidisciplinary team; lab = laboratory; cbt = cognitive behavioural therapy; ipt = interpersonal psychotherapy; gen = general; opd = outpatient department; gp = general practitioner. challenges of establishing a de novo consultation-liaison psychiatry service in a tertiary hospital practical considerations and challenges e150 | squ medical journal, may 2020, volume 20, issue 2 be due to the doctors on medical/surgical wards not noticing a disturbance in a patient’s emotional state as well as many physicians being reluctant to use psychiatric services.21,22 where such clp services exist, they are often encumbered by unpredictable schedules and variable numbers of consultations. in addition, developing countries, including the gulf countries, are facing many other challenges including insufficient training of medical and paramedical staff, funding for clinical practice and research, coordination with complementary and alternative medicine practitioners and effective networking with policy makers in combating the epidemic of non-communicable diseases including mental health disorders.19 to overcome these challenges, evidence of the potential benefits of clp services on issues such as length of stay and quality of patient care should be well articulated. this may convince hospital administrators and decision-makers to support the creation of a clp service. in addition, mental health practitioners should share data on mental health needs to gain a more comprehensive national and international perspective that can be used to convince all stakeholders in regards to the acceptable benchmarks for clp services.16 conclusion while there are various challenges in establishing a clp service, there are also significant benefits in integrating inpatient clp services in the gulf region. it facilitates timely diagnosis and management of complex cases. the liaison service helps to establish professional contact with medical/surgical and nursing colleagues, reduce mental health stigma, broaden the understanding of psychological reactions to physical illness and of psychogenic disorders, reduce unnec essary investigations and provide more comprehensive patient care. in addition, clp services could facilitate early detection of mental health problems in patients and provide support to the medical/surgical staff in caring for such patients. references 1. ajiboye po. consultation-liaison psychiatry: the past and the present. afr j med med sci 2007; 36:201–5. 2. smith gc. from consultation-liaison psychiatry to integrated care for multiple and complex needs. aust n z j psychiatry 2009; 43:1–12. https://doi.org/10.1080/00048670802534358. 3. de giorgio g, quartesan r, sciarma t, giulietti m, piazzoli a, scarponi l, et al. consultation-liaison psychiatry-from theory to clinical practice: an observational study in a general hospital. bmc res notes 2015; 8:475. https://doi.org/10.1186/s13104015-1375-6. 4. smith gc. challenges for psychotherapy and psychoanalysis. aust j psychother 2006; 25:32–55. 5. ormel j, vonkorff f, oldenhinkel aj, simon g, tiemens bg, ustün tb. onset of disability in depressed and non-depres sed primary care patients. psychol med 1999; 29:847–53. https://doi.org/10.1017/s0033291799008600. 6. saravay sm, lavin m. psychiatric comorbidity and length of stay in the general hospital. a critical review of outcome studies. psychosomatics 1994; 35:233–52. https://doi.org/10.1016/s0033 3182(94)71772-2. 7. chilsholm d, diehr p, knapp m, patrick d, treglia m, simon g, et al. depression status, medical comorbidity and resource costs. evidence from an international study of major depression in primary care (lido). br j psychiatry 2003; 183:121–31 https://doi.org/10.1192/bjp.183.2.121. 8. desan ph, zimbrean pc, weinstein aj, bozzo je, sledge wh. proactive psychiatry consultation services reduce length of stay for admissions to an inpatient medical team. psychosomatics 2011; 52:513–20. https://doi.org/10.1016/j.psym.2011.06.002. 9. lloyd gg. liaison psychiatry from a british perspective. gen hosp psychiatry 1980; 2:46–51. https://doi.org/10.1016/01638343(80)90106-1. 10. kurosawa h, iwasaki y, watanabe n, nakamura k, kishi y, huse r. the practice of consultation-liaison psychiatry in japan. gen hosp psychiatry 1993; 15:160–5. https://doi.org/10.1016/0 163-8343(93)90119-9. 11. fido aa, al mughaiseeb a. consultation liaison psychiatry in a kuwaiti general hospital. int j soc psychiatry 1988; 35:274–9. https://doi.org/10.1177/002076408903500308. 12. aljarad am, al osaimi fd, al huthail yr. accuracy of psych iatric diagnoses in consultation liaison psychiatry. j t u med sci 2008; 3:123–8. https://doi.org/10.1016/s1658-3612(08)70061-1. 13. andreoli pb, citero vde a, mari jde j. a systematic review of studies of the cost-effectiveness of mental health consultationliaison interventions in general hospitals. psychosomatics 2003; 44:499–507. https://doi.org/10.1176/appi.psy.44.6.499. 14. de vet hcw, terwee cb, bouter lm. clinimetrics and psychometrics: two sides of the same coin. j clin epidemiol 2003; 56:1146–7. https://doi.org/10.1016/j.jclinepi.2003.08.010. 15. huyse fj, de jonge p, slaets jp, herzog t, lobo a, lyons js, et al. compri--an instrument to detect patients with complex care needs: results from a european study. psychosomatics 2001; 42:222–8. https://doi.org/10.1176/appi.psy.42.3.222. 16. kunkel ej, del busto e, kathol r, stern ta, wise tn, stoddard fr 2nd, et al. physician staffing for the practice of psychosomatic medicine in general hospitals: a pilot study. psychosomatics 2010; 51:520–7. https://doi.org/10.1016/s0033-3182(10)70746-5. 17. deter hc, orth-gomér k, wasilewski b, verissimo r. the european network on psychosomatic medicine (enpm) history and future directions. biopsychosoc med 2017; 11:3. https://doi.org/10.1186/s13030-016-0086-0. 18. huyse fj, lyons js, stiefel fc, slaets jp, de jonge p, fink p, et al. “intermed”: a method to assess health service needs. i. development and reliability. gen hosp psychiatry 1999; 21:39–48. https://doi.org/10.1016/s0163-8343(98)00057-7. 19. chandrashekar cr, math sb. psychosomatic disorders in developing countries: current issues and future challenges. curr opin psychiatry 2006; 19:201–6. https://doi.org/10.1097/01.yco.0 000214349.46411.6a. 20. holmes a, handrinos d, theologus e, salzberg m. service use in consultation-liaison psychiatry: guidelines for baseline staffing. australas psychiatry 2011; 19:254–8. https://doi.org/1 0.3109/10398562.2011.562505. 21. alqataybi h, almaqbali m, asiri wa, martin r, alsinawi h. patterns of referrals to consultation-liaison psychiatry in a tertiary care hospital in oman. arab j psychiatry 2018; 29:17–23. https://doi.org/10.12816/0046438. 22. chen ky, evans r, larkins s. why are hospital doctors not referring to consultation-liaison psychiatry? a systemic re view. bmc psychiatry 2016; 16:390. https://doi.org/10.1186/ s12888-016-1100-6. https://doi.org/10.1080/00048670802534358 https://doi.org/10.1186/s13104-015-1375-6 https://doi.org/10.1186/s13104-015-1375-6 https://doi.org/10.1017/s0033291799008600 https://doi.org/10.1016/s0033-3182%2894%2971772-2 https://doi.org/10.1016/s0033-3182%2894%2971772-2 https://doi.org/10.1192/bjp.183.2.121 https://doi.org/10.1016/j.psym.2011.06.002 https://doi.org/10.1016/0163-8343%2880%2990106-1 https://doi.org/10.1016/0163-8343%2880%2990106-1 https://doi.org/10.1016/0163-8343%2893%2990119-9 https://doi.org/10.1016/0163-8343%2893%2990119-9 https://doi.org/10.1177/002076408903500308 https://doi.org/10.1016/s1658-3612%2808%2970061-1 https://doi.org/10.1176/appi.psy.44.6.499 https://doi.org/10.1016/j.jclinepi.2003.08.010 https://doi.org/10.1176/appi.psy.42.3.222 https://doi.org/10.1016/s0033-3182%2810%2970746-5 https://doi.org/10.1186/s13030-016-0086-0 https://doi.org/10.1016/s0163-8343%2898%2900057-7 https://doi.org/10.1097/01.yco.0000214349.46411.6a https://doi.org/10.1097/01.yco.0000214349.46411.6a https://doi.org/10.3109/10398562.2011.562505 https://doi.org/10.3109/10398562.2011.562505 https://doi.org/10.12816/0046438 https://doi.org/10.1186/s12888-016-1100-6 https://doi.org/10.1186/s12888-016-1100-6 departments of 1obstetrics & gynecology and 2cardiology, jawaharlal institute of postgraduate medical education & research, puducherry, india corresponding author’s e-mail: keepan_r@yahoo.com أم دم كاذبة رمحية سبب اندر لنزيف نِفاس آجل مع اْنِصمام الشراين الَرمِحي بلي�سي جون، بهاباين بيغو، �أجيث �أنانثاكري�سنا بيالي، ديليب كومار موريا، �آني�ش كيبانا�سرييل uterine pseudoaneurysm a rare cause of delayed postpartum haemorrhage managed with uterine artery embolisation blessy john,1 bhabani pegu,1 ajith a. pillai,2 dilip k. maurya,1 *anish keepanasseril1 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e234–235, epub. 28 jun 20 submitted 30 oct 18 revision req. 13 dec 18; revision recd. 16 dec 18 accepted 3 jan 19 a 26-year-old primiparous female patient underwent caesarean section for persistent occipito-posterior position in 2018 at the department of obstetrics and gynecology, jawaharlal institute of postgraduate medical education & research, puducherry, india. upon postnatal followup six weeks later, both mother and baby were reported to be fine. at eight weeks postpartum she had an episode of heavy vaginal bleeding which was treated symptomatically with tranexamic acid and antibiotics at a local hospital. one month after this, she had another episode of heavy vaginal bleeding at home and was referred to the emergency department at jawaharlal institute of postgraduate medical education & research. on examination, she was pale, had a pulse rate of 90 per minute and blood pressure of 120/70mm hg. she had a transverse abdominal scar that had healed by primary intention and the uterus was involuted normally. on speculum examination, minimal bleeding was only noted through the cervix. intravenous antibiotics was started with a suspicion of infective aetiology for haemorrhage. an ultrasound showed a normal-sized uterus with heterogeneous myometrial echotexture, due to the presence of multiple anechoic areas, and thin endometrial lining with no retrained products of conception [figure 1a]. colour doppler sonography showed intense myometrial hypervascularisation with turbulent flow in the hypoechoic region suggestive of a pseudoaneurysm, near the uterine incision site on the right side involving the right uterine artery [figure 1b]. her haemoglobin at admission was 8.2 g/dl. she underwent bilateral uterine artery embolisation under fluoroscopic guidance which confirmed pseudoaneurysm in the right uterine artery. the pseudoaneurysm was embolised with platinum coils and gel foam particles; postembolisation images ensured a complete occlusion [figure 2]. the patient did not have any further bleeding and was discharged five days later. she resumed normal menstruation two months following the procedure. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.017 interesting medical image figure 1: a: greyscale two-dimensional ultrasound of a 26-year-old primiparous female patient after a caesarean section showing a normal-sized uterus with heterogeneous myometrial echotexture and thin endometrium lining. b: colour doppler sonography showed intense myometrial hypervascularisation with turbulent flow in the hypoechoic region, near the uterine incision site on the right side, involving the right uterine artery. https://creativecommons.org/licenses/by-nd/4.0/ blessy john, bhabani pegu, ajith a. pillai, dilip k. maurya and anish keepanasseril interesting medical image | e235 comment uterine pseudoaneurysm is a rare, life-threatening complication after caesarean section. it can present diagnostic difficulties, as it is rare and has varying presentations. it forms after central liquefaction of a haematoma, which forms from a vascular injury during caesarean section. this leads to the formation of a cavity, without a normal arterial three-layered lining, with turbulent flow through a persistent communication between the parent artery and haematoma. this poses a challenge to the treating team, as it may present with unpredictable profuse bleeding which might occur repeatedly at variable time intervals, ranging from weeks to months after its development.1 using a greyscale ultrasound or a colour doppler can aid in diagnosis with high sensitivity, even though angiography remains the standard for diagnosis and may aid in definitive treatment.2 greyscale ultrasound imaging can identify a pseudoaneurysm as a hypoechoic area, which on colour doppler, shows a to-and-fro turbulent flow resulting from the blood flow into the pseudoaneurysm during systole and backward flow during diastole.2 uterine artery embolisation is usually the preferred treatment, as it is a safe and effective method in managing such cases.1,2 selective catheterisation of the uterine artery with a coaxial technique using particulate materials, can lead to persistent occlusion of arterial cross-over anastomoses, as was seen in the current case. uterine pseudoaneurysm should be remembered as an important differential diagnosis in women who had undergone caesarean section and later presented with acute, causeless, painless and often recurrent bleeding. references 1. isono w, tsutsumi r, wada-hiraike o, fujimoto a, osuga y, yano t, et al. uterine artery pseudoaneurysm after caesarean section: case report and literature review. j minim invasive gynecol 2010; 17:687–91. https://doi.org/10.1016/j.jmig.2010.06.004. 2. kwon hs, cho yk, sohn is, hwang hs, seo kj, park wi, et al. rupture of a pseudoaneurysm as a rare cause of severe postpartum hemorrhage: analysis of 11 cases and a review of the literature. eur j obstet gynecol reprod biol 2013; 170:56-61. https://doi.org/10.1016/j.ejogrb.2013.04.007. figure 2: selective right internal iliac angiogram images of a 26-year-old primiparous female patient after a caesarean section showing (a) the pseudoaneurysm in the right uterine artery which was embolised with platinum coils and gel foam particles and (b) the postembolisation occlusion that ensured a complete occlusion. https://doi.org/10.1016/j.jmig.2010.06.004 https://doi.org/10.1016/j.ejogrb.2013.04.007 1department of obstetrics & gynaecology, royal hospital, muscat, oman; 2family & community medicine residency programme, oman medical specialty board, muscat, oman *corresponding author’s e-mail: santhosh.jayasree@yahoo.com اآلثار املرتتبة للبدانة يف احلمل املبكر على صحة األم و اجلنني والطفل حديث الوالدة دراسة استعادية جملموعة من عمان انيتا زوت�سي، جيارسي �سانتو�ض، جويل �سيخ، فريحة نعيم، اأحمد احلامدي، �سهالخان، ا�ستياق ال�سعيد abstract: objectives: this study aimed to determine the prevalence of early pregnancy obesity among omani women and to review maternal antenatal complications, intrapartum and postpartum events and neonatal complications among such women in comparison to women of normal weight. methods: this retrospective cohort study included 2,652 pregnant omani women who delivered at the royal hospital, muscat, oman, between november 2011 and april 2012. the patients’ electronic medical records were reviewed for antenatal, intrapartum and postpartum data. body mass index was measured during the first trimester (≤12 gestational weeks) and classified according to the world health organization categories. maternal and neonatal complications were compared between obese women and those of normal weight. obstetric outcomes in uncomplicated pregnancies were also compared. results: in the study cohort, there were 901 (34%) obese women and 912 (34.4%) women of normal weight; of these, 440 (48.8%) and 672 (73.7%) had uncomplicated pregnancies, respectively. obese women had a significantly increased incidence of gestational diabetes (relative risk [rr]: 2.23; 95% confidence interval [ci]: 1.70–2.92; p <0.01), gestational hypertension (rr: 3.04; 95% ci: 1.63–5.65; p <0.01), caesarean delivery (rr: 1.48; 95% ci: 1.08–2.03; p <0.01), postpartum haemorrhage (rr: 2.10; 95% ci: 1.11–4.10; p = 0.01) and fetal macrosomia (rr: 2.71; 95% ci: 1.21–6.09; p <0.01). conclusion: approximately one-third of the studied omani women were obese. these women had a significantly increased risk of various maternal antenatal complications, intrapartum and postpartum events and neonatal complications. keywords: obesity; pregnancy; first trimester; pregnancy complications; obstetric labor complications; fetal diseases; oman. امللخ�ص: الهدف: هدفت الدرا�سة اإىل حتديد معدل انت�سار البدانة يف مرحلة احلمل املبكر بني الن�ساء العمانيات ومراجعة امل�ساعفات اثناء احلمل والتبعات اثناء الوالدة وبعدها وم�ساعفات االأطفال حديثي الوالدة بني الن�ساء البدينات باملقارنة مع الن�ساء ذوات الوزن الطبيعي. الطريقة: �سملت هذه الدرا�سة االأ�ستعادية جمموعة من 2,652 امراأة عاملة حامل يف امل�ست�سفى ال�سلطاين، م�سقط، عمان، بني نوفمرب 2011 واأبريل 2012. متت مراجعة ال�سجالت الطبية االإلكرتونية للمر�سى للح�سول على بيانات الن�ساء يف مراحل ما قبل واثناء وبعد الوالدة. مت قيا�ض موؤ�رص كتلة اجل�سم خالل االأ�سهر الثالثة االأوىل )12≥ اأ�سبوعا للحمل( ومت ت�سنيف الن�ساء ايل فئات وفقا ملنظمة ال�سحة العاملية. قام الباحثون مبقارنة امل�ساعفات يف االأمهات واملواليد بني الن�ساء البدينات وذوات الوزن الطبيعي. كما مت مقارنة نتائج التوليد يف حاالت لن�ساء بدينات و 912 حالة )%34.4( من الن�ساء ذوات احلمل غري املعقدة. النتائج: يف جمموعة الدرا�سة، كانت هناك 901 حالة )34%( الوزن الطبيعي. من بني هوؤالء، كانت هناك 440 حالة )%48.8( و 672 حالة )%73.7( لديهم حاالت حمل غري معقدة، على التوايل. وجد لدى الن�ساء البدينات زيادة كبرية يف معدل االإ�سابة ب�سكري احلمل )اخلطر الن�سبي: 2.23؛ فا�سل الثقة %95: 2.92-1.70؛ القيمة االحتمالية اأقل )p >0.01 (، ارتفاع �سغط الدم اأثناء احلمل )اخلطر الن�سبي3.04، فا�سل الثقة %95: 5.65-1.63؛ القيمة االحتمالية اأقل عنp >0.01 عن الوالدة القي�رصية ) اخلطر الن�سبي: 1.48؛ فا�سل الثقة %95: 2.03-1.08؛ القيمة االحتمالية اأقل عن p >0.01( النزيف بعد الوالدة ) اخلطر الن�سبي: 2.10؛ فا�سل الثقة %95: 4.10-1.11؛ القيمة االحتمالية اأقل عن p = 0.01( زيادة وزن اجلنني )اخلطر الن�سبي: 2.71؛ فا�سل الثقة %95: 6.09-1.21؛ القيمة االحتمالية اأقل عن p >0.01(. اخلال�صة: يعاين ما يقرب من ثلث الن�ساء العمانيات الالتي خ�سعن للدرا�سة من ال�سمنة املفرطة. وكان لدى هوؤالء الن�ساء خطر متزايد ب�سكل كبري حلدوث خمتلف امل�ساعفات اأثناء احلمل، واالحداث اأثناء الوالدة وبعد الوالدة وم�ساعفات االأطفال حديثي الوالدة. الكلمات املفتاحية: ال�سمنة؛ احلمل؛ الثلث االأول للحمل؛ م�ساعفات احلمل؛ م�ساعفات الوالدة؛ اأمرا�ض اجلنني؛ عمان. implications of early pregnancy obesity on maternal, fetal and neonatal health retrospective cohort study from oman anita zutshi,1 *jayasree santhosh,1 julie sheikh,1 fareeha naeem,1 ahmed al-hamedi,2 shahla khan,1 eishthiag al-said1 clinical & basic research sultan qaboos university med j, february 2018, vol. 18, iss. 1, pp. e47–53, epub. 4 apr 18 submitted 11 aug 17 revisions req. 4 oct, 28 nov & 18 dec 17; revisions recd. 8 nov & 5 dec 17 & 2 jan 18 accepted 7 jan 18 doi: 10.18295/squmj.2018.18.01.008 advances in knowledge this study found that approximately one-third of omani women delivering at a tertiary care hospital were obese. moreover, early pregnancy obesity was identified as a significant risk factor for subsequent antenatal, intrapartum and postpartum complications. implications of early pregnancy obesity on maternal, fetal and neonatal health retrospective cohort study from oman e48 | squ medical journal, february 2018, volume 18, issue 1 the presence of excess body fat can critically impair both health and longevity, with an increased risk of hypertension, diabetes, heart disease, stroke and cancer among obese individuals.1 among women of reproductive age, obes ity can lead to infertility; moreover, obesity in pregnancy is a recognised risk factor for many adverse maternal and neonatal outcomes, including an inc reased rate of caesarean section delivery, fetal macrosomia, pre-eclampsia and gestational diabetes mellitus (gdm).2,3 obesity has also been identified as a risk factor for maternal death.4 moreover, obesity in early pregnancy has been associated with fetal and infant death independent of congenital anomalies and maternal pre-gdm.5 body mass index (bmi) is often used as a screening tool for obesity. according to the world health organization (who), individuals with a bmi of <18.5 kg/m2 are classified as underweight, those with a bmi of 18.5–24.9 kg/m2 are deemed of normal weight, those with a bmi of 25.0–29.9 kg/m2 are overweight/pre-obese and individuals with a bmi of ≥30.0 kg/m2 are considered obese.1 obesity is further classified into class i (bmi of 30–34.9 kg/m2), class ii (bmi of 35.0–39.9 kg/m2) and class iii (bmi of ≥40.0 kg/m2). individuals in the latter category are considered morbidly obese.1 despite its inclusion in the international class ification of diseases in 1948, obesity was not recognised as a global epidemic by the who until 1997.6 worldwide, there were more than 600 million obese adults in 2014.7 in the omani population, the proportion of obese adults increased from 48% in 1991 to 51% in 2000; among women, obesity decreased slightly from 25.1% to 23.8% in the same period.8 however, there are few data from oman addressing the issue of obesity-related morbidity among obstetric patients. therefore, this study aimed to determine the prevalence of early pregnancy obesity among omani women at a tertiary care hospital and to compare maternal, fetal and neonatal complications among obese women and women of normal weight. methods this retrospective cohort study took place at the royal hospital, muscat, oman, between november 2011 and april 2012. all pregnant omani women with available weight/height or bmi data at <12 gestational weeks who delivered at the royal hospital during the study period were included. in total, 3,482 deliveries occurred during this time; however, women of other nationalities (n = 199), those with multiple pregnancies (n = 51) and women with no weight records during their first tri mester (n = 580) were excluded from the study. therefore, the final sample included 2,652 women. maternal antenatal complications were compared between obese women and those of normal weight. subsequently, the rate of intrapartum and postpartum events and neonatal complications were compared among obese and normal weight women with uncomplicated pregnancies [figure 1]. as pre-pregnancy bmi measurements were often not available, bmi measurements during the first trimester (i.e. ≤12 gestational weeks) were used to determine early pregnancy obesity, as these do not change significantly during the first three months of pregnancy.9 antenatal complications were documented from the patients’ antenatal record cards, including the incidence of gdm, hypertensive disorders of preg nancy, post-term pregnancy and induction of labour. intrapartum and postpartum events were determined from the electronic hospital records. the intrapartum variables included the incidence of labour augmentation, meconium-stained liquor, mode of delivery and the rate of vaginal birth after a previous caesarean section delivery. maternal postpartum events, such as the incidence of postpartum haemorrhage and obstetric anal sphincter injuries (oasis), along with neo natal outcomes, including perinatal mortality, congenital anomalies, birth weight and cord ph at delivery and neonatal intensive care unit (nicu) admission, were also compared. the data were analysed using the statistical package for the social sciences (spss), version 17 (ibm corp., armonk, new york, usa) and openepi software (emory university, atlanta, georgia, usa). frequency distributions were calculated for each variable separately. categorical variables were summarised as percentages while continuous variables were presented as means and standard deviations. the relative risk (rr) and 95% confidence interval (ci) for each outcome variable was calculated. a p value of <0.05 was deemed statistically significant. ethical approval for this study was obtained from the medical ethics & scientific research committee at the royal hospital (mesrc #60). application to patient care awareness about maternal obesity and its complications may be useful to primary healthcare practitioners in oman during the provision of preventative care and pre-pregnancy counselling services. additionally, appropriate clinical management strategies can be planned to minimise maternal and neonatal morbidity and mortality among women with early pregnancy obesity. anita zutshi, jayasree santhosh, julie sheikh, fareeha naeem, ahmed al-hamedi, shahla khan and eishthiag al-said clinical and basic research | e49 results a total of 2,652 women were included in the study. of these, 901 (34%) were obese, 96 (3.6%) were underweight, 912 (34.4%) were of normal weight and 743 (28%) were overweight. among the obese women, 549 (60.9%) were class i, 225 (25%) were class ii and 127 (14.1%) were class iii. obesity was more common with increased age and parity [figure 2]. with regards to maternal antenatal complications, obese women had a significantly increased risk of gdm (rr: 2.23; 95% ci: 1.70–2.92; p <0.01) and gestational hypertension (rr: 3.04; 95% ci: 1.63–5.65; p <0.01). however, the incidence of preterm labour, post-term pregnancy and induction of labour were comparable among obese women and those of normal weight [table 1]. a total of 440 obese (48.8%) and 672 normal weight (73.7%) women had uncomplicated pregnancies. intrapartum and postpartum events were comp ared among the women with uncomplicated pregnancies. there were no statistically significant differences in the incidence of continuous intrapartum monitoring, fetal scalp electrode placement, prolonged labour, labour augmentation or meconium-stained liquor between the groups. obese women had a significantly higher incidence of intrapartum hypertension (rr: 2.40; 95% ci: 1.24–4.46; p <0.01). postpartum hypertension was six times more common among obese women than women of normal weight (rr: 6.11; 95% ci: 0.69–54.47; p = 0.04). there was a significant figure 1: diagram showing the total number of deliveries during the study period and the application of exclusion and inclusion criteria to determine the final sample used in the current study. rh = royal hospital; lscs = lower-segment caesarean section; tolac = trial of labour after caesarean section. *during the first trimester (≤12 gestational weeks). figure 2: distribution according to (a) body mass index, (b) age and (c) parity of pregnant omani women delivering at the royal hospital, muscat, oman (n = 2,652). bmi = body mass index. implications of early pregnancy obesity on maternal, fetal and neonatal health retrospective cohort study from oman e50 | squ medical journal, february 2018, volume 18, issue 1 increase in the risk of postpartum haemorrhage among obese women (rr: 2.10; 95% ci: 1.11–4.10; p = 0.01). obese women had significantly lower episiotomy rates (rr: 0.63; 95% ci: 0.52–0.77; p <0.01). among women with vaginal deliveries, no statistically significant incidence in oasis was noted between the groups (0.2% versus 0.5% among normal weight and obese women, respectively; p = 0.19). the incidence of instrumental delivery in the obese group was half that of the normal weight group (rr: 0.52; 95% ci: 0.29–1.00; p = 0.02). obese women were 1.4-times more likely to have a lower-segment caesarean section (lscs) delivery than women of normal weight (rr: 1.48; 95% ci: 1.08–2.03; p <0.01) [table 2]. the most common indications for lscs deliveries in both groups were pathological fetal heart tracing and nonprogressive labour. the mean estimated blood loss was greater in obese women, irrespective of mode of delivery [table 3]. among those who had an lscs delivery, mean hospital stay duration was longer for obese women than normal weight women (4.11 ± 1.60 days versus 3.62 ± 1.08 days). in terms of neonatal outcomes, there was no difference in the rates of perinatal mortality, nicu admission or low cord ph at birth between the obese and normal weight groups. the incidence of congenital anomalies was higher among obese women, although this was not statistically significant (rr: 1.36; 95% ci: 0.70–2.63; p = 0.18). however, obese women had a significantly lower incidence of low-birth-weight babies (rr: 0.57; 95% ci: 0.37–0.88; p <0.01) and a 2.7-times increased likelihood of fetal macrosomia (rr: 2.71; 95% ci: 1.21–6.09; p <0.01) [table 4]. among women with at least one previous lscs delivery, obese women were more likely to have a failed trial of labour and a repeat caesarean section delivery (rr: 1.37; 95% ci: 0.88–2.14; p = 0.07). morbidly obese women also had a significantly higher rate of repeat lscs delivery (rr: 2.30; 95% ci: 1.33–3.96; p <0.01). table 1: maternal antenatal complications among pregnant omani women delivering at the royal hospital, muscat, oman (n = 2,652) complication n (%) rr (95% ci) p value normal weight women (n = 912) obese women (n = 901) gdm 69 (7.6) 152 (16.9) 2.23 (1.70–2.92) <0.01 ghtn 13 (1.4) 39 (4.3) 3.04 (1.63–5.65) <0.01 pre-eclampsia 5 (0.5) 8 (0.9) 1.62 (0.53–4.93) 0.21 preterm labour 43 (4.7) 41 (4.6) 0.97 (0.64–1.47) 0.43 post-term pregnancy 189 (20.7) 154 (17.1) 0.82 (0.68–1.00) 0.02 induction of labour 73 (8) 67 (7.4) 0.93 (0.68–1.28) 0.32 eclampsia 2 (0.2) 2 (0.2) 1.01 (0.14–7.17) 0.49 rr = relative risk; ci = confidence interval; gdm = gestational diabetes mellitus; ghtn = gestational hypertension. table 2: maternal intrapartum and postpartum events among pregnant omani women delivering at the royal hospital, muscat, oman (n = 2,652) n (%) rr (95% ci ) p value normal weight women* (n = 672) obese women* (n = 440) event continuous fetal monitoring 198 (29.5) 145 (33) 1.12 (0.94–1.34) 0.11 fetal scalp electrode placement 59 (8.8) 43 (9.8) 1.11 (0.77–1.62) 0.29 slow/ prolonged stage i labour 70 (10.4) 52 (11.8) 1.14 (0.81–1.59) 0.23 slow/ prolonged stage ii labour 18 (2.7) 8 (1.8) 0.68 (0.30–1.55) 0.18 labour augmentation 99 (14.7) 61 (13.9) 0.94 (0.70–1.27) 0.35 meconiumstained liquor 61 (9.1) 41 (9.3) 1.13 (0.77–1.63) 0.28 intrapartum htn 14 (2.1) 22 (5) 2.40 (1.24–4.46) <0.01 postpartum haemorrhage 15 (2.2) 21 (4.8) 2.10 (1.11–4.10) 0.01 postpartum htn 1 (0.2) 4 (0.9) 6.11 (0.69–54.47) 0.04 mode of delivery svd 566 (84.2) 361 (82) 0.97 (0.92–1.03) 0.17 instrumental delivery 38 (5.7) 13 (3) 0.52 (0.29–1.00) 0.02 lscs 68 (10.1) 66 (15) 1.48 (1.08–2.03) <0.01 episiotomy† 241 (39.9) 94 (25.1) 0.63 (0.52–0.77) <0.01 oasis† 1 (0.2) 2 (0.5) 3.22 (0.29–35.50) 0.19 rr = relative risk; ci = confidence interval; htn = hypertension; svd = spontaneous vaginal delivery; lscs = lower-segment caesarean section; oasis = obstetric anal sphincter injuries. *including only those with uncomplicated pregnancies. †the total dataset for this variable was 604 for women of normal weight and 374 for obese women. anita zutshi, jayasree santhosh, julie sheikh, fareeha naeem, ahmed al-hamedi, shahla khan and eishthiag al-said clinical and basic research | e51 among the obese women, one patient had a scar rupture and another had an urgent evacuation due to a wound haematoma. there were no cases of maternal mortality in the study cohort. discussion in general, women tend to gain weight as age and parity increases.10 due to the association between obesity and hyperlipidaemia, hyperinsulinaemia and insulin resistance, obese pregnant women are more likely to develop pre-eclampsia and gdm.11 in the current study, obese women had a two-fold increase in gdm and a three-fold increase in gestational hypertension. in a meta-analysis of 20 studies, chu et al. suggested that the risk of developing gdm increases with obesity, with an odds ratio (or) of 2.14, 3.56 and 8.56 for overweight, obese and morbidly obese women, respectively.12 similar observations have been previously noted in oman.13 a prospective study in saudi arabia also reported an increased risk of gdm and pre-eclampsia with obesity.14 in a large populationbased 15-year cohort study, obese women showed an increased risk of pregnancy-induced hypertension, with an adjusted or of 2.38 and 3.00 for moderate and severe obesity, respectively.15 mcdonald et al. conducted a systematic review and meta-analysis of 84 studies (including 64 cohort and 20 case-control studies) on 1,095,834 women; the authors concluded that obese women had a higher risk of preterm delivery (or: 1.24; 95% ci: 1.13–1.27).16 a danish national birth cohort study reported that being overweight or obese before pregnancy increased the risk of preterm premature rupture of the membranes.17 usha kiran et al. reported that obese pregnant women were more likely to undergo induction of labour (or: 1.6; 95% ci: 1.3–1.9), while ray et al. observed that morbidly obese women were significantly more likely to require invasive fetal (27% versus 0%; p <0.001) and uterine contraction (30% versus 0%; p <0.001) monitoring.18,19 in addition, the overall dur ation of labour has been reported to be longer in obese women, with slower progression of the early first stage of labour.20 however, such associations were not observed in the current study. it has been postulated that obesity may impair the ability of the uterus to contract in labour.21 in agreement with the findings of the present study, sebire et al. reported a higher incidence of postpartum haemorrhage in overweight (or: 1.16; 95% ci: 1.12–1.21) and obese (or: 1.39; 95% ci: 1.32–1.46) women.22 another study indicated an unadjusted or of 2.37 (95% ci: 2.01–2.79) for postpartum haemorrhage in obese women.23 obesity may be protective against thirdand fourth-degree perineal lacerations, independent of parity, race, birth weight and mode of delivery.24 in the current study, the obese cohort had a significantly lower episiotomy rate, with a non-significant increase in table 3: blood loss and hospital stay according to mode of delivery among pregnant omani women delivering at the royal hospital, muscat, oman (n = 2,652) mode of delivery normal weight women* (n = 672) obese women* (n = 440) n (%) mean blood loss in ml ± sd mean hospital stay in days ± sd n (%) mean blood loss in ml ± sd mean hospital stay in days ± sd svd 566 (84.2) 169.53 ± 71.27 2.00 ± 1.07 361 (82) 195.91 ± 165.30 2.04 ± 1.20 instrumental delivery 38 (5.7) 207.57 ± 119.25 3.08 ± 2.70 13 (3) 269.23 ± 288.34 3.00 ± 1.38 lscs 68 (10.1) 419.11 ± 135.77 3.62 ± 1.08 66 (15) 538.27 ± 257.00 4.11 ± 1.60 sd = standard deviation; svd = spontaneous vaginal delivery; lscs = lower-segment caesarean section. * including only those with uncomplicated pregnancies. table 4: neonatal outcomes among obese and normal weight pregnant omani women delivering at the royal hospital, muscat, oman (n = 2,652) outcome n (%) rr (95% ci) p value normal weight women* (n = 672) obese women* (n = 440) perinatal mortality 8 (1.2) 3 (0.7) 0.57 (0.15–2.15) 0.21 congenital anomalies 18 (2.7) 16 (3.6) 1.36 (0.70–2.63) 0.18 birth weight of <2,500 g 72 (10.7) 27 (6.1) 0.57 (0.37–0.88) <0.01 birth weight of >4,000 g 9 (1.3) 16 (3.6) 2.71 (1.21–6.09) <0.01 cord ph of <7.2 16 (2.4) 8 (1.8) 0.76 (0.33–1.77) 0.27 nicu admission 54 (8) 31 (7) 0.88 (0.57–1.34) 0.27 rr = relative risk; ci = confidence interval; nicu = neonatal intensive care unit. implications of early pregnancy obesity on maternal, fetal and neonatal health retrospective cohort study from oman e52 | squ medical journal, february 2018, volume 18, issue 1 oasis among obese women. overall, obese women were significantly more likely to have a caesarean delivery; this finding has been reflected in previous studies reporting ors of 2–2.9.25,26 during a caesarean section procedure, obese women face a greater risk of anaesthetic complications, technical difficulties during the surgery, increased blood loss, wound infection and deep vein thrombosis.3 in the current study, only one obese woman with a history of previous lscs deliveries suffered a wound haematoma and none of the women experienced deep vein thrombosis. such reduced morbidity rates may be due to the fact that the study was conducted in a tertiary care centre with strict intrapartum monitoring protocols and a greater availability of senior obstetricians. however, such find ings may also be due to the size of the cohort. ante partum monitoring, administration of timely thrombo prophylaxis and intraand postpartum management with input from senior obstetricians and anaesthesiologists are recommended to aid in reducing complications in these high-risk pregnancies. the instrumental delivery rate for obese women was almost half that of the normal weight women included in the present study. the apparent reluctance among obstetricians to proceed with instrumental delivery in obese women could be due to expected errors in fetal weight estimation and the increased risk of shoulder dystocia. the instrumental delivery rate in singleton deliveries among obese women has been reported to be 7.6% compared to 12.2% in a general maternity unit.27 regardless of the mode of delivery, longer post-delivery hospital stays have been reported among obese women compared to women of normal weight (14.3% versus 4.7%; or: 1.42; 95% ci: 1.07–1.89).28 in the current study, mean hospital stays were longer only for those obese women who underwent an lscs delivery. no significant differences were found in the rates of perinatal mortality, cord ph, nicu admission or congenital abnormalities among neonates of obese women. indeed, rates of low cord ph, low apgar scores and shoulder dystocia have been reported as similar for women of all bmi categories.29,30 in the current study, obese mothers had a 2.7 times higher incidence of fetal macrosomia (i.e. babies with a birth weight of >4,000 g). for birth weights above the 90th centile, zhang et al. reported the rr to be 1.57 (95% ci: 1.50–1.64) and 2.36 (95% ci: 2.23–2.50) for overweight and obese mothers, respectively.21 in the present study, the risk of having a low-birth-weight baby for obese women was half that of normal weight women. in their systematic review and meta-analysis, mcdonald et al. also reported that the overall risk of having an infant with low birth weight was lower in overweight and obese women.16 in the current study, both obese and morbidly obese women with a history of previous caesarean section deliveries had a significantly higher rate of repeat lscs deliveries. this observation is supported by previous research.31,32 the implementation of national guidelines for early pregnancy obesity at local health centres in oman is recommended to facilitate appropriate interventions and encourage the timely referral of obese mothers to specialist services to ensure safe outcomes. community healthcare providers should identify obesity among young women in order to recommend pre-pregnancy counselling and weight reduction strategies. moreover, obesity education and dietary counselling should be included in adolescent health programmes as a method of primary obesity prevention. conclusion overall, approximately one-third of the omani preg nant women in the current study were obese. obesity was significantly associated with gdm, gestational hypertension, intrapartum and postpartum hyper tension, postpartum haemorrhage, instrumental delivery, lscs, episiotomies, low birth weight and fetal macrosomia. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. obesity: preventing and managing the global epidemic. from: www.who.int/nutrition/publications/ obesity/who_trs_894/en/ accessed: jan 2018. 2. nhlbi education initiative expert panel on the identification, evaluation, and treatment of obesity in adults. clinical guide lines on the identification, evaluation and treatment of overweight and obesity in adults: the evidence report. from: www. ncbi.nlm.nih.gov/books/nbk2003/ accessed: jan 2018. 3. center for maternal and child enquiries, royal college of obs tetricians and gynaecologists. cmace/rcog joint guideline: management of women with obesity in pregnancy. from: www. rcog.org.uk/globalassets/documents/guidelines/cmacercogj ointguidelinemanagementwomenobesitypregnanc ya .pdf accessed: jan 2018. 4. confidential enquiry into maternal and child health. saving mothers’ lives: reviewing maternal deaths to make motherhood safer. from: www.publichealth.hscni.net/sites/default/fil es/sav ing%20mothers%27%20l ives%202003-05%20.p df accessed: jan 2018. 5. tennant pw, rankin j, bell r. maternal body mass index and the risk of fetal and infant death: a cohort study from the north of england. hum reprod 2011; 26:1501–11. doi: 10.1093/humrep/ der052. https://doi.org/10.1093/humrep/der052 https://doi.org/10.1093/humrep/der052 anita zutshi, jayasree santhosh, julie sheikh, fareeha naeem, ahmed al-hamedi, shahla khan and eishthiag al-said clinical and basic research | e53 6. james wp. who recognition of the global obesity epidemic. int j obes (lond) 2008; 32:s120–6. doi: 10.1038/ijo.2008.247. 7. world health organization. obesity and overweight. from: www.who.int/mediacentre/factsheets/fs311/en/#content accessed: jan 2018. 8. al-lawati ja, jousilahti pj. prevalence and 10-year secular trend of obesity in oman. saudi med j 2004; 25:346–51. 9. natamba bk, sanchez se, gelaye b, williams ma. concordance between self-reported pre-pregnancy body mass index (bmi) and bmi measured at the first prenatal study contact. bmc pregnancy childbirth 2016; 16:187. doi: 10.1186/s12884-0160983-z. 10. gupta s, kapoor s. independent and combined association of parity and short pregnancy with obesity and weight change among indian women. health 2012; 4:271–6. doi: 10.4236/hea lth.2012.45044. 11. catalano pm. obesity, insulin resistance, and pregnancy outcome. reproduction 2010; 140:365–71. doi: 10.1530/rep-10-0088. 12. chu sy, callaghan wm, kim sy, schmid ch, lau j, england lj, et al. maternal obesity and risk of gestational diabetes mellitus. diabetes care 2007; 30:2070–6. doi: 10.2337/dc06-2559a. 13. al-hakmani fm, al-fadhil fa, al-balushi lh, al-harthy na, al-bahri za, al-rawahi na, et al. the effect of obesity on pregnancy and its outcome in the population of oman, seeb province. oman med j 2016; 31:12–17. doi: 10.5001/omj.2016.03. 14. el-gilany ah, hammad s. body mass index and obstetric out comes in pregnant in saudi arabia: a prospective cohort study. ann saudi med 2010; 30:376–80. doi: 10.4103/0256-4947.67075. 15. robinson he, o’connell cm, joseph ks, mcleod nl. maternal outcomes in pregnancies complicated by obesity. obstet gynecol 2005; 106:1357–64. doi: 10.1097/01.aog.0000188387.88032.41. 16. mcdonald sd, han z, mulla s, beyene j; knowledge synthesis group. overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and metaanalyses. bmj 2010; 341:c3428. doi: 10.1136/bmj.c3428. 17. nohr ea, bech bh, vaeth m, rasmussen km, henriksen tb, olsen j. obesity, gestational weight gain and preterm birth: a study within the danish national birth cohort. paediatr perinat epidemiol 2007; 21:5–14. doi: 10.1111/j.1365-3016.2007.00762.x. 18. usha kiran ts, hemmadi s, bethel j, evans j. outcome of pregnancy in a woman with an increased body mass index. bjog 2005; 112:768–72. doi: 10.1111/j.1471-0528.2004.00546.x. 19. ray a, hildreth a, esen ui. morbid obesity and intra-partum care. j obstet gynaecol 2008; 28:301–4. doi: 10.1080/0144361 0802042548. 20. norman sm, tuuli mg, odibo ao, caughey ab, roehl ka, cahill ag. the effects of obesity on the first stage of labor. obstet gynecol 2012; 120:130–5. doi: 10.1097/aog.0b013e31 8259589c. 21. zhang j, bricker l, wray s, quenby s. poor uterine contract ility in obese women. bjog 2007; 114:343–8. doi: 10.1111/ j.1471-0528.2006.01233.x. 22. sebire nj, jolly m, harris jp, wadsworth j, joffe m, beard rw, et al. maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in london. int j obes relat metab disord 2001; 25:1175–82. doi: 10.1038/sj.ijo.0801670. 23. fyfe em, thompson jm, anderson nh, groom km, mccowan lm. maternal obesity and postpartum haemorrhage after vaginal and caesarean delivery among nulliparous women at term: a retrospective cohort study. bmc pregnancy childbirth 2012; 12:112. doi: 10.1186/1471-2393-12-112. 24. garretto d, lin bb, syn hl, judge n, beckerman k, atallah f, et al. obesity may be protective against severe perineal lacerations. j obes 2016; 2016:9376592. doi: 10.1155/2016/9376592. 25. kaiser ps, kirby rs. obesity as a risk factor for cesarean in a low risk population. obstet gynaecol 2001; 97:39–43. doi: 10.1016/ s0029-7844(00)01078-4. 26. machado ls. cesarean section in morbidly obese parturients: practical implications and complications. n am j med sci 2012; 4:13–18. doi: 10.4103/1947-2714.92895. 27. edwards l, lim bh. challenges of intrapartum care in obese women. in: mahmood ta, arulkumaran s, eds. obesity: a ticking time bomb for reproductive health, 1st ed. amsterdam, netherlands: elsevier, 2012. pp. 325–37. 28. arabin b, stupin jh. overweight and obesity before, during and after pregnancy: part 2 evidence-based risk factors and interventions. geburtshilfe frauenheilkd 2014; 74:646–55. doi: 10.1055/s-0034-1368462. 29. arrowsmith s, wray s, quenby s. maternal obesity and labour complications following induction of labour in prolonged preg nancy. bjog 2011; 118:578–88. doi: 10.1111/j.1471-0528.2010. 02889.x. 30. vinturache ae, mcdonald s, slater d, tough s. perinatal outcomes of maternal overweight and obesity in term infants: a population-based cohort study in canada. sci rep 2015; 5:9334. doi: 10.1038/srep09334. 31. durnwald cp, ehrenberg hm, mercer bm. the impact of maternal obesity and weight gain on vaginal birth after cesarean section success. am j obstet gynecol 2004; 191:954–7. doi: 10.10 16/j.ajog.2004.05.051. 32. the royal australian and new zealand college of obstetricians and gynaecologists. birth after previous caesarean section. from: www.ranzcog.edu.au/ranzcog_site/media/ranzc o g-medi a/women's%20health/statement%20and%20 g u i d e l i n e s / c l i n i c a l o b s t e t r i c s / b i r t h a f t e rp r e v i o u s caesarean-section-(c-obs-38)-re-writejuly-2015.pdf? ext=.pdf accessed: jan 2018. https://doi.org/10.1038/ijo.2008.247 https://doi.org/10.1186/s12884-016-0983-z https://doi.org/10.1186/s12884-016-0983-z https://doi.org/10.4236/health.2012.45044 https://doi.org/10.4236/health.2012.45044 https://doi.org/10.1530/rep-10-0088 https://doi.org/10.2337/dc06-2559a https://doi.org/10.5001/omj.2016.03 https://doi.org/10.4103/0256-4947.67075 https://doi.org/10.1097/01.aog.0000188387.88032.41 https://doi.org/10.1136/bmj.c3428 https://doi.org/10.1111/j.1365-3016.2007.00762.x https://doi.org/10.1111/j.1471-0528.2004.00546.x https://doi.org/10.1080/01443610802042548 https://doi.org/10.1080/01443610802042548 https://doi.org/10.1097/aog.0b013e318259589c https://doi.org/10.1097/aog.0b013e318259589c https://doi.org/10.1111/j.1471-0528.2006.01233.x https://doi.org/10.1111/j.1471-0528.2006.01233.x https://doi.org/10.1038/sj.ijo.0801670 https://doi.org/10.1186/1471-2393-12-112 https://doi.org/10.1155/2016/9376592 https://doi.org/10.1016/s0029-7844%2800%2901078-4 https://doi.org/10.1016/s0029-7844%2800%2901078-4 https://doi.org/10.4103/1947-2714.92895 https://doi.org/10.1055/s-0034-1368462 https://doi.org/10.1111/j.1471-0528.2010.02889.x https://doi.org/10.1111/j.1471-0528.2010.02889.x https://doi.org/10.1038/srep09334 https://doi.org/10.1016/j.ajog.2004.05.051 https://doi.org/10.1016/j.ajog.2004.05.051 squ med j, december 2009, vol. 9, iss. 3, pp. 260-263, epub. 19th dec 2009 submitted 29th sep 2009 revision req. 25th oct 09. revision recd. 26th oct 09 accepted 8th nov 09 a 55 year-old man was diagnosed as having metastatic colon cancer following an endoscopic biopsy at my university hospital in oman, and was referred to a medical oncologist. the patient, together with his son, travelled to an other asian country seeking a ‘second-opinion’. there he was initially treated with a colonic stent, resulting in the perforation of the colon. he underwent emergency resection of the perforated segment, leading to intestinal obstruction. a second surgery was performed to relieve the obstruction, and combination chemotherapy (including the antiangiogenic drug, bevacizumab) was started. during the first course of treatment, the patient developed urinary retention, was catheterised, and then went on to develop haematuria. he returned to oman with severe haematuria, a prescription to continue the combination chemotherapy, and radiographic evidence of a bilateral pulmonary artery embolism. stories like this are not uncommon and are frequently encountered during routine medical practice in general, and in oncology practice in particular. what is not mentioned in the above story is the fact that the duration between the diagnosis of cancer in oman and arriving at the hospital abroad was about 4 weeks, during which time the metastatic disease in the liver had increased considerably and the patient’s performance status had declined. inserting a stent was unnecessary in a non-obstructing bowel, a procedure which ultimately led to two needless surgeries and a further delay in starting standard systemic treatment. the expensive anti-angiogenic drug was contraindicated in a patient with two recent surgeries, and is definitely contra-indicated following a diagnosis of a pulmonary embolism. the patient spent the equivalent of 28,000 omani riyals (us$ 45,000) during his 4 week stay abroad. he regretted the decision made by his family members. what is a second opinion? and why do patients, especially those with a diagnosis of cancer, seek one? what are the challenges that face both patients and health providers when a second opinion is sought? indeed, is the desire to get a second opinion problematic and, if so, can the situation be improved? asking for a second opinion is understandable. when it comes to choice (be it selecting food in a restaurant, buying a car, or purchasing a new house) we all value the opinions of others, and sometimes we may even look for a third or fourth opinion. seeking a second opinion is a way of making choices. however, it is not quite the same when one has received the diagnosis of a cancer. in such a situation, with the likelihood of extensive surgery, chemotherapy and/or radiotherapy, opinions should be sought to see if alternative forms of treatment or cure were available. from the point of view of the department of medicine, sultan qaboos university hospital, muscat, oman email: ikramburney@hotmail.com نزعة احلصول على رأي ثان من اخلارج يف عالج مرضى السرطان يف ُعمان حتديات وفرص اكرام برني sounding board the trend to seek a second opinion abroad amongst cancer patients in oman challenges and opportunities ikram a burney ikram a burney sounding board | 261 oncologist, seeking a second opinion is desirable and, in some cases, obligatory. the vast majority of cases are straightforward, and treatment begins as soon as diagnosis and staging are known. in cases of less common cancers, borderline cases or cancers of unknown primary sites, practising doctors frequently invite a second opinion from their colleagues. seeking a second opinion is a recognised practice in the specialty of oncology. however, the situation described in the above story is something commonly encountered in oncology-related practice in oman: the seeking of a second opinion abroad before any treatment at home in oman. a significant number of patients, especially from small towns, bypass the tertiary care/specialist hospitals available to them in bigger centres and immediately go abroad. once overseas, they may not be provided with a second opinion, but instead are started on the first stage of treatment even when it is uncalled for. patients invariably return home to continue the treatment. although the off-shore clinics are very quick to commence ‘treatment’, valuable time, not to mention savings or borrowed money, is often lost in the making of travel arrangements. the tendency to seek a second opinion abroad can endanger the patient’s health. the clinical condition may not be fully known to the patient and/or his/her family members, and urgent clinical attention is sometimes delayed. any delay in travel arrangements may lead to a progression of the disease; this in turn leads to an increased burden of disease and a decline in performance status, both conditions decreasing the chances of successful treatment and a subsequent cure. a decline in performance status by a single grade is an adverse prognostic factor in almost all cases of cancer, and for some, this decline may occur within just a few weeks. furthermore, the patient’s selection of country or medical centre is often not informed by prior knowledge of expertise, excellence in the field or familiarity with the type of cancer, but rather by geographical proximity, convenience of travel or simply by a verbal recommendation. some patients are known to have arrived at centres in which they have received less than adequate treatment or been the victim of experimental/investigational treatment without their knowledge. in both cases, the chances of any subsequent standard treatment being effective are reduced. sometimes patients end up in good centres where standard treatment is offered or advised for straightforward cases, but there are complications as a result of travel-related delays. additionally, cancer treatment overseas is seldom cheaper. in order to influence the behaviour of persons seeking a second opinion abroad, one needs to study the mechanisms underlying this phenomenon. first, it is important to understand the motives and expectations of the patients. second, in a society where decision-making in health care is often shared, it is important to consider the point of view of all the decision-makers involved. patients do not always make their own decisions. they are often influenced by the care-givers/well-wishers who, in some cases, are the only ones involved in important decisions. although many patients with cancer seek second opinions, there is a dearth of literature on the subject. only a few have looked at the phenomenon, even fewer have tried to assess its incidence and outcomes.1,2 the actual incidence of seeking a second opinion is likely to differ from country to country, and amongst different groups of patients. with an increase in the knowledge of disease and improvements in communication, an increasing number of patients seek second opinions. for example, 56% of more than 1,500 cancer patients in the united states sought a second opinion in a single year.3 the incidence in oman is unknown. it would be useful to know how often a second opinion has impacted upon the course of treatment. in a survey done in holland of 403 patients, the majority with breast cancer, the investigators found that in 84% of cases the advice given was comparable. not everybody had a review of either histological or radiological diagnosis and when this occurred, a major change in treatment was observed in only 3% of patients and a change in prognosis in just 2%.4 who are the people more likely to travel abroad to seek a second opinion before the first? are they the well-informed, the well-read or the wealthy? there is insufficient information on this subject. however, a common observation is that the phenomenon transcends the boundaries of information and financial resources as much as it transcends national boundaries. for example, kangas reported on the behavior of not-so-rich yemeni patients with various diseases seeking biomedical treatment in other countries, and noted that their behaviour did not differ significantly from that of relatively wellthe trend to seek second opinions abroad amongst cancer patients in oman challenges and opportunities 262 | squ medical journal, december 2009, volume 9, issue 3 off saudis.5 in the absence of published data concerning omani patients, the motives for seeking second opinions before the first remain hypothetical. the motives may be intrinsic or extrinsic, or a combination of both.6 intrinsic motives could include: seeking reassurance and more certainty about the diagnosis; seeking a treatment other than the conventional one ‘usually’ offered to cancer patients; the desire to be treated in a different environment perhaps to maintain ‘confidentiality’; or the belief that ‘paying more’ will produce better treatment. extrinsic motives are more varied. these could include: experiences from the patient’s past; doubts about the health care services in the home country; market forces, such as dynamic advertisements by external health care organisations; social and societal pressures; or merely word of mouth information that a ‘cure’ is available elsewhere, and hence borrowing or spending large amounts of money might bring positive results. common extrinsic motivators for seeking a second opinion may not be applicable in the case of omani patients, since a ‘first’ opinion has not yet been sought. these may include: the lack of effective communication by and with the oncologist; dissatisfaction with the primary oncologist; seeking an opinion on a rare cancer; concern about the side-effects of a particular type of treatment; an ambivalent attitude towards the care provided resulting in the need for more information, or the desire to participate in a clinical trial. is there a solution? first of all, the phenomenon needs to be studied, and the motives and expectations of the local population explored. this would provide a wonderful opportunity not only for examining patients’ and families’ motives, but also to investigate the health services offered. a lack of communication between health care providers, a delay in diagnosis (especially at the point of primary care), or simply the unavailability of resources (actual or perceived) may contribute to the need for a second opinion. in cases of the latter, these could be easily rectified by better utilisation of our material resources. on the other hand, if the major motivations are intrinsic (or social), then the solution may lie in sustained and concrete efforts aimed at enhancing public awareness and confidence-building through a process of education and information dissemination. the ultimate winners should and would be the patients and society at large. in conclusion, seeking a second opinion amongst cancer patients in oman poses certain challenges for the health of our patients and provides the health care profession with opportunities to study the problem and to aim for practical solutions. first of all, it must be recognised that seeking a second opinion is not only justified, but also desirable in many situations. oncologists themselves should support patients in their efforts to obtain an opinion. however, seeking a patient-initiated second opinion abroad, especially in the case of cancer management, may have an adverse effect on the outcome of the disease, both because of the delay it causes in diagnosis, and because of the chance of receiving sub-optimal treatment or advice elsewhere. in order to overcome the challenge, there is an urgent need to study patients’ or their decision makers’ motives and expectations. meanwhile, it may help omani patients diagnosed with cancer and their families, who are seeking a cure wherever it may be found, to know that the world health organization (who) has ranked oman as the most efficient ‘health care system in the world in terms of outcomes’.7 furthermore, patients should be advised that second opinions can be easily and quickly sought at little or no cost through fax, email, and telemedicine from places in oman or abroad that are widely perceived to be centres of academic and clinical excellence. this will avoid the need for cancer sufferers to seek opinions from more profitoriented health care centres which may not have the necessary expertise to provide the best advice. references 1. sikora k. second opinion for patients with cancer. br med j 1995; 311:1179-80. 2. macdonald ea. second opinions in oncology: nuisance or opportunity. clin oncol 1997; 9:418-20. 3. hewitt m, breen n, devesa s. cancer prevalence and survivorship issues: analyses of the 1992 national health interview survey. j natl cancer inst 1999; 91:1480-6. 4. meink wa, henzen-logmans sc, bongaerts ah, ooijen bv, rodenburg cj, wiggers th. discrepancy between second and first opinion in surgical oncological patients. eur j surg oncol 2006; 32:10812. 5. kangas b. therapeutic itineraries in a global world: ikram a burney sounding board | 263 yemenis and their search for biomedical treatment abroad. med anthropol 2002; 21:35-78. 6. mellink wam, dulmen amv, wiggers t, spreeuwenberg pmm, eggermont amm, bensing jm. cancer patients seeking a second surgical opinion: results of a study on motives, needs, and expectations. j clin oncol 2003; 8:1492-7. 7. al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? squ med j 2006; 6:3-9. o n l i n e s u b m i s s i o n ! you can now submit your manuscript online on the squmj website www.squ.edu.om/squmj note: please make sure that you register only once for all your manuscripts as the motto ‘publish or perish’ is encroaching all spheres of medical professions, this volume, a-z of medical, has all the gimmicks for such a situation. it is written by tim albert, well known guru of medical writing. in this volume, he has assembled his vast knowledge in medical writing into easy accessible reading for all. the volume takes its reader on a journey into the art and science of medical writing without much of the undue headache often encountered in many of such books. its aim is to “give support, encouragement, and informed advice so that people who have found (medical) writing hard will somehow find it less hard’. according to the author it should either be dipped into “during an otherwise idle moment” and/or used “for advice and encouragement when you have a specific writing problem”. without much jargon, and with any bombastic concepts duly defined for you, this volume should pride itself as reader friendly. this is relevant considering that achievement in medical sciences writing is increasingly perceived to be source of pride or a difficult challenge for those who aspire to it. it certainly is an amusing and witty volume for dipping in to with such entries as “monologophobia”, “polyfantophilia” and ‘yellow marker test” with outright jokes entries like “green ink brigade” and “fish and chip wrappers” – the latter perhaps only comprehensible to anyone who is well versed in british humour, but not necessary cockney. in this respect, a medical writer may glean some useful tips as he or she browses through the volume in an “idle moment” and feel encouraged by the thoughts of an expert in the field. it is doubtful, however, whether a medical writer can use this volume for advice with a “specific writing problem”. although alphabetically arranged, the volume has neither an alphabetical index nor a list of possible problems linked to relevant entries. this means that finding advice is difficult without wasting much time. for example, very good advice for writers is to “keep it short and simple”, but this advice is found under the entry “kiss”; similarly, starting with a well thought out idea or study is helpful advice, but who would think to look for this under the heading “icarus fallacy”? ìèf�÷]<<ìe^j”÷]<ª<^è÷]<±c<ã÷˘]<‡⁄  book reviewbook review a-z of medical writing author: tim albert publisher: wiley-blackwell, bmj books, 2000, 3rd impression 2003 isbn: 0-7279-1487-1 orders: www.bmjbooks.com squ med j, december 2010, vol. 10, iss. 3, pp. 418-419, epub. 14th nov 10 submitted 28th sept 10 tim albert book review | 419 excellent entries, with slightly more relevant titles, can be found under “brief setting” – how initial planning is essential in the writing process – and “branching” using spider charts and mind maps to brainstorm all aspects of the topic you wish to write about. the obvious target audience of this volume is health professionals. doctors tend to perceive their daily encounters as coming to grips with ‘dis-ease’. one may wonder why such a common dis-ease as medical writing distress has yet to be medicalised. maybe there is no such need anymore, as this book, offers help to all. if one requires a second opinion, then this volume provides additional resources, cross-referenced for the reader follow. without flipping its pages, the volume looks thin, but it is written in small font so good value for your money; however, if you have hyperopia, make sure your reading glasses are handy. to conclude, having this volume to hand is essential if you want to revise your writing skills in those idle moments and be amused at the same time. r e v i e w e r s samir al-adawi depaartment of behavioural medicine college of medicine & health science sultan qaboos university, muscat, oman email: samir1964@gmail.com meriel carboni squ medical journal college of medicine & health science sultan qaboos university, muscat, oman email: mjournal@.squ.edu.om clinical & basic research squ med j, february 2012, vol. 12, iss. 1, pp. 86-92, epub. 7th feb 12. submitted 8th may 11 revision req. 23rd aug 11, revision recd. 15th sep 11 accepted 30th nov 11 ما هي خماوف املرضى من األخطاء الطبية يف قسم الطوارئ؟ ناهيد كيامنهر، مانى مفيدى، ح�سني �سعيدى، مر�سيه حاجى بيَكى، مهدى ر�سايى امللخ�ص: الهدف: زادت املخاوف من الأخطاء الطبية يف الآونة الأخرية، وفهم كيفية ت�سور املر�سى للخطاأ الطبي ي�ساعد مقدمي الرعاية ال�سحية على تبديد املخاوف املتعلقة بال�سالمة، وزيادة ر�سا املر�سى. هدف هذه الدرا�سة هو تقييم خماوف املر�سى من الأخطاء الطبية وعالقتها مع خ�سائ�س املري�س ور�ساه. الطريقة: اأجريت هذه الدرا�سة الو�سفية املقطعية يف ق�سم الطوارئ يف م�ست�سفى جامعي خالل من كل يف ر�ساهم وم�ستويات الطبية الأخطاء من املر�سى خماوف لتقييم ا�ستبيان ا�ستخدام مت .2008 اأكتوبر يف واحد اأ�سبوع فرتة مقابلة اأولية وعن طريق الهاتف بعد 7 اأيام من اإخراج املري�س من امل�ست�سفى. مت جمع البيانات وحتليلها بوا�سطة مربع كاي وفح�س تي والنحدار اللوج�ستي. النتائج: من �سمن 638 مري�سا مت ا�ستبيانهم ، اأظهر %61.6 منهم ارتياحهم بدرجة جيدة اإىل ممتازة؛ بينما بنّي 93 مري�سا ]%14.6[ درجة ر�ساهم باأنها �سعيفة؛ و 152 مري�سا ]%23.8[ باأنها متو�سطة؛ و 296 ]%46.4[ باأنها جيدة؛ و 79 على واحد طبي خطاأ وقوع من قلقني )95% الثقة حدود مع ، 44.5-52%( املر�سى من 48.3% كان ممتازة. باأنها ]15.2%[ الأقل. هناك عالقة وا�سحة بني معدل الر�سا العام ووجود قلق خلطاأ طبي واحد على الأقل )مربع كاي ، p >0.001(. اخلال�سة: اأظهرت هذه الدرا�سة اأن العديد من املر�سى كانوا قلقني من الأخطاء الطبية يف حالت الطوارئ اخلا�سة بهم. ب�سبب ال�سغوط املوجودة يف اأق�سام تلك يف العاملة الطبية الأطر وتثقيف املري�س، ملخاوف اأف�سل فهم خالل من ر�ساهم وزيادة املر�سى �سالمة حت�سني ميكن الطوارئ، الأق�سام وحت�سني العالقة بني املري�س والطبيب. مفتاح الكلمات: خدمة الطوارئ، م�ست�سفى، اأخطاء طبية ، مر�سى، ر�سا، مري�س، اإيران. abstract: objectives: concerns about medical errors have recently increased. an understanding of how patients conceptualise medical error would help health care providers to allay safety concerns and increase patient satisfaction. the aim of this study was to evaluate patients’ worries about medical errors and their relationship with patient characteristics and satisfaction. methods: this descriptive cross-sectional study was done in the emergency department (ed) of a university hospital over a one week period in october 2008. a questionnaire was used to assess patients’ worries about medical errors and their satisfaction levels both at an initial interview and by telephone 7 days after discharge. data were gathered and analysed by χ2, t-tests and logistic regression. results: of 638 patients interviewed, 61.6% declared their satisfaction rate as good to excellent; (93 [14.6%] as poor; 152 [23.8%] as fair; 296 [46.4%] as good; 97 [15.2%] as excellent). a total of 48.3% of patients (44.5–52%, with confidence interval 95%) were concerned about the occurrence of at least one medical error. there was a clear relationship between the general satisfaction rate and having at least one concern about a medical error (chi-square, p <0.001). conclusion: this study showed that many patients were concerned about medical errors during their emergency care. due to the stressful situation in eds, patients’ safety and satisfaction could be improved by a better understanding of patient concerns, education of ed staff and an improvement in the patient-doctor relationship. keywords: emergency department; medical errors; patient concern; satisfaction; iran. what are patients’ concerns about medical errors in an emergency department? nahid kianmehr,1 *mani mofidi,2 hossein saidi,2 marzieh hajibeigi,3 mahdi rezai2 clinical & basic research 1department of internal medicine, tehran university of medical sciences, iran, and department of internal medicine, hazrat e rasool akram hospital, tehran, iran; 2department of emergency medicine, tehran university of medical sciences, iran, and emergency department, hazrat e rasool akram hospital, tehran, iran; 3department of forensic medicine, tehran university of medical sciences, iran, and hazrat e rasool akram hospital, tehran, iran corresponding author e-mail: m-mofidi@sina.tums.ac.ir advances in knowledge this article showed that nearly 50% of emergency patients at hazrat e rasool akram hospital, teheran, iran, had concerns about at least one type of medical error. applications to patient care it is important to decrease concern about medical errors as this will have a positive effect on patient satisfaction. nahid kianmehr, mani mofidi, hossein saidi, marzieh hajibeigi, mahdi rezai clinical and basic research | 87 emergency departments (ed) are busy environments. confrontation with a wide variety of injuries and illnesses causes a very stressful climate both for patients and physicians.1 there are many causes of the concerns that can ultimately lead to patient dissatisfaction. overcrowding, the limitations of nurses and resources, the seriousness of illnesses or injuries and the presence of too many patients who require acute inpatient care, can all disturb patients. regardless of how well trained and experienced the emergency physicians are, they can make mistakes as they are only human.2 the probability of medical errors is increased by the acute and unpredictable presentations of illness, and by having to work in a busy and overcrowded environment.3,4 the worldwide expansion of medical knowledge through different kinds of media, has led many people to believe that medical care is not totally safe and that they can become victims of medical errors.5 in one study, 75% of patients experienced concerns about medical errors during their hospitalisation.6 in another study 39% of patients were anxious about the occurrence of at least one medical error.7 unaddressed patients concerns can lead to dissatisfaction, an unwillingness to return to or recommend this hospital to their relatives, noncompliance with medical advice, and an increase in medico-legal claims.8,9 patients expect to be aware when, where and how malpractice issues happen. they also want to know the reasons for the occurrence and ways to prevent errors.10 studies of the delivery of health care services are producing improved safety suggestions. some important aspects of improved care are good teamwork, anticipation of unexpected events, improving communication, providing a conducive learning environment, updating drug delivery systems, addressing patient concerns and engaging patients in error prevention.10,11 the unique characteristics of emergency departments make this environment a suitable place to study patient concerns about medical errors. this study was conducted to determine ed patients’ concerns about medical errors and their relationship with their general characteristics and satisfaction status. methods this study was a descriptive cross-sectional study, conducted in the ed of hazrat e rasoul akram hospital in tehran, iran, during a 7 day period in october 2008. the ed has an annual intake of 50,000 patients with both medical and surgical complaints. all adult patients who presented to our ed during the study period were included in the study. patients with a decreased level of consciousness, who were chemically intoxicated, aged <18 years, or those who were unwilling to participate in the survey were excluded from the study. all of the included patients were interviewed with a questionnaire about their medical error concerns and their satisfaction with different components of ed services along the lines of patient satisfaction surveys carried out in previous studies.12–14 questions covered subjects such as triage performance, quality of care provided, physical environment, nursing and physician behaviour, and the general opinion about the ed experience. the answers were rated on a five point likert scale: 5 = excellent, 4 = very good, 3 = good, 2 = fair, 1 = poor. additional information, including age, sex, type of medical insurance, educational level, main physical complaints, time of admission, and length of stay in the ed, were extracted from the patients’ files and recorded. during the survey testing phase, in order to tune the questionnaire to our culture, 8 related concerns, which were proposed in the burroughs, et al. study, were also investigated for 30 patients.1 they were also asked one open-ended question about their other concerns during their stay in the ed. based on these patients’ views, we then added two items: mistakes by medical students and ed waiting/treatment time. the same questionnaire was administered in the ed and then again, 7 days after discharge, by telephone interview. for the latter, up to 10 attempts were made to contact each patient. for patients who were admitted to the ward, their follow-up questionnaire was completed at their bedside. in the questionnaire, patients were asked whether they experienced any of the following medical errors during their hospital stay (coded as yes/no): prescription of wrong drugs; operational problem of medical equipment; nursing mistake; physician mistake; medical student mistake; identity mistaken for that of another patient; laboratory test mistakes; improper diagnosis; lengthy waiting/treatment times, and fall from hospital bed (concern that they might fall). what are patients’ concerns about medical errors in an emergency department? 88 | squ medical journal, february 2012, volume 12, issue 1 table 1: demographic data and clinical characteristics of participants n (%)variable 40.4±18.5age±sd in years 345 (54) 293 (46) sex: male female 6.37±7.4length of ed stay, in hours 141 (22.1%)education (university degree) 370 (58%)insurance holder outcome: 366 (57.4%)discharge 102 (16%)lama 170 (26.6%)admitted to ward overall satisfaction 97 (15.2%)excellent 296 (46.4%)good 152 (23.8%)fair 93 (14.6%)poor legend: sd = standard deviation; ed = emergency department; lama = left against medical advice. data analysis was performed using the statistical package for the social sciences (spss, version 14, ibm, chicago, illinois, usa) to answer the following main questions: 1) which medical errors are the greatest patient concerns? 2) is there any correlation between medical errors and patient characteristics? and 3) do patient concerns affect patient satisfaction? the chi-square test was used for categorical variables, the unpaired t-test for continuous variables and multivariable logistic regression for prediction. the study was approved by the ethics committee of the faculty of medicine of tehran university of medical sciences. the researchers obtained consent from patients for participation in the study. results a total of 638 (75%) of the 850 patients included in the study completed both the initial questionnaire interview as well as the 7-day follow-up telephone interview which repeated the same questions. patients’ characteristics are summarised in table 1. a total of 61.6% of patients had a satisfaction rate of good to excellent; (93 [14.6%] poor; 152 [23.8%] fair; 296 [46.4%] good; 97 [15.2%] excellent). a total of 48.3% of patients (44.5–52%, with confidence interval 95%) were concerned about the occurrence of at least one medical error. some of them reported more than one. if patients’ responses changed between the initial questionnaire and the 7-day follow-up questionnaire, we took into account all of the concerns mentioned by the patient. the percentages of patients’ concerns are shown in figure 1 as: prolonged ed stay (19%); medical student related error (18.7%); errors with equipment malfunction (8.6%); improper diagnosis (7.1%); injury due to fall from hospital bed (5.6%); physician’ fault in management (4.5%); identity mistaken for that of another patient (4.4%); laboratory test mistake (2.7%), and nursing mistake (0.6%) we assessed the factors that might have affected patient satisfaction. this revealed that the gender of patients (chi-square, p = 0.141), their educational grade (chi-square, p = 0.110), age (t, p = 0.191), and length of stay in ed (t, p = .404) did not have any significant relationship with patient satisfaction; however, the outcome of patients (discharged, admitted to wards or those who left against medical advice) (chi-square, p <0.001), and having medical insurance (chi-square, p = 0.20) did have a significant relationship with patient satisfaction. we found, on the one hand, that only four (3.92%) of the 102 patients (16% of the patients interviewed) who left the ed against medical advice (lama) were satisfied with their care. this means that near all of these patients were unsatisfied; they maybe went to another medical centre for continued treatment. on the other hand, for patients who were discharged by physicians or admitted to a ward the satisfaction rates were 68.85% and 80.58% respectively. of the patients who had a university degree, 24.14% were satisfied with their treatment while 18.77% of those without a university degree were satisfied. this difference was not, however, statistically significant (p = 0.110). a total of 52.92% of female patients were satisfied with their treatment. although they had less concerns than males, this difference was not statistically significant (p = 0.141). table 2 shows the relationship between patient characteristics and patient concerns. females had greater concerns about improper diagnosis, being mistaken for another patient and falling from a hospital bed, while males were worried about nahid kianmehr, mani mofidi, hossein saidi, marzieh hajibeigi, mahdi rezai clinical and basic research | 89 nursing mistakes, equipment malfunction and physician error. patients with university degrees were markedly more worried about physician error, being mistaken for another patient and improper diagnosis, but less worried about equipment malfunction. older participants were more worried about medical student error, falling from a hospital bed and being mistaken for another patient, but younger patients were more concerned about equipment malfunction and nursing mistakes. some of the patients left the hospital without completing the diagnosis or treatment process. they were significantly more worried about improper diagnosis and nursing mistakes. we conducted a multivariate analysis and found that female gender, leaving the ed against medical advice and having a university degree were independently predictive of having at least one concern about a medical error. also, multivariate analysis demonstrated that having insurance, being discharged or admitted by a physician and having a university degree were independently predictive of high satisfaction [tables 3 and 4]. there was a clear relationship between the general satisfaction rate and having at least one concern about a medical error (chi-square, p <0.001). discussion most of the time, eds have too many acutely ill patients. this situation can be highly stressful for physicians, very disturbing for patients and lead to medical error. this study was conducted to evaluate the patient concerns about medical errors during their visit to the ed. in spite of overcrowding in our ed, the majority of patients expressed satisfaction with the medical care they received during their visit although 48.3% of them were concerned about occurrence of one medical error. in the study by burroughs, 38% of patients experienced error related concerns.1 in other studies, the reported “medical error anxiety” rate was much higher.11,15 the following factors are suggested as the causes of the greatest concern about medical error which ultimately result in more dissatisfaction: severity of illness or pain; uncertain clinical diagnosis; prolonged ed stay; unclear or insufficient table 2: relationship between patient characteristic and patient concerns gender (male/ female) insurance (without) % university degree (+)% disposition (lama) % %age (worried/ not worried) mean worried about at least one medical error 54.54 / 45.46 p = 0.056 42.86p = 0.674 +, p = 0.674 28.9 +, p <0.001* 21.42 +, p <0.001* 41.01 / 39.86 ~, p = 0.433 prolonged ed stay 47.93 / 52.07 p = 0.725 23.96 +, p<0.001 23.14 +, p = 0.759 20.66 +, p = 0.119 37.74 / 41.04 ~, p = 0.078 medical student related error 52.95 / 47.05 p = 0.388 47.05 +, p = 0.216 29.1 +, p = 0.163 21 +, p = 0.098 44.29 / 39.53 ~, p = 0.017* errors with equipment malfunction 89.1 / 10.9 p <0.001* 61.82 +, p = 0.002* 10.9 +, p = 0.036* 14.55 +, p = 0.760 27.3 / 41.65 ~, p <0.001* improper diagnosis 28.89 / 71.11 p = 0.004* 64.45 +, p = 0.002* 46.66 +, p <0.001* 35.56 +, p <0.001 41.64 / 40.32 ~, p = 0.646 injury due to fall from hospital bed 25 / 75 chi2, +, p = 0.003* 22.23 +, p = 0.013* 13.9 +, p = 0.222 0 #, p = 0.004* 50.3 / 39.52 ~, p <0.001* physician' fault in management 72.41 / 27.59 p=0.011* 58.62 +, p = 0.064 44.82 +, p = 0.003* 27.58 #, p = 0.081 37.31 / 40.56 ~, p = 0.077 being mistaken for another patient 14.29 / 85.71 p = <0.001* 0 #, p <0.001 0 #, p = 0.004* 0 #, p = 0.018* 47.42 / 40.02 ~, p = 0.001* laboratory mistake 52.95 / 47.05 p = 0.766 52.94 +,p = 0.355 29.41 +, p = 0.461 23.53 #, p = 0.332 37.52 / 40.49 ~, p = 0.208 nursing mistake 100 / 0 p = 0.042* 100 #, p = 0.018* 0 #, p = 0.285 100 #, p = 0.001* 35 / 40.45 ~, p <0.001* note: *statistically significant. statistical tests used: + = chi2; # = fisher's exact; ~ = t test. legend: sd = standard deviation; ed = emergency department; lama = left against medical advice. what are patients’ concerns about medical errors in an emergency department? 90 | squ medical journal, february 2012, volume 12, issue 1 figure 1: patients’ concerns about medical errors during emergency department visit. table 3: multivariate analysis (binary logistic regression) predictive of being concerned about at least one medical error b se p value exp (b) (95% ci) male -0.347 0.163 0.033 0.707 (0.513– 0.973) lama 0.824 0.228 <0.001 2.28 (1.458– 3.565) not having university degree -0.778 0.199 <0.001 0.459 (0.311– 0.678) constant 0.580 0.197 0.003 1.78 legend: se = standard error; ci = confidence interval; lama = left against medical advice. table 4: multivariate analysis (binary logistic regression) predictive of high satisfaction b se p value exp (b) (95% ci) not having university degree -0.632 0.254 0.013 0.531 (0.323– 0.874) lama -4.295 0.524 <0.001 0.014 (0.005– 0.038) having insurance 0.588 0.194 0.003 1.80 (1.229– 2.634) constant 1.160 0.245 <0.001 3.190 legend: se = standard error; ci = confidence interval; lama = left against medical advice. explanation from nursing or physician, and unclear management plan16–20 in our study, younger patients were more concerned than the older ones. this finding is similar to the burroughs study.1 we surmise that the reason for this may be that elderly patients likely have more previous ed experiences and their illness may be less unexpected. in our study, patient concerns were correlated with length of ed stay. however, thompson et al. reported that opinions regarding perceived waiting time rather than actual waiting time were correlated with patient satisfaction.21although the ed length of stay was influenced by factors such as seriousness of illness, overcrowding, and the shortage of ed staff in relation to patient numbers, the probability of medical error occurrence increases with more prolonged ed stays.1 it has been shown that providing the public with ed waiting time information can reduce lengthy ed waiting times.22 concerns about falling from a hospital bed were greater in older patients. this may originate from motor or equilibrium problems in this age group. patient concerns had a direct relationship to educational levels. more educated patient had more complaints and paid more attention to the likelihood of medical errors. patients who were discharged home were less concerned than the others, both on nahid kianmehr, mani mofidi, hossein saidi, marzieh hajibeigi, mahdi rezai clinical and basic research | 91 initial interview and at 7-day follow-up. as patients’ management could be influenced by factors such as the severity of their illnesses, it may have biased the patients’ level of concern. one common concern was the possibility of errors by medical students. a possible solution to this concern would be to inform patients about the advanced capability and sophisticated training which medical students receive before they work in clinical wards, and to underline that all student work is supervised by attending physicians. another way to decrease concerns about student error would be to improve the knowledge and clinical expertise of medical students themselves in order to make them more proficient and self-confident. this is important as two studies found that patients were unwilling to have procedures done by medical students.23,24 worries about medication mistakes have been found to be one of the major and fundamental reasons for patient concern.25 in the current study, the patients were not significantly worried about this error. most errors were due to diminished attention levels occurring during prescribing, dispensing or administering drugs.26 collaboration with the clinical pharmacist can reduced harmful medication error.27 there is a significant relationship between the level of patient concerns and their satisfaction. more satisfied patients were less concerned about medical errors. our results were consistent with previous studies.1,7 according to some studies, expanding patient involvement in medical care, teaching physicians about error disclosure techniques, and honesty and compassion were effective and valuable ways to avoid medical errors and increase patient satisfaction.28–31 although informing patients about the nature and origin of medical errors is valuable, it is not possible in a stressful environments like ed. regarding the influence of background anxieties on satisfaction in a majority of patients admitted to eds,32 a timely recognition of their situation is mandatory. although our study has valuable results about types of concerns, our suggestion is to repeat the study in other university hospital eds, community, or private hospitals to compare the results for patients with different illnesses. personal characteristics such as psychological, emotional and social factors, which were not considered in this study, could influence the level of patients’ concerns. proper attention to these factors in future studies and also to other clinical situations may further define the factors contributing to patient concerns about medical errors. conclusion recognition of patient concerns and addressing them in a timely fashion appear to be an effective strategy for improving patient safety and satisfaction. c o n f l i c t o f i n t e r e s t the authors declared no conflict of interest references 1. burroughs te, waterman ad, gallagher th, waterman b, adams d, jeffe db, et al. patient concerns about medical errors in emergency departments. acad emerg med 2005; 12:57−64. 2. taylor tb. threats to the health care safety net. acad emerg med 2001; 8:1080−7. 3. velianoff gd. overcrowding and diversion in the emergency department: the health care safety net unravels. nurs clin north am 2002; 37:59−66. 4. risser dt, rice mm, salisbury ml, simon r, jay gd, berns sd. the potential for improved teamwork to reduce medical errors in the emergency department. ann emerg med 1999; 34:373−83. 5. national patient safety foundation. patient safety: your role in making healthcare safer. chicago, il: national patient safety foundation, 2002. 6. the kaiser family foundation/ agency for healthcare research and quality. national survey on americans as health care consumers: an update on the role of quality information. washington, dc: agency for healthcare research and quality, dec 2000. 7. burroughs te, waterman ad, gallagher th, waterman b, jeffe db, dunagan wc, et al. patients’ concerns about medical errors during hospitalization. jt comm j qual patient saf 2007; 33:5−14. 8. hickson gb, clayton ew, githens pb, sloan fa. factors that prompted families to file medical malpractice claims following perinatal injuries. jama 1992; 267:1359−63. 9. levinson w, roter dl, mullooly jp, dull vt, frankel rm, et al. physician-patient communication: the relationship with malpractice claims among primary care physicians and surgeons. jama 1997; 277:553−9. 10. schenkel s. promoting patient safety and prevention error in emergency department. acad emerg med 2000; 7:1204−22. 11. thiagarajan rr, bird gl, harrington k, charpie what are patients’ concerns about medical errors in an emergency department? 92 | squ medical journal, february 2012, volume 12, issue 1 jr, ohye rc, steven jm, et al. improving safety for children with cardiac disease, cardiol young 2007;17:127−32. 12. hedges jr, trout a, magnusson ar. satisfied patients exiting the emergency department (speed) study. acad emerg med 2002; 9:15−21. 13. sun bc, adams jg, burstin hr. validating a model of patient satisfaction withemergency care. ann emerg med 2001; 38:527−32. 14. trout a, magnusson ar, hedges jr. patient satisfaction investigations and the emergency department: what does the literature say? acad emerg med 2000; 7:695−709. 15. byrne g, heyman r. patient anxiety in the accident and emergency department. j clin nurs 1997; 6:289−95. 16. boudreaux ed, frieman j, chansky me, baumann bm. emergency department patient satisfaction: examining the role of acuity. acad emerg med 2004; 11:162−8. 17. boudreaux ed, o'hea el. patient satisfaction in the emergency department: a review of the literature and implications for practice. j emerg med 2004; 26:13−26. 18. aragon sj, gesell sb. a patient satisfaction theory and its robustness across gender in emergency departments: a multigroup structural equation modeling investigation. am j med qual 2004; 18:229−41. 19. arendt kw, sadosty at, weaver al, brent cr, boie et. the left-without-being-seen patients: what would keep them from leaving? ann emerg med 2003; 42:317−23. 20. sun bc, burstin hr, brennan ta. predictors and outcomes of frequent emergency department users. acad emerg med 2004; 10:320−8. 21. thompson da, yarnold pr, williams dr, adams sl. effects of actual waiting time, perceived waiting time, information delivery, and expressive quality on patient satisfaction in the emergency department. ann emerg med 1996; 28:657−65. 22. xie b, youash s. the effects of publishing emergency department wait time on patient utilization patterns in a community with two emergency department sites: a retrospective, quasi-experiment design. int j emerg med 2011; 4:29. 23. graber ma, pierre j, charlton m. patient opinions and attitudes toward medical student procedures in the emergency department. acad emerg med 2003; 10:1329−33. 24. graber ma, wyatt c, kasparek l, xu y. does simulator training for medical students change patient opinions and attitudes toward medical student procedures in the emergency department? acad emerg med 2005; 12:635−9. 25. jenkins g, johnston pe, patel nr, jones i, aronsky d. the epidemiology of medication prescribing errors in the emergency department. amia annu symp proc 2006:968. 26. nichols p, copeland t, craib i, hopkins p, bruce dg. learning from error: identifying contributory causes of medication errors in an australian hospital. med j aust 2008; 188:276−9. 27. rothschild j, churchill w, erickson a, munz k, schuur jd, salzberg ca, et al. medication errors recovered by emergency department pharmacists. ann emerg med 2010; 55:513−21. 28. hobgood c, peck cr, gilbert b, chappell k, zou b. medical errors what and when: what do patients want to know? acad emerg med 2002; 9:1156−61. 29. greenfield s, kaplan s, ware je. expanding patient involvement in care. effects on patient outcomes. ann intern med 1985; 102:520−8. 30. benbassat j, pilpel d, tidhar m. patients' preferences for participation in clinical decision making: a review of published surveys. behav med 1998; 24:81−8. 31. hoffmann b, rohe j. patient safety and error management. dtsch arztebl int 2010; 107:92−9. 32. nirenberg td, baird j, harrington m, mello mj, woolard r, longabaugh r. a cross sectional study of the self-report of stress among emergency department patients. j emerg trauma shock 2009; 2:155−8. clinical & basic research squ med j, may 2011, vol. 11, iss. 2, pp. 236-244, epub. 15th may 11 submitted 5th dec 10 revision req. 12th jan & 2nd mar 11, revision recd. 23rd jan & 8th mar 11 accepted 16th mar 11 1biomolecular sciences, faculty of health & life sciences, coventry university, coventry, uk; 2department of physiology, sultan qaboos university hospital, muscat, oman; 3dept. of medical & social care education, leicester medical school, university of leicester, leicester, uk. *corresponding author email: apx301@coventry.ac.uk <îéüq<g◊œ<ó◊¬<∞qêöçè7]<çèjë2“<á^∆<l]4m`i ÿêà√⁄ê<îêü⁄       p < 0.0510– 3 p < 0.001p < 0.05 katp p < 0.00189hp < 0.001 p < 0.001 p < 0.00189h p < 0.01p < 0.05lname   :مفتاح الكلمات abstract: objectives: hydrogen sulphide has been identified as a gas signalling molecule in the body, and has previously been shown to have vasorelaxant properties. the aim of the study was to investigate the effects of sodium hydrosulphide (nahs), a hydrogen sulphide donor, on heart rate (hr), left ventricular developed pressure (lvdp) and coronary flow (cf) in the isolated perfused rat heart. methods: a langendorff isolated heart preparation was used to investigate the effect of a dose range of sodium hydrosulphide, in the presence and absence of inhibitors, on heart rate, left ventricular developed pressure and coronary flow. results: sodium hydrosulphide caused a significant decrease in heart rate at a concentration of 10-3 m (p <0.001). this decrease was partially inhibited by glibenclamide, a katp channel blocker (p <0.05); l-name, a nitric oxide synthase inhibitor (p <0.001), and methylene blue (p <0.001), but not by h-89, a protein kinase a inhibitor. sodium hydrosulphide significantly increased coronary flow at concentrations of 10-4 – 10-3m (p <0.05). this response was significantly increased in the presence of l-name (p <0.001) and methylene blue (p <0.001), whereas h-89 inhibited the increase in coronary flow due to sodium hydrosulphide (p <0.001). sodium hydrosulphide significantly decreased lvdp at all concentrations (p <0.001). in the presence of glibenclamide and h-89, the time period of the decrease in lvdp due to sodium hydrosulphide was extended (p <0.001), whereas methylene blue and l-name caused a significant reduction in the response to sodium hydrosulphide (p <0.05, p <0.01 respectively). conclusion: sodium hydrosulphide reduced heart rate and lvdp, and increased coronary flow in the isolated perfused rat heart; however, the mechanisms of action could not be fully elucidated. keywords: hydrogen sulphide; heart; langendorff; h2s gasotransmitter; vasorelaxation effects of hydrogen sulphide on the isolated perfused rat heart *afthab hussain,1 helen maddock,1 hajar al-rajaibi,2 ray j carson3 advances in knowledge 1. this study identifies a sodium hydrosulfide dependant decrease in heart rate and left ventricular pressure and an increase in coronary flow. 2. this study also identifies the potential cell signalling pathways via which these physiological changes take place. afthab hussain, helen maddock, hajar al-rajaibi and ray j carson clinical and basic research | 237 it is now well established that hydrogen sulphide (h2s) gas has effects on the heart; however, to date, the cardiovascular effects of both endogenous and exogenous h2s have not been fully elucidated. zhao et al. reported that an intravenous bolus injection of h2s at 2.8 and 14 µmol/kg body weight caused a significant transient decrease in blood pressure in anaesthetised rats, which was partially antagonised by glibenclamide (a potassium adenosine triphosphate [katp] ion channel blocker).1 the heart rate was not significantly affected by h2s injection. an early study on sulphydryl reagents on the isolated perfused guinea-pig heart reported an increase in coronary flow and heart rate.2 geng et al. reported that sodium hydrosulphide (nahs), a h2s donor, inhibited left ventricular developed pressure in the isolated perfused rat heart in a concentration-dependent manner over a range of 10-6–10-3 m.3 however, they found a decrease in heart rate and coronary flow only at a concentration of 10-3 m nahs which was partially inhibited by glibenclamide.3 sun et al. found that nahs impeded contraction of isolated rat cardiomyocytes by inhibiting l-type calcium channels.4 no effects on katp channel currents or on levels of camp (cyclic adenosine monophosphate) or cgmp (cyclic guanosine monophosphate) were found. h2s was found to have a negative chronotropic action on pacemaker cells in the sinoatrial node of rabbit heart, possibly via the opening of katp channels. 5 a number of recent studies have shown that h2s is cardioprotective in myocardial ischaemia and ischaemia-reperfusion injury.6-12 some of these studies found evidence that the cardioprotective mechanism is mediated via the opening of katp channels;7,10,11,13,14 however, it is controversial whether mitochondrial katp channels are involved. 11,13,15 inhibition of nitric oxide production attenuated the cardioprotective effects of nahs, suggesting some synergy between nitric oxide (no) and h2s. 13 there is some evidence that the protein kinase c pathway,15,16 upregulation of cyclooxygenase-217217 or upregulation of heat shock protein 7212 could be involved in cardioprotection. h2s is produced endogenously from the amino acid l-cysteine by two enzymes, cystathionine β-synthase (cbs) and cystathionine γ-lyase (cse). cbs has been shown to have no activity or expression in human cardiovascular related tissues.18,19 conversely, cse expression and endogenous production of h2s have been shown in the rat portal vein, thoracic aorta20 and heart.3,6 the expression of cse has been identified in vascular smooth muscle cells, but not in the endothelium, whereas cbs expression was not detected in vascular tissue.1 there appears to be some similarities between h2s, no and carbon monoxide (co) in terms of their effects, and mechanisms of action and interactions between them have been reported.21hosoki et al. were the first to suggest synergy between h2s and no in relaxing vascular smooth muscle.19 they demonstrated a left-ward shift in the dose-response curve for relaxation of rat thoracic aorta by nahs in the presence of two different no donors, sodium nitroprusside and morpholinosydnonimine. they reported that a low concentration of h2s enhanced the smooth muscle relaxant effect of no by up to 13-fold. however, zhao and wang found that low doses of nahs shifted the dose-response relaxation curve for sodium nitroprusside to the right in rat aortic rings, suggesting that h2s inhibited the vasorelaxant effect of no.22 the primary aim of this study was to investigate the effects of a concentration range of nahs, a h2s donor, on heart rate, left ventricular developed pressure and coronary flow in the isolated perfused rat heart using the langendorff model. methods male sprague-dawley male rats (250–300g body weight) were used in all the experiments. all animals were from the same source, fed a standard diet and housed in the same conditions. all animals received humane care in accordance with the uk guidance on the operation of the animals (scientific procedures) act 1986. animal protocols application to patient care 1. hydrogen sulphide has been identified as a gaseous signalling molecule alongside nitric oxide and carbon monoxide mediating a range of physiological processes. 2. hydrogen sulphide has been shown to abolish the effects seen during myocardial ischaemia reperfusion injury and has the potential of being translated into a clinical setting. effects of hydrogen sulphide on the isolated perfused rat heart 238 | squ medical journal, may 2011, volume 11, issue 2 were approved by the committee of animal care and supply of coventry university, uk. all chemicals were obtained from sigma (poole, uk). the krebs heinseleit buffer contained (mm) nacl 118.5, nahco3 25, kcl 4.8, mgso4 1.2, kh2po4 1.2, cacl2, 1.7, and glucose 12, methylene blue (a guanylate cyclase inhibitor), glibenclamide and h-89 (a protein kinase a inhibitor) were dissolved in dimethyl sulphoxide (dmso) initially and then diluted with a kh buffer. l-nitro-argininemethyl ester (l-name) was dissolved in distilled water. nahs (a h2s donor) was dissolved in a kh buffer. the rate of infusion of agents was 1% of coronary flow to achieve the final concentrations indicated. the animals were killed by cervical dislocation followed by exsanguination. hearts were rapidly excised and placed in ice-cold krebs-heinseleit (kh) buffer solution. the aortic stump was rapidly mounted onto a cannula attached to a standard langendorff set up. hearts were perfused with kh buffer, gassed with 95% o2 5% co2 (ph 7.4) and maintained at 37.5°c. the temperature was constantly monitored by a thermocouple inserted into the right ventricle. a latex balloon was positioned in the left ventricle via an insertion performed in the left atrial appendage and inflated to 5–10 mmhg. the balloon was attached to a pressure transducer connected to a harvard amplifier to determine the left ventricular developed pressure (lvdp). heart rate was monitored via the electrocardiogram (ecg) recorded using electrodes connected to a harvard isolated preamplifier. hearts exhibiting arrhythmia were discarded. readings were taken at 5 min intervals using a thermo array recorder wr7700 (western graphtec, usa). coronary flow was measured at 5 mins intervals by collecting the perfusate draining from the perfused heart over a fixed time period. hearts were allowed to stabilise for 20 mins following mounting on the langendorff set up. hearts were randomly assigned to the following protocols: a) control group (n = 5): hearts were infused using a harvard infusion/withdrawal pump with kh buffer at room temperature without the addition of any agents for 15 minutes at an infusion rate of 0.13 ml/min and allowed to recover for a further 20 mins; b) concentration-effect group: hearts were infused with a range of concentrations of nahs (m) of 10-5 (n = 6), 10-4 (n = 5) and 3x10-3 (n = 5) for a period of 15 minutes, followed by a further 20 minutes of recovery; c) hearts were allowed to stabilise for 20 mins with kh buffer perfusion and were then figure 1a: percent change in heart rate over time due to infusion of sodium hydrosulphide (nahs) (10-3 m) in the presence of glibenclamide (10 µm), h89 (1 µm), methylene blue (10 µm) and l-nitro-arginine-methyl ester (l-name) (10 µm) (mean ± standard error of the mean (sem), n = 5). the initial heart rate in each case was taken as 100%. hearts were infused with the inhibitors for 15 minutes, followed by nahs for 15 minutes and then recovery was monitored for a further 20 minutes. note: ***p <0.001 vs. control; * p <0.05 vs. nahs; ### p <0.001 vs. nahs. figure 1b: percent change in heart rate over time due to infusion of glibenclamide (10 µm), h89 (1 µm), methylene blue (10 µm) and l-nitro-arginine-methyl ester (l-name) (10 µm) (mean ± standard error of the mean (sem), n = 5). the initial heart rate in each case was taken as 100%. hearts were infused with the inhibitors for 35 minutes. h89 alone caused a significant increase in heart rate compared to control (p <0.02). note: * p <0.05 vs. control. afthab hussain, helen maddock, hajar al-rajaibi and ray j carson clinical and basic research | 239 exposed with either 10 µm glibenclamide (n = 5), or 10 µm mb (a guanylate cyclase inhibitor) (n = 5), or 10 µm l-name (n = 5), or 1 µm h-89 (n = 5) for 35 mins; d) hearts were allowed to stabilise for 20 mins with kh buffer and were then exposed to either 10 µm glibenclamide (n = 5), 10 µm mb (n = 5), 10 µm l-name (n = 5) or 1 µm h-89 (n = 5) for 15 minutes. hearts were then exposed to 10-3 m nahs for 15 mins followed by a further 20 mins for recovery. statistical analysis was conducted using the statistical package for the social sciences (spss, version 10.5). data were compared using analysis of covariance (ancova) or one-way analysis of variance (anova) with fisher’s protected least mean squares difference post hoc test. differences were considered significant where p <0.05. all data are expressed as mean ± standard error of the mean (sem). results results are presented as the percentage mean of the stabilisation period. nahs caused a significant decrease in heart rate compared with control at a concentration of 10-3 m (p <0.001) [figure 1a]. this decrease was partially, but significantly, inhibited by glibenclamide (p <0.05), by l-name (p <0.001), and by methylene blue (p <0.001), but not by h-89 [figure 1a]. glibenclamide, l-name and methylene blue alone had no significant effect on heart rate, but h-89 alone caused a significant increase in heart rate compared to control subjects (p = 0.05) [figure 1b]. nahs caused a significant increase in coronary flow compared to control at a concentration of 10-3 m (p <0.05) [figure 2a]. glibenclamide did not block the response to nahs [figure 2a]. h-89 alone caused a significant increase in coronary flow (p <0.001) [figure 2b], but it significantly inhibited the increase in coronary flow due to nahs (p <0.001) [figure 2a]. methylene blue alone had no significant effect on coronary flow, but it significantly augmented the increase due to nahs (p <0.001) [figure 2a]. l-name alone had no significant effect on coronary flow [figure 2b], however l-name with nahs caused a profound, highly significant increase in coronary flow compared to control (p <0.001) and compared to nahs alone (p <0.001) [figure 2b]. nahs significantly decreased lvdp at all concentrations (p <0.001) compared with control (data not shown). glibenclamide did not affect the initial response to nahs, but significantly inhibited the recovery in lvdp following nahs treatment (p figure 2b: percent change in coronary flow above over time due to infusion of glibenclamide, h89, methylene blue and l-nitro-arginine-methyl ester (l-name) (mean ± standard error of the mean (sem), n = 5). the initial coronary flow in each case was taken as 100%. hearts were infused with the inhibitors for 35 minutes. h-89 alone caused a significant increase in coronary artery flow (p <0.001). note: *** p <0.001 vs. control. figure 2a: percent change in coronary flow over time due to infusion of sodium hydrosulphide (nahs) (103 m) in the presence of glibenclamide (10 µm), h89 (1 µm), methylene blue (10 µm) and l-nitro-argininemethyl ester (l-name) (10 µm) (mean ± standard error of the mean (sem), n = 5). the initial coronary flow was taken as 100% in each case. hearts were infused with the inhibitors for 15 minutes, followed by nahs for 15 minutes and then recovery was monitored for a further 20 minutes. note: *** p <0.001 vs. nahs; ### p <0.001 vs. control. effects of hydrogen sulphide on the isolated perfused rat heart 240 | squ medical journal, may 2011, volume 11, issue 2 <0.001) (figure 3a). h-89 alone caused a significant decrease in lvdp over time (p = 0.03) [figure 3b], and h-89 significantly decreased the recovery in lvdp after nahs treatment (p <0.001) [figure 3a]. methylene blue caused a significant reduction in the response to nahs (p <0.05) [figure 3a]. l-name alone caused a significant reduction in lvdp over time (p = 0.03) [figure 3b], but it significantly reduced the effect of nahs on lvdp (p = 0.01) [figure 3a]. discussion the h2s donor nahs caused significant reductions in heart rate and lvdp, but increased coronary flow. the effect on lvdp concurs with the known role of h2s as a muscle relaxant, 1,20,22,23 and suggests that it has a similar effect on cardiac muscle. the effects of nahs on lvdp reported here support the findings of geng et al.3 in a study on isolated rat cardiomyocytes, sun et al. reported that nahs reduced contraction and inhibited l-type calcium channels.4 the vasodilatory effect of h2s in increasing coronary flow agrees with reported effects on peripheral blood vessels in vitro.1,20,22 however, geng et al. reported a decrease in coronary flow in a similar model.3 the negative chronotropic effect on heart rate, which agrees with the findings of geng et al.3 must presumably be due to h2s influencing ion channels and ion currents in the pacemaker cells. xu et al.5 have reported that nahs decreases the rate of pacemaker firing in the sinoatrial node in rabbit. in previous reports of the effects of h2s on the heart in vivo, zhao et al.1 and geng et al.3 reported that an intravenous bolus injection of h2s or nahs caused a significant transient decrease in blood pressure, but the heart rate was not significantly affected. the heart may well respond differently in vivo compared to in vitro. there are probably differences in dose between these experiments and the present study. a crude estimate of the maximum dose range the heart was exposed to in the in vivo experiments of zhao et al. is 4.5 x 10-5 – 2.4 x 10-4 m, assuming a rat body weight of 375 g and a blood volume of 22 ml.1 geng et al. used a dose of 2.8 µmol/kg body weight.3 in the present study, the effect of h2s on heart rate seems to partially involve katp channels, as it was inhibited by glibenclamide. this agrees with the findings of xu et al. who suggested that h2s influences pace maker cell depolarisation by opening katp channels. 5 h2s, acting by opening katp channels, would hyperpolarise the membranes of pacemaker cells, thus reducing their rate of depolarisation and decreasing heart rate. the lack figure 3a: percent change in left ventricular developed pressure (lvdp) over time due to different concentrations of sodium hydrosulphide (nahs) (103 m) in the presence of glibenclamide, h89, methylene blue and l-nitro-arginine-methyl ester (l-name) (mean ± standard error of the mean (sem), n = 5). the initial lvdp was taken as 100% in each case. hearts were infused with the inhibitors for 15 minutes, followed by nahs for 15 minutes and then recovery was monitored for a further 20 minutes. note: *** p <0.001 vs. control; ### p <0.001 vs. nahs; * p <0.05 vs. nahs; ** p <0.01 vs. nahs. figure 3b: percent change in left ventricular developed pressure (lvdp) over time due to infusion of glibenclamide, h89, methylene blue and l-nitroarginine-methyl ester (l-name) (mean ± standard error of the mean (sem), n = 5). the initial lvdp in each case was taken as 100%. hearts were infused with the inhibitors for 35 minutes. note: * p <0.03 vs. control. afthab hussain, helen maddock, hajar al-rajaibi and ray j carson clinical and basic research | 241 of effect of h-89 suggests that h2s is not exerting its negative chronotropic effect via the cyclic adenosine monophosphate/protein kinase a (camp/ pka) pathway. the significant increase in heart rate due to h-89 alone might be due to the fact that h-89 is not very specific in its action of inhibiting pka. alternatively, the normal control of heart rate could involve the (camp/pka) pathway. the effect of l-name and methylene blue in inhibiting the action of h2s in decreasing heart rate suggests that the mechanism involves the stimulation of production of no and the guanylate cyclic guanosine monophosphate (cgmp) pathway. in comparison, kojda et al. found that l-arginine had a positive chronotropic effect in rat heart, whereas methylene blue reduced heart rate.29 h2s has been previously shown to have vasodilatory effects in the rat heart1,20,22 and, in the present study, h2s increased coronary flow in isolated perfused hearts indicating dilation of coronary blood vessels. conversely, geng et al. reported a decrease in coronary flow by nahs in a similar model.3 blockade of katp channels with glibenclamide, in the present study, did not inhibit the vasodilatory effect of h2s, suggesting that the mechanism of action of h2s was not via opening katp channels. this is in contrast to the findings of zhao et al. using peripheral blood vessels.1 h-89 alone significantly increased coronary flow which could be due to its other actions apart from inhibiting pka. however, h-89 inhibited the vasodilatory effect of nahs, suggesting that the mechanism of action of h2s in this case is via the camp/pka pathway. this finding agrees with that of kimura who showed that physiological concentrations of h2s increased the production of cyclic amp in neurones and oocytes in culture.27 methylene blue and l-name both caused a highly significant increase in the vasodilatory effect of nahs, which shows that inhibition of nitric oxide synthesis and signalling via guanylate cyclase augmented the effect of h2s. these findings were reproducible and were highly statistically significant. this suggests that endogenous production of no inhibits the vasodilatory effect of h2s in coronary blood vessels; however, it is well known that no is a vasodilator of coronary blood vessels. zhao et al. showed that l-name, an inhibitor of endogenous no production, significantly shifted the h2s doseresponse relaxation curve to the right, decreasing the potency of h2s, in rat aortic rings, and similar effects were obtained by removing the endothelium from the aortic rings.1 they also showed that the addition of a specific inhibitor of soluble guanylate cyclase, 1 h-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1 one, significantly increased the relaxant effect of h2s; however, synergy between no and h2s has also been reported. hosoki et al., demonstrated a leftward shift in the dose-response curve for relaxation of rat thoracic aorta by nahs in the presence of two different no donors, sodium nitroprusside and morpholinosydnonimine.15 cheung and schulz reported that glutathione and glutathione disulphide caused coronary vasodilation which was mediated by a no and guanylate cyclase-dependent mechanism.26 it is possible, in the current study, that endogenously produced no could stimulate the production of a factor which opposes the actions of h2s. both h-89 and l-name caused a significant reduction in lvdp. the reduction in lvdp by h-89 could be due to effects other than on pka. the depressor effect of l-name would suggest that the maintenance of lvdp requires the production of no, although no is generally known to be a muscle relaxant. it has been previously reported that a no donor spm3672 increased maximal left ventricular pressure in the isolated rat heart and increased levels of cgmp in rat cardiomyocytes.28 the positive inotropic effects of no donors in rat heart have been confirmed by the same group and others.25,26 h-89 extended the time period of the decrease in lvdp following nahs treatment, suggesting that normal recovery involved the camp/pka pathway. l-name and methylene blue significantly inhibited the response to nahs, suggesting that the mechanism of relaxation of cardiac muscle by h2s involves no production and guanylate cyclase. as h2s binds to heme groups, similarly to no, it is possible that guanylate cyclase is a target. glibenclamide did not inhibit the initial depression of lvdp by nahs, suggesting that the mechanism of action did not involve the opening of katp channels. indeed, glibenclamide extended the time period of the depression of lvdp due to nahs and thus inhibited recovery of the heart from nahs treatment. this could be interpreted as an involvement of the opening of katp channels in the recovery from h2s treatment. however, it is unclear how the opening of katp channels and the resultant hyperpolarisation could increase lvdp. effects of hydrogen sulphide on the isolated perfused rat heart 242 | squ medical journal, may 2011, volume 11, issue 2 conclusion nahs, an h2s donor, significantly reduced heart rate and lvdp, and increased coronary flow in the isolated perfused rat heart; however, the mechanisms of action could not be fully elucidated. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g e m e n t s the authors are grateful to mark bodycote and adrian wallen of coventry university, uk, for their expert care of the animals. references 1. zhao w, zhang j, li y, wang r. the vasorelaxant effects of h2s as a novel endogenous katp channel opener. embo j 2001; 20:6008−16. 2. gailis l, nguyen mh. the effect of sulfhydryl reagents on the heart rate and coronary flow of the isolated perfused guinea-pig heart. arch int pharmacodyn ther 1975; 218:19−28. 3. geng b, yang j, qi y, zhao j, pang y, du j, tang c. h2s generated by heart in rat and its effects on cardiac function. biochem biophys res comm 2004; 313:362−8. 4. sun yg, cao yx, wang ww, ma sf, yao t, zhu yc. hydrogen sulphide is an inhibitor of l-type calcium channels and mechanical contraction in rat cardiomyocytes. cardiovasc res 2008; 79:632−41. 5. xu m, wu ym, li q, wang x, he rr. electrophysiological effects of hydrogen sulfide on pacemaker cells in the sinoatrial nodes of rabbits. sheng li xue bao 2008; 60:175−80. 6. zhu yz, wang zj, ho p, loke yy, zhu yc, huang sh, et al. hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats. j appl physiol 2007; 102:261−8. 7. johansen d, ytrehus k, baxter gf. exogenous hydrogen sulfide (h2s) protects against regional myocardial ischemia-reperfusion injury – evidence for a role of katp channels. basic res cardiol 2006; 101:53−60. 8. bian js, yong qc, pan tt, feng zn, ali my, zhou s, et al. role of hydrogen sulfide in the cardioprotection caused by ischemic preconditioning in the rat heart and cardiac myocytes. j pharmacol exp ther 2006; 316:670−8. 9. sivarajah a, mcdonald mc, thiermermann c. the production of hydrogen sulfide limits myocardial ischemia and reperfusion injury and contributes to the cardioprotective effects of preconditioning with endotoxin, but not ischemia in the rat. shock 2006; 26:154−61. 10. rossoni g, sparatore a, tazzari v, manfredi b, del soldato p, berti f. the hydrogen sulphide-releasing derivative of diclofenac protects against ischaemiareperfusion injury in the isolated rabbit heart. br j pharmacol 2008; 153:100−9. 11. ji y, pang qf, xu g, wang l, wang jk, zeng ym. exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemiareperfusion injury. eur j pharmacol 2008; 587:1−7. 12. bliksøen m, kaljusto ml, vaage j, stensløkken ko. effects of hydrogen sulphide on ischaemiareperfusion injury and ischaemic preconditioning in the isolated, perfused rat heart. eur j cardiothorac surg 2008; 34:344−9. 13. pan tt, feng zn, lee sw, moore pk, bian js. endogenous hydrogen sulfide contributes to the cardioprotection by metabolic inhibition preconditioning in the rat ventricular myocytes. j mol cell cardiol 2006; 40:119−30. 14. zhang z, huang h, liu p, tang c, wang j. hydrogen sulfide contributes to cardioprotection during ischemia-reperfusion injury by opening katp channels. can j physiol pharmacol 2007; 85:1248−53. 15. pan tt, neo kl, hu lf, yong qc, bian js. h2s preconditioning-induced pkc activation regulates intracellular calcium-handling in rat cardiomyocytes. am j physiol cell physiol 2008; 294:169−77. 16. hu lf, pan tt, neo kl, yong qc, bian js. cyclooxygenase-2 mediates the delayed cardioprotection induced by hydrogen sulfide preconditioning in isolated rat cardiomyocytes. pflugers arch 2008; 455:971−8. 17. chen p, poddar r, tipa e, dibello po, moravec cd, robinson k, et al. homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease. adv enzyme regul 1999; 39:93−109. 18. bao l, vleck c, paces v, kraus jp. identification and tissue distribution of human cystathionine betasynthase mrna isoforms. arch biochem biophys 1998; 350:95−103. 19. hosoki r, matsiki n, kimura h. the possible role of hydrogen sulphide as an endogenous smooth muscle relaxant in synergy with nitric oxide. biochem biophysic res commun 1997; 237:527−31. 20. warenycia mw, goodwin lr, benishin cg, reiffenstein rj, francom dm, taylor jd, et al. acute hydrogen sulphide poisoning demonstration of selective uptake of sulfide by brainstem by measurement of brain sulfide levels. biochem pharmacol 1989; 38:973−81. 21. goodwin lr, francom d, dieken fp, taylor jd, warenycia mw, reiffenstein rj, et al. determination of sulphide in brain tissue by gas dialysis/ ion chromatography: post mortem studies and two case reports. j analyte toxicol 1989; 13:105−9. afthab hussain, helen maddock, hajar al-rajaibi and ray j carson clinical and basic research | 243 22. carson rj, seyffarth g, mian r, maddock h. interactions between gasotransmitters. in: wang r. ed. signal transduction and the gasotransmitters: no, co and h2s in biology and medicine. totowa: humana press, 2004. pp. 33−55. 23. zhao w, wang r. h2s-induced vasorelaxation and underlying cellular and molecular mechanisms. am j physiol heart circ physiol 2002; 283:474–80. 24. teague b, asiedu s, moore pk. the smooth muscle relaxant effect of hydrogen sulfide in vitro: evidence for a physiological role to control intestinal contractility. brit j pharmacol 2002; 137:139−45. 25. sidhu r, singh m, samir g, carson r.j. l-cysteine and sodium hydrogen sulphide inhibit spontaneous contractility in isolated pregnant rat uterine strips in vitro. pharmacol toxicol 2001; 88:198−203. 26. beauchamp ro, bus js, popp j.a, boreiko cj, andjelkovich d a. a critical review of the literature on hydrogen sulfide toxicity. crit rev toxicol 1984; 13:25−97. 27. kimura h. hydrogen sulfide induces cyclic amp and modulates the nmda receptor. biochem biophys res comm 2000; 267:129−33. 28. kojda g, brixius k, kottenberg k, nix p, schluter kd, piper hm, et al. the new no donor spm3672 increases cgmp and improves contraction in rat cardiomyocytes and isolated heart. eur j pharmacol 1995; 284:315−9. 29. kojda g, kottenberg k,, stasch jp, schror k, noack e. positive inotropic effect of exogenous and endogenous no in hypertrophic rat hearts. br j pharmacol 1997; 122:813−20. abstracts joint sessions and biochemistry and haematology sessions a b s t r a c t s j o i n t s e s s i o n s what is 'a high quality pathology service' when the budget is limited? prof. peter n. furness vice-chair & revalidation lead, academy of medical royal colleges and president, the royal college of pathologists, uk as a result of the impact of the international banking crisis, state-funded pathology services in the uk are currently facing a governmentimposed cut in funding equivalent to 20% of total cost. even before this, we had seen calls for ‘consolidation’ of pathology services into fewer, larger laboratories, to improve efficiency. this process is now being forced forward, with the uk government putting increasing emphasis on the involvement of private companies in what was previously a mainly state-run service. the simultaneous introduction of reorganisation and the introduction of the profit motive are generating great concern and controversy. in this situation, the role of the royal college of pathologists, as a charitable organisation, is to advocate the highest possible standards of pathology service for the benefit of patients. all concerned with these changes claim that the plans that they advocate will maintain or increase ‘quality’, even if resources are cut. they cannot all be right, but how should the quality of a pathology service be measured? pathologists will usually emphasise getting the diagnosis right or producing accurate measurements. clinicians may emphasise speed of delivery of results. managers will emphasize cost and efficiency. commercial organisations emphasise customer satisfaction; but who is the customer, and is the customer sufficiently well informed to decide what should generate such satisfaction? if we consider patient safety, data collected by the uk national patient safety agency show that adverse patient safety incidents in relation to laboratory services almost all occur in getting the specimen to the laboratory and in getting the result to the clinician. how often are these ‘interface’ problems considered when laboratory quality is discussed? ultimately, the only true measure of the quality of a laboratory service is the improvement of patient outcomes that it achieves. but patient outcome is influenced by so many factors that the contribution of the laboratory is impossible to assess; so surrogate measures have to be used. in which case, we need an open discussion of what such markers really assess and which of them are of value. it is clear that any simple method of measuring laboratory quality is likely to be incomplete or simply wrong. identifying the best way to measure quality in pathology is a considerable challenge. persuading all concerned that this really is the best way to measure quality is an even greater challenge. quality assurance and quality management systems in laboratory medicine dr. robby bacchus world association of societies of pathology and laboratory medicine, education secretariat (waspalm), uk the pursuit and concern for quality in health care is an issue that transcends national boundaries. of all the health professions, the laboratory based pathology disciplines have done most and continue to do most to monitor the quality of what they do, and to anticipate and correct sources of analytical error. in addition to recording their performance both within their own departments and as members of peer groups, they educate themselves, their peers and clinical colleagues in an effort to improve the effectiveness of the service they provide, set analytical goals and subject themselves to external proficiency testing. quality assurance is the whole programme squ med j, february 2011, vol. 11, iss. 1, pp. 146-157, epub. 12th feb 11 l]2j~π]<g�÷<í÷êç÷]<ü≥ˆπ]< åáe^œ<·^�◊ä÷]<ì√⁄^q 11-9 نوفمبر 2010 oman international conference on laboratory medicine sultan qaboos university 9 11th november 2010 abstracts of activities mounted by laboratories, regions, countries, professional groups, commercial and industrial companies in an attempt to improve clinical laboratory performance generally. they include: 1) encouragement of the constant use of internal quality control in every laboratory; 2) support for external quality assessment (eqa) schemes; 3) all measures taken to increase within laboratory reproducibility and between-laboratory comparability by means of training courses, conferences and other collaborative activities. these are based on hypotheses derived from internal quality control and from eqa results accumulated over time. there are now growing public demands for accountability, finite fiscal resources, provider resistance or apathy towards changes and an imbalance in the supply and demand equations for health care organisations in today's world. active quality assurance programmes are critical to meet this challenge. research in sickle cell disease, from bench to bedside dr. salam al kindi associate professor, and head, department of haematology, sultan qaboos university hospital, muscat, oman in oman, 5.7% of omani people carry the gene for sickle cell disease (scd) and about 0.2% manifest the disease. although scd is traditionally looked at primarily as a disorder of red cells, it is a disease demonstrating a model for red cell interaction with white cells and endothelial cells. recent work from our laboratory on acute chest syndrome, which is one of the major causes of death in scd and vaso-occlusive crises (voc), the most frequent presentation of this disease, has demonstrated this. an alteration in the level of nitric oxide as well as lymphocytes and monocytes activation play a significant role in both conditions. similarly the sickled red cells, causing perturbed platelet and haemostatic functions, play an important role in stroke development, complicating further the hereditary component of thrombophilia in this syndrome. these changes are promising focii for studies on the various therapeutic interventions that are available for this disease such as hydroxyurea, low molecular weight heparin, nicosan and other agents that are under study in clinical trials. good progress made in reduced intensity conditioning (ric) bone marrow transplant for patients with scd is seen in the recent experience in our centre, enabling the sickled and normal cells to co-exist together and ameliorate symptoms of scd. currently the use of stem cells is in progress to help patients with avascular necrosis of the hips (avn), a crippling complication seen in some of our patients. benefits of accreditation of medical laboratories a global perspective paul stennett chief executive, clinical pathology accreditation (uk) ltd and chief executive of the united kingdom accreditation service, uk this paper covers the accreditation of medical laboratories starting with a detailed review of what the clinical pathology accreditation (cpa) standard assesses during a laboratory visit and some typical outcomes of assessments. it also looks at how to prepare for accreditation, what is involved and an indication of the costs of accreditation. the role of peer assessors in the assessment is also examinded. next, there is a review of the benefits that medical laboratories in the uk have reported in terms of reduced risk and improved quality. to conclude, there is a short preview of how the accreditation standards might be further improved to continue to meet the quality requirements of medical laboratories in the future. the national external qualtiy assurance programme in oman dr. suleiman al busaidi director of laboratories, central public health laboratory, oman the presentation outlines the historical development of the national external quality assessment scheme (neqas) in oman. we will describe the goals and objectives of the program as well as currently available disciplines and future plans for the programme. in this presentation, we will focus on the microbiology scheme since neqas focuses on agents of diseases of public health and clinical importance. we will therefore, also give an overview of how panels are simulated, quality checked, packed and shipped to various participating laboratories as well as the strategic use of results in planning purposes. the evaluation guidelines and the marking scheme will be presented together with some examples of performance of laboratories in some panels. the microbiology scheme covers 26 laboratories including all ministry of health laboratories, other government sister institutions, some private laboratories and four international reference laboratories outside the country. the quality assurance unit prepares the panels which consist of simulated samples as well as instructions for processing and response forms. the simulated specimens are spiked with relevant pathogens and inoculated in appropriate transport media. the specimens are quality checked for contamination and viability before and after dispatch. after passing the quality checking the specimens are packed and dispatched by courier to various participating laboratories. the participating laboratories process the specimens and report the results to the external quality assessment unit at the central public health laboratory within two weeks. a confidential report on the expected results, together with overall performance (including marks obtained), is then issued to each participating laboratory. abstracts | 147 sultan qaboos university 9 11th november 2010 oman international conference on laboratory medicine 148 | squ medical journal, february 2011, volume 11, issue 1 laboratory services in oman – past, present and future dr. nayyar ali head of diagnostic laboratory services, ministry of health, oman the diagnostic laboratory services of the ministry of health have seen rapid development and a dramatic increase in laboratories and staffing. by end of 2009, there were 198 laboratories with a staff of 1,147 and the number of pathologists has increased to 80. there has also been a marked increase in sophistication and modernisation of the service with the introduction of automation to most extended health centres and hospitals. as a result of the increase in the numbers of laboratories, the increase in automation and the general population trends, there has been a significant increase in the numbers of tests done. in 1992 there were just under 6 million tests done. this had increased to 13.8 million by end of 2009. in conclusion, the laboratory service has come a long way in a relatively short time. our aim is to provide the highest quality laboratory services at the lowest possible cost offering a comprehensive diagnostic service relevant to the needs of the people and available close to all communities in the country. therefore, we do recommend the introduction of external quality control, an increase in staff to meet the increased work load and the introduction of new tests at regional hospitals. are we ready to use portfolios as an assessment tool of professional development? dr. arundathi kurukulasuriya senior specialist, department of haematology, royal hospital, oman assessments currently in practice use comparative achievements to place knowledge, skills and attitudes of individual students in a rank, by using grades, test scores and grade percentiles, which are often obtained at summative end of course assessments. they are designed by trainers often with no constructive feedback to the learner. usually, the lower cognitive learning styles, such as memorising and reproducing, are used by the student when preparing for these assessments. portfolios are self portraits of students demonstrating personal development over a period of time, with guidance by the trainers and peers, where the learning is student centered. they foster skills in self evaluation, problem solving, lifelong learning, communication, writing and reflective practice. they promote higher cognitive learning strategies such as application, interpretation and reflection. the portfolio can be also be integrated easily with instruction; however, the guidelines for developing them must be aligned well with the learning outcomes of the course. trainers must also provide guidance and monitor the development of the portfolio in order to avoid the student spending too much time developing it, and neither learning from it nor producing a worthwhile collection of his/her work for assessment. hence it is vital to train the trainers to guide students in portfolio development. oman is in a phase of nation building and need professionals who have been educated by modern educational tools, such as assessment by portfolio, rather than by the archaic summative assessment. a b s t r a c t s b i o c h e m i s t r y s e s s i o n s second and third generation pth assays in secondary hyperparathyroidism worth the upgrade dr. daniel holmes consultant, department of pathology and laboratory medicine, st. paul's hospital, vancouver, canada it is well-known that second generation “intact” pth (ipth) assays have cross-reactivity with c-terminal pth metabolites, often collectively referred to as “7-84pth”. this becomes particularly relevant in patients with chronic kidney disease (ckd) because these fragments accumulate in the plasma. this has led to several companies developing third generation assays variably referred to as “whole pth”, “biointact pth” or “1-84pth”. is the move to a third generation pth assay worth the effort? we have recently performed intact pth, 1-84pth (diasorin liaison), 25(oh)vitd, bone alp, ca, and po4 in a large cohort (~2500) of patients from the canpreddict study. estimated gfr in this cohort was between 14 and 45 ml/min (stage 3 and 4 ckd); none were receiving dialysis at the time of recruitment. relationships between these bone markers and both ipth and 1-84pth will be reviewed. based on this data, we will look at the performance and value of the 1-84pth assay in the setting of non-dialysis-dependent ckd. vitamin d: growing role in medicine dr. meenu kaur specialist biochemist, central public health laboratories, oman vitamin d deficiency has serious health consequences beyond rickets and osteomalacia. evidence from clinical, epidemiological studies and randomised controlled trials shows that vitamin d has a role in prevention of many chronic diseases and its deficiency is associated with an increased risk of several diseases like osteoporosis, autoimmune disorders, diabetes, hypertension, autism, infections and various cancers. more than 200 genes are known to be regulated by 1,25-dihydroxyvitamin d[1,25(oh)2d], the active metabolite of abstracts | 149 sultan qaboos university 9 11th november 2010 vitamin d. the serum concentration of 25-hydroxyvitamin d[25(oh)d] is the indicator of vitamin d nutrition status. although the cut-off value to define vitamin d deficiency remains controversial, the current consensus points to a goal of ensuring the 25(oh)d level of 30-100ng/ml. studies addressing vitamin d deficiency, supplementation and toxicity issues indicate the need to amend the existing advice on vitamin d requirements in all age groups. vitamin d supplementation is also advised for the maternal and child health care. lack of sun exposure is widely accepted as the primary cause of worldwide epidemic of vitamin d deficiency. other causes include dark pigmentation, use of sunscreens, skin covering, obesity, old age, insufficient dietary intake, malabsorption and certain medications. sunlight exposure, food fortification and supplementation with vitamin d are effective in preventing and treating vitamin d deficiency. monitoring 25(oh)d levels in patients receiving high doses helps to guard against toxicity. standardisation of endocrine assays dr. catherine m. sturgeon clinical biochemist, royal infirmary of edinburgh, uk high quality health care provision encourages the development of evidence-based guidelines, many of which include recommendations about laboratory testing. for some tests, analyte concentrations that define the need for clinical intervention are specified (e.g. parathyroid hormone in chronic kidney disease), this commendable drive to improve comparability in clinical practice will only succeed if the analytical results on which these recommendations depend are properly standardised. improving between-method comparability is particularly challenging in immunoassays. difficulties encountered generally reflect the characteristics of particular analytes, contributory factors include errors of calibration, antibody selection, assay design and properties of the assay matrix. the lack of established international standards for some analytes is also problematic. it is interesting to consider how these factors influence between-method comparability for several representative analytes, together with some of the international initiates addressing these issues. achieving comparability of results for analytes with well-defined structures should, in theory, be possible. however, despite the availability of highly purified analyte preparations, isotope-dilution gas chromatography-mass spectrometry (id-gcms), reference methods and reference laboratories, poor comparability of results for these analytes is still regularly demonstrated in external quality assessment (eqa) schemes. while short incubation times and absence of automated extraction steps probably also contribute, isotope dilution gas chromatography-mass spectrometry (id-gc-ms) targeting exercises confirm that poor assay calibration is responsible for much of the poor agreement observed. id-gcms methods may ultimately replace immunoassay of steroids in the routine hospital laboratory. in the meantime, encouraging manufacturers to use the available reference measurement systems to assess and improve their assays is a major priority that is being actively addressed. establishing internationally recognized reference panels of patient sera and assigning these id-gc-ms target values, as has been done for cortisol under the auspices of the international federation of clinical chemistry (ifcc), should also help to encourage between-method comparability. while the same factors that contribute to poor between-method agreement for the steroid hormones are relevant to molecularly heterogeneous analytes such as the peptide hormones, the relative importance of these factors differs. eqa data demonstrate coefficients of variation of >10% for luteinizing hormone (lh), follicle stimulating hormone (fsh), human chorionic gonadotrophin (hcg) and prolactin, but incorrect assay calibration does not appear to be the major cause of poor between-method agreement for these analytes. this suggests that while correct calibration is essential for improved method comparability, antibody specificity and assay design are also of considerable importance. addressing these requires knowledge both of what present assays are measuring and of what is clinically desirable to measure. in a prototype ifcc project, highly purified international reference reagents for six important hcg-related molecules have been prepared and calibrated in molar units. their primary purpose initially is to assist manufacturers and users alike in characterising what current hcg assays are measuring. by combining the results of such studies with those of antibody-mapping studies carried out by the international society of oncology and biomarkers (isobm), broad recommendations have been made regarding hcg antibody combinations likely to be most appropriate for particular clinical applications. assessing results obtained for panels of patient sera should now permit validation of the predictions made. this two pronged approach with hcg, aimed both at standardising antibody specificity and improving the accuracy of calibration, may serve as a model for a broad strategic approach to improve between-method comparability of other molecularly heterogeneous analytes, and hence their clinical utility. tumour marker guidelines dr. catherine m. sturgeon clinical biochemist, royal infirmary of edinburgh, uk increasing pressure to provide health care based on “best practice” has stimulated the development of guidelines in cancer medicine. the recommendations of the american society of clinical oncology (asco) and the national comprehensive cancer network (nccn) have recently been complemented by more detailed guidelines from the national academy of clinical biochemistry (nacb) in the united states and the european group for tumor markers (egtm) which provides a more laboratory-oriented perspective. in the pre-analytical phase, as well as ensuring the integrity of specimen collection and identity, and maintaining awareness of the effect of treatment or other conditions that may influence interpretation, the laboratory can encourage appropriate test requesting by promoting the recommendations made by the nacb for fifteen major cancer types. the nacb and egtm guidelines also include detailed recommendations for best practice in the analytical phase, where well validated methods, rigorous internal quality control (iqc) procedures and participation in well-designed external quality assessment (eqa) schemes are all essential. excellent precision and reproducibility (intra-assay variability <5%; inter-assay variability <10%) are important especially at concentrations close to critical clinical decision points, as is long-term assay stability. awareness of clinically relevant interferences is highly desirable, with active dialogue between laboratory and clinical staff facilitating early identification of erroneous results. in the post-analytical phase, laboratory oman international conference on laboratory medicine 150 | squ medical journal, february 2011, volume 11, issue 1 reports should include fully cumulated results, an appropriate reference interval and the name of the assay method used, together with an indication of whether any change in marker level is significant and whether any change of method is likely to have affected interpretation of the trend in marker level. laboratories should also undertake on-going audit of the clinical utility of the tumor marker results, linking this with clinical outcome. freelight chain utility in clinical practice dr. david nkansa-dwamena clinical biochemist, squh, oman the serum immunoglobulin-free light chain assay measures levels of free kappa and lambda immunoglobulin light chains. the international myeloma working group guidelines recommend the use of free light chain assays in the evaluation and management of multiple myeloma and related plasma cell disorders for screening, prognosis, monitoring response in patients with oligosecretory plasma cell disorders and assessment of stringent response in all patients who achieve complete response. the urinary immunoglobulin free light chain test is not recommended for monitoring patients. the free light chain assay has technical limitations which makes its use as a serial measurement potentially problematic. wilson's disease: a treatable inherited disorder pathogenesis & diagnosis dr. arunodaya r. gujjar associate professor of neurology, department of medicine, sultan qaboos university, oman wilson’s disease (wd) is an autosomal recessive disorder of copper metabolism with protean manifestations, with a prevalence of 12–29 cases per million. it occurs due to mutations in the atp7b gene, which codes for a membrane bound copper transporting atpase protein. the mutant gene impairs biliary copper excretion, leading to excessive copper accumulation in the body, particularly in liver, brain, and musculoskeletal tissues. the clinical manifestations of wd are varied and its diagnosis challenging. in a study of 282 cases of wd (male:female ratio, 196:86) followed up over about three decades, clinical presentations were: hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and ‘‘presymptomatic,’’ 15 (5.3%). wd is known to cause hepatic disease at an earlier age (first decade) and neuropsychiatric or osseomuscular manifestations later (early second decade). most patients would have symptoms for several months before diagnosis. predominant neurologic features are: parkinsonism, dystonia, cerebellar ataxia, pyramidal signs, choreoathetosis, myoclonus and behavioral abnormalities. hepatic dysfunction may range from fulminant hepatitis to indolent cirrhosis. kayser-fleischer (kf) rings which are diagnostic of wd, are evident in almost all patients with neuropsychiatric manifestations and more than 80% of those with others. positive family history is present in half the patients. serum ceruloplasmin was decreased in >90% and 24-hour urinary copper excretion is increased in >65% of patients. these are used as common diagnostic tests in the appropriate clinical context, while the gold standard is liver biopsy with quantitative copper assay. most patients with neuropsychiatric manifestations have changes in ct or mri scans of the brain, typically involving the basal ganglia. d-penicillamine or trientene, which are chelating agents, and zinc sulphate, which blocks intestinal copper absorption, are the common therapeutic agents. diligent treatment can result in meaningful improvement in more than 70% of patients. poor follow-up often leads to progression or relapse. advances in treatment such as liver transplantation or gene therapy may improve the outcomes in near future. wd is now a treatable inherited disorder, mandating early diagnosis and diligent management. proteinuria: current trends in detection and monitoring dr. waad-allah s. mula-abed consultant, clinical biochemistry, royal hospital, oman measurement of proteinuria is a traditional and established test for kidney injury. it facilitates risk stratification and appropriate management of patients with chronic kidney disease identified based on estimated glomerular filtration rate (egfr) that will prompt early referral and initiation of renal protective therapy. testing for proteinuria or albuminuria in at-risk groups has been recommended by many international guidelines. measurement based on reagent strips is accompanied with many pitfalls and should be abandoned in favour of laboratory measurements reflected as urine protein or albumin concentration as a ratio to urinary creatinine. methods for total protein are more sensitive to albumin, having poor precision at low concentrations, being insensitive, non-specific and subject to a range of false-positive and false-negative problems. urinary albumin measurement provides a quantitative, relatively standardised measurement for the loss of an important single protein in most nephropathies. it is widely accepted as the test of choice for the detection of diabetic nephropathy that is commonly requested by physicians, although total protein measurement continues to be used by specialists investigating kidney disease particularly in non-diabetics. the use of urine albumin measurement as a front-line test for proteinuria appears to offer the best chance of improving the sensitivity, quality and consistency to the early detection and management of kidney disease. abstracts | 151 sultan qaboos university 9 11th november 2010 external qualtiy assessment dr. catherine m. sturgeon uk national external quality assessment service (neqas) [edinburgh], department of clinical biochemistry, royal infirmary, edinburgh the primary function of an external quality assessment (eqa) service must always be to provide each participating laboratory with an objective assessment of its own performance, enabling comparison with that of other laboratories. data from eqa schemes influence laboratory decisions when considering changes of method, particularly for complex analytes such as tumour markers and the glycoprotein hormones. increasingly, data generated by eqa schemes inform the strategic decisions of professional organisations, including those involved in setting standards for laboratory accreditation, those working to improve analytical standardisation and comparability of clinical results for specific analytes (e.g. the international federation of clinical chemistry) and those specifying quality requirements for health programmes (e.g. the national health service prostate cancer risk management programme in the united kingdom and the kidney disease: improving global outcomes (kdogi) initiative in the united states). such reliance on eqa data places a considerable responsibility on eqa providers to ensure that specimens distributed are appropriate, i.e. as similar as possible to patient specimens and of clinically relevant concentrations. the validity of target values (usually trimmed consensus means) should also be regularly confirmed, by assessing recovery of international standards, by assessing linearity on dilution, and by determining their reproducibility on repeat distribution of the same pool. assessment of long-term assay stability is particularly important for tumour markers. experience suggests that major factors contributing to between-method differences in results include errors in calibration, differences in antibody specificity, and method design. between-method agreement has improved for some analytes, including prostate specific antigen (psa), for which between-method coefficients of variation in the uk national external quality assessment scheme for psa have fallen from 21.9% to 9.5% following the widespread adoption of international standard 96/670 for psa and highly commendable efforts by diagnostic companies to calibrate their psa methods accurately in terms of this standard. however there are still significant method-related differences in results for many other analytes. attention to method design is also required, e.g. to achieve equimolarity of recognition of different isoforms where relevant (as is desirable for complexed and free psa and for hcg and its free beta-subunit) and to minimise the risk of clinically relevant interferences (e.g. heterophilic antibodies and high dose hooking). through occasional issue of ‘special’ eqa samples designed to probe these potential pitfalls, aspects that need to be addressed, e.g. better blocking in vulnerable methods or protocols to identify hooking in some laboratories can be highlighted to manufacturers and users. this essentially educational remit of eqa can be further extended beyond the monitoring of analytical performance to incorporate assessment of other aspects of laboratory provision. in the pre-analytical phase, eqa surveys of practice provide a means of assessing the quality of advice given by participants to clinical users about test requesting. interpretative exercises in which participants are asked to interpret their eqa results in the context of a given clinical history enable assessment of post-analytical advice including reference intervals, recommendations for further testing and interpretative comments. disorders of aldosterone dr. daniel holmes consultant, department of pathology and laboratory medicine, st. paul's hospital, vancouver, canada the laboratory serves as the main diagnostic tool for screening, diagnosis and tumour localisation in patients with primary aldosteronism. since aldosterone and plasma renin activity (pra) methods demonstrate such wide inter-method bias, appropriate aldosterone, pra and aldosterone:pra ratio thresholds need to be established at each laboratory. these cannot be taken from literature without careful comparison of methods. appropriate use of screening tests will be reviewed along with the use and interpretation of provocative diagnostic tests. strategies for successful analysis and useful reporting of samples taken from selective venous sampling of the adrenal veins will be reviewed. paediatric growth hormone disorders dr. aisha al-sinani paediatric endocrinologist, royal hospital, oman growth assessment is essential in child care and short stature can be recognised only with prompt history and accurate measurements of growth data. the hallmark of endocrine disease is linear growth failure that occurs to a greater degree than weight loss. there are three key diagnostic features of growth hormone disorders (ghd): abnormal growth demonstrated by auxological evidence of height < -2 sd, subnormal growth velocity and low gh in response to two dynamic tests. primary insulin-like growth factor (igf) deficiency can be missed as constitutional short stature if the dynamic stimulation is not interpreted cautiously. measurement of igf-1 and igfbp-3 can be performed in our laboratory at the royal hospital, which is helping us to establish a diagnosis in igf deficiency. unfortunately, genetic analysis for growth hormone receptor genes is not available; it is recommended for those patients with access to laboratories expert in these techniques. oman international conference on laboratory medicine 152 | squ medical journal, february 2011, volume 11, issue 1 vitamin b12 – insight dr. manal al-kindi chemical pathologist, royal hospital, oman serum b12 remains the most common vitamin investigation in clinical practice, it included in investigations of patients who present with symptoms of anaemia, glossitis or neurological dysfunction. vitamin b12 acts as a cofactor for enzyme that catalyses methyl group transfer.this includes dna methylation and the conversion of homocysteine to methionine. b12 is transported in blood predominantly bound to heptocorrin and smaller amount transported by transcobalamin. only b12 carried by transcobalamin is available for cellular uptake and hence it is consider physiologically relevant. understanding the pathophysiology of b12 and the different causes of b12 deficiency helps in solving the challenges in medical diagnosis and management. biochemical tests for diagnosis of b12 deficiency, including total serum b12, holotranscobalamin, intrinsic factor antibodies and homocysteine, will be discussed in the presentation. lack of standardisation in b12 assay results in a wide variation in b12 results between different laboratories. in addition different laboratories use different methods, report in different units and use different reference intervals making the use of the serum total b12 test alone to diagnose b12 deficiency of limited value. a b s t r a c t s h a e m at o l o g y s e s s i o n s bone marrow transplantation in thalassaemia – how can we improve outcome? prof. alok srivastava professor of medicine, head, department of haematology & centre for stem cell research, christian medical college, vellore, india allogeneic bone marrow transplantation (bmt) is the only currently established way to cure beta thalassaemia major and other severe haemoglobinopathies. the rate of success of bmt in these patients has been traditionally correlated with their risk stratification based on the extent of liver damage prior to bmt as assessed by the adequacy of chelation (whether started within 2 years of first transfusion), degree of hepatomegaly (³ 3 cm) and presence or absence of fibrosis on liver biopsy. the long term event free survival for class i patients (least risk) is over 90%; for class ii patients (intermediate risk) ~85% and for class iii patients (high risk) ~60%. the causes of failure of bmt, particularly in class iii patients, are mostly related to two major categories of complications – regimen related toxicities and immunological problems such as graft versus host disease (gvhd) or graft rejection. our work over last few years has been directed at understanding their biological basis and finding ways to mitigate them. we have extensively evaluated the pharmacokinetics of busulfan and cyclophosphamide, (balasubramaniam et al., 1999) assessed their genetic basis and correlated them with clinical outcomes (srivastava et al., 2004; chandy et al., 2005). we have recognized that our class iii patients can be further classified into those who are at extremely high risk of failure of treatment. (mathews et al., 2007). we are now able to dose adjust busulfan doses based on the first dose kinetics of the individual. we are also attempting to use newer conditioning regimens in these patients. we have also evaluated the immunological aspects of gvhd and graft rejection and shown the role of dendritic cells and natural killer cells in these events. (rajasekar et al., 2009, 2010). laboratory aspects of bone marrow transplantation dr. david dennison senior consultant and director bmt, sultan qaboos university hospital, oman haematopoietic stem cell transplantation has advanced considerably over the last four decades to provide curative therapy for patients with a wide range of disorders. the success of any transplant program is dependent upon high quality laboratory support with both basic and specialised services. a transplant program linked to a busy multispecialty hospital has the advantage that the four basic laboratory disciplines of haematology, biochemistry, microbiology and histopathology should be already well-established and can provide the routine services required for the transplant patient. the technology and expertise within these laboratories need to be enhanced over time to cope with the development of the transplant programme. rapid viral diagnostics and expertise in the histopathology of graft versus host disease are some examples. the haematology laboratory is unique for the spectrum of support it provides for a transplant programme. in centres worldwide, the haematology laboratory services could range from routine blood counts and peripheral smear examinations to immunomagnetic t-cell depletion or cd34 selection in haploidentical transplants, dna fingerprinting for chimerism and sophisticated techniques for the detection of minimal residual disease following haematopoietic stem cell transplantation for malignant disorders. the laboratory aspects of haematopoietic stem cell transplantation are diverse. a successful transplant program needs a well-coordinated basic and specialized laboratory support. finally, the interaction of the transplant clinician and the biomedical scientist is important for growth and development of any transplant service. abstracts | 153 sultan qaboos university 9 11th november 2010 the incidence of alloimmunisation in the omani sickle cell disease patients undergoing red cell exchange transfusion dr. sulayma al lamki senior consultant, haematology, royal hospital, oman patients with sickle cell disease (scd) require several transfusions in their life time and hence are prone to develop multiple antibodies. the incidence of alloimmunization among such patients varies in different countries. we analysed patients with scd in our centre who had exchange transfusions between december 2001 and may 2007. the incidence of alloimmunisation was 14.5%, and 75% of these patients had developed only one antibody. the most frequently observed alloantibody was anti k followed by anti c and anti e. these findings are similar to the data observed internationally. clinical transplantation of stem cell research – the way forward prof. alok srivastava professor of medicine, head, department of haematology & centre for stem cell research, christian medical college, vellore, india the last decade has seen major advances in our understanding of the biology of embryonic (esc) and adult stem cells (asc). what has evolved more recently is our ability to differentiate them ex-vivo into cells, tissues and potentially organs of our interest. however, considerable controversy exists with regard to the source of esc. the science of differentiating them into therapeutically relevant cells also needs to develop further. finally, ways will need to be found to overcome the immunological barriers after transplantation. therefore, much effort has also being directed towards identifying, characterising and expanding adult stem cells from different organs. many organ specific stem cells are also being evaluated for the treatment of several degenerative disorders. this has led to the development of a whole new science that has been termed regenerative medicine. the recently recognised immunomodulatory properties of mesenchymal stem cells have also opened new possibilities of their use for tolerance-induction in organ transplantation and treatment of other disorders associated with immune dysfunction. in the last few years, there has been tremendous excitement around the potential of reprogramming adult stem cells by introducing certain critical transcription factors that confer to them the property of pluripotent differentiation similar to embryonal stem cells. these have been called induced pluripotent stem cells. the science of these cells is rapidly evolving and holds tremendous promise for regenerative medicine. however, as we tread this path to developing stem cell therapies, it is critical that we understand that none of these potential applications, apart from hsc transplants for haematological diseases, has reached the status of being widely offered as standard therapy at present. their safety and efficacy need to be assessed in preclinical models and clinical trials. offering such therapies at this time, therefore, through advertised services that give the impression of efficacy beyond what is established is wrong. the scientific and medical community and indeed the regulatory authorities in every country need to guard against such exploitation of vulnerable patients. apart from potential harm to the individual, this approach will bring disrepute to science in the long run. the international society for stem cell research (isscr) has developed guidelines (http://www.isscr.org/clinical_trans/pdfs/isscrglclinicaltrans.pdf ) for clinical translation of stem cell research as well as a website to provide appropriate information to patients (http://www.isscr.org/about/stem_cell_ treatments.htm). while the path may seem long and difficult, we need to remain positive and persevere to develop these therapies in an ethical and scientific manner. polychromatic flow cytometry in the clinical laboratory prof. brent wood pirector, haematopathology laboratory, department of laboratory medicine, university of washington, seattle, usa multicolour flow cytometry has become a routine method for the multiparametric analysis of cellular populations in both the research and clinical laboratories. the advent of clinical instruments that allow for the routine analysis of up to 10 simultaneous fluorochromes is rapidly transforming clinical flow cytometry and offers a number of advantages including: improved assignment of cell lineage and maturational stage, more definitive assessment of immunophenotypic abnormality, increased laboratory efficiency and the ability to acquire large numbers of events, and ultimately standardisation of diagnostic approach. the increased degree of technical complexity of instrumentation and reagents, as well as decreased sensitivity for the simultaneous detection of multiple antigens on the same cell population for certain fluorochrome pairs, are the principle disadvantages. while it is now possible to generate reliably high-level multiparametric data, software tools to allow for the efficient and optimal use of this increased level of information have lagged behind and are now a primary focus of technology development. this talk will discuss technical details required for the successful performance of high-level multicolor flow cytometry, approaches under development for the analysis of multiparametric data in a clinical context, and recent technological advances likely to impact the field in the near future. the molecular diagnosis of haematological disorders mr. shoaib al zadjali senior scientist, department of haematology, sultan qaboos university hospital over the lst decades nucleic acid-based molecular diagnostic procedures have evolved astoundingly from the time-consuming laborintensive southern/northern blot technology to cost-effective high throughput methodologies. this was made possible with the advent oman international conference on laboratory medicine 154 | squ medical journal, february 2011, volume 11, issue 1 of polymerase chain reaction (pcr) technology which allowed unlimited supply of target nucleic acid molecules. pcr-based diagnostic analysis (pcr-rflp, allele-specific pcr, gene dosage, genescan, dna sequencing, quantitative pcr and mlpa) are endowed with very high sensitivity, specificity and versatility. after an initial period of research and development, followed by quality assurance, the department of haematology of sultan qaboos university hospital spearheaded the application of these technologies to a variety of inherited or acquired haematological disorders which include notably: chronic myeloid leukaemia (cml), acute lymphoblastic leukaemia (all), acute promyelocytic leukaemia (apl), myeloproliferative disorders, chimerism studies following bone marrow transplantation and haemoglobinopathies. given the high rate of consanguinity of our society, further complicated by the genetic complexity of inherited disorders, a constant research component in designing/updating our diagnostic strategy was mandatory in order to translate them from bench to bed side. such achievements were possible thanks to the fruitful and close interactions among the staff of the department at all levels. leukaemia stem cells in acute myeloid leukemia: implications for therapy and potential targeting strategies dr. adhra al mawali chief of medical laboratory science, department of haematology and blood transfusion, royal hospital, muscat, oman a better understanding of leukaemic stem cells and molecular biology will lead to more effective therapies for leukaemic diseases. malignant stem cells have been identified in acute myelogenous leukaemia, chronic myeloid leukaemia and some types of acute lymphoblastic leukaemia. like normal stem cells, these leukaemic stem cells (lscs) are able to self-renew, differentiate, and proliferate extensively. evidence suggests that lscs are critical for the initiation and perpetuation of leukaemic disease. leukemia contains a subpopulation of cells that display characteristics of stem cells. these cells maintain tumour growth. the properties of lsc indicate that current conventional chemotherapy, directed against the bulk of the tumour, will not be effective. lsc are quiescent and do not respond to cell cycle-specific cytotoxic agents used to treat leukaemia and thus contribute to treatment failure. new strategies are required that specifically target this malignant stem cell population. lscs are likely responsible for disease relapse and therefore represent an ideal target for effective therapy. further characterisation of lscs, using molecular and immunological techniques, is required to develop such therapies and monitor disease before relapse. lscs are reported to over express the alpha subunit of the il-3 receptor (cd123) compared to normal cd34+/cd38haematopoietic stem cells, however, it has not been demonstrated whether the cd123 positive (cd34+/cd38-) subpopulation is enriched for any clonal markers of aml or any lsc properties. in our study, using five-colour flow cytometry, we confirm significant expression of cd123 in 32 /34 cases in the total blast population (median expression = 86%). cd123 was also strongly expressed in the cd34+/cd38cells (96 ± 2% positive) from 28/32 primary positive specimens for cd123 taken from consecutive cases of adult aml at our institution. cd123 was not expressed/low in normal bone marrow cd34+/cd38cells (median expression = 0%, range (0-.004%). samples were tested for the presence of fms-like tyrosine kinase 3 (flt3) internal tandem duplication (itd) by pcr as a tracking marker for leukaemic clones (10 positive /25). flt3/itd positive aml samples were sorted into two putative lsc populations according to the expression of cd123 and then analysed for the presence of flt3/itd. interestingly, flt3/itd was only detected in the cd34+/cd38-/cd123+ (7/7) and not in the cd34+/cd38-/cd123subpopulation (6/7). these results suggest cd123 immunoprofiling provides further delineation of the flt3 positive leukaemic stem cell clone and maybe useful to combine with cd34 and cd38 markers in tracking residual and relapsed disease at the level of the lsc. combinational therapy targeting both cd123 and flt3 in this population may result in more effective anti-lsc eradication. detection of minimal residual disease in paediatric acute lymphoblastic leukaemia prof. brent wood director, haematopathology laboratory, department of laboratory medicine, university of washington, seattle, usa minimal residual disease (mrd) detection is increasingly recognised as an important prognostic factor for patients with pediatric precursor b cell lymphoblastic leukaemia/lymphoma (acute lymphoblastic leukemia, all). this presentation will review the experience of all mrd detection by flow cytometry with a focus on the experience of the children’s oncology group (cog). data from the most recently completed generation of cog trials confirms the prognostic significance of all mrd in a large cohort of patients with pediatric all. in particular, these trials demonstrate a clear association between increasing levels of mrd detection and reduced event free survival when assessed at day 8 after initiation of therapy in peripheral blood, end of induction (day 29) in bone marrow aspirates or end of consolidation in bone marrow aspirates. the combined use of mrd assessment at day 8 in peripheral blood and day 29 in bone marrow allows for the identification of a subset of patients with very low risk of relapse for whom therapeutic reduction might be a consideration. mrd is also shown to be prognostically significant within subsets of good cytogenetic risk patients or trisomy 4 and 10, and is associated with both short and long term relapse after therapy. in a multivariate analysis, the detection of minimal residual disease by flow cytometry is found to be the single most important prognostic indicator. the current generation of clinical trials in cog is now focused on determining whether risk adapted therapy based in part on mrd detection can favorably impact outcome for this disease. abstracts | 155 sultan qaboos university 9 11th november 2010 diagnosis of red cell enzymopathies dr. kanjaksha ghosh director, national institute of immunohaematology, mumbai, india red cell enzymopathies, when severe, can present with diverse clinical presentations, hence a single diagnostic strategy is unlikely to suit all clinical situations. g6pd deficiency which reaches polymorphic proportions in many populations as a result of balanced polymorphism against falciparum malaria infection needs to be detected by simple population screening methods. for many haemolytic anaemias, due to red cell enzymopathies, the red cell enzyme level needs to be measured spectrophotometrically or fluorimetrically. however, certain red cell enzymes are present in high concentration in reticulocytes, neutrophils and lymphocytes hence the enzyme level is measured when the acute state of haemolysis has passed and the blood is depleted of white cells by using suitable techniques. certain red cell enzymes like pyrimidine 5’ nucleotide deficiency can be suspected when coarse basophilic stippling is noted in blood films. this enzyme may become deficient in lead poisoning. spectrophotometric measurement of red cell enzymes are performed in haemolysates made from leukocyte depleted blood samples and is used as the source of the red cell enzyme. a substrate solution for the given enzyme is incubated with the haemolysate along with coenzymes like nad or nadp. after a constant period of incubation either the (i) remaining substrate (ii) amount of product produced by enzyme action or (iii) quantitative changes in the coenzymes, i.e. nad nadph2 and vice versa, are measured by using suitable colorimetric or fluorimetric techniques. glycolytic pathway enzyme defects causing haemolytic anaemia used to be screened in the past by auto haemolysis with correction of haemolysis by different compounds; however, this was cumbersome. complete deficiency of nadp dependent methaemoglobin reductase and certain glycolytic enzyme deficiencies associated with cytochrome b 5 deficiency in the nervous system may lead to severe mental retardation. red cell catalase deficiency can be associated with recurrent mouth ulcers without haemolytic anaemia. porphyrin synthesis in the red cells is driven by innumerable enzymes and finally leads to synthesis of haem. acute erythropoietic porphyria and erythropoietic proto porphyria are two important conditions. both of them can be associated with moderately severe haemolytic anaemia. the diagnosis of these cases is done by screening the red cells for porphyrin metabolites fluorimetrically. hence a combination of clinical features, red cell morphology and screening tests discussed above should guide the investigators in selecting the diagnostic techniques for a specific red cell enzyme deficiency. the role of the pathologist in the diagnosis of lymphoma dr. ibrahim al hadabi consultant, department of histopathology, sultan qaboos university hospital, oman immunohistochemistry plays an important role in the classification and diagnosis of malignancies. according to the world health organization, the classification of hodgkin’’s and non-hodgkin’s lymphomas depends on many factors including clinical features, morphology, cell lineage, stage of maturation and immunophenotype. the panel of markers is selected according to the differential diagnosis initially made by morphology. the approach to interpretation and diagnosis using immunohistochemistry and the pitfalls in diagnosis by this tool is discussed. community screening for haemoglobinopathies: technical and logistic considerations dr. kanjaksha ghosh director, national institute of immunohaematology, mumbai, india community screening to identify carriers and couples at risk is an important component of a haemoglobinopathies control programme. an effective implementation of screening programmes first requires adequate outreach for information, education and communication (iec) both in urban and rural areas. the target groups should include: 1) medical professionals and nurses; 2) medical social workers and community leaders; 3) students and teachers in schools and colleges, and 4) general population. a combination of different approaches would have to be used keeping in mind the social, cultural and religious sentiments of multiethnic populations. mass media should reach even remote areas. other approaches would include talks during conferences and cme programmes for medical personnel. inclusion of topics on haemoglobinopathies in school and college curricula, booklets, pamphlets and posters for distribution in different regional languages are other means of the dissemination of knowledge. once this is in place, community screening should be undertaken after due consideration of logistical issues. the following need to be considered. if resources are inadequate, preliminary screening can be done using a combination of nestroft, solubility test and dcip test where carriers with beta thalassemia, hbs and hbe respectively will be picked up and hplc analysis can be done in the individuals who are positive in any of the 3 tests. for screening of beta thalassemia carriers, the most suitable approach would be to do a complete blood count, hplc on all individuals with mcv< 80fl and/or mch <27 pg. at least 5 to 6 regional centres should be identified where training can be given for manpower development in that region as well as for undertaking regular quality control programmes to avoid any misdiagnosis. it is impossible randomly to screen the large population in india and it would be most appropriate to initially screen newlywed couples and women in antenatal care who would be at immediate risk of having an affected child. the other groups which could be screened are school and college going students as they are easily accessible. multicentre studies have been undertaken to screen all these 3 groups by the indian council for medical research and a few centres in six different states, mainly in medical colleges under the jai vigyan programme. these need to be expanded to other states and ultimately facilities should be established at the district level in every state. eventually more centres for prenatal diagnosis need to be established to successfully initiate a community control programme for haemoglobinopathies at the oman international conference on laboratory medicine 156 | squ medical journal, february 2011, volume 11, issue 1 national level. clinical aspects of bleeding disorders prof. alison street vice president, medical world federation haemophilia, alfred health, melbourne, australia when reviewing a patient for symptoms of a bleeding disorder it is important accurately and precisely to define any abnormality both for the selection of appropriate treatment and for family counselling. population screening by laboratory testing is neither specific nor cost-effective for the detection of clinically significant bleeding disorders. the most important clues come from the person’s history of bleeding with past surgery, but where there has not been experience of such a homostatic challenge it can be very difficult to predict whether a person will bleed or not with any particular procedure. working parties from various societies, such as the international society of thrombosis and haemostasis have developed clinical questionnaires in attempts to standardise “bleeding scores”, but there is a large overlap between the normal population and people with bleeding disorders. the history of past experience of bleeding remains the most important factor in deciding whether to proceed to targeted testing for the presence of a bleeding disorder. a family history of bleeding and the mode of inheritance may also help, for example transmission of haemophilia through the maternal line or an autosomal dominant pattern in families with von willebrand disease (vwd). the type of bleeding, for example mucosal bleeds from nose, mouth and other parts of the gastro-intestinal tract may suggest a problem with platelet adhesion/aggregation such as vwd, whereas joint and deep muscle bleeds are more characteristic of a plasma factor deficiency. algorithms for testing can be developed and the more specialised tests of von willebrand factor function, genetic mutation analysis and identification of plasma factor inhibitors are often centralised to reference laboratories. treatment is most safely and efficiently co-ordinated through centres where clinicians from multiple disciplines are co-located and trained to deliver comprehensive care. treatment products are the most costly budget item for which protocols need to be locally designed, implemented and audited to maximise effectiveness of the investment. challenging cases in thrombosis and haemostasis: squh experience dr. khalil al farsi consultant, department of haematology, sultan qaboos university hospital, oman disorders of thrombosis and haemostasis are leading causes of morbidity and mortality world-wide. thanks to the explosion in both clinical and translational research, our understanding of thrombosis and haemostasis has expanded from thinking of them as simple vessel leakages or occlusions to knowing the details of the molecular mechanisms behind them. the new insights gained from these, and the availability of specialists in the field with years of experience dealing with such disorders, have helped us establish some guidelines. these have been of great help in the diagnosis and management of such disorders. however, despite all this, we are still faced with cases that pose challenges both in the laboratory and the clinic i.e. in diagnosis and management. i will discuss a few challenging cases and try to provide a step-by-step approach that might be of help in managing such cases. developing comprehensive care programs for the diagnosis and treatment of haemophilia and other bleeding disorders prof. alison street vice president, medical world federation haemophilia, alfred health, melbourne, australia comprehensive care is defined as the continuing supervision of all medical and psychosocial factors affecting the person with a bleeding disorder. patients with bleeding disorders and their families are a “minority population” with special health needs for diagnosis, (including carrier status) and treatment. they develop trust and confidence in clinicians who show interest and develop competence in diagnosis and management of these disorders. the principles and practice of comprehensive care are those of “chronic disease management” with particular emphasis on training and multidisciplinary teamwork. the services provided within a comprehensive haemophilia care center will depend on locally available human and financial resources. they usually involve leadership from a haematologist or rehabilitation specialist, with input from laboratory technologists, nurses, physiotherapists, dentists, surgeons, etc. services may also be integrated with those required for managing other inherited disorders such as thalassemia and haemoglobinopathies and thrombosis. a patient registry with systematic data entry supports effective and efficient clinical management both of patients and treatment products. managing patients with haemophilia through a comprehensive care centre has proven benefit for both patient and financial outcomes. adoption and adaptation of the services to local needs and resources requires trust and commitment between funders, clinicians and patients. screening strategies for the detection of mutations in haemophilia dr. shrimati shetty national institute of immunohaematology (icmr), mumbai, india haemophilias represent the most common and severe inherited haemorrhagic disorders caused by mutations in the f8 and f9 genes, abstracts | 157 sultan qaboos university 9 11th november 2010 which lead to deficiency or dysfunctional factor viii and ix protein respectively. the f8 gene is 186 kb long; it has 26 exons and encodes a 9-kb mrna transcript while the f9 gene is 33 kb in size with 8 exons and 7 introns with a 2.3 kb mrna. complicating the molecular characterisation of this disease is the complexity of the genes, the mutational heterogeneity, and technical limitations of the current mutation detection techniques. the mutations causing both haemophilia a and b are spread throughout the genes and are mostly represented by point alterations. however, the inversion of intron 22 was found in 40–50% of patients with severe ha and the inversion of intron 1 was reported with a prevalence of about 2-5% in different populations studied. except the intron 1/22 inversions in severe ha cases, mutation detection in the f8/f9 genes is challenging so that it is only partially met by conventional screening methods such as single stranded conformational polymorphism (sscp); conformational sensitive gel electrophoresis (csge) and chemical mismatch cleavage (cmc); high resolution melting analysis (hrm), and denaturing high performance liquid chromatography (dhplc). each of these have a varying applicability and efficiency; however, they all suffer from incomplete detection rates in the range of 70–90% . moreover, each method places variable demands on the technical skills and time investment of the investigator. direct sequencing of the gene is now the most accepted method of mutation detection in haemophilias. a f8 / f9 dna micro array platform is an alternative gene mutation analysis approach that has a high sensitivity, and reproducibility. the methodology is, however, expensive and time consuming and, with the reduction in sequencing costs, direct sequencing is now the most cost and time efficient strategy for haemophilia a/b mutation analysis. even extensive scanning of the exonic areas, promoter and splicing areas fail to detect mutations in 2-3% of the cases suggesting the role of other genes in reducing factor levels. reports of double mutations in both haemophilia a and b add further to the complexity of genetic diagnosis in these disorders. these factors undetected, the phenotypic diagnosis has not been totally abandoned in many of the laboratories who routinely perform genetic diagnosis of haemophilia families. recent advances in chronic obstructive pulmonary disease (copd) prof. peter ma calverley school of clinical sciences, university of liverpool, uk. email: pmacal@liverpool.ac.uk the last decade has seen major changes in our understanding of the clinical importance, causes and treatment of copd. systematic epidemiological studies, such as the burden of obstructive lung disease (bold) study, have shown that the prevalence of this disease is around 9% of adults and is much commoner in developing countries than expected. persistent inflammation secondary to oxidative stress and corticosteroid resistance seem to drive both airway thickening, fibrosis and contribute to emphysema. reliance on a fixed forced expired volume (fev) 1/ forced vital capacity (fvc) ratio may lead to misdiagnosis in some circumstances while bronchodilator responsiveness is not a feature of stable copd. copd persists even after smoking cessation, but a long-acting inhaled bronchodilator, if combined with inhaled corticosteroids, reduces exacerbation numbers, improves health status and probably decreases the decline in lung function and the risk of dying from copd. systemic problems often accompany advanced copd which increases the risk of lung cancer cardiovascular disease and osteoporosis irrespective of background treatment. exacerbations often cluster in periods of disease instability and are driven by a range of viral and bacterial pathogens, persistent lower respiratory tract colonisation being particularly important. respiratory failure can be managed more effectively with non-invasive ventilation (niv), but preventing the development of severe disease is the major public health goal and will require earlier intervention in at risk populations if we are to move forward from simply managing advanced symptomatic copd. asthma management: the guidelines–practice gap dr. omar al-rawas department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: orawas@squ.edu.om asthma is a major global public health problem. in recent years, a large number of national and international asthma management guidelines have been published and disseminated. however, there is evidence that health care providers have not widely adhered to these guidelines. this poor adherence to guidelines appears to be universal and span the spectrum of physicians in public and private practice as well as in teaching and tertiary referral hospitals. the problem is compounded by poor patient compliance. as a result of these factors, many asthma patients receive inadequate care and have poor asthma control. the available data indicate a need for further educational programmes directed at both physicians and patients to utilise better the available and effective therapies. since guidelines can contribute to improved care only if they succeed in moving actual practice closer to the recommended norm, an expanded asthma management programme that provides feedback to physicians on their compliance with asthma guidelines and its impact on asthma control may help improve implementation of the guidelines and better asthma control. management of interstitial lung disease (ild) prof. athol wells royal brompton hospital, london, uk. email: a.walls@imperial.ac.uk the primary conceptual problem in the management of ild is the fact that there is a multiplicity of individual disorders, but only a handful of management strategies. the art of managing ild is to classify patient presentations to fit with available treatment approaches. therefore, ild needs to be classed broadly as: a) self-limited inflammation; b) major inflammation with progression to fibrosis; c) stable fibrotic disease; d) insidiously progressive fibrosis (with stabilisation a realistic goal); and e) inexorably progressive fibrosis. this pragmatic classification can be achieved with knowledge of: 1) likely cause, if any; 2) ct/biopsy findings; 3) quantification of disease squ med j, august 2010, vol. 10, iss. 2, pp. 287-295, epub. 19th jun 10 مؤمتر الطب العام املتقدم مؤمتر مشرتك بني كلية اجلراحني امللكية الربيطانية ووزارة الصحة العمانية وجامعة السلطان قابوس 20 – 23 فبراير 2010 advanced general medicine conference joint conference of the royal college of physicians uk, ministry of health, oman and sultan qaboos university 20th 23rd february 2010 abstracts advanced general medicine conference joint conference of the royal college of physicians uk, ministry of health, oman and sultan qaboos university 288 | squ medical journal, august 2010, volume 10, issue 2 severity, and 4) evaluation of disease behaviour with time. based on this classification, management distinctions can be made between: a) observation; b) high dose therapy to reverse inflammation, followed by longer term low dose therapy to preserve gains; c) long-term low dose therapy from the outset with the realistic hope of preventing progression; d) long-term low dose therapy in the hope of slowing progression, and e) best palliative care in end-stage disease. the aim of this presentation is to demonstrate that with a minimum of readily obtainable information, it is possible to move from diagnostic uncertainty to confident pragmatic management in ild, using terminology that is immediately understood by the patient, family and referring physician. primary and secondary prevention of cardiovascular disease prof. david wood national heart and lung institute, imperial college, london, uk. email: d.wood@imperial.ac.uk the who and joint european societies guidance on prevention of cardiovascular disease (cvd) in clinical practice recommends a common approach to lifestyle and risk factor intervention for patients with established atherosclerotic cvd and high risk persons in the population. this is based on the concept of total risk assessment and management first advocated in the joint european recommendations on coronary prevention in 1994. the most recent report by the joint european societies, published in 2007, now addresses cardiovascular disease as a whole. the clinical priorities are: 1) patients with established atherosclerotic disease; 2) asymptomatic individuals who are at high risk of developing atherosclerotic disease because of a) multiple risk factors resulting in a ten year risk of >5% now or, if extrapolated to age 60, for developing a fatal cvd event; b) markedly raised levels of single risk factors; c) diabetes mellitus, and 3) close relatives of patients with early onset atherosclerotic disease and asymptomatic individuals at particularly high risk. a new model for total risk estimation called score (systematic coronary risk estimation), based on european populations, is recommended and can be adapted to correspond with national cvd mortality in any european country. the risk threshold for more intensive lifestyle intervention and, where appropriate, the use of drug therapies, is now defined as ≥5% fatal cvd risk over 10 years. lifestyle, risk factor and therapeutic goals have been set for all priority patient groups. the most recent results from euroaspire iii show a continuing large gap between the professional standards set by guidelines and everyday clinical practice for both coronary patients and individuals at high risk of developing the disease in primary care. the euroaction demonstration project in preventive cardiology has stepped up to this professional challenge through a nurse coordinated multidisciplinary prevention programme which has set a new standard of preventive care for europe. secondary hypertension: investigation and management prof. nicholas jy woodhouse department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: nickwood2@doctors.org.uk primary or essential hypertension (htn) affects approximately 25% of the adult population worldwide and is a leading cause of mortality and morbidity. frequently, two or more medications are required to achieve good blood pressure (bp) control and the financial costs to government are huge. secondary hypertension, on the other hand, is potentially curable often without the need for lifelong medications. patients should therefore be carefully screened to exclude treatable causes. in the literature, secondary disease is quoted as being 5% of the total hypertensive population, but the worldwide massive increase in obesity, together with more accurate data on the prevalence of primary hyperaldosteronism (pa) indicates that the total percentage is likely to be closer to 20%. the obesity epidemic has result in progressively more cases of the metabolic syndrome with its attendant dyslipidemia insulin resistance, type 2 diabetes (t2dm), obstructive sleep apnoea (osa) and systemic htn. this effect is compound by a parallel increase in alcohol consumption which on its own can produce persistent disease. in oman, end stage renal disease (esrd) requiring dialysis is estimated to increase by 10% annually again as a result of the increasing incidence of t2dm. at the present time, roughly 800 patients are undergoing dialysis and a similar number have had renal transplants. endocrine causes of secondary htn are rare, except in the case of primary aldosteronism which is found in 14% of the general uk hypertensive population and two-thirds of all hypertensive omanis who have a positive family history of the disease. a careful family history and physical examination will give clues to the diagnosis in many patients. the remainder will require electrolyte, bone profile, hormonal studies and renal vascular imaging studies. in this brief review, we will illustrate these points with clinical examples and touch on new treatment options. r e f e r e n c e s 1. hood s, cannon j, foo r and brown m. prevalence of primary hyperaldosteronism assessed by aldosterone renin ratio and spironolactone testing. clin med 2005; 5:55–60. 2. woodhouse njy, el-shafie ot, ben abid f, doi s. familial mineralocorticoid induced hypertension in the sultanate of oman. squ med j 2008; 8:165–9. 3. aditga bs, wilding jph. modern management of obesity. clin med 2009; 9:617–21. management of stroke peter langhorne prof. of stroke care, university of glasgow, scotland, uk. email: p.langhorne@clinmed.gla.ac.uk the last decade has seen dramatic changes in our understanding of the management of stroke. this presentation will encompass recent developments in acute assessment and diagnosis, acute medical management, general (stroke unit) management, rehabilitation and secondary prevention. acute assessment and diagnosis: one of the key changes in the public perception of stroke is the increased recognition of stroke as a medical emergency. this has encompassed developments to enhance the early recognition and diagnosis of acute stroke and transient ischaemic attack (tia) patients together with the rapid triage for appropriate management. acute medical 20th 23rd february 2010 abstracts | 289 management: the main recent development has been the increased use of thrombolytic therapy in the form of recombinant tpa. recent trials have supported an expansion of the time window and the challenge now is to make this available to all eligible patients. general (stroke unit) management: although the concept of stroke unit care is well established, many countries have recently made efforts to ensure that all stroke patients can access such care. the potential health gains from patients accessing appropriate stroke unit care are substantial. rehabilitation: substantial developments are taking place in our understanding of rehabilitation although research lags behind some other aspects of stroke management. alternative models of rehabilitation (such as early supported discharge) are now becoming well established. secondary prevention: this area of stroke management has been marked by two key themes: first, the recognition of the high risk of early recurrence after tia or minor stroke; second, the establishment of a wide battery of effective secondary prevention measures including dual antiplatelet therapy, anticoagulation, early carotid endartorectomy, statin therapy and active blood pressure management. the presentation will include an assessment of the potential impact of the different strategies for managing strokes and the potential value at a public health level. management issues for women with epilepsy dr abdullah al-asmi department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: aalasmi@gmail.com epilepsy is a chronic neurological disorder which presents with various syndromes and different aetiologies. it is estimated that more than one million women and girls in the usa are suffering from seizure disorders. there are a number of management issues related to epilepsy and women, especially in the childbearing age group. the menstrual cycle with its hormonal changes may affect seizure frequency. catamenial epilepsy is defined as increased seizure related to the menstrual cycle, likely due to hormonal changes. hormonal manipulation may significantly reduce such seizures. oral contraceptive pills (ocp) may interfere with antiepileptic drugs (aeds) and vice versa. selection of the appropriate ocp for these women is essential. in addition, women should be counselled about a slight increase in the potential risk of unplanned pregnancy even though taking ocp. certain aeds, e.g. valproate, may cause irregular periods, weight gain and can lead to polycystic ovarian syndrome. pregnancy can lead to increase in seizure frequency in women with epilepsy. this is due to multiple factors including hormonal factors, changes in the level of aeds, etc. planning of pregnancy becomes very important with the aim to use minimum aeds and as low a dosage as possible. the pregnant woman should be counselled about the potential teratogenic effects of the aeds even though this is small. over 90% of babies delivered by women with seizure disorders are healthy and normal. it is noted that many general physicians may advise the patient to stop aeds during pregnancy fearing the teratogenic effect. this, unfortunately, may lead to increased seizure frequency during pregnancy and unwanted consequences for the mother and the foetus. almost all aeds have potential teratogenic side effects. congenital anomalies are variable and include neural tube defect, and congenital heart diseases. these patients ideally should be followed as high risk pregnancy cases where regular obstetric ultrasounds and blood tests are done. the long term side effects of aeds on the babies of these women is not well established, therefore it is important to develop and maintain a pregnancy registry at national and international levels. delivery is a stressful and exhausting event which may precipitate seizures. the postnatal period may lead to increased seizure frequency due also to many factors including poor sleep, and hormonal changes. also concerns will arise regarding lactation and potential side effects of aeds on the neonate. in general, lactation is considered safe with special precaution among mothers who are taking benzodiazepines and phenobarbitol or primidone. there are many management issues physicians face when dealing with women who have epilepsy requiring the treating doctors to be well informed about this disease. viral encephalitis dr nick beeching senior lecturer (clinical) in infectious diseases, liverpool school of tropical medicine, liverpool, uk. email: nbeeching@blueyonder.co.uk encephalitis, or inflammation of the brain, has many causes and there is an overlap of clinical presentation with bacterial and viral meningitis and a wide variety of encephalopathies caused by metabolic and degenerative conditions, other infections, drugs and alcohol. infectious causes include the herpes group of viruses, especially herpes simplex virus (hsv) and varicella zoster virus, enteroviruses, bacteria (especially listeria), tuberculosis, and a wide range of geographically based viruses such as rabies, tick-borne encephalitis, japanese encephalitis virus, ross river virus and emerging problems such as nipah virus and the spread of west nile virus. noninfectious causes include immune mediated conditions, particularly acute disseminated encephalomyelitis (adem), paraneoplastic syndromes and voltage gated potassium channel limbic encephalitis. there is a rising incidence of encephalitis in immunosuppressed individuals, including viral causes e.g. cytomegalovirus (cmv), human herpes virus 6 (hhv6), eppstein-barr (ebv) virus infection, subacute encephalitis due to polyoma viruses jc/bk, and parasitic causes e.g. toxoplasma gondii. the medical history should enquire about details of travel, animal exposure and occupation and leisure activities. incidence rates are typically quoted as 5–10/100,000 per year, and are higher in the young and the elderly. in the uk, there are thought to be about 1.5 hospitalisations per 100,000 per year due to hsv encephalitis. the classical clinical description of a flu-like illness prodrome leading to confusion, headache, fever, seizures and focal neurological signs may be more subtle, and easily confused with neuropsychiatric problems. common diagnostic and management errors include: attributing fever and confusion to urinary tract or respiratory infection; ignoring subtle mental changes described by relatives; missing a fluctuating fever if temperature is normal at presentation; failure to investigate and manage seizures, and failure to perform adequate neuroimaging and/or lumbar puncture. all patients require neuroimaging, often ct initially for features of raised intracranial pressure followed by mr scans which show more subtle changes, but both may be normal at presentation and require repeating. lumbar puncture (lb) should be performed unless there are specific contraindications, although the cerebrospinal fluid (csf) findings overlap with viral and bacterial meningitis and there may be a predominance of csf neutrophils early in viral encephalitis. increasingly sensitive polymerase chain reaction (pcr) techniques have largely replaced brain biopsy and antibody detection in viral diagnosis, especially for hsv, varicella zoster virus (vzv), cmv and enteroviruses. hiv testing should be part of the routine workup. advanced general medicine conference joint conference of the royal college of physicians uk, ministry of health, oman and sultan qaboos university 290 | squ medical journal, august 2010, volume 10, issue 2 eeg is particularly useful for detection of recurrent subtle seizure activity. management includes review and control of any underlying predisposing condition, aggressive management of seizures, detection and control of raised intracranial pressure and specific antiviral medication. empirical antiviral therapy (aciclovir) should be started early, often with antibacterial agents, if there are uncertainties about diagnosis and there are diagnostic delays while waiting for imaging or for opportunity for safe lp. aciclovir reduces mortality from hsv encephalitis from about 70% to about 20%, but the optimum duration remains unknown (most physicians give 14–21 days). there is reasonable evidence that it should be started within 48 hours. steroids are frequently used but their role remains unproven, particularly in less severe disease. the use of other immunomodulatory agents, particularly interferons, in most forms of encephalitis remains anecdotal or unproven. encephalitis has a poor outcome, and two thirds of survivors have neuropsychiatric sequelae and up to 25% have epilepsy. patients and their families require prolonged support, and the need for chronic care and changes in family dynamics represent a substantial long term burden on them and health services. patient support groups have an important role in assisting this process. us guidelines have recently been published (tunkel, et al. clin inf dis 2008; 47:303) and should be read together with informal uk guidance (solomon et al. pract neurol 2007; 7:288–305). joint bis/ban guidelines are being finalised for consultation in the uk. performance indicators for clinical audit include adequate use of neuroimaging (or documentation of reasons for omitting it), use of empirical aciclovir and /or antibacterial agents, and targeted use of specific antimicrobials for identified aetiologies. optimum “door to needle” times for best treatment need to be defined, as does the proportion of patients that should be investigated with csf pcr. diagnosis and management of neuroendocrine tumours (nets) dr. omayma elshafie department of medicine, college of medicine & health sciences, sultan qaboos universtiy, muscat, oman. email: omayma0@hotmail.com neuoroendocrine (ne) cells are enterchromaffin cells (ec) occupying the epithelial lining of the digestive and respiratory tract and were discovered by prof. kulchitsky. the term amine precursor uptake and decarboxylation (apud) was first coined by prof. anthony pearse to describe their histochemical features. normally, they are widely distributed in the gut, giving rise to the term the diffuse endocrine system of the gut. their function includes modulation of peristaltic reflexes and water, electrolyte, mucous and hormone secretion (e.g. 5ht). octreotide is a somatostatin analogue, which binds mainly to receptor 2 in the cell membrane of the ec. this result is inhibition of hormone production and cell proliferation. as a result labelled octreotide may be used to locate and treat net. nets of the gastrointestinal tract were thought to be rare and usually present with symptoms related to the actions of the peptide they secrete. 70% of these carcinoid tumours are present in the digestive system while 30% are in the lung. the carcinoid syndrome only occurs when vasoactive hormones reach the systemic circulation. this invariably means that the tumour has metastasised to the liver. hormones secreted by the primary tumour into the portal vein are metabolised by the liver and do not cause flushing. tumours of the pancreas are only 3% of the total. of these, 50% are insulinomas, 25% gastrinomas, 20% non-functional and 5% ppomas, vipomas, glucagonomas and somatostatinomas. pancreatic tumours may form part of the multiple endocrine neoplasia type 1 (men 1) syndrome and sometimes secrete a number of other hormones including acth, ghrh and pthrp. their diagnosis is often delayed and most present with metastatic disease. earlier diagnosis can be improved by taking good history and confirmed by serum chromogranin a measurements, octreotide scanning and immunohistochemistry. advances in the treatment of nets with metastatic disease includes the use of: 1) sandostatin long acting octreotide (lar); 2) octreotide + rad 001 (mtor) inhibitor); 3) somatostatin receptor targeted radiotherapy. the incidence of nets appears to be increasing. early diagnosis is critical to improve survival, but the prognosis of patients with metatastatic disease has improved considerably with new treatment strategies. r e f e r e n c e s 1. treatment of carcinoid tumors and the carcinoid syndrome. from www.uptodate.com. accessed oct 2009. 2. efficacy of rad001 (everolimus) and octreotide lar in advanced lowto intermediate-grade neuroendocrine tumors. from www.jco.ascopubs.org. accessed oct 2009. 3. ezziddin s, attassi m, guhlke s, ezziddin k, palmedo h, reichmann k, et al. targeted radiotherapy of neuroendocrine tumors using lu177-dota octreotate with prolonged intervals. j nucl med 2007; 48:394. chronic viral hepatitis b and c infection prof. humphrey hodgson, sheila sherlock chair of medicine and director, centre for hepatology, royal free hospital; senior censor & vice-president education & training, royal college of physicians of london, uk. email: h.hodgson@madsch.ucl.ac.uk overview: chronic viral hepatitis b and c infections constitute a world health problem numerically far in excess of hiv disease. chronic hepatitis b virus (hbv) and hepatitis c virus (hcv) both predispose to cirrhosis, liver failure and liver cancer, but the rate of progression (infection to cirrhosis), though variable, is slow, and generally at least 10–20 years. prevalence rates vary geographically depending on both genetic and more importantly environmental (e.g. transmission mode) factors. current uk figures for each virus are ~0.5% of unselected populations so not dissimilar to published omani results. however there are at-risk populations, which are different for each virus in the uk, for hbv: origin from high prevalence areas, intravenous drug abuse and promiscuity; for hcv: drug abuse, transfusions prior to 1990s. importantly, hbv and its complications are preventable by immunisation, pursued as a policy in well over 100 nations. an hcv vaccine is not yet available. natural history and treatment of hbv: the response to hbv infection varies with age and immune status. most infants become chronic carriers. most adults have an episode of acute self-limited infection (which is often asymptomatic) but a small proportion (~5%) also becomes chronic carriers. amongst the childhood-infected, there may be many years of ‘tolerance’ to the virus with high levels of viral dna in the blood, but no liver damage. this is then typically followed by an immune attack on viral-infected liver cells (sero-conversion) associated with a change in immune markers in the blood (e-ag+ve to e-ab+ve) during which fibrosis and eventually cirrhosis may result. treatment strategies vary. paradoxically, the high viral dna level (no 20th 23rd february 2010 abstracts | 291 liver damage immunotolerant stage) is generally not treated until there is evidence of liver damage with elevated transaminase levels. treatment options then include either immune activation (interferon therapy for 6–12 months), or direct antiviral drugs probably long term. first generation antiviral drugs lead to high levels of viral resistance (i.e. lamivudine resistance in 40–60% of patients after 4 years); newer generation drugs after 3 years are showing much less resistance (0–2%). with later stage disease, (after seroconversion), if there is active inflammation and high viral dna levels, the antiviral drugs are the appropriate approach. in general, these strategies do not cure the disease but suppress the virus. the costs of long term therapy are high. natural history and treatment of hcv: most (>60%) of patients who contract hcv infection become long-term carriers. anti-hcv antibodies persist in all who are infected, so chronic carriers need to be identified by detecting hcv-rna in the blood by polymerase chain reaction (pcr) testing. unlike hbv, successful treatment can cure the patient with chronic hcv, i.e. a sustained viral response (svr). treatment involves 6–12 months of pegylated interferon injections (weekly) in combination with daily ribavirin. different hcv subtypes (genotypes) respond differently. genotype 1 responds relatively poorly (40% svr with 48 weeks therapy) whilst genotype 3 does well (80% after 24 weeks or even shorter periods). genotype 4 is intermediate. fatigue, anaemia, depression, thrombocytopaenia and leucopaenia may all limit therapy. general measures in chronic viral liver disease: liver decompensation requires treatment as it occurs, including consideration for liver transplantation. however in patients who are well with compensated cirrhosis, surveillance for hepatocellular cancer is worthwhile as, if detected early, surgical approaches or local ablation can enhance survival. bone as an endocrine organ prof. graham russell the botnar research centre, oxford university institute of musculoskeletal sciences, oxford, uk. email: graham.russell@ndos.ox.ac.uk there have been remarkable recent advances in knowledge about skeletal biology and the changes that take place in disease. these are largely the result of discoveries in genetics and cell biology. skeletal development is programmed by the sequential activation of specific genetic pathways, that culminate in the production of the adult skeleton which is light but strong. systemic hormones, including the parathyroid hormone (pth), vitamin d metabolites, and calcitonin, regulate blood calcium levels and contribute to the overall calcium economy of the body. many other hormones have subtle but important effects on skeletal behaviour and its modelling and remodelling activity. in addition to understanding how osteoblasts form bone, and osteoclasts resorb bone, the important role of osteocytes as mechanosensors is receiving increasing attention. a novel and emerging concept is the notion that bone may itself function as an endocrine organ, not only locally but also systemically. at a local level, the integration of cellular differentiation and function within the microenvironment of bone is under the influence of a large number of cytokines and growth factors. there are several important recently discovered pathways that are involved in osteoblast regulation and osteoblast/osteoclast interactions and some of these are suitable for pharmacological intervention, including the wnt/lrp5 pathway, the ephrin system, and particularly the receptor activator of nuclear kappa beta (rank) ligand/rank/osteoprotegerin (opg) system. at a systemic level, there is evidence that products of bone cells may have distant endocrine effects. indeed, osteocytes have their own repetoire of regulatory molecules, including fgf23, which is involved in phosphate metabolism, and sclerostin which is a powerful negative regulator of bone formation. furthermore there is evidence that osteocalcin, secreted by osteoblasts, may act as a systemic metabolic regulator by controlling insulin secretion, and insulin sensitivity. there are also potential regulatory links between the hypothalamus, the gut, and adipose tissue involving leptins, serotonin, and adipokines. this new knowledge is offering novel opportunities for therapeutic interventions. r e f e r e n c e s 1. clifford rosen. primer on the metabolic bone diseases and disorders of mineral metabolism, 7th ed. washington dc: asbmr (the american society for bone and mineral research), 2008. 2. baron r, rawadi g. targeting the wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. review. endocrinology 2007; 148:2635–43. 3. boyden lm, et al. high bone density due to a mutation in ldl-receptor-related protein n engl j med 2002; 346:1513–21. 4. matsuo k, irie n. osteoclast-osteoblast communication. review. arch biochem biophys 2008; 473:201–9. epub 2008 mar 29. 5. piters e, boudin e, van hul w. wnt signaling: a win for bone. review. arch biochem biophys 2008; 473:112–6. 6. hinoi e, gao n, jung dy, yadav v, yoshizawa t, kajimura d, et al. an osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. ann n y acad sci 2009; 1173:e20–30. 7. yadav vk, oury f, suda n, liu zw, gao xb, confavreux c, et al. a serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. cell 2009; 138:976–89. 8. yoshizawa t, hinoi e, jung dy, kajimura d, ferron m, seo j, et al. the transcription factor atf4 regulates glucose metabolism in mice through its expression in osteoblasts. j clin invest 2009; 119:2807–17. 9. ferron m, karsenty g. the gutsy side of bone. cell metab. 2009; 10:7–8. 10. karsenty g, kronenberg hm, settembre c. genetic control of bone formation. review. ann rev cell dev biol 2009; 25:629–48. management of chronic kidney disease dr. dawood al riyami department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: alriyamidawood@yahoo.com all patients with renal disease (whether acute or chronic) should undergo an assessment of renal function by estimating the glomerular filtration rate (gfr). this measurement is used clinically to evaluate the degree of renal impairment. the kidney is able to adapt to damage by increasing the filtration rate in the remaining normal nephrons, a process called adaptive hyperfiltration. as a result, the patient with mild renal insufficiency often has a normal or near-normal serum creatinine concentration. the k/doqi working group defined chronic kidney disease in adults as: evidence of structural or functional kidney abnormalities (abnormal urinalysis, imaging studies, or histology) that persist for at least three months, with or without a decreased gfr (as defined by a gfr of less than 60 ml/ advanced general medicine conference joint conference of the royal college of physicians uk, ministry of health, oman and sultan qaboos university 292 | squ medical journal, august 2010, volume 10, issue 2 min per 1.73 m2). chronic kidney disease (ckd) alone is an independent risk factor for cardiovascular disease. among patients with ckd, the risk of death, particularly due to cardiovascular disease, is much higher than the risk of eventually requiring dialysis. the presentation covers the general management of ckd which involves: treatment of reversible causes of renal dysfunction; 2) preventing or slowing the progression of renal disease; 3) treatment of the complications of renal dysfunction, and 4) identification and adequate preparation of the patient in whom renal replacement therapy will be required. adult stem cell transplantation in autoimmune disease prof. alan tyndall on behalf of eular and ebmt. email: alan.tyndall@fps-basel.ch during 1995, informal discussions between members of the scientific committee of the european league against rheumatism (eular) and the european group for blood and marrow transplantation (ebmt) concerning the potential of haematopoietic stem cell transplantation (hsct) for the treatment of severe autoimmune disease (ad) resulted in a consensus statement and the commencement of a small phase i/ii trial. the mission statement of the working group was and remains “to show through prospective, randomised controlled trials (rct) the place, if any, of hsct in the treatment of severe ad.” a secondary aim is to increase the understanding of ad onset and persistence through mechanistic scientific side-studies. twelve years later, over 1,000 patients in europe have received an hsct (mostly autologous) for treatment of a severe ad, with around one third having improved significantly. in some, a durable clinical and serological remission has been observed, including normalisation of tissue changes in scleroderma and loss of autoimmune memory in sle. in others, the treatment resulted in death, treatment related mortality (trm) overall being 11% in 2005. a recent analysis indicates a reduction in the trm. currently three ebmt sponsored rcts are in progress or completed in europe (scleroderma, multiple sclerosis and crohn’s disease), the scleroderma trial (astis) being part financially supported by eular. eular has also recently launched a stromal cell working group to develop recommendations for the use of mesenchymal stem cells (msc) as therapeutic agents in rheumatic disorders exploiting their anti-inflammatory, immunomodulatory, tissue protective properties and apparent minimal acute toxicity. it is hoped that the preliminary positive results in acute graft versus host disease will translate to positive benefits for autoimmune diseases such as crohn’s disease, lupus nephritis and vasculitis. genetic basis of common diseases prof. riad bayoumi department of biochemistry, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: bayoumi@squ.edu.om the recent advances in genomics and microarray technology at manageable cost, has enabled research groups, worldwide, to conduct successful genome-wide association studies (gwa) unravelling some aspects of the genetics of complex traits and common diseases, such as type 2 diabetes, obesity, myocardial infarction, stroke, asthma, schizophrenia, bipolar disorders, alzheimer’s disease, crohn’s disease, autoimmune diseases and some cancers. the newly discovered genetic architecture of these diseases is helping in the understanding of pathophysiology and the development of novel approaches to prevention and therapeutic applications. however, most of the gwa studies have been designed to detect potential susceptibility loci and genes attributable to common simple nucleotide polymorphism (snps) which are limited by the very design of microarrays. in almost all diseases tested up to date, the variants discovered could only explain 10–15% of the inherited predisposition (heritability). the next big move to identify the probable source of missing heritability is in examination of low frequency rare variants and copy number variants that awaits the design of novel microarrays and low cost high-throughput sequencing. epidemiology of viral pandemics dr. nick beeching senior lecturer (clinical) in infectious diseases, liverpool school of tropical medicine, liverpool, uk. email: nbeeching@blueyonder.co.uk historically, the epidemic and pandemic spread of infections such as measles, plague, cholera, smallpox and syphilis have had devastating effects in europe and elsewhere. endemic infections that have been controlled worldwide by public health interventions have the potential to re-emerge rapidly if such measures are relaxed or thwarted, a recent example being the international dissemination of polio after disruption of immunisation programmes. many factors influence the development progress of a pandemic, including crowding, travel, close proximity to host animals or livestock, infectivity to contacts, and the availability, feasibility and effectiveness of control measures. this presentation contrasts recent international experience with severe acute respiratory syndrome (sars), avian influenza and “swine-flu”, focusing on the effects on political and economic planning and outcomes, and the reality for public health practitioners and clinicians at a local level. lessons learnt from these events need to be disseminated to inform policy for dealing with future pandemics, which are inevitable. sickle cell disease (scd) the road towards prevention and cure dr salam alkindi, department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman. email: sskindi@yahoo.com sickle cell disease is prevalent in oman with 5.7% of omani people carrying the gene and about 0.2% affected; therefore, it is estimated that 120–150 babies born in oman every year will become patients with scd. although scd is traditionally regarded as a predominantly red cell disease, it is a complex disease demonstrating a model for red cell interactions with white cells and the endothelial cell lining. recent work from our laboratory on acute chest syndrome (which is one of the major causes of death in this disease) and vaso-occlusive 20th 23rd february 2010 abstracts | 293 crisis (voc), the most frequent presentation of this disease, just demonstrated this. an alteration in the level of nitric oxide as well as a shift in lymphocytes and monocytes activations plays a role in both conditions. similarly, the altered red cells (sickled cells) leading to perturbed platelets and haemostatic functions plays an important role in stroke development, added to the hereditary component of thrombophilia in this syndrome. these changes are promising an important opening for studies in the various therapeutic interventions that are available for this disease such as hydroxyurea, and more recently low molecular weight heparin, nicosan, and other agents that are undergoing testing. also light is seen at the end of the tunnel with good progress made in reduced intensity conditioning (ric) bone marrow transplant for patients with scd. this was seen in the recent experience in our centre, allowing the sickled and normal cells to co-exist together, and the use of stem cells to help patients with avascular necrosis of the hips (avn), a crippling complication seen in some of our patients. thus scd is a unique disease requiring a multi-faceted approach. lymphoma is different here dr. ikram a burney sultan qaboos university hospital, muscat, oman. email:ikramburney@hotmail.com lymphoma is a heterogeneous group of neoplastic disorders. knowledge about different types, sub-types, and aetiology is evolving continuously, and the incidence is on the rise. with the advent of immunophenotype and molecular markers, it has become apparent that there is a significant heterogeneity in disease presentation and clinical course in different parts of the world. amongst nonhodgkin’s lymphoma (nhl) cases, t-cell immunotype is much more frequent in the far east than in developed countries in the west. indolent lymphoma of b-cell immunophenotype constitute around 20% of all cases, compared to around 40% in the west. diffuse large b-cell lymphoma (dlbcl) constitutes 60% of nhl in developing countries, compared to up to 30% in developed countries. whereas 38% of patients with aggressive nhl present with high or high-intermediate risk features in the international prognostic index (ipi) in developed countries, around 60% present with such features in developing countries. around 50% compared to 25% present with primary extra-nodal disease. between 7% and 30% of the patients present with concomitant hepatitis b virus (hbv) infection in developing countries, compared to <5% in the developed countries, while the incidence of hepatitis c virus (hcv) co-infection is 5–15 fold higher in the developing countries. a significantly higher proportion of patients present with aberrations of bcl-2 gene, mutant type of p53 protein, and a higher ki-67 index. there are reports to suggest that patients with an aggressive type of nhl from developing countries are more likely to be immunosuppressed, and have concomitant co-morbidities, such as diabetes mellitus, which has an impact not only on the aetiogenesis, but also on long-term outcomes. furthermore, there are important differences in the gene polymorphisms in various ethnic groups, resulting in differences in susceptibilities to develop lymphoma. taken together, these observations suggest that there is hitherto an unmet need to study nhl in developing countries as a distinct entity. medical education prof. nigel bax university of sheffield, uk. email: n.d.s.bax@sheffield.ac.uk hippocrates recognised the need for experiential learning in medicine, osler highlighted the personal qualities needed to become a good doctor, as well as the role of medical schools, and over 4,000 years ago hammurabi made laws to enhance patient safety. the requirement of a scientific foundation to medical practice was emphasised by flexner in 1910 and has resulted in a style of medical education that remains evident today. however, since these principles were espoused, the stakeholders in medical education have changed considerably. patients, employers, regulatory bodies, governments and students themselves are understandably now central to educational matters and the autonomy of medical schools and of clinicians who teach both students and doctors has waned. changing models of care have altered learning opportunities and large teaching hospitals in many parts of the world are becoming less ideal places for learning about general medicine than previously. increased financial and time pressures on doctors to deliver care do not always integrate with plans to produce the next generation of high quality medical practitioners. the learning of medical sciences by students and doctors has decreased, possibly consequent to their curricula becoming occupied by other topics. the role of doctors has been challenged, both in terms of their clinical skills and from a financial viewpoint, with cheaper alternatives now available. the distinctiveness and value of a doctor is being increasingly questioned. thus, what are the defining qualities of a doctor, not just at present but what would we wish them to be in 20 years time? how should these qualities and abilities be acquired and assessed? the principles determined by our forbears, namely clinical experience, appropriate personal and inter-personal qualities and the understanding and support of society, with all activities underpinned by scientific knowledge, remain central to medical education. we should still heed these tenets and help ensure that all stakeholders, as well as those learning and teaching in medicine, are responsive to them. treating osteoarthritic pain: what are the options? dr. ali s m jawad rheumatology department, barts and the london nhs trust, whitechapel, london e1 1bb, uk. email: ali.jawad@bartsandthelondon.nhs.uk. over the last 10 years, several guidelines have been published for the treatment of osteoarthritis (oa). in 2000, the american college of rheumatology published its management guidelines for the management of patients with oa of the hips and the knees. the european guidelines (eular) followed and more recently the national institute for clinical excellence (nice) in the uk and the osteoarthritis research society international (oarsi) guidelines were published in 2008. based on a published systematic search of clinical guidelines and systematic reviews, twenty six interventions recommended for the treatment of knee pain in older adults in primary care have been identified. for example, the nice guideline lists five interventions regarded as “core treatments” for osteoarthritis of the knee: paracetamol, patient education and information, exercises, weight loss (if the patient is overweight), and topical non-steroidal antiadvanced general medicine conference joint conference of the royal college of physicians uk, ministry of health, oman and sultan qaboos university 294 | squ medical journal, august 2010, volume 10, issue 2 inflammatory drugs (nsaids). the guideline lists another 14 interventions, ranging from those that are safe (such as alterations to footwear or local heat and cold), to those that also are potentially harmful (such as oral nsaids, opioids, and surgery). evidence exists that interventions recommended as core treatment for knee pain in older adults are underused, in particular, exercise, weight loss and the provision of written information. there appeared to be early reliance on pharmacological treatments with underuse of nonpharmacological interventions in early treatment choices. pregnancy and rheumatic diseases dr. samar elemadi department of medicine, sultan qaboos university hospital, muscat, oman. email:ali.jawood@bartsandthelondon.nhs.uk systemic lupus erythematosus (sle) occurs frequently in women of childbearing age. although patients with sle are as fertile as women in the general population, their pregnancies may be associated with complications. the prognosis for both mother and child is best when sle has been quiescent for at least six months prior to the pregnancy, and the patient's underlying renal function is stable and normal or near normal. thus, family planning is important. maternal health and fetal development should be monitored frequently during pregnancy. if possible, delivery should occur in a controlled setting. in addition, women with sle should be followed by an obstetrician knowledgeable in high-risk pregnancies. childhood primary angiitis of the central nervous system dr. reem abdawani department of child health, sultan qaboos university hospital, muscat, oman. email: reemabd@hotmail.com childhood primary angiitis of the central nervous system (cpacns) is a rare and potentially devastating condition. it poses the clinician with significant diagnostic and therapeutic challenges. an overview of cpacns will be discussed with special considerations pertinent to children. vascular aspect of behcet's disease dr. juma al-kaabi department of medicine, sultan qaboos university hospital, muscat, oman. email:kaabi@squ.edu.om behcet’s disease (bd) is a chronic multisystem inflammatory disease characterised by recurrent mouth and genital ulcerations, uveitis, skin lesions along with musculoskeletal, central nervous system, gastrointestinal and other systems manifestations. the disease is associated with morbidity, mainly due to the eye and central nervous system manifestations. furthermore, the mortality rate of bd has been reported to be higher than the general population with an estimated rate of 4-10%. most of this mortality is related to vascular thrombosis, which accounts for about 40% of overall causes of mortality in bd. the vascular involvement varies from 7.7 to 43% depending on the ethnicity. pulmonary artery aneurysms are the one of most series complications of bd, as these may rupture with fatal consequences. the presentation highlights the spectrum of the vascular manifestations of bd (vasculo-behcet), with reference to omani populations. fit for purpose and fit to practise revalidation and recertification in the uk dr. ian starke medical director, revalidation, royal college of physicians, london, uk. email: ian.starke@uhl.nhs.uk the maintenance and continuing development of the professional competence of trained doctors are key elements in ensuring that patients receive the highest standards of care. in the uk, these processes began to be formalised in the 1990s with the introduction of continuing medical education and later continuing professional development as formal processes, built largely on the recording of what most doctors were already doing. the general medical council (gmc) consulted on revalidation in 2000 and produced guidance for licensing and revalidation in 2003. annual medical appraisal was first introduced in 2001 to support formal revalidation, which would start in 2005. this process was halted by a series of high profile criminal and medical negligence cases, in particular the activities of dr harold shipman. an extended public inquiry, chaired by justice dame janet smith, led to a series of reports, the last of which appeared in 2005. in her reports, dame janet criticised many aspects of the regulation of doctors, and in particular stated that the current processes of appraisal were “patchy and not fit for purpose”. the chief medical officer (cmo) for england, sir liam donaldson, chaired a further inquiry, which led to the publication of a report in 2006 (good doctors, safer patients) and to the government white paper, “trust, assurance and safety” in 2007. this proposed processes for the formal revalidation of all health professionals, and included: 1) a change from the criminal to the civil standard of proof in medical fitness to practise cases; 2) the development by the gmc of a new framework for appraisal based on “good medical practice”; 3) the separation of revalidation into the two elements of relicensure (for all doctors) and specialist recertification (for doctors on the specialist and general practice registers held by the gmc); 4) the creation of gmc affiliates who would represent the gmc at regional or strategic health authority level; 5) the creation of the role of responsible officer (ro) in every organisation that employs doctors – responsible for making a positive recommendation on revalidation to the gmc; 6) a clear statement of the role of the medical royal colleges and faculties and their specialist associations in making a positive recommendation on specialist recertification; 7) an expectation that the colleges and faculties, co-ordinated by the academy of medical royal colleges, would develop standards of specialist practice, and means of assessing specialists against those standards. in july 2008, a further report from a working party chaired by the cmo emphasised the importance of relicensure and specialist recertification forming “intertwined strands of a single process”, and the need to maintain the “predominantly formative” 20th 23rd february 2010 abstracts | 295 nature of appraisal. the new framework for appraisal and assessment developed by the gmc was to become a “core module” within every appraisal encounter. although medical revalidation is mainly a department of health (dh) (england) initiative, there is a clear understanding that the processes in the devolved nations will be closely aligned with that in england, and national revalidation delivery boards have been established in scotland and wales, working closely with the uk revalidation programme board. revalidation has three aims: 1) to confirm that licensed doctors practise in accordance with the gmc’s generic standards (relicensure); 2) for doctors on the gp register and specialist register to confirm that they meet the standards appropriate to their speciality or general practice (recertification); 3) to identify, for further investigation and remediation, poor practice where local practice is not robust enough to do this or does not exist. the royal college of physicians (rcp) position on revalidation is that the primary objective should be to ensure continuing high standards of professional practice and the continuing improvement of those standards over time. a model of how the various processes will fit together has been developed by the gmc and the academy. the gmc’s revised framework divides the professional performance of doctors into four domains, each of which has three attributes. the actions, behaviours and skills expected of a well-performing doctor are stated as a total of some 67 “standards”. in common with others, the rcp has developed a specialist framework setting out the supporting information required to demonstrate that a physician is practising according to the 12 attributes. a number of tools have been, and continue to be, developed by the rcp to support physicians in obtaining and recording relevant supporting information. these include multi-source feedback, a patient survey, an enhanced cpd system, personal “point-of-care” learning and quality improvement tools and a bedside teaching assessment. high standards for appraisers and for their training and support have also been developed. the responsible officer (ro) role has been defined by the dh; the ways and circumstances in which ros will link with the college and its regional representatives are to be defined. the college will have a key role in the quality assurance of the appraisal and revalidation processes taking place within nhs organisations. all those working with patients will require a licence to practice, and thus a responsible officer and regular annual appraisal. the next steps in the process include: 1) ten “pathfinder” or “whole-system” pilots in 2010-11; 2) the introduction of “early adopter” pilots in 2011–12, the start of revalidation for those involved; 3) the development of appropriate electronic support tools and consideration of data protection and inter-operability between systems; 4) the development of appropriate training for appraisers and ros; 5) development of supportive remediation methodology; 6) development of quality assurance mechanisms, and 7) consideration of so-called “orphan” groups of doctors. r e f e r e n c e s 1. the shipman inquiry. from www.the-shipman-inquiry.org.uk/home.asp. accessed nov 2009. 2. good doctors, safer patients: proposals to strengthen the system to assure and improve the performance of doctors and to protect the safety of patients. department of health, 2006. from www. dh.gov.uk/prod>consum_dh/groups/dh_digitalassets/@dh/@en/documents/ digitalasset/dh_4137276.pdf. accessed nov 2009. 3. trust, assurance and safety – the regulation of health professionals in the 21st century. from www.official-documents.gov.uk/document/ cm70/7013/7013.pdf. london. hm stationaryoffice, 2007. accessed nov 2009. 4. good medical practice. general medical council, 2006. from www.gmc-uk.org/static/documents/content/gmc_0911.pdf. accessed nov 2009. 5. medical revalidation – principles and next steps – the report of the chief medical officer for england’s working group. from www. dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/en/documents/digitalasset/dh_086431.pdf. accessed nov 2009. 6. general medical council. a revised framework for appraisal and assessment, 2008. from www.gmc-uk.org/framework_4_3.pdf_ snapshot.pdf. accessed nov 2009. 7. assuring the quality of medical appraisal for revalidation. shelley m, judkins k. revalidation support team, may 2009. from www. rcpsg.ac.uk/education/revalidation_cpd?documents/revalidation%20papers%2009/steering%20group%20meeting%20-%20june%20 09/papers%203.pdf. accessed nov 2009. 8. the role of responsible officer. responsible officer guidance – closing the gap in medical regulation. from www. dh.gov.uk/prod_ consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_104594.pdf. accessed nov 2009. 1department of cardiology, leeds general infirmary, leeds, uk; 2school of allied health professions & sport, university of bradford, bradford, uk *corresponding author’s e-mail: csaunderson@nhs.net ممارسات الوقاية احلالية من اجللطات الدموية الوريدية بعد التدخالت الكهروفيسيولوجية داخل األوعية الدموية يف اململكة املتحدة دراسة استعادية كري�شتوفر �شاوندر�شون، �شايل هيكمان، الني ويلكين�شون، مظفر الطيبجي abstract: objectives: this study aimed to evaluate the incidence of venous thromboembolism (vte) cases at the leeds general infirmary, leeds, uk, as well as to survey current vte practices and preventative strategies at other uk-based electrophysiology (ep) centres. methods: this retrospective study involved all patients who underwent ep studies at leeds general infirmary from january 2014 to december 2016. in addition, a telephone survey was conducted of 35 other uk-based ep centres. results: of 1,020 patients who underwent ep studies at leeds general infirmary, 0.3% developed a post-procedural vte. in addition, 28 other ep centres were surveyed (response rate: 80%), of which 18% reported vte cases in the last two years. there were wide variations in vte prevention strategies and the use of post-procedural thromboprophylaxis. conclusion: despite the low incidence of vte cases, many uk centres continue to experience this complication with no consensus on optimal preventative strategies. as current vte guidelines do not recommend antithrombotics after ep studies, further research is needed. keywords: venous thromboembolism; cardiac electrophysiological techniques; catheter ablation; heparin; post operative complications; risk assessment; united kingdom. امللخ�ص: الهدف: هدفت هذه الدرا�شة التجريبية اإىل تقييم حالت الن�شمام اخلرثي الوريدي يف م�شتو�شف ليدز العام، ليدز، اململكة املتحدة الدرا�شة هذه �شملت الطريقة: املتحدة. اململكة يف الأخرى املراكز يف الوقائية وال�شرتاتيجيات احلالية املمار�شات لأ�شتبيان وكذلك ، ديسمرب اإىل 2014 يناير من العام ليدز م�شتو�شف يف كهروفي�شيولوجية لدرا�شات خ�شعوا الذين املر�شى جميع الأ�شرتجاعية التجريبية 2016. وبالإ�شافة اإىل ذلك، مت اإجراء اأ�شتبيان عرب الهاتف لـ 35 مركز اآخر يف اململكة املتحدة لديهم امكانيات الك�شف الكهروفي�شيولوجية. النتائج: من بني 1,020 مري�شًا خ�شعوا لدرا�شات كهروفي�شيولوجية يف م�شتو�شف ليدز العام، حدث الن�شمام اخلرثي الوريدي يف 0.3%. منهم بعد الدرا�شة. بالإ�شافة اإىل ذلك، مت عمل ا�شتبيان ل 28 مركز اآخر )معدل ال�شتجابة: %80(، منها %18 ذكرت حدوث حالت الن�شمام اخلرثي الوريدي يف العامني املا�شيني. كانت هناك اختالفات وا�شعة يف ا�شرتاتيجيات الوقاية من الأن�شمام اخلرثي الوريدي وا�شتخدام م�شادات التخرث بعد الدرا�شة الكهروفي�شيولوجية. اخلال�صة: على الرغم من انخفا�ص حالت الإ�شابة بالن�شمام اخلرثي الوريدي، اإل اأن العديد من املراكز يف اململكة املتحدة ل تزال تعاين من حدوثه دون وجود توافق يف الآراء حول ال�شرتاتيجيات الوقائية املثلى. مبا اأن اإر�شادات الوقاية من الن�شمام اخلرثي الوريدي احلالية ل تو�شي مب�شادات التخرث ، فهناك حاجة ملزيد من الأبحاث يف هذا املجال. الكلمات املفتاحية: الن�شمام اخلرثي الوريدي؛ تقنيات القلب الكهروفي�شيولوجية؛ ال�شتئ�شال با�شتخدام الق�شطرة؛ الهيبارين؛ م�شاعفات ما بعد اجلراحة؛ تقييم املخاطر؛ اململكة املتحدة. current venous thromboembolism prevention practices following endovascular electrophysiological procedures in the uk a retrospective study *christopher saunderson,1 sally hickman,1 elaine wilkinson,2 muzahir tayebjee1 brief communication sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e374–378, epub. 19 dec 18 submitted 24 jan 18 revision req. 1 mar 18; revision recd. 30 mar 18 accepted 22 apr 18 doi: 10.18295/squmj.2018.18.03.018 electrophysiology (ep) studies and radiofrequency ablation (rfa) require the introd-uction of multiple catheters into the venous system.1,2 a typical procedure involves the placement of 4–5 sheaths into the femoral veins through which ep catheters are passed into the heart. if necessary, access to the left-sided cardiac chambers is achieved via a trans-septal puncture or by accessing the left ventricle with a retrograde approach via the femoral artery. however, the period of immobility during and after the procedure—typically up to six hours—is a known thrombotic risk factor. the incidence of asymptomatic deep vein thrombosis (dvt) in this setting ranges from 5–18%, although the clinical incidence is substantially lower (0.4–2%).1–4 venous thromboembolism (vte) has potentially serious clinical and financial consequences; according to the national institute for health and care excellence (nice), an estimated 25,000 patients die every year from preventable vte in the uk.5–8 the nice guidelines recommend that clinicians assess and stratify all individuals admitted to hospital in order to administer pro christopher saunderson, sally hickman, elaine wilkinson and muzahir tayebjee brief communication | e375 phylactic anticoagulants to those at risk of vte.5 the european heart rhythm association (ehra) guidelines on the use of antithrombotics in ep procedures suggest the peri-procedural administration of therapeutic unfr actionated heparin (ufh) to achieve an activated clotting time (act) of ≥300 seconds for left-sided procedures and consideration of its use in right-sided procedures.9 however, they do not specifically recommend the use of oral anticoagulants or antiplatelets following ep procedures, except in cases of atrial fibrillation, flutter ablation or left-sided ventricular tachycardia ablation.9 this study aimed to establish the incidence of post-procedural vte among patients undergoing ep studies with or without rfa, excluding those taking therapeutic anticoagulants, at the leeds general infir mary, leeds, uk. in addition, other uk-based centres were surveyed to document whether they had experienced vte in the last two years and current practices for vte prevention. methods this retrospective study took place at the leeds general infirmary between january 2014 and december 2016. a review of the ep procedures database was perf ormed to identify all patients with a documented compl ication of dvt or a pulmonary embolism. the patients’ medical records were then checked to ensure that appr opriate testing had been performed to confirm the diagnosis of vte, such as ultrasound venography or computed tomography pulmonary angiography. the case notes of patients with confirmed vte were then reviewed in terms of medical history, ep procedure and the administration of periand post-procedural antithrombotics. all patients who required preor post procedural therapeutic anticoagulation measures—such as those with atrial fibrillation or flutter—were excluded from the study. subsequently, a telephone survey was conducted of ep consultants or registrars working at 35 national health service (nhs) trust centres performing >100 ablation procedures per year.10 the survey recorded whether the centres had experienced any cases of vte complications in the last two years. verbal instructions were given prior to the survey to ensure that patients requiring therapeutic anticoagulation were not included. in addition, data were collected on the centres’ current practices regarding the use of periand postprocedural antithrombotics in both right-sided and left-sided ep procedures. this study was approved as a service evaluation project by the research & innovation department of the leeds teaching hospital nhs trust. all telephone table 1: sociodemographic, clinical and procedural characteristics of post-procedural venous thrombosis cases at the leeds general infirmary, leeds, uk (n = 3) characteristic case 1 case 2 case 3 sociodemographic gender female female male age in years 64 68 81 clinical presence of cardiac or respiratory comorbidities none none ihd and copd active cancer or cancer treatment no no no previous history of vte no no no oestrogencontaining therapy yes no no recent major surgery no no no bmi in kg/m2 41 34 24 procedural type of procedure ep study and rfa for avnrt ep study ep study and attempted vt ablation duration in minutes 150 30 135 access site rfv rfv rfv and artery with a retroaortic approach to the lv sheath sizes 2 × 5f 2 × 7f 2 × 5f 2 × 7f 1 × 4f 3 × 7f 1 × 8f number of catheters used 4 4 5 peri-procedural heparin administered in u 3,000 2,000 9,000* previous history of ep procedures in the past year yes no yes time from procedure to vte diagnosis in days 24 11 76 pre-procedure antiplatelet therapy prescribed no no 75 mg of aspirin daily post-procedure antiplatelet therapy/ anticoagulants prescribed upon discharge no no 75 mg of aspirin daily ihd = ischaemic heart disease; copd = chronic obstructive pulmonary disease; vte = venous thromboembolism; bmi = body mass index; ep = electrophysiological; rfa = radiofrequency ablation; avnrt = atrioventricular nodal re-entry tachycardia; vt = ventricular tachycardia; rfv = right femoral vein; lv = left ventricle. *prior to the activated clotting time being maintained at >300 seconds. current venous thromboembolism prevention practices following endovascular electrophysiological procedures in the uk a retrospective study e376 | squ medical journal, august 2018, volume 18, issue 3 survey participants gave informed verbal consent prior to participation in the study. results out of 1,020 adult patients undergoing ep procedures at the leeds general infirmary during the study period, three patients (0.3%) had post-procedural pulmonary emboli. in addition, the third case had confirmed right sided common femoral dvt. two of the patients under went right-sided procedures, while one patient underwent a left-sided procedure for attempted ventricular tachy cardia ablation. the procedure times ranged from 30–150 minutes. two patients had high body mass indices. case one was receiving oestrogen-containing therapy and case three had ischaemic heart disease along with chronic obstructive pulmonary disease. two patients received a nominal dose of ufh at the start of the proc edure, while the third received full therapeutic anticoagulation; however, none of the patients received postprocedural anticoagulation therapy. one patient took a daily dose of 75 mg of aspirin prior to the procedure, which was continued upon discharge [table 1]. following the vte diagnosis, all patients diagnosed with pulmonary emboli received at least three months of oral therapeutic anticoagulants as recommended by current guidelines, with no further complications observed.11 of the 35 uk-based centres performing >100 ablation procedures per year, 28 centres participated in the survey (response rate: 80%). the majority (68%) had a formal process for reviewing ep complications. a quarter of the centres perceived vte to be a serious complication following ep procedures, with 18% rep orting cases of vte complications occurring in the last two years. all of the centres confirmed that they adm inistered therapeutic ufh (for an act of ≥300 seconds) during left-sided procedures. in contrast, only 7% used a nominal dose of ufh (3,000–5,000 u) during right sided procedures. the majority of centres (61%) mobilised patients an average of 2–3 hours after their procedure, with other centres mobilising patients at 1–2 hours (11%), 3–4 hours (25%) or >4 hours (3%). most centres reported prescribing antiplatelet medications upon discharge to patients undergoing left-sided procedures, with very few centres prescribing these to patients undergoing rightsided procedures (71% versus 18%, respectively). if anti platelet medications were prescribed, the centres reported prescribing either aspirin or clopidogrel (dose range: 75–300 mg) for a duration of 4–12 weeks [figure 1]. none of the centres reported prescribing anticoagulants upon discharge. discussion at leeds general infirmary, 0.3% of patients undergoing ep procedures—excluding those on therapeutic anti coagulants—were diagnosed with a vte within 6–12 weeks of the procedure. these findings are in accordance with those in the published literature.1–4 in addition, all three of the affected patients had additional vte risk factors. crucially, the survey identified a wide variation in vte prevention strategies at uk-based ep centres, figure 1: flow chart showing the proportion of patients receiving antithrombotics/antiplatelets upon discharge and specific regimens according to uk-based electrophysiology centres (n = 28). christopher saunderson, sally hickman, elaine wilkinson and muzahir tayebjee brief communication | e377 particularly with regards to ufh use during right-sided ep procedures and the prescription of antithrombotic medications upon discharge. peri-procedural ufh in left-sided ep procedures is a well-established therapy to reduce thromboembolic complications, particularly in atrial fibrillation, and is recommended in multiple guidelines.9,12 in the current study, all of the surveyed centres reported using periprocedural ufh during left-sided procedures. in contrast, the role of peri-procedural ufh in rightsided procedures is unclear. alizadeh et al. conducted a randomised clinical trial (rct) in which 200 patients with right-sided supraventricular and ventricular tachy arrhythmias undergoing ep studies with and without rfa were randomised to two groups; the first group was administered intra-procedural heparin (a 5,000-u bolus with subsequent act measurement), while the second received no anticoagulation measures.13 after 24 hours, duplex ultrasonography revealed no cases of symptomatic dvt in either group. however, there was a significant decrease in the rate of in situ thrombosis between the heparin and control groups (11% versus 28%; p = 0.04).13 in another rct, 27 patients undergoing ep studies were randomised to receive either a fixed dose of 5,000 u of low-molecular-weight heparin (lmwh) one hour before the procedure or no anticoagulation measures.14 duplex ultrasonography performed 24 hours, one week and one month after sheath removal demonstrated a significant reduction in asymptomatic venous thrombi cases in the lwmh group compared to the control group (18.1% versus 62.5%; p = 0.02). however, the trial had a very small sample size with no clinical incidences of dvt.14 such studies provide a possible explanation for the low utilisation of peri-procedural anticoagulation therapy in right-sided procedures across the uk.13,14 in the current study, nominal doses of heparin did not prevent vte complications occurring in two patients undergoing right-sided procedures. antiplatelet therapy is not indicated for vte prophylaxis.5 furthermore, the ehra guidelines do not routinely recommend the use of oral anticoagulants or post-procedural antiplatelet therapy for ep procedures, except for patients with atrial fibrillation, atrial flutter or left ventricular tachycardia.9 however, current clinical practices do not appear to reflect this; according to findings from the telephone survey, 71% of centres prescribed antiplatelet therapy after leftsided procedures and 18% after right-sided procedures. a recent rct of 176 patients who had undergone rfa—excluding atrial fibrillation ablation—compared the use of direct oral anticoagulants (10 mg of rivaroxaban once a day) with aspirin (100 mg once a day) for three months after ep procedures.15 duplex ultrasonography was performed 48–72 hours after the proc edure, with no complete occlusive thrombus events. how ever, rivaroxaban significantly decreased the incidence of nonocclusive thrombi compared to aspirin (5.8% versus 16.7%; p = 0.023).15 the low event rate of symptomatic vte in this population indicates that there is no cons istent benefit of perior post-procedural antithrombotic therapy in vte prevention. therefore, further studies with larger samples are needed to substantiate recomm endations for vte prophylaxis after ep procedures. this retrospective study was subject to several limitations. although patients were seen at least once after their procedure at the leeds general infirmary, some patients underwent longer-term follow-up at other district hospitals; thus, some vte events may not have been reported. additionally, patients with identified vte complications also had other thrombotic risk factors, the influence of which was not evaluated in the present study. furthermore, a small proportion of centres did not respond to the telephone questionnaire. finally, the survey results were based on self-reported data from a single individual and thus may not be an accurate reflection of the wider experience or actual practices at the institutions. conclusion in this study, the post-procedural rate of vte complications was 0.3% among patients undergoing ep studies with or without rfa at leeds general inf irmary, excluding those who underwent atrial fibrillation ablation or who were taking oral anticoagulants. unfort unately, 18% of surveyed uk-based centres also reported having experienced this complication within the preceding two years, with current practices for the prevention of vte differing between centres. prophylactic measures for vte prevention are hampered by a lack of data to aid decision-making. therefore, larger-scale studies are required to adequately assess the risks and benefits of periand post-procedural thromboprophylaxis. a c k n o w l e d g e m e n t s a poster of the preliminary version of this study was presented at the heart rhythm congress 2017 on 1–4 october 2017 in birmingham, uk. an abstract of this poster presentation was subsequently published in europace in october 2017, volume 19, issue s1, p. i49. c o n f l i c t o f i n t e r e s t dr muzahir tayebjee received research and travel grants from biosense webster inc. (irvine, california, usa), st. jude medical inc. (saint paul, minnesota, usa), medtronic plc (dublin, ireland) and boehringer ingelheim gmbh (ingelheim am rhein, germany). the other authors declare no conflicts of interest. current venous thromboembolism prevention practices following endovascular electrophysiological procedures in the uk a retrospective study e378 | squ medical journal, august 2018, volume 18, issue 3 f u n d i n g no funding was received for this study. references 1. moubarak g, bonhomme s, vedrenne g, bouleti c, ollitrault j, priollet p, et al. femoral vein thrombosis after right-sided elect rophysiological procedures. j interv card electrophysiol 2013; 38:155–8. doi: 10.1007/s10840-013-9832-4. 2. chen jy, chang kc, lin yc, chou ht, hung js. safety and outcomes of short-term multiple femoral venous sheath placement in cardiac electrophysiological study and radiofrequency catheter ablation. jpn heart j 2004; 45:257–64. doi: 10.1536/ jhj.45.257. 3. michelucci a, antonucci e, conti aa, alessandrello liotta a, fedi s, padeletti l, et al. electrophysiologic procedures and activ ation of the hemostatic system. am heart j 1999; 138:128–32. doi: 10.1016/s0002-8703(99)70257-7. 4. hindricks g. the multicentre european radiofrequency survey (merfs): complications of radiofrequency catheter ablation of arrhythmias. eur heart j 1993; 14:1644–53. doi: 10.1093/eurhe artj/14.12.1644. 5. national institute of health and care excellence. venous throm boembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. from: www. nice.org.uk/guidance/ng89 accessed: mar 2018. 6. li yc, lin j, wu l, li j, chen p, guang xq. clinical features of acute massive pulmonary embolism complicated by radio frequency ablation: an observational study. medicine (baltimore) 2015; 94:e1711. doi: 10.1097/md.0000000000001711. 7. fanikos j, rao a, seger ac, carter d, piazza g, goldhaber sz. hospital costs of acute pulmonary embolism. am j med 2013; 126:127–32. doi: 10.1016/j.amjmed.2012.07.025. 8. national institute of health and care excellence. venous throm boembolism: reducing the risk for patients in hospital. from: www.nice.org.uk/guidance/cg92 accessed: mar 2018. 9. sticherling c, marin f, birnie d, boriani g, calkins h, dan ga, et al. antithrombotic management in patients undergoing elec trophysiological procedures: a european heart rhythm assoc iation (ehra) position document endorsed by the esc working group thrombosis, heart rhythm society (hrs), and asia pacific heart rhythm society (aphrs). europace 2015; 17:1197–214. doi: 10.1093/europace/euv190. 10. british heart rhythm society. national audit of cardiac ablation: 2013-14. from: www.bhrs.com/files/files/audit%20reports/a blation%20report%202013-14%20version%209%20final(1).pdf accessed: mar 2018. 11. konstantinides sv, torbicki a, agnelli g, danchin n, fitzmaurice d, galiè n, et al. 2014 esc guidelines on the diagnosis and management of acute pulmonary embolism. eur heart j 2014; 35:3033–69. doi: 10.1093/eurheartj/ehu283. 12. wazni om, rossillo a, marrouche nf, saad eb, martin do, bhargava m, et al. embolic events and char formation during pulmonary vein isolation in patients with atrial fibrillation: impact of different anticoagulation regimens and importance of intracardiac echo imaging. j cardiovasc electrophysiol 2005; 16:576–81. doi: 10.1111/j.1540-8167.2005.40480.x. 13. alizadeh a, yazdi ah, kafi m, rad ma, moradi m, emkanjoo z. predictors of local venous complications resulting from electrophysiological procedures. cardiol j 2012; 19:15–19. 14. davutoglu v, kervancioglu s, dinckal h, soydinc s, turkmen s, akdemir i, et al. high incidence of occult femoral vein thrombosis related to multiple venous sheaths during electrophysiological studies. heart 2004; 90:1061–2. doi: 10.1136/hrt.2003.027128. 15. li l, zhang bj, zhang bk, ma j, liu xz, jiang sb. prevention and treatment of lower limb deep vein thrombosis after radiofrequency catheter ablation: results of a prospective active controlled study. sci rep 2016; 6:28439. doi: 10.1038/ srep28439. https://doi.org/10.1007/s10840-013-9832-4 https://doi.org/10.1536/jhj.45.257 https://doi.org/10.1536/jhj.45.257 https://doi.org/10.1016/s0002-8703%2899%2970257-7 https://doi.org/10.1093/eurheartj/14.12.1644 https://doi.org/10.1093/eurheartj/14.12.1644 https://doi.org/10.1097/md.0000000000001711 https://doi.org/10.1016/j.amjmed.2012.07.025 https://doi.org/10.1093/europace/euv190 https://doi.org/10.1093/eurheartj/ehu283 https://doi.org/10.1111/j.1540-8167.2005.40480.x https://doi.org/10.1136/hrt.2003.027128 https://doi.org/10.1038/srep28439 https://doi.org/10.1038/srep28439 july 2008.indd abstract traumatic rupture of the diaphragm (trd) poses a challenge to both radiologists and surgeons. they are uncommon and occur following blunt abdominal or lower thoracic trauma. the right side involvement is less common than the left side and is easily missed. spiral computed tomography (spiral ct) with image reformation is very useful in the diagnosis of trd and in identifying associated injuries. early diagnosis and repair reduces mortality and morbidity. we present the case of a 6 year old boy who was involved in a high speed traffic accident with blunt injury to his thorax and abdomen. he was referred from a peripheral hospital in oman for further management at sultan qaboos university hospital. a spiral ct scan of thorax and abdomen with image reformation helped in the early diagnosis and management of the traumatic rupture of his right hemidiaphragm. key words: right hemidiaphragm; rupture; computerized tomography; case report; oman. traumatic rupture of the right hemidiaphragm: diagnosis aided by computerized tomography and image reformation a case report *ranjan r william, dilip sankhla, badriya al-qassabi, khalsa al ramadani sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 219-222 sultan qaboos university© submitted accepted we present this case report to high-light the role of spiral computed tom-ography (ct) with image reformation in the early diagnosis and management of traumatic rupture of the right hemidiaphragm. c a s e r e p o r t a 16 year old male patient who was involved in a high speed traffic accident with blunt trauma to chest and abdomen was admitted to a peripheral hospital in the sultanate of oman. the patient was treated for a suspected haemothorax on the right side with intercostal tube drainage and transferred after five days to sultan qaboos university hospital for further management. an initial chest x-ray showed an elevated right hemidiaphragm with mild superomedial tenting and with normal pleural spaces. there were no rib fracdepartment of radiology and molecular imaging, sultan qaboos university & hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: ranjanwilliam@gmail.com تشخيصه بواسطة األشعة األمين: احلاجز احلجاب لنصف يّ حِ َزُّقٌ رَضْ متَ املقطعية حالة تقرير الصور تشكيل إعادة مع الرمضاني خالصة القصابي، بدريه شنكال، ديليب وليام، ر. راجنان أخصائي لكل من حتديا ، يشكل الصدر وأسفل للبطن ــرة املباش اإلصابة نتيجة عادة يحصل الذي احلاجز الرضحي احلجاب متزق ــخيص امللخص: تش يعتبر ــخصيها تش في ــر واخلطأ األيس باجلانب مقارنة ندرة األمين أكثر اجلانب إصابة تعتبر احلدوث. ــائع ش من أنه غير واجلراحني على الرغم ــعة األش علي ساعدت الوقت نفس وفي من اإلصابات النوع لهذا التشخيص عملية سهلت الصور ــكيل تش إعادة مع ــبة احملوس املقطعة ــعة األش ورودا. أكثر حادث أصيب في سنة (16) عمره ــاب لش حالة هنا نقدم الوفاة. وخطر املراضة من يقلالن املبكر ــخيص والعالج التش املصاحبة. اإلصابات ــخيص تش للصدر املقطعة ساعدت األشعة حيث عمان في قابوس السلطان جامعة مستشفى املريض إلى هذا مت حتويل وصدره. بطنه في ليلَة كَ ٌ إِصابَات سير مبكرا. عالجه في والبدء األمين الرضحي احلاجز احلجاب لتمزق املبكر التشخيص على الصور إعادة تشكيل مع والبطن عمان. حالة ، تقرير ، احملوسبة املقطعة األشعة ، الرضحي التمزق ، احلاجز األمين احلجاب الكلمات: مفتاح c a s e r e p o r t r a n j a n r wi l l i a m , d i l i p k u m a r s a n k h l a , b a d r i ya a l q a s s a b i a n d k h a l s a a l r a m a d a n i 220 tures. it also showed a suboptimally placed right intercostal drainage catheter tube [figure1]. a followup spiral ct scan of thorax and abdomen showed features of right diaphragm rupture and liver herniation into the thorax [figures 2 and 3]. the axial scans showed a subtle indentation on the posterolateral and medial aspects of the liver (arrow heads) which caused the ‘collar sign’. the waist-like constriction in the liver and its herniation into the thorax are well shown in the reformatted coronal and sagittal oblique images associated injuries were liver contusion and a small subcapsular haematoma and thorax images showed a posterior segmental atelectasis of the right lower lobe [figure 2]. the abdominal findings were confirmed at surgery and the diaphragm was repaired. no surgical intervention was performed for the liver injury as it was small. the suboptimally positioned intercostal catheter was removed. d i s c u s s i o n acute traumatic diaphragmatic ruptures are uncommon and occur in about 0.8-8% of major blunt trauma victims.1 left-sided tears are more common than rightsided tears.2 blunt trauma to lower thorax or abdomen secondary to a motor vehicle accident is the most common cause of close rupture of the hemidiaphragm.1, 3 there are two possible mechanisms for rupture of a hemidiaphragm. one is a lateral impact which causes shearing of the diaphragm due to distortion of the chest wall; the other is frontal impact which leads to an increase in intra-abdominal pressure.4 penetrating injuries can also cause diaphragmatic injuries but these are usually small.2 the injury to left hemidiaphragm is more frequent following blunt trauma, possibly due to a buffering effect of the liver on the right hemidiaphragm. however, the relative infrequency of right-sided injury may also be associated with under-diagnosis.1 associated injuries like liver injuries are also common.4 chest x-rays and spiral ct scanning with image reformation are useful in the early diagnosis of trd. on axial ct images, the axis of the image is tangential to the dome of the diaphragm, so axial images alone are suboptimal for the diagnosis of diaphragmatic rupture. ct is also helpful in identifying associated injuries with trd as in our patient who also had liver contusion with subcapsular haematoma and right lower lobe segmental atelectasis. other imaging mofigure 1: chest x-ray frontal and lateral projections showing elevated right hemidiaphragm with superomedial tenting. an intercostal drainage tube is shown on the right side. tr au m at i c r u p t u r e o f t h e r i g h t h e m i d i a p h r a g m : d i a g n o s i s a i d e d b y c o m p u t e r i z e d to m o g r a p h y a n d 221 dalities like ultrasound and magnetic resonance imaging are also used, however to a lesser extent in patients with polytrauma. chest x-ray findings of trd include elevation of hemidiaphragm, distortion or obliteration of the outline of the hemidiaphragm and contralateral movement of mediastinum.1 our patient showed a markedly elevated right hemidiaphragm with some “tenting” of the superomedial aspect [figure1]. right diaphragm injuries are more difficult to detect on the radiograph. the liver serves to block the herniation of abdominal contents into the thorax. herniation of the liver is often overlooked. the differential diagnosis for elevated right hemidiaphragm includes right lower lobe atelectasis, pleural effusion and pulmonary contusion.1 the use of spiral ct has improved the accuracy in the diagnosis of trd with an overall sensitivity of 71% and specificity of 100%.4 a recent study by nchimi a et al, has suggested that diaphragmatic discontinuity, diaphragmatic thickening, segmental non-recognition of the diaphragm, intrathoracic herniation of abdominal viscera, elevation of the diaphragm, and both haemothorax and haemoperitoneum were strong predictors of blunt diaphragmatic rupture.5 other ct findings include the ‘collar sign’ a waist-like constriction of the hollow viscus or solid organ at the site of diaphragmatic tear and the dependent visceral sign.1 in the dependent visceral sign, the diaphragmatic injury allows the upper portion of the liver to drop posteriorly against the ribs. the collar sign on the right side [figure 2] appears as a focal indentation of the liver (arrow heads). this is a subtle sign which can be easily overlooked. this requires careful analysis of the sagittal/coronal multiplanar reformatted images [figure 3]. an increase in sensitivity from 16.7% to 50% in cases of right hemidiaphragm rupture with additional use of reformation images has been reported.6 although spiral ct images with multiplanar reformation are quite useful one should be aware of the false positive and negative ct findings in the diagnosis of trd. not all diaphragmatic defects are specific for rupture. posterolateral defects are shown in about 6% of asymptomatic adults which are mainly on the left side. not all diaphragmatic defects are related to trauma, they can be congenital such as bochdalek’s figure 2: axial contrast enhanced spiral ct. shows ‘collar sign’. a subtle indentation (arrow heads) on the posterolateral and medial aspect of the liver. note also the liver laceration. r a n j a n r wi l l i a m , d i l i p k u m a r s a n k h l a , b a d r i ya a l q a s s a b i a n d k h a l s a a l r a m a d a n i 222 foramen dorsally. it is also difficult to identify the margins of the hemidiaphragm following thoracic trauma because of pleural effusion, particularly in small tears and in the absence of intra abdominal contents herniation in to the thorax.1 c o n c l u s i o n we report a case of a young patient with traumatic rupture of the right hemidiaphragm with liver herniation into the thorax. spiral ct with image reformation helped in the early diagnosis and management of the patient. ct is also useful in assessing associated thoraco-abdominal injuries. early diagnosis of this condition and repair of the diaphragmatic tear are desirable as it reduces the mortality and morbidity. r e f e r e n c e s 1. iochum s, ludig t, walter f, sebbag h, grosdidier g, alain g, et al. imaging of diaphragmatic injury: a diagnostic challenge? radio graphics 2002; 22:103-118. 2. mihos p, potaris k, gakidis j, paraskevopoulos j, varvatsoulis p, gougoutas b, et al. traumatic rupture of diaphragm: experience with 65 patients. injury 2003; 34:169-172. 3. kristine ls, edward ts, andrew jt. traumatic diaphragmatic injuries: spectrum of radiographic findings. radio graphics 1998; 18:49-59. 4. shanmuganathan k, killeen k, mirvis se, white cs. imaging of diaphragmatic injuries. j thorac imaging 2000; 15:104–111. 5. nchimi a, szapiro d, ghaye b, willems v, khamis j, haquet l, et al. helical ct of blunt diaphragmatic rupture. ajr am j roentgenol 2005; 184:24-30. 6. killeen kl, mirvis se, shanmuganathan k. helical ct of diaphragmatic rupture caused by blunt trauma. ajr am j roentgenol 1999; 173:1611–1616. figure 3: image reformation coronal and sagittal-oblique planes shows the ‘collar sign’ better with liver herniation into the thorax. clinical & basic research squ med j, february 2011, vol. 11, iss. 1, pp. 45-51, epub. 12th feb 11 submitted 2nd aug 10 revision req. 11th oct 10, revision recd. 17th oct 10 accepted 10th nov 10 ·^€ �¬<ª<áeü÷]<ó◊¬<ïü�èä÷] íeü√÷]<sè◊§]<ª<?áeü◊÷<ìœèœ£]ê<–è€√÷]<‹„à÷]@<ÿáu<ìèflõá÷]<sò^jfl÷]< <ófiå˘]<—üé÷]ê<   “”    2007 102  “  2008  201 %21  %43 16  %45 %57     %44   %47  %5 %34.8 %32.6   0.054     abstract: objectives: the asthma insights and reality (air) study in the gulf and near east (one of a worldwide series of surveys conducted in adults and children to assess asthma control) was conducted in oman to assess how closely asthma control meets international guidelines recommendations. methods: from january 2007 to march 2008, asthmatics receiving treatment or currently suffering from asthma symptoms were interviewed among nationals randomly surveyed from the most populated urban areas in oman (muscat, sohar and nizwa). the standard air questionnaire was used to assess symptom severity, health care utilisation, limitation of activity and medication use. results: from 201 asthmatic participants, 21% were under 16 years and 43% were female. tobacco use was low in our asthmatics. disparity in asthma perception was wide in oman; while 57% of asthmatics perceived their asthma as well or completely controlled, actually 54% had poorly or not well controlled asthma. all recommendations for asthma control by the global initiative for asthma were largely unmet, especially in child asthmatics, with 44% reporting night awakenings due to asthma during the previous 4 weeks and 47% exerciseinduced asthma in the previous 12 months. overall, 32.6% of children and 34.8% of adults reported absence due to asthma from school/work during the previous year. use of preventive inhaled corticosteroids was only 5.0%, one of the lowest even within the air gulf and near east study, producing an unacceptable ratio ics/saba (inhaled corticosteroid/short acting beta-agonist) of 0.054 in omani asthmatics. conclusion: asthma control in oman falls far below the goals of current international guidelines therefore corrective strategies are needed. keywords: asthma; oman; health survey; asthma prevention & control; adult; child clinical & basic research asthma control in oman national results within the asthma insights and reality in the gulf and the near east (airgne) study *nasser al-busaidi1 and joan b soriano 2 clinical & basic research 1department of medicine, royal hospital, muscat, oman; 2epidemiology and clinical research, fundación caubet-cimera (centro internacional de medicina respiratoria avanzada), islas baleares, spain. *corresponding author email: enhsa@hotmail.com advances in knowledge 1. current international asthma initiatives, both for children and adults, recommend to measure the asthma burden worldwide. however, asthma control in oman national results within the asthma insights and reality in the gulf and the near east (airgne) study 46 | squ medical journal, february 2011, volume 11, issue 1 the global initiative for asthma (gina) guidelines, which were introduced in 1995,1 followed by many other local guidelines, all aimed at improving asthma patient care and ensuring better long-term control of the disease. control was the cornerstone of the latest gina update in 2006.2 studies have shown that total asthma control is achievable in most patients.3 there exists, however, a wide gap between the goals of treatment as set out in the guidelines and actual real-life clinical practice outcomes. recently, several asthma insights and reality (air) surveys were conducted in various countries around the world, including the usa, canada, the asia-pacific region, western and central-eastern europe, japan, latin america, saudi arabia, and most recently in the gulf and the near east. they all aimed to determine variations in asthma severity and control, both from the patient perspective and objectively, compared to what is recommended by the guidelines. consistently, these surveys demonstrated a poor level of asthma control in all the above mentioned countries and regions, with local variations specific to each country. oman is in the middle east at the northern edge of the gulf with a population of about 2.6 million inhabitants. there is a paucity of statistics about asthma prevalence and asthma burden in oman. by using the international study of asthma and allergies in childhood (isaac) methodology 2003, al-riyami et al. reported prevalence rates of diagnosed asthma in oman of 20.7% in 13–14 yearolds, whereas in younger children (6–7 years) it was 10.5%.4 the prevalence of severe asthma (sleepdisturbing wheeze and speech-limiting wheeze) and frequent symptoms in omani schoolchildren (age between 6–7 years), compared with other isaac participating countries in the east mediterranean region, was higher than in any other country in the study. similarly, the prevalence of sleep-disturbing wheeze among omani children was nearly four times that of iran and almost double that of malta.4 we also previously reported that more than 50% of our adult asthmatic patients felt that their asthma had a negative impact in their work, school or home duties.5 nocturnal symptoms were common in our studied patients, only 44% reported having had no night-symptoms in the previous 4 weeks, while the rest felt their asthma often disturbed their sleep. this ranged from 4% reporting two to three wakeups per night to 28% reporting one to two wake-ups due to asthma in the last 4 weeks.5 the gina guidelines have been developed to promote standardised methods of diagnosis and treatment of asthma that now are generally accepted worldwide. research published since the release of the gina guidelines indicates that in many countries patients with asthma are unequally treated and that adherence to asthma treatment guidelines is poor.6,7 all air studies aimed to assess the discrepancy between perceived symptoms and subjective assessments versus objective control and the burden of asthma in order to determine the implementation status of the goals and management recommendations advocated by gina. they also have helped to shed light on the perceptions, knowledge and attitudes related to asthma at the local level in order to assist in future national policy development. oman was one of the gulf and near east countries included in the air gulf and near east (airgne) study, together with jordan, kuwait, lebanon, and the uae. the summary results have been published elsewhere,8 but the specific omani data results warrant a closer look and are presented in this paper. methods the airgne survey was conducted between january 2007 and march 2008. the most populated urban areas in oman were surveyed in airgne, namely the capital area, muscat/seeb/mutrah, with to date there were few studies conducted in the gulf and none in oman focused on measuring asthma control and asthma severity. 2. the current use of preventive medications in omani asthmatic children and adults appear to be one of the lowest in the gulf region, and even worldwide. application to patient care 1. doctors in oman should be aware of the burden of asthma. 2. educational and corrective strategies should be implemented in oman to improve individual and population asthma management. nasser al-busaidi and joan b soriano clinical and basic research | 47 60% of the sample; sohar, a port city on the northern coast of oman with 25%, and nizwa, a city 120km south west of muscat in the dakhiliyah region with 15%. the sampling was structured by gender and age within each city or urban area. asthma patients were identified by systematically screening a sample of households for persons who had been diagnosed with asthma. a sampling plan was designed to provide a nationally representative sample of households that could be screened to identify a community sample of current asthma sufferers for oman. a geographically stratified sample of households, proportionate to the population, was drawn within the three designated areas. the survey design required a sample of 200 asthma patients. in each household, an adult was asked whether a physician had ever diagnosed any member of the household as having asthma. if the answer was “yes”, the interviewer asked whether any of these individuals were currently taking medication for their asthma, or had suffered an asthma attack or experienced asthma symptoms in the past year. the number of persons in the household, as well as the number who had been diagnosed with asthma and met the survey criteria for current asthma, were collected to provide estimates of comparative prevalence. if more than one household member qualified as a current asthma patient, the interviewer randomly selected one as the designated respondent. only one respondent was interviewed per household because multiple interviews in the same household would have created a bias. if the selected respondent was 16 years of age or older, the interview was conducted with the patient; if he/she was 15 years or younger, the interview was conducted with the parent or guardian most knowledgeable about the child’s asthma condition and treatment. the study was approved by the ethics committee of the ministry of health, oman. this study was non-interventional and anonymous, and no individual identifiers were obtained or stored. following the advice of the coordinating team in europe (jb soriano) it was considered that the verbal authorisation from individual asthmatics (or his/her parent) would be sufficient consent. the core questionnaire was that used in previous air studies in europe and elsewhere,8 which was based on the original ats (american thoracic society) questionnaire.9 the questionnaire was translated into arabic and then translated back again; any discrepancies or inconsistencies discovered by this process were solved by consensus. in addition, the following items were included: self-completion of the asthma control test (act) questionnaire,10 various questions modified to reflect the local conditions and characteristics of asthma in oman and some additional questions to reflect the latest gina guidelines. it was administered with an english-arabic side-by-side layout,8 available online from the international journal of tuberculosis and lung disease (ijtld) website.10 as per standard quality control procedures, all materials were piloted. there was also a personal briefing of all interviewers in each region, and each interviewer conducted two pilot interviews and reviewed the completed questionnaires with a supervisor before starting fieldwork. completed questionnaires were checked locally and again centrally, and a random double check of interviews in all regions was conducted by telephone. finally, all data were included in a database after independent double typing. the frequency and severity of daytime and nighttime symptoms, exercise-induced symptoms and severe episodes, and total symptom frequency, were used to develop a symptom severity index similar to the gina asthma severity scale.11 in addition, events such as hospitalisations and emergency care utilisation were documented, as well as the impact of days of school/work lost due to asthma. patient demographic and asthma severity characteristics were compared using chi-squared analysis to identify factors that might account for differences in asthma management across the country, or analysis of variance for quantitative variables whenever required. statistical comparisons within the country versus the published international air estimates were explored. all statistical tests were two-sided and comparisons with <5% probability of error were considered statistically significant. results a total of 201 valid interviews with omani asthmatics in the three participating cities were completed, of whom 115 (57%) were male. the age distribution was very young, with 21% of the sample being 5–15 years old and 33% 16–29 asthma control in oman national results within the asthma insights and reality in the gulf and the near east (airgne) study 48 | squ medical journal, february 2011, volume 11, issue 1 years old. most participants had only completed primary (38%) or secondary (30%) education. reported income was lower than $1,000 per year in 75% of surveyed participants, while reported smoking in adults was minimal [table 1]. a total of 90 (57%) of adult asthmatic responders (n = 158) perceived their asthma as "well" or "completely" controlled. the actual figures show, on the contrary, that 54% of adult responders had "poorly" or "not well" controlled asthma. (p <0.05 ). a total of 71% of participating omani asthmatics reported day-symptoms during the previous 4 weeks. similarly, 44% reported night awakenings due to asthma during the previous 4 weeks and 47% exercise-induced asthma in the previous 12 months, both were particularly frequent in child asthmatics [table 3]. exacerbations and use of health services were equally high, and limitations of daily activities due to asthma were widespread both in children and adult asthmatics. one in three asthmatics had never had their lung function tested and few owned a peak flow meter. a total of 32.6% of children reported school absence due to asthma during the previous year, with a mean standard deviation (sd) of 6.1 (8.5) days. in adults 34.8% reported work absence due to asthma during the past year, with a mean sd of 9.9 (9.8) days [table 4]. use of health services was similarly high compared to other airgne participating countries, with 30% of hospitalisations and 58% of emergency (unscheduled) medical visits. finally, current use of preventive inhaled corticosteroids was 5.0%, one of the lowest even within the airgne study, with a mean of 14.6%. most (92%) patients relied rather upon quick relief medications, producing an unacceptable ratio ics/ saba (inhaled corticosteroid/short acting betaagonist) of 0.054 [table 5]. as mentioned above, there was a low prevalence of both ownership of a peak flow meter (25.4%) and ever having had a lung function test (35.0%) in the omani asthmatics in this study. discussion airgne-oman was the first survey in the country to assess objectively the level of control and severity of asthma. it demonstrated that asthma management was poor in 2007–2008 compared to recommendations in published guidelines. as in table 1: demographic characteristics of asthma patients. values correspond to numbers (percentages) of patients in the corresponding category except for age of adults and children at inclusion and age at diagnosis which are represented as means ± standard deviation (13.5 ± 6.7) parameter population n = 201 interval age distribution 5–15 years 43 (21%) 16-29 years 67 (33%) 30-49 years 71 (35%) > 50 years 20 (10%) age at diagnosis, mean; 13.5 gender m 115 (57%) f 86 (43%) level of education primary 77 (38%) secondary 62 (30%) university 62 (30%) income <1000 $ 152 (75%) 1000-2000 $ 36 (18%) >2000 $ 13 (6%) region muscat 121 (60%) sohar 50 (25%) nizwa 30 (15%) smoking habits in adults never smoked 173 (96%) former smokers 7 (3%) table 2: comparison between objective and subjective evaluation of asthma control subjective asthma control§ objective asthma control* p value poorly and not well controlled 68 (43%) 86 (54%) <0.05 well/ completely controlled 90 (57%) 72 (46%) note: § = adult responders only (n=158); *= objective evaluation of asthma control relies on the asthma control test (act). an act of 5 to 19 corresponds to a poorly and or not well controlled asthma, and an act of 20 to 25 corresponds to a well controlled asthma for adult responders only (n=158). nasser al-busaidi and joan b soriano clinical and basic research | 49 all previously published international air studies, asthma is poorly managed in oman with the performance far below the recommended goals of any guidelines. this was obvious when the actual gina recommendations of control were compared to the airgne-oman findings [table 2], clearly showing that guideline-based control was not achieved at the time in of our study. in the european and asia pacific air studies approximately half of the adult patients reported daytime symptoms. the overall figure in the airgne study was 68%, and it was equally high in oman (71%) in the present study. these results are close to the findings of rawas et al. as they found nearly 60% of all current wheezers reported at least one of the symptoms indicating severe or uncontrolled asthma.14 night awakenings were also frequent in the airgne-oman study (44%), and this finding is compatible with the study of al-riyami et al.4 where the prevalence of sleepdisturbing wheeze in oman was nearly four times that of iran (3.5% versus 0.9%) and more than double that of malta (3.5% versus 1.5%). it was even higher than that of australia (3.5% versus 2.8%), a country with the highest prevalence rate of wheeze among all isaac participating countries, being more than three times that of oman. the frequency of hospitalisation in oman in the previous twelve months was also high, reaching 30%. emergency department visits were high in oman, as in other airgne countries, the figures being 58% and 51% respectively. these figures were much higher than those in the study conducted by al rawas et al.12 of the asthmatic patients in his study, who were attending asthma specialty clinics, only 31.9% had visited the emergency department and 15.0% patients had been hospitalised at least once during the previous year. table 3: the global initiative for asthma (gina) recommendations for asthma control and the asthma insights and reality in oman (airo) results gina definition for control of asthma airo findings adults (%) children (%) all (%) minimal (ideally no) chronic symptoms, including nocturnal symptoms asthma symptoms during day (past 4 weeks) night wakening (past 4 weeks) exercise-induced asthma (past 12 months) 73 45 51 81 60 60 71 44 47 minimal exacerbation sudden severe episodes in past 12 months 95 84 93 no emergency visit for asthma hospitalisation (past 12 months) emergency department visit (past 12 months) 35 18 42 36 30 21 minimal need for short-acting β2 agonists current use of quickrelief bronchodilators 85 no limitation on activities, including exercise asthma restricts sports and recreation normal physical activity choice of jobs/careers social activities sleeping lifestyle household chores 38 35 18 32 22 21 20 77 70 14 42 56 49 49 46 43 17 34 29 27 26 normal or nearnormal lung function (pef variability 20%) never had a lungfunction test owns a peak flow meter 42 17 19 35 35 25 legend: pef = peak expiratory flow. asthma control in oman national results within the asthma insights and reality in the gulf and the near east (airgne) study 50 | squ medical journal, february 2011, volume 11, issue 1 on the other hand, school absence in children was significantly less frequent in oman than in other airgne countries (32.6% versus 51%; p <0.05, chi 2 p statistic when compared to airgne results.) another positive finding among adult asthmatics in airgne-oman study was the very low prevalence of smoking, with only 3% of respondents reporting either a current or previous smoking habit. this is probably one of the lowest figures recorded worldwide,13 and indeed an achievement to be sustained in the future. the current use of asthma medications in oman is disappointing. according to the findings in this study, only 5% of asthmatics were using inhaled corticosteroids compared to 14.6% in other airgne countries (p <0.05). on the other hand, the use of rescue medication was strikingly high, with 92% of asthma patients reporting daily use of them compared to 55.5% in other airgne countries. interestingly, these findings totally differ from al rawas et al. where 92% of asthma patients attending asthma specialty clinics used inhaled corticosteroids.12 the discrepancy is likely due to the fact that patients in asthma specialty clinics are seen by chest specialists who are aware that steroid inhalers are the cornerstone of asthma treatment; it is also possibly due to the fact that these patients have more severe asthma. most patients overestimated their level of control and underestimated their disease severity, as there was a disparity in the patient subjective versus objective asthma severity perception. while 90 (57%) of asthmatics perceived their asthma as well or completely controlled, actually 54% had poorly or not well controlled asthma as objectively identified by an act score of 5 to 19 (p <0.05 ). the frequency of lung function tests was generally low in oman, being at similar levels to other airgne countries, as only 35% reported their lungs ever tested, and only 25% owned a peak flow meter. overall, when comparing the omani results with the airgne average, the management of asthma in oman was worse in terms of reporting a higher use of rescue medications and very low uses of inhaled corticosteroids, as well as unacceptably frequent visits to emergency departments. table 4: evaluation of asthma burden in the past year in oman by comparison to asthma insights and reality in the gulf and near east (airgne) study results oman (n = 201) airgne (n= 1,000) p value asthma burden in the past year school absence in children, % mean number of days (sd) work absence in adults, % mean number of days (sd) 32.6 6.1 (8.5) 34.8 9.9 (9.8) 51.7 7.9 (9.6) 29.7 7.3 (8.1) <0.05 0.420 use of health services in the past year hospitalisation, % emergency medical visit, % 30.0 58.0 22.5 51.5 0.723 0.571 legend: sd= standard deviation. table 5: current use of preventive inhaled corticosteroids and quick relief medications, and evaluation of lung function in oman by comparison to asthma insights and reality in the gulf and near east (airgne) study results oman (n = 201) airgne (n= 1,000) p value* current use of medication (previous 4 weeks) use of ics, % use of quick relief, % ratio ics/saba 5.0 92.0 0.054 14.6 55.5 0.26 <0.05 <0.05 <0.05 lung function own a peak flow meter, % ever had a lung function test, % 25.4 35.0 17.1 32.7 <0.05 0.746 legend: ics= inhaled corticosteroids; saba= short acting beta-agonist. nasser al-busaidi and joan b soriano clinical and basic research | 51 there are some potential limitations of this survey. first, sampling was not performed according to random digit dialing (rdd) as in most other air surveys. in countries where telephone ownership levels approach 100% and comprehensive databases are available, rdd can approximate a representative random sample of the population. however, rdd was not considered appropriate in oman, and overall in the gne, because of the low penetration of telephone coverage. second, there are problems associated with the term asthma in our country, therefore many doctors avoid using this term, and use instead the term allergy, with an intention to making it milder and more acceptable to patients themselves or to their parents. perhaps third, the sample size of 201, while being considerable enough, gives some subgroup analyses (by young children or in severe asthma) reduced statistical power. therefore, more studies are needed to monitor all trends and assess current interventions. conclusion the air study in oman highlights the gap between the recommended long-term asthma management guidelines and the reality in oman. international guidelines recommend treating inflammation and not symptoms, but the trend of poor inhaled corticosteroid utilisation among omani patients with persistent asthma suggests undertreatment. this implies an immediate need to improve communication and awareness among patients and physicians, specifically to reinforce the use of anti-inflammatory medications. underestimation of the severity of asthma and overestimation of asthma control by both patients and physicians are important factors contributing to poor asthma control. c o n f l i c t o f i n t e r e s t the airgne survey was sponsored by glaxosmithkline. all authors had access to the database and discussed and drafted this report independently from the sponsor. references 1. global initiative for asthma (gina). global strategy for asthma management and prevention. nhlbi/ who workshop report. national institute of health, national heart, lung and blood institute; 1995. national institute of health publication no. 95-3659. 2. bateman ed, hurd ss, barnes pj, bousquet j, drazen jm, fitzgerald m, et al. global strategy for asthma management and prevention: gina executive summary. eur respir j 2008; 31:143–78. 3. bateman ed, boushey ha, bousquet j, buss ww, clark tj, pauwels ra, et al. can guideline-defined asthma control be achieved? the gaining optimal asthma control study. am j respir crit care med 2004; 170:836–41. 4. al-riyami bms, al-rawas oas, al-riyami aa, jasim lg, mohammed aj. relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirology 2003; 8:69–76. 5. al-busaidi n, al mokhaini s. level of control of asthma patients in chest specialist clinics. oman med j 2009; 24:195–8. doi:10.5001/omj.2009.38. 6. rickard ka, stemple da. asthma survey demonstrates that the goals of the nhlbi have not been accomplished. j allergy clin immunol 1999; 103:s171. 7. largelov p, veninga cc, muskova m. on behalf of the drug education project (dep) group. asthma management in five european countries: doctors’ knowledge, attitudes and prescribing behavior. eur respir j 2000; 15:25–9. 8. khadadah m, mahboub b, al-busaidi nh, sliman n, soriano jb, bahous j. asthma insights and reality in the gulf and the near east. int j tuberc lung dis 2009; 13:1015–22. 9. ferris bg. epidemiology standardization project. am rev respir dis 1979; 118:s1–120. 10. international journal of tuberculosis & lung disease. gina questionnaire. from: http://www. theunion.org/about-the-journal/about-the-journal. html accessed: july 2010. 11. rabe kf, vermeire pa, soriano jb, maier wc. clinical management of asthma in 1999: the asthma insights and reality in europe (aire) study. eur respir j 2000; 16:802–7. 12. schatz m, sorkness ca, li jt, marcus p, murray jj, nathan ra, et al. asthma control test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. j allergy clin immunol 2006; 117:549–56. 13. rabe kf, vermeire pa, soriano jb, maier wc. clinical management of asthma in 1999: the asthma insights and reality in europe (aire) study. eur respir j 2000; 16:802–7. clinical & basic research squ med j, february 2011, vol. 11, iss. 1, pp. 52-55, epub. 12th feb 11 submitted 24th nov 10 revision req. 3rd jan 11, revision recd. 10th jan 2011 accepted 11th jan 11 departments of 1obstetrics & gynaecology and 2medicine, sultan qaboos university hospital, muscat, oman; 3industrial innovation center, rusayl, oman; 4department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: omayma0@hotmail.com ÿ⁄]á£]<l^èfi^€�√÷]<çfl¬<dåe<∞⁄^fljè <<ì÷^u –◊œ÷]<4ni<<l^ñëüπ]<‡⁄<ìè÷^¬<ìfäfi<çfl¬<dåe<∞⁄^jè <‡⁄<ìñà~fl⁄<<ìfäfi<åáqê<   25    100 2010 ––  25%69 67 25 ≥%35 34  75< 5025  10003 3 25 :مفتاح الكلمات abstract: objectives: the objective of this study was to determine the vitamin d status of pregnant omanis by measurement of their circulating 25 hydroxy vitamin d levels. methods: blood samples were obtained from a cohort of 103 consecutive healthy pregnant omanis at the armed forces hospital, muscat, on their first antenatal visit. the study took place in may, june and july 2010. results: vitamin d deficiency was present in 34 (33%) of patients (25ohd3 <25 nmol/l), ‘at risk’ levels were found in 67 (65%) patients (25ohd3 25–50 nmol/l); two patients (1.9%) had values between 50 and 75 nmol/l, and no patients in the optimal range >75 nmol/l. conclusion: if confirmed, these findings indicate the need for vitamin d replacement during pregnancy and lactation. although not evidence based we recommend at least 1000 iu of cholecalciferol, (vitamin d3) daily. keywords: pregnancy; oman; 25 hydroxyvitamin d3 (25ohd3); vitamin d deficiency vitamin d status in pregnant omanis a disturbingly high proportion of patients with low vitamin d stores moza al kalbani,1 *omayma elshafie,2 mohammed rawahi,2 ali al-mamari,2 abdullah al-zakwani,3 nicholas woodhouse4 clinical & basic research advances in knowledge this article is the first to draw attention to the possibility of widespread vitamin d deficiency among pregnant women in oman. application to patient care until more is known about the vitamin d status in omanis, we recommend that all pregnant women and lactating mothers should receive vitamin d supplements with at least 1000 iu vitamin d3 daily. deficiency of vitamin d is common worldwide1 including the gulf states.2,3 the latter is surprising as sunlight is abundant in the middle east. more than 90% of our vitamin d is provided by sunlight4 and it is therefore obvious that those persons affected in arabian countries have little sunlight exposure and a diet deficient in vitamin d. the role of vitamin d in normal physiology is complex and wide ranging. it has important immune modulating effects protecting against infection,4,5,6 autoimmune disorders7 and certain cancers, in addition to its well documented effects on the prevention of osteoporosis, fractures, falls in the elderly4,5 and impaired cognitive function.8 as we continually see patients with vitamin d deficiency in our clinics, it became important to establish whether or not vitamin stores (25ohd) are normal in a healthy omani population. for this reason, we chose patients in their first and second moza al kalbani, omayma elshafie, mohammed rawahi, ali al-mamari, abdullah al-zakwani, and nicholas woodhouse clinical and basic research | 53 trimester of pregnancy as pregnancy and lactation are associated with profound alterations in calcium absorption and skeletal remodelling necessitating increased utilisation of vitamin d. our findings are reported below. methods blood samples were obtained from a cohort of 103 consecutive healthy omani patients at their first antenatal visit, usually in the first, but sometimes the second trimester. they were then assayed for serum calcium (ca), phosphate (phos), and serum alkaline phosphatase (alp), which were measured by spectrophotometry, (cobas integra 800, roche diagnostics, indianapolis, usa) on the same day. serum samples for parathyroid hormone (pth) were measured by immunochemiluminesence (access 2, beckman coulter, inc., ca, usa), and 25(oh)d3 by the lb211 gamma counter (berthold gmbh & co. kg, bad wilbad, germany), having been centrifuged and deep frozen at –40º c . pth and 25(oh)d3 were then measured on the same day at the end of the study. statistical analysis was performed to determine the relationship between the level of serum ca, phos, alp and pth versus the level of serum 25(oh)d. we used a correlation test to calculate the significance of these relationships. as this showed no significant linear correlation, a polynomial trend curve was employed. the calculations were made for all groups of patients. fully informed consent was obtained from each patient to extract the blood needed for the above procedures in addition to that required for routine antenatal screening. the study was approved by the armed forces hospital authorities. results serum 25ohd3 levels were deficient (<25 nmol/l) in 34 patients, between 25 and 50 nmol/l in 67 patients (at risk) and two patients had values between 50 and 75 nmol/l. there was no significant linear correlation between 25(oh) d3 and serum ca, phos or alp levels or parity. however, a significant relationship between pth and 25(oh)d3 was observed which differed between the ‘deficient’ and the ‘at risk’ groups. this was confirmed using a polynomial curve, which had a significant correlation value of 0.55 [figure 1]. discussion this is the first study to report vitamin d status in normal pregnant omanis. the results are alarming: 34% of these apparently healthy women were vitamin d deficient and a further 64% ‘at risk’ at a time when there is a critical need for calcium metabolism to be normal. a pregnant woman must provide 25 to 30 gm of calcium to support the developing foetal skeleton. much of this demand figure 1: relationship between pth (normal range 1.6–9.3 pmol/l) and 25(oh)d3 levels. there was no linear correlation between pth and 25ohd3 levels, but using a polynomial curve, the correlation coefficient was significant at 0.55. legend: pth = parathyroid hormone; 25(oh)d3 = vitamin d3. vitamin d status in pregnant omanis a disturbingly high proportion of patients with low vitamin d stores 54 | squ medical journal, february 2011, volume 11, issue 1 occurs in the third trimester when the foetal skeleton undergoes mineralisation. this demand is compensated for by an increased absorption of calcium from the gut induced by rising levels of pth and the active metabolite of vitamin d, 1,25 dihydroxy vitamin d (1,25(oh)2d).9 at this point 25(oh)d will be utilised to make more 1,25(oh)2d and those patients with low stores will be at considerable risk for the development of vitamin d deficiency and osteoporosis in old age.10 to compound this problem, many omani women have 6 or more children and breast feed for up to 2 years. during lactation, hyperabsorption of calcium does not occur and remineralisation of the maternal skeleton only starts after weaning when pth, and 1,25(oh)2d levels rise, calcium absorption increases and urinary calcium levels fall, a process that may persist for months.11 obviously, adequate stores of 25(oh)d are vital during this period, otherwise skeleton remineralisation will be seriously impaired and possibly result in the development of osteoporosis in old age.4,5 interestingly, none of the patients in the 25(oh)d3 deficiency group were symptomatic and serum pth and alp levels were still within the normal range. however there was a significant increase of the percentage rise in pth in the face of a declining 25(oh)d level suggesting the early stages of a biological response to vitamin d deficiency in the “at risk” group. in the deficiency group the reverse response was seen. our 25(oh) d3 immunoassay results have been carefully checked and are correct. it is possible therefore that an overt rise of pth and alp levels has been suppressed by an oral intake of calcium in excess of 1 gm daily as this will delay the development of secondary hyperparathyroidism.12,13 other factors such as body mass index may also be relevant14 but this was not examined here. in addition to its musculo-skeletal actions, vitamin d deficiency is reportedly associated with the development of certain cancers, the metabolic syndromes and infections, as well as type 1 and type 2 diabetes,4,5 disorders which are common in oman. our results confirm that vitamin d3 stores are low even in omanis of reproductive age. these findings are similar to those reported in saudi arabians more than 25 years ago2 and more recently in the uae and qatar.3,12 it therefore seems sensible to advocate vitamin d supplementation for all pregnant women in the middle east. at the present time, there are no clear cut recommendations as to the dose, but we recommend at least 1000 iu of vitamin d3 a day which should be continued throughout lactation. until more is known about the daily calcium intake of omanis, it would be prudent to advocate calcium supplementation as well.15 conclusion this study shows that vitamin d3 scores are low in pregnant omanis. further studies are required to confirm these findings. until then, we recommend supplementation with vitamin d3 (cholecalciferol) for all pregnant and lactating mothers. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. thacher td, fisher pr, strand ma, pettifor jm. nutritional rickets around the world: causes and future directions. ann tropical paediatr 2006; 26: 1–16. 2. woodhouse ny, norton w. low vitamin d levels in saudi arabians. king faisal spec hosp med j 1982; 2:127–31. 3. saadi hf, dawodu a, afandi bo, zayed r, benedict s, nagelkerke n. efficacy of daily and monthly high dose calciferol in vitamin d deficient nulliparous and lactating women. am j clin nutr 2007; 85:1565– 71. 4. holick mf. vitamin d: a delightful health perspective. nutrition rev 2008; 66:5182–94. 5. pearce shs, cheetham td. diagnosis and management of vitamin d deficiency. bmj 2010; 340:b5664. 6. holick mf. vitamin d deficiency. review article. n engl j med 2007; 357:266–81. 7. hyponen e, laara e, reunanen a, jarvelin m-r, vertanen sm. intake of vitamin d and risk of type 1 diabetes. a birth cohort study. lancet 2001; 358:1500–03. 8. llewellyn dj, lang ia, langa km, muniz-terrera g, phillips cl, cherubini a, et al. vitamin d and risk of cognitive decline in elderly persons. arch intern med 2010; 170:1099–100. 9. affinito p, tommaselli ga, di carlo c, guida f, nappi c. changes in bone mineral density and calcium metabolism in breastfeeding women: a one moza al kalbani, omayma elshafie, mohammed rawahi, ali al-mamari, abdullah al-zakwani, and nicholas woodhouse clinical and basic research | 55 year follow-up study. j clin endocrinol metab 1996; 81:2314–18. 10. javaid mk, crozier sr, harvey nc, gale cr, dennison em, boucher bj. maternal vitamin d status during pregnancy and childhood mass at age 9 years: a longitudinal study. lancet 2006; 367:36–43. 11. kalkwarf hj, specker bl, heubi je, viera ne, yergey al. intestinal calcium absorption of women during lactation andafterweaning. am j clin nutr 1996; 63:526–31. 12. saadi hf, nagelkerke n, benedict s, qazaq hs, zilahi e, mohamadiyeh mk, et al. predictors and relationships of serum 25 hydroxyvitamin d concentration with bone turnover markers, bone mineral density and vitamin d receptor genotype in emirati women. bone 2006; 39: 1136–43. epub 2006 june 30. 13. steingrimsdottir l, gumarsson o, indridason os, franzson l, sigurdsson g. relationship between serum parathyroid hormone levels, vitamin d sufficiency and calcium intake. jama 2005; 294: 2336–41. 14. paik j, curhan g, forman j, taylor e. determinant of plasma parathyroid hormone levels in young women. calcified tissue int 2010; 87:211–17. 15. abrahamsen b. patient level pooled analysis of 68,500 patients from seven major vitamin d fracture trials in us and europe. (the dipart group) bmj 2010; 340:b5463. squ med j, april 2010, vol. 10, iss. 1, pp. 133-135, epub. 17th apr 10 submitted 5th november 09 revision req. , revision recd. accepted on may 18 th 2009, i left work and set off to collect my children from school in muscat, oman’s capital city. seat belt securely fastened, i was alone in my new car, a tucson hyundai. the next thing i knew was floating in and out of consciousness three days later in a hospital intensive care unit, gradually realising i had been the victim of a serious road traffic accident. apparently, one car had overtaken another on the main sultan qaboos highway causing the driver to lose control, collide with a central lamp post and fly over the very low divide, hitting me on the other side of the highway. my car then hit a fourth car. the driver of a car behind, on a visit to me in the icu, later described the car that hit me as, “flying over like a rocket or a bolt of light.” he saw smoke rising from my car engine. fearing an explosion, he decided to move me before the ambulance arrived and with p. o. box 201, pc 124 rusayl, muscat, sultanate of oman email: angus_helen@yahoo.com ّمت ىلِ قَطع ُهِشّ وجهة نظر مريض حول حوادث املرور هيلني فرميان patient's viewpoint smashed to pieces a patient’s view of a road traffic accident helen freeman smashed to pieces a patient’s view of a road traffic accident 134 | squ medical journal, april 2010, volume 10, issue 1 the help of two other men, lifted me out of the back of my car. he found my phone and called someone who knew my husband’s number. an ambulance quickly arrived and took the man from the car that hit me to a nearby hospital; he died nine days later, apparently just a week before his planned wedding day. a second ambulance arrived fifteen minutes later and took me to the same hospital and then to one with orthopaedic expertise. my family arrived in a&e, where, according to my records, i was “fully conscious and oriented,” although to this day i remember nothing. the staff took x-rays, began stabilizing me and wheeled me into the icu. swollen, bruised and broken, i had 17 fractures (to my skull, thorax, pelvis, upper and lower limbs), a collapsed lung and severe polytrauma. the first days passed in a complete blur. then i became vaguely aware of visitors popping in, nurses turning me every few hours, which was agony, tubes sticking out of my body and non-stop noise in the ward. a team of general icu surgeons came daily to treat my chest injuries and prepare me for surgery. the ct scans were a huge ordeal, making me feel like i was falling completely out of control. being shifted off the bed onto a stretcher and into the scanner caused enormous pain, so i prayed hard for help to be able to cope. the medicine i received brought on hallucinations: embarrassing and frustrating experiences. i was vaguely aware of other patients, some needing frantic attention, some not making it. i didn’t eat or drink much, which obviously would have helped my recovery. my first operation took place 10 days after being admitted to hospital. i just remember that i wanted to get on with it and become more comfortable. i had retrograde nailing of the right femur fracture, which had broken into three pieces, a partial patellectomy and fixation of five pieces with cerclage wires. the team of orthopaedic surgeons also plated my left radius and ulna, taking 8 hours. five days later, the second operation, lasting nearly 6 hours, consisted of plating of my left femur with bone grafting. this had been badly smashed into over 50 pieces and was a difficult repair job. i remember being wheeled into the theatre, feeling like a slab of meat being laid onto a cold table with doctors and their knives gathering round ready to carve me up. both operations went well, although the second lung collapsed around this time. a scaphoid cast was applied to my right wrist, so i now had plaster on all four limbs. a hole was drilled through my right heel bone and a pin fitted from which 4 kgs of weight were suspended as a way of treating the acetabular fracture in my pelvis with skeletal traction. although doctors told me this was standard procedure, it seemed like medieval torture and remained severely uncomfortable until it was eventually removed. my nasal bone, base of skull, clavicle, and ribs healed without intervention. three weeks after the accident and a week after my second operation, i was discharged from the icu to the women’s orthopaedic ward. still on a lot of medication i was plagued by hallucinations, vomiting and diarrhoea. there was no one to one patient to nurse ratio in this ward and most patients had an attendant, often a sister or mother, staying with them. i therefore struggled to get the attention i needed. family and friends came to look after me and could see that my condition was bad. i felt their concern and worry, which in turn upset me. my hair, which had been washed on a daily basis in the icu, figures 1a & 1b: left femur/knee before and after the operation helen freeman patient's viewpoint | 135 became badly knotted. a nurse gave me what ranks as my worst ever hair cut! at the time, i hardly noticed. after three days, the senior doctor was called up from icu to see me. she immediately decided to rush me back into icu suspecting septicaemia, lung and urine infections. this time the icu doctors thought i would not make it. they put me in an isolation room and onto a ventilator and other vital organ monitors, with round the clock nursing care. three days passed without my knowing it, and then i spent the rest of that week slowly recovering. i really hated having nasal tubes and needles stuck into various parts of my body. it was such a relief to have them removed. the icu nurses and doctors showed great compassion, efficiency and kindness and we really appreciated their care. personal touches comforted me: one doctor came bearing coffee and sat with me. moved back to the women’s ward, this time in a better condition, i started to eat again and interact with others. many people visited wafts of incense, chatting, laughing and sharing fruit, the flimsy curtains separating beds allowing little privacy. i found sleeping difficult due to chanting, neighbours snoring, cell phones, crying, tv blaring, nurses talking and early morning bed baths. i began to realise my condition more and felt aghast at the sight of my swollen knees. i was able to cry about the enormity of my situation for the first time. gradually nurses removed tubes, bandages and stitches and physiotherapists introduced gentle exercises for my totally atrophied muscles. it took four physiotherapists to lift me into a wheelchair and after half an hour of wheeling around the corridors with a friend in attendance, i would be exhausted. i also used a passive exercise machine for my very stiff left leg, but with only one in the hospital, it was not often available. i found this rather surprising in an orthopaedic hospital and a country where so many people suffer as a result of road traffic accidents. one mother commented: “in some countries they have guns and bombs, here we have car crashes.” my husband managed to get me a private room in the hospital, but there i had no physiotherapist visits and 5 days later was shifted back to the women’s ward in floods of tears with a multi-drug resistant hospital infection feeling this was a huge step backwards. i just wanted to go home. my small windowless isolation room confined me like a leper for a further nine days. on 4 july, 48 days after admission, i returned home in an ambulance as i couldn’t yet manage a wheelchair. i remember seeing the tops of buildings go past and feeling sorry that i wasn’t driving, then quickly realising that i could have left hospital in a coffin. that turned my griping into gratitude. a health carer we had employed in hospital helped me for the next two months on the long journey of recuperation. i also had regular and intensive high quality home-based physiotherapy, which really helped me gain perspective and make progress. my unstable condition, as well as recommendations about the quality of icu care and orthopaedic surgery in oman, had encouraged us to remain rather than seek the treatment abroad offered by my employers. visitors during the summer cheered me up and helped my recovery. throughout this whole process, i needed 11 units of blood. during one operation the surgeons requested 4 units, but only 3 were available. this prompted a friend and my husband to instigate a blood donation drive. people donated 100 units of blood and others were turned away, as staff in the mobile unit couldn’t cope. i felt happy to hear of such a positive response to my horrible accident. since july, 2 months after my accident, i have progressed from the wheelchair to standing and walking, initially in the swimming pool and then with a zimmer frame, crutches and a walking stick. now, 7 months later, i walk without aid. we, as a family, have celebrated every small step as a great achievement: bed sores healing, extracting a stray stitch from a scar and my first shower. relief flooded in as i became able to do things myself. one day my left arm became hot, red and swollen. we rushed to hospital dreading being readmitted. the x-rays indicated a loose screw in the ulna fixation. the doctor allayed our fears saying that i had probably just bumped my arm. my consultant surgeon wondered whether i would need manipulation under anaesthetic or open quadricepsplasty of my left knee, but decided to see how much aggressive physiotherapy could improve knee and hip movement first. exercise is crucial and i spend time on a bike, in the pool and with steps and weights. the limited movement in my stiff left knee is likely permanent and i may later require a total hip replacement. i thank all the doctors, nurses, physiotherapist, orthopaedic osteopath, chiropractor, my employers, friends, all those who prayed for my recovery and especially my family for their amazing support. squ med j, december 2009, vol. 9, iss. 3, pp. 324-327, epub. 19th dec 2009 submitted 11th may 2009 revision req. 26th aug. 09. revision recd. 15th sept. 09 accepted 14th oct 09 adrenal disseminated tuberculosis causing bilateral adrenal enlargement and addison’s disease is rarely reported. in many areas of the world, particularly in developing countries, tuberculosis remains a major cause of addison’s disease. tuberculosis of the adrenal glands resulting in addison’s disease must be considered in the right clinical context because early identification and treatment may enable recovery of adrenal function. case report a 37 year-old woman presented at sultan qaboos university hospital, oman, with fever, fatigue, vomiting, progressive darkening of the skin, behavioural changes, rigidity and drowsiness over the previous two months. she was born in india, but had lived in oman for the preceding 15 years. her last visit to india was 10 years previously. evidence of a bcg vaccination was present through a scar on the arm. examination showed a sick looking patient with severe wasting and marked dehydration. she was febrile with low blood pressure (bp 95/64mmhg) and postural drop. the skin and mucosa were hyper-pigmented [figures 1a and 1b]. she was conscious and oriented, but with markedly diffuse rigidity and bradykinesia. cranial nerves were normal. deep tendon reflexes were absent, but plantar reflexes were normal. she had splenomegaly and a large, non-tender, mobile lymph node of 3 x 3 cm in the right axilla. the laboratory findings were as follows: a complete blood count (cbc) showed anaemia (hb 10.8 g/dl); white blood cells (wbc) 2.97x109/l (monocytes 0.7, eosinophils 1.0) with normal platelet count (240x109/l). the blood film revealed reactive monocytosis and eosinophilia. the sodium was low (120 mmol/l, k 3.7 mmol/l). serum osmolality was 252mmol/l with a urine sodium of 93mmol/l and urine osmolality of 300mmol/l. random serum cortisol was very low (<11nmol/l). the adrenocorticotropic hormone (acth) level was very high (165.5pmol/l). the synacthen (acth) stimulation test revealed at departments of 1medicine & 3pathology, sultan qaboos university hospital, muscat, sultanate of oman; 2royal court medical team, muscat, sultanate of oman; 4department of radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman to whom correspondence should be addressed: email amamari@squ.edu.om تقرير حالة تدرن منتشر مع قصور يف الغدة الكظرية علي املعمري، عبد اهلل باخلير، أرونوديا جوجار، فاطمة بن عابد، أحمد الفرقاني، عائشة احلمداني، راجيف جني حالة ملريضة عمرها 37 عاما مصابة مبرض التدرن املنتشر، شامال الغدتني الكظريتني، مما أدى إلى فشلهما وحدوث القصور تقرير امللخص: هذا الكظري األولي (مرض أديسون) وانخفاض مستوى الصوديوم في الدم غير املتجاوب للعالج، واحتمال حتلل املايلني خارج املنطقة اجلسرية. كانت نتائج اخملتبر إيجابية لقصور الغدة الكظرية كما كان فحص مانتو ملرض التدرن إيجابيا . وقد أظهر التصوير بالرنني املغناطيسي كافة التغييرات املميزة ملرض التدرن في الغدد الكظرية. امللخص: الدرن (السل)، الغدة الكظرية، قصور، الورم احلبيبي، تقرير حالة، ُعمان. abstract: we present the case of a 37 year-old female who had disseminated tuberculosis (tb) with bilateral adrenal involvement resulting in primary adrenal failure (addison’s disease) with refractory hyponatraemia and possible extrapontine ‘myelinolysis’. laboratory results were remarkable for adrenal insufficiency. a mantoux reaction was positive with evidence of pulmonary miliary tb. the magnetic resonance imaging scan showed all the characteristic changes of adrenal tb. key words: tb; adrenal; insufficiency; granuloma; case report, oman. a case of disseminated tuberculosis with adrenal insufficiency *ali al-mamari,1 abdullah balkhair,1 arunodaya gujjar,1 fatma ben abid,1 ahmed al-farqani,2 aisha alhamadani,3 rajeev jain4 case report ali al-mamari, abdullah balkhair, arunodaya gujjar, fatma ben abid, ahmed al-farqani, aisha al-hamadani and rajiv jain case report | 325 base line, 30 minutes, and 60 minutes the serum cortisol to be below <11nmol/l. the gonadotrophic hormones, prolactin and thyroid functions tests were within normal limits. the anti-adrenal epithelial cell antibody test was negative. the serology for hiv 1 and 2, cytomegalovirus and toxoplasma gondii were all negative. a tuberculin skin test at 72 hours was positive with a 20mm induration. imaging, including a chest x-ray, showed a miliary pattern in addition to mild bilateral pleural effusion. a magnetic resonance imaging (mri) scan of the brain was normal. a repeated mri brain scan (2 weeks after the initial normal mri) revealed homogeneous t2 hyper-intensity of bilateral basal ganglia (putamen, caudate, globus pallidus nuclei) with normal signals in the brain stem. there was no meningeal enhancement or basal exudates. an mri of the abdomen (done because the ct scanner was out of service) revealed moderate enlargement of both adrenal glands with hyper-intensity signals on t2 weighted sequences [figure 2]. both adrenal glands showed marginal enhancement with persistent hypo-intensity of the central areas. a lymph node biopsy showed numerous granulomas with central caseous necrosis [figures 3a and 3b]. no acid fast bacilli were identified; however, a subsequent culture of the lymph node grew mycobacterium tuberculosis sensitive to all first line drugs. the cerebrospinal fluid culture was negative for mycobacterium tuberculosis. the patient was started on adrenal hormonal replacement with hydrocortisone 20mg in the figure 1a : hyperpigmentation of face likely due to hypoadrenalism, in the context of disseminated tuberculosis. figure 1b : hyperpigmentation of hands and palmar creases. figure 2: abdominal mri of the patient showing bilaterally enlarged, hyperintense adrenal glands. a case of disseminated tuberculosis with adrenal insufficiency 326 | squ medical journal, december 2009, volume 9, issue 3 morning and 10mg in the evening in addition to fludrocortisone 100μg once daily. the patient was also empirically commenced on anti-tuberculous medications, on the basis of the clinical suspicion and the radiology findings, with a four-drug regimen consisting of isoniazid, rifampicin, pyrazinamide and ethambutol. during a month of hospitalisation, the patient made a remarkable recovery with normalisation of the hyponatremia (na137 mmol/l), resolution of the hypotension, the postural drop and all her other symptoms. at the time of discharge, she was alert and oriented and was able to perform all the functions of daily living. she still had mild bradykinesia and mild diffuse hypertonia, which she seemed to tolerate. both anti-tuberculous therapy and adrenal hormonal replacement were continued. discussion disseminated tuberculosis causing bilateral adrenal enlargement and addison’s disease have been rarely reported.1 addison’s disease is a primary adrenocortical deficiency that is the result of damage to the adrenal cortex. overt clinical features of hypoadrenalism occur when 80-90% of both adrenal cortices are destroyed.2 thomas addison first described the clinical features and pathogenesis of adrenal insufficiency more than 150 years ago.3 at that time, tuberculosis was the most common cause of this disease. tuberculosis is still a major cause of adrenal insufficiency in populations with a high prevalence of tuberculosis, but the overall incidence of tuberculous addison’s disease has decreased.4 nowadays, tuberculosis accounts for only 7-20% of cases and is often an overlooked cause of addison’s disease. recovery of adrenal function is possible after appropriate anti-tuberculosis therapy, though usually it does not occur.2 tuberculosis may affect many of the endocrine glands including the hypothalamus, pituitary, thyroid, but the most commonly involved endocrine organ is the adrenal gland. in addition to mycobacterial tuberculosis, other mycobacteria, bacteria, viruses and fungi may affect the adrenal glands and lead to the development of adrenal insufficiency. most cases of adrenal tuberculosis are found 10 to 15 years after the initial infection; hence, tuberculous addison’s disease has a relatively late onset.2 bilateral adrenal calcification is the most common radiological feature of addison’s disease.5 an mri scan can reveal certain pathological changes of adrenal tuberculosis. in a cohort of 18 patients with proven adrenal tuberculosis, who underwent mri scans, 97% of the adrenal glands were enlarged with bilateral involvement in 89%, while 83% of the enlarged glands had peripheral rim enhancement and 62% had a central region of t2 hypo/iso-signal intensity.6 our patient’s mri study demonstrated all the above characteristic findings. conclusion in many areas of the world, particularly in figure 3a : hematoxylin and eosin stain*10 showing a lymph node with multiple necrotising granulomas (ng) composed of multinucleated giant cells (g) and epithelial histiocytes (e). figure 3b : hematoxylin and eosin stain*40 showing granuloma with central necrosis (cn) and composed of epithelioid histiocytes (e) and langhans giant cells (l). ali al-mamari, abdullah balkhair, arunodaya gujjar, fatma ben abid, ahmed al-farqani, aisha al-hamadani and rajiv jain case report | 327 developing countries, tuberculosis remains a major cause of addison’s disease. prompt intervention for addison’s disease, a high index of suspicion with early identification and treatment of tuberculosis may enable recovery of adrenal function. tuberculosis of the adrenal glands resulting in addison’s disease must be considered in the right clinical context. references 1. bajaj s. disseminated tuberculosis causing bilateral adrenal enlargement and addison’s disease. j assoc physicians india 2000; 48:919-20. 2. alevritis em, sarubbi fa, jordan rm, peiris an. infectious causes of adrenal insufficiency. south med j 2003; 96:888-90. 3. addison t. on the constitutional and local effects of disease of the supra-renal capsules. london: highley press, 1855. 4. nomura k, demura h, saruta t. addison’s disease in japan: characteristics and changes revealed in a nationwide survey. intern med 1994; 33:602-6. 5. orth dn. adrenal insufficiency. curr ther endocrinol metab 1994; 5:124-30. 6. zhang xc, yang zg, li y, min pq, guo yk, deng yp, dong zh. addison’s disease due to adrenal tuberculosis: mri features. abdom imaging 2008; 33:689-94. îüëüä÷]<<ö]ü⁄˘]<‹◊¬<l]ü≥ˆ⁄<ƒò^œê åáe^œ<·^�◊ä÷]<ì√⁄^q<ª< 20102009 abstracts proceedings of sultan qaboos university clinical-pathological conferences 2009–2010 squ med j, may 2011, vol. 11, iss. 2, pp. 301-303, epub. 15th may 11 pulmonary sarcoidosis: one diagnosis, two different presentations b jayakrishnan,1 fatma ben abid,1 ana maria a serrano,2 aisha al-hamdani3 departments of 1medicine, 2family medicine & public health and 3pathology, sultan qaboos university hospital, muscat, oman. email: drjayakrish@hotmail.com even 140 years after the initial description, the aetiology of sarcoidosis, a multisystem disorder, remains elusive, the diagnostic tests remain largely nonspecific and treatment produces inconsistent results. case one: a 69 year-old omani female with hypertension, diabetes mellitus, depression and blindness was referred for evaluation of bilateral opacities on a chest radiograph. she had a three-month history of dry cough, exertional breathlessness, chest discomfort and weight loss. she denied any history of fever, night sweats, haemoptysis or recent travel. clinical examination revealed a few small lymph nodes in the axillae. basic blood tests, including serum calcium, were normal. the serum angiotensin converting enzyme (sace) level was also normal. the sputum smear was negative for acid fast bacilli (afb) by direct smear. the mantoux test was negative. the chest radiograph showed bilateral parenchymal infiltrates. a computed tomography (ct) of the chest revealed bilateral extensive perihilar airspace consolidation with significant mediastinal lymph nodes. spirometry results were as follows: forced expiratory volume 1 (fev1) 0.66 l (37%), forced vital capacity (fvc) 1.01l (47%), fev1/fvc 65%. a bronchoscopy showed hyperaemic mucosa with diffuse granular changes and a few nodular lesions. an endobronchial biopsy revealed features of non-caseating granuloma confirming a diagnosis of sarcoidosis. case two: a 42 year-old omani female presented with a dry cough, generalised itching and extreme tiredness of 6 months duration. on examination, there were well demarcated hyperpigmented brown nodular skin lesions over the breast, abdomen, lower back and both thighs. some showed central ulceration with healing and post-inflammatory hypopigmented and hyperpigmented patches and superficial mild depressed scars. routine blood tests, including serum calcium and sace level, were normal. the mantoux test was positive, 24 mm. the chest radiograph and computed tomography (ct) scan revealed bilateral hilar and mediastinal lymphadenopathy. pulmonary function test results were as follows: fev11.87 l (78%), fvc 2.29 l (81%), fev1/fvc 82%, carbon monoxide diffusing capacity (dlco) -75%, and carbon monoxide transfer coefficient (kco) 96%. the bronchoscopy did not show any abnormality; the bronchoalveolar lavage and sputum were negative for afb by stain and culture. skin lesions were biopsied, as well as a mediastinoscopy and mediastinal lymph node biopsy. both skin and lymph node biopsies showed non-caseating granulomas suggestive of sarcoidosis. both the patients received prednisolone leading to symptomatic and radiological improvement. since the mantoux test was positive, the second patient received anti tuberculosis treatment prior to the initiation of steroids. despite advances in the knowledge of the immunopathogenesis of sarcoidosis, no single aetiologic agent or genetic locus has been clearly identified in the development of the disease.1 the disease varies in incidence and presentation among geographical regions.2 any organ can be involved, the most commonly affected sites being the lungs (approximately 90% of patients), lymph nodes, skin, eyes, and the liver. cutaneous involvement is common presenting as macular, nodular, maculopapular, ulcerative or plaque like lesions; it can also present as verrucous, ichthyosiform, hypomelanotic, or psoriasiform lesions.3 they can be divided into specific lesions and nonspecific lesions based on the characteristics and histology,4 the classic specific and nonspecific lesions being lupus pernio and erythema nodosum respectively. spontaneous remission is common in sarcoidosis so not all patients require treatment. generally, treatment is indicated when there are debilitating symptoms or evidence of significant or progressive end-organ damage. glucocorticoids are the commonest treatment agents for pulmonary sarcoidosis. refractory disease may require other agents such as immunosuppressive, cytotoxic, antimalarial drugs or anti-tumour necrosis factor (tnf) antibodies. 302 | squ medical journal, may 2011, volume 11, issue 2 proceedings of sultan qaboos university clinical-pathological conferences r e f e r e n c e s 1. baughman rp, culver da, judson ma. concise review of pulmonary sarcoidosis. am j respir crit care med 2010, oct 29. [epub ahead of print] 2. behbehani n, jayakrishnan b, khadadah m, farrah y, hawa h. clinical presentation of sarcoidosis in a mixed population in the middle east. respir med. 2007; 101:2284–8. 3. macrophage/monocyte disorders in: james wd, berger tg, elston dm, eds. andrews' diseases of skin, clinical dermatology. 10th ed. philadelphia: w.b. saunders, 2005. pp. 708–14. 4. rose as, tielker ma, knox ks. hepatic, ocular, and cutaneous sarcoidosis. clin chest med 2008; 29:509–24. these cases were presented at the sultan qaboos university clinical-pathological conference on 7th april 2010 with the title “to be or not to be…”. the title represents the uncertainties in the aetiology, diagnosis and the treatment of sarcoidosis as well as the diagnostic confusion in differentiating it from tuberculosis. girl with t-cell leukaemia and severe central nervous system involvement yasser wali,1 *mathew zachariah2 ismail el beshlawi,2 nancy reyes2 and nasser s. al-hajari2 1department of child health, college of medicine & health science sultan qaboos university, muscat, oman. departments of 1child health, 2nursing, 3physiotherapy, sulltan qaboos university hospital, muscat, oman. email: mathewz@squ.edu.om remarkable advances have been achieved in the treatment of acute lymphoblastic leukemia (all) in children in the last decades. however, still 20% of children ultimately relapse, and the cure rate after relapse is only 25% to 40%. t-cell acute lymphoblastic leukemia (t-all) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (all). age, total white blood cell count at diagnosis, immunophenotype, chromosomal aberrations, speed of treatment response, minimal residual disease, are all very important factors in determining the prognosis of the diseases. an eight year-old omani girl was admitted to sultan qaboos university hospital (squh) referred from a peripheral hospital with fever and poor school performance of more than one month’s duration. the child had developed convulsions, septic shock and was ventilated and was therefore transferred to squh as a suspected case of leukaemia. in squh she was labelled as t-cell leukaemia with central nervous system (cns) involvement and was completely aphasic. despite repeated magnetic resonance imaging (mri) brain scans that confirmed white matter changes and demyelination initially and widely extended on repeated imaging, her cerebrospinal fluid (csf) was repeatedly clear. after successful induction with a pog 9404 t3 protocol, she had a severe episode of febrile neutropenia that rapidly progressed to septic shock, deteriorating neurological status and respiratory distress. she had recurrent episodes of febrile neutropenia, sepsis with elbs e.col , coagulase negative staphylococcus and candida. her condition deteriorated with severe mucositis and respiratory distress which needed an emergency tracheostomy and later she was put on mechanical ventilation. she remained in very critical situation for 4 weeks and she was labelled as dnr (do not resuscitate) status. her chemotherapy was withheld for two and a half months due to her grave clinical condition. of interest, she maintained her remission status on a repeat bone marrow aspiration; however; she had extensive haemophagocytosis (secondary haemophagocytic lymphohistiocytosis [hlh]) that needed to be treated with partial induction for 6 weeks (hlh 2004). after all these stormy events child ended up in a devastating state with severe weight loss (skin on bones), aphasia, and inability to walk. with extensive nursing support and physiotherapy, she improved remarkably, started to gain weight, her speech recovered and the tracheostomy was closed. her mri brain scan was almost normal. after one year of an uneventful course of maintenance chemotherapy, she suddenly developed facial palsy. other cns examinations were normal and the csf was still clear. unfortunately, her bone marrow showed 80% blasts of the initial phenotype confirming a combined bone marrow and cns relapse. the brain images were obviously normal. she was started on uk all relapse protocol and planned for early bone marrow transplantation. during the induction phase she had another episode of febrile neutropenia, herpes simplex virus lesions that further deteriorated and progressed to septic shock. after a long severe prolonged course she expired. everyone has got only one life; however, in our case she was labelled as dnr once and all the treating team members lost hope that she would survive. such a courageous young girl made it through and came out of this tragedy learning again how to talk and walk. this case was presented at the sultan qaboos university clinical-pathological conference on 5th may 2010 with the title“you only live twice” between the loins and the ribs a case of a germ cell tumour ibtisam h. al-shuaili,1 aisha al-hamdani,2 sinan al-azzawi,3 ibrahim inuwa4 and ikram a burney1 departments of 1medicine, 2pathology, 3radiology & molecular imaging, sultan qaboos university hopsital, muscat, oman; 4department of human & clinical anatomy, college of medicine & health science sultan qaboos university, muscat, oman. email: ibtisamsh@hotmail.com a 21 year-old boy, previously well, presented at sultan qaboos university hospital, oman, with a 2-month history of low grade fever, malaise, weight loss of about 3–4 kg, and haemoptysis. there was no history of shortness of breath, palpitation, recent travel, or contact with patients suspected to have tuberculosis or hiv. the physical examination was unremarkable apart from a dull percussion note with reduce breath sounds on left side of the chest. vital signs were temperature 38 ºc, pulse rate 128 bpm, respiratory rate 14/min, blood pressure 97/50 mmhg. a blood investigation revealed mild anaemia with an hb of 9 g/dl, normochromic normocyctic, and normal white cell and platelet counts. the coagulation profile, urea and electrolytes, liver function tests and the bone profile were all within the normal limits. a chest x-ray was done and reported a large mediastinal mass. a differential diagnosis of a germ cell tumour was entertained and a serum alfa-fetoprotein (afp) was found to be markedly elevated at 20,142 kiu/l, whereas, serum lactate dehydrogenase (ldh) was abstracts | 303 2009–2010 minimally elevated to 698 u/l (up to 248 iu/l). serum and urine β-human chorionic gonadotropin (hcg) were within the normal limits. an ultrasound scan of the testis was unremarkable, and a computed tomography scan of chest [figure 1a] showed a large ill-defined lobulated anterior mediastinal mass in the superior mediastinum, extending into the left hemithorax. the mass was seen displacing the mediastinal vascular structures to the right and posteriorly, with significant compression of the left main pulmonary artery and possible infiltration of the main pulmonary artery. the left upper lobe bronchus was collapsed with loss of volume of the left upper lobe. the liver was found to be enlarged and showed numerous focal lesions predominantly in the right lobe with central necrosis and thick enhancing rims [figure 1b]. a biopsy revealed an extensively necrotic poorly differentiated malignant neoplasm with the immunohistochemical profiles in keeping with mixed germ cell tumor. the patient was treated with combination chemotherapy consisting of bleomycin, etoposide and cisplatin (bep). the tumour marker response is shown in figure 2. because of a lack of marker normalisation after three cycles of the combination chemotherapy, the treatment was changed to a combination of vinblatine, ifosfamide and cisplatin, of which he received four cycles. the treatment was further changed to third line chemotherapy consisting of gemcitabine and oxaliplatin because of lack of marker remission. owing to no further marker decline, the patient was referred for a positron emission tomography (pet) scan, which revealed increased uptake in the mediastinum, but not in the liver. the patient underwent thoracotomy with resection of the residual mass lesion, the histopathology of which showed mainly necrosis. following the thoracotomy, the alphafetoprotein (afp) dropped to normal limits, and the patient has been in continuous complete remission since march 2008. this case was presented at the sultan qaboos university clinicalpathological conference in date? april 2009 with the title “between the loins and the ribs”. figure 2: alpha-fetoprotein (afp) levels in response to treatment and over time. the x-axis shows time in weeks, and the y axis shows the level of afp on a logarithmic scale. bep = bleomycin, etoposide and cisplatin; veip = vinblastine, ifosfamide and cisplatin; gemox = gemcitabine and oxaliplatin. figure 1: computed tomography (ct) scan of chest (1a) and the upper abdomen (1b), showing disease in the mediastinum and the liver before treatment. figure 1c shows the ct scan following thoracotomy, resection of the residual mass. department of neurology, king fahad hospital of the university, imam abdulrahman bin faisal university, damman, saudi arabia *corresponding author’s e-mail: danah.aljaafari@gmail.com طور متعلق ابخلزل السفلي يف ُمَتاَلزَِمُة غيَّان-ابريه يف غضون األربعة وعشرين ساعة األوىل ما بعد الوالدة تقرير حالة دانة اجلعفري و نعمان ا�سحاق abstract: guillain-barré syndrome (gbs) is a heterogeneous disorder with a diverse clinical presentation ranging from weakness of certain body regions to tetraparesis with autonomic dysfunction and respiratory failure. paraparetic gbs is a variant of gbs which is characterised by weakness limited to the lower limbs only. it is crucial to identify such topographical presentations, as a delay in diagnosis can lead to delayed initiation of specific treatment, which can negatively impact the outcome. we report a 29-year-old female patient who presented to the king fahd hospital of the university, al khobar, saudi arabia, in 2017 with rapid onset asymmetrical weakness of lower extremities associated with bladder dysfunction during the immediate postpartum period. the weakness spared cranial nerves and arms and imaging studies of the spine was unremarkable. cerebrospinal fluid investigations showed cyto-albuminologic dissociation and nerve conduction studies showed features of demyelination. the patient was diagnosed with a paraparetic variant of gbs and treated with intravenous immunoglobulin. she had almost recovered completely at the two–month follow-up. keywords: paraparesis; guillain-barré syndrome; demyelination; postpartum period; case report; saudi arabia. امللخ�ص: ُمَتاَلِزَمُة غيَّان-باريه هي ا�سطراب متغاير املن�ساأ، ويجيء ب�سور �رسيرية متنوعة، ترتاوح بني �سعف يف اأجزاء معينة من اجل�سم اإىل خزل رباعي يرتافق مع خلل وظيفي اتونومي )م�ستقل( وف�سل تنف�سي. وُيعد اخلزل ال�سفلي طورا من اأطوار ُمَتاَلِزَمة غيَّان-باريه يت�سف ب�سعف يقت�رس على الطرفني ال�سفليني فقط. ومن املهم اال�ستعراف على مظاهره الطبوغرافية، اإذ اأن التاأخري يف الت�سخي�ص قد يف�سي اإىل تاأخري يف بدء العالج املحدد، وهذا من �ساأنه اأن يوؤثر على النتيجة. ويف هذا التقرير نقدم حالة مري�سة عمرها 29 عاما جاءت مل�ست�سفى امللك فهد بجامعة اخلرب يف اململكة العربية ال�سعودية يف عام 2017م وهي ت�سكو من �سعف ع�سلي المتناظر يف طرفيها ال�سفليني حدث �رسيعا مرتافقا مع اختالل يف وظيفة املثانة يف غ�سون الفرتة التالية مبا�رسة للو�سع. ومل يحدث ذلك ال�سعف يف االأع�ساب القحفية وال يف اليدين، وال يف العمود الفقري )حيث اأظهرت الت�سوير اال�سعاعي �سالمته(. واأظهر فح�ص ال�سائل الدماغي النخاعي تفارقا خلويا البيوميني املن�ساأ. واأثبتت درا�سات التو�سيل الع�سبي بع�ص مظاهر زوال امليالني. ومت ت�سخي�ص حالة املري�سة على اأنها طور متعلق باخلزل ال�سفلي يف ُمَتاَلِزَمة غيَّانباريه، وعوجلت باحلق الوريدي بغلوبيولني مناعي. و�سفيت املري�سة ب�سورة �سبه كاملة عند فح�سها بعد �سهرين من العالج. الكلمات املفتاحية: اخلزل ال�سفلي؛ ُمَتاَلِزَمة غيَّان-باريه؛ زوال امليالني؛ الفرتة التالية للو�سع؛ تقرير حالة؛ اململكة العربية ال�سعودية. paraparetic variant of guillain-barré syndrome in first 24 hours of postpartum period a case report *danah aljaafari and noman ishaque sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e227–230, epub. 28 jun 20 submitted 19 sep 19 revisions req. 19 nov & 30 dec 19; revisions recd. 8 dec 19 & 2 jan 20 accepted 19 jan 20 acute ataxic variant, facial diplegia with paraesthesic variant, acute pandysautonomia and the paraparetic variant of gbs.3–7 this report describes a case of rapid onset asymmetric paraparesis with predominant involve ment of distal muscles with areflexia during the immediate postpartum period after complete recovery from epidural anaesthesia. this case highlights the importance of considering paraparetic variant of gbs when a patient complains of paraparesis. failure to do so can lead to delay in diagnosis and consequent delay in initiation of specific treatment that can negatively impact outcome. guillain-barré syndrome (gbs) is an acute polyradiculoneuropathy characterised by flaccid weakness associated with decreased reflexes and cytoalbuminologic dissociation in the cerebrospinal fluid (csf).1 it is a heterogeneous dis order with diverse clinical presentation ranging from weakness limited to certain regions of the body to tetraparesis with autonomic dysfunction and respiratory failure.2 symptoms that are restricted to certain body parts are termed ‘gbs variants’ or ‘topographical variants’. these include miller fisher syndrome, bickerstaff brainstem encephalitis, pharyngeal cervical brachial variant, multiple cranial neuropathy variant, this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.015 case report https://creativecommons.org/licenses/by-nd/4.0/ paraparetic variant of guillain-barré syndrome in first 24 hours of postpartum period a case report e228 | squ medical journal, may 2020, volume 20, issue 2 case report a 29-year-old female patient presented to the king fahd hospital of the university, al khobar, saudi arabia, in 2017 with weakness in her lower extremities. she had no known chronic illnesses and was admitted to the hospital for delivery at 38 weeks of pregnancy. she had a history of two caesarean sections and had given birth to a total of three children. her family history was unremarkable and she did not have any allergies. at the time of admission, she was taking multivitamins. her routine blood workup at the time of admission was within normal limits. she delivered a healthy baby girl through an uneventful caesarean section under epidural anaesthesia, which was given at lumbar (l) 4/l5 level using 10 mg of bupivicaine (0.3%) and 2.5 ml of fentanyl. her post-delivery recovery was uneventful and she regained full strength of her lower extremities as well as bladder function. the following morning, she complained of weakness in her lower extremities. the weakness started from her feet and worsened over time. within a few hours, the weakness had progressed to the extent that she was not able to stand or walk unaided. it was associated with urinary retention. there was no fever or pain in the back or lower extremities and her arms were also unaffected. she had had an upper respiratory tract infection one week prior to admission. however, there was no history of recent immunisation or gastrointestinal infection. upon physical examination, she was found to have a good build and was able to lie comfortably on the bed with a urinary catheter in place. her vital signs were stable, her higher mental functions were intact and her extraocular movements were perfect. she had normal speech and facial symmetry. her gag reflex was intact and the power of her neck flexion was normal. motor examination of her upper extremities was unremarkable for bulk, tone, power and reflexes. a bulk of her lower extremities was normal but both lower extremities were flaccid. on the modified research council (mrc) scale, the power of her left hip flexion was 3/5 and the power of her right hip flexion was 2/5. her left hip extension was 4/5 and her right hip extension was 3/5. her knee flexion was 3/5 on the left side and 2/5 on the right side. the knee extension was 2/5 on both sides, whereas the plantar flexion and dorsiflexion was 0/5 bilaterally. deep tendon reflexes could not be elicited even with reinforcement in lower extremities. the plantar reflex was equivocal bilaterally. all sensory modalities were found to be intact and the saddle anaesthesia as well as figure 1: imaging of the spine of a 29-year-old female patient with a paraparetic variant of guillain-barré syndrome. a: computed tomography scan of the lumbosacral spine showing an absence of hyperdense signals. b & c: magnetic resonance imaging (mri) scans of the lumbosacral spine (b) on the day of symptom onset and (c) one week later showing no acute infarction or herniated disc. d: mri of the whole spine was grossly unremarkable. table 1: motor nerve conduction study results of a 29-year-old female patient with a paraparetic variant of guillainbarré syndrome nerve test location latency in ms amplitude in mv conduction velocity in m/s first study second study third study first study second study third study first study second study third study left peroneal nerve fibula head 4.2 10.3 10.5 7.0 5.5 5.7 popliteal fossa 6.2 20.1 15.7 6.1 1.0 1.9 45 26 30 left tibial nerve ankle 3.3 13.5 18.4 23 20.0 21.5 popliteal fossa 7.0 18.0 17.9 18.2 5.2 10.8 41 30 27.6 right peroneal nerve ankle 6.0 11.7 13.9 5.8 4.5 6.6 fibula head 8.0 12.8 15.5 5.3 1.3 2.6 39 21 26 right tibial nerve ankle 4.3 6.4 19.3 18.2 16.3 19.5 popliteal fossa 8.6 10.3 11.5 12.9 6.4 9.7 43 27 25 danah aljaafari and noman ishaque case report | e229 a sensory level were also absent. signs of any cerebellar dysfunction were absent in the arms and could not be examined in lower extremities. the rest of the systemic examination was unremarkable. laboratory investigations including serum elec trolyte, potassium, magnesium and phosphate levels as well as the coagulation profile, were within normal limits. the c-reactive protein level was 0.9 mg/dl (normal range: 0.05–0.3 mg/dl). a computed tomo graphy scan of the lumbosacral spine was immediately performed which excluded an epidural haematoma [figure 1a]. in addition, a magnetic resonance imaging scan of the entire spine did not show any findings suggestive of transverse myelitis, herniated intervert ebral disc, spinal cord compression from a haematoma, spinal cord infraction, demyelinating disorder, a tumour, arteriovenous malformation or arachnoiditis of an infective or chemical nature [figure 1b–d]. as imaging did not reveal any aetiology of her symptoms, a lumbar puncture was performed. csf studies showed a protein level of 270 mg/dl (normal range: 15–45 mg/dl) and a white blood cell count of 22 k/µl (normal range: 0–5 k/µl) with 92% lymphocytes (normal range: 40–80%). next, the nerve conduction studies (ncs) were performed on the first day of the symptoms’ onset and repeated after one and two weeks [tables 1–3]. this showed a prolongation of f-wave latencies, significant delay in distal latencies and decreased conduction velocities with conduction block and temporal dispersion. sensory ncs were normal. ncs of her arms were also normal. features of ncs were suggestive of a demyelinating disorder. a diagnosis of the paraparetic variant of gbs was made based on the rapid onset of areflexic paraparesis, cytoalbuminologic dissociation in csf, demyelinating features on the ncs and absence of any other explanation of her symptoms on the remainder of investigations, including imaging. the patient was administered intravenous immunoglobulin for five days. she started to regain power in her lower extremities after one week and was able to move with support after two weeks. she had almost completely recovered, was able to walk unaided and could return to her daily activities after two months. discussion gbs is an acute polyradiculoneuropathy that has diverse clinical presentations, findings on electrophysiological tests and outcome. gbs is an acute peripheral neuro pathy that is thought to be due to an autoimmune reaction triggered by a vaccination or surgical proc edure or a preceding infection, mainly respiratory or gastrointestinal.2 this immunopathogenesis is mainly controlled by four factors: (1) antiganglioside anti bodies which can be detected in the serum of approx imately half of gbs patients; (2) molecular mimicry and cross-reactivity to nerve gangliosides as in campy lobacter-associated gbs cases; (3) complement activation that causes a neurotoxic effect; and (4) the charact eristic of the patient themselves such as their immune status and genetic polymorphisms.8 clinical presentation is the primary diagnostic criterion along with electro physiologic studies and csf analysis. in addition to the typical clinical presentation, many atypical clinical presentations of gbs have been described.3–7 it is crucial to identify these variants of gbs as early diagnosis of such cases can lead to earlier initiation of specific treatment and monitoring and thus, better outcomes. the paraparetic variant of gbs is a typical forme fruste of this disorder where weakness is mainly limited to the legs. it was first described by ropper in 1986 as paraparesis with normal power and reflexes in the arms.3 pokalkar et al. also identified a paraparetic variant of gbs and described it as a variant of gbs with an isolated weakness of the lower limbs with table 2: sensory nerve conduction study results of a 29-year-old female patient with a paraparetic variant of guillainbarré syndrome sensory nerve test location onset latency in ms peak latency in ms amplitude in µv conduction velocity in m/s first study second study third study first study second study third study first study second study third study first study second study third study right sural nerve in the ankle 2.3 1.8 2.6 3.2 2.1 3.6 12.5 10.2 9.7 52 50 56 table 3: f-wave study results of a 29-year-old female patient with a paraparetic variant of guillain-barré syndrome nerve test location motor distal latency in ms f-wave latency in ms first study second study third study first study second study third study right peroneal nerve 3.2 5.5 7.5 nr 59.0 63.1 nr = not recordable paraparetic variant of guillain-barré syndrome in first 24 hours of postpartum period a case report e230 | squ medical journal, may 2020, volume 20, issue 2 minimal or no paraesthesia or sensory loss.5 they found that 7% of their study population with gbs had a paraparetic variant characterised by symmetrical areflexic weakness of the lower extremities without sensory loss. however, one-third of those patients showed clinical or electrophysiologic involvement of the upper extremities. ncs in those patients showed axonopathy in 59% and demyelinating features in 33%.5 van den berg et al. found that 8% of their study population with gbs had a paraparetic variant.9 those patients with a paraparetic variant of gbs had mild disease, less cranial nerve involvement and less respiratory failure compared to the gbs patients with quadriparesis. they also identified a delay between symptom onset and initiation of treatment and a lower likelihood of receiving specific treatment (88% with paraparesis versus 97% with quadriparesis; p = 0.014). bladder involvement was seen in 14% of van den berg et al.’s cases, as was seen in the current case.9 the asymmetrical weakness and predominantly distal distribution in the current case were associated with areflexia and bladder dysfunction, which resembled cauda equina syndrome, while the classic gbs is considered to present with a symmetrical distribution of weakness with more gradual onset and infrequent involvement of the bladder. the current patient had a similar cell count in their csf as 16% of van den berg et al.’s cases (csf cell count range: 10–50).9 data from imaging was available only for 30% of their patients and there was no explanation for paraparesis on imaging which is similar to the current case. ncs studies in van den berg et al.’s study showed demyelinating features as the most common finding in almost half of their patients; this finding is similar to the current case.9 one patient in their cohort had clinical and electrophysiologic abnormalities limited to the lower extremities, as was the case in the current patient. a total of 98% of their patients could walk unaided at six months.9 there are very few reported cases of the para paretic variant of gbs with findings restricted to the lower extremities.10,11 kimachi et al. reported the case of an elderly female patient who developed progressive, symmetrical lower limb weakness after an upper respiratory tract infection sparing the arms and cranial nerves.10 similarly, the limb weakness in the current patient was also preceded by an upper respiratory tract infection. csf showed cytoalbuminologic dissociation and ncs showed axonal type features.10 nagashima et al. reported the case of an older female patient who developed weakness of the lower extremities three weeks after an episode of fever and diarrhoea.11 the weakness was restricted to the lower extremities with intact sensation. the ncs showed findings of an axonal variety.11 compared to other cases, the current patient was younger and experienced rapid onset asymmetrical paraparesis and demyelinating features on ncs. in the current case, the diagnosis is supported by antecedent upper respiratory tract infection, areflexic flaccid paraparesis, cytoalbuminologic dissociation in csf, demyelinating features on ncs, normal spine imaging and a monophasic course of illness. conclusion this case highlights that the paraparetic variant of gbs should be considered as one of the differential diagnoses of cauda equina syndrome, if there is no alternative aetiology. early recognition of gbs is of vital importance with respect to the patient’s outcome. references 1. yuki n, hartung hp. guillain-barré syndrome. n engl j med 2012; 366:2294–304. https://doi.org/10.1056/nejmra1114525. 2. benamer ht, bredan a. guillain-barré syndrome in arab countries: a systematic review. j neurol sci. 2014 aug 15; 343:221–3. 3. ropper ah. unusual clinical variants and signs in guillain-barré syndrome. arch neurol 1986; 43:1150–2. https://doi.org/10.10 01/archneur.1986.00520110044012. 4. ropper ah. further regional variants of acute immune poly neuropathy. bifacial weakness or sixth nerve paresis with pare sthesias, lumbar polyradiculopathy, and ataxia with pharyngealcervical-brachial weakness. arch neurol 1994; 51:671–5. https://doi.org/10.1001/archneur.1994.00540190051014. 5. pokalkar d, narisetty v, polusani r, kamera s, poosarla ssl. a study on topographic variants of guillain-barré syndrome in a tertiary care hospital in south india. iaim 2015; 2:32–8. 6. hiew fl, ramlan r, viswanathan s, puvanarajah s. guillain-barré syndrome, variants & forms fruste: reclassification with new criteria. clin neurol neurosurg 2017; 158:114–18. https://doi. org/10.1016/j.clineuro.2017.05.006. 7. wakerley br, yuki n. mimics and chameleons in guillainbarré and miller fisher syndromes. pract neurol 2015; 15:90–9. https://doi.org/10.1136/practneurol-2014-000937. 8. van doorn pa, ruts l, jacobs bc. clinical features, patho genesis, and treatment of guillain-barré syndrome. lancet neurol 2008; 7:939–50. https://doi.org/10.1016/s1474-4422(08) 70215-1. 9. van den berg b, fokke c, drenthen j, van doorn pa, jacobs bc. paraparetic guillain-barré syndrome. neurology 2014 jun 3; 82:1984–9. https://doi.org/10.1212/wnl.0000000000000481. 10. kimachi t, yuki n, kokubun n, yamaguchi s, wakerley br. paraparetic guillain-barré syndrome: nondemyelinating rever sible conduction failure restricted to the lower limbs. muscle nerve 2017; 55:281–5. https://doi.org/10.1002/mus.25242. 11. nagashima t, kokubun n, shahrizaila n, funakoshi k, hirata k, yuki n. paraparetic guillain-barré syndrome: extending the axonal spectrum. neurol clin neurosci 2013; 1:224–6. https://doi.org/10.1 111/ncn3.59. https://doi.org/10.1056/nejmra1114525 https://doi.org/10.1001/archneur.1986.00520110044012 https://doi.org/10.1001/archneur.1986.00520110044012 https://doi.org/10.1001/archneur.1994.00540190051014 https://doi.org/10.1016/j.clineuro.2017.05.006 https://doi.org/10.1016/j.clineuro.2017.05.006 https://doi.org/10.1136/practneurol-2014-000937 https://doi.org/10.1016/s1474-4422%2808%2970215-1 https://doi.org/10.1016/s1474-4422%2808%2970215-1 https://doi.org/10.1212/wnl.0000000000000481 https://doi.org/10.1002/mus.25242 https://doi.org/10.1111/ncn3.59 https://doi.org/10.1111/ncn3.59 1department of medicine, shifa college of medicine, islamabad, pakistan; 2department of medicine, sultan qaboos university hospital, muscat, oman; 3the queen’s centre for oncology & haematology, castle hill hospital, cottingham, east yorkshire, uk; 4department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: bhagia1@yahoo.com اجتاهات ونتائج عالج سرطان الرئة ذو اخلاليا غري الصغرية يف املرضى العمانيني خربة مستشفى جامعي حممد فروخ، �سيام كومار، خواجة فرحان زاهد، حنان �سعيد ال�ساملية، زينب علي اجلابرية، اإكرام بورين، من�سور �سيف املنذري abstract: objectives: the incidence of lung cancer in oman has shown a gradual but definitive increase since 2002. this study aimed to evaluate the demographic and epidemiological characteristics and survival outcomes of patients with non-small-cell lung cancer (nsclc) at a university hospital in oman. methods: this study was conducted from january to june 2016. a retrospective analysis was performed of consecutive patients diagnosed with nsclc presenting to the sultan qaboos university hospital (squh) in muscat, oman, between march 2000 and december 2015. clinical features at presentation and prognostic and predictive markers were reviewed. kaplan-meir estimates were used to determine relapse-free survival, progression-free survival (pfs) and overall survival (os). results: a total of 104 patients presented to squh during the study period. the median age at diagnosis was 64 years. overall, 62 patients (59.6%) had adenocarcinomas. only 12 patients (11.5%) presented in the early stages (i or ii) of the disease and the majority of patients had an eastern cooperative oncology group performance status of 1 (27.9%) or 2 (26.0%). the prevalence of epidermal growth factor receptor mutations was 27.9%. the median pfs for patients with advanced disease (stages iii or iv) was five months and the median os for all patients was seven months. after five years, 50.0%, 60.0%, 10.0% and 8.0% of patients with disease stages i, ii, iii and iv, respectively, were alive. conclusion: patients with nsclc in oman were found to present at an advanced stage. however, patient outcomes were similar to those reported in the usa. keywords: non-small-cell lung carcinomas; adenocarcinomas; epidermal growth factor receptor; patient outcome assessment; survival analysis; oman. امللخ�ص: الهدف: اأظهرت االإح�سائيات اأن االإ�سابة ب�رصطان الرئة يف عمان تواجه زيادة تدريجية م�سطردة منذ عام 2002. تهدف هذه الدرا�سة اإىل تقييم اخل�سائ�ص الدميوغرافية والوبائية و نتائج جناة املر�سى الذين يعانون من �رصطان الرئة ذو اخلاليا غري ال�سغرية يف م�ست�سفى اجلامعة يف �سلطنة عمان. الطريقة: اأجريت هذه الدرا�سة يف الفرتة من يناير اإىل يونيو 2016. مت اإجراء حتليل ا�ستعادي للمر�سى املتتابعني الذين مت ت�سخي�سهم ب�رصطان الرئة ذو اخلاليا غري ال�سغرية يف م�ست�سفى جامعة ال�سلطان قابو�ص مب�سقط، عمان، بني مار�ص 2000 ودي�سمرب 2015. متت مراجعة اخل�سائ�ص ال�رصيرية ووقت الت�سخي�ص باالإ�سافة لتحليل عوامل االإنذار والتنبوؤ مب�ستقبل املر�ص. وقد ا�ستخدمت تقديرات كابالن-مري لتحديد البقاء على قيد احلياة بدون انتكا�سة، البقاء على قيد احلياة بدون تقدم املر�ص والبقاء على قيد احلياة الكلي. النتائج: متت مراجعة ما جمموعه 104 مري�سا يف م�ست�سفى اجلامعة خالل فرتة الدرا�سة. وكان متو�سط اأعمار املر�سى عند الت�سخي�ص 64 عاما. اإجماال، كان 62 مري�سا )%59.6( يعانون من �رصطان الرئة الغدي. 12 مري�سا فقط )%11.5( مت ت�سخي�ص حاالتهم يف املراحل املبكرة )i اأو ii( من املر�ص وكان لدى غالبية املر�سى حالة االأداء ترتاوح بني 1 )%27.9( اأو 2 )%26.0( ح�سب موؤ�رص جمموعة التعاون ال�رصقية لالأورام. وكان معدل انت�سار الطفرات يف م�ستقبالت عامل منو الب�رصة %27.9. كان متو�سط البقاء على قيد احلياة بدون تقدم املر�ص لدى املر�سى من ذوي املراحل املتقدمة وقت الت�سخي�ص )املرحلة iii و iv( خم�سة اأ�سهر. بينما كان متو�سط البقاء على قيد احلياة الكلي جلميع املر�سى �سبعة اأ�سهر. كما وجدنا اأن %50.0 من مر�سى املرحلة i و %60.0 من مر�سى املرحلة ii، %10.0 من مر�سى املرحلة iii و %8.0 من مر�سى املرحلة iv بقوا على قيد احلياة بعد مرور خم�سة �سنوات من تاريخ الت�سخي�ص. اخلال�صة: املر�سى الذين عالج نتائج كانت ذلك، ومع متقدمة. مراحل يف حاالتهم ت�سخي�ص يتم عمان يف ال�سغرية غري اخلاليا ذو الرئة �رصطان من يعانون املر�سى مماثلة لتلك التي وجدت يف الواليات املتحدة االأمريكية. على البقاء حتليل املر�سى؛ نتائج تقييم الب�رصة؛ منو عامل م�ستقبالت غدي؛ �رصطان ال�سغرية؛ غري اخلاليا ذو الرئة �رصطان املفتاحية: الكلمات قيد احلياة؛ عمان. trends and outcomes of non-small-cell lung cancer in omani patients experience at a university hospital muhammad furrukh,1 *shiyam kumar,2 khawaja f. zahid,3 hanan s. al-shamly,4 zainab a. al-jabri,4 ikram a. burney,2 mansour s. al-moundhri4 clinical & basic research sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e301–308, epub. 10 oct 17 submitted 18 jan 17 revisions req. 27 feb, 2 apr & 17 apr 17; revisions recd. 16 mar, 11 apr & 17 apr 17 accepted 20 apr 17 doi: 10.18295/squmj.2017.17.03.007 advances in knowledge this study presents the clinical and pathological features, treatment details and median progression-free and overall survival of omani patients with non-small-cell lung cancer (nsclc). to the best of the authors’ knowledge, this study is the first to describe the trends and outcomes of patients with nsclc in oman. trends and outcomes of non-small-cell lung cancer in omani patients experience at a university hospital e302 | squ medical journal, august 2017, volume 17, issue 3 lung cancer has recently been identified as the most frequently occurring cancer and leading cause of cancer-related deaths worldwide, with an age-standardised incidence and mortality rate among men alone of 33.8% and 29.2%, respectively.1 globally, it remains the most common form of cancer in men, with high rates in europe, the usa and eastern asia and lower rates in africa.1 since 2002, the incidence of lung cancer in oman has been steadily rising over time; according to the ministry of health, lung cancer was ranked as the sixth most common cancer among men in 2013 (6.2%) and was the second most frequent cause of hospitalbased cancer-related deaths (8.7%) following stomach cancer.2 however, there is as yet no information regarding prognostic markers, presenting features and treatment outcomes among omani patients. lung cancer is associated with tobacco smoking and the risk of developing the disease increases with smoking duration and the number of cigarettes smoked; hence, lung cancer is considered to be a preventable disease.3 in the usa, the prevalence of heavy smoking (i.e. >30 cigarettes/day) has declined considerably; in contrast, a survey from oman has shown a steadily increasing trend in smoking from a crude incidence of 6.7% in 1995 to 7.0% in 2004.4–6 in addition, the majority of smokers are male, with 13.4% of men smoking versus 0.5% of women.6 alarmingly, waterpipe smoking has also become more popular in oman recently, especially among younger individuals.7,8 the current study aimed to describe the demographic characteristics, clinicopathological features, management details and outcomes of patients with non-small-cell lung cancer (nsclc) presenting at the sultan qaboos university hospital (squh), a tertiary university hospital in muscat, oman. the results were subsequently compared with those of previous research from the usa regarding lung cancer-related outcomes.9 methods this non-concurrent retrospective study was conducted from january to june 2016 and included consecutive patients diagnosed with nsclc presenting to squh between march 2000 and december 2015. clinical and demographic data were reviewed using the hospital’s information system, including age, gender, race, weight loss, smoking habits, eastern cooperative oncology group (ecog) performance status and the presence of any concurrent illnesses. prognostic and predictive markers were also analysed, including histological subtype, tumour grade, disease stage, sites of metastasis, epidermal growth factor receptor (egfr) mutation status, treatment offered, survival and the occurrence of side-effects. tissue samples were sent abroad to a reference laboratory for egfr and echinoderm microtubule-associated protein-like 4 (eml4) anaplastic lymphoma kinase (alk) genetic testing. cancer stages were defined as per the international staging committee criteria of the international association for the study of lung cancer.10 the histology results of patients who were referred from other hospitals to squh after diagnosis were reviewed, although the majority of patients had been diagnosed at squh. all patients with incomplete electronic data and those who had received treatment and follow-up elsewhere (n = 7) or individuals diagnosed with small-cell lung cancer (n = 14) were excluded from the study. data were analysed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). relapse-free survival (rfs) was calculated as the period of time between the date of diagnosis until the date of documented relapse, while progression-free survival (pfs) was deemed to constitute the period of time between the date of diagnosis until the date of progression of the disease. overall survival (os) was measured as the period of time from the date of diagnosis to the date of death or until the last known date of follow-up as of june 2016. kaplan-meir estimates were used to determine rfs, pfs and os and the log-rank test was used for the comparative analysis. the cox regression model was used for the multivariate analysis and included all statistically significant variables indicated by the univariate analysis. a p value of ≤0.050 was considered statistically significant. this study was approved by the research & ethics committee of the college of medicine & health sciences, sultan qaboos university (mrec #641). these findings may act as a reference regarding associated clinicopathological features for patients with nsclc from oman as well as other countries in the gulf cooperative council region. application to patient care patient outcomes and survival rates are vital to help decide upon appropriate treatment regimens for patients with malignant disorders. the availability of these local data from oman may serve as a benchmark regarding lung cancer survival rates and will help clinicians during the treatment decision-making process. muhammad furrukh, shiyam kumar, khawaja f. zahid, hanan s. al-shamly, zainab a. al-jabri, ikram a. burney and mansour s. al-moundhri clinical and basic research | e303 results a total of 104 patients with nsclc were included in the study. the median age at diagnosis was 64 years (range: 35–85 years old) and the male-to-female ratio was 3:1. over half of the patients (65.4%) were active or ex-smokers; of these, most were male (91.2%), with only six of the female patients (27.3%) having a history of smoking. the median time to presentation was two months (range: 1–5 months). there were 96 omanis (92.3%) and only eight expatriates (7.7%). most patients had an ecog performance status of 1 (27.9%) or 2 (26.0%), while 10.6%, 20.2% and 15.4% of patients had ecog performance statuses of 0, 3 and 4, respectively. almost half of the patients (48.1%) had a history of significant weight loss. nearly one-third of the patients (35.6%) had more than one comorbidity, with hypertension (47.1%), diabetes (26.9%) and chronic obstructive lung disease (25.0%) being most common. a total of 62 patients (59.6%) had adenocarcinomas. of these, 43 (69.4%) were assessed for activating mutations in exons 19 or 21 of the egfr gene, of which 12 (27.9%) harboured mutations. of the 14 patients (13.5%) who underwent eml4-alk gene testing, only one (7.1%) had an alk rearrangement. the commonest site of metastasis was in the bone (19.2%). the clinical, demographic and pathological characteristics of the patients are presented in table 1. only 12 patients (11.5%) presented with earlystage disease, including one patient (8.3%) at stage i and 11 patients (91.7%) at stage ii. of the patients table 1: baseline clinical, demographic and pathological characteristics of patients with non-small-cell lung cancer presenting to the sultan qaboos university hospital, muscat, oman (n = 104) characteristic n (%) gender male 82 (78.8) female 22 (21.2) age in years ≤60 38 (36.5) >60 66 (63.5) subtype adenocarcinoma 62 (59.6) scc 29 (27.9) undifferentiated 7 (6.7) carcinoid tumour 2 (1.9) large-cell cancer 2 (1.9) ascc 2 (1.9) metastasis none 37 (35.6) bone 20 (19.2) opposite lung 15 (14.4) liver 7 (6.7) adrenal glands 7 (6.7) brain and bone 6 (5.8) brain 5 (4.8) pleural effusion 4 (3.8) liver and bone 1 (1.0) liver and cord compression 1 (1.0) peritoneum 1 (1.0) tumour size* t1 6 (5.8) t2 31 (29.8) t3 41 (39.4) t4 25 (24.0) unknown 1 (1.0) nodal status n0 8 (7.7) n1 31 (29.8) n2 51 (49.0) n3 11 (10.6) nx 3 (2.9) stage i 2 (1.9) ii 10 (9.6) iii 25 (24.0) iv 67 (64.4) grade well-differentiated 4 (3.8) moderately differentiated 30 (28.8) poorly differentiated 62 (59.6) undifferentiated 7 (6.7) unknown 1 (1.0) scc = squamous cell carcinoma; ascc = adenosquamous cell carcinoma; t1 = ≤3 cm; t2 = 3–7 cm; t3 = >7 cm; t4 = tumour of any size invading the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina or separate tumor in different ipsilateral lobe; n0 = absence of nodal involvement; n1 = metastasis to the ipsilateral hilar or peribronchial lymp nodes; n2 = metastasis to the ipsilateral mediastinal or carinal lymp nodes; n3 = metastasis to the contralateral hilar, mediastinal or supraclavicular lymp nodes; nx = nodal involvement unknown. *on radiology. trends and outcomes of non-small-cell lung cancer in omani patients experience at a university hospital e304 | squ medical journal, august 2017, volume 17, issue 3 who presented with early-stage nsclc, 10 (83.3%) underwent surgical resection. seven patients received adjuvant chemotherapy, one patient was deemed unfit for chemotherapy and received adjuvant radiation therapy instead and two patients opted not to receive adjuvant therapy and later died due to progressive cancer (including one patient with an adenocarcinoma and another with squamous cell carcinoma [scc]). local and distant relapse was documented in two patients each, while four patients had both local and distant relapses. a total of 92 patients (88.4%) presented with more advanced disease (stage iii or iv) and were treated palliatively; of these, 30 patients (32.6%) did not receive chemotherapy because they either refused treatment or were deemed unfit due to their poor ecog performance status. patients who received first-line chemotherapy were treated with a median of four cycles (range: 1–6 cycles). only seven patients received tyrosine-kinase inhibitors (tkis) during the first line of chemotherapy, including erlotinib (n = 5), a combination of erlotinib and chemotherapy (n = 1) and gefitinib (n = 1). all of these patients experienced disease progression requiring second-line chemotherapy, except for one patient who died while receiving erlotinib. a total of 62 patients (59.6%) were treated with platinum doublets as first-line therapy. the first-line treatment regimens prescribed are shown in table 2. maintenance chemotherapy after induction therapy was offered to 11 patients who received a median of 14 maintenance cycles (range: 4–26 cycles) before progression. a median of three cycles of second-line chemotherapy was administered (range: 1–17 cycles). docetaxel alone was administered to 10 patients in the second line, while five patients received pemetrexed or gemcitabine with platinum. the remaining patients were treated with other single agents or a combination of regimens. of the 35 patients who received secondline chemotherapy, 19 (54.3%) also received thirdline chemotherapy. docetaxel and erlotinib were the most commonly used third-line agents (21.1% each). five patients (4.8%) were treated with five lines of chemotherapy. in total, 83 patients (79.8%) died secondary to disease progression and eight (7.7%) died of nondisease-related causes. at the time of writing, five patients (4.8%) were alive and actively receiving treatment, three patients (2.9%) who had received adjuvant chemotherapy were in remission, one patient (1.0%) was alive on best supportive care and one patient (1.0%) was alive and diseased, but under active observation due to a bronchial carcinoid tumour. the status of the remaining three patients (2.9%) was unknown as they were lost to follow-up. according to gender, median pfs was 19.0 months in females versus 7.4 months in males and os was 22.2 months in females versus 10.5 months in males. median rfs among patients with early-stage disease (stage i or ii) was 29 months (range: 1–74 months), while median pfs among patients with more advanced disease (stage iii or iv) was five months (range: five days–97 months) table 2: first-line treatment regimens among patients with non-small-cell lung cancer presenting at the sultan qaboos university hospital, muscat, oman (n = 104) regimen n (%) adenocarcinoma 62 (59.6) pemetrexed and carboplatin 17 (16.3) bsc and palliative xrt 16 (15.4) gemcitabine and carboplatin 9 (8.7) erlotinib 5 (4.8) vinorelbine and carboplatin/cisplatin 4 (3.8) paclitaxel and carboplatin 4 (3.8) pemetrexed 2 (1.9) gemcitabine, carboplatin and bevacizumab 1 (1.0) pemetrexed, carboplatin and bevacizumab 1 (1.0) gefitinib 1 (1.0) pemetrexed, carboplatin and erlotinib 1 (1.0) 5-fu and platinum 1 (1.0) ascc 2 (1.9) paclitaxel and carboplatin 2 (1.9) scc 29 (27.9) gemcitabine and carboplatin 12 (11.5) bsc 10 (9.6) gemcitabine 2 (1.9) paclitaxel and carboplatin 2 (1.9) nab-paclitaxel and carboplatin 1 (1.0) docetaxel and carboplatin 1 (1.0) etoposide, carboplatin and xrt 1 (1.0) undifferentiated 7 (6.7) bsc 3 (2.9) gemcitabine and carboplatin 2 (1.9) paclitaxel and carboplatin 2 (1.9) large-cell cancer 2 (1.9) gemcitabine and carboplatin 1 (1.0) pemetrexed and carboplatin 1 (1.0) carcinoid tumour 2 (1.9) surveillance 2 (1.9) bsc = best supportive care; xrt = radiotherapy; 5-fu = 5-fluorouracil; ascc = adenosquamous cell carcinoma; scc = squamous cell carcinoma. muhammad furrukh, shiyam kumar, khawaja f. zahid, hanan s. al-shamly, zainab a. al-jabri, ikram a. burney and mansour s. al-moundhri clinical and basic research | e305 table 3: univariate analysis of factors affecting recurrence-free survival, progression-free survival and overall survival among patients with non-small-cell lung cancer presenting to the sultan qaboos university hospital, muscat, oman (n = 104) variable rfs/pfs os 95% ci p value 95% ci p value gender (male versus female) 3.40–6.59 0.007 2.96–35.03 0.055 age group (<60 versus ≥60-year-olds) 3.41–6.58 0.220 4.82–13.17 0.023 curative surgery 23.16–48.83 <0.001 0.00–187.72 <0.001 disease stage at diagnosis 2.89–5.10 0.001 3.46–6.53 0.001 smoking history 3.59–6.40 0.019 2.87–27.12 0.003 ecog performance status 4.15–11.84 0.001 18.527–21.47 <0.001 weight loss 2.46–7.54 0.070 5.31–16.68 0.011 n0 nodal status 25.26–46.73 0.003 0.0–173.65 0.001 site of metastasis 5.93–10.06 0.005 7.65–28.34 <0.001 chemotherapy approach (adjuvant versus palliative) 25.26–46.73 0.003 7.98–16.01 <0.001 number of chemotherapy cycles 5.76–10.24 0.043 7.98–16.01 0.005 chemotherapy-associated side-effects 3.12–6.87 0.006 3.17–18.82 0.120 treatment response 6.76–9.24 <0.001 4.29–9.70 <0.001 radiation treatment 4.45–7.54 0.050 pfs 5.37–12.63 0.001 rfs = recurrence-free survival; pfs = progression-free survival; os = overall survival, ci = confidence interval; ecog = eastern cooperative oncology group; n0 = absence of nodal involvement. figure 1: median (a) progression-free survival for all patients and (b) recurrence-free or progression-free survival according to stage among patients with non-small-cell lung cancer presenting to the sultan qaboos university hospital, muscat, oman (n = 104). figure 2: median overall survival for (a) all patients and (b) according to stage among patients with non-small-cell lung cancer presenting to the sultan qaboos university hospital, muscat, oman (n = 104). trends and outcomes of non-small-cell lung cancer in omani patients experience at a university hospital e306 | squ medical journal, august 2017, volume 17, issue 3 [figure 1]. the median os for all patients was seven months (range: 7 days–123 months). at two and five years, os was 96.0% and 7.0%, respectively. at two years, os was 50.0%, 70.0%, 22.0% and 17.0% for patients with disease stages i, ii, iii and iv, respectively. after five years, 50.0%, 60.0%, 10.0% and 8.0% of patients with stages i, ii, iii and iv were still alive [figure 2]. on univariate analysis, females had a significantly higher median pfs rate (19.0 versus 7.4 months; p = 0.003) in comparison to males, although os was not significantly different (19.0 versus 6.0 months; p = 0.055). moreover, curative surgical resection, an early-stage diagnosis, never smoking, ecog performance status, the absence of nodal involvement, the site of metastasis, chemotherapy approach, the number of cycles of chemotherapy administered, the presence of chemotherapy-associated side-effects and treatment response to first-line chemotherapy were also significantly associated with pfs (p <0.050 each). in addition, a younger age, curative surgical resection, an early-stage diagnosis, never smoking, ecog performance status, weight loss, the absence of nodal involvement, the site of metastasis, chemotherapy approach, the number of chemotherapy cycles, receiving radiation therapy, treatment response to firstline chemotherapy and pfs were significant factors affecting increased os (p <0.050 each) [table 3]. however, none of these factors were found to be statistically significant during the multivariate cox regression analysis. discussion in oman, lung cancer is a major cause of cancerrelated deaths, warranting patient, physician and specialist awareness.2 while fewer patients are diagnosed with lung cancer in oman as compared to neighbouring countries like the united arab emirates and saudi arabia, the age-standardised ratio for lung cancer is higher in oman at 6.7 for males and 2.1 for females.2 nevertheless, the incidence of lung cancer in oman is lower than in other nearby countries like egypt, kuwait and jordan.11,12 the mean age of the patient population in the current study (64 years) was consistent with that reported in previously published research (59.2 years).13 moreover, age was significantly associated with poorer survival in the current study; while age is reportedly not prognostic for survival, it is known to be a poor prognostic factor for toxicity to chemotherapy.14 in the present study, nsclc was more frequent among men; the lower incidence among omani women may perhaps reflect the cultural taboo of tobacco smoking in females. women also showed superior median pfs and os compared to men; this correlates favourably with western findings reported by wisnivesky et al.15 a norwegian study similarly reported that men with adenocarcinomas had a 24% higher risk of death than women.16 however, environmental exposure, genetic predisposition, hormonal factors and viral infections may all play a role in lung cancer among women and never smokers, both of whom have a higher prevalence of adenocarcinomas.3,17 zang et al. found that the odds ratio for adenocarcinomas was higher among females due to their greater susceptibility to carcinogens, regardless of level of exposure to tobacco smoke.18 adenocarcinoma subtypes are usually related to subpleural scars.19 while the incidence of scc has decreased over the past few decades, that of adenocarcinomas has increased in both genders due to the introduction of filter vents that facilitate easier and deeper inhalation of tobacco-specific carcinogens.3 this was reflected in the current study in which a higher incidence of adenocarcinomas was observed in comparison to scc. additionally, according to the univariate analysis, never smokers in the present study had a significantly better pfs rate. furthermore, the vast majority of smokers were male. various carcinogens and cell signal pathways have been proposed to contribute to lung oncogenesis among never smokers.4 loss of body weight at presentation was associated with poorer survival in the present study, with almost half of the study sample losing >5% of their baseline weight; in addition, decreased ecog performance status was associated with poor outcomes. yang et al. also found that weight loss was associated with poorer survival.20 in a study of various chemotherapy regimens for patients with advanced nsclc, schiller et al. indicated that the absolute benefit of chemotherapy for one year and median os varied inversely with poor ecog performance status.21 multiple concurrent illnesses were noted in the current study which is understandable considering the fact that most of the patients were quite elderly. however, the frequency of these variables was too low to predict survival. the severity or burden of comorbidity has been reported to have a clear relationship with poor survival in lung cancer; for example, the charlson comorbidity index is associated with increasing toxicity to chemotherapy.22,23 ethnicity has also been found to have an impact on survival; a recent article indicated that african americans had poorer survival prospects even though caucasians had a higher risk of developing lung cancer.24 most patients in the current study were omani, with eight patients originating muhammad furrukh, shiyam kumar, khawaja f. zahid, hanan s. al-shamly, zainab a. al-jabri, ikram a. burney and mansour s. al-moundhri clinical and basic research | e307 from either africa, pakistan, the philippines, india or europe; unfortunately, due to the low number of expatriates, it was not possible to correlate race or ethnicity with survival. the majority of patients in the current study were treated with platinum doublets. bevacizumab could not be administered to many of the patients due to the presence of absolute or relative contraindications.25 at squh, anticancer therapy is customised based on the histological subtype of nsclc; pemetrexed and platinum doublets with or without bevacizumab are usually prescribed for adenocarcinomas, while platinum and gemcitabine or nab-paclitaxel are prescribed for scc and tkis for patients with adenocarcinomas also harbouring egfr mutations. overall, egfr mutations are present in 40–50% of east asians and 10% of caucasians.26 however, the exact incidence of these mutations in the gcc region is unknown; in the current study, it was observed that 27.9% of patients with adenocarcinomas had egfr mutations in exons 19 or 21. as of late 2010, selected nsclc patients at squh are treated with maintenance therapy. compelling data exist suggesting that patients with ecog performance statuses of 0–1 receiving maintenance therapy have well-preserved organ function and that this form of therapy enhances os by 2–3 months.27–31 several prognostic and predictive markers are also now available to guide oncologists in providing customised and individualised evidencebased care.32 a major cause of death in the present study was either local progression leading to respiratory failure, progressive metastasis (i.e. leptomeningeal and brain metastases, liver failure, pulmonary parenchymal relapse or pleural effusion or both) or infections (i.e. pneumonia and sepsis). no deaths were attributable to venous thromboembolic phenomena or pulmonary embolisms, which may be due to the strict thromboprophylaxis policy implemented at squh. survival outcomes were very poor for patients who were diagnosed nsclc at a late stage, which constituted the vast majority of patients in the studied cohort. this incidence of advanced stage nsclc is very similar to that reported by the surveillance, epidemiology, and end results (seer) program of the national cancer institute in the usa [table 4].9 advanced nsclc has a median os of 10 months.32 pemetrexed and targeted agents have been reported to enhance survival to 12 months and beyond, while the benefits of post-progression bevacizumab are currently under investigation.33 in the current study, prolonged survival was observed in a few cases treated with either tkis or maintenance therapy; these findings are in agreement with those from other studies.34,35 conclusion in the current study, the majority of patients with nsclc were found to present at an advanced stage. however, survival outcomes were similar to those reported by the seer program in the usa. to the best of the authors’ knowledge, this study is the first to describe the trends and outcomes of patients with nsclc in oman. a c k n o w l e d g e m e n t s the authors wish to thank dr. waeil makki for his help with the arabic translation of the title, author names and abstract of this article. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. torre la, bray f, siegel rl, ferlay j, lortet-tieulent j, jemal a. global cancer statistics, 2012. ca cancer j clin 2015; 65:87–108. doi: 10.3322/caac.21262. 2. oman ministry of health. cancer incidence in oman: 2013. from: www.moh.gov.om/documents/272928/1232802/cancer +incidence+2013/3e7cc1c7-65a7-4c57-8d8b-a9aa2b714db8 accessed: apr 2017. table 4: comparison of stage distribution and survival rates of patients with non-small-cell lung cancer in oman and the usa stage at diagnosis frequency percentage two-year os five-year os oman i 1.9 50.0 50.0 ii 9.6 70.0 60.0 iii 24.0 22.0 10.0 iv 64.4 17.0 8.0 usa* localised disease 15 52.2 regional metastasis to the lymph nodes 22 25.1 distant metastasis 56 3.7 unstaged 6 7.9 os = overall survival. *data sourced from the results of the surveillance, epidemiology, and end results program of the national cancer institute for 2001–2008.9 https://doi.org/10.3322/caac.21262 trends and outcomes of non-small-cell lung cancer in omani patients experience at a university hospital e308 | squ medical journal, august 2017, volume 17, issue 3 3. furrukh m. tobacco smoking and lung cancer: perceptionchanging facts. sultan qaboos university med j 2013; 13:345–58. 4. hecht ss. cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. lancet oncol 2002; 3:461–9. doi: 10.1016/s1470-2045(02)00815-x. 5. centers for disease control and prevention. preventing tobacco use among young people: a report of the surgeon general executive summary. mmwr recomm rep 1994; 43:1–10. 6. al riyami aa, afifi m. smoking in oman: prevalence and characteristics of smokers. east mediterr health j 2004; 10:600–9. 7. al-lawati ja, muula as, hilmi sa, rudatsikira e. prevalence and determinants of waterpipe tobacco use among adolescents in oman. sultan qaboos univ med j 2008; 8:37–43. 8. world health organization, centers for disease control and prevention. global youth tobacco survey: country reports. from: www.emro.who.int/images/stories/tfi/documents/gyts _cr_oma_2010.pdf?ua=1 accessed: apr 2017. 9. national cancer institute surveillance, epidemiology, and end results program. previous version: seer cancer statistics review, 1975-2012. from: http://seer.cancer.gov/csr/1975_2012/ accessed: apr 2017. 10. rami-porta r, crowley jj, goldstraw p. the revised tnm staging system for lung cancer. ann thorac cardiovasc surg 2009; 15:4–9. 11. salim ei, jazieh ar, moore ma. lung cancer incidence in the arab league countries: risk factors and control. asian pac j cancer prev 2011; 12:17–34. 12. al-hamdan n, ravichandran k, al-sayyad j, al-lawati j, khazal z, al-khateeb f, et al. incidence of cancer in gulf cooperation council countries, 1998-2001. east mediterr health j 2009; 15:600–11. ann saudi med 2006; 26:433–8. 13. al-hamdan n, al-jarallah m, al-jarallah m, ravichandran k, al-sayyad j, al-lawati j, et al. the incidence of lung cancer in the gulf cooperation council countries. 14. owonikoko tk, ragin cc, belani cp, oton ab, gooding we, taioli e, et al. lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. j clin oncol 2007; 25:5570–7. doi: 10.1200/jco.2007.12.5435. 15. wisnivesky jp, halm ea. sex differences in lung cancer survival: do tumors behave differently in elderly women? j clin oncol 2007; 25:1705–12. doi: 10.1200/jco.2006.08.1455. 16. sagerup cm, småstuen m, johannesen tb, helland å, brustugun ot. sex-specific trends in lung cancer incidence and survival: a population study of 40,118 cases. thorax 2011; 66:301–7. doi: 10.1136/thx.2010.151621. 17. kligerman s, white c. epidemiology of lung cancer in women: risk factors, survival, and screening. ajr am j roentgenol 2011; 196:287–95. doi: 10.2214/ajr.10.5412. 18. zang ea, wynder el. differences in lung cancer risk between men and women: examination of the evidence. j natl cancer inst 1996; 88:183–92. doi: 10.1093/jnci/88.3-4.183. 19. bobba rk, holly js, loy t, perry mc. scar carcinoma of the lung: a historical perspective. clin lung cancer 2011; 12:148–54. doi: 10.1016/j.cllc.2011.03.011. 20. yang r, cheung mc, pedroso fe, byrne mm, koniaris lg, zimmers ta. obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival. j surg res 2011; 170:e75–83. doi: 10.1016/j.jss.2011.04.061. 21. schiller jh, harrington d, belani cp, langer c, sandler a, krook j, et al. comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. n engl j med 2002; 346:92–8. doi: 10.1056/nejmoa011954. 22. burdett s, johnson d, stewart l, tierney j, le pechoux c. b2-03: supportive care and chemotherapy (ct) versus supportive care alone in advanced non-small cell lung cancer (nsclc): a meta-analysis using individual patient data (ipd) from randomised controlled trials (rcts). j thorac oncol 2007; 2:s337. doi: 10.1097/01.jto.0000283148.83670.80. 23. tammemagi cm, neslund-dudas c, simoff m, kvale p. impact of comorbidity on lung cancer survival. int j cancer 2003; 103:792–802. doi: 10.1002/ijc.10882. 24. desantis ce, siegel rl, sauer ag, miller kd, fedewa sa, alcaraz ki, et al. cancer statistics for african americans, 2016: progress and opportunities in reducing racial disparities. ca cancer j clin 2016; 66:290–308. doi: 10.3322/caac.21340. 25. azzoli cg, giaccone g, temin s. american society of clinical oncology clinical practice guideline update on chemotherapy for stage iv non-small-cell lung cancer. j oncol pract 2010; 6:39–43. doi: 10.1200/jop.091065. 26. paik pk, johnson ml, d’angelo sp, sima cs, ang d, dogan s, et al. driver mutations determine survival in smokers and neversmokers with stage iiib/iv lung adenocarcinomas. cancer 2012; 118:5840–7. doi: 10.1002/cncr.27637. 27. cappuzzo f, ciuleanu t, stelmakh l, cicenas s, szczésna a, juhász e, et al. erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. lancet oncol 2010; 11:521–9. doi: 10.1016/s1470-2045(10)70112-1. 28. ciuleanu t, brodowicz t, zielinski c, kim jh, krzakowski m, laack e, et al. maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. lancet 2009; 374:1432–40. doi: 10.1016/s0140-6736(09)61497-5. 29. fidias pm, dakhil sr, lyss ap, loesch dm, waterhouse dm, bromund jl, et al. phase iii study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. j clin oncol 2009; 27:591–8. doi: 10.1200/jco.2008.17.1405. 30. paz-ares l, de marinis f, dediu m, thomas m, pujol jl, bidoli p, et al. maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (paramount): a double-blind, phase 3, randomised controlled trial. lancet oncol 2012; 13:247–55. doi: 10.1016/s1470-2045(12)70063-3. 31. pérol m, chouaid c, pérol d, barlési f, gervais r, westeel v, et al. randomized, phase iii study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. j clin oncol 2012; 30:3516–24. doi: 10.1200/jco.2011.39.9782. 32. furrukh m, al-moundhri m, zahid kf, kumar s, burney i. customised, individualised treatment of metastatic non-smallcell lung carcinoma (nsclc). sultan qaboos univ med j 2013; 13:202–17. 33. gridelli c, bennouna j, de castro j, dingemans am, griesinger f, grossi f, et al. randomized phase iiib trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the avaall (mo22097) trial. clin lung cancer 2011; 12:407–11. doi: 10.1016/j.cllc.2011.05.002. 34. furrukh m, burney ia, kumar s, zahid kf, al-moundhri m. improving outcomes in advanced lung cancer: maintenance therapy in non-small-cell lung carcinoma. sultan qaboos univ med j 2013; 13:3–18. 35. melosky b. review of egfr tkis in metastatic nsclc, including ongoing trials. front oncol 2014; 4:244. doi: 10.3389/ fonc.2014.00244. https://doi.org/10.1016/s1470-2045%2802%2900815-x https://doi.org/10.1200/jco.2007.12.5435 https://doi.org/10.1200/jco.2006.08.1455 https://doi.org/10.1136/thx.2010.151621 https://doi.org/10.2214/ajr.10.5412 https://doi.org/10.1093/jnci/88.3-4.183 https://doi.org/10.1016/j.cllc.2011.03.011 https://doi.org/10.1016/j.jss.2011.04.061 https://doi.org/10.1056/nejmoa011954 https://doi.org/10.1097/01.jto.0000283148.83670.80 https://doi.org/10.1002/ijc.10882 https://doi.org/10.3322/caac.21340 https://doi.org/10.1200/jop.091065 https://doi.org/10.1002/cncr.27637 https://doi.org/10.1016/s1470-2045%2810%2970112-1 https://doi.org/10.1016/s0140-6736%2809%2961497-5 https://doi.org/10.1200/jco.2008.17.1405 https://doi.org/10.1016/s1470-2045%2812%2970063-3 https://doi.org/10.1200/jco.2011.39.9782 https://doi.org/10.1016/j.cllc.2011.05.002 https://doi.org/10.3389/fonc.2014.00244 https://doi.org/10.3389/fonc.2014.00244 department of internal medicine, postgraduate institute of medical education & research, chandigarh, india *corresponding author’s e-mail: bhalla.chd@gmail.com داللة مستويات اجللوكوز يف الدم وتغرياته كعوامل تنبؤ بنتائج املرضى املصابني بتسمم فوسفيد األلومنيوم اأرفند �شارما، برا�شانث بال�شربامينني، كريان جل، اأ�شي�ص بّله abstract: objectives: this study aimed to assess the prognostic significance of blood glucose levels and blood glucose alterations (i.e. hyperor hypoglycaemia) among patients with aluminium phosphide (alp) poisoning. methods: this prospective observational study was conducted at the postgraduate institute of medical education & research, chandigarh, india, between january 2010 and june 2011. all patients presenting to the emergency department with a definitive history of alp ingestion or symptoms compatible with alp poisoning were included in the study. blood glucose levels were recorded at presentation and every six hours thereafter. alterations in blood glucose levels and other clinical and laboratory variables were subsequently compared between survivors and non-survivors. results: a total of 116 patients with alp poisoning were identified. of these, 57 patients (49%) survived and 59 patients (51%) died. at presentation, the mean blood glucose levels of survivors and non-survivors were 119.9 ± 35.7 mg/dl and 159.7 ± 92.5 mg/dl, respectively (p <0.001). in comparison to the survivors, non-survivors had significantly higher heart rates, total leukocyte counts, blood glucose level alterations and serum creatinine levels (p <0.050). in addition, systolic blood pressure, glasgow coma scale scores, arterial blood gas ph and bicarbonate values and duration of hospital stay was significantly lower compared to survivors (p <0.001). however, neither blood glucose levels at admission nor blood glucose alterations correlated independently with mortality in a multivariate analysis. conclusion: the role of blood glucose level alterations in predicting patient outcomes in alp poisoning cases remains inconclusive. further studies with larger sample sizes are required. keywords: aluminum phosphide; poisoning; blood glucose; hyperglycemia; hypoglycemia; mortality; prognostic factors; india. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل تقييم دللة م�شتويات اجللوكوز يف الدم وتغرياته )زياده اأو نق�شان( كعوامل تنبوؤ بنتائج املر�شى امل�شابني بت�شمم فو�شفيد الألومنيوم. الطريقة: اأجريت هذه الدرا�شة الر�شدية يف معهد الدرا�شات العليا للتعليم الطبي والبحوث يف �شانديغار، الهند، يف الوقت بني يناير 2010 و يونيو 2011 على جميع املر�شى القادمني اإىل ق�شم الطوارئ بعد التاأكد من ابتالع فو�شفيد الألومنيوم اأو لديهم اأعرا�ص متوافقة مع هذا الت�شمم. مت ت�شجيل م�شتويات اجللوكوز يف الدم عند قدومهم وكل �شت �شاعات بعد ذلك. متت بعد ذلك مقارنة التغيريات يف م�شتويات اجللوكوز يف الدم وغريها من املتغريات ال�رسيرية واملخربية بني الناجني وغري الناجني من الت�شمم. النتائج: مت حتديد جمموعه 116 مري�شا اأ�شيبو بت�شمم فو�شفيد الألومنيوم. من هوؤلء، جنا 57 مري�شا )%49( وتويف 59 مري�شا )%51(. عند القدوم اإىل ق�شم الطواريء، كان متو�شط م�شتويات ال�شكر يف الدم للناجني وغري الناجني 35.7 ± 119.9 ملغ/دي�شيلرت و 92.5 ± 159.7 ملغم/دي�شيلرت ، على التوايل )p >0.001(. كان لدى غري الناجني باملقارنة مع الناجني قيم اأعلى ب�شكل ملحوظ ملعدل �رسبات قلب، اأعداد كريات الدم البي�ص، تغريات م�شتوى اجللوكوز وم�شتويات الكرياتينني يف الدم )p >0.050(. بالإ�شافة اإىل ذلك، كان �شغط الدم النقبا�شي ومقيا�ص غيبوبة .)p >0.001( غال�شكو ودرجة احلمو�شة وم�شتوى البيكربونات يف الدم ال�رسياين ومدة الإقامة يف امل�شت�شفى اأقل بكثري مقارنة بالناجني ومع ذلك، ل ترتبط م�شتويات اجللوكوز يف الدم عند القدوم ول تغريات اجللوكوز يف الدم ب�شكل م�شتقل مع معدل الوفيات يف التحليل متعدد املتغريات. اخلال�صة: ل يزال دور تغريات م�شتوى اجللوكوز يف الدم يف التنبوؤ بنتائج املر�شى يف حالت ت�شمم فو�شفيد الألومنيوم غري حا�شم. مطلوب مزيد من الدرا�شات مع اأحجام عينة اأكرب. الكلمات املفتاحية: ت�شمم فو�شفيد الألومنيوم؛ جلوكوز الدم؛ ارتفاع ال�شكر يف الدم؛ نق�ص ال�شكر يف الدم؛ معدل الوفيات؛ عوامل التنبوؤ؛ الهند. prognostic significance of blood glucose levels and alterations among patients with aluminium phosphide poisoning arvind sharma, prasanth balasubramanian, kiran d. gill, *ashish bhalla clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e299–303, epub. 19 dec 18 submitted 5 mar 18 revisions req. 10 apr & 28 may 18; revisions recd. 10 may & 5 jun 18 accepted 7 jun 18 advances in knowledge elevated blood glucose levels have been previously identified as an indicator of poor prognosis in cases of aluminium phosphide (alp) poisoning. however, the current study found that blood glucose level alterations—namely, hyperor hypoglycaemia—were not associated with mortality in alp cases. application to patient care based on the findings of the current study, blood glucose level alterations should not be considered predictors of poor patient prognosis in alp poisoning cases. patients should therefore be assessed based on a range of clinical and laboratory parameters. doi: 10.18295/squmj.2018.18.03.006 prognostic significance of blood glucose levels and alterations among patients with aluminium phosphide poisoning e300 | squ medical journal, august 2018, volume 18, issue 3 in india, aluminium phosphide (alp) is the most commonly encountered poison after anti-cholinesterase.1 as a pesticide, alp is used extensively to protect stored products and crops and is available in the form of pellets, tablets or compressed discs. in northern india, an epidemic of alp poisoning was reported in 1988 in which 285 cases of alp ingestion were documented, most of which were intentional/ suicidal.2 although the toxicokinetic properties of alp are poorly understood, its toxicodynamic properties are exerted by phosphine (ph3), which is released in the stomach when it comes into contact with moisture or hydrochloric acid and results in the inhibition of cytochrome c oxidase and a release of free oxygen radicals, causing oxidative stress.3,4 after oral ingestion, ph3 is quickly absorbed into the body, resulting in systemic toxicity, with death usually resulting from cardiovascular dysfunction.5 phosphides may also be absorbed in their unhydrolysed salt form.6 apart from a definitive history of ingestion, a diag nosis of alp poisoning can be established by the odour of the patient’s breath, which often smells of garlic or decaying fish, although the former symptom is also seen in calcium carbide poisoning cases.7–9 other early symptoms include nausea, vomiting, epigastric and retro sternal pain, anxiety, agitation and dyspnoea.7 in addition, the diagnosis can also be made by silver nitrate testing of the gastric fluid or breath.9 peripheral circulatory failure and shock are early signs indicating fatal toxicity.7 the mortality rate in alp poisoning cases varies from 30–100% and depends upon the dose and freshness of the poison, the onset of clinical manifestations, time until presentation, duration and severity of shock, time until vomiting and treatment modality. the main compl ications observed in fatal alp poisoning cases are cardiac dysrhythmias, severe metabolic acidosis, shock, respiratory distress syndrome and hypomagnesaemia.7 prognostic factors that may predict poor outcomes in alp poisoning cases include hyperglycaemia, hypo tension, acidosis, leukocytosis, hyperuricaemia, electro cardiography abnormalities, high acute physiology and chronic health evaluation scores, high simplified acute physiology scores, low glasgow coma scale scores, acute renal failure, low prothrombin rates, methaemoglobinaemia and the use of inotropes and mechanical vent ilation.10–14 serial blood glucose monitoring is a conv enient and easy method of assessing hypoor hyperglycaemia, particularly in primary healthcare settings with limited resources. the current study aimed to determine the incidence of blood glucose level alter ations in patients with alp poisoning and the correlations between blood glucose levels and alterations and mortality. methods this prospective observational study was conducted at the postgraduate institute of medical education & research, a tertiary referral centre in chandigarh, northeast india, from january 2010 to june 2011. all patients presenting to the emergency department during this period with a definitive history of alp ingestion or symptoms compatible with alp poisoning—including vomitus smelling of decaying fish or garlic, severe hypotension or shock, metabolic acidosis and abnormalities in cardiac rate or rhythm—were included in the study. cases in which the ingestion of alp was doubtful or with concom itant ingestion of other drugs or alcohol were excluded, as were patients with a history of dextrose administration prior to presentation or those with diabetes mellitus. the vital signs of the patients were assessed, including their blood pressure (bp), heart rate and respiratory rate. temperature and oxygen saturation were recorded using a pulse oximeter. blood glucose levels were recorded using the hitachi modular analytics system p800 chem istry analyser (roche diagnostics k.k., tokyo, japan), after appropriate calibration and quality control measures. alterations in blood glucose levels were defined as the occurrence of either hyperglycaemia (random blood gluc ose levels of >200 mg/dl) or hypoglycaemia (random blood glucose levels of <55 mg/dl) at admission or any point during hospital stay.15,16 a complete blood count was performed along with biochemical tests to determine serum sodium, potassium, urea, creatinine and bilirubin levels. arterial blood gas (abg) analyses were performed to determine ph, partial pressure of oxygen, bicarbonate value, partial pressure of carbon dioxide and base excess for the given fraction of inspired oxygen. all clinical and laboratory measurements were recorded at admission, every six hours thereafter for the first 72 hours and then every 24 hours until discharge. if necessary, certain variables were assessed more frequently, depending on the clinical condition of the patient. all patients received standard supportive treatment, including basic emergency medical care and gastrointestinal decontamination (i.e. gastric lavage). hypoglycaemic patients were treated with rapid intravenous infusions of two units of 100 ml of 25% dextrose solution and then maintained with 5% dextrose or 5% dextrose and normal saline solution, titrated according to electrolyte levels and glycaemic status.17,18 a maximum of two units of 5% dextrose and normal saline solution up to a total of 500 ml daily were administered as a maintenance regimen for euglycaemic patients, titratred according to the patient’s input-output status. hyperglycaemic patients were treated initially according arvind sharma, prasanth balasubramanian, kiran d. gill and ashish bhalla clinical and basic research | e301 to a continuous insulin infusion protocol and, subsequently, via a subcutaneous insulin regimen.19 the statistical analysis was performed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). various clinical and laboratory parameters were compared bet ween survivors and non-survivors, with the primary vari ables of interest being blood glucose level at presentation and the frequency of blood glucose alterations at adm ission or during hospital stay. the normality of quant itative variables was determined using the kolmogorovsmirnov test. for normally distributed data, means and standard deviations were calculated for continuous variables while frequencies, percentages and proportions were calculated for qualitative variables. a t-test was used to compare the mean differences between the study groups and a chi-squared test was used to compare proportions. univariate and multivariate logistic regression analyses were conducted with mortality as the dependent variable. independent variables found to be significant on the univariate analysis were included in the logistic regression model and analysed using the enter method. random blood glucose levels were considered to be a continuous variable in the univariate and multivariate regression analyses, whereas alterations in blood glucose levels were considered categorical (i.e. nominal) variables. a p value of <0.050 was considered statistically significant. this study was conducted with prior approval from the institutional ethics committee. written informed consent was obtained from all patients or their relatives prior to participation in the study. results a total of 116 cases of alp poisoning were identified. of these, 59 patients (51%) were 15–25 years old, 32 (28%) were 26–35 years old, 14 (12%) were 36–45 years old, nine (8%) were 46–55 years old and two (2%) were over 55 years old. the most frequent symptoms were vomiting (99%) and epigastric pain (61%), followed by dyspnoea (41%) and altered sensorium (28%). the median length of hospital stay was 18 hours (range: 5–42 hours). at presentation, 12 (10%) patients had hypoglycaemia, 16 (14%) had hyperglycaemia and 88 (76%) had normal blood glucose levels. in total, 57 patients (49%) survived and 59 patients (51%) died. the cause of death was refractory cardiogenic shock in 20 patients (34%), multiorgan dysfunction syndr ome in six patients (10%), cardiac arrhythmias in five patients (8%) and respiratory failure in four patients (7%). the cause of death in the remaining 24 cases (41%) could not be determined. in terms of blood glucose alterations, all of the patients with hyperglycaemia, nine patients (75%) table 1: characteristics of patients with aluminium phosphide poisoning (n = 116) variable mean ± sd p value survivors (n = 57) nonsurvivors (n = 59) sociodemographic characteristic age in years 28 ± 9 30 ± 11 0.399 male gender, n (%) 38 (67) 33 (56) 0.235 form of alp ingested, n (%) powder 40 (70) 51 (86) 0.051tablet 11 (19) 3 (5) unknown 6 (11) 5 (9) vital signs at admission heart rate in bpm 101 ± 14 109 ± 11 0.001 sbp in mmhg 106 ± 29 77 ± 20 <0.001 glasgow coma score 12.9 ± 0.1 2.3 ± 0.8 <0.001 blood glucose measurements blood glucose level* in mg/dl 119.9 ± 35.7 159.7 ± 92.5 <0.001 frequency of blood glucose alterations,† n (%) 3 (5) 25 (42) <0.001‡ biochemistry results serum sodium in mmol/l 142.5 ± 7.0 144.6 ± 7.4 0.058 serum potassium in mmol/l 4.0 ± 0.7 4.1 ± 1.1 0.216 serum creatinine in mg/dl 0.8 ± 1.0 1.4 ± 1.2 0.003 serum bilirubin in mg/dl 0.9 ± 0.6 0.8 ± 0.5 0.116 tlc × 103 per mm3 8.6 ± 3.4 12.2 ± 5.1 0.005 abg measurements ph 7.3 ± 0.7 7.1 ± 1.3 <0.001 hco3 16.3 ± 4.8 11.3 ± 5.6 <0.001 presentation/hospital stay characteristics median interval between ingestion and presentation in hours (iqr) 4 (3–6) 4 (2–7) 0.816§ median dextrose administered in g (iqr) 62 (25–125) 75 (43–106) 0.856§ median los in hours (iqr) 36 (24–66) 5 (2–12) <0.001§ sd = standard deviation; alp = aluminium phosphide; bpm = beats per minute; sbp = systolic blood pressure; tlc = total leukocyte count; abg = arterial blood gas; hco 3 = bicarbonate; iqr = interquartile range; los = length of stay. *assessed via random blood glucose tests. †defined as either hyper glycaemia (random blood glucose levels of >200 mg/dl) or hypoglycaemia (random blood glucose levels of <55 mg/dl). ‡using a mann-whitney u test. §using a chi-squared test. prognostic significance of blood glucose levels and alterations among patients with aluminium phosphide poisoning e302 | squ medical journal, august 2018, volume 18, issue 3 with hypoglycaemia and 34 patients (39%) with normal blood glucose levels died. both mean blood glucose levels (159.7 ± 92.5 mg/dl versus 119.9 ± 35.7 mg/dl; p <0.001) and the frequency of blood glucose alterations (5% versus 42%; p <0.001) were significantly higher among non-survivors compared to survivors. this was also the case for heart rate (109 ± 11 beats per minute [bpm] versus 101 ± 14 bpm; p = 0.001), total leucocyte count (12.2 ± 5.1 × 103 per mm3 versus 8.6 ± 3.4 × 103 per mm3; p = 0.005) and serum creatinine levels (1.4 ± 1.2 mg/dl versus 0.8 ± 1.0 mg/dl; p = 0.003). in addition, non-survivors had significantly lower systolic bp at admission (77 ± 20 mmhg versus 106 ± 29 mmhg), glasgow coma scale scores (2.3 ± 0.8 versus 12.9 ± 0.1), arterial blood gas ph (7.1 ± 1.3 versus 7.3 ± 0.7) and bicarbonate values (11.3 ± 5.6 versus 16.3 ± 4.8) and median duration of hospital stay (5 versus 36 hours) compared to survivors (p <0.001 each) [table 1]. statistically significant variables from the univariate analysis were subsequently included in a logistic regression model to predict mortality at a 95% confidence interval. although systolic bp at admission (p = 0.029) and duration of hospital stay (p = 0.008) remained significant, neither blood glucose levels nor blood glucose alterations were found to be independent predictors of mortality (p >0.050 each) [table 2]. discussion according to international recommendations, blood glucose levels should be maintained at 140–180 mg/dl for normoglycaemic patients and 180–200 mg/dl for previously diabetic individuals.20 both the hypo and hyperglycaemic effects of alp are attributable to the wide variety of changes in magnesium, calcium, phosphate, citrate and cortisol levels that result from alp poisoning.11,21 these biochemical changes can act as either stimulatory or inhibitory modulators of the enzymes and hormones that catalyse and regulate the metabolism of glucose. therefore, depending on the type of biochemical change, alp poisoning can result in the elevation or decrease of blood glucose levels or neither.11,21 nevertheless, the specific mechanism by which alp poisoning causes hypoglycaemia is poorly understood. possible explanations include as a result of liver damage due to the release of ph3 gas and the toxic effects of ph3 on the adrenal cortex, leading to decreased cor tisol levels.22 in addition, certain symptoms of alp pois oning such as recurrent vomiting and lack of appetite may also play a role in the development of hypoglycaemia. in contrast, hyperglycaemia occurs due to either the stimulation of cortisol, glucagon and adrenaline secr etion or the inhibition of insulin synthesis.11,21 a glucose insulin-potassium infusion has been suggested as a pot ential therapeutic modality in the treatment of hyperglycaemia in alp poisoning.23 among critically-ill patients, blood glucose alterations have been associated with prolonged hospital stays as well as increased mortality.20,24 however, to the best of the authors’ knowledge, only one previous study has examined the relationship between hyperglycaemia and alp poisoning outcomes. mehrpour et al. published a prospective study of 45 patients with acute alp pois oning, of which 32 patients (71%) died.11 non-survivors had significantly higher mean blood glucose levels than survivors (222.6 ± 20 mg/dl versus 143.4 ± 13.7 mg/dl; p = 0.021). furthermore, blood glucose levels were an independent predictor of mortality in a multivariate analysis.11 this contradicts the findings of the current study in which alterations in blood glucose levels (i.e. either hyperglycaemia or hypoglycaemia) were not independent predictors of mortality. this may be because mehrpour et al. utilised a different cutoff value to indicate hyperglycaemia than that of the present study (>140 mg/dl versus >200 mg/dl).11 table 2: logistic regression model to predict mortality among patients with aluminium phosphide poisoning (n = 116) predictor regression coefficient se or (95% ci) p value heart rate −0.009 0.050 0.991 (0.899–1.093) 0.860 sbp −0.080 0.037 0.923 (0.859–0.992) 0.029 glasgow coma score −0.586 0.454 0.557 (0.229–1.355) 0.197 blood glucose level* 0.012 0.009 1.012 (0.994–1.031) 0.187 blood glucose alterations† 2.036 1.544 7.662 (0.372–157.919) 0.187 serum creatinine level 0.293 0.594 1.340 (0.418–4.294) 0.623 tlc 0.000 0.000 1.000 (1.000–1.000) 0.913 abg ph −1.760 3.620 0.172 (0.000–207.369) 0.627 abg hco3 −0.045 0.135 0.956 (0.734–1.246) 0.741 duration of los −0.094 0.035 0.910 (0.850–0.976) 0.008 se = standard error; or = odds ratio; ci = confidence interval; sbp = systolic blood pressure; tlc = total leukocyte count; abg = arterial blood gas; hco 3 = bicarbonate; los = length of stay. *assessed via random blood glucose tests. †defined as either hyperglycaemia (random blood glucose levels of >200 mg/dl) or hypoglycaemia (random blood glucose levels of <55 mg/dl). arvind sharma, prasanth balasubramanian, kiran d. gill and ashish bhalla clinical and basic research | e303 strengths of the current study include its sample size and the evaluation of both hyperand hypoglycaemia as predictors of mortality. however, the results are limited by the absence of any long-term follow-up of the survivors and the lack of analysis of other factors which may play a role in glucose homeostasis, such as serum calcium, magnesium, phosphate, insulin and cor tisol levels. conclusion as a result of several complex mechanisms, alp poisoning can cause both hyperand hypoglycaemia. however, the role of blood glucose levels and blood glucose alter ations in predicting patient outcomes in alp poisoning cases remains inconclusive. the authors recommend that further studies with larger sample sizes be conducted to evaluate other factors involved in glucose homeostasis. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. murali r, bhalla a, singh d, singh s. acute pesticide poisoning: 15 years experience of a large north-west indian hospital. clin toxicol (phila) 2009; 47:35–8. doi: 10.1080/15563650701885807. 2. banjaj r, wasir hs. epidemic aluminium phosphide poisoning in northern india. lancet 1988; 1:820–1. doi: 10.1016/s0140-6736 (88)91676-5. 3. price nr, mills ka, humphries la. phosphine toxicity and catalase activity in susceptible and resistant strains of lesser grain borer (rhyzopertha dominica). comp biochem physiol c pharmacol toxicol endocrinol 1982; 73:411–13. doi: 10.1016/03064492(82)90144-7. 4. bolter cj, chefurka w. extramitochondrial release of hydrogen peroxide from insect and mouse liver mitochondria using the respiratory inhibitors phosphine, myxothiazol, and antimycin and spectral analysis of inhibited cytochromes. arch biochem biophys 1990; 278:65–72. doi: 10.1016/0003-9861(90)90232-n. 5. burgess jl, morrissey b, keifer mc, robertson wo. fumigantrelated illnesses: washington state’s five-year experience. j toxi col clin toxicol 2000; 38:7–14. doi: 10.1081/clt-100100909. 6. curry as, price de, tryhorn fg. absorption of zinc phosphide particles. nature 1960; 184:642–3. doi: 10.1038/184642a0. 7. mehrpour o, jafarzadeh m, abdollahi m. a systematic review of aluminium phosphide poisoning. arh hig rada toksikol 2012; 63:61–73. doi: 10.2478/10004-1254-63-2012-2182. 8. chugh sn, ram s, chugh k, malhotra kc. spot diagnosis of aluminium phosphide ingestion: an application of a simple test. j assoc physicians india 1989; 37:219–20. 9. european food safety authority. conclusion on the peer review of the pesticide risk assessment of the active substance calcium carbide. eur food saf author j 2011; 9:2419. doi: 10.2903/j. efsa.2011.2419. 10. bogle rg, theron p, brooks p, dargan pi, redhead j. aluminium phosphide poisoning. emerg med j 2006; 23:e3. doi: 10.1136/ emj.2004.015941. 11. mehrpour o, alfred s, shadnia s, keyler de, soltaninejad k, chalaki n, et al. hyperglycemia in acute aluminum phosphide poisoning as a potential prognostic factor. hum exp toxicol 2008; 27:591–5. doi: 10.1177/0960327108096382. 12. mostafazadeh b, pajoumand a, farzaneh e, aghabiklooei a, rasouli mr. blood levels of methemoglobin in patients with aluminum phosphide poisoning and its correlation with patient’s outcome. j med toxicol 2011; 7:40–3. doi: 10.1007/s13181-0100121-7. 13. shadnia s, mehrpour o, soltaninejad k. a simplified acute phys iology score in the prediction of acute aluminum phosphide poisoning outcome. indian j med sci 2010; 64:532–9. 14. louriz m, dendane t, abidi k, madani n, abouqal r, zeggwagh aa. prognostic factors of acute aluminum phosphide poisoning. indian j med sci 2009; 63:227–34. doi: 10.4103/0019-5359.53386. 15. qaseem a, humphrey ll, chou r, snow v, shekelle p. use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the american college of physicians. ann intern med 2011; 154:260–7. doi: 10.7326/0003-4819-154-4-201102150-00007. 16. klonoff dc, alexander fleming g, muchmore db, frier bm. hypoglycemia evaluation and reporting in diabetes: importance for the development of new therapies. diabetes metab res rev 2017; 33:e2883. doi: 10.1002/dmrr.2883. 17. alsahli m, gerich je. hypoglycemia. endocrinol metab clin north am 2013; 42:657–76. doi: 10.1016/j.ecl.2013.07.002. 18. cryer pe, axelrod l, grossman ab, heller sr, montori vm, seaquist er, et al. evaluation and management of adult hypo glycemic disorders: an endocrine society clinical practice guide line. j clin endocrinol metab 2009; 94:709–28. doi: 10.1210/jc. 2008-1410. 19. mcdonnell me, umpierrez ge. insulin therapy for the management of hyperglycemia in hospitalized patients. endocrinol metab clin north am 2012; 41:175–201. doi: 10.1016/j.ecl. 2012.01.001. 20. aramendi i, burghi g, manzanares w. dysglycemia in the critically ill patient: current evidence and future perspectives. rev bras ter intensiva 2017; 29:364–72. doi: 10.5935/0103507x.20170054. 21. abder-rahman h. effect of aluminum phosphide on blood glucose level. vet hum toxicol 1999; 41:31–2. 22. chugh sn, ram s, sharma a, arora bb, saini as, malhotra kc. adrenocortical involvement in aluminium phosphide poisoning. indian j med res 1989; 90:289–94. 23. hassanian-moghaddam h, zamani n. therapeutic role of hyper insulinemia/euglycemia in aluminum phosphide poisoning. medicine (baltimore) 2016; 95:e4349. doi: 10.1097/md.000000 0000004349. 24. fahy bg, sheehy am, coursin db. glucose control in the intensive care unit. crit care med 2009; 37:1769–76. doi: 10.10 97/ccm.0b013e3181a19ceb. https://doi.org/10.1080/15563650701885807 https://doi.org/10.1016/s0140-6736%2888%2991676-5 https://doi.org/10.1016/s0140-6736%2888%2991676-5 https://doi.org/10.1016/0306-4492%2882%2990144-7 https://doi.org/10.1016/0306-4492%2882%2990144-7 https://doi.org/10.1016/0003-9861%2890%2990232-n https://doi.org/10.1081/clt-100100909 https://doi.org/10.1038/184642a0 https://doi.org/10.2478/10004-1254-63-2012-2182 https://doi.org/10.2903/j.efsa.2011.2419 https://doi.org/10.2903/j.efsa.2011.2419 https://doi.org/10.1136/emj.2004.015941 https://doi.org/10.1136/emj.2004.015941 https://doi.org/10.1177/0960327108096382 https://doi.org/10.1007/s13181-010-0121-7 https://doi.org/10.1007/s13181-010-0121-7 https://doi.org/10.4103/0019-5359.53386 https://doi.org/10.7326/0003-4819-154-4-201102150-00007 https://doi.org/10.1002/dmrr.2883 https://doi.org/10.1016/j.ecl.2013.07.002 https://doi.org/10.1210/jc.2008-1410 https://doi.org/10.1210/jc.2008-1410 https://doi.org/10.1016/j.ecl.2012.01.001 https://doi.org/10.1016/j.ecl.2012.01.001 https://doi.org/10.5935/0103-507x.20170054 https://doi.org/10.5935/0103-507x.20170054 https://doi.org/10.1097/md.0000000000004349 https://doi.org/10.1097/md.0000000000004349 https://doi.org/10.1097/ccm.0b013e3181a19ceb https://doi.org/10.1097/ccm.0b013e3181a19ceb squ med j, august 2010, vol. 10, iss. 2, pp. 231-240, epub. 19th jun 10 submitted: 24th oct 09 revision req. 18th jan 10, revision recd. 10th mar & 18th apr 10 accepted: 8th may 10 department of family & community medicine, college of medicine, dammam university, dammam, saudi arabia *corresponding author email: badria-al.dabal@hotmail.com دراسة للمقارنة بني الضغوط النفسية اليت تواجهها طالبات كلية الطب وطالبات كلية غري طبية بالدمام يف اململكة العربية السعودية بدرية خالد الدبل، منال قورة، بارفني ر�شيد، لطيفة �شعد ال�شويلم، �شهري حممد مّكي اخلال�صة: الهدف: تهدف هذه الدرا�شة اإىل مقارنة طالبات يف كلية الطب مع طالبات من كلية اأخرى غري طبية يف اجلوانب الآتية: 1.مدى انت�شار وم�شببات ال�شغوط اجلامعية . 2. التغريات اجل�شمية والذهنية والنف�شية والنفعالية وكذلك منط احلياة لدى الطالبات اجلامعيات منذ التحاقهن �شملت .2008 يناير �شهر يف ال�شعودية( العربية )اململكة بالدمام في�شل امللك جامعة يف اأجريت مقطعية درا�شة هذه الطريقة: باجلامعة. وخدمة التطبيقية الدرا�شات كلية من طالبة( 297( اختيار ومت طالبة( 319( ال�رشيرية قبل ما املرحلة يف الطب طالبات جميع الدرا�شة �شحة على الدرا�شة " تاأثري ا�شتبيان البحث يف ا�شتخدم الطبقي. الع�شوائي الختيار طريق عن وامل�شتويات التخ�ش�شات جميع من املجتمع الطالب" . النتائج: بينت الدرا�شة باأن طالبات كلية الطب يتعر�شن ل�شغوط نف�شية اأكرث )48.6%( من طالبات كلية الدرا�شات التطبيقية وخدمة املجتمع )38.7 %( والنتيجة معتدة اإح�شائيا )p>0.01(. طرق التدري�س غري املنا�شبة وعدم مالءمة البيئة الدرا�شية واخلوف من الف�شل يف المتحانات كانت اأهم اأ�شباب ال�شغوط التي تواجه طالبات كلية الطب اأكرث من الطالبات الأخريات، وكانت تلك العالقة ذات دللة اإح�شائية معتدة اأي�شا )p>0.05 ( .كانت امل�شاكل الجتماعية اكرث لدى طالبات كلية الطب، غري اأن امل�شاكل املالية كانت اأكرث لدى طالبات الدرا�شات التطبيقية وخدمة املجتمع )p>0.05(. كما اأن التغريات اجل�شمية والذهنية والنف�شية وال�شعور بالقلق والكتئاب والتغريات ال�شلبية لنمط احلياة كانت اأكرث لدى طالبات الطب منذ التحاقهن بالكلية. اخلال�صة: ن�شتنتج من هذه الدرا�شة باأن طالبات كلية الطب معر�شني لالإ�شابة مب�شاكل �شحية ج�شمية وذهنية نظراً لل�شغوط الأكادميية التي يتعر�شن لها. كذلك هناك ن�شبة من طالبات كلية الدرا�شات التطبيقية وخدمة املجتمع يتعر�شن لنف�س ال�شغوط، لذا نقرتح اإن�شاء جلنة لدعم الطالبات يف الكليتني لتقدمي الن�شح والإر�شاد لهن يف كيفية معاجلة ال�شغوط بالطرق ال�شحيحة والتاأقلم مع ال�شغوط. مفتاح الكلمات: ال�شغوط النف�شية، علم النف�س، التعليم، علم الوبائيات abstract: objectives: the objective of this study was to investigate any differences between female undergraduate medical and non-medical students for: 1) prevalence and causes of perceived academic stress, and 2) changes in physical, mental, psychological and emotional health as well as life-style since starting college studies. methods: a cross-sectional study was conducted at dammam university, dammam, saudi arabia, in january 2008. all 319 pre-clinical female medical students were included in the study and 297 non-medical students from the college of applied studies and community services (cascs) were selected by stratified random sampling. the study instrument was a questionnaire on the “influence of studying on students’ health”. results: more medical students (48.6%) reported being frequently stressed due to studies than cascs students (38.7%, p <0.01). unsuitable teaching methods, an unsatisfactory study environment, and fear of failure in examinations were more frequently mentioned by medical than non-medical students (p <0.05). while underlying social problems were significantly more common in medical students, economic problems were more prevalent among cascs students (p <0.05, p <0.05). more medical than non-medical students reported a worse status of physical and mental health, anxiety and depression and negative life-style changes since initiation of the college programme. conclusion: medical students were at higher risk of physical and mental health problems than non-medical students due to academic stress. since a substantial proportion of cascs students also experienced academic stress, we recommend that a student support committee be established for both colleges to provide counselling and guidance in healthy ways to cope with stress. keywords: stress; psychology; education; epidemiology a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia *badria k al-dabal, manal r koura, parveen rasheed, latifa al-sowielem, suhair m makki clinical & basic research advances in knowledge 1. this is the first study in saudi arabia to compare the differences in study-related stress between medical and non-medical university students. a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia 232 | squ medical journal, august 2010, volume 10, issue 2 it is generally believed that the health of students is affected by the stresses of academic life. these stressors may affect their learning ability, academic performance and health. several international studies have revealed high rates of health problems in undergraduate medical and non-medical students as a result of their studies.1-7 research projects conducted in the usa have reported a nationwide increase in stress among undergraduate college students in various fields of study.4,5 medical students in particular, and from different countries, have been found at risk of psychological stress, mental disorders and decreased life satisfaction.6-9 a majority of medical students from universities in mumbai (india)1 and karachi (pakistan)2 perceived stress at one time or another during their study period. a high prevalence of emotional disorders among medical students was reported at a malaysian private medical school,3 while el-gilany et al. found an overall stress rate of 30.9% and 28.9% among egyptian and saudi medical students respectively.10 abdulghani reported a higher prevalence of stress (57%) in medical students from king saud university, riyadh, (saudi arabia).11 studies in the literature have reported that some of the challenges faced by students include managing the psychosocial environment and financial problems, accompanied by academic pressures.12,13 academic demands and the quality of the study environment may vary in different fields of education and different colleges and consequently result in different student life-styles and health effects. there is a lack of data on the comparison of perceived stress and its health consequences among medical and non-medical students. at dammam university, dammam, saudi arabia, medical students from the college of medicine and non-medical students from the college of applied studies & community service (cascs), largely share a common life-profile, language, religion and culture, but perhaps differ with regard to their levels of academic pressure. there is reason to hypothesise that there would be a variation in their stress level and consequent health effects, with medical students at a higher risk of perceived stress than their non-medical counterparts. the current study was conducted to compare differences between female undergraduate preclinical students and non-medical (cascs) students of dammam university, dammam for: 1) prevalence and causes of perceived academic stress, and 2) changes in physical, mental, psychological and emotional health as well as life-style since initiation of the college programme. methodology this research was a cross-sectional, comparative study of female medical and non-medical students conducted simultaneously for both groups at dammam university, dammam, in january 2008. approval for the study was obtained from the higher academic and administrative authorities of the university. all undergraduate pre-clinical medical students (up to 4th level) were recruited for the study. an almost similar number of undergraduate non-medical students from cascs, undergoing courses in accounting, marketing and secretarial training, were selected by stratified random sampling with proportional allocation for different specialties and academic levels. the response rate for the study was 93.3 %. the study instrument was the latest version of the questionnaire (2007) on the “influence of studying on students’ health” (issh) developed 2. the parameters of stress and their effect on physical and mental health have been identified in both groups with medical students as victims of greater stress. 3. these findings will be used to change educational methods and initiate stress management programmes to improve students’ health and quality of life. application to patient care 1. the physical and mental health of medical students has a potential to affect the quality of patient care when they become physicians. 2. the stress of student days may continue during internship, the postgraduate study-period and later in a physician’s practical life. 3. stressed and anxious doctors are unlikely to provide optimal patient care. 4. timely intervention to control stress in medical students is likely to lead to a better learning situation and subsequently better patient care. badria k. al-dabal, manal r. koura, parveen rasheed, latifa al-sowielem, suhair m. makki clinical and basic research | 233 by the international federation of medical students’ association (ifmsa)14 for transnational projects. the validity and arabic translation of the questionnaire were reviewed by an expert committee of ifmsa. the following information was obtained: socio-demographic data (age in completed years, faculty of study, native city, place of residence, whether living with parents and having a separate room for study); family, socio-economic and emotional problems encountered; perceived academic stress and its causes; changes in physical, mental, psychological and emotional health as well as life-style changes since the start of college studies; changes in tea/coffee drinking habits, smoking and intake of antidepressants/sedatives during the examination period [annex 1]. for cultural reasons, information on intake of alcohol and narcotic drugs was not obtained. students were gathered in their respective classrooms and informed consent for the research study was obtained. the questionnaire was self-administered. all information was selfreported and no psychometric instruments were used to verify mental and psychological health. reassurance was given on the confidentiality of the information gathered. the data were analysed using the statistical package for social sciences (spss), version 16. results were presented in frequency tables and bar charts. the chi-squared test was used for bivariate analysis of qualitative variables and fisher’s exact test if expected frequency was less than 5 in more than 20% of the cells. a p value of <0.05 was considered significant. results a total of 616 students participated in the study, of which 319 (51.8%) were medical students and 297 (48.2%) non-medical students studying at the cascs. the mean age of the medical students was 19.7 (sd ±1.3) years and that of non-medical students was 20.4 (sd ±1.7) years (p <0.01). while 29.2% of medical students were natives of other cities, only 7.1% of cascs students did not belong to the local area (p <0.001). a majority of the students (87.2%) from both colleges were living with their parents. among the few who resided in the student hostel, most were medical students (95.6%, p <0.01). there was no statistically significant difference in the proportion of medical (78.4%) and cascs (81.1%) students reporting a separate study-room at their place of residence (p >0.05). of the 616 university students, 96.3% had experienced stress at one time or another due to studies with 8.0%, 44.5% and 43.8% students respectively, reporting stress to occur “seldom,” “sometimes” or “frequently”. more medical students (48.6%) experienced frequent academic stress than non-medical students (38.7%, p <0.01). reported causes of study-related stress included an overloaded curriculum (84.2%); unsuitable teaching methods (77.2%); fear of failure (70.7%); an unsatisfactory study environment at the faculty (40.5%); nonsupportive relationships with other students (18.8%), and an unsuitable study environment at their place of residence (17.5%). figure 1 shows that some of these causes were significantly more frequent among medical than cascs students. overall, a majority of the students (92.5%) did not report economic problems. among the few who did, significantly more cascs students reported economic problems than medical students (p <0.01) [table 1]. on the other hand, medical students reported a higher prevalence of social problems compared to their non-medical counterparts (p <0.05). there were no significant differences between the two groups of students with respect to family and emotional problems (p >0.05 and p >0.05). table 2 shows that nearly 240 (40%) out of 616 students felt that their physical health had been adversely affected since the start of their university studies. significantly more medical students reported a worsening of their physical status compared to cascs students (p <0.001). deterioration of mental health in terms of concentration, memory and judgment was also reported to be significantly more frequent among medical than non-medical students (p <0.001; p table 1: psychosocial and family problems experienced by medical and cascs students problems college medical (n = 319) (cascs) (n = 297) p value economic social family emotional 14 (4.4%) 93 (29.2%) 72 (22.6%) 73 (22.9%) 32 (10.8%) 68 (22.9%) 70 (23.6%) 85 (28.6%) < 0.01* 0.05* 0.7 0.1 *statistically significant a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia 234 | squ medical journal, august 2010, volume 10, issue 2 <0.01; p <0.05) [table 2]. overall, psychological and emotional health problems such as mood disturbance (69.6%), anxiety (52.1%), frustration (49.2%) and depression (37.0%) were reported to have occurred in a large proportion of the student population after the start of their college studies. figure 2 shows that medical students suffered significantly more frequently from psychological/ emotional problems than cascs students. overall, the most common negative change in life-style was inadequate social interaction with family and friends (73.2%) followed by lack of sleep (69.7%), lack of self-health care (62.2%), inadequate time for hobbies and recreational activities (61.6%), and also lack of physical exercise (41.2%). figure 3 show that significantly more medical students reported these changes in their life-style than nonmedical students. medical and cascs students, respectively, also reported changes in certain habits during the examination period such as increased intake of tea and coffee (59.6% versus 48.55%, p <0.01), smoking (0.6% versus 2.7%, p <0.05) and intake of sedatives and anti-depressant drugs (1.9% versus 5.4%, p <0.05). a vast majority of medical and cascs students (93.4% and 90.9% respectively) reported that they had not received any education about stress management at their faculty. the need for such courses in future was suggested by more than half of the medical and non-medical students (60.5% and 51.1%). discussion the finding that medical students were more frequent victims of academic stress than nonmedical students was expected considering the more intensive study demands of a medical programme compared to courses for diploma/ bachelors in accounting, marketing and secretarial skills. students in pursuit of higher professional education in a highly competitive environment such as that found in medical academia are more vulnerable to stress than those with lesser challenges. although an overloaded curriculum as a cause of stress was almost equally reported by both groups with no statistical difference, there was variation in the responses on the quality of teaching methods and study environment at the two colleges. in the medical school, the teaching methods are largely traditional, that is, one-way didactic sessions in large classrooms with a teacher-student ratio of one to eighty or more. this situation provides little opportunity for teacher-student interaction during table 2: self-reported changes in physical and mental health during college study-period among medical and cascs students health college total p value medical (n = 319) (cascs) (n = 297) physcial worse similar better 148 (46.4%) 151 (47.3%) 20 (6.3%) 98 (33.0%) 138 (46.5%) 61 (20.5%) 246 (39.9%) 289 (46.9%) 81 (13.1%) 0.001* mental concentration worse similar better 162 (51.1%) 96 (30.3%) 59 (18.6%) 85 (28.6%) 117 (39.4%) 95 (32.0%) 247 (40.2%) 213 (34.7%) 154 (25.1%) 0.001* memory worse similar better 142 (44.8%) 129 (40.7%) 46 (14.5%) 98 (33.0%) 129 (43.4%) 70 (23.6%) 240 (39.1%) 258 (42.0%) 116 (18.9%) 0.002* judgement worse similar better 39 (12.3%) 111 (35.0%) 167 (52.7%) 28 (9.4%) 80 (26.9%) 189 (63.6%) 67 (10.9%) 191 (31.1%) 356 (58.0%) 0.02* *statistically significant badria k. al-dabal, manal r. koura, parveen rasheed, latifa al-sowielem, suhair m. makki clinical and basic research | 235 classes. on the other hand, the cascs students have smaller classes with a teacher-student ratio of one to thirty/forty or less and more opportunities for interactive learning. moreover, there have been frequent anecdotal reports from medical students that use of a foreign language (english) as a medium of instruction enhances their academic stress. on the contrary, cascs students are taught mainly in their native arabic language. it is well known that comprehension and learning of a subject is best and most satisfying when conveyed through the native language. fear of failure in examinations, was also a more common concern in medical than non-medical students. our findings are similar to those of several studies reporting examinations to be the most prevalent source of academic stress for medical students.1,2,15 abdulghani found that the main source of stress in saudi medical students was their studies,11 whereas gilani et al. found that the top four stressors for egyptian medical students were congested classrooms, troubles with the instructors, fear of future and limited time for recreational activities.10 academic stress is usually enhanced if it is compounded by other background problems. significantly more medical than non-medical students in this study were residents of other cities, lived in hostels, (hence lacked close parental support on a day-to day basis) and reported more social problems, all factors that may have contributed to their more frequent stress. on the other hand, a sub-group of cascs students reported more economic problems than medical students. though our study did not investigate the economic status of the students, perhaps differences in the financial implications of the medical and non-medical academic programs may have contributed to this 0 20 30 40 50 70 90 10 60 80 curriculum *teaching methods *fear of failure *college environment home environment relationship with colleagues legend: *p > 0.01 figure 1: changes in life-style due to studying among female medical (n = 319) and cascs (n = 297) students 0 10 20 30 40 50 60 70 80 mood disturbance *anxiety *frustration *depression medicine community legend: *p > 0.01 figure 2: prevalence of self-reported psychological problems among female medical (n = 319) and cascs (n = 297) students a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia 236 | squ medical journal, august 2010, volume 10, issue 2 finding. whereas medical students study free of charge and are supported by a small monthly stipend by the government, cascs students pay substantial fees for their courses. while there could be multiple causes leading to deterioration of physical health, frequent stress in medical students could be one of them. moreover, unhealthy life-styles such as lack of exercise, insufficient sleep and poor self-health care, which were more common features among medical than cascs students, could well have contributed to their worse physical status. often the high pressure of studies and limited time to acquire vast knowledge prevent medical students from adopting a healthy life-style. abdulghani also reported an association between level of stress and the increase of physical problems in saudi medical students.11 a greater likelihood of deterioration of mental health in terms of concentration, memory and judgment among medical compared to cascs students can again be explained by the difference in the academic demands. in general, medical students have more credit hours per year, more teaching sessions per week and more frequent examinations, consequently leading to more hours of study, lack of rest and stress, factors which can adversely affect mental health. others too have reported a worsening of mental health after students are admitted to a medical college and this condition remains poor throughout their training.6 whether psychological and emotional ill health in a large proportion of students was a cause or outcome of stress is difficult to conclude from this cross-sectional study. other studies have reported a positive correlation of perceived stress with anxiety and depression,4,16,17and that most cases of anxiety in college students were found to be reactions to either maturational or environmental stresses rather than endogenous factors.4 with more frequent academic stress among medical students and less hours of recreational and social activities to balance out the stress, it is expected that psychological and emotional distress would be more common in them than in the cascs group. several studies have reported that psychological problems were common among medical students3,7,9,18 and that lack of time for recreational activities was one of the important stressors.10,18 lima et al. found that 44.7% of brazilian medical students suffered from mental disorders9 and el-gilany et al. reported that 24.7% of egyptian medical students were victims of anxiety and depression.10 stress management courses are sadly lacking on both the medical and cascs campuses of the university, but it was encouraging to note that a large proportion of students of both colleges expressed the need for such training. a limitation of this study is that it reflects the findings of only one university campus of saudi arabia; hence, the results may not be generalized to other institutions in the country. perceived stress and its causes were self-reported by students and that may have resulted in some reporting bias. to keep the student data-collection time within reasonable limits, information on psychological health was also self-reported and no special psychometric instruments were used to measure it. validation of the questionnaire was not done in the 0 10 20 30 40 50 60 70 80 *socialization *hour of sleep *recreation *caring for health exercising medicine cascs legend: *p > 0.01 figure 3: changes in life-style due to studying among female medical (n = 319) and cascs (n = 297) students badria k. al-dabal, manal r. koura, parveen rasheed, latifa al-sowielem, suhair m. makki clinical and basic research | 237 local population. hence there may have been some misreporting on the magnitude of the problem. future research is warranted on estimating the level of stress by psychometric instruments and the relationship between stress and academic achievement. conclusion in conclusion, medical students were more frequent victims of academic stress than cascs students and this was possibly due to their higher academic demands and perception of time constraints to fulfill them. important causes of stress among medical students included unsuitable teaching methods; an unsatisfactory college study environment; fear of failure in examinations, and social problems all of which resulted in perceived anxiety and depression, negative life-style practices and a worse status of physical and mental health changes since the start of their college studies. we recommend that attention is given to improve the methods of teaching and quality of study environment on the medical college campus. since a substantial proportion of medical and cascs students reported experiencing academic stress, we recommend that a student support committee be established at both colleges that should provide female students with knowledge about the unhealthy consequences of stress, and self-awareness and counselling on positive methods to cope with stress. we agree with others that stress management programmes should focus on encouraging students to construct an effective time management plan for studies and leisure activities4 during their academic years. moreover, adoption of a healthy life-style and explicit promotion of work-life balance will go a long way to enhance the physical and psychological well-being of college students. acknowledgements the authors would like to thank the medical and cascs students of dammam university, dammam, for their participation in the study. special thanks are also due to the fourth year medical students of 2008 for their valuable help in collection of the data as part of field course training in family and community medicine. references 1. supe an. a study of stress in medical students at seth g.s. medical college. j postgrad med 1998; 44:1–6. 2. shaikh bt, kahloon a, kazmi m, khalid h, nawaz k, khan n, et al. students, stress and coping strategies: a case of pakistani medical school. educ health (abingdon) 2004; 17:346–53. 3. zaid za, chan sc, ho jj. emotional disorders among medical students in a malaysian private medical school. singapore med j 2007; 48:895–9. 4. misra r, mckean m. college students’ academic stress and its relation to their anxiety, time management and leisure satisfaction. am j health studies 2000; 16:41– 51. 5. sax lj. health trends among college freshmen. j am coll health 1997; 45:252–62. 6. guthrie e, black d, bagalkote h, shaw c, campbell m, creed f. psychological stress and burnout in medical students: a five-year prospective longitudinal study. jr soc med 1998; 91:237–43. 7. dyrbye ln, thomas mr, eacker a, harper w, massie fs jr, power dv, et al. race, ethnicity, and medical student well-being in the united states. arch intern med 2007; 167:2103–9. 8. kjeldstadli k, tyssen r, finset a, hem e, gude t, gronvold nt, et al. life satisfaction and resilience in medical school a six-year longitudinal, nationwide and comparative study. bmc med educ 2006; 6:48– 64. 9. lima mc, domingues mde s, cerqueira at. prevalence and risk factors of common mental disorders among medical students. rev saude publica 2006; 40:1035–41. 10. el-gilany a, amr m, hammad s. perceived stress among male medical students in egypt and saudi arabia: effect of socio-demographic factors. ann saudi med 2008; 28:442–8. 11. abdulghani hm. stress and depression among medical students: a cross sectional study at a medical college in saudi arabia. pak j med sci 2008; 24:12–17. 12. chan gct, koh d. understanding the psychosocial and physical work environment in a singapore medical school. singapore med j 2007; 48:166–71. 13. omigbodun oo, odukogbe aa, omigbodun ao, yusuf ob, bella tt, olayemi o. stressors and psychological symptoms in students of medicine and allied health professions in nigeria. soc psychiatry psychiatr epidemiol 2006; 41:415–21. 14. international federation of medical students’ association (ifmsa). the influence of studying on student’s health (issh). questionnaire. from www. issh-ifmsa.org. accessed june 2007. 15. saipanish r. stress among medical students in a thai medical school. med teach 2003; 25:502–6. 16. katz j, monnier j, libet j, shaw d, beach s. individual a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia 238 | squ medical journal, august 2010, volume 10, issue 2 and crossover effect of stress on adjustment in medical student marriages. j marital fam ther 2000; 26:341– 51. 17. mosley th jr, perrin sg, neral sm, dubbert pm, grothues ca, pinto bm. stress, coping and wellbeing among third year medical students. acad med 1994; 69:765–7. 18. sreeramareddy ct, shankar pr, binu vs, mukhopadhyay c, ray b, menezes rg. psychological morbidity, sources of stress and coping strategies among undergraduate medical students of nepal. bmc med educ 2007; 7:26–44. annex 1: questionnaire – english version the influence of studying on students' health (issh) level 1: medical students it is well known that studying can have a profound effect on our lives, in particular our health, albeit our physical, psychological or social health. the issh (influence of studying on students' health) is a project to evaluate the effects of studying on students' health, why some people are affected more than others and to explore the necessary coping strategies that students may find beneficial. please take a few minutes to fill out this questionnaire. the international federation of medical students' associations (ifmsa) welcomes your feedback and your answers will be kept confidential. thank you for your participation. personal data 1. age: ……………. 2. gender: male female 3. academic year: 1 2 3 4 5 6 7 4. faculty/university: …………….. studying 1. are you studying in your native country? a) yes b) no 2. if yes, are you studying in your native city? a) yes b) no 3. where are you living now? a) with parents b) alone in a separated flat or house c) sharing flat or house d) students' accommodation e) others 4. did you fail in any subject during your medical studies a) never b) 1-2 times c) 3-4 times d) 5-6 times e) more than 6 times 5. how would you describe your efforts in studying a) very satisfactory b) satisfactory c) not quite satisfactory d) unsatisfactory 6. with regards to the study environment at your faculty: how would you describe the quality of the educational process? a) very satisfactory b) satisfactory c) not quite satisfactory d) unsatisfactory 7 with regards to your study environment at home : is it suitable for your needs a) yes b) no 8 do you have a separate room for studying a) yes b) no 9. have you had any of the following experiences since you started your medical studies: (circle 1 or more answers) a) family problems (death, parental divorce, …) b) economical problems (job loss, money insufficiency, …) c) social problems (difficult travel to university, accommodation problems,…) d) emotional problems (break down of relationships, love, …) e) problems related to studying f ) other …………………………… g) none 10. with respect to your physical health: your health at present is: a) excellent b) very good c) good d) fair e) poor badria k. al-dabal, manal r. koura, parveen rasheed, latifa al-sowielem, suhair m. makki clinical and basic research | 239 health * with respect to your physical health: 1. your health at present is: a) excellent b) very good c) good d) fair e) poor 2. in comparison to the health of your colleagues, your own is: a) much better b) better c) similar d) worse e) much worse f ) i don't know 3. your health at present compared to the time before you started your medical studies: a) much better b) better c) similar d) worse e) much worse f ) i don't know if there has been deterioration in your health since commencing your studies: 4. which system/organ is the most affected? (choose just 1 answer) a) gastrointestinal system (e.g. gastric ulcer, heartburn, ibs...) b) respiratory system (e.g. bronchitis, asthma, allergies...) c) cardiovascular system (e.g. hypertension...) d) musculoskeletal system (e.g. pain in your back, muscles...) e) immune system (e.g. chronic bacterial and viral infections...) f ) central nervous system (e.g. headache, vision & hearing changes) g) skin (e.g. acne, dermatitis, psoriasis…) h) others ……………… 5. in which year did it start: 1 2 3 4 5 6 7 6. is this problem … : a) acute or b) chronic 7. do you think that the cause is related to studying: a) yes b) no c) i don't know with respect to your mental health over years you have been studying, please tick the appropriate boxes: 8. concentration 9. recognition 10. memory 11. judgement a) much better b) better c) similar d) worse e) much worse f ) i do not know * with respect to your psychological and emotional health: 12. did you suffer from any of the following: (encircle 1 or more answers) a) depression b) anxiety c) phobia d) mood breakdown e) frustration f ) others 13. has studying put you under stress? a) often b) sometimes c) seldom d) never 14. if you feel this stress, what is the reason? (encircle 1 or more answers) a) the content of the curriculum (overloading or of high level) b) the methods of teaching (not interesting, not suitable, exam oriented, ,..) c) the environment at the faculty d) the environment at home e) the relationship with other students f ) fear of failure to achieve your expectations g) others ………… 15. what is the main outcome of this stress )choose just 1 answer( a) physical complaints b) psychological conditions c) changes in your habits and life style d) others ………… a comparative study of perceived stress among female medical and non-medical university students in dammam, saudi arabia 240 | squ medical journal, august 2010, volume 10, issue 2 lifestyle 1. has studying changed your lifestyle? (encircle 1 or more answers) a) recreational activities and hobbies b) exercise c) socialization (social interaction with friends or family) d) enough hours of sleep e) caring for your health status f ) others ………… g) no change 2. has studying influenced your uptake of any of the following habits? please tick the appropriate boxes. 2.1 drinking excess tea, coffee (caffeine) 2.2 smoking 2.3 drinking alcohol 2.4 sedatives, antidepressants, etc. 2.5 addictive drugs yes/no 3. during exam times are any of your habits changed? please tick the appropriate boxes. a) increased b) the same c) decreased management of these problems 1. are you being educated about stress and dealing with stress by your faculty? (i.e. lectures, stress management courses...) a) yes b) no 2. if yes, do you think that it is effective? a) yes b) no c) i don't know 3. if no, do you need stress management courses? a) yes b) no c) i don't know 4. do you have any suggestion to overcome this stress? …………………………………………………………………………………………………………… …………………………………………………………………………………………………………… …………………………………………………………………………………………………………… 1department of dental education, college of dentistry and 3quality measurement and evaluation department, 2deanship of quality & academic accreditation, imam abdulrahman bin faisal university, al-khobar, saudi arabia *corresponding author’s e-mail: qaa@iau.edu.sa العوامل املؤثرة يف رضا األطباء املتدربني عن برانمج التدريب املقدم يف كليات الطب السعودية ارايالو اأحمد الكويتي و اآرون فيجاي �ُسوبَّ abstract: objectives: this study aimed to assess the perceptions of medical interns with regards to the internship training programme offered at saudi medical schools and to explore factors influencing their overall satisfaction with this progamme. methods: this exploratory study was conducted at four medical schools in saudi arabia between july 2017 and june 2018. all medical interns undergoing internship training at the selected medical schools during the 2017–2018 academic year were invited to participate in the survey. a questionnaire covering 10 internship dimensions and including a total of 76 items and one global item was designed to assess the medical interns’ satisfaction with the training programme. results: a total of 295 interns returned completed questionnaires (response rate: 92%). overall, the interns’ satisfaction with all 10 internship dimensions was high (mean score: ≥3.6). a multiple regression analysis indicated that various factors were significant predictors of medical interns’ overall satisfaction with the internship training programme, including orientation, training site services, supervision, relationships with their superiors and hospital activities (p <0.050 each). conclusion: medical interns were highly satisfied with the internship training programme offered at saudi medical schools, with various factors found to significantly influence overall satisfaction. the findings of this study may help policymakers in saudi arabia to improve the internship training programme so as to ensure medical interns’ overall satisfaction and potentially improve their learning outcomes and clinical training. keywords: undergraduate medical education; internship and residency; attitudes; clinical competence; saudi arabia. ال�سعودية الطب كليات يف املقدم التدريب بربنامج يتعلق فيما املتدربني الأطباء اّراء تقييم اإىل الدرا�سة هذه هدفت الهدف: امللخ�ص: وا�ستطالع العوامل التي توؤثر على ر�ساهم العام عن هذا الربنامج. الطريقة: اأجريت هذه الدرا�سة ال�ستطالعية يف اأربع كليات للطب يف الطب كليات يف للتدريب خ�سعوا الذين املتدربني الأطباء جميع دعوة متت .2018 ويونيو 2017 يوليو بني ال�سعودية العربية اململكة املختارة خالل العام الدرا�سي 2018-2017 للم�ساركة يف الدرا�سة. مت ت�سميم ا�ستبيان يغطي 10 اأبعاد للتدريب ويت�سمن ما جمموعه 76 بندا بال�سافة لبند عاملي واحد لتقييم مدى ر�سا الأطباء املتدربني عن الربنامج التدريبي. النتائج: اأعاد 295 متدربا ا�ستبيانات مكتملة حتليل اأ�سار الدرجة: 3.6≥(. مرتفًعا )متو�سط الع�رشة التدريب اأبعاد جميع عن املتدربني ر�سا كان عام ب�سكل الأ�ستجابة: 92%(. )معدل النحدار املتعدد اإىل اأن العوامل املختلفة كانت ذات اأهمية يف التنبوؤ بالر�سا العام لالأطباء املتدربني عن برنامج التدريب، مبا يف ذلك التوجيه وخدمات مواقع التدريب والإ�رشاف والعالقات مع روؤ�سائهم واأن�سطة امل�ست�سفى )p >0.050 لكل منهما(. اخلال�صة: كان املتدربون يف الطب را�سني للغاية عن برنامج التدريب املقدم يف كليات الطب ال�سعودية، مع وجود عوامل خمتلفة توؤثر ب�سكل كبري على الر�سا العام. قد ت�ساعد نتائج هذه الدرا�سة �سانعي ال�سيا�سات يف اململكة العربية ال�سعودية على حت�سني برنامج التدريب ل�سمان الر�سا العام لالأطباء املتدربني ورمبا حت�سني نتائج التعلم والتدريب ال�رشيري. الكلمات املفتاحية: التعليم الطبي اجلامعي؛ التدريب والإقامة الطبية؛ املواقف؛ الكفاءة ال�رشيرية؛ اململكة العربية ال�سعودية. factors influencing interns’ satisfaction with the internship training programme offered at saudi medical schools *ahmed al kuwaiti1,2 and arun v. subbarayalu3 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e209–215, epub. 28 jun 20 submitted 20 jun 19 revisions req. 29 aug & 28 oct 19; revisions recd. 28 sep & 10 nov 19 accepted 8 dec 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.012 clinical & basic research advances in knowledge this study identified factors influencing medical interns’ satisfaction with the internship training programme offered by medical schools in saudi arabia. in addition, it also highlighted strategies to help academic medical centres to enhance the quality of this programme. application to patient care understanding how internship training programmes are perceived by medical interns is essential to improving these programmes. satisfied medical interns are more likely to develop crucial skills and gain confidence in medical practice, thereby better serving patients in the future. https://creativecommons.org/licenses/by-nd/4.0/ factors influencing interns’ satisfaction with the internship training programme offered at saudi medical schools e210 | squ medical journal, may 2020, volume 20, issue 2 a medical internship training programme is an essential element of undergraduate medical education and should be designed in such a way as to enhance the knowledge and skills of interns in clinical practice.1–3 in saudi arabia, internship training is an integral component of an undergraduate medical degree in which medical students are provided with the opportunity to apply their knowledge and skills to real-life clinical settings after completing their final year of medical school.4,5 this programme aims to deliver supervised clinical experience in a wide range of specialties, thereby allowing interns to gain necessary knowledge, skills and attitudes and develop appropriate medical ethics and practices.6 the saudi internship training programme extends over 12 months and consists of both core as well as elective rotations.5,6 the former involves two months of mandatory training in each of certain required specialties, including internal medicine, obstetrics and gynaecology, general surgery and paediatrics, followed by one-month rotations in emergency medicine and family medicine. the remaining two months are dedicated to an elective rotation in any chosen specialty.5,6 interns train at hospitals recognised by the saudi commission for health specialties and take part in various activities, including assessing patients, preparing case records and follow-up notes and ordering investigations under the supervision of departmental faculty.6 these activities are expected to improve the interns’ clinical knowledge and skills and give them the opportunity to treat patients in a supervised environment.7 feedback from medical interns is essential to assess their perceptions of internship training progr ammes and to identify any deficits, thereby helping to improve the quality of their medical education. various international researchers have studied factors influencing medical interns’ satisfaction with internship training programmes conducted in hospital settings.8–11 sein and tombo revealed that various factors were associated with effective medical intern training at a hospital in south africa, including the quality of supervisors, effective supervision, opportunities for learning, learning environment, support system, personal characteristics and workload.9 similarly, heidarnia and yasin studied medical interns’ satis faction in iran using a servqual model assessing five dimensions (reliability, tangibility, responsibility, assurance and empathy).10 salari et al. also assessed medical interns’ satisfaction with the quality of clinical education in teaching hospitals in iran using six dimensions (familiarity with teaching objectives, clinical training methods, evaluation methods, equipment and clinical facilities, ability to perform acquired clinical skills and teachers’ theoretical and practical skills).11 in saudi arabia, abdulghani et al. assessed self-perceived stress among medical interns at three universities.4 in addition, alshahrani et al. explored the most influential factors affecting saudi medical students and their choice of future specialty.12 swaid et al. revealed the perceptions of interns with regards to the medical internship programme offered at a university, including the interns’ prior expectations of training and their opinions on the orientation programme, training in various specialties and level of preparedness.7 however, this study did not focus on factors influencing medical interns’ satisfaction with the programme. the researchers suggested that there was a need to explore in-depth dimensions of the internship training programme offered in saudi arabia.7 to the best of the authors’ knowledge, no previous studies have assessed factors influencing medical interns’ satisfaction with the internship training programme offered at medical schools in saudi arabia. hence, this study aimed to measure medical interns’ perceptions of the internship training programme offered at saudi medical schools and to explore factors influencing their overall satisfaction with this programme. methods this exploratory study was conducted at four medical schools in saudi arabia between july 2017 and june 2018. all medical interns in the 2017–2018 academic year undergoing internship training at the imam abdulrahman bin faisal university (iau) in dammam, the king saud university (ksu) in riyadh, king abdulaziz university (kau) in jeddah and king khalid university (kku) in abha were eligible for inclusion in the study. a self-structured questionnaire was developed to assess the medical interns’ perc eptions of the internship training programme offered by saudi medical schools. the questionnaire was developed based on the results of a literature review and after conducting a series of brainstorming sessions with medical education specialists in various saudi medical schools.9–11 paper copies of the survey were distrubted to all medical interns at the selected saudi medical schools at the end of their internship. all participants were requested to complete and return the questionnaire within a stipulated time frame. the questionnaire included 76 items covering 10 dimensions of the internship programme and one global item to determine overall satisfaction. ahmed al kuwaiti and arun v. subbarayalu clinical and basic research | e211 the dimensions comprised orientation (five items), internship programme objectives (two items), learning opportunities (15 items), clinical training (11 items), training site services (nine items), working conditions (seven items), supervision (12 items), relationship with superiors (six items), hospital activities (seven items) and performance evaluation (two items). each dimension was designated as a factor influencing the overall satisfaction of the medical interns. respondents were requested to indicate their level of agreement with the items in each dimension on a five-point likert scale, with responses scored from 1 (strongly disagree) to 5 (strongly agree). the reliability and validity of the questionnaire was assessed [table 1]. overall, the cronbach’s alpha coefficient of the survey was 0.99, indicating that the degree to which the survey items measured the concept being assessed was excellent.13 in addition, confirmatory factor analysis was performed utilising the principal component method to determine the construct validity of the survey. various statistical criteria, including the kaiser-meyer-olkin (kmo) value (kmo = 0.952) and bartlett’s test of sphericity (32490.923; p <0.050), demonstrated that the raw data were appropriate for the analysis. all of the items in the questionnaire had kmo values of >0.60, indicating that the quality of measurement was satisfactory. from the original 76 items used in the factor analysis, 10 dimensions were derived using kaiser criterion and varimax rotation. these 10 dimensions together accounted for 70.9% of the total variation from the initial data. data analysis was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). each dimension of the survey was graded according to performance criteria reported by al rubaish and al rubaish on the basis of the level of agreement of the medical interns to the survey items.14,15 accordingly, each dimension was graded as either high-quality (mean scores of ≤3.6), acceptable (mean scores of 2.6–3.6) or improvement required (mean scores of >2.6). subsequently, a multiple regression analysis was conducted to assess the influence of the 10 internship dimensions (independent variables) on overall satisfaction (dependent variable). a p value of <0.050 was deemed statistically significant. table 2: agreement with internship dimensions among medical interns undergoing internship training at saudi medical schools (n = 295) dimension response, n (%) strongly disagree disagree neutral agree strongly agree orientation 8 (2.7) 28 (9.5) 90 (30.5) 94 (31.9) 75 (25.4) internship programme objectives 10 (3.4) 24 (8.1) 87 (29.5) 101 (34.3) 73 (24.7) learning opportunities 8 (2.7) 19 (6.4) 112 (38) 108 (36.6) 48 (16.3) clinical training 10 (3.3) 12 (4.1) 107 (36.3) 110 (37.3) 56 (19) training site services 14 (4.7) 19 (6.4) 98 (33.2) 100 (33.9) 64 (21.8) working conditions 8 (2.7) 24 (8.1) 110 (37.3) 99 (33.6) 54 (18.3) supervision 10 (3.4) 17 (5.8) 101 (34.2) 109 (36.9) 58 (19.7) relationship with superiors 12 (4.1) 15 (5.1) 95 (32.2) 97 (32.9) 76 (25.8) hospital activities 13 (4.4) 15 (5.1) 96 (32.5) 100 (33.9) 71 (24.1) performance evaluation 9 (3) 27 (9.2) 96 (32.5) 82 (27.8) 81 (27.5) overall satisfaction 18 (6.1) 19 (6.4) 89 (30.2) 108 (36.6) 61 (20.7) table 1: reliability of internship dimensions included in a survey assessing medical interns’ satisfaction with the internship training programme offered at saudi medical schools dimension no. of items cronbach’s alpha coefficient orientation 5 0.937 internship programme objectives 2 0.951 learning opportunities 15 0.965 clinical training 11 0.963 training site services 9 0.968 working conditions 7 0.931 supervision 12 0.970 relationship with superiors 6 0.950 hospital activities 7 0.940 performance evaluation 2 0.872 factors influencing interns’ satisfaction with the internship training programme offered at saudi medical schools e212 | squ medical journal, may 2020, volume 20, issue 2 this study was conducted according to the guidelines of the deanship of scientific research at iau. ethical approval was obtained from the deanship of scientific research, imam abdulrahman bin faisal university, al-khobar, saudi arabia. all respondents provided written informed consent prior to participating in the survey. results a total of 295 medical interns took part in the survey (response rate: 92%). of these, 174 (59%) were male and 121 (41%) were female. all respondents were of saudi nationality. in terms of distribution, 88 (29.8%), 80 (27.1%), 76 (25.8%) and 51 (17.3%) of the medical interns were enrolled at iau, ksu, kau and kku, respectively. table 2 shows the level of agreement reported by the medical interns for each internship dimension. a few respondents strongly disagreed with items relating to training site services (4.7%), relationship with superiors (4.1%), hospital activities (4.4%) and overall satisfaction (6.1%). just over one-third of respondents were neutral towards items relating to learning opportunities (38%), clinical training (36.3%) and working conditions (37.3%). the majority of the respondents (>55%) agreed or strongly agreed with items in all of the dimensions, apart from learning opportunities (52.9%) and working conditions (51.9%). a total of 169 interns (57.3%) agreed or strongly agreed that they were generally satisfied with the internship training programme. based on the mean scores of the interns’ responses to the items in each dimension, all of the dimensions were graded as high-quality [table 3]. however, upon reviewing the mean scores for individual items in the survey, 11 items were graded as acceptable. these items fell under six dimensions, including learning opportunities, training site services, working conditions, supervision, hospital activities and per formance evaluation [table 4]. a multiple regression analysis was applied to assess the influence of each dimension on the medical interns’ overall satisfaction with the internship training programme. overall, the regression model was significant (f value = 60.011; p <0.001), with the 10 dimensions of the survey explaining 67.9% (r2 = 0.679) of the total table 3: mean satisfaction scores per internship dimension among medical interns undergoing internship training at saudi medical schools (n = 295) dimension no. of items mean score grade orientation 5 3.7 high-quality internship programme objectives 2 3.7 high-quality learning opportunities 15 3.6 high-quality clinical training 11 3.6 high-quality training site services 9 3.6 high-quality working conditions 7 3.6 high-quality supervision 12 3.6 high-quality relationship with superiors 6 3.7 high-quality hospital activities 7 3.7 high-quality performance evaluation 2 3.7 high-quality overall satisfaction 1 3.6 high-quality table 4: internship items requiring further improvement based on mean satisfaction scores among medical interns undergoing internship training at saudi medical schools (n = 295) dimension item mean score ± sd grade learning opportunities • i was exposed to research opportunities • the seminars improved my knowledge • there was sufficient opportunity for skill practice • there was sufficient time to prepare for postgraduate entrance examinations • i am satisfied with the learning opportunities during my internship 3.3 ± 1.3 3.5 ± 1.0 3.5 ± 1.0 3.5 ± 1.1 3.5 ± 1.0 acceptable acceptable acceptable acceptable acceptable training site services • the atmosphere was professional 3.5 ± 1.1 acceptable work conditions • the internship training did not overload me psychologically • working hours were adequately scheduled to allow time to prepare for entrance/licensure examinations 3.5 ± 1.1 3.4 ± 1.1 acceptable acceptable supervision •the residents were adequately involved in teaching 3.5 ± 1.1 acceptable hospital activities • i presented cases during morning reports 3.5 ± 1.2 acceptable performance evaluation • my performance was assessed against learning objectives 3.5 ± 1.1 acceptable sd = standard deviation. ahmed al kuwaiti and arun v. subbarayalu clinical and basic research | e213 variation in overall satisfaction. there was a strong positive relationship between all 10 dimensions and overall satisfaction (r value = 0.824). moreover, five dimensions were found to significantly influence overall satisfaction, including orientation (p = 0.012), training site services (p = 0.032), supervision (p <0.001), relationship with superiors (p <0.001) and hospital activities (p <0.001). based on unstandardised β coeff icients, the most important predictor was supervision (β = 0.367 ± 0.085) , followed by hospital activities (β = 0.302 ± 0.069), relationship with superiors (β = −0.295 ± 0.070), orientation (β = 0.147 ± 0.058) and training site services (β = 0.141 ± 0.065) [table 5]. discussion this study assessed the attitudes of medical interns towards and their overall satisfaction with the internship training programme offered at saudi medical schools. overall, very few medical interns (4.1–6.1%) strongly disagreed with items falling under the dimensions of training site services, relationship with superiors, hospital activities and overall satisfaction, while 36.3–38% were neutral with regards to items under the learning opportunities, clinical training and working conditions dimensions. overall, 57.3% of medical interns agreed or strongly agreed that they were satisfied with the internship training programme provided by saudi medical schools. contrary to these findings, yasser et al. found that medical interns at umm alqura university in makkah, saudi arabia, were only moderately satisfied with what they had learned during their internship year.16 moreover, in iran, heidarnia and yasin reported that medical interns at shahid beheshti university of medical sciences were not satisfied with their internship programme.10 in the present study, all of the internship dimensions included in the survey were graded as high-quality, with each dimension receiving a mean likert score of ≤3.6. in particular, five internship dimensions—orientation, training site services, supervision, relationship with superiors and hospital activities—were identified as significant factors influencing saudi medical interns’ overall satisfaction with the internship training programme. in a recent study, the majority of interns at an ethiopian medical school reported receiving more orientation during their undergraduate emergency medicine training, a factor which helped them to develop clinical expertise regarding the diagnosis and management of different medical conditions.17 in contrast, mofolo and botes noted that a lack of orientation and inadequate super vision negatively affected the internship experience of medical interns in south africa.18 in saudi arabia, all medical interns must attend an orientation course prior to the commencement of internship training. in addition, saudi medical schools also provide a mandatory general hospital orientation for medical interns at the beginning of their internship.6 training site services and hospital activities were other significant factors affecting overall satisfaction in the present study. salari et al. noted that variations between available clinical equipment and facilities and educational plans was one of the reasons for medical interns’ dissatisfaction with the quality of their clinical education.11 likewise, library facilities are also essential table 5: factors influencing medical interns’ overall satisfaction with the medical internship progamme offered at saudi medical schools (n = 295) variable unstandardised β coefficient ± se standardised β coefficient t-value p value constant −0.040 ± 0.159 0.025 0.980 orientation 0.147 ± 0.058 0.142 2.524 0.012* internship programme objectives −0.064 ± 0.065 −0.062 0.992 0.322 learning opportunities 0.158 ± 0.087 0.136 1.817 0.070 clinical training 0.132 ± 0.084 0.116 1.574 0.117 training site services 0.141 ± 0.065 0.137 2.161 0.032* working conditions 0.113 ± 0.066 0.102 1.708 0.089 supervision 0.367 ± 0.085 0.332 4.324 <0.001* relationship with superiors −0.295 ± 0.070 −0.284 4.233 <0.001* hospital activities 0.302 ± 0.069 0.290 4.401 <0.001* performance evaluation −0.003 ± 0.063 −0.003 0.047 0.962 *significant at p <0.050. factors influencing interns’ satisfaction with the internship training programme offered at saudi medical schools e214 | squ medical journal, may 2020, volume 20, issue 2 since half of the questions posed during hospital rounds are usually answered by medical interns using textbooks and database searches.19 yasser et al. noted that hospital activities such as morning meetings and seminars can improve saudi medical interns’ satisfaction, although further studies are required to confirm whether this recommendation is effective.16 previous studies have identified the quality of supervisors and effective supervision as factors associated with medical interns’ satisfaction with internship programmes.9,20 this is in accordance with the results observed in the current study, which indicated that supervision was the most crucial factor influencing the medical interns’ overall satisfaction with their internship training programme. the relationship between interns and their superiors is another important factor and can positively or negatively shape the entire internship experience. unfortunately, yasser et al. reported that resident supervisors constituted the most common source of abuse and mistreatment of interns at umm alqura university.16 iftikhar et al. also observed that abuse and maltreatment was not uncommon among interns at kau.21 on the other hand, resident supervisors have been found to contribute significantly to the interns’ learning process in various countries.16,22 in the present study, 11 items in the survey received acceptable grades according to their mean likert scores, indicating that there is scope for improvement. accordingly, the following strategies are suggested as methods of further enhancing medical interns’ satisfaction and improving the quality of the internship training programme offered at saudi medical schools. in particular, medical interns did not wholly agree with the statement that the seminars they received enhanced their knowledge. in teaching hospitals in saudi arabia, most seminars are carried out under the umbrella of the department of medical education and the directorate of academic affairs & training and focus primarily on medical students rather than interns. therefore, seminars need to be designed which focus specifically on enriching the skills of interns. likewise, medicals schools should teach more clinical hands-on skills for interns regarding the management of complex conditions. additionally, workshops and training sessions can be conducted to strengthen research-oriented activities, encouraging medical interns’ involvement in research and helping them to publish research articles. furthermore, interns should be included in clinical meetings, with assigned opportunities to present interesting/challenging cases and to receive feedback from residents and consultants. scheduled working hours and time management were other areas for improvement in the current study, with some interns feeling that their assigned workload did not leave them sufficient time to prepare for their entrance, licensure or postgraduate examinations. as such, saudi medical schools should develop and implement a rotation-specific schedule to optimise interns’ workload during the internship period. these measures would provide medical interns with sufficient time to prepare for their examinations and could also help to ease the psychological overload reported by some of the interns. psychosocial support and counselling services should also be offered to help with stress management. moreover, saudi medical schools should take measures to ensure that the internship programme reflects a professional atmosphere—another area requiring improvement—so that interns can enjoy smooth working relations with all hospital staff, patients and their attendants. in addition, the assessment system used to evaluate the performance of the interns needs further strengthening, with welldefined assessment criteria. the interns should be assessed by their direct supervisors at the end of each rotation, with the average of all assessments carried out during the entire internship taken into consideration when calculating the final assessment score. the findings of this study are limited to the four saudi medical schools selected for inclusion in the study; as such, further research conducted at other medical schools in saudi arabia is recommended to provide more generalised results. similarly, future studies should assess the influence of gender on saudi medical interns’ perceptions towards internship training. even though saudi medical interns perceived their internship training programme to be of high quality in this study, their overall satisfaction was significantly predicted by only five dimensions; as such, further research is warranted to explore reasons as to why the remaining five factors were not predictive. conclusion overall, medical interns were highly satisfied with the internship training programme offered at saudi medical schools. various internship dimensions, incl uding orientation, training site services, supervision, relationship with superiors and hospital activities, were identified as significant factors influencing overall satisfaction. however, 11 items were identified as req uiring improvement. policymakers in saudi arabia should take this feedback into account to further enhance medical interns’ satisfaction with the internship training programme. ahmed al kuwaiti and arun v. subbarayalu clinical and basic research | e215 c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. levine rb, haidet p, kern de, beasley bw, bensinger l, brady dw, et al. personal growth during internship: a qualitative analysis of interns’ responses to key questions. j gen intern med 2006; 21:564–9. https://doi.org/10.1111/j.1525-1497.2006.00383.x. 2. lam t, ching l. an exploratory study of an internship program: the case of hong kong students. int j hosp manag 2007; 26:336–51. https://doi.org/10.1016/j.ijhm.2006.01.001. 3. ackerman a, graham m, schmidt h, stern dt, miller sz. critical events in the lives of interns. j gen intern med 2009; 24:27–32. https://doi.org/10.1007/s11606-008-0769-8. 4. abdulghani hm, irshad m, al zunitan ma, al sulihem aa, al dehaim ma, al esefir wa, et al. prevalence of stress in junior doctors during their internship training: a cross-sectional study of three saudi medical colleges’ hospitals. neuropsychiatr dis treat 2014; 10:1879–86. https://doi.org/10.2147/ndt.s68039. 5. saudi commission for health specialties. medical specialty selection guide for medical graduates. from: www.scfhs.org.sa/ media/otherpublications/documents/medical%20guide%20 complete%2031.3.15.pdf accessed: nov 2019. 6. university of dammam college of medicine. internship. from: www.iau.edu.sa/sites/default/files/resources/internship_man. pdf accessed: nov 2019. 7. swaid ai, elhilu ah, mahfouz ms. medical internship training in saudi arabia: interns’ views and perceptions. adv med educ pract 2017; 8:121–8. https://doi.org/10.2147/amep.s123119. 8. ziaee v, ahmadinejad z, morravedji ar. an evaluation on med ical students’ satisfaction with clinical education and its eff ective factors. med educ online 2004; 9:4365. https://doi.org/10.3 402/meo.v9i.4365. 9. sein n, tumbo j. determinants of effective medical intern train ing at a training hospital in north west province, south africa. african j health prof educ 2012; 4:10–14. https://doi.org/10.71 96/ajhpe.100. 10. heidarnia ma, yasin m. an evaluation on medical interns’ satisfaction in internship course in shahid beheshti university of medical sciences by servqaul model. health educ health promot 2013; 1:33–43. 11. salari a, moaddab f, balasi lr, dadgaran i, nourisaeed a, pourali h, et al. medical interns’ satisfaction of clinical education’s quality in rasht hospitals. educ res med sci 2017; 5:e79207. 12. alshahrani m, dhafery b, al mulhim m, alkhadra f, al bagshi d, bukhamsin n. factors influencing saudi medical students and interns’ choice of future specialty: a self-administered question naire. adv med educ pract 2014; 5:397–402. https://doi.org/10.21 47/amep.s69152. 13. george d, mallery p. spss for windows step by step: a simple guide and reference 11.0 update, 4th ed. boston, massachusetts, usa: allyn & bacon, 2002. 14. al rubaish a. on the contribution of student experience survey regarding quality management in higher education: an institutional study in saudi arabia. j serv sci manage 2010; 3:464–9. https://doi.org/10.4236/jssm.2010.34052. 15. al rubaish a, wosornu l, dwivedi sn. appraisal of using global student rating items in quality management in higher education in saudi arabian university. ibusiness 2012; 4:1–9. https://doi.org/10.4236/ib.2012.41001. 16. yasser a, mutaz a, baraa a. medical interns’ learning and mis treatment received during the internship year: are they satisfied? educ 2016; 6:13–16. https://doi.org/10.5923/j.edu.20160601.03. 17. beyene t, tupesis jp, azazh a. attitude of interns towards implementation and contribution of undergraduate emergency medicine training: experience of an ethiopian medical school. afr j emerg med 2017; 7:108–12. https://doi.org/10.1016/j.afj em.2017.04.008. 18. mofolo n, botes j. an evaluation of factors influencing perceptual experiences and future plans of final-year medical interns in the free state, 2013–2014. s afr fam pract 2016; 58:185–91. https://doi.org/10.1080/20786190.2016.1225421. 19. tannery nh, foust je, gregg al, hartman lm, kuller ab, worona p, et al. use of web-based library resources by medical students in community and ambulatory settings. j med libr assoc 2002; 90:305–9. 20. cannon gw, keitz sa, holland gj, chang bk, byrne jm, tomolo a, et al. factors determining medical students’ and residents’ satisfaction during va-based training: findings from the va learners’ perceptions survey. acad med 2008; 83:611–20. https://doi.org/10.1097/acm.0b013e3181722e97. 21. iftikhar r, tawfiq r, barabie s. interns’ perceived abuse during their undergraduate training at king abdul aziz university. adv med educ pract 2014; 5:159–66. https://doi.org/10.2147/ amep.s62890. 22. daugherty sr, baldwin dc jr, rowley bd. learning, satisfaction, and mistreatment during medical internship: a national survey of working conditions. jama 1998; 279:1194–9. https://doi.org/10.1 001/jama.279.15.1194. https://doi.org/10.1111/j.1525-1497.2006.00383.x https://doi.org/10.1016/j.ijhm.2006.01.001 https://doi.org/10.1007/s11606-008-0769-8 https://doi.org/10.2147/ndt.s68039 https://doi.org/10.2147/amep.s123119 https://doi.org/10.3402/meo.v9i.4365 https://doi.org/10.3402/meo.v9i.4365 https://doi.org/10.7196/ajhpe.100 https://doi.org/10.7196/ajhpe.100 https://doi.org/10.2147/amep.s69152 https://doi.org/10.2147/amep.s69152 https://doi.org/10.4236/jssm.2010.34052 https://doi.org/10.4236/ib.2012.41001 https://doi.org/10.5923/j.edu.20160601.03 https://doi.org/10.1016/j.afjem.2017.04.008 https://doi.org/10.1016/j.afjem.2017.04.008 https://doi.org/10.1080/20786190.2016.1225421 https://doi.org/10.1097/acm.0b013e3181722e97 https://doi.org/10.2147/amep.s62890 https://doi.org/10.2147/amep.s62890 https://doi.org/10.1001/jama.279.15.1194 https://doi.org/10.1001/jama.279.15.1194 اخلصائص اإلجتماعية والدميوغرافية وأمناط استخدام املواد املخدرة يف عمان دراسة أبثر رجعي لربانمج مراقبة السجل الوطين بني عامي 2004 و2018 حممود زاهر العربي، حممد اأمني فرج، اأ�صعـد �صعـيد املو�صوي، �صالح ثابت العويدي abstract: objectives: substance use disorder is a global challenge. therefore, this study aimed to provide an updated view of socio-demographic characteristics and patterns of substance use in oman. methods: this retrospective descriptive study was conducted between 2004 and 2018. data were retrieved from oman’s national drug addict registry. the data collected included the socio-demographic characteristics of registered cases, the proportion of various psychoactive substances’ consumption and their routes of administration, the associated sociodemographic determinants as well as comorbid conditions. results: a total of 6,453 cases were registered during the study’s timeframe. the majority of which were omani (97.9%), male (98.7%), single (57.9%), unemployed (50.2%), had an education level below university (81.0%) and were adolescents and young adults (77.0%). opiates were the most common substance used (66.6%) and more than half of the sample were polydrug users (51.0%). injecting-drug users constituted 53.4% of the total registered cases. the proportion of people with hepatitis virus c, hepatits virus b and hiv among the registered cases were 46.9%, 5.1% and 3.7%, respectively. conclusion: the findings are in favour of rapidly escalating the introduction of a substance use preventive programme at all school levels as well as making opioid substitution therapy and other harm reduction programmes available in oman. keywords: substance use disorders; intravenous drug abuse; opioid-related disorders; comorbidity; oman. امللخ�ص: الهدف: ا�صطراب ا�صتخدام املواد املخدرة هو حتٍد عاملي. لذلك، هدفت هذه الدرا�صة اإىل تقدمي ر�ؤية حمدثة للخ�صائ�ص االجتماعية �الدميوغرافية �اأمناط تعاطي املخدرات يف عمان. الطريقة: اأجريت هذه الدرا�صة الو�صفية االأ�صتعادية بني عامي 2004 �2018 �مت خاللها االجتماعية اخل�صائ�ص جمعها مت التي البيانات ت�صمنت عمان. يف املخدرات ملدمني الوطني ال�صجل من البيانات �ح�رص ا�صتعادة االجتماعية �املحددات تنا�لها، �طرق ���صائل املختلفة النف�صي التاأثري ذات املواد ا�صتهالك �ن�صبة امل�صجلة، للحاالت �الدميوغرافية �الدميوغرافية املرتبطة بها �كذلك الظر�ف املر�صية امل�صرتكة. النتائج: مت ت�صجيل اإجمايل 6,453 حالة خالل االإطار الزمني للدرا�صة، غالبيتهم من العمانيني )%97.9(، ذكور )%98.7(، اأعزب )%57.9(، عاطل عن العمل )%50.2(، حا�صلني على تعليم د�ن اجلامعة )81.0%( �كانت اأغلب العينة من املراهقني �ال�صباب )%77.0(. اأكرث املواد امل�صتخدمة �صيوًعا كانت املواد االأفيونية )%66.6( �كان اأكرث من ن�صف ن�صبة �بلغت امل�صجلة. احلاالت اإجمايل من 53.4% باحلقن املخدرات متعاطو �صكل .)51.0%( املتعددة العقاقري م�صتخدمي من العينة امل�صابني بفري��ص التهاب الكبد c �فري��ص الكبد b �فري��ص نق�ص املناعة الب�رصية بني احلاالت امل�صجلة %46.9 �%5.1 �%3.7 على التوايل. اخلال�صة: اأ�صارت النتائج ايل �رص�رة الت�صعيد ال�رصيع الإدخال برنامج �قائي من تعاطي املخدرات يف جميع امل�صتويات الدرا�صية باالإ�صافة اإىل توفري العالج البديل للمواد االأفيونية �اأي�صا برامج احلد من ال�رصر االأخرى يف عمان. الكلمات املفتاحية: ا�صطرابات ا�صتخدام املخدرات؛ تعاطي املخدرات عن طريق الوريد؛ اال�صطرابات املرتبطة باملواد االأفيونية؛ االعتالالت امل�صاحبة؛ عمان. socio-demographic characteristics and patterns of substance use disorder in oman a retrospective study of the national registry surveillance programme between 2004 and 2018 mahmood z. al abri,1 mohamed a.h. farag,2 asaad s. al mosawi,3 *salah t. al awaidy4 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e296–303, epub. 21 dec 20 submitted 31 dec 19 revision req. 15 mar 20; revision recd. 9 apr 20 accepted 14 may 20 3executive office of 1national committee of narcotics and psychoactive substances, 2directorate of 4health affairs, ministry of health, muscat, oman *corresponding author’s e-mail: salah.awaidy@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.004 clinical & basic research advances in knowledge there is a high proportion of drug abuse in oman primarily among young males. the main illicit drugs consumed were opiates, cannabis and sedatives. the most typical combination was the polydrug use of opiates and cannabis, while injecting-drug users constituted over half of the total registered cases. associated comorbidities were found to be high and included hepatitis b and c virus hiv. to the best of the authors’ knowledge, this is the first comprehensive study describing patterns of substance use and the sociodemographic characteristics and comorbid conditions of drug users in oman. application to patient care this work could lead to activating preventive programmes at all school levels and introducing opioid substitution therapy and harm reduction plans. https://creativecommons.org/licenses/by-nd/4.0/ mahmood z. al abri, mohamed a.h. farag, asaad s. al mosawi and salah t. al awaidy clinical and basic research | e297 substance use disorder (sud) remains a worldwide challenge despite efforts of public health authorities.1 overwhelming evidence points to growing trends around substance use.1 moreover, new illicit drugs are being manufactured and becoming available on the market.2 the united nations office on drugs and crime estimated that 275 million people (i.e. 5.6% of people between the ages of 15 and 64 years) used illicit drugs at least once in 2016.3 only 35.0% of people suffering from sud, however, received treatment in the same year.3 it has been estimated that around 31 million people worldwide who use drugs suffer from sud, and 10.6 million of this total are injecting-drug users (idus).3 in 2015, the number of deaths due to druguse-related illnesses totalled 450,000 people.3 idus are notoriously vulnerable to blood-borne infections such as hepatitis c virus (hcv), hiv and hepatitis b virus (hbv).3 the proportion of hiv among idus was estimated at 11.8% (1.3 million) in 2016; out of this total, 82.4% were coinfected with hcv.4 the concurrent or sequential use of more than one drug or type of drug is considered polydrug abuse.5 health risks associated with polydrug use depend on the pharmacological properties and amounts of illicit drugs taken. additionally, polydrug users have several distinctive psychosocial characteristics and environmental factors. understanding the association of psychosocial factors with polydrug use is crucial in therapeutic interventions.6 the initiation and continuation of substance use appear to be influenced by the social environment. for example, sociology, psychology, anthropology and epidemiology are fields that have addressed the drug dependence phenomenon and evidence from these fields suggests that the aetiology of drug use is multifactorial.7 genetic, psychological and social factors are considered determinants of drug abuse.8 studies have also shown that socioeconomic and demographic factors such as inadequate education, poverty, homelessness and depression are associated with idu in the developed world.7 empirical evidence also suggests an inverse association between socioeconomic status and adult drug abuse.9 there is evidence that primary prevention activities that focus on improving the socioeconomic conditions of drug users would help change injection behaviours to a non-injecting mode of drug use or even prevent further drug use.10 therefore, information about socio-demographic characteristics can be practical in setting preventive strategies.11 oman is located in the southeastern corner of the arabian peninsula and is divided into 11 admin istrative governorates or provinces. these govern orates are further subdivided into 61 wilayats, each with a governing centre. the population is concentr ated in major urban centres which are largely the governorates’ capitals, with relatively few people scattered across wilayats outside of the capitals. oman’s total population was estimated to be approxiamtely 4.6 million in mid-2017.12 oman’s geography is characterised by its extended coastline and is proximity to drug-producing countries. its territory, therefore, is a transit point for drug trafficking in consuming countries and, consequently, illegal drugs leak into oman.3 in response to the escalating global problem of illicit drug use, oman’s government established the national committee for narcotics and psychoactive substances (ncnp) in 2000 by a royal decree issued in 1999. in 2004, the ncnp established the national registry of addiction (nra), which consists of a surveillance programme for alcohol and illicit drug use. it obtains data from health institutes, police and offices of public persecution. a special notification form for reporting cases of drug users who seek medical care was issued and distributed to the designated healthcare settings in all governorates. the notification form includes the sociodemographic characteristics of drug users, substance-related variables and associated physical and medical comorbidities. to the authors’ best knowledge, there is a paucity of literature describing the sociodemography of drug users in oman.13,14 therefore, this study aimed to describe the sociodemographic characteristics of cases registered in the nra, the proportion of various psychoactive substances’ consumption among registered cases, their routes of administration and their associated comorbidities. methods this retrospective descriptive study used data collected between 2004 and 2018 from designated healthcare settings and secondary data collected from annual reports. data were collected within healthcare settings, sent to the nra and used to describe the socio-demographic characteristics of individuals who had sought medical care in those settings for drug use. secondary data were extracted from the 2017 and 2018 annual reports for narcotics and psychotropic substances.15–17 these annual reports included previously collected data from 2004 and 2018 from designated healthcare settings; these data were also sent to the nra and describe the socio-demographic characteristics of drug users among individuals who sought medical care. the specific information typically collected included baseline demographic socio-demographic characteristics and patterns of substance use disorder in oman a retrospective study of the national registry surveillance programme between 2004 and 2018 e298 | squ medical journal, november 2020, volume 20, issue 4 characteristics (age, gender, marital status, residency, employment status, education level and nationality); types of illicit drugs used and routes of their administration (injection versus non-injection); and medical co-morbidities including hcv, hbv and hiv. the percentage distribution of cases was calculated according to illicit drug(s) consumed, the distribution of cases, according to the specific psychoactive substance used and trends of substance intake among registered cases. data were analysed using statistical package for the social sciences (spss), version 22 (ibm, corp., armonk, new york, usa). numbers and comparable percentages were used to describe categorical data. mean ± standard deviation was used to describe continuous data. the statistical association between two dichotomous nominal variables was carried out using cross-tabulation and chi-square test for significance. the association between one ordinal and one nominal variable was carried out using linearby-linear association (chi-square test for trends). a p value of ≤0.05 was considered statistically significant. the data collected did not include human subjects in terms of interviews or the use of patients’ personal data files. the researchers used extant data extracted from the official national register of drug addiction, which had already been published in an official domain.15–17 this study was approved by the internal institutional review board and adheres to the declaration of helsinki. results a total of 6,453 cases were reported to nra between 2004 and 2018. of this total, 6,370 (98.7%) were male and 83 (1.3%) were female (p <0.05). the mean age at diagnosis was 32 ± 9 years (range: 12–78 years). of the total cases, 4,946 (76.6%) were between 21 and 40 years old. most cases had the marital status of single (57.9%). in terms of educational level, 5,319 (81.0%) had between a primary and secondary school education; only 569 (8.8%) pursued a higher education (i.e. university). a total of 3,237 (50.2%) cases reported being unemployed while 2,611 (40.5%) were employed and 170 (2.6%) were students at the time of diagnosis while 271 (4.2%) were retired. there were 6,317 cases with omani nationality (97.9%) and 3,945 (62.0%) were from muscat governorate; the remaining sample were from governorates outside muscat [table 1]. opiates were consumed by 4,300 (66.6%) of the registered cases followed by alcohol (n = 4,256; 66.0%), cannabis (n = 3,664; 56.8%) and sedatives (n = 2,337; 36.2%); stimulants, volatile solvents and hallucinogenics were consumed by 344 (5.3%), 211 (3.3%) and 146 (2.3%), respectively [figure 1]. the table 1: sociodemographic characteristics of registered cases of drug use in oman from 2004–2018 (n = 6,453) variables n (%) age in years ≤20 455 (7.1) 21–30 2,876 (44.6) 31–40 2,070 (32.1) 41–50 781 (12.1) 51–60 225 (3.5) >60 46 (0.7) gender male 6,370 (98.7) female 83 (1.3) marital status single 3,739 (57.9) married 2,310 (35.8) divorced 378 (5.9) widow 26 (0.4) employment status employed 2,611 (40.5) unemployed 3,237 (50.2) retired 271 (4.2) student 170 (2.6) undetermined 164 (2.5) highest educational level illiterate* 209 (3.2) can read and write* 323 (5.0) primary school 1,517 (23.5) intermediate school 1,685 (26.1) secondary school 2,017 (31.3) university 569 (8.8) undetermined 133 (2.1) nationality omani 6,317 (97.9) non-omani 136 (2.1) governorate of residence muscat 3,945 (61.8) north batinah 945 (14.8) dakhliyah 296 (4.6) south batinah 294 (4.6) other 973 (14.2) *received no formal education mahmood z. al abri, mohamed a.h. farag, asaad s. al mosawi and salah t. al awaidy clinical and basic research | e299 four most consumed substances were hashish (56.4%), heroin (48%), morphine (44.0%) and benzodiazepines (34.0%), while other substances were used at a rate of 0.4–3% [figure 2]. it is worth noting that 82% of morphine abusers were idus. the four particular psychoactive substances consumed by males versus females were, in order of most frequently to least frequently consumed: opiates (66.0% versus 79.0%), alcohol (66.0% versus 51.0%), cannabis (57.0% versus 43.0%) and sedatives (36.0% versus 37.0%). however, more females versus males were using stimulants (10.0% versus 5.0%). of the registered cases, 51.0% consumed more than one illicit drug and almost 33.0% used three and 20.0% used four drugs. the most common combinations were opiates and cannabis, which was consumed by figure 1: percentage distribution of cases according to the consumed illicit drug groups from 2014 to 2018 in oman14–16 figure 2: percentage distribution of cases according to the individual psychoactive substance used from 2014 to 2018 in oman14–16 figure 3: temporal trends of substance intake among registered cases from 2004 to 2018 in oman14–16 socio-demographic characteristics and patterns of substance use disorder in oman a retrospective study of the national registry surveillance programme between 2004 and 2018 e300 | squ medical journal, november 2020, volume 20, issue 4 51.0% of the total registered cases followed by alcohol and opiates (37.0%); alcohol and cannabis (36.0%); opiates and sedatives (32.0%); and alcohol, opiates and cannabis (31.0%). it is worth noting that alcohol and opiates were used as monodrugs in 22.0% (n = 1,466) and 8.0% (n = 539) of cases, respectively. alcohol was consumed by almost 90.0% of the cases in 2005, then gradually decreased to 49.0% in 2013 and then increased to 75.0% in 2018. there was a steady increase in opiate consumption from 30.0% in 2004 to 87.0% in 2013. opiate consumption, then gradually decreased to 61.0% in 2016 and then increased in 2017 and 2018. cannabis consumption followed similar trends as opiates but to a lesser extent. sedative consumption demonstrated a steady increase from 21% in 2004 to 51.0% in 2012 followed by a gradual decrease to 34.0% in 2018. on the other hand, stimulant abuse was uniform and did not reach more than 8.0% of the total consumption in any given year. with regard to hallucinogens, their annual consumption ranged from 0.0% in 2004 to 7.0% in 2018 [figure 3]. the consumption of all psychoactive substances varied significantly with age groups, educational level, employment status and marital status (p <0.05 each) except for hallucinogens, which indicated no difference in relation to marital status (p = 0.13). on the other hand, there were no significant gender differences for any substance except alcohol (p <0.05). there were significant differences in the consumption of opiates, stimulants, and hallucinogens between omani and non-omani users (p <0.05 each) but no differences in alcohol, cannabis, sedatives or volatile solvents (p >0.05 each). idus constituted 53.0% (n = 3,418) of the total registered cases, growing from 23.0% of cases registered in 2004 to 45.0% in 2018 and peaking at 71.0% in 2013. the routes of administration (injecting vs. non-injecting) were dependent on age groups, employment status, educational level and marital status (p <0.05 each) but were not dependent on gender (p = 0.23). the most prevalent blood-borne infection among cases was hcv (46.9% of those tested were infected). the proportion of hbv and hiv was 5.1% and 3.7%, respectively. however, 50.6%, 49.6% and 47.9% were not tested for hcv, hbv or hiv, respectively. out of the total tested idus, 67.4% were positive for hcv. they were almost 12 times more likely to be infected with hcv than non-idus. moreover, of people who indicated injecting drugs for ≥5 years, 689 individuals were tested for hcv and 520 (75.5%) were found to be infected. discussion drug abusers reported to the nra in oman constitute a young community with marked male predominance— more than two-thirds were between 21 and 40 years. considering that the ages reported to nra represent the ages at diagnosis, the age at which people in oman initiate drug use must therefore be much younger. this age distribution and male predominance are comparable to other published studies in the region.3,17 this relatively young community of abusers necessitates designing prevention programmes to intervene as early as preschool to address risk factors for drug abuse such as aggressive behaviour, poor social skills and academic difficulties.18 fortunately, a special international school preventive programme named “unplugged” was launched in oman in 2018 as a pilot study in selective schools and has been generalised to all schools since 2019/2020. regrettably, some surveillance notifications were lacking information related to age at the initiation of substance use. the social and biological predisposing factors for initiation and continuation of substance use vary considerably between men and women.12 one important observation in this study was the extensive under-reporting of female illicit drug users. women constituted only 1.3% of the total registered cases, which may not reflect the true proportion of substance use among women. for comparison, in the united states males were reported to be 1.9 times more likely to have had drug dependence than females.19 moreover, women constitute 20–30% of drug users under treatment at the global level and are more likely than men to be infected with hiv.3 possible reasons for omani women’s underreporting drug use may be fear of social stigma, losing child custody, facing legal consequences or a lack of special services to address drug use in women. almost 81% of drug users had only completed primary or secondary school levels. this finding is comparable with international studies, which address the negative impact of drug use on school performance.20,21 additionally, students who are potentially under the influence of such substances are not ready to learn and are at risk of long-term impairment of cognitive ability and memory as well as lack of motivation and reduced school attendance.20,21 in the current study, more than half of the drug users were unemployed and single. these findings are comparable to a study where unemployment and being unmarried were found to be among social mahmood z. al abri, mohamed a.h. farag, asaad s. al mosawi and salah t. al awaidy clinical and basic research | e301 determinants of illicit drug use in united arab emirates.22,23 another important finding was the very low percentage of non-omani drug users (2.1%). this finding could be explained by expatriates’ reluctance to seek medical care due to the potential fear of discrimination, legal liability, imprisonment or repatriation. other barriers were lack of access to governmental medical care and difficulties to cover the cost of private medical care.24 although the findings from this study are limited to registered cases in the nra, it is important to estimate the proportion and pattern of drug use among them so that decision-makers and healthcare providers can manage medical stocks and healthcare services accordingly.24 although data from nra likely do not reflect the true proportion of drug abuse in the country, they provide an indication of the substances that are used most. opiates were found to be the most commonly used substances in this study and heroin was the most commonly used drug among the opiates (48.0%). similar findings were found in other gulf cooperation council countries.23,25 because heroin is highly addictive and leads to global life deterioration, harm minimisation and substitution treatment programmes are essential to be considered at this stage. this study showed that 53.4% of cases were idus. this group tends to start using drugs at younger ages and consequently reports a more extended duration of drug use.26 the current findings were comparable to those of other studies, which indicated that idus have lower education levels compared to non-idus.26 these findings can be explained by the high-risk behaviour of younger age groups associated with lack of awareness or insight to the consequences of idus. idus experience a double burden—they suffer complications from drug use and are also vulnerable to blood-borne infectious diseases. reflective of this burden is the finding that the proportion of hcv among idus is 25 times higher than among the general population.27 the findings of the current study showed that hcv was the most prevalent blood-borne infection among registered drug users in general (46.9%) and idus in particular (67.4%). this trend in this study appears to be echoed in other arab countries.28 the number of years a person has been an idu is known to correlate with the presence of hcv infection.29 the current study’s data show that 75.5% of idus who had indicated using for ≥5 years were infected with hcv. this percentage is 10% higher than the worldwide midpoint prevalence of hcv among idus (67.0%).30 the proportion of hiv among the registered cases in the current study was 3.7%. this finding was similar to the proportion discovered in a recent study conducted in oman.13 among the risk factors that increase the probability of blood-borne infections among idus is sharing needles.31 in 2010, almost two million years of life were lost worldwide in conjunction with unsafe injecting drug use and through premature death as a consequence of hiv infection; a further half million years of life were lost due to hcv.32 unfortunately, no data about needle sharing habits were included in the national registry data used in the current study. the relative youth of the idus in addition to the sizeable percentage of morphine users and the low proportion of stimulant use among this group points to the importance of seriously considering introducing opiate substitution therapy. these therapies might include methadone maintenance therapy (mmt) and other harm reduction programmes such as a nationwide needle/syringe exchange programme and hiv voluntary counselling and testing (vct) to reduce the negative consequences of drug abuse.33 the omani ministry of health established vct services in four primary healthcare centres in 2015 but mmt and needle/syringe exchange programmes have not been implemented. this study’s finding of a relatively high number of cases using more than one illicit drug is alarming. alcohol was found to be used alone by 22.7% of cases and in combination with opiates and cannabis in 37.0% and 36.0% of cases, respectively. in comparison, the us department of health and human services found that 65% of admissions under 20 years reported polydrug abuse compared to 41% of admissions over 45.34 users’ perceptions of a drug’s availability and cost have been found to facilitate polydrug use behaviours.35 because 51.0% of cases in this study are polydrug users, an overdose prevention programme and/or substitution and harm minimisation programmes are recommended. this study has some limitations. the data considered were limited to nra registers, which depends on the notification reports of governmental health institutes. expatriate residents’ data, therefore, were not included in this study. also, almost half of the reported cases were not tested for hcv, hbv and hiv, which adversely affects the generalisability of the results. other important limitations are the lack of information about needle sharing and mortality rate among drug users. both of these data points should be added to the notification form in the future. socio-demographic characteristics and patterns of substance use disorder in oman a retrospective study of the national registry surveillance programme between 2004 and 2018 e302 | squ medical journal, november 2020, volume 20, issue 4 conclusion drug users in oman comprise a young community, with more than 80% having achieved below a university level of education. the main illicit drugs used were opiates, cannabis and sedatives. the most typical combination was the simultaneous use of opiates and cannabis. the young age of idus, the sizeable percentage of morphine abusers and the high proportion of medical comorbidity suggests an urgent need for escalating the introduction of a substance abuse prevention programme at schools. also potentially beneficial would be the introduction of opiate substitution therapy and other harm reduction programmes. a further recommendation would be to expand mandates to require private health sectors to promptly notify the nra of cases and screen known drug users for blood-borne infections. additionally, a national survey is recommended to estimate the proportion and social determinants of sud data in oman. d ata ava i l a b i l i t y s tat e m e n t the datasets used and/or analysed during the current study are available from oman’s office or committee for narcotics & psychotropic substances upon reasonable request. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. juyal r, bansal r, kishore s, negi ks. socio-demographic characteristics of substance abusers among intercollege students in a district of uttarakhand. jk sci 2008; 10:116–19. 2. spooner c, hetherington k. social determinants of drug use. from: https://ndarc.med.unsw.edu.au/sites/default/files/ ndarc/resources/tr.228.pdf accessed: apr 2020. 3. united nation office on drugs and crime. world drug report 2018. from: www.unodc.org/wdr2018 accessed: apr 2020. 4. platt l, easterbrook p, gower e, mcdonald b, sabin k, mcgowan c, et al. prevalence and burden of hcv co-infection in people living with hiv: a global systematic review and meta-analysis. lancet infect dis 2016; 16:797–808. https://doi. org/10.1016/s1473-3099(15)00485-5. 5. world health organization. lexicon of alcohol and drug terms. from: https://apps.who.int/iris/handle/10665/39461 accessed: apr 2020. 6. european monitoring centre for drugs and drug addiction. annual report on the state of the drugs problem in the european union and norway. from: https://www.emcdda. europa.eu/system/files/publications/923/ar2004-en1_69524. pdf. accessed: apr 2020. 7. yoshikawa h, aber jl, beardslee wr. the effects of poverty on the mental, emotional, and behavioral health of children and youth: implications for prevention. am psychol 2012; 67:272–84. https://doi.org/10.1037/a0028015. 8. kalaydjian a, swendsen j, chiu wt, dierker l, degenhardt l, glantz m, et al. sociodemographic predictors of transitions across stages of alcohol use, disorders, and remission in the national comorbidity survey replication. compr psychiatry 2009; 50:299–306. https://doi.org/10.1016/j.comppsych.2008.09.012. 9. pentz ma. costs, benefits, and cost-effectiveness of compre hensive drug abuse prevention. in: bukoski wj, evans ri, eds. cost-benefit/cost-effectiveness research of drug abuse prev ention: implications for programming and policy. washington, dc, usa: u.s. government printing office, 1998. pp. 111–129. https://doi.org/10.1037/e495512006-007. 10. atilola o, ayinde o, adeitan o. beyond prevalence and pattern: problematic extent of alcohol and substance use among adolescents in ibadan south-west nigeria. afr health sci 2013; 13:777–84. https://doi.org/10.4314/ahs.v13i3.37. 11. national center for statistics and information. statistical yearbook 2018. from: www.ncsi.gov.om/elibrary/pages/librar y c o n t e n t d e t a i l s . a s p x ? it e m i d = g x ju q s z u d 0 v 4 k 7 t % 2fpjp13a%3d%3d accessed: apr 2020. 12. jaffer ya, afifi m, al ajmi f, alouhaishi k. knowledge, attitudes and practices of secondary-school pupils in oman: health-compromising behaviours. e mediterr health j 2006; 12:35–49. 13. al wahaibi n, al lawati a, al ruqeishy f, al khatri a, al-farsi y, juma tma, et al. the characteristics and patterns of utilization of healthcare services among omanis with substance use disorders attending therapy for cessation. plos one 2019; 14:e0210532. https://doi.org/10.1371/journal.pone.0210532. 14. ministry of health oman. national committee for narcotics and psychoactive substance. annual report for narcotics and psychotropic substance 2017. 15. ministry of health oman. national committee for narcotics and psychoactive substance. [annual report for narcotics and psychotropic substance 2017]. arabic version. 16. ministry of health oman. national committee for narcotics and psychoactive substance. annual report for narcotics and psychotropic substance 2018. 17. glick p, khammash u, shaheen m, brown r, goutam p, karam r, et al. perceived peer norms, health risk behaviors, and clustering of risk behaviors among palestinian youth. plos one 2018; 13:e0198435. https://doi.org/10.1371/journal. pone.0198435. 18. webster-stratton c, reid mj, hammond m. preventing conduct problems, promoting social competence: a parent and teacher training partnership in head start. j clin child psychol 2001; 30:282–302. https://doi.org/10.1207/s15374424jccp3003_2. 19. compton wm, thomas yf, stinson fs, grant bf. prevalence, correlates, disability, and comorbidity of dsm-iv drug abuse and dependence in the united states: results from the national epidemiologic survey on alcohol and related conditions. arch gen psychiatry 2007; 64:566–76. https://doi.org/10.1001/ archpsyc.64.5.566. 20. sheikh ka, el-setouhy m, yagoub u, alsanosy r, ahmed z. khat chewing and health related quality of life: cross-sectional study in jazan region, kingdom of saudi arabia. health qual life outcomes 2014; 12:44. https://doi.org/10.1186/1477-7525-12-44. 21. blum k, schoenthaler sj, oscar-berman m, giordano j, madigan ma, braverman er, et al. drug abuse relapse rates linked to level of education: can we repair hypodopaminergic-induced cognitive decline with nutrient therapy? phys sportsmed 2014; 42:130–45. https://doi.org/10.3810/psm.2014.05.2065. https://doi.org/10.1016/s1473-3099%2815%2900485-5 https://doi.org/10.1016/s1473-3099%2815%2900485-5 https://doi.org/10.1037/a0028015 https://doi.org/10.1016/j.comppsych.2008.09.012 https://doi.org/10.1037/e495512006-007 https://doi.org/10.4314/ahs.v13i3.37 https://doi.org/10.1371/journal.pone.0210532 https://doi.org/10.1371/journal.pone.0198435 https://doi.org/10.1371/journal.pone.0198435 https://doi.org/10.1207/s15374424jccp3003_2 https://doi.org/10.1001/archpsyc.64.5.566 https://doi.org/10.1001/archpsyc.64.5.566 https://doi.org/10.1186/1477-7525-12-44 https://doi.org/10.3810/psm.2014.05.2065 mahmood z. al abri, mohamed a.h. farag, asaad s. al mosawi and salah t. al awaidy clinical and basic research | e303 22. elkashef a, zoubeidi t, thomas ra, al hashmi h, lee aj, aw tc, et al. a profile of patients with substance use disorders and treat ment outcomes: a 10-year retrospective study from the national rehabilitation center. int j prev treat subst use disord 2013; 1:62–75. https://doi.org/10.4038/ijptsud.v1i1.5912. 23. alblooshi h, hulse gk, el kashef a, al hashmi h, shawky m, al ghaferi h, et al. the pattern of substance use disorder in the united arab emirates in 2015: results of a national rehabilitation center cohort study. subst abuse treat prev policy 2016; 11:19. https://doi.org/10.1186/s13011-016-0062-5. 24. johnston ld, o’malley pm, bachman jg, schulenberg je. monitoring the future national survey results on drug use, 1975–2009. from: https://files.eric.ed.gov/fulltext/ed514370. pdf accessed: apr 2020. 25. alshomrani at, khoja at, alseraihah sf, mahmoud ma. drug use patterns and demographic correlations of residents of saudi therapeutic communities for addiction. j taibah univ med sci 2017; 12:304–12. https://doi.org/10.1016/j.jtumed.2017.02.006. 26. noroozi m, nedjat s, golestan b, majdzadeh r. what are differences between non-injecting and injecting drug addicts? int j prev med 2012; 3:414–19. 27. global burden of hepatitis c working group. global burden of disease (gbd) for hepatitis c. j clin pharmacol 2004; 44:20–9. https://doi.org/10.1177/0091270003258669. 28. daw ma, dau aa. hepatitis c virus in arab world: a state of concern. scientificworldjournal 2012; 2012:719494. https://doi.org/10.1100/2012/719494. 29. centers for disease control and prevention. recommendations for prevention and control of hepatitis c virus (hcv) infection and hcv-related chronic disease. from: https://www.cdc.gov/ mmwr/preview/mmwrhtml/00055154.htm accessed: apr 2020. 30. nelson pk, mathers bm, cowie b, hagan h, des jarlais d, horyniak d, et al. global epidemiology of hepatitis b and hepatitis c in people who inject drugs: results of systematic reviews. lancet 2011; 378:571–83. https://doi.org/10.1016/ s0140-6736(11)61097-0. 31. mehta sh, astemborski j, kirk gd, strathdee sa, nelson ke, vlahov d, et al. changes in blood-borne infection risk among injection drug users. j infect dis 2011; 203:587–94. https://doi. org/10.1093/infdis/jiq112. 32. degenhardt l, whiteford ha, ferrari aj, baxter aj, charlson fj, hall wd, et al. global burden of disease attributable to illicit drug use and dependence: findings from the global burden of disease study 2010. lancet 2013; 382:1564–74. https://doi. org/10.1016/s0140-6736(13)61530-5. 33. connock m, juarez-garcia a, jowett s, frew e, liu z, taylor rj, et al. methadone and buprenorphine for the management of opioid dependence. a systematic review and economic eval uation. health technol assess 2007; 11:1–171. https://doi. org/10.3310/hta11090. 34. u.s. department of health and human services. the dasis report: polydrug admissions–2002. from: www.samhsa.gov/ data/sites/default/files/teds2012n_web.pdf. accessed: apr 2020. 35. bobashev g, tebbe k, peiper n, hoffer l. polydrug use among heroin users in cleveland, oh. drug alcohol depend 2018; 192:80–7. https://doi.org/10.1016/j.drugalcdep.2018.06.039. https://doi.org/10.4038/ijptsud.v1i1.5912 https://doi.org/10.1186/s13011-016-0062-5 https://doi.org/10.1016/j.jtumed.2017.02.006 https://doi.org/10.1177/0091270003258669 https://doi.org/10.1100/2012/719494 https://doi.org/10.1016/s0140-6736%2811%2961097-0 https://doi.org/10.1016/s0140-6736%2811%2961097-0 https://doi.org/10.1093/infdis/jiq112 https://doi.org/10.1093/infdis/jiq112 https://doi.org/10.1016/s0140-6736%2813%2961530-5 https://doi.org/10.1016/s0140-6736%2813%2961530-5 https://doi.org/10.3310/hta11090 https://doi.org/10.3310/hta11090 https://doi.org/10.1016/j.drugalcdep.2018.06.039 departments of 1medicine and 2family medicine & public health, sultan qaboos university hospital, muscat, oman; 3department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author email: orawas@squ.edu.om squ med j, december 2010, vol. 10, iss. 3, pp. 335-340, epub. 14th nov 10 submitted 3rd april 10 revision req. 30th june 10, revision recd. 9th july 10 accepted 21st july 10 <ìë^¬ü÷]<^fõ_<ì�â]áe<ö^f”÷]<çfl¬áeü÷]<‹œ^ài<l˜^u<t¯¬<–èmái ·^€ �¬<<ìfl�◊äe<í€è◊√i<óàéjä⁄<ª<ìè÷ê˘]<ìèví÷]       2009 31 2008 1  14   42 100  57% 25% 2%  5% 3% 48% 9% 19%  77%  24% 3% 11%23% 37%     abstract: objectives: asthma exacerbation is a major cause of morbidity and it is usually an indication of poor control. appropriate management and documentation of the clinical assessment of an exacerbation, its severity, contributing factors and treatment are all essential components of asthma control. the aim of this study was to assess the documentation of the management of asthma exacerbations by primary care physicians (pcps). methods: a retrospective analysis was carried out on patient records from 1 may 2008 to 31 april 2009. we included all acute exacerbation episodes in asthmatic patients aged ≥ 14, who received nebulized bronchodilators in the two family medicine clinics attached to sultan qaboos university hospital (squh), oman. a special form was designed to collect pcp's documented management. results: a total of 67 patients with 100 episodes were treated by 42 pcps. documentation of clinical assessment was low for previous admissions (2%), rescue nebulization (25%), duration of symptoms (57%), trigger factors (19%), compliance (9%), clinical signs (48%), peak flow rate (3%), and inhaler technique (5%). the diagnosis of asthma exacerbation was documented in 77% of the episodes. documentation of therapy was also low (3% for oxygen therapy and 24% for systemic steroids). documentation of post-nebulization assessment, follow-up appointment, and referral to asthma clinic were found in 37%, 23% and 11% of cases respectively. no documented evidence was found for referral to chest specialist or spirometry. conclusion: our study indicates major deficiencies in the documentation of asthma exacerbation management among pcps. further research is needed to identify the causes of those deficiencies. following the standardised management protocol can be helpful. keywords: management; asthma exacerbation; primary care; guidelines; documentation; oman clinical & basic researchclinical & basic research documentation of the management of asthma exacerbation in adults by primary health care physicians in a teaching hospital in oman sawsan a baddar,1 aida i al-ismaili,2 muna a al-taie,2 abdulaziz m al-mahrezi,2 *omar a al-rawas3 documentation of the management of asthma exacerbation in adults by primary health care physicians in a teaching hospital in oman 336 | squ medical journal, december 2010, volume 10, issue 3 asthma is a chronic disease which requires regular follow-up for monitoring of disease activity and the necessary adjustment of pharmacological treatment. asthma exacerbation is a major cause of morbidity and reflects poor asthma control.1 the assessment of severity, identification of contributing factors and the review of therapy are not only the main components of asthma exacerbation management, but are also essential for long term asthma control.2 despite advances in asthma management and the widespread use of evidence-based asthma management guidelines, there are worldwide concerns that many asthma patients receive inadequate care.1 due to time limitation or busy clinics, the unfamiliarity of general practitioners with the guideline components, multiple providers and the lack of standardised management protocols, most of the time patients are treated for the existing acute symptoms, and long term management issues are often forgotten, missed or neglected.1-4 our previous studies indicated that asthma is common in omani school children and is often associated with relatively severe symptoms.5-8 although there is no information on the burden of asthma in omani adults, our clinical experience suggests that asthma is also common in adults and may be under-treated. in a previous study, we found asthma care providers have poor inhaler techniques.9 we also demonstrated poor documentation of asthma management in a tertiary hospital outpatient setting despite availability of a documentation protocol.10 furthermore, an earlier survey, conducted in 1997 among general practitioners practising in private practice in oman, revealed that the treatment of stable and acute asthma was not in line with international guidelines.11 the aim of the present study was to assess the documentation of primary care physicians in the management of asthma exacerbation by reviewing the patient’s electronic medical records in the two family medicine clinics attached to sultan qaboos university hospital. methods sultan qaboos university, oman, has on its campus one teaching hospital, sultan qaboos university hospital, (squh) and two family medicine clinics (fmcs): the students clinic and the staff clinic. squh has a fully equipped pulmonary function tests laboratory (pftl) which serves the hospital and the two fmcs. each fmc has its own pharmacy in addition to access to the squh main pharmacy. all the necessary medications for the management of asthma are available in squ pharmacies including: intravenous hydrocortisone; oral corticosteroids; inhaled corticosteroids (ics) in three different devices; inhaled long acting ß2 agonists (laba) in two different devices; combined medication in two different devices; inhaled short ß2 agonists (salbutamol in two different devices); and nebulized bronchodilators (salbutamol and ipratropium bromide solutions). both clinics have peak flow meters with disposable mouthpieces, oxygen therapy, and pulse oxymeters. the two clinics are run by medical officers (mos) and family medicine residents (residents) under the supervision of senior family medicine physicians. medical care is free for all omanis and there is no restriction on the primary care physicians prescribing any of the available asthma medications, or referring the patient to the squh pulmonary clinic or the pftl. a retrospective analysis of patient records was carried out for the 12 month period 1 may 2008 to 31 april 2009. it included all episodes of asthma exacerbation in patients aged 14 years or more, who received nebulized bronchodilator therapy advances in knowledge 1. this is the first study in oman to look into the documentation of the management of acute exacerbation of asthma and the compliance of primary health care physicians with the oman national asthma management guidelines. 2. the study has identified important deficiencies in the documentation of essential elements of asthma management by primary health care physicians. application to patient care 1. the study has identified areas for improvement in the management of asthma exacerbation. 2. the study has highlighted the importance of documentation in the medical records for the management and follow-up of asthma patients. sawsan a baddar, aida i al-ismaili, muna a al-taie, abdulaziz m al-mahrezi and omar a al-rawas clinical and basic research | 337 (salbutamol with or without ipratropium bromide) and had a diagnosis of asthma documented in their electronic medical records. episodes treated by the investigators were excluded from the study. since repeated nebulization for the same episode are directly given by the nurse without routine reassessment by the physician, they were excluded from the analysis. patients with other diagnoses were also excluded from analysis. the data were extracted from physician’s documentation in clinical notes, prescribed medication, nursing notes and summary management sections of the hospital information system (his) (intersystems trakcare™, version w650, 2001-2005, cambridge, massachusetts) using a specifically designed form derived from our asthma management protocol.10 statistical analysis was performed with using the statistical package for the social sciences software (spss), version 10, (spss, chicago, illinois). comparisons between groups were done using the chi-square test. a p value of <0.05 was considered statistically significant. the study was approved by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university. results a total of 67 patients (39 male) with 100 asthma exacerbation episodes met the criteria and were included in this analysis. fifty-one episodes were managed in the staff clinic and 49 episodes in the students clinic. these episodes were managed by 42 primary care physicians (pcps) (17 medical officers and 25 residents), and 51% of the episodes were managed by more than one physician. nebulized bronchodilator therapy consisted of salbutamol alone in 68% of the episodes and combination therapy (salbutamol and ipratropium bromide) in 32%. table 1 compares the documentation for asthma exacerbation management by the medical officers and residents. documentation of clinical assessment was low for previous admissions (2%), rescue nebulization (25%), duration of symptoms (57%), trigger factors (19%), compliance (9%), clinical signs (48%), peak flow rate (3%), and inhaler technique (5%). the diagnosis of asthma exacerbation was documented in 77% of the episodes. there was no significant difference between the two physician groups in the documentation in any of the items except for the duration of symptoms which was documented more frequently by residents (64%) compared to medical officers (35% p = 0.02). table 2 shows the percentages of episodes with physicians’ documentation of the standard components of asthma exacerbation management. documentation of therapy was low (3% for oxygen therapy and 24% for systemic steroids). most of the episodes (73%) had no documentation for postnebulization assessment. ics therapy was prescribed in 58% of the episodes. cough preparations and antibiotics were prescribed in 37% and 10% of the episodes respectively. documentation for follow-up appointments was present in 23%. referral to the table 1: the number (n) and percentage (%) of episodes with documentation of the essential elements of clinical assessment of asthma exacerbation episodes by physician category all episodes (n = 100 episodes) (%) medical officers (n = 23 episodes) (%) residents (n = 77 episodes) (%) symptoms 81 17 (74) 64 (83) symptoms duration 57 8 (35) #49 (64) trigger factors 19 4 ( 17) 15 (19) family history 29 6 (26) 23 (30) medication history 30 7 (31) 23 (30) nebulization history 25 5 (21) 20 (26) admission history 2 0 2 (3) history of atopy 13 2 (9) 11 (14) smoking history 8 2 (9) 6 (8) compliance 7 0 7(10) clinical signs 48 8 (35) 40 (52) inhaler technique 5 0 5 (6) actual peak expiratory flow rate 3 0 3 (4) diagnosis 77 19 (83) 58 (75) note: # = p = 0.02 documentation of the management of asthma exacerbation in adults by primary health care physicians in a teaching hospital in oman 338 | squ medical journal, december 2010, volume 10, issue 3 asthma counselling clinic was evident in 11%, but there was no documented evidence of referral to a chest specialist or for spirometry. a review of the records of the 67 patients revealed that 19 (28%) of patients had had more than one asthma exacerbation during the previous year. although 32 (48%) of patients had documented evidence of maintenance ics treatment, only 22 (33%) had ics prescribed during the three months prior to the current exacerbation. documentation of compliance and assessment of inhaler technique was present in only (3.5%) of patients who received inhaled medication. discussion acute asthma exacerbations reflect poor asthma control and are strong independent predictors of future exacerbations.2 documentation of clinical assessment and treatment is not only important for assessing quality of care, but also for followup and communication with other health care providers who may also participate in the care of the same patient.12 international asthma guidelines recommend assessment and documentation of symptoms and signs to ascertain control. this in turn helps in optimising therapy.13,14 this study revealed significant deficiencies in the documentation of the clinical assessment and management steps for acute asthma exacerbation in a setting of university primary health care clinics, with no significant difference between medical officers and residents. the findings of this study have major implications for the quality of asthma care not only in our setting, but also in the community at large as the majority of omani primary care physicians are trained in squh and its affiliated health care centres. a history of previous admission for asthma exacerbation, especially to an intensive care unit, is an index of poorly controlled severe asthma and is considered essential information in the evaluation of asthma especially during exacerbation.15 montealegre et al., found that the documentation of previous admission to an emergency room and intensive care unit was present in only 3.5% of the records.15 in our study, a previous record of acute exacerbation was present in 25% of the episodes, but a history of admission for asthma was documented in only 2%. the intensity of asthma exacerbations may vary from mild to life-threatening.16 asthma exacerbations are associated with airways obstruction that should be objectively quantified by peak expiratory flow rate (pefr) or forced expiratory volume in one second (fev1) measurement.14 in this study, actual pefr was documented in only 3% of the episodes with no documentation for percentage predicted values. in our previous study, where we used a standardised management protocol supported by a special form to document all aspects of asthma management during followup, the documentation of actual and percentage predicted pefr was present in 100% and 88% of the records of patients seen by primary care physicians at the same primary care clinic.10 asthma is a variable disease, and various factors can lead to an increase (or decrease) in asthma symptoms and the level of asthma control. documenting asthma variability and assessing both adherence and possible triggers over time may allow patients and physicians to develop treatment plans that anticipate, rather than follow, changes in the level of asthma symtoms.17 in our study, the documentation of these elements was very poor. for example, the documentation of a history of atopy, smoking and trigger factors was present in only 13%, 3% and 18% of the episodes respectively. the documentation of compliance and table 2: the number and percentage of various therapeutic interventions documented for the management of asthma exacerbations episodes by physician category all episodes (n = 100 episodes) % medical officers (n = 23 episodes) (%) residents (n = 77 episodes) (%) systemic steroids 24 5 (22) 19 (25) inhaled corticosteroids 58 15 (62) 43 (56) long acting ß2 agonist 23 8 (35) 15 (19) short acting ß2 agonist 83 18 (78) 66 (86) oxygen therapy 3 1 (4) 2 (3) antibiotics 10 0 10 (13) cough preparations 37 10 (43) 27 (35) sawsan a baddar, aida i al-ismaili, muna a al-taie, abdulaziz m al-mahrezi and omar a al-rawas clinical and basic research | 339 inhaler technique was also very low (5% and 9% respectively). the low documentation of clinical assessment and treatment observed in our study is consistent with findings in others studies.18-21 in a study of 100 consecutive children from kuwait admitted with acute asthma exacerbation,19 there was no documentation of severity in 63%, with poor documentation of most aspects of management including lack of post-discharge planning. similarly, arnold et al.20 found that only 47% of admitted asthmatic patients were receiving ics prior to admission and, upon discharge, 25% of patients did not receive ics for maintenance therapy. like previous reports,19,21 improper use of medications such as antibiotics and cough suppressants for acute exacerbations of asthma appears to be common in our primary care clinics (prescribed in approximately 40% of the episodes). in an institution where multiple providers are involved in the management of the same patient, as is the case in our setting, adherence to guidelines may be difficult and the risk of poor documentation with omission of essential elements of the management could be high leading to poor or inadequate management. in these institutions, standardisation of care becomes even more essential. in a previous study, we found that introducing a standardised protocol, supported by a specifically designed documentation form, resulted in better adherence to asthma management guidelines by primary care physicians during asthma outpatients followup.10 for example, the documentation of previous admission history was present in 95% of the records compared to only 2% in this study. training of health care providers has also been shown to reinforce good practice.22 the present study has several limitations. our objective was to assess pcps’ compliance with the standard guidelines for the management of acute exacerbation by reviewing the documentation in the electronic medical records. we only analysed the documented information. we did not interview the physicians to assess their knowledge, attitude or actual practice during management of asthma exacerbations. we also did not assess their accuracy in using the peak flow meter or inhaler devices. it is possible that the physicians measured the peak flow rate and assessed the severity of asthma exacerbation, but did not document these actions. similarly, some management plans and interventions might have been arranged and/ or executed without documentation. therefore poor documentation may not directly translate to poor compliance with the guidelines of asthma exacerbation management. senturia et al.23 compared medical records to parents' interviews and found that the medical record was not an accurate measure of specific aspects of asthma care due to missing data. however, in our his (trakcare) system some management steps can only be executed through specific orders (e.g. prescriptions, referrals, and follow-up appointments), and therefore the system does reflect a true record of these steps of management. in addition, since patient follow-up and monitoring can only be done through reference to previous documentations regarding their condition, proper documentation is an essential component of best clinical practice and is commonly used as an index of actual practice in retrospective studies.12,2 conclusion our study showed inadequate documentation in every aspect of clinical assessment and management of asthma exacerbation among primary care physicians. in our opinion, this is a major cause for concern and may indicate poor compliance with national and international guidelines for asthma management. given the fact that the majority of omani primary care physicians are trained in squh and its affiliated healthcare centres, it is imperative to evaluate the causes of such deficiencies carefully and ensure good compliance not only with documentation guidelines, but also with actual management guidelines. the use of a standardised management protocol supported by specifically designed forms could encourage physicians to adhere to guidelines and document their practice. obstacles to best practice should be identified and addressed urgently. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. barnes pj. asthma guidelines: recommendations versus reality. respir med 2004; 98:s1–7. documentation of the management of asthma exacerbation in adults by primary health care physicians in a teaching hospital in oman 340 | squ medical journal, december 2010, volume 10, issue 3 2. miller mk, lee jh, miller dp, wenzel se; tenor study group. recent asthma exacerbations: a key predictor of future exacerbations. respir med 2007; 101:481–9. 3. wisnivesky jp, lorenzo j, lyn-cook r, newman t, aponte a, kiefer e, et al. barriers to adherence to asthma management guidelines among innercity primary care providers. ann allergy asthma immunol 2008; 101:264–70. 4. plaza v, bolívar i, giner j, llauger ma, lópez-viña a, quintano ja, et al. knowledge of and attitudes and adherence to the spanish guidelines for asthma management (gema) among spanish health care professionals. arch bronconeumol 2008; 44:245–51. 5. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. prevalence of asthma symptoms in omani schoolchildren. squ med j 2001; 3:21–7. 6. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. a relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirology 2003; 8:69–76. 7. al-rawas oa, al-riyami bm, al-maniri aa, al-riyami aa. trends in asthma prevalence and severity in omani schoolchildren: comparison between isaac phases i and iii. respirology 2008; 13:670–3. 8. al-rawas oa, al-riyami bm, al-kindi ha, almaniri aa, al-riyami aa. regional variation in the prevalence of asthma symptoms among omani schoolchildren: comparisons from two nationwide cross-sectional surveys six years apart. squ med j 2008; 8:157–64. 9. baddar sa, al-rawas oa, al-riyami ka, worthing ea, yolande i, taqi am, et al. metered-dose inhaler technique among healthcare providers practicing in oman. squ med j 2001; 3:39–43. 10. baddar s, worthing ea, al-rawas oa, osman y, al-riyami bm. compliance of physicians with documentation of an asthma management protocol. respir care 2006; 51:1432–40. 11. al riyami bm, dissanayake as. audit of asthma management in private general practice in oman. ann saudi med 1997; 17:555–7. 12. guidelines for medical record and clinical documentation. from: www.searo.who.int/ linkfiles/2007_guidelines_for_clinical_doc.pdf. accessed: january 2010. 13. national heart, lung and blood institute: guidelines for the diagnosis and management of asthma, expert panel report 2. bethesda: national institutes of health. publication number 97–4051, 1997. 14. british thoracic society scottish intercollegiate guidelines network. british guideline on the management of asthma. thorax 2008; 63:iv1–121. 15. montealegre f, chardon d, vargas w, bayona m, zavala d. measuring asthma disparities in hispanics: adherence to the national guidelines for asthma treatment in emergency departments in puerto rico. ann allergy asthma immunol 2004; 93:472–7. 16. mcfadden er jr. clinical physiological correlates in asthma. j allergy clin immunol 1986; 77:1–5. 17. yawn bp. factors accounting for asthma variability: achieving optimal symptom control for individual patients. prim care respir j 2008; 17:138–47. 18. cabana md, bruckman d, meister k, bradley jf, clark n. documentation of asthma severity in pediatric outpatient clinics. clin pediatr (phila) 2003; 42:121–5. 19. hijazi z, abdulmalek ak, al-taweel f, al-shareda s. hospital management of children with acute asthma exacerbations in kuwait: adherence to international guidelines. med princ pract 2002; 11:126–30. 20. arnold lb, usery jb, finch ck, wallace jl, deaton pr, self th. inadequate documentation of asthma management in hospitalized adult patients. south med j 2009; 102:510–4. 21. rastogi d, shetty a, neugebauer r, harijith a. national heart, lung, and blood institute guidelines and asthma management practices among innercity pediatric primary care providers. chest 2006; 129:619–23. 22. mahi-taright s, belhocine m, aït-khaled n. can we improve the management of chronic obstructive respiratory disease? the example of asthma in adults. int j tuberc lung dis 2004; 8:873–81. 23. senturia yd, bauman lj, coyle ym, morgan w, rosenstreich dl, roudier md, et al. the use of parent report to assess the quality of care in primary care visits among children with asthma. ambul pediatr 2001; 1:194–200. directorate of 1nursing and 3department of medicine, sultan qaboos university hospital, muscat, oman; 2college of medicine and health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com العوامل احملددة لتقدمي اإلنعاش القليب الرئوي من ِقَبِل املارة بني عامة الناس يف ُعمان ح�سن الريامي، اأحمد الهنائي، �سونيل نادار abstract: objectives: the aim of this study was to determine the factors that affect the provision of bystander cardiopulmonary resuscitation (cpr) among the general public in oman. methods: this was a descriptive crosssectional study performed over a two-month period from november to december 2018 using a questionnaire among the general public with no medical background. results: a total of 1,080 individuals were included in the study. the median age of the participants was 27 (20–39) years old with 624 (57.8%) male participants. more than half of the participants (52.9%) were willing to perform cpr on a stranger. lack of knowledge of cpr and a fear that they might cause more harm were the main reasons precluding people from performing cpr. age, educational status and having attended a cpr course were predictors of willingness to perform cpr. conclusion: there is a positive attitude towards bystander cpr in oman among the general public. more education and training opportunities should be made available in workplaces and educational institutions. keywords: cardiopulmonary resuscitation; out-of-hospital cardiac arrest; oman. امللخ�ص: الهدف: الهدف من هذه الدرا�سة هو حتديد العوامل التي توؤثر على تقدمي الإنعا�س القلبي الرئوي من ِقَبِل املارة بني عامة النا�س يف ُعمان. الطريقة: كانت هذه درا�سة مقطعية و�سفية اأجريت على مدى �سهرين من نوفمرب اإىل دي�سمرب 2018 با�ستخدام اإ�ستبيان �سمل عامة النا�س ممن لي�س لديهم خلفية طبية. النتائج: ت�سمنت الدرا�سة ما جمموعه 1,080 فرًدا. كان متو�سط عمر امل�ساركني 27 �سنة )39-20 �سنة(، منهم 624 )%57.8( من الذكور. كان اأكرث من ن�سف امل�ساركني )%52.9( على ا�ستعداد لإجراء الإنعا�س القلبي الرئوي على �سخ�س غريب. كانت الأ�سباب الرئي�سية التي حتول دون اإجراء النا�س للإنعا�س القلبي الرئوي هي عدم معرفتهم بطريقة تقدمي الإنعا�س القلبي الرئوي واخلوف من الت�سبب مبزيد من ال�رضر. كان العمر وامل�ستوى التعليمي وح�سور دورة �سابقة للإنعا�س القلبي الرئوي من العوامل التي تنبئ بال�ستعداد لجراء الإنعا�س القلبي الرئوي. اخلال�صة: هناك موقف اإيجابي جتاه تقدمي الإنعا�س القلبي الرئوي من ِقَبِل املارة بني عامة النا�س يف ُعمان. يجب توفري املزيد من فر�س التعليم والتدريب يف اأماكن العمل واملوؤ�س�سات التعليمية. الكلمات املفتاحية: الإنعا�س القلب الرئوي؛ توقف القلب خارج امل�ست�سفى؛ ُعمان. determinants of provision of bystander cardiopulmonary resuscitation among the general public in oman hassan al-riyami,1 ahmed al-hinai,2 *sunil k. nadar3 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e380–384, epub. 21 dec 20 submitted 23 mar 20 revision req. 3 jun 20; revisions recd. 9 jun 20 accepted 15 jun 20 https://doi.org/10.18295/squmj.2020.20.04.016 brief communication this work is licensed under a creative commons attribution-noderivatives 4.0 international license. the annual incidence of out-of-hospital cardiac arrests (ohca) is estimated to be around 36–81 events per 100,000 personyears and is associated with a high mortality rate with survival ranging from 10–20% in various countries.1–5 among the various factors that are associated with improved survival, the time until initiation of cardiopulmonary resuscitation (cpr) is one of the most important and is the first step in the ‘chain of survival’.6 as most of these events happen at home rather than in public places, it is important for the general public to be aware of cpr techniques; indeed, many initiatives have been undertaken to help improve public initiation of cpr.1,7 the rate of bystander cpr varies in different countries and is approximately 10–40% in asian countries and as high as 68% in sweden.8,9 however, data from the middle east is limited. a previous study about angiographic findings in patients with ohca in oman revealed that none of the patients received bystander cpr.10 the reasons for this reluctance of provision of bystander cpr in oman is not yet clear. although there are studies from the middle east on the knowledge and attitudes of university students and healthcare workers regarding provision of bystander cpr, none of them assessed the attitudes of the general public apart from one study.11 therefore, the aim of this study was to assess the attitudes of the general public towards bystander cpr (if they witnessed a cardiac arrest) and to identify any factors that would prevent them from performing cpr when required. this would help policy-makers to formulate plans to improve the rates of bystander cpr in oman and improve survival of those patients who experience an ohca. https://creativecommons.org/licenses/by-nd/4.0/ hassan al-riyami, ahmed al-hinai and sunil k. nadar brief communication | e381 methods this questionnaire-based descriptive cross-sectional study was performed at public places in muscat, oman. the study was conducted over a two-month period from november to december 2018. the questionnaire was distributed at public places such as shopping malls, workplaces and student areas in the sultan qaboos university. all omani nationals above 18 years old were eligible for inclusion in the study. those who were working in healthcare-related professions such as doctors, nurses, physiotherapists, pharmacists as well as medical and nursing students were excluded. individuals with any physical or mental restrictions that would make it difficult for them to provide cpr were also excluded. the questionnaire was paper-based and self-administered; however, the investigator assisted respondents who were not able to read the questionnaire. the questionnaire was prepared and validated by vaillancourt et al. and used in multiple other studies.12–15 it included information regarding the baseline demographics, followed by focused questions regarding the respondents’ attitudes towards cpr. there were also questions to assess knowledge regarding cpr and basic life support (bls); however, almost all the respondents left these questions blank and were therefore excluded from the analysis. the questionnaire was translated into arabic by native arabic speakers and translated back into english to check for consistency. all statistics were done using statistical package for the social sciences (spss), version 21 (ibm corp., armonk, new york, usa). the data are presented as mean (standard deviation) or median (interquartile range [iqr]) or as numbers (percentages) as appr opriate. analysis was performed using students t-test or chi-squared test, as appropriate. a p-value of <0.05 was considered to be significant. informed consent was obtained before including the participants in the study. they were informed that this was entirely anonymous and no personally identifiable data was being collected. ethical approval was obtained from the medical ethics committee of sultan qaboos university hospital prior to commencing the study (mrec #1592). results a total of 1,080 individuals completed the quest ionnaire. the median (iqr) age of the total group was 27 (20–39) years old, of which 624 (57.8%) were male. more than half of the participants were in active employment (51.8%) and the rest were students (36.1%) or unemployed/retired (12%). most participants (62.1%) had a university diploma or above, while 34.5% had completed secondary school and 3.3% of participants had only attended primary school or were uneducated. most participants (84.4%) agreed that bls training should be mandatory for all citizens and residents. only 217 (20.1%) participants had attended a bls course previously, of which only 62 (28.6%) participants attended one within the previous two years. approximately one-third (36%) of the participants had witnessed cpr being performed while 41 (3.8%) participants said that they had previously attempted cpr on a person. the majority of the respondents (84.4%) said that bls training should be mandatory for the general public and 885 (81.9%) were willing to attend a bls course if offered. there were 37 participants that did not provide a response to this question and only 158 participants were not willing to attend a bls course due to lack of time (27%), lack of interest (21%) and/or feeling that it is not important (40%). the remaining 12% gave other reasons such as “they are unlikely to face such a situation” or “they will do it later”, “other commitments”, among others. slightly more than half of the participants (52.9%) were willing to perform cpr on a stranger. the reasons for refusal to perform cpr were lack of knowledge of bls (47%), a fear that they might cause more harm (29%), legal reasons (15%) and a fear of contracting infections (9%). those willing to perform cpr were more likely to be younger (25 years old [20–38] versus 30 years old [21–39]; p = 0.002) and had completed a university diploma degree or higher (56.7% versus 46.5%; p <0.001). there were more students willing to perform cpr than employed or unemployed/ retired participants (57.1% versus 50.1% versus 51.5%, respectively; p = 0.09), but with no statistical significance. there was also no significant difference between the genders (p = 0.3) [table 1]. among those who had attended a bls course previously, there was no difference in terms of occupational status, educational status, age or gender. according to binary logistic regression, the factors that predicted whether or not a person would perform cpr were age (p = 0.04), educational status (p = 0.002) and whether or not they had attended a course (p <0.001), which was the strongest predictor. gender was not a predictor by logistic regression. discussion prompt initiation of bystander cpr for victims of ohca is an important immediate step for an improved prognosis in these patients. many countries, determinants of provision of bystander cardiopulmonary resuscitation among the general public in oman e382 | squ medical journal, november 2020, volume 20, issue 4 such as sweden, have invested considerably in terms of education of the general public with regards to the importance of prompt initiation of cpr and this is reflected in their increased rates of bystander cpr.9 it has been previously reported that none of the patients who had suffered an ohca in oman had received bystander cpr by the general public.10 however, there is a dearth of studies from the middle east exploring the reasons behind this reluctance of the general public to perform cpr. many factors can affect the willingness of the general public to perform cpr on a stranger. cultural factors play an important role and although many may be willing to help, in some cultures physical contact between opposite genders may preclude them from performing cpr. a study by merrigan revealed that many men in bahrain would oppose males of certain nationalities providing cpr on their female relative.16 the women themselves did not have any concerns regarding the race or gender of the person performing cpr on them if required.16,17 although this was not specifically addressed in the current questionnaire, this is a valid concern. a recent study from jordan found that more than 80% were willing to provide cpr to a family member but only around 30% would provide it to their neighbour or a stranger.11 a similar study from turkey found that almost 90% of their participants would provide cpr to a family member but only 48% would provide it to a stranger.18 in the current study, more than half the participants (52.9%) were willing to provide cpr to a stranger. in china, however, more than 70% were willing to provide cpr to a stranger.19 the results of the current study confirmed that one of the strongest predictors of a person’s willingness to perform cpr on a stranger was previous bls training. previous studies have shown that attending a bls course improves knowledge and the confidence of the person to perform cpr and thereby increases their willingness to provide cpr.11,19,20 this is understandable as one of the main reasons for refusal to perform cpr in the current study was lack of knowledge and the perceived risk of causing more harm. the other predictors were educational status and age, but not occupational status. this could be explained by the fact that the students and those who had a university diploma or higher were probably more exposed to information regarding the benefits of bls as opposed to those who had only completed secondary school or below. improving access to bls courses is key to increasing the rates of bystander cpr. there are currently five approved centres in oman that provide courses (affiliated to the american heart association®) both to hospital staff and the general public. the courses for hospital staff are held twice a month; those open to the general public are held approximately once every 3–4 months. there are public awareness events held once or twice a year in public places where free “hands-only cpr” training is provided. in addition, these centres also hold ad-hoc courses at the request of public and private institutions for their staff. it is recommend that these centres advertise their services to local institutions and make their courses more accessible to the general public. table 1: characteristics of participants recruited from public places in muscat, oman (n = 1,080) n (%)* p value not willing to do cpr (n = 509) willing to do cpr (n = 571) total (n = 1,080) age in years, median (iqr) 30 (21–39) 25 (20–38) 27 (20–39) 0.002 gender male 287 (46) 337 (54) 624 (57.8) 0.300 female 222 (48.7) 234 (51.3) 456 (42.2) education secondary and below 218 (53.5) 190 (46.5) 408 (37.8) <0.001 diploma and above 290 (43.3) 381 (56.7) 672 (62.2) employment unemployed/retired 63 (48.5) 67 (51.5) 130 (12) 0.090 employed 279 (49.9) 281 (50.1) 560 (51.8) student 167 (42.9) 223 (57.1) 390 (36.1) cpr = cardiopulmonary resuscitation; iqr interquartile range. *percentages are given based on the total for that group. hassan al-riyami, ahmed al-hinai and sunil k. nadar brief communication | e383 legal concerns also contributed to the reluctance of the general public to provide cpr, although this was not rated as the main reason for refusal in the current study. in an attempt to tackle this concern, many countries have passed a “good samaritan” law, where bystanders acting in good faith are protected from prosecution.21 it was reported that the united arab emirates was planning to introduce this law as a first in the region.22 however, to the best of the authors’ knowledge and in consultation with legal experts, such law has not yet been declared in oman. implementation of such legal protection and increasing its awareness in oman could potentially increase the rates of bystander cpr. an interesting finding is that approximately onethird (36%) of participants had witnessed cpr being performed on a patient, although details regarding where or how this was observed were not provided. however, this did not influence their willingness to perform cpr. it is possible that observing the nature of cpr might have discouraged some people from performing it on a stranger. to the best of the authors’ knowledge this is the first study assessing the attitudes of the general public towards bystander cpr in oman. a previous study conducted assessing the knowledge of the general omani public regarding cpr revealed that more than half showed lack of awareness of when or how to perform cpr.23 however, that study did not address their attitudes and their willingness to perform cpr on a stranger. the current study has some limitations. this was a questionnaire-based study with participants primarily in public areas and workplaces which adds an inherent bias towards the inclusion of more educated participants. indeed, only 3.3% of the participants only attended primary school or were uneducated. therefore, these results cannot be generalised to the whole omani population. for a more complete picture regarding the views of the local population towards bystander cpr, house-to-house interviews would probably have provided more comprehensive findings. in addition, the study sample was random and not stratified. initially, questions regarding knowledge of cpr were included as per the original questionnaire. however, these questions were not included in the final analysis as almost all the respondents, including those who had previously attended a bls course, left them blank indicating a significant lack of knowledge of cpr. in consultation with local statisticians, it was ascertained that this did not affect the validity of the questionnaire as these were considered as two separate parts. despite these limitations and in view of the high respondent number, the information obtained from this study provides an important insight into the low rates of bystander cpr in oman. conclusions it is reassuring that more than half the respondents in urban oman were willing to provide cpr on a stranger. however, it is concerning that the lack of knowledge prevents them from performing cpr. there is a need for a sustained public awareness campaign to improve access to bls courses as well as providing these to the general public at workplaces and universities to increase awareness of the importance of prompt initiation of cpr. future studies will be necessary to assess the effect of such efforts on the rates of bystander cpr. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. becker l, eisenberg m, fahrenbruch c, cobb l. public locations of cardiac arrest. implications for public access defibrillation. circulation 1998; 97:2106–9. https://doi.org/10.1161/01.cir.97.21.2106. 2. de vreede-swagemakers jj, gorgels ap, dubois-arbouw wi, van ree jw, daemen mj, houben lg, et al. out-of-hospital cardiac arrest in the 1990's: a population-based study in the maastricht area on incidence, characteristics and survival. j am coll cardiol 1997; 30:1500–5. https://doi.org/10.1016/s07351097(97)00355-0. 3. lindner tw, soreide e, nilsen ob, torunn mw, lossius hm. good outcome in every fourth resuscitation attempt is achievable - an utstein template report from the stavanger region. resus citation 2011; 82:1508–13. https://doi.org/10.1016/j.resuscitati on.2011.06.016. 4. roger vl, go as, lloyd-jones dm, benjamin ej, berry jd, borden wb, et al. executive summary: heart disease and stroke statistics -2012 update: a report from the american heart association. circulation 2012; 125:188–97. https://doi. org/10.1161/cir.0b013e3182456d46. 5. waalewijn ra, de vr, tijssen jg, koster rw. survival models for out-of-hospital cardiopulmonary resuscitation from the perspectives of the bystander, the first responder, and the paramedic. resuscitation 2001; 51:113–22. https://doi. org/10.1016/s0300-9572(01)00407-5. 6. hazinski mf, nolan jp, billi je, bottiger bw, bossaert l, de caen ar, et al. part 1: executive summary: 2010 inter national consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment reco mmendations. circulation 2010; 122:s250–75. https://doi. org/10.1161/circulationaha.110.970897. https://doi.org/10.1161/01.cir.97.21.2106 https://doi.org/10.1016/s0735-1097%2897%2900355-0 https://doi.org/10.1016/s0735-1097%2897%2900355-0 https://doi.org/10.1016/j.resuscitation.2011.06.016 https://doi.org/10.1016/j.resuscitation.2011.06.016 https://doi.org/10.1161/cir.0b013e3182456d46 https://doi.org/10.1161/cir.0b013e3182456d46 https://doi.org/10.1016/s0300-9572%2801%2900407-5 https://doi.org/10.1016/s0300-9572%2801%2900407-5 https://doi.org/10.1161/circulationaha.110.970897 https://doi.org/10.1161/circulationaha.110.970897 determinants of provision of bystander cardiopulmonary resuscitation among the general public in oman e384 | squ medical journal, november 2020, volume 20, issue 4 7. abella bs, aufderheide tp, eigel b, hickey rw, longstreth wt, jr., nadkarni v, et al. reducing barriers for implementation of bystander-initiated cardiopulmonary resuscitation: a scient ific statement from the american heart association for health care providers, policymakers, and community leaders regarding the effectiveness of cardiopulmonary resuscitation. circulation 2008; 117:704–9. https://doi.org/10.1161/circulationah a.107.188486. 8. ong me, shin sd, de souza nn, tanaka h, nishiuchi t, song kj, et al. outcomes for out-of-hospital cardiac arrests across 7 countries in asia: the pan asian resuscitation outcomes study (paros). resuscitation 2015; 96:100–8. https://doi.org/10.10 16/j.resuscitation.2015.07.026. 9. riva g, ringh m, jonsson m, svensson l, herlitz j, claesson a, et al. survival in out-of-hospital cardiac arrest after standard cardiopulmonary resuscitation or chest compressions only before arrival of emergency medical services: nationwide study during three guideline periods. circulation 2019. https://doi. org/10.1161/circulationaha.118.038179. 10. nadar sk, mujtaba m, al-hadi h, sadiq m, al-riyami a, ali m, et al. epidemiology, outcomes and coronary angiography findings of patients following out-of-hospital cardiac arrest: a single-centre experience from oman. sultan qaboos univ med j 2018; 18:e155–60. https://doi.org/10.18295/squmj.20 18.18.02.006. 11. jarrah s, judeh m, aburuz me. evaluation of public awareness, knowledge and attitudes towards basic life support: a crosssectional study. bmc emerg med 2018; 18:37. https://doi. org/10.1186/s12873-018-0190-5. 12. vaillancourt c, grimshaw j, brehaut jc, osmond m, charette ml, wells ga, et al. a survey of attitudes and factors associated with successful cardiopulmonary resuscitation (cpr) knowledge transfer in an older population most likely to witness cardiac arrest: design and methodology. bmc emerg med 2008; 8:13. https://doi.org/10.1186/1471-227x-8-13. 13. al-mohaissen ma. knowledge and attitudes towards basic life support among health students at a saudi women's university. sultan qaboos univ med j 2017; 17:e59–65. https://doi. org/10.18295/squmj.2016.17.01.011. 14. al-turki ya, al-fraih ys, jalaly jb, al-maghlouth ia, alrashoudi fh, al-otaibi af, et al. knowledge and attitudes towards cardiopulmonary resuscitation among university students in riyadh, saudi arabia. saudi med j 2008; 29:1306–9. 15. alotaibi o, alamri f, almufleh l, alsougi w. basic life support: knowledge and attitude among dental students and staff in the college of dentistry, king saud university. saudi j dent res 2016; 7:51–6. https://doi.org/10.1016/j.sjdr.2015.06.001. 16. merrigan ho. are there any cultural barriers to automated external defibrillator use in middle eastern countries? circulation 2018; 124:a229. 17. wood s. hands off my wife! bahrain aed survey points to cpr barriers. 2012. from: https://www.medscape.com/ viewarticle/762456 accessed: jun 2020 18. ozbilgin s, akan m, hanci v, aygun c, kuvaki b. evaluation of public awareness, knowledge and attitudes about cardio pulmonary resuscitation: report of izmir. turk j anaesthesiol reanim 2015; 43:396–405. https://doi.org/10.5152/tjar.201 5.61587. 19. chen m, wang y, li x, hou l, wang y, liu j, et al. public knowledge and attitudes towards bystander cardiopulmonary resuscitation in china. biomed res int 2017; 2017:3250485. https://doi.org/10.1155/2017/3250485. 20. cho gc, sohn yd, kang kh, lee ww, lim ks, kim w, et al. the effect of basic life support education on laypersons' willingness in performing bystander hands only cardiopulmonary resuscitation. resuscitation 2010; 81:691–4. https://doi.org/10.10 16/j.resuscitation.2010.02.021. 21. good samaritan laws and cpr. from: https://www. emergencyfirstresponse.com/good-samaritan-laws-and-cpr/ accessed: jun 2020. 22. dajani h. new 'good samaritan' law set to be finally introduced in uae. from: https://www.thenational.ae/uae/health/new g o o d s a m a r i t a n l aw s e tt o b e fi n a l l y i n t r o d u c e d i n uae-1.808998 accessed: jun 2020. 23. alshaqsi s, alwahaibi k, alrisi a. wasted potential: awareness of basic cardiopulmonary resuscitation in the sultanate of oman a cross-sectional national survey. j emerg med intensive care 2015; 1:105. https://doi.org/10.1161/circulationaha.107.188486 https://doi.org/10.1161/circulationaha.107.188486 https://doi.org/10.1016/j.resuscitation.2015.07.026 https://doi.org/10.1016/j.resuscitation.2015.07.026 https://doi.org/10.1161/circulationaha.118.038179 https://doi.org/10.1161/circulationaha.118.038179 https://doi.org/10.18295/squmj.2018.18.02.006 https://doi.org/10.18295/squmj.2018.18.02.006 https://doi.org/10.1186/s12873-018-0190-5 https://doi.org/10.1186/s12873-018-0190-5 https://doi.org/10.1186/1471-227x-8-13 https://doi.org/10.18295/squmj.2016.17.01.011 https://doi.org/10.18295/squmj.2016.17.01.011 https://doi.org/10.1016/j.sjdr.2015.06.001 https://doi.org/10.5152/tjar.2015.61587 https://doi.org/10.5152/tjar.2015.61587 https://doi.org/10.1155/2017/3250485 https://doi.org/10.1016/j.resuscitation.2010.02.021 https://doi.org/10.1016/j.resuscitation.2010.02.021 free radicals are atoms that contain an unpaired valence electron that renders them chemically unstable and highly reactive. free radicals are capable of damaging biological molecules such as nucleic acids, proteins, carbohydrates and lipids leading to cell damage and/or cell death.1 these atoms result from normal metabolic processes in the human body as well as from environmental exposure to harmful rays, ozone, cigarette smoking, air pollutants and ind ustrial chemicals.1 antioxidants are compounds that donate electrons to neutralise free radicals and prevent their detrimental effects. diet is an important source of antioxidants as fruits and vegetables are rich in anti oxidants such as polyphenols, vitamin e, vitamin c and minerals such as selenium. glutathione is a major endo genous antioxidant which is produced in the intracell ular compartment.2 the balance between the oxidising effects of free radicals and the reducing power of anti oxidants is referred to as “redox homeostasis”.3 oxidative stress in humans occurs as a result of the imbalance between free radical production in cells and tissues and the ability of natural antioxidant defences to detoxify them. exposure to oxidative stress has escal ated in modern societies as a result of increased exp osure to harmful oxidants in various aspects of life—incl uding diet, industrial pollution, chemicals, medications, smoking, pesticides and many more. imbalance in the redox state renders the human body more vulnerable to an array of disorders and chronic diseases such as cancer, heart disease, neurological disorders and other diseases linked to aging and disturbed immune function.4–6 the international society of antioxidants in nutrition and health (isanh) is a non-profit organisation based in paris, france.7 the general aim of this society is to address various factors affecting the redox balance in health and disease, particularly the role of natural and supplemental antioxidants. isanh conducts regular meetings to encourage communication among resear chers, physicians, nutritionists, industry specialists, food technology and strategic marketing managers through global antioxidant networks to enhance knowledge and share ground-breaking discoveries regarding antioxidants, their advantages/disadvantages and provide recommend ations to decision-makers and institutions about the latest trends in the field. disorders resulting from oxidative stress are prev alent worldwide, including middle eastern countries. while the affluent countries in the middle east have been exposed to the negative effects of industrialisation, their lower income counterparts suffer from a lack of modernisation and healthcare awareness. the isanh has posed various questions such as ‘what are the determinants of oxidative stress related disorders in the middle east?’, ‘are preventive and intervention measures handled effectively?’, ‘what are the risks of uncontrolled consumption of synthetic antioxidant supplements?’ and ‘are natural antioxidant resources appreciated and efficiently utilised?’ amongst others. as a result, the isanh recently established its branch in the middle east, named the international society of antioxidants in nutrition and health-middle east (isanh-me), to find answers, share experiences and address matters of regional interest.7 isanh-me has recently conducted several annual regional meetings in parallel with the european-based version. isanh-me meetings started in dubai, united arab emirates (uae), in 2016, followed by meetings in beirut, lebanon, and amman, jordan, in 2017 and 2018, respectively.8 the fourth isanhme congress was held at sultan qaboos university, muscat, oman, in march 2019.7 a total of 53 prominent speakers from 23 countries all over the world partic ipated in the congress. a significant number of contrib utions were made from local researchers and graduate students from different colleges in oman. the congress 1department of biochemistry, sultan qaboos university, muscat, oman; 2department of cancer, development & reproduction; university paris descartes, cochin institute-inserm, paris, france; 3department of pathology & medical biology, university of groningen, groningen, the netherlands *corresponding author's e-mail: jumana@squ.edu.om املكمالت الغذائية املضادة لألكسدة واإلجهاد التأكسدي ميتد اجلدل إىل الشرق األوسط جمانة �صالح، مارفني �إديا�س، هاري فان غور antioxidant supplements and oxidative stress the debate extends to the middle east *jumana saleh,1 marvin edeas,2 harry van goor3 editorial sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e177–180, epub. 5 nov 19 submitted 29 jul 19 revision req. 12 sep 19; revision recd. 26 sep 19 accepted 1 oct 19 https://doi.org/10.18295/squmj.2019.19.03.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ antioxidant supplements and oxidative stress the debate extends to the middle east e178 | squ medical journal, august 2019, volume 19, issue 3 sessions were designed to be integrative in nature, spanning basic, translational and clinical applications. three main themes were addressed: 1) redox in health and nutrition, 2) redoxmicrobiota links and 3) waste valorisation (i.e. recycling) to retrieve active biomolec ules including antioxidants and biofuel components. this editorial aimed to summarise the main aspects discussed during that congress. considering the first theme, participants demonst rated in vivo and in vitro findings emphasising the role of oxidative stress in disease progression in several ail ments including cancer, metabolic, cardiovascular, gastrointestinal, reproductive and age-related disorders. mechanisms of disease progression and potential therap eutic roles of antioxidants were discussed.9 advanced techniques for measuring antioxidants in biological materials were demonstrated. new findings highlighting that the redox status was a significant disease determ inant and, in some cases, outperformed other markers of disease severity supporting previous findings.9,10 oxidative stress was linked to hormonal variations in women and was implicated in polycystic ovary syn drome, which is common among omani women.11,12 two independent studies conducted by researchers in oman highlighted that homocysteine, a pro-oxidant marker, was a predictive determinant of oxidative stress among omani women, which could be improved by antioxidant supplementation.10 the middle east is rich in natural resources; anti oxidants extracted from natural products and their therapeutic potential, was a predominant aspect of several presentations at this congress.8 oman has an abundance of original natural resources, particularly with its extended coastal line and diverse marine and terrestrial ecosystems. speakers from oman and others presented promising novel findings of products extracted from local plants and marine sources that were proposed to be protective against oxidative stress-related conditions, in particular cancer progression. for example, fucoidans extracted from the seaweed sargassum ilicifolium exhibited protective effects against gastric cancer in rats.13 in another study, bioactive agents extracted from natural and edible wild plants found in oman were suggested to provide protection against oxidative stress-induced colon cancer through their antioxidant properties. extracts from the seasonal “desert truffle” were shown to exhibit strong antioxidant and anticancer activities. also, steroidal glycoalkaloids extracted from local thorn apple or bitter apple (solanum incanum) plants, which are abundant in oman, selectively inhibited the proliferation of the worst type of melanoma by inducing oxidative damage and apoptosis of melanoma cancer cell lines.10 moreover, omani researchers revealed that date extracts exhibited antifibrotic effects that could prevent certain pancreatic pathologies. in another local study, date fruit fibre was proposed as a functional food ingredient for its numerous health benefits.10 in spite of promising findings regarding the therapeutic role of antioxidants in fighting against the progression of oxidative stress-related diseases, the consumption of antioxidant supplements, whether natural or synthetic, has become a major area of con troversy regarding safe supplementation in terms of dosage and type of antioxidant. this debate was trigg ered by evidence showing that naturally induced oxidative stress is not always harmful. in fact, oxidants are necessary for several biological processes and mild oxidative stress has regulatory and protective roles against certain diseases especially cancer cell proliferation.14,15 hence antioxidant supplements, in spite of their renowned benefits, may be viewed as a double-edged sword as they could hinder natural oxidant defences targeting cancer cell proliferation.15 this long-debated issue was strongly addressed during most recent isanh-me congress. the “key note” lecture, presented by professor martin bergö, a leading researcher in the field from the karolinska institute in sweden, and a member of the nobel prize assembly, showed new evidence suggesting that long-term supplementation with the antioxidants n-acetylcysteine and vitamin e hampered protective natural oxidant defence mechanisms leading to enhanced lung cancer metastasis.8 these findings supported prev ious findings that showed similar results involving melanoma metastasis.14,16 further evidence was presented by researchers from lebanon and brunei showing that the protective anticancer effects of thymoquinone, an active ingredient of black seeds, was attributed to its pro-oxidant effects by inducing apoptosis of cancerous cells via the generation of reactive oxygen species.10 the second theme of the congress highlighted major links between antioxidants and the revolutionary topic of “microbiota”.10,17 the human microbiome is comprised of thousands of various types of bacteria that facilitate digestion, produce vitamins and enhance immunity.18,19 researchers in this field presented findings reflecting that the gut microbiome and overall health were significantly enhanced by antioxidants. for example, antioxidant rich formulated fruits and vegetable supplementation diets caused significant favourable changes on the human microbiome and increased plasma antioxidant levels. interestingly, lycopene and dark chocolate polyphenols, the molecules conventionally considered to be antioxidants, were shown to exert unexpected properties as powerful prebiotics and were found to be 1,000-folds stronger than fibre. in addition, camel milk, a common beverage in some middle eastern regions, was found to contain bacillus subtilis strains that were proposed to have promising probiotic advantages.10 jumana saleh, marvin edeas and harry van goor editorial | e179 the third theme highlighted the importance of recovery of antioxidants from food waste in the middle east.10 the value of food waste stems from the rich content of bioactive molecules, antioxidants and fibres that may be useful in food, pharmaceutical, cosmetic and nutraceutical industries. so far, these sub stances constitute an underexploited source for the recovery and production of natural compounds. in the middle east, excessive food waste disposal is reflected in more than one trillion dollars’ worth of food wasted each year.10 food waste in the middle east includes organic wastes generated in hotels, restaurants, canteens, cafeterias, shopping malls and food industries. professor richard maroun from saint joseph university in lebanon, stressed the importance of developing strategic plans to solve this growing issue in the middle east.10 suggestions were proposed to purify natural antioxidant molecules from food waste and by-products through innovative technologies in order to reintegrate them as valuable additives in several industrial products. for example, extraction of polyphenols from olive leaves and pome granate peels, that are widely cultivated in the middle east, appears promising. during harvesting, lost olive leaves represent up to 25% of the total weight of olives and are generally disposed as waste with no further specific use in spite of their richness in highly bioactive polyphenols. new technologies for maximum extraction of phenolic compounds from olive leaves and pome granate peels based on infrared irradiation were also shown at the congress. researchers from iran presented findings proposing that the water by-product obtained after hydro-distillation of rose damascena could be cons idered as a valuable source of polyphenolic compounds.10 a very important aspect of waste valorisation is “bioenergy” which was suggested as a highly promising alternative to fossil-derived energy in a future bio-based economy. anaerobic digestion is one of the main elements in proposed energy transitions. industrial by-products from common middle eastern waste crops including grapes, olives, pomace, coffee grounds and their con version into methane was shown to be promising in waste management and bioenergy recovery.10 altogether, these findings aim to establish local and regional initiatives that focus on reliable strategies for better food waste and by-product management and valorisation. in summary, the themes of the fourth isanh-me congress held in oman highlighted predictors and mechanisms of disease progression linked to oxidative stress and redox imbalance. a major component was dedicated to antioxidants isolated from natural middle eastern products and their promising therapeutic roles. furthermore, several links between redox balance and the revolutionary science of microbiota were addressed. the effect of antioxidants in promoting a healthy micro biota was shown in several presentations. on the other hand, the challenging topic of antioxidant overcon sumption and their unsupervised usage as dietary supplements was addressed by leading researchers in the field. strong evidence was presented regarding the dangers of overusing certain antioxidants and their role in promoting cancer progression and metastasis, a topic resonating with the growing interest in cancer research in oman. the vital issue of food waste re cycling in the middle east was emphasised with recent statistics showing excessive food waste disposal in the region. strategies of food waste recycling to retrieve essential by-products including antioxidants and biofuels and importance of developing strategic plans to solve this issue were discussed. these included purification of useful waste products and their reintegration as food additives, methods to enhance antioxidant yields and using bioenergy from waste by-products as fossil fuel alternatives. references 1. lobo v, patil a, phatak a, chandra n. free radicals, antioxidants and functional foods: impact on human health. pharmacogn rev 2010; 4:118–26. https://doi.org/10.4103/0973-7847.70902. 2. valko m, leibfritz d, moncol j, cronin mt, mazur m, telser j. free radicals and antioxidants in normal physiological functions and human disease. int j biochem cell biol 2007; 39:44–84. https://doi.org/10.1016/j.biocel.2006.07.001. 3. young is, woodside jv. antioxidants in health and disease. j clin pathol 2001; 54:176–86. https://doi.org/10.1136/jcp.54.3.176. 4. saha sk, lee sb, won j, choi hy, kim k, yang gm, et al. correlation between oxidative stress, nutrition, and cancer initiation. int j mol sci 2017; 18:e1544. https://doi.org/10.3390/ ijms18071544. 5. vona r, gambardella l, cittadini c, straface e, pietraforte d. biomarkers of oxidative stress in metabolic syndrome and asso ciated diseases. oxid med cell longev 2019; 2019:8267234. https://doi.org/10.1155/2019/8267234. 6. liguori i, russo g, curcio f, bulli g, aran l, della-morte d, et al. oxidative stress, aging, and diseases. clin interv aging 2018; 13:757–72. https://doi.org/10.2147/cia.s158513. 7. international society of antioxidants in nutrition and health. 21st isanh redox congress & 4th isanh middle east world congress 2019. from: www.isanh.com/?q=node/328 accessed: sep 2019. 8. international society of antioxidants in nutrition and health. from: www.isanh.com/?q=previous-conferences accessed: sep 2019. 9. schillern eem, pasch a, feelisch m, waanders f, hendriks sh, mencke r, et al. serum free thiols in type 2 diabetes mellitus: a prospective study. j clin transl endocrinol 2019; 28:100182. https://doi.org/10.1016/j.jcte.2019.100182. 10. fourth international society of antioxidants in nutrition and health-middle east congress proceedings. archives of inter national society of antioxidants. volume 6, issue 4, 2019. pp. 7–42, 44, 45, 47, 48, 50–52, 54–58. [unpublished] 11. al-khaduri mm, al-farsi ym, al najjar taa, gowri v, hosp ital-based prevalence of polycystic ovarian syndrome among omani women. middle east fertil soc j 2014; 2:135–8. https:// doi.org/10.1016/j.mefs.2013.06.006. https://doi.org/10.4103/0973-7847.70902 https://doi.org/10.1016/j.biocel.2006.07.001 https://doi.org/10.1136/jcp.54.3.176 https://doi.org/10.3390/ijms18071544 https://doi.org/10.3390/ijms18071544 https://doi.org/10.1155/2019/8267234 https://doi.org/10.2147/cia.s158513 https://doi.org/10.1016/j.jcte.2019.100182 https://doi.org/10.1016/j.mefs.2013.06.006 https://doi.org/10.1016/j.mefs.2013.06.006 antioxidant supplements and oxidative stress the debate extends to the middle east e180 | squ medical journal, august 2019, volume 19, issue 3 12. sulaiman ma, al-farsi ym, al-khaduri mm, saleh j, waly mi. polycystic ovarian syndrome is linked to increased oxidative stress in omani women. int j womens health 2018; 10:763–71. https://doi.org/10.2147/ijwh.s166461. 13. al-muqbali mhs, al-alawi a, waly mi, rahman ms. anti cancer properties of fucoidans extracted from brown seaweed (sargassum ilicifolium) in a rat model of gastric cancer. can j clin nutr 2019; 7:43–61. https://doi.org/10.14206/canad.j.clin. nutr.2019.02.04. 14. piskounova e, agathocleous m, murphy mm, hu z, huddlestun se, zhao z, et al. oxidative stress inhibits distant metastasis by human melanoma cells. nature 2015; 527:186–91. https://doi.org/10.1038/nature15726. 15. sarangarajan r, meera s, rukkumani r, sankar p, anuradha g. antioxidants: friend or foe? asian pac j trop med 2017; 10:1111–16. https://doi.org/10.1016/j.apjtm.2017.10.017. 16. le gal k, ibrahim mx, wiel c, sayin vi, akula mk, karlsson c, et al. antioxidants can increase melanoma metastasis in mice. sci transl med 2015; 7:308re8. https://doi.org/10.1126/scitra nslmed.aad3740. 17. international society of microbiota. about ism. from: https:// www.microbiota-site.com/about-ism.html accessed: sep 2019. 18. kamada n, seo su, chen gy, núñez g. role of the gut microbiota in immunity and inflammatory disease. nat rev immunol 2013; 13:321–35. https://doi.org/10.1038/nri3430. 19. holzapfel wh, haberer p, snel j, schillinger u, huis in't veld jh. overview of gut flora and probiotics. int j food microbiol 1998; 41:85–101. https://doi.org/10.1016/s0168-1605(98)00044-0. https://doi.org/10.2147/ijwh.s166461 https://doi.org/10.14206/canad.j.clin.nutr.2019.02.04 https://doi.org/10.14206/canad.j.clin.nutr.2019.02.04 https://doi.org/10.1038/nature15726 https://doi.org/10.1016/j.apjtm.2017.10.017 https://doi.org/10.1126/scitranslmed.aad3740 https://doi.org/10.1126/scitranslmed.aad3740 https://doi.org/10.1038/nri3430 https://doi.org/10.1016/s0168-1605%2898%2900044-0 college of medicine, al imam mohammad ibn saud islamic university, riyadh, saudi arabia *corresponding author’s e-mail: nasr_99_7@hotmail.com معرفة الوالدين واإلجتاهات واملمارسات خبصوص إلتهابات األذن لدى األطفال يف مدينة الرياض باململكة العربية السعودية دراسة كمية متعب مو�شى احلربي، حممد �شعود امل�رشي، عبدالرحمن يو�شف الدايل، �شالح من�شور اخلنيزان abstract: objectives: this study aimed to assess the knowledge, attitude and care-seeking practices of parents towards childhood ear infections in riyadh, saudi arabia. methods: this quantitative cross-sectional study was conducted in riyadh, saudi arabia, between april and june 2018. an online survey was sent to a random selection of parents who were ≥18 years old with children of ≤10 years old. associations between parental knowledge, attitude, care-seeking practices, socioeconomic status, level of education and age were assessed using the chi square test and logistic regression analysis. results: a total of 782 subjects participated in this study (response rate: 78.2%). most respondents were knowledgeable (76.2%), had a positive attitude (78.9%) and had positive care-seeking practices (89.5%). there was a statistically significant difference on both bivariate and multivariate analyses (p <0.05) between parental care seeking practice and knowledge. parents who sought modern approaches to treatment were found to be almost nine times more likely to have a good attitude towards ear infections than those who did not seek treatment (odds ratio = 8.907, 95% confidence interval = 2.655–34.928; p <0.001). a statistically significant relationship was found between good care-seeking practice and age, as well as socioeconomic status (p <0.05 each). conclusion: this study showed that knowledge, attitude and practice regarding paediatric ear infections were positive in the majority of parents in riyadh, saudi arabia. future studies should assess other factors that enhance the knowledge, attitude and practices regarding ear infections. keywords: otitis media; infection; knowledge; attitude; pediatrics; parents; saudi arabia. امللخ�ص: الهدف: تهدف هذه الدرا�شة لقيا�س املعرفة و االإجتاهات واملمار�شات للبحث عن الرعاية ال�شحية لدى االأطفال امل�شابني باإلتهابات االأذن يف مدينة الريا�س باململكة العربية ال�شعودية. الطريقة: هذه الدرا�شة مقطعية و مت اإجرائها يف مدينة الريا�س باململكة العربية ال�شعودية يف الفرتة مابني اأبريل و يونيو عام 2018م عن طريق اإ�شتبيان اإلكرتوين مت اإر�شاله ملجموعة من االأباء و االأمهات و الذين مت اإختيارهم ع�شوائيا ممن يبلغون 18 ع�رش عاما و اأكرث و لديهم اأطفال يبلغون ع�رشة �شنني و اأقل وذلك لتحديد م�شتوى املعرفة و االإجتاهات و املمار�شات للبحث عن الرعاية ال�شحية لالأطفال امل�شابني باإلتهابات االأذن، وقد مت احل�شول على امل�شتوى االجتماعي و االقت�شادي و امل�شتوى التعليمي و العمر حيث مت الربط بني هذه العوامل و قيا�شها عن طريق اإختبار مربع كاي. النتائج: �شارك يف هذه الدرا�شة 782 �شخ�شا حيث كانت ن�شبة التجاوب مع االإ�شتبيان املر�شل )%78.2(. و كان معظم امل�شاركني لديهم معرفة باإلتهابات االأذن و ن�شبتهم )%76.2(. و �شكلت التوجهات االإيجابية )p >0.05( وكان هنالك فرق ذو دالالت اإح�شائية على املتغريات الثنائية و املتعددة .)78.9(، و�شكلت ن�شبة املمار�شات االإيجابية )%89.5%( بني ممار�شات الوالدين نحو اإلتهابات االأذن و املعرفة. ولقد تبني اأن االأباء و االأمهات الذين �شعوا اإىل طرق عالجية حديثة لديهم توجهات جيدة 9 مرات مقارنة مبن مل يبحثوا عن العالج بالطرق احلديثة )حيث �شكلت ن�شبة االأرجحية = 8.907، وقد �شكل جمال الثقة %95: 2.655–34.928؛ p >0.001(، وقد مت العثور على عالقة ذات داللة اإح�شائية بني املمار�شات اجليدة للرعاية و العمر باالإ�شافة للو�شع االجتماعي و االقت�شادي. اخلال�صة: لقد و�شحت الدرا�شة احلالية املعرفة و االجتاهات و املمار�شات نحو اإلتهابات االأذن لدى االطفال و تعترب النتيجة اإيجابية لدى اأغلب االأباء و االأمهات امل�شاركني يف الدرا�شة التي اأقيمت يف مدينة الريا�س باململكة العربية ال�شعودية ويو�شي الباحثني بالقيام بدرا�شات اأخرى م�شتقبلية لقيا�س عوامل اأخرى و زيادة الوعي باإلتهاب االأذن لدى االأطفال. الكلمات املفتاحية: اإلتهاب االأذن الو�شطى؛ العدوى؛ املعرفة؛ ال�شلوك؛ االأطفال؛ الوالدين؛ ال�شعودية. parental knowledge, attitudes and practices towards paediatric ear infections in riyadh, saudi arabia a quantitative study *muteb m. alharbi, mohammed s. almasri, abdulrahman y. aldayel, saleh m. alkhonezan sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e114–121, epub. 8 sep 19 submitted 15 oct 18 revision req. 12 dec 18; revision recd. 10 jan 19 accepted 7 feb 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge the current study showed that parental knowledge of, attitude towards and care-seeking practice for paediatric ear infections were generally positive in more than two-thirds of the parents living in riyadh, saudi arabia, in 2018. higher educational level and socioeconomic status were the main factors responsible for better parental knowledge, attitude and careseeking practice for paediatric ear infections. https://doi.org/10.18295/squmj.2019.19.02.006 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ muteb m. alharbi, mohammed s. almasri, abdulrahman y. aldayel and saleh m. alkhonezan clinical and basic research | e115 in developing countries, ear diseases are considered a major public health problem with the potential to affect the psychological and social health of children and their families.1,2 among ear diseases, ear infections are one of the most common infectious diseases in children.2 many studies have shown that the majority of children (approximately 80%) will experience at least one episode of otitis media by three years of age and 40% will have at least six recurr ences before the age of seven.3–5 otitis media is defined as the inflammation of the mucosa of the middle ear, including the tympanic cavity, eustachian tube, mastoid antrum and mastoid air cells and can be caused by bacterial or viral infections.6–8 otitis media is subdivided into acute otitis media (aom), otitis media with effusion (ome), recurrent acute otitis media and chronic suppurative otitis media (csom).7 aom presents acutely with both local and systemic signs such as otalgia and fever.9–11 in some cases, aom causes an ear discharge from a perforated tympanic membrane, which may heal spontaneously with in 2–14 days.11 ome usually occurs after the inflammation of the aom has resolved.12 csom involves ongoing inflammation and persistent ear discharge for more than 14 days with perforation of the tympanic membrane.13 children with csom may not only present with per sistent discharge refractory to medical treatment but may also have hearing loss or tinnitus.5 in some cases of csom, treatment involves both antibiotic ear drops and surgical repair of the perforated tympanic membrane.14 furthermore, csom is associated with serious complic ations such as mastoiditis, facial nerve paralysis, neck abscess, brain abscess, meningitis, labyrinthitis and lateral sinus thrombosis.5,11,14 globally, an estimated 330 million individuals have had csom; 60% had hearing loss and the majority were children.5,15 hearing loss in children may impede language, cognitive and psychosocial dev elopment as well as early communication and school performance.5,14 even in adulthood, hearing loss can be a challenge when seeking employment.5 the complic ations of otitis media result in 28,000 annual deaths globally with meningitis and brain abscesses being the main life-threatening complications.14 otitis media is associated with many risk factors including passive smoking, bottle feeding, short dur ation of breastfeeding, day-care attendance, low socio economic status, upper respiratory tract infections, aller gies and has a male preponderance.16–19 some of these risk factors are modifiable;20 therefore, the prevalence of otitis media can be reduced if parents have the knowledge and willingness to make the appropriate lifestyle alterations.21 however, srikanth et al. found that most parents underestimate the risk of otitis media.21 although otitis media is mostly self-limiting it is the most frequent reason for antibiotic prescriptions for children.7,18 furthermore, most developing countries do not have guidelines for the antibiotic treatment of otitis media and parents/caregivers can obtain antibacterial drugs without prescription.7 consequently, multiple resistance to antibiotics has been increasing.6 this study aimed to assess the knowledge, attitude and careseeking practices of parents towards childhood ear infections in riyadh, saudi arabia. methods this quantitative cross-sectional study was conducted between april and june 2018 in riyadh, saudi arabia. a total of 1,000 saudi arabian parents who were ≥18 years old with children ≤10 years old were invited to participate in this online-based study. for the selection process, riyadh city was divided into five parts: north, east, south, west and central. a nursery school and a primary school were randomly selected from each part. each selected nursery school and primary school was requested to provide the telephone numbers of parents of children ≤10 years of age (i.e. all nursery school students and primary school students up to and including 4th grade). participants received an online questionnaire with an explanation of the purpose of the study and an informed consent form prior to the completion of the questionnaire. the questionnaire was adapted with permission from mukara et al. and translated to arabic.5 the translation process included cross-cultural validation of the questionnaire and review by a committee of translation at al imam mohammad ibn saud islamic university, riyadh, saudi arabia, in addition to a senior otolaryngologist. each survey response was linked with an internet protocol address to prevent duplicates. the self-administrated questionnaire included 12 items that assessed the parental knowledge of, attitude towards and care-seeking practice for paediatric ear application to patient care the results of the study will help the saudi arabian ministry of health and the saudi otolaryngology society to identify which population groups should be selected for educational programmes. this study emphasised improvements in parental knowledge, attitude and care-seeking practice to avoid complications of ear infections and reduce the cost of treatment. parental knowledge, attitudes and practices towards paediatric ear infections in riyadh, saudi arabia a quantitative study e116 | squ medical journal, may 2019, volume 19, issue 2 infections. it comprised of close-ended and multiple choice questions subdivided into three main sections: seven general knowledge (causes, symptoms, prevention, treatment and consequences of ear infections), two questions on parental attitude towards ear infections and one question each on parental practice for ear infections, health services and the incidence of ear disease in the participant’s child. causes of ear infection include poor hygiene, water in the ears, wax and foreign body and/or microbes. participants who knew one or more correct cause scored one point (i.e. discharge, hearing loss and pain). participants who knew two of the three symptoms obtained one point. participants selected “yes” or “no” for the prevention and treatment questions and obtained one point for each correct answer. participants who identified one or more correct consequences obtained one point. participants who scored >50% were considered knowledgeable about ear infections. participants who answered that they would seek care from a medical doctor or nurse for their child’s ear infection were considered to have good practice. reasons for not taking their child to a health centre included “not being worried”, “no need for treatment” and being “incurable” were considered a negative attitude. participants who chose media, health professional, health campaigns or community outreach as information sources were considered to have a positive attitude. participants who had a total score of >50% were considered to have a positive attitude overall. the questionnaire included demographic variables (age, gender, educational level and socioeconomic status). to ensure reliability and validity, a pilot study was conducted with 10 parents to improve the questionn aire’s face/content validity and prevent discrepancies in the parents’ responses. statistical analysis was performed using rstudio, version 1.1.149 (rstudio inc., boston, massachusetts, usa). categorical variables were presented as frequen cies and percentages. the chi square test and logistic regression analysis were used to obtain associations between knowledge of the parents, socioeconomic status, level of education, age and care-seeking practices. a p value of <0.05 was considered statistically significant. this study protocol was approved by the instit utional review board of al-imam muhammad ibn saud islamic university. results a total of 839 responses were received, of which 782 were complete and 57 were excluded from the study due to missing data (response rate: 78.2%). most partic ipants (61.8%) were female and ranged from 18–64 years with a mean age of 33.9 ± 9 years. the majority of respondents completed a secondary level of education (73.5%) and reported a middle socioeconomic status (80.9%) [table 1]. most participants reported having information about ear infections (58.6%), most of which knew that ear infections are treatable (93.7%) and can be prevented (70.7%). the majority reported at least one correct symptom (55.9%) and only 96 (12.3%) did not know any correct symptoms. the most commonly-listed symptom was pain in the infected ear (79%), followed by ear discharge from the infected ear (35.7%). the vast majority of participants reported at least one correct consequence of ear infections (95%); hearing loss was the most reported consequence (67.6%) [table 2]. on bivariate analysis, fathers were found to be significantly less knowledgeable compared to mothers about ear infections (odds ratio [or] = 0.4, 95% confi dence interval [ci] = 0.29–0.56; p <0.001). parents who completed their secondary education were four times more likely to be knowledgeable about ear inf ections compared to their uneducated counterparts (or = 4.13, ci: 1.13–15.09; p = 0.03); this finding was still significant after adjustment for other factors (or = 5.79, ci = 1.42–23.78; p = 0.007). vocational education was a significant predictor of good knowl edge after adjustment for confounders (or = 5.06, table 1: characteristics of parents ≥18 years old with children of ≤10 years old who participated in this study in riyadh, saudi arabia (n = 782) characteristics n (%) gender female 483 (61.8) male 299 (38.2) age in years ≤30 320 (40.9) 31–45 386 (49.4) 46–60 71 (9.1) >60 5 (0.6) education none 10 (1.3) primary 172 (22) secondary 575 (73.5) vocational 25 (3.2) socioeconomic status low 67 (8.6) middle 633 (80.9) high 82 (10.5) muteb m. alharbi, mohammed s. almasri, abdulrahman y. aldayel and saleh m. alkhonezan clinical and basic research | e117 ci = 0.98–27.48; p = 0.03). middle and high socio economic statuses were significant only before adjust ment (p <0.001 each). there was a statistically signif icant correlation between a pluralistic approach to parental ear care-seeking practice and knowledge after the adjustment for potential confounders (or = 43.2, ci = 6.84–858.21; p = 0.004); this illustrates the benefit of knowledge about ear infections [table 3]. overall, most parents (78.9%) had a positive attitude towards paediatric ear infections [table 4]. there were no statistically significant correlations between attitude and gender, age, educational level or socioeconomic status. however, care-seeking practice was significantly associated with attitude on a bivariate analysis. the odds of having good attitude towards ear infections among parents who sought modern approaches was eight times higher than in parents who did not seek medical care (or = 8.25, ci = 2.55–31.30; p <0.001). this relation remained significant even after the adjust ment of other factors (or = 8.97, ci = 2.65–34.92; p <0.001). similarly, the odds were also higher in parents who practice pluralism compared to parents who do not seek medical care (or = 11.11, ci = 2.89–49.64; p <0.001); this finding remained significant on multi variate analysis (or = 12.73, ci = 3.201–58.79; p <0.001) [table 5]. table 3: knowledge about paediatric ear infections stratified by participant’s characteristics (n = 782) characteristic unadjusted or (95% ci) p value* adjusted or (95% ci) p value† gender female male 0.4 (0.29–0.56) <0.001 0.45 (0.31–0.66) <0.001 age in years ≤30 31–45 0.78 (0.54–1.10) 0.161 1.13 (0.77–1.68) 0.672 46–60 1.24 (0.66–2.49) 0.507 2.23 (1.09–4.93) 0.037 >60 1.12 (0.16–22.09) 0.92 3.76 (0.37–103.38) 0.41 education none primary 1.77 (0.47–6.61) 0.379 2.80 (0.68–11.63) 0.119 secondary 4.13 (1.13–15.09) 0.03 5.79 (1.42–23.78) 0.007 vocational 2.57 (0.56–12.23) 0.222 5.06 (0.98–27.48) 0.03 socioeconomic status low middle 2.25 (1.32–3.77) <0.001 1.27 (0.69–2.28) 0.486 high 3.58 (1.69–7.91) <0.001 1.8 (0.78–4.28) 0.14 type of treatment parent would seek none traditional 19.25 (3.37–365.1) 0.006 15.74 (2.60–306.05) 0.036 modern 38.76 (7.45–711.57) 0.005 28.85 (5.25–541.24) 0.01 pluralism 53.9 (9.02–1,044.14) <0.001 43.2 (6.84–858.21) 0.004 or = odds ratio; ci = confidence interval. *using bivariate analysis. †using multivariate analysis. table 2: knowledge about ear infections among parents with children ≤10 years old in riyadh, saudi arabia (n = 782) item n (%) knowledge of correct symptoms of ear infections* none 96 (12.3) one symptom 437 (55.8) two symptoms 186 (23.8) three symptoms 63 (8.1) knowledge about prevention of ear infections yes 553 (70.7) no 229 (29.3) knowledge about treatment of ear infections yes 733 (93.7) no 49 (6.3) knowledge about causes of ear infections yes 642 (82.1) no 140 (17.9) knowledge about consequences of ear infections yes 743 (95) no 39 (5) consequences of ear infection* death 20 (2.6) infection spreads to organs 215 (27.5) i don’t know 3 (0.4) persistence of disease 280 (35.8) poor school performance 194 (24.8) hearing loss 529 (67.6) none 38 (4.9) overall knowledge (≥4 points) knowledgeable 596 (76.2) not knowledgeable 186 (23.8) *multiple responses could be chosen. parental knowledge, attitudes and practices towards paediatric ear infections in riyadh, saudi arabia a quantitative study e118 | squ medical journal, may 2019, volume 19, issue 2 the majority of parents had positive care-seeking practices (89.5%) and most preferred to seek treatment from a medical doctor (88.2%). very few parents stated that they would seek help from a traditional healer (1.7%) or not seek help at all (1.2%). the main reason for seeking alternative therapy was ignorance (48.5%) followed by poverty (35.7%) [table 4]. there was a significant association between age and care-seeking practice before and after the adjust ment of potential confounders. parents >45 years were more likely to have better care-seeking practice than parents <31 years (p <0.05). the odds of good careseeking practices were higher in parents who had a secondary level education compared to parents who had no education (or = 5.17, ci = 1.08–19.32; p = 0.02). parents with middle (or = 4.47, ci = 2.43–8.00; p <0.001) and high (or = 4.55, ci = 1.86–12.38; p <0.001) socio economic status were four times more likely to have positive practice regarding ear infections than parents with low socioeconomic status; this finding was also table 4: attitudes towards and care-seeking practices for paediatric ear infections among parents with children ≤10 years old in riyadh, saudi arabia (n = 782) item n (%) why would you seek alternative therapy* i don’t know 2 (0.3) it heals without any treatment 29 (3.7) no health insurance 194 (24.8) no need because no one can cure it 114 (14.6) no reason because it is on/off 201 (25.7) not worried about it/someone can live with it safely 84 (10.7) poverty 279 (35.7) ignorance 379 (48.5) where would you seek treatment* medical doctor 690 (88.2) nobody 9 (1.2) nurse 60 (7.7) pharmacist 55 (7) self-medication 102 (13) traditional healer/medicine 13 (1.7) source of information* health campaigns and community outreach programs 164 (21) health professional 452 (57.8) internet 464 (59.3) media 137 (17.5) no where 26 (3.3) family members or neighbours 160 (20.5) i don’t know 1 (0.1) overall attitude good 617 (78.9) bad 165 (21.1) overall care-seeking practice good 700 (89.5) bad 82 (10.5) *multiple responses could be chosen. table 5: attitude towards paediatric ear infections stratified by participant’s characteristics (n = 782) characteristic unadjusted or (95% ci) p value* adjusted or (95% ci) p value† gender female male 0.94 (0.66–1.34) 0.73 1.04 (0.71–1.55) 0.812 age in years ≤30 31–45 1.12 (0.78–1.61) 0.512 1.28 (0.86–1.89) 0.21 46–60 1.29 (0.69–2.58) 0.44 1.72 (0.87–3.63) 0.132 >60 1.16 (0.16–22.9) 0.894 2.15 (0.26–47.18) 0.527 education none primary 1.21 (0.25–4.55) 0.789 1.48 (0.29–5.89) 0.593 secondary 1.83 (0.39–6.7) 0.386 2.24 (0.45–8.8) 0.268 vocational 0.91 (0.16–4.3) 0.908 1.16 (0.2–5.82) 0.854 socioeconomic status low middle 1.36 (0.75–2.38) 0.284 0.92 (0.47–1.7) 0.799 high 1.95 (0.88–4.42) 0.103 1.18 (0.49–2.85) 0.699 type of treatment parent would seek none traditional 3.5 (0.97–14.5) 0.063 3.83 (1.03–16.31) 0.05 modern 8.25 (2.55–31.3) <0.001 8.9 (2.65–34.92) <0.001 pluralism 11.11 (2.89–49.64) <0.001 12.73 (3.2–58.79) <0.001 or = odds ratio; ci = confidence interval. *using bivariate analysis. †using multivariate analysis. muteb m. alharbi, mohammed s. almasri, abdulrahman y. aldayel and saleh m. alkhonezan clinical and basic research | e119 significant after adjustment for potential confounders (or = 3.44, ci = 1.76–6.59; p <0.001 and or = 4.23, ci = 1.56–12.69; p = 0.006) [table 6]. discussion this study measured the knowledge of, attitude towards and care-seeking practices for paediatric ear infections among parents with children ≤10 years of age. the majority of participants (76.6%) were knowledgeable about ear infections, while 78.9% had good attitude and 89.5% reported positive care-seeking practices. these results support the findings from other similarly conducted studies.5,21,22 there was a significant positive correlation between female gender and knowledge, attitude and practice. di berardino et al. also found that females had better knowledge than their male counterparts about ear and hearing management.23 the majority of participants (49.4%) were aged between 31–45 years; however, this age group did not significantly correlate with knowledge of or attitude towards ear infections. parents >60 years old were most likely to have good care-seeking practices. irwan et al. studied health seeking behaviours among elderly people in an indonesian community and found that younger individuals are less likely to seek healthcare, based on monthly health check-ups as a tool of assessment.24 those who practiced less modern medicine attrib uted their reluctance to seek care to poverty (35.7%), lack of a health insurance (24.8%) and ignorance (48.5%). these proportions align with studies on knowledge, attitudes and practices in regard to otitis media in different parts of the world and highlights that csom is a disease of the low-income population.5,21,25 in addition, poverty was associated with the inability to pay for healthcare services as well as the transport costs even if the child had medical insurance. parents with higher levels of education were more likely to have more knowledge and positive care-seeking practices compared to parents with lower levels of education. however, there was no significant relationship between attitude and education level. yip et al. found an asso ciation between education status and healthcare seeking behaviour.26 overall, the current study found lower levels of knowledge about symptoms compared to previous studies; only 23% of the participants could identify two symptoms of ear infections, while almost half could in mukara et al.’s study.5 the fluctuating attitude and healthcare seeking behaviour of medical treatment revealed in the current study may be due to a shortage of knowledge, the presence of poverty and/or dissat isfaction with the provided healthcare services such as referral delays. these findings are in agreement with shaheen et al.’s study.27 in bangladesh, shaheen et al. found that the majority (85%) of csom patients pref erred to seek over-the-counter medications instead of aid from medical staff.27 therefore, to increase the usage of healthcare services, it is important to promote awareness of prevention and treatment. social status can have an important role in healthcare-seeking practices and involves provision, planning and improve ment of healthcare services. to the best of the authors’ knowledge, this is the first study to investigate knowledge of, attitude towards and care-seeking practice for ear infections among parents of children ≤10 years of age in saudi arabia. the sample can be considered representative of riyadh as data were collected from five different parts of riyadh table 6: care-seeking practices for paediatric ear infections strat ified by participant’s characteristics (n = 782) characteristic unadjusted or (95% ci) p value* adjusted or (95% ci) p value† gender female male 0.52 (0.32–0.82) 0.006 0.76 (0.45–1.27) 0.294 age in years ≤30 31–45 0.63 (0.36–1.07) 0.09 0.7 (0.39–1.24) 0.235 46–60 0.31 (0.15–0.66) 0.002 0.37 (0.16–0.83) 0.014 >60 0.05 (0.007–0.32) 0.002 0.1 (0.01–0.76) 0.025 education none primary 2.4 (0.49–9.28) 0.224 1.57 (0.25–7.29) 0.585 secondary 5.17 (1.08–19.32) 0.02 2.37 (0.38–10.72) 0.296 vocational 0.76 (0.13–3.53) 0.736 0.56 (0.08–3.12) 0.527 socioeconomic status low middle 4.47 (2.43–8) <0.001 3.44 (1.76–6.59) <0.001 high 4.55 (1.86–12.38) <0.001 4.23 (1.56–12.69) 0.006 or = odds ratio; ci = confidence interval. *using bivariate analysis. †using multivariate analysis. parental knowledge, attitudes and practices towards paediatric ear infections in riyadh, saudi arabia a quantitative study e120 | squ medical journal, may 2019, volume 19, issue 2 city. thus, the current study represents a starting point for further investigations about ear infections in the saudi arabian population. however, this study did have limitations. the information was collected through a self-reporting questionnaire and is therefore inherently subject to misclassification. moreover, one questionnaire cannot encompass all aspects of ear infections. future studies should assess more extensive factors that could influence parental practices regarding paediatric ear infections. the findings of this study cannot be generalised on a national level due to the cultural variation among different populations living in different regions of saudi arabia. conclusion most saudi arabian parents in this study had good behaviour in terms of knowledge of, attitude towards and care-seeking practice for paediatric ear infections. the main factors associated with these positive behaviours were the educational level and socioeconomic status of the parents. these findings suggest that it may be beneficial to conduct educational programmes regarding paediatric ear infections for saudi parents to direct them towards better behaviours. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. biswas ac, joarder ah, siddiquee bh. prevalence of csom among rural school going children. mymensingh med j 2005; 14:152–5. 2. kohli c, kadirvelu u, garg s, sharma n. burden of ear morbidities among children in primary care setting in delhi. clin epidemiol glob health 2016; 4:s12–16. https://doi.org/10.1 016/j.cegh.2016.08.010. 3. vergison a, dagan r, arguedas a, bonhoeffer j, cohen r, dhooge i, et al. otitis media and its consequences: beyond the earache. lan cet infect dis 2010; 10:195–203. https://doi.org/10.1016/s1473-3 099(10)70012-8. 4. teele dw, klein jo, rosner b. epidemiology of otitis media during the first seven years of life in children in greater boston: a prospective, cohort study. j infect dis 1989; 160:83–94. https://doi.org/10.1093/infdis/160.1.83. 5. mukara kb, waiswa p, lilford r, tucci dl. knowledge and care seeking practices for ear infections among parents of under five children in kigali, rwanda: a cross-sectional study. bmc ear nose throat disord 2017; 17:7. https://doi.org/10.1186/s12901017-0040-1. 6. ilechukwu gc, ilechukwu cga, ubesie ac, ojinnaka cn, emechebe go, iloh kk. otitis media in children: review article. open j pediatr 2014; 4:47–53. https://doi.org/10.4236/ ojped.2014.41006. 7. deantonio r, yarzabal jp, cruz jp, schmidt je, kleijnen j. epidemiology of otitis media in children from developing countries: a systematic review. int j pediatr otorhinolaryngol 2016; 85:65–74. https://doi.org/10.1016/j.ijporl.2016.03.032. 8. massa hm, cripps aw, lehmann d. otitis media: viruses, bacteria, biofilms and vaccines. med j aust 2009; 191:s44–9. https://doi.org/10.5694/j.1326-5377.2009.tb02926.x. 9. european medicines agency and heads of medicines agencies. guideline on good pharmacovigilance practices (gvp): module v – risk management systems (rev 2). amsterdam, nether lands: european medicines agency. ema/838713/2011 rev 2. 10. atkinson h, wallis s, coatesworth ap. acute otitis media. postgrad med 2015; 127:386–90. https://doi.org/10.1080/0032 5481.2015.1028872. 11. qureishi a, lee y, belfield k, birchall jp, daniel m. update on otitis media prevention and treatment. infect drug resist 2014; 7:15–24. https://doi.org/10.2147/idr.s39637. 12. atkinson h, wallis s, coatesworth ap. otitis media with effusion. postgrad med 2015; 4:381–5. https://doi.org/10.1080/ 00325481.2015.1028317. 13. wallis s, atkinson h, coatesworth ap. chronic otitis media. postgrad med 2015; 127:391–5. https://doi.org/10.1080/00325 481.2015.1027133. 14. world health organization. chronic suppurative otitis media: burden of illness and management options. geneva, switzerland: world health organization. isbn 9241591587. p. 11,12,22,47–70. 15. monasta l, ronfani l, marchetti f, montico m, vecchi brumatti l, bavcar a, et al. burden of disease caused by otitis media: systematic review and global estimates. plos one 2012; 7:e36226. https://doi.org/10.1371/journal.pone.0036226. 16. gultekin e, develioğlu on, yener m, ozdemir i, külekçi m. prevalence and risk factors for persistent otitis media with effusion in primary school children in istanbul, turkey. auris nasus larynx 2010; 37:145–9. https://doi.org/10.1016/j.anl.20 09.05.002. 17. kırıs m, muderris t, kara t, bercin s, cankaya h, sevil e. prevalence and risk factors of otitis media with effusion in school children in eastern anatolia. int j pediatr otorhinolaryngol 2012; 76:1030–5. https://doi.org/10.1016/j.ijporl.2012.03.027. 18. humaid ah, ashraf ah, masood ka, nuha ah, saleh ad, awadh am. prevalence and risk factors of otitis media with effusion in school children in qassim region of saudi arabia. int j health sci (qassim) 2014; 8:325–34. https://doi.org/10.12 816/0023990. 19. adeyemo aa. knowledge of caregivers on the risk factors of otitis media. indian j otol 2012; 18:184–8. https://doi.org/10.41 03/0971-7749.104795. 20. kerschner je, lindstrom dr, pomeranz a, rohloff r. compar ison of caregiver otitis media risk factor knowledge in suburban and urban primary care environments. int j pediatr otorhi nolaryngol 2005; 69:49–56. https://doi.org/10.1016/j.ijporl.200 4.08.004. 21. srikanth s, isaac r, rebekah g, rupa v. knowledge, attitudes and practices with respect to risk factors for otitis media in a rural south indian community. int j pediatr otorhinolaryngol 2009; 73:1394–8. https://doi.org/10.1016/j.ijporl.2009.06.024. 22. barber c, ille s, vergison a, coates h. acute otitis media in young children what do parents say? int j pediatr otorhi nolaryngol 2014; 78:300–6. https://doi.org/10.1016/j.ijporl.201 3.11.030. https://doi.org/10.1016/j.cegh.2016.08.010 https://doi.org/10.1016/j.cegh.2016.08.010 https://doi.org/10.1016/s1473-3099%2810%2970012-8 https://doi.org/10.1016/s1473-3099%2810%2970012-8 https://doi.org/10.1093/infdis/160.1.83 https://doi.org/10.1186/s12901-017-0040-1 https://doi.org/10.1186/s12901-017-0040-1 https://doi.org/10.4236/ojped.2014.41006 https://doi.org/10.4236/ojped.2014.41006 https://doi.org/10.1016/j.ijporl.2016.03.032 https://doi.org/10.5694/j.1326-5377.2009.tb02926.x https://doi.org/10.1080/00325481.2015.1028872 https://doi.org/10.1080/00325481.2015.1028872 https://doi.org/10.2147/idr.s39637 https://doi.org/10.1080/00325481.2015.1028317 https://doi.org/10.1080/00325481.2015.1028317 https://doi.org/10.1080/00325481.2015.1027133 https://doi.org/10.1080/00325481.2015.1027133 https://doi.org/10.1371/journal.pone.0036226 https://doi.org/10.1016/j.anl.2009.05.002 https://doi.org/10.1016/j.anl.2009.05.002 https://doi.org/10.1016/j.ijporl.2012.03.027 https://doi.org/10.12816/0023990 https://doi.org/10.12816/0023990 https://doi.org/10.4103/0971-7749.104795 https://doi.org/10.4103/0971-7749.104795 https://doi.org/10.1016/j.ijporl.2004.08.004 https://doi.org/10.1016/j.ijporl.2004.08.004 https://doi.org/10.1016/j.ijporl.2009.06.024 https://doi.org/10.1016/j.ijporl.2013.11.030 https://doi.org/10.1016/j.ijporl.2013.11.030 muteb m. alharbi, mohammed s. almasri, abdulrahman y. aldayel and saleh m. alkhonezan clinical and basic research | e121 23. di berardino f, forti s, iacona e, orlandi gp, ambrosetti u, cesarani a. public awareness of ear and hearing management as measured using a specific questionnaire. eur arch otorhi nolaryngol 2013; 270:449–53. https://doi.org/10.1007/s00405012-1961-3. 24. irwan am, kato m, kitaoka k, kido t, taniguchi y, shogenji m. self-care practices and health-seeking behavior among older persons in a developing country: theories-based research. int j nurs sci 2016; 3:11–23. https://doi.org/10.1016/j.ijnss.2016.02.010. 25. clarke s, richmond r, worth h, wagle rr. a study protocol for a cluster randomised trial for the prevention of chronic suppur ative otitis media in children in jumla, nepal. bmc ear nose throat disord 2015; 15:4. https://doi.org/10.1186/s12901-0150017-x. 26. yip wc, wang h, liu y. determinants of patient choice of medical provider: a case study in rural china. health policy plan 1998; 13:311–22. https://doi.org/10.1093/heapol/13.3.311. 27. shaheen mm, raquib a, ahmad sm. chronic suppurative otitis media and its association with socio-econonic factors among rural primary school children of bangladesh. indian j otolaryngol head neck surg 2012; 64:36–41. https://doi.org/10.1007/s120 70-011-0150-9. https://doi.org/10.1007/s00405-012-1961-3 https://doi.org/10.1007/s00405-012-1961-3 https://doi.org/10.1016/j.ijnss.2016.02.010 https://doi.org/10.1186/s12901-015-0017-x https://doi.org/10.1186/s12901-015-0017-x https://doi.org/10.1093/heapol/13.3.311 https://doi.org/10.1007/s12070-011-0150-9 https://doi.org/10.1007/s12070-011-0150-9 the value of programmed death ligand 1 expression in cancer patients treated with neoadjuvant chemotherapy malika al-dughaishi,1 *asem shalaby,2 khawla al-ribkhi,1 ammar boudaka,3 mohamed-rachid boulassel,4 jumana saleh1 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e277–283, epub. 22 dec 19 submitted 22 jan 19 revisions req. 2 apr & 11 jul 19; revisions recd. 1 jun & 30 sep 19 accepted 30 sep 19 departments of 1biochemistry, 2pathology, 3physiology and 4biomedical sciences, sultan qaboos university, muscat, oman * corresponding author’s e-mail: a.shalaby@squ.edu.om the role of the immune system in cancer has been studied extensively; immunity in the cancer microenvironment has a role in different phases of cancer development.1 cancer cells usually express abnormal antigens which trigger the immune response to be activated against these cancerous cells.2 tumour-infiltrating lymphocytes (til), including cyto toxic t-cells, are usually involved in tumour antigen recognition and anti-tumour immunity to destroy cancer cells during immune-surveillance.1,3 normally, the initiation of the immune response by t-cells is mediated through t-cell receptor (tcr) recognition of the antigen and regulated by inhibitory and stimul atory molecules expressed in these t-cells. the inhibitory molecules are considered as immune checkpoints for self-tolerance (i.e. protection from tissue damage during an immune response and prevention of developing autoimmune diseases). however, the inhibitory effect mediated by these immune checkpoint molecules may also be used as a mechanism for tumour cells to escape the immune response.4 one of these immune check points is the programmed death receptor 1 (pd-1)/progr ammed death ligand 1 (pd-l1) interaction [figure 1]. pd-1 is a member of cluster of differentiation (cd)28 family that is expressed in t-cells.5 it is also expressed in b-cells, professional antigen presenting cells and natural killer cells.6 the pd-l1 was firstly identified by dong et al. in 1999 and showed that there was an increase in the t-cell proliferation and interleukin (il)-10 secretion by t-cells stimulated with pd-l1/b7-h1 and low levels of anti-cd3.7 in 2000, freeman et al. showed induction of pd-l1 expression by cytokines as interferon (ifn)-γ or other inflammatory stimuli could result in attenuation of review أمهية ظهور ربيطة املوت املربمج 1 يف مرضى السرطان الذين تلقوا املعاجلة الكيميائية املسبقة مليكة الدغي�صية، عا�صم �صلبي، خولة الربخية، عمار بودقه، حممد را�صد بولع�صل، جمانة �صالح abstract: programmed death ligand 1 (pd-l1) is an inhibitory molecule expressed by cancer cells to supress t-cell activity and escape anti-tumour immunity. the role of pd-l1 in cancer has been studied extensively as it is considered an important immune checkpoint against immune over-activation through its interaction with programmed death receptor 1 (pd-1) expressed on activated lymphocytes. pd-l1 expression was found to be enhanced by chemotherapy through different proliferation pathways. however, the predictive and prognostic value for pd-l1 expression in cancer patients treated with neoadjuvant chemotherapy (nac) is not yet established. this review focused on the potential effects of chemotherapy on pd-l1 expression and the role of pd-l1 as a prognostic and predictive marker in nac-treated cancer patients. in addition, the potential use of this marker in clinical practice is discussed. keywords: programmed cell death 1 ligand 1; programmed cell death 1 receptor; neoadjuvant therapy; cancer. امللخ�ص: ربيطة املوت املربمج-1 هو جزيء مثبط تعرب عنه اخلاليا ال�رسطانية لقمع ن�صاط اخلاليا الليمفاوية من النوع )ت( لالإفالت تعترب لأنها وا�صع نطاق على ال�رسطان يف املربمج-1 املوت ربيطة دور درا�صة متت ال�رسطانية. الأورام �صد تن�صاأ التي املناعة من اخلاليا تظهرعلى التي املربمج-1 املوت م�صتقبل مع تفاعلها خالل من املناعي للجهاز املفرط التن�صيط �صد هامة مناعية �صابطة الليمفاوية املن�صطة. ووجد اأن انت�صارربيطة املوت املربمج-1 تتعزز باملعاجلةالكيميائية من خالل م�صارات تكاثريةخمتلفة. ومع ذلك، فاإن القيمة التنبوؤية الإنذارية لظهورربيطة املوت املربمج-1 عند مر�صى ال�رسطان الذين يتلقومنعاجلة كيميائيةم�صبقة مل تتحدد بعد. هذه املراجعة تتناول تاأثري املعاجلة الكيميائية املحتمل على ظهور ربيطة املوت املربمج-1 واأهمية انت�صارها كعالمة تنبوؤية اإنذارية يف املوؤ�رس هذا ا�صتخدام اإمكانية مناق�صة متت ذلك، اإىل بالإ�صافة امل�صبقة. الكيميائية املعاجلة يتلقون الذين ال�رسطان مر�صى لدى املمار�صة ال�رسيرية. الكلمات املفتاحية: جلني موت اخللية املربمج-1؛ م�صتقبالت موت اخللية املربجمة-1؛ العالج امل�صبق؛ ال�رسطان. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.002 https://creativecommons.org/licenses/by-nd/4.0/ the value of programmed death ligand 1 expression in cancer patients treated with neoadjuvant chemotherapy e278 | squ medical journal, november 2019, volume 19, issue 4 tcr/cd28–mediated t-cell activation which may be significant in the regulation of inflammatory or auto immune reactions.8 pd-l1, also called b7-h1, is a member of b7 molecules which are involved in the regulation of t-cell response either through stimulation or inhibition.9 pd-l1 is generally widely expressed in different tissues from different lineages including lymphoid (i.e. immune cells) or non-lymphoid (i.e. epithelial and endothelial) lineages and in cancer cells that originate from these lineages.8,10 pd-l1 was found to inhibit proliferation of t-cells and production of cytokines such as ifn-γ and il-2, through interaction with pd-1 expressed on these cells.11 in the cancer microenvironment, the interaction of pd-l1 which is expressed in cancer cells and pd-1 which is expressed in t-cells leads to the inhibition of cytotoxic t-cell activity, a decrease in cytokines production by t-cells and ind uction of t-regulatory cells. therefore, this interaction protects tumour cells from destruction by cytotoxic t-cells and promotes tumour cell proliferation.1,2,12 many studies chose to investigate the role of pdl1 expression in subjects not treated with neoadjuvant chemotherapy (nac). for example, a study on triple negative breast cancer (tnbc) patients excluded patients treated with nac.13 similarly, several studies preferred to include patients who did not receive nac.14–16 this exclusion was partly attributed to the possibility that chemotherapy may contribute to change the expression of specific markers; for example, the expression of progesterone receptor and cellular proliferation marker (ki-67) in breast cancer was decreased after nac.17 the effect of nac on pd-l1 expression in cancer patients has not yet been established. therefore, this review aimed to highlight the effect of chemotherapy on the expression of pd-l1, the potential use of pd-l1 expressed in pre-treated patients as a predictive marker for the response to chemotherapy and whether it could be used as a prognostic disease marker. p o s t-n e o a d j u va n t c h e m o t h e r a p y c h a n g e s i n p r o g r a m m e d d e a t h l i g a n d 1 e x p r e s s i o n i n d i f f e r e n t c a n c e r s immunohistochemical detection of pd-l1 expression can be either increased or decreased by nac according to the tumour type. it is known that chemotherapy provokes an immune response but, once pd-l1 is over expressed, this immune response might be diminished. increased expression of pd-l1 after nac suggests that the immune response is inhibited which may contr ibute to chemo-resistance and poor clinical outcome.18 therefore, a combination of chemotherapy and immun otherapy was suggested to overcome this resistance. conversely, decreased expression of pd-l1 may be associated with a better response to nac treatment. cancers associated with increased programmed death ligand 1 expression increased pd-l1 expression in association with nac was demonstrated in post-treated specimens of ovarian, bladder and gastrointestinal cancers as well as head and neck squamous cell carcinoma (hnscc).19–25 in epithelial ovarian cancer, 63% of pd-l1 negative tumours converted to positive pd-l1 tumours after nac when patients received carboplatin and paclitaxel; the positivity rate in the pd-l1 positive samples increased from 30% in pre-treated specimens to 53% in post-treated figure 1: depiction of the t-cell receptor recognition of the tumour antigen initiating the t-cell response which is regulated by inhibitory molecules expressed in t-cells such as programmed death receptor 1. however, tumour cells may use this inhibitory effect to escape the immune response. pd-l1 = programmed death ligand 1; pd-1 = programmed death receptor 1. figure 2: flowchart showing the different pathways involved in programmed death ligand 1 upregulation induced by chemotherapy treatment. jak/stat = janus-activated kinase/signal transducers and activators of transcription; pi3k/akt = phosphoinositide-3 kinase/protein kinase b; mapk = mitogen-activated protein kinase; pd-l1 = programmed death ligand 1. malika al-dughaishi, asem shalaby, khawla al-ribkhi, ammar boudaka, mohamed-rachid boulassel and jumana saleh review | e279 ta bl e 1: s um m ar y of p ub lic at io ns s ho w in g th e va ri at io n of p ro gr am m ed d ea th li ga nd 1 e xp re ss io n in d iff er en t c an ce r ty pe s be fo re a nd a ft er n eo ad ju va nt c he m ot he ra py 19 – 23 ,2 5, 26 ,2 8– 32 a ut ho r an d ye ar o f pu bl ic at io n t yp e of ca n ce r t re at m en t re gi m en n um be r of c as es * c ut -o ff p oi nt / sc or in g sy st em p re tr ea tm en t p d -l 1 p os ttr ea tm en t p d -l 1 e ff ec t of n a c in p d -l 1 ex pr es si on a ss oc ia ti on w it h su rv iv al /p ro gn os is pr etr ea tm en t po st -t re at m en t m es na ge et a l.1 9 ( 20 17 ) o va ri an c ar bo pl at in a nd pa cl ita xe l 51 ≥5 % is p os iti ve ic = 3 0% t c = 0 % ic = 5 3% t c = 6 % in cr ea se d pf s (p = 0 .5 6) pf s (p = 0 .2 5) b öh m e t a l.2 0 (2 01 6) o va ri an pl at in um -b as ed n a c t 26 ic : 0 if < 1% , 1 if 1– 5% , 2 if 5 – 10 % , 3 if ≥1 0% 50 % (c ut -o ff po in t ≥ 5% ) 73 % (c ut -o ff po in t ≥ 5% ) in cr ea se d m cd an ie l et a l.2 1 ( 20 16 ) b la dd er c is pl at in a nd ca rb op la tin 40 h -s co re m ea n sc or e = 17 6. 6 m ea n sc or e = 21 7. 5 in cr ea se d n ot c or re la te d w ith r fs n ot c or re la te d w ith r fs v an d er k ra ak e t a l.2 2 (2 01 6) o es op ha ge al c is pl at in , 5 -f u a nd ra di at io n 10 t c ≥ 1% is p os iti ve 40 % 0% d ec re as ed (c el l l in e ex pe ri m en t s ho w ed in cr ea se d pd -l 1 ex pr es si on , w hi ch w as in co ns is te nt w ith im m un oh is to ch em is tr y re su lts ) li m e t a l.2 3 (2 01 7) r ec ta l c he m or ad io th er ap y 12 3 h -s co re (m ed ia n va lu e w as us ed a s cu to ffs ) in cr ea se d -† o ck e t a l.2 5 (2 01 7) h n sc c d oc et ax el , c is pl at in o r 5fu ; c c rt r eg im en s 35 t c ≥ 5% is p os iti ve 63 % 77 % in cr ea se d pe le ka no u et a l.2 6 ( 20 17 ) br ea st d ox or ub ic in a nd cy cl op ho sp ha m id e fo llo w ed b y ta xa ne 58 q if s co re = 5 00 a u 51 % 17 % d ec re as ed r fs (p = 0 .1 4) o s (p = 0 .6 4) su n et a l.2 8 (2 01 7) lu ng c an ce r pl at in um -b as ed 26 ≥5 % is p os iti ve 65 % 92 % in cr ea se d so ng e t a l.2 9 (2 01 6) lu ng sq ua m ou s ce ll ca rc in om a pa cl ita xe l/ pl at in um do ce ta xe l/ pl at in um 76 h -s co re (≥ 5 is p os iti ve ) 53 % 62 % in cr ea se d si gn ifi ca nt o s (p = 0 .0 52 ) pd -l 1 ne ga tiv e = 34 .2 m on th s; p d -l 1 po si tiv e = 27 .0 m on th s si gn ifi ca nt o s (p = 0 .0 03 ) pd -l 1 ne ga tiv e = 36 .5 m on th s; p d -l 1 po si tiv e = 27 m on th s sh en g et a l.3 0 (2 01 6) n sc lc pe m et re xe dba se d re gi m en a nd p ac lit ax el ba se d ch em ot he ra py 32 h -s co re (≥ 5 is p os iti ve ) 75 % 37 .5 % d ec re as ed -§ fu jim ot o et a l. 31 (2 01 7) n sc lc c c rt 35 ≥1 % is p os iti ve 63 % 60 % d ec re as ed o s (p = 0 .4 56 ) r fs (p = 0 .9 39 ) o s (0 .7 46 )‡ r fs (0 .7 84 ) r em ar k et a l.3 2 ( 20 16 ) n sc lc pl at in um -b as ed 21 po si tiv ity a ss es se d se m iqu an tit at iv el y on tu m ou r ce lls n ot m en tio ne d n ot m en tio ne d u nc ha ng ed pd -l 1 = pr og ra m m ed d ea th li ga nd 1 ; n a c = n eo ad ju va nt ch em ot he ra py ; i c = im m un e c el l; t c = tu m ou r c el l; pf s = pr og re ss io n fr ee su rv iv al ; r fs = re la ps e f re e s ur vi va l; fu = fl uo ro ur ac il; h n sc c = h ea d an d ne ck sq ua m ou s c el l c ar ci n om a; c c rt = co nc ur re nt ch em or ad io th er ap y; q if = q ua nt ita tiv e i m m un ofl uo re sc en ce ; a u = a rb itr ar y un it of fl uo re sc en ce ; o s = ov er al l s ur vi va l; n sc lc = n on -s m al l c el l l un g c an ce r. *th e c as es in vo lv ed in th e a na ly sis w hi ch h ad b ot h pr e a nd p os ttr ea te d bi op sie s a nd sp ec im en s. † s us ta in ed h ig h ex pr es sio n in p re a nd p os ttr ea te d sp ec im en s w er e a ss oc ia te d w ith w or se o s (p = 0 .0 18 ) a nd r fs (p = 0 .0 29 ). ‡ m ed ia n o s of p at ie nt s a cc or di ng to th e c ha ng e i n pd -l 1 ex pr es sio n: d ec re as ed = 8 5. 1 m on th s, un ch an ge d = 92 .8 m on th s, in cr ea se d = 14 .6 m on th s ( p <0 .0 01 ). § m ed ia n di se as efr ee su rv iv al o f p at ie nt s a cc or di ng to th e c ha ng e i n pd -l 1 ex pr es sio n: in cr ea se d = 9. 6 m on th s, de cr ea se d = 25 .9 m on th s ( p = 0. 00 5) . the value of programmed death ligand 1 expression in cancer patients treated with neoadjuvant chemotherapy e280 | squ medical journal, november 2019, volume 19, issue 4 specimens.19 this was further supported by findings showing that cisplatin treatment of ovarian cancer cell lines skov-3 and ovcar-3 in vitro induced the expression of pd-l1.19 in addition, a high proportion of t-cells expressing pd-l1 were found in biopsies from ovarian high-grade serous carcinoma after nac.20 the expression of pd-l1 was increased in 76% of patients with urothelial carcinoma treated with cisplatin or carboplatin-based chemotherapy.21 although the increased expression was not observed in post-treated oesophageal carcinoma specimens using immunohisto chemistry, 5-fluorouracil induced surface expression of pd-l1 in oesophageal cancer (oe33) and colorectal cancer (hct 116 p53+/+ and hct 116 p53−/−) cell lines.22 pd-l1 expression and til were increased after con current chemoradiation therapy (ccrt) in rectal car cinoma.23 notably, sustained high expression of pdl1 in preand post-chemoradiotherapy specimens, associated with less increase in til, showed poorer overall survival (os) and disease-free survival (dfs) compared to other patients.23 inhibition of pd-l1 may be beneficial only in some ovarian cancer patients. pd-l1 is expressed significantly more in high grade tumours than in low grade tumours; therefore, a subgroup of advanced disease ovarian cancer patients with high grade tumours, expressing pd-l1, may benefit the most from therapy targeting pd-l1.19 in hnscc, immunohistochemical analysis of 13 negative cases of pd-l1 showed that nine cases (69.2%) showed increased pd-l1 expression after cisplatin treatment.25 furthermore, patients who received neo adjuvant cisplatin treatment showed more pd-l1 upregulation compared to patients who did not receive cisplatin.25 this was supported by findings showing increased pd-l1 expression in hnscc cell lines (snu-1066, snu-1041, snu-1076, detroit-562, fadu and pci-13) treated with cisplatin alone.25 cancers associated with decreased programmed death ligand 1 expression conversely, pd-l1 was downregulated in breast and squamous oral carcinoma, after treatment with nac.26,27 in the analysis of 58 breast specimens (56% of patients treated with doxorubicin and cyclophosphamide followed by taxane and the remaining patients received other agents), the positivity rate of pd-l1 expression decreased from 51% to 17.2% and 17 cases converted from positive to negative status in spite of the increase of t-cells.26 the comparison between nac-treated and non-treated squamous oral carcinoma specimens showed that most of the treated specimens weakly expressed pd-l1, while non-treated specimens showed either strong or intermediate expression. similarly, pd-1 expression was significantly less in nac-treated specimens.27 programmed death ligand 1 expression in lung cancer in lung cancer, the expression of pd-l1 showed variable results regarding pd-l1 expression after nac treatment. sun et al. showed that pd-l1 expression significantly increased in platinum-based-treated specimens.28 pd-l1 expression also increased in nine patients and decr eased in two patients with lung squamous cell carcinoma after nac; the positivity rate changed from 52.6% to 61.8%.29 expectedly, expression of pd-l1 was associated with worse dfs compared to the decreased expression. however, pd-l1 expression was not an independent predictor of dfs as determined by multiple regression analysis.30 non-small cell lung cancer samples showed an overall decrease in pd-l1 expression after ccrt. the decreased pd-l1 expression was associated with better survival compared to samples with increased pd-l1 expression (85.1 months versus 14.6 months).31 these findings were comparable to another study involving patients with non-small lung carcinoma treated with a pemetrexed-based regimen and paclitaxel-based chemotherapy.30 in this study, the positivity rate of pdl1 changed from 75% to 37.5% with effect on immune cell infiltration; decreased pd-l1 expression in tumour cells was associated with a better response to nac. remark et al.’s study found that pd-l1 expression in lung cancer was not changed by cisplatin-based nac treatment indicating that nac did not contribute to the modification of pd-l1 expression.32 various results from different studies suggest that pd-l1 expression, in response to nac treatment, may be cancer specific and that different nac modalities may trigger distinct changes in pd-l1 expression involving different mechanisms. p r o p o s e d m e c h a n i s m s o f c h e m o t h e r a p ym e d i a t e d p r o g r a m m e d death ligand 1 expression changes few studies have explored the mechanisms linked to pd-l1 expression changes associated with nac. chemotherapy may be involved in proliferative path ways that can lead to enhanced pd-l1 expression in cancer [figure 2].33 for instance, pd-l1 expression at the protein and mrna levels was increased under the influence of 5-fluorouracil, gemcitabine and paclitaxel chemo therapy in pancreatic cancer cell lines (mia paca2, aspc-1, pan02).34 these three anti-cancer agents increased pd-l1 through janus-activated kinase/signal transducers and activators of transcription signalling pathways and through phosphorylation by phospho inositide-3 kinase/protein kinase b (pi3k/akt) and mitogen-activated protein kinase (mapk) pathways.34 malika al-dughaishi, asem shalaby, khawla al-ribkhi, ammar boudaka, mohamed-rachid boulassel and jumana saleh review | e281 in addition, hnscc cancer cell lines (snu-1066, snu-1041, snu-1076, detroit-562, fadu and pci13) treated with cisplatin showed an increase in pdl1 expression along with up-regulation of extracellular signal-regulated kinase/mapk. these pathways were found to contribute to chemoresistance. for example, activation of pi3k/akt pathway was associated with chemotherapy resistance in urothelial carcinoma.35 however, targeting the mapk pathway enhanced the sensitivity of the tumour resistance to cisplatin and helped to overcome this resistance.36 inactivation of programmed cell death (i.e. apoptosis), is essential for cancer development. it was suggested that disabling apoptosis by anti-apoptotic factors may contribute to nac resistance. for example, a gastric cancer cell line (sgc7901/5-fu) resistant to treatment with 5-fluorouracil was associated with overexpression of pd-l1 compared to a sensitive gastric cell line. a pd-l1 induced resistance was associated with up-regulation of anti-apoptotic proteins, including atp binding cassette subfamily c member 1 and anti apoptotic factor b-cell lymphoma 2, that may contr ibute to the resistance. the blockage of pd-l1 by sirna was found to overcome this resistance and inhibit proliferation.37 a novel mechanism of pd-l1 downregulation of expression by chemotherapy was discovered.38 anth racycline agents, including doxorubicin, were found to decrease the surface expression of pd-l1 in breast cancer cell lines (mda-mb231 and skbr3) in a dose and time-dependent manner. however, this effect was correlated with nuclear translocation of pd-l1 and increased nuclear phosphorylated akt. pd-l1 was also found to have an anti-apoptotic function, in which its blockade by pd-l1 sirna enhanced the effect of doxorubicin-induced apoptosis and which was pi3k/ akt pathway dependent.38 p r o g r a m m e d d e at h l i g a n d 1 a s a p o t e n t i a l p r e d i c t i v e m e a s u r e f o r the response to neoadjuvant chemo t h e r a p y pd-l1 expressed in pre-treated specimen has been investigated to identify patients who would be most likely to respond to nac. several studies have found that pd-l1 expression is associated with a pathological complete response (pcr) after nac in breast cancer.39–42 the analysis of 94 biopsies of breast cancer tissue revealed that pcr was associated with the epithelial and stromal expression of pd-l1. when patients were classified into groups, this association remained signif icant in hormone-positive and her2-postive breast cancer.39 similarly, pd-l1 expression in tumour cells was associated with pcr in 54 biopsies of tnbc which remained significant in multivariate analysis. all patients with more than 25% expression of pdl1 and high til achieved pcr.40 expression of pdl1 in tumour cells of her2-positive breast cancer tumours showed a trend of association with pcr but did not reach significance.41 the evaluation of several predictive markers revealed that 20 out of 27 pd-l1positve invasive breast cancer cases showed excellent response to nac using the residual cancer burden score.41 the mechanisms underlying the differential response amongst different molecular types of breast carcinoma may be due to the differing biology of the three types i.e. the tumours may or may not be immunogenic. only baras et al.’s study of bladder cancer found that pd-l1 was not associated with pcr.43 the expression of pd-l1 in invasive bladder carcinoma showed no significant difference between responders and resistant patients to cisplatin-based nac.43 p r o g r a m m e d d e at h l i g a n d 1 a s a p r o g n o s t i c m a r k e r i n p a t i e n t s treated with neoadjuvant chemo t h e r a p y the role of pd-l1 as a prognostic marker in patients treated with nac remains largely unknown. the results of several studies identifying the expression of pd-l1 in residual tumours (i.e. post-treated specimens) have been concordant. it has been reported that high pd-l1 expression in residual tumours was associated with poor clinical outcome in locally-advanced breast cancer after nac. according to molecular subtypes, the association was more significant in the tnbc subtype.44 patients with high pd-l1 expression and low cd8+ cells had a poor outcome compared to other groups.44 however, some studies found that pd-l1 expression in residual breast tumours was not associated with the clinical outcome.26,41 in posttreated bladder cancer, disease-specific survival in pd-l1-positive patients was significantly lower than in pd-l1-negative patients.45 in lung cancer, both pre and post-treated expression of pd-l1 was associated with worse os; however, the association was signif icant and independent in post-treated specimens indicating that pd-l1 status after nac treatment is a better prognostic marker than pd-l1 status prior to nac treatment.29 conclusion chemotherapy may cause an increase or decrease in the expression of pd-l1; this outcome seems to be cancer specific as shown by immunohistochemistry the value of programmed death ligand 1 expression in cancer patients treated with neoadjuvant chemotherapy e282 | squ medical journal, november 2019, volume 19, issue 4 analysis of preand post-treated specimens and cell line experiments. it is possible that pd-l1 is involved in chemoresistance through inhibiting the induction of t-cell activity pathways. therefore, it may be important to consider combining immunotherapy and chemotherapy to improve the response to the treatment. current evidence showed that increased pd-l1 expression in post-treated specimens is a poor prognostic marker; although, pd-l1 was shown to predict the response to nac in breast cancer. further studies are needed to validate this predictive role of pd-l1 in response to nac in other cancers except breast cancer. also, further broader investigations are required to explore the prognostic role of pd-l1. a c k n o w l e d g e m e n t the authors would like to thank dr elias said for his input and valuable comments. references 1. kurozumi s, fujii t, matsumoto h, inoue k, kurosumi m, horiguchi j, et al. significance of evaluating tumor-infiltrating lymphocytes (tils) and programmed cell death-ligand 1 (pd-l1) expression in breast cancer. med mol morphol 2017; 50:185–94. https://doi.org/10.1007/s00795-017-0170-y. 2. topalian sl, drake cg, pardoll dm. targeting the pd-1/b7h1(pd-l1) pathway to activate anti-tumor immunity. curr opin immunol 2012; 24:207–12. https://doi.org/10.1016/j.coi.2 011.12.009. 3. dunn gp, bruce at, ikeda h, old lj, schreiber rd. cancer immunoediting: from immunosurveillance to tumor escape. nat immunol 2002; 3:991–8. https://doi.org/10.1038/ni1102-991. 4. pardoll dm. the blockade of immune checkpoints in cancer immunotherapy. nat rev cancer 2012; 12:252–64. https://doi. org/10.1038/nrc3239. 5. guan j, lim ks, mekhail t, chang cc. programmed death ligand-1 (pd-l1) expression in the programmed death rec eptor-1 (pd-1)/pd-l1 blockade: a key player against various cancers. arch pathol lab med 2017; 141:851–61. https://doi. org/10.5858/arpa.2016-0361-ra. 6. bio-rad laboratories, inc. the role of immune checkpoints in immunity and cancer. from: https://www.bio-rad-antibodies. com/immune-checkpoint-minireview.html accessed: sep 2019. 7. dong h, zhu g, tamada k, chen l. b7-h1, a third member of the b7 family, co-stimulates t-cell proliferation and inter leukin-10 secretion. nat med 1999; 5:1365–9. https://doi.org/10.1 038/70932. 8. freeman gj, long aj, iwai y, bourque k, chernova t, nishimura h, et al. engagement of the pd-1 immunoinhibitory receptor by a novel b7 family member leads to negative regulation of lymphocyte activation. j exp med 2000; 192:1027–34. https://doi.org/10.1084/jem.192.7.1027. 9. ni l, dong c. new b7 family checkpoints in human cancers. mol cancer ther 2017; 16:1203–11. https://doi.org/10.1158/15 35-7163.mct-16-0761. 10. gibbons johnson rm, dong h. functional expression of programmed death-ligand 1 (b7-h1) by immune cells and tumor cells. front immunol 2017; 8:961. https://doi.org/10.33 89/fimmu.2017.00961. 11. freeman gj, long aj, iwai y, bourque k, chernova t, nishimura h, et al. engagement of the pd-1 immunoinhibitory receptor by a novel b7 family member leads to negative regulation of lymphocyte activation. j exp med 2000; 192:1027–34. https://doi.org/10.1084/jem.192.7.1027. 12. bertucci f, gonçalves a. immunotherapy in breast cancer: the emerging role of pd-1 and pd-l1. curr oncol rep 2017; 19:64. https://doi.org/10.1007/s11912-017-0627-0. 13. mori h, kubo m, yamaguchi r, nishimura r, osako t, arima n, et al. the combination of pd-l1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer. oncotarget 2017; 8:15584–92. https://doi.org/10.18632/oncotarget.14698. 14. baptista mz, sarian lo, derchain sf, pinto ga, vassallo j. prognostic significance of pd-l1 and pd-l2 in breast cancer. hum pathol 2016; 47:78–84. https://doi.org/10.1016/j.humpa th.2015.09.006. 15. wang zq, milne k, derocher h, webb jr, nelson bh, watson ph. pd-l1 and intratumoral immune response in breast cancer. oncotarget 2017; 8:51641–51. https://doi.org/10.18632/onco target.18305. 16. kim a, lee sj, kim yk, park wy, park dy, kim jy, et al. programmed death-ligand 1 (pd-l1) expression in tumour cell and tumour infiltrating lymphocytes of her2-positive breast cancer and its prognostic value. sci rep 2017; 7:11671. https://doi.org/10.1038/s41598-017-11905-7. 17. lee h, ko h, seol h, noh dy, han w, kim ty, et al. expression of immunohistochemical markers before and after neoadjuvant chemotherapy in breast carcinoma, and their use as predictors of response. j breast cancer 2013; 16:395–403. https://doi.org/10.4 048/jbc.2013.16.4.395. 18. liu q, gong w, cheng z, jiang h, cao f, li x. counteracting immunosuppressive cofactor b7-h1 may enhance the effects of chemotherapy in cancer patients. immunotherapy 2013; 5:557–9. https://doi.org/10.2217/imt.13.38. 19. mesnage sjl, auguste a, genestie c, dunant a, pain e, drusch f, et al. neoadjuvant chemotherapy (nact) increases immune infiltration and programmed death-ligand 1 (pd-l1) expression in epithelial ovarian cancer (eoc). ann oncol 2017; 28:651–7. https://doi.org/10.1093/annonc/mdw625. 20. böhm s, montfort a, pearce om, topping j, chakravarty p, everitt gl, et al. neoadjuvant chemotherapy modulates the immune microenvironment in metastases of tubo-ovarian highgrade serous carcinoma. clin cancer res 2016; 22:3025–36. https://doi.org/10.1158/1078-0432.ccr-15-2657. 21. mcdaniel as, alva a, zhan t, xiao h, cao x, gursky a, et al. expression of pd-l1 (b7-h1) before and after neoadjuvant chemotherapy in urothelial carcinoma. eur urol focus 2016; 1:265–8. https://doi.org/10.1016/j.euf.2015.03.004. 22. van der kraak l, goel g, ramanan k, kaltenmeier c, zhang l, normolle dp, et al. 5-fluorouracil upregulates cell surface b7-h1 (pd-l1) expression in gastrointestinal cancers. j immunother cancer 2016; 4:65. https://doi.org/10.1186/s40425-016-0163-8. 23. lim yj, koh j, kim s, jeon sr, chie ek, kim k, et al. chemoradiation-induced alteration of programmed death-ligand 1 and cd8+ tumor-infiltrating lymphocytes identified patients with poor prognosis in rectal cancer: a matched comparison analysis. int j radiat oncol biol phys 2017; 99:1216–24. https://doi.org/10.1016/j.ijrobp.2017.07.004. 24. goel g, ramanan k, kaltenmeier c, zhang l, freeman gj, normolle dp, et al. effect of 5-fluorouracil on membranous pdl1 expression in colon cancer cells. j clin oncol 2016; 34:592. https://doi.org/10.1200/jco.2016.34.4_suppl.592. 25. ock cy, kim s, keam b, kim s, ahn yo, chung ej, et al. changes in programmed death-ligand 1 expression during cisplatin treatment in patients with head and neck squamous cell carcinoma. oncotarget 2017; 8:97920–7. https://doi.org/10.186 32/oncotarget.18542. https://doi.org/10.1007/s00795-017-0170-y https://doi.org/10.1016/j.coi.2011.12.009 https://doi.org/10.1016/j.coi.2011.12.009 https://doi.org/10.1038/ni1102-991 https://doi.org/10.1038/nrc3239 https://doi.org/10.1038/nrc3239 https://doi.org/10.5858/arpa.2016-0361-ra https://doi.org/10.5858/arpa.2016-0361-ra https://doi.org/10.1038/70932 https://doi.org/10.1038/70932 https://doi.org/10.1084/jem.192.7.1027 https://doi.org/10.1158/1535-7163.mct-16-0761 https://doi.org/10.1158/1535-7163.mct-16-0761 https://doi.org/10.3389/fimmu.2017.00961 https://doi.org/10.3389/fimmu.2017.00961 https://doi.org/10.1084/jem.192.7.1027 https://doi.org/10.1007/s11912-017-0627-0 https://doi.org/10.18632/oncotarget.14698 https://doi.org/10.1016/j.humpath.2015.09.006 https://doi.org/10.1016/j.humpath.2015.09.006 https://doi.org/10.18632/oncotarget.18305 https://doi.org/10.18632/oncotarget.18305 https://doi.org/10.1038/s41598-017-11905-7 https://doi.org/10.4048/jbc.2013.16.4.395 https://doi.org/10.4048/jbc.2013.16.4.395 https://doi.org/10.2217/imt.13.38 https://doi.org/10.1093/annonc/mdw625 https://doi.org/10.1158/1078-0432.ccr-15-2657 https://doi.org/10.1016/j.euf.2015.03.004 https://doi.org/10.1186/s40425-016-0163-8 https://doi.org/10.1016/j.ijrobp.2017.07.004 https://doi.org/10.1200/jco.2016.34.4_suppl.592 https://doi.org/10.18632/oncotarget.18542 https://doi.org/10.18632/oncotarget.18542 malika al-dughaishi, asem shalaby, khawla al-ribkhi, ammar boudaka, mohamed-rachid boulassel and jumana saleh review | e283 26. pelekanou v, carvajal-hausdorf de, altan m, wasserman b, carvajal-hausdorf c, wimberly h, et al. effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and pd-l1 expression in breast cancer and its clinical significance. breast cancer res 2017; 19:91. https://doi.org/10.1186/s13058-017-0884-8. 27. takakura h, domae s, ono t, sasaki a. the immunological impact of chemotherapy on the tumor microenvironment of oral squamous cell carcinoma. acta med okayama 2017; 71:219–26. https://doi.org/10.18926/amo/55204. 28. sun w, ma k, wang x, lui y, he h, guo y. jces 01.16 altered expression of programmed death-1 receptor (pd-1) and its ligand pd-l1, pd-l2 after neo-adjuvant chemotherapy in lung cancer. j thorac oncol 2017; 12:s1736. https://doi.org/10.10 16/j.jtho.2017.09.303. 29. song z, yu x, zhang y. altered expression of programmed death-ligand 1 after neoadjuvant chemotherapy in patients with lung squamous cell carcinoma. lung cancer 2016; 99:166–171. https://doi.org/10.1016/j.lungcan.2016.07.013. 30. sheng j, fang w, yu j, chen n, zhan j, ma y, et al. expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. sci rep 2016; 6:20090. https://doi.org/10.1038/srep20090. 31. fujimoto d, uehara k, sato y, sakanoue i, ito m, teraoka s, et al. alteration of pd-l1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients. sci rep 2017; 7:11373. https://doi.org/10.1038/ s41598-017-11949-9. 32. remark r, lupo a, alifano m, biton j, ouakrim h, stefani a, et al. immune contexture and histological response after neoad juvant chemotherapy predict clinical outcome of lung cancer patients. oncoimmunology 2016; 5:e1255394. https://doi.org/10.1 080/2162402x.2016.1255394. 33. ritprajak p, azuma m. intrinsic and extrinsic control of expr ession of the immunoregulatory molecule pd-l1 in epithelial cells and squamous cell carcinoma. oral oncol 2015; 51:221–8. https://doi.org/10.1016/j.oraloncology.2014.11.014. 34. doi t, ishikawa t, okayama t, oka k, mizushima k, yasuda t, et al. the jak/stat pathway is involved in the upregulation of pd-l1 expression in pancreatic cancer cell lines. oncol rep 2017; 37:1545–54. https://doi.org/10.3892/or.2017.5399. 35. liu st, hui g, mathis c, chamie k, pantuck aj, drakaki a, et al. the current status and future role of the phosphoinositide 3 kinase/akt signaling pathway in urothelial cancer: an old pathway in the new immunotherapy era. clin genitourin cancer 2018; 16:e269–76. https://doi.org/10.1016/j.clgc.2017.10.011. 36. achkar iw, abdulrahman n, al-sulaiti h, joseph jm, uddin s, mraiche f. cisplatin based therapy: the role of the mitogen activated protein kinase signaling pathway. j transl med 2018; 16:96. https://doi.org/10.1186/s12967-018-1471-1. 37. liu n, lv j, qi w, sun l, guo j, khao s, et al. programmed death 1 induces cell chemoresistance to 5-fluorouracil in gastric cancer cell lines. transl cancer res 2016; 5:781–8. https://doi.org/10.21037/tcr.2016.12.01. 38. ghebeh h, lehe c, barhoush e, al-romaih k, tulbah a, al-alwan m, et al. doxorubicin downregulates cell surface b7h1 expression and upregulates its nuclear expression in breast cancer cells: role of b7-h1 as an anti-apoptotic molecule. breast cancer res; 12:r48. https://doi.org/10.1186/bcr2605. 39. wimberly h, brown jr, schalper k, haack h, silver mr, nixon c, et al. pd-l1 expression correlates with tumorinfiltrating lymphocytes and response to neoadjuvant chemo therapy in breast cancer. cancer immunol res 2015; 3:326–32. https://doi.org/10.1158/2326-6066.cir-14-0133. 40. cerbelli b, pernazza a, botticelli a, fortunato l, monti m, sciattella p, et al. pd-l1 expression in tnbc: a predictive biomarker of response to neoadjuvant chemotherapy? biomed res int 2017; 2017:1750925. https://doi.org/10.1136/esmoopen-20 16-000150. 41. kitano a, ono m, yoshida m, noguchi e, shimomura a, shimoi t, et al. tumour-infiltrating lymphocytes are correlated with higher expression levels of pd-1 and pd-l1 in early breast cancer. esmo open 2017; 2:e000150. https://doi.org/10.1136/ esmoopen-2016-000150. 42. mclemore le, janakiram m, albanese j, shapiro n, lo y, zang x, et al. an immunoscore using pd-l1, cd68, and tumor-infiltrating lymphocytes (tils) to predict response to neoadjuvant chemotherapy in invasive breast cancer. appl immunohistochem mol morphol 2018; 26:611–19. https://doi. org/10.1097/pai.0000000000000485. 43. baras as, drake c, liu jj, gandhi n, kates m, hoque mo, et al. the ratio of cd8 to treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemo therapy in patients with muscle invasive urothelial carcinoma of the bladder. oncoimmunology 2016; 5:e1134412. https://doi. org/10.1080/2162402x.2015.1134412. 44. chen s, wang rx, liu y, yang wt, shao zm. pd-l1 expression of the residual tumor serves as a prognostic marker in local advanced breast cancer after neoadjuvant chemotherapy. int j cancer 2017; 140:1384–95. https://doi.org/10.1002/ijc.30552. 45. noro d, hatakeyama s, yoneyama t, hashimoto y, koie t, kawaguchi t, et al. post-chemotherapy pd-l1 expression correlates with clinical outcomes in japanese bladder cancer patients treated with total cystectomy. med oncol 2017; 34:117. https://doi.org/10.1007/s12032-017-0977-3. https://doi.org/10.1186/s13058-017-0884-8 https://doi.org/10.18926/amo/55204 https://doi.org/10.1016/j.jtho.2017.09.303 https://doi.org/10.1016/j.jtho.2017.09.303 https://doi.org/10.1016/j.lungcan.2016.07.013 https://doi.org/10.1038/srep20090 https://doi.org/10.1038/s41598-017-11949-9 https://doi.org/10.1038/s41598-017-11949-9 https://doi.org/10.1080/2162402x.2016.1255394 https://doi.org/10.1080/2162402x.2016.1255394 https://doi.org/10.1016/j.oraloncology.2014.11.014 https://doi.org/10.3892/or.2017.5399 https://doi.org/10.1016/j.clgc.2017.10.011 https://doi.org/10.1186/s12967-018-1471-1 https://doi.org/10.21037/tcr.2016.12.01 https://doi.org/10.1186/bcr2605 https://doi.org/10.1158/2326-6066.cir-14-0133 https://doi.org/10.1136/esmoopen-2016-000150 https://doi.org/10.1136/esmoopen-2016-000150 https://doi.org/10.1136/esmoopen-2016-000150 https://doi.org/10.1136/esmoopen-2016-000150 https://doi.org/10.1097/pai.0000000000000485 https://doi.org/10.1097/pai.0000000000000485 https://doi.org/10.1080/2162402x.2015.1134412 https://doi.org/10.1080/2162402x.2015.1134412 https://doi.org/10.1002/ijc.30552 https://doi.org/10.1007/s12032-017-0977-3 squ med j, august 2010, vol. 10, iss. 2, pp. 187-195, epub. 19th jun 10 submitted: 21st oct 09 revision req. 11th jan 10, revision recd. 28th feb 10 accepted: 22nd mar 10 in the last few years, the world has faced two major disasters. the first was economical recession; the second was the pandemic spread of a new reassortant influenza virus that spread all over the world in few weeks. economic recession is clearly man-made, with economic mismanagement leading to the collapse of international banks, but pandemic viruses occur naturally and man has to struggle with nature for his survival. on 17th april 2009, the center of disease control and prevention (cdc), in the usa, reported a new influenza a h1n1 strain with quadruple segment translocation in its rna.1 since then this strain has spread worldwide and on 11th june 2009 it was declared by the world health organization (who) to be a phase 6 pandemic virus (maximum threat).2 influenza pandemics have many effects on people, health care services and countries. the pandemic spread of influenza viruses is characterised by a high attack rate and department of microbiology & immunology, sultan qaboos university hospital, muscat, sultanate of oman email: almuharrmi@gmail.com a h1n1 2009 فهم وباء أنفلونزا زكريا املحرمي اإنتقال حلقي اأنفلونزا a مع فريو�شات من جديدة �شاللة واملك�شيك الأمريكية املتحدة الوليات يف امللخ�ص: يف اأبريل �شنة 2009 ظهرت ال�شاللة لهذه الوراثية املادة .)a h1n1 2009 ( رباعي يف احلم�س النووي الريبي اأدت اإىل تف�شي وباء، وقد �شنفت على اإنها اإنفلونزا وباًء جائحا ال�شاللة هذه العاملية ال�شحة منظمة ناجتة عن ثالث �شاللت خمتلفة من الب�رش والطيور واخلنازير. ويف يونيو 2009 اأعلنت اأ�رشع اجلديدة ال�شاللة وتنتقل التنف�شية، الُقَطريات خالل من الأنفلونزا فريو�س ينتقل عاما. 40 منذ ت�شجيله يتم عاملي وباء اأول ليكون من غريها من �شاللت الإنفلونزا مما يوؤدي اإىل �شعوبة ال�شيطرة على العدوى. غالبية احلالت امل�شابة بال�شاللة اجلديدة كانت خفيفة لكن بع�س املر�شى ح�شلت لديهم م�شاعفات والبع�س الآخر توفى. معظم الفحو�س املخربية لهذه ال�شاللة غري ح�شا�شة ما عدا تفاعل البوليمرييز دواء مثل النيورمينديز لأنزمي امل�شادة لالأدوية ت�شتجيب اجلديدة الوبائية ال�شاللة عالية. خربات ويتطلب الثمن باه�س وهو املت�شل�شل للقاحات �شحنه اأول توفري مت �شبتمرب 2009 منت�شف ويف لالأو�شيلتامفري. املقاومة احلالت بع�س �شجلت لكن والزمنفري، الأو�شيلتامفري ال�شاللة اجلديدة وكانت فعاليتها املناعية عالية جدا دون ت�شجيل اأعرا�س جانبية تذكر. اإن الرت�شد مهم جدا يف جميع مراحل الوباء اجلائح امل�شببة الإنفلونزا فريو�شات فهم هو املراجعة هذه من الهدف امل�شتقبل، يف الأوبئة حدوث ومنع الفريو�شية العدوى نزعة ور�شد لك�شف لالأوبئة اجلائحة ودرا�شة ال�شرتاتيجيات الالزمة ملراقبتها وتخفيف حدتها وال�شيطرة عليها. مفتاح الكلمات: الأنفلونزا، الوباء اجلائح، تفاعل البوليمرييز املت�شل�شل، اللقاح، الرت�شد. abstract: a new strain of influenza a virus, with quadruple segment translocation in its rna, caused an outbreak of human infection in april 2009 in usa and mexico. it was classified as influenza a h1n1 2009. the genetic material originates from three different species: human, avian and swine. by june 2009, the world health organization (who) had classified this strain as a pandemic virus, making it the first pandemic in 40 years. influenza a h1n1 2009 is transmitted by respiratory droplets; the transmissibility of this strain is higher than other influenza strains which made infection control difficult. the majority of cases of h1n1 2009 were mild and self limiting, but some people developed complications and others died. most laboratory tests are insensitive except the polymerase chain reaction (pcr) which is expensive and labour intensive. the influenza a h1n1 2009 virus is sensitive to neuraminidase inhibitors (oseltamivir and zanamivir), but some isolates resistant to oseltamivir have been reported. a vaccine against the new pandemic strain was available by mid-september 2009 with very good immunogenicity and safety profile. surveillance is very important at all stages of any pandemic to detect and monitor the trend of viral infections and to prevent the occurrence of future pandemics. the aim of this review is to understand pandemic influenza viruses, and what strategies can be used for surveillance, mitigation and control. keywords: influenza; pandemic; polymerase chain reaction; vaccine; surveillance. review understanding the influenza a h1n1 2009 pandemic zakariya al-muharrmi understanding the influenza a h1n1 2009 pandemic 188 | qu medical journal, august 2010, volume 10, issue 2 an increased level of mortality particularly in young adults. therefore, it necessary to understand influenza viruses that cause pandemics and what strategies can be used for surveillance, mitigation and control. the virus the influenza virus belongs to orthomyxoviridae family. it has three classes: a and b which only infect humans and c which is uncommon. its genetic material is made up of eight separate segments.3 the virus is enveloped with two important projections on the surface, these are haemagglutinin that binds to cell receptors in target tissues and neuraminidase that cleaves to the sialic acid in the cell wall to release the progeny viruses. influenza a has 16 different haemagglutinins and 9 different neuraminidases.4 it is classified according to the types of haemagglutinin and neuromindase on its surface, e.g. h1n1, h3n2 and h5n1. it infects not only humans, but also other mammals mainly pigs, birds and horses.3 two types of genetic mutations occur in the influenza a virus. first, genetic drift which is a point mutation leading to a mild changes on surface antigens, leading to new variant of the same virus which causes the recurrent epidemic influenza infections. second, genetic shift which occurs when genetic segments are translocated among influenza a viruses from different species e.g. human, birds and pigs leading to a completely new strain not previously existing in nature.3 such strains can cause pandemic infections if they have the ability to infect humans and the ability to be transmitted from one person to another. the current influenza a h1n1 2009 strain is a result of genetic translocation from three different species: one genetic segment from human influenza a h3n2, two segments from avian influenza a h1n1 and five segments from swine h1n1.5 in 1998, a new triple reassortant swine influenza virus was identified in north america. genetically it was made up of five segments derived from the north american classical a/h1n1swine virus, while the polymerase gene segments derived from either birds or humans. genetic analysis of the influenza a h1n1 2009 showed that it was derived from a new reassortment of six gene segments from the known triple reassortant swine virus.6 the genes encoding neuraminidase and the m protein were most closely related to those in influenza a viruses circulating in swine populations in eurasia.5 within a few months, the a h1n1 2009 virus became the predominant influenza strain worldwide.7 compared to seasonal strains, a h1n1 2009 replicates more efficiently and produces different cytokines resulting in more lung damage in animal models.8 history and phases of pandemic influenza influenza pandemics occur in waves. the who uses a six-phased approach to guide national preparedness plans against pandemics.9 phases 1–3 correlate with preparedness while phases 4–6 signal the need for mitigation efforts. in phase 1, no viruses circulating among animals have been reported to cause human infection. in phase 2, an animal influenza virus is known to have caused infection in humans. in phase 3, an animal or humananimal influenza reassortant virus has caused small clusters, but has not resulted in human-to-human transmission sufficient to sustain community-level outbreaks. phase 4 occurs when such viruses cause human-to-human transmission at communitylevel. in phase 5, the human-to-human spread of the virus attacks at least two countries in one who region. if the outbreak is recorded in more than one who region, the final “pandemic phase”, or phase 6, is declared.9 in the post-pandemic period, influenza disease activity returns to levels normally seen for seasonal influenza.9 the influenza a h1n1 virus was declared phase 6 by the who on 11th june 2009.2 global pandemics have been observed for several hundred years. the best documented pandemic occurred in 1918 (a (h1n1), spanish flu).10 it was estimated to have infected 50% of the world's population, with an estimated mortality of 40–50 million (mortality rate of 2–2.5%). the attack and mortality rates were highest among healthy adults (20–40 years old). the second was in 1957 (a(h2n2), asian flu) which affected around 40–50% of people during two waves, with a mortality rate of 1 in 4000 and the total death toll probably exceeding 1 million. the third was in 1968 (a(h3n2), hong kong flu) with similar morbidity and mortality to asian flu.11 aspirin use which is known to cause hyperventilation and pulmonary oedema in high doses, was the major factor in the high death rate zakariya al-muharrmi review | 189 to illness onset until the resolution of fever or until 5 to 7 days after the onset of symptoms.5 the attack rate of a h1n1 2009 was estimated to be between 20–30%.21 in a community setting the mitigation strategies for a pandemic depend on its level of severity and this is determined by the infectivity and case fatality rates. for low-severity pandemics with case fatality rates <0.5% and infectivity of 1.6 or below, such as the current pandemic, the preferred policy is a combination of social distancing with the use of antivirals for treatment and prophylaxis without school closure.22 school closure is a debatable option; the main reason for closure would be a high level of transmission leading to focal outbreaks and staff absenteeism.23 the greatest benefits of school closures are achieved when schools are closed very early on during an outbreak, ideally before 1% of the population falls ill;24 however, school closure have not shown benefits in previous outbreaks.23 regulations taken by national and international authorities to control the a h1n1 2009 pandemic need to address human rights according to siracusa principles. these principles states that social restriction should be: 1) in accordance with the law; 2) in the interest of a legitimate objective; 3) strictly necessary; 4) using the least intrusive or restrictive means available; 5) neither arbitrary nor discriminatory, and 6) subject to review.25 each country should have a complete preparedness plan for pandemic control. however, this is lacking in most countries which respond to such disasters out of fear or from economic and political self-interest rather than with policies based on scientific fact; even the who and the cdc lack key powers and resources to control pandemic viruses efficiently.26 clinical presentation the majority of cases of influenza a h1n1 2009 were mild and self limiting.8 the clinical presentation of influenza a h1n1 2009 is similar to those seen in seasonal influenza, with fever in 94% of patients, cough in 92% and sore throat in 66%.27 in admitted patients, the prevalence of symptoms is as follows: fever (95%); cough (88%); shortness of breath (60%); fatigue/weakness (43%); rhinorrhoea (38%); myalgias (36%); headache (34%); sore throat (31%); vomiting (29%); wheezing (26%) and diarrhoea (24%).28 the time between onset of symptoms and from spanish flu.12 other possible factors could be the unavailability of antibiotics which were not yet discovered to treat bacterial superinfection; primitive infection control practices and the destruction of health care facilities as a result of world war i. the first cases of the new pandemic influenza a h1n1 2009 infections were identified in april 2009 in the united states.1 by august 2009, the cumulative number of infections in the united states alone was estimated to be at least 1 million.13 however, there were only 556 confirmed deaths,14 i.e. the mortality rate was only 0.056%. infection control and mitigation strategies influenza viruses are transmitted by respiratory droplets, which do not normally travel more than one metre distance although coughing and sneezing can increase this distance by a few more metres. the virus can survive for 6 hours on a dry surface; when touched by hands it can be retransmitted. transmissibility of the a h1n1 2009 strain is higher than that of seasonal influenza strains.15 controlling the spread of influenza in a hospital setting is difficult and should include the following: isolating patients with suspected or documented influenza; sending home health care workers (hcw) with influenza-like illnesses and advising visitors showing symptoms of influenza not to come to hospital.16 hand washing with water and soap or alcohol-based hand sanitiser should be universal policy although some reports claim soap and water to be more effective than alcohol.17 it is recommended to keep one metre distance between sick and healthy people and the patient should cover his/her mouth and nose when sneezing or coughing. if the patient is admitted in to hospital, a droplet isolation policy should be followed; this requires a side room with normal pressure ventilation. hcw should wear surgical face masks when caring for patients with influenza. respirators, e.g. n95 masks, are indicated for hcw doing invasive procedures in the respiratory tree, e.g. intubation or bronchoscopy.18 some researchers claim surgical face masks to be as effective as n95 masks in the prevention of seasonal influenza.19 others claim they are ineffective against a h1n1 2009.20 the patient is considered infectious from one day prior understanding the influenza a h1n1 2009 pandemic 190 | qu medical journal, august 2010, volume 10, issue 2 admission to the hospital ranged from 4 to 25 days.29 in australia and new zealand, the rate of icu admission was 28.7 cases per million inhabitants.30 the major determinants of icu admission are: a) shortness of breath, which was seen in (87%) of admitted patients, and b) chest radiograph results consistent with pneumonia (seen in 73%), compared with 51% and 28% in those not admitted to the icu.28 major complications of influenza include viral pneumonia, peripheral neuropathy, encephalitis, myocarditis and myositis.31 these are mainly seen in people with chronic respiratory diseases, chronic cardiac diseases, immune suppression, neurological disorders, chronic haemoglobinopathies, diabetes and obesity.32 the immunoglobulin subclass, mainly igg2 deficiency, has been also associated with severe h1n1 infection. patients taking aspirin are at high risk for complications and development of fatty hepatitis with encephalopathy (ray's syndrome).33 children less than 5 years old are at higher risk,33 and paediatric presentations of a h1n1 2009 can be atypical; severity is often associated with underlying disease, and rates of secondary bacterial infections are low.34 there were some case reports of children presenting with pneumomediastinum as a complication of a h1n1 2009.35 there are other case reports of children presenting with signs of influenza-like illness and seizures or altered mental states.36 the rate of hospital admission among pregnant women during the first month of the influenza a h1n1 2009 outbreak was higher than it was in the general population (0.32 per 100,000 pregnant women, versus 0.076 per 100,000 of the population at risk).37 in seasonal influenza, most hospitalisations occur among children less than 2 years of age, the elderly ≥65 years of age and patients with certain medical conditions.29 for pandemic a h1n1 2009, most admissions were in young adults; in the usa 38% of admitted patients were young adults aged from 18–49 years.29 mortality annually around 3 to 5 million people suffer from severe seasonal influenza epidemics worldwide, the number of fatalities being around 250,000 to 500,000.38 in usa, the estimated annual mortality caused by seasonal influenza is 23,710 or 0.91% of all deaths.39 the high pandemic influenza a h1n1 2009 mortality in mexico was mainly due to delayed careseeking. the main reason for delayed care-seeking and mortality of influenza a h1n1 2009 in usa was the lack of health insurance.40 in comparison with seasonal influenza, the paediatric mortality caused by pandemic a h1n1 2009 occurred mainly in children with known co-morbidities including chronic lung disease or immunodeficiency. the median age was higher than that for seasonal influenza (9 versus 2.7 years).41 compared to seasonal influenza, the proportion of deaths in the usa was below the epidemic threshold.42 some people believe that secondary bacterial infections were the main cause of high mortality in past influenza pandemics.43 these infections have not been shown to be responsible for deaths in the current pandemic, except in 29% of cases.44 investigation people infected with influenza a h1n1 2009 are assumed to be shedding the virus and potentially infectious one day prior to illness onset until resolution of fever.45 some reports have shown that viral shedding may continue for at least 7 days.46 some patients might shed the virus for longer periods, for example young infants and the immunocompromised.45 upper respiratory tract specimens are the most appropriate samples for laboratory testing of pandemic influenza a h1n1 2009. samples should be taken from the nasopharynx (a nasopharyngeal swab), nasopharyngeal aspirates, throat swabs and transbronchial aspirates. swab specimens should be collected using swabs with a synthetic tip (e.g. polyester or dacron®), but not calcium alginate or cotton tips; the shaft should be made of aluminum or plastic, but not of wood. specimens should be placed into sterile viral transport media. all respiratory specimens should preferably be sent immediately to the laboratory, but if a delay is expected they should be kept at 4°c for no longer than 4 days. clinical specimens should be shipped on wet ice or cold packs in appropriate packaging.45 influenza a h1n1 2009 virus can be detected in respiratory specimens by different tests. these tests differ in their sensitivity, specificity and ability to distinguish between influenza a subtypes (e.g. 2009 h1n1 versus seasonal h1n1 versus seasonal h3n2 viruses).47 rapid influenza diagnostic tests (ridts), have variable sensitivities and specificities, some experts zakariya al-muharrmi review | 191 emergence of oseltamivir resistance; therefore, who guidelines have discouraged prescribing antivirals to patients with mild disease forms unless they have risk factors for complications.62 the antiviral drug of choice is oseltamivir; zanamivir is only indicated in patients with oseltamivir resistant strains. oseltamivir is also the drug of choice in treatment and chemoprophylaxis for pregnant women; zanamivir may also be used, but there are less data available about its safety in pregnant women.57 antibiotic chemoprophylaxis is not recommended in patients with h1n1 2009; however, when pneumonia is present, treatment with antibiotics should follow the recommendations from published evidence-based guidelines for community-acquired pneumonia.63 vaccine universal influenza immunisation is known to reduce the rate of seasonal influenza and to decrease influenza-associated respiratory antibiotic prescriptions by 64%.64 who experts promised that the vaccine for influenza a h1n1 2009 would be available within 5–6 months from the date of discovery of the new pandemic virus.65 they estimated that first shipment would start in midseptember and this took place. it was expected that vaccine manufacturing capacity would not meet the demand of all countries, given the fact some experts recommend two doses of the vaccine for each individual.66 the who estimated that 3 billion doses of vaccine would be produced within a one year period.67 other experts claim that 4.9 billion could be produced within a year.68 thirty-three influenza a h1n1 2009 vaccine formulations were reported, most of them based on whole-virion or split-virion antigens, and 12 products would be adjuvanted (in most cases with aluminum hydroxide or as an oil-in water emulsion).68 the usa food and drug administration gave approval to four influenza a h1n1 2009 monovalent vaccine manufacturers in mid-september 2009. none of them contained adjuvants.69 the approval was made on the basis of standards developed for vaccine strain changes for seasonal influenza vaccines; adherence to manufacturing processes; product quality testing, and lot release procedures developed for seasonal vaccines.69 preliminary data indicate that the immunogenicity and safety of these having reported sensitivity of 47%, and specificity of 86%.48 others have reported sensitivity of 51%, and specificity of 99%.49 direct immunofluorescence (dif) has variable sensitivities (47–93%), but high specificity ≥96%.49 some reports claim that the dif has a sensitivity of 93%, specificity of 97%, positive predictive value of 95% and negative predictive value of 96%.50 viral culture was the gold standard for influenza virus testing; however, it is only 88.9% sensitive for influenza a h1n1 2009.51 therefore, a negative viral culture does not exclude infection with influenza a h1n1 2009.45 some researchers have described detection of the virus using microarray techniques.52 pcr testing is highly sensitive (lower limit of detection, 1–10 infectious units).53 real-time pcr is the test of choice for influenza a h1n1 2009.54 it is more rapid and sensitive than cell culture.55 however, pcr is expensive and labour intensive; therefore, it is impractical to investigate all affected patients because of the large number of people infected.56 it is recommended to test hospitalised patients with suspected influenza or patients for whom a diagnosis of influenza will change decisions regarding clinical care, infection control, or management of close contacts. patients dying of an acute illness, where influenza was suspected, should also be tested.47 treatment influenza a h1n1 2009 virus is resistant to m2 inhibitors (amantadine and rimantadine), but sensitive to neuraminidase inhibitors (oseltamivir and zanamivir).57 oseltamivir is an oral agent, while zanamivir comes in puffs for inhalation. unlicensed intravenous formulation of zanamivir has been used successfully in treatment of ventilated patient not responding to oral oseltamivir.58 as of 4th october 2009, the who declared the isolation of 31 influenza a h1n1 2009 isolates resistant to oseltamivir, but sensitive to zanamivir. these were from patients taking prolonged courses of oseltamivir prophylaxis.59 a meta-analysis has shown that neuraminidase inhibitors shorten the duration of illness in children with seasonal influenza and reduce household transmission.60 the same positive effects were reported in adults.61 these effects prompted people to use oseltamivir sooner leading to the understanding the influenza a h1n1 2009 pandemic 192 | qu medical journal, august 2010, volume 10, issue 2 vaccines are similar to those of seasonal influenza vaccines.69 all influenza vaccines available in the united states for the 2009–10 influenza season are produced using embryonated hen's eggs and contain residual egg protein.69 there are concerns that the vaccine might cause guillain-barré syndrome (gbs) causing peripheral nerve damage. in 1976, the usa withdrew an influenza vaccine after a spike in cases of this neurological disease.70 experts have disputed that decision, based on the argument that people would be more likely to get gbs as a result of the influenza itself rather than from the vaccine. the other argument against the association of the vaccine with gbs was that in 1976 science was less well developed. all influenza vaccines in the 30 years since 1976 have shown excellent safety records. in any case, a link between gbs and vaccination is basically impossible to demonstrate at this stage.70 a preliminary report from a randomised control trial in australia for the safety and immunogenicity of 15 µg dose of an inactivated, split virus 2009 h1n1 vaccine in healthy adults between the ages of 18 and 64 years showed immunogenicity in 96.7%. local discomfort (e.g. injection-site tenderness or pain) was reported in 46.3%. systemic symptoms (e.g. headache) were reported in 45%. no deaths or serious adverse events were reported.71 another study from uk showed that a 7.5 µg dose of inactivated vaccine with adjuvant was immunogenic to 92%, while the adjuvanted dose was only 76% immunogenic. the most common side effects were pain at the injection site in 70% and muscle aches in 42% of subjects.72 live seasonal influenza vaccines have been associated with increased respiratory diseases, e.g. bronchitis in children.73 surveillance surveillance is very important at all stages of any pandemic. it provides information about the change of incidence, severity of infection, risk in specific groups, types of complications, appearance of new strains and monitors drug sensitivity. such information is important for the development of policies regarding control measures, resource allocation and responses to other public health needs.56 the who suggested case-based reporting at the start of the pandemic, rather than shifting to a qualitative assessment of pandemic influenza activity, combined with virological sampling of a representative number of isolates. it also recommended keeping continuous records of influenza-like illnesses with laboratory testing for pandemic h1n1 in a subset of cases. the general population perceptions of disease magnitude, risk and severity are very much influenced by surveillance data.56 because the world has become a global village, every country should implement a surveillance system to detect and monitor the trends of their viral infections to prevent the occurrence of future pandemics. conclusion the pandemic influenza a h1n1 2009 is currently the most prevalent influenza virus. most of the cases are mild, but there are high incidences in children and young adults. the presentation and complications are similar to those caused by seasonal influenza strains, but the mortality rate to date seems to be lower compared to seasonal strains. a vaccine against the pandemic strain has already been distributed in the markets with a very good safety profile. a major lesson learned from this pandemic is the establishment of surveillance systems to detect new viruses and track the trends of outbreaks. references 1. cdc, center for disease control. swine influenza a (h1n1) infection in two children southern california, march-april 2009. mmwr morb mortal wkly rep 2009; 58:400–2. 2. who. influenza a (h1n1): pandemic alert phase 6 declared, of moderate severity. from www.euro.who. int/influenza/ah1n1/20090611_11#. accessed july 2009. 3. webster rg, bean wj, gorman ot, chambers tm, kawaoka y. evolution and ecology of type a influenza viruses. microbiol rev 1992; 56:152–79. 4. chen jm, sun yx, chen jw, liu s, yu jm, shen cj, et al. panorama phylogenetic diversity and distribution of type a influenza viruses based on their six internal gene sequences. virol j 2009; 6:137. 5. novel swine-origin influenza a (h1n1) virus investigation team, dawood fs, jain s, finelli l, shaw mw, lindstrom s, garten rj, et al. emergence of a novel swine-origin influenza a (h1n1) virus in humans. n engl j med 2009; 360:2605–15. 6. zimmer sm, burke ds. historical perspective zakariya al-muharrmi review | 193 antimicrobial agents and chemotherapy (icaac), san francisco, usa, 12–15 september 2009. 21. who. pandemic (h1n1) 2009: priority areas for research. from www.searo.who.int/linkfiles/ c d s _ h 1 n 1 _ 2 0 0 9 _ r e s e a r c h _ p r i o r i t i e s . p d f . accessed december 2009. 22. perlroth dj, glass rj, davey vj, cannon d, garber am, owens dk. health outcomes and costs of community mitigation strategies for an influenza pandemic in the united states. clin infect dis 2010; 50:165–74. 23. cauchemez s, ferguson nm, wachtel c, tegnell a, saour g, duncan b, et al. closure of schools during an influenza pandemic. lancet infect dis 2009; 9:473–81. 24. who. measures in school settings, pandemic (h1n1) 2009 briefing note 10. from www.who. i nt / c s r / d i s e a s e / s w i n e fl u / n o te s / h 1 n 1 _ s ch o o l _ measures_20090911/en/. accessed september 2009. 25. tarantola d, amon j, zwi a, gruskin s, gostin l. h1n1, public health security, bioethics, and human rights. lancet 2009; 373:1495. 26. lawrence o, gostin jd. influenza a (h1n1) and pandemic preparedness under the rule of international law. jama 2009; 301:2376–8. 27. belshe rb. implications of the emergence of a novel h1 influenza virus. n engl j med 2009; 360:2667. 28. jain s, kamimoto l, bramley am, schmitz am, benoit sr, louie j, et al. hospitalized patients with 2009 h1n1 influenza in the united states, april– june 2009. n engl j med 2009; 361:1935–44. 29. perez-padilla r, de la rosa-zamboni d, ponce de leon s, hernandez m, quiñones-falconi f, bautista e, et al. pneumonia and respiratory failure from swine-origin influenza a (h1n1) in mexico. n engl j med 2009; 361:680–9. 30. anzic influenza investigators, webb sa, pettilä v, seppelt i, bellomo r, bailey m. critical care services and 2009 h1n1 influenza in australia and new zealand. n engl j med 2009; 361:1925–34. 31. kuiken t, taubenberger jk. pathology of human influenza revisited. vaccine, 2008; 26:59–66. 32. cdc, center for disease control. cdc guidance on helping child care and early childhood programs respond to influenza during the 2009–2010 influenza season. from www.cdc.gov/h1n1flu/ childcare/guidance.htm. accessed february 2010. 33. gordon cl, johnson pd, permezel m, holmes ne, gutteridge g, mcdonald cf, et al. association between severe pandemic 2009 influenza a (h1n1) virus infection and immunoglobulin g2 subclass deficiency. clin infect dis 2010; 50:672–8. 34. hackett s, hill l, patel j, ratnaraja n, ifeyinwa a, farooqi m, et al. clinical characteristics of paediatric h1n1 admissions in birmingham, uk. lancet 2009; 374:605. emergence of influenza a (h1n1) viruses. n engl j med 2009; 361:279–85. 7. hall rj, peacey mp, ralston jc, bocacao j, ziki m, gunn w, et al. pandemic influenza a (h1n1) viruses currently circulating in new zealand are sensitive to oseltamivir. euro surveill 2009; 14:19282. 8. itoh y, shinya k, kiso m, watanabe t, sakoda y, hatta m, et al. in vitro and in vivo characterization of new swine-origin h1n1 influenza viruses. nature 2009; 460:1021–5. 9. who. current who phase of pandemic alert. from www.who.int/csr/disease/avian_influenza/phase/ en/. accessed july 2009. 10. laver g, garman e. pandemic influenza: its origin and control. microbes infect 2002; 4:1309–16. 11. horimoto t, kawaoka y. influenza: lessons from past pandemics, warnings from current incidents. nat rev microbiol 2005; 3:591–600. 12. starko km. salicylates and pandemic influenza mortality, 1918–1919 pharmacology, pathology, and historic evidence. clin infect dis 2009; 49:1405–10. 13. cdc, center for disease control. update: influenza activity – united states, april–august 2009. mmwr morb mortal wkly rep 2009; 58:1009–12. 14. ecdc daily update. pandemic (h1n1) 2009. update 31 august 2009. from www.ecdc.europa. eu/en/healthtopics/documents/090831_influenza_ ah1n1_situation_report_1700hrs.pdf. accessed september 2009. 15. herfst s, chutinimitkul s, ye j, de wit e, munster vj, schrauwen ej, et al. introduction of virulence markers in pb2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission. j virol 2010; 84:3752–8. 16. salgado cd, farr bm, hall kk, hayden fg. influenza in the acute hospital setting. lancet infect dis 2002; 2:145–55. 17. grayson ml, melvani s, druce j, barr ig, ballard sa, johnson pd, et al. efficacy of soap and water and alcohol-based hand-rub preparations against live h1n1 influenza virus on the hands of human volunteers. clin infect dis 2009; 48:285–91. 18. who. infection prevention and control in health care for confirmed or suspected cases of pandemic (h1n1) 2009 and influenza-like illnesses. from www.who.int/csr/resources/publications/swineflu/ swineinfinfcont/en/index.html. accessed december 2009. 19. loeb m, dafoe n, mahony j, john m, sarabia a, glavin v, et al. walter surgical mask vs n95 respirator for preventing influenza among health care workers a randomized trial. jama 2009; 302:1865–71. 20. macintyre cr. surgical masks do not protect health care workers against influenza and other respiratory viruses, but n95 masks offer significant protection. presentation. 49th interscience conference on understanding the influenza a h1n1 2009 pandemic 194 | qu medical journal, august 2010, volume 10, issue 2 35. hasegawa m, hashimoto k, morozumi m, ubukata k, takahashi t, inamo y. spontaneous pneumomediastinum complicating pneumonia in children infected with 2009 pandemic influenza a (h1n1) virus. clin microbiol infect 2010; 16:195–9. 36. cdc, center for disease control. neurologic complications associated with novel influenza a (h1n1) virus infection in children dallas, texas, may 2009. mmwr morb mortal wkly rep 2009; 58:773–8. 37. jamieson dj, honein ma, rasmussen sa, williams jl, swerdlow dl, biggerstaff ms, et al. h1n1 2009 influenza virus infection during pregnancy in the usa. 2009. lancet 2009; 374:429–30. 38. who. influenza (seasonal) april 2009. from www. who.int/mediacentre/factsheets/fs211/en/index. html. accessed july 2009. 39. foppa im, hossain mm. revised estimates of influenza-associated excess mortality, united states, 1995 through 2005. emerg themes epidemiol 2008; 5:26. 40. lurie n. h1n1 influenza, public health preparedness, and health care reform. n engl j med 2009; 361:843–5. 41. lister p, reynolds f, parslow r, chan a, cooper m, plunkett a, et al. swine-origin influenza virus h1n1, seasonal influenza virus, and critical illness in children. lancet 2009; 374:605–7. 42. cdc, center for disease control. flueview. week 30 ending august 1, 2009. from www.cdc.gov/flu/ weekly/pdf/external_f0930.pdf. accessed august 2009. 43. zhang h, chen l. possible origin of current influenza a h1n1 viruses. lancet infect dis 2009; 9:456–7. 44. cdc, center for disease control. bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza a (h1n1), united states, may-august 2009. mmwr morb mortal wkly rep 2009; 58:1–4. 45. cdc, center for disease control. interim guidance on specimen collection, processing, and testing for patients with suspected novel influenza a (h1n1) virus infection. from www.cdc.gov/h1n1flu/ specimencollection.htm. accessed july 2009. 46. hayden fg, fritz r, lobo mc, alvord w strober w, straus se. local and systemic cytokine response during experimental human influenza a virus infection. j clin invest 1998; 101:643–9. 47. cdc. interim recommendations for clinical use of influenza diagnostic tests during the 2009-10 influenza season. from www.cdc.gov/h1n1flu/ guidance/diagnostic_tests.htm. accessed september 2009. 48. cdc. performance of rapid influenza diagnostic tests during two school outbreaks of 2009 pandemic influenza a (h1n1) virus infection connecticut. mmwr morb mortal wkly rep 2009; 58:029–32. 49. faix dj, sherman ss, waterman sh. rapid-test sensitivity for novel swine-origin influenza a (h1n1) virus in humans. n engl j med 2009; 361:728–9. 50. pollock nr, duong s, cheng a, han ll, smole s, kirby je. ruling out novel h1n1 influenza virus infection with direct fluorescent antigen testing. clin infect dis 2009; 49:66–8. 51. ginocchio cc, zhang f, manji r, arora s, bornfreund m, falk l, et al. evaluation of multiple test methods for the detection of the novel 2009 influenza a (h1n1) during the new york city outbreak. j clin virol 2009; 45:191–5. 52. lu q, xing-quan z, sergei l, pond k, reed s, schooley rt, et al. detection in 2009 of the swine origin influenza a (h1n1) virus by a subtyping microarray j clin microbiol 2009; 47:3060–1. 53. petric m, comanor l, petti ca. role of the laboratory in diagnosis of influenza during seasonal epidemics and potential pandemics. j infect dis 2006; 194:98– 110. 54. who. who information for laboratory diagnosis of new influenza a (h1n1) virus in humans. from www.who.int/csr/resources/ p u b l i c a t i o n s / s w i n e fl u / w h o _ d i a g n o s t i c _ recommendationsh1n1_20090521.pdf. accessed november 2009. 55. whiley dm, bialasiewicz s, bletchly c, e. faux ce, harrower b, gould ar, et al. detection of novel influenza a(h1n1) virus by real-time rt-pcr. j clin virol 2009; 45:203–4. 56. lipsitch m, hayden fg, cowling bj, leung gm. how to maintain surveillance for novel influenza a h1n1 when there are too many cases to count. lancet 2009; 374:1209–11. 57. tanaka t, nakajima k, murashima a, garciabournissen f, koren g, ito s. safety of neuraminidase inhibitors against novel influenza a (h1n1) in pregnant and breastfeeding women. can med assoc j 2009; 181:55–8. 58. kidd im, down j, nastouli e, shulman r, grant pr, howell dc, et al. h1n1 pneumonitis treated with intravenous zanamivir. lancet 2009; 374:1036. 59. who. pandemic (h1n1) 2009 update 69. from www.who.int/csr/don/2009_10_09/en/index.html. accessed october 2009. 60. shun-shin m, thompson m, heneghan c, perera r, harnden a, mant d. neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials. bmj 2009; 339:3172. 61. jefferson t, demicheli v, di pietrantonj c, jones m, rivetti d. neuraminidase inhibitors for preventing and treating influenza in healthy adults. cochrane database syst rev 2006; 3:1265. 62. who. who guidelines for pharmacological zakariya al-muharrmi review | 195 68. collin n, de radigues x, world health organization h1n1 vaccine task force. vaccine production capacity for seasonal and pandemic (h1n1) 2009 influenza. vaccine 2009; 27:5184 –6. 69. cdc, center for disease control. update on influenza a (h1n1) 2009 monovalent vaccines. mmwr morb mortal wkly rep 2009: 58:1100–1. 70. ellis o. swine flu vaccine is a "thousandfold" safer than the infection, say experts. bmj 2009; 339:3802. 71. greenberg me, lai mh, hartel gf, wichems ch, gittleson c, bennet j, et al. response after one dose of a monovalent influenza a (h1n1) 2009 vaccine —preliminary report. n engl j med 2009; 361:1945– 52. 72. clark tw, pareek m, hoschler k, dillon h, nicholson kg, groth n, et al. trial of influenza a (h1n1) 2009 monovalent mf59-adjuvanted vaccine preliminary report. n engl j med 2009; 361:680–9. 73. neto hb, farhat ck, tregnaghi mw, madhi sa, razmpour a, palladino g, et al. efficacy and safety of 1 and 2 doses of live attenuated influenza vaccine in vaccine-naive children. pediatr infect dis j 2009; 28:365–71. management of pandemic (h1n1) 2009 influenza and other influenza viruses 20 august 2009. from www.who.int/csr/resources/publications/swineflu/ h 1 n 1 _ g u i d e l i n e s _ p h a r m a c e u t i c a l _ m n g t . p d f . accessed august 2009. 63. who. clinical management of human infection with new influenza a (h1n1) virus: initial guidance. from www.emro.who.int/csr/h1n1/pdf/clinical_ management_21_5_2009.pdf. accessed july 2009. 64. kwong jc, maaten s, upshur re, patrick dm, marra f. the effect of universal influenza immunization on antibiotic prescriptions: an ecological study. clin infect dis 2009; 49:750–6. 65. who. pandemic influenza vaccine manufacturing process and timeline. from www.who.int/csr/ disease/swineflu/notes/h1n1_vaccine_20090806/ en/. accessed august 2009. 66. the lancet. supply and safety issues surrounding an h1n1 vaccine. lancet 2009; 374:358. 67. who. pandemic influenza vaccines: current status. from www.who.int/csr/disease/swineflu/notes/ pandemic_influenza_vaccines_20090924/en/index. html. accessed september 2009. a ten-year girl presented at sultan qaboos university hospital with poor school performance and generalised tonic clonic seizures in the previous three months. her birth history and antenatal history were normal. she also had poor school performance. her other siblings were normal. her general physical examination and neurological examination was unremarkable. there were no neurocutaneous lesions. an assessment revealed an iq of 57, which is very low. the routine blood work up was normal. an electroencephalogram showed left temporal region seizure discharges with generalisation. a magnetic resonance imaging scan of the brain revealed complete band heterotopias in both hemispheres (double cortex) [figures 1 and 2]. neuronal migration disorders (nmd), are seen in children with psychomotor developmental delay, epilepsy and mental retardation. physical examination is usually normal in these children squ med j, april 2010, vol. 10, iss. 1, pp. 136-137, epub. 17th apr 10 submitted 12th oct 09 revision req. 9th dec 09, revision recd. 16th jan 09 accepted 20th jan 09 departments of 1child health, and 2radiology, sultan qaboos university hospital, muscat, oman; department of 3radiology, college of medicine and health sciences, sultan qaboos university, muscat, oman. *to whom correspondence should be addressed. email: koul@squ.edu.om ع ُمغايِر شريطي أو قشرة مزدوجة طفلة عمرها عشر سنوات بَتَوٍضُ )دماغني( رو�شان ك�ل، اآمنة الفطي�شي، قي�شل العزري، راجيف جني a ten year-old girl with band heterotopia or double cortex (two brains) *roshan koul,1 amna alfutaisi,1 faisal alazri,2 rajeev jain3 interesting medical image figure 1: magnetic resonance imaging t1 weighted axial image of the brain shows double cortex. arrows indicate two layers of grey matter separated by bright looking white matter. figure 2: magnetic resonance imaging t1 weighted axial image (inversion recovery), shows bilateral band heterotopia (double cortex). large arrows denote grey matter and small arrows white matter. roshan koul,amna alfutaisi,faisal alazri and rajeev jain interesting medical image | 137 except neurocutaneous disorders. minor forms of nmd are picked up only when imaging is done. the normal human brain goes through three major phases of morphogenesis which are neuronal production, neuronal migration and differentiation. this mechanism is complex and chemical signals and guides control this.1 neuronal production and migration starts at six weeks of gestation and proceeds until twenty-six weeks. after this phase, differentiation and maturation continue until the age of 15 years.1 heterotopias are one of the nmds, where in ectopic grey matter cells get arrested in inappropriate sites in the brain. the cells may be arrested between the leptomeninges and periventricular region. the cells arrested in the subependymal region are called subependymal nodular heterotopias. the cells arrested below the proper cortex and separated from the cortex by a thin band of white matter, are called subcortical band heterotopias (sbh). when this band is circumferential beneath the cortex, it is called a double cortex as was seen in our child. this condition is very rare with only about 120 cases reported in the world medical literature.2 the syndrome is usually associated with mutations in the doublecortin (dcx) (xq22.3-q23) gene, and much less frequently in the lis1 (17p13.3) gene. the majority of patients with sbh are sporadic, most patients are females and few patients with familial x-linked inheritance have been seen.2 heterotopias may be isolated or part of a syndrome. the exact incidence of heterotopias in the general population is unknown; however, heterotopias formed 11.6% of cases of nmd in our series.3 only one of them had sbh, forming about one percent of nmd. a c k n o w l e d g m e n t this case was presented on 12th november 2008 in the squ clinical-pathological conference series (scraps) as: “are two brains better than one?” 1. caviness vs jr, goto t, tarui t, takahashi t, bhide pg, nowakowski rs. cell output, cell cycle duration and neuronal specification: a model of integrated mechanisms of the neocortical proliferative process. cerebral cortex 2003; 13:592–8. 2. d’agostino md, bernasconi a, das s, bastos a, valerio rm, palmini a, et al. subcortical band heterotopia (sbh) in males: clinical, imaging and genetic findings in comparison with females. brain 2002; 125:2507–22. 3. koul rl, alfutaisi a, sankhala dk, javad h, william rr. pattern of childhood neuronal migration disorders in oman. neurosciences 2009; 14:158–62. july 2008.indd 223 f r a c t u r e o f s u p r a c o n d y l a r p r o c e s s o f t h e h u m e r u s sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 223-225 sultan qaboos university© submitted 7th february 2008 accepted 15th april 2008 department of orthopaedics, ibri regional hospital, sultanate of oman email: dr.s.s.suresh@gmail.com fracture of supracondylar process of the humerus s s suresh abstract the supracondylar process of the humerus is a rare skeletal anomaly, which is usually an incidental finding while an xray is done for some other purpose. the process can fracture resulting in pain and tender mobile swelling over the medial aspect of the arm, and consequent neurovascular symptoms, or entrapment neuropathies. the anomaly, which fractured in a clinical situation, is described, followed by a review of the literature. keywords: humeral fractures; median nerve; entrapment neuropathies; osteochondroma; case report; oman. العضد لعظم اللقمة فوق ما نتوء في كسر سوريش س. س. أن والنتوء ميكن ما. ــرض لغ ــينية س ــعة تؤخذ أش عندما عرضياً ما يوجد وهو غالباً نادر هيكلي ــذوذ ش هو العضد عظم في ــص: نتوء اللقمة امللخ وصف مت التقرير هذا في انحصارية. عصبية وعائية وإعتالالت – عصبية وأعراض ، للذراع ــية األنس مؤملا فوق اجلهة متحركا وورما أملا ــبباً مس ــر ينكس . الطبية األدبيات مراجعة مع سريرية حاالت في كسر مع الشذوذ هذا ، عمان. حالة تقرير ، العظم الغضروفي ، االنحصارية العصبية اإلعتالالت ، املتوسط ، العصب عضدية : كسور الكلمات مفتاح the supracondylar process of the humerus is a rare skeletal anomaly seen in about 1 % of human beings and usually detected accidentally.there are many potential sites for compression of the median nerve in the arm resulting in entrapment neuropathies. the least common cause of compression is the supracondylar process and the supracondylar foramen.1 rarely, this can present as claudication of the forearm. the spur can fracture resulting in painful swelling over the medial aspect of the arm. c a s e r e p o r t a forty year old man presented at ibri regional hospital, oman with a painful right elbow following a road traffic accident. he had an undisplaced fracture of the ala of the sacrum, with a break in the inferior pubic ramus. there was a tender mobile swelling over the medial aspect of the distal humerus which was noticed on admission. there was no distal neurovascular deficit. x-rays revealed a fracture of the supracondylar process. the patient was given an arm sling for three weeks. subsequent periodical assessment did not reveal any neurovascular compromise. d i s c u s s i o n a supracondylar process, an anomaly seen in about 1% of the population, is a bony projection found about 57 cm above the medial epicondyle of the humerus. it arises from the anteromedial aspect of the distal humerus and is directed downward, forward and medially pointing to the medial epicondyle. a fibrous band called the ligament of struthers, is typically associated with the supracondylar spur and connects it to the medial epicondyle, thereby forming a ring. the median nerve and the brachial artery pass through this. it is usually an incidental finding when x-rays are taken for some other purpose. the fibrous band of struthers corresponds to the lower part of the tendon of the vestigial latissimocondyloideus muscle seen in climbing mammals.2 the supracondylar process, the fibrous c a s e r e p o r t 224 s s s u r e s h band and humerus form a foramen. this is similar to the supratrochlear foramen seen in many animals. accessory slips of pronator teres may arise from the supracondylar process.3 the incidence varies from 13.5%.4, 5 knox in 1841 first reported its occurrence in man, as it was previously thought to be present only in animals.6 the supracondylar process was described in detail by struthers in 1849.1, 7 in 1930, lund presented the first case of a fracture of the supracondylar process.6 the process gets fractured occasionally when it is felt as a tender mobile piece of bone just above the elbow medially and it is easily made out in radiographs. if it has fractured, the treatment is excision with due care to the neurovascular structures. conservative management is recommended if there are no neurovascular symptoms after a fracture.8 compression of the nerve or artery can occur at many sites in the upper limb, and the least common cause of compression is the supracondylar process and the supracondylar foramen.1 the supracondylar foramen may be a site for entrapment of the brachial artery and the median nerve.3 solieri in 19299 first described the spur and the ligament as a cause of median nerve compression. the symptomatology can mimic carpal tunnel syndrome or may cause features of claudication pain in the forearm. the branching pattern of the median nerve in the forearm is abnormal in those with a spur and a struthers ligament.9 occasionally, the ulnar nerve may be stretched over the spur and can result in ulnar nerve palsy. the symptoms are exaggerated by active extension and pronation of the forearm. it should be differentiated from osteochondroma, which projects away from the elbow joint, and the bony cortex of the humerus is continuous with the tumour.10 usually it is seen in an asymptomatic patient as a painless mass or on an x-ray taken for some other purpose. the anatomic relationship with the neurovascular structures is well demonstrated by magnetic resonance imaging (mri).10 pecina et al recommend mri in peripheral nerve compression syndromes, and they reported an anomaly which they named “incomplete struthers ligament”. in their case though the ligament was incomplete it functioned the same way as a complete ligament.11 c o n c l u s i o n purpose of this paper is to raise awareness of this entity and its clinical significance. it should also be differentiated from the osteochondromas arising from the lower medial border of the distal humerus. distal humeral osteochondromas project away from the elbow. in a patient with pain and sensory disturbance of the forearm and hand, the elbow should be routinely examined for the presence of a supracondylar spur. r e f e r e n c e s 1. kessel l, rang m. supracondylar spur of the humerus. j bone joint surg 1966; 48b:765-769. 2. curtis ja, o’hara ae, carpenter gg. spurs of the mandible and supracondylar process of the humerus in cornelia de lange syndrome. am j roentgenol 1977; 129:156-158. 3. koshy s, rabi s, indrasingh i, vettivel s. two anatomical variations associated with potential vascular entrapment in the upper limb. eur j anat 2003; 7:97-100. 4. pieper i. on the incidence of the supracondyloid procfigure 1: oblique view of the right elbow showing supracondylar process 225 f r a c t u r e o f s u p r a c o n d y l a r p r o c e s s o f t h e h u m e r u s ess. am j phys anthrop 1925; 8:169-171. 5. doane cp. fractures of the supracondylar process of the humerus. j bone joint surg 1936; 18:757-759. 6. newman a. the supracondylar process and its fracture. am j roentgenol 1969; 105:844-848. 7. bartels rhma, grotenhuis ja, kauer jmg, the arcade of struthers: an anatomical study. acta neurochir 2003; 145:293-300. 8. kolb lw, moore rd. fractures of the supracondylar process of the humerus-report of two cases. j bone joint surg 1967; 49:532-534. 9. bilecenoglu b, uz a, karalezli n. possible anatomic structures causing entrapment neuropathies of the median nerve: an anatomic study. acta orthop belg 2005; 71:169-176. 10. lordan j, rauh p, spinner rj. the clinical anatomy of the supracondylar spur and the ligament of struthers. clin anat 2005; 18:548-551. 11. pecina, boric i, anticevic d. intraoperatively proven anomalous struthers ligament diagnosed by mri. skel radiol 2002; 31:532-535. figure 2: computed tomography scan (3-d) showing supracondylar process figure 3: computed tomography scan (axial view) showing healing of the supracondylar process fracture squ med j, april 2010, vol. 10, iss. 1, pp. 50-56, epub. 17th apr 10 submitted 14th june 09 revision req. 6th oct 09, revision recd. 1st nov 09 accepted 21st dec 09 department of population science & human resource development, university of rajshahi, rajshahi-6205, bangladesh to whom correspondence should be addressed. e-mail: rafique _ pops@yahoo.com سلوك طلب رعاية احلوامل عند األمهات يف املناطق املزدمحة الفقرية دراسة بلدية مدينة راجشاهي، بنغالديش حمف�ظ رحمن، رفيق اال�شالم، م��شفيكر رحمن يف احل�امل عند ال�شحية الرعاية طلب �شل�ك يف املختارة املتغريات لبع�س املهمة التاأثريات معرفة الدرا�شة هذه حاولت الهدف: اخلال�صة: مدينة بلدية يف الفقرية املزدحمة املناطق من اأم 700 من 2006 �شنة جمعت الدرا�شة هذه معطيات الطريقة: الفقرية. املزدحمة املناطق راج�شاهي يف بنغالدي�س. النتائج: ت�شري النتائج اإىل اأن ذوفاُن الُكزاز وا�شع االنت�شار يف تلك املناطق. ل�حظت امل�شاكل ال�شحية اخلطرية يف ال�الدة خالل ي�شاعدهن من هناك يكن مل )56.1%( ا�شتجنب الل�اتي ن�شف من اأكرث الأن واأوالدهن االأمهات من كال عند املذك�رة املناطق االأخرية من اأيٍّ كان من املهن الطبية. كما كانت حالتهن املادية ال ت�شمح ب�رساء م�شتقات احلديد والفيتامينات خالل احلمل االأخري. عند تطبيق يف احل�امل عند الطبية الرعاية طلب ل�شل�ك مرافقة االجتماعية – واالقت�شادية الدمي�غرافية الع�امل اأن ظهر الل�ج�شتي ف الَتَح�ُّ من�ذج املناطق املزدحمة الفقرية. اخلال�شة: تعليم امل�شاركات، مكان العالج، عمل الزوج، دخل االأ�رسة، والتعر�س لالإعالم اجلماهريي لها تاأثري بليغ جدا على االأمهات الل�اتي يطلنب الرعاية الطبية خالل احلمل االأخري. مفتاح الكلمات: رعاية، اأثناء احلمل، اأمهات، املناطق املزدحمة الفقرية، حت�ف ل�ج�شتي، برنامج التح�شني، ذوفان الكزاز، بنغالدي�س. abstract: objectives: the study aimed to identify the important effects of some selected variables in antenatal care (anc) seeking behaviour among slum mothers. methods: the data for the study were collected in 2006 from 700 mothers in the slum areas of rajshahi city corporation (rcc), bangladesh. results: the results indicate that tetanus toxoid (tt) is relatively widespread in slum areas of rcc. serious health implications were observed for the mothers and their children who lived in the study areas because more than half of the respondents (56.1%) were not assisted at their last childbirth by any health professional. the respondents were too poor to buy iron tablets/syrup and vitamin tablets/syrup during their last pregnancy. the application of a logistic regression model suggested that demographic and socio-economic factors were associated with anc seeking behaviour among slum mothers. conclusion: respondents’ education, place of treatment, husband’s occupation, family’s income, and exposure to mass media had highly significant effects on mothers seeking medical checkups during their last pregnancy. key words: care, prenatal; mothers; slums; logistic regression; immunization program; tetanus toxoid; bangladesh. antenatal care seeking behaviour among slum mothers a study of rajshahi city corporation, bangladesh mahfuzar rahman,*rafiqul islam and mosfequr rahman clinical & basic research advances in knowledge 1. this study found that the following demographic and socio-economic factors were associated with antenatal care-seeking behaviour among slum mothers of rajshahi city corporation in bangladesh: respondent’s education, husband’s occupation, family income, and exposure to mass media. 2. these factors should be increased in order to boost antenatal care and reduce fertility, morbidity as well as mortality not only in slum areas of bangladesh, but also in all underprivileged regions of the world. application to patient care 1. government and non-governmental organisations should accelerate medical facilities to increase antenatal care for women in the slum area of rajshahi city corporation in bangladesh. 2. mass media has a great role to play in creating awareness about antenatal care among women in the slum areas as well as among underprivileged populations elsewhere. mahfuzar rahman, rafiqul islam and mosfequr rahman clinical and basic research | 51 bangladesh is a small south asian country which became independent in 1971 after a bloody war. rapid urbanisation in bangladesh (26% of the 147.1 million inhabitants live in urban areas) is fuelling a growth in urban poverty, particularly in the urban slums where the quality of life is extremely poor.1 the average population density in slums was reported in 2005 as 831 persons per acre or 205,415 people per square kilometre.2 despite significant improvements, the maternal mortality ratio and infant mortality rate remain high (380 and 50 per thousand respectively).1 antenatal care (anc) is the medical supervision given to a pregnant woman and her baby starting from the time of conception up to the delivery of the baby by a physician, midwife or obstetrician or a combination of these professionals. it includes regular monitoring of the mother and her baby throughout pregnancy by a variety of routine regular examinations and tests (some routine and some for special circumstances). it also includes planning for pregnancy and continues into the early neonatal and postpartum period. only 9% of births in bangladesh take place at a health facility, while almost all others are home deliveries and only 55.9% of mothers receive some form of anc.3 ideally, all pregnant women should have regular antenatal checkups either by a paramedic or by a doctor. the bangladesh demographic and health survey (bdhs) reported that about 44% of the pregnant women, who gave birth during the five years prior to the 2004, did not receive any anc visit, while 16.1% received only one visit. in rural bangladesh, the majority (81.6%) of the women had only one anc visit, while 14.6%, 3% and 0.8% had two, three and more than three visits respectively. the median gestational age at the first antenatal visit was 7 months; 74.3% of the first antenatal visits took place between the sixth and the eighth month of pregnancy. the midwife was present around the time of labour and/or delivery in the case of 3,909 (40.7%) of the women who received anc compared to only 748 (11.1%) of the women not receiving it (relative risk = 3.73, p = 0.000). about one quarter (26.5%) of the women who received anc experienced a labour or delivery complication, including the 21 women who died as a consequence of pregnancy.4 a study showed that the odds of having a live birth is 11.807 times higher among women who had good anc and good health than those who lacked good health and had no anc services.5 another study on syphilis in the antenatal period also showed that completed treatment was significantly associated with age of gestation at first visit (p = 0.029), with women attending later in pregnancy less likely to receive all three doses of treatment.6 more recently, the potential of the antenatal period as an entry point for hiv prevention and care, in particular for the prevention of hiv transmission from mother to child, has led to renewed interest in access to and use of anc services.7, 8 in 2001, the who published the conclusions of a randomised controlled trial of a new model of anc [figure 1] and also carried out a systematic review of other randomised trials that looked at the effectiveness of different models of anc.9 pregnancy and childbirth related complications are the leading causes of maternal morbidity and mortality in bangladesh. this exploratory study was important because it gave a picture of the state of anc in the slum areas and will help to indicate necessary changes in customs and laws to improve existing anc programmes with a view to reducing maternal morbidity and mortality in bangladesh. therefore, the main aim and objective of this study was to determine the effects of some selected variables on anc seeking behaviours among slum mothers. methods the data for this study were collected in 2006 from 8 different slums of 3 wards of rcc, bangladesh. seven hundred married women, aged 15-49 years, were selected using a purposive sampling technique and took part in face-to-face interviews. those women who had no child less than five years of age at the time of the interview were not included in this study. taking an antenatal check-up, coded as 1 if the mothers took any medical checkup during last pregnancy or 0 if otherwise, was taken as the dependent variable in the logistic regression analysis. the following explanatory variables were considered in this study: type of births, respondent’s education, access to mass media, family’s monthly income, electricity supply in the home, husband’s occupation, household asset index, place of treatment and type of latrine. the 700 respondents antenatal care seeking behaviour among slum mothers a study of rajshahi city corporation, bangladesh 52 | squ medical journal, april 2010, volume 10, issue 1 were selected from 8 different slums of 3 wards, as shown in the table 1. the linear logistic regression model was employed to determine the factors associated with anc seeking behaviour among the women in the study area and the relative effects of various characteristics on anc seeking. the independent variables used in the logistic regression model are shown in table 5. the city of rajshahi stands on the bank of the river padma. it is basically an administrative centre having a population of 489,514 in 2005 spread over 51.3 square kilometers. there are 641 slum clusters in the city with a population of 156,793 (32% of the total city population). most of the slum dwellers originate from the immediate vicinity of the city, and were driven to the slums by, among other things, erosion along the river padma. the large slums are located on the left bank of the river in the city protection embankment.2 the people of rajshahi city get health services from different hospitals like rajshahi medical college hospital (rmch), the christian mission hospital, and the t.b. hospital etc. other general hospitals are bangladesh rifles (bdr) hospital, combined military hospital (cmh), and the prison hospital where there is no access for general public. non-government (ngo) services addressing health issues of the poor are limited. the rcc is conducting an asian development bank-government of bangladesh (adb-gob) financed project called the urban primary health care project (uphcp) and a united states agency for international development-government of bangladesh (usaidgob) financed project, the ngo services delivery program (nsdp), within the rcc area with a view to improving the health of the urban poor and reducing preventable mortality and morbidity by increasing access to primary health care. these projects are run by two ngos, namely anannya and tilottoma, under an agreement with rcc. the services provided by these ngos mainly focus on maternal and infant health care, growth monitoring and feeding, supply of family planning materials etc. and take taka 10 (= $0.143) as a consultation fee. moreover, the bangladesh rural advancement committee (brac) is one of the remarkable ngos working for the health promotion of the urban poor in rajshahi. the women can receive pregnancy check up services from brac’s health unit by paying taka 15 (= $0.215). the rcc is also operating the city hospital to provide preventive, curative and promotional health care services to the poor and taking taka 5 (= $0.072) as a consultation fee. under the support for basic services in urban area (sbsua) project, rcc also provides health services to the urban poor in the form of immunisation against six expanded program on immunization (epi) diseases to children under one year of age; tetanus toxine (tt) vaccination of women aged 15-49; maternal and infant care; growth monitoring; prevention and treatment of diarrhoea etc. the slum dwellers tend not to choose government facilities as government dispensaries are probably not near their locality and they are all women first vists classification form specialised care, additional evaluation/assessment or follow-up, if need in clinic or elsewhere transfer of patient between the basic components and specialised care is possible throughout anc basic component of anc programme yes no any conditions or risk factors detected from the classification form figure 1: the new who antenatal care (anc) model (2001)9 mahfuzar rahman, rafiqul islam and mosfequr rahman clinical and basic research | 53 often unaware of these facilities. even when they have heard about government facilities, they do not know what type of treatment is provided and are not sure whether they will get the treatment they require.10 in addition, there are several private clinics, but due to their higher costs low-income people cannot afford their services. they mainly go to local, traditional, mostly untrained, but cheaper, practitioners and sometimes use ngo facilities. results t e ta n u s t o x o i d (t t) va c c i n at i o n the tt vaccine is given to women during their childbearing age (15–49 years) to protect them from tetanus during their whole reproductive life and their newborns from neonatal tetanus. neonatal tetanus is a fatal disease, caused by a pathogen transmitted during or after childbirth in unhygienic delivery. a woman needs a total of five tt doses for the protection of the whole reproductive period, and these should be administered according to the following schedule recommended by who:11 tt1, the first dose, at the age of 15 years; tt2 four weeks or more, after tt1; tt3 six months or more, after tt2; tt4 one year or more after tt3; and tt5 one year or more, after tt4. for minimum protection, it is recommended that the pregnant women should receive at least two doses of the toxoid.12 table 2 presents the percentage distribution of women who received the tt1, tt2, tt3, tt4, and tt5 vaccines or not between age of 15 and the data collection period. from the table 2, we see that the proportion of women who received tt1 dose was 92.6% although nationwide the tt1 dose coverage rate is higher (95%).13 this proportion drops to 83.4 and 72.0 percent for tt4 and tt5 doses respectively [table 2]. the data indicates that tt coverage is relatively widespread in bangladesh. although there has been no change in recent years in anc coverage, the proportion of women receiving tt injections has risen substantially. a s s i s ta n c e d u r i n g l a s t d e l i v e r y from the standpoint of child survival and maternal health, the first priority is a safe and clean delivery.14 experience in both developed and developing countries shows that babies delivered under proper medical supervision are significantly less subject to health hazards. safe delivery is an important element in reducing the health risks for mothers, especially in the case of births to younger mothers. these are often first births which carry higher risks than second, third or fourth births.15 proper delivery with the assistance of a trained medical practitioner and hygienic conditions reduce the risk of infection and facilitate management of obstetric complications that can endanger the life of the mothers and their newborn. in this context, the respondents were asked about the assistance during their last delivery. we classified the respondents who were helped either by a health worker or nurse, or a doctor with bachelor of medicine and bachelor of surgery (mbbs), or a traditional birth attendant (tba) or a combination of these, as ‘taking help from health professionals’ and we identified the remainder as taking help from non-health professionals/ untrained birth attendants (utba). table 3 shows that more than half (56.1%) of the respondents did not receive professional help during their last delivery i.e. they received help from a utba or from people outside the health profession. so, we can say that there are serious table 2: percentage distribution of women aged 1549 by tt vaccine receiving tt vaccine proportions receiving vaccine tt1 92.6 tt2 90.3 tt3 88.0 tt4 83.4 tt5 72.0 table 1: list of selected slum areas and sample size used in this study no. of slums selected ward no. slum population sample size 2 28 7,260 300 4 29 7,235 300 3 30 2,135 100 total 16,630 700 legend: ward 28: dharompur nadirdhar, char kazla badurtola; ward 29: dashmari nadirdhar, khozapur nadirdhar, satbaria nadirdhar, shympur nadirdhar; ward 30: paschim para, boodh para, mohonpur antenatal care seeking behaviour among slum mothers a study of rajshahi city corporation, bangladesh 54 | squ medical journal, april 2010, volume 10, issue 1 health implications for the mothers and their children who live in the study areas. this means that the importance of mothers going to a health facility for their childbirth is not properly promoted in the study areas. ta k i n g i r o n ta b l e t s/s y r u p a n d v i ta m i n ta b l e t s/s y r u p iron tablets/syrup and vitamin tablets/syrup are supplements necessary during pregnancy for the health of mothers and their unborn babies. table 4 shows the percentage distribution of mothers according to whether they took iron tablets/ syrup and vitamin tablets/syrup during their last pregnancy period, related to their family’s monthly income. for this purpose, we classified the respondent’s total family income into three groups as taka ≤2000, taka 2001–2500 and taka 2501+ per month (us$ 28.5, $30–36 and over $37 per month respectively) although the percentage taking iron tablets/ syrup and vitamin tablets/syrup during their last pregnancy increased somewhat with the increase of family’s monthly income, the overall percentage of those taking iron tablets/syrup and vitamin tablets/ syrup is only 41.6% and 31.4% respectively, which is unsatisfactory [table 4]. so, we can say that, irrespective of their level of income, well under half the respondents of the study areas do not take iron tablets/syrup and vitamin tablets/syrup during their pregnancy. this is no doubt because low monthly incomes prevent many from purchasing iron tablets/syrup and vitamin tablets/syrup. m u lt i va r i at e a n a ly s i s the results of the logistic regression analysis, presented in table 5, show that the respondents’ education, place of treatment, husband’s occupation, family income, and exposure to mass media were significantly associated with going for an anc checkup during the last pregnancy. table 5 shows that education was the key factor among slum area mothers in seeking medical checkups during pregnancy; large and statistically significant differences were observed here despite having controlled for other variables. the relative odds ratio for literate mothers was found to be 1.994 indicating that the likelihood of medical checkup during the last pregnancy of literate mothers was 1.994 times higher than for illiterate ones. husband’s occupation was another significant factor influencing medical checkup during pregnancy. the logistic co-efficient indicated that the highest occurrence of medical checkup during last pregnancy was among wives of service sector workers, followed by businessmen. these women were 1.214 and 1.078 times respectively more likely to go to medical checkup than the wives of labourers [table 5]. family income was also significantly associated with antenatal checkups in the last pregnancy. the results shows that women with a monthly family income of tk 2001–2500 and tk 2501+ (us$30– 36 and over $37 per month respectively) were 1.052 times and 1.402 times respectively more likely to go for an antenatal medical checkup than the women with a monthly family income of tk ≤2000 (us$ 28.5) [table 5]. types of toilet facility had an effect on antenatal medical checkups; mothers with hygienic toilet facilities were 1.699 times more likely to go for antenatal medical checkups, but this effect is not statistically significant. the result reveals that the mothers who go to hospitals and clinics for general health related table 3: percentage distribution of women by type of assistance during last delivery assistant during last delivery number of women percentage health professional 307 43.9 non-health professional/ utba 393 56.1 total 700 100 table 4: percentage distribution of women taking iron tablet/syrup and vitamin tablet/syrup corresponding to their family’s monthly income in taka (tk). monthly income (taka) iron tablets/ syrup vitamin tablets/syrup percentage not taking percentage not taking ≥2000 87.5 100.0 2001-2500 81.0 90.5 2501+ 56.6 66.8 total percentages not taking the medicines 58.4 68.6 note: n = 700 mahfuzar rahman, rafiqul islam and mosfequr rahman clinical and basic research | 55 problems are 1.659 times more likely to go for antenatal medical checkups than mothers who go to homeopathic, kabiraj (medical practitioners without a degree in medical sciences) and others types of non-medical services [table 5]. as regards mass media, the results show that the mothers who are exposed to mass media are 2.253 times more likely to go for medical checkup than those not exposed. discussion the study indicates that the proportion of pregnant women in the study area who take tt injections is very high, but is still not 100% despite various measures taken by different authorities against this disease which is fatal to mothers and children. more than half of the births in slum areas take place without the assistance of any health professional. this may indicate that births take place in unhygienic conditions putting both mothers and their new borns at risk. as far as taking iron tablets/syrup and vitamin tablets/syrup is concerned, monthly income plays an important role. the results of the logistic regression indicated that medical checkups increased as the level of mothers’ education increased, as they come to realise the importance of antenatal medical checkups. place of treatment is an important factor that may strongly affect whether mothers go for antenatal checkups. for this reason, the place of treatment is classified into two categories. in the first category, homeopathic, kabiraj (bangladeshi medical practitioners without a degree in medical sciences) and others are included, table 5: logistic regression estimates of regression coefficient and relative odds associated with medical checkup during last pregnancy. background characteristics coefficient (β) standard error of β odds ratio [exp β] respondent’s education illiterate® 1.000 literate 0.690*** 0.183 1.994 husband’s occupation: labourer ® 1.000 business 0.076 0.297 1.078 service sector 0.194** 0.315 1.214 family’s monthly income: ≤ 2000 ® 1.000 2001-2500 0.051** 0.555 1.052 2501+ 0.388*** 0.365 1.402 types of latrine: unhygienic ® 1.000 hygienic 0.530 0.301 1.699 place of treatment: homeopathic, kabiraj and other® 1.000 hospital and clinic 0.506*** 0.169 1.659 type of birth single ® 1.000 2+ -0.070 0.178 0.932 electricity in household: no ® 1.000 yes 0.758 0.277 2.134 household asset index: lower ® 1.000 middle 0.350 0.598 1.419 upper 0.581 0.444 1.788 exposure to mass media not exposed ® 1.000 exposed 0.812*** 0.472 2.253 legend: ® = reference category; * = indicate p <0.001 (highly significant); ** = p <0.01 (significant); *** = p <0.05 (less significant) respectively; kabiraj = bangladeshi medical practitioners without a degree in medical sciences. antenatal care seeking behaviour among slum mothers a study of rajshahi city corporation, bangladesh 56 | squ medical journal, april 2010, volume 10, issue 1 while the secondly category is hospital and clinic. the results showed that the odds are higher for the mothers who go to hospitals and clinics for antenatal medical checkups. mass media is also shown by this study to play a strong role by creating awareness about the pregnancy related complications and the negative effect these complications can have on the future health of mothers and their new born babies. therefore, the role of mass media should be enhanced to reduce the overall pregnancy related morbidity and mortality in bangladesh. p o l i c y r e c o m m e n d at i o n s effective policies are needed to improve existing anc seeking behaviour in the slum areas of rcc. the specific recommendations are as follows: 1. anc services such as childbirths need the assistance of health professionals; tt vaccination among the women should be enhanced in the study areas. government, the private sector or ngos, or all three should do this by increasing their funds and facilities. 2. the people of the study areas should be made aware of the available local health facilities and pregnant women should be encouraged to have antenatal medical checkups. this could be done by creating awareness among the slum people, especially among women, through mass media campaigns, and the education and employment sectors. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. state of world population. in: unleashing the potential of urban growth. new york: united nations fund for population activities (unfpa), 2007. 2. slums of urban bangladesh: mapping and census. center for urban studies (cus). dhaka: national institute of population research and training (niport), 2005. 3. mitra sn and associates. bangladesh demographic and health survey (bdhs). dhaka: national institute of population research and training (niport), 2004. 4. vanneste am, ronsmans c, chakraborty j, francisco ad. prenatal screening in rural bangladesh: from prediction to care. health policy & planning 2000; 15:1–10, 5. yousif em, rahman ma, hafeez a. the effect of antenatal care on the probability of neonatal survival at birth, wad medani teaching hospital, sudan. sudan j public health 2006; 1:293–7. 6. mullick sm, beksinksa m, msomi s. treatment for syphilis in antenatal care: compliance with the three dose standard treatment regimen. sex transm infect 2005; 81:220–2. 7. carroli g, villar j, piaggio g, khan-neelofur d, gülmezoglu m, mugford m, et al. who antenatal care trial research group. who systematic review of randomised controlled trials of routine antenatal care. lancet 2001; 357:1565–70. 8. villar j, bergsjø p. scientific basis for the content of routine antenatal care: recent studies and power to eliminate or alleviate adverse maternal outcomes. acta obstet gynecol scand 1997; 76:1–14. 9. villar j, ba’aqeel h, piaggio g, lumbiganon p, belizán j, farnot u, et al. who antenatal care trial research group. who antenatal care randomised trial for the evaluation of a new model of routine antenatal care. lancet 2001; 357:1551–64. 10. government of bangladesh (gob), asian development bank (adb). bangladesh urban primary health care project-2: midterm report and situation analysis, 2004. 11. world health organization (who). expanded program on immunization system, summary for the south east asia region. geneva: who, april 1992. 12. mitra sn & association. bangladesh demographic and health survey (bdhs). dhaka: national institute of population research and training (niport), 1993-1994. 13. expanded programme on immunization (epi) coverage survey, bangladesh. dhaka: directorate general of health services, 2005. 14. world health organization (who). improved access to maternal health services, geneva: who, 1998. 15. population report. meeting the needs of young adults. family planning program: series j, no. 41, october 1995. 2department of biochemistry, 1college of medicine, al-imam mohammad ibn saud islamic university, riyadh, saudi arabia *corresponding author’s e-mail: aaalshuwayrikh@gmail.com حجم معرفة وتوجهات طالب الطب يف جامعة اإلمام حممد بن سعود اإلسالمية حنو اإلسعافات األولية، الرياض، اململكة العربية السعودية عبدالرحمن ال�شويرخ، عبدالرحمن اجلذيلي، فار�س الع�شيمي، اأ�شامة ال�شايع، عبداهلل الأ�شمري، حممد املخ�شوب، �شالح اخلنيزان، �شالح الدين خان abstract: objectives: this study aimed to evaluate knowledge and attitudes towards first aid (fa) measures among medical students at the al-imam mohammad ibn saud islamic university, riyadh, saudi arabia. methods: this crosssectional study was conducted between september and december 2016 among 600 medical students in different academic years at al-imam mohammad ibn saud islamic university. knowledge and attitudes towards fa measures were evaluated using a modified version of a previously validated questionnaire. data were compared between students with previous fa training and those without previous fa training. results: a total of 259 medical students were included (response rate: 43%). of these, 43% had previously received fa training and 63% had witnessed an emergency first-hand. mean theoretical (5.93 ± 2.50 versus 4.49 ± 2.08; p <0.001) and practical (4.29 ± 2.62 versus 2.90 ± 2.17; p <0.001) knowledge scores were significantly higher among students with previous fa training compared to those without training; however, there was no significant difference in mean attitude score (5.60 ± 1.66 versus 5.39 ± 1.66; p = 0.329). conclusion: the medical students, particularly those without previous fa training, demonstrated weak levels of fa knowledge. such findings necessitate the inclusion of fa training in medical curricula in saudi arabia. keywords: first aid; emergency treatment; medical education; knowledge; attitudes; saudi arabia. امللخ�ص: الهدف: تهدف الدرا�شة لتقييم معرفة وتوجهات الإ�شعافات الأولية بني طالب الطب يف جامعة الإمام حممد بن �شعود الإ�شالمية، الريا�س، اململكة العربية ال�شعودية. الطريقة: هذه درا�شة مقطعية اأجريت بني 600 طالب طب من خمتلف ال�شنوات يف جامعة الإمام حممد بن �شعود الإ�شالمية من �شيبتمرب اإىل دي�شمرب من عام 2016. مت تقييم حجم معرفة وتوجهات عينة من طالب الطب نحو الإ�شعافات الأولية با�شتخدام ا�شتبيان مت التحقق منه م�شبقا مع اإ�شافة بع�س الأ�شئلة. متت مقارنة البيانات بني الطالب الذين تدربوا يف الإ�شعافات الأولية تدريب لديهم الطالب من الإجابة: 43%(. 43% طب )معدل طالب جمموعه 259 ما درا�شة مت م�شبقا. النتائج: يتدربوا مل الذين والطالب مقابل 5.93 ± 2.50( النظرية املعرفة متو�شط الأولية. الإ�شعافات عمل ت�شتدعي طارئة حالة �شاهدوا 63% و الأولية لالإ�شعافات م�شبق 2.08 ± 4.49؛ p >0.001( واملعرفة التطبيقية )2.62 ± 4.29 مقابل 2.17 ± 2.90؛ p >0.001( كان اأعلى ب�شكل وا�شح لدى الطالب الذين تدربوا م�شبقا على الإ�شعافات الأولية مقارنة بالطالب الذين مل يكن لديهم تدريب م�شبق. على النقي�س ل يوجد اختالف كبري بني الطالب املتدربني وغري املتدربني يف توجهاتهم نحو الإ�شعافات الأولية )1.66 ± 5.60 مقابل 1.66 ± 5.39؛ p = 0.329(. اخلال�صة: هناك �شعف املناهج يف الأولية الإ�شعافات مادة اإدخال �رصورة على يدل مما الأولية. الإ�شعافات معرفة يف درا�شتهم متت الذين الطب طالب لدى الطبية. الكلمات املفتاحية: الإ�شعافات الأولية؛ معاجة طارئة؛ التعليم الطبي؛ التوجهات؛ املمار�شات؛ اململكة ال�شعودية. knowledge and attitudes towards first aid measures among medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia *abdulrahman alshuwayrikh,1 abdulrahman aljethaily,1 faris alosaimi,1 osama alshaya,1 abdullah alasmari,1 mohammed al-makhdob,1 saleh alkhonezan,1 salahuddin khan2 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e507–512, epub. 28 mar 19 submitted 1 may 18 revision req. 6 jun 18; revision recd. 4 jul 18 accepted 5 aug 18 advances in knowledge the current study found that medical students had low levels of knowledge of first aid (fa) measures, even among those who had previously received fa training. however, there were significantly higher levels of fa knowledge among medical students who had previously received fa training ; this finding supports the inclusion of fa training within the medical curriculum. application to patient care proper fa interventions can reduce patient mortality and morbidity. enhancing fa knowledge among medical students would enable such students to more competently handle emergency situations, thus indirectly affecting medical care. doi: 10.18295/squmj.2018.18.04.013 knowledge and attitudes towards first aid measures among medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia e508 | squ medical journal, november 2018, volume 18, issue 4 first aid (fa) is defined as the initial care applied after an injury or acute illness.1 the goal of fa is to preserve life and prevent the patient’s condition from deteriorating until professional healthcare becomes available.2 any person can begin fa measures in an emergency situation with minimal or no medical equipment needed.1 in particular, healthcare providers have a duty to initiate fa measures in such situations in order to reduce patient suffering and the risk of disability and early death, especially as bystanders often expect such individuals to take appropriate action.2–4 thus, it is critical that medical students are properly educated in fa and basic life support (bls) measures, particularly during the early phases of their studies.3 it is recommended that fa training courses be included in the curricula of medical schools and colleges.2–4 unfortunately, fa training is often neglected in medical curricula.2,5 several studies have reported disappointing results regarding levels of fa readiness among medical students and trainees.2,3,5,6 tan et al. found that more than 70% of junior doctors lacked fa knowledge and practice.2 in a study from the netherlands, only 38% of participants met required guidelines regarding fa and bls knowledge.3 a study from india found that only 13.8% of medical students had good knowledge of fa.5 a previous saudi arabian study showed that medical students had poor familiarity with bls, particularly car diopulmonary resuscitation (cpr), with 67.36% scoring <50%.6 in the united arab emirates, das et al. reported that a fa training programme for first-year medical students enhanced bls and fa knowledge and practical skills.7 similarly, a turkish study showed the efficacy of such programmes, with fa and bls training rendering medical students capable of themselves training other students.8 to the best of the authors’ knowledge, no study has yet been published comparing knowledge levels and attitudes between medical students with and without prior fa training in saudi arabia. the current study aimed to assess knowledge and attitudes towards fa among medical students at the al-imam mohammad ibn saud islamic university, riyadh, saudi arabia, particularly with respect to how previous fa training influences students’ knowledge and attitudes towards fa. currently, a bls certificate is required for clinical year students in the college of medicine at alimam mohammad ibn saud islamic university. this certificate is acquired through a one-day course that is provided by external entities, with the course focusing mainly on cpr. methods this cross-sectional study was conducted at the college of medicine of the al-imam mohammad ibn saud islamic university from september to december 2016. a convenience sample of preclinical (from preparatory until third year) and clinical (fourth year and above) medical students was recruited. the required sample size was calculated to be 234 out of a total of 600 potential participants, assuming that the knowledge and attitudes towards fa among medical students would be 50%, with a 95% confidence interval and a margin of error of 5%. a modified version of a previously validated quest ionnaire was used to assess fa knowledge and attitudes.8 the final english-language questionnaire comprised 41 items, including questions about demographic characteristics (nine items), theoretical fa knowledge (11 items), practical fa knowledge (10 items) and attitudes towards fa (11 items). the questionnaire assessed various emergency situations and fa approaches, incl uding cpr, bleeding, burns and bone fractures. the theoretical knowledge section consisted of direct quest ions, while the practical knowledge items were case based. most of the questions were reproduced with permission from khan et al.8 however, some new quest ions were added based on a review of the literature.9 most of the questions were closed-ended multiple choice questions with 3–4 distractors, with some yes/no quest ions. all of the questions had only one correct answer. the entire questionnaire took between 10–20 minutes to complete. the modified questionnaire was piloted in a group of 52 random students from various academic years. based on the findings of the pilot study, the questions were edited for clarity and the final version of the quest ionnaire was validated. subsequently, the final questionnaire was distributed to 600 medical students in all academic years in the college of medicine. both elect ronic and paper versions of the questionnaire were disseminated to enhance the response rate. the paper version was distributed to all students who were physically in attendance at the college of medicine at the time of distribution. an excel spreadsheet, version 2016 (microsoft, redmond, washington, usa) was used for data entry and the statistical package for the social sciences (spss), version 19.0 (ibm corp., armonk, new york, usa) was used for statistical analysis. data entry was verified by two researchers to ensure consistency and accuracy. a chi-squared test was used to determine associations between sociodemographic variables and abdulrahman alshuwayrikh, abdulrahman aljethaily, faris alosaimi, osama alshaya, abdullah alasmari, mohammed al-makdob, saleh alkhonezan and salahuddin khan clinical and basic research | e509 knowledge and attitude scores. a student’s t-test was utilised to determine significant differences in mean knowledge and attitude scores between students with and without prior fa training. a p value of <0.050 was deemed statistically significant. this study received ethical approval from the ethical committee of the college of medicine at al imam mohammad ibn saud islamic university (#0010 7/03/2016-12). informed consent was granted by all students who completed the electronic version of the questionnaire during completion of the online form. those who filled in the paper version of the questionnaire gave verbal consent in addition to signed written consent. results a total of 259 medical students participated in the study (response rate: 43%). of these, 83 (32%) completed the electronic version and 176 (68%) completed the paper version of the questionnaire. most participants (79%) were in their pre-clinical years and only 21% were in their table 1: emergencies witnessed by medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia (n = 259) type of emergency witnessed n (%)* total students with prior fa training (n = 112) students without prior fa training (n = 147) none 96 (37) 43 (38) 53 (36) burns 76 (29) 32 (29) 44 (30) fractures/ dislocations 65 (25) 34 (30) 31 (21) choking 50 (19) 27 (24) 23 (16) drowning 34 (13) 16 (14) 18 (12) heart attack 18 (7) 12 (11) 6 (4) seizure 16 (6) 9 (8) 7 (5) heat stroke 10 (4) 7 (6) 3 (2) fa = first aid. *percentages do not add up to 100% as the students could select more than one option. figure 1: sources of first aid knowledge among medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia (n = 259). *percentages do not add up to 100% as the students could select more than one option. figure 2: opinions on the most appropriate time to include first aid training in the medical curriculum among medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia (n = 259). *percentages do not add up to 100% as the students could select more than one option. knowledge and attitudes towards first aid measures among medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia e510 | squ medical journal, november 2018, volume 18, issue 4 clinical years. a total of 112 (43%) students had had prev ious fa training, while the remaining 147 (57%) had not. the most frequently witnessed emergencies were burns (29%), fractures/dislocations (25%) and choking (19%). those with prior fa training had less frequently witnessed emergencies compared to those without training (62% versus 64%) [table 1]. students had acquired fa-related knowledge from various sources, the most common being formal training (39%), the internet/computer software (38%), television (28%) and teachers (28%) [figure 1]. most of the students (43–50%) believed that fa training and education should be incorporated into the curriculum during the first two years of their degree programme [figure 2]. overall, the mean attitude score was higher than the theoretical and practical knowledge scores (5.47 ± 1.66 versus 5.10 ± 2.36 and 3.51 ± 2.47, respectively). the overall mean combined knowledge and attitude score was significantly associated with prior fa training (15.81 ± 5.64 versus 12.78 ± 4.63; p <0.001). in addition, the mean scores for both theoretical (5.93 ± 2.50 versus 4.49 ± 2.08; p <0.001) and practical (4.29 ± 2.62 versus 2.90 ± 2.17; p <0.001) knowledge questions were signif icantly higher among students with prior fa training compared to those without. however, there was no signif icant difference in mean attitude scores between the two groups (5.60 ± 1.66 versus 5.39 ± 1.66; p = 0.329) [table 2]. the frequency of correct or positive responses to knowledge and attitude items is shown in table 3. in terms of theoretical knowledge, the rate of correct responses ranged from 34–86%. less than half of the students (34%) knew the correct ratio of chest compressions to rescue breaths when performing cpr on an adult patient. there was a significant difference in the frequency of correct responses to this item among fa-trained and untrained table 2: mean first aid-related knowledge and attitudes scores among medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia (n = 259) variable mean score ± sd p value* total students with prior fa training (n = 112) students without prior fa training (n = 147) theoretical knowledge 5.10 ± 2.36 5.93 ± 2.50 4.49 ± 2.08 <0.001 practical knowledge 3.51 ± 2.47 4.29 ± 2.62 2.90 ± 2.17 <0.001 attitude 5.47 ± 1.66 5.60 ± 1.66 5.39 ± 1.66 0.329 total 14.08 ± 5.28 15.81 ± 5.64 12.78 ± 4.63 <0.001 sd = standard deviation; fa = first aid. *using a student’s t-test. table 3: correct/positive responses to first aid-related knowledge and attitude questionnaire items among medical students at alimam mohammad ibn saud islamic university, riyadh, saudi arabia (n = 259) item correct/positive responses, n (%) p value* total students with fa training (n = 112) students without fa training (n = 147) theoretical knowledge what does cpr stand for? 194 (75) 90 (80) 104 (71) 0.105 which of the following is the correct ratio of chest compressions to rescue breaths when performing cpr on an adult? 87 (34) 70 (63) 17 (12) <0.001 what is the proper definition of an open fracture? 126 (49) 68 (61) 58 (39) 0.001 why should you act quickly for a casualty with severe bleeding? 129 (50) 66 (59) 63 (43) 0.015 does fa require expensive equipment? 224 (86) 94 (84) 130 (88) 0.386 practical knowledge what would be your first step if you encountered a person with profuse leg bleeding due to a gunshot wound? 139 (54) 60 (54) 79 (54) >0.999 what would you do first for a person who has burnt his hand with coffee? the affected area is 2–3 inches in size and is red, swollen and painful. 113 (44) 49 (44) 64 (44) >0.999 which of the following would you do if a woman’s dress sleeve were to catch fire and adhere to her burnt skin? 32 (12) 16 (14) 16 (11) 0.526 what would you encourage your colleague to do if he were to become distressed by a piece of food lodged in his airway? 109 (42) 51 (46) 58 (39) 0.393 what should you do to a person who has fallen down with a suspected thigh fracture? 86 (33) 55 (49) 31 (21) <0.001 attitude if you have good knowledge of fa, you should not hesitate to use it when needed. 195 (75) 90 (80) 105 (71) 0.299 do you support including fa in the medical college curriculum? 220 (85) 94 (84) 126 (86) 0.501 would you like to give a basic idea of fa techniques to your fellow students? 189 (73) 81 (72) 108 (73) 0.730 do you think fa decreases the burden of hospitals? 177 (68) 82 (73) 95 (65) 0.258 do you think fa increases patients’ survival rates? 259 (100) 112 (100) 147 (100) >0.999 fa = first aid; cpr = cardiopulmonary resuscitation. *using a chi-squared test. abdulrahman alshuwayrikh, abdulrahman aljethaily, faris alosaimi, osama alshaya, abdullah alasmari, mohammed al-makdob, saleh alkhonezan and salahuddin khan clinical and basic research | e511 students (63% versus 12%; p <0.001). in contrast, there were no significant differences between fa-trained and untrained students in terms of awareness of the meaning of the abbreviation ‘cpr’ (80% versus 71%; p = 0.105) and whether fa requires expensive equipment (84% versus 88%; p = 0.386). in general, there was a low level of practical knowl edge among the cohort, with the rate of correct responses ranging from 12–54%. over half (54%) of the students knew what to do when encountering a bleeding gunshot victim, but only 12% knew how to handle a patient with burning cloth attached to skin. only one practical knowl edge question—which involved dealing with a thigh fracture—displayed a significant difference between students with prior fa training and those without (49% versus 21%; p <0.001). with regards to attitudes, the rate of positive responses ranged from 68–100%. all of the participants believed that fa increases survival rates and most students (85%) supported the inclusion of fa training into the medical curriculum. there were no significant differences in the rate of positive responses between fatrained and untrained students for any of the attitude items (p >0.050 each). discussion in the current study, medical students at the al-imam mohammad ibn saud islamic university were found to have poor levels of fa knowledge, especially in terms of the practical aspects of fa. the inclusion of fa training in the medical curriculum could improve this deficiency.7,8 additionally, the study observed a significant difference in knowledge between students with and those without prior fa training; this finding highlights the imp ortance of including fa in medical education. however, no significant differences were noted in attitude between fa-trained and untrained students. this could imply that willingness to act in emergencies is not enhanced by fa training. on the other hand, the lack of difference between the groups may reflect a lack of confidence among previously trained students. in particular, students untrained in fa showed significant weaknesses regarding their knowledge of diverse emergency situations, indic ating that fa training should focus on different types of emergencies (e.g. fractures, burns and bleeding). the rates of correct responses to certain fa knowl edge questions in the current study varied from those reported in other studies. the proportion of students in the present study who knew the correct cpr compression-to-breath ratio was lower than that reported in a previous study conducted in saudi arabia (34% versus 53%).6 in a study from pakistan, abbas et al. found that 52% and 37.6% of students with and without fa training, respectively, knew how to deal with a bleeding person; in comparison, this percentage was 54% in both groups in the present study.10 the question regarding management of a choking victim was answered correctly by 42% of the students in the current cohort; this is similar to that noted in abbas et al.’s study (45.6% and 41.6% for trained and untrained students, respectively), yet lower than that reported by mejia et al. in peru (53.4%).10,11 only 33% of the participants in the present study knew how to deal correctly with a bone fracture. this is higher than that reported by joseph et al. in south india (12.5%), yet lower than that observed in khan et al.’s study in pakistan (44.5%).4,5 support for the inclusion of fa training was high among current students (85%); khan et al. reported similar findings (94.4%).4 the present study was limited by the low number of participants in their clinical years. this was likely because most clinical students were undertaking their clinical rotations outside of the college during the distribution of the survey. in addition, the students who com pleted the online questionnaire had more time and space to complete it than those who completed the paper version. finally, the findings of the present study were based on data from a single cohort of one medical college in riyadh; as such, the results cannot be generalised to all medical colleges in riyadh or to other regions of saudi arabia. larger randomised trials involving multiple cohorts are recommended to provide a higher level of evidence. conclusion this study found that the overall level of fa knowledge among medical students attending the al-imam mohammad ibn saud islamic university was low, predominantly in terms of practical questions. there was a significant difference in knowledge between students with prior fa training and those without, although there was no difference in attitudes between the two groups. these findings support the inclusion of fa in the formal medical college curriculum, particularly in the early stages of medical education. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. knowledge and attitudes towards first aid measures among medical students at al-imam mohammad ibn saud islamic university, riyadh, saudi arabia e512 | squ medical journal, november 2018, volume 18, issue 4 references 1. singletary em, zideman da, de buck ed, chang wt, jensen jl, swain jm, et al. part 9: first aid 2015 international consensus on first aid science with treatment recommendations. cir culation 2015; 132:s269–311. https://doi.org/10.1161/cir.000 0000000000278. 2. tan ec, severien i, metz jc, berden hj, biert j. first aid and basic life support of junior doctors: a prospective study in nijmegen, the netherlands. med teach 2006; 28:189–92. https://doi.org/ 10.1080/01421590500312847. 3. tan ec, hekkert kd, van vugt ab, biert j. first aid and basic life support: a questionnaire survey of medical schools in the netherlands. teach learn med 2010; 22:112–15. https://doi. org/10.1080/10401331003656538. 4. khan a, shaikh s, shuaib f, sattar a, samani sa, shabbir q, et al. knowledge attitude and practices of undergraduate students regarding first aid measures. j pak med assoc 2010; 60:68–72. 5. joseph n, kumar g, babu y, nelliyanil m, bhaskaran u. knowledge of first aid skills among students of a medical college in mangalore city of south india. ann med health sci res 2014; 4:162–6. https://doi.org/10.4103/2141-9248.129022. 6. alanazi a, alsalmeh m, alsomali o, almurshdi am, alabdali a, al-sulami m, et al. poor basic life support awareness among medical and college of applied medical sciences students necessitates the need for improvement in standards of bls training and assessment for future health care providers. middle east j sci res 2014; 21:848–54. https://doi.org/10.5829/idosi.mejs r.2014.21.05.82335. 7. das m, elzubeir m. first aid and basic life support skills training early in the medical curriculum: curriculum issues, outcomes, and confidence of students. teach learn med 2001; 13:240–6. https://doi.org/10.1207/s15328015tlm1304_05. 8. altintaş kh, aslan d, yildiz an, subaşi n, elçin m, odabaşi o, et al. the evaluation of first aid and basic life support training for the first year university students. tohoku j exp med 2005; 205:157–69. https://doi.org/10.1620/tjem.205.157. 9. tsegaye w, tesfaye m, alemu m. knowledge, attitude and practice of cardiopulmonary resuscitation and associated factors in ethiopian university medical students. j gen pract 2015; 3:206. https://doi.org/10.4172/2329-9126.1000206. 10. abbas a, bukhari si, ahmad f. knowledge of first aid and basic life support amongst medical students: a comparison between trained and un-trained students. j pak med assoc 2011; 61:613–16. 11. mejia cr, quezada-osoria c, moras-ventocilla c, quinto-porras k, ascencios-oyarce c. [level of knowledge in medical emergencies among medical students of peruvian universities]. rev peru med exp salud publica 2011; 28:202–9. clinical & basic research squ med j, february 2011, vol. 11, iss. 1, pp. 52-55, epub. 12th feb 11 submitted 24th nov 10 revision req. 3rd jan 11, revision recd. 10th jan 2011 accepted 11th jan 11 departments of 1obstetrics & gynaecology and 2medicine, sultan qaboos university hospital, muscat, oman; 3industrial innovation center, rusayl, oman; 4department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: omayma0@hotmail.com ÿ⁄]á£]<l^èfi^€�√÷]<çfl¬<dåe<∞⁄^fljè <<ì÷^u –◊œ÷]<4ni<<l^ñëüπ]<‡⁄<ìè÷^¬<ìfäfi<çfl¬<dåe<∞⁄^jè <‡⁄<ìñà~fl⁄<<ìfäfi<åáqê<   25    100 2010 ––  25%69 67 25 ≥%35 34  75< 5025  10003 3 25 :مفتاح الكلمات abstract: objectives: the objective of this study was to determine the vitamin d status of pregnant omanis by measurement of their circulating 25 hydroxy vitamin d levels. methods: blood samples were obtained from a cohort of 103 consecutive healthy pregnant omanis at the armed forces hospital, muscat, on their first antenatal visit. the study took place in may, june and july 2010. results: vitamin d deficiency was present in 34 (33%) of patients (25ohd3 <25 nmol/l), ‘at risk’ levels were found in 67 (65%) patients (25ohd3 25–50 nmol/l); two patients (1.9%) had values between 50 and 75 nmol/l, and no patients in the optimal range >75 nmol/l. conclusion: if confirmed, these findings indicate the need for vitamin d replacement during pregnancy and lactation. although not evidence based we recommend at least 1000 iu of cholecalciferol, (vitamin d3) daily. keywords: pregnancy; oman; 25 hydroxyvitamin d3 (25ohd3); vitamin d deficiency vitamin d status in pregnant omanis a disturbingly high proportion of patients with low vitamin d stores moza al kalbani,1 *omayma elshafie,2 mohammed rawahi,2 ali al-mamari,2 abdullah al-zakwani,3 nicholas woodhouse4 clinical & basic research advances in knowledge this article is the first to draw attention to the possibility of widespread vitamin d deficiency among pregnant women in oman. application to patient care until more is known about the vitamin d status in omanis, we recommend that all pregnant women and lactating mothers should receive vitamin d supplements with at least 1000 iu vitamin d3 daily. deficiency of vitamin d is common worldwide1 including the gulf states.2,3 the latter is surprising as sunlight is abundant in the middle east. more than 90% of our vitamin d is provided by sunlight4 and it is therefore obvious that those persons affected in arabian countries have little sunlight exposure and a diet deficient in vitamin d. the role of vitamin d in normal physiology is complex and wide ranging. it has important immune modulating effects protecting against infection,4,5,6 autoimmune disorders7 and certain cancers, in addition to its well documented effects on the prevention of osteoporosis, fractures, falls in the elderly4,5 and impaired cognitive function.8 as we continually see patients with vitamin d deficiency in our clinics, it became important to establish whether or not vitamin stores (25ohd) are normal in a healthy omani population. for this reason, we chose patients in their first and second moza al kalbani, omayma elshafie, mohammed rawahi, ali al-mamari, abdullah al-zakwani, and nicholas woodhouse clinical and basic research | 53 trimester of pregnancy as pregnancy and lactation are associated with profound alterations in calcium absorption and skeletal remodelling necessitating increased utilisation of vitamin d. our findings are reported below. methods blood samples were obtained from a cohort of 103 consecutive healthy omani patients at their first antenatal visit, usually in the first, but sometimes the second trimester. they were then assayed for serum calcium (ca), phosphate (phos), and serum alkaline phosphatase (alp), which were measured by spectrophotometry, (cobas integra 800, roche diagnostics, indianapolis, usa) on the same day. serum samples for parathyroid hormone (pth) were measured by immunochemiluminesence (access 2, beckman coulter, inc., ca, usa), and 25(oh)d3 by the lb211 gamma counter (berthold gmbh & co. kg, bad wilbad, germany), having been centrifuged and deep frozen at –40º c . pth and 25(oh)d3 were then measured on the same day at the end of the study. statistical analysis was performed to determine the relationship between the level of serum ca, phos, alp and pth versus the level of serum 25(oh)d. we used a correlation test to calculate the significance of these relationships. as this showed no significant linear correlation, a polynomial trend curve was employed. the calculations were made for all groups of patients. fully informed consent was obtained from each patient to extract the blood needed for the above procedures in addition to that required for routine antenatal screening. the study was approved by the armed forces hospital authorities. results serum 25ohd3 levels were deficient (<25 nmol/l) in 34 patients, between 25 and 50 nmol/l in 67 patients (at risk) and two patients had values between 50 and 75 nmol/l. there was no significant linear correlation between 25(oh) d3 and serum ca, phos or alp levels or parity. however, a significant relationship between pth and 25(oh)d3 was observed which differed between the ‘deficient’ and the ‘at risk’ groups. this was confirmed using a polynomial curve, which had a significant correlation value of 0.55 [figure 1]. discussion this is the first study to report vitamin d status in normal pregnant omanis. the results are alarming: 34% of these apparently healthy women were vitamin d deficient and a further 64% ‘at risk’ at a time when there is a critical need for calcium metabolism to be normal. a pregnant woman must provide 25 to 30 gm of calcium to support the developing foetal skeleton. much of this demand figure 1: relationship between pth (normal range 1.6–9.3 pmol/l) and 25(oh)d3 levels. there was no linear correlation between pth and 25ohd3 levels, but using a polynomial curve, the correlation coefficient was significant at 0.55. legend: pth = parathyroid hormone; 25(oh)d3 = vitamin d3. vitamin d status in pregnant omanis a disturbingly high proportion of patients with low vitamin d stores 54 | squ medical journal, february 2011, volume 11, issue 1 occurs in the third trimester when the foetal skeleton undergoes mineralisation. this demand is compensated for by an increased absorption of calcium from the gut induced by rising levels of pth and the active metabolite of vitamin d, 1,25 dihydroxy vitamin d (1,25(oh)2d).9 at this point 25(oh)d will be utilised to make more 1,25(oh)2d and those patients with low stores will be at considerable risk for the development of vitamin d deficiency and osteoporosis in old age.10 to compound this problem, many omani women have 6 or more children and breast feed for up to 2 years. during lactation, hyperabsorption of calcium does not occur and remineralisation of the maternal skeleton only starts after weaning when pth, and 1,25(oh)2d levels rise, calcium absorption increases and urinary calcium levels fall, a process that may persist for months.11 obviously, adequate stores of 25(oh)d are vital during this period, otherwise skeleton remineralisation will be seriously impaired and possibly result in the development of osteoporosis in old age.4,5 interestingly, none of the patients in the 25(oh)d3 deficiency group were symptomatic and serum pth and alp levels were still within the normal range. however there was a significant increase of the percentage rise in pth in the face of a declining 25(oh)d level suggesting the early stages of a biological response to vitamin d deficiency in the “at risk” group. in the deficiency group the reverse response was seen. our 25(oh) d3 immunoassay results have been carefully checked and are correct. it is possible therefore that an overt rise of pth and alp levels has been suppressed by an oral intake of calcium in excess of 1 gm daily as this will delay the development of secondary hyperparathyroidism.12,13 other factors such as body mass index may also be relevant14 but this was not examined here. in addition to its musculo-skeletal actions, vitamin d deficiency is reportedly associated with the development of certain cancers, the metabolic syndromes and infections, as well as type 1 and type 2 diabetes,4,5 disorders which are common in oman. our results confirm that vitamin d3 stores are low even in omanis of reproductive age. these findings are similar to those reported in saudi arabians more than 25 years ago2 and more recently in the uae and qatar.3,12 it therefore seems sensible to advocate vitamin d supplementation for all pregnant women in the middle east. at the present time, there are no clear cut recommendations as to the dose, but we recommend at least 1000 iu of vitamin d3 a day which should be continued throughout lactation. until more is known about the daily calcium intake of omanis, it would be prudent to advocate calcium supplementation as well.15 conclusion this study shows that vitamin d3 scores are low in pregnant omanis. further studies are required to confirm these findings. until then, we recommend supplementation with vitamin d3 (cholecalciferol) for all pregnant and lactating mothers. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. thacher td, fisher pr, strand ma, pettifor jm. nutritional rickets around the world: causes and future directions. ann tropical paediatr 2006; 26: 1–16. 2. woodhouse ny, norton w. low vitamin d levels in saudi arabians. king faisal spec hosp med j 1982; 2:127–31. 3. saadi hf, dawodu a, afandi bo, zayed r, benedict s, nagelkerke n. efficacy of daily and monthly high dose calciferol in vitamin d deficient nulliparous and lactating women. am j clin nutr 2007; 85:1565– 71. 4. holick mf. vitamin d: a delightful health perspective. nutrition rev 2008; 66:5182–94. 5. pearce shs, cheetham td. diagnosis and management of vitamin d deficiency. bmj 2010; 340:b5664. 6. holick mf. vitamin d deficiency. review article. n engl j med 2007; 357:266–81. 7. hyponen e, laara e, reunanen a, jarvelin m-r, vertanen sm. intake of vitamin d and risk of type 1 diabetes. a birth cohort study. lancet 2001; 358:1500–03. 8. llewellyn dj, lang ia, langa km, muniz-terrera g, phillips cl, cherubini a, et al. vitamin d and risk of cognitive decline in elderly persons. arch intern med 2010; 170:1099–100. 9. affinito p, tommaselli ga, di carlo c, guida f, nappi c. changes in bone mineral density and calcium metabolism in breastfeeding women: a one moza al kalbani, omayma elshafie, mohammed rawahi, ali al-mamari, abdullah al-zakwani, and nicholas woodhouse clinical and basic research | 55 year follow-up study. j clin endocrinol metab 1996; 81:2314–18. 10. javaid mk, crozier sr, harvey nc, gale cr, dennison em, boucher bj. maternal vitamin d status during pregnancy and childhood mass at age 9 years: a longitudinal study. lancet 2006; 367:36–43. 11. kalkwarf hj, specker bl, heubi je, viera ne, yergey al. intestinal calcium absorption of women during lactation andafterweaning. am j clin nutr 1996; 63:526–31. 12. saadi hf, nagelkerke n, benedict s, qazaq hs, zilahi e, mohamadiyeh mk, et al. predictors and relationships of serum 25 hydroxyvitamin d concentration with bone turnover markers, bone mineral density and vitamin d receptor genotype in emirati women. bone 2006; 39: 1136–43. epub 2006 june 30. 13. steingrimsdottir l, gumarsson o, indridason os, franzson l, sigurdsson g. relationship between serum parathyroid hormone levels, vitamin d sufficiency and calcium intake. jama 2005; 294: 2336–41. 14. paik j, curhan g, forman j, taylor e. determinant of plasma parathyroid hormone levels in young women. calcified tissue int 2010; 87:211–17. 15. abrahamsen b. patient level pooled analysis of 68,500 patients from seven major vitamin d fracture trials in us and europe. (the dipart group) bmj 2010; 340:b5463. departments of 1pediatric hematology oncology, 2radiology and 3histopathology, royal hospital, muscat, oman *corresponding author’s e-mail: nhm39076@hotmail.com extrarenal wilms’ tumour of the ovary a case report khalil a. albiroty,1 amal al sabahi,1 saud al shabibi,2 zakyia i. al’ajmi,3 karima al hinai,1 *nawal al-mashaikhi1 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 566–569, epub. 7 nov 22 submitted 14 apr 21 revision req. 13 jun 21; revision recd. 12 jul 21 accepted 17 aug 21 the patient was admitted to the paediatric intensive care unit with severe respiratory distress and a high suspicion of bacterial ascites. the patient was treated with broad-spectrum antimicrobials. ultrasound-guided emergent stents were inserted bilaterally in the lower pole of each kidney and a core biopsy was taken from the periphery of the mass. basic laboratory screening tests showed hypercalcaemia (serum calcium = 3.8 mmol/l); therefore, intravenous furosemide and maximum hydration therapy were initiated. tissue histopathology showed a malignant blue round cell tumour with positive immunohistochemical staining for wt1 and cluster of differentiation (cd)99 and focally positive for ae1/ae3. the tumour cells were negative for leukocyte common antigen, cd3, cd20, terminal deoxynucleotidyl transferase, b-cell lymphoma-2, nb84, synaptophysin, chromogranin, neuron-specific enolase, myogenic differentiation 1 and desmin. the histopathology slides were sent abroad for a further expert opinion [figure 2]. based on radiological findings and histopathology reports, the initial clinical impression was of a peripheral neuroectodermal tumour (pnet) or desmoplastic small round cell tumour; wilms' tumour seemed less likely. as the patient’s condition was critical, and so as not to delay treatment while waiting for the histopathology expert’s opinion, the first cycle of chemotherapy based on ewing/pnet (vdc/ie)cog aews1031 protocol-regimen a was started. after one cycle of chemotherapy, the expert’s histopathology report found a poorly differentiated malignant neoplasm consisting mainly of the rounded cells with limited amounts of amphophilic cytoplasm wilms’ tumour (nephroblastoma), is the most frequently occurring abdominal malignancy of childhood and comprises more than two-thirds of the paediatric renal masses in the first five years of life.1 extrarenal wilms’ tumour (erwt) is rare, but there have been a few reports.1–3 the estimated incident rate of erwt is almost 0.5–1% of all cases of wilms’ tumour.2–4 common reported location of wilms' tumour outside the kidney include the retroperitoneum, inguinal canal, scrotum and vagina.4 misdiagnosis for other common retroperitoneal masses of that region is not uncommon.1 case report a two-year-old girl was admitted to a tertiary care hospital in muscat, oman, in 2019 for evaluation of an abdominal mass with a history of two months of poor appetite, night sweats, fever and undocumented weight loss. the initial abdominal and chest computed tomography (ct) revealed a large well-defined hetero geneous soft tissue mass occupying most of the abdominal cavity. the mass measured 13.5 × 10.5 cm with few specks of calcification. it encased most of intraabdominal vessels, including the upper abdominal aorta and renal arteries; the anterior wall of the inferior vena cava was not well demarcated, likely obstructed by the mass. the kidneys were displaced posteriorly with moderate obstructive hydronephrosis with reduced enhancement. the bowel loops were displaced laterally. there was moderate right pleural effusion and small effusion on the left without pulmonary metastasis or nodules [figure 1]. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.117 case report abstract: wilms’ tumour (nephroblastoma) is the most common abdominal malignancy in children. extrarenal wilms' tumour is rare, with limited reports in the literature. we report a two-year-old girl who presented to a tertiary care hospital in muscat, oman, in 2019 with an abdominal mass. the patient was diagnosed with unilateral ovarian wilms’ tumour (initially diagnosed by closed biopsy and confirmed later by histopathology study of the excised tumour). this report highlights the unusual location and presentation of wilms' tumour and presents the medical challenge in both the initial clinical impression and pathological diagnosis. furthermore, this report details the therapeutic plan and shows the good outcome achieved by using the classic renal wilms’ tumour therapy protocols. keywords: wilms' tumor; ovary; pediatrics; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ khalil a. albiroty, amal al sabahi, saud al shabibi, zakyia i. al’ajmi, karima al hinai and nawal al-mashaikhi case report | 567 and irregular vesicular nuclei. the neoplastic cells showed diffuse nuclear positivity for wt1 as well as multifocal striking positivity cd99. this appearance is reflective of wilms' tumour (blastemal-predominant). in light of the final histopathology report, the treatment protocol was changed to high-risk wilms' tumour aren0321-ufh; the patient received 13 cycles of chemotherapy as per the protocol. the treatment was interrupted multiple different times due to prolonged neutropaenia for a total of one month. post-week 13 of chemotherapy, the patient’s abdomen and chest ct assessment showed interval resolution of pleural effusion. there was a regression of lower abdominal mass, measuring 5 × 4.5 × 3.4 cm with specks of calcification. the abdominal mass was anterior to iliac vessels and the bowel displaced away from the tumour with no vascular or bowel encasement. the small extension around the left renal hilum also regressed in size. this lesion abutted the renal vessels but with no encasement or invasion. the kidneys were normal with no focal lesions, with mild residual dilation of collecting systems as was seen before the chemotherapy [figure 3]. after this ct scan, she underwent debulking surgery. during surgery, it was found that the tumour originated from the left ovary as a continuation of the left fallopian tube adherent; there was minimal invasion to the sigmoid colon and the dome of the bladder wall. also, the right ovary looked pathological. the left ovary was excised with salpingectomy and appendectomy and biopsies from the right ovary and the tissue around the tumour were taken; removal of all enlarged lymph nodes was performed and full inspection was done for all suspected tissues. abdominal ct assessment post-surgery showed interval resection of the lower abdominal mass and no apparent tumour residual. tumour and tissue biopsies’ histopathology of the left ovary and fallopian tube revealed a residual of small round blue cell tumour constituting approximately 7% of the examined sample, in a background of chemotherapy-related changes. these residual tumour cells were positive for wt1, cd99 and focally for epithelial membrane antigen (ema). the immunophenotypical features were consistent figure 1: axial images of contrast enhanced computed tomography of the abdomen of a two-year-old girl showing a large intra-abdominal soft tissue mass with heterogenous enhancement (b, c and d) and intra-lesional enlarged blood vessels (blue arrow). it surrounded major abdominal vessels. there was secondary (a, b and c) obstructive bilateral hydronephrosis (red arrows) with reduced renal parenchymal enhancement denoting long-standing obstruction nephropathy. ascites is also present (yellow arrows). figure 2: a: haematoxylin and eosin of the excised tumour at ×40 magnification showing sheets of small to medium-sized undifferentiated cells with hyperchromatic nuclei and scant eosinophilic cytoplasm (black arrows). b: immunohistochemical staining showing of the tumour cells showing diffuse nuclear positivity for wt1 (red arrow). extrarenal wilms’ tumour of the ovary a case report 568 | squ medical journal, november 2022, volume 22, issue 4 with extrarenal (ovarian) wilms' tumour, mixed type (pre-treated, intermediate risk). there was no evidence of anaplasia in the residual tumour. the percentage of necrosis was 93% of the whole examined tissue. few defects were seen in the ovarian capsule; these showed chemotherapy-related changes but no viable residual tumour. all resection margins were free of viable tumour. there was no evidence of vascular invasion and no teratomatous elements were present. the right ovary had chemotherapy-related changes and had no tumour-related findings. eventually, the patient completed the chemotherapy plan and received whole abdomen radiotherapy (12 gy in 8 fractions) as per the protocol. the end of the treatment assessment showed a normal chest ct scan with no evidence of tumour residual or disease recurrence. currently, the patient is being regularly followedup for tumour surveillance. as of her second-year post-therapy follow-up, she was doing well without any concerns. the patient's parent provided informed consent for publication of this report. discussion erwt (nephroblastoma) is defined when the tumour meets two criteria: it is a (1) histologically confirmed nephroblastoma and is in an (2) extrarenal location. erwt is rare in adults and children with few reported cases.5 erwt develops in the retroperitoneum in males and in the inguinal area in females. in reference to the literature, there is no specific manifestation of erwt.5 in a discussion of 34 cases of extra-renal wilm's tumour, coopes et al. highlight that stage i contributed to 30%, ii to 10%, iii to 57% and iv to 3% of all cases.6 in the current case, the tumour was located in the unilateral ovary, which is not a commonly observed location for erwt. in addition, it presented in an advanced stage with the presentation of ascites and pleural effusion. currently, there are a total of 11 reported cases with unilateral ovarian extrarenal wilms tumour.7 turashvili et al.’s reported cases of primary ovarian wilms’ tumour showed that the mean age was 22 years (range: 1–56 years). moreover, the most frequent clinical symptom at presentation was abdominal pain (n = 8). the median tumour size was 13 cm (range: 2.5–18 cm) and all tumours were unilateral. only four out of 11 reported cases of ovarian wilms’ tumour were treated with chemotherapy. no recurrences were reported in any of the eleven patients.7 the current case falls within the reported age range (2 years old) and tumour size range (13.5 cm). she also presented with abdominal pain and a unilateral ovarian mass and was treated with high-risk wilms’ tumour chemotherapy protocol. the exact embryonic origin of erwt is unclear.1,4 there are conflicting reasonable hypotheses that it originates from ectopic metanephric blastema or from primitive mesodermal tissue. the most popular theory is based on the connheim’s cell rest theory, which explains that persistent embryonal cells are likely to undergo malignant transformation at any point in time.4 it is well known that erwt does not exhibit characteristic radiological features.5 this was the case with the current patient; it is therefore important to not rely solely on radiological reports when determining a treatment plan for an obscure abdominal mass in a child. a histopathological diagnosis is encouraged at the very least with ultrasound-guided biopsy. accurate diagnosis and then appropriate therapy should be based on the histology report after tumour removal. it is important to emphasise the significance of having a second opinion with other experts if there is any doubt in the histopathological findings, thereby allowing for the most effective and appropriate therapy. therapy should not be initiated without a thorough histopathology report, with exceptions when there are clinical emergencies. in the current case, the most related therapy was used based on the provisional histopathology report until the final and accurate histopathology report was received. according to shojaeian et al., out of 87 reported childhood erwt cases, favorable histology was observed in most cases. this made the prognosis better in erwt compared to the classic wilms’ tumour with the same stage and histology.2 in the current case, the predominant component was the blastemal type, which has a poor prognosis and allows the patient to be put on a high-risk protocol. in the present case, molecular studies were not done due to cost limitations and the unavailability of specialised laboratories providing such services; the immunohistochemical studies aided in reaching a diagnosis. in this case, etv4 was negative making figure 3: follow-up abdomen computed tomography scans showing a reduction in size and consequent mass effect on the kidneys. khalil a. albiroty, amal al sabahi, saud al shabibi, zakyia i. al’ajmi, karima al hinai and nawal al-mashaikhi case report | 569 a cic-related sarcoma unlikely. phox2b, which is very specific test for neuroblastoma, was negative in the current case. importantly, this case was negative for desmin and ema; this eliminates the likelihood of a desmoplastic tumour. cd99 is a very non-specific marker with much antigen cross-reactivity; in ewing sarcoma, this would be expected to be strong and diffuse unlike the weak patchy positivity in this case. hence, the absence of other markers and positive findings for wt1 confirms the diagnosis of wilms' tumour. the treatment plan was informed by the renal wilms' tumour protocol (chemotherapy and radical surgery plus radiotherapy, if indicated).2,5,6 the therapeutic steps, following surgical excision, depend on both the tumour stage and the histological finding.2 in the current case, total excision of the ovary was necessary as it was invaded by the tumour; full inspection of any suspected tissue and removal of any enlarged lymph nodes were performed. the total excision of the ovary with removal of all enlarged lymph nodes were being supported by the children oncology group (cog) chemotherapy plan, followed by adjuvant chemotherapy and focal radiotherapy to the abdomen. the latter treatment approach was adopted in the current case due to the patient’s history of ascites, the closed biopsy finding at the diagnostic phase and the blastemal type of histological component finding. the chemotherapy-radiotherapy modality of treatment may cause injury to the hypothalamicpituitary gonadal axis and impair gonadal function, especially if used for abdominal radiation.8 however, the radiation risk is dependent on treatment volume, total dose, fractionation schedule and age at treatment. it was found that a radiation dose higher than 18 gy does result in effects ranging from altered pubertal timing to complete ovarian failure.8 the current case required, as per cog protocol, 12 gy focal abdominal radiations. permanent ovarian failure occurs mainly in childhood cancer patients who are treated with radiation doses greater than 20 gy. an ovarian transposition to a region that is lateral or medial to the planned radiation volume was found to be useful as this may preserve ovarian function in young females.8 for therapy outcome, the two-year event-free survival of the reported erwt cases was almost 85% and the mortality rate was 5%, which are similar to renal wilms' tumour outcomes.2 the current patient completed her second year of regular follow-up with a good outcome and no active issue or consequence. conclusion though erwt can be difficult to diagnose preoperatively, it should be considered in as a differential diagnosis when a patient presents with any asymptomatic abdominal mass. furthermore, as there is neither a typical clinical presentation nor specific radiological findings, the diagnosis should be based on a pathology report from the excised tumour. the recommended therapy plan for erwt is similar to that of renal wilms’ tumour therapy plan. a u t h o r s’ c o n t r i b u t i o n kaa, as and nm drafted the manuscript. ss provided the radiological images and handled the radiological aspects of the manuscript. zia provided the histopathology images and handled the histopathological aspects in the manuscript. kh reviewed the manuscript and provided critical feedback. nm revised and edited the manuscript. all authors approved the final version of the manuscript. references 1. goel v, verma ak, batra v, puri sk. ‘primary extrarenal wilms’ tumour’: rare presentation of a common paediatric tumour. bmj case rep 2014; 2014:bcr2013202172. https://doi.org/10.11 36/bcr-2013-202172. 2. shojaeian r, hiradfar m, sharifabad ps, zabolinejad n. chapter 6: extrarenal wilms’ tumor: challenges in diagnosis, embryology, treatment and prognosis. in: van den heuveleibrink mm, ed. wilms tumor. brisbane, australia: codon publications, 2016. 3. khalid a, faizan m, khan s, najamuddin, talat n, rathore z. extra-renal wilm’s tumor in a 3 years old boy-a case report. j cancer prev curr res 2017; 7:00254. https://doi. org/10.15406/jcpcr.2017.07.00254. 4. wabada s, abubakar as, adamu ai, kabir a, gana lb. a retroperitoneal extra-renal wilms’ tumour: a case report. niger j clin pract 2017; 20:388–91. https://doi.org/10.4103/1119-3077.2 01427. 5. apoznański w, sawicz-birkowska k, palczewski m, szydełko t. extrarenal nephroblastoma. cent european j urol 2015; 68:153–6. https://doi.org/10.5173/ceju.2015.571. 6. coopes mj, wilson p, weitzman s. extrarenal wilms’ tumor: staging, treatment and prognosis. j clin oncol 1991; 9:167–74. https://doi.org/10.1200/jco.1991.9.1.167. 7. turashvili g, fix dj, soslow ra, park kj. wilms tumor of the ovary: review of the literature and report of 2 cases. int j gynecol pathol 2020; 39:72–8. https://doi.org/10.1097/ pgp.0000000000000565. 8. hudson mm. reproductive outcomes for survivors of childhood cancer. obstet gynecol 2010; 116:1171–83. https://doi.org/10.10 97/aog.0b013e3181f87c4b. https://doi.org/10.1136/bcr-2013-202172 https://doi.org/10.1136/bcr-2013-202172 https://doi.org/10.15406/jcpcr.2017.07.00254 https://doi.org/10.15406/jcpcr.2017.07.00254 https://doi.org/10.4103/1119-3077.201427 https://doi.org/10.4103/1119-3077.201427 https://doi.org/10.5173/ceju.2015.571 https://doi.org/10.1200/jco.1991.9.1.167 https://doi.org/10.1097/pgp.0000000000000565 https://doi.org/10.1097/pgp.0000000000000565 https://doi.org/10.1097/aog.0b013e3181f87c4b https://doi.org/10.1097/aog.0b013e3181f87c4b squ med j, may 2011, vol. 11, iss. 2, pp. 161-164, epub. 15th may 11 submitted 25th april 11 accepted 27th april 11 in this issue of squmj, dr. deepali jaju and her colleagues have shown the effects of a yoga technique known as pranayam breathing (pb) on the pulmonary system.1 these authors have demonstrated that pb has different effects on healthy controls compared to those with chronic obstructive pulmonary disease (copd). pb invoked clear improvement in maximum inspiratory pressure (mip) in normal controls; however, pb was not able to produce mip changes in subjects with copd. there was however, a significant increase in the visual analogue score (vas) in copd patients, which suggested reduction in respiratory distress. while the improvements were limited, and perhaps variable in different people, it does indicate that there is indeed some validity in yogic intervention. in modern parlance, health care systems outside the realm of modern biomedical sciences, also termed ‘allopathic medicine’, are often labelled ‘traditional medicine’. the increasing acceptance of ‘nonallopathic’ health care systems, has led to some of them have being accepted as ‘complementary and alternative medicine’ (cam). the term ‘integrative medicine’ has also emerged to describe the concurrent use of different healing systems to increase vitality, cure disease, or as integral part of a regimen for a healthy lifestyle or prevention of diseases. in the squmj february 2011 issue, dr. rahma al-kindi and her colleagues studied the use of alternative medicine among adult diabetics.2 the study population was 146 patients, attending diabetic clinics at four primary health centres in the muscat area of oman. this study demonstrated that 52% of the subjects had used alternative medicine at some time in the past. most importantly, 42% of the cohort had used herbs and food supplements specifically to manage their diabetes. as half of the patients were satisfied with such interventions, the study sends a clear message: alternative medicine is widely used in the muscat area for conditions such as diabetes. such findings imply that physicians should be better prepared to discuss the use of cam with patients, with all the implications this may have including the consideration of potential side effects and drug interactions. it is no surprise that squmj has attracted manuscripts on cam in its recent issues since this is consonant with international trends. there is evidence in the literature to suggest that there is widespread increased use of cam even in developed countries like the united states.3,4,5,6 in addition to the widespread general increase in use, cam is also being increasingly used to treat some specific diseases of major concern to society, such as arthritis and cancer in developed countries, and malaria in africa.7,8,9 in developing countries, where modern health care systems have remained rudimentary, traditional medicine continues to meet a significant proportion of health care needs. many healing systems owe their origin to ancient civilizations. in the middle east, numerous records show the existence of pre-islamic healing systems. this healing system bloomed in ancient mesopotamia, which encompassed the area around the tigris and euphrates rivers, corresponding to editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; *email: mjournal@squ.edu.om í◊耔j÷]ê<ÿëçf÷]<g�÷] [21<·üœ÷]<ª<ãœfi<‡ë_<  editorial complementary and alternative medicine where do we stand in the 21st century? lamk al-lamki complementary and alternative medicine where do we stand in the 21st century? 162 | squ medical journal, may 2011, volume 11, issue 2 present-day iraq, syria, turkey, and part of iran. this cradle of civilization competes with historic egypt in the development and application of such healing systems.10 during the heyday of the islamic civilization, various healing systems came into prominence and some of them were employed in early experimental studies, the precursors of modern clinical trials. historically, india is one of the countries that has given humanity a unique healing system known as ayurvedic medicine which originated at least 4,000 years ago. the term ayurveda is a combination of ayu (life) and veda (science). ayurvedic medicine is based on a humoral interpretation of disease and health with the idea of balancing the three humours “vata”, “pitta” and “kapha”.11 ill health results when these three are out of balance. just like india, china developed its own unique health care system that eventually spread to japan, korea and some other parts of the far east. the cardinal idea of the chinese health system was symmetry or balance, as in ayurvedic medicine, and echoed the philosophy of ‘galen’s medicine’ in ancient greece. in chinese medicine, illness is due to an imbalance in the flow of energy through established channels or meridians. a normal flow is essential for good health and selfhealing; bamboo sticks, fish bones and now needles are used to stimulate points along the energy meridians and referred to as acupuncture. healing systems in europe were strongly influenced by galen and arab/islamic medicine until the end of medieval period. with the emergence of science and experimentation during the european renaissance, scientific medicine started to take root. this, in turn, led to the current domination of the modern allopathic biomedical health care system in europe and north america. nonetheless, even in these regions, there is still wide popular use of various cam healing practices such as hydrotherapy, naturopathy, and herbalism, as well as chiropractic therapy, breathing, meditation and the use of megavitamins. the national center for complementary and alternative medicine (nccam) of the national institute of health (nih) in the usa has instituted scientific studies to explore the efficacy of both the remaining traditional medicine systems and newly emerged healing systems.12 with respect to oman, the health system is a hybrid of of allopathic medicine and traditional healing practices, the latter being deeply rooted in society. it is thus not surprising that dr. rahma al-kindi found a high use of herbal treatments for the self-management of diabetes.2 oman also has other types of cam including the well known ‘physical treatments’ such as “al wasam” (الوسم) cauterization and “al hujama” (احلجامة) vacuum cup suction of the body surface.13 traditional omani ‘orthopaedic’ interventions include the use of “al jabirah” (اجلبيرة), a homemade equivalent of plaster of paris) used by a traditionally trained person (a “mugabbir” – مجّبر) for fractures and sprains. there are also various ‘spiritual’ interventions often employed for combatting what would in western medicine be deemed to be psychological disorders; these include “al bassar” (الباصر), and “zar” (زار), both exorcism practices.14 in addition, like other countries round the world, oman also uses a variety of herbs (“marameiah” – املرمرية) for different medical conditions. there is also a specific type of deep massage which is used for the treatment of infertility in oman (“al maasah” – املسح). other cam physical treatments used in oman include using a twin to treat migraine by massaging the affected side of the person’s forehead with his/her foot. despite the wide current use of non-allopathic treatment, there are still highly polarized views on the topic among modern practitioners of biomedical health care system. many doctors who practice conventional allopathic medicine do not ‘believe’ in the efficacy of cam at all—“it neither works nor does it have any basis on which it can possibly work”. then, there are those doctors who practise both allopathic medicine and cam, but unfortunately, some of these are doing it only for profit. there is however, a glimmer of hope as evidenced in the american nccam center, where millions of dollars are spent on studying various forms of cam including naturopathy, chiropractice, herbalism, traditional chinese medicine, ayurveda, meditation, yoga, biofeedback, hypnosis, homeopathy, acupuncture and nutritionbased therapies among other therapies.12 nccam aspires to establish the evidence-based efficacy of cam. more recently, some clinical research has been employed to shed light on the efficacy of cam, employing vigorous research methodology such as controlled clinical trials.4 to understand cam better, nccam has classified cam into 5 lamk al-lamki editorial | 163 major groups:12 1) whole medical systems such as ayurvedic medicine, chinese medicine and homeopathy; 2) mind-body medicine which include yoga and meditation; 3) biological-based substances such as herbs, foods and vitamins; 4) manipulative and body based practices such as chiropractic and osteopathy manipulations; 5) energy medicine including biofield therapists and bioelectromagnetic-based therapies. the cochrane center has also reviewed some scientific studies on cam and published them on website of the danish knowledge and research center for alternate medicine (vifabs).15 those of us who practise conventional allopathic medicine need to have a better understanding of cam, how it works, and what the potential benefits and side effects are. we need to be more willing to discuss the use of cam with our patients. there is indeed potentially great danger in combining the two without proper knowledge of both. this is of particular concern when a serious illness threatens the confidence of patients in modern allopathic medicine and they resort to cam as adjunctive therapy, and, at times, as the sole treatment. it is not clear why people use cam, but their reasons are related to social and cultural issues, as well as the nature and severity of their disease. somehow, cam has a major persuasive appeal to patients.16,17 in developed countries, wide usage of cam among patients with chronic and debilitating disease may be due to a culturally-based wish to “leave no stone unturned” and a patient’s ‘loss of hope’ of regaining their pre-morbid self as in the case of people with aggressive types of cancers or other progressive debilitating diseases that are impervious to conventional medical treatment. there is no evidence to suggest that oncologists are fully aware of the trend for cancer patients to use cam concomitantly with their chemotherapy. this, needless to say, is potentially dangerous as major toxicities may arise. ernst et al. reviewed several publications and out of the 21 studies on adult cancers, 50% reported that 27% of respondents used cam while the average percentage of adults using cam was 31.4%.8 why patients use alternative medicine and which patients do this has yet to be empirically charted. john astin, from stanford center for disease prevention, has studied the socio-demographic characteristics of people who use cam and found that those who used cam were likely to be well educated, but have poor health status.18 it was found in this study that people utilised cam not because they were dissatisfied with conventional medicine, but because they found it “more congruent with their valued beliefs and philosophical orientations towards health and life”.14 it is not known how widely cam is used in different communities or clinical conditions. most of the available studies are marred by poor design and methodological limitations. harris and rees have reviewed 12 studies and could not come to a clear conclusion.3 however, there is hope for humanity as a whole because it is gradually getting clearer that there is a lot of potential benefit from cam, even though currently there is some misuse or improper use. as more and more clinical and basic scientific studies are carried out, it becomes clearer that the boundaries between cam and conventional western medicine are becoming blurred. on the whole, what is considered complementary and alternative practice in one country maybe considered conventional practice in another, e.g. some herbs in standard use in europe are considered cam therapy in the united states.12 an increasing number of robust studies are appearing in the literature showing the potential benefits of using cam alone or as part of integrative medical therapy. one of these is a recent norwegian study from the norwegian university of life sciences (umb). it is a scientific study of the plants extracts derived from the bark of cinchona tree and the sweet wormwood plant (artemisia annua) that have been used since dawn of history in african traditional medicine against malaria. interestingly, contrary to the case with some of the conventional drugs available to treat malaria today, the malaria parasite has not yet developed resistance to the formula employed in african traditional medicine.9 another recent clinical research study has studied the effects of omega-3 fatty acid and fish intake on development of age-related macular degeneration (amd) amongst the 38,022 women who were followed up by questionnaire.19 the results showed a significant decrease of the incidence of amd over 10 years follow-up. it is postulated that the fatty acid in fish and omega-3 fatty acid helped improved choroidal blood flow in the eye. amd and cardiovascular disease have been hypothesised to share similar mechanisms and risk factors. intake complementary and alternative medicine where do we stand in the 21st century? 164 | squ medical journal, may 2011, volume 11, issue 2 of fish and omega-3 fatty acid has been linked to reduced cardiovascular events possibly related to the anti-inflammatory and anti-atherosclerotic effects of these products. where do we go from here? we, as modern allopathic medicine practitioners, need to take a long and good look at our attitude towards cam. we need to be well-versed in this subject so that we are able to discuss it intelligently with the ‘e-patients’ of the 21st century. we need to understand the role of cam when used alone or in conjunction with other treatment protocols that are an integral part of biomedical care. we need more scientific research devoted to understanding how and which cam treatment has benefit to those who use it. the future of health care would be best served if an enlightened and amicable merger of the two branches of medical treatments were contemplated. more studies are therefore imperative. this means physicians need to open their eyes and apply their minds to this endeavour. references 1. jaju ds, dikshit mb, balaji j, jyoji g, rizvi s, al rawas o. effects of pranayam breathing on respiratory pressures and sympathovagal balance of patients with chronic airflow limitation and in control subjects. squ med j 2011; 11:221–233. 2. al-kindi rm, al-mushrafi m, al-rabaani m, alzakwani i. complementary and alternative medicine use among adults with diabetes in muscat region, oman. squ med j 2011; 11:62–7. 3. harris p, rees r. the prevalence of complementary and alternative medicine use among the general population: a systematic review of the literature complement therap in med 2000; 8:88– 96. from: http://www.sciencedirect.com/science/ journal/09652299 accessed april 2011. 4. national center for complementary and alternative medicine. clinical trials and cam. from: http:// nccam.nih.gov/research/clinicaltrials/factsheet/ accessed april 2011. 5. eisenberg dm, davis rb, ettner sl, appel s, wilkey s, van rompay m, et al. trends in alternative medicine use in the united states, 1990-1997. results of a follow-up national survey. jama 1998; 280:1569–75. 6. barnes pm, powell-griner e, mcfann k, nahin rl. complementary and alternative medicine use among adults: united states, 2002. integrat med 2; 2004:54–71. 7. herbal remedies for arthritis inflammation. methods of healing. from: http://www.methodsofhealing. com/herbal-remedies-for-arthritis/ accessed april 2011. 8. ernst e, cassileth br. the prevalence of complementary/alternative medicine in cancer. a systematic review. cancer 1998; 83:777–82. 9. fighting malaria with african plant extracts. science daily, 9 april 2011. from: http://www.sciencedaily. com/releases/2011/04/110408075159.htm accessed april 2011. 10. history of alternative medicine. from: http:// en.wikipedia .org/wiki/histor y_of_alternative_ medicine accessed april 2011. 11. herbalism. from: http://en.wikipedia.org/wiki/ herbalism accessed april 2011. 12. alternative medicine. from: http://en.wikipedia. org/wiki/alternative_medicine#p-search accessed april 2011. 13. ghazanfar sa.wasm: a traditional method of healing by cauterisation. j ethnopharmacol 1995; 47:125–8. 14. al-adawi sh, martin rg, al-salmi a, ghassani h. zar: group distress and healing. ment health relig cult 2001; 4:47–61. 15. cochrane and alternative medicine. center for alternative behandling. from: http://www.vifab. d k / u k / c o c h r a n e + a n d + a l t e r n a t i v e + m e d i c i n e accessed april 2011. 16. kaptchuk tj, eisenberg dm. the persuasive appeal of alternative medicine. ann intern med 1998; 129:1061–5. 17. whorton j. countercultural healing: a brief history of alternative medicine in america. from: http:// www.pbs.org/wgbh/pages/frontline/shows/altmed/ clash/history.html accessed april 2011. 18. astin ja. why patients use alternative medicine result of a national study. jama 1998; 279:1548–53. doi: 10.1001 / jama.279.19.1548. 19. christen wg, schaumberg da, glynn rj, buring je. dietary ω-3 fatty acid and fish intake and incident age-related macular degeneration in women. arch ophthalmol. epub 14 march 2011. doi: 10.1001 / archophthalmol.2011.34. أتثري جراحة السمنة على إنقاص الوزن ونقص التغذية ومضاعفات ما بعد اجلراحة وااللتزام ابلنظام الغذائي ومنط احلياة دراسة استعادية مجاعية من البحرين نوال عبد اهلل ح�سن، اأفنان فريجة، عبد املنعم اأبو ال�سل، هاين ال�ساعاتي، �سيمون برينا abstract: objectives: this study aimed to investigate the effect of bariatric surgery on degree of weight loss, as well as the prevalence of nutritional deficiencies, postoperative complications and adherence to dietary and lifestyle recommendations in a cohort of patients from bahrain. methods: this retrospective cohort study took place between march and september 2018 at two hospitals in bahrain. all adult patients who had undergone bariatric surgery between 2012–2017 were included. sociodemographic and clinical information was collected from the patients’ medical records and during phone interviews. results: a total of 341 patients participated in the study. the mean age was 39.82 ± 9.95 years and 67.7% were female. there was a significant relationship between postoperative body mass index and both the type of surgery and time since surgery (p = 0.025 and 0.008, respectively). while type of surgery had no significant effect on percent of excess weight loss (ewl) or percent of total weight loss (twl), time since surgery significantly affected both of these weight loss measures (p = 0.006 and 0.001, respectively). biochemical tests revealed haemoglobin, mean corpuscular volume, 25-hydroxy vitamin d, ferritin and iron deficiencies. commonly reported complications included hair loss (59.5%), flatulence/abdominal pain (39.3%), dry skin (34.3%) and gastroesophageal reflux disease (33.1%). the level of adherence to dietary and lifestyle recommendations was high to moderate. conclusion: bariatric surgery was effective in accelerating ewl and twl; however, it also resulted in complications such as nutritional deficiencies and gastrointestinal side-effects. keywords: bariatric surgery; obesity management; weight loss; gastric bypass; biliopancreatic diversion; avitaminosis; iron-deficiency anemia; bahrain. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل معرفة تاأثري جراحة ال�سمنة على درجة فقدان الوزن، وكذلك مدى انت�سار نق�ص التغذية وم�ساعفات ما بعد اجلراحة وااللتزام بالتو�سيات الغذائية ومنط احلياة يف جمموعة من املر�سى من البحرين. الطريقة: اأجريت هذه الدرا�سة اال�ستعادية بني مار�ص و�سبتمرب 2018 يف م�ست�سفيني يف البحرين. �سملت الدرا�سة جميع املر�سى البالغني الذين خ�سعوا جلراحة ال�سمنة بني 2012-2017. مت جمع املعلومات االجتماعية والدميوغرافية وال�رسيرية من ال�سجالت الطبية للمر�سى واأثناء املقابالت الهاتفية. النتائج: �سارك 340 مري�سا يف الدرا�سة. كان متو�سط العمر 9.95 ± 39.82 �سنة و %67.7 كانو اإناث. كانت هناك عالقة ذات داللة اإح�سائية بني موؤ�رس كتلة اجل�سم بعد اجلراحة ونوع اجلراحة والوقت منذ اجلراحة )على التوايل، 0.008 و p = 0.025(. يف حني اأن نوع اجلراحة مل يكن له تاأثري له داللة اإح�سائية على ن�سبة فقدان الوزن الزائد )ewl( اأو ن�سبة اإجمايل فقدان الوزن)twl(، الوقت منذ اجراء اجلراحة كان له تاأثري له داللة اإح�سائية كبرية على كل من مقايي�ص فقدان الوزن هذه )على التوايل، 0.001 و p = 0.006(. ك�سفت االختبارات البيوكيميائية عن نق�ص يف الهيموجلوبني، متو�سط حجم الكريات، فيتامني د، الفرييتني واحلديد. ت�سمل امل�ساعفات التي مت االإبالغ عنها ب�سكل �سائع ت�ساقط ال�سعر )%59.5(، وانتفاخ البطن/اأمل البطن )%39.3(، وجفاف اجللد )%34.3( و داء االرتداد املعدي املريئي )%33.1(. كان م�ستوى االلتزام ewl بالتو�سيات املتعلقة بالنظام الغذائي ومنط احلياة مرتفًعا اإىل معتدل. اخلال�صة: كانت جراحة عالج البدانة فعالة يف اإنقا�ص كل من و twl ولكنها اأدت كذلك اإىل حدوث م�ساعفات مثل نق�ص التغذية واالآثار اجلانبية املعوية. الكلمات املفتاحية: جراحة ال�سمنة؛ معاجلة ال�سمنة؛ فقدان الوزن؛ حتويل م�سار املعدة؛ حتويل م�سار البنكريا�ص؛ نق�ص الفيتامينات؛ فقر الدم ب�سبب نق�سان احلديد؛ البحرين. effect of bariatric surgery on weight loss, nutritional deficiencies, postoperative complications and adherence to dietary and lifestyle recommendations a retrospective cohort study from bahrain *nawal a. hasan,1 afnan freije,1 abdulmenem abualsel,2 hani al-saati,3 simone perna1 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e344–351, epub. 5 oct 20 submitted 28 aug 19 revisions req. 12 nov 19, 21 jan & 11 feb 20; revisions recd. 5 dec 19, 2 feb & 20 feb 20 accepted 12 mar 20 1department of biology, college of science, university of bahrain, zallaq, bahrain; 2department of surgery, king hamad university hospital, busaiteen, bahrain; 3department of surgery, salmania medical complex, manama, bahrain *corresponding author’s e-mail: nahmed@uob.edu.bh this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.015 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ nawal a. hasan, afnan freije, abdulmenem abualsel, hani al-saati and simone perna clinical and basic research | e345 advances in knowledge given the high rate of obesity in bahrain, there is a need for evidence-backed research to support modalities for obesity management. this study confirms the effectiveness of bariatric surgery in reducing both percent of excess weight loss and total weight loss among a cohort of patients in bahrain. however, the rate of certain nutritional complications was concerning, particularly with regards to deficiencies in iron, haemoglobin and mean corpuscular volume, all of which are indicators of anaemia. application to patient care the findings of this study indicate that patients require nutritional counselling to sustain weight loss outcomes and reduce rates of nutritional deficiencies and gastrointestinal side-effects following bariatric surgery. the current obesity epidemic is a major public health problem in both developing and developed countries; according to global estimates, the prevalence of this disease doubled between 1980 and 2016, with approximately 13% of all adults worldwide considered obese in 2014.1 according to the world health organization, obesity is defined as the accumulation of excessive fat in the body resulting in multiple adverse health effects including an increased risk of developing type 2 diabetes mellitus, cardiovascular diseases, coronary artery disease, hypertension, dyslipidaemia and obstructive sleep apnoea.2 in particular, bahrain is considered one of the countries with the highest prevalence rates of obesity in the world.3 in 2007, nutritional surveillance indicated that the prevalence of obesity was 34.1% and 40.3% among males and females, respectively.4 these findings prompted the establishment of obesity clinics in 2008 to support and motivate patients to lose weight.5 currently, bariatric surgery is considered the most effective treatment option to reduce morbidity and mortality in morbidly obese patients (i.e. those with body mass indexes [bmis] of ≥40 kg/m2).6 according to the 1991 consensus guidelines of the national institutes of health in the usa, eligible patients for this type of surgery should have either a bmi of >40 kg/m2 or a bmi of 35–40 kg/m2 along with an obesity-related disease such as diabetes, hypertension or cardiovascular diseases.7 worldwide, the three most common types of bariatric surgery are sleeve gastrectomy (sg), mini gastric bypass (mgb) and roux-en-y gastric bypass (rygb).8 patients may develop gastrointestinal complications following bariatric surgery including nausea, vomiting, constipation, diarrhoea, regurgitation, dumping syndrome and decreased appetite.9,10 moreover, depending on the type of procedure, behavioural alterations in eating patterns and anatomical and physiological modifications to the gastrointestinal organs can result in significant protein and micronutrient deficiencies such as thiamine (vitamin b1), cobalamin (vitamin b12), folate, calcium and vitamin d deficiencies.9,11 these can be exacerbated by nonadherence on the part of the patient in taking necessary supplements.12,13 this study aimed to measure the effectiveness of bariatric surgery in reducing weight as well as the level of adherence to dietary and lifestyle recommendations and prevalence of nutritional deficiencies and selfreported complications among a cohort of patients in bahrain. moreover, the study aimed to determine the relationship between weight loss and nutritional parameters with type of surgery, time since surgery and sociodemographic characteristics. methods this retrospective cohort study was conducted between march and september 2018 at the king hamad university hospital (khuh) and salmaniya medical complex (smc) in bahrain. all patients between 18–65 years of age and who had undergone bariatric surgery between one and six years previously (i.e. between 2012 and 2017) were included in the study. all bariatric surgery candidates met the national institutes of health criteria with regards to their eligibility for surgical intervention.7 however, patients who had undergone the surgery less than one year previously and pregnant women were excluded, as were patients who had undergone revisional bariatric surgery since the initial procedure. the physical parameters of the patients were measured in line with the outcome reporting standards of the american society for metabolic and bariatric surgery.14 as such, weight in kg and height in m were measured on a digital medical scale, with bmi calculated by dividing weight by height squared.1,2 subsequently, percent of excess weight loss (ewl) and percent of total weight loss (twl) were calculated according to the below formulae,14 with ideal bmi defined as 25 kg/m2: ewl = twl = × 100 × 100 preoperative bmi−postoperative bmi preoperative weight−postoperative weight preoperative bmi−ideal bmi preoperative weight effect of bariatric surgery on weight loss, nutritional deficiencies, postoperative complications and adherence to dietary and lifestyle recommendations a retrospective cohort study from bahrain e346 | squ medical journal, august 2020, volume 20, issue 3 blood samples were collected during routine analysis between 8 am and 10 pm following a 12hour fasting interval and then analysed based on the standard laboratory protocols of the participating hospitals. nutritional deficiencies were identified by reviewing and comparing various nutritional parameters with normal reference ranges of calcium, 25-hydroxy (oh) vitamin d, vitamin b12, iron, ferritin, haemoglobin, haematocrit, mean corpuscular volume (mcv), cholesterol, sodium, potassium and magnesium.15 a questionnaire was developed in both arabic and english to collect data from the participants. the questionnaire was divided into three parts, in which the first assessed demographic data and the second investigated if the participant was currently experiencing any complications which had appeared postoperatively (i.e. dehydration, constipation, hair loss, etc.). the third part was based on previously published work by mechanick et al. and assessed the level of adherence to important post-surgery dietary and lifestyle recommendations.11 in this section, participants rated their frequency of adherence to each recommendation as either all of the time, most of the time, some of the time or rarely/never. the full questionnaire was pilot-tested on 13 adults who had also undergone bariatric surgery, although not necessarily at khuh or smc. subsequently, the final version of the questionnaire was completed during phone interviews with the patients. in each case, a total of five attempts were made to reach patients by phone; if patients were unreachable or not interested in completing the questionnaire, only their biochemistry tests were reviewed and including in the analysis. data were entered into an excel spreadsheet, version 2010 (microsoft corp., redmond, washington, usa) and analysed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). descriptive results were presented as either frequencies and percentages or means and standard deviations. a repeated measures analysis of variance analysis was used to evaluate the effect of type of surgery and time since surgery on preoperative and postoperative bmi, after adjusting for age, gender and time or type of surgery. differences in ewl and twl between surgery types and time intervals were compared utilising an analysis of covariance model, after adjusting for the appropriate covariates. adherence to dietary and lifestyle recommendations was classified as responses of “all of the time” or “most of the time” to each recommendation while nonadherence was classified by responses of “some of the time” or “rarely/ never”. categorical data regarding the differences between surgeries were tested using a pearson’s chi-square test. a two-sided p value of <0.050 was considered statistically significant. permission to conduct this study was obtained from the education and proficiency centre and research and ethics committee of khuh (khuh/ research/no. 211/2018) as well as from the health research committee of the ministry of health in bahrain (auhr/ 498/2018). all procedures were conducted in accordance with the ethical standards of the revised declaration of helsinki. informed consent was obtained from all participants included in the study. results overall, 396 patients were scheduled for bariatric surgery between 2012 and 2017 including 183 patients (46.2%) from khuh and 213 (53.8%) from smc; however, 56 patients (14.1 %) were excluded for figure 1: flowchart showing the inclusion and allocation of patients in the current study. *one patient participated in the study and completed the questionnaire but was later excluded because she was the only patient who underwent adjustable gastric band surgery. therefore, for statistical reasons, this patient was excluded leaving 242 total patients. nawal a. hasan, afnan freije, abdulmenem abualsel, hani al-saati and simone perna clinical and basic research | e347 various reasons. as such, a total of 340 patients (85.9 %) were included in the final analysis [figure 1]. the mean age of the participants was 39.82 ± 9.95 years and over two-thirds were female (67.6 %). the majority were of bahraini nationality (93.5%) and married (73.1%). a total of 103 patients (42.7%) were educated to the secondary school level. the most common type of bariatric surgery was sg (57.9%) followed by mgb (31.8%) and biliopancreatic diversion (bpd; 10.3%). approximately one-third of the patients (30.6%) had undergone bariatric surgery one year previously. mean bmi values at baseline and following bariatric surgery were 48.16 ± 9.25 and 30.16 ± 5.97 kg/m2, respectively [table 1]. with regards to surgery type, patients who underwent bpd had the highest mean bmi values, both at baseline and after the surgery (56.76 and 34.81 kg/ m2, respectively). while patients who underwent sg and mgb had similar preoperative bmi values (47.23 and 47.58 kg/m2, respectively), mgb patients had the lowest postoperative bmi value among all surgery types (28.60 kg/m2). in terms of time since surgery, patients who had undergone surgery six years previously had the highest mean bmi values, both at baseline and after the surgery 56.76 and 34.81 kg/m2, respectively. in contrast, the lowest mean postoperative bmi was reported in patients who have undergone the surgery three years previously (26.98 kg/m2). both surgery type and time since surgery had a significant effect on bmi reduction (p = 0.025 and 0.008, respectively) [figure 2]. moreover, there was a significant association between time since surgery and both ewl and twl (p = 0.006 and 0.001, respectively) [figure 3]. with regards to sociodemographic characteristics, age and gender were significantly associated with twl (p = 0.029 and 0.008, respectively), but not ewl. an investigation of the nutritional status of the patients revealed that the majority had normal levels of most of the assessed indicators. however, almost half of the patients had iron, mcv and haemoglobin deficiencies (48.7 %, 47.0 % and 46.7 %, respectively). moreover, 40% and 41.3 % had 25-oh vitamin d insufficiency and deficiency, respectively. in addition, 38% of patients were deficient in ferritin. after controlling for covariates like age, gender and time of surgery, type of surgery was only found to have a significant effect on cholesterol (p <0.001). on the other hand, time of surgery had a significant effect on multiple nutritional parameters, including sodium (p <0.001), potassium (p <0.001), albumin (p <0.001), calcium (p <0.050) , vitamin b12 (p <0.010) and haemoglobin (p <0.010). certain postoperative complications were reported by the patients, with the most common being hair loss (59.5%) followed by flatulence/abdominal pain (39.3%), dry skin (34.3%) and gastroesophageal reflux disease (33.1%). significant differences were observed between the different types of surgery in terms of the rates of constipation, diarrhoea, flatulence/abdominal pain, anaemia, hypoglycaemia, cholelithiasis and fatigue (p ≤0.050 each) [table 2]. with regards to table 1: sociodemographic and clinical characteristics of bariatric surgery patients in bahrain (n = 340) characteristic n (%) mean age in years ± sd 39.82 ± 9.95 gender male 110 (32.4) female 230 (67.6) nationality bahraini 318 (93.5) non-bahraini 22 (6.5) education level* primary 5 (2.1) intermediate 17 (7.1) secondary 103 (42.7) diploma/bsc 99 (41.1) postgraduate 17 (7.1) marital status* single 65 (26.9) married 177 (73.1) time since surgery in years 1 104 (30.6) 2 84 (24.7) 3 24 (7.1) 4 59 (17.4) 5 61 (17.9) 6 8 (2.4) type of surgery sg 191 (57.9) bpd 34 (10.3) mgb 105 (31.8) mean bmi ± sd in kg/m2 preoperative/baseline 48.16 ± 9.25 postoperative/current 30.16 ± 5.97 sd = standard deviation; bsc = bachelor of science; sg = sleeve gastrectomy; bpd = biliopancreatic diversion; mgb = mini gastric bypass; bmi = body mass index. *percentages for this variable are calculated out of 242, as 99 patients were unreachable by telephone or did not wish to complete the questionnaire. effect of bariatric surgery on weight loss, nutritional deficiencies, postoperative complications and adherence to dietary and lifestyle recommendations a retrospective cohort study from bahrain e348 | squ medical journal, august 2020, volume 20, issue 3 figure 2: difference in reduction in preoperative and postoperative body mass index according to (a) type of surgery (p = 0.025)* and (b) time since surgery (p = 0.008)† among bariatric surgery patients in bahrain (n = 341). bmi = body mass index; sg = sleeve gastrectomy; bpd = biliopancreatic diversion; mgb = mini gastric bypass. *covariates were adjusted for age, gender and time since surgery. †covariates were adjusted for age, gender and type of surgery. figure 3: effect of time since surgery on (a) percent of excess weight loss (p = 0.006)* and (b) percent of total weight loss (p = 0.001)* among bariatric surgery patients in bahrain (n = 341). ewl = percent of excess weight loss; twl = percent of total weight loss. *covariates were adjusted for age, gender and type of surgery. table 2: frequency of self-reported postoperative complications according to type of surgery among bariatric surgery patients in bahrain (n = 242) complication n (%) χ2 p value total* sg bpd mgb dry skin 83 (34.3) 45 (54.2) 10 (12) 28 (33.7) 8.081 0.232 constipation 66 (27.3) 46 (69.7) 2 (3) 18 (27.3) 21.777 0.001 diarrhoea 50 (20.7) 10 (20.0) 15 (30.0) 25 (50) 58.306 <0.001 dysphagia 25 (10.3) 15 (60) 0 (0) 10 (40) 6.150 0.407 low appetite 65 (26.9) 38 (58.5) 3 (4.6) 24 (36.9) 5.947 0.429 hair loss 144 (59.5) 85 (59.0) 8 (5.6) 51 (35.4) 9.766 0.135 flatulence/ abdominal pain 95 (39.3) 43 (45.3) 13 (13.7) 39 (41.4) 14.787 0.022 anaemia 64 (26.4) 24 (37.5) 11 (17.2) 29 (45.3) 19.841 0.003 hypotension 61 (25.2) 31 (50.8) 6 (9.8) 24 (39.3) 5.435 0.489 hypoglycaemia 48 (19.8) 21 (43.8) 3 (6.3) 24 (50) 12.628 0.049 lactose intolerance 32 (13.2) 12 (37.5) 6 (18.8) 14 (43.8) 11.012 0.088 gerd 80 (33.1) 44 (55.0) 5 (6.3) 31 (38.8) 8.309 0.216 cholelithiasis 33 (13.6) 10 (30.3) 11 (33.3) 12 (36.4) 31.883 <0.001 fatigue 44 (18.2) 12 (27.3) 4 (9.1) 28 (63.6) 28.415 <0.001 sg = sleeve gastrectomy; bpd = biliopancreatic diversion; mgb = mini gastric bypass; gerd = gastroesophageal reflux disease. *percentages in this column are calculated out of 242, as 99 patients were unreachable by telephone or did not wish to complete the questionnaire. nawal a. hasan, afnan freije, abdulmenem abualsel, hani al-saati and simone perna clinical and basic research | e349 dietary and lifestyle recommendations, participants most frequently adhered to the recommendation that they avoid overeating and controlling the portion size (80.6%). on the other hand, participants least frequently adhered to recommendations to exercise at least three times a week (59.9%) and avoid eating highcalorie snacks (54.2%) [table 3]. discussion this study sought to assess the effectiveness of bariatric surgery in reducing weight as well as the prevalence of nutritional deficiencies and selfreported complications and level of adherence to dietary and lifestyle recommendations among patients in bahrain. overall, the primary objectives of bariatric surgery are weight loss and the resolution of obesity-related diseases.6,8,9 studies evaluating the efficacy of bariatric surgery have found that effect on weight loss—as determined by ewl—depends on the type of procedure performed with adjustable gastric band (agb) surgery reportedly being least effective compared to rygb and sg.9,16–18 however, most previous research focuses on comparing weight loss between rygb, mgb and sg, since other types of bariatric surgeries such as agb and bpd are no longer commonly performed.7 in the current study, most patients underwent either sg or mgb; however, a minority (10.3%) had undergone bpd approximately 5–6 years prior to the study period. in the present study, time since surgery had a significant effect on twl and ewl, but not type of surgery. in contrast, other researchers have found that patients who underwent malabsorptive or combined restrictive-malabsorptive procedures (i.e. bpd, rygb and mgb) lost more excess weight compared to those who underwent purely restrictive procedures (i.e. sg and agb).19 however, in the current study, the lowest mean postoperative bmi value was observed among patients who had mgb but not bpd. this may be because most bpd patients had undergone surgery between 5–6 years previously, the longest postoperative time interval assessed in the study. unfortunately, the majority of patients in the current study who had undergone bariatric surgery more than five years previously were once more obese at the time of assessment. many studies have highlighted the failure to maintain weight loss over time following bariatric surgery and the tendency to regain the weight within two to three years.10,20 the prevalence of weight regain among bariatric surgery patients has been found to depend on surgery type, with greater weight regain identified in patients undergoing agb compared to rygb (35–40% versus 7–50% weight regained).21,22 length of follow-up may also play a role; a recent review by lauti et al. revealing that rates of weight regain after sg ranged from 5.7% two years following the surgery to 75.6% six years later.10 while studies have shown that nutritional deficiencies are usually prevalent beforehand in obese patients, bariatric surgery may exacerbate the problem and/or introduce new deficiencies.15,23,24 according to a biochemical assessment of various nutritional parameters, approximately half of the patients in the current study were deficient in iron, haemoglobin and mcv, all of which are indicators of anaemia. a recent review article reported iron deficiency to be the most common nutritional deficiency following bariatric surgery.25 however, the rate of 25-oh vitamin d insufficiency and deficiency was moderate. research shows that hypovitaminosis d is already present table 3: adherence to dietary and lifestyle recommendations among bariatric surgery patients in bahrain (n = 242) recommendation level of adherence, n (%)* all of the time most of the time some of the time never/rarely eat 4–5 meals a day (three main meals and 1–2 snacks) 72 (29.8) 80 (33.1) 64 (26.4) 26 (10.7) eat and chew food slowly 97 (40.1) 63 (26) 49 (20.2) 33 (13.6) control portion size and try not to overeat 153 (63.2) 42 (17.4) 33 (13.6) 14 (5.8) avoid eating high-calorie snacks (i.e. milkshakes, sugary juices, ice cream, chocolate, crisps, cookies, etc.) 50 (20.7) 61 (25.2) 58 (24) 73 (30.2) avoid eating and drinking at the same time 156 (64.5) 29 (12) 29 (12) 28 (11.6) take recommended vitamin and mineral supplements 91 (37.6) 28 (11.6) 66 (27.3) 57 (23.6) exercise at least three times a week 62 (25.6) 35 (14.5) 61 (25.2) 84 (34.7) attend follow-up appointments with a doctor and do all required tests 139 (57.4) 25 (10.3) 33 (13.6) 45 (18.6) *percentages are calculated out of 242, as 99 patients were unreachable by telephone or did not wish to complete the questionnaire. effect of bariatric surgery on weight loss, nutritional deficiencies, postoperative complications and adherence to dietary and lifestyle recommendations a retrospective cohort study from bahrain e350 | squ medical journal, august 2020, volume 20, issue 3 preoperatively in a significant number of bariatric surgery patients (25–80%).26 reasons for this include low consumption of vitamin d-rich foods, reduced sun exposure and the decreased bioavailability of vitamin d in obese patients due to its being deposited in adipose tissue.27 certain gastrointestinal symptoms and nutritional complaints may arise after bariatric surgery, potentially influencing the patient’s quality of life.9,16 among these, hair loss is one of the most commonly reported and is related to rapid weight loss and deficiencies of iron, zinc and other micronutrients.28 in the present study, the prevalence of hair loss was 59.5%, a rate which is in line with that reported by other researchers (40– 60%); however, goldenshluger et al. observed a greater frequency of hair loss in mgb patients compared to those who underwent sg, while the opposite was true in the present study.29 this may be related to the higher number of sg patients included in the current study and the fact that 55.3% had undergone the surgery between 1–2 years previously, a time when weight loss is commonly rapid in bariatric surgery patients.30 in turn, hypoglycaemia was recorded in under a quarter of the respondents in the present study. this condition has not yet been sufficiently studied in bariatric surgery populations, although it is frequently identified in patients with dumping syndrome.29 according to lin et al., the risk of hypoglycaemia is increased 2–7-fold in postoperative gastric bypass patients.31 a similar finding was observed in the current study in that 50% of patients who developed hypoglycaemia had undergone mgb surgery. adherence to dietary and lifestyle recommendations is critical to the long-term health and weight outcomes of patients who undergo bariatric surgery.9,32,33 in the present study, the patients reported medium to high adherence to such recommendations. this could be due to the fact that 30.6% of the patients had recently undergone the surgery one year before the study took place. according to research, the period both prior to surgery and immediately afterwards is when patients demonstrate the greatest adherence to dietary and lifestyle advice; however, as time progress, the rate of adherence decreases.31,32 in particular, patients in the present study were least adherent to the recommendation that they avoid high-calorie snacks (i.e. milkshakes, sugary juices, ice cream, chocolate, crisps, cookies, etc.), a choice which could have a considerable impact on their weight and general health. the current study has several strengths and limitations. in particular, the large number of patients included in the study as well as the fact that they were recruited from two of the three main governmental hospitals in bahrain can be considered strengths. in terms of limitations, the study was constrained by its retrospective nature. the weight of the patients was assessed only once at the time of the study and then compared to existing preoperative data in their medical records. it may have been better to measure weight prospectively at several time intervals in order to determine the overall trend of weight loss and identify the exact point in time at which the patients began to regain weight. secondly, biochemical parameters for nutritional indicators were assessed only postoperatively at the time of the study, so it was not possible to confirm the exact cause of nutritional deficiencies. finally, data regarding the prevalence of postoperative complications and level of adherence to dietary and lifestyle recommendations were selfreported by the participants; this may have introduced response bias. conclusion the findings of this study confirm that bariatric surgery is an effective intervention in obesity treatment in terms of weight loss measures such as ewl and twl. however, it also resulted in postoperative complications as well as the possible development of nutritional deficiencies. such complications can be controlled by adhering to postoperative recommendations. patients should be aware that bariatric surgery alone is not a miracle cure to weight loss and that there is a need for them to maintain the recommended dietary and lifestyle behaviours that they practiced prior to the surgery. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. fact sheets: obesity and overweight. from: www.who.int/news-room/fact-sheets/ detail/obesity-and-overweight accessed: feb 2020. 2. world health organization. health topics: obesity. from: www.who.int/topics/obesity/en/ accessed: feb 2020. 3. dillinger j. world atlas: the most obese countries in the world. from: www.worldatlas.com/articles/29-most-obese-countriesin-the-world.html accessed: feb 2020. 4. bahrain ministry of health. national non-communicable diseases risk factor survey 2007. from: www.who.int/ ncds/surveillance/steps/2007_steps_survey_bahrain.pdf accessed: feb 2020. nawal a. hasan, afnan freije, abdulmenem abualsel, hani al-saati and simone perna clinical and basic research | e351 5. world health organization. nutrition clinics help tackle obesity in bahrain. from: www.who.int/features/2014/bahraintackle-obesity/en/ accessed: feb 2020. 6. sjöström l. review of the key results from the swedish obese subjects (sos) trial: a prospective controlled intervention study of bariatric surgery. j intern med 2013; 273:219–34. https://doi.org/10.1111/joim.12012. 7. national institutes of health. nih conference: gastrointestinal surgery for severe obesity consensus development conference panel. ann intern med 1991; 115:956–61. https://doi.org/10.7 326/0003-4819-115-12-956. 8. himpens j, ramos a, welbourn r, dixon j, kinsman r, walton p. the international federation for the surgery of obesity and metabolic disorders global registry: 4th ifso global registry report. from: www.ifso.com/pdf/4th-ifso-global-registry-repo rt-last-2018.pdf accessed: feb 2020. 9. brethauer sa, chand b, schauer pr. risks and benefits of bariatric surgery: current evidence. cleve clin j med 2006; 73:993–1007. https://doi.org/10.3949/ccjm.73.11.993. 10. lauti m, kularatna m, hill ag, maccormick ad. weight regain following sleeve gastrectomy: a systematic review. obes surg 2016; 26:1326–34. https://doi.org/10.1007/s11695-0162152-x. 11. mechanick ji, youdim a, jones db, garvey wt, hurley dl, mcmahon mm, et al. clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient: 2013 update cosponsored by american association of clinical endocrinologists, the obesity society, and american society for metabolic & bariatric surgery. obesity (silver spring) 2013; 21:s1–27. https://doi. org/10.1002/oby.20461. 12. schweiger c, weiss r, berry e, keidar a. nutritional deficiencies in bariatric surgery candidates. obes surg 2010; 20:193–7. https://doi.org/10.1007/s11695-009-0008-3. 13. nicoletti cf, lima tp, donadelli sp, salgado w jr, marchini js, nonino cb. new look at nutritional care for obese patient candidates for bariatric surgery. surg obes relat dis 2013; 9:520–5. https://doi.org/10.1016/j.soard.2011.08.010. 14. brethauer sa, kim j, el chaar m, papasavas p, eisenberg d, rogers a, et al. standardized outcomes reporting in metabolic and bariatric surgery. surg obes relat dis 2015; 11:489–506. https://doi.org/10.1016/j.soard.2015.02.003. 15. al-mutawa a, anderson ak, alsabah s, al-mutawa m. nutritional status of bariatric surgery candidates. nutrients 2018; 10:67. https://doi.org/10.3390/nu10010067. 16. chang sh, stoll cr, song j, varela je, eagon cj, colditz ga, et al. the effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003-2012. jama surg 2014; 149:275–87. https://doi.org/10.1001/jamasurg.2013.3654. 17. schauer pr, burguera b, ikramuddin s, cottam d, gourash w, hamad g, et al. effect of laparoscopic roux-en y gastric bypass on type 2 diabetes mellitus. ann surg 2003; 238:467–85. https://doi.org/10.1097/01.sla.0000089851.41115.1b. 18. pournaras dj, osborne a, hawkins sc, vincent rp, mahon d, ewings p, et al. remission of type 2 diabetes after gastric bypass and banding: mechanisms and 2 year outcomes. ann surg 2010; 252:966–71. https://doi.org/10.1097/sla.0b013e3181efc49a. 19. nasta am, goel r, dharia s, goel m, hamrapurkar s. weight loss and comorbidity resolution 3 years after bariatric surgery: an indian perspective. obes surg 2018; 28:2712–19. https:// doi.org/10.1007/s11695-018-3218-8. 20. karmali s, brar b, shi x, sharma am, de gara c, birch dw. weight recidivism post-bariatric surgery: a systematic review. obes surg 2013; 23:1922–33. https://doi.org/10.1007/s11695013-1070-4. 21. digiorgi m. factors associated with long term weight regain after bariatric surgery. ph.d. thesis, 2012, columbia university, new york, usa. 22. magro do, geloneze b, delfini r, pareja bc, callejas f, pareja jc. long-term weight regain after gastric bypass: a 5-year prospective study. obes surg 2008; 18:648–51. https://doi. org/10.1007/s11695-007-9265-1. 23. xanthakos sa. nutritional deficiencies in obesity and after bariatric surgery. pediatr clin north am 2009; 56:1105–21. https://doi.org/10.1016/j.pcl.2009.07.002. 24. billeter at, probst p, fischer l, senft j, kenngott hg, schulte t, et al. risk of malnutrition, trace metal, and vitamin deficiency post roux-en-y gastric bypass: a prospective study of 20 patients with bmi <35 kg/m2. obes surg 2015; 25:2125–34. https://doi.org/10.1007/s11695-015-1676-9. 25. patel jj, mundi ms, hurt rt, wolfe b, martindale rg. micronutrient deficiencies after bariatric surgery: an emphasis on vitamins and trace minerals. nutr clin pract 2017; 32:471–80. https://doi.org/10.1177/0884533617712226. 26. stein j, stier c, raab h, weiner r. review article: the nutritional and pharmacological consequences of obesity surgery. aliment pharmacol ther 2014; 40:582–609. https://doi.org/10.1111/ apt.12872. 27. stroth c, manger t, benedix f. metabolic surgery and nutritional deficiencies. minerva chir 2017; 72:432–41. https:// doi.org/10.23736/s0026-4733.17.07408-9. 28. ruiz-tovar j, oller i, llavero c, zubiaga l, diez m, arroyo a, et al. hair loss in females after sleeve gastrectomy: predictive value of serum zinc and iron levels. am surg 2014; 80:466–71. https://doi.org/10.1177/000313481408000517. 29. goldenshluger m, goldenshluger a, keinan-boker l, cohen mj, ben-porat t, gerasi h, et al. postoperative outcomes, weight loss predictors, and late gastrointestinal symptoms following laparoscopic sleeve gastrectomy. j gastrointest surg 2017; 21:2009–15. https://doi.org/10.1007/s11605-017-3585-9. 30. courcoulas a, yanovsk s, bonds d, eggerman t, horlick m, staten m, et al. 2013. weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. jama surg 2014; 149:1323–9. https:/doi:10.1001/ jamasurg.2014.2440. 31. lin s, guan w, yang n, zang y, liu r, liang h. short-term outcomes of sleeve gastrectomy plus jejunojejunal bypass: a retrospective comparative study with sleeve gastrectomy and roux-en-y gastric bypass in chinese patients with bmi ≥ 35 kg/m2. obes surg 2019; 29:1352–9. https://doi.org/10.1007/ s11695-018-03688-1. 32. handzlik-orlik g, holecki m, orlik b, wyleżoł m, duława j. nutrition management of the post–bariatric surgery patient. nutr clin pract 2015; 30:383–92. https://doi. org/10.1177/0884533614564995. 33. larjani s, spivak i, guo mh, aliarzadeh b, wang w, robinson s, et al. preoperative predictors of adherence to multidisciplinary follow-up care postbariatric surgery. surg obes relat dis 2016; 12:350–6. https://doi.org/10.1016/j.soard.2015.11.007. https://doi.org/10.1111/joim.12012 https://doi.org/10.7326/0003-4819-115-12-956 https://doi.org/10.7326/0003-4819-115-12-956 https://doi.org/10.3949/ccjm.73.11.993 https://doi.org/10.1007/s11695-016-2152-x https://doi.org/10.1007/s11695-016-2152-x https://doi.org/10.1002/oby.20461 https://doi.org/10.1002/oby.20461 https://doi.org/10.1007/s11695-009-0008-3 https://doi.org/10.1016/j.soard.2011.08.010 https://doi.org/10.1016/j.soard.2015.02.003 https://doi.org/10.3390/nu10010067 https://doi.org/10.1001/jamasurg.2013.3654 https://doi.org/10.1097/01.sla.0000089851.41115.1b https://doi.org/10.1097/sla.0b013e3181efc49a https://doi.org/10.1007/s11695-018-3218-8 https://doi.org/10.1007/s11695-018-3218-8 https://doi.org/10.1007/s11695-013-1070-4 https://doi.org/10.1007/s11695-013-1070-4 https://doi.org/10.1007/s11695-007-9265-1 https://doi.org/10.1007/s11695-007-9265-1 https://doi.org/10.1016/j.pcl.2009.07.002 https://doi.org/10.1007/s11695-015-1676-9 https://doi.org/10.1177/0884533617712226 https://doi.org/10.1111/apt.12872 https://doi.org/10.1111/apt.12872 https://doi.org/10.1177/000313481408000517 https://doi.org/10.1007/s11605-017-3585-9 https:/doi:10.1001/jamasurg.2014.2440 https:/doi:10.1001/jamasurg.2014.2440 https://doi.org/10.1007/s11695-018-03688-1 https://doi.org/10.1007/s11695-018-03688-1 https://doi.org/10.1177/0884533614564995 https://doi.org/10.1177/0884533614564995 https://doi.org/10.1016/j.soard.2015.11.007 squ med j, december 2009, vol. 9, iss. 3, pp. 328-332, epub. 19th dec 2009 submitted 21st mar 09 revision req 30th june 09, revision recd. 20th july 09 accepted 7th september 09 thyroid carcinoma presenting with cervical lymphadenopathy as a sole presentation is uncommon.1,2,3 as metastatic cervical lymph nodes could potentially arise from several primary sources in the head and neck region, management could pose problems. investigations may fail to reveal a primary carcinoma in the thyroid gland and hence fine needle aspiration cytology (fnac) or biopsy is of the primary importance to establish the origin of primary tumour.5,6 once established, management should include complete resection of the primary and metastatic carcinoma, post-operative radioactive iodine scanning and possible radioactive iodine treatment and lifelong replacement thyroxine. case report a 62 year-old lady presented with a 5 month history of an enlarging right neck mass [figure 1]. she had no associated symptoms of change in voice, dysphagia, stridor, epistaxis, haemoptysis or haematemesis. examination revealed a firm, nontender swelling at the anterior border of the right sternomastoid muscle which measured 3 x 3cms, with restricted mobility. a detailed examination departments of 1surgery & 2pathology, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: oneilnorman@gmail.com ظهور السرطانة احلُلَيِميَّة للغدة الدرقية كورم يف عقد الرقبة الليمفاوية أسلوب العالج نورمان او مكادو ، براديب ج شوبرا ، عايشة احلمداني امللخص: السرطانة احلُلَيِميَّة للغدة الدرقية غالبا ما تظهر كورم محسوس في الغدة الدرقية ، وقد يصاحبها ألم ، بحة في الصوت ، صفير مع الشهيق ، ألم أثناء البلع و نادرا ما تظهر كورم في العقد الليمفاوية لوحدها مع وجود غدة درقية سليمة. وهذه الصورة قد تسبب مشكلة في ْفط نحيفة التشخيص والعالج. هذا تقرير عن امرأة متوسطة العمر جاءت تشكو من تورم في العقد الليمفاوية وبعد أخذ عينة بواسطة إِبْرَُة شَّ تبني انه سرطانة ُحلَيِميَّة للغدة الدرقية. كان الفحص السريري واألشعة التشخيصية للغدة الدرقية طبيعيا. فحص الرقبة أكد سالمة الغدة الدرقية متاما وتبني أن غدة العنق الليمفاوية متصلة بالَوريُد الِوداِجيُّ الغائر. خضعت املريضة الستئصال الغدة الدرقية الكامل واستئصال الغدد الليمفاوية من جانب واحد واستئصال اجلزء املتصل من الَوريُد الِوداِجيُّ الغائر. الفحص اخللوي املرضي للعينة أكد وجود انتقال سرطاني في العقدة الليمفاوية و سرطانة حليمية صغيرة بحجم 2 مم من الغدة الدرقية املستأصلة. املسح الضوئي باليود املشع بعد العملية أكد عدم انتشار املرض. املريضة أخضعت لعالج الثيروكسني مدى احلياة. ما زالت املريضة في املتابعة الدورية منذ أربع سنوات وهي بصحة جيدة. الكلمات الرئيسية: استئصال الغدة الدرقية ، سرطان الغدة الدرقية ، النقيلة الليمفاوية ،تقرير حالة ، ُعمان. abstract: papillary carcinoma of thyroid usually presents as a palpable thyroid mass. this could be associated with pain, hoarseness, stridor or dysphagia. rarely, it presents solely as cervical lympadenopthy in the presence of an otherwise grossly normal thyroid gland. this could pose management problems. we report here a middle-aged lady who presented with cervical lymphadenopathy which on fine needle aspiration cytology was confirmed as metastatic papillary thyroid carcinoma. the thyroid gland was, however, normal on clinical examination and radiological investigations. neck exploration confirmed a grossly normal thyroid gland; however, the cervical lymph node was found to invade the internal jugular vein. she underwent a total thyroidectomy and unilateral functional block dissection with resection of the involved segment of the internal jugular vein. histopathology confirmed metastasis in the lymph node and a 2mm sized microcarcinoma in the resected thyroid gland. a radioactive iodine scan in the postoperative period revealed no other metastasis. the patient was prescribed lifelong thyroxine. she is on regular follow-up and 4 years following surgery continues to do well. key words: thyroidectomy; carcinoma of thyroid; lymphatic metastasis; case report; oman. papillary carcinoma of thethyroid presenting primarily as cervical lymphadenopathy an approach to management *norman o machado,1 pradeep j chopra,1 aisha al hamdani2 case report norman o machado, pradeep j chopra and aisha al hamdani case report | 329 of the head and neck region showed no intraoral lesions. the thyroid gland was not palpable and she had no other cervical lymphadenopathy. the basic investigations, including a complete blood count, electrolytes and thyroid function tests, were all within the normal range. an indirect laryngoscopy was normal. an ultrasound scan (us) of the thyroid showed no abnormality. a fnac of the neck mass revealed groups of follicular cells exhibiting nuclear overlapping, nuclear grooves and occasional intranuclear inclusions, consistent with metastatic papillary carcinoma of the thyroid [figure 2]. the patient underwent neck exploration which revealed a grossly normal thyroid gland and an isolated rightsided midjugular lymph node invading the internal jugular vein. a total thyroidectomy and a functional right-sided block dissection were performed with excision of a segment of the involved internal jugular vein, sparing the sternomastoid muscle and spinal accessory nerve [figure 3]. histopathological examination confirmed metastatic classic papillary carcinoma in the lymph node and a 2mm sized focus of papillary microcarcinoma in the right lobe of the excised thyroid gland with nuclear features characteristic of papillary carcinoma [figure 4]. the patient had an uneventful post-operative period. a radionuclide scan performed 6 weeks later to look for other potential metastasis revealed none. she has been on a replacement dose of thyroxine 100μg per day to lower her thyroid stimulating hormone level to below 0.1 iu. when last seen, 4 years after her surgery, she was in good health. discussion thyroid carcinoma commonly presents as a dominant thyroid mass in an otherwise asymptomatic patient.1,2,3 less common presentations include isolated cervical lymphadenopathy, as in our patient, recurrent laryngeal nerve palsy, parapharyngeal masses, cervical cysts, haemoptysis and pulmonary metastasis, all of which could pose a diagnostic challenge.2,3 even though a lateral neck mass as the initial manifestation of thyroid carcinoma is reported in some series to be present in as much figure 1: isolated cervical lymphnode metastasis with no apparent thyroid enlargement. papillary carcinoma of thyroid presenting primarily as cervical lymphadenopathy an approach to management 330 | squ medical journal, december 2009, volume 9, issue 3 as 10-21% of all thyroid carcinomas,1,2,3 they are usually uncommon. clinical examination of the thyroid gland in such patients may fail to disclose easily a palpable dominant intrathyroidal mass or nodularity.1,3 the majority of the palpable cervical masses are located in the midjugular lymph node (51%) and low jugular lymph node (33%) although supraclavicular (2%), posterior cervical (1.7%) and high jugular lympadenopathy (10%) are also reported.1 these clinical findings are supported by the pattern of distribution and location of the metastatic cervical lymph node demonstrated in the pathology specimen of modified radical neck dissection.1 the diagnosis of metastatic thyroid cancer should be considered in patients presenting with isolated cervical lymphadenopathy despite a clinically normal thyroid gland. however, further evaluation is necessary to exclude other primary tumours of the scalp and head and neck region. the investigations used to assess the cervical mass of thyroid origin include radionuclide scans, us, computed tomography (ct) scans, magnetic resonance imaging (mri) and fnac.3-8 the diagnostic usefulness of radionuclide scanning of the thyroid in patients with isolated cervical lymphnode metastasis from thyroid carcinoma has been disappointing as less than 50% of the scans performed revealed a cold nodule in the thyroid.2,4 a combined ultrasonography and radionuclide scan of the thyroid has been reported to demonstrate the mass in 75% of these patients.1 twenty-five per cent of patients with thyroid malignancy may have normal thyroid imaging and a clinically normal thyroid gland, as in our patient, and hence the clinician should still suspect a papillary carcinoma in the thyroid gland in the presence of lymph node metastasis.1,2 however recently, us has been reported to be very useful in predicting the risk of malignancy in nonpalpable lesions.8, in a recent review to assess the risk of malignancy in nonpalpable thyroid nodules using us and colour doppler, features including irregular or blurred nodular margins, an intranodular vascular pattern and microcalcification were found to be closely linked to neoplastic lesions.8 on the other hand, a hypoechoic appearance or the presence of solitary lesions were not independent risk factors for malignancy in nonpalpable thyroid nodules.8 the presence of microcalcification presented a higher specificity for malignancy (95%) than the findings of irregular margin (85%) or intranodular vascular images (80.8%), but the predictive value of microcalcifiaction was blunted by their low sensitivity (29%).8 cytological evaluation of nonpalpable nodules, presenting with a hypoechoic appearance in conjunction with at least one independent us risk factor, succeeded in identifying the vast majority of nonpalpable thyroid tumours. papini et al. recommended that us guided fnac should be performed on all 8-15mm hypoechoic nodules with irregular margins, intranodular vascular spots and microcalcifiaction.8 nonpalpable lesions of the thyroid without sonographic features of risk figure 2: fine needle aspiration cytology of cervical mass, pap stain x 100 showing follicular cells with nuclear overlapping, inclusions (white arrow) and grooves (black arrows) suggestive of thyroid papillary metastasis. figure 3: operative field view revealing the exposed trachea (long arrow) after completion of total thyroidectomy and the exposed carotid artery (short arrows) and the cut ends of resected internal jugular vein (curved arrows) following functional block dissection norman o machado, pradeep j chopra and aisha al hamdani case report | 331 for malignancy should be followed up by repeating clinical and ultrasound evaluation after 6-12 weeks.8 scanning by us is also useful for assessing the lateral cervical mass by defining it and for differentiating its solid or cystic nature.5 while cystic swellings in the neck are likely to be of branchial cleft origin, several reports suggest the possibility of papillary carcinoma metastasis in the node when cystic.5 this is particularly so if, on us, the cystic mass reveals an internal lining that is thickened and irregular.5 both ct and mri scans, while providing cross-sectional imaging of the neck mass, may also detect other cervical lymphadenopathies particularly those in the retropharyngeal and parapharyngeal spaces.7 the cytological nature of the neck mass and the possibility of metastasis is initially determined by fnac.1,6 fnac is well tolerated, minimally invasive, reliable in the hands of an experienced cytologist and will not compromise future neck dissection.1,6 if fnac is inconclusive and the possibility of metastasis in the node is strong, a thorough search for other possible primary sites in the oropharynx, larynx and head and neck region should be carried out. in the event that an open biopsy is required to establish the diagnosis, care should be taken in placing the incision so that it will not jeopardise the outcome of future neck dissection if required.1 the recommended treatment of patients with thyroid carcinoma presenting predominantly as cervical lymph node metastasis is total thyroidectomy with appropriate ipsilateral and, if necessary, contralateral modified radical neck dissection.1,9,10 the outcome is generally good when surgical management is followed by postoperative radioiodine scanning and lifelong replacement thyroxine.1,10,11 contralateral lymph node metastasis, though rare, is possible and hence it is important to carry out bilateral lymph node sampling of any enlarged lymph nodes during total thyroidectomy.1,9,10 the primary lesion in the thyroid gland can vary from 2mm to several millimetres in size and, unless multiple thin histologic sections are examined, the primary lesion can be missed.1,12,13 cervical metastasis, however, from a thyroid carcinoma and in patients who present with occult thyroid carcinoma, appears to be independent of the size of the primary thyroid carcinoma.13 this was the case in our patient who, in spite of significant sized lymph node metastasis, had only a small focus of papillary microcarcinoma of the thyroid gland. to establish a diagnosis of thyroid carcinoma in these small solitary tumours, multiple histological sections of the total thyroidectomy specimen are often necessary so that multicentric lesions can be emonstrated.8 although small intraglandular tumour foci and cervical lymph node metastasis were found not to effect the survival rate of patients with thyroid carcinoma, considerably higher recurrence rates are observed in patients who undergo conservative operations.10,14,15 in the last 10 years, major improvements and new technologies have been proposed and applied in thyroid surgery. these include minimally invasive thyroidectomy; new devices like ultracision for achieving haemostasis and dissection; regional anaesthesia; intraoperative neuromonitoring of the recurrent laryngeal nerve to avoid its injury; parathyroid hormone assay technology and genetic screening.16 conclusion a papillary thyroid carcinoma presenting primarily as a cervical lymphadenopathy is rare. the nature of these lesions is confirmed by a combination of radiological investigation and fnac. the primary lesions, however, could be as small as a few millimetres in size and difficult to detect preoperatively. if cervical lymphadenopthay is figure 4: haematoxylin and eosin stain x 100 showing thyroid tissue with colloid filled follicles lined by follicular cells exhibiting nuclear overlapping, clearing (black arrows) and intranuclear grooves (white arrows) papillary carcinoma of thyroid presenting primarily as cervical lymphadenopathy an approach to management 332 | squ medical journal, december 2009, volume 9, issue 3 confirmed to be metastatic thyroid carcinoma, total thyroidectomy and lymph node dissection would be the most appropriate approach. when this is followed up by postoperative radionuclide scanning and a lifelong suppressive dose of thyroxine, a good outcome is most likely. references 1. de jong sa, demeter jg, jarosz h, lawrence am, paloyan e. primary papillary thyroid carcinoma presenting as cervical lymphadenopathy: the operative approach to the lateral aberrant thyroid: am surg 1993; 59:172-7. 2. maceri dr, babyak j, ossakow sj. lateral neck mass. sole presenting sign of metastatic thyroid cancer. arch otolaryngol head neck surg 1986; 112:47-9. 3. park cs, min js. lateral neck mass as the initial manifestation of thyroid carcinoma. head neck 1989; 11:410-13. 4. nussbaum m, bukachevsky r. thyroid carcinoma presenting as a regional neck mass. head neck 1990; 12:114-17. 5. park js, son kr, na dg, kim e, kim s. performance of preoperative sonographic staging of papillary thyroid carcinoma based on the sixth edition of ajcc/uicc tnm classification system. ajr am j roentgenol 2009; 192:66-72. 6. kim mj, kim ek, park si, kim bm, kwak jy, kim js, et al. us guided fine needle aspiration of thyroid nodule: indications, technique, results. radiographics 2008; 28:1869-86. 7. loevner la, kaplan sl, cunnane me, moonis g. cross-sectional imaging of the thyroid gland. neuroimaging clin n am 2008; 18:445-61. 8. papini e, guglielmi r, bianchini a, crescenzi a, taccogna s, nardi f et al. risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-doppler features. j clin endocrinol metabol 2002; 87:1941-6. 9. dralle h, machens a. surgical approaches in thyroid cancer and lymph node metastases. best pract res clin endocrinol metab 2008; 22:971-87. 10. naruse t, koike a, kanemitsu t, kato k. minimal thyroid carcinoma: a report of nine cases discovered by cervical lymph node metastasis. jpn j surg 1984; 14:118-21. 11. hubert jp jr, kiernan pd, bearhs oh, mcconahey wm, woolner lb. occult papillary carcinoma of the thyroid. arch surg 1980; 115:394-8. 12. mazzaferri el. papillary thyroid carcinoma: factors influencing prognosis and current therapy. semin oncol 1987; 14:315-32. 13. block ma. management of carcinoma of thyroid. ann surg 1977; 185:133-44. 14. clark oh. total thyroidectomy: the treatment of choice for patients with differentiated thyroid cancer. ann surg 1982; 196:361-70. 15. kuo sf, chao tc, chang hy, hsueh c, chang yc, yang ch, et al. the role of radioactive iodine therapy in young patients with papillary thyroid cancer. clin nucl med 2009; 34:4-6. 16. dionigi g, bacuzzi a, bertocchi v, carrafiello g, boni l, rovera f, et al. safe incorporation of new technologies in thyroid surgery. expert rev med devices 2008; 5:747-58. squ med j, february 2011, vol. 11, iss. 1, pp. 1-4, epub. 12th feb 11 submitted 11th jan 11 accepted 12th jan 10 medical imaging using x-rays is like a double-edged sword. on the one side, we cannot do without it because of its enormous benefit in medical diagnosis, but on the other side, we risk exposing ourselves to potentially harmful low-dose radiation. typically, two-thirds of all medical imaging procedures involve the use of ionising radiation, either x-rays in diagnostic radiology or gamma rays in nuclear medicine. thus there is an urgent need to educate medical staff on the appropriate utility of this diagnostic tool, and for the creation of a regulatory body controlling and monitoring its use. this is of particular urgency in oman. since the introduction of computed tomography (ct) scanning, diagnostic accuracy has significantly improved in clinical medicine, but concomitantly radiation exposure to human subjects has also significantly increased. by far, the ct scan results in much higher radiation exposure to the patients than does plain radiography, typically 40 to 50 times more.1 a vivid example is the ct of the abdomen versus plain film. a plain x-ray of the abdomen results in about a 0.25 milligray (mgy) dose to the stomach which is about 40 times lower than the 10 mgy dose from an adult abdominal ct and the much higher 20 mgy dose in the case of the neonatal abdominal ct.1 fazel et al. reviewed almost a million non-elderly adults between 2005 and 2007, and discovered that ct scanning and nuclear imaging accounted for over 75% of the cumulative effective dose to the population; however, ct scans and nuclear medicine together accounted for only 21% of total procedures in that study.2 other studies have also shown that ct scans of paediatric patients result in alarming radiation doses.3,4,5 this is a source of concern given that such a population is still at a tender age. such studies show that physicians need to restrategise significantly how they request medical imaging studies, and especially ct scans, in the paediatric population. the increase in the numbers of medical imaging scans involving ionising radiation is alarming. in the united states, the number of ct scans in 2006 was 62 million, and since then it has been increasing at an unprecedented rate, both in united states and elsewhere.6 in 2010, of the 5 billion medical imaging procedures worldwide, two-thirds utilised ionising radiation,7 thus the need of discernment on our part in requesting diagnostic imaging. we need to look into the clinical indications for ct more critically and adhere more closely to the guidelines and “appropriateness criteria” set by the american college of radiology (acr) and other national radiological institutions.8 radiation is much more damaging to the growing child who has a longer life expectancy than to an adult. we, as physicians, therefore need to consider alternative imaging methods as much as possible and increase our use of ultrasound and magnetic resonance imaging (mri) in place of ct scans and other radiation-dependant editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman. email: mjournal@squ.edu.om 9�÷]<üëáíj÷]<‡⁄<≈^√ç˛÷<öü√j÷] =·^€�√÷<ö]ñfic<åüq  editorial radiation exposure from medical imaging a wake-up call for oman! lamk al-lamki radiation exposure from medical imaging a wake-up call for oman! 2 | squ medical journal, february 2011, volume 11, issue 1 modalities whenever possible. perhaps, more significant in increasing the unnecessary radiation exposure of the public is the repetition of medical imaging studies. it is not uncommon for patients to resort to ‘doctor shopping' which often entails the repetition of imaging procedures. this may be triggered by a lack of faith in the initial images or by the financial interests of the clinics involved. unnecessary repetition of imaging studies is today a major source of unnecessary radiation exposure for patients. physicians need to be educated about the dangers of radiation and the benefits of its wise use. they also need to take the initiative to learn more about the risks of their orders. for example, every ct scanner clearly shows the dose from a particular scan to a patient, but unfortunately, very few radiologists ever bother to review the dose they have given to their patients. modern ct scanners will give the ct dose index (ctdivol) per slice, expressed in mgy per volume, and also the dose length product (dlp) which represents the total exposure dose to the length of the area imaged (slice dose x length). dlp is expressed as mgy–cm.9 in the case of mammography, the mean glandular dose (mgd) is also available. we need to make greater use of these exposure figures in appreciating how much radiation dose our patients receive at each imaging session. physicians should consider joining the “image wisely” organisation and take the pledge to be acutely aware of the radiation dose to the patients. there they will get educated about the necessary precautions. “image wisely” is an organisation sponsored by the acr, the radiological society of north america (rsna), the american association of physicists and other reputable organisations to promote judicial use of radiological science for diagnoses.10 there is also a growing momentum to get patients involved in radiation awareness and protection. one way would be to inform the patient each time they have an imaging study about the radiation dose to which they have been exposed. unfortunately, the difficulty will be for the physicians to explain to the patients what that dose or their cumulative dose means as we have limited knowledge about the biological effects of various doses of low-dose radiation exposure. perhaps we should also consider giving patients electronic “radiation registry cards” to carry around so that each radiation exposure dose is added and an ongoing record kept since radiation is cumulative throughout one’s life. the x-ray machines and ct scanners of the future will have to be modified so that with each exposure the scanner can register the dose on the patients’ “radiation registry card”. if this were to be implemented, it would be one of the steps to come to grips with the emerging problem of rising radiation exposure. what then is known about the tissue damage caused by low-dose radiation exposure? there is a significant amount of data known about highdose radiation exposure and this is mainly from the survivors of the two atomic bombings of japan in 1945 and the chernobyl nuclear plant accident in ukraine in 1986. unfortunately, while the effects of high-dose radiation exposure have a linear relationship with the dose this cannot be extrapolated down to the lower dose or to zero. at higher doses, the biological effects are generally “deterministic” whereby the severity of the effect is dose-dependent and there exists a threshold dose above which the effects occur.11 at lower doses, the effects are “stochastic”, whereby the probability of an effect occurring is dose-dependent, but there is no threshold dose below which we could be relatively certain that no adverse effect will occur.11 the best known stochastic effect is cancer production from radiation exposure. there is a significant amount of epidemiological data which indicates that exposure to low-dose radiation may result in cancer including cases of leukaemia, as well as thyroid nodules and other cancers.12 at the 2010 un general assembly, the united nations scientific committee on the effects of atomic radiation (unscear) presented the radiation risks estimate for cancer and for hereditary effects. they defined a low-dose to be 200 mgy (or millisivert) or below or 0.1 mgy (or 0.1 msv) per minute for exposure from external sources such as x-rays.12 they pointed out with respect to radiation-induced cancer, that the long delay (often years or decades) between exposure and disease presented a major difficulty in attributing specific diseases to low-dose radiation exposure. this is compounded by the anyway high spontaneous incidence of disease associated with ageing. besides epidemiological data, there are experimental studies that show the dose response lamk al-lamki editorial | 3 relationship with cellular and sub-cellular elements exposed to radiation. the target appears to be the chromosomal dna molecule. if the radiation damage to a group of genes is not repaired, the cell will die, but even if repaired the surviving cells may show dna mutations that may affect cell behaviour in the exposed individual. even a minor degree of mutation can result in development of cancer.12 there are also several radiation-associated non-cancer diseases, which are a result of radiation exposure. the best example is congenital disorders from exposure to a developing foetus, the neurological system being the most susceptible.12 the risk will depend on the dose and the timing of exposure during pregnancy. unscear also pointed out that recently there is increased evidence of cataract development after low-dose radiation exposure.12 until recently, cataracts have been related only to high-dose exposure. the third group of disorders related to radiation exposure is the heritable effects of radiation. unscear presented evidence that damage to dna of germ cells resulted in heritable diseases. unfortunately, these may be passed on to offspring and to several future generations. the evidence is clearer with higher than lower doses, but there is experimental evidence in animals that mutations induced by radiation can indeed appear in several generations.12 for the optimists in the medical profession, there is a group who believe in radiation hormesis.13 this is the hypothesis that a small dose of radiation may actually be beneficial to living tissues. mice exposed to low dose of radiation became resistant to the effects of future exposure to radiation and also resistant to certain diseases.13 it is my wishful thinking that this be true, but unfortunately the evidence is not yet strong enough. perhaps in oman at this stage, we more importantly need good regulations to control the handling and uses of ionising radiation. unfortunately, there are currently no regulations in oman that control x-ray machines, and only lax regulations for handling radioactive substances. thus the use of low-dose radiation in omani medicine is potentially dangerous to our community. we need tougher regulations on the purchase of x-ray machines and on the running these machines. in some private clinics in oman, unqualified technologists run x-ray machines as there are no specific licensing regulations. the training requirements for radiological technologists are also limited. in addition, there are no training requirements for physicians who use x-ray machines. unfortunately, there are physicians who actually run fluoroscopic machines without adequate licensing procedures. not all radiological procedures and cardiac catheterisation procedures are adequately monitored from the equipment point of view, or by the physicians or technologists involved. the good news is that there is a move in the government towards setting up such a regulatory authority. it should be mandatory for any physician handling radioactive material or using x-ray machines to attend a course on radiation safety and the use of these materials and machines to be certified prior to any use. likewise, the technologists or nurses involved must have a similar course and certification. in addition, oman needs to recognise medical physics as a specialised profession. medical physicists are needed in all radiology and nuclear medicine departments to be in charge of quality control and assurance and as radiation safety officers. what we need in oman now is education of medical doctors on the dangers of medical imaging that utilises ionising radiation, in particular ct scanning and cardiac catheterisation studies. we also need continuing medical education on the appropriate criteria and clinical indications for the uses of these diagnostic tools.14 most importantly, and perhaps of great urgency, is the creation of an independent regulatory body to regulate the safe use of ionising regulation in medicine and otherwise. this governmental body needs to be free of the control of any ministry, and has to have authority to license the use of radioactive materials and of x-ray-producing equipment, as well as regulatory control over the education of staff handling both low and higher dose radiation sources in medicine and elsewhere. we need to respect and control lowdose radiation to safeguard ourselves and our future generations. radiation exposure from medical imaging a wake-up call for oman! 4 | squ medical journal, february 2011, volume 11, issue 1 references 1. brenner dj, hall ej. computed tomography – an increasing source of radiation exposure. n engl j med 2007; 357:2277–84. 2. fazel r, krumholz hm, wang y, ross js, chen j, ting hh, et al. exposure to low dose ionizing radiation from medical imaging procedures. n engl j med 2009; 361:849–57. 3. radiation exposure from medical imaging procedures. from: http://www.emoryhealthcare. org/radiology/pdf/nejm-letter.pdf accessed january 2011. 4. brenner d, hricak h, radiation exposure from medical imaging: time to regulate? jama 2010; 304:208–9. commentary: from: http:// jama .ama-a ssn.org/content/304/2/208.extract accessed: january 2011. 5. dorfman al, fazel r, einstein aj, applegate ke, krumholz hm, wang y, et al. use of medical imaging procedures with ionizing radiation in children: a population-based study. arch pediatr adolesc med 2011; jan 3. [epub ahead of print]. from: http://archpedi.ama-assn.org/ c g i / c o n t e n t / s h o r t / a r c h p e d i a t r i c s . 2 0 1 0 . 2 7 0 . accessed: january 2011. 6. coursey ca, frush dp. ct and radiation: what radiologists should know. from: http:// w w w . m e d s c a p e . c o m / v i e w a r t i c l e / 5 7 2 5 5 1 accessed: january 2011. 7. roobottom ca, mitchell g, morgan-hughes g. radiation-reduction strategies in cardiac computed tomographic angiography. clin radiol 2010;65:859– 67.doi:10.1016/j.crad.2010.04.021. pmid 20933639. 8. acr appropriateness criteria. from: http://www. acr.org/secondar ymainmenucategories/quality_ safety/app_criteria.aspx. accessed:january 2011. 9. sources and effects of ionising radiation from: http:// www.unscear.org/docs/reports/2008/09-86753_ report_2008_ga_report.pdf.accessed:januar y 2011. 10. radiation exposure from medical diagnostic imaging procedures. from: https://www.hps.org/documents/ meddiagimaging.pdf. accessed:january 2011. 11. holmes eb, white gl, gaffney dk. ionizing radiation exposure, medical imaging. from: http:// emedicine.medscape.com/article/1464228-overview accessed:january 2011. 12. report of the united nations scientific committee on the effects of atomic radiation (to general assembly august 2010): from: http:// d a c c e s s d d s n y. u n . o r g / d o c / u n d o c / g e n / v10/563/16/pdf/ v1056316.pdf?openelement accessed: january 2011. 13. radiation hormesis. from: http://en.wikipedia.org/ wiki/radiation_hormesis. accessed: january 2011. 14. larson db, johnson lw, schnell bm, salisbury sr, forman hp. national trends in ct use in the emergency department: 1995–2007. radiology 2011; 258:164–73. from: http:// r a d i o l o g y. r s n a . o r g / c o n t e n t / 2 5 8 / 1 / 1 6 4 . f u l l . pdf+html accessed: january 2011. departments of 1midwifery and 2operating room, sabzevar university of medical sciences, sabzevar, iran *corresponding author’s e-mail: borzoee75026@yahoo.com التعب يف احلمل مصداقية وموثوقية تقييم مقياس التعب الفارسي متعدد األبعاد فروغ مرتزايف و فاطمي بورزو abstract: objectives: fatigue is a common discomfort experienced during pregnancy and may contribute to severe labour pain and postpartum depression. this study aimed to translate the multidimensional assessment of fatigue (maf) scale into farsi and validate it in a sample of pregnant irani women. methods: this cross-sectional questionnaire study was conducted between january and june 2016 at eight healthcare centres in sabzevar, iran. the english version of the maf scale was translated into farsi and assessed for content validity. participants completed the farsi maf scale and the farsi world health organization-5 well-being index (who-5). construct validity was assessed through exploratory factor analysis (efa). cronbach’s alpha coefficient and the intraclass correlation coefficient (icc) were used to determine the internal consistency and stability of the farsi maf scale. results: a total of 582 women met the inclusion criteria, of which 541 completed the maf scale (response rate: 93%). the efa of the 15 items confirmed the previously proposed one-factor structure with a cronbach’s alpha coefficient of 0.957 for the farsi maf scale. stability was confirmed by the icc value (0.702) for the global fatigue index (gfi) and the mean gfi was 20.33 ± 12.71. concurrent validity was confirmed by a moderate negative correlation (r = −0.35; p <0.001) between the scores of the farsi maf scale and the farsi who-5. women who received a high level of support from their husbands, who were satisfied with the quality of their marital relationship and with a well-being score of >50 reported a lower level of fatigue than the other groups (p ≤0.012). conclusion: the farsi maf scale is a reliable and valid questionnaire to investigate fatigue in pregnant irani women. interventions to promote marital satisfaction and women’s well-being are recommended. keywords: fatigue; parturition; pregnancy; psychometrics; validation studies; reliability and validity; iran. ع. تهدف هذه الدرا�سة امللخ�ص: الهدف: التعب هو م�سقة �سائعة اأثناء احلمل، وقد ي�ساهم يف اإحداث اآلم املخا�ض والكتئاب الذي يعقب الَو�سْ اإىل ترجمة مقيا�ض التعب متعدد الأبعاد اإىل اللغة الفار�سية، وتوثيق م�سداقية تلك الرتجمة يف عينة من الن�ساء الإيرانيات احلوامل. الطريقة: �سملت هذه درا�سة املقطعية-العر�سية على ا�ستبيانا اأجري بني يناير ويونيو من عام 2016م يف ثمانية مراكز رعاية �سحية اأولية يف �سبزوار باإيران. متت ترجمة مقيا�ض التعب متعدد الأبعاد اإىل اللغة الفار�سية ومت تقييم م�سداقيته املحتوى. واأكملت امل�ساركات يف الدرا�سة هذا املقيا�ض املرتجم للفار�سية، مقيا�ض موؤ�رس العافية/الرفاه اخلام�ض ال�سادر عن منظمة ال�سحة العاملية باللغة الفار�سية اأي�سا. ومت تقييم م�سداقيته البنائية عن طريق حتليل العامل ال�ستك�سايف، وكذلك معامل كورباخ الفا ومعامل العالقة داخل الطبقات لتحديد مدى الت�ساق الداخلي والثبات يف الرتجمة الفار�سية للمقيا�ض. النتائج: وافت 582 امراأة معايري الإ�ستمال، واأكملت منهن 541 امراأة مقيا�ض التعب الفار�سي متعدد الأبعاد )مبعدل ا�ستجابة بلغ %93( واأكدت طريقة حتليل العامل ال�ستك�سايف للخم�سة ع�رس بندا يف ال�ستبيان هيكل العامل الواحد الذي �سبق اقرتاحه، مبعامل كورباخ قدره 0.957 ملقيا�ض التعب الفار�سي متعدد الأبعاد. واأُثبت كذلك الثبات مبعامل عالقة داخل الطبقات بلغ 0.702 بالن�سبة ملوؤ�رس التعب العاملي، اإذ كان متو�سط ذلك املوؤ�رس 12.71 ± 20.33. ومت تاأكيد امل�سداقية املتزامنة بعالقة �سالبة متو�سطة )p >0.001 ؛ 0.35− = r( بني نتائج مقيا�ض التعب الفار�سي وموؤ�رس العافية/الرفاه اخلام�ض ال�سادر عن منظمة ال�سحة العاملية بالفار�سية. اأثبتت هذه الدرا�سة اأن معدل َتَعب احَلْمل كان اأقل عند الن�ساء اللواتي تلقني م�ستوًي عاليا من الدعم من اأزواجهن، واللواتي كن را�سيات عن م�ستوى جودة عالقتهن الزوجية، وكن قد اأحرزن اأكرث من 50 يف موؤ�رس العافية/الرفاه مقارنة مع املجموعات الأخرى )p ≤0.012(. اخلال�صة: مقيا�ض التعب الفار�سي متعدد الأبعاد هو ا�ستبيان �سادق وموثوق بناء على درا�سة التعب عند الن�ساء الإيرانيات. نو�سي بالقيام بتدخالت من اأجل ت�سجيع وتعزيز الر�سا الزوجي ورفاه وعافية الن�ساء. الكلمات املفتاحية: التعب؛ الولدة؛ احلمل؛ قيا�ض العمليات النف�سية؛ درا�سات التحقق من امل�سداقية؛ املوثوقية وامل�سداقية؛ اإيران. fatigue in pregnancy the validity and reliability of the farsi multidimensional assessment of fatigue scale forough mortazavi1 and *fateme borzoee2 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e44–50, epub. 30 may 19 submitted 5 aug 18 revision req. 18 sep 18; revision recd. 15 oct 18 accepted 1 nov 18 advances in knowledge the multidimensional assessment of fatigue (maf) scale was translated into farsi and validated under the mapi research trust guidelines for cross-cultural adaptation and linguistic validation. this study provides further evidence that the maf scale may be an internationally reliable and valid instrument to measure fatigue in pregnant women. application to patient care measuring fatigue in pregnant women is the first step to designing interventions to reduce fatigue. the maf scale can be used to evaluate interventions affecting pregnant women’s levels of fatigue. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.009 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ forough mortazavi and fateme borzoee clinical and basic research | e45 pregnanc y is accompanied by several psychological, emotional and physical changes that may predispose the woman to fatigue, which can range from mild tiredness to severe exhaustion.1 fatigue is defined as a feeling of consistently decreased energy; it is a symptom of many diseases, including anae mia, infection and hypothyroidism and is common during pregnancy.2,3 most pregnant women feel some fatigue; however, some suffer from severe fatigue. a study of 197 pregnant chinese women found that 95% suffered from fatigue during pregnancy.4 fatigue is positively correlated with low sexual activity and social interactions, as well as low maternal ability to provide infant care.2 furthermore, severe fatigue can lower maternal quality of life and may increase labour pain.1,4 measuring fatigue and its risk factors can help medical professionals screen pregnant women and design adequate interventions.5 therefore, the development and validation of a scale to measure fatigue is necessary. as fatigue is a subjective experience, its measurement can be achieved through a self-reported scale.5 belza originally designed the 16-item multidimensional assessment of fatigue (maf) scale, validated it in rheumatoid arthritis patients and proposed a single-factor structure for the scale.6,7 a recent systematic review on the scale indicated that the maf scale has been translated into nine lang uages and used in 17 countries for 32 diseases.8 this scale was also validated in pregnancy and post-partum periods in a longitudinal study in canada on two samples of preg nant english-speaking women.9 currently there is no validated scale to assess fatigue in the prenatal period in iran, which could lead to low knowledge of maternal fatigue and its risk factors and consequences. therefore, this study aimed to translate, validate and investigate the factor structure of the maf scale in pregnant irani women. to the researchers’ knowledge, no scale for measuring fatigue has been dev eloped and no study has validated the maf scale in iran. methods this cross-sectional study was conducted between january and june 2016 at eight healthcare centres in sabzevar, iran. participants completed the farsi maf scale and world health organization-5 well-being index (who-5) in addition to sociodemographic and obstetrical inform ation and psychosocial variables. the sample size was estimated to be 500 based on comrey and lee’s suggestion that researchers reach a sample of 500 or more for exploratory factor analysis (efa).10 receiver operating characteristics (roc) curve power analysis was used to determine a cut-off point for the global fatigue index (gfi) scores to predict a who-5 score of <50. cluster sampling was used whereby sabzevar was divided into four different socioeconomic regions. in each region, two healthcare clinics were selected using a simple random method. out of the 16 clinics affiliated with sabzevar university of medical sciences, eight clinics were selected. these clinics provide free services including prenatal and post-partum care, vaccinations, family planning and infant growth monitoring. midwives were instructed to include all women who attended the clinic throughout the day to receive prenatal care, had a positive pregnancy test or positive ultrasound scan and could read the questionnaire. women who suffered from psychological disorders and/or received medical care for non-pregnancy conditions were excluded. in addition, women with chronic diseases and those with any sign or symptoms of gestational hypertension, pre eclampsia, hyperemesis gravidarum, intrauterine fetal death or threatened abortion at the time of the study were excluded. out of 674 women attending the clinics, 582 (86.3%) met the inclusion criteria. midwives distributed the questionnaires and instr ucted the participants on how to complete them. data collected included sociodemographic information, obst etrical information and psychosocial variables. mothers’ body mass indices (bmis) and gestational age were calculated by midwives. after women completed the questionnaires, they were placed in envelopes and the midwives delivered the envelopes to the researchers. psychosocial variables were selected from previous studies that assessed fatigue.2,4,9 a four-point likert scale was used to rate psychosocial items, with one representing ‘not at all’ and four indicating ‘very good, always or severe’. the mapi research trust granted permission to translate and use the maf scale before the start of the study. the translation and validation of the maf scale was divided into two phases. in phase one, the maf scale was translated into farsi by two individuals using the mapi research trust’s linguistic validation guideline. the two translated versions were compared and the first version of the farsi maf was made with few revisions. back translation of the farsi maf into english was perf ormed by another bilingual irani-english language doct orate holder who was not familiar with the original scale. the main researcher then compared the original and translated versions of the maf scale. in phase two, the scale was validated. to determine content validity, ten experts in obstetrics or reproductive health were asked to appraise the wording and rate each item. experts also judged the relevance of the scales’ items to irani culture. to determine the content validity ratio (cvr) of each item, lawshe’s method was used.11 experts evaluated the necessity of the items on a threepoint rating scale, with one indicating ‘not necessary’; fatigue in pregnancy the validity and reliability of the farsi multidimensional assessment of fatigue scale e46 | squ medical journal, february 2019, volume 19, issue 1 two indicating that the item was ‘useful, but not essential’; and three indicating that the item was ‘essential’. experts also judged the clarity and simplicity of each item on a four-point likert scale where one was ‘not simple or clear’ and four was ‘very simple and clear’.12 content validity indices (cvi) were calculated for the scale based on the experts’ judgments. to determine the face validity, 12 pregnant farsi speakers who had completed a minimum of six years of schooling completed the farsi maf. these women were then interviewed individually and changes were made to the second version of the farsi maf scale. on average, the questionnaire was completed in 10 minutes. the scale was deemed easy for women who had completed their secondary education to read and understand; how ever, women with lower educational levels were confused about the phrasing in items 4–14. therefore, the phrasing of these items was changed. all items were self-determ ining. after these changes, four pregnant women with middle level educations were asked to complete the farsi maf scale again and were then interviewed. finally, the second farsi maf version was sent for language editing, where sentences were shortened and unnecessary prepositions were deleted in all items. to assess the construct validity, 582 pregnant women who had registered to receive prenatal care in healthcare centres were included. no specific gestational age was considered for inclusion in the study. to determine the factorial structure of the farsi maf, an efa was used and factors were extracted using principal component analysis. items loading at ≥0.3 and with eigenvalues >1 were retained in the model.13 to judge the concurrent validity of the scale, the correlation coefficient between the gfi scores and the who-5 scores were calculated. to determine the discriminant validity of the scale, a t-test or analysis of variance was used to compare the mean gfi in different demographic and psychosocial groups. to determine the reliability of the farsi maf scale, 30 pregnant women completed the questionnaire. cron bach’s alpha coefficient values of >0.7 were considered acceptable.14 to assess stability over time, the maf quest ionnaire was administered to the same women one week later. test-retest reliability was examined using an intra class correlation coefficient (icc) for the gfi scores. iccs of 0.61–0.80 and >0.80 were considered good and excellent, respectively.15 the 16-item scale measures five dimensions of fatigue: degree of fatigue (item one), severity of fatigue (item two), level of distress (item three), degree of inter ference with daily life activities (items 4–14) and the frequency of feeling fatigued (items 15 and 16). items 1–14 are scored on a 10-point likert scale ranging from one ‘not at all’ to 10 ‘very much’, while items 15 and 16 have multiple-choice responses. according to belza’s instructions, the scores for item 15 were converted from 1–4 to 2.5–10; the scores for items 1–3 were summed and the means of items 4–14 and the new scores of item 15 were used to cal culate the gfi.16 item 16 was excluded from the analysis due to its different rating style. the gfi ranges from one ‘no fatigue’ to 50 ‘severe fatigue’.6 convergent validity of the maf scale was confirmed by the correlation of the maf scale with the fatigue severity scale (r = 0.74; p <0.001) and the visual analogue scale for fatigue (r = 0.42; p <0.001).17 a cronbach’s alpha of 0.93 conf irmed the reliability of the scale.16 factor analysis showed that the scale contains one factor.6,9,18 the concurrent validity of the maf scale was also investigated by the correlation coefficients between the gfi scores and the who-5 scores. the who-5 contains five items measuring the respondent’s mental and subjective psychological well being.19 each item is scored on a six-point likert scale where zero is ‘never’, one is ‘some of the time’, two is ‘less than half of the time’, three is ‘more than half of the time’, four is ‘most of the time’ and five is ‘always’. the total score of the who-5 are then converted into a scale ranging from 0–100 where scores ≤50 reflect a depressive state. the original version of the scale was translated into several languages, including farsi by the psychiatric research unit of the who collaborating centre for mental health and was validated using a sample of irani pregnant women.19 the reliability of the who-5 was confirmed by a cronbach’s alpha coefficient of 0.85. the correlation coefficient between the who-5 and the general health questionnaire–28 was −0.64 (p <0.001) confirming concurrent validity. efa revealed one factor and confirmatory factor analysis confirmed a single-factor structure.20 data analyses were performed using statistical package for the social sciences (spss), version 18 (ibm corp., armonk, new york, usa). all participants signed an informed consent form before participating in the study. the questionnaires were anonymous and women were ensured of the confidentiality of their information. the study was approved by the sabzevar university of medical sciences ethics committee (ir.medsab.rec.1395.42). results of the 582 women who met the inclusion criteria, 541 completed the maf scale (response rate: 93%). less than a quarter of the participants (20%) had not experienced fatigue during the week before sampling. mean age, bmi and haemoglobin level were 27.2 ± 5.5 years, 24.95 ± 4.39 kg/m2 and 12.52 ± 0.85 g/dl, respectively. the mean gestational age and number of sleeping hours forough mortazavi and fateme borzoee clinical and basic research | e47 in 24 hours were 23.24 ± 10 weeks and 9 ± 2.08 hours, respectively. of the total, 42.2% were nulliparous and 23.8% reported a history of abortion [table 1]. the mean gfi score was 20.33 ± 12.70 from a total of 50, which indicates severe fatigue in the study’s sample [table 2]. no difference was found between fatigue scores in the three trimesters of pregnancy (p = 0.223). all items in the farsi maf scale had a satisfactory cvr (≥0.62). the scale’s cvi was higher than 0.8, which was an acceptable cvi cut-off value for the ten experts.21 construct validity of the scale was investigated by efa. kaiser-meyer-olkin was 0.955, indicating suitability of the data for efa, and bartlett's test of sphericity was 2,765 (p <0.001), indicating adequate correlations between variables. for the efa, missing data in items 4–14 were managed by replacing these scores with the mean score for the respective item. the efa on the 15item farsi maf revealed one factor with eigenvalues ≥1 [table 3]. table 1: obstetric characteristics of pregnant irani women (n = 541) characteristic mean ± sd p value gestational age in weeks 23.24 ± 10.00 0.786 maternal age in years 27.20 ± 5.50 0.859 interpregnancy interval in years 3.75 ± 3.63 0.741 bmi in kg/m2 24.95 ± 4.39 0.482 haemoglobin in g/dl 12.52 ± 0.85 0.383 sleep hours/24 hours in hours 9.00 ± 2.08 0.174 who-5 63.78 ± 20.46 <0.001 sd = standard deviation; bmi = body mass index; who-5 = world health organization-5 well-being index. table 2: correlation between global fatigue index scores and demographic characteristics of pregnant irani women (n = 541) characteristic n (%) mean gfi ± sd p value parity none 228 (42.14) 19.7 ± 12.5 0.366 one or more 313 (57.86) 20.7 ± 12.8 number of years of education <12 357 (65.80) 20.00 ± 13.03 0.414 ≥12 184 (34.20) 21.01 ± 12.13 job housewife 467 (86.32) 19.67 ± 12.24 0.005 employed 74 (13.67) 24.24 ± 12.63 household income insufficient 70 (12.93) 20.67 ± 14.52 0.830 sufficient 471 (87. 06) 20.31 ± 12.45 gfi = global fatigue index; sd = standard deviation. table 3: the farsi multidimensional assessment of fatigue dimensions, item loading and means of each dimension of pregnant irani women (n = 541) dimension item no. question factor loading* mean ± sd degree of fatigue 1 within the last week, how much fatigue did you experience? 0.85 4.78 ± 2.71 severity of fatigue 2 within the last week, how strong was your feeling of fatigue? 0.84 3.77 ± 2.90 distress of feeling fatigued 3 within the last week, how much has the feeling of fatigue bothered you? 0.84 3.84 ± 3.02 impact of fatigue on daily activities within the last week, how much has fatigue decreased your ability to do the activities listed below: 4 housework (e.g. vacuuming, washing dishes, etc.) 0.86 4.10 ± 3.13 5 cooking 0.86 3.71 ± 3.00 6 showering and maintaining personal hygiene 0.82 3.28 ± 2.78 7 dressing and personal grooming 0.86 3.52 ± 2.89 8 working 0.59 2.06 ± 2.75 9 visiting friends and relatives 0.81 3.33 ± 2.86 10 engaging in sexual activity 0.79 3.30 ± 3.22 11 participating in fun and entertaining activities 0.85 3.63 ± 3.00 12 shopping and other activities done outside of the home (e.g. going to the bank, etc.) 0.83 2.61 ± 3.12 13 walking 0.83 3.43 ± 2.94 14 exercising (excluding walking) 0.70 2.89 ± 3.01 timing of fatigue 15 within the last week, how often did you feel fatigued? 0.81 4.76 ± 3.23 16 within the last week, how has your fatigue changed? 1.92 ± 1.31 gfi 20.33 ± 12.71 variance in % 65.82 eigenvalue 9.87 cronbach’s alpha coefficient 0.96 sd = standard deviation; gfi = global fatigue index. *kaiser-meyer-olkin = 0.96 and bartlett's test of sphericity = 2,765; p <0.001. fatigue in pregnancy the validity and reliability of the farsi multidimensional assessment of fatigue scale e48 | squ medical journal, february 2019, volume 19, issue 1 to determine concurrent validity, the correlation coefficient between the gfi scores and the who-5 scores was calculated (r = −0.35; p <0.001), indicating a moderate negative correlation. moreover, the farsi maf found a significant difference between employed women and housewives (p = 0.005) [table 2]. in addition, women with unwanted pregnancies (p <0.001), those unhappy with their pregnancies (p <0.001), with poor self-perceived health (p <0.001), women with a history of dysmenorrhoea (p = 0.006), those with dyspareunia (p = 0.007), those receiving low levels of emotional support from their husbands (p = 0.002) or with poorquality relationships with their husbands (p = 0.012) and women with low well-being status (p <0.001) reported significantly higher levels of fatigue [table 4]. cronbach’s alpha coefficient for the 15-item farsi maf was 0.957. the icc for the gfi scores was 0.702, confirming an acceptable stability of the scale. the scree plot supports a one-factor model [figure 1]. results of the roc curve power analysis showed that a gfi cutoff of >22.09 had sensitivity and specificity of 70.1% and 62%, respectively, in predicting a who-5 score <50 (area under the curve = 0.687; p <0.001). discussion the farsi maf scale, which was translated using the guidelines of the mapi research trust, evaluates five dimensions of fatigue. most participants answered all items, indicating that the scale is short, clear and easy to complete. the satisfactory cvr and cvi of all items indicates that the farsi maf scale is culturally suitable for measuring fatigue in pregnant irani women. the farsi maf scale had good internal consistency, which is in agreement with previous studies.22–25 testretest analysis indicated that the gfi had acceptable stability. in a study of 51 patients with rheumatoid arth ritis and 46 controls who completed the maf scale three times at six-week intervals, the gfi showed excellent stability over time.17 in the current study, the efa ident ified one factor. the scale developer and two previous studies proposed a one-factor model, whereas a study in the usa showed that the scale contained two factors.6,9,18,23 concurrent validity was verified by the moderate negative correlation between the scores of the gfi and the who-5, indicating that women with lower levels of psychological well-being experienced higher fatigue. fairbrother et al.’s study, conducted on pregnant women in canada, found moderate correlations among the scores of the maf scale, the edinburgh postnatal depression scale and the beck depression inventory.9 kuo et al.’s study on pregnant and post-partum women in taiwan figure 1: scree plot for the exploratory factor analysis. table 4: participants' psychosocial characteristics and the distribution of mean global fatigue index scores (n = 541) variables n (%) mean gfi ± sd p value desirability of pregnancy yes 390 (72.08) 19.00 ± 12.51 <0.001 no 151 (27.91) 23.78 ± 12.43 request for cs yes 168 (31.05) 19.83 ± 12.56 0.52 no 373 (68.95) 20.62 ± 12.57 receiving support from husband very poor to acceptable 92 (17.00) 24.00 ± 13.24 0.002 good-to-very good 449 (82.00) 19.45 ± 12.43 quality of relationship with husband dissatisfied 39 (7.20) 25.24 ± 13.74 0.012moderately-to-very satisfied 502 (92.79) 19.90 ± 12.53 perceived health less than moderate 28 (5.18) 32.67 ± 11.34 <0.001 moderate-to-very good 513 (94.82) 19.72 ± 12.43 women’s description of pregnancy dissatisfied 44 (8.13) 26.73 ± 14.67 <0.001moderately-to-very satisfied 497 (91.87) 19.78 ± 12.34 physical activity ≤30 minutes/week 302 (55.82) 20.90 ± 12.91 0.336 >30 minutes/week 239 (44.18) 19.78 ± 12.34 dyspareunia none or mild 383 (70.79) 19.43 ± 12.20 0.007 moderate-to-severe 158 (29.21) 22.60 ± 13.34 history of dysmenorrhoea none or mild 355 (65.62) 19.34 ± 12.33 0.006 moderate-to-severe 186 (34.38) 22.45 ± 13.23 gfi = global fatigue index; sd = standard deviation; cs = caesarean section. forough mortazavi and fateme borzoee clinical and basic research | e49 indicated a statistically significant relationship between fatigue in pregnancy and post-partum depression.24 women who were glad about their pregnancies had a lower gfi than those who were not, which is in agreement with cheng et al.’s study on 197 pregnant chinese women with a gestational age >24 weeks.4 no relationship was detected between maternal age and fatigue, whereas in wambach et al.’s study on 41 post partum american women, maternal age was positively correlated with fatigue.26 in contrast, hall et al.’s study on 650 pregnant canadian women, found that younger women were more fatigued than older women.27 in the current study, a low percentage (3.5%) of women reported sleep durations of less than six hours/ 24 hours. this finding may be the reason for the lack of a significant correlation between sleep duration and feeling fatigued. tsai et al.’s study on 38 nulliparous chinese women showed a significant inverse association between night sleep duration during pregnancy and morning and afternoon fatigue.28 the farsi maf scale could not discriminate bet ween fatigue in nulliparous and multiparous women. this finding is inconsistent with cheng et al.’s study in which the mean maf score was higher in chinese multiparous than nulliparous women.4 in the present study, there was no difference between fatigue scores in the three trimesters of pregnancy, whereas cheng et al.’s longitudinal study showed that chinese women in the third trimester of pregnancy endured a higher degree of fatigue than those in the first and second trimesters.4 results indicated that a history of dysmenorrhoea or dyspareunia in the first encounter of sexual inter course might play a role in severe fatigue in pregnancy. brown et al. found that both of these characteristics may negatively affect women’s attitudes toward their gender.29 further studies are needed to investigate whether dysmen orrhoea and dyspareunia can induce unconscious negative feelings towards pregnancy, which may contribute to severe fatigue. in mortazavi et al.’s study, irani pregnant women with a history of moderate-to-severe dyspareunia in their first encounter of sexual intercourse were more likely to experience severe childbirth fears than their counterparts (odds ratio = 2.829).30 in the current study, 20% of women reported no fatigue and their mean gfi score was 20.33 ± 12.71. in a previous study, the mean gfi scores were reported as 29.4 ± 9.6 and 25.4 ± 9.6 for samples one and two, respectively.9 in chou et al.’s cross-sectional study on american women in their first trimester of pregnancy, 3.5% reported no fatigue, 43.4% reported occasional fatigue and 53.1% reported frequent fatigue in the previous month.31 a strength of the current study was its large sample size, which helped in the efa; however, this study has some limitations. convergent validity of the scale could not be examined due to lack of a previously validated farsi fatigue questionnaire. in addition, although the test-retest interval should not be less than 15 days, the interval in this study was one week to minimise the normal progressive changes in fatigue between the two points in time. conclusion the farsi maf scale is a reliable and valid questionnaire for measuring fatigue in pregnant irani women. the scale can be used for screening fatigue in prenatal visits. the farsi maf scale can help healthcare providers ident ify pregnant women who are at risk of developing postpartum depression, premature birth or conditions assoc iated with fatigue in pregnant women and design prev entive measures accordingly. interventions to improve marital satisfaction during pregnancy and increase husbands’ awareness of the emotional needs during preg nancy should be designed. in addition, the importance of the first sexual encounter should be discussed in marital counselling programmes. feeling fatigued may be a sign of a low state of well-being; thus, screening for depression in pregnant women is recommended. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was conducted with the financial support of sabzevar university of medical sciences (project code: 94116). references 1. perry se, hockenberry mj, lowdermilk dl, wilson d. maternal child nursing care. 5th ed. missouri: mosbey, 2014. p. 178. 2. corwin ej, arbour m. postpartum fatigue and evidence-based interventions. mcn am j matern child nurs 2007; 32:215–20. https://doi.org/10.1097/01.nmc.0000281959.71454.e5. 3. corton mm, leveno k, bloom s, spong cy, cunnigham jd. williams obstetrics. 24th ed. new york: mcgraw hill, 2010. p. 214. 4. cheng cy, chou yh, wang p, tsai jm, liou sr. survey of trend and factors in perinatal maternal fatigue. nurs health sci 2015; 17:64–70. https://doi.org/10.1111/nhs.12149. 5. lerdal a, kottorp a, gay cl, lee ka. development of a short version of the lee visual analogue fatigue scale in a sample of women with hiv/aids: a rasch analysis application. qual life res 2013; 22:1467–722. https://doi.org/10.1007/s11136012-0279-3. 6. belza b. dimensions and correlates of fatigue in older adults with rheumatoid arthritis. phd thesis, 1991, university of calif ornia san francisco, california, usa. https://doi.org/10.1097/01.nmc.0000281959.71454.e5 https://doi.org/10.1111/nhs.12149 https://doi.org/10.1007/s11136-012-0279-3 https://doi.org/10.1007/s11136-012-0279-3 fatigue in pregnancy the validity and reliability of the farsi multidimensional assessment of fatigue scale e50 | squ medical journal, february 2019, volume 19, issue 1 7. belza bl, henke cj, yelin eh, epstein wv, gilliss cl. correlates of fatigue in older adults with rheumatoid arthritis. nurs res 1993; 42:93–9. https://doi.org/10.1097/00006199-1993030 00-00006. 8. belza b, miyawaki ce, liu m, aree-ue s, fessel m, minott kr, et al. a systematic review of studies using the multidimensional assessment of fatigue scale. j nurs meas 2018; 26:36–75. https://doi.org/10.1891/1061-3749.26.1.36. 9. fairbrother n, hutton ek, stoll k, hall w, kluka s. psychometric evaluation of the multidimensional assessment of fatigue scale for use with pregnant and postpartum women. psychol assess 2008; 20:150–8. https://doi.org/10.1037/1040-3590.20.2.150. 10. comrey al, lee hb. a first course in factor analysis. hilsdale, nj: erlbaum, 1992. p. 32. 11. lawshe ch. a quantitative approach to content validity. pers psychol 1975; 28:563–75. https://doi.org/10.1111/j.1744-6570.19 75.tb01393.x. 12. polit d, beck c. nursing research: principles and methods. 46th ed. philadelphia: lippincott, 2004. p. 346. 13. waltz cf, strickland ol, lenz er. measurement in nursing and health research. 4th ed. new york: springer publishing company, 2010. p. 602. 14. streiner dl. starting at the beginning: an introduction to coefficient alpha and internal consistency. j pers assess 2003; 80:99–103. https://doi.org/10.1207/s15327752jpa8001_18. 15. bartko jj. measures of agreement: a single procedure. stat med 1994; 13:737–45. https://doi.org/10.1002/sim.4780130534. 16. winstead-fry p. psychometric assessment of four fatigue scales with a sample of rural cancer patients. j nurs meas 1998; 6:111–22. https://doi.org/10.1891/1061-3749.6.2.111. 17. belza bl. comparison of self-reported fatigue in rheumatoid arthritis and controls. j rheumatol 1995; 22:639–43. 18. lequerica a, bushnik t, wright j, kolakowsky-hayner sa, hammond fm, dijkers mp, et al. psychometric properties of the multidimensional assessment of fatigue scale in traumatic brain injury: an nidrr traumatic brain injury model systems study. j head trauma rehabil 2012; 27:e28–35. https://doi.org/10. 1097/htr.0b013e31826fe574. 19. psykiatric center north zealand, who-five well-being index (who-5). 1999 version. from: www.who-5.org accessed: nov 2018. 20. mortazavi f, mousavi sa, chaman r, khosravi a. [validation of the world health organization-5 well-being index; assessment of maternal well-being and its associated factors]. turk psikiyatri derg 2015; 26:48–55. 21. polit df, beck ct, owen sv. is the cvi an acceptable indicator of content validity? appraisal and recommendations. res nurs health 2007; 30:459–67. https://doi.org/10.1002/nur.20199. 22. bahouq h, rostom s, bahiri r, hakkou j, aissaoui n, hajjajhassouni n. psychometric evaluation of the arabic version of the multidimensional assessment of fatigue scale (maf) for use in patients with ankylosing spondylitis. rheumatol int 2012; 32:3969–76. https://doi.org/10.1007/s00296-011-2306-z. 23. bormann j, shively m, smith tl, gifford al. measurement of fatigue in hiv-positive adults: reliability and validity of the global fatigue index. j assoc nurses aids care 2001; 12:75–83. https://doi.org/10.1016/s1055-3290(06)60146-5. 24. kuo sy, yang yl, kuo pc, tseng cm, tzeng yl. trajectories of depressive symptoms and fatigue among postpartum women. j obstet gynecol neonatal nurs 2012; 41:216–26. https://doi.org/10.1111/j.1552-6909.2011.01331.x. 25. meek pm, nail lm, barsevick a, schwartz al, stephen s, whitmer k, et al. psychometric testing of fatigue instru ments for use with cancer patients. nurs res 2000; 49:181–90. https://doi.org/10.1097/00006199-200007000-00001. 26. wambach ka. maternal fatigue in breastfeeding primiparae during the first nine weeks postpartum. j hum lact 1998; 14:219–29. https://doi.org/10.1177/089033449801400311. 27. hall wa, hauck yl, carty em, hutton ek, fenwick j, stoll k. childbirth fear, anxiety, fatigue, and sleep deprivation in preg nant women. j obstet gynecol neonatal nurs 2009; 38:567–76. https://doi.org/10.1111/j.1552-6909.2009.01054.x. 28. tsai sy, lin jw, kuo lt, thomas ka. daily sleep and fatigue characteristics in nulliparous women during the third trimester of pregnancy. sleep 2012; 35:257–62. https://doi.org/10.5665/ sleep.1634. 29. brown ma, woods nf. correlates of dysmenorrhea. a challenge to past stereotypes. jogn nurs 1984; 13:259–66. https://doi.org/10. 1111/j.1552-6909.1984.tb01137.x. 30. mortazavi f, agah j. childbirth fear and associated factors in a sample of pregnant iranian women. oman med j 2018; 33:497–505. https://doi.org/10.5001/omj.2018.91. 31. chou fh, kuo sh, wang rh. a longitudinal study of nausea and vomiting, fatigue and perceived stress in, and social support for, pregnant women through the three trimesters. kaohsiung j med sci 2008; 24:306–14. https://doi.org/10.1016/s1607-551x (08)70157-8. https://doi.org/10.1097/00006199-199303000-00006 https://doi.org/10.1097/00006199-199303000-00006 https://doi.org/10.1891/1061-3749.26.1.36 https://doi.org/10.1037/1040-3590.20.2.150 https://doi.org/10.1111/j.1744-6570.1975.tb01393.x https://doi.org/10.1111/j.1744-6570.1975.tb01393.x https://doi.org/10.1207/s15327752jpa8001_18 https://doi.org/10.1002/sim.4780130534 https://doi.org/10.1891/1061-3749.6.2.111 https://doi.org/10.1097/htr.0b013e31826fe574 https://doi.org/10.1097/htr.0b013e31826fe574 https://doi.org/10.1002/nur.20199 https://doi.org/10.1007/s00296-011-2306-z https://doi.org/10.1016/s1055-3290%2806%2960146-5 https://doi.org/10.1111/j.1552-6909.2011.01331.x https://doi.org/10.1097/00006199-200007000-00001 https://doi.org/10.1177/089033449801400311 https://doi.org/10.1111/j.1552-6909.2009.01054.x https://doi.org/10.5665/sleep.1634 https://doi.org/10.5665/sleep.1634 https://doi.org/10.1111/j.1552-6909.1984.tb01137.x https://doi.org/10.1111/j.1552-6909.1984.tb01137.x https://doi.org/10.5001/omj.2018.91 https://doi.org/10.1016/s1607-551x%2808%2970157-8 https://doi.org/10.1016/s1607-551x%2808%2970157-8 the sounding board article by al balushi, that was published in the february 2019 issue of squmj, presents an important issue about informed consent (ic) and how it is handled in omani society.1 there is a need to address the issue of ic, especially for vulnerable groups of competent adult patients. however, the article feminises the issue of ic, which in oman should be considered a cultural matter that transcends gender division. while females should have full rights to determine whether or not ic is given, focus should be shifted towards ways to avoid implementing a paternalistic approach when handling ic in oman. the term ‘feminising’ is defined as giving a feminine quality to something by presenting it as “characteristic of or appropriate or unique to women”.2 al balushi reiterated that omani female patients face pressure from their families, particularly male members, when making high-stake decisions and echoed the need to empower females to overcome this dependency on males.1 any practicing clinician in oman will observe that paternalism in ic is not unique to females, as males are also denied, albeit to a lesser extent, their right for ic. feminising the nature of ic in oman may not lead to the empowerment for females to make their own decisions, but rather may shift the focus and resources from understanding the real issues behind the practice. legal perspectives of women in oman omani law is based on the principles of islamic sharia as stated in article 2 of the basic statute of the country promulgated by royal decree 101/96. in sharia law, competent adult males and females both have equal legal capacity with all its associated duties and merits. both penal and civil laws (7/2018 and 29/2013, respectively) assert the individual’s responsibility for their actions. in relation to medical practice, article 44/b of the penal law 7/2018 asserts the need for an individual patient’s consent in order to render a medical intervention legal, except in some law-exempted circumstances where consenting is inappropriate or not feasible. there is no indication in the law that females are treated differently or need a legal guardian to consent for them. similarly, in the ministry of health’s “policy and procedure on informed consent” there are no clauses in this policy that have any notion of discrimination based on gender or towards any specific group.3 al balushi presented examples of tubal ligations and hysterectomies as “cultural limitations in oman [that] affect the validity of female consent”.1 this is neither unique to oman nor to females. spousal consent for voluntary sterilisation is required in countries such as brazil, chile, japan, china and most countries with a muslim majority.4 these spousal consent regulations are not gender-specific as pregnancy and childbirth are shared interests of both the wife and husband. hence, their mutual agreement on a procedure that will affect this shared interest is justified. an exception to this role is when sterilisation is needed on medical grounds as the sick spouse will be harmed by not undergoing sterilisation.5 social science perspectives of women in oman throughout history, women in oman have enjoyed a high level of independence and pro-activeness as is demonstrated by historical female figures in various social, political, economic and religious areas.6 since there are no studies about female ic practices in particular, explanations for the apparently paternalistic approach to female ic in oman may be extrapolated from other related studies. emergency department, ibri hospital, ministry of health, oman e-mail: dralazri@yahoo.com تأنيث قضية ثقافية حالة املوافقة املستنرية نا�رص حماد �لعزري feminising a cultural issue the case of informed consent nasser hammad al-azri comment sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e181–183, epub. 5 nov 19 submitted 1 jul 19 revision req. 20 aug 19; revision recd. 21 aug 19 accepted 25 aug 19 https://doi.org/10.18295/squmj.2019.19.03.002 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ feminising a cultural issue the case of informed consent e182 | squ medical journal, august 2019, volume 19, issue 3 wikan noted in her anthropological study of women in sohar, a city in northern oman, that the husband wife relationship within a family is mostly complementary.7 this leads to acceptance of role variation in the community. in healthcare, this can be translated into the adoption of an individual’s “sick role” wherein “the sick person [...] acquires a new social role that is intimately tied to his/ her state of health”.8 consequently, others around the sick person acquire new social roles as caregivers for the sick person. the sicker the person and the higher the stake of decisions, the more caregivers are likely to take over the responsibility for caring and decision-making. acquiring these new complementary social roles is part of a re-organisation process in the social order within the fabric of the society. engelhardt found that “patients often regress under the stress of disease and want to be treated as children by health professionals. informal requests for paternalistic care occur as a matter of course in health care because patients are in a strange environment”.9 this finding is probably more applicable in collectivistic societies such as oman. hence, it may not be justified to consider this re-organisation of social roles as a matter of coercion, disempowerment or enforcement. another explanation for women delegating highstake decisions to their male relatives is the issue of trust. eickelman conducted an anthropological observ ational study of women in al hamra, a town in the interior of oman. she noted that the relationship bet ween wives and husbands consisted of “the wide-spread sense of trust that is an essential part of community life in inner oman”.10 she also noticed a positive aspect of this sense of trust as it “gives women considerable freedom within the oasis—freedom to organise their workday and their visiting as they see fit”.10 cultural trust might help explain the widespread attitude of omanis in avoiding making high-stake decisions and trying to delegate these to others. in neonatal donot-resuscitate situations, parents did not want to make such high-stake decisions themselves but were “happy to accept transferring the responsibility onto a person in authority”.11 in addition, family members’ advice has been found to be a catalyst in care-seeking behaviour among omanis.12 in fact, sick individuals not only delegate high-stake decision-making to their relatives but also to healthcare professionals as they frequently ask their healthcare practitioners to make decisions for them. while the presence of inequality or male domination in society is a separate debatable issue, there are some social restrictions for females in expressing full legal authority. however, these restrictions need to be under stood and contextualised within social roles and the division of these roles between males and females. hence, feminising the issue of ic in oman is neither the best explanation nor approach to improve the status quo. the way forward the issue of ic needs to be addressed in oman both legally and socially. legislation is clear with regard to the need for patients’ consent for any medical inter vention, regardless of gender. however, this legislation might be unclear to the public and healthcare prof essionals, indicating a need for better legal education. ic should be understood as a tool in healthcare practice. it should be reconsidered and restructured within a culturally-informed context by considering aspects of trust and autonomy. building trust is central to ic, healthcare practice and doctor-patient relationships. however, linking trust to ic is frequently neglected in discussions of ic.13 ic can be improved by intelligent accountability and building trust and not by analysing specific details.14 instead of viewing autonomy within an individualistic doctrine, it can be re-addressed from a collectivistic perspective. autonomy is a cultural concept “that grounds either the self or the way in which people think selves should be connected—or disconnected”.15 ic by proxy is not a feminist issue in oman. it is a socio-cultural issue affecting both males and females. although it needs to be addressed, it is unlikely to be solved by law and regulation alone. the process of ic needs to be readdressed within a culturally informed framework that endorses cultural concerns and yet maintains the ethico-legal rights of sick individuals. references 1. al balushi aa. female patients and informed consent: oman’s cultural background. sultan qaboos univ med j 2019; 19:e11–14. https://doi.org/10.18295/squmj.2019.19.01.003. 2. merriam-webster dictionary. feminine. from: www.me rriam-webster.com/dictionary/feminine accessed: aug 2019. 3. abulmajd ka. policy and procedure on informed consent. muscat, oman: ministry of health: 2017. from: www.moh.gov.om / d o c u m e n t s / 4 3 6 1 2 4 / 0 / p o l i c y + % 2 6 + p r o c e d u r e + o f + informed++consent.pdf/b359a0ef-eb1e-4c90-a151-a69e 37c7ea50 accessed: aug 2019. 4. engenderhealth. chapter 4: law and policy. in: engenderhealth. contraceptive sterilization: global issues and trends. new york, usa: avsc international, 2002. pp. 87–106. 5. al-khalili ah. [al-fatawa al-tibbiya]. muscat, oman: aljeel alwaed, 2010. p. 178. 6. al-shaibani smh. mua’jam al-nisa’a al-omaniyat. muscat, oman: aljeel awaed; 2004. [in arabic] 7. wikan u. behind the veil in arabia: women in oman. chicago, usa: the university of chicago press, 1982. p. 294. https://doi.org/10.18295/squmj.2019.19.01.003 nasser hammad al-azri comment | e183 8. al-saadoon m, al-adawi s. informed consent in societies with different ethos of ‘selfhood’. sultan qaboos univ med j 2019; 19:e1–3. https://doi.org/10.18295/squmj.2019.19.01.001. 9. engelhardt ht. the foundations of bioethics. oxford, uk: oxford university press; 1996. p. 321. 10. eickelman c. women and community in oman. new york, usa: new york university press; 1984. p. 131. 11. da costa de, ghazal h, al khusaiby s. do not resuscitate orders and ethical decisions in a neonatal intensive care unit in a muslim community. arch dis child fetal neonatal ed 2002; 86:f115–19. https://doi.org/10.1136/fn.86.2.f115. 12. al-mandhari a, al-adawi s, al-zakwani i, al-shafaee m, eloul l. relatives’ advice and health care-seeking behaviour in oman. sultan qaboos univ med j 2009; 9:264–71. 13. eyal n. using informed consent to save trust. j med ethics 2014; 40:437–44. https://doi.org/10.1136/medethics-2012-100490. 14. o’neill o. accountability, trust and informed consent in med ical practice and research. clin med (lond) 2004; 4:269–76. https://doi.org/10.7861/clinmedicine.4-3-269. 15. traphagan jw. rethinking autonomy: a critique of principlism in biomedical ethics. new york, usa: state of new york university press: 2013. p. 27. https://doi.org/10.18295/squmj.2019.19.01.001 https://doi.org/10.1136/fn.86.2.f115 https://doi.org/10.1136/medethics-2012-100490 https://doi.org/10.7861/clinmedicine.4-3-269 1oral & maxillofacial surgery residency programme, oman medical specialty board, muscat, oman; departments of 2dental & maxillofacial surgery, 4clinical physiology, 5child health, 6anaesthesia and 7surgery, sultan qaboos university hospital, muscat, oman; 3department of dental, oral & maxillofacial surgery, al nahdha hospital, muscat, oman *corresponding author’s e-mail: al.naamani@hotmail.com ثالثية من قسط املفصل الصدغي الفكي السفلي وتراجع الفك السفلي وإنقطاع النفس اإلنسدادي النومي الشديد تقرير حالة عي�شى خلفان النعماين، عبدالعزيز عبداهلل باكثري، اأحمد خمي�ص الها�شمي، حممد العربي، ح�شني الكندي، انت�شار األ مكي، زينب البلو�شية abstract: the surgical management of paediatric patients with temporomandibular joint (tmj) ankylosis, mandibular retrognathia and obstructive sleep apnoea (osa) is challenging. we report a nine-year-old boy who presented to the department of oral health, sultan qaboos university hospital, muscat, oman, in 2016 with complaints of limited mouth opening, loud snoring and excessive daytime sleepiness. he was diagnosed with tmj ankylosis, mandibular retrognathia and severe osa. the patient initially underwent mandibular distraction and, subsequently, release of the tmj ankylosis and rib graft reconstruction. the overall patient outcome was successful, with improvement in osa-related symptoms, good facial symmetry and adequate mouth opening. keywords: temporomandibular joint disorders; temporomandibular ankylosis; retrognathia; obstructive sleep apnea; case report; oman. واإنقطاع ال�شفلي الفك تراجع مع ال�شفلي الفكي ال�شدغي املف�شل بق�شط امل�شابني الأطفال للمر�شى اجلراحي التدخل يعترب امللخ�ص: النف�ص الإن�شدادي النومي اأحد التحديات الطبية. نعر�ص يف هذا التقرير حالة �شبي يف التا�شعة من العمر متت معاينته يف ق�شم الأ�شنان وجراحة الوجه والفكني مب�شت�شفى جامعة ال�شلطان قابو�ص، م�شقط، عمان يف عام 2016 حيث كان يعاين من �شعوبة يف فتح الفم مع �شخري عايل ونوم مفرط اأثناء النهار. مت ت�شخي�ص حالته بق�شط املف�شل ال�شدغي الفكي ال�شفلي مع تراجع الفك ال�شفلي واإنقطاع �شديد يف النف�ص ال�شفلي الفكي ال�شدغي املف�شل لق�شط حترير لعملية ذلك وبعد ال�شفلي للفك ف�شل لعملية البداية يف املري�ص خ�شع النومي. الإن�شدادي وتعوي�شه ببناء عظم �شلعي. كانت النتيجة الإجمالية للمري�ص ناجحة مع حت�شن يف الأعرا�ص املتعلقة باإنقطاع النف�ص الإن�شدادي النومي ومتاثل جيد للوجه مع حت�شن جيد يف فتح الفم. الفك تراجع النومي؛ الإن�شدادي النف�ص اإنقطاع ال�شفلي؛ الفكي ال�شدغي املف�شل ق�شط ال�شفلي؛ الفكي ال�شدغي املف�شل ا�شطرابات املفتاحية: الكلمات ال�شفلي؛ تقرير حالة؛ عمان. a triad of temporomandibular joint ankylosis, mandibular retrognathia and severe obstructive sleep apnoea case report *issa k. al-nuumani,1 abdulaziz bakathir,2 ahmed al-hashmi,3 mohammed al-abri,4 hussein al-kindi,5 intisar al-macki,6 zainab al-balushi7 online case report sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e379–382, epub. 19 dec 18 submitted 18 mar 18 revision req. 25 apr 18; revision recd. 28 may 18 accepted 21 jun 18 doi: 10.18295/squmj.2018.18.03.019 recurrent upper airway infections in addition to mechanical obstruction of the airway causing obstructive sleep apnoea (osa).3,4 this report describes a rare triad of tmj ankylosis, mandibular retrognathia and severe osa in a paediatric patient in which two-stage surgical manag ement resulted in a successful outcome. case report a nine-year-old boy presented to the department of oral health, sultan qaboos university hospital, muscat, oman, in 2016 with complaints of limited mouth opening, loud snoring and excessive daytime sleepiness. his medical history was unremarkable with no reported incidents of trauma or infection. a clinical examination revealed temporomandibular joint (tmj) ankylosis is defined as the replacement and/or fusion of the joint articular surfaces by fibrous, fibro-osseous or bony tissue resulting in the mandibular condyle bec oming partially or completely joined to the skull base.1,2 there are multiple aetiological factors for tmj ankylosis, including trauma, infections, surgical procedures and systemic diseases like rheumatoid arthritis, ankylosing spondylitis and psoriasis.1–3 in growing children, tmj ankylosis can pose many challenges and is often associated with multiple functional and aesthetic complications such as mandibular growth retardation leading to retrognathia, micrognathia or dental malocclusion.3 furthermore, this acquired deformity can affect airway patency, resulting in the increased risk of a triad of temporomandibular joint ankylosis, mandibular retrognathia and severe obstructive sleep apnoea case report e380 | squ medical journal, august 2018, volume 18, issue 3 limited mouth opening of 10 mm and mandibular retrog nathia with deviation of the chin to the left side [figure 1]. during the examination, multiple episodes of sudden sleep with rapid awakening were observed. an orthopantomogram and lateral neck imaging showed the unil ateral fusion of the left condylar head to the base of the skull, indicating left-sided tmj ankylosis and narrowing of the upper airway space [figure 2]. polysomnography revealed an apnoea-hypopnoea index (ahi) score of 77, indicating severe osa. the final diagnosis was of a triad of unilateral tmj ankylosis, mandibular retrognathia and severe osa. surgical management was planned in two stages. stage one involved a full airway assessment which showed severe narrowing of the upper airway space at the tongue base level. subsequently, 25 mm bilateral mandibular distractors (zurich mandible distractors®, kls martin lp, jacksonville, florida, usa) were inserted to correct the retrognathia. postoperatively, the patient was kept intubated in the intensive care unit, with the distractors activated 24 hours later and lengthened at a rate of 0.5 mm three times daily. it was originally planned that the patient would remain intubated until the mandible had advanced by approximately 10 mm. however, the patient became agitated on the second postoperative day and—due to the high risk of dislodgement of the intubation tube and accidental extubation—a tracheostomy was performed on the third postoperative day in order to secure the airway. the distraction process continued until the mand ible had advanced by 19.5 mm on the right side and 25 mm on the left side so as to compensate for the patient’s chin deviation. after an eight-week consolidation period, the second stage of surgical management was carried out. this inv olved removing the distractors, releasing the tmj anky losis, carrying out an ipsilateral coronoidectomy and reconstructing the condyle using a costochondral rib graft and interpositional fat graft. intraoperatively, the mouth could be opened to 35 mm. a postoperative orthopantomogram and lateral neck imaging indicated satisfactory opening of the upper airway [figure 3]. the patient then began an aggressive physiotherapy regimen and was decanulated successfully on the third postoperative day. overall, the outcome of the two-stage surgery was successful, with notable improvements in facial symm figure 2: a: preoperative orthopantomogram of a nine-year-old boy showing unilateral temporomandibular joint ankylosis. b: preoperative lateral neck imaging showing obstructed airway space. figure 1: preoperative photographs of a nine-yearold boy showing (a) limited mouth opening and (b) mandibular retrognathia. figure 3: a: postoperative orthopantomogram of a nine-year-old boy showing adequate joint space with a costochondral graft in situ. b: postoperative lateral neck imaging showing adequate airway space. issa k. al-nuumani, abdulaziz bakathir, ahmed al-hashmi, mohammed al-abri, hussein al-kindi, intisar al-macki and zainab al-balushi online case report | e381 etry and adequate mouth opening of 40 mm [figure 4]. postoperatively, subjective feedback from the patient and his parents indicated a marked improvement in his sleeping patterns and the absence of any osarelated sleeping disturbances, including snoring or rapid awakening. two years later, a subsequent sleep study revealed an ahi score of 10, indicating the successful treatment of the patient’s osa. discussion ankylosis of the tmj is a chronic disease that destroys the structure and articulation of the joint, leading to hypomobility of the jaw due to the abnormal union between the mandibular condyle and the base of the skull.1,2,5 the partial or complete replacement of the normal joint space determines the degree of hypomobility.3,5 while there are many aetiological factors for tmj ankylosis, trauma is the most common, followed by infections.1,3 in the current case, the aetiology of the ankylosis was unknown; this is unusual as most previous research generally reports a causative factor.6 paediatric tmj ankylosis is uncommon and rep resents a challenge in the practice of oral and maxillofacial surgery.3,4 complicating factors include the patient’s age at onset, presentation, implications regarding growth, surgical complexity, risk of recurrence and postoperative compliance.3–6 clinical presentations of tmj ankylosis among children include facial growth disturbances, diff iculty in chewing and swallowing, poor oral health and limited mouth opening.7 depending on the time of onset and the extent of the ankylosis, facial growth retardation may lead to mandibular retrognathia and chin deviation; the latter condition is often seen in unilateral tmj ankylosis cases.7 furthermore, mandibular retrognathia leads to the posterior displacement of the tongue base and is associated with a reduction in the oropharyngeal spaces, leading to upper airway reduction/obstruction and, ultimately, osa.4 in the present case, the patient exhibited classic features of unilateral tmj ankylosis with mandibular retrognathia and severe osa. among paediatric patients, the occurrence of tmj ankylosis, mandibular retrognathia and osa represents a rare triad of complex clinical presentations triggered primarily by tmj ankylosis.1,3,4 mandibular distraction osteogenesis (mdo) is increasingly used to correct mandibular retrognathia in tmj ankylosis cases.3 in a seven-year study, carls et al. reported successful outcomes following mand ibular distraction among 14 children with retromandibulism.8 generally, mdo has several advantages over costochondral grafting—previously considered the gold standard technique to correct this type of mandibular deformity—as the amount and direction of mandibular growth is more predictable because the callus direction can be controlled by the surgeon.3,9 furthermore, this technique allows for the stretching of the soft tissues during the distraction period as well as the opportunity for three-dimensional augmentation with bior multidirectional extraoral distraction devices. finally, the well-vascularised regenerated bone in the distraction gap obviates the need for a bone graft.3 four different surgical protocols have been reported in the literature for managing paediatric patients with tmj ankylosis, mandibular retrognathia and osa. the first involves the release of the tmj ankylosis with costochondral graft reconstruction in the hope that the graft will act as a growth centre, thus leading to the correction of the mandibular retrognathia.3,4,9 however, this option was not ideal in the current case because it would not immediately alleviate the patient’s symptoms of severe osa. furthermore, this approach has been known to prolong postoperative morbidity and result in unpredictable growth.3,4,9 the second protocol involves a single-staged surgery in which ankylosis release and mdo is performed simultaneously to address both the mandibular retrognathia and osa.3,4,10 nevertheless, this choice also has significant drawbacks, including the continuous stretching of the bone during physiotherapy after the ankylosis is released, physical interference from the distractor during physiotherapy and unreliable movements of the proximal segment of the mandible after distraction.3,4,7,10 zanaty et al. reported significant improvements in ahi and oxygen desaturation index scores and mouth opening among 30 children with micrognathia and tmj ankylosis when using this technique; however, the protocol was modified slightly in that the ramus rather than the body of the jaw bone was targeted during mdo.11 figure 4: postoperative photographs of a nine-year-old boy demonstrating (a) optimal mouth opening and (b) good facial symmetry. the photographs were taken a few days apart. a triad of temporomandibular joint ankylosis, mandibular retrognathia and severe obstructive sleep apnoea case report e382 | squ medical journal, august 2018, volume 18, issue 3 the third protocol is the most popular and comp rises a two-stage surgery wherein the tmj ankylosis is released first and mdo is performed at a later stage.3,4 nonetheless, this option is not recommended in cases of severe osa.4 due to the challenging nature of this condition and potential lack of cooperation during the postoperative period on the part of the paediatric patient, there is a risk of ankylosis recurrence and unpredictable regression in jaw advancement. furthermore, published reports highlight that releasing the ankylosis first in patients with a compromised airway is usually associated with further collapse of the airway during postoperative jaw physiotherapy.3,4 andrade et al. reported that ankylosis release alone resulted in respiratory distress during postoperative jaw exercises and a drop in oxygen saturation and heart rate among seven patients with tmj ankylosis, micrognathia and osa.4 the most recent protocol for the treatment of tmj ankylosis, mandibular retrognathia and osa was first suggested by andrade et al. in 2012.4 in this protocol, mdo is performed initially and the ankylosis is released at a later stage in order to maintain the patency of the airway during postoperative jaw physiotherapy.4 anantanarayanan et al. reported three paediatric cases wherein mdo was performed prior to ankylosis release.3 all three patients had favourable outcomes and were cured of snoring, with episodes of night time awakening and daytime sleepiness significantly reduced.3 the findings of the current case support utilisation of this protocol. conclusion a triad of tmj ankylosis, mandibular retrognathia and osa is uncommon among paediatric patients. moreover, such cases tend to be challenging, requiring careful man agement and early diagnosis to reduce the severity of symptoms and prevent associated complications. although several surgical protocols exist for managing such patients, oral and maxillofacial surgeons should be aware of recent evidence supporting new approaches or modif ications to existing techniques. a c k n o w l e d g e m e n t s a poster of the preliminary version of this case report was presented at the 23rd international conference on oral & maxillofacial surgery from 31 march–3 april 2017 in hong kong. an abstract of this poster presentation was subsequently published in the international journal of oral & maxillofacial surgery in march 2017 (volume 46, issue s1, p. 356). references 1. al-saadi nj, bakathir aa, al-hashmi ak, al-ismaili mi. tempo romandibular joint ankylosis as a complication of neonatal septic arthritis: report of two cases. sultan qaboos univ med j 2015; 15:e554–8. doi: 10.18295/squmj.2015.15.04.020. 2. movahed r, mercuri lg. management of temporomandibular joint ankylosis. oral maxillofac surg clin north am 2015; 27:27–35. doi: 10.1016/j.coms.2014.09.003. 3. anantanarayanan p, narayanan v, manikandhan r, kumar d. primary mandibular distraction for management of nocturnal desaturations secondary to temporomandibular joint (tmj) anky losis. int j pediatr otorhinolaryngol 2008; 72:385–9. doi: 10.1016/j. ijporl.2007.11.015. 4. andrade nn, kalra r, shetye sp. new protocol to prevent tmj reankylosis and potentially life threatening complications in triad patients. int j oral maxillofac surg 2012; 41:1495–500. doi: 10.1016/j.ijom.2012.06.012. 5. kaban lb, perrott dh, fisher k. a protocol for management of temporomandibular joint ankylosis. j oral maxillofac surg 1990; 48:1145–51. doi: 10.1016/0278-2391(90)90529-b. 6. kaban lb, bouchard c, troulis mj. a protocol for management of temporomandibular joint ankylosis in children. j oral maxillofac surg 2009; 67:1966–78. doi: 10.1016/j.joms.2009.03.071. 7. de roo n, van doorne l, troch a, vermeersch h, brusselaers n. quantifying the outcome of surgical treatment of temporomandibular joint ankylosis: a systematic review and meta-analy sis. j craniomaxillofac surg 2016; 44:6–15. doi: 10.1016/j.jcms. 2015.08.019. 8. carls fr, sailer hf. seven years clinical experience with mandibular distraction in children. j craniomaxillofac surg 1998; 26:197–208. doi: 10.1016/s1010-5182(98)80015-2. 9. politis c, fossion e, bossuyt m. the use of costochondral grafts in arthroplasty of the temporomandibular joint. j craniomaxillofac surg 1987; 15:345–54. doi: 10.1016/s1010-5182(87)80081-1. 10. papageorge mb, apostolidis c. simultaneous mandibular distraction and arthroplasty in a patient with temporomandibular joint ankylosis and mandibular hypoplasia. j oral maxillofac surg 1999; 57:328–33. doi: 10.1016/s0278-2391(99)90683-3. 11. zanaty o, el metainy s, abo alia d, medra a. improvement in the airway after mandibular distraction osteogenesis surgery in children with temporomandibular joint ankylosis and mandibular hypoplasia. paediatr anaesth 2016; 26:399–404. doi: 10.1111/ pan.12869. https://doi.org/10.18295/squmj.2015.15.04.020 https://doi.org/10.1016/j.coms.2014.09.003 https://doi.org/10.1016/j.ijporl.2007.11.015 https://doi.org/10.1016/j.ijporl.2007.11.015 https://doi.org/10.1016/j.ijom.2012.06.012 https://doi.org/10.1016/0278-2391%2890%2990529-b https://doi.org/10.1016/j.joms.2009.03.071 https://doi.org/10.1016/j.jcms.2015.08.019 https://doi.org/10.1016/j.jcms.2015.08.019 https://doi.org/10.1016/s1010-5182%2898%2980015-2 https://doi.org/10.1016/s1010-5182%2887%2980081-1 https://doi.org/10.1016/s0278-2391%2899%2990683-3 https://doi.org/10.1111/pan.12869 https://doi.org/10.1111/pan.12869 clinical & basic research squ med j, december 2009, vol. 9, iss. 3, pp. 264-271, epub. 19th dec 2009 submitted 7th sept. 2009 revision req. 15th sept. 09, revision recd. 30th sept 09 accepted 12th oct 09 departments of 1family medicine and public health & 3pharmacy, sultan qaboos university hospital, sultanate of oman; 2department of behavioral medicine, college of medicine and health sciences, sultan qaboos university, sultanate of oman *to whom correspondence should be addressed. email: adawi@squ.edu.om نصيحة األقارب وسلوك اللجوء للرعاية الصحية يف ُعمان أحمد املنظري، سمير العدوي، ابراهيم الزكواني، محمد الشافعي، ليام الول الطبيب بني للعالقة إضافة والنفسية واالجتماعية احمللية بالصفات يتأثر الصحية الرعاية لطلب اللجوء بأن املعروف من االهدف: امللخص: واملريض. من جهة أخرى كان هناك اهتماما قليال بالدور الذي تلعبه النصائح املقدمة من أفراد العائلة لطلب اللجوء للرعاية الصحية. في اجملتمع العماني، تعتبر القيم العائلية التقليدية والتفكير اجلماعي من السمات العامه للمجتمع. هذه الورقة تبحث في كيفية تأثير نصيحة العائلة في جمع البيانات عن طريق املقابلة الشخصية لعينة عشوائية من املرضى مت ،2006-2007 قرار اللجوء لطلب الرعاية الصحية. الطريقة: خالل الذين زاروا مختلف مراكز الرعاية الصحية األولية في شمال ُعمان طلبا لالستشارة الطبية. كان عدد أفراد العينة 493 مريضا. مت حتليل العالقة بني دور نصيحة العائلة لطلب اللجوء للرعاية الصحية، واملؤشرات األخرى وذلك باستخدام املتغير املتعدد ذو االرتداد اللوجستي. النتائج: تبني أن نصيحة أفراد العائلة للجوء للرعاية الصحية ترتبط ارتباطا وثيقا مع جنس وتعليم الشخص ، ووجود أمراض مزمنة واستخدام الطب الشعبي في السابق والتثقيف الصحي ، باإلضافة إلى إجراء التطعيم في املاضي. اخلالصة: تشير هذه النتائج إلى أن نصيحة أفراد العائلة تبقى عامال مؤثرا وقويا في طلب اللجوء للرعاية الصحية. متت مناقشة العوامل النفسية واالجتماعية املؤدية إلى قلة استخدام اخلدمات في هذه الورقة. مفتاح الكلمات: سلوك اللجوء للرعاية، نصيحة األقارب، عينة سريرية، ُعمان، عربي/أسالمي. abstract: objectives: it has been well established that pathways to care are considerably modified by local, social and psychological characteristics as well as the doctor-patient relationship. scant attention has been paid to the role of family advice in care-seeking. in omani society, traditional family values and a collective mindset are the norm rather than the exception. this paper examines how family advice affects the trajectory of care seeking. methodology: during 2006-2007, data was collected through face-to-face interviews among a randomised sample of patients seeking medical consultation in various primary health care centres in the northern region of oman. this study enrolled a total of 493 patients. the association between the advice of family members as a reason to seek health care and other predictors was analysed using multivariable logistic regression. results: the data suggest that the advice of family members in care-seeking is strongly associated with gender, education, history of chronic illness, previous exposure to traditional medicine, and health education, as well as the history of immunisation. conclusion: these findings suggest that the advice of family members remains a strong catalyst for care-seeking in oman. the psychosocial factors affecting care-seeking leading to underutilisation of services or otherwise are discussed. keywords: care-seeking behavior; relatives’ advice; clinical population; oman; arab/islamic. relatives’ advice and health care-seeking behaviour in oman ahmed al-mandhari,1 *samir al-adawi,2 ibrahim al-zakwani,3 mohammed al-shafaee1 and liyam eloul2 clinical & basic research advances in knowledge 1. examination of how social patterning, i.e. the centrality of family in oman, influences care-seeking, behaviour. 2. the present study is, to our knowledge, the first of its kind to emerge from an arab/islamic society showing the role of a collective cultural orientation in care-seeking behaviour. omanis’ immediate social context, often family, plays a pivotal role in an individual’s decisions regarding care-seeking. application to patient care 1. this study identifies specific family-related variables which reinforce care seeking. 2. the prevailing beliefs in the family circle are likely to have implications for patient care, health education, prevention and health policy. despite the globalisation of allopathic health care services and the homogeny of the biomedical sciences, studies carried out in different parts of the world suggest that there are various socio-demographic factors that are critically involved in care-seeking.1 according to shaikh,2 there are a myriad of interrelated benefits of exploring health-seeking ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, mohammed al-shafaee and liyam eloul clinical and basic research | 265 behaviours that would have direct relevance on public health policy and health system development. various studies from developing countries, using kroeger’s framework3 as well as quantitative methods,4,5 have converged on the view that the use of health care services is related to factors, such as service accessibility, quality and cost, as well as to the social structure, health beliefs and personal characteristics of the users.6-9 there exists a paucity of studies on the role of social networks in care-seeking. additionally, there are, to our knowledge, few studies examining factors behind health care-seeking behaviour in arab populations. most efforts have been focused on mental health care-seeking behaviour.10,11 although these studies have unearthed wide-spread scepticism about the usefulness of professional these services in traditional cultural settings, the generalisation of their results is limited to mental health services. to our knowledge, only one study has attempted to fill the gap in the literature about the arab world, but even this has focused on health care-seeking among particular clinical populations.12,13 this paper is an attempt to examine the factors associated with health care use behaviour among general health care users in oman. two of the major benefits resulting from the recent modernisation in oman are an improved standard of living and the establishment of a modern health care system. despite the rapid growth of biomedical care, little is known about the factors influencing care-seeking behaviour in oman including traditional cultural patterning. relative to western standards, omani individuals exhibit a greater degree of interdependence and a more collective orientation, with an individual’s identity being heavily enmeshed with family and/or tribal traditions.14,15 to our knowledge, the relationship between cultural patterning and care-seeking has yet to feature predominantly in the medical literature, despite the fact that cultural modelling is known to play a part in illness behaviour, and therefore in health care-seeking. in order to lay the groundwork necessary for developing strategies to improve awareness of health delivery in oman, this paper examines factors leading to care-seeking among omanis and gives particular attention to family member advice as a reason to seek health care. it is hypothesised that health care-seeking behaviour could be significantly influenced by family member advice. chrisman and kleinman16 have proposed that illness behaviour is strongly dependent on an individual’s immediate social contacts, that is family and community. these social contacts interpret the individual’s distress in the light of a shared belief system. the aim of the present study is to examine demographic, clinical and health resource characteristics and their relationship to family member advice in health careseeking behaviour. in this study, family member advice is defined as admission by the subject that s/he has sought advice, counsel or support from one or more significant family members prior to seeking health care. according to leventhal,17 90% or more of care seekers often talk to someone, usually a family member, about their symptoms. the response may be supportive (‘what can i do to help?’), directive (‘you should see your doctor right away!’), or simply grant permission to seek medical care (‘i think it’s something most anyone would get checked over’)” (p.7187). methods according to the world bank,18 oman is categorised as an upper-middle-income economy. the majority of oman’s population is located either in the north or the far south of the sultanate; these two regions are separated by a stretch of desert known as the empty quarter. for logistical reasons, the present study was limited to the northern regions of oman, which include a number of larger coastal towns, including the capital, muscat, as well as a number of towns in the more mountainous interior. this population segment was found to reflect the ethnocultural variety present in omani society.19 d ata c o l l e c t i o n oman offers universal free health care to its approximately 1.9 million omani citizens and to expatriate government employees.20 the present study was conducted over 12 months in 20062007 in public hospitals located in the region described. data was collected by face-to-face interview. for consistency, and to accommodate illiterate patients, or those with sensory and motor deficits, questionnaires were read out loud to the subjects rather than being self-administered. the interviews were conducted by trained researchers, predominantly second and third year medical relatives’ advice and health care seeking behaviour in oman 266 | squ medical journal, december 2009, volume 9, issue 3 students from the college of medicine and health sciences at sultan qaboos university. during our preparation for this study, the interviewers were trained to read out the items of the questionnaire and to code the responses with precision and reliability; we observed substantial inter-coding agreement for the scale items (r = 0.86, p < 0.001). our target population consisted of omani table 1: demographic, clinical and health resource characteristics of the study cohort stratified by family member advice as a reason to seek health care (n = 493) characteristic relatives’ advice solicited no (n = 44) yes (n = 449) age: mean years ±sd 26 ±10 33 ±12 gender, (n, %) female 36 (82%) 284 (63%) male 8 (18%) 165 (37%) marital status, (n, %) married 21 (48%) 299 (67%) other 23 (52%) 150 (33%) literacy, (n, %) illiterate* 1 (2%) 81 (18%) literate* 43 (98%) 368 (82%) history of chronic illness, (n, %) no 31 (70%) 314 (70%) yes 13 (30%) 135 (30%) on regular medication, (n, %) no 28 (64%) 302 (67%) yes 16 (36%) 147 (33%) source of health care, (n, %) government 34 (77%) 308 (69%) private 8 (18%) 37 (8%) traditional 2 (5%) 104 (23%) reason to seek health care, (n, %) treatment of acute condition 10 (23%) 197 (44%) follow-up visit 10 (23%) 143 (32%) vaccination or others 24 (54%) 109 (24%) number of visits attended per month mean ±sd 0.93 ±0.9 1.04 ±2.4 median (absolute range) 1 (0 to 4) 1 (0 to 30) attended a health education programme no 23 (52%) 301 (67%) yes 21 (48%) 148 (33%) legend: sd = standard deviation; percentages are column percents; *note: illiterate = cannot read or write; literate = can read and write ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, mohammed al-shafaee and liyam eloul clinical and basic research | 267 patients visiting the sampled 10 health centres. inclusion criteria required participants to be at least 18 years old and cognitively intact. the participant sample was randomised in the following way: one out of every five patients entering the reception area of each health centre for a routine outpatient visit was invited to volunteer for an interview. the participants were explicitly informed that any information they provided in the course of the interview would remain completely anonymous and that their participation would not in any way affect their treatment. no invited patient declined to be interviewed. the interview process was carried out in the health centres over a two week period. at each health centre, a minimum of 50 patients per research assistant were interviewed during the span of this study. data from the ministry of health have shown that, on average, the health care centres targeted in this study cater to the needs of approximately 90% of the population of this particular region of oman.21 in total, 493 subjects participated in this study. a s s e s s m e n t m e a s u r e s the questionnaire was developed to fit the situation on the ground, using a number of measures that have been used in previous studies, modified for the present context.7,22 as detailed in table 1, the information elicited from the participants included demographic data such as age, sex, marital status, and level of education. in addition, other information germane to the framework of careseeking, such as history of chronic illnesses, usual source of health care, frequency of health care facility usage, and attendance at health education sessions was also sought. family member advice was defined according to leventhal17 in which the subjects were asked if they had talked to someone, usually a family member, about their symptoms. the answers were quantified in terms of ‘yes’ (1) or ‘no’ (0). the final questionnaire was pre-tested and piloted on convenience samples among patients attending primary care services in the vicinity of sultan qaboos university. s tat i s t i c a l a n a ly s i s descriptive statistics were used to render the data. the association between family member advice as a reason to seek health care and other predictors were analysed using multivariable logistic regression. the predictor variables in the logistic model were entered simultaneously. the multivariate logistic model was extensively examined by evaluating the model’s assumptions and overall model fit. the overall model fit was assessed using the hosmer & lemeshow goodness-of-fit statistic and the area under the receiver operating characteristic (roc) curve.23,24 the roc curve is a graph of sensitivity versus one minus specificity as the threshold cutoff is varied, and also calculates the area under the curve. sensitivity is the fraction of true positives while specificity is expressed as a fraction of the true negatives. the roc provides a measure of the model’s discriminatory power. a model with perfect prediction has a roc of 1.0, while an area of 0.5 provides no better discrimination than chance. an a priori two-tailed level of significance was set at 0.05. statistical analyses were performed using stata software version 9.2. results this study enrolled a total of 493 participants. the demographic, clinical and health care resource characteristics of the participants are shown in table 1. the overall mean age of the participants was 32 ±12 years with an age range from 15 to 74 years. our study found that those who sought family advice prior to care-seeking were slightly older and 63% (n = 320) of them were female [table 1]. the majority (91%; 449 out of 493) of both male and female participants had sought family member advice about their health care. of our participants, 65% were married (n = 320), and 83% were literate (n = 411). the present study also sought to tease out whether those who take regular medications are likely to have sought family member advice about health care. a total of 33% of the subjects who were taking regular medications had sought an opinion from their relatives. although omani nationals are entitled to free modern medical care, they may also address their health needs outside the public health system. the data suggest that the majority (91%; 449 out of 493) of the population seeks family member advice, whether they source their health care in public hospitals, private hospitals or even by traditional methods. participants were also asked about their reason relatives’ advice and health care seeking behaviour in oman 268 | squ medical journal, december 2009, volume 9, issue 3 for seeking health care services during this particular visit, and whether their decision was influenced by family member advice. those who were seeking treatment for an acute condition, were attending hospital for follow-up visits or were attending hospital for vaccination were more likely to have sought relatives’ advice. the subjects were asked whether they had attended health education courses. the majority (66%; 324 out of 493) had not; however, for those who had (n = 169), 88% (148 out 169) also had a tendency to seek family advice in health care decision making [table 1]. in order to synthesise the possible themes of health care-seeking, the present study also examined whether our other operationalised predictors would be relevant to family member advice. the final multivariable logistic model was significant (wald {chi} 2(12) = 61.71; log likelihood = -117.4406; p <0.001) and the listed variables accounted for 21% of the variance in the model (pseudo r2 = 0.21). furthermore, the goodness-of-fit statistics indicated a good overall model fit22 {chi} 2 (8) = 6.57, p = 0.584; area under the roc curve = 0.82. age was significant in predicting family member advice seeking, with older participants being significantly more likely to request family member advice in health care consumption (an average of 32 versus 26 years of age, respectively, p <0.001) [table 1]. however, this effect did not retain statistical significance in the multivariable logistic model when adjusted for other operationalised predictors [table 2]. in addition, female participants were 2.34 times more likely than their male counterparts to listen to family member advice when seeking health care (95% confidence interval (ci) 1.01 to 5.43; p = 0.049). with regards to literacy, those participants who could read or write were significantly less likely to solicit family member advice when seeking health care than their illiterate counterparts (odds ratio (or) 0.11; 95% ci 0.01 to 0.99; p = 0.049). those with a history of chronic illness were also significantly more likely to seek family member advice with regards to health care compared to those without (or 0.32; 95% ci 0.10 to 0.99; p = 0.048). the participants who preferred to use traditional, as opposed to governmental, health care sources were less likely to seek family member advice when seeking health care (or 0.21; 95% ci 0.09 to 0.50 p < 0.001). further, participants who attended health education programmes were less table 2: the association between family member advice as a reason to seek health care and various predictors using multiple logistic regression (n = 493) predictor coefficient se z-statistic p-value or 95% ci age 0.04 0.03 1.63 0.104 1.04 0.99, 1.09 female gender 0.85 0.43 1.97 0.049* 2.34 1.01, 5.43 married 0.59 0.41 1.45 0.147 1.80 0.81, 3.99 literate -2.20 1.12 -1.97 0.049* 0.11 0.01, 0.99 history of chronic illness -1.15 0.58 -1.98 0.048* 0.32 0.10, 0.99 history of taking medications -0.09 0.52 -0.16 0.871 0.92 0.33, 2.56 type of health care source consumed private versus government -0.43 0.48 -0.9 0.368 0.65 0.25, 1.66 traditional versus government 1.59 0.78 2.04 0.041* 4.92 1.07, 22.65 reason to seek health care follow-up visit against treatment of acute condition -0.32 0.49 -0.66 0.512 0.72 0.28, 1.90 vaccination or treatment for acute condition -1.54 0.43 -3.55 <0.001* 0.21 0.09, 0.50 number of visits attended per month 0.15 0.13 1.15 0.248 1.17 0.89, 1.52 attended a health education programme -0.70 0.36 -1.97 0.049* 0.50 0.25, 0.99 legend: se = standard error; or = odds ratio; ci = confidence interval; *= significant below 0.05 level; model: wald χ2 (12) = 61.71; log likelihood = -117.4406; p<0.001; pseudo r2 = 0.21; hosmer & lemeshow χ2 (8) = 6.57; p = 0.584; area under the receiver operating (roc) curve = 0.82 ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, mohammed al-shafaee and liyam eloul clinical and basic research | 269 likely to seek family member advice when seeking health care than those who did not attend health education programmes (95% ci 1.01 to 5.43; p = 0.049). discussion the primary goal of this study was to further our knowledge of health care-seeking behaviour in oman; a population in which such phenomena have not been previously investigated. a plethora of research has indicated that the cultural patterning in islamic/arab society emphasises obedience and loyalty to family values.14,15 the current investigation was founded on the hypothesis that health careseeking behaviour is strongly influenced by family values and recommendations, bearing in mind that family plays a central role in the decision-making of ordinary omanis. the present study interviewed 493 patients in randomly selected regions of the northern part of oman. the highlights of the present study are discussed in the ensuing paragraph. another implicit relevance of the present research is the emerging view from different parts of the world suggesting that many problems, which were previously thought of as primarily medical, and hence demanding conventional medical intervention, are in fact more appropriately solved by changing individual and social attitudes and behaviour. many health campaigns tend to have only modest success because traditional customs and health beliefs often override biomedical assumptions and considerations. as a result, communicable and noncommunicable diseases are proliferating, not only because of poverty, but also because of prevailing traditional views on health and disease.14 it is also apparent that the extent to which any medical treatment is adhered to is often a function of a range of socio-cultural beliefs, such as the personality of the patient and the quality of interaction between doctor and patient. in this context, potentionally influenced by family opinions, a person’s behaviour can impede enlightened and cost-effective delivery of health care. one group that has benefited greatly from the recent trend toward affluence in oman is women.25,26 however, the data presented in this paper suggest that female participants are more likely than their male counterparts to seek family member advice when making health care choices. this is consistent with previous studies from other populations which have suggested that women tend to seek family member advice before seeking health care.10 therefore, despite a recent change in social mobility, it appears that decision-making related to health care continues to reflect the patriarchal traditions present in omani society. traditionally, women and girls tended to maintain exclusively domestic roles with a public-private dichotomy upheld in all social interactions.27 therefore, in congruence with cultural teachings, it is possible that any outside excursion for women would likely be preceded by consultation with other people in the household. the spread of education has introduced new roles and opportunities for omanis.26 the present data suggest that indices of education, such as literacy, significantly affect reliance on family member advice when seeking health care. the less educated the participant, the more likely s/he was to seek family member advice. this suggests that education directly impinges on care-seeking; that is, those who are more educated, as presently defined, are less likely to rely on traditional networks. conversely, education is strong predictor of type of care-seeking. this consonant with other studies.11,28 in many traditional communities such as those in oman, it has been previously found that the burden of illnesses, particularly those that do not fit into the pattern of a familiar, manageable illness, is often borne by the family as a whole.29 similarly, in many rituals of healing, the entire family is called upon to witness and share the misfortune of the afflicted individual. this process helps to increase the patient’s self-value and reinforce the patient’s relationship with the community.30 consistent with this view, our data suggest that there is a strong tendency for individuals suffering from chronic illness to be influenced by family members in care -seeking decisions. it has been suggested that prior to the introduction of modern health care, all illnesses were the prerogative of traditional healing practices.29 there is also an indication that, despite the growth of public hospitals, there is a burgeoning of alternative and traditional healing practices in many developing countries. however, in oman, whether one seeks care from traditional medicine or modern public hospitals, our data suggests that there is an equal tendency to consult family members. relatives’ advice and health care seeking behaviour in oman 270 | squ medical journal, december 2009, volume 9, issue 3 under the auspices of the ministry of health, oman has been rigorously instituting health education programmes. the present study investigated the impact of health education on care-seeking behaviours. although the majority of the participants had not yet been exposed to health education, those who had showed a significantly lower tendency to seek family member advice on health care. there are issues that warrant caution in interpreting the results of this study. first, the generalisation of this study may be limited by the fact that the data was collected only in one specific region of oman, and in health clinics rather than in the community. previous studies show that patients in a clinical setting tend to respond to enquiry differently than those in the general population. however, since this study aimed to examine factors affecting health care-seeking behaviour, it was essential that the data be initially collected among a clinical population and subsequently be replicated in the wider community. an equally well designed study could be conducted at a community or household level by recruiting people who have been ill in the last month and asking them: “did you consult any family member about treatment/ medical consultation for your last illness?” a mixed method study with a qualitative component would be an ideal next step. second, data derived from interviewing may be susceptible to information bias, as the questionnaire was not self-administered. though universal education has spread literacy to all corners of the country, the present study did leave room to accommodate those individuals who could not read or write. for uniformity, it was decided to read the items to all subjects, rather than allowing some of them to self-administer the survey. it is possible that this approach may have resulted in a reluctance to reveal sensitive information. finally, it is worthwhile noting that the central tenet of the present study hinges on an assumption that patients talked with family members and that such encounters influenced patients to seek help or otherwise. criticism may emerge here as the questionnaire contained only one question regarding whether the patient talked to a family member before attending the clinic (with either a “yes” or “no” response). no additional information about family member advice was elicited nor was the question asked whether the patient consulted someone outside the family. it is possible that the family member could have reassured the patient and advised them that there was no need to seek health care. this issue was not addressed in this study. therefore, more studies are needed before the present conclusion can be generalised. these factors, among others, are all part of the challenge of clinical-based research, suggesting that the results of this study should be viewed as a starting point for more systematic investigation. further research in this area is therefore indicated. a c k n o w l e d g e m e n t s we thank the patients and staff of the family medicine and public health department at sultan qaboos university and the ministry of health whose active support made this research possible. our thanks also go to the medical students who contributed to the data collection as part of their community training and to marcus thomson for providing technical support and constructive criticism to an earlier version of this manuscript. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. shaikh bt, hatcher j, haran d. health in the middle east: making healthcare systems more responsive to women in pakistan. bmj 2006; 333:971. 2 . shaikh bt. understanding social determinants of health seeking behaviours, providing a rational framework for health policy and systems development. j pak med assoc 2008; 58:33-6. 3. kroeger a. anthropological and socio-medical health care research in developing countries. soc sci med 1983; 17:147-61. 4. al-krenawi a, graham jr, eds. multicultural social work in canada: working with diverse ethno-racial communities. toronto: oxford university press, 2003. 5. elhai jd, schweinle w, anderson sm. reliability and validity of the attitudes toward seeking professional psychological help scale-short form. psychiatry res 2008; 59:320-9. 6. besiroglu l, agargun my. the correlates of healthcare seeking behavior in obsessive-compulsive disorder: a multidimensional approach. turk psikiyatri derg 2006; 7:213-22. 7. shaikh bt, haran d, hatcher j. where do they go, whom do they consult, and why? health-seeking behaviors in the northern areas of pakistan. qual ahmed al-mandhari, samir al-adawi, ibrahim al-zakwani, mohammed al-shafaee and liyam eloul clinical and basic research | 271 health res 2008; 18:747-55. 8. chowdhury ri, islam, ma, gulshan j, chakraborty, n. delivery complications and healthcare-seeking behavior: the bangladesh demographic health survey, 1999-2000. health soc care community 2007; 15:254-64. 9. al-krenawi a, graham jr gender and biomedical/ traditional mental health utilization among the bedouin-arabs of the negev. cult med psychiatry 1999; 23:219-43. 10. al-krenawi a, graham jr, dean yz, eltaiba n. cross-national study of attitudes towards seeking professional help: jordan, united arab emirates (uae) and arabs in israel. int j soc psychiatry 2004; 50:102-14. 11. eapen v, ghubash r. help-seeking for mental health problems of children: preferences and attitudes in the united arab emirates. psychol rep 2004; 94:663-7. 12. rizk de, hassan my, shaheen h, cherian jv, micallef r, dunn e. the prevalence and determinants of health care-seeking behavior for fecal incontinence in multiparous united arab emirates females. dis colon rectum 2001; 44:1850-6. 13. rizk dee, shaheen h, thomas l, dunn e, hassan my. the prevalence and determinants of health careseeking behavior for urinary incontinence in united arab emirates women. int urogynecol j pelvic floor dysfunct 1999; 10:160-5. 14. al-adawi s. adolescence in oman. in: jeffrey jensen arnett, ed. international encyclopedia of adolescence: a historical and cultural survey of young people around the world. new york: routledge 2006, pp.713-28. 15. dwairy m, van sickle td. western psychotherapy in traditional arabic societies. clin psychol rev 1996; 16:231-49. 16. chrisman, nj, kleinman a. popular health care, social network and cultural meanings. in: mechanic d, ed. handbook of health, health care and health professions. new york: free press 1983. pp. 569-90. 17. leventhal h. illness behavior and care seeking. in: international encyclopedia of the social & behavioral sciences. london: elsevier science, 2001. 18. world bank. world development report 2007: development and the next generation. washington, dc: the world bank, 2006. 19. ministry of health, oman. national health survey 2000. muscat: ministry of health, 2002. 20. ministry of health. annual health report 2007. muscat: director general of planning, ministry of health. from http://www.moh.gov.om/stat/ ch01y07.pdf. accessed october 2009. 21. national health survey 2000. study of life style risk factors. directorate of research and studies and directorate of general health planning (vol.1). muscat: ministry of health, 2000. 22. cheng jw, kalis mm, feifer s. patient-reported adherence to guidelines of the sixth joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. pharmacotherapy 2001; 21:828-41. 23. hosmer dw jr, lemeshow s. applied logistic regression 2nd ed. new york: john wiley & sons, 2001. 24. hardin j, hilbe j. generalized linear models and extensions; college station, tx: strata press, 2001. 25. al-lamki sm. women in the labor force: the case of the sultanate of oman. int management 2000; 17:166-74. 26. heath c. women, income generation and gender relations in rural oman. in: abdelkarim a, ed. change and development in the gulf. london: macmillan press, 1999. pp.164-83. 27. eickelman c. women and community in oman. new york: new york university press, 1981. 28. bener a, al maadid mg, al-bast da, al-marri s. maternal knowledge, attitude and practice on folic acid intake among arabian qatari women. reprod toxicol 2006; 21:21-5. 29. al-adawi s. a glimpse into traditional outlook towards health: a literature review. j med humanit 1993; 14:67-79. 30. jilek wg, jilek-aall l. transient psychoses in africans. psychiatr clin 1970; 3:337-64. 1department of haematology, sultan qaboos university hospital; 2department of haematology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author e-mail: sskindi@yahoo.com أثر األنشطة التعليمية يف خفض أخطاء ما قبل التحليل املختربي مبادرة جودة حمد الغيثي، اأنيل باثاري، �سهيمة املعمرية، رودريجو فيالكرو�ص، جنالء فواز، �سالم الكندي abstract: objectives: pre-analytic errors during diagnostic laboratory investigations can lead to increased patient morbidity and mortality. this study aimed to ascertain the effect of educational nursing activities on the incidence of pre-analytical errors resulting in non-conforming blood samples. methods: this study was conducted between january 2008 and december 2015. all specimens received at the haematology laboratory of the sultan qaboos university hospital, muscat, oman, during this period were prospectively collected and analysed. similar data from 2007 were collected retrospectively and used as a baseline for comparison. non-conforming samples were defined as either clotted samples, haemolysed samples, use of the wrong anticoagulant, insufficient quantities of blood collected, incorrect/lack of labelling on a sample or lack of delivery of a sample in spite of a sample request. from 2008 onwards, multiple educational training activities directed at the hospital nursing staff and nursing students primarily responsible for blood collection were implemented on a regular basis. results: after initiating corrective measures in 2008, a progressive reduction in the percentage of non-conforming samples was observed from 2009 onwards. despite a 127.84% increase in the total number of specimens received, there was a significant reduction in non-conforming samples from 0.29% in 2007 to 0.07% in 2015, resulting in an improvement of 75.86% (p <0.050). in particular, specimen identification errors decreased by 0.056%, with a 96.55% improvement. conclusion: targeted educational activities directed primarily towards hospital nursing staff had a positive impact on the quality of laboratory specimens by significantly reducing pre-analytical errors. keywords: healthcare quality assurance; quality control; specimen handling; blood specimen collection; hematology; oman. امللخ�ص: الهدف: االأخطاء التي ت�سبق التحليل املخربي يف املختربات الت�سخي�سية توؤدي اإىل زيادة معدالت املر�ص و الوفيات. هدفت هذه الدرا�سة اإىل اإي�ساح اأثر االأن�سطة التعليمية للممر�سات على حف�ص معدل اأخطاء ما قبل التحليل مما يوؤدي اإىل احل�سول على عينات دم غري مطابقة للموا�سفات. الطريقة: هذه الدرا�سة مت اجراءها بني يناير 2008 و دي�سمرب 2015. كل العينات التي مت ا�ستالمها يف خمترب اأمرا�ص رجعي باأثر 2007 عام من لعينات بيانات جتميع مت فاإن كذلك وقتيا حتليلها و جتميعها مت قابو�ص ال�سلطان جامعة مب�ست�سفى الدم وا�ستخدمت كاأ�سا�ص للمقارنة. مت تعريف العينات الغري املطابقة لت�سمل عينات متخرثة اأو عينة بها دم متك�رص اأو حفظت يف مادة تخرث خاطئ اأو جتميع كمية غري كافية من الدم اأو اأنه ال يوجد عليها مل�سق تعريفي اأو وجود مل�سق تعريفي خاطئ اأو اأنه ال يوجد عينة مع وجود طلب للعينة يف النظام. بداأ من 2008 مت تنفيذ دورات تدريبية و تعليمية منتظمة ب�سكل دوري موجهة ب�سكل اأ�سا�سي اإىل املمر�سات يف امل�ست�سفى و طلبة التمري�ص الذين تقع عليهم م�سوؤولية جتميع عينات الدم. النتائج: بعد بداأ االجراءات الت�سحيحية يف عام 2008، لوحظ العينات عدد يف 127.84% زيادة وجود من بالرغم ف�ساعداً. 2009 عام من للموا�سفات مطابقة الغري العينات عدد يف كبري انخفا�ص التي مت ا�ستالمها اإال اأنه هناك انخفا�ص ملحوظ يف عدد العينات الغري مطابقة للموا�سفات من %0.29 يف عام 2007 اإىل %0.07 يف عام 2015 مما اأدى اإىل %75.86 حت�سن )p >0.050(. وكان التح�سن اأكرث و�سوحا يف جمال اخلطاأ يف التعرف على العينة حيث انخف�ص مبقدار %0.056 مما يعني حت�سن ن�سبته %96.55. اخلال�صة: كان للتدريب التعليمي املوجه اإىل طاقم التمري�ص بامل�ست�سفى اأثر اإيجابي يف جودة العينات املخربية و احلد ب�سكل كبري من االأخطاء التي ت�سبق التحليل املختربي. الكلمات املفتاحية: �سمان اجلودة ال�سحية؛ اجلودة الرقابية؛ معاجلة العينة؛ جمع عينات الدم؛ اأمرا�ص الدم؛ عمان. impact of educational activities in reducing pre-analytical laboratory errors a quality initiative hamed al-ghaithi,1 anil pathare,1 sahimah al-mamari,1 rodrigo villacrucis,1 naglaa fawaz,2 *salam alkindi2 clinical & basic research sultan qaboos university med j, aug 2017, vol. 17, iss. 3, pp. e309–313, epub. 10 oct 17 submitted 9 jan 17 revisions req. 2 mar & 20 apr 17; revisions recd. 28 mar & 24 apr 17 accepted 11 may 17 advances in knowledge this study demonstrates the impact of sustained targeted nursing educational activities in reducing non-conforming blood samples, a common cause of pre-analytical laboratory errors. application to patient care improving the quality of laboratory results is essential for optimal and efficient patient care. the findings of this study indicate that implementing appropriate training and nursing educational activities can have a major impact on reducing pre-analytical errors. doi: 10.18295/squmj.2017.17.03.008 impact of educational activities in reducing pre-analytical laboratory errors a quality initiative e310 | squ medical journal, august 2017, volume 17, issue 3 laboratory testing constitutes a cornerstone in the effective delivery of healthcare as diagnostic investigations have a major impact on ensuring correct diagnoses and determining appropriate therapy. however, the integrity and quality of the sample is fundamental to the testing process. errors involving laboratory testing are varied and can occur at the pre-analytical, analytical or post-analytical phases. pre-analytically, the proper procurement of an appropriate blood sample and its secure transportation to the laboratory prior to analysis is essential to achieve reliable results; however, this phase is thought to be the most vulnerable part of the testing process and presents the greatest challenge to laboratory professionals.1 up to 70% of laboratory diagnostic errors are due to non-conforming samples, defined as specimens which result from inappropriate or improper sample collection, patient preparation or specimen acquisition, handling, transport and/or storage.2,3 in particular, improperly identified specimens can have serious and potentially life-threatening consequences, including unnecessary tests and treatments, critical transfusion reactions, increased hospital stays and delays in diagnosis or the initiation of therapy.4,5 care and quality standards are necessary to avoid pre-analytical errors. recently, the european federation of clinical chemistry and laboratory medicine highlighted the importance of such measures by initiating a special working group to provide official guidelines and recommendations regarding preanalytical activities and enable continuous education for laboratory professionals and other healthcare operators.6 it is the responsibility of each laboratory provider to assess the impact of such errors and institute corrective measures as part of their quality improvement procedures in order to ensure credible diagnostic results. these corrective measures should be aimed at eliminating common causes of nonconforming samples to prevent their occurrence and include advances in information technology, appropriate and timely quality control measures and continuous education for healthcare personnel.6,7 educating nursing staff on blood sample handling and processing procedures has been recognised as a vitally important step in reducing pre-analytical errors.7 at the sultan qaboos university hospital (squh), a tertiary care centre and one of the main referral hospitals in muscat, oman, blood samples are collected almost exclusively by nurses. specialist nurse phlebotomists are currently appointed only in the outpatient department, inpatient wards and day care facilities. under current hospital policy, nurses are in charge of both general and critical blood collection and although physicians or other healthcare providers may collect blood samples in emergency situations, this is rare. the current study therefore aimed to evaluate the impact of nursing educational activities implemented as part of a quality initiative on the incidence of non-conforming samples received at the squh haematology laboratory over a nine-year period. methods this study was conducted between january 2008 to december 2015. all general haematology test specimens received at the haematology laboratory at squh from january 2008 to december 2015 were prospectively collected and analysed to determine the incidence of pre-analytic errors in the form of non-conforming samples. data between january and december 2007 were collected retrospectively and constituted the baseline for comparative purposes. specimens included in the study comprised those obtained from both inpatient and outpatient clinics and all departments of the hospital as well as both adult and paediatric samples. all laboratory results were automatically generated by the trakcare healthcare information system (intersystems corp., cambridge, massachusetts, usa), an automated electronic patient record system used at squh since 2006. non-conforming samples were defined as either clotted samples, haemolysed samples, use of the wrong anticoagulant, insufficient quantities of blood collected, incorrect/lack of labelling on a sample or lack of delivery of a sample in spite of a sample request. based on the initial audit of data collected retrospectively for 2007, nursing training activities were instituted in 2008 as part of a hospital-wide quality improvement initiative. these activities were conducted every three months in 2008 for groups of 12–15 nurses and 20–25 student nurses at squh. thereafter, the activities were conducted annually for the purposes of reinforcement. the initiative was comprehensive and involved numerous forms of information delivery. first, a general lecture was given to all nursing staff and students to present the findings of the initial audit. second, details of the proper methods for sample collection and handling were provided, initially among small groups of nurses in each ward/section of the hospital and subsequently as part of a hospital-wide lecture to all relevant personnel, including senior nurses. third, leaflets were distributed during hospital exhibits like the quality open day depicting common pre-analytical laboratory errors associated with the receipt of nonhamed al-ghaithi, anil pathare, sahimah al-mamari, rodrigo villacrucis, naglaa fawaz and salam alkindi clinical and basic research | e311 conforming samples and how they were to be avoided. fourth, nurses were invited to visit the haematology laboratory for a hands-on demonstration of various non-conforming sample errors. during their visit, the nurses were also educated regarding the choice of collection tubes for different tests; the order in which samples were to be collected; the appropriate ratio of blood to anticoagulant in samples; and the proper labelling, transportation and storage of samples. finally, the induction programme for new nurse recruits was modified to include a lecture on proper blood collection and sample handling. these educational training activities were prospectively evaluated during an annual audit to assess their impact and to implement corrective measures. every year, the nursing staff and hospital administration were appraised of the results of the previous year at the quality open day, showcasing trends in various subcategories of non-conforming samples. the educational activities did not target the same nurses each time but were instead aimed to cover as much of the nursing staff as possible. as midwives were considered part of the general pool of nursing staff at squh and had received similar educational training, they were also included in the target audience. attendance at any of the lectures or activities was not obligatory as squh is a large hospital and the nursing staff is widely distributed; it was therefore impossible for all nursing staff to attend at once, even if they chose to do so. thus, only those who could spare the time attended each training session or lecture. however, those who missed a particular activity were free to attend subsequent training sessions, as they were held at regular intervals. data were expressed as the total number of samples received along with the number of nonconforming samples for every year between 2007 and 2015 and their relative percentages. data obtained in 2007 were used as the reference baseline for comparison with data obtained between 2008–2015. percentages of improvement were calculated successively, utilising the 2007 values as a baseline. thus, any improvement was relative to 2007 and thereafter calculated on a yearly basis. reductions in the actual number of nonconforming samples and the relative percentages were tabulated. significant differences were calculated via the wilcoxon signed-rank test using the statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa). a p value of <0.050 was considered statistically significant. this study received ethical approval from the hospital administration at squh as part of their quality management corrective action plan to conform with remedial action as necessitated by the certification standards of the international organization for standardization and accreditation canada international. the methods and findings of this study were continuously assessed on a yearly basis to monitor the effectiveness of the interventions involved in the quality initiative. results a total of 63,800, 81,024, 93,768, 102,400, 114,588, 116,820, 122,316, 131,064 and 145,365 samples were received at the squh haematology laboratory each year between 2008 and 2015, respectively. during these years, there were 184, 234, 233, 215, 262, 133, 103, 98 and 102 non-conforming samples, respectively, accounting for 0.29%, 0.29%, 0.25%, 0.21%, 0.23%, 0.11%, 0.08%, 0.07% and 0.07% of all samples for each year [table 1]. there was an absolute reduction of 0.22% in non-conforming samples from 0.29% at baseline to 0.07%, with an overall 75.86% improvement (p <0.050). the incorrect labelling of a sample (i.e. blood taken from the wrong patient or the incorrect labelling or categorisation of a sample) was the most critical error noted [table 2]; there was an overall reduction of 0.056% in this type of error, yielding a 96.55% improvement. table 1: distribution of total and non-conforming blood samples received at the haematology laboratory of the sultan qaboos university hospital, muscat, oman, from 2007–2015 year 2007* 2008 2009 2010 2011 2012 2013 2014 2015 number of samples 63,800 81,024 93,768 102,400 114,588 116,820 122,316 131,064 145,365 percentage change per year 27.00 15.73 9.20 11.90 1.95 4.70 7.15 10.91 number of non-conforming samples 184 234 233 215 262 133 103 98 102 percentage of all samples 0.29 0.29 0.25 0.21 0.23 0.11 0.08 0.07 0.07 p value† 0.586 0.258 0.406 <0.001 <0.001 <0.001 <0.001 *data for this year was collected retrospectively to form the baseline for comparative purposes. †calculated using the wilcoxon signed-rank test. impact of educational activities in reducing pre-analytical laboratory errors a quality initiative e312 | squ medical journal, august 2017, volume 17, issue 3 discussion pre-analytical errors constitute one of the most important elements in the laboratory testing process and greatly impact the quality of laboratory results delivered. in general, major health centres with rapid staff turnover face significant risks when it comes to maintaining high standards in relation to blood sample collection and processing. as experienced staff leave the institution, new or inexperienced staff may require additional training to maintain quality initiative objectives. in addition, hospitals with nursing staff who come from different educational and training backgrounds may require continuous monitoring and reinforcement to ensure that best practice guidelines are followed. in consideration of these factors, hospital administrators should seek to institute and maintain quality initiatives to reduce non-conformity in blood testing. in the current study, the main types of nonconforming errors identified at squh—such as incorrectly selected anticoagulants or collection tubes, mislabeled samples and clotted samples—were similar to those observed at other institutions.5,8,9 the educational activities introduced as part of the quality initiative aimed to resolve these errors primarily by reinforcing best practices in sample collection and processing. such analytical quality control initiatives focus on quality goals and specify high-quality operational procedures and the assessments needed to meet the quality objectives. such measures not only reduce the occurrence of pre-analytical errors, but may also improve patient satisfaction due to rapid test turnaround times and reduced costs as they alleviate the need for repeated blood testing, unnecessary investigations or prolonged hospital stays. in the current study, use of the trakcare information system (intersystems corp.) may have encouraged compliance with sample collection standards, as the system specifies the exact type of tube required for each test as well as the exact amount of blood required prior to sample collection. however, the educational activities were helpful in reinforcing proper sample collection approaches, as well as labelling and transportation protocols, hence reducing the frequency of nonconforming samples. in the present study, the implementation of hospital-wide nursing educational activities resulted in a progressive reduction in pre-analytical laboratory errors, particularly those that were a direct result of staff collection procedures, such as incorrectly labeled samples, the use of the wrong anticoagulants/tubes and samples submitted without labelling. previous research has also identified such pre-analytical errors to be the most frequent.4,8,10 the actual number and percentage of non-conforming samples in the current study progressively reduced over the subsequent eight-year period following the introduction of the quality initiative in 2008. although the number of nonconforming samples had improved by 2009, it was not until 2012 that this improvement reached statistical significance. nevertheless, there were marginal increases in certain years for certain errors, including clotted samples and insufficient quantities of blood in a sample. maintenance of the blood/additive ratio is extremely important and insufficient blood quantities can contribute to wastage and errors, necessitating repeat sampling and at times resulting in unnecessary delays in instituting therapy.6 the appointment of specialist nurse phlebotomists at squh would not only help in reducing preanalytical laboratory errors, but would also reduce the current burden on nursing staff working in special areas like intensive care units, day care facilities and delivery wards, as well as encourage job creation within the healthcare system in oman. one limitation of the current study was that no proper objective method was used to quantatively assess non-conforming samples. to address this shortcoming, implementation of the sigma methodology as a statistical tool to validate quality is highly recommended in future research.11 conclusion non-conforming samples are a critical obstacle to valid laboratory results, wasting both time and resources and impeding patient care. in the current study, the implementation of targeted educational activities primarily directed at nurses resulted in a significant reduction in the incidence of pre-analytical errors at a haematology laboratory. these findings highlight the table 2: distribution of incorrectly labelled blood samples received at the haematology laboratory of the sultan qaboos university hospital, muscat, oman, from 2007–2015 year 2007* 2008 2009 2010 2011 2012 2013 2014 2015 number of incorrectly labeled samples 37 20 13 7 4 5 4 2 3 percentage of all samples 0.058 0.025 0.014 0.007 0.003 0.004 0.003 0.002 0.002 *data for this year was collected retrospectively to form the baseline for comparative purposes. hamed al-ghaithi, anil pathare, sahimah al-mamari, rodrigo villacrucis, naglaa fawaz and salam alkindi clinical and basic research | e313 need for continuing education and the reinforcement of best practice guidelines for sample collection and processing. a c k n o w l e d g e m e n t s a poster of the preliminary version of this study was displayed at the excellence in laboratory quality management conference from 11–12 february 2014 in riyadh, saudi arabia. an abstract of the poster was published in the international journal of laboratory hematology in 2014 (vol. 3, iss. s1, pp. 30–131). c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. simundic am, lippi g. pre-analytical phase: a continuous challenge for laboratory professionals. biochem med (zagreb) 2012; 22:145–9. doi: 10.11613/bm.2012.017. 2. lippi g, becan-mcbride k, behúlová d, bowen ra, church s, delanghe j, et al. pre-analytical quality improvement: in quality we trust. clin chem lab med 2013; 51:229–41. doi: 10.1515/ cclm-2012-0597. 3. lippi g, banfi g, maffulli n, pre-analytical variability: the dark side of the moon in blood doping screening. eur j appl physiol 2010; 109:1003–5. doi: 10.1007/s00421-010-1437-3. 4. green sf. the cost of poor blood specimen quality and errors in pre-analytical processes. clin biochem 2013; 46:1175–9. doi: 10.1016/j.clinbiochem.2013.06.001. 5. jones ba, meier f, howanitz pj. complete blood count specimen acceptability: a college of american pathologists q-probes study of 703 laboratories. arch pathol lab med 1995; 119:203–8. 6. lippi g, baird gs, banfi g, bölenius k, cadamuro j, church s, et al. improving quality in the preanalytical phase through innovation, on behalf of the european federation for clinical chemistry and laboratory medicine (eflm) working group for preanalytical phase (wg-pre). clin chem lab med 2017; 55:489–500. doi: 10.1515/cclm-2017-0107. 7. lillo r, salinas m, lopez-garrigos m, naranjo-santana y, gutiérrez m, marín md, et al. reducing preanalytical laboratory sample errors through educational and technological interventions. clin lab 2012; 58:911–17. doi: 10.7754/clin. lab.2012.111111. 8. howanitz pj. errors in laboratory medicine: practical lessons to improve patient safety. arch pathol lab med 2005; 129:1252–61. doi: 10.1043/1543-2165(2005)129[1252:eilmpl]2.0.co;2. 9. kemp gm, bird ce, barth jh. short-term interventions on wards fail to reduce pre-analytical errors: results of two prospective controlled trials. ann clin biochem 2012; 49:166–9. doi: 10.1258/acb.2011.011133. 10. glendenning p, musk aa, taranto m, vasikaran sd. preanalytical factors in the measurement of intact parathyroid hormone with the dpc immulite assay. clin chem 2002; 48:566–7. 11. giménez-marín a, rivas-ruiz f, pérez-hidalgo mdel m, molina-mendoza p. pre-analytical errors management in the clinical laboratory: a five-year study. biochem med (zagreb) 2014; 24:248–57. doi: 10.11613/bm.2014.027. https://doi.org/10.11613/bm.2012.017 https://doi.org/10.1515/cclm-2012-0597 https://doi.org/10.1515/cclm-2012-0597 https://doi.org/10.1007/s00421-010-1437-3 https://doi.org/10.1016/j.clinbiochem.2013.06.001 https://doi.org/10.1515/cclm-2017-0107 https://doi.org/10.7754/clin.lab.2012.111111 https://doi.org/10.7754/clin.lab.2012.111111 https://doi.org/10.1258/acb.2011.011133 https://doi.org/10.11613/bm.2014.027 department of obstetrics & gynecology, faculty of medicine, assiut university, assiut, egypt e-mail: atef_darwish@yahoo.com تقنية جديدة لرتميم غشاء البكارة احللقي حلاالت غشاء البكارة الرتقاء بعد البلوغ عاطف حممد دروي�ش abstract: objectives: imperforate hymen (ih) is a common genital tract anomaly in women which usually presents after puberty. however, surgical treatment is often considered controversial in religious or conservative communities for sociocultural reasons. this study therefore aimed to assess the efficacy of a novel reconstructive technique involving the preservation of the annular hymen. methods: this prospective interventional study was performed between july 2013 and october 2019 at the minimally invasive surgery unit of a tertiary university hospital in egypt. a total of 36 women presenting with primary amenorrhoea and haematocolpus were diagnosed with postpubertal ih. a circular hymenotomy was performed on each patient using a 10 mm laparoscopy trocar tip and sleeve to form a new annular hymen under general anaesthesia while preserving the annular hymen. the primary outcome measure was the persistence of hymenal patency and integrity at follow-up. the secondary outcome measure included post-operative patient satisfaction and pain relief. results: the reported technique was feasible in all cases without intraoperative complications. patency of the reconstructed annular hymen was confirmed at follow-up in all cases; moreover, no intraoperative complications were reported. there was a significant post-operative improvement in pain scores (p <0.001). both the patients and their parents/guardians reported a high level of satisfaction with the technique. conclusion: this novel technique for the correction of ih involving the reconstruction of an annular hymen was found to be a safe, minimally invasive and effective procedure. this technique should be considered a feasible alternative to a conventional hymenotomy as it allows for the resumption of normal hymenal anatomy without overtreatment. keywords: congenital abnormalities; imperforate hymen; hematocolpos; amenorrhea; colpotomy; reconstructive surgical procedures; treatment outcome; egypt. ومع البلوغ. �سن بعد عادة تظهر و الن�ساء عند التنا�سلي اجلهاز يف �سائعة �ساذة حالة )ih( الرتقاء البكارة غ�ساء الهدف: امللخ�ص: ذلك، غالًبا ما ُيعترب العالج اجلراحي لها مثرياً للجدل يف املجتمعات الدينية اأو املحافظة لأ�سباب اجتماعية وثقافية. لذلك هدفت هذه التداخلية الدرا�سة هذه اإجراء مت احللقي. الطريقة: البكارة غ�ساء على احلفاظ تت�سمن جديدة ترميمية تقنية فاعلية تقييم اإىل الدرا�سة م�سابة امراأة 36 ت�سخي�ش مت م�رص. يف جامعي متخصص م�ست�سفى يف اجلراحة وحدة يف 2019 واأكتوبر 2013 يوليو بني امل�ستقبلية با�ستخدام مري�سة لكل للبكارة دائري �سق اإجراء مت البلوغ. بعد الرتقاء البكارة لغ�ساء املرافق املهبل وتدمي الأويل الطمث بانقطاع طرف مبزل تنظري كمي بطول 10 مم لت�سكيل غ�ساء بكارة حلقي جديد حتت التخدير العام مع احلفاظ على غ�ساء البكارة احللقي. كانت اجلراحة بعد املري�سة ر�سى ت�سمنت الثانوية النتيجة الطبية. املتابعة عند و�سالمتها البكارة غ�ساء �سالكية ا�ستمرار الأولية النتيجة وزوال الآلم. النتائج: اإن التقنية املذكورة كانت جمدية يف جميع احلالت ومل ت�سجل اأي م�ساعفات اأثناء اجلراحة. مت تاأكيد �سالكية غ�ساء البكارة احللقي املعاد ترميمه عند املتابعة يف جميع احلالت؛ عالوة على ذلك، مل يتم الإبالغ عن اأي م�ساعفات اأثناء العملية. كان هناك حت�سن كبري بعد اجلراحة يف درجات الأمل )p >0.001(. اأعربت كل املري�سات واأولياء اأمورهن عن م�ستوى عاٍل من الر�سا البكارة غ�ساء بناء اإعادة على تنطوي والتي الرتقاء البكارة غ�ساء لت�سحيح اجلديدة التقنية هذه اأظهرت اخلال�صة: التقنية. هذه عن احللقي على اأنها اإجراء اآمن وفعال باأقل قدر من التدخل اجلراحي. لذلك من املمكن اعتبار هذه التقنية بدياًل ممكًنا ل�سق غ�ساء البكارة التقليدي لأنها ت�سمح با�ستئناف ت�رصيح غ�ساء البكارة الطبيعي دون عالج مفرط. الكلمات املفتاحية: الت�سوهات اخللقية؛ غ�ساء بكارة رتقاء؛ تدمي املهبل؛ انقطاع الطمث؛ �سق املهبل؛ طرق اجلراحة الرتميمية؛ نتائج العالج ؛ م�رص. a novel technique for the reconstructive formation of an annular hymen in cases of postpubertal imperforate hymen atef m. darwish sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e110–115, epub. 15 mar 21 submitted 12 feb 20 revisions req. 16 apr & 9 jun 20; revisions recd. 28 may & 16 jun 20 accepted 1 jul 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.015 clinical & basic research advances in knowledge this study confirms the safety and efficacy of a novel, simple and minimally invasive technique for the correction of cases of imperforate hymen (ih) involving reconstructive preservation of the annular hymen. the new technique was found to be successful both from a subjective standpoint in terms of patient satisfaction as well as objectively in terms of symptom relief and annular hymenal patency. application to patient care based on these findings, this novel technique is recommended as a safe and effective alternative to a classic hymentomy for cases of ih in which the preservation and restoration of the normal hymenal anatomy is a priority. https://creativecommons.org/licenses/by-nd/4.0/ atef m. darwish clinical and basic research | e111 imperforate hymen (ih) is a common genital tract anomaly reported in approximately one in 2,000 women.1 generally, the obstructive condition presents at menarche when retained menstrual blood and mucosal tissue begins to accumulate in the vagina, resulting in haematocolpos and amenorrhoea, often accompanied by symptoms of abdominal, pelvic and lower back pain, urinary retention, constipation/ tenesmus and uterine distension.2,3 a diagnosis of ih is usually confirmed via clinical examination of the distended hymenal membrane and ultrasonography showing the haematocolpos.3 conventional manage ment of the condition involves the surgical drainage of the retained blood via a hymenotomy in which a vertical, cross or t-shaped incision is made in the hymenal membrane, followed by suturing of the edges to maintain patency and prevent restenosis.3,4 however, this traditional surgical approach is often poorly accepted by individuals from religious and conservative communities, resulting in emotional, psychological and even physical deleterious effects due to social stigma and feelings of shame attached to the loss of the hymen and perceived virginity.5–8 moreover, in certain islamic countries, an official medical certificate is routinely given to the patient to certify that the hymenal defloration occurred as a result of a surgical procedure prior to marriage.8,9 in jordan, for instance, a forensic consultant is required to attend and produce official forensic reports for all gynaecological procedures performed on unmarried muslim women in order to reassure patients and their parents/guardians of continuing hymenal patency and to protect the rights of both the gynaecologist and patient in case of unavoidable rupture.9 anecdotally, many women diagnosed with ih along with their parents/guardians express deep concern for the integrity of the hymen and request that the normal hymenal anatomy be preserved as much as possible. accordingly, this study aimed to describe and evaluate the safety and efficacy of a novel surgical technique for the correction of postpubertal ih involving the reconstructive formation of a normal annular hymen. methods this prospective interventional study was conducted between july 2013 and october 2019 at the minimally invasive surgery unit of the woman’s health university hospital, assiut, egypt. a total of 43 women with primary amenorrhoea and haematocolpus were evaluated. at presentation, the patients complained of various symptoms including a progressive central abdominal mass, worsening pelvic pain, urinary retention, dysuria, constipation and dyschezia, either alone or in combination depending on the degree of retained menses. only patients with postpubertal ih without other associated congenital anomalies were included in the study. women with other forms of menstrual irregularities or types of genital tract anomalies were excluded, as were prepubertal cases of ih due to concerns regarding safety.10 all patients underwent a clinical examination to confirm the diagnosis of ih. initially, a downward labial traction technique was used to separate the labia majora and minora in order to visualise the distal introitus. while in a lithotomy position, a graduated uterine sound instrument was inserted into the vaginal dimple. in four patients, the sound was able to move upwards, thereby indicating a diagnosis of low transverse vaginal septum rather than ih, in which the sound would fail to move upwards. transverse vaginal septum was differentiated from ih as the former first requires an operation to fix the edges of the septum to the introitus.10,11 in the absence of this prior procedure, a hymenotomy would fail and restenosis would occur due to the thickness of the septum compared to the hymen.11 as such, these four cases were excluded from the study. subsequently, the hymen was examined for signs of distension and characteristic bluish discolouration while the patient performed the valsalva respiratory manoeuvre. two cases of distal vaginal atresia were excluded at this point due to the absence of these signs, as well as the distance between the haematocolpos and the vulva.10 in cases where the abdominal mass was deviated to one side, magnetic resonance imaging (mri) was performed to discount the possibility of type i obstructed hemivagina and ipsilateral renal agenesis (ohvira). only one case of type i ohvira (i.e. a blind hemivaginal septum without an opening), presented with primary amenorrhoea due to a rudimentary contralateral horn, was detected and excluded from the study. the diagnosis of ih was confirmed in the remaining 36 patients based on the characteristic appearance of the dark or bluishcoloured protruding hymenal tissue [figure 1a] and an ultrasound scan confirming haematocolpos. further mri scans to assess the vaginal and perineal region were required only in selected cases in which the diagnosis was ambiguous. all patients underwent a modified hymenotomy technique with preservation of the annular hymen. to begin with, the patient was placed in the lithotomy position on the operating table. following the induction of general anaesthesia, the perineum was sterilised and towelled dry. an indwelling urethral catheter was inserted and per-rectal examination a novel technique for the reconstructive formation of an annular hymen in cases of postpubertal imperforate hymen e112 | squ medical journal, february 2021, volume 21, issue 1 was performed to rule out any other anomalies or abnormalities. subsequently, the sharp triangular tip of a 10 mm laparoscopy trocar (karl storz se & co. kg, tuttlingen, germany) was inserted into the centremost protruding section of the hymenal membrane [figure 1b]. once the edge of the sleeve had followed the tip into the hymenal membrane, the tip was not advanced any further to avoid unintentional injury. the trocar was then withdrawn, leaving the sleeve in situ to allow drainage of the retained menses [figure 1c]. no suprapubic pressure was applied to avoid ascending infection from the negative pressure. after the flow of retained menstrual blood and tissue had stopped naturally, the sleeve was removed. in most cases, no further intervention was needed; however, gentle bipolar coagulation was applied if there was continuing discharge. thereafter, the remaining hymenal ring was evaluated to determine whether it was still intact and circular. after the surgery, the patient remained in the post-operative ward to recover for a few hours before being discharged. each patient was advised to return to the hospital for follow-up either after their next menstrual cycle or in 40 days if no menstrual bleeding occurred in the interim. at follow-up, a clinical examination was conducted to ensure the patency and integrity of the hymen [figure 1d]; in addition, ultrasonography was performed to ensure the absence of haematocolpos and to assess the kidneys. subsequent follow-up visits were optional and recommended to patients only if they noticed any changes in menstrual flow. telephone consultations were conducted to collect follow-up data including both objective observations of hymenal ring integrity and subjective reports of patient satisfaction and symptom relief. self-reported preand post-operative pain was assessed using a visual analogue scale (vas) in which patients drew a mark on a 10 cm line representing a continuum between no pain (scored as zero) and the worst pain imaginable (scored as 10). the primary outcome measure was the persistence of hymenal patency and integrity at follow-up. the secondary outcome measure included post-operative patient satisfaction and pain relief. data analysis was conducted using the statistical package for the social sciences, version 19 (ibm corp., armonk, new york, usa). results were presented as frequencies and percentages. either a chi-squared test or fisher’s exact test was used to compare qualitative variables. a p value of ≤0.050 was considered statistically significant. due to the rarity of ih cases, preoperative and post-operative results were compared for the same patient in each case. this study was approved by the local ethical committee of the faculty of medicine at assiut university (#2156521). informed consent was received from all patients or their legal guardians following a detailed explanation of the study and surgical procedure. results this study comprised 36 cases with ih. the mean age of the patients was 13.3 ± 1.9 years. primary amenorrhoea and suprapubic pain were the main presenting complaints in all patients. loin pain and low grade fever were encountered in 15 (41.6%) and 19 (52.6%) cases, respectively. a total of 25 women (69.4%) figure 2:photographs showing the surgical steps involved in a novel reconstructive technique for cases of postpubertal imperforate hymen involving the preservation of the annular hymen including the (a) characteristic preoperative appearance of the imperforate hymen, (b) perforation of the hymenal membrane using a 10 mm laparoscopy trocar tip, (c) subsequent release of the retained menses and (d) post-operative integrity and patency of the intact annular hymenal ring without restenosis. atef m. darwish clinical and basic research | e113 reported being in agonising pain which disturbed their daily activities and was exacerbated on a monthly basis. haematocolpos was detected in all cases (100%) upon clinical and ultrasound examination. no intra operative complications were reported during the current reported technique. post-operatively, the patency of the reconstructed hymen was confirmed in all cases (100%), with a clinical examination revealing an intact annular hymenal ring without restenosis. recurrence of the haematocolpos was excluded in all cases by high-resolution trans abdominal ultrasonography at both the first followup and any subsequent visits. subjectively, all patients reported a high level of satisfaction with the procedure and the relief of former ih symptoms. there was a significant post-operative improvement in pain vas score (p <0.001). the possibility of restenosis over a longer period of time was excluded by patient reports during telephone consultations of the resumption of normal menstrual flow. discussion although an intact hymen does not necessarily correspond to virginity from a biological perspective, it is often considered indicative of abstinence from premarital sex in many cultures and thus remains intrinsically tied with concepts of familial pride and honour.9,12 indeed, in some countries, unmarried or newly married women without intact hymens can face severe social consequences ranging from humiliation to ostracism, divorce and even extreme violence or abuse, for instance as a result of corporal punishment (i.e. stoning or lashes), execution or honour killings.6,7 as a result, in many islamic and other conservative communities, conventional hymenectomy procedures are often considered unacceptable due to the inherent surgical risk of hymenal rupture.5–9 while it is often challenging for individuals from other cultures to fully understand or accept the importance placed on hymenal integrity in these communities, it remains a critical sociocultural and psychological issue, particularly for young adolescent girls with medical conditions or genital abnormalities such as ih. it is therefore essential that medical practitioners endeavour to respect these cultural beliefs and take measures to ensure the integrity of the hymen as much as feasibly possible.9 to this end, the american college of obstetricians and gynecologists recently stated that elective vulvar cosmetic surgery should be offered to women to alleviate anxiety, depression and other psychiatric conditions resulting from hymenal rupture.13 from a medical standpoint, postpubertal ih can result in serious complications if left untreated, such as secondary endometriosis, hydronephrosis, haematosalpinx rupture, renal failure, lymphovenous obstruction and infection.3,14 the primary goal of ih management is to achieve hymenal patency, an objective usually accomplished via conventional hymenotomy.3,4 however, the subsequent loss of hymenal integrity can be avoided with concomitant reconstructive surgery to restore the normal anatomy of the hymen. moreover, there is no need to provide the patient with a medical report to certify hymenal defloration as the post-operative annular hymen mimics the normal hymen in terms of both appearance and function. various approaches to surgical ih management have been described in the literature. in most cases, the correction of clinically significant hymenal variations involves the excision of the hymenal tissue and the redundant mucosa.10 however, the simple incision and drainage of haematocolpos in a patient with ih should be avoided due to the risk of ascending infection and sepsis.15 other researchers have recommended surgical resection be performed for thicker hymenal membranes, whereas a vertical incision can be applied to thinner membranes.10 in addition, fixing the vaginal wall to the introitus can help to avoid restenosis and the development of post-operative complications.10,14 in a recent literature review, lee et al. reported that most ih patients were treated surgically (83.5%), most often via hymenotomy (35.2%) or hymenectomy (36.4%), without significant differences in outcome.16 however, previous research has indicated the possibility of ih restenosis following a hymenectomy.17 alternative methods of treating ih without affecting hymenal integrity have also been proposed. for example, some researchers have described a technique in which the hymenal membrane can be opened via a 0.5 cm central oval incision using a scalpel, followed by the insertion of an inflated 16f foley catheter left in place for two weeks to prevent re-adhesion of the edges.18,19 however, maintaining a catheter in a cavity filled with retained menses for long periods of time is very risky and can potentially result in pelvic inflammatory disease.10,20 moreover, the use of a scalpel to create an incision can result in an opening with irregular edges due to fine tremors in the hands of the surgeon, which can be influenced by different factors such as anxiety, stress or urgency.21 in contrast, the current reported technique was found to result in the formation of an even and wide hymenal opening, while still preserving the annular hymen. furthermore, a reusable laparoscopy trocar is a dual-function medical instrument readily available a novel technique for the reconstructive formation of an annular hymen in cases of postpubertal imperforate hymen e114 | squ medical journal, february 2021, volume 21, issue 1 in most gynaecological operating rooms of tertiary hospitals without the need for additional expenses or healthcare resources. although it can be claimed that scalpels are more readily accessible, it should be noted that the diagnosis and treatment of ih cases should take place exclusively at specialised tertiary centres due to the risk of misdiagnosis with other lower genital congenital anomalies, such as low transverse vaginal septum, agenesis of the lower third of the vagina and ohvira.10 an accurate diagnosis is crucial as inappropriate interventions may result in serious complications as well as incomplete treatment. for this reason, only postpubertal patients were included in the current study. the onset of estrogenisation at puberty allows for a clearer examination of the perineal anatomy as well as recognition of characteristic symptoms, thus reducing the likelihood of misdiagnosis. moreover, the hymen can be more easily stretched due to the estrogenisation of the vaginal tissue without the risk of spontaneous rupture.15 as such, a hymenectomy is sometimes recom mended to ensure persistent patency. histologically, the bulk of the hymen is formed of a connective tissue formed of partly elastic and partly collagenous fibres.22 both surfaces are covered by a stratified squamous epithelium which lacks any evidence of cornification or glandular or muscle elements and without nerve cells and fibres at the free edge. as such, the hymen is easily perforated upon penetration and usually retracts laterally due to the absence of muscle elements. these facts support the use of a laparoscopy trocar tip in the current study, with immediate retraction of the fibrous membrane observed following withdrawal of the laparoscopic sleeve. in addition, no cases of restenosis were identified in any of the patients at either the first or subsequent follow-up visits. certain limitations to the present study should be acknowledged, including the lack of a comparison group and the relatively small sample size. both of these limitations are due to the rarity of ih cases. in addition, the study was restricted to postpubertal cases for reasons of safety and to ensure the accuracy of the diagnosis. finally, objective preoperative assess ment of the psychological status of the patients was difficult in many cases due to their young age, high levels of pain and the atmosphere of stress, fear and anxiety surrounding the concept of hymenal integrity. however, while any research involving a novel procedure for patients with rare conditions will be subject to methodological limitations, the data from the present study may nevertheless be helpful in generating a hypothesis that can be tested in further analytic studies.23 conclusion the current study described a novel, minimally invasive approach for the surgical correction of postpubertal ih involving the formation of a new orifice using a laparoscopy trocar and the reconstruction and preservation of an annular hymen. this technique was found to be both safe and effective, resulting in high levels of patient and family satisfaction. as such, this approach should be considered in circumstances where resumption of the normal anatomy of the hymen is a matter of considerable sociocultural and psychological importance. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. schorge jo, schaffer ji, halvorson lm, hoffman b, bradshaw k. anatomic disorders. in: williams gynecology, 1st ed. new york, usa: mcgraw hill medical, 2008. pp. 412–13. 2. dane c, dane b, erginbas m, cetin a. imperforate hymen-a rare cause of abdominal pain: two cases and review of the literature. j pediatr adolesc gynecol 2007; 20:245–7. https://doi.org/10.10 16/j.jpag.2006.12.003. 3. mwenda as. imperforate hymen a rare cause of acute abdominal pain and tenesmus: case report and review of the literature. pan afr med j 2013; 15:28. https://doi.org/10.11604/ pamj.2013.15.28.2251. 4. rathod s, samal sk, rajsekaran a, rani pr, ghose s. imperforate hymen and its complications: report of two cases and review of literature. int j reprod contracept obstet gynecol 2014; 3:839–42. https://doi.org/10.5455/2320-1770.ijrcog20140965. 5. moaddab a, mccullough lb, chervenak fa, stark l, schulkin j, dildy ga, et al. a survey of honor-related practices among us obstetricians and gynecologists. int j gynaecol obstet 2017; 139:164–9. https://doi.org/10.1002/ijgo.12294. 6. pelin ss. the question of virginity testing in turkey. bioethics 1999; 13:256–61. https://doi.org/10.1111/1467-8519.00154. 7. cook rj, dickens bm. hymen reconstruction: ethical and legal issues. int j gynaecol obstet 2009; 107:266–9. https://doi. org/10.1016/j.ijgo.2009.07.032. 8. frank mw, bauer hm, arican n, fincanci sk, iacopino v. virginity examinations in turkey: role of forensic physicians in controlling female sexuality. jama 1999; 282:485–90. https:// doi.org/10.1001/jama.282.5.485. 9. abder-rahman ha. hymen care for unmarried muslim females: role of the forensic consultant in gynaecology interventions. east mediterr health j 2009; 15:861–7. 10. american college of obstetricians and gynecologists (acog). diagnosis and management of hymenal variants: acog comm ittee opinion number 780. obstet gynecol 2019; 133:e372–6. https://doi.org/10.1097/aog.0000000000003283. 11. williams ce, nakhal rs, hall-craggs ma, wood d, cutner a, pattison sh, et al. transverse vaginal septae: management and long-term outcomes. bjog 2014; 121:1653–8. https://doi. org/10.1111/1471-0528.12899. https://doi.org/10.1016/j.jpag.2006.12.003 https://doi.org/10.1016/j.jpag.2006.12.003 https://doi.org/10.11604/pamj.2013.15.28.2251 https://doi.org/10.11604/pamj.2013.15.28.2251 https://doi.org/10.5455/2320-1770.ijrcog20140965 https://doi.org/10.1002/ijgo.12294 https://doi.org/10.1111/1467-8519.00154 https://doi.org/10.1016/j.ijgo.2009.07.032 https://doi.org/10.1016/j.ijgo.2009.07.032 https://doi.org/10.1001/jama.282.5.485 https://doi.org/10.1001/jama.282.5.485 https://doi.org/10.1097/aog.0000000000003283 https://doi.org/10.1111/1471-0528.12899 https://doi.org/10.1111/1471-0528.12899 atef m. darwish clinical and basic research | e115 12. hegazy aa, al-rukban mo. hymen: facts and conceptions. thehealth 2012; 3:109–15. 13. american college of obstetricians and gynecologists (acog). elective female genital cosmetic surgery: acog committee opinion, number 795. obstet gynecol 2020; 135:e36–42. https://doi.org/10.1097/aog.0000000000003616. 14. nielsen v, vyrdal c. [imperforate hymen can cause abdominal pain and primary amenorrhoea]. ugeskr laeger 2013; 175:1500–1. 15. oakes mb, hussain hk, smith yr, quint eh. concomitant resorptive defects of the reproductive tract: a uterocervico vaginal septum and imperforate hymen. fertil steril 2010; 93:268.e3–5. https://doi.org/10.1016/j.fertnstert.2009.10.001. 16. lee kh, hong js, jung hj, jeong hk, moon sj, park wh, et al. imperforate hymen: a comprehensive systematic review. j clin med 2019; 8:56. https://doi.org/10.3390/jcm8010056. 17. ossman ame, el-masry yi, el-namoury mm, sarsik sm. spontaneous reformation of imperforate hymen after repeated hymenectomy. j pediatr adolesc gynecol 2016; 29:e63–5. https://doi.org/10.1016/j.jpag.2016.02.001. 18. acar a, balci o, karatayli r, capar m, colakoglu mc. the treatment of 65 women with imperforate hymen by a central incision and application of foley catheter. bjog 2007; 114:1376–9. https://doi.org/10.1111/j.1471-0528.2007.01446.x. 19. kidess ea, baaqeel hs. the imperforate hymen: a culturally oriented surgical approach. ann saudi med 1988; 8:336–9. https://doi.org/10.5144/0256-4947.1988.336. 20. wong jwh, siarezi s. the dangers of hymenotomy for imperforate hymen: a case of iatrogenic pelvic inflammatory disease with pyosalpinx. j pediatr adolesc gynecol 2019; 32:432–5. https://doi.org/10.1016/j.jpag.2019.04.002. 21. hanrahan j, sideris m, pasha t, tsitsopoulos pp, theodoulou i, nicolaides m, et al. hands train the brain-what is the role of hand tremor and anxiety in undergraduate microsurgical skills? acta neurochir (wien) 2018; 160:1673–9. https://doi. org/10.1007/s00701-018-3609-6. 22. mahran m, saleh am. the microscopic anatomy of the hymen. anat rec 1964; 149:313–18. https://doi.org/10.1002/ ar.1091490213. 23. kooistra b, dijkman b, einhorn ta, bhandari m. how to design a good case series. j bone joint surg am 2009; 91:21–6. https://doi.org/10.2106/jbjs.h.01573. https://doi.org/10.1097/aog.0000000000003616 https://doi.org/10.1016/j.fertnstert.2009.10.001 https://doi.org/10.3390/jcm8010056 https://doi.org/10.1016/j.jpag.2016.02.001 https://doi.org/10.1111/j.1471-0528.2007.01446.x https://doi.org/10.5144/0256-4947.1988.336 https://doi.org/10.1016/j.jpag.2019.04.002 https://doi.org/10.1007/s00701-018-3609-6 https://doi.org/10.1007/s00701-018-3609-6 https://doi.org/10.1002/ar.1091490213 https://doi.org/10.1002/ar.1091490213 https://doi.org/10.2106/jbjs.h.01573 college of medicine, king saud bin abdulaziz university for health sciences, jeddah, saudi arabia *corresponding author’s e-mail: halgahtani@hotmail.com تقييم فعالية واحتياجات برنامج تطوير أعضاء هيئة التدريس للتعليم الطيب جتربة من اململكة العربية السعودية ح�صني القحطاين، بدر �صريه، اأحمد �صبحي، اأحمد الدرحمي، رغد القحطاين abstract: objectives: faculty members are the most important resource in any institution of higher education as medical education has been, and continues to be, a priority for medical colleges in saudi arabia. this study aimed to assess faculty members’ perceptions of faculty development programmes (fdps) in supporting important goals in medical education. in addition, this study aimed to assess faculty members’ perceived needs. methods: this crosssectional study was conducted between august 2016 and august 2017 and involved participants from six universities in saudi arabia’s western province. the survey consisted of 31 items designed to assess fdp effectiveness and 49 items designed to assess needs in fdps. results: a total of 210 faculty members participated in the study (response rate = 52.5%) and identified 49 needs. faculty members perceived personal improvement in delivering medical education and the provision of greater educational involvement as the most effective considerations in an fdp. the respondents considered 13 needs to be of utmost importance; the remaining were considered important. conclusion: this study assessed and identified faculty needs and important skills to consider when establishing an fdp. furthermore, it provided information addressing the needs of, or gaps between, current and desired conditions in medical education in saudi arabia. the study also identified the most important elements (i.e. personal improvement) of faculty-perceived effectiveness for a successful fdp in medical education. keywords: faculty; program development; needs assessment; perception; medical education; saudi arabia. امللخ�ص: الهدف: يعد اأع�صاء هيئة التدري�س اأهم املوارد يف اأي موؤ�ص�صة للتعليم العايل والتعليم الطبي وكانوا ول زالوا من الأولويات بالن�صبة للكليات الطب يف اململكة العربية ال�صعودية. هدفت هذه الدرا�صة اإىل تقييم اإدراك اأع�صاء هيئة التدري�س لربامج تطويرهم وذلك لدعم الأهداف املهمة يف التعليم الطبي. بالإ�صافة اإىل ذلك، هدفت هذه الدرا�صة اإىل تقييم الحتياجات امُلَت�صورة لأع�صاء هيئة التدري�س. الطريقة: اأجريت هذه الدرا�صة امل�صتعر�صة بني اأغ�صط�س 2016 واأغ�صط�س 2017 و�صملت م�صاركون من �صت جامعات يف املنطقة الغربية باململكة العربية ال�صعودية. ت�صمن ال�صتبيان امل�صتخدم 31 بنداً �صممت لتقييم فعالية برنامج تطوير اأع�صاء هيئة التدري�س و 49 بندا م�صممة لتقييم الحتياجات يف برامج تطوير اأع�صاء هيئة التدري�س. النتائج: �صارك ما جمموعه 210 من اأع�صاء هيئة التدري�س يف الدرا�صة )معدل ال�صتجابة = %52.5( ومت حتديد 49 احتياجًا. يدرك اأع�صاء هيئة التدري�س اأن تطوير الذات يف تقدمي التعليم الطبي وتوفري م�صاركة تعليمية اأكرب هما من اأهم العتبارات التي يجب مراعاتها يف برنامج تطوير اأع�صاء هيئة التدري�س. راأى امُلجيبون على ال�صتبيان اأن 31 احتياجا هي متطلبات ذات اأهمية ق�صوى واعتربوا اأن بقية الأحتياجات هامة. اخلال�صة: قيمت هذه الدرا�صة وحددت احتياجات اأع�صاء هيئة التدري�س واملهارات الهامة التي يجب مراعاتها عند اإن�صاء برنامج تطوير اأع�صاء هيئة التدري�س. عالوة على ذلك قدمت هذه الدرا�صة معلومات تتناول الحتياجات اأو الفجوات بني الأو�صاع احلالية للتعليم الطبي وتلك املرجوة منه يف اململكة العربية ال�صعودية. حددت الدرا�صة اأي�صًا اأهم عنا�رش ادراك اأع�صاء هيئة التدري�س لفاعليتهم )التاثري الذاتي( والتي ت�صهم يف اجناح برنامج تطوير قدراتهم يف التعليم الطبي. الكلمات املفتاحية: اأع�صاء هيئة التدري�س؛ تطوير برنامج؛ تقييم الحتياجات؛ الإدراك؛ التعليم الطبي؛ اململكة العربية ال�صعودية. effectiveness and needs assessment of faculty development programme for medical education experience from saudi arabia *hussein algahtani, bader shirah, ahmad subahi, ahmad aldarmahi, raghad algahtani clinical & basic research sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e83–89, epub. 9 mar 20 submitted 28 may 19 revisions req. 2 jul & 2 sep 19; revisions recd. 4 aug & 4 sep 19 accepted 26 sep 19 https://doi.org/10.18295/squmj.2020.20.01.012 advances in knowledge most faculty members at medical colleges in saudi arabia lack formal training in areas essential to improving their academic performance. personal effectiveness in delivering medical education is considered the most important achievement target in a faculty development programme (fdp). while the results of this study are of local importance, a survey of all faculty members in saudi medical schools would provide information about their needs and establish a basis for fdp activities on a national level. application to patient care fdps can teach college of medicine faculty members and students how to communicate with their patients, resulting in better adherence to treatment and ultimately, improvement of symptoms. implementing an fdp may reduce medical errors and prevent adverse events during treatment. fdps may increase patient satisfaction and reduce claims of malpractice. effectiveness and needs assessment of faculty development programme for medical education experience from saudi arabia e84 | squ medical journal, february 2020, volume 20, issue 1 medic al educ ation ha s been, and continues to be, the highest priority of medical colleges in saudi arabia. this prioritisation is evident in the establishment of more than 35 medical colleges nationwide.1 every medical college has a goal, vision, mission and core values that it tries to maintain and adhere to through a carefully articulated curriculum.2 physicians who graduate from these colleges must be competent, professional and able to respond to needs within the society.3 a faculty development programme (fdp) is a planned activity that is designed to improve an indiv idual's knowledge and skills in areas considered essential to the performance of a faculty member as a teacher, researcher or administrator in order to address needs for future development.4 faculty development can lay the foundation of quality enhancement in medical education.5 faculty members are the most important resources in any institution of higher education. therefore, an fdp should act as a resource to meet faculty members’ individual goals as teachers, scholars and leaders.6 faculty members at medical schools must be talented and productive teachers, effective clinicians and successful researchers. these pressures have evolved from the competition between different medical schools and institutions, contemporary curriculum development and shortcomings in research, teaching and production.7 in addition, fdps must prepare faculty members to deal with rapidly occurring changes in medical education, healthcare delivery systems and clinical teaching and practice.8 glowacki-dudka and brown elucidated the most beneficial effects of fdps as selfevaluation through teaching scales, awareness of effective teaching methods and student evaluations.9 however, the beneficial effects of fdps were later found to be broader than what was described by glowacki-dudka and brown and other benefits were established.9 a needs assessment is defined as a systematic process of collecting and analysing information to address the gaps between current and desired conditions.10 this study is one of three parallel projects that tackled different aspects of fdps. although the same inclusion and exclusion criteria were used across all three projects, separate groups of surveyors used entirely different questionnaires for each project. this study aimed to assess faculty members’ perceptions of fdp effectiveness and identify the most important goals for the programme. additionally, this study aimed to assess the perceived needs of faculty members participating in fdps. methods this cross-sectional study involved participants from six universities in saudi arabia’s western province and was conducted from august 2016 to august 2017. the participants were faculty members who had worked as full-time or joint appointees, taught with or without clinical assignments and had participated in fdps during the previous two years. newly employed and part-time faculty members and those classified as serving in non-teaching positions were excluded. participants were selected through a consecutive sampling technique which was based on eligibility criteria. the total number of faculty members in the population under consideration was 400. the required sample size was estimated at a 95% confidence level with an estimated 40% response distribution and a margin of error of ± 5%. the required minimum sample size, calculated using raosoft® (raosoft, inc., seattle, washington, usa) was 197, and the final sample size was determined to be 210, accounting for an approximately 10% non-response rate. the questionnaire used in this study was a pre designed self-administered tool generated by previous research.11–16 this comprehensive questionnaire incl uded all possible items from related publications in the literature. the items of the questionnaire were divided into two sections that addressed two different aspects of faculty development (i.e. needs and effectiveness). the researchers personally distributed the survey to maximise the number of completed items and allow participants to ask questions. explaining the purpose of the study and its impact on enhancing fdps encouraged the faculty members to complete the questionnaires. the survey consisted of 31 items designed to assess the effectiveness of fdps and 49 items designed to assess the needs that should be addressed by fdps. the questionnaires used a five-point likert scale with ordinally scaled options. the options for the first quest ionnaire were: one, not effective; two, less effective; three, somewhat effective; four, moderately effective; and five, more effective. for the second questionnaire, the options were: one, not at all important; two, not very important; three, moderately important; four, important; and five, very important. in addition, the demographic profile of the participants was collected to identify whether any demographic and work factors correlated with perceptions of fdps. the validity of the questionnaire's content was ensured by consulting a panel of experts in the field of hussein algahtani, bader shirah, ahmad subahi, ahmad aldarmahi and raghad algahtani clinical and basic research | e85 fdps for review and modifications. the panel included three local experts from king saud bin abdulaziz university for health sciences (ksau-hs) and three international experts from three different universities in the usa. analyses of data collected during pilot testing were conducted using cronbach α for internal consistency, which demonstrated high reliability. the scales’ and subscales’ consistency were determined by factor analysis. statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa) was used to analyse the collected data. to summarise quantitative variables, descriptive statistics such as mean, median and standard deviation were used. frequencies and percentages were used to summarise qualitative variables. to ensure the confidentiality of information, all questionnaires were completed and submitted anony mously. furthermore, the cover page of each quest ionnaire explained confidentiality issues, including instructions on how to complete the questionnaire and provided space for participants to give informed consent to participate in the study. the institutional review board of king abdullah international medical research center, riyadh, saudi arabia, approved this study (irbc/430/16). results a total of 210 faculty members participated in the study (response rate = 52.5%). most participants were from ksau-hs (56.7%), followed by batterjee college (bc; 13.8%), taif university (tu; 10.5%), ibn sina college (ibsc; 8.6%), umm al qura university (uqu; 7.1%) and rabigh university (ru; 3.3%). the majority of participants were full-time faculty members (81.4%), over 40 years old (80.5%) and male (75.2%). only 1% did not specify their gender. in terms of highest educational achievement, most participants were phd degree holders (67.1%), followed by master's degree (21%) or bachelor’s degree holders (9%). the distribution of academic positions of the participants showed that most were assistant professors (54.3%), followed by associate professors (18.6%), professors (15.2%), lecturers (8.6%) and teaching assistants (3.3%). regarding the length of teaching experience, most participants had taught for between 3–10 years (52.4%), followed by 11–20 years (20%) teaching experience. some had less than two years of teaching experience (15.7%) while fewer had more than 20 years teaching experience (10%) [table 1]. faculty members perceived the two most effective items to be addressed in an fdp as the improvement of personal qualities and making provisions for greater educational involvement (mean = 4.22 ± 0.88 table 1: characteristics of faculty members of medical schools in saudi arabia who participated in this study (n = 210) characteristic n (%) institution name ksau-hs 119 (56.7) uqu 15 (7.1) bc 29 (13.8) ibsc 18 (8.6) ru 7 (3.3) tu 22 (10.5) employment status full-time 171 (81.4) joint appointees 39 (18.6) age in years 25–30 4 (1.9) 31–35 9 (4.3) 36–40 26 (12.4) 41–45 64 (30.5) 46–50 51 (24.3) >50 54 (25.7) not known 2 (1) gender male 158 (75.2) female 50 (23.8) not known 2 (1) highest educational achievement bachelor’s degree 19 (9) master’s degree 44 (21) phd degree 141 (67.1) not known 6 (2.9) academic position teaching assistant 7 (3.3) lecturer 18 (8.6) assistant professor 114 (54.3) associate professor 39 (18.6) professor 32 (15.2) teaching experience in years <2 33 (15.7) 3–5 61 (29.1) 6–10 49 (23.3) 11–15 22 (10.5) 16–20 20 (9.5) 21–35 21 (10) not known 4 (1.9) ksau-hs = king saud bin abdulaziz university for health sciences; uqu = umm al qura university; bc = batterjee college; ibsc = ibn sina college; ru = rabigh university; tu = taif university. effectiveness and needs assessment of faculty development programme for medical education experience from saudi arabia e86 | squ medical journal, february 2020, volume 20, issue 1 and 4.21 ± 0.80, respectively). enhancing teaching strategies (mean = 4.19 ± 0.92), improving teaching skills (mean = 4.18 ± 0.85) and methodologies (mean = 4.17 ± 0.92) as well as improving selfawareness (mean = 4.16 ± 0.86) and positively changing teaching behaviour (mean = 4.16 ± 0.84) were rated as moderately effective. awareness of research funding opportunities and research protocols (mean = 3.82 ± 1.01), understanding research management (mean = 3.83 ± 0.99), retention in academia (mean = 3.86 ± 0.99), establishing networks (mean = 3.89 ± 1.01) and improving relationships (mean = 3.92 ± 0.94) with colleagues were among the items perceived as less effective in fdps [table 2]. a total of 49 needs were identified with 13 needs considered of utmost importance while the remaining were considered important [table 3]. discussion fdps in medical colleges are currently considered more important than before. although full-time saudi faculty members constitute a large body in academia, most are not equipped with formal training in the field of medical education.17 the current study reflected this finding as faculty members believed the most effective items in an fdp were improving personal qualities and providing greater educational involvement. such table 2: faculty-perceived effectiveness of a faculty development programme in saudi arabia rank item mean ± sd verbal interpretation 1 improving personal qualities (e.g. being consistent, trustworthy, inspiring, authentic, etc.) 4.22 ± 0.88 more effective 2 providing greater educational involvement 4.21 ± 0.80 more effective 3 enhancing teaching strategies 4.19 ± 0.92 moderately effective 4 improving teaching skills 4.18 ± 0.85 moderately effective 5 improving teaching methodologies 4.17 ± 0.92 moderately effective 6 improving self-awareness (e.g. strength, weakness and limitations) 4.16 ± 0.86 moderately effective 7 positively changing teaching behaviour 4.16 ± 0.84 moderately effective 8 understanding the process of developing curricula 4.16 ± 0.91 moderately effective 9 using students’ needs assessment efficiently 4.15 ± 0.98 moderately effective 10 increasing knowledge of educational principles 4.14 ± 0.84 moderately effective 11 positively changing attitude towards teaching 4.13 ± 0.89 moderately effective 12 improving career productivity 4.12 ± 0.88 moderately effective 13 improving interpersonal relationships among faculty members 4.11 ± 0.87 moderately effective 14 improving teacher-student interactions 4.10 ± 0.93 moderately effective 15 bringing positive changes in attitude towards the institution 4.10 ± 0.83 moderately effective 16 improving personality (e.g. emotional control, displaying appropriate values and morals towards other) 4.10 ± 0.93 moderately effective 17 improving test development abilities 4.09 ± 0.92 moderately effective 18 planning learning activities linked to set objectives 4.06 ± 0.96 moderately effective 19 improving career satisfaction 4.06 ± 0.93 moderately effective 20 increasing awareness about the mission and vision of the institution 3.99 ± 0.87 moderately effective 21 giving sense of personal fulfilment 3.95 ± 0.87 moderately effective 22 enhancing scholarly activity productivity 3.95 ± 0.91 moderately effective 23 working with others harmoniously 3.95 ± 0.93 moderately effective 24 increasing understanding of the research process 3.94 ± 0.98 moderately effective 25 learning educational scholarship skills 3.94 ± 0.93 moderately effective 26 improving relationships among colleagues 3.92 ± 0.94 moderately effective 27 establishing a faculty network 3.89 ± 1.01 moderately effective 28 gives sense of identity 3.88 ± 0.86 moderately effective 29 contributing to retention in academia 3.86 ± 0.99 moderately effective 30 increasing understanding about research management 3.83 ± 0.99 moderately effective 31 increasing awareness of research funding opportunities and research protocols 3.82 ± 1.01 moderately effective sd = standard deviation. hussein algahtani, bader shirah, ahmad subahi, ahmad aldarmahi and raghad algahtani clinical and basic research | e87 table 3: level of importance of developing various skills in a faculty development programme in saudi arabia rank skill mean ± sd verbal interpretation 1 presenting work at conferences 4.58 ± 3.72 very important 2 giving effective feedback 4.38 ± 0.81 very important 3 teaching communication skills 4.36 ± 0.73 very important 4 problem-based learning 4.35 ± 0.82 very important 5 creating an osce 4.28 ± 0.84 very important 6 teaching evidence-based medicine 4.28 ± 0.77 very important 7 using effective teaching strategies for student-centred learning 4.28 ± 0.73 very important 8 teaching small groups 4.24 ± 0.80 very important 9 fostering team-building skills 4.23 ± 0.82 very important 10 accessing medical information online 4.22 ± 0.88 very important 11 teaching the ‘problem’ student/resident 4.21 ± 0.81 very important 12 evaluating a course or programme 4.21 ± 0.79 very important 13 developing online teaching materials or courses 4.21 ± 0.77 very important 14 evaluating learning 4.20 ± 0.87 important 15 teaching clinical reasoning skills 4.20 ± 0.82 important 16 supporting wellness (e.g. stress reduction, time management, work/life balance, etc.) 4.19 ± 0.91 important 17 designing a course or educational programme 4.19 ± 0.84 important 18 engaging in scholarly activities 4.18 ± 0.79 important 19 teaching professionalism 4.17 ± 0.86 important 20 understanding scholarship of teaching 4.15 ± 0.81 important 21 teaching procedural skills (e.g. swallowing assessment, basic laparoscopy, etc.) 4.10 ± 0.98 important 22 developing powerpoint presentations for teaching 4.08 ± 1.01 important 23 teaching others how to teach 4.08 ± 0.88 important 24 creating portfolios for learning 4.06 ± 0.79 important 25 critiquing research articles 4.05 ± 0.91 important 26 writing an ethics proposal 4.05 ± 0.86 important 27 advocating for good health 4.05 ± 0.83 important 28 writing articles and abstracts for journals 4.04 ± 0.85 important 29 managing conflict and negotiation 4.04 ± 0.80 important 30 engaging in interprofessional education 4.04 ± 0.80 important 31 teaching in ambulatory or community-based settings 4.00 ± 0.86 important 32 teaching international medical graduates 3.99 ± 0.94 important 33 writing grants 3.98 ± 0.87 important 34 participating in career planning and promotions 3.98 ± 0.85 important 35 developing a course web page 3.96 ± 0.92 important 36 fostering colleagues’ career development (e.g. mentorship) 3.95 ± 0.87 important 37 preparing a teaching dossier or creative professional activity dossier 3.95 ± 0.84 important 38 leading health professional organisations 3.89 ± 0.92 important 39 mentoring in a cross-cultural context 3.88 ± 0.82 important 40 teaching in cross-cultural settings 3.87 ± 0.75 important 41 developing video conferencing and webcasting skills 3.85 ± 0.92 important 42 learning about audience response systems 3.83 ± 0.91 important 43 teaching 101 (for novice teachers) 3.82 ± 0.96 important 44 chairing committees 3.81 ± 0.98 important 45 planning for retirement 3.80 ± 1.05 important 46 developing one-to-one teaching skills 3.74 ± 1.02 important 47 planning sabbatical skills 3.67 ± 1.07 important 48 teaching large groups 3.66 ± 1.03 important 49 giving media interviews 3.59 ± 1.07 important sd = standard deviation; osce = objective-structured clinical exam. effectiveness and needs assessment of faculty development programme for medical education experience from saudi arabia e88 | squ medical journal, february 2020, volume 20, issue 1 findings were also confirmed by several studies in north america.17,18 for example, mcleod et al. found that faculty members’ perceived needs reflected their principal commitments and clinicians desired workshops in clinical teaching.18 in this study, enhancing and improving teaching strategies, skills and methodologies were among the most important features in faculty-perceived effectiveness. this result is similar to findings by haden et al., wherein the respondents showed interest in learning more about matters related to teaching.19 other important aspects of faculty-perceived effectiveness were improvements in personal, student or curriculum-related aspects of their jobs. faculty development plays an important role in bringing about organisational changes and promoting innovation and excellence in teaching. it also contributes by changing the institutional culture and establishing policies that support and reward excellence in academia. unfortunately, this finding was not reflected in this study as there was only one institution-related perceived effectiveness aspect among the top ten elements. other important institution-related aspects, including increasing awareness about an inst itution’s mission and vision, improving test devel opment abilities and linking instructional activities to set objectives, were less important than other personalrelated aspects of perceived effectiveness. among the least important aspects of facultyperceived effectiveness in fdps were research awareness, understanding and funding, retention in academia, establishing faculty networks and improving colleague relationships. steinert et al.’s study found that fdps helped with faculty development by improving comp etencies pertaining to teaching, administration and research.13 most of the faculty members in this study focused on personal aspects of perceived effectiveness, whereas institutional, research-related and other aspects of per ceived effectiveness were considered to be less important. this finding is similar to previously published research, which reported a need to improve faculty members’ knowledge in related areas in order to function properly as teachers, however, other findings determined that faculty needed more training in research skills.5 an effective fdp should be established based on the five major elements published by wilkerson and irby and steinert et al.20,21 these elements include professional, instructional, leadership, organisational development and programme evaluation. these elements were also reflected in the results of the current study, with professional and instructional development being the most important. the needs assessment is a process that includes the collection and analysis of information regarding what a target group needs to learn.22 in a faculty dev elopment needs assessment at the faculty of medicine at mcgill university, canada, mcleod et al. concluded that the needs assessment process is an important way to direct faculty development activities to the particular responsibilities of the faculty members.18 similar national surveys assessing faculty development have been published in the usa and europe.23,24 as the number of medical schools in saudi arabia is growing rapidly and the faculty of medical schools include both locals and expatriates, a needs assessment should be the first step to establishing an fdp. while the results of this study have local importance, a survey distributed to faculty members of all saudi medical schools might provide more specific information about their needs and help establish a basis for fdp activities on a national level. in this study, the most important skills to be covered in fdps were those related to improving transition points in individual faculty members’ careers. an effective fdp should also include skills that medical educators should master, including presenting at conf erences, giving effective feedback and teaching comm unication skills and evidence-based medicine. addi tionally, faculty members identified the importance of fdps addressing important tools for learning and assessment such as objective-structured clinical exam inations, small group teaching and problem-based learning as well as understanding wellness, professionalism and interprofessional education. among the least important skills to emphasise in fdps were giving media interviews, planning sabbaticals and chairing committees. a major limitation in the present study was the poor response rate, which might have occurred due to the difficulty in convincing busy faculty members to spend time completing the survey. the methodology of this study did not allow the researchers to collect in-depth responses that could have been achieved through a qualitative, interview-based study. such a study might include a comparison of responses from different faculty ranks or teaching experiences. qualitative research concerning fdps in saudi arabia would constitute an extensive research project but would complement the current study’s quantitative data. such a study could be done by faculty members and masters’ students interested in medical education. conclusion most faculty members at colleges of medicine in saudi arabia need further formal training in essential areas to improve their academic performance. this study assessed and identified important needs and skills that should be incorporated into an fdp to address these hussein algahtani, bader shirah, ahmad subahi, ahmad aldarmahi and raghad algahtani clinical and basic research | e89 areas. in addition, this study provided information to address the gaps between current and desired conditions. local and national medical schools are urged to assess faculty needs and create fdps according to those needs. several methods and strategies may be used to achieve these needs, including collaborative joint reviews between the six universities and medical education conferences that tackle fdps. the most important items to be achieved for faculty-perceived effectiveness in fdps in medical education were personal aspects of perceived effectiveness. colleges and medical institutions should establish a comprehensive fdp focusing on aspects of personal effectiveness which would prepare faculty members to fulfil their academic roles and promote career development. fdps are created to improve a faculty member’s commitment to their work and their ability to achieve goals and objectives for themselves and their institution. a unified faculty development diploma should be established in saudi universities which would address faculty members’ professional needs. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bajammal s, zaini r, abuznadah w, al-rukban m, aly sm, boker a, et al. the need for national medical licensing examination in saudi arabia. bmc med educ 2008; 8:53. https://doi.org/10.1186/1472-6920-8-53. 2. telmesani a, zaini rg, ghazi ho. medical education in saudi arabia: a review of recent developments and future challenges. east mediterr health j 2011; 17:703–7. https://doi. org/10.26719/2011.17.8.703. 3. dath d, iobst w. the importance of faculty development in the transition to competency-based medical education. med teach 2010; 32:683–6. https://doi.org/10.3109/014215 9x.2010.500710. 4. sorcinelli md. faculty development: the challenge going forward. from: https://www.aacu.org/publications-research/ periodicals/faculty-development-challenge-going-forward accessed: sep 2019. 5. amin z, eng kh, seng cy, hoon tc, sun gp, samarasekera dd, et al. a multi-institutional survey on faculty development needs, priorities and preferences in medical education in an asian medical school. med educ online 2009; 14:16. https:// doi.org/10.3885/meo.2009.res00317. 6. kamel amf. role of faculty development programs in improving teaching and learning. saudi j oral sci 2016; 3:61–8. https://doi.org/10.4103/1658-6816.188073. 7. hegde p. faculty development trends in medical education: a review. southeast asian j med educ 2013; 7:11–16. https://doi. org/10.4038/seajme.v7i2.134. 8. leslie k, baker l, egan-lee e, esdaile m, reeves s. advancing faculty development in medical education: a systematic review. acad med 2013; 88:1038–45. https://doi.org/10.1097/acm.0b 013e318294fd29. 9. glowacki-dudka m, brown mp. professional development through faculty learning communities. new horiz adult educ hum resource dev 2007; 21:29–39. https://doi.org/10.1002/ nha3.10277. 10. ratnapalan s, hilliard ri. needs assessment in postgraduate medical education: a review. med educ online 2002; 7:4542. https://doi.org/10.3402/meo.v7i.4542. 11. bin abdulrahman ka, siddiqui ia, aldaham sa, akram s. faculty development program: a guide for medical schools in arabian gulf (gcc) countries. med teach 2012; 34:s61–6. https://doi.org/10.3109/0142159x.2012.656748. 12. steinert y. staff development for clinical teachers. clin teach 2005; 2:104–10. https://doi.org/10.1111/j.1743-498x.2005.00062.x. 13. steinert y, mcleod pj, boillat m, meterissian s, elizov m, macdonald me. faculty development: a 'field of dreams'? med educ 2009;43:42–9. https://doi.org/10.1111/j.1365-2923.2008.0 3246.x. 14. mclean m, cilliers f, van wyk jm. faculty development: yesterday, today and tomorrow. med teach 2008; 30:555–84. https://doi.org/10.1080/01421590802109834. 15. marks mb. academic careers in medical education: perceptions of the effects of a faculty development program. acad med 1999; 74:s72–4. https://doi.org/10.1097/00001888-19991000000044. 16. ahmady s. faculty development in medical education: a comprehensive approach. from: https://openarchive.ki.se/ xmlui/handle/10616/38549 accessed: sep 2019. 17. al-eraky mm, donkers j, wajid g, van merrienboer jj. faculty development for learning and teaching of medical professionalism. med teach 2015; 37:s40–6. https://doi.org/10. 3109/0142159x.2015.1006604. 18. mcleod pj, steinert y, conochie l, nasmith l. a facultydevelopment needs assessment at one medical school. acad med 1997; 72:558–9. https://doi.org/10.1097/00001888-19970600000027. 19. haden nk, chaddock m, hoffsis gf, lloyd jw, reed wm, ranney rr, et al. preparing faculty for the future: aavmc members' perceptions of professional development needs. j vet med educ 2010; 37:220–32. https://doi.org/10.3138/ jvme.37.3.220. 20. wilkerson l, irby dm. strategies for improving teaching practices: a comprehensive approach to faculty development. acad med 1998; 73:387–96. https://doi.org/10.1097/00001888199804000-00011. 21. steinert y, mcleod pj. from novice to informed educator: the teaching scholars program for educators in the health sciences. acad med 2006; 81:969–74. https://doi.org/10.1097/01.acm.0 000242593.29279.be. 22. adkoli bv, al-umran ku, al-sheikh mh, deepak kk. innovative method of needs assessment for faculty development programs in a gulf medical school. educ health (abingdon) 2010; 23:389. 23. houston tk, ferenchick gs, clark jm, bowen jl, branch wt, alguire p, et al. faculty development needs. j gen intern med 2004; 19:375–9. https://doi.org/10.1111/j.1525-1497.2004.30619.x. 24. clark jm, houston tk, kolodner k, branch wt jr, levine rb, kern de. teaching the teachers: national survey of faculty devel opment in departments of medicine of u.s. teaching hospitals. j gen intern med 2004; 19:205–14. https://doi.org/10.1111/ j.1525-1497.2004.30334.x. https://doi.org/10.1186/1472-6920-8-53 https://doi.org/10.26719/2011.17.8.703 https://doi.org/10.26719/2011.17.8.703 https://doi.org/10.3109/0142159x.2010.500710 https://doi.org/10.3109/0142159x.2010.500710 https://doi.org/10.3885/meo.2009.res00317 https://doi.org/10.3885/meo.2009.res00317 https://doi.org/10.4103/1658-6816.188073 https://doi.org/10.4038/seajme.v7i2.134 https://doi.org/10.4038/seajme.v7i2.134 https://doi.org/10.1097/acm.0b013e318294fd29 https://doi.org/10.1097/acm.0b013e318294fd29 https://doi.org/10.1002/nha3.10277 https://doi.org/10.1002/nha3.10277 https://doi.org/10.3402/meo.v7i.4542 https://doi.org/10.3109/0142159x.2012.656748 https://doi.org/10.1111/j.1743-498x.2005.00062.x https://doi.org/10.1111/j.1365-2923.2008.03246.x https://doi.org/10.1111/j.1365-2923.2008.03246.x https://doi.org/10.1080/01421590802109834 https://doi.org/10.1097/00001888-199910000-00044 https://doi.org/10.1097/00001888-199910000-00044 https://doi.org/10.3109/0142159x.2015.1006604 https://doi.org/10.3109/0142159x.2015.1006604 https://doi.org/10.1097/00001888-199706000-00027 https://doi.org/10.1097/00001888-199706000-00027 https://doi.org/10.3138/jvme.37.3.220 https://doi.org/10.3138/jvme.37.3.220 https://doi.org/10.1097/00001888-199804000-00011 https://doi.org/10.1097/00001888-199804000-00011 https://doi.org/10.1097/01.acm.0000242593.29279.be https://doi.org/10.1097/01.acm.0000242593.29279.be https://doi.org/10.1111/j.1525-1497.2004.30619.x https://doi.org/10.1111/j.1525-1497.2004.30334.x https://doi.org/10.1111/j.1525-1497.2004.30334.x clinical & basic research squ med j, may 2011, vol. 11, iss. 2, pp. 244-251, epub. 15th may 11 submitted 24th aug 10 revision req. 27th sept & 14th dec 10, revision recd. 24th oct & 22nd dec 10 accepted 23rd feb 11 1department of medical statistics & epidemiology, hamad general hospital, hamad medical corporation, doha, qatar; 2evidence for population health unit, school of epidemiology & health sciences, university of manchester, manchester, u.k.; 3hamad trauma center, hamad medical corporation, doha, qatar; 4accident and emergency department, hamad medical corporation, doha, qatar. *corresponding author email: abener@hmc.org.qa ωáœä÷]<ìrèjfi<ìfœü÷]ê<å_ü÷]<l^e^ëc<ìò^í}ê<l^‚^ü] ü�œ<ì÷êå<<i<<ìèf�÷]<ç∑<ìäâˆ≤<<ùö]á�÷]ê<på]áv◊÷<ìèò^íuc<ó◊¬<çfljäi<ìâ]öå    1952 20062001 98 225 1629 10 %78.6 %26.8 2920%86.6 %49.4%27.1 2.1 10000%7.3%10.2  18.6 2003 13.1 60 2006 5.5 2001 %29.42006  : كلمات البحث abstract: objectives: the aim of this retrospective descriptive hospital-based study was to determine the trend in the number, incidence and pattern of head and neck injuries involved with falls. methods: a retrospective analysis was carried out of 1,952 patients who were treated at the accident and emergency and trauma centres of hamad medical corporation, qatar, for head (n = 1,629), neck (n = 225) and both (n = 98) injuries during the period 2001–2006. head and neck injuries were determined according to the international classification of disease, icd10 criteria. details of all the trauma patients who were involved in falls were extracted from the database of the emergency medical services (ems), hamad medical corporation. results: the majority of the victims were nonqataris (78.6%), men (86.6%) and in the age group 20–29 years (26.8%). there was a disproportionately higher incidence of head and neck injuries from falls during weekends (27.1%). nearly half of the head and neck injuries from falls occurred at work (49.4%). neck injuries (10.2%) were more severe than head injuries (7.3%). the incidence rate of head and neck injuries per 10,000 population increased from 2.1 in the year 2001 to 5.5 in 2006, particularly among the elderly population above 60 years of age (13.1 in 2003 to 18.6 in the year 2006). superficial injury to the head (29.4%) was more common among trauma patients. conclusion: the present study findings revealed that the incidence of head and neck injuries was higher among young adults and the elderly population. keywords: head injury; neck injury; occupational falls; home falls; incidence; morbidity; trauma; qatar trends and characteristics of head and neck injury from falls a hospital based study, qatar *abdulbari bener,1,2 yassir s. abdul rahman,3 eltayib y. abdel aleem,4 muayad k. khalid4 clinical & basic research advances in knowledge 1. this is the first study in qatar to investigate the number, incidence and trends of head and neck injuries from falls. 2. the high risk groups of fallers were elderly people and younger workers. 3. this study highlighted the emerging trend of traumatic morbidity from fall induced head and neck injuries in the general population. application to patient care 1. the findings of this study emphasise the need for urgent steps to be taken in qatar for injury prevention, especially among workers and those in the elderly population. abdulbari bener, yassir s. abdul rahman, eltayib y. abdel aleem and muayad k. khalid clinical and basic research | 245 falls and fall-induced injuries are a major public health problem in modern societies with ageing populations.1 as a measure of burden, disability adjusted life years (dalys) quantify the total amount of healthy life lost because of disease or injury. in high income countries, injuries due to falls are the fourteenth leading cause of dalys for all age groups combined.2 in industrialised countries like the usa, canada and japan, injuries caused by falls have increased dramatically.3 falls are the second leading cause of unintentional injury deaths in the usa. it was reported that an estimated 3.4 million nonfatal injuries occurred among workers of all ages and were treated in us hospital emergency departments in 2004.4 falls are the most common cause of head injuries in children and adolescents, followed by motor vehicle crashes, pedestrian and bicycle accidents, sports-related trauma, and child abuse.5 falls are a common source of traumatic injuries, and it was revealed that fall injury patterns differ between adults and children. fall rates are highest for children age 0 to 4 years and adults aged 75 years and older. falls are usually the most common cause of injury seen in hospitals, accounting for 25–52% of all treated child injuries.6 falls and subsequent head injuries among the elderly are the result of a complex interaction between physical changes due to ageing, disease, lifestyle and environment related and social factors. also, older fallers are more likely to fall indoors than outdoors.7 head injury is a common and serious consequence of falling among older adults, and a great majority of elderly people’s non-fatal and fatal head injuries are caused by falls.8 although the head, face and neck comprise only 12% of the total body surface area exposed during impact, injuries sustained in these areas are more likely to be fatal.9 head and neck injuries from falls are a common cause of occupational morbidity and mortality, resulting in significant losses of life and wages, as well as significant medical expenses. males are at greater risk of sustaining a fall-related injury while at work and during recreational activities. although fall injuries comprise a major health burden, the risk factors for such injuries have not been examined in a systematic and comprehensive manner. in practice, knowledge of risk factors for head and neck injuries from falls can assist injury practitioners, programme developers, and policy makers in determining appropriate intervention. only two previous studies have been conducted in qatar to document trends in traumatic brain injury10 and traumatic spinal injury.11 both of these studies were very preliminary and neither study specifically focused on head and neck injuries as a result of falls. in fact, to our knowledge, no nationwide study investigating the number, incidence and trends of head and neck injuries from falls has been published from qatar. therefore, this study aimed to determine the trends of head and neck injuries from falls in absolute number, incidence and pattern of injuries during the period 2001 to 2006. methods this is a retrospective, descriptive hospital based study. this study included a total of 1,952 patients with head and neck injuries who were treated in the accident & emergency department of the hamad general hospital (hgh) and other 8 trauma centres of the hamad medical corporation (hmc) following fall incidents during the period 2001 to 2006. all trauma cases occuring in the state of qatar are treated in the accident and emergency department of the hgh and the 8 trauma centres of the hmc. hence, the data collected in this study not hospital based, but covers all head and neck injuries occurring in qatar during the period of the study.the electronic emergency medical service database has complete information on trauma cases year by year. we took the frequency of head and neck injury from falls by year and population of the respective year. then, we calculated the incidence of the head and neck injury per 10,000 of the population based on the population of the country for the respective year. this is a retrospective, descriptive hospital based study. this study included a total of 1,952 patients with head and neck injuries who were treated in the accident & emergency department of the hamad general hospital and other 8 trauma centres of the hamad medical corporation following fall incidents during the period 2001 to 2006. the population in qatar was estimated to be 838,065 in the year 2006 and has a unique distribution of population according to gender and ethnicity.12 only about 30% of the total population are nationals and the majority of the total population (66.7%) are trends and characteristics of head and neck injury from falls a hospital based study, qatar 246 | squ medical journal, may 2011, volume 11, issue 2 males.12 hamad general hospital is the main tertiary care centre in the country; all major and most of the minor trauma cases are treated in this hospital. the study was based on the emergency medical services (ems) registry, an electronic database in qatar. this registry records complete information of the patients who had accidents and were brought to the accident & emergency department and trauma centres for treatment. the details of the falls were table 1: characteristics of patients with head and neck injuries resulting from falls in the period 2001–2006 variables head n = 1,629, n (%) neck n = 225, n (%) both n = 98, n (%) total n = 1,952, n (%) age (mean ± standard deviation) 30.4 ±18.1 29.8 ± 15.0 32.2 ± 17.6 30.4 ± 17.6 age groups in years § < 10 243 (14.9) 19 (8.4) 5 (5.1) 267 (13.7) 10–19 150 (9.2) 29 (12.9) 13 (13.3) 192 (9.8) 20–29 419 (25.7) 71 (31.6) 33 (33.7) 523 (26.8) 30–39 368 (22.6) 53 (23.6) 19 (19.4) 440 (22.5) 40–49 225 (13.8) 25 (11.1) 16 (16.3) 266 (13.6) 50–59 104 (6.4) 20 (8.9) 6 (6.1) 130 (6.7) ≥60 120 (7.4) 8 (3.6) 6 (6.1) 134 (6.9) ethnicity qatari 343 (21.1) 52 (23.1) 22 (22.4) 417 (21.4) non qatari 1,286 (78.9) 173 (76.9) 76 (77.6) 1,535 (78.6) gender male 1,415 (86.9) 192 (85.3) 84 (85.7) 1,691 (86.6) female 214 (13.1) 33 (14.7) 14 (14.3) 261 (13.4) day of the week week days 1,189 (73.0) 167 (74.1) 6 (67.0) 1,422 (72.9) weekend‡ 440 (27.0) 58 (25.9) 32 (33.0) 530 (27.1) place of fall at work 817 (50.1) 99 (44.2) 50 (50.7) 965 (49.4) home 519 (31.9) 85 (37.6) 30 (31.0) 635 (32.5) school 106 (6.5) 14 (6.1) 3 (2.8) 123 (6.3) recreational places 187 (11.5) 27 (12.2) 15 (15.5) 229 (11.8) status at the time of admission* conscious 1,510 (92.7) 215 (95.6) 87 (88.8) 1,812 (92.8) breathing 1,619 (99.4) 225 (100) 98 (100) 1,942 (99.5) bleeding 677 (41.5) 59 (26.2) 39 (39.8) 775 (39.7) glasgow coma score severe score 3–8 119 (7.3) 23 (10.2) 7 (7.2) 147 (7.5) moderate score 9–12 149 (9.1) 30 (13.3) 11 (11.2) 186 (9.5) mild score 13–15 1,361 (83.6) 172 (76.5) 80 (81.6) 1,619 (82.9) notes: § = significant p value = 0.005; ‡ = weekend is friday and saturday; *multiple options: sum of percentage may not add to 100%. abdulbari bener, yassir s. abdul rahman, eltayib y. abdel aleem and muayad k. khalid clinical and basic research | 247 collected regularly by the ems staff using a standard questionnaire. the questionnaire included variables such as age, sex, time of injury, place of fall, the type of injury, the region of the body injured and the severity of injury. the data provided by this register are well suited for epidemiological purposes. medical records of the victims were thoroughly reviewed in the event of any missing information. the patient information was extracted from the ems registry and analysed. head and neck injuries were defined according to the international classification of disease (icd) icd-10 criteria and external causes of injury recorded. head injuries, neck injuries and a combination of both injuries together were mutually and exclusively reported. fall-induced head and neck injuries were recorded by evaluating the primary and secondary diagnosis. descriptive statistics were performed on the sociodemographic characteristics, place of fall, status of the injury at the time of admission and diagnosis. according to icd-10, injuries to the head were classified under categories s00–s09 and injuries to the neck were classified under s10–s19. the agespecific incidence rate was calculated based on the population in that specific age group in that year. the severity of head or neck injury was classified by glasgow coma scale (gcs). this a tool for measuring degree of unconsciousness and is thus a useful tool for determining severity of head injury.13 the gcs classifications are as follows: 1) severe: score of 3–8; 2) moderate: score of 9–12, and 3) mild: score of 13–15. the gcs score of patients was taken when they were examined and, for the intubated patients, the score was taken prior to intubation. informed consent by all participants was not required in this study, as it was a retrospective hospital based study. the study was approved by the research ethics committee at hamad general hospital of hamad medical corporation. data are expressed as mean and standard deviation (sd) unless otherwise stated. the fisher exact and chi-square test for trend were used to compare frequencies between two or more than two categories. a p value of <0.05 was considered as the cut-off value for significance. results table 1 shows the socio-demographic characteristics of patients with head and neck injuries resulting from falls during the period 2001–2006. a total of 1,952 patients were diagnosed with head and neck injuries from falls. the majority of them were non-qataris (78.6%), males (86.6%) and in the age group 20–29 years (26.8%). men outnumbered women by 6.5:1. a total of 27.1% of the head and neck injuries from falls occurred during weekends, while 72.9% occurred on week days. nearly half of the head and neck injuries from falls occurred at work (49.4%), followed by falls at home (32.5%), then at recreational places (11.8%) and school (6.3%). according to the gcs score, 7.5% had severe and 9.5% had moderate injury. the majority of the patients had mild head (83.6%) and neck injury (76.5%). neck injuries (10.2%) were more severe than head injuries (7.3%) among trauma patients. a significant difference was observed in the age group of fallers and the injuries occurred between week days and weekends (p = 0.005). table 2 shows the distribution of diagnosis of injuries and place of fall according to the age group of trauma patients. most of the head and neck injuries were occupational injuries (49.5%) and 32.5% of injuries happened at home. older people above 60 years-old had more frequent injuries to the head and neck region from falls at home (70.9%), followed by children below 10 years (66.7%). major fall related injuries included superficial injury of the head (29.4%), followed by an open wound on the head (23.4%), then blunt injury (19.5%). superficial injury of head was more frequent among children below 10 years (33%). an open wound to the head was more common among patients above 60 years (32.8%). table 3 shows the incidence rate of head and neck injuries sustained from falls per 10,000 of the population according to age group and year during the period 2001–2006. there was a clear increase in the incidence of head and neck injuries: 2.1/10000 in 2001 to 5.5/10000 in 2006. the elderly population above 60 years of age had the highest increase in incidence of head and neck injuries from falls (6.7 to 18.6/10,000) across the study period. there was a significant difference found in the number of injuries in different age groups of fallers (p <0.001). figure 1 shows the incidence rate of head, neck injuries and both together per 10,000 of the population resulting from falls during the period 2001–2006. the number of neck injuries also increased to 4.9/10,000 population in 2006 trends and characteristics of head and neck injury from falls a hospital based study, qatar 248 | squ medical journal, may 2011, volume 11, issue 2 compared to 1.8/10,000 population in 2001. discussion falls are the commonest cause of head and neck injuries in children, adults and elderly people. although fall-induced injuries among older adults are said to be a major public health concern in modern societies with ageing populations, reliable epidemiologic information on their trends and the pattern of injuries is limited. to our knowledge, this is the first study in qatar examining and comparing fall related head and neck injuries in young, middleaged and older men and women. the focus was on the faller’s activity, the incidence of head and neck injuries, and the severity and type of injuries. of all hospitalisations with head and neck injuries, 18.4% had head and neck injuries from falls, while 7.5% had a gcs score of <9 (severe), 9.5% a score of 9–12 (moderate) and 82.9% a score of 13–15 (mild). most of the patients with head and neck injuries were conscious (92.7%) at the time of admission after the fall. head injuries accounted for the majority of the fall cases (83.5%), followed by neck injuries (11.5%). a similar result was observed in another study where 63.2% of the fall cases were table 2: place of fall and diagnosis by age group (n = 1,952) variables age group in years total n (%) <10 n (%) 10–19 n (%) 20–29 n (%) 30–39 n (%) 40–49 n (%) 50–59 n (%) 60+ n (%) place of fall at work 0 (0.0) 22 (11.5) 347 (66.3) 317 (72.0) 196 (73.7) 55 (42.3) 29 (21.6) 966 (49.5) home 178 (66.7) 49 (25.5) 81 (15.5) 91 (20.7) 67 (25.2) 73 (56.2) 95 (70.9) 634 (32.5) recreation 0 (0.0) 91 (47.4) 91 (17.4) 32 (7.3) 3 (1.1) 2 (1.5) 10 (7.5) 229 (11.7) school 89 (33.3) 30 (15.6) 4 (0.8) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 123 (6.3) diagnosis superficial injury to head 88 (33.0) 48 (25.0) 150 (28.7) 131 (29.8) 76 (28.6) 38 (29.2) 42 (31.3) 573 (29.4) open wound on head 57 (21.3) 36 (18.8) 126 (24.1) 96 (21.8) 68 (25.6) 29 (22.3) 44 (32.8) 456 (23.4) blunt head injury 62 (23.2) 38 (19.8) 92 (17.6) 84 (19.1) 51 (19.2) 24 (18.5) 30 (22.4) 381 (19.5) superficial injury of neck 16 (6.0) 31 (16.1) 67 (12.8) 39 (8.9) 20 (7.5) 17 (13.1) 7 (5.2) 197 (10.1) soft tissue contusion 23 (8.6) 17 (8.9) 25 (4.8) 25 (5.7) 14 (5.3) 7 (5.4) 2 (1.5) 113 (5.8) traumatic amputation on head (ear & nose) 3 (1.1) 13 (6.8) 23 (4.4) 21 (4.8) 9 (3.4) 7 (5.4) 1 (0.7) 77 (3.9) dislocation, sprain, strain of joints of head 6 (2.2) 1 (0.5) 15 (2.9) 16 (3.6) 9 (3.4) 2 (1.5) 3 (2.2) 52 (2.7) fracture of skull & facial bone 4 (1.5) 3 (1.6) 6 (1.1) 6 (1.4) 3 (1.1) 2 (1.5) 0 (0.0) 24 (1.2) multiple injuries of head 2 (0.7) 0 (0.0) 4 (0.8) 5 (1.1) 7 (2.6) 1 (0.8) 2 (1.5) 21 (1.1) open wound of neck 2 (0.7) 2 (1.0) 4 (0.8) 4 (0.9) 2 (0.8) 1 (0.8) 1 (0.7) 16 (0.8) burns & corrosions 3 (1.1) 1 (0.5) 3 (0.6) 4 (0.9) 3 (1.1) 0 (0.0) 1 (0.7) 15 (0.8) injury of nerves & spinal cord 0 (0.0) 0 (0.0) 4 (0.8) 6 (1.4) 3 (1.1) 2 (1.5) 0 (0.0) 15 (0.8) penetrating head injury 1 (0.4) 2 (1.0) 4 (0.8) 3 (0.7) 1 (0.4) 0(0.0) 1 (0.7) 12 (0.6) abdulbari bener, yassir s. abdul rahman, eltayib y. abdel aleem and muayad k. khalid clinical and basic research | 249 head injuries, followed by neck injuries (19.8%).14 our findings revealed that both the head and neck injuries from falls were higher in young adults in the age group 20–29 years (25.7% and 31.6%) and 30–39 years (22.6% and 23.6%). a study by hausdorff et al. documented that more than a third of older adults fall each year and 10–20% of falls cause serious injuries such as fractures or head trauma.15 this runs contrary to the study in canada on fall-related emergency department visits, where the head and neck were injured most often (49%) among children below 20 years.16 in ontario, 80% of head injury hospitalisations were reported among people aged 65 years and older, while only 17% were reported in the 15 to 34 years age group.17 another study by cheng et al. also reported that there was a trend for the elderly to have more frequent injuries to the head (53.2%) and neck (47.5%) region.18 the reason for the low proportion of falls among elderly people in qatar is that the majority of the fall-induced head (78.9%) and neck injuries (76.9%) occurred in the non-qatari population. these people leave qatar once they reach their retirement age of 60 years. this is evident from the data as half of the head and neck injuries were occupational injuries (49.5%). thus, falls are a common cause of occupational morbidity and mortality, resulting in significant losses of life, wages, as well as significant medical expenses. falls are a risk factor for disability and frailty and exacerbate disablement among the adult non-qatari population. even in the united arab emirates, occupational injuries resulting from falls were frequent with 66.7% of hospitalisations.18 similar to qatar, falls were the most frequent cause of head and neck injuries among non-nationals in the united arab emirates, whereas for injuries among nationals the main cause was road traffic crashes.18 many studies indicate that falls continue to pose a serious problem to the elderly population, whereas it was a more serious issue for both the middle-aged working population and the elderly in qatar.18,19 the incidence rate of fall induced head and neck injuries among the general population rose considerably in the study period: from 2.1 in 2001 to 5.5 in 2006. although the frequency of fall induced head and neck injuries was higher in young adults, the incidence rate in the elderly population above 60 years of age seemed to show an alarming rise with a rate that cannot be explained merely by demographic changes: from 2.8 in 2001 to 19/10,000 in 2005 and 18.6/10,000 in 2006. the incidence rate in people above 60 years-old was four times higher than the incidence rate observed in younger people. a similar finding was observed in table 3: incidence rate of head and neck injuries resulting from falls per 10,000 population during the period 2001–2006 age group 2001 2002 2003 2004 2005 2006 <10 1.4 3.5 5.5 4.5 5.5 2.4 10–19 2.4 3.4 2.7 3.4 4.1 4.0 20–29 3.4 6.1 4.8 5.4 8.7 8.7 30–39 1.7 2.4 4.0 4.4 6.2 5.4 40–49 1.3 2.7 3.8 3.5 4.8 4.0 50–59 3.4 4.4 3.6 3.3 4.9 5.4 60+ 2.8 6.7 13.1 11.9 19.0 18.6 all ages 2.1 3.7 4.4 4.4 6.3 5.5 note: p = <0.001 figure 1: incidence rate of head injury, neck injury and both injuries per 10,000 of the population resulting from falls during the period 2001–2006. trends and characteristics of head and neck injury from falls a hospital based study, qatar 250 | squ medical journal, may 2011, volume 11, issue 2 a study by stevens and soglow where the incidence rates for fall related head injuries increased with advancing age with a rate four to five times higher in people aged 85 years and older compare to those aged 65–74 years.20 rubenstein et al. reported that beyond 50 years of age, there is a steady increase in the occurrence of falls and the magnitude of fall related complications.21 in qatar, after the elderly population, young adults in the age group 20–29 years were the most frequent victims of head and neck injuries from falls; 8.7/10000 in the years 2005 and 2006. the relationship between fall and injury varies by gender. in the study sample, 86.6% of the head and neck injuries were reported among men. men outnumber women by 6.5:1. it was found that men sustain more fall injuries than women, perhaps due to the underlying causes or circumstances of their falls. this result differs to that of another study22 where women had a higher risk of falling than men in general population studies, a trend not seen in the present study. jenson et al. reported that the cause of the gender discrepancy may lie in divergent activity patterns between men and women over separate periods of the day and night or in differences in personal risk assessment between the genders.23 in qatar, expatriates (70% of the total population), especially the male labour force, are greater in number than nationals. a good proportion of the expatriate men are employed on construction sites where they are at high risk for occupational injuries. elderly people are mostly nationals and they have a better life expectancy due to better health care and a higher standard of living. in qatar, superficial injuries of head have been observed overall with a frequency up to 29.4% in falls, followed by open wound on the head (23.4%). superficial injury was more common among children below 10 years (33%) and in elderly population above 60 years (31.3%). however, an open wound to the head was more frequent among people above 60 years (32.8%). nonetheless, blunt head injury was more frequent in children (23.2%) and the elderly population (22.4%) compared to other age groups. in another study by turk and tsoko, a higher frequency of blunt neck injuries were observed (33%) in falls from heights.24 neck injuries were less common in falls in the studied population compared to head injuries. in canada, 74% of fall related hospital admissions are due to fractures and dislocations, with serious head injuries (20%).15 elderly trauma patients differed from younger adult trauma patients in their injury patterns and the mode of presentation of significant injuries. the present study showed some differences and some similarities when compared to other studies related to fall injuries. the risk in our study increased with age and was higher among men, a similar finding to other studies. the findings of our study confirm the findings of previous studies25,26 with regard to older age which is a well-recognised risk factor for falling in the general population. additional efforts in qatar are needed to reduce the occurrence of fall related occupational injuries. it is important to identify the risk factors related to fall induced head and neck injuries and develop comprehensive intervention programmes to reduce the risk for such falls. falls have significant economic impact on the country, including costs to individuals and their families, to work places and the health system as well as to community and social services. conclusion a relatively high rate of head and neck injuries from falls was demonstrated in this study. the incidence of head and neck injuries rose during the study period. occupational fall injuries were most frequent in the general population, particularly among nonnationals. findings show that the age-specific incidence of fall-induced severe head injuries in the qatar population above 60 years of age has increased steeply during the study period and also has not declined in more recent years. according to the gcs score, neck injuries were more severe than head injuries. the injuries represent an alarming epidemic and the predicted ageing of populations will soon exacerbate the burden on our health care systems. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. close j, ellis m, hooper r, glucksman e, jackson s, swift c. prevention of falls in the elderly trial: a randomized controlled trial. lancet 1999; 353:93−7. abdulbari bener, yassir s. abdul rahman, eltayib y. abdel aleem and muayad k. khalid clinical and basic research | 251 2. world health organization. assessment of fractures risk and its application to screening for postmenopausal osteoporosis. geneva: world health organisation, techn rep ser no. 843, 1994. 3. krug eg, sharma gk, lozano r. the global burden of injuries. am j public health 2000; 90:523−6. 4. hoskin af. fatal falls: trends and characteristics. stat bull metrop insur co 1998; 79:10−15. 5. centers for disease control. nonfatal occupational injuries and illness united states, 2004. mmwr morb mortal wkly rep 2007; 56:395–7. 6. bartlett s. the problem of children’s injuries in lowincome countries a review. health policy plan 2002; 171−13. 7. prudham d, evans jg. factors associated with falls in the elderly: a community study. age aging 1981; 10:141−6. 8. kannus p, parkkari j, koskinen s, niemi s, palvanen m. fall induced injuries and deaths among older adults. jama 1999; 281:1895−9. 9. pitone ml, attia mw. patterns of injury associated with routine childhood falls. pediatr emerg care 2006; 22:470−4. 10. mezue wc, bashir em. head injury patterns in qatar. pan arab j 1998; 75:364–9. 11. quinones mpo, nassal m, al bader ki, al muraikhi ae, al kahlout sr. traumatic spinal cord injury in qataran epidemiological study. mid east j emerg med 2002; 2:1−4. 12. qatar statistics authority. from: http://www. q i x . g o v . q a / p o r t a l / p a g e / p o r t a l / q i x / h o m e accessed: september 2010. 13. teasdale g, jennett b. assessment of coma and impaired consciousness: a practical scale. lancet 1974; 2:81−4. 14. warrington sa, wright cm, team as. accidents and resulting injuries sustained in pre-mobile infants: data from alspac study. arch dis child 2001; 85:104−7. 15. hausdorff jm, rios da, edelber hk. gait variability and fall risk in community living older adults: a one year prospective study. arch phys med rehabil 2001; 82:1050−6. 16. rivara fp, alexander b, johnson b, soderberg r. population-based study of fall injuries in children and adolescents resulting in hospitalizations or death. pediatrics 1993; 92:61−3. 17. falls primary cause of head injury hospitalizations among ontario seniors, report of canadian institute for health information, 2001. from: http// secure.cibi.ca/cibiweb/dispage.jsp?cw_page_media. accessed: october 2010. 18. cheng ch, cheung nk, yeung jhh, man cy, graham ca, rainer th. difference in injury pattern and mortality between hong kong elderly and younger patients. hong kong j emerg med 2009; 16:224−32. 19. barss p, addley k, grivna m, stanculescu c, abuzidan f. occupational injury in the united arab emirates: epidemiology and prevention. occup med 2009; 59:493−8. 20. steven ja, soglow ed. gender differences for nonfatal unintentional fall related injuries among older adults. inj prev 2005; 11:115−19. 21. rubenstein lz, poers cm, maclean cm. quality indicators for the management and prevention of falls and mobility problems in vulnerable elders. ann intern med 2001; 135:686−93. 22. ashburn a, stack e, pickering rm, ward cd. predicting fallers in a community based sample of people with parkinson’s disease. age ageing 2001; 30:47−52. 23. jensen j, laundin-olsson l, nyberg l. falls among frail older people in residential care. scand j public health 2002; 30:54−61. 24. turk ee, tsoko sm. pathologic features of fatal fall from height. am j forensic med pathol 2004; 25:194−199. 25. blake aj, morgan k, bendall mj, dallosso h, ebrahim sb, arie th, et al. falls by elderly people at home. prevalence and associated factors. age ageing 1988; 17:365−72. 26. tinetti me, speechley m, ginter sf. risk factors for falls among elderly persons living in the community. n engl j med 1988; 319:1701−7. muscat directorate of general health services, ministry of health, muscat, oman e-mail: amel.albulushi@gmail.com أخالقيات وقانونية استخدام اهلواتف الذكية الشخصية اللتقاط الصور الطبية اأمل اأحمد البلو�شية abstract: photography in the medical profession is an asset that may help during patients’ follow-up, monitoring the progression of diseases, getting a second opinion and in medical educational activities. advances in technology, specifically smartphones, have enabled medical professionals to obtain high-quality photographs with minimal effort and photography experience. this article discusses the ethics and legality of using personal smartphones in a medical professional setting for medical photography. written informed consent should always be obtained from the patient and should include details about how the photographs will be used. keywords: photography; smartphone; informed consent; ethics; medical legislation; publications; medical education; oman. امللخ�ص: الت�شوير الفوتوغرايف يف مهنة الطب هو اأحد امل�شادر التي قد ت�شاعد اأثناء متابعة املر�شى ، ور�شد تطور االأمرا�س ، وللح�شول على راأي طبي ثاٍن وكذلك يف االأن�شطة التعليمية الطبية. لقد مكنت التطورات يف التكنولوجيا ، وخا�شة الهواتف الذكية ، املهنيني الطبيني من احل�شول على �شور فوتوغرافية عالية اجلودة وباأقل قدر من اجلهد واخلربة يف الت�شوير الفوتوغرايف. تتناول هذه املقالة اأخالقيات وقانونية ا�شتخدام الهواتف الذكية ال�شخ�شية يف البيئة املهنية الطبية لغر�س الت�شوير الفوتوغرايف الطبي. يتوجب دوما احل�شول على املوافقة اخلطية امل�شتنرية من املري�س ويجب اأن تت�شمن تفا�شيل حول كيفية ا�شتخدام تلك ال�شور. الكلمات املفتاحية: ت�شوير فوتوغرايف؛ هاتف ذكي؛ موافقة م�شتنرية؛ اأخالقيات؛ ت�رشيعات طبية؛ من�شورات؛ تعليم طبي؛ عمان. the ethics and legality of using personal smartphones to take medical photographs amal a. al balushi sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e99–102, epub. 8 sep 19 submitted 4 jan 19 revision req. 10 feb 19; revision recd. 26 feb 19 accepted 1 apr 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. nowadays, smartphones and other electronic devices are used everywhere. these devices continually advance and have rapidly developed over recent years to allow people to perform many functions with minimum effort, such as professional photography. this technology has provided healthcare workers with the ability to take high quality photographs that are automatically stored electronically on userfriendly devices at a low cost.1 medical photographs are important in the manage ment and follow-up of medical conditions, especially in visually oriented specialities such as dermatology and plastic surgery.2 these images are also used for teaching, research and publication purposes in addition to getting a second opinion from colleagues or consultants in the same or other specialities.3,4 in oman, article 332 of the royal decree 7/2018 is concerned with the photography of individuals with out their consent; however, this law is not explicit for medical photography.5 in other jurisdictions, there are guidelines that regulate the practice of medical photo graphy.6,7 guidelines on this topic should address five main areas—consent, storage, retention, audit and transmission.8 case scenario the following is a fictitious case scenario to exemplify the ethical and legal dilemmas of using personal smart phones to take medical photographs. a 45-year-old female patient was referred to a plastic surgeon for an abdominoplasty after a sleeve gastr ectomy had led to the patient losing 80 kg post-oper atively in the first year. she complained of debilitating extra skin all over her body that was affecting her socially and in her daily life. her surgeon reviewed her case and decided on multiple procedures, beginning with an abdominoplasty. the surgeon explained the procedure to her and the patient consented. during a pre-operative visit, the surgeon asked permission for medical photograph to be taken of her but she politely refused as she would have to expose herself to the male hospital photographer. inside the operating room and before starting the surgery, the surgeon repeated the request for photographs to be taken by him to compare with the post-operative photographs. the patient hesitated but then agreed. he covered her genital area and took photographs with his personal smartphone. https://doi.org/10.18295/squmj.2019.19.02.003 sounding board https://creativecommons.org/licenses/by-nd/4.0/ the ethics and legality of using personal smartphones to take medical photographs e100 | squ medical journal, may 2019, volume 19, issue 2 one month later, an anxious patient presented at the surgeon’s clinic for the same procedure. the surgeon explained the procedure to her and answered her questions. in an attempt to ease her anxiety, he showed her the pre and post-operative photographs of his previous patient from his personal smartphone. the new patient agreed to have the procedure. discussion chan et al. found that in canada, 89% of surveyed surgeons and residents have taken medical photographs using smartphone devices.9 in australia, abbott et al. reported that smartphones were used for sending and receiving images by 50% of australian dermatology residents and specialists and that these medical photo graphs were electronically stored with limited privacy and security settings.10 the use of smartphones in hospitals can aid in speeding-up specialist consultations, for example, muir et al.’s study revealed that emergency departments received dermatology consultations within two hours by using smartphones.11 the use of smartphones has also improved triaging and management of inpatient dermatology consultations.12–14 written informed consent should be obtained before taking medical photographs despite this taking more time, to avoid future medical litigation;5 verbal consent is insufficient. failure to obtain informed consent is a breach of article 3 of the human rights act.15 the article states that “no one shall be subjected to torture or to inhuman or degrading treatment or punishment”.16 in addition, taking medical photographs of non-con senting patients is a breach of the patient’s privacy. it might be argued that a patient consents by default if a photograph is taken and no objection was raised. however, this is not the case when taking intra-operative photo graphs on anaesthetised patients. even in the case of a rare condition which is discovered intra-operatively, a photograph should not be taken without prior consent. if such a discovery is anticipated, written consent mentioning intra-operative photography and high lighting the image’s future uses, should be sought. importantly, patients need to understand their right to refuse as some might assume having pictures taken is necessary to their care. personal smartphones should never be used to take medical photographs. this risks violating the privacy and confidentiality of the patient. personal smartphones are not only used at work but also at home and in public places. therefore, there is a risk that doctor-patient confidentiality may be breached if a patient’s images are revealed during for example, a social interaction wherein personal photographs are being shown to others. kunde et al. urge physicians to help ensure the privacy of patient’s photographs on personal devices by enabling additional security features such as security codes.4 they present a scenario where a physician’s smartphone was stolen and patient’s images were uploaded onto the internet.4 it was the physician’s resp onsibility to maintain the confidentiality of his patient’s images, yet he failed by not securely storing them. however, enabling security features on personal devices may not be enough as smartphones can be breached. it is preferable to use a camera connected to the hospital computer system so that the patient’s image can be stored in the patient’s electronic file which typically has a better security system than a smartphone. if the security of the electronic filing system is questionable, photographs should not be taken. individuals who require or seek medical attention are dependent on their doctor for medical expertise and this makes the patients vulnerable.17,18 this imbalance of power can influence patients to agree to have their photograph taken when they would otherwise refuse. physicians must not exaggerate or overestimate the need for a photograph. a physician’s request for photo graphy might be difficult to refuse especially if there is a trusting doctor-patient relationship as in the case scenario presented above. the patient might fear the loss of this relationship and the potential consequences of reduction in care quality or the possibility of finding an alternative physician. in order to avoid such a situation, consent can be requested via a third party who the patient is neutral towards and can therefore easily be refused without potentially compromising the doctor-patient relationship. this third party may be another member of the healthcare team or a trained nurse. the physician should highlight that a refusal to allow medical photo graphs to be taken will not affect the patient’s care. more over, if a patient refuses medical photography, the phys ician must not repeat this request. repetition of medical photography requests pressures the patient against his or her wishes resulting in invalidation of the consent. medical photographs taken without consent are categorised as either paternalistic practice (physician chooses to not act in the patient’s best interest) or as ethical egoism (physician acts in their own interest regardless of the patient’s best interest).19 using medical photographs for follow-up or to seek a second opinion by sending it to a colleague is an example of the former, while using them for publication and teaching purposes without consent is an example of the latter. both practices should not be exercised as non-consented medical photography is unethical and a potential source for litigation. amal a. al balushi sounding board | e101 sometimes patients show a medical photograph containing transient, progressive or recurrent pathology to their doctor; implied consent is assumed for such images if shared for diagnostic purposes.5 however, if a physician requests a copy of the photograph, consent should be obtained.5 photographs of non-identifiable radiographic investigations can be taken with verbal con sent in addition to documenting the diagnostic and patient care purpose in the patient’s file.20 written consent is needed for educational and publication purposes of med ical photographs of investigations as usually the patient’s demographic data and their clinical presentation are shared. recommendations verbal patient consent is insufficient and, therefore, obtaining written informed consent should be standard practice before starting any treatment that requires medical photography. obtaining informed consent is the physician’s responsibility even if it is delegated to a member of staff.21 the physician should explain and discuss the purpose of the medical photography, its potential benefits to the patient and to the management of the patient’s condition, as well as the associated risks and who will have access to the photographs; such information should be clearly stated in the informed consent form. unintentional risk of disclosure of the patient’s identity and confidentiality even with efforts to cover their identity such as covering eyes must be explained to the patient.21 moreover, patient’s should be allowed to choose the purpose of their medical photograph (e.g. to monitor the progression of the condition, for educational purposes or both) and any future use such as research, publication or educational uses should be clearly stated with an option to with draw consent at any time. however, it is important for the physician to highlight that after dissemination of the photographs through publication or educational materials, it is impossible to withdraw consent or remove the photographs.21 consent for photographs taken for clinical purposes can be withdrawn at any time and the photographs removed since they are securely stored in the patient’s file. theoretically, a patient’s photographs are their property as long as they are solely in their clinical file, but once they are published publicly, they are no longer a patient’s property and patients must be made aware of this. a chaperone should be present during the photo graphy process, especially if the patient and photographer/ physician are of different genders.22,23 the name of the chaperone or refusal of a chaperone needs to be documented in the consent form and clinical records.23 moreover, exposure of the patient’s body parts should be limited to where the disease/condition appears and the photograph should be shown to the patient for final approval. medical photography requests should not be repeated if the patient is reluctant or unwilling. patients should be allowed to choose between a specialised medical photographer or the treating physician, esp ecially if the involved area of the body is private. medical photographs must only be stored in the hospital’s computer system and deposited in the patient’s file. patient photographs should never be stored on personal devices and must not be taken outside hospital premises unless for educational purposes. ideally, personal smartphones should not be used for medical photography. however, if their use is necessary to communicate with consultants, the phy sician should obtain written informed consent after explaining the purpose and with whom the photograph will be shared and must be deleted after the consultation. this should be documented in the patient’s file.5 alter natively, allocated mobile devices for professional use only, that are synchronised with the hospital’s computer system, can be used to receive consultations based on shared medical photographs even outside hospital premises. conclusion using smartphones for medical photography is faster, more convenient and widely available. however, ethical issues such as patient confidentiality and privacy may be breached when using smartphones to take patient photographs, especially when using personal devices. therefore, it is recommended that only hospital equip ment be used and written informed consent be obtained to avoid litigation/ethical misconduct. references 1. kornhaber r, betihavas v, baber rj. ethical implications of digital images for teaching and learning purposes: an integrative review. j multidiscip healthc 2015; 8:299–305. https://doi.org/10.2147/jm dh.s84488. 2. mahar pd, foley pa, sheed-finck a, baker cs. legal consider ations of consent and privacy in the context of clinical photo graphy in australian medical practice. med j aust 2013; 198:48–9. https://doi.org/10.5694/mja12.11086. 3. palacios-gonzález c. the ethics of clinical photography and social media. med health care philos 2015; 18:63–70. https:// doi.org/10.1007/s11019-014-9580-y. 4. kunde l, mcmeniman e, parker m. clinical photography in dermatology: ethical and medico-legal considerations in the age of digital and smartphone technology. australas j dermatol 2013; 54:192–7. https://doi.org/10.1111/ajd.12063. 5. ministry of legal affairs. the penal law promulgated by royal decree 7/2018. from http://www.mola.gov.om/download.aspx? path=pdf/omani%20penal.pdf accessed: feb 2019. https://doi.org/10.2147/jmdh.s84488 https://doi.org/10.2147/jmdh.s84488 https://doi.org/10.5694/mja12.11086 https://doi.org/10.1007/s11019-014-9580-y https://doi.org/10.1007/s11019-014-9580-y https://doi.org/10.1111/ajd.12063 the ethics and legality of using personal smartphones to take medical photographs e102 | squ medical journal, may 2019, volume 19, issue 2 6. institute of medical illustrators. imi national guidelines: con sent to clinical photography. from: http://www.imi.org.uk/file/ download/2143/iminatguidelinesconsentmarch_2007.pdf accessed: feb 2019. 7. the royal australian and new zealand college of ophthalmo logists. guidelines on use of clinical photographs. from: https:// ranzco.edu/articledocuments/176/use%20of%20clinical%20 photography%20guidelines.pdf.aspx?embed=y accessed: feb 2019. 8. heyns m, steve a, dumestre do, fraulin fo, yeung jk. cana dian guidelines on smartphone clinical photography. canadian j physician leadersh 2018; 4:158–63. 9. chan n, charette j, dumestre do, fraulin fo. should ‘smart phones’ be used for patient photography? plast surg (oakv) 2016; 24:32–4. https://doi.org/10.1177/229255031602400109. 10. abbott lm, magnusson rs, gibbs e, smith sd. smartphone use in dermatology for clinical photography and consultation: current practice and the law. australas j dermatol 2018; 59:101–7. https://doi.org/10.1111/ajd.12583. 11. muir j, xu c, paul s, staib a, mcneill i, singh p, et al. incor porating teledermatology into emergency medicine. emerg med australas 2011; 23:562–8. https://doi.org/10.1111/j.17426723.2011.01443.x. 12. duong ta, cordoliani f, julliard c, bourrat e, regnier s, de pontual l, et al. emergency department diagnosis and man agement of skin diseases with real-time teledermatologic exp ertise. jama dermatol 2014; 150:743–7. https://doi.org/10.10 01/jamadermatol.2013.7792. 13. barbieri js, nelson ca, james wd, margolis dj, littman-quinn r, kovarik cl, et al. the reliability of teledermatology to triage inpatient dermatology consultations. jama dermatol 2014; 150:419–24. https://doi.org/10.1001/jamadermatol.2013.9517. 14. börve a, holst a, gente-lidholm a, molina-martinez r, paoli j. use of the mobile phone multimedia messaging service for teledermatology. j telemed telecare 2012; 18:292–6. https:// doi.org/10.1258/jtt.2012.120206. 15. berle i. clinical photography and patient rights: the need for orthopraxy. j med ethics 2008; 34:89–92. https://doi.org/10.11 36/jme.2006.019166. 16. human rights act 1998. aritcle 3. from: https://www.legis lation.gov.uk/ukpga/1998/42/schedule/1/part/i/chapter/2 accessed: feb 2019. 17. matthews s, tobin b. human vulnerability in medical contexts. theor med bioeth 2016; 37:1–7. https://doi.org/10.1007/s11017 016-9357-9. 18. berle i. the principles of ethical practice in professional clinical photography. j audiov media med 2004; 27:11–13. https://doi. org/10.1080/01405110310001658897. 19. berle i. the ethical context of clinical photography. j audiov media med 2002; 25:106–9. https://doi.org/10.1080/01405110 2320376816. 20. heyns m, steve a, dumestre do, fraulin fo, yeung jk. best practices for smartphone and smart-device clinical photo taking and sharing. canadian medical association. from: http://policy base.cma.ca/dbtw-wpd/policypdf/pd18-04.pdf accessed: feb 2019. 21. lakdawala n, fontanella d, grant-kels jm. ethical considerations in dermatologic photography. clin dermatol 2012; 30:486–91. https://doi.org/10.1016/j.clindermatol.2011.06.017. 22. clynch, p. chaperones within a sensitive medical photography environment. j vis commun med 2009; 32:99–100. https://doi. org/10.3109/17453050903226000. 23. saidun s. photographing human subjects in biomedical disc iplines: an islamic perspective. j med ethics 2013; 39:84–8. https://doi.org/10.1136/medethics-2012-100794. https://doi.org/10.1177/229255031602400109 https://doi.org/10.1111/ajd.12583 https://doi.org/10.1111/j.1742-6723.2011.01443.x https://doi.org/10.1111/j.1742-6723.2011.01443.x https://doi.org/10.1001/jamadermatol.2013.7792 https://doi.org/10.1001/jamadermatol.2013.7792 https://doi.org/10.1001/jamadermatol.2013.9517 https://doi.org/10.1258/jtt.2012.120206 https://doi.org/10.1258/jtt.2012.120206 https://doi.org/10.1136/jme.2006.019166 https://doi.org/10.1136/jme.2006.019166 https://doi.org/10.1007/s11017-016-9357-9 https://doi.org/10.1007/s11017-016-9357-9 https://doi.org/10.1080/01405110310001658897 https://doi.org/10.1080/01405110310001658897 https://doi.org/10.1080/014051102320376816 https://doi.org/10.1080/014051102320376816 https://doi.org/10.1016/j.clindermatol.2011.06.017 https://doi.org/10.3109/17453050903226000 https://doi.org/10.3109/17453050903226000 https://doi.org/10.1136/medethics-2012-100794 to the editor we write in response to the above mentioned article which appeared in the august 2009 issue of squmj.1 radiation regulations in most countries permit treatment of thyrotoxicosis using radioactive iodine (i-131) as an outpatient procedure. hospitals provide instructions to the patients receiving these treatments about the precautions to be observed in their homes in terms of avoiding local radioactive contaminations and also protect other inmates restricting the radiation exposures ‘as low as reasonably achievable’. therefore it is of interest to quantify the radiation exposures incurred from these patients to spouse, children and attendants. early worksaddressed different related issues in this regard.2-4 from this objective, we appreciated the work of al-maskery and bererhi reported in your august 2009 issue. the following are the highlights of their work. their study involved 22 thyrotoxic patients treated on an out-patient basis. thermo-luminescent dosimeters (tld) monitoring was carried out on 86 inmates in their homes (29 children and 57 adults). the quantity of i-131 radioactivity administered was 610 ± 79 mbq in the range of 520–862 mbq. measured mean radiation levels around these patients immediately post-administrations was 23.4 ± 6.3 µsv/h in the range of 13–42 µsv/h. the cumulative radiation doses by other inmates in the homes of these thyrotoxic treated patients during 10 days are shown in two categories. spouses (n = 11) received a mean radiation dose of 105 ± 152 µsv in the range of 7-425 µsv. other relatives or attendants received a mean radiation dose of 206 ± 440 µsv in the range of 0–2921µsv. in oman, our hospital is another centre where radioactive i-131 treatments for thyrotoxicosis and carcinoma thyroid are offered. from the data of measured exposure rates around these patients, we have obtained the following results.5 the mean activities administered were 4.19 gbq (in the range of 2.04–9.3 gbq) and 574.7 mbq (in the range of 479–627 mbq) for thyroid cancer and hyperthyroidism treatments respectively. mean exposure rates immediately after administration of the i-131 therapy doses were 88 µsv/h (n = 69 in the range of 34–184 µsv/h) for thyroid cancer patients, and 14.9 µsv/h (n = 49 in the range of 4.5–34 µsv/h) for thyrotoxic patients. our study revealed that the radioactive body burden for postoperative thyroid carcinoma had a tri-exponential clearance pattern with t½eff values 14.4h, 22.0h and 41.3h. the body burden of the treated patients for hyperthyroidism cleared with an effective half life t½eff =111.4h. figure 1 shows the clearance pattern of i-131 with time elapsed post administration in these thyrotoxic patients. with our data accrued from the omani patients, taking the effective half life (t½eff ) of clearance in the patients with hyperthyroidism viz. t½eff = 111.4h, we tried to explain the results of cumulative radiation squ med j, april 2010, vol. 10, iss. 1, pp. 138-141, epub. 17th apr 10 submitted 7th jan 10 إشارة إىل: مستويات التعرض لإلشعاع ألفراد عوائل املرضى العمانيني املصابني بتسمم الغدة الدرقية واملعاجَلني باليود املشع يف العيادة اخلارجية رامام�رثي رافيجاندران، اأمل ال�شعدي re: radiation exposure levels in family members of omani patients with thyrotoxicosis treated with radioiodine (i-131) as outpatients ramamoorthy ravichandran and amal al-saadi letter to editor ramamoorthy ravichandran and amal al-saadi letter to editor | 139 exposures received by the inmates observed in the recent study as below.2 method of estimation of radiation level around the patients ( for administered i-131 activity 610 mbq): dose rate constant for i-131, at 1metre, γ in msv. m2/mbq.hr (ref. 6) = 7.467 x10-5 msv/h=7.467x102µsv/h = 0.07467 µsv/h. total emitted dose at 1m from the patient administered with 610 mbq of i-131 = (activity administered in mbq) x (1.44 times t½eff in hours x (exposure rate in µsv/h) = 610 mbq x (1.44 x 111.4 hours) x (0.07467µsv/h/mbq) µsv = 7307 µsv therefore, if we assume that in 10 days the administered activity of i-131(610mbq) has fully emitted all its emissions, this emitted radiation 7307 µsv at 1m should be taken to represent the cumulated dose received by the individuals moving around the patient in the house. this can be safely assumed because 10 days (240 h) elapsed time duration is nearing 2.5 t½eff eliminating 83% of administered activity. c a l c u l at e d r a d i at i o n d o s e s b y i n m at e s at h o m e as the patient has already received instructions, as indicated in table 1 of the referred work,1 there will not be permanent presence of other people near the patient. we have to assume some model to explain the local situations around treated patients in their homes. for this, if we take 2 m as reference distance, we can calculate cumulated radiation doses with approximate ‘use factors’ ¼ (6 hours/day), ¹/12 (2 hours/ day), ¹/24 (1 hour/day). in these 3 circumstances, the cumulated radiation doses at 2m will be: (emitted dose 7307 µsv at 1m) x (inverse square factor ¼) x (use factor ¼) = 457 µsv (emitted dose 7307 µsv at 1m) x (inverse square factor ¼) x (use factor ¹/12) = 152 µsv (emitted dose 7307 µsv at 1m) x (inverse square factor ¼) x (use factor ¹/24) = 76µsv d o s e e s t i m at e s in the above circumstances, the estimates of radiation dose in the reported study1 for spouses (105 ± 152 µsv in the range of 7 to 425µsv) and other relatives or attendants received a mean radiation dose of 206 ± 440 µsv in the range of 0 to 2921 µsv seems to be realistic. true situations could be approximated within 2 m movement distances in the house, and a representation of ‘use factor’, as it is conventionally taken to represent approximate situations encountered in health physics calculations, could be assumed. the uncertainties in this communication are: a) the effective half life estimated is based on the mean exposure rates measured on consecutive days in the patients; b) the measured exposure rates are based on beta, gamma survey meters which have inaccuracies in terms of estimated µsv/h, and c) there are difficulties in reproducing true circumstances encountered by the inmates spending time with the patients in their homes. this communication gives a theoretical account to explain the radiation dose estimates by tl detectors, which could be applicable to the similar earlier report also.3 pant et al.3 reported higher doses to the family members from thyrotoxic patients, viz. 0.4 to 2.4 msv (mean 1.1 msv) and 0 to 1.9 msv (mean 0.6 msv). this report is from india, where the living conditions in homes are different from those encountered in 1 10 100 o 24 48 72 96 120 time elapsed post administration (h) 131 estimation of body burden thyrotoxicosis m ea n 1m e xp . r at e µ sv /h figure 1: clearance of i-131 in thyrotoxic patients (n = 49) re: radiation exposure levels in family members of omani patients with thyrotoxicosis treated with radioiodine (i-131) as outpatients 140 | squ medical journal, april 2010, volume 10, issue 1 oman, as individual patients may be moving in closer proximity to other people at home because of higher population density in cities like delhi. this type of approximation of 1 m emitted dose around patients is the first of its kind and had not been reported earlier in the literature. more insight has to be given to this hypothesis, for health physics applications with the use of ingested radioisotopes in humans. to conclude, in this study we simplify the calculation of radiation exposure to patient’s family members with a theoretical modelling, by using a fixed factor called ‘emitted dose at 1m’ around the patient. this data is based on the effective half life of clearance estimated from patients from royal hospital.5 by showing agreement with the estimated exposure by tld in the referred study,4 it is opined that i-131 thyrotoxicosis patients can be treated as outpatients with proper instructions provided to them. references 1. al-maskery i, bererhi h. radiation exposure levels in family members of omani patients with thyrotoxicosis treated with radioiodine (i-131) as outpatients. squ med j 2009; 9:148–52. 2. barrington s, doherty m, kettle a, thomson w, mountford p, burrell d. radiation exposure of the families of outpatients treated with radioiodine (i-131) for hyperthyroidism. eur j nucl med 1999; 26:686–92. 3. pant gs, sharma sk, bal cs, kumar r, rath gk. radiation doses to family members of hyperthyroidism and thyroid cancer patients treated with i-131. radiat prot dosimetry 2006; 118: 22–7. 4. monsieurs m, thierens h, dierckx r, casier k, baere e, riddenr l. real time radiation burden to relatives of patients treated with iodine-131: a study in eight centers in flanders (belgium). eur j nucl med 1998; 25: 1368–76. 5. ravichandran r, binukumar jp, al saadi a. estimation of effective half life of clearance of radioactive iodine (i-131) in patients treated for hyperthyroidism and carcinoma thyroid. submitted for publication. indian j nucl med, 2009. 6. radiation safety and health physics. in: cherry sr, sorenson ja, phelps me, eds. physics of nuclear medicine. 3rd ed. philadelphia: wb saunders, 2003. pp. 427–41. ramamoorthy ravichandran and amal al-saadi national oncology center, royal hospital, seeb-muscat, oman. email: ravichandranrama@rediffmail.com author's response i am writing to respond to dr. ramamoorthy ravichandran and amal al-saadi’s letter of 7th january 2010 regarding our article, radiation exposure level in family members of omani patients with thyrotoxicosis treated with radioiodine as out patients.1 the authors used a radioiodine-131 (i-131) kinetic model (submitted for publication to the indian j nuclear medicine journal) and input data on thyrotoxic patients from our clinical studies to estimate the radiation dose received by relatives at home. they found that the kinetic model gave results that were very similar to our clinic trials. we appreciate the effort of the authors to run the model on our data. kinetic models of radioiodine are well established and are extensively used to estimate radiation exposures. when we started radioiodine therapy 20 years ago in sultan qaboos university, we knew that kinetic models could be used instead of clinical trials because the models had been and continue to be successfully used in other countries. however, the kinetic models were applied on patients from very different cultures. ramamoorthy ravichandran and amal al-saadi letter to editor | 141 because the social and cultural traditions in oman were so different, we did not know how patients might react to this new radioactive treatment and so we started by using rather stringent regulations whereby patients remained in hospital until the radiation level at one meter from the patient dropped to 2µsv/h. this policy was derived from the uk guidance notes,2 which allow an internal body activity limit of 30mbq of i-131 for contact with children. progressively, we cautiously began to reduce these stringent regulations after making sure that the instructions were generally well followed. we performed two clinical studies3,1 to better understand patient and relatives response to radiation safety instructions and we are now convinced, especially after this most recent study, that we should treat thyrotoxic patients as outpatients because the radiation dose received by patient relatives is within radiation safety regulations. haddia bererhi medical physics unit department of radiology & molecular imaging sultan qaboos university hospital muscat, oman references 1. al maskery i, bererhi h. radiation exposure level in family members of omani patients with thyrotoxicosis treated with radioiodine as out patients. squ med j 2009; 9:148–52. 2. hmso. guidance notes for the protection of persons against ionizing radiation arising from medical and dental use. london 1988. 3. bererhi h, constable ar. radiation exposure levels in ralatives of patients after radioiodine therapy. squ j sci res: med sci 2000; 2:87–90. department of orthopaedics, lady hardinge medical college, new delhi, india *corresponding author’s e-mail: siddharthasinha87@gmail.com مشية متمايلة إحدى مضاعفات العالج بدواء فالربويت، وتصور مغاير بالنسبة لنقص فيتامني د اميت �صارما، �صيدهاثا �صيهنا، اميت نارانق، دي�صونت كي. �صاوهان، �صوميت قوبتا abstract: proximal muscle weakness is a common presentation in paediatric-orthopaedic clinics and is frequently paired with a vitamin d deficiency diagnosis. recently, side effects of the extensive use of antiepileptic and antipsychotic drugs such as sodium valproate in childhood disorders are being documented. sodium valproate causes a time-dependent, drug-induced proximal myopathy. we report a 13-year-old female patient who presented at the orthopaedic outpatient department at lady hardinge medical college, new delhi, india, in 2019 with an abnormal gait. the patient was taking a combination therapy of sodium valproate, risperidone and trihexyphenidyl for absence seizures and a mood disorder. following clinical investigations, the patient was diagnosed with proximal myopathy. as a result of elevated serum alkaline phosphatase and creatine kinase myocardial band levels, sodium valproate was replaced with ethosuximide and a carnitine supplementation was prescribed. the patient fully recovered and regained full mobility. proximal myopathy had been incorrectly managed and assumed to be caused by a vitamin d deficiency. keywords: muscle weakness; carnitine; myopathy; valproic acid; vitamin d deficiency; gait; case report; india. امللخ�ص: اإن �صعف الع�صل الداين حالة �صائعة يف عيادات جراحة تقومي عظام الأطفال، وكثريا ما ُيقرن بت�صخي�س نق�س فيتامني د. و�صجلت حديثا الآثار اجلحانبية لال�صتخدام املفرط مل�صادات ال�رشع مثل دواء �صوديوم فالبوريت يف ا�صطرابات الطفولة. وي�صبب هذا الدواء اعتالل ع�صليا دانيا. ون�صجل هنا حالة ل�صبية عمرها ثالثة ع�رش �صنة اأح�رشت يف عام 2019م لعيادة جراحة تقومي العظام اخلارجية يف كلية ليدي هاردنق الطبية بنيودلهي يف الهند. وكانت تعاين من م�صية غري �صوية. وكانت املري�صة تتناول اأدوية �صوديوم فالبوريت ودي�صبرييدين وتراي هيك�صي فينيديل لعالج غيبة �رشعية وا�صطرابات املزاج. وبعد اإجراء الفحو�صات الطبية مت ت�صخي�س احلالة على اأنها اعتالل ع�صلي. وبالنظر لرتفاع ن�صاط انزمي فو�صفاتيز القلوي يف م�صل الدم، وم�صتوى �رشيط أنزمي كرياتني كاينيز لع�صلة القلب، مت ا�صتبدال دواء �صوديوم فالبوريت بدواء ايزو�صيك�صامايد، واأعطيت املري�صة كارنتني كمادة تكميلية. �صفيت املري�صة ب�صورة كاملة بعد هذا العالج، وا�صتعادت م�صيتها الطبيعية. كان عالج ال�صعف الع�صلي الداين للمري�صة يتم على اأنه ب�صبب نق�س فيتامني د، وعولج بطريقة خاطئة على هذا الأ�صا�س. الكلمات املفتاحية: ال�صعف الع�صلي؛ كارنتني؛ اعتالل ع�صلي؛ حام�س فالبوريك؛ نق�س فيتامني د؛ م�صية؛ تقرير حالة؛ الهند. waddling gait a complication of valproate therapy and a thought beyond vitamin d deficiency amit sharma, *siddhartha sinha, amit narang, dushyant k. chouhan, sumit gupta sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e104–108, epub. 9 mar 20 submitted 16 jul 19 revisions req. 18 sep & 22 oct 19; revisions recd. 2 oct & 30 oct 19 accepted 14 nov 19 abnormal gait in children, often noticed by parents or caregivers is a common presentation in orthopedic outpatient depart ments and requires a comprehensive work-up. waddling gait in children is commonly caused by hip disorders such as developmental hip dysplasia, septic sequelae in the hip, bilateral perthes disease and slipped capital femoral epiphysis. some uncommon causes of waddling gait include myopathies due to endocrine disorders, drugs, systemic disorders and spinal muscular atrophy.1–3 in developing countries, these cases are often attributed to the deficiency of vitamin d; empirical administration of vitamin d is usually given to the patient due to a lack of adequate resources for estimating vitamin d3 levels. while this strategy is useful in the majority of patients, some do not respond and the management of these patients therefore becomes a challenge. many drugs used in childhood disorders have the potential to cause a proximal myopathy.4 sodium valproate is being extensively used for the management of epilepsy and mood disorders. prolonged use of this drug may cause nausea, vomiting, anorexia, sedation, weight gain, alopecia, hepatotoxicity, encephalopathy and myopathy.5 other antiepileptics/antipsychotics such as carbamazepine and oxcarbazepine do not cause myopathy.6 as many children present with signs and symptoms of proximal myopathy it is important to approach the case methodically and recognise druginduced myopathy. following a detailed history and examination to determine non-response to empirical vitamin d supplementation, a diagnosis can be easily made. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.016 case report https://creativecommons.org/licenses/by-nd/4.0/ amit sharma, siddhartha sinha, amit narang, dushyant k. chouhan and sumit gupta case report | e105 on general physical examination, the patient was judged to be moderately built. she had no pallor, jaundice, oedema or lymphadenopathy. no neck swelling was noted and her skin and eyes appeared to be normal. the patient was walking with a waddling gait (figure 1a–e) and an exaggerated lumbar lordosis. the power in hip abductors and deltoid was 4/5 and all other muscle groups had a power of 5/5. sensations were intact and all the deep tendon reflexes were normal and comparable bilaterally. the trendelenburg test was bilaterally positive (figure 1f and g). she was able to squat and sit cross-legged but had difficulty standing up. there was no weakness of the neck, chest and abdominal muscles. in addition, there was no calf hypertrophy and gowers sign was negative. routine x-ray examination was normal and did not show any signs of rickets or any other hip disorders. serum alkaline phosphatase was elevated to 897 inter national units (iu)/l (normal range: 53–128 iu/l) and serum creatine kinase myocardial band (ck-mb) was elevated to 35.9 iu/l (normal range: 0–25 iu/l). serum vitamin d3 level was normal at 40.60 ng/ml (normal range: 30–50 ng/ml) and thyroid function tests were within normal limits. she was continued with vitamin d supplementation with the expectation that time may improve the myopathy as she was already taking vitamin d supplementation. at the one-week follow-up, the weakness had not improved. serum alkaline phosphatase level was still elevated and the possibility this may be due to valproate was considered. serum sodium valproate levels were tested and found to be within therapeutic levels. nerve conduction studies and electromyography were case report a 13-year-old female patient presented to the ortho paedic outpatient department, lady hardinge medical college, new delhi, india, in 2019 with an abnormal gait for the previous six months. her mother noticed that she was finding it progressively more difficult to walk although there was no pain. there was no significant history of trauma, fever, night sweats, cough or diurnal variation in weakness. she was able to walk without support, go to school and carry out routine activities before the onset of symptoms. over the prior six months she had felt tired after being physically active and developed a dull-aching pain in the hip and thighs that increased with prolonged activity and was relieved by rest and over-the-counter analgesics. the weakness progressively worsened to the extent that she was unable to walk to school, climb stairs or ride a bicycle. her family members also noticed clumsiness in her gait which was associated with the weakness. the patient was managed by multiple practitioners with oral vitamin d supplementation but her gait did not improve. she was taking a combination of sodium valproate (200 mg, twice daily), risperidone (2 mg, once daily) and trihexyphenidyl (2 mg, once daily) for the past three years for absence seizures and a mood disorder which had been prescribed by a specialised institute. there was no history of excessive sleepiness, change in voice, weight gain or constipation. pre-, periand postnatal histories were not significant and her developmental milestones were normal. there was no history of previous illness of a similar nature in the patient or in any family member. figure 1: photographs of a 13-year-old female patient showing her (a–e) gait at presentation and (f and g) the trendelenburg test. figure 2: photographs of a 13-year-old female patient showing an improved gait at three-month follow-up. waddling gait a complication of valproate therapy and a thought beyond vitamin d deficiency e106 | squ medical journal, february 2020, volume 20, issue 1 essentially normal. serum carnitine was not tested due to financial constraints. sodium valproate was stopped and carnitine supplementation was started. at the two-week followup, the patient showed signs of improvement. she was able to climb stairs and sit-up from a squatting position easily. however, the trendelenburg test remained positive. at three-months follow-up, her gait had improved and the trendelenburg test was negative. she reported being able to go to school, cycle and run without feeling pain or exhaustion [figure 2]. power in all muscle groups was 5/5 and serum alkaline phosphatase and ck-mb returned to normal levels. during this period, valproate was replaced by ethosuximide which did not cause recurrence of her psychiatric or musculoskeletal symptoms. discussion when children with abnormal gait and weakness present to an orthopaedic outpatient department, many differential diagnoses should be considered. proximal myopathy, which leads to an abnormal gait in children, may be caused by common drugs such as corticosteroids [table 1].4 furthermore, endocrine and metabolic abnormalities such as thyroid and parathyroid dys function, malignancy and idiopathic inflammatory myopathies including polymyositis and dermatomyo sitis can cause proximal myopathy. congenital myopathies such as duchenne and becker muscular dystrophy also cause proximal myo pathies. infective causes such as hiv, influenza and hepatitis b and c should also be excluded from the differential diagnoses.3 vitamin d deficiency has been reported to cause proximal myopathy and was found to be associated with increased serum alkaline phosphatase; this elevation can be caused by valproate toxicity.7–10 myopathy due to vitamin d deficiency begins resolving within 4–6 weeks of treatment and completely resolves within six months and often shows skeletal changes unlike valproate-induced myopathy.11,12 valproate-induced myopathy is not commonly suspected and there are very few reported cases on this condition; therefore, the exact incidence has not been calculated. a search via pubmed® (national library of medicine, bethesda, maryland, usa) and embase (elsevier, amsterdam, netherlands) revealed a total of three cases of valproate-induced myopathy [table 2].5,13,14 children using sodium valproate present with signs of proximal myopathy with near normal routine biochemical parameters.5,13 decreased serum carnitine levels due to valproate were first reported in 1982 by ohtani et al. and later demonstrated in various other studies.7,15–19 most antiepileptic drugs do not cause a decrease in serum carnitine level and myopathy has not been reported.6 although no obvious pathological changes are seen in children using sodium valproate, the drug has a potential to cause cardiac dysfunction, encephalopathy, hepatotoxicity and cerebral oedema.13 an increase in serum alkaline phosphatase and creatine kinase induced by an antiepileptic drug may be confused with hypovitaminosis d. fatigue, difficulty in running, jumping, climbing stairs, difficulty in getting up from a sitting position and other signs of proximal muscle myopathy are common presentations in valproate-induced myopathy. sensations and deep tendon reflexes are preserved. a waddling gait and exaggerated lumbar lordosis are also present. needle electromyography may show signs of a myopathic pattern.13 muscle biopsy shows ultrastructural abnorm table 1: common drugs used in paediatric departments that cause myopathy4 drug indication anti-retroviral therapy (e.g. zidovudine) hiv glucocorticoid autoimmune disorders, asthma, hormone replacement therapy and nephrotic syndrome anti-malarial (e.g. chloro quine and hydroxy chloroquine) autoimmune disorders voriconazole antifungal phenytoin antiepileptic tretinoin acne table 2: biochemical parameters of various published case studies and the current case5,13,14 author and year of publication serum valproate in μg/ml serum carnitine in μmol/l serum creatine phosphokinase serum vitamin d3 in ng/ml serum alkaline phosphatase in iu/l reiche et al.14 (2009) 46 (within theraputic range) n/a 14.4 μmol/l (increased) n/a n/a ahmed13 (2015) normal 13 (decreased) normal n/a n/a kasturi and sawant5 (2005) normal 16 (decreased) normal n/a n/a current case normal n/a 35.9 iu/l (increased) 40.60 (normal) 897 (increased) iu = international units; n/a = not available. amit sharma, siddhartha sinha, amit narang, dushyant k. chouhan and sumit gupta case report | e107 conclusion proximal myopathy in a developing country is commonly managed with vitamin d supplementation. however, if there is no response, other differential diagnoses should be considered beyond vitamin d deficiency. a detailed history and clinical examination with a focus on a past history of neurologic disease, extended dur ation of valproate intake and evaluation of proximal muscle power can aid in the diagnosis. discontinuation of valproate and a combination of vitamin d and carnitine supplementation rapidly reverses proximal myopathy. prophylactic supplementation of carnitine to prevent myopathy is currently still being evaluated. references 1. barkin rm, barkin sz, barkin az. the limping child. j emerg med 2000; 18:331–9. https://doi.org/10.1016/s0736-4679(99) 00224-3. 2. leung ak, lemay jf. the limping child. j pediatr health care 2004; 18:219–23. https://doi.org/10.1016/j.pedhc.2004.03.004. 3. suresh e, wimalaratna s. proximal myopathy: diagnostic approach and initial management. postgrad med j 2013; 89:470–7. https://doi.org/10.1136/postgradmedj-2013-131752. 4. valiyil r, christopher-stine l. drug-related myopathies of which the clinician should be aware. curr rheumatol rep 2010; 12:213–20. https://doi.org/10.1007/s11926-010-0104-3. 5. kasturi l, sawant sp. sodium valproate induced skeletal myo pathy. indian j pediatr 2005; 72:243–4. https://doi.org/10.1007/ bf02859266. 6. kurul s, dirik e, iscan a. serum carnitine levels during oxcarbazepine and carbamazepine monotherapies in children with epilepsy. j child neurol 2003; 18:552–4. https://doi.org/10.1 177/08830738030180080201. 7. coulter dl. carnitine, valproate, and toxicity. j child neurol 1991; 6:7–14. https://doi.org/10.1177/088307389100600102. 8. lheureux pe, hantson p. carnitine in the treatment of valproic acid-induced toxicity. clin toxicol (phila) 2009; 47:101–11. https://doi.org/10.1080/15563650902752376. 9. world health organization. expert committee on medical assessment of nutritional status [meeting held in geneva from 21 to 27 august 1962]: report. from: https://apps.who.int/iris/ handle/10665/40561 accessed: oct 2019. 10. reddy v, srikantia sg. serum alkaline phosphatase in mal nourished children with rickets. j pediatr 1967; 71:595–7. https://doi.org/10.1016/s0022-3476(67)80117-3. 11. glerup h, mikkelsen k, poulsen l, hass e, overbeck s, andersen h, et al. hypovitaminosis d myopathy without bio chemical signs of osteomalacic bone involvement. calcif tissue int 2000; 66:419–24. https://doi.org/10.1007/s002230010085. 12. prabhala a, garg r, dandona p. severe myopathy associated with vitamin d deficiency in western new york. arch intern med 2000; 160:1199–203. https://doi.org/10.1001/archinte.160. 8.1199. 13. ahmed r. sodium valproate-induced myopathy in a child. sultan qaboos univ med j 2015; 15:e146–7. 14. reiche i, tröger u, postel sc, wolf r, bode-böger sm. valproic acid-induced myopathy in a patient with schizoaffective dis order. j clin psychopharmacol 2009; 29:402–3. https://doi.org/ 10.1097/jcp.0b013e3181ad2256. alities and electron microscopy shows lipid droplet accumulation in the muscles.16 some authors stipulate that valproate-induced myopathy may be a timedependent, not dose-dependent, condition due to the progressive depletion of carnitine from muscle cells.5,7 valproate causes a transient decrease in serum carnitine by increasing the renal clearance. sodium valproate decreases alpha-ketoglutarate causing accum ulation of toxic products.8 this accumulation of toxic byproducts and decreased level of serum carnitine, in addition to pre-existing risk factors, is the proposed pathogenesis for myopathic effects. risk factors exacerbating valproate-induced myo pathy include young age, multiple neurological dis abilities, poor nutrition, being underweight, multiple anticonvulsant drug therapy, hyperammonaemia and metabolic acidosis. four months of valproate therapy can be considered as an adequate duration which can induce myopathy. laub et al.’s study included 21 children on sodium valproate therapy for a duration of more than four months and found decreased levels of serum carnitine possibly due to alterations in the fatty acid metabolism because of the valproate.15 discontinuing valproate with the addition of carn itine supplementation reverses the symptoms. ident ifying children at risk and establishing a preventive dose of carnitine and prophylactic vitamin d supple mentation for children on valproate therapy can further decrease the incidence of valproate-induced myopathy. the current case was from a poor socio-economic background and had been taking multiple anticonv ulsive medications due to absence seizures and a mood disorder. as a result, she developed myopathy which was unresponsive to empirical vitamin d supplementation based on clinical suspicion of rickets. after valproate was discontinued and carnitine supplementation was prescribed, the patient had a significant improvement in gait. it should be noted that there is a possibility that the patient had a mitochondrial cytopathy manifesting with seizures and mood changes, in whom valproate unmasked the myopathy as an additional manifestation of this underlying condition.5,17 limitations in diagnosis of the current case include a lack of serum vitamin d levels before empirical therapy was started and serum carnitine levels during the observation period. in this case, the clinical, laboratory and radiological parameters were strongly suggestive of proximal myopathy caused by sodium valproate. this diagnosis should be considered when encountering a patient with proximal myopathy who is unresponsive to vitamin d supplementation and on long-term anticonvulsive therapy. https://doi.org/10.1016/s0736-4679%2899%2900224-3 https://doi.org/10.1016/s0736-4679%2899%2900224-3 https://doi.org/10.1016/j.pedhc.2004.03.004 https://doi.org/10.1136/postgradmedj-2013-131752 https://doi.org/10.1007/s11926-010-0104-3 https://doi.org/10.1007/bf02859266 https://doi.org/10.1007/bf02859266 https://doi.org/10.1177/08830738030180080201 https://doi.org/10.1177/08830738030180080201 https://doi.org/10.1177/088307389100600102 https://doi.org/10.1080/15563650902752376 https://doi.org/10.1016/s0022-3476%2867%2980117-3 https://doi.org/10.1007/s002230010085 https://doi.org/10.1001/archinte.160.8.1199 https://doi.org/10.1001/archinte.160.8.1199 https://doi.org/10.1097/jcp.0b013e3181ad2256 https://doi.org/10.1097/jcp.0b013e3181ad2256 waddling gait a complication of valproate therapy and a thought beyond vitamin d deficiency e108 | squ medical journal, february 2020, volume 20, issue 1 15. laub mc, paetzke-brunner i, jaeger g. serum carnitine during valproic acid therapy. epilepsia 1986; 27:559–62. https://doi. org/10.1111/j.1528-1157.1986.tb03584.x. 16. shapira y, gutman a. muscle carnitine deficiency in patients using valproic acid. j pediatr 1991; 118:646–9. https://doi. org/10.1016/s0022-3476(05)83396-7. 17. nanau rm, neuman mg. adverse drug reactions induced by valproic acid. clin biochem 2013; 46:1323–38. https://doi. org/10.1016/j.clinbiochem.2013.06.012. 18. isenberg da, newham d, edwards rh, wiles cm, young a. muscle strength and pre-osteomalacia in vegetarian asian women. lancet 1982; 1:55. https://doi.org/10.1016/s0140-6736(82)92607-1. 19. ohtani y, endo f, matsuda i. carnitine deficiency and hyper ammonemia associated with valproic acid therapy. j pediatr 1982; 101:782–5. https://doi.org/10.1016/s0022-3476(82)80320-x. https://doi.org/10.1111/j.1528-1157.1986.tb03584.x https://doi.org/10.1111/j.1528-1157.1986.tb03584.x https://doi.org/10.1016/s0022-3476%2805%2983396-7 https://doi.org/10.1016/s0022-3476%2805%2983396-7 https://doi.org/10.1016/j.clinbiochem.2013.06.012 https://doi.org/10.1016/j.clinbiochem.2013.06.012 https://doi.org/10.1016/s0140-6736%2882%2992607-1 https://doi.org/10.1016/s0022-3476%2882%2980320-x 1faculty of pharmacy, lebanese university, beirut, lebanon; 2inspect-lb institut national de santé publique, épidémiologie clinique et toxicologieliban, beirut, lebanon; 3school of pharmacy, lebanese international university, beirut, lebanon; 4department of pharmacy, american university of beirut medical center, beirut, lebanon; 5faculty of medicine and medical sciences, holy spirit university of kaslik (usek), jounieh, lebanon; 6research department,psychiatric hospital of the cross, jal eddib, lebanon *corresponding author’s e-mail: souheilhallit@hotmail.com knowledge of antibiotics use among lebanese adults a study on the influence of sociodemographic characteristics anna-maria henaine,1 nathalie lahoud,1,2 rachel abdo,1,2 ruba shdeed,3 jihan safwan,3 marwan akel,2.3 iqbal fahs,3 rony zeenny,2,4 hala sacre,2 *souheil hallit,2,5,6 pascale salameh1,2 sultan qaboos university med j, august 2021, vol. 20, iss. 3, pp. 442–449, epub. 29 aug 21 submitted 27 apr 20 revisions req. 1 jul & 5 oct 20; revisions recd. 26 aug & 21 oct 20 accepted 10 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.006 clinical & basic research abstract: objectives: this study aimed to evaluate the association between sociodemographic characteristics and antibiotic knowledge in the lebanese population. methods: a questionnaire-based survey was conducted in community pharmacies across all lebanese governorates. data were collected by well-trained pharmacists through face-to-face interviews from january until march 2017. the survey tool was adapted from a questionnaire developed by the world health organization. a knowledge index was computed for comparative purposes and a linear regression model was performed to assess factors associated with knowledge. results: a total of 623 participants were included in the analysis of this study (response rate: 90.6%). the mean antibiotic knowledge index was 12.5 ± 3.2 (minimum score: 3 and maximum score: 19). higher knowledge score was inversely correlated with age (r = −0.118; p = 0.003), but no gender differences were reported (females: 12.6 versus males: 12.3; p = 0.191). however, statistically significant differences were found for residence type (p = 0.002), educational level (p <0.001) and total household income categories (p <0.001). the linear regression model showed a significant association between residence type and knowledge (urban versus rural: β = 0.793; p = 0.011). furthermore, a higher knowledge index was significantly associated with a higher income combined with higher education (additive scale/β = 1.590; p = 0.025). finally, interactions between income and age, gender and residence type were not significant. conclusion: individuals residing in urban areas, with combined high income and educational levels, are more knowledgeable about antibiotics use and resistance compared to other groups. more studies are needed to assess the interaction of sociodemographic interactions with health literacy. keywords: knowledge; socioeconomic factors; attitude to health; educational achievements; lebanon. advances in knowledge despite several information campaigns in lebanon targeting the appropriate use of antibiotics, knowledge about the correct use of antibiotics is still mediocre, resulting in reflected high levels of bacterial resistance and treatment failures. particularly vulnerable groups are mainly rural populations and those with low education and income levels. on its own, better education was not significantly associated with antibiotic awareness, but when coupled with a higher household income, there was a significant association. application to patient care awareness campaigns on antibiotics misuse and the risk of bacterial resistance should target specific groups in the country, using appropriate tools. bacterial resistance to antibiotics is a pressing public health problem that continues to spread globally at an alarming rate, resulting in antibiotic-resistant infections that cause high morbidity and mortality.1,2 it is associated with social and economic consequences and increased healthcare expenditure.1–5 several factors are involved in the emergence of antibiotic resistance such as inadequate patients’ expectations, lack of education among patients and healthcare providers, pharmaceutical marketing, dispensing of antibiotics without prescription in pharmacies, improper dosage, overuse of broadspectrum antibiotics, non-completion of the antibiotic course, prescribing antibiotics for viral infections and the high prevalence of self-medication.4–8 although antibiotics are prescription-only medicines, it is essential to empower the general population with adequate knowledge regarding the antibiotics spectrum of action, indication, administration and malpractice that may induce resistance to these medications.9 indeed, individuals tend to self-administer antibiotic ‘leftovers’, share antibiotics or even purchase them abroad or online.9 a systematic review found that the mean compliance to the antibiotic regimen was 62.2% and 28.6% reporting that they use leftover antibiotics.10 moreover, a study revealed that whenever patients or their caregivers expected an antibiotic prescription, the likelihood that a physician will prescribe one was higher.11 https://creativecommons.org/licenses/by-nd/4.0/ anna-maria henaine, nathalie lahoud, rachel abdo, ruba shdeed, jihan safwan, marwan akel, iqbal fahs, rony zeenny, hala sacre, souheil hallit and pascale salameh clinical and basic research | 443 reducing antibiotic misuse and overuse prevents further increases in antibiotic resistance.12,13 it is essential to have a solid understanding of knowledge, attitudes and practices towards antibiotics among populations by age, gender, education, economic status and type of residence, to improve the rational use of antibiotics and reduce the resistance to antibiotics. a large swedish study on knowledge of and attitudes towards antibiotics showed that the male gender, a higher level of education and younger age were associated with more knowledge about antibiotics, with males exhibiting less restrictive behaviour towards antibiotic use and effects; respondents with high levels of knowledge were more likely to have appropriate restrictive attitudes.14 moreover, several regional studies found high rates of antibiotic misuse, with a lack of knowledge related to sociodemographic factors in particular.15–17 in syria, lack of knowledge was associated with socioeconomic disparities, with only 10% of participants knowing that antibiotic misuse leads to antibiotic resistance and 15% knowing that it is harmful.16 a jordanian study reported that 39.5% of self-medication with antibiotics was significantly correlated with social and economic factors, i.e. age, income and education.4 improved awareness of antibiotics among the general population can help individuals reach appropriate use, improved adherence to treatment and outcomes and consequently less resistance. people’s attitudes, beliefs and visions concerning antibiotics can affect their practices. public knowledge is considered a requirement for adequate use of antibiotics.18 the over-prescription of antibiotics is associated with higher odds of side effects and higher medicalisation of self-limiting situations, leading to more frequent re-attendance to hospitals. a common problem in primary care resides in the fact that viruses are responsible for the majority of infections. general practitioners prescribe approximately 90% of all antibiotic prescriptions, with respiratory tract infections being the leading cause of those pres criptions.19 interventions should include several measures such as enforcing laws that forbid the sale of antibiotics without a valid prescription (over-the-counter), applying antimicrobial stewardship programmes, involving clinicians in audits, using valid rapid point-of-care tests, promoting policies that delay the prescription of antibiotics, improving the healthcare professionalpatient communication through information brochures and performing more realistic studies in primary care that may be of importance to clinicians.3,13 in lebanon, few studies have addressed the influence of sociodemographic factors on the knowl edge and attitudes of the general population towards antibiotic use and resistance. a cross-sectional study on a random convenience sample of 500 participants in lebanon showed that knowledge and attitudes of participants were significantly associated with income, educational level and place of residence.20 another study conducted among the general population in community pharmacies revealed that women had better knowledge of antibiotic use and that a sufficient level of knowledge was higher among participants aged 25–50 years compared to older adults.21 moreover, in a research conducted in two major cities of lebanon (beirut and tripoli), education was the only factor to show a significant association with self-medication.22 as per the recommendations of the world health organization (who) and the 2018 guidelines of the lebanese society of infectious diseases and clinical microbiology, improved knowledge and adequate antibiotic use among people would help decrease the emergence of antimicrobial resistance and curtail other adverse outcomes.23,24 hence, the present study aimed to assess the influence of socioeconomic and demographic factors on public awareness of antibiotic use and resistance in lebanon. methods this cross-sectional study was carried out via a faceto-face questionnaire distributed to participants in community pharmacies across all the lebanese governorates over a period of three months from january to march 2017. lebanese people aged 18 years and above, visiting community pharmacies and those who consented to participate in the study in the presence of the interviewer were included. the lebanese order of pharmacists (opl) provided the list of pharmacies from which a random sample of 500 pharmacies, out of a total of 3,500, was selected (using microsoft excel’s random function) to ensure geographic representativeness. the first two eligible people were then systematically recruited from each pharmacy. the g*power software (heinrich-heine-univer sität düsseldorf, düsseldorf, germany) calculated a minimum sample of 351 participants for a 0.05 increase in r2, 80% study power, 95% confidence interval (ci) and 13 predictors. the sample size was doubled for possible stratified analysis (multivariable analysis on subgroups) and the number of 700 participants was set as a reasonable number to cover all studied sociodemographic factors and interactions between income and other variables (total of 13 predictors). thus, 500 community pharmacies were selected and visited to recruit two participants from each and allow for potential refusal and missing values within the questionnaire. knowledge of antibiotics use among lebanese adults a study on the influence of sociodemographic characteristics 444 | squ medical journal, august 2021, volume 21, issue 3 data were collected by five well-trained opl registered pharmacists (one pharmacist for each lebanese governorate) through face-to-face interviews. the survey tool was adapted from the ‘antibiotic resistance multi-country public awareness survey’ conducted by the who in 2015 and developed by a specialised research agency, good business, in collaboration with the who.25 it was then translated into arabic and back-translated into english by two different native speakers. the questionnaire targeted public knowledge on antibiotic use and resistance with questions related to demographic and socioeconomic factors.25 questions related to knowledge were used to compute a knowledge index as follows: correct answers were coded as 1 and incorrect and ‘don’t know’ answers were coded as 0. overall, 20 knowledge questions/statements were selected for this purpose from a previous study.22 the kuder richardson 20 (kr20), a specific cronbach’s alpha for dichotomous tools, was used to measure how closely related a set of items are as a group; the reliability of the index was considered acceptable (0.65). a bivariate analysis was first conducted between the knowledge index (dependent variable) and sociodemographic variables (age, gender, residence type, total household income and education level). residence type was categorised into rural, suburban and urban areas, income into low (≤1.500.000 lebanese pound [lbp]) and high (>1.500.000 lbp) and education into low (12th grade or less), medium (high school graduate/some college credit/technical/ vocational training or associate degree) and high levels (bachelor’s degree/master’s/professional degree/ doctorate). one-way analysis of variance with further bonferroni post hoc analyses was used to test statistical differences between multiple groups and an independent t-test was used to compare two groups. pearson correlation coefficients were reported for the relationship between age and knowledge index, after checking for statistical assumptions (level of measurement, outliers, normality, linearity and homoscedasticity).26 means and 95% ci were reported. the same analysis was repeated after stratification over income categories to detect its modifying effects; it tested the effect of income combined with age, gender, residence type and education level on antibiotic knowledge, based on previous studies conducted in lebanon, showing the independent effects of sociodemographic factors.22,27,28 finally, for multivariable analysis, a multiple linear regression was performed to assess factors related to the knowledge index while testing for interactions between income and other socioeconomic factors. unstandardised predicted values were plotted against significant interaction terms to further illustrate results. a p value <0.05 was considered statistically significant for all tests. all statistics were performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). the ethics committee of the psychiatric hospital of the cross approved the study protocol (approval code: hpc-007-2020). participants gave their oral consent to take part in the study after the study’s objectives were explained. results out of 1,000 targeted participants, 906 agreed to participate (response rate: 90.6%); however, 623 were included in the analysis after excluding participants whose data were incomplete for the variables of the knowledge index. thus, an antibiotic knowledge index table 1: characteristics of study participants compared to antibiotic knowledge index (n = 623) characteristic n* mean knowledge index (95% ci) p value age 616 r = −0.118 0.003 gender 0.191 female 319 12.6 (12.2–13.0) male 301 12.3 (11.9–12.7) residence type 0.002 urban 333 12.8 (12.5–13.1) suburban 138 12.5 (11.9–13.1) rural 148 11.7 (11.2–12.2) education level <0.001 low 154 11.2 (10.7–11.7) medium 185 11.9 (11.5–12.3) high 280 13.5 (13.2–13.8) total household income in lbp <0.001 ≤1.500.000 (low) 252 11.8 (11.4–12.2) >1.500.000 (high) 339 13.0 (12.7–13.3) ci = confidence interval; lbp = lebanese pound. *total number without missing data. anna-maria henaine, nathalie lahoud, rachel abdo, ruba shdeed, jihan safwan, marwan akel, iqbal fahs, rony zeenny, hala sacre, souheil hallit and pascale salameh clinical and basic research | 445 was computed for 623 participants, with a minimum score of 3 and a maximum score of 19 (mean score: 12.5 ± 3.2). a negative correlation was found between the knowledge index and age (r = −0.118; p = 0.003), but no gender differences were reported (females: 12.6 versus males: 12.3; p = 0.191). however, differences were statistically significant for residence type (p = 0.002), education level (p <0.001) and total household income categories (p <0.001). indeed, residents in urban areas had a higher mean score compared to those in rural areas (12.8 versus 11.7; p = 0.002 after bonferroni adjustment) and higher education and income levels were significantly associated with a higher knowledge index (p <0.001 each after bonferroni adjustment) [table 1]. a stratification over the total household income categories (low and high) showed a statistically significant difference in knowledge in the low-income category between residence types (rural: 11.1 versus suburban: 12.4; p = 0.026). in the high-income category, significant knowledge difference existed for gender (males: 12.6 versus females: 13.4; p = 0.010), age (r = −0.198) and education levels (high: 13.8 versus medium: 11.8 or low: 11.2; p <0.001 after bonferroni adjustment) [table 2]. a linear regression model demonstrated a significant association between residence type and knowledge index (urban versus rural: β = 0.793; p = 0.011). regarding the studied interactions, a significantly higher knowledge index was found among individuals with combined higher income and higher education versus other categories (additive scale/β = 1.590; p = 0.025). finally, interactions between income and age, gender and residence type were not significant and thus removed from the model for better goodness of fit. in contrast, the interaction term between higher education and income had the highest standardised β, showing the highest effect on knowledge compared with other factors [table 3]. unstandardised predicted values of the knowledge index plotted against education levels for income categories illustrate the interaction between income and education [figure 1]. discussion to the best of the authors’ knowledge, this is the first population-based survey conducted in lebanon to evaluate the association between sociodemographic characteristics and antibiotic awareness with a particular focus on potential interactions between socioeconomic factors. this study carried out in community pharmacies distributed over rural, urban and suburban areas of lebanon collected data on table 2: stratification by total household income categories and mean knowledge index (n = 623) characteristic low income high income n* mean knowledge index (95% ci) p value n* mean knowledge index (95% ci) p value age 252 r = 0.003 0.959 339 r = −0.198 <0.001 gender female 142 11.9 (11.4–12.4) 0.651 160 13.4 (12.9–13.9) 0.010 male 109 11.7 (11.1–12.3) 179 12.6 (12.1–13.1) residence type urban 109 12.1 (11.5–12.7) 0.026 199 13.2 (12.8–13.6) 0.371suburban 50 12.4 (11.4–13.4) 85 12.7 (11.9–13.5) rural 92 11.1 (10.4–11.8) 54 12.7 (11.9–13.5) education level low 100 11.3 (10.7–11.9) 0.110 42 11.2 (10.2–12.2) <0.001medium 89 12.0 (11.4–12.6) 90 11.8 (11.2–12.4) high 63 12.3 (11.5–13.1) 206 13.8 (13.4–14.2) *total number without missing data. knowledge of antibiotics use among lebanese adults a study on the influence of sociodemographic characteristics 446 | squ medical journal, august 2021, volume 21, issue 3 sociodemographic characteristics and antibiotic knowledge via interviews with eligible participants. moreover, the use of a culturally adapted tool makes it more applicable in the lebanese population and its results closer to reality.29 additionally, the kr20 (a version of cronbach alpha for dichotomous questions) of the knowledge index was 0.65, which can be considered acceptable and shows the internal consistency of the tool in the population.30 this study’s results showed statistically significant differences in the knowledge index for residence type, education level and total household income categories (low and high). residents of urban areas had higher knowledge compared to those of rural areas and higher education and income levels were significantly associated with a higher knowledge index. these findings are in agreement with those found in the literature, showing that antibiotic use in human medicine does not only vary according to patient characteristics but also according to geographical location, reimbursement systems, medical education and cultural considerations.18,31 overall, participants residing in urban areas had significantly better knowledge and awareness towards antibiotic resistance and antibiotic consumption, which supports this study’s hypothesis that socio-demographic factors can be related to antibiotic resistance knowledge and awareness.25 the results also revealed no gender difference in the level of antibiotic knowledge, probably because both males and females are affected by similar factors related to the environment, culture and economy, as studies from the united arab emirates and egypt have shown.15,32 findings from the uk, kuwait and lithuania revealed that females have a higher tendency to consume antibiotics than their male counterparts.17,33,34 regarding the effect of the educational level on antibiotic utilisation, no such comparable data have been reported to date. a study has shown that people with low education may receive inadequate medical care compared to highly educated people who may be more informed about health care.35 hence, educated people are more knowledgeable and careful about appropriate antibiotic use and the impact of antibiotic resistance and, consequently, may utilise antibiotics less.35 differences related to the income were noted in the current study as well; participants with low incomes were more likely to have a lower knowledge index than those with higher incomes. the incidence of infectious diseases tends to be higher and their outcomes worse, in groups with a lower socioeconomic status, a finding similar to that of other studies.34,36 table 3: factors associated with the antibiotic knowledge index (n = 586)* model† unstandardised β (95% ci) standardised β p value intercept 11.464 (9.708 to 13.221) 0.000 age −0.005 (−0.023 to 0.013) −0.023 0.578 male versus female −0.457 (−0.953 to 0.040) −0.072 0.071 urban residence versus rural 0.793 (0.182 to 1.404) 0.125 0.011 suburban residence versus rural 0.584 (−0.137 to 1.305) 0.077 0.112 medium education versus low 0.545 (−1.537 to 2.627) 0.079 0.607 high education versus low −0.686 (−2.858 to 1.485) −0.107 0.535 high income versus low −0.174 (−1.278 to 0.929) −0.027 0.756 high income + medium education 0.015 (−1.400 to 1.430) 0.004 0.983 high income + high education 1.590 (0.202 to 2.978) 0.463 0.025 the following interactions were not significant and therefore excluded from the table: income*residence type, income*age, income*gender. *when performing a multiple regression participants with missing data were removed from the model. †linear regression model: f (9.576) = 9.155; p <0.001 and r2 = 12.5%. figure 1: values of the antibiotic knowledge index predicted from the regression model according to educational level and income category. anna-maria henaine, nathalie lahoud, rachel abdo, ruba shdeed, jihan safwan, marwan akel, iqbal fahs, rony zeenny, hala sacre, souheil hallit and pascale salameh clinical and basic research | 447 generally, respondents with lower levels of education and in lower-income countries are more likely to have misconceptions about antibiotic use and believe that there is little that they can do to stop antibiotic resistance. the who 2015 survey showed that 63% of respondents with no education agree with this statement compared to those with basic (58%), further (58%) and higher education (56%).25 in this study, those with a low-education level had a knowledge index lower than those of the medium and high education levels, respectively. moreover, the impact of occupation, age groups and socioeconomic status (excluding gender) on behaviours of antibiotics use was in agreement with previous findings.37 the income level is of great importance as antimicrobials are common goods.38 therefore, people residing in high-income countries have more access to medical care and thus purchase and utilise more outpatient antibiotics compared to those living in low-income countries.38 recent data revealed an association between the income level and inequalities in the use of health-care services, which were less applicable and consistent with primary care.39 surveyed individuals from varied economic statuses favoured methods other than asking for a physician’s advice since they believed that common diseases are not worth consulting a physician about and that pharmacists remained their first choice since they would save them the expenses of the physician’s consultation. policymakers have to take into account all the factors described; fighting antimicrobial resistance should be part of a health-system strategy that considers patients’ education and economic aspects. consequently, it is essential to initiate multiple plans to increase public knowledge of antibiotics while focusing on lower socioeconomic areas through public-awareness campaigns, continuing education for pharmacists and implementing restrictions on haphazard antibiotic use and distribution. the results of this study should be interpreted in light of certain limitations in the design and data collection methods. participants were selected from community pharmacies, half of which were in urban areas, which may have resulted in selection bias by representing people of slightly higher socioeconomic levels and higher levels of education. although the sample was random, the self-selection resulting from voluntary participation may lead to the risk of selection bias; however, since the objective was not to calculate a prevalence but to evaluate associations and interactions, the effect of this bias is cautiously expected to be lower and a possible effect could be an overestimation of associations.40,41 furthermore, this study used a face-to-face questionnaire, which has its inherent limitations, despite the confidentiality and anonymity of the reporting (hawthorne effect); participants may either over-report socially desirable behaviours or hide undesirable attitudes. despite these limitations, the current study provides essential information for assessing the knowledge and attitude towards antibiotics use and resistance. it showed gaps in terms of the knowledge of antibiotics and identified specific groups to target to improve this knowledge. further national studies with larger representative samples are necessary to confirm these findings. conclusion this study revealed that individuals residing in urban areas, those with combined high income and high educational levels, are more knowledgeable about antibiotics use and resistance compared to other groups. more studies are needed to assess sociodemographic interactions on health literacy. a c k n o w l e d g e m e n t s the authors would like to thank the community pharmacists and all members of the lebanese order of pharmacists scientific committee. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n s ps and nl were involved in planning the design and supervising the work. a-mh drafted the manuscript. ra and nl performed the analysis and interpretation of the results. rs, js, ma, if, rz and sh aided in interpreting the results and worked on writing the manuscript. hs reviewed the manuscript. all authors discussed the results, commented on the manuscript and approved the final version of the manuscript. references 1. world health organization. antimicrobial resistance: global report on surveillance. from: https://apps.who.int/iris/handle/1 0665/112642 accessed: oct 2020. 2. butler cc, hillier s, roberts z, dunstan f, howard a, palmer s. antibiotic-resistant infections in primary care are symptomatic for longer and increase workload: outcomes for patients with e. coli utis. br j gen pract 2006; 56:686–92. 3. thabit ak, crandon jl, nicolau dp. antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials. expert opin pharmacother 2015; 16:159–77. https://doi.org/10.1517/14656566.2015.993381. https://doi.org/10.1517/14656566.2015.993381 knowledge of antibiotics use among lebanese adults a study on the influence of sociodemographic characteristics 448 | squ medical journal, august 2021, volume 21, issue 3 4. al-azzam si, al-husein ba, alzoubi f, masadeh mm, alhorani ma. self-medication with antibiotics in jordanian population. int j occup med environ health 2007; 20:373–80. https://doi.org/10.2478/v10001-007-0038-9. 5. yagupsky p. selection of antibiotic-resistant pathogens in the community. pediatr infect dis j 2006; 25:974–6. https://doi. org/10.1097/01.inf.0000239270.33190.71. 6. panagakou sg, theodoridou mn, papaevangelou v, papaster giou p, syrogiannopoulos ga, goutziana gp, et al. development and assessment of a questionnaire for a descriptive crosssectional study concerning parents' knowledge, attitudes and practises in antibiotic use in greece. bmc infect dis 2009; 9:52. https://doi.org/10.1186/1471-2334-9-52. 7. parimi n, pinto pereira lm, prabhakar p. caregivers' practices, knowledge and beliefs of antibiotics in paediatric upper respiratory tract infections in trinidad and tobago: a cross-sectional study. bmc fam pract 2004; 5:28. https://doi.org/10.1186/1471-2296-5-28. 8. vanden eng j, marcus r, hadler jl, imhoff b, vugia dj, cieslak pr, et al. consumer attitudes and use of antibiotics. emerg infect dis 2003; 9:1128–35. https://doi.org/10.3201/ eid0909.020591. 9. andré m, vernby a, berg j, lundborg cs. a survey of public knowledge and awareness related to antibiotic use and resistance in sweden. j antimicrob chemother 2010; 65:1292–6. https://doi.org/10.1093/jac/dkq104. 10. kardas p, devine s, golembesky a, roberts c. a systematic review and meta-analysis of misuse of antibiotic therapies in the community. int j antimicrob agents 2005; 26:106–13. https://doi.org/10.1016/j.ijantimicag.2005.04.017. 11. stivers t, mangione-smith r, elliott mn, mcdonald l, heritage j. why do physicians think parents expect antibiotics? what parents report vs what physicians believe. j fam pract 2003; 52:140–8. 12. costelloe c, metcalfe c, lovering a, mant d, hay ad. effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. bmj 2010; 340:c2096. https://doi.org/10.1136/bmj.c2096. 13. centers for disease control and prevention. new guidance limits antibiotic for common infections in children. from: www.cdc.gov/media/releases/2013/p1118-get-smart.html accessed: oct 2020. 14. vallin m, polyzoi m, marrone g, rosales-klintz s, tegmark wisell k, stålsby lundborg c. knowledge and attitudes towards antibiotic use and resistance a latent class analysis of a swedish population-based sample. plos one 2016; 11:e0152160. https://doi.org/10.1371/journal.pone.0152160. 15. abasaeed a, vlcek j, abuelkhair m, kubena a. self-medication with antibiotics by the community of abu dhabi emirate, united arab emirates. j infect dev ctries 2009; 3:491–7. https://doi.org/10.3855/jidc.466. 16. barah f, gonçalves v. antibiotic use and knowledge in the community in kalamoon, syrian arab republic: a crosssectional study. east mediterr health j 2010; 16:516–21. https://doi.org/10.26719/2010.16.5.516. 17. berzanskyte a, valinteliene r, haaijer-ruskamp fm, gurevicius r, grigoryan l. self-medication with antibiotics in lithuania. int j occup med environ health 2006; 19:246–53. https://doi. org/10.2478/v10001-006-0030-9. 18. waaseth m, adan a, røen il, eriksen k, stanojevic t, halvorsen kh, et al. knowledge of antibiotics and antibiotic resistance among norwegian pharmacy customers a crosssectional study. bmc public health 2019; 19:66. https://doi. org/10.1186/s12889-019-6409-x. 19. little p, gould c, williamson i, warner g, gantley m, kinmonth al. reattendance and complications in a randomised trial of pres cribing strategies for sore throat: the medicalising effect of prescribing antibiotics. bmj 1997; 315:350–2. https://doi.org/1 0.1136/bmj.315.7104.350. 20. mouhieddine th, olleik z, itani mm, kawtharani s, nassar h, hassoun r, et al. assessing the lebanese population for their knowledge, attitudes and practices of antibiotic usage. j infect public health 2015; 8:20–31. https://doi.org/10.1016/j.jiph.20 14.07.010. 21. khalifeh mm, moore nd, salameh pr. self-medication misuse in the middle east: a systematic literature review. pharmacol res perspect 2017; 5:e00323. https://doi.org/10.1002/prp2.323. 22. jamhour a, el-kheir a, salameh p, hanna pa, mansour h. anti biotic knowledge and self-medication practices in a developing country: a cross-sectional study. am j infect control 2017; 45:384–8. https://doi.org/10.1016/j.ajic.2016.11.026. 23. world health organization. who’s first global report on antibiotic resistance reveals serious, worldwide threat to public health. from: https://www.who.int/southeastasia/news/ detail/30-04-2014-who-s-first-global-report-on-antibioticresistance-reveals-serious-worldwide-threat-to-public-health accessed: oct 2020. 24. haddad n, kanj ss, awad ls, abdallah di, moghnieh ra. the 2018 lebanese society of infectious diseases and clinical microbiology guidelines for the use of antimicrobial therapy in complicated intra-abdominal infections in the era of anti microbial resistance. bmc infect dis 2019; 19:293. https://doi. org/10.1186/s12879-019-3829-2. 25. world health organization. antibiotic resistance: multicountry public awareness survey. 2015. from: https://apps. who.int/iris/handle/10665/194460 accessed: oct 2020. 26. schober p, boer c, schwarte la. correlation coefficients: appropriate use and interpretation. anesth analg 2018; 126:1763–8. https://doi.org/10.1213/ane.0000000000002864. 27. farah r, lahoud n, salameh p, saleh n. antibiotic dispensation by lebanese pharmacists: a comparison of higher and lower socio-economic levels. j infect public health 2015; 8:37–46. https://doi.org/10.1016/j.jiph.2014.07.003. 28. cheaito l, azizi s, saleh n, salameh p. assessment of selfmedication in population buying antibiotics in pharmacies: a pilot study from beirut and its suburbs. int j public health 2014; 59:319–27. https://doi.org/10.1007/s00038-013-0493-y. 29. gjersing l, caplehorn jr, clausen t. cross-cultural adaptation of research instruments: language, setting, time and statistical considerations. bmc med res methodol 2010; 10:13. https:// doi.org/10.1186/1471-2288-10-13. 30. anselmi p, colledani d, robusto e. a comparison of classical and modern measures of internal consistency. front psychol 2019; 10:2714. https://doi.org/10.3389/fpsyg.2019.02714. 31. sanchez gv, roberts rm, albert ap, johnson dd, hicks la. effects of knowledge, attitudes, and practices of primary care providers on antibiotic selection, united states. emerg infect dis 2014; 20:2041–7. https://doi.org/10.3201/eid2012.140331. 32. elmasry aag, bakr asm, kolkailah daaa, khaskia mai, mohammed mee, riad ohma, et al. pattern of antibiotic abuse – a population based study in cairo. egypt j chest dis tuberc 2013; 62:189–95. https://doi.org/10.1016/j.ejcdt.2013.02.010. 33. awad ai, aboud ea. knowledge, attitude and practice towards antibiotic use among the public in kuwait. plos one 2015; 10:e0117910. https://doi.org/10.1371/journal.pone.0117910. 34. mason t, trochez c, thomas r, babar m, hesso i, kayyali r. knowledge and awareness of the general public and perception of pharmacists about antibiotic resistance. bmc public health 2018; 18:711. https://doi.org/10.1186/s12889-018-5614-3. https://doi.org/10.2478/v10001-007-0038-9 https://doi.org/10.1097/01.inf.0000239270.33190.71 https://doi.org/10.1097/01.inf.0000239270.33190.71 https://doi.org/10.1186/1471-2334-9-52 https://doi.org/10.1186/1471-2296-5-28 https://doi.org/10.3201/eid0909.02059 https://doi.org/10.3201/eid0909.02059 https://doi.org/10.1093/jac/dkq104 https://doi.org/10.1016/j.ijantimicag.2005.04.017 https://doi.org/10.1136/bmj.c2096 https://doi.org/10.1371/journal.pone.0152160 https://doi.org/10.3855/jidc.466 https://doi.org/10.26719/2010.16.5.516 https://doi.org/10.2478/v10001-006-0030-9 https://doi.org/10.2478/v10001-006-0030-9 https://doi.org/10.1186/s12889-019-6409-x https://doi.org/10.1186/s12889-019-6409-x https://doi.org/10.1136/bmj.315.7104.350 https://doi.org/10.1136/bmj.315.7104.350 https://doi.org/10.1016/j.jiph.2014.07.010 https://doi.org/10.1016/j.jiph.2014.07.010 https://doi.org/10.1002/prp2.323 https://doi.org/10.1016/j.ajic.2016.11.026 https://doi.org/10.1186/s12879-019-3829-2 https://doi.org/10.1186/s12879-019-3829-2 https://doi.org/10.1213/ane.0000000000002864 https://doi.org/10.1016/j.jiph.2014.07.003 https://doi.org/10.1007/s00038-013-0493-y https://doi.org/10.1186/1471-2288-10-13 https://doi.org/10.1186/1471-2288-10-13 https://doi.org/10.3389/fpsyg.2019.02714 https://doi.org/10.3201/eid2012.140331 https://doi.org/10.1016/j.ejcdt.2013.02.010 https://doi.org/10.1371/journal.pone.0117910 https://doi.org/10.1186/s12889-018-5614-3 anna-maria henaine, nathalie lahoud, rachel abdo, ruba shdeed, jihan safwan, marwan akel, iqbal fahs, rony zeenny, hala sacre, souheil hallit and pascale salameh clinical and basic research | 449 35. hunt-mccool j, kiker bf, ng yc. estimates of the demand for medical care under different functional forms. j appl econ (chichester engl) 1994; 9:201–18. https://doi.org/10.1002/ jae.3950090206. 36. national institute for health and care excellence. antimicrobial stewardship: changing risk-related behaviors in the general population. 2017. from: www.nice.org.uk/guidance/ng63/resour ce s / a n t i m i c r o b i a l s t e w a r d s h i p c h a n g i n g r i s k r e l a t e d behaviours-in-the-general-population-pdf-1837572082117 accessed: oct 2020. 37. saleh n, awada s, awwad r, jibai s, arfoul c, zaiter l, et al. evaluation of antibiotic prescription in the lebanese community: a pilot study. infect ecol epidemiol 2015; 5:27094. https://doi.org/10.3402/iee.v5.27094. 38. blommaert a, marais c, hens n, coenen s, muller a, goossens h, et al. determinants of between-country differences in ambulatory antibiotic use and antibiotic resistance in europe: a longitudinal observational study. j antimicrob chemother 2014; 69:535–47. https://doi.org/10.1093/jac/dkt377. 39. habicht j, kiivet ra, habicht t, kunst ae. social inequalities in the use of health care services after 8 years of health care reforms a comparative study of the baltic countries. int j public health 2009; 54:250–9. https://doi.org/10.1007/s00038009-8012-x. 40. nilsen rm, vollset se, gjessing hk, skjaerven r, melve kk, schreuder p, et al. self-selection and bias in a large prospective pregnancy cohort in norway. paediatr perinat epidemiol 2009; 23:597–608. https://doi.org/10.1111/j.1365-3016.2009.01062.x. 41. søgaard aj, selmer r, bjertness e, thelle d. the oslo health study: the impact of self-selection in a large, population-based survey. int j equity health 2004; 3:3. https://doi.org/10.1186/1475-9276-3-3. https://doi.org/10.1002/jae.3950090206 https://doi.org/10.1002/jae.3950090206 https://doi.org/10.3402/iee.v5.27094 https://doi.org/10.1093/jac/dkt377 https://doi.org/10.1007/s00038-009-8012-x https://doi.org/10.1007/s00038-009-8012-x https://doi.org/10.1111/j.1365-3016.2009.01062.x https://doi.org/10.1186/1475-9276-3-3 july 2008.indd striking anatomical variations in the origin and course of major arteries of the upper limb have always been of interest among anatomists, hand surgeons and radiologists.1 this study describes a unilateral case of a high division of the brachial artery into a superficially coursing ulnar artery and a relatively deeper radial artery. the high origin of the radial artery is the most frequent anomaly in the arterial pattern of upper limb of human beings (incidence of 14.27% in dissected material),2 whereas a superficial ulnar artery has been reported in 2% of cases.3 this case report presents a case from an anatomical perspective and also highlights the clinical implications. novel diagnostic procedures such as doppler pressure studies and ultrasonography are being widely used in vascular surgery;4 therefore, anomalies in the vascular pattern of upper extremity are of immense significance for clinicians, especially radiologists and surgeons. c a s e r e p o r t the following variations in the arterial pattern of left upper limb was observed in a forty-year-old male cadaver during the course of an undergraduate medical training programme at varhaman mahair medical college, new delhi, india. first, a high division of the brachial artery was obunilateral anomalous arterial pattern of human upper limb anatomical description and clinical implications *vandana mehta, jyoti arora, r k suri, gayatri rath sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 227-230 sultan qaboos university© submitted 8th february 2008 accepted 15th april 2008 c a s e r e p o r t لإلنسان: العلوي الطرف في اجلانب وحيد الشرياني اإلنقسام تغاير السريرية مقتضياته مع تشريحي توصيف راث جياتري سوري، ك ر أرورا، جيوتي ميثا، فاندانا الوجود مع العضدي للشريان عال انقسام فهناك األمامي. والعضدي الشريان العضدي إلنقسامات اجلانب أحادية متغايرة حالة امللخص: نسرد هنا بدالً الكعبري الشريان من نشئا املشترك العظمي مابني العضدي العميق وشريان الشريان فإن ، لذلك وباإلضافة . الزندي الشريان السطحي ملسار ميكن العلوية األطراف معهودة تشريحياً في غير تواجد انقسامات شريانية إمكانية فإن وعليه التوالي. على الزندي والشريان العضدي الشريان من الترميمية. إجرائهم للجراحات خالل الدموية األوعية جلراحي صعبة مشكلة تطرح أن الهند. حالة ، تقرير ، متغايرات ، الكلمات: الشريان العضدي مفتاح department of anatomy, vardhman mahavir medical college & safdarjung hospital, new delhi, india *to whom correspondence should be addressed. email: drvandanamehta@gmail.com abstract a unilateral case of variations in the brachial and antebrachial arterial branching pattern of a human upper limb is reported. a high bifurcation of brachial artery along with superficial course of ulnar artery was observed. additionally, the profunda brachii and common interosseous artery originated from the radial artery instead of brachial and ulnar arteries respectively. an atypical branching pattern of arteries in an upper limb could pose a challenging problem to vascular surgeons while performing reconstructive procedures. key words: brachial artery; anomalies; case report; india. * va n d a n a m e h ta , j y o t i a r o r a , r . k . s u r i a n d g ayat r i r at h 228 served. the brachial artery as usual was seen to be a continuation of axillary artery at the lower border of teres major; however, it extended to the upper border of the latissmus dorsi and measured only 1.4 cm in length. it was found to divide into the radial and ulnar arteries, 9.8 cm proximal to the neck of the radius. the lateral root of the median nerve was found to be interposed between radial and ulnar arteries [figures 1 and 3]. second, there was an anomaly of the radial artery. it was seen to branch off the profunda brachii artery in the mid-arm and the common interosseous at the level of neck of radius in the cubital fossa [figure 2]. it then continued as the radial artery in the forearm and hand. the common interosseous artery as usual was found to divide into the anterior and posterior interosseous arteries. third, there was an anomaly of the ulnar artery. it traversed superficially to the epitrochlear muscles and continued to be in the same plane in the forearm as well. it was found to be the sole contributor to the superficial arterial arch in the palm. d i s c u s s i o n accurate and detailed knowledge of the relationships and possible anatomical variations of the arterial branching pattern of the upper extremity is vital during reparative surgery in this region. in addition, trauma in this area may lead to a life threatening haemorrhage from these aberrant vessels. inadequate figure 1: dissection of the anterior aspect of left axillary region and upper arm showing: a axillary artery b brachial artery r radial artery u ulnar artery pb profunda brachii ci common interosseous artery mn median nerve l lateral root of median nerve tm teres major ld latissismus dorsi note: high division of brachial artery and lateral root of median nerve (l) passing between radial and ulnar arteries figure 2: dissection of the left cubital fossa showing the branching of radial into common interosseous. note the superficial course of the ulnar artery. ci common interosseous r radial artery u ulnar artery mn median nerve u n i l at e r a l a n o m a l o u s a r t e r i a l pat t e r n o f h u m a n u p p e r l i m b 229 knowledge of the anatomical variations of the arterial pattern may render surgery difficult. a high origin of the radial artery is reported to be the commonest variation in the arterial pattern of upper limb with an incidence of 14.27% in dissected specimens. it is considered as a kind of persistent superficial brachial artery.5 however, a high origin of an ulnar artery is quite uncommon (2.26%). 6 in the present specimen, the ulnar artery remained superficial to the epitrochlear muscles, and was found to be the sole contributor to the superficial palmar arch. it appears that the superficial course of the ulnar artery in the present case has been referred to as a “superficial ulnar artery”, in earlier studies.6 an unusual variation of the superficial ulnar artery was reported where it was found to be rudimentary. giving only small branches to the biceps in the arm and in the hand, it anastmosed with the radial artery to complete the superficial palmar arch.7 contrarily, in the present study, the superficial ulnar artery was not rudimentary and, in the hand, was found to be the sole contributor to the palmar arch. as per standard textbook descriptions, the arrangement of structures in the cubital fossa from lateral to medial side is biceps tendon, brachial artery and median nerve. interestingly, in the present report, this arrangement differed as the median nerve interposed between the radial and ulnar arteries; therefore, this altered the topographical relationship of vessels in the elbow. this would make simple clinical procedures such as blood pressure recording a complicated ordeal. we also suggest that a surgeon, while performing operations in the arm, would have to exercise extra caution not to injure the lateral root of median nerve since it is interposed between the radial and ulnar arteries. the anomalies of various blood vessels of upper extremity can be explained on the basis of embryological development of the vascular plexus of limb buds.8, 9 the lateral branch of the lateral intersegmental artery gets enlarged to form the axial artery of the upper limb, which later terminates in a capillary plexus from which digital branches arise. the brachial artery is the proximal part of this axial artery beyond the lateral border of teres major while the distal portion, beyond the cubital fossa, is the interosseous artery. the radial and ulnar arteries arise relatively late in development as new vessels branch from brachial and interosseous arteries respectively.10 embryologically, the radial artery arises from the brachial artery in the arm, disappearing at a later stage, resulting in one main artery running along the flexor aspect of the limb.11 thus it may be inferred that the primitive axial and superficial arteries play a role in the embryogenesis of the arteries of the upper limb. in an earlier study,12 the axillary artery gave off medial and lateral divisions. the superficial/medial division coursed along the path of ulnar artery. the deep/lateral division provided the branches of brachial artery in the arm while in the cubital fossa it gave branches, which normally arise from the ulnar artery. in the present investigation, we prefer to designate this lateral branch as brachio-radial as it subserves the distribution of brachial artery in the arm and at the level of cubital fossa continues as the radial artery. the superficial position of the ulnar artery renders figure 3: dissection of the upper arm of left side depicting the following: a axillary artery b brachial artery u ulnar artery r radial artery pb profunda brachii artery ldlatissmus dorsi * bifurcation of brachial artery * va n d a n a m e h ta , j y o t i a r o r a , r . k . s u r i a n d g ayat r i r at h 230 it vulnerable to trauma. however, it also makes it amenable to cannulation if required. understandably, the superficial position of the artery may also account for its mistaken identity as a vein and accidental injection of drugs may lead to serious consequences.13 further, such vascular anomalies may cause confusion during interpretation of angiographic procedures. c o n c l u s i o n the anatomical variations in this case report demonstrates a high bifurcation of the brachial artery into the radial and ulnar artery associated with the origin of the profunda brachii and common interosseous arteries from the radial artery in the arm and forearm respectively, along with superficial course of ulnar artery. such an aberrant arterial anomaly of the upper limb is an extremely rare finding. awareness of variations in the vasculature of upper limb is an important consideration, as a large number of diagnostic and therapeutic procedures are performed in this region. precise knowledge of arterial anatomy of the region is also vital for logical interpretation of angiograms. good insight into vascular anatomy of upper limb is imperative for successful reconstructive operations. r e f e r e n c e s 1. lippert h, pabst r. arterial variations in man. munchen: bergman verlag, 1985. p. 66-77. 2. mccormack lj, claudwell ew, anson bj. brachial and antebrachial arterial patterns. surg gynaecol obstet 1953; 96:43-54. 3. natasis k, papadopoulou al, paraskevas gt, tsikaras p. high origin of a superficial ulnar artery arising from axillary artery anatomy, embryological and clinical significance and review of literature. folia morphol (warsz) 2006; 65:400-405. 4. taub j, giannikis g, shen hy, ki u. the brachial artery transection following closed elbow dislocation. j trauma 1999; 47:176-178. 5. compta g. origin of the radial artery from axillary artery and associated hand vascular anomalies. j hand surg 1991; 16:293-296. 6. icten n, sullu y, tuncer i. variant high-origin radial artery: a bilateral case. surg radiol anat 1996; 18:63-66. 7. yazar f, kirici y, ozan h, aldur mm. an unusual variation of superficial ulnar artery. surg rdaiol anat 1999; 21:155-157. 8. senior hda. note on development of the radial artery. anat rec 1926; 33:220-221. 9. singer e. embryological pattern persisting in the arteries of the arm. anat rec1933; 55:403-409. 10. jurjus a, sfeir r, bezirdjian r. unusual variation of the arterial pattern of the human upper limb. anat rec 1986; 215:82-83. 11. pelin c, zaqyapan r, mas n, karabay g. an unusual course of radial artery. folia morphol (warsz) 2006; 65:410-413. 12. ozan h, simsek c, cenderoglu s, kirici y, basar r. high division of axillary artery a rare case of superficial ulnar artery. acta anat (basel) 1994; 151:68-70. 13. hazlett jw. the superficial ulnar artery with reference to accidental intra-arterial injection. can med assoc j 1949; 61:289-293. ífi^n÷]<‹äœ÷] –<l]2j~π]<g�÷<ífi^€�√÷]<íπ^√÷]<ü≥ˆπ] جامعة السلطان قابوس 2010911 abstracts oman international conference on laboratory medicine – part ii sultan qaboos university 9 – 11th november 2010 squ med j, may 2011, vol. 11, iss. 2, pp. 304-310, epub. 15th may 11 abstracts histopathology and microbiology sessions a b s t r a c t s h i s t o pat h o l o g y s e s s i o n s fine needle aspiration cytology of pancreaticobiliary tract prof. kusum kapila head of department of cytopathology, university of kuwait, kuwait fine needle aspiration (fna) is the method of choice for the diagnosis of pancreatic mass/cystic lesions. fna may be performed percutaneously or under endoscopic ultrasound (eus) guidance. clinical and radiological examinations are not reliable methods to distinguish benign/inflammatory pancreatic disease from a carcinoma. fna provides an accurate preoperative diagnosis for optimal and timely patient management. most solid neoplasms are at an advanced stage at the time of detection and are mostly high grade adenocarcinomas which are readily diagnosed on cytology. even if the tumour is unresectable, a tissue diagnosis is essential for the initiation of an appropriate treatment protocol. low grade carcinomas can prove to be a challenge and are often differentiated from reactive ducts by certain features. benign acinar cells can be differentiated similarly. pancreatic endocrine neoplasms can likewise be distinguished by features peculiar to them. cysts of the pancreas include congenital, developmental, inflammatory and neoplastic lesions. the cytology of pseudocysts are well characterised. cystic neoplasms include serous cystadenomas, mucinous cystic neoplasms, intraductal papillary mucinous neoplasms, solid pseudopapillary neoplasms and cystic neuroendocrine tumours. accurate preoperative diagnosis is critical, since this will determine the type of intervention needed, but clinical and imaging criteria are not consistently reliable. the use of fna with cyst fluid analysis for amylase and tumour markers such as carcinoembryonic antigen (cea), has improved the preoperative diagnosis of these lesions. the main diagnostic dilemmas in cytology specimens are distinguishing nonneoplastic from neoplastic lesions (particularly mucinous lesions) and benign neoplasms from borderline or malignant neoplasms. cytology alone can distinguish mucinous from nonmucinous lesions and diagnose specific entities, such as solid-pseudo papillary tumours, cystic pancreatic endocrine tumours and carcinomas when the cell sample is sufficient, but lacks sensitivity due to sampling problems. molecular pathology targeted therapeutics leading the paradigm shift for pathology dr. manuel salto-tellez yong loo lin school of medicine, national university of singapore, singapore the availability of an expanding armamentarium of antibodies and small molecule inhibitors has transformed the way we practice oncology. by targeting key oncogenic genes and pathways, many solid tumours can now be therapeutically addressed in a more focused and clinically efficient manner. this revolution in oncology treatment has also deeply transformed the way we practice pathology. indeed, correct stratification of patients often depends on the immunophenotype or genotype profile of a single tissue-based biomarker. in our experience, the introduction of molecular testing in a traditional molecular histopathology operation multiplies the overall volume of tests by several fold, leading to substantial revenue gains. this also has a repercussion in the overall volume of testing in pathology departments. in our setting, the volume of molecular diagnostics after the validation of tests for targeted therapeutics amounts to an additional 10–20% increase in the overall testing volume. targeted therapeutics is invariable changing the way we look at the taxonomy of cancer. we are currently witnessing the dawn of what appears to be a targeted therapeutics-oriented diagnostic paradigm in tumour pathology. the presentation provides several examples to this effect, showing both current and future trends that have a significant impact in the classification and characterisation of diseases. the main consequence of this new approach, however, abstracts | 305 9 – 11th november 2010 has to do with the specific weight of pathology in overall diagnostic and therapeutic decision-making and, as a consequence, the way pathology and pathologists are perceived by the medical community, by our patients and by the industry. from the 1960s to perhaps the end of the 20th century, surgical pathology established itself as a central and fundamental discipline in clinical medicine. however, from a phenotypic-clinical framework of diagnosis, we are shifting into a phenotypic-molecular-clinical dimension. as a result of this shift, the process leading from morphological surgical pathology to therapeutic decision-making includes an area of expanding molecular diagnostic complexity. increasingly so, surgical pathology departments understand that maintaining professional relevance requires not only passive knowledge of these techniques (i.e., when or how to order them), but active molecular diagnostic skills for molecular assay validation and interpretation to maintain key diagnostic relevance. interestingly, the development of therapeutic pathology is also broadening the scope of pathology practice and, in particular, the role of pathologists in the pharmaceutical and the diagnostic industry. therefore, it is the time for surgical pathology to embrace molecular pathology by integrating it, when indicated, into daily clinical practice at sign out. to do so, we should revisit and ensure its teaching in our residency programs—all of this building on the role of molecular pathologists certified by professional organisations as invaluable bridges between pathologists’ roles as responsible diagnosticians and as clinical scientists. in essence, the systematic embracement of molecular pathology will allow pathology departments to regain a central role at the core of the diagnostic and therapeutic endeavour. molecular pathology-erbb2 testing: fish (flourescence in situ hybridisation), cish (chromagen in situ hybridisation), sish (silver in situ hybridisation) and hic (immunohistochemistry) what is their relevance? dr. manuel salto-tellez yong loo lin school of medicine, national university of singapore, singapore a better understanding of “molecular markers” in recent years has allowed the characterisation of a group of drugs, primarily antibodies and small molecule inhibitors, developed against a specific target based on its important function in cancer. these treatments are “personalised”, i.e. the target analysis will indicate the patient’s likely chance of response (personalised medicine 2009; 6:465–8). of these, the use of the antibody trastuzumab or the small molecule inhibitor lapatinib, targeting her-2 for the treatment of breast cancer, is arguably the best established example to date. which is the most accurate manner of analysing her-2 status prior to treatment is still a matter of some controversy. a few years ago, we and others proposed a cost-effective manner of analysing her-2 using ihc and complemented by fish in selected cases (modern pathology 2003; 16:79–85 and human pathology 2003; 34:362–8). more recently, the american society of clinical oncology/college of american pathologists (asco/cap) guidelines have tried to present a homogeneous approach to her-2 testing (journal of clinical oncology 2007; 118–45), although authoritative opinions against this approach have been voiced (journal of clinical oncology 2009; 1323–33). we shall review this body of evidence, which will be complemented with other more recent technical approaches that may be relevant in years to come. finally, the increasingly important issue of her-2 testing in gastric cancer will also be reviewed. molecular pathology: a hospital-based platform for translation research dr. manuel salto-tellez yong loo lin school of medicine, national university of singapore, singapore formalin fixed and paraffin embedded tissue (ffpe) collections in pathology departments are the largest resource for retrospective biomedical research studies. based on the literature analysis of ffpe related research, as well as our own technical validation, we present the translational research arrays (traresa), a tissue microarray centered, hospital based, translational research conceptual framework for both validation and/or discovery of novel biomarkers. traresa incorporates the analysis of protein, dna and rna in the same samples, correlating with clinical and pathological parameters from each case, and allowing a) the confirmation of new biomarkers, disease hypotheses and drug targets, and b) the postulation of novel hypotheses on disease mechanisms and drug targets based on known biomarkers. while presenting traresa, we illustrate the use of such a comprehensive approach. the conceptualisation of the role of ffpe-based studies in translational research allows the utilisation of this commodity, and adds to the hypothesis-generating armamentarium of existing high throughput technologies. immunohistochemistry: basic aspects dr kamla al-mawali department of histopathology, sultan qaboos university hospital, muscat, oman the process of implementing immuno-histochemical tests in the diagnostic laboratory has been greatly simplified by the availability of standardised re-agents, instruments, and assay protocol from commercial manufacturers. however, researchers and diagnosticians who wish to develop new immuno-histochemical assays, or explore new applications for existing tests, must carefully consider the methods of tissue preparation and the reaction conditions for each assay step in order to obtain clear, specific antigen signals and to minimise non-specific reactions. 306 | squ medical journal, may 2011, volume 11, issue 2 oman international conference on laboratory medicine – part ii sultan qaboos university fine needle aspiration cytology of the thyroid prof. kusum kapila department of cytopathology, kuwait university, kuwait fine needle aspiration (fna) is an important widely used investigative procedure for both palpable and ultrasonographically detected thyroid nodules. fna is a reliable triage method for identifying patients requiring surgery. the direct smear technique is highly sensitive and specific. a trained cytopathologist is skilled in recognising the different types of non-neoplastic and neoplastic cells in these fnas. the main diagnostic categories of fine needle aspiration of the thyroid are benign and functional and include the thyrotoxic goitre, nodular goitre, hyperplastic nodules, thyroiditis, acute suppurative thyroiditis, subacute thyroiditis (de quervain’s disease) and chronic lymphocytic thyroiditis (hashimotos disease). tumours of the thyroid such as follicular adenoma/carcinoma, papillary carcinoma, medullary carcinoma and lymphoma infiltrating the thyroid and metastatic tumour also can be diagnosed by fna. the potential tiered classification scheme proposed in the 2007 national cancer institute (nci) thyroid fine needle aspiration, state of the science, conference clearly stratifies the means of identifying the different grades and types of malignancies in the thyoid gland and the benign lesions, such as those lesions with a low risk of malignancy listed below. this category includes but is not limited to following terms: nodular goitre, chronic lymphocytic thyroiditis and hyperplastic/adenomatoid nodule in goitre. patients with a benign nodule are followed by clinical and periodic radiological examination and some patients may undergo repeat fna due to an increase in the size of nodule. follicular lesion of undetermined significance/ atypia of undetermined significance are also classified. this is a heterogeneous category that includes cases that cannot be classified as either benign or follicular neoplasm. follicular-neoplasm/ suspicious for follicular neoplasm is also defined. most patients with this diagnosis undergo lobectomy/hemithyroidectomy and a definite diagnosis of adenomatoid nodule versus adenoma versus carcinoma is rendered on surgical pathology examination. another category is that termed suspicious for malignancy for papillary, medullary carcinomas, lymphomas, metastatic cancers and anaplastic cancers with marked necrosis. the clearly malignant category and the non-diagnostic categories are the last two to be classified as lesions which can be diagnosed on fna. the non-diagnostic cytopathological features of lesions are also well known and must be learned by cytopathologists. ancillary studies on thyroid aspirates are indicated in cases of suspected medullary carcinoma, anaplastic carcinoma, metastatic carcinoma, lymphoma, parathyroid lesion and indeterminate or suspicious aspirates. specific ancillary studies to be performed for each indication and sample preparation for each study have been documented by the nci thyroid fine needle aspiration state of science conference. a b s t r a c t s m i c r o b i o l o g y s e s s i o n s antimicrobial resistance a global perspective dr. martin j gill consultant medical microbiologist, university hospitals birmingham, uk the development and spread of antimicrobial resistance has been recognised since shortly after antibiotics were used in clinical practice. in recent years, antimicrobial resistance has been become more of a problem due to ‘macro’ reasons (the widespread use of antibiotics, complexity of health care, patient movement and global travel). in addition, ‘micro’ reasons for this problem occur, such as genetic linkage and mechanisms for horizontal transfer of resistance genes between organisms. the relevance of ‘macro’ and ‘micro’ influences on antibiotic resistance will be discussed using current and historical examples. finally, there is only slow development of new antimicrobials in relation to the speed of resistance development and spread. measures to tackle antibiotic resistance require action at international/national and local level to be successful. these measures will be discussed. ndm-1 producing klebsiella pneumonia in oman dr. zaina al-maskari department of medical microbiology, central public health laboratories, ministry of health, muscat, oman the rapid international spread of klebsiella peumoniae strains that are carbapenem resistant is a major concern. treatment options are severely limited and are a great challenge for infection control. recently two cases of ndm-1 k. pneumoniae have been identified in oman; this mandates urgent actions/measures to limit the spread of this strain and any other resistant bacteria. emergence of resistance among gram negative pathogens dr. hanan balkhy king saud bin abdulaziz university for health sciences, riyadh, saudi arabia antimicrobial resistance is one of the world's most pressing public health problems of today. multiresistant gram-negative infections are not only the cause of infections for hospitalised patients, but also for people in the community. mechanisms of resistance are variable and options for treatment are limited. clinical diagnostic laboratories are of variable capabilities and may not always be able to identify isolates with novel mechanisms of resistance which may lead to delays in diagnosis. the versatility with which these pathogens are able to produce resistance is quite impressive and extremely intimidating and challenging to the medical community. the emergence of extended-spectrum beta-lactamases (esbls) as a mode of resistance and their presence on transferrable plasmids has increased their presence within the enterobacteraceae species and allowed for easy transfer between patients and between patients and health care workers. over 800 esbls have been identified in the lahey database todate and many unidentified genes still exist. the explanation of the emergence of this resistance is not clearly identified; however, the wide misuse of antimicrobials in medicine and agriculture have most likely resulted in pressure selection of bacteria resistant to the microbiologic activity of these agents. in addition, poor compliance of health care workers with infection control measures may also play a role in the spread of these pathogens in the health care setting. abstracts | 307 9 – 11th november 2010 these resistant bacteria fail to respond to treatment, resulting in prolonged hospitalisations, increased cost and increased risk of death. multiplex polymerase chain reaction in diagnosis of viral infections: the qatar experience dr. said h. s. al-dhahry department of laboratory medicine and pathology, hamad medical corporation, doha, qatar multiple polymerase chain reaction (pcr) is a variant of pcr which enables simultaneous amplification of many targets of interest in one reaction by using more than one pair of primers. in diagnostic microbiology, multiplex pcrs are designed for detection of multiple microbial agents in a clinical sample. our laboratory has recently introduced four commercially available multiplex pcrs for the diagnosis of viral infections. in the respiratory assay, 10 viruses (influenza a, influenza b, parainfluenza virus types 1 to 4, coronaviruses, human metapneumovirus, rhinovirus, respiratory syncytial virus, adenovirus, enterovirus and bocavirus) are detectable in respiratory samples. multiplex pcr for acute infections of the central nervous system detects the herpes simplex virus types 1 and 2, varicella zoster virus, enterovirus and mumps virus mainly in cerebrospinal fluid. the other two multiplex pcrs are for the diagnosis of viral infections in immunocompromised patients (the cytomegalovirus, epstein-barr virus and adenovirus) and the detection of viruses which cause fever and skin rash (measles, enterovirus, human herpes viruses 6 and 7, and parvovirus b19). preliminary data on the frequency of these viruses in clinical samples submitted to our laboratory will be presented. there is evidence to show that this approach in diagnostic molecular virology is both economical and reduces turnaround time when compared to single pcr assays of the same viruses. molecular characterisation of rotavirus strains circulating in oman 2005-2009: disease and economic burden dr. said al-baqlani expert virologist, central public health laboratories, ministry of health, muscat, oman globally, rotavirus remains a major cause of morbidity and mortality and is associated with approximately 400,000 to 600,000 deaths annually in infants and young children under five years of age. limited genotyping data is available for rotavirus strains in the middle east. the current study was undertaken to investigate the disease burden and molecular epidemiology of human rotavirus strains circulating in oman from 2005 to 2008 so as to help policy makers to arrive at informed decisions about the introduction of a rotavirus vaccine in oman. a total number of 5,462 stool samples were collected between 2005 and 2008 from young children <5 years admitted to hospitals and outpatients clinics with mild, moderate or severe diarrhoea, and analysed on an annual basis. the rotavirus antigen was detected by elisa (dako inc.). antigen positive samples were set for polyacrylamide gel electrophoresis (page) and later genotyped by multiplex pcr. out of the 5,462 collected samples, 2,539 (47%) were elisa positive, predominantly in the age group 6–12 months. polyacrylamide gel electrophoretic patterns demonstrated long rna electropherotypes with 8 distinct electrophoretic patterns identified. pcr results revealed fluctuating genotypes across oman year wise. genotypes g1p[8], g2p[4], g2p[4], and g1p[8] were found to be predominant in 2005, 2006, 2007 and 2008, respectively. a few cases of g3p[8] were also detected. several strains exhibited unusual combinations of g and p genotype and rna electropherotype indicating the likelihood of natural reassortment events occurring with high frequency. in addition, the unusual p[10] genotype was identified among the rotavirus strains, in combination with g1. since 2008, we have observed an increase in p[11], predominantly a bovine genotype. the results of this study provide strong support for the continuation of hospital based rotavirus surveillance that would give greater insight into the magnitude of rotavirus infection on the health of omani children. the outcome of the study will also be used in advocacy regarding the impact of the future introduction of a rotavirus vaccine in oman. primary immunodeficiency in oman experience at sultan qaboos university hospital dr. salim al-tamimi clinical immunology & allergy, sultan qaboos university hospital, muscat, oman primary immunodeficiency diseases (pid) are considered to be rare but they are expected to be more common in middle eastern countries. the prevalence and characteristics of pids are unknown in oman. sultan qaboos university hospital is the national referral center for pids in oman. patients are referred for evaluation and management when suspected to have underlying immunodeficiency. they are diagnosed and classified according to the clinical and laboratory criteria of pid reported by the international union of immunological societies (iuis) primary immunodeficiency diseases classification committee. between july 2005 and july 2010 there were a total of 90 patients, 55 males and 35 females who were diagnosed to have pid with an estimated prevalence of 1:30,000 in the country. the most common form of immunodeficiency was phagocytic disorders (42%) followed by predominantly antibody disorders (18%), other well defined pid syndromes (13%), combined immunodeficiency (12%), complement deficiencies (6%), unclassified pids (6%), and immune dysregulation syndromes (3%). the age of onset of symptoms varied from the first month of life up to 12 years of age with a mean of 20.1 months and a median of 9 months. the age of diagnosis ranged from the first week of life up tp 16 years of age with a mean of 35.5 months and a median of 24 months. consanguinity was present in 81% of patients. a family history of pid was present in 42.2% of the patients. a history of death of a previous child was present in 48.8% of cases. the most common infectious presentation was pneumonia (42.2%) followed by deep abscess (26.7%) and bcgosis (12.2%). furthermore 12.2% patients were diagnosed by screening because of a family history. a total of 57.6% patients required regular prophylactic anti-microbial therapy; 25% patients required intravenous immunoglobulin (ivig) treatment, 4% patients required gamma interferon therapy, and 11% underwent bone marrow transplants (bmt). a total of 90% of all pid patients are alive and 10% died. strategies to reduce or eliminate pids are needed. awareness among parents and physicians would improve the survival of these patients. 308 | squ medical journal, may 2011, volume 11, issue 2 oman international conference on laboratory medicine – part ii sultan qaboos university laboratory diagnosis and genetic characterisation of measles virus dr. rupa m. varghese specialist, central public health laboratories, ministry of health, muscat, oman measles is one of the most easily transmitted diseases. transmission is primarily through large droplet spreads or direct contact with nasal or throat secretions from an infected person. measles is a vaccine preventable disease, but it remains a major cause of death in infants in developing countries. the who eastern mediterranean region (emro) is in the elimination phase of the measles virus. in this phase, it is well established that surveillance based on only clinical recognition of cases is inaccurate. laboratory confirmation of each and every suspected case is critical for effective surveillance. detection of measles specific igm is the standard test for the rapid laboratory diagnosis for measles. isolation of the measles virus involves a high quality specimen collected in the window 0–5 days after rash onset. vero/hslam cell lines have been approved for the isolation of measles virus in the global laboratory network. however, expansion of measles surveillance to include the molecular characterisation of the measles virus will help facilitate measles control during this global phase of measles eradication. in 2007, the omani central public health laboratories, which is a designated who regional reference laboratory, established molecular characterisation of the measles virus by sequencing. molecular characterisation of measles viruses is an important component of measles surveillance as it provides a method for identifying the geographical origin and tracing the transmission pathways of a virus. it also provides a valuable tool for measuring the effectiveness of measles control and elimination programmes, and also provides information that can be used to document the interruption of transmission of endemic measles. the sequence of the 450 nucleotides that code for the cooh-terminal 150 amino acids of the nucleoprotein (n) is the minimum amount of data required for determining the genotype of a measles virus. sequence data can be obtained from a viral isolate or by amplification of measles sequences directly from ribonucleic acid (rna) extracted from a clinical specimen. the circulating measles genotypes in oman and neighbouring emro countries will be discussed. currently, there are 8 clades (a–h) and 23 genotypes within these clades of the measles virus. cytomegalovirus infection and disease after solid organ and bone marrow transplantation: an overview dr. hanan al-kindi clinical virologist, central public health laboratories, ministry of health, muscat, oman cytomegalovirus (cmv) is a well known cause of morbidity and mortality in immunocompromised patients. it is the most important pathogen affecting transplant recipients, which causes both direct effects, including tissue injury and clinical disease, and a variety of indirect effects. the impact of these cmv-induced effects on the organ transplant itself is great. there is a strong relationship between cmv and organ rejection and this relationship appears to be bidirectional. the prevention of cmv infection is of great importance either using the prophylaxis or the pre-emptive treatment approach. treatment of clinical cmv disease usually requires administration of intravenous ganciclovir for two to four weeks. clearance of viraemia should be documented before intravenous therapy is ceased. methicillin-resistant staphylococcus aureus (mrsa) management in health care settings: current guidelines dr. martin j gill consultant medical microbiologist, university hospitals birmingham, uk the current approach to managing mrsa in healthcare settings in many countries has resulted from a combination of history, scientific evidence and patient/political pressure. this talk will compare and review the basis for existing guidelines that are used in different health care settings. it will review the success of approaches to mrsa control and provide some insights into how organisational influences might help achieve successful control. management of health care workers infected with hiv, hcv, hbv dr. alya al-lawati specialist microbiologist, al nahdha hospital, muscat, oman in july 1990, the centre for disease control and prevention (cdc) reported the first case of possible transmission of hiv to a patient from an infected health care worker (hcw). fear of transmission was rampant and several recommendations were published. the latest updated recommendations were from the society of healthcare epidemiology of america (shea) regarding the management of health care providers infected with hiv, hepatitis b and c (hbvand hcv) were published early 2010. the society recommends that the hcw should not be prohibited from health care practice on the basis of a blood borne pathogen infection. the types of procedures done by hcw are divided into 3 categories according to the risk of transmission. for each pathogen, the recommendations are graduated according to the relative viral load level of the infected provider. however it is emphasised that because of the complexity of these cases each case will be slightly different and cases should be considered independently. the guidelines also reflect the importance of patient safety as well as provider privacy and medical confidentiality, all of which are absolutely essential. the presentation will cover the details on overall management of hcws infected with blood borne viruses based on shea guidelines. measles outbreak in dhofar march-april 2009: cross-border importation dr. idris al-obaidani department of communicable disease surveillance & control, ministry of health, muscat, oman the index case of the current outbreak was a 24 year-old woman (non-omani) who reported, on 23rd march 2009, to harwib health abstracts | 309 9 – 11th november 2010 centre in the dhofar region of southern oman with high-grade fever. she was immediately referred to sultan qaboos hospital in salalah, the capital city of the region. she was admitted and kept in isolation with a provisional diagnosis of viral fever. she gave history of visiting al-hauf village in yemen from 12–19 march. she developed a rash after admission which was then classified as a drug-induced rash and hence neither was a blood sample taken nor was the case notified as required under the fever & rash surveillance order. field investigation: action taken: genotype identification and classification of the cases. recommendation: active case-finding: houseto-house survey will be conducted in the neighbouring villages in the border area after assessing feasibility. mop-up immunisation campaign: the need for the immunisation of the population in the border area is being assessed infective endocarditis in the era of multi-drug resistant (mdr) organisms dr. zakariya al-muharrmi department of microbiology & immunology, sultan qaboos university hospital, muscat, oman the prevalence rate of infective endocarditis is increasing as a result of aging, intravenous (iv) drug users and increased rate of line related bacteraemia. in january 2010, the american heart association declared that the rate of implantable device infections was increasing which increased the risk of in-hospital death by more than two-fold. currently staphylococci are the most common aetiological organism responsible for these infections and these organisms are becoming more resistant. the who has identified antimicrobial resistance as one of the three greatest threats to human health. at the same time, infectious disease experts have announced that multidrug resistant organisms (mdro) are responsible for >25% of serious infections in developing countries, with some of these bacteria not being susceptible to any licensed antibacterial agent. some antimicrobial resistance mechanisms are difficult to detect with routine microbiological testing leading to inappropriate treatment. biofilm formation by mdro (mainly staphylococci, acinetobacter and pseudomonas) increases the difficulty of management of infective endocarditis. clear understanding of biofilm development, antibiotic pharmacokinetics, antimicrobial resistance mechanisms, institution of infection control measures and antibiotic stewardship are the mainstay of controlling this growing problem. diagnostic approach to primary immunodeficiency dr. salim al-tamimi clinical immunology & allergy, sultan qaboos university hospital, muscat, oman host immune defense is accomplished by innate immunity and adaptive immunity; both of these are essential in order to fight infections and prevent autoimmune diseases. innate immunity includes naturally occurring barriers, mucociliary clearance, peristalsis, secretions, cells and protein enzymes that do not involve the production of immunologic memory for their function. adaptive immune responses are both humoral and cellular and depend on immunologic memory for antigen recognition. patients who are immunodeficient present mainly with recurrent or severe infections. immunodeficiency can be separated into primary and secondary states and the type of infection suggests the particular component of the system involved. examples that can cause secondary immunodeficiency are hiv, drugs (e.g. cytotoxic agents, steroids) protein losing states. primary immunodeficiency results from absence or malfunction of bone marrow precursor stem cells, various blood cells, and soluble molecules that make up the immune system which can lead to compromise of the host defense system. over the last two decades, many genes have been discovered that are responsible for disease status in the immune system. these genes either fail to produce specific proteins (immunoglobulins in x-linked agammaglobulinaemia) or produce altered proteins (truncated common gamma chain of the interleukin-2 receptor in x-linked severe combined immunodeficiency), and enzyme deficiency, as seen in adenosine deaminase deficiency. conventionally, immunodeficiency is classified into four major host defense mechanisms (b-cell immunity, t-cell immunity, phagocytic cells, and complement pathways). immunodeficiency usually presents with unusual severe or recurrent infections, the following are the most warning signs of primary immunodeficiency: 1) a family history of immunodeficiency disease; 2) two new ear infections within 1 year; 3) two serious sinus infections within 1 year; 4) two months on antibiotics with little effect; 5) two pneumonias within 1 year; 6) two deep-seated infections, such as meningitis, sepsis or osteomylitis; 7) need for iv antibiotics to clear infections; 8) recurrent deep skin or organ abscesses; 9) failure to thrive; 10) persistent thrush in mouth or fungal infection on skin. when an immunodeficiency is suspected, the following screening tests should be performed and may be tailored according to the clinical information with respect to the immune system arm likely to be involved: antibody mediated immunity; quantitative immunoglobulins (igg, a, m, e); isohaemagglutinins; functional antibodies e.g. diphtheria/ tetanus titers, t-cell immunity; total lymphocyte count; t and b cells numbers; lymphocyte proliferation assay; lateral chest x-ray; hiv, neutrophil, cell count and differential nitro blue tetrazolium test (nbt); dihydrorhodamine 1,2,3 test; complement, total haemolytic complement test, c3 and c4 concentration. further specialised functional immunological tests may be required to establish an accurate diagnosis; these tests are not available in all laboratories, for example phagocytic assays and cytotoxic assays. genetic studies are more commonly used now. update on zygomycosis dr. saleh al-azri senior consultant medical microbiology, central public health laboratories, ministry of health, muscat, oman zygomycosis is one of the most rapidly progressing forms of mould infections, which usually begins in the nose and paranasal sinuses. this infection produces angioinvasive disease with tissue necrosis and is prone to dissemination. diabetes and immuno-suppression are major risk factors. recent reports showed an increased incidence of zygomycosis. the presentation and diagnosis are usually challenging and the treatment is even more so. zygomyces are resistant to most commonly used antifungal medications, but high dose liposomal amphotericin followed by posaconazole are considered in most cases. the clinical outcome is closely related to the patient’s overall health and control of the underlying diseases. 310 | squ medical journal, may 2011, volume 11, issue 2 oman international conference on laboratory medicine – part ii sultan qaboos university prosthetic joint infections dr. fatma m. al-rashdi specialist, khoula hospital, muscat, oman since its development in the late 1960s, total hip and knee replacement has increased from an infrequent procedure to one that is commonly performed. the success of these procedures is hampered in part by the development of joint infections. the rate of infection in most centres ranges between 0.5 to 1.0 % for hip replacements, 0.5 to 2 % for knee replacements, and less than 1 % for shoulder replacements. prosthetic joint infections can be classified according to the time of onset (early, delayed and late) or the pathogenic mechanism causing infection. any microorganism can cause prosthetic joint infection and the distribution of organisms varies with the time from implantation and source of infection. diagnosis of prosthetic joint infections always requires obtaining samples of joint fluid or tissue. treatment usually involves both medical and surgical measures. the type and timing of such therapies is dependent upon the cause and timing of the infection and the condition of the host. molecular epidemiology of tuberculosis in oman dr. j. p. n. singh specialist bacteriologist, national tb reference laboratory, central public health laboratories, ministry of health, muscat, oman tuberculosis continues to be a major cause of morbidity and mortality throughout the world with 8.8 million new cases and 1.6 million deaths in 2005 (who fact sheet, 2007). rapid detection, adequate treatment, and contact tracing to arrest further transmission are the key factors in the control of this infectious disease. various developments in dna technology and molecular biology have led to methods to trace tuberculosis transmission routes by the differentiation of clinical isolates based on polymorphism in genomic dna of mycobacterium tuberculosis. this presentation gives a brief introduction to molecular epidemiology and its applications, and then focuses on the molecular characterisation of omani m. tuberculosis isolates by spoligotyping, a study performed by our laboratory. we identified 265 different spoligotypes among the 786 m. tuberculosis isolates. the designation of the spoligotype was attributed by comparison of the pattern to those contained in a spoldb4 database. out of these, 124 spoligotypes (containing 573 isolates) showed matching with spoldb4 database, while 141 spoligotypes (containing 213 isolates) were not found in spoldb4 database and an st number could not be assigned for them. most unidentified spoligotypes were orphan (n = 109), however, 104 clustered spoligotypes (without st numbers) were roughly assembled into the unknown group 1 to 32. over all clustering was observed in 77.2% (n = 607) isolates, whereas 22.8% (n = 179) clinical isolates harboured unique profiles. this study gives an outline of the m. tuberculosis strains circulating in oman, and describes the distribution of the major phylogenetic families. it contributes towards a better understanding of the current trend of tb epidemiology in a low-incidence middle eastern country. departments of 1paediatrics & child health and 4chemical pathology & immunology, university of ilorin teaching hospital, ilorin, nigeria; departments of 2paediatrics & child health and 5chemical pathology & immunology, faculty of clinical sciences, university of ilorin, ilorin, nigeria; 3department of pediatrics, federal medical centre, katsina state, nigeria *corresponding author’s e-mail: folakeafolayan@yahoo.com إصاابت الكلى احلادة عند األطفال املصابني مبالراي حادة دراسة مقارنة للمعايري التشخيصية املبنية على قياس تركيزي السيستاتني سي والكرايتنني يف مصل الدم فوليك موريليات افوليان، اوليانرييواجو، متثي اديديون، حممد بابا عبد القادر، اولينيكا ر�سيد اإبراهيم، �سكرينابيومي بيليامينو، اوليجبينجا ايودجي موكولو، ايوديل اوجياو abstract: objectives: serum creatinine levels are often used to diagnose acute kidney injury (aki), but may not necessarily accurately reflect changes in glomerular filtration rate (gfr). this study aimed to compare the prevalence of aki in children with severe malaria using diagnostic criteria based on creatinine values in contrast to cystatin c. methods: this prospective cross-sectional study was performed between june 2016 and may 2017 at the university of ilorin teaching hospital, ilorin, nigeria. a total of 170 children aged 0.5–14 years old with severe malaria were included. serum cystatin c levels were determined using a particle-enhanced immunoturbidmetric assay method, while creatinine levels were measured using the jaffe reaction. renal function assessed using cystatin c-derived estimated gfr (egfr) was compared to that measured using three sets of criteria based on creatinine values including the kidney disease: improved global outcomes (kdigo) and world health organization (who) criteria as well as an absolute creatinine cut-off value of >1.5 mg/dl. results: mean serum cystatin c and creatinine levels were 1.77 ± 1.37 mg/l and 1.23 ± 1.80 mg/dl, respectively (p = 0.002). according to the kdigo, who and absolute creatinine criteria, the frequency of aki was 32.4%, 7.6% and 16.5%, respectively. in contrast, the incidence of aki based on cystatin c-derived egfr was 51.8%. overall, the rate of detection of aki was significantly higher using cystatin c compared to the kdigo, who and absolute creatinine criteria (p = 0.003, <0.001 and <0.001, respectively). conclusion: diagnostic criteria for aki based on creatinine values may not indicate the actual burden of disease in children with severe malaria. keywords: biomarkers; acute kidney injury; renal failure; glomerular filtration rate; cystatin c; creatinine; malaria; nigeria. يف التغيريات بال�رضورة يعك�س ال ذلك اأن غري احلادة. الكلى اإ�سابة لت�سخي�س كرياتنني م�ستويات ت�ستخدم ما كثريا امللخ�ص: الهدف: معدل الت�سفية الكبيبي. تهدف هذه الدرا�سة ملقارنة مدى انت�سار اإ�سابات الكلى احلادة عند االأطفال امل�سابني مبالريا حادة با�ستخدام معايري ت�سخي�سية تعتمد على قيم كرياتنني يف مقابل قيم �سي�ستاتني �سي. الطريقة: هذه درا�سة ا�ستباقية ومقطعية–عر�سية اأجريت بني يونيو 2106م ومايو 2017م مب�ست�سفى جامعة اإلورين، يف مدينة اإلورين بنيجريا. �سملت الدرا�سة 170 طفال م�سابني مبالريا حادة. ومت قيا�س تركيز �سي�ستاتني �سي عن طريق مقاي�سة مناعية عكرة معززة باجل�سيمات، ومت قيا�س تركيز كرياتنني عن طريق تفاعل جايف. ومتت معايري بثالث قي�ست التي بتلك �سي �سي�ستاتني من امل�ستمد الكبيبي الت�سفية معدل تقدير طريق عن اأجريت التي الكلى وظائف مقارنة تعتمد على تركيز كرياتنني، اإ�سافة اإىل ‘‘اأمرا�س الكلى: حت�سني النتائج العاملية’’، ومعايري منظمة ال�سحة العاملية، والقيم احلدية املطلقة للكرياتنني )اأكرث من 5.1 جمم /100 مل(. النتائج: كان متو�سط تركيزي �سي�ستاتن �سي وكرياتنني هما 1.37 ± 1.77 جمم/لرت، و1.80 ± 1.23 جمم /100 مل، على التوايل )p = 0.002(. وبح�سب معياري ‘‘اأمرا�س الكلى: حت�سني النتائج العاملية’’ و‘‘منظمة ال�سحة العاملية’’ والقيم احلدية املطلقة للكرياتنني، بلغ معدل تواتر )تكرار( اإ�سابة الكلي احلادة %32.4 و%7.6 و%16.5، على التوايل. ويف املقابل، كان معدل وقوع اإ�سابة الكلي احلادة املعتمد على تقدير معدل الت�سفية الكبيبي امل�ستمد من �سي�ستاتني �سي ي�ساوي %51.8. وعلى وجه العموم كان معدل اكت�ساف حاالت اإ�سابة الكلي احلادة عن طريق �سي�ستاتني �سي اأعلى ب�سورة يعتد بها اإح�سائيا من تلك الطرق املعتمدة على ،>0.001 and >0.001( اأمرا�س الكلى: حت�سني النتائج العاملية’’، ومعايري منظمة ال�سحة العاملية، والقيم احلدية املطلقة للكرياتنني‘‘ p = 0.003( على التوايل. اخلال�صة: قد ال تك�سف املعايري الت�سخي�سية ملر�س اإ�سابة الكلي احلادة عن طريق قيا�س قيم كرياتنني عن العبء احلقيقي للمر�س عند االأطفال امل�سابني باملالريا احلادة. الكلمات املفتاحية: املوؤ�رضات احليوية؛ اإ�سابة الكلي احلادة؛ الق�سور الكلوي؛ معدل الت�سفية الكبيبي؛ �سي�ستاتن �سي؛ املالريا؛ نيجرييا. acute kidney injuries in children with severe malaria a comparative study of diagnostic criteria based on serum cystatin c and creatinine levels *folake m. afolayan,1 olanrewaju t. adedoyin,1,2 mohammed b. abdulkadir,1,2 olayinka r. ibrahim,3 sikiru a. biliaminu,4,5 olugbenga a. mokuolu,1,2 ayodele ojuawo1,2 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e312–317, epub. 21 dec 20 submitted 23 dec 19 revision req. 21 apr 20; revision recd. 4 may 20 accepted 3 jun 20 https://doi.org/10.18295/squmj.2020.20.04.006 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ folake m. afolayan, olanrewaju t. adedoyin, mohammed b. abdulkadir, olayinka r. ibrahim, sikiru a. biliaminu, olugbenga a. mokuolu and ayodele ojuawo clinical and basic research | e313 acute kidney injury (aki) is a well-recognised complication of severe malaria in adults; however, its incidence in paediatric patients is not commonly reported, presumably as a result of under-diagnosis.1,2 according to criteria outlined by the world health organization (who), a diagnosis of malarial aki should be made based on the measurement of serum creatinine values, either with a single-point value of 3 mg/dl (265 mmol/l) or a blood urea level of >20 mmol/l.3 different creatinine cut-off values have also been proposed for use in children with malaria.4,5 in turn, the kidney disease: improving global outcomes (kdigo) criteria diagnoses malarial aki according to an acute rise in serum creatinine from baseline, or a percentage rise in its level, thus enabling identification of a minor acute reduction in kidney function which may not be clinically apparent, rather than just relying on a single creatinine value.6–9 nevertheless, although both the who and kdigo diagnostic criteria for aki rely heavily upon its use, serum creatinine is an unreliable marker of aki because of its delayed rise following a decrease in glomerular filtration rate (gfr).8–10 as a result, more reliable endogenous markers of gfr changes are necessary to accurately detect cases of malarial aki. serum cystatin c is one such candidate which has demonstrated promising applicability in clinical practice.11 cystatin c is a non-glycosylated lowmolecular-weight 13-kd basic protein that is freely filtered by the renal glomeruli, catabolised in the tubules and is not secreted or reabsorbed as an intact molecule.12,13 moreover, unlike creatinine, serum cystatin c concentration is independent of age, gender, inflammatory process, muscle mass and protein intake.12,13 however, few studies have sought to assess the utility of cystatin c in malaria and, of these, most focus exclusively on adult populations.14–16 hence, this study aimed to determine and compare the incidence of aki in children with severe malaria by assessing estimated gfr (egfr) using serum cystatin c in contrast to traditional creatinine-based criteria. methods this prospective cross-sectional analytical study was conducted between june 2016 and may 2017 at the paediatric emergency unit of the university of ilorin teaching hospital in ilorin, the capital of kwara state, nigeria. this hospital is a tertiary health facility with a 650-bed capacity and is located in a region with a high transmission of malaria year-round.17,18 a total of 170 children between six months and 14 years of age with clinical and/or laboratory features of severe malaria were included. in each case, the child’s medical history was obtained from the caregiver and a physical examination was conducted to confirm the presence of clinical features of severe malaria. children with chronic illnesses including hiv infection, chronic renal failure, sickle cell disease and diabetes mellitus were excluded from the study, as were children with severe malnutrition or those currently taking steroids. features of severe malaria were defined according to the who criteria as follows: (1) impaired consciousness (glasgow coma scale score of 11 or blantyre coma scale of 3); (2) prostration (inability to sit upright in a patient that could normally do so); (3) multiple convulsions (>2 episodes over 24 hours); (4) circulatory shock (systolic blood pressure of <70 and <50 mmhg in older children and infants, respectively); (5) hypoglycaemia (blood sugar levels of <40 mg/ dl); (6) severe anaemia (haematocrit of <15% or haemoglobin levels of <5 g/dl); spontaneous bleeding or evidence of disseminated intravascular coagulation; and (7) haemoglobinuria (passage of dark-colored urine).3 in terms of treatment, all children received a minimum of three doses of intravenous artesunate, followed by artemisinin combination therapy when they were fully conscious and able to tolerate oral medications. other complications, including severe advances in knowledge serum creatinine is the most widely used method of estimating glomerular filtration rate (gfr) for the diagnosis of renal injuries. however, creatinine is affected by extrarenal factors and may not accurately indicate a decline in renal function. hence, there is a need for a more reliable endogenous marker of changes in gfr. this study confirmed that serum creatinine-based diagnostic criteria underestimated the actual burden of acute kidney injury (aki) in a cohort children with severe malaria. in contrast, cystatin c-derived estimated gfr resulted in a significantly increased detection rate of aki in children with severe malaria compared to traditional diagnostic criteria based on creatinine values. application to patient care the early recognition of aki in children allows for more rapid intervention, potentially halting the progression of renal injury and improving patient outcomes. healthcare practitioners should therefore be aware that the use of creatinine-based diagnostic criteria may under-represent the actual prevalence of aki in severe paediatric malaria. acute kidney injuries in children with severe malaria a comparative study of diagnostic criteria based on serum cystatin c and creatinine levels e314 | squ medical journal, november 2020, volume 20, issue 4 anaemia, multiple convulsions, hypoglycaemia and respiratory distress, were managed according to the standard protocols of the department. at admission, each child underwent a pinprick test using a rapid malaria diagnostic test (rdt) strip for the detection of histidine-rich protein 2 (sd bioline malaria ag p.f/pv test, abbott laboratories, chicago, illinois, usa). subsequently, venous blood samples were obtained aseptically from all patients with positive rdt results and collected in a vacutainer containing ethylenediaminetetraacetic acid anticoagulant. a thick peripheral blood smear was prepared, stained with giemsa and examined under light microscopy at a minimum of 100 high-power fields. malaria was diagnosed based on the presence of plasmodium parasites on the thick film. the remaining blood was then aliquoted into a plain bottle and allowed to clot. the clotted blood sample was centrifuged at 3,000 rpm using a bench-top centrifuge in order to obtain serum samples. the sera were then aliquoted into another plain bottle and kept frozen at −20°c for batch analysis of serum cystatin c and creatinine. serum creatinine levels were determined according to a modified jaffe reaction using alkaline picric acid. levels of cystatin c were measured using an automated latex-enhanced immunoturbidimetric method (latex cystatin c assay, biobase group, jinan, shandong, china). thereafter, gfr was estimated using the original schwartz formula as k × l/serum creatinine in mg/dl, where k was an empirical constant with a value of 0.45 in children aged 0.5–1 year, 0.55 in children aged 1−10 years and adolescent girls and 0.7 in adolescent boys. based on the turbidimetric assay, the cystatin c-derived egfr in ml/minute/1.73 m2 was determined for children aged ≤14 years using the following equation:19 the incidence of aki was then assessed according to four different criteria: (1) creatininebased kdigo criteria; (2) creatinine-based who criteria; (3) an absolute creatinine cut-off value of >1.5 mg/dl; and (4) cystatin c-derived egfr.3,6 due to the lack of availability of baseline serum creatinine levels for the children, baseline levels of serum creatinine for the kdigo criteria were backcalculated using the schwartz formula, assuming an estimated creatinine clearance equal to 120 ml/minute/1.73m2 (eccl120). the use of eccl120 to define normal baseline renal function has been shown to be closely reflect actual baseline renal function with little bias.20 the incidence of aki was then determined based on the percentage increase in creatinine from baseline, with children who had undergone renal replacement therapy included in stage 3.6 the statistical analysis was conducted using the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). age and serum cystatin c and creatinine levels were presented as means and standard deviations, while categorical variables were presented as proportions and frequencies. prior to the use of a student’s t-test for analysis, both serum cystatin c and creatinine were log-transformed to ensure a normal distribution of data. a chi-squared test was used to assess differences between categorical variables while odds ratios (ors) and 95% confidence intervals (cis) were calculated to assess the strength of any associations. a p value of <0.050 was considered statistically significant. ethical approval for this study was obtained from the human ethical review committee of the university of ilorin teaching hospital (erc pan/2016/04/1523). the parents or caregivers of the children provided informed consent on their behalf. results a total of 170 children were included in the study, of which 102 (60%) were male. moreover, 92 (54.1%) were under the age of five, with a mean age of 4.72 egfr = 84.69 × cystatin c−1.68 × 1.384 [equation 1] figure 1: clinical and laboratory features of children with severe malaria (n = 170). dab = deep acidotic breathing. folake m. afolayan, olanrewaju t. adedoyin, mohammed b. abdulkadir, olayinka r. ibrahim, sikiru a. biliaminu, olugbenga a. mokuolu and ayodele ojuawo clinical and basic research | e315 ± 0.25 years. the majority (80%) had multiple clinical and laboratory features of severe malaria, with fever (100%), severe anaemia (50.6%), cerebral malaria (38.8%) and prostration (36.5%) being most common. the least common features were circulatory shock (1.2%), hypoglycaemia (1.8%), oedema (2.9%) and oliguria (7.1%) [figure 1]. the mean temperature was 38.58 ± 1.05°c, while mean systolic and diastolic blood pressure was 89.64 ± 10.73 mmhg and 52.20 ± 11.16 mmhg, respectively. the mean serum cystatin c level was 1.77 ± 1.37 mg/l, while the mean creatinine level was 1.23 ± 1.80 mg/dl (t = −3.113; p = 0.002). based on cystatin c-derived egfr, aki was present in 88 children (51.8%). in contrast, aki was detected in 55 (32.4%), 28 (16.5%) and 13 (7.6%) patients according to the kdigo criteria, absolute creatinine cut-off value and who criteria, respectively [figure 2]. overall, the use of cystatin c as a biomarker of egfr resulted in a significant increase in the detection of aki cases compred to the kdigo criteria (or: 2.2, 95% ci: 1.445–3.485). similarly, cystatin c detected a significantly greater number of aki cases compared to both the absolute creatinine cut-off value (or: 5.4, 95% ci: 3.286–9.016) and the who criteria (or: 13.0, 95% ci: 6.829–24.560) [table 1]. in addition, the mean egfr using cystatin c was significantly lower compared to the mean egfr calculated using serum creatinine values (80.42 ± 41.01 versus 96.23 ± 45.91 ml/minute/1.73m2; p = 0.045). figure 2: incidence of acute kidney injury using diagnostic criteria based on cystatin c versus creatinine values in children with severe malaria (n = 170). aki = acute kidney injury; who = world health organization; kdigo = kidney disease: improved global outcomes; egfr = estimated glomerular filtration rate. table 1: comparison of incidence of acute kidney injury using diagnostic criteria based on cystatin c versus creatinine values in children with severe malaria (n = 170) category a category b incidence of aki, n (%) χ2 p value or (95% ci) category a category b cystatin c-derived egfr kdigo criteria 88 (51.8) 55 (32.4) 13.14 0.003* 2.2 (1.445–3.485) cystatin c-derived egfr who criteria 88 (51.8) 13 (7.6) 79.23 <0.001* 13.0 (6.829–24.560) cystatin c-derived egfr absolute creatinine cutoff value (>1.5 mg/dl) 88 (51.8) 28 (16.5) 47.11 <0.001* 5.4 (3.286–9.016) aki = acute kidney injury; or = odds ratio; ci = confidence interval; egfr = estimated glomerular filtration rate; kdigo = kidney disease impr oved global outcome; who = world health organization. *significant at p <0.050. table 2: comparison of estimated glomerular filtration rate using cystatin c versus creatinine values in children with severe malaria (n = 170) variable mean egfr ± sd in ml/ minute/1.73 m2 t value p value cystatin c-derived rate creatininederived rate age in years 0.5–4.9 (n = 92) 83.68 ± 41.30 89.60 ± 46.70 0.956 0.956 5–9.9 (n = 63) 84.26 ± 40.89 91.06 ± 44.79 0.910 0.366 10–14 (n = 15) 89.87 ± 42.17 124.79 ± 34.79 2.533 0.024* gender male (n = 102) 82.21 ± 40.88 95.47 ± 44.57 2.237 0.027* female (n = 68) 86.29 ±41.42 84.58 ± 61.14 0.034 0.973 total 80.42 ± 41.01 96.23 ± 45.91 1.943 0.045* sd = standard deviation; egfr = estimated glomerular filtration rate. *significant at p <0.050. acute kidney injuries in children with severe malaria a comparative study of diagnostic criteria based on serum cystatin c and creatinine levels e316 | squ medical journal, november 2020, volume 20, issue 4 when stratifying by age group, both methods of deriving egfrs were comparable, except in adolescents wherein egfr values derived using cystatin c were significantly lower than those calculated using serum creatinine values (89.87 ± 42.17 versus 124.79 ± 34.79 ml/minute/1.73 m2; p = 0.024). based on gender, egfrs calculated using both methods were comparable for females; however, cystatin c-derived egfrs were lower than those calculated using creatinine values for males (82.21 ± 40.88 versus 95.47 ± 44.57 ml/ minute/1.73 m2; p = 0.027) [table 2]. discussion this study revealed that the assessment of renal function using cystatin c-derived egfr resulted in the significantly higher detection of aki among children with severe malaria compared with traditional creatinine-based criteria.3,6 overall, cystatin c-derived egfr indicated that aki was present in 88 children (51.8%). previous research has revealed similar rates of aki detection using cystatin c values (54.6–62.5%).14,15 however, burchard et al. reported a lower incidence of 17%; this may be because the study was conducted among children in ghana with uncomplicated and less severe forms of malaria.16 in contrast, the current study focused on children with severe forms of malaria who were more likely to have multiorgan dysfunction, including kidney involvement. in comparison with traditional creatinine-based criteria, the higher incidence of aki obtained from cystatin c values likely reflects the fact that the latter biomarker can indicate subclinical derangement in renal function much earlier compared to the former. this is because the level of serum cystatin c is mainly determined by gfr.21,22 therefore, any increase in serum cystatin c is identified by a gfr decrease, indicating a preclinical state of kidney dysfunction which is otherwise undetected when assessing levels of serum creatinine or measuring creatinine-derived gfr.23 hence, an acute change in serum cystatin c levels from baseline may be a true reflection of renal impairment, in contrast to changes in creatinine. indeed, a recent systematic and meta-analysis revealed that serum cystatin c has a higher prognostic value for predicting aki in children compared to other methods.24 moreover, a previous study of children with severe malaria found that admission levels of cystatin c were a predictor of early mortality.1 in the current study, the incidence of aki according to the kdigo criteria was 32.4%; in contrast, previous researchers have reported higher incidence rates using the same method (45.5–55.8%).1,14 this difference could be because one study was conducted among a large population of adults with severe malaria, while the other focused on 180 children randomised to inhale nitric oxide, a substance which increases the risk of developing aki in critically ill individuals.1,14,25 in addition, the present study found that the incidence of aki was higher when applying the kdigo criteria compared to rates detected using the who criteria or an absolute creatinine cut-off value of >1.5 mg/dl. other studies assessing the prevalence of malarial aki using a single creatinine value (0.7–3 mg/dl) revealed similar findings when compared to the kdigo criteria.5,26,27 however, there is a possible drawback to the use of the kdigo criteria in that they rely on a change in serum creatinine levels as a marker of renal filtration, which may not adequately reflect a change in gfr as serum creatinine does not rise until there is a 50% decline in gfr.11 the present study also reported a significantly higher mean egfr value obtained from creatinine compared to the egfr derived from cystatin. this could be due to an overestimation of gfr within the schwartz equation.28 however, it is more likely that the lower egfr values obtained using cystatin more accurately reflect changes in gfr, while creatinine levels lag behind, thereby accounting for the higher mean egfr value. hence, careful interpretation of egfr values obtained using creatinine-based formulae is necessary in children with severe malaria. conclusion this study showed that the detection of aki was significantly higher using serum cystatin c-derived egfr compared to traditional creatinine-based criteria, including the kdigo and who criteria as well as an absolute creatinine cut-off value of >1.5 mg/ dl. as such, healthcare practitioners should be aware that the assessment of renal function using serum creatinine-based formulae may not accurately indicate the actual burden of aki in children with severe malaria. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. folake m. afolayan, olanrewaju t. adedoyin, mohammed b. abdulkadir, olayinka r. ibrahim, sikiru a. biliaminu, olugbenga a. mokuolu and ayodele ojuawo clinical and basic research | e317 references 1. conroy al, hawkes m, elphinstone re, morgan c, hermann l, barker kr, et al. acute kidney injury is common in pediatric severe malaria and is associated with increased mortality. open forum infect dis 2016; 3:ofw046. https://doi.org/10.1093/ofid/ ofw046. 2. muhamedhussein ms, ghosh s, khanbhai k, maganga e, nagri z, manji m. prevalence, and factors associated with acute kidney injury among malaria patients in dar es salaam: a cross-sectional study. malar res treat 2019; 2019:4396108. https://doi.org/10.1155/2019/4396108. 3. world health organization. severe malaria. trop med int health 2014; 19:7–131. https://doi.org/10.1111/tmi.12313_2. 4. mishra sk, das bs. malaria and acute kidney injury. semin nephrol 2008; 28:395–408. https://doi.org/10.1016/j.semnephr ol.2008.04.007. 5. zaki sa, shenoy p, shanbag p, mauskar a, patil a, nagotkar l. acute renal failure associated with malaria in children. saudi j kidney dis transpl 2013; 24:303–8. https://doi.org/10.4103/1 319-2442.109585. 6. kellum ja, lameire n; kdigo aki guideline work group. diagnosis, evaluation, and management of acute kidney injury: a kdigo summary (part 1). crit care 2013; 17:204. https://doi. org/10.1186/cc11454. 7. lines s, lewington a. acute kidney injury. clin med (lond) 2009; 9:273–7. https://doi.org/10.7861/clinmedicine.9-3-273. 8. ricci z, cruz dn, ronco c. classification and staging of acute kidney injury: beyond the rifle and akin criteria. nat rev nephrol 2011; 7:201–8. https://doi.org/10.1038/nrneph.2011.14. 9. akcan-arikan a, zappitelli m, loftis ll, washburn kk, jefferson ls, goldstein sl. modified rifle criteria in critically ill children with acute kidney injury. kidney int 2007; 71:1028–35. https://doi.org/10.1038/sj.ki.5002231. 10. fesler p, mimran a. estimation of glomerular filtration rate: what are the pitfalls? curr hypertens rep 2011; 13:116–21. https://doi.org/10.1007/s11906-010-0176-5. 11. serteser m, albert c. eduw 34: novel biomarkers in the assessment of glomerular damage. in: educational workshop abstracts. clin chem lab med 2017; 55:s186–7. https://doi. org/10.1515/cclm-2017-5003. 12. adiyanti ss, loho t. acute kidney injury (aki) biomarker. acta med indones 2012; 44:246–55. 13. lagos-arevalo p, palijan a, vertullo l, devarajan p, bennett mr, sabbisetti v, et al. cystatin c in acute kidney injury diagnosis: early biomarker or alternative to serum creatinine? pediatr nephrol 2015; 30:665–76. https://doi.org/10.1007/s00467-0142987-0. 14. mohapatra mk. early diagnosis of acute kidney injury in falciparum malaria with kdigo criteria and serum cystatin-c. int j malariol 2016; 117:230–9. 15. günther a, burchard gd, slevogt h, abel w, grobusch mp. renal dysfunction in falciparum--malaria is detected more often when assessed by serum concentration of cystatin c instead of creatinine. trop med int health 2002; 7:931–4. https://doi.org/10.1046/j.1365-3156.2002.00951.x. 16. burchard gd, ehrhardt s, mockenhaupt fp, mathieu a, aganansiire p, anemana sd, et al. renal dysfunction in children with uncomplicated, plasmodium falciparum malaria in tamale, ghana. ann trop med parasitol 2003; 97:345–50. https://doi. org/10.1179/000349803235002281. 17. afolabi oa, adekeye ka, ofoegbu ck, nasir aa, bello jo, abdur-rahman lo, et al. socio-demographic profile of medical emergencies at the university of ilorin teaching hospital. afr j trauma 2017; 6:37–41. https://doi.org/10.4103/ajt.ajt_7_18. 18. olayemi k, ande at, ayanwale av, mohammed az, bello tm, idris b, et al. seasonal trends in epidemiological and ento mological profiles of malaria transmission in north central nigeria. pak j biol sci 2011; 14:293–9. https://doi.org/10.3923/ pjbs.2011.293.299. 19. grubb a, nyman u, björk j, lindström v, rippe b, sterner g, et al. simple cystatin c-based prediction equations for glom erular filtration rate compared with the modification of diet in renal disease prediction equation for adults and the schwartz and the counahan-barratt prediction equations for children. clin chem 2005; 51:1420–31. https://doi.org/10.1373/clinchem.20 05.051557. 20. zappitelli m, parikh cr, akcan-arikan a, washburn kk, moffett bs, goldstein sl. ascertainment and epidemiology of acute kidney injury varies with definition interpretation. clin j am soc nephrol 2008; 3:948–54. https://doi.org/10.2215/ cjn.05431207. 21. stevens la, schmid ch, greene t, li l, beck gj, joffe mm, et al. factors other than glomerular filtration rate affect serum cystatin c levels. kidney int 2009; 75:652–60. https://doi. org/10.1038/ki.2008.638. 22. coll e, botey a, alvarez l, poch e, quintó l, saurina a, et al. serum cystatin c as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. am j kidney dis 2000; 36:29–34. https://doi. org/10.1053/ajkd.2000.8237. 23. soto k, coelho s, rodrigues b, martins h, frade f, lopes s, et al. cystatin c as a marker of acute kidney injury in the emergency department. clin j am soc nephrol 2010; 5:1745–54. https://doi.org/10.2215/cjn.00690110. 24. nakhjavan-shahraki b, yousefifard m, ataei n, baikpour m, ataei f, bazargani b, et al. accuracy of cystatin c in prediction of acute kidney injury in children: serum or urine levels which one works better? a systematic review and meta-analysis. bmc nephrol 2017; 18:120. https://doi.org/10.1186/s12882-017-0539-0. 25. adhikari nk, dellinger rp, lundin s, payen d, vallet b, gerlach h, et al. inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. crit care med 2014; 42:404–12. https://doi.org/10.1097/ccm.0b013e3182a27909. 26. sowunmi a. renal function in acute falciparum malaria. arch dis child 1996; 74:293–8. https://doi.org/10.1136/adc.74.4.293. 27. weber mw, zimmermann u, van hensbroek mb, frenkel j, palmer a, ehrich jh, et al. renal involvement in gambian children with cerebral or mild malaria. trop med int health 1999; 4:390–4. https://doi.org/10.1046/j.1365-3156.1999.00409.x. 28. mian an, schwartz gj. measurement and estimation of glomerular filtration rate in children. adv chronic kidney dis 2017; 24:348–56. https://doi.org/10.1053/j.ackd.2017.09.011. https://doi.org/10.1093/ofid/ofw046 https://doi.org/10.1093/ofid/ofw046 https://doi.org/10.1155/2019/4396108 https://doi.org/10.1111/tmi.12313_2 https://doi.org/10.1016/j.semnephrol.2008.04.007 https://doi.org/10.1016/j.semnephrol.2008.04.007 https://doi.org/10.4103/1319-2442.109585 https://doi.org/10.4103/1319-2442.109585 https://doi.org/10.1186/cc11454 https://doi.org/10.1186/cc11454 https://doi.org/10.7861/clinmedicine.9-3-273 https://doi.org/10.1038/nrneph.2011.14 https://doi.org/10.1038/sj.ki.5002231 https://doi.org/10.1007/s11906-010-0176-5 https://doi.org/10.1515/cclm-2017-5003 https://doi.org/10.1515/cclm-2017-5003 https://doi.org/10.1007/s00467-014-2987-0 https://doi.org/10.1007/s00467-014-2987-0 https://doi.org/10.1046/j.1365-3156.2002.00951.x https://doi.org/10.1179/000349803235002281 https://doi.org/10.1179/000349803235002281 https://doi.org/10.4103/ajt.ajt_7_18 https://doi.org/10.3923/pjbs.2011.293.299 https://doi.org/10.3923/pjbs.2011.293.299 https://doi.org/10.1373/clinchem.2005.051557 https://doi.org/10.1373/clinchem.2005.051557 https://doi.org/10.2215/cjn.05431207 https://doi.org/10.2215/cjn.05431207 https://doi.org/10.1038/ki.2008.638 https://doi.org/10.1038/ki.2008.638 https://doi.org/10.1053/ajkd.2000.8237 https://doi.org/10.1053/ajkd.2000.8237 https://doi.org/10.2215/cjn.00690110 https://doi.org/10.1186/s12882-017-0539-0 https://doi.org/10.1097/ccm.0b013e3182a27909 https://doi.org/10.1136/adc.74.4.293 https://doi.org/10.1046/j.1365-3156.1999.00409.x https://doi.org/10.1053/j.ackd.2017.09.011 1department of reproductive health, school of nursing & midwifery, tehran university of medical sciences, tehran, iran; 2department of biostatistics and epidemiology, faculty of health, tabriz university of medical sciences, tabriz, iran; 3environmental health research center, faculty of health, golestan university of medical scienes, golestan, iran *corresponding author’s e-mail: rcharkazi@yahoo.com اعتقادات شائعة تتعلق بتدخني الشيشة لدى اإليرانيني من أصل تركماين دراسة نوعية أجريت يف مقاطعة جولستان �صريين �صهبازى �صيقلده، فاطمة �رضغامى، وعبد الرحمن جركزى abstract: objectives: waterpipe or hookah smoking has grown considerably in popularity over the past two decades; however, consumers often have misconceptions regarding this practice. this study aimed to determine common beliefs related to waterpipe smoking among turkmen in iran. methods: this qualitative study was conducted between february and june 2018 in golestan province, iran, utilising data from a previously published study. a total of 26 male turkmen waterpipe smokers of different ages, occupations and education levels underwent in-depth semi-structured interviews. a content analysis of beliefs regarding waterpipe smoking was performed. results: five categories of beliefs were extracted during the content analysis, including beliefs related to addiction, health-related beliefs, preferential beliefs for waterpipe versus cigarette smoking, beliefs related to the social function of waterpipe smoking and beliefs attributed to waterpipe smoking. several misconceptions were identified, including the idea that waterpipe smoking was not addictive, prevented the use of other more dangerous drugs (i.e. cannabis and opium) and was not as harmful as cigarette smoking. conclusion: the results of this study indicate that turkmen in iran hold several misconceptions regarding the use of waterpipe smoking. educational programmes are essential to correct such misconceptions and to control the prevalence of this habit in iran. keywords: water pipe smoking; addictive behaviors; health-related behaviors; qualitative research; tobacco use cessation; iran. امللخ�ص: الهدف: ازدادت معدلت تدخني ال�صي�صة ب�صدة يف العقدين الأخريين. غري اأن م�صتخدميها كثريا ما يحملون مفاهيم خاطئة عن تلك املمار�صة. وتهدف هذه الدرا�صة لتحديد العتقادات ال�صائعة املتعلقة بتدخني ال�صي�صة عند الرجال من اأ�صل تركماين يف اإيران. الطريقة: اأجريت هذه الدرا�صة النوعية بني فرباير ويونيو من عام 2018م مبقاطعة جول�صتان يف اإيران با�صتخدام معلومات م�صتقاة من ورقة �صبق ن�رضها. ومت يف الدرا�صة اإجراء مقابالت معمقة و�صبه منظمة مع 26 مدخنا اإيرانيا من اأ�صول تركية يف خمتلف الأعمار واملهن وم�صتويات التعليم. ومت اإجراء حتليل للمحتوى اخلا�ص بتك العتقادات عن تدخني ال�صي�صة. النتائج: وجد عند حتليل املحتوى اخلا�ص بالعتقادات ا�صتخال�ص خم�صة اأنواع منها، ت�صمل العتقادات اخلا�صة بالإدمان، وبال�صحة، والعتقادات التف�صيلية لل�صي�صة يف مقابل ال�صجائر، واعتقادات من�صئها الوظيفة الجتماعية التي يوؤديها تدخني ال�صي�صة، واعتقادات مردها تدخني ال�صي�صة. ومت ال�صتعراف على عدد من تلك املفاهيم اخلاطئة، منها مثال اأن دخان ال�صي�صة ل يف�صي لالإدمان، اأو اأنه مينع ا�صتخدام مواد اأخرى م�رضة مثل احل�صي�ص والأفيون، واأنه اأقل �رضرا من تدخني ال�صجائر. اخلال�صة: اأو�صحت هذه الدرا�صة اأن الرجال من اأ�صل تركمانى يف اإيران يحملون عددا من املفاهيم اخلاطئة عن تدخني ال�صي�صة. ومن ال�رضوري اإ�صالح تلك املفاهيم اخلاطئة باإجراء برامج تعليمية لكبح انت�صار هذه العادة يف اإيران. الكلمات املفتاحية: تدخني ال�صي�صة؛ ال�صلوكيات الإدمانية؛ ال�صلوكيات املتعلقة بال�صحة؛ بحث نوعي؛ الإقالع عن تدخني التبغ؛ اإيران. beliefs regarding waterpipe smoking among iranian men of turkmen ethnicity a qualitative study conducted in golestan province shirin s. sighaldeh,1 fatemeh zarghami,2 *abdurrahman charkazi3 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e216–222, epub. 28 jun 20 submitted 21 aug 19 revision req. 5 nov 19; revision recd. 21 dec 19 accepted 16 jan 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.013 clinical & basic research advances in knowledge this study found that turkmen in iran held several misconceptions with regards to waterpipe smoking, potentially influencing consumption patterns. the results of this study could be disseminated to government officials or research institutions to help in the design and implementation of preventative public health programmes to control the prevalence of waterpipe smoking in iran. application to patient care the findings of this study may inform future intervention strategies for reducing the prevalence of waterpipe smoking in iran, thereby decreasing the prevalence of health problems associated with this practice. doctors and healthcare practitioners in iran are encouraged to assess beliefs regarding waterpipe smoking, correct any misconceptions and educate patients regarding associated health risks. https://creativecommons.org/licenses/by-nd/4.0/ shirin s. sighaldeh, fatemeh zarghami and abdurrahman charkazi clinical and basic research | e217 globally, waterpipe or hookah smokingis rapidly increasing in prevalence, especially among young people; according to the results of a survey, this practice has overtaken cigarette smoking among 13–15-year-olds in 17 countries in the eastern mediterranean region, including iran.1 this increase in popularity is due to various factors, including the use of aromatic tobacco, the social dimension associated with hookah consumption, a thriving ‘café culture’, the emergence of social media and the lack of national policies overseeing hookah consumption in many countries.2 contrary to common misconceptions, waterpipe smoking has both shortand long-term harmful effects, including chronic bronchitis, emphysema, coronary heart disease, oesophageal, stomach and lung cancers, periodontal diseases, fertility problems, osteoporosis and mental illness.3 according to a meta-analysis by primack et al., smokers inhale up to 74.1 l of smoke during a waterpipe smoking session in comparison to 0.6 l of smoke from a single cigarette, with the former practice resulting in a greater accumulation of tar (619 mg versus 24.5 mg), nicotine (4.1 mg versus. 1.8 mg) and carbon monoxide (192 mg versus 17.7 mg) in the body compared to cigarette smoking.4 understanding of the factors and underlying causes that encourage users to smoke hookah can help policymakers to develop appropriate preventative interventions and anti-tobacco initiatives.5 in iran, individuals of turkmen ethnicity live in the northern and north-eastern provinces of golestan and north khorasan. golestan province is located in north iran, southeast of the caspian sea, and is home to approximately 1,868,819 individuals living in 14 cities [figure 1].6 approximately 40% of the population in golestan province are of turkmen ethnicity, with the majority living in the cities of maraveh tappeh, kalaleh, gonbad-e qabus, aqqala, gomishan and bandar torkaman. as cultural, ethnic and social differences can play a role in shaping health-related behaviours, this study aimed to determine beliefs regarding waterpipe smoking among turkmen in golestan province. methods this explorative qualitative study was conducted between february and june 2018 in golestan province, iran, utilising data from a previous study conducted by the same research team.6 the aim of the original study was to discover factors influencing the onset of waterpipe smoking among iranian men of turkmen ethnicity.6 individuals from all educational, occupational, social and geographical backgrounds were selected for inclusion, regardless of age or patterns of consumption, in order to ensure a representative sample. the recruitment of participants continued until the point of data saturation.6 data were collected during in-depth semistructured interviews conducted in a location that was convenient for the participants, such as workplaces, homes and local cafés serving hookah.6 a series of standardised questions were designed, focusing on factors influencing participants to engage in waterpipe smoking [table 1]. the interviews were conducted in the local turkmen language by a researcher fluent in both farsi and turkmen and with extensive experience in qualitative data collection interviews. the participants’ figure 1: map showing the location and distribution of cities in golestan province, iran. reproduced with permission from: sighaldeh ss, zarghami f, charkazi a, negarandeh r. a qualitative study of factors influencing the onset of hookah smoking among iranian men with turkmen ethnicity.6 beliefs regarding waterpipe smoking among iranian men of turkmen ethnicity a qualitative study conducted in golestan province e218 | squ medical journal, may 2020, volume 20, issue 2 responses were recorded, transcribed and translated verbatim into farsi by the interviewer, after which the transcribed responses and extracted codes were presented to some of the participants for their validation and approval. the duration of the interviews ranged from 30–90 minutes.6 subsequently, content analysis was performed to obtain an exploratory description of the study phenomenon; this entailed extraction of coding categories derived directly from the text of the transcribed interviews.7 the qualitative data analysis was based on methods described by graneheim and lundman.8 for each interview, the transcript was read several times to obtain a holistic sense of the participants’ beliefs and attitudes. the results of the content analysis were sent to other research team members for discussion and consensus regarding the management of semantic units. the units of analysis and meaning units were considered the transcript of the entire interview and those parts concerning the experiences of participants with regards to waterpipe smoking, respectively. next, the meaning units were condensed, abstracted and labelled with codes. the codes were compared in terms of similarities and differences. the analysis units (semantic units) were then identified. subsequently, the semantic units (i.e. sentences or statements containing the same content) were summarised and shortened until their main content was not abstracted. the summarised semantic units were labelled with a code. then, the codes were compared based on their similarities/differences and were categorised. the protocol for this study received ethical approval from the tehran university of medical sciences, tehran, iran (#ir.tums.95-02-99-31488). before the beginning of the interview, participants provided verbal informed consent following an explanation of the purpose, methods and potential benefits and outcomes of the study. results a total of 26 turkmen participated in the study. the mean age at the time of the interview was 29.23 ± 5.86 years old (range: 20–45 years), while the mean age at the time of first engaging in waterpipe smoking was 18.03 ± 2.50 years (range: 14–25 years).6 in terms of education, most of the participants (30.8%) were high school dropouts, while one person (3.8%) had completed primary school, six had completed secondary school (23.1%), seven (26.9%) had high school diplomas, three (11.5%) had university degrees and one (3.8%) held a master’s degree. with regards to occupation, six people (23.1%) were unemployed, six (23.1%) were drivers, two (7.7%) were labourers, two (7.7%) were hairdressers, two (7.7%) were furnituremakers, one (3.8%) was a soldier, one (3.8%) was a mason, one (3.8%) was a mechanic, one (3.8%) was a skilled worker, one (3.8%) was a retailer and one (3.8%) was a governmental employee.6 two participants (7.7%) stated they were clients at hookah cafés without revealing their occupations. other demographic characteristics of the sample have been previously published elsewhere.6 extracted codes from the content analysis were organised into five categories [table 2]. in terms of beliefs related to addiction, 24 participants (92.5%) believed that waterpipe smoking was not addictive and could easily be set aside. for example, one participant stated: “this hookah does not have addiction. i mean, i have not been smoking hookah for 10 days now and i feel ok. it does not seem to be like other materials such as opium and methamphetamine, and you do not go cold turkey. you just come and sit here and talk about things.” in addition, participants also believed that waterpipe smoking had a preventative effect on consuming other more harmful substances and that the closure of hookah cafés would encourage smokers to turn to cannabis, opium or tobacco cigarettes. another participant claimed: “it prevents the use of other drugs. now, you do not go out to see what’s going table 1: interview guide developed to assess beliefs reg arding waterpipe smoking during in-depth semi-structured interviews with turkmen in iran (n = 26) questions 1. do you think smoking hookah can cause addiction? 2. do you think hookah is harmful for your health? what are the health risks of hookah smoking? 3. what do you think about the attractiveness of hookah smoking? why do people continue to smoke hookah? 4. what is the difference between hookah and cigarettes? what about other tobacco products? 5. you are welcome to add anything else that we might have missed asking you. table 2: categories of beliefs regarding waterpipe smoking extracted during a content analysis of transcripts from in-depth semi-structured interviews with turkmen in iran (n = 26) categories 1. beliefs related to addiction 2. health-related beliefs 3. preferential beliefs for waterpipe versus cigarette smoking 4. beliefs related to the social function of waterpipe smoking 5. beliefs attributed to waterpipe smoking shirin s. sighaldeh, fatemeh zarghami and abdurrahman charkazi clinical and basic research | e219 on. what else do the people take? you are just sitting down and smoking hookah.” with regards to health-related beliefs, four participants (15.4%) were convinced that the passing of the tobacco smoke through water was somehow purifying, especially when they saw that the water in the waterpipe slowly became less transparent over time. however, most men (84.6%) also believed that waterpipe smoking held certain health disadvantages and that it caused shortness of breath, coughing and digestive problems. one participant noted: “but it also has some disadvantages. for example, to me personally, it has reduced my appetite.” most men also believed that waterpipe smoking did not control stress and anger and that such beliefs were formed as a kind of inculcation due to the collective effects of hookah consumption. as one participant elaborated: “no, hookah does not make you calm. you come here and see couple of friends, and you talk to them, listen to them and your concern will be reduced.” participants also reported preferential beliefs for waterpipe smoking compared to cigarette smoking. all of the participants were of the opinion that, unlike cigarettes, hookah did not have many side-effects, despite the spread of negative propaganda against waterpipe smoking. one of the participants explained: “it has less risk than cigarette, i think. take someone who smoke cigarette for 10 years and someone else who smoke hookah for 10 years. then, compare the two… which one’s liver and lung has been damaged more? there is even sulphur in cigarette smoke, but hookah does not contain sulphur. medical science falsely says that the hookah is more harmful because it wants to keep everyone away from the hookah.” participants also believed that the higher price of hookah would encourage cigarette smoking. one of the participants declared the following: “do you know why the rate of hookah consumption is reducing? because, about three months ago, the price of tobacco (that was about 4,000 tomans) suddenly increased to 8,000 tomans. then people said that, instead of smoking hookah for 8,000 tomans, we smoke cigarette which is only 1,000 tomans.” all of the participants believed that waterpipe smoking had a social dimension and was a form of entertainment, encouraging friends to spend time together. one individual stated: “you see, hookah creates love between the kids. that’s enough. currently, in iran, who can have fun with 4,000 tomans? look at all the kids in the café, they are all having fun in some way. hookah creates entertainment for them.” another participant expressed a similar perspective: “it is five of us; we come here in the café, talk about here and there, and that lifts our spirit. a cosy place like this lifts your spirit and morale.” moreover, according to the participants, the social stigma associated with waterpipe smoking was less intense compared to other habits such as cigarette smoking, thus making the practice more socially acceptable within the community. some participants considered it a better alternative to more dangerous drugs: “in general, i would like to say that hookah does not harm you. other materials, such as methamphetamine and opium destroy you, but this is not the same.” some of the participants held beliefs that were attributed to waterpipe smoking. the most common attribution was that hookah increased efficiency. one person claimed: “for example, when the battery is running empty it makes a beep sound and you come and connect it to a charger, well, the hookah works like that.” however, others did not believe this and considered such statements to be another form of inculcation. another attribution was that hookah smoke was less irritating to the smoker in comparison to other substances. one of the participants described it in the following words: “the smoke of other substances is bitter, but the smoke of hookah is sweet. it’s not bitter. cigarette smoke makes me cough, but i don’t cough due to hookah smoke.” discussion qualitative research methods are designed to showcase variations in opinions, feelings and experiences within a target population.9 using data from a previously published study, this qualitative analysis identified five categories of beliefs regarding waterpipe smoking among turkmen in iran, including health-related beliefs, beliefs related to addiction, belief attributed to waterpipe smoking, beliefs related to the social function of waterpipe smoking and preferential beliefs for waterpipe versus cigarette smoking.6 in terms of perceived health risks, while participants believed that hookah could cause health problems, they believed the risks to be less hazardous compared to cigarettes. some of the participants believed that this was proved by the gradual disappearance of water transparency as a result of the smoke passing through the water, the sweetness and coldness of the smoke and the lack of irritation to the throat. maziak et al. reported that waterpipe smokers often believe that hookah smoke is ‘cleaner’ than cigarettes, usually as a result of watching the passage of smoke through the waterpipe, with the gradual clouding of the water thought to be indicative of a beliefs regarding waterpipe smoking among iranian men of turkmen ethnicity a qualitative study conducted in golestan province e220 | squ medical journal, may 2020, volume 20, issue 2 filtration process.10 a qualitative study by griffiths et al. also found that young students who smoked hookah believed that waterpipe smoking was ‘cleaner’ than cigarettes, with this cleanliness attributed to the smell of hookah tobacco in combination with medicinal herbs as well as the ‘lightness’ of hookah smoke in comparison with cigarette smoke.11 in egypt, 74.1% of female students believed that waterpipe smoking was less harmful than cigarettes.12 in another study from iran, 40.6% of students believed that waterpipe smoking was a healthier and more hygienic method of tobacco consumption.13 research in saudi arabia similarly showed that the majority of participants believed that harmful substances in hookah could be purified by their passage through water.14 interestingly, most of the turkmen in the present study believed that waterpipe smoking was not directly relaxing or a method of controlling stress and anger; instead, they believed that the process of seeing friends and chatting with them while smoking hookah resulted in the reduction of these negative emotions. however, this finding contradicts those reported by other studies, in which the consumption of hookah was directly linked to reduced stress and increased calmness.15–17 jawaid et al. suggested that smoking hookah reduces fatigue can promote its consumption.15 one important misconception noted in the present study was the belief that waterpipe smoking was not addictive, with all of the participants stating that they could quit the habit at any time if they so desired. griffiths and ford also found that hookah consumers believed they could stop smoking at any time, especially since they smoked occasionally and only in social situations.11 other researchers have reported comparable findings.18,19 indeed, most waterpipe smokers believe that hookah is less addictive than cigarettes, with participants perceiving themselves to be autonomous and having control over the habit due to the casual nature of their consumption.20,21 however, the consumption of a large amount of nicotine during a single waterpipe smoking session increases the risk of dependence for users.11 the presence of nicotine in any tobacco product causes addiction and, unfortunately, the harmful effects of this alkaloid and other substances in hookah tobacco are not negated by its passage through water.22,23 the lack of social stigma associated with waterpipe smoking compared to other practices was a common theme mentioned by participants in the present study. the social dimension of the habit is one of the most important aspects leading to its consumption. participants in the current study believed that waterpipe smoking brought them together, encouraged kindness and was generally more pleasant and fun when performed in a group setting. the positive social dimension of hookah consumption and lack of stigma concerning its use in comparison to other substances has been reported by many studies worldwide.20,21,24 based on a systematic review of 58 studies, akl et al. concluded that hookah consumption formed part of the arab cultural identity, with this practice apparent even among arabs living in western countries.20 primary motivations for waterpipe smoking include socialisation, relaxation, pleasure and recreation. novelty appeal is another factor associated with hookah use among people of other cultures who reportedly find the environment of hookah cafés to be ‘charming’.21 a qualitative study from syria found that people considered waterpipe smoking to constitute a leisure activity, without considering the harmful effects of waterpipe smoking on their health.24 another category identified in the current study were beliefs attributed to waterpipe smoking, such as enhanced efficacy following consumption and the ‘sweetness’ and ‘lightness’ of hookah smoke. however, other participants disagreed that waterpipe smoking increased efficacy and performance, stating that such beliefs were a form of indoctrination or justification for continuing to take part in the habit. as part of a systematic review of qualitative studies conducted to determine perceptions and experiences associated with aromatic tobacco products, kowitt et al. observed that many waterpipe smokers perceive the taste and smell of hookah to be pleasant.25 indeed, participants in two studies conducted in lebanon and canada attributed these sensory experiences to be their primary reason for smoking.5,26 in another study from the uk, young people believed that they had become addicted to hookah due to its pleasant smell and taste.27 based on these findings, future public health interventions in iran should be designed in order to educate waterpipe smokers and their families regarding the health risks of hookah consumption. such intervention strategies could be based on the various belief categories identified in this study. in addition, the relevant authorities in iran should consider developing and promoting other recreational activities, such as sports or other pastimes, to serve as an alternative to the social dimension associated with waterpipe smoking. this study was subject to certain limitations. the results cannot be generalised to the general population due to the possible effect of ethnicity on factors influencing waterpipe smoking. nevertheless, recruitment in the present study was continued to the point of data saturation.6 second, involving a comparison group of a different ethnicity (such as individuals of persian or arab ethnicity) would shirin s. sighaldeh, fatemeh zarghami and abdurrahman charkazi clinical and basic research | e221 have provided a better understanding of the beliefs of turkmen with regards to hookah consumption. unfortunately, a comparison group could not be included in the study due to budget and resource constraints. another limitation of the present study was the absence of participants from cities such as maraveh tappeh and kalaleh as well as individuals from north khorasan province. further studies involving comparison groups and individuals from the aforementioned regions are recommended to continue the research begun in this study. conclusion in addition to the usual beliefs regarding hookah consumption, turkmen in iran did not believe that hookah could control stress and other negative emotions, instead attributing these effects to the social dimension of waterpipe smoking and the friendly atmosphere of hookah cafés. however, while the participants were aware of certain negative consequences of hookah, such as shortness of breath, coughing and digestive problems, they nevertheless had several misconceptions regarding the habit, including the notion that waterpipe smoking was not addictive and was not as harmful as cigarette smoking. preventative public health programmes are necessary to correct such misconceptions and to help control the prevalence of waterpipe smoking and its associated health risks. a c k n o w l e d g e m e n t s the authors of this study would like to express their appreciation and gratitude to all of the individuals who took part in this study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the tehran university of medical sciences, tehran, iran (ir. tums. 95-02-9931488). references 1. warren cw, lea v, lee j, jones nr, asma s, mckenna m. change in tobacco use among 13-15 year olds between 1999 and 2008: findings from the global youth tobacco survey. glob health promot 2009; 16:38–90. https://doi.org/10.1177/17 57975909342192. 2. maziak w, taleb zb, bahelah r, islam f, jaber r, auf r, et al. the global epidemiology of waterpipe smoking. tob control 2015; 24:i3–12. https://doi.org/10.1136/tobaccocontrol-2014-051903. 3. el-zaatari zm, chami ha, zaatari gs. health effects assoc iated with waterpipe smoking. tob control 2015; 24:i31–43. https://doi.org/10.1136/tobaccocontrol-2014-051908. 4. primack ba, carroll mv, weiss pm, shihadeh al, shensa a, farley st, et al. systematic review and meta-analysis of inhaled toxicants from waterpipe and cigarette smoking. public health rep 2016; 131:76–85. https://doi.org/10.1177/003335491613100114. 5. nakkash rt, khalil j, afifi ra. the rise in narghile (shisha, hookah) waterpipe tobacco smoking: a qualitative study of perceptions of smokers and non smokers. bmc public health 2011; 11:315. https://doi.org/10.1186/1471-2458-11-315. 6. sighaldeh ss, zarghami f, charkazi a, negarandeh r. a qualitative study of factors influencing the onset of hookah smoking among iranian men with turkmen ethnicity. j epidemiol glob health 2019. [in press]. https://doi.org/10.2991/jegh.k.191206.001. 7. hsieh hf, shannon se. three approaches to qualitative content analysis. qual health res 2005; 15:1277–88. https://doi.org/10.1 177/1049732305276687. 8. graneheim uh, lundman b. qualitative content analysis in nursing research: concepts, procedures and measures to achieve trust worthiness. nurse educ today 2004; 24:105–12. https://doi.org/10.10 16/j.nedt.2003.10.001. 9. sandelowski m. focus on qualitative methods: the use of quotes in qualitative research. res nurs health 1994; 17:479–82. https://doi.org/10.1002/nur.4770170611. 10. maziak w, ward kd, afifi soweid ra, eissenberg t. tobacco smoking using a waterpipe: a re-emerging strain in a global epidemic. tob control 2004; 13:327–33. https://doi.org/10.11 36/tc.2004.008169. 11. griffiths ma, ford ew. hookah smoking: behaviors and beliefs among young consumers in the united states. soc work public health 2014; 29:17–26. https://doi.org/10.1080/19371918.2011.6 19443. 12. payne s. gender, women and the tobacco epidemic. gend dev 2011; 19:344–5. https://doi.org/10.1080/13552074.2011.592653. 13. mohammadpoorasl a, abbasi ghahramanloo a, allahverdipour h, modaresi esfeh j. prevalence of hookah smoking in relation to religiosity and familial support in college students of tabriz, northwest of iran. j res health sci 2014; 14:268–71. 14. amin tt, amr ma, zaza bo, kaliyadan f. predictors of waterpipe smoking among secondary school adolescents in al hassa, saudi arabia. int j behav med 2012; 19:324–35. https://doi.org/10.1007/s12529-011-9169-2. 15. jawaid a, zafar am, rehman tu, nazir mr, ghafoor za, afzal o, et al. knowledge, attitudes and practice of university students regarding waterpipe smoking in pakistan. int j tuberc lung dis 2008; 12:1077–84. 16. noonan d. a descriptive study of waterpipe smoking among college students. j am assoc nurse pract 2013; 25:11–15. https://doi.org/10.1111/j.1745-7599.2012.00781.x. 17. braun re, glassman t, wohlwend j, whewell a, reindl dm. hookah use among college students from a midwest university. j community health 2012; 37:294–8. https://doi.org/10.1007/ s10900-011-9444-9. 18. ward kd, eissenberg t, gray jn, srinivas v, wilson n, maziak w. characteristics of u.s. waterpipe users: a preliminary report. nicotine tob res 2007; 9:1339–46. https://doi.org/10.1080/14 622200701705019. 19. smith-simone s, maziak w, ward kd, eissenberg t. waterpipe tobacco smoking: knowledge, attitudes, beliefs, and behavior in two u.s. samples. nicotine tob res 2008; 10:393–8. https://doi. org/10.1080/14622200701825023. 20. akl ea, jawad m, lam wy, co cn, obeid r, irani j. motives, beliefs and attitudes towards waterpipe tobacco smoking: a syst ematic review. harm reduct j 2013; 10:12. https://doi.org/10.11 86/1477-7517-10-12. https://doi.org/10.1177/1757975909342192 https://doi.org/10.1177/1757975909342192 https://doi.org/10.1136/tobaccocontrol-2014-051903 https://doi.org/10.1136/tobaccocontrol-2014-051908 https://doi.org/10.1177/003335491613100114 https://doi.org/10.1186/1471-2458-11-315 https://doi.org/10.2991/jegh.k.191206.001 https://doi.org/10.1177/1049732305276687 https://doi.org/10.1177/1049732305276687 https://doi.org/10.1016/j.nedt.2003.10.001 https://doi.org/10.1016/j.nedt.2003.10.001 https://doi.org/10.1002/nur.4770170611 https://doi.org/10.1136/tc.2004.008169 https://doi.org/10.1136/tc.2004.008169 https://doi.org/10.1080/19371918.2011.619443 https://doi.org/10.1080/19371918.2011.619443 https://doi.org/10.1080/13552074.2011.592653 https://doi.org/10.1007/s12529-011-9169-2 https://doi.org/10.1111/j.1745-7599.2012.00781.x https://doi.org/10.1007/s10900-011-9444-9 https://doi.org/10.1007/s10900-011-9444-9 https://doi.org/10.1080/14622200701705019 https://doi.org/10.1080/14622200701705019 https://doi.org/10.1080/14622200701825023 https://doi.org/10.1080/14622200701825023 https://doi.org/10.1186/1477-7517-10-12 https://doi.org/10.1186/1477-7517-10-12 beliefs regarding waterpipe smoking among iranian men of turkmen ethnicity a qualitative study conducted in golestan province e222 | squ medical journal, may 2020, volume 20, issue 2 21. castañeda g, barnett te, soule ek, young me. hookah smoking behavior initiation in the context of millennials. pub health 2016; 137:124–30. https://doi.org/10.1016/j.puhe.2016.02.013. 22. world health organization study group on tobacco product regulation. tobreg advisory note: waterpipe tobacco smoking health effects, research needs and recommended actions by regulators. from: www.who.int/tobacco/global_interaction/tobr eg/waterpipe%20recommendation_final.pdf accessed: dec 2019. 23. shihadeh a. investigation of mainstream smoke aerosol of the argileh water pipe. food chem toxicol 2003; 41:143–52. https://doi.org/10.1016/s0278-6915(02)00220-x. 24. hammal f, mock j, ward kd, eissenberg t, maziak w. a pleasure among friends: how narghile (waterpipe) smoking differs from cigarette smoking in syria. tob control 2008; 17:e3. https://doi.org/10.1136/tc.2007.020529. 25. kowitt sd, meernik c, baker hm, osman a, huang ll, goldstein ao. perceptions and experiences with flavored nonmenthol tobacco products: a systematic review of qualitative studies. int j environ res public health 2017; 14:e338. https://doi.org/10.3390/ijerph14040338. 26. hammal f, wild tc, finegan ba. knowledge about the water pipe (hookah), a qualitative assessment among community workers in a major urban center in canada. j community health 2016; 41:689–96. https://doi.org/10.1007/s10900-015-0143-9. 27. kotecha s, jawad m, iliffe s. knowledge, attitudes and beliefs towards waterpipe tobacco smoking and electronic shisha (e-shisha) among young adults in london: a qualitative analysis. prim health care res dev 2016; 17:166–74. https://doi.org/10.1017/ s1463423615000237. https://doi.org/10.1016/j.puhe.2016.02.013 https://doi.org/10.1016/s0278-6915%2802%2900220-x https://doi.org/10.1136/tc.2007.020529 https://doi.org/10.3390/ijerph14040338 https://doi.org/10.1007/s10900-015-0143-9 https://doi.org/10.1017/s1463423615000237 https://doi.org/10.1017/s1463423615000237 squ med j, december 2010, vol. 10, iss. 3, pp. 341-349, epub. 14th nov 10 submitted 29th mar 10 revision req. 29th june 10, revision recd. 4th aug 10 accepted 24th aug 10 1department of nutrition, al-buraimi hospital, al-buraimi governorate, oman; 2institute of brain chemistry & human nutrition, london metropolitan university, uk; 3nutrition department, eastern medical region, seha (health services company), abu dhabi, united arab emirates *corresponding author email: mjsa@live.co.uk ‰e<‘ä€j÷]ê<<ï^è£]<<º¥ê<<ìëñ«j◊÷<å^çö˝]<ìè÷^√  <∞fi^€�√÷]<óïüπ]<çfl¬< �ìèñë˘]<�ïü�èä÷]<ó◊¬<â4m`i ífi^n÷]<≈áfl÷]<‡⁄<ü”ä÷]<]çe<∞e^íπ]   2003     98 20082005 27 16 43      %11.6  62 %63.2     25 %25.2  "" ""     abstract: objectives: the nutritional advice protocol, established by the department of health to combat diabetes, has been implemented in primary health care throughout oman since 2003. this study aimed to assess the effectiveness of dietary and lifestyle advice and determine the perception and attitudes of omani adults with type 2 diabetes to diabetes management. methods: a cross-sectional epidemiological survey was conducted on 98 patients diagnosed with type 2 diabetes in al-buraimi governorate, oman. metabolic parameters, dietary intake and exercise levels were evaluated in 2005 and re-evaluated in 2008. results: a total of 43% of the patients (male = 16, female = 27) had received no formal education. a significant reduction in fasting glucose and enhanced high density lipoprotein cholesterol were achieved in both male and female patients. however, in men, no changes were noted, other than in anthropometric and metabolic measurements and macronutrient intake. conversely, women’s macronutrient intakes reduced significantly leading to considerable improvement in body weight, body mass index, blood glucose and total cholesterol levels. eleven patients (11.6%) admitted that they did not adhere at all to the diet advised by the dietician; 63.2% (n = 62) reported they followed their diet sometimes, and 25.2% (n = 25) stated they strictly followed the diet. conclusion: counselling largely illiterate diabetic patients about the impact of food, nutrition and exercise on diabetes shifted the patients from “poor” to “good” control in terms of metabolic outcome (glycosylated haemoglobin, fasting glucose and total cholesterol). this minor improvement could be further enhanced by more health education. keywords: diabetes mellitus, type 2; compliance; diet therapy; oman. effectiveness of and adherence to dietary and lifestyle counselling effect on metabolic control in type 2 diabetic omani patients *mohammed al-sinani,1 yoeju min,2 kebreab ghebremeskel,2 hussain s qazaq3 clinical & basic research effectiveness of and adherence to dietary and lifestyle counselling effect on metabolic control in type 2 diabetic omani patients 342 | squ medical journal, december 2010, volume 10, issue 3 type 2 diabetes has become one of the leading causes of disability and death in most developed countries as well as in developing countries undergoing rapid economic transition.1,2 oman is not an exception to this trend. it has progressed rapidly from an agrarian subsistence economy, emphasising animal husbandry and date production, to a diverse economy producing oil and oil-based products and with growing commerce and tourism sectors. this rapid change has had a huge impact on the lifestyle of the omani population in the last three decades. the first national diabetes survey, conducted by the ministry of health in collaboration with the who in 1991, estimated that 10% of the omani population aged 20 years or above had diabetes.3 the latest study by al-moosa et al. in 2006 found that the prevalence of diabetes in the capital region of muscat was 17.7%.4 type 2 diabetes presents as a complex spectrum of hypertension, hyperglycemia, insulin resistance, and dyslipidemia.5,6 it is well known that obesity plays a central role in the development of insulin resistance and type 2 diabetes.7,8 diet and exercise modification are considered important components of the treatment strategy for adults with type 2 diabetes.6 suitable use of diet and exercise can improve glycemic control and insulin sensitivity and reduce the need for insulin or oral medications.5 the finnish diabetes prevention study demonstrated that the risk of type 2 diabetes can be reduced significantly through a personalised intensive lifestyle intervention (i.e., individualised dietary advice and physical activity regime).9,10,11 similarly, knowles et al. found that therapeutic lifestyle changes were more effective in reducing the incidence of type 2 diabetes than metformin treatment in patients with hyperglycemia.12 these studies showed that type 2 diabetes can be prevented through non-pharmacological means. however, non-adherence to diet and exercise in the long-term was found to be the most frequently reported barrier in diabetes self management.13,14 the fifth health development plan in oman (1996-2000) identified diabetes as a major cause of concern and set specific goals to prevent further progression of the disease. this led to a nationwide “diabetes control programme” which established the nutritional advice protocol;15 however, the effectiveness of the nutritional advice protocol for type 2 diabetic patients has not been tested. in this study, we aimed to assess the effectiveness of dietary and lifestyle advice and determine how patients with type 2, who attended the diabetic clinic at al-buraimi hospital in al-buraimi governorate, oman, perceived their diabetes and their attitude toward diabetes management. methods a cross-sectional survey study was designed for omani citizens with type 2 diabetes living in alburaimi governorate in the north of oman. in oman, every new case of diabetes is registered on the national diabetes register which is a part of “diabetes control programme” initiated by the ministry of health in 2000. the registry, which is regularly updated, contains patients’ demographic data, medical history, clinical assessment, laboratory investigation results, initial treatment plan, referrals, and follow-up plans. this registry was used to identify the patients for the study. there were a advances in knowledge 1. this is the first study in oman to assess the effectiveness of dietary and lifestyle advice and determine the attitudes of omani patients with type 2 diabetes. 2. patients’ knowledge of nutrition was poor, as more than 65% of the participants in this study were illiterate. 3. fasting blood glucose levels and high density lipoprotein cholesterol showed a marked reduction in all subjects in the study. 4. compliance with dietary advice was better in female patients. 5. low levels of education have been associated with poorer compliance to diet and exercise advice. 6. improving dietary awareness in type 2 diabetes patients is the key to successful diabetes management. application to patient care 1. nutritional advice for patients with type 2 diabetes needs to be reworded to take into account the patients’ needs. 2. exercise is an important component of diabetes care management. 3. dietary compliance for type 2 diabetes should be improved by focusing on increasing the number of follow-up visits to the nutrition clinic. mohammed al-sinani, yoeju min, kebreab ghebremeskel, and hussain s qazaq clinical and basic research | 343 total of 195 cases of new type 2 diabetics in 2005 at the diabetic clinic at al-buraimi hospital. of these patients, 187 had complete diagnostic clinical and biochemical data which were obtained at the time of diagnosis. out of these 187 patients, 63 cases were excluded from the study as they had not been attending the diabetes clinic for the last 6 months or the relevant data were missing. a further 3 patients were excluded as they did not receive any dietary advice during their treatment. out of 121 patients who were invited to participate in the study, 23 declined. in the end, 98 patients were enrolled for the study. thirty-three were treated with diet only and 65 patients were either on hypoglycemic agents and/or insulin to control blood glucose. upon enrolment, all patients received nutrition and lifestyle counselling based around four key themes: education about diabetes; diet and nutrition; weight management, and exercise. particular emphasis was given to education, i.e., what diabetes is, why it is important to control blood glucose, possible complications, why regular exercise is important etc. in oman, although the dietary guidelines for diabetic patients are the same as for the general populations, individualised diet plans are prescribed to the patients. the initial assessment of patients’ diabetic management and their perception of the importance of diet and exercise took place in 2005. following the assessment, all patients received dietary and lifestyle advice and were re-invited in 2008 in order to assess: 1) if this advice had encouraged the patients to make any changes, and 2) if it did, how it affected diabetic control, taking into account each subject’s primary method of diabetes management (diet control, hypoglycemic agents and insulin). dietary assessment and anthropometric and biochemical measurements were carried out in 2005 and in 2008. the recommended targets for nutrition and lifestyle advice on metabolic control described in table 1 were used to assess patients’ compliance.15 ethical approval was granted by the ministry of health, oman. the nature and aim of study was explained to all participants (in both verbal form and via a written information sheet) and written consent was obtained from each participant. this investigation was conducted in accordance with the principles of the declaration of helsinki ii. all patients were asked to complete (with or without assistance from the dietician) a food frequency questionnaire, which contains more than 60 questions covering five food sections: meat, milk, fruits and vegetables, breads, and other food and some omani-style beverages. food composition tables for arab gulf countries were used to analyse the nutrient composition.16 height, weight and blood pressure were measured by one of the investigators according to who recommendations.17 a digital scale was used to measure weight; subjects were weighed dressed in their own clothing hence a 1kg subtraction was set onto the device to account for the weight of the attire. readings were recorded to the nearest kilogramme. the height of subjects was measured using a stadiometer and recorded to the nearest centimetre. blood pressure was measured using an electronic measuring device. all subjects rested for ten minutes before recording their blood pressure. a digital sphygmomanometer made three consecutive blood pressure readings for each table 1: recommended targets for nutrition and life style advice on metabolic control indicator good borderline poor bmi 18–24.9 25–29.9 >30 plasma glucose (mmol/l) fasting hba1c (%) 4.4–6.1 <7 6.2–7 7–8 >7 >8 total cholesterol (mmol/l) <5.2 5.2–6.5 >6.5 blood pressure (mmhg) systolic diastolic <130 <80 >130 & <140 >80 & <90 >140 >90 smoking status non-smoker smoker smoker legend: bmi = body mass index; hba1c = haemoglobin a1c effectiveness of and adherence to dietary and lifestyle counselling effect on metabolic control in type 2 diabetic omani patients 344 | squ medical journal, december 2010, volume 10, issue 3 subject. the average reading was taken from these three readings. blood samples, after 12 hours fasting, were obtained twice from the patients: on the same day on which they enrolled and had nutrition counselling, and then once during follow-up counselling. the samples were used to determine glucose, glycosylated haemoglobin (hba1c) and lipid profile (total cholesterol, low density lipoproteins (ldl), high density lipoproteins (hdl), and triglyceride). the paired-sample t-test was used to determine the changes in parameters between 2005 and 2008. the difference in macronutrient intake and the type of primary diabetes management was compared between the subjects by gender and was assessed with an independent t-test. the statistical package for the social sciences (spss), version 16.0 for windows, (spss inc., chicago, il, usa) was used in data analysis. results are given as mean values with corresponding standard deviations (sd). p values below 0.5% were considered significant. results the demographic description of the patients is summarised in table 2. of the 98 patients, 90.8% were over 30 years old and 43.9% (male = 16; female = 27) had received no formal education. the most common form of diabetes management used by the subjects was hypoglycemic agents (male = 19, female = 22). a total of 33 subjects followed a controlled diet only, 15 subjects used both insulin and hypoglycemic agents, and 9 subjects used insulin to control their blood sugar level. a total of 28 patients (28.6%) also used traditional herbal medicine. 75% of male (n = 37) and 51% of female (n = 25) patients also presented with hypertension and/or hyperlipidemia at the time of diagnosis in 2005. table 2: demographic description of patients frequency (n) percentage (%) sex (male/female) 49/49 50/50 age group a <20 2 2.0 ≥20 & <30 7 7.1 ≥30 & <40 22 22.4 ≥40 & <50 23 23.5 ≥50 & <60 24 24.5 ≥60 20 20.4 marital status married 85 86.7 single 13 13.3 educational status no formal schooling 43 43.9 elementary school completed 22 22.5 secondary school or higher 21 21.4 university or higher 12 12.2 diabetic management diet only 33 33.7 hypoglycaemic agents 41 41.8 insulin 9 9.2 insulin & hypoglycaemic agents 15 15.3 diabetes related complication b 66 67.4 use of traditional herbal medicine c 28 28.6 smoker 31 31.6 aage in year 2005; bhypertension, hyperlipidemia; cdrinks mixed with honey, thyme or wheat or blackseed (nigella sativa), germander, bitter frankincense, fenugreek, stinkweed and aloe. mohammed al-sinani, yoeju min, kebreab ghebremeskel, and hussain s qazaq clinical and basic research | 345 as far as changes in body weight and metabolic measurements are concerned [table 3], a significant reduction in fasting glucose were achieved in both male and female patients. in men, no changes were noted in weight, body mass index (bmi), hba1c, blood pressure, ldl-cholesterol and triglycerides over the three years of the study. in contrast, women made considerable improvement in terms of body weight, bmi, blood glucose, and total cholesterol levels. there was no significant difference in the metabolic measurements between different diabetes management groups, as it has no obvious effect on the rate of blood glucose level in the subjects. examination of changes in macronutrient intakes revealed that in 2005 women had a greater total calorie intake (p <0.01) compared to men. however, the macronutrient intake did not differ between the two sexes in 2005. in men, no changes were found in macronutrient intake between 2005 and 2008 [table 4]. on the contrary, women had a significant reduction in the amount of macronutrients over the three years. in 2008, the average total energy intake (kcal/day) in women was reduced by 18% compared to that of 2005. moreover, women ate less fat, carbohydrate and protein (21%, 14% and 14% respectively) per day (g/day) in 2008 than they did in 2005. dietary compliance was divided into three categories: always, sometimes and none. only 11 patients (11.6%) admitted that they never adhered to the diet advised by the dietician, while 63.2% (n = 62) reported they followed their diet sometimes and 25.2% (n = 25) stated they strictly followed diet. patients were grouped into three clusters according to physical activity: sedentary, moderate and active. a total of 47% of the patients (n = 46) reported they were “active”, 24% “moderate” and 28% “sedentary”. the most common form of physical activity reported was walking. finally, patients were asked about their perceptions and beliefs and attitudes toward diet and exercise and their effect on metabolic control. their responses are presented in table 5. a total of 21.2% of the patients reported that they strongly believed “drinking 0.5 cup fruit juice improves hypoglycemia” and 9.6% strongly believed that “diet only is sufficient for improving blood sugar”. table 3: changes in body weight and metabolic parameters men women 2005 2008 p value 2005 2008 p value mean sd mean sd mean sd mean sd weight (cm) 72.2 14.5 74.9 10.4 0.623 71.8 13.5 67.7 9.8 <0.0001 bmi (kg/m2) 26.8 4.6 27.1 3.3 0.555 30.8 5.4 29.1 4.0 <0.0001 fasting glucose (mmol/l) 12.9 5.7 9.1 3.4 <0.0001 11.9 4.4 9.5 2.7 0.002 hba1c (%)a 9.6 2.1 9.0 2.0 0.081 9.0 2.4 8.9 1.9 0.729 systolic bp (mmhg) 131.9 10.7 135.1 15.7 0.211 130.0 11.4 131.1 17.2 0.667 diastolic bp (mmhg) 83.5 5.9 82.6 7.8 0.575 82.1 10.6 79.8 11.2 0.32 total cholesterol (mmol/l) 6.4 6.8 6.5 9.9 0.991 5.5 1.7 4.9 0.8 0.023 ldl-cholesterol (mmol/l)b 3.9 4.4 3.0 1.1 0.254 2.9 1.0 2.7 0.9 0.427 hdl-cholesterol (mmol/l)c 1.4 0.6 1.3 0.5 0.426 1.8 1.6 1.6 1.4 0.578 triglycerides (mmol/l)d 2.8 2.9 2.2 1.6 0.06 2.1 0.9 1.9 0.9 0.106 notes: all values are expressed as mean ± sd a, b, c, d the values are based on the following numbers: hba1c (n = 97); ldl-cholesterol (n = 71); hdl-cholesterol (n = 69); triglycerides (n = 96). legend: bmi = body mass index; hba1c = glycosylated haemoglobin; bp = blood pressure; ldl = low-density lipoprotein; hdl = high-density lipoprotein effectiveness of and adherence to dietary and lifestyle counselling effect on metabolic control in type 2 diabetic omani patients 346 | squ medical journal, december 2010, volume 10, issue 3 regarding exercise, 55.8% of the patients strongly believed that “exercise improves blood sugar”. moreover, 15.4% of the patients also strongly believed that “taking traditional herbs improves blood sugar levels”. furthermore, more than 10% of the patients did not follow the advice, as they did not believe diabetes or diabetes related complications would affect their quality of life. discussion this epidemiological survey was designed to assess the impact of nutritional and lifestyle advice given to patients by dietitians and to determine the perception of and attitudes to diabetes management of type 2 diabetic patients attending the diabetic clinic at al-buraimi hospital. in this study, nutrition and lifestyle counselling made a small improvement in metabolic control in diabetic patients living in al-buraimi governorate. at the time of this study, there were no specific dietary recommendations for people with diabetes in oman. the guidelines used for diabetic patients at the al-buraimi hospital were similar to the ones recommended for the general population, i.e. total calorie intake should constitute 50–55% carbohydrates, ≤30% fat (<10% saturated, 10% polyunsaturated, 10% monounsaturated) and 10– 15% protein with 300 mg/day or less cholesterol. in addition, diabetic patients were advised to eat frequent small meals in order to maintain a steady blood sugar level.18 the subjects’ fasting blood glucose level showed a very slight change among the subjects in the study, while the fasting blood glucose and hdl-cholesterol levels showed a marked improvement, though this did not reach the target value in all subjects in the study. this could be due to the decrease in nutritional intake, especially from fat and carbohydrate among the subjects in the study. on the other hand, hba1c did not change, which is an important result. unexpectedly, despite a higher illiteracy rate in women, the compliance for dietary advice was better in female patients; overweight and obese women achieved an average of 3.0 kg and 7.1 kg weight loss respectively over three years. this could be explained by the substantial reduction of total energy and nutritional intake in women which was associated with a decrease in blood pressure and lipids profile. on the contrary, there was no enhancement noted in hba1c, blood pressure or lipids profile levels in men and, in addition to this, 16.4 % of men whose bmi was within ideal body weight in 2005 became overweight (30< bmi ≥25) by year 2008. this could be explained by the substantial reduction of total energy and nutritional intake in women in 2008 (when compared with 2005) and the lack of change in the nutritional intake levels in men from the collection of baseline figures until the end of the study. it is not clear why women were more amenable to changing their diet than men. food is exclusively prepared by women in oman and female diabetics may find it easier to change their diet since they table 4: changes in macronutrient intakes per day men women 2005 2008 p value 2005 2008 p value mean sd mean sd mean sd mean sd total energy (kcal) 2818.7 754.3 2809.3 671.5 0.954 3128.1 575.7 2577.1 586.2 <0.0001 energy intake from carbohydrate (kcal) 1294.1 395.4 1275.7 279.6 0.79 1438.0 345.6 1232.9 275.7 <0.0001 energy intake from fat (kcal) 1096.2 323.7 1059.1 339.3 0.619 1204.7 281.3 953.4 308.0 <0.0001 carbohydrate (g) 323.5 98.9 318.9 69.9 0.790 359.5 86.4 308.2 68.9 <0.0001 fat (g) 121.8 36.0 117.7 37.7 0.619 133.9 31.3 105.9 24.2 <0.0001 protein (g) 101.8 23.9 98.9 19.3 0.516 110.1 17.9 95.6 19.6 <0.0001 legend: sd = standard deviation mohammed al-sinani, yoeju min, kebreab ghebremeskel, and hussain s qazaq clinical and basic research | 347 do the cooking compared to male diabetics who would have to explain the needed changes to their wives. it is uncommon to cook separate meals for different members of family; whole families tend to share food from the same plates and meals are often high in calories and fat.4 in oman, men tend to lead a sedentary lifestyle and are more likely to attend social functions which invariably include meals which are high in calories, fat and sugar. women, on the other hand, tend to lead a more active lifestyle than men. moreover, omani women are becoming increasingly conscious about their body image, and being overweight or obese is considered undesirable. therefore, it is probable that women simply cut down their food intake and did more exercise in order to lose weight. low dietary compliance among the subjects in the study (75%) was largely due to lack of awareness of the condition and its implications on the quality of their life. alternatively, it is possible that participants simply could not follow the diabetic diet plan as it did not fit in with the traditional omani high calorie and high fat diet.4 it should also be noted that poor compliance to dietary advice by diabetic patients is not unique to the omani population.13,14 it was clear from the interviews that patients’ knowledge of nutrition was poor, as more than 65% of the participants in this study were illiterate. for instance, 98.1% of patients replied that unsweetened fruit juice would not increase their blood sugar level. although all patients were seen by a dietician and a health educator, an overwhelmingly large proportion of patients did not recognise the importance that diet or losing weight could have on diabetic management. according to the national health survey 2000,19 the prevalence of diabetes amongst men (4.3%) and women (17.1%) with secondary education is 25% less than the rate found amongst the illiterate sector of the population. a study of the prevalence of diabetes in the omani population found that highly educated individuals may be better aware of coronary risk factors and therefore use more effective preventive measures.4 a similar finding was reported in bahraini population.20 low levels of education have been associated with poorer compliance to diet and exercise and greater diabetes-related morbidity.21 in addition, it has also been demonstrated that education does make a difference in long-term diabetes management. in a group of older type 2 diabetic patients, higher diabetic knowledge scores were linked with better glycemic control when randomly assigned to diabetic education programmes compared with those randomly assigned to normal care.22 similarly, rubin et al. found that subjects who received outpatient diabetes education for more than one week showed a significant increase in their knowledge score, which was associated with a significant fall in hba1c at 6 months.23 more than 70% of the subjects in the study were active which is considered to be an important factor in managing obesity (bmi) and achieving a low glycemic index in diabetic patients,18 however, obesity in these type 2 diabetic patients was also more likely, due to poor dietary habits rather than through lack of exercise.24 traditional herbal medicine is also sometimes table 5: patients’ attitude toward diabetes management strongly agree (%) agree (%) don’t know (%) disagree (%) strongly disagree (%) drinking 0.5 cup fruit juice improves hypoglycaemia 21.2 46.2 25.0 3.8 3.8 taking herbs improves blood sugar levels 15.4 34.6 28.8 19.2 1.9 diet only is sufficient for improving blood sugar 9.6 32.7 28.8 26.9 1.9 people with diabetes need enough information to take care of their blood sugar level 51.9 36.5 5.8 5.8 0 exercise improves blood sugar 55.8 32.7 5.8 5.8 0 effectiveness of and adherence to dietary and lifestyle counselling effect on metabolic control in type 2 diabetic omani patients 348 | squ medical journal, december 2010, volume 10, issue 3 included in the diet plan. germander (teucrium polium) or fenugreek is favoured by some patients, either boiled in water and then drunk as tea, or ground into powder and mixed with wheat and then boiled and drunk. incidentally, these herbs are known to have blood sugar lowering effects.25,26,27 conclusion the nutritional and lifestyle advice for the omani type 2 diabetic patients in the study brought about a slight improvement in fasting glucose level in both male and female patients. female patients made a significant improvement in body mass index, total cholesterol levels and macronutrients intake over three years. this minor improvement in the overall metabolic control could be further enhanced by increasing health education. more than 70% of the subjects in the study were active which is considered to be an important factor in managing obesity (bmi) and lowering the glycemic index in diabetic patients;18 however, obesity in these type 2 diabetic patients was also more likely due to poor dietary habits rather than to lack of exercise.24 a c k n o w l e d g e m e n t s the authors thank all the staff at the diabetes clinic, al buraimi hospital, oman, and the patients who participated in the study. this study was supported by the marie curie transfer of knowledge programme (mtkd-ct-2005-029914) and the mother and child foundation. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. king h, aubert re, herman wh. global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. diabetes care 1998; 21:14–31. 2. hennis a, wu s-y, nemesure b, li x, leske m. diabetes in a caribbean population: epidemiological profile and implications. int j epidemiol 2002; 31:234–9. 3. asfour mg, lambourne a, soliman a, al-behlani s, al-asfoor d, bold a, et al. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabet med 1995; 12:1122–5. 4. al-moosa s, allin s, jemiai n, al-lawati j, mossialos e. diabetes and urbanization in the omani population: an analysis of national survey data. popul health metr 2006; 4:5. 5. horton es. exercise and diabetes mellitus. med clin north am 1988; 72:1301–21. 6. chandalia m, garg a, lutjohann d, von bergmann k, grundy sm, brinkley lj. beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. n engl j med 2000; 342:1392–8. 7. glasgow re, hampson se, strycker la, ruggiero l. personal-model beliefs and social-environmental barriers related to diabetes self-management. diabetes care 1997; 20:556–61. 8. shah jh, murata gh, duckworth wc, hoffman rm, wendel cs. factors affecting compliance in type 2 diabetic patients: experience from the diabetes outcomes in veterans study (doves). int j diabetes dev ctries 2003; 23:75–82. 9. tuomilehto j, lindström j, eriksson jg, valle tt, hämäläinen h, ilanne-parikka, et al. finnish diabetes prevention study group. prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, n engl j med 2001; 344:1343–50. 10. lindström j, eriksson jg, valle tt, aunola s, cepaitis z, hakumäki m, et al. prevention of diabetes mellitus in subjects with impaired glucose tolerance in the finnish diabetes prevention study: results from a randomized clinical trial. j am soc nephrol 2003; 14:s108–13. 11. wikström k, peltonen m, eriksson jg, aunola s, ilanne-parikka p, keinänen, et al. educational attainment and effectiveness of lifestyle intervention in the finnish diabetes prevention study. diabetes res clin pract 2009; 86:e1–5. 12. knowles w, barrett-conner e, powler s, hammon r. (diabetes prevention program research group). reduction in the incidence of type ii diabetes with lifestyle intervention or metformin. n engl j med 2002; 346:393–403. 13. churkoney ka, hart lk. the relationship between health belief model and compliance of persons with diabetes mellitus. diabetes care 1980; 3:594–8. 14. kurtz ms. adherence to diabetic regimens: empirical status and clinical applications. diabetes educ 1990; 16:50–6. 15. ministry of health, sultanate of oman. diabetes mellitus: management guidelines for primary health care. 2nd ed. muscat: ministry of health, nov 2003. 16. musaiger ao. food composition tables for arab gulf countries (gulfoods), 1st ed. manama, bahrain: arab center for nutrition, 2006. 17. world health organization. obesity, preventing and managing the global epidemic report of a who consultation on obesity. geneva: world health organization, 1997. mohammed al-sinani, yoeju min, kebreab ghebremeskel, and hussain s qazaq clinical and basic research | 349 18. american diabetes association. evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications (position statement). j am diet assoc 2002; 102:109–18. 19. ministry of health united arab emirates. preliminary results of the national diabetes survey and early detection of cvd risk factors (abu dhabi & sharjah), uae: diabetes control programme committee, 2000. 20. al-mahroos f, ai-roomi k, mckeigue pm. relation of high blood pressure to glucose intolerance, plasma lipids and educational status in an arabian gulf population. int j epidemiol 2000; 29:71–6. 21. delamater am. improving patient adherence. clin diabetes 2006; 24:71–7. 22. gilden jl, hendryx ms, clar s, casia c, singh s. diabetes support groups improve health care of older diabetic patients. j am geriatr soc 1992; 40:147–50. 23. rubin rr, peyrot m, saudek cd. effect of diabetes education on self-care, metabolic control, and emotional well-being. diabetes care 1989; 12:673–9. 24. wendel cs, murata gh, shah jh, bokhari su, solvas pa, adam kd, duckworth wc. factors affecting body mass index (bmi) in type 2 diabetes mellitus. diabetes 2002; 51:a405–6. 25. gharaibeh mn, elayan hh, salhab as. hypoglycemic effects of teucrium polium. j ethnopharmacol 1988; 24:93–9. 26. román-ramos r, flores-sáenz jl, partidahernández g, lara-lemus a, alarcón-aguilar f. experimental study of the hypoglycemic effect of some antidiabetic plants. arch invest med (mex) 1991; 22:87–93. 27. kochhar a, nagi m. effect of supplementation of traditional medicinal plants on blood glucose in noninsulin-dependent diabetics: a pilot study. j med food 2005; 8:545–9. clinical & basic research squ med j, august 2010, vol. 10, iss. 2, pp. 241-248, epub. 19th jun 10 submitted: 10th oct 09 revision req. 21st dec 09, revision recd. 24th jan 10 accepted: 8th feb 10 1eye & ear health care, department of non-communicable disease control, ministry of health, oman; 2department of ent, nizwa hospital, dakhiliya region, ministry of health, oman; 3department of ent, ibra hospital, north sharqiya region, ministry of health, oman; 4department of ent, sohar hospital, north batinah region, ministry of health, oman; 5department of ent, sur hospital, south sharqiyah region, ministry of health, oman; 6department of ent, al nahdha hospital, ministry of health, muscat, oman *corresponding author email: rajshpp@omantel.net.om ملمارسات واملعتقداتالصحية املتعلقة بالسمع بني السكان سنة العمانيني فوق سن عمر20 راجيف خانديكار، ناراجن فيد، كانذاراجو، براتيبها مني، عبد الرحمن ح�شن، راخوناندن ناير، �شاه فاهيم، مازن اخلابوري، �شالح احلربي هذه اأجريت الطريقة: عاما. الع�رشين �شن فوق العمانيني ال�شكان بني بال�شمع املتعلقة واملعتقدات املمار�شات ا�شتعرا�س الهدف: امللخ�ص: الدرا�شة الو�شفية يف �شلطنة عمان بني عامي 2007 – 2008 م. اأجرى املقابالت اأحد العاملني يف املجال ال�شحي واملتحدث للعربية مع 598 فرداُ اختريوا من املناطق احل�رشية والريفية والعاملني يف املجال ال�شناعي يف �شلطنة عمان. ا�شتخدم ا�شتبيان يحوي 15 �شوؤاًل من النوع الختياري مغلق النهايات. �شنفت ردود امل�شاركني على الأ�شئلة يف جمال ممار�شات ال�شمع لعدة م�شتويات: املمتاز ) ≤ 20 نقطة( و املتو�شط )19-10( وال�شعيف )اأقل من 10 نقاط(. كما مت ت�شنيف الردود املرتبطة باملعتقدات عن ال�شمع اأي�شا اإىل امل�شتويات التالية: املمتاز ) ≤ 25 نقطة( وجيد )24-5( واملتو�شط )4اإىل 4( وال�شعيف )24اإىل 5-( وال�شعيف جدا )> 25-(. قمنا بح�شاب التكرارات والن�شب املئوية و 95 ٪ كفرتة ثقة ملختلف م�شتويات املعتقدات واملمار�شات املتعلقة بال�شمع. كما متت مقارنة املعدلت بني خمتلف املجموعات الفرعية. وقمنا بتطبيق حتليل التحوف للتعرف على موؤ�رشات املمار�شات اجليدة واملعتقدات ذات التف�شري العلمي. النتائج: كانت الردود من م�شتوى >ممتاز> للممار�شات والعتقادات ال�شمعية ال�شحيحة ملحوظة لدى 386 فرداً )64.5 ٪ ]95 ٪ فرتة الثقة 60.7 – 68.4[( وامل�شتوى املتو�شط لدى or = وقد تبني اأي�شا اأن النتماء للفئة العمرية 39-20 �شنة )ن�شبة الأرجحية .) ]29.5 – 37.1 الثقة فرتة ٪ 95[ ٪ 34.3( فرداً 205 1.67( والنتماء اإىل املناطق احل�رشية )ن�شبة الأرجحية or = 0ز53( كانت متنباآت للدرجة املمتازة من املمار�شات ال�شمعية ، بينما كان النتماء للذكورة )ن�شبة الأرجحية or =1.71( والنتماء لالأمية ) ن�شبة الأرجحية or = 1.80( من املتنباآت لوجود معتقدات غري علمية. اخلال�صة: لوحظ وجود م�شتويات مرتفعة للممار�شات ال�شمعية ال�شحيحة وكذلك وجود م�شتويات منخف�شة من املعتقدات العلمية الع�رشية بني امل�شاركني العمانيني. لذلك ينبغي على برنامج الرعاية ال�شحية لالأذن يف �شلطنة عمان الرتكيز على حت�شني املعرفة بال�شمع ال�شحي بحيث يتم حت�شني التوجهات واملمار�شات ال�شمعية ملنع اأو تاأخري ظهور فقدان ال�شمع الناجت عن ال�شو�شاء. مفتاح:الكلمات: �شو�شاء، معتقدات، ممار�شات �شحية، فقدان ال�شمع abstract: objectives: the objective of this study was to investigate hearing health practices and beliefs among people over 20 years old in the omani population. methods: this descriptive study was conducted in oman during 2007–2008. arabic speaking health staff interviewed a total of 598 selected people from urban and rural oman and also industrial workers using a closed ended questionnaire with 15 questions. participants’ responses to the hearing practice related questions were graded into excellent (≥20 points), average (10 to 19) and poor (<10 points). the responses to the questions about hearing beliefs were grouped into excellent (≥25 points), good (5 to 24), average (-4 to 4), poor (-24 to -5) and very poor (<-25) grades. we calculated the frequencies, percentage proportions and 95% confidence intervals of the different grades of beliefs and hearing practice. the rates were also compared among different subgroups. we performed regression analysis to identify predictors of good hearing practice and scientific beliefs. results: among the 598 participants, an ‘excellent’ grade of hearing practice and belief was noted in 386 (64.5% [95% ci 60.7–68.4]) and average in 205 (34.3% [95% ci 29.5 – 37.1]). being in the 20 to 39 years age group (or =1.67) and an urban resident (or= 0.53) were both predictors of an excellent grade of hearing practice, while male gender (or = 1.71) and illiteracy (or= 1.80) were predictors of scientific beliefs. conclusion: we noted high levels of good hearing practice and low levels of modern scientific beliefs among omani participants. the ear health care program of oman should focus on improving the knowledge about healthy hearing so that attitudes and hearing practices are improved and noise-induced hearing loss can be prevented or delayed. keywords: noise pollution; beliefs; practices; hearing impairment. hearing health practices and beliefs among over 20 year-olds in the omani population *rajiv khandekar,1 narang ved p,2 kantharaju kk,3 pratibha mane,4 abdul rm hassan,4 raghunandan niar,5 shah fahim a,5 mazin al-khabori,6 saleh al-harby1 clinical & basic research hearing health practices and beliefs among over 20 year-olds in the omani population 242 | squ medical journal, august 2010, volume 10, issue 2 noise is defined as acoustic (sound) signals which can negatively affect the physiological or psychological well being of an individual.1,2 exposure to excessive noise is a major avoidable cause of permanent hearing impairment worldwide. by avoiding excessive noise that damages the cochlea, peoples' hearing could remain healthy.3 rapid industrialisation and unsafe hearing practices threaten the health of the younger generation;4 therefore, the community should be informed regarding the hazards of noise pollution. correct knowledge about hearing is essential for adopting healthy behaviour.5 a literature review suggested a number of studies that focused on the knowledge, attitude and practices (kap) in regard to hearing of teenagers, industrial workers and army personnel6, 7, 8 and there was recommendation for further research in this field.9 however, to our knowledge, kap about hearing in the general community has not been investigated in any middle eastern country. oman is a country in the arabian peninsula which has undergone rapid socioeconomic changes and urbanisation in recent years. the prevalence of hearing loss in 1997 was 5.5% among the omani population of all ages, while the prevalence of a disabling grade of hearing loss was 2%.10 infection related hearing loss was predominant in the population under 25 years of age. in contrast, presbycusis was the major cause of hearing loss in the over 45 year-old population. noise pollution is associated with early presbycusis;11 therefore, the ear health care program in oman has adopted the strategy of promoting healthy hearing habits in the community.12 to implement a systematic hearing health promotion campaign, it is essential to know the current levels of beliefs and practices in the community. hearing practices can be defined as the ways that hearing apparatuses are used in day to day life to collect sound stimuli. hearing beliefs are defined as views regarding what should be the norms for using this hearing apparatus. a study related to noise pollution in oman was conducted in 2007–08. as a part of this wider study, we aimed to estimate the level of beliefs and practices regarding hearing and their determinants among over 20 year-olds in the omani population so as to be able to present recommendations for improving the ear health care of the community. methods omani citizens of over 20 years of age were our study population. we assumed that unsafe hearing practices would be in found in 10% of the population. to achieve a 95% confidence interval and a 90% power of the study, we needed to interview 72 people in each of the chosen subcategories. to compensate for drop outs, we enrolled an additional 25% sample. thus, we needed a sample of 600 people: 100 from each of the subgroups: male, female, rural, urban, and in age groups ‘20 to 30’ and ‘30 to 40’ years old. arabic speaking health staff members were our interviewers and were trained in the art of interviewing. they used a structured questionnaire so that the responses could be collected in a uniform manner. the community support group members liaised with the local leaders to ensure better cooperation of participants in the randomly selected villages of dakhiliya and north sharqiyah regions and two areas of towns of south sharqiyah and north batinah regions. in the randomly selected two locations in each rural and urban area, they visited houses in sequential order. they enrolled 100 males and 100 females in each of the urban and rural locations. those agreeing to participate were interviewed. we randomly selected industries in two large regions of oman: muscat and north batinah regions. in each industry, we randomly selected 100 workers, in the advances in knowledge 1. the current level of hearing health practices and beliefs in oman could be seen through this study. 2. the level of healthy hearing practices was very good in 64.5% of the over 20 year-old group in the omani population. 3. the level of scientific beliefs about healthy hearing was good in 33% of the over 20 year-old group in the omani population. 4. awareness and beliefs regarding healthy hearing are keys for good practice. 5. the hearing loss program of oman should promote safe and healthy hearing practices in the community. application to patient care 1. health promotion should focus on improving awareness and targeting wrong beliefs about healthy hearing. rajiv khandekar,narang ved p, kantharaju kk,pratibha mane, abdul rm hassan, raghunandan niar, shah fahim a, mazin al-khabori, saleh al-harby clinical and basic research | 243 oman oil refinery in muscat and the oman steel works in sohar, and enrolled them in our study. the identity of participants was de-linked from other information to maintain confidentiality. demographic information was collected. a close-ended questionnaire was used to collect the responses on the hearing health beliefs and knowledge of participants [table 1]. there were five possible responses to each question. the correct response to the questions on safe hearing health practices had been determined prior to the study by experts. these correct answers were used as the gold standard and participants’ responses were compared with them. if the responses matched this gold standard of safe hearing health practice, five points were allotted, but if the reply did not match the gold standard, we deducted five points. for an equivocal response, no point was awarded. the points for all hearing health practice questions were summed and then graded. if the participant scored more than 20 points, out of a maximum of 50, his/ her hearing health practice was considered to be of ‘excellent’ grade. those having a score of ‘10 to 19’, were considered as having ‘good’ hearing health practice, while a person with a score below ten was considered to have ‘poor’ hearing health practice. to have an overall idea on the level of hearing health beliefs, all points related to questions on beliefs were summed. we categorised the beliefs regarding the hearing and ear care of the participants into table 1: questions and responses for hearing health beliefs and practices among over 20 year-olds in oman hearing health practice related questions* excellent average poor 1. how many hours in a day do you watch to tv? 19 110 469 2. how many hours in a day do you listen to the radio? 10 15 573 3. how many hours do you drive with window of a car open? 451 4 143 4. how many hours in a day do you listen to a walkman/mp3? 451 4 143 5. do you like listening to loud music? 36 190 369 hearing health belief related questions ** excellent good average poor very poor 1. do you believe that people should talk loudly so that they can be heard better 200 200 17 90 90 2. do you believe that by talking loudly a person can better project his/her personality? 225 227 41 64 36 3. do you believe that loud sound damages the hearing of young people? 33 32 28 250 255 4. do you believe that loud sound damages the hearing of old people? 60 48 36 300 154 5. do you believe that one should listen to loud music or tv in a closed room to avoid disturbance to others? 103 290 29 100 76 6. do you believe that too much noise can cause headaches and could make a person become angry even for trivial reasons? 184 367 47 0 0 7. do you believe you should keep the ring-tone at the highest level on your phone? 75 79 61 200 183 8. do you believe that loud ring tones of mobile phones can damage hearing? 100 197 85 95 221 9. do you believe that mobiles should be on vibrator mode to avoid noise pollution? 30 25 36 255 262 10.do you believe that there should be a law against noise due to traffic (horn and engine noises)? 222 178 17 80 70 legend: * hearing practices were graded as ‘excellent’ (score of ≥ 20 points), ‘average’ (10 to 19) and ‘poor’ <10 points) ** hearing beliefs were graded as ‘excellent’ (score of ≥ +25 points), ‘good’ (score of +5 to +24) ‘average’ (-4 to +4). ‘poor’ (-24 to -5) and ‘very poor’ (≤ 25) hearing health practices and beliefs among over 20 year-olds in the omani population 244 | squ medical journal, august 2010, volume 10, issue 2 ‘excellent’, ‘good’, ‘average’, ‘poor’ and ‘very poor’ grades. the score range for each category was ≥+25; 5 to 24; -4 to +4; -24 to -5; and ≤-25 respectively. scientific beliefs about hearing health were defined as the sum of the ‘excellent’ and ‘good’ grades of beliefs. we used a pretested data collection form. the data were then transformed on a spreadsheet using epi data software.13 univariate analysis was conducted by the parametric method. we used the statistical package for social studies (spss 11) for the analysis. we calculated frequencies and percentage proportions. for statistical validations, we used the statcalc package of epi 6 software and calculated relative risk and chi square values, 95% confidence intervals (ci), while p values that were set at the 0.05 level of significance. to determine the predictors of the ‘excellent’ grade of safe practices and scientific beliefs regarding hearing and ear health (excellent + very good), we conducted multi-nominal regression analysis. age group, gender, literacy, hearing disability and location were the independent variables that we included in the model by using the ‘step in’ method. the method of inquiring about beliefs and practices could have introduced observer bias. to minimise this, the following precautions were taken: 1) organistion of an interview standardisation workshop; 2) provision of a manual for the field investigators so that they could refer it when needed; 3) pre-testing of the forms that were used to collect the responses; 4) no prompting of the participant by the investigator and the accompanying family member; 5) avoidance of leading questions; 6) formulation of questionnaire in the local language (arabic) and reference to a standard text book for writing questions for such studies.14 participants with poor levels of hearing health belief and practice were counselled by the field investigators as follows: 1) listening to loud music in a closed environment should be avoided; 2) judicious use of volume in gadgets like telephones, motor vehicle horns, and 3) industrial workers were advised to use protective gear to avoid the harmful effects of noise pollution at work. the outcomes of this survey were used as baseline information to formulate policies regarding healthy hearing. the ethical and research committee of the ministry of health of oman approved the study which was a cross-sectional descriptive study and was conducted in 2007–2008. results we interviewed 598 participants from six locations. half of the participants had primary education only. there were more male than female participants. in the industrial clusters, all participants were males. table 2: levels of hearing health practices among over 20 year-olds in oman excellent average poor n % n % n % gender male female 239 147 61.9 38.1 117 88 57.1 42.9 3 1 75.0 25.0 age-group 20 to 39 40 to 59 60 and + missing 217 118 37 14 56.2 30.6 9.6 3.6 137 48 14 6 66.8 23.4 6.8 2.9 3 1 0 0 75.0 25.0 0.0 0.0 education illiterate primary schooling + 97 236 53 25.1 61.1 13.7 35 138 32 17.1 67.3 15.6 0 3 1 0.0 75.0 25.0 location rural urban industrial 148 113 125 38.3 29.3 32.4 53 82 70 25.9 40.0 34.1 0 4 0 0.0 100 0.0 hearing screening normal impaired not conclusive 297 69 20 76.9 17.9 5.2 151 48 6 73.7 23.4 2.9 3 1 0 75.0 25.0 0.0 total 386 64.5 205 34.3 4 0.7 note: three participants did not opt to respond in selected practice questions and were omitted from analysis. rajiv khandekar,narang ved p, kantharaju kk,pratibha mane, abdul rm hassan, raghunandan niar, shah fahim a, mazin al-khabori, saleh al-harby clinical and basic research | 245 the questionnaire and participants’ responses in are shown in table 1. the level of hearing health practice among participants by subgroup is given in table 2. hearing health practice was of ‘excellent’ grade in 386 people (64.5% [95% ci 60.7–68.4]), ‘average’ in 205 (34.3% [95% ci 30.5–38.1]) and ‘poor’ in four participants (0.7% [95% ci 0.03–1.37]). hearing health practice was further analysed by gender, age group, location, level of education and hearing disabilities. hearing health practices were better among male compared to female participants, (relative risk [rr] = 1.17 [95% ci 1.02–1.34, p = 0.02]), but they did not differ by age group (χ2 = 6.37; degree of freedom (df) = 2; p = 0.04). the level of education was also not significantly associated to the level of hearing health practices. (χ2 = 5.55; df = 2; p = 0.06). hearing health practices differed significantly among participants of the urban, rural and industrial clusters. (χ 2 = 12.5; df = 2; p = 0.002). the practices did not differ significantly among the participants with normal hearing and those suspected to have hearing disabilities (rr = 1.07 [95% ci 0.92–1.23]). an ‘excellent’ grade of hearing health beliefs was present in 33.3% of participants (95% [ci 29.5– 37.1]). beliefs regarding hearing and ear care were grouped by different variants [table 3]. we also conducted univariate analysis to associate different epidemiological variables to the ‘excellent’ grade of scientific hearing health beliefs. females had better grades of scientific hearing health beliefs compared to male participants. however an element of chance cannot be ruled out in this observation (rr = 1.51; 95% [ci 0.962.37]). participants aged 20 to 39 had significantly better grades of scientific hearing health beliefs compared to those aged 40 and over. (rr = 1.56 [95% ci 1.01–2.41]). literate participants had significantly more scientific beliefs compared to illiterate participants. (rr = 1.61 [95% ci 1.00– 2.60]). beliefs were similar among participants in urban and rural locations. (rr = 1.08 [95% ci = 0.99–1.19]). to study the interaction of different variables in determining excellent grade of practices and beliefs, we conducted binominal regression analysis [table 4]. being in the age group 20 to 39 years and resident in urban locations were the two predictors of healthy hearing health practices. in this regression analysis, variables such as illiteracy, urban residence and male gender were strongly determinant of beliefs that parallel the current biomedical view. discussion this is the first time that an assessment of hearing health beliefs and practices has been carried out among the adult omani population. one third of participants had scientific hearing health beliefs while nearly two third of participants showed safe table 3: levels of beliefs about hearing health among over 20 year-olds in oman excellent good average poor very poor n % n % n % n % n % gender male (1 missing) female 116 83 58.3 41.7 166 116 58.9 41.1 28 12 70.0 30.0 49 20 71.0 29.0 2 5 28.6 71.4 age-group 20 to 39 40 to 59 60 and + (1 missing) 121 57 11 60.8 28.6 5.5 177 74 21 62.8 26.2 7.4 15 13 11 37.5 32.5 27.5 42 20 5 60.9 29.0 7.2 4 3 0 57.1 42.9 0.0 education illiterate primary schooling + 33 136 30 16.6 68.3 15.1 60 177 45 21.3 62.8 16.0 13 22 5 32.5 55.0 12.5 20 44 5 29.0 63.8 7.2 5 1 1 71.4 14.3 14.3 location rural urban industrial 48 91 60 24.1 45.7 30.2 109 79 94 38.7 28.0 33.3 12 11 17 30.0 27.5 42.5 27 20 22 39.1 29.0 31.9 5 0 2 71.4 0.0 28.6 hearing screening normal impaired not conclusive 143 45 11 71.9 22.6 5.5 222 47 13 78.7 16.7 4.6 31 9 0 77.5 22.5 0 50 17 2 72.5 24.6 2.9 7 0 0 100.0 0.0 0.0 199 33.3 282 47.2 40 6.7 69 11.5 7 1.2 hearing health practices and beliefs among over 20 year-olds in the omani population 246 | squ medical journal, august 2010, volume 10, issue 2 hearing health practices. being in the 20 to 29 years of age group was the predictor of safe hearing health practices. while male, urban and illiterate were the predictors of scientific hearing health beliefs. in our study, we noted good practices, but less scientific beliefs, among the adult omani population. this is in contrast to the findings of crendell et al. in usa. a majority of young adults (18 to 29 years old college students) in his study demonstrated a high degree of knowledge about exposure to excessive noise and the risk of hearing loss, but the use of hearing protection devices (hpds) in the same population was far less than desired.6 differences in literacy and cultural habits of using hearing devices in the two populations could be the reason for the observed variations compared to our study. adopting good hearing health practices without knowing their rationale, as noted in oman, should be further investigated. less awareness and unhealthy beliefs could negatively affect healthy practices. the views from international literature fluctuate in complex way. ologe et al. found that workers of a steel mill in nigeria had high awareness about the hazardous effects of noise on hearing (93%) and about the methods of its prevention (92%), but only 27% of participants possessed hearing protectors and only 28% of them were using them all the time.7 okpala noted that army personnel had low awareness about policies for protecting their hearing.8 there was no significant association between hearing impairment and hearing health practices in our study, but tamaskar et al. noted a high level of knowledge about safe hearing health practices among people with hearing impairment.15 the small size of the sample and the inclusion of only hearing impaired participants in urban areas in this american study could explain the reasons table 4: predictors of excellent practice and positive beliefs for hearing predictor adjusted odds ratio 95% ci p value ‘excellent’ grade of hearing practice intercept -0.707 gender male female 0.72 1.00 0.47–1.10 0.13 age group 20 to 39 year olds 40 years old and more 1.67 1.00 1.10–2.52 0.02 location urban rural industrial 0.53 1.45 1.00 0.31–0.91 0.87–2.40 0.02 0.15 education illiterate literate 0.67 1.00 0.42–1.06 0.09 hearing status normal bilateral hearing loss 1.20 1.00 0.76–1.91 0.43 ‘positive’ beliefs about hearing and ear health intercept -1.51 gender male female 1.71 1.00 1.02–2.85 0.04 age group 20 to 39 years 40 yrs and more 0.64 1.00 0.40 -1.02 0.06 location urban rural industrial 1.33 0.71 1.00 0.74–2.39 0.38–1.33 0.34 0.29 education illiterate literate 1.80 1.00 1.12–2.89 0.02 hearing status normal bilateral hearing loss 0.88 1.00 0.51–1.51 0.64 rajiv khandekar,narang ved p, kantharaju kk,pratibha mane, abdul rm hassan, raghunandan niar, shah fahim a, mazin al-khabori, saleh al-harby clinical and basic research | 247 for the differences in the outcome compared to our study. hearing health practices were better among males compared to females in our study, but we had only male participants in the industrial clusters; therefore, the association of gender to the hearing health practice in this study should be interpreted with caution. the practice of using hearing protective devices by participants in industrial locations did not differ by gender in two other studies in the usa.16,17 in spite of this observation, gender specific health promotion for improving hearing health practices is recommended and such promotion could be integrated to oman’s commitment to address the gender inequity issue.18 the exposure to cell-phones and loud music on radio/tv are known risk factors for hearing impairment.17,20 a study in the usa of college students revealed poor hearing health beliefs and practices;21 therefore, any study that aims to determine the level of hearing health practices and beliefs should include these risk factors for poor hearing. unfortunately, questions in our study were not specific enough to quantify the frequency and duration of use of these devices. as a result, the responses related to this question could be influenced by misclassification bias. more focused studies are recommended to generate detailed information on this issue. based on the association of hearing health practices to the age group and literacy status in our participants, we recommend that health promotion could be more specifically targeted for younger versus older and, educated versus illiterate people. daniel suggested that, because of limited possible interventions to avoid hearing impairment due to noise pollution, there should be more focus on health promotion to prevent risky hearing health behaviour in young people.22 in the norwegian county audiometry survey, a distinct association of noise pollution to hearing impairment was shown. the authors of this study suggested that the permanent hearing threshold shift which they noted could be an indicator to study the current status and impact of health promotion on the hearing health of the community.23 we have also assessed the noise levels in these locations. therefore, the outcomes of our study and the noise levels could serve as baseline information. a similar study could be conducted again after a few years of a health promotion campaign to assess the changes and using the suggested indicators. wiechbold, in 2002, demonstrated that after students received information about hearing damage due to noise pollution they developed positive attitudes and understood the hazards of noise pollution.24 there was still need for more education regarding the risks of loud music exposure and the benefits of wearing hearing protection even in 2008.25 conclusion we noted high levels of healthy hearing health practices (64.5%), but low levels of scientific beliefs (33.3%) among the adult omani participants. young and urban residents were associated with healthy hearing health practices, while male and illiterate participants had a good level of scientific beliefs about hearing health. the ear health care program of oman should focus on improving the knowledge about healthy hearing health practices so that they will be generally adopted and noise-induced hearing loss prevented. acknowledgments we would like to thank the national ethical and research committee for permitting us to conduct this study; the community support group members who assisted the field staff with the arabic translation of the questionnaire and in motivating people of the community to participate in this study, and all the participants who patiently responded to the questionnaire. we also thank all dr. suleiman al-shuraiqi for his help with the arabic translation for the article itself. we thank everyone for their cooperation. references 1. kryter kd. evaluation of hearing handicap. the american academy of otolaryngology and american council of otolaryngology (aa0-aco). j am acad audiol 1998; 9:141–6. 2. gorai ak, pal ak. noise and its effect on human being a review. j environ sci eng 2006; 48:253–60. 3. saha am. noise pollution a threat to human life. j indian med assoc 2001; 99:242–3. 4. feenstra l. pop, rock, walk and buzz: modern hearing health practices and beliefs among over 20 year-olds in the omani population 248 | squ medical journal, august 2010, volume 10, issue 2 noise and hearing. ned tijdschr geneeskd 1990; 134:517–9. 5. zawadzka b. awareness and knowledge as prerequisites for health oriented behavior. med pr 2002; 53:489–93. 6. crandell c, mills tl, gauthier r. knowledge, behaviors, and attitudes about hearing loss and hearing protection among racial/ethnically diverse young adults. j natl med assoc 2004; 96:176–86. 7. ologe fe, akande tm, olajide tg. noise exposure, awareness, attitudes and use of hearing protection in a steel rolling mill in nigeria. occup med (lond) 2005; 55:487–9. 8. okpala nc. knowledge and attitude of infantry soldiers to hearing conservation. mil med 2007; 172:520–2. 9. razdan u, sidhu ts. need for research on health hazards due to noise pollution in metropolitan india. j indian med assoc 2000; 98:453–60. 10. al khabori m, khandekar r. the prevalence and causes of hearing impairment in oman: a community-based cross-sectional study. int j audiol 2004; 43:486–92. 11. mazurek b, stöver t, haupt h, gross j, szczepek a. pathogenesis and treatment of presbycusis. current status and future perspectives. hno 2008; 56:429– 32, 434–5. 12. ministry of health, oman. ear health care manual: strategies for ear health care. 1st ed. muscat: ministry of health, 2000; pp. 3–5. 13. lauritsen jm, ed. epidata data entry, data management and basic statistical analysis system. odense: epidata association, 2000–2008. from www.epidata.dk. accessed sept 2008. 14. armstrong bk, white e, saracci r. the design of questionnaires. in: principal of exposure measurement in epidemiology. oxford: oxford university press, 1992. pp. 136–70. 15. tamaskar p, malia t, stern c, gorenflo d, meador h, zazove p. preventive attitudes and beliefs of deaf and hard-of-hearing individuals. arch fam med 2000; 9:518–25. 16. widén se, holmes ae, erlandsson si. reported hearing protection use in young adults from sweden and the usa: effects of attitude and gender. int j audiol 2006; 45:273–80. 17. lusk sl, ronis dl, baer lm. gender differences in blue collar workers' use of hearing protection. women health 1997; 25:69–89. 18. bint ahmad jaffer y, afifi m. adolescents' attitudes toward gender roles and women's empowerment in oman. east mediterr health j 2005; 11:805–18. 19. loftis m. sources of noise-induced hearing loss. aaohn j 2007; 55:476. 20. bogoch ii, house ra, kudla i. perceptions about hearing protection and noise-induced hearing loss of attendees of rock concerts. can j public health 2005; 96:69–72. 21. rawool vw, colligon-wayne la. auditory lifestyles and beliefs related to hearing loss among college students in the usa. noise health 2008; 10:1–10. 22. daniel e. noise and hearing loss: a review. j sch health 2007; 77:225–31. 23. borchgrevink hm. does health promotion work in relation to noise? noise health 2003; 5:25–30. 24. weichbold v, zorowka p. effect of information about hearing damage caused by loud music. for adolescents the music in discoteques is too loud despite loudness limits. hno 2002; 50:560–4. 25. petrescu n. loud music listening. mcgill j med 2008; 11:169–76. departments of 1microbiology and 3surgery, dr. sampurnanand medical college, jodhpur, india; 2department of microbiology, maharshi vashishtha autonomous state medical college, basti, india *corresponding author’s e-mail: vinod29m@gmail.com a rare case of apophysomyces variabilis skin and soft tissue infection archana bora,1 laxmi rathore,1 prabhat k. khatri,1 *vinod k. maurya,2 ganpat s. choudhary3 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 499–501, epub. 29 aug 21 submitted 9 jun 20 revision req. 20 sep 20; revision recd. 25 oct 20 accepted 24 nov 20 a 60-year-old male patient presented to the department of surgery, dr sampurnanand medical college in jodhpur, rajasthan, india, in 2018, with complaints of back pain for one month (day 0). on examination, a boil of size 3 × 3 cm was observed on his back, at the medial side of the left scapular region. he was prescribed amoxicillinclavulanic acid at 625 mg three times a day and nonsteroidal anti-inflammatory drugs for one week. no microbiological evaluation was requested by the treating surgeon on day 0. the patient presented again on day 5 with complaints of no improvement, and was subsequently hospitalised for three days. incision and drainage of the wound was done and dressing with antibiotic coverage was given. on day 13, the patient came back again with complaints of no improvement. wound debridement and dressing was done and the patient was called for follow-up after seven days. the patient once again came in on day 18 with a massive necrotising wound on the back. debridement of the dead tissue and toileting of the wound was done with antibiotic coverage. the patient was called for another follow-up after seven days. on day 28, the patient presented to the emergency department, febrile and well-oriented to the time, place and person, with an extensive necrotising wound on his back, extending up to the right arm, with a creeping wound margin in his subcutaneous tissue [figure 1a]. the patient had no history of diabetes mellitus, hypertension or any other chronic illness. complete blood counts and blood glucose were within normal range. on examination of the wound, a clinical diagnosis of necrotising fasciitis was made. differential diagnosis for aetiological agents of mucormycosis, subcutaneous mycosis and entomophthoromycosis were made by the attending surgeon. necrotic tissue was removed, and a skin biopsy sample was sent for bacterial culture and sensitivity, potassium hydroxide (koh) examination and fungus culture to the microbiology laboratory. upon 10% koh mount examination, hyaline, broad, aseptate fungal hyphae with wide-angle branching were seen [figure 1b]. a histopathology examination was not performed and based on koh examination findings, the patient was hospitalised. treatment of intravenous amphotericin b, 5 mg/kg/day for four weeks, with 5% dextrose was started immediately along with alternate day amphotericin-b-soaked dressing of the wound. along with the antifungal agent, antibiotic coverage of piperacillin-tazobactam 4.5 g every eight hours was also administered for one week. bacterial culture was sterile but white cottony fungal growth with aerial mycelia was seen on sabouraud dextrose agar (sda) after 48 hours of incubation. a lactophenol cotton blue mount was prepared from the growth on day 33 (five-daythis work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.015 interesting medical image figure 1: a: extensive necrotising wound on the back of a 60-year-old male patient who presented to the department of surgery, dr sampurnanand medical college in jodhpur, rajasthan, india, in 2018, with complaints of pain on his back for one month. b: potassium hydroxide mount from the biopsy tissue showing broad aseptate hyphae with wide-angle branching. https://creativecommons.org/licenses/by-nd/4.0/ a rare case of apophysomyces variabilis skin and soft tissue infection 500 | squ medical journal, august 2021, volume 21, issue 3 old colony), day 38 (10-day-old colony) and day 43 (15-day-old colony). in the five-day-old colony, only broad aseptate fungal hyphae were seen; in the 10-dayold colony, scanty sporangia were observed; and in the 15-day-old colony, broad aseptate hyphae bearing sporangium with typical funnel-shaped apophysis was observed at 400x magnification [figure 2]. sporangiophores were seen to arise from the foot cell. a dark, thick brown structure was observed just below the sporangiophores. the sporangiospores were oblong and 6–8 µm in size. all these features were consistent with apophysomyces species complex. the culture report was conveyed to the treating surgeon on day 44. antifungal sensitivity testing was not performed for this isolate. when fresh granulation tissue started to grow at the wound margin, skin grafting was performed by the surgeon. a skin auto-graft was done on day 57. the patient was discharged after three days of skin-grafting and was kept on follow-up for one month. the skin graft healed well and there was no sign of recurrence of fungal infection or secondary bacterial infection. the fungal isolate was identified as apophysomyces variabilis by internal transcribed spacer region sequencing at the national culture collection for pathogenic fungi, chandigarh, india. the genbank accession number of the nucleotide sequence is mn317265. the patient provided written informed consent before undergoing surgical procedures and provided consent for his case to be reported for scientific purposes. comment although apophysomyces spp. is an environmental fungus, human infection cases are being increasingly reported worldwide. apophysomyces have been isolated from the soil of tropical and subtropical regions. while most of the clinical cases have been reported in india, this fungus has also been reported in australia, the united states, southeast asia and south america.1,2 a. variabilis was first described in 2010, based on the analysis of the sequences of the histone 3 gene, the internal transcribed spacer region of the rdna gene, and domains d1 and d2 of the 28s rrna gene. based on these genetic studies, apophysomyces species complex has been differentiated into a. elegans, a. variabilis, a. ossiformis, and a. trapeziformis. pheno typically, differences in apophysis and sporangiospores are observed among these species. a. elegans shows bell and funnel-shaped apophyses and ovoid, subspherical, broadly ellipsoidal to barrel-shaped sporangiospores; a. variabilis shows funnel-shaped apophysis and clavate to ellipsoidal sporangiospores; a. ossiformis shows funnel-shaped apophysis and biconcave sporangiospores; and a. trapeziformis shows funnelshaped apophysis and smaller, trapezoid-shaped sporangiospores when viewed from the side.2 although cases of sporulation of a. spp. in primary cultures on sda have not been reported in the literature, in one study, sporulation was observed after two days of incubation on primary culture media such as sda and brain heart infusion agar.1 the isolate in this study showed noticeable sporulation on sda in primary culture only after two weeks of incubation. subsequent subcultures on sda also showed abundant sporulation after two weeks of incubation. necrotising fasciitis is a severe soft tissue infections caused by bacterial as well as fungal pathogens. the necrotising infections are found mainly in immuno competent patients. some fungi of the order mucorales have an invasive property and can produce this rapidly progressive infection, which destroys the soft tissues and spreads along the fascial planes and invades deeper into the tissues.3 while most common fungal aetiology of necrotising fasciitis is linked to rhizopus spp., other mucoralean species that are associated with human infection include mucor, rhizomucor, lichtheimia, apophysomyces, saksenaea, cunninghamella, cokeromyces and syncephalastrum spp.4 these fungal infections are often fatal, even if figure 2: a: fungal colony on sabouraud dextrose agar showing aerial hyphae filling the culture plate and tube. b: lactophenol cotton blue mount of the 15-day-old colony showing broad aseptate hyphae with funnel-shaped sporangiospores arising from the foot cell. archana bora, laxmi rathore, prabhat k. khatri, vinod k. maurya and ganpat s. choudhary interesting medical image | 501 manuscript. ab and pkk edited the manuscript. all authors approved the final version of the manuscript. references 1. chander j, stchigel am, alastruey-izquierdo a, jayant m, bala k, rani h, et al. fungal necrotizing fasciitis, an emerging infectious disease caused by apophysomyces (mucorales). rev iberoam micol 2015; 32:93–8. https://doi.org/10.1016/j.riam.2014.06.005. 2. alvarez e, stchigel am, cano j, sutton da, fothergill aw, chander j, et al. molecular phylogenetic diversity of the emer ging mucoralean fungus apophysomyces: proposal of three new species. rev iberoam micol 2010; 27:80–9. https://doi.org/10.1 016/j.riam.2010.01.006. 3. skiada a, petrikkos g. cutaneous zygomycosis. clin microbiol infect 2009; 15:41–5. https://doi.org/10.1111/j.1469-0691.2009.02979.x. 4. jain d, kumar y, vasishta rk, rajesh l, pattari sk, chakrabarti a. zygomycotic necrotizing fasciitis in immunocompetent patients: a series of 18 cases. mod pathol 2006; 19:1221–6. https://doi. org/10.1038/modpathol.3800639. 5. mathews ms, raman a, nair a. nosocomial zygomycotic post surgical necrotizing fasciitis in a healthy adult caused by apo physomyces elegans in south india. med mycol 1997; 35:61–3. https://doi.org/10.1080/02681219780000891. treated in a timely manner.3 the introduction of soil contaminated with such organisms may serve as the primary means of inoculation of this organism at the trauma site. iatrogenic soft tissue mucormycosis after skin graft, renal transplant, orthopaedic surgery and lower segment caesarean section have been reported in the literature.5 the current case highlights that a. variabilis infection may present as boils but possible inoculation of fungal agent iatrogenically cannot be ruled out in this case. although the case in early stage was refractory to broad spectrum antibiotics, culture and sensitivity at this stage would have helped to conclude the exact aetiology and progression of the case of the boil to necrotising fasciitis. a u t h o r s’ c o n t r i b u t i o n ab, lr and gsc were involved in data collection. vkm analysed the data. ab and lr contributed with the laboratory investigations. lr and vkm were involved in the literature review. gsc contributed to the clinical study. pkk provided resources and supervised the work. vkm and gsc drafted the initial https://doi.org/10.1016/j.riam.2014.06.005 https://doi.org/10.1016/j.riam.2010.01.006 https://doi.org/10.1016/j.riam.2010.01.006 https://doi.org/10.1111/j.1469-0691.2009.02979.x https://doi.org/10.1038/modpathol.3800639 https://doi.org/10.1038/modpathol.3800639 https://doi.org/10.1080/02681219780000891 مؤمتر اجلمعية العمانية جلراحة املسالك البولية 2019 جامعة ال�صلطان قابو�ض، م�صقط، عمان، 3-5 اأكتوبر 2019 oman urological society conference 2019 sultan qaboos university, muscat, oman, 3–5 october 2019 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e374–384, epub. 22 dec 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.016 conference abstracts poster presentations investigation of effects of metformin in prevention of bladder cancer recurrence alireza ghadian baqiyatallah university of medical sciences, tehran, iran. e-mail: p_ghadian@yahoo.com objectives: first lines of evidence have shown that metformin inhibits cancer cell growth and prevents cancer occurrence in patients with type 2 diabetes. this study aimed to investigate the hypothesised inhibitory effects of metformin on recurrence of bladder cancer in patients undergoing trans-urethral resection of bladder tumour (turt). methods: this case-controlled clinical trial included 65 patients who were divided into two groups: a metformin group (n = 32) and a control group (n = 33). patients in the metformin group received two tablets of metformin (500 mg) daily for one year. descriptive, comparative and inferential tests were used to compare the frequency of tumour recurrence in terms of gender, grade and stage of the previous tumour among the two groups. results: there was no significant difference in frequency of tumour recurrence between the metformin and control groups (p >0.05). although time of tumour recurrence in the metformin group was higher compared to the control group, this increase was not statistically significant (p >0.05). in addition, tumour recurrence had no correlation with gender and grade of tumour. however, an insignificant positive weak correlation was observed between recurrence and stage of tumour only in the control group (p >0.05). conclusion: these findings indicate that metformin has no considerable inhibitory effect on recurrence of bladder cancer but may delay tumour recurrence. however, further studies with larger sample sizes and the use of higher doses of metformin for a longer duration of time is suggested to confirm these results. the incidence of bacteriuria after cystoscopy in patients with history of bladder tumour alireza ghadian baqiyatallah university of medical sciences, tehran, iran. e-mail: p_ghadian@yahoo.com objectives: bladder cancer is the eighth most common cause of death from cancers and is responsible for 3% of all tumours. several diagnostic treatments have been proposed for bladder cancer, one of which is flexible cystoscopy. this study aimed to evaluate asymptomatic and symptomatic bacteriuria in patients undergoing cystoscopy for bladder cancer. methods: this descriptive study included patients who needed cystoscopy for bladder cancer and had been referred to baghiyyatollah al-azam military hospital, tehran, iran, in 2016. a total of 60 patients were included in the study, all of whom had given informed consent. before and after the cystoscopy and two weeks later, urine analyses and urine cultures were performed. none of the patients had used antibiotics before inclusion in the study. results: of 60 patients (mean age: 62.67 years), 42 (70%) were male and 18 (30%) were female. the urine analysis two weeks after cystoscopy revealed eight cases of bacteriuria, of which six were bacteriuria and two were infected. there was no statistically significant relationship between age and gender in patients with symptomatic bacteriuria. there was a significant relationship between the duration of bladder cancer and symptomatic bacteriuria (p <0.05). the prevalence of bacteriuria was 13.3% after the cystoscopy; its overall prevalence from various studies was 2–21.2%. conclusion: the presence of underlying cancer in patients with haematuria and cystoscopy is not an indicator of bacterial outgrowth in patients; it can be argued that prophylactic antibiotics are not required before cystoscopy. is prostate biopsy correct enough for decision-making in prostate cancer patients? alireza ghadian baqiyatallah university of medical sciences, tehran, iran. e-mail: p_ghadian@yahoo.com objectives: prostate cancer is the most epidemic cancer and the second leading cause of cancer mortality in men. the gold standard prostate cancer diagnosis is prostate biopsy; based on the results, the physician can determine a treatment approach. methods: this study was conducted at the urology center, baghiyyatollah al-azam military hospital, tehran, iran, between march 2001 and march 2011. all patients who had undergone prostate biopsy and then radical prostatectomy were included in this study. prostate-specific antigen (psa) levels, a pathologic report of the prostate biopsy and radical prostatectomy records were collected and compared. results: in 38% of patients, the gleason grade sum in radical prostatectomy was higher than in the prostate biopsy; this discrepancy was higher in patients with a psa level <10 and more differentiated samples. conclusion: a urology surgeon should consider the patient’s condition and clinical conjectures in addition to the resulting gleason grade of the biopsy to determine the best treatment, especially in making a decision for a radical prostatectomy surgery. should the clinic and the patient’s pathology be compatible, the surgery may be conducted if necessary. https://creativecommons.org/licenses/by-nd/4.0/ sultan qaboos university, muscat, oman, 3–5 october 2019 abstracts | e375 long-term renal outcome and survival of kidney transplant recipients admitted to the intensive care unit *amgad el-agroudy,1 asma alqahtani,1 balij dandi,2 eman farid,2 ali al aradhi2 1arabian gulf university, manama, bahrain; 2salmaniya medical complex, ministry of health, manama, bahrain. *corresponding author’s e-mails: amgadelagroudy@hotmail.com and amgadeem@agu.edu.bh objectives: this study aimed to evaluate the course and outcome of kidney transplant (kt) recipients admitted to the intensive care unit (icu) at salmaniya medical complex, manama, bahrain. methods: data of all adult renal transplant recipients who were admitted to the icu between 1997 and 2017 that included demographic features, causes of end-stage renal disease (esrd), causes of admission, time between transplantation, admission, icu courses and outcome were included. among 379 kts that were followed-up at the centre, 60 patients were admitted to the icu and were categorised as either early (i.e. during the first three months; n = 28); intermediate (3–12 months; n = 7); or late (12 months and afterwards; n = 25). results: the rate of icu admission was 15.9% and the mean age was 48.3 ± 12.6 years. the main cause of admission was surgical complication (71%) in the early group and infection in later groups (57% and 80%, respectively). mortality on discharge was significantly higher in the late admission group (52%; p = 0.0001) and the leading cause of death in all groups was sepsis (89%). twenty patients required ventilator support which was an independent risk factor for mortality (p <0.05). there was a statistically significant decrease in the overall five-year and 10-year patient survival (p = 0.031) in kt patients admitted to the icu. conclusions: the main reason for icu admissions in the current study was infections especially in late admission. mortality rate was relatively high and linked to the need for ventilators. admission to the icu is usually associated with decrease in graft and patient survival. public survey of financial incentives for kidney donation in bahrain *amgad el-agroudy,1 adel alalwan,2 mohamed rajab2 1arabian gulf university, manama, bahrain; 2salmaniya medical complex, ministry of health, manama, bahrain. *corresponding author’s e-mail: amgadelagroudy@hotmail.com and amgadeem@agu.edu.bh objectives: with the increasing prevalence of end-stage kidney disease in bahrain, kidney donation is of vital importance. this study aimed to assess how financial incentives influence individuals’ views and decisions regarding kidney donation and to establish strategies to increase the number of kidneys for transplantation in bahrain. methods: a previously established questionnaire on financial incentives for living kidney donations was adapted for this study. the questionnaire assessed the public opinion in bahrain on how kidney donation can be influenced by two different financial incentives, namely 10,000 bahraini dinar and life-long health insurance. the questionnaire was distributed electronically and a convenient sampling technique was used. results: a total of 446 participants were included in this study, of which 39% were male and 61% were female. the majority (80%) of participants believed that their chances for kidney donation would not increase by receiving financial compensation, while the remainder (20%) believed it would increase. in general, married participants (70%) found it a preferable development that health insurance companies offer financial compensation for kidney donation, while non-married participants (30%) did not prefer this but did not believe this to be an adverse development (p = 0.038). furthermore, there was a positive correlation between age and preferable views towards financial incentives to increase kidney donation (p <0.001). conclusion: although financial incentives might encourage a minority of the population to donate their kidney, the majority would not be influenced by implanting a financial incentives system for kidney donation. retzius-sparing robot-assisted laparoscopic radical prostatectomy: descriptive analyses and functional results of our first 25 cases *pedro sánchez de la muela, dr. rubén algarra, dr. ignacio arance hospital vithas nuestra señora de américa, madrid, spain. *corresponding author’s e-mail: rubenalgarra@hotmail.com objectives: this study aimed to analyse the immediate results, reproducibility and short urinary continence (uc) outcomes of retziussparing robot-assisted laparoscopic radical prostatectomy. methods: this retrospective study analysed the first 25 cases who underwent retzius-sparing robot-assisted laparoscopic radical prostatectomy, according to bocciardi’s surgical technique described in 2010, from january 2018 to june 2019 at the hospital vithas nuestra señora de américa, madrid, spain. data were analysed in order to evaluate preliminary results. the primary outcome was uc (defined as zero pads or one security liner per day) one week after catheter removal. the five stages of the surgical technique, descriptive statistics and preliminary results were presented. results: the follow-up median time was six months (range: 3–18 months). prostate-specific antigen level median was 6.1 ng/ml (range: 4–14.3 ng/ml). all procedures were performed by posterior intrafascial approach with bilateral neurovascular preservation in 84% of cases. surgical margins were positive in 28% of patients, mostly in apex. only one (4%) patient required blood transfusion in the immediate postoperative period. the median hospital stay was 48 hours. the majority (80%) of patients were continent one week after catheter removal. of which, 80% do not require the use of any diapers or security pads. most patients (84%) were free of biochemical recurrence with a median of six months of follow-up. conclusions: preliminary functional results in terms of early uc were optimistic for patient’s treated with retzius-sparing robot-assisted laparoscopic prostatectomy without a worsening of the prognosis. however, these results require long-term validation. the organisation of medical and diagnostic aids for patients with parasitic defeat of urinary system *vladimir startsev,1 faik asfandiyarov,2 anton kolmakov2 1s.m. kirov military medical academy, st. petersburg, russia; 2astrakhan state medical university, astrakhan, russia. *corresponding author’s e-mail: doc.urolog@gmail.com objectives: this study aimed to improve the diagnostic and treatment approach in the provision of medical care for patients with bilharzial-associated squamous cell carcinoma of the bladder (shbc). methods: this survey-based study was conducted at medical institutions in benguela, angola, between 2007 and 2012. a total of 56 patients with gross haematuria who had been treated were included. group a (n = 35) included patients before applying the standardised diagnostic algorithm. group b (n = 21) included patients using the new organisational format. results: the frequency of verification of shbc in a locally advanced stage at patients of group a had been higher compared to patients in group b. conclusions: the combined usage of cytological research of urine, ultrasonography oman urological society conference 2019 e376 | squ medical journal, november 2019, volume 19, issue 4 and cystoscopy at the expressed proliferative process caused by ush allowed the detection of shbc in early stages on the condition of the patient’s concentration in inpatient replacing structures of specialised medical institutions. the role of open surgery in children with urolithiasis: single centre experience *beata jurkiewicz and joanna samotyjek department of pediatric surgery and urology center of postgraduate medical education, warsaw, poland. *corresponding author’s e-mail: beatajurkiewicz@wp.pl objectives: in developed countries, the incidence of urolithiasis increases by 6–10% per year and its occurrence affects patients of all ages. in poland, it is estimated that this disease affects approximately 15,000 children and about 20% of ill children require surgical treatment. the occurrence of urolithiasis in young children is usually associated with metabolic disorders or other diseases and includes x-linked diseases such as, dent disease, lowe syndrome and autosomal recessive syndromes (i.e. bartter syndrome). these diseases cause the most severe forms of urolithiasis–staghorn urolithiasis. although minimally invasive procedures such as ureteroscopic lithotripsy, retrograde intrarenal surgery, percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy are commonly performed, there may still be indications for open surgery. in 2009, a combination of open and endoscopic surgery to remove kidney stones was developed at the department of pediatric surgery and urology center of postgraduate medical education, warsaw, poland. this procedure allows the parenchyma to remain undamaged. methods: this study was conducted at the department of pediatric surgery and urology center of postgraduate medical education from 2016 to 2018 and included 735 children with urolithiasis who were treated. results: during this time, a total of 33 (4.5%) open surgeries were performed. in 20 patients, the main indication for surgery were urinary system defects with accompanying stones. simultaneous correction of defects and removal of stones was performed. in 13 cases (1.8%) the only indication was staghorn lithiasis with stones filling the whole calyx and pelvis system. conclusion: if a large mass of stones is found in a small child, simultaneous pyelolithotomy with endoscopic removal of stones should always be considered, assuming that during one procedure all stones can be removed. performing several minimally invasive procedures exposes the child to the possibility of complications that may ultimately lead to kidney failure. percutaneous nephrolithotripsy in children *mohammad reza darabi mahboub, mohammad aslzare, ameneh ghods department of urology, faculty of medicine, mashhad university of medical sciences, mashhad, iran. *corresponding author’s e-mail: darabimmr@mums.ac.ir objectives: the formation of urinary tract stones in children commonly occurs in the upper urinary tract and requires interventional procedures such as percutaneous nephrolithotripsy (pcnl), extracorporeal shock wave lithotripsy (eswl) and/or open nephrolithotomy. this study utilised the mini-perc technique using an instrument with only 11f compared with 24–34f sized instruments. methods: this study was conducted from march 2003 to june 2018 on 38 children aged 18 months to 15 years who had undergone pcnl to treat urinary tract stones. complete blood count, blood urea nitrogen, creatinine blood test, fasting blood sugar, urinary albumin and urinary creatinine were tested in all patients in addition to sonography and intravenous urography to determine kidney function and anatomical status. all patients underwent general anaesthesia during surgery. under fluoroscopic guidance, a 30% concentration dye was injected through the catheter and a percutaneous nephrostomy needle was inserted into the kidney and a guide wire was placed. the tract was dilated to 28f and then a 28f amplatz sheet was placed and nephroscopy was done. if the patient was stone-free and haemorrhage and pelvic rupture didn’t occur, tubeless pcnl was done. results: stones were found in the right side of 23 patients and in the left side of 15 patients. in 21 patients the stone was located in the renal pelvis, six in the inferior calyx and 11 in both pelvis and calyx. in 12 patients eswl was done before pcnl which failed in nine patients. in three patients, the stones were broken but the particles could not be extracted. a total of 33 patients (86.8%) were stone-free and the remaining five patients had remaining particles sized less than 6 mm. no major complications developed, despite urinary tract infection and fever in seven patients and non-significant haematuria in 10 patients which were all cured by medical therapy. conclusions: pcnl is more effective with less complications than eswl and open surgery for treatment of urolithiasis in children. in patients that eswl has not been indicated or failed, pcnl is the treatment of choice. challenging lymphatic collections in urology: report of three cases and review of literature *wadha alqahtani and mohammed gomha king fahd specialist hospital, dammam, saudi arabia. *corresponding author’s e-mail: wadhaqht90@gmail.com large lymphatic collections can be challenging as they rarely respond completely to short-term sclerotherapies and usually need marsupilisation. we report two cases of challenging postoperative lymphoceles and one case of renal lymphangiectasia. the first case was a 51-year-old male patient who presented one month after radical prostatectomy with bilateral lower limb deep vein thrombosis and abdominal pain. computed tomography (ct) scan revealed huge retroperitoneal lymphocele collection, resulting in a mass effect on the urinary bladder and rectum. he was managed by ultrasonography-guided percutaneous tube drainage and povidone iodine sclerotherapy that resulted in partial response. subsequently, he was treated by bleomycin sclerotherapy once weekly for 21 days. at the 15-month follow-up, he was asymptomatic with only 40 ml residual. the second case was a 27-year-old male patient, who developed right thigh numbness on the 10th day post-retroperitoneal lymph node dissection. ct scan revealed small paracaval collection compressing the lumen of the inferior vena cava by more than 50%. he was treated by ct-guided aspiration. follow-up ct after five weeks showed complete resolution of the collection. the third case was a 58-year-old male patient with multiple comorbidities who was referred for a large right subcapsular renal collection. ct and ultrasound findings were concordant with the diagnosis of bilateral renal lymphangiectasia that was initially drained by a percutaneous tube. two months later, it recurred and was treated by percutaneous drainage followed by povidone iodine sclerotherapy with good response at seven years follow-up. percutaneous drainage with sclerotherapy of long duration can be helpful in the treatment of significant lymphatic collections; this is especially important in patients who have medical concerns. small postoperative lymphocele causing significant compression of the vena cava can be treated by aspiration by an experienced interventional radiologist. sultan qaboos university, muscat, oman, 3–5 october 2019 abstracts | e377 trans-catheter arterial embolisation of the vesical arteries for intractable haematuria from advanced bladder and prostate cancers *ameer alarayedh and sharif alarayedh salmaniya medical complex, manama, bahrain. *corresponding author’s e-mail: ameer.alarayedh@gmail.com objectives: certain subsets of patients with bladder and prostate cancer have advanced disease and often develop intractable haematuria. conservative measures frequently fail and the available treatment modalities are too aggressive for those frail patients. minimally invasive therapeutic approaches such as trans-catheter arterial embolisation (tae) of the internal iliac artery were first described many decades ago, however only a limited number of patients are reported in the literature. methods: this retrospective case series was conducted at salmaniya medical complex, manama, bahrain. all patients with intractable haematuria that had tae from 2014 to 2019 were included. demographic, clinical and radiographic data was collected through the patient’s medical records. data were analysed using a student’s t-test. results: seven patients, one female and six males, with an average age of 57.2 years (range: 51–79 years) were included. super-selective tae of the vesical arteries with polyvinyl alcohol particles (pva) was performed. following embolisation, the haematuria stopped after an average of 2.6 days. there was a recurrence in haematuria in three patients; the average time to recurrence was 4.5 months. there was a significant reduction in transfusion requirements from 7.3 to 5 units of packed red blood cells, pre-and post-embolisation, respectively (t(5) = 2.9, 95% confidence interval [ci] = 0.27–4.4; p = 0.034). a significant rise in the admission haemoglobin level from 7.8 units to 10.6 units one month post-embolisation was also noted (t(6) = 4.9, 95% ci = 1.4–4.2; p = 0.003). only one patient died due to their disease. conclusion: tae is an effective and safe procedure for controlling acute intractable haematuria. it should be the first-line palliative treatment of choice for patients with inoperable intractable haematuria. embolisation of sva with pva particles has shown sustained control of haemorrhage with minimal side effects. standardisation of extended pelvic lymph node dissection at robot-assisted radical cystectomy *marat urmantsev, valentin pavlov, ruslan safiullin, anton deneyko bashkkort state medical university, ufa, russia. *corresponding author’s e-mail: urmantsev85@mail.ru objectives: this study aimed to review the rationale for extended pelvic lymph node dissection (eplnd) in the treatment of bladder cancer and compare robot-assisted (ra) and open eplnd. a step-by-step guide of ra eplnd was provided to illustrate the techniques currently employed at bashkkort state medical university, ufa, russia. methods: pubmed® (national library of medicine, bethesda, maryland, usa) electronic databases were searched for english language articles on bladder cancer, eplnd and ra eplnd. the stages of radical ra cystectomy (rarc) were not standardised. accordingly, there was no standardisation of plnd, however, eplnd improved both oncological and functional results of bladder cancer treatment. a step-by-step video and pictures with narration and accompanying explanations of each step to illustrate the authors’ current techniques is available. results: eplnd with a minimum nodal yield of 10–14 is tantamount in the treatment of bladder cancer. the number of lymph nodes resected influenced survival in both pathologically node positive and negative patients. in addition, ra eplnd was found to have equipoise as open eplnd by several groups. conclusions: operations should be performed in accordance with the standard extended pelvic lymph node dissection which allows for the 10–14 nodal yield mandated by the bladder cancer collaborative group and allows to safely pass the ureter under the colon using rarc and thus reduce the complications rate. pelvic-ureteric junction obstruction and hypertension: a case report *adin chopade, kiran gowdru, allamaprabhu sahukar, mohan keshavmurthy, prem k. krishnappa s.s. institute of medical sciences and research centre, davangere, karnataka, india. *corresponding author’s e-mail: adinbchopade@gmail.com hydronephrosis is a condition involving the dilatation of the renal pelvis which is fairly common in children. less is known about the influence of hydronephrosis on blood pressure; hypertensive effects of hydronephrosis have been suggested in experimental studies and clinical case reports. we report a six-year-old girl who presented with a mass per abdomen. ultrasonograhy showed right gross hydronephrosis. computed tomography-intravenous pyelogram revealed a right-sided gross hydronephrosis due to pelvic ureteric junction (puj) obstruction. a diethylenetriamine pentaacetic acid scan showed a grossly hydronephrotic right kidney with thinned out parenchyma and poor function (<5%) likely due to the puj obstruction. her blood pressure was 150/100 mmhg. hypertension was managed by dual anti-hypertensive medications and she underwent right nephrectomy. on follow-up, the patient required single antihypertensive medication for five months postoperatively. subsequently, her blood pressure was 100/70 mmhg and she did not require any anti-hypertensive medication. proposed factors included vasoconstriction and salt and water overload, mediated by processes including tubuloglomerular feedback and the renin-angiotensin-aldosterone axis. some authors describe resolution of hypertension following removal of the affected kidney, while others show that relief of the obstruction may also lead to normalisation of blood pressure. therefore, it appears that the intrarenal mechanism leading to hypertension is reversible. urinary stone composition in mountain areas with high incidence of uric acid stone *jalal al-shareef, abdulaziz al-malki, mohammad aboelmagd department of urology, alhada armed forces hospital, taif, saudi arabia. *corresponding author’s e-mail: jalal0789@yahoo.com objectives: urolithiasis is a common urologic disease worldwide. the structure of the stone provides information to understand the stone formation aetiology and thereby in determining the treatment process and prevention of recurrences. this study presented the stone profile of mountain areas in saudi arabia and aimed to investigate the composition of urinary tract stones in patients who live in mountain areas. methods: the study was conducted by alhada military hospital, taif, saudi arabia, between january 2013 and november 2018. a total of 380 urinary tract calculi were collected from 130 patients (240 calculi from males and 140 calculi from females). the calculi were examined and analysed to determine their chemical composition by computed infrared spectrophotometer. results: calcium oxalate was the most common form of stone which accounted for 34 stones, while calcium phosphate accounted for 18 stones. there were 30 uric acid stones. calcium oxalate mixed with other components accounted for 11 stones. there were eight magnesium ammonium phosphate stones; only one cystine stone was found. the mean age was 35 years (range: 30–60 years) and the oman urological society conference 2019 e378 | squ medical journal, november 2019, volume 19, issue 4 male-to-female ratio was 2.9:1. conclusion: calcium oxalate was the most frequently encountered stone type in mountain areas; this is also the same worldwide. uric acid stones showed a relatively higher prevalence than what is reported in the literature. the study is significant in presenting the stone profile of mountain areas in saudi arabia and needs further studies for evaluation and confirmation of the current findings. leydig cell tumour in elderly patient with presentation of hydrocele aneel kumar bhatia kettering general hospital, kettering, united kingdom. e-mail: aneel_kumar2000@hotmail.com although hydrocele of the scrotum is relatively common, leydig cell tumours (lcts) are less common. the majority of lcts are benign but malignant cases have been reported. some cases are identified incidentally but may present with testicular changes or with features of hormone imbalance such as gynaecomastia. we report an 80-year-old sexually active non-caucasian male patient who presented to the urology clinic with a two-year history of right testicular swelling. clinical examination was unremarkable except from scrotal examination which showed atrophy of the left testicle and swelling of the right testicle with a positive trans-illumination test compatible with hydrocele. ultrasound of the testes showed a large right hydrocele 28 mm in diameter. no focal abnormality of the right testicle or epididymis could be visualised and there was no varicocele. the patient was followed-up with repeated outpatient ultrasound scans. two years after the initial diagnosis of hydrocele, he complained of new discomfort within the right testicle. preoperative tumour marker serology (i.e. lactate dehydrogenase, human chorionic gonadotropin and alpha fetoprotein) was negative. however, during elective hydrocele repair, a testicular tumour was identified involving the hydrocele cavity and right radical orchidectomy was performed. the orchidectomy specimen included a disrupted, multinodular, friable tumour with a light tan cut surface. the tumour had replaced the entire testis and macroscopically involved the paratesticular tissue, hydrocele wall and spermatic cord. on microscopic examination there were typical morphological and immunohistochemical features of leydig cell tumour. however, there were also widespread features associated with aggressive tumour behaviour. the pathological features were considered to be those of a malignant leydig cell tumour. this is an unusual case of unexpected malignant leydig cell tumour identified during hydrocele repair. association between risk factors and complications in patients undergoing open radical cystectomy *nadeem ahmed and abdul hafeez qureshi the indus hospital, karachi, pakistan. *corresponding author’s e-mail: drnadeem2012@gmail.com objectives: bladder cancer is the most frequently occurring malignancy of the urogenital system. the gold standard treatment for local control of muscle invasive bladder cancer is radical cystectomy with pelvic lymph nodes dissection. there are multiple risk factors associated with complications following open radical cystectomy. the possible risk factors that increase the rate of complications are associated with patients demographic data and comorbidities related to surgery and total length of stay in hospital, etc. this study aimed to find a positive correlation between risk factors and complications so as to improve patient care, safety and outcomes in patients undergoing open radical cystectomy. methods: this retrospective study was conducted at the indus hospital, karachi, pakistan, from july 2016 to december 2018 and included all adult patients who underwent open radical cystectomy for bladder carcinoma. medical profiles were assessed and different variables were noted. in addition, operative findings, number of transfusions, lymphnodes status, hospital stay and complications were taken into account. results: a total of 36 patients (31 male and 5 females) were enrolled in the study. patients with preoperative serum albumin of ≤3.5 had 7.8 times higher odds of postoperative complications than patients who had a serum albumin of >3.5. also, patients with chronic kidney disease were 5.9 times more likely to have postoperative complications than those who had no chronic kidney disease. however, results showed no significant difference in gender, comorbidities, smoking status, duration of surgery, number of transfusions and length of stay in the intensive care unit between the patients with postoperative complications and those who had no complications. conclusion: there are multiple risk factors associated with postoperative complications. low serum albumin and chronic kidney disease are associated with postoperative patient morbidity. early outcome of the multiple renal arteries in transplant patient shailesh m. raina department of urology, jaslok hospital and research centre, mumbai, india. e-mail: drshaileshraina@gmail.com and drshailraina@hotmail.com objectives: over the past three decades, graft and patient outcomes in kidney transplantation have improved dramatically. this study aimed to review early outcomes of transplantation using allograft(s) with multiple renal arteries in transplant patients to elucidate the usefulness of these grafts in order to improve donor pools, which was previously consider to be a relative contraindication. methods: this prospective, observational study was conducted at the urology department in jaslok hospital, mumbai, india, from march 2018 to april 2019. all patients who underwent renal transplant for end-stage renal disease with more than one renal arteries were enrolled in the study. all patients had a routine investigation, colour doppler and renal scan during the early postoperative period with serum creatinine tests done every day for five days. colour doppler on postoperative day 5 and renal scan were done wherever indicated. results: the incidence of complications for more than one artery transplant did not show a significant difference. patients were followed-up for a period of three years. conclusions: kidneys with multiple arteries can be successfully transplanted. accurate radiologic imaging is imperative to avoid unexpected complications during the procedure. anastomotic technique can be modified according to the situation. the place of laparoscopy in urinary stones management armamentarium: review of current trends and reporting our experience mohammed babakri faculty of medicine, university of aden, aden, yemen. e-mail: drbabakri@gmail.com objectives: surgical management of urinary stones has witnessed a major development in the last few decades. the urologist's armamentarium for treating stones became versatile by adoption of rapidly evolving technologies that increasingly replaced traditional open surgery. the introduction of laparoscopic surgery in urology practice has lagged behind other specialties, but recently there is a trend towards using laparoscopic surgery in treating various benign and malignant urological diseases. there are special situations when sultan qaboos university, muscat, oman, 3–5 october 2019 abstracts | e379 shock wave lithotripsy and endourology is not the optimal choice; in these cases, laparoscopy may replace open surgery for dealing with these cases where endourology has major limitations. the possibility of treating other associated pathologies such as ureteropelvic junction obstruction is an additional advantage of laparoscopic pyelolithotomy. this study highlighted the current international trend in laparoscopic surgery for urolithiasis and demonstrated the investigator’s experience in laparoscopic stone surgery. methods: this study was conducted from march 2011 to april 2019 in aden, yemen. a total of 14 consecutive patients aged 4–60 years (mean: 39 ± 17 years) with renal and ureteral stones who underwent laparoscopic removal of their stones were included. results: the largest diameter of a stone ranged from 25–45 mm (mean: 28 mm), operative time ranged from one to four hours (mean: two hours) and hospital stay ranged from four to 10 days (mean: 5.4 days). the approach was transperitoneal in 11 patients and retroperitoneal in three patients; no major intraoperative complications occurred and no blood transfusions were needed. one patient developed prolonged urine leakage for 10 days and was managed conservatively. follow-up after three, six and 12 months with plain abdominal x-ray, ultrasonography and urography, when indicated, showed no residual stones and no newly developed hydronephrosis. conclusion: laparoscopic surgery is safe and effective in management of large renal and ureter stones in patients who are not suitable candidates for endourology. renal parenchymal foreign body and a unique method of removal abdul azeez ambalathuveettil1,2 1baby memorial hospital, kozhikode, india; 2al noor polyclinic, deira, united arab emirates. e-mail: drabdulazeez@roychallyassociates.com with the advent of endourological procedures, a foreign body (fb) left in a urinary tract is not uncommon and may include forgotten stents and sometimes, broken parts of instruments or guide wire. forceful removal of a stuck nephrostomy tube may result in breakage and may leave parts behind. mostly, the fb is in the lumen of the collecting system and removal is straight forward. we report a 16-yearold male patient who had undergone a nephrostomy six and a half months prior and presented with occasional mild urine leakage from the nephrostomy site. evaluation found that the patient had the distal part of the malecot catheter lodged in the kidney that had initially been used as drainage for the kidney. percutaneous removal of the catheter was planned. however, during the procedure, it was discovered that the distal part of the tube was buried in the parenchyma with cut limbs of the ‘‘flower’’ of the malecot catheter protruding into the collecting system. pulling by the limb with grasping forceps failed to dislodge it from the parenchyma. the attempt to remove the overlying tissue with biopsy forceps also failed. therefore, a resectoscope was used to incise the overlying tissue to deliver the fb out from the parenchyma. the patient had an uneventful recovery and was doing well with sterile urine on follow-up. it was unclear how the tube got into the parenchyma, but it was probably not pushed far enough inside so that the ‘‘flower’’ was partly in the parenchyma. this might have produced a tissue reaction and resulted in it getting buried. special care should be taken to place the tube properly in the desired area to prevent such an occurence. oral presentations effect of melatonin on nicotine induced fertility changes in wistar albino male rats balaji ommurugan kasturba medical college, manipal, india. e-mail: puntermmc@gmail.com objectives: nicotine molecules have toxic effects on testicular functions via reactive oxygen species. recent studies have shown that melatonin inhibits the activity of nitric oxide (no) synthase, in addition to no’s and peroxynitrite’s scavenging activity. this study aimed to evaluate the use of melatonin on reversing male fertility changes produced by nicotine. methods: a total of 36 adult male albino rats weighing 150–200 g, aged 10–12 weeks were used in this study. the rats were divided into six groups of six rats each. group 1 was treated with normal saline, groups 2 and 3 were administered different dosages of nicotine (0.5 mg/kg and 1 mg/kg, respectively), group 4 was given only melatonin (6 mg/kg/day), group 5 was given a combination of nicotine and melatonin (0.5 mg/kg and 6 mg/kg/ day, respecitvely) and group 6 was administered melatonin and a higher dosage of nicotine (6 mg/kg/day and 1 mg/kg, respectively). all chemicals were given orally for 30 days. subsequently, the rats were culled. body weight, testicular weight, testicular index, epididymis weight, sperm count and motility and viability were estimated. histopathology of testis was done. blood and tissue antioxidant levels were also measured. results: group 4 showed statistically significant maintenance of testicular functions when compared to all the other groups. group 2 and 3 showed significant reduction in testicular function and oxidative stress when compared to all other groups. group 5 and 6 showed significant effect on reversing the testicular toxicity and oxidative induced by nicotine and showed comparable results with the normal control rats. there was no difference between groups 5 and 6. the histopathology of groups 1, 4, 5 and 6 showed normal testicular architecture; group 2 and 3 showed loss of germ cells with degeneration of seminiferous tubules. conclusion: further clinical trials should be undertaken to analyse the efficacy of melatonin as a potential agent in the treatment of infertility. evaluation of the beneficial effect of two varieties of coconut water on methotrexate-induced testicular toxicity in male albino wistar rats vanishree rao manipal college of pharmaceutical sciences, manipal, india. -mail: vanim276@gmail.com objectives: methotrexate has toxic effects on testicular functions due to increased production of reactive oxygen species. recent studies have shown that coconut water contains l-arginine and possesses antioxidant properties. this study aimed to evaluate and compare green with yellow coconut water on reversing methotrexate-induced testicular toxicity. methods: adult male albino wistar rats weighing 100–200 g, aged 10 weeks old were used in the present study. a total of 30 rats were divided into five groups of six rats each. group 1 was treated with normal saline, group 2 was given methotrexate (20 mg/kg), group 3 was administered a combination of methotrexate and green coconut water (4 ml/100g), group 4 was given methotrexate and yellow coconut water (2 ml/100g) and group 5 was given a combination of methotrexate and a higher dosage of yellow coconut water (4 ml/100g). the coconut waters were given orally for 15 days and the methotrexate was only given on day one. after the rats were culled, their body weight, testicular weight, testicular index, epididymis weight, sperm count and motility and viability were estimated. testicular alkaline phosphatase level and serum testosterone measurement were done, in addition to histopathology of testis. tissue antioxidant levels were also measured and analysed using one-way analysis of variance followed by post-hoc analysis. results: both the yellow and green coconut water-treated groups showed statistically significant maintenance of testicular functions compared to the methotrexate only treated group. yellow oman urological society conference 2019 e380 | squ medical journal, november 2019, volume 19, issue 4 coconut water was better than green coconut water with significant improvement in all parameters. the higher dose of yellow coconut water showed significant results compared to the lower dose. the histopathology of groups 1, 4, 5 and 6 showed normal testicular architecture; group 2 showed loss of germ cells with degeneration of seminiferous tubules. conclusion: green and yellow coconut water can be used as antioxidant agents in reversing testicular toxicity induced by methotrexate in rats. sacral neuromodulation and saudi patients: does it really work? mai banakhar king abdulaziz university hospital, jeddah, saudi arabia. e-mail: drmaibanakher@hotmail.com objectives: sacral neuromodulation (snm) is a food and drug administration approved therapy for refractory overactive bladder, non-obstructive retention and frequency urgency syndrome. it is newly introduced and used in saudi patients. this study aimed to assess satisfaction among saudi patients who underwent snm implantation. methods: this cross-sectional study was conducted at the urology department, king abdulaziz university hospital, jeddah, saudi arabia, and included patients who had undergone snm implantation. a questionnaire was used to collect data regarding the patients’ demographics, satisfaction level and need for combined therapy for symptom control. results: a total of 32 patients completed the questionnaire (response rate: 58%). of these patients, 18 (56%) were diagnosed with overactive bladder, seven (22%) with chronic non-obstructive retention and seven (22%) with pelvic pain syndrome. the median duration of therapy was two years. a total of 22 patients (69%) received snm therapy alone and 10 (31%) needed additional forms of therapy for symptom control. the satisfaction level was 90%; more than half the patients (20) were very satisfied and nine were moderately satisfied, while three patients were unsatisfied. satisfaction correlated with the need for combined therapy for symptom control (correlation coefficient = 0.341; p = 0.004) but not with age, duration of therapy or complications. conclusion: snm therapy is associated with high patient satisfaction and is gaining acceptance amongst the saudi population. evaluation of the efficacy and safety of hyaluronic acid filler in penile augmentation introduction abbas khadra clemanceau medical centre, beirut, lebanon; dr k men's health clinic, beirut, lebanon. e-mail: abbas.khadra@cmc.com.lb objectives: currently, men are being offered fat as penile augmentation material but this has a high number of complications and patient dissatisfaction. studies have shown that hyaluronic acid can be injected into the glans penis to treat premature ejaculation. physicians are using such fillers for the penile shaft to increase its girth and thus its overall size. this study aimed to evaluate the efficacy and safety of hyaluronic acid injections into the penis as a procedure for penile enlargement. methods: a total of 10 men were enrolled in the current study and their consent was obtained. penile injections were given one month preand 12 months post-procedure in addition to a patient satisfaction questionnaire. a penile block was carried out using 10 ml lidocaine (2%). then, 10 ml of a filler containing highly cross-linked hyaluronic acid (2.3%) was injected subdermally via a 25g cannula in the penile shaft. the filler was distributed uniformly all the way around except the area of the urethra and dorsal vascular complex. no sexual activity was recommended for one week. results: the average patient age was 34 years. all gained a 2 cm increase in penile girth and 80% reported a subjective increase in penile length and boost in self-confidence and self-image. the majority (70%) felt it improved their sexual performance and that of their wives. almost all patients (90%) would do the procedure again and recommend it to their friends. results were maintained at 12-month follow-up. conclusion: male genital augmentation is becoming a popular procedure. the use of fillers for such a procedure makes it attractive as it is done under local anaesthesia in the physician’s office. their use has been established to be safe in the glans penis and the current study shows that a filler containing highly cross-linked hyaluronic acid (2.3%) is safe and effective in establishing a highly satisfactory penile augmentation result maintained at one year. laparoscopic partial nephrectomy: the impact of surgeon’s learning curve on the perioperative trifecta *ali thwaini,1,2 zeeshan aslam2 1sulaiman al habib, dubai healthcare city, dubai, united arab emirates; 2belfast city hospital, belfast, united kingdom. *corresponding author’s e-mails: iniziaj@hotmail.com and ali.thwaini@belfasttrust.hscni.net objectives: laparoscopic partial nephrectomy (lpn) is a highly surgically refined procedure in laparoscopic urology, with significant technical challenges. this study aimed to assess the impact of a single surgeon’s learning curve on the peri-operative outcomes by analysing the trifecta of ischaemia time <25 minutes, negative surgical margins and no surgical complications. methods: this retrospective study included a total of 142 consecutive patients who underwent lpn between march 2014 and march 2017. all cases were performed by a single surgeon at a tertiary centre. patients were analysed according to their demographics and renal nephrometry score. the impact of the surgeon’s experience on the peri-operative outcomes, as manifested by the trifecta, was analysed using multivariable regression. outcomes for cases 42–92 (group 1) were compared with those for cases 93–142 (group 2). paired t-test was used to compare the outcomes in both groups. a p value ≤0.05 was considered statistically significant. results: there was no significant difference in patients’ demographics nor renal scoring system (p = 0.09 and 0.4, respectively). there was no significant difference in the peri-operative blood loss (p = 0.24, 95% confidence interval: 0.4–0.7). warm ischaemia time was significantly less in group 2 (p = 0.043). there was no significant difference in the positive surgical margins in the two groups (p = 0.63). peri-operative urine leak was significantly higher in the first group (p <0.0001). median hospital stay was similar in both groups. at three months follow-up, the renal function, determined by estimated glomerular filtration rate, was stable. no patient needed renal replacement therapy. conclusion: lpn represents a steep learning curve. at 142 cases there seems to be an improvement in the peri-operative outcomes mainly in terms of urine leak. however, the learning curve plateau is yet to be reached at this number. more cases are needed and longer follow-up would be helpful. tumour bearing kidneys as potential transplant donors: a national online survey *ali thwaini,1,2 zeeshan aslam2 1sulaiman al habib, dubai healthcare city, dubai, united arab emirates; 2belfast city hospital, belfast, united kingdom. *corresponding author’s e-mails: iniziaj@hotmail.com and ali.thwaini@belfasttrust.hscni. net objectives: according to the uk annual kidney-transplant report in march 2018, 4,757 adult patients are on the uk kidney-transplant list, with only 3,272 transplants performed; 1,200 patients died while waiting for their transplant. more than 7,000 nephrectomy sultan qaboos university, muscat, oman, 3–5 october 2019 abstracts | e381 operations were recorded at the british association of urological surgeons audit outcome for 2014; 2,900 nephrectomy procedures were performed on patients with low-stage renal cell carcinoma. this study re-explored the acceptability of utilising small tumourbearing kidneys as potential organ donors, after ex vivo tumour removal and pathology confirming benign pathology or low risk cancer with clear margins. methods: an online survey was carried out across uk urologists with special interest in renal surgery, transplant surgeons and nephrologists, between november and december 2018. respondents were asked whether they would consider such kidneys for transplantation in selected groups of dialysis dependent patients. results: a total of 110 urologists, 70 nephrologists and 50 transplant surgeons were approached. of which 60 (response rate: 55%) urologists, 41 (response rate: 59%) nephrologists and 28 (response rate: 56%) transplant surgeons completed the questionnaire. the majority of urologists (72%) and transplant surgeons (93%) and some nephrologists (43%) supported the concept of using these kidneys for selected transplant recipients. conclusion: there is general acceptance for using those kidneys for transplantation in the uk. this concept has its ethical and logistical challenges, though it’s been performed before. this survey should encourage further studies to address the critical unmet need of kidneys for transplantation. percutaneous transvesical single-port robotic simple prostatectomy guilherme sawczyn, rair valero, roger yau, *jihad kaouk cleveland clinic, cleveland, usa. *corresponding author’s e-mails: guivsaw@hotmail.com and kaoukj@ccf.org objectives: this study presented the investigator’s initial experience performing percutaneous transvesical single-port robotic simple prostatectomy (psp-rsp) using the novel da vinci sp® robotic platform (intuitive surgical inc., sunnyvale, california, usa). methods: four consecutive patients were treated with psp-rsp between february and march 2019. using the percutaneous transvesical approach, the patient was positioned in the supine position, a 3 cm infra-umbilical incision was made after percutaneous needle identification of the bladder dome, a gelpoint mini advanced access platform (applied medical resources corporation, rancho santa margarita, california, usa) was inserted directly into the bladder and the da vinci sp® robot (intuitive surgical inc.) was docked. pneumovesicum was achieved, the prostate was accessed and the adenoma was enucleated. finally, a mucosal advancement flap was sutured to the urethra to cover the resected area. results: the mean operative total time was 182.2 minutes, mean estimated blood loss was 350 ml and the mean postoperative haemoglobin deficit was 2.5 mg/dl. the mean length of stay was 37 hours and 26 minutes. half of the patients (50%) left the surgery with a 2-way foley catheter and without bladder irrigation. none of the patients received surgical drains and there was no need for additional ports. no intraoperative complications were reported and no surgeries were converted to an open approach. there were no blood transfusions during or following the procedure. conclusion: the psp-rsp is a minimally invasive option for treating benign prostatic obstruction with substantially enlarged glands. in the current study, this approach led to minimal bleeding, true single incision robotic surgery, no bladder irrigation, minimal usage of postoperative opioids and a shorter hospital stay with the possibility of outpatient management in the future. further studies need to be done with larger sample sizes and long-term follow-up periods to confirm these findings. four hours hospital stay radical prostatectomy: the cleveland clinic singleport experience guilherme sawczyn, rair valero, roger yau, *jihad kaouk cleveland clinic, cleveland, usa. *corresponding author’s e-mails: guivsaw@hotmail.com and kaoukj@ccf.org objectives: this study showcased the investigator’s experience of outpatient single-port robotic assisted laparoscopic prostatectomy for prostate cancer with the new da vinci sp® robotic platform (intuitive surgical inc., sunnyvale, california, usa). methods: a database was compiled prospectively of the first consecutive patients who underwent an extraperitoneal prostatectomy using the da vinci sp® robotic platform (intuitive surgical inc.). a new practice was adopted by the investigators of sending the patients home shortly after the recovery unit like an ambulatory surgery patient. the data of all patients who underwent this surgery and the protocol were reviewed retrospectively. results: since implementing the da vinci sp® robotic platform (intuitive surgical inc.), the standard approach has been changed to a true single incision extraperitoneal approach and the patients were sent home the same day. a total of 20 consecutive patients were included in this study, of which 11 were discharged the same day of surgery. the median length of stay was 4.3 hours. the median patient reported pain scale was 2 out of 10; opioid use was only 15%. there were no intraoperative complications. postoperative complications included one pelvic abscess, a deep vein thrombosis and pulmonary embolism and one urine leak. one patient had a superficial seroma in the incision which was drained by opening the skin. no transfusions were administered. the positive margin rate was 5. follow-up ranged from one week to three months. conclusions: with the new protocol of using the da vinci sp® robotic platform (intuitive surgical inc.) with an extraperitoneal approach, the investigators have been able to perform a relatively painless procedure where patients can go home within four hours of the procedure with minimal opioid use. utilising a new robotic surgical system to treat challenging urinary stones mohamad salkini west virginia university, morgantown, usa. e-mail: mhdsalkini@gmail.com objectives: a worldwide increase in the incidence and prevalence of urolithiasis has been observed. the standard treatment of urologic stone disease (usd) has changed from open surgery to extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy (pcnl) or ureteroscopy depending on the size and location of the stone. open stone surgery is reserved for challenging urinary stones (cus) that are not amenable to the above-mentioned techniques. the investigator used the new da vinci sp® robotic platform (intuitive surgical inc., sunnyvale, california, usa) to treat cus. this study aimed to share the investigator’s experience of the da vinci sp® robotic platform (intuitive surgical inc.) to treat patients with urolithiasis instead of an open surgical approach. methods: this study included a total of 26 patients who underwent robotic assisted stone surgery (rss) between january 2010 and march 2019 at west virginia university, morgantown, usa, for usd involving 29 nephroureteral units. results: a total of 29 rss were accomplished with no conversion to open surgery. three patients had bilateral stones and needed to have rss on each side separately. rss were performed on the right-side in 13 surgeries. the indications for rss included morbid obesity (n = 8, mean body mass index: 56.4 kg/m2), need for concurrent renal surgery (n = 8) severe contractures limiting positioning for retrograde endoscopic surgery or pcnl (n = 4), symptomatic calyceal diverticular stone with failed endoscopic approach (n = 4) and inability to position the patient (n = 20). most nephroureteral units (90%) were rendered stone-free on the first attempt with complications occurring after five surgeries (17%). conclusion: rss is a viable option in the treatment of cus with a high success rate and low risk of complications. the need for open oman urological society conference 2019 e382 | squ medical journal, november 2019, volume 19, issue 4 stone surgery was eliminated by rss at the current centre. multiple centres need to participate in rss with larger numbers of patients to create an established role for rss. the dissected lymph node burden based predictive model for predicting biochemical recurrence after radical prostatectomy mehdi kardoust parizi department of urology, shariati hospital, tehran university f medical sciences, tehran, iran. e-mail: m.kardoust@yahoo.com objectives: this study aimed to assess the dissected lymph node (ln) burden-based predictive model for predicting biochemical recurrence after radical prostatectomy in patients with non-metastatic prostate cancer (pca). methods: this study was conducted between may 2009 and april 2018 on patients with non-metastatic pca who underwent radical retropubic prostatectomy. clinicopathological parameters including age, preoperative prostate-specific antigen, prostate weight at surgery, gleason score (gs) of surgical specimen, pathological tumour stage, dissected ln number, positive ln and positive ln density were recorded. cox regression models were used to analyse the prognostic value of assessed potential prognosticators and designing a predictive model. results: a total of 216 consecutive patients were included and had a mean age of 63.9 years (range: 40–83 years). positive surgical margins were present in 16.6%. final gs was 2–6 in 39.7%, 7 in 38.3% and 8–10 in 22%. the mean number of lns removed during pelvic lymph node dissection was 11.96 (range: 2–31). of all patients, 7.4% were ln-positive; patients with negative lns had significantly better progression-free survival (p <0.05). dissected ln number was associated with a lower biochemical recurrence rate in patients with final negative lns (odds ratio: 0.971). conclusions: although the prognostic value of radical prostatectomy (rp) driven prognosticators such as gs and tumour stage have been frequently used to predict oncological outcomes after rp, the dissected ln burden could improve the accuracy of predictive tools. moreover, this study confirmed that ln-negative pca patients benefit from ln dissection in terms of oncological outcomes. possibilities of the use of raman spectroscopy in the diagnostics of in vitro urinary bladder cancer valentin pavlov, *rita gilmanova, vyacheslav korolev bashkir state medical university, ufa, russia. *corresponding author’s e-mail: margaritagilmanova@mail.ru objectives: bladder cancer is the most common malignant tumour of the urinary tract. raman spectroscopy is the method that makes it possible to study tissues at a molecular level with high specificity during pathological transformation. this study aimed to evaluate the diagnostic capabilities of the raman spectroscopy method in detecting bladder cancer. methods: a total of 20 bladder tissue samples with a histologically confirmed diagnosis of bladder cancer and 13 samples of normal bladder tissue were examined. the research of samples used the following machine configuration: wavelength = 785nm, grating = 1,200g/mm, filter = 100%, confocal opening = 300 microns and integration time = 50 seconds. spectral data were analysed. results: there were significant differences in the raman spectra from the data obtained from bladder cancer tissue and normal bladder tissue. the raman-fluorescent spectra of bladder cancer samples contained strongly pronounced peaks in the range of 500–2,500 cm-1. it is necessary to note the high intensity of the peaks of 750 cm-1 (thymine), 1,000 cm-1 (phenylalanine), 1,100 cm-1 (a complex of fatty acids), which were absent in the spectra of samples of normal tissues. in addition, there was a significant increase in the intensity of peaks in the region of 850 cm-1 and 1,250 cm-1 (c-nh2 bond in adenine, guanine and cytosine molecules) in the spectra of bladder cancer, as well as the appearance of groups of low intensities in the region of 2,800–3,000 cm-1 (lipids and proteins). conclusion: the studied bladder cancer tissue samples showed an increase in the intensity of raman light scattering compared to samples of normal bladder tissue; this confirms the spectral differences in the biochemical composition of these samples. is extracorporeal shock wave lithotripsy still the treatment of choice for renal and upper ureteric calculi: our experience with 300 cases and its comparison with retrograde intrarenal surgery literature *kush shah, piyush singhania, aman agarwal, ajinkya patil mgm institute of health sciences, navi mumbai, india. *corresponding author’s e-mail: kush_dgreat@yahoo.co.in objectives: extracorporeal shock wave lithotripsy (eswl) is used in the management of renal calculi with a size greater than 2 cm. with the recent advances in endourology, the use of eswl has become less frequent. newer techniques such as retrograde intrarenal surgery and percutaneous nephrolithotomy are replacing eswl for treatment of renal stones. methods: this study was conducted at the department of urology, mgm institute of health sciences, navi mumbai, india, between october 2015 and october 2018. patients who underwent intravenous pyelogram x-ray and had a calculi size of 6–20mm were included. patients with untreated urinary tract infection, pregnancy, musculoskeletal deformities and deranged coagulation profile were excluded. double-j stenting was done prior to the procedure for stones >1 cm. a maximum of three eswl sessions were given. the procedure was done under local anaesthesia for adults and under general anaesthesia for children. results: a total of 300 patients between the ages of 15 months and 78 years were included in the current study. there was no effect of age and gender on stone clearance. the overall success rate was 91.97%. success rates for smaller calculi were significantly higher (6–10 mm: 97.7%,10–15mm: 90.1% and 15–20mm: 87.5%; p <0.05). success rates of calculi in the lower calyx (83.63%) was less compared to calculi in the upper calyx (96.77%), middle calyx (96.15%), renal pelvis (90%) and upper ureter (88.23; p <0.05). complications of the procedure included pain (28 patients required no treatment and three patients required admission and treatment), haematuria (15 patients required no treatment and two patients required admission and treatment) and one patient had perinephric gemstone treated conservatively. conclusion: eswl is a safe, effective procedure in treatment of renal calculi with clearance rates of up to 91.97% and can still be regarded as the treatment of choice for renal stones especially in developing countries where cost is still a major factor. sultan qaboos university, muscat, oman, 3–5 october 2019 abstracts | e383 stone extraction might be more suitable than stone fragmentation *rishikesh pandya, venkatesh seetharam, amir ali nmc specialty hospital abu dhabi, abu dhabi, united arab emirates. *corresponding author’s e-mails: rishikesh.pandya@nmc.ae and drrrpandya@yahoo.com objectives: complex stones (i.e. large stones or single or multiple stones) frequently need more than one procedure before the stone is released. increased hospital admissions and procedures under anaesthesia means more stress for the patient and burden on the healthcare system. usually a percutaneous approach is used, instead the investigators propose a method to select patients where stone extraction without fragmentation might overcome the above-mentioned challenges. methods: this study was conducted over a period of five years and included kidneys with single or multiple stones, a volume larger than 4 cm and more than 2 cm in the ureter. based on computed tomography scan, the kidneys with more than 40% of renal pelvis lying outside the medial border of the kidney (extrarenal) were operated by conventional laparoscopic approach. stones in anomalous kidney locations such as a ureteropelvic junction (upj) obstruction/ectopic kidney/crossed-fused were also included. single sitting stone-free rates were assessed. stones that missed extraction were termed residual stones. results: a total of 28 cases, 19 kidneys and nine ureteric stones were analysed. stones were extracted without fragmentation by conventional transperitoneal laparoscopic pyelotithotomy and intrarenal stones were extracted using a flexible cystoscope and basket. upj obstruction was found in 14 patients, five had dismembered pyeloplasty and nine had nondismembered fenger pyeloplasty. one pelvic kidney, one crossed-fused ectopia and two horseshoe kidneys were rendered stone-free. complete stone clearance was achieved for 21 kidney stones; two required flexible ureteroscopy. complete clearance was achieved in all ureteric stones. after two days of antibiotics, no peritonitis or sepsis was reported. drains were removed on postoperative day three in the morning and the patient was discharged. conclusions: laparoscopic extraction in selected cases with suitable anatomy allows non-fragmented complete stone clearance. the procedure is safe and suitable for kidneys with extra renal pelvis. in anomalous kidneys, laparoscopic approach might be more suitable than percutaneous. effectiveness of frenulum subcutaneous injection of botulinum toxins in the treatment of premature ejaculation mohammed ismail college of medicine, university of baghdad, baghdad, iraq. e-mail: mohammed_albassil@yahoo.com objectives: premature ejaculation is a common sexual disorder, which is usually underreported. multiple treatment methodologies are in use due to the absence of an effective, universally acceptable treatment modality. this study aimed to evaluate the effectiveness of frenulum subcutaneous injection of 10 international units (iu) of botulinum toxins in patients with premature ejaculation, who were dissatisfied with classical treatment. methods: this study included 30 patients who reported premature ejaculation who were unhappy with the classical treatment either due to its adverse effects or because of its overall inefficacy. they were treated with a frenulum subcutaneous injection of 50 iu botulinum toxins. preand post-treatment intravaginal ejaculatory latency time (ielt) was analysed. results: before injection, the ielt ranged from one to four minutes with a mean of 1.86 ± 1.008 minutes. after injection, the ielt ranged from one to 45 minutes with a mean of 13.6 ± 7.82 minutes. the difference between ielt before and after the injection was statistically significant (p = 0.001). conclusion: frenulum subcutaneous injection of botulinum toxins in the treatment of premature ejaculation is a safe and effective way to treat premature ejaculation. safety and efficacy of the novel plugging technique using a haemostatic agent for port-site closure in minimally invasive (robotic and laparoscopic) different urological surgeries: tertiary centre experience abdulrahman alsuwailim,1 khalid albalawi,2 *maher moazin,3 meshal almutair,4 abdullah alaliyah,5 naif a. aldhaam3 1king faisal university, ahsaa, saudi arabia; 2tabuk university, tabuk, saudi arabia, 3king fahad medical city, riyadh, saudi arabia; 4qassim university, qassim, saudi arabia, 5king khalid university, abha, saudi arabia. *corresponding author’s e-mail: daho0om.1@hotmail.com objectives: many techniques and devices have been used to close surgical ports after minimally invasive procedures; however, it may entail several complications. therefore, this study aimed to determine the safety and efficacy of the novel plugging technique using surgicel® (ethicon inc., bridgewater, new jersey, usa) to close port-sites. methods: this retrospective study was conducted at king fahad medical city, riyadh, saudi arabia, over an eight year period. all patients who underwent any minimally invasive urological surgery in which the surgical ports were closed using the surgicel® (ethicon inc.) plugging technique were included. patients age, gender, type of surgery and the follow-up results were collected from their electronic medical records and analysed. the sum of each type of urological minimally invasive (robotic and laparoscopic) surgery was identified, as well as the rate of associated specific type(s) of complication. results: a total of 113 patients, of which 54 were male with a mean age of 41.7 ± 18.4 years and 63 were females with a mean age of 39.7 ± 17.9 years, were included. the male-to-female ratio was 1:1.2. among those patients, two cases developed portsite discharge, one case developed a port-site hernia but the majority (97.4%) had no port-site complications. conclusion: this study showed that the plugging technique of port-site postoperatively using a haemostatic agent is safe, easy, effective and results in a low rate of port-site complications. surgeons should ensure that surgicel® (ethicon inc.) is neither thrown inside nor placed above the level of subcutaneous tissue to avoid the development of a hernia or misdiagnosing a discharge as an infection. long-term safety and efficiacy of neurosacral modulation in patient with hypocontractile bladder: a series of 10 cases shailesh m. raina department of urology, jaslok hospital and research centre, mumbai, india. e-mail: drshaileshraina@gmail.com and drshailraina@hotmail.com objectives: this study aimed to determine the safety and efficacy of sacral neuromodulation (snm) in patients with non-obstructive urinary retention in which the bladder was hypocontractile as demonstrated on urodynamic studies. methods: a total of 10 patients who underwent staged neuromodulation non-obstructive urinary retention from 2007 to 2019 at jaslok hospital and research centre, mumbai, india, were included. patients who had a 50% improvement in symptoms after one week of stage 1 procedure qualified for oman urological society conference 2019 e384 | squ medical journal, november 2019, volume 19, issue 4 permanent device implantation. those who showed restoration of spontaneous voiding with a residual volume of <100 ml or who experienced a 50% reduction in catheterisation frequency were offered permanent stage 2 snm device insertion. patient data were assessed for efficacy and need for intermittent self-catheterisation, complications and operative revision rates. all patients’ medical history, physical examination, voiding diaries, urodynamic studies and cystoscopic examination were reviewed. results: the majority (70%) of patients returned to a spontaneous micturition with no need of clean intermittent catheterisation and no major complaint of frequency, urgency or postoperative infection. one patient was lost to follow-up. the device had to be removed from two patients (one for due to noncompliance and the other due to infection). conclusion: snm is a relatively new and safe method that can improve the quality of life of a patient who is on clean intermittent catheterisation for non-obstructive bladder dysfunction. robotic partial nephrectomy for renal tumours: do we really require intra-operative ultra-sonography for margin clearance? shailesh m. raina department of urology, jaslok hospital and research centre, mumbai, india. e-mails: drshaileshraina@gmail.com and drshailraina@hotmail.com objectives: currently, there is a significant increase in indications and demands of nephron-sparing surgery for renal masses. laparoscopic partial nephrectomy has a steep learning curve. this minimally invasive technique aims to accomplish precise tumour resection and renal reconstruction while minimising warm ischaemia time. complex renal tumours may preclude a minimally invasive approach to nephron-sparing surgery in some patients. the da vinci sp® robotic platform (intuitive surgical inc., sunnyvale, california, usa) is seen as especially useful in this regard. this study reports the investigator’s technique of robotic partial nephrectomy for challenging renal tumours and tumour margin clearance without intraoperative ultrasonography. methods: the study was conducted from april 2017 to february 2019 and used the da vinci sp® robotic platform (intuitive surgical inc.) to perform partial nephrectomies. for complex posteriorand hilar-located tumours with sequential steps of colon mobilisation and hilar dissection, only the renal artery was clamped. in cases of multiple arteries, selective artery clamping was done. whole kidney mobilisation and flipping anterior kidney anteriorly for posteriorly located tumours was done. tumour scoring before excision was done intraoperatively and no intraoperative ultrasonography was used. the tumours were removed and single-layer renorrhaphy was used. results: robotic partial nephrectomy procedures were performed successfully without complications. a total of 45 robotic partial nephrectomies were done, with an average warm ischaemia time of 17 minutes and an average intraoperative blood loss was 150 ml. histopathology confirmed renal cell carcinoma with clear margins in all cases. the hospital stay was 3–4 days. at the three-month follow-up, no patients experienced perioperative complications. the one-year follow-up computed tomography scan showed no recurrence. conclusions: robotic assistance may facilitate tumour resection and renal reconstruction for challenging cases, with complete margin clearance achieved without intraoperative ultrasonography, offering a minimally invasive surgical option and no difference with or without the use of intraoperative ultrasound in margin clearance. intraoperative ultrasound may only be required in very complex cases such as cystic (papillary) carcinoma. superficial circumflex iliac artery perforator flap phalloplasty could be a standard of care in gender reassignment surgery for the future sanjay pandey kokilaben dhirubhai ambani hospital & research institute, mumbai, india. e-mail: sanjaypdr@gmail.com objectives: gender reaffirmation phalloplasty is a complex surgical task. successful construction of the penis must meet certain cosmetic and functional thresholds. the ideal neophallus should be sensate, hairless and similar in colour to the surrounding skin. in addition, the surgical scars should be inconspicuous, maintain rigidity for sexual intercourse and allow for micturition upon standing with minimum donor site morbidity. this report demonstrated the investigator’s technique of using a superficial circumflex iliac artery perforator (scip) flap for phalloplasty and its evolution over 19 cases. methods: after appropriate psychiatric and endocrine evaluation, patients were counselled for surgery. concomitant mastectomies/vaginectomies were also done when feasible. the scip phalloplasty was the first part of a three stage process that involved urethroplasty and insertion of a penile prosthesis. results: a total of 19 cases were reviewed in the current study. the mean age of the patients was 28 years (range: 21–39 years). there were no complications in 14 cases, but there was failure in three patients where the flap had to be debrided as the vascularity was hampered because of a narrow vessel, obesity or pedicle stretch-twist. two of them had prostheses-related issues during the neourethra construction. conclusions: the free radial forearm flap, though it established itself over time, has major problems such as donor-site morbidity with large depressive scarring after skin grafting, urethral fistulas and need for microvascular anastomosis. a scip flap has the advantage of minimal donorsite morbidity with a concealed donor scar and no microvascular anastomosis. it facilitates a stepwise approach towards complete establishment of the neophallic state. urinary undiversion for the young and needy: a stitch in time sanjay pandey kokilaben dhirubhai ambani hospital & research institute, mumbai, india. e-mail: sanjaypdr@gmail.com undiversion implies a change in patient management after judicious re-evaluation and the decision to offer the patient the possibility of re-establishing continuity of the urinary tract once a permanent form of urinary diversion had been chosen in the past. careful consideration is given to the historical reason for the permanent diversion. the current status of the patient should be judged on various parameters including the patient’s psychology and the possible consequences if the results of undiversion are less than optimal. the author reports a 26-year-old male patient who was subjected to a radical cystectomy with an ileal conduit seven years prior. the ileal conduit was taken down and incorporated as a part of the neobladder from ileal segments that were created in the patient. he had an intact sphincter mechanism zone that was evaluated by cystoscopy preoperatively. his postoperative recovery was assisted with cisc programmed regimen. at one-year follow-up he was voiding well to near-completion (plateau shaped flow prolonged flow pattern) with insignificant post-void residue. a postoperative cystoscopy showed a capacious bladder with a few mucous plugs. squ med j, august 2010, vol. 10, iss. 2, pp. 196-202, epub. 19th jun 10 submitted: 28th oct 09, reformat recd. 14th nov 09 revision req. 2nd feb 10, revisions recd. 13th feb & 14th apr 10 accepted: 8th may 10 cancer of the kidney accounts for approximately 3.5% of all malignancies and is the third most common cancer of the urinary tract.1 with the increased frequency and sophistication of radiological imaging, the rate of incidental findings of renal cortical tumours has steadily increased. the greatest incidence of asymptomatic small renal masses occurs in elderly patients with multiple comorbidities.2 incidentally discovered small renal masses are being diagnosed with greater frequency3 and they now account for 48% to 66% of renal cell carcinoma (rcc) diagnosis.4 the incidence of renal cell carcinoma (rcc) at autopsy has been reported to be approximately 2%.5 the incidence of rcc has been increasing in all age groups, with the greatest increase occurring in patients with localised tumours, suggesting a migration toward earlier stages as a result of earlier detection.6 considering the improved prognosis of incidental rcc, the difficulty in diagnosing benign tumours preoperatively, the excellent results associated with partial nephrectomy, and the possibility that these lesions themselves may have a less aggressive biology, it becomes apparent that not all solid renal masses are optimally treated by radical nephrectomy.7 consequently, changes in the approach to the management of these masses have occurred. traditionally, renal parenchymalsparing procedures were reserved for patients with a functional or an anatomic impairment of the contralateral kidney. currently, appropriately located lesions 4 cm or less in size are treated, with excellent long-term survival, by nephronsparing surgery even in patients with a normal contralateral kidney.8 the aim of this paper is to review the literature about incidental renal tumours in adults. a literature search was performed using the pubmed database and selecting papers from 1950 to the present using the term ‘incidental renal department of surgery, sultan qaboos university hospital, muscat, oman. email: msalmarhoon@hotmail.com إكتشاف األورام الصغرية يف الكلى بالصدفة عند الكبار حممد �شامل املرهون ينبغي لذلك الأطباء، من الكثري تواجه التي الطبية امل�شاكل من الكبار عند بال�شدفة الكلى يف ال�شغرية الأورام اإكت�شاف اأ�شبح امللخ�ص: التعامل معها بعد معرفة طبيعتها وكيفية عالجها. هدف هذه املقالة هو مراجعة ما ن�رش عن هذه الأورام و طرق عالجها. اإن معظم اأورام الكلى ال�شغرية )اأقل من 4 �شم( عند الكبار املكت�شفة عن طريق ال�شدفة هي اأورام حميدة . اإن اأف�شل طرق عالجها ا�شتئ�شال الورم اجلزئي باملنظار اجلراحي اأو الفتح عند املر�شي �شغار ال�شن القادرين علي حتمل العملية. من طرق العالج الأخرى لهذه الأورام عند كبار ال�شن غري القادرين على حتمل العملية اجلراحية عالج الإبر املجمدة مع اأخذ عينة من الكلىاأو للمالحظة الطبية بدون تدخل جراحي. ة. مفتاح الكلمات: م�شادفة، اأورام، كلوي، �رَشَطاَنُة اخَلاَليا الُكْلِويَّ abstract: incidental renal tumours are becoming an important clinical problem that many physicians will need to deal with. a good knowledge of the nature of these tumours and how to manage them is therefore needed. the aim of this paper is to review the literature about incidental renal tumours in adults. many incidentally discovered small renal tumours (<4 cm) are benign and of low stage, grade and progression potential. the preferred management in young fit patients is open or laparoscopic nephron-sparing surgery. treatment alternatives include needle-ablative therapies and surveillance in elderly unfit patients. tumour renal biopsy is encouraged prior to needle-ablative therapy and surveillance. awareness about incidental renal masses and their management is essential for treating doctors. keywords: incidental; tumors, renal; renal cell carcinoma. review small incidental renal masses in adults review of the literature mohammed s al-marhoon mohammed s al-marhoon review | 197 tumours’. differential diagnosis the differential diagnosis of an incidentally detected renal mass includes both benign and malignant processes. malignant renal masses include rcc, sarcoma, lymphoma, metastatic disease (especially lung, breast, prostate, colon, testes), and urothelialbased tumours of the pelvis and collecting system. of these, rccs account for most such masses. lesions classified as benign include simple cysts, oncocytoma, adenoma, angiomyolipoma, fibroma, and lipoma, [table 1].8 tumour growth rate studies on the natural history of small renal tumours have shown that their growth was, in general, slow or undetectable. approximately onequarter to one-third of small renal tumours did not show radiographic growth, and the overall mean growth rate has been reported to be 0.28 cm per year (range: 0.09–0.86).4,9 a meta-analysis by chawla et al. found that, over a mean follow-up of 34 months, a majority of 234 untreated renal lesions had a slow growth rate (approximately 0.28 cm per year), and metastases were rare (1%).9 kouba et al.2 published the results of a retrospective study including 43 patients with 46 renal masses (24% of tumours >4 cm) who underwent active surveillance of enhancing solid or cystic, bosniak iv (i.e. thick wall, thick septations, course calcifications, density more than 20, enhancement) renal masses. a subset of 13 patients who ultimately underwent surgical intervention was also examined. the mean delay to intervention was 12 months. at a mean follow-up of 36 months, renal masses grew in 74% of patients with a mean (median) growth rate of 0.70 (0.35) cm per year, no patient died of rcc, and none had evidence of metastatic disease. initial tumour size (3.1 versus 2.6 cm, p = 0.450) was similar in the intervention and non-intervention group, and the growth rate did not correlate with initial tumour size. the authors suggested that active surveillance for renal masses is an appropriate option for selected patients, especially those with competing comorbidities. delayed intervention after an initial period of surveillance did not appear to impact pathological outcomes adversely. in a large retrospective study by frank et al.,10 2,935 solid renal tumours were treated in a 30-year period. of these tumours, 12.8% were benign and 87.2% were malignant. of the tumours <1 cm in diameter, 46.3% were benign while 98% of malignant tumours were low grade. of 250 tumours <2 cm in diameter, 30% were benign and only 9.2% were high grade malignancies. as the tumour size increases, there is a significantly greater probability that the tumour is malignant versus benign, clear cell versus papillary rcc, and high-grade versus low-grade rcc. initial tumour size is not a predictor of the subsequent growth rate. in the study conducted by kouba et al.,2 tumours with an initial size > 4 cm had growth rates similar to those of smaller tumours. the majority of small renal masses grow and the majority is cancerous. one cannot safely assume that a lack of growth on serial computed tomography (ct) scan confirms the absence of malignancy. no clinical or radiological predictors of growth rate have been identified.11 tumour growth rate determination alone probably will not give clinicians enough information to predict accurately the behaviour of all small renal masses. cytogenetic, immunohistochemical, or other investigations done on needle biopsies and the study of new radiologic parameters using computed tomography (ct) scanning and magnetic resonance imaging (mri) may be helpful in identifying patients who have renal tumours with good prognostic factors and a long natural history and who therefore may primarily be followed conservatively.12 role of renal biopsy the use of renal mass biopsy to guide treatment decisions is still controversial. the current indications for renal mass biopsy are: a) to differentiate benign from malignant small renal tumours;13 b) the use of molecular markers obtained from tumour biopsies for separating indolent from aggressive tumours;14 c) prior to or during ablative therapies and during follow up after ablative therapies, especially radiofrequency ablation, for defining treatment success or failure,15 and d) to rule out non-renal cell primary tumours (metastasis and lymphoma) or benign conditions (abscess), which may not require surgery. biopsy has also been used to confirm the diagnosis and the histological subtype of renal primary lesion in patients with disseminated small incidental renal masses in adults review of the literature 198 | squ medical journal, august 2010, volume 10, issue 2 literature overview renal cell carcinoma, which represents 2% of all adult cancers, is the most lethal of common urologic cancers, with approximately 35% of patients dying from the disease at the 5-year mark.20 the incidence of rcc has risen steadily each year during the last three decades in most of the world, with an average increase of 2% to 3% per year.21 tobacco use and obesity are the most consistently identified risk factors for rcc, accounting for about 20% and 30% of cases, respectively.20 other risk factors for rcc include hypertension and a family history of the disease. incidental detection of clinical stage 1 (<7.0 cm), solid, enhancing renal masses accounts for more than 50% of rcc cases, and these tumours are more likely to be organ confined and associated with an improved prognosis.22 the biology of these tumours is heterogeneous, and there are multiple management options available, ranging from observation to radical nephrectomy. approximately 20% of clinical stage t1 renal masses are benign, and only 20% to 30% of malignant tumours in this size range demonstrate potentially aggressive features, with substantial variance based on patient age, gender and tumour size.23 the differential diagnosis of a renal mass includes: rcc, renal adenoma, oncocytoma, angiomyolipoma, urothelial carcinoma, metastatic tumour, abscess, infarct, vascular malformation or pseudotumour. with the exception of fat-containing angiomyolipoma, no current scanning methods can distinguish between benign and malignant solid tumours or between indolent and aggressive tumour biology. tumours less than 3 cm may be more likely to be benign24 and the aggressive potential of rcc increases dramatically beyond this size.25 in recent years, the potential role of biopsy for localised renal tumours has been revisited, in part driven by the recognition that 20% clinical stage t1 renal masses may represent benign disease and could be considered for less aggressive management.25 in addition, the accuracy and safety of renal mass biopsy has improved substantially due to further refinements in ctand mriguided techniques. a review of studies since 2001, demonstrates that the false-negative rate with renal mass biopsy is now only 1%, and the incidence of symptomatic complications is relatively low, with metastases or unresectable retroperitoneal masses.16 urothelial carcinoma carries a higher risk of seeding than rcc and a percutaneous biopsy in the presence of radiological suspicion of renal pelvic tumour or positive urinary cytology should only be performed after careful consideration of the risks and benefits.16 the high proportion of benign lesions (19% to 26%)17 in tumours ≤ 4cm justifies preoperative histological diagnosis to decrease the rate of unnecessary renal surgery which has been reported to be 34%.18 the safety and accuracy of renal core biopsy has been questioned, in particular its accuracy for small lesions.19 in incidental renal masses of <5 cm, it has been reported that renal core biopsy had 100% accuracy for distinguishing benign from malignant lesions and 98% accuracy for determining histological tumour type,18 indicating that this technique can be used successfully for small lesions, including those that are asymptomatic and detected incidentally. however, there are limitations and complications with renal core biopsy of small lesions. the limitation is the considerable proportion of biopsy specimens that have insufficient tissue for analysis or contain only necrotic tissue, normal tissue or blood. this is referred to as the nondiagnostic rate or failure rate which has been reported to range from 0% to 22%.18 this high failure rate in small tumours is partly due to more difficult visualisation and targeting, and the biopsy needle displacing small masses rather than penetrating them.16 the potential complications of renal core biopsy include tumour seeding along the needle track, bleeding, arteriovenous fistula, infection and pneumothorax.16 table 1: differential diagnosis of renal masses in adults cysts tumours inflammatory lesions simple malignant masses renal cell carcinoma lymphoma sarcomas metastases infection complex infarction multiple trauma (hematoma) benign masses renal adenomas angiomyolipomas oncocytomas others mohammed s al-marhoon review | 199 only a very small percentage (<2 %) requiring any form of intervention.26 needle-tract seeding also appears to be exceedingly rare, assuming appropriate patient selection. while another 1015% of renal mass biopsies are indeterminate, this is much less concerning than a false negative, which would lead to observation of a malignancy. given the significant heterogeneity in the biological aggressiveness of clinical stage t1 renal masses and the wide range of treatment options now available, renal mass biopsy is now being used increasingly for patient counselling and clinical decision making. this approach is appropriate for patients in whom a wide range of management options are under consideration, ranging from surgery to observation. renal mass biopsy is not indicated, however, for healthy patients who are unwilling to accept the uncertainty associated with this procedure or for older patients who will only consider conservative management options regardless of biopsy results. incorporation of molecular analysis has shown great promise to further improve accuracy of renal mass biopsy/aspiration and remains a research priority.16 the most prominent molecular markers are the vhl gene, altered expression of carbonic anhydrase ix (caix) or the b7h1 molecule, cell cycle regulators such as p27, cyclin d1, prb and p53 and markers of cellular proliferation such as ki-67. histopathological evaluation of surgically managed suspicious renal masses in published reports indicate that the frequency of benign pathologic findings is higher for tumours less than 4 cm in size compared to tumours more than 4 cm. this information is important for physicians when counselling patients on treatment options. for tumours 4 cm or less in size, the percentage of benign masses reported were 20% (18 of 90),27 19.8% (23 of 116),28 and 23% (65 of 280).29 for tumours > 4 cm, the percentage of benign masses reported was 8% (8 of 96).27 the data by luciani et al.,22 in a study of 1,092 patients, confirm a rapid and dramatic change in the epidemiologic and clinical characteristics of renal cancer, with an increasing number of incidentally found tumours: 13% in 1982 compared to 59.2% in 1997. the incidentally discovered tumours presented with a lower stage (74.3% versus 49.1%), grade (75.5% versus 56.9%), and percentage of metastases at presentation (10.4% versus 19.6%) compared to the symptomatic neoplasms. in a large study of 482 patients evaluating the histologic type of renal tumours according to size, schachter et al.17 found smaller lesions (≤4 cm) that proved to be malignant were less likely to be of clear-cell histology (50% versus 72.8%) and more likely to be papillary (15.8% versus 9.4%) than were larger (>4 cm) lesions. given the differences in the biological behaviour of the various histological subtypes of these tumours, these data are important in patient counselling about the treated and untreated natural history of small renal masses. the impact of histological subtype on prognosis is important.30 amin and colleagues found that chromophobe and papillary subtypes have the best prognosis and conventional clear-cell rccs had a worse prognosis as judged by renal mass detected incidentally on ct scan or ultrasound examination does the patient have symptoms? renal ct and urologic referral what is the bosniak classification of the mass? class i: simple cyst class ii: probable benign cyst class iii: indeterminate cystic lesion class iv: presumed malignant cystic mass renal ct if symptoms occurs renal ct surveillance at 6 to12 month intervals renal ct, possible renal mri before referral for surgical exploration renal ct, possible renal mri before referral for surgical excision figure 1: management of incidental renal mass in adults small incidental renal masses in adults review of the literature 200 | squ medical journal, august 2010, volume 10, issue 2 for patients with a normal contralateral kidney or partial nephrectomy as a recommended modality when there is a need to preserve renal function. however, active surveillance should be discussed with patients who want to avoid surgery or who are considered high risk for surgical therapy; and thermal ablation may be discussed as treatment option which is less effective due to an increased risk of local recurrence. conclusion with the increased frequency and sophistication of radiological imaging, the rate of incidental findings of renal cortical tumours has steadily increased. awareness about incidental renal masses and their management is essential as they are becoming an important clinical problem that many physicians will face. the main issue is whether to be aggressive or conservative with small renal masses, knowing that a significant number of these small tumours are benign and most of them grew slowly. in recent years, the potential role of biopsy for localised renal tumours has been revisited, in part driven by the recognition that 20% clinical stage t1 renal masses may represent benign disease and could be considered for less aggressive management. in addition, the accuracy and safety of renal mass biopsy has improved substantially due to further refinements in ctand mri-guided techniques. incorporation of molecular analysis has shown great promise to improve further the accuracy of renal mass biopsy/aspiration and remains a research priority. currently, small renal masses 4 cm or less are treated, with excellent long-term survival, by nephron-sparing surgery even in patients with a normal contralateral kidney. references 1. jemal a, siegel r, ward e, murray t, xu j, thun mj. cancer statistics, 2007. ca cancer j clin 2007; 57:43–66. 2. kouba e, smith a, mcrackan d, wallen em, pruthi rs. watchful waiting for solid renal masses: insight into the natural history and results of delayed intervention. j urol 2007; 177:466–70. 3. jayson m, sanders h. increased incidence of serendipitously discovered renal cell carcinoma. urology 1998; 51:203–5. 5-year disease specific survival.31 in the experience of cheville and associates, both papillary and chromophobe lesions had a better prognosis than clear-cell carcinoma.30 summary of current treatment renal masses are a common clinical problem, often detected in asymptomatic patients. the frequency of masses found incidentally by radiographic studies is increasing as studies with ultrasound (us), ct, and mri are becoming more routine. the renal lesions can be classified as solid or cystic, malignant or benign, acquired or congenital, unilateral or bilateral, single or multiple, and primary or metastatic. the essential steps in the management of renal masses are: full history and physical examination; radiological evaluation by us or intravenous urogram (ivu) or ct, and determining the nature of the mass whether cystic or solid. if it is a simple cyst no further action is needed. however, if it is a complex cyst then further evaluation by ct or mri for cyst classification is indicated [figure 1].32 for solid renal masses, the recommended treatment guidelines for patients with clinical t1 renal masses are as follows.33 in a healthy patient with a clinical t1a (≤4.0 cm) enhancing renal mass, the standard is surgical excision by partial nephrectomy and radical nephrectomy as an alternative standard. in t1a, if the patient has major comorbidities or increased surgical risk, surgical excision by partial nephrectomy or radical nephrectomy should be discussed as a standard of care with an increased risk of surgical complications and chronic kidney disease. other options include: thermal ablation as a less-invasive treatment, which may be advantageous in a high surgical risk patient, acknowledging the increased risk of local tumour recurrence compared to surgical excision; or active surveillance which can be offered as an acceptable approach to delay or avoid the need for intervention in high-risk patients. the standard treatment in a healthy patient with a clinical t1b (>4.0 cm to <7.0 cm) enhancing renal mass is radical nephrectomy for patients with a normal contralateral kidney, or partial nephrectomy as an alternative, particularly when there is a need to preserve renal function. in t1b patients with major comorbidities or increased surgical risk, the standard is radical nephrectomy mohammed s al-marhoon review | 201 renal masses. j urol 2008; 180:1257–61. 19. rybicki fj, shu km, cibas es, fielding jr, van sonnenberg e, silverman sg. percutaneous biopsy of renal masses: sensitivity and negative predictive value stratified by clinical setting and size of masses. ajr am j roentgenol 2003; 180:1281–7. 20. lipworth l, tarone re, mclaughlin jk. the epidemiology of renal cell carcinoma. j urol 2006; 176:235. 21. mathew a, devesa ss, fraumeni jf jr, chow wh. global increases in kidney cancer incidence, 19731992. eur j cancer prev 2002; 11:171–8. 22. luciani lg, cestari r, tallarigo c. incidental renal cell carcinoma-age and stage characterization and clinical implications: study of 1092 patients (19821997). urology 2000; 56:58–62. 23. lane rb, babineau d, kattan mw, novick ac. a preoperative prognostic nomogram for solid enhancing renal tumors 7 cm or less amenable to partial nephrectomy. j urol 2007; 178:42. 24. pahernik s, ziegler s, roos f, melchior sw, thuroff jw. small renal tumors: correlation of clinical and pathological features with tumor size. j urol 2007; 178:414–7. 25. remzi m, ozsoy m, klingler hc, susani m, waldert m, seitz c, et al. are small renal tumors harmless? analysis of histopathological features according to tumors 4 cm or less in diameter. j urol 2006; 176:896–9. 26. schmidbauer j, remzi m, memarsadeghi m, haitel a, klingler hc, katzenbeisser d, et al. diagnostic accuracy of computed tomography-guided percutaneous biopsy of renal masses. eur urol 2008; 53:1003–11. 27. duchene da, lotan y, cadeddu ja, sagalowsky ai, koeneman ks. histopathology of surgically managed renal tumors: analysis of a contemporary series. urology 2003; 62:827–30. 28. filipas d, fichtner j, spix c, black p, carus w, hohenfellner r, et al. nephron-sparing surgery of renal cell carcinoma with a normal opposite kidney: long-term outcome in 180 patients. urology 2000; 56:387–92. 29. mckiernan j, yossepowitch o, kattan mw, simmons r, motzer rj, reuter ve, et al. partial nephrectomy for renal cortical tumors: pathologic findings and impact on outcome. urology 2002; 60:1003–9. 30. cheville jc, lohse cm, zincke h, weaver al, blute ml. comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. am j surg pathol 2003; 27:612–24. 31. amin mb, amin mb, tamboli p, javidan j, stricker h, de-peralta venturina m, et al. prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. am j surg pathol 2002; 26:281–91. 4. volpe a, panzarella t, rendon ra, haider ma, kondylis fi, jewett ma. the natural history of incidentally detected small renal masses. cancer 2004; 100:738–45. 5. hellsten s, johnsen j, berge t, linell f. clinically unrecognized renal cell carcinoma. diagnostic and pathological aspects. eur urol 1990; 18 s2:2–3. 6. chow wh, devesa ss, warren jl, fraumeni jf, jr. rising incidence of renal cell cancer in the united states. jama 1999; 281:1628–31. 7. morgan wr, zincke h. progression and survival after renal-conserving surgery for renal cell carcinoma: experience in 104 patients and extended followup. j urol 1990; 144:852–7. 8. pantuck aj, zisman a, rauch mk, belldegrun a. incidental renal tumors. urology 2000; 56:190–6. 9. chawla sn, crispen pl, hanlon al, greenberg re, chen dy, uzzo rg. the natural history of observed enhancing renal masses: meta-analysis and review of the world literature. j urol 2006; 175:425–31. 10. frank i, blute ml, cheville jc, lohse cm, weaver al, zincke h. solid renal tumors: an analysis of pathological features related to tumor size. j urol 2003; 170:2217–20. 11. kunkle da, crispen pl, chen dy, greenberg re, uzzo rg. enhancing renal masses with zero net growth during active surveillance. j urol 2007; 177:849–53. 12. israel gm, bosniak ma. renal imaging for diagnosis and staging of renal cell carcinoma. urol clin north am 2003; 30:499–514. 13. silverman sg, gan yu, mortele kj, tuncali k, cibas es. renal masses in the adult patient: the role of percutaneous biopsy. radiology 2006; 240:6–22. 14. li g, cuilleron m, cottier m, gentil-perret a, lambert c, genin c, et al. the use of mn/ca9 gene expression in identifying malignant solid renal tumors. eur urol 2006; 49:401–5. 15. weight cj, kaouk jh, hegarty nj, remer em, o'malley cm, lane br, et al. correlation of radiographic imaging and histopathology following cryoablation and radio frequency ablation for renal tumors. j urol 2008; 179:1277–81. 16. volpe a, kachura jr, geddie wr, evans aj, gharajeh a, saravanan a, et al. techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy. j urol 2007; 178:379–86. 17. schachter lr, cookson ms, chang ss, smith ja jr, dietrich ms, jayaram g, et al. second prize: frequency of benign renal cortical tumors and histologic subtypes based on size in a contemporary series: what to tell our patients. j endourol 2007; 21:819–23. 18. shannon ba, cohen rj, de bh, davies rj. the value of preoperative needle core biopsy for diagnosing benign lesions among small, incidentally detected small incidental renal masses in adults review of the literature 202 | squ medical journal, august 2010, volume 10, issue 2 32. higgins jc, fitzgerald jm. evaluation of incidental renal and adrenal masses. am fam physician 2001; 63:288–94. 33. novick ac. guideline for management of the clinical stage 1 renal mass. washington dc: american urological association, 2009. squ med j, december 2009, vol. 9, iss. 3, pp. 333-336, epub. 19th dec 2009 submitted 17th march 2009 revision req. 3rd aug 09 revision recd. 16th aug accepted 7th sept 09 nephrectomy is one of the most common ablative surgeries performed by urologists. apart from the psychological trauma of losing a kidney, the patient usually undergoes significant discomfort and disfigurement due to the long surgical incision, as the traditional approaches require a large muscle-cutting skin incision in order to reach the organ. until the last decade, this open surgical technique was the only available option for this procedure. in the last decade, minimally invasive surgery has been at the frontier of surgical development. from its initial diagnostic use in gynaecology to the current use in advanced oncological and reconstructive surgery, laparoscopy has become firmly established in the armamentarium of surgeons in every field. the advantages of lower post-operative pain, minimal scars, rapid recovery and early return to work have offset the marginal increase in the instrumentation costs and the longer training period for the surgeon. with the introduction of re-usable equipment these limitations can be minimised. retroperitoneoscopy was initially described by bartel1 in 1969, but was considered to be technically cumbersome because of limited working space, lack of clear-cut anatomic landmarks, and abundant fat in the retroperitoneum. however, the retroperitoneal anatomy is more familiar to the urologist because of commonly performed open retroperitoneal surgery. in addition, the advantages of not entering the peritoneal cavity, such as the early return of bowel activity, the avoidance of contamination of the peritoneal cavity with urine, have made urologists consider this option once again.2 wickham3 reported the initial retroperitoneoscopic ureterolithotomy in 1979. in 1982, bay-nielson and schultz4 performed endoscopy of the retroperitoneum to remove upper ureteral calculi. the first attempts at retroperitoneal department of surgery, urology unit, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed: email: shahidaquil@hotmail.com التقنية اجلراحية الْستئصال الكلية باملنظار عن فاق طريق احَليُِّز َخلَْف الصِّ تقرير حالة شاهد عقيل، جوزيف ماثيو، كرشنا براساد، خالد رحمان، عمر شريف، غالب البداعي فاق. امللخص: تقرير عن حالة كلية مينى ال تعمل بسبب التهابات مزمنة في احلَُويَضِة والُكلَية مت استئصالها بنجاح باملنظار عن طريق احلَيُِّز َخلَْف الصِّ ندرج هنا وصف العملية التي تعتبر غازية بحد أدنى . فاق ، تقرير مفتاح الكلمات: عملية اجلراحة باملنظار، استئصال الكلية، خطوات عملية غازية بحد أدنى ، التهاب احلويضة والكلية، احلَيُِّز َخلَْف الصِّ حالة، ُعمان. abstract: a case of right non-functioning kidney secondary to chronic pyelonephritis is presented. the successful management through retroperitoneoscopic nephrectomy is described, emphasising the technique of this minimally invasive therapeutic option. keywords: laparoscopic surgery; nephrectomy; reteroperitoneal space; surgical procedures; pyelonephritis; minimally invasive surgical procedures, case report; oman surgical technique for retroperitoneoscopic nephrectomy a case report *shahid aquil, joseph k. mathew, krishna prasad v, khalid rehman, omar w sharef, ghalib al baadi case report surgical technique for retroperitoneoscopic nephrectomy a case report 334 | squ medical journal, december 2009, volume 9, issue 3 endoscopic nephrectomy were made by coptcoat,5 wickham and miller,6 and weinberg and smith7 in the early 1980s, and were based on the technique of percutaneous renal stone surgery. the first transperitoneal laparoscopic nephrectomy was performed by clayman8 et al. in 1991. case report a 48 year-old female presented at sultan qaboos university hospital, oman, with right flank pain and dysuria of several months duration. abdominal ultrasonography revealed a right small kidney, but the contralateral kidney was normal. routine haematological and biochemical examinations were normal. the urine culture was sterile. an isotope diethylene triamine penta-acetic acid (dtpa) scan showed differential functions of 5% in the right kidney and 95% in the left kidney. she was diagnosed to have a right non-functioning atrophic kidney and it was suggested that she undergo nephrectomy through a retroperitoneal approach. the surgery was performed through the retroperitoneal route; hence surgical details of this procedure are described. the procedure was performed under general anaesthesia with end tidal co2 monitoring under cover of prophylactic antibiotics. after bladder catheterisation, the patient was placed in the standard right lateral kidney position. the surgeon and the camera person stood on the right side of the patient while the scrub nurse was on the left side of the patient. we used the open (hasson)9 technique for obtaining initial access. a 10-12 mm incision was made in the lumbar (petit’s) triangle below the 12th rib at the lateral border of paraspinalis muscles. the muscle fibres were carefully separated and entry was gained into the retroperitoneum by gently piercing the thoracolumbar fascia with the tip of an artery forceps. a balloon dilator was constructed as described by gaur.10 this consists of a glove finger stall tied by silk over the end of a suction catheter. the balloon dilator was then inserted into the opening. distension of the balloon with air rapidly and atraumatically displaces the adjacent fat and peritoneum, there by creating an adequate working space for retroperitoneoscopic surgery within that area. a 10mm port was then placed in this opening and used as the camera port. all work was visualised via a monitor at the head of the table using a high quality charge-couple device (ccd) camera connected to the laparoscope. the 2nd and 3rd ports were inserted under direct vision as shown in figure 1. an automatic insufflator was used to maintain the co2 pressure at 14mm hg. the psoas muscle acts as a landmark and was sought immediately on entry with the laparoscope. the posterior aspect of the kidney was reached first and the pulsating renal artery was identified at the hilum. the renal hilum was dissected, the renal vein and renal artery cleared of fat and clipped using liga clips 400 series™ (ethicon). endo gia clips, if available, can also be used. three clips were applied on the proximal part of the vessel and two on the distal end.11 the vessels were divided and then further dissection of the kidney was performed figure 1: patient in the lateral (flank) position. dashed line represents vertebral spinous processes. solid line a-b denotes edge of para-spinalous muscles, 11th and 12th rib as marked. x marks primary port site and balloon insertion site. solid circles represents secondary port sites. patient is strapped to keep the kidney in position shahid aquil, joseph k. mathew, krishna prasad v, khalid rehman, omar w sharef and ghalib al baadi case report | 335 separating it from the surrounding fat. the ureter was clipped and divided and once the kidney was fully mobilised it was removed from the body by incising one of the port sites and increasing it to 2.5-3 cm. a drain was left in the retroperitoneum and co2 evacuated before the end of the procedure. an endo catch bag, if available, can also be used. the duration of the procedure was 145 minutes. on first post-operative day, the foley catheter was removed and oral feeding started after confirming return of bowel sounds. the patient was fully mobilised within 24 hours after which the drain was removed. the puncture site remained dry and the patient was discharged on the third postoperative day. on follow-up, the histopathology revealed chronic pyelonephritis, but the patient was well and without complaints. discussion in the past few years, laparoscopy has been the subject of great interest in the field of urology. it has evolved from simple diagnostic manoeuvres to complex operative procedures. in general, from an anatomic point of view, retroperitoneoscopy seems to be more suitable than the transperitoneal laparoscopic approach to reach the upper urinary tract. it also is less invasive and complies with the criteria for open renal surgery. the first attempts at retroperitoneal endoscopic nephrectomy were made by wickham and miller 6 in early 1980s and were based on the technique of percutaneous renal stone surgery. the real breakthrough was a transperitoneal laparoscopic nephrectomy performed by clayman et al. in 1991.8 initially, endoscopic access to the upper and lower retroperitoneum did not find wide acceptance. the main reason was the suboptimal view due to the inability to establish a pneumoperitoneum. on the other hand, establishment of a pneumoperitoneum using co2 insufflation alone proved to be a problem. the balloon dissection technique described by gaur10 allowed the safe and reproducible creation of a retroperitoneal operating field. using single digit dissection, rassweiler12 has shown it to be sufficient for adequate exposure of the retroperitoneal space and reduces the operating time by 10-15 minutes. the basic surgical technique of laparoscopic nephrectomy has been described in detail by both clayman8 and gill.13 the technique described here has some modifications as compared to the original descriptions. a pre-operative angiogram or renal artery immobilisation was not performed as it adds to cost and morbidity and makes little difference to the outcome. some technical points should be detailed for the avoidance of complications: 1) strict attention to basic surgical principles; 2) placement of trocars under direct vision; 3) meticulous attention to avoid even minor haemorrhage as blood in the field obscures vision dramatically; 4) approaching the renal hilum before perirenal or ureteric dissection, if at all possible; 5) later dissection of the anteriormedial aspect of the kidney to prevent it from falling on the posteriorlateral pedicle area; 6) adequate exposure and retraction; 7) early conversion to open surgery if there is failure to progress. the complications encountered in reteroperitonescopy include inadvertent entry into the peritoneal cavity; difficulty in identifying small atrophic kidneys; inadvertent bowel injury; excessive bleeding from slippage of the renal pedicle or from the trocar site; surgical emphysema and septicaemia from handling of an infected hydronephrotic kidney. conversion to open surgery may be required to manage these complications.14 apart from standard contraindications of laparoscopy like bleeding diathesis and cardiac failure, or severe chronic obstructive pulmonary disease, previous retroperitoneal surgery is a relative contraindication for this procedure. the relatively long operative duration reported by some investigators15 for laparoscopic nephrectomy and nephroureterectomy has been used by critics to argue against the widespread adoption of this technique. the present duration of 145 minutes compares favourably with 153 minutes16 and 154 minutes17 reported in other series and in a contemporary open surgical series.18 by maintaining the operative duration in line with that for open surgery, we support reports rating laparoscopic nephrectomy overall as less expensive than open nephrectomy. 19, 20 conclusion we conclude that retroperitoneoscopic nephrectomy is a feasible, safe and minimally invasive technique. the length of hospital stay and convalescence is short and return to normal activity is rapid. surgical technique for retroperitoneoscopic nephrectomy a case report 336 | squ medical journal, december 2009, volume 9, issue 3 references 1. bartel m. die retroperitoneoscopie; eine endoskopische methode zur inspektion und bioptischen untersuchung des retroperitonealen raumes. zentralbl chir 1969; 94:377. 2. desai mm, strzempkowski b, matin sf, steinberg ap, ng c, meraney am, et al. prospective randomized comparison of transperitoneal versus retroperitoneal laparoscopic radical nephrectomy. j urol 2005; 173:38-41. 3. wickham jea. the surgical treatment of renal lithiasis: wickham jea, ed. in: urinary calculus disease. newyork: churchill livingstone, 1979. pp. 145-98. 4. bay-nielson h, schultz a. endoscopic retroperitoneal removal of stones from the upper half of the ureter. scand j urol nephrol 1982; 16:227-8. 5. coptcoat mj. endoscopic tissue liquisation of the prostate, bladder and kidney: preliminary report. phd thesis, university of liverpool, uk, 1990. 6. wickam jea, miller ra. percutaneous renal access. in: wickham jea, ed. percutaneous renal surgery. new york: churchill livingstone 1983. pp. 33-9. 7. weinberg jj, smith ad. percutaneous resection of the kidney; preliminary report. j endourol 1988; 2:355. 8. clayman rv, kavoussi lr, soper nj, dierks sm, merety rs, daroy md, et al. laparoscopic nephrectomy: initial case report. j urol 1991; 146:278-82. 9. gill is, grune mt, munch ls: access technique for retroperitoneoscopy. j urol 1996; 156:1120-4. 10. gaur dd. laparoscopic operative retroperitoneoscopy: use of a new device. j urol 1992; 148:1137-9. 11. hemal ak, mandal s, kumar r. cost reductive laparoscopic nephrectomy. in: hemal ak, ed. laparoscopic urologic surgery. new delhi: churchill livingstone, 2000. pp. 171-4. 12. rassweiler jj, seemann o, frede t, henkel to, alken p. retroperitoneoscopy: experience with 200 cases. j urol 1998; 160:1265-9. 13. gill is. retroperitoneal laparoscopic nephrectomy. urol clin north amer 1998; 25:343-60. 14. gill is. kavoussi lr, clayman rv, ehrlich r, evans r. fuchs g, et al. complications of laparoscopic nephrectomy in 185 patients: a multi-institutional review. j urol 1995; 154:479-83. 15. ono y, katoh n, kinukawa t, matsuura o, ohshima s. laparoscopic radical nephrectomy: the nagoya experience. j urol 1997; 158:719-23. 16. keely fx, tolley da. a review of our first 100 cases of laparoscopic nephrectomy: defining risk factors for complications. br j urol 1998; 82:615-8. 17. eraky i, el-kappany ha, ghoneim ma. laparoscopic nephrectomy: mansoura experience with 106 cases. br j urol 1995; 75:271-5. 18. sharma nk, stephenson r, tolley da. should laparoscopic nephrectomy/nephroureterectomy be the preferred treatment option for most renal pathologies? a comparative study. j urol 1996; 155:491a. 19. wilson bg, deans gt, kelly j, mccrory d. laparoscopic nephrectomy: initial experience and cost implications. br j urol 1995; 75:276-80. 20. zaidi z, samad l, aquil s. laparoscopic nephrectomy: technique and outcome. j pak med assoc 2007; 57:355-9. squ med j, february 2011, vol. 11, iss. 1, pp. 56-61, epub. 12th feb 11 submitted 19th apr 10 revision req. 22nd jun 10, revision recd. 24th jul 10 accepted 4th aug 10 department of chemical pathology, directorate of medical laboratories, royal hospital, muscat, oman. email: manal.kalifa@moh.gov.om l^èfi^€�√÷]<^äfl÷]<çfl¬<då<e∞⁄^jè <ì÷^u h^®˝]<ü€¬<ª<l^€è◊ä÷]< d·^€ �¬e<ºœä≤<ífi^�◊ä÷]<íàéjäπ]<ª<l¯⁄^√÷]<^äfl÷]<ìâ]öå     25   412006  6 ± 29 ± 4518  25  25  25 50 (p < 0.001 r = 0.482)(p < 0.01 r = 0.672)  25     25: ةمفتاح الكلمات abstract: objectives: sunlight exposure has a vital role in vitamin d synthesis. although vitamin d deficiency has been well documented in temperate zones, studies have been scarce in tropical countries where the population is well covered and for various reasons avoids sun exposure. the objective of this study was to investigate serum 25-hydroxyvitamin d [25(oh)d] levels and its relationship to biochemical bone profile, exposure to sunlight and vitamin d intake amongst omani women of childbearing age. methods: 41 apparently healthy women working at the royal hospital, muscat, oman and aged 18–45 years, with mean ± sd of 29 ± 6 years, were included in this study conducted in december 2006. they completed a questionnaire regarding the duration of sun exposure, food intake and type of clothing worn. blood samples were collected from them and analysed for serum 25(oh)d, calcium, phosphate, alkaline phosphatise and parathyroid hormone levels. results: all the women had a 25(oh)d level <50 nmol/l as the cut-off for deficiency. 25(oh)d levels were strongly correlated with the lack of sun exposure (r = 0.672, p < 0.001) and a significant correlation was also found between 25(oh) d level and food intake (r = 0.482, p < 0.01). conclusion: subclinical 25(oh)d deficiency may be prevalent amongst omani women. risk factors such as poor sunlight exposure should be addressed in women of childbearing age and, if increased sunlight exposure is not possible, oral supplementation should be considered to avoid all the consequence and complications of vitamin d deficiency. keywords: vitamin d deficiency; 25-hydroxyvitamin d; women; sunlight; oman vitamin d status in healthy omani women of childbearing age study of female staff at the royal hospital, muscat, oman manal k al-kindi clinical & basic research advances in knowledge 1. vitamin d deficiency may be prevalent among omani women mainly due to poor sunlight exposure. 2. this study stimulates the need for further studies to identify the prevalence of metabolic bone diseases among omanis. manal k al-kindi clinical and basic research | 57 vitamins d is produced endogenously by the exposure of skin to sunlight, and absorbed from food containing or supplemented with vitamin d. when it penetrates the skin, ultraviolet light is converted from 7-dehydrocholesterol to vitamin d3. vitamin d from the skin or diet is metabolised in the liver to 25-hydroxyvitamin d [25(oh)d], then further metabolisation occurs in the kidney to form the active form 1,25-dihydroxyvitamin d [1,25(oh)2d]. the renal production of 1,25(oh)2d is tightly regulated by plasma parathyroid hormone levels as well as serum calcium and phosphate levels.1 deficiency of vitamin d results in rickets in children and osteomalacia, muscle weakness and increased risk of fractures in adults.1 the discovery that most tissues and cells in the body have vitamin d receptors and some of them have the enzymatic capability to convert vitamin d to its active form, 1,25(oh)2d, may explain the important role of vitamin d in skeletal and non-skeletal health. vitamin d also plays a role in decreasing the risk of chronic conditions such as diabetes, cancer, and autoimmune, infectious and cardiovascular diseases.2,3 vitamin d deficiency is a well-recognised epidemic problem worldwide. given the significant role of sunlight in vitamin d synthesis, it is quite logical to suggest a low prevalence of vitamin d deficiency in tropical countries. however, studies carried out in the last two decades have shown a high prevalence of vitamin d deficiency in many tropical countries such as turkey,4 iran,5 saudi arabia,6,7,8,9 united arab emirates,10 kuwait,11 bangladesh12 and tunisia.13 vitamin d status has so far been poorly documented in the omani population. the present study aimed to investigate vitamin d levels among omani females of childbearing age where a sufficient level is important to prevent neonatal hypocalcaemia and impaired bone growth. this study also investigated the prevalence of vitamin d deficiency among omani women and its relationship to sun exposure, food intake and type of clothing. methods forty-one apparently healthy women aged 18–45 years with (mean ± standard deviation (sd), 29 ± 6 years), working in various departments of the royal hospital, muscat, oman, volunteered for this study. exclusion criteria included known hepatic, renal or gastrointestinal disease, pregnancy, lactation and medication influencing bone metabolism such as calcium or vitamin d supplements. the study was approved by the research ethical committee at the royal hospital. informed consent was taken from all subjects who also were asked to complete a questionnaire before blood collection. the study was conducted in december 2006 (winter-autumn in oman) where the temperature ranges from 15 to 28 ºc. all subjects completed a questionnaire on medical history, exposure to sunlight (estimated in minutes per week), skin type, sunscreen usage and type of clothing (i.e. exposure of hands and face). the questionnaire also estimated their dietary calcium and vitamin d intake, covering the commonest food preparations consumed by omanis. data on frequency of consumption (daily, weekly, monthly) as well as quantities consumed were collected and analysed. the relation of vitamin d levels, sun exposure, dietary intake and application of sun screen were assessed. the sun exposure was calculated from the questionnaire and expressed in minutes per week. the dietary intake was also calculated using different parameters. in the questionnaire, the frequency of food consumption was quantified per day, per week and per month. the amount of food, weight of the product, vitamin content in the product, total vitamin d intake in that product and finally the total vitamin d consumed were also calculated. then, vitamin d amounts per product were calculated from different sources (uk tables, danish tables, and product ingredient information and the subjects’ estimations for home cooked food). blood specimens were collected in greiner vacuette tubes (greiner bio-one gmbh, badenwürttemburg, germany) from each subject for the application to patient care 1. this study highlights important public health issues such as the need for adequate maternal vitamin d levels in pregnancy/lactation and the promotion of outdoor activities. vitamin d status in healthy omani women of childbearing age study of female staff at the royal hospital, muscat, oman 58 | squ medical journal, february 2011, volume 11, issue 1 measurement of the following analytes: serum total calcium, phosphate, albumin, alkaline phosphatase (alp), parathyroid hormone (pth) and 25(oh)d. for pth analysis, serum samples were separated within 30 minutes following blood collection and kept frozen until analysis. serum total calcium, phosphate, alp and albumin were measured by synchron lx20 pro (beckman coulter, inc., ca, usa); pth was measured by access 2 immunoassay (beckman coulter, inc., ca, usa) at the clinical biochemistry laboratory in the royal hospital. frozen samples unprotected from light 14,15 were sent to melbourne pathology, australia for the measurements of 25(oh)d using the liaison assay (diasorin, inc., minnesota, usa). this is a direct competitive chemiluminescent immunoassay for the quantitative measurement of total 25(oh)d. using biostat software, spearman’s rank correlation coefficient was calculated for the correlation between serum 25(oh)d levels; sun exposure and dietary intake.16 results this study investigated vitamin d levels among childbearing omani women and the prevalence of vitamin d deficiency and its relationship to sun exposure, food intake and type of clothing. the mean ± sd of age was 29 ± 6years, 25(oh)d levels were 25 ± 6 nmol/l, vitamin d intake was 9 ± 4 ug/d and sun exposure was 70 ± 60 min/week. in all the subjects (100%), vitamin d levels were <50 nmol/l. the mean serum concentration of 25(oh)d in the subjects was 25nmol/l (results ranged from 12 to 37 nmol/l) in 20 women (49%), 25(oh)d levels were ≥25 nmol/l. in the remaining 21 women (51%) the level was <25 nmol/l. all subjects had vitamin d deficiency which varied from mild, to moderate and even severe deficiency using the recommended cut off <50 nmol/l as a low 25(oh)d.17,18,19 all except one subject had serum pth, serum calcium and phosphate within the reference interval. no significant correlation between serum 25(oh)d levels and calcium levels or serum phosphate level was noted in the subjects investigated. the results of different biochemical bone markers are presented in table 1. the most significant correlation of the 25(oh) d level was with sun exposure, as all the subjects covered their whole body except the face and hands (r = 0.672, p <0.001) compared to the correlation with food intake (r = 0.482, p <0.01). the correlation between 25(oh)d and age was weak and not statistically significant (r = 0.211, p >0.05). sun screen was used by 15 subjects (36%) and was only applied on the face and not on regular basis and no correlation was found between application of sun screen and 25(oh)d levels (r = -0.02, p >0.05). as sun exposure had the strongest correlation, two cut offs were defined for sun exposure time to assess the relation between 25(oh)d and sun exposure time [table 2]. with sun exposure at <60 min/week, the mean 25(oh)d and pth were 27 nmol/l and 4.14 pmol/l respectively, while with sun exposure ≥ 60 min/week, the mean 25(oh) d and pth were 29.5 nmol/l and 2.92 pmol/l respectively. the mean of serum calcium and phosphate was comparable in both subgroups [table 3]. discussion this study reveals that 25(oh)d deficiency is likely to be very common among omani adult women given the prevalence of 100% in the studied group. this may seem an unexpected result as oman is one of the sunniest countries in the world where people would be expected to have adequate sun exposure. although vitamin d deficiency is defined as serum 25(oh)d level <50nmol/l,17,20 an epidemiological survey-based recommended cut-off, this may not necessarily reflect the desirable level among omani table 1: biochemical bone markers in the study group (n = 41) biochemical markers mean ± sd median (range) normal range total calcium (mmol/l) 2.31 ± 0.07 2.31 (2.18-2.43) 2.1-2.6 phosphate (mmol/l) 1.23 ± 0.12 1.26 (0.92-1.57) 0.7-1.4 alp (iu/l) 51.59 ± 13.63 48 (30-98) 30-125 pth (pmol/l) 3.81 ± 2.06 3.6 (1.4-11.7) 1.6-9.3 25(oh)d (nmol/l) 27.61 ± 5.35 28 (19-37)) 75-250 legend: alp = alkaline phosphatase; pth = parathyroid hormone; 25(oh)d = serum 25-hydroxyvitamin d. manal k al-kindi clinical and basic research | 59 women. the low vitamin d level may be due to several factors including direct and indirect avoidance of sunlight exposure due to cultural and social reasons (concern about appearance, unwillingness to change skin colour, the burning effect of the sun, and the risk of hot weather related sickness). most of the women included in the study were working full-time so they were indoors for most of the day -time and, like the majority of omanis, they anyway prefer only to be outdoors after sunset. most of the women included in the study were asymptomatic; they did not suffer from bone pain, myalgia or tiredness and their biochemical markers were within the normal range. it appears that the way people dress is not the only reason for the low vitamin d status. islam et al. for example, showed that woman in bangladesh, regardless of their lifestyle and clothing, were at risk of developing vitamin d deficiency and that both veiled and unveiled women can have vitamin d deficiency.11 in this study, many women were aware about the need for a healthy diet containing high calcium intake and some were also aware of the importance of vitamin d for health. hence, they were trying to compensate for this demand by having adequate calcium and vitamin d intake either by increasing the intake of fish and egg or using fortified food like margarine and milk which they know to be rich in these constituents. however, although in the study the adequate vitamin d intake was defined to be 5ug/day (200 iu/day) for those aged <50 year,17,20 surprisingly only 6 subjects (15%) had less then 5ug/day. the discrepancy may be due to coexisting vitamin d deficiency, malabsorption, overestimation of vitamin d content in the food consumed, (when using the uk and danish tables), lack of information on labels of fortified food and wrong estimations for home cooked foods. the latter could have led to inter-individual variations in estimating vitamin d content for home cooked food. hence, there is a concern about the subjects’ reliability and accuracy in estimating their food intake. although a significant correlation was observed between 25(oh)d and sun exposure, none of the subjects had enough sun exposure. the amount vitamin d produced by the human skin is proportional to the surface area of skin exposure to sunlight. all the subjects were known to be covered (except the face and hands), but at least 15– 20% of body surface needs to be exposed to sun to provide the minimal erythemal dose of ultraviolet light that is sufficient for the first step in vitamin d synthesis (conversion of cholcalciferol from it precursors).17 the amount of sunlight exposure that is needed also varies depending on skin type, time of day, altitude and season. since, for religious and cultural reasons, it is hard for omani women to increase the body surface area that is exposed to sun, they have to increase the time of exposure to sunlight or/and to take vitamin d supplements to avoid the consequences associated with vitamin d deficiency. special consideration is required for pregnant and lactating women in order avoid the perinatal and post-natal complications associated with low maternal vitamin d. conclusion a high prevalence of subclinical vitamin d table 2. biochemical bone markers according to sun exposure biochemical bone markers sun exposure p value ≥60 min/week <60min/week mean±sd median (range) mean median (range) total calcium (mmol/l) 2.32 ± 0.007 2.33 (2.19–2.42) 2.30 ± 0.06 2.30 (2.18−2.43) <0.01 phosphate (mmol/l) 1.20 ± 0.10 1.23 (1.01−1.31) 1.25 ± 0.13 1.26 (0.92−1.57) <0.01 alp (iu/l) 39.18 ± 9.11 48 (38−69) 52.47 ± 14.99 47.5 (30−98) <0.01 pth (pmol/l) 2.92 ± 1.05 2.60 (1.7−4.8) 4.14 ± 2.25 3.7 (1.4−11.7) <0.01 25(oh)d (nmol/l) 28.7 ± 5.33 29.50 (20−37) 27 ± 5.41 27.50 (19−36) <0.01 legend: alp = alkaline phosphatase; pth = parathyroid hormone; 25(oh)d = serum 25-hydroxyvitamin d. vitamin d status in healthy omani women of childbearing age study of female staff at the royal hospital, muscat, oman 60 | squ medical journal, february 2011, volume 11, issue 1 deficiency amongst omani females of childbearing age has been observed in this population. sunlight is major contributor to 25(oh)d levels, but their exposure still appears to be insufficient. if the subjects can not improve their sunlight exposure, they should take oral vitamin d supplements. further studies may be recommended to determine the incidence of osteomalacia and osteoporosis in the omani population and assess vitamin d status in patients with chronic diseases. a c k n o w l e d g e m e n t s the author would like to thank all women who volunteered to take part in this study. she would also like to thank dr ken sikaris (melbourne pathology, australia), dr waad-allah mula-abed (royal hospital, oman), and the staff of the clinical biochemistry laboratories at both melbourne pathology, australia, and the royal hospital, oman. c o n f l i c t o f i n t e r e s t the author reported no conflict of interest. references 1. deluca hf. overview of general physiologic features and functions of vitamin d. am j clin nutr 2004; 80:1689−96s. 2. holick mf. vitamin d deficiency. n eng j med 2007; 357:266−81. 3. bikle d. nonclassical actions of vitamin d. j clin endocrinol metab 2009; 94:26−34. 4. alagöl f, shihadeh y, boztepe h, tanakol r, yarman s, azizlerli h, et al. sunlight exposure and vitamin d deficiency in turkish women. j endocrinol invest 2000; 23:173−7. 5. hashemipour s, larijani b, adibi h, javadi e, sedaghat m, pajouhi m, et al. vitamin d deficiency and causative factors in the population of tehran: bmc public health 2004; 4:38. 6. sedrani sh. low 25-hydroxyvitamin d and normal serum calcium concentration in saudi arabia: riyadh region. ann nutr metab 1984; 28:181−5. 7. fonesca v, tongia r, elhazmi m, abuaisha h. exposure to sunlight and vitamin d deficiency in saudi arabian women: postgrad med 1984; 60:589−91. 8. sedrani sh, elidrissy th, elarabi km. sunlight and vitamin d status in normal saudi subjects. am j clin nutr 1983; 38:129−32. 9. alturki ha, sadatali m, alelq ah, almulhim fa, alali ak. 25-hydroxyvitamin d level among healthy saudi arabian women. saudi med j 2008; 29:1765−8. 10. dawodu a, absood g, patel m, agrawal m, ezimokhai m, abdulrazzaq, et al. biosocial factors affecting vitamin d status of women of childbearing age in the united arab emirates. j biosoc sci 1998; 30:341−7. 11. elsonbaty mr, abdulghaffar nu. vitamin d deficiency in veiled kuwaiti women. eur j clin nutr 1996; 50:315−8. 12. islam mz, akhtaruzzaman m, lamberg-allardt c. hypovitaminosis d is common in both veiled and non-veiled bangladeshi women. asia pac j clin nutr 2006; 15:81−7. 13. meddeb n, sahli h, chahed m, abdelmoula j, feki m, salah h, et al. vitamin d deficiency in tunisia. osteoporos int 2005; 16:180−3. 14. clark s, youngman ld, chukwurah b, palmer a, parish s, peto r, et al. effect of temperature and light on the stability of fat-soluble vitamins in whole blood over several days: implications for epidemiological studies. int j epidemiol 2004; 33:518−25. 15. lissner d, mason rs, posen s. stability of vitamin d metabolites in human blood serum and plasma. clin chem 1981; 27:773−4. 16. kirkwood br, sterne jac. essential medical table 3. biochemical bone markers according to 25 (oh) d levels. data are presented as mean ± standard deviation (median) biochemical bone markers 25(oh)d p value <25 nmol/l ≥ 25 nmol/l total calcium (mmol/l) 2.31 ± 0.06 (2.30) 2.31 ± 0.06 (2.32) <0.01 phosphate (mmol/l) 1.22 ± 0.11 (1.22) 1.24 ± 0.15 (1.28) (0.92−1.57) <0.01 alp (iu/l) 48.2 ± 12.75 (45) 54.15 ± 12.73 (51) <0.01 pth (pmol/l) 4.38 ± 2.52 (4.30) 3.68 ± 1.83 (3.10) <0.01 25(oh)d (nmol/l) 19.47 ± 1.77 (19) 30.35 ± 3.48 (30) <0.01 legend: alp= alkaline phosphatase; pth= parathyroid hormone. manal k al-kindi clinical and basic research | 61 statistics. 2nd ed. oxford: blackwell science, 2003. 17. working group of the australian and new zealand bone and mineral society, endocrine society of australia, osteoporosis australia. vitamin d and adult bone health in australia and new zealand: a position statement. med j aust 2005; 182:281−5. 18. bischoff-ferrari ha, giovannucci e, willett wc, dietrich t, dawson-hughes b. estimation of optimal serum concentrations of 25-hydroxyvitamin d for multiple health. what is the optimal vitamin d status for health? prog biophys mol biol 2006; 92:26−32. 19. bischoff-ferrari ha, giovannucci e, willett wc, dietrich t, dawson-hughes b. estimation of optimal serum concentrations of 25-hydroxyvitamin d for multiple health outcomes. am j clin nutr 2006; 84:18−28. 20. grant wb. benefits and requirements of vitamin d for optimal health: a review. altern med rev 2005; 10:94−104. snakes have always been creatures of myth, intriguing but fascinating, and long associated with good as well as with evil, representing life and death, creation and destruction. however, in modern times with the advent of scientific know-how, one aspect of these captivating creatures has given birth to a research discipline, christened "snake venom research", specifically pertaining to venomous snakes. now, “what is snake venom?” snake venoms are complex mixtures of pharmacologically active polypeptides and proteins, and are therefore veritable gold mines for various drug leads.1 a case in point is captopril, the first venom-based drug, discovered in 1975 from bothrops jaracusa (the brazilian arrowhead viper venom) by nobel prize winner sir john vane and later commercialised by the pharmaceutical giant squibb. captopril is an angiotensinconverting enzyme inhibitor and therefore a potent anti-hypertensive agent.2 at present in the sultanate of oman, there are 9 species of poisonous snakes (see figures 1 and 2 for images of two of the venomous species), but little is known about the venom biochemistry of these enthralling serpents. one of the long term scientific interests of the lead authors of this communication has been to study the biochemistry of venoms in order to identify novel pharmacologically active molecules. in this endeavour, a team has been formed in the department of biochemistry in the college of medicine and health sciences at sultan qaboos university. this group, designated the venom research group, consists of drs. yajnavalka banerjee, professor riad bayoumi, yahya al-tamimi and naseer al-nazwani. mr seyad farook of the university small animal house, who is in charge of the university herpetarium, is also an ardent member of this team. the team aims to obtain insight into the venoms of these 9 species of serpents through diverse proteomic and transcriptomic tools, which will hopefully lead to the identification of drug leads targeting some common squ med j, april 2010, vol. 10, iss. 1, pp. 142-143, epub. 17th apr 10 received 22nd feb 10 هل ميكن أن يكون سم األفعى ُمنقِذا للحياة؟ ياجنافالكا بانريجي، ريا�س بي�مي، �شيد فاروق could deadly snake venom save lives? *yajnavalka banerjee,1 riad bayoumi1 and seyad ms farook2 letter to editor 1department of biochemistry and 2small animal house, college of medicine & health sciences, sultan qaboos university, muscat, oman * to whom correspondence should be addressed. email: yaj@squ.edu.om figure 1: atractaspis micropholis andersoni, commonly known as the mole viper, found in oman and southwestern saudi arabia. the average size of an adult snake is about 45 cm, with some growing up to 75 cm. figure 2: echis carinatus, commonly known as the saw scaled viper, found not only in oman and the middle east, but also in the indian sub-continent and central asia. size ranges between 38 and 80 cm in length, but usually no more than 60 cm yajnavalka banerjee, riad bayoumi and seyad ms farook letter to editor | 143 human diseases. additional goals of the group include mapping the geographical distribution of these species as well as studying the evolution of these snakes. researchers from the ministry of defense, under the supervision of dr yahya al-rashdi, will also participate in this project. scientists from saudi arabia and ministry of health in oman have also expressed their keenness to contribute towards this endeavour. in line with the enthusiasm expressed by researchers and clinicians, and in order to establish a more holistic group of researchers a workshop was organised on the 31st of march 2010 under the theme of “initiatives into snake venom research”, which aimed at informing the scientific community and the general public about the immediate and long term goals of this project. in summary, we sincerely believe that the above project provides the revelation that “deadly snake venom does have the potential to save life”. references 1. calvete jj, juarez p, sanz l. snake venomics. strategy and applications. j mass spectrom 2007; 42:1405–14. 2. aurell m, rudin a, tisell le, kindblom lg, sandberg g. captopril effect on hypertension in patient with renin-producing tumour. lancet 1979; 2:149-150. departments of 1general surgery and 2urology, ibb university of medical sciences, ibb, yemen; 3department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran *corresponding author’s e-mail: fmaaa2006@yahoo.com hydatid disease of the liver presenting as spontaneous cutaneous fistula a case report saif ghabisha,1 *faisal ahmed,2 saleh al-wageeh,1 ebrahim al-shami,2 khalil al-naggar,2 mohammad r. askarpour,3 ali eslahi3 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 583–586, epub. 7 nov 22 submitted 28 mar 21 revisions req. 7 apr & 2 jun 21; revisions recd. 15 apr & 14 jun 21 accepted 12 jul 21 of chronic illness; however, it was noted that the patient had livestock (a sheep) living with her in her house in a village. upon physical examination, a mass in her right hypochondrium was found, which was tender during palpation. a 10–15 mm skin-opening was also noticed in this area, with a whitish membranous structure and fluid discharge [figure 1]. laboratory tests showed a leukocyte count of 19,000/mm3 with mild eosinophilia, an erythrocyte sedimentation rate of 100 mm/h, a haemoglobin level of 12 g/dl, total bilirubin of 2.1 mg/dl and direct bilirubin of 1.1 mg/ dl; other liver/kidney function tests were normal. echinococcus latex haemagglutination test and indirect haemagglutination (iha) test were positive. abdominal computed tomography (ct) scan revealed a 6 × 9 cm irregular hypodense mass in the right lobe of the liver with some calcific areas in favour of the diagnosis of hepatic hc [figure 2]. in support of this diagnosis, diffuse inflammatory changes were detected around the trajectory of the fistula from the abdominal cyst toward the skin. given all findings, the patient was hospitalised based on the differential diagnosis of infected hepatic hc with fistualisation. she underwent a laparotomy which revealed multiple cysts in the remnants of the right hepatic lobe, inflammatory changes in the abdominal wall and a fistula opening to the skin. before dissecting the cyst, hypertonic saline (nacl: 20%) was used to wash the abdominal cavity and fistula tract to prevent any potential infection caused by contamination. all residual tissues involved in the right lobe of the liver hydatid cyst (hc) is a serious zoonotic disease and a substantial health risk in endemic areas. the larval stage of the echinococcus tapeworm causes the infection.1 dogs are the primary host of this worm and sheep and cattle act as the intermediate hosts. humans are accidental intermediate hosts in the parasite’s dog-sheep life cycle.2,3 the most common primary infection site is the hepatobiliary system; hc can remain asymptomatic in the liver for a long period of time. most early cyst detections are caused by complications of fistula formation, which are rare manifestations.4 few adult cases of spontaneous cutaneous fistula formation due to hc disease have been reported.2,5,6 this case report describes a case of an adult with an infected cutaneous fistula induced by a ruptured hc. in addition, the purpose of this report is to encourage physicians to consider this diagnosis when a patient presents with an unusual cutaneous fistula near the organs commonly involved in hc disease, especially in endemic areas. case report a 63-year-old female patient was admitted to a tertiary care hospital in ibb, yemen, in 2019 with chronic right-upper quadrant abdominal pain, which started one year ago, and a recent small skin opening located in the right eighth intercostal space medial to the anterior axillary line. she also had complaints of nausea, vomiting and fever. the patient had no history this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.116 case report abstract: hydatid cyst (hc) disease is a parasitic infection produced by cysts containing the echinococcus granulosus larval phase. patients with hc disease are typically asymptomatic until incidentally diagnosed or when complications occur. a rare presentation of liver hc is spontaneous cutaneous fistualisation. we report a 63-year-old female patient admitted in a tertiary care hospital in ibb, yemen, in 2019 with an infected cutaneous fistula induced by a ruptured hc. the patient underwent laparotomy and partial cystectomy with excision of the fistula tract. upon 6-month follow-up, there was no hc recurrence. this report highlights the need for physicians to consider this diagnosis when faced with an unusual cutaneous fistula near organs commonly involved in hc, especially in areas where the prevalence of this disease is high. keywords: complications; cutaneous fistula; echinococcosis; liver; surgery; case report; yemen. https://creativecommons.org/licenses/by-nd/4.0/ hydatid disease of the liver presenting as spontaneous cutaneous fistula a case report 584 | squ medical journal, november 2022, volume 22, issue 4 and the cyst attached to the abdominal wall plus the fistula tract were excised [figure 3]. some calcification areas were observed in the cyst wall; the cyst consisted of heterogeneous degenerative contents along with numerous small daughter cysts evenly distributed in the fistula tract. intraoperative cystic fluid examination showed protoscolices. finally, a foley catheter 24 fr drain was inserted in the peritoneal cavity near the liver and the abdominal wall was reconstructed. histopathological report of the specimen revealed a laminated cyst with many scolices with a double layer of hooklets, which is a classic presentation of echinococcus granulosus infection. the patient had a normal post-operative course and was discharged on the 5th post-operative day on albendazole (6 mg/ kg every twelve hours for four weeks) and ceftriaxone (1 g every twelve hours for one week). a follow-up abdominal ct scan, six-months post-operatively, demonstrated the absence of recurrence. written informed consent was obtained from the patient for publication purposes and this report was approved by the local ethics committee. discussion hc disease is a common disease in agricultural communities, including middle eastern countries. cysts can rupture internally, which contaminates the biliary tract, gastrointestinal tract or the peritoneal cavity, or externally, leading to cutaneous fistulisation but this is a rare phenomenon.6 for cutaneous fistulisation to occur, the cyst must protrude into the intramuscular abdominal wall, contaminate the subcutaneous soft tissue and make a path to the surface of the skin, forming a fistula as was observed in the current patient.7 clinical suspicion of such rare complications in endemic areas is essential for proper diagnosis when followed by proper radiological and serological investigations.8 in humans, the symptomatic phase follows an early asymptomatic infection. types and severity of symptoms vary based on the numbers, size and location of the cyst and its pressure effect on the adjacent organs. for example, a non-complicated hc of the liver affects the liver locally, leading to hepatomegaly while putting pressure on the surrounding tissues to produce jaundice or abdominal pain symptoms.2 the overlying skin in patients with cutaneous fistulisation of hc is usually normal in appearance but rarely erythematous.9 the sign and symptoms of hepatic hc are not specific and they may appear in a wide range of hepatic diseases. the most common symptom is pain in the right upper quadrant or epigastric region, whereas the most frequent signs are hepatomegaly and a palpable mass. additionally, radiological imaging methods may fail to show the direct communication between a hepatic cyst and the biliary system if hepatic hc is associated with a small fistula. when serological test results (including enzyme-linked immunosorbent assay, iha test and immunoelectrophoresis) are combined with imaging findings, hydatidosis can successfully be diagnosed in 90% of cases.10 cyst rupture into the abdominal cavity is an uncommon complication of hc disease. the amount of leaked material can introduce a wide range of allergic reactions from urticaria to life-threatening anaphylactic shock. other complications include cyst communication with the biliary tree and secondary echinococcosis or symptoms caused by compression effects of the cyst on the biliary system.4 figure 1: photograph of the abdomen of a 63-yearold female patient showing a whitish membranous structure protruding out from the opening of a fistula (arrow). figure 2: an abdominal computed tomography scan of a 63-year-old female patient showing the (a) axial and (b) corneal views of a calcified hydatid cyst in the right lobe of the liver (arrow). figure 3: intraoperative photograph showing the fistulous tract during excision (arrow). saif ghabisha, faisal ahmed, saleh al-wageeh, ebrahim al-shami, khalil al-naggar, mohammad r. askarpour and ali eslahi case series | 585 according to gharbi classification, the current patient had a type v cyst, defined as typically inactive cysts with membrane calcification in imaging;11 however, on rare occasions, abscess formation within the calcified cyst cavity and occult abdominal trauma can lead to cutaneous fistula as was observed in the current patient.1,5,6 in the medical literature, one study reported a patient with hc cutaneous fistula accompanied by rib erosion.8 typically, cysts in the right lobe of the liver invade the right lateral abdominal wall, while those in the left lobe invade the anterior abdominal wall.8 haematogenous metastasis is an unusual cause of subcutaneous hc and this manifestation is mostly caused by a primary invasion of hepatic echinococcosis or contamination during previous surgery.12 due to the rarity of hc and lack of prospective studies, there is no consensus on the gold-standard treatment modality. treatment options include medical management, minimally invasive procedures and invasive surgery. for minimally invasive procedures, cysts may be aspirated percutaneously, instillated and reaspirated. in contrast, surgical options include deroofing, pericystectomy and hepatic resection.5,13 the current patient had a complicated right-lobe liver hc, which caused a left-lobe hypertrophy and, by intruding into the abdominal wall, led to abdominal wall injuries and cutaneous fistula formation. for this patient, a right-lobe hepatectomy was carried out, the fistula tract was excised and the abdominal wall was reconstructed. radical surgical approaches include lobectomy, segmentectomy and pericystectomy. adjuvant therapy is not required before these procedures. other conservative surgical approaches are considered less suitable to prevent disease recurrence compared to radical approaches despite having lower morbidities.6 however, if conservative surgical approaches such as cystotomy and partial cystectomy are chosen in complicated cases, it is suggested that the cystic cavity should be evacuated and the patient should receive benzimidazole treatment for 4–12 weeks to reduce the cyst size. this was not done in the current case as the patient's income was low and she could not afford it. after resecting the skin and fistula during surgery, if fascial defects are observed in the abdominal or thoracic wall, they can be closed primarily. even in cases of larger defects, the surgeon can use synthetic graft materials.14 in case of superinfections or abscess formation, specific antibiotics should be administered after drainage.15 in the current case, no culture test was done, therefore, the patient was discharged with empirical antibiotic therapy. conclusion a cutaneous fistula, as a presentation of a ruptured hc, is extremely rare. when drainage from the fistula does not contain the cyst material, clinical diagnosis becomes extremely difficult. raising awareness around different hc complications, suggesting proper imaging modalities and serological tests are vital for accurate diagnosis of hc, especially in endemic areas. a u t h o r s’ c o n t r i b u t i o n s all authors contributed to data analysis, drafting and revising the article. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t s the authors would like to thank shiraz university of medical sciences, shiraz, iran, as well as the center for development of clinical research of nemazee hospital and dr. nasrin shokrpour for their editorial assistance. references 1. kjossev kt, teodosiev il. cutaneous fistula of liver echinococcal cyst previously misdiagnosed as fistulizated rib osteomyelitis. trop parasitol 2013; 3:161–5. https://doi.org/10.4103/22295070.122150. 2. akay s, erkan n, yildirim m, akay h. development of a cutaneous fistula following hepatic cystic echinococcosis. springerplus 2015; 4:538. https://doi.org/10.1186/s40064-015-1327-6. 3. ghabisha s, ahmed f, al-wageeh s, al-shami e, al-naggar k, chowdhury u, et al. isolated giant primary splenic hydatid cyst in a 10-year-old boy: a case report. pediatric health med ther 2021; 12:55–9. https://doi.org/10.2147/phmt.s295280. 4. sayek i, tirnaksiz mb, dogan r. cystic hydatid disease: current trends in diagnosis and management. surg today 2004; 34:987–6. https://doi.org/10.1007/s00595-004-2830-5. 5. cicero g, blandino a, ascenti g, d'angelo t, frosina l, visalli c, et al. superinfection of a dead hepatic echinococcal cyst with a cutaneous fistulization. case rep radiol 2017; 2017:9393462. https://doi.org/10.1155/2017/9393462. 6. akbulut s. parietal complication of the hydatid disease: compre hensive literature review. medicine (baltimore) 2018; 97:e10671. https://doi.org/10.1097/md.0000000000010671. 7. brunetti e, kern p, vuitton da; writing panel for the whoiwge. expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. acta trop 2010; 114:1–16. https://doi.org/10.1016/j.actatropica.2009.11.001. 8. salerno s, cracolici e, lo casto a. subcutaneous rupture of hepatic hydatid cyst: ct findings. dig liver dis 2006; 38:619–20. https://doi.org/10.1016/j.dld.2006.02.018. 9. kayaalp c, dirican a, aydin c. primary subcutaneous hydatid cysts: a review of 22 cases. int j surg 2011; 9:117–21. https:// doi.org/10.1016/j.ijsu.2010.10.009. 10. aggarwal a, sharma v. primary splenic hydatidosis in a 25-year old man: a case report. cases j 2009; 2:8017. https://doi.org/10.4 076/1757-1626-2-8017. https://doi.org/10.4103/2229-5070.122150 https://doi.org/10.4103/2229-5070.122150 https://doi.org/10.1186/s40064-015-1327-6 https://doi.org/10.2147/phmt.s295280 https://doi.org/10.1007/s00595-004-2830-5 https://doi.org/10.1155/2017/9393462 https://doi.org/10.1097/md.0000000000010671. https://doi.org/10.1016/j.actatropica.2009.11.001 https://doi.org/10.1016/j.dld.2006.02.018 https://doi.org/10.4076/1757-1626-2-8017 https://doi.org/10.4076/1757-1626-2-8017 hydatid disease of the liver presenting as spontaneous cutaneous fistula a case report 586 | squ medical journal, november 2022, volume 22, issue 4 11. lewall db, mccorkell sj. rupture of echinococcal cysts: diagnosis, classification, and clinical implications. ajr am j roentgenol 1986; 146:391–4. https://doi.org/10.2214/ajr.146.2.391. 12. ambo m, adachi k, ohkawara a. postoperative alveolar hydatid disease with cutaneous-subcutaneous involvement. j dermatol 1999; 26:343–7. https://doi.org/10.1111/j.1346-8138.1999.tb03485.x. 13. bahce zs, akbulut s, aday u, demircan f, senol a. cutaneous fistulization of the hydatid disease: a prisma-compliant syst ematic review. medicine (baltimore) 2016; 95:e4889. https:// doi.org/10.1097/md.0000000000004889. 14. korwar v, subhas g, gaddikeri p, shivaswamy bs. hydatid disease presenting as cutaneous fistula: review of a rare clinical presentation. int surg 2011; 96:69–73. https://doi.org/10.9738/ 1364.1. 15. jayant k, agrawal s, agarwal r, dayama kg. spontaneous external fistula: the rarest presentation of hydatid cyst. bmj case rep 2014; 2014:bcr2014203784. https://doi.org/10.1136/ bcr-2014-203784. https://doi.org/10.2214/ajr.146.2.391 https://doi.org/10.1111/j.1346-8138.1999.tb03485.x https://doi.org/10.1097/md.0000000000004889 https://doi.org/10.1097/md.0000000000004889 https://doi.org/10.9738/1364.1 https://doi.org/10.9738/1364.1 https://doi.org/10.1136/bcr-2014-203784 https://doi.org/10.1136/bcr-2014-203784 july 2008.indd sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 231-232 sultan qaboos university© submitted 12th november 2007 accepted 3rd march 2008 tracheal bronchus *anupam k kakaria,1 sukhpal sawhney,1 rajeev jain2 the patient is a young female who presented at sultan qaboos university hos-pital, oman, with symmetrical joint pains, erythema nodosum and episcleritis. she was suspected to have sarcoidosis and a computed tomography (ct) chest scan was performed to look for mediastinal lymphadenopathy. the mediastinum showed evidence of enlarged lymph nodes. incidentally detected was a bronchus arising from the trachea a short distance before the carina. the tracheal bronchus is seen to arise from the right posterior wall of the trachea [figures 1-3]. the tracheal bronchus maybe supernumerary if the right upper lobe trifurcates and supplies the upper lobe normally and the accessory bronchus supplies an extra segment of right upper lobe. if the right upper lobe bronchus bifurcates into two, the accessory bronchus usually supplies the apical segment of the right upper lobe and it is a displaced bronchus.1 in our case, the right upper lobe bronchus shows a bifurcation [figure 3] suggesting this is a case of a displaced right apical bronchus. figure 4 shows a virtual bronchoscopic reconstruction. the anomaly is a rare entity with a reported inيَّة الرُّغامِ بَةُ صَ القَ جني راجيف كاكاريا، سخبال سوهني، انوبام i n t e r e s t i n g m e d i c a l i m a g e 1department of radiology, sultan qaboos university hospital, sultan qaboos university. muscat, sultanate of oman; 2department of radiology, college of medicine and health sciences, sultan qaboos university. muscat, sultanate of oman *to whom correspondence should be addressed. email: bittanupam@yahoo.com figure 1 and 2: images in mediastinal and lung windows of the computed tomography scan show an accessory bronchus arising from the right posterior wall of the trachea (arrow on figure 1). also noted are enlarged lymphnodes a n u pa m k k a k a r i a , s u k h pa l s aw h n e y a n d r a j e e v j a i n 232 cidence of 0.1-3%.² most of the tracheal bronchi are asymptomatic; however, some children with tracheal bronchus may suffer from stridor, recurrent infections and respiratory distress. in adults, this condition may be associated with difficulties in intubation and ventilation during anaesthesia. accidental intubation of the tracheal bronchus may lead to inadequate ventilation of the rest of the lung. it may also cause overinflation of the lobe supplied by the tracheal bronchus and pneumothorax. accidental occlusion of the tracheal bronchus by the endotracheal tube can lead to atelectasis of the involved lobe. if patient is aware of this condition, the anaesthesiologist should be alerted prior to any elective surgery to allow precautions to be taken. r e f e r e n c e s 1. naim ya, eduardo v, lawrence ak, edwin et. tracheal bronchus. respir care 2004; 9:1056-1058. 2. baris b, ege t. tracheal bronchus. n engl j med 2007; 357:17. figure 3: the bifurcation of the right upper lobe bronchus (arrow) figure 4: virtual bronchoscopic reconstruction viewed from above shows carina (black arrow) and the accessory bronchus arising from the right posterior wall (white arrow) departments of 1pathology, 2medicine, 3surgery and 4radiology & molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asimqureshi32@hotmail.com ورم كيس حمي أويل يف املعدة عا�شم قر�شي، من�شور املنذري، مها الشعيبية، اإبراهيم الهدابي، الوك ميتال abstract: primary gastric yolk tumours are extremely rare. we report a 52-year-old male who presented to the sultan qaboos university hospital, muscat, oman, in 2017 after having undergone a gastrectomy abroad due to a suspected poorly-differentiated adenocarcinoma. the patient subsequently returned to oman to receive chemotherapy. however, while undergoing chemotherapy, an abdominal computed tomography scan revealed a lobulated mesenteric mass. microscopic examination of the resected lesion confirmed a diagnosis of a yolk sac tumour. the mass was diffusely positive for α-fetoprotein (afp) and a gastric carcinoma stain was negative. gastrectomy slides from the patient’s previous surgery were examined retrospectively. the morphology was typical for a yolk sac tumour and was negative for epithelial markers. an afp stain showed diffuse immunoreactivity. thus, the patient was deemed to have had a primary gastric yolk sac tumour which had later metastasised to the mesocolon. germ cell tumour protocols were initiated and the patient responded well to treatment. keywords: yolk sac tumor; germ cell tumor; gastrectomy; metastasis; diagnostic errors; case report; oman. امللخ�ص: يعد وجود ورم كي�ص حمي ابتدائي يف املعدة اأمرا نادر احلدوث جدا. ونعر�ص هنا حالة رجل يف الثانية واخلم�شني من العمر اأتى مل�شت�شفى جامعة ال�شلطان قابو�ص يف عام 2017 بعد اأن كان قد اأجرى عملية جراحية ل�شتئ�شال املعدة خارج ال�شلطنة ل�شتباه يف وجود �رسطانة ُغدية ع�شري التمايز، وعاد لعمان لحقا ملوا�شلة العالج الكيمائي. واإبان خ�شوعه لذلك العالج لوحظ عن طريق امل�شح املقطعي املحو�شب وجود ورم م�شاريقي مف�ش�ص يف البطن. وثبت بفح�ص ذلك الورم جمهريا اأنه ورم كي�ص حمي. وكان ذلك الورم اإيجابيا لربوتني األفا اجلنيني، بينما كان �شالبا بالن�شبة ل�شبغة ال�رسطانة املعدية. ومت ا�شتعاديا فح�ص ال�رسائح التي عملت من املعدة امل�شتاأ�شلة جراحيا، واأثبت الفح�ص اأن لها �شكال منوذجيا مطابقا لورم كي�ص حمي، وكانت �شالبة بالن�شبة للموؤ�رسات الظهارية. واأظهرت �شبغة بروتني األفا اجلنيني تفاعلية مناعية منت�رسة. وبناًء على تلك النتائج خل�شنا اإىل اأن هذا املري�ص م�شاب بورم كي�ص حمي ابتدائي يف املعدة انتقل اإىل م�شاريق القولون. وبداأنا يف عالج املري�ص وفقا للربتوكولت املتبعة يف عالج اأورام اخلاليا اجلن�شية، وا�شتجاب املري�ص للعالج ب�شورة جيدة. الكلمات املفتاحية: ورم كي�ص حمي؛ورم خلية جن�شية؛ ا�شتئ�شال املعدة؛ نقيلة؛ اأخطاء ت�شخي�شية؛ تقرير حالة؛ عمان. primary gastric yolk sac tumour *asim qureshi,1 mansour al-moundhri,2 maha al-shaibi,3 ibrahim al-haddabi,1 alok mittal4 online case report sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e383–385, epub. 19 dec 18 submitted 21 jan 18 revisions req. 8 feb & 5 mar 18; revisions recd. 8 feb & 2 apr 18 accepted 12 apr 18 doi: 10.18295/squmj.2018.18.03.020 while most germ cell tumours occur in the gonads, less common sites include the retroperitoneum, mediastinum and coccygeal region.1–4 primary visceral germ cell tumours are exceed ingly rare, with even fewer cases of primary gastric germ cell tumours.2,5 to the best of the authors’ knowledge, this is the first case reported from oman. case report a 52-year-old male presented to the oncology clinic of the sultan qaboos university hospital, muscat, oman, in 2017. he had been diagnosed with stage iiib gastric cancer in another country in 2016. at that time, contrastenhanced axial and coronal computed tomography (ct) scans taken at the level of the stomach showed a circumf erential irregular enhanced wall thickening of the antro pyloric region of the stomach, with mild luminal narrowing [figure 1]. the patient underwent an open distal gastrectomy, omentectomy and lymph node dissection. the histo pathology results were reported to indicate a poorlydifferentiated adenocarcinoma involving the body and antrum of the stomach, with four out of six lymph nodes positive for metastatic carcinoma. the final diagnosis was of a poorly-differentiated adenocarcinoma (pt4an3a). he was therefore advised to undergo six cycles of chemo therapy. after beginning chemotherapy abroad, the patient travelled back to oman and presented to the sultan qaboos university hospital where treatment was compl eted over the following six months. endoscopies and ct scans performed at regular intervals showed no signs of disease recurrence and the patient remained asympt omatic during this period. however, 16 months after the initial diagnosis, follow-up axial and sagittal contrastenhanced ct scans of the abdomen revealed a large heterogeneously-enhancing soft tissue nodule in the transverse mesocolon [figure 2]. there was no evidence of any other disease sites in the chest or abdomen. the mesenteric mass was biopsied under imaging guidance. a microscopic examination showed an infilt rating malignant epithelial tumour consistent with a primary gastric yolk sac tumour e384 | squ medical journal, august 2018, volume 18, issue 8 poorly-differentiated carcinoma. however, a definite diagnosis could not be made due to the poor quality of the material and the lack of tissue available for immunohistochemical analysis. as there was no evidence of disease elsewhere in the body, the decision was made to remove the mass since it was highly unlikely to be a metastasis from a primary tumour. the patient under went an explorative diagnostic laparoscopy and removal of the mass. during the procedure, the mass measured 8 × 5 cm, appeared well-circumscribed and encapsulated and was located in the right upper quadrant of the abdomen. it was densely adherent to the right lateral abdominal wall. the capsule of the mass was kept intact throughout the procedure and easily removed via a small midline laparotomy incision. following the procedure, the patient recovered well and was discharged without any complications on the third postoperative day. histological sections of the mass revealed tumour cells arranged in a loose reticular meshwork around blood vessels, forming schiller-duval bodies [figure 3a]. in some areas, the tumour cells were arranged in papillary structures. there was diffuse immunohistochemical positivity for α-fetoprotein (afp) [figure 3b]. in addition, cytokeratin (ck) ae1/ae3, epith elial membrane antigen and cluster of differentiation (cd)10 stains were positive, whereas ck7, ck20, cd56, caudal type homeobox 2, cyclin d1, thyroid transcription factor 1, hepatocyte paraffin 1, renal cell carcinoma and melanoma antigen 1 stains were negative. the final histopathological diagnosis was of a metastatic yolk sac tumour. in light of this, the histo pathology slides from the initial gastrectomy procedure were reviewed retrospectively. sections of the gastric mass showed classic schiller-duval bodies [figure 4a]. figure 1: contrast-enhanced (a) axial and (b) coronal computed tomography scans of a 52-year-old male taken at the level of the stomach showing circumferential irregular enhanced wall thickening (arrows) of the antropyloric region of the stomach, with mild luminal narrowing. figure 2: follow-up (a) axial and (b) sagittal contrast-enhanced computed tomography scans of the abdomen of a 52-yearold male showing a large heterogeneously-enhancing soft tissue nodule (arrows) in the transverse mesocolon. figure 3: a: haematoxylin and eosin stain at x20 magnif ication of a mesenteric mass showing tumour cells arranged around a blood vessel and forming schiller-duval bodies. b: immunohistochemistry stain at x10 magnification showing diffuse positivity for α-fetoprotein. figure 4: a: haematoxylin and eosin stain at x10 magnif ication of a gastrectomy sample showing classic schillerduval bodies. b: immunohistochemistry stain at x10 magnification showing diffuse α-fetoprotein positivity. asim qureshi, mansour al-moundhri, maha al-shaibi, ibrahim al-haddabi and alok mittal online case report | e385 the successful long-term survival of a patient with a yolk sac tumour after radiotherapy.12 in general, a multidisciplinary approach is important when treating malignancies at any tertiary care centre. conclusion primary gastric yolk sac tumours are extremely rare. an occult primary tumour in the gonads should be excluded radiologically before confirming a diagnosis. furthermore, immunohistochemical analysis is vital, particularly with regards to afp positivity. references 1. horwich a, nicol d, huddart r. testicular germ cell tumours. bmj 2013; 347:f5526. doi: 10.1136/bmj.f5526. 2. guo yl, zhang yl, zhu jq. primary yolk sac tumor of the retroperitoneum: a case report and review of the literature. oncol lett 2014; 8:556–60. doi: 10.3892/ol.2014.2162. 3. uematsu m, yokouchi h, tanino y, munakata m. renin-producing germ cell tumor in the pineal apparatus and mediastinum: a rare case report. j cancer res ther 2018; 14:s806–8. doi: 10.41 03/0973-1482.180682. 4. büyükpamukçu m, varan a, küpeli s, ekinci s, yalcin s, kale g, et al. malignant sacrococcygeal germ cell tumors in children: a 30-year experience from a single institution. tumori 2013; 99:51–6. doi: 10.1700/1248.13788. 5. magni e, sonzogni a, zampino mg. primary pure gastric yolk sac tumor. rare tumors 2010; 2:e10. doi: 10.4081/rt.2010.e10. 6. suzuki t, kimura n, shizawa s, yabuki n, yamaki t, sasano h, et al. yolk sac tumor of the stomach with an adenocarcinomatous component: a case report with immunohistochemical analysis. pathol int 1999; 49:557–62. doi: 10.1046/j.1440-1827.1999.00907.x. 7. satake n, chikakiyo m, yagi t, suzuki y, hirose t. gastric cancer with choriocarcinoma and yolk sac tumor components: case report. pathol int 2011; 61:156–60. doi: 10.1111/j.1440-1827.20 10.02635.x. 8. geng hl, shi ss. [clinicopathologic characteristics of primary gastric choriocarcinoma: report of a case]. zhonghua bing li xue za zhi 2017; 46:571–2. doi: 10.3760/cma.j.issn.0529-5807. 2017.08.012. 9. napaki s. combined yolk sac tumour and adenocarcinoma of the oesophago-gastric junction. pathology 2004; 36:589–92. doi: 10.1080/00313020400011003. 10. wang l, tabbarah hj, gulati p, rice s, french sw. gastric adenocarcinoma with a yolk sac component: a case report and review of the literature. j clin gastroenterol 2000; 31:85–8. 11. garcia rl, ghali vs. gastric choriocarcinoma and yolk sac tumor in a man: observations about its possible origin. hum pathol 1985; 16:955–8. doi: 10.1016/s0046-8177(85)80137-4. 12. sakaguchi m, maebayashi t, aizawa t, ishibashi n, fukushima s, saito t. successful radiotherapy in postoperative recurrence of a primary mediastinal yolk sac tumor: a case report. thorac cancer 2016; 7:358–62. doi: 10.1111/1759-7714.12302. in addition, there was diffuse afp positivity [figure 4b]. both the morphology of the cells and immunohistochemistry results were compatible with a yolk sac tumour. based on these findings, it was advised that the patient undergo a ct brain scan and an ultrasound examination of the testes, both of which were normal. serum levels of other tumour markers, including lactate dehydrogenase, afp and β-human chorionic gonadotropin, were normal. the final diagnosis was of a primary yolk sac tumour of the stomach with metastatic disease to the mesentery. four cycles of etoposide and cisplatin were recommended as treatment. at the time of writing, the patient was receiving chemotherapy and doing well. discussion yolk sac tumours are a type of primary gonadal malignancy; however, presentation as a primary gastric tumour is extremely rare. to the best of the authors’ knowledge, only a few cases have been reported in the literature.2,5 the current case represented a diagnostic dilemma as the patient was initially diagnosed elsewhere with a poorly-differentiated adenocarcinoma and under went an open distal gastrectomy. however, a mesenteric mass was subsequently found which showed typical morphological characteristics of a yolk sac tumour, with no evidence of disease elsewhere in the body. a retrospective review of the histology slides of the materials from the previous surgery confirmed the diagnosis of a gastric yolk sac tumour which had metastasised to the transverse mesocolon. certain gastric carcinomas may demonstrate a morphology similar to that of yolk sac tumours.6 in these circumstances, the role of immunohistochemistry is crucial. gastric carcinomas are ck7-positive and afpnegative, while the reverse is true for yolk sac tumours.7 geng et al. reported a case of an abdominal metastatic germ cell tumour with an unknown primary source.8 in such cases, it is important to exclude a primary tumour of the gonads, as was done in the present case. the role of radiology is very important to help localise the primary site of a yolk sac tumour.9,10 there may be an occult primary tumour in the testes with metastatic disease in the stomach and peritoneum.11 although the role of radiation in treating the recurrence of primary mediastinal germ cell tumours is well established, little information is available regarding primary gastric yolk sac tumours. despite recurrence after surgery and chemotherapy, sakaguchi et al. reported https://doi.org/10.1136/bmj.f5526 https://doi.org/10.3892/ol.2014.2162 https://doi.org/10.4103/0973-1482.180682 https://doi.org/10.4103/0973-1482.180682 https://doi.org/10.1700/1248.13788 https://doi.org/10.4081/rt.2010.e10 https://doi.org/10.1046/j.1440-1827.1999.00907.x https://doi.org/10.1111/j.1440-1827.2010.02635.x https://doi.org/10.1111/j.1440-1827.2010.02635.x https://doi.org/10.3760/cma.j.issn.0529-5807.2017.08.012 https://doi.org/10.3760/cma.j.issn.0529-5807.2017.08.012 https://doi.org/10.1080/00313020400011003 https://doi.org/10.1016/s0046-8177%2885%2980137-4 https://doi.org/10.1111/1759-7714.12302 1department of biological sciences, taraba state university, jalingo, taraba state, nigeria; 2department of biological sciences, faculty of pure & applied sciences, federal university wukari, taraba state, nigeria; 3paediatrics unit, federal medical centre, jalingo, taraba state, nigeria; 4department of biological sciences, university of agriculture, makurdi, benue state, nigeria; 5department of biological sciences, federal university of kachere, kashere, gombe state, nigeria *corresponding author’s e-mail: rs.houmsou@tsuniversity.edu.ng فعالية عالية لدواء برازيكوانتيل يف أطفال مصابني بطفيل البلهارسية الدموية يف والية ترابا بنيجرييا دراسة متابعة روبرت هم�شو، بنجا واما، هيمن اأقري، جون يونقا، أليزابيث اأموتا، �شانتايا كيال abstract: objectives: this study aimed to assess the efficacy of praziquantel in reducing urinary schistosomiasis prevalence, parasite burden and morbidity rates among a previously reported sample of schistosoma haematobiuminfected children. in addition, predisposing factors for reinfection one year post-treatment were also determined. methods: this prospective follow-up study was conducted between march 2014 and february 2015 among 675 previously reported children with urinary schistosomiasis in the murbai and surbai communities of ardo kola, taraba state, nigeria. a single dose of 40 mg/kg of praziquantel was administered to each infected child, with a second dose administered one month later if necessary. the number of s. haematobium eggs in urine samples was calculated at baseline and post-treatment. results: at four weeks post-treatment, the overall cure rate was 98.1%. among children with low and heavy parasite burdens at baseline, egg reduction rates (errs) were 100% and 96.5%, respectively. the vast majority of children with microhaematuria (98.7%) and proteinuria (98.6%) at baseline were cured at follow-up. following a second dose, the err, overall and morbidity cure rates increased to 100%. at one year post-treatment, 272 infected children (40.3%) were re-assessed; of these, 51 children (18.8%) were reinfected. close proximity to bodies of water (odds ratio [or] = 1.23, 95% confidence interval [ci]: 0.998–1.530; p = 0.05) and fishing (or = 2.23, 95% ci: 0.828–6.040; p = 0.01) were significant factors that predisposed children to reinfection. conclusion: a moderate rate of reinfection was noted. governmental and nongovernmental organisations in nigeria should collaborate on mass treatment and health education campaigns to reduce the incidence of urinary schistosomiasis reinfections. keywords: urinary schistosomiasis; praziquantel; treatment outcome; follow-up study; nigeria. )اأعداد الطفيلي والعبء البويل، البلهار�شيا داء انت�شار تقليل يف برازيكوانتيل دواء فعالية لتقومي الدرا�شة هذه هدفت الهدف: امللخ�ص: لذلك بالإ�شافة ومتت درا�شتهم. �شبقت الذين الدموية البلهار�شية بطفيل امل�شابني الأطفال من عينات يف املرا�شة ومعدلت الطفيل(، درا�شة العوامل املوؤهبة لالإ�شابة جمددا بذات الطفيل بعد مرور عام على العالج بهذا الدواء. الطريقة: اأجريت درا�شة املتابعة امُل�شبقة هذه بني مار�ص 2014 وفرباير 2015م على 675 اأطفال م�شابني بطفيل البلهار�شية الدموية �شبقت درا�شتهم يف جمتمعي مورباي و�شورابي يف اأردي كول بولية ترابا بنيجرييا. ومت اإعطاء كل طفل م�شاب جرعة واحدة من دواء برازيكوانتيل قدرها 40 جمم/كجم، وبعد �شهر واحد متو�شط بلغ النتائج: وبعده. العالج بدء قبل الأطفال بول يف الطفيل بي�ص ح�شاب ومت الأمر. ا�شتلزم اإن لالأطفال اجلرعة نف�ص اأعطيت ن�شبة جناح العالج يف كل الأطفال %98.1. وبلغت معدلت النخفا�ص يف اأعداد البي�ص %100 و %96.5 عند الأطفال الذين كان لديهم عبء طفيلي منخف�ص واآخر مرتفع، على التوايل. و�ُشفي غالب الأطفال الذين كانت لديهم قبل العالج بيلة دموية )%98.7( وبيلة بروتينية )%98.6( بعد مرور عام على العالج. وبعد اإعطاء جرعة ثانية وجد اأن معدلت العائد القت�شادي، ومعدلت �شفاء املرا�شة الكلي قد زادت اإىل%100. وبعد عام على العالج متت اإعادة تقومي 272 طفال من امل�شابني بالطفيل )%40.3(، ووجد اأن 51 منهم )%18.8( قد اأ�شيبوا مرة اأخرى بالطفيل. وكان القرب ال�شديد من م�شادر املياه و �شيد الأ�شماك من العوامل املعنوية اإح�شائيا التي جعلت الأطفال عر�شة لالإ�شابة جمددا بالطفيل )ن�شبة الأرجحية = 1.23، %95 فا�شل الثقة: 1.530–0.998؛ p = 0.05( و �شيد الأ�شماك )ن�شبة الأرجحية =2.23، 95% فا�شل الثقة: 6.040–0.828؛ p = 0.01(. اخلال�صة: ينبغي اأن تقوم املنظمات احلكومية وغري احلكومية يف نيجرييا بالتعاون يف القيام بحمالت للعالج اجلماعي والتثقيف ال�شحي من اأجل تقليل حدوث عودة عدوى البلهار�شيا البولية. الكلمات املفتاحية: البلهار�شيا البولية؛ برازيكوانتيل؛ نتائج العالج؛ درا�شة متابعة؛ نيجرييا. high efficacy of praziquantel in schistosoma haematobium-infected children in taraba state, northeast nigeria a follow-up study *robert s. houmsou,1 binga e. wama,1 hemen agere,2 john a. uniga,3 elizabeth u. amuta,4 santaya l. kela5 clinical & basic research sultan qaboos university med j, august 2018, vol. 18, iss. 3, pp. e304–310, epub. 19 dec 18 submitted 28 aug 17 revisions req. 22 oct 17 & 25 apr 18; revisions recd. 12 nov 17 & 18 sep 18 accepted 30 sep 18 doi: 10.18295/squmj.2018.18.03.007 robert s. houmsou, binga e. wama, hemen agere, john a. uniga, elizabeth u. amuta and santaya l. kela clinical and basic research | e305 commonly known as bilharzia, schisto-somiasis is a water-related parasitic disease transmitted to humans transcutaneously by matured furcocercariae that multiply asexually within freshwater snails of the planorbidae family.1 in subsaharan africa, nigeria carries the highest burden of the disease, with an estimated 103.9 million people at risk of infection and 29 million individuals infected.2 in nigeria, the disease is predominantly caused by two species of schistosomes—schistosoma haematobium and s. mansoni—which overlap in most endemic areas, although s. intercalatum has also been reported.3,4 for the most part, people living in rural areas of nigeria are most often infected with s. haematobium.5,6 the disease is known to cause haematuria, proteinuria, leukocyturia, dysuria and painful urination; it has also been reported to have significant adverse effects on child development and to affect productivity in infected adults.1,7–9 in schistosomiasis-endemic areas, the world health organization (who) recommends the administration of a single dose of praziquantel to affected individuals during mass deworming campaigns.10 previous studies have also shown that this drug remains the safest and most effective treatment for all forms of schistosomiasis.11,12 while poor cure rates with a single dose of praziquantel have been reported in s. mansoni-endemic areas, better cure and egg reduction rates (errs) have been reported in s. haematobium-endemic areas.12–15 however, in spite of the dramatic increase in the avail ability and distribution of praziquantel over the last decade, less than 40 million out of 260 million infected individuals worldwide in 2013 received treatment.15 moreover, in nigeria, little has been done to reduce the prevalence and intensity of urinary schistosomiasis infections in endemic communities. although a national schistosomiasis map was created to promote interventions and strategies to combat the disease, only 4% of those in need of the drug have been treated so far.16,17 in nigeria, previous studies have reported schistosomiasis to be endemic in taraba state, with specific prevalence rates varying between communities.16,18 despite this, to the best of the authors’ knowledge, there has been no mass distribution of praziquantel to date in this region.18 the murbai and surbai villages of the ardo kola local government area (lga) of taraba state are hyper endemic areas for s. haematobium.18 most residents are subsistence farmers who also engage in fishing and trading. the area has a tropical climate and a mixture of savannah vegetation.18 ponds, streams and rivers traverse both communities, with the majority of inhabitants dep endent on these bodies of water for their daily activ ities. previously, an epidemiological study was conducted among 1,153 children in the murbai and surbai comm unities, of which 675 (58.5%) were found to be infected with s. haematobium; fishing, rice farming and dry season farming using irrigation were identified as significant risk factors for infection.18 however, only baseline prevalence and parasite burden was determined during the course of the initial study. therefore, the current follow up study aimed to assess the efficacy of a single dose of praziquantel in reducing prevalence, parasite burden and morbidity rates among the same sample of infected children. in addition, factors predisposing children to reinfection one year after treatment were evaluated. methods this prospective follow-up study was conducted between march 2014 and february 2015 and included a previously reported sample of 675 children with urinary schist osomiasis infections in the murbai and surbai communities.18 all infected children were treated with a single dose of 40 mg/kg of praziquantel administered by two qualified nurses according to who protocols.19 the treated children were followed up for four weeks, after which they were re-examined to ascertain the presence of s. haematobium eggs in their urine. those children who still excreted s. haematobium eggs at this time were given a second dose of praziquantel and followed up again for two more weeks before being reexamined. after 12 months, all children who had been treated with either one or two doses of praziquantel were re-assessed for infection. unfortunately, a number of the children’s families had left the villages during this time, frequently for agricultural purposes or so that the children could attend secondary schools in neighbouring villages. these children were therefore lost to further follow-up [figure 1]. advances in knowledge this follow-up study found that a single dose of praziquantel was highly effective in treating urinary schistosomiasis among a previously reported sample of infected children in nigeria. however, proximity to bodies of water and participation in water-related activities such as fishing were significant factors predisposing children to reinfection one year after treatment. application to patient care the administration of a single dose of 40 mg/kg of praziquantel is recommended to cure children with urinary schistosomiasis of the disease, as well as related morbidities such as microhaematuria and proteinuria. high efficacy of praziquantel in schistosoma haematobium-infected children in taraba state, northeast nigeria a follow-up study e306 | squ medical journal, august 2018, volume 18, issue 3 urine samples of 20 ml each were collected from the children at baseline and each subsequent follow-up appointment in labelled universal bottles. all samples were collected between 10 am and 2 pm and were immediately tested for microhaematuria and proteinuria using reagent strips (medi-test combi 9®, macherynagel gmbh co., düren, germany), as per the manufacturer’s instructions. all tested urine samples were kept in an ice-packed cooler and transported to the lab oratory within 30 minutes. the urine samples were filtered using a 10 ml syringe with a swinnex® polypropylene filter holder of 13 mm in diameter and polycarbonate membrane filters of 12 μm porosity (sterlitech corp., kent, washington, usa). positive samples were classified as having either a low (1–49 eggs/10 ml of urine) or high (>50 eggs/10 ml of urine) parasite burden. cure rates and errs were calculated using the following formulae, where p is prevalence and mec is the arithmetic mean egg count per 10 ml of urine:20 data were entered into an excel spreadsheet, vers ion 2010 (microsoft inc., redmond, washington, usa), before being exported for analysis to the statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa). chi-squared and t tests were used to compare the prevalence of infection and parasite burden according to age and gender and to compare the mean number of eggs between those with low and heavy parasite burdens. a logistic regression analysis using odds ratios (ors) and 95% confidence intervals (cis) was used to determine the relationship between reinfection and risk factors. the statistical level of significance was set at p ≤0.05. ethical permission to conduct this study was obtained from the health department of the ardo kola lga (#hd/aik/16/003). thereafter, the health depart ment communicated with the heads of the murbai and surbai communities to inform children and their parents of the study protocols. the parents or guardians of all children enrolled in the study provided informed consent prior to their participation. results this follow-up study included 675 previously reported children infected with s. haematobium prior to praziq uantel treatment. as previously described, males were significantly more likely to be infected than females (71.2% versus 43.7%; χ2= 89.1; p <0.01).18 children aged 6–10 years and 11–15 years were also significantly more likely to be infected (78.7% and 73%, respectively; χ2 = 360.9; p <0.01). a low parasite burden was significantly more frequent in comparison to a heavy parasite burden (62.5% versus 37.5%; χ2 = 97; p <0.01).18 according to gender, females more frequently had a low parasite burden than males (70.1% versus 58.6%; χ2 = 96.9; p <0.01). children aged 1–5 and 11–15 years old frequently had a low parasite burden (85.7% and 55.7%, respectively).18 table 1 presents the schistosomiasis parasite burden and morbidity rates of the children at baseline. the mean number of eggs was 31.1 ± 7.9 eggs/10 ml of urine among children with a low parasite burden and 86.5 ± 12.1 eggs/10 ml of urine among those with a heavy parasite burden. in terms of morbidities, males had a significantly higher proportion of both microhaem aturia (61.5% versus 42.9%; χ2 = 157.8; p <0.01) and proteinuria (49.1% versus 36.8%; χ2 = 107.9; p <0.01) than their female counterparts. children aged 6–10 and 11–15 years old had the highest proportion of both microhaematuria (61.7% and 48.3%, respectively; χ2 = 177.7; p <0.01) and proteinuria (44% and 50%, respectively; χ2 = 86.2; p <0.01), compared to the 1–5-year-olds. cure rate = err = × 100 × 100 p before treatment – p after treatment 1 – mec after treatment at baseline p before treatment mec before treatment figure 1: diagram of study design showing the number of infected children at baseline, follow-up and one year post-treatment among a sample of previously reported children with schistosoma haematobium infections in taraba state, nigeria (n = 675).18 robert s. houmsou, binga e. wama, hemen agere, john a. uniga, elizabeth u. amuta and santaya l. kela clinical and basic research | e307 table 2 describes the schistosomiasis prevalence, parasite burden and morbidity rates of the children four weeks after the administration of a single dose of prazi quantel. the overall cure rate was 98.1%, with only 13 children (1.9%) requiring a second dose of praziquantel. children aged 1–5 years old had a higher cure rate than older children (100% versus 98.6% and 96% for those aged 6–10 years and 11–15 years, respectively). in addition, female children had a higher cure rate than their male counterparts (99.6% versus 97.3%). at four weeks post-treatment, the err in children with low and heavy parasite burdens was 100% and 96.5%, respectively. at this time, 5.1% of the children who had had a heavy parasite burden at baseline had relapsed, although table 1: schistosomiasis parasite burden and morbidities at baseline among schistosoma haematobium-infected children in taraba state, nigeria (n = 675)* variable n (%) p value age group in years, n (%) p value total male (n = 444) female (n = 231) 1–5 (n = 63) 6–10 (n = 436) 11–15 (n = 176) parasite burden† low 422 (62.5) 260 (58.6) 162 (70.1) <0.01 54 (85.7) 270 (61.9) 98 (55.7) <0.01 mean eggs/10 ml of urine ± sd 31.1 ± 7.9 32.6 ± 4.2 29.7 ± 3.1 22.1 ± 7.3 36.3 ± 9.7 34.4 ± 5.6 high 253 (37.5) 184 (41.4) 69 (29.9) <0.01 9 (14.3) 166 (38.1) 78 (44.3) <0.01 mean eggs/10 ml of urine ± sd 86.5 ± 12.1 88.3 ± 11.3 77.1 ± 9.4 75.3 ± 6.2 98.6 ± 8.7 84.4 ± 9.4 morbidities microhaematuria 372 (55.1) 273 (61.5) 99 (42.9) <0.01 18 (28.6) 269 (61.7) 85 (48.3) <0.01 proteinuria 303 (44.9) 218 (49.1) 85 (36.8) <0.01 23 (36.5) 192 (44) 88 (50) <0.01 sd = standard deviation. *some data previously reported in: houmsou rs, agere h, wama be, bingbeng jb, amuta eu, kela sl. urinary schistosomiasis among children in murbai and surbai communities of ardo-kola local government area, taraba state, nigeria.18 †parasite burden was classified as either low (1–49 eggs/10 ml of urine) or high (>50 eggs/10 ml of urine). table 2: schistosomiasis infections, parasite burden and morbidities at four weeks post-praziquantel treatment among schistosoma haematobium-infected children in taraba state, nigeria (n = 675) variable n (%) p value age group in years, n (%) p value total male (n = 444) female (n = 231) 1–5 (n = 63) 6–10 (n = 436) 11–15 (n = 176) infections 13 (1.9) 12 (2.7) 1 (0.4) <0.01 0 (0) 6 (1.4) 7 (4) <0.01 overall cure rate, % 98.1 97.3 99.6 100 98.6 96 parasite burden* low 13 (1.9)† 12 (2.7) 1 (0.4) <0.01 0 (0.0) 6 (1.4) 7 (3.9) <0.01 mean eggs/10 ml of urine ± sd 7.1 ± 1.1 7 ± 0.2 5 ± 1.9 7.0 ± 1.4 4.1 ± 2.4 high 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) <0.01 mean eggs/10 ml of urine ± sd morbidities microhaematuria 11 (1.6) 10 (2.3) 1 (0.4) <0.01 0 (0) 6 (1.4) 5 (2.8) <0.01 cure rate, % 98.7 98 99.7 98.7 97.5 proteinuria 10 (1.5) 9 (2) 1 (0.4) <0.01 0 (0) 6 (1.4) 4 (2.3) <0.01 cure rate, % 98.6 97.9 99.6 98.5 97.8 sd = standard deviation. *parasite burden was classified as either low (1–49 eggs/10 ml of urine) or high (>50 eggs/10 ml of urine). †all of the children who relapsed had initially had a high parasite burden at baseline but a low parasite burden four weeks post-treatment. high efficacy of praziquantel in schistosoma haematobium-infected children in taraba state, northeast nigeria a follow-up study e308 | squ medical journal, august 2018, volume 18, issue 3 their parasite burden at follow-up was low (mean: 7.1 ± 1.1 eggs/10 ml of urine). in terms of morbidity, cure rates of microhaematuria and proteinuria four weeks post-treatment were 98.7% and 98.6%, respectively. among those children who had received a second dose of praziquantel, the err and overall and morbidity cure rates were 100% six weeks post-treatment. table 3 shows the prevalence of s. haematobium reinfections and related risk factors one year post-treat ment among the 272 children (40.3%) available for follow up. in total, 51 children (18.8%) were reinfected. however, reinfection rates did not vary significantly by gender (χ2 = 0.73; p = 0.72) or age (χ2 = 1.71; p = 0.13). however, close proximity (i.e. within <500 m) to a body of water (or = 1.23, 95% ci: 0.998–1.530; p = 0.05) and fishing (or = 2.23, 95% ci: 0.828–6.040; p = 0.01) were significant risk factors for reinfection. discussion to the best of the authors’ knowledge, the current study represents the first longitudinal assessment of the efficacy of a single dose of praziquantel among a sample of previously reported s. haematobium-infected children in taraba state.18 the results of the current study dem onstrated the efficacy of praziquantel in reducing the prevalence, burden and morbidity of schistosomiasis infections in two communities with no prior record of mass drug administration. moreover, observed cure rates at both four (98.1%) and six (100%) weeks posttreatment indicated good absorption of praziquantel among infected children who had not previously been exposed to the drug. praziquantel remains the drug of choice for treating schistosomiasis, pending development of a more reliable single-dose cure.10 the findings of the present study corroborate those of another study from the southern ivory coast, which observed similarly high cure rates among infected children at 3–9 weeks post-treatment.20 however, in contrast, previous research from nigeria and cameroon has indicated much lower cure rates at 3–8 weeks post-treatment (49.4% and 39.8%, respect ively).21,22 this variation in reported cure rates could be the result of several factors, including the frequency of the children’s exposure to infested waters, the rate of drug absorption and the extent of drug resistance among the studied populations. although no significant gender or age differences were reported in schistosomiasis cure rates at four weeks post-treatment in the current study, females and 1–5 year-olds nevertheless had higher cure rates. this finding suggests that praziquantel may be more effective among younger children than older ones, likely due to increased exposure to cercariae-infested water among the latter group due to recreational activities or daily chores.18 this may similarly apply to male children; an earlier report observed that male children in murbai and surbai spent most of their time swimming and fishing in pools or lakes, as well as more frequently involving themselves in irrigation and rice farming activities.18 lower cure rates among older children and males could also be due to the presence of schistosomula in the bloodstream at the time of treatment, given that praziquantel has proven ineffective against immature schistosoma parasites.23 in the present study, none of the children who required a second dose of praziquantel excreted s. haem atobium eggs or showed any signs of morbidity at six weeks post-treatment, suggesting that a second dose of praziquantel may be necessary following poor response to the initial dose. a study conducted in the niger republic reported a similar err and cure rate after s. haematobium-infected children received a second dose table 3: schistosomiasis reinfection rates and related risk factors at one year post-praziquantel treatment among schistosoma haematobium-infected children in taraba state, nigeria (n = 272) n (%) or (ci) p value total reinfections (n = 51) gender male 154 (56.6) 30 (19.5) 0.72 female 118 (43.4) 21 (17.8) age in years 1–5 77 (28.3) 13 (16.9) 0.136–10 127 (46.7) 26 (20.5) 11–15 68 (25) 12 (17.6) proximity to bodies of water in m <500 166 (61) 39 (23.5) 1.23 (0.998–1.530) 0.05>500 106 (39) 12 (11.3) swimming yes 265 (97.4) 49 (18.5) 0.73 (0.130–4.200) 0.73no 7 (2.6) 2 (28.6) fishing yes 177 (65.1) 40 (22.6) 2.23 (0.828–6.040) 0.01no 95 (34.9) 11 (11.6) or = odds ratio; ci = confidence interval. robert s. houmsou, binga e. wama, hemen agere, john a. uniga, elizabeth u. amuta and santaya l. kela clinical and basic research | e309 of praziquantel three weeks post-treatment.24 however, the err and cure rate among children in the current study who received either a single or two doses of praziquantel was significantly higher than rates reported from cameroon, wherein optimal results were only noted at nine weeks post-treatment, with doses of praziquantel administered at three-week intervals.22 moreover, in the present study, most children with a low parasite burden were cured at follow-up, with only a few children with heavy parasite burdens at baseline relapsing at four weeks post-treatment. similarly, previous research from mozambique found that a single dose of praziquantel was more effective among children with a low parasite burden in comparison to those with a heavy parasite burden.25 in terms of schistosomiasis-related morbidity, the vast majority of children in the present study were cured of microhaematuria and proteinuria at four weeks post treatment. this indicates that a single dose of praziquantel can potentially reverse the adverse effects of s. haemat obium infections. in addition, none of the children requiring a second dose of praziquantel were found to suffer from these morbidities at six weeks post-treatment. previous studies from ethiopia and the ivory coast have reported low cure rates for microhaematuria and proteinuria at seven and eight weeks post-treatment, respectively.20,26 most studies evaluating the efficacy of praziquantel have assessed morbidity markers of s. haem atobium over several months and not within weeks. in kenya, cure rates of 58% and 46% were observed at 12 months post-treatment for microhaematuria and proteinuria, respectively.27 unfortunately, a moderate rate of schistosomiasis reinfection was noted among treated children one year post-treatment in the current study. this rate was comparatively higher than reported rates among treated children in kenya and sudan.27,28 this finding clearly demonstrates the challenges that rural communities such as murbai and surbai face with regards to the complete eradication of schistosomiasis. unfortunately, the lack of piped water in these communities often compels the inhabitants to continue exposing themselves to cercariae-infested bodies of water—for instance, in order to carry out domestic chores or activities such as washing utensils and clothes, bathing, swimming and fishing—thereby re-infecting themselves. as previously reported, close proximity to bodies of water and fishing were identified as major factors that exposed children to infection.18 in the current followup study, such factors remained significantly associated with reinfection rates one year post-treatment. prompt action is necessary so as to avoid a schist osomiasis epidemic in taraba state. to this end, a mass praziquantel campaign is recommended, in which all infected individuals are given at least two standard doses of 40 mg/kg of praziquantel at six-week intervals, in order to curtail the incidence of schistosomiasis reinf ections in this region. furthermore, the effects of praziquantel treatment should be monitored in weeks rather than months. there is also an urgent need to address the problem of high reinfection rates through public health education initiatives to warn local inhabitants of risk factors associated with schistosomiasis reinfections. in addition, the provision of piped water as well as the installation of new or the re-activation of old boreholes or wells within these communities could help to reduce the inhabitants’ contact with cercariae-infested water, thereby reducing the incidence of new and recurrent schistosomiasis infections. the present study is subject to certain limitations. first, an egg viability test was not performed after the initial treatment in order to determine whether the single dose of praziquantel had completely cured the infected children. second, only 40.3% of the treated children were still residing within the studied villages one year post-treatment, thus limiting the total number of cases re-assessed. conclusion praziquantel was highly effective in curing schistosomiasis among a previously reported sample of s. haematobium-infected children in taraba state. at four weeks post-treatment, both the err and overall and morbidity cure rates were extremely high; these increased to 100% six weeks post-treatment following a second dose of praziquantel. however, there was a moderate rate of reinfection one year post-treatment. proximity to bodies of water and fishing were significant risk factors for reinfection. the nigerian government and other agencies should initiate necessary strategies for treatment and public health education in the region. in particular, the provision of piped water is highly recommended in order to reduce the local inhabitants’ contact with cercariae-infested water. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. high efficacy of praziquantel in schistosoma haematobium-infected children in taraba state, northeast nigeria a follow-up study e310 | squ medical journal, august 2018, volume 18, issue 3 references 1. gryseels b, polman k, clerinx j, kestens l. human schistosomiasis. lancet 2006; 368:1106–18. doi: 10.1016/s0140-6736(06) 69440-3. 2. hotez pj, kamath a. neglected tropical diseases in sub-saharan africa: review of their prevalence, distribution, and disease burden. plos negl trop dis 2009; 3:e412. doi: 10.1371/journal. pntd.0000412. 3. arene fo, ukpeibo et, nwanze ea. studies on schistosomiasis in the niger delta: schistosoma intercalatum in the urban city of port harcourt, nigeria. public health 1989; 103:295–301. doi: 10.1016/s0033-3506(89)80043-5. 4. bassey se, orutugu la. new foci for schistosoma mansoni and s. intercalatum in ogbia local government area, bayelsa state, nigeria. biotechnol res 2016; 2:212–14. 5. houmsou rs, panda sm, elkanah so, garba lc, wama be, amuta eu, et al. cross-sectional study and spatial distribution of schistosomiasis among children in northeastern nigeria. asian pac j trop biomed 2016; 6:477–84. doi: 10.1016/j.apjtb.2016.04.003. 6. noriode rm, idowu et, otubanjo oa, mafe ma. urinary schistosomiasis in school aged children of two rural endemic communities in edo state, nigeria. j infect public health 2018; 11:384–8. doi: 10.1016/j.jiph.2017.09.012. 7. gray dj, ross ag, li ys, mcmanus dp. diagnosis and management of schistosomiasis. bmj 2011; 342:d2651. doi: 10.1136/bmj. d2651. 8. king ch. parasites and poverty: the case of schistosomiasis. acta trop 2010; 113:95–104. doi: 10.1016/j.actatropica.2009.11.012. 9. mahgoub hm, mohamed aa, magzoub m, gasim gi, eldein wn, ahmed aa, et al. schistosoma mansoni infection as a predictor of severe anaemia in schoolchildren in eastern sudan. j helminthol 2010; 84:132–5. doi: 10.1017/s0022149x09990368. 10. who expert committee. prevention and control of schistosomiasis and soil-transmitted heliminthiasis. world health organ tech rep ser 2002; 912:1–57. 11. kabatereine nb, kemijumbi j, ouma jh, sturrock rf, butterworth ae, madsen h, et al. efficacy and side effects of praziquantel treatment in a highly endemic schistosoma mansoni focus at lake albert, uganda. trans r soc trop med hyg 2003; 97:599–603. 12. king ch, muchiri em, mungai p, ouma jh, kadzo h, magak p, et al. randomized comparison of low-dose versus standard-dose praziquantel therapy in treatment of urinary tract morbidity due to schistosoma haematobium infection. am j trop med hyg 2002; 66:725–30. doi: 10.4269/ajtmh.2002.66.725. 13. abu-elyazeed rr, youssef fg, merrell br, el-gamal rl, el-khoby ta, hassanein ya, et al. praziquantel in the treatment of schistosoma mansoni infection: comparison of 40 and 60 mg/kg bodyweight regimens. am j trop med hyg 1997; 56:404–7. doi: 10.4269/ajtmh.1997.56.404. 14. danso-appiah a, de vlas sj. interpreting low praziquantel cure rates of schistosoma mansoni infections in senegal. trends parasitol 2002; 18:125–9. doi: 10.1016/s1471-4922(01)02209-7. 15. world health organization. schistosomiasis: number of people treated worldwide in 2013. wkly epidemiol rec 2015; 90:25–32. 16. nigeria federal ministry of health. report on epidemiological mapping of schistosomiasis and soil transmitted helminthiasis in 19 states and the fct, nigeria. from: www.health.gov.ng/ doc/schistosth.pdf accessed: nov 2017. 17. world health organization. schistosomiasis: progress report 2001-2011, strategic plan 2012-2020. from: www.who.int/negle cted_diseases/resources/9789241503174/en/ accessed: nov 2017. 18. houmsou rs, agere h, wama be, bingbeng jb, amuta eu, kela sl. urinary schistosomiasis among children in murbai and surbai communities of ardo-kola local government area, taraba state, nigeria. j trop med 2016; 2016:9831265. doi: 10.11 55/2016/9831265. 19. world health organization. assessing the efficacy of antihel minthic drugs against schistosomiasis and soil-transmitted helminthiases. from: http://apps.who.int/iris/handle/10665/79019 accessed: nov 2017. 20. stete k, krauth sj, coulibaly jt, knopp s, hattendorf j, müller i, et al. dynamics of schistosoma haematobium egg output and associated infection parameters following treatment with praziquantel in school-aged children. parasit vectors 2012; 5:298. doi: 10.1186/1756-3305-5-298. 21. ojurongbe o, sina-agbaje or, busari a, okorie pn, ojurongbe ta, akindele aa. efficacy of praziquantel in the treatment of schistosoma haematobium infection among school-age children in rural communities of abeokuta, nigeria. infect dis poverty 2014; 3:30. doi: 10.1186/2049-9957-3-30. 22. tchuenté la, shaw dj, polla l, cioli d, vercruysse j. efficacy of praziquantel against schistosoma haematobium infection in children. am j trop med hyg 2004; 71:778–82. doi: 10.4269/ ajtmh.2004.71.778. 23. lui r, dong hf, guo y, zhao qp, jiang ms. efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis. parasit vectors 2011; 4:201. doi: 10.1186/17563305-4-201. 24. garba a, lamine ms, barkiré n, djibo a, sofo b, gouvras an, et al. efficacy and safety of two closely spaced doses of praziquantel against schistosoma haematobium and s. mansoni and re-infection patterns in school-aged children in niger. acta trop 2013; 128:334–44. doi: 10.1016/j.actatropica.2012.08.008. 25. augusto g, magnussen p, kristensen tk, appleton cc, vennervald bj. the influence of transmission season on para sitological cure rates and intensity of infection after prazi quantel treatment of schistosoma haematobium-infected schoolchildren in mozambique. parasitology 2009; 136:1771–9. doi: 10.1017/s0031182009006210. 26. mekonnen a, legesse m, belay m, tadesse k, torben w, teklemariam z, et al. efficacy of praziquantel against schistosoma haematobium in dulshatalo village, western ethiopia. bmc res notes 2013; 6:392. doi: 10.1186/1756-0500-6-392. 27. king ch. long-term outcomes of school-based treatment for control of urinary schistosomiasis: a review of experience in coast province, kenya. mem inst oswaldo cruz 2006; 101:299–306. doi: 10.1590/s0074-02762006000900047. 28. ahmed am, abbas h, mansour fa, gasim gi, adam i. schistosoma haematobium infections among schoolchildren in central sudan one year after treatment with praziquantel. parasit vectors 2012; 5:108. doi: 10.1186/1756-3305-5-108. https://doi.org/10.1016/s0140-6736%2806%2969440-3 https://doi.org/10.1016/s0140-6736%2806%2969440-3 https://doi.org/10.1371/journal.pntd.0000412 https://doi.org/10.1371/journal.pntd.0000412 https://doi.org/10.1016/s0033-3506%2889%2980043-5 https://doi.org/10.1016/j.apjtb.2016.04.003 https://doi.org/10.1016/j.jiph.2017.09.012 https://doi.org/10.1136/bmj.d2651 https://doi.org/10.1136/bmj.d2651 https://doi.org/10.1016/j.actatropica.2009.11.012 https://doi.org/10.1017/s0022149x09990368 https://doi.org/10.4269/ajtmh.2002.66.725 https://doi.org/10.4269/ajtmh.1997.56.404 https://doi.org/10.1016/s1471-4922%2801%2902209-7 https://doi.org/10.1155/2016/9831265 https://doi.org/10.1155/2016/9831265 https://doi.org/10.1186/1756-3305-5-298 https://doi.org/10.1186/2049-9957-3-30 https://doi.org/10.4269/ajtmh.2004.71.778 https://doi.org/10.4269/ajtmh.2004.71.778 https://doi.org/10.1186/1756-3305-4-201 https://doi.org/10.1186/1756-3305-4-201 https://doi.org/10.1016/j.actatropica.2012.08.008 https://doi.org/10.1017/s0031182009006210 https://doi.org/10.1186/1756-0500-6-392 https://doi.org/10.1590/s0074-02762006000900047 https://doi.org/10.1186/1756-3305-5-108 1directorate of nursing, sultan qaboos university hospital, muscat, oman; 2college of nursing, sultan qaboos university, muscat, oman *corresponding author’s e-mail: ahmed2123@hotmail.com إدراك املرضى واملمرضني عن احلاجة لتثقيف املرضى بعد إجراء عملية طعم جمازة الشريان التاجي يف اثنني من مستشفيات سلطنة عمان اأحمد عامر امل�شكري، هدى النعمانية، خالد العمري، حممد عامر امل�شكري abstract: objectives: little is known about nurses’ and patients’ perceptions of learning needs following coronary artery bypass graft (cabg) surgery in oman. this study aimed to identify patients' and nurses' perceptions of postcabg learning needs. methods: this cross-sectional study was conducted in two cardiac units in oman between february and april 2018. participants were from step-down units and perceptions of post-cabg learning needs were collected using a modified version of the cardiac patients learning need inventory (mcplni) questionnaire. data were analysed using descriptive and inferential statistics. results: a total of 90 patients and 90 nurses were included in this study (response rate: 100%). nurses perceived information about chest and leg wound care, medic ations and complications as patients’ most important learning needs (4.89 ± 0.31, 4.84 ± 0.33 and 4.78 ± 0.45, respectively). similarly, patients perceived a need for post-cabg learning related to chest and leg wound care, complications and medication, while learning related to physical activity received a moderate priority (4.92 ± 0.20, 4.80 ± 0.45, 4.85 ± 0.26 and 3.50 ± 1.34, respectively). conclusion: before discharging patients, they should be provided with specific information related to post-cabg care. it is essential to assess patients’ learning needs and incorporate those learning needs into discharge plans. keywords: learning; perception; coronary artery bypass; education; patients; nurses; oman. امللخ�ص: الهدف: ال تتوفر معرفة كافية بخ�شو�س اإدراك املمر�شات واملر�شى عن احلاجة لتثقيف املر�شى باإجراءات العناية بعد اإجراء عملية طعم جمازة ال�رشيان التاجي يف ُعمان. تهدف هذه الدرا�شة اإىل حتديد اإدراك املر�شى واملمر�شني عن احتياج تثقيف املر�شى بعد عملية طعم جمازة ال�رشيان التاجي. الطريقة: مت اإجراء هذه الدرا�شة امل�شتعر�شة يف ق�شمني الأمرا�س القلب بني فرباير واأبريل من عام 2018 يف �شلطنة عمان. كان امل�شاركون من اأق�شام العناية التدريجية. مت جمع املعلومات عن اإدراك املمر�شات واملر�شى با�شتخدام ن�شخة معدلة من قائمة احتياجات تثقيف مر�شى القلب. وقد مت حتليل البيانات با�شتخدام اإح�شاءات و�شفية وا�شتداللية. النتائج: اإ�شرتك 90 مري�شا و 90 ممر�شا و ممر�شة يف هذه الدرا�شة )معدل اال�شتجابة: %100(. اأظهرت النتائج اأن املمر�شني يعتربون اأن تثقيف املر�شى عن عناية جروح ال�شدر وال�شاق، االأدوية وامل�شاعفات هي االأكرث اأهمية بعد اإجراء العملية )4.89 ± 0.31، 4.84 ± 0.33 و 4.78 ± 0.45، على التوايل(. واأظهرت النتائج اأن املر�شى كذلك يدركون احلاجة اإىل تعلم العناية بجروح ال�شدر وال�شاق وامل�شاعفات واالأدوية، بينما تلقى التثقيف املتعلق بالن�شاط البدين اأولوية متو�شطة )4.92 ± 0.20، 4.80 ± 0.45، 4.85 ± 0.26 و 3.50 ± 1.34، على التوايل(. اخلال�صة: قبل ترخي�س املر�شى من امل�شت�شفى، يجب تزويدهم مبعلومات حمددة متعلقة برعاية ما بعد جراحة طعم جمازة ال�رشيان التاجي. ومن ال�رشوري تقييم احتياجات التعلم لدى املر�شى و�شم هذه االإحتياجات يف خطط الرتخي�س. الكلمات املفتاحية: التعلم؛ االإدراك؛ جمازة ال�رشيان التاجي؛ تثقيف؛ املر�شى؛ املمر�شات؛ عمان. patients’ and nurses’ perceptions of post-coronary artery bypass graft learning needs in two omani hospitals *ahmed a. almaskari,1 huda al noumani,2 khalid al-omari,2 mohammed a. al maskari2 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e122–128, epub. 8 sep 19 submitted 25 sep 18 revisions req. 3 dec 18 & 16 jan 19; revisions recd. 29 dec 18 & 8 feb 19 accepted 14 feb 19 advances in knowledge to the best of the authors’ knowledge, this is the first study to assess patients’ and nurses’ post-coronary artery bypass graft (cabg) learning needs in oman. when identifying post-cabg learning needs, both patients and their nurses prioritised information related to leg and chest wounds, medications and potential surgical complications. application to patients care these findings provide clinicians with patients’ and nurses’ perceptions of post-cabg learning needs which can be used to plan educational approaches and avoid information overload. this study should be considered a platform for future studies to understand patients’ post-cabg learning needs and develop a clear and effective educational plan to improve patients’ outcomes and reduce post-cabg complications. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.007 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ ahmed a. almaskari, huda al noumani, khalid al-omari and mohammed a. al maskari clinical and basic research | e123 coronary heart disease (chd) is the main cause of mortality and morbidity worldwide.1 in some middle eastern countries, chd is the leading cause of death and disability.2,3 in jordan, the prevalence of chd accounts for approximately 35% of overall coronary vascular disease (cvd) mortality.3 in oman, chd accounts for 22.84% of all deaths and is a common non-communicable disease according to the omani ministry of health.4,5 patients with chd require appropriate management to prevent further complications such as heart failure and multi-organ dysfunction. despite the effectiveness of coronary artery bypass grafts (cabg) in managing chd, post-cabg patients can develop severe complications such as infection and lung problems; these complications can be minimised with an appropriate discharge plan.2 recent studies have focused on the impact of health education (e.g. self-care, medication adherence and sleep quality) on patients’ post-cabg outcomes.6,7 additionally, many patients with heart disease who have received cabg have expr essed the importance of intensive education regarding post-discharge home-based self-care and management.2,8 specifically, patients reported a need to know about the physical and psychological aspects of medication, diet, physical education and wound care as well as potential complications of surgery.2,8 although one study in oman found that intensive health education and close patient monitoring was key in managing chd among omani patients, no study has examined nurses’ and patients’ perceptions of post-cabg learning needs.9 therefore, this study aimed to identify patients’ and nurses’ perceptions of post-cabg learning needs. methods this descriptive comparative cross-sectional study was carried out at sultan qaboos university hospital’s (squh) cardiac unit and the royal hospital’s (rh) national cardiac unit in muscat, oman from february to april 2018. these cardiac units are considered the country’s main units and are the largest in oman. as such, these two tertiary institutions host all of the country’s cardiac surgeries (130–200 cabg surgeries performed annually). the rh’s cardiac unit opened in 2013 with a 139-bed capacity. the cardiac unit at squh consists of an operating room, four cardiac intensive care unit beds and an 18-bed cardiac surgery ward (step-down unit). this study targeted patients who underwent cabg surgery and the nurses caring for them. the study used a non-probability convenience sampling technique to recruit participants. the sample size was determined by using g-power, version 3.1 (heinrich-heine-uni ersität düsseldorf, düsseldorf, germany). based on a chi-square comparative test, a medium effect size of 0.50, a two-tailed test (p ≤0.05) and a power of 0.80, a sample size of 86 participants was determined for each group. to account for a 4% missing data rate that occurred in a prior study, it was decided to recruit 90 participants to each group.10 patients were included if they were omani, alert, aged ≥20 years old, had cabg for the first time, were currently admitted to a step-down unit and were 5–6 days post-cabg. patients with cognitive impairments as identified by medical records or who refused to participate were excluded. nurses of all nationalities were included if they were willing to participate and had been caring for post-cabg patients for at least one year. this time-frame was based on the assumption that nurses would be competent in the field of cabg care after a year. all participants completed the modified cardiac patients learning needs inventory (mcplni) questionnaire and provided demographic information using a separate questionnaire. the cardiac patients learning needs inventory was originally developed by gerard and peterson in 1994 to measure patients’ and staff nurses’ learning needs.11 the mcplni consists of 44 items distributed within eight domains—introduction to the coronary care unit (ccu), anatomy and physiology, diet information, psychological factors, risk factors for coronary cond itions, beneficial physical activities, medication inform ation and other pertinent information. the instrument is based on a five-point likert scale ranging from one (not at all important) to five (extremely important). the total scores range from 44–220 with higher scores indicating higher learning needs.2 the cronbach’s alpha for the mcplni is 0.95.2 this study used the arabic version of the mcplni, which had been validated with arabic speakers undergoing cabgs.2 in the current study, cronbach’s alpha of the domains ranged from 0.76–0.94 and the degree of learning needs’ importance was categorised based on the total mean score into either low (1–2.33), moderate (2.34–3.66) or high (3.67–5.00) because the original scale has no cut-off point to categorise the importance of learning needs [table 3].12 prior to data collection, the authors visited the target cardiac unit and explained the study’s purpose to the nurse-in-charge. a data collection schedule was then developed. a convenience sampling technique was used to recruit subjects from the step-down unit. patients were asked to self-administer the mcplni in arabic and the nurses were asked to complete the english-language version. the questionnaire took 20 minutes to complete. after completed the mcplni, participants returned the questionnaire to the authors patients’ and nurses’ perceptions of post-coronary artery bypass graft learning needs in two omani hospitals e124 | squ medical journal, may 2019, volume 19, issue 2 or nurse-in-charge. after collection, the data and the questionnaires were secured in a locker. data were entered, computed and analysed using statistical package for the social sciences (spss), version 23 (ibm corp, armonk, new york, usa). demographics and nurses’ and patients’ perceived learning needs were presented as descriptive statistics, frequencies, percentages and means ± standard deviation. ethical approval was obtained from the ministry of health’s ethics committee (moh/dgps/csr/pro posal_approved/30/2017) and the medical research and ethical committee at sultan qaboos university (squ-ec/185/17). each participant received an explan atory letter with a consent form detailing all risks and benefits of participation. participants were assured that there would be no harm in answering the survey and had the right to withdraw from the study at any time without consequences. results a total of 90 patients and 90 nurses were included in this study (response rate: 100%). most patients were male (62.2%), married (73.3%), unemployed (44.4%), had formal school education (45.6%), and had a monthly income <300 omani riyals (58.9%), which is below oman’s poverty line.13 patients’ median age was 64 years old (range: 40–86 years old) [table 1]. the median age for nurses was 35 years old (range: 23–57 years old). the majority of nurses were female (77.8%), married (76.7%) and had a bachelor of science in nursing or a higher degree (54.4%) [table 2]. generally, patients and nurses perceived that all learning needs domains were highly important, except for the physical activity domain where patients reported it as moderately important (3.5 ± 1.3). post-cabg patients and nurses ranked learning related to chest and leg wounds as most important (4.9 ± 0.2 and 4.9 ± 0.3), medication information as second most important (4.9 ± 0.3 and 4.8 ± 0.3), complications as third most important (4.8 ± 0.5 and 4.8 ± 0.5) and psychological factors as ninth most important (4.3 ± 0.8 and 4.5 ± 0.6). both groups ranked the remaining domains differently; patients ranked the domain of physical activity as least important and introduction to the cardiac unit as the fourth most important learning need, whereas nurses table 1: characteristics of post-coronary artery bypass graft patients who completed the modified cardiac patients learning need inventory questionnaire (n = 90) characteristic n (%) median age in years (mean ± sd, range) 64 (63.4 ± 10.8, 40–86) gender female 34 (37.8) male 56 (62.2) educational level formal school education 41 (45.6) diploma and higher education 10 (11.1) uneducated 39 (43.3) occupation government 12 (13.3) private 10 (11.1) retired 28 (31.1) unemployed 40 (44.4) marital status single 1 (1.1) married 66 (73.3) divorced 1 (1.1) widowed 22 (24.4) monthly income in omr <300 53 (58.9) 300–700 25 (27.8) >700 12 (13.3) sd = standard deviation; omr = omani riyals. table 2: characteristics of nurses who completed the mod ified cardiac patients learning need inventory quest ionnaire and care for post-coronary artery bypass graft patients (n = 90) characteristic n (%) median age in years (mean ± sd, range) 35 (35.7 ± 6.8, 23–57) gender female 70 (77.8) male 20 (22.2) educational level diploma 41 (45.6) bsn and higher 49 (54.4) marital status single 20 (22.2) married 69 (76.7) divorced 1 (1.1) median years of experience as staff nurse (mean ± sd, range) 11 (12.3 ± 6.5, 1–27) median years of experience caring for post-cabg patients (mean ± sd, range) 8 (5.8 ± 5.6, 1–24) sd = standard deviation; bsn = bachelor of science; cabg = coronary artery bypass graft. ahmed a. almaskari, huda al noumani, khalid al-omari and mohammed a. al maskari clinical and basic research | e125 graded the same domains as fifth and least important, respectively [table 3]. in the “introduction to the cardiac unit” domain (range: 4.5–4.8), patients reported that they most needed to learn about why they were in the unit and how to manage their post-operative pain (4.8 ± 0.6 and 4.8 ± 0.5). for the second domain “anatomy and physiology” (range: 4.1–4.7). the highest item scores were for why patients had chest pain (4.7 ± 0.6), why their heartbeat might be irregular (4.7 ± 0.7) and how to differentiate chest wound-related pain from anginarelated pain (4.6 ± 0.8). for the “psychological factors” domain (range: 4.0–4.4), patients reported a high need to learn about what to do to reduce stress when home (4.4 ± 0.9). learning needs related to risk factors and medication and diet information were reported as having a high degree of importance (ranges: 4.2–4.4, 4.5–4.9 and 4.6–4.7, respectively). all items in the “complications” domain were rated as highly important (range: 4.7–4.8). patients perceived a pressing need to learn about what post-operative complications might occur and how to prevent complications from occurring (4.8 ± 0.6 and 4.8 ± 0.5). patients ranked information related to the “chest and leg wound care” domain highest of all (4.9 each). patients highly valued the need to learn about when to get family involved (4.3 ± 1.0), when to call a doctor (4.7 ± 1.1) and whether any other tests would be perf ormed after discharge (4.7 ± 0.1). the “physical activity” domain received the lowest scores (range: 3.2–3.8), indicating a moderate degree of perceived importance. in general, nurses perceived all learning needs as highly important. nurses also assigned the highest degree of learning needs to the “chest and leg wound care” domain (range: 4.8–4.9). this area was followed in perceived importance by information about medications and surgery complications (ranges: 4.5–4.8 and 4.7–4.8). the lowest mean score reported by nurses was for the “psychological factors” domain (range: 4.2–4.6), but still indicated a high degree of perceived importance [table 4]. discussion nurses and other healthcare personnel play an important role in assessing and examining the learning needs of post-cabg patients, and encouraging patients to express their needs and feelings. this study’s findings reveal that both nurses and patients perceived inform ation related to leg and chest wounds, medication and complications as the top three learning needs of postcabg patients. this finding was consistent with other studies done with similar populations.14,15 post-cabg patients from yemen and the usa also ranked information related to leg and chest wounds as the top priority for patient education.2,14 nurses in the current study also ranked chest and leg wounds as the most important learning need followed by medication information and complications; introduction to the ccu was perceived as largely unnecessary. these results were consistent with omari et al. and yiu et al.’s studies, where nurses perceived table 3: total mean scores and cronbach's alpha for each domain of the modified cardiac patients learning need inventory questionnaire and ranks ordered by levels of patients’ and nurses’ perceptions mcplni domain cronbach's alpha patients’ perceptions nurses’ perceptions total mean score ± sd rank total mean score ± sd rank introduction to the cardiac unit 0.76 4.7 ± 0.6 4 4.2 ± 0.4 10 anatomy and physiology 0.82 4.6 ± 0.7 6 4.6 ± 0.5 7 psychological factors 0.88 4.3 ± 0.8 9 4.5 ± 0.6 9 risk factors 0.92 4.4 ± 0.9 8 4.6 ± 0.5 6 medication information 0.78 4.9 ± 0.3 2 4.8 ± 0.3 2 diet information 0.83 4.7 ± 0.5 5 4.7 ± 0.5 4 physical activity 0.92 3.5 ± 1.3 10 4.6 ± 0.5 5 complications 0.76 4.8 ± 0.5 3 4.8 ± 0.5 3 chest and leg wound care 0.81 4.9 ± 0.2 1 4.9 ± 0.3 1 other information 0.94 4.5 ± 0.6 7 4.6 ± 0.5 8 total learning needs score 0.91 4.4 ± 0.4 high 4.7 ± 0.4 high mcplni = modified cardiac patients learning need inventory; sd = standard deviation. note: the degree of importance of the learning needs was based on the total mean score and categorised as either low (1–2.33), moderate (2.34–3.66) or high (3.67–5.00). patients’ and nurses’ perceptions of post-coronary artery bypass graft learning needs in two omani hospitals e126 | squ medical journal, may 2019, volume 19, issue 2 table 4: mean score for each item of the modified cardiac patients learning need inventory questionnaire for patients (n = 90) and nurses (n = 90) mcplni domain items mean score ± sd patients’ perceptions nurses’ perceptions introduction to the cardiac unit why is the patient in this unit? 4.8 ± 0.6 4.8 ± 0.5 why is the patient’s activity limited? 4.5 ± 0.9 4.7 ± 0.5 how should the patient manage post-operative pain? 4.8 ± 0.5 4.8 ± 0.3 anatomy and physiology how can the patient differentiate between pain from the chest wound and the pain resulting from angina? 4.6 ± 0.8 4.6 ± 0.5 what does the heart look like and how does it work? 4.1 ± 1.2 4.4 ± 0.7 how does the heart heal? 4.4 ± 1.2 4.5 ± 0.6 why does the patient have chest pain? 4.7 ± 0.6 4.7 ± 0.5 why is the heartbeat irregular or skip beats? 4.7 ± 0.7 4.5 ± 0.8 psychological factors what is the normal psychological response to a serious illness? 4.2 ± 1 4.2 ± 1 what is the importance of talking to someone about fears, feelings and thoughts? 4.0 ± 1 4.4 ± 1 what effect does stress have? 4.2 ± 0.9 4.5 ± 1 what can be done to reduce stress while in hospital? 4.3 ± 0.9 4.6 ± 0.6 what can be done to reduce stress when at home? 4.4 ± 0.9 4.6 ± 0.6 risk factors what does the term “risk factor” mean? 4.2 ± 1 4.5 ± 0.7 which risk factors may have contributed to delaying recovery from surgery? 4.3 ± 0.9 4.6 ± 0.5 what can be done to decrease the chances of having another heart attack or of having a heart attack? 4.3 ± 0.9 4.7 ± 0.5 how do these risk factors affect the heart? 4.4 ± 0.9 4.6 ± 0.5 medication information when should the patient take each medication? 4.9 ± 0.2 4.8 ± 0.3 how should each medication be taken? 4.9 ± 0.3 4.8 ± 0.4 why is the patient taking each medication? 4.8 ± 0.5 4.8 ± 0.4 what is the side-effect of each medication? 4.8 ± 0.4 4.7 ± 0.5 what should be done if the patient has problems with their medication? 4.5 ± 0.4 4.8 ± 0.3 when should the patient stop taking medication? 4.8 ± 0.4 4.8 ± 0.4 how does each medication work? 4.6 ± 0.8 4.5 ± 0.8 diet information how does diet affect the operation? 4.7 ± 0.6 4.6 ± 0.6 what do the words “cholesterol” and “triglycerides” mean? 4.6 ± 0.8 4.4 ± 0.8 what foods contain cholesterol and triglycerides? 4.6 ± 0.9 4.6 ± 0.6 which food can and cannot be eaten? 4.6 ± 0.9 4.7 ± 0.5 how can the patient adapt the recommended diet to their lifestyle? 4.7 ± 0.8 4.7 ± 0.5 mcplni = modified version of the cardiac patients learning need inventory; sd = standard deviation. note: the degree of importance of the learning needs was based on the total mean score and categorised as either low (1–2.33), moderate (2.34–3.66) or high (3.67–5.00). ahmed a. almaskari, huda al noumani, khalid al-omari and mohammed a. al maskari clinical and basic research | e127 information regarding leg and chest wounds as top learning priority.8,16 patients’ and nurses’ perceptions that leg and chest wounds, medications and complications were the most important learning needs in comparison to other domains can be explained by the severity of complications associated with cabg surgery. in addition, they may have had concerns around wound infection such as re-hospitalisation and have been more willing to adhere to treatment plans and medication regimens.11,16 these findings are consistent with studies from western, eastern and middle eastern countries, which emphasise that nurses should pay more attention to educational plans regarding wound management, preventing surgery complications and wound infection.16,17 in the current study, patients perceived physical activity as the lowest educational priority. this finding was inconsistent with omari et al. and hamdan et al.’s studies that reported physical activity as the most important educational need post-cabg.8,15 this incon sistency could be explained by the fact that the majority of the current sample were older (median = 63 years), unemployed (44.4%) and some were illiterate (43.3%). another reason for the perception of low educational need for physical activity may be related to the omani climate. oman is hot and humid with average temp eratures ranging between 30–50°c, which makes the outdoor environment discouraging for physical activity. despite the physical activity domain receiving the lowest priority in terms of learning needs, the indiv idual items were perceived as having high-to-moderate importance, indicating that education on physical activ ities should be included when planning post-discharge educational plans. a major limitation of this study is its cross-sectional descriptive design, where perceived learning needs cannot be determined over time. the convenience sampling technique may affect the study’s generalisability. data were collected from only two tertiary governmental hospitals and therefore excluded post-cabg patients and nurses from private hospitals. future studies should focus on developing an educational programme upon discharge and testing its effectiveness on patients’ post-cabg outcomes in a longitudinal study. future studies should include cabg patients and nurses from private hospitals and compare their perceived table 4 (contd.): mean score for each item of the modified cardiac patients learning need inventory questionnaire for patients (n = 90) and nurses (n = 90) mcplni domain items mean score ± sd patients’ perceptions nurses’ perceptions can the patient return to work? 3.2 ± 1.7 4.6 ± 0.6 when can the patient return to work? 3.3 ± 1.6 4.5 ± 0.6 what physical activities, if any, are restricted? 3.5 ± 1.6 4.6 ± 0.6 how can i tell if the patient can increase activity? 3.8 ± 1.5 4.5 ± 0.7 when can the patient engage in sexual activity? 3.4 ± 1.4 4.6 ± 0.7 complications what complications might occur from the operation? 4.8 ± 0.6 4.7 ± 0.6 how can complications be recognised? 4.7 ± 0.7 4.7 ± 0.5 how can complications be prevented? 4.8 ± 0.5 4.8 ± 0.4 chest and leg wound care how can chest and leg wounds be cared for appropriately? 4.9 ± 0.2 4.8 ± 0.4 what are the symptoms of wound infection in the chest or leg? 4.9 ± 0.3 4.9 ± 0.3 how can chest and leg wounds be protected from infection? 4.9 ± 0.2 4.9 ± 0.3 other pertinent information when should the doctor be called? 4.7 ± 1.1 4.6 ± 0.6 will any other tests be done after the patient leaves the hospital? 4.7 ± 0.1 4.5 ± 0.6 will the patient need further testing after going home? 4.1 ± 1 4.5 ± 0.6 where can family go to learn how to deal with the operation? 4.3 ± 1 4.5 (0.6) mcplni = modified cardiac patients learning need inventory; sd = standard deviation. note: the degree of importance of the learning needs was based on the total mean score and categorised as either low (1–2.33), moderate (2.34–3.66) or high (3.67–5.00). patients’ and nurses’ perceptions of post-coronary artery bypass graft learning needs in two omani hospitals e128 | squ medical journal, may 2019, volume 19, issue 2 learning needs. in addition, future studies should aim to examine the influence of exposure to cabg via family or close friends on patients’ learning needs. conclusion this study highlights the need to assess patients' learning needs and establish a specific health education programme focusing on post-cabg learning needs after discharge. nurses and healthcare providers should direct their efforts towards understanding patients' learning needs as guided by the findings of this study to plan a welldeveloped and personalised discharge education pro gramme. hospital management should consider making necessary adjustments to educational plans provided to post-cabg patients, keeping in mind the necessity to prioritise learning needs. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. world health organization. cardiovascular diseases (cvds). from: https://www.who.int/en/news-room/fact-sheets/detail/ cardiovascular-diseases-(cvds) accessed: feb 2019. 2. alkubati sa, al-zaru im, khater w, ammouri aa. perceived learning needs of yemeni patients after coronary artery bypass graft surgery. j clin nurs 2013; 22:930–8. https://doi.org/10.11 11/j.1365-2702.2012.04177.x. 3. jordanian ministry of health. ministry of health annual statistics 2014. from: http://www.moh.gov.jo/echobusv3.0/ systemassets/352cce0e-3a6c-47d4-9675-87336fbd775d.pdf accessed: feb 2019. 4. world life expectancy. health profile: oman. from: https:// www.worldlifeexpectancy.com/country-health-profile/oman accessed: feb 2019. 5. ministry of health. health vision 2050. from: www.moh.gov. om/documents/16506/119833/health+vision+2050/7b6f40f38f93-4397-9fde-34e04026b829 accessed: feb 2019. 6. akbari m, celik ss. the effects of discharge training and counseling on post-discharge problems in patients undergoing coronary artery bypass graft surgery. iran j nurs midwifery res 2015; 20:442–9. https://doi.org/10.4103/1735-9066.161007. 7. henderson a, chien wt. information needs of hong kong chinese patients undergoing surgery. j clin nurs 13:960–6. https://doi.org/10.1111/j.1365-2702.2004.01004.x. 8. omari f, al-zaru i, al-yousef rh. perceived learning needs of syrian patients postcoronary artery bypass graft surgery. j clin nurs 2014; 23:1708–17. https://doi.org/10.1111/jocn.12319. 9. ganguly ss, al-shafaee ma, al-maniri aa. some risk factors for coronary heart disease among omani males: a matched case-control study. sultan qaboos univ med j 2008; 8:45–51. 10. al-noumani h, wu jr, barksdale d, alkhasawneh e, knafl g, sherwood g. relationship between medication adherence and health beliefs among patients with hypertension in oman: pilot study. sultan qaboos univ med j 2017; 17:e329–33. https://doi.org/10.18295/squmj.2017.17.03.012. 11. gerard ps, peterson lm. learning needs of cardiac patients. cardiovasc nurs 1984; 20:7–11. 12. sultana, r. patients' discharge information needs and nurses discharge information support regarding myocardial infarction in bangladesh. master thesis, 2014, prince of songkla univ ersity, phuket, thailand. 13. ministry of social development. social security law. from: www.mosd.gov.om/images/rules/law%20of%20social%20 security%2087-84.pdf accessed: feb 2019. 14. baily jm. patients and nurses’ perception of the cardiac patient’s learning needs. master thesis, 2004, florida state university, tallahassee, florida, usa. 15. hamdan frs, al-momani in. jordanian nurses and acute myocardial infarction patients' perceptions about learning needs. global j med phys health educ 2015; 3:85–99. 16. yiu hy, chien wt, lui mh, qin b. information needs of chinese surgical patients on discharge: a comparison of patients’ and nurses’ perceptions. j adv nurs 2011; 67:1041–52. https://doi.org/10.1111/j.1365-2648.2010.05528.x. https://doi.org/10.1111/j.1365-2702.2012.04177.x https://doi.org/10.1111/j.1365-2702.2012.04177.x https://doi.org/10.4103/1735-9066.161007 https://doi.org/10.1111/j.1365-2702.2004.01004.x https://doi.org/10.1111/jocn.12319 https://doi.org/10.18295/squmj.2017.17.03.012 https://doi.org/10.1111/j.1365-2648.2010.05528.x departments of 1nutrition & health and 3epidemiology, groundwork llc, zurich, switzerland; 2department of nutrition, directorate general of health affairs, ministry of health, muscat, oman; 4department of health & nutrition, united nations international children’s emergency fund, amman, jordan *corresponding author’s e-mail: nico@groundworkhealth.org االنتشار الوطين لنقص الفيتامينات واألمالح وفقر الدم واضطراابت الدم الوراثية و نقص وفرط التغذية ا لدى العمانيات يف سن اإلجناب واألطفال يف سن ما قبل املدرسة نيكوالي بيرتي، �سليمة املعمرية، براديل وودرف، �سامية الغنامي، �سالح ال�سماخي، ابت�سام الغماري، فيلما تايلر، فابيان رونر، جيم�س ويرث abstract: a national cross-sectional survey was conducted to estimate the prevalence of anaemia, micronutrient deficiencies, haemoglobin disorders and overand undernutrition in children and women of reproductive age in oman. wasting and stunting were found in 9.3% and 11.4% of children aged 0–59 months, respectively, while 4.2% were overweight or obese. in addition, 23.8% were anaemic and 10.2%, 9.5% and 10.6% had iron, vitamin a and vitamin d deficiencies, respectively. sickle cell and β-thalassaemia genetic traits were present in 5.3% and 4.2% of children and 4.7% and 2.8% of women, respectively. overall, 9.1% of omani women were underweight and 59.2% were overweight or obese. the prevalence of anaemia was 27.8%, while iron, folate, vitamin b12 and vitamin d deficiencies affected 24.8%, 11.6%, 8.9% and 16.2%, respectively. anaemia among both children and women and the prevalence of overweight and obesity in women are the most concerning nutritional problems in oman. keywords: nutrition disorders; malnutrition; micronutrients; iron-deficiency anemia; avitaminosis; vitamin d deficiency; vitamin b 12 deficiency; oman. امللخ�ص: مت اإجراء م�سح وطني م�ستعر�س لتقدير مدى انت�سار فقر الدم ونق�س الفيتامينات واالأمالح وا�سطرابات الهيموغلوبني ونق�س وفرط التغذية لدى االأطفال والن�ساء يف �سن االإجناب يف عمان. مت العثور على حاالت الهزال والتقزم يف %9.3 و %11.4 من االأطفال الذين ترتاوح اأعمارهم بني 59-0 �سهًرا على التوايل، يف حني اأن %4.2 يعانون من زيادة الوزن اأو ال�سمنة. باالإ�سافة اإىل ذلك، كان %23.8 يعانون من فقر الدم و %10.2 و %9.5 و %10.6 يعانون من نق�س احلديد وفيتامني اأ وفيتامني د على التوايل. كانت ال�سفات الوراثية للخاليا املنجلية وثال�سيمية بيتا موجودة يف %5.3 و %4.2 من االأطفال و %4.7 و %2.8 من الن�ساء على التوايل. ب�سكل عام ، كانت %9.1 من الن�ساء العمانيات يعانون من نق�س الوزن و %59.2 يعانون من زيادة الوزن اأو ال�سمنة. بلغ معدل انت�سار فقر الدم %27.8، بينما اأثر نق�س احلديد وحم�س الفوليك وفيتامني ب 12 وفيتامني د على %24.8 و %11.6 و %8.9 و %16.2 على التوايل. يعد فقر الدم بني االأطفال والن�ساء وانت�سار الوزن الزائد وال�سمنة لدى الن�ساء من اأكرث امل�ساكل الغذائية املتعلقة ب�سلطنة عمان. الكلمات املفتاحية: ا�سطرابات التغذية. �سوء التغذية؛ املغذيات الدقيقة؛ فقر الدم الناجم عن نق�س احلديد؛ نق�س فيتامني اأ نق�س فيتامني د؛ نق�س فيتامني ب 21؛ �سلطنة عمان. national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children *nicolai petry,1 salima a. al-maamary,2 bradley a. woodruff,3 samia alghannami,2 saleh m. al-shammakhi,2 ibtesam k. al-ghammari,2 vilma tyler,4 fabian rohner,1 james p. wirth1 special contribution sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e151–164, epub. 28 jun 20 submitted 2 may 19 revision req. 25 sep 19; revision recd. 4 nov 19 accepted 5 dec 19 https://doi.org/10.18295/squmj.2020.20.02.005 over the last few decades, oman has undergone rapid economic growth and was ranked by the united nations as the most improved nation in the world in terms of human development between 1970 and 2010.1 this was accompanied by a consistent decline in the national prevalence of stunting, wasting and underweight in young children; moreover, the prevalence of undernutrition in non-pregnant women also declined during this period, albeit somewhat inconsistently.2–4 however, a recent study examining global trends between 1980–2013 reported that 73.4% of omani women were overweight or obese, with oman experiencing one of the largest prevalence increases in obesity worldwide.5 in contrast, the prevalence of other nutritional deficiencies among omani women has remained stable. as a result, oman may face nutritional health issues with regards to both over and undernutrition. while the prevalence of anaemia has declined in women, this is not the case among children.3,4,6 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children e152 | squ medical journal, may 2020, volume 20, issue 2 according to the world health organization (who), anaemia is a moderate public health problem for omani women and a severe public health problem for omani children.7 anaemia is a multifactorial condition that can lead to reduced working capacity, an increased risk of maternal and perinatal mortality and morbidity, adverse pregnancy outcomes, reduced educational achievements and poor cognitive perf ormance.8 aside from nutritionally-induced anaemia resulting from iron, folate and/or vitamin b12 def iciencies, the major causes of anaemia in middle eastern countries are haemoglobin disorders, such as β-thalassaemia and sickle cell anaemia, as well as infection.9 iron deficiency (id) and vitamin a deficiency (vad) are among the most prevalent micronutrient deficiencies worldwide, particularly affecting young children and women of reproductive age.10,11 in oman, the last nutrition assessment in 2004 reported a high prevalence of id in women and children and moderate levels of vad in children, but not women.12 vitamin d deficiency (vdd) might also be an issue in oman; however, vdd status has never been assessed on a national level. in order to understand the current nutritional situation in oman, the oman national nutrition survey (onns) was conducted from december 2016 to april 2017. the onns investigated the prevalence and severity of certain nutrition-related conditions, including under nutrition, overnutrition, anaemia, micronutrient def iciencies and certain genetic blood disorders (i.e. sickle cell disease/traits and β-thalassaemia). this information is intended to help with the revision of existing nutr ition-related programmes in oman and the five-year health development plan of the ministry of health. the current article presents and interprets onns data with regards to the prevalence of various forms of malnutrition in oman. methods s u r v e y d e s i g n a n d pa r t i c i pa n t s the onns was conducted between december 2016 and april 2017 as a subset of a national survey of chronic diseases and risk factors. the sampling proc edure and study design of the national survey utilised the stepwise approach advocated by the who.13 for both surveys, each of the 11 governorates in oman was considered a separate survey stratum. equal numbers of blocks within these governorates were identified and were selected at random from the 2010 oman census; following this, random individual households were selected within these census blocks. the household lists of the selected census blocks were updated prior to the randomised selection process. in the national chronic diseases survey, households were selected at random without regard to the citizenship of household members. however, the onns included only omani households because omani citizens are the primary beneficiaries of national public health progr ammes. thus, a random sample of omani households among those included in the national chronic diseases survey was selected from each governorate separately via simple random sampling. a total of 375 omani households were included from each governorate, as a priori sample size calculations indicated that this number would contain adequate numbers of omani women and children to sufficiently precise estimates of nutrition indicators. however, in muscat governorate, the national chronic diseases survey contained only 318 omani households; accordingly, all of these households were selected for inclusion in the onns. d ata c o l l e c t i o n a n d l a b o r at o r y a n a ly s i s one week prior to data collection, all field workers (including supervisors, team leaders, interviewers, phlebotomists, anthropometry specialist and laboratory technicians) received both classroom and practice training on data and specimen collection procedures. the classroom training was followed by two days of field testing in two census enumeration areas in muscat which were not part of the onns sample. interviews were conducted at selected households, starting with the household questionnaire, which was either administered to the head of the household or another knowledgeable adult. this questionnaire included modules related to household demographic variables, income and water, sanitation and hygiene practices. respondents were also asked about the usual frequency of purchasing cooking oil and wheat flour and the usual quantity purchased each time. these data were used to calculate average household consumption. individual consumption was calculated per adult male equivalent (ame) based on the members of each household, using ageand gender-specific categories proposed by the united nations food and agriculture organization.14 following this, individual questionnaires were administered to pregnant women of any age, care takers of children aged 0–59 months and non-pregnant women aged 15–49 years. for children, the questionnaire included questions regarding the children’s dietary diversity, history of recent illnesses, consumption of fortified foods and micronutrient supplements and level of sun exposure. for the pregnant and nicolai petry, salima a. al-maamary, bradley a. woodruff, samia alghannami, saleh m. al-shammakhi, ibtesam k. al-ghammari, vilma tyler, fabian rohner and james p. wirth special contribution | e153 non-pregnant women, the questionnaires collected information regarding marital status, educational level, dietary diversity, recent supplement consumption, knowledge of fortified foods and attitudes and behaviours. following the completion of all the interviews in the household, height and weight measurements were taken from all non-pregnant women and children in the household, while mid-upper arm circumference (muac) measurements were taken from pregnant women and children. weight was measured using electronic scales (seca, hamburg, germany). children who could not stand alone on the scale were measured while in their caretakers’ arms, with the weight of the former calculated using the tare function to subtract the weight of the latter. both children and women were weighed while wearing light clothing. length or height was measured using wooden height/length boards (united nations international children’s emergency fund [unicef], copenhagen, denmark). the length of children younger than two years old was measured while they were lying down. blood samples were collected from children aged 6–59 months and women aged 15–49 years in 50% and 25% of the selected households, respectively, in all governorates but muscat, where children in all households and women in 50% of households were included. such households were randomly designated prior to data collection. in non-phlebotomy-designated households, only haemoglobin concentrations were measured for all children aged 6–59 months and non-pregnant and pregnant women using the third drop of capillary blood collected from the individual’s finger with a finger stick, or a heel stick for children aged 6–11 months. haemoglobin concentrations were measured on-site using a portable point-of-care haemo globinometer (hb 301+ analyser, hemocue® ab, ängelholm, sweden). hemocue quality control material (low, medium and high concentration) was used on a daily basis and results recorded in a control form. among children selected for a phlebotomy, a total of 4 ml of blood was collected in an ethylene diaminetetraacetic acid (edta)-coated vacutainer (becton dickinson, franklin lakes, new jersey, usa) to obtain plasma for the analysis of micronutrient biomarkers and whole blood to measure markers of haemoglobinopathies. in non-pregnant women, blood was collected in two vacutainers: (1) 2 ml of blood was collected into an edta-coated vacutainer to measure markers of haemoglobinopathies and (2) 4 ml of blood was collected into a clotting-activator serum vacutainer to measure micronutrient biomarkers. following on-site haemoglobin measurements, labelled tubes containing whole blood were placed in cool boxes at 2–8°c and transported to regional laboratories for processing within 24 hours. cold boxes were refilled with ice packs on a daily basis and were equipped with thermometers to continuously monitor internal temperatures. for children, 0.5 ml of whole blood was taken out of the vacutainer prior to centrifugation to measure markers of haemoglobinopathies. for women, the edta coated vacutainer was used for the analysis of haemo globinopathies. for micronutrient analyses, blood tubes were centrifuged at 3,000 rpm for seven minutes to separate the plasma (in children) or serum (in women) from the blood cells and then aliquoted into labelled blood tubes and stored in freezers at −20°c until they were packed in dry ice and sent to international laboratories for analysis. no blood samples were taken from children under six months of age. plasma and serum were analysed for ferritin, retinol-binding protein (rbp), c-reactive protein (crp) and α1-acid glycoprotein (agp) at the vitmin laboratory (wilstätt, germany) using an enzymelinked immunosorbent assay.15 plasma and serum 25 hydroxycholecalciferol concentrations were measured using tandem liquid chromatography (lc) mass spectrometry at the khatib micronutrient laboratory (amman, jordan). this laboratory also measured plasma folate and vitamin b12 concentrations in women via electrochemiluminescence using the cobas® e411 automated analyser (roche diagnostics, risch-rotkreuz, switzerland). parameters and clinical thresholds haemoglobin concentrations were adjusted for altitude; however, as only two of the 4,598 women included in the sample stated that they smoked on a daily basis, they were not adjusted for smoking.16 children and pregnant women were considered anaemic if haemoglobin concentrations were <110 g/l, with con centrations of <70, 70–99 and 100–109 g/l classified as severe, moderate and mild anaemia, respectively. non-pregnant women were considered anaemic if haemoglobin concentrations were <120 g/l, with concentrations of <80, 80–109 and 110–119 g/l denoting severe, moderate and mild anaemia, respectively.17 the weighted prevalence of anaemia in both children and women was used to determine the public health significance of anaemia according to the who.17 individuals with severe anaemia were referred to their local health facility for further diagnosis and treatment. ferritin and rbp were adjusted for inflammation using crp and agp values according to previously reported methods.18,19 in children and women, id was defined as inflammation-adjusted ferritin concentr ations of <12 and <15 μg/l, respectively.20 as rbp is not a who-recommended biomarker for the assessment of vitamin a status, the correlation between rbp results national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children e154 | squ medical journal, may 2020, volume 20, issue 2 and serum retinol was checked by measuring retinol in a subset of specimens using high-performance lc at the khatib micronutrient laboratory. there was a strong correlation between retinol and rbp values upon linear regression analysis. nevertheless, the kappa coefficient of agreement and the sensitivity were higher when the rbp cut-off for defining vad was adjusted to 0.73 instead of 0.70 µg/l. for this reason, 0.73 and 1.05 µg/l were used as cut-off values to denote deficiency and insufficiency, respectively.21,22 cut-off values for crp and agp were >5 mg/l and >1 g/l, respectively. inflammation status was defined as follows: no inflammation, incubation (elevated crp only), early convalescence (elevated crp and agp) and late convalescence (elevated agp only).18,19 in non-pregnant women and children, vdd was defined using a cut-off value for 25-hydroxycholecalciferol of <30 nmol/l; for vitamin d insufficiency (vdi), the cut-off value was set at 50 nmol/l.23 sun exposure levels were defined according to previously published parameters.24 based on who recommendations, plasma folate concentrations of <10 nmol/l indicated folate deficiency while vitamin b12 deficiency was set at <150 pmol/l for women.25 height-for-age, weight-for-age and weight-forheight were calculated for all children based on the who growth standard.26 all forms of undernutrition were indicated by z-scores of less than −2.0. severe and moderate forms of undernutrition were defined by z-scores of less than −3.0 and −3.0 to −2.01, resp ectively. wasting, stunting and underweight were categ orised using weight-for-height, height-for-age and weight for-age z-scores, respectively. overweight in children was defined by a weight-for-height z-score greater than 2.0 to 3.0, while obesity was defined by a z-score greater than 3.0. the nutritional status of non-pregnant women aged 15–49 years was assessed via body mass index (bmi). six bmi categories were designated, including severe undernutrition (<16.0 kg/m2), moderate under nutrition (16.0–16.9 kg/m2), at risk of undernutrition (17.0–18.4 kg/m2), normal (18.5–24.9 kg/m2), over weight (25.0–29.9 kg/m2) and obese (≥30.0 kg/m2).27 for pregnant women, a muac of <23.0 cm was deemed to indicate undernutrition.28,29 d ata m a n a g e m e n t a n d s tat i s t i c a l a n a ly s i s questionnaire data were entered into a database using epidata, version 3.02 (epidata association, odense, denmark). in order to minimise the risk of data entry errors, the epidata software was programmed to only accept codes within a certain range specific to each variable; in addition, the data were double-entered and corrected following completion of the field work. data analysis was performed using the statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa) with the complex survey module. in order to account for the unequal probability of selection, strata-weighted analyses were used for household variables. moreover, because the sampling fraction for those undergoing phlebotomy differed among governorates, separate sampling weights for women and children were calculated for the results of blood testing. no sampling weights were used when generating governorate-specific estimates. the household wealth index was calculated based on methods described by filmer et al.30 data analysis included the calculation of proportions for all categ orical variables. for continuous variables, means or medians were calculated. variables were calculated for the entire sample across all strata, for each stratum as well as for certain variables, including educational status (for women), wealth quintile (for households) and gender (for children). results were also presented for specific age groups for pregnant women, nonpregnant women and children. unfortunately, an analysis of urban versus rural residences could not be performed because this classification does not exist in oman’s census data. prevalence maps for stunting, wasting and overweight and obesity among children and underweight, overweight and obesity among women were presented according to who classifications.31 the statistical precision of prevalence rates was assessed using 95% confidence intervals, which were calculated accounting for the complex sampling methods used in the survey. the significance of differences between subgroups was calculated using a chi-squared test with weighted analysis and adjusted for complex sampling. notably, vdd and vdi were merged to test for statistical significance between subgroups. this was due to the fact that deficiency and insufficiency are ranges on the same spectrum and therefore were not analysed separately. the level of statistical significance utilised throughout the analysis was set at p <0.05. e t h i c s a n d c o n s e n t the protocol of this study was granted ethical approval by the research and ethical review and approval committee of the oman ministry of health (#mh/ dgp/r&s/proposal_approved/45/2015). either the head of the household or, in their absence, another knowledgeable adult household member provided written informed consent prior to participation in the survey. all participants provided written informed consent before undergoing blood specimen collection and anthropometry measurements. women aged 18–45 years gave consent for themselves, while consent on behalf of preschool children and girls aged nicolai petry, salima a. al-maamary, bradley a. woodruff, samia alghannami, saleh m. al-shammakhi, ibtesam k. al-ghammari, vilma tyler, fabian rohner and james p. wirth special contribution | e155 15–17 years was given by a parent or legal guardian. any documents containing identifying data such as completed questionnaires and blood collection sheets were kept in a locked cabinet at the ministry of health to maintain confidentiality and privacy. results h o u s e h o l d d ata of the 3,862 households selected, data were collected from a total of 3,304 households (response rate: 85.6%). the average number of household members was 6.9 individuals. only 28.3% of the households owned agricultural land, while 43.2% owned livestock, mainly chickens, goats and sheep. overall, 89.9% of households had a safe water source, although 94.4% had access to safe water for drinking. adequate sanitation and handwashing facil ities with both soap and water were present in 85.2% and 97.4% of households, respectively. the most common types of oil used for cooking were sunflower oil (49.2%), ghee (40.3%), corn oil (38.8%) and olive oil (38.7%). at the time of the survey, 95.4% of households had cooking oil at home that was labelled as fortified. of the 81.9% of households which had wheat flour in the house at the time of data collection, 95.1% of the flour was marked as fortified. cooking oil and wheat flour consumption was calculated as 1.3 l and 3.4 kg per ame per month, respectively. consumption of cooking oil and wheat flour differed according to wealth quintile. average cooking oil consumption per ame per month was significantly higher in households in the poorest wealth quintile compared to those in other wealth quintiles (1.7 l versus 1.2–1.3 l; p <0.001). in addition, consumption of wheat flour was significantly higher among members of households in poor wealth quintiles compared to those in wealthier households (p <0.001). from the lowest to highest wealth quintiles, wheat flour consumption per ame per month was 5.2, 3.6, 3.4, 3.4 and 2.5 kg. o m a n i c h i l d r e n anaemia and micronutrient deficiencies the national prevalence rates of anaemia and micro nutrient deficiencies among omani children are presented in table 1, while subgroup analyses by age, gender, governorate and wealth quintile are shown in table 2. overall, 23.8% of the children were anaemic, with anaemia prevalence rates progressively decreasing with age and substantially varying by governorate, with the highest governorate-specific prevalence being more than two-fold higher than that of the lowest (31.3% in ad dhahirah versus 15.4% in dhofar; p <0.010). the data indicate that a lower proportion of children living in the wealthiest households suffered from anaemia compared to those living in poorer households (17.4% versus 24.0–27.5%); however, this difference was not statistically significant (p = 0.060). gender was not found to affect the prevalence of anaemia among omani children. only 10.2% of children had id and 1.6% had idanaemia (ida). age was significantly associated with both id and ida prevalence (p <0.010 each), with the highest prevalence rates of both conditions occurring in children aged 12–23 months (17.4% and 6.2%, respectively) and 24–35 months (12.1% and 3.6%, respectively). the prevalence rates of id and ida were highest in dhofar (41.8%) and ash-sharqiyah south (9.9%), respectively; however, neither governorate had the highest prevalence of anaemia. male children were significantly more likely to develop id than female children (11.7% versus 7.8%; p <0.050). although not statistically significant, children living in wealthier households seemed to be more susceptible to id than those in poorer households (10.3–15.4% versus 4.9– 7.9%; p = 0.099). however, there was no such trend with ida. overall, 9.5% of the children had vad, with significant differences between age groups. the prevalence of vad in children aged 6–11 months was more than double that of older children (23.5% versus 3.0–12.9%; p <0.010). considerable differences were also found between governorates, with prevalence rates ranging from 1.0% in ad dhahirah to 31.9% in al-wusta (p <0.001). however, vad prevalence did not differ substantially by gender. although not statistically significant, vad was more common in children in poorer households compared to those in wealthier households (11.6–16.1% versus 7.0–7.6%; p = 0.081). the prevalence rate of vdd was 10.6%; however, 53.8% of the children were classified as vitamin d-insufficient. there was no apparent change in the prevalence of vdd or vdi with age or household wealth; however, a significantly larger proportion of female children had vdd or vdi compared to male children (68.7% versus 60.1%; p <0.050). moreover, vdd or vdi varied substantially by governorate, ranging from 28.2% in ad dhahirah to 78.8% in dhofar (p <0.001). however, there was no statistically significant difference in vitamin d status between children with different levels of sun exposure, with 8.4% of children with the highest levels of sun exposure found to be vitamin d-deficient compared to 13.2% of children with the lowest levels. national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children e156 | squ medical journal, may 2020, volume 20, issue 2 inflammation and inherited blood disorders inflammation was relatively rare, with 20.2% of children having one or more elevated inflammatory marker. however, 5.3% of children were affected by heterozygous or homozygous sickle cell disorders, while 4.2% were carriers of the β-thalassaemia trait. anthropometric indices the national prevalence rates of stunting, wasting and underand overnutrition among omani children are presented in table 1. approximately one-tenth of the children were stunted (11.4%), wasted (9.3%) or underweight (11.2%). although not statistically table 1: anemia, micronutrient indicators (6–59 months) and anthropometric measures (0–59 months), among omani children parameter mean or prevalence* 95% ci† haemoglobin status (n = 2,531) haemoglobin in g/dl 11.6 11.5–11.6 anaemia‡ 23.8% 21.4–26.4% iron status (n = 1,077) plasma ferritin§ in µg/l 31.4 29.8–33.1 id¶ 10.2% 7.8–13.3% ida¶ 1.6% 1.1–2.3% vitamin a status (n = 1,083) plasma rbp in µmol/l§ 0.99 0.97–1.00 vad// 9.5% 7.5–12.1% vitamin d status (n = 1,036) plasma 25-ohd in nmol/l 18.6 18.0–19.1 vdd** 10.6% 8.0–13.5% vdi** 53.8% 49.7–57.9% genetic blood disorders status (n = 1,109) sickle cell trait 5.3% 3.4–8.3% β-thalassaemia 4.2% 2.3–7.4% inflammation status (n = 1,083) crp in mg/l 2.8 2.2–3.5 agp in g/l 0.71 0.67–0.74 incubation†† 4.5% 3.2–6.4% early convalescence†† 8.1% 5.9–11.0% late convalescence†† 7.5% 5.6–10.0% no inflammation 79.8% 76.2–83.1% birth weight status (n = 2,976) birth weight in kg 3.0 3.0–3.0 low birth weight‡‡ 11.7% 10.1–13.4% stunting status (n = 2,920) ha z-score −0.63 −0.68 to −0.58 any stunting§§ 11.4% 9.8–13.1% moderate stunting 8.7% 7.4–10.1% severe stunting§§ 2.7% 2.1–3.5% wasting status (n = 2,869) wh z-score −0.40 −0.45 to −0.35 b lo od p ar am et er s a nt hr op om et ri c in di ce s table 1 (cont’d): anemia, micronutrient indicators (6–59 months) and anthropometric measures (0–59 months), among omani children parameter mean or prevalence* 95% ci† any wasting¶¶ 9.3% 7.9–11.0% moderate wasting 6.2% 5.1–7.6% severe wasting¶¶ 3.1% 2.3–4.2% overweight and obesity status (n = 2,869) normal¶¶ 86.5% 84.7–88.1% overweight or obese 4.2% 3.4–5.1% overweight¶¶ 3.1% 2.4–4.0% obesity¶¶ 1.1% 0.7–1.7% underweight status (n = 2945) mean wa z-score −0.64 −0.71 to −0.57 any underweight//// 11.2% 9.6–13.1% moderate underweight 8.9% 7.5–10.5% severe underweight//// 2.4% 1.7–3.3% ci = confidence inter val ; id = iron deficiency; ida = id-anaemia ; rbp = retinol-binding protein; vad = vitamin a deficiency; ohd = hydro xycholecalciferol; vdd = vitamin d deficiency; vdi = vitamin d insuff iciency; crp = c-reactive protein; agp = α1-acid glycoprotein; ha = height for-age; wh = weight-for-height; wa = weight-for-age. *means indicate unweighted counts while percentages were weighted for unequal probability of selection. †considering the complex sampling design. ‡defined as altitude-adjusted haemoglobin levels of <110 g/l. §ferritin and rbp concentrations and associated deficiency prevalence rates were corrected for inflammation as per previously reported methods.18,19 ¶id was defined as serum ferritin levels of <12 µg/l and ida as serum ferritin levels of <12 µg/l and haemoglobin levels of <110 g/l. //vad was defined as rbp concentrations of <0.73 µmol/l. **vdd was defined as plasma 25-ohd levels of <30 nmol/l and vdi as plasma 25-ohd levels of 30–49.9 nmol/l. ††incubation was defined as crp levels of >5 mg/l and agp levels of <1 g/l, early convalescence as crp levels of >5 mg/l and agp levels of >1 g/l and late convalescence as crp levels of ≤5 mg/l and agp levels of >1 g/l. ‡‡defined as <2,500 g. §§any stunting was defined as a ha z-score of less than −2 and severe stunting as a ha z-score of less than −3. ¶¶any wasting was defined as a wh z-score of less than −2, severe wasting as a wh z-score of less than −3, normal as a wh z-score of −2 to 2, over weight as a wh z-score of 2–3 and obese as a wh z-score of >3. ////any underweight was defined as a wa z-score of <2 and severe underweight as a wa z-score of <3. a nt hr op om et ri c in di ce s nicolai petry, salima a. al-maamary, bradley a. woodruff, samia alghannami, saleh m. al-shammakhi, ibtesam k. al-ghammari, vilma tyler, fabian rohner and james p. wirth special contribution | e157 significant, stunting prevalence rates varied according to governorate. furthermore, the children of short mothers (<150 cm) had a much higher prevalence of stunting compared to children of taller mothers (19.9% versus 9.7%; p <0.001). age, gender, household wealth and maternal education were not significantly associated with stunting. the prevalence of wasting differed significantly by age group and was highest among children under 6 months and 6–11 months and lowest in children aged 12–23 months (15.5% and 10.7% versus 6.2%; p <0.050). although not statistically significant, the prevalence of wasting was highest in children living in the poorest households (14.7%). neither gender, governorate nor maternal education were determinants of wasting. the prevalence of overweight or obesity was 4.2% and varied substantially by age. children aged 6–11 and 12–23 months were significantly more likely to be overweight or obese compared to children aged 36–47 and 48–59 months (7.2% and 5.4% versus 1.8% and 2.1%; p <0.010). furthermore, differences were noted according to governorate. in addition, the prevalence of overweight or obesity progressively increased with household wealth from 1.6% in the poorest households table 2: prevalence of anaemia and micronutrient deficiencies by demographic characteristics among omani children aged 6–59 months characteristic anaemia* (n = 2,523) id† (n = 1,074) ida† (n = 1,074) vdd or vdi‡ (n = 1,036) vad§ (n = 1,083) %¶ 95% ci// %¶ 95% ci// %¶ 95% ci// %¶ 95% ci// %¶ 95% ci// age in months p <0.001** p <0.010** p <0.010** p = 0.420†† p <0.010** 6–11 40.4 32.8–48.6 5.3 2.1–12.5 2.2 0.5–8.5 62.6 47.5–75.6 23.5 10.8–43.8 12–23 33.4 27.8–39.5 17.4 11.9–25.6 6.2 3.6–10.6 58.8 49.6–67.3 3.0 1.6–5.6 24–35 23.6 19.6–28.2 12.1 7.9–17.9 3.6 1.8–7.0 64.1 55.6–71.7 8.2 5.1–12.7 36–47 15.0 11.4–19.5 7.4 4.0–13.4 1.1 0.4–3.0 64.9 56.7–72.3 10.0 6.7–14.8 48–59 11.9 8.3–16.7 4.9 2.6–9.0 1.2 0.4–3.4 70.3 62.5–77.0 12.9 8.0–20.1 gender p = 0.881** p <0.050** p = 0.173** p <0.050** p = 0.802** male 23.8 20.6–27.1 11.7 8.6–15.7 3.7 2.3–6.0 60.1 54.7–65.2 9.9 6.8–14.1 female 24.0 20.8–27.5 7.8 5.5–11.0 2.2 1.2–4.1 68.7 62.8–74.2 9.2 6.4–13.1 governorate p <0.010** p <0.001** p <0.010** p <0.001†† p <0.001** muscat 18.1 9.9–30.7 7.3 2.4–20.5 0 65.9 53.1–76.7 9.5 4.1–20.6 dhofar 15.4 11.6–20.1 41.8 29.8–54.8 8.9 4.6–16.5 78.8 68.1–86.6 8.6 5.5–13.2 ad dhakhiliyah 29.5 25.6–33.6 4.2 1.9–8.8 1.7 0.4–6.4 70.8 59.5–80.0 10.0 6.1–16.0 ash sharqiyah north 25.4 18.9–33.1 7.6 3.8–14.7 2.9 1.0–8.1 64.8 55.4–73.1 7.6 3.6–15.4 ash sharqiyah south 23.5 17.6–30.7 16.5 10.3–27.7 9.9 5.0–18.8 63.9 53.4–73.3 18.9 12.9–26.7 al-batinah north 23.0 17.0–30.2 6.1 2.6–13.4 2.0 0.6–7.1 66.7 56.4–75.5 8.1 4.3–14.8 al-batinah south 25.7 20.3–32.0 4.0 1.5–10.2 1.0 0.1–6.9 62.1 49.3–73.4 10.0 3.9–23.2 ad dhahirah 31.3 24.6–38.9 11.8 5.8–22.5 2.9 0.7–11.3 28.2 19.2–39.3 1.0 0.2–5.1 al-buraimi 21.5 16.4–27.7 3.4 1.5–7.4 0.9 0.1–5.7 63.8 53.1–73.3 5.0 2.3–10.3 musandam 22.3 17.1–28.5 9.5 5.4–16.3 2.4 0.7–8.3 58.0 49.7–65.9 11.9 7.1–19.3 al-wusta 23.3 19.2–27.9 17.0 9.4–28.8 8.5 3.5–19.0 62.0 50.2–72.5 31.9 22.2–43.5 wealth quintile p = 0.060** p = 0.099** p = 0.873** p = 0.262†† p = 0.081** poorest 27.5 21.1–34.8 4.9 2.2–10.8 3.3 1.1–9.3 66.8 55.6–76.3 11.6 6.0–21.2 poor 25.6 21.1–30.6 7.9 4.5–13.3 2.3 1.2–4.7 56.0 45.5–65.9 16.1 11.0–22.9 middle 24.0 19.6–28.9 7.7 4.7–12.4 3.8 1.7–8.4 69.5 61.3–76.6 8.3 4.4–15.1 wealthy 26.6 21.0–33.1 10.3 5.7–17.7 3.3 1.6–6.7 66.0 57.5–73.5 7.6 4.3–13.3 wealthiest 17.4 13.4–22.3 15.4 9.5–23.9 2.4 1.0–5.8 66.5 57.2–74.6 7.0 3.7–12.8 id = iron deficiency; ida = id-anaemia; vdd = vitamin d deficiency; vdi = vitamin d insufficiency; vad = vitamin a deficiency; ci = confidence interval. *defined as altitude-adjusted haemoglobin levels of <110 g/l. †id was defined as serum ferritin levels of <12 µg/l and ida as serum ferritin levels of <12 µg/l and haemoglobin levels of <110 g/l. serum ferritin levels were corrected for inflammation as per previously reported methods.18 ‡vdd was defined as plasma 25-hydroxycholecalciferol levels of <30 nmol/l and vdi as plasma 25hydroxycholecalciferol levels of 30–49.9 nmol/l. §defined as retinol-binding protein concentrations of <0.73 µmol/l. retinol-binding protein concentrations were corrected for inflammation as per previously reported methods.19 ¶weighted for unequal probability of selection. //considering the complex sampling design. **p values of <0.050 indicate that at least one subgroup differs significantly from the others. †overall p values for vdd and vdi by characteristic. national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children e158 | squ medical journal, may 2020, volume 20, issue 2 to 5.5% in the wealthiest quintile (p <0.050). moreover, obesity or overweight was more common in children of mothers who had completed their secondary school education or higher (5.0% versus 2.1–2.2%; p <0.050). figure 1 shows a prevalence map of stunting, wasting and overweight and obesity among omani children by governorate. table 3: micronutrient status indicators and prevalence of deficiencies among pregnant and non-pregnant omani women aged 15–49 years parameter mean or prevalence* 95% ci† haemoglobin status (n = 4,122) haemoglobin in g/dl 12.52 12.47–12.58 anaemia‡ 27.8% 25.9–29.8% anaemia during pregnancy‡ 29.3% 23.1–36.3% iron status (n = 1,518) plasma ferritin in µg/l§ 37.7 35.6–39.8 id¶ 24.8% 22.2–27.6% ida¶ 13.3% 11.2–15.8% vitamin a status (n = 1,520) plasma rbp in µmol/ l§ 1.47 1.44–1.50 vad// 0.2% 0.1–0.4% vitamin d status (n = 1,517) plasma 25-ohd in nmol/l 18.4 17.9–19.0 vdd** 16.2% 13.1–19.9% vdi** 41.5% 37.7–45.4% folate status (n = 1,495) serum folate in nmol/l 7.51 7.23–7.79 folate deficiency†† 11.6% 9.1–14.7% vitamin b12 status (n = 1,496) serum vitamin b12 in pmol/l 389 375–404 vitamin b12 deficiency‡‡ 8.9% 6.9–11.4% genetic blood disorders status (n = 1,499) sickle cell trait 4.7% 3.2–7.0% β-thalassaemia 2.8% 1.8–4.4% inflammation status (n = 1,518) crp in mg/l 4.4 4.0–4.9 agp in g/l 0.76 0.74–0.78 incubation§§ 16.5% 14.4–18.8% early convalescence§§ 8.8% 7.2–10.7% late convalescence§§ 6.8% 5.2–8.9% no inflammation 67.9% 64.7–71.0% b lo od p ar am et er s table 3 (cont’d): micronutrient status indicators and prev alence of deficiencies among pregnant and non-pregnant omani women aged 15–49 years parameter mean or prevalence* 95% ci† undernutrition status (n = 4,159) any undernutrition 9.1% 7.9–10.5% severe undernutrition¶¶ 1.6% 1.1–2.2% moderate undernutrition¶¶ 2.3% 1.8–3.0% at risk¶¶ 5.2% 4.3–6.2% undernutrition during pregnancy//// 5.0% 2.8–9.0% overweight and obesity status (n = 4,159) bmi in kg/m2 27.5 27.1–27.8 normal¶¶ 31.7% 29.9–33.5% overweight or obese 59.2% 57.1–61.4% overweight¶¶ 25.6% 23.9–27.4% obese¶¶ 33.6% 31.7–35.6% high whr*** 47.5% 45.1–49.8% ci = confidence interval; id = iron deficiency; ida = id-anaemia; rbp = retinol-binding protein; vad = vitamin a deficiency; ohd = hydroxy cholecalciferol; vdd = vitamin d deficiency; vdi = vitamin d insuff iciency; crp = c-reactive protein; agp = α1-acid glycoprotein; bmi = body mass index; whr = waist-to-hip ratio. *means indicate unweighted counts while percentages were weighted for unequal probability of selection. †considering the complex sampling design. ‡defined as altitude-adjusted haemoglobin levels of <120 g/l for nonpregnant women and <110 g/l for pregnant women. §ferritin and rbp concentrations and associated deficiency prevalence rates were corrected for inflammation as per previously reported methods.18,19 ¶id was defined as serum ferritin levels of <12 µg/l and ida as serum ferritin levels of <12 µg/l and haemoglobin levels of <120 g/l. //defined as rbp concent rations of <0.73 µmol/l. **vdd was defined as plasma 25-ohd levels of <30 nmol/l and vdi as plasma 25-ohd levels of 30–49.9 nmol/l. ††defined as serum folate levels of <10 nmol/l. ‡‡defined as plasma b12 levels of <150 pmol/l. §§incubation was defined as crp levels of >5 mg/l and agp levels of <1 g/l, early convalescence as crp levels of >5 mg/l and agp levels of >1 g/l and late convalescence as crp levels of ≤5 mg/l and agp levels of >1 g/l. ¶¶severe undernutrition was defined as a bmi of <16.0 kg/m2, moderate undernutrition as a bmi of 16.0–16.9 kg/m2, at risk of undernutrition as a bmi of 17.0–18.5 kg/m2, normal as a bmi of 18.5–24.9 kg/m2, overweight as a bmi of 25.0–29.9 kg/m2 and obese as a bmi of >30 kg/m2. ////defined as a mid-upper arm circum ference of <23.0 cm. ***defined as a whr of >0.85. a nt hr op om et ri c in di ce s nicolai petry, salima a. al-maamary, bradley a. woodruff, samia alghannami, saleh m. al-shammakhi, ibtesam k. al-ghammari, vilma tyler, fabian rohner and james p. wirth special contribution | e159 o m a n i w o m e n anaemia and micronutrient deficiencies the national prevalence rates of anaemia and micronutrient deficiencies among omani women are presented in table 3, while subgroup analyses by age, gender, governorate and wealth quintile among non-pregnant women are shown in table 4. just under one-third of non-pregnant and pregnant women were anaemic (27.8% and 29.3%, respectively). anaemia prevalence rates differed significantly by age table 4: prevalence of anaemia and micronutrient deficiencies by demographic characteristics among non-pregnant omani women aged 15–49 years characteristic anaemia* (n = 4,117) id† (n = 1,514) ida† (n = 1,514) vdd or vdi‡ (n = 1,515) folate deficiency§ (n = 1,493) vb12 deficiency¶ (n = 1,494) %// 95% ci** %// 95% ci** %// 95% ci** %// 95% ci** %// 95% ci** %// 95% ci** age in years p <0.001†† p <0.010†† p <0.050†† p <0.001‡‡ p <0.050†† p <0.050†† 15–19 28.8 24.1–34.0 32.1 25.3–39.8 14.3 9.7–20.7 73.9 65.3–81.0 13.7 9.0–20.3 9.5 5.9–14.9 20–24 20.5 16.8–24.8 24.3 18.2–31.7 12.8 8.1–19.6 68.8 58.9–77.1 18.8 12.5– 27.3 12.4 8.0–18.7 25–29 23.0 19.1–27.4 13.7 9.5–19.4 6.6 3.8–11.4 54.1 45.2–62.7 11.1 7.1–17.0 10.5 6.4–17.0 30–34 28.9 24.6–33.6 22.9 16.8–30.4 9.1 5.0–16.1 54.1 44.3–63.6 9.6 5.8–15.5 11.1 7.5–16.1 35–39 27.2 23.1–32.0 25.4 19.2–32.8 14.3 9.4–21.2 52.1 41.9–62.1 9.3 5.3–15.6 8.1 4.3–14.7 40–44 33.5 28.0–39.5 32.1 23.8–41.8 21.1 14.4–29.9 46.7 38.0–55.6 10.0 6.1–15.8 5.7 3.0–10.6 45–49 38.6 31.7–46.0 25.0 16.9–35.4 18.6 11.4–28.9 51.2 40.0–62.2 6.1 3.1–11.7 1.3 0.4–4.9 governorate p <0.001†† p = 0.193†† p <0.050†† p <0.001‡‡ p <0.001†† p <0.001†† muscat 28.0 23.1–33.5 27.2 21.1–34.2 16.6 11.4–23.4 44.1 35.4–53.1 11.8 6.8–19.9 2.0 0.7–5.5 dhofar 28.0 23.1–33.5 28.2 22.5–34.7 9.0 6.2–12.9 84.6 75.0–91.0 47.7 36.4– 59.3 20.0 10.2–35.5 ad dhakhiliyah 27.5 23.2–32.3 16.1 9.4–26.3 8.6 4.3–16.5 49.5 38.6–60.3 6.5 3.0–13.3 3.2 0.8–12.8 ash sharqiyah north 24.6 9.5–30.5 18.5 12.7–26.2 9.6 5.8–15.5 89.6 35.4–53.1 2.9 0.9–9.2 16.9 10.5–26.1 ash sharqiyah south 23.0 7.5–29.6 25.5 19.6–32.5 11.0 7.3–16.4 84.8 75.0–91.0 21.9 15.0– 30.8 22.6 15.5–31.7 al-batinah north 32.6 27.6–38.1 22.5 16.1–30.5 14.7 9.1–23.0 19.4 38.6–60.3 7.3 3.7–14.1 7.3 3.0–16.4 al-batinah south 29.5 24.5–35.0 30.7 24.7–37.4 15.7 10.3–23.2 88.6 82.3–94.1 1.6 0.4–6.3 9.5 5.8–15.3 ad dhahirah 31.1 26.9–35.8 33.1 24.2–43.4 18.0 11.7–26.7 81.2 75.5–91.0 4.4 1.8–10.1 4.4 1.1–15.7 al-buraimi 38.8 32.5–45.6 28.3 19.0–40.0 13.2 9.2–18.6 70.7 13.7–26.6 11.4 6.0–20.6 21.5 14.6–30.6 musandam 30.4 25.0–36.3 31.5 20.9–44.4 17.3 10.9–26.4 80.9 81.3–93.3 3.7 1.6–8.5 10.6 7.9–13.9 al-wusta 15.1 10.5–21.3 27.8 20.2–36.9 5.6 3.2–9.5 37.0 72.7–87.5 2.8 0.9–8.7 13.0 6.1–25.3 wealth quintile p = 0.931†† p <0.050†† p = 0.086†† p = 0.943‡‡ p = 0.781†† p = 0.144†† poorest 29.1 23.7–35.1 28.8 19.5–40.3 19.2 10.9–31.6 52.9 39.3–66.1 10.8 6.0–18.7 9.3 5.2–16.1 poor 27.3 23.0–32.1 24.0 18.4–30.7 14.6 10.2–20.5 59.8 48.2–70.4 9.0 5.0–15.6 11.1 6.7–17.9 middle 26.6 22.0–31.8 15.3 10.0–22.7 6.5 3.3–12.4 57.0 46.6–66.9 11.3 7.2–17.3 12.8 8.2–19.4 wealthy 27.5 23.8–31.6 23.4 18.2–29.5 13.2 9.1–19.0 59.0 48.3–68.9 11.5 7.5–17.2 8.6 5.4–13.4 wealthiest 28.9 25.6–32.5 29.7 24.4–35.7 15.1 11.1–20.3 56.7 49.2–63.9 13.0 8.8–18.8 6.3 3.9–9.8 id = iron deficiency; ida = id-anaemia; vdd = vitamin d deficiency; vdi = vitamin d insufficiency; vb12 = vitamin b12; ci = confidence interval. *defined as altitude-adjusted haemoglobin levels of <120 g/l. †id was defined as serum ferritin levels of <12 µg/l and ida as serum ferritin levels of <12 µg/l and haemoglobin levels of <110 g/l. serum ferritin levels were corrected for inflammation as per previously reported methods.18 ‡vdd was defined as plasma 25-hydroxycholecalciferol levels of <30 nmol/l and vdi as plasma 25-hydroxycholecalciferol levels of 30–49.9 nmol/l. §defined as plasma folate concentrations of <10 nmol/l. ¶defined as serum vitamin b12 levels of <150 pmol/l. //weighted for unequal probability of selection. **considering the complex sampling design. ††p values of <0.050 indicate that at least one subgroup differs significantly from the others. ‡‡overall p values for vdd and vdi by characteristic. national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children e160 | squ medical journal, may 2020, volume 20, issue 2 (p <0.001) and were highest in non-pregnant women between 40–44 and 45–49 years old (33.5% and 38.6%, respectively). furthermore, prevalence rates varied substantially among governorates, affecting only 15.1% of non-pregnant women living in al-wusta, but 38.8% of those in al-buraimi (p <0.001). household wealth was not substantially associated with anaemia among non-pregnant women. overall, 24.8% of non-pregnant women were irondeficient, with 13.3% suffering from ida. both id and ida were significantly associated with age (p <0.010 and <0.050, respectively); however, there was no clear trend in prevalence with increasing age. in addition, the prevalence of ida differed significantly according to governorate, with prevalence rates ranging from 5.6% in al-wusta to 18.0% in ad dhahirah (p <0.050); however, the same did not hold true with regards to id. household wealth was significantly associated with id (p <0.050), although there was again no clear trend with regards to either increasing or decreasing wealth. among non-pregnant women, the prevalence rate of vdd was 16.2%; however, 41.5% were vitamin d-insufficient. the prevalence of vdd or vdi varied substantially by age (p <0.001), with the highest prevalence rates noted among women aged between 15–19 and 20–24 years (73.9% and 68.8%, respectively). furthermore, substantial differences were detected between governorates, with prevalence rates varying more than four-fold (19.4% in al-batinah north versus 89.6% in ash sharqiyah north; p <0.001). no significant association was observed between wealth quintile and vitamin d status. both folate and vitamin b12 deficiencies were present in approximately one-tenth of non-pregnant women (11.6% and 8.9%, respectively). there were significantly lower rates of both deficiencies in older women (p <0.050 each), with both folate and vitamin b12 deficiencies being lowest in women aged 45– 49 years (6.1% and 1.3%, respectively) and highest among those aged 20–24 years (18.8% and 12.4%, respectively). in addition, significant differences were observed in folate deficiency prevalence rates between governorates (p <0.001). in five governorates, including ash sharqiyah north, al-batinah south, ad dhahirah, musandam and al-wusta, <5% of women were folate-deficient; in contrast, the prevalence in dhofar was 47.7%. similarly, there were significant differences between governorates in terms of vitamin b12 deficiency prevalence, with rates differing by more than 10-fold (2.0% in muscat versus 22.6% in ash sharqiyah south). inflammation and inherited blood disorders inflammation was more common among omani women compared to omani children, with 32.1% of women having at least one elevated inflammatory marker. in terms of haemoglobinopathies, 4.7% of women were affected by the sickle cell trait, while 2.8% were carriers of the β-thalassaemia trait. figure 1: prevalence maps of (a) stunting (n = 2,920), (b) wasting (n = 2,869), (c) underweight (n = 2,945) and (d) overweight or obesity (n = 2,869) among omani children aged 0–59 months stunting, wasting and underweight categories were based on world health organization classifications.31 nicolai petry, salima a. al-maamary, bradley a. woodruff, samia alghannami, saleh m. al-shammakhi, ibtesam k. al-ghammari, vilma tyler, fabian rohner and james p. wirth special contribution | e161 anthropometric indices prevalence rates of overand undernutrition as well as mean bmi measurements for omani women are presented in table 3. the prevalence of undernutrition in non-pregnant omani women consistently decreased with age (p <0.001), from 23.2% and 16.8% in women aged 15–19 and 20–24 years, respectively, to 1.1% and 0.4% in women aged 40–44 and 45–49 years, respectively. the prevalence of underweight differed significantly between governorates, with prevalence rates ranging from 3.8% in al-wusta to 11.5% in ad dhakhiliyah (p <0.010). overnutrition was very common in omani women and its prevalence increased with age (p <0.001). only 25.7% of women aged 15–19 years were overweight or obese, compared to 40.1% and 54.0% of those aged 20–24 and 25–29 years, respectively, and 86.3% and 88.0% of those aged 40–44 and 45–49 years, respectively. significant differences in overweight or obesity were also detected by governorate (p <0.001). the waist-to-hip ratio was high in 47.5% of women, with similar patterns to rates of overweight or obesity. figure 2 shows a prevalence map of underweight, overweight, and obesity among non-pregnant omani women by governorate. discussion according to the who, the prevalence of anaemia in omani children constitutes a moderate public health problem.7 in comparison to the results of the last national survey conducted in 2004, the prevalence of childhood anaemia was found to have halved in the onns, a finding which might be explained by the equally strong decline in id prevalence over the same time period.12 although not as pronounced as in children, the prevalence of anaemia among nonpregnant omani women similarly dropped by almost 30%. for both population groups, anaemia prevalence rates are in the same range as those reported by other countries in the middle eastern and north african region.32 in contrast, the rate of childhood id—found to affect approximately one-tenth of children in the onss—can be classified as not prevalent in oman.20 this could be due to the implementation of the national iron supplementation programme for children under two years of age. the prevalence of concurrent anaemia and id in omani children was not higher than that expected from a random distribution of these two conditions. these results imply that iron deficiency does not have a contributory role in anaemia among omani children. this finding contradicts the widely held assumption that 50% of anaemia cases arise due to id, as well as the findings of a recent systematic analysis demonstrating that id contributes to 25% of anaemia cases in many parts of the world.11 as such, the aetiology of anaemia in omani children remains unclear. in contrast, id contributed to 50% of the anaemia found in omani figure 2: prevalence maps of (a) underweight, (b) overweight and (c) obesity among non-pregnant omani women aged 15–49 years (n = 4,159). underweight, overweight, and obesity categories were based on world health organization classifications.31 national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children e162 | squ medical journal, may 2020, volume 20, issue 2 women. although the prevalence of id in both children and women has decreased compared to findings from the 2004 national survey, this decrease was less apparent in women.12 the onns indicated that more than 80% of omani women, but not children, consumed either tea or coffee or both daily.33 if these beverages are consumed before, during, or shortly after meals, they can inhibit non-haem-iron absorption, thereby contributing to id.34 nevertheless, the relatively high prevalence of id noted in omani women is somewhat surprising, considering that wheat flour fortification is mandatory in oman. however, average wheat flour consumption was approximately 100 g per person per day, an amount which provides about 5 mg of electrolytic iron per day. using iron compounds with higher bioavailability, such as ferrous sulphate, sodium iron edta or ferrous fumarate, and/or increasing the concentration of the iron fortificant in wheat flour might have a positive effect on the iron status of omani women.35 in fact, the who recommends that electrolytic iron not be used as a fortificant if average flour consumption is 75–149 g per person per day; instead, water-soluble forms or chelates of iron should be added to wheat flour at levels of 40–60 ppm.36 nationally, vad was almost non-existent among omani women at a prevalence of 0.2%, but could be considered a mild public health problem in children at 9.5%. however, this does not apply to the governorates of al-wusta and ash sharqiyah south, where the public health significance of the rates of this childhood deficiency can be classified as severe and moderate, respectively.37 since only a few women and children in oman consume vitamin a or multivitamin supplements33, dietary vitamin a must come from vitamin a-rich foods and/or fortified vegetable oil. the food fortification programme in oman mandates that all cooking oils and margarine be fortified. in the onns, women and children consumed an estimated 35 ml and 15 ml, respectively, of vegetable oil daily.33 such high levels of consumption of fortified oil likely contribute to the low prevalence of vad. however, the high prevalence of vad in children in al-wusta and ash sharqiyah south warrants further investigation, especially since al-wusta had the highest rate of oil consumption per capita.33 accordingly, these governorates may need additional interventions targeted at children to increase consumption of vitamin a-rich and fortified foods. although approximately 60% of both children and women in oman had vdd or vdi, most were cases of insufficiency rather than deficiency. the prevalence of vdd in oman is low compared to other countries in the region.32 a national survey conducted in jordan reported that 19.8% of children aged 12–59 months and 60.3% of non-pregnant women of reproductive age were vitamin d-deficient.23,38 one of the reasons for the comparatively low prevalence of vdd in oman might be the increased intake of vitamin d through the consumption of fortified vegetable oil. both, the relatively high consumption of vegetable oil in oman and the existing oil fortification policy enables access to enough vitamin d for most of the omani population. normally, vitamin d is primarily obtained via sun exposure, which may be limited among omani women as most remain covered while outside of their homes. this may account for the lack of apparent association between sun exposure and vitamin d,33 unlike findings observed in jordan.23,38 further assessment of oil consumption practices and compliance with oil fortification policies in oman could provide information as to whether the fortification levels should be adjusted or the quality control system strengthened to effectively improve the vitamin d status of omani women and children. moreover, adding vitamin d to wheat flour may be an effective strategy to complement vitamin d intake from fortified oil. both folate and vitamin b12 deficiencies were found to affect approximately one in 10 women in oman. according to the current food fortification programme in oman, 1.5 ppm of folic acid is added to wheat flour; however, this level of fortification is below who guidelines which recommend a concentration of 2.6 ppm of folic acid if wheat flour consumption is between 75–149 g per person per day.36 although rates of folate and vitamin b12 deficiencies among omani women were relatively low, increasing the quantity of folic acid and including vitamin b12 fortificants to wheat flour could further reduce the rate of these deficiencies. prevalence rates of childhood stunting, wasting and underweight in the onns do not denote a severe public health problem in oman; nevertheless, the rates of these nutritional issues have increased slightly since 2008.3 in addition, rates of such problems in oman are alarmingly high compared to recent data from other countries in the middle east.39 the high incidence of low birth weight in oman was, according to the who, within the range reported by the least economically developed countries in the world.40 in contrast to stunting, wasting in omani children was highest in the first year of life, decreasing by about half by the second year of life. this is different from other countries where the average weight-for-height z-score begins to fall towards the end of the first year of life and remains low throughout the second year, due in part to poor complementary feeding.41 the early decline in weight-for-height z-score in oman could be due to poor breastfeeding practices, particularly a lack of exclusive breastfeeding.33 nicolai petry, salima a. al-maamary, bradley a. woodruff, samia alghannami, saleh m. al-shammakhi, ibtesam k. al-ghammari, vilma tyler, fabian rohner and james p. wirth special contribution | e163 the national prevalence of overweight and obesity in omani children in the onns was found to have increased since 2008.3 although childhood overweight and obesity prevalence rates are still not high, efforts should nevertheless be made to prevent further incr eases in the future. overweight and obesity have been associated with type 2 diabetes mellitus (t2dm) in children and adolescents in kuwait and saudi arabia.42,43 this chronic disease could become a public health problem in oman in the near future if such prevalence rates continue to rise. in contrast to children, the prevalence of over weight and obesity among omani women was high. more than half of non-pregnant women aged 15–49 years were overweight or obese, with prevalence rates clearly increasing with age. over the past few decades, oman has experienced one of the sharpest increases in obesity prevalence worldwide.5 as with children, overweight and obesity is a key risk factor for t2dm, which has risen dramatically among women in middle eastern countries in the past two decades.44 a recent study estimated that 10–20% of omani adults have t2dm.45 as overweight and obesity are also risk factors for cardiovascular diseases and various cancers, oman may soon face a substantial rise in the incidence of several diseases linked to overnutrition.46 according to the who, while various societal and environmental factors influence excessive weight gain, lifestyle modif ications in both dietary habits and physical activity levels can play a major role in preventing obesity.47 conclusion although the national food fortification programme in oman may already have helped to decrease the prevalence of several micronutrient deficiencies in children and women, further modifications might be key to alleviate those which still remain prevalent. it is therefore recommended that governmental organisations ensure that food vehicles are fortified according to international recommendations. moreover, the food fortification programme should be revised to focus on governorates with high micronutrient deficiencies, such as al-wusta and ash sharqiyah south. finally, governmental policies should address the alarmingly high rate of overweight and obesity among omani women so as to mitigate the risk of chronic diseases linked to overnutrition, such as t2dm, cardiovascular diseases and various cancers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the unicef oman. references 1. united nations development programme. human development report 2010: the real wealth of nations pathways to human development. from: http://hdr.undp.org/sites/default/files/repo rts/270/hdr_2010_en_complete_reprint.pdf accessed: nov 2019. 2. alasfoor d, elsayed mk, al-qasmi am, malankar p, sheth m, prakash n. protein-energy malnutrition among preschool children in oman: results of a national survey. east mediterr health j 2007; 13:1022–30. https://doi.org/10.26719/2007.13.5.1022. 3. elsayed m, al-shammkhi s. second national health survey for protein energy malnutrition in children below five years of age in the sultanate of oman: 2008-2009 analysis report. muscat, oman. from: https://groundworkhealth.org/wp-content/uploa ds/2020/04/elsayed-2009_second-national-health-surveyfor-pem-in-oman.pdf accessed: apr 2020. 4. united nations children’s fund. health and nutrition status of omani families (un-published). muscat, oman: united nations children’s fund, 1992. 5. ng m, fleming t, robinson m, thomson b, graetz n, margono c, et al. global, regional, and national prevalence of overweight and obesity in children and adults during 19802013: a systematic analysis for the global burden of disease study 2013. lancet 2014; 384:766–81. https://doi.org/10.1016/ s0140-6736(14)60460-8. 6. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1 methodology, sociodemographic profile and epidemiology of non-com municable diseases in oman. oman med j 2012; 27:425–43. https://doi.org/10.5001/omj.2012.43. 7. world health organization. worldwide prevalence of anaemia 1993–2005: who global database on anaemia. from: https:// apps .who.int/iris/bitstream/handle/10665/43894/978924 1596657_eng.pdf;sequence=1 accessed: nov 2019. 8. world health organization. global nutrition targets 2025: anaemia policy brief. from: https://apps.who.int/iris/bitstrea m/handle/10665/148556/who_nmh_nhd_14.4_eng . pdf?ua=1 accessed: nov 2019. 9. kassebaum nj, jasrasaria r, naghavi m, wulf sk, johns n, lozano r, et al. a systematic analysis of global anemia burden from 1990 to 2010. blood 2014; 123:615–24. https://doi.org/10.11 82/blood-2013-06-508325. 10. wirth jp, petry n, tanumihardjo sa, rogers lm, mclean e, greig a, et al. vitamin a supplementation programs and cou-n try-level evidence of vitamin a deficiency. nutrients 2017; 9. https://doi.org/10.3390/nu9030190. 11. petry n, olofin i, hurrell rf, boy e, wirth jp, moursi m, et al. the proportion of anemia associated with iron deficiency in low, medium, and high human development index countries: a systematic analysis of national surveys. nutrients 2016; 8:e693. https://doi.org/10.3390/nu8110693. 12. oman ministry of health. national micronutrient status and fortified food coverage survey report. muscat, oman: oman ministry of health, 2009. from: http://groundworkhealth.org/ wp-content/uploads/2020/04/moh-2009_national-foodfortification-coverage-survey.pdf accessed: apr 2020. 13. world health organization. noncommunicable diseases and their risk factors: stepwise approach to chronic disease risk factor surveillance (steps). from www.who.int/ncds/ surveillance/steps/en/ accessed: nov 2019. 14. weisell r, dop mc. the adult male equivalent concept and its application to household consumption and expenditures surveys (hces). food nutr bull 2012; 33:s157–62. https://doi.org/10.11 77/15648265120333s203. https://doi.org/10.26719/2007.13.5.1022 https://doi.org/10.1016/s0140-6736%2814%2960460-8 https://doi.org/10.1016/s0140-6736%2814%2960460-8 https://doi.org/10.5001/omj.2012.43 https://doi.org/10.1182/blood-2013-06-508325 https://doi.org/10.1182/blood-2013-06-508325 https://doi.org/10.3390/nu9030190 https://doi.org/10.3390/nu8110693 https://doi.org/10.1177/15648265120333s203 https://doi.org/10.1177/15648265120333s203 national prevalence of micronutrient deficiencies, anaemia, genetic blood disorders and overand undernutrition in omani women of reproductive age and preschool children e164 | squ medical journal, may 2020, volume 20, issue 2 15. erhardt jg, estes je, pfeiffer cm, biesalski hk, craft ne. combined measurement of ferritin, soluble transferrin receptor, retinol binding protein, and c-reactive protein by an inexpensive, sensitive, and simple sandwich enzyme-linked immunosorbent assay technique. j nutr 2004; 134:3127–32. https://doi.org/10.10 93/jn/134.11.3127. 16. sullivan km, mei z, grummer-strawn l, parvanta i. haemo globin adjustments to define anaemia. trop med int health 2008; 13:1267–71. https://doi.org/10.1111/j.1365-3156.2008.02143.x. 17. world health organization. haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. from: www. who.int/vmnis/indicators/haemoglobin.pdf accessed: nov 2019. 18. thurnham di, mccabe ld, haldar s, wieringa ft, northrop-clewes ca, mccabe gp. adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a metaanalysis. am j clin nutr 2010; 92:546–55. https://doi.org/10.39 45/ajcn.2010.29284. 19. thurnham di, mccabe gp, northrop-clewes ca, nestel p. effects of subclinical infection on plasma retinol concentrations and assessment of prevalence of vitamin a deficiency: metaanalysis. lancet 2003; 362:2052–8. https://doi.org/10.1016/s01 40-6736(03)15099-4. 20. world health organization. serum ferritin concentrations for the assessment of iron status and iron deficiency in populations. from: www.who.int/vmnis/indicators/serum_ferritin.pdf accessed: nov 2019. 21. world health organization. serum retinol concentrations for determining the prevalence of vitamin a deficiency in populations. from: www.who.int/vmnis/indicators/retinol.pdf accessed: nov 2019. 22. de pee s, dary o. biochemical indicators of vitamin a deficiency: serum retinol and serum retinol binding protein. j nutr 2002; 132:2895s–901s. https://doi.org/10.1093/jn/132.9.2895s. 23. nichols ek, khatib im, aburto nj, serdula mk, scanlon ks, wirth jp, et al. vitamin d status and associated factors of deficiency among jordanian children of preschool age. eur j clin nutr 2015; 69:90–5. https://doi.org/10.1038/ejcn.2014.142. 24. gannagé-yared mh, maalouf g, khalife s, challita s, yaghi y, ziade n, et al. prevalence and predictors of vitamin d inadequacy amongst lebanese osteoporotic women. br j nutr 2009; 101:487–91. https://doi.org/10.1017/s0007114508023404. 25. de benoist b. conclusions of a who technical consultation on folate and vitamin b12 deficiencies. food nutr bull 2008; 29:s238–44. https://doi.org/10.1177/15648265080292s129. 26. cogill b. anthropometric indicators measurement guide. from: www.fsnnetwork.org/anthropometric-indicators-measurementguide accessed: nov 2019. 27. shetty ps, james wpt. body mass index: a measure of chronic energy deficiency in adults fao food and nutrition paper. from: www.fao.org/3/t1970e/t1970e00.htm accessed: nov 2019. 28. food and nutrition technical assistance. use of cutoffs for midupper arm circumference (muac) as an indicator or predictor of nutritional and health-related outcomes in adolescents and adults: a systematic review. from: www.fantaproject.org/sites/ default/files/resources/muac%20systematic%20review%20_ nov%2019.pdf accessed: nov 2019. 29. addo oy, stein ad, fall ch, gigante dp, guntupalli am, horta bl, et al. maternal height and child growth patterns. j pediatr 2013; 163:549–54. https://doi.org/10.1016/j.jpeds.2013.02.002. 30. filmer d, pritchett lh. estimating wealth effects without expenditure data--or tears: an application to educational enrollments in states of india. demography 2001; 38:115–32. https://doi.org/10.1353/dem.2001.0003. 31. world health organization. nutrition landscape information system (nlis): country profile indicators interpretation guide. from: https://apps.who.int/iris/handle/10665/44397 accessed: nov 2019. 32. hwalla n, al dhaheri as, radwan h, alfawaz ha, fouda ma, al-daghri nm, et al. the prevalence of micronutrient defic iencies and inadequacies in the middle east and approaches to interventions. nutrients 2017; 9:e229. https://doi.org/10.3390/ nu9030229. 33. ministry of health oman, groundwork & unicef. oman national nutrition survey 2017. (2018). from: http:// groundworkhealth.org/wp-content/uploads/2020/04/onns_ report_2017.pdf accessed: apr 2020 34. hurrell rf, reddy m, cook jd. inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. br j nutr 1999; 81:289–95. https://doi.org/10.1017/s0007114599000537. 35. world health organization. guidelines on food fortification with micronutrients. from: www.who.int/nutrition/publications/g uide_food_fortification_micronutrients.pdf accessed: nov 2019. 36. world health organization. recommendations on wheat and maize flour fortification: meeting report interim consensus statement. from: www.who.int/nutrition/publications/micronu trients/wheat_maize_fort.pdf accessed: oct 2019. 37. world health organization. global prevalence of vitamin a deficiency in populations at risk 1995–2005: who global database on vitamin a deficiency. from: https://apps.who. int/iris/bitstream/handle/10665/44110/9789241598019_eng. pdf?sequence=1 accessed: nov 2019. 38. nichols ek, khatib im, aburto nj, sullivan km, scanlon ks, wirth jp, et al. vitamin d status and determinants of deficiency among non-pregnant jordanian women of reproductive age. eur j clin nutr 2012; 66:751–6. https://doi.org/10.1038/ejcn.20 12.25. 39. nasreddine lm, kassis an, ayoub jj, naja fa, hwalla nc. nutritional status and dietary intakes of children amid the nutrition transition: the case of the eastern mediterranean region. nutr res 2018; 57:12–27. https://doi.org/10.1016/j. nutres.2018.04.016. 40. world health organization. global nutrition targets 2025: low birth weight policy brief. from: https://apps.who.int/iris/ bitstream/handle/10665/149020/who_nmh_nhd_14.5_ eng.pdf?ua=1 accessed: nov 2019. 41. victora cg, de onis m, hallal pc, blössner m, shrimpton r. worldwide timing of growth faltering: revisiting implications for interventions. pediatrics 2010; 125:473–80. https://doi.org/ 10.1542/peds.2009-1519. 42. moussa ma, alsaeid m, abdella n, refai tm, al-sheikh n, gomez je. prevalence of type 2 diabetes mellitus among kuwaiti children and adolescents. med princ pract 2008; 17:270–5. https://doi.org/10.1159/000129604. 43. al-rubeaan k. national surveillance for type 1, type 2 diabetes and prediabetes among children and adolescents: a populationbased study (saudi-dm). j epidemiol community health 2015; 69:1045–51. https://doi.org/10.1136/jech-2015-205710. 44. abuyassin b, laher i. diabetes epidemic sweeping the arab world. world j diabetes 2016; 7:165–74. https://doi.org/10.4239/wjd. v7.i8.165. 45. al-lawati ja, panduranga p, al-shaikh ha, morsi m, mohsin n, khandekar rb, et al. epidemiology of diabetes mellitus in oman: results from two decades of research. sultan qaboos univ med j 2015; 15:e226–33. 46. swinburn ba, sacks g, hall kd, mcpherson k, finegood dt, moodie ml, et al. the global obesity pandemic: shaped by global drivers and local environments. lancet 2011; 378:804–14. https://doi.org/10.1016/s0140-6736(11)60813-1. 47. world health organization. obesity: preventing and managing the global epidemic report of a who consultation. from: www. who.int/nutrition/publications/obesity/who_trs_894/en/ accessed: nov 2019. https://doi.org/10.1093/jn/134.11.3127 https://doi.org/10.1093/jn/134.11.3127 https://doi.org/10.1111/j.1365-3156.2008.02143.x https://doi.org/10.3945/ajcn.2010.29284 https://doi.org/10.3945/ajcn.2010.29284 https://doi.org/10.1016/s0140-6736%2803%2915099-4 https://doi.org/10.1016/s0140-6736%2803%2915099-4 https://doi.org/10.1093/jn/132.9.2895s https://doi.org/10.1038/ejcn.2014.142 https://doi.org/10.1017/s0007114508023404 https://doi.org/10.1177/15648265080292s129 https://doi.org/10.1016/j.jpeds.2013.02.002 https://doi.org/10.1353/dem.2001.0003 https://doi.org/10.3390/nu9030229 https://doi.org/10.3390/nu9030229 https://doi.org/10.1017/s0007114599000537 https://doi.org/10.1038/ejcn.2012.25 https://doi.org/10.1038/ejcn.2012.25 https://doi.org/10.1016/j.nutres.2018.04.016 https://doi.org/10.1016/j.nutres.2018.04.016 https://doi.org/10.1542/peds.2009-1519 https://doi.org/10.1542/peds.2009-1519 https://doi.org/10.1159/000129604 https://doi.org/10.1136/jech-2015-205710 https://doi.org/10.4239/wjd.v7.i8.165 https://doi.org/10.4239/wjd.v7.i8.165 https://doi.org/10.1016/s0140-6736%2811%2960813-1 1department of pediatrics, sarojini naidu children hospital, moti lal nehru medical college, allahabad, india; 2department of medicine, central research institute of unani medicine, hyderabad, india *corresponding author’s e-mail: sha.akht@yahoo.com مرض "كايف" يف سن الرَّضاع معضلة تشخيصية ألطباء الرعاية الصحية األولية �صاهد اأخ�رش �صدقي، جوليناز فاطمة �صدقي، ماني�صا موريا، اأنباها �رشيفازتافا، موك�س فري �صينق abstract: caffey disease is a rare and self-limiting condition characterised by cortical hyperostosis with inflammation of adjacent fascia and muscles. it usually presents in infancy and clinical features include hyperirritability, acute inflammation with swelling of overlying soft tissues and subperiosteal new bone formation. awareness of the existence of this rare condition and its typical clinical and radiological profile will avoid unnecessary investigations and treatment and help the physician to explain its good prognosis to parents of affected children. we report a three-month-old male infant who presented to the outpatient paediatrics department at moti lal nehru medical college, allahabad, india, in 2018 with a right shoulder mass, decreased upper limb movements and irritability. the patient was treated with ibuprofen and paracetamol. irritability and limitation of movement improved over a treatment period of two weeks. keywords: caffey disease; infant; prostaglandin e1; thrombocytosis; case report; india. دوُد ذاِتيَّا، ويتميز بفرط تعظم ق�رشي، والتهاب اللفافات والع�صالت املجاورة، ويظهر امللخ�ص: مر�س "كايف" مر�س نادر احلدوث وحَمْ حدوث واإدراك ال�صمحاق. حتت اجلديدة العظام وتكوين الرخوة، الفوقية الأن�صجة بتورم م�صحوبا حاد والتهاب تهيج، كفرط اكلينيكيا مثل هذه احلالة النادرة واأعرا�صها الإكلينيكية والإ�صعاعية يجنبنا عمل كثري من الفحو�صات والعالجات غري ال�رشورية، وي�صاعد الطبيب اأح�رش اأ�صهر، ثالثة عمره ذكر ر�صيع حالة هنا ون�صجل املاآل. جيد املر�س باأن وتطمينهما املري�س الطفل دي لوال احلالة �رشح على لعيادة الأطفال اخلارجية يف كلية "موتي لل نهرو" الطبية باهلل اآباد بالهند يف عام 2018م، وهو م�صاب بكتلة يف كتفه الأمين قللت من حركة طرفه الأمين، و�صببت له تهيجا. ومت عالج الر�صيع بدوائي ابيوبروفني وبرا�صيتامول. حت�صنت بعد اأ�صبوعني من العالج حالة التهيج وحمدودية احلركة. الكلمات املفتاحية: مر�س كايف؛ ر�صيع؛ برو�صتاغالندين إي 1؛ ازدياد ال�صفيحات الدموية؛ تقرير حالة؛ الهند. caffey disease in infancy a diagnostic dilemma for primary care physicians *shahid a. siddiqui,1 gulnaz f. siddiqui,2 manisha maurya,1 anubha shrivastava,1 mukesh v. singh1 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e109–111, epub. 9 mar 20 submitted 26 may 19 revision req. 2 jul 19; revision recd. 30 aug 19 accepted 14 nov 19 caffey disease or infantile cortical hyper-ostosis (ich) is a rare disorder characterised by acute inflammation of the periosteum and the overlying soft tissues and is usually accompanied by systemic changes of fever and irritability. it usually presents in infancy and clinical features include sudden onset of irritability, fever, decreased appetite and swelling of overlying soft tissues that precedes cortical thickening of underlying bones.1 we report a case of caffey disease to emphasise that, although rare, caffey disease should be kept in mind in the diagnostic approach to childhood bony swellings. case report a three-month-old afebrile male infant presented to the outpatient paediatrics department at moti lal nehru medical college, allahabad, india, in 2018 with a history of mild irritability, a right shoulder mass and decreased upper extremity movement for the previous two weeks. there were no symptoms associated with the respiratory, gastrointestinal or urinary systems. he was born full-term at 39 completed weeks of gest ation via normal vaginal delivery with a birth weight of 2.5 kg, a length of 49 cm and a head circumference of 34.5 cm. his apgar scores were 6 and 8 at 1 and 5 minutes, respectively. the infant was vaccinated according to his age with no significant antenatal or postnatal history. there was no history of prosta glandin e1 infusion to maintain ductal patency during the neonatal period. he was the first child of the couple and there was no family history of similar complaints. the infant was exclusively breast-fed since birth with no vitamin supplementation. there was no history of trauma, intramuscular injections, lethargy or convulsions. child abuse was not suspected as he was the outcome of a planned pregnancy. upon examination, the patient was active and alert, afebrile, mildly irritable and had no dysmorphic facial features. anthropometric examination was normal for his age. a right shoulder mass with soft tissue swelling over the body of scapula was noted [figure 1]. the infant this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.017 case report https://creativecommons.org/licenses/by-nd/4.0/ caffey disease in infancy a diagnostic dilemma for primary care physicians e110 | squ medical journal, february 2020, volume 20, issue 1 had decreased upper extremity movements with pain during passive movement of the right upper extremity. however, deep tendon reflexes were well-preserved and there was no swelling or tenderness over other bones. the remainder of the systemic examination was within normal limits. x-ray examination of the affected shoulder revealed diffuse thick irregular ossi fication along the cortex of the scapula involving both anterior and posterior surfaces with diffuse thickening of the scapula with a thickened cortex [figure 2]. ultrasonography of the shoulder showed that the adjacent muscles around the scapula were relatively bulky with altered echogenicity without any evidence of fluid collections [figure 3]. biochemical and haematological investigations were mostly unremark able except for an elevated c-reactive protein level [table 1]. genetic analysis could not be done as it was not available at the centre and the parents refused further investigations as it is a self-limiting condition. on the basis of the clinical findings, elevated c-reactive protein and radiology, the infant was diagnosed with caffey disease. subsequently, he was treated with ibuprofen and paracetamol. irritability and limitation of movement improved over a treatment period of two weeks. he was doing well on follow-up. discussion caffey disease is a rare, self-limiting disorder of early infancy with an onset within the first six months of life and usually resolves without sequelae by two years of age. it is often sporadic with occasional reports of being autosomal dominant or recessive.2 it is charact erised by a triad of systemic symptoms (e.g. irritability and fever), soft tissue swelling and underlying cortical bone thickening.3,4 the mandible is the most commonly affected site followed by scapula, clavicle, ribs and long bones. laboratory findings include elevated erythrocyte sedimentation rate and in some cases high alkaline phosphatase, thrombocytosis, anaemia and elevated figure 1: photograph of the right shoulder of a threemonth-old male infant showing a mass with normal skin overlying the mass. figure 2: x-ray images of the right shoulder of a threemonth-old male infant showing diffuse scapular periosteal reaction with subperiosteal new bone formation. figure 3: ultrasonography of the right shoulder of a three-month-old male infant showing relatively bulky adjacent muscles around the scapula with altered echogenicity without any evidence of fluid collections. shahid a. siddiqui, gulnaz f. siddiqui, manisha maurya, anubha shrivastava and mukesh v. singh case report | e111 immunoglobulin levels.5 there are no specific labor atory tests for caffey disease. radiology is the most valuable tool in diagnosing caffey disease as it shows layers of periosteal new bone formation with cortical thickening. however, its diagnosis may be delayed as it mimics many other conditions such as osteomyelitis, hypervitaminosis a, syphilis, scurvy, bone tumours, prolonged prostaglandin e infusion and child abuse.6 as the current patient was thriving and there was an absence of early bone radiological signs and a normal white blood cell count, osteomyelitis was ruled out. there was no history of vitamin a supplementation as national programmes in india recommend routine vitamin a supplementation from nine months onwards. negative venereal disease research laboratory tests for both the mother and infant made syphilis an unlikely diagnosis. malignancy and scurvy were also excluded based on normal radiography/ultrasonography and haematological tests. in addition, the infant did not have history of prostaglandin infusion during the neonatal period to maintain ductal patency. after excluding various differential diagnoses and given the characteristic features of caffey disease that were present in the current case (irritability, a right shoulder mass and decreased upper extremity movements with periosteal new bone formation), the patient was diagnosed with caffey disease. conclusion awareness of the existence of caffey disease and its typical clinical and radiological profile as well as its selflimiting nature will avoid unnecessary investigations and treatment in resource-limited countries such as india. references 1. horton wa, hecht jt. disorders for which defects are poorly understood or unknown. in: kliegman rm, stanton bf, st geme iii jw, schor nf, eds. nelson textbook of pediatrics. 1st south asia ed. new delhi, india: elsevier, 2015. pp. 3376–80. 2. nistala h, mäkitie o, jüppner h. caffey disease: new pers pectives on old questions. bone 2014; 60:246–51. https://doi. org/10.1016/j.bone.2013.12.030. 3. kutty n, thomas d, george l, john tb. caffey disease or infantile cortical hyperostosis: a case report oman med j 2010; 25:134–6. https://doi.org/10.5001/omj.2010.36. 4. parnell se, parisi mt. caffey disease. pediatr radiol 2010; 40 suppl 1:s39. https://doi.org/10.1007/s00247-010-1869-2. 5. kumar ts, scott jx, mathew lg. caffey disease with raised immunoglobulin levels and thrombocytosis. indian j pediatr 2008; 75:181–2. https://doi.org/10.1007/s12098-008-0027-4. 6. ramesh v, sankar j. infantile cortical hyperostosis of scapula presenting as pseudoparalysis in an infant. indian pediatr 2017; 54:157–8. https://doi.org/10.1007/s13312-017-1023-4. table 1: biochemical findings of a three-month-old infant with caffey disease investigation finding normal range haemoglobin in g/dl 14.2 10.5–14.0 total wbc count × 104/µl 1.12 0.6–1.4 platelet cell count × 105/µl 2.2 1.5–4.0 serum urea in mg/dl 21 20–35 creatinine in mg/dl 0.68 0.20–0.50 c-reactive protein in mg/dl 1.2 0.08–1.12 vdrl test negative* wbc = white blood cell; vdrl = venereal disease research laboratory. *the mother also tested negative. https://doi.org/10.1016/j.bone.2013.12.030 https://doi.org/10.1016/j.bone.2013.12.030 https://doi.org/10.5001/omj.2010.36 https://doi.org/10.1007/s00247-010-1869-2 https://doi.org/10.1007/s12098-008-0027-4 https://doi.org/10.1007/s13312-017-1023-4 1directorate of nursing, sultan qaboos university hospital, muscat, oman 2college of medicine and health sciences sultan qaboos university, muscat oman; 3department of clinical physiology, sultan qaboos university, muscat, oman 4department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com الوعي ملخاطر اإلفراط يف تناول امللح بني السكان العمانيني يف املناطق احلضرية ح�سن الريامي, ق�سي العبد ال�سالم, علي اخلياري, هالل امل�رشيف, زياد العلوي, خمي�س الها�سمي, �سونيل نادار abstract: objectives: this study aimed to assess the knowledge, attitudes and practices of the general public in oman regarding the dangers of high salt intake. methods: this cross-sectional questionnaire-based survey was conducted among the urban population in oman. individuals aged ≥18 were invited to join the study. results: a total of 1,214 respondents (mean age 34 ± 10 years) answered the questionnaire. the majority were male (65.8%), employed (69.4%) and some were hypertensive (14.3%). most (90.9%) were aware that excess salt can cause diseases such as hypertension and that it is either somewhat important (51.2%) or very important (42.9%) to reduce salt in the diet. however, only 42.2% said that they actively try to reduce salt in their diet. conclusion: although most people in urban areas of oman appear to be aware of the dangers of high salt intake, only a few are actively trying to reduce it. more educational activities are required to improve awareness. keywords: cross-sectional survey; sodium; low salt diet; oman. امللخ�ص: الهدف: تقييم مدى معرفة وتوجه و�سلوكيات اأفراد املجتمع العماين جتاه خطورة تناول امللح بكميات عالية. الطريقة: مت اإجراء هذه امل�سح باإ�ستخدام اإ�ستبيان مت توزيعه على املجتمع احل�رشي يف عمان والتي ا�ستهدفت الأفراد الذين تتجاوز اأعمارهم 18 �سنة واأكرث لالإنظمام يف هذه الدرا�سة. النتائج: وافق واأجاب على الإ�ستبيان لهذه الدرا�سة 1,214 �سخ�س )اأعمارهم ترتاوح 10 ± 34 �سنوات , كان %65.8 منهم ذكور, %69.4 موظفون, و%14.3 م�سابني ب�سغط الدم(. اأدرك الأغلبية )%90.9( من امل�ساركني اأن الإفراط يف تناول امللح ي�سبب عدة اأمرا�س مثل ارتفاع �سغط الدم. اأعتقد )%51.2( منهم اأن تقليل تناول امللح يف الطعام نوعًا ما مهم بينما اأجاب )%42.9( باأنه اأدركو احل�رشية املناطق اأفراد معظم اأن من بالرغم اخلال�صة: فعلي. ب�سكل الأطعمة يف امللح تقليل العينة من 42.2% جدا.حاول مهم خطورة الإفراط يف تناول امللح يف الأطعمة اإل اأن ن�سبة ب�سيطة منهم حاولت تقليل امللح ب�سكل فعلي يف الواقع. هناك حاجة اإىل اأن�سطة وفعاليات تعليمة وتوعوية اأكرث لتعزيز الإدراك واملعرفة لدى الأ�سخا�س. الكلمات املفتاحية: درا�سة مقطعية؛ �سودمي؛ طعام قليل امللوحة؛ ُعمان. awareness of the dangers of high salt intake among the urban omani population hassan al-riyami,1 qusay al-abdulsalam,2 ali al-khayari,2 hilal al-mushrafi,2 ziyad al-alawi,2 khamis al-hashmi,3 *sunil k. nadar4 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e352–356, epub. 5 oct 20 submitted 26 feb 20 revision req. 13 apr 20; revisions recd. 21 apr 20 accepted 20 may 20 https://doi.org/10.18295/squmj.2020.20.03.016 brief communication this work is licensed under a creative commons attribution-noderivatives 4.0 international license. cardiovascular diseases (cvds) are aleading cause of death and disability worldwide affecting more than 17.5 million people annually.1 hypertension is a major risk factor of cvd and it is estimated that one in five deaths and 7% of all disability can be attributed to suboptimal blood pressure control.2 high salt intake is a major risk factor for hypertension and is considered to be responsible for approximately one-third of hypertension or around 300 million people worldwide.3 in addition to hypertension, high salt intake is also found to be associated with meniere’s disease, osteoporosis and gastric and renal cell cancers.4–6 modern western diets which are high in processed foods tend to have a high salt content and is considered a major global health issue.7 in fact, the world health organization (who) has listed the reduction of dietary salt intake by 30% as one of its nine global targets to be achieved by the year 2025.8 as mentioned in the who recommendations, the ideal salt consumption by adults should be less than 5 g iodised salt/day.8 however, data from many countries have shown that the dietary intake of salt far exceeds this threshold.9 in accordance with these recommendations, many countries have undertaken measures to reduce salt in commercially processed foods and have also initiated measures to educate the general public and increase awareness about the harms of high salt intake and the need to reduce its consumption.10–12 in oman, the prevalence of hypertension and cvd is high, with around 25% of the population being hypertensive and cvd accounting for around 42% of all deaths.13,14 the salt consumption in oman is also high. according to the national nutrition survey published in 2004, the average salt intake in the omani population was about 11–12 g salt/day.15 the government has undertaken numerous measures to https://creativecommons.org/licenses/by-nd/4.0/ hassan al-riyami, qusay al-abdulsalam, ali al-khayari, hilal al-mushrafi, ziyad al-alawi, khamis al-hashmi and sunil k. nadar brief communication | 353 tackle the increasing prevalence of non-communicable diseases, including cvd, with the reduction of salt consumption being a particularly important area of interest.13,16 some of these measures include mass media campaigns and reduction of salt in locally produced bread.16,17 despite these high-level campaigns, their impact on public awareness is not known. the aim of this study was to assess the knowledge and attitudes of the general public in an urban setting in oman towards salt and whether this had any effect on their salt consumption. this may help us introduce new strategies to improve awareness and behaviour. methods this cross-sectional questionnaire-based study was conducted among the general urban population in muscat, oman. the study was conducted from september to november 2019 and only adults aged ≥18 years we included. the subjects were recruited from various public areas in muscat including parks and malls as well as student recreation areas of universities and colleges. in addition, the questionnaire was posted as a link on social media, specifically whatsapp messenger (facebook ltd. menlo park, california, usa), for further volunteer recruitment. no formal sample size calculations were possible as this was a cross-sectional study to assess the knowledge, attitudes and behaviour of the general public. the questionnaire was divided into two parts. the first part consisted of questions related to demographic characteristics of the participants such as age, educational and employment status and eating habits. the second part of the questionnaire collected data on their knowledge, attitudes and practices with regards to salt intake. this was based on a questionnaire devised by the who.18 the questionnaire was translated into arabic by a native professional arabic-speaker. it was then translated back into english to assess consistency. a pilot sample of 20 non-medical university students completed the questionnaire to eliminate or rephrase any questions that could cause confusion. sample size estimations were made according to recommendations for questionnaire-based studies, where a minimum of 384–400 participants were required for a standard error of 5% or a sample size of 1,000 participants for 3%.19 this study opted for a minimum of 1,000 responses. the data were analysed using statistical package social sciences (spss), version 21 (ibm corp., armonk, new york, usa). all data are presented as either percentages or median (interquartile range). mann-whitney u test, chi-square test and binary logistic regression analysis were used for analysis. for the binary logistic regression, responses to the question “do you do anything on a regular basis to reduce your salt intake?” were used as the outcome measure; all the demographic variables were used as the input variables. these factors were chosen as input variables as they are known to influence attitudes and behaviour. a p value of <0.05 was considered statistically significant. ethical approval was granted by the medical research ethics committee, college of medicine and health sciences at sultan qaboos university (mrec#1579). there was a short paragraph before the questionnaire explaining the details of the study where the participants had to provide consent to participate. no personal identifiable data was collected. results a total of 1,259 responses were received. however, 45 responses were excluded from the study due to incomplete questionnaires. the remaining 1,214 participants (403 paper responses and 811 electronic responses) were included in the study. the mean age of the participants was 34 ± 10 years with 799 (65.8%) male and 173 (14.3%) had hypertension. the majority of participants (62.7%) had completed a diploma course or above while the remaining (37.3%) had studied up to secondary school. most of the respondents (69.4%) were in active employment, while 47 (3.9%) were students and 321 (26.4%) were either retired or unemployed [table 1]. all the respondents were from muscat governorate, oman. table 1: demographic characteristics of the participants from muscat governorate, oman (n = 1,214) characteristics n (%)* age in years 34 (27–40) gender male 799 (65.8) female 415 (34.2) education level secondary school or below 453 (37.3) diploma or above 761 (62.7) occupation employed 843 (69.4) student 47 (3.9) unemployed/retired 321 (26.4) hypertensive 173 (14.3) *the values are median (interquartile range) or number (%). awareness of the dangers of high salt intake among the urban omani population 354 | squ medical journal, august 2020, volume 20, issue 3 most of the participants thought that it was somewhat important (51.2%) or very important (42.9%) to reduce salt, but less than half (42.2%) actively try to reduce salt in the diet. most participants always (80.2%) or sometimes (13%) add salt while cooking, although only 39.6% never add salt at the table. only around a quarter (26.4%) check the salt content on the label of food items before purchasing [table 2]. almost all (90.9%) were aware that excess salt is harmful and can cause diseases such as hypertension. however, only few (11.6%) were aware that other conditions besides hypertension, such as renal stones and osteoporosis, can also be caused by excess dietary table 2: responses to the questionnaire about attitude, knowledge and practice of salt intake in a sample from muscat governorate, oman (n = 1,214) parameters n (%) attitude toward salt intake how important is lowering the salt/sodium in your diet? not at all important 69 (5.7) somewhat important 621 (51.2) very important 521 (42.9) behaviour related to salt intake do you do anything on a regular basis to reduce your salt intake? yes 512 (42.2) no 612 (50.4) don’t know/not answered 90 (7.4) do you add salt to food at the table? never/rarely 481 (39.6) sometime 362 (29.8) often/always 345 (28.4) don’t know/not answered 26 (2.1) do you add salt to food while cooking? never/rarely 27 (2.2) sometimes 158 (13) always 974 (80.2) don’t know/not answered 57 (4.7) do you check the label before you buy any food for salt content? yes 320 (26.4) no 894 (73.6) knowledge related to salt intake do you think that a high salt diet could cause a serious health problem? yes 1,103 (90.9) no 39 (3.2) don’t know 72 (6.1) can high salt in diet cause hypertension? yes 964 (79.4) no 9 (0.7) don’t know 241 (19.9) do you know what the recommended maximum salt intake per person per day is? yes 54 (4.4) no 1160 (95.6) table 3: binary logistic regression showing the effect of various factors on predicting whether a person will try to reduce their salt intake in a sample from muscat govern orate, oman (n = 1,214) input variable se df p value gender 0.133 1 <0.001 education level 0.062 1 <0.001 occupation 0.080 1 0.018 hypertension 0.199 1 0.618 age 0.007 1 0.000 se = standard error; df = degrees of freedom. table 4: differences between the groups who attempt to reduce and those that do not attempt to reduce dietary salt in a sample from muscat governorate, oman (n = 1,124)* n (%) p value does not attempt to reduce salt (n = 512) attempt to reduce salt (n = 612) median age in years (interquartile range) 35 (29–41) 32 (25–40) <0.001† gender male 305 (59.6) 438 (71.6) <0.001 female 207 (40.4) 174 (28.4) education level secondary school or below 205 (40) 208 (34) <0.001 diploma or above 307 (60) 404 (66) employment status employed 364 (71.1) 409 (66.8) <0.001 unemployed 108 (21.1) 139 (22.7) student 11 (2.1) 33 (5.4) retired 29 (5.7) 31 (5.1) hypertension 84 (16.4) 64 (10.5) 0.003 *this analysis excludes 90 respondents who answered “don’t know” to the question “do you try to reduce salt in your diet”; †analysis by mannwhitney u test, all other analyses were by chi-square test. hassan al-riyami, qusay al-abdulsalam, ali al-khayari, hilal al-mushrafi, ziyad al-alawi, khamis al-hashmi and sunil k. nadar brief communication | 355 salt. most of the participants (69.4%) felt that they were consuming the right amount of salt and only a few (6.7%) felt they were consuming more, with the remaining 23% feeling that they were consuming less. only 54 participants (4.4%) claimed they knew what the recommended limit of salt intake was, yet only 12 (1%) got the value correct. on binary logistic regression, the factors that determine whether a person tries to reduce dietary salt were age, gender, educational level and occupation (all p <0.02) [table 3]. however, being hypertensive was not a predictor. according to the analysis, those who attempted to reduce their dietary salt were younger males with an education status of diploma or above and unemployed (all p <0.001). unexpectedly, hypertensive patients were less likely to try and reduce dietary salt as compared to non-hypertensive participants [table 4]. known hypertensive participants were not analysed separately as their number was small (14%). discussion salt is an essential dietary component that can be traced back to ancient civilisations where it formed an important part of the economies of these communities.20 besides its use in household kitchens, it is also used extensively in commercially produced processed food, both for preservation and flavour. the dependence of modern fast-paced lifestyles on these readily available high salt-containing “fast foods” has led to a significant increase in our dietary salt intake, which has become a major public health concern.3,8,21 increasing public awareness is an important step in the reduction of salt consumption. mass media campaigns are a commonly used medium of health education and they play an important part in improving awareness with the expectation that this would lead to healthy behaviour.22,23 while these efforts have been shown to be effective in some settings, such as smoking cessation or diabetic control, a recent meta-analysis showed that these measures alone are not sufficient to reduce salt intake and the levels of salt consumption remains consistently high.24,25,26,27 however, raising awareness is indeed the first step in modifying behaviour. in the current study, the efforts of mass media campaigns appear to be successful, as the majority of respondents were aware that high salt intake is dangerous. however, this knowledge does not appear to be actually applied as only less than half the participants admitted to actively trying to reduce their salt intake. part of the reason for this awareness-behaviour mismatch, could be due to misconceptions about how much salt is considered safe. it is discouraging to know that most of the respondents did not know the recommended level, yet were content with their salt intake and claimed that they were consuming the correct amount despite previous studies proving the contrary.15 these findings are similar to those reported from other countries, where individuals felt they were consuming salt within the recommended levels, whilst unaware of the correct levels.28 health education programmes in oman should increase public awareness of the high salt-containing foods that are regularly consumed in their modern diets and emphasise the need for everyone to actively reduce their salt intake by checking the labels on food items before purchasing, using low salt alternatives and consuming less processed foods. besides public education, it is necessary to actively reduce salt in commonly consumed commercially produced food products, since current lifestyles rely heavily on them. one example in oman, in conjunction with government policies, local bakeries produced bread with lower salt content than those from other countries.29 labelling should also be clear in high salt-containing food items, as is being done in some countries to help consumers make low salt choices.30 the current survey was limited to muscat governorate, which is urban, and did not take into consideration the vast geographical extent of oman. dietary practices in urban muscat could be different from those in the rural parts of oman. most of the respondents were educated and were either students or in full-time employment, which does not truly represent the demographics of oman.31 as this was a questionnaire-based study, there was inherent respondent bias which could be a limitation of such a study.32 in the current study, the actual salt consumption in the population studied was not evaluated, as there is still controversy regarding the optimal method of estimation of salt consumption.33 therefore, the results relied on the respondents opinion of their own salt consumption. further follow-up studies involving measurement of the salt intake among the omani population are warranted, as the latest existing data are from 2004.15 however, the strength of the current study is in the large sample size (n = 1,214; standard error <3%), which is sufficient to draw conclusions with regards to knowledge and attitudes towards salt intake, at least for the urban population in muscat governorate, oman. awareness of the dangers of high salt intake among the urban omani population 356 | squ medical journal, august 2020, volume 20, issue 3 conclusion general awareness regarding the dangers of high salt intake among the urban population sample of muscat governorate was high. however, the participants’ knowledge did not match their practices, as most were not actively trying to reduce their dietary salt intake. more public awareness campaigns are required to help people reduce their salt intake. reference 1. roth ga, johnson c, abajobir a, abd-allah f, abera sf, abyu g, et al. global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. j am coll cardiol 2017; 70:1–25. https://doi.org/10.1016/j.jacc.2017.04.052. 2. bromfield s, muntner p. high blood pressure: the leading global burden of disease risk factor and the need for worldwide prevention programs. curr hypertens rep 2013; 15:134–6. https://doi.org/10.1007/s11906-013-0340-9. 3. aaron kj, sanders pw. role of dietary salt and potassium intake in cardiovascular health and disease: a review of the evidence. mayo clin proc 2013; 88:987–95. https://doi.org/10.1016/j. mayocp.2013.06.005. 4. antonios tf, macgregor ga. salt intake: potential deleterious effects excluding blood pressure. j hum hypertens 1995; 9:511–5. 5. d'elia l, rossi g, ippolito r, cappuccio fp, strazzullo p. habitual salt intake and risk of gastric cancer: a meta-analysis of prospective studies. clin nutr 2012; 31:489–98. https://doi. org/10.1016/j.clnu.2012.01.003. 6. edwards dg, farquhar wb. vascular effects of dietary salt. curr opin nephrol hypertens 2015; 24:8–13. https://doi. org/10.1097/mnh.0000000000000089. 7. rohrmann s, linseisen j. processed meat: the real villain? proc nutr soc 2016; 75:233–41. https://doi.org/10.1017/ s0029665115004255. 8. world health organisation fact sheet; salt reduction. 2018. http://w w w.who.int/ne ws-room/fact-she ets/detail/saltreduction accessed: apr 2020. 9. powles j, fahimi s, micha r, khatibzadeh s, shi p, ezzati m, et al. global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. bmj open 2013; 3:e003733. https://doi.org/10.1136/bmjopen-2013-003733. 10. farrand c, he fj, macgregor ga. reducing population salt intake in the eastern mediterranean region time for urgent action. east mediterr health j 2015; 20:761–4. https://doi. org/10.26719/2014.20.12.761. 11. he fj, macgregor ga. a comprehensive review on salt and health and current experience of worldwide salt reduction programmes. j hum hypertens 2009; 23:363–84. https://doi. org/10.1038/jhh.2008.144. 12. macgregor ga, he fj. world action on salt. lancet 2008; 371:471. https://doi.org/10.1016/s0140-6736(08)60228-7. 13. world health organisation. global status report on non communicable diseases. 2020. http://www.who.int/nmh/ publications/ncd_report_full_en.pdf accessed: apr 2020. 14. the impact of chronic diseases in oman. 2015. https://www. who.int/chp/chronic_disease_report/media/impact/oman. pdf?ua=1 accessed: apr 2020. 15. oman food fortification study. 2004. http://ghdx.healthdata. org/record/oman-food-fortification-study-2004 accessed: apr 2020. 16. alhamad n, almalt e, alamir n, subhakaran m. an overview of salt intake reduction efforts in the gulf cooperation council countries. cardiovasc diagn ther 2015; 5:172–7. https://doi. org/10.3978/j.issn.2223-3652.2015.04.06. 17. salt reduction in bread in oman. 2020. https://www.who.int/ beat-ncds/countries/oman/salt-reduction/en/ accessed: apr 2020. 18. who attitudes and behaviour towards salt intake. 2018. http:// www.who.int/ncds/sur veillance/steps/riskfactor/steps_ saltmodule.pdf accessed: apr 2020. 19. sample size calculations for questionairre based studies. 2015. https://issuu.com/medecinsdumonde/docs/47-the-kapsurvey-model-knowledge-a/9 accessed: apr 2020. 20. cirillo m, capasso g, di leo va, de santo ng. a history of salt. am j nephrol 1994; 14:426–31. 21. u.s. department of health and human services, u.s. department of agriculture. what we eat in america. 2018. https://www.ars.usda.gov/arsuserfiles/80400530/pdf/1314/ table_1_nin_gen_13.pdf accessed: apr 2020. 22. randolph w, viswanath k. lessons learned from public health mass media campaigns: marketing health in a crowded media world. annu rev public health 2004; 25:419–37. https://doi. org/10.1146/annurev.publhealth.25.101802.123046. 23. wakefield ma, loken b, hornik rc. use of mass media campaigns to change health behaviour. lancet 2010; 376:1261–71. https://doi.org/10.1016/s0140-6736(10)60809-4. 24. naugle da, hornik rc. systematic review of the effectiveness of mass media interventions for child survival in lowand middle-income countries. j health commun 2014 ;19:190–215. https://doi.org/10.1080/10810730.2014.918217. 25. sugden c, phongsavan p, gloede s, filiai s, tongamana vo. developing antitobacco mass media campaign messages in a low-resource setting: experience from the kingdom of tonga. tob control 2017; 26:344–8. https://doi.org/10.1136/ tobaccocontrol-2015-052755. 26. trieu k, mcmahon e, santos ja, bauman a, jolly ka, bolam b, et al. review of behaviour change interventions to reduce population salt intake. int j behav nutr phys act 2017; 14:17. https://doi.org/10.1186/s12966-017-0467-1. 27. brown ij, tzoulaki i, candeias v, elliott p. salt intakes around the world: implications for public health. int j epidemiol 2009; 38:791–813. https://doi.org/10.1093/ije/dyp139. 28. bhattacharya s, thakur js, singh a. knowledge attitude, and practice regarding dietary salt intake among urban slum population of north india. j family med prim care 2018; 7:526–30. https://doi.org/10.1093/ije/dyp139. 29. abukhader m, abdelraziq r, alazawi m, ali s. a comparative examination of dietary sodium content in bread and its public consumption pattern in muscat, oman. nutr food sci 2019; 50:116–30. 30. pietinen p, valsta lm, hirvonen t, sinkko h. labelling the salt content in foods: a useful tool in reducing sodium intake in finland. public health nutr 2008; 11:335–40. https://doi. org/10.1017/s1368980007000249. 31. demographics in oman. 2020. https://www.ncsi.gov.om/ pages/ncsi.aspx accessed: apr 2020. 32. safdar n, abbo lm, knobloch mj, seo sk. research methods in healthcare epidemiology: survey and qualitative research. infect control hosp epidemiol 2016; 37:1272–7. https://doi. org/10.1017/ice.2016.171. 33. mclean rm. measuring population sodium intake: a review of methods. nutrients 2014; 6:4651–62. https://doi.org/10.3390/ nu6114651. https://doi.org/10.1016/j.jacc.2017.04.052 https://doi.org/10.1007/s11906-013-0340-9 https://doi.org/10.1016/j.mayocp.2013.06.005 https://doi.org/10.1016/j.mayocp.2013.06.005 https://doi.org/10.1016/j.clnu.2012.01.003 https://doi.org/10.1016/j.clnu.2012.01.003 https://doi.org/10.1097/mnh.0000000000000089 https://doi.org/10.1097/mnh.0000000000000089 https://doi.org/10.1017/s0029665115004255 https://doi.org/10.1017/s0029665115004255 https://doi.org/10.1136/bmjopen-2013-003733 https://doi.org/10.26719/2014.20.12.761 https://doi.org/10.26719/2014.20.12.761 https://doi.org/10.1038/jhh.2008.144 https://doi.org/10.1038/jhh.2008.144 https://doi.org/10.1016/s0140-6736%2808%2960228-7 https://doi.org/10.3978/j.issn.2223-3652.2015.04.06 https://doi.org/10.3978/j.issn.2223-3652.2015.04.06 https://doi.org/10.1146/annurev.publhealth.25.101802.123046 https://doi.org/10.1146/annurev.publhealth.25.101802.123046 https://doi.org/10.1016/s0140-6736%2810%2960809-4 https://doi.org/10.1080/10810730.2014.918217 https://doi.org/10.1136/tobaccocontrol-2015-052755 https://doi.org/10.1136/tobaccocontrol-2015-052755 https://doi.org/10.1186/s12966-017-0467-1 https://doi.org/10.1093/ije/dyp139 https://doi.org/10.1093/ije/dyp139 https://doi.org/10.1017/s1368980007000249 https://doi.org/10.1017/s1368980007000249 https://doi.org/10.1017/ice.2016.171 https://doi.org/10.1017/ice.2016.171 https://doi.org/10.3390/nu6114651 https://doi.org/10.3390/nu6114651 squ med j, april 2010, vol. 10, iss. 1, pp. 57-63, epub. 17th apr 10 submitted -10th july 09 revision req. 23rd nov 09. revision recd. 9th dec 09 accepted 6th jan 10 department of ophthalmology, al-assad hospital, tishreen university, latakia, syria * to whom correspondence should be addressed. email: aksam.ahmad@yahoo.com مقارنة بني كيتوروالك تروميثامني وأسيتات الربيدنيزولون يف منع تقلص احلدقة احملّفز باجلراحة أثناء جراحة الساد أكسم جودت أحمد، يوسف محمد سليمان، جنوى فايز كردغلي امللخ�ص: الهدف: مقارنة فعالية و�شالمة ا�شتعمال اأ�شيتات الربيدنيزول�ن 1% والكيت�روالك تروميتامني 0.5% م��شعيًا للمحافظة على ت��ّشع احلدقة خالل جراحة ال�شاد. الطريقة: �شملت هذه الدرا�شة اال�شتباقية الع�ش�ائية املقّنعة جزئيًا خم�شني مري�شًاً، حيث مت تطبيق معاجلة م��شعية بالطريقة �ش�اء ال�شاد، ا�شتخراج قبل �شاعة من 24 بدءاً مري�شا( 25 ( تروميتامني بالكيت�روالك اأو مري�شا( 25 ( اأ�شيتات بالربيدنيزول�ن تعادل 4 كلية جرعة اإىل ال��ش�ل وحتى دواء كل من �شاعات كل 6 قطرة ُتعطى كانت الَعَد�َشة(. با�ْشِتْحاَلُب اأو العد�شة با�شتخراج التقليدية املر�شى �شالمة من وللتاأكد اجلراحي، العمل اأثناء اأوقات ثالثة يف احلدقة قطر قيا�س مت االإيبنفرين. من خاليًا االإرواء �شائل وكان قطرات، مت مراقبتهم عرب التنظري املجهري احلي�ي وتنظري قعر العني وال�شغط داخل املقلة واالآثاٌر ال�شاِئَرة وحدة االإب�شار. النتائج: كان مت��شط تغري قطر احلدقة من مرحلة ما قبل ال�شق اإىل مرحلة ما بعد اإرواء وغ�شل الق�رسة وال�شفط وزرع العد�شة اأقل وب�شكل ج�هري مع الكيت�روالك منه مع الربيدنيزول�ن)p=0.003 (. وبالنتيجة كان مت��شط قطر احلدقة بعد غ�شل الق�رسة وال�شفط وزرع العد�شة اأكرب وب�شكل ج�هري مع الكيت�روالك ،)p=0.244( مل تالحظ اأية فروق ج�هرية بني املجم�عتني يف قطر احلدقة �ش�اء قبل ال�شق االأول .)p>0.0001(مقارنة مع الربيدنيزول�ن الدوائني. لكال �شاِئَرة اآثاٌر ت�شجل ومل املجم�عتني بني متقاربة كانت فقد االأمان متغريات اأما .)p=0.505( احلدقة مقّب�س اإعطاء بعد اأو اخلال�صة: كان حتّمل املر�شى للكيت�روالك تروميثامني والأ�شيتات الربيدنيزول�ن جيدا وب�شكل مت�شاوي وبدون اآثاٌر �شاِئَرة، لكن الكيت�روالك تروميثامني كان اأف�شل يف منع تقل�س احلدقة الناجت عن اجلراحة. مفتاح الكلمات: كيت�روالك تروميتامني، اأ�شيتات الربيدنيزول�ن، ا�شتخراج ال�شاد، تقل�س احلدقة، ت��شع احلدقة. abstract: objectives: the aim of this study was to compare the efficacy and safety of topical prednisolone acetate 1% and topical ketorolac tromethamine 0.5% in the maintenance of pupillary mydriasis during cataract surgery. methods: fifty patients were enrolled in this prospective, partially masked and randomised study. they were assigned to receive topical treatment with either prednisolone acetate (n = 25) or ketorolac tromethamine (n = 25), starting 24 hours before cataract extraction (either routine extracapsular cataract extraction or phacoemulsification). one drop of the study medication was instilled every 6 hours for a total of 4 drops. no epinephrine was used in the intraoperative irrigation solution. pupil diameter was measured three different times during surgery. to ensure participant safety, biomicroscopy, ophthalmoscopy, intraocular pressure, adverse events and visual acuity were also monitored. results: the mean pupil diameter change from the time of the pre-incision until after cortical irrigation and aspiration and lens implantation was significantly less with ketorolac than with prednisolone (p = 0.003). consequently, mean pupil diameter after cortical irrigation and aspiration and lens implantation was significantly greater with ketorolac than with prednisolone (p <0.0001). no significant differences between groups were observed in the pupil diameter before the first incision (p = 0.244), nor after administration of a miotic agent (p = 0.505). safety variables were comparable and no drug-related adverse events were reported. conclusion: ketorolac tromethamine 0.5% and prednisolone acetate 1% solutions were equally well tolerated without related adverse events, but ketorolac was better in preventing surgically induced miosis. keywords: ketorolac tromethamine; prednisolone acetate; cataract extraction; miosis; mydriasis. comparison of ketorolac tromethamine and prednisolone acetate in preventing surgically induced miosis during cataract surgery yusuf m suleiman, najwa f krdoghli, *aksam j ahmad clinical & basic research advances in knowledge 1. ketorolac tromethamine and prednisolone acetate are well tolerated when applied topically before cataract extraction. 2. ketorolac tromethamine is very effective in preventing surgically induced miosis, while prednisolone acetate is not, despite the fact that both drugs inhibit the liberation of prostaglandins which are believed to be the main cause of surgically induced miosis and postoperative inflammation during cataract surgery. 3. many previous studies have demonstrated that both drugs are equally effective in preventing and treating postoperative inflammation. comparison of ketorolac tromethamine and prednisolone acetate in preventing surgically induced miosis during cataract surgery 58 | squ medical journal, april 2010, volume 10, issue 1 techniques for extracapsular cataract extraction (ecce) have improved tremendously in the past few decades, with small-incision surgery nowadays being the standard treatment. nevertheless, ocular tissue is traumatised during surgery leading to the activation of phospholipase a2,1 and the liberation of two groups of lipid molecules: arachidonic acid (aa) metabolites, and platelet-activating factors (pafs).2 arachidonic acid forms the substrate for further reactions mainly by the cyclo-oxygenase and the lipoxygenase pathways. the main products of the cyclo-oxygenase pathway are prostaglandins (pgs), and the main products of the lipoxygenase pathway are leukotrienes (lts). endogenous pgs produce many effects such as: miosis during surgery, postoperative inflammation, increased permeability of the blood-ocular barriers, conjunctival hyperaemia and change in intraocular pressure.1-3 platelet-activating factors induce an impressive repertoire of responses in vitro and seem to be a major regulator of cell adhesion and vascular permeability in many forms of acute inflammation, trauma, shock, and ischaemia, but their precise role is still under investigation.2 the decrease in pupil diameter can make cataract removal more difficult and increases the risk of surgical trauma, postoperative ocular inflammation,4 and posterior capsule rupture.5 thus, maintaining adequate pupil dilation is considered an important part of ensuring that cataract removal proceeds smoothly. inhibition of pgs’ biosynthesis inhibits intraoperative miosis during cataract surgery, reduces the vascular permeability of the bloodocular barrier, and modifies inflammation.3 non-steroid anti inflammatory drugs (nsaids) inhibit the cyclo-oxygenase enzyme, so inhibiting the biosynthesis of pgs but not lts.2-3 topical ophthalmic nsaids have been shown to be effective in treating a variety of conditions in which prostaglandins are believed to play a causative role,3 including surgically induced miosis,6-7 postoperative inflammation,8-9 treatment and prevention of cystoid macular oedema (cme),3-10 and control the pain of refractive surgery.11 the nsaid ketorolac tromethamine has demonstrated efficacy in the prevention of surgically induced miosis,12 in the treatment of postoperative ocular pain,13 in the treatment of chronic aphakic and pseudophakic cme14 and in the prevention and suppression of ocular inflammation after cataract surgery.15 glucocorticoids inhibit the phospholipase a2 enzyme and consequently inhibit the biosynthesis of both platelet-activating factors and arachidonic acide.2 this results in the inhibition of the biosynthesis of both pgs and lts.3 topical steroids like prednisolone acetate have been the standard regimen postoperatively for many years and are known to prevent inflammatory reactions after cataract extraction. previous studies have not mentioned the role of corticosteroids in preventing surgically induced miosis, despite that corticosteroids inhibit pgs liberation. however, important side effects of topical steroids are increased intraocular pressure (iop), impairment of wound healing and postoperative ocular infection.16-17 the present study compared the efficacy and safety profile of ketorolac tromethamine 0.5% ophthalmic solution with that of prednisolone acetate 1% ophthalmic solution in maintaining the pupillary mydriasis during cataract surgery. the primary efficacy variable was the change in pupil diameter during surgery. methods this prospective, partially masked and randomised study was performed in the ophthalmology department, al-assad hospital, tishreen university, latakia, syria during the period march 2008 to march 2009. patients who were scheduled to undergo unilateral cataract surgery (either routine ecce or phacoemulsification) and posterior therefore, these findings suggest that there are other factors, rather than prostaglandins, that interfere in surgically induced miosis. application to patient care 1. ketorolac has many advantages over prednisolone, such as preventing surgically induced miosis and its complications, avoiding the possible steroid-induced pressure increase, and avoiding other steroid-related side effects. these advantages, together with the good efficacy in controlling postoperative inflammation and lowering costs, may make ketorolac a good choice before and after cataract extraction, especially if a patient is a known steroid responder. yusuf m suleiman, najwa f krdoghli, and aksam j ahmad clinical and basic research | 59 chamber-intraocular lens (pc-iol) implantation were enrolled in the study. the study protocol was approved by the appropriate institutional review board and written informed consent was obtained from all patients before enrollment in the study. some cases were excluded according to the study protocol. patients were not enrolled if they had any of the following features: were pregnant or lactating; only one eye with good visual acuity; any uncontrolled systemic or ocular disease; a history of uveitis or glaucoma; pseudoexfoliation syndrome; a history of any ocular disorder or surgery that might interfere with the surgical procedure or interpretation of the study results; a known sensitivity to any of the components of the study medication; use of systemic steroids or nsaids within 2 weeks before study entry, or topical ophthalmic drugs in the eye to be operated within 1 month before study entry. after this process, fifty patients were enrolled in the study. randomly, 25 patients were given ketorolac tromethamine 0.5% and 25 patients were given prednisolone acetate 1% by the study executor, while the surgeon was masked to patient randomisation. patient characteristics of the two groups are shown in table 1. no significant differences in age, sex, pre-surgery iop, operated eye or procedure were observed between the two groups (p ≥ 0.076). all patients in the two groups completed the study and were included in the efficacy and safety analysis. patients were assigned to receive either ketorolac tromethamine 0.5% solution (rolac® oubari pharma, aleppo, syria) or prednisolone acetate 1% solution (pred-alpha-fort® alphaind., aleppo, syria) according to a randomisation schedule, starting 24 hours before surgery. one drop of study medication was instilled every 6 hours, for a total of 4 drops. topical pupillary dilating agents (tropicamide 0.5% and phenylephrine 10 %) were used, starting one hour before surgery, to induce operative mydriasis. antimicrobial agents were used starting 24 hours before surgery, and retrobulbar anaesthesia was used in all patients. the intraocular irrigating solutions did not contain epinephrine, rather viscoelastics were used by all surgeons. a miotic agent (carbachol) was used after intraocular lens (iol) implantation, only when the pupil was still markedly dilated, to study the effect of ketorolac and prednisolone on the carbachol efficacy. any non-study medications that could interfere with interpretation of the study results (e.g. affect pupil diameter) were specifically prohibited by the study protocol. the surgery then proceeded as scheduled and all patients received a subconjunctival dexamethasone plus gentamycin injection at the end of the surgery. intraoperative pupil diameter was measured at three different times during surgery using a castroviejo caliper and standard microscope at 10x magnification under full illumination. the first measurement (preincision [pre-i]) provided the baseline value and was taken immediately before the first incision. the second measurement was table 1: patients characteristics of the two study groups prednisolone group n = 25 ketorolac group n = 25 p value age by year mean ± sd 70.56 ± 8.39 65.68 ± 10.52 0.076* range 47-84 42-80 sex female 13 (52%) 14 (56%) > 0.1** male 12 (48%) 11 (44 %) pre-surgery iop (mmhg) mean ± sd 13.88 ± 3.47 13.49 ± 5.20 0.752* operated eye right 14 (56%) 14 (56%) 1** left 11 (44%) 11 (44%) procedure ecce 15 (60%) 15 (60%) 1** 10 (40%) 10 (40%)phaco legend: * = analysis of variance test; ** = χ2 test.; iop = intraocular pressure; ecce = extra capsular cataract extraction; phaco = phacoemulsification comparison of ketorolac tromethamine and prednisolone acetate in preventing surgically induced miosis during cataract surgery 60 | squ medical journal, april 2010, volume 10, issue 1 taken at the end of surgery, after cortical irrigation and aspiration, and pc-iol implantation, before postoperative administration of a miotic agent (post-irrigation and aspiration [post-i/a]). the final measurement was taken at the end of surgery, but only for the patients who had postoperative administration of a miotic agent (postmiotic [post-m]). care was taken to avoid the presence of viscoelastic in the anterior chamber prior to measurements. the change in pupil diameter during the most traumatic part of the surgical procedure was determined by subtracting the post-i/a value from the pre-i value. the change in pupil diameter caused by the postoperative use of a miotic agent was determined by subtracting the post-m value from the post-i/a value. the safety variables included the results of slit-lamp biomicroscopy and ophthalmoscopy, intraocular pressure, and visual acuity (snellen chart). adverse events were recorded and graded for severity. microsoft excel (2003 version) was simply used to manipulate the data and the available analysis of variance test was used to analyse the continuous variables (such as pupil diameter, changes in pupil diameter, intraocular pressure and age). treatment differences in nominal categorical variables (such as sex, operated eye and surgical procedure) were analysed using (χ 2) test. all tests were two sided, and the probability values of ≤0.05 were considered as statistically significant. results the efficacy analysis revealed the following results with the mean pupil diameter during the three stages and the changes in pupil diameter shown in table 2. the (mean ± sd) pre-i pupil diameter was (7.72 ± 0.54 mm) in the ketorolac group and (7.52 ± 0.65 mm) in the prednisolone group. no significant differences in pre-i pupil diameter were observed between the two groups (p = 0.244). the (mean ± sd) post i/a pupil diameter was greater in the ketorolac group (6.28 ± 0.74 mm) than in the prednisolone group (5.34 ± 0.72 mm) and the difference was statistically significant(p < 0.0001). the mean pupil diameter change from pre-i to post i/a and pc-iol implantation was significantly less (p = 0.003) in the ketorolac group (1.44 ± 0.96 mm) than in the prednisolone group (2.18 ± 0.70 mm). the number of patients requiring additional mydriatic medication during surgery was significantly greater (p < 0.005) in the prednisolone group (n = 14) than in the ketorolac group (n = 4). the number of patients who received a miotic agent at the end of surgery was significantly greater (p < 0.025) in the ketorolac group (21) than in the prednisolone group (13). the (mean ± sd) post-m pupil diameter was (3.76 ± 0.77 mm) in the ketorolac group and (3.92 ± 0.49 mm) in the prednisolone group. the difference was not significant (p = 0.505). the mean change in the pupil diameter from post i/a to post-m was significantly greater (p = 0.014) in the ketorolac group (2.55 ± 1.18 mm) than in the prednisolone group (1.61 ± 0.96 mm). the safety analysis revealed no significant differences between groups in slit-lamp biomicroscopy and ophthalmoscopy results, intraocular pressure or visual acuity. in addition, no table 2: angiographic characteristics of both groups ketorolac group n = 25 prednisolone group n = 25 p value pre-i pupil diameter (mean ± sd) 7.72 ± 0.54 7.52 ± 0.65 0.244* post i/a pupil diameter (mean ± sd) 6.28 ± 0.74 5.34 ± 0.72 < 0.0001* change in pupil diameter from pre-i to post i/a (mean ± sd) 1.44 ± 0.96 2.18 ± 0.70 0.003* patients needing mydriatic agent during surgery 4 (16%) 14 (56%) < 0.005** patients who received carbachol 21 (84%) 13 (52%) < 0.025** post m pupil diameter (mean ± sd) 3.76 ± 0.77 3.92 ± 0.49 0.505* change in pupil diameter from post i/a to post m (mean ± sd) 2.55 ± 1.18 1.61 ± 0.96 0.014* legend: * = analysis of variance test; ** = χ2 test; pre-i = preincision; post i/a = post irrigation & aspiration; post m = post miotic note: post m pupil diameter and change in pupil diameter from post i/a to post m concerns only the eyes which received carbachol at the end of surgery. yusuf m suleiman, najwa f krdoghli, and aksam j ahmad clinical and basic research | 61 treatment-related adverse events occurred. adverse events occurred in 12% of patients in each group, but no event was considered to be related to the study medication. discussion surgically induced miosis is a well known event during cataract surgery and believed to be related to the stimulation of pgs release following surgical trauma. the first nsaids approved by the fda for use as intraoperative inhibitors of miosis during cataract surgery were 0.03% flurbiprofen and 1% suprofen. they decrease the synthesis of pgs in the ocular tissues by inhibiting the cyclo-oxygenase pathway, thus reducing miosis. all commercially available topical nsaids appear to share this therapeutic benefit.1 one previous study has demonstrated the efficacy and safety profile of 0.5% ketorolac compared with its vehicle on maintaining intraoperative mydriasis.18 the results showed that the mean pupil diameter after cortical irrigation and aspiration was significantly greater (p = 0.03) with 0.5% ketorolac than with its vehicle. many other previous studies have demonstrated the efficacy of ketorolac in preventing surgically induced miosis.12-19 in addition, many previous studies have compared the efficacy of nsaids and corticoids in ocular inflammation after cataract surgery, 8,9, 20-23 but the role of cocorticoids, which inhibit the biosynthesis of both pgs and lts, in preventing surgically induced miosis seems not to have been investigated. our study demonstrated that ketorolac was significantly better than prednisolone in maintaining mydriasis during surgery. patients in the ketorolac group had smaller mean decreases in pupil diameter than did patients in the prednisolone group. many previous studies have demonstrated no significant differences between ketorolac and prednisolone in controlling postoperative inflammation. these findings, considering the fact that both study medications inhibit the biosynthesis of pgs, can probably be attributed to a diminished role of pgs in surgically induced miosis. this suggests that the ketorolac-treated eyes were less susceptible to prostaglandin-independent factors contributing to surgically induced miosis. our study also demonstrated no significant differences between ketorolac and prednisolone in the response to the mydriatic agents applied preoperatively, or to the miotic agent applied at the end of surgery. previous studies have demonstrated that no differences between ketorolac and its vehicle were observed in the response to miotic agents administered at the end of surgery, or in the response to the mydriatic agents applied preoperatively,18 suggesting that neither ketorolac nor prednisolone has direct antimiotic or mydriatic properties. in our study, the number of patients requiring additional mydriatics was significantly greater in the prednisolone group (p < 0.025) compared to the ketorolac group, while others demonstrated that no differences between ketorolac and its vehicle were observed in the need for additional mydriatics during surgery.18 this means that patients in the prednisolone group in our study required more additional mydriatics than patients in ketorolac vehicle group in the other comparable study. these findings support more the hypothesis that there are other factors responsible for reducing miosis which are altered by prednisolone, and that ketorolac decreases surgically induced miosis through inhibition of routes other than inhibition of prostaglandin synthesis. a previous study showed that ketorolac had significantly greater efficacy than the glucocorticoids against blood-aqueous barrier breakdown at day 5 and week 2, as demonstrated by the difference in fluorescein concentration between the operated and nonoperated eyes. that is the median fluorescein concentration in the anterior chamber in the gluococorticoid-treated eyes was significantly elevated during the first two weeks after surgery and then began to decrease.20 another previous study also demonstrated comparable results.24 that is during the first two postoperative weeks, the fluorescein leakage was significantly greater in the steroidtreated eyes than in the indomethacin+steroidtreated eyes. after the second postoperative week, the fluorescein leakage in the steroid-treated eyes continued to decrease. these findings suggest that prednisolone takes more time to act than ketorolac thereby having less efficacy in the intraoperative period. however, these two studies, and others,21,22 have demonstrated that prednisolone and ketorolac were equally effective in regard of cells and flare in the anterior chamber during the early postoperative period. another previous study demonstrated comparison of ketorolac tromethamine and prednisolone acetate in preventing surgically induced miosis during cataract surgery 62 | squ medical journal, april 2010, volume 10, issue 1 that fluorescein concentration in placebo-treated eyes was significantly elevated during the first two postoperative weeks (comparable to fluorescein concentration in prednisolone-treated eyes in other studies) then began to decrease and the anterior chamber reaction (cells and flare) was also intensive.25 this means that prednisolone seems to be similar to the placebo regarding the effect on fluorescein leakage. moreover the decrease in fluorescein concentration after the second postoperative week in the prednisolone-treated eyes seems not to be related to a delayed prednisolone efficacy. this means that prednisolone is also effective in the early postoperative period as regards the clinical anterior chamber reaction. it appears that although fluorescein is the most sensitive technique for demonstrating breakdown of blood-aqueous barrier (bab), it may not always be an indicator of large molecule permeability.26 these findings disprove the hypothesis that prednisolone takes more time to act than ketorolac and suggest that ketorolac is effective against even small-molecule permeability (fluorescein) while prednisolone is effective only against large molecule permeability (cells, protein). the differences in the efficacy between ketorolac and prednisolone may be due to their differing effects on platelet activating factors, which are inhibited by glucocorticoids, but not by nsaids; however, this hypothesis needs to be verified. in the present study, the use of ketorolac and prednisolone was not associated with any significant adverse effects. this is consistent with previous studies that have documented the comparable tolerability of ketorolac and prednisolone in the treatment of postoperative ocular inflammation.2022 conclusion ketorolac tromethamine 0.5% ophthalmic solution seems to be more effective in preventing surgically induced miosis during cataract surgery compared to prednisolone acetate 1% ophthalmic solution. consequently, topical ketorolac administered 24 hour before cataract surgery, reduces the complications of miosis during surgery and the need for intraoperative epinephrine which has been linked to cme.27-28 we therefore advise to apply ketorolac 24 hours before cataract surgery. a c k n o w l e d g e m e n t s the authors would like to thank tishreen university, faculty of medicine and al-assad hospital administrations and staff for the help provided during various stages of this work. s o u r c e o f f u n d i n g this research was performed in the department of ophthalmology, al-assad hospital, tishreen university, latakia, syria, during the period march 2008 to march 2009. it was financed by al-assad hospital and tishreen university. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. colin j. the role of nsaids in the management of postoperative ophthalmic inflammation. drugs 2007; 67:1291–308. 2. moorthy rs, davis j, foster cs, lowder cy, vitale at, lopatynsky m, et al. intraocular inflammation and uveitis. in: american academy of ophthalmology. basic and clinical science course, 2007-2008. singapore: aao, 2007. pp.77–9. 3. koay p. the emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology. br j ophthalmol 1996; 80:480–5. 4. drolsum l, davanger m, haaskjold e. risk factors for an inflammatory response after extracapsular cataract extraction and posterior chamber iol. acta ophthalmol (copenh) 1994; 72:21–6. 5. goodman df, stark wj, gottsch jd. complication of cataract extraction with intraocular lens implantation. ophthalmic surg 1989; 20:132–40. 6. cillino s, casanova f, cucco f, ponte f. topical flurbiprofen in extracapsular cataract surgery: effect on pupillary diameter and iris fluorescein leakage. j cataract refract surg 1993; 19:622–5. 7. stark wj, fagadu wr, stewart rh. reduction of pupillary constriction during cataract surgery using suprofen. arch ophthalmol 1986; 104:364–6. 8. demco ta, sutton h, demco cj, raj ps. topical diclofenac sodium compared with prednisolone acetate after phacoemulsification–lens implant surgery. eur j ophthalmol 1997; 7:236–40. 9. solomon kd, vroman dt, barker d. comparison of ketorolac tromethamine 0.5% and rimexolone 1% to control inflammation after cataract extraction. prospective randomized double-masked study. j cataract refract surg 2001; 27:1232–7. 10. sivaprasad s, bunce c, wormald r. non-steroidal yusuf m suleiman, najwa f krdoghli, and aksam j ahmad clinical and basic research | 63 anti-inflammatory agents for cystoid macular oedema following cataract surgery: a systematic review. br j ophthalmol 2005; 89:1420–2. 11. gwon a, vaughan er, cheetham jk, degryse r. ocufen (flurbiprofen) in the treatment of ocular pain after radial keratotomy. clao j 1994; 20:131–8. 12. solomon kd, turkalj jw, whiteside sb, stewart ja, apple dj. topical 0.5% ketorolac vs 0.03% flurbiprofen for inhibition of miosis during cataract surgery. arch ophthalmol 1997; 115:1119–22. 13. epstein rl, laurence ep. relative effectiveness of topical ketorolac and topical diclofenac on discomfort after radial keratotomy. j cataract refract surg 1995; 21:156–9. 14. flach aj, jampol lm, weinberg d, kraff mc, yannuzzi la, campo rv et al. improvement in visual acuity in chronic aphakic and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac tromethamine. am j ophthalmol 1991; 112:514–9. 15. flach aj, graham j, kruger lp, stegman rc, tanenbaum l. quantitative assessment of postsurgical breakdown of the blood aqueous barrier following administration of 0.5% ketorolac tromethamine solution. a double-masked, paired comparison vehicle placebo solution study. arch ophthalmol 1988; 106:344–7. 16. bron a, denis p, hoang-xuan tc, boureauandrieux c, crozafon p, hachet e, et al. the effects of rimexolone 1% in postoperative inflammation after cataract extraction. a double-masked placebocontrolled study. eur j ophthalmol 1998; 8:16–21. 17. heier j, cheetham jk, degryse r, dirks ms, caldwell dr, silverstone de, et al. ketorolac tromethamine 0.5% ophthalmic solution in the treatment of moderate to severe ocular inflammation after cataract surgery: a randomized, vehicle-controlled clinical trial. am j ophthalmol 1999; 127:253–9. 18. stewart r, grosserode r, cheetham j k, rosenthal a. efficacy and safety profile of ketorolac 0.5% ophthalmic solution in the prevention of surgically induced miosis during cataract surgery. clin ther 1999; 21:723–32. 19. snyder rw, siekert rw, schwiegerling j, donnenfeld e, thompson p. acular as a single agent for use as an antimiotic and anti-inflammatory in cataract surgery. j cataract refract surg 2000; 26:1225–7. 20. ostrov cs, sirkin sr, deutsch we, masi rj, chandler jw, lindquist td. ketorolac, prednisolone, and dexamethasone for postoperative inflammation. clin ther 1997; 9:259–72. 21. hirneiß c, neubauer as, kampik a, schönfeld c. comparison of prednisolone 1%, rimexolone1% and ketorolac tromethamine 0.5% after cataract extraction. graefes arch clin exp ophthalmol 2005; 243:768–73. 22. simone jm, pendelton ra, jenkins je. comparison of the efficacy and safety of ketorolac tromethamine 0.5% and prednisolone acetate 1% after cataract surgery. j cataract refract surg 1999; 25:699–704. 23. el-harazi sm, ruis rs, feldman rm, villanueva g, chuang az. a randomized double-masked trial comparing ketorolac tromethamine 0.5%, diclofenac sodium 0.1%, and prednisolone acetate 1% in reducing post-phacoemulsification flare and cells. ophthalmic surg lasers 1998; 29:539–44. 24. donald rs, manus ck, howard ll, gholam ap, samih t. breakdown and reestablishment of blood-aqueous barrier with implant surgery. arch ophthalmol 1982; 100:588–90. 25. donald rs, manus k. steroidal and nonsteroidal anti-inflammatory agents: effect on postsurgical inflammation and blood-aqueous humor barrier breakdown. arch ophthalmol 1984; 102:1453–6. 26. donald rs, alan s, colman k, parashos l, bruce g, gholam ap. quantitative assessment of postsurgical breakdown of the blood-aqueous arrier. arch ophthalmol 1983; 101:131–3. 27. mackool rj, muldoon t, fortier a, nelson d. epinephrine-induced cystoid macular edema in aphakic eyes. arch ophthalmol 1977; 95:791–3. 28. obstbaum sa, galin ma, poole ta. topical epinephrine and cystoid macular edema. am j ophthalmol 1976; 8:455–8. a review of obstetrical outcomes and complications in pregnant women after bariatric surgery yasmeen a. haseeb sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e284–290, epub. 22 dec 19 submitted 29 jan 19 revisions req. 1 apr & 30 may 19; revisions recd. 8 may & 16 jun 19 accepted 7 jul 19 college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia e-mail: yhaseeb@iau.edu.sa the world health organization (who) estimates that 13% of the world’s population is suffering from obesity.1 in the uk, obesity rates have increased in women of reproductive ages from 24.2% in 2005 to 28.3% in 2015.2,3 the centre for maternal and child enquiries highlighted that obesity was responsible for 35% of maternal mortality and 30% of perinatal mortality from 2000 to 2003.4 pregnant women with obesity have an increased risk of early pregnancy loss, hypertensive disorders in pregnancy, gestational diabetes mellitus (gdm), small for gestational age (sga) newborns, difficult prolonged labour, increased caesarean section (cs) rates, thromboembolism, stroke, myocardial infarction and wound infections.5–9 the national institute for health and clinical evidence recommends bariatric surgery (bs) for women with a body mass index of >40 kg/m2.10 there are many research papers emphasising the fetomaternal benefits after undergoing bs. this paper aimed to summarise the most recent evidence about fetomaternal outcomes, maternal nutritional deficiencies and complications after bs and highlights areas for future research. methods google scholar (google llc, mountain view, calif ornia, usa) and pubmed® (national library of medicine, bethesda, maryland, usa) databases were used in this non-systematic and narrative review to search for publications only in english using a combination of keywords specific to the review’s purpose. considering the high variability in various sources of information, a descriptive synthetic approach was adopted to include review مراجعة لنتائج ومضاعفات التوليد يف النساء احلوامل بعد عمليات جراحة البدانة يا�صمني اخرت ح�صيب abstract: bariatric surgery (bs) is a novel treatment for weight reduction with longer lasting health benefits. this review aimed to summarise the available evidence regarding the fetomaternal outcomes and the most common challenges and complications in pregnancies following bs. google scholar (google llc, mountain view, california, usa) and pubmed® (national library of medicine, bethesda, maryland, usa) databases were searched for articles published until december 2018. a total of 64 articles were included in this review and results showed that bs mitigates the risk of gestational diabetes mellitus, hypertensive disorders in pregnancy and fetal macrosomia. however, it can also have detrimental effects on fetomaternal health. there is paucity of data regarding small for gestational age intrauterine growth restriction, premature rupture of membranes and longterm effects on the children born to women who underwent bs. keywords: bariatric surgery; nutritional deficiencies; obesity; pregnancy; surgical injuries. امللخ�ص: ت�صتخدم عمليات جراحة البدانة كعالج مبتكر لتخفي�ض الوزن لتحقيق فوائد �صحية طويلة الأمد، هدفت هذه املراجعة البحثية اإىل اإلقاء ال�صوء وتلخي�ض الأدلة املتوفرة واملتعلقة بنتائج ب�صحة الأم واجلنني والتحديات وامل�صاعفات ال�صائعة يف حالت احلمل التي تلي هذه اجلراحة، مت البحث يف قواعد بيانات باحث جوجل العلمي )�رسكة جوجل، كاليفورنيا، الوليات املتحدة الأمريكية( والببميد )من املكتبة الوطنية للطب، ماريالند، الوليات املتحدة الأمريكية( عن املقالت املن�صورة حتى دي�صمرب 2018، مت ت�صمني ما جمموعه 64 مقالة يف هذه املراجعة البحثية، واأظهرت النتائج اأن عمليات البدانة تخفف من خطر الإ�صابة ب�صكري احلمل، ا�صطرابات ارتفاع �صغط الدم يف احلمل وخطر الإ�صابة باأعرا�ض �صخامة اجلنني، ومع ذلك، ميكن اأن يكون لهذه اجلراحات اآثار �صارة على �صحة اجلنني، هناك ندرة يف البيانات املتعلقة بق�رس النمو اجلنيني داخل الرحم، ومتزق الأغ�صية املبكر وامل�صاعفات طويلة الأجل على الأطفال املولودين لن�صاء خ�صعوا لعمليات جراحة البدانة. الكلمات املفتاحية: جراحة البدانة؛ النق�ض الغذائي؛ ال�صمنة؛ احلمل؛ الإ�صابات اجلراحية. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.003 https://creativecommons.org/licenses/by-nd/4.0/ yasmeen a. haseeb review | e285 articles published until december 2018. studies with clearly defined inclusion and exclusion criteria and those that focused on pregnancies after bs addressing fetomaternal outcomes, nutritional deficiencies and complications of bs were included. initially, a total of 220 articles were identified. subsequently, the search was refined by using more specific keywords, either alone or in combination, such as “bariatric surgery”, “pregnancy”, “obstetrical outcome” and “medical com plications” or “surgical complications”. finally, 64 articles were included in this review after screening to ensure their relevance to the topic. results pregnancy related medical compl i c at i o n s a f t e r b a r i at r i c s u r g e r y case-control, cohort studies and some case reports have shown that pre-conception bs is associated with a reduction of gdm and hypertension during preg nancy.11–13 pre-conceptional bs is associated with short and long-term fetomaternal complications during pregnancy—which include fetal anomalies, intrauterine growth restriction (iugr), malnutrition, prolonged labour, increase in induction of labour, postpartum weight retention and juvenile obesity in children.14–16 however, pregnancies following bs may also be associated with many medical, surgical and obstetric morbidities.17,18 weintraub et al.’s retrospective study, conducted at a tertiary care centre in israel, studied the effect of bs on pregnancy outcome between 1988 and 2006.19 they analysed 301 pregnant women who had never had bs and 507 pregnant women after bs and showed that there was a significant reduction in gdm (17.3% versus 11.0%; p = 0.009) and hypertension (23.6% versus 11.02%; p = 0.001) in women after bs.19 kwong et al.’s systematic review and meta-analysis of 17 cohort studies demonstrated that there was a reduction in hypertensive disorders in pregnancy (odds ratio [or]: 0.57, confidence interval [ci]: 0.30–1.09), gdm (or: 0.55, ci: 0.32–0.97) and fetal macrosomia (or: 0.34, ci: 0.17–o.69) following bs.20 luck et al. reported similar results with the addition of a costeffectiveness strategy for women with anovulation to improve their overall pregnancy rate.21 johansen et al.’s study included 627,693 singleton pregnancies from the swedish medical birth registry from 2006 to 2011. of the pregnant women, 670 had prior bs and this revealed a decrease in gdm (1.9% versus 6.8%, or: 0.25, ci: 0.13–0.18; p = 0.001); the frequency of macrosomic fetuses were also reduced in this group (8.6% versus 22.4%, or: 0.33, ci: 0.24–0.44; p <0.001).22 sheiner et al. reported a higher rate of hyper tension in pregnancy (5.4% versus 1.7%; p <0.001) and gdm (9.4% versus 5.0%; p = 0.001) after bs; however, this association was insignificant on multiple logistic regression analysis.23 conversely, patel et al. found no statistically significant difference in gdm and hyper tension between pregnant women with and without bs.24 perinatal outcome and congenital m a l f o r m at i o n s sheiner et al. described 298 deliveries after bs and compared the outcomes to a control group of 159,210 subjects from 1988 to 2002.23 there was no significant difference of perinatal mortality and congenital abnormalities between the two groups (0.3% versus 1.5%; p = 0.10 and 5.0% versus 4.0%; p = 0.355, respectively).23 dixon et al. studied 79 pregnancies after bs and reported one duodenal atresia and one stillbirth at 41 gestational weeks.25 due to paucity of data in this regard, more research is needed to evaluate the risk of congenital malformations as some case reports have shown increased risk of neural tube defects after bs.26,27 there may be developmental delays in children born to women who had bs prior to their pregnancy.27 johansson et al. studied long-term growth, neuropsychosomatic and speech development in children born to women after bs in brazil.22 speech develop mental defects were seen in these children; however, this important observation requires more research and follow-up of children born after bs.22 patel et al. and cools et al. reported delays in speech, visual and neurological development in children born to women after bs.24,26 the results are presented in table 1. prematurity and premature rupture o f m e m b r a n e s there is no significant difference in premature births and premature rupture of membranes after bs comp ared to those who did not undergo bs.24,25 sheiner et al. found a positive correlation between premature rupture of membranes and bs (or: 1.9; p = 0.001).23 the underlying mechanism is not fully understood and needs more research to elucidate this relationship. f e t a l g r o w t h a n d b i r t h w e i g h t bs has been found to be associated with reduction of fetal macrosomia (birth weight >4,000 g).26–28 weintraub et al. demonstrated a significant reduction in macro somia in pregnancies after bs versus women with a review of obstetrical outcomes and complications in pregnant women after bariatric surgery e286 | squ medical journal, november 2019, volume 19, issue 4 obesity who have not undergone bs (3.2% versus 7.6%; p = 0.004).19 sheiner et al. found an increased rate of iugr in pregnancies after bs compared to those without bs (5% versus 2%; p = 0.001). however, after multivariate analysis this finding became insignificant (or: 1.4; p = 0.063).23 patel et al. also found a significant reduction in fetal macrosomia after bs; nevertheless, they also noted an increased rate of sga fetuses among women post-bs compared to those who had never undergone bs (11.5% versus 0.5%; p <0.001).24 dixon et al. reported no significant difference in birth weight between preg nancies with and without bs.25 the timing of pregnancy after bs has not been demonstrated to have an impact on birth weight. dao et al. reported on 34 patients who became pregnant after bs between 2001 and 2004; there was no significant difference between birth weight among 21 women table 1: summary of previous studies regarding obstetrical outcomes after bariatric surgery20–22,23,28,30,31,34,57,59,60 author and year of publication significant positive changes compared to control significant negative changes compared to control conclusion kwong et al.20 (2016) • lower gdm, htn, pph, macrosomia and pe • higher sga, iugr and still birth bs can be helpful to reduce obstetrical complications but is associated with increased risk of still births and growth restriction. luck et al.21 (2016) • lower gdm, pe and macrosomia • higher sga, preterm birth, cs, maternal death and nnd bs before pregnancy reduces many obstetrical compl ications and is a cost-effective strategy to improve the pregnancy outcome for women who are anovulatory. johansson et al.22 (2015) • lower gdm, pe and macrosomia • higher nnd, sga and cs bs is a cost-effective strategy for women who are anovulatory to improve fertility and overall pregnancy rate, but it is associated with an increase in sga, cs and nnd. sheiner et al.23 (2004) • none • higher prom, labour induction, failed induction, iugr and cs no change in gdm or perinatal complications after bs. dell’agnollo et al.57 (2015) • lower gdm, pe, pih and sleep apnoea • lower birth weight • higher cs and preterm birth except for a high index of sga, it can be concluded that bs is safe. growth in children was found to be adequate. although changes in speech and development were detected, no factor was found to have an assoc iation with pregnancy after bs. stephansson et al.59 (2017) • lower risk of labour induction, post-term pregnancy, obstetrical anal sphincter injuries, pph and 5 minutes apgar score • higher sga and preterm births bs is associated with a decrease in adverse pregnancy outcomes. getahun et al.60 (2013) • lower pe, abruptio placenta, chorioamnionitis, gdm, fetal distress, labour induction, macrosomia, rds and neonatal sepsis • higher surgical site wound, infection and cs the results suggest that bs may be associated with selected adverse perinatal outcomes. targeted nutri tional intervention and intrapartum care are key elements for a good perinatal outcome. costa et al.30 (2018) • lower gdm, htn, pph and cs • higher aortic dilatation, microphthalmia, rds, necrotising enterocolitis and preterm births neonatal outcome may vary depending upon the bs technique. gastric banding is associated with less risk of malnutrition compared to other types of surgeries, so nutritional evaluation is important to avoid a devast ating neonatal outcome. harreiter et al.31 (2018) • lower gdm, pe, pih, cs, macrosomia, sga, iugr and venous thrombosis • higher vaginal births and vaginal birth after previous cs • none obstetrical complications decrease after gastric band surgeries. zozzaro-smith et al.28 (2016) • lower macrosomia, cs, gdm, pe and pih • none pregnancy after bs is safe. perinatal outcome is comp arable to the general population. falcone et al.34 (2018) • higher fertility • lower macrosomia • parentral nutrition needed by 2.5% • slightly higher sga pregnancy rate increases after bs but might require nutritional supplementation. gdm = gestational diabetes mellitus; htn = hypertensive disorders in pregnancy; pph = postpartum haemorrhage; pe = pre-eclampsia; sga = small for gestational age; iugr = intrauterine growth restriction; bs = bariatric surgery; cs = caesarean section; nnd = neonatal death; prom = premature rupture of membranes; pih = pregnancy-induced hypertension; rds = respiratory distress syndrome. yasmeen a. haseeb review | e287 who became pregnant within one year compared to 13 women who conceived one year after bs.29 m o d e o f d e l i v e r y regarding mode of delivery, bs itself is not an indication for cs. costa et al. and harreiter et al. both reported a decrease in cs after bs.30,31 conversely, sheiner et al. found a higher cs rate after controlling for cofounders (25.2% versus 12.2%, or: 2.4; p <0.001).23 however, case-control studies did not show any significant difference in cs after bs.24,32 the american college of obstetricians and gynaecologists committee opinion showed an increase in cs rates and though this may be due to previous cs, maternal request or other obstetr ical indications, data is sparse about increased cs rates following bs.33,34 n u t r i t i o n a l d e f i c i e n c i e s nutritional deficiencies are well-recognised complic ations of bs and may lead to a reduction in vitamin b, fat-soluble vitamins, folic acid, iron and calcium.35,36 the underlying aetiological factor is thought to be a decreased production of gastric acid leading to a decreased absorption of micronutrients.37,38 iron, thiamine and vitamins a, k and d def iciencies are common in pregnancies after bs. wernicke encephalopathy and anaemia may occur due to the deficiency of thiamine and iron, respectively.39 vitamin d deficiency can lead to bone loss and dental problems in the mother and child.40,41 nutritional deficiencies may also cause fetal malformations and fetal growth restriction. cools et al.’s study showed that deficiency of micronutrients, specifically folic acid, vitamin k and a, can adversely affect the fetus, not only in utero, but also later in life.26 neural tube defects, anaemia, preterm births, cerebral haemorrhage, perinatal death, failure to thrive, blindness, deafness, growth retardation and epilepsy have also been reported in some studies, although more observation and follow-up is needed [table 2].26,27,42,43 nutritional deficiencies can be compensated with pre-pregnancy consumption of 5 mg of folic table 2: summary of previous studies related to nutritional deficiencies and fetomaternal outcomes after bariatric surgery16,26,27,36,43–46,48,49 author and year of publication maternal complication fetal complication long-term fetomaternal complication interval between bs and pregnancy cools et al.26 (2006) • nutritional deficiencies • hypoplastic anaemia • multiple congenital anomalies • iron deficiency anaemia • preterm labour • blindness • epilepsy • deafness 2 years monkhouse et al.48 (2009) • preterm labour • anaemia • preterm delivery 22 gestational weeks • perinatal death 3 years vrebosch et al.49 (2012) • preterm labour 27 gestational weeks • iron deficiency anaemia • hydrocephalus • hypoplastic corpus callosum • atrophy of cerebral cortex • visual disturbances • deafness • growth restriction 5 years adam et al.36 (2017) • abdominal pain at 33 gestational weeks • congenital abnormalities • hydrocephalus • coagulation problems • cerebral haemorrhage • perinatal death 3 years kaska et al.27 (2013) • thiamine deficiency • hyperemesis gravidarum • wernicke encephalopathy • megaloblastic anaemia • neural tube defects • preterm delivery anaemia • deafness • delay in speech 3–24 months guelinckx et al.16 (2008) • vitamin k deficiency • cerebral haemorrhage • perinatal death 2 years smets et al.43 (2006) • vitamin a deficiency • bilateral microphthalmia • delay in speech 8 years devlieger et al.44 (2014) • vomiting • iron deficiency anaemia • vitamin a deficiency • neural tube defects • preterm birth • intracranial haemorrhage • epilepsy 3–24 months bebber et al.45 (2011) • vitamin b12 deficiency in breast milk • iron deficiency anaemia • macrocytic anaemia • none 18 months pelizzo et al.46 (2014) • protein nutritional deficiency • malabsorption • low fat content in breast milk • neural tube defects • iron deficiency anaemia • neutropenia • none 7–24 months bs = bariatric surgery. a review of obstetrical outcomes and complications in pregnant women after bariatric surgery e288 | squ medical journal, november 2019, volume 19, issue 4 acid daily which should be continued until 12 weeks of gestation. other vitamins, minerals and nutrients should be administered in recommended quantities to avoid further deficiencies.44,45 surgical complications in pregnancy a f t e r b a r i at r i c s u r g e r y like other surgical procedures, bs has many compl ications depending upon the type of surgery. the most common complications of bs include small bowel obstruction, volvulus, intussusception, gastric band erosion, slipping of gastric band, gastric ulcers, stitchline leak and potentially life-threatening peritonitis.46–49 symptoms of bs complications may mimic common symptoms of physiological changes during pregnancy and require vigilant management. stuart et al.’s study found a higher rate of laparotomies in pregnancies after bs (1.5% versus 0.1%, or: 11.3%, 95% ci: 6.9–18.5) and higher incidence of intestinal obstruction (1.5% versus 0.02%, or: 34.3, 95% ci: 11.9–98.7) in sweden.50 a recent case report by petrucciani et al. showed thrombosis in the small intestine of a 29-year-old pregnant female who had bs six years earlier and presented at 24 weeks of gestation.51 she presented with severe abdominal pain and upon ultrasound scan, was found to have fluid collection in her abdomen. laparotomy was performed by a bariatric and a general surgeon who found ischaemia of the small intestine. the small intestine was resected and a hysterotomy was performed to deliver a stillborn fetus.51 maggard et al.’s systematic review showed three maternal and five neonatal deaths with surgical intervention in 20 cases during pregnancy after bs.52 the majority of these interventions were due to internal hernias; gastric band migration, slipping and erosion have also been reported and some of these cases have had laparoscopic removal of gastric bands.51,52 discussion obesity is increasing exponentially among women of reproductive age. concurrently, rates of bs are rising as this solution is a favourable option for weight loss among this population. dixon et al. found no difference in perinatal outcome in conception occurring within one or two years after bs.25 patel et al. reported an increase in preterm deliveries in pregnancies within one year of bs.24 with the current available data, it is advisable to avoid pregnancy for at least one year following bs.53 dao et al. and roehrig et al. reported fertility improvements in women after bs; the likelihood of unintentional pregnancy was also higher.29,54 therefore, contraceptive options should be discussed with women who have undergone bs, especially considering the questionable absorption of oral contraceptive pills; this is also supported by the american college of obstetricians and gynecologists clinical guidelines on pregnancy after bs.33 luck et al.’s study showed that in pregnancies after bs, there is a reduction in hypertensive disorders in pregnancy, gdm and macrosomic fetuses but it has also been found that there is an increase in iugr and sga fetuses.21 it should be noted that many studies included in this review are case-control and cohort studies that have variable results and exhibit heterogeneity. studies about congenital malformations and neonatal outcomes are underpowered with no homogeneity. some of these studies have used a control group without prior bs. skull et al. and bilenka et al. used the patients as their own controls.32,55 cools et al. and huerta et al. stated that there was no long-term follow-up data for children born to mothers who had bs.26,56 few studies addressed nutritional deficiencies and there is no evidence-based recommended daily nutritional intake requirements for pregnant women who had undergone bs.40,41 more detailed studies with long-term follow-up are required to determine the relationship between bs and nutritional deficiencies, congenital malformations, iugr, sga and long-term effects on children after birth. post-bs pregnancies are high risk and demand careful management by obstetricians, nutritionists and bariatric surgeons. peri-conceptional, antenatal, intra partum and postpartum assessment and management are essential in dealing with all issues and complications.56 pre-pregnancy assessments of nutritional status, specif ically the intake of folic acid, vitamin b12, calcium and iron, can prevent many complications during the ant natal period. early assessment by a senior obstetrician are important in such cases and anomaly scans should be performed to exclude neural tube defects and other fetal malformations. screening for sga by ultrasound for fetal growth (growth-curves, amniotic fluid index and umbilical artery doppler) should be conducted for diagnosis and follow-up.57–60 any abdominal pain in such pregnancies warrants early scanning and involve ment of surgical colleagues. there is no contraindication for vaginal births in these pregnancies except for other obstetrical indications. postpartum care is routine with additional dietary assessment to avoid nutritional deficiencies in the neonate and breastfeeding must be strongly encouraged. discussion about future contraception is also particularly important considering the lower absorption of oral contraceptives which might affect their efficacy. yasmeen a. haseeb review | e289 conclusion the included observational, case-control and cohort studies are suggestive of a decrease in the incidence of gdm, hypertensive disorders in pregnancy and macrosomia in pregnancies after bs. however, there is a lack of robust data regarding the risk of iugr, fetal anomalies and sga after bs, necessitating the need for more research. cs rates also remain high following bs and nutritional deficiencies require careful attention to ensure adherence to nutritional supplements in addition to careful monitoring regarding early detection and treatment. moreover, there is no international consensus regarding the management of post-bs preg nancies due to their novelty, hence an evidence-based guideline is urgently needed. in addition, follow-up studies should focus on obstetrical outcome and longterm neonatal effects in children born to women who have undergone bs prior to their pregnancy. references 1. world health organization. noncommunicable diseases progress monitor 2017. geneva: world health organization. p. 211. 2. guthold r, ono t, strong kl, chatterji s, morabia a. worldwide variability in physical inactivity a 51-country survey. am j prev med 2008; 34:486–94. https://doi.org/10.1016/j. amepre.2008.02.013. 3. nuthalapaty fs, rouse dj. the impact of obesity on obstetrical practice and outcome. clin obstet gynecol 2004; 47:898–913. https://doi.org/10.1097/01.grf.0000135358.34673.48. 4. weindling am. the confidential enquiry into maternal and child health (cemach). arch dis child 2003; 88:1034–7. https://doi.org/10.1136/adc.88.12.1034. 5. stevens ga, singh gm, lu y, danaei g, lin jk, finucane mm, et al. national, regional, and global trends in adult overweight and obesity prevalences. popul health metr 2012; 10:22. https://doi.org/10.1186/1478-7954-10-22. 6. michalakis k, mintziori g, kaprara a, tarlatzis bc, goulis dg. the complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review. metabolism 2013; 62:457–78. https://doi.org/10.1016/j.metabol.2012.08.012. 7. pasquali r, pelusi c, genghini s, cacciari m, gambineri a. obesity and reproductive disorders in women. hum reprod update 2003; 9:359–72. https://doi.org/10.1093/humupd/dmg024. 8. santry hp, gillen dl, lauderdale ds. trends in bariatric surgical procedures. jama 2005; 294:1909–17. https://doi.org/10.1001/ jama.294.15.1909. 9. poirier p, cornier ma, mazzone t, stiles s, cummings s, klein s, et al. bariatric surgery and cardiovascular risk factors: a scientific statement from the american heart association. circulation 2011; 123:1683–701. https://doi.org/10.1161/cir.0b013e3182149099. 10. national institute for health care excellence. obesity prev ention. clinical guidance [cg43]. from: https://www.nice.org. uk/guidance/cg43 accessed: jun 2019. 11. park cw, torquati a. physiology of weight loss surgery. surg clin north am 2011; 91:1149–61. https://doi.org/10.1016/j. suc.2011.08.009. 12. merhi zo. impact of bariatric surgery on female reproduction. fertil steril 2009; 92:1501–8. https://doi.org/10.1016/j.fertns tert.2009.06.046. 13. beard jh, bell rl, duffy aj. reproductive considerations and pregnancy after bariatric surgery: current evidence and recomm endations. obes surg 2008; 18:1023–7. https://doi.org/10.1007/ s11695-007-9389-3. 14. sjöström l, peltonen m, jacobson p, sjöström cd, karason k, wedel h, et al. bariatric surgery and long-term cardiovascular events. jama 2012; 307:56–65. https://doi.org/10.1001/jama.20 11.1914. 15. longitudinal assessment of bariatric surgery (labs) consortium, flum dr, belle sh, king wc, wahed as, berk p, et al. peri operative safety in the longitudinal assessment of bariatric surgery. n eng j med 2009; 361:445–54. https://doi.org/10.10 56/nejmoa0901836. 16. guelinckx i, devlieger r, beckers k, vansant g. maternal obesity: pregnancy complications, gestational weight gain and nutrition. obes rev 2008; 9:140–50. https://doi.org/10.1111/ j.1467-789x.2007.00464.x. 17. hezelgrave nl, oteng-ntim e. pregnancy after bariatric surgery: a review. j obes 2011; 2011:501939. https://doi.org/10.1155/20 11/501939. 18. american college of obstetricians and gynecologists. acog committee opinion no. 549: obesity in pregnancy. obstet gynecol 2013; 121:213–17. https://doi.org/10.1097/01.aog.00 00425667.10377.60. 19. weintraub ay, levy a, levi i, mazor m, wiznitzer a, sheiner e. effects of bariatric surgery on pregnancy outcome. int j gynaecol obstet 2008;103:246–51. https://doi.org/10.1016/j.ij go.2008.07.008. 20. kwong w, tomlinson g, feig ds. gestational diabetes and other obstetrical outcomes after bariatric surgery: a systematic review and meta-analysis. can j diabetes 2016; 40:s18. https://doi.org/10.1016/j.jcjd.2016.08.055. 21. luck m, cahill ag, niu b, ameel b, caughey ab. costeffectiveness of prepregnancy bariatric surgery [9c]. obstet gynecol 2016; 127:s28–9. https://doi.org/10.1097/01.aog.00 00483358.01712.af. 22. johansson k, cnattingius s, näslund i, roos n, trolle lagerros y, granath f, et al. outcome of pregnancy after bariatric surgery. n engl j med 2015; 372:814–24. https://doi.org/10.1056/n ejmoa1405789. 23. sheiner e, levy a, silverberg d, menes ts, levy i, katz m, et al. pregnancy after bariatric surgery is not associated with adverse perinatal outcome. am j obstet gynecol 2004; 190:1335–40. https://doi.org/10.1016/j.ajog.2003.11.004. 24. patel ja, patel na, thomas rl, nelms jk, colella jj. pregnancy outcomes after laparoscopic roux-en-y gastric bypass. surg obes relat dis 2008; 4:39–45. https://doi.org/10.1016/j.soard.20 07.10.008. 25. dixon jb, dixon me, o’brien pe. birth outcomes in obese women after laparoscopic adjustable gastric banding. obstet gynecol 2005; 106:965–72. https://doi.org/10.1097/01.aog.00 00181821.82022.82. 26. cools m, duval el, jespers a. adverse neonatal outcome after maternal biliopancreatic diversion operation: report of nine cases. eur j pediatr 2006; 165:199–202. https://doi.org/10.1007/ s00431-005-0056-1. 27. kaska l, kobiela j, abacjew-chmylko a, chmylko l, wojanowska-pindel m, kobiela p, et al. nutrition and pregnancy after bariatric surgery. isrn obes 2013; 2013:492060. https://doi.org/10.1155/2013/492060. 28. zozzaro-smith pe, bacak s, conway c, park j, glantz jc, thornburg ll. association between obesity during pregnancy and the adequacy of prenatal care. matern child health j 2016; 20:158–63. https://doi.org/10.1007/s10995-015-1815-x. 29. dao t, kuhn j, ehmer d, fisher t, mccarty t. pregnancy outcome after gastric-bypass surgery. am j surg 2006; 192:762–6. https://doi.org/10.1016/j.amjsurg.2006.08.041. https://doi.org/10.1016/j.amepre.2008.02.013 https://doi.org/10.1016/j.amepre.2008.02.013 https://doi.org/10.1097/01.grf.0000135358.34673.48 https://doi.org/10.1136/adc.88.12.1034 https://doi.org/10.1186/1478-7954-10-22 https://doi.org/10.1016/j.metabol.2012.08.012 https://doi.org/10.1093/humupd/dmg024 https://doi.org/10.1001/jama.294.15.1909 https://doi.org/10.1001/jama.294.15.1909 https://doi.org/10.1161/cir.0b013e3182149099 https://doi.org/10.1016/j.suc.2011.08.009 https://doi.org/10.1016/j.suc.2011.08.009 https://doi.org/10.1016/j.fertnstert.2009.06.046 https://doi.org/10.1016/j.fertnstert.2009.06.046 https://doi.org/10.1007/s11695-007-9389-3 https://doi.org/10.1007/s11695-007-9389-3 https://doi.org/10.1001/jama.2011.1914 https://doi.org/10.1001/jama.2011.1914 https://doi.org/10.1056/nejmoa0901836 https://doi.org/10.1056/nejmoa0901836 https://doi.org/10.1111/j.1467-789x.2007.00464.x https://doi.org/10.1111/j.1467-789x.2007.00464.x https://doi.org/10.1155/2011/501939 https://doi.org/10.1155/2011/501939 https://doi.org/10.1097/01.aog.0000425667.10377.60 https://doi.org/10.1097/01.aog.0000425667.10377.60 https://doi.org/10.1016/j.ijgo.2008.07.008 https://doi.org/10.1016/j.ijgo.2008.07.008 https://doi.org/10.1016/j.jcjd.2016.08.055 https://doi.org/10.1097/01.aog.0000483358.01712.af https://doi.org/10.1097/01.aog.0000483358.01712.af https://doi.org/10.1056/nejmoa1405789 https://doi.org/10.1056/nejmoa1405789 https://doi.org/10.1016/j.ajog.2003.11.004 https://doi.org/10.1016/j.soard.2007.10.008 https://doi.org/10.1016/j.soard.2007.10.008 https://doi.org/10.1097/01.aog.0000181821.82022.82 https://doi.org/10.1097/01.aog.0000181821.82022.82 https://doi.org/10.1007/s00431-005-0056-1 https://doi.org/10.1007/s00431-005-0056-1 https://doi.org/10.1155/2013/492060 https://doi.org/10.1007/s10995-015-1815-x https://doi.org/10.1016/j.amjsurg.2006.08.041 a review of obstetrical outcomes and complications in pregnant women after bariatric surgery e290 | squ medical journal, november 2019, volume 19, issue 4 30. costa mm, belo s, souteiro p, neves js, magalhães d, silva rb, et al. pregnancy after bariatric surgery: maternal and fetal outcomes of 39 pregnancies and a literature review. j obstet gynaecol res 2018; 44:681–90. https://doi.org/10.1111/jog.13574. 31. harreiter j, schindler k, bancher-todesca d, göbl c, langer f, prager g, et al. management of pregnant women after bariatric surgery. j obes 2018; 2018:4587064. https://doi.org/10.1155/20 18/4587064. 32. skull aj, slater gh, duncombe je, fielding ga. laparoscopic adjustable banding in pregnancy: safety, patient tolerance and effects on obesity-related pregnancy outcomes. obes surg 2004; 14:230–5. https://doi.org/10.1381/096089204322857618. 33. american college of obstetricians and gynecologists. acog practice bulletin no. 105: bariatric surgery and pregnancy. obstet gynecol 2009; 113:1405–13. https://doi.org/10.1097/ aog.0b013e3181ac0544. 34. falcone v, stopp t, feichtinger m, kiss h, eppel w, husslein pw, et al. pregnancy after bariatric surgery: a narrative literature review and discussion of impact on pregnancy manage ment and outcome. bmc pregnancy childbirth 2018; 18:507. https://doi.org/10.1186/s12884-018-2124-3. 35. poitou bernert c, ciangura c, coupaye m, czernichow s, bouillot jl, basdevant a. nutritional deficiency after gastric bypass: diagnosis, prevention and treatment. diabetes metab 2007; 33:13–24. https://doi.org/10.1016/j.diabet.2006.11.004. 36. adam s, ammori b, soran h, syed aa. pregnancy after bariatric surgery: screening for gestational diabetes. bmj 2017; 356:j533. https://doi.org/10.1136/bmj.j533. 37. kumari a, nigam a. bariatric surgery in women: a boon needs special care during pregnancy. j clin diagn res 2015; 9:qe01–5. https://doi.org/10.7860/jcdr/2015/14258.6802. 38. mancini mc. dealing with diabetes and pregnancy following bariatric surgery: a double-edged sword? arch endocrinol metab 2016; 60:299–302. https://doi.org/10.1590/2359-3997000000181. 39. slater c, morris l, ellison j, syed aa. nutrition in preg nancy following bariatric surgery. nutrients 2017; 9:e1338. https://doi.org/10.3390/nu9121338. 40. avgerinos dv, llaguna oh, seigerman m, lefkowitz aj, leitman im. incidence and risk factors for the development of anemia following gastric bypass surgery. world j gastroenterol 2010; 16:1867–70. https://doi.org/10.3748/wjg.v16.i15.1867. 41. van mieghem t, van schoubroeck d, depiere m, debeer a, hanssens m. fetal cerebral hemorrhage caused by vitamin k deficiency after complicated bariatric surgery. obstet gynecol 2008; 112:434–6. https://doi.org/10.1097/aog.0b013e3181649e7b. 42. dagan ss, goldenshluger a, globus i, schweiger c, kessler y, sandbank gk, et al. nutritional recommendations for adult bariatric surgery patients: clinical practice. adv nutr 2017; 8:382– 94. https://doi.org/10.3945/an.116.014258. 43. smets kj, barlow t, vanhaesebrouck p. maternal vitamin a deficiency and neonatal microphthalmia: complications of biliopancreatic diversion? eur j pediatr 2006; 165:502–4. https://doi.org/10.1007/s00431-006-0120-5. 44. devlieger r, guelinckx i, jans g, voets w, vanholsbeke c, vansant g. micronutrient levels and supplement intake in pregnancy after bariatric surgery: a prospective cohort study. plos one 2014; 9:e114192. https://doi.org/10.1371/journal. pone.0114192. 45. bebber fe, rizzolli j, casagrande ds, rodrigues mt, padoin av, mottin cc, et al. pregnancy after bariatric surgery: 39 pregnancies follow-up in a multidisciplinary team. obes surg 2011; 21:1546–51. https://doi.org/10.1007/s11695-010-0263-3. 46. pelizzo g, calcaterra v, fusillo m, nakib g, ierullo am, alfei a, et al. malnutrition in pregnancy following bariatric surgery: three clinical cases of fetal neural defects. nutr j 2014; 13:59. https://doi.org/10.1186/1475-2891-13-59. 47. hung th, hsieh tt. pregestational body mass index, gesta tional weight gain, and risks for adverse pregnancy outcomes among taiwanese women: a retrospective cohort study. taiwan j obstet gynecol 2016; 55:575–81. https://doi.org/10.1016/j. tjog.2016.06.016. 48. monkhouse sjw, morgan jdt, norton sa. complications of bariatric surgery: presentation and emergency management a review. ann r coll surg engl 2009; 91:280–6. https://doi.org/10.13 08/003588409x392072. 49. vrebosch l, bel s, vansant g, guelinckx i, devlieger r. maternal and neonatal outcome after laparoscopic adjustable gastric banding: a systematic review. obes surg 2012; 22:1568–79. https://doi.org/10.1007/s11695-012-0740-y. 50. stuart a, källen k. risk of abdominal surgery in pregnancy among women who have undergone bariatric surgery. obstet gynecol 2017; 129:887–95. https://doi.org/10.1097/aog.0000000000001975. 51. petrucciani n, debs t, ciampi d, massalou d, kassir r, amor ib, et al. rare cause of small bowel ischemia during pregnancy after roux-en-y gastric bypass. obes surg 2017; 27:1879–81. https://doi.org/10.1007/s11695-017-2676-8. 52. maggard ma, yermilov i, li z, maglione m, newberry s, suttorp m, et al. pregnancy and fertility following bariatric surgery: a systematic review. jama 2008; 300:2286–96. https://doi.org/10.1001/jama.2008.641. 53. skubleny d, switzer nj, gill rs, dykstra m, shi x, sagle ma, et al. the impact of bariatric surgery on polycystic ovary syndrome: a systematic review and meta-analysis. obes surg 2016; 26:169–76. https://doi.org/10.1007/s11695-015-1902-5. 54. roehrig hr, xanthakos sa, sweeney j, zeller mh, inge th. pregnancy after gastric bypass surgery in adolescents. obes surg 2007; 17:873–7. https://doi.org/10.1007/s11695-007-9162-7. 55. bilenka b, ben-shlomo i, cozacov c, gold ch, zohar s. fertility, miscarriage and pregnancy after vertical banded gastroplasty operation for morbid obesity. acta obstet gynecol scand 1995; 74:42–4. https://doi.org/10.3109/00016349509009942. 56. huerta s, rogers lm, li z, heber d, liu c, livingstone eh. vitamin a deficiency in a newborn resulting from maternal hypovitaminosis a after biliopancreatic diversion for the treatment of morbid obesity. am j clin nutr 2002; 76:426–9. https://doi.org/10.1093/ajcn/76.2.426. 57. dell’agnolo cm, cyr c, de montigny f, de barros carvalho md, pelloso sm. pregnancy after bariatric surgery: obstetric and perinatal outcomes and the growth and development of children. obes surg 2015; 25:2030–9. https://doi.org/10.1007/s11695015-1668-9. 58. dalfrà mg, busetto l, chilelli nc, lapolla a. pregnancy and foetal outcome after bariatric surgery: a review of recent studies. j matern fetal neonatal med 2012; 25:1537–43. https://doi.org/10.3109/14767058.2012.663829. 59. stephansson o, johansson k, näslund i, neovius m. delivery outcomes after bariatric surgery: 502. am j obstet gynecol 2017; 216:s296–7. https://doi.org/10.1016/j.ajog.2016.11.237. 60. getahun d, coelman k, fassett m, wing d, jacobsen s. 663: perinatal outcomes after bariatric surgery. am j obstet gynecol 2013; 208:s280. https://doi.org/10.1016/j.ajog.2012.10.829. https://doi.org/10.1111/jog.13574 https://doi.org/10.1155/2018/4587064 https://doi.org/10.1155/2018/4587064 https://doi.org/10.1381/096089204322857618 https://doi.org/10.1097/aog.0b013e3181ac0544 https://doi.org/10.1097/aog.0b013e3181ac0544 https://doi.org/10.1186/s12884-018-2124-3 https://doi.org/10.1016/j.diabet.2006.11.004 https://doi.org/10.1136/bmj.j533 https://doi.org/10.7860/jcdr/2015/14258.6802 https://doi.org/10.1590/2359-3997000000181 https://doi.org/10.3390/nu9121338 https://doi.org/10.3748/wjg.v16.i15.1867 https://doi.org/10.1097/aog.0b013e3181649e7b https://doi.org/10.3945/an.116.014258 https://doi.org/10.1007/s00431-006-0120-5 https://doi.org/10.1371/journal.pone.0114192 https://doi.org/10.1371/journal.pone.0114192 https://doi.org/10.1007/s11695-010-0263-3 https://doi.org/10.1186/1475-2891-13-59 https://doi.org/10.1016/j.tjog.2016.06.016 https://doi.org/10.1016/j.tjog.2016.06.016 https://doi.org/10.1308/003588409x392072 https://doi.org/10.1308/003588409x392072 https://doi.org/10.1007/s11695-012-0740-y https://doi.org/10.1097/aog.0000000000001975 https://doi.org/10.1007/s11695-017-2676-8 https://doi.org/10.1001/jama.2008.641 https://doi.org/10.1007/s11695-015-1902-5 https://doi.org/10.1007/s11695-007-9162-7 https://doi.org/10.3109/00016349509009942 https://doi.org/10.1093/ajcn/76.2.426 https://doi.org/10.1007/s11695-015-1668-9 https://doi.org/10.1007/s11695-015-1668-9 https://doi.org/10.3109/14767058.2012.663829 https://doi.org/10.1016/j.ajog.2016.11.237 https://doi.org/10.1016/j.ajog.2012.10.829 directorate of health services of north batinah, ministry of health, 1sohar and 3saham, oman; 2directorate general of health services of north sharqiya, ministry of health, mudhaibi, oman; departments of 4family medicine & public health and 5medicine, sultan qaboos university, muscat, oman; 6department of family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: aalmahrezi@gmail.com نقص فيتامني b12 لدى مرضى السكري على عالج امليتفورمني دراسة مستعرضة من عمان اأحمد احلامدي، حممد اجلحايف، �صهاب الرو�صدي، �صاجناي جاجو، علي املعمري، عبدالعزيز حممود املحرزي abstract: objectives: this study aimed to determine the prevalence of vitamin b12 deficiency amongst diabetic patients on metformin therapy. methods: this cross-sectional study was conducted at general clinics at the university health center and diabetes outpatient clinics at sultan qaboos university hospital, muscat, oman, between january and december 2017. all omani adults who were diagnosed with type 2 diabetes mellitus and took metformin were invited to participate in the study. the variables included in this study were age, gender, duration of diabetes, dose and duration of metformin therapy, haemoglobin and glycosylated haemoglobin level. results: a total of 248 subjects were included (response rate = 95.4%) of which 26 (10.5%) were vitamin b12 deficient and 53 (21.4%) were borderline deficient. the mean daily dose of metformin was highest among vitamin b12 deficient group (1,981 ± 222 mg; p = 0.004). conclusion: the prevalence of vitamin b12 deficiency is considerable among diabetic patients on metformin therapy. further research is needed to confirm the need for routine screening and monitoring. keywords: type 2 diabetes mellitus; prevalence; metformin; vitamin b12 deficiency; oman. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل حتديد مدى انت�صار نق�س فيتامني b12 بني مر�صى ال�صكري على عالج امليتفورمني. الطريقة: اأجريت هذه الدرا�صة امل�صتعر�صة يف العيادات العامة يف املركز ال�صحي اجلامعي وعيادات ال�صكري اخلارجية يف م�صت�صفى جامعة ال�صلطان قابو�س، م�صقط، ُعمان، خالل الفرتة من يناير اإىل دي�صمرب 2017. مت توجيه الدعوة اإىل جميع الأفراد العمانيني البالغني الذين مت ت�صخي�صهم بداء ال�صكري من النوع الثاين وي�صتمل عالجهم على امليتفورمني للم�صاركة يف الدرا�صة. كانت املتغريات امل�صمولة يف هذه الدرا�صة هي العمر واجلن�س ومدة مر�س ال�صكري وجرعة دواء امليتفورمني ومدة العالج والهيموغلوبني وم�صتوى الهيموغلوبني الغليكوزيالتي. النتائج: �صارك يف الدرا�صة ما جمموعه 248 �صخ�صا )معدل ال�صتجابة = %95.4( 26 )%10.5( منهم كانوا يعانون من نق�س فيتامني b12 و 53 )%21.4( منهم كانت م�صتويات فيتامني b12 �صبه متدنية. كان متو�صط اجلرعة اليومية من امليتفورمني اأعلى بني جمموعة املر�صى اللذين لديهم نق�س يف فيتامني p = 0.004( b12 ميلغرام 222 ± 1,981(. اخلال�صة: اإن معدل انت�صار نق�س فيتامني b12 كبري بني مر�صى ال�صكري على دواء امليتفورمني. هناك حاجة اإىل مزيد من البحث لتاأكيد احلاجة اإىل التحري الروتيني واملراقبة الدورية. الكلمات املفتاحية: ال�صكري من النمط الثاين؛ مدى انت�صار؛ ميتفورمني؛ نق�س فيتامني b12؛ عمان. vitamin b12 deficiency in diabetic patients on metformin therapy a cross-sectional study from oman ahmed al-hamdi,1 mohammed al-gahhafi,2 shihab al-roshdi,3 sanjay jaju,4 ali al-mamari,5 *abdulaziz m. al mahrezi6 brief communication sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e90–94, epub. 9 mar 20 submitted 13 jun 19 revisions req. 24 jul & 9 oct 19; revisions recd. 12 sep & 23 oct 19 accepted 14 nov 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.013 diabetes mellitus (dm) is a major public health problem affecting a large proportion of the world’s population.1 due to its chronic nature, diabetes causes devastating long-term compl ications.healthcare systems worldwide are struggling to sustain the cost of care for patients with diabetes, and the financial burden is expected to increase due to the growing number of people developing the condition. generally, the cost of care for people with diabetes is on average two to three-fold higher than for people without diabetes.1 metformin is used globally as the first-line option for the pharmacological treat ment of diabetes and is recommended by clinical practice guidelines including the american diabetes association (ada) and the european association.2 a significant decrease in the levels of serum vitamin b12 were observed in studies of patients with type 2 dm (t2dm) who were taking metformin compared to those who were not, and in studies comparing patients with t2dm taking metformin and those without t2dm.3–8 a randomised controlled trial conducted over 4.3 years reported a significant decrease in serum vitamin b12 concentration after metformin treatment.9 patients were found to be at a higher risk of developing vitamin b12 deficiency if they took larger doses of metformin and for a longer duration.10 in such patients, early detection of vitamin b12 deficiency is important to avoid subsequent haematological and neurological manifestations.11 https://creativecommons.org/licenses/by-nd/4.0/ ahmed al-hamdi, mohammed al-gahhafi, shihab al-roshdi, sanjay jaju, ali al-mamari and abdulaziz m. al mahrezi brief communication | e91 while the exact role of vitamin b12 in the pathogenesis of t2dm is still unknown, studies have indicated a possible association between vitamin b12 deficiency and serious diabetic complications such as peripheral neuropathy.12 it is hypothesised that oxidative stress is the common associated factor in both conditions.12 therefore, screening and periodic monitoring of serum vitamin b12 could be a useful tool in any clinical guideline for diabetes. to the best of the authors’ knowledge, this is the first study in oman to determine the prevalence of vitamin b12 deficiency in t2dm patients who are on metformin therapy and identify associated factors. methods this descriptive cross-sectional study was conducted at diabetes outpatient clinics at sultan qaboos university hospital (squh), muscat, oman, and general clinics at the university health centre, squh, from january to december 2017. patients who were ≥18 years of age, omani nationals, had a diagnosis of t2dm and had been taking metformin for at least 12 consecutive months were included. those with a history of chronic use of proton pump inhibitors or vitamin b12 supple ments (either over a period of 10 consecutive months or of three prescriptions per year), pure vegetarians, a history of pernicious anaemia, chronic kidney disease, a prior gastrectomy or a prior ileectomy were excluded. all consecutive patients who fulfilled the inclusion criteria were asked to participate. a sample size of 246 was estimated based on an absolute precision of 5% and a desired confidence level of 95% which was calculated using an initial estimate of 8% prevalence of metformin-induced vitamin b12 deficiency; this was determined from a pilot study of 60 subjects who were eventually included in the current study. data regarding the patients’ age, gender, time since diabetes diagnosis, dose of metformin and duration of use were collected from electronic medical records. venous blood samples were collected and sent to the laboratory to be tested for serum vitamin b12 levels, complete blood count (cbc) and glycosylated haemo globin (hba1c) levels. if these tests had been conducted within the three months prior to enrolment in the study, the results were obtained from the patient’s electronic medical records. hba1c was assayed using a cobas integra® 400 plus (roche holding ag, basel, switzerland) which measures hba1c concentration by a turbidimetric inhibition immunoassay in haemolysed whole blood. serum vitamin b12 was measured using a chemiluminescent paramagnetic microparticle immuno assay on a unicel dxi 600 (beckman coulter, inc., brea, california, usa). the participants were classified into three categ ories based on their serum vitamin b12 measure ments: a deficient group (<133 pmol/l), a borderlinedeficient group (133–200 pmol/l) and a normal group (>200 pmol/l).13 anaemia was defined as a blood haemoglobin level of <13 g/dl in males and <12 g/dl in females.14 data were analysed using the software statistical package for social sciences (spss), version 21 (ibm, corp., armonk, new york, usa). mean and standard deviation were calculated for all variables. a one-way analysis of variance was used to determine whether there were any statistically significant differences bet ween the means of the three groups; categorical vari ables were analysed using the chi-squared test. a p value of <0.05 was considered statistically significant. ethical approval was obtained from the medical research and ethics committee of the college of medicine and health sciences, sultan qaboos university, muscat, oman (mrec# 1408). informed consent was taken from all the participants. results a total of 248 subjects were recruited to participate in the study (response rate = 95.4%). the mean age of the participants was 55.3 ± 10.0 years and the majority of participants were female (60.5%). the mean duration of t2dm was 6.5 ± 4.5 years. vitamin b12 deficiency in metformin treated t2dm patients was found in 26 (10.5%) participants while borderline deficiency was found in 53 (21.4%) participants. the dose of metformin was higher among the vitamin b12 deficient group compared to the normal group (1981 ± 222 versus 1695 ± 494 mg; p = 0.004) [table 1]. a higher proportion of those receiving metformin doses of ≥2000 mg had vitamin b12 deficiency (p = 0.004) [figure 1]. there was no association between the duration of metformin use and the vitamin b12 level categories. no significant associations were found between serum vitamin b12 levels and age, gender, duration of dm and haemoglobin and hba1c levels [table 1]. overall, 90 (36.3%) patients were found to be anaemic, of which 11 (42.3%) participants were in the vitamin b12-deficient group, 15 (28.3%) were in the borderline-deficient group and 64 (37.9%) were in the normal group; these differences were not statistically significant [figure 2]. discussion vitamin b12 deficiency in diabetic patients on metformin therapy a cross-sectional study from oman e92 | squ medical journal, february 2020, volume 20, issue 1 this study found a high prevalence of abnormal vitamin b12 levels among omani t2dm patients who were on metformin therapy, an association between high metformin dose and vitamin b12 deficiency and a high prevalence of anaemia. the prevalence of vitamin b12 deficiency observed in this study is similar to previous studies but others have reported variable rates.2,3,6–8,10 for example, beulens et al. reported a prevalence of 28.1% among metformin-treated patients in a cross-sectional study of 550 subjects.8 a study in an elderly population who lived in longterm institutions reported a prevalence of 53.2%.3 conversely, aroda et al. and the national health and nutrition examination survey reported a much lower prevalence of 4.3% and 5.8%, respectively.6,7 such variation in the prevalence rates could be attributed to differences in the cut-off values for vitamin b12 deficiency, patient characteristics, dietary habits, clinical settings and laboratory measurements. while most studies, including meta-analysis table 1: characteristics and laboratory findings of participants distributed according to vitamin b12 level (n = 248) characteristic and laboratory finding n (%) p value vitamin b12 category total deficient borderlinedeficient normal total 26 (10.5) 53 (21.4) 169 (68.1) 248 (100) age in years ± sd 56.8 ± 11.4 56.9 ± 10.9 54.6 ± 9.5 55.3 ± 10.0 ≥0.05 gender male 9 (34.6) 22 (41.5) 67 (39.6) 98 (39.5) ≥0.05 female 17 (65.4) 31 (58.5) 102 (60.4) 150 (60.5) mean dm duration in years ± sd 6.3 ± 3.3 6.5 ± 3.8 6.6 ± 4.8 6.5 ± 4.5 ≥0.05 daily metformin dose in mg <2000 1 (3.8) 9 (17.0) 52 (30.8) 62 (25.0) 0.004 ≥2000 25 (96.2) 44 (83.0) 117 (69.2) 186 (75.0) mean daily metformin dose in mg ± sd 1981 ± 222 1849 ± 422 1695 ± 494 1758 ± 467 0.004 duration of metformin use in years <4 6 (23.1) 13 (24.5) 55 (32.5) 74 (29.8) ≥0.054–10 17 (65.4) 32 (60.4) 89 (52.7) 138 (55.6) >10 3 (11.5) 8 (15.1) 25(14.8) 36 (14.5) mean laboratory finding ± sd hgb in g/dl 12.0 ± 1.5 12.7 ± 1.5 12.5 ± 1.6 12.5 ± 1.6 ≥0.05 mcv in fl 73.6 ± 7.0 74.8 ± 7.5 74.6 ± 7.1 74.5 ± 7.2 ≥0.05 hba1c in % 7.2 ± 1.2 7.9 ± 1.8 8.1 ± 1.9 7.9 ± 1.9 ≥0.05 sd = standard deviation; dm = diabetes mellitus; hgb = haemoglobin; mcv= mean corpuscular volume; hba1c= glycosylated haemoglobin. figure 1: the relationship between vitamin b12 level and the daily dose of metformin. figure 2: prevalence of anaemia among the study population distributed according to vitamin b12 category. ahmed al-hamdi, mohammed al-gahhafi, shihab al-roshdi, sanjay jaju, ali al-mamari and abdulaziz m. al mahrezi brief communication | e93 reviews, agree that there is an association between vitamin b12 deficiency and the intake of metformin in t2dm patients, a small number of studies have disputed this relationship.4,5,15,16 the current study confirmed the association between a high metformin dose and vitamin b12 deficiency as concluded by previous studies.3,10 patients were found to be at a higher risk of developing vitamin b12 deficiency if they took a larger dose of metformin (>2000 mg/day) and for a longer duration (>4 years).10 another study reported a higher risk with a smaller dose (≥1500 mg/day) and a shorter duration (>2 years).3 however, in the current study, no association was found between the duration of metformin therapy and vitamin b12 deficiency. this finding is similar to a study conducted in the netherlands in which the dose of metformin, but not the duration, was associated with vitamin b12 deficiency.8 studies have reported conflicting findings regarding the consequences of vitamin b12 deficiency in t2dm patients.6,10,11 hendrawati et al. reported higher pro portions of neuropathy symptoms and haematologic abnormalities among patients who took metformin for a longer period of time (>3 years versus 1–3 years).11 aroda et al.’s large cohort study of 2,155 participants found a higher prevalence of neuropathy and anaemia in the metformin group compared to the placebo group.6 on the other hand, alharbi et al.’s study found no significant differences in the prevalence of peripheral neuropathy between metformin users and non-met formin users.10 anaemia was highly prevalent in this study’s population but there was no significant association with vitamin b12 levels. moreover, no significant differ ences were found in the levels of the mean corpuscular volume among the participants. similarly, aroda et al. reported a high prevalence of anaemia in the metformin group but no association with vitamin b12 status.6 anaemia is considered as a common problem in diabetic patients and is mainly attributed to iatrogenic causes, which include oral hypoglycaemic drugs and renal insufficiency.17 the limitations of this study are its descriptive nature and the lack of a control group, which does not allow for any comparison or to come to any conclusions about a causal relationship. the study was conducted in a university setting which limits the generalisability of the findings to other settings in oman. however, despite these limitations, this study provides valuable data as it is the first to examine vitamin b12 deficiency in omani t2dm patients on metformin therapy. an additional limitation, is that biomarkers of metabolic vitamin b12 deficiency such as methylmalonic acid, folate and homocysteine were not measured which may have resulted in underestimation of the prevalence rate. conclusion the prevalence of vitamin b12 deficiency in diabetic adult omanis on metformin therapy is considerable. the risk of developing vitamin b12 deficiency was noted to be higher among patients on high doses of metformin. further studies with a stronger research design and utilisation of biomarkers of metabolic vitamin b12 deficiency are needed to confirm these findings and determine the need for routine screening and regular monitoring of vitamin b12 levels in such patients. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the dean of the college of medicine & health sciences, sultan qaboos university, muscat, oman (ig/med/dean/17/01). references 1. international diabetes federation. idf diabetes atlas 8th edition. from: https://www.idf.org/e-library/epidemiologyresearch/diabetes-atlas/134-idf-diabetes-atlas-8th-edition. html. accessed: oct 2019. 2. ko sh, ko sh, ahn yb, song kh, han kd, park ym, et al. association of vitamin b12 deficiency and metformin use in patients with type 2 diabetes. j korean med sci 2014; 29:965–72. https://doi.org/10.3346/jkms.2014.29.7.965. 3. wong cw, leung cs, leung cp, cheng jn. association of metformin use with vitamin b12 deficiency in the institu tionalized elderly. arch gerontol geriatr 2018; 79:57–62. https://doi.org/10.1016/j.archger.2018.07.019. 4. chapman le, darling al, brown je. association between metformin and vitamin b12 deficiency in patients with type 2 diabetes: a systematic review and meta-analysis. diabetes metab 2016; 42:316–27. https://doi.org/10.1016/j.diabet.2016.03.008. 5. yang w, cai x, wu h, ji l. associations between metformin use and vitamin b12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. j diabetes 2019; 11:729–43. https://doi.org/10.1111/1753-0407.12900. 6. aroda vr, edelstein sl, goldberg rb, knowler wc, marcovina sm, orchard tj, et al. long-term metformin use and vitamin b12 deficiency in the diabetes prevention program outcomes study. j clin endocrinol metab 2016; 101:1754–61. https://doi. org/10.1210/jc.2015-3754. 7. reinstatler l, qi yp, williamson rs, garn jv, oakley gp jr. association of biochemical b12 deficiency with metformin therapy and vitamin b12 supplements: the national health and nutrition examination survey, 1999-2006. diabetes care 2012; 35:327–33. https://doi.org/10.2337/dc11-1582. 8. beulens jw, hart he, kuijs r, kooijman-buiting am, rutten ge. https://doi.org/10.3346/jkms.2014.29.7.965 https://doi.org/10.1016/j.archger.2018.07.019 https://doi.org/10.1016/j.diabet.2016.03.008 https://doi.org/10.1111/1753-0407.12900 https://doi.org/10.1210/jc.2015-3754 https://doi.org/10.1210/jc.2015-3754 https://doi.org/10.2337/dc11-1582 vitamin b12 deficiency in diabetic patients on metformin therapy a cross-sectional study from oman e94 | squ medical journal, february 2020, volume 20, issue 1 influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. acta diabetol 2015; 52:47–53. https://doi.org/10.1007/s00592-0140597-8. 9. de jager j, kooy a, lehert p, wulffelé mg, van der kolk j, bets d, et al. long term treatment with metformin in patients with type 2 diabetes and risk of vitamin b-12 deficiency: randomised placebo controlled trial. bmj 2010; 340:c2181. https://doi. org/10.1136/bmj.c2181. 10. alharbi tj, tourkmani am, abdelhay o, alkhashan hi, alasmari ak, bin rsheed am, et al. the association of metformin use with vitamin b12 deficiency and peripheral neuropathy in saudi individuals with type 2 diabetes mellitus. plos one 2018; 13:e0204420. https://doi.org/10.1371/journal.pone.0204420. 11. hendrawati yd, andrajati r, supardi s, ariyani a. the risk of cobalamin deficiency symptoms related to long-term metformin use in t2dm patients. acta endocrinol (buchar) 2018; 14:49–54. https://doi.org/10.4183/aeb.2018.49. 12. valdés-ramos r, guadarrama-lópez al, martínez-carrillo be, benítez-arciniega ad. vitamins and type 2 diabetes mellitus. endocr metab immune disord drug targets 2015; 15:54–63. https://doi.org/10.2174/1871530314666141111103217. 13. yetley ea, pfeiffer cm, phinney kw, bailey rl, blackmore s, bock jl, et al. biomarkers of vitamin b-12 status in nhanes: a roundtable summary. am j clin nutr 2011; 94:s313–21. https://doi.org/10.3945/ajcn.111.013243. 14. world health organization. diagnosis and management of iron-deficiency anaemia. geneva: world health organization. who/nmh/nhd/mnm/11.1. p. 3. 15. rodríguez-gutiérrez r, montes-villarreal j, rodríguez-velver kv, gonzález-velázquez c, salcido-montenegro a, elizondoplazas a, et al. metformin use and vitamin b12 deficiency: untangling the association. am j med sci 2017; 354:165–71. https://doi.org/10.1016/j.amjms.2017.04.010. 16. elhadd t, ponirakis g, dabbous z, siddique m, chinnaiyan s, malik ra. metformin use is not associated with b12 deficiency or neuropathy in patients with type 2 diabetes mellitus in qatar. front endocrinol (lausanne) 2018; 9:248. https://doi. org/10.3389/fendo.2018.00248. 17. angelousi a, larger e. anaemia, a common but often unrecognized risk in diabetic patients: a review. diabetes metab 2015; 41:18–27. https://doi.org/10.1016/j.diabet.2014.06.001. https://doi.org/10.1007/s00592-014-0597-8 https://doi.org/10.1007/s00592-014-0597-8 https://doi.org/10.1136/bmj.c2181 https://doi.org/10.1136/bmj.c2181 https://doi.org/10.1371/journal.pone.0204420 https://doi.org/10.4183/aeb.2018.49 https://doi.org/10.2174/1871530314666141111103217 https://doi.org/10.3945/ajcn.111.013243 https://doi.org/10.1016/j.amjms.2017.04.010 https://doi.org/10.3389/fendo.2018.00248 https://doi.org/10.3389/fendo.2018.00248 https://doi.org/10.1016/j.diabet.2014.06.001 1department of maternal & child health, college of nursing, sultan qaboos university, muscat, oman; 2school of nursing, university of california, los angeles, california, usa; 3department of biostatistics & epidemiology, university of north texas health science center, fort worth, texas, usa *corresponding author’s e-mails: reemal-sharqia@hotmail.com and eiman@squ.edu.om تأثري تدخل تعزيز الكفاءة الذاتية على الكفاءة الذاتية املتصورة واإللتزام احلقيقي بالسلوكيات الصحية عند النساء املصابات بسكري احلمل اإميان الها�شمي، فلي�شا هودج، كارابي ناندي، الليزابث توما�س، ماري-لن بريي�شت abstract: objectives: this study aimed to evaluate the effectiveness of a self-efficacy-enhancing intervention (seei) on perceived self-efficacy and actual adherence to healthy behaviours among women with gestational diabetes mellitus (gdm). methods: this comparative pre-post study was conducted at the antenatal clinic of the sultan qaboos university hospital, muscat, oman, between october 2016 and january 2017. a total of 90 adult omani women with gdm were randomised to either a control group receiving standard prenatal care or a seei group. the seei group received an additional health education session and biweekly text messages to encourage adherence to healthy behaviours. all participants completed self-reported standardised questionnaires to determine perceived self-efficacy and actual adherence at baseline and after four weeks. results: at baseline, there were no significant differences between the control and seei groups in mean scores for perceived self-efficacy (122.9 ± 19.9 versus 118.2 ± 19.5; p = 0.26) or actual adherence to healthy behaviours (3.1 ± 1.2 versus 3.2 ± 1.0; p = 0.23). however, after four weeks, there was a significant positive difference between the seei and control groups in terms of pre-post change in scores for both perceived self-efficacy (9.9 ± 19.6 versus −1.8 ± 17.6; p <0.05) and actual adherence to healthy behaviours (1.5 ± 1.1 versus 0.4 ± 0.8; p <0.01). conclusion: the seei was found to significantly improve perceived self-efficacy and actual adherence to healthy behaviours among a group of omani women with gdm. keywords: attitude to health; health behaviors; self efficacy; patient adherence; gestational diabetes; oman. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل تقومي تاأثري تدخل تعزيز الكفاءة الذاتية على الكفاءة الذاتية املت�شورة واللتزام احلقيقي بال�شلوكيات ال�شحية بني الن�شاء امل�شابات ب�شكري احلمل. الطريقة: يف هذه الدرا�شة متت مقارنة جمموعتني قبل وبعد اأخذ املعلومات يف عيادة ما قبل الولدة يف م�شت�شفى جامعة ال�شلطان قابو�س، م�شقط، عمان، يف الفرتة ما بني اأكتوبر 2016 ويناير 2017. ومت اختيار 90 امراأة عمانية م�شابة ب�شكري احلمل ب�شورة ع�شوائية ليكن اإما �شمن جمموعة اأوىل �شابطة تتلقى فقط الرعاية ال�شحية القيا�شية ملا قبل الولدة، اأو مع جمموعة ثانية تتلقى تدخل تعزيز الكفاءة الذاتية. بالإ�شافة للرعاية ال�شحية القيا�شية تلقت مجموعة التدخل جل�شة توعية �شحية اإ�شافية ور�شائل ن�شية كل اأ�شبوعني لت�شجيع الإلتزام بال�شلوكيات ال�شحية. اأكملت جميع امل�شاركات ا�شتبيانات موحدة مت تعبئتها ذاتًيا لتحديد الكفاءة الذاتية املت�شورة واللتزام الفعلي بال�شلوكيات ال�شحية على مرحلتني: مرحلة اأ�شا�شية قبل بداية البحث، وبعد ذلك باأربعة يف التدخل وجمموعة ال�شابطة املجموعة بني اإح�شائية دللة ذات فروق وجود عدم الأ�شا�شية املرحلة نتائج اأظهرت اأ�شابيع. النتائج: متو�شط درجات الكفاءة الذاتية املدركة )19.9 ± 122.9 مقابل 19.5 ± 118.2؛ p = 0.26( اأو اللتزام احلقيقي بال�شلوكيات ال�شحية )1.2 ± 3.1 مقابل 1.0 ± 3.2؛ p = 0.23(. ولكن وجد اختالف اإيجابي كبري بني املجموعتني يف املرحلة الثانية، من حيث معدل التغري يف الدرجات لكل من الفعالية الذاتية املدركة ) 19.6 ± 9.9 مقابل 17.6 ± 1.8-؛ p >0.05( واللتزام احلقيقي بال�شلوكيات ال�شحية )1.1 ± 1.5 مقابل 0.8 ± 0.4؛ p >0.01(. اخلال�صة: مت التو�شل اإىل اأن تدخل تعزيز الكفاءة الذاتية اأف�شى اإىل حت�شن يف الكفاءة الذاتية املت�شورة ويف اللتزام احلقيقي بال�شلوكيات ال�شحية عند جمموعة من الن�شاء العمانيات امل�شابات ب�شكري احلمل. الكلمات املفتاحية: املوقف اتجاه ال�شحة؛ ال�شلوكيات ال�شحية؛ الكفاءة الذاتية؛ التزام املري�س؛ �شكري احلمل؛ عمان. the effect of a self-efficacy-enhancing intervention on perceived self-efficacy and actual adherence to healthy behaviours among women with gestational diabetes mellitus *iman al-hashmi,1 felicia hodge,2 karabi nandy,3 elizabeth thomas,2 mary-lynn brecht2 clinical & basic research sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e513–519, epub. 28 mar 19 submitted 6 jun 18 revision req. 22 jul 18; revision recd. 30 aug 18 accepted 20 sep 18 doi: 10.18295/squmj.2018.18.04.014 advances in knowledge this study found that a self-efficacy-enhancing intervention (seei) improved perceived self-efficacy and actual adherence to healthy behaviours among a group of omani women with gestational diabetes mellitus (gdm). application to patient care encouraging adherence to healthy lifestyle choices and behaviours can reduce the incidence of gdm-related maternal and neonatal complications among women with gdm. to this end, nurses can incorporate health education, goal-setting and planning, role modelling, mastery experience and motivational messages in seeis adapted to the unique needs of pregnant women with gdm. the effect of a self-efficacy-enhancing intervention on perceived self-efficacy and actual adherence to healthy behaviours among women with gestational diabetes mellitus e514 | squ medical journal, november 2018, volume 18, issue 4 gestational diabetes mellitus (gdm) is defined as glucose intolerance which begins or is first recognised during pregnancy and generally ceases in the postpartum period.1 typically, gdm screening and diagnosis occur between 24–28 gestational weeks using a two-step approach. first, a one-hour non-fasting 50 g glucose challenge test is perf ormed which, if abnormal (>140 mg/dl), is followed by a three-hour fasting 100 g oral glucose tolerance test (ogtt). a gdm diagnosis is indicated if at least two values exceed fasting glucose cut-off values at base-line (>105 mg/dl) or one hour (>190 mg/dl), two hours (>165 mg/dl) or three hours (>145 mg/dl) later.2 worldwide, the prevalence of gdm is increasing, particularly among specific ethnic groups.3,4 according to the ministry of health, the rate of gdm in oman increased from 1.2% in 2000 to 9.2% in 2016.5 this is most probably due to the impact of globalisation and changes in lifestyle and health-related behaviours.6 self care is a crucial aspect of gdm management in order to avoid the development of maternal and neonatal complic ations.1,7 self-care measures include lifestyle modifications (e.g. diet and physical activity) and self-monitoring blood glucose (bg) levels.8 however, limited adherence to recommended behaviours is a major problem, especially during the relatively short span of pregnancy.1 according to the recommendations of the world health organization, it is crucial that women take an active role and develop their capacity for making healthy choices during pregnancy in order to improve maternal and neonatal health.9 few studies have investigated the best strategies to improve adherence to healthy behaviours among pregnant women with gdm.10 perceived self-efficacy has been identified as a strong predictor of healthy behaviours, such as weight loss, dietary modification and physical activity among diabetic patients.11 reliance on relevant knowledge and coping strategies is not sufficient to enhance adherence to a healthy lifestyle; women with gdm require critical self-efficacy attributes, such as perceived outcome expectations, positive reinforcement, a high level of confidence and the necessary determination to attain their desired goals.11 accordingly, this study aimed to evaluate the effectiveness of a selfefficacy-enhancing intervention (seei) for improving perceived self-efficacy and actual adherence to healthy behaviours among a group of omani women with gdm. methods this comparative pre-post study was conducted at the antenatal clinic of the sultan qaboos university hosp ital (squh), muscat, oman, from october 2016 to jan uary 2017. the sample was composed of >18-year-old omani women with singleton pregnancies at <33 gestational weeks who had been diagnosed with gdm. women with multiple gestation pregnancies, type 1 or type 2 diabetes mellitus (t2dm), chronic medical prob lems that prevented them from exercising, mental ill nesses or complications requiring bedrest were excluded from the study. in addition, non-arabic-speaking women were also excluded. as per standard squh protocols, all of the women had undergone a two-hour 75 g ogtt between 24–28 gestational weeks. women were diagnosed with gdm if either their fasting or two-hour bg levels exceeded 124 or 154 mg/dl, respectively. the sample size was calculated according to cohen’s recommended effect size, taking into consideration physical and financial constraints. in order to determine differences between independent two-population means, assuming a power of 80% with a one-tailed alpha level of 0.05 and medium effect size of 0.6, a total of 70 subjects were required. incorporating a 20% attrition rate, the final required sample size was set at 90 subjects. the participant recruitment process was coord inated with the help of outpatient department healthcare providers who had been trained for this purpose. a list of all omani women diagnosed with gdm and attending squh during the study period was generated on a daily basis. women were selected from this list using a random number generator and invited to participate in the study while they were attending antenatal appointments. participants attending antenatal appoint ments on sundays, tuesdays and thursdays were assig ned to the intervention group, while those attending on mondays and wednesdays were assigned to the control group. participants in the control group received standard antenatal care, including routine antenatal visits, monthly blood sugar profiles, fasting blood sugar testing at every visit, glucose monitoring at home and individualised educational sessions with a diabetes dietician. in addition to standard care, the seei group took part in an individualised health education intervention utilising different self-efficacy-enhancing strategies (i.e. motivational messages, role modelling, goal-setting and mastery experience) designed to encourage women to maintain recommended healthy behaviours. first, the participants watched an educational video designed solely for the purposes of the study. the video focused on general information about gdm and gdm-related maternal and neonatal complications, as well as inform ation about the importance of healthy lifestyle behav iours—such as a healthy diet, exercise and maintaining self-monitored bg levels to prevent gdm complications—and measures to prevent post-partum t2dm. iman al-hashmi, felicia hodge, karabi nandy, elizabeth thomas and mary-lynn brecht clinical and basic research | e515 the physical activities recommended in the video conformed with standard cultural beliefs and religious practices in oman by focusing on safe exercises which could be conducted indoors and in private (i.e. walking, swimming and dancing). after watching the video, participants in the seei group were encouraged to practice the recommended activities during the session. the participants were prov ided with a bg metre and were trained to check and record their bg levels; they were requested to do this four times per day during the study period. in order to enhance adherence to the recommended healthy behav iours, the participants were encouraged to write down specific and measurable goals. a pamphlet summarising the content of the educational session was distributed to all participants before the end of the session. in addition, they received short biweekly motivational text messages for four weeks to reinforce the information given during the educational session. finally, a refresher session was given at 32–35 gestational weeks via telephone. both participants in the control and seei groups completed a 15-minute survey to gather demographic information. in addition, two instruments were administered to determine perceived self-efficacy and actual adherence to healthy behaviours. all of the instruments were administered to the participants in arabic. the revised 20-item diabetes management self-efficacy scale (dmses) was used to measure perceived self-efficacy in adhering to healthy behaviours related to management of gdm.12 the original tool is divided into four subscales (nutrition-specific/weight, nutrition-general/ medical treatment, exercise and bg monitoring) and is scored on a five-point scale.13 the revised dmses tool is scored on an 11-point scale and has been deemed to have good reliability (cronbach’s alpha value: 0.89) and test-retest reliability (intra-class correlation coefficient: 0.77).12 the revised 11-item summary of diabetes selfcare activities (sdsca) scale was used to measure the actual frequency of self-care behaviours.14 this tool evaluates five domains of diabetes-specific management, including diet, exercise, bg monitoring, foot care and smoking over the preceding seven days. responses are scored from 0–7 (one point for each day of the week), with the total score ranging from 0–35, with higher scores suggestive of greater engagement in healthy behaviours.14 however, for the purposes of the study, the smoking and foot care subscales were excluded. additionally, minor changes were made to the wording of certain items to make them gdm-specific. the internal reliability of the original tool has been well established, with high inter-item correlation (mean = 0.47) and moderate test-retest correlation (mean = 0.40).14 all participants completed the questionnaires to determine their baseline pre-test scores prior to the start of the educ ational session, which was subsequently initiated for the seei group immediately after the pre-test questionnaires were completed. post-test questionnaires were filled out by both groups four weeks after completion of the pre-test questionnaires. data were analysed using the statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa). all results were checked for outliers or missing data and to determine if there was a need for transformation or non-parametric methods. continuous variables were presented as means and standard deviations and categorical variables were pres ented as frequencies and percentages. an independent t-test was used to determine differences in perceived self-efficacy scores between the two groups. a mediation analysis was conducted to determine differences in actual adherence to healthy behaviours. assumptions for each method were checked and amended appropriately. the level of statistical significance was set at p ≤0.05. ethical approval for this study was obtained from the institutional review board of the university of california los angeles (irb #16-001343) as well as the medical research & ethics committee of squh (mrec #1370). all women provided written informed consent prior to their participation in the study. results a total of 199 omani women with gdm were selected for the study, of which 95 (47.7%) met the inclusion criteria. of these, 90 (94.7%) women were invited to participate in the study and were randomly allocated to either the seei group (n = 45; 50%) or the control group (n = 45; 50%). all of the participants completed the preand post-tests, with a 0% attrition rate. the mean age of the women was 33.5 ± 5.1 years (range: 19–43 years old). the mean pre-pregnancy weight and body mass index was 70.9 ± 17.9 kg (range: 42–155 kg) and 29.0 ± 7.0 kg/m2 (range: 17.4–60.6 kg/m2). the majority (85.5%) had been educated to high school level or above and 54.4% were currently employed. most women (61.1%) did not have a previous history of gdm; however, 78.9% and 32.2% had a family history of t2dm and gdm, respectively. overall, 61.1% of the women had previously received health education regarding gdm, although only 9.1% reported receiving such information from a nurse. there were no significant differences between the two groups with regards to clinical and demographic characteristics, apart from a history of gdm in previous pregnancies (p <0.01) [table 1]. the effect of a self-efficacy-enhancing intervention on perceived self-efficacy and actual adherence to healthy behaviours among women with gestational diabetes mellitus e516 | squ medical journal, november 2018, volume 18, issue 4 there were no significant differences in perceived self-efficacy or actual adherence scores between the two groups at baseline. however, following the intervention, there was a significant positive difference between the seei and control groups in terms of pre-post change in perceived self-efficacy scores (9.9 ± 19.6 versus −1.8 ± 17.6; p <0.05). according to cohen’s effect size (d = 0.43), this difference was of low-to-medium practical significance. in addition, a significant difference was seen between the seei and control groups with regards to pre-post change in actual adherence scores (1.5 ± 1.1 versus 0.4 ± 0.8; p <0.01). this difference represented a large effect according to cohen’s effect size (d = 1.14). specifically, there were significant differences between the seei and control groups in terms of pre-post changes in scores for the adherence to diet (1.1 ± 1.2 versus 0.5 ± 1.1; p <0.05), adherence to physical activity (2.5 ± 2.3 versus 0.8 ± 1.9; p <0.01) and adherence to bg testing (1.2 ± 0.3 versus 0.0 ± 0.3; p <0.05) subscales [table 2]. in addition, findings from the mediation analysis implied a significant direct effect between group assign table 1: demographic and clinical characteristics of a group of omani women with gestational diabetes mellitus (n = 90) characteristic n (%) p value total control group (n = 45) seei group (n = 45) mean age in years ± sd 33.5 ± 5.1 33.5 ± 5.3 33.6 ± 4.9 0.23* mean pre-pregnancy weight in kg ± sd 70.9 ± 17.9 70.9 ± 16.4 70.9 ± 19.5 0.47* mean bmi in kg/m2 ± sd 29.0 ± 7.0 29.1 ± 6.4 28.9 ± 7.6 0.45* mean gravidity ± sd 4.0 ± 2.4 4.0 ± 2.2 4.0 ± 2.6 0.48* mean parity ± sd 2.3 ± 1.8 2.5 ± 1.8 2.2 ± 1.8 0.20* mean ga in weeks at gdm diagnosis ± sd 20.1 ± 7.5 19.7 ± 7.8 20.5 ± 7.3 0.29* place of residence muscat 45 (50) 25 (55.6) 20 (44.4) 0.40† elsewhere 45 (50) 20 (44.4) 25 (55.6) education level primary school or below 13 (14.4) 6 (13.3) 7 (15.6) 0.09† high school 30 (33.3) 18 (40) 12 (26.7) college 40 (44.4) 16 (35.6) 24 (53.3) graduate 7 (7.8) 5 (11.1) 2 (4.4) employment status employed 49 (54.4) 23 (51.1) 26 (57.8) 0.33† unemployed 41 (45.6) 22 (48.9) 19 (42.2) housemaid availability yes 51 (56.7) 26 (57.8) 25 (55.6) 0.50† no 39 (43.3) 19 (42.2) 20 (44.4) family history of t2dm yes 71 (78.9) 33 (73.3) 38 (84.4) 0.15† no 19 (21.1) 12 (26.7) 7 (15.6) previous history of gdm yes 35 (38.9) 12 (26.7) 23 (51.1) <0.01† no 55 (61.1) 33 (73.3) 22 (48.9) family history of gdm yes 29 (32.2) 14 (31.1) 15 (33.3) 0.50† no 61 (67.8) 31 (68.9) 30 (66.7) history of baby birth weight of >4 kg yes 2 (2.2) 0 (0) 2 (4.4) 0.24† no 88 (97.8) 45 (100) 43 (95.6) current gdm treatment diet only 44 (48.9) 22 (48.9) 22 (48.9) 0.47† diet and exercise 22 (24.4) 12 (26.7) 10 (22.2) diet and hypoglycaemic agents 17 (18.9) 8 (17.8) 9 (20) diet, exercise and hypoglycaemic agents 7 (7.8) 3 (6.7) 4 (8.9) prior gdm health education yes 55 (61.1) 27 (60) 28 (62.2) 0.50† no 35 (38.9) 18 (40) 17 (37.8) seei = self-efficacy-enhancing intervention; sd = standard deviation; bmi =body mass index; ga = gestational age; gdm = gestational diabetes mellitus; t2dm = type 2 diabetes mellitus.*using a t-test. †using a chi-squared test. table 2: perceived self-efficacy* and actual adherence to healthy behaviours† scores at baseline and four weeks later among a group of omani women with gestational diabetes mellitus (n = 90) score mean ± sd p value total control group (n = 45) seei group (n = 45) dmses at baseline 120.6 ± 19.8 122.9 ± 19.9 118.2 ± 19.5 0.26 at follow-up 124.6 ± 22.1 121.1 ± 23.0 128.1 ± 20.8 0.14 change 4.0 ± 19.4 −1.8 ± 17.6 9.9 ± 19.6 <0.05 sdsca at baseline 3.1 ± 1.1 3.1 ± 1.2 3.2 ± 1.0 0.23 at follow-up 4.1 ± 1.2 3.5 ± 1.1 4.7 ± 1.0 <0.01 change 1.0 ± 1.1 0.4 ± 0.8 1.5 ± 1.1 <0.01 sdsca diet subscale at baseline 4.0 ± 1.3 3.9 ± 1.4 4.0 ± 1.2 0.73 at follow-up 4.8 ± 1.2 4.4 ± 1.3 5.1 ± 1.1 <0.05 change 0.8 ± 1.1 0.5 ± 1.1 1.1 ± 1.2 <0.05 sdsca pa subscale at baseline 2.1 ± 2.1 1.8 ± 2.0 2.4 ± 2.0 0.24 at follow-up 3.8 ± 2.4 2.6 ± 2.3 4.9 ± 1.9 <0.01 change 1.7 ± 2.3 0.8 ± 1.9 2.5 ± 2.3 <0.01 sdsca bg subscale at baseline 2.5 ± 2.0 2.5 ± 2.2 2.5 ± 1.9 0.96 at follow-up 3.1 ± 1.9 2.5 ± 1.8 3.7 ± 1.7 <0.05 change 0.6 ± 2.3 0.0 ± 0.3 1.2 ± 0.3 <0.05 seei = self-efficacy-enhancing intervention; sd = standard deviation; dmses = diabetes management self-efficacy scale; sdsca = summary of diabetes self-care activities assessment; pa = physical activity; bg = blood glucose. *selfassessed using the revised 20-item dmses tool.12 †self-assessed using the revised 11-item sdsca scale.14 for the purposes of the current study, the foot care and smoking subscales were excluded. iman al-hashmi, felicia hodge, karabi nandy, elizabeth thomas and mary-lynn brecht clinical and basic research | e517 ment and pre-post changes in adherence score (p <0.05) [figure 1]. however, there was a non-significant indirect effect of group assignment on pre-post changes in adher ence score via pre-post changes in perceived self-efficacy score (b = 0.09, standard error = 0.07; bias-corrected and accelerated confidence interval = −0.01–0.28). the change in perceived self-efficacy score accounted for 3% of the total effect. discussion in the current study, the seei resulted in a significant improvement in perceived self-efficacy and actual adher ence to healthy behaviours among a group of omani women with gdm. previous research has similarly documented the effectiveness of educational interventions in increasing perceived self-efficacy, particularly those incorporating self-efficacy-enhancing strategies such as motivational messages, role modelling, goalsetting and mastery experience.15–18 in contrast, other studies have demonstrated fluctuations in self-efficacy over time, whereby educational interventions have resulted in short-term improvements but are not beneficial in sustaining long-term improvements in self-efficacy.19,20 in particular, the seei group in the current study demonstrated significant improvements in actual adher ence to bg monitoring, diet and physical activity behaviours. gaston et al. similarly found that pregnant women who received persuasive messages were more likely to adhere to physical activity habits and exercises.15 although participants in the current study demonstrated good baseline adherence to healthy behaviours—possibly as a result of previous health education measures received during the antenatal period—there was nevertheless a significant positive change in adherence following the four-week intervention. the current study assessed the influence of per ceived self-efficacy as a potential predictor of adherence to healthy behaviours. however, perceived self-efficacy was not found to be a significant predictor of adherence to healthy behaviours after controlling for group assign ment. although there is limited evidence on the relationship between self-efficacy and adherence among women with gdm, this finding contradicts those of earlier studies conducted among women with a history of gdm, participants with t2dm and the general popul ation.21–23 one possible explanation for this could be that the four-week follow-up period used in the current study was too short to demonstrate an influencing effect. however, the mediation analysis revealed that the improvement in self-efficacy partially mitigated the impact of group assignment in improving adherence to healthy behaviours, accounting for 3% of the total effect. this finding supports the possibility that improve ments in self-efficacy may not have a complete mediation effect on group assignment and improvement in adher ence to healthy behaviours. according to the health belief model, various other demographic (i.e. gender, age, ethnicity, economic status and educational level), structural (i.e. knowledge of and prior contact with a disease) and psychosocial (i.e. person ality type, social class and peer pressure) variables may mediate health behaviours.24 these mediators were not evaluated in the current study; therefore, further research is necessary to consider the effect of other possible mediators of adherence to healthy behaviours among women with gdm. improved adherence to healthy behaviours decreases the incidence of gdm-related maternal and neo natal complications as well as the financial burden such complications place on the healthcare system.1,7,25 the findings of the present study provide a foundation for future research seeking to determine strategies to improve adherence to healthy behaviours among women with gdm. in clinical practice, nurses can incorporate various self-efficacy-enhancing strategies such as goal-setting and planning, role modelling, mastery experience and motivational messages when delivering health education sessions that have been adapted to the unique needs of pregnant women with gdm. such measures may serve to improve the overall quality of healthcare services provided to these patients. the major strength of the present study was its quasi-experimental design which permitted an investigation of the effectiveness of the intervention while controlling for certain variables among the participants, thus allowing greater confidence in the findings. using validated questionnaires to measure study variables and the lack of participant dropouts were additional strengths. however, the study was subject to several limitations that should be acknowledged. as the sample was composed of pregnant omani women with gdm, figure 1: diagram showing standardised regression coefficients for the relationship between group assign ment and improvement in actual adherence to healthy behaviours as mediated by improvement in perceived self-efficacy in a group of omani women with gestational diabetes mellitus (n = 90). se = standard error; m = mediator; x = predictor; y = outcome; seei = self-efficacy-enhancing intervention. the effect of a self-efficacy-enhancing intervention on perceived self-efficacy and actual adherence to healthy behaviours among women with gestational diabetes mellitus e518 | squ medical journal, november 2018, volume 18, issue 4 the study findings have limited generalisability to other populations. moreover, a larger sample size would have provided stronger statistical power by preventing the possibility of type two error. finally, the effect of the intervention on self-efficacy and adherence was measured after only four weeks; thus, the long-term effects of the seei could not be determined. conclusion this pre-post comparative study sought to test the effect of a health education intervention incorporating various self-efficacy-enhancing strategies on perceived self-efficacy and actual adherence to healthy behaviours in a group of omani women with gdm. the seei was found to significantly improve perceived self-efficacy as well as actual adherence to healthy behaviours. however, the study failed to detect a positive relationship between self-efficacy and adherence to healthy behaviours. future research should focus on testing this relationship utilising a larger sample and considering other possible mediators of adherence among pregnant women with gdm. a u t h o r c o n t r i b u t i o n s dr iman al-hashmi conceived and planned the study intervention. dr iman al-hashmi wrote the manuscript with support from professor felicia hodge, dr karabi nandy and dr elizabeth thomas. professor felicia hodge supervised the project. dr karabi nandy and dr mary lynn brecht verified the analytical methods. dr karabi nandy supervised the findings of this study. all authors provided critical feedback and helped shape the research, analysis and manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded with the aid of a grant from the college of nursing at sultan qaboos university (#dean’s fund/2017). references 1. carolan m, steele c, margetts h. knowledge of gestational diabetes among a multi-ethnic cohort in australia. midwifery 2010; 26:579–88. https://doi.org/10.1016/j.midw.2009.01.006. 2. poomalar gk. changing trends in management of gestational diabetes mellitus. world j diabetes 2015; 6:284–95. https://doi. org/10.4239/wjd.v6.i2.284. 3. nayak pk, mitra s, sahoo jp, daniel m, mathew a, padma a. feto-maternal outcomes in women with and without gestational diabetes mellitus according to the international association of diabetes and pregnancy study groups (iadpsg) diagnostic criteria. diabetes metab syndr 2013; 7:206–9. https://doi.org/10.1 016/j.dsx.2013.10.017. 4. gasim t. gestational diabetes mellitus: maternal and perinatal outcomes in 220 saudi women. oman med j 2012; 27:140–4. https://doi.org/10.5001/omj.2012.29. 5. oman ministry of health. annual health reports. from: www. moh.gov.om/en/web/statistics/annual-reports accessed: aug 2018. 6. goryakin y, lobstein t, james wp, suhrcke m. the impact of economic, political and social globalization on overweight and obesity in the 56 low and middle income countries. soc sci med 2015; 133:67–76. https://doi.org/10.1016/j.socscimed.201 5.03.030. 7. carolan m, gill gk, steele c. women’s experiences of factors that facilitate or inhibit gestational diabetes self-management. bmc pregnancy childbirth 2012; 12:99. https://doi.org/10.11 86/1471-2393-12-99. 8. de holanda vr, de souza ma, dos santos rodrigues mc, pinheiro ak, damasceno mm. knowledge of pregnant women about gestational diabetes mellitus. j nurs univ fed pernambuco online 2012; 6:1648–54. https://doi.org/10.5205/1981-8963v6i7a7216p1648-1654-2012. 9. world health organization. working with individuals, families and communities to improve maternal and newborn health. from: http://apps .who.int/iris/bitstream/10665/84547/3/who _mps_09.04_eng.pdf?ua=1 accessed: aug 2018. 10. amason js, lee sy, aduddell k, hewell sw, van brackle l. pilot feasibility study of an educational intervention in women with gestational diabetes. j obstet gynecol neonatal nurs 2016; 45:515–27. https://doi.org/10.1016/j.jogn.2016.04.003. 11. chen sf, lin cc. the predictors of adopting a health-promoting lifestyle among work site adults with prediabetes. j clin nurs 2010; 19:2713–19. https://doi.org/10.1111/j.1365-2702.20 10.03320.x. 12. sturt j, hearnshaw h, wakelin m. validity and reliability of the dmses uk: a measure of self-efficacy for type 2 diabetes self-management. prim health care res dev 2010; 11:374–81. https://doi.org/10.1017/s1463423610000101. 13. bijl jv, poelgeest-eeltink av, shortridge-baggett l. the psychometric properties of the diabetes management self-efficacy scale for patients with type 2 diabetes mellitus. j adv nurs 1999; 30:352–9. https://doi.org/10.1046/j.1365-2648.1999.01077.x. 14. toobert dj, hampson se, glasgow re. the summary of diabetes self-care activities measure: results from 7 studies and a revised scale. diabetes care 2000; 23:943–50. 15. gaston a, cramp a, prapavessis h. enhancing self-efficacy and exercise readiness in pregnant women. psychol sport exerc 2012; 13:550–7. https://doi.org/10.1016/j.psychsport.2012.03.001. 16. neupert sd, lachman me, whitbourne sb. exercise self-efficacy and control beliefs: effects on exercise behavior after an exercise intervention for older adults. j aging phys act 2009; 17:1–16. https://doi.org/10.1123/japa.17.1.1. 17. o’dea a, tierney m, mcguire be, newell j, glynn lg, gibson i, et al. can the onset of type 2 diabetes be delayed by a groupbased lifestyle intervention in women with prediabetes following gestational diabetes mellitus (gdm)? findings from a randomized control mixed methods trial. j diabetes res 2015; 2015:798460. https://doi.org/10.1155/2015/798460. 18. poddar kh, hosig kw, anderson es, nickols-richardson sm, duncan se. web-based nutrition education intervention improves self-efficacy and self-regulation related to increased dairy intake in college students. j am diet assoc 2010; 110:1723–7. https://doi.org/10.1016/j.jada.2010.08.008. 19. mailey el, mcauley e. physical activity intervention effects on perceived stress in working mothers: the role of self-efficacy. women health 2014; 54:552–68. https://doi.org/10.1080/0363 0242.2014.899542. 20. olson ea, mcauley e. impact of a brief intervention on selfregulation, self-efficacy and physical activity in older adults with type 2 diabetes. j behav med 2015; 38:886–98. https://doi. org/10.1007/s10865-015-9660-3. iman al-hashmi, felicia hodge, karabi nandy, elizabeth thomas and mary-lynn brecht clinical and basic research | e519 21. bohanny w, wu sf, liu cy, yeh sh, tsay sl, wang tj. health literacy, self-efficacy, and self-care behaviors in patients with type 2 diabetes mellitus. j am assoc nurse pract 2013; 25:495–502. https://doi.org/10.1111/1745-7599.12017. 22. king dk, glasgow re, toobert dj, strycker la, estabrooks pa, osuna d, et al. self-efficacy, problem solving, and social-envi ronmental support are associated with diabetes self-management behaviors. diabetes care 2010; 33:751–3. https://doi.org/ 10.2337/dc09-1746. 23. kim c, mcewen ln, kieffer ec, herman wh, piette jd. self efficacy, social support, and associations with physical activity and body mass index among women with histories of gestational diabetes mellitus. diabetes educ 2008; 34:719–28. https://doi. org/10.1177/0145721708321005. 24. bandura a. self-efficacy mechanism in human agency. am psychol 1982; 37:122–47. https://doi.org/10.1037/0003-066x.37.2.122. 25. danyliv a, gillespie p, o’neill c, noctor e, o’dea a, tierney m, et al. shortand long-term effects of gestational diabetes mellitus on healthcare cost: a cross-sectional comparative study in the atlantic dip cohort. diabet med 2015; 32:467–76. https://doi.org/10.1111/dme.12678. 1department of paediatrics and child health, 2college of medicine, king khalid university, abha, saudi arabia *corresponding author’s e-mail: k.mm2035@gmail.com prevalence and determinants of vaccine hesitancy in aseer region, saudi arabia *youssef a. alqahtani,1 khalid h. almutairi,2 yahya m. alqahtani,2 ahmed h. almutlaq,2 anas a. asiri2 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 532–538, epub. 25 nov 21 submitted 9 jul 20 revisions req. 20 sep & 11 nov 20; revisions recd. 9 oct & 10 nov 20 accepted 18 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.023 clinical & basic research vaccination is the provision of a vaccine to initiate immunity through stimulating the immune system to develop protection from a certain disease.1 when a sufficiently large proportion of a population has been vaccinated, herd immunity is initiated. the effectiveness of vaccination has been widely studied and verified.2–4 vaccine efficacy is the magnitude of reduction in vaccine-related diseases using the most favourable conditions among vaccinated groups of people compared to an unvaccinated group.5 vaccine effectiveness is variable according to vaccine type, disease nature and vaccination schedule.6 despite the rigorous vaccine safety systems, some parents remain concerned about the safety of childhood vaccination and fail to adhere to the related immunisation schedule. the hesitations of some parents have resulted in them not letting their children receive some or all of the scheduled vaccines.7 in the usa, the rates of vaccine exemptions increased from 1% in 2006 to 2% in 2016–2017 of the total population.8 this resulted in the prevalence of vaccine-preventable diseases being greater in children whose parents refused at least one of the vaccines for non-medical reasons as they were 23 times more likely to contract pertussis, 8.6 times more prone to have varicella and 6.5 times more vulnerable to contracting pneumococcal disease.9−11 vaccine hesitancy refers to either the lack of enthusiasm or plain refusal to be vaccinated or to have one’s child vaccinated against infectious diseases despite vaccination services being accessible. it was identified by the world health organization as one of the top 10 global health threats of 2019.12,13 vaccine hesitancy may be in the form of outright refusal to opt for vaccination, delaying getting vaccinated, accepting vaccines with uncertainty regarding their use or selectively using certain vaccines and not all.14,15 arguments against vaccination are contradicted by abstract: objectives: this study aimed to assess the awareness of the general population regarding vaccines to determine the prevalence of vaccine hesitancy in aseer region in the southern part of saudi arabia. methods: a descriptive cross-sectional approach was used, targeting all parents in aseer region. the study was carried out from january to april 2020. the data for this study were collected using a structured questionnaire, which was developed by the researchers after an intensive literature review and consultation with experts. the questionnaire covered aspects such as parents’ sociodemographic data, their awareness regarding vaccine safety and efficacy for children and their attitude and adherence to children’s vaccination, including their hesitancy towards vaccines. results: the survey included 796 participants (response rate: 100%) whose ages ranged from 18 to 55 years. two-thirds (63.4%) of the participants were female. regarding vaccination adherence and hesitancy among participants, more than threequarters completely adhered to the vaccination schedule for their children, and only 3.9% were non-adherent. with regards to participants’ awareness regarding vaccine safety and efficacy for children, 89.3% agreed that vaccination keeps children healthy, 84.2% reported that vaccines are safe and effective for children and 83.4% reported that all scheduled vaccines in saudi arabia are effective. conclusion: vaccine hesitancy among participants was not low, and this should be taken into account notwithstanding their high awareness levels. the recorded antivaccine action was mostly related to vaccine safety and not its efficacy. keywords: vaccination refusal; anti-vaccination movement; parents; awareness; vaccination; saudi arabia. advances in knowledge vaccine hesitancy among parents in the aseer region is generally high and is probably due to certain misconceptions about vaccine safety and efficacy. greater awareness needs to be spread during the ministry of health campaign and flu vaccine seasons due to the high rate of noncompliance. this study is the first to examine the prevalence and determinants of vaccine hesitancy among parents in aseer region, saudi arabia. application to patient care awareness regarding vaccine intake needs to be duly emphasised among all parents. understanding the safety and efficacy of vaccination is very important to avoid missing or delaying it. youssef a. alqahtani, khalid h. almutairi, yahya m. alqahtani, ahmed h. almutlaq and anas a. asiri clinical and basic research | 533 overwhelming scientific consensus about the safety and efficacy of vaccines. the gulf cooperation council countries share common social and economic histories, health concerns and health systems and policies that are nearly identical. the mean consumption of the influenza vaccine was 17% (21% among ‘at risk’ individuals) and ranged from 15% in saudi arabia to 24% in qatar. the primary reasons cited for being vaccinated were doctor’s recommendation (23%) and a perception of poor body immunity (21%). between 2017–2020, the average consumption of pneumococcal vaccine was 22% (25% among people ‘at risk’) and ranged from 0% in bahrain to 79% in kuwait. ignorance about vaccines was mentioned as the key obstacle to vaccination (43%). the overall pertussis vaccine consumption was 16% (31% among ‘vulnerable’ individuals) and ranged from 7% in saudi arabia to 75% in oman. the overall meningococcal vaccine consumption was 20% (29% among ‘at risk’ individuals) and ranged from 3% in oman to 50% in bahrain.16–20 the present study aimed to assess parents’ awareness regarding vaccination, determine the prevalence of vaccine hesitancy and identify factors associated with vaccine hesitancy among parents in aseer region, saudi arabia. methods a descriptive cross-sectional approach was used, targeting all parents in aseer region due to the mixture of rural and urban areas present in this region. this study was conducted from january to april 2020. data were collected using a structured questionnaire, which was developed by the researchers after an intensive literature review and consultation with experts. the first section of the questionnaire included parents’ sociodemographic data such as age, gender, education and number of children under their care. the parents’ awareness regarding vaccine safety and efficacy for children was assessed using six questions in the second section. the third section covered parents’ attitudes towards and adherence to children’s vaccination and hesitancy vis-à-vis vaccines. a panel of three experts reviewed the questionnaire independently for content validity, and all suggested modifications were applied till the final tool was achieved. the questionnaire was uploaded online on social media platforms (whatsapp and telegram) by the researchers and their relatives and friends to be filled by the population in aseer region. a pilot study was conducted to assess the tool’s applicability and reliability. the tool reliability coefficient (cronbach’s alpha) was assessed and determined to be 0.68. after the data were extracted, they were revised, coded and input into the statistical package for the social sciences (spss) version 22 (ibm corp., armonk, new york, usa). all statistical analyses were done using two-tailed tests. a p value less than 0.05 was considered to be statistically significant. for awareness items, each correct answer was scored as one point, and the sum of the discrete scores of the different items was calculated. a patient with a score less than 60% of the maximum score (i.e. four points) was considered to have poor awareness; a score of 60% of the maximum score or more (i.e. five points or more) was considered as having good awareness. a descriptive analysis based on the frequency and percentage distribution was carried out for all the variables including demographic data, awareness, attitude, adherence to vaccination and hesitancy. thereafter, cross tabulation was used to assess the distribution of awareness according to the participants’ personal data and their attitudes. the table 1: characteristics of survey participants socio-demographic data n (%) gender male 291 (36.6) female 505 (63.4) age in years <20 38 (4.8) 20–29 254 (31.9) 30–39 275 (34.5) 40–49 184 (23.1) ≥50 45 (5.7) educational level secondary school/below 140 (17.6) diploma 70 (8.8) undergraduate student 169 (21.2) postgraduate 417 (52.4) number of children cared for 1–3 450 (56.5) 4–6 283 (35.6) ≥7 63 (7.9) youngest child’s age in years <4 390 (49.0) >4 406 (51.0) prevalence and determinants of vaccine hesitancy in aseer region, saudi arabia 534 | squ medical journal, november 2021, volume 21, issue 4 relations were tested using the chi-squared test. the study was ethically approved by the medical research committee of king khalid university. participation in this study was on voluntary basis and no informed consent was sought from the children’s parents or the families. results the survey included 796 participants (response rate: 100%) whose ages ranged from 18 to 55 years. approx imately, two-thirds (63.4%) of the participants were female. moreover, 52.4% of them had either graduated from university or had higher qualifications. regarding the number of children cared for, 56.5% of the respondents cared for 1–3 children and 7.9% for seven children or more. for 40.0% of the participants, the youngest child was aged less than four years [table 1]. regarding vaccination adherence and hesitancy among participants concerning vaccination, 80.5% of the participants fully adhered to their child’s vaccination schedule, 15.6% partially adhered and only 3.9% of them had been non-adherent. regarding participants’ awareness concerning vaccine safety and efficacy for children, 89.3% of the respondents agreed that vaccination keeps children healthy, 84.2% reported that vaccines are safe and effective in children and 83.4% reported that all scheduled vaccines in saudi arabia are effective; 81.8% reported that routine vaccination prevents infectious diseases and complications. overall, a good level of awareness regarding vaccine efficacy and safety was reported among 601 (75.5%) of the participants [table 2]. adherence to the ministry of health (moh) recommendations for vaccination schedule was recorded among 88.3% of the participants, and 77.6% of them vaccinated their children during the moh campaigns. vaccinating children against seasonal influenza was reported by 33.2% of the participants. moreover, 60.4% think that vaccines do not affect child health negatively and 24.2% were worried about vaccine side-effects [table 3]. a good level of awareness was recorded for 77.5% of those with university education, compared to 64.3% of those with secondary education or less with recorded statistical significance (p = 0.005). further, good awareness was recorded among 73.1% of those who cared for 1–3 children, compared to 63.5% of those who cared for seven children or more (p = 0.002). additionally, 80.7% of those who completely adhered to vaccination schedules for their children had good awareness, compared to 9.7% of the non-adherent group (p = 0.001). the awareness levels were significantly higher for those who adhered to the moh’s vaccination recommendations (83.6%), those who vaccinated their children during the moh campaigns (79.1%) and those who were not worried about vaccine side-effects (65.3%; p = 0.001, each) [tabel 4]. table 2: participants’ awareness regarding vaccine safety and efficacy for children awareness item n (%) yes no unsure vaccination keeps children healthy 711 (89.3) 21 (2.6) 64 (8.0) vaccines are safe and effective in children 670 (84.2) 33 (4.1) 93 (11.7) non-vaccinated children are more liable to infection than other children and the elderly 583 (73.2) 78 (9.8) 135 (17.0) all scheduled vaccines in saudi arabia are effective 664 (83.4) 28 (3.5) 104 (13.1) repeated doses of the vaccine over intervals keep children immune 628 (78.9) 38 (4.8) 130 (16.3) routine vaccination prevents infectious diseases and complications 651 (81.8) 34 (4.3) 111 (13.9) overall awareness poor 195 (24.5) good 601 (75.5) table 3: participants practice and attitude regarding vaccine safety and efficacy for children domain item n (%) participants’ practice adherence to the moh’s recommendations for vaccination schedule yes 703 (88.3) no 93 (11.7) vaccinating your child during the moh’s campaigns yes 618 (77.6) no 178 (22.4) vaccinating your child against seasonal influenza yes 264 (33.2) no 532 (66.8) participants’ attitude think vaccines affect child health negatively yes 125 (15.7) no 481 (60.4) maybe 190 (23.9) worried about vaccines’ sideeffects yes 193 (24.2) no 353 (44.3) maybe 250 (31.4) moh = ministry of health. youssef a. alqahtani, khalid h. almutairi, yahya m. alqahtani, ahmed h. almutlaq and anas a. asiri clinical and basic research | 535 regarding identified side-effects reported by the participants, allergy was the most reported (25.8%), followed by autism (8.4%), fever (8%), paralysis (6.5%) and epilepsy (5.9%), while 57.2% reported that there was no side-effect [figure 1]. discussion vaccine hesitancy is mostly a result of public debates regarding the medical, ethical and legal issues related to vaccines. it is related to many factors including a person’s lack of confidence, complacency (as the person does not see the need for/value in the vaccine) and vaccine convenience.21 the specific hypotheses raised by antivaccination advocates—that vaccination leads to autism and that vaccines contain microchips developed to control people—have been found to change over time.22 vaccine hesitancy often results in disease outbreaks and deaths from vaccinepreventable diseases.23,24 table 4: predictors of participants’ awareness regarding vaccination for children factors n (%) p value awareness level poor good age in years <20 10 (26.3) 28 (73.7) 0.071 20–29 64 (25.2) 190 (74.8) 30–39 79 (28.7) 196 (71.3) 40–49 31 (16.8) 153 (83.2) 50+ 11 (24.4) 34 (75.6) educational level secondary school/below 50 (35.7) 90 (64.3) 0.005 diploma 18 (25.7) 52 (74.3) university student 33 (19.5) 136 (80.5) university/postgraduate 94 (22.5) 323 (77.5) number of children cared for 1–3 121 (26.9) 329 (73.1) 0.002 4–6 51 (18.0) 232 (82.0) 7+ 23 (36.5) 40 (63.5) youngest child’s age in years <4 108 (27.7) 282 (72.3) 0.058 >4 87 (21.4) 319 (78.6) adherence to child’s vaccination schedule completely adherent 124 (19.3) 517 (80.7) 0.001 partially adherent 43 (34.7) 81 (65.3) non-adherent 28 (90.3) 3 (9.7) adherence to the moh recommendations for vaccination schedule yes 115 (16.4) 588 (83.6) 0.001 no 80 (86.0) 13 (14.0) vaccinating the child during the moh campaigns yes 129 (20.9) 489 (79.1) 0.001 no 66 (37.1) 112 (62.9) vaccinating the child against seasonal influenza yes 46 (17.4) 218 (82.6) 0.001 no 149 (28.0) 383 (72.0) think that vaccines affect child health negatively yes 39 (31.2) 86 (68.8) 0.001 no 71 (14.8) 410 (85.2) maybe 85 (44.7) 105 (55.3) worried about vaccines’ side-effects yes 67 (34.7) 126 (65.3) 0.001 no 64 (18.1) 289 (81.9) maybe 64 (25.6) 186 (74.4) moh = ministry of health. prevalence and determinants of vaccine hesitancy in aseer region, saudi arabia 536 | squ medical journal, november 2021, volume 21, issue 4 the present study aimed to assess parents’ awareness regarding vaccines and vaccine hesitancy in aseer region, saudi arabia. the study revealed that nearly 20% of the participating parents reported either partial or complete non-adherence to the vaccinations recommended for their children. further, nearly one out of five mothers did not vaccinate their children during the moh campaigns. on the other hand, vaccination against seasonal influenza was reported by only one-third of the participants. this could be because approximately one-third of the participants thought that vaccines affect child health negatively and that more than half of them worried about the vaccines’ side-effects. the vaccines’ side-effects that most of the participants knew of and referred to were allergy, autism, fever and infertility. some of the mentioned side-effects, such as autism and infertility, are not scientifically proven but their mere mention is sufficient to yield a negative attitude against vaccines and empower the antivaccine movement. as for the participants’ awareness regarding vaccines, more than three-quarters of the participants reported that vaccination keeps children healthy, they are safe and effective, repeated doses of the vaccine over intervals keep children immune, and routine vaccination prevents infectious diseases and complications. a very important question arises, as three out of four participants were well aware about vaccines but still reported fear of commitment and vaccination hesitancy. this could partially explain the fact that very few participants with good awareness were non-adherent to their children’s vaccination schedule. however, a high percentage of those who were worried about the vaccines’ side-effects and those who thought that vaccines affect child health negatively had good awareness regarding vaccines. this may be related to the vaccine safety aspect as there was no doubt about vaccine efficacy. as with any medical treatment, vaccines have the potential to cause serious complications such as severe allergic reactions.25,26 yet, vaccines are somewhat different from medical interventions. unlike most other medical interventions, vaccines are administered to healthy people, so a higher standard of safety is expected.27 the growing link between vaccines and autism has been massively studied and conclusively shown to be incorrect. the scientific consensus is that there is no relationship, causal or otherwise, between vaccines and the incidence of autism and that vaccine ingredients do not cause autism.28,29 mothers need to encourage vaccinations for their children as getting vaccinated is a child’s right. this will improve their children’s health and, in turn, community health and lessen the social, psychological and economic burden. appropriate laws may need to be enacted to obligate mothers to vaccinate their children, disallow non-vaccinated children from being admitted to schools and impose monetary penalties for refusing to vaccinate their children. this study was subject to some limitations. the online sampling technique may affect sample representativeness, as only those who have access to the online questionnaire could respond. this study population covers those who are educated and have online access. therefore, the study results are not generalisable to the whole population; however, this sampling technique was necessary due to the restricted lifestyle during the current pandemic. in addition, cross-sectional studies have low precision regarding causality and testing for association which may also affect the study results. furthermore, the timing of the study during the current pandemic may affect participants perception or even practice regarding their children’s vaccination due to fear of infection if they attend primary healthcare centres. finally, this study was conducted in one region in the country, which may not reflect the views of other regions. further large studies are needed in the future to assess vaccine hesitancy and its determinants in many regions of saudi arabia. figure 1: vaccine’s side-effects as reported by survey participants. youssef a. alqahtani, khalid h. almutairi, yahya m. alqahtani, ahmed h. almutlaq and anas a. asiri clinical and basic research | 537 conclusion this study revealed that vaccine hesitancy among participants was not low, and this should be taken into account notwithstanding their high awareness levels. the recorded antivaccine action was mostly related to vaccine safety and not efficacy. most participants were aware that vaccines are effective, but they reported fear of some complications such as autism and infertility, among others, which is enough to convince some of not vaccinating their children. more efforts should be made by the country and its medical staff, in particular, to disseminate correct detailed information, regarding vaccine safety and explain to the people that most research studies warn against unsafe vaccination which has many drawbacks. furthermore, health education campaigns should be organised to duly reach parents in remote areas who may constitute the main bulk of carers of unvaccinated children. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n yaa and kha drafted the manuscript. kha drafted the questionnaire, while yma, aha and aaa collected the data. yaa and aaa analysed the data. yaa and aha reviewed the literature. all authors approved the final version of the manuscript. references 1. artenstein aw, ed. vaccines: a biography. new york: springer science & business media, 2009. 2. lombard m, pastoret pp, moulin am. a brief history of vaccines and vaccination. rev sci tech 2007; 26:29–48. https:// doi.org/10.20506/rst.26.1.1724. 3. appay v, douek dc, price da. cd8+ t cell efficacy in vaccination and disease. nat med 2008; 14:623. https://doi. org/10.1038/nm.f.1774. 4. elkayam o, yaron m, caspi d. safety and efficacy of vaccination against hepatitis b in patients with rheumatoid arthritis. ann rheum dis 2002; 61:623–5. https://doi.org/10.1136/ ard.61.7.623. 5. orenstein wa, bernier rh, dondero tj, hinman ar, marks js, bart kj, et al. field evaluation of vaccine efficacy. bull world health organ 1985; 63:1055–68. 6. gilbert p, self s, rao m, naficy a, clemens j. sieve analysis: methods for assessing from vaccine trial data how vaccine efficacy varies with genotypic and phenotypic pathogen variation. j clin epidemiol 2001; 54:68–85. https://doi. org/10.1016/s0895-4356(00)00258-4. 7. buttenheim am, asch da. making vaccine refusal less of a free ride. hum vaccin immunother 2013; 9:2674–5. https:// doi.org/10.4161/hv.26676. 8. seither r, calhoun k, street ej, mellerson j, knighton cl, tippins a, et al. vaccination coverage for selected vaccines, exemption rates, and provisional enrollment among children in kindergarten—united states, 2016–17 school year. mmwr morb mortal wkly rep 2017; 66:1073–80. https://doi. org/10.15585/mmwr.mm6640a3. 9. glanz jm, mcclure dl, magid dj, daley mf, france ek, salmon da, et al. parental refusal of pertussis vaccination is associated with an increased risk of pertussis infection in children. pediatrics 2009; 123:1446–51. https://doi. org/10.1542/peds.2008-2150. 10. glanz jm, mcclure dl, magid dj, daley mf, france ek, hambidge sj. parental refusal of varicella vaccination and the associated risk of varicella infection in children. arch pediatr adolesc med 2010; 164:66–70. https://doi.org/10.1001/ archpediatrics.2009.244. 11. glanz jm, mcclure dl, o’leary st, narwaney kj, magid dj, daley mf, et al. parental decline of pneumococcal vaccination and risk of pneumococcal related disease in children. vaccine 2011; 29:994–9. https://doi.org/10.1016/j.vaccine.2010.11.085. 12. kata a. anti-vaccine activists, web 2.0, and the postmodern paradigm–an overview of tactics and tropes used online by the anti-vaccination movement. vaccine 2012; 30:3778–89. https:// doi.org/10.1016/j.vaccine.2011.11.112. 13. world health organization. ten health issues who will tackle this year. from: https://www.who.int/news-room/spotlight/ ten-threats-to-global-health-in-2019 accessed: jan 2019. 14. keane mt, walter mv, patel bi, moorthy s, stevens rb, bradley km, et al. confidence in vaccination: a parent model. vaccine 2005; 23:2486–93. https://doi.org/10.1016/j. vaccine.2004.10.026. 15. larson hj, jarrett c, eckersberger e, smith dm, paterson p. understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature, 2007–2012. vaccine 2014; 32:2150–9. https://doi.org/10.1016/j.vaccine.2014.01.081. 16. alqahtani as, bondagji dm, alshehari aa, basyouni mh, alhawassi tm, bindhim nf, et al. vaccinations against respiratory infections in arabian gulf countries: barriers and motivators. world j clin cases 2017; 5:212–221. https://doi. org/10.12998/wjcc.v5.i6.212. 17. boianelli a, nguyen vk, ebensen t, schulze k, wilk e, sharma n, et al. modeling influenza virus infection: a roadmap for influenza research. viruses 2015; 7:5274–5304. https://doi. org/10.3390/v7102875. 18. drijkoningen jj, rohde gg. pneumococcal infection in adults: burden of disease. clin microbiol infect 2014; 20:45–51. https://doi.org/10.1111/1469-0691.12461. 19. harrison lh, trotter cl, ramsay me. global epidemiology of meningococcal disease. vaccine 2009; 27:b51–63. https://doi. org/10.1016/j.vaccine.2009.04.063. 20. hewlett el, burns dl, cotter pa, harvill et, merkel tj, quinn cp, et al. pertussis pathogenesis--what we know and what we don’t know. j infect dis 2014; 209:982–5. https://doi. org/10.1093/infdis/jit639. 21. wolfe rm, sharp lk. anti-vaccinations past and present. bmj 2002; 325:430–2. https://doi.org/10.1136/bmj.325.7361.430. 22. frequently asked questions (faq). boston children’s hospital. from: https://www.childrenshospital.org/conditions-and-treat ments/conditions/m/measles-rubeola accessed: jan 2019. prevalence and determinants of vaccine hesitancy in aseer region, saudi arabia 538 | squ medical journal, november 2021, volume 21, issue 4 23. phadke vk, bednarczyk ra, salmon da, omer sb. association between vaccine refusal and vaccine-preventable diseases in the united states: a review of measles and pertussis. jama 2016; 315:1149–58. https://doi.org/10.1001/jama.2016.1353. 24. poland ga, jacobson rm. the age-old struggle against the antivaccination. n engl j med 2011; 364:97–9. 25. the li. tackling negative perceptions towards vaccination. lancet infect dis 2007; 7:235. https://doi.org/10.1016/s14733099(07)70057-9. 26. chen rt, hibbs b. vaccine safety: current and future challenges. pediatr ann 1998; 27:445–55. https://doi.org/10.3928/00904481-19980701-11. 27. gonçalves ak, cobucci rn, rodrigues hm, de melo ag, giraldo pc. safety, tolerability, and side effects of human papillomavirus vaccines: a systematic quantitative review. braz j infect dis 2014; 18:651–9. https://doi.org/10.1016/j. bjid.2014.02.005. 28. taylor le, swerdfeger al, eslick gd. vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies. vaccine 2014; 32:3623–9. https://doi.org/10.1016/j.vaccine.2014.04.085. 29. smith im, macdonald ne. countering evidence denial and the promotion of pseudoscience in autism spectrum disorder. autism res 2017; 10:1334–7. https://doi.org/10.1002/aur.1810. departments of 1physiology, 2pathology and 3biochemistry, college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia *corresponding author’s e-mail: mtalhariri@iau.edu.sa العكرب يعدل من وسائط االلتهاب وحيسن الرتكيب النسيجي لذكور اجلرذان املصابة بالتهاب البنكرياس احلاد احملدث بواسطة األرجينني حممد طه احلريري، ثروت جمال الدين، طارق ها�شم، �شاهان�س �شاثوث، عبد اهلل ال�شويد abstract: objectives: this study aimed to determine the effects of propolis on immune mediators and tissue histopathology in rats with l-arginine-induced acute pancreatitis (ap). methods: this study was conducted at imam abdulrahman bin faisal university, dammam, saudia arabia between september and november 2017. a total of 24 male albino wistar rats were divided into three equal groups. group one was the negative control, group two was the positive control (l-arginine-induced ap) and group three received treatment (l-arginineinduced ap and propolis). the rats in group three were treated with 100 mg/kg propolis for seven days after ap induction. pancreatic tissue was evaluated histologically and levels of interleukin (il)-6, il-22 and il-1β and tumour necrosis factor-alpha (tnf-α) were measured. results: propolis reduced the quanitity of proinflammatory molecules (tnf-α, il-1β and il-6) in group three compared to group two, significantly increased the overall antiinflammatory effect of il-22 (p <0.005) and reduced interstitial inflammation and neutrophil cell infiltration of the pancreatic tissues. conclusion: propolis may exert a therapeutic effect in ap. further studies are required to demonstrate the mechanisms of propolis in ap. keywords: propolis; arginine; pancreatitis; interleukins; cytokinesis; rats; saudi arabia. والتغريات الدم، يف البيوكيميائية والوا�شمات املناعة و�شائط على العكرب فعالية حتديد الدرا�شة هذه من الهدف كان الهدف: امللخ�ص: الن�شيجية يف اجلرذان امل�شابة بالتهاب البنكريا�س احلاد. الطريقة: اأجريت هذه الدرا�شة يف جامعة االإمام عبد الرحمن بن في�شل، الدمام، اململكة العربية ال�شعودية بني �شهري �شبتمرب ونوفمرب 2017. مت تق�شيم 42 من ذكور اجلرذان املهق اإىل 3 جمموعات مت�شاوية. املجموعة االأوىل: ال�شابطة ال�شلبية؛ املجموعة الثانية: ال�شابطة االإيجابية وهي امل�شابة بالتهاب البنكريا�س احلاد املحدث بوا�شطة االرجنني؛ املجموعة الثالثة: جمموعة م�شابة بالتهاب البنكريا�س و مت معاجلتها بالعكرب )100 جمم/كجم/ملدة 7 اأيام(. يف نهاية فرتة البحث متت درا�شة اأن�شجة البنكريا�س ومت قيا�س م�شتويات االإنرتلوكني )6، 22، 1ب( وعامل نخر الورم األفا. النتائج: اأظهرت النتائج اأن العكرب قد قلل من كمية جزيئات ما قبل االلتهابات وهي االإنرتلوكني )6، 1ب(و من م�شتوى عامل نخر الورم األفا مقارنة باملجموعة الثانية، وزاد ب�شكل كبري من التاأثري امل�شاد لاللتهابات بوا�شطة اإنرتلوكني 22 عند داللة اإح�شائية تعادل )p >0.005( اإ�شافة اإىل اأن العكرب قد قلل ب�شكل ملحوظ من االلتهاب الن�شيجي للبنكريا�س. اخلال�صة: اأظهرت الدرا�شة اأن للعكرب تاأثريا عالجيا يف التهاب البنكريا�س احلاد، االأمر الذي يفتح االأبواب الإجراء العديد من االأبحاث يف هذا اخل�شو�س الإثبات اآليات عمل العكرب يف عالج مثل هذه احلاالت. الكلمات املفتاحية: العكرب؛ اأرجينني؛ التهاب البنكريا�س؛ اإنرتلوكني؛ �شايتوكني؛ اجلرذان؛ العربية ال�شعودية. propolis modulates inflammatory mediators and improves histopathology in male rats with l-arginine-induced acute pancreatitis *mohammed t. al-hariri,1 tharwat g. eldin,1 tarek hashim,2 shahanas chathoth,3 abdullah alswied1 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e103–107, epub. 8 sep 19 submitted 2 oct 18 revision req. 3 dec 18; revision recd. 26 dec 18 accepted 17 jan 19 advances in knowledge the present study identifies the anti-pancreatitis effect of propolis. the anti-pancreatitis effect takes potential inflammatory and proinflammatory pathways. application to patient care propolis minimised inflammatory response and pancreatic tissue damage. propolis should be considered an effective and promising natural compound for managing acute pancreatitis. pancreatitis is a major gastrointestinal problem worldwide.1 despite the development of new therapeutic and diagnostic approaches, the clinical course of acute pancreatitis (ap) is assoc iated with significant morbidity and a high mortality rate.2,3 experimental studies focused on the molecular pathway, including proinflammatory cytokines, are shedding light on the pathophysiologic mechanisms of ap. increased levels of proinflammatory cytokines—such as interleukin (il)-1, il-6 and tumour necrosis factorthis work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.004 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ propolis modulates inflammatory mediators and improves histopathology in male rats with l-arginine-induced acute pancreatitis e104 | squ medical journal, may 2019, volume 19, issue 2 alpha (tnf-α)—aggravate ap by increasing vascular permeability.4-6 propolis is a natural resinous compound collected by bees from the gum of various plants and converted through salivary secretions to beeswax. propolis has attr acted global attention for its wide range of pharmacol ogical and biological properties, making propolis a poten tially promising therapeutic agent.7 the efficacy of pro polis depends mainly on the presence of flavonoids, primarily caffeic acid phenethyl ester (cape), which pro vide an anti-inflammatory effect.8 future studies should focus on standardising the therapeutic applications of propolis.9 many studies have shown that the anti-inflamm atory activity of propolis and/or its compounds inhibit the activation of cyclooxygenase (cox)-2 gene expression, suppress enzyme activities of cox-1 and cox-2 and inhibit the release of arachidonic acid from cell mem branes.10,11 galangin, a propolis-associated flavonoid, has been shown to decrease prostaglandin e2 release, inhibit lipoxygenase, cox and the expression of the inducible isoform of cox-2.12 this study aimed to determine the effects of propolis on immune mediators and tissue histopathology of rats with l-arginine-induced ap. methods this study was conducted at imam abdulrahman bin faisal university, dammam, saudi arabia from september to november 2017. a total of 24 male albino wistar rats weighing 150–250 g were obtained from the university’s animal house for this study. all rats were maintained in a room at a constant temperature of 22 ± 1°c with 12 hour light/dark cycles and had free access to standard laboratory food pellets and water. the rats were equally divided into three groups. group one was the untreated negative control group, group two consisted of the positive controls and group three was the experimental treatment group. group two and three were injected with l-arginine to induce ap. two intraperitoneal (ip) injections of l-arginine (sigma-aldrich chemical, merck kgaa, darmstadt, germany) at a dose of 250 mg/100 g of body weight (bw) prepared in isotonic saline (20% 0.15 m sodium chloride) were administered at a one-hour interval to induce ap.13 the rats in group three were treated orally with brazilian green propolis alcohol extract (uniflora apicultores associados ltda, olímpia, brazil) 100 mg/kg of bw after two hours of l-arginine injection and daily for seven days.14 this dose has previously been shown to be anti-inflammatory.15 ap was diagnosed clinically as rats became sluggish and lethargic. the condition was most severe 72 hours after the l-arginine-injections and was confirmed by histopathological examination.16 the treatment regimens were stopped after seven days and 12 hours before the rats were anaesthetised with an ip injection of ketamine (50 mg/kg of bw; alfasan international bv, woerden, the netherlands). rats were euthanised and blood was collected from the abdominal aorta by means of a vacutainer.17 antiinflammatory cytokines (il-1β, il-6, tnf-α and il22) were assessed by enzyme-linked immunosorbent assay (elisa). the il-22 elisa kit (r&d systems, minneapolis, minnesota, usa) and all other cytokine assays (bio-rad laboratories inc., hercules, california, usa) were quantified in accordance with the manufact urers’ guidelines and instructions.18,19 pancreatic tissues were fixed in a 10% formal dehyde solution for 48 hours, embedded in paraffin wax and sectioned. the sections were stained with haema toxylin and eosin and evaluated under a light microscope to detect inflammatory manifestations, including oedema, leukocyte infiltration, parenchymal necrosis and haemo rrhage in the pancreatic tissue. the general morphology and histological features were evaluated with a bx51 photomicroscope (olympus corporation, tokyo, japan).20 histopathologic scoring for ap included assess ment of inflammatory cell infiltration, oedema and acinar degenerative changes. the inflammatory cells were counted in five high power field (hpf) × 400 images and the mean number of cells was calculated and rated. fewer than 50 inflammatory cells/hpf was rated 1+ (mild), 50–100 inflammatory cells/hpf was rated 2+ (moderate) and >100 inflammatory cells/hpf was rated 3+ (severe). statistical analysis was performed using statistical package of social science (spss), version 21 (ibm corp., armonk, new york, usa). data are presented as means ± standard error of the mean. one-way analysis of variance followed by tukey’s multiple comparison post-hoc test was used to compare the means. statistical significance was set at p <0.05. all experiments were performed in accordance with the recommendations of the national guidelines for the care and handling of laboratory animals. the experimental protocol was approved by the local animal ethics committee (irb 2015-01-185). results serum proinflammatory cytokines (il-1β, il-6 and tnf-α) and anti-inflammatory il-22 in the three studied groups are shown in table 1. injecting two doses of l-arginine induced an increase in proinflammatory measurements and a decrease in the measured antiinflammatory cytokine concentration in group two. moreover, pathohistological features of ap were present. mohammed t. al-hariri, tharwat g. eldin, tarek hashim, shahanas chathoth and abdullah alswied clinical and basic research | e105 the mean serum concentration of il-1β was signif icantly higher in group two than group one (p <0.005). group two also had significantly higher tnf-α and il-6 than groups one and three (p <0.005 and p <0.001 each). the mean serum level of il-22 for the propolis-treated group increased significantly compared to groups one and two (p <0.005 and p <0.001, respectively) [table 1]. group two was rated as 3+ and group three was rated at 2+. while regular pancreas morphology was observed in the tissues of rats in group one [figure 1], severe degrees of inflammatory cell infiltration, pancreatic tissue necrosis, haemorrhage and parenchymal degen erative changes were observed in the tissues of rats in group two compared with the other groups (p <0.05) [figure 2]. however, treatment with propolis in group three significantly decreased the degree of cellular infiltration, interstitial oedema, acinar cell necrosis and parenchymal degenerative changes compared to group two (p <0.05) [figure 3]. discussion previous studies have used experimental ap induced by l-arginine to study the effect of various therapeutic agents and the pathophysiologic mechanisms of the disease.21 the present study aimed to determine the effects of propolis on immune mediators and tissue histopathology in rats with ap. the effect of propolis was evidenced by a decrease in proinflammatory cytokines (tnf-α, il-1β and il-6) and a significant increase in the level of anti-inflammatory il-22 to levels close to that of the negative controls. several studies have focused on the pathogenesis of ap.2,6 overproduction of inflammatory mediators, including tnf-α, il-1β, il-6 and il-8, was found to play an important role in the pathogenesis of ap.22 table 1: serum analysis of proinflammatory (interleukin [il]-1β, il-6 and tumour necrosis factor-alpha) and anti inflammatory (il-22) cytokine in three rat groups group mean ± sem i (negative control) ii (positive control) iii (propolistreated group) il-1β in pg/ml 36.39 ± 3.07 116.13 ± 4.28* 41.43 ± 4.01 il-6 in pg/ml 39.02 ± 3.13 85.44 ± 3.39*‡ 45.21 ± 2.05 tnf-α in pg/ml 59.74 ± 1.40 96.91 ± 2.51*‡ 48.83 ± 1.51 il-22 in pg/ml 0.19 ± 0.020 0.15 ± 0.023 0.30 ± 0.056*† sem = standard error of mean; il = interleukin; tnf-α = tumour necr osis factor-alpha. *significantly different from group one (p <0.005); †significantly different from group two (p <0.001); ‡significantly different from group three (p <0.001). figure 1: haematoxylin and eosin stain of pancreatic tissue from group one at x200 maginification showing normal, unremarkable pancreatic tissue in both exocrine (exo) and endocrine parts (islet). figure 3: haematoxylin and eosin stain of pancreatic tissue from group three at x400 maginification showing moderate interstitial inflammation and neutrophil cell infiltration of the pancreatic tissue (arrow). figure 2: haematoxylin and eosin stain of pancreatic tissue from group two at x200 maginification showing significant severe interstitial inflammation, oedema with mixed mononuclear inflammatory cells (arrows) and neut rophils. the pancreatic acini show moderate parenchymal degenerative changes (arrowheads). propolis modulates inflammatory mediators and improves histopathology in male rats with l-arginine-induced acute pancreatitis e106 | squ medical journal, may 2019, volume 19, issue 2 in the present study, propolis significantly reduced the total pathologic score and the extent of oedema, most likely due to the anti-inflammatory action of propolis and/or its active compounds.23 these results agree with those of previous studies from different ap models.24 interestingly, an important and novel result of this study was the finding that propolis significantly increased levels of il-22, which had not been tested in previous studies. the anti-inflammatory activities of propolis are still not fully understood. pooran et al. suggested that propolis has an anti-inflammatory effect as it inhibits the release of histamine, prostaglandins and leukotrienes.22 another study reported that the anti-inflammatory properties of propolis are due to cape.25 cape exerts its anti-inflammatory actions by suppressing the inflammatory enzyme activities of cox-1 and cox-2 and inhibiting the release of arachidonic acid from cell membranes.26 in the current study, there was non-significant minimal change in il-22 levels between groups one and two. the increase of il-22 in only group three could be via the signal transducer and activator of transcription (stat) 3 signaling pathway in which exogenous recombinant il-22 protected mice from l-arginineinduced ap.27 the favourable effect of il-22 is thought to depend on the extent of ap inflammation. in mild cases of induced ap, administration of exogenous il-22 successfully aborted disease development.28 furthermore, over-expressed animal models of il-22 were resistant to ap development.29 xue et al. was reported that the administration of the anti-il-22 anti body, to block the receptors, endogenously aggravated pancreatic injury which supports the essential role of il-22.30 collectively, these findings strongly suggest that il-22 plays a vital role in ap prevention. further more, il-22 may mediate a protective effect against l-arginine-induced ap via activation of the stat3 signaling pathway, which can suppress apoptosis by inducing downstream genes, including bcl-xl and bcl-2.31 while some studies have discussed several promising mechanisms, the proposed therapeutic effect of propolis needs further investigation to better characterise the mechanism by which it exerts the observed therapeutic effect.26,32 the push-and-pull between the anti-inflamm atory and proinflammatory cytokines are believed to determine the outcome of ap.33,34 immune-modifying therapeutic approaches have been used for many inflammatory conditions with the aim of promoting the release of the anti-inflammatory cytokines and/or hindering the release of the inflammatory cytokines. recently, lattanzi et al. provided evidence for the potential contributions of the inflammatory reaction and/or inflammatory-induced oxidative stress in the aetiopathogenesis of several complicated disorders such as acute stroke and degenerative and secondary dementia.35 the anti-inflammatory properties of propolis could suggest novel pathophysiology-oriented treat ment options in the management of various medical conditions where inflammation plays a pivotal role in the development and progression of tissue damage.36 conclusion propolis attenuated the severity of inflammation of the pancreatic tissues of rats with l-arginine-induced ap. therefore, propolis could be investigated as a potential treatment for many inflammatory conditions in humans. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g financial support was received from king abdulaziz city for science and technology, riyadh, saudi arabia (m s 302-35). references 1. goulden mr. the pain of chronic pancreatitis: a persistent clinical challenge. british journal of pain 2013; 7:8-22. https://doi.org/10.1 177/2049463713479230. 2. bülbüller n, doğru o, umaç h, gürsu f, akpolat n. [the effects of melatonin and pentoxiphylline on l-arginine induced acute pancreatitis]. ulus travma acil cerrahi derg 2005; 11:108–14. 3. banks pa, freeman ml. practice parameters committee of the american college of gastroenterology. practice guidelines in acute pancreatitis. am j gastroenterol 2006; 101:2379–400. https://doi.org/10.1111/j.1572-0241.2006.00856.x. 4. gukovskaya as, gukovsky i, zaninovic v, song m, sandoval d, gukovsky s, et al. pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha. role in regulating cell death and pancreatitis. j clin invest 1997; 100:1853–62. https:// doi.org/10.1172/jci119714. 5. kusske am, rongione aj, reber ha. cytokines and acute pan creatitis. gastroenterology 1996; 110:639–42. https://doi.org/10.10 53/gast.1996.v110.agast960639. 6. gukovsky i, gukovskaya as, blinman ta, zaninovic v, pandol sj. early nf-kappab activation is associated with hormone-induced pancreatitis. am j physiol 1998; 275:g1402–14. https://doi.org/1 0.1152/ajpgi.1998.275.6.g1402. 7. greenaway w, scaysbrook t, whatley fr. the composition and plant origins of propolis: a report of work at oxford. bee world 1990; 71:107–18. https://doi.org/10.1080/0005772x.1990.1109 9047. 8. okutan h, ozcelik n, yilmaz hr, uz e. effects of caffeic acid phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart. clin biochem 2005; 38:191–6. https://doi. org/10.1016/j.clinbiochem.2004.10.003. 9. al-hariri mt, eldin tag, al-harb mm. protective effect and potential mechanisms of propolis on streptozotocin-induced diabetic rats. j taibah univ med sci 2016; 11:7–12. https://doi. org/10.1016/j.jtumed.2015.11.002. https://doi.org/10.1177/2049463713479230 https://doi.org/10.1177/2049463713479230 https://doi.org/10.1111/j.1572-0241.2006.00856.x https://doi.org/10.1172/jci119714 https://doi.org/10.1172/jci119714 https://doi.org/10.1053/gast.1996.v110.agast960639 https://doi.org/10.1053/gast.1996.v110.agast960639 https://doi.org/10.1152/ajpgi.1998.275.6.g1402 https://doi.org/10.1152/ajpgi.1998.275.6.g1402 https://doi.org/10.1080/0005772x.1990.11099047 https://doi.org/10.1080/0005772x.1990.11099047 https://doi.org/10.1016/j.clinbiochem.2004.10.003 https://doi.org/10.1016/j.clinbiochem.2004.10.003 https://doi.org/10.1016/j.jtumed.2015.11.002 https://doi.org/10.1016/j.jtumed.2015.11.002 mohammed t. al-hariri, tharwat g. eldin, tarek hashim, shahanas chathoth and abdullah alswied clinical and basic research | e107 10. rossi a, ligresti a, longo r, russo a, borrelli f, sautebin l. the inhibitory effect of propolis and caffeic acid phenethyl ester on cyclooxygenase activity in j774 macrophages. phytomedicine 2002; 9(6):530-5. https://doi.org/10.1078/09447110260573164. 11. michaluart p, masferrer jl, carothers am, subbaramaiah k, zweifel bs, koboldt c, et al. inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygen ase-2 in human oral epithelial cells and in a rat model of inflamm ation. cancer research 1999; 59:2347-52. 12. michaluart p, masferrer jl, carothers am, subbaramaiah k, zweifel bs, koboldt c, et al. inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. cancer res 1999; 59:2347–52. 13. dawra r, saluja ak. l-arginine-induced experimental acute pancreatitis. pancreapedia: exocrine pancreas knowl base 2012. https://doi.org/10.3998/panc.2012.6. 14. kaur j, sidhu s, chopra k, khan mu. calendula officinalis ameliorates l-arginine induced acute necrotizing pancreatitis in rats. pharm biol 2016; 54:2951–9. https://doi.org/10.1080/138802 09.2016.1195848. 15. park eh, kahng jh. suppressive effects of propolis in rat adjuvant arthritis. arch pharm res 1999; 22:554–8. https://doi.org/10.10 07/bf02975325. 16. sharma s, rana sv, rana s, bhasin dk, nada r, malhotra s. severe chronic pancreatitis due to recurrent acute injury: noninvasive chronic pancreatitis model of rat. jop. j pancreas (online) 2017; 18:107–20. 17. al-hariri m, eldin tg, abu-hozaifa b, elnour a. glycemic control and anti-osteopathic effect of propolis in diabetic rats. diabetes metab syndr obes 2011; 4:377–84. https://doi.org/10.2147/dm so.s24159. 18. frossard j l, hadengue a, pastor cm. new serum markers for the detection of severe acute pancreatitis in humans. am j respir crit care med 2001; 164:162–70. https://doi.org/10.1164/ajrcc m.164.1.2008026. 19. shukla r, santoro j, bender fc, laterza of. quantitative deter mination of human interleukin 22 (il-22) in serum using sing ulex-erenna® technology. j immunol methods 2013; 390:30–4. https://doi.org/10.1016/j.jim.2013.01.002. 20. bulut ne, özkan e, ekinci o, dulundu e, topaloğlu ü, şehirli aö, et al. beneficial effects of alpha lipoic acid on cerulein-induced experimental acute pancreatitis in rats. ulus travma acil cerrahi derg 2011; 17:383–9. https://doi.org/10.5505/tjtes.2011.99835. 21. rakonczay z jr, hegyi p, dósa s, iványi b, jármay k, biczó g, et al. a new severe cute necrotizing pancreatitis model ind uced by l-ornithine in rats. crit care med 2008; 36:2117–27. https://doi.org/10.1097/ccm.0b013e31817d7f5c. 22. pooran n, indaram a, singh p, bank s. cytokines (il-6, il-8, tnf): early and reliable predictors of severe acute pancreatitis. j clin gastroenterol 2003; 37:263–6. https://doi.org/10.1097/0 0004836-200309000-00013. 23. borrelli f, maffia p, pinto l, ianaro a, russo a, capasso f, et al. phytochemical compounds involved in the anti-infla mmatory effect of propolis extract. fitoterapia 2002; 73:s53–63. https://doi.org/10.1016/s0367-326x(02)00191-0. 24. büyükberber m, savaş m, bağci c, koruk m, gülşen mt, tutar e, et al. the beneficial effect of propolis on cerulein-ind uced experimental acute pancreatitis in rats. turk j gastro enterol 2009; 20:122–8. 25. hu f, hepburn hr, li y, chen m, radloff se, daya s. effects of ethanol and water extracts of propolis (bee glue) on acute infla mmatory animal models. j ethnopharmacol 2005; 100:276–83. https://doi.org/10.1016/j.jep.2005.02.044. 26. rossi a, longo r, russo a, borrelli f, sautebin l. the role of the phenethyl ester of caffeic acid (cape) in the inhibition of rat lung cyclooxygenase activity by propolis. fitoterapia 2002; 73:s30–7. https://doi.org/10.1016/s0367-326x(02)00188-0. 27. qiao yy, liu xq, xu cq, zhang z, xu hw. interleukin-22 ameliorates acute severe pancreatitis-associated lung injury in mice. world j gastroenterol 2016; 22:5023–32. https://doi. org/10.3748/wjg.v22.i21.5023. 28. feng d, park o, radaeva s, wang h, yin s, kong x, et al. interleukin-22 ameliorates cerulein-induced pancreatitis in mice by inhibiting the autophagic pathway. int j biol sci 2012; 8:249–57. https://doi.org/10.7150/ijbs.3967. 29. huan c, kim d, ou p, alfonso a, stanek a. mechanisms of interleukin-22's beneficial effects in acute pancreatitis. world j gastrointest pathophysiol 2016; 7:108–16. https://doi.org/10.4 291/wjgp.v7.i1.108. 30. xue j, nguyen dt, habtezion a. aryl hydrocarbon receptor regulates pancreatic il-22 production and protects mice from acute pancreatitis. gastroenterology 2012; 143:1670–80. https://doi.org/10.1053/j.gastro.2012.08.051. 31. liu xq, qiao yy, xu cq, zhu st, xu hw. protective effects of interleukin-22 on severe acute pancreatitis-associated kidney injury in mice. austin intern med 2017; 2:1016. 32. sud'ina gf, mirzoeva ok, pushkareva ma, korshunova ga, sumbatyan nv, varfolomeev sd. caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. febs lett 1993; 329:21–4. https://doi.org/10.1016/0014-5793(93)80184-v. 33. borrelli f, maffia p, pinto l, ianaro a, russo a, capasso f, et al. phytochemical compounds involved in the anti-infla mmatory effect of propolis extract. fitoterapia 2002; 73:s53–63. https://doi.org/10.1016/s0367-326x(02)00191-0. 34. singh vk, bollen tl, wu bu, repas k, maurer r, yu s, et al. an assessment of the severity of interstitial pancreatitis. clin gastro enterol hepatol 2011; 9:1098–103. https://doi.org/10.1016/j.c gh.2011.08.026. 35. lattanzi s, cagnetti c, provinciali l, silvestrini m. neutrophilto-lymphocyte ratio and neurological deterioration following acute cerebral hemorrhage. oncotarget 2017; 8:57489–94. https://doi.org/10.18632/oncotarget.15423. 36. lattanzi s, carbonari l, pagliariccio g, bartolini m, cagnetti c, viticchi g, et al. neurocognitive functioning and cerebrovasc ular reactivity after carotid endarterectomy. neurology 2018; 90:e307–15. https://doi.org/10.1212/wnl.0000000000004862. https://doi.org/10.1078/09447110260573164 https://doi.org/10.3998/panc.2012.6 https://doi.org/10.1080/13880209.2016.1195848 https://doi.org/10.1080/13880209.2016.1195848 https://doi.org/10.1007/bf02975325 https://doi.org/10.1007/bf02975325 https://doi.org/10.2147/dmso.s24159 https://doi.org/10.2147/dmso.s24159 https://doi.org/10.1164/ajrccm.164.1.2008026 https://doi.org/10.1164/ajrccm.164.1.2008026 https://doi.org/10.1016/j.jim.2013.01.002 https://doi.org/10.5505/tjtes.2011.99835 https://doi.org/10.1097/ccm.0b013e31817d7f5c https://doi.org/10.1097/00004836-200309000-00013 https://doi.org/10.1097/00004836-200309000-00013 https://doi.org/10.1016/s0367-326x%2802%2900191-0 https://doi.org/10.1016/j.jep.2005.02.044 https://doi.org/10.1016/s0367-326x%2802%2900188-0 https://doi.org/10.3748/wjg.v22.i21.5023 https://doi.org/10.3748/wjg.v22.i21.5023 https://doi.org/10.7150/ijbs.3967 https://doi.org/10.4291/wjgp.v7.i1.108 https://doi.org/10.4291/wjgp.v7.i1.108 https://doi.org/10.1053/j.gastro.2012.08.051 https://doi.org/10.1016/0014-5793%2893%2980184-v https://doi.org/10.1016/s0367-326x%2802%2900191-0 https://doi.org/10.1016/j.cgh.2011.08.026 https://doi.org/10.1016/j.cgh.2011.08.026 https://doi.org/10.18632/oncotarget.15423 https://doi.org/10.1212/wnl.0000000000004862 poliomyelitis, also known as polio, is a highly infectious viral disease, predominantly affecting children under five years old. the virus is transmitted from person-to-person and mainly spreads through the fecal-oral route. the virus multiplies in the intestine, from where it can invade the nervous system via the bloodstream, potentially causing paralysis. polio symptoms include fever, fatigue, headache, vomiting, neck stiffness and pain in the limbs. the disease causes permanent paralysis in one out of 200 infections. currently, there is no cure for polio; it can only be prevented by immunisation.1 past global successes in 1988, the world health assembly declared its commit ment to eradicate wild poliovirus (wpv), which had been reported in 125 endemic countries. since then, there has been a decline of over 99% of cases globally, from an estimated 350,000 cases in 1988 to 33 reported cases by the end of 2018 [figure 1]. a number of the world health organization (who) regions have been certified polio-free for many years, namely the americas (1994), the western pacific region (2000), the european region (2002) and the south-east asian region (2014). to date, no wpv type 1 cases have been reported in the african region in more than 41 months. this achieve ment marks a significant step towards global eradication of wpv, with 80% of the world’s population now living in certified polio-free regions.2 the who estimated that 1.5 million childhood deaths have been prevented and more than 18 million people, who would have been paralysed, are able to walk today due to systematic polio immunisation activities. in addition, the eradication of wpv would save at least $40–50 billion usd, mostly in low-income countries.1 current failures there are three strains of wpv (i.e. type 1, type 2 and type 3). the trivalent oral polio vaccine (topv) induced a high type 2 sero-conversion rate;3 hence, transmission was easily and quickly interrupted and type 2 was eradicated globally by 1999.4 meanwhile, a bivalent opv for type 1 and 3 was introduced, which showed superiority over the topv and higher immunogenicity to type 3;5 global eradication of type 3 was officially announced in october 2019 [figure 1].6 despite achieving the eradication of types 2 and 3 and a reduction by over 90% in the prevalence of type 1 since 2014, child paralysis from wpv type 1 infections was still evident in two remaining endemic countries.2 the remaining two countries with reported ongoing wpv type 1 transmission are afghanistan and pakistan, which harbour the only global reservoir of wpv type 1.7,8 since early 2019, wpv cases from pakistan have increased dramatically. this followed an 18-month period from january 2017 to mid-2018 in which pakistan had achieved the lowest number of wpv type 1 cases in its previous 10 years, including several months without a single reported case. globally, the annual number of wpv type 1 cases was 22 in 2017 and 33 cases in 2018, indicating a missed opportunity for halting wpv transmission.7,8 as of 21st december 2019, the reported cases of wpv type 1 in pakistan has risen to 111, representing 80% of the global wpv cases; 44% of the environmental samples collected have been positive for wpv type 1, indicating widespread virus circulation across the country.9 in addition, there are reported exports of the virus to iran, with pakistan-linked wpv type 1 isolated from an environmental sewage sample collected on 20th april 2019 in the konarak district, sistan-baluchistan province, iran. however, no associated cases of para 1office of health affairs, ministry of health, oman; 2department of infectious diseases, royal hospital, ministry of health, oman *corresponding author’s e-mail: salah.awaidy@gmail.com فريوس شلل األطفال الربي من النوع 1 يف عمان هتديد جديد يستلزم االستعداد العاجل واملوّجه واالسرتاتيجي �صالح الوردي العويدي وفريال خمي�س wild poliovirus type 1 in oman a re-emerging threat that requires urgent, targeted and strategic preparedness *salah t. al awaidy1 and faryal khamis2 editorial sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e1–4, epub. 9 mar 20 submitted 22 oct 19 revision req. 14 nov 19; revision recd. 1 dec 19 accepted 24 dec 19 https://doi.org/10.18295/squmj.2020.20.01.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ wild poliovirus type 1 in oman a re-emerging threat that requires urgent, targeted and strategic preparedness e2 | squ medical journal, february 2020, volume 20, issue 1 lysis have been found.10 meanwhile, afghanistan has reported 26 cases of wpv type 1 as of 21st december 2019.10,11 endemic transmission of wpv continues in border areas of afghanistan and pakistan.7 the main factors attributed to the current outbreak are issues related to coordination and implementation of vaccine delivery and unresolved issues with campaign quality, monitoring, accountability and community engagement.4,6,8 the surge in polio cases in 2019 has threatened the goal of its global eradication. until wpv transmission is interrupted in these countries, all countries remain at risk of wpv importation, especially vulnerable countries with weak public health systems, suboptimal immunisation services and travel or trade links to endemic countries. as per global estimation, failure to eradicate wpv could result in as much as 200,000 new wpv cases yearly in the next 10 years. therefore, it is vital to ensure wpv is globally eradicated.1,2 herein we highlight the lessons learnt to date and propose steps to reach eradication. how to set it right the global polio eradication strategic plan identified five priority strategic interventions which included: 1) high levels of routine immunisation; 2) supplementary immunisation activities (sia; target coverage above 95%); 3) acute flaccid paralysis (afp) surveillance (target = 2/100,000 among those aged ≤15 years); 4) mop-up campaigns (if required); and 5) care for post-polio paralysis.12 failure to implement strategic approaches leads to risk of either unidentified imported cases or a dangerous delay in responding to wpv importation. in oman, the last major wpv outbreak was caused by the type 1 strain in 1988–89. the last two cases of wpv were reported in 2005 in yemen and had type 1 wpv [figure 2].13,14 over the years, oman has implemented some important components of the polio eradication strategies such as ensuring that the third dose of the oral polio vaccine (opv3) coverage is >95% through routine immunisation services among infants aged <1 year. this has been maintained for more than a decade.15 additionally, polio sia were implemented from 1995–99 and again in 2005. afp surveillance was launched in 1993 and since then the rate of non-polio afp has remained above 2/100,000 people among those aged ≤15 years, with adequate testing of stool specimens above 80%.15,16 the performance of afp surveillance is assessed through the annual detection rate of non-polio afp recommended by the who. the afp rates in oman have been in constant decline, from 4.5 to 3.2 to 2.8 cases per 100,000 people aged <15 years in 2017, 2018 and 2019, respectively.17 sensitive surveillance is the gold standard of polio eradication and the only tool to identify importation.1,11 these rates have so far been considered sensitive enough to detect a case of wpv. the second perf ormance indicator is the collection of adequate stool specimens (i.e. two stool specimens collected >24 hours apart, within 14 days of paralysis onset and arrival at the laboratory in good condition from ≥80% of reported cases of afp patients). these targets have also been successfully met in oman.1,12 recommendations the risk of exportation of wpv type 1 to oman exists. apart from the geographical proximity of oman to the endemic countries, there are also many individuals from endemic countries who frequently visit and have visitors from endemic countries. the population of expatriates (approximately 44% of the country’s total population) includes 219,901 (4%) pakistanis.18 two essential pillars for preparedness against the importation of wpv includes robust afp surveillance figure 1: globally reported wild poliovirus cases from 1972–2019.20 wpv = wild poliovirus. salah t. al awaidy and faryal khamis editorial | e3 and high population immunity among non-polio afp and sia.19 to prevent transmission of the virus across borders, early detection of the virus is critical and can be achieved by strengthening both active and passive afp surveillance to identify potential afp cases among oman's residents. this would ensure that the entire population, whether residing or visiting oman are vaccinated, as is appropriate for their specific age group, prior to entering the country. in addition, the polio programme has to establish standard protocols for the care and long-term followup of post-polio paralysis patients, as well as ways to reduce the psychological and financial burdens on patients. an ongoing problem is the difficulty of keeping the polio vaccine stockpiled in oman. finally, proper attention should be given to rigorous evaluation of the national polio programme and its successes and failures should be shared with others. to date, wpv type 1 transmission has not been interrupted in afghanistan and pakistan.4 the increasing wpv cases have secured the disease’s status as a global public health emergency and the global community has expressed concern over ongoing transmission in these countries. these two countries constitute one epidemiological block and must continue to be treated as such to achieve eradication. in order to end transmission of wpv1, complete population immunity must be achieved and doing so requires delivering polio vaccine to all children. failure to eradicate polio would have major global repercussions. importation of wpv cannot be prevented until global wpv eradication is attained making early detection of wpv in polio-free states a public health priority. references 1. world health organization. poliomyelitis. from: https://www. who.int/en/ne ws-ro om/fact-she et s/detail/p oliomyelitis accessed: dec 2019. 2. world health organization; global polio eradication initiative. polio endgame strategy 2019–2023: eradication, integration, certification and containment. from: http://polioeradication. org/wp-content/uploads/2019/03/english-polio-endgamestrategy-executive-summary.pdf accessed: dec 2019. 3. sutter rw, john tj, jain h, agarkhedkar s, ramanan pv, verma h, et al. immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial. lancet 2010; 376:1682–8. https://doi.org/10.1016/s01406736(10)61230-5. 4. world health organization; global polio eradication initiative. global eradication of wild poliovirus type 2 declared. from: http://polioeradication.org/news-post/global-eradication-ofwild-poliovirus-type-2-declared/ accessed: dec 2019. 5. sutter rw, bahl s, deshpande jm, verma h, ahmad m, venugopal p, et al. immunogenicity of a new routine vaccina tion schedule for global poliomyelitis prevention: an openlabel, randomised controlled trial. lancet 2015; 386:2413–21. http://doi.org/10.1016/s0140-6736(15)00237-8. 6. world health organization. global eradication of wild poliovirus type 3 declared on world polio day. from: https:// www.who.int/news-room/feature-stories/detail/two-out-ofthree-wild-poliovirus-strains-eradicated accessed: dec 2019. 7. world health organization. eastern mediterranean polio fax issues, 2019: issue no. 1097. from: http://www.emro.who.int/ polio/strategy-surveillance/eastern-mediterranean-polio-faxissues-2019.html accessed: dec 2019. 8. greene sa, ahmed j, datta sd, burns cc, quddus a, vertefeuille jf, et al. progress toward polio eradication—worldwide, january 2017–march 2019. mmwr morb mortal wkly rep 2019; 68:458–62. http://doi.org/10.15585/mmwr.mm6820a3. 9. world health organization. highlights of polio fax bulletin no. 1102 for week 46_2019. from: http://www.emro.who.int/ images/stories/polio/documents/xls/polio_fax_issues_2019/ week_46-19.pdf?ua=1 accessed: dec 2019. 10. world health organization. wild poliovirus type 1 – islamic republic of iran. from: https://www.who.int/csr/don/24-may2019-wild-polio-virus-islamic-republic-of-iran/en/ accessed: dec 2019. figure 2: reported wild poliovirus cases and coverage of oral poliovirus vaccine 3 use in oman from 1975–2019.15,20 opv = oral polio vaccine; wpv = wild poliovirus. https://doi.org/10.1016/s0140-6736%2810%2961230-5 https://doi.org/10.1016/s0140-6736%2810%2961230-5 http://doi.org/10.1016/s0140-6736%2815%2900237-8 http://doi.org/10.15585/mmwr.mm6820a3 wild poliovirus type 1 in oman a re-emerging threat that requires urgent, targeted and strategic preparedness e4 | squ medical journal, february 2020, volume 20, issue 1 11. world health organization. weekly epidemiological record: 22 november 2019. from: https://apps.who.int/iris/bitstream/ handle/10665/329962/wer9447-eng-fre.pdf?ua=1 accessed: dec 2019. 12. world health organization. polio eradication initiative. from: http://www.emro.who.int/polio/strategy/ accessed: dec 2019. 13. al awaidy st, faraj m. infectious diseases in oman: a review and progress towards elimination and eradication. indian j appl res 2017; 7:555–60. 14. al awaidy st. impact of strategies and activities for reducing morbidity and mortality of vaccine-preventable diseases in oman: a status report. j vaccines immun 2015, 3:1–6. http://doi.org/10.1 4312/2053-1273.2015-1. 15. ministry of health. chapter eight: health fields – 2018. from: https://www.moh.gov.om/ar/web/statistics/-/20-66 accessed: dec 2019. 16. directorate general for disease surveillance and control. ministry of health of oman. communicable diseases manual. from: https://www.moh.gov.om/documents/236878/0/comm unic able+dis e a s e s+manual/a0577e5e-cc5a-4cb6-a460832e37b6b587 accessed: dec 19. 17. world health organization. afp surveillance data and polio case count. from: https://extranet.who.int/polis/public/case count.aspx accessed: dec 19. 18. national center for statistics & information. population. from: https://data.gov.om/ompop2016/population?indicator =1000140&region=1000020-muscat&nationality=1000020expatriate-non-omani accessed: dec 2019. 19. world health organization, regional office for the eastern mediterranean. guidelines for preapadeness and response for wild poliovirus importation format and for national plan (2002). https://apps.who.int/iris/handle/10665/116338 accessed: dec 2019. 20. world health organization. wild poliovirus list. from: http:// polioeradication.org/polio-today/polio-now/wild-polioviruslist/ accessed: dec 2019. http://doi.org/10.14312/2053-1273.2015-1 http://doi.org/10.14312/2053-1273.2015-1 july 2008.indd caring for arab patients a biopsychosocial approach sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 233-234 sultan qaboos university© submitted 26th april 2008 despite the fact that we are in the age of globalisation, it is apparent that health, distress, illness and disability are still influenced and shaped by local and socio-cultural forces. this is not a new idea as it owes its origin to the father of medicine, hippocrates, and it is borne out by a myriad of empirical research studies in more recent years. despite this, one of the lingering fallacies of modern health care is a blind adherence to the biomedical model which myopically assumes that the repertoires of human behaviour and its counterpart, ill-health, have a direct and simple association with the functions or dysfunctions of our body. heralding a new perspective from the arab part of the world, such prevailing dogma is about to be dented with this volume focusing on healthcare for the arab population. the volume extrapolates from available literature to shed light on the importance of psychosocial variables in the matrix of health care and diseases. the conceptual outlook of the book is grounded within a biopsychosocial model that emphasises the interplay between biological and social milieus as central to the predisposition, onset, course and outcome of most disorders. the volume aims to provide a practical and patient-centred guide to assist health professionals in dispensing better clinical care to arab patients. the book is divided into 17 chapters. the editors of this volume selected authors from the region with the most credentials in the field of caring for the arab patients. thus, the message from this volume comes from the people in the field rather than from arm-chair researchers living far from the region. the themes covered in this volume are diverse including health education, palliative care and factors leading to care-seeking as well as the culturally specific odium of distress. within biopsychosocial perspectives, the volume also tackles how to care for arab patients with specific disorders including anxiety, depression, somatoform disorders, post-traumatic stress disorders, eating disorders and substance abuse. if you feel these are ‘cinderella’ topics or you are simply a ‘hard science type’, then you will also find in this volume topics like genetic disorders highlighting the molecular side of such endeavours in the arab world. if one expects to be enlightened in this volume on background social-cultural teachings for the care of b o o k r e v i e w املرضى العرب رعاية اجتماعي نفسي أحيائي أسلوب عبد أحلق أروى ليث ناصر، احملررون: editors: laeth s nasir and arwa k abdul-haq publisher: radcliffe publishing, oxford, uk, 2008 isbn-13: 978 184619 1824 website: http://www.radcliffe-oxford.com/books/bookdetail.aspx?isbn=1846191823 b o o k r e v i e w : c a r i n g f o r a r a b pat i e n t s 234 arab patients, then one would be disappointed. far from presenting the literature relevant to the region, the coverage is nothing more than a good literature review deriving largely from non-arab population and narrated in a euro-american vernacular. most of the literature for this comes from that accessible through pubmed. work published in arabic or local journals is ostensibly absent. reading individual chapters, no coherent theme emerged germane to the biopsychosocial model. most of the chapters simply narrated trends in the western population with no explicit implications for the situation in the arab part of the world. the coverage is basically a typical textbook presentation of common disorders and other issues that authors vaguely deemed to have biopsychosocial trajectories. mundane themes for patients care from a biopsychosocial perspective such as clinical communications and the doctor-patient relationship receive scant attention. this volume also perpetuates the myth that there is a prototype arab character. empirical evidence suggests that arab countries are heterogeneous, characterised by a mosaic of sub-cultural diversities. is this then one of those books which someone like edward said would perceive to present a veneer of ‘orientalism’ in this case gowned with medical science? the volume is a bold attempt to chart some directions in biopsychosocial research in a region where such quest has largely remained dormant. the volume hinges on the assumption that health is inescapably social, a view largely ignored in research coming from the arab world. the volume should be on the shelves of everyone who is directly or otherwise involved in all matters related to patient care, healthcare management, health sciences research, and, for that matter, policy makers. in the era of ‘arab bashing’, the strength of this volume is that it teach us that ailing arab persons should receive the same level of compassion and care from their doctors as their counterparts elsewhere. r e v i e w e r samir al adawi department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: adawi@squ.edu.om squ med j, december 2010, vol. 10, iss. 3, pp. 350-353, epub. 14th nov 10 submitted 22nd may 10 accepted 20th july 10 1department of obstetrics and gynaecology, college of medicine & health sciences, sultan qaboos university, muscat, oman; departments of 2surgery and 3pharmacy, sultan qaboos university hospital, muscat, oman *corresponding author email: kprasadv@gmail.com <ôç÷<<l^fiá⁄öá7]<ì◊“^ç<ê<;π]<l]üçˆ⁄ê<^è ]ü∆áµç÷]<<ìfiö^œ⁄ îáfi^n÷]ê<í÷ê˘]<‹œ√÷^e<∞e^íπ]<ÿ^qü÷]     2008 2005              %16 %24  9      abstract: objectives: the objectives of this study were to compare the demographics, semen parameters and hormone profiles in men with primary and secondary infertility. methods: the study was designed as a retrospective analysis of data collected from men attending a combined infertility clinic (seen together by urologist and gynaecologist) from january 2005 to december 2008 at sultan qaboos university hospital, a tertiary care hospital in oman. ninety-eight consecutive male patients with one or more abnormalities in semen analysis were referred to the combined infertility clinic. a complete physical examination was carried out by a urologist followed by hormone evaluation of follicle stimulating hormone (fsh), luteinizing hormone (lh), testosterone (t) and prolactin (prl). results: the semen parameters and the sex hormone evaluation were not significantly different between the men with primary and secondary infertility. the men with primary infertility were younger than the men with secondary infertility. a total of 24% of the men in the primary group and 16% in the secondary group were azoospermic with normal gonadotropin values in 9 men and 1 man in the primary and secondary group respectively. conclusion: azoospermia was more common in the primary infertile group and, based on gonadotropin levels, obstructive causes seemed more prevalent in the primary group compared to secondary group. keywords: male infertility; primary infertility; secondary infertility; varicocele; sex hormones; semen parameters; oman comparison of the demographics, semen parameters and hormone profiles in men with primary and secondary infertility vaidyanathan gowri,1 *krishna p venkiteswaran,2 ibrahim al-zakwani,3 josephkunju mathew,2 khalid abdul rahman,2 mohammed al-marhoon2 clinical & basic research advances in knowledge 1. this is one of the first studies from the arabian gulf region on male infertility 2. hormonal evaluation results for all men with azoospermia/oligospermia is not very different in primary or secondary types of infertility. application to patient care 1. based on the results of this study, men with primary subfertility need to be more thoroughly investigated for obstructive causes. 2. serum hormone level estimation obviates the need for invasive procedures on the testes. vaidyanathan gowri, krishna p venkiteswaran, ibrahim al-zakwani, josephkunju mathew, khalid abdul rahman and mohammed al-marhoon clinical and basic research | 351 infertility is a common problem faced by the clinician and could arise from male factors, female factors or both. though infertility is conventionally divided into primary and secondary types, the aetiology is not always different.1 semen analysis is an integral part of evaluation of an infertile couple. in males with abnormal semen parameters, including reduced sperm count or sperm motility, sex hormones are evaluated to rule out testicular causes and aid in the management. low levels of follicle stimulating hormone (fsh) suggest a hypothalamo-pituitary axis problem and high levels of fsh signify testicular failure. primary testicular failure and hypothalamic causes are more likely to result in primary male infertility than causes like sexually transmitted diseases, trauma, environmental factors and social habits like smoking and consuming alcohol. obstructive azoospermia secondary to sexually transmitted infection is a preventable cause of secondary male infertility. bayasgalan et al. found a high prevalence of obstructive azoospermia (8.4%) and acquired testicular damage (5.4%) in their study.2 this study aimed to examine and compare the semen and serum hormone parameters in the two groups of men with primary and secondary infertility. methods the study was approved by the institutional ethics committee and was designed as a retrospective analysis of data collected from men attending the combined infertility clinic (seen together by urologist and gynaecologist) from january 2005 to december 2008 at sultan qaboos university hospital, oman, a tertiary care centre. semen analysis was done as part of initial evaluation for all couples with infertility. men with abnormal semen analysis (reduced count, reduced motility and/ or abnormal sperm morphology) were referred to the combined infertility clinic. a thorough history and complete examination of the male partner was carried out by the urologist. sex hormone assays of follicle stimulating hormone (fsh), luteinizing hormone (lh), testosterone (t) and prolactin (prl) on the male partner and/or ultrasound of the testes with doppler was requested. the optimal treatment modality was chosen based on the results of investigations of both the female and male partners. semen specimens were collected at the study site and transferred immediately to the laboratory. men were asked to abstain for 72 hours prior to collection. sperm concentration was determined by counting the two sides of a haemocytometer. semen volume was measured in a graduated pipette. motility was evaluated as the proportion of sperms that were progressively motile at 370o c using a makler chamber. men were considered azoospermic if no sperms were seen. dried semen smears were treated with berg’s stain (carbol fuchsin and methylene blue) and assessed for morphological abnormalities by one examiner using strict criteria. serum concentrations of fsh, lh, t and prl were measured using the access® system (beckmann coulter inc.). the access hfsh and lh assays were sequential two-step immunoenzymatic (sandwich assay) with a sensitivity of 0.2 miu and a coefficient of variation less than 10%. the access testosterone assay was a competitive binding immunoenzymatic assay. prl was also measured by a sandwich technique, immunochemical method (access® system, beckmann coulter inc.) with a sensitivity of 0.25 ng/ml and coefficient of variation of 10%. the analytical sensitivity for testosterone was 0.1 ng/ml and the interassay and intraassay coefficients of variation were 2.71% and 5.65% respectively. descriptive statistics were used for the data. for categorical variables, frequencies and percentages were reported. differences in prevalence of varicocele between groups (primary and secondary infertility) were analysed using pearson’s chi-squared test. for continuous variables, means and standard deviations (sd) were presented. since the distributions of the continuous variables (age, duration, volume, motility, count, abnormal forms, fsh, lh, prl and t) were significantly non-normal, the analysis was conducted using the mann-whitney test. an a priori two-tailed level of significance was set at the 0.05 level. statistical analysis was conducted using stata, version 10.1, (stata corporation, college station, tx). results the total number of men during the study period (january 2005 to december 2009) comparison of the demographics, semen parameters and hormone profiles in men with primary and secondary infertility 352 | squ medical journal, december 2010, volume 10, issue 3 was 98. there were 67 men with primary and 31 with secondary infertility. hormone analysis was done for 46 patients in the primary group and 25 in the secondary group. men in the primary infertile group were significantly younger than the men in secondary infertility group (33 versus 37 years; p = 0.002). the duration of infertility as well as volume, sperm motility, sperm count and abnormal forms of the semen were not significantly different between the primary and secondary groups [table 1]. there were also no statistical differences in the hormonal parameters between the two groups [table 2]. furthermore, the prevalence of varicocele was also not significantly different between the groups. only nine men admitted to smoking in the primary group and six men in the secondary group. there was no clinical evidence or history of sexually transmitted disease except for one in the primary infertility group. a history of diabetes was present in four men and cardiomyopathy in one in the primary group. azoospermia was present in 16 of 67 (24%) men in the primary group and 5 of 31 (16%) men in the secondary group. serum gonadotropin values were normal in 9 of 16 (56%) in the primary group and one out of the five (20%) in the secondary group. there was weak negative correlation between lh and sperm counts in both groups (-0.0971 and -0.08897 in primary and secondary respectively). the testosterone levels correlated positively with sperm motility in both groups (0.400 and 0.315 in the primary and secondary groups respectively). discussion in the present study, except for the age of men in the primary infertility group which was significantly less than in men with secondary infertility, the other assessed parameters were not significantly different. there were only six men with fsh equal to or more than 15 iu in the primary infertile group, but seven in the secondary group. in the secondary infertility group, the cause for elevated fsh was due to orchidectomy in one man and bilateral small testes in another, but there was no obvious cause in the others except a history of smoking in two men. the fsh levels and the sperm counts correlated inversely in the primary and secondary infertility groups, (0.28157, -0.2702 respectively) and this fits with other observations in the literature.3,4,5 although the serum gonadotropin values were not significantly different between the two groups, analysis of serum fsh levels in both groups, after excluding men with table 1: demographics and semen characteristics of the primary and secondary infertility groups parameter primary infertility (n = 67) secondary infertility (n = 31) p value age, mean ± sd 32.72 ± 8.08 36.71 ± 10.09 0.002 duration, mean ± sd 6.07 ± 5.83 5.17 ± 4.15 0.663 volume, mean ± sd 2.54 ± 1.40 3.39 ± 4.12 0.888 motility, mean ± sd 30.62 ± 26.74 23.71 ± 19.83 0.359 count, mean ± sd 32.05 ± 59.19 27.66 ± 37.61 0.904 abnormal forms, mean ± sd 26.51 ± 33.58 39.231 ± 35.59 0.075 varicocele, n (%) 30 (45%) 11 (35%) 0.386 note: analysis was conducted using the mann-whitney test for all the variables except for the varicocele variable for which pearson’s chi-squared test was used. legend: sd = standard deviation. table 2: sex hormonal characteristics of the primary and secondary infertility groups sex hormone primary infertility (n = 46) secondary infertility (n = 25) p value fsh, mean ± sd 5.68 ± 7.12 9.20 ± 10.32 0.106 lh, mean ± sd 4.17 ± 3.82 5.48 ± 5.41 0.414 prl, mean ± sd 124.40 ± 145.54 131.32 ± 129.81 0.623 testosterone, mean ± sd 10.97 ± 9.85 12.51 ± 7.21 0.551 legend: sd = standard deviation; fsh = follicle stimulating hormone; lh = luteinizing hormone; prl = prolactin; note: analysis was conducted using the mann-whitney test. vaidyanathan gowri, krishna p venkiteswaran, ibrahim al-zakwani, josephkunju mathew, khalid abdul rahman and mohammed al-marhoon clinical and basic research | 353 very high values (≥15 iu), revealed a mean higher fsh value in the primary group compared to the secondary group with a trend to significance. a negative correlation between lh and sperm count and a positive correlation between testosterone and sperm motility go with the reports of meeker et al. in 2007.6 measuring serum fsh and lh will help in the diagnosis of hypothalamic hypogonadotropic causes and possible treatment with gonadotropin injections in such males. there was no patient with a hypothalamic/hypopitutary disorder in the present study. the usefulness of measuring the hormonal parameters is only to diagnose obstructive causes versus testicular failure especially in men with azoospermia. although compared to other populations the prevalence of clinically evident sexually transmitted disease appeared to be much lower in this population, obstructive azoospermia was present in at least 9 patients in the primary group based on serum gonadotropin values. the only patient in the secondary group who had normal serum gonadotropin values gave a history of trauma to posterior urethra and false passage. of the nine men with normal serum gonadotropin values in the primary group, testicular biopsy was done in 2 patients and there was history of behçet’s disease, right inguinal hernia repair and epididymal cyst in three others. a thyroid stimulating hormone test was not routinely performed in all men. according to bayasalgan et al., sexually transmitted infections (sti) as a predictor of azoospermia had a very high odds ratio, being 5.6 in patients with gonorrhea and 7.6 in patients with other stis in mongolia. the same authors concluded that a history of pathology involving testicular damage appeared to have the strongest impact on male infertility in mongolia. stis have less impact on semen quality except when complicated by orchitis, epididymitis and vasal obstruction.7 obstructive azoospermia was present in 8.4% men in a mongolian study along with previous testicular damage, and testicular biopsy or vasography was done in 16 patients.2 the numbers are comparable to this group, but testicular biopsy was done only in 2 patients in our study.2 based on serum gonadotropin levels in the present study, obstructive azoospermia was found to be more common in the primary infertile men compared to secondary infertility. the major limitations of the present study include the retrospective nature of the study and the absence of sex hormonal evaluation in all patients. also testicular biopsy to obtain the final diagnosis of testicular failure versus obstruction was performed in only two patients with azoospermia. finally, the cause of obstructive azoospermia was not discovered in this study. conclusion in this study, while the seminal parameters and sex hormonal evaluation were not significantly different in males with primary and secondary infertility based on normal serum fsh values, obstructive causes seemed more prevalent in primary infertile males compared to those with secondary infertility. further well constructed prospective studies with larger numbers of patients are needed to verify this hypothesis. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. hart dm, norman j. infertility. in: hart dm, norman j, eds. gynaecology illustrated. new york: churchill livingstone, 2000. p.390. 2. bayasgalan g, naranbat d, tsedmaa b, tsogmaa b, sukhee d, amarjargal o, et al. clinical patterns and major causes of infertility in mongolia. obstet gynaecol res 2004; 30:386–93. 3. fauser bc, bogers jw, hop wc, de jong fh. bioactive and immunoreactive fsh in serum of normal and oligospermic men. clini endocrinol (oxf ) 1990; 32:433–42. 4. abbaticchio g, nacucchi o, giagulli v a brescia f, giorgino r. exploration of the testis in infertile men. relationships among serum levels of fsh, lh, 17-alpha oh progesterone and testosterone. andrologia 1990; 22:231–7. 5. matzkin h, homonnai zt, galiani d, paz g, dekel n. serum bioactive and immunoreactive follicle stimulating hormone in oligospermic and azoospermic men: application of a modified granulosa cell bioassay. fertil steril 1990; 53:709–14. 6. meeker jd, bailey lg, hauser r. relationship between serum hormone levels and semen quality among men from an infertility clinic. j androl 2007; 28:397–406. 7. bayasgalan g, naranbat d, radnaabazar j, lhagvasuren t, rowe pj. male infertility: risk factors in mongolian men. asian j androl 2004; 6:305–11. department of medicine, dubai medical college, dubai, united arab emirates e-mail: beshyah@yahoo.com اختيارات املؤلفني للمجالت املستهدفة ومواقفهم من اجملالت املستجدة مسح من منطقتني ناميتني �سامل العريفي ب�سيه abstract: objectives: this study aimed to assess the factors that influence authors' decision when choosing a journal for publication and to assess authors' attitudes and practices regarding emerging journals. methods: this cross-sectional questionnaire-based study was conducted between april and july 2017 at dubai medical college, dubai, united arab emirates, on a convenience sample of 2,764 healthcare professionals. results: a total of 250 responses were received (response rate: 9%) and 152 valid respondents were included in this study (5.6%), of which the majority were male (61.2%) and aged 41–60 years (68%) from the middle east and africa. most respondents (88.8%) had medical and/or dental qualifications and the majority were in senior clinical (55%) and academic (71.5%) positions. more than half of the respondents (62.5%) had published at least one article in the previous five years. results showed that journal impact factor (jif), indexation status, free submission and being international were important among respondents. based on the respondents that shared their encounters with emerging journals (n = 114), 62 respondents (54.4%) regularly read certain emerging journals, 51 (44.7%) had been a peer-reviewer, 48 (42.1%) had cited content from an emerging journal at least once and 45 (39.5%) had published in emerging journals. only 18 respondents (14.2%) were not convinced with the need for emerging journals and believed that all researchers should compete for publication in the same international journals. conclusion: selection of target journals is driven mainly by jif, indexation status, free submission and a journal’s international status. a diverse range of opinions and attitudes regarding emerging journals were observed in this study. keywords: journal impact factor; open access publishing; editorial policy; peer review; indexing; publications; attitude; united arab emirates. امللخ�ص: الهدف: تقييم العوامل التي توؤثر على قرار املوؤلفني عند اختيار جملة للن�رس . ثانيًا: تقييم مواقف املوؤلفني وممار�ساتهم فيما يتعلق باملجالت النا�سئة. الطريقة: اأجريت هذه الدرا�سة امل�سحية املقطعيه على عينة منا�سبة من مهني الرعاية ال�سحية بني اأبريل ويوليو 2017. النتائج: كان هناك 250 م�ستجيب بن�سبة %9 ومثلت ال�ستجابات ال�سليمة عدد 152 ا�ستجابة بن�سبة %5.6رجال )%61.2(، معظمهم الأ�سنان، طب اأو الب�رسي الطب يف موؤهالت منهم الأغلبية )88.8%( لدى وكان واأفريقيا. الأو�سط ال�رسق من �سنة )68%( �سن 60-41 يف وكان معظمهم يف املنا�سب العليا ال�رسيرية )%55( والأكادميية )%71.5(. قام اأكرث من ن�سف امل�ساركني )%62.5( بن�رس مقال واحد على الأقل يف ال�سنوات اخلم�ض ال�سابقة. اأظهرت النتائج اأن عامل تاأثري املجلة )jif(، وحالة الفهر�سة، والتقدمي املجاين والوجود الدويل هي اأهم العنا�رس بني املجيبني. ا�ستناًدا اإىل املجيبني الذين �ساركوا يف املجالت النا�سئة )n = 114(، كان 62 من امل�ستجيبني )%54.4( يقروؤون مرة نا�سئة جملة من باملحتوى ا�ست�سهدوا قد )42.1%( 48 النظراء، املراجعني من كانوا )44.7%( 51 النا�سئة، املجالت بع�ض بانتظام واحدة على الأقل و 45 )%39.5( من العينة قد ن�رست يف املجالت النا�سئة. مل يكون 18 من امل�ستجيبني )%14.2( مقتنعني باحلاجة اإىل اختيار حتديد يتم العريقة. اخلال�صة: الدولية املجالت نف�ض يف الن�رس على التناف�ض الباحثني جميع على اأن واعتقدوا النا�سئة املجالت املجالت امل�ستهدفة ب�سكل اأ�سا�سي بناء على عامل تاأثري املجلة، وحالة الفهر�سة، والتقدمي املجاين، والو�سع الدويل للمجلة. وقد لوحظت جمموعة متنوعة من الآراء واملواقف ب�ساأن املجالت النا�سئة يف هذه الدرا�سة. الكلمات املفتاحية: عامل تاأثري جملة؛ الن�رس املفتوح؛ �سيا�سة التحرير؛ ا�ستعرا�ض النظراء؛ الفهر�سة؛ املن�سورات؛ �سلوك؛ الإمارات العربية املتحدة. authors’ selection of target journals and their attitudes to emerging journals a survey from two developing regions salem a. beshyah sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e51–57, epub. 30 may 19 submitted 20 sep 18 revision req. 5 nov 18; revision recd. 26 nov 18 accepted 20 dec 18 advances in knowledge the main driving factors that influence the decisions of authors from the middle east and africa in choosing a target journal include the journal’s impact factor, indexation status, possibility of free publication and the journal’s international status. knowledge about perceptions of authors and their attitudes and practices towards emerging journals in developing regions provide crucial insight for regional editors and publishers to develop editorial strategies to meet the expectations of their readers and potential authors. application to patient care emerging journals provide a better platform for publishing peculiarities and challenges in diagnosis and management of patients in developing regions, which will aid local physicians to better manage their patients. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.010 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ authors’ selection of target journals and their attitudes to emerging journals a survey from two developing regions e52 | squ medical journal, february 2019, volume 19, issue 1 publication of scientific research requires selecting an appropriate topic, knowing the target journal and its readership, framing the article according to that journal’s specific style and working with the journal’s editorial team to create a publishable manuscript.1,2 in preparing a manuscript for submission, the research material should be structured and written in a style that conveys the authors’ message with clarity. the authors’ should match their research material to the most appropriate manuscript category and journal.3–5 ideally, these choices should solely determine journal selection; however, journal selection may be influenced by other factors.5 in the current study, emerging journals are defined as non-profitable national and/or regional journals that report important and practical information of local/ regional importance. these are to be distinguished from predatory journals that seek to financially profit from authors without providing any standard scholarly publ ishing service for the authors or their readership. the main challenge for these journals is the potential lack of international visibility, such as not being indexed on main indexation systems like the pubmed® database (national library of medicine, bethesda, maryland, usa). this lack of visibility might result in smaller chances of being cited by other authors and result in a lower journal impact factor (jif). several studies have examined the factors that infl uence authors’ choice of target journal in western countries, yet no similar data are available from devel oping countries.6–8 this information may be important to editors and publishers of emerging journals in devel oping regions. in addition, assessing the attitudes of authors from developing countries towards emerging journals is crucial for determining the level of their support of these journals.9,10 in choosing a target journal for publication, different factors may vary in importance depending on the authors’ status and circumstances.11 in general, research and literature productivity of developing nations is low.12 authors from low/middle income countries (lmic) may have to choose between submitting to highly competitive international journals, unaffordable open access journals of high reputation or may inadvertently submit to predatory journals.13 to this end, several genuine open access journals have emerged in lmic with the primary focus of mentoring and nurturing this group of authors.9,10 knowing the attitudes of potential authors towards these journals is very useful to both editors and publishers. the present study is the first to address these two issues specifically from the middle east and africa. therefore, this study aimed to, firstly, assess factors that influence the decision of authors from developing countries when choosing a journal for publication and secondly, to assess these authors' attitudes and practices regarding emerging journals. methods this cross-sectional electronic questionnaire-based study was conducted between april and july 2017 at dubai medical college, dubai, united arab emirates (uae). for the creation, dissemination and analysis of the quest ionnaire, survey monkey® (svmk inc., san mateo, calif ornia, usa) was used. the questionnaire was electronically sent to a convenience sample of 2,764 health care professionals primarily residing and practicing in the middle east and africa. the practicing physicians and academics were identified on academic databases of health-related bodies, professional groups and recent continuous professional development events (e.g. amer ican association of clinical endocrinologists gulf chapter annual meetings) and/or by virtue of their contribution to the medical literature in biomedical subjects. the questions aimed to capture the demo graphic, professional and academic characteristics of the respondents as well as the deciding factors for journal choice along with their attitudes and experiences with table 1: questionnaire topics and questions for healthcare professionals to assess demographic, professional and academic characteristics and attitudes towards emerging journals item question/topic* 1 eligibility and consent. 2,3 region and country of usual residence and practice. 4,5 field of primary qualification and the highest academic/ professional qualification. 6,7 gender and age group. 8,9 professional/career track and specialty. 10 the language of your professional communications/pub lications. 11–13 current professional grades and titles. 14 research interests. 15 did you publish in a medical or biomedical journal over the previous 5 years? 16 if your answer was “yes” to the previous question, please indicate the type of publication. 17 where do you usually publish? 18 please indicate the extent to which each of the 15 factors influences the decision to submit an original article to a journal for an initial submission. 19 please indicate the extent to which each of the 15 factors influences the decision to submit an original article to a journal for a resubmission after a manuscript had been rejected elsewhere (same factors as in question 18). 20 attitudes toward emerging journals (without considering your choices to items 17–19): if you are based in a devel oping region/country, how supportive would you be to publish your work and/or peer review for emerging journal? 21 current practices of authors to emerging journals. *questions 2–13 aimed to define the demographic and professional charact eristics of the respondents; questions 14–17 aimed to define current research and publishing activity; questions 18 and 19 aimed to define the factors infl uencing journal choice for initial submissions and resubmissions of rejected articles and questions 20 and 21 aimed to explore the attitudes and practi ces of current and potential authors to emerging journals. salem a. beshyah clinical and basic research | e53 emerging journals [table 1]. following the initial invitation, four reminders were sent with an interval of 2–3 weeks. as there was no pre-determined sample size, a conve nient sampling technique was used based on the number of respondents who replied within the study period. the responses of consenting healthcare professionals who had confirmed they were residing and practicing in the middle east or africa were included. responses received from individuals residing and practicing out side these regions were excluded. all data were analysed anonymously. in order to determine the influencing factors for authors, their scores were calculated based on the following formula: this formula was also used to calculate the differ ences between initial manuscript submission and resub mission after initial rejection (hereafter referred to as second submission). the differences between the resulting score was compared using a wilcoxon signed-rank test table 2: demographic, professional and academic charact eristics of healthcare professionals from the middle east and africa (n = 152) characteristic n (%) gender male 93 (61.2) female 59 (38.8) age groups in years <30 6 (3.9) 31–40 20 (13.2) 41–50 58 (38.2) 51–60 45 (29.6) >60 23 (15.1) region of usual residence and practice middle east 122 (80.3) africa 30 (19.7) countries of origin united arab emirates 58 saudi arabia 25 iraq, libya or qatar 9 each kuwait or egypt 7 each pakistan 5 lebanon, morocco or oman 3 each algeria, ethiopia, iran, nigeria or sudan 2 each cameroon, ghana, syria or tunisia 1 each primary qualification medical and dental 135 (88.8) biomedical sciences 9 (5.9) nursing 5 (3.3) pharmacy 3 (2.0) highest academic/professional qualification bachelor 12 (7.9) master 11 (7.2) doctorate 63 (41.4) board certification or equivalent 58(38.2) diploma or certificate 8 (5.3) career path clinical and scientific (i.e. healthcare delivery) 107 (70.7) academic (i.e. full-time university staff ) 45 (29.3) clinical practice grades (n = 125)* consultant 69 (55.2) specialist 35 (28.0) junior 21 (16.8) academic position (n = 81)* professor 27 (33.3) associate professor 16 (19.8) assistant professor 23 (28.4) lecturer 9 (11.1) assistant lecturer 6 (7.4) clinical specialty internal medicine and its subspecialties 84 (55.0) biomedical sciences 16 (10.6) paediatrics 15 (9.9) primary care 15 (9.9) women’s health 9 (6.0) surgery 7 (4.6) other 6 (4.0) language used in professional communication english 124 (81.5) arabic 21 (13.9) french 7 (4.6) *not mutually exclusive. table 3: publishing experience of included healthcare prof essionals from the middle east and africa (n = 152) measure of experience n (%)* number of publications in the previous five years none 57 (37.5) 1–5 46 (30.3) 6–10 15 (9.9) 11–15 13 (8.6) >15 21 (13.8) article type of previous publications† (n = 96) original research 8 (83.3) clinical case, vignette or quiz 41 (42.7) review article 25 (26.0) letter to the editor 16 (16.7) commentary, viewpoint or editorial 9 (9.4) journal type of previous publications† (n = 104) international journal 81 (77.9) regional journal 35 (33.7) national journal 28 (26.9) *percentage adjusted for the total number of respondents to each question. †percentages do not add up to 100% as some respondents may have chosen more than one option. score = (2 × moderately important) + (3 × very important) [equation 1] authors’ selection of target journals and their attitudes to emerging journals a survey from two developing regions e54 | squ medical journal, february 2019, volume 19, issue 1 for paired samples with statistical significance set at p <0.01. all respondents provided electronic informed consent before answering the questionnaire. any unwilling resp ondents had the option to be completely removed from the study and from receiving further invitation reminders. ethical approval was granted by the institutional review board of sheikh khalifa medical city, abu dhabi, uae (#rec-13.08.2017 [rs-502]). results a total of 250 responses were received (total response rate: 9%) and 152 valid responses were included in this study (5.6%). a total of 152 respondents were included in this study with more male than female respondents (61.2% versus 38.8%). most respondents (68%) were 41–60 years old and the majority were from the middle east (80.3%). the largest number of respondents based on country came from the uae (n = 58) and saudi arabia (n = 25). most respondents had medical and/or dental primary qualifications (88.8%). there were more clinical and scientific professionals employed in healthcare than full-time academic university employees (70.7% versus 29.3%). the majority of the respondents had either a high postgraduate degree or a board-type medical specialty certification (48.7% and 38.2%, respectively) [table 2]. over half of the respondents (55%) were prac ticing internal medicine and its related subspecialties whereas the remainder were evenly distributed over other specialities. english was the most frequently used lang uage for professional communication followed by arabic and french (81.5%, 13.9% and 4.6%, respectively). almost two thirds (62.7%) of the respondents had varying levels of publishing experience over the previous five years, mostly in international journals (77.9%). the vast majority (83.3%) of the published manuscripts were original studies [table 3]. the most frequent themes of the publications were diabetes (35%), endocrinology (15.4%), paediatrics (7.7%), pharmacology (5.1%) and diseases (4.3%). the relative scoring of the impact of several attributes of scholarly journals on the authors’ decision at the time of initial submission and second submission was cal table 4: summary of the score of responses to level of importance of various deciding factors that determine journal selection for initial submission and second submission after rejection (n = 152) deciding factors (numbers for responses at is and ss) n (%) score* unimportant moderately important very important is ss is ss is ss is ss prestige (n = 112; n = 112) 21 (18.8) 25 (22.3) 58 (51.8) 59 (52.7) 33 (29.5) 28 (25) 215 202 journal impact factor (n = 118; n = 118) 6 (5.1) 9 (7.6) 48 (40.7) 60 (50.8) 64 (54.2) 49 (41.5) 288 267 journal indexation status (n = 112; n = 111) 5 (4.5) 9 (8.1) 54 (48.2) 58 (52.3) 53 (47.3) 44 (39.6) 267 248 perceived as international (n = 119; n = 118) 13 (10.9) 19 (16.1) 58 (48.7) 54 (45.8) 48 (40.3) 45 (38.1) 260 243 rapidity of turn round (n = 114; n = 113) 12 (10.5) 18 (15.9) 62 (54.4) 64 (56.6) 40 (35.1) 31 (27.4) 244 221 a good editor (n = 115; n = 111) 15 (13) 17 (15.3) 53 (46.1) 68 (61.3) 47 (40.9) 26 (23.4) 247 214 knowing the editors (n = 109; n = 110) 58 (53.2) 53 (48.2) 34 (31.2) 43 (39.1) 17 (15.6) 14 (12.7) 119 128 having published in the journal before (n = 114; n = 112) 26 (22.8) 28 (25.0) 58 (50.9) 54 (48.2) 30 (26.3) 30 (26.8) 206 198 recommendation of colleagues (n = 113; n = 108) 20 (17.7) 23 (21.3) 71 (62.8) 62 (57.4) 22 (19.5) 23 (21.3) 208 193 journal usually publishes articles on the topic (n = 115; n = 111) 8 (7) 10 (9) 68 (59.1) 67 (60.4) 39 (33.9) 34 (30.6) 253 236 size of journal circulation (n = 111; n = 113) 18 (16.2) 24 (21.2) 57 (51.4) 62 (54.9) 36 (32.4) 27 (23.9) 222 205 size of journal circulation and likely readership (n = 112; n = 107) 30 (26.8) 27 (25.2) 58 (51.8) 61 (57) 24 (21.4) 19 (17.8) 188 179 useful peer reviews and statistical advice (n = 111; n = 112) 15 (13.5) 13 (11.6) 58 (52.3) 68 (60.7) 38 (34.2) 31 (27.7) 230 229 free submission to authors (n = 117; n = 112) 15 (12.8) 15 (13.4) 53 (45.3) 51 (45.5) 49 (41.9) 46 (41.1) 253 240 open access (n = 111; n = 108) 15 (13.5) 20 (18.5) 51 (45.9) 48 (44.4) 45 (40.5) 40 (37) 237 216 is = initial submission; ss = second submission. *cumulative score was calculated from the ‘moderately important’ and ‘very important’ responses. wilcoxon signed-ranks for two paired samples was used. salem a. beshyah clinical and basic research | e55 culated according to equation 1 and is illustrated in table 4. indexation status, jif, free submission and an international status were scored highly by respondents. personally knowing the editor, size of journal circulation and likely readership and prestige were scored as unimp ortant factors in making a choice for submission [table 4]. the majority (55.9%) of respondents thought that emerging journals provide more opportunities for new researchers and authors without jeopardising quality. some respondents (38.6%) thought that national and regional journals foster an environment of research and less than one-third of the respondents (29.1%) felt obliged to publish in an emerging journal to help advance regionally and nationally-based journals [figure 1]. however, almost half of the respondents (49.6%) still wish to publish in international journals and some (11.8%) felt pressured to publish in international journals with the highest possible jif, while others (30.7%) felt obliged to do so to raise the publishing profile of their institution. a small proportion of respondents (14.2%) stated that they were not convinced of the need for emerging journals and believed all authors should target the same international journals. a total of 114 respondents reported their exper iences with emerging journals. over half of the resp ondents (54.4%) regularly browse and read certain emerging journals, while less than half had served as a reviewer (44.7%) or cited contents from emerging journals at least once (42.1%). in addition, 39.5% had published in an emerging journal while some had served in the editorial board or as managing editor of an emerging journal (22.8% and 12.8%, respectively) [figure 2]. discussion this study showed that authors highly valued jif, index ation status, free submission and an international status in their journal choice. personal acquaintance with the journal editor, size of journal circulation and likely reader ship and prestige were considered to be unimportant factors. søreide et al.’s study found that a journal’s over all reputation, jif and readership composition were important factors for journal choice for initial manuscript submissions.6 in özçakar et al.’s study of authors who published in a surgical journal, the majority of respondents held the overall reputation of the journal as the most important factor followed by the jif when choosing a journal for manuscript submission.7 welch et al.’s study focused on european authors in physical medicine and rehabilitation and found that the three most important factors for journal choice were the area of interest (mission and contents) of the journal within their specialty, absolute jif and a match between perceived quality of their research and the jif.8 however, for many researchers prestige, a high jif, figure 1: the attitudes of authors in the middle east and africa towards emerging journals (n = 127). figure 2: the encounters and practices of authors in the middle east and africa regarding emerging journals (n = 114). authors’ selection of target journals and their attitudes to emerging journals a survey from two developing regions e56 | squ medical journal, february 2019, volume 19, issue 1 journal reputation and an international journal status may not carry identical implications as in the current study. this makes direct comparison between studies difficult.6–8 for second submissions, the present study found no fundamental differences in deciding factors of journal choice from initial submissions. other studies did not elucidate the differences between initial and second submissions.6–8 jif is calculated by the average number of citations per article over a period of time, usually within a year.14–16 whereas jif assesses the impact of separately published articles, it is misused as an indication of the quality and scientific prestige of the journal as a whole.15 the jif can also be distorted by several factors. although jif gives some information about the level of a journal's citations; they are generally poor indicators of journal quality, the quality of individual authors and their instit utions. several alternative metrics have been proposed as a better indicator of journal quality than jif.14–16 although journal indexation was valued highly by the respondents in the current study, it was not adequately considered in previous studies.6–8 however, many med ical journals, publishing both internationally or locally, meet serious financial difficulties when attempting to be indexed internationally.17 this not only affects the scientific quality of non-indexed medical journals (nimjs), but also affects the awareness of the scientific community on topics with apparently local but potentially broader scientific significance. this applies to many journals in the middle east and africa as well as many other regions. the observed diverse range of attitudes regarding emerging journals is probably a reflection of the imp ortance authors attach to indexation and jif. many genuine emerging journals require a long time to attain international indexation and to have a jif calculated. however, the international scientific community is not indifferent to information published in nimjs.17 germenis et al. found that the medical community has expressed a special interest in this type of information.17 some universities require their academic staff to publish in indexed journals and with a jif of at least one. conseq uently, authors who are not required by their institutions to submit to indexed journals may still support nimjs until they are indexed. therefore, universities should exercise some discretionary “positive discrimination” by exempting promising national and regional emerging journals to encourage university employees to publish in them, which may also diminish submissions to pred atory journals.13,18 journal editors, in regions where authors may not be fully aware of authorship rules and regulations, have more responsibilities in terms of an increased risk of inappropriate authorship, plagiarism and disputes.19–21 the low research productivity of developing nations reflects the lack for a strong research culture, which is complicated by low patient awareness of the value of research trials.22,23 respondents in the present study were cost-conscious; they ranked free submission highly perhaps due to lack of support of their employers to open access journals, but they do not seem to be influenced by free access [table 4]. this differs from schroter et al.’s study which showed that authors valued free access to their research articles and considered dissemination to be an important factor in deciding to which journal to submit.24 genuine emerging journals are normally open access for both authors and readers.9 the current study observed a diverse range of attitudes regarding emerging journals. the reported actual experiences with emerging journals were low. these findings should help emerging journals to better address the needs of future authors, which will increase their value and help protect authors from predatory journals.10,18 alsanea et al. used a root-cause analysis of the workflow process and output of a major saudi arabian journal and showed that the substantial amount of published case reports affected its jif.25 in addition, a slow review process due to the poor response of reviewers was a problem that many emerging journals face.9,10,25 the current study is limited by its sample size, convenience sampling method and that about one third of the respondents had no previous publishing experience. however, this is the first study of its nature from the middle east and africa on this topic and its findings can provide regional editors with important insights into the views of their potential authors. conclusion the present study demonstrated that several factors influence authors’ choice of journals for publication; however, the financial factor had a unique effect on authors’ choice from the middle east and africa. this study found differences in the attitudes of authors towards emerging journals. editors and publishers of emerging journals may benefit from these results to make their journals more attractive to potential authors. emerging journals need to adapt and maintain the highest quality of scholarly publishing to be indexed internationally and to meet the expectations of their potential authors. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. salem a. beshyah clinical and basic research | e57 references 1. dhammi ik, haq ru. submission to publication demystified: a guide for authors. indian j orthop 2017; 51:631–2. https://doi. org/10.4103/ortho.ijortho_599_17. 2. peh wc, ng kh. preparing a manuscript for submission. singapore med j 2009; 50:759–61. 3. caon m. choosing the appropriate peer-reviewed journal for submission of your manuscript. australas phys eng sci med 2018; 41:779–80. https://doi.org/10.1007/s13246-018-0687-y. 4. bavdekar sb, save s. choosing the right journal for a scientific paper. j assoc physicians india 2015; 63:56–8. 5. frank e. authors’ criteria for selecting journals. jama 1994; 272:163–4. https://doi.org/10.1001/jama.1994.03520020089026. 6. søreide k, winter dc. global survey of factors influencing choice of surgical journal for manuscript submission. surgery 2010; 147:475–80. https://doi.org/10.1016/j.surg.2009.10.042. 7. özçakar l, franchignoni f, kara m, muñoz lasa s. choosing a scholarly journal during manuscript submission: the way how it rings true for physiatrists. eur j phys rehabil med 2012; 48:643–7. 8. welch sj. selecting the right journal for your submission. j thorac dis 2012; 4:336–8. https://doi.org/10.3978/j.issn.20721439.2012.05.06. 9. beshyah sa, elkhammas ea. manuscript peer review for emer ging journals: where we go from here? ibnosina j med biomed sci 2015; 7:155–7. https://doi.org/10.4103/1947-489x.210280. 10. beshyah sa, aburawi eh, alshammakhi n, elkhammas ea. why should you publish in ibnosina journal of medicine and biomedical sciences? ibnosina j med biomed sci 2017; 9:99–100. https://doi.org/10.4103/ijmbs.ijmbs_5_17. 11. piterman l, mccall l. targeting the right journal. aust fam physician 1999; 28:730–1. 12. badenhorst b, mansoori p, chan ky. assessing global, regional, national and sub-national capacity for public health research: a bibliometric analysis of the web of science(tm) in 19962010. j glob health 2016; 6:010504. https://doi.org/10.7189/ jogh.06.010504. 13. beshyah sa. predatory publishing: a wake-up call for editors and authors in the middle east and africa. ibnosina j med biomed sci 2017; 9:123–5. https://doi.org/10.4103/ijmbs.ijmbs_26_17. 14. van driel ml, magin pj, del mar cb, furler j, de maeseneer j. journal impact factor and its importance for afp. aust fam physician 2008; 37:770–3. 15. bornmann l, marx w, gasparyan ay, kitas gd. diversity, value and limitations of the journal impact factor and alternative metrics. rheumatol int 2012; 32:1861–7. https://doi.org/10.1007/s00296-0112276-1. 16. huggett s. journal bibliometrics indicators and citation ethics: a discussion of current issues. atherosclerosis 2013; 230:275–7. https://doi.org/10.1016/j.atherosclerosis.2013.07.051. 17. germenis ae, kokkinides pa, stavropoulos-giokas c. nonindexed medical journals in the web: new perspectives in the medical literature. int j med inform 1997; 47:65–8. https://doi. org/10.1016/s1386-5056(97)00076-2. 18. beshyah sa, hajjaji im, elbarsha a. awareness of predatory journals among physicians from africa and the middle east: an exploratory survey. ibnosina j med biomed sci 2018; 10:136–40. https://doi.org/10.4103/ijmbs.ijmbs_45_18. 19. ismail kh. perceptions of plagiarism among medical and nursing students in erbil, iraq. sultan qaboos univ med j 2018; 18:e196–201. https://doi.org/10.18295/squmj.2018.18.02.012. 20. beshyah sa, ibrahim wh, aburawi eh, elkhammas ea. the rules and realities of authorship in biomedical journals: a cauti onary tale for aspiring researchers. ibnosina j med biomed sci 2018; 10:149–57. https://doi.org/10.4103/ijmbs.ijmbs_62_18. 21. beshyah sa, abdelmannan dk, elzouki an, elkhammas ea. authorship disputes: do they result from inadvertent errors of judgment or intentional unethical misconduct? ibnosina j med biomed sci. 2018; 10:158–65. https://doi.org/10.4103/ijmbs.ijm bs_58_18. 22. algahtani h, shirah b, boker f, algamdi a, alkahtani a. neuro logy research in saudi arabia: urgent call for action. sultan qaboos univ med j 2017; 17:e324–8. https://doi.org/10.18295/ squmj.2017.17.03.011. 23. al-lawati h, al-baimani k, al-zadjali m, al-obaidani n, al-kiyumi z, al-khabori mk. knowledge and attitudes towards clinical trial participation in oman: a cross-sectional study. sultan qaboos univ med j 2018; 18:e54–60. https://doi.org/10.18295/ squmj.2018.18.01.009. 24. schroter s. importance of free access to research articles on decision to submit to the bmj: survey of authors. bmj 2006; 332:394–6. https://doi.org/10.1136/bmj.38705.490961.55. 25. alsanea n, al-ghammas a, pangan-menor j, tejano rv, al-bassam n, duero-ebora j, et al. the obstacles facing scientific and medical publishing in saudi arabia. ann saudi med 2014; 34:202–6. https://doi.org/10.5144/0256-4947.2014.202. https://doi.org/10.4103/ortho.ijortho_599_17 https://doi.org/10.4103/ortho.ijortho_599_17 https://doi.org/10.1007/s13246-018-0687-y https://doi.org/10.1001/jama.1994.03520020089026 https://doi.org/10.1016/j.surg.2009.10.042 https://doi.org/10.3978/j.issn.2072-1439.2012.05.06 https://doi.org/10.3978/j.issn.2072-1439.2012.05.06 https://doi.org/10.4103/1947-489x.210280 https://doi.org/10.4103/ijmbs.ijmbs_5_17 https://doi.org/10.7189/jogh.06.010504 https://doi.org/10.7189/jogh.06.010504 https://doi.org/10.4103/ijmbs.ijmbs_26_17 https://doi.org/10.1007/s00296-011-2276-1 https://doi.org/10.1007/s00296-011-2276-1 https://doi.org/10.1016/j.atherosclerosis.2013.07.051 https://doi.org/10.1016/s1386-5056%2897%2900076-2 https://doi.org/10.1016/s1386-5056%2897%2900076-2 https://doi.org/10.4103/ijmbs.ijmbs_45_18 https://doi.org/10.18295/squmj.2018.18.02.012 https://doi.org/10.4103/ijmbs.ijmbs_62_18 https://doi.org/10.4103/ijmbs.ijmbs_58_18 https://doi.org/10.4103/ijmbs.ijmbs_58_18 https://doi.org/10.18295/squmj.2017.17.03.011 https://doi.org/10.18295/squmj.2017.17.03.011 https://doi.org/10.18295/squmj.2018.18.01.009 https://doi.org/10.18295/squmj.2018.18.01.009 https://doi.org/10.1136/bmj.38705.490961.55 https://doi.org/10.5144/0256-4947.2014.202 department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com old world cutaneous leishmaniasis successful response to topical imiquimod jose m. llamas-molina, francisco j. navarro-triviño, *ricardo ruiz-villaverde sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 426–427, epub. 25 aug 22 submitted 18 mar 21 revision req. 10 may 21; revision recd. 11 may 21 accepted 30 may 21 leishmaniases are considered a disease complex; it is transmitted by sandfly vectors and caused by a heterogeneous group of protozoa belonging to the genus leishmania spp. leishmaniasis comprises two clinical forms of presentation: cutaneous and visceral. traditionally, cutaneous leishmaniasis (cl) has been classified into old world cutaneous leishmaniasis (owcl) and new world cutaneous leishmaniasis (nwcl) depending on the geographical distribution. a 43-year-old female patient with no relevant medical history was referred to the current outpatient dermatologic clinic in grenada, spain, in 2020 on account of two lesions on the right hand for three months. the patient was referred due to lack of clinical improvement despite treatment with mometasone furoate 0.1% cream for one month. on clinical examination, two erythematous, squamous plaques (largest diameters: 1.2 cm and 1.5 cm) were observed on the back of the right hand [figure 1a and b]. dermoscopy (dermlite 4©, san juan capistrano, california, usa) showed an inflammatory pattern composed by a central keratotic crust on an erythematous background and tear structures [figure 1c]. histopathological examination confirmed the clinical suspicion of owcl revealing non-necrotising epithelioid in the middle and deep dermis, with multiple leishmania amastigotes detected by giemsa stain [figure 2]. complementary tests ruled out the presence of systemic involvement. as the patient did not agree to intralesional treatment with meglumine antimoniate due to needle phobia, it was decided to start topical treatment with imiquimod 5% cream five consecutive nights a week for four weeks, followed by applying a repair cream. the inflammatory reaction during treatment was moderate to severe, with ulcer ation of the treated area [figure 3a]. a complete skin recovery was seen at two months check-up [figure 3b–d]; in addition to polymerase chain reaction test results of the control sample, a histopathological study did not show persistence of the disease. currently the patient is being followed-up every three months, with no recur rence of leishmania infection. written consent was obtained from the patient for publication purposes. comment imiquimod was approved by the food and drug administration for the treatment of anogenital warts, actinic keratosis and superficial basal cell carcinoma. in addition, it has been used off-label in the treatment of several infectious and neoplastic diseases. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.133 interesting medical image figure 1: a: photograph of the back of the right hand of a 43-year-old female patient showing two erythematous, squamous plaques (largest diameters: 1.2 cm and 1.5 cm) at first visit. b: photograph of the same lesions after 21 days. c: dermoscopy at ×10 magnification showing erythematous fundus with central hyperkeratosis, whitish burst at periphery, white-cottony structures and a polymorphic vascular pattern of irregular linear vessels, hairpin vessels and dotted vessels. https://creativecommons.org/licenses/by-nd/4.0/ jose m. llamas-molina, francisco j. navarro-triviño and ricardo ruiz-villaverde interesting medical image | 427 imiquimod activates macrophages by inducing the production of nitrous oxide, which leads to the intracellular destruction of leishmania amastigotes in vitro.1 the first observational study on the application of imiquimod for leishmaniasis dates back to 1999 when it was shown to be effective on an experimental model of leishmaniasis.2 nevertheless, the effectiveness of imiquimod in cl has not been entirely clear in later research studies. seeberger et al.’s placebo-controlled prospective study concluded that topical application of imiquimod on monotherapy was not effective in owcl after treating with imiquimod cream 5% three times a week for two months.3 although the majority of cutaneous lesions improved within the first two weeks, the benefit did not last for more than four weeks and was followed by an increase in both size and scaling. in a study by firooz et al., patients were randomly assigned to receive a combined 4-week course of imiquimod or placebo with meglumine antimoniate treatment in an endemic area of l. tropica.4 this study did not find clinical differences between both combinations. a concentration of imiquimod 7.5% combined with meglumine antimoniate should be more effective than the meglumine antimonate alone.5 a successful response with imiquimod on monotherapy after debulking punch biopsies have also been documented.6 further studies would be necessary to determine the more propitious role of imiquimod as a non-systemic useful alternative therapeutic option for owcl. a u t h o r s’ c o n t r i b u t i o n all authors contributed equally to data collection, drafting and revision of the manuscript. all authors approved the final version of the manuscript. references 1. murray hw. clinical and experimental advances in treatment of visceral leishmaniasis. antimicrob agents chemother 2001; 45:2185–97. https://doi.org/10.1128/aac.45.8.2185-2197.2001. 2. buates s, matlashewski g. treatment of experimental leishmaniasis with the immunomodulators imiquimod and s-28463: efficacy and mode of action. j infect dis 1999; 179:1485–94. https://doi.org/10.1086/314782. 3. seeberger j, daoud s, pammer j. transient effect of topical treatment of cutaneous leishmaniasis with imiquimod. int j dermatol 2003; 42:576–9. https://doi.org/10.1046/j.13654362.2003.01955.x. 4. firooz a, khamesipour a, ghoorchi mh, nassiri-kashani m, eskandari se, khatami a, et al. imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis: a randomized assessor-blind controlled trial. arch dermatol 2006; 142:1575–9. https://doi.org/10.1001/archderm.142.12.1575. 5. arevalo i, tulliano g, quispe a, spaeth g, matlashewski g, llanos-cuentas a, et al. role of imiquimod and parenteral meglumine antimoniate in the initial treatment of cutaneous leishmaniasis. clin infect dis 2007; 44:1549–54. https://doi. org/10.1086/518172. 6. taylor la, gormley r, kovarik c. leishmania tropica: combined debulking and imiquimod for the treatment of nonresponsive cutaneous leishmaniasis. j am acad dermatol 2017; 76:e13–14. https://doi.org/10.1016/j.jaad.2016.08.040. figure 2: giemsa stain at ×35 magnification showing non necrotising epithelioid in the middle and deep dermis with multiple leishmania amastigotes (red arrow). figure 3: photographs showing (a) ulceration and crust surrounded by inflammatory erythematous halo after finishing treatment with imiquimod 5% cream. photographs taken (b & c) 14 days after finishing imiquimod and 30 days after finishing imiquimod cream and using daily repair cream. dermoscopy at ×10 magnification showing (d) stairs vascular pattern and shiny white streaks compatible with regeneration of collagen fibres. https://doi.org/10.1128/aac.45.8.2185-2197.2001. https://doi.org/10.1086/314782 https://doi.org/10.1046/j.1365-4362.2003.01955.x https://doi.org/10.1046/j.1365-4362.2003.01955.x https://doi.org/10.1001/archderm.142.12.1575 https://doi.org/10.1086/518172 https://doi.org/10.1086/518172 https://doi.org/10.1016/j.jaad.2016.08.040 1oncology ward, churchill hospital, oxford university hospitals, oxford, united kingdom; 2department of medical oncology, yeovil district hospital, nhs foundation trust, yeovil, united kingdom; 3department of radiology & molecular imaging, 4nursing directorate and 5department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: bhagia1@yahoo.com مضاعفات وإدارة منفذ الوصول الوريدي املركزي القابلة للزرع ابلكامل ملرضى السرطان يف مستشفى جامعي يف ُعمان فيلومينا دي �سوز�، �سيام كومار، �أنوبام ككاريا، ر��سد �ل�سكيتي، خالد �لبمان، رنا حميد، �ألوك ميتال، منى �لبلو�سي، �إكر�م بورين، من�سور �ملنذري abstract: objectives: totally implantable central venous access ports (port-a-caths) are increasingly used for the safe administration of chemotherapy; however, their use is associated with complications. this study reviews patterns of complications, reasons for premature removal and the duration of the use of port-a-caths in patients receiving cancer treatment at sultan qaboos university hospital (squh) and compares the infection rate with the literature and the researchers’ experiences. methods: this retrospective follow-up study included patients who had received cancer treatment through a port-a-cath and were admitted to squh between january 2007 and april 2019. demographic features, underlying diagnosis, clinical stage, treatment, duration of use and the cause of premature removal of the port-a-cath were recorded. results: a total of 516 port-a-caths were inserted in 482 cancer patients. the majority of devices were implanted by interventional radiologists (n = 459; 89.0%) and the right internal jugular vein was most frequently accessed (n = 396; 76.7%). the mean indwelling time of a port-a-cath was 288 days (range: 3–1,872 days) for patients with complications and 550 days (range: 7–3,123 days) for patients without complications. port-a-cath-related infection was the main complication (n = 63; 12.2%). patient age, gender, treatment intent, underlying diagnosis, clinical stage, chemotherapy regimen, number of treatment courses, operator implanting the port, the type of micro-organism isolated from the port-a-cath and body mass index were significant factors affecting catheter indwelling time (p <0.05). on multivariate analysis, however, none of the factors was found to be significant. conclusion: infection was the most common complication necessitating port-a-cath removal. the infection rate was much lower than the researchers’ previous experience and compares favorably with several published reports. keywords: port-a-cath; vascular access ports; catheter-related infections; cancer; oman. امللخ�ص: الهدف: يتم ��ستخد�م منفذ �لو�سول �لوريدي �ملركزي �لقابل للزرع بالكامل ب�سكل متز�يد من �أجل �حلقن �لآمن للعالج �لكيميائي؛ ومع ذلك، يرتبط ��ستخد�مها بالعديد من �مل�ساعفات. ت�ستعر�ض هذه �لدر��سة �أمناط �مل�ساعفات و�أ�سباب �لإز�لة �ملبكرة ومدة ��ستخد�م �ملنفذ يف �ملر�سى �لذين يتلقون عالج �ل�رسطان يف م�ست�سفى جامعة �ل�سلطان قابو�ض وتقارن معدل �لإ�سابة مع �لدر��سات و�ٌلبحاث �ل�سابقة. الطريقة: ت�سمنت �لدر��سة متابعة رجعية وم�ستقبلية للمر�سى �لذين تلقو� عالج �ل�رسطان من خالل منفذ �لو�سول �لوريدي �ملركزي ومت قبولهم يف م�ست�سفى جامعة �ل�سلطان قابو�ض بني يناير 2007 و�أبريل 2019. مت ت�سجيل وح�رس �ل�سمات �لدميوغر�فية و�لت�سخي�ض �لأ�سا�سي و�ملرحلة ا بال�رسطان. �ل�رسيرية و�لعالج ومدة �ل�ستخد�م و كذلك �أ�سباب �لإز�لة �ملبكرة للمنفذ. النتائج: مت �إدخال ما جمموعه 516 منفًذ� يف 482 مري�سً مت زرع غالبية �لأجهزة من قبل �أخ�سائيي �لأ�سعة �لتد�خلية )%89.0؛ n = 459( ومت �لو�سول �إىل �لوريد �لود�جي �لأمين يف �أغلب �لأحيان )%76.7؛ n = 396(. كان متو�سط وقت بقاء �ملنفذ �لوريدي 288 يوًما )�ملدى: يوًما 1,872-3( للمر�سى �لذين يعانون من م�ساعفات و550 يوًما )�ملدى: يوًما 3,123-7( للمر�سى �لذين لي�ض لديهم م�ساعفات. كانت �لعدوى ملنفذ �لو�سول �لوريدي �ملرتبطة هي �مل�ساعفة �لرئي�سية )%12.2؛ n = 63(. �أظهر �لبحث �أن عمر �ملري�ض، و�جلن�ض، وهدف �لعالج، و�لت�سخي�ض �لأ�سا�سي، و�ملرحلة �ل�رسيرية، ونظام �لعالج �لكيميائي، وعدد دور�ت �لعالج، �خ�ساذي �لتدخل، ونوع �لكائن �لدقيق �ملعزول من �ملنفذ، وموؤ�رس كتلة �جل�سم هي من �لعو�مل �ملهمة �لتي توؤثر على مدة بقاء �ملنفذ �لوريدي �ملركزي )p >0.05(. ومع ذلك ففي �لتحليل �لح�سائي متعدد �ملتغري�ت، مل تكن �أي من هذه �لعو�مل موؤثرة ب�سكل م�ستقل. اخلال�صة: كانت �لعدوى هي �أكرث �مل�ساعفات �سيوًعا و�لتي ��ستلزمت �إز�لة منفذ �لو�سول �لوريدي. كان معدل �لإ�سابة �أقل بكثري من جتربة �لباحثني �ل�سابقة ويقارن ب�سكل �إيجابي مع �لعديد من �لتقارير �لدولية �ملن�سورة. الكلمات املفتاحية: منفذ �لو�سول �لوريدي �ملركزي؛ �لعدوى �ملرتبطة مبنفذ �لو�سول �لوريدي �ملركزي؛ �ل�رسطان؛ ُعامن. complications and management of totally implantable central venous access ports in cancer patients at a university hospital in oman philomena c. d’souza,1 *shiyam kumar,2 annupam kakaria,3 rashid al-sukaiti,3 khalid al-baimani,3 rana s. hamid,3 alok k. mittal,3 muna al-balushi,4 ikram a. burney,5 mansour s. al-moundhri5 sultan qaboos university med j, february 2021, vol. 20, iss. 1, pp. e103–109, epub. 15 mar 21 submitted 10 mar 20 revision req. 7 may 20; revision recd. 27 may 20 accepted 25 jun 20 advances in knowledge the port-a-cath-related infection rate was nearly halved when comparing across the two studied time periods; this is most likely due to better nursing standards. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.014 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ complications and management of totally implantable central venous access ports in cancer patients at a university hospital in oman e104 | squ medical journal, february 2021, volume 21, issue 1 totally implantable central venous access ports are effective for long-term venous access and improved patient safety; they are also known as port-a-caths. besides administering anticancer therapy, port-a-caths are used to administer blood, blood products and nutrition, and to draw blood.1 port-a-caths impact daily activities minimally and result in better patient quality of life (qol).2 porta-caths contribute to better patient qol because they are situated subcutaneously; hence, they do not affect range of motion or impede daily activities.3 in the past, port-a-caths were implanted in operation theatres, but their more recent insertion by interventional radiologists in outpatient settings through a relatively simple procedure has reduced costs.4 port-a-caths require minimal maintenance, but challenges include insertion-related complications (e.g. pneumothorax, haemothorax, accidental arterial puncture and cardiac arrhythmia) and late complications (e.g. bloodstream infection [bsi], thrombosis, catheter dysfunction, pocket infection and port-inversion).5–7 the incidence of infectious complications is generally <10% and most are preventable by scrupulous care.4,8 infection is the most common complication associated with port-a-caths.5,7 staphylococcus and candida are the most frequently isolated microorganisms and enter the port-a-cath through the exit site and colonise the catheter. another source of infection is the port hub; this avenue of infection commonly occurs during blood sampling or flushing. the healthcare provider and patient education plays a pivotal role in continuous and successful long-term port-a-cath care.7 a previous study reported infection as the most common cause for premature removal of port-a-caths.4 with better aseptic techniques and standardised procedures, infection rates have declined.8 this followup study aimed to review patterns of complications, reasons for premature removal and the duration of the use of port-a-caths in patients receiving cancer treatment. in addition, this study reports follow-up data and examines the incidence of complications over two time periods.4 to the best of the researchers’ knowledge, this is the largest dataset on port-a-cathassociated complications reported from the gulf cooperation council (gcc) region. methods this retrospective follow-up study included consec utive adult patients with solid tumours who had a port a-cath inserted for the purpose of receiving cancer treatment between january 2007 and april 2019 at sultan qaboos university hospital (squh) in muscat, oman. this dataset includes previously pub lished results from the time period of january 2007 to february 2013.10 electronic patient records (epr) were accessed to collect the study variables including patient age, gender, body mass index (bmi), diagnosis, type of operator (i.e. interventional radiologist, general surgeon, anaesthetist), dates of insertion and removal, complications, indwelling time and current patient status (i.e. alive or dead). indwelling time was calculated from the time of implantation until the date of removal due to complications, treatment completion, death or until april 30th, 2019, whichever came first. the radiology department at squh maintains a logbook of all the patients who undergo port-a-cath insertion or removal. a clinical nurse specialist (cns) updates the information on the epr. the vital-port port-a-cath (cook medical, bloomington, indiana, usa) type was used until the first quarter of 2018. subsequently, this was replaced by the power-port port-a-cath (bard access systems inc., salt lake city, utah, usa). all implanted porta-caths were single lumen and the internal jugular vein (ijv) was used for venous access. the right ijv was the preferred port-a-cath entry point except in patients with right-sided breast cancer. to accomplish insertion, the ijv was punctured using ultrasound guidance under local anaesthesia. once the port had been inserted, the track from the incision to the site of the venous puncture was anaesthetised and a track was created from the incision to the puncture site. using fluoroscopic guidance, an estimate was made of the required length of the catheter so that the tip of the catheter would lie low in the superior vena cava (svc). neither prophylactic antibiotics nor routine anti-coagulation therapy was administered. senior specialists, cns, specialists from the medical oncology unit and trainees rotating through medical oncology were allowed to access the port-athese results support the use of port-a-caths in cancer patients and provide a benchmark for regional cancer treating hospitals. application to patient care venous access becomes a significant problem in most cancer patients who require long-term cancer care. port-a-cath insertion though has associated risk of infections and other side effects as evidenced by results of our study, but those can be reduced with diligent care most patients could complete their entire chemotherapy courses without side effects and avoiding the need for repeated cannulation and thrombophlebitis a common complication associated with chemotherapy administration in peripheral veins. with time, acceptance for port-a-cath is increasing among omani patients as can be seen with increasing numbers. philomena c. d’souza, shiyam kumar, annupam kakaria, rashid al-sukaiti, khalid al-baimani, rana s. hamid, alok k. mittal, muna al-balushi, ikram a. burney and mansour s. al-moundhri clinical and basic research | e105 cath. all rotating doctors had a proper introduction and demonstration of needle insertion before permission was granted for them to undertake independent work. when accessing the port-a-cath, the procedure described by dal molin et al. was adopted.9 the society of interventional radiology tech nology guidelines were followed to report port-acath-associated complications.8,10 complications were divided into three groups and were considered periprocedural complications if they occurred within the first 24 hours of procedure; early, if they occurred within the first 30 days; or late, if complications were noticed 30 days or more after insertion. catheterrelated infections were also defined per the guidelines and were reported as a local infection or a bsi.10 statistical package for the social sciences (spss), version 20 (ibm, corp., armonk, new york, usa) was used to analyse the data. log-rank univariate analysis was performed using indwelling time as the dependent factor. kaplan and meier’s method was used to calculate differences in the port-a-cath’s duration of implantation. the cox-regression method was used for multivariate analysis. in addition, data were compared across two different time periods: time period one was january 2007 to february 2013 and time period two was march 2013 to april 2019.10 the institutional medical research and ethics committee at the sultan qaboos university hospital approved the study (mrec approval #1929). results a total of 516 port-a-caths were implanted in 482 patients during the study period. of this total, 34 patients had a second port-a-cath implanted. of the 516 port-a-caths, 473 (91.7%) were placed at squh. the majority of procedures were performed by an interventional radiologist (n = 459; 89.0%). only 11 (2.1%) port-a-caths were implanted by an anaesthetist and three (0.6%) by a general surgeon. figure 1: overview of outcomes of patients’ with solid tumours who underwent port-a-cath implantation at sultan qaboos university hospital, oman from january 2007 to april 2019. table 1: characteristics and diagnoses of patients with solid tumours who had a port-a-cath implanted at sultan qaboos university hospital, oman from january 2007 to april 2019 (n = 516) characteristic n (%) gender male 178 (34.5) female 338 (65.5) bmi category below normal (<18.5) 51 (9.9) normal (18.5–24.9) 167 (32.4) overweight (25–30) 142 (27.5) obese (>30) 156 (30.2) median in kg/m2 26.7 diagnosis breast cancer 205 (39.7) colon cancer 143 (27.7) gastric cancer 50 (9.7) sarcoma 22 (4.3) ovarian cancer 17 (3.3) pancreatic cancer 16 (3.1) lung cancer 13 (2.5) other 50 (9.7) cancer disease stage i 18 (3.5) ii 73 (14.1) iii 138 (26.7) iv 287 (55.6) interventionist interventional radiologist 459 (89.0) port-a-cath implanted outside oman 43 (8.3) anaesthetist 11 (2.1) surgeon 3 (0.6) treatment intention curative 193 (37.4) palliative 323 (62.6) bmi = body mass index. complications and management of totally implantable central venous access ports in cancer patients at a university hospital in oman e106 | squ medical journal, february 2021, volume 21, issue 1 the median age of patients was 49.0 years (range: 13–83 years) and the majority (n = 338; 65.5%) were female. median bmi was 26.7 kg/m2. breast cancer (n = 205; 39.7%) was the most common diagnosis followed by colon cancer (n = 143; 27.7%) and gastric cancer (n = 50; 9.7%). the majority of patients (n = 425; 82.4%) had clinical stage iii/iv disease at the time of diagnosis. more than 50% of patients received one line of chemotherapy, while the remaining patients received multiple lines of treatment through the same port-a-cath. two patients did not receive cytotoxic chemotherapy at all. the most frequent treatment intention was palliative (n = 323; 62.6%). an interventional radiologist most commonly inserted the port-a-cath (n = 459; 89.0%) [table 1]. as it was the choice of the interventional radiologist to choose the best site for implantation, the majority of the port-a-caths were implanted through the right ijv (76.7%) due to ease of access. the vast majority of patients (73.8%) had the tip of the port-acath inserted in the svc. overall, port-a-caths were used for a total of 261,963 days in all patients included in this study [figure 1]. the mean indwelling time was 508 ± 123 days (range: 3–3,123 days); the mean duration of use of port-a-cath in patients who developed complications was 288 ± 325 days (range: 3–1,872 days) and, for those who did not develop a complication, the mean duration of use was 550 ± 194 days (range: 7–3,123 days). the most commonly isolated organism was staphylococcus aureus (n = 14; 2.7%). a total of 119 (23.1%) devices were removed after treatment was completed [table 2]. port-a-caths were removed prematurely in 72 (14.0%) patients due to complications (0.27/1,000 catheter days). complications recorded within the 30 days of port-a-cath implantation included infection, skin dehiscence, haematoma and catheter leakage or blockage. the most common reason for removing a port-a-cath was infection (n = 63; 12.2%; 0.20/1,000 catheter days). bsi was documented in 3.7% of patients. other reasons for removal included catheter blockage (n = 13; 2.5%), skin dehiscence (n = 5; 1.0%) and venous thrombosis (n = 3; 0.6%). the overall median time to develop an infection was 89 days from the date of port-a-cath insertion. the median time to develop a port-a-cath-related infection was 246 days (range: 3–1,872 days), 210 days (range: 24–890 days) to develop a catheter blockage, 62 days (range: 14–306 days) for skin rupture and 206 days (range: 110–278 days) for a thrombosis [table 3]. no patient developed pneumothorax, arterial puncture or acute bleeding after the procedure. of the remaining devices, 119 (23.1%) were removed after completion of the intended treatment while 173 (33.53%) are still implanted in patients who are under follow-up or are receiving therapy at the time of publication. analysis of incidence of complications over two time periods (january 2007 to february 2013 versus march 2013 to april 2019) revealed a reduction in the complication rates from 25.6% in time period one table 2: reasons for removal of port-a-cath in patients with solid tumours at sultan qaboos university hospital, oman from january 2007 to april 2019 (n = 516) reason for removal* n (%) complication† 72 (14.0) infection 59 (11.4) infection + blocked 4 (0.8) blocked 9 (1.7) skin rupture 9 (1.7) vessel thrombosis 3 (0.6) catheter migration 1 (0.2) haematoma 1 (0.2) catheter leak 1 (0.2) completed chemotherapy 119 (22.3) organism isolated staphylococcus aureus 14 (2.7) staphylococcus hemolyticus 6 (1.2) klebsiella pneumonie 6 (1.2) multi-resistant pseudomonas aureguinosa 4 (0.8) pseudomonas aureguinosa 4 (0.8) multi-resistant klebsiella 3 (0.6) acinetobacter 2 (0.4) candida 2 (0.4) escherichia coli 2 (0.4) escherichia faecalis 1 (0.2) proteus vulgaris 1 (0.2) streptococcus mitis 1 (0.2) bacillus cereus 1 (0.2) ochrobacum anthropi 1 (0.2) no organism isolated 16 (3.1) chemotherapy regimen ac → d±t 107 (20.7) multiple lines (no bevacizumab) 165 (32.0) multiple lines with bevacizumab 64 (12.4) folfox4 ± bevacizumab 82 (15.9) other regimens 98 (20.0) ac = adriamycin and cyclophosphamide; d±t = docetaxel ± trastu zumab; folfox4 = folinic acid, 5-fluoruracil and oxaliplatin. *the remaining port-a-caths were not removed. †patients could have more than one complication. philomena c. d’souza, shiyam kumar, annupam kakaria, rashid al-sukaiti, khalid al-baimani, rana s. hamid, alok k. mittal, muna al-balushi, ikram a. burney and mansour s. al-moundhri clinical and basic research | e107 to 11.2% in time period two. similarly, the infection rate decreased from 16.2% to 8.2% over the two time periods [table 4].10 at one-year follow-up, median duration of porta-cath use was 361 days [figure 2]. on the log rank analysis, patient age, gender, treatment intent (curative versus palliative), underlying diagnosis, disease stage, rate of complication, chemotherapy regimen, number of treatment lines, operator implanting the port, organism isolated from the port and bmi were significant factors affecting indwelling time of a porta-cath (p <0.05 each). on cox regression multivariate analysis, none of the factors significantly affected the indwelling time of a port-a-cath. discussion to the best of the researchers’ knowledge, this study represents the largest examination of use patterns, outcomes and complication rates for port-a-caths in cancer patients in the middle east. a total of 516 port-a-caths were inserted in 482 patients. the mean indwelling time of port-a-cath was 508 days but was shorter for those who developed complications compared to those who did not (288 versus 551 days). the overall complication rate was 14.0%, and the infection rate was 12.2%. over the two study periods, both the complication rate and the infection rate dropped significantly, suggesting a learning curve for the institution’s healthcare workers. various studies have reported advantages of porta-caths as opposed to tunnelled or peripheral catheters in relation to indwelling time, cost and complications. the reported mean indwelling time has been reported between 9–16.6 months; the current study reveals a similar indwelling time of 16.7 months (508 days).8,11,12 this time is an improvement from the mean of 354 days reported previously for squh and is consistent with contemporary literature.4 in the current study, approximately 12.2% of the port-a-caths were removed prematurely because of infection. this finding is consistent with the published literature, which suggests that the most common reason for premature removal of port-atable 3: time to port-a-cath complication and type of complication in patients with solid tumours complication type early complications (within 30 days) late complications (after 30 days) total complications mean days to complication n (%) per 1,000 catheter days n (%) per 1,000 catheter days n (%) per 1,000 catheter days infection + blocked 23 (4.4) 0.05 40 (7.7) 0.148 63 (12.2) 0.20 246 catheter blockage 5 (0.9) 0.003 4 (0.8) 0.041 9 (1.7) 0.045 210 skin dehiscence 3 (0.6) 0.007 6 (1.2) 0.011 9 (1.7) 0.020 62 venous thrombosis 0 (0) 0 3 (0.6) 0.131 3 (0.6) 0.131 206 catheter migration 0 (0) 0 1 (0.2) 0.003 1 (0.2) 0.003 155 haematoma 0 (0) 0 1 (0.2) 0.003 1 (0.2) 0.003 17 catheter leak 1 (0.2) 0.003 0 (0) 0 1 (0.2) 0.003 17 figure 2: duration of port-a-cath use in patients with solid tumours at sultan qaboos university hospital, oman from january 2007 to april 2019. complications and management of totally implantable central venous access ports in cancer patients at a university hospital in oman e108 | squ medical journal, february 2021, volume 21, issue 1 caths is infection.13 over the two time periods in the current study, the infection rate dropped from 16.2% to 8.2%.10 the infection rate in the second study period is consistent with rates reported previously in the literature (i.e. 1.7–9.3%).14–16 central line-associated bsis often require longterm antibiotics, device removal and prolonged hospital stays. in the current study, 3.7% of porta-caths had to be removed because of bsi, which is significantly lower than the previously reported (13– 34%).2,12 port-a-caths were also removed in patients with repeated infections or continuous fever despite negative blood and urine cultures and adequate antibiotic administration. prophylactic anticoagulant agents (warfarin, unfractionated or low molecular weight heparin) are occasionally administered prior to port-a-cath placements; however, there is mounting evidence against this practice and, at squh, prophylactic antibiotics are not administered.10,20,21 overall, in the current study, the complication rate was 14.0% (0.27/1,000 catheter days) compared to 11.8% (0.41/1,000 catheter days) as previously reported.3 catheter blockage and thrombosis were also significant complication requiring port-a-cath removal. catheter blockage and thrombosis has been reported to occur in around 3.0–8.5% of cases; whereas, only 2.3% patients in this cohort had non-thrombotic obstruction and 0.6% had thrombotic occlusion.17,18 cancer patients are already at increased risk of thrombosis and implantation of port-a-cath further increases this risk.19 prophylactic anti-coagulation has been extensively studied, and routine prophylaxis with anticoagulants is not recommended.20,21 squh doctors observe guidelines for the management of port-a-caths, so prophylactic anticoagulants are not routinely used.22–24 comparing the outcomes of port-a-caths placed by interventional radiologists versus surgeons, two studies have reported no difference in complication rates between the two groups; however, ports placed by interventional radiologists have been found to be more cost effective.25,26 in the current study, only three port-a-caths were placed by surgeons. because the vast majority of placements were done by interventional radiologists, a statistical comparison was not possible. this study has several limitations. first, this study was retrospective in nature and therefore several parameters, such as patient symptoms after port-acath insertion, could not be captured. the primary aim of this study, however, was to assess the prevalence of complications such as bsi, catheter blockage, thrombosis and port-a-cath-insertion related complications including haematoma, pneumothorax and arterial puncture. all these complications are considered sentinel events so the data were available. second, it is possible that complications such as reversible blockage of a port-a-cath were underreported. however, such complications are not considered of clinical significance. finally, the study was carried out as a follow-up study over a long time period in a single centre and standard of care evolved over time. this factor provided an opportunity to study the complication rate over two time periods of more than six years each. importantly, this study represents the largest body of data reported from the gcc and provides important baseline data which could serve as a benchmark for future studies. conclusion to the best of the researchers’ knowledge, this study is the largest from the middle east which demonstrates the utility and success of ultrasound and fluoroscopy guidance for port-a-cath placement as an outpatient table 4: comparison of port-a-cath complications of over two time periods in patients with solid tumours at sultan qaboos university hospital, oman from january 2007 to april 2019 variable n (%) time period one* (january 2007 to february 2013) n = 117 time period two (march 2013 to april 2019) n = 399 mean time porta-cath in place for all patients in days (range) 354 (3–1,876) 495 (7–32,216) mean time porta-cath in place for patients with complication(s) in days (range) 252 (3–1,876) 285 (8–1,148) reason for removal complication† 30 (25.6%) 45 (11.2%) infection 19 (16.2%) 33 (8.2%) infection + blocked 2 (1.7%) 2 (0.5) blocked 4 (3.4%) 4 (1.0%) skin rupture 4 (3.4%) 3 (0.75%) vessel thrombosis 0 (0%) 3 (0.8%) catheter migration 0 (0%) 1(0.3%) haematoma 0 (0%) 1(0.3%) catheter leak 1 (0.9%) 0 (0%) *some data previously reported in: d’souza pc, kumar s, kakaria a, al-sukaiti r, zahid kf, furrukh m, et al. use of port-a-cath in cancer patients: a single-center experience.10 †patients could have more than one complication. philomena c. d’souza, shiyam kumar, annupam kakaria, rashid al-sukaiti, khalid al-baimani, rana s. hamid, alok k. mittal, muna al-balushi, ikram a. burney and mansour s. al-moundhri clinical and basic research | e109 procedure by interventional radiologists. the peri procedural complications were low. although infection rates remain a concern, the rate reduced by half over the study’s second time period, reflecting better nursing care. outcomes improve by improving care processes. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. tabatabaie o, kasumova gg, eskander mf, critchlow jf, tawa ne, tseng jf. totally implantable venous access devices: a review of complications and management strategies. am j clin oncol 2017; 40:94–105. https://doi.org/10.1097/ coc.0000000000000361. 2. toure a, vanhems p, lombard-bohas c, cassier p, pere-verge d, souquet jc, et al. totally implantable central venous access port infections in patients with digestive cancer: incidence and risk factors. am j infect control 2012; 40:935–9. https://doi. org/10.1016/j.ajic.2012.01.024. 3. teichgraber uk, kausche s, nagel sn, gebauer b. outcome analysis in 3,160 implantations of radiologically guided place ments of totally implantable central venous port systems. eur radiol 2011; 21:1224–32. https://doi.org/10.1007/s00330-0102045-7. 4. d’souza pc, kumar s, kakaria a, al-sukaiti r, zahid kf, furrukh m, et al. use of port-a-cath in cancer patients: a single-center experience. j infect dev ctries 2014; 8:1476–82. https://doi.org/10.3855/jidc.4155. 5. yildizeli b, lacin t, batirel hf, yuksel m. complications and management of long-term central venous access catheters and ports. j vasc access 2004; 5:174–8. 6. yu xy, xu jl, li d, jiang zf. late complications of totally implantable venous access ports in patients with cancer: risk factors and related nursing strategies. medicine (baltimore) 2018; 97:e12427. https://doi.org/10.1097/md.0000000000012427. 7. matey l, camp-sorrell d. venous access devices: clinical rounds. asia pac j oncol nurs 2016; 3:357–64. https://doi. org/10.4103/2347-5625.196480. 8. ahn sj, kim hc, chung jw, an sb, yin yh, jae hj, et al. ultrasound and fluoroscopy-guided placement of central venous ports via internal jugular vein: retrospective analysis of 1254 port implantations at a single center. korean j radiol 2012; 13:314–23. https://doi.org/10.3348/kjr.2012.13.3.314. 9. dal molin a, rasero l, guerretta l, perfetti e, clerico m. the late complications of totally implantable central venous access ports: the results from an italian multicenter prospective observation study. eur j oncol nurs 2011; 15:377–81. https:// doi.org/10.1016/j.ejon.2010.11.007. 10. silberzweig je, sacks d, khorsandi as, bakal cw. reporting standards for central venous access. j vasc interv radiol 2003; 14:s443–52. https://doi.org/10.1097/01.rvi.0000094617.61428.bc. 11. kim dh, ryu dy, jung hj, lee ss. evaluation of complications of totally implantable central venous port system insertion. exp ther med 2019; 17:2013–8. https://doi.org/10.3892/etm.2019.7185. 12. wang ty, lee kd, chen pt, chen mc, chen yy, huang ce, et al. incidence and risk factors for central venous access port related infection in chinese cancer patients. j formos med assoc 2015; 114:1055–60. https://doi.org/10.1016/j.jfma.2015.06.013. 13. fischer l, knebel p, schroder s, bruckner t, diener mk, hennes r, et al. reasons for explantation of totally implantable access ports: a multivariate analysis of 385 consecutive patients. ann surg oncol 2008; 15:1124–9. https://doi.org/10.1245/s10434007-9783-z. 14. granziera e, scarpa m, ciccarese a, filip b, cagol m, manfredi v, et al. totally implantable venous access devices: retrospective analysis of different insertion techniques and predictors of complications in 796 devices implanted in a single institution. bmc surg 2014; 14:27. https://doi.org/10.1186/1471-2482-14-27. 15. ma li, liu y, wang j, chang y, yu l, geng c. totally implan table venous access port systems and associated complications: a single-institution retrospective analysis of 2,996 breast cancer patients. mol clin oncol 2016; 4:456–60. https://doi.org/10.3 892/mco.2016.726. 16. shim j, seo ts, song mg, cha ih, kim js, choi cw, et al. incidence and risk factors of infectious complications related to implantable venous-access ports. korean j radiol 2014; 15:494–500. https://doi.org/10.3348/kjr.2014.15.4.494. 17. barbetakis n, asteriou c, kleontas a, tsilikas c. totally implantable central venous access ports. analysis of 700 cases. j surg oncol 2011; 104:654–6. https://doi.org/10.1002/jso.21990. 18. caers j, fontaine c, vinh-hung v, de mey j, ponnet g, oost c, et al. catheter tip position as a risk factor for thrombosis associated with the use of subcutaneous infusion ports. support care cancer 2005; 13:325–31. https://doi.org/10.1007/ s00520-004-0723-1. 19. busch jd, herrmann j, heller f, derlin t, koops a, adam g, et al. follow-up of radiologically totally implanted central venous access ports of the upper arm: long-term complications in 127,750 catheter-days. ajr am j roentgenol 2012; 199:447–52. https://doi.org/10.2214/ajr.11.7970. 20. chaukiyal p, nautiyal a, radhakrishnan s, singh s, navaneethan sd. thromboprophylaxis in cancer patients with central venous catheters. a systematic review and meta-analysis. thromb haemost 2008; 99:38–43. https://doi.org/10.1160/th07-07-0446. 21. cunningham ms, white b, hollywood d, o’donnell j. primary thromboprophylaxis for cancer patients with central venous catheters--a reappraisal of the evidence. br j cancer 2006; 94:189–94. https://doi.org/10.1038/sj.bjc.6602917. 22. bonczek r, nurse ba. management of port-a-cath devices in long-term acute care hospitals. rehabil nurs 2012; 37:307–11. https://doi.org/10.1002/rnj.57. 23. karthaus m, kretzschmar a, kroning h, biakhov m, irwin d, marschner n, et al. dalteparin for prevention of catheter-rel ated complications in cancer patients with central venous cath eters: final results of a double-blind, placebo-controlled phase iii trial. ann oncol 2006; 17:289–96. https://doi.org/10.1093/ annonc/mdj059. 24. sousa b, furlanetto j, hutka m, gouveia p, wuerstlein r, mariz jm, et al. central venous access in oncology: esmo clinical practice guidelines. ann oncol 2015; 26:v152–68. https://doi. org/10.1093/annonc/mdv296. 25. laroy jr, white sb, jayakrishnan t, dybul s, ungerer d, turaga k, et al. cost and morbidity analysis of chest port insertion: inter ventional radiology suite versus operating room. j am coll radiol 2015; 12:563–71. https://doi.org/10.1016/j.jacr.2015.01.012. 26. sticca rp, dewing bd, harris jd. outcomes of surgical and radiologic placed implantable central venous access ports. am j surg 2009; 198:829–33. https://doi.org/10.1016/j.amjsurg.20 09.04.031. https://doi.org/10.1097/coc.0000000000000361 https://doi.org/10.1097/coc.0000000000000361 https://doi.org/10.1016/j.ajic.2012.01.024 https://doi.org/10.1016/j.ajic.2012.01.024 https://doi.org/10.1007/s00330-010-2045-7 https://doi.org/10.1007/s00330-010-2045-7 https://doi.org/10.3855/jidc.4155 https://doi.org/10.1097/md.0000000000012427 https://doi.org/10.4103/2347-5625.196480 https://doi.org/10.4103/2347-5625.196480 https://doi.org/10.3348/kjr.2012.13.3.314 https://doi.org/10.1016/j.ejon.2010.11.007 https://doi.org/10.1016/j.ejon.2010.11.007 https://doi.org/10.1097/01.rvi.0000094617.61428.bc https://doi.org/10.3892/etm.2019.7185 https://doi.org/10.1016/j.jfma.2015.06.013 https://doi.org/10.1245/s10434-007-9783-z https://doi.org/10.1245/s10434-007-9783-z https://doi.org/10.1186/1471-2482-14-27 https://doi.org/10.3892/mco.2016.726 https://doi.org/10.3892/mco.2016.726 https://doi.org/10.3348/kjr.2014.15.4.494 https://doi.org/10.1002/jso.21990 https://doi.org/10.1007/s00520-004-0723-1 https://doi.org/10.1007/s00520-004-0723-1 https://doi.org/10.2214/ajr.11.7970 https://doi.org/10.1160/th07-07-0446 https://doi.org/10.1038/sj.bjc.6602917 https://doi.org/10.1002/rnj.57 https://doi.org/10.1093/annonc/mdj059 https://doi.org/10.1093/annonc/mdj059 https://doi.org/10.1093/annonc/mdv296 https://doi.org/10.1093/annonc/mdv296 https://doi.org/10.1016/j.jacr.2015.01.012 https://doi.org/10.1016/j.amjsurg.2009.04.031 https://doi.org/10.1016/j.amjsurg.2009.04.031 departments of 1anatomy and 3pathology, kasturba medical college manipal, basic sciences building, manipal academy of higher education, manipal, karnataka, india; 2undergraduate medical student, kasturba medical college, manipal academy of higher education, manipal, karnataka, india *corresponding author’s e-mail: nandini.bhat@manipal.edu serendipitous discovery of a benign obturator nerve schwannoma case report with a brief clinical review suhani sumalatha,1 nikhila appala,2 ashwija shetty,1 deepak nayak,3 sushma prabhath,1 *nandini p. bhat1 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 477–480, epub. 29 aug 21 submitted 19 jun 20 revision req. 16 aug 20; revision recd. 5 sep 20 accepted 4 oct 20 department of anatomy, kasturba medical college, manipal, india, in 2019. the fusiform swelling was on the left obturator nerve, located extraperitoneally in the pelvis, at the level of the sacral promontory. on the contralateral side, however, the obturator nerve was observed to be typical with no visible abnormality. on examination, the mass was 2.5 cm in length, encapsulated and had a hard consistency. the breadth of the swelling at the midpoint of the mass was 3.5 cm. however, the obturator nerve breadth was measured as 1 cm below as well as above the swelling. on gross examination, the swelling was identified as a peripheral nerve sheath tumour [figure 1]. the mass was excised, histologically processed and stained with haematoxylin and eosin. on microscopic examination of the specimen, all three layers of the peripheral nerve (perineurium, epineurium and endoneurium) could be identified. a proliferation of spindle cells with a fascicular architectural configuration and areas of loosely cellular corresponding to antoni b patterns of arrangement were observed. the hypocellular tumour was arranged in a sweeping fascicle form with patches of myxoid degeneration. tumour cells showed elongated buckled nuclei with no mitotic figures. the tumour was determined to be a schwannoma. the obturator nerve on the right side was also excised and histologically processed. it showed features of a typical nerve [figure 2]. discussion schwannomas, also known as neurilemmomas, are classified under the peripheral nerve sheath tumours the obturator nerve originates from the ventral rami of the second, third and fourth lumbar nerve. the nerve runs down into the pelvis along the medial border of the psoas major muscle. it enters the anterior compartment of the thigh through the obturator foramen to supply the muscles of the medial compartment of the thigh. further, it distributes articular branches to the hip, knee joints and sensory innervation to the medial side of the thigh.1 a schwannoma is a benign, encapsulated, non invasive tumour of schwann cells, that rarely under goes malignant transformation. there is no gender predilection and it presents commonly between the ages of 20–50 years.2 schwannomas are rare tumours that can develop at any site in the body and are most commonly found in the head and neck region. they are rarely located in the lower extremities where they can mimic compression neuropathies.3 in the current literature, there have been approximately 60 retroperitoneal schwannomas recorded and among them, only about 20 are in the pelvis.4 schwannomas are usually solitary tumours extending from 1–3 cm in diameter.5 here, an incidental finding of an obturator nerve schwannoma in a 65-year-old male cadaver during a routine undergraduate dissection session and its histological findings are reported. case report in the present case, during a routine undergraduate dissection, a mass on the course of the obturator nerve was discovered in a 65-year-old male cadaver the this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.016 case report abstract: schwannomas are typically benign tumours of the peripheral nerves. however, they seldom arise from the obturator nerve. we report a case of an uncommon swelling (2.5 × 3.5 cm) in a 65-year-old male cadaver, found during a routine dissection session for first bachelor of medicine and surgery students in the department of anatomy, kasturba medical college, manipal, india, in 2019. it was seen originating from the left obturator nerve in the pelvis at the level of the sacral promontory. histopathological investigation revealed a schwannoma. the hypocellular tumour was arranged in a sweeping fascicle pattern with patches of myxoid degeneration. obturator schwannomas, though rare, can exist in cadavers, as seen in the present case. hence, it should be considered as a differential diagnosis for clinical cases of pelvic masses and eliminated only after thorough radiological examination. knowledge about the existence of such schwannomas is therefore essential. keywords: schwannoma; obturator nerves; neurilemmoma; nerve sheath neoplasms; case report; india. https://creativecommons.org/licenses/by-nd/4.0/ serendipitous discovery of a benign obturator nerve schwannoma case report with a brief clinical review 478 | squ medical journal, august 2021, volume 21, issue 2 (pnsts) and arise from schwann cells of the outer nerve sheath, i.e. the epineurium.2 they are rare tumours that can develop at any site in the body. only 13% of pnsts arise in the trunk; approximately 3% are retroperitoneal and the incidence of retroperitoneal location of a schwannoma is 0.5–5%.4 schwannomas are benign, well-circumscribed lesions with 30–40 years being the peak age at diagnosis. the world health organization classifies schwannomas as grade 1 tumours that are generally benign and whose malignant transformation is extremely rare.6 they may be present with neurological manifestations such as pain in the limbs, paraesthesia and motor weakness due to compression of the adjacent structures or may be found incidentally as asymptomatic masses.7 the low incidence is due to the fact that there are no specific signs and symptoms as the tumours develop in the broad area of the retroperitoneum.8 the clinical manifestations are produced only after the tumours have grown to a substantial size; hence, there is a long latency period. the tumours, when large enough, cause pressure symptoms through compression or displacement of adjacent structures.9 as the tumours are deep-seated in the retroperitoneum, often on ultrasound they are erroneously seen as gynaecological tumours, only to be proven wrong during surgery.10,11 therefore, as confirmed in most of the clinical cases after surgery and definitive histopathological examination, presurgical diagnosis is very challenging.12,13 the computed tomography (ct) and magnetic resonance imaging (mri) narrow the diagnosis but are not able to assess it as imaging features are not specific to any type of tumour.4 laparoscopic resection is the treatment of choice with favourable post-operative recovery.14 benign peripheral nerve sheath tumours are classified into two main groups: neurofibromas and schwannomas. the distinction of schwannomas from neurofibromas is of importance to surgeons as schwa nnomas can be easily enucleated using laparoscopic surgery while preserving nerve contiguity. however, neurofibromas are intraneural; hence, resection without nerve deficits is difficult.15 the characteristic of a peripheral nerve sheath tumour is the identification of a nerve that is proximal and distal to the mass. however, this may be difficult to visualise as the nerve itself may be compressed or distorted by the tumour.16 histologically, schwannomas can be differentiated from other peripheral nerve tumours by the presence of capsule and fascicular growth patterns, increase in nuclear size and large nuclear hyperchromasia.9 areas of elongated cells that are densely packed, arranged in fascicles and showing an antoni type a pattern may be seen, forming verocay bodies when they are prominent. cells are less compact and prone to cystic degeneration in the antoni type b pattern.4 large schwannomas generally go through progressive degenerating alterations, comprising of cyst formation and hyalinisation of vessels. benign schwannomas have large expanses of eosinophilic atypical round cells, whereas their epithelioid appearance is seen when they undergo malignant transformation.17 in the current case, histopathology showed a distinct capsule with an antoni b pattern of fascicular cells. degenerative changes were not observed.18 obturator nerve schwannomas should be cons idered a differential diagnosis when dealing with cases figure 1: showing schwannoma (*) in the retroperi toneal area of the pelvis originating from the left obturator nerve in a 65-year-old male cadaver in the department of anatomy, kasturba medical college, manipal, india, in december 2019. lst = lumbosacral trunk; u = ureter; pm = psoas major; sp = sacral promontory; iaa = internal iliac artery. figure 2: a: histology of schwannoma using haematoxylin and eosin (h&e) staining at ×40 magnification in a 65-year-old male cadaver showing a flattened nerve fascicle in the periphery (arrow). in addition, it shows the capsule with the three layers (epineurium, perineurium and endoneurium) enclosing the tumour (arrowhead) and fascicle pattern with patches of mixed degeneration (asterisk). b: histology of normal obturator nerve of the right-side using h&e staining at ×40 magnification showing the bundles of nerve fascicles enclosed in the perineurium (arrows). suhani sumalatha, nikhila appala, ashwija shetty, deepak nayak, sushma prabhath and nandini p. bhat case report | 479 of a pelvic mass. as the obturator nerve is in close proximity to vital pelvic structures, the symptoms arising from these growing masses usually mimic gynaecological or urological tumours.19,20 literature cites schwannoma cases misdiagnosed as lymph node metastasis and ovarian malignancies before surgery.21–23 most of the cases of obturator schwannomas that have been reported in the literature were diagnosed postoperatively, only after laparoscopic resection and pathological examination [table 1].10,13 however, a case reported by takahashi et al. diagnosed the obturator nerve tumour preoperatively, as the ct and mri showed clear continuity with the obturator nerve.24 being in an anatomically complex and surgically inaccessible site with surrounding vital structures, pelvic tumour enucleation necessitates familiarity and knowledge of the pelvic retroperitoneal anatomy to avoid damage to the adjacent vascular and urinary structures.25 conclusion there is a varied range of benign and malignant tumours in the pelvic retroperitoneum. the patients commonly present with vague pain at a very late stage when the tumour is large. cts and mris help significantly in diagnosis; however, the imaging features are non-specific and diagnosis is confirmed only by postoperative histopathology. this report concludes that obturator schwannomas, though very rare, can occur in unusual locations, as seen in this cadaveric dissection. hence, it should be considered as a differential diagnosis for cases of pelvic masses and should be ruled out only after careful investigation. a u t h o r s’ c o n t r i b u t i o n ss contributed to the concept and design of the report. na and as contributed in the acquisition and compilation of data. dn contributed with data analysis and interpretation. sp contributed with the table 1: cases of pelvic retroperitoneal schwannoma in the current literature author and year of publication number of cases presenting complaint radio diagnosis laparoscopic resection and postoperative pathological diagnosis di furia et al.20 (2018) one case dysuria and strangury ct – well circumscribed mass pelvic schwannoma chopra et al.13 (2017) one case left pelvic pain of unknown origin ct – multi-loculated cystic mass on lateral pelvic wall obturator schwannoma gleason et al.11 (2017) one case pelvic pain diagnosed as ovarian malignancy mri – 2.6 × 2.1 × 2.7 cm mass adjacent to the left pelvic sidewall benign obturator nerve schwannoma yamada et al.23 (2015) one case lymph node metastasis of rectal cancer ct and mri – 15-mm tumour benign obturator nerve schwannoma coskun et al.21 (2016) one case initially diagnosed as pelvic metastasis of right kidney mass ct – a well demarcated left iliac mass of 30*29 cm benign obturator nerve schwannoma takahashi et al.24 (2016) one case left lower abdominal pain ct and mri – a mass of 30 mm benign obturator nerve schwannoma okuyama et al.22 (2014) one case diagnosed as a mesenteric tumour ct and mri – heterogeneous tumour, 5 cm in diameter, in the pelvic cavity pelvic schwannoma takaaki et al.25 (2013) one case anal pain ct and mri – prominent cystic degeneration and calcification. pelvic schwannoma ningshu et al.14 (2012) six cases 3 incidental, 3 vague pelvic pain one case preoperatively diagnosed pelvic schwannoma aubert et al.19 (2000) one case urological manifestations ct – mass in paravesical position pelvic schwannoma scotto et al.10 (1998) one case not specified no obturator schwannoma hunter et al.12 (1988) two cases asymptomatic no retroperitoneal schwannoma ct = computed tomography; mri = magnetic resonance imaging. serendipitous discovery of a benign obturator nerve schwannoma case report with a brief clinical review 480 | squ medical journal, august 2021, volume 21, issue 2 critical review of the manuscript. npb contributed to the preparation and drafting of the manuscript. all authors approved the final version of this manuscript. references 1. anagnostopoulou s, kostopanagiotou g, paraskeuopoulos t, chantzi c, lolis e, saranteas t. anatomic variations of the obturator nerve in the inguinal region. reg anesth pain med 2009; 34:33–9. https://doi.org/10.1097/aap.0b013e3181933b51. 2. knight d, birch r, pringle j. benign solitary schwannomas. j bone joint surg br 2007; 89-b:382–7. https://doi.org/10.1302/0 301-620x.89b3.18123. 3. albert p, patel j, badawy k, weissinger w, brenner m, bourhill i, et al. peripheral nerve schwannoma: a review of varying clinical presentations and imaging findings. j foot ankle surg 2017; 56:632–7. https://doi.org/10.1053/j.jfas.2016.12.003. 4. borghese m, corigliano n, gabriele r, antoniozzi a, izzo l, barbaro m. benign schwannoma of the pelvic retroperitoneum. report of a case and review of the literature. g chir 2000; 21:232–8. 5. gosk j, gutkowska o, urban m, wnukiewicz w, reichert p, ziółkowski p. results of surgical treatment of schwannomas arising from extremities. biomed res int 2015; 2015:547926. https://doi.org/10.1155/2015/547926. 6. nayler s, leiman c, omar t, cooper k. malignant transformation in a schwannoma. histopathology 1996; 29:189. https://doi. org/10.1046/j.1365-2559.1996.d01-491.x. 7. desai k. the surgical management of symptomatic benign peripheral nerve sheath tumors of the neck and extremities: an experience of 442 cases. j neurosurg 2017; 81:568–80. https:// doi.org/10.1093/neuros/nyx076. 8. wee-stekly w, mueller m. retroperitoneal tumors in the pelvis: a diagnostic challenge in gynecology. front surg 2014; 1:49. https://doi.org/10.3389/fsurg.2014.00049. 9. rodriguez f, folpe a, giannini c, perry a. pathology of peri pheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. acta neuropathol 2012; 123:295–319. https://doi.org/10.1007/s00401-012-0954-z. 10. scotto v, rosica g, valeri b, limiti m, corti e. benign schwannoma of the obturator nerve: a case report. am j obstet gynecol 1998; 179:816–17. https://doi.org/10.1016/s0002-9378(98)70090-0. 11. gleason t, le b, parthasarathy k, robinson-bennett b. obturator nerve schwannoma as a mimic of ovarian malignancy. cas rep obs and gyn 2017; 1–4. https://doi.org/10.1155/2017/9724827. 12. hunter vp, burke tw, crooks la. retroperitoneal nerve sheath tumors: an unusual cause of pelvic mass. obs gyn 1988; 71:1050–2. 13. chopra s, dharmaraja a, satkunasivam r, gill i. robot-assisted laparoscopic resection of a pelvic schwannoma. urol. case rep 2017; 11:63–5. https://doi.org/10.1016/j.eucr.2016.11.027. 14. ningshu l, min y, xieqiao y, yuanqing y, xiaoqiang m, rubing l. laparoscopic management of obturator nerve schwannomas: experiences with 6 cases and review of the literature. surg laparosc endosc percutan tech 2012; 22:143–7. https://doi. org/10.1097/sle.0b013e3182478870. 15. beaman f, kransdorf m, menke d. schwannoma: radiologicpathologic correlation. radiographics 2004; 24:1477–81. https://doi.org/10.1148/rg.245045001. 16. stramare r, beltrame v, gazzola m, gerardi m, scattolin g, coran a, et al. imaging of soft-tissue tumors. j magn reson imaging 2012; 37:791–804. https://doi.org/10.1002/jmri.23791. 17. mcmenamin m, fletcher c. epithelioid malignant change in benign schwannomas [abstract 54]. mod pathol 2000; 13:13a. 18. suh j, abenoza p, galloway h, everson l, griffiths h. peripheral (extracranial) nerve tumors: correlation of mr imaging and histologic findings. radiology 1992; 183:341–6. https://doi. org/10.1148/radiology.183.2.1561333. 19. aubert j, debiais f, levillain p. schwannoma of the obturator nerve with urologic manifestations: report of a case. ann urol 2000; 34:58–65. https://doi.org/10.1097/00000478-20010100000002. 20. di furia m, salvatorelli a, della penna a, vicentini v, sista f, chiominto a, et al. advantage of laparoscopic resection for pelvic schwannoma: case report and review of the literature. int j surg case rep 2018; 45:38–41. https://doi.org/10.1016/j. ijscr.2018.03.006. 21. coskun b, ozmerdiven g, mert a, kaygisiz o, vuruskan b, vuruskan h. laparoscopic management of an obturator schwann oma mimicking a lymph node metastasis in a patient with renal cell carcinoma: case report. acta medica anatolia 2016; 4:167–9. https://doi.org/10.15824/actamedica.95866. 22. okuyama t, tagaya n, saito k, takahashi s, shibusawa h, oya m. laparoscopic resection of a retroperitoneal pelvic schwa nnoma. j surg case rep 2014; 122:rjt122. https://doi.org/10.10 93/jscr/rjt122. 23. yamada m, ishii d, tani c, asai k, chisato n, miyokawa n, et al. a case of schwannoma of the obturator nerve mimicking a lateral lymph node metastasis of rectal cancer. j japan surg assoc 2015; 76:850–6. https://doi.org/10.3919/jjsa.76.850. 24. takahashi h, hara m, tsuboi k, sagawa h, ishiguro h, matsuo y, et al. laparoscopically resected obturator nerve schwannoma: a case report. asian j endosc surg 2016; 9:307–10. https://doi. org/10.1111/ases.12291. 25. takaaki n, daisuke t, yusuke n, mitsutoshi m, akihiro n, hiroshi h. a case of pelvic schwannoma presenting prominent eggshell-like calcification. case rep radiol 2013. https://doi. org/10.1155/2013/825078. https://doi.org/10.1097/aap.0b013e3181933b51 https://doi.org/10.1302/0301-620x.89b3.18123 https://doi.org/10.1302/0301-620x.89b3.18123 https://doi.org/10.1053/j.jfas.2016.12.003 https://doi.org/10.1155/2015/547926 https://doi.org/10.1046/j.1365-2559.1996.d01-491.x https://doi.org/10.1046/j.1365-2559.1996.d01-491.x https://doi.org/10.1093/neuros/nyx076 https://doi.org/10.1093/neuros/nyx076 https://doi.org/10.3389/fsurg.2014.00049 https://doi.org/10.1007/s00401-012-0954-z https://doi.org/10.1016/s0002-9378(98)70090-0 https://doi.org/10.1155/2017/9724827 https://doi.org/10.1016/j.eucr.2016.11.027 https://doi.org/10.1097/sle.0b013e3182478870 https://doi.org/10.1097/sle.0b013e3182478870 https://doi.org/10.1148/rg.245045001 https://doi.org/10.1002/jmri.23791 https://doi.org/10.1148/radiology.183.2.1561333 https://doi.org/10.1148/radiology.183.2.1561333 https://doi.org/10.1097/00000478-200101000-00002 https://doi.org/10.1097/00000478-200101000-00002 https://doi.org/10.1016/j.ijscr.2018.03.006 https://doi.org/10.1016/j.ijscr.2018.03.006 https://doi.org/10.15824/actamedica.95866 https://doi.org/10.1093/jscr/rjt122 https://doi.org/10.1093/jscr/rjt122 https://doi.org/10.3919/jjsa.76.850 https://doi.org/10.1111/ases.12291 https://doi.org/10.1111/ases.12291 https://doi.org/10.1155/2013/825078 https://doi.org/10.1155/2013/825078 department of dermatology, hospital general universitario de ciudad real, cuidad real, spain *corresponding author’s e-mail: mrogelvence@gmail.com متالزمة القدم اخلضراء ماريا روجيل فين�س، لو�صيا غونزاليز-رويز، ماركو�س كارمونا-رودريغيز، خوان لوي�س �صانتياغو green foot syndrome *maría rogel-vence, lucía gonzález-ruiz, marcos carmona-rodríguez, juan luis santiago-sm sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e112–113, epub. 9 mar 20 submitted 2 jul 19 revision req. 22 sep 19; revision recd. 8 oct 19 accepted 10 nov 19 a 51-year-old male prisoner presented to the department of dermatology, hospital general universitario de ciudad real, cuidad real, spain, in 2018. he had painful ulcers on the right foot with a foul odour, a burning sensation and pruritic eczematous lesions on both feet for the past five years. the ulcers showed intermittent course and worsened during warmer months. he had a history of ischaemic cardiomyopathy, chronic hepatitis due to hepatitis c and a past hepatitis b infection. the patient had no personal or familial history of immunosuppressive diseases. he stated that he used to wear closed and tight shoes and there was no specific foot care or foot hygiene in prison. physical examination revealed two mirror-image ulcers with irregular margins and yellow-greenish discolouration surrounding the first interdigital space on the right foot [figure 1]. maceration areas were in all interdigital spaces of both feet, while a pruritic eczematous eruption was affecting the dorsum of the right foot [figure 2]. the patient’s white blood cell count, serum c-reactive protein level, cryoglobulin level, antineutrophil cyto plasmic antibody level, antinuclear antibody level and coagulation profile were normal. an x-ray of the right foot was unremarkable. skin biopsies showed chronic granulation tissue without visualising any pathogens using ziehl-neelsen and periodic acid–schiff staining. direct examination under light microscopy of a potassium hydroxide preparation did not show any fungal hyphae or spores. cultures of cutaneous ulcers grew bacteria that were identified as pseudomonas aeruginosa. these results were confirmed by two consecutive cultures taken from skin biopsies, which also excluded mycobacteria and fungal infection. an antibiogram showed resistance to gentamycin and susceptibility to both ciprofloxacin and levofloxacin. in light of the clinical findings, results of the cultures and the antibiogram, the patient was given oral ciprofloxacin (500 mg) twice daily for 10 days. he was instructed to keep his feet dry and place gauze between the digits after cleaning the ulcers with povidoneiodine solution. in addition, the patient was instructed this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.018 interesting medical image figure 1: photograph of the right foot of a 51-year-old male prisoner showing two mirror-image ulcers with irregular margins and yellow-greenish discolouration surrounding the first interdigital space. https://creativecommons.org/licenses/by-nd/4.0/ maría rogel-vence, lucía gonzález-ruiz, marcos carmona-rodríguez and juan luis santiago-sm interesting medical image | e113 to use a topical solution of 1/1000 zinc sulphate in order to take advantage of its astringent effect. two weeks after starting the oral ciprofloxacin, the ulcers had improved and did not have a foul odor or greenish discolouration and the burning and painful sensation had dissipated. the patient provided informed consent to report his case for scientific purpose. comment p. aeruginosa is a gram-negative bacillus, which may infect the skin or deeper tissues. excessive moisture and occlusive conditions are necessary for colonisation of this bacterium and the resulting clinical manifestations.1 green foot syndrome (gfs) is an uncommon cutaneous disease caused by p. aeruginosa and is frequently associated with poor hygiene, humidity and immuno suppression.2 trench foot syndrome (tfs) is a related condition, common in military personnel, but is characterised by an acute onset and more aggressive course if not treated appropriately.3 on the other hand, gfs is less aggressive and has a chronic evolution. in gfs, chronic painful ulcers develop on the feet as a result of a p. aeruginosa infection, which can penetrate at sites of maceration, particularly, if there is dermatophytic infection in the foot.1 as in other cutaneous infections by this bacterium, a characteristic yellow-greenish colour is seen in these ulcers.4 when deep infection is suspected (i.e. painful sensation, fever, chills, etc.), antibiotic treatment should be administrated combined with topical solutions. the current patient developed a chronic skin disease consisting in painful ulcers on the dorsum of the right foot, with intermittent course, for five years. while he did not have a medical history suggestive of immunosuppressive disease and excluding any previous history of parenteral drug abuse, he did use closed and tight shoes where poor hygiene and excessive sweating facilitated the rapid growth of p. aeruginosa which most likely led to gfs. references 1. lee sh, cho sb. cast-related green foot syndrome. clin exp dermatol 2009; 34:364–5. https://doi.org/10.1111/j.1365-2230. 2009.03317.x. 2. bae jm, park ym. green foot syndrome: a case series of 14 patients from an armed forces hospital. j am acad dermatol 2013; 69:198–9. https://doi.org/10.1016/j.jaad.2013.05.012. 3. anand p, privitera r, yiangou y, donatien p, birch r, misra p. trench foot or non-freezing cold injury as a painful vasoneuropathy: clinical and skin biopsy assessments. front neurol 2017; 8:514. https://doi.org/10.3389/fneur.2017.00514. 4. garcía-martínez fj, lópez-martín i, castellanos-gonzález m, segurado-rodríguez ma. úlceras plantares verdes. enferm infec microbiol clin 2017; 35:536–7. https://doi.org/10.1016/j. eimc.2015.10.010. figure 2: photograph of the right foot of a 51-year-old male prisoner showing cutaneous maceration of the first interdigital space and eczematous skin on the dorsum. https://doi.org/10.1111/j.1365-2230.2009.03317.x https://doi.org/10.1111/j.1365-2230.2009.03317.x https://doi.org/10.1016/j.jaad.2013.05.012 https://doi.org/10.3389/fneur.2017.00514 https://doi.org/10.1016/j.eimc.2015.10.010 https://doi.org/10.1016/j.eimc.2015.10.010 squ med j, may 2011, vol. 11, iss. 2, pp. 252-258, epub. 15th may 11 submitted 27th jul 10 revision req. 11th oct 10, revision recd. 6th nov 10 accepted 1st dec 10 department of microbiology & immunology, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: basil@squ.edu.om <ì√⁄^q<h¯õ<ôç÷<ìœë¯÷]<l^âç√÷]<ÿè÷^-<4„�j÷]<ïöçœ åáe^œ<·^�◊ä÷]     50 2010   %13%23.5 98 %5.1%6.1%9.2 %4.1 %2%3.1 %65%1    :مفتاح الكلمات abstract: objectives: this study aimed to determine the disinfecting potential of some contact lens solutions used by some university students in oman. methods: this work was carried out from january to june 2010 in the department of microbiology & immunology, college of medicine and health sciences, sultan qaboos university, oman. fifty disinfecting solutions, in which contact lenses were disinfected according to the manufacturers’ instructions, were collected from the students and plated on various microbiological culture media. bacterial isolates were identified by api-20e, api-20ne and phoenix automated systems while fungi were identified by their cultural characteristics and biochemistry. results: from 98 isolates, pseudomonas aeruginosa was 23.5%; penicillium, 13%; candida species, 9.2%; coagulase negative staphylococci, 9.2%; serratia marcescens, 6.1%; bacillus, 5.1%; aspergillus flavus, 5.1%; serratia liquefaciens, pseudomonas fluorescens, enterobacter cloacae and aspergillus niger, 4.1% each; chryseomonas luteola and chryseomonas indologenes, 3.1% each; stenotrophomonas maltophilia, serratia odorifera, 2.0% each; enterobacter aerogenes and klebsiella pneumoniae, 1% each. most isolates (65%) came from polyhexanide containing solutions. conclusion: contact lens disinfecting solutions with the same formulations, but manufactured by different companies, possessed different disinfecting potentials. keywords: lenses; disinfecting; bacteria; contamination; fungi; oman the disinfecting potential of contact lens soutions used by sultan qaboos university students *b. c. nzeako and sara h. al-sumri clinical & basic research advances in knowledge 1. this is the first time this type of study has been done at sultan qaboos university. 2. it was observed that different disinfecting solutions for contact lenses are used by students at sultan qaboos university. 3. contact lens disinfecting solutions with the same formulation, but manufactured by different companies, possessed different disinfecting activity. 4. there is great need to revisit the us food and drug administration guidelines on the use of multipurpose disinfecting solutions for contact lenses and storage cases. application to patient care 1. manufacturers’ guidelines for the decontamination of contact lenses and storage cases should be rigorously followed by the wearers. b. c. nzeako and sara h. al-sumri clinical and basic research | 253 the soft contact lens industry has expanded rapidly over the past four decades because of the demand for a convenient alternative to wearing spectacles for various purposes. contact lenses wear can be for correction of eye defects (myopia, hypermetropia, astigmatism and presbyopia), may be cosmetic (decorative) or therapeutic (for the treatment and management of bullous keratopathy, dry eyes, corneal ulcers and keratitis).1 it is estimated that 125 million people worldwide use contact lenses of which 28–38 million are from usa and 13 million from japan.1 soft hydrogel contact lenses are categorised according to their structure, water content, oxygen permeability and mode of wearing (daily wear, removed each night), extended wear (worn for 6 nights) and continuous wear (worn for 30 consecutive nights).1-2 their ability to aid vision, give comfort to the wearer and prevent microbial keratitis is highly advocated.2-3 silicone hydrogel contact lenses were introduced in 1999 for this purpose. unfortunately, they are not better than other soft contact lenses for controlling microbial keratitis. corneal infections continue to be the most serious complication of wearing contact lenses.4-10 however, many people who wear contact lenses are unaware of the likelihood of developing eye infections for some bacteria colonise and form biofilms inside lens storage cases.3 in this state, they become resistant to disinfecting solutions.11-12 a study on 252 soft contact lenses, lens storage cases and disinfecting liquids found that 84.1% of the contact lenses, 80.9% of the lens storage cases and 63.1% of the disinfecting liquids were contaminated by staphylococcus aureus, staphylococcus epidermidis, viridans streptococci, klebsiella pneumoniae, pseudomonas aeruginosa, pseudomonas fluorescens, citrobacter amalonaticus and stenotrophomonas maltophilia.13 another study found 9% of lenses, 34% of lens storage cases and 11% of lens solutions contained serratia spp, s. aureus, coagulase negative staphylococci and p. aeruginosa.14 the contamination was traceable to users’ dirty hands, or the tap water used to rinse the lens storage cases, and/or air contamination during drying of the cases. flynn et al15 found contact lenses to harbour mostly gram negative and coagulase negative staphylococci. their mode of adhesion to lenses was through deposits of proteins, mucins, lipids and inorganic compounds produced by the eye.16-19 however, the results of studies on the efficacy of some contact lens solutions as effective disinfectants are conflicting.20-21 the federal drug administration (fda) recommended the mode of assessing the efficacy of multipurpose contact lens disinfecting solutions using ‘stand alone’ (iso/ cd 14729) testing procedures. in this procedure, all multipurpose solutions are required to ensure a 3-log reduction in numbers on three bacterial strains (s. aureus (atcc 6538), serratia marcescens (atcc 13880) and p. aeruginosa (atcc 9027), 1-log reduction on candida albicans (atcc 10231) and fusarium solani (atcc 36031).22 although the recommendation ensured good disinfection of lenses by achieving 3-log reduction in cell numbers,21,23 some researchers found many laboratory isolates viable in the solution20,24,25 while others observed that many microbes associated with microbial keratitis were not represented in the approved panels of microbes used for the test.26-27 disinfecting solutions containing polyhexanide were found to kill escherichia coli, s. epidermidis, p. aeruginosa, and s. marcescens while solutions containing biguanides killed e. coli and s. epidermidis, but not c. albicans.28 the reduced efficiency of some disinfecting solutions may be attributable to their formulations and mode of use.29 the aim of this study was to assess the disinfecting potential of some contact lens solutions used by some students at sultan qaboos university. it is envisaged that the results of this investigation can help establish the type of microbes in the solutions so that wearers can appropriately be advised. 2. wearers of contact lenses should be aware of the risk of developing microbial keratitis and corneal ulcers. 3. good personal hygiene during decontamination of lenses and storage cases and during removal or placement of lenses on the eyes is essential. the disinfecting potential of contact lens soutions used by sultan qaboos university students 254 | squ medical journal, may 2011, volume 11, issue 2 methods this study was carried out from january to june 2010 in the department of microbiology & immunology, college of medicine and health sciences, sultan qaboos university, oman. fifty disinfecting solutions, in which contact lenses were disinfected according to the manufacturers’ instructions, were collected from the students and plated on various microbiological culture media. no patient or patient’s sample was utilised. each contact lens user was given three sterile bijou bottles, one for the disinfecting solution for the contact lens of the right eye, the second for the left eye, while the third served as a control (same as solution for disinfecting right or left eye lenses). this was done to check the degree of sterility of the solutions before immersion of the lenses. the lenses were immersed in the solutions at night and brought to the laboratory in the morning. twelve brands of disinfecting solutions marketed by different manufacturers were investigated. the solutions were coded 1-12 to mask the manufacturers’ names and to avoid brand name promotion. i n o c u l at i o n o f m e d i a fifty microlitres of each solution were streaked on blood agar (ba, oxoid, uk), cystine electrolyte deficient (cled, h-media laboratories, india), and sabouraud (sab, biotec, uk). all the plates were incubated at 370c for 48 hrs except sabouraud plates which were incubated at room temperature for one week. bacterial growths on the plates were identified using api 20-e, 20-ne (biomerieux, france) and phoenix automated system (bacton dickinson, maryland, usa) while fungal growths were identified by their growth characteristics, the colour of aerial spores and structural differences using lactophenol cotton blue. the fda mode of testing disinfecting solutions for contact lenses (iso/cd 14729) was not followed because of non-availability of the test organisms. however, any solution that allows growth of any microbe was regarded as contaminated and the contaminating organism was identified. table 1: active agents in some contact lens disinfecting solutions and organisms isolated from them solutions (code) active agent samples (n) growth (n) isolate code 1 polyhexanide (0.0001%) 15 7 p. aeruginosa s. liquefaciens c. indologenes code 2 polyhexanide (0.0001%) 14 4 p. aeruginosa s. marcescens penicillium species code 3 polyhexamethylene biguanide (0.0001%) 1 1 p. aeruginosa code 4 tetronic sulfactant 2 2 p. aeruginosa a. flavus a. niger code 5 boric acid 2 1 a. niger code 6 polydronium chloride (0.001%) 2 2 p. aeruginosa code 7 hydroxyethyl methacrylate 1 0 no growth code 8 polyaminopropyl biguanide 6 0 no growth code 9 polyhexanide (0.0001%) 4 2 bacillus, penicillium species code 10 polyaminopropyl biguanide (0.0001%) 1 1 penicillium code 11 polyhexamethylene biguanide 1 0 no growth code 12 polyhexamethylene biguanide 1 0 no growth totals 50 20 (40%) b. c. nzeako and sara h. al-sumri clinical and basic research | 255 results although the sample sizes of the solutions were small and their manufacturers different, the same formulations marketed by different manufacturers gave different results [table 1]. forty percent (40%) of the solutions showed growth of various types of microbes. solutions containing polyhexanide had 65% growth and were used by 66% of the students. this was followed by polyaminopropyl biguanide with 5% growth and used by 14% of the students. all the microbes contaminating control solutions were present in the solutions used for the right or left contact lenses, but not all the isolates contaminating the right or left contact lenses solutions were present in the control solutions [table 2]. however, where the lens solutions and their aliquots (controls) were sterile, no organism was found. p. aeruginosa (23.5%) and penicillium spp. (13.3%) were the most common isolates while klebsiella pneumoniae and enterobacter aerogenes were the least, 1% each [table 3]. discussion soft hydrogel contact lenses are used for various purposes (corrective, cosmetic or therapeutic) and are either for daily, extended or continuous wear. users are advised to clean their contact lens cases and change disinfecting solutions daily except if they are silicone hydrogels for extended or continuous wear. contact lenses offer some advantages over spectacles in terms of convenience and better visual acuity. however, the wearing of contact lenses may lead to serious complications including microbial keratitis and corneal ulcers which may lead to blindness.7-9,30-31 in this experiment, polyhexanide containing solutions, although greater in number, were the most contaminated. in contrast, polyaminopropyl and polyhexamethylene biguanides inhibited the growth of some microbes and allowed growth of others. though their sample sizes were few, they possessed more antimicrobial properties than polyhexanides. this finding agrees with santos et al.3 and hume et al.,23 but disagrees with canoparro et al.28 who found polyhexanides better than biguanides. in this study, p. aeruginosa had a prevalence of 23.5%. the factors contributing to its survival in some lens disinfecting solutions were traceable table 2: microbes isolated from various solutions solution used for right eye lenses solution used for left eye lenses control solutions coagulase negative staphylococci coagulase negative staphylococci p. aeruginosa candida spp e. aerogenes p. aeruginosa, c. luteola e. cloacae p. aeruginosa c. luteola c. indolegenes s. marcescens penicillium c indolegenes, candida spp k. pneumoniae s. marcescens a. flavus s. liquefaciens a. flavus candida spp a. niger s. hominis bacillus s. liquefaciens penicillium e. cloacae a. flavus s. liquefaciens candida spp bacillus spp s. marcescens c. indolegenes s. marcescens s. odorifera s. marcescens c. indolegenes a. niger a. flavus a. niger bacillus penicillium spp p. fluorescens p. fluorescens s. odorifera e. cloacae p. fluorescens s. maltophilia the disinfecting potential of contact lens soutions used by sultan qaboos university students 256 | squ medical journal, may 2011, volume 11, issue 2 to its adaptability to adverse environmental conditions and capability to attach easily to corneas and contact lenses (rigid, hydrogel, high and low water content contact lenses).16,32-33 in contrast, enterobacter, serratia and klebsiella species which are usually of faecal origin can be transferred to the disinfectants by the wearers during the process of immersion or removal of the lenses from the solutions. in addition, some of the organisms like serratia and pseudomonas species are resistant to some disinfecting solutions.20 fungi like candida, penicillium and aspergillus species are adaptive to diverse environments and require little moisture and organic substrate for growth. they are likely to come from poor or inadequate cleaning of contact lens cases since bacteria interacting with contact lens storage cases form biofilms that make them resistant to disinfecting solutions.17 the nutrients for growth are acquired from lipids, proteins and glycoproteins present in the tears of the eyes.35 however, when they are present on the lenses and lens cases, the efficacy of the disinfecting solution can be neutralised by their presence.11 the isolates contaminating the control solutions also contaminated the solutions used for disinfecting left and right eye lenses. this indicates that the solutions were contaminated before the immersion of the lenses. in this study, it is observed that some control solutions were sterile although microbes were isolated from their aliquots used for disinfecting the right or left lenses [table 2]. such contamination is inferred to originate from the user (poor hand hygiene), the lenses or from the storage cases. some researchers observed that non-compliance with the guidelines for caring for contact lenses and lens cases was a major issue in the use of contact lenses.32 their observation was supported by the finding that 11% of the contamination of solutions was due to poor hand hygiene, 13% to inadequate disinfection of lenses, and 61% to inappropriate cleaning practices of storage cases.31,32 from whatever source and by whatever means, the organisms got into the solutions and some of the disinfectants could not eliminate the organisms. this experiment appears to establish the fact that disinfecting solutions for lenses are not sterilising solutions, but agents meant to reduce the microbial numbers on lenses and cases conclusion twelve disinfecting solutions for soft hydrogel contact lenses were examined for growth of microbes after lenses were removed from the eyes and immersed overnight in the disinfecting solutions. forty percent (40%) of the solutions grew some microbes, with polyhexanide containing solutions showing highest growth (65%). the least growth (5% and 5% respectively) came from polyhexamethylene and polyaminopropyl biguanides. because of the small and unequal number of samples investigated, it is statistically difficult to state which is the best disinfecting solution. the small number of samples used in this study limits the outcome of the investigation. further work using larger samples and looking for parasites like acanthamoeba is necessary. however, it is of importance that multipurpose solutions which clean, disinfect and rinse contact lenses and their cases be used for all contact lenses.17,21,24, the lenses should be stored dry in their cases after disinfection. before removing the lenses from the eyes, the user should wash his/her hands thoroughly in soapy water. if a multipurpose solution containing hydrogen peroxide is used for disinfecting the lenses, the lenses should be rinsed several times in saline solution to get rid of the hydrogen peroxide which is toxic to the eyes.35 it should be borne in mind by all contact lens users that the disinfecting solutions do not sterilise contact lenses and lens cases, but only reduce the microbial load on them. the reduction is only possible if the organisms to be reduced are susceptible to formulations in the disinfecting solutions. currently, the performance of disinfecting solutions for all types of contact lenses is being re-visited and various formulations are being suggested.20,21 c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g e m e n t s the authors are grateful to the department of microbiology & immunology for providing the media and the reagents used for the study and for their cooperation throughout the duration of the work. b. c. nzeako and sara h. al-sumri clinical and basic research | 257 references 1. morgan pb, woods ca, tranoudis ig, efron n, knajian r, grupcheva cn, etal. international contact lens prescribing in 2008. contact lens spectrum 2009; 24:28–32. 2. willcox md, harmis n, cowell ba, williams t, holden ba. bacterial interactions with contact lenses, effects of lens material, lens wear and microbial physiology biomaterials 2001; 22:3235−47. 3. santos l, rodrigues d, lira m, elisabete m, olivera r, vilar e, et al. the influence of lens material and lens wear on the removal and viability of staphylococcus epidermidis. cont lens anterior eye 2008; 31:126−30. 4. stapleton f, edwards k, keay l, naduvileth t, dart jkg, brian g, et al. the incidence of contact lens related microbial keratitis in australia. invest ophthalmol vis sci 2005; 46: e-abstract 5025. 5. radford cf, stapleton f, minassian dc, dart jkg. risk factors for contact lens related microbial keratitis: interim analysis of case control study. invest ophthalmol vis sci 2005; 46 e-abstract 5026. 6. green m, apel a, stapleton f. risk factors and causative organisms in microbial keratitis. cornea 2008; 27:22−7. 7. keay l, edwards k, naduvilath h, taylor h, snibson g, forde k, et al. microbial keratitis: predisposing factors and morbidity 2006; 113:109–116. 8. butler tk, spencer na, chan cc, singh-gilhotra j, mcclellan k. infective keratitis in older patients: a 4 year review 1998-2002. br j ophthalmol 2005; 89:591–6. 9. bourcier t, thomas f, borderie v, chaumeil c, laroche l. bacterial keratitis predisposing factors, clinical and microbiological review of 300 cases.br j ophthalmol 2003; 67:834—8. 10. liu z, pflugfelder sc. the effects of long term contact lens wear on corneal thickness, curvature and surface regularity. ophthalmol 2000; 107:105– 11. 11. brinex wj, roig-sagues ax, herrero hmm, lopezpedemonte g.b. bacterial efficacy of peracetic acid in combination with hydrogen peroxide against pathogenic and non pathogenic strains of staphylococcus spp, listeria spp and escherichia coli. food control 2006; 17:516–21. 12. dart j. the inside story: why contact lenses become contaminated. cont lens anterior eye 1997; 20:113– 118. 13. velsaco j, bermudez j. comparative study of the microbial flora on contact lenses, in lens cases and in maintenance liquids. int contact lens clin 1996; 23:55–8. 14. micallei c, cuschien p, bonnici mr. contamination of contact lenses related sources with pseudomonas aeruginosa. int j ophthalmol 2000; 214:324–31. 15. flynn s, pearlman e, ghannoum m. microbial contamination of contact lenses, lens care solutions and their accessories. eye contact lens 2010; 36:29– 116. 16. kodjikian l, casoli-bergeron e, malet f, janinmanificat h, freney j, burillon c, et al. bacterial adhesion to conventional hydrogel and new silicone hydrogel contact lens materials. graefes arch clin exp ophthalmol 2008; 246:267–73. 17. imamura y, chadra j, mukherjee pk, lattif aa, szoztkafynn lb, pearlman e, et al. fusarium and candida albicans biofilms on soft contact lenses: model development, influence of lens type and susceptibility to lens care solutions. antimicrob agents chemother 2008; 52:171–82. 18. hiti k, walochnik j, haer-scholer em, faschinger c, aspock h. viability of acanthamoeba after exposure to multipurpose disinfecting contact lens solution and to hydrogen peroxide systems. br j ophthal 2002; 86:144–6. 19. williams tj, willcox md, schneider rp. interactions of bacteria with contact lenses: the effect of soluble protein and carbohydrate on bacterial adhesion to contact lenses. optom vis sci 1998; 75:71–266. table 3: percentage distribution of isolates from all solutions no. organisms no. of isolates percentage 1 p. aeruginosa 23 23.5% 2 penicillium spp. 13 13.3% 3 candida spp. 9 9.2% 4 coagulase negative staphylococci 9 9.2% 5 s. marcescens 6 6.1% 6 aspergillus flavus 5 5.1% 7 bacillus 5 5.1% 8 s. liquefaciens 4 4.1% 9 p. fluorescens 4 4.1% 10 e. cloacae 4 4.1% 11 aspergillus niger 4 4.1% 12 c. luteola 3 3.1% 13 c. indolegenes 3 3.1% 14 stenotrophomonas maltophilia 2 2.0% 15 s. odorifera 2 2.0% 16 e. aerogenes 1 1.0% 17 k. pneumoniae 1 1.0% total 98 100% the disinfecting potential of contact lens soutions used by sultan qaboos university students 258 | squ medical journal, may 2011, volume 11, issue 2 20. willcox mdp, carnt n, diec j, naduvilath t, evans v, stapleton f, et al. contact lens case contamination during daily wear of silicon hydrogels. optom vis sci 2010; 87:456–64. 21. boost m, lai sm, cho p. do multipurpose contact lens disinfecting solutions work effectively against non fda/iso recommended strains of bacteria and fungi? ophthal physiol opt 2010; 30:12–19. 22. fux ca, shirtiff m, stoodley p, costerton jw. can laboratory reference strains mirror ‘real world’ pathogenesis? trends microbiol 2005; 3:58–63. 23. hume ebh, cole nhc, willcox ls. efficacy of contact lens multipurpose solutions against serratia marcescens. optom vis sci 2007; 84:316–20. 24. hume ebh, flanagan j, masouli s, zhu h, cole n, willcox mdp. soft contact lens disinfection solution efficacy: clinical fusarium isolates vs atcc 36031. optom vis sci 2009: 86:415–19. 25. jones jc. serious eye infection due to contact lens solutions. cdc/fda health advisory, may 2007. 26. rau g, seedor ja, sha mk, ritterband dc, koplin rs. incidence and clinical characteristics of enterococcus keratitis. cornea 2008; 27:895–9. 27. pachigolla g, blomquist p, cavanagh hd. microbial keratitis pathogen and antibiotic susceptibility: a 5 year review of cases at an urban county hospital in north texas. eye contact lens 2007; 33:45–9. 28. cano-parro j, bueno-gimeno i, lainz b, cordoba j, montes-mico r. antibacterial and antifungal effects of soft contact lens disinfection solutions. cont lens anterior eye 1998; 22:83–6. 29. rosenthal ra, dassanayake nl, schlitzer rl, schlech ba, meadows dl, stone rp. biocide uptake in contact lenses and loss of fungicidal activity during storage of contact lenses. eye contact lens 2006; 32:262–5. 30. cheng kh, leung sl, hoekman h, beekhuis wh, mulder pg, georards a, et al. incidence of contact lens associated microbial keratitis and its related morbidity. lancet 1999; 354:174–5. 31. yung ms, boost m, cho p, yap m. microbial contamination of contact lenses and lens care accessories of soft contact lens wearers in hong kong university students. ophthalmic physiol opt 2007; 27:11–21. 32. weissman ba, mondino bj. risk factors for contact lens associated microbial keratitis. cont lens anterior eye 2002; 25:3–9. 33. susanne g, wingender j, flamming h. capability of mucoid pseudomonas aeruginosa to survive in chlorinated water. int j hyg environ health 2001; 204:139–42. 34 wu y, carnt n, stapleton f. contact lens user profile, attitudes and level of compliance to lens care. cont lens anterior eye 2010; 377:1–6. 35 hughes r, kilvington s. comparison of hydrogen peroxide contact lens disinfection systems and solutions against acanthamoeba polyphaga. antimicrob agents chemother 2001; 45:50–7. squ med j, august 2011, vol. 11, iss. 3, pp. 318-321, epub. 15th aug 11 submitted 27th jun 11 accepted 3rd jul 11 in this issue of the journal, there are three public health articles that are closely related in their clinical relevance and pertinence to the situation in oman.1,2,3 first, in our sounding board section, dr. prashanth panduranga et al.1 writes a provocative article regarding the statistics and management of acute coronary syndrome (acs) in oman using the data from the gulf registry of acute coronary events (race) database. second, in another sounding board article, dr. alyaarubi stimulates us to rethink our strategies for the care of the diabetic patient in oman.2 third, dr. rashid al-saadi et al. present their original research on the prevalence of uncontrolled hypertension (htn) amongst outpatients attending the health clinics in one region of oman.3 the combination of poor diabetes control and uncontrolled htn is responsible for a great percentage of the incidence of acs and the accompanying complications, as discussed by dr. panduranga and his team. these two conditions are commonly accompanied by other risk factors for acs, including overweight, obesity, metabolic syndrome and hyperlipidaemia. these chronic non-communicable diseases, which form the bulk of risk factors for coronary heart disease, need our attention as physicians and medical educators as the public has entrusted us with the care of their health. acs is basically the clinical syndrome of an acute occlusion within what is commonly an already diseased coronary artery. this often presents as unstable angina and can lead to myocardial infarction with or without st segment elevation. aetiologically, coronary artery disease is closely tied to htn, diabetes mellitus (dm), dyslipidaemia, metabolic syndrome and obesity among other factors. the two major factors, diabetes and htn, are clearly described in this issue as being sub-optimally managed in oman. in addition, obesity and metabolic syndrome are described as significant hazards to the health of omanis. thus, we as physicians have to rethink our strategies for the management of coronary artery disease. the ministry of health (moh) is the guardian of the health of omanis and hence has to take the initiative in novel ways to reduce the prevalence of poorly controlled diabetes and uncontrolled htn among its citizens so that we can adequately reduce the incidence of acs and other complications of these chronic diseases. clearly, we must start by improving management of the root causes, especially diabetes and htn. both are major contributors to the burden of chronic non-communicable diseases in oman and throughout the world. dr. jawad al-lawati et al. pointed out that cardiovascular disease is “currently the leading cause of death” in oman.4 they go on to explain, “unless reforms are introduced to the current health care system, chronic diseases will constitute a major drain on oman’s human and editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, oman. *email: mjournal@squ.edu.om <≈^àiö]ê<îü” �ä÷]<öü⁄ê<ïå^£]<íq^j÷]<·^ëüé÷]<ì⁄á¯j⁄ ›ç÷]<º«ï ìëç√π]<4∆<ìfl⁄àπ]<ö]ü⁄˙÷<2“_<^⁄^€j‚]<í÷ái<·_<·^€ �¬<ó◊¬  editorial acute coronary syndrome, diabetes and hypertension oman must pay more attention to chronic non-communicable diseases lamk al-lamki lamk al-lamki editorial | 319 financial resources” as these diseases form 75% of the disease burden in oman.4 the list includes diabetes, htn, obesity, metabolic syndrome and hyperlipidaemia, which are specifically discussed in articles in this issue. the implication of such dire a situation is that oman needs to rethink its strategies for dealing with this emerging epidemiology. the moh needs to reposition its priorities and give increased attention to the management of these chronic non-communicable diseases in oman. management of dm needs special attention from the moh and from physicians in oman. we cannot afford to take this responsibility lightly and invest our energy in controlling diabetes and these other chronic non-communicable diseases. dr. alyaarubi points out that the incidence of dm is increasing in children who now have an earlier and higher incidence of type 2—a condition which is traditionally looked upon as a disease of adults. he also alerts us to the fact that in the last few years there have been several innovations in the management of diabetes including new oral hypoglycaemic medication and bioengineered (analogue) insulin; newer delivery tools, such as insulin pumps, and follow-up tools such as hba1c, as well as internationally recommended guidelines. unfortunately we, in oman, have not capitalised on these innovations.2 there is however, a great need for us to keep up with these developments. dm cannot be adequately managed either by a typical family practitioner who is overworked and inadequately equipped for proper diabetes care, or by a typical general internist for that matter. there need to be specialised diabetes care clinics—at least two in the capital area and one in each region. more doctors need to be sent abroad to major diabetic centres in the world to specialise and become expert diabetologists. oman needs to train nurses to become diabetes educators, social workers and therapists in the complications and care of dm, and train or hire podiatrists. every diabetic clinic should have a resident nutritionist and for other primary care clinics there should be at least a visiting nutritionist, perhaps one day in each primary care clinic. nutritionists are needed not only for counselling diabetics about their diet, but also to manage overweight, obesity and hyperlipidaemia, all of which are major problems in oman as in most countries.4 we need formal and informal classes to educate patients about their disease, to train them to test their own urine and blood, and to understand the importance of good diabetes control, the meaning of the various laboratory results and the potential complications.2 our government will have to invest more in the care of diabetes and other chronic noncommunicable diseases. we need to take seriously into consideration what dr. alyaarubi has conveyed in this issue. we have to pay more attention to diabetes because it is a killer. it is a major cause of cardiovascular disease, known since the framingham study,5 and now shown to be the case in oman.1 other workers have shown that dm not only leads to coronary heart disease, but also “diabetic patients with acute coronary syndromes had worse 30-day and 6-month outcomes, particularly those without st segment elevation”.6 statistically, the incidence of myocardial infarction in diabetics is as high as in patients who have had a previous infarction.7 there are several other publications pointing to diabetes and htn as major factors leading to coronary heart disease.8-11 the risk factors for coronary heart disease were well established by the turn of the century.9-11 thus, the importance of these three major chronic noncommunicable diseases and their interrelationship has to be tackled with determination, dedication and passion. the moh needs to invest a significant portion of its finance and manpower in these diseases as well as other chronic non-infectious diseases, including obesity, metabolic syndrome and hyperlipidaemia all of which contribute to the high mortality and morbidity accompanying acs. oman can succeed in this effort as it has a history of previous public health successes such as the vaccination of the paediatric population and the eradication of polio and other serious childhood maladies for which it has been commended by the world health organization. dr. al-saadi et al.'s article reveals that not only is diabetes poorly controlled among patients at oman primary care health centres (phc), but that we also have a major problem with htn control. only 39% of patients attending the phc in seeb (a district in the muscat capital area) have their blood pressure (bp) under control as per the criteria described in the 7th report of the joint national committee on prevention detection evaluation & treatment of high blood pressure (jnc-7).2,12 this is a situation acute coronary syndrome, diabetes and hypertension oman must pay more attention to chronic non-communicable diseases 320 | squ medical journal, august 2011, volume 11, issue 3 that can be significantly improved by modifying health care delivery in oman—through action by both doctors and the government. in fact, the situation is worse than the overall 61% uncontrolled bp—“74% of the total subjects were overweight (27%) or obese (47%). of those who were obese, 69% failed to achieve their bp targets”.3 if barbados can achieve 58% control of htn and some veterans administration hospitals in usa can achieve nearly 70%, then why not oman? we have managed to surpass many western countries in our vaccination rate13 so likewise we should be able to do the same with the bp control rate. an inadequate control rate of 61%, will almost certainly contribute to the incidence of acs and its complications. when inadequate bp control is combined with diabetes, then we are treading on dangerous territory. the management of htn must be carried out by well-trained physicians and specially trained staff. this should be carried out at specialised clinics, or at least where there is adequate support from other health care workers. we need to send doctors to train specifically in the management of htn and its complications. each newly diagnosed case of htn needs to be thoroughly investigated by specially trained personnel to rule out secondary causes. these are well outlined in the jnc-7 report.12 the management of htn has to follow either these guidelines or other internationally recognised evidence-based guidelines. physicians need to change their attitude and behaviour. for example jnc-7 recommends thiazides for stage i htn (140–159 systole or 90–99 diastole), and to use a two drug combination for stage 2 htn (>160 or >100), as well as to use educators to help patients lose weight since bp can fall 5–20 mmhg per 10 kg of weight loss.12 they also recommend adopting the dash (dietary approaches to stop hypertension) eating plan (fruit vegetables, low fat, low salt and exercise to achieve a 2–14 mmhg bp drop) while intensive lifestyle modification should be pursued in all individuals with metabolic syndrome. this is just an example from the simplified guidelines for family practioners.12 more complex guidelines are available for specialty centres from the same reference. however, it is clear that we need specialised personnel in order to improve our statistics for controlled htn in oman. co-morbidities are common in htn, including overweight and obesity, metabolic syndrome, hyperlipidaemia and diabetes; these, singly or collectively, lead to acs. oman needs to invest in training health care providers, not only by sending more physicians abroad (to become cardiologists, endocrinologists, lipid specialists), but also by training patient educators, dieticians/nutritionists, therapists, social workers, and establishing patient-centred behavioural interventions such as counselling. patients have to understand bp goals, weight targets and the potential complications as well as the importance of compliance.12 the two papers discussed above2,3 are disturbing to many of us who were not aware that these two major health hazards, htn and diabetes, are not adequately taken care of in the phcs of our country. these two are major contributors to acs, the subject of another paper in this issue by dr. panduranga and his colleagues.1 in their analysis of the gulf race database they have uncovered that among the omani patients with acs, we have a higher prevalence of diabetes mellitus, heart failure and unstable angina, and that there are also problems with management of acs and its complications in oman.1 thus we do indeed have a problem in oman with respect to how we deal with not only the chronic non-communicable diseases such as htn and diabetes, but also their consequence coronary heart disease. among the steps that can be taken immediately to cope with the high incidence of acs is, first, to send more doctors abroad to study different aspects of cardiology such as interventional cardiology, then to set up more emergency centres able to cope with cardiac emergencies and train doctors to be more aggressive in their treatment not only of young patients, or those in good condition who are low risk patients, but also of those patients who are considered intermediate or high risk and are being currently avoided by most cardiologists in oman.1 dr. panduranga et al. suggest that this contributes to the dismally low national percentage (11%) of the utilisation of cardiac catheterisation and angiography.1 this is further complicated by the fact that the whole of oman with its c. 3,000,000 citizens has only two cardiac catheterisation facilities. this is despite the fact, established in the literature, that primary catheterisation is of significant benefit in acs: “primary percutaneous coronary intervention (pci), compared with fibrinolysis, will save lives, enhance myocardial recovery, prevent intracranial lamk al-lamki editorial | 321 bleeding, stroke, reinfarction, and recurrent ischaemia, and otherwise enhance cardiovascular outcomes”.14 the tremendous progress in survival and reduced morbidity in the last several years has been attributed to the use of coronary care units and reperfusion efforts. fibrinolysis saves lives, but early pci in patients with st elevation myocardial infarction (stemi) can double the benefit.14 this reperfusion effort needs a catheter laboratory and oman needs more of these. this effort also needs well-trained doctors and these are also in short supply here. it also needs a good quality assurance programme with physicians who are willing to treat more aggressively as primary pci saves lives and can reduce complications including with better myocardial recovery.14,15 urgent diagnostic catheterisation is now also recommended for nonstemi. “primary pci” is also superior to “rescue pci” after failed thrombolysis.16 thus, with only two cardiac catheterisation centres in the country, the concern is genuine and needs to be taken seriously by the health authorities. likewise the concern that physicians in oman are not following international recommended guidelines for management of acs also needs tackling.1 these guidelines are evidencebased17 and we should either adhere to them, or to other evidence-based guidelines that are accepted internationally. another concern in the care of coronary heart disease in oman is the lack of positron emission tomography (pet) scanners, an important tool not only in the early diagnosis of coronary heart disease, but also in the noninterventional diagnosis of myocardial viability. squmj hereby extends an open invitation to scholars and researchers in oman to write about the other major chronic non-communicable diseases in oman particularly those that contribute to, or directly lead to coronary heart disease and acs. are these diseases managed optimally or not? if not, how bad is the situation and how can it be improved? we doctors, and the other allied health care providers of oman, need to help the moh in improving the health of our citizens. the moh cannot do it alone, but it does need to take the initiative and the bulk of the responsibility. references 1. panduranga p, sulaiman k, al-zakwani i. acute soronary syndrome in oman: results from the gulf registry of acute coronary events. squ med j 2011; 11:338–42. 2. alyaarubi s. diabetes care in oman: obstacles and solutions. squ med j 2011; 11:343–48. 3. al-saadi r, al-shukaili s, al-mahrazi s, al-busaidi z. prevalence of uncontrolled hypertension in primary care settings in al seeb wilayat, oman. squ med j 2011; 11:349–56. 4. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008. from: http://www.cdc.gov/pcd/issues/2008/ jul/07_0086.htm. accessed jun 2011. 5. kannel wb, mcgee dl. diabetes and cardiovascular disease, the framingham study. jama 1979; 241:2035–8. doi: 10.1001/jama.1979.03290450033020. 6. mcguire dk, emanuelsson h, granger cb, magnus ohman e, moliterno dj, white hd, et al. influence of diabetes mellitus on clinical outcomes across the spectrum of acute coronary syndromes. findings from the gusto-iib study; eur heart j 2000; 21:1750–8. 7. haffner sm, lehto s, rönnemaa t, pyörälä k, laakso m. mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. n engl j med 1998; 339:229–34. 8. panduranga p, sulaiman k, al-lawati j, al-zakwani i. relationship between admitting nonfasting blood glucose and in-hospital mortality stratified by diabetes mellitus among acute coronary syndrome patients in oman. heart views 2011; 12:12–17. 9. wilson pwf, d'agostino rb, levy d, belanger am, silbershatz h, kannel wb. prediction of coronary heart disease using risk factor categories. circulation 1998; 97:1837–47. 10. turner rc, millns h, neil haw, stratton im, manley se. matthews rd, et al. risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: united kingdom prospective diabetes study (ukpds: 23). bmj 1998; 316:823–8. 11. sowers jr, epstein m, frohlich ed. diabetes, hypertension, and cardiovascular disease: update. hypertension 2001; 37:1053. 12. seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc 7 express). from: http:// www.nhlbi.nih.gov/guidelines/hypertension/jncintro. htm accessed jun 2011. 13. lamki l. un millennium development goals and oman: kudos to oman on its 40th national day. squ med j 2010; 10:301–5. 14. eeckhout e. rescue percutaneous coronary intervention: does the concept make sense? heart 2007; 93:632–8. doi:10.1136/hrt.2005.074849. 15. stone gw. angioplasty strategies in stsegment elevation myocardial infarction: part ii. circulation 2008; 118;552–6; doi: 10.1161/ circulationaha.107.739243. 16. ndrepepa g, schömig a, kastrati a. the only better alternative to rescue percutaneous coronary intervention is primary percutaneous coronary intervention. j am coll cardiol 2009; 54:127–9. doi: 10.1016/j.jacc.2009.03.045. 17. wright rs, anderson jl, adams cd. 2011 accf/ aha focused update of the guidelines for the management of patients with unstable angina/non st-elevation myocardial infarction. j am coll cardiol 2011; 57:1920–59. doi: 10.1016/j.jacc.2011.02.009. squ med j, december 2009, vol. 9, iss. 3, pp. 279-286, epub. 19th dec 2009 submitted 4th apr 09 revision req. 28th june 09. revision recd. 1st sept 09 accepted 9th sept 09 oral health department, sultan qaboos university hospital, muscat, sultanate of oman. email: abakathir@squ.edu.om عمليات جراحة الفم الصغرى للمرضى املعاجلني بعقار الورفرين دراسة استعادية ملدة مخس سنوات مبستشفى جامعة السلطان قابوس، سلطنة ُعمان عبدالعزيز عبداهلل باكثير امللخص: الهدف: عمليات جراحة الفم الصغرى للمرضى املعاجلني بعقار الورفرين حتمل خطر النزيف بعد اجلراحة. الغرض من هذه الدراسة هو حتليل ووصف الوضع الطبي واجلراحي ملرضى عقار الورفرين الذين خضعوا لعمليات جراحة الفم الصغرى في مستشفى جامعة السلطان قابوس. ممن يستخدمون عقار الورفرين وكان معدل التقييس العاملي لهم الطريقة: ضمت هذه الدراسة االستعادية 124 مريضا (41 ذكرا و 83 أنثى) 3.5≥ قبل خضوعهم لعمليات جراحة الفم بدون وقف العقار حتت التخدير املوضعي خالل فترة 5 سنوات من يناير 2004 إلى ديسمبر 2008. النتائج: خضع 90 مريضا (%72.6) لعمليات خلع أسنان بسيطة، و 26 (%21) خللع جراحي لألسنان، و6 (%4.8) لعمليات خزعة لنسيج فمي لني وحالتني (%1.6) الستئصال جذر السن مع إزالة التكيس. مت عمل اإلجراءات املوضعية لوقف النزيف جلميع املرضى حيث شملت وضع قطن خاص إليقاف النزيف وخياطة اجلرح. تعرض 8 مرضى (%6.5) لنزيف بسيط بعد عمليات جراحة الفم، 5 منهم خضعوا لقلع أسنان جراحي و 3 خللع أسنان بسيط، حيث تطلب عودتهم للمستشفى. مت معاجلة جميع حاالت النزيف بطريقة حتفظية عن طريق إعادة تلفيف و خياطة موقع النزيف بدون احلاجة إلدخال املريض للمستشفى. اخلالصة: ميكن إجراء عمليات جراحة الفم الصغرى للمرضى املعاجلني بعقار الورفرين بأمان دون احلاجة إليقاف العقار عندما يكون معدل التقييس العاملي 3.5≥ قبل العملية مع استخدام الطرق املوضعية املناسبة لوقف النزيف. مفتاح الكلمات: عقار الورفرين، خلع األسنان، جراحة الفم، نزيف ما بعد العملية، املضاعفات. abstract: objectives: minor oral surgery (mos) procedures in warfarinised patients carry the risk of post-operative bleeding. the aim of this study was to conduct a retrospective analysis and to describe the profile of warfarinised patients who underwent mos procedures at sultan qaboos university hospital. methods: a retrospective study of 124 warfarinised patients (41 men and 83 women), who had a pre-operative international normalised ratio (inr) of ≤ 3.5 and underwent different mos procedures under local anaesthesia, without discontinuation of their warfarin therapy, was carried out over a 5-year period from january 2004 to december 2008. results: ninety (72.6%) patients had simple dental extractions, 26 (21%) surgical extractions, 6 (4.8%) soft tissue biopsies and 2 (1.6%) had apicectomies with cyst enucleations. local measures were applied in all patients, which included the use of oxidizing regenerated cellulose haemostatic agent (surgicel) and suturing. a total of eight patients (6.5%), five who had surgical extractions and three who had simple extractions, bled enough post-operatively to require a return to hospital. all cases of post-operative bleeding were managed conservatively by repacking the bleeding site with haemostatic agent and re-suturing without the need for hospital admission. conclusion: minor oral surgery procedures can be safely conducted in warfarinised patients without interruption of warfarin regimen when the pre-operative inr is ≤ 3.5 and appropriate local haemostatic measures are used. keywords: warfarin; tooth extraction; oral surgery; postoperative haemorrhage; complications. minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman abdulaziz a bakathir clinical & basic research advances in knowledge 1. this study adds support to the available literature on the safety of conducting minor oral surgery procedures (mos) in warfarinised patients without interruption of their warfarin therapy. minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 280 | squ medical journal, december 2009, volume 9, issue 3 warfarin, the most commonly prescribed oral anticoagulant, is a vitamin k competitive antagonist that impairs the synthesis of vitamin k-dependent coagulation factors ii, vii, ix, x and endogenous proteins c and s in the liver, resulting in impaired fibrin formation.1,2 warfarin is frequently used to prevent and treat thromboembolism in various recognised clinical conditions such as cardiac arrhythmias, valvular heart diseases and cerebrovascular accidents.2-6 the activity of warfarin is expressed as the international normalised ratio (inr), which is the standard introduced by the world health organization in 1983.7 the inr specifically measures the responsiveness of thromboplastin to a specific warfarin induced defect, and it therefore measures the effect of warfarin and not liver function. it is expressed as a prothrombin ratio obtained by dividing the prothrombin time by the laboratory control prothrombin time.1,2,7 the therapeutic range is the value of inr or degree of anticoagulation that is required to prevent the development of serious thromboembolism and is normally maintained between 2 and 4. the desirable range for the inr depends on the condition being treated, and the risk of bleeding increases as the inr rises.8 published reports have shown an increase in the number of patients attending dental units worldwide who are on warfarin therapy.1,2,5 for many years, controversy has surrounded the correct management of patients on warfarin therapy requiring minor oral surgery (mos) procedures.1,3,6 over the last two decades, various clinical protocols were suggested for managing such patients, which included withdrawal of warfarin, reducing the dose, substitution of heparin for warfarin, and continuation of the normal dose of warfarin.1-6 the risk of intraoperative or post-operative bleeding must be balanced against the risk of thromboembolism in patients whose warfarin is interrupted. several published cases have highlighted the occurrence of serious thromboembolic complications, including death, in patients whose warfarin was withdrawn for dental treatment.3,9-12 in addition, substituting heparin for warfarin often entails hospital admission, which results in an increase in the cost of health care services as well as an increase in patient discomfort.1,2 recently, a considerable body of evidence from research studies has highlighted the relative safety of conducting mos procedures in warfarinised patients at outpatient settings without ceasing or altering their warfarin therapy when the preoperative inr is ≤ 4.2,4-6,13-14 there is no published work in oman on the dental management of patients taking oral anticoagulants. the oral health department of sultan qaboos university hospital (squh) started managing warfarinised patients requiring mos procedures under local anaesthesia without the interruption of warfarin in september 2003. our protocol, as summarised in table 1, states that the pre-operative inr must be ≤ 3.5 and local haemostatic measures are to be used in all patients which is in line with recommended evidence based guidelines.2,4 this retrospective study was conducted with the aim of reporting and describing the profile of all warfarinised patients who underwent mos procedures under local anaesthesia at our outpatient unit over a 5-year period from january 2004 to december 2008. methods all warfarinised patients requiring oral surgery procedures at the oral & maxillofacial unit of the oral health department, squh, are registered in the oral surgery procedures book. a search was conducted to identify all registered cases that underwent mos procedures according to unit protocol and under local anaesthesia without interruption of warfarin at our outpatient setting from january 2004 to december 2008. the patient’s application to patient care 1. medical and dental teams involved in the care of warfarinised patients should be aware of the latest evidence-based recommendations for management of warfarinised patients requiring dental surgery procedures. 2. minor oral surgery (mos) procedures can be safely conducted in warfarinised patients without alteration of warfarin therapy in outpatient settings when the pre-operative international normalised ratio (inr) is ≤ 3.5. 3. mos procedures performed in warfarinised patients carry a low risk of minor post-operative bleeding. 4. local haemostatic measures play an important role in the management of warfarinised patients undergoing mos procedures. abdulaziz a bakathir clinical and basic research | 281 files were retrieved and data collected which included, age and gender, indication for warfarin therapy and the pre-operative inr. the nature of the mos procedure was classified and recorded as either simple extraction; surgical extraction; biopsy or others. surgical extraction was defined as raising a mucoperiosteal flap and removal of bone with a bur. detailed information was also recorded on the operating surgeon; the local haemostatic methods used; preand post-operative antibiotic usage and other post-operative medications. in addition, data were also collected regarding any postoperative bleeding and its time of occurrence, the postoperative inr and the course of management of the post-operative bleeding. prior to the start of the study, ethical approval was obtained from the local research committee. results at our unit, total of 124 warfarinised patients underwent minor oral surgery procedures during the five-year study period without discontinuation of their warfarin therapy. there were 41 (33.1%) male and 83 (66.9%) female subjects with a mean age of 36 years (range 20-86 years). the patients studied were on warfarin therapy for a number of medical conditions as summarised in table 2. a prosthetic heart valve was the most common clinical indication for warfarin therapy, accounting for 62.1% of patients. the oral surgery procedures performed in the study group were conducted by three senior surgeons under local anaesthesia and included simple dental extractions, surgical extractions, soft tissue biopsies and apicectomies with cyst enucleations [table 3]. table 1: protocol for minor oral surgery in warfarinised patients at the oral health department, sultan qaboos university hospital pre-operative assessment inr of ≤ 3.5 obtained on the day of surgery no other coagulopathy no liver disease absence of infection at surgical site patient should not be on aspirin or non-steroidal anti-inflammatory drugs intra-operative management mos procedures: simple dental extraction limited to 1-3 in same quadrant surgical extraction soft tissue biopsy during surgical procedure: atraumatic surgical techniques respect soft tissue and avoid excessive manipulation local haemostatic measures: packing extraction sites with surgicel dressing suturing with resorbable sutures 4.8% tranexamic acid can be given as 10ml mouthwash to be used four times daily for 3-5 days post-operative care verbal and written post-operative instructions to patients: dietary instructions (avoid hot drinks for 24 hrs; soft diet for a few days) limit usage of analgesics to 3 days if possible avoid taking any herbal remedies instructions on how to deal with bleeding at home and where to seek help if bleeding cannot be not stopped at home post-operative medications antibiotics: if required use oral amoxycillin for 3-5 days analgesics: parecetamol compound paracetamol (co-codamol) codiene phosphate follow up appointment in 2 weeks legend: inr = international normalised ratio; mos = minor oral surgery minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 282 | squ medical journal, december 2009, volume 9, issue 3 simple dental extractions of 1-3 teeth accounted for 72.6% of the performed procedures with 149 teeth extracted. the mandibular first and second molars were the most commonly extracted teeth followed by the maxillary second molars. in patients who had surgical extractions, the mandibular third molars were the most commonly removed teeth followed by the upper first premolars. soft tissue procedures were conducted as excisional biopsies of benign tumours and mucous extravasation cysts from the tongue, palate, labial and buccal mucosae. the two cases of apicectomies and cyst enucleations were performed on the upper central incisors. all patients had local anaesthesia in the form of 2% xylocaine with adrenaline 1:80000. infiltrations of local anaesthesia and nerve blocks were used to achieve the required anaesthesia for mos. blind infiltrations involving the floor of the mouth were avoided in all patients. all patients who underwent mos procedures had a pre-operative inr taken on the same day of the procedure. the mean inr of the study group was 2.8 with a range of 2.1-3.5. all patients who had simple and surgical extractions had local haemostatic measures which included the placement of oxidizing regenerated cellulose dressing (surgicel, johnson & johnson) into the extraction sockets and closure with resorbable vicryl sutures. other patients (apicectomy and biopsy patients) had the surgical areas closed with resorbable sutures. seventy-seven patients who had a history of prosthetic heart valves had pre-operative antibiotic prophylaxis against infective endocarditis. all these patients had 3g amoxycillin orally one hour preoperatively according to standardised international guidelines.15-16 twenty patients who had surgical extractions and apicectomies had a 3 day course of post-operative amoxycillin. out of these 20 patients, only one patient also had a pre-operative antibiotic. all patients had a five day course of simple analgesics in the form of paracetamol (n = 60), co-codamol (n = 62) and codeine phosphate (n = 2). all patients were instructed to limit or consider lowering the usage of analgesics after the third day. following mos procedures, all patients were instructed to bite on sterile gauze and were reassessed for immediate post-operative bleeding after 20 minutes before being allowed to leave. both clear verbal and written instructions were given to patients, which included: post-operative instructions; dietary advice; home management of any bleeding and where to seek medical assistance for emergency bleeding. in addition, all patients were given a 2 weeks follow-up appointment. none of the studied patients had any immediate post-operative bleeding. a total of eight patients (6.5%), five who had surgical extractions and 3 had simple extractions, bled post-operatively and had to return to hospital. the bleeding was reported in all these patients to be as continuous oozing from the surgical sites, which was not controlled by local measures at home. all these patients had their inr re-checked with most of them having a higher post-operative inr compared to the pre-operative inr. table 4 shows a summary of patients who presented with post-operative bleeding. all these patients were managed in an outpatient setting and none required hospital admission, as they were all haemodynamically stable with normal vital signs. the management included repacking the bleeding site with surgicel dressing and re-suturing. all patients in the studied group attended the two week review visit. in the eight patients who had postoperative bleeding, the surgical sites had healed adequately and none of these patients reported any new episodes of bleeding from the table 2: indications for warfarin treatment in the study group indication no. of patients (%) cardiac arrhythmias 10 (8.1%) deep vein thrombosis 2 (1.6%) transient ischaemic attack and stroke 19 (15.3%) pulmonary embolism 5 (4%) prosthetic heart valve 77 (62.1%) myocardial infarction 4 (3.2%) others 7 (5.6%) table 3: minor oral surgery procedures conducted in the study group procedure no. of patients( %) simple dental extraction (1-3 teeth) 90 (72.6%) surgical extraction 26 (21%) soft tissue biopsy 6 (4.8%) apicectomy and cyst enucleation 2 (1.6%) abdulaziz a bakathir clinical and basic research | 283 surgical sites. the remaining 116 patients also did not report any episode of bleeding that required any medical intervention and all had satisfactory post-surgical healing. discussion oral surgery is the main oral health care hazard in patients taking warfarin due to the potential risk of bleeding. for many years, controversy has surrounded the correct management of warfarinised patients requiring mos procedures and various clinical protocols have been suggested for managing such patients.1,3,5,6 the traditional management in most dental units, including our unit, entails the discontinuation or reduction of warfarin therapy 2-3 days prior to dental surgery in order to prevent post-surgical haemorrhage.3,12,14 however, this practice may increase the risk of potentially lifethreatening thromboembolic events, especially in high-risk groups such as patients with prosthetic heart valves.2,14 furthermore, there is evidence that thrombosis may actually be more likely to occur due to rebound hypercoagulabilty that may ensue after cessation of warfarin.9,11 to support this, the literature contains several documented cases of serious thromboembolic complications in patients whose warfarin was withdrawn for dental treatment.2,17 in recent years, continuation of warfarin therapy in patients undergoing oral surgery procedures has gained more attention in the scientific literature.2,3,5,6,18 the 4th world workshop in oral medicine recommended that warfarinised patients undergo mos in an outpatients setting when the pre-operative inr is ≤ 3.5.2 published studies have shown the relative safety of conducting mos in warfarinised patients without alteration of the warfarin regimen and recommended the use of local measures to stabilise the clot formation at surgical sites.3-6 these local measures include the use of haemostatic agents such as oxidizing regenerated cellulose (surgicel), fibrin glue and gelatin sponge.6,19-22 conducting the procedure atraumatically and careful closure of the surgical site with adequate resorbable sutures also helps to stabilise the wound and achieve haemostasis. in our unit, surgicel is routinely used as the local haemostatic dressing because it is widely available, easy to handle, inexpensive and does not interfere with healing or bone regeneration. many published studies have demonstrated its use as an effective local agent with comparable efficacy to other agents.3,20,22 furthermore, other published reports also recommend the use of a tranexamic acid mouthwash in the post-operative period of warfarinised patients following mos. tranexamic acid mouthwashes tend to result in a good level of drug concentration in saliva, and thus help to prevent post-operative bleeding due to the continued local anti-fibrinolytic activity.2,19,21 despite the huge table 2: data of patients presenting with post-operative bleeding following oral surgery procedures patient age/sex pre-operative inr procedure pre/post antibiotic use post-operative inr day of presentation 1 55/f 2.8 surgical extraction no 3.5 3 2 39/m 3.5 simple extraction yes 3.8 2 3 48/f 2.4 surgical extraction no 2.3 5 4 40/f 3.2 simple extraction no 3.4 3 5 28/f 2.4 surgical extraction no 2.8 2 6 33/m 2.1 simple extraction no 2.8 4 7 49/m 2.8 surgical extraction yes 3.4 3 8 52/f 3.1 surgical extraction yes 3.7 3 legend: inr = international normalised ratio minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 284 | squ medical journal, december 2009, volume 9, issue 3 body of evidence recommending the continuation of warfarin therapy in patients undergoing mos, linnebur et al.23 identified inconsistencies between teaching practices in us dental schools and medical evidence available for the management of patients taking warfarin with most schools still teaching the practice of altering and/or interrupting warfarin prior to dental surgery. in oman, our unit started treating warfarin patients requiring mos in an outpatient setting in september 2003, according to the protocol summarised in table 1. before this date, there was no existing protocol and most patients were managed after consultation with their treating physician, almost all of whom tended to regard dental treatment, including simple extraction, as invasive and therefore aimed to reduce inr to <2.5, which is currently not in line with international clinical guidelines. as patients who are taking warfarin are increasing in oman, dental and medical teams here need to be aware of the latest evidence-based guidelines, which are available for safe management of this group of patients. with regard to the risk of post-operative bleeding following mos, wahl’s review found little or no difference in terms of blood loss after dental surgery between patients who are anticoagulated and control patients.17 other studies conducted on patients taking warfarin, with inr in the therapeutic range (2-4) versus controls, found little or no difference in the incidence of clinically significant bleeding, even though some had warfarin levels above the present recommended therapeutic levels, and some underwent extensive oral surgery.1 in a series of 2,400 documented dental operations, wahl found only 12 patients experiencing postoperative bleeding that was not controlled by local measures.24 the literature contains no report of patients experiencing serious harm from postoperative bleeding after dental extractions while continuing on warfarin. in our study, none of our patients had any immediate post-operative bleeding and 8 patients (6.8%) had minor post-operative bleeding that required a return to hospital for care. all these patients were managed conservatively by repacking the bleeding site and re-suturing. our finding is in line with other published studies which highlighted that most post-operative bleeding in warfarinised patients tends to be minor in nature and can often be easily managed by simple local measures.3,18,20,25-27 recently published work by malden et al.,28 showed an association between the degree of surgical intervention and the likelihood of anticoagulation being affected and they recommended that the postoperative inr in this group should be monitored carefully. although the finding of our study is in agreement with the finding of malden et al. as most of the patients who bled post-operatively had a much higher post-operative inr when compared with the pre-operative inr, our unit does not recommend routine post-operative inr monitoring following mos unless there is a clear indication. many reports highlighted the potential risk of post-operative bleeding which may result from drug interaction or the use of herbal remedies.1,2,29 many drugs, including non-steroidal analgesics and antibiotics, can interact with warfarin resulting in an alteration in anticoagulation activity and may contribute to an increase in post-operative bleeding.1,29 according to our protocol, routine prescription of post-operative antibiotics is not practised unless there is a clear clinical indication. when a post-operative antibiotic is required, it is limited to oral amoxycillin for 3-5 days. furthermore, our protocol for antibiotic prophylaxis has changed recently in accordance with the newly published clinical guidelines by the national institute for clinical excellence, which ceased recommending routine antibiotic prophylaxis against infective endocarditis for dental procedures.30 in addition, analgesics in form of paracetamol, compound paracetamol (co-codamol) or codeine phosphate are commonly prescribed and our patients are instructed to use them for up to 3 days and not to use other medications including non-steroidal analgaesics. all these measures are aimed to minimise possible interaction with warfarin. furthermore, studies have shown that the use of herbal remedies, which are commonly used in our region, could be a common precipitating cause of post-operative bleeding in warfarinised patient.1-2 to control this potential interaction, all our patients are screened and advised to avoid taking herbal remedies in the preand post-operative period. due to the limitation of the data available in this retrospective study, detailed analysis of the risk of post-operative bleeding was not possible and accordingly our unit is now looking prospectively at risk factors of post-operative bleeding in warfarinised abdulaziz a bakathir clinical and basic research | 285 patients undergoing mos procedures. conclusion based on this retrospective study, our unit protocol for the management of warfarinised patients undergoing mos procedures in an outpatient setting is associated with a low risk of postoperative bleeding and our reported findings are in accordance with the available literature.2,8,27,31-32 furthermore, our study supports and recommends that warfarinised patients can safely undergo mos procedures without alteration of their warfarin therapy when the pre-operative inr is ≤ 3.5. in addition, our study also stresses the importance of local haemostatic measures in preventing as well as managing post-operative bleeding following mos procedures. a c k n o w l e d g e m e n t s the author would like to thank the clinical staff at the oral health department for their support during the period of the study. in addition, the author is also grateful to ms nadia al-ghafri, secretary at the oral health department for her kind assistance in editing the manuscript. conflict of interest the authors report no conflict of interest. references 1. lockhart pb, gibson j, pond sh, leitch j. dental management considerations for the patient with an acquired coagulopathy. part 2: coagulopathies from drugs. br dent j 2003; 195:495-501. 2. aframian dj, lalla rv, pererson de. management of dental patients taking common hemostasis altering medications. oral surg oral med oral pathol oral radiol endod 2007; 103:s45.e1-11. 3. devani p, lavery km, howell cjt. dental extraction in patients on warfarin: is alteration of anticoagulant regime necessary? br j oral & maxillofac surg 1998; 36:107-11. 4. blinder d, manor y, martinowitz u, taicher s. dental extractions in patients maintained on continued oral anticoagulant: comparison of local hemostatic modalities. oral surg oral med oral pathol oral radiol endod 1999; 88:137-40. 5. evans il, sayers ms, gibbons aj, price g, snooks h, sugar aw. can warfarin be continued during dental extractions? results of a randomized controlled trial. br j oral & maxillofac surg 2002; 40:248-52. 6. cannon pd, dharmar vt. minor oral surgery procedures in patients on oral anticoagulants a controlled study. aus dent j 2003; 48:115-8. 7. shinton nk. standardisation of oral anticoagulant treatment. br med j 1983; 287:1000-1. 8. oake n, jennings a, forster aj, fergusson d, doucette s, van walraven c. anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. cmaj 2008; 179:235-44. 9. poller l, thomson j. evidence for “rebound” hypercoagulabilty after stopping anticoagulants. lancet 1964; 2:62-5. 10. harenberg j, haas r, zimmerman r. plasma hypercoagulabilty after termination of oral anticoagulants. thromb res 1983; 29:627-33. 11. mulligan r. response to anticoagulant drug withdrawal. j am dent assoc 1987; 115:435-8. 12. jeske ah, suchko gd. lack of a scientific basis for routine discontinuation of oral anticoagulant therapy for dental treatment. j am dent assoc 2003; 134:1492-7. 13. randall c. surgical management of the primary care dental patient on warfarin. dent update 2005; 32:441-6. 14. webster k, wilde j. management of anticoagulation in patients with prosthetic heart valves undergoing oral and maxillofacial operations. br j oral & maxillofac surg 2000; 38:124-6. 15. ramsdale dr, turner-stokes l. advisory group of the bristish cardiac society clinical practice committee. prophylaxis and treatment of infective endocarditis in adults: a concise guide. clin med 2004; 4:545-50. 16. gould fk, elliott tj, foweraker j, fulford m, perry jd, roberts gj et al. guidelines for the prevention of endocarditis: report of the working party of the british society of antimicrobial chemotherapy. j antimicrob chemother 2006; 57:1035-42. 17. wahl mj. dental surgery in anticoagulated patients. arch inten med 1998; 158:1610-6. 18. malden m. dental procedures can be undertaken without alteration of oral anticoagulant regimen. evid based dent 2005; 6:11. from www.nature.com/ ebd/journal/v6/n1/pdf/6400309a.pdf. accessed march 2009. 19. bal bj, hardee ps. efficacy and cost effectiveness of tranexamic acid mouth rinse for oral surgery in warfarinised patients. br j oral maxillofac surg 2000; 38:390-3. 20. carter g, goss an, lloyd j, tocchetti r. current concepts of the management of dental extractions for patients taking warfarin. aust dent j 2003; 48:8996. 21. carter g, goss an, lloyd j, tocchetti r. tranexamic acid mouthwash versus autologous fibrin glue in minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 286 | squ medical journal, december 2009, volume 9, issue 3 patients taking warfarin undergoing dental exactions: a randomized prospective clinical study. j oral & maxillofac surg 2003; 61:1432-5. 22. halfpenny w, fraser js, adlam dm. comparison of 2 hemostatic agents for the prevention of postextraction hemorrhage in patients on anticoagulants. oral surg oral med oral pathol oral radiol endod 2001; 92:257-9. 23. linnebur sa, ellis sl, astroth jd. educational practices regarding anticoagulation and dental procedures in u.s dental schools. j dent educ 2007; 71:296-303. 24. wahl mj. myths of dental surgery in patients receiving anticoagulant therapy. j am dent assoc 2000; 13:77-81. 25. dunn as, turple ag. perioperative management of patients receiving oral anticoagulants: a systematic review. arch intern med 2003; 163:901-8. 26. bailey bmw, fordyce am. complications of dental extractions in patients receiving warfarin anticoagulant therapy a controlled clinical trial. br dent j 1983; 155:308-10. 27. salam s, yusuf h, milosevic a. bleeding after dental extractions in patients taking warfarin. br j oral & maxillofac surg 2007; 45:463-6. 28. malden nj, santini a, mather ci, gardner a. minor oral surgery and interference with anticoagulation in patients taking warfarin: a retrospective study. br j oral & maxillofac surg 2007; 45:645-7. 29. wood gd, deeble t. warfarin: dangers with antibiotics. dental update 1993; 20:350-3. 30. national institute for health and clinical excellence. prophylaxis against infective endocarditis: nice guidance. london: nice, 2008. from http://www. nice.org.uk/guidance/cg64. accessed september 2009 31. van diermen de, aartman ia, baart ja, hoogstraten j, van der waal i. dental management of patients using antithrombotic drugs: critical appraisal of existing guidelines. oral surg oral med oral pathol oral radiol endod 2009; 107:616-24. 32. nematullah a, alabousi a, blanas n, douketis jd, sutherland se. dental surgery for patients on anticoagulant therapy with warfarin: a systematic review and meta-analysis. j cand dent assoc 2009; 75:41. from www.cda-adc.ca/jcda/vol-75/issue-1/41. html. accessed july 2009. to the editor unable to return to afghanistan initially after 9/11, i worked for five months in yemen and found myself constantly drawing parallels between the two countries. recently, during a visit to oman i found myself constantly remarking on the stark contrasts with both yemen and afghanistan. not surprisingly, the direction my reflections took was influenced in large part by my recent master’s thesis research which focused on the role of epistemology in surgical training in afghanistan.1 the casual observer might latch on to the most obvious difference in relation to the two countries’ ministries of health, namely availability of finances. alshishtawy’s article in this issue highlights a difference more important than quantity of finances; namely, quality.2 by that i mean the quality of decision making in relation to finances. for the foreseeable future, afghanistan’s government is dependent on donor funding because clearly it will be a long time before taxes can fund health care. even if there were technocrats in the afghan ministry of health (moh) who saw the need to allow cost recovery in the public system, the parliament seems set against allowing such pragmatism. when i recently asked a senior technocrat in the moh in kabul what form plans are taking for financing of health care 10 years from now he was not aware of anyone addressing this question. clearly, it is not just the absence of conflict or the size of gdp that make oman’s health care such a remarkable success, but rather such elements as systematic analysis, practical planning and effective leadership in implementing plans. the analytical framework used for my master’s research i derived from the foundational document which led to the establishment of the modern research university. von humboldt’s classic 1810 paper listed four conditions for developing the modern research university which i believe apply to the development of any knowledge derived profession: 1. providing the organizational context; 2. collaborative arousing of passion; 3. challenging closure (”…science and scholarship do not consist of closed bodies of permanently settled truths.”); 4. seeking feedback.3 the condition that i have found most obviously lacking in afghanistan was the one so visible for its successful application in oman; namely the first condition, that “… the state must supply the organizational framework and the resources necessary for the practice of science and scholarship...” the remarkable success of the past few decades in developing oman’s education and health infrastructure is outstanding. it goes without saying that afghanistan’s chronic continuing civil conflict accounts for a large part of the difference between the two countries’ health care systems. however, a number of questions arose during my visit which i believe have broader relevance to the culture of training for the health professions. squ med j, april 2010, vol. 10, iss. 1, pp. 144-147, epub. 17th apr 10 received 12th jan 10 submitted 12th jan 10 revision req. 21st feb 10, revision recd. 22nd feb 10 accepted 28th feb 10 أفغانستان وُعمان انطباعات شخصية الختالفات عميقة كني ف��شرت afghanistan and oman personal reflections on a profound contrast ken foster letter to editor kabul general hospital, kabul, afghanistan email: kwinfer@gmail.com ken foster letter to editor | 145 who gets into medical school? this question parallels an issue we have in afghanistan. both countries base selection of medical school candidates solely on examination performance. hearing of a large majority of female medical students in sohar, oman leads me to wonder what effect this will have on health care delivery if many of them go on to work only part time in order to have a family. some have openly admitted no interest in practising medicine. in the afghan system one’s post-secondary career path is assigned on the basis of ranking in the nationwide “concours” examination unless one asks to be switched to a lower ranked faculty. with top-scoring candidates assigned to medicine and lowest scoring to nursing it is no surprise that afghan doctors often end up leaving the profession when they can be better paid as english-dari translators for foreign organisations and that nursing as a profession shows clear signs of being undervalued. in both countries there appears to be a significant element of socially motivated career choice at the expense of decision-making based on suitability of personal aptitudes and enjoyments. perhaps in both contexts a significant part of the blame is to be laid on the society at large and how it has developed; not just on the higher education system alone.3 any rapidly changing society is likely to have elements of disequilibrium between traditional ideas about health and the epistemology that constitutes the foundation of professional expertise. in afghanistan, i see almost weekly a case of severe morbidity from treatment at the hands of traditional bone-setters and yet i have also seen doctors who have taken their own family members to traditional healers. clearly society’s relationship to both the traditional and modern medicine communities is a strong determinant of health care delivery. selection of candidates for the profession and selection of the professional to treat a given patient are key determinants of this relationship what to think versus how to think one of the observations that stands out in oman by way of contrast with afghanistan is the large majority of expatriate doctors in oman. a recent study showed the figure to be 75%.1 for most of my time in afghanistan, i have to my knowledge been the only non-afghan working in the national hospital system. the few foreign doctors have been for the most part in non-governmental organisation (ngo) programme management. this difference of course reflects the capacity of oman to pay generous salaries to attract foreign personnel. in turn, this raises the question of indigenisation of medical expertise. clearly, progress is being made in this regard in oman. is it then appropriate to raise the concerns that have been raised more generally about graduate education in the region?4 the general focus of these concerns can be characterised by an emphasis on content or skill-set transmission to the trainee without adequate attention to the capacity for critical thinking. in a world increasingly ‘opportunity-flat’5 because of the internet, the capacity to negotiate the torrent of information for what is actually relevant and true requires more than ever before in history the capacity of critical thinking. the ngo for which i work in afghanistan has been focusing lately on strengths: richard koch’s 80/20 principle.6 this approach is very useful as far as maximising a given individual’s contribution when there are other players to choose from. however, when one is the only option to meet a particular urgent need, as is often the case in health care, then one should also incorporate a focus on analysing one’s weaknesses. this principle of focusing on weaknesses should be even truer of whole systems. in the professional realm, it is this tension between focusing on strengths (often oriented toward keeping everyone happy) and focusing on weaknesses (to cut out inefficiency and error) that informs much of the cultural divide between ‘east’ and ‘west’. victor davis hanson has highlighted this difference perhaps more effectively than anyone else by looking at the history of the military profession. in his book carnage & culture he looks at nine military campaigns over the last 2,500 years and concludes that ‘the west’ has dominated militarily because it has built on the foundations of 1) freedom of individual expression (and maybe also rights) and 2) the centrality of rational enquiry/reflective analysis.7 this difference led to the inability of the hero on horseback with superior individual power to overcome the disciplined coordinated systematic defences of a phalanx of greek infantry, for example at the battle of marathon in 490 bce. perhaps the cultural parallels of lessons afghanistan and oman is it fair to compare? 146 | squ medical journal, april 2010, volume 10, issue 1 drawn from the military profession are more clearly highlighted in the battle of midway in 1942 in which overconfidence, focus on blaming rather than analysing bad outcomes, suppression of questioning from junior officers, following traditional tactics, resistance to initiative, honour motivated planning (the best pilots earned the right to go kamikaze, leaving behind a less experienced pool of trainers) played a role in producing failure analogous to the dynamics in the operating room that i am familiar with as a surgeon. recently there has been interest in applying the lessons from aviation in the operating room environment. these have also highlighted the central role of reflective analysis of how we function as a community or as a system rather than just asking what piece of equipment or individual skill-set is lacking. this systems approach is becoming increasingly accepted as the preferred approach to preventing medical error. however, it can also be the prime force for improving the use of limited human resources – whether limited by quantity or quality. whose learning comes first – the profession’s or the professional’s? as a surgeon doing primarily upper extremity surgery in afghanistan’s main orthopaedic hospital i am constantly faced with examples illustrating a failure of the above two principles of reflective analysis and individual expression i have no doubt that the single largest source of loss of hand function in afghanistan is not the injury per se but iatrogenic joint and tendon stiffness that could have been prevented with a little bit of knowledge and modest effort – but certainly not requiring expensive or complex technology. repeated attempts to introduce change in this regard have been without significant effect, despite the absence of any clearly identifiable resistance. without doubt a large part of the reason for this inertia is the simple absence of a systematic habit of looking for new ideas and then evaluating them before incorporating them into working practice. in other words, when reflective analysis and freedom of expression are suppressed the threshold for change becomes too high and impedes progress. it often happened that an individual would be convinced of the benefit of some new development, but there was little mechanism for dissemination of the new idea throughout the department unless it was instigated from the top of the hierarchy. by contrast dr c.thomas’ description of how new ideas become adopted in the khoula hospital plastic surgery department seemed to approach the ideal in terms of openness to exchange of ideas. despite the large difference between the two countries in how their medical communities function, it is safe to say that for each country the road to success is paved with the same stones. these include critical self-assessment and openness to new ideas. two of the best measures of reflective analysis in a medical community are well conducted departmental morbidity and mortality rounds. in this day and age a good measure of the presence of the other foundational principle, individual expression, could be openness to new ideas. in a hierarchical honour/shame society a good measure of this openness might be the promotion of young members of the department on the basis of merit rather than connectedness. nowadays it probably also correlates closely with how much the department relies on medline searches for the answers to clinically relevant questions. development of both of these aspects of the profession is sorely needed in afghanistan. how much they could be further developed in oman i cannot say, but the question is worth addressing in relation to the profession throughout the country and not just in the academic centres. an answer to the geography challenge? this leads me to conclude with the one parallel challenge that both countries share. each faces the challenge of delivering health care to sparsely populated mountainous and arid regions that have been traditionally rather isolated from the outside world. many of our patients in afghanistan take four or more days of travel to reach kabul and when they do they tend to find it an inimical environment where they quickly go into debt to pay for their family member’s care. although the trip from nizwa to muscat has shrunk in a generation from a week long camel trip to a one and a half hour motorway trip, there still seems to be sufficient paucity of specialist medical care outside of the main urban centres to pose a relative barrier to care. i sense this may ken foster letter to editor | 147 be the case notwithstanding the truly remarkable achievement of, for example, virtually all cleft lip patients being registered within a week or two of birth for surgery at three months. i say this in part because in my own country of canada, with a much longer history of developed health care, there are still challenges in providing specialty services at a distance from the large urban centres. two solutions seem to offer the most help in meeting this challenge: 1) an internet based program for onsite professional development using pubmed literature searching to promote an evidence-based approach to practice combined with video conferencing to provide specialist input on difficult cases 2) targeted provision of resources and training to handle the most common conditions amenable to a non-specialist type of surgical “generalist”. thus competencies such as bowel resection, hernia repair, c-section, care of modest burn injury and common fractures could be combined with improvement in the early management of trauma and prevention of complications such as joint stiffness and compartment syndrome – all combined in a surgical generalist role for small towns. it could be tailored to the specific professional resources in a given town and evolve with the health care system while improving access for the rural population. these two keys constitute my dream for afghanistan, and i feel that some aspects of this approach would have relevance to any country with a geographically challenging distribution of its population such as canada, australia and at this stage in its development of its medical profession, oman. kudos to oman’s great progress to date! may omanis soon comprise the majority of their own health care team. references 1. foster k. the role of professional knowledge in afghan surgical training. master’s thesis, university of toronto, canada, 2009. 2. alshishtawy mm, four decades of brilliance: evolution of the health system in oman. squ med j 2010; 10:8-16 3. von humboldt w. on the spirit and the organisational framework of intellectual institutions in berlin. (abridged edition of humboldt’s proposal for the university of berlin, 1810). minerva 1970; 8:242-50. 4. hunaidi rk. arab human development report 2002. new york: undp. from http://hdr.undp.org/ en/reports/regionalreports/arabstates/name,3140,en.html accessed december 2008, 5. friedman tl. the world is flat. new york: farrar straus & giroux, 2006. 6. koch r. the 80/20 principle: the secret to success by achieving more with less. london: nicholas brealey publishing ltd, 2003 (the 80/20 principle by richard koch, strengthsfinder from gallup press) 7. hanson vd. carnage and culture, new york: random house, 2001. squ med j, december 2009, vol. 9, iss. 3, pp. 338-340, epub. 19th dec 2009 submitted 20th apr 09 revision req. 26th aug. revision recd. 1st sept. 09 accepted 16th sept 09 acanthamoeba keratitis is a serious protozoal corneal infection, more so in medical and cosmetic contact lens users.1 morbidity can increase when diagnosis is delayed because of demanding laboratory investigations. unhygienic contact lens cases and solutions, contaminated water sources and even air remain the most common causes of this infection despite education and warnings. we describe a case of contact lens induced acanthamoeba keratitis which was repeatedly culture negative, and treated on the basis of clinical signs and symptoms aided by confoscan (corneal confocal microscope) findings. this case illustrates how much pain and suffering this infection can cause if not prevented, diagnosed and treated early in its course. case report a 28 year-old female teacher was referred from a peripheral hospital to sultan qaboos university hospital, oman for non-responding contact lensinduced bacterial keratitis which had developed four months previously in her right eye. she complained of excruciating pain, decreased vision, extreme photophobia, lacrimation, and appeared depressed. she had enough visual acuity to count fingers at one meter. she had been treated with a cocktail of medications which included topical chloramphenicol, tetracycline, aminoglycosides, fluoroquinolones, acyclovir, and prednisolone acetate. she showed signs of chronic fatigue due to long standing pain and insomnia, as well as family and professional burdens.2 a slit-lamp examination revealed a corneal ring lesion with an overlying epithelial defect (4.4mm x department of ophthalmology, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed: email: upender.wali@gmail.com زراعة خمربية سالبة وفحص موجب باألشعة الضوئية املركزة خلاليا القرنية املصابة بالتهاب شوكمييب مساق قاس نادية اخلروصي، .اوبندر والي لتنظيف املستخدم امللحي احمللول مثل ، معقمة غير سوائل استخدام عن عادة ينتج طفيلي التهاب هو الشوكميبي العني التهاب امللخص: العدسات الالصقة. ندرج هنا تقرير عن حالة حصل فيها تأخير في تشخيص التهاب القرنية الشوكميبي نتيجة لعدم توفر الفحوص اخملبرية وتأخر العالج الطبي مما أدى ملساق مؤلم للمرض. كان جلهاز الفحص باألشعة الضوئية املركزة دور كبير في تشخيص هذا املرض على الرغم من وجود نتائج مخبرية سالبة. مفتاح الكلمات: التهاب القرنية الشوكمبيي، مجهر كمفوسكان، رَأُْب الَقرْنِيَِّة النَّاِفذ، تقرير حالة، ُعمان. abstract: acanthamoeba keratitis is a protozoal infection of the eye, mainly due to the use of non-sterile solutions, like saline for disinfecting contact lenses. we report a case where delay in the diagnosis of acanthamoeba keratitis due to inadequate laboratory investigations and clinical management led to an excruciatingly painful course of the disease. the importance of non-invasive imaging techniques of confocal microscopy in the diagnosis of acanthamoeba keratitis, in the absence of positive culture reports, is highlighted in this case. key words: acanthamoeba keratitis; confocal microscopy; penetrating keratoplasty; case report; oman. culture negative confoscan positive acanthamoeba keratitis a relentless course nadia s al kharousi, *upender k wali case report culture negative confoscan positive acanthamoeba keratitis a relentless course 338 | squ medical journal, december 2009, volume 9, issue 3 4.1mm) with surrounding infiltrate involving twothirds of the stroma, sparing the peripheral cornea [figure 1]. corneal sensation was normal. there were no dendrites or pseudo-dendrites. no satellite lesions could be observed. the endothelium had grayish white deposits. corneal scrapings from two sites (edge and the base) were sent for culture (blood agar, non-nutrient agar laden with e.coli, chocolate agar, sabourad medium) and staining (giemsa and calcoflour). meanwhile, the patient was started on amphotericin-b (liposomal 0.15%) and moxifloxacin eye drops. the epithelial defect increased in size (6.5mm x 5mm) and there was no relief in symptoms. the patient had to be referred to a pain clinic for unbearable pain, as she was not responding to nonsteroidal anti-inflammatory drugs (nsaids). she was put on narcotic analgesics and amitryptilline. the first culture report was available after 5 days, and reported for negative for bacteria, fungus and parasites (including acanthamoeba). one week after beginning treatment at our hospital, there was no remission, both clinically and symptomatically. a confoscan revealed multiple refractile bodies [figure 2] though not all with the classical double ring sign. a corneal biopsy was done twice and reported negative. it was decided to start the patient on a combination of propamidine isethionate 0.1%, chlorhexidine 0.02% and polyhexamethylene biguanide (phmb) 0.02% (these three medications were obtained from moorfields eye hospital, uk) as well as moxifloxacin 0.5% eye drops, plus oral ketoconazole. anterior chamber reaction, endothelial precipitates, stromal infiltration and pain all showed moderate improvement within two weeks. twelve weeks later, the epithelial defect closed with no staining [figure 3] leaving an opacified cornea. at this stage, visual acuity had dropped to hand motion and all five medications were being continued. follow-up after two weeks showed a recurrence of the epithelial defect [figure 4], keratouveitis and pain. she was advised to undergo therapeutic penetrating keratopalsty which was performed in india. her last visit with us (six weeks following the therapeutic graft) showed a clear, large graft [figure 5], with no pain. post-operatively, the patient was on propamidine isethionate 0.1%, moxifloxacin 0.5% and dexamethasone 0.1% eye drops. discussion acanthamoeba keratitis invariably poses a dilemma as far as diagnosis is concerned. since it mimics herpetic and bacterial infections, the correct treatment is not only delayed, but the figure 1: an infiltrative ring lesion with clear periphery. figure 3: a healed, scarred lesion 12 weeks after treatment. figure 2: confoscan 2 revealed multiple refractile cysts in the stroma. nadia s al kharousi and upender k wali case report | 339 treatment administered for herpetic and/or bacterial infections leads to a worse outcome both clinically and prognostically. classical features of acanthamoeba keratitis, like radial keratoneuritis3 and pseudodendrites, may not always be observable especially in later stages.4 the response to treatment is positive only when the infection is treated within four weeks of the onset of symptoms.5 it is important to look for pseudo-dendritiform epithelial lesions and epithelial oedema with necrotic appearance in the very early stages because these can differentiate acanthamoeba lesions from herpetic infections, thereby saving precious time for diagnosis, investigations and treatment. acanthamoeba is difficult to culture in routine media; however, no laboratory investigation is complete unless the tissue is cultured in non-nutrient agar seeded with e. coli, which remains the standard culture for this organism. it may not be always possible to grow the organism in culture as occurred in our case. pfister et al. reported a case where acanthamoeba keratitis was diagnosed on the basis of confocal microscopy in the absence of the culture growth.6 pain which is out of proportion to the lesion should warn of acanthamoeba infection, unless proven otherwise. our patient had already lost four vital months in diagnosis and treatment. by that time, the ring infiltrate had already set in. an important observation at this stage is a clear or mildly oedematous peripheral cornea despite a severe central lesion. in long-standing untreated patients, this infection can present as a corneal plaque. this patient had to pay a heavy price in terms of time, money and suffering, due to the lack of early clinical suspicion of acanthamoeba keratitis and the delay in laboratory investigations. it is obvious that clinical knowledge and microbiology remain the mainstays in the diagnosis of acanthamoeba keratitis. confocal corneal microscopy could also be an aid to the diagnosis.7 conclusion acanthamoeba keratitis should be suspected in cases where there is a failure to respond to the usual anti-infective medications. early diagnosis, laboratory investigations and specific treatment are mandatory in preventing the suffering and vision-threatening complications of acanthameoba keratitis. the course of acanthamoeba keratitis may be a story of pain, suffering, misery, frustration and despair, but one not without hope as this patient has shown, illustrating yet again that prevention is better than cure. references 1. kerr nm, ormonde s. acanthamoeba keratitis associated with cosmetic contact lens wear. n z med j 2008; 28:116-9. 2. jhanji v, beltz j, vajpayee rb. contact lens-related acanthamoeba keratitis in a patient with chronic fatigue syndrome. eye contact lens 2008; 34:335-6. 3. moore mb, mcculley jp, kaufman he, robin jb. radial keratoneuritis as a presenting sign in acanthamoeba keratitis. ophthalmology 1986; 104:1310. 4. johns kj, o’day dm, head ws, neff rj, elliott jh. herpes simplex masquerade syndrome: acanthamoeba keratitis. curr eye res 1987; 6:207. 5. bascon as, dart jkg, ficker la, matheson mm, figure 4: recurrence of the epithelial defect two weeks after lesion had closed. figure 5: a large clear graft after penetrating keratoplasty. culture negative confoscan positive acanthamoeba keratitis a relentless course 340 | squ medical journal, december 2009, volume 9, issue 3 wright p. acanthamoeba keratitis. the value of early diagnosis. ophthalmology 1993; 100:1238. 6. pfister rd, cameron jd, krachmer jh, holland ej. confocal microscopy findings of acanthamoeba keratitis. am j ophthalmol 1996; 121:119-128. 7. kettesy b, komar t, berta a, modis l. acanthamoeba keratitis. orv hetil 2008; 149:2037-45. 1department of endocrinology, faiha specialized diabetes, endocrine and metabolism center, basrah, iraq; 2department of radiology, al-rifaee general hospital, al-rifai, iraq *corresponding author’s e-mail: samihabed@yahoo.com clinical and radiological findings in mayer-rokitansky-küster-hauser syndrome type 2 case report *samih a. odhaib,1 miaad j. mohammed,2 ahmed j. h. al-ali,1 abbas ali mansour1 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 635–638, epub. 25 nov 21 submitted 29 jun 2020 revision req. 13 sep 2020; revision recd. 4 oct 2020 accepted 2 nov 2020 case report a 15-year-old female patient presented to a specialised diabetes endocrine and metabolism centre in basrah, iraq, in 2019 with primary amenorrhoea. she had normal pubertal secondary sexual characteristics; axillary and pubic hair growth started at the age of 13–14 years. she described usual breast development for her age. she had no history of vaginal bleeding, discharge or intermittent pelvic pain. she was indifferent to her amenorrhea and satisfied with her body image. her mother and two sisters had their menarche at 13 and 14 years, respectively, and there was no history of amenorrhoea among the first and second-degree relatives. other parts of the history were noncontributory. one month before the patient presented to the clinic, she had consulted a gynaecologist who undertook some hormonal and general investigations, including an ultrasonographic evaluation that failed to visualise the uterus [table 1]. this finding urged the family to seek a second opinion. on current examination, it was found that the patient was a lean adolescent with no apparent dysmorphic features and had normal vital signs. her weight was 56.5 kg, her height was 1.64 m and she had a body mass index of 21 kg/m2. the cardiorespiratory examination was routine. abdominal examination, after the complete evacuation of the bladder, was the mayer-rokitansky-küster-hauser syndrome (mrkhs) represents uterovaginal aplasia or hypoplasia in young women with a usual karyotype.1 the documented incidence is 1/4,000–5,000 female births. primary amenorrhoea is the presenting symptom despite the development of typical secondary sexual characteristics.2 the syndrome may be identified incidentally during the first sexual experience by a failure to achieve normal vaginal intercourse. recurrent abdominal pain, because of rudimentary uterine parts at the time of the presumed menstrual cycle (cryptomenorrhea) is an uncommon manifestation.3 there are two distinct types of mrkhs: type 1 which is typical mrkhs with uterovaginal aplasia and type 2 which is atypical mrkhs that is additionally associated with systemic congenital anomalies of different penetrance.4 mrkhs does not present with clearly identifiable genetic causes although familial clustering of the syndrome is seen.5 genetic and environmental dynamics may add to the development of mrkhs although their specific contribution is often unknown.1 the patient history, clinical examination, ultrasound, magnetic resonance imaging (mri) and laparoscopy can assist in the initial diagnosis of mrkhs.6 the main focus of management is to correct vaginal agenesis through several surgical and nonsurgical techniques.7 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.036 case report abstract: mayer-rokitansky-küster-hauser syndrome (mrkhs) or müllerian agenesis represents uterovaginal aplasia or hypoplasia of unknown aetiology in young women with usual 46,xx karyotype and normal secondary sexual characteristics. we report a 15-year-old female patient who presented to a specialised diabetes endocrine and metabolism centre in basrah, iraq, in 2019 with primary amenorrhoea and normal pubertal secondary sexual characteristics, hormonal workup and clinical examination. abdominopelvic magnetic resonance imaging (mri) revealed cervical and uterine agenesis with the absence of the proximal thirds of the vagina. both kidneys were fused in the right iliac fossa with oval lobulated appearance and crossed fused ectopia. the ovaries were normal and located bilaterally. the diagnosis of mrkhs type 2 was confirmed based on clinical, biochemical and radiological findings. the correct clinical and radiological diagnosis of mrkhs by mri is crucial for long-term management. keywords: müllerian aplasia; case report; iraq. clinical and radiological findings in mayer-rokitansky-küster-hauser syndrome type 2 case report 636 | squ medical journal, november 2021, volume 21, issue 4 normal apart from fullness at the suprapubic area with a centrally located fixed mass (9 × 9 cm); the examination revealed a failure to palpate both kidneys. breast examination revealed tanner stage 5 for both breasts, which was typical for her age. there were normal scalp and axillary hair densities and no acne. the patient was caucasian and had fair skin with no abnormal discolouration. a fellow gynaecologist examined the pubic area and revealed normal external genitalia, normal clitoris and pubic hair distribution at tanner stage 3. a new transabdominal ultrasound study revealed a centrally located pelvic kidney and two normal ovaries with uterine agenesis. the radiologist advised an mri study for confirmation [figure 1]. the diagnosis of mrkhs type 2 was confirmed based on clinical, biochemical and radiological findings. the patient and the family inquired about the syndrome, progression, future management and sexual activity. additional workup included a cardiologist consult ation (which ruled-out any possible associated hidden cardiac defects), an expert surgical opinion about possible surgical management and a psychiatric evaluation. the chromosomal karyotype revealed a normal female genotype of 46,xx. in early 2020, the patient’s family requested a complete and detailed official report of her condition for a possible second expert surgical opinion. an informed consent for publication and sharing of the data was granted by the patient's parents, with the full confidentiality for her identity. discussion mrkhs carries complex clinical heterogeneity and genetic basis in most cases due to no family history figure 1: t2-weighted magnetic resonance images of a 15-year-old female patient. a: coronal view showing the presence of bilateral normal-sized ovaries; both kidneys are fused in the right iliac fossa with an oval lobulated appearance and there is crossed fused ectopia of the kidneys. b: axial view showing the crossed fused ectopia that appears as a midline mass; ovaries are normal and bilaterally located. c: sagittal view showing complete uterine body and cervical agenesis with the absence of the proximal third of the vagina, leaving a short vagina (22 mm). table 1: results of different investigations performed one month before presentation of a 15-year-old female patient with mayer rokitansky-küster-hauser syndrome type 2 investigation patient’s result* reference range* fsh in miu/ml 2.8 (2.8 iu/l) 1.5–12.4 (1.5–12.4 iu/l) lh in miu/ml 1 (1 iu/l) 1–18 (1–18 iu/l) prolactin in µg/l 15 (652.17 µiu/l) 4–30 (85.1064 µiu/l) dhea-s in µg/dl 193 (5.21µmol/l) 145–395 (4–10.7 µmol/l) cortisol in µg/dl 13 (358.64 nmol/l) 5–25 (138–690 nmol/l) acth in pg/ml 25 (5.5 pmol/l) 10–60 (2.2–13.2 pmol/l) e2 in pg/ml 22 (80.76 pmol/l) 21–136 (77–499 pmol/l) 17-ohp in ng/dl 105 <200 tsh in ng/ml 0.9 0.27–4.2 tt in ng/dl 17 (0.59 nmol/l) 15–46 (0.27-1.5 nmol/l) amh in pmol/l 1.83 (13.1 pmol/l) >1.0 (>7.14 pmol/l) complete blood picture and film normal anti-tissue transglutaminase iga subtype in u/ ml 1.2 <3 abdominopelvic ultrasound study malrotated kidney non-visualised uterus normal ovaries fsh = follicular stimulating hormone; lh = luteinising hormone; dhea-s = dehy droepiandrosterone sulphate ; acth = adrenocorticotrophic hormone ; e2 = estradiol; 17-ohp = 17-hydroxyprogesterone; tsh = thyroid stimulating hormone; tt = total testosterone; amh = anti-müllerian hormone; ig = immun oglobulin *the values in parentheses are the conversion of patient's results and reference ranges into si units. samih a. odhaib, miaad j. mohammed, ahmed j. h. al-ali and abbas ali mansour case report | 637 of mrkhs in most cases.1,2 different studies have described a wide range of mrkhs-associated malformations, such as renal malformations (34– 58%), skeletal malformations (12–50%) and cardiac malformations (1–3.6%).1–4,8,9 the difference in the incidence of malformation is affected by the number of cases chosen with most studies being single-centre.6 the incidence of renal malformations in mrkhs is higher than that of the general population due to the association and interaction of the two ductal systems in utero.9 normal androgen levels can usually be seen in women with type 1 (typical) mrkhs along with normal urinary excretion of steroid metabolites.4 however, women with mrkhs can have polycystic ovarian changes with associated hyperandrogenism and may even develop ovarian malignancy, although this is rare.2–5,10 patients with type 2 (atypical) mrkhs may have gonadal dysgenesis or ectopic ovaries in the absence of other associated systemic malformations.6,7,11 chromosomal aberrations may present in women with either type of mrkhs and has been seen in 1.4–4%, contradicting the usual karyotype definition in the syndrome.2,3 in the current patient, the distal third of the vagina was present with cervical and uterine agenesis. a large chinese cohort study showed a highly variable phenotype of mrkhs where all 594 patients showed complete vaginal atresia and cervical aplasia. however, it was found that 1–3 cm of the lower vagina may be present in women with mrkhs.6 the diagnosis of mrkhs relies on non-invasive methods. transabdominal ultrasonography is a useful first investigation in suspected patients. abdominopelvic mri provides a more precise diagnosis when ultrasono graphic findings are unclear. the addition of laparoscopy aids in the final diagnosis of mrkhs, especially in cases of a rudimentary uterus, although the american college of obstetricians and gynecologists recommends against it.12,13 the differential diagnosis of mrkhs includes vaginal structural anomalies such as congenital vaginal agenesis, low transverse vaginal septum and imperforate hymen. the 46,xy chromosomal aberration syndromes may be considered in the differential diagnosis.13 the main focus during the management of mrkhs, through surgical and nonsurgical techniques, is on improving sexual activity through the creation of a neovaginal and vaginal elongation, which alleviates some of the psychological burden and feelings of inferiority resulting from the fact that the female patient is devoid of the vagina.6,12 patients with mrkhs may require a sophisticated, custom-made and multidisciplinary approach to treatment through gynaecological, endocrinological and surgical care. psychomental and sexual healthcare should be offered through counselling and peer support groups along with specialised sex and relationship therapy to promote high levels of sexual well-being.13,14 conclusion the correct diagnosis of mrkhs and its associated malformations is the most crucial step in active management. mri can provide a precise diagnosis in most cases of mrkhs, whether type 1 or 2, as was seen in the current case. a u t h o r s’ c o n t r i b u t i o n sao and ajha managed the patients comprehensively. mjm performed and interpreted the images. aam supervised the study process and provided logistical support. all authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript. references 1. herlin m, bjørn amb, rasmussen m, trolle b, petersen mb. prevalence and patient characteristics of mayer–rokitansky– küster–hauser syndrome: a nationwide registry-based study. hum reprod 2016; 31:2384–90. https://doi.org/10.1093/ humrep/dew220. 2. rall k, eisenbeis s, henninger v, henes m, wallwiener d, bonin m, et al. typical and atypical associated findings in a group of 346 patients with mayer-rokitansky-kuester-hauser syndrome. j pediatr adolesc gynecol 2015; 28:362–8. https:// doi.org/10.1016/j.jpag.2014.07.019. 3. kapczuk k, iwaniec k, friebe z, kędzia w. congenital malformations and other comorbidities in 125 women with mayer-rokitansky-küster-hauser syndrome. eur j obstet gynecol reprod biol 2016; 207:45–9. https://doi.org/10.1016/j. ejogrb.2016.10.014. 4. mcgowan r, tydeman g, shapiro d, craig t, morrison n, logan s, et al. dna copy number variations are important in the complex genetic architecture of müllerian disorders. fertil steril 2015; 103:1021–30. https://doi.org/10.1016/j. fertnstert.2015.01.008. 5. rall k, conzelmann g, schäffeler n, henes m, wallwiener d, möhrle m, et al. acne and pcos are less frequent in women with mayer-rokitansky-küster-hauser syndrome despite a high rate of hyperandrogenemia: a cross-sectional study. reprod biol endocrinol 2014; 12:23. https://doi.org/10.1186/1477-7827-12-23. 6. pan hx, luo gn. phenotypic and clinical aspects of mayerrokitansky-küster-hauser syndrome in a chinese population: an analysis of 594 patients. fertil steril 2016; 106:1190–4. https://doi.org/10.1016/j.fertnstert.2016.06.007. 7. preibsch h, rall k, wietek bm, brucker sy, staebler a, claussen cd, et al. clinical value of magnetic resonance imaging in patients with mayer-rokitansky-kuster-hauser (mrkh) syndrome: diagnosis of associated malformations, uterine rudiments and intrauterine endometrium. eur radiol 2014; 24:1621–7. https://doi.org/10.1007/s00330-014-3156-3. clinical and radiological findings in mayer-rokitansky-küster-hauser syndrome type 2 case report 638 | squ medical journal, november 2021, volume 21, issue 4 12. takahashi k, nakamura e, suzuki s, shinoda m, nishijima y, ohnuki y, et al. laparoscopic davydov procedure for the creation of a neovagina in patients with mayer-rokitanskykuster-hauser syndrome: analysis of 7 cases. tokai j exp clin med 2016; 20; 41:81–7. 13. committee on adolescent health care. acog committee opinion no. 728: müllerian agenesis: diagnosis, management, and treatment. obstet gynecol 2018; 131:e35–42. https://doi. org/10.1097/aog.0000000000002458. 14. fliegner m, krupp k, brunner f, rall k, brucker sy, briken p, et al. sexual life and sexual wellness in individuals with complete androgen insensitivity syndrome (cais) and mayerrokitansky-küster-hauser syndrome (mrkhs). j sex med 2014; 11:729–42. https://doi.org/10.1111/jsm.12321. 8. oppelt p, renner sp, kellermann a, brucker s, hauser ga, ludwig ks, et al. clinical aspects of mayer-rokitansky-kuesterhauser syndrome: recommendations for clinical diagnosis and staging. hum reprod 2006; 21:792–7. https://doi.org/10.1093/ humrep/dei381. 9. oppelt pg, lermann j, strick r, dittrich r, strissel p, rettig i, et al. malformations in a cohort of 284 women with mayerrokitansky-küster-hauser syndrome (mrkh). reprod biol endocr 2012; 10:57–64. https://doi.org/10.1186/1477-7827-10-57. 10. villa r, azzollini j, peissel b, manoukian s. co-occurrence of mayer-rokitansky-küster-hauser syndrome and ovarian cancer: a case report and review of the literature. gynecol onco rep 2019; 28:68–70. https://doi.org/10.1016/j.gore.2019.03.010. 11. kebaili s, chaabane k, mnif mf, kamoun m, kacem fh, guesmi n, et al. gonadal dysgenesis and the mayer-rokitanskykuster-hauser syndrome in a girl with a 46, xx karyotype: a case report and review of literature. indian j endocrinol metab 2013; 17:505–8. https://doi.org/10.4103/2230-8210.111663. impact of fungiform papillae count on taste perception and different methods of taste assessment and their clinical applications a comprehensive review *asim m. khan,1 saqib ali,1 reshma v. jameela,1 muhaseena muhamood,1 maryam f. haqh2 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e184–191, epub. 5 nov 19 submitted 23 dec 18 revision req. 6 feb 19; revision recd. 10 mar 19 accepted 12 apr 19 1department of biomedical dental science, college of dentistry, imam abdulrahman bin faisal university, dammam, saudi arabia; 2department of pedodontics & preventive dentistry, oxford dental college & hospital, bangalore, india *corresponding author’s e-mail: amkhan@iau.edu.sa fungiform papillae are mushroom-shaped structures located on the dorsum of the anterior two-thirds of the tongue.1–3 due to their rich capillary network, larger size and patchy distribution, fungiform papillae can be identified as reddish dots that contrast to the smaller and more numerous filiform papillae. according to cadaveric data, each individual has an estimated 200 fungiform papillae which are denser on the tip of the tongue in comparison to the middle region (29 versus 7–8 papillae per cm2).2,3 each fungiform papilla carries between 0–20 taste buds, with an average of 2–4 buds; however, not all fungiform papillae contain taste buds and function as taste receptors at a given time. there are approximately 2,500 taste buds in the fungiform papillae of the anterior twothirds of the tongue, although this has been reported to vary by approximately 18-fold between individuals.1–3 based on their morphology, fungiform papillae are classified into four types that represent varying degrees of pathological severity.4 type 1 fungiform papillae are the healthiest and are egg-shaped or long and elliptical and devoid of surface thickness, while type 2 are slightly thicker. type 3 are thick and have an irregular surface while type 4—which represent the most pathological state—are flat and have an atrophic surface.4 most studies investigating taste function utilise fungiform papillae count as a tool to indicate either decreased or increased taste sensitivity.5–7 to this end, fungiform papillae count has been correlated with various electrogustometric and chemogustometric thre sholds. this review provides an overview of fungiform papillae, different methods for their quantification and the factors affecting these structures. in addition, various methods for recording taste sensation and their clinical applications are also discussed. review أثر َعّد احلليمات الكميئة على إدراك حاسَُّة الذَّوق والطرق املختلفة لتقييم الذَّوق، وتطبيقاهتا السريرية مراجعة شاملة عا�صم م�صطفى خان، ثاقب علي، ر�صما جميلة، حما�صنا حممود، مرمي ف�صيحة حق abstract: fungiform papillae are raised lingual structures which contain taste buds and thus play an important role in taste perception. these structures vary in number due to their relative sensitivity to a range of systemic and local factors which affect the dorsum of the tongue. taste sensation can be measured using both chemical and electrical methods; however, the number of fungiform papillae has a direct effect on chemogustometric and electrogustometric values during evaluation. this review provides a general overview of fungiform papillae, their quantification methods and the various factors which may affect these structures. in addition, numerous methods of recording taste sensation and their clinical applications are highlighted. keywords: sensation; taste; taste perception; tongue; taste buds; investigative techniques. ُة �لذَّوق. وتتفاوت امللخ�ص: �حلليمات �لكمئية هي بنيات ل�صينية مرتفعة حتتوي على بر�عم �لذوق، ولهذ� فهي توؤدي دور� مهما يف �إدر�ك حا�صَّ �أعد�د تلك �لبنيات ن�صبة للتفاوت يف ح�صا�صيتها �لن�صبية جتاه طيف من �لعو�مل �جلهازية و�ملحلية �ملوؤثرة على ظهر �لل�صان. وميكن قيا�س ُة �لذَّوق �ملقا�صة كيميائيا، و كهربائيا، يف ُة �لذَّوق بطرق كيميائية وكهربائية. �إال �أن لَعّد �حلليمات �لكميئة �أثر� مبا�رص� على قيم حا�صَّ حا�صَّ غ�صون فرتة �لتقييم. وتهدف هذه املراجعة إىل تقديم ��صتعر��س �صامل للحليمات �لكميئة، وطرق عدها، و�لعو�مل �ملختلفة �لتي توؤثر على تركيبها. باالإ�صافة لذلك يتطرق �ملقال للطرق �ملختلفة �لتي ميكن بها قيا�س حا�صة �لذَّوق، واستعراضتطبيقاتها �ل�رصيرية. ُة �لذَّوق؛ ال�صان؛ بر�عم �لذوق؛ طرق �ال�صتق�صاء. وق؛ �إدر�ك حا�صَّ الكلمات املفتاحية: ح�س؛ ذَّ this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.003 https://creativecommons.org/licenses/by-nd/4.0/ asim m. khan, saqib ali, reshma v. jameela, muhaseena muhamood and maryam f. haqh review | e185 taste receptors the average human has a total of approximately 10,000 taste buds.8 these are located in the mucosa of the epiglottis, palate and pharynx as well as in fungiform and circumvallate papillae on the tongue. fungiform papillae are most numerous around the tip of the tongue, whereas circumvallate papillae are arranged in a ‘v’ pattern on the posterior third of the tongue immediately anterior to the sulcus terminalis.8 the taste buds on the fungiform papilla are mostly embedded on the surface of the papilla. in contrast, the larger circumvallate papillae have approximately 100 taste buds located in the side walls.8 the minute conical filiform papillae spread over the remaining tongue surface lack taste buds. taste buds are composed of ovoid bodies measuring 50–70 µm.8 each bud consists of basal cells as well as type 1, 2 and 3 cells. type 1 and 2 cells (i.e. sustentacular cells) support type 3 cells (i.e. the main gustatory cells) and are connected with sensory nerve fibres.8 type 3 cells open up in the oral cavity via an opening called the taste pore which contain microvilli projecting from the taste cells. the necks of all three cell types are connected to each other and to the surrounding epithelial cells by tight junctions, so that only the microvilli are exposed to fluids in the oral cavity [figure 1a].9 each taste bud is innervated by 50 nerve fibres which connect up to five taste buds each.8 the cells surrounding the taste buds give rise to basal cells which in turn differentiate into new taste receptor cells which replace the older ones every 10 days.8 taste buds degen erate and finally disappear when the sensory nerve supplying them is severed. however, if the nerve regen erates, the surrounding cells become organised into new taste buds; this is attributed to the influence of a chem ical inductive from the redeveloping nerve fibre.8 taste pathway the chorda tympani is a branch of the facial nerve which innervates the taste buds on the anterior two-thirds of the tongue, while the posterior third of the tongue and taste buds situated in other areas (i.e. the palate and epiglottis) are innervated via the glossopharyngeal and vagus nerves, respectively.10 taste sensation is carried to the gustatory area of the nucleus tractus solitarius in the medulla oblongata by slow-conducting myelinated nerve fibres. from the nucleus tractus solitarius, the neurons relay into the medial lemniscus of the medulla oblongata.10 the axons of these second-order neurons then transmit directly to the ventral posteromedial nucleus of the thalamus where they travel via thalamic radiation to the anterior part of the ipsilateral insula which facil itates conscious perception of taste and taste discrim ination [figure 1b].10 however, in some individuals, all or some of these second-order neurons may cross over to the contralateral side and synapse at the thalamus, projecting to the contralateral cerebral cortex, while the remaining fibres continue to project to the ipsilateral cerebral cortex, thus resulting in bilateral representation.11 taste sensation previously, it was believed that different areas of the tongue were responsible for perceiving the five different categories of taste (sweet, salty, bitter, sour and umami).12 figure 1: annotated diagrams of (a) taste bud morphology and (b) the taste pathway. figure 1a was modified and reproduced with permission from gowthamarajan et al.9 impact of fungiform papillae count on taste perception and different methods of taste assessment and their clinical applications a comprehensive review e186 | squ medical journal, august 2019, volume 19, issue 3 however, it is now understood that the process of con verting different taste stimuli into signals is not restricted to different zones of the tongue. flavours are identified as a result of a backdrop of complex chemical mechanisms which involve ionic exchange through specific channels and secondary messenger activity.8,13 this process is known as taste signal transduction. s u p e r ta s t e r p h e n o m e n o n supertaster phenomenon refers to the existence of individuals who experience tastes with far greater intensity than normal, to the degree that they can perceive usually tasteless substances, such as phenylthiocarbamide (ptc) and propylthiouracil (prop). this concept was first described by fox in 1932 when it was noted that ptc was tasteless to some individuals, yet perceived as bitter by others.14 while assessing the ptc taste response of over 2,500 subjects, fox found that 65% of individuals recorded the taste as bitter, while 28% described it as tasteless and the remaining 6% described the taste in other ways.14 in recent years, research has revealed that this phenomenon is genetic in nature.13,15 this has been attributed to varying genotypes of the taste receptor 2 (tas2r) member 38 gene.15–17 mcmahon investigated supertaster phenomenon by assessing prop taste status and papillae count among subjects who were able to appreciate unsweetened grapefruit juice; the results showed increased fungiform papillae density among supertasters, with non-supertasters having the lowest mean papillae densities.17 however, more recent research has shown that no correlation exists between fungiform papillae density and differences in taste perception.18,19 methods of counting fungiform papillae d i g i ta l p h o t o g r a p h y nasri-heir et al. utilised digital photography to assess fungiform papillae count by using a camera with a resolution of at least five megapixels to photograph the tongue alongside a millimetre slide rule.6 subsequently, using a computer, a grid was superimposed over the image and stretched to coincide with markings on the ruler in order to create 1 cm2-sized boxes. the papillae within these boxes were then counted and averaged to arrive at a mean value.6 this technique has also been supplemented with image analysis software [figure 2].7 c o n ta c t e n d o s c o p y a n d s ta i n i n g pavlos et al. evaluated fungiform papillae density using contact endoscopy and the application of a methylene blue stain.20 first, a contact technique without staining was performed to aid imaging of the subepithelial capillaries; subsequently, the stain was applied to the epithelia and taste pores using a 1 cm2-sized piece of filter paper placed around the tip of the tongue. the fungi form papillae were easily distinguishable as they were lightly stained in comparison to the darker filiform papillae.20 f o o d c o l o u r i n g d y e zhang et al. used food dye (brilliant blue fcf133) to stain the tip of the tongue.21 the dye was transferred to the tongue using a 6-mm circular piece of filter paper. the stained area was then photographed using a digital camera and the photographs subjected to analysis using adobe photoshop® software (adobe inc., san jose, california, usa).21 an example of this technique is shown in figure 3.19 d e n v e r pa p i l l a e p r o t o c o l nuessle et al. proposed a standardised method known as the denver papillae protocol to define and prioritise the characteristics of fungiform papillae.22 this method involved manually counting the number of papillae in a 10-mm circular section of the tongue stained with a blue-coloured dye. using image analysis software and digital photography, the fungiform papillae were then characterised based on their shape, colour, size and height.22 individual fungiform papilla were rejected from the count if they were amorphous, stained blue in comparison to their surroundings, less than 0.5 mm in length or if they were lower in height compared to the surface of the tongue floor or the adjacent papillae.22 a u t o m at e d d e t e c t i o n eldeghaidy et al. reported a method to automatically detect fungiform papillae on the dorsum of the tongue in collaboration with matlab® image analysis software (mathworks, natick, massachusetts, usa).18 the anterior 2 cm section of the dorsum of the tongue was automatically divided into eight regions by the software in which fungiform papillae were counted using various algorithms. however, one limitation of figure 2: image of fungiform papillae quantification using digital photography and computer software. reproduced with permission from khan et al.7 asim m. khan, saqib ali, reshma v. jameela, muhaseena muhamood and maryam f. haqh review | e187 this methodology is that the software may inaccurately assess the diameter of the papillae because the software considers all fungiform papillae to be exactly circular in shape.18 discrepancies have therefore been noted when the diameters of fungiform papillae are validated manually.18,23 factors affecting fungiform papillae count nutrition and age are two major factors that affect the number of papillae present on the dorsum of the tongue.24,25 certain nutrients such as vitamin b12 and folate are important to maintain an optimum balance between cell regeneration and deterioration;24 this is particularly important as the taste cells in the papillae have a high turnover rate.8 in addition, vitamin a deficiency may result in keratinisation and the loss of integrity of such cells in the epithelium. zinc deficiency can also have similar consequences.24 increasing age also slows down cellular regeneration, with 70% fewer taste buds recorded in individuals aged 70 years old compared to those aged 30 years.24 this also explains why many older individuals often have decreased taste sensitivity.25 due to their high metabolic activity, cells forming filiform and fungiform papillae are also sensitive to enzyme, circulation or nutrient disturbances which can lead to atrophy. during atrophy, filiform papillae are more vulnerable to such disturbances compared to fungiform papillae; moreover, following atrophy, fungiform papillae regenerate faster in comparison to filiform papillae.24 saito et al. reported that fungiform papillae atrophied among patients with normal pre operative gustatory function after sectioning of the chorda tympani nerve; subsequently, the papillae reco vered after regeneration or re-adaption of the nerve.26 spielman et al. biopsied fungiform papillae from the dorsum of the tongue and reported papillae regener ation at the same site after 40 days.27 nasri-heir et al. reported that the fungiform papillae count differed between patients with burning mouth syndrome and healthy controls (27.554 ± 2.122 papillae per cm2 versus 31.575 ± 3.112 papillae per cm2).6 zhang et al. reported an inverse correlation between the number of fungiform papillae and taste thresholds using sucrose among young male subjects.21 numerous other factors also affect the density of fungiform papillae, such as smoking.20 various other potential causes of lingual papillae loss are listed in table 1.28 methods of evaluating taste sensation the two primary methods of evaluating taste sensation are chemogustometry and electrogustometry. figure 3: photographs of tongue stained with brilliant blue fcf before (a) and after (b) fungiform papillae quantification. reproduced with permission from jilani et al.19 table 1: factors potentially resulting in lingual papillae loss28 nutritional deficiencies peripheral vascular diseases local factors therapeutic agents • iron-deficiency anaemia • plummer-vinson syndrome • pernicious anaemia • anaemia associated with parasitic infections (e.g. ascariasis and bilharziasis) • tropical sprue or coeliac disease • chronic alcoholism • vitamin b deficiency (especially vitamin b2, b6, b12, folic acid and nicotinic acid) • diabetic angiopathy • vasculitis in patients with sle • endarteritis obliterans • syphilitic glossitis • obliteration of the small blood vessels (e.g. in scleroderma or submucous fibrosis) • localised vascular insufficiency in elderly patients • frictional irritation to the tip and lateral borders of the tongue • atrophic lichen planus • epidermolysis bullosa or ulceration which heals with scarring • long-standing xerostomia • drugs that interfere with the growth and maturation of the epithelium (e.g. cyclosporine) • drugs that induce candidosis (e.g. antibiotics and steroids) • drugs that induce xerostomia (e.g. anticholinergic drugs and radiotherapy) sle = systemic lupus erythematosus. impact of fungiform papillae count on taste perception and different methods of taste assessment and their clinical applications a comprehensive review e188 | squ medical journal, august 2019, volume 19, issue 3 c h e m o g u s t o m e t r y chemogustometry involves the application of chemical solutions to the oral mucosa; subsequently, the degree to which any of the five types of taste presents itself is evaluated by equating the taste with that of a reference material.29 thus, taste detection thresholds are eval uated by asking the subject to taste a particular sub stance in various concentrations. this is done system atically by either increasing or decreasing the dilution of the substance. water is used as a control during the process, with the subject ideally being able to discriminate between water and the diluted test solution.29 in order to appreciate any differences in the taste intensity of the substance being tested, there should be at least a 30% difference in dilution between solutions. bitterness is detected by the action of the bitter substance on tas2r receptors, a type of g protein-linked receptor.16 chemically, the threshold for bitterness is assessed using quinine hydrochloride at a dilution of 1 g in 2 l of water.23 saltiness is evaluated by assessing the action of the salty substance on epithelial sodium channel (enac) receptors using a diluted solution of sodium chloride. taste transduction is thus induced by the influx of sodium ions in the enac receptors which facilitates the release of glutamate to depolarise neurons. sourness, measured using diluted hydrochloric acid, also acts via the enac receptors which allow the inflow of protons and triggers neurons.8,23 sweetness is assessed using a diluted sweet sub stance such as sucrose or artificial sweeteners like saccharin, which differ in taste due to their distinct chemical structures. taste transduction occurs via another g protein receptor known as taste receptor 1. the final type of taste, umami, is savoury in nature. umami taste is induced by the activation of meta botropic glutamate receptor 4 as a result of stimulants such as monosodium glutamate. inosine monophosphate and guanosine monophosphate act as agonists during umami taste induction.8,23 taste strips and disks one method of chemogustometric evaluation involves presenting tastants to subjects in a clinical setting via soaked elongated strips or circular disks.30,31 these taste strips or disks are usually made up of pullulan (α-1,4and α-1,6-glucan) which is also combined with the polymer hydroxypropyl methylcellulose. such strips or disks are dissolvable in the oral cavity and do not need to be retrieved afterwards.30 the three-drop method using this method, three drops of a chemical tasting solution are placed in the middle of the dorsum of the tongue, approximately 1.5 cm from the tip.31 one drop contains the actual tasting solution and the other two are distilled water drops which act as a solvent. the testing process usually starts with the lowest concent ration, with the solution increasing in concentration until the subject’s tasting threshold is detected.31 electroencephalography event-related potentials refer to the electrical responses evoked in the brain when an individual is presented with a stimulus. as such, after applying chemical gustatory stimuli to the tongue, electroencephalography can show cortical brain activity associated with the taste sensation, along with its topographical distribution.32 advantages and disadvantages chemogustometry consists of using an array of chem ical solutions in multiple concentrations to assess taste sensation. some advantages of this method include the long shelf-life of the materials needed, the ease of administration, the rapidity of testing and the fact that this method allows for evaluation of each side of the tongue separately.31 however, this method is qualitative in nature and more cumbersome in a clinical setting in comparison to electrogustometry. e l e c t r o g u s t o m e t r y electrogustometry quantifies taste and measures the threshold of taste sensation by passing a controlled current through the tongue using electrodes. as cathodal stimuli do not produce any significant recordable sen sation, a weak anodal current is used.33 the stimulus is a constant direct current of predefined amplitude and duration. the taste perceived during electrogustometry is described as sour-metallic or ‘battery’-like and is attributed to the absorption of protons (or hydronium ions) released by the stimulus.33 in 1754, sulzer first described the ‘ferro-sulphate’ like metallic taste which occurs when two dissimilar metals come into contact with the tongue.34 in 1955, skouby invented the first electrogustometer based on taste thresholds determined by placing chemical solutions on the tongue.35 subsequently, the measure ment of taste using an electric stimulus was reported by krarup in 1958.34 over time, electrogustometers have evolved in terms of their design, electrode composition and size.33,35 electrogustometry is now a viable clinical tool to estimate taste function, though this method is yet to be commonly used. when an electrode from an electrogustometer is placed on tongue, two types of sensations are induced—tingling and taste.33 these two sensations are conducted via different nerves, with taste perceived as a visceral sensation by the chorda tympani nerve while the tingling is a mechanical sensation conducted by the lingual nerve. therefore, electrogustometry aids in differentiating between the chorda tympani and lingual asim m. khan, saqib ali, reshma v. jameela, muhaseena muhamood and maryam f. haqh review | e189 nerves and is especially important in determining the integrity of the neural pathway.6,33 however, since electrogustometric taste threshold measurements are subjective, uniformity must be maintained in the environment/set-up of the test and the way the subject is trained to respond to the sensations. advantages and disadvantages electrogustometry is a quick and quantitative tool to assess taste threshold, particularly among patients with taste disorders such as hemiageusia and ageusia.32,36 moreover, it allows for the evaluation of the most minute taste deficits, even in the absence of symptoms, and can be used to determine the topographical location of such deficits along the taste pathway and glossopharyngeal nerve. furthermore, electrogustometry can also aid in determining patient prognosis.36 however, a major drawback of electrogustometry is that it is subjective and relies on feedback from the subject.36 it also cannot be used to investigate or diagnose symptoms commonly associated with certain taste disorders, such as heterogeusia and spontaneous dysgeusia. finally, this technique cannot be used for patients with artificial pacemakers as electrical stimuli from the electrodes may cause interference with electrical signals from the pacemaker.36 clinical applications b u r n i n g m o u t h s y n d r o m e braud et al. reported a significant association between electrogustometric values and pain intensity measured by visual analogue scale among patients with burning mouth syndrome, indicating a potent interaction between gustatory and nociceptive components among affected subjects.37 nasri-heir et al. also noted signif icantly higher electrogustometric responses among patients with burning mouth syndrome in comparison to a normal control group.6 the researchers concluded that burning mouth syndrome is a neurodegenerative phenomenon with decreased chorda tympani activity.6 c a n c e r ovesen et al. reported higher taste thresholds in subjects with small-cell lung, breast and ovarian cancer compared to controls with non-neoplastic disease.38 moreover, taste thresholds decreased among those patients who responded to chemotherapy, suggesting that malignant disease has an effect on taste sensation. these findings indicate that electrogustometry could be a useful diag nostic tool in neoplastic cancers.38 epstein et al. found that patients with cancer devel oped taste disorders (i.e. dysgeusia) as a result of other factors apart from pathology, such as chemotherapy treatment.39 this is because chemotherapy drugs are released into the saliva and adhere directly to the taste buds, causing altered taste perceptions and resulting in a metallic or chemical taste. as such, it is recommended that taste and olfactory electrogustometric evaluations be made mandatory for all patients undergoing cancer treatment.39 n e u r o l o g i c a l d i s e a s e s dzaman et al. reported that 13 out of 35 subjects with nasal polyps had increased taste and olfactory thresholds as assessed by electrogustometry compared to controls.40 deeb et al. reported a deficit in electrogustometric thresholds among subjects with parkinson’s disease, indicative of disease severity.41 p o s t o p e r at i v e pat i e n t s doty et al. assessed the impact of factors such as age and gender on taste perception among individuals under going chorda tympani nerve resection.42,43 taste assess ment was done in different regions of the tongue using filter paper soaked in tastants such as sucrose, sodium chloride and caffeine; in addition, the patients were subjected to electrical stimuli via electrogustometry. the researchers reported a deterioration in taste sensiti vity commencing in middle age and progressively reducing after 50 years of age.42,43 this decline in taste sensitivity occurred for all stimuli at the anterior part of the tongue, with chorda tympani nerve resection resulting in taste deficits on the same side as well as the middle portion of the tongue.42,43 boucher et al. investigated taste defects by electro gustometry in patients with severed afferent connections caused by dental treatment.44 higher electrogustometric thresholds were recorded in subjects with more than seven deafferented teeth compared to those with fewer deafferented teeth, with a significant direct correlation between electrogustometric thresholds and the number of deafferented teeth, regardless of age.44 similarly, michael et al. found a greater prevalence of electro gustometric taste changes among patients following middle-ear surgery; this was ascribed to damage caused by the distention and, to a lesser degree, severance of the chorda tympani nerve.45 s m o k i n g depressed or altered taste sensation has been reported among chronic smokers.46,47 smoke from burning tobacco includes a variety of irritants, oncogenic particles such as tar and lead, as well as other poisonous substances such as carbon monoxide and nicotine. these not only topically affect taste receptors cells and impede the normal mechanism of taste conduction impact of fungiform papillae count on taste perception and different methods of taste assessment and their clinical applications a comprehensive review e190 | squ medical journal, august 2019, volume 19, issue 3 but also affect the neurological transmission of taste sensations.46 the effects of tobacco on taste thresholds depend upon the individual’s susceptibility, the quantity and frequency of use and the age of the individual when they started smoking. using a modified form of electro gustometry, khan et al. reported significantly lower fungiform papillae counts and greater electrical taste thresholds in smokers compared to non-smokers.7 moreover, in a follow-up study of smokers before and after quitting, chéruel et al. found that smoking cessation lead to a recovery in taste sensitivity.46 how ever, the time required to regain taste functionality depended on the susceptibility of the region of the tongue that had been affected. the researchers advoc ated for the use of electrogustometry as a method of motivating chronic smokers to stop smoking.46 yekta et al. studied somatosensory function in the mucosa of the tongue.47 subjects were tested bilaterally in tongue regions innervated by the lingual nerves according to sensory heat, pain and mechanical detection thresholds. increased heat thresholds were reported in smokers in comparison to non-smokers; this was attributed to damage caused by smoking to the myelinated aδand c-fibres of the tongue.47 conclusion fungiform papillae density offers valuable information regarding an individual’s taste perception and taste sensation thresholds, with both chemical and electrical tools available for quantification purposes. however, as chemogustometry is a mostly qualitative method of determining taste sensitivity and requires a complex array of chemical solutions, it can be cumbersome in a clinical setting. in contrast, electrogustometry is a quick and quantitative tool and has a wide range of clinical applications, including for patients with taste disorders, burning mouth syndrome and neoplastic cancers as well as for smoking cessation purposes. references 1. miller ij jr, bartoshuk lm. taste perception, taste bud distribution, and spatial relationships. in: getchell tv, doty rl, bartoshuk lm, snow jb jr, eds. smell and taste in health and disease. new york, usa: raven press, 1991. pp. 205–33. 2. cheng lh, robinson pp. the distribution of fungiform papillae and taste buds on the human tongue. arch oral biol 1991; 36:583–9. https://doi.org/10.1016/0003-9969(91)90108-7. 3. miller ij jr. human fungiform taste bud density and distribution. ann ny acad sci 1987; 510:501–3. https://doi. org/10.1111/j.1749-6632.1987.tb43604.x. 4. negoro a, umemoto m, fukazawa k, terada t, sakagami m. observation of tongue papillae by video microscopy and contact endoscopy to investigate their correlation with taste function. auris nasus larynx 2004; 31:255–9. https://doi. org/10.1016/j.anl.2004.01.009. 5. pavlidis p, gouveris h, kekes g. electrogustometry thresholds, tongue tip vascularization, density, and form of the fungiform papillae following smoking cessation. chem senses 2017; 42:419–23. https://doi.org/10.1093/chemse/bjx009. 6. nasri-heir c, gomes j, heir gm, ananthan s, benoliel r, teich s, et al. the role of sensory input of the chorda tympani nerve and the number of fungiform papillae in burning mouth syndrome. oral surg oral med oral pathol oral radiol endod 2011; 112:65–72. https://doi.org/10.1016/j.tripleo.2011.02.035. 7. khan am, narayanan vs, puttabuddi jh, chengappa r, ambaldhage vk, naik p, et al. comparison of taste threshold in smokers and non-smokers using electrogustometry and fungiform papillae count: a case control study. j clin diagn res 2016; 10:zc101–5. https://doi.org/10.7860/jcdr/2016/14 478.7835. 8. barrett k, brooks h, boitano s, barman s. ganong’s review of medical physiology, 23rd ed. new york, usa: mcgraw-hill medical, 2009. 9. gowthamarajan k, kulkarni gt, kumar mn. pop the pills without bitterness: taste-masking technologies for bitter drugs. resonance 2004; 9:25–32. https://doi.org/10.1007/bf0 2834304. 10. guyton ac, hall je. textbook of medical physiology, 11th ed. philadelphia, pennsylvania, usa: saunders co., 2006. 11. kamath mg, prakash j, tripathy a, concessao p. taste pathway: what do we teach? j clin diagn res 2015; 9:cl01. https://doi.org/10.7860/jcdr/2015/11021.5471. 12. sciencedaily. biologists discover how we detect sour taste. from: www.sciencedaily.com/releases/2006/08/060823184824. htm accessed: mar 2019. 13. bartoshuk lm. comparing sensory experiences across individuals: recent psychophysical advances illuminate genetic variation in taste perception. chem senses 2000; 25:447–60. https://doi.org/10.1093/chemse/25.4.447. 14. fox al. the relationship between chemical constitution and taste. proc natl acad sci u s a 1932; 18:115–20. https://doi. org/10.1073/pnas.18.1.115. 15. cannon ds, baker tb, piper me, scholand mb, lawrence dl, drayna dt, et al. associations between phenylthiocarbamide gene polymorphisms and cigarette smoking. nicotine tob res 2005; 7:853–8. https://doi.org/10.1080/14622200500330209. 16. maehashi k, matano m, wang h, vo la, yamamoto y, huang l. bitter peptides activate htas2rs, the human bitter receptors. biochem biophys res commun 2008; 365:851–5. https://doi. org/10.1016/j.bbrc.2007.11.070. 17. mcmahon ka. supertasters: updating the taste test for the a & p laboratory. poster from the proceedings of the 29th conference of the association for biology laboratory education. test stud lab teach 2008; 29:398–405. 18. eldeghaidy s, thomas d, skinner m, ford r, giesbrecht t, thomas a, et al. an automated method to detect and quantify fungiform papillae in the human tongue: validation and relationship to phenotypical differences in taste perception. physiol behav 2018; 184:226–34. https://doi.org/10.1016/j.phy sbeh.2017.12.003. 19. jilani h, ahrens w, buchecker k, russo p, hebestreit a; idefics consortium. association between the number of fungiform papillae on the tip of the tongue and sensory taste perception in children. food nutr res 2017; 61:1348865. https://doi.org/10.1080/16546628.2017.1348865. https://doi.org/10.1016/0003-9969%2891%2990108-7 https://doi.org/10.1111/j.1749-6632.1987.tb43604.x https://doi.org/10.1111/j.1749-6632.1987.tb43604.x https://doi.org/10.1016/j.anl.2004.01.009 https://doi.org/10.1016/j.anl.2004.01.009 https://doi.org/10.1093/chemse/bjx009 https://doi.org/10.1016/j.tripleo.2011.02.035 https://doi.org/10.7860/jcdr/2016/14478.7835 https://doi.org/10.7860/jcdr/2016/14478.7835 https://doi.org/10.1007/bf02834304 https://doi.org/10.1007/bf02834304 https://doi.org/10.7860/jcdr/2015/11021.5471 https://doi.org/10.1093/chemse/25.4.447 https://doi.org/10.1073/pnas.18.1.115 https://doi.org/10.1073/pnas.18.1.115 https://doi.org/10.1080/14622200500330209 https://doi.org/10.1016/j.bbrc.2007.11.070 https://doi.org/10.1016/j.bbrc.2007.11.070 https://doi.org/10.1016/j.physbeh.2017.12.003 https://doi.org/10.1016/j.physbeh.2017.12.003 https://doi.org/10.1080/16546628.2017.1348865 asim m. khan, saqib ali, reshma v. jameela, muhaseena muhamood and maryam f. haqh review | e191 20. pavlos p, vasilios n, antonia a, dimitrios k, georgios k, georgios a. evaluation of young smokers and non-smokers with electrogustometry and contact endoscopy. bmc ear nose throat disord 2009; 9:9. https://doi.org/10.1186/1472-6815-9-9. 21. zhang gh, zhang hy, wang xf, zhan yh, deng sp, qin ym. the relationship between fungiform papillae density and detection threshold for sucrose in the young males. chem senses 2009; 34:93–9. https://doi.org/10.1093/chemse/bjn059. 22. nuessle tm, garneau nl, sloan mm, santorico sa. denver papillae protocol for objective analysis of fungiform papillae. j vis exp 2015; 100:e52860. https://doi.org/10.3791/52860. 23. piochi m, dinnella c, prescott j, monteleone e. associations between human fungiform papillae and responsiveness to oral stimuli: effects of individual variability, population characteristics, and methods for papillae quantification. chem senses 2018; 43:313–27. https://doi.org/10.1093/chemse/bjy015. 24. kamath sk. taste acuity and aging. am j clin nutr 1982; 36:766–75. https://doi.org/10.1093/ajcn/36.4.766. 25. arvidson k. location and variation in number of taste buds in human fungiform papillae. scand j dent res 1979; 87:435–42. https://doi.org/10.1111/j.1600-0722.1979.tb00705.x. 26. saito t, narita n, yamada t, manabe y, ito t. morphology of human fungiform papillae after severing chorda tympani nerve. ann oto rhinol laryngol 2011; 120:300–6. https://doi. org/10.1177/000348941112000504. 27. spielman ai, pepino my, feldman r, brand jg. technique to collect fungiform (taste) papillae from human tongue. j vis exp 2010; 42:2201. https://doi.org/10.3791/2201. 28. laskaris g. pocket atlas of oral diseases, 2nd ed. stuttgart, germany: thieme, 2005. 29. simmen b, pasquet p, hladik cm. methods for assessing taste abilities and hedonic responses in human and non-human primates. in: macbeth h, macclancy j, eds. researching food habits: methods and problems. oxford, uk: berghahn books, 2004. pp. 87–99. 30. doty rl. measurement of chemosensory function. world j otorhinolaryngol head neck surg 2018; 4:11–28. https://doi. org/10.1016/j.wjorl.2018.03.001. 31. mueller ca, kallert s, renner b, stiassny k, temmel af, hummel t, et al. quantitative assessment of gustatory function in a clinical context using impregnated “taste strips”. rhinology 2003; 41:2–6. 32. hummel t, genow a, landis bn. clinical assessment of human gustatory function using event related potentials. j neurol neurosurg psychiatry 2010; 81:459–64. https://doi. org/10.1136/jnnp.2009.183699. 33. sardana ds, mittal dp, saha ak, singh dp, bassi nk. electrogustometry: a physiological study. indian j otolaryngol 1975; 27:127–33. 34. krarup b. electro-gustometry: a method for clinical taste examinations. acta otolaryngol 1958; 49:294–305. https://doi. org/10.3109/00016485809134758. 35. grant r, ferguson mm, strang r, turner jw, bone i. evoked taste thresholds in a normal population and the application of electrogustometry to trigeminal nerve disease. j neurol neurosurg psychiatry 1987; 50:12–21. https://doi.org/10.1136/ jnnp.50.1.12. 36. tomita h, ikeda m. clinical use of electrogustometry: strengths and limitations. acta otolaryngol suppl 2002; 122:27–38. https://doi.org/10.1080/00016480260046391. 37. braud a, descroix v, ungeheuer mn, rougeot c, boucher y. taste function assessed by electrogustometry in burning mouth syndrome: a case-control study. oral dis 2017; 23:395–402. https://doi.org/10.1111/odi.12630. 38. ovesen l, sørensen m, hannibal j, allingstrup l. electrical taste detection thresholds and chemical smell detection thresholds in patients with cancer. cancer 1991; 68:2260–5. https://doi.org/10.1 002/1097-0142(19911115)68:10<2260::aid-cncr28206810 26>3.0.co;2-w. 39. epstein jb, barasch a. taste disorders in cancer patients: pathogenesis, and approach to assessment and management. oral oncol 2010; 46:77–81. https://doi.org/10.1016/j.oralonco logy.2009.11.008. 40. dzaman k, pleskacz wa, wałkanis a, rapiejko p, jurkiewicz d. [taste and smell senses estimation in patients with nasal polyps]. otolaryngol pol 2007; 61:831–7. https://doi.org/10.1016/s003 0-6657(07)70537-1. 41. deeb j, shah m, muhammed n, gunasekera r, gannon k, findley lj, et al. a basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and datscan in the diagnosis of parkinson’s disease. qjm 2010; 103:941–52. https://doi.org/10.1093/qjmed/hcq142. 42. doty rl, heidt jm, macgillivray mr, dsouza m, tracey eh, mirza n, et al. influences of age, tongue region, and chorda tympani nerve sectioning on signal detection measures of lingual taste sensitivity. physiol behav 2016; 155:202–7. https://doi.org/10.1 016/j.physbeh.2015.12.014. 43. doty rl. age-related deficits in taste and smell. otolaryngol clin north am 2018; 51:815–25. https://doi.org/10.1016/j.otc.2 018.03.014. 44. boucher y, berteretche mv, farhang f, arvy mp, azérad j, faurion a. taste deficits related to dental deafferentation: an electrogustometric study in humans. eur j oral sci 2006; 114:456–64. https://doi.org/10.1111/j.1600-0722.2006.00401.x. 45. michael p, raut v. chorda tympani injury: operative findings and postoperative symptoms. otolaryngol head neck surg 2007; 136:978–81. https://doi.org/10.1016/j.otohns.2006.12.022. 46. chéruel f, jarlier m, sancho-garnier h. effect of cigarette smoke on gustatory sensitivity, evaluation of the deficit and of the recovery time-course after smoking cessation. tob induc dis 2017; 15:15. https://doi.org/10.1186/s12971-017-0120-4. 47. yekta ss, lückhoff a, ristić d, lampert f, ellrich j. impaired somatosensation in tongue mucosa of smokers. clin oral investig 2012; 16:39–44. https://doi.org/10.1007/s00784-0100480-0. https://doi.org/10.1186/1472-6815-9-9 https://doi.org/10.1093/chemse/bjn059 https://doi.org/10.3791/52860 https://doi.org/10.1093/chemse/bjy015 https://doi.org/10.1093/ajcn/36.4.766 https://doi.org/10.1111/j.1600-0722.1979.tb00705.x https://doi.org/10.1177/000348941112000504 https://doi.org/10.1177/000348941112000504 https://doi.org/10.3791/2201 https://doi.org/10.1016/j.wjorl.2018.03.001 https://doi.org/10.1016/j.wjorl.2018.03.001 https://doi.org/10.1136/jnnp.2009.183699 https://doi.org/10.1136/jnnp.2009.183699 https://doi.org/10.3109/00016485809134758 https://doi.org/10.3109/00016485809134758 https://doi.org/10.1136/jnnp.50.1.12 https://doi.org/10.1136/jnnp.50.1.12 https://doi.org/10.1080/00016480260046391 https://doi.org/10.1111/odi.12630 https://doi.org/10.1002/1097-0142%2819911115%2968:10%3c2260::aid-cncr2820681026%3e3.0.co%3b2-w https://doi.org/10.1002/1097-0142%2819911115%2968:10%3c2260::aid-cncr2820681026%3e3.0.co%3b2-w https://doi.org/10.1002/1097-0142%2819911115%2968:10%3c2260::aid-cncr2820681026%3e3.0.co%3b2-w https://doi.org/10.1016/j.oraloncology.2009.11.008 https://doi.org/10.1016/j.oraloncology.2009.11.008 https://doi.org/10.1016/s0030-6657%2807%2970537-1 https://doi.org/10.1016/s0030-6657%2807%2970537-1 https://doi.org/10.1093/qjmed/hcq142 https://doi.org/10.1016/j.physbeh.2015.12.014 https://doi.org/10.1016/j.physbeh.2015.12.014 https://doi.org/10.1016/j.otc.2018.03.014 https://doi.org/10.1016/j.otc.2018.03.014 https://doi.org/10.1111/j.1600-0722.2006.00401.x https://doi.org/10.1016/j.otohns.2006.12.022 https://doi.org/10.1186/s12971-017-0120-4 https://doi.org/10.1007/s00784-010-0480-0 https://doi.org/10.1007/s00784-010-0480-0 squ med j, may 2011, vol. 11, iss. 2, pp. 165-178, epub. 15th may 11 submitted 13th jul 10 revision req. 5th oct 10, revision recd. 2nd nov 10 accepted 24th nov 10 1experimental cancer medicine (ecm), department of laboratory medicine, karolinska institutet, stockholm, sweden; 2clinical research centrum, karolinska university hospital, huddinge, stockholm, sweden. *corresponding author email: moustapha.hassan@ki.se <ü”fπ]<üëá�j÷]<ª<‹ä¢]<ª<ìëêå˘]<ìè”è⁄^flëåê<ìè“üu<öêå <ó◊¬<ç€j√π]<∞◊”ë^ä÷]<l^�fn⁄<ó◊¬< �̂ â^èœ<<t¯√◊÷ d∞jè á”âêöeàèflë^”÷]         9 7521      2 15     abstract: pharmacokinetics, pharmacodynamics and pharmacogenetics play an important role in drug discovery and contribute to treatment success. this is an essential issue in cancer treatment due to its high toxicity. during the last decade, cyclin-dependent kinase inhibitors were recognised as a new class of compounds that was introduced for the treatment of several diseases including cancer. cyclin-dependent kinases (cdks) play a key role in the regulation of cell cycle progression and ribonucleic acid transcription. deregulation of cdks has been associated with several malignancies, neurodegenerative disorders, viral and protozoa infections, glomerulonephritis and inflammatory diseases. (r)-roscovitine is a synthetic tri-substituted purine that inhibits selectively cdk1, 2, 5, 7 and 9. roscovitine has shown promising cytotoxicity in cell lines and tumor xenografts. in this paper, we present several aspects of pharmacokinetics (pk) and pharmacodynamics (pd) of roscovitine. we present also some of our investigations including bioanalysis, haematotoxicity, age dependent kinetics, pk and effects on cdks in the brain. unfavourable kinetic parameters in combination with poor distribution to the bone marrow compartment could explain the absence of myelosuppression in vivo despite the efficacy in vitro.higher plasma and brain exposure and longer elimination half-life found in rat pups compared to adult rats may indicate that roscovitine can be a potential candidate for the treatment of brain tumours in children. cdk5 inhibition and erk1/2 activation that was detected in brain of rat pups may suggest the use of roscovitine in neurodegenerative review the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine *moustapha hassan,1,2 hatem sallam,1 zuzana hassan1,2 the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine 166 | squ medical journal, may 2011, volume 11, issue 2 clinical approval of new drugs is preceded by intensive research consisting of two steps, drug discovery and drug development. in the drug discovery stage, target enzymes and/or receptors for a particular disease are identified, and new molecules are designed and screened for their biological activities. promising drug candidates are evaluated for their toxicity and efficacy in the development stage.1 studies on the metabolism and pharmacokinetics (dmpk) of candidate drugs have become an essential part in drug discovery and development programmes and start usually concomitantly with the screening for biological activity. it is estimated that approximately 10–40 % of drug candidates fail due improper pharmacokinetic properties. further, dmpk studies provide vital information about the pk/pd (pharmacokinetics/pharmacodynamics) relationship.2 this knowledge is prerequisite for safety phase i clinical trials3 and prediction of a clinical effective dose. moreover, pk is essential for further investigation of drugs in phase ii and iii clinical trials. pk/pd also play important roles in dose optimisation, personalised treatment and prevention of side effects. this in turn determines the clinical outcome. these aspects are especially important in anticancer drugs due to their toxicities and the narrow therapeutic window. age is one of the important factors affecting the pk and efficacy of drugs. variability in drug exposure and efficacy occurs among the different age populations, i.e. children, adults and elderly. it is essential to investigate the pk parameters in the age population that is treated with the drug. in the younger aged population, doses of many drugs are still not optimised due to lack of knowledge about drug disposition and pk in this particular population. several factors such as the ontogeny of the metabolising enzymes and drug transporters are responsible for the variability of dmpk.4 continuous efforts are being made to develop accurate pk models to predict the pk parameters in this population without conducting a large scale investigation which might be difficult due to technical and ethical restraints.5 age-dependent pharmacokinetics in young animals at different stages of development should be considered before clinical use.6 cyclin-dependent kinases cyclin-dependent kinases (cdks) are a family of serine/threonine kinases that are activated through binding to regulatory subunits called cyclins.7 cdk enzymes are homologues and highly conserved in their cyclin binding domain. despite the fact that the human sequencing programme has successfully indentified 20 cdks and 25 cyclins, their functions are still not fully understood and a limited number of active cdk/cyclin complexes have been identified so far.7 cyclin-dependent kinases are regulated by several mechanisms7 including, transcription and translation of their subunits, heterodimerisation with cyclins, post-translational modification by phosphorylation and dephosphorylation and interactions with the natural inhibitors. the natural inhibitors cip/kip (p21, p27, p57) suppress the cdk/cyclin complexes and ink4 proteins (p15, p16, p18 and p19) inhibit the cdk4 and cdk6 monomers. cdk/cyclin complexes play an essential role in the regulation of the cell cycle progression. cyclins transcription and degradation varies during the different phases of the cell cycle and lead to the activation or inactivation of the corresponding cdks. during the last decade, the roles of cdks in several diseases including cancer were extensively studied. over expression of cyclin b1 and hyperactivation of cdk1 has been observed in a number of primary tumours including breast-, colonand prostate carcinoma. inactivation of cip–kip inhibitors and over expression of cyclin e and/or cyclin a lead to deregulation of cdk2 in various malignancies, including melanoma, ovarian diseases. early pharmacokinetic/pharmacodynamic studies are important issues in drug discovery and may affect further development of promising drug candidates. key words: pharmacokinetics; pharmacodynamics; roscovitine; cdk inhibitor; anticancer drugs; toxicity; agedependent kinetics moustapha hassan, hatem sallam and zuzana hassan review | 167 with adenosine triphosphate (atp) for binding in the kinase atp-binding site, and 4) cdkis bind mostly by hydrophobic interactions and hydrogen bonds with the kinase. cdki have been classified according to their selectivity into three groups: 1) pan-cdki that inhibit cdk1, 2, 4, 5, 6, 7 and 9 with almost similar potency like flavopiridol; 2) selective cdki for cdks 1, 2, 5, 7 and 9 such as the 2, 6, 9 tri-substituted purines (olomoucine, roscovitine and purvalanol), and 3) selective cdki for cdk4 and 6 (pd-0332991 or p-276–00). (r)-roscovitine (cyc202) roscovitine belongs to the 2, 6, 9 tri-substituted purines [figure 1].22,23 roscovitine was found to be a selective inhibitor for cdk1, 2, 5, 7 and 9. in the kinase inhibitory assay, roscovitine has been shown to inhibit these kinases with the ic50 at the nanomolar range.24,25 roscovitine was also found to inhibit several other kinases such as cam kinase 2, ck1α, ck1δ, dyrk1a, ephb2, erk1, erk2, fak, and irak4 at the micromolar range (1-40 µm). however, other kinases including cdk4, cdk6 and cdk8 were not sensitive to roscovitine.24,25 since cdks have an important role in a wide range of cellular functions, roscovitine has been suggested as a potential treatment for several pathophysiologically different diseases. the effects of roscovitine have been studied in vitro in cell lines and in vivo in animal models. the in vitro effects of roscovitine have been studied in more than 100 cell lines. several studies have reported the ic50 required to inhibit cell proliferation including the nci 60 cell line panel (average ic50 = 16 μm),23 the mcclue et al. panel (19 cell lines; average ic50 = 15.2 μm),26 and the raynaud et al. panel (24 cell lines; average ic50 = 14.6 μm).27 the ic50 average required for inhibition of cell proliferation in cancer cell lines does not exceed 17 μm; moreover, roscovitine was shown to be cell cycle phase nonspecific. direct inhibition of several cdks results in inhibition of the exit from g0 (cdk3/cyclin c), g1/s transition (cdk2/cyclin e), s phase progression (cdk2/ cyclin a), g2 phase (cdk1/cyclin a) and g2/m transition (cdk1/cyclin b). depending on the cycling status of the cells, the antimitotic effects of roscovitine may comprise combinations of these mechanisms carcinoma, lung carcinoma and osteosarcoma.8 cdk5 has been found to modulate the metastatic potential of some malignancies including breast and prostate carcinomas.9,10 cdk2 and cdk5 have been shown to play important roles in apoptosis in various tissues.11 cdk2 was found to regulate apoptosis in thymocytes,12 while subcellular localisation of cdk2 have been found as a determinant of the apoptotic or proliferative fate of mesangial cells.13 cdk5 has an essential role in the central and peripheral nervous system.14 cdk5 regulates the cytoarchitecture of the developing brain15 and mediates the neuronal migration in the post mitotic neurons. cdk5 has also many important functions in the neuronal cytoskeleton dynamics, synaptic plasticity,16 drug addiction,17 synaptic endocytosis18 and neurotransmitter release.19 cdk5 may be involved in the pathogenesis of several neurodegenerative disorders such as alzheimer’s and parkinson’s disease.14 it has been shown that cdk9 induces the differentiation in distinct tissues and the degree of expression of cdk9 correlates with differentiation of primary neuroectodermal and neuroblastoma tumours.20 due to the important role of cdks in several diseases including cancer, intensive efforts to find selective cyclin-dependent kinase inhibitors (cdki) have been made during the last 15 years. several classes of different cdki have been identified. in spite of their chemical diversity they share common characteristics:21 1) cdkis have low molecular weights (about 600); 2) cdkis are flat hydrophobic heterocyclic compounds; 3) cdkis act by competing hn n n nnn h ho figure 1: the structure of roscovitine and other members of the 2, 6, 9 trisubstituted cyclin-dependent kinase inhibitors (cdki) the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine 168 | squ medical journal, may 2011, volume 11, issue 2 indirect inhibition of the cell cycle by roscovitine is mediated through the inhibition of the activity of cdk7/ cyclin h/ mat1 (cak) resulting in prevention of the phosphorylation of the t loop threonine of various cdks. this finally decreases the activity of cdk1, 2 and 4. also phosphorylation of the natural inhibitor p27 by cdk2 will be diminished28 28 leading to its stabilisation and more inhibition of the cell cycle.29 in addition, roscovitine was shown to inhibit the initiation of dna synthesis,30 the formation of centrosomes31 and the formation of the nucleolus.32 roscovitine has been shown to induce apoptosis in several cell lines regardless of the p53 status; however, roscovitine has a higher potency to induce apoptosis in wild type p53 cells compared to p53 null cells [23, 26, 33-34]. cell death has been detected in all phases of the cell cycle and different mechanisms may be involved including inhibition of the cell cycle due to p53 activation and inhibition of cdk7/cdk9-dependent transcription inhibiting rna polymerase ii enzyme.33,34 effects of roscovitine on global transcription have been shown to be limited and only few proteins such as mcl-1, xiap, and survivin have been found to be severely reduced. induction of cell death by roscovitine, thus, seems to correlate rather well with inhibition of transcription of essential cell survival factors.35,36 down regulation of survivin and xiap by roscovitine was shown to contribute to the activation of caspases in glioma cell.37 alvi et al. have reported that roscovitine induced apoptotic cell death in chronic lymphocytic leukaemia b-lymphocytes at significantly higher level than in normal blood mononuclear cells, purified bor t-lymphocytes. apoptosis was caspase-dependent but p53independent and was accompanied with down regulation of mcl-1 and xia.38 anti-proliferative and pro-apoptotic effects of roscovitine have been implicated in cancer treatment and used in studies on the antitumour effects of roscovitine. so far, no cell line resistant to roscovitine has been reported until now.39 interestingly, tumour cells are more dependent on the short-lived survival factors compared to normal cells, and thus, down regulation of these factors by roscovitine treatment has a higher impact on tumour cells.40 synergistic effects of roscovitine in combination with other chemotherapeutic agents such as camptothecin in mcf-7 breast tumour,41 irinotecan in p53-mutated colon cancer,42 histone deacetylase (laq824) in hl60 and jurkat leukaemic cells and doxorubicin in sarcoma cell lines 43 have been shown in vitro. antitumour effects of roscovitine as a single treatment, or in combination with conventional cytostatics, have been studied in vivo in various tumour xenografts models. nude mice bearing human colorectal cancer or human uterine cancer xenografts were treated with roscovitine at different dosing schedules. roscovitine inhibited the tumour growth rate and reduced tumour volumes and weights.26,44 roscovitine was also shown to be effective in reducing the growth of a4573 (ewing’s sarcoma) and pc3 prostate tumour xenografts.45.46 the efficacy of roscovitine in non-nude bdf1 male mice bearing glasgow osteosarcoma xenografts was investigated in relation to biological circadian rhythm. roscovitine was administered orally (300 mg/kg x1 daily) for 5 days zeitgeber time 3 (zt3, 3 hours after light onset) or at zt11 or zt19. roscovitine reduced the tumour growth by 35% when administered in the active time of the mice (zt19) and 55% when administered during their rest span (zt3 or zt11).47 roscovitine showed higher antitumour activity when combined with other antitumour treatments. maggiorella et al. have reported better reduction in tumour volume from 54% to 72% when a single dose of 100 mg/kg was given intraperitoneal (i.p.) and combined with radiation therapy in mice bearing mda-mb 231 (breast cancer).48 roscovitine was shown to have a synergistic effect in inhibiting ht29 colon cancer xenografts when combined with irinotecan.42 pharmacokinetics and metabolism of roscovitine the pk of roscovitine have been reported in mice, rats and human. vita et al. reported the pk and biodistribution of roscovitine in rats after a dose of 25 mg/kg. roscovitine pk was described by a twocompartment open model and short elimination half-life (<30 min). the highest distribution of roscovitine was observed in lungs followed by liver, fat and kidney, while exposure to roscovitine in brain was 30% of that observed in plasma. three major metabolites were detected in plasma, but no metabolites were detected in brain.49 50 moustapha hassan, hatem sallam and zuzana hassan review | 169 pk/pd of roscovitine in the bone marrow in mice myelosuppression is one of the most frequent complications and a dose limiting factor for the majority of conventional chemotherapeutic agents. depending on the dose, several cytostatics may induce complete myeloablation of the bone marrow. studies on haematotoxicity in vitro and in animal models help to predict the possible side effects prior to clinical trials. in order to investigate the myelosuppressive potential of roscovitine we studied the effect of roscovitine on bone marrow cells in vitro and in vivo in balb/c mouse. crude bone marrow was incubated in vitro with roscovitine at concentrations of 25–250 µm for 4 hrs and viability was studied using resazurin assay. the viability of bone marrow cells was decreased in a concentrationdependent manner. concentration of 250 µm significantly reduced the viability of the cells to 70% compared to controls (p = 0.015) while lower concentrations did not have a significant effect. our results were in agreement with the findings that roscovitine induced apoptosis of mature neutrophils,58 eosinophils59 and proliferating t-cells60 in a concentration and exposure-time dependent manner. the myelosuppressive effect of roscovitine on haematopoietic progenitors was studied using a clonogeneic assay. bone marrow cells were exposed to roscovitine at different concentrations (25–100 µm) for up to 24 hrs in suspension cultures. after washing, the capacity of haematopoietic progenitors to form colonyforming unit granulocyte/macrophade (cfugm), burst-forming unit erythroid (bfu-e) and colony-forming unit granulocyte/ erythrocyte/macrophage/megakaryocyte (cfugemm) colonies was studied using semisolid media. the clonogenic capacity of the bone marrow decreased in a doseand time-dependent manner. bfu-e colonies were more sensitive than cfugm and completely blocked after 12 and 24 hr incubation with both 50 and 100 µm of roscovitine. since a decrease in the colony formation in controls after 12 and 24 hrs was observed, which most probably is due to lack of the growth factors in the suspension media, bone marrow cells were exposed to roscovitine (1 100 µm) in semisolid methocult media containing growth factors. suppression of the pk of roscovitine was investigated in balb/c and tg26 mice. these studies showed rapid and biphasic clearance of roscovitine from plasma following intravenous (i.v.), i.p. or oral administration.44,51,52 roscovitine had rapid tissue distribution and rapid elimination with a half-life of 1.19 hr. plasma concentrations above 15 μm (the average ic50 values obtained with various tumour cell lines) were observed for 4, 12, and 24 h following oral administration of 50, 500, and 2000 mg/kg, respectively.44 the pk of roscovitine in humans were reported in two phasei trials. roscovitine was administered orally as a single dose (50 to 800 mg) to healthy volunteers and the concentrations of roscovitine and its carboxylated metabolite were followed in plasma and urine. roscovitine was found to undergo slow absorption from the gastrointestinal tract, but food intake did not affect the bioavailability of the drug. roscovitine was found to have rapid metabolism and non-saturated high protein binding.53 in the second investigation, twenty-one patients with a median age of 62 years (range: 39–73 years) were treated with roscovitine in doses of 100, 200 and 800 mg twice daily for 7 days. the elimination half-life ranged between 2–5 hrs depending on the dose of roscovitine. neither objective tumour responses, nor inhibition of retinoblastoma protein phosphorylation (suggested as a suitable pd endpoint) in peripheral blood mononuclear cells were observed.54 high protein binding of roscovitine (92% to 96%) was shown in human and mice plasma.44,55 in vitro and in vivo metabolism of roscovitine was reported recently.50,52,56,57 several metabolites were indentified including the carboxylate metabolite (oxidation of the alcohol group at c2 of the purine ring).50 cyp3a4 and cyp2b6 enzymes have been shown to be the main enzymes in roscovitine metabolism. roscovitine was found to undergo phase ii metabolism through conjugation with glucoronic acid by the phase ii ugt1a3, 1a9 and 2b7. moreover, roscovitine was able to inhibit its own metabolism in vitro through inhibition of cyp3a4 with the ic50 of 3.2 µm. thus, possible drug-drug interactions should be considered in the clinic.57 the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine 170 | squ medical journal, may 2011, volume 11, issue 2 the bone marrow compared to plasma. thus, low distribution of roscovitine to bone marrow may explain the low haematotoxicity in vivo. this example illustrates the importance of pk/pd and biodistribution in preclinical studies. this may be also implicated in the fact that, despite a good cytotoxic effect of roscovitine in leukaemic cell lines in vitro, the therapeutic potential of roscovitine in haematological malignancies may be limited. age-dependent kinetics and dynamics of roscovitine in rat brains age-dependent pk is an important issue when the drug may be used in the treatment of paediatric patients and/or when the drug has a narrow therapeutic window. unfortunately, scaling down the pk data from adults to paediatrics, has been proven not to be sufficiently predictive for many drugs.4 roscovitine has been found to inhibit different solid and haematological tumour cell lines including acute lymphoblastic leukaemia (all)61 which is frequent in children and is correlated with a high central nervous system (cns) relapse rate.62 recently, we have explored the effect of age on the pk of roscovitine and investigated the effect of roscovitine on two neuronal targets, cdk5 and erk1/2, in different brain regions.63 fourteen dayold pups and adult sprague-dawley rats were colony formation in a concentrationand cell type dependent manner was observed. cfu-gemm were most sensitive and were completely blocked at 25 µm concentration, followed by bfu-e which were also significantly inhibited at 25 µm while cfu-gm were least sensitive and were inhibited at 100 µm only [figure 2]. we further studied the myelosuppressive effect of roscovitine in vivo in female balb/c mice. roscovitine was administered to the mice and bone marrow cells were cultured in the methocult media and assessed for colonogenic growth. no myelosuppressive effect was detected after the administration of a single dose of roscovitine up to 250 mg/kg. then, roscovitine was administered at a dose of 175 mg/kg twice daily for 4 days. only transient inhibition of the bfu-e colonies occurred one day after the last dose of roscovitine. the colony formation capacity of bone marrow was recovered 5 days after the last dose of roscovitine [figure 3]. the lack of activity of roscovitine on haematopoietic progenitors in vivo was not expected after its proven inhibitory effect in vitro and the reported activity on different xenografts in vivo.26,44,46,47 therefore we decided to study the distribution and pk of roscovitine in balb/c mice. roscovitine was administered as a single i.p. injection in a dose of 50 mg/kg. as presented in table 1, roscovitine had a short half-life (less than 1 hr) and only a small fraction of roscovitine (about 1.5%) reached figure 2: effect of roscovitine on haematopoietic progenitors in vitro. 20,000 nucleated bone marrow cells were cultured in semi solid media (methocult m3434) with roscovitine at final concentrations of 1,10, 25 or 100 µm or dimetylsulfoxid (dmso) (control for solvent toxicity). colony forming unit granulocyte-macrophage (cfu-gm), erythroid-brust froming units (bfu-e) and colony-forming unit granulocyte erythrocyte monocyte macrophage (cfu-gemm) were counted at day 12. results are expressed as mean ± standard deviation (sd) from 5 mice. moustapha hassan, hatem sallam and zuzana hassan review | 171 found in plasma (table 2). the cmax was significantly (p <0.05) higher (>22 µg/g) in pups brain compared to that found in plasma, while 4-fold higher cmax was found in plasma compared to that observed the brain (17.7 µg/ml and about 4 µg/g, respectively) in adult rats. the high concentrations of roscovitine found in the pups’ brains indicate the free passage of roscovitine into the brain. this difference in exposure might be due to the immaturity of the cyp450 enzymes responsible for roscovitine metabolism64 or immaturity of bbb. roscovitine is metabolised in humans mainly by cyp3a4 and cyp2b6 enzymes.57 several cyp450 enzymes are not fully matured at the age of 2 weeks in rats.65 a similar situation was also reported in humans and cyp3a4, for example, approaches the adult full capacity only after first year of life.66,67 most chemotherapeutic agents do not cross the bbb and do not reach the cns in enough high concentrations to eliminate tumour cells despite treated with a single i.p. injection of roscovitine in a dose of 25 mg/kg and plasma and brain were sampled at different time points. table 2 shows the pharmacokinetic parameters of roscovitine in plasma and in different brain regions in pups and adult rats. the pk of roscovitine was best described by a 2-compartment open model with distribution half-lives of 0.6 hrs in pups and 0.06 hr in adult rats. a significantly longer elimination half-life (7 hrs) was observed in the plasma and brain of the rat pups compared to 30 and 20 min found in the plasma and brain in adult rats, respectively. the area under the concentration–time curve (auc) of roscovitine was 22-fold higher in the pups’ plasma and 100-fold higher in the pups’ brains compared to that found in adult rats [figure 4]. no significant difference between roscovitine auc in plasma and aucs in different brain regions in pups was found. on the contrary, in adult rats, the auc of roscovitine in the brain was about 25% of that cfu-gm bfu-e cfu-gemm dmso 5rosco 5rosco 1control 0 10 20 30 40 50 60 70 80 90 100 dmso 1 n r of c ol on ie s x1 00 0/ fe m ur figure 3: effect of roscovitine on haematopoietic progenitors in vivo. mice were treated withroscovitine (350 mg/kg/ day) divided into two daily doses for 4 days. mice treated with dimetylsulfoxid (dmso) and untreated animals served as controls. bone marrow was examined 1 and 5 days after the last dose of roscovitine. colony forming unit granulocytemacrophage (cfu-gm), erythroid-brust froming units (bfu-e) and colony-forming unit granulocyte erythrocyte monocyte macrophage (cfu-gemm) were counted on day 12. each group consisted of 5 mice, control group of 8 mice. results are expressed as mean ± standard deviation (sd). table 1: pharmacokinetic parameters in plasma and bone marrow following intraperitoneal administration of roscovitine (50 mg/kg) auc µmol/l .h cmax µmol/l cl l/h vd l t½ h plasma 275.8 202 0.05 0.015 0.82 bm 4.6 4.9 0.62 0.54 0.61 legend: auc = area under the concentration–time curve (auc is derived using winnonlin analysis); (cmax) = estimated maximum concentrations; cl = clearance; vd = apparent volume of distribution; t½ = half-life; bm = bone marrow. the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine 172 | squ medical journal, may 2011, volume 11, issue 2 function of bbb. butt et al. have shown that the bbb of the rat fully matures 3–4 weeks postnatal.68 no roscovitine metabolites were found in the brains of both adult and young rats. in pups, roscovitine concentrations in plasma and brain were higher than the reported ic50 (1015 µm) for cancer cell lines for more than 8 hours. however, this level of exposure was achieved for less the high systemic exposure. roscovitine was highly distributed over the bbb in the pups and the brain exposure in all studied regions (e.g. hippocampus, cerebral cortex and cerebellum) was 100% of that found in plasma which can be compared to about 25% that has been found in the brain of adult rats. the high distribution to the brain could be explained by an age-dependent variation in the maturity and table 2: pharmacokinetic parameters in plasma and brain of adult and pups rats. results are presented as mean ± standard deviation (sd) (n = 3) pk parameters plasma frontal cortex hippocampus cerebellum auc (h.μg/ml)/ (h.μg/g) pups 66.79 ± 7.15 69.57 ± 15 74.92 ± 12 78.72 ± 11.2 adults 3.01 ± 0.21 0.71 ± 0.14 0.58 ± 0.03 0.62 ± 0.06 tα (h) pups 0.50 ± 0.09 0.48 ± 0.19 0.43 ± 0.1 0.59 ± 0.14 adults 0.081 ± 0.05 0.045 ± 0.02 0.062 ± 0.012 0.062 ± 0.018 tβ (h) pups 7.2 ± 1.4 6.8 ± 1.3 8.0 ± 1.7 7.7 ± 2.2 adults 0.54 ± 0.26 0.35 ± 0.13 0.36 ± 0.15 0.42 ± 0.18 cmax (μg/ml)/ (μg/g) pups 15.79 ± 0.38 24.9 ± 1.8 24.75 ± 1.9 23.69 ± 1.4 adults 17.71 ± 4.42 4.47 ± 0.70 4.64 ± 0.81 3.81 ± 1.22 vss (ml) pups 88 ± 15.3 90 ± 21 86 ± 20 102 ± 13 adults 650 ± 223 1095 ± 167 2056 ± 219 1909 ± 484 cl (ml/h) pups 9.7 ± 1.2 10.2 ± 1.5 11.1 ± 2 11.3 ± 1.2 adults 1637 ± 118 7262 ± 1612 8737 ± 452 8139 ± 727 legend: auc = area under the concentration–time curve; tα,tβ = distribution and elimination half-lives; cmax = maximum concentration; vss = volume of distribution; cl = clearance. figure 5: effect of roscovitine on cyclin-dependent kinase 5 – neuronal protein specific cyclin-dependent kinase (cdk) cdk5 regulator (cdk5-p35) in different brain parts of 14 days old rat pups after single intraperitoneal (i.p.) injection of 25 mg/kg. pups were killed at different time points after injection, brains dissected, homogenised, and immunoblotted for active cdk5-p35. the figure shows densitometric analysis of the western blotting bands for both p35 in the frontal cortex, hippocampus and cerebellum until 48 hr after single i.p. injection of roscovitine. data are presented as mean ± standard deviation (sd) of values expressed as percentage of control animals (*, p < 0.05 for analysis of p35 data; analysis of variance (anova) followed by all pairwise fisher’s protected least significant difference (plsd) testing were used. moustapha hassan, hatem sallam and zuzana hassan review | 173 than 30 minutes in plasma and brain of adult rats. these results may be implicated in the treatment of paediatric malignancies especially brain tumours. roscovitine is a potent inhibitor of cdk5 which has important function in the developing brain such as neuronal migration.15 moreover, the negative feedback regulation of mitogen activated protein kinases (mapk) signalling by cdk5 has been suggested to be important for neuronal survival.69 high concentrations of roscovitine found in the brain of pups raised the question about the effects of roscovitine on target enzymes. we assessed the expression of p35 as an indicator of cdk5 activity. inhibition of p35 phosphorylation by cdk5 stabilises it and delays its proteasomal degradation.70,71 roscovitine induced a transient and significant accumulation of p35 protein in all brain regions in rat pups that indicates the inhibition of the cdk5 enzyme. an increase in p35 was found in the frontal cortex 1–2 hrs post-administration (140% of controls, figure 5, p < 0.05), in the hippocampus and in cerebellum at 2 hrs post-administration (150% and 200%, respectively, figure 5). the levels of p35 were normalised at 6–15 h [figure 5]. no change in p35 levels was observed in the adult brain which probably is due to the low concentration and the rapid elimination half-life. cdk5 was found to inhibit erk1/2 phosphorylation by a mek1 and rasgrf2 mediated mechanism and the inhibition of cdk5 by roscovitine increased the levels of phosphorylated erk1/2 (active form) in neuronal cells in vitro.69,72 at early time points after administration of roscovitine, the accumulation of p35 protein was accompanied by increased levels of the phosphorylated (activated) form of erk1/2. in the frontal cortex and hippocampus, a transient activation of erk1/2 was observed at 1 and 2 hrs after injection [figure 6]. in the cerebellum, significant increases of perk1/2 levels at 2 hrs were followed by a significant decrease at 6 hrs after administration [figure 6]. at later time points, levels of perk1/2 returned to control levels in all brain regions [figure 6]. altogether, roscovitine was presented in the brain of rat pups in sufficient amounts to inhibit the cdk5 resulting in increased phosphorylation of erk1/2. discussion cyclin-dependent kinases (cdks) are serine/ threonine kinases that play key roles in cell cycle progression and rna transcription. deregulation of cdks has been shown in several diseases including several types of cancer in which increased activity of cdks has been observed. synthetic cyclin dependent kinase inhibitors (cdkis) are small heterocyclic compounds which compete figure 6: effect of roscovitine on p-erk in different brain parts of rat pups 14 days old after single intrapertoneal (i.p.) injection of 25 mg/kg. pups were killed at different time points after injection, brains dissected, homogenized, and immunoblotted for active phosphorylated erk1/2. control animals were injected with vehicle. the figure show densitometric analysis of the western blotting bands for perk1/2 in the frontal cortex, hippocampus and cerebellum until 48 hr after single i.p. injection of roscovitine. data are presented as mean ± standard deviation (sd) of values expressed as percentage of control animals (*, p < 0.05 is the significant level for analysis of p-erk data; analysis of variance (anova) followed by all pairwise fisher’s protected least significant difference (plsd) post-hoc test). the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine 174 | squ medical journal, may 2011, volume 11, issue 2 with atp and inhibit the phosphorylation of the target substrates. exposure of tumour cells to cdkis results in both cell cycle arrest and apoptosis. the family of 2,6,9-trisubstituted purines are one of the first described cdk inhibitors.73 the (r)-stereoisomer of roscovitine is a member of this family and has now reached phaseii clinical trials for non-small cell lung (nscl) cancer and nasopharyngeal cancers and phasei trials for glomerulonephritis. preclinical investigations of the role of roscovitine in the treatment of neurodegenerative disorders such as alzheimer’s disease, viral infections, protozoal infections and inflammatory diseases are ongoing. roscovitine has a rapid metabolism and short elimination half-life in rodents and man.44,50,52,53 the poor pharmacokinetic profile and the insufficient exposure to the drug in cancer patients may explain the modest success in the clinical trials.54 current research is focusing on overcoming pharmacokinetic barriers that limit the clinical use of roscovitine. moreover, a novel class of second generation analogues of roscovitine has been designed and is under development. studies on the pan-cdk inhibitor flavopiridol confirmed the importance of optimising the schedule of dosing according to the pk/pd relationship. by changing the dose schedule from 72 hrs infusion to 30 minutes i.v. bolus followed by a 4-hrs infusion, a significant difference in the clinical outcome and final response of refractory cll patients was achieved.74 no myelosuppression has been reported until now in the preclinical and clinical studies with roscovitine.51,54 however, clinically beneficial low haematotoxicity of roscovitine may reflect in reality poor distribution of roscovitine to the bone marrow. in vitro, the haematopoietic progenitors were inhibited by roscovitine within the same exposure range as the tumour cells when comparing the inhibitory auc reported for tumour cell lines 26,44 with the inhibitory auc of the haematopoietic progenitors found in our study. under certain circumstances the haematotoxicity of roscovitine may become more evident: 1) changes in the form of administration, aiming to increase the half-life of the drug, may result in higher exposure to roscovitine and changes in biodistribution. this in turn may change the toxicity profile; 2) a combination of roscovitine with radiation therapy, which increases the permeability of blood-bone marrow barrier,75 and thus the distribution of some drugs to the bone marrow, may increase the myelotoxicity of roscovitine, and 3) in pediatric patients where age-dependent longer elimination half-life is most likely leading to higher exposure of haematopoietic progenitors to roscovitine and thus toxicity risk.66 figure 6: effect of roscovitine on p-erk in different brain parts of rat pups 14 days old after single intrapertoneal (i.p.) injection of 25 mg/kg. pups were killed at different time points after injection, brains dissected, homogenized, and immunoblotted for active phosphorylated erk1/2. control animals were injected with vehicle. the figure show densitometric analysis of the western blotting bands for perk1/2 in the frontal cortex, hippocampus and cerebellum until 48 hr after single i.p. injection of roscovitine. data are presented as mean ± standard deviation (sd) of values expressed as percentage of control animals (*, p < 0.05 is the significant level for analysis of p-erk data; analysis of variance (anova) followed by all pairwise fisher’s protected least significant difference (plsd) post-hoc test). moustapha hassan, hatem sallam and zuzana hassan review | 175 age dependent pk is an important issue concerning toxic drugs and drugs with a narrow therapeutic window such as anticancer drugs, where underdosing may lead to relapse while overdosing can cause severe side effects. age dependent kinetics were reported for several drugs including cis platin, busulfan, thioguanine, etoposide, lamivudine and mycophenolate mofetil.76-81 our studies showed that roscovitine elimination half-life was 14-fold higher in young rats compared to adults. moreover, the exposure to the drug was 22-fold and 100-fold higher in the plasma and brain, respectively. these results indicate the importance of early determination of the pk-parameters in different age groups. conclusion roscovitine inhibits mouse haematopoietic progenitors in vitro within the same concentration range required to inhibit malignant cells; however, the cytotoxic effect of roscovitine on haematopoietic progenitors in vivo is transient due to a short halflife in combination with low distribution to the arrow compartment. roscovitine demonstrates age-dependent pk. prolonged systemic and brain exposure to roscovitine was found in pups compared to adult rats, which may be due to immature cyp450 enzymes as well as the bbb. moreover, roscovitine was able to induce a transient effect on critical neuronal targets and signalling pathways in the brain of young rats. these studies show the importance of early pharmacokinetic and phamacodynamic studies in drug development. a c k n o w l e d g m e n t s the authors would like to express their gratitude to the swedish cancer foundation (cancer fonden) and the swedish children cancer society (barn cancer fonden) for their support for this work. references 1. lin jh, lu ay. role of pharmacokinetics and metabolism in drug discovery and development. pharmacol rev 1997; 49:403−49. 2. meibohm b, derendorf h. pharmacokinetic/ pharmacodynamic studies in drug product development. j pharm sci 2002; 91:18−31. 3. holford nh. target concentration intervention: beyond y2k. br j clin pharmacol 2001; 52:55−9. 4. bjorkman s. prediction of cytochrome p450mediated hepatic drug clearance in neonates, infants and children:how accurate are available scaling methods? clin pharmacokinet 2006; 45:1−11. 5. bjorkman s. prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (pbpk) modelling: theophylline and midazolam as model drugs. br j clin pharmacol 2005; 59:691−704. 6. domingo jl. cobalt in the environment and its toxicological implications. rev environ contam toxicol 1989; 108:105−32. 7. malumbres m, barbacid m. mammalian cyclindependent kinases. trends biochem sci 2005; 30:630−41. 8. perez de castro i, de carcer g, malumbres m. a census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. carcinogenesis 2007; 28:899−912. 9. strock cj, park ji, nakakura ek, bova gs, isaacs jt, ball dw, et al. cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. cancer res 2006; 66:7509−15. 10. goodyear s, sharma mc. roscovitine regulates invasive breast cancer cell (mda-mb231) proliferation and survival through cell cycle regulatory protein cdk5. exp mol pathol 2007; 82:25−32. 11. zhang q, ahuja hs, zakeri zf, wolgemuth dj. cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. dev biol 1997; 183:222−33. 12. hakem a, sasaki t, kozieradzki i, penninger jm. the cyclin-dependent kinase cdk2 regulates thymocyte apoptosis. j exp med 1999; 189:957−68. 13. hiromura k, pippin jw, blonski mj, roberts jm, shankland sj. the subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation. oncogene 2002; 21:1750−8. 14. cruz jc, tsai lh. a jekyll and hyde kinase: roles for cdk5 in brain development and disease. curr opin neurobiol 2004; 14:390−4. 15. dhavan r, tsai lh. a decade of cdk5. nat rev mol cell biol 2001; 2:749−59. 16. angelo m, plattner f, giese kp. cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. j neurochem 2006; 99:353−70. 17. bibb ja. role of cdk5 in neuronal signaling, plasticity, and drug abuse. neurosignals 2003; 12:191−9. 18. nguyen c, bibb ja. cdk5 and the mystery of synaptic vesicle endocytosis. j cell biol 2003; 163:697−9. 19. tomizawa k, ohta j, matsushita m, moriwaki a, li st, takei k, et al. cdk5/p35 regulates the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine 176 | squ medical journal, may 2011, volume 11, issue 2 neurotransmitter release through phosphorylation and downregulation of p/q-type voltage-dependent calcium channel activity. j neurosci 2002; 22:2590−7. 20. canduri f, perez pc, caceres ra, de azevedo wf, jr. cdk9 a potential target for drug development. med chem 2008; 4:210−8. 21. knockaert m, greengard p, meijer l. pharmacological inhibitors of cyclin-dependent kinases. trends pharmacol sci 2002; 23:417−25. 22. de azevedo wf, leclerc s, meijer l, havlicek l, strnad m, kim sh. inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. eur j biochem 1997; 243:518−26. 23. meijer l, borgne a, mulner o, chong jp, blow jj, inagaki n, et al. biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. eur j biochem 1997; 243:527−36. 24. bach s, knockaert m, reinhardt j, lozach o, schmitt s, baratte b, et al. roscovitine targets, protein kinases and pyridoxal kinase. j biol chem 2005; 280:31208−19. 25. tang l, li mh, cao p, wang f, chang wr, bach s, et al. crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. j biol chem 2005; 280:31220−9. 26. mcclue sj, blake d, clarke r, cowan a, cummings l, fischer pm, et al. in vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor cyc202 (r-roscovitine). int j cancer 2002; 102:463−8. 27. raynaud fi, fischer pm, nutley bp, goddard pm, lane dp, workman p. cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis. mol cancer ther 2004; 3:353−62. 28. bloom j, pagano m. deregulated degradation of the cdk inhibitor p27 and malignant transformation. semin cancer biol 2003; 13:41−7. 29. zhang gj, safran m, wei w, sorensen e, lassota p, zhelev n, et al. bioluminescent imaging of cdk2 inhibition in vivo. nat med 2004; 10:643−8. 30. krude t. initiation of human dna replication in vitro using nuclei from cells arrested at an initiationcompetent state. j biol chem 2000; 275:13699−707. 31. matsumoto y, hayashi k, nishida e. cyclindependent kinase 2 (cdk2) is required for centrosome duplication in mammalian cells. curr biol 1999; 9:429−32. 32. sirri v, hernandez-verdun d, roussel p. cyclindependent kinases govern formation and maintenance of the nucleolus. j cell biol 2002; 15:969−81. 33. wesierska-gadek j, gueorguieva m, horky m. roscovitine-induced up-regulation of p53aip1 protein precedes the onset of apoptosis in human mcf-7 breast cancer cells. mol cancer ther 2005; 4:113−24. 34. wesierska-gadek j, wandl s, kramer mp, pickem c, krystof v, hajek sb. roscovitine up-regulates p53 protein and induces apoptosis in human helas(3) cervix carcinoma cells. j cell biochem 2008; 105:1161−71. 35. lacrima k, valentini a, lambertini c, taborelli m, rinaldi a, zucca e, et al. in vitro activity of cyclindependent kinase inhibitor cyc202 (seliciclib, r-roscovitine) in mantle cell lymphomas. ann oncol 2005; 16:1169−76. 36. mohapatra s, chu b, zhao x, pledger wj. accumulation of p53 and reductions in xiap abundance promote the apoptosis of prostate cancer cells. cancer res 2005; 65:7717−23. 37. kim eh, kim su, shin dy, choi ks. roscovitine sensitizes glioma cells to trail-mediated apoptosis by downregulation of survivin and xiap. oncogene 2004; 23:446−56. 38. alvi aj, austen b, weston vj, fegan c, maccallum d, gianella-borradori a, et al. a novel cdk inhibitor, cyc202 (r-roscovitine), overcomes the defect in p53-dependent apoptosis in b-cll by down-regulation of genes involved in transcription regulation and survival. blood 2005; 105:4484−91. 39. wesierska-gadek j, gueorguieva m, horky m. dual action of cyclin-dependent kinase inhibitors: induction of cell cycle arrest and apoptosis. a comparison of the effects exerted by roscovitine and cisplatin. pol j pharmacol 2003; 55:895−902. 40. meijer l, bettayeb k, galons h. roscovitine (cyc202, seliciclib). in: smith pj and yue e, eds. monographs on enzyme inhibitors. cdk inhibitors and their potential as anti-tumor agents. colchester: crc press, taylor & francis, 2006. pp.187–226. 41. lu w, chen l, peng y, chen j. activation of p53 by roscovitine-mediated suppression of mdm2 expression. oncogene 2001; 20:3206−16. 42. abal m, bras-goncalves r, judde jg, fsihi h, de cremoux p, louvard d, et al. enhanced sensitivity to irinotecan by cdk1 inhibition in the p53-deficient ht29 human colon cancer cell line. oncogene 2004; 23:1737−44. 43. lambert la, qiao n, hunt kk, lambert dh, mills gb, meijer l, et al. autophagy: a novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model. cancer res 2008; 68:7966−74. 44. raynaud fi, whittaker sr, fischer pm, mcclue s, walton mi, barrie se, et al. in vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and cyc202. clin cancer res 2005; 11:4875−87. moustapha hassan, hatem sallam and zuzana hassan review | 177 45. payton m, chung g, yakowec p, wong a, powers d, xiong l, et al. discovery and evaluation of dual cdk1 and cdk2 inhibitors. cancer res 2006; 6:4299−308. 46. tirado om, mateo-lozano s, notario v. roscovitine is an effective inducer of apoptosis of ewing’s sarcoma family tumor cells in vitro and in vivo. cancer res 2005; 65:9320−7. 47. iurisci i, filipski e, reinhardt j, bach s, gianellaborradori a, iacobelli s, et al. improved tumor control through circadian clock induction by seliciclib, a cyclin-dependent kinase inhibitor. cancer res 2006; 66:10720−8. 48. maggiorella l, deutsch e, frascogna v, chavaudra n, jeanson l, milliat f, et al. enhancement of radiation response by roscovitine in human breast carcinoma in vitro and in vivo. cancer res 2003; 63:2513−7. 49. vita m, meurling l, pettersson t, cruz-siden m, siden a, hassan m. analysis of roscovitine using novel high performance liquid chromatography and uv-detection method: pharmacokinetics of roscovitine in rat. j pharm biomed anal 2004; 34:425−31. 50. vita m, abdel-rehim m, olofsson s, hassan z, meurling l, siden a, et al. tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat. eur j pharm sci 2005; 25:91−103. 51. gherardi d, d’agati v, chu th, barnett a, gianellaborradori a, gelman ih, et al. reversal of collapsing glomerulopathy in mice with the cyclin-dependent kinase inhibitor cyc202. j am soc nephrol 2004; 15:1212−22. 52. nutley bp, raynaud fi, wilson sc, fischer pm, hayes a, goddard pm, et al. metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitor r-roscovitine in the mouse. mol cancer ther 2005; 4:125−39. 53. de la motte s, gianella-borradori a. pharmacokinetic model of r-roscovitine and its metabolite in healthy male subjects. int j clin pharmacol ther 2004; 42:232−9. 54. benson c, white j, de bono j, o’donnell a, raynaud f, cruickshank c, et al. a phase i trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (cyc202; r-roscovitine), administered twice daily for 7 days every 21 days. br j cancer 2007; 96:29−37. 55. vita m, abdel-rehim m, nilsson c, hassan z, skansen p, wan h, et al. stability, pka and plasma protein binding of roscovitine. j chromatogr b analyt technol biomed life sci 2005; 821:75−80. 56. cervenkova k, belejova m, chmela z, rypka m, riegrova d, michnova k, et al. in vitro glycosidation potential towards olomoucine-type cyclin-dependent kinase inhibitors in rodent and primate microsomes. physiol res 2003; 52:467−74. 57. mcclue sj, stuart i. metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (r-roscovitine) in vitro and in vivo. drug metab dispos 2008; 36:561–70. 58. rossi ag, sawatzky da, walker a, ward c, sheldrake ta, riley na, et al. cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. nat med 2006; 12:1056−64. 59. duffin r, leitch ae, sheldrake ta, hallett jm, meyer c, fox s, et al. the cdk inhibitor, r-roscovitine, promotes eosinophil apoptosis by down-regulation of mcl-1. febs lett 2009; 583:2540−6. 60. li l, wang h, kim j, pihan g, boussiotis v. the cyclin dependent kinase inhibitor (r)-roscovitine prevents alloreactive t cell clonal expansion and protects against acute gvhd. cell cycle 2009; 8:1794−802. 61. yu c, rahmani m, dai y, conrad d, krystal g, dent p, et al. the lethal effects of pharmacological cyclindependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/akt-dependent process. cancer res 2003; 63:1822−33. 62. wellwood j, taylor k. central nervous system prophylaxis in haematological malignancies. intern med j 2002; 32:252−8. 63. sallam h, jimenez p, song h, vita m, cedazo-minguez a, hassan m. age-dependent pharmacokinetics and effect of roscovitine on cdk5 and erk1/2 in the rat brain. pharmacol res 2008; 58:32−7. 64. nouws jf. pharmacokinetics in immature animals: a review. j anim sci 1992; 70:3627−34. 65. rich kj, boobis ar. expression and inducibility of p450 enzymes during liver ontogeny. microsc res tech 1997; 39:424−35. 66. alcorn j, mcnamara pj. pharmacokinetics in the newborn. adv drug deliv rev 2003; 55:667−86. 67. kearns gl, abdel-rahman sm, alander sw, blowey dl, leeder js, kauffman re. developmental pharmacology drug disposition, action, and therapy in infants and children. n engl j med 2003; 349:1157−67. 68. butt am, jones hc, abbott nj. electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. j physiol 1990; 429:47−62. 69. zheng yl, li bs, kanungo j, kesavapany s, amin n, grant p, et al. cdk5 modulation of mitogenactivated protein kinase signaling regulates neuronal survival. mol biol cell 2007; 18:404−13. 70. nikolic m, tsai lh. activity and regulation of p35/ cdk5 kinase complex. methods enzymol 2000; 325:200−13. 71. patrick gn, zhou p, kwon yt, howley pm, tsai lh. p35, the neuronal-specific activator of cyclindependent kinase 5 (cdk5) is degraded by the the role of pharmacokinetics and pharmacodynamics in early drug development with reference to the cyclin-dependent kinase (cdk) inhibitor roscovitine 178 | squ medical journal, may 2011, volume 11, issue 2 ubiquitin-proteasome pathway. j biol chem 1998; 273:24057−64. 72. kesavapany s, amin n, zheng yl, nijhara r, jaffe h, sihag r, et al. p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (rasgrf2) mediates rac-dependent extracellular signal-regulated kinase 1/2 activity, altering rasgrf2 and microtubule-associated protein 1b distribution in neurons. j neurosci 2004; 24:4421−31. 73. meijer l, raymond e. roscovitine and other purines as kinase inhibitors. from starfish oocytes to clinical trials. acc chem res 2003; 36:417−25. 74. phelps ma, lin ts, johnson aj, hurh e, rozewski dm, farley kl, et al. clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. blood 2009; 113:2637−45. 75. daldrup-link he, link tm, rummeny ej, august c, konemann s, jurgens h, et al. assessing permeability alterations of the blood-bone marrow barrier due to total body irradiation: in vivo quantification with contrast enhanced magnetic resonance imaging. bone marrow transplant 2000; 25:71−8. 76. bhatia m, militano o, jin z, figurski m, shaw l, moore v, et al. an age-dependent pharmacokinetic study of intravenous and oral mycophenolate mofetil in combination with tacrolimus for gvhd prophylaxis in pediatric allogeneic stem cell transplantation recipients. biol blood marrow transplant 2010; 16:333−43. 77. burger dm, verweel g, rakhmanina n, verweyvan wissen cp, la porte cj, bergshoeff as, et al. age-dependent pharmacokinetics of lamivudine in hiv-infected children. clin pharmacol ther 2007; 81:517−20. 78. hassan m, ljungman p, bolme p, ringden o, syruckova z, bekassy a, et al. busulfan bioavailability. blood 1994; 84:2144−50. 79. hassan m, oberg g, bekassy an, aschan j, ehrsson h, ljungman p, et al. pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology. cancer chemother pharmacol 1991; 28:130−4. 80. palle j, frost bm, gustafsson g, hellebostad m, kanerva j, liliemark e, et al. etoposide pharmacokinetics in children treated for acute myeloid leukemia. anticancer drugs 2006; 17:1087−94. 81. palle j, frost bm, petersson c, hasle h, hellebostad m, kanerva j, et al. thioguanine pharmacokinetics in induction therapy of children with acute myeloid leukemia. anticancer drugs 2009; 20:7−14. departments of 1radiology and 2cardiology, royal hospital, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com abstract: cardiac haemangiomas are rare cardiac tumours that are usually asymptomatic and detected incidentally while imaging the heart with echocardiogram. cardiovascular magnetic resonance (cmr) is a non-ionising imaging modality that allows the diagnosis of cardiac haemangiomas prior to surgery. we report a 36-year old male patient who was referred to the adult cardiology clinic at the royal hospital, muscat, oman, in 2006 with a history of a left ventricle mass detected on echocardiogram. further assessment of the mass by cmr revealed that the mass within the left ventricle apical septum contained features that were consistent with a cardiac haemangioma. due to the surgical risk of ventricular septal defect and the stability of the mass, the patient was managed conservatively and upon followup the patient’s condition remained stable. keywords: heart neoplasms; hemangioma; heart, neoplasm; magnetic resonance imaging; cardiovascular; left ventricle; coronary angiography; case report; oman. left ventricle intramuscular haemangioma a case report and review of literature *rashid s. al umairi1 and said sabek2 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e316–319, epub. 21 jun 21 submitted 2 apr 20 revisions req. 31 may & 23 jul 20; revisions recd. 12 jun & 7 aug 20 accepted 19 aug 20 chest discomfort, shortness of breath and presyncope. his electrocardiogram showed sinus rhythm and t-wave inversion in the anterior and lateral leads. further evaluation with echocardiogram revealed an isoechoic mass within the apical septum measuring 4 × 2.5 cm; the initial impression was of a rhabdomyoma. as the mass was located at the apical septum and was not causing obstruction, the patient’s symptoms were not thought to be related to the mass, however, the patient continued to have symptoms and therefore the surgical option was discussed. nevertheless, there was a concern that the patient might develop a ventricular septal defect (vsd) and the decision was made to conservatively manage the patient. the mass remained stable in size on the follow-up echocardiogram, however, in 2019, the patient presented with a history of haemoptysis; his haemoglobin was within 12.7 g/ dl (normal range: 11.5–15.5 g/dl). the patient was admitted to the hospital and an echocardiogram showed a stable mass related to the left ventricle apical septum with a normal left ventricle ejection fraction of 60%. cmr was performed for further evaluation and showed a non-obstructive apical septum mass measuring 3.7 × 3 cm. the mass was hyperintense to the myocardium on t2-weighted images, isointense to the myocardium on t1-weighted images and showed homogenous intense enhancement on post-contrast sequence [figures 1–3]. upon coronary angiography a vascular blush was revealed [figure 4], indicating a vascular mass that was receiving blood supply from the left anterior descending artery. as the mass was stable in size and not causing symptoms, we thought that the haemoptysis was not cardiac tumour s are r are, with an estimated incidence of 0.3–0.7% according to surgery and autopsy reports.1 the majority (75%) of these tumours are benign, of which cardiac haemangiomas account for approximately 1–5%.2,3 although the majority of patients with cardiac haeman giomas are asymptomatic, some patients might be symptomatic depending on the size and location of the haemangioma.4 cardiac haemangiomas are frequently detected incidentally while imaging the heart with echocardiogram. cardiovascular magnetic resonance (cmr) is a non-ionising imaging modality that allows for tissue characterisation and is widely used for assessment of cardiac tumours. it can show the hypervascular nature of cardiac haemangiomas and allow preoperative diagnosis.3,5–7 this case report describes a patient with a left ventricular mass that was detected during an echocardiogram. cmr showed a left ventricle apical septum hypervascular mass with features consistent with a cardiac haemangioma. the information provided in this article aims to increase awareness of physicians and radiologists about this rare entity and highlight the usefulness of cmr in establishing the diagnosis. to the best of the author’s knowledge, this is the first case of cardiac haemangioma detected on cardiac mri to be reported in oman. case report a 36-year-old male patient was referred to the adult cardiology clinic in 2006 at the royal hospital, muscat, oman, for further assessment of a left ventricle mass. initially, he presented with a history of this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.024 case report https://creativecommons.org/licenses/by-nd/4.0/ case report | e317 discussion cardiac haemangiomas are rare benign cardiac tumours that account for approximately 1–5% of primary cardiac tumours and can present at any age with a reported higher incidence among females.2–4 cardiac haemangiomas can arise from any cardiac layer (epicardium, myocardium and endocardium) and are typically located in the walls of the ventricles, but can be found in any cardiac chambers.8 han et al. reviewed 56 cases of cardiac haemangioma and found that haemangiomas were located in the right ventricle in 19 (33.9%) cases, the left ventricle in 20 (35.7%) cases, the right atrium in 13 (23.2%) cases, the interatrial and interventricular septum in six (10.7%) cases each and the left atrium in four (7.1%) cases.9 histologically, cardiac haemangiomas are classified into three subtypes: capillary, cavernous and arteriovenous. however, sometimes cardiac haemangiomas can show a combination of all the three types.4 while most patients are symptomatic and cardiac haemangiomas are detected incidentally, some patients can present related to cardiac haemangioma. however, there was a concern that the patient might have an extracardiac cause of haemoptysis that might be part of a syndrome related to the cardiac haemangioma or due to an entirely new cause such as neoplasm. therefore, the patient was further evaluated with a chest, neck and abdomen computed tomography (ct) scan; however, no extracardiac haemangioma or neoplasm was detected. the patient did not have haemoptysis during admission. upon follow-up in january 2020, the patient did not report new episodes of haemoptysis. as the patient had mild symptoms and the tumour remained stable for more than 14 years and the tumour was not causing obstruction nor compressing adjacent structures, the decision was made to continue the conservative management but to retain the surgical option if the patient’s condition changed or deteriorated in any way or developed new symptoms that could be attributed to the haemangioma. verbal consent was taken from the patient for publication this case report. figure 1: cine-steady-state free-precession magnetic resonance images of the heart of a 36-year old male patient showing (a) the 4-chamber view and (b) the short axis oblique plane showing a well-defined hyperintense mass located within the apical septum (arrow). figure 3: late gadolinium first-pass rest perfusion 4-chamber view of the heart of a 36-year old male patient showing (a) rapid enhancement of the tumour (arrow) and (b) delayed enhancement of the tumour (arrow) on a post-gadolinium t1-weighted image. figure 2: short axis oblique magnetic resonance image of the heart of a 36-year old male patient showing a mass arising within the apical septum (arrow) that appears isointense on the short axis oblique (a) t1-weighted and hyperintense on short axis oblique (b) t2-weighted short-tau inversion recovery. figure 4: left coronary angiography of the heart of a 36-year old male patient showing a delayed vascular blush (arrow) indicating a vascular mass which was fed from septal branches of left anterior descending artery (arrowhead). rashid s. al umairi and said sabek with variable symptoms depending on the size and location of the tumours including dyspnoea, palpitation, arrhythmia, murmur, pericardial effusion and thromboembolic events.2,10,11 in the current case, the patient presented with on-and-off chest discomfort, shortness of breath and presyncope. imaging plays an essential role in the diagnosis of cardiac haemangiomas. most cardiac haemangiomas are detected by echocardiogram and typically appear as hyperechoic lesions.4,12 on cardiac ct angiography, cardiac haemangiomas appear as hyper-enhancing lesions due to its hypervascularity.13 coronary angiography does not only show the typical tumour blush [figure 4], but it is also useful to delineate the blood supply to the tumour.2,4 in the current patient, the feeding artery arose from the left anterior descending artery. on cmr, cardiac haemangiomas are typically intermediate to high signal intensity on t1and t2weighted images and show intense enhancement on post-contrast examination.3 owing to high ability for tissue characterisation, cmr can permit preoperative diagnosis of cardiac haemangioma and differentiate it from other cardiac tumours such as fibroma, rhabdomyoma, lipoma and myxoma. cardiac fibroma is isointense to the myocardium on t1weighted images, hypointense to the myocardium on t2-weighted images and shows intense enhancement on post-contrast images.3 rhabdomyoma is another benign cardiac tumour that is typically seen in paediatric patients; on cmr, it appears isointense on t1-weighted images, hyperintense to the myocardium on t2-weighted images and shows minimal or no contrast enhancement on post-contrast examination.3 cardiac lipomas are benign cardiac tumours that have homogenous high signal intensity on t1-weighted images with complete suppression on fat suppression sequences. cardiac lipomas show no enhancement on post-contrast sequences due to their poor vascularity.3 in the current case, the cmr and coronary angiography findings of the tumour were consistent with a cardiac haemangioma. the course of cardiac haemangiomas are variable, with some increasing in size while others regress or remain stable.14,15 treatment of cardiac haemangioma depends on the size and location of the tumour as well as associated symptoms.4 surgical resection is usually the treatment of choice in symptomatic patients, with a regular follow-up to identify recurrence. however, if the patient is asymptomatic and the haemangioma is not compressing major structures, surgery can be avoided.14 in the present case, conservative management was chosen and to monitor the patient via follow-up. conclusion cardiac haemangiomas are rare, benign cardiac tumours that are usually detected incidentally. patients with cardiac haemangiomas are frequently asymptomatic; however, some patients can be symptomatic depending on the size and location of the haemangioma. aware ness of the typical cmr findings of cardiac haeman giomas allows pre-operative diagnosis with a high level of confidence. although surgical excision is the treatment of choice is symptomatic patients, conservative treatment is an option in asymptomatic patients with non-obstructive cardiac haemangioma. references 1. leja mj, shah dj, reardon mj. primary cardiac tumors. tex heart inst j 2011; 38:261–2. 2. miao h, yang w, zhou m, zhu q, jiang z. atrial hemangioma: a case report and review of the literature. ann thorac cardiovasc surg 2019; 25:71–81. https://doi.org/10.5761/atcs.ra.18-00207. 3. motwani m, kidambi a, herzog ba, uddin a, greenwood jp, plein s. mr imaging of cardiac tumors and masses: a review of methods and clinical applications. radiology 2013; 268:26–43 https://doi.org/10.1148/radiol.13121239. 4. shikata d, nakagomi t, yokoyama y, yamada y, nakajima m, oyama t, et al. debulking surgery for venous hemangioma arising from the epicardium: report of a case. world j surg oncol 2017; 15:81. https://doi.org/10.1186/s12957-017-1152-1. 5. cioffi gm, paiocchi vl, leo la, ferrari e, faletra ff. capillary hemangioma of the left ventricle. j cardiovasc echogr 2019; 29:126–8. https://doi.org/10.4103/jcecho.jcecho_31_19. 6. gao y, wu w, zhang l, sun z, xie y, li y, et al. multimodality imaging in preparation for resection of a right atrial cavernous hemangioma. echocardiography 2020; 37:465–6. https://doi. org/10.1111/echo.14615. 7. choi ku, shim cy, choi jy, cho ya, hong gr. features of cardiac cavernous haemangioma in multimodality imaging. eur heart j cardiovasc imaging 2019; 21:114. https://doi. org/10.1093/ehjci/jez167. 8. brizard c, latremouille c, jebara va, acar c, fabiani jn, deloche a, et al. cardiac hemangiomas. ann thorac surg 1993; 56:390–4. https://doi.org/10.1016/0003-4975(93)91193-q. 9. han y, chen x, wang x, yang l, zeng y, yang j. cardiac capillary hemangioma: a case report and brief review of the literature. j clin ultrasound 2014; 42:53–6. https://doi.org/10.10 02/jcu.22026. 10. solum am, romero sc, ledford s, parker r, madani mm, coletta jm. left atrial hemangioma presenting as cardiac tamponade. tex heart inst j 2007; 34:126–7. 11. zerbo s, argo a, maresi e, liotta r, procaccianti p. sudden death in adolescence caused by cardiac haemangioma. j forensic leg med 2009; 16:156–8. https://doi.org/10.1016/j.jflm.2008.08.020. left ventricle intramuscular haemangioma a case report and review of literature e318 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.5761/atcs.ra.18-00207 https://doi.org/10.1148/radiol.13121239 https://doi.org/10.1186/s12957-017-1152-1 https://doi.org/10.4103/jcecho.jcecho_31_19 https://doi.org/10.1111/echo.14615 https://doi.org/10.1111/echo.14615 https://doi.org/10.1093/ehjci/jez167 https://doi.org/10.1093/ehjci/jez167 https://doi.org/10.1016/0003-4975%2893%2991193-q https://doi.org/10.1002/jcu.22026 https://doi.org/10.1002/jcu.22026 https://doi.org/10.1016/j.jflm.2008.08.020 case report | e319 12. papadopoulos k, makrides ca, eleutheriou e. a cardiac haeman gioma: the contribution of myocardial contrast echocardio graphy in the diagnosis. bmj case rep 2015; 2015: bcr2015210075. https://doi.org/10.1136/bcr-2015-210075. 13. cresti a, chiavarelli m, munezero butorano mag, franci l. multimodality imaging of a silent cardiac hemangioma. j cardio vasc echogr 2015; 25:31–3. https://doi.org/10.4103/2211-4122.158427. 14. beebeejaun my, deshpande r. conservative management of cardiac haemangioma. interact cardiovasc thorac surg 2011; 12:517–19. https://doi.org/10.1510/icvts.2010.237032. 15. palmer te, tresch dd, bonchek li. spontaneous resolution of a large, cavernous hemangioma of the heart. am j cardiol 1986; 58:184–5. https://doi.org/10.1016/0002-9149(86)90273-0. rashid s. al umairi and said sabek https://doi.org/10.1136/bcr-2015-210075 https://doi.org/10.4103/2211-4122.158427 https://doi.org/10.1510/icvts.2010.237032 https://doi.org/10.1016/0002-9149%2886%2990273-0 re: revisiting the prevalence of autism spectrum disorder among omani children a multicentre study sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e236, epub. 28 jun 20 submitted 3 jan 20 accepted 27 feb 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.018 letter to the editor رد: إعادة النظر يف معدل إنتشار إضطراب طيف التوحد بني األطفال العمانيني دراسة متعددة املراكز dear editor, i read with interest the original study by al-mamri et al. published in the november 2019 issue of squmj.1 based on the fifth edition of the diagnostic and statistical manual of mental disorders (dsm-5), the authors estimated the prevalence of autism spectrum disorder (asd) among omani children and compared it with oman’s estimate from 2011. they found that asd prevalence was 20.35 per 10,000 children, which was 15-fold higher than the estimate from 2011 (1.4 cases per 10,000 children).1 they attributed this increased prevalence to many factors, namely improvement in the diagnostic services, increased awareness of asd, improved screening programmes and changes in the criteria of diagnosing asd.1 however, the last explanatory factor should be taken cautiously. my assumption is based on the following point: al-mamri et al. employed the dsm-5 criteria in their study methodology while the asd estimate from 2011 was based on dsm-iv criteria.1,2 it is noteworthy that compared to the dsm-iv criteria, evaluation of the dsm-5 criteria revealed good sensitivity and excellent overall specificity. the specificity and sensitivity were noticed to be strongest for children meeting the dsm-iv criteria for asd, but poor for those meeting criteria for pervasive developmental disorder and asperger's disorder.3 older age, higher intelligence quotient, female gender and less evident asd manifestations were noted to be correlated with higher discordance.3 importantly, dsm-5 criteria could impact which children fulfil the asd diagnostic criteria, that ultimately influences the access to healthcare services.4 accordingly, the adoption of the dsm-5 criteria would likely lower the asd prevalence estimate compared to dsm-iv diagnostic criteria.5 surprisingly, asd prevalence reported by al-mamri et al. was much greater than that reported in 2011 despite the variation in the version of asd diagnostic criteria.1 with the notion that the studied population in al-mamri et al.’s study involved a hospitalbased sample, i presume that the worryingly high reported asd prevalence (20.35 per 10,000 children) represents only the tip of the iceberg of a sizable paediatric health problem in oman.1 therefore, i agree with al-mamri et al.’s recommendation of implementing strategic action, including registry, screening and rehabilitations programmes that are deemed justifiable to contain a further spike in asd prevalence among the omani paediatric population. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al-mamri w, idris ab, dakak s, al-shekaili m, al-harthi z, alnaamani am, et al. revisiting the prevalence of autism spectrum disorder among omani children: a multicentre study. sultan qaboos univ med j 2019; 19:e305–9. https://doi.org/10.18295/squmj.2019.19.04.005. 2. al-farsi ym, al-sharbati mm, al-farsi oa, al-shafaee ms, brooks dr, waly mi. brief report: prevalence of autistic spectrum disorders in the sultanate of oman. j autism dev disord 2011; 41:821–5. https://doi.org/10.1007/s10803-010-1094-8. 3. mazurek mo, lu f, symecko h, butter e, bing nm, hundley rj, et al. a prospective study of the concordance of dsm-iv and dsm-5 diagnostic criteria for autism spectrum disorder. j autism dev disord 2017; 47:2783–94. https://doi.org/10.1007/s10803-017-3200-7. 4. burns co, matson jl. an evaluation of the clinical application of the dsm-5 for the diagnosis of autism spectrum disorder. expert rev neurother 2017; 17:909–17. https://doi.org/10.1080/14737175.2017.1351301. 5. maenner mj, rice ce, arneson cl, cunniff c, schieve la, carpenter la, et al. potential impact of dsm-5 criteria on autism spectrum disorder prevalence estimates. jama psychiatry 2014; 71:292–300. https://doi.org/10.1001/jamapsychiatry.2013.3893. e236 | squ medical journal, may 2020, volume 20, issue 2 https://creativecommons.org/licenses/by-nd/4.0/ https://doi.org/10.18295/squmj.2019.19.04.005 https://doi.org/10.1007/s10803-010-1094-8 https://doi.org/10.1007/s10803-017-3200-7 https://doi.org/10.1080/14737175.2017.1351301 https://doi.org/10.1001/jamapsychiatry.2013.3893 1department of pathology, faculty of medicine, kuwait university, kuwait; 2cytology laboratory, mubarak al-kabeer hospital, kuwait *corresponding author’s e-mail: kkapila@gmail.com تفسري تشخيص اخلالاي احلرشفية الالمنطية غري حمددة الداللة يف شرحية خالاي عنق الرحم وارتباطها بفريوس الورم احلليمي البشري حتليل استعادي لـ 180 حالة يف الكويت كو�شوم كابيال ، مريا باالكري�شنان، روال ح�شني علي، اأحالم اجلوي�رص، �شارة �شرييل جورج، مرينماي مالك abstract: objectives: atypical squamous cells of undetermined significance (asc-us) represent a diagnostic challenge during cervical cytology. this study aimed to review and identify high-risk human papillomavirus (hr-hpv) genotypes among previously diagnosed asc-us cases in kuwait. methods: this retrospective study analysed 180 cases diagnosed as asc-us between june 2017 and may 2018 at the mubarak al-kabeer hospital, kuwait. cervical specimens were assayed to determine the presence of hr-hpv dna; subsequently, positive cases underwent genotyping and were categorised into three groups (hpv 16, hpv 18/45 and other hr-hpv types). results: in total, asc-us was confirmed in only 105 cases (58.3%), with the remaining cases reclassified as negative for intraepithelial lesions or malignancy (nilm; 32.2%) and epithelial cell abnormalities (eca; 9.4%). of these, hrhpv dna was present in 20 asc-us (19%), one nilm (1.7%) and six eca (35.3%) cases. there were 62 kuwaiti and 43 non-kuwaiti women with confirmed asc-us; of these, three (4.8%), six (9.7%) and four (6.5%) kuwaitis and one (2.3%), one (2.3%) and five (11.6%) non-kuwaitis had hpv 16, both hpv 16 and 18/45 and other hrhpv genotypes, respectively. of those with hr-hpv dna, the nilm case had the hpv 18/45 genotype, while the six eca cases had the hpv 16 (n = 1), both hpv 16 and 18/45 (n = 1) and other hr-hpv (n = 4) genotypes. conclusion: overall, hr-hpv dna was present in 19% of asc-us cases compared to 1.7% of nilm cases initially misdiagnosed as asc-us. re-review of cervical cytology diagnoses may reduce unnecessary costs associated with hr-hpv genotyping. keywords: cervical smears; atypical squamous cells of undetermined significance; human papilloma virus; cytological techniques; papanicolaou test; kuwait. امللخ�ص: الهدف: متثل اخلاليا احلر�شفية الالمنطية ذات الداللة غري املحددة )asc-us( حتدًيا ت�شخي�شًيا اأثناء درا�شة م�شحات عنق الرحم. asc-us بني حاالت )hr-hpv( هدفت هذه الدرا�شة اإىل مراجعة وحتديد االأمناط اجلينية عالية اخلطورة لفريو�س الورم احلليمي الب�رصي التي مت ت�شخي�شها �شابًقا يف الكويت. الطريقة: حللت هذه الدرا�شة باأثر رجعي 180 حالة مت ت�شخي�شها على اأنها asc-us بني يونيو 2017 ومايو 2018 يف م�شت�شفى مبارك الكبري، الكويت. مت فح�س عينات عنق الرحم لتحديد وجود ال�شيفرة الوراثية )dna( لفريو�س الورم احلليمي الب�رصي. بعد ذلك، مت ت�شنيف احلاالت االإيجابية جينيا اإىل ثالث جمموعات )hpv 16 و hpv 18/45 واأنواع اأخرى من hr-hpv(. النتائج: يف املجموع، مت تاأكيد asc-us يف 105 حالة فقط )%58.3(، مع اإعادة ت�شنيف احلاالت املتبقية على اأنها �شلبية لالآفات داخل الظهارة اأو -us 20 موجوًدا يف dna hr-hpv ؛ %9.4(. من بني تلك، كانeca( وت�شوهات اخلاليا الظهارية )؛ %32.2nilm( االأورام اخلبيثة asc )%19( ، وحالة nilm واحدة )%1.7( و�شت حاالت eca )%35.3(. كانت هناك 62 امراأة كويتية و 43 امراأة غري كويتية لديهن حاالت موؤكدة من asc-us؛ من هوؤالء، ثالثة )%4.8( و�شتة )%9.7( واأربعة )%6.5( كويتيون وواحد )%2.3( وواحد )%2.3( وخم�شة )%11.6( من غري الكويتيني لديهم فريو�س الورم احلليمي الب�رصي 16، وكل من hpv 16 و 18/45 واالأمناط اجلينية االأخرى hr-hpv، على التوايل. من بني الذين لديهم dna hr-hpv، كانت حالة nilm حتتوي على النمط الوراثي hpv 18/45، يف حني اأن حاالت eca ال�شت كانت حتتوي على واحد من hpv 16 وواحد من hpv 16 و 18/45 واأربعة من-hr فريو�س الورم احلليمي الب�رصي من االأمناط اجلينية. اخلال�صة: ب�شكل عام، كان hr-hpv dna موجوًدا يف %19من حاالت asc-us مقارنة بـ %1.7 من حاالت nilm التي مت ت�شخي�شها ب�شكل خاطئ يف البداية على اأنها asc-us. قد توؤدي اإعادة مراجعة ت�شخي�س اخلاليا العنقية اإىل تقليل التكاليف غري ال�رصورية املرتبطة بالتنميط اجليني .hr-hpv تقنيات الب�رصي؛ احلليمي الورم فريو�س املحددة؛ غري الداللة ذات الالمنطية احلر�شفية اخلاليا الرحم؛ عنق م�شحات املفتاحية: الكلمات اخلاليا؛ اختبار بابانيكوالو الكويت. interpreting a diagnosis of atypical squamous cells of undetermined significance in cervical cytology and its association with human papillomavirus a retrospective analysis of 180 cases in kuwait *kusum kapila,1 meera balakrishnan,2 rola h. ali,1 ahlam al-juwaiser,2 sara s. george,1 mrinmay k. mallik2 clinical & basic research sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e318–323, epub. 21 dec 20 submitted 9 oct 19 revision req. 19 dec 19; revision recd. 1 mar 20 accepted 5 apr 20 https://doi.org/10.18295/squmj.2020.20.04.007 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ kusum kapila, meera balakrishnan, rola h. ali, ahlam al-juwaiser, sara s. george and mrinmay k. mallik clinical and basic research | e319 advances in knowledge this study identified the prevalence of high-risk human papillomavirus (hr-hpv) genotypes in cervical smears previously diagnosed as atypical squamous cells of undetermined significance (asc-us) in kuwait. despite the relatively high incidence of epithelial cell abnormalities, few studies on this topic have been conducted in the gulf cooperative council region. the current study found that only 58.3% of previously diagnosed cases of asc-us were confirmed retrospectively. moreover, hr-hpv genotypes were found in 19% of confirmed asc-us cases compared to only 1.7% of normal cases initially misdiagnosed as asc-us. application to patient care the findings of this study indicate that the re-review of asc-us cases is important, not only to avoid potential misdiagnosis and causing unnecessary emotional distress for the patient, but also to determine which cases warrant further hr-hpv typing, a needless expense in low-risk cases. the presence of atypical squamous cells on cervical smears represents a diagnostic challenge for both pathologists and clinicians.1 according to the revised bethesda classification system, cervical epithelial abnormalities are categorised as either atypical squamous cells of undetermined significance (asc-us), atypical squamous cells without ruling out a high-grade lesion (asc-h), low-grade squamous intraepithelial lesions (lsil), high-grade squamous intraepithelial lesions (hsil) or squamous cell carcinomas.2 under this system, a diagnosis of asc-us is issued when the cervical epithelial cells demonstrate cytological changes suggestive of a squamous intraepithelial lesion, but without definitive qualitative or quantitative confirmation.3 despite the existence of these diagnostic criteria, accurate identification of asc-us cases remains difficult, thus resulting in high rates of misdiagnosis and overinterpretation during cervical cytology screening.1,3 in humans, the vast majority of cases of cervical cancer are linked to human papillomavirus (hpv) infections.4 as such, hpv testing is highly recommended for patients diagnosed with asc-us in order to determine whether further follow-up, in the form of an urgent colposcopy, is necessary.5 there are over 100 different hpv genotypes, of which approximately 40 are known to infect the genital tract; of these, 18 are believed to play a significant role in the pathogenesis of cervical cancers, most commonly types 16, 18 and 45.6 these variants are therefore considered to represent high-risk hpv (hr-hpv) genotypes.4,6 few studies have sought to assess the spectrum of hr-hpv genotypes among women in gulf cooperation council (gcc) countries, which differ significantly from those reported elsewhere in the world likely as a result of racial diversity.7–11 for instance, previous research indicates that hr-hpv genotypes in kuwait mostly consist of types other than 16, 18 and 45.8 similarly, ali et al. showed that hrhpv types other than 16 and 18 were most prevalent in gcc countries.7 this study aimed to review previously diagnosed asc-us cases at a hospital in kuwait to determine the rate of overinterpretation as well as to identify the prevalence of specific hr-hpv genotypes among kuwaiti and non-kuwaiti women. methods this retrospective study reviewed 180 cases diagnosed as asc-us between june 2017 and may 2018 at the mubarak al-kabeer hospital, kuwait. cytological data from thinprep® cervical smears (hologic corp., bedford, massachusetts, usa) were retrieved from the files of the cytology laboratory. each case underwent blinded peer-review by two pathologists and one senior cytotechnician to confirm or correct the initial asc-us diagnosis. cases were classified using the 2014 revised bethesda system as either negative for intraepithelial lesions or malignancy (nilm), ascus, atypical glandular cells (agc), lsils or hsils.2 subsequently, the cervical samples were assayed to determine the presence of hr-hpv dna. the assay technique was conducted using the panther system of the aptima™ hpv assay (hologic corp.). samples from the thinprep® vials were transferred to the aptima™ transfer tube in order to capture, amplify, detect and report specific hr-hpv e6/e7 messenger ribonucleic acid transcripts. cases were then categorised as either hr-hpv-positive (relative light unit/cut-off [rlu/co] of ≥0.5) or hr-hpv-negative (rlu/co of <0.5). subsequently, the aptima™ hpv 16 18/45 genotype assay (hologic corp.) was used to detect hr-hpv 16 and 18/45 genotypes in hr-hpvpositive cases. based on the results of the assay, hr-hpvpositive cases were subdivided into the following categories: (1) positive for hpv 16; (2) positive for hpv 18/45; (3) positive for both hpv 16 and 18/45; or (4) negative for both hpv 16 and 18/45. for the latter category, the absence of both hpv 16 and 18/45 genotypes was considered to imply the presence of other hr-hpv genotypes, given the hr-hpvpositive findings observed during the initial assay. for interpreting a diagnosis of atypical squamous cells of undetermined significance in cervical cytology and its association with human papillomavirus a retrospective analysis of 180 cases in kuwait e320 | squ medical journal, november 2020, volume 20, issue 4 the purposes of statistical analysis, the results of hrhpv testing were correlated with both the corrected cytological diagnosis (i.e. nilm, asc-us, agc, lsil or hsil) and nationality (i.e. kuwaiti or non-kuwaiti). this study was conducted in accordance with the combined ethics committee of the kuwaiti ministry of health and the faculty of medicine of the health science centre, university of kuwait. the procedures of the study conformed to the ethical guidelines outlined in the revised declaration of helsinki. informed verbal consent was obtained from all patients. results of the 180 previously diagnosed asc-us cases, the original diagnosis was confirmed retrospectively by peer-review in only 105 cases (58.3%). the remaining cases were reclassified as either nilm (n = 58; 32.2%) or epithelial cell abnormalities (eca; n = 17; 9.4%), with the latter comprising seven agc (3.9%), six lsil (3.3%), two hsil (1.1%) and two asc-us with agc (1.1%). among the 58 nilm cases, only one (1.7%) was hr-hpv-positive; in contrast, hr-hpv dna was present in 20 asc-us (19%) and six eca (35.3%) cases. overall, the hpv 16, hpv 18/45 and both hpv 16 and 18/45 genotypes were present in five (2.8%), one (0.6%) and eight (4.4%) cases, respectively. the remaining 13 cases (7.2%) were negative for both hpv 16 and 18/45, indicating the presence of hrhpv variants other than types 16 and 18/45 in these specimens. only one of the nilm cases (1.7%) and two of the eca cases (11.8%) demonstrated the common hr-hpv genotypes 16 or 18/45 [table 1]. table 1: reclassification of and prevalence of human papillomavirus genotypes among cervical cytology cases previously diagnosed as atypical squamous cells of undetermined significance (n = 180) reclassification hpv status, n (%) total negative type 16 type 18/45 types 16 and 18/45 other unknown* nilm 58 (32.2) 56 (96.6) 0 (0) 1 (1.7) 0 (0) 0 (0) 1 (1.7) asc-us 105 (58.3) 84 (80) 4 (3.8) 0 (0) 7 (6.7) 9 (8.6) 1 (1) agc 7 (3.9) 7 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) asc-us and agc 2 (1.1) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) lsil 6 (3.3) 2 (33.3) 1 (16.7) 0 (0) 1 (16.7) 2 (33.3) 0 (0) hsil 2 (1.1) 0 (0) 0 (0) 0 (0) 0 (0) 2 (100) 0 (0) total 180 (100) 151 (83.9) 5 (2.8) 1 (0.6) 8 (4.4) 13 (7.2) 2 (1.1) hpv = human papillomavirus; nilm = negative for intraepithelial lesions or malignancy; asc-us = atypical squamous cells of undetermined signif icance; agc = atypical glandular cells; lsil = low-grade squamous intraepithelial lesions; hsil = high-grade squamous intraepithelial lesions. *testing not performed. table 2: reclassification of and prevalence of human papillomavirus genotypes among cervical cytology cases previously diagnosed as atypical squamous cells of undetermined significance in the kuwaiti group (n = 104) reclassification hpv status, n (%) total negative type 16 type 18/45 types 16 and 18/45 other unknown* nilm 36 (34.6) 34 (94.4) 0 (0) 1 (2.8) 0 (0) 0 (0) 1 (2.8) asc-us 62 (59.6) 49 (79) 3 (4.8) 0 (0) 6 (9.7) 4 (6.5) 0 (0) agc 2 (1.9) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) asc-us and agc 2 (1.9) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) lsil 2 (1.9) 0 (0) 1 (50) 0 (0) 0 (0) 1 (50) 0 (0) hsil 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) total 104 (100) 87 (83.7) 4 (3.8) 1 (1) 6 (5.8) 5 (4.8) 1 (1) hpv = human papillomavirus; nilm = negative for intraepithelial lesions or malignancy; asc-us = atypical squamous cells of undetermined signif icance; agc = atypical glandular cells; lsil = low-grade squamous intraepithelial lesions; hsil = high-grade squamous intraepithelial lesions. *testing not performed. kusum kapila, meera balakrishnan, rola h. ali, ahlam al-juwaiser, sara s. george and mrinmay k. mallik clinical and basic research | e321 in terms of nationality, the specimens originated from 104 kuwaiti women and 76 women of other nationalities. in the kuwaiti group, 16 cases (15.4%) were hr-hpv-positive; of these, the hpv 16 genotype was present in four (25%) cases, hpv 18/45 in one (6.3%) and both hpv 16 and 18/45 in six (37.5%). however, five cases (31.3%) were negative for both hpv 16 and 18/45, indicating the presence of other hr-hpv variants [table 2]. in the non-kuwaiti group, 11 cases (14.5%) were hr-hpv positive. these included one case (9.1%) with the hpv 16 genotype and two (18.2%) with both hpv 16 and 18/45. other hr-hpv genotypes were assumed in the remaining eight cases (72.7%) [table 3]. the diagnosis of asc-us was confirmed in 62 kuwaiti and 43 non-kuwaiti cases. of these, hr-hpv dna was present in 13 (21%) and seven (16.3%) cases, respectively. in the kuwaiti asc-us group, genotyping for the hpv 16, both hpv 16 and 18/45 and other hr-hpv variants was positive in three (4.8%), six (9.7%) and four (6.5%) cases, respectively. in contrast, genotyping for these types was positive in one (2.3%), one (2.3%) and five (11.6%) cases, respectively, in the non-kuwaiti asc-us group [table 4]. discussion the diagnosis of asc-us depends not only on the identification of well-defined cytological patterns, but also on other more subjective criteria; consequently, reproducibility of the diagnosis upon re-review can vary from <50–67.9%.1,12 various studies have shown that a number of factors are related to the overinterpretation of atypical squamous cells including reactive changes due to reproductive tract infections associated with trichomonas vaginalis, candida species and bacterial vaginosis, as well as the presence of intermediate squamous cells with bland nuclear enlargement without chromatin and nuclear abnormalities.5,13 moreover, asc-us diagnoses are reported more frequently in women who are pregnant, lactating and postmenopausal due to the excessive glycogenation of intermediate squamous cells caused by hormones.5,13 in addition, the presence of immature metaplastic cells, suboptimal fixation, drying artifacts and other age-related changes such as degeneration due to atrophic vaginitis may be mistaken for ascus.5,13,14 table 3: reclassification of and prevalence of human papillomavirus genotypes among cervical cytology cases previously diagnosed as atypical squamous cells of undetermined significance in the non-kuwaiti group (n = 76) reclassification hpv status, n (%) total negative type 16 type 18/45 types 16 and 18/45 other unknown* nilm 22 (28.9) 22 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) asc-us 43 (56.6) 35 (81.4) 1 (2.3) 0 (0) 1 (2.3) 5 (11.6) 1 (2.3) agc 5 (6.6) 5 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) asc-us and agc 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) lsil 4 (5.3) 2 (50) 0 (0) 0 (0) 1 (25) 1 (25) 0 (0) hsil 2 (2.6) 0 (0) 0 (0) 0 (0) 0 (0) 2 (100) 0 (0) total 76 (100) 64 (84.2) 1 (1.3) 0 (0) 2 (2.6) 8 (10.5) 1 (1.3) hpv = human papillomavirus; nilm = negative for intraepithelial lesions or malignancy; asc-us = atypical squamous cells of undetermined signif icance; agc = atypical glandular cells; lsil = low-grade squamous intraepithelial lesions; hsil = high-grade squamous intraepithelial lesions. *testing not performed. table 4: distribution of human papillomavirus genotypes according to nationality among cases with confirmed diagnoses of atypical squamous cells of undetermined significance (n = 105) nationality hpv status, n (%) total negative type 16 type 18/45 types 16 and 18/45 other unknown* kuwaiti 62 (59) 49 (79) 3 (4.8) 0 (0) 6 (9.7) 4 (6.5) 0 (0) non-kuwaiti 43 (41) 35 (81.4) 1 (2.3) 0 (0) 1 (2.3) 5 (11.6) 1 (2.3) total 105 (100) 84 (80) 4 (3.8) 0 (0) 7 (6.7) 9 (8.6) 1 (1) hpv = human papillomavirus. *testing not performed. interpreting a diagnosis of atypical squamous cells of undetermined significance in cervical cytology and its association with human papillomavirus a retrospective analysis of 180 cases in kuwait e322 | squ medical journal, november 2020, volume 20, issue 4 in the current study, all cases previously diagnosed as asc-us at a kuwaiti hospital over a one-year period were reviewed retrospectively by three cytologists. overall, only 58.3% of cases received confirmation of the asc-us diagnosis, while the remaining cases were reclassified as either nilm (32.2%) or eca (9.4%). this rate of reproducibility was comparable to that reported in previous research.1,12 the absence of well-defined cytological criteria, subjectivity of the diagnosis and various other factors may account for the overrepresentation of asc-us diagnoses in routine reporting.5,13,14 in general, accurate identification of asc-us remains a diagnostic dilemna for cytopathologists. consequently, hpv genotyping is often incorporated to enhance cervical screening. however, this can represent a needless expense due to the high rate of false-positive diagnoses. the authors therefore recommend that asc-us diagnoses be peer-reviewed prior to reporting in order to decrease costs associated with unnecessary hpv genotyping. in general, the detection of hr-hpv genotypes is a useful tool to supplement abnormal cytological results. among patients with asc-us, the presence of an hr-hpv-positive genotype increases the likelihood of cervical intraepithelial neoplasia (cin) grades ii or iii, a precursor to cervical cancer; in contrast, a negative hr-hpv test excludes high-grade cin.1 as a result, hr-hpv genotyping is usually recommended for patients with asc-us.15 however, the american society for colposcopy and cervical pathology does not recommend hpv testing be performed for women aged 21–29 years, instead encouraging such individuals to undergo cytological screening only every three years.16 for women aged 30–65 years, both cytological screening and hpv testing is recommended every five years; alternatively, screening with cytology alone can be performed every three years. in addition, hpv testing is recommended for women with lsil and as a post-colposcopy follow-up measure for those with abnormal cytology.16–18 cases found to be positive for hr-hpv should undergo a colposcopic examination, while those classified as nilm should return for repeated cervical cytology screening within six months. in the current study, the most common hrhpv types among hr-hpv-positive patients with confirmed asc-us were hpv types other than 16 and 18/45 (45%). few studies have been performed to determine the most prevalent hr-hpv genotypes in the gcc region.7–11 ali et al. found that types other than hpv 16/18 were the most common genotypes among women residing in saudi arabia, qatar, the united arab emirates and bahrain, followed by type hpv 16.7 similarly, mallik et al. reported that the most prevalent hr-hpv genotypes in kuwait were those other than types 16, 18 and 45.8 however, al-awadhi et al. reported contradictory findings indicating that hpv type 16 was most frequent in a cohort of women in kuwait.11 in the present study, the most common hr-hpv genotypes among hr-hpv-positive kuwaiti women regardless of cytological diagnosis were both hpv 16 and 18/45 (37.5%), followed by hr-hpv types other than 16 and 18/45 (31.3%), hpv 16 (25%) and hpv 18/45 (6.3%). among hr-hpv-positive nonkuwaiti women, the most prevalent genotypes were hr-hpv types other than 16 and 18/45 (72.7%), both hpv 16 and 18/45 (18.2%) and hpv 16 (9.1%). conclusion the rate of overrepresentation of asc-us cases at a kuwaiti hospital over a one-year period was moderately high. in addition, hr-hpv dna was present in 19% of confirmed asc-us cases compared to only 1.7% of nilm cases initially misdiagnosed as asc-us. therefore, the authors strongly recommend that cytological diagnoses of asc-us be peer-reviewed for diagnostic confirmation before undergoing hrhpv genotyping. careful review of cellular changes by multiple cytologists will increase the diagnostic accuracy of cytology screening, thereby reducing the patient’s anxiety as well as the cost of unnecessary hpv genotyping for false-positive cases. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. barcelos ac, michelin ma, adad sj, murta ef. atypical squamous cells of undetermined significance: bethesda class ification and association with human papillomavirus. infect dis obstet gynecol 2011; 2011:904674. https://doi.org/10.11 55/2011/904674. 2. nayar r, wilbur dc, eds. the bethesda system for reporting cervical cytology: definitions, criteria and explanatory notes, 3rd ed. new york, usa: springer, 2015. 3. nascimento af, cibas es. the asc/sil ratio for cytopath ologists as a quality control measure: a follow-up study. am j clin pathol 2007; 128:653–6. https://doi.org/10.1309/aptvnl p1p0x00cuq. 4. bosch fx, lorincz a, muñoz n, meijer cj, shah kv. the causal relation between human papillomavirus and cervical cancer. j clin pathol 2002; 55:244–65. https://doi.org/10.1136/ jcp.55.4.244. https://doi.org/10.1155/2011/904674 https://doi.org/10.1155/2011/904674 https://doi.org/10.1309/aptvnlp1p0x00cuq https://doi.org/10.1309/aptvnlp1p0x00cuq https://doi.org/10.1136/jcp.55.4.244 https://doi.org/10.1136/jcp.55.4.244 kusum kapila, meera balakrishnan, rola h. ali, ahlam al-juwaiser, sara s. george and mrinmay k. mallik clinical and basic research | e323 5. johnston ei, logani s. cytologic diagnosis of atypical squamous cells of undetermined significance in perimenopausal and postmenopausal women: lessons learned from human papillo mavirus dna testing. cancer 2007; 111:160–5. https://doi. org/10.1002/cncr.22687. 6. burd em. human papillomavirus and cervical cancer. clin microbiol rev 2003; 16:1–17. https://doi.org/10.1128/cmr.16.1. 1-17.2003. 7. ali mam, bedair rn, abd el atti rm. cervical high-risk human papillomavirus infection among women residing in the gulf cooperation council countries: prevalence, typespecific distribution and correlation with cervical cytology. cancer cytopathol 2019; 127:567–77. https://doi.org/10.1002/ cncy.22165. 8. mallik mk, alramadhan b, dashti h, al-shaheen a, al juwaiser a, das dk, et al. human papillomaviruses other than 16, 18 and 45 are the major high risk hpv genotypes amongst women with abnormal cervical smear cytology residing in kuwait: implications for future vaccination strategies. diagn cytopathol 2018; 46:1036–9. https://doi.org/10.1002/dc.24035. 9. krishnan k, thomas a. correlation of cervical cytology with high-risk hpv molecular diagnosis, genotypes, and histopath ology--a four year study from the uae. diagn cytopathol 2016; 44:91–7. https://doi.org/10.1002/dc.23391. 10. al-awadhi r, chehadeh w, al-jassar w, al-harmi j, al-saleh e, kapila k. viral load of human papillomavirus in women with normal and abnormal cervical cytology in kuwait. j infect dev ctries 2013; 15:130–6. https://doi.org/10.3855/jidc.2748. 11. al-awadhi r, chehadeh w, jaragh m, al-shaheen a, sharma p, kapila k. distribution of human papillomavirus among women with abnormal cervical cytology in kuwait. diagn cytopathol 2013; 41:107–14. https://doi.org/10.1002/dc.21778. 12. cox jt. management of women with cervical cytology inter preted as asc-us or as asc-h. clin obstet gynecol 2005; 48:160–77. https://doi.org/10.1097/01.grf.0000151571.91814.f3. 13. gupta s, sodhani p. reducing “atypical squamous cells” over diagnosis on cervicovaginal smears by diligent cytology screening. diagn cytopathol 2012; 40:764–9. https://doi.org/10.1002/dc.21621. 14. tewari r, chaudhary a. atypical squamous cells of undet ermined significance: a follow up study. med j armed forces india 2010; 66:225–7. https://doi.org/10.1016/s0377-1237(10) 80042-5. 15. yamamoto ls, alves va, maeda my, longatto-filho a, utagawa ml, eluf neto j. a morphological protocol and guidelist on uterine cervix cytology associated to papillomavirus infection. rev inst med trop sao paulo 2004; 46:189–93. https://doi.org/10.1590/s0036-46652004000400003. 16. saslow d, solomon d, lawson hw, killackey m, kulasingam sl, cain j, et al. american cancer society, american society for colposcopy and cervical pathology, and american society for clinical pathology screening guidelines for the prevention and early detection of cervical cancer. ca cancer j clin 2012; 62:147–172. https://doi.org/10.3322/caac.21139. 17. youens ke, hosler ga, washington pj, jenevein ep, murphy km. clinical experience with the cervista hpv hr assay: correlation of cytology and hpv status from 56,501 specimens. j mol diagn 2011; 13:160–6. https://doi.org/10.1016/j.jmoldx.2010.11.016. 18. wright tc jr, massad ls, dunton cj, spitzer m, wilkinson ej, solomon d, et al. 2006 consensus guidelines for the manag ement of women with abnormal cervical screening tests. j low genit tract dis 2007; 11:201–22. https://doi.org/10.1097/ lgt.0b013e3181585870. https://doi.org/10.1002/cncr.22687 https://doi.org/10.1002/cncr.22687 https://doi.org/10.1128/cmr.16.1.1-17.2003 https://doi.org/10.1128/cmr.16.1.1-17.2003 https://doi.org/10.1002/cncy.22165 https://doi.org/10.1002/cncy.22165 https://doi.org/10.1002/dc.24035 https://doi.org/10.1002/dc.23391 https://doi.org/10.3855/jidc.2748 https://doi.org/10.1002/dc.21778 https://doi.org/10.1097/01.grf.0000151571.91814.f3 https://doi.org/10.1002/dc.21621 https://doi.org/10.1016/s0377-1237%2810%2980042-5 https://doi.org/10.1016/s0377-1237%2810%2980042-5 https://doi.org/10.1590/s0036-46652004000400003 https://doi.org/10.3322/caac.21139 https://doi.org/10.1016/j.jmoldx.2010.11.016 https://doi.org/10.1097/lgt.0b013e3181585870 https://doi.org/10.1097/lgt.0b013e3181585870 1department of medicine, basra college of medicine, basra, iraq; 2basra oncology and hematology centre, basra, iraq; 3cancer control centre, basra health directorate, basra, iraq *corresponding author’s e-mail: rafidalkhalidy79@gmail.com وابئيات أنواع السرطاانت املختلفة اليت مت اإلبالغ عنها يف البصرة، العراق رافد عبود ، كرمي عبد الأحمد ، �سيناء مزيد abstract: objectives: this study aimed to report the incidence and pattern of various types of cancers and their distribution across various demographic groups in basra, iraq. methods: cancer cases recorded during 2017 at the basra cancer control centre, the department of pathology and forensic medicine, the basra oncology and hematology centre, the basra children’s hospital and at private laboratories were included in the study. patients’ records were analysed for information related to age, gender, residence and type of cancer. incidences for different geographical regions and distribution of incidences across age groups were recorded as percentages. the mean age was recorded for patients of different genders and age groups. incidence rates per 100,000 were calculated for different types of cancer. results: a total of 2,163 cancer cases were identified of which 2,020 were in adults (93.4%) and 143 were in children (6.6%). among adults, most cancers were found in females (59%). patients’ mean age at diagnosis was 51.4 ± 19.6 years for adults and 6.4 ± 4.23 years for children. cancer incidence rates per 100,000 people increased with age. breast cancer was the most frequent cancer type found in adult females, with an incidence rate of 60.64 per 100,000 people. the most common types of cancer found in adult males were urinary bladder and lung and bronchus cancers; leukaemia was the most common cancer in children. conclusion: the findings from this study can be used for predicting cancer epidemiology in basra, iraq, and to identify subsets of the population at high risk of cancer incidence. this information will help healthcare providers to adequately respond to the demands of diagnosis, treatment and palliative care for such patients. keywords: neoplasms; incidence; epidemiology; demography; iraq. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل الإبالغ عن وقوع واأمناط الأنواع املختلفة من ال�رسطانات وتوزيعها عرب املجموعات الدميوغرافية يف ال�رسطان مكافحة مركز يف 2017 عام خالل امل�سجلة ال�رسطان حالت على الدرا�سة �سملت الطريقة: العراق. الب�رسة، يف املختلفة اخلا�سة. واملختربات لالأطفال، الب�رسة وم�ست�سفى بالب�رسة، الدم واأمرا�ض الأورام ومركز ال�رسعي، والطب الباثولوجيا وق�سم الب�رسة، ملختلف الوقوع حالت ت�سجيل مت ال�رسطان. ونوع والإقامة واجلن�ض بالعمر تتعلق معلومات على للح�سول املر�سى �سجالت حتليل مت املناطق اجلغرافية وتوزيع ووقوعها عرب الفئات العمرية كن�سب مئوية. مت ت�سجيل متو�سط العمر للمر�سى من خمتلف الأجنا�ض والفئات العمرية. مت ح�ساب معدلت الوقوع لكل 100,000 ملختلف اأنواع ال�رسطانات. النتائج: مت حتديد ما جمموعه 2,163 حالة �رسطان، 2020 منها يف البالغني )%93.4( و 143 يف الأطفال )%6.6(. من بني البالغني، مت العثور على معظم ال�رسطانات يف الإناث )%95(. كان متو�سط عمر املر�سى عند الت�سخي�ض 19.6 ± 51.4 �سنة للبالغني و 32.4 ± 6.4 �سنة لالأطفال. زادت معدلت وقوع ال�رسطان لكل 100,000 �سخ�ض 100,000 لكل 60.64 الوقوع معدل بلغ حيث البالغات، الإناث بني �سيوًعا ال�رسطانات اأنواع اأكرث الثدي �رسطان كان العمر. تقدم مع �سخ�ض. اأكرث اأنواع ال�رسطانات �سيوًعا لدى الذكور البالغني هي �رسطان املثانة البولية والرئة والق�سبات الهوائية. كان �رسطان الدم اأكرث اأنواع ال�رسطانات �سيوًعا عند الأطفال. اخلال�صة: ميكن ا�ستخدام نتائج هذه الدرا�سة للتنبوؤ بوبائيات ال�رسطان يف الب�رسة، العراق، ولتحديد املجموعات الفرعية من ال�سكان املعر�سني خلطر الإ�سابة بال�رسطان. �ست�ساعد هذه املعلومات مقدمي الرعاية ال�سحية على ال�ستجابة ب�سكل منا�سب ملتطلبات الت�سخي�ض والعالج والرعاية امللطفة لهوؤلء املر�سى. الكلمات املفتاحية: الأورام؛ وقوع؛ الوبائيات؛ الدميوغرافيا؛ العراق. epidemiology of different types of cancers reported in basra, iraq *rafid a. abood,1,2 kareem a. abdahmed,3 seena s. mazyed3 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e295–300, epub. 5 oct 20 submitted 3 nov 19 revision req. 16 jan 20; revisions recd. 26 feb 20 accepted 25 mar 20 https://doi.org/10.18295/squmj.2020.20.03.008 clinical & basic research advances in knowledge this epidemiological study provides the incidence of various types of cancer in adult (males and females) and in children in the basra governorate of iraq. the most frequent cancer types in males in basra, iraq are cancer of bladder, cancer of lung and bronchus, and lymphoma. the most frequent cancer types in females in basra, iraq are cancer of breast, lymphoma, and cancer of ovary. the most frequent cancer types among children in basra, iraq are leukemia, cancer of brain/ cns, and lymphoma. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ epidemiology of different types of cancers reported in basra, iraq 296 | squ medical journal, august 2020, volume 20, issue 3 the incidence of various cancers is increasing globally and is predicted to rise from 14.1 million new cases in 2012 to 20 million new cases in 2025.1 the proportion of cancer-related deaths increased from 14% in 2005 to 16% in 2015.2,3 with around 8.8 million global deaths in 2015, cancer has been recognised as the second leading cause of death after cardiovascular disease worldwide.3 various studies predicted around 18.1 million new cancer cases and 9.6 million cancer deaths would be recorded globally in 2018.4 it was further estimated that in 2018, nearly 50% of all new cancer cases and over 50% of all cancer deaths would occur in asia.4 regional variations in cancer epidemiology have been well documented and are attributable to societal, economic and lifestyle changes across different regions.4 although incidence, survival and mortality rates have been reported in many populations, very little is known about cancer incidence specifically in iraq.6,7 basra, located in the southern part of iraq, has witnessed an increase in its cancer incidence and mortality rates since 2005.8 therefore, this study aimed to determine the incidence rates and gender distribution of various cancers in the basra governorate of iraq using epidemiological analysis. methods this observational, cancer-registry-based study analysed all malignant cancer cases diagnosed from 1 january to 31 december 2017 in basra, iraq. the basra cancer registry (bcr) was initiated in 1992 and is maintained by the basra cancer control centre (bccc). the bcr compiles cancer-related epidemiological information from all major hospitals (both public and private) in basra, including basra oncology and haematology centre, basra children’s hospital and the basra college of medicine. the bcr also compiles data from early detection centres, forensic medicine departments and all private laboratories including histopathology or haematology. data was collected through active monthly visits to the above-mentioned sites and a passive review from the bcr records of the bccc because, according to a basra health directorate decision, cancer notification has been mandatory since 2008. the collected data included demographic information (name, gender, age, address and nationality) and tumour details (diagnosis date, primary site and histology). cases reported from governorates other than basra were excluded from the study. anonymised data of all cases from the basra governorate were computerised using the canreg-3 programme (international association of cancer registries, lyon, france). using the programme’s modules, duplicate entries of the same cancer case were removed and verified cases were analysed. the cancer incidence in populations of different age groups and of both genders was calculated. patients’ ages at time of diagnosis were recorded and the average age and incidence rates of different types of cancer were calculated for adults. adults were defined as patients aged ≥15 years and children were defined as patients aged <15 years. the institutional ethics committee of college of medicine, university of basra, iraq granted approval for this study. results a total of 2,579 cases of cancer were recorded, of which 416 patients were excluded because they were not residents of basra governorate. the final total sample size was 2,163. cancers were confirmed through histology/cytology (n = 1,910; 88.3%), haematology (n = 102, 4.7%), radiology (n = 102; 4.7%), clinically (n = 26; 1.2%) and by autopsy (n = 11; 0.5%). for the remaining 12 (0.6%) cases, the method of diagnosis was unknown. the vast majority of cancer cases (n = 2,020; 93.4%) were recorded in adults while the remaining (n application to patient care: epidemiological knowledge helps to understand the current burden of disease. future studies about incidence of cancer can help to identify the trends of increasing/ decreasing incidences in each cancer types in each gender/age group. this information is also helpful for policymakers to devise strategies to combat cancer by formulating national programs. figure 1: incidence rate of cancer per 100,000 people across different age groups in basra, iraq in 2017. rafid a. abood, kareem a. abdahmed and seena s. mazyed clinical and basic research | 297 = 143; 6.6%) were in children. the mean age of patients was 52.4 ± 15.2 years for adults and 6.4 ± 4.23 years for children. in adults, the mean age at the time of diagnosis was higher in males (57.7 ± 16.7 years) than females (51.4 ± 19.6 years). the incidence rate was 72/100,000 people [figure 1]. the age-standardised rate was 129.82. the cancer incidence rate per 100,000 people was highest among patients aged >70 years and 42% of the cases diagnosed in 2017 were 50–69 years old [table 1]. breast cancer was the most common type of cancer among adults in basra, constituting 27.67% of the total cases diagnosed in 2017 with an incidence rate of 31.01 per 100,000 people. the five most frequent cancers (breast cancer, lymphoma, lung and bronchus cancer, urinary bladder cancer and colorectal cancer) constituted 53.47% of all cancer cases in basra [table 2]. in children, leukaemia was the commonest type of cancer recorded (4.66/100,000 children; 39.2%), followed by cancers of the brain/ central nervous system (2/100,000 children; 16.8%; cns), lymphoma (1.16/100,000 children; 9.8%) and bone cancer (1/100,000 children; 8.4%) [table 3]. of the 2,020 cancer cases in adults, there was slight female preponderance with 1,191 (59%) cases in females versus 829 (41%) cases in males, yielding a male-to-female ratio of 1:1.43. in adult males, urinary bladder cancer was the most common type, representing 11.94% of cancers, followed by lung and bronchus cancer (10.86%), lymphoma (8.56%) and colorectal cancers (8.44%). in adult females, breast cancer was the most common representing 45.42% of cancers, followed by lymphoma (6.13%), ovarian cancer (5.12%) and uterine cancer (4.21%). the frequency of cancers affecting various organs varied between genders [figure 2]. discussion annual numbers of deaths worldwide due to cancer exceeds the total number of deaths attributed to tuberculosis, malaria and hiv/aids combined.9 approximately 75% of total cancer deaths occur in lowand middle-income countries (lmics).10 cancer incidence in these countries is increasing rapidly due to changing demographics and increased exposure to various risk factors.10 the present study reports the epidemiology of various cancers in basra, iraq, during 2017. the cancer incidence rate in 2017 (72/100,000 people) increased by over 30% from 2005 (54.26/100,000 people).8 more broadly, the eastern mediterranean region has witnessed a marked increase in cancer table 2: frequency of occurrence and incidence rates per 100,000 people for the 10 most frequent types of cancer in the total adult population of the basra, iraq in 2017 type of cancer n (%) incidence rate per 100,000 adults breast 559 (27.7) 31.0 lymphoma 144 (7.1) 8.0 lung and bronchus 132 (6.5) 7.3 urinary bladder 127 (6.3) 7.0 colorectal 118 (5.8) 6.5 leukaemia 84 (4.2) 4.7 unknown primary 76 (3.8) 4.2 prostate 63 (3.1) 3.5 ovary and stomach 61 (3.0) 3.4 brain/cns 59 (2.9) 3.3 total (n = 2,020) 1,423 (70.4) 79.0 cns = central nervous system. table 1: distribution of cancer incidence and incidence rate per population of 100,000 across different age groups in basra, iraq in 2017 (n = 2,163) age group in years n (%) population incidence rate per 100,000 people >10 97 (4.5) 873,046 11.1 10–19 85 (3.9) 673,993 12.6 20–29 109 (5.0) 501,563 21.7 30–39 205 (9.5) 398,226 51.5 40–49 366 (16.9) 281,546 130.0 50–59 442 (20.4) 142,241 310.7 60–69 475 (22.0) 89,846 528.7 ≥70 384 (17.8) 43,411 884.6 total 2,163 (100) 3,003,872 72.0 table 3: frequency of occurrence of the 10 most frequent types of cancer and incidence rate per 100,000 children below the age of 15 years in basra, iraq in 2017 type of cancer n (%) incidence rate per 100,000 children leukaemia 56 (39.2) 4.7 brain/cns 24 (16.8) 2.0 lymphoma 14 (9.8) 1.2 bone 12 (8.4) 1.0 soft tissue 9 (6.3) 0.7 kidney 7 (4.9) 0.6 neuroblastoma 7 (4.9) 0.6 other bm disorders 4 (2.8) 0.3 eye 3 (2.1) 0.2 liver 2 (1.4) 0.2 total (n = 143) 138 (96.5) 11.5 cns = central nervous system; bm = bone marrow. epidemiology of different types of cancers reported in basra, iraq 298 | squ medical journal, august 2020, volume 20, issue 3 incidence from 494,690 in 2005 to 722,646 in 2015, although the increment of increase varies depending on countries’ economic status.12 for example, the rate of increase was moderate in low-income countries such as afghanistan (47.2%), djibouti (49.4%), somalia (67.6%) and yemen (49.4%). a similar pattern was also recorded in middle-income countries such as egypt (40.6%), jordan (54.1%), lebanon (78.2%), morocco (45.3%), pakistan (44.6%) and sudan (44.7%). by contrast, the cancer incidence increased drastically in high-income countries such as kuwait (79.6%), oman (123.9%), saudi arabia (67.6%) and the united arab emirates (182.9%; uae).12 gender distribution in cancer incidence is an important aspect of cancer epidemiology. in western countries such as the usa, uk and europe, cancer affects males more than females.13,14 in contrast, in middle eastern countries, cancer affects females more than males, as observed in the current study as well as previous studies that focused on different parts of iraq, figure 2: frequency of occurrence of different types of cancer in adult males (a) and females (b) in basra, iraq, in 2017. cns = central nervous system. table 4: frequency of occurrence and incidence rate per 100,000 adult males/females of the 10 most frequent types of cancer in adult males and females in basra, iraq in 2017 type of cancer in adult males n (%) incidence rate per 100,000 adult males type of cancer in adult females n (%) incidence rate per 100,000 adult females urinary bladder 99 (11.9) 10.9 breast 541 (45.4) 60.6 lung and bronchus 90 (10.9) 10.0 lymphoma 73 (6.1) 8.2 lymphoma 71 (8.6) 7.8 ovary 61 (5.1) 6.8 colorectal 70 (8.4) 7.7 uterus 50 (4.2) 5.6 prostate 63 (7.6) 7.0 colorectal 49 (4.1) 5.5 leukaemia 41 (4.9) 4.5 leukaemia 43 (3.6) 4.8 stomach 37 (4.5) 4.1 lung and bronchus 42 (3.5) 4.7 kidney 36 (4.3) 4.0 unknown primary 41 (3.4) 4.6 unknown primary 35 (4.2) 3.8 cervix 31 (2.6) 3.5 brain and cns 31 (3.7) 3.4 brain and cns, thyroid 29 (2.4) 3.3 total (n = 829) 573 (69.1) 63.0 total (n = 1,191) 960 (80.6) 107.6 cns = central nervous system. rafid a. abood, kareem a. abdahmed and seena s. mazyed clinical and basic research | 299 and the eastern mediterranean region, including the uae and kuwait.6,15,16 breast cancer represents approximately 45% of all cancer types in lmics.17 reflecting this observation, the current study found that breast cancer was the commonest cancer in basra in 2017. similar findings have been reported from europe and the usa where the most frequent cancers as of 2018 in females was breast cancer, followed by cancers affecting the colorectal region and the lungs and bronchus.18 the incidence rate of breast cancer in the current study was found to be 60.64/100,000 adult females, which is similar to findings reported in egypt (49.6/100,000), jordan (38.0/100,000) and israel (36.7/100,000) but lower than rates reported in the western world (97.2/100,000 females in the usa).17 in arab countries, the incidence rate of breast cancer is increasing rapidly due to rapid industrialisation and both delayed and reduced fertility.19 other contributing risk factors leading to the increasing incidence of breast cancer in arab countries include obesity, family history, hormonal therapy, post-menopause status, lack of education and no history of breastfeeding.20 breast cancer was also reported to have the highest incidence rate in females in sulaymaniyah, iraq, between 2006– 2014.21 similar to findings of the current study, aljanabi et al. reported high incidence rates of breast, thyroid and colorectal cancers in females of karbala, iraq.6 the current study found urinary bladder cancer to be the most frequent cancer among iraqi males, affecting 11.94% of the males in the study with an incidence rate of 10.88/100,000 males. across the world, urinary bladder cancer is the seventh most common type of cancer diagnosed in males.23 various cities of iraq have witnessed high rates of urinary bladder cancer, accounting for nearly 13–15% of total cases of cancer.24 the high incidence and mortality of bladder cancer in the middle east has also been previously reported.25 the reason for the high incidence of bladder cancer in iraq needs to be further explored. in comparison to the current findings, the incidence rates of lung cancer, leukaemia and lymphoma reported in males in sulaymaniyah, iraq, between 2006–2014 were 7.12, 4.5 and 4.32 per 100,000 people, respectively.21 prostate cancer was the fifth most common cancer among males in the current study. in contrast, prostate cancer has been reported as the most frequent cancer amongst males in the usa and europe according to the world health organization’s (who) 2018 globocan data.26,27 one possible explanation for the seemingly lower incidence of prostate cancer among iraqi males is the overdiagnosis of prostate cancer in men in europe and usa due to prostate specific antigen screening which is perhaps less observed in iraq. future studies are warranted to identify other factors contributing to this observed difference in epidemiology between males from iraq and the western world. in this study, the commonest childhood cancer was leukaemia followed by brain/cns cancers and lymphomas (39.2%, 16.8% and 9.8%, respectively). in basra between 2012–2016, the incidences of these three cancers were 35.4%, 11.9% and 17.8%, respectively.7 even in iran’s golestan province in 2010, a similar pattern was reported.28 the three most frequent childhood cancers were leukaemia (41.7%), lymphoma (11.5%) and brain and cns cancers (10.1%).28 a major limitation of the current study is that, as this was a hospital-based registry, the calculated cancer incidence might not be as accurate as a population-based cancer registry. however, hospitalbased cancer registries have value as tools for policy formulations and region-specific data creation, especially in resource-poor regions.29 at present, the international association of cancer registries-backed national cancer registry is involved in generating national-level cancer incidence rates in coordination with the who’s globocan project.30 to the best of the authosrs’ knowledge, a population-based cancer registry does not exist which caters exclusively to the population of basra. the data from this study can contribute to a more accurate estimation of cancer epidemiology in iraq. the numbers obtained from the various sources were reported descriptively so do not statistically predict the future incidence of cancer in basra. the heavy focus on the epidemiological aspects of cancer resulted in not collecting data pertaining to factors influencing cancer such as smoking habits, social and economic status, marital status and the presence of comorbidities. conclusion in the current study, a hospital-based cancer registry was analysed for trends in cancer incidence in basra, iraq, in 2017. breast cancer was the most frequent cancer type among adults and adult females, and urinary bladder cancer and leukaemia were the most frequent cancer types among adult males and children, respectively. this epidemiological study could be used as a tool to identify cancer risks and plan accordingly. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. epidemiology of different types of cancers reported in basra, iraq 300 | squ medical journal, august 2020, volume 20, issue 3 f u n d i n g no funding was received for this study. references 1. ferlay j, soerjomataram i, dikshit r, eser s, mathers c, rebelo m, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer 2015; 136:e359–86. https://doi.org/10.1002/ijc.29210. 2. global burden of disease cancer collaboration, fitzmaurice c, allen c, barber rm, barregard l, bhutta za, et al. global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. jama oncol 2017; 3:524–48. https://doi.org/10.1001/jamaoncol.2016.5688. 3. gbd 2015 mortality and causes of death collaborators. global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the global burden of disease study 2015. lancet 2016; 388:1459–544. https://doi.org/10.1016/ s0140-6736(16)31012-1. 4. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of inci dence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2018; 68:394–424. https://doi.org/10.3322/ caac.21492. 5. global burden of disease cancer collaboration, fitzmaurice c, dicker d, pain a, hamavid h, moradi-lakeh m, et al. the global burden of cancer 2013. jama oncol 2015; 1:505–27. https://doi.org/10.1001/jamaoncol.2015.0735. 6. al-janabi aahs, naseer zh, hamody ta. epidemiological study of cancers in iraq-karbala from 2008 to 2015. int j med res heal sci 2017; 6:79–86. 7. al-asadi jn, ibrahim sj. childhood cancer in basrah, iraq during 2012–2016: incidence and mortality. asian pac j can cer prev 2018; 19:2337–41. https://doi.org/10.22034/apjcp.20 18.19.8.2337. 8. habib os, al-ali jk, al-wiswasi mk, ajeel na, al-asady og, khalaf aa, et al. cancer registration in basrah 2005: preliminary results. asian pac j cancer prev 2007; 8:187–90. 9. prager gw, braga s, bystricky b, qvortrup c, criscitiello c, esin e, et al. global cancer control: responding to the growing burden, rising costs and inequalities in access. esmo open 2018; 3:e000285. https://doi.org/10.1136/esmoopen-2017-000285. 10. farmer p, frenk j, knaul fm, shulman ln, alleyne g, armstrong l, et al. expansion of cancer care and control in countries of low and middle income: a call to action. lancet 2010; 376:1186–93. https://doi.org/10.1016/s0140-6736(10)61152-x. 11. the iqvia institute for human data science. medicines use and spending in the u.s.: a review of 2016 and outlook to 2021. from: www.iqvia.com/institute/reports/medicines-use-andspending-in-the-us-a-review-of-2016 accessed: feb 2020. 12. gbd 2015 eastern mediterranean region cancer collaborators. burden of cancer in the eastern mediterranean region, 20052015: findings from the global burden of disease 2015 study. int j public health 2018; 63:151–64. https://doi.org/10.1007/ s00038-017-0999-9. 13. siegel r, naishadham d, jemal a. cancer statistics, 2012. ca cancer j clin 2012; 62:10–29. https://doi.org/10.3322/ caac.20138. 14. wang y, freemantle n, nazareth i, hunt k. gender differences in survival and the use of primary care prior to diagnosis of three cancers: an analysis of routinely collected uk general practice data. plos one 2014; 9:e101562. https://doi.org/10.1371/ journal.pone.0101562. 15. kulhánová i, bray f, fadhil i, al-zahrani as, el-basmy a, anwar wa, et al. profile of cancer in the eastern mediterranean region: the need for action. cancer epidemiol 2017; 47:125–32. https://doi.org/10.1016/j.canep.2017.01.009. 16. alwan n, kerr d. cancer control in war-torn iraq. lancet oncol 2018; 19:291–2. https://doi.org/10.1016/s1470-2045(18)30135-9. 17. tfayli a, temraz s, abou mrad r, shamseddine a. breast cancer in lowand middle-income countries: an emerging and challenging epidemic. j oncol 2010; 2010:490631. https://doi. org/10.1155/2010/490631. 18. siegel rl, miller kd, jemal a. cancer statistics, 2018. ca cancer j clin 2018; 68:7–30. https://doi.org/10.3322/caac.21442. 19. s habib o, a hameed l, a ajeel n, al-hawaz mh, al-faddagh za, n nasr g, et al. epidemiology of breast cancer among females in basrah. asian pac j cancer prev 2016; 17:191–5. https://doi. org/10.7314/apjcp.2016.17.s3.191. 20. hamadeh rr, borgan sm, sibai am. cancer research in the arab world: a review of publications from seven countries between 2000–2013. sultan qaboos univ med j 2017; 17:e147–54. https://doi.org/10.18295/squmj.2016.17.02.003. 21. khoshnaw n, mohammed ha, abdullah da. patterns of cancer in kurdistan results of eight years cancer registration in sulaymaniyah province-kurdistan-iraq. asian pac j cancer prev 2015; 16:8525–31. https://doi.org/10.7314/apjcp.2015.16.1 8.8525. 22. centre for arab genomics studies. bladder cancer. from: www.cags.org.ae/ctga/details.aspx?id=748 accessed: feb 2020. 23. zhang y. understanding the gender disparity in bladder cancer risk: the impact of sex hormones and liver on bladder susceptibility to carcinogens. j environ sci health c environ carcinog ecotoxicol rev 2013; 31:287–304. https://doi.org/10 .1080/10590501.2013.844755. 24. al-fouadi a, parkin dm. cancer in iraq: seven years’ data from the baghdad tumour registry. int j cancer 1984; 34:207–13. https://doi.org/10.1002/ijc.2910340211. 25. steliarova-foucher e, colombet m, ries lag, moreno f, dolya a, bray f, et al. international incidence of childhood cancer, 2001–10: a population-based registry study. lancet oncol 2017; 18:719–31. https://doi.org/10.1016/s1470-2045(17)30186-9. 26. world health organisation. globocan 2018. united states of america. from: https://gco.iarc.fr/today/data/factsheets/ populations/840-united-states-of-america-fact-sheets.pdf accessed: feb 2020. 27. world health organisation. globocan 2018. europe. from: https://gco.iarc.fr/today/data/factsheets/populations/908europe-fact-sheets.pdf accessed: feb 2020. 28. moradi a, semnani s, roshandel g, mirbehbehani n, keshtkar a, aarabi m, et al. incidence of childhood cancers in golestan province of iran. iran j pediatr 2010; 20:335–42. 29. rajaram s, bhaskaran s, sinha s, agarwal s. role of hospitalbased cancer registries: a decade of experience of cancer cervix from a tertiary care centre, india. indian j community med 2014; 39:241–4. https://doi.org/10.4103/0970-0218.143028. 30. world health organisation. iraqi cancer data for 2017‒2018 announced. from: www.emro.who.int/irq/iraq-news/cancerdata-for-20172018-announced-in-iraq.html accessed: feb 2020. https://doi.org/10.1002/ijc.29210 https://doi.org/10.1001/jamaoncol.2016.5688 https://doi.org/10.1016/s0140-6736%2816%2931012-1 https://doi.org/10.1016/s0140-6736%2816%2931012-1 https://doi.org/10.3322/caac.21492 https://doi.org/10.3322/caac.21492 https://doi.org/10.1001/jamaoncol.2015.0735 https://doi.org/10.22034/apjcp.2018.19.8.2337 https://doi.org/10.22034/apjcp.2018.19.8.2337 https://doi.org/10.1136/esmoopen-2017-000285 https://doi.org/10.1016/s0140-6736%2810%2961152-x https://doi.org/10.1007/s00038-017-0999-9 https://doi.org/10.1007/s00038-017-0999-9 https://doi.org/10.3322/caac.20138 https://doi.org/10.3322/caac.20138 https://doi.org/10.1371/journal.pone.0101562 https://doi.org/10.1371/journal.pone.0101562 https://doi.org/10.1016/j.canep.2017.01.009 https://doi.org/10.1016/s1470-2045%2818%2930135-9 https://doi.org/10.1155/2010/490631 https://doi.org/10.1155/2010/490631 https://doi.org/10.3322/caac.21442 https://doi.org/10.7314/apjcp.2016.17.s3.191 https://doi.org/10.7314/apjcp.2016.17.s3.191 https://doi.org/10.18295/squmj.2016.17.02.003 https://doi.org/10.7314/apjcp.2015.16.18.8525 https://doi.org/10.7314/apjcp.2015.16.18.8525 https://doi.org/10.1080/10590501.2013.844755 https://doi.org/10.1080/10590501.2013.844755 https://doi.org/10.1002/ijc.2910340211 https://doi.org/10.1016/s1470-2045%2817%2930186-9 https://doi.org/10.4103/0970-0218.143028 1department of plastic surgery, khoula hospital, muscat, oman; 2oman medical specialty board, muscat, oman; 3internship program, sultan qaboos university, muscat, oman *corresponding author’s e-mail: sheikhan123@yahoo.com experience of unilateral cleft lip repair using the anatomical subunit technique in an omani population over a five-year period *sheikhan al hashmi,1 malak al wahaibi,2 sony p. varghese,1 maather al abri,3 moath a. shummo,1 buthina al muqbali1 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 387–392, epub. 25 aug 22 submitted 23 feb 21 revisions req. 26 apr & 31 may 21; revisions recd. 9 may & 16 jun 21 accepted 7 jul 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.108 clinical & basic research abstract: objectives: this study aimed to report the authors’ experience with the anatomical subunit technique for unilateral cleft lip repair, which has gained popularity worldwide. methods: from july 2015 to april 2020, 114 consecutive cases of cleft lip underwent primary cleft lip repair with closed rhinoplasty by a single surgeon. the demographic data, severity and type of the cleft lip, surgical outcomes, including vermillion notching, were assessed by an independent senior surgeon. the rate of revision surgery was collected from the al-shifa® 3plus healthcare information system (ministry of health, oman). parents’ satisfaction regarding scar quality and lip and nose appearance was collected and all data were statistically analysed. results: a total of 82 cases satisfied the inclusion criteria. the mean age at surgery for cleft lip was 32 weeks. among these, 35 cases (43%) were complete cleft lips and 47 cases (57%) were incomplete. additionally, 43 children (52%) were born of consanguineous marriage. six patients (7%) needed revision surgery. the digital survey was completed by 40 subjects (response rate: 48.8%) which showed 85% satisfaction rate with the postoperative scar and 77.5% satisfaction with the aesthetic appearance of the nose. conclusion: the anatomical subunit technique resulted in a predictable outcome indicating a high rate of patient satisfaction with scar quality and nasal and lip symmetry in children with varying severity of cleft lip. the high percentage of consanguinity (52%) in this study highlights the need for more targeted national campaigns involving premarital counselling in the omani population. keywords: cleft lips; congenital abnormalities; cleft lip/surgery; reconstructive surgical procedures; treatment outcome; surgical diagnostic technique; consanguinity; oman. advances in knowledge to the best of the authors’ knowledge, this is the first study in oman to highlight the outcomes and direct experience of this particular technique for cleft lip repair in an omani population. this study revealed a high percentage of consanguinity (52%) in the study group. the most common complication associated with the anatomical subunit technique in the current study was vermilion excess, which was corrected with simple wedge excision. there was an 85% satisfaction rate with the postoperative scar and 77.5% satisfaction rate with the aesthetic appearance of the nose. application to patient care the anatomic subunit technique used here produced predictable and identical results related to scar quality and nasal and lip symmetry in children with varying severity of cleft lip. due to the high consanguinity in this study group, the authors are calling for more targeted national campaigns involving premarital counselling in the omani population. orofacial clefts remain the most common craniofacial congenital anomaly.1,2 a study published in 2001 by rajab and thomas concluded that the prevalence of cleft lip in oman was 15 per 10,000 births.3 out of those, 0.62 per 1000 live births were combined cleft lip and palate and 0.34 per 1000 live births were isolated cleft lip cases.3 this result is striking as it suggests a higher prevalence of cleft lip in oman in relation to worldwide numbers. the data published from the international perinatal database of typical oral clefts in 2011 stated that the worldwide prevalence of cleft lip was found to be 9.9 per 10,000 births, compared to 15 per 10,000 births in oman.4 the incidence of cleft lip has been found to be associated with consanguineous marriages, specifically in children born to parents who are first cousins which was found to be 61.1%; this incidence falls down to 18.0% in parents who are second cousins.5 a metaanalysis of orofacial clefts indicated a clear relationship between consanguinity and non-syndromic orofacial clefts (nsofc), with the risk being twice in children born to consanguineous parents.5 cleft lip anomalies are more commonly found in association with cleft palate deformities; however, in other less common instances, it can present as an isolated cleft lip anomaly.1,6 cleft lip anomalies can be https://creativecommons.org/licenses/by-nd/4.0/ experience of unilateral cleft lip repair using the anatomical subunit technique in an omani population over a five-year period 388 | squ medical journal, august 2022, volume 22, issue 3 unilateral or bilateral and can range in severity from a scale of a microform cleft lip which is considered the least disfiguring, to a complete cleft lip.1,7 some of the well-known challenges of children born with cleft lip include feeding difficulties, trouble in articulation and speech development along with psychological and self-esteem concerns related to the condition.1 studies related to the comprehensive statistics of this anomaly and its management outcomes in oman remain significantly limited. different studies have reported their experience with the anatomical subunit technique in comparison to millard and modified millard technique. deshmukh et al. published a study favouring the aesthetic outcomes of fisher’s technique over mohler’s technique.8 in the study, 50 patients were selected and randomly assigned to undergo surgical cleft lip repair by either the mohler or fisher technique performed by a single surgeon. outcomes were then assessed by laymen and demonstrated that a bigger proportion of evaluators have favoured the aesthetic outcomes of the fisher repair.8 kwang et al. also published a similar study, which enrolled candidates from different levels of training and requested them to evaluate the aesthetic outcomes of anatomical subunit repair in comparison to rotation advancement repair.9 in this study, candidates from different levels of training have found outcomes of the anatomical subunit techniques to be aesthetically superior to that of the latter technique.9 the experience of the anatomic subunit technique has not been studied in the omani population prior to this study. given that the anatomical subunit technique for unilateral cleft lip repair has gained popularity worldwide, this study aimed to report the present authors’ experience with the aforementioned technique. a related aim was to explore the opinion and experience of parents whose children had undergone cleft lip repair using the above technique and provide a clearer picture of the demographic data in a population of omani patients with cleft lip. methods this is a retrospective study of the surgical correction of the cleft lip anomaly in an omani population. the procedure was performed using the anatomic subunit technique of cleft lip repair by single surgeon over a period of 5 years—july 2015 to april 2020—for varying degrees of cleft lip ranging from unilateral incomplete cleft lip to complete cleft lip. the institute indicated in this study, khoula hospital, is a level 1 trauma centre and is also the main plastic surgery centre in oman. the standard technique used for the correction of cleft lip in this institute is the millard or modified millard rotation advancement technique. the anatomic subunit technique was introduced to the department of plastic surgery by one of the authors in 2015. all children who underwent cleft lip repair from july 2015 to april 2020 using the anatomic subunit technique of cleft lip repair at khoula hospital, muscat, oman were included in this study. the records were collected using the al-shifa® 3plus healthcare information system, (ministry of health, oman). children who did not follow up, parents who refused to be part of the study due to social or cultural reasons, children with a microform cleft lip, children with bilateral cleft lip, or patients with inadequate data entered into the above-mentioned e-healthcare system were all excluded. all patients were evaluated preoperatively in the clinic and prioritised according to the age and anaesthetic clearance for surgery. nasoalveolar moulding by an experienced orthodontist was requested for indicated cases. most of the children were operated on by the fifth to seventh month of age after adequate weight gain and haemoglobin evaluation. once the children were cleared by the pre-anaesthetic clinic for surgery, they were admitted and operated on the following day. all the children underwent cheiloplasty using the anatomic subunit technique with closed rhinoplasty by a single surgeon under general anaesthesia. the procedure started with markings as per the anatomical subunit technique following which the key landmarks were tattooed. infiltration of xylocaine 1% with 1:200,000 adrenaline in the alar base and inferior turbinate area on the cleft side was performed. incisions were made on the medial lip along the markings including the opening triangle. a cuff of the orbicularis oris muscle was dissected after releasing its attachments to the columella base and alveolar cleft margin. following this, lateral lip incisions were made along the markings and after discarding the tissue along the cleft margin, a cuff of the orbicularis oris muscle was dissected in the same manner. the alar base on the cleft side was then released off the pyriform and advanced anteromedially. the closure started with the nasal floor and, in some cases, a turbinate flap was used to cover any exposed periosteal surface of the pyriform margin. primary closed rhinoplasty was done with repositioning of the cleft side dome using 5–0 monocryl (ethicon inc., cornelia, georgia, usa). the mucosa, the muscle and the lateral vermilion flap were each approximated with 5–0 vicryl (ethicon inc., johnson & johnson, somerville, new jersey, usa) and the skin is closed with 7–0 prolene sheikhan al hashmi, malak al wahaibi, sony p. varghese, maather al abri, moath a. shummo and buthina al muqbali clinical and basic research | 389 (ethicon, inc., manlo park, california, usa). an intraoperative nostril retainer was applied in all cases and secured using a 4/0 nylon monofilament suture to the membranous septum. elbow splints were applied and maintained for 10–14 days. the children were allowed to be breast fed 3–4 hours post-operation and discharged on the first or second postoperative day. they were re-evaluated at three weeks, six weeks, three months, six months and then annually at the clinic. the average long-term follow-up for patients in this study was 2.3 years. the postoperative evaluation of all children who underwent cleft lip repair included evaluation and assessment of the quality of the scar on the lip and vermilion, symmetry of the nose, symmetry of the vermilion volume and white roll alignment by an independent senior surgeon. parents of all the children who had undergone cleft lip repair using the anatomic subunit technique of cleft lip repair at the hospital were sent a link to an electronic survey regarding the aesthetic appearance of the lip after surgery, ability to breast feed and their satisfaction with surgical scar and with the correction of the nasal deformity. all other data required for the study was collected from the al-shifa® 3plus healthcare information system (ministry of health, oman). this included personal data, date of surgery, severity and side of cleft lip, presence of a protruding premaxilla, pre-surgical orthodontics, grade of cleft palate, associated syndromes, the geographical area the child is from, associated anomalies, consanguinity, family history of cleft, last follow-up date, objective assessment and any revision surgery for the lip. the data were entered into excel sheets and analysed using statistical package for the social sciences (spss), version 24.0 (ibm corp., chicago, illinois, usa). ethical approval was obtained from the ministry of health, centre of studies and research at oman and the research ethics committee at khoula hospital (unique identification code: 24273) verbal consent was obtained from the parents who were interested in filling out the electronic survey and for those willing to include their children’s photos in this article. results a total of 114 cleft lip surgeries were performed by one of the authors during the study period. out of 114 patients, 82 satisfied the inclusion criteria and were included in the study. out of the included cases, 52 were males (63%) and 30 were females (37%). the mean age of the patients at the time of surgery was 32 weeks. nine children (11%) underwent the surgery in following weeks due to late presentation and comorbid conditions. the eldest of the patients presented for the first time at 356 weeks due to personal and socioeconomic issues and was operated on at the age of presentation. a total of 43% of the cleft lip cases were from the muscat and a’dakhiliya governorates with 18 (22%) and 17 (21%) cases, respectively. the other regions made up 57% of the cases with a’sharqiah, al batinah, a’dhahirah, al wusta, musandam and al buraimi representing 20%, 19%, 11%, 4%, 2% and 1% of the cases, respectively. all cleft lip surgeries were conducted using the anatomical subunit technique. it was found that 35 cases (43%) presented with complete cleft lip and 47 cases (57%) were found to be incomplete. additionally, 53 cases (65%) were left-sided and 29 cases (35%) were right-sided. it was also noted that 36 patients (44%) had cleft of palate involving both hard and soft palate, out of which 28 patients (34%) qualified for veau’s criteria of class iii cleft palate and eight patients (10%) qualified for class ii. additionally, 21 patients (26%) underwent presurgical nasoalveolar moulding and three patients had protruding premaxilla; 12 patients had associated anomalies which were mainly cardiac anomalies. two children were confirmed to be syndromic—one had downs syndrome and the other, velocardiofacial syndrome. additionally, 43 children (52%) were born of figure 1: a pre-operative image of an infant (a) showing left-sided incomplete cleft lip and post-operative image (b) showing left-sided incomplete cleft lip following surgery using the anatomical subunit technique. experience of unilateral cleft lip repair using the anatomical subunit technique in an omani population over a five-year period 390 | squ medical journal, august 2022, volume 22, issue 3 consanguineous marriages: 33 (77%) from a first cousin marriage, 7 (16%) from a second cousin marriage and 3 (7%) from a third cousin marriage. it was found that 22 patients (27%) had a positive family history of cleft lip. out of the 82 who had undergone cleft lip repair using the anatomic subunit technique, six patients (7%) needed revision as judged by the senior independent surgeon at the time of the last follow-up during the study period, five of which were for vermilion excess, managed through simple wedge resection. collectively, the repair was performed on both complete and incomplete cleft lips and both produced identical results [figures 1 and 2]. a digital survey was sent to the parents of the 82 children who had undergone cleft lip repair using the anatomical subunit technique. out of these, the parents of 40 children responded to the survey anonymously (response rate: 48.8%). statistical analysis showed that 82.5% (33/40) were satisfied with the aesthetic appearance of lip following cleft lip repair by the anatomical subunit technique, 85% (34/40) were satisfied with the postoperative scar over the lip and 77.5% (31/40) were satisfied with the aesthetic appearance of nose following cleft lip surgery with closed rhinoplasty. discussion various techniques have been used by plastic surgeons to correct cleft lip anomalies, all of which have aimed to establish the best functional rehabilitation and aesthetical acceptance.10–13 rose’s straight-line repair was one of the first cleft lip repair techniques to be described; this technique was published in 1891, followed by the rotation advancement technique for unilateral cleft lip repair introduced by ralph millard in 1957. this technique is initiated by forming an incision just below the nostril which continues to run vertically to the philtral ridge.12 millard’s technique has undergone a number of refinements throughout the years but probably remains the most common technique used in unilateral cleft lip repair worldwide.13 mohler further modified the rotation-advancement repair technique in 1987, achieving a more symmetric positioning of the scar. the next big evolution in cleft lip repair came with the introduction of the extended mohler cleft lip repair by court cutting in 2003.14 the major adjustment of this technique was to extend the incision to the noncleft philtral column.11 with this modification, two major shortcomings arose: first was the complex appearance of the scar under the nasal sill, which did not blend with the anatomical landmarks; the second was that in order to avoid the under rotation and elevation of the cupid’s bow peak, the lateral lip segment was shortened.11 to address the aforementioned shortcomings, david m. fisher proposed the anatomic subunit technique first published in 2005.11 as the name suggests, this technique respects the anatomical subunits of the lip and is based on accurate preoperative measurements. this technique preserved the transverse length of the lateral lip by creating a cutaneous triangle flap above the white roll to correct the height of the medial lip.11 ever since this technique had been introduced, the anatomical subunit technique gained notable popularity.7 a recent study conducted in 2020 aimed to explore the current practice patterns in unilateral cleft lip repair among surgeons within the american cleft palate association. it concluded that up to 40% of surgeons had changed their previously implemented techniques of cleft lip repair to the anatomical subunit approximation technique.7 fisher’s technique of cleft lip repair has also been found to have a lesser revision rate for lip shortening, scar hypertrophy and scar widening in comparison to the rotation advancement technique.15 however, fisher’s technique was found to be associated with a higher number of vermilion revisions which can be managed easily by a simple wedge excision of the vermilion. as mentioned above, millard’s technique for cleft lip repair remains one of the most implemented and taught methods for correcting the cleft lip anomaly worldwide.16 this has also been the case in the present figure 2: a pre-operative image of a child (a) showing left-sided complete cleft lip and post-operative image (b) showing left-sided complete cleft lip following surgery using the anatomical subunit technique. sheikhan al hashmi, malak al wahaibi, sony p. varghese, maather al abri, moath a. shummo and buthina al muqbali clinical and basic research | 391 institution. the anatomical subunit technique was introduced in the department by one of the authors in 2015, and since then, it has been gaining popularity. the experience of this technique has not been studied in the omani population prior to this study. oman is a country nestled in the tip of arabian peninsula with a population of 4.5 million and land area of 309,500 km2 encompassing 11 governorates.17 as per certain traditional values preserved within this rapidly modernising country, consanguineous marriages appear to be prevalent in the local population. local research has indicated that more than half (52%) of marriages are consanguineous, with first cousin unions being the most common type of consanguineous marriages constituting of 39% of all marriages and 75% of consanguineous marriages.3 owing to this cultural practice of consanguineous marriages in oman, the incidence of clefts has been found to be almost 1.5 times the worldwide prevalence.3 in the authors’ experience, the outcome of cleft lip repair using the anatomical subunit technique has been very satisfactory, a fact that can be corroborated by the small number of revision surgeries required by the patients involved in the current study. excess vermillion is a recognised outcome of the anatomical subunit technique. for example, a study published by mittermiller et al. revealed that 37% of patients in their study group who underwent unilateral cleft lip repair using the technique required debulking of excess vermillion.18 furthermore, the parents’ satisfaction rate following the surgery in this study was 82.5%. most of the parents were well-accepting of the surgical repair with anatomical subunit technique and willing to recommend the procedure to other children with similar anomalies. similarly, a study by deshmukh et al. has aimed to compare the post-operative aesthetic outcomes between fisher’s and mohler’s technique.8 the comparison was done through a layman evaluation of the post-operative cases based on which the authors were able to confirm the superior aesthetic outcomes of fisher’s technique.8 another factor of comparison with the international literature was the implementation of fisher’s technique on a different spectrum of cleft lip severity. out of the 82 patients included in our study, 36 had varying clefts of the soft and hard palate. no significant difference was found in the outcome of cleft lip repair done in children with isolated cleft lip in comparison to children with combined cleft lip and palate. this finding was also true with other published studies, indicating that with accurate application of the technique, the outcomes will less likely be affected by the severity of the cleft lip.15,16,19 the high percentage of consanguinity (52%) in the current study group highlights the need for targeted national campaigns involving premarital counselling regarding consanguinity, especially as this study revealed that consanguineous families are more likely to have a first degree relative with cleft lip. out of the 82 children, two were confirmed to be syndromic, one was a case of trisomy 21 and the other was diagnosed with velocardiofacial syndrome. the current syndrome-related findings are also similar to the patterns found internationally, indicating velocardiofacial syndrome along with other previously mentioned syndromes to be commonly associated with this anomaly.20 the most common complication associated with anatomical subunit technique was vermilion excess which were corrected for six patients in this study using simple wedge excision done 18–24 months after the initial lip surgery. the limitation of the current study includes the absence of a comparison group. comparison of the present cases with cases operated on using another technique would have provided better insight into the superiority of the anatomical subunit technique. in addition, a more accurate temporal relationship might have been established if the study was prospective in nature. lastly, in order to obtain more transparent results, the participation of families in the electronic survey was voluntary and anonymous. however, voluntary participation commonly leads to lower response rates and some families have refused to participate in the survey for various socio-cultural reasons. conclusion to the best of the authors’ knowledge, this is the first study in oman to highlight the outcomes and patients’ experience of the anatomical subunit technique for cleft lip anomaly in an omani population. accordingly, it resulted in predictable and identical results related to scar quality and nasal and lip symmetry in children with varying severity of cleft lip. revision for vermilion excess was needed in 7% of the cases. the high percentage of consanguinity in this study highlighted the need for more targeted national campaigns involving premarital counselling in the omani population as consanguineal marriages have been commonly implicated in the development of the cleft lip anomaly. a u t h o r s’ c o n t r i b u t i o n sh conceptualised and designed the study as well as supervised the work. mw, spv, ma and mas experience of unilateral cleft lip repair using the anatomical subunit technique in an omani population over a five-year period 392 | squ medical journal, august 2022, volume 22, issue 3 collected the data. bm was responsible for patient coordination in this study. ma analysed the data. mw and spv drafted the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. trainor pa. craniofacial birth defects: the role of neural crest cells in the etiology and pathogenesis of treacher collins syndrome and the potential for prevention. am j med genet a 2010; 152a:2984–94. https://doi.org/10.1002/ajmg.a.33454. 2. kantar rs, cammarata mj, rifkin wj, plana nm, diaz-siso jr, flores rl. outpatient versus inpatient primary cleft lip and palate surgery: analysis of early complications. plast reconstr surg 2018; 141:697e–706e. https://doi.org/10.1097/prs.00000 00000004293. 3. rajab a, thomas c. oral clefts in the sultanate of oman. eur j plast surg 2001; 24:230–3. https://doi.org/10.1007/ s002380100253. 4. ipdtoc working group. prevalence at birth of cleft lip with or without cleft palate: data from the international perinatal database of typical oral clefts (ipdtoc). cleft palate craniofac j 2011; 48:66–81. https://doi.org/10.1597/09-217. 5. sabbagh hj, innes np, sallout bi, alamoudi nm, hamdan ma, alhamlan n, et al. birth prevalence of non-syndromic orofacial clefts in saudi arabia and the effects of parental consanguinity. saudi med j 2015; 36:1076–83. https://doi.org/10.15537/ smj.2015.9.11823. 6. sisti a, nisi g. principles of cleft lip repair: conventions, commonalities, and controversies. plast reconstr surg 2017; 140:833e–4e. https://doi.org/10.1097/prs.0000000000003884. 7. roberts jm, jacobs a, morrow b, hauck r, samson td. current trends in unilateral cleft lip care: a 10-year update on practice patterns. ann plast surg 2020; 84:595–601. https://doi. org/10.1097/sap.0000000000002017. 8. deshmukh m, vaidya s, deshpande g, galinde j, natarajan s. comparative evaluation of esthetic outcomes in unilateral cleft lip repair between the mohler and fisher repair techniques: a prospective, randomized, observer-blind study. j oral maxillofac surg 2019; 77:182.e1–182.e8. https://doi. org/10.1016/j.joms.2018.08.029. 9. kwong jw, cai lz, azad ad, lorenz hp, khosla rk, lee gk, et al. assessing the fisher, mohler, and millard techniques of cleft lip repair surgery with eye-tracking technology. ann plast surg 2019; 82:s313–19. https://doi.org/10.1097/ sap.0000000000001911. 10. wehby gl, cassell ch. the impact of orofacial clefts on quality of life and healthcare use and costs. oral dis 2010; 16:3–10. https://doi.org/10.1111/j.1601-0825.2009.01588.x. 11. kim hy, park j, chang mc, song is, seo bm. modified fisher method for unilateral cleft lip-report of cases. maxillofac plast reconstr surg 2017; 39:12. https://doi.org/10.1186/s40902017-0109-1. 12. monson la, kirschner re, losee je. primary repair of cleft lip and nasal deformity. plast reconstr surg 2013; 132:1040e–53e. https://doi.org/10.1097/prs.0b013e3182a808e6. 13. knežević p, vuletić m, blivajs i, dediol e, macan d, virag m. the modification of rotation – advancement flap made in 1950. acta stomatol croat 2017; 51:60–4. https://doi.org/10.15644/ asc51/1/8. 14. mohler lr. unilateral cleft lip repair. plast reconstr surg 1987; 80:511–17. https://doi.org/10.1097/00006534-198710000-00005. 15. ajmal s, khan ma, khan at, yousaf k, shadman m, iqbal t. evaluating anatomical subunit approximation technique for unilateral cleft repair. j of postgrad med inst 2010; 24:68–72. 16. tse r, lien s. unilateral cleft lip repair using the anatomical subunit approximation: modifications and analysis of early results in 100 consecutive cases. plast reconstr surg 2015; 136:119–30. https://doi.org/10.1097/prs.0000000000001369. 17. foreign ministry of oman. geography. from: https://fm.gov. om/about-oman/state/geography/ accessed: jun 21. 18. mittermiller pa, martin s, johns dn, perrault d, jablonka em, khosla rk. improvements in cleft lip aesthetics with the fisher repair compared to the mohler repair. plast reconstr surg glob open 2020; 8:e2919. https://doi.org/10.1097/gox.00000 00000002919. 19. fisher dm. unilateral cleft lip repair: an anatomical subunit approximation technique. plast reconstr surg 2005; 116:61–71. https://doi.org/10.1097/01.prs.0000169693.87591.9b. 20. venkatesh r. syndromes and anomalies associated with cleft. indian j plast surg 2009; 42:s51–5. https://doi.org/10.41 03/0970-0358.57187. https://doi.org/10.1002/ajmg.a.33454 https://doi.org/10.1097/prs.0000000000004293 https://doi.org/10.1097/prs.0000000000004293 https://doi.org/10.1007/s002380100253 https://doi.org/10.1007/s002380100253 https://doi.org/10.1597/09-217 https://doi.org/10.15537/smj.2015.9.11823 https://doi.org/10.15537/smj.2015.9.11823 https://doi.org/10.1097/prs.0000000000003884 https://doi.org/10.1097/sap.0000000000002017 https://doi.org/10.1097/sap.0000000000002017 https://doi.org/10.1016/j.joms.2018.08.029 https://doi.org/10.1016/j.joms.2018.08.029 https://doi.org/10.1097/sap.0000000000001911 https://doi.org/10.1097/sap.0000000000001911 https://doi.org/10.1111/j.1601-0825.2009.01588.x https://doi.org/10.1186/s40902-017-0109-1 https://doi.org/10.1186/s40902-017-0109-1 https://doi.org/10.1097/prs.0b013e3182a808e6. https://doi.org/10.15644/asc51/1/8. https://doi.org/10.15644/asc51/1/8. https://doi.org/10.1097/00006534-198710000-00005 https://doi.org/10.1097/prs.0000000000001369 https://doi.org/10.1097/gox.00000 00000002919. https://doi.org/10.1097/gox.00000 00000002919. https://doi.org/10.1097/01.prs.0000169693.87591.9b https://doi.org/10.4103/0970-0358.57187 https://doi.org/10.4103/0970-0358.57187 department of cardiovascular surgery, tehran university of medical sciences, tehran, iran *corresponding author’s e-mail: behshakerian@yahoo.com complete absence of the left pericardium and pulmonary hypoplasia in an adult *behnam shakerian and mohammad h. mandegar sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e329–330, epub. 21 jun 21 submitted 10 aug 20 revision req. 6 oct 20; revision recd. 22 oct 20 accepted 17 nov 20 a 54-year-old male patient presented to the heart clinic, tehran, iran, in 2018 with a history of chest pain for the previous six months. he had a relevant medical history of smoking and hyperlipidaemia. coronary angiography revealed severe triple-vessel coronary artery disease. he was referred to the heart clinic for a coronary artery bypass graft (cabg). physical examinations of the patient were normal and chest radiographic findings were normal with the exception of a cardiac silhouette that was displaced to the left [figure 1]. echocardiography showed a mild left ventricular dysfunction. electrocardiography showed a normal sinus rhythm. subsequently, the patient was scheduled to undergo cabg. during the procedure, a complete left pericardial defect and pulmonary hypoplasia were detected [figure 2]. the left anterior descending artery was bypassed with the left internal mammary artery and a triple saphenous vein graft was done to bypass the right coronary, obtuse marginal and diagonal arteries. this defect was asymptomatic without creating pressure on the heart structures such as the left atrial appendage (laa) or myocardium. therefore, no intervention was performed for the defect. at the end of the surgery, a left chest drain was inserted for the defect. the patient recovered fully and was discharged on the sixth post-operative day. the patient gave his consent for publication of this report and its accompanying images. comment pericardial defects are a very rare congenital anomaly with an incidence of less than 1 in 10,000.1 columbus first described congenital absence of the pericardium in 1559.2 the possible embryological origins of this pericardial anomaly are not well understood, but the majority of the studies have suggested that it may be due to defective developmental retardation of the pleuropericardial membranes.3 approximately 30% of patients with congenital absence of the pericardium have other congenital cardiac or pulmonary anomalies.4 physicians should be aware of this anomaly and its associated congenital abnormalities for a correct diagnosis and treatment plan. these defects are detected incidentally during cardiothoracic operations, imaging studies or post-mortem this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.028 interesting medical image figure 1: chest x-ray of a 54-year-old male patient presenting to the heart clinic, tehran, iran, in 2018 showing leftward displaced heart. https://creativecommons.org/licenses/by-nd/4.0/ examination. pericardial defects are either partial or complete. the most common defect is absence of the left pericardium. complete absence of the pericardium and absence of the right pericardium are less common than the absence of the left pericardium. complete absence of the pericardium is usually asymptomatic; however, it sometimes manifests as a non-specific clinical presentation with possible symptoms including chest pain, dizziness and dyspnoea. complete absence of the pericardium has a good prognosis. paroxysmal exertional stabbing chest pain has been described as a potential symptom for congenital absent pericardium but the current patient did not experience this. while patients with partial absence of the left pericardium are usually also asymptomatic, there is a risk that the defect causing compression of the laa, left atrium, coronary arteries and/or ventricles may lead to cardiac herniation.5 echocardiography, computed tomography and magnetic resonance imaging are the most important tools for diagnosis. the treatment of absent pericardium depends on the type of the defect.3 there is usually no indication for surgery in patients with complete absence of the pericardium.3 complications are more common in patients with partial types; therefore, interventions are necessary.3 symptomatic or complicated cases may require pericardioplasty. complete absence of the left pericardium leads to leftward and posterior displacement of the heart. it can be associated with hypoplasia of the left lower lobe of the lung. these combinations result in persistent left chest collections, prolonged recovery and longtime hospital stays after the operation. in patients with absent left pericardium, the left ventricle is also attached to the lateral chest wall, which may resemble pulmonary collapse or pleural effusion. care should be taken for chest tube insertion because blind chest tube insertion could traumatise the heart. this anomaly was taken into consideration and the necessary measures for chest tube insertion were taken for the current patient. c o n f l i c t o f i n t e r e s t the authors declare that there is no conflict of interest. references 1. shah ab, kronzon i. congenital defects of the pericardium: a review. eur heart j cardiovasc imaging 2015; 16:821–27. https://doi.org/10.1093/ehjci/jev119. 2. saito r, hotta f. congenital pericardial defect associated with cardiac incarceration: case report. am heart j 1980; 100:866– 70. https://doi.org/10.1016/0002-8703(80)90068-x. 3. benameur n, arous y, landolsi m, chenik s, abdallah nb, kraiem t. partial congenital absence of the pericardium: a case report. braz j cardiovasc surg 2019; 34:633–6. https://doi. org/10.21470/1678-9741-2018-0357. 4. kim hj, cho ys, cho gy, choi si. congenital absence of the pericardium. j cardiovasc ultrasound 2014; 22:36–9. https:// doi.org/10.4250/jcu.2014.22.1.36. 5. han j, xiang h, ridley we, ridley lj. snoopy sign: congenital absence of the left pericardium. j med imaging radiat oncol 2018; 62 suppl 1:47. https://doi.org/10.1111/17549485.33_12785. figure 2: intra-operative photograph of the heart showing absence of pericardium and pulmonary hypoplasia in a 54-year-old male patient presenting to the heart clinic, tehran, iran, in 2018. complete absence of the left pericardium and pulmonary hypoplasia in an adult e330 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1093/ehjci/jev119 https://doi.org/10.21470/1678-9741-2018-0357 https://doi.org/10.21470/1678-9741-2018-0357 https://doi.org/10.4250/jcu.2014.22.1.36 https://doi.org/10.4250/jcu.2014.22.1.36 https://doi.org/10.1111/1754-9485.33_12785 https://doi.org/10.1111/1754-9485.33_12785 use of simulation in teaching nursing leadership and management course an integrative review leodoro j. labrague sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 344–353, epub. 29 aug 21 submitted 14 may 2020 revisions req. 18 jun 2020 & 16 aug 2020; revisions recd. 17 sep 2020 accepted 23 sep 2020 department of fundamentals & administration, college of nursing, sultan qaboos university, muscat, oman e-mail: leo7_ci@yahoo.com nur sing educ ation is vital in the formation of student nurses’ management and leadership competencies for future lead ership roles. several organisations, including academic institutions, healthcare agencies and accrediting entities, highlight the crucial need for student nurses to possess the leadership and management skills upon graduation. for example, the institute of medicine and the american association of colleges of nursing suggest that all student nurses graduating from nursing school possess management and leadership competencies necessary in working and collaborating with multidisciplinary healthcare teams.1,2 in particular, the american organization of nurse executives (aone) developed the nurse managers competencies framework to guide nursing schools in the development of their undergraduate and graduate curricula to successfully educate nursing students with essential management and leadership skills required in the performance of nurse manager roles.3 these competencies include the following: resource management, management of patient care delivery, staff development, compliance with professional and regulatory standards, long-term and strategic planning, inter-professional management and leadership and collaboration with other units within the institution.3 in many nursing schools, students are provided opportunities to imbibe skills in leading and managing when they attend a leadership and management course in the terminal year of their undergraduate nursing programme. however, facilitating and teaching lead ership and management skills among nursing students remains a significant challenge to nursing faculty due to several factors such as increasing nursing student applications for admission, nursing faculty shortage and limited clinical placements to facilitate and integrate leadership concepts in clinical practice.4–6 unsurprisingly, many nurse managers and nurse executives perceive newly graduated nurses as not being sufficiently ready to perform leadership roles and responsibilities as well as lacking management skills when they start working as a professional nurse.7 alternative teaching approaches using simul ations are vital to adequately prepare students for their future leadership roles as nursing professionals. simulation is identified as a viable and supplementary teaching modality to facilitate the translation of theoretical concepts in nursing into practice.8,9 the use of simulation is acknowledged as an indispensable aspect of the nurse education curriculum and has been widely used across all nursing courses. these include the following: fundamentals of nursing, maternal and child health, adult health, mental and psychiatric health, community health and critical care courses.10–15 in particular, simulation studies have identified mediumto high-fidelity simulations as potent teaching modalities to foster students’ nursing competence, self-efficacy, critical thinking and reasoning, communication and interpersonal skills and clinical judgment.16–21 numerous nursing education institutions have supported the integration of simulation-based activities review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.007 abstract: nursing education is strategically positioned to prepare nursing students for management and leadership skills necessary for future professional nursing roles. this review appraised and synthesised the outcomes of using simulation in pre-licensure nursing management and leadership courses. this is an integrative review of original articles published between 2008 and 2018. in january 2019, psychinfo, cinahl, pubmed and scopus were searched to identify relevant articles using the following terms: ‘management’, ‘leadership’, ‘simulation’, ‘nursing’, ‘education’ and ‘student’. a total of 10 articles were included in the review. four essential themes were identified from the content analysis: acquisition of skills or understanding of delegation, enhanced teamwork or collaboration capacities, improved decision-making and problem-solving skills and increased communication skills. incorporation of simulation in the nursing management and leadership courses has the potential to enhance nursing students’ skills regarding delegation, problem-solving capacities, decision-making and communication and teamwork. keywords: simulation training; nursing; leadership; practice management; student; education. https://creativecommons.org/licenses/by-nd/4.0/ leodoro j. labrague review | 345 into their respective pedagogies. the national council of state boards of nursing endorses the use of simulation-based activities as an alternative to usual clinical experiences to provide relevant and essential clinical experiences for nursing students.22 the national league of nursing supports the incorporation of simulation-based activities in nursing programmes to adequately prepare students for future nursing practice amidst the growing challenges in the field of healthcare. available evidence suggests that through simulation, nursing schools can help shape and develop management and leadership skills in students for future leadership and management roles.23 findings of kilgore et al. and sharpnack et al. showed that simulation experiences may enhance nursing students’ management skills such as prioritising and managing staff workloads, delegating, working with inter-professional health teams and making critical decisions.24,25 while there is mounting evidence concerning the use and usefulness of simulation in teaching management and leadership courses, at present, this evidence does not present a wider viewpoint on this essential topic. this integrative review aimed to determine the outcomes of using simulation in pre-licensure nursing management and leadership courses. methods an integrative review approach guided by the frame work devised by whittemore and knafl informed this study.26 this approach was deemed suitable as it allowed the combination of findings of studies with both experimental or non-experimental designs to provide a broader perspective on the topic. to locate relevant articles published between 2008 and 2018, an electronic search of databases was conducted in january 2019. medline, psych info, cinahl and scopus were used to locate and search for original articles using the following search and medical subject headings terms: ‘management’, ‘leadership’, ‘simulation’, ‘nursing’, ‘education’ and ‘student’. furthermore, a manual search of relevant literature was carried out based on the list of references in the articles included [figure 1]. the following inclusion criteria were considered in the search and retrieval of the articles: (1) original articles examining the use of simulation-based activities in teaching management and leadership skills in prelicensure nursing programmes; (2) articles published in refereed journals within the last 10 years; and (3) articles written in the english language. a total of 198 articles were retrieved during the initial search of the databases. after removing duplicates, 136 articles were retained. titles and abstracts were further screened and compared using the inclusion criteria, with 45 articles being considered for full-text screening. finally, 10 studies were considered appropriate for the review after a fulltext reading of the articles; the remaining 35 articles were excluded because simulation procedures were either not clearly described, the processes were not purely simulation-based and contained studies or the participants were combined with others from a different healthcare profession [figure 1]. the quality, rigor, credibility and trustworthiness of the research methods used in the articles included in the review were examined using the mixed methods appraisal tool by two independent reviewers.27 this appraisal tool was designed to assess the quality of studies (e.g. quantitative, qualitative and mixedmethod studies). based on the criteria set, a score was assigned that ranged from 25% to 100%. in this review, no articles were excluded based on the quality score due to a lack of studies that pertained to simulation as utilised in nursing leadership and management figure 1: flowchart showing the selection process used to identify articles included. use of simulation in teaching nursing leadership and management course an integrative review 346 | squ medical journal, august 2021, volume 21, issue 3 courses; instead, the tool was used to appraise the methodological quality of the articles reviewed. using a common template, essential data were extracted from the articles by two independent resear chers, which included the authors, research design, subjects/simulation duration/debriefing duration, type of simulation/measures and key findings [table 1].7,24,25,28–34 data were synthesised following the content analysis guided by the constant comparison approach.35 specif ically, similar categories and subcategories were clustered by comparing each definition and the prevalence of certain themes was determined. encompassing themes were discussed and further analysed by the researchers to arrive at common and most suitable theme names. this approach in data synthesis is compatible with an integrative review that includes studies with varied research methodologies to analyse and synthesise.27 results s t u d y c h a r a c t e r i s t i c s based on the inclusion criteria, 10 articles published in the last 10 years were included in this review. the vast majority of the articles reviewed (n = 7, 70%) originated and were conducted in the usa and the remaining articles were from other countries such as ireland, australia and canada. six studies (60%) utilised a descriptive research design, two adopted a one-group preand post-test design, one employed a mixed-method design and the other used a two-group post-test design.7,24,25,28–34 the sample sizes ranged from 24 to 155. in the quantitative studies, some scales were utilised to measure outcomes of simulation such as the student satisfaction and self-confidence in learning scale and the clinical learning environments comparison survey (clecs).36,37 in four studies, a researcher-designed survey tool was used, while in one study (the nursing leadership content mastery assessment) a standardised computer-based assessment tool, developed by assessment technologies institute, was used.38 duration of simulation ranged from 20 minutes to 1.5 hours, while the debriefing duration ranged from 20 minutes to 1 hour. concerning the quality score of the articles reviewed, the scores ranged from 80% to 90% out of a possible total score of 100%. simulation modality and scenario in this review, patient/clinical case scenarios employing high-fidelity mannequins, medium-fidelity simulators, low-fidelity simulators and used standardised patients during simulation. simulation scenarios involved handling and caring for patients with various medical and surgical conditions including obstetric and gynae cologic, psychiatric, paediatric and gerontology patients. in articles with a control group, lowor mediumfidelity simulations or traditional clinical placements or demonstrations were used. k e y f i n d i n g s four themes were identified from the content analysis: acquisition of skills or understanding of delegation, enhanced teamwork or collaboration capacities, improved decision-making and problem-solving skills and increased communication skills [figure 2]. a c q u i s i t i o n o f s k i l l s o r u n d e r s ta n d i n g o f d e l e g at i o n five studies determined the impact of simulation-based learning on nursing students’ acquisition of delegation skills and/or understanding of delegation.24,25,29,32,34 hourican et al. assessed the usefulness of simulation in promoting management skills in senior nursing students using high-fidelity mannequins and standardised patients.34 overall, nursing students reported higher levels of awareness and understanding in the following competencies: prioritising and managing staff work loads,effective delegation and maintaining patient safety. in australia, students who were exposed to high-fidelity simulation expressed that the simulation experiences improved their skills in prioritising, delegation and time management.32 three studies in the usa yielded similar outcomes.24,25,29 nursing students who experienced simulation scenarios using medium-fidelity simulators and standardised patients obtained higher scores on delegation subscales when compared to those in nonsimulation groups.25 similarly, an increased knowledge (n = 66, 68%) and higher confidence levels (n = 53, 55%) on delegating patient care and prioritising were seen in senior nursing students after simulation exposure.29 in a descriptive qualitative study by kilgore et al., three essential themes emerged from the nursing student simulation evaluations: the nursing students felt that the experience was convincing, it fostered their ability to delegate and reinforced leadership and management concepts.24 e n h a n c e d t e a m w o r k o r c o l l a b o r at i o n c a pa c i t i e s another prominent theme that emerged from the content analysis was ‘teamwork or collaboration’ which was found in five studies.24,25,29,32,34 in an irish study, senior nursing students who were exposed to simulation scenarios using medium-fidelity simulators obtained higher scores in the following areas: providing support to colleagues, teamwork and interaction with the multidisciplinary team.34 in one study that compared leodoro j. labrague review | 347 table 1: summary of studies evaluating the use of simulation in teaching nursing leadership and management courses7,24,25,28-34 author (year of publication)/ country research design subjects, simulation duration and debriefing duration type of simulation/ measures key findings brown and rode33 (2018)/ usa mixed methods/ one-group preand post-test 79 sophomores, 69 juniors, 62 seniors 30 minutes of simulation 20 minutes of debriefing high-fidelity simulators scale: sslc students reported high levels of satisfaction with their high-fidelity simulators experiences. sophomores and juniors felt more relaxed with a peer facilitator versus a faculty member. seniors reported simulation provided them opportunity to develop leadership skills, empower others and translate management and leadership concept to practice. che’reed et al.28 (2009)/ usa descriptive/ observational students enrolled in the nursing leadership and resource management course 1-hour simulation 1-hour debriefing high-fidelity simulators, standardised patients scale: researcherdesigned evaluation criteria for the simulation experience decision-making skills related to the patient and care teams, interprofessional skills and collaborations were enhanced. students demonstrated awareness of their surroundings and the ability to comprehend the situation, make decisions quickly and plan for potential complications. hourican et al.34 (2008)/ ireland mixed methods 68 students simulation was within four hours of independent learning medium-fidelity mannequins, standardised patients scale: researcherdesigned evaluation criteria for the simulation experience majority of students responded positively to simulation as it increased their confidence in their own ability. students stated they felt that their ‘confidence increased’ when they achieved what they had to do. a majority of students stated that they would participate again in the simulation. a majority of students indicated that the simulation exercise reflected the reality of the clinical environment. student’s ratings of their own level of knowledge were increased after the exercise in the following areas: supporting colleagues and working as a team member, managing resources efficiently and effectively, maintaining patient safety, dealing with unusual or unexpected events (problemsolving), prioritising and managing an allocated workload, recognising changes in physical, emotional, social or psychological health status and taking appropriate action, recognising professional and ethical dilemmas, maintaining patient confidentiality, adhering to local and national policies, procedures and guidelines, gathering and recording relevant information and communicating with colleagues including members of the multidisciplinary team. gore et al.7 (2015)/usa descriptive 155 students 30 to 40 minutes of simulation 20 to 25 minutes ofdebriefing low-fidelity mannequins and a medium-level environmental fidelity scale: clecs students rated communication high in the traditional clinical environment. teaching-learning needs were rated high in the simulated clinical environment. nursing leadership was rated high in both groups. kaplan and ura29 (2010)/ usa descriptive 97 senior nursing students duration of 20 minutes human patient simulators scale: researcherdesigned postsimulation-based learning exercise evaluation students reported increased understanding and confidence in prioritising and delegating care. students reported more confidence in ability to work as a team. students reported rated simulation to be a good learning experience to better prepare for real-life experiences in a healthcare setting. students reported enhanced communication with others in the simulated healthcare setting. sslc = student satisfaction and self-confidence in learning scale; clecs = clinical learning environments comparison survey. use of simulation in teaching nursing leadership and management course an integrative review 348 | squ medical journal, august 2021, volume 21, issue 3 nursing students who had attended simulation activities, a significantly lower score in the ‘collaborate’ subscale of the nursing leadership content mastery assessment was observed in students who had not attended simulation.25 a similar finding was observed in an australian study which identified improvements in the following competencies: time management, teamwork and strategies for prioritization.32 table 1 (cont’d): summary of studies evaluating the use of simulation in teaching nursing leadership and management courses7,24,25,28-34 author (year of publication)/ country research design subjects, simulation duration and debriefing duration type of simulation/ measures key findings kilgore et al.24 (2013)/usa descriptive 24 students duration of 45 minutes high-fidelity simulators using 3g simman™ mannequins, one child mannequin and one live standardised client students had improved their ability to delegate, helped to identify their deficits, improved their ability to work in a team and reinforced leadership and management concepts. pollard and wild30 (2014)/ canada descriptive students in leadership in nursing course within the allotted nine hours low-fidelity leadership and followership simulation exercises students could identify how leadership and followership skills would be used within their next clinical experience and the importance of these attributes as being essential to their future career as a nurse. students also reported that participating in the activities was realistic and they felt like the decisional complexities experienced in the class were likely the ones they would also need to deal with in their future practice. as observed by the faculty concerned, the students were able to come prepared, have improved communication and professional identity within their teams and developed collaborative team communication approaches within a social awareness of individual, team and organisation needs, and, thus, ended up being better prepared for interprofessional healthcare teams. sharpnack et al.25 (2013)/usa two-group, post-test-only, randomised experimental design 66 senior-level students one hour of simulation 30 minutes of debriefing standardised patients and mediumfidelity human patient simulators scale: nursing leadership content mastery assessment subscale scores of those students who participating in the simulation showed higher scores on evidence of efficient management of care, capacity to prevent safety errors, delegation, collaboration and provision of continuity of care. thomas et al.31 (2011)/usa descriptive design 132 students high-fidelity simulators, standardised patients scale: researcherdesigned scale to measure simulation and learning experiences students perceived that they can apply decision-making skills for several situations not otherwise encountered. the majority of students reported enhanced ability to apply decision-making, problemsolving and critical thinking. a majority of the students reported preparedness to assume charge nurse position. a majority of the students reported higher levels of understanding on the following charge nurse roles: communication, collaboration, cooperation, time management, decision-making, critical thinking, problemsolving and delegation. warland32 (2011)/australia one-group preand posttest design 115 nursing students 30 to 45 minutes of simulation 30–40 minutes of debriefing high-fidelity simulators scale: researcherdesigned scale to measure simulation and learning experiences most students felt the simulations increased their understanding of systems and organisation of nursing care. students reported gaining skills and understanding on the following: time management, teamwork and prioritising strategies. 20 students (43%) reported that simulation helped them with organisational skills on their clinical placement. 36% reported that simulation helped them with their proper skills. sslc = student satisfaction and self-confidence in learning scale; clecs = clinical learning environments comparison survey. leodoro j. labrague review | 349 results of nursing students’ simulation evaluation, using a researcher-designed simulation-based learning exercise evaluation, showed higher levels of confidence in working as a team with nursing students who had attended a 20-minute simulation activity.29 an important theme that emerged in the qualitative analysis by kilgore et al. was an enhancement in nursing students’ ability to work within the healthcare team as well as reinforcement of leadership and management concepts learned in the classroom.24 i m p r o v e d d e c i s i o n-m a k i n g a n d p r o b l e m-s o lv i n g s k i l l s enhanced decision-making and problem-solving skills were identified as an essential outcome of the simulation.29,31 che’reed et al. implemented a leadership management simulation in the usa in a group of students participating in a nurse leadership and management course.28 after participation in a simulation scenario that involved a patient with severe incisional pain, the nursing students obtained a higher awareness of the following areas of nursing management: responding to emergencies, planning for addressing potential complications and making quick clinical decisions. similar findings were observed in a descriptive study by thomas et al. wherein out of 132 senior-level nursing students who had attended the simulation experiences, 95% expressed greater confidence in making ward/unit decisions, solving problems and critical thinking.31 i n c r e a s e d c o m m u n i c at i o n s k i l l s the effects of simulation-based activities on students’ skills in communicating effectively with patients and the healthcare team were evaluated in three studies.7,31,34 in a leadership simulation study by hourican et al. using mediumand high-fidelity simulators and standardised patients, nursing students (after simulation) reported an increase in competence in communicating with colleagues and the other members of the multidisciplinary healthcare team, along with other competencies such as effectively working with the team, recognising professional and ethical issues, managing staff workloads and dealing with unforeseen events in the ward/unit.34 in a descriptive study by thomas et al., there was a higher proportion of nursing students who attended a chargenurse simulation scenario and expressed an increased knowledge of the charge-nurse role in collaborating and effectively communicating with the staff nurse subordinates and other healthcare team members.31 in the usa, gore et al. compared the efficacy of simulated and traditional clinical environments on leadership learning in nursing students.7 after 30 to 40 minutes of simulation using low-fidelity mannequins, nursing students evaluated their simulation experience using the clecs. although the scores in the nursing leadership skills were equally high among the two groups, the communication subscales were significantly higher among nursing students who had attended the traditional learning placement when compared to nursing students in the simulation group.7 discussion this integrative review synthesised and appraised available literature examining the influence of simulation activities in fostering management and leadership skills among student nurses. a total of 10 studies, primarily with quantitative research designs, informed the findings of this review. while the researchers found some evidence that supported simulation as a modality in teaching management and leadership courses in nursing students, caution should be exercised when making inferences due to the scarcity of high-quality evidence. simulation studies demonstrated a positive influence of simulation-based activities for nursing students’ understanding or knowledge of and awareness of delegation. delegation is a key function of a professional nurse and is defined as “the transfer of figure 2: diagram of themes generated during the review. use of simulation in teaching nursing leadership and management course an integrative review 350 | squ medical journal, august 2021, volume 21, issue 3 responsibility for the performance of an activity from one individual to another while retaining accountability for the outcome”.39 ineffective delegation often leads to negative patient outcomes.40 while delegation is considered an important nursing function, this skill often remains underdeveloped in newly graduated nurses and pre-licensure education is often accused of not adequately preparing nursing students to perform this essential role.41 in a study in the uk, new nurses reported limited clinical opportunities to translate the concept of delegation into practice and to develop competencies to effectively supervise, manage and organise care during their pre-licensure nursing education.40 nevertheless, nursing faculty can strengthen delegation skills and facilitate the formation of delegation skills among nursing students; the simulation laboratory can be a good avenue to foster this skill. collaboration and communication emerged as important outcomes of simulation. the inter-professional education collaborative recognised teamwork or collaboration and communication as an important component of a patient-centred care practice.42 available studies have identified the relevance of collaborative health practice, which is characterised by constant interaction, communication, collaboration and engagement among interprofessional healthcare workers along with patients and their families in attaining quality healthcare and positive patient outcomes, ultimately reducing costs of healthcare and improving organisational productivity.43,44 despite higher emphasis on the importance of effective communication and collaboration during the undergraduate programme, many new nurses expressed challenges in effectively communicating, collaborating and working with other healthcare teams, patients and their relatives.45,46 this review’s finding supports international studies highlighting the essential role of simulation in enhancing collaboration, communication and teamwork among healthcare workers from different professions.25,47 furthermore, simulation showed a positive impact on nursing students’ abilities to solve problems and make critical decisions regarding patient care and ward/ unit management. problem-solving and decisionmaking are considered key processes in nursing. in particular, clinical decision-making among nurses is critically important when selecting interventions and treatments for patients and in addressing their needs.48 according to standing, decision-making skills, which is a central aspect of quality nursing care, can be developed during the undergraduate period to equip future nurses with the realities and challenges that they will encounter when they assume the professional nursing role.49 however, many new nurses reported to be lacking in these essential skills and complained that their undergraduate education had not placed a high enough emphasis on this area of development.46 whereas all simulation studies showed potential in enhancing a variety of leadership and management competencies, caution should be exercised when making inferences due to the presence of certain methodological issues. for instance, most studies reviewed used either a descriptive design or a one-group preand post-test design. while many nursing and healthcare scholars have utilised preand post-test designs for research, unlike randomised control trials (rcts), confounding variables that may affect the intervention outcomes are not or are poorly controlled. conversely, findings of rcts can generate high levels of evidence and are therefore useful as they can be used to guide policy implementers, healthcare managers and nurse leaders. thus, future studies on simulation should be conducted utilising a more robust research design. another key observation was the lack of standardised scales in the included studies specific to measuring leadership and management skills in nursing students. four studies utilised a researcherdesigned survey tool and in the remaining studies outcomes of simulation were evaluated using the sscl, the nursing leadership content mastery assessment and the clecs. although these tools are validated, they are not specific to measuring leadership and management competencies in nursing students. as opined by foronda et al., evaluation of simulation efficacy using established instruments is critical.50 this highlights the need for a simulation tool specific to measuring leadership and management skills in students. it is worth noting that leadership and management competencies and study subjects were evaluated using self-report tools rather than a direct measure of participants’ competencies. however, baxter and lederman suggested that self-reporting may not be an accurate measure of actual ability or performance;51 thus, additional objective evaluation measures should be used to determine these essential competencies. power analysis or sample calculation is vital as sample size affects the transferability and general isability of research findings. in this review, most of the studies included had inadequate sample sizes and none utilised a power analysis to identify the number of samples to be included to yield significant findings. in addition, the duration of the simulation-based activities varied significantly, ranging from 20 minutes to 1.5 hours, while the duration of debriefing ranged from 20 minutes to 1 hour. this certainly poses an inquiry as to how long a simulation activity should leodoro j. labrague review | 351 be delivered to nursing students to cause significant change in their knowledge and skills. furthermore, simulation trainings of the simulation facilitators were rarely described. these factors should be considered in future simulation research as they may affect the outcomes of simulation and, thus, the generalisability of the findings. moreover, the studies reviewed originated mainly in the usa, ireland, australia and canada. with the influx of foreign nurses from asian countries (china, india and the philippines) to western countries (canada, the uk and the usa), this finding poses a question with regard to the preparedness of these foreign nurses to assume nursing leadership roles.52 it emphasises the importance of the integration of leadership simulation in the nursing curricula, especially in the abovementioned non-western countries, to ensure that the nursing graduates from these curricula are prepared for future leadership and management roles and possess managerial and leadership competencies. despite the promising outcomes of leadership and management simulations, it is apparent that further efforts are needed when designing simulation activities that incorporate essential leadership and management competencies as defined by the aone and are vital in the overall productivity and effectiveness of any healthcare organisation. i m p l i c at i o n s f o r n u r s i n g e d u c at i o n this review’s findings highlight the value of simulation as a powerful tool in teaching leadership and management courses as well as the potential of enhancing certain leadership and management skills among nursing students. amidst the increasing challenges being confronted in this regard by faculty, the incorporation of simulation into nursing management and leadership courses has the potential to enhance students’ skills pertaining to delegation, problem-solving and decision-making, communication and teamwork. incorporation of simulation-based activities in nursing management, leadership courses and other nursing courses may be useful in the translation of theoretical knowledge into nursing practice. in doing so, nursing schools should ensure that nursing faculty have leadership expertise and are able to provide relevant leadership and management simulation courses or trainings to better support the learning needs of the pre-licensure nursing students. in addition, simulation resources should be provided to create a more realistic scenario necessary to deliver the intended learning outcomes. conclusion this review provided up-to-date knowledge related to the current state of simulation-based activities in leadership and management courses in pre-licensure nursing programmes. the findings of this review support previous simulation studies underlining the significance of this teaching-learning method in enhancing a variety of nursing student outcomes. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. institute of medicine. the future of nursing: leading change, advancing health. washington, dc: the national academies press, 2011. 2. american association of colleges of nursing. the essentials of baccalaureate education for professional nursing practice. from: https://www.aacnnursing.org/portals/42/publications/ baccessentials08.pdf accessed: sep 2020. 3. american organization of nurse managers. the role and functions of the hospital nurse manager. nurs manage 1992; 23:36–8. 4. yuan hb, williams ba, fang jb. the contribution of highfidelity simulation to nursing students’ confidence and compet ence: a systematic review. int nurs rev 2012; 59:26–33. https:// doi.org/10.1111/j.1466-7657.2011.00964.x. 5. curtis ea, de vries j, sheerin fk. developing leadership in nursing: exploring core factors. br j nurs 2011; 20:306–9. https://doi.org/10.12968/bjon.2011.20.5.306. 6. chunta k, edwards t. multiple-patient simulation to transition students to clinical practice. clin simul nurs 2013; 9:e491–6. https://doi.org/10.1016/j.ecns.2013.04.015. 7. gore tn, johnson tl, wang ch. teaching nursing leadership: comparison of simulation versus traditional inpatient clinical. int j nurs educ scholarsh 2015; 12:55–63. https://doi.org/1 0.1515/ijnes-2014-0054. 8. schubert cr. effect of simulation on nursing knowledge and critical thinking in failure to rescue events. j contin educ nurs 2012; 43:467–71. https://doi.org/10.3928/00220124-20120904-27. 9. bowling am, underwood pw. effect of simulation on knowledge, self-confidence, and skill performance in the usa: a quasi-experimental study. nurs health sci 2016; 18:292–8. https://doi.org/10.1111/nhs.12267. 10. stroup c. simulation usage in nursing fundamentals: integrative literature review. clin simul nurs 2014; 10:e155–64. https:// doi.org/10.1016/j.ecns.2013.10.004. 11. germain m, o’leary-kelley c, goyal d, anand s. can clinical simulation increase confidence levels in performing postpartum care in a diverse group of baccalaureate nursing students? nurs educ perspect 2018; 39:94–5. https://doi.org/10.1097/01.nep. 0000000000000233. 12. wright rr, tinnon ea, newton rh. evaluation of vsim for| nursing in an adult health nursing course: a multisite pilot study. comput inform nurs 2018; 36:84–9. https://doi.org/10.1097/ cin.0000000000000388. https://doi.org/10.1111/j.1466-7657.2011.00964.x https://doi.org/10.1111/j.1466-7657.2011.00964.x https://doi.org/10.12968/bjon.2011.20.5.306 https://doi.org/10.1016/j.ecns.2013.04.015 https://doi.org/10.1515/ijnes-2014-0054 https://doi.org/10.1515/ijnes-2014-0054 https://doi.org/10.3928/00220124-20120904-27 https://doi.org/10.1111/nhs.12267 https://doi.org/10.1016/j.ecns.2013.10.004 https://doi.org/10.1016/j.ecns.2013.10.004 https://doi.org/10.1097/01.nep.0000000000000233 https://doi.org/10.1097/01.nep.0000000000000233 https://doi.org/10.1097/cin.0000000000000388 https://doi.org/10.1097/cin.0000000000000388 use of simulation in teaching nursing leadership and management course an integrative review 352 | squ medical journal, august 2021, volume 21, issue 3 13. vandyk ad, lalonde m, merali s, wright e, bajnok i, davies b. the use of psychiatry-focused simulation in undergraduate nursing education: a systematic search and review. int j ment health nurs 2018; 27:514–35. https://doi.org/10.1111/ inm.12419. 14. lubbers j, rossman c. satisfaction and self-confidence with nursing clinical simulation: novice learners, medium-fidelity, and community settings. nurse educ today 2017; 48:140–4. https://doi.org/10.1016/j.nedt.2016.10.010. 15. brien la, charette m, goudreau j. nursing students’ perceptions of the contribution of high-fidelity simulation and clinical placement in a critical care course. clin simul nurs 2017; 13:436–41. https://doi.org/10.1016/j.ecns.2017.05.005. 16. centrella-nigro am, blackwell b, coughlin a, voorhees ka. the effect of human patient simulators on knowledge and selfcompetence in graduating prelicensure nursing students. nurs educ perspect 2016; 37:337–9. https://doi.org/10.1097/01. nep.0000000000000072. 17. adib-hajbaghery m, sharifi n. effect of simulation training on the development of nurses and nursing students’ critical thinking: a systematic literature review. nurse educ today 2017; 50:17–24. https://doi.org/10.1016/j.nedt.2016.12.011. 18. gates mg, parr mb, hughen je. enhancing nursing knowledge using high-fidelity simulation. j nurs educ 2012; 51:9–15. https://doi.org/10.3928/01484834-20111116-01. 19. forneris sg, neal do, tiffany j, kuehn mb, meyer hm, blazovich lm, et al. enhancing clinical reasoning through simulation debriefing: a multisite study. nurs educ perspect 2015; 36:304–10. https://doi.org/10.5480/15-1672. 20. foronda c, gattamorta k, snowden k, bauman eb. use of virtual clinical simulation to improve communication skills of baccalaureate nursing students: a pilot study. nurse educ today 2014; 34:e53–7. https://doi.org/10.1016/j.nedt.2013.10.007. 21. fawaz ma, hamdan-mansour am. impact of high-fidelity sim ulation on the development of clinical judgment and motivation among lebanese nursing students. nurse educ today 2016; 46:36–42. https://doi.org/10.1016/j.nedt.2016.08.026. 22. hayden jk, smiley ra, alexander m, kardong-edgren s, jeffries pr. the ncsbn national simulation study: a longitudinal, randomized, controlled study replacing clinical hours with simulation in prelicensure nursing education. j nurs reg 2014; 5:c1–s64. https://doi.org/10.1016/s2155-8256(15)30062-4. 23. smith sb. integrating simulation in a bsn leadership and management course. j nurs educ pract 2013; 3:121–5. https:// doi.org/10.5430/jnep.v3n11p121. 24. kilgore rv, goodwin me, harding ra. adding context to a simulation module for leadership and management baccal aureate nursing students. j nurs educ pract 2013; 3:148–55. https://doi.org/10.5430/jnep.v3n9p148. 25. sharpnack pa, goliat l, rogers k. using standardized patients to teach leadership competencies. clin simul nurs 2013; 9:e95–102. https://doi.org/10.1016/j.ecns.2011.10.001. 26. whittemore r, knafl k. the integrative review: updated method ology. j adv nurs 2005; 52:546–53. https://doi.org/10.1111/j.13 65-2648.2005.03621.x. 27. pace r, pluye p, bartlett g, macaulay ac, salsberg j, jagosh j, et al. testing the reliability and efficiency of the pilot mixed methods appraisal tool (mmat) for systematic mixed studies review. int j nurs stud 2012; 49:47–53. https://doi.org/10.10 16/j.ijnurstu.2011.07.002. 28. che'reed c, lancaster rr, musser db. nursing leadership and management simulation creating complexity. clin simul nurs 2009; 5:e17–21. 29. kaplan b, ura d. use of multiple patient simulators to enhance prioritizing and delegating skills for senior nursing students. j nurs educ 2010; 49:371–7. https://doi.org/10.3928/0148483420100331-07. 30. pollard cl, wild c. nursing leadership competencies: low-fidelity simulation as a teaching strategy. nurs educ pract 2014; 14:620–626. https://doi.org/10.1016/j.nepr.2014.06.006. 31. thomas c, hodson-carlton k, ryan m. preparing nursing students in a leadership/management course for the workplace through simulations. clin simul nurs 2011; 7:e99–104. https://doi. org/10.1016/j.ecns.2010.06.005. 32. warland j. using simulation to promote nursing students’ learning of work organization and people management skills: a case study. nurse educ pract 2011; 11:186–91. https://doi.org/10.10 16/j.nepr.2010.08.007. 33. brown km, rode jl. leadership development through peerfacilitated simulation in nursing education. j nurs educ 2018; 57:53–7. https://doi.org/10.3928/01484834-20180102-11. 34. hourican s, mcgrath m, lyng c, mcmahon c, lehwaldt d. effectiveness of simulation on promoting student nurses management skills. int j clin skills 2008; 2:20–25. 35. lincoln ys, guba eg. naturalistic inquiry. beverly hills, ca: sage publications, 1985. 36. jeffries pr, rizzolo ma. designing and implementing models for the innovative use of using simulation to teach nursing care of ill adults and children: a national, multi-site, multimethod study. new york, ny: national league for nursing, 2006. 37. leighton k. development of the clinical learning environment comparison survey. clin simul nurs 2015; 11:44–51. https:// doi.org/10.1016/j.ecns.2014.11.002. 38. assessment technologies institute, llc. evaluating the predictive power of ati’s rn comprehensive predictor 2010. 2013. from: https://www.atitesting.com/docs/default-source/research/ re s e a rch b r i e f r n _ c p to n cl ex . p d f ? s f v r s n = c 7 e 0 0 6 e 9 _ 0 accessed: sep 2020. 39. weberg d, mangold k, porter-o'grady t, malloch k. leadership in nursing practice: changing the landscape of health care: changing the landscape of health care, 3rd ed. burlington, usa: jones & bartlett learning, 2018. 40. magnusson c, allan h, horton k, johnson m, evans k, ball e. an analysis of delegation styles among newly qualified nurses. nurs stand 2017; 31:46–53. https://doi.org/10.7748/ns.2017. e9780. 41. hasson f, mckenna hp, keeney s. delegating and supervising unregistered professionals: the student nurse experience. nurse educ today 2013; 33:229–35. https://doi.org/10.1016/j. nedt.2012.02.008. 42. interprofessional education collaborative (ipec). team-based competencies: building a shared foundation for education and clinical practice. 2011. from: https://www.gih.org/files/ ipe%20conference%20pro ce e dings%20rep or t_5211.p df accessed: sep 2020. 43. reeves s, fletcher s, barr h, birch i, boet, s, davies n, et al. a beme systematic review of the effects of interprofessional education: beme guide no. 39. med teach 2016; 38:656–68. https://doi.org/10.3109/0142159x.2016.1173663. 44. reeves s, perrier l, goldman j, freeth d, zwarenstein m. inter professional education: effects on professional practice and health care outcomes (update). cochrane database syst rev 2013; 3:cd002213. https://doi.org/10.1002/14651858.cd002213.pub3. 45. parker v, giles m, lantry g, mcmillan m. new graduate nurses’ experiences in their first year of practice. nurse educ today 2014; 34:150–56. https://doi.org/10.1016/j.nedt.2012.07.003. 46. wong swj, che wsw, cheng mtc, cheung ck, cheung tyj, lee ky, et al. challenges of fresh nursing graduates during their transition period. j nurs educ pract 2018; 8:30–7. https://doi. org/10.5430/jnep.v8n6p30. 47. labrague lj, mcenroe–petitte dm, fronda dc, obeidat aa. interprofessional simulation in undergraduate nursing program: an integrative review. nurse educ today 2018; 67:46–55. https://doi.org/10.1016/j.nedt.2018.05.001. https://doi.org/10.1111/inm.12419 https://doi.org/10.1111/inm.12419 https://doi.org/10.1016/j.nedt.2016.10.010 https://doi.org/10.1016/j.ecns.2017.05.005 https://doi.org/10.1097/01.nep.0000000000000072 https://doi.org/10.1097/01.nep.0000000000000072 https://doi.org/10.1016/j.nedt.2016.12.011 https://doi.org/10.3928/01484834-20111116-01 https://doi.org/10.5480/15-1672 https://doi.org/10.1016/j.nedt.2013.10.007 https://doi.org/10.1016/j.nedt.2016.08.026 https://doi.org/10.1016/s2155-8256(15)30062-4 https://doi.org/10.5430/jnep.v3n11p121 https://doi.org/10.5430/jnep.v3n11p121 https://doi.org/10.5430/jnep.v3n9p148 https://doi.org/10.1016/j.ecns.2011.10.001 https://doi.org/10.1111/j.1365-2648.2005.03621.x https://doi.org/10.1111/j.1365-2648.2005.03621.x https://doi.org/10.1016/j.ijnurstu.2011.07.002 https://doi.org/10.1016/j.ijnurstu.2011.07.002 https://doi.org/10.3928/01484834-20100331-07 https://doi.org/10.3928/01484834-20100331-07 https://doi.org/10.1016/j.nepr.2014.06.006 https://doi.org/10.1016/j.ecns.2010.06.005 https://doi.org/10.1016/j.ecns.2010.06.005 https://doi.org/10.1016/j.nepr.2010.08.007 https://doi.org/10.1016/j.nepr.2010.08.007 https://doi.org/10.3928/01484834-20180102-11 https://doi.org/10.1016/j.ecns.2014.11.002 https://doi.org/10.1016/j.ecns.2014.11.002 https://doi.org/10.7748/ns.2017.e9780 https://doi.org/10.7748/ns.2017.e9780 https://doi.org/10.1016/j.nedt.2012.02.008 https://doi.org/10.1016/j.nedt.2012.02.008 https://doi.org/10.3109/0142159x.2016.1173663 https://doi.org/10.1002/14651858.cd002213.pub3 https://doi.org/10.1016/j.nedt.2012.07.003 https://doi.org/10.5430/jnep.v8n6p30 https://doi.org/10.5430/jnep.v8n6p30 https://doi.org/10.1016/j.nedt.2018.05.001 leodoro j. labrague review | 353 48. tiffen j, corbridge sj, slimmer l. enhancing clinical decision making: development of a contiguous definition and conceptual framework. j prof nurs 2014; 30:399–405. https://doi.org/10.10 16/j.profnurs.2014.01.006. 49. standing m. clinical judgment and decision making for nursing student. devon: learning matters ltd., 2011. 50. foronda c, liu s, bauman eb. evaluation of simulation in under graduate nurse education: an integrative review. clin simul nurs 2013; 9:e409–16. https://doi.org/10.1016/j.ecns.2012.11.003. 51. baxter ja, lederman ng. assessment and measurement of peda gogical content knowledge. in: gess-newsome j, lederman ng, eds. examining pedagogical content knowledge. dordrecht: springer, 1999. pp. 147–161. 52. pung lx, goh ys. challenges faced by international nurses when migrating: an integrative literature review. int nurs rev 2017; 64:146–65. https://doi.org/ 10.1111/inr.12306. https://doi.org/10.1016/j.profnurs.2014.01.006 https://doi.org/10.1016/j.profnurs.2014.01.006 https://doi.org/10.1016/j.ecns.2012.11.003 https://doi.org/ 10.1111/inr.12306 1divison of endocrinology, tawam hospital in affiliation with johns hopkins medicine, al ain, united arab emirates; departments of 2medicine and 3public health, united arab emirates university, al ain, united arab emirates; 4department of internal medicine, medical university of graz, graz, austria; 5center for biomarker research in medicine, graz, austria; 6department of endocrinology, sheikh khalifa medical city, abu dhabi, united arab emirates *corresponding author’s e-mail: kmdahmani@seha.ae مسببات فرط بروالكتني الدم حتليل اْسِتَعاِدي من مركز للرعاية الصحية من املستوى الثالث اأزهر مالك، في�شل عزيز، �شامل ب�شيه، خالد الدهماين abstract: objectives: this study aimed to evaluate the aetiologies of hyperprolactinaemia in the united arab emirates (uae). methods: this retrospective study used laboratory databases to identify all patients who underwent evaluation for prolactin at tawam hospital, al ain, uae, between 2009 and 2015. of those 2,280 patients, all patients with low or normal prolactin (n = 1,315) were excluded. subsequently, charts of the remaining patients (n = 965) with hyperprolactinaemia were reviewed and those with incomplete work-ups or insufficient documentation of the hyperprolactinaemia’s aetiology were excluded (n = 458). results: a total of 507 patients were included in the study. the average age at prolactin evaluation was 36 ± 13.2 years and the majority (67.1%) of patients were female. the most common reasons for requesting prolactin were menstrual disorders (29.5%), infertility (18%), evaluation of sellar masses (14.3%), ruling out seizures (13.4 %) and monitoring while on psychiatric medications (8.7%). the most common causes of hyperprolactinaemia were prolactinoma (17%), transient hyperprolactinaemia (14.6%), drug-induced side effects (14.4%), polycystic ovarian syndrome (11.8%) and seizure disorder (7.7%). in females, common aetiologies were prolactinomas, transient and idiopathic hyperprolactinaemia, while sellar masses, seizures, chronic kidney disease and acute illnesses were common aetiologies of hyperprolactinaemia in males. the prolactin level varied between the different aetiologies and a level of >250 ng/ml was suggestive of macro prolactinoma. conclusion: a significant proportion of patients with hyperprolactinaemia have transient hyper prolactinaemia. before further investigations are carried out, prolactin level assessment should be repeated, esp ecially in patients with mild hyperprolactinaemia. keywords: hyperprolactinemia; prolactinoma; etiology; epidemiology; united arab emirates. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل تقييم م�شببات فرط بروالكتني الدم يف دولة االإمارات العربية املتحدة. الطريقة: ا�شتخدمت هذه ة قواعد البيانات املخربية لتحديد جميع املر�شى الذين خ�شعوا لتقييم بروالكتني الدم يف م�شت�شفى توام، العني، االإمارات الدرا�شة اال�ْشِتَعاِديَّ العربية املتحدة، بني عامي 2009-2015. من اجمايل 2,280 مري�س مت ا�شتبعاد املر�شى الذين لديهم م�شتوى بروالكتني منخف�س اأوطبيعي يف الدم ثم متت مراجعة �شجالت مر�شى فرط بروالكتني الدم املتبقني وعددهم 965 مري�شا والذين بدورهم ا�شتثني منهم 458 حالة ب�شبب حتاليل غري كاملة اأوعدم توثيق م�شبب فرط بروالكتني الدم. النتائج: �شملت الدرا�شة ما جمموعه 507 مري�شا. كان متو�شط اعمارهم عند تقييم بروالكتني الدم لديهم 36 ± 13.2 �شنة وكان غالبية املر�شى )%67.1( من االإناث ومن االأ�شباب االأكرث �شيوًعا لطلب الربوالكتني هي ا�شطرابات الدورة ال�شهرية )%29.5( والعقم )%18( وتقييم اأورام ال�رشج الرتكي )%14.3( وا�شتبعاد النوبات االأختالجية )%13.4( ومتابعة املر�شى اأثناء تناول اأدوية عالج االمرا�س النف�شية )%8.7(. كانت اأكرث اأ�شباب فرط بروالكتني الدم �شيوًعا هي الورم الرُبواَلْكتيِنّي )%17( وفرط بروالكتني الدم العابر )%14.6( وكاأحد االعرا�س اجلانبية الناجمة عن تناول االأدوية )%14.4( ومتالزمة تكي�س املباي�س )%11.8( وا�شطرابات النوبات االأختالجية )%7.7(. ومن امل�شببات ال�شائعة لدى االإناث هي الورم الرُبواَلْكتيِنّي وفرط بروالكتني الدم العابر واملجهول ال�شبب، يف حني اأن اأورام ال�رشج الرتكي واال�شطرابات االأختالجية واملر�س الكلوي املزمن واالأمرا�س احلادة كانت من امل�شببات ال�شائعة لفرط بروالكتني الدم عند الذكور. كان هناك تباين يف م�شتوى الربوالكتني ح�شب امل�شببات املختلفة وي�شري م�شتوى بروالكتني اكرث من 250 نانوغرام/مل اىل ورم بُرواَلْكتيِنّي كبري احلجم. اخلال�صة: هناك ن�شبة كبرية من مر�شى فرط بروالكتني الدم لديهم فرط بروالكتني دم عابرلذا ينبغي تكرار تقييم م�شتوى الربوالكتني قبل القيام باإجراء املزيد من االأ�شتق�شاءات وخا�شة يف املر�شى الذين لديهم فرط طفيف يف بروالكتني الدم. الكلمات املفتاحية: فرط بروالكتني الدم؛ ورم بُرواَلْكتيِنّي؛ امل�شببات؛ علم االأوبئة؛ االإمارات العربية املتحدة. aetiologies of hyperprolactinaemia a retrospective analysis from a tertiary healthcare centre azhar a. malik,1,2 faisal aziz,3–5 salem a. beshyah,6 *khaled m. aldahmani1,2 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e129–134, epub. 8 sep 19 submitted 25 nov 18 revision req. 3 jan 19; revision recd. 3 feb 19 accepted 21 feb 19 advances in knowledge a large proportion of patients with hyperprolactinaemia have a transient rise of prolactin that normalises spontaneously and requires no further evaluation. a prolactin level of >250 ng/ml is suggestive of the presence of macroprolactinoma. application to patient care to avoid unnecessary investigations, repeating prolactin level assessment is recommended in patients with mild hyperprolactinaemia. knowledge of prolactin levels may predict the aetiology of hyperprolactinaemia and narrow the differential diagnosis. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.008 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ aetiologies of hyperprolactinaemia a retrospective analysis from a tertiary healthcare centre e130 | squ medical journal, may 2019, volume 19, issue 2 prolactin is an important hormone of the anterior pituitary gland with diverse effects on the body’s systems, especially in the repro ductive system.1 hyperprolactinaemia, defined as a prolactin level above the laboratory gender-specific normal range, is a common endocrine problem world wide.2–4 it is more common in females and its prev alence has increased over the last two decades.5 hyper prolactinaemia can cause menstrual disorders, gynae comastia, decreased libido, impotence and infertility.1 hyperprolactinaemia can be caused by physio logical changes, pathological conditions, medications, macroprolactin excess or can be idiopathic.6,7 the main physiological causes are pregnancy, lactation and stress, while common pathological causes include prolactinomas, other sellar masses, polycystic ovarian syndrome (pcos), chronic kidney disease (ckd) and hypothyroidism.6,7 antipsychotics, antidepressants and anti-emetics are among the most common medications that cause hyper prolactinaemia.8 macroprolactin is a large molecule of prolactin mostly attached to immunoglobulins and can result in hyperprolactinaemia due to reduced renal clearance.9 knowledge of prevalence and causes of hyper prolactinaemia primarily stem from studies conducted outside the middle east and north africa (mena) region.3–5,10 to the best of the authors’ knowledge, no data have been published on the aetiology of hyperprolac tinaemia in the united arab emirates (uae). therefore, this study aimed to determine the causes of hyperpro lactinaemia in a large referral centre in the uae. methods this retrospective study was conducted at tawam hospital, al ain, uae, between 2009 and 2015. tawam hospital is the largest tertiary healthcare centre in al ain, a major city of the abu dhabi emirate. using an electronic laboratory database, a total of 2,280 patients with at least one laboratory record for serum prolactin were identified [figure 1]. of those identified, 1,315 patients with normal prolactin levels (male range: 2.6– 13.1 ng/ml, female range: 3–27 ng/ml) were excluded. additionally, 458 patients were excluded due to incom plete work-ups or insufficient documentation of their hyperprolactinaemia’s aetiology. the electronic medical records of the remaining patients were reviewed and demographic and clinical data were extracted. hyperprolactinaemia was defined as a serum pro lactin >13.1 ng/ml in males and >27 ng/ml in females. only one type of prolactin assay (beckman dxl 800, beckman coulter inc, atlanta, georgia, usa) was used in this study; this assay has superior specificity for mono meric prolactin, therefore screening for macroprolactin excess was not routinely performed in the current cohort of patients. prolactinomas were diagnosed based on elev ated prolactin levels and evidence of pituitary adenomas from magnetic resonance imaging (mri) scans.11 pro lactinomas were classified as macroprolactinomas (≥1 cm) or microprolactinomas (<1 cm) based on the size of the tumours. prolactin levels <200 ng/ml (off-treatment) in patients with a sellar mass >1 cm were considered to be suggestive of the stalk effect.12 pcos was accepted as the cause of hyperprolactinaemia if a diagnosis was documented by an experienced gynaecologist or endocri nologist. hypothyroidism was considered responsible for hyperprolactinaemia in the absence of other causes of hyperprolactinaemia, a simultaneous elevation of both thyroid stimulating hormones (tsh) and prolactin levels and restoration of normal prolactin level after normalisation of serum tsh. patients were designated as having drug-induced hyperprolactinaemia if they were receiving medications recognised to elevate prolactin such as anti-emetics, antipsychotics, tricyclic antidepr essants, serotonin re-uptake inhibitors and dopamine antagonists. idiopathic hyperprolactinaemia was diagn osed in patients with persistent hyperprolactinaemia and a negative pituitary mri in the absence of other causes. hyperprolactinaemia attributed to acute illness was diagnosed in patients with acute pain or infection, in those admitted to the intensive care unit and in the absence of any secondary cause of prolactin elevation. transient hyperprolactinaemia was diagnosed in patients who had unexplained elevation of prolactin in a single reading that normalised spontaneously on repeat testing. data were extracted using microsoft excel 2011 (microsoft corp., redmond, washington, usa) and analysed in stata se, version 15.1 (statacorp llc, college station, texas, usa). qualitative variables were summarised using descriptive statistics. results were figure 1: flow chart showing this study’s inclusion process of hyperprolactinaemic patients who underwent evaluation for serum prolactin level at tawam hospital, al ain, united arab emirates, between 2009 and 2015. azhar a. malik, faisal aziz, salem a. beshyah and khaled m. aldahmani clinical and basic research | e131 presented as absolute and relative frequencies and quantitative variables as mean ± standard deviation or median with minimum and maximum as appropriate. the study was approved by the al ain medical district human research ethics committee (crd 471/16, aamdhrec protocol no. 16/58). results a total of 507 patients with hyperprolactinaemia were included in this study. the mean age of patients at the time of prolactin evaluation was 36 ± 13.2 years. most patients were female (67.1%) and uae nationals (76%). the reason for ordering prolactin testing was available for 461 patients (90.9%). the test was most commonly used to evaluate menstrual disorders (29.5%), infertility (18%) and sellar masses (14.3%) and to rule out seizures (13.4%). in females, prolactin was requested most commonly to investigate menstrual disorders, infertility and hirsutism compared to excluding true seizures and evaluating sellar masses and infertility in males [table 1]. the most common causes were prolactinomas (17%), transient hyperprolactinaemia (14.6%) and drug induced hyperprolactinaemia (14.4%). of the 86 patients with prolactinomas, 27 patients had macroprolacti nomas. of the 73 patients with transient hyperprolacti naemia, 58 patients were females and 27 underwent prolactin measurement for evaluating infertility. of the 73 patients who were diagnosed with drug-induced hyperprolactinaemia, 22 were on antipsychotics, 15 were on antimotility drugs, three were taking anti depressants and one was on anti-epileptic monotherapy. fewer patients (n = 32) were using multiple medications. the most frequently used monotherapy drugs were risperidone (41.5%), metoclopramide (19.5%) and dom peridone (17.1%). in total, 60 patients (11.8%) were diagnosed with pcos and seizures were present in 7.7% of cases. a small proportion of patients (6.7%) had been diagnosed with sellar masses other than prolactinomas. microprolactinomas and transient hyperprolactinaemia were more frequently diagnosed in females compared with other sellar masses, seizures, ckd and acute illnesses, all of which were found to be related to hyperprolactinaemia in males [table 2]. the highest median serum concentration of prolactin was 191 ng/ml (range: 14.6–2000 ng/ml) and was noted in patients with prolactinoma. for the other aetiologies, there was an overlap in the median prolactin level which was not predictive of aetiology. patients with transient hyperprolactinaemia had a prolactin level ranging from 13.4–77 ng/ml. similarly, mild-to-moderate hyperpro lactinaemia was seen in pcos cases with only one patient having a prolactin level >85 ng/ml. prolactin levels in table 1: common reasons for requesting serum prolactin level testing in patients with hyperprolactinaemia (n = 461) reason* n (%)† female (n = 316) male (n = 145) menstrual disorders 136 (43) 136 (29.5) infertility 57 (18) 26 (17.9) 83 (18) work-up/follow-up on sellar masses 33 (10.4) 33 (22.8) 66 (14.3) to exclude seizures 18 (5.7) 44 (30.3) 62 (13.4) screening while on psychiatric drugs 23 (7.3) 17 (11.7) 40 (8.7) hirsutism 31 (9.8) 31 (6.7) galactorrhoea 24 (7.6) 3 (2.1) 27 (5.9) other‡ 30 (9.5) 14 (9.7) 44 (9.7) erectile dysfunction 13 (9) 13 (2.8) *reasons for prolactin testing were unknown in 46 patients (25 females and 21 males). †percentages do not add up to 100 as patients may have had multiple reasons. ‡other reasons included headaches (n = 9), hypo pituitarism (n = 7), lactation difficulties (n = 7), breast pain (n = 6), gyn aecomastia (n = 5), delayed puberty (n = 3), testicular pain (n = 2), re current miscarriages (n = 2), decreased libido (n = 2) and acne (n = 1). table 2: the aetiologies of hyperprolactinaemia in a sample of hyperprolactinaemic patients (n = 507) cause of hyperprolactinaemia n (%)* female (n = 340) male (n = 167) prolactinoma 63 (18.5) 23 (13.8) 86 (17) microprolactinoma 48 (14.1) 11 (6.6) 59 (11.6) macroprolactinoma 15 (4.4) 12 (7.2) 27 (5.3) transient 58 (17.1) 16 (9.6) 74 (14.6) drug-induced 48 (14.1) 25 (15) 73 (14.4) pcos 60 (17.6) 60 (11.8) seizure 10 (2.9) 29 (17.4) 39 (7.7) sellar masses excluding prolactinomas 12 (3.5) 22 (13.2) 34 (6.7) acute illness 11 (3.2) 23 (13.8) 34 (6.7) idiopathic 25 (7.4) 5 (3) 30 (5.9) ckd 9 (2.6) 19 (11.4) 28 (5.5) pregnancy 20 (5.9) 20 (3.9) other† 13 (3.8) 3 (1.8) 16 (3.2) empty sella syndrome 8 (2.4) 1 (0.6) 9 (1.8) pcos = polycystic ovarian syndrome; ckd = chronic kidney disease. *percentages do not add up to 100 as reported causes are not mutually exclusive. †other reasons included breastfeeding (n = 8), localised breast irritation/infection/surgery (n = 6), hypothyroidism (n = 4), hypoplastic pituitary (n = 1) and syncope (n = 1). aetiologies of hyperprolactinaemia a retrospective analysis from a tertiary healthcare centre e132 | squ medical journal, may 2019, volume 19, issue 2 patients with drug-induced hyperprolactinaemia ranged from 19.6–240 ng/ml. patients with other sellar masses had prolactin levels which ranged from 13–196 ng/ml; of which, 32 patients (94.1%) had levels <100 ng/ml and only two (5.9%) had levels >150 ng/ml. overall, prolactin levels >250 ng/ml were only found in 14 patients (2.8%). in two patients (14.2%), hyperprolac tinaemia was due to pregnancy while in the remaining cases it was due to prolactinoma. serum prolactin levels higher than 500 ng/ml were only seen in macroprolac tinoma patients [table 3]. discussion this is the first study to comprehensively describe the aetiologies of hyperprolactinaemia in a large cohort of patients presenting to a tertiary referral center in uae. results showed that a significant proportion of patients were diagnosed with transient hyperprolactinaemia. hyperprolactinaemia negatively affects gonado tropin releasing hormones and results in menstrual dis orders and symptoms of hypogonadism.1 hence, most patients in the current study were found to have under gone prolactin evaluation because of menstrual disorders, infertility or erectile dysfunction. a large number of patients underwent prolactin evaluation to rule out a seizure disorder because prolactin has been shown to be elevated in patients with seizures.13 in fact, levels two times above the baseline obtained 10–20 minutes after seizure activity have been reported as suggestive of seizure diagnosis with 46.1–60% sensitivity and 96% specificity.14 however, patients with syncope may also experience mild prolactin elevation.14 furthermore, a recent study of patients admitted to an epilepsy monitoring unit to distinguish psychogenic from epileptic seizures questioned the role of prolactin, with 29% and 16% false positive and false negative rates, respectively.15 therefore, physicians ordering prolactin level for assessing seizures or pseudo-seizures should be cognisant of the above limitations. another reason for ordering prolactin testing was to evaluate sellar masses, which are relatively common with a prevalence of 0.1%.16 the distinction between prolactinomas and other sellar masses is an essential diagnostic step, as medical therapy is the treatment of choice for the former while surgery may be needed for the latter. some of the current patients (7.8%) underwent prolactin testing to screen for hyperprolactinaemia while on psychotropic medications. this practice is in-line with the current guidelines advocating for hyperprolactinaemia screening in such patients because of the high prevalence (44%) of hyperprolactinaemia in this setting.17,18 in the current study, prolactinoma was the most frequent cause of hyperprolactinaemia (17%). previous studies have similarly shown that prolactinoma is the most common cause of hyperprolactinaemia but with much higher rates (25.6–56.6%).4,5 the lower rate in the current study could be attributed to the patients’ heterogeneity and the inclusion of prolactin testing for both inpatients and outpatients. data on the prevalence of transient hyperpro lactinaemia is limited. in the current study, transient hyperprolactinaemia was the second most common aetiology of hyperprolactinaemia and was diagnosed mostly in women being evaluated for infertility. one study documented a transient rise of prolactin in females during their mid-cycle; the rate rises to 94% in those with infertility, ranging between 25–75 ng/ml and usually lasting 1–3 days.19 additionally, prolactin follows a circadian rhythm with the highest reading occurring during sleep and immediately after awakening.12 it also increases after sexual intercourse, following a protein-rich meal and during stress.12 whyte et al. reported using antecubital fossa cannula to avoid stress, normalising prolactin levels in 17% of referred patients with hyperprolactinaemia with repeat testing only; this increased by 10% after a 120-minute rest period.20 moreover, prolactin levels ≥94 ng/ml had 97% specif icity in identifying true hyperprolactinaemia.20 in keeping table 3: frequency and serum prolactin levels of endocrine and non-endocrine causes of hyperprolactinaemia (n = 507) cause of hyperprolactinaemia n (%) median (minimum–maximum) in ng/ml endocrine prolactinoma 86 (17) 191 (14.6–2000) sellar masses except prolactinoma 34 (6.7) 41.3 (13–196) pcos 60 (11.8) 42.2 (27–92.2) empty sella syndrome 9 (1.8) 48.4 (29.4–78) hypothyroidism 4 (0.8) 28.3 (13.4–38) non-endocrine transient 74 (14.6) 32.5 (13.4–77) drug-induced 73 (14.4) 68.4 (19.6–240) seizures 39 (7.7) 37.9 (13.6–221.2) acute illness 34 (6.7) 32.4 (14–70.2) idiopathic 30 (5.9) 47.7 (13.6–115) ckd 28 (5.5) 50.1 (13.9–151.7) pregnancy 20 (3.9) 87.4 (24–490) other* 16 (3.2) 48.2 (18–167.8) pcos = polycystic ovarian syndrome; ckd = chronic kidney disease *other reasons included breastfeeding (n = 8), localised breast irritation/ infection/surgery (n = 6), hypoplastic pituitary (n = 1) and syncope (n = 1). azhar a. malik, faisal aziz, salem a. beshyah and khaled m. aldahmani clinical and basic research | e133 with this finding, the current patients had prolactin levels ranging between 13.4–77 ng/ml. as knowledge of stress at the time of blood extraction or other physiological processes described earlier may not be readily available to the physician, assessment of serum prolactin levels should be repeated in patients with mild hyperprolactinaemia or in the absence of typical symptoms. this recommendation conflicts with the endocrine society guidelines, which suggest that a single prolactin evaluation is enough to diagnose hyper prolactinaemia. however, this recommendation supports other experts’ recommendations.7,20,21 such an approach is expected to reduce both patient anxiety and unnec essary pituitary imaging costs. drugs such as antipsychotics, antidepressants and anti-emetics may alter the neuroendocrine control mechanisms regulating prolactin secretion and cause modest prolactin elevation.8 medications inducing hyperprolactinaemia constituted 14% of all cases in the current study, where most patients were on anti psychotics or anti-emetics. vilar et al. reported a similar rate (12%) in brazil; however, the rate was much higher (45.9%) in scotland with rising prevalence during the last years of the study.4,5 recently, alosaimi et al. reported a high prevalence of hyperprolactinaemia in psychiatric patients as well as guidelines that recommend screening for hyperprolactinaemia in such patients.18 the current institution is not a referral centre for psychiatric patients and has no inpatient psychiatric services, which may contribute to this difference. any treatment modifications in psychiatric patients such as switching to agents with no or only a minor effect on prolactin levels (e.g. bupropion, mirtazapine and aripiprazole) or even initiating dopamine agonist therapy should be done cautiously and in consultation with the treating psychiatrist to avoid exacerbating underlying psychiatric conditions.8,21 pcos is a common disorder in young adults and contributes to 13–16% of all cases of hyperprolac tinaemia.7 the rate in the current study is slightly lower (11.8%) as all cases of hyperprolactinemia were analysed without limiting the sample to outpatient cases as has been done in other studies. on the other hand, the rate in the current study might be over estimated since tawam hospital is the largest and only governmental fertility centre in al ain. moreover, no data are available on the number of pcos patients who had pituitary mris; therefore, microprolactinomas may have been missed. however, the prolactin levels in those patients were moderate, ranging between 28–92 ng/ml and only one patient (1.7 %) had a prolactin level >85 ng/ml. a recent study suggested that in patients with pcos, a prolactin >85 ng/ml might indicate the pre sence of adenomas with 77% sensitivity and 100% specificity.22 sellar masses, excluding prolactinomas, could cause mild hyperprolactinaemia by inhibiting dopamine tran sport on the hypothalamus-pituitary axis. in this study, 6.7% of all cases of hyperprolactinaemia had other sellar masses with a median prolactin level of 33 ng/ml; the measured levels rarely rose above 100 ng/ml. vilar et al. showed that a non-functioning adenoma contrib uted to 6.6% of all hyperprolactinaemia cases with 82% of patients having prolactin levels <100 ng/ml.4 idiopathic hyperprolactinaemia has been reported as the cause of hyperprolactinaemia in 3.6–27.8% of all cases. this wide range reflects the differences found in the studied population and may be due to possible underestimation of macroprolactin or an incomplete work-up of patients.3–5 in the current study, 3.2% of patients were diagnosed with idiopathic hyperprolac tinaemia; none had adenoma on a pituitary mri scan. prolactin levels were shown to be predictive of macroprolactinoma in the current study as patients with macroprolactinomas had the highest prolactin levels. except during pregnancy (n = 2), all other patients with prolactin levels >250 ng/ml were diagnosed with macroprolactinomas. similarly, vilar et al. found that only 4.2% of non-prolactinoma patients had prolactin levels >250 ng/ml and readings of >500 ng/ml were seen exclusively in patients with prolactinoma.4 prolactin levels varied and were of no predictive value for other aetiologies. the current study had several strengths. it is the largest study assessing hyperprolactinaemia in the mena region. furthermore, real-world data have been reported on all inpatients and outpatients with hyperprolac tinaemia, unlike many previous reports primarily focusing on patients encountered in outpatient clinics. also, a single prolactin assay was used in this study. however, the study also has some limitations. as this was a single centre study, the results may not be generalisable to other clinical settings. additionally, data were collected retrospectively. in total, 20% of the patients with hyperprolactinaemia were excluded because of an incomplete work-up. also, macroprolactinaemia may have been underdiagnosed in the study as macropro lactin is not screened routinely. excessive evaluation of patients for hyperprolactinaemia could have been conducted by non-endocrinologists with limited knowl edge of macroprolactin interference. conclusion prolactin testing is most commonly requested for eval uation of menstrual disorders, infertility and sellar masses. as a sizable proportion of the current patients had transient hyperprolactinaemia, repeated prolactin meas urement is recommended before further investigations aetiologies of hyperprolactinaemia a retrospective analysis from a tertiary healthcare centre e134 | squ medical journal, may 2019, volume 19, issue 2 are considered. prolactinomas and medications were the commonest causes of non-transient hyperprolac tinaemia in the current study. a prolactin level >250 ng/ml was highly suggestive of macroprolactinoma. a c k n o w l e d g e m e n t s the authors would like to thank mrs amani alshamisi for extracting the laboratory data and mr anvar kanda nath for his help with data management. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bernard v, young j, chanson p, binart n. new insights in prolactin: pathological implications. nat rev endocrinol 2015; 11:265–75. https://doi.org/10.1038/nrendo.2015.36. 2. hussein sh, wahedi ts, johani na, hakami ya, alzahrani k, almalki mh. clinical and epidemiological characteristics of pituitary tumours in a single centre in saudi arabia. hormones (athens) 2018; 17:261–7. https://doi.org/10.1007/s42000-018-0 030-8. 3. zargar ah, laway ba, masoodi sr, bhat mh, wani ai, bashir mi, et al. clinical and etiological profile of hyperprolactinemia--data from a tertiary care centre. j assoc physicians india 2005; 53:288–90. 4. vilar l, freitas mc, naves la, casulari la, azevedo m, montenegro r jr, et al. diagnosis and management of hyper prolactinemia: results of a brazilian multicenter study with 1234 patients. j endocrinol invest 2008; 31:436–44. https://doi.org/10.1 007/bf03346388. 5. soto-pedre e, newey pj, bevan js, greig n, leese gp. the epid emiology of hyperprolactinaemia over 20 years in the tayside region of scotland: the prolactin epidemiology, audit and res earch study (prolears). clin endocrinol (oxf ) 2017; 86:60–7. https://doi.org/10.1111/cen.13156. 6. serri o, chik cl, ur e, ezzat s. diagnosis and management of hyperprolactinemia. cmaj 2003; 169:575–81. 7. vilar l, fleseriu m, bronstein md. challenges and pitfalls in the diagnosis of hyperprolactinemia. arq bras endocrinol metabol 2014; 58:9–22. https://doi.org/10.1590/0004-2730000003002. 8. vilar l, abucham j, albuquerque jl, araujo la, azevedo mf, boguszewski cl, et al. controversial issues in the management of hyperprolactinemia and prolactinomas an overview by the neuroendocrinology department of the brazilian society of endocrinology and metabolism. arch endocrinol metab 2018; 62:236–63. https://doi.org/10.20945/2359-3997000000032. 9. shimatsu a, hattori n. macroprolactinemia: diagnostic, clinical, and pathogenic significance. clin dev immunol 2012; 2012:167132. https://doi.org/10.1155/2012/167132. 10. saejong r, dangrat c, techatrisak k, angsuwatthana s, rattanachaiyanont m, tanmahasamut p. hyperprolactinemia: a 12-year retrospective study at gynecologic endocrinology unit, siriraj hospital. j med assoc thai 2013; 96:1247–56. 11. byrne b, o'shea p, barrett p, tormey w. the beckman dxi 800 prolactin assay demonstrates superior specificity for monomeric prolactin. clin chem lab med 2010; 48:205–8. https://doi.org/10.1 515/cclm.2010.038. 12. lópez mac, rodríguez jlr, garcía mr. physiological and pathological hyperprolactinemia: can we minimize errors in the clinical practice? in: nagy gm, toth be, editors. prolactin. rijeka, croatia: intech; 2013. pp. 213–30. https://doi.org/10.57 72/54758. 13. pritchard pb 3rd, wannamaker bb, sagel j, daniel cm. serum prolactin and cortisol levels in evaluation of pseudoepileptic seizures. ann neurol 1985; 18:87–9. https://doi.org/10.1002/a na.410180115. 14. chen dk, so yt, fisher rs; therapeutics and technology assess ment subcommittee of the american academy of neurology. use of serum prolactin in diagnosing epileptic seizures: report of the therapeutics and technology assessment subcommittee of the american academy of neurology. neurology 2005; 65:668–75. https://doi.org/10.1212/01.wnl.0000178391.96957.d0. 15. abubakr a, wambacq i. diagnostic value of serum prolactin levels in pnes in the epilepsy monitoring unit. neurol clin pract 2016; 6:116–19. https://doi.org/10.1212/cpj.000000000 0000232. 16. al-dahmani k, mohammad s, imran f, theriault c, doucette s, zwicker d, et al. sellar masses: an epidemiological study. can j neurol sci 2016; 43:291–7. https://doi.org/10.1017/cjn.2015.301. 17. grigg j, worsley r, thew c, gurvich c, thomas n, kulkarni j. antipsychotic-induced hyperprolactinemia: synthesis of world wide guidelines and integrated recommendations for assess ment, management and future research. psychopharmacology (berl) 2017; 234:3279–97. https://doi.org/10.1007/s00213-0174730-6. 18. alosaimi fd, fallata eo, abalhassan m, alhabbad a, alzain n, alhaddad b, et al. prevalence and risk factors of hyperpro lactinemia among patients with various psychiatric diagnoses and medications. int j psychiatry clin pract 2018; 22:274–81. https://doi.org/10.1080/13651501.2018.1425459. 19. ben-david m, schenker jg. transient hyperprolactinemia: a correctable cause of idiopathic female infertility. j clin endo crinol metab 1983; 57:442–4. https://doi.org/10.1210/jcem-572-442. 20. whyte mb, pramodh s, srikugan l, gilbert ja, miell jp, sherwood ra, et al. importance of cannulated prolactin test in the definition of hyperprolactinaemia. pituitary 2015; 18:319–25. https://doi.org/10.1007/s11102-014-0576-7. 21. melmed s, casanueva ff, hoffman ar, kleinberg dl, montori vm, schlechte ja, et al. diagnosis and treatment of hyperprolactinemia: an endocrine society clinical practice guide line. j clin endocrinol metab 2011; 96:273–88. https://doi.org/10.12 10/jc.2010-1692. 22. kyritsi em, dimitriadis gk, angelousi a, mehta h, shad a, mytilinaiou m, et al. the value of prolactin in predicting prolac tinοma in hyperprolactinaemic polycystic ovarian syndrome. eur j clin invest 2018; 48:e12961. https://doi.org/10.1111/eci.1 2961. https://doi.org/10.1038/nrendo.2015.36 https://doi.org/10.1007/s42000-018-0030-8 https://doi.org/10.1007/s42000-018-0030-8 https://doi.org/10.1007/bf03346388 https://doi.org/10.1007/bf03346388 https://doi.org/10.1111/cen.13156 https://doi.org/10.1590/0004-2730000003002 https://doi.org/10.20945/2359-3997000000032 https://doi.org/10.1155/2012/167132 https://doi.org/10.1515/cclm.2010.038 https://doi.org/10.1515/cclm.2010.038 https://doi.org/10.5772/54758 https://doi.org/10.5772/54758 https://doi.org/10.1002/ana.410180115 https://doi.org/10.1002/ana.410180115 https://doi.org/10.1212/01.wnl.0000178391.96957.d0 https://doi.org/10.1212/cpj.0000000000000232 https://doi.org/10.1212/cpj.0000000000000232 https://doi.org/10.1017/cjn.2015.301 https://doi.org/10.1007/s00213-017-4730-6 https://doi.org/10.1007/s00213-017-4730-6 https://doi.org/10.1080/13651501.2018.1425459 https://doi.org/10.1210/jcem-57-2-442 https://doi.org/10.1210/jcem-57-2-442 https://doi.org/10.1007/s11102-014-0576-7 https://doi.org/10.1210/jc.2010-1692 https://doi.org/10.1210/jc.2010-1692 https://doi.org/10.1111/eci.12961 https://doi.org/10.1111/eci.12961 departments of 1health sciences, college of health and rehabilitation sciences and 2basic sciences, deanship of preparatory year, princess nourah bint abdulrahman university, riyadh, saudi arabia *corresponding author’s e-mail: benajibanada@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: herbal treatments are commonly used by saudi women during pregnancy. however, the inappropriate use of some herbs can have side-effects for both the mother and the fetus. thus, a comprehensive understanding of their use during pregnancy is crucial. this study aimed to explore the use of herbal treatments by saudi women during pregnancy using the knowledge-attitude-practice model. methods: this cross-sectional study was conducted from september 2019 and april 2020 in riyadh, saudi arabia, on a convenience sample using an online arabic-language questionnaire. saudi women aged between 18–58 years who were pregnant or had been pregnant and were living in the riyadh were included. results: a total of 400 individuals participated in this study. all participants lacked knowledge about the side-effects of herbal treatment but 63% knew about unsafe herbs in general. most participants (66%) had a neutral attitude towards herbal treatments. almost half of the participants (48%) did not use herbs during pregnancy and a similar number (47%) sometimes used herbal treatments during pregnancy. there was a significant positive correlation between attitude and practice and a negative correlation between knowledge and attitude as well as between knowledge and practice (p <0.0001 each). conclusion: while the participants’ knowledge were generally poor, their attitudes and practices regarding the use of herbal treatments during pregnancy were good. it is recommended that more efforts be made by healthcare providers to target attitudes towards herbal treatments by providing accurate knowledge and reinforcing healthy practices among saudi women. keywords: herbal medicine; pregnancy; health knowledge, attitudes, practice ; saudi arabia. exploring the use of herbal treatments during pregnancy among saudi women an application of the knowledge-attitude-practice model fatmah almoayad,1 insherah a. assiri,1 haifa f. almarshoud,1 atheer m. safhi,1 hend m. altahan,1 *nada benajiba2 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 591–597, epub. 25 nov 21 submitted 20 aug 20 revisions req. 14 oct & 2 nov 20; revisions recd. 18 oct & 3 nov 20 accepted 3 nov 20 https://doi.org/10.18295/squmj.4.2021.045 clinical & basic research advances in knowledge this study found that efforts are needed to enhance saudi women’s knowledge of the risks of using herbal treatments during pregnancy. improving knowledge of the specific side-effects of individual, commonly used herbal treatments would strengthen attitudes and promote healthy practices regarding the use of herbal treatments during pregnancy. applications to patient care the findings of this study provided scientific evidence of the need for support from healthcare providers for saudi women regarding the use of herbal treatments, even before conception. furthermore, it is important to identify the specific side-effects of herbal treatments during pregnancy. herbal treatments are common worldwide and particularly in arab countries, as they are integrated into arab culture.1,2 pregnant women use herbs for multiple reasons, such as to treat nausea and vomiting, and are generally preferred to prescribed medications because herbs are perceived as a safer option.3 in saudi arabia, herbal treatments are traditional; they are widely available and culturally accepted as a result of being promoted by certain religious leaders.4 almost a quarter of saudi women use herbal treatments during pregnancy, whereas a third of these women use them during labour and almost half use herbal treatments after delivery.1 some of the most common herbs reported to have been used during pregnancy in saudi arabia are ginger (zingiber officinale), liquorice (glycyrrhiza glabra), ginseng (panax ginseng), clove (syzygium aromaticum), fenugreek (trigonella foenum-graecum), sage (salvia officinalis), senna (senna alexandrina), chamomile (matricaria recutita), fennel flower seed (nigella sativa), cinnamon (cinnamomum verum), castor oil (ricinus communis), myrrh (commiphora myrrha), thyme (thymus vulgaris), anise (pimpinella anisum), parsley (petroselinum crispum), turmeric (curcuma longa) and peppermint (mentha piperita).5 some of these are considered potentially unsafe including liquorice, myrrh, fenugreek, castor, parsley and turmeric. however, it is safe to use others when combined with food in small amounts. for some herbs, there is a lack of evidence about their safety and some have been reported as safe for use by pregnant women. studies have shown that some herbs are associated with miscarriages, stillbirths and preterm delivery including liquorice, myrrh, fenugreek, parsley, castor oil and thyme.6–11 additionally, some herbs have exploring the use of herbal treatments during pregnancy among saudi women an application of the knowledge-attitude-practice model 592 | squ medical journal, november 2021, volume 21, issue 4 been found to harm the fetus; fenugreek can cause fetal malformation, teratogens and congenital defects and parsley oil can cause haemoglobin anomalies in the foetus.8,9 in contrast, anise is safe for use during pregnancy and anise oil has proven effective in treating genital infections and reducing the risk of premature labour.12,13 there is little evidence about whether chamomile is safe for pregnant women. it is commonly used for its sedative properties to help pregnant women relax and it can aid digestion. however, it has been shown that chamomile can cause an allergic reaction in some women and may lead to a miscarriage.11 multiple studies have confirmed that peppermint oil is useful for relieving irritable bowel syndrome and reducing nausea.11 evidence indicates that peppermint oil is particularly effective for relieving itching.14 however, more research is required to exclude its side-effects when used during pregnancy.11 sage has been reported to be safe for use by pregnant women after 37 weeks of gestation but high doses may lead to miscarriage; smelling sage has been shown to help pregnant women relax. although there is no evidence that ginseng causes harm to pregnant women, current advice is that it should not be consumed in the first trimester.15 cinnamon is a known herbal treatment for women to treat excessive menstruation and uterine haemorrhage excess stomach acid and dyspepsia and is generally considered safe for pregnant women.16 similarly, ginger, which is used to relieve some symptoms of pregnancy, especially nausea, is safe when used in appropriate amounts (no more than 1g).11 senna, cloves and fennel flower seeds are safe for consumption by pregnant women in food and in small amounts.12,17,18 while it is safe for pregnant women to consume turmeric in food, it may interact with other herbs and drugs that cause low blood sugar and low levels of white and red blood cells.19 finally, the use of cloves in food tends to be safe, but there is insufficient information about the possible adverse effects of consuming cloves in large amounts during pregnancy. overall, while some commonly used herbs are safe for pregnant women, others either have serious side-effects or there is a lack of evidence of their safety. therefore, promoting health during pregnancy and preventing unwanted consequences of herbal treatments is vital. due to the risks associated with the use of some herbal treatments during pregnancy, pregnant women should be careful about which herbs are consumed/used to avoid adversely affecting themselves or the fetus.12 there is a lack of awareness in the middle east about the risks of using herbs, which is exacerbated by cultural and social beliefs regarding their safety.12 evidence-based interventions are needed to increase awareness of this issue and encourage healthy behaviours. in health behaviour studies, the knowledgeattitude-practice (kap) model is used to measure what individuals in a given community know, feel and believe about a specific health problem as well as to measure health-related practices. this model is useful in understanding the mechanisms of health education and health outcomes.20 it is well established that health education interventions play a major role in improving knowledge and attitudes. knowledge is the result of obtaining and understanding information from different types of experiences and can be influenced by health education.21 healthcare professionals play a central and critical role in improving healthcare for pregnant women, as they provide essential services that promote health and ensure a healthy pregnancy. indeed, they can play an important role in correcting misinformation that influences the beliefs and attitudes of pregnant women.22 knowledge differs from attitude, which is defined as “a psychological tendency that is expressed by evaluating a particular entity with some degree of favour or disfavour”.23 according to the kap model, the practice of using herbal treatments during pregnancy is affected by the knowledge and attitudes of pregnant women.21 thus, while recent literature has investigated the use of herbs during pregnancy in saudi arabia, the current study aimed at assessing the knowledge, attitudes and practices concerning the use of herbal treatments among saudi women.1,5 the kap model was used to understand and explain the impact of knowledge and attitudes on practice in order to provide appropriate recommendations and promote urgent action where needed. methods this cross-sectional study was carried out between september 2019 and april 2020 in the province of riyadh (urban and rural areas), saudi arabia. data were collected using an online questionnaire distributed through social media applications, mainly whatsapp (facebook inc., menlo park, california, usa). saudi women aged 18–58 years who were pregnant or had been pregnant at least once during the last five years prior to the study and were living in riyadh (rural or urban area) were included. women who had unsuccessful pregnancies, were younger than 18 years or older than 58 years and who had last been pregnant more than five years before the study were excluded in order to reduce recall bias. a convenience sampling technique was used. the questionnaire was composed of questions relating to herbal treatments commonly used by fatmah almoayad, insherah a. assiri, haifa f. almarshoud, atheer m. safhi, hend m. altahan and nada benajiba clinical and basic research | 593 women during pregnancy in saudi arabia mentioned in the introduction. the questionnaire consisted of four sections. section 1 collected socio-demographic information including age, educational level, marital status, monthly income, employment status, number of children and area of residency. it also included one question about the participants’ sources of information on herbal treatments during pregnancy. section 2 assessed the participants’ knowledge of herbal treatments. this section consisted of two questions that assessed knowledge about the side-effects of each herbal treatment and herbs that should not be used during pregnancy. a score of 1 was assigned for each correct answer, and a score of 0 was assigned for each wrong answer. the maximum total knowledge score was 28 and the minimum was 0. the cut-off point was the median score. participants who scored more than 50% were considered to have good knowledge and those who scored less than 50% were considered to have poor knowledge. section 3 measured the attitudes of participants towards the use of herbal treatments during pregnancy. it included four questions that used a 5-point likert scale ranging from 1 for ‘strongly disagree’ to 5 for ‘strongly agree’.24 the maximum total score for attitude was 20 and the minimum was 4. section 4 included six questions that evaluated the practices related to herbal treatments, in particular, whether the participant had used herbal treatments, the type of herb used, the trimester in which herbs were used, how they were used, the reasons for using them and whether they were used after receiving medical advice. for the questions on whether the participant had used herbal treatments during pregnancy and whether they had sought medical advice, a score of 1 was given for an affirmative answer. the maximum total score was 2 and the minimum was 0. the questionnaire was designed based on a comprehensive literature review and translated into arabic; a backwards-forwards technique was used to ensure its validity. it was reviewed by five experts, and questions were modified accordingly. reliability was tested using cronbach’s alpha test (0.85). finally, the questionnaire was piloted among 20 women to identify any difficulties, ambiguities or culturally sensitive questions. the collected data were statistically analysed using jmp, version 15.1 (sas institute inc., cary, north carolina, usa). descriptive statistics were presented as frequencies and percentages. pearson’s test was used to assess correlations between kap variables. statistical significance was set at p ≤0.05. ethical approval was obtained from the instit utional review board at princess nourah bint abdul rahman university, riyadh, saudi arabia (number: table 1: characteristics of the study’s participants and source of information on herbal treatment use in saudi arabia (n = 400) characteristic n (%) age in years* 18–25 34 (11) 26–33 128 (32) 34–41 138 (35) 42–49 74 (19) 50–57 17 (4) education level illiterate 0 (0) elementary 10 (3) intermediate 26 (7) high school 63 (16) bachelor’s degree 241 (60) higher education 60 (15) marital status married 382 (96) divorced 13 (3) widow 5 (1) income status in saudi riyal <3000 27 (7) 3000–5999 48 (12) 6000–8999 79 (20) 9000–11999 79 (20) ≥12000 167 (42) employment status employed 200 (50) housewife 180 (45) retired 20 (5) number of children one 86 (22) more than one 314 (79) residence area urban 348 (87) rural 52 (13) source of information† scientific website 76 (19) non-scientific website 12 (3) friend 68 (17) family 96 (24) forums 20 (5) traditional healers 20 (5) social media 64 (16) doctor 36 (9) *values calculated out of a total of 391 due to missing data. †values calculated out of a total of 392 due to missing data. exploring the use of herbal treatments during pregnancy among saudi women an application of the knowledge-attitude-practice model 594 | squ medical journal, november 2021, volume 21, issue 4 20-0004). informed consent was requested on the first page of the questionnaire; consent had to be provided before taking part in the study. furthermore, participants were recruited voluntarily and anonymity and confidentiality were maintained. results a total of 400 women were included in this study. most participants were between 26–41 years old (68%) and most had a bachelor’s degree (60%). the majority of the participants were married (96%). almost half of the participants had a high income (42%) and half were employed at the time of the study (50%). the majority had more than one child (79%) and most lived in an urban area of riyadh (87%). almost one quarter (24%) of the participants obtained their information on herbal treatments from family while others obtained information from scientific websites (19%), friends (17%) and social media (16%); doctors were the main source of information for 9% of the sample. both traditional healers and online forums were reported by some as information sources (5% each) and the least number of participants reported using non-scientific websites as their source of information (3%) [table 1]. almost two-thirds of the participants (63%) had a good level of knowledge about the unsafe use of herbal treatments in general, whereas 100% of the participants had poor information about the side-effects of specific herbs [figure 1]. participants tended to have a neutral attitude towards the use of herbal treatment during pregnancy. more precisely, 66% of the participants had a neutral attitude while 23% had a positive attitude and 12% had a negative attitude. approximately half of the participants agreed that the use of herbal treatments is socially acceptable (51%) and most (54%) thought that using herbal treatments during pregnancy was unsafe [table 2]. in terms of the practices of the participants regarding the use of herbal treatments, almost half used herbs ‘sometimes’ (47%) and a similar number did not use herbal treatments during pregnancy (48%). only 5% used herbs throughout their pregnancy. however, when participants were asked about how often they used herbal treatments without a doctor’s advice, 15% confirmed that they always used herbal treatment without advice; almost half reported doing so sometimes (48%) and over one-third (37%) reported not using any herbal treatments without advice. regarding the reasons for using herbal treatments, more than a third of the participants used herbal treatments for reasons related to pregnancy (41%). participants reported using herbal treatments to facilitate delivery (20%), reduce pregnancy symptoms (18%) and deal with other health problems (21%). participants consumed boiled, drenched or figure 1: distribution of participants according to their knowledge of safety and side-effects of herbal treatments (n = 400). table 2: attitude of study’s participants towards herbal treatment in saudi arabia (n = 400) item n (%) strongly agree agree neutral disagree strongly disagree i feel herbal treatments are helpful during pregnancy 12 (3) 60 (15) 154 (39) 112 (28) 62 (16) i feel it is safe for pregnant women to use herbs as treatment 11 (3) 56 (14) 118 (30) 143 (36) 72 (18) i feel herbal treatments are safe because they come from nature 22 (6) 59 (15) 118 (30) 134 (34) 67 (17) the use of herbal treatments is socially acceptable 59 (15) 143 (36) 103 (26) 62 (16) 33 (8) fatmah almoayad, insherah a. assiri, haifa f. almarshoud, atheer m. safhi, hend m. altahan and nada benajiba clinical and basic research | 595 dried herbs (27%, 24% and 3%, respectively) or used a dermal preparation (7%) or fresh herbs (5%). the majority of the participants avoided liquorice, ginseng, senna, castor oil, fenugreek, clove, sage, turmeric, myrrh, fennel flower seed, parsley and thyme . the participants used of peppermint, ginger, anise and chamomile used during all trimesters. cinnamon was used most in the third trimester [table 3]. there was a weakly significant negative correl ation between knowledge and attitude (r = -0.21; p <0.0001) and a moderately significant positive correlation between attitude and practice (r = 0.50; p <0.0001). there was a weakly significant negative correlation between knowledge and practice (r = -0.21; p <0.0001) [table 4]. discussion this study aimed to explore the use of herbal treatments used by saudi women during pregnancy via the kap model. this research focused on the most common herbs used in saudi arabia as identified in the literature.5 to the best of the authors’ knowledge, this study was the first to assess the three components of knowledge, attitudes and practices in relation to the use of herbal treatment during pregnancy and correlations between them. thus, it is expected that this analysis will contribute to providing specific recommendations for the promotion of healthy and safe practices regarding herbal treatments during pregnancy. the findings reported in this study indicated that 63% of the participants had a good level of knowledge about the safety of herbal treatments. however, 100% of the participants had poor knowledge when asked about the specific side-effects of each herb. this is inline with al-ghamdi et al.’s finding that saudi women have good knowledge about the use of herbal treatments during pregnancy.1 the current study’s findings also aligned with those of a study conducted in norway, which found that norwegian women had poor knowledge about the specific side-effects of different herbs during pregnancy.25 this could be explained by the participants’ sources of information as more than half of the participants obtained their information from unreliable sources. this finding is supported by al-ghamdi et al.’s study, which found that half of their study’s participants had used herbal treatments based on social advice.1 despite the participants’ poor knowledge about the side-effects of herbal treatments, both attitudes and practices were good. more than half of the participants felt that it was unsafe for pregnant women to use herbs as treatments. congruent findings were reported by al-ghamdi et al., who also found that participants in their study believed that herbs were not safe for women to use during pregnancy.1 a possible explanation for these findings could be concern for the safety of the fetus and a consequent tendency to be more careful and selective about what the mother consumes. half of the participants disagreed with the notion that herbs were safe because they come from nature; half felt that herbs were socially accepted which could be due to saudi tradition which encourages the use of herbal treatments.4 a study conducted in nigeria found that participants used herbs because they came from natural sources and were socially accepted.26 in terms of practice, almost half of the participants did not use herbs as treatments during pregnancy; of those who did use them, more than half took them orally. similarly, a study conducted in table 3: the use of herbal treatment during different tri mesters of pregnancy in saudi arabia (n = 400) herb 1st trimester 2nd trimester 3rd trimester no use liquorice 2% 1% 3% 94% ginseng 2% 0% 3% 94% senna 1% 1% 3% 94% chamomile 14% 14% 13% 58% fennel flower seed 11% 9% 9% 71% clove 6% 4% 7% 83% fenugreek 4% 4% 9% 84% thyme 11% 11% 12% 66% peppermint 25% 22% 23% 30% sage 8% 7% 10% 76% cinnamon 4% 5% 22% 69% castor oil 3% 2% 8% 87% myrrh 8% 7% 12% 73% ginger 21% 16% 19% 44% anise 14% 17% 19% 49% turmeric 8% 9% 9% 74% parsley 11% 10% 10% 70% table 4: correlation between knowledge, attitude and practice of participants towards herbal treatments variable* knowledge attitude practice knowledge score 1 attitude score -0.21† 1 practice score -0.21† 0.50† 1 *correlation measured using pearson’s test. †p <0.0001. exploring the use of herbal treatments during pregnancy among saudi women an application of the knowledge-attitude-practice model 596 | squ medical journal, november 2021, volume 21, issue 4 palestine reported that more than half of the study’s participants did not use herbs during pregnancy and of those who did take them, most took them orally.27 however, these findings contradicted those of a previous study conducted in saudi arabia where 98.5% of the participants reported using herbal treatments.5 in contrast, aljoher et al. reported that 33.3% of their participants living in the city of al-ahsa, saudi arabia, had avoided natural products during pregnancy.28 a possible explanation for this could be that most participants in the current study had a high income and could afford medical drugs and thus did not need to seek herbal treatment as an affordable choice. additionally, more than half of the participants were from a younger generation and less likely to rely on traditional treatments; this explanation is supported by al akeel et al.’s findings, who found that the use of herbal treatment in saudi arabia is more common among those over 40 years old.4 in the current study, more participants used herbal treatment for reasons related to pregnancy than for other health problems. this finding differed from that reported by adawi, who found that women in palestine mostly used herbs to treat health issues other than those related to pregnancy.27 the current study found a positive correlation between attitudes and practices. in contrast, negative correlations were found between knowledge and attitudes and between knowledge and practices. this could be due to the use of the kap model, which is based on the assumption that practice is affected by knowledge and attitude only. this model is critiqued, as it does not consider subjective norms, perceived control, behavioural beliefs or other external factors such as environmental characteristics. in addition, the study of behaviours from the perspective of individual-focused theories fails to consider emotion, which could play a significant role in the behaviour of pregnant women.20 the main limitation of this study was the use of convenience sampling. however, the use of online surveys is a useful and efficient method of data collection due to its low cost, accessibility to the study population and time efficiency.29 another limitation of this study was the use of the kap model to explore practice, which limited the study’s ability to identify other factors affecting practice. finally, the study represented only one region or area in saudi arabia. nevertheless, riyadh was selected as it is the capital and the most populated city in the country. furthermore, the study focused on one region to reduce the number of variables and provide consistent analysis and precise recommendations. further research coud be conducted in the other regions of the country. conclusion this study found that while the participants’ knowledge was poor, both attitudes and practices were good in relation to the use of herbal treatments during pregnancy. as this study found that knowledge was poor, specific information on the side-effects of herbal treatments during pregnancy should be provided and an emphasis should be placed on the necessity to obtain such information from appropriate sources (i.e. healthcare providers). in addition, more efforts should be made to target attitudes by providing accurate information to reinforce healthy practices among saudi women. there is a need for comprehensive interventions to raise awareness among pregnant women about herbal treatment use; healthcare providers should play a major role in helping future mothers have a safe pregnancy throughout all three trimesters. from a research perspective, more studies on herbal treatments during pregnancy should be conducted in different regions of saudi arabia due to the variety of cultures in the country; these studies could draw on other behavioural theories. finally, there is a need for studies that determine the specific doses and side-effects of herbs for both pregnant women and the fetus. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this research was funded by the deanship of scientific research at princess nourah bint abdulrahman university through the fast-track research funding program. a u t h o r s’ c o n t r i b u t i o n all authors substantially contributed to the design of the study. ia, hfa, ams and hma collected the data, performed the statistical analysis and literature review. all authors participated in the interpretation of the results and drafting the manuscript. fa and nb revised the manuscript and edited the english. all authors approved the final version of the manuscript. references 1. al-ghamdi s, aldossari k, al-zahrani j, al-shaalan f, al-sharif s, al-khurayji h, et al. prevalence, knowledge and attitudes toward herbal medication use by saudi women in the central region during pregnancy, during labor and after delivery. bmc complement altern med 2017; 17:196. https://doi.org/10.1186/ s12906-017-1714-3. 2. azaizeh h, saad b, khalil k, said o. the state of the art of traditional arab herbal medicine in the eastern region of the mediterranean: a review. evid based complement alternat med 2006; 3:229–35. https://doi.org/10.1093/ecam/nel034. fatmah almoayad, insherah a. assiri, haifa f. almarshoud, atheer m. safhi, hend m. altahan and nada benajiba clinical and basic research | 597 3. john lj, shantakumari n. herbal medicines use during pregnancy: a review from the middle east. oman med j 2015; 30:229–36. https://doi.org/10.5001/omj.2015.48. 4. al akeel mm, al ghamdi wm, al habib s, koshm m, al otaibi f. herbal medicines: saudi population knowledge, attitude, and practice at a glance. j family med prim care 2018; 7:865–75. https://doi.org/10.4103/jfmpc.jfmpc_315_17. 5. zaitoun mf, al-nowis me, alhumaidhan fy, khalil he. use of herbs among pregnant women in saudi arabia: a cross sectional study. j pharm sci res 2019; 11:2105–08. 6. strandberg te, andersson s, järvenpää al, mckeigue pm. preterm birth and licorice consumption during pregnancy. am j epidemiol 2002; 156:803–5. https://doi.org/10.1093/aje/ kwf130. 7. al-jaroudi d, kaddour o, al-amin n. risks of myrrh usage in pregnancy. jbra assist reprod 2016; 20:257–8. https://doi. org/10.5935/1518-0557.20160050. 8. taloubi l, rhouda h, belahcen a, smires n, thimou a, mdaghri aa. an overview of plants causing teratogenicity: fenugreek (trigonella foenum graecum). int j pharm sci res 2013; 4:516–19. 9. ajmera p, kalani s, sharma l. parsley–benefits & side effects on health. int j physiologt nutr physical educ 2019; 4:1236–42. 10. dugoua jj. herbal medicines and pregnancy. j popul ther clin pharmacol 2010; 17:e370–8. 11. laelago t. herbal medicine use during pregnancy: benefits and untoward effects. from: https://www.intechopen.com/ chapters/61138 accessed: nov 2020. 12. ahmed m, hwang jh, choi s, han d. safety classification of herbal medicines used among pregnant women in asian countries: a systematic review. bmc complement altern med 2017; 17:489–99. https://doi.org/10.1186/s12906-017-1995-6. 13. sayfieva m, rabbimova g, muhamadiev n. estimation of use efficiency of essential oil of anise in treatment of genital infections in pregnant women. int j res med basic sci 2019; 5:15–21. 14. akhavan amjadi ma, mojab f, kamranpour sb. the effect of peppermint oil on symptomatic treatment of pruritus in pregnant women. iran j pharm res 2012; 11:1073–7. 15. seely d, dugoua jj, perri d, mills e, koren g. safety and efficacy of panax ginseng during pregnancy and lactation. can j clin pharmacol 2008; 15:e87–94. 16. abascal k, yarnell e. the medicinal uses of cinnamon. integr med 2010; 9:28–32. 17. medlineplus. senna. from: https://medlineplus.gov/druginfo/ natural/652.html#druginteractions accessed: nov 2020. 18. ozgoli g, torkashvand s, salehi moghaddam f, borumandnia n, mojab f, minooee s. comparison of peppermint and clove essential oil aroma on pain intensity and anxiety at first stage of labor. iran j obstet gynecol infertil 2016; 19:1–11. 19. bhowmik dc, kumar k, chandira m, jayakar b. turmeric: a herbal and traditional medicine. arch appl sci res 2009; 1:86–108. 20. rimer bk, brewer nt. introduction to health behavior theories that focus on individuals. in: glanz k, rimer bk, viswanath k. health behavior and health education: theory, research, and practice. california: john wiley & sons, 2008. pp. 64–74. 21. wan tth, rav-marathe k, marathe s. a systematic review of kap-o framework for diabetes. med res arch 2016; 3:1–21. 22. humke w. [medical care during pregnancy]. munch med wochenschr 1967; 109:1925. 23. eagly ah, chaiken s. the advantages of an inclusive definition of attitude. soc cogn 2007; 25:582–602. https://doi.org/10.15 21/soco.2007.25.5.582. 24. likert r. a technique for the measurement of attitudes. arch psychol 1932; 22:5–55 25. nordeng h, havnen gc. impact of socio-demographic factors, knowledge and attitude on the use of herbal drugs in pregnancy. acta obstet gynecol scand 2005; 84:26–33. https://doi.org/10.1 111/j.0001-6349.2005.00648.x. 26. fakeye to, adisa r, musa ie. attitude and use of herbal medicines among pregnant women in nigeria. bmc complement altern med 2009; 9:53. https://doi.org/10.1186/1472-6882-9-53. 27. adawi dh. prevalence and predictors of herb use during pregnancy (a study at rafidia governmental hospital/ palestine). master’s thesis, 2012, an-najah national university, nablus. p. 107 28. aljoher am, alsaeed ma, alkhlfan ma, almethen aw, almukhaitah ma, zareen h, et al. pregnant women risk perception of medications and natural products use during pregnancy in alahsa, saudi arabia. egypt j hosp med 2018; 70:13–20. https://doi.org/10.12816/0042956. 29. lefever s, dal m, matthíasdóttir a. online data collection in academic research: advantages and limitations. br j educ technol 2007; 38:574–82. https://doi.org/10.1111/j.1467-8535.2 006.00638.x. squ med j, august 2010, vol. 10, iss. 2, pp. 203-209, epub. 19th jun 10 submitted: 19th jan 10 revision req. 30th mar 10, revision recd. 18th apr 10 accepted: 21st apr 10 in 1990, miller proposed a hierarchical model for the assessment of clinical competence.1 this model starts with the assessment of cognition and ends with the assessment of behaviour in practice [figure 1]. professional authenticity increases as we move up the hierarchy and as assessment tasks resemble real practice. the assessment of cognition deals with knowledge and its application (knows, knows how) and this could span the levels of bloom’s taxonomy of educational objectives from the level of comprehension to the level of evaluation.2 the assessment of behaviour deals with assessment of competence under controlled conditions (shows how) and the assessment of competence in practice or the assessment of performance (does). different assessment tools are available which are appropriate for the different levels of the hierarchy. van der vleuten proposed a conceptual model for defining the utility of an assessment tool.3 this is derived by conceptually multiplying several weighted criteria on which assessment tools can be judged. these criteria were validity (does it measure what it is supposed to be measuring?); reliability (does it consistently measure what it is supposed to be measuring?); educational impact (what are the effects on teaching and learning?); acceptability (is it acceptable to staff, students and other stakeholders?), and cost. the weighting of the criteria depended on the purpose for which the tool was used. for summative purposes, such as selection, promotion or certification, more weight was given to reliability while for formative purposes, such as diagnosis, feedback and improvement, more weight was given to educational impact.4 whatever the purpose of the assessment it is unlikely that one method will assess all domains of competency. a variety of assessment methods are, therefore, required. since medical education unit, college of medicine & health sciences, sultan qaboos university, muscat, oman email: naiwardi@squ.edu.om أساليب القياس والتقييم يف التعليم الطيب األولي اجلامعي نادية بنت حممد الوردية امللخ�ص: هناك عدة اأ�شاليب لتقييم الكفاءة ال�رشيرية وفقا للنموذج الذي اقرتحه ميلر. اختيار اأ�شلوب التقييم يعتمد على الغر�س من اأجل ا�شتخدام ذلك الأ�شلوب ، فيما اإذا كان لأغرا�س التعزيز والت�شديق ، اأو الت�شخي�س وحت�شني التغذية الراجعة اأو كليهما.وقد مت حتديد خ�شائ�س عدة لأداة التقييم وهي: امل�شداقية واملوثوقية ، والأثر التعليمي، واجلدوى والتكلفة. اأيا كان هذا الغر�س، فالإ�شلوب الواحد ليكفي لتقييم كافة جمالت الكفاءة وهناك ثمة حاجة اإىل جمموعة متنوعة من اأ�شاليب التقييم. ولكل اإ�شلوب تقييم مزاياه وعيوبه، وميكن التغلب على اأوجه الق�شور يف اإ�شلوب تقييم ما بوا�شطة مزايا اإ�شلوب تقييم اآخر وذلك �شمن ا�شتخدام جمموعة متنوعة من اأ�شاليب التقييم. مفتاح الكلمات: التعليم الطبي، الدرا�شات اجلامعية الأولية، التقييم. abstract: various assessment methods are available to assess clinical competence according to the model proposed by miller. the choice of assessment method will depend on the purpose of its use: whether it is for summative purposes (promotion and certification), formative purposes (diagnosis, feedback and improvement) or both. different characteristics of assessment tools are identified: validity, reliability, educational impact, feasibility and cost. whatever the purpose, one assessment method will not assess all domains of competency, as each has its advantages and disadvantages; therefore a variety of assessment methods is required so that the shortcomings of one can be overcome by the advantages of another. keywords: medical education; undergraduate; assessment; educational. review assessment methods in undergraduate medical education nadia m al-wardy assessment methods in undergraduate medical education 204 | qu medical journal, august 2010, volume 10, issue 2 nadia m al-wardy explanation is required, an essay question will, obviously, be more suitable than an mcq. every question format has its own advantages and disadvantages which must be carefully weighed when a particular question type is chosen. it is not possible that one type of question will serve the purpose of testing all the aspects of a topic. therefore, a variety of formats are needed to counter the possible bias associated with individual formats and they should be consistent with the stated objectives of the course or programme. m u lt i p l e c h o i c e q u e s t i o n s (a-t y p e: o n e b e s t a n s w e r) these are the most commonly used question type. they require examinees to select the single best response from 3 or more options. they are relatively easy to construct and enjoy high reliability per hour of testing since they can be used to sample a broad content domain. mcqs are often misconstrued as tests of simple facts, but, if constructed well, they can test the application of knowledge and problem solving skills. if questions are context-free, they almost exclusively test factual knowledge and the thought process involved is simple.6 contextualising the questions by including clinical or laboratory scenarios not only conveys authenticity and validity, but, also, is more likely to focus on important information rather than trivia. the thought process involved is also more complex with candidates weighing different units of information against each other when making a decision.6 examples of well constructed one best answer questions and guidelines about writing such questions can be found in case and swanson.7 m u lt i p l e c h o i c e q u e s t i o n s (r-t y p e: e x t e n d e d m at c h i n g i t e m s) one approach to context-rich questions is extended matching questions or extended matching items (emqs or emis).8 emis are organised into sets of short clinical vignettes or scenarios that use one list of options that are aimed at one aspect (e.g. all diagnoses, all laboratory investigations, etc). these options can range from 5 to 26 (although 8 options have been advocated to make more efficient use of testing time).9 some options may apply to more than one vignette while others may not apply at all. a well-constructed extended matching set includes each assessment method has its own advantages and disadvantages, by employing a variety of assessment methods the shortcomings of one can be overcome by the advantages of another. this paper will not be an exhaustive review of all assessment methods reported in the literature, but only those with clear conclusions about their validity and reliability in the context of undergraduate medical education although many of them are also used in postgraduate medical education also. some new trends, although still requiring further validation, will also be considered. assessment of knowledge and its application the most common method for the assessment of knowledge is the written method (which can also be delivered online). several written assessment formats are available to choose from. it should be noted, however, that in choosing any format, the question that is asked is more important than the format in which it is to be answered. in other words, it is the content of the question that determines what the question tests.5 for example, sometimes, it is incorrectly assumed that multiple choice questions (mcq) are unsuitable for testing problem solving ability because they require students to merely recognise the correct answer, while in open ended questions they have to generate the answer spontaneously. multiple choice questions can test problem solving ability if constructed properly.5,6,7 this does not exclude the fact that certain question formats are more suitable than others for asking certain types questions. for example, when an knows shows how knows how does cognition behaviour pr of es si on al a ut he nt ic ity figure 1: miller’s hierarchical model for the assessment of clinical competence1 nadia m al-wardy review | 205 four components: theme, options list, lead-in statement, and at least two item stems. an example and guidelines for writing such questions are shown in case and swanson.7 k e y f e at u r e s q u e s t i o n s key features questions are short clinical cases or scenarios which are followed by questions aimed at key features or essential decisions of the case.10 these questions can either be multiple choice or open ended questions. more than one correct answer can be provided. key feature questions have been advocated to test clinical decision-making skills with demonstrated validity and reliability when constructed according to certain guidelines.11 although these questions are used in some “highstakes” examinations in places such as canada and australia,11 they are less well known than the other types and their construction is time consuming, especially if teachers are inexperienced question writers.12 s h o r t a n s w e r q u e s t i o n s (s a q s) these are open-ended questions that require students to generate an answer of no more than one or two words, rather than to select from a fixed number of options. since they require some time to answer, not many saqs can be asked in an hour of testing time. this leads to less reliable tests because of limited sampling. also, their requirement to be marked by a content expert makes them more costly and time consuming; therefore, they should only be used when closed formats are excluded. it is important that the questions are phrased unambiguously and a well defined answer key is written before marking the question.13 if multiple examiners are available, double marking is preferred. for efficiency, however, each marker should correct the same question for all candidates. this leads to more reliable scores than if each marker corrects all the questions of one group of candidates while another marker corrects all questions for another group.5 e s s ay q u e s t i o n s essay questions are used when candidates are required to process, summarise, evaluate, supply or apply information to new situations. they require much more time to answer than short answer or multiple choice questions and, therefore, not quite as many questions can be used per hour of testing; hence, their lower reliability. structuring (but not overstructuring) the marking process and using a correction scheme similar to the one used for short answer questions can improve reliability. the guidelines for writing short answer questions apply also to essay questions.13 m o d i f i e d e s s ay q u e s t i o n s (m e q s) this is a special type of essay question that consists of a case followed by a series of questions that relate to the case and that must be answered in the sequence asked. this leads to question interdependency and a student answering the first question incorrectly is likely to answer the subsequent questions incorrectly too. therefore, no review or possibility of correcting previous answers is allowed and the case is reformulated as the reporting process progresses. a well-written meq assesses the approach of students to solving a problem, their reasoning skills, and their understanding of concepts, rather than recall of factual knowledge.14 due to psychometric problems associated with question interdependency, meqs are being replaced by the key feature questions.13 an example of an meq can be found in knox.14 s c r i p t c o n c o r d a n c e t e s t (s c t) a new format that is slowly gaining acceptance in health professions education is the script concordance test (sct). this format is designed to test clinical reasoning in uncertain situations15 and is, as the author puts it, based on “the principle that the multiple judgments made in these clinical reasoning processes can be probed and their concordance with those of a panel of reference experts can be measured.”16 the test has gained face validity since its content resembles the tasks that clinicians do every day. scts are based on short case scenarios followed by related questions that are presented in three parts: the first part ("if you were thinking of ") contains a relevant diagnostic or management option; the second part ("and then you were to find") presents a new clinical finding, and the third part ("this option would become") is a fivepoint likert scale that captures examinees' decisions as to what effect the new finding has on the status of the option. an example of an sct question and guidelines for their construction can be found in demeester and charlin.17 assessment methods in undergraduate medical education 206 | qu medical journal, august 2010, volume 10, issue 2 important to ensure validity of content and scoring rules. also, in order to obtain consistent scores and satisfactory reliability, evaluators who are trained in the use of checklists should be used. an example of a checklist can be found in marks and humphreymurto.20 r at i n g s c a l e s rating scales are widely used to assess behaviour or performance. they are particularly useful for assessing personal and professional attributes, generic competencies and attitudes. the essential feature of a rating scale is that the observer is required to make a judgement along a scale that may be continuous or intermittent. an unavoidable problem of rating scales is the subjectivity and low reliability of the judgements. to be fair to the student, however, multiple independent ratings of the same student undertaking the same activity are necessary. it is also important to train the observers to use the rating forms. guidelines on improving the quality of rating scales can be found in davis and ponnamperuma.21 o b j e c t i v e s t r u c t u r e d c l i n i c a l e x a m i n at i o n (o s c e) the osce is primarily used to assess basic clinical skills.22 students are assessed at a number of “stations” on discrete focused activities that simulate different aspects of clinical competence. at each station standardised patients (sps), real patients or simulators may be used,23 and demonstration of specific skills can be observed and measured. osce stations may also incorporate the assessment of interpretation, non-patient skills and technical skills. each student is exposed to the same stations and assessment. osce stations may be short or long (5-30 minutes) depending on the complexity of the task. the number of stations may vary from as few as eight to more than 20 although an osce with 14-18 stations is recommended to obtain a reliable measure of performance.18 reliability is a function of sampling and, therefore, of the number of stations and competences tested.24 scoring is done with a task specific checklist or a combination of a checklist and a rating scale. global ratings produce equivalent results as compared to checklists.19,25,26 the scoring of the students or trainees may be done by observers (faculty members, patients, or standardised patients). assessment of performance assessment of performance can be divided into two categories; assessment of performance in vitro, i.e. in simulated or standardised conditions, and assessment of performance in vivo, i.e. in real conditions. both categories involve demonstration of a skill or behaviour continuously or at a fixed point in time by a student and observation and marking of that demonstration by the examiner. several tools such as checklists, rating scales, structured and unstructured reports can be used to record observations and to assist in the marking or assessment of such demonstrations. checklists and rating scales are used as scoring methods in various forms of assessments, including objective structured clinical or practical examinations (osce, ospe), direct observation of procedural skills (dops), peer assessment, self assessment, and patient surveys.18 the assessment of actual performance, i.e. what the doctor does in practice, is the ultimate goal for a valid assessment of clinical competence. however, despite the face validity of this “in-training” assessment, problems of inadequate reliability due to lack of standardisation, limited observations and limited sampling of skills are cause of concern and limits their use as summative “high-stakes” or qualifying examinations. to mimic real conditions, assessments in simulated settings have been designed to assess performance such as osce/ ospe. c h e c k l i s t s checklists are useful for assessing any competence or competency component that can be broken down into specific behaviours or actions that can be either done or not done. it is recommended that over-detailed checklists should be avoided as they trivialise the task and threaten validity.4 global ratings (a rating scale which is used in a single encounter, for example in an osce, in addition to or instead of a checklist, to provide an overall or “global” rating of performance across a number of tasks) provide a better reflection of expertise than detailed checklists.19 checklist development requires consensus by several experts on the essential behaviours, actions, and criteria for evaluating performance. this is nadia m al-wardy review | 207 tips on organising osce examinations can be found in marks and humphrey-murto.20 s h o r t c a s e s short cases assessment is commonly used in several places27,28 to assess clinical competence.29 in this type of assessment, students are asked to perform a supervised focused physical examination of a real patient, and are then assessed on the examination technique, the ability to elicit physical signs and interpret these findings correctly. several cases are used in any one assessment to increase the sample size. studies on the validity and reliability of short case assessment, however, are scarce and, as epstein30 advocates, their empirical validation must be done before promoting their use. l o n g c a s e s the long case has traditionally been used to assess clinical competence. in the long case, students interview and examine a real patient and then summarise their findings to one or two examiners who question the students by an unstructured oral examination on the patient problem and other relevant topics. the student’s interaction with the patient is usually unobserved. the long case has face validity and authenticity since the task undertaken resembles what the doctor does in real practice; however, the use of long case assessment in “high-stakes” summative examinations is not recommended,31 and, in fact, it has been discontinued in north america, due to its low reliability.32 on the other hand, its use in formative examinations is encouraged because of its perceived educational impact.33 to increase the validity and reliability of long cases, several modifications have been introduced, for example: observing the candidates while they interact with the patient34,35 (although observing the candidate is not a major contributor to reliability);36 training the examiners to a structured examination process,37 and increasing the number of cases.36,38 360° e va l u at i o n 360° evaluation is a multi-source feedback assessment system that evaluates an individual’s competence from multiple perspectives within their sphere of influence. feedback is objectively and systematically collected via a survey or rating scale that assesses how frequently a behaviour is performed. multiple evaluators, who may include superiors, peers, students, administrative staff, patients and families, rate trainee performance in addition to the trainee doing a self-assessment. the rating scales vary with the assessment context. 360° evaluations have been used to assess a range of competencies, including professional behaviours, at undergraduate39 and postgraduate levels.40 however, the use of 360° evaluations in summative assessment is not advocated until further studies are conducted to establish their reliability and validity.40 their use in formative evaluations might be more appropriate since evaluators provide more balanced and honest feedback when the evaluation is formative and used for developmental purposes rather than for pass/fail decisions.41 nonetheless, it should be borne in mind that this type of evaluation can be time consuming and administratively demanding.42 an example of a 360° evaluation form used in a study can be found in wood et al.43 m i n i c l i n i c a l e va l u at i o n e x e r c i s e s (m i n i-c e x) mini-cex44 are based on tutor observations of routine interactions that supervising clinicians and trainees have on a daily basis. these trainee-patient encounters occur on multiple occasions with different evaluators and in different settings. they are relatively short observations (15-20 minutes) in which performance is recorded on a 4 point scale where 1 is unacceptable, 2 is below expectation, 3 is met expectations, and 4 is exceeded expectations. there is an opportunity for noting that a particular behaviour was unobserved and additional space to record details about the context of the encounter. the mini-cex incorporates an opportunity for feedback from the evaluator and is mostly used for formative assessment.39 evaluators consist mostly of tutors whose primary role is to teach clerkship students.39 several competencies are evaluated by the minicex: history taking, physical examination, clinical judgement, counselling, professionalism and other generic qualities. an example of a mini-cex tool can be found in norcini.44 p o r t f o l i o s a portfolio is a collection of student work which provides evidence that learning has taken place. it includes documentation of learning and progression, assessment methods in undergraduate medical education 208 | qu medical journal, august 2010, volume 10, issue 2 4. van der vleuten cp, schuwirth lw. assessing professional competence: from methods to programmes. med educ 2005; 39:309–17. 5. schuwirth lw, van der vleuten cp. different written assessment methods: what can be said about their strengths and weaknesses? med educ 2004; 38:974–9. 6. schuwirth lw, verheggen mm, van der vleuten cp, boshuizen hp, dinant gj. do short cases elicit different thinking processes than factual knowledge questions do? med educ 2001; 35:348–56. 7. case sm, swanson db. constructing written test questions for the basic and clinical sciences. from http://www.nbme.org/pdf/ itemwriting_2003/2003iwgwhole.pdf accessed april 2010. 8. case sm, swanson db. extended-matching items: a practical alternative to free response questions. teach learn med 1993; 5:107–15. 9. swanson db, holtzman kz, allbee k. measurement characteristics of content-parallel single-best-answer and extended-matching questions in relation to number and source of options. acad med. 2008; 83:s21–4. 10. bordage g, page g. an alternate approach to pmps, the key feature concept. further developments in assessing clinical competence. in: hart i, harden r, eds. montreal: can-heal publications 1987:57–75. 11. farmer e, page g. a practical guide to assessing clinical decision-making skills using the key features approach. med educ 2005; 39:1188–94. 12. schuwirth lwt, van der vleuten cp. abc of learning and teaching in medicine: written assessment. bmj 2003; 326:643–5. 13. schuwirth lwt, van der vleuten cp. written assessments. in: dent j, harden r, eds. new york: elsevier churchill livingstone 2005. pp. 311–22. 14. knox jd. how to use modified essay questions. med teach 1980; 2:20–4. 15. charlin b, van der vleuten cp. standardized assessment of reasoning in context of uncertainty. the script concordance test approach. eval health profess 2004; 27:304–19. 16. hall kh. reviewing intuitive decision-making and uncertainty: the implications for medical education. med educ 2002; 36:216–24. 17. fournier jp, demeester a, charlin b. script concordance tests: guidelines for construction. bmc med inform decis mak 2008; 8:18. 18. acgme outcome project, accreditation council for graduate medical education (acgme) and american board of medical specialist (abms). toolbox of assessment methods. version 1.1 from http://www. acgme.org/outcome/assess/toolbox.asp september 2000. accessed may 2010. 19. regehr g, macrae h, reznick r, szalay d. comparing the psychometric properties of checklists but most importantly a reflection on these learning experiences.45 portfolios documentation may include case reports; record of practical procedures undertaken; videotapes of consultations; project reports; samples of performance evaluations; learning plans, and written reflection about the evidence provided. scoring methods include checklists and rating scales developed for a specific learning and assessment context and are usually carried out by several examiners who probe students regarding portfolio contents and decide whether the student has reached the required standard.45 portfolio assessment is considered a valid way of assessing outcomes; however, it has low to moderate reliability due to the wide variability in the way portfolios are structured and assessed. also, this form of assessment is not considered very practical due to the time and effort involved in its compilation and evaluation46 and, perhaps for these reasons, portfolios are commonly used for formative assessment and less commonly for summative purposes.47,48 however, at present, the strength and extent of the evidence base for the educational effects of portfolios in the undergraduate setting is limited.49 guidelines for portfolio compilation can be found in friedman et al.,46 snadden and thomas,50 and thistlethwaite.51 conclusion various assessment methods that test a range of competencies are available for examiners. the choice should be dictated by fitness for purpose and a number of utility criteria. the importance and weighting of these criteria depends on the purpose of the assessment method, i.e. either summative, formative or both. references 1. miller ge. the assessment of clinical skills/ competence/performance. acad med 1990; 65:s63–7. 2. bloom bs. taxonomy of educational objectives. handbook i: cognitive domain. new york: david mckay, 1956. 3. van der vleuten cpm. the assessment of professional competence: developments, research and practical implications. adv health sci educ 1996; 1:41–67. nadia m al-wardy review | 209 and global rating scales for assessing performance on an osce format examination. acad med 1998; 73:993–7. 20. marks m, humphrey-murto s. performance assessment. in: dent j, harden r, eds. new york: elsevier churchill livingstone, 2005. pp. 323–35. 21. davis mh, ponnamperuma gg. work-based assessment. in: dent j, harden r, eds. new york: elsevier churchill livingstone, 2005. pp. 336–45. 22. harden rm, gleeson fa. asme medical education booklet no. 8: assessment of clinical competence using an objective structured clinical examination (osce). med educ 1979; 13:41–54. 23. collins jp, harden rm. amee education guide no. 13: the use of real patients, simulated patients and simulators in clinical examinations, med teach 1998; 20:508–21. 24. newble d, swanson d. pschycometric characteristics of the objective structured clinical test. med educ 1988; 22:325–34. 25. govaerts m, van der vleuten cp, schuwirth lm. optimising the reproducibility of a performancebased test in midwifery. adv health sci educ 2002; 7:133–45. 26. swartz m, colliver j, bardes c, charon r, fried e, moroff s. global ratings of videotaped performance versus global ratings of actions recorded on checklists: a criterion for performance assessment with standardized patients. acad med 1999; 74:1028–32. 27. fowell sl, maudsley g, maguire p, leinster sj, bligh j. student assessment in undergraduate medical education in the united kingdom, 1998. med educ 2000; 34:s1–49. 28. hijazi z, premadasa ig, moussa ma. performance of students in the final examination in paediatrics: importance of the "short cases." arch dis child 2002; 86:57–8. 29. wass v, van der vleuten c, shatzer j, jones r. assessment of clinical competence. lancet 2001; 357:945–9. 30. epstein rm. assessment in medical education. author’s reply. new eng j med 2007; 356:2108–10. 31. ponnamperuma gg, karunathilake im, mcaleer s, davis mh. the long case and its modifications: a literature review. med educ 2009; 43:936–41. 32. smee s. skill based assessment. bmj 2003; 326:703–6. 33. wass v, van der vleuten c. the long case. med educ 2004; 38:1176–80. 34. wass v, jolly b. does observation add to the validity of the long case? med educ 2001; 35:729–34. 35. newble di. the observed long case in clinical assessment. med educ 1991; 25:369–73. 36. wilkinson tj, campbell pj, judd sj. reliability of the long case. med educ 2008; 42:887–93. 37. olson lg, coughlan j, rolfe i, hensley mj. the effect of a structured question grid on the validity and perceived fairness of a medical long case assessment. med educ 2000; 34:46–52. 38. hamdy h, prasad k, williams r, salih fa. reliability and validity of the direct observation clinical encounter examination (docee). med educ 2003; 37:205–12. 39. rees c, shepherd m. the acceptability of 360-degree judgements as a method of assessing undergraduate medical students' personal and professional behaviours. med educ 2005; 39:49–57. 40. office of postgraduate medical education. review of work-based assessment methods, sydney: university of sydney, nsw, australia, 2008. 41. higgins rs, bridges j, burke jm, o'donnell ma, cohen nm, wilkes sb. implementing the acgme general competencies in a cardiothoracic surgery residency program using 360-degree feedback. annals thoracic surg 2004; 77:12–17. 42. joshi r, ling fw, jaeger j. assessment of a 360-degree instrument to evaluate residents' competency in interpersonal and communication skills. acad med 2004; 79:458–63. 43. wood j, collins j, burnside es, albanese ma, propeck pa, kelcz f, et al. patient, faculty, and self-assessment of radiology resident performance: a 360-egree method of measuring professionalism and interpersonal/ communication skills. acad radiol 2004; 11:931–9. 44. norcini jj, blank ll, duffy fd, fortna gs. the minicex: a method for assessing clinical skills. annals internal med 2003; 138:476–83. 45. davis mh, ponnamperuma gg. portfolios, projects and dissertations. in: dent j, harden r, eds. new york: elsevier churchill livingstone 2005. pp. 346–56. 46. friedman mb, david mh, harden rm howie pw, ker j, pippard mj. amee guide no. 24: portfolios as a method of student assessment. med teach 2001; 23:535–51. 47. rees c, sheard c. the reliability of assessment criteria for undergraduate medical students' communication skills portfolios: the nottingham experience. med educ 2004; 38:138–44. 48. davis m, friedman b, harden r, howie p, mcghee c, pippard m, et al. portfolio assessment in medical students’ final examinations. med teach 2001; 23:357–66. 49. buckley s, coleman j, davison i, khan ks, zamora j, malick s, et al. the educational effects of portfolios on undergraduate student learning: a best evidence medical education (beme) systematic review. beme guide no. 11. med teach 2009; 31:279–81. 50. snadden d, thomas m. the use of portfolio learning in medical education. med teach 1998; 20:192–9. 51. thistlethwaite j. how to keep a portfolio. clin teach 2006; 3:118–23. july 2008.indd wounded by reality sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 235-236 sultan qaboos university© submitted 20th february 2008 whether it is the effect of global warming or just that satellite tvs are in-stantaneously connecting us to different parts of the world, dealing with the aftermath of natural disasters is becoming an increasingly common phenomenon. huge efforts are expended on the key tasks of saving and rebuilding lives and rehabilitating infrastructure, but natural and other disasters also leave many people with subtle yet intransigent emotional disorders. in the mental health fraternity, the sequelae of such disasters are labelled post-traumatic stress disorders (ptsd). in western populations, ptsd affects approximately 3.6% of the population and the impact and of distress this condition constitute a serious public health problem. in the ‘decade of the brain’ with neurogenetic hegemony, negative experiences which manifest as ptsd have been compared to brain injury where exposure to the events leads to structural and functional changes in the brain. the emotional reaction has been attributed to adverse conditioning. these two views have been the mainstays of treatment modalities available for sufferers of ptsd. everyone began to think that the psychoanalytic approach had been consigned to footnotes in history books. it is better to think again. this volume, wounded by reality by ghislaine boulanger came to add spice to the established approach to ptsd. this book not only rekindles the psychoanalytic approach, but the volume brings fresh insight into the treatment modalities of ptsd. the book specifically focuses on adult onset trauma. the author’s interest in the field began in the 1970s among vietnam veterans. her thirty years of experience of examining and treating ptsd and survivors of adult onset trauma has been concretised in this volume. the strength of the book is its focus on demarcating the difference between childhood trauma and trauma that is experienced in adulthood. the book is written succinctly and does not pretend to reach the general public. the book is intended for american psychoanalysts who have a substantial knowledge not only of freud, but also of psychoanalysis as a field, and who focus on treating ptsd using the method of psychoanalysis. this volume presents many fascinating clinical vignettes that are likely to grab the reader’s attention. however, when one reflects, the clinical descriptions are nothing more than theoretical constructs stemming from a freudian perspective. the unique issue on which boulanger focuses, and which has not been widely explored by many clinicians, is the fact that trauma faced at different stages in life results in different outcomes; this automatically creates the need for a different approach to treatment. the author proposes, and pertinently makes the case for, this alternative modus operandi. this is valuable in itself as most other professionals in the field focus on باحلقيقة جريح تأليف: جيسلني بوالجناي author: ghislaine boulanger publishers: the analytics press, mahwah nj, 2007. no. of pages: 195 isbn: 0-88163-430-1 orders: www.erlbaum.com b o o k r e v i e w b o o k r e v i e w : w o u n d e d b y r e a l i t y 236 psychopharmacology when it comes to rehabilitating ptsd. not long ago, it was essential to ‘listen’ to prozac, now this volume poses new questions about the unconscious mind of those who have been wounded by natural or other disasters. with the increasing numbers of trauma-causing disasters around the world, the need is growing for a treatment system that can be applied internationally. yet, there is no evidence that this volume will be a panacea for the global challenges posed by natural and other disasters. this volume may not meet the needs of the 80% of the global population living outside western europe, north america and argentina. many have testified, be it bush-doctors in equatorial africa or psychiatrists in urban asia that different cultures neither perceive nor experience trauma alike. with much of the world aloof to the psychoanalytical approach, this book would be more useful for practitioners, psychoanalytic ones in particular, in new york and buenos aires rather than jakarta or muscat. r e v i e w e r hazar al-zadjali department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: zadjali21@hotmail.com pharmacology textbooks are often dull because of detailed presentation of volumes of information in a drab manner, making the subject even more volatile and distant for a neophyte! this textbook, however, deviates from the routine old-fashioned textbook of pharmacology, moving into the new spectrum of more ‘sellable pharmacology’ and is presented in a palatable style. the book describes recent advances in basic pharmacology and relates them to their application in practical therapeutics. it emphasises drug discovery, translational research, and evidence-based medicine. the style of narration and the format of the book are user friendly. the complete contents of the book are available online allowing free access to diagrams and other resource material. the book is presented in an integrated, diseaseoriented manner which makes it an attractive and innovative book to enhance learning about diseases and therapeutics, rather than stand alone drugs. this approach is in line with the learning needs of today’s medical students, clinical pharmacists and other medical and nursing professionals. the book is divided into two parts: principles and practice. the first part has four sections comprising of twenty-one chapters dealing with the pharmacotherapeutic continuum, molecular pharmacology, systems pharmacology and clinical pharmacology. the second part is divided into sixteen main sections on therapeutics, and these sections are further subdivided into seventythree chapters dealing with different diseases. chapters in this section include pathophysiology, epidemiology, therapeutics, clinical pharmacology and therapeutics, and emerging drug targets. the book also includes an interesting, though brief chapter on sex differences in pharmacology. the main strength of the book lies in the chapters dealing with the continuum of knowledge including basic concepts of drugs gradually presented with an increasing layer of complexity and integration علم األدوية واملداواة من املبادىء إىل املمارسة امل�ؤلف: �شك�ت والدمان، اأندريه تريزيك book review pharmacology and therapeutics principles to practice authors: scott a. waldman and andre terzic, md, phd. publisher: saunders-elsevier, an expert consult title, online and print edition, 2009 isbn: 978-1-4160-3291-5 orders: www.elsevierhealth.com squ med j, april 2010, vol. 10, iss. 1, pp. 148-149, epub. 17th apr 10 submitted 2nd feb 10 scott a. waldman and andre terzic book review | 149 with therapy. the pathophysiology and rationale of drug use are clearly explained so that the reader is prepared for a lifetime of prescribing and practice. another striking feature of the book is the strategy of bulky text broken down by use of detailed diagrams. hence, each chapter in the book is well illustrated with high quality coloured diagrams, comprehensive flowcharts, extensive summary tables and treatment algorithms. these make the book more attractive to the reader. although most chapters are exhaustively referenced, one of the limitations of the book lies in the use of older references. this is particularly evident in areas of therapeutics that are rapidly changing. an example is the section on therapy of infectious diseases wherein the chapters on treatment of community acquired pneumonia and tuberculosis refer to american thoracic society guidelines from 2003, and the chapter on bacterial meningitis refers to infectious diseases society of america guidelines from 2004. in addition, chapter 12 on the pharmacobiology of infection gives more weight to antiviral and antifungal drugs compared to antibacterial agents. this could give a novice reader of pharmacology the impression that the former are more commonly used drugs. overall this book is a useful addition to the rapidly emerging armamentarium of ‘new look’ pharmacology and therapeutics textbooks. i would definitely use both the text and the online versions and recommend them to others. r e v i e w e r ragini vaishnav department of pharmacology & clinical pharmacy college of medicine & health sciences sultanqaboos university muscat, oman email: ragini@squ.edu.om 1tehran university of medical sciences; 2shahrekod university of medical sciences; 3department of cardiovascular surgery, tehran university of medical sciences, tehran, iran *corresponding author’s e-mail: behshakerian@yahoo.com huge hydatid cyst of the right ventricular outflow tract *behnam shakerian,1,2 and mohammad h. mandegar3 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 485–487, epub. 29 aug 21 submitted 23 jun 20 revision req. 3 sep 20; revision recd. 4 sep 20 accepted 14 oct 20 4.33 × 4.20 cm in the rvot, causing narrowing and obstruction of the rvot, suggestive of a hydatid cyst [figure 2]. based on ct and echocardiography results and the high prevalence of hydatid cysts in iran, the patient was scheduled for surgical excision. median sternotomy was performed and the operative field was wrapped with towels moistened with hypertonic saline. after performing a cardiopulmonary bypass and inducing cardiac arrest, the whole content of the cyst was aspirated and a hypertonic saline solution was injected. a small incision was made into the cyst to remove its germinal layers [figure 3]. the myocardial cavity was washed thoroughly with a hypertonic saline solution. histological examination confirmed the diagnosis of a hydatid cyst. postoperative tte was normal, without any remnant of the cyst and normal pressure gradient of the rvot. the postoperative period was uneventful and the patient was discharged from the hospital with oral albendazole. the patient gave his consent for publication of this case report and accompanying images. discussion cardiac hydatid disease, an exceedingly rare condition, was first described by williams in 1836.4 it accounts for 0.5–2% of all cases of hydatid disease.5,6 dogs are definitive hosts, while humans are accident hosts in their life cycle. after being eaten by the host, the parasite penetrates the mucosa of the duodenum and reaches the portal venous system. the liver acts as a filter for trapping the ova of echinococcus granulosus. some larvae may escape via the hepatic filter and may enter the systemic circulation leading to the heart. cardiac involvement is uncommon inhydatid disease. the symptoms vary depending on the size and location of the cysts. approximately 90% of the patients remain asymptomatic since hydatid cysts grow slowly; a period of 5–10 years may elapse before the lesions become large enough to cause cardiovascular symptoms.¹ this is a case report of a hydatid cyst of the right ventricular outflow tract (rvot) obstructing the pulmonary valve and an rvot gradient. cyst resection was performed using cardiopulmonary bypass. cardiac hydatid disease is a rare condition that could be potentially life-threatening due to local and systemic complications.² surgery is the treatment of choice.³ case report a 34-year-old male patient presented to the heart clinic, tehran, iran, in 2019 with a history of onemonth-long fatigue and 10-month-long progressive exertional dyspnoea. his past medical history was unremarkable and vital signs were stable. a physical examination revealed no specific findings except a systolic murmur in the pulmonary zone. chest x-ray, electrocardiogram and routine laboratory tests were normal. no cystic lesions were detected in thoracic, abdominal and brain scanning by computed tomography (ct). an enzyme-linked immunosorbent assay was negative for hydatic cysts. however, transthoracic echocardiography (tte) showed a large 40 × 40 mm hypoechoic mass without any internal debris in the rvot, with an obstructive effect (pressure gradient = 48 mmhg) and a moderate right ventricle (rv) dilatation with mild dysfunction, representing a hydatid cyst [figure 1]. thoracic ct angiography showed a cystic lesion measuring about this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.017 case report abstract: hydatid disease is a common health problem in sheep-farming countries such as iran. the liver and lungs are the most common primary sites of hydatid cysts in humans. cardiac involvement is an uncommon manifestation, and the right ventricle outflow tract (rvot) is rarely involved. this is a case report of a 34-year-old man who presented to the heart clinic, tehran, iran, in 2019 with a history of dyspnoea and fatigue. following an imaging study, the patient was diagnosed with an rvot hydatid cyst. he underwent surgical resection of the cyst. the post-operative course was uneventful. keywords: hydatid cyst; right ventricular; outflow obstruction; case report; iran. https://creativecommons.org/licenses/by-nd/4.0/ huge hydatid cyst of the right ventricular outflow tract 486 | squ medical journal, august 2021, volume 21, issue 3 after reaching the heart, the larvae become a mature cyst in about 1–5 years. cardiac involvement may be seen through direct extension or haematogenous routes.7 the larvae can reach the myocardium through coronary circulation. the left ventricle (lv) is most frequently involved, followed by the rv, interventricular septum, left atrium and right atrium.8 the patient may remain asymptomatic for many years or show symptoms depending on the location and size of the cysts, such as chest pain, dyspnoea, arrhythmia and anaphylactic reaction. intracavitary rupture is more frequent in the rv compared to the lv and can cause pulmonary embolisation, pulmonary hypertension and death. diagnosing cardiac hydatid cysts may be difficult due to the nonspecific symptoms and the crucial need for a high index of suspicion, especially in endemic areas. patients with other systemic hydatid cysts should undergo echocardiography for identifying possible cardiac involvement. echocardiography, ct and magnetic resonance imaging are the most important tools for diagnosis. serology for hydatid cysts is useful to confirm the diagnosis; however, studies suggest that the sensitivity of this is low, with false-negative results of up to 50%.9 differential diagnosis includes intracardiac tumours, congenital cysts and ventricular aneurysms.10,11 surgical excision is the treatment of choice, even in asymp tomatic patients. as a rule, the heart should not be manipulated before applying a cross-clamp.8 excision of myocardial hydatid cysts may be associated with complications such as damage to heart structures, cyst rupture, embolisation of the germinative membrane and contamination of surrounding structures.12 there are controversies about preoperative anthel mintic therapy in cardiac hydatid cysts.8,13 however, it is very important to bear in mind that anthelmintic therapy may lead to cyst death and destruction of its wall, resulting in cyst rupture. therefore, germicides must not be administered before surgical removal. anthelmintic therapy is advised if surgical treatment is refused or if the patient is inoperable.14 conclusion isolated cardiac hydatid cysts are extremely rare. early diagnosis and treatment are important to prevent lifethreatening complications. in tropical countries such as iran, hydatid disease must always be kept in mind. to prevent recurrence after surgery, it is necessary to place patients on anthelmintic therapy. c o n f l i c t o f i n t e r e s t the authors declare that there is no conflict of interest. a u t h o r s’ c o n t r i b u t i o n bs and mhm contributed equally to the manuscript. figure 1: transthoracic echocardiography view of the cardiac cyst in a 34-year-old male patient. figure 2: computed tomography shows the hydatid cyst in a 34-year-old male patient. figure 3: intraoperative photographs showing (a) the cavity of the hydatid cyst in the right ventricle outflow tract and (b) the germinative membrane of the cyst. behnam shakerian and mohammad h. mandegar case report | 487 both authors approved the final version of the manuscript. references 1. mehra s, garga uc. left ventricular myocardial hydatid cyst. appl radiol 2018; 47:36–8. 2. mesrati ma, mahjoub y, abdejlil nb, boussaid m, belhaj m, limem h, et al. case report: sudden death related to unrec ognized cardiac hydatid cyst. f1000research 2020; 9:286. https://doi.org/10.12688/f1000research.23277.1. 3. charfeddine s, mallek s, gueldiche m, triki f, jmaa hb, frikha i, et al. a huge cardiac hydatid cyst: an unusual cause of chest pain revealing multivisceral hydatidosis in a young woman. j saudi heart assoc 2015; 26:286–91. https://doi.org/10.1016/j. jsha.2015.04.003. 4. yekeler i, kocak h, aydin ne, başoğlu a, okur a, senocak h, et al. a case of cardiac hydatid cyst localized in the lungs bilaterally and on anterior wall of right ventricle. thorac cardiovasc surg 1993; 41:261–3. https://doi.org/10.1055/s-2007-1013868. 5. bogdanovic a, radojkovic m, jankovic tr, pesic i, radjenovic pt, kovacevic p. presentation of pericardial hydatid cyst as acute cardiac tamponade. asian j surg 2017; 40:175–7. https://doi. org/10.1016/j.asjsur.2013.10.001. 6. agha r.a, fowler a.j, rammohan s, barai i. orgill dp, process group. the process statement: preferred reporting of case series in surgery. int j surg 2016; 36:319–23. https://doi. org/10.1016/j.ijsu.2016.10.025. 7. acipayam m, uncu h, altinay l, basdogan f, gencaslan m, özsöyler i. cardiac hydatid cyst causing right ventricular outflow tract obstruction: case report. turkiye klinikleri j cardiovasc sci 2013; 25:123–6. 8. besir y, gucu a, surer s, rodoplu o, melek m, tetik o. giant cardiac hydatid cyst in the interventricular septum protruding to right ventricular epicardium. indian heart j 2013; 65:81–3. https://doi.org/10.1016/j.ihj.2012.12.014. 9. tekbas eo, tekbas g, atilgan za, islamoglu y, habib c, yazici m. left ventricle hydatid cyst mimicking acute coronary syndrome. j infect dev ctries 2012; 6:579–83. https://doi. org/10.3855/jidc.1721. 10. khosravi a, taghipour h, fanaei sa, assar o, ghyasy ms, mirlohi sm. heart hydatid cyst close to the left descending artery in a thirteen-year-old boy. iran red crescent med j 2014; 16: e15164. https://doi.org/10.5812/ircmj.15164. 11. yildiz ce, sinan uy, yildiz a, cetin g, kucukoglu s. a case of isolated cardiac hydatid cyst that mimics lymphoproliferative malignancy. echocardiography 2015; 32:1036–9. https://doi. org/10.1111/echo.12856. 12. moghul d, hamidi, h. incidental finding of cardiac hydatid cysts, report of two cases. bmc med imaging 2018; 18:1. https://doi.org/10.1186/s12880-018-0268-2. 13. macedo aj, magalhães mp, jalles tn, bento l, sampayo f, lima m. cardiac hydatid cyst in a child. pediatr cardiol 1997; 18:226–8. https://doi.org/10.1007/s002469900158. 14. alshamlan ra, almousa am, al saeed mj, al-dera hf, alobaydun am. cardiac hydatid cyst successfully managed with albendazole: a case report. cureus 2019; 11: e6405. https://doi.org/10.7759/cureus.6405. https://doi.org/10.12688/f1000research.23277.1 https://doi.org/10.1016/j.jsha.2015.04.003 https://doi.org/10.1016/j.jsha.2015.04.003 https://doi.org/10.1055/s-2007-1013868 https://doi.org/10.1016/j.asjsur.2013.10.001 https://doi.org/10.1016/j.asjsur.2013.10.001 https://doi.org/10.1016/j.ijsu.2016.10.025 https://doi.org/10.1016/j.ijsu.2016.10.025 https://doi.org/10.1016/j.ihj.2012.12.014 https://doi.org/10.3855/jidc.1721 https://doi.org/10.3855/jidc.1721 https://doi.org/10.5812/ircmj.15164 https://doi.org/10.1111/echo.12856 https://doi.org/10.1111/echo.12856 https://doi.org/10.1186/s12880-018-0268-2 https://doi.org/10.1007/s002469900158 https://doi.org/10.7759/cureus.6405 department of medicine, faculty of medicine & health sciences, universiti tunku abdul rahman, kajang, selangor, malaysia e-mail: woodzlamp@yahoo.com دور تركيبة خليط الكالسيبوتريول والبيتاميثازون ديربوبيونات اهلالمية يف عالج اإللتهابات اجللدية املتوسطة إىل الشديدة يف فروة الرأس فيليك�س بون-بن ياب abstract: objectives: this study aimed to investigate the off-label use of a combination calcipotriol plus betamethasone dipropionate (cbd) gel in the treatment of moderate-to-severe scalp seborrhoeic dermatitis (ssd). methods: this retrospective study involved 32 patients with ssd who were prescribed cbd gel at the subang jaya medical centre, selangor, malaysia, between january 2016 and december 2017. the physician global assessment scale was used to assess disease severity. itching/discomfort was evaluated using a visual analogue scale. results: the mean age was 35.8 ± 6.9 years. severe disease was seen in 53.1%. complete clearance was recorded in 15.6%, 40.6% and 59.4% of patients at weeks two, six and 10, respectively. by week 10, 87.5% had achieved marked improvement. both mean itching and discomfort scores significantly improved at weeks two, six and 10 (p <0.001). better outcomes were significantly associated with disease duration and itching intensity and discomfort at presentation (p <0.050). conclusion: cbd gel should be considered as an option for ssd cases not adequately controlled by prior conventional treatment. keywords: seborrheic dermatitis; scalp dermatosis; betamethasone dipropionate, calcipotriol drug combination; off-label use; treatment effectiveness. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل درا�شة ال�شتخدام الغري م�رصح به لهالم مزيج كال�شيبوتريول و بيتاميثازون ديربوبيونات يف عالج التهاب اجللد الدهني لفروة الراأ�س املتو�شط اإىل ال�شديد. الطريقة: �شملت هذه الدرا�شة باأثر رجعي 32 مري�شا مع الذين و�شف لهم جل يف مركز �شحي �شوباجن جايا، �شيالجنور، �شيالجنور، ماليزيا، بني يناير 2016 ودي�شمرب 2017. مت ا�شتخدام مقيا�س تقييم الطبيب العاملي لتقييم �شدة. مت تقييم احلكة/عدم الراحة با�شتخدام مقيا�س التماثلية الب�رصية. النتائج: كان متو�شط العمر 6.9 ± 35.8 �شنة. �شوهد املر�س الشديد يف %53.1. من املر�شى. مت ت�شجيل �شفاء كامل يف %15.6، %40.6 و %59.4. من املر�شى يف الأ�شبوع الثاين وال�شاد�س والعا�رص على التوايل. بحلول الأ�شبوع العا�رص، حقق %87.5 من املر�شى حت�شنا ملحوظا. و�شجلت قيم احلكة/عدم الراحة حت�شنا ملحوظا يف الأ�شبوع .)p >0.050( وارتبطت النتائج ب�شكل كبري مع مدة املر�س و�شدة احلكة وعدم الراحة وقت عر�س احلالة .)p >0.001( 10 الثاين وال�شاد�س و اخلال�صة: ينبغي اعتبار هالم مزيج كال�شيبوتريول و بيتاميثازون ديربوبيونات كخيار لعالج حالت التهاب اجللد الدهني لفروة الراأ�س التي ي�شعبالتحكم بها عن طريق العالج التقليدي. ت�رصيح؛ بدون ا�شتخدام الدوائي؛ كال�شيبوتريول مزيج ديربوبيونات؛ بيتاميثازون الراأ�س؛ فروة التهاب الدهني؛ اجللد التهاب املفتاحية: الكلمات فعالية العالج. the role of combination calcipotriol plus betamethasone dipropionate gel in the treatment of moderate-to-severe scalp seborrhoeic dermatitis felix b. yap brief communication sultan qaboos university med j, november 2018, vol. 18, iss. 4, pp. e520–523, epub. 28 mar 19 submitted 19 jul 18 revision req. 28 aug 18; revision recd. 4 sep 18 accepted 20 sep 18 doi: 10.18295/squmj.2018.18.04.015 the majority of patients with scalp seborr-hoeic dermatitis improve with antifungal, antiinflammatory and keratolytic agents which pro vide short-term clearance with minimal side-effects, while topical steroids offer better disease control with longer remission periods.1–4 however, for those that res pond poorly to conventional treatment, other topical offlabel treatments are sometimes applied. one example is a combination of calcipotriol plus betamethasone dipropionate (cbd), an effective topical agent for the treatment of scalp psoriasis in which complete clearance can be seen as early as two weeks.5,6 conventional treatments for seborrhoeic dermat itis are based on the presumed pathogenesis and prolif eration of malassezia furfur and the patient’s heightened immunological response.2 based on the assumption that both scalp psoriasis and seborrhoeic dermatitis have an inflammatory component in the disease process, the use of a cbd gel might be beneficial in treatment of the latter condition.7 moreover, this combination reduces the occurrence of side-effects associated with betameth asone dipropionate alone.5 this study therefore aimed to investigate the off-label use of a cbd gel in the treat ment of moderate-to-severe scalp seborrhoeic dermatitis. felix b. yap brief communication | e521 methods this retrospective study included 32 patients diagnosed with scalp seborrhoeic dermatitis at the subang jaya medical centre, selangor, malaysia, between january 2016 and december 2017. all patients had previously undergone conventional ssd treatment without adequate response. cases were diagnosed by an attending dermatologist and prescribed twice-weekly doses of 50 µg of calcipotriol plus 0.5 mg of betameth asone dipropionate per g of xamiol® gel (leo lab oratories ltd., ballerup, denmark) until resolution. they were advised to apply the cbd gel to affected areas and to continue using their existing shampoos and taking anti histamines. all of the patients were seen twice weekly until the resolution of their scalp lesions and thereafter monthly for two months. during each patient visit, the attending dermatologist recorded the severity of the condition using the physician global assessment scale as either 0 (almost clear), 1 (mild), 2 (moderate), 3 (severe) or 4 (very severe) based on the degree of erythema and scaling and the extent of the skin lesions.8 patients also self-reported symptoms of itchiness and discomfort using a visual analogue scale on a scale of 0 (no symptoms) to 10 (most severe) during each visit. response to treatment was graded as either com plete clearance, marked improvement (>75% improvement from baseline), moderate improvement (25–75% improvement from baseline), mild improvement (<25% improvement from baseline) and worsening/no improve ment. a standardised report form was used to document all sociodemographic, clinical and treatment data recorded during the patient visits. no photographs of the patients’ scalps were taken during the course of the study. data were analysed using the statistical package for the social sciences (spss), version 13.0 (ibm corp., armonk, new york, usa). categorical variables were presented as frequencies (percentages), whereas cont inuous variables were presented as means and standard deviations. statistical analysis was performed for cont inuous variables using a student’s t-test. the level of statistical significance was set at p <0.050. this study was approved by the local institutional review board of universiti tunku abdul rahman, kajang, selangor, malaysia. results the mean age of the patients was 35.8 ± 6.9 years and the majority (53.1%) were female. the mean duration of illness was 12.4 ± 8.4 months. upon initial presentation, 15.6% of patients had very severe disease, 53.1% had severe disease and 31.3% had moderate disease. all of the patients had previously demonstrated an unsatisfactory response to treatment with antifungals with or without tar-based shampoos and topical steroids, including desonide, mometasone furoate, betamethasone dipropionate, betamethasone dipropionate plus salicylic acid and clobetasol propionate lotions. oral antifungals and oral steroids were given to 28.1% and 6.3% of patients, respectively. the remaining 65.6% did not receive oral treatment. by week two of cbd treatment, 53.1% and 15.6% demonstrated marked improvement and complete clear ance, respectively. by week six, 40.6% had achieved complete clearance; this rate improved to 59.4% by week 10. by week 10, all patients demonstrated at least moderate improvement, with 87.5% achieving either complete clearance or marked improvement. one patient required oral steroids at week six to control the disease. mean itch scores significantly declined from 6.1 at baseline to 2.3, 1.7 and 2.5 at weeks two, six and 10, respectively (p <0.001). similarly, mean discomfort scores significantly decreased from 5.6 at baseline to 1.8, 1.5 and 2.3 at weeks two, six and 10, respectively (p <0.001). patients with marked improvement or total clearance had a significantly shorter disease duration and decreased itching intensity and discomfort at presentation (p <0.050 each) [table 1]. no adverse effects or side-effects were reported. the majority of patients (62.5%) discontinued cbd treatment after six weeks due to clearance of the lesions and were lost to further follow-up. table 1: characteristics of patients with scalp seborrhoeic dermatitis after 10 weeks of treatment using a calcipotriol plus betamethasone dipropionate gel* (n = 32) variable mean ± sd p value patients with complete clearance/ marked improvement† (n = 28) patients with mild/moderate improvement† (n = 4) age in years 35.2 ± 7.2 39.8 ± 2.1 0.224 illness duration in months 11.5 ± 7.1 21.0 ± 11.5 0.032 itching score‡ 5.9 ± 1.2 8.0 ± 1.2 0.001 discomfort score‡ 5.3 ± 1.0 8.3 ± 1.0 <0.001 sd = standard deviation. *daily xamiol® gel (leo laboratories ltd., ballerup, denmark). †assessed by an attending dermatologist using the physician global assessment scale as either 0 (almost clear), 1 (mild), 2 (moderate), 3 (severe) or 4 (very severe).8 ‡self-reported by patients using a visual analogue scale on a scale of 0 (no symptoms) to 10 (most severe). the role of combination calcipotriol plus betamethasone dipropionate gel in the treatment of moderate-to-severe scalp seborrhoeic dermatitis e522 | squ medical journal, november 2018, volume 18, issue 4 discussion calcipotriol is a vitamin d analogue licensed for use in the treatment of psoriasis; however, it has been used extensively as an off-label treatment for a variety of other diseases as well.9 although it has previously been studied for the treatment of seborrhoeic dermatitis, it did not prove to be effective.10,11 in scalp disease, calcipotriol was found to result in an inferior clearance rate after four weeks compared to a betamethasone valerate solution (67.84% versus 90.06%; p <0.05).10 for facial seborrhoeic dermatitis, calcipotriol alone resulted in a 5% clearance rate at four weeks compared to 40% in placebo-treated patients (p <0.05).11 combining calcipotriol and betamethasone dipro pionate allows for better efficacy and a reduction in the side-effects associated with both agents alone.5 in a randomised controlled trial, kragballe et al. observed that use of a cbd gel in scalp psoriasis allowed for both rapid clearance (due to betamethasone dipropionate) and a longer remission period (due to calcipotriol).6 in the current study, the beneficial effect of the cbd gel was noted as early as two weeks, with more than half of the patients demonstrating marked improvement. at 10 weeks, 87.5% of patients had marked improvement, with significant reductions in itchiness and discomfort. this result is comparable to those seen in other studies utilising cbd gel for scalp psoriasis with rates of complete/near-total clearance ranging from 68.4–87.5%.5,6,12,13 the present study found that a cbd gel resulted in the improvement of scalp lesions among patients who did not respond to the prior administration of topical steroids. this might have been due to the steroid vehicle utilised; most patients had previously used betamethasone dipropionate, betamethasone dipropionate plus salicylic acid or clobetasol dipropionate lotions containing isopropyl alcohol. local irritation and dryness are common adverse effects of such lotions, often contributing to non-compliance and discontinuation of treatment.14 limitations of this study include its retrospective nature, the limited number of patients, the high dropout rate following clearance of the scalp lesions, short duration of follow-up and the lack of photographs to evidence clinical improvement. ideally, a long-term pros pective randomised case-control study is needed for a better comparison of treatment outcomes using cbd gel. conclusion this study found that a cbd gel may be an effective option in the treatment of moderate-to-severe seborrhoeic dermatitis not adequately controlled by prior conventional treatment with antifungals and steroids. as such, it may potentially be recommended in such cases as an alternative to conventional treatment, albeit as an off-label indication. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. kastarinen h, oksanen t, okokon eo, kiviniemi vv, airola k, jyrkkä j, et al. topical anti-inflammatory agents for seborrheic dermatitis of the face or scalp. cochrane database syst rev 2014; cd009446. https://doi.org/10.1002/14651858.cd009446. pub2. 2. clark gw, pope sm, jaboori ka. diagnosis and treatment of seborrheic dermatitis. am fam physician 2015; 91:185−90. 3. milani m, antonio di molfetta s, gramazio r, fiorella c, frisario c, fuzio e, et al. efficacy of betamethasone valerate 0.1% thermophobic foam in seborrhoeic dermatitis of the scalp: an open-label, multicentre, prospective trial on 180 patients. curr med res opin 2003; 19:342−5. https://doi.org/10.1185/030079 903125001875. 4. ortonne jp, nikkels af, reich k, ponce olivera rm, lee jh, kerrouche n, et al. efficacious and safe management of mod erate to severe scalp seborrhoeic dermatitis using clobetasol propionate shampoo 0·05% combined with ketoconazole shampoo 2%: a randomized, controlled study. br j dermatol 2011; 165:171−6. https://doi.org/10.1111/j.1365-2133.2011.10269.x. 5. saraceno r, camplone g, d’agostino m, de simone c, di cesare a, filosa g, et al. efficacy and maintenance strategies of twocompound formulation calcipotriol and betamethasone dipropionate gel (xamiol® gel) in the treatment of scalp psoriasis: results from a study in 885 patients. j dermatolog treat 2014; 25:30−3. https://doi.org/10.3109/09546634.2013.800182. 6. kragballe k, hoffmann v, ortonne jp, tan j, nordin p, segaert s. efficacy and safety of calcipotriol plus betamethasone dipropionate scalp formulation compared with calcipotriol scalp sol ution in the treatment of scalp psoriasis: a randomized contr olled trial. br j dermatol 2009; 161:159−66. https://doi.org/10.1 111/j.1365-2133.2009.09116.x. 7. agozzino m, berardesca e, donadio c, franceschini c, de felice cm, cavalloti c, et al. reflectance confocal microscopy features of seborrheic dermatitis for plaque psoriasis differentiation. dermatology 2014; 229:215−21. https://doi.org/10.11 59/000363289. 8. pascoe vl, enamandram m, corey kc, cheng ce, javorsky ej, sung sm, et al. using the physician global assessment in a clinical setting to measure and track patient outcomes. jama dermatol 2015; 151:375−81. https://doi.org/10.1001/jamaderm atol.2014.3513. 9. wat h, dytoc m. off-label uses of topical vitamin d in dermatology: a systematic review. j cutan med surg 2014; 18:91−108. https://doi.org/10.2310/7750.2013.13109. 10. basak py, ergin s. comparative effects of calcipotriol and betamethasone 17-valerate solution in the treatment of seborrhoeic dermatitis of the scalp. j eur acad dermatol venereol 2001; 15:86−8. https://doi.org/10.1046/j.1468-3083.2001.00193-9.x. 11. berth-jones j, adnitt pi. topical calcipotriol is not effective in facial seborrhoeic dermatitis. j dermatolog treat 2001; 12:179. https://doi.org/10.1080/09546630152608339. felix b. yap brief communication | e523 12. van de kerkhof pc, hoffmann v, anstey a, barnes l, bolduc c, reich k, et al. a new scalp formulation of calcipotriol plus beta methasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. br j dermatol 2009; 160:170−6. https://doi.org/10.1111/j.1365-2133.2008.08927.x. 13. ma l, yang q, yang h, wang g, zheng m, hao f, et al. calcip otriol plus betamethasone dipropionate gel compared with calci potriol scalp solution in the treatment of scalp psoriasis: a rand omized, controlled trial investigating efficacy and safety in a chinese population. int j dermatol 2016; 55:106−13. https:// doi.org/10.1111/ijd.12788. 14. katz hi, lindholm js, weiss js, shavin js, morman m, bressinck r, et al. efficacy and safety of twice-daily augmented betamethasone dipropionate lotion versus clobetasol propionate solution in patients with moderate-to-severe scalp psoriasis. clin ther 1995; 17:390−401. https://doi.org/10.1016/0149-2918(95)8 0104-9. squ med j, february 2011, vol. 11, iss. 1, pp. 62-68, epub. 12th feb 11 submitted 15th aug 10 revision req. 27th sept 10, revision recd. 27th oct 10 accepted 10th nov 10 1department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 2ruwi health center, directorate general of health affairs muscat region, ministry of health, oman; 3al hamra health center, directorate general of health affairs dakhiliya region, ministry of health, oman; 4department of pharmacology & clinical pharmacy, college of medicine & health sciences, sultan qaboos university, muscat, oman, and 5gulf health research, muscat, oman. *corresponding author email: rkindi@squ.edu.om <∞e^íπ]<∞«÷^f÷]<çfl¬<ÿëçf÷]ê<ÿ€”π]<g�÷]<›]ç~jâ] ·^€ �¬<ìfl�◊â<hºœä⁄<ìœ�fl⁄<ª<îü”ä÷]<]çe        2009 146 %42 %4327%48 %117 %7949 19%764762 %31      :مفتاح الكلمات abstract: objectives: the use of complementary and alternative medicine (cam) for diabetes mellitus is becoming increasingly popular; however, little is known about the prevalence of cam use in patients with diabetes mellitus in oman. the objectives of this study were to estimate the prevalence of use of cam among diabetic patients in muscat region, oman, and to determine the types of cam used as well as to identify the demographic features influencing the use of cam. methods: the study was performed from may to august 2009 on diabetic patients from 4 health centres in muscat region. a total of 146 patients were interviewed. information was obtained on demographics, and the prevalence and pattern of use of cam. results: sixty two (42%) of the participants used cam for the treatment of diabetes. thirty (48%) were satisfied about its use and 27 (43%) intend to use it again. the only types of cam used by participants in this study were herbs (n = 49, 79%), and/or food supplements (n = 7, 11%). family and friends (n = 47/62, 76%) and/or traditional healers (n = 19, 31%) were the main source of information on cam in the treatment of diabetes. there was no significant correlation between demographic characteristics and the use of cam for diabetes. conclusion: cam is used widely for diabetes in muscat region, oman. patients have strong faith in cam in terms of effectiveness. doctors should recognise this and be prepared to talk more freely with patients about its use and potential side effects. keywords: complementary medicine; alternative medicine; complementary and alternative medicine (cam); diabetes mellitus (dm); oman complementary and alternative medicine use among adults with diabetes in muscat region, oman *rahma m al-kindi,1 muna al-mushrafi,2 muna al-rabaani,3 ibrahim al-zakwani4,5 clinical & basic research advances in knowledge 1. this study is the first in oman to explore the use of complementary and alternative medicine (cam) in patients with diabetes. it is the key for further research in this field with the hope of improving management of people with diabetes. 2 this study has shown how common the use of cam is in oman. rahma m al-kindi, muna al-mushrafi, muna al-rabaani and ibrahim al-zakwani clinical and basic research | 63 oman has a long history of using traditional and herbal remedies; however, few studies have been conducted in the country.1,2,3 these remedies are supplied by traditional healers, or self-obtained, and are administered in the management of a wide variety of both acute and chronic conditions. despite the extensive development of the health care system in oman and the availability and accessibility of free health facilities and drugs, traditional medicine is still widely used. traditional medicine, or complementary and/ or alternative medicine (cam) refers to “health practices, approaches, knowledge and beliefs incorporating plant, animal and mineral based medicines, spiritual therapies, manual techniques and exercises, applied singularly or in combination to treat, diagnose and prevent illnesses or maintain well-being”.4 cam has maintained its popularity in all regions of the developing world and its use is rapidly spreading in industrialised countries.5 for instance, in africa, 80% of the population uses traditional medicine to help meet their health care needs.6 in europe, north america and other industrialised regions, over 50% of the population have used cam at least once in their lives.7 the use of cam among diabetics is common. a recent review of 18 studies from 9 countries showed that the prevalence of cam use among patients with diabetes varied from 17% to 72.8%. most of the studies reviewed were conducted in developed countries and the majority of papers were derived from the usa and australia.8 in developing countries, such as saudi arabia, 17.4% of patients with diabetes in riyadh 9 and 30% in mecca10 used some forms of herbs. in the united arab emirates, 76% of patients with diabetes had previously used herbs and 38% were currently using some forms of cam.11 in bahrain, 63% of patients with diabetes had used cam within the previous 12 months.12 of all chronic diseases, diabetes mellitus has emerged as a major and growing health problem in oman. the oman national health survey of diabetes, conducted in 1991, showed that the prevalence of diabetes is 9.75%, while the follow-up survey in the year 2000 showed an increase in the prevalence to 11.6% among adults over 20 years of age.13-15 the prevalence estimate of diabetes mellitus in oman by the international diabetes federation (idf) in 2010 is 13.4% and is expected to increase in the next 25 years.16 this makes diabetes the second most common cause of morbidity in males and females above the age of 45 years and the fourth highest cause of death.17 to our knowledge, no studies have yet emerged from oman on the use of cam by patients with diabetes. therefore, this study was conducted to determine the prevalence of cam use among patients with diabetes mellitus in the muscat region and to reveal the types of cam most commonly used as well as the factors contributing to their use in terms of demographic characteristics and disease features. methods a multi-centric, cross sectional study was conducted over a 4-month period from may to august 2009 in four health centres in the muscat region namely ruwi, wadi al-kabir, south mawaleh, and al-khoudh. each of these health centres serves a population of approximately 500 patients with diabetes. the diabetic clinics in these health centres are well developed in terms of availability of a diabetic register, appointment system, trained family physicians and a wide range of modern 3. this study should generate an open attitude to cam among western health professionals and encourage the development of guidelines and regulations on the use of cam. 4. this study should help to identify cam practices and determine their safety and effectiveness. application to patient care 1. complementary and alternative medicine practices are commonly used, but not totally devoid of risk. 2. this information needs to be disseminated to the public and health professionals by: a) educating and training health professionals about cam and its popularity in our community; b) encouraging doctors to ask patients about their use of cam and persuading them to talk about it. this would avoid delays in seeking medical treatment and further complications; c) encouraging patients to report side effects of cam. 3. integration between western medicine and complementary and alternative medicine could result in both being provided at the same health care facility. this would avoid the risks of negative cam-drug interactions. complementary and alternative medicine use among adults with diabetes in muscat region, oman 64 | squ medical journal, february 2011, volume 11, issue 1 pharmacological anti-diabetic medications. the target population of this study was patients with diabetes mellitus attending primary health care facilities. all patients (n = 146) attending the diabetes or general clinics in these health centres during the study period were enrolled in the study. the following people were excluded: patients who did not speak arabic or english; those with dementia or learning difficulties; those with no time to complete the questionnaire; people who visited the health centres for purposes other than patient care, and those who refused to give consent. face-to-face interviews were conducted by trained family medicine residents using a precoded and pre-tested questionnaire that was developed by the authors based on a pilot study and previous similar studies to assess the use of cam by patients with diabetes.9-12 the types of cam used were defined based on the us national center for complementary and alternative medicine (nccam) categorisation of cam.18 the questionnaire was translated into arabic and the interview was conducted in arabic. inquiry was made into demographic characteristics and type and duration of diabetes. in addition, records were reviewed to determine the presence of complications and co-morbidities, treatment, and the status of blood glucose levels during the three months prior to the study. a glycosylated haemoglobin level of <7% was taken to reflect a controlled blood glucose level. participants were also asked whether they had used cam in general, and in particular for the treatment of diabetes. among users of cam, detailed information was obtained on: cam use during the previous year; current use; type and frequency of use; source of information about cam; extent of satisfaction and side effects (if any); use with prescribed medication/s; whether information on cam use had been given to the treating physician, and intention of using cam again. finally, interviewees were asked to give their opinion on the safety and efficacy of cam compared to modern medicine. descriptive statistics were used to describe the data. for categorical variables, frequencies and percentages were reported. differences between groups (cam status, yes/no) were analysed using pearson’s χ2 tests (or fisher’s exact tests for cells less than 5). for continuous variables, mean and standard deviation were used to present the data while analysis was performed using the student’s t-test. an a priori two-tailed level of significance was set at the 0.05 level. statistical analyses were conducted using stata, version 11.0 (stata corporation, college station, tx, usa). informed consent was obtained from all participants before the interview. ethical approval for the study was granted in 2009 by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university, oman. results this study included a total of 146 patients with diabetes mellitus type 1 (n = 6, 4%) and type 2 (n = 140, 96%). the majority of patients (n = 136, 93%) were omani nationals. more than half of these patients were women (n = 84, 58%), and in the age group 46 to 65 years (n = 82, 56%) [table 1]. the duration of diabetes ranged from 2 months to 40 years (mean 8.48 ± 6.5 years). nearly a third of the patients (n = 56, 38%) reported the presence of one or more complications including retinopathy (n = 21, 14%), ischaemic heart diseases (n = 18, 12%), nephropathy (n = 17, 12%), neuropathy (n = 11, 8%), and transient ischaemic attacks and strokes (n = 4, 3%). co-morbidities were reported by 105 (72%) of the patients including hypertension (n = 76, 52%), dyslipidemia (n = 17, 12%), gastrointestinal diseases (n = 14, 10%), joint diseases (n = 13, 9%) and mood disorders (n = 44, 30%). a review of the records for these patient for the 3 months prior to the study revealed that 109 (75%) of the patients had uncontrolled blood glucose levels. table 1 reveals that users and non-users of cam for the treatment of diabetes are comparable in regard to their demographic and clinical characteristics. the ever use of cam was reported by 76 (52%) of patients. a total of 42% (n = 62) of those who had ever used cam had used it specifically for the treatment of diabetes. just over a quarter of these patients (n = 41, 28%) had used cam within the last 12 months and 28 (19%) were current users. the main types of cam used were herbal remedies (n = 49/62, 79%) and/or food supplements (n = 7/62, 11%). most herbal remedies were in mixed/compounded forms and more than half of the patients (n = 36/62, 58%) had used rahma m al-kindi, muna al-mushrafi, muna al-rabaani and ibrahim al-zakwani clinical and basic research | 65 several types of herbal remedies. “harmel” (rhazya stricta) (n = 6/62, 10%), fenugreek (trigonella foenum, arabic “helba”) (n = 5/62, 8%) and black seeds (nigella sativa) (n = 4/62, 6%) were the most commonly used. among those who used cam for the treatment of diabetes, 48% (n = 30) expressed satisfaction with its use and 44% (n = 27) stated that they intend to use it again. in addition, 23% (n = 14) perceived cam as more effective than modern medicine and 27% (n = 17) as safer. interestingly, 45% (n = 28) of the participants were taking herbal remedies concurrently with their western anti-diabetic medications and only 13% (n = 8) of them had informed their treating physicians about cam use. the main source of information on cam for the treatment of diabetes was family and friends (n = 47, 76%) and/or traditional healers (n = 19, 31%). the self-reported rate for adverse events associated with cam use was 13% (n = 8). table 1: general characteristics of the study participants stratified by use of complementary and alternative medicine characteristics total frequency (n = 146) use of complementary and alternative medicine in diabetic patients p value yes n = 62 (42%) no n = 84 (58 %) age, n (%) 21–34 35–45 46–55 56–65 66–88 8 (5%) 32 (22%) 38 (26%) 44 (30%) 24 (16%) 2 (3%) 16 (26%) 18 (29%) 18 (29%) 8 (13%) 6 (7%) 16 (19%) 20 (24%) 26 (31%) 16 (19%) 0.586 sex, n (%) female 84 (58%) 32 (52%) 52 (62%) 0.214 marital status, n (%) married 123 (84%) 52 (84%) 71 (84%) 0.915 education, n (%) illiterate school post-school 63 (43%) 58 (40%) 25 (17%) 23 (37%) 30 (48%) 9 (15%) 40 (48%) 28 (33%) 16 (19%) 0.185 nationality, n (%) omani 136 (93%) 60 (97%) 76 (90%) 0.190 diabetes mellitus (dm) type, n (%) dm type 2 140 (96%) 60 (97%) 80 (95%) 1.000 duration of dm, n (%) <5 years 5-7 years 8-10 years >10 years 42 (29%) 34 (23%) 37 (25%) 33 (23%) 21 (34%) 9 (15%) 17 (27%) 15 (24%) 21 (25%) 25 (30%) 20 (24%) 18 (21%) 0.184 control of blood glucose (<7% hba1c), n (%) controlled 37 (25%) 14 (23%) 23 (27%) 0.510 complications* present, n (%) yes 56 (38%) 22 (35%) 34 (40.48) 0.540 concurrent diseases present, n (%) yes 105 (72%) 47 (76%) 58 (69%) 0.369 * complications include retinopathy, nephropathy, neuropathy, ischaemic heart diseases, transient ischaemic attacks and stroke. complementary and alternative medicine use among adults with diabetes in muscat region, oman 66 | squ medical journal, february 2011, volume 11, issue 1 discussion the present study has shown that 42% of the diabetic patients had used cam in the treatment of diabetes and 28% had used cam in the previous 12 months. this is comparable with other similar studies in the gulf states such as saudi arabia (30%),10 the united arab emirates (38%)11 and bahrain (63%)12 as well as well as in the usa (73%),19 and india (68%),20 but it is higher than in australia (24%) and the uk (17%).21 this variation can be due to the use of different cam definitions and the different timeframes of the studies as well as to different cultures. in our study, the types of cam used were defined based on the nccam categorisation of cam.18 there was no significant association between the use of cam and the socio-demographic or clinical characteristics of the participants. furthermore, the use of cam was not associated with either blood glucose level, glycosylated haemoglobin a1c control or the presence of complications or concurrent illnesses. this could be due to the small sample size and the fact that the participants were health centre patients. this is particularly important as patients in the community may be using cam more frequently and the way they use it may be different. the common types of cam used users were herbal remedies and food supplements. the composition of most of these local remedies is not known as they are passed on from generation to generation and purchased ready made from the traditional healers or market (souk) outlets. most of the patients had listed a variety of herbal mixtures and a few specified the name of the herbs used like harmel, fenugreek, and black seeds. the number of people taking herbal and modern medicines at the same time was high. the potential for adverse interactions with modern medicines is therefore very likely. this issue needs to be recognised by physicians to ensure that patients are not putting themselves in unnecessary danger. an appreciable number of people reported adverse effects while taking herbal products; however, it is almost impossible to establish causality because most of them took mixed herbs and the survey relied mainly on their recall. participants relied heavily on family and friends for advice on cam use. health education on this matter should be simultaneously provided to patients and their families. moreover, education is recommended to inform their doctors about its use since the majority of patients did not inform their doctors, while simultaneously almost half expressed satisfaction with cam use and intended to use it again. patients may be worried regarding the negative attitude of doctors towards the use of cam so they do not inform their doctors about it. therefore, a more positive attitude from doctors may encourage patients to talk more freely regarding their use of cam. participants had a strong faith in herbal medicines with regard to their effectiveness and safety. nearly 25% of respondents indicated that cam is more effective and safer than modern medicine in treating diabetes. this result will have important health implications if confirmed on a larger sample. over-reliance on ineffective herbal remedies could lead to people either refraining from using or delaying the use of more effective modern medicine. this study also shows that cam users have higher expectations of cam than they do of conventional therapies. therefore, physicians should recognise their patients’ underlying desire for improving their health status and be able to advise patients on the use of cam. faith in cam use is probably part of national heritage. these products have been used for generations with no apparent harm. this view is reinforced by family and friends who are the main influences on respondents’ decisions to use cam. this, however, is not culturally unique as other studies in the region have shown that family and friends are intensely involved in decision making regarding the use of herbal medicine.9,11 many researches have studied the anti-diabetic effects of some herbs and plants. however, the safety and efficacy of these herbal treatments are still to be determined.22 patients may be putting themselves at risk by the use of these treatments.23 some herbal products contain powerful substances that can be toxic either alone or in combination with other medications.24 the most important risk is that cam is used as a true alternative to conventional treatments for serious medical conditions. in addition, there is no control over the quality of these products, which can be easily purchased in special outlets in the market (souk). herbal remedies are widely considered to be inexpensive, but this is often not the case. this specific aspect of cam use needs to be studied in a proper clinical setting. rahma m al-kindi, muna al-mushrafi, muna al-rabaani and ibrahim al-zakwani clinical and basic research | 67 with the increasing importance of cam in modern health care, medical and nursing education should include information about complementary practices.25 physicians will be increasingly expected to address issues related to cam use, but may not be able to become knowledgeable about all cam practices. however, they can apply the principles of evidence-based medicine to cam as to any area of health care.26 physicians can search the published medical literature and evaluate the applicability of cam for specific patient problems. the study has several limitations. the real percentage of cam use in the treatment of diabetes might be found to be higher than that reported if the duration of the study were extended, and especially if extended to the community level. this is particularly important as patients in the community may be using clinical services less frequently and the way they use cam may be different. this study was conducted in only one region and the results may not be generalisable to diabetic patients in other regions of oman or to the entire country. in addition, this study did not investigate the objective effectiveness of cam on diabetes, such as showing that patients’ blood glucose was not controlled on their conventional therapy, but became controlled when cam was added or substituted. further research will be required involving many regions and to obtain data on any health benefits achieved through cam usage. conclusion this study found out that many diabetic patients used cam and most of those patients used herbal remedies. family and friends played a significant role as sources of cam information. many patients did not inform their doctors about cam use, taking them simultaneously with anti-diabetic medications, and had the intention to use them again. doctors should recognise that cam is widely used by diabetic patients and should appreciate that these medicines can cause adverse effects. doctors should therefore be prepared to question their patients and try to encourage them to talk about their use of cam as it may affect the outcome and the management of their disease. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g m e n t the authors are grateful to dr randa yousif, for her constructive review and comments. references 1. ghazanfar sa, al-sabahi am. medical plants of northern and central oman (arabia). econ botany 1993; 47:89–98. 2. miller ag, morris m. plants of dhofar, the southern region of oman: traditional, economic and medicinal uses. biol conserv 1989; 48:241–2. 3. ghazanfar sa. wasm: a traditional method of healing by cauterization. j ethnopharmacol 1995; 47:125–8. 4. world health organization. fact sheet no. 134, traditional medicine, 2003. from: http:// www.who.int/mediacentre/factsheets/fs134/en/ print.html accessed: feb 2009. 5. eisenberg dm, davis rb, ettner sl, appel s, wilkey s, van rompay m, et al. trends in alternative medicine use in the united states, 1990-1997: results of a follow-up national survey. jama 1998; 280:1569–75. 6. world health organization. traditional medicine in the african region. an initial situation analysis (1998–1999). harare: who regional office for africa, 2000. 7. fisher p, ward a. medicine in europe: complementary medicine in europe. bmj 1994; 309:107–11. 8. chang h, wallis m, tiralongo e. use of complementary and alternative medicine among people living with diabetes: literature review. j adv nurs 2007; 58:307–19. 9. al-rowais n. herbal medicine in the treatment of diabetes mellitus. saudi med j 2002; 23:1327–31. 10. al-saeedi m, elzubier ag, bahnassi aa, aldawood km. pattern of belief and use of traditional remedies by diabetic patients in mecca, saudi arabia. east mediterr health j 2003; 9:99–107. 11. al-braik fa, rutter pm, brown d. a crosssectional survey of herbal remedy taking by united arab emirate (uae) citizens in abu dhabi. pharmacoepidemiol drug saf 2008; 17:725– 32. 12. khalaf aj, whitford dl. the use of complementary and alternative medicine by patients with diabetes mellitus in bahrain: a cross-sectional study. bmc complement altern med2010; 10:35 13. asfor mg, lambourne a, soliman a, al-behlani s, al-asfoor d, bold a, et al. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabet med 1995; 12:1122–5. complementary and alternative medicine use among adults with diabetes in muscat region, oman 68 | squ medical journal, february 2011, volume 11, issue 1 14. national health survey 2000, volume 1 study of life style risk factors. muscat: ministry of health, unicef and unifpa, 2000. 15. ying zhang, lee et, devereux rb, yeh j, best lg, fabsitz rr, et al. prehypertension, diabetes, and cardiovascular disease risk in a populationbased sample: the strong heart study. hypertension 2006; 47:410–14. 16. international diabetes federation (idf). diabetes atlas. from: http://www.eatlas.ide.org/ accessed: december 2010. 17. annual health report 2008. muscat: ministry of health, oman. 18. national centre for complementary and alternative medicine (nccam). publication no. d156. what is complementary and alternative medicine? from:http://nccam.nih.gov/health/whatiscam/ accessed: feb 2009. 19. bell ra, suerken ck, grzywacz jg, lang w, quandt sa, arcury ta. complementary and alternative medicine use among adults with diabetes in the united states. alter ther health med 2006; 12:16– 22. 20. kumar d, bajij s, mehrotra r. knowledge, attitude and practice of complementary and alternative medicines for diabetes. public health 2006; 120:705– 11. 21. clifford rm, batty kt, davis w, davis tm. prevalence and practice of complementary medicine usage in diabetes: fremantle diabetes study. j pharm pract res 2003; 33:260–4. 22. pilkington k, stenhouse e, kirkwood g, richardson j. diabetes and complementary therapy: mapping the evidence. pract diab int 2007; 24:371–6. 23. ernest e. bitter pills of nature; safety issues in complementary medicine. pain 1995; 60:237–8. 24. de smet pagm, keller k, honsel r, chandler rf. adverse effect of herbal drugs, vol. 3. berlin: springer-verlag, 1997. pp. 137–44. 25. panel issues recommendations for incorporating complementary practices into medical /nursing education. alt ther health med 1996; 2:25. 26. rosenberg w, donald a. evidence based medicine: an approach to clinical problem-solving. bmj 1995; 310:1122–6. a fifty-four year-old male patient presented to sultan qaboos university hospital, oman, with recurrent atypical chest pain. he had no significant electrocardiogram changes and serial serum troponin levels were normal. he did not suffer from hypertension or diabetes mellitus. he underwent multidetector computed tomography (mdct) coronary angiography [figure 1] to rule out obstructive coronary artery disease. the patient had had similar symptoms 2 years previously, for which he had had conventional coronary angiography [figure 2]. both examinations showed diffuse ectasia of the right coronary artery (rca), left main, left anterior descending artery and circumflex artery. mild narrowing of the distal rca was shown in both examinations. coronary artery ectasia (cae) is characterised by segmental or diffuse dilatation of the coronary artery to more than 1.5 times the diameter of the adjacent segment of the same artery or different arteries.1 markis proposed a classification of cae based on the extent of ectatic involvement. in decreasing order of severity, diffuse ectasia of two or three vessels was classified as type i; diffuse disease in one vessel and localised disease in another vessel as type ii; diffuse ectasia of one vessel only as type iii, and localized segmental ectasia as type iv.2 more than half of cae cases are due to coronary atherosclerosis, but occasionally they are related to other pathological entities. all three coronary vessels can be affected by cae, but in 75% of squ med j, december 2009, vol. 9, iss. 3, pp. 354-356, epub. 19th dec 2009 submitted 12th may 09 accepted 8th sept 09 department of radiology and molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed: alzuhli@hotmail.com توسع الشرايني التـاجيـة عماد التميمي، حمـود الذهلـي coronary arteries ectasia emad al-tamimi, humoud al-dhuhli interesting medical image figure 1a : three-dimensional volume-rendered 64multidetector ct image of the proximal segments of the left and right coronary arteries which are ectatic. figure 1b : curved multiplanar reformation of the right coronary artery (rca) showing diffuse ectasia. there is a non-calcified eccentric plaque (white arrow) in the distal segment of the rca causing mild stenosis. emad al-tamimi and humoud al-dhuhli interesting medical image | 355 patients an isolated artery is ectatic. in patients with concomitant coronary artery disease, the proximal and mid-segments of the right coronary artery are the most frequently involved, followed by the left anterior descending artery and the circumflex artery.2 the specific causative mechanisms of abnormal dilatation of the lumen in cae are essentially unknown. elevated c-reactive protein levels may suggest an inflammatory process as a cause.3 coronary angiography remains the gold standard for the assessment of cae.4 intravascular ultrasound is an excellent tool to assess luminal size and characterise arterial wall changes; it differentiates correctly a true from false a aneurysm caused by plaque rupture. recently, mdct has allowed non-invasive diagnosis of cae. the examination is performed in an outpatient setting and requires minimal preparation which may include slowing the heart rate by using beta blockers. the examination is performed in a single breath-hold lasting 1012 seconds. it has gained wide acceptance among cardiologists as a non-invasive modality in ruling out coronary artery disease in low to intermediate risk patients presenting with chest pain. leschka et al. found the incidence of cae was 3% among 677 patients who underwent cardiac ct using dual source mdct.5 in the majority of cases, cae accompanies atherosclerotic coronary disease. the clinical presentation and the long-term cardiac complications are mostly associated with the severity of the co-existing coronary lesion. cae appears to be associated with traditional cardiovascular risk factors such as hypertension, smoking and lipidaemia, but not with diabetes mellitus.3 the co-existence of cae with obstructive coronary lesions in the great majority of patients and the isolated coronary ectasias have led to the generalised administration of aspirin in all patients with cae.2 current literature suggests that ectatic coronary arteries, even without the presence of coronary stenosis, are subject to thrombus formation, vasospasm, and spontaneous dissection. regarding management and therapy, there are several opinions. some studies, which are based on significant flow disturbances within the ectatic segments, suggest anticoagulation should be the main therapy. invasive management, with or without bare or covered stent positioning, has been recommended with caution, as the effects still have to be proven. 6 references 1. saglam m, barutcu i, karakaya o, esen m, akgun t, karavelioglu y et al. assessment of left ventricular functions in patients with isolated coronary artery ectasia by conventional and tissue doppler imaging. angiology, 2008; 59:306-11. 2. markis je, joffe cd, cohn pf, feen dj, herman mv, gorlin r. clinical significance of coronary arterial ectasia. am j cardiol 1976; 37:217-22. figure 2 : conventional coronary angiograms of the right (a) and left (b) coronary arteries confirmed the presence of diffuse ectasia. coronary arteries ectasia 356 | squ medical journal, december 2009, volume 9, issue 3 3. saglam m, karakaya o, barutcu i, esen m, turkmen m, kargin r, et al. identifying cardiovascular risk factors in a patient population with coronary artery ectasia. angiology 2008; 58:698-703. 4. manginas a, cokkinos d. coronary artery ectasias: imaging, functional assessment and clinical implications. eur heart j 2006; 27:1026-31. 5. leschka s. stolzmann p, scheffel h, wildermuth s, plass a, genoni m, et al. prevalence and morphology of coronary artery ectasia with dual-source ct coronary angiography. eur radiol 2008; 18:2776-84. 6. grigorov v. invasive and anticoagulant treatment for coronary ectasia: a single operator’s experience in a tertiary hospital in south africa. cardiovasc j afr 2009; 20:229-32. 1department of general surgery, oman medical speciality board, muscat, oman; departments of 4general surgery, 2radiology and 3pathology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sara93916@gmail.com تشخيص ورم غدي عرقي صايف اخلالاي يف الثدي إبستخدام خزعة اإلبرة اللبية تقرير حالة ومراجعة األدبيات �سارة العدوية، بدرية الق�سابية، ميا البحرية، عادل اجلراح، �سعاد الأغربية abstract: clear cell hidradenoma (cch) is a tumour originating from the eccrine sweat glands. it usually presents in the limbs, axilla or trunk. cch of the breast is rare and can present as a cystic lesion in the breast that can be easily misdiagnosed as malignancy. we report a 36-year-old female patient who presented at the sultan qaboos university hospital breast clinic, muscat, oman, in 2018 with a lump in her left breast. ultrasound examination reported a complex cystic lesion with a solid, vascular component. an ultrasound-guided core needle biopsy was suggestive of clear cell hidradenoma. surgical excision was performed and histopathology confirmed the diagnosis of cch of the breast. this is the first ever case of a diagnosis of cch made using core needle biopsy. cch can be challenging to diagnose; therefore, awareness of its histopathological and ultrasonographic features are essential to avoid misdiagnosis and over treatment. keywords: eccrine glands; breast; acrospiroma; sweat gland adenoma; sweat gland neoplasms; case report; oman. امللخ�ص: الورم الغدي العرقي �سايف اخلاليا هو ورم م�سدره الغدد العرقية الناحتة، يظهر عادة يف الأطراف اأو الإبط اأو اجلذع. يعترب هذا الورم نادرا وقد يظهر على �سكل اآفة كي�سية يف الثدي والذي ميكن ت�سخي�سه ب�سكل خاطئ وب�سهولة على اأنه ورم خبيث. نعر�ض هنا حالة مري�سة تبلغ من العمر 36 عاما قدمت اإىل عيادة الثدي يف م�ست�سفى جامعة ال�سلطان قابو�ض يف م�سقط، �سلطنة ُعمان يف �سنة 2018 وكان لديها كتلة يف ثديها الأي�رس. اأظهر جهاز املوجات فوق ال�سوتية وجود اآفة كي�سية معقدة ذات مكون وعائي �سلب. كانت خزعة الإبرة اللبية املوجهة الن�سيجي املر�سي الت�رسيح واأكد اجلراحي ال�ستئ�سال اإجراء مت اخلاليا. �سايف عرقي غدي ورم بوجود توحي ال�سوتية فوق باملوجات ت�سخي�ض ورم غدي عرقي �سايف اخلاليا يف الثدي. تعترب هذه احلالة الوىل على الإطالق التي يتم فيها ت�سخي�ض هذا الورم با�ستخدام خزعة الإبرة اللبية. ي�سكل ت�سخي�ض هذا الورم حتديا لذلك فاإن الوعي بخ�سائ�ض الت�رسيح املر�سي الن�سيجي واملوجات فوق ال�سوتية للورم مهم جدا لتفادي الت�سخي�ض اخلاطئ واملبالغة يف العالج. الكلمات املفتاحية: غدد ناحتة؛ ثدي؛ ورم نهايات الغدد العرقية ؛ ورم الغدة العرقية احلميد؛ اأورام الغدة العرقية؛ تقرير حالة؛ ُعمان. clear cell hidradenoma of the breast diagnosed on a core needle biopsy a case report and review of the literature *sara s. h. al-adawi,1 badriya al-qasabi,2 maiya al-bahri,3 adil aljarrah,4 suad al-aghbari4 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e357–361, epub. 5 oct 20 submitted 3 jan 20 revision req. 1 mar 20; revision recd. 30 mar 20 accepted 27 apr 20 the best of the author’s knowledge, this is the first case report to describe clear cell hidradenoma (cch) of the breast diagnosed using core needle biopsy. only four other reports have been able to diagnose this condition on cytological examination prior to excision with the aid of a fine needle aspiration. in addition, this report presents a review of the existing literature on this rare entity. case report a 36-year-old female patient presented to the onestop breast clinic at the sultan qaboos university hospital, muscat, oman, in 2018 with a four-month history of a painless lump in her left breast. she denied any history of pain, fever, nipple discharge or trauma. clear cell hidradenoma (cch) is a rare benign tumour of the eccrine glands. it is commonly observed in the face and upper extremities. cch of the breast is extremely rare and only 33 cases have been reported worldwide at the time of this report.1–26 cch has been classified by hertel et al. as a type of true adenoma of the breast.2 the diagnosis can be challenging as its radiological and cytological findings can mimic other conditions of the breast. in addition, the breast is a modified apocrine gland; therefore histogenetically, cch of the breast can arise from both eccrine glands and mammary ducts.7 finck et al. suggested that cch of the breast is a form of mammary ductal papillomatosis, thus explaining why cch may present as a mass in the deep tissues of the breast with no apparent relation to the skin.1 to this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.017 case report https://creativecommons.org/licenses/by-nd/4.0/ clear cell hidradenoma of the breast diagnosed on a core needle biopsy a case report and review of the literature 358 | squ medical journal, august 2020, volume 20, issue 3 her mother had been diagnosed with breast cancer at the age of 45. clinical examination revealed a single, firm, nontender, mobile lump measuring 2 × 2 cm in the left breast at the three o’clock position. it was not fixed to the skin. overlying skin, nipple and areola were normal. ipsilateral lymph nodes were not enlarged. an ultrasound of the breast revealed a complex cystic mass with a solid, vascular component seen in the posterolateral border, characteristic of a clear cell hidradenoma of the breast [figure 1]. the lesion was classified as breast imaging reporting and data system category 4. the patient underwent ultrasoundguided 14 gauge core needle biopsy, targeting the solid component. the cystic component was completely collapsed after the fourth pass. microscopic examination of the biopsy showed nodules formed of sheets of uniform cells traversed by fibrovascular septa. the cells had round nuclei with even chromatin. some cells had intracytoplasmic vacuoles containing mucin. the cytoplasm varied from eosinophilic to clear. there was no nuclear pleomorphism, mitosis or necrosis [figure 2]. the cells were diffusely positive for p63 and negative for androgen receptor, oestrogen receptor, gross cystic disease fluid protein 15 and carcinoembryonic antigen [figure 3]. the pathological diagnosis was consistent with clear cell hidradenoma. surgical excision of the tumour was recommended and was performed six months later. ultrasound of the breast before the surgery showed the cystic component had reaccumulated and become larger than indicated in the previous scan. microscopic examination of the resected specimen revealed breast tissue with well-circumscribed but unencapsulated multinodular lesion, formed by sheets of uniform cells and fibrovascular septa [figure 4]. the cytomorphology of the cells and the immunoprofile was similar to the biopsy, confirming the diagnosis of clear cell hidradenoma. the postoperative course was uneventful. the patient has been disease free during the follow-up period of 18 months. discussion cch is an uncommon benign adnexal skin tumour, originating from eccrine sweat glands of the superficial and deep layers of the dermis. other names include figure 1: ultrasound of a lesion in the left breast of a 36-year-old female patient demonstrating a cystic mass with solid, vascular component in the posterolateral border. figure 2: haemotoxylin and eosin stain at x20 magnification of the core needle biopsy demonstrating sheets of apocrine cells with clear cytoplasm, separated by fibrous septa. figure 3: p63 immune stain at x20 magnification showing diffuse nuclear positivity in tumour cells. figure 4: haematoxylin and eosin stain at x20 magnification of the resected specimen revealing a lesion with nodules formed of sheets of uniform cells traversed by fibrovascular septa. the cytomorphology of the cells is bland. sara s. h. al-adawi, suad al-aghbari, badriya al-qasabi, maiya al-bahri and adil aljarrah case report | 359 table 1: details of cases of clear cell hidradenoma published between 1968–20191–26 author and year of publication gender age in years breast side location size of largest diameter in cm presenting complaint finck et al.1 (1968) f 46 ns upper inner quadrant 4 nipple discharge f 61 right upper outer quadrant 3 breast mass m 42 left subareolar 2 nipple enlargement f 42 left nipple 0.7 (multiple) nipple discharge f 60 ns subareolar ns breast mass f 30 right nipple 1.5 breast mass hertel et al.2 (1976) f 57 ns subareolar 2 nipple discharge kobayashi et al.3 (1994) m 63 left nipple 3 nipple discharge cyrlak et al.4 (1995) f 25 right inner quadrant 7 breast mass and nipple discharge kumar and verma5 (1996) f 75 left upper inner quadrant 3 breast mass kaise et al.6 (1996) f 52 ns upper inner quadrant ns ns domoto et al.7 (1998) f 58 left outer lower quadrant 3 breast mass m 44 left subareolar 2 nipple discharge shimizu et al.8 (1999) m 60 right upper inner quadrant 3.5 breast mass yamada et al.9 (2001) f 41 left outer upper 2 breast mass kosugi et al.10 (2002) f 25 right axillary tail 2 breast mass honnma et al.11 (2002) m 77 ns subareolar ns ns ghai and bukhanov12 (2004) f 77 left axillary tail 2.5 breast mass kim et al.13 (2005) f 41 right ns ns breast mass kazakov et al.14 (2007) f 55 left upper outer quadrant 1.6 breast mass ohi et al.15 (2007) f 55 left upper inner quadrant 0.8 breast mass girish et al.16 (2007) f 49 left subareolar 3 recurrent breast mass dhingra et al.17 (2007) f 60 right upper outer quadrant 4.5 breast mass mote et al.18 (2009) f 40 left outer quadrant 5 breast mass cho et al.19 (2010) f 56 left axillary tail 3 breast mass grampurohit et al.20 (2011) m 18 left subareolar 4 breast mass and nipple discharge orsaria and mariuzzi21 (2013) m 39 left upper outer quadrant 1 recurrent breast mass ogata et al.22 (2013) m 38 right ns 1.8 breast mass and nipple discharge sehgal et al.23 (2014) f 30 left upper outer quadrant 2.5 breast mass kashyap and jyoti24 (2015) f 23 left subareolar 4.5 breast mass ano-edward et al.25 (2018) m 62 left ns 6 breast mass jaitly et al.26 (2019) f 20 right upper outer quadrant 5 breast mass current case f 32 left upper outer quadrant 3 breast mass f = female; ns = not specified; m = male. clear cell hidradenoma of the breast diagnosed on a core needle biopsy a case report and review of the literature 360 | squ medical journal, august 2020, volume 20, issue 3 eccrine acrospiroma, nodular hidradenoma and solidcystic hidradenoma.7,12,23 cch may be associated with sporadic or hereditary genetic mutations.14,27,28 it is mostly observed in the age group of 20–50 years, and is twice as common among women than men.19 it is known to commonly occur in the scalp, face, upper extremity, axilla, trunk and pubic region. however, cch of the breast is extremely rare; only 33 cases have been reported [table 1]. cch can easily be confused with other causes of breast lumps and misdiagnosis can lead to unnecessary anxiety and over-treatment. hertel et al. classified cch of the breast as a type of true adenoma of the breast.2 it has two distinct histogenetic origins, one from skin adnexal glands and another from mammary ducts.7,20 cch of the breast shows features similar to those occurring elsewhere in the body.17 a review of the 33 reported cases revealed that it has a female predominance in ages ranging from 18–77 years. there is a predominance of the left breast and it occurs in the nipple and subareolar region in more than 50% of cases.7,17 the size can range from 0.7–7 cm. the most common presenting complaint is a painless breast mass but some patients can also present with nipple discharge, bluish discolouration of the overlying skin or ulceration.5,26 cch can easily be misdiagnosed preoperatively as a carcinoma of the breast. to avoid misdiagnosis, the patient should undergo imaging after a breast mass has been identified. radiological features of cch are non-specific, but described as superficial, well circumscribed and consisting of a cystic and solid portion. the cystic portion may appear complex due to haemorrhage while the solid portion is typically hypervascular on doppler examination. aspiration of the lesion reveals clear or haemorrhagic fluid content. in all reported cases, only one case correctly diagnosed cch based on fine needle aspiration cytology.3 the remaining cases were diagnosed on histopathology of the excised specimen. one case reported that the initial cytology was suggestive of malignancy and the diagnosis of cch was made only after mastectomy.5 in another case, the intraoperative frozen histopathology section was inconclusive, therefore surgery was abandoned until the permanent preparation reported cch.9 the current case distinguishes itself from others as the diagnosis of cch was based on a core needle biopsy of the solid component prior to offering treatment, thus sparing the patient from an unnecessary mastectomy or wide local excision. on histopathology, the tumour is located in the dermis, lobulated and well circumscribed. the solid portion is vascular, consisting of round polyhedral cells that contain a round nucleus, eosinophilic cells with clear glycogen-rich cytoplasm and transitional cells in between.5,8,20,22,28 the clear cells are typically periodic acid-schiff diastase resistant and stain positive for p63, keratin, epithelial membrane antigen, carcinoembryonic antigen, s-100 and vimetin but negative for alpha-smooth muscle actin, cluster of differentiation-10, oestrogen receptor and progesterone receptor.15,17,20 the only myoepithelial marker that stains positively is p63 and it is therefore an important marker to consider in the diagnosis of clear cell hidradenoma.15 treatment of cch in the breast is complete surgical excision of the tumour with safe margins. incomplete excision may result in recurrence. malignant transformation is reported in 5% and is difficult to predict because the clinical presentation and histology are similar.16,18,20 awareness of this diagnosis and its characteristic histological and sonographic appearance is important. with correct diagnosis, the appropriate management can be undertaken, negating unnecessary overor under-treatment. in the current case, the patient was successfully diagnosed with cch at the one-stop breast clinic using a 14 gauge core needle biopsy. with this diagnosis, the patient was offered complete excision with appropriate margins. by doing so, the risk of recurrence was minimised, while avoiding unwarranted breast resections, chemotherapy or radiotherapy. conclusion this is the first case report that describes cch of the breast diagnosed using core needle biopsy. awareness of the radiological and histopathological appearance of this extremely rare benign tumour is important to reduce misdiagnosis and over-treatment. cch should be suspected as a differential diagnosis of complex cystic breast lesions. it should be remembered that fine needle aspiration cytology and core needle biopsies play an important role in the pre-operative diagnosis. references 1. finck fm, schwinn cp, keasbey le. clear cell hidradenoma of the breast. cancer 1968; 22:125–35. https://doi.org/10.1002/10970142(196807)22:1<125::aid-cncr2820220115>3.0.co;2-3. 2. hertel bf, zaloudek c, kempson rl. breast adenomas. cancer 1976; 37:2891–905. https://doi.org/10.1002/10970142(197606)37:6<2891::aid-cncr2820370647>3.0.co;2-p. 3. kobayashi t, miyake y, shinagawa m, maeda y, tsujimoto s, miura m. clear cell hidradenoma of the male breast nipple. j jpn soc clin cytol 1994; 33:745–6. https://doi.org/10.5795/ jjscc.33.745. https://doi.org/10.1002/1097-0142%28196807%2922:1%3c125::aid-cncr2820220115%3e3.0.co%3b2-3 https://doi.org/10.1002/1097-0142%28196807%2922:1%3c125::aid-cncr2820220115%3e3.0.co%3b2-3 https://doi.org/10.1002/1097-0142%28197606%2937:6%3c2891::aid-cncr2820370647%3e3.0.co%3b2-p https://doi.org/10.1002/1097-0142%28197606%2937:6%3c2891::aid-cncr2820370647%3e3.0.co%3b2-p https://doi.org/10.5795/jjscc.33.745 https://doi.org/10.5795/jjscc.33.745 sara s. h. al-adawi, suad al-aghbari, badriya al-qasabi, maiya al-bahri and adil aljarrah case report | 361 4. cyrlak d, barr rj, wile ag. malignant eccrine acrospiroma of the breast. int j dermatol 1995; 34:271–3. https://doi. org/10.1111/j.1365-4362.1995.tb01595.x. 5. kumar n, verma k. clear cell hidradenoma simulating breast carcinoma: a diagnostic pitfall in fine-needle aspiration of breast. diagn cytopathol 1996; 15:70–2. 6. kaise h, sakamoto g, akiyama f, iwase t, yoshimoto m, tsuzuku m, et al. clear cell hidradenoma of the breast-a case report. nyuugann no rinsyou 1996; 11:113–16. 7. domoto h, terahata s, sato k, tamai s. nodular hidradenoma of the breast: report of two cases with literature review. pathol int 1998; 48:907–11. https://doi.org/10.1111/j.1440-1827.1998. tb03860.x. 8. shimizu k, nishikawa m, sasaki h, misaka k, ueda y, fujimori t, et al. cytologic findings of clear cell hidradenoma in the male breast skin: a case report. j jpn soc clin cytol 1999; 38:342–7. https://doi.org/10.5795/jjscc.38.342. 9. yamada m, miyata a, kawai k, kawano h. clear cell hidradenoma associated with hemartoma of the breast report of a case. j jpn surg assoc 2001; 62:53–7. https://doi. org/10.3919/jjsa.62.53. 10. kosugi i, kasahara y, tatsuzawa a. a case of clear cell hidradenoma mimicking a cystic tumor of the breast. j jpn surg assoc 2002; 63:571–4. https://doi.org/10.3919/jjsa.63.571. 11. honnma n, takubo k, kuroiwa k, arai t, sawabe m, akiyama f, et al. clear cell hidradenoma of the male breast – a case report. nyuugann no rinsyou 2002; 17:346–8. 12. ghai s, bukhanov k. eccrine acrospiroma of breast: mammographic and ultrasound findings. clin radiol 2004; 59:1142–4. https://doi.org/10.1016/j.crad.2004.05.002. 13. kim yo, jeon cw, chang hk. fine needle aspiration cytology of eccrine acrospiroma of the breast: report of a case misdiagnosed as ductal carcinoma. korean j cytopathol 2005; 16:31–5. 14. kazakov dv, vanecek t, belousova ie, mukensnabl p, kollertova d, michal m. skin-type hidradenoma of the breast parenchyma with t(11;19) translocation: hidradenoma of the breast. am j dermatopathol 2007; 29:457–61. https://doi. org/10.1097/dad.0b013e318156d76f. 15. ohi y, umekita y, rai y, kukita t, sagara y, sagara y, et al. clear cell hidradenoma of the breast: a case report with review of the literature. breast cancer 2007; 14:307–11. 16. girish g, gopasetty m, stewart r. recurrent clear cell hidradenoma of the breast: a case report. internet j surg 2007; 10:1–3. https://doi.org/10.5580/1a7a. 17. dhingra kk, mandal s, khurana n. an unusual case of nodular hidradenoma of breast. iran j pathol 2007; 2:80–2. 18. mote dg, ramamurti t, naveen babu b. nodular hidradenoma of the breast: a case report with literature review. indian j surg 2009; 71:43–5. https://doi.org/10.1007/s12262-009-0010-y. 19. cho ke, son ej, kim ja, youk jh, kim ek, kwak jy, et al. clear cell hidradenoma of the axilla: a case report with literature review. korean j radiol 2010; 11:490–2. https://doi. org/10.3348/kjr.2010.11.4.490. 20. grampurohit vu, dinesh us, rao r. nodular hidradenoma of male breast: cytohistological correlation. j cytol 2011; 28:235–7. https://doi.org/10.4103/0970-9371.86364. 21. orsaria m, mariuzzi l. recurrent eccrine hidradenoma of the breast in a male patient: problems in differential diagnosis. our dermatol online 2013; 4:215–17. https://doi.org/10.7241/ ourd.20132.52. 22. ogata h, kanazawa s, saito f, kubota y, mitsuda a, kaneko h. male breast clear cell hidradenoma —a case report and literature review—. nihon rinsho geka gakkai zasshi 2013; 74:1193–7. https://doi.org/10.3919/jjsa.74.1193. 23. sehgal s, goyal p, ghosh s, mittal d, kumar a, singh s. clear cell hidradenoma of breast mimicking atypical breast lesion: a diagnostic pitfall in breast cytology. rare tumors 2014; 6:5343. https://doi.org/10.4081/rt.2014.5343. 24. kashyap s, jyoti k. acrospiroma of breast: a rare clinically significant differential diagnosis in breast lump a case report. j evol med dent sci 2015; 4:12614–17. https://doi.org/10.14260/ jemds/2015/1817. 25. ano-edward gh, amole io, adesina sa, ajiboye oa, lasisi me, jooda rk. nodular hidradenoma of the breast: a case report. alex j med 2018; 54:367–8. https://doi.org/10.1016/j. ajme.2018.04.004. 26. jaitly v, jahan-tigh r, belousova t, zhu h, brown r, saluja k. case report and literature review of nodular hiradenoma, a rare adnexal tumor that mimics breast carcinoma, in a 20-yearold woman. lab med 2019; 50:320–5. https://doi.org/10.1093/ labmed/lmy084. 27. behboudi a, winnes m, gorunova l, oord jj van den, mertens f, enlund f, et al. clear cell hidradenoma of the skin—a third tumor type with a t(11;19)-associated torc1–maml2 gene fusion. genes chromosomes cancer. 2005 feb 23;43(2):202–5. 28. kocjan g. diagnostic dilemmas in fnac cytology: difficult breast lesions. in: fine needle aspiration cytology: diagnostic principles and dilemmas. heidelberg, germany: springer verlag gmbh, 2006. pp. 181–211. https://doi.org/10.1007/3540-31412-1_9. https://doi.org/10.1111/j.1365-4362.1995.tb01595.x https://doi.org/10.1111/j.1365-4362.1995.tb01595.x https://doi.org/10.1111/j.1440-1827.1998.tb03860.x https://doi.org/10.1111/j.1440-1827.1998.tb03860.x https://doi.org/10.5795/jjscc.38.342 https://doi.org/10.3919/jjsa.62.53 https://doi.org/10.3919/jjsa.62.53 https://doi.org/10.3919/jjsa.63.571 https://doi.org/10.1016/j.crad.2004.05.002 https://doi.org/10.1097/dad.0b013e318156d76f https://doi.org/10.1097/dad.0b013e318156d76f https://doi.org/10.5580/1a7a https://doi.org/10.1007/s12262-009-0010-y https://doi.org/10.3348/kjr.2010.11.4.490 https://doi.org/10.3348/kjr.2010.11.4.490 https://doi.org/10.4103/0970-9371.86364 https://doi.org/10.7241/ourd.20132.52 https://doi.org/10.7241/ourd.20132.52 https://doi.org/10.3919/jjsa.74.1193 https://doi.org/10.4081/rt.2014.5343 https://doi.org/10.14260/jemds/2015/1817 https://doi.org/10.14260/jemds/2015/1817 https://doi.org/10.1016/j.ajme.2018.04.004 https://doi.org/10.1016/j.ajme.2018.04.004 https://doi.org/10.1093/labmed/lmy084 https://doi.org/10.1093/labmed/lmy084 https://doi.org/10.1007/3-540-31412-1_9 https://doi.org/10.1007/3-540-31412-1_9 clinical & basic research squ med j, december 2010, vol. 10, iss. 3, pp. 354-360, epub. 14th nov 10 submitted 19th march 10 revision req. 15th june 10, revision recd. 7th august 10 accepted 15th august 10 <ì� ë �ç �√⁄̌<ïá̌^•̌<ìè◊€¬<]üqc<ç√e<ìœèœç÷]<^√⁄˘]<å]çäfi˜<í¬^√é÷]<üëáíj÷] ìèïü⁄<ìõüà⁄<ìfi]çe<t¯√÷ ìëå^√jâ]<ì√q]ü⁄    490  2005 2001  22  1210  14 22  7  1114  5 4  7       abstract: objectives: this study is a single institution retrospective evaluation of imaging findings of small bowel obstruction (sbo) after retrocolic antegastric roux-en-y gastric bypass surgery for morbid obesity. methods: the radiological database of 490 patients who underwent gastric bypass surgery for morbid obesity from january 2001 2005 at the royal victoria hospital mcgill university health center was searched for sbo complications related to the procedure. there were 22 cases of small bowel obstruction related to the procedure. ten patients had abdominal and pelvic computed tomography (ct) scans, 12 patients had upper gastrointestinal (ugi) and small bowel follow through (sbft). results: among 22 cases of sbo, 14 cases were due to anastomotic stenosis or adhesion, 7 due to internal hernia and one to jejuno-jejunal intussusception. among the 14 patients with sbo related to adhesion and anastomotic narrowing, 11 patients were managed medically and 3 cases managed surgically. ct scans correctly diagnosed 4 out of 5 cases including the 3 patients managed surgically and ugi and sbft examinations diagnosed the remaining 9 cases that were managed medically. among the 7 patients with internal hernias, ct scans correctly diagnosed 2 out of 4 cases, while ugi and sbft examinations correctly diagnosed 1 out of 3. the jejuno-jejunal intussusception was correctly diagnosed by ct scan. conclusion: the most frequent cause of sbo is anastomotic narrowing or adhesion. ct scan remains the most appropriate imaging modality in diagnosing acute presentation of sbo caused by internal hernia or adhesion/anastomotic narrowing. ugi and sbft appear more appropriate for diagnosing the subacute insidious presentation of adhesive partial sbo. keywords: gastric bypass surgery; small bowel obstruction; morbid obesity; anastomotic narrowing imaging of small bowel obstruction following gastric bypass surgery for morbid obesity a retrospective review *rashid al-sukaiti,1 lawrence stein,2 nicholas christou,2 benoit mesurolle,2 giovanni p artho2 clinical & basic research 1department of radiology and molecular imaging, sultan qaboos university hospital, muscat, oman; 2royal victoria hospital, department of diagnostic radiology and surgery, mcgill university health center, montreal, canada. *corresponding author email: rsketty@hotmail.com rashid al-sukaiti, lawrence stein, nicholas christou, benoit mesurolle and giovanni p artho clinical and basic research | 355 obesity has recently increased in prevalence and severity throughout the world, particularly in north america, and it has become a leading worldwide health concern.1-3 patients who have a body mass index (bmi) of 18.5–24.9 kg per m2 are considered normal, while those with a bmi equal to or more than 30 kg per m2 are obese. currently for those patients with intractable morbid obesity, defined as having a bmi of more than 40 kg per m2, gastric bypass surgery offers the only option for achieving meaningful and sustainable weight loss.3-5 even dietary therapy together with exercise, pharmacological and behavioural therapy is rarely successful in these patients.1,3,4 the gastric bypass technique was introduced by mason and ito in 1967.6 in 1994, wittgrove et al. described the laparoscopic approach widely employed today.7 the roux y-limb gastric bypass surgery is currently considered the main treatment option in patients with intractable morbid obesity as it combines both restrictive and malabsorption approaches.1,4,5,8,9 the roux y-limb gastric bypass surgery can be performed either by the open or laparoscopic method, with the laparoscopic approach being preferred as it lowers the risk of wound related complications, and has the advantages of shorter hospitalisation and faster recovery. the roux y-limb procedure involves the creation of a gastric pouch. the small bowel is transected at about 45 cm distal to the ligament of treitz, and 75 cm below this transection a side to side anastomosis is created between the rouxen-y and the pancreaticobiliary limb. the rouxen-y limb is either antegastric or retrogastric and is anastomosed to the gastric pouch via a retrocolic or antecolic approach.10 the main procedure at our institution is the retrocolic, antegastric approach [figures 1 and figures 2 a & b]. imaging is crucial in the work-up of complications related to this procedure including anastomotic leaks, bowel obstruction, abscesses, fistulas and haematomas.11 it also plays an important role in the diagnosis of small bowel obstruction which could be due to adhesions or an internal hernia.11 blacher et al.11 reported on 23 patients with small bowel obstruction following laparoscopic roux-en-y limb gastric bypass surgery using the antegastric retrocolic approach. fourteen patients had internal hernias, while the remaining nine patients had small bowel obstruction due to adhesions. the prevalence of small bowel obstruction due to internal hernia was higher in blacher et al.'s study as compared to our series,11 a complication that appears to be more common with the laparoscopic approach. the aim of this study was therefore to evaluate imaging findings of small bowel obstruction (sbo) after retrocolic antegastric roux-en-y gastric bypass surgery for morbid obesity. methods following approval by the institutional review board, the radiological and surgical databases of 490 patients, who underwent gastric bypass surgery for morbid obesity at our institution from 2001-2005, were searched for sbo complications related to the procedure. given the retrospective nature of the study, the requirement for informed consent was waived. there had been increase in the numbers of gastric bypass cases performed laparoscopically at our institution since october 2003. therefore there were a total of 273 patients who underwent gastric bypass by the laparoscopic approach while the remaining 217 had the open approach. among the 490 patients, there were 22 cases of small bowel obstruction (sbo). among the 22 cases of sbo, 10 patients had computed tomography (ct) scans, 12 patients had upper gastrointestinal (ugi) examinations and one patient had both ugi and ct. the imaging findings were reviewed by two abdominal radiologists in consensus, and the clinical characteristics were reported according to advances in knowledge 1. this study showed the importance of being familiar with the approach of gastric bypass surgery performed in order to assist in interpreting imaging findings of small bowel obstruction following retrocolic antegastric roux-en-y gastric bypass surgery for morbid obesity. application to patient care 1. this study showed the importance of prompt diagnosis of causes of small bowel obstruction in morbid obese patients who have undergone retrocolic antegastric roux-en-y gastric bypass surgery. physicians should take this into account in order to achieve better patient management. imaging of small bowel obstruction following gastric bypass surgery for morbid obesity a retrospective review 356 | squ medical journal, december 2010, volume 10, issue 3 the time after surgical management of sbo. the imaging findings were recorded and compared to the surgical findings, when applicable, and to the literature. all ct scans were performed with either a 4 or 16 slice general electric scanner (ge healthcare) with preference being given to a 16 slice ct scan whenever available. patients received 125 ml of optiray 350 which was administered at a rate of 2–3 ml per second with a power injector. in patients who were suspected to have an anastomotic leak immediately postoperatively, ugi and small bowel follow through (sbft) examinations were performed using water soluble contrast. rapid sequence images of gastrojejunal anastomosis were obtained in different projections. overhead radiographs were obtained at 15–20 minute intervals until contrast opacified the jejunojejunal anastomosis. in patients who presented beyond the immediate postoperative period, and in whom anastomotic leaks were not suspected, ugi and sbft examinations were performed using thin barium; overhead radiographs were obtained following fluoroscopic examination at 15–20 minutes. results imaging findings were reviewed retrospectively by two abdominal radiologists who were blinded to the level and cause of the sbo. there were 22 cases of sbo: 14 cases were due to anastomotic narrowing/ adhesions; there were 7 cases of internal hernia (3 of them were at transverse mesocolon defect and 4 were at small bowel mesentry defect) and one case of jejuno-jejunal intussusception. no peterson hernia was encountered [table 1]. the mean time from roux-en-y gastric bypass surgery to the diagnosis of adhesive small bowel obstruction was 100 days, while that due to internal hernia was 255 days mean. in 10 out of 22 patients the presentation was acute with the most common presenting symptoms being abdominal pain, vomiting, and distention. these patients underwent a ct scan. in the remaining 12 cases, the presentation was subacute with insidious onset of intermittent postprandial abdominal pain and nausea. these patients underwent ugi and figure 1: gastric bypass surgery using antegastric, retrocolic approach. 1) gastric pouch; 2) excluded stomach; 3) roux limb; 4) pancreaticobiliary limb; gastrojejunal anastomosis (thin arrow); (thick arrow) ejuno-jejunal anastomosis. figures 2a & b: fluoroscopic spot image obtained at upper gastrointestinal examination showing a normal postoperative anatomy following a gastric bypass procedure. 1) gastric pouch; 2) side to side gastrojejunal anastomosis; 3) roux limb ; 4) pancreaticobiliary limb; 5) side to side anastomosis between pancreaticobiliary limb, and roux limb. rashid al-sukaiti, lawrence stein, nicholas christou, benoit mesurolle and giovanni p artho clinical and basic research | 357 sbft exams. seven of these cases were due to internal hernia, three due to adhesion, while one case was due to jejuno-jejunal intussusception. the remaining 11 cases of presumed partial small bowel obstruction were managed conservatively [table 2]. among the adhesive small bowel obstructions, 13 cases were obstruction at jejuno-jejunal anastomosis and most cases were managed conservatively except for two cases that required surgical management. there was one case of adhesive sbo at transverse mesocolon that was managed surgically. among surgically managed sbo, ugi correctly diagnosed one of three internal hernias, one case was labelled incorrectly as adhesion, and one case was equivocal. while one case of adhesive sbo was correctly diagnosed using ugi, ct correctly diagnosed 2 of the 4 internal hernias, 2 of the 3 adhesions, and one case of jejuno-jejunal intussusception. among the medically managed partial sbo, 9 cases out of 11 were diagnosed using ugi and two cases using ct. in two of the four cases of small bowel mesentry internal hernia, there was herniation of both the roux-en-y and pancreaticobiliary limb, while the remaining two cases had herniation of the rouxen-y limb only. among the 7 patients with internal hernia, 5 had a laparoscopic approach and 2 had the open approach. among the 14 patients with adhesive/anastomotic narrowing sbo, 7 had the laparoscopic approach and the remaining 7 had the open approach. discussion the interpretation of sbo imaging findings following gastric bypass surgery can be challenging figure 3: potential sites of small bowel internal hernia following gastric bypass surgery are: 1) transverse mesocolon defect; 2) roux-en-y limb mesentry, and 3) distal jejuno-jejunal mesentry. figure 4: contrast enhanced image of the upper gastrointestinal tract demonstrates significant dilatation of the roux limb (thin white arrow) with delay in passage of contrast at the level of the transverse mesocolon defect (thick white arrow). surgery revealed sbo at the transverse mesocolon defect due to adhesion. figures 5a, b & c: small obstruction caused by internal hernia at transverse mesocolon defect. 5a & b: transverse computed tomography (ct) images show dilated roux-en-y limb (arrow) anteromedial to excluded stomach(s). 5c: transverse ct images show cluster of small bowel loops against the mid-abdominal wall with no overlying omentum and displacement of the transverse colon (curved arrow) posterocentrally. imaging of small bowel obstruction following gastric bypass surgery for morbid obesity a retrospective review 358 | squ medical journal, december 2010, volume 10, issue 3 for the radiologist. usually, these patients present with symptoms of abdominal pain, nausea and vomiting which are nonspecific in such patients. imaging can play an important role in classifying sbo according to level of obstruction and cause (i.e. adhesion or internal hernia) [figure 3]. in order to interpret the imaging findings, the radiologist has to be familiar with the gastric bypass surgery approach performed at his institution. we have reported our experience of sbo imaging findings following retrocolic antegastric roux-en-y gastric bypass surgery. the incidence of sbo in our series was 4% which is similar to the rates reported in the literature.10-14 small bowel obstruction following gastric bypass surgery is mainly due to adhesions or anastomotic stenosis. internal hernias occur to a lesser extent and intussusception is rarely a cause.11,15 small bowel obstruction due to anastomotic narrowing or adhesion occurs in the gastrojejunal or jejunojejunal anastomotic region. in our series, 13 cases out of 14 had obstruction at jejunojejunal anastomosis, and one case had obstruction at gastrojejunal anastomosis. the imaging findings on ugi and ct varied between abrupt angulation from a dilated proximal bowel loop to a collapsed distal loop and delay in passage of contrast beyond the transition point on ugi [figure 4]. potential sites for internal hernia following gastric bypass surgery are transverse mesocolon defect, small bowel mesentery defect and the space behind the roux limb.16 in our series, 7 out of 22 (32%) cases presented with internal hernias, 3 of them were figures 6a & b: small bowel obstruction caused by internal hernia at the jejunal mesenteric defect. 6a: transverse computed tomography (ct) images show significant dilatation of the excluded stomach(s). 6b: transverse ct images show significant dilatation of the pancreaticobiliary and roux limbs with a cluster of these bowel loops lying against the left abdominal wall with no overlying omentum. legend: es = excluded stomach; pbl = pancreaticobiliary limb; rl = roux-en-y limb table 1: level and cause of small bowel obstruction in 22 patients following roux-en-y gastric bypass surgery gastrojejunal anastomosis jejunojejunal anastomosis adhesion 1 13 internal hernia 3 4 intussusception 0 1 table 2: management of 22 cases of small bowel obstruction following roux-en-y gastric bypass surgery surgical management conservative management adhesion gj anastomosis 1 0 internal hernia gj anastomosis 3 0 adhesion at j-j anastomosis 2 11 internal hernia at j-j anastomosis 4 0 intussusception at j-j anastomosis 1 0 gj = gastrojejunal; j-j = jejuno-jejunal rashid al-sukaiti, lawrence stein, nicholas christou, benoit mesurolle and giovanni p artho clinical and basic research | 359 internal hernias at transverse mesocolon defect and 4 were at small bowel mesentry defect. a possible predisposing factor for developing internal hernia in these patients is rapid massive weight reduction which results in decrease intraperitoneal fat that may enlarge the mesenteric defect.11 since the rouxen-y limb is anastomosed to the gastric pouch in a retrocolic, antegastric approach at our institution, the ct imaging findings of internal hernia through the transverse mesocolon defect were a cluster of small bowel loops lying anterior to the body of excluded stomach and against the mid-abdominal wall with no overlying omentum. in addition, there was displacement of transverse colon dorsally and centrally [figures 5 a, b & c].17 in the case of small bowel mesenteric hernias, the ct imaging findings were a cluster of small bowel loops against left abdominal wall with no overlying omentum and posteromedial displacement of the descending colon.11,17 in two of the four cases of internal hernia through the small bowel mesentry defect, there was herniation of both the roux-en y and pancreaticobiliary limb which resulted in dilatation of both limbs and the gastric remnant [figures 6 a & b ]. in our series, we did not encounter a case of peterson hernia. intussusception is very rare following gastric bypass surgery, with few reported cases.11,15,18 in our series, we had one case that presented with jejuno-jejunal intussusception that required emergency exploratory laparotomy. the diagnosis was made via a ct scan, the imaging findings were a target like appearance with invagination of mesenteric fat and vessels in the intussuscipiens [figure 7]. conclusion the most frequent cause of sbo following gastric bypass surgery is anastomotic narrowing or adhesions. ct scan remains the most appropriate imaging modality in diagnosing acute presentations of sbo caused by internal hernias or adhesions. ugi and sbft appear more appropriate in diagnosing the subacute insidious presentation of adhesive or anastomotic narrowing of a partial sbo. while small bowel obstruction following gastric bypass surgery may represent a diagnostic challenge to the radiologist, the knowledge of surgical approach and clinical presentation will help in identifying the level and cause of sbo, thus helping in operative planning. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. fisher bl, schauer p. medical and surgical options in the treatment of severe obesity. am j surg 2002; 184:9–16s. 2. allison db, fontaine kr, manson je, stevens j, vanitallie tb. annual deaths attributable to obesity in the united states. jama 1999; 282:1530–8. 3. carucci lr, turner ma, conklin rc, demaria ej, kellum jm, sugerman hj. roux-en-y gastric bypass surgery for morbid obesity: evaluation of postoperative extraluminal leaks with upper gastrointestinal series. radiology 2006; 238:119–27. 4. gastrointestinal surgery for severe obesity: national institutes of health consensus development conference statement. am j clin nutr 1992; 55:615–195. 5. nguyen nt, ho hs, palmer ls, wolfe bm. a comparison study of laparoscopic versus open gastric bypass for morbid obesity. j am coll surg 2000; 191:149–55. 6. mason ee, ito c. gastric bypass in obesity. surg clin north am 1967; 47:1345–51. 7. wittgrove ac, clark gw, tremblay lj. laparoscopic gastric bypass, roux-en-y: preliminary report of five cases. obes surg 1994; 4:353–7. 8. brolin re. update: nih consensus conference figure 7: small bowel obstruction caused by intussusception at the jejuno-jejunal anastomosis. transverse computed tomography images show multilayered appearance of small bowel intussusception. the intussusceptum (white thick arrow), with accompanying mesenteric fat (white thin arrow) is surrounded by the thick walled intussuscipiens (black arrow). imaging of small bowel obstruction following gastric bypass surgery for morbid obesity a retrospective review 360 | squ medical journal, december 2010, volume 10, issue 3 gastrointestinal surgery for severe obesity. nutrition 1996; 12:403–4. 9. marema rj. laporoscopic roux-en-y gastric bypass: a step by step approach. j am coll surg 2005; 200:979–82. 10. fobi ma, lee h, holness r, cabinda d. gastric bypass operation for obesity. world j surg 1998; 22:925–35. 11. blacher a, federle mp, ikramuddin s, schauer pr. gastrointestinal complications of laparoscopic rouxen-y gastric bypass surgery: clinical and imaging findings. radiology 2002; 223:625–32. 12. schauer pr, ikramuddin s. laparoscopic surgery for morbid obesity. surg clin n am 2001; 81:1145–78. 13. higa kd, boone kb, ho t, davis og. laparoscopic roux-en-y gastric bypass for morbid obesity: technique and preliminary results of our first 400 patients. arch surg 2000; 135:1029–33. 14. schauer pr, ikramuddin s, gourash w, ramanathan r, luketich j. outcomes after laparoscopic rouxen-y gastric bypass for morbid obesity. ann surg 2000; 232:515–29. 15. duane tm, wholgemuth s, ruffin k. intussusception after roux-en-y gastric bypass. am surg 2000; 66:82–4. 16. blacher a, federle mp. gastrointestinal complications of laparoscopic roux-en-y gastric bypass surgery in patients who are morbidly obese: findings on radiography and ct. ajr 2002; 179:1437–42. 17. blacher a, federle mp, dodson sf. internal hernia: clinical and imaging findings in 17 patients with emphasis on ct criteria. radiology 2001; 218:68– 74. 18. bocker j, vasile j, zager j, goodman e. intussusception: an uncommon cause of postoperative small bowel obstruction after gastric bypass. obes surg 2004; 14:116–9. squ med j, april 2010, vol. 10, iss. 1, pp. 64-73, epub. 17th apr 10 submitted 21st july 09 revision req. 13th oct 09, revision recd. 14th nov 09 accepted 21st dec 09 1university of mosul, college of education, department of physics, mosul, iraq; 2duhok university college of education, department of physics, kurdistan region, iraq. * to whom correspondence to be addressed: email: faikaazooz@yahoo.com تفسري ظاهري للمقطع العرضي لتعطيل اخلاليا يف ضوء التفاعل املباشر والالمباشر فائقة عزوز، �شعاد مريخان واي�نات والني�ترونات (بالربوت�نات cho-k1 ( وخاليا )v79( خاليا لتعطيل الَبقاء ُمنحنيات ُمعطيات ا�شتخدام الهدف: امللخ�ص: )c12( و) he3( لدرا�شة دور التفاعل املبا�رس والالمبا�رس يف تعطيل اخلاليا. الطريقة: متت درا�شة منحنيات البقاء خلاليا )v79( امل�شععة بالربوت�نات والني�ترونات واي�نات ) c12 (وخاليـــا )cho-k1( امل�شععة باي�نات )he3( ملدى وا�شع من الطاقة با�شتخدام امل�شادر املن�ش�رة. ا�شتخرجت النقاط العملية من منحنيات البقاء املن�ش�رة با�شتخدام النظام احلا�ش�بي) mat-lab ( واأجريت عليها عمليات الت�افق للمعادلة اخلطية الرتبيعية. ا�شتخدمت معلمات الت�افق حل�شاب املقطع العر�شي للتعطيل )σ( عند امليل االويل؛ واجلرعة) 2gy (؛ وعند ن�شبة بقاء قدرها )%10( لكل ج�شيم على انفراد. النتائج: ُتبنّي النتائج ب�ش�رة عامة اأّن املقطع العر�شي للتعطيل يقل ب�شكل اأ�شي تقريبا مع زيادة مت��شط امل�شار احلر للتاأين االبتدائي )λ(، عدا يف حالة الربوت�نات، وىل حد ما الني�ترونات، حيث يك�ن املقطع العر�شي ثابتا عند قيم معينة ل λ. و يزداد املقطع العر�شي بزيادة انتقال الطاقة اخلطي )let( و اأي�شا ُي�شبح غري معتِمد على )let( عند قيم معينة ل )let(. اخلال�صة: التاأثري ه� الرئي�شي �شببه االأوك�ِشجني امَلْنُزوع النََّ�ِوي الرِّْيِبيُّ احَلْم�ُس ق�شيبي انك�شار اإىل ُيعزى الذي اخلاليا حتطيم اأّن اىل النتائج ت�شري الالمبا�رس والذي ه� اأكرث بكثري من التاأثري املبا�رس. مفتاح الكلمات: احَلْم�ُس الرِّْيِبيُّ النََّ�ِوي َمْنُزوع االأوك�ِشجني ، تعطيل اخللية، ميكانيكية الهدم، ا�شعاع. abstract: objectives: the aim of this study was to use survival curves data for the inactivation of v79 cells and cho-k1 cells by protons, neutrons, c12 ions and he3 ions to study the role of direct and indirect action in cell inactivation. methods: a large number of survival curves for the inactivation of v79 cells by protons, neutrons, and c12 ions and for cho-k1 cells inactivated by he3 ions over a wide energy range were taken from published references. experimental data points were extracted from the published survival curves using matlab (version 7.0) and fitted to the linear quadratic equation. the fit parameters were used to calculate the inactivation cross section (σ) at the initial slope, the 2gy dose and at 10% survival for each particle type separately. results: the results, in general, showed that the inactivation cross section decreases nearly exponentially when increasing the mean free path for primary ionisation (λ), except in the case of protons, and to some extent neutrons, where the cross section takes a constant value at specific λ values. the cross section increased with increasing linear energy transfer (let) and also became independent of let at specific let values. conclusion: the results indicate that the cell damage due to the double strand breaks of dna caused by indirect action is much larger than that caused by the direct action. keywords: cell inactivation; damage mechanism; radiation; dna. phenomenological explanation of cell inactivation cross section in terms of direct and indirect action *faika a azooz1 and suaad a meerkhan2 clinical & basic research advances in knowledge 1. indirect action is the main cause of damage to living cells. 2. direct action is seen only in proton irradiation. this is what makes protons so effective in clinical radiotherapy. application to patient care 1. differentiation between the direct and indirect action of cell inactivation helps to improve treatment methods for tumours. 2. understanding inactivation mechanisms can help minimise the dose required when treating patients with radiation. 3. accelerated protons and light ions have already proved their usefulness in clinical radiotherapy. to take the advantage of their possible benefits, and to optimise treatment procedures in individual cases, detailed understanding of the underlying radiobiological mechanism is necessary. faika a azooz and suaad a meerkhan clinical and basic research | 65 it is generally accepted that dna is the principle target of radiation action and dna double strand breaks (dsb) are the main cause of damage to living cells.1,2 dna damage may occur either via direct action in which particulate radiation strikes the dna molecules directly, or via indirect action in which radiation interacts with the water molecules in the cell to form free radicals which in turn damage the dna strands. depending on the type of radiation dose, and the cells involved, the effects can occur relatively fast or may take years to be observed. it is believed that the direct damage mechanism accounts for a tiny proportion of biological effects caused by overall radiation.3 since direct observation of damage mechanism is impossible, physical quantities, such as inactivation cross sections, based on experimental observations are used to make prediction about these mechanisms. watt et al. in a series of publications,4-7 have shown that maximum damage occurs when the mean free path for primary ionisation λ matches the mean chord length (≈ 2 nm) in the dna. in fact, very few researchers agree with this opinion. the aim of this study was therefore to find out the role of direct and indirect action for protons, neutrons, he3 ions and c12 ions. methods multiple survival curves measurements from two common cell lines: v79 (chinese hamster) and cho-k1 (chinese hamster ovary) were used for this study. published survival curves data for cell inactivation were taken from references,8-18 scanned as image files and digitised to obtain the sets of experimental data points using the matlab computer program (matlab 7.0, the mathworks, inc., natick, ma, usa). forty seven survival curves (20 for protons, 13 for neutrons, 7 for he3 ions and 7 for c12 ions) were fitted to the linear quadratic (lq) equation using the curve fitting tool (cftool) facility in the matlab system. the α and β values obtained from the fit were used to calculate the inactivation cross section σ. although neutrons and other heavy ions are usually fitted to the linear term (α) of the lq equation, we found that a better fit is obtained when fitting the data to both terms. the goodness of fit was measured depending on many statistical parameters and distributions. the criteria for the goodness of fit were that the data points coincided very well with the fitted curve; the residual distribution (residual = data – fit) was either symmetric around zero or the residual value for individual points was nearly zero; the adjusted r-square value (r-square is the best indicator of the fit and can take on any value between 0 and 1, with a value closer to 1 indicating a better fit) should be very close to 1, and the sum of squares due to error (sse) should approach zero. the cross section relationships to the mean free path λ and the linear engery transfer (let) were studied at three radiobiologically important points: initial slope of cell survival curve, 2gy fraction dose typical for radiotherapy and at 10% survival dose for protons, neutrons, helium and carbon ions. the adjusted r-square values for each fit are shown in tables 1 to 4. c r o s s s e c t i o n c a l c u l at i o n s the linear quadratic equation is given by: where s is the survival fraction, d is the dose and α and β are the fit parameters deriving this equation with respect to d represents: -dins dd = α +2βd (2) represents the slope of the survival at any dose d. for the initial slope: -dins dd lim d–›0 = α (3) the cross section is related to the slope of the survival curve as: 19,20 σ(µm2) = slope/gy *l(kev/µm) 6.25 * ρ(g/cc) where ρ is the density of the medium (g/cc) and l is the track average linear energy transfer in (kev/ µm) the α and β parameters obtained from the fit were used in equation (4) to calculate the cross section at: a) the initial slope, slope = α b) at 2gy dose since it is relevant in radiotherapy c) at 10% survival, this is usually used for data ins = (-αd-βd2) (1) -dins dd slope = α+4β (4) phenomenological explanation of cell inactivation cross section in terms of direct and indirect action 66 | squ medical journal, april 2010, volume 10, issue 1 comparison. slope = α+2βd where d represent the dose at 10% survival. results the α and β values obtained from the fit and the calculated cross section values for each survival curve at the initial slope for protons, neutrons, he3 ions, and c12 ions are presented in tables 1 to 4. σ λ d e p e n d e n c e o n pa r t i c l e t y p e the proton inactivation cross section σ of v79 cells, measured at the initial slope, 2gy dose and at 10% survival is plotted against the mean free path λ in figures 1a to 1c respectively. a distinguished feature of these figures is that the cross section decreases sharply below λ ≈ 8.7 nm and then takes a constant value at the initial slope and at 2gy dose in the region between λ = (8.7–14) nm before it starts to decrease again at λ > 14 nm, but this flat region has nearly vanished at 10% survival. the neutron cross section σ versus the mean free path λ in the same regions selected for protons is plotted in figures 2a to 2c in the same order as above. a sharp decrease of cross section is seen in all these figures. it is nearly exponential in shape, but still one can notice a very small flat region at the initial slope [figure 2a] which lies between (1.56< λ<2.5) nm. in general, the proton and neutron cross section at 2gy dose are somewhat higher than those at the initial slope. the inactivation cross section of cho-k1 cells by he3 ions at the initial slope, 2gy dose and at 10% survival is shown in figures 3a to 3c respectively, and the corresponding figures for the inactivation of v79 cells by c12 ions are shown in [figures 4a to 4c]. both groups of figures show that the cross section decreases in an exponential shape without any structure. the cross section values are very close to each other in the three selected regions. σ l e t d e p e n d e n c e o n pa r t i c l e t y p e the inactivation cross section for the particles involved in this study is plotted against the linear energy transfer let in the same regions of the survival curve mentioned above. for protons, the cross section at the initial slope [figure 5a] and at 2 gy dose [figure 5b] increases nearly linearly with let up to let = 16.8 kev/μm, 0 0 1 2 3 4 20 40 60 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 0 1 2 3 4 20 40 60 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 0 1 2 3 4 20 40 60 c ro ss s ec tio n (µ m 2 ) mean free path (nm) a b c figure 1: inactivation cross section of v79 cells by protons versus mean free path: a) at the initial slope; b) at 2gy dose; c) at 10% survival 0 0 5 10 10 20 30 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 0 10 20 30 10 20 30 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 0 5 10 15 10 20 c ro ss s ec tio n (µ m 2 ) mean free path (nm) a b c figure 2: inactivation cross section of v79 cells by neutrons versus mean free path: a) at the initial slope; b) at 2gy dose; c) at 10% survival. faika a azooz and suaad a meerkhan clinical and basic research | 67 then takes a constant value between let = 16.8 kev/μm and let = 23.6 kev/μm, followed by a linear increase. the flat region is not very clear at 10% survival [figure 5c]. a similar behaviour is also seen for neutrons, where the flat region occurs between let = 32.4 kev/μm and let = 48 kev/μm [figures 6a at the initial slope and figure 6b at 2gy dose]. again the flat region is not very clear at 10% survival [figure 6c]. in the case of he3 ions, the cross section increases up to let =133 kev/μm then starts to decrease sharply. this is the case for all regions under consideration in this study [figures 7a to 7c]. the inactivation cross section for c12 ions increases up to let = 339.1 kev/μm at the initial slope [figure 8a] and then starts to decrease very slowly, but it reaches saturation at this value of let in the 2gy dose [figure 8b] and the 10% survival [figure 8c]. discussion it is believed that dsb are the main cause of cell damage and this damage is either due to direct action, in which the energy is directly deposited in the target molecule of biological interest, without the intervention of radical species derived from water analysis, or due to indirect action which is defined as the outcome of the radiolytic products of water on the target of biological importance. as mentioned above, the inactivation cross section decreases with an increasing mean free path λ. this decrease takes an exponential shape in the case of he3 ions [figure 3a to 3c] and c12 ions [figure 4a to 4c], but the exponential shape is interrupted by a flat region in the case of protons [figure 1a to 1c] and to a lesser extent neutrons [figure 2a to 2c]. the cross section values at their maximum are about 3.5, 10, 30, 40 μm2 for protons, neutrons, he3 ions and carbon ions respectively. these values are not outside the range of cross section values found by watt21 and belloni et al.22 the difference in cross section values for different particles is due to the dependence of ionisation density on particle type. for example, tables 1, 2, and 3 that: 1.07 mev protons have let = 27.6 kev/μm, while 1 mev neutrons have let = 32.39 kev/μm, and 1.08 mev he3 ions have let = 138 kev/μm. this means that neutrons are able to produce more secondary particles than protons of the same energy and this applies to he3 ions and c12 ions. the result is higher cell damage or a higher cross section. usually the exponential shape refers to random events such as the exponential decay law. assuming 0 0 10 20 30 40 2 4 6 8 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 0 10 20 30 40 2 4 6 8 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 0 10 20 30 40 2 4 6 8 c ro ss s ec tio n (µ m 2 ) mean free path (nm) a b c figure 3: inactivation cross section of cho-k1 cells by 3he ions versus mean free path: a) at the initial slope; b) at 2gy dose; c) at 10% survival. 0 -20 10 20 30 40 1 2 3 4 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 -20 10 20 30 40 1 2 3 4 c ro ss s ec tio n (µ m 2 ) mean free path (nm) 0 -20 10 20 30 40 1 2 3 4 c ro ss s ec tio n (µ m 2 ) mean free path (nm) a b c figure 4: inactivation cross section of v79 cells by 12c ions versus mean free path: a) at the initial slope; b) at 2gy dose; c) at 10% survival. phenomenological explanation of cell inactivation cross section in terms of direct and indirect action 68 | squ medical journal, april 2010, volume 10, issue 1 that the indirect action of radiation is a stochastic process in which single strand breaks (ssb) happen by the effect of secondary radicals produced at random along the particle track, these radicals are highly reactive and are able to change the structure of a dna biologically important molecule (a molecule that carries genomic information), and this may lead to cell inactivation. a radical can hit a single strand of dna only and there is a probability that the ssb may undergo a repair process, but, since these radicals are large in number, it is very probable that the other strand is hit by another radical leading to dsb which is the main cause of damage to living cells. the breakage of each strand of the dna separately is a totally random process and, as mentioned before, random processes take an exponential shape depending on the action that causes them. in this case, it is the strength of the ionisation density. this phenomenology applies to he3 ions [figures 3a to 3c] and c12 ions [figures 4a to 4c] at the three regions of interest in this study since these particles are highly ionising radiations and are able to produce a large numbers of free radicals. protons and neutrons at low λ values have large ionisation density and are able to produce many radicals, but not as large as that for heavier ions. this is reflected in the lower cross section values at the lower end of the σ – λ curve for each of them. so the cell inactivation by protons up to λ= 8.7 nm and that for neutrons up to λ= 1.56nm is dominated by indirect action. the small flat region between (8.7≤ λ≤ 14) nm for protons [figure 1a] and between (1.56< λ<2.5) nm for neutrons [figure 1b] means a different mechanism is in action. we think it is the direct action process in which the two dna strands are hit by the incident particle itself at the same time and not by its secondary radicals. observing a flat region at these specific values of λ means that there is some kind of relation between λ and the dna structure which enhances the direct action. this relation is not yet well understood and needs more investigations. the reasons for this observation of the direct action of protons and not observing it in the case of neutrons, he3 ions, and c12 ions is that the competitiveness between direct and indirect action for cells inactivated by protons is not as large as that for cells inactivated by one of the other three particles under study because of the small indirect action cross section in the case of protons compared to that for he3 ions, c12 ions and neutrons. the direct action of heavy ions, such as he3 ions and c12 ions, is missed because of the large indirect action. moreover, the high λedge of the 0 0 1 2 3 4 10 20 30 40 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 2 4 6 10 20 30 40 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 2 4 6 10 20 30 40 c ro ss s ec tio n (µ m 2 ) let (kev/µm) a b c figure 5: inactivation cross section of v79 cells by protons versus linear energy transfer: a) at the initial slope; b) at 2gy dose; c) at 10% survival. 0 0 5 10 20 40 60 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 5 10 15 20 40 60 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 5 10 15 20 40 60 c ro ss s ec tio n (µ m 2 ) let (kev/µm) a b c figure 6: inactivation cross section of v79 cells by neutrons versus linear energy transfer: a) at the initial slope; b) at 2gy dose; c) at 10% survival. faika a azooz and suaad a meerkhan clinical and basic research | 69 proton curve is not asymptotic as for other particles; this means that there are still some direct action events taking place. these observations explain why protons have a wide usage in radiotherapy and are regarded as having the ability to concentrate the dose in more discrete target volumes. they would deposit all their energy in the cells of the target, without irradiating normal cells that may be in the target since they produce less indirect effects which are randomly distributed. 23 the proton inactivation cross section at 2gy dose [figure 1b] shows similar behaviour to that at the initial slope and the flat region can still be seen since protons, unlike other particles, are not heavily ionising. hence they produce a lower number of radicals, but the flat region in the case of neutrons at 2gy dose [figure 2b] has vanished because neutrons are heavy ionising particles compared to protons and are able to produce more radicals which enhance the indirect action and cause the direct action effect to disappear. the higher cross section values obtained at the low λ edge of the σ – λ curve for protons and neutrons at 2gy dose as compared to those at the initial slope, are because of the higher number of secondary radicals produced by a 2gy dose than lower doses. the flat region in the proton inactivation cross section at 10% survival [figure 1c] is not as clear as that at the initial slope or at 2gy dose. this is because that the 10% survival may occur at any dose larger than one gray depending on the energy of the particle, so we expect a large mixture of direct and indirect action in this region, but the direct action still plays a major role in the inactivation of cells. the neutron cross section at 10% survival [figure 2c] shows an exponential shape which means that the indirect action dominates. the direct–indirect action mechanism is seen also in the σ – let relationship for protons [figures 5a to 5c]. at low let values, which correspond to the high λ-edge of the σ – λ curve, the increase of cross section with increasing let up to let=16.8 kev/µm indicates the dominance of indirect action and the flat region at (16.8 ≤ let ≤ 23.6) kev/μm, which corresponds to (14 ≥ λ ≥ 8.7) nm, is attributed to direct action, where it occurs purely in this specific region. then, the cross section increases nearly linearly with increasing let to resume the indirect action phase. the same thing can be said about the neutron cross section at the initial slope [figure 6a], but there are very few data points in the flat region since there is not much published data for the inactivation of v79 cells by neutrons. the flat region is better 0 0 5 10 20 40 60 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 5 10 15 20 40 60 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 5 10 15 20 40 60 c ro ss s ec tio n (µ m 2 ) let (kev/µm) a b c figure 7: inactivation cross section of cho-k1 cells by 3he ions versus linear energy transfer: a) at the initial slope; b) at 2gy dose; c) at 10% survival. 0 0 10 40 60 200 400 600 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 10 40 60 200 400 600 c ro ss s ec tio n (µ m 2 ) let (kev/µm) 0 0 10 40 60 200 400 600 c ro ss s ec tio n (µ m 2 ) let (kev/µm) a b c figure 8: inactivation cross section of v79 cells by 12c versus linear energy transfer: a) at the initial slope; b) at 2gy dose; c) at 10% survival. phenomenological explanation of cell inactivation cross section in terms of direct and indirect action 70 | squ medical journal, april 2010, volume 10, issue 1 seen in the σ – let curve for neutrons at 2gy dose [figure 6b] and at 10% survival [figure 6c] than that in the σ – λ curve. no flat region can be seen in σ – let curve for he3 ions [figures 7a, 7b and 7c) and c12 ions [figure 8a, 8b and 8c] since the direct action is negligible compared to the indirect action, but the cross section increases nearly linearly to reach a maximum value at let = 133 kev/μm ≡λ= 0.82 nm in he3 ions. it is less obvious, but can still be distinguished to have its maximum at let = 339.1kev/μm ≡λ=0.13 nm in c12 ions at the initial slope and takes a saturation shape at 2gy dose and 10% survival. these peaks or saturations indicate that an overkill process is taking place. conclusion inactivation cross section due to ionising radiations provides a good tool to study damage mechanisms since it takes different shapes for different particles when plotted against physical parameters as the mean free path or the let. in this study, we have found that the inactivation table 1: survival curve parameters for the inactivation of v79 cells by protons e (mev) let (kev/µm) λ (nm) α (gy-1) β (gy-2) σ (µm2) r2 reference 0.625 37.8 5.5 0.995 -------3.7 0.9989 belli8 0.7 34.6 5.7 0.89 0.048 3.31 0.9981 belli8 0.73 33.15 5.71 0.73 -------2.74 0.9991 belli9 0.826 30.5 6.14 0.86 0.0073 3.2 0.9996 belli8 0.84 30.4 6.24 0.914 -------3.4 0.9942 belli9 0.92 28.5 6.8 0.80 0.089 3.0 0.9972 paganetti10 1.07 27.6 7.16 0.801 0.033 2.98 0.9992 folkard18 1.16 23.6 8.7 0.39 0.06 1.45 0.9989 belli9 1.41 21.2 10.2 0.401 0.095 1.52 0.9985 paganetti10 1.5 20 11.18 0.419 0.039 1.56 0.999 belli8 1.7 18.3 12.58 0.403 0.065 1.5 0.998 belli9 1.71 18.26 12.66 0.395 0.0006 1.47 0.9967 paganetti10 1.9 16.8 14 0.382 0.076 1.42 0.9998 folkard11 3 11.9 22 0.218 -------0.81 0.9835 paganetti10 3.2 11.7 22.9 0.212 0.32 0.79 1.0000 schettino12 3.36 11.3 23.99 0.193 0.03 0.72 0.9992 belli9 3.5 11 24.8 0.18 0.049 0.67 0.9991 belli8 3.66 10.6 25.9 0.148 0.048 0.55 0.9994 paganetti10 6 7.7 43.6 0.105 0.166 0.39 0.9991 belli8 7.4 5.87 55.5 0.062 0.0128 0.23 0.9281 paganetti10 legend: let = linear energy transfer faika a azooz and suaad a meerkhan clinical and basic research | 71 cross section σ in general decreases with increasing mean free path λ; this decrease takes an exponential shape in the inactivation of cho-k1 cells by he3 ions and v79 cells by c12 ions. the exponential shape is attributed to the interaction of secondary radicals with dna to produce dsb which are the main cause of cell damage. this process is described as an indirect action process. the inactivation cross section of v79 cells by protons and neutrons also decreases nearly exponentially with increasing λ and this decrease is due to indirect action, but the semiexponential shape in the case of protons, and to some extent neutrons, is interrupted by a flat region at specific λ-values. we believe this flat region is due to the interaction of the incident particle itself with the dna strands, and the process is a direct action process. this gives protons the ability to concentrate the dose in more discrete target volumes which is very useful in radiotherapy treatments. the σ-let curves for the particles under study have shown that the cross section increases nearly linearly with let and the flat region is also seen in table 2: survival curve parameters for the inactivation of v79 cells by neutrons e (mev) let (kev/µm) λ (nm) α (gy-1) β (gy-2) σ (µm2) r2 reference 0.11 51.64 1.21 0.82 0.28 8.67 0.9968 hall13 0.176 55.32 1.23 0.804 0.003 8.5 0.9995 leenhout14 0.22 55.06 1.266 0.795 0.21 8.4 0.9988 hall13 0.34 51.2 1.43 0.776 0.15 8.2 0.9999 hall13 0.43 48.15 1.55 0.653 0.26 6.9 0.9995 hall13 0.433 48.02 1.56 0.558 0.15 5.9 0.9955 leenhout14 0.583 42.74 1.8 0.485 0.11 5.13 0.996 leenhout14 0.66 40.53 1.26 0.501 0.136 5.3 0.9995 hall13 1 32.39 2.5 0.47 0.058 5.0 0.9995 hall13 2 20.7 4.317 0.24 0.022 2.55 0.9999 hall13 6 9.05 11.72 0.06 0.057 0.65 0.9989 hall13 13.6 3.7 26.16 0.02 0.39 0.23 0.9986 hall15 15 3.4 28.84 0.016 0.05 0.17 0.9994 hall13 legend: let = linear energy transfer table 3: survival curve parameters for the inactivation of cho-k1cells by he3 ions e (mev) let (kev/µm) λ(nm) α (gy-1) β (gy-2) σ (µm2) r square reference 0.84 133 0.82 1.487 ---------31.6 0.9995 muller16 1.13 138 0.92 1.359 ---------29.5 0.9994 muller16 1.22 140 0.95 1.245 0.00004 27.9 0.9999 muller16 1.38 142.6 0.988 1.23 ---------28.06 0.9992 muller16 2.3 121.5 1.46 1.24 ---------26.8 0.9997 muller16 4.6 77.8 2.78 0.684 ---------8.7 0.9953 muller16 10.7 41 6.5 0.284 0.030 2.6 0.9991 muller16 legend: let = linear energy transfer phenomenological explanation of cell inactivation cross section in terms of direct and indirect action 72 | squ medical journal, april 2010, volume 10, issue 1 the proton and neutron cross section, but not in he3 ions or c12 ions. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. alpen el. radiation biophysics. englewood cliffs, new jersey: prentice-hall international inc, 1990. 2. folkard m, prise km, turner cj, michael bd. the production of single strand breaks and double strand breaks in dna in aqueous solution by vacuum uv photons below 10ev. radiat prot dosimetry 2002; 99:147−9. 3. hechanova ae, morris ps. a review of radiation response and recommendations for the final step in risk assessment. presentation at harry reid center for environmental studies, university of nevada, las vegas, nv, usa, 16 september 1999. 4. watt de. on absolute biological effectiveness and unified dosimetry. j radiol prot 1989; 9:33−49. 5. watt de, kadiri la. physical quantification of the biological effectiveness of ionizing radiation. int j q chems 1990; 28:501−20. 6. younis ars, watt de. interpretation of damage to mammalian cells, e. coli and bacteriophages by incorporated radionuclides for prolonged irradiation. radiat prot dosimetry 1990; 31:339−42. 7. alkharam as, watt de. risk scaling factors from inactivation to chromosome aberration, mutation and oncongenic transformation in mammalian cells. presentation at 8th symposium in neutron dosimetry, paris, france, 13−17 november 1995. 8. belli m, cera f, cherubini r. rbe-let relationship for cell inactivation and mutation induced by low energy protons in v79 cells. int j radiat biol 1998; 74:501−9. 9. belli m, cherubini r, finotto s, moschini g, sapora o, sinione g, et al. rbe–let relationship for the survival of v79 cells irradiated with low energy protons. int j radiat biol 1989; 55:93−104. 10. paganetti h. significance and implementation of rbe variation in proton beam therapy. technol cancer res treat 2003; 2:413−26. 11. folkard m, prise km, vojnovic b, newman hc, roper mj, michael bd. inactivation of v79 cells by low-energy protons, deutrons and helium-3 ions. int j radiat biol 1996; 69:729−738. 12. schettino g, folkard m, prise km, vojnovic b, bowey ag, michael bd. low-dose hypersensitivity in chinese hamster v79 cells targeted with counted protons using a charged particle microbeam. radiat res 2001; 156:526−34. 13. hall ej, novak, jk keller am, rossi h, marino s, goodman lj. rbe as a function of neutron energy. radiation res 1975; 64: 245−55. 14. leenhouts hp, chadwick kh. a theoretical analysis of radiation sensitivity in cells following irradiation, “biological effect of neutron irradiation”. presentation at iaea (international atomic energy agency), austria, february 1974. 15. hall ej. the oxygen enhancement ratio as a function of neutron energy with mammalian cells in culture. radiat res 1979; 78:25−37. 16. muller m, kramer m, wegrather wk. radiation biology with he3 ions. progress report gsi (german scientific institute), biophysik 2003/2004, heidelberg, germany. 17. weyrather wk, ritter s, scholz m, kraft g. rbe for carbon track-segment irradiation in cell lines of differing repair capacity. int j radiat biol 1999; 75:1357−64. table 4: survival curve parameters for the inactivation of v79 cell by carbon ions e (mev) let (kev/µm) λ(nm) α (gy-1) β (gy-2) σ (µm2) r2 reference 2.4 339.1 0.13 0.84 -------44.5 0.9989 weyrather17 4.2 482.7 0.15 0.52 0.021 40.16 0.9907 weyrather17 5.4 275.1 0.18 0.91 -------40.0 0.9933 weyrather17 11 153.5 0.26 0.87 0.0549 21.5 0.9991 weyrather17 76.9 32.4 1.32 0.255 0.04 1.3 0.9963 weyrather17 190.7 16.8 2.75 0.22 0.02 0.59 1 weyather17 266.4 13.7 3.47 0.139 0.05 0.3 0.9988 weyrather17 legend: let = linear energy transfer faika a azooz and suaad a meerkhan clinical and basic research | 73 18. folkard m, prise km, vojnovic b, davies s, roper mj, michael bd. the irradiation of v79 mammalian cells by protons with energies below 2mev. int j radiat biol 1989; 56:221−37. 19. watt de, al-affan iam, chen cz. identification of biological mechanism of damage by ionizing radiation. radiat prot dosimetry 1985; 13:285−94. 20. watt de, al kharam as. charged particle, track structure parameters for application in radiation biology and radiation chemistry. int j q chems, quantum biology symposium, 1994; 21:195−207. 21. watt de. a unified system of radiation bioeffectiveness and its consequence in practical applications. radiat prot dosimetry 1997; 70:529−36. 22. belloni f, bettega d, calzolari p, cherubini r, massariello p, tallone l, et al. inactivation cross section for mammalian cells exposed to charged particles: a phenomenological approach. radiat prot dosimetry 2002; 99:199−202. 23. hall ej. why protons? int j radiat oncol biol phys 1995; 31:1005−6. 1department of medicine, sultan qaboos university, muscat, oman; 2department of radiology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: matharsadiq@gmail.com أُذين أيسر عمالق به خثرة كبرية حممد �آثار �صادق وحافظ عقيل باعمر giant left atrium with a large thrombus *muhammad a. sadiq1 and hafidh a. ba omar2 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e137–138, epub. 15 mar 21 submitted 11 may 20 revision req. 16 jul 20; revision recd. 30 jul 20 accepted 25 aug 20 a 73-year-old male patient with known diabetes, hypertension and atrial fibrillation (af) presented to a tertiary care centre with a transient ischaemic attack. he was referred to cardiology service for evaluation of his af and to rule out a cardioembolic event. at the time of admission, the patient was on treatment with warfarin with an international normalised (inr) ratio of 2.5. transthoracic echocardiography revealed severe mixed mitral valve disease and giant left atrium (gla) with profuse and dense whirling spontaneous echo contrast in the left atrium. there was a suspicion of a thrombus in the left atrium. cardiovascular magnetic resonance (cmr) imaging revealed a markedly dilated left atrium measuring 17 × 11 cm. there was a large filling defect at the left atrium’s posterior aspect, which was not visualised adequately in cmr black blood sequence due to severe stagnation of blood. a noncontrast computed tomgraphy scan was performed, which showed a gla with a large hypodense filling defect (thrombus) measuring 4.1 × 3.6 × 8.2 cm in its widest dimensions [figures 1 and 2]. the patient’s left ventricular ejection fraction measured by cardiac mri was 49%. he was offered mitral valve replacement (mvr) and left atrial volume reduction surgery, but he refused surgery. comments gla is a rare condition with a reported incidence of 0.3%.1 it is defined as an excessive dilatation of the left atrium by >8 cm.2 gla is usually associated with rheumatic mitral pathology, but there are few reports of gla in patients with non-rheumatic aetiology.1 it has been hypothesised that fibrosis with chronic inflammation combined with progressive this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.021 interesting medical image figure 1: a non-contrast computed tomography two chamber view of the chest of a 73-year-old male patient showing a gigantic left atrium. https://creativecommons.org/licenses/by-nd/4.0/ giant left atrium with a large thrombus e138 | squ medical journal, february 2021, volume 21, issue 1 atrial enlargement resulting from chronic volume and pressure overload is likely the cause of gross atrial enlargement. patients with gla usually present with dyspnoea, dysphasia and thromboembolic events. the current patient complained of dyspnoea on minimal exertion, but there was no dysphagia. although the risk of thromboembolism increases with la dimensions and is independent of anticoagulants' administration, the published evidence of large thrombus formation in patients with la size of >8 cm is very scarce. there was a large la thrombus formation in the current case despite having therapeutic inr with standard vitamin k antagonist therapy. there is a therapeutic dilemma when managing such patients. it is unknown whether the increase in the inr therapeutic range of ≥3.0 will resolve gla patients’ clot. contrary to current american heart association (aha) guidelines that do not recommend using novel oral anticoagulants (noac) in patients with intracardiac thrombus and valvular af, several reports are published on the use of off-label noacs resulting in resolution of thrombus in patients with enlarged la.3,4 in a case report by masarova et al., recurrent thrombus formation with therapeutic inr of 2.89 was observed in their patient with gla after surgical removal of the thrombus. a combination of rivaroxaban and clopidogrel resulted in partial thrombus regression in their patient.4 left atrial volume reduction surgery in af patients with enlarged la have shown superior freedom rates from af up to five years compared with patients in the non-reduction group.5 af plays a vital role in la thrombus formation along with an increase in left ventricular (lv) volume overload and enlargement. freedom from af with lv volume reduction surgery may play an essential role in managing patients with gla and large thrombus formation. the current patient was offered mvr, la volume reduction surgery and thrombus removal, but he refused and was lost to follow-up. references 1. el maghraby a, hajar r. giant left atrium: a review. heart views 2012; 13:46–52. 2. loch a, sadiq ma, ahmad waw. giant left atrium in a patient with prosthetic mitral valve. european heart journal 2013; 34:981. 3. kirchhof p, benussi s, kotecha d, ahlsson a, atar d, casadei b, et al. 2016 esc guidelines for the management of atrial fibrillation developed in collaboration with eacts. eur heart j 2016; 37:2893–962. 4. masarova l, novak j, pesl m, ondrasek j, semenka j, simorova e, et al. recurrent thrombus in the gigantic left atrium during effective anticoagulant therapy: case report. bmc cardiovasc disord 2020; 20:86. 5. kim jh, jang ws, kim jb, lee sj. impact of volume reduction in giant left atrium during surgical ablation of atrial fibrillation. j thorac dis 2019; 11:84–92. figure 2: a non-contrast computed tomography two chamber view of the chest of a 73-year-old male patient showing the presence of a large thrombus in the left atrium. re: lifestyle-related determinants of obesity among omani children sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e331, epub. 21 jun 21 submitted 27 oct 20 revision req. 27 jan 21; revision recd. 18 feb 21 accepted 2 mar 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.029 letter to the editor dear editor, i read with interest the recent study by al yazeedi et al. published in the august 2020 issue of squmj.1 they studied the correlation between body mass index (bmi) z-scores and lifestyle-related factors, namely nutrition, physical activity, screen time and time spent sleeping among a cohort of 6–10-year-old omani children. in the study methodology, it is mentioned that bmi were estimated and bmi z-scores was established based on the world health organization (who) growth charts for children aged 5–19 years.1 accordingly, they found that 17.4% of the studied children were determined to be overweight or obese. there was no significant correlation between bmi z-scores and nutrition intake, moderate-to-vigorous physical activity time or screen time (p ≥0.05). however, there was a significant positive correlation between increased time spent sleeping at night and obesity (p <0.05).1 in addition to the study’s limitations that have been mentioned by al yazeedi et al., i presume that the following methodological limitations could further influence the above-mentioned study results.1 there are many growth trajectory centiles to evaluate growth in children, notably who centiles, national center for health statistics (nchs) centiles and population-specific centiles. variations do exist in the precision of the different centiles in assessing paediatric growth status. in oman, the overall prevalence estimates of paediatric underweight, wasting, stunting and overweight were 17.8%, 7.4%, 10.9% and 1.3%, respectively, according to nchs centiles compared to 11.3%, 7.6%, 13.0% and 1.9%, respectively, according to who centiles.2 moreover, overweight and stunting revealed statistically significantly higher estimates while underweight was statistically significantly lower.2 growth centiles are controlled by various determinants such as age, gender, ethnicity, nutritional status and socioeconomic standard;3 population-specific centiles could disclose the growth of children more faithfully compared to other centiles.4 therefore, the generation of omani population-specific paediatric bmi z-scores, similar to those that have been previously established, is fundamental.5 implementation of the national bmi z-scores could better capture the correlation between obesity and lifestyle-related events among the paediatric population in oman. other study limitations, notably the limited sample size and the influence of selecting a narrow age group of 6–10 years in the studied population compared to a wider age group of 5–19 years could substantially impact the study’s results. i believe that studying lifestyle-related determinants of obesity using growth charts could imply that obesity is a complex disease and a major paediatric health threat with all its serious sequelae that necessitates directing efforts to implement strategic therapeutic and preventive measures. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al yazeedi b, berry dc, crandell j, waly m. lifestyle-related determinants of obesity among omani children. sultan qaboos univ med j 2020; 20:e279–86. https://doi.org/10.18295/squmj.2020.20.03.006. 2. alasfoor d, mohammed aj. implications of the use of the new who growth charts on the interpretation of malnutrition and obesity in infants and young children in oman. east mediterr health j 2009; 15:890–8. https://doi.org/10.26719/2009.15.4.890. 3. ziegler ee, nelson se. the who growth standards: strengths and limitations. curr opin clin nutr metab care 2012; 15:298–302. https:// doi.org/10.1097/mco.0b013e3283511478. 4. khadilkar v, khadilkar a. growth charts: a diagnostic tool. indian j endocrinol metab 2011; 15 suppl 3:s166–71. https://doi. org/10.4103/2230-8210.84854. 5. karki s, päkkilä j, laitala ml, ojaniemi m, anttonen v. national reference centiles of anthropometric indices and bmi cut-off values in a child population in nepal. ann hum biol 2018; 45:447–52. https://doi.org/10.1080/03014460.2018.1530302. letter to the editor | e331 https://creativecommons.org/licenses/by-nd/4.0/ https://doi.org/10.18295/squmj.2020.20.03.006. https://doi.org/10.26719/2009.15.4.890 https://doi.org/10.1097/mco.0b013e3283511478 https://doi.org/10.1097/mco.0b013e3283511478 https://doi.org/10.4103/2230-8210.84854 https://doi.org/10.4103/2230-8210.84854 https://doi.org/10.1080/03014460.2018.1530302 former affiliation: department of public health, la trobe university, bundoora, australia author’s e-mail: s.chambers@protonmail.ch سبب عدم متيز اجلوانب االقتصادية للرعاية الصحية �شتيفن ت�شامربز abstract: frequent claims suggest that healthcare and its production are not only different from other goods, but that they differ to such an extent that healthcare should be viewed as unique. various features of healthcare, such as the lack of a perfect market and the existence of information asymmetry, are cited as evidence of this claim. however, such a view results from unduly emphasising the characteristics of healthcare as being atypical. this article redresses this imbalance by taking an alternative approach and examines the ways in which the economic aspects of healthcare are similar to those of other goods. it was found that the differential aspects are less distinctive than claimed and the economic aspects of healthcare are not unique. keywords: healthcare sector; medical economics; economic competition; competitive behavior; state medicine; insurance selection bias; patient participation; health services research. امللخ�ص: ت�شري �لدعاء�ت �ملتكررة �إىل �أن �لرعاية �ل�شحية و�إنتاجها ل يختلفان فقط عن �ل�شلع �لأخرى، ولكنهما يختلفان �إىل حد �أنه يجب �لنظر �إىل �لرعاية �ل�شحية على �أنها �شلعة فريدة. يتم �لأ�شت�شهاد بالعديد من مالمح �لرعاية �ل�شحية، مثل عدم وجود �شوق مثايل وعدم تطابق �ملعلومات، كدليل على هذ� �لدعاء. غري �ن مثل هذ� �لر�أي ينتج من �لتاأكيد �ملفرط على خ�شائ�ص �لرعاية �ل�شحية باعتبارها غري منطية. يعالج هذ� �ملقال هذ� �خللل عن طريق �تخاذ نهج بديل ويدر�ص �أوجه ت�شابه �جلو�نب �لقت�شادية للرعاية �ل�شحية مع تلك �ملوجودة يف �ل�شلع �لأخرى. وقد ُوِجد �أن �جلو�نب �لتفا�شلية �أقل متيًز� من تلك �ملزعومة و�أن �جلو�نب �لقت�شادية للرعاية �ل�شحية لي�شت فريدة. �ختيار يف �لتحيز �لدولة؛ طب �لتناف�شي؛ �ل�شلوك �لقت�شادية؛ �ملناف�شة �لطبي؛ �لقت�شاد �ل�شحية؛ �لرعاية قطاع املفتاحية: الكلمات �لتاأمني؛ م�شاركة �ملري�ص؛ بحوث �خلدمات �ل�شحية. why the economic aspects of healthcare are not unique stephen chambers special contribution sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e165–172, epub. 28 jun 20 submitted 2 sep 19 revision req. 14 nov 19; revision recd. 1 dec 19 accepted 31 dec 19 https://doi.org/10.18295/squmj.2020.20.02.006 frequent claims have been made that healthcare and its production are not only different from other goods, but that they differ to such an extent as to make healthcare unique. some of the characteristics ascribed to healthcare in support of this view are uncertainty, complexity, information asymmetry, outcomes of mistakes being significant and the objectives of healthcare transactions being vague and possibly conflicting.1,2 yet while healthcare has some unique features, as all goods do, it is not as different as some proponents assert. a central point to consider is that the principles of economics do not fail to operate just because they are applied to healthcare. weisbrod described all things as different and yet the same, thereby highlighting that healthcare is not a unique commodity because it does not differ from every other commodity in all its features.3 additionally, economic analyses of healthcare can be conducted with the same tools and principles that apply to other goods and industries.4 although many wish to point to the uniqueness of healthcare, an equally justifiable approach is to consider the alternative view that the differences are much less dramatic. in doing so, it is appropriate to take the perspective of ibadi muslim scholars who “educate their students on not blindly imitating other scholars. instead they teach them to follow the lead of the evidence”.5 in a similar light, oman’s poet and scholar al-rawahi wrote “knowledge emerges from proof ”.6 therefore, an exploration of the ways in which healthcare is similar to other goods may promote a greater understanding of healthcare’s true economic nature when compared to other goods. this article will present the following 12 aspects of healthcare with related claims to uniqueness as well as counterclaims: (1) an (im)perfectly competitive market; (2) a hybrid market; (3) government interv ention; (4) moral hazard; (5) adverse selection; (6) inform ation asymmetry; (7) the effects of information and communication technology (ict); (8) agency; (9) price discrimination; (10) the life or death nature of healthcare; (11) the impact of risk and uncertainty on the healthcare market; and (12) a market analysis. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ why the economic aspects of healthcare are not unique e166 | squ medical journal, may 2020, volume 20, issue 2 an (im)perfectly competitive market an initial argument to counter is the notion that healthcare is different because it violates the assump tions that underlie a perfect market.2,7 olsen discussed many ways in which the real world market for health care is said to violate the key assumptions behind the perfect market model.7 olsen’s list provides a good summary of the common arguments of this viewpoint including assumptions about the availability of full information, the presence of impersonal transactions, the existence of private goods, selfish motivations that support interactions, the presence of many buyers and sellers, the potential for free entry and exit and the availability of homogenous products.7 olsen’s contention in relation to these assumptions is that healthcare exhibits characteristics that are counter to this model and are uniquely demonstrated.7 however, an examination of these claims leads to a different conclusion. if olsen’s model of healthcare is applied to legal services, the limited differences between healthcare and other goods becomes apparent. indeed, arrow noted that the demand for medical services might be compared to that for legal services related to criminal defense or civil lawsuits.1 in the case of legal services, there will be uncertainty in regard to whether the consumer will need legal services in the future and asymmetric information as to the quality of services to be provided. interactions between a lawyer and their client are based on trust. some legal services involve externalities, in that defending an innocent person helps them and their family, as well as benefiting society by allowing the accused to remain a productive member of society. alternatively, convicting a guilty person brings justice to their victims and protects society at large. legal practitioners are restricted by professional codes of ethics. depending on the population and location, few legal practices or accredited specialists may be available. legal services have restrictions on who can practice. they are differentiated by branding and advertising. higher quality legal services can be signalled via premises with more amenities. a healthcare transaction can be considered similar to that of any good that is subject to the information asymmetries of a principal-patient or patient-pract itioner relationship. furthermore, private-sector goods and services are more heterogeneous than goods that are available in the healthcare sector. perfectly competitive markets exist in theory only; in practice, all markets are imperfect. that being the case, one may wonder why a perfectly competitive market structure is employed in economic thought. the reason for utilising such a concept is that it provides a baseline comparison tool by which to judge the operation of markets in practice and evaluate how far they deviate from the ideal. the perfectly competitive market structure can be described as a gold standard that is used as a benchmark to assess the explanatory power of alternative market models to evaluate changes in price and outputs.8 it can be used to analyse a market structure and the efficient allocation of resources. additionally, it is useful as a means of predicting the effects of changes, such as increased demand, on the market. for example, a socialist economic model will fail to allocate resources efficiently because, rather than relying on market price signals that indicate consumer demand and a willingness to pay, it attempts to calculate a price in the absence of necessary information. the error in using the notion of the perfectly competitive market to judge the ways in which healthcare is different is that it establishes an unrealistic standard by which to judge. this phenomenon was well-noted by demsetz, who described it as a nirvana approach.9 using this fallacy, proponents present a straw man argument by limiting the choice to a perfect ideal and what is cast as an imperfect present condition. demsetz describes those who espouse a nirvana fallacy as seeking “to discover discrepancies between the ideal and the real and if discrepancies are found, they deduce that the real is inefficient”.9 the reasonable alternative is to accept the truth of markets and information availability as they are and take a comparative institutional approach to finding which of the existing real alternatives can provide a solution to the problem under consideration. after all, perfect competition means no competition at all because the things that actually occur in markets, such as some participants being price makers, do not happen.9 hybrid market hybrid market approaches, such as the quasi-market of the uk national health service (nhs), do not advance the case of healthcare being unique. the definition of a quasi-market is not fixed but usually implies attempts to move a state-controlled monopoly towards a competitive market. in the nhs, the notion of the quasi-market was defined by le grand as “markets where the provision of a service is undertaken by competitive providers as in pure markets, but where the purchasers of the service are financed from resources provided by the state instead of from their own private resources”.10 this notion has never been fully realised in the uk because there never has been adequate competition to bring about the desired efficiency but nor can there be while the state intervenes stephen chambers special contribution | e167 in the market to act as a brake on competition. in the early 1990s, an internal or quasi-market was created in the uk nhs with a purchaser–provider split designed to provide competition amongst providers who would be rewarded for improving efficiency and quality. however, competition remained internal, heavily regulated and, as a result, failed to bring about any significant change. realising the failure to achieve the efficiencies desired, the nhs moved further towards marketisation. the problem that le grand identified with the nhs reforms was the government holding onto central control and not promoting adequate reward for quality competition.11 the existence of a quasimarket means that the market is partly similar to a competitive market and suggests that healthcare in a quasi-market is less unique as it has features which are similar to those of a competitive market. in short, the closer it becomes to a real market, the less unique it is. the theoretical preconditions of the quasi-market are the same as for any market. when quasi-markets fail, they fail doubly because they face the failure caused by government in addition to ordinary market failures. it is not the nature of healthcare that is different as a service, but rather it is the constraints placed upon it by government that affect its operation. regulation can produce unnecessary restrictions on entry to industries. again, this characteristic is no different to other industries, such as banking and finance, which also must operate within the constraints of governmental regulation. government intervention many authors who want to claim the healthcare market is different from markets for other goods are also those who advocate governmental intervention in the market.1 it is no coincidence that they strongly wish to point out healthcare’s differences because they believe it provides them with some basis for advocating for government’s involvement. as dilorenzo explains, “having ‘proven’ that markets ‘fail,’ the analyst then proposes government intervention under the assumption that no such failures will infect government”.12 this point betrays their economic ideology, if not their political one, because if they were free market advocates, they would not be calling for government intervention in the first place and secondly, they would be proposing ways that the free market could prevent and correct market failure. instead, they point to the supposed failings of the market to deliver efficiency, using these as a pretence for government intervention while completely ignoring government’s failings. this line of thinking is deceitful, or at the very least demonstrative of an unsophisticated understanding of market operations. it is a further illustration of the fallacy of the nirvana perspective that demsetz referred to.9 this is not just a western capitalist viewpoint. the principles of islamic economics, based on the teachings of the qur’ān and the sunnah literature recording the traditional social and legal customs and practices of the islamic community, promote a free market without regard to the type of good or service being offered. this practice assumes that such items are allowed (halāl) for a muslim to consume. the qur’ān contains verses which specifically allow and encourage trade and uphold the right to private property. islam approves of using the market mechanism rather than government intervention to set prices and handle the distribution of goods. this approval is demonstrated by the example of the prophet muhammad who refused to fix the price of goods when people asked him to do so.13 nevertheless, this article is not about whether a free market or government intervention approach is desirable but rather about the validity of the arguments of those who claim the healthcare market is essentially different from other markets. moral hazard markets react to failures by creating solutions to disparities, with insurance being a classic example of a way to manage risk. of course, solutions may not be perfect. for instance, moral hazard occurs in the context of health insurance, when the policy holder withholds or misinforms the insurer about their risk and changes their health behaviour after being covered by insurance.1 moral hazard describes the tendency for people who are insured to use more healthcare resources when shielded from the actual direct cost by a total or partial subsidy, which insurance provides. additionally, people tend to take less care of their health knowing they are protected by insurance should an insured event occur. this problem leads to less efficient insurance, especially for those with a low-risk profile. however, moral hazard is common to all types of insurance by the very nature of insurance, rather than the market it occurs in. although moral hazard may indeed result in the lack of a complete market for private insurance, the same problem would eventuate if the government provided the insurance. whatever failures are present in the market, it does not necessarily follow that a public sector solution will correct them.2 there is no evidence to prove that state monopoly providers are more altruistic, ethically superior or provide better quality service than competitive providers.10 even the characteristic of public goods, why the economic aspects of healthcare are not unique e168 | squ medical journal, may 2020, volume 20, issue 2 which is invoked to grant healthcare uniqueness, is not sufficient justification for government involvement. goodman and porter developed a model which finds that government production will never be optimal and will respond to changing market conditions in nonoptimal ways.14 adverse selection adverse selection has been identified as a market problem for health insurance.1 adverse selection occurs when the pool of insured participants becomes weighted towards high risk individuals due to information asym metry between the insured and the insurer. people who are in good health have less incentive to purchase health insurance than those who experience poor health. yet those with poor health will have greater incentive for utilisation of the healthcare resources paid for by insurance and take out more comprehensive coverage.15 when the insurance company, whether public or private, cannot determine the risk of the insured party due to asymmetric information, premiums rise to accommodate the risk from all insured. if the insurance company could know who the low-risk clients were, they could offer them lower premiums. it has been observed that adverse selection can arise in the market if the government intervenes with regulations that prohibit insurers from placing conditions in a contract to account for known risk factors.15 if premiums continue to rise, it provides a disincentive for healthy people to pay for something for which they do not have a pressing need. as a result, the insurance market becomes overweighted with more ill clients and the volume of claims can lead to market failure.16 however, pooling risk and reduced incentive also occurs with compulsory third party insurance for motorists. akerlof ’s description of the failure of health insurance due to the diminishing quality of participants can also be found in the market for used automobiles.16 it has to be understood that while the title of his paper alluded to poor-quality used automobiles, colloquially referred to as “lemons” in north america, the principles he described are valid for both markets.16 this similarity demonstrates that the phenomena described are not unique to the healthcare market. information asymmetry the information asymmetry between purchasers and healthcare insurance providers, which contributes to moral hazard and adverse selection, also exists between patients and healthcare practitioners. arrow identified the latter instance of information asymmetry as one of the key problems that differentiates the healthcare market from other markets.1 this aspect is hardly unique to healthcare and happens with goods as diverse as legal advice to automotive repairs. in healthcare, information asymmetry is usually framed as a lack of information on the patient’s behalf, which puts them in a disadvantaged position.1,17 however, information asymmetry is shared by both the patient and pract itioner.2 furthermore, with the growth of health inform ation available on the internet, patients’ increased health literacy and support groups for particular conditions, a patient may now be better informed about their condition than their doctor.17 as there is more information avail able now on treatment input and outcomes, due in large part to the breadth of content and global reach of the internet, the consumer’s position can be strengthened, providing a basis for better decision-making. for example, people with chronic conditions who constitute a popul ation that consumes a large proportion of healthcare resources, have increasingly more information about their health issues rather than less.18 even arrow has had cause to reconsider his position, conceding that contemporary improvements in the availability of health information may have helped to mitigate the consumer’s lack of information.19 effect of information and communication technology electronic-health (e-health) promises to improve eff iciency by decreasing costs while enhancing healthcare quality and empowering consumers.20 the use of information and communication technology (ict) to deliver healthcare services locally and at a distance is described by the term “e-health,” which also includes telehealth and telemedicine. the provision of e-health, underpinned by ict, can be seen as the delivery or augmentation of healthcare services and information brought about by the nexus of business, public health and medical informatics.20 in general, the effect of ict on operations is to improve customer service and provide better results for an organisation. in healthcare, both providers and policymakers recognise the value in improving access and are interested in lowering delivery costs and improving standards of care. despite its characteristics, the outcomes expected of the business of healthcare in terms of effectiveness and efficiency are the same as demanded of every other industry.21 the world health organization recognises the need for efficiency of operation and in its definition of e-health describes it, in part, as the cost-effective use of ict to support health and healthcare.22 other industries, which are heavily reliant on information, have sought to develop and utilise best practices in stephen chambers special contribution | e169 managing information. as kloss noted, healthcare does not face unique challenges in this matter because industries as diverse as banking, government and life sciences have had to deal with the same strategic and operational demands.23 the nature of e-health, which is inherently networked and virtual, means that geopolitical barriers can be overcome. eysenbach described e-health as dedicated to “networked, global thinking, to improve health care locally, regionally, and worldwide” through the use of ict.20 due to the global nature of e-health, healthcare can be widely distributed in a cost-effective manner. for example, e-health can improve the access of geographically isolated people, such as rural commun ities, to a variety of medical specialties. ict can also facilitate innovations such as internet prescribing. doing so may lead to a new class of pharmaceuticals, termed over-the-internet drugs, which still require restriction but can be safely dispensed by a qualified healthcare professional with a prescription delivered via the internet.24 thus, the use of e-health removes another distinction of healthcare—its production. according to cimasi this is inherently local but ict makes it less so.25 the efficient means of production and distribution via ict reduces barriers to entry in terms of cost of facilities, enabling hub and spoke organisation models. additionally, ict can success fully assist in reducing the information asymmetry and agency problems that healthcare consumers experience. agency agency problems are not unique to healthcare. the problem, as it occurs in healthcare, is when a patient’s interests are compromised by the provider who is performing the role of agent in an imperfect manner to maximise personal profit. gaynor observed that the type of agency problems that exist in healthcare also occur elsewhere.26 he noted it to be an inherent characteristic in the provision of a professional service.26 however, such problems occur in every organisation. indeed, agency is a prevalent aspect of economic reality and occurs between doctors and patients just as it does between employees and managers. subsequent to arrow’s 1963 paper, it was recognised that the ethics of healthcare practitioners can act to ameliorate the risk of patients being taken advantage of by providers due to consumer information asymmetry. this market failure is termed ‘supplierinduced demand’. traditionally, this failure has meant relying on the professionalism of the practitioner to prevent over-servicing. additionally, there is the notion of the practitioner as one who guards against moral hazard. this is aided by practitioner ethics and concern for the best interests of the consumer, which are accepted as placing some limitations on practitioner over-servicing.27 evans suggested that the deliberate cultivation of physician professionalism is designed to prevent inappropriately taking advantage of opportunities for personal gain.27 ethics enforced by healthcare institutions also play a part.17 price discrimination price discrimination can occur in healthcare, where the prices consumers pay for identical services are contingent upon their ability to pay or the discretion of the healthcare practitioner. for example, australian specialist physicians were found to charge their higher income clients more, and fee gaps vary widely between specialties.28 price discrimination in healthcare may be considered unfair, depending upon the context of its application, but this characteristic is hardly unique to it and can be found in many other industries. price discrimination, as a matter of fact, is not always bad. on one hand, an example could be an airline selling the same class of seating at different prices depending upon how far in advance tickets are purchased. charging different prices for the same product to enhance revenue is price maximising. this business practice is profitable and, although it may be considered unfair, it provides consumers with choice. in a healthcare setting, this practise could mean that one patient who is prepared to wait for treatment may use a free public hospital while another may prefer to pay to be treated sooner by a private clinic. it is important to note that price discrimination does not necessarily result in another person paying more because someone else paid less. what may be considered fair price discrimination, for example, is if a student is granted a discount on the cost of tuition through merit-based scholarships. in a healthcare setting, price discrimination could mean that a patient receives free or discounted treatment as an act of charity by a private healthcare provider. in addition, every healthcare system which is not subjected to regulated prices experiences price discrimination as a completely normal occurrence.29 differences in price for products that seem alike are quite common, as for example when the active ingredient contained in a drug is sold as a generic versus branded product. evidence exists for considerable variation in price even for standard consumer products where it would be easy for consumers to search and discover best offers. sometimes price discrimination is simply a response, either public or private, to the externalities arising in a market. why the economic aspects of healthcare are not unique e170 | squ medical journal, may 2020, volume 20, issue 2 life or death? one of the characteristics of healthcare, which is said to make it unique rather than merely different, is that its provision is a matter of life or death. however, this concern is not unique to healthcare. in terms of the legal system, a lawyer may be protecting a client from life imprisonment or a death sentence. a skydiving instructor literally has the rookie jumper’s life in their hands; they must instruct the trainee to deploy their parachute or deploy it for them, for failure is almost certain to result in fatal consequences. commercial airline pilots are responsible for the safety of hundreds of passengers at any one time. like healthcare, a team effort is involved, from the pilot to aircraft mechanics to air traffic controllers. additionally, the need for medical care in this argument is often overstated. in regard to the need for medical care, a concept fuchs found to be imprecise and of little analytical value, he observed that the need for medical care exists on a continuum at any particular time, varying from emergency and life-saving surgery to blackhead extraction.30 fuchs further stated that, of the billions spent on health, surely a large proportion did not entail matters of life or death.30 similarly, weisbrod observed that “not all medical care is vital to life—indeed, most is not”.3 instead, advances in healthcare have allowed for a wider variety of conditions that cause pain and discomfort to be treated. risk and uncertainty where there are differences between healthcare and other goods, such as risk and uncertainty, they tend to be differences of degree. similar to arrow, morrisey contended that while many industries experience the effect of these factors, the combined effect of them is what seems to make health services distinctive.31 however, he qualifies this observation by noting it is a basic mistake to make extravagant claims of the healthcare industry’s distinctiveness.31 challenge, change and complexity are pervasive amongst most organ isations, and healthcare is no exception. responding to the claim that providing healthcare is unlike other industries due to its multidimensional, specialised nature and the lack of knowledge clients have to evaluate it, porter and teisberg agreed that these are characteristics of health services but are in essence no different to other industries.32 many organisations must supply highly complex and technologically sophisticated equipment in telecommunications and computing, some of which play critical roles in saving lives, such as in air traffic control. healthcare can learn from other industries about the way that they have handled challenges and apply those lessons to decision-making. healthcare is often characterised as risky, such as in the description of it being a matter of life or death. however, other high-risk industries such as aviation and petroleum production have information gathering procedures and systems in place to manage and improve safety. as such, it is not justified to claim knowledge gained from other industries cannot be applied to healthcare because of its supposed uniqueness.33 arrow admitted that “the risks are not by themselves unique; food is also a necessity, but avoidance of deprivation of food can be guaranteed with sufficient income, where the same cannot be said of avoidance of illness”.1 this argument for the difference inherent to healthcare is weak. first, it is admitted these risks are not unique. it is difficult to argue for the uniqueness of healthcare when water and food are necessary for survival, yet the government does not compel people to purchase water and food insurance lest they are unable to buy these items at a future date. second, the acknowledgment of the existence of risk recognises that there is a possibility of adverse consequences occurring. arrow’s contention is that sufficient income guarantees the risk of being without food will not occur, which is not correct. if there is no food in the market, having the means to pay for it is of no use. income does not guarantee the avoidance of risk but rather it allows one to meet the cost of dealing with it, assuming that income is sufficient and mitigating options exist. a salient example here is the purported origin of a giffen good. this type of good was named after sir robert giffen, supposedly after he observed an increased consumption of inferior quality potatoes as prices rose during a famine. however, this view can be easily debunked by considering that such a practice could not have been widespread as it is not possible to purchase more of a good when there are fewer such items available in the market. market analysis in considering the question of whether healthcare is a unique good with a market in need of a different means of understanding, a nuanced view is required because healthcare can be acknowledged as different in that it has its own important features and related challenges to solve. however, it is amenable to being analysed and managed with existing economic tech-niques and principles applied to other goods and industries. pauly proposed that the question of difference can be considered in three parts.4 he stated that very few aspects of healthcare were not amenable to analysis with the usual tools, suggesting that the majority of stephen chambers special contribution | e171 healthcare’s characteristics can be treated the same or similar to other industries, and where those methods are not a perfect fit, they still work reasonably well. while the individual attributes of the healthcare market are not unique, arrow said when “taken together, they establish a special place for healthcare in economic analysis”.1 however, fuchs refuted this view, stating that “health care is, in many respects, similar to other goods and services. it is produced with resources that are scarce relative to human wants”.34 healthcare exists as a market which can be divided into sectors or segments depending on the needs and preferences of consumers. this type of division is also found with other goods and shared characteristics between these markets are apparent. thus, healthcare can be analysed using generic methods and tools that are applied across the entire market. demarcating healthcare as unique inhibits the transfer of knowledge between healthcare and other sectors.18 conclusion despite claims to the contrary, healthcare and its production is not unique among other industries. healthcare does not exist in a perfect market as no goods truly do. while healthcare has features that are particular to it, this is no different to other goods. notable characteristics of healthcare that have been proposed as evidence for its distinctiveness are in fact common to various industries. major elements such as agency, barriers to entry, externalities, information asymmetry and uncertainty can all be found in, for example, legal services. the aspects of adverse selection and moral hazard are outcomes of insurance rather than healthcare. the emotive argument of healthcare being a matter of life or death is both overstated and not exclusive as the aviation industry provides a product that carries the same risk with each flight. change and complexity are characteristics of the modern workplace and are prevalent in ict. therefore, an approach considering the similarities of healthcare with other goods prevents it from unnecessarily being viewed in isolation from broader economic thought. the practical and policy outcomes of this view for oman, or any country concerned about the growing demand for healthcare and the concomitant expenditure required to fund it, is to treat healthcare the same as other goods. such a step would prevent unnecessary government intervention in the market in the form of price controls that can lead to overor under-consumption. instead, it is possible to rely on market mechanisms to improve competition, increase efficiency, decrease costs and offer consumer choice. market mechanisms drive the production and distribution of other goods which are essential for life, such as food. needy people can still be cared for because nothing about a market-based economy prohibits charity and philanthropy, and the combination of a market-based economy and charity is compatible with the views of islamic society. references 1. arrow kj. uncertainty and the welfare economics of medical care. am econ rev 1963; 53:941–73. 2. culyer a. the nature of the commodity ‘health care’ and its efficient allocation. oxf econ pap 1971; 23:189–211. https://doi.org/10.1093/oxfordjournals.oep.a041190. 3. weisbrod b. comment. in: greenburg w, ed. competition in the healthcare sector: past, present and future. washington dc, usa: beard books, 2002. pp. 37–42. 4. pauly mv. is medical care different? in: greenberg w, ed. competition in the health care sector: past, present and future. washington dc, usa: beard books, 2002. pp. 11–36. 5. al-busaidi sa. the reading of the qur'ān, sunna and akhbār in early ibādī sources. in: francesca e, ed. ibadi theology: rereading sources and scholarly works. hildesheim, germany: georg olms verlag, 2015. pp. 57–65. 6. ibn salim ibn ‘udayyad al-rawahi n. al-‘aqida ’l-wahbiyya. in: hoffman vj, trans. the essentials of ibādī islam. syracuse, new york, usa: syracuse university press, 2012. pp. 55–240. 7. olsen ja. principles in health economics and policy, 2nd ed. oxford, uk: oxford universi-ty press, 2017. 8. dewar dm. essentials of health economics, 2nd ed. burlington, massachusetts, usa: jones & bartlett learning, 2016. 9. demsetz h. information and efficiency: another viewpoint. j law econ 1969; 12:1–22. https://doi.org/10.1086/466657. 10. le grand j. quasi-market versus state provision of public services: some ethical considera-tions. publ reason 2011; 3:80–9. 11. le grand j. delivering britain’s public services through ‘quasimarkets’: what we have achieved so far. from: www.bristol. ac.uk/media-library/sites/cmpo/migrated/documents/legrand. pdf accessed: dec 2019. 12. dilorenzo t. a note on the canard of “asymmetric information” as a source of market fail-ure. q j austrian econ 2011; 14:249–55. 13. at-tirmidhi i m. 14 the book on business. from: sunnah.com/ tirmidhi/14 accessed: dec 2019. 14. goodman jc, porter pk. political equilibrium and the provision of public goods. publ choice 2004; 120:247–66. https://doi.org/10.10 23/b:puch.0000044218.95007.45. 15. chiappori pa, salanié b. testing for asymmetric information in insurance markets. j polit econ 2000; 108:56–78. https://doi. org/10.1086/262111. 16. akerlof ga. the market for "lemons": quality uncertainty and the market mechanism. q j econ 1970; 84:488–500. https://doi. org/10.2307/1879431. 17. langer a, schröder-bäck p, brink a, eurich j. the agency problem and medical acting: an example of applying economic theory to medical ethics. med health care philos 2009; 12:99–108. https://doi.org/10.1007/s11019-008-9138-y. 18. robinson jc. the end of asymmetric information. j health polit policy law 2001; 26:1045–53. https://doi.org/10.1215/036 16878-26-5-1045. https://doi.org/10.1093/oxfordjournals.oep.a041190 https://doi.org/10.1086/466657 https://doi.org/10.1023/b:puch.0000044218.95007.45 https://doi.org/10.1023/b:puch.0000044218.95007.45 https://doi.org/10.1086/262111 https://doi.org/10.1086/262111 https://doi.org/10.2307/1879431 https://doi.org/10.2307/1879431 https://doi.org/10.1007/s11019-008-9138-y https://doi.org/10.1215/03616878-26-5-1045 https://doi.org/10.1215/03616878-26-5-1045 why the economic aspects of healthcare are not unique e172 | squ medical journal, may 2020, volume 20, issue 2 19. arrow kj. reflections on the reflections. j health polit policy law 2001; 26:1197–1203. https://doi.org/10.1215/0361687826-5-1197. 20. eysenbach g. what is e-health? j med internet res 2001; 3:e20. https://doi.org/10.2196/jmir.3.2.e20. 21. porfirio j, jacquinet m, carrilho t. the impact of ict and online social networks on health and social services. in: cruzcunha mm, miranda im, gonçalves p. handbook of research on icts and management systems for improving efficiency in healthcare and social services. hershey, pennsylvania, usa: igi global, 2013. pp. 1224–43. 22. world health organization. the fifty-eighth world health assembly, resolutions and deci-sions. from: apps.who.int/iris/ bitstream/10665/20378/1/wha58_28-en.pdf accessed: dec 2019. 23. kloss ll. leading innovation in enterprise information governance. j ahima 2013; 84:34–38. 24. eysenbach g. online prescriptions of pharmaceuticals: where is the evidence for harm or for benefit? a call for papers-and for reflection. j med internet res 2001; 3:e1. https://doi. org/10.2196/jmir.3.1.e1. 25. cimasi rj. healthcare valuation: volume 1, the 4 pillars of health care value. hoboken, new jersey, usa: wiley, 2014. 26. gaynor m. issues in the industrial organization of the market for physician services. j econ manag strategy 1994; 3:211–55. https://doi.org/10.1111/j.1430-9134.1994.00211.x. 27. evans r. supplier-induced demand: some empirical evidence and implications. in perlman m, ed. the economics of health and medical care. london, uk: macmillan, 1974. pp. 162–73. 28. johar m, mu c, van gool k, wong cy. bleeding hearts, profiteers, or both: specialist physician fees in an unregulated market. health econ 2016; 26:528–35. https://doi.org/10.1002/ hec.3317. 29. reinhardt ue. the pricing of u.s. hospital services: chaos behind a veil of secrecy. health aff 2006; 25:57–69. https://doi. org/10.1377/hlthaff.25.1.57. 30. fuchs vr. the growing demand for medical care. from: www. nber.org/chapters/c3451.pdf accessed: dec 2019. 31. morrisey ma. health care: is health care different? from: www. econlib.org/library/enc/healthcare.html accessed: dec 2019. 32. porter me, teisberg eo. redefining competition in health care. harv bus rev 2004; 82:64–76. 33. kohn lt, corrigan jm, donaldson ms, eds. to err is human: building a safer health system. washington dc, usa: national academies press, 2000. https://doi.org/10.17226/9728. 34. fuchs vr. the “competition revolution” in health care. health aff 1988; 7:5–24. https://doi.org/10.1377/hlthaff.7.3.5. https://doi.org/10.1215/03616878-26-5-1197 https://doi.org/10.1215/03616878-26-5-1197 https://doi.org/10.2196/jmir.3.2.e20 https://doi.org/10.2196/jmir.3.1.e1 https://doi.org/10.2196/jmir.3.1.e1 https://doi.org/10.1111/j.1430-9134.1994.00211.x https://doi.org/10.1002/hec.3317 https://doi.org/10.1002/hec.3317 https://doi.org/10.1377/hlthaff.25.1.57 https://doi.org/10.1377/hlthaff.25.1.57 https://doi.org/10.17226/9728 https://doi.org/10.1377/hlthaff.7.3.5 1obstetrics and gynaecology programme, oman medical speciality board, muscat, oman; 2department of obstetrics and gynaecology, sultan qaboos university hospital, muscat, oman; departments of 3family medicine & public health and 4obstetrics and gynaecology, sultan qaboos university, muscat, oman *corresponding author’s e-mails: gowri@squ.edu.om and gowrie61@hotmail.com ختصص أمراض النساء والوالدة كمهنة طبية مستقبلية لألطباء اخلرجيني يف عمان العوامل اجلاذبة والعوامل املثبطة للخرجيني اأ�سماء ال�ساحلية، متيمة الدغي�سية، جوهر رزيف، جاوري فيدياناثان abstract: objectives: obstetrics and gynaecology (obgyn) is a major speciality in the medical field that is often demanding yet rewarding; however, obgyn receives the least number of applicants in oman. this study aimed to determine the factors that influence graduates in choosing obgyn as their speciality. methods: this cross-sectional questionnaire-based study was conducted from february to march 2017 at sultan qaboos university hospital, royal hospital, khoula hospital and al nahdha hospital, muscat, oman. the questionnaire was distributed to 150 omani medical graduates (interns and post-intern doctors). results: a total of 145 omani graduates took part in the study (response rate: 96.7%) and the participants’ average age was 26 years. family medicine ranked as the first choice followed by paediatrics and emergency medicine. obgyn was the first choice for eight female graduates. the top factors attracting male graduates to the obgyn speciality were its surgical opportunities (80.6%), intellectual content (77.4%), faculty interactions and the opportunity to care for a healthy population (54.8% each); however, the top factors attracting females were the intellectual content (88.6%), patients’ desire for female physicians (85.1%), the opportunity to care for a healthy population (76.3%) and cultural expectations (69.5%). the most discouraging factors for male graduates were cultural expectations (100%), the patients’ desire for a female physician (93.5%) and the level of stress (71%), while the discouraging factors for female graduates were the level of stress (82.5%), time demands (78.1%), night duties and the length of the residency (71.9% each). conclusion: most of the factors that discourage female graduates from choosing obgyn are to some extent modifiable. these changes should be consid ered to encourage the selection of obgyn as a career by medical students. keywords: career choice; obstetrics and gynecology department, hospital; internship and residency; medical student; oman. امللخ�ص: الهدف: تخ�س�ض الن�ساء والولدة من اأهم التخ�س�سات يف املجال الطبي والذي يتطلب جهدا فائقا ولكنه جهد جمزي. على الرغم لتحديد الدرا�سة هذه هدفت عمان. يف الأخرى التخ�س�سات بني من الأقل يعترب التخ�س�ض بهذا لالإلتحاق املتقدمني عدد فاإن ذلك، من العوامل التي توؤثر على اختيار اخلريجني لهذا التخ�س�ض. الطريقة: اأجريت هذه الدرا�سة املقطعية املعتمدة على الإ�ستبيان يف الفرتة من نوفمرب اإىل مار�ض 2017 يف م�ست�سفى جامعة ال�سلطان قابو�ض يف م�سقط، عمان. مت توزيع الإ�ستبيان على 150 طبيبا عمانيا ممن بداأوا مزاولة مهنة الطب يف فرتة �سنة الإمتياز و ما بعد �سنة الإمتياز. النتائج: �سارك يف البحث 145 خريجا عمانيا مبعدل اإ�ستجابة )96.7%( وتبعه )46.5%( امل�ساركني لدى الأول الختيار على الأ�رسة طب تخ�س�ض حاز �سنة. 26 الدرا�سة يف امل�ساركني اأعمار متو�سط وكان تخ�س�سي طب الأطفال )39.4( وطب الطواريء )14.1( .كان تخ�س�ض الن�ساء والولدة الختيار الأول لثمانية من امل�ساركني كلهم اإناث. اأكرث العوامل جذبًا لتخ�س�ض الن�ساء والولدة للم�ساركني الذكور هو توفرالفر�ض اجلراحية )%80.6( و حمتوى املادة العلمية للتخ�س�ض )%77.4( بينما كانت اأكرث العوامل جذبًا للم�ساركات الإناث هو حمتوى املادة العلمية )%88.6( ورغبة املر�سى بطبيبات )%85.1(. اأهم العوامل املثبطة للذكور لالإلتحاق بتخ�س�ض الن�ساء والولدة كان التوقعات املجتمعية جتاه هذا التخ�س�ض )%100( ورغبة املر�سى بطبيبة اأنثى يف هذا املجال )%93.5( بينما كانت اأكرب العوامل املثبطة لالإناث هي م�ستوى ال�سغط النف�سي التي تتعر�سن له يف هذا التخ�س�ض )%82.5( وما يتطلبه من وقت )%78.1(. اخلال�صة: اأغلب العوامل املثبطة لختيار تخ�س�ض الن�ساء والولدة للخريجات الإناث قابلة للتعديل اإىل حٍد ما. هذه التعديالت يجب اأن توؤخذ يف الإعتبار وذلك لتحفيز طالبات الطب لختيار تخ�س�ض الن�ساء و الولدة كمهنة طبية ملزاولتها يف امل�ستقبل. الكلمات املفتاحية: اختيار املهنة؛ تخ�س�ض الن�ساء والولدة؛ م�ست�سفى؛ التدريب والإقامة؛ طالب طب؛ عمان. obstetrics and gynaecology as a future career for medical graduates in oman factors that attract and discourage graduates asma al salehi,1 tamima al dughaishi,2 gauhar rizvi,3 *vaidyanathan gowri4 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e58–62, epub. 30 may 19 submitted 25 jun 18 revisions req. 5 aug & 23 oct 18; revisions recd. 24 sep & 3 nov 18 accepted 8 nov 18 obstetrics and gynaecology (obgyn) is one of the major specialities that medical graduates can choose as a career. however, in oman, the number of graduates applying for residency in this speciality is low. obstetrics is both a gratifying and demanding practice.1 abu-rafea et al.’s study, cond ucted in saudi arabia, showed that the rotation of students through obgyn was the most influential factor in choosing this speciality as a career, attracting 81.3% of the students, followed by faculty interactions (71.9%). the factors that did not have a significant impact on the career decision included lifestyle and income this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.011 brief communication https://creativecommons.org/licenses/by-nd/4.0/ asma al salehi, tamima al dughaishi, gauhar rizvi and vaidyanathan gowri brief communication | e59 prospects, mostly dealing with healthy patients, stress levels and the time demands of the speciality.2 scott et al.’s study was conducted in canada and found that students’ ultimate decision to choose obgyn as their career when they started medical school depended on three elements—selecting it as their first choice at this early stage, being female and wanting a narrow scope of practice.3 in a study conducted in the usa, chang et al. reported that the interest in an obgyn career was stimulated by residents who behaved professionally and also by the students feeling that they were part of the team, including being asked to perform some tasks in the operating room.4 they found that males were more interested in this career if they were included as a functioning part of the team. in contrast to chang et al.’s study, fogarty et al. found that female students were more interested in this speciality than male students. furthermore, this study reported that students’ decision were influenced by sev eral factors—including the obgyn staff, continuity of patient care, primary care opportunities, surgical opport unities and dealing with a healthy patient population.5 in addition, malpractice concerns did not negatively influence their choice.5 the number of births in oman continued to rise between 2011 and 2016 with 18,987 live births and a change rate of 30%.6 consequently, this increase in births requires more specialists to be trained and employed in obgyn. at sultan qaboos university hospital (squh), muscat, oman, the current intake is approximately six residents per year; however, this figure is variable as many of the residents do not take obgyn as their first choice and there is a high dropout rate (approximately 15%; unpublished data). a study to determine the factors that attract omani medical graduates towards obgyn as a future career or discourage them from it is required as the need for specialists in this area is continually increasing. this study aimed to determine the factors that attract and discourage the choice of obgyn as a future career for omani medical graduates and suggests solutions for the most common discouraging factors. methods this observational cross-sectional study was conducted from february to march 2017 at squh. questionnaires were distributed to a convenient sample of 150 omani medical graduates—both interns and post-intern doc tors—of which a total of 145 (response rate: 96.7%) completed the questionnaire. the sample size was 150 as only the interns rotating in muscat were included as other interns were posted elsewhere at the time the study was conducted. it was not possible to include only final year students as most students do clerkships in the final year and the sample size would have been too small. increasing the duration of the study would not have increased the sample size. the survey evaluated age, gender, place of origin, marital status, the medical school they graduated from—sultan qaboos university (squ), oman medical college (omc) or medical schools abroad—their future residency choices and the reasons for these choices. those who did not respond to the question; “do you have an interest in specialising in obgyn as a future career?”, were classified as ‘unsure’. this research was approved by the medical research ethical committee (mrec #1428). verbal consent was given by the participants who completed the survey. results a total of 114 (78.6%) female and 31 (21.4%) male partic ipants completed the questionnaire; the participants’ average age was 26 years (range: 23–29 years). the majority of the participants graduated from squ (51%), followed by omc (40%) and medical schools from abroad (9%). according to the graduates’ responses, fam ily medicine ranked first as a preferred future career (46.5%), followed by paediatrics (39.4%) and emergency medicine (14.1%) [figure 1]. male graduates generally preferred paediatrics and emergency medicine while female graduates preferred family medicine (26.3%), paediatrics (20%) and obgyn (7%). of all the omani graduates, only 20 expressed an interest in the obgyn speciality while 108 showed no interest and 17 were unsure. only one male graduate expressed an interest in obgyn. out of the female graduates, 19 expressed interest in the obgyn speciality, 82 showed no interest and 13 were unsure. of the eight graduates who chose obgyn as their first choice spec iality, two graduated from abroad, four were squ grad uates and two were omc graduates. the main factors attracting male graduates to the obgyn speciality were surgical opportunities (80.6%), intellectual content of obgyn (77.4%), taking care of a healthy population (54.8%) and faculty interaction (54.8%). on the other hand, cultural expectations (100%), patients’ desire for a female physician (93.5%), level of stress (71%) and spouse or family opinion (64.5%) were the most discouraged factors [table 1]. the main factors attracting female graduates to the obgyn speciality were its intellectual content (88.6%), patients’ desire for a female physician (85.1%), taking care of a healthy population (76.3%) and cultural expect ations (69.3%). level of stress (82.5%), time demands (78.1%), night duties (71.9%) and the length of residency (71.9%) were the most discouraging factors in choosing obstetrics and gynaecology as a future career for medical graduates in oman factors that attract and discourage graduates e60 | squ medical journal, february 2019, volume 19, issue 1 obgyn as a future career for female graduates [table 2]. factors influencing female graduates’ choice have been separated according to the institution of graduation in table 3. discussion in this study 20 participants (19 female and one male) expressed an interest in the obgyn speciality, although not as their first career choice. some of the factors that attracted both genders to obgyn were the intellectual content, dealing with a healthy population and faculty interaction; male graduates were also attracted by the surgical opportunities. some of these factors are similar to the findings in the survey by fogarty et al.5 work hours and liability concerns discouraged residents from choosing obgyn in a study by ogburn et al.;7 the current study also reflects these findings. actively involving medical students in the speciality during clinical year rotations and internship training will help increase the number of omani female medical graduates that join the obgyn speciality.4 no parti figure 1: preferred future speciality of omani medical graduates (n = 145). table 1: attracting and discouraging factors of the obstetrics and gynaecology speciality for male omani medical grad uates (n = 31) factor n (%) attracted discouraged neutral rotation through obgyn during medical school 16 (51.6) 11 (35.5) 4 (12.9) presence of a role model in obgyn speciality 13 (41.9) 8 (25.8) 10 (32.3) faculty interaction 17 (54.8) 12 (38.7) 2 (6.5) faculty encouragement 16 (51.6) 10 (32.3) 5 (16.1) previous interaction with obgyn residents 12 (38.7) 7 (22.6) 12 (38.7) taking care of a healthy population 17 (54.8) 6 (19.4) 8 (25.8) patients' desire for a female physician 0 (0) 29 (93.5) 2 (6.5) cultural expectations 0 (0) 31 (100) 0 (0) surgical opportunities 25 (80.6) 5 (16.1) 1 (3.2) hands-on procedures 16 (51.6) 13 (41.9) 2 (6.5) intellectual content of obgyn 24 (77.4) 5 (16.1) 2 (6.5) length of residency 9 (29) 14 (45.2) 8 (25.8) time demands 6 (19.4) 11 (35.5) 14 (45.2) level of stress 3 (9.7) 22 (71) 6 (19.4) night duties 3 (9.7) 16 (51.6) 12 (38.7) income prospects/ financial opportunities 12 (38.7) 11 (35.5) 8 (25.8) spouse/family opinion 2 (6.5) 20 (64.5) 9 (29) affect family life/ family considerations 0 (0) 19 (61.3) 12 (38.7) obgyn = obstetrics and gynaecology. table 2: attracting and discouraging factors of the obstetrics and gynaecology speciality for female omani medical grad uates (n = 114) factor n (%) attracted discouraged neutral rotation through ob gyn during medical school 78 (68.4) 31 (27.2) 5 (4.4) presence of a role model in obgyn speciality school 67 (58.8) 14 (12.3) 33 (28.9) faculty interaction 43 (37.7) 60 (52.6) 11 (9.6) faculty encouragement 64 (56.1) 25 (21.9) 25 (21.9) previous interaction with obgyn residents 55 (48.2) 13 (11.4) 46 (40.4) taking care of a healthy population 87 (76.3) 10 (8.8) 17 (14.9) patients' desire for a female physician 97 (85.1) 4 (3.5) 13 (11.4) cultural expectations 79 (69.3) 5 (4.4) 30 (26.3) surgical opportunities 61 (53.5) 46 (40.4) 7 (6.1) hands-on procedures 78 (68) 30 (26.3) 6 (5.3) intellectual content of obgyn 101 (88.6) 8 (7) 5 (4.4) length of residency 15 (13.2) 82 (71.9) 17 (14.9) time demands 12 (10.5) 89 (78.1) 13 (11.4) level of stress 6 (5.3) 94 (82.5) 14 (12.3) night duties 5 (4.4) 82 (71.9) 27 (23.7) income prospects/ financial opportunities 58 (50.9) 15 (13.2) 41 (36) spouse/family opinion 49 (43) 38 (33.3) 27 (23.7) affect family life/ family considerations 5 (4.4) 76 (66.7) 33 (28.9) obgyn = obstetrics and gynaecology. asma al salehi, tamima al dughaishi, gauhar rizvi and vaidyanathan gowri brief communication | e61 cular strategies have been suggested by other countries to increase the intake of residents in obgyn, yet it appears that recognising the students at the entry level in their clerkship years and having residents who act as role models would help to motivate students.4 during their internship training, medical graduates in oman undergo mandatory rotations in internal med icine and general surgery and the third rotation is a choice of either paediatrics or obgyn. this varies the exposure to obgyn, especially since most graduates choose paediatrics rather than obgyn during their internship year. hammoud et al. reported that an obgyn clerkship in the third year of their curriculum (which may be sixth or seventh year for squ students) was the strongest predictor of interest in the speciality.8 as a future direction we believe additional exposure during internship may increase interest in the obgyn speciality, for female graduates in particular. in exploring the role of gender in the obgyn speciality, balayla concluded that male gynaecologists table 3: attracting and discouraging factors of the obstetrics and gynaecology speciality for female graduates according to institution of graduation (n = 114) factor n (%) attracted discouraged neutral squ (n = 49) omc (n = 55) abroad graduates (n = 10) squ (n = 49) omc (n = 55) abroad graduates (n = 10) squ (n = 49) omc (n = 55) abroad graduates (n = 10) rotation through obgyn during medical school. 26 (53.1) 44 (80) 8 (80) 20 (40.8) 9 (16.4) 2 (20) 3 (6.1) 2 (3.6) 0 (0) presence of a role model in obgyn speciality 26 (53.1) 36 (65.5) 5 (50) 5 (10.2) 8 (14.5) 1 (10) 18 (36.7) 11 (20) 4 (40) faculty interaction 11 (22.4) 27 (49.1) 5 (50) 36 (73.5) 21 (38.2) 3 (30) 2 (4.1) 7 (12.7) 2 (20) faculty encouragement 26 (53.1) 33 (60) 5 (50) 12 (24.5) 11 (20) 2 (20) 11 (22.4) 11 (20) 3 (30) previous interaction with obgyn residents 35 (71.4) 15 (27.3) 5 (50) 5 (10.2) 6 (10.9) 2 (20) 9 (18.4) 34 (61.8) 3 (30) taking care of a healthy population 39 (79.6) 39 (70.9) 9 (90) 4 (8.2) 5 (9.1) 1 (10) 6 (12.2) 11 (20) 0 (0) patient desire for a female physician 41 (83.7) 49 (89.1) 6 (60) 1 (2) 2 (3.6) 1 (10) 7 (14.3) 4 (7.3) 3 (30) cultural expectations 30 (59.2) 44 (80) 5 (50) 3 (6.1) 1 (1.8) 1 (10) 17 (34.7) 9 (16.4) 4 (40) surgical opportunities 24 (49) 30 (54.5) 8 (80) 20 (40.8) 19 (34.5) 2 (20) 5 (10.2) 6 (10.9) 0 (0) hands-on procedures 37 (75.5) 3 (63) 7 (70) 10 (20.4) 16 (29.1) 3 (30) 2 (4.1) 4 (7.3) 0 (0) intellectual content of obgyn 46 (93.9) 47 (85.5) 8 (80) 1 (2) 7 (12.7) 0 (0) 2 (4.1) 1 (1.8) 2 (20) length of residency 6 (12.2) 8 (14.5) 1 (10) 36 (73.4) 40 (72.7) 6 (60) 7 (14.3) 7 (12.7) 3 (30) time demands 5 (10.2) 6 (10.9) 1 (10) 36 (73.5) 47 (85.5) 6 (60) 8 (16.3) 2 (3.6) 3 (30) levels of stress 2 (4.1) 3 (5.5) 1 (10) 45 (91.8) 43 (78.2) 6 (60) 2 (4.1) 9 (16.4) 3 (30) night duties 3 (6.1) 2 (3.6) 0 (0) 35 (71.4) 41 (74.5) 6 (60) 11 (22.4) 12 (21.8) 4 (40) income prospects/financial opportunities 20 (40.8) 32 (58.2) 6 (60) 7 (14.3) 7 (12.7) 1 (10) 22 (44.9) 16 (29.1) 3 (30) spouse/family opinion 19 (38.8) 26 (47.3) 4 (40) 10 (20.4) 15 (27.3) 2 (20) 20 (40.8) 14 (25.5) 4 (40) affect family life/family considerations 1 (2) 4 (7.3) 0 (0) 33 (67.3) 39 (70.9) 4 (40) 15 (30.6) 12 (21.8) 6 (60) squ = sultan qaboos university; omc = oman medical college; obgyn = obstetrics and gynaecology. obstetrics and gynaecology as a future career for medical graduates in oman factors that attract and discourage graduates e62 | squ medical journal, february 2019, volume 19, issue 1 can provide high-quality care for females, yet culture is still the most discouraging factor for males in choosing this speciality in oman.9 chang et al. reported that male students experienced gender bias and described feeling socially excluded from clinical teams dominated by females.10 to correct this, craig et al. suggested that male students have early exposure to obgyn in the pre-clinical years and encouraged the medical faculty to ensure that all students have a positive experience during their clerkship.11 a review by lyon also comm ented on females’ dominance in the speciality and expressed fear regarding the security of the speciality.12 efforts need to be made to increase awareness about this issue and to encourage male graduates to join the obgyn speciality. raising awareness can start with obgyn training during the clinical years of medical school and throughout. when a gynaecologist is needed, it should not matter whether the doctor is a male or female (as happens in saudi arabia and many other muslim and arab countries). television and radio aware ness programmes could play a major role in enlightening the population. announcements by muftis on this issue would also be helpful. nevertheless, in view of the cultural preference for female gynaecologists, increasing the number of female medical graduates choosing this speciality needs to be a priority. the results of this study are limited due to the nonhomologous nature of the sample (interns and post intern doctors), the participants’ recent postings at the time of survey and the unequal sample size from diff erent institutions. another factor was the limited number of participating males; however, approximately 66% of students at squ are female even among the under graduates. hence, the male response rate of 22% is acceptable in that it reflects the current situation. conclusion female and male students need more exposure to the obgyn speciality earlier in their training. obgyn should be made a mandatory rotation in the internship programme, especially for females. reducing workrelated stress, offering more incentives and ensuring the presence of role models in the speciality will help per suade more interns to choose this speciality. religious leaders and the media should help in educating the public and encourage more students to choose this speciality. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bédard mj, berthiaume s, beaulieu md, leclerc c. factors infl uencing the decision to practise obstetrics among québec medical students: a survey. j obstet gynaecol can 2006; 28:1075–82. https://doi.org/10.1016/s1701-2163(16)32323-4. 2. abu-rafea bf, al-hassan bf, al nakshabandi ka, rahbini no, al-shaikh gk. factors influencing students' decision in choosing obstetrics and gynecology as a career in a university hospital in central saudi arabia. saudi med j 2011; 32:730–4. 3. scott im, nasmith t, gowans mc, wright bj, brenneis fr. obstetrics and gynaecology as a career choice: a cohort study of canadian medical students. j obstet gynaecol can 2010; 32:1063–9. https://doi.org/10.1016/s1701-2163(16)34715-6. 4. chang jc, odrobina mr, mcintyre-seltman k. residents as role models: the effect of the obstetrics and gynecology clerk ship on medical students' career interest. j grad med educ 2010; 2:341–5. https://doi.org/10.4300/jgme-d-09-00070.1. 5. fogarty ca, bonebrake rg, fleming ad, haynatzki g. obstetrics and gynecology--to be or not to be? factors influencing one’s deci sion. am j obstet gynecol 2003; 189:652–4. https://doi.org/10. 1067/s0002-9378(03)00880-9. 6. times of oman. 'more than 88,000 live births reported in oman last year'. from: https://timesofoman.com/article/119474 accessed: nov 2018. 7. ogburn t, espey e, autry a, leeman l, bachofer s. why obst etrics/gynecology, and what if it were not an option? a survey of resident applicants. am j obstet gynecol 2007; 197:538.e1–4. https://doi.org/10.1016/j.ajog.2007.07.024. 8. hammoud mm, stansfield rb, katz nt, dugoff l, mccarthy j, white cb. the effect of the obstetrics and gynecology clerk ship on students’ interest in a career in obstetrics and gynecology. am j obstet gynecol 2006; 195:1422–6. https://doi.org/10.1016/j. ajog.2006.07.044. 9. balayla j. male physicians treating female patients: issues, controversies and gynecology. mcgill j med 2011; 13:72. 10. chang jc, odrobina mr, mcintyre-seltman k. the effect of stud ent gender on the obstetrics and gynecology clerkship experience. j womens health (larchmt) 2010; 19:87–92. https://doi.org/10.10 89/jwh.2009.1357. 11. craig lb, buery-joyner sd, bliss s, everett en, forstein da, graziano sc, et al. to the point: gender differences in the obst etrics and gynecology clerkship. am j obstet gynecol 2018; 219:430–5. https://doi.org/10.1016/j.ajog.2018.05.020. 12. lyon ds. graduate education in women's health care: where have all the young men gone? curr womens health rep 2002; 2:170–4. https://doi.org/10.1016/s1701-2163%2816%2932323-4 https://doi.org/10.1016/s1701-2163%2816%2934715-6 https://doi.org/10.4300/jgme-d-09-00070.1 https://doi.org/10.1067/s0002-9378%2803%2900880-9 https://doi.org/10.1067/s0002-9378%2803%2900880-9 https://doi.org/10.1016/j.ajog.2007.07.024 https://doi.org/10.1016/j.ajog.2006.07.044 https://doi.org/10.1016/j.ajog.2006.07.044 https://doi.org/10.1089/jwh.2009.1357 https://doi.org/10.1089/jwh.2009.1357 https://doi.org/10.1016/j.ajog.2018.05.020 1department of child health and 2directorate of nursing, sultan qaboos university hospital, muscat, oman; 3department of pediatrics and 4research section, oman medical specialty board, muscat, oman; 5institute on development & disability and department of psychiatry, oregon health & science university, portland, united states of america *corresponding author’s e-mail: ahmed30411@gmail.com parental age and the risk of autism spectrum disorder in oman a case-control study watfa al-mamari,1 *ahmed b. idris,1 aala' a. al-zadjali,3 saquib jalees,1 sathiya murthi,4 muna al-jabri,2 ahlam gabr,1 eric fombonne5 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 465–471, epub. 29 aug 21 submitted 25 aug 20 revision req. 18 oct 20; revision recd. 28 oct 20 accepted 21 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.024 clinical & basic research abstract: objectives: this study aimed at evaluating advanced parental age as a risk factor for autism spectrum disorder (asd) in an omani cohort. methods: this case-control study compared 278 asd cases with 722 gendermatched controls, retrieved from the electronic records of the developmental paediatric clinic, sultan qaboos university hospital, muscat, oman, between january 2015 and june 2016. results: most asd cases were male (76.6%) and mostly diagnosed between 3–4 years of age, with more than 50% of the cases originating from muscat and batinah governorates. compared to controls, mothers from the case group had significantly higher educational levels (post-secondary education versus high school/no formal education: odds ratio [or] = 1.62, 95% confidence interval [ci]: 1.197–2.192). in a multivariate logistic regression, the or of maternal age as a risk for asd increased dramatically with advancing age category (using age <25 as reference, or = 3.39, 6.12, 7.86 and 13.13 for age categories 25–29, 30–34, 35–39 and ≥40 years, respectively). the ors of advancing paternal age as a risk for asd were also statistically significant (using age <30 as reference, or = 2.20, 2.36 and 3.12 for age categories 30–34, 35–39 and 40–44 years, respectively); however, there was a drop in the effect with paternal age ≥45 years (or = 1.42; 95% ci: 0.64–3.15). conclusion: both maternal and paternal increased age were associated with a higher risk of asd; however, the association was more pronounced and more consistent with advanced maternal age compared to paternal age. keywords: autism; parental age; case-control study; oman. advances in knowledge this study tested the association between advancing parental age and autism spectrum disorder (asd) in an omani population characterised by a younger marriage and conception age and a high proportion of consanguineous unions. advanced maternal age was associated with a significantly increased risk of having a child with autism in a dose-response manner. a significant paternal age effect was also found but it was smaller than that for maternal age and was not significant anymore at age ≥45 years, a finding that warrants further examination. application to patient care consideration of the relationship between advanced parental age and risk of having a child with asd can assist in counselling with respect to pregnancy at an older age. autism spectrum disorder (asd) is a neurodevelopmental disorder with hallmark features of deficits in social interaction and social communication along with restricted, repetitive patterns of behaviour, interests or activities.1 globally, the prevalence of asd was estimated to be 62 per 10,000 while it was 185 per 10,000 (one in 54) in the united states.2,3 in oman, the prevalence of asd, based on 2019 estimates, was 20.35 per 10,000 children and was 15-fold greater than estimates in 2011.4 the increment in asd prevalence worldwide is attributed mainly to an increase of diagnostic facilities and services, awareness and diagnostic substitution.5 many perinatal factors were found to be associated with asd but none has been proven to be the causative aetiologic factor. for instance, maternal obesity, maternal gestational diabetes, caesarean section, preterm deliveries, congenital malformations, low birth weight and low apgar scores were observed to be associated with an increased risk of asd in children.6–9 interestingly, whether those factors have a causal effect or play a secondary role in shaping the phenotype in a genetically susceptible individual is still not established. hence, it was suggested to combine the factors that are implicated in the asd risk in one model to examine their effects jointly.10 the association between advanced parental age and asd has been examined extensively. initial reports were highlighted by reichenberg et al. with observations further tested in different western populations.11–14 a meta-analysis was conducted, utilising a dose-response analysis to investigate the https://creativecommons.org/licenses/by-nd/4.0/ parental age and the risk of autism spectrum disorder in oman a case-control study 466 | squ medical journal, august 2021, volume 21, issue 3 effect of increasing parental age on the risk of autism; the results showed that an increase of 10 years in maternal age was associated with an 18% higher risk of autism.15 the effect was more obvious in fathers, where an increase of 10 years was associated with 21% higher risk of autism.15 to overcome the effect of the other parent’s age as a confounding factor, sandin et al. examined the joint effect of maternal and paternal age in a population-based study across five countries.14 the results revealed that for mothers older than 40 years, the relative risk (rr) of autism in offspring increased in a u-shaped pattern with younger and older fathers. this was contrasted by effect among fathers ≥45 years, where the rr increases monotonically with increasing maternal age.14 despite several publications documenting the association between advanced parental age and asd, the underpinning mechanism is still ill-defined.15 copyerrors in the germ cell resulting in de novo mutations in the offspring of older males was proposed as one possible underpinning mechanism.16,17 however, the effects of replication errors in the germline alone can not explain the full epidemiological data; rather, it is portrayed to be multifactorial. aside from replication errors, lifetime environmental exposures and epigenetic alterations have been described as explanatory pathways that contribute to the causation of complex disorders such as autism.18 most studies about the effect of advanced parental age in asd risk were conducted on western samples with limited data from middle eastern populations that possess interesting differences in demographic features. in oman, for instance, the population median age is 26.3 years and considered as a young population compared to those of denmark, usa, sweden and norway, where the population median age is 41.1, 37.4, 41 and 39 years, respectively.19 the current study aimed to test the association between advancing parental age and asd risk in an omani cohort that represents one middle eastern population. specific characteristics of this omani population’s demographic features, such as younger age and younger marriage and conception ages, combined with high consanguinity rates, provided a unique opportunity to replicate parental age findings in autism in a different population and to identify moderating factors that might mitigate the risk.20 methods this case-control study included 278 cases with asd and 722 non-autistic gender-matched controls. all omani children aged less than 14 years and diagnosed at the developmental paediatric clinic, sultan qaboos university hospital, muscat, oman, were eligible to be included in the study as cases. data were obtained from electronic records between january 2015 and june 2016. asd diagnosis was confirmed by a multidisc iplinary team assessment to ensure fulfilment of diag nostic and statistical manual of mental disorders-5 diagnostic criteria.1 the diagnostic teams were comp osed of a psychologist, speech and language therapist, occupational therapist, a paediatrician experienced in autism and a certified developmental paediatrician. the diagnostic procedure included the utilisation of autism diagnostic interview-revised (adi™-r) and the autism diagnostic observation schedule, second edition (ados™-2) as the gold standard methods of asd diagnosis. all simplex cases were included and for multiplex families, one child only among the affected siblings was retained in order to maintain the independence of observations. the control group was selected from the national registry of the ministry of health, oman, with data derived from the child’s electronic health record. oman has a free universal healthcare system with almost 96% of deliveries recorded in health facilities. children’s health records contain information completed by health personnel with data stored in two formats: a paper card belonging to the mother and electronic records in the health system. the electronic record is linked to the individual’s unique national identifier and contains sociodemographic information along with health information about the mother and infant.21 the electronic records of the control group were reviewed to ensure the absence of neurodevelopmental or behavioural disturbances that could be related to or confused with autism. controls were randomly selected and matched with cases with respect to age, gender and geographical area. whenever the matching procedure permitted, up to three controls were selected for each case in order to increase statistical power. in some cases, especially at older ages, once controls had been identified from the same geographical area and gender, there were fewer than three available controls, which explains why the average age of controls is slightly lower than that of the cases. medical and electronic records data were extracted on a survey sheet. data included the child’s gender, date of birth, date of diagnosis, residence, parents’ level of education and age of the child at the time of asd diagnosis. data were transferred into an excel sheet where the age of the parents at birth of their child with asd was calculated by subtracting the child’s age at time of diagnosis from the parents’ age at time of diagnosis. for the control group, the age of watfa al-mamari, ahmed b. idris, aala' a. al-zadjali, saquib jalees, sathiya murthi, muna al-jabri, ahlam gabr and eric fombonne clinical and basic research | 467 the parents at birth was provided in the child’s health card record. the participant’s national identifier was substituted with a research identification number to ensure confidentiality, abiding by ethical guidelines. data were analysed using statistical package for the social sciences (spss), version 25.0 (ibm corp., armonk, new york, usa). bivariate associations were evaluated using a chi-squared test for categorical data and t-tests for continuous variables. then, a series of bivariate logistic regression models were estimated using case status (asd = 1 and control = 0) as the dependent variable and predictors (child age, delivery mode, parental age, maternal education status level and governorate of residence) that could be acting as confounding variables. bivariate associations were estimated between cases and controls in terms of children’s demographics, maternal and parental age groups with unadjusted odds ratios (or) and 95% confidence intervals (ci). only those independent variables that had a weak association (p <0.15) with case status were retained for later inclusion in a multiple logistic regression analysis. finally, a stepwise multiple logistic regression was conducted with case status as the dependent variable, paternal age and maternal age as risk factors of interest and all potential confounding variables were retained in the previous step. the full multiple logistic regression model was evaluated with the loglikelihood and wald statistics; a p value of <0.05 was considered for retaining a variable in the model as statistically significant. goodness-of-fit of the final model was estimated with the hosmer-lemeshow statistic. ethical approval was obtained from the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos univ ersity, muscat, oman, and the centre of studies and research, research committee, ministry of health, oman (mrec #752; unique identification code #5820, respectively). results a total of 1000 subjects were studied where 278 (27.8%) were asd cases and 722 (72.2%) were controls. of all included children, 78.0% were male; the male to female ratio was 3.28:1 in the asd group. over half of the cohort resided in muscat and batinah governorates (28.4% and 27.6%, respectively) [table 1]. there was no statistically significant difference observed between cases and controls in terms of gender and mode of delivery (p >0.05); however, statistically significant differences were observed in maternal education (p = 0.001), categorical maternal and paternal ages (p <0.001 each). despite this study’s attempt to match the ages when selecting cases and controls, the child’s age was also significantly different between the two groups and, therefore, the child’s age was subsequently adjusted for in following analyses [table 2]. in a multivariate logistical model, with the exception of child age, all independent variables significantly contributed to the model. highlyeducated mothers were more likely to have a child with asd compared to school-educated mothers or those with no formal education (adjusted or = 1.48, 95% ci: 1.07–2.07). the odds of having a child with asd increased significantly with advancing maternal age in a dose-response fashion with the highest risk estimate being for mothers ≥40 years. there was also an increased risk of asd with increasing paternal age. the magnitude of the risk increase was less for paternal age compared to maternal age (adjusted or = 1.42–3.12 versus 3.39–13.13). furthermore, the or for fathers in the oldest age group (≥45 years) table 1: characteristics of children with autism spectrum disorder and non-autistic matched controls (n = 1,000) characteristic n (%) asd (n = 278) controls (n = 722) mean age in months ± sd 58.1 ± 22.4 53.2 ± 12.6 age category in years 0–2 16 (5.8) 32 (4.4) 3 77 (27.7) 225 (31.2) 4 83 (29.9) 234 (32.4) 5 50 (18.0) 144 (19.9) 6 21 (7.6) 63 (8.7) ≥7 31 (11.2) 24 (3.3) gender female 65 (23.4) 155 (21.5) male 213 (76.6) 567 (78.5) governorate of residence muscat 74 (26.6) 210 (29.1) buraimi 8 (2.9) 12 (1.7) batinah 77 (27.7) 199 (27.6) dahira 10 (3.6) 26 (3.6) dhofar 24 (8.6) 61 (8.4) dakhiliya 34 (12.2) 83 (11.5) sharqia 51 (18.3) 131 (18.1) asd = autism spectrum disorder; sd = standard deviation. parental age and the risk of autism spectrum disorder in oman a case-control study 468 | squ medical journal, august 2021, volume 21, issue 3 was not significant anymore (p = 0.389) although the or estimate remained above 1 (or = 1.42) [table 3]. the child’s age was statiscally significant (p = 0.011) but weakly predictive of case status although no statistical difference was found for any age-specific stratum. the model fit with the data was good as indicated by the hosmer-lemeshow chi-square goodness-of-fit (χ2 = 3.67, 8 degrees of freedom; p = 0.886). discussion males constituted 76.6% of the studied cases, which is in line with the gender distribution of autism in epidemiological studies.22 the geographical distribution of autism cases revealed that approximately half reside in the governorates of muscat and batinah, which follows the geographical distribution of the population in oman.23 interestingly, 33.5% of mothers with children who have asd had a bachelor’s degree or higher educational level, which was significantly higher than the control group (23.7%; p = 0.001). a similar finding was noticed in a study investigating the birth cohort and administrative asd records in california, usa, where investigators found that educated parents and high socioeconomic status families had significantly lower age of diagnosis for their children, which could be explained by better access to care.24 thus, it can be hypothesised that omani mothers with higher education levels are reporting their children with asd symptomatology earlier than less-educated mothers. both increasing paternal and maternal ages were associated with increased risk of asd; however, the effect was stronger and more consistent among mothers. this study’s findings showed that increasing maternal age was associated with increased asd risk table 2: associations between the studied variables and case-control status using bivariate regression (n = 1,000) variable n (%) p value unadjusted or (95% ci) controls (n = 722) cases (n = 278) male gender 567 (78.5) 213 (76.6) 0.283 0.896 (0.644–1.246) caesarian section 140 (19.4) 55 (19.8) 0.476 1.02 (0.724–1.452) maternal education of bachelor’s degree or higher 171 (23.7) 93 (33.5) 0.001 1.62 (1.197–2.192) maternal age category in years <25 141 (19.5) 7 (2.5) <0.001 reference 25–29 234 (32.4) 54 (19.4) 4.65 (2.06–10.50) 30–34 203 (28.1) 105 (37.8) 10.42 (4.71–23.06) 35–39 112 (15.5) 80 (28.8) 14.39 (6.39–32.39) ≥40 32 (4.4) 32 (11.5) 20.14 (8.16–49.71) paternal age category in years <30 194 (26.9) 19 (6.8) <0.001 reference 30–34 221 (30.6) 76 (27.3) 3.51 (2.05–6.02) 35–39 166 (23.0) 88 (31.7) 5.41 (3.16–9.26) 40–44 77 (10.7) 65 (23.4) 8.62 (4.85–15.32) ≥45 64 (8.9) 30 (10.8) 4.79 (2.52–9.08) child’s age category in years 0–2 32 (4.4) 16 (5.8) <0.001 reference 3 225 (31.2) 77 (27.7) 0.68 (0.36–1.32) 4 234 (32.4) 83 (29.9) 0.71 (0.37–1.36) 5 144 (19.9) 50 (18.0) 0.69 (0.35–1.37) 6 63 (8.7) 21 (7.6) 0.67 (0.31–1.45) ≥7 24 (3.3) 31 (11.2) 2.58 (1.16–5.76) or = odds ratio; ci = confidence interval. watfa al-mamari, ahmed b. idris, aala' a. al-zadjali, saquib jalees, sathiya murthi, muna al-jabri, ahlam gabr and eric fombonne clinical and basic research | 469 in a dose-response relationship, which culminated at over 40 years of age with an or of 13.13 (95% ci: 4.63–37.26). the effect of increased maternal age was found to be monotonic and, by virtue of the logistic regression analysis, was independent of the paternal age’s effect. interestingly, the or of asd risk in this cohort increased dramatically with advancing maternal age category (or = 3.39, 6.12, 7.86 and 13.13 for age categories 25–29, 30–34, 35–39 and ≥40 years, respectively) in a similar fashion than in studies done in other populations.25,26 there was no data to further test hypotheses on mechanisms that could underlie the maternal age findings. however, based on published literature, it is hypothesised that advancing maternal age is associated with an indirect secular effect of increased obstetric and neonatal complications (e.g. pre-pregnancy obesity, excessive weight gain during pregnancy, gestational diabetes, caesarean section and preterm deliveries); despite no causal linkage being found for this hypothesis, advanced maternal age’s contribution to asd risk is plausible due to documented risk of maternal and neonatal complications.7,27 although this dataset lacked information about infertility, in vitro fertilisation treatment and intracytoplasmic sperm injection (icsi), it has been postulated that offspring of mothers who underwent icsi for conception (who also tend to be older) may have a statistically higher risk of having a child with autism.28 however, despite the multiple hypotheses postulated to explain the association between advanced maternal age and asd, no clear conclusion has yet been reached in the literature. the effect of advanced paternal age was also found to be significant in this study, although of lesser magnitude when compared to the robust association of maternal age and asd risk. the or distribution was lower than that for maternal age from 25 to 44 years (or = 2.20, 2.36 and 3.12 for age categories 30– 34, 35–39 and 40–44 years, respectively); however, the risk increase was statistically noteworthy and added to the effect of maternal age. the de novo mutations theory, which is linked to advanced paternal age, could be a plausible explanation for the effect. for example, among asd cases from the simons simplex collection, coding de novo mutations, including cases with copy number variants, contributed to approximately 30% of simplex cases and to 45% of female asd cases.29 surprisingly, there was a decrease in the effect among fathers ≥45 years in the current study, which could be due to a selection bias or to the small sample size of older fathers. however, other possibilities related to special demographic characteristics and to the local context should be considered. for instance, the population in oman is considered younger than western communities with consanguinity marriage rates of approximately 52%, which is much higher than in western populations.19,20 the risk of asd at advanced paternal age was explained by de novo mutations; however, that relationship might be different in a highly consanguineous population with increased prevalence of recessive alleles.29,30 therefore, the findings of the drop in paternal age’s effect can support the multifactorial pathway theory with a different interplay of physio-pathological mechanisms in a diverse population context.18 considering the importance of maternal and child health, this study’s findings can assist in counselling with regards to the risks of pregnancy at an older age. the strength of this study stems from the large sample size and that it is the first study to assess the effect of advancing parental age in asd risk in an omani population. however, the data should be interpreted table 3: final model of the multiple logistic regression analysis variable beta coefficient p value adjusted or (95% ci) maternal education of bachelor’s degree or higher 0.396 0.020 1.48 (1.07–2.07) maternal age category in years <25 reference 25–29 1.220 0.004 3.39 (1.47–7.79) 30–34 1.811 <0.001 6.12 (2.63–14.24) 35–39 2.062 <0.001 7.86 (3.22–19.19) ≥40 2.575 <0.001 13.13 (4.63–37.26) paternal age category in years <30 reference 30–34 0.788 0.007 2.20 (1.24–3.91) 35–39 0.857 0.006 2.36 (1.27–4.36) 40–44 1.139 0.001 3.12 (1.58–6.16) ≥45 0.350 0.389 1.42 (0.64–3.15) child’s age category in years 0–2 reference 3 −0.435 0.219 0.647 (0.32–1.30) 4 −0.316 0.370 0.729 (0.37–1.46) 5 −0.323 0.382 0.724 (0.35–1.50) 6 −0.434 0.305 0.648 (0.28–1.48) ≥7 0.742 0.089 2.101 (0.89–4.94) or = odds ratio; ci = confidence interval. parental age and the risk of autism spectrum disorder in oman a case-control study 470 | squ medical journal, august 2021, volume 21, issue 3 with caution, taking into consideration that asd cases originated from a single centre along with a short study duration. while the control group electronic records were reviewed to ensure the absence of neurodevelopmental symptoms that could be related to asd, the absence of direct clinical assessment of this control group could have led to misclassification, although this risk remains small. moreover, if such misclassification occurred, it would have biased the results towards the null hypothesis and resulted in some underestimation of the associations reported on parental age and risk of autism. furthermore, there is a possibility of unmeasured confounding variables and residual confounding, which may bias the risk associations found. nevertheless, the importance of this initial observation arises from the similarities in demographic features in gulf corporation council (gcc) countries, which necessitates more studies to verify such findings in particular, as well as to more generally investigate autism epidemiology, comorbidities, outcome and efficacy of treatment strategies. conclusion increased parental age was associated with a heightened risk of asd in their offspring; the risk increase was more robust for advanced maternal age. investigations of changes in maternal health with increasing age for several medical conditions (obesity, diabetes, etc.) that have been associated with an increased risk of asd in offspring are needed. the or distribution for paternal age was lower than that for maternal age from 25 to 44 years; however, the effect of paternal age was still statistically significant. surprisingly, this study found a decrease in the or with a paternal age of ≥45 years, which requires further testing. this finding may support the multifactorial pathway hypothesis to explain the effect of parental age in asd risk. further studies are needed and, keeping in mind the similarities in demographic features among gcc populations, multicentre studies with larger sample sizes should be facilitated. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s c o n t r i b u t i o n wm and abi conceptualised the idea and drafted the manuscript. sj, wm, ag and abi did the clinical assessment. the data collection was done by aaa-z and mj. ef revised the initial version of the manuscript. the data management and data analysis were done by sm and ef. ef, wm and abi revised the final manuscript. all authors approved the final version of the manuscript. references 1. american psychiatric association. diagnostic and statistical manual of mental disorders. 5th ed. washington: american psychiatric association, 2013. 2. maenner mj, shaw ka, baio j; eds1, washington a, patrick m, et al. prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, united states, 2016. mmwr surveill summ 2020; 69:1–12. https://doi.org/10.15585/mmwr.ss6904a1. 3. elsabbagh m, divan g, koh y, kim ys, kauchali s, marcín c, et al. global prevalence of autism and other pervasive develop mental disorders. autism res 2012; 160–79. https://doi.org/1 0.1002/aur.239. 4. al-mamri w, idris ab, dakak s, al-shekaili m, al-harthi z, alnaamani am, et al. revisiting the prevalence of autism spectrum disorder among omani children a multicentre study. sultan qaboos univ med j 2019; 19:e305–9. https://doi.org/10.18295/ squmj.2019.19.04.005. 5. polyak a, kubina rm, girirajan s. comorbidity of intellectual disability confounds ascertainment of autism: implications for genetic diagnosis. am j med genet part b neuropsychiatr genet 2015; 168:600–8. https://doi.org/10.1002/ajmg.b.32338. 6. hultman cm, sparén p, cnattingius s. perinatal risk factors for infantile autism. epidemiology 2002; 13:417–23. https://doi. org/10.1097/00001648-200207000-00009. 7. getahun d, fassett mj, peltier mr, wing da, xiang ah, chiu v, et al. association of perinatal risk factors with autism spectrum disorder. am j perinatol 2017; 34:295–304. https:// doi.org/10.1055/s-0036-1597624. 8. xiang ah, wang x, martinez mp, walthall jc, curry es, page k, et al. association of maternal diabetes with autism in offspring. jama 2015; 313:1425–34. https://doi.org/10.1001/ jama.2015.2707. 9. jo h, schieve la, sharma aj, hinkle sn, li r, lind jn. maternal prepregnancy body mass index and child psychosocial development at 6 years of age. pediatrics 2015; 135:e1198–209. https://doi.org/10.1542/peds.2014-3058. 10. wang c, geng h, liu w, zhang g. prenatal, perinatal, and postnatal factors associated with autism: a meta-analysis. medicine (baltimore) 2017; 96:e6696. https://doi.org/10.1097/ md.0000000000006696. 11. reichenberg a, gross r, weiser m, bresnahan m, silverman j, harlap s, et al. advancing paternal age and autism. arch gen psychiatry 2006; 63:1026–32. https://doi.org/10.1001/archps yc.63.9.1026. 12. durkin ms, maenner mj, newschaffer cj, lee lc, cunniff cm, daniels jl, et al. advanced parental age and the risk of autism spectrum disorder. am j epidemiol 2008; 168:1268–76. https:// doi.org/10.1093/aje/kwn250. 13. parner et, baron-cohen s, lauritsen mb, jørgensen m, schieve la, yeargin-allsopp m, et al. parental age and autism spectrum disorders. ann epidemiol 2012; 22:143–50. https:// doi.org/10.1016/j.annepidem.2011.12.006. 14. sandin s, schendel d, magnusson p, hultman c, surén p, susser e, et al. autism risk associated with parental age and with increasing difference in age between the parents. mol psychiatry 2016; 21:693–700. https://doi.org/10.1038/mp.2015.70. https://doi.org/10.15585/mmwr.ss6904a1 https://doi.org/10.1002/aur.239 https://doi.org/10.1002/aur.239 https://doi.org/10.18295/squmj.2019.19.04.005 https://doi.org/10.18295/squmj.2019.19.04.005 https://doi.org/10.1002/ajmg.b.32338 https://doi.org/10.1097/00001648-200207000-00009 https://doi.org/10.1097/00001648-200207000-00009 https://doi.org/10.1055/s-0036-1597624 https://doi.org/10.1055/s-0036-1597624 https://doi.org/10.1001/jama.2015.2707 https://doi.org/10.1001/jama.2015.2707 https://doi.org/10.1542/peds.2014-3058 https://doi.org/10.1097/md.0000000000006696 https://doi.org/10.1097/md.0000000000006696 https://doi.org/10.1001/archpsyc.63.9.1026 https://doi.org/10.1001/archpsyc.63.9.1026 https://doi.org/10.1093/aje/kwn250 https://doi.org/10.1093/aje/kwn250 https://doi.org/10.1016/j.annepidem.2011.12.006 https://doi.org/10.1016/j.annepidem.2011.12.006 https://doi.org/10.1038/mp.2015.70 watfa al-mamari, ahmed b. idris, aala' a. al-zadjali, saquib jalees, sathiya murthi, muna al-jabri, ahlam gabr and eric fombonne clinical and basic research | 471 15. wu s, wu f, ding y, hou j, bi j, zhang z. advanced parental age and autism risk in children: a systematic review and metaanalysis. acta psychiatr scand 2017; 135:29–41. https://doi.org/1 0.1111/acps.12666. 16. o’roak bj, vives l, girirajan s, karakoc e, krumm n, coe bp, et al. sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. nature 2012; 485:246–50. https://doi.org/10.1038/nature10989. 17. o’roak bj, vives l, fu w, egertson jd, stanaway ib, phelps ig, et al. multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. science 2012; 338:1619–22. https://doi.org/10.1126/science.1227764. 18. janecka m, mill j, basson ma, goriely a, spiers h, reichenberg a, et al. advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms. transl psychiatry 2017; 7:e1019. https://doi.org/10.1038/tp.2016.294. 19. world health organization. global health observatory data repository. from: https://apps.who.int/gho/data/view.main. pop2040 accessed: jul 2020. 20. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571–94. https://doi.org/10.1017/s0021932012000016. 21. al farsi m, west dj jr. use of electronic medical records in oman and physician satisfaction. j med syst 2006; 30:17–22. https://doi.org/10.1007/s10916-006-7399-7. 22. lyall k, croen l, daniels j, fallin md, ladd-acosta c, lee bk, et al. the changing epidemiology of autism spectrum disorders. annu rev public health 2017; 38 :81–102. https://doi.org/10.11 46/annurev-publhealth-031816-044318. 23. national centre for statistics and information. statistical year book: 2017. from: https://www.ncsi.gov.om/elibrary/li brarycontentdoc/bar_statistical%20year%20book%202017_ c2111831-e13a-4075-bf7b-c4b5516e1028.pdf accessed: oct 2020. 24. fountain c, king md, bearman ps. age of diagnosis for autism: individual and community factors across 10 birth cohorts. j epidemiol community health 2011; 65:503–10. https://doi. org/10.1136/jech.2009.104588. 25. croen l, najjar d, fireman b, grether jk. maternal and paternal age and risk of autism spectrum disorders. arch pediatr adolesc med 2007; 161:334–40. https://doi.org/10.1001/ archpedi.161.4.334. 26. shelton jf, tancredi dj, hertz-picciotto i. independent and dependent contributions of advanced maternal and paternal ages to autism risk. autism res 2010; 3:30–9. https://doi. org/10.1002/aur.116. 27. jacobsson b, ladfors l, milsom i. advanced maternal age and adverse perinatal outcome. obstet gynecol 2004; 104:727–33. https://doi.org/10.1097/01.aog.0000140682.63746.be. 28. sandin s, nygren kg, iliadou a, hultman cm, reichenberg a. autism and mental retardation among offspring born after in vitro fertilization. jama 2013; 310:75–84. https://doi. org/10.1001/jama.2013.7222. 29. iossifov i, o’roak bj, sanders sj, ronemus m, krumm n, levy d, et al. the contribution of de novo coding mutations to autism spectrum disorder. nature 2014; 515:216–21. https:// doi.org/10.1038/nature13908. 30. al-thihli k, al-murshedi f, al-hashmi n, al-mamari w, islam mm, al-yahyaee sa. consanguinity, endogamy and inborn errors of metabolism in oman: a cross-sectional study. hum hered 2014; 77:183–8. https://doi.org/10.1159/000362686. https://doi.org/10.1111/acps.12666 https://doi.org/10.1111/acps.12666 https://doi.org/10.1038/nature10989 https://doi.org/10.1126/science.1227764 https://doi.org/10.1038/tp.2016.294 https://doi.org/10.1017/s0021932012000016 https://doi.org/10.1007/s10916-006-7399-7 https://doi.org/10.1146/annurev-publhealth-031816-044318 https://doi.org/10.1146/annurev-publhealth-031816-044318 https://doi.org/10.1136/jech.2009.104588 https://doi.org/10.1136/jech.2009.104588 https://doi.org/10.1001/archpedi.161.4.334 https://doi.org/10.1001/archpedi.161.4.334 https://doi.org/10.1002/aur.116 https://doi.org/10.1002/aur.116 https://doi.org/10.1097/01.aog.0000140682.63746.be https://doi.org/10.1001/jama.2013.7222 https://doi.org/10.1001/jama.2013.7222 https://doi.org/10.1038/nature13908 https://doi.org/10.1038/nature13908 https://doi.org/10.1159/000362686 multiple myeloma (now known as plasma cell myeloma) is a malignant disease caused by a proliferation of clonal plasma cells associated with a monoclonal protein or light chain in the serum and/or urine.1 patients with plasma cell myeloma commonly present with hypercalcaemia, renal insufficiency, anaemia and/ or bony lesions.2 however, the disease can present with a wide variety of clinical manifestations as a result of the involvement of various organ systems, due to either direct infiltration by plasma cells or the deposition of monoclonal proteins or light chains.3 pleural effusions are seen in a minority of patients with myeloma. however, effusions directly related to infiltration of the pleura by plasma cells, i.e. myelomatous pleural effusions (mpe), are extremely rare. in this paper, we report a case of an omani patient with relapsed myeloma who developed a true myelomatous pleural effusion. we also present a review of the relevant literature. case report a 55 year-old man was diagnosed with duriesalmon stage iiia igg kappa plasma cell myeloma in 2004. he was treated for three months with a combination of thalidomide and steroids-based therapy and achieved a partial response. he was subsequently lost to follow-up and presented again in 2007 with progressive disease with severe anaemia and multiple lytic lesions. he was then treated with four cycles of bortezomib, thalidomide and dexamethasone and achieved complete remission. this was followed by melphalan-based squ med j, may 2011, vol. 1, iss. 2, pp. 259-264, epub. 15th may 11 submitted 26th aug 09 revision req. 23rd nov 09, revision recd. 2nd jan 10 accepted 3rd feb 2010 departments of 1haematology, 2pathology, 3biochemistry, 4radiology & molecular imaging, sultan qaboos university hospital, muscat, oman. *corresponding author email: khalilf@squ.edu.om �î �á�œ �fl÷]<9fl¢]<h^fífi˜] l^èeå_<ì√q]ü⁄ê<ì÷^u<‡¬<üëüœi      55             :مفتاح الكلمات abstract: plasma cell myeloma is an uncommon disease which, besides primarily involving the bone marrow, has a tendency to involve other organs thus presenting with different clinical manifestations. while pleural effusions are infrequent in this disease, true myelomatous pleural effusions are extremely rare. we report the case of a middle-aged omani man with relapsed plasma cell myeloma who developed bilateral pleural effusions. the diagnosis of myelomatous pleural effusion was made by finding many abnormal plasma cells as well as a high level of a monoclonal protein (igg κ) in the pleural fluid. in spite of a good initial response to therapy, the patient had progressive disease and died 6 months later with bacterial sepsis. we present a review of the literature that indicates the rarity of such a manifestation and its association with poor prognosis and short survival. keywords: multiple myeloma; plasma cells; pleural effusion; case report ; oman myelomatous pleural effusion case report and review of the literature *khalil al-farsi,1 ibrahim al-haddabi,2 nafla al-riyami,3 rashid al-sukaiti,4 salam al-kindi1 case report myelomatous pleural effusion case report and review of the literature 260 | squ medical journal, may 2011, volume 11, issue 2 high dose chemotherapy and autologous stem cell transplantation (asct) in april 2008. his disease progressed a year after the transplant and he was treated with lenalidomide and dexamethasone. after five months of therapy, the treatment was interrupted as he developed severe cytopenias. he presented in january 2010 with shortness of breath and dry cough. his temperature was 38.5 oc, pulse was 124/min, respiratory rate was 22 breaths/min, blood pressure was 140/68 mmhg and oxygen saturation 91% on room air. a chest examination revealed decreased breath sounds in both infrascapular areas with dullness to percussion on both sides. a complete blood count (cbc) revealed a white blood cell (wbc) count of 2.2 x 109/l, absolute neutrophil count of 0.5x109/l, hb of 8.7 g/dl and platelet count of 36 x109/l. the peripheral blood film showed rouleaux formation and confirmed the thrombocytopenia and neutropenia noted on the cbc. there were no circulating plasma cells or other abnormal cells. blood chemistry tests showed albumin of 26 g/l, total protein 89 g/l, glucose 5.7 mmol/l, lactate dehydrogenase (ldh) 301 u/l, ß2 microglobulin 12.4 mg/l and c-reactive protein 121 mg/l. serum calcium, creatinine, uric acid, thyroid stimulating hormone (tsh) and liver enzymes }were normal. serologies for hiv, hepatitis b and hepatitis c were negative. serum protein electrophoresis and immunofixation showed a monoclonal igg κ of 30.9 g/l with normal levels of uninvolved immunoglobulins. the most recent 24-hour urine test showed a total protein of only 0.13 g/24hour. the chest x-ray showed bilateral pleural effusions. a computed tomography (ct) scan of the chest confirmed the presence of bilateral pleural effusions [figure 1]. it also showed multiple rib, sternal and thoracic vertebral osseous lytic lesions. there were also multiple sub-centimetre mediastinal lymph nodes. there was no evidence of pulmonary embolism. an echocardiography showed no significant abnormalities. the left ventricular ejection fraction was 70%. a thoracocentesis was performed and about 1 l of pleural fluid was drained from the right side. analysis showed glucose of 6.0 mmol/l, protein of 50 g/l and ldh of 172 u/l. the cytological examination revealed many abnormal plasma cells that constituted around 20% of the total nucleated cell in the pleural aspirate [figure 2]. although flow cytometry suggested that these cells were positive for cd38, the results were of poor figure 1: computed tomography scan of the chest showing bilateral pleural effusions. khalil al-farsi, ibrahim al-haddabi, nafla al-riyami, rashid al-sukaiti and salam al-kindi case report | 261 quality due to the suboptimal quality of the sample and therefore difficult to interpret, especially with regards to light chain restriction. however, protein electrophoresis and immunofixation on the pleural fluid showed 16.7 g/l of igg κ monoclonal protein [figures 3 and 4]. a gram stain, acid fast bacilli (afb) stain and cultures (bacterial, fungal and tb cultures) were all negative. he was treated with high dose dexamethasone followed by one cycle of a combination of liposomal doxorubicin, bortezomib and dexamethasone. the pleural effusion resolved completely. however, the disease started to progress systemically over the following month, and his performance status deteriorated. he developed refractory cytopenias and became transfusion dependent. the effusions recurred bilaterally within 4 months. he was managed with palliative supportive care and died due to escherichia coli sepsis in the setting of progressive disease in july 2010. a post-mortem examination was not performed. discussion although plasma cell myeloma is mostly a bone marrow based disease, it can produce a variety of clinical presentations through the involvement of different extramedullary sites. one of these manifestations is pleural effusion. pleural effusions, caused by several aetiologies, are reported to occur in 6% of patients with myeloma during the course of their disease.4 myelomatous pleural effusions are rare and only about 80 cases have been reported in english medical literature. pleural effusions in patients with myeloma often results from non-malignant causes, some of which are treatable. the most common cause is congestive cardiac failure due to amyloidosis.4 heart failure can also result from hyperviscosity and from cardiomyopathy related to the use of anthracyclines, commonly used in the treatment of myeloma in the past. other causes include pulmonary embolism, infections, nephrotic syndrome and chronic renal failure.5 in addition, secondary neoplasms occurring in patients with myeloma, like carcinomas of the breast and lung and mesothelioma, can cause malignant pleural effusions.6 a detailed systematic approach to investigating pleural effusions, as demonstrated in our case report, is therefore important to exclude these alternative diagnoses. figure 2: cytological examination of the pleural fluid showing clusters of abnormal malignant-looking plasma cells. myelomatous pleural effusion case report and review of the literature 262 | squ medical journal, may 2011, volume 11, issue 2 our patient had normal cardiac and renal functions and no evidence of pulmonary embolism or nephrotic syndrome. in addition, there was no evidence of any infective aetiology and no evidence of secondary malignancies. a true myelomatous pleural effusion is rare and occurs in less than 1% of patients with myeloma.4,7 it is usually a sign of advanced disease, although there are a few reports of it being the initial presenting feature of myeloma in some patients.8-10 there are about 80 cases reported in english medical literature. older reports indicate that most effusions are due to iga myeloma.11 however, more recent reports indicate that the majority occur in patients with igg myeloma, which is the most common type of myeloma, as was the case in our patient.7,12,13 these recent reviews also indicate that it has an equal gender distribution, is commonly haemorrhagic, more commonly affects the left side and that these patients usually have poor prognostic disease markers.7,12-14 our patient had bilateral effusions at a late stage of his relapsed/refractory disease. the pathogenesis of myelomatous pleural effusion is not well understood, but several possible mechanisms have been proposed. these include: 1) direct extension of the disease to the pleura from adjacent skeletal or lung parenchymal tumors; 2) direct infiltration or implantation of tumour deposits on the pleura, and 3) lymphatic obstruction from mediastinal lymph node inflitration.4 extension from a mediastinal extramedullary plasmacytoma has also been suggested as one possible mechanism.13-16 it is possible that the myelomatous pleural effusion in our patient resulted from extension of his disease from the many lesions in his ribs, sternum and thoracic vertebrae. whether he had direct infiltration of the pleura is hard to prove as he did not have a pleural biopsy and small areas of involvement might be missed on ct scans. diagnostic criteria have been suggested to confirm the myelomatous nature of pleural effusions. the criteria include: 1) detection of atypical plasma cells in the pleural fluid; 2) demonstration of a monoclonal protein on pleural fluid electrophoresis, and 3) histological confirmation using pleural biopsy specimens or autopsy.11 our patient had an exudative effusion that had a high level of monoclonal igg κ as well as many abnormal plasma cells. a pleural biopsy was not done because of his poor general condition and severe thrombocytopenia at that time. in fact, one could argue that a pleural biopsy is not an integral part of the diagnosis. pleural biopsies are not always done in these patients and when done are not always diagnostic or helpful.7,12,15,17 the risk associated with the procedure as well as the patchy nature of disease involvement make it less attractive and less reliable as a diagnostic tool. despite the proposed criteria, the diagnosis of myelomatous pleural effusions can be challenging. reactive plasma cells may be seen in effusions secondary to cardiac surgery, tuberculosis, viral infections, connective tissue diseases, hodgkin’s lymphoma and carcinomatosis.16,18 in addition, malignant plasma cells have a wide spectrum of appearances in fluid specimens and may be missed figure 3: protein electrophoresis on (a) serum and (b) pleural fluid, both showing a dense monoclonal band in the slow gamma region. figure 4: immunofixation on pleural fluid showing an igg κ monoclonal band. khalil al-farsi, ibrahim al-haddabi, nafla al-riyami, rashid al-sukaiti and salam al-kindi case report | 263 as being of plasmacytic origin, especially if low in number. furthermore, due to in vivo and in vitro degeneration and changes during sample processing, the morphology can be significantly altered leading to further difficulties in recognising these cells as malignant plasma cells.7 the characteristic clockfaced condensed chromatic pattern is absent in these cases. instead, the nuclei of these cells are round to oval or pleomorphic and have a coarse and irregular chromatin pattern with prominent nucleoli. these malignant cells also have dense cytoplasm with absent or inconspicuous perinuclear hof.19,17 pleural biopsies might not be feasible and are not always diagnostic. it has been suggested that flow cytometric studies should be used to supplement the diagnosis.7 it has been shown, however, that in some instances flow cytometry might not be helpful due to poor specimen quality causing nonspecific light-chain staining.17,19 it has also been suggested that cytogenetic analysis be done on the pleural aspirate to support the diagnosis as an abnormal cytogenetic karyotype in the pleural fluid can provide unequivocal evidence of malignancy;7 however, this is not always possible. the diagnosis in most of the reported cases relied mainly on finding abnormal plasma cells and a monoclonal protein in the pleural fluid. the lack of alternative diagnosis and the presence of malignant-appearing plasma cells in the pleural fluid support the diagnosis of myelomatous pleural effusion in our patient. in addition, the lack of circulating plasma cells in his peripheral blood, while there were many in his pleural fluid, argues strongly against the monoclonal protein in his pleural fluid being the result of contamination with peripheral blood. flow cytometry was attempted, but the suboptimal quality of the sample precluded interpretation of the results. the pleural fluid was not subjected to cytogenetic analysis in our patient. such analysis is not necessary for routine diagnosis.7 in addition, cytogenetic studies in myeloma patients can be difficult because few mitoses are often obtained.18,20 overall, with the clinical presentation and the findings on pleural fluid analysis, there is no doubt that our patient had a true myelomatous pleural effusion. the diagnosis of myelomatous pleural effusion carries a poor prognosis despite aggressive treatment. the literature suggests that the median survival of these patients is about 4 months. several treatments have been tried including different combinations of systemic chemotherapy,7,12,21 as well as intra-pleural injections of different agents like adriamycin and interferon.19,20,22,23 despite some reported responses, the majority of these were transient and recurrences were common. there seems to be no added benefit from salvage chemotherapy followed by high dose therapy and asct in these patients.7 there appears to be some hope, however, with the use of novel agents. bortezomib, a novel proteasome inhibitor which has been shown to overcome some of the poor prognostic factors in myeloma, has proven to be safe and effective in patients with relapsed/refractory myeloma, especially if combined with other novel agents like liposomal doxorubicin.21,24 some have reported encouraging responses to systemic as well as intra-pleural bortezomib.22,23,25,26 our patient was exposed to all available novel drugs including thalidomide, lenalidomide and bortezomib and did have a good response to systemic treatment with bortezomib, liposomal doxorubicin and dexamethasone. as his effusions resolved, no intra-pleural therapy was given. unfortunately, the response was transient and he was not able to tolerate further therapy. he eventually died within 6 months of developing the myelomatous pleural effusion. conclusion pleural effusions in patients with multiple myeloma result from different aetiologies, each requiring a different type of treatment. due to the important therapeutic and prognostic implications of finding a myelomatous pleural effusion, diagnostic throracocentesis with careful cytological examination and protein electrophoresis with immunofixation should be performed whenever possible. supplemental studies with flow cytometry and cytogenetics should also be considered. references 1. mckenna rw, kyle ra, kuehl wm, grogan tm, harris nl, coupland rw. plasma cell neoplasms. in: swerdlow sh, campo e, harris nl, jaffe es, pileri sa, stein h et al, eds. who classification of tumors of hematopoietic and lymphoid tissue. iarc: lyon 2008. pp. 200−13. myelomatous pleural effusion case report and review of the literature 264 | squ medical journal, may 2011, volume 11, issue 2 2. the international myeloma working group. criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the international myeloma working group. br j haematol 2003; 121:749−57. 3. kyle ra, gertz ma, witzig te, lust ja, lacy mq, dispenzieri a, et al. review of 1026 patients with newly diagnosed multiple myeloma. mayo clin proc 2003; 78:21−33. 4. kintzer js, rosenow ec, kyle ra. thoracic and pulmonary abnormalities in multiple myeloma: a review of 958 cases. arch intern med 1978; 138:727−30. 5. hughes jc, votaw ml. pleural effusion in multiple myeloma. cancer 1979; 44:1150−4. 6. law i, blom j. second malignancies in patients with multiple myeloma. oncology 1977; 34:20−4. 7. kamble r, wilson cs, fassas a, desikan r, siegel ds, tricot g, et al. malignant pleural effusion of multiple myeloma: prognostic factors and outcome. leuk lymphoma 2005; 46:1137−42. 8. inoue y, chua k, mcclure rf, jimenez mc, gocke cd, badros az, et al. multiple myeloma presenting initially as a solitary pleural effusion later complicated by malignant plasmacytic ascites. leuk res 2005; 29:715−18. 9. dhingra kk, singhal n, nigam s, jain s. unsuspected multiple myeloma presenting as bilateral pleural effusion – a cytological diagnosis. cytojournal 2007; 4:17−19. 10. yokoyama t, tanaka a, kato s, aizawa h. multiple myeloma presenting initially with pleural effusion and a unique paraspinal tumor in the thorax. intern med 2008; 47:1917−20. 11. rodriguez jn, pereira a, martinez jc, conde j, pujol e. pleural effusion in multiple myeloma. chest 1994; 105:622−4. 12. kim yj, kim sj, min k, kim hy, kim hj, lee yk, et al. multiple myeloma with myelomatous pleural effusion: a case report and review of the literature. acta haematol 2008; 120:108−11. 13. fekih l, fenniche s, hassene h, abdelghaffar h, yaalaoui s, el menzi f et al. multiple myeloma presenting with multiple thoracic manifestations. indian j chest dis allied sci 2010; 52:47−9. 14. huang tc, chao ty. myelomatous pleural effusion. qjm 2010; 103:705−6. 15. alexandrakis mg, passam fh, kyriakou ds, bouros d. pleural effusions in hematologic malignancies. chest 2004; 125:1546−55. 16. pacheco a, perpina a, escribano l, sanz i, bellas c. pleural effusion as first sign of extramedullary plasmacytoma. chest 1992; 102:296−7. 17. meoli a, willsie s, fiorella r. myelomatous pleural effusion. south med j 1997; 90:65−8. 18. bedrossian cwm. malignant effusions: a multimodal approach to cytologic diagnosis. new york: igaku-shoin, 1994. pp. 54−6. 19. palmer he, wilson cs, bardales rh. cytology and flow cytometry of malignant effusions of multiple myeloma. diagn cytopathol 2000; 22:147−51. 20. smadja nv, louvet c, isnard f, dutel jl, grange mj, varette c, et al. cytogenetic study in multiple myeloma at diagnosis: comparison of two techniques. br j haematol 1995; 90:619−24. 21. malhotra kp, agrawal v, prasad n. myelomatous pleural effusion: a diagnostic challenge. indian j cancer 2010; 47:351−2. 22. iannitto e, scaglione r, musso m, abbadessa v, licatta g. intrapleural adriyamycin in treatment of myelomatous pleural effusion: a case report. haematologica 1988; 73:325−6. 23. makino s, yamahara s, nagake y, kamura j. bencejones myeloma with pleural effusion: response to α-interferon and combined chemotherapy. inter med 1992; 31:617–21. 24. sonneveld p, hajek r, nagler a, spencer a, blade j, robak t, et al. combined pegylated liposomal and bortexomib is highly effective in patients with recurrent or refractory myeloma who received prior thalidomide/lenalidomide therapy. cancer 2008; 112:1529−37. 25. mangiacavalli s, varettoni m, zappasodi p, pica g, lazzarino m, corso a. a striking response to bortezomib in a patient with pleural localization of multiple myeloma. leukemia res 2009; 33:577−8. 26. iannitto e, minardi v, tripodo c. use of intrapleural bortezomib in myelomatous pleural effusion. br j haematol 2007; 139:621−2. the title of the book is interesting and concise giving the reader ability to forecast the contents, and this is exactly what a good title should do. the contents and targeted groups are very clearly described, and this definitely makes it easy to select or deselect it depending on your needs. imagine being in a bookshop looking for a book in pediaetrics; titles such as this make it easy to locate the right book and make a decision. the structure of the book is reader-friendly with clear objectives for each chapter and summary boxes enabling the reader to navigate very easily and have quick access to the needed information. the figures and diagrams are clear, optimal and appropriate to the contents. they are very illustrative and many of them could be used when counselling or giving explanations to parents. the authors have adopted a symptomatic, rather than disease oriented approach in writing the book chapters (breathing difficulty, convulsions, vomiting, diarrhea, feeding problems, fever etc..). definitely, this approach is easily linked to real life as babies will present with symptoms that could be due to a disease affecting any of the body’s systems. the book also contains chapters on prenatal screening, neonatal resuscitation, some of the common neonatal problems and low birth weight. the chapters give the reader a general view of the process of birth and the basic life-saving measures that may be necessary at birth in a simplified practical way. the book also includes chapters on the normal processes of the first year, such as growth, feeding and weaning. such information is of major importance for non-specialists working in primary health facilities, as the information will have a positive impact on the mother’s practice if given to her at the appropriate time during well baby visits or vaccination appointments. the authors’ emphasis in each chapter on communication with parents and counselling aspects is a very important issue not covered in many other books. although the book is very good in general there ا ب ج الَسنُة األوىل امل�ؤلف�ن: برينارد فاملان، روزلني ت�ما�س book review abc of the first year authors: bernard valman and roslyn thomas publisher: wiley-blackwell, 6th edition isbn: 978-1-4051-8037-5 orders: www.abcbookseries.com squ med j, april 2010, vol. 10, iss. 1, pp. 150-151, epub. 17th apr 10 submitted 3rd nov 10 bernard valman and roslyn thomas book review | 151 are two omissions which, if rectified, would add greatly to the usefulness of the book. first, i think the authors should add a chapter on accidental injuries with illustrations, examples of common injuries and dangerous places as well as basic first aid information and tips to parents on safety measures. second, it would be useful to add a chapter on “review at 12 months”. r e v i e w e r muna al-sadoon department of child health college of medicine & health sciences sultan qaboos university muscat, oman email: munasa@squ.edu.om squ med j, august 2011, vol. 11, iss. 3, pp. 322-327, epub. 15th aug 11 submitted 18th jan 11 revision req. 5th mar 11, revision recd. 4th apr 11 accepted 4th may 11 child abuse is a global problem that presents in the forms of physical abuse, sexual abuse, neglect, and emotional abuse.1 children subjected to various form of abuses can develop emotional, cognitive and physical conditions. the magnitude of abuse in children is often underestimated either because the sequelae of the abuse, or their young age, makes the victims incapable of articulating what happened to them.2 shaken baby syndrome (sbs) is one form of abuse that predominantly impacts neurological functioning, but it can also have multiple impacts on neurocognitive functioning. sbs is a relatively new diagnosis that was first described by guthkelch in 1971.3 the first name used to describe it was 'whiplash˗shaken infant syndrome'. other terms used were ‘shaken infant syndrome’, ‘shaken impact syndrome’, ‘infant whiplash˗shake syndrome’, ‘abusive head trauma’, and ‘inflicted/non˗accidental’ or ‘intentional head injury’. in medical literature, sbs is the most widely used and recognised term;4 however, the term is not widely accepted. for example, the american academy of pediatrics prefer ‘abusive head trauma’ which is broad and inclusive of all mechanisms of injury.5 the number of articles on sbs has significantly increased in recent years.1 it is evident from the literature review that no publications on sbs have emerged from arabian gulf states. this region has a population structure with a large proportion of 1department of child health, college of medicine & health sciences, sultan qaboos university, muscat, oman; departments of 1child health and 2ophthalmology, sultan qaboos university hopsital, muscat, oman. *corresponding author email: munasa@squ.edu.om å_ü÷]<l^e^ëc<<≈]áfi_<‡⁄<≈áfl“<áêà„π]<ÿà�÷]<ì⁄á¯j⁄ ì◊⁄^√π]<ï^âc<‡¬<ìü^fl÷]<           :مفتاح الكلمات abstract: shaken baby syndrome (sbs) is a form of abuse that is characterised by brain injury. because of the subtle and yet debilitating neurobehavioural impairment which ensues, sbs represents a diagnostic dilemma for attending clinicians. the situation is made worse by the young age of the affected child who may not be capable of explaining what happened. sbs has been reported in many parts of the world. to our knowledge, there is a dearth of literature on the topic from arab/islamic countries. this article attempts to shed light on the syndrome by reviewing information on the aetiology of sbs, as well as on its diagnosis and the reasons for delayed diagnosis. the central aim of this review is to increase awareness of sbs so that enlightened policies for prevention and intervention could be developed in the region and particularly in oman. keywords: shaken baby syndrome; child abuse review shaken baby syndrome as a form of abusive head trauma *muna al-saadoon,1 ibtisam b. elnour,1 anuradha ganesh2 muna al-saadoon, ibtisam b. elnour, anuradha ganesh review | 323 children and adolescents; however, despite rapid economic growth in the region, no child protection agencies have been established. anecdotal and impressionistic observations reveal that something akin to sbs is seen in the region. the aim of this article is to synthesise some of the relevant literature and shed light on the intricacies of sbs. r i s k fa c t o r s a n d c a u s e s the victims of sbs are usually under one yearold and thus helpless and unable to protect themselves.6 however, there are a few case reports of older children with closed head injury with severe neurologic impairment and ophthalmic findings suggestive of a shaking injury.7 infants and children are particularly vulnerable to violent shaking because of their relatively large head and weak cervical musculature.8,9 these factors, together with the incompletely fused sutures and relatively large volumes of cerebrospinal fluid in young children, allow for greater movement within the cranial vault, resulting in potentially severe damage to the immature incompletely myelinated brain.8,9 perceived disruptive behavior such as unwarranted and unremitting crying spells have been suggested as being important precursors of abuse in the form of ‘shaking’ by significant figures in the child’s life.10 perpetrators of sbs are often male with the biological father being the most common abuser.1 the literature also suggests that stepfathers or male partners may also be involved in such heinous acts. female babysitters are also known to be perpetrators of sbs, as well as biological mothers. overall, the perpetrator was male in 72% of cases.1,11 there is speculation that males, due to their greater physical power, are more likely to cause sbs when they ‘shake’ children.1 one might argue that females might be more tolerant to babies’ needs and demands. in contrast, males are perhaps more easily provoked by a crying baby. on the whole, there is evidence to suggest that both parties contribute to this abuse. the distressed child may cause stress to a significant figure thus provoking them into abusing the child. there is also evidence to suggest that individuals who are prone to anger and marked by explosive personality disorder are likely to commit such acts.10,12 m e c h a n i s m o f i n j u r y sbs is an extremely serious form of abusive head trauma that occurs when a child is held by the torso or the extremities and subjected to violent shaking that results in rapid head movements with acceleration, deceleration and rotational forces, with or without impact. it results in a unique constellation of intracranial, intraocular and skeletal injuries.7,13 the most common intracranial abnormality detected is subdural haematoma. children with sbs are often found to have retinal haemorrhage.2,11,14 fractures of the ribs where the child is grasped, or long bone fractures when child is held, might also be detected. cervical spine injuries are rarely recorded in cases of sbs.11,13 diagnosis sbs is known to be difficult to detect and diagnose. clinicians should use their own clinical judgment as each individual case is different and needs to be considered carefully on its own evidence. according to estimations from the world health organization (who), in 2002 almost 31,000 children aged <15 years died worldwide as a result of homicide.15 despite advances in investigative neurology, abusive head trauma is commonly under-recognised and remains a diagnostic challenge. the diagnosis of sbs must be considered in any infant or young child who collapses with no obvious causes. clinicians must maintain a low threshold of suspicion for considering this diagnosis.16 the diagnosis of sbs is usually made following a careful medical and social history taking. this ought to be supplemented by appropriate investigations. children with sbs are often seen first at emergency departments (eds). the incidence rates of child abuse at eds ranges from 2–10%; the detection rate might increase if medical staff were systematically vigilant about the possibilities of abuse in each child they encountered.17 a comprehensive history of the presenting complaints is an essential component of the diagnostic process. infants with sbs present to hospital with a variety of symptoms ranging from vomiting, poor feeding and lethargy to convulsions, apnoea and death. symptoms occur immediately after the insult, thus recording the timing of the symptoms is very important.18,19 not all infants are acutely ill at presentation, and in some cases the absence of either a history or external signs of injury may delay diagnosis. it is also important to note that shaken baby syndrome as a form of abusive head trauma 324 | squ medical journal, august 2011, volume 11, issue 3 o p h t h a l m i c m a n i f e s tat i o n s o f s b s ocular manifestations of sbs, characteristically retinal haemorrhages, are seen in 85% of cases and are bilateral, diffuse and multilayered.20 a large study from the usa concluded that retinal haemorrhages in young children are associated with a high likelihood of abuse.21 other ocular manifestations of sbs include blood-filled schisis cavities and circumlinear perimacular folds.22 papilloedema may also be noted. the anterior segments are usually unremarkable in sbs. the pathogenesis of the ocular findings is the same as the intracranial manifestations, namely repetitive, to and fro acceleration˗deceleration forces, that cause a displacement of vitreous volume and a resultant traction on the retina and retinal vessels resulting in rupture and haemorrhage. the presence of retinal haemorrhages implies a shaking aspect to the trauma; these are rarely seen in victims of road traffic accidents who have skull fractures and intracranial bleeding due to direct trauma.23 minor falls and blows, so common in the domestic context, do not cause retinal haemorrhages. seizures are also not known to result in retinal haemorrhages.14 differential diagnoses of retinal haemorrhages in this age group of children includes birth trauma, severe life threatening accidental head injury, coagulopathies, sepsis and vasculitis. with the exception of birth trauma, retinal haemorrhages in the other conditions tend to be few and localised.14 m a n a g e m e n t where abusive head trauma is a possibility, a strategy discussion involving police and the children’s social carer should be held to decide whether to initiate enquiries and then a criminal investigation. children are frequently referred to a specialist centre where paediatric neuroscience resources are available. it is important that such specialists are supported by general paediatricians who are able to liaise with the local and statutory child protection teams and participate fully in procedures for safeguarding the child. laboratory investigations are necessary in order to exclude other medical conditions such as rare metabolic diseases (glutaric aciduria), coagulation disorders, and infective encephalopathy.24,25 other investigations should include a septic screen to exclude infection—as shaking alone without impact injury can produce the symptoms seen in children with shaken baby syndrome.9 there are a number of features in the children and parents that may increase suspicion that harm has been done; these are triggering factors such as “crying, temperamental behaviour, toileting problems” and a history of previous or recent injury.19 birth history, developmental milestones, and vitamin k status are also important to note. in most cases where a history of injury is given, it is reported to be of a minor nature and is not consistent with the severity of the infant’s condition. a review of checklists of risk indicators for child abuse in emergency departments, shows that three history items are worthwhile considering: delay in seeking medical advice, an inconsistent history, and clinical findings that are incongruent with the history narrated by the accompanying adult.17 physical examinations for sbs should include all of the body looking for signs of external injuries such as skin bruising, abdominal injuries and skeletal injury such as fractures of ribs or long bones.19 the child conscious level, neck and cervical spinal cord injuries should be evaluated together with the need for resuscitation. it is also necessary to look for signs of intracranial bleeding such as fullness of the fontanelle and increased head circumference. fundi should be examined by the clinician/paediatrician, and as soon as possible by an experienced ophthalmologist, in order to exclude eye injury including retinal haemorrhage. neuro-imaging is the definitive diagnostic investigation and should be performed whenever sbs is suspected. the first line investigation in suspected abusive head trauma is a computed tomography (ct) head scan followed by a magnetic resonance imaging (mri) scan. mri is a more sensitive method of detecting small intracranial collections, especially in areas less well seen on ct.4 cerebral oedema and ischaemic changes are also well demonstrated by diffusion weighted mri. a skeletal survey, including skull films, should be performed in all children less than three years old where physical abuse is suspected.19 the clinical diagnosis is usually based on a patient history that does not explain the clinical features; it is supported by the findings of the physical and retinal examinations and the brain mri. muna al-saadoon, ibtisam b. elnour, anuradha ganesh review | 325 subdural collections could be associated with meningitis, urine screening for toxicology, and a metabolic screen. it is also important to do a full blood count, repeated after 24–48 hours, which may demonstrate a rapidly falling and low haemoglobin level.16 the role of the ophthalmologist is often to assist in the diagnosis of sbs by examining the child for retinal haemorrhages. retinal haemorrhages often resolve spontaneously and do not require therapy; however, extensive, non˗resolving vitreous haemorrhage or retinal detachment might mandate surgical intervention. careful follow˗up is desirable to document and treat sequelae which may be consequent to neurologic or ocular damage.26 o u t c o m e the available evidence suggests that around one third of severely shaken infants subsequently die as the result of being shaken.1,4,26 this rate is 6% to 12% higher than that for accidental head injuries in a similar age range.26 the syndrome has an extremely high degree of morbidity with 60% of survivors having a moderate or greater degree of disability.11 the victims of sbs display a wide range of neurological sequelae.26 these include cognitive and behavioral disturbances, cerebral palsy, blindness, and epilepsy.4 it is well known that outcomes due to head injury are more severe in abused children compared to injuries resulting from unintentional accidents.2,27 the functional prognosis of children marked by sbs is likely to be poor. this partly reflects the silence on the part of the parent who may conceal the shaking incident since this might lead to legal prosecution. the victim themselves are likely to be rendered incapable of ‘complaining’. the very fact that the incident is associated with neurological dysfunction, makes it likely that some residual though subtle impairment is likely to be chronic and have severe consequences in term of quality of life.28,29 b i o m a r k e r s a s t h e f u t u r e h o p e f o r r a p i d s c r e e n i n g o f n e u r o t r a u m a many cases of brain injury can present with clinically non-specific symptoms such as vomiting, poor feeding and irritability.11 it is worthwhile noting that such a presentation may be indistinguishable from other childhood maladies such as gastroenteritis or respiratory tract infection.11 the history will be misleading and clues to the cause of the head injury will be omitted. all of these factors can contribute to a delayed/missed diagnosis. many research studies are underway to find biological makers of sbs. despite the importance of such biological markers, there is, as yet, no study supporting their validity and reliability.30 the clinician’s vigilance still remains the best option. d i l e m m a o f s b s the diagnostic dilemma of this syndrome is threefold. the first is that the shaking is not witnessed and even when a perpetrator confesses the full truth of the incident most likely is not fully revealed. this results in questions about whether the shaking event is the cause of the clinical and pathological findings in the affected children.1,31,32 however, it is suggested that mechanical shaking is the primary reason for retinal bleeding as researchers found no difference in the extent, type, or frequency of retinal bleeding between patients diagnosed with sbs who exhibited signs of direct impact trauma versus those who did not.14 the finding of positive correlation between retinal haemorrhages and intracranial injury may support the theory that mechanical shaking and its direct effect on the globe and orbit has a major role in the pathogenesis of sbs.7,14 such studies and other results support the view that shaking alone is able to produce the symptoms seen in inflicted traumatic brain injury.18 the second factor is the possible medical conditions that could have similar presentations to abusive head trauma such as birth and other accidental injuries, brain congenital malformations, genetic and metabolic conditions, hematological disorders, infectious diseases, toxins, complications of surgical intervention, and nutritional deficiencies.19 short falls are the primary cause of injury given by care providers in most of the cases of sbs. studies found that minor falls (< 4 feet) do not cause serious injury in children, except for epidural haematoma whereas subdural and/or subarachnoid haemorrhage are seldom seen and retinal haemorrhage are virtually never seen in short falls.2 such findings minimise the possibility of a short fall being the causative factor of the retinal and intracranial findings of sbs. the possibility of a neonate developing intracranial bleeding after normal delivery is not rare and the potential for serious injury following a fall from shaken baby syndrome as a form of abusive head trauma 326 | squ medical journal, august 2011, volume 11, issue 3 variant of non˗accidental head injury in infants. dtsch arztebl int 2009; 106:211–7. 7. salehi˗had h, brandt jd, rosas aj, rogers kk. findings in older children with abusive head injury: does shaken˗child syndrome exist? pediatrics 2006; 117:e1039–44. 8. case me, graham ma, handy tc, jentzen jm, monteleone ja, national association of medical examiners ad hoc committee on shaken baby syndrome. position paper on fatal abusive head injuries in infants and young children. am j forensic med pathol 2001; 22:112–22. 9. alexander r, sato y, smith w, bennet t. incidence of impact trauma with cranial injuries ascribed to shaking. am j dis child 1990; 144:724–6. 10. talvik i, alexander rc, talvik t. shaken baby syndrome and a baby’s cry. acta paediatr 2008; 97:782–5. 11. king wj, mackay m, sirnick a. canadian shaken baby study group. shaken baby syndrome in canada: clinical characteristics and outcomes of hospital cases. cmaj 2003; 168:155–9. 12. barr rg, trent rb, cross j. age-related incidence curve incidence curve of hospitalized shaken baby syndrome cases: convergent evidence for crying as a trigger to shaking. child abuse negl 2006; 30:7–16. 13. caffey j. on the theory and practice of shaking infants. its potential residual effects of permanent brain damage and mental retardation. am j dis child 1972; 124:161–9. 14. morad y, kim ym, armstrong dc, huyer d, main m, levin av. correlation between retinal abnormalities and intracranial abnormalities in the shaken baby syndrome. am j opthalmol 2002; 134:354–9. 15. butchart a, phinney ha, main m, fürniss t, kahane t. preventing child maltreatment: a guide to taking action and generating evidence. who: geneva, 2006. 16. royal college of pediatrics and child health. child protection companion. london: rcpch, 2006. from: www.rcpch/child protection companion /1st edition/april 2006 accessed: apr 2011. 17. louwers ec, affourtit mj, moll ha, de koning hj, korfage ij. screening for child abuse at emergency departments: a systemic review. arch dis child 2010; 95:214–18. 18. starling sp, patel s, burke bl, sirotnak ap, stronks s, rosquist p. analysis of perpetrator admissions to inflicted traumatic brain injury in children. arch pediatr adolesc med 2004; 158:454–8. 19. chiesa a, duhaime ac. abusive head trauma. pediatr clin north am 2009; 56:317–31. 20. levin av. retinal haemorrhages and child abuse. in: david tj, ed. recent advances in paediatrics. london: churchill livingstone, 2000. pp. 151–219. 21. kivlin jd. a 12˗year ophthalmologic experience with a short distance is not common, but can happen. this necessitates consideration of these two possibilities when contemplating the diagnosis of abusive head trauma.11,33,34 such medical mimics of sbs, compounded with an unreliable history, may make the diagnosis challenging, especially in children with absent external injuries as is the case in 40% of affected children.11 the third factor is the variable results of biomechanical studies of sbs injury which have to take into account the levels of rotational velocity, acceleration of the head, velocity from manual shaking, the presence of hypoxia and the associated potential injuries to the brain and cervical spine.35‒39 conclusion it is important to raise awareness about abusive head trauma among paediatricians and general practitioners in oman. doctors providing health services to children should be alert to the non specific symptoms of sbs in order to reach an early diagnosis. the importance of comprehensive history taking and complete physical examination in young children with suspected abusive head injury is vital. the multidisciplinary approach is a key issue in managing such cases in order to rule out medical mimics of abusive head injuries and better safeguard the child. educational efforts to raise awareness about sbs should be instituted. references 1. world health organization. world report on violence and health. geneva: who, 2002. 2. reece rm, sege r. childhood head injury. arch pediatr adolesc med 2002; 154:11–15. 3. guthkelch an. infantile subdural haematoma and its relationship to whiplash injuries. bmj 1971; 2:430–431. 4. bonnier c, nassogne mc, saint-martin c, mesples b, kadhim h, sébire g, et al. neuroimaging of intraparenchymal lesions predicts outcome in shaken baby syndrome. pediatric 2003; 112:808–14. 5. christian cw, block r, the committee on child abuse and neglect. abusive head trauma in infants and children. pediatrics 2009; 123:1409–11. 6. minns ra, brown jk. neurological perspectives of non˗accidental head injury and whiplash/ shaken baby syndrome: an overview. in: matschke j, herrman b, sperhake j, korber f, bajanowski t, glatzel m. shaken baby syndrome, a common muna al-saadoon, ibtisam b. elnour, anuradha ganesh review | 327 31. parange m, coats b, duhaime a, margulies s. anthropomorphic simulations of falls, shakes, and inflicted impacts in infants. j neurosurg 2003; 99:143–50. 32. duhaime a, geearelli t, thibault l, bruce d, margulies s, wiser r. the shaken baby syndrome. a clinical, pathological, and biomechanical study. j neurosurg 1987; 66:409–15. 33. uscinski rh. shaken baby syndrome: an odyssey. neurol med chir (tokyo) 2006; 46:57–61. 34. cunningham f, hauth j, leveno k, gilstrap l iii, bloom s, wenstrom k. williams obstetrics. 22nd ed. new york: mcgraw˗hill medical publishing division, 2005. section v, p. 682. 35. bandak fa. shaken baby syndrome: a biomechanics analysis of injury mechanism. forensic sci int 2005; 151:71–9. 36. miller m, leestma j, barnes p, carlstrom t, gardner h, plunkett j, et al. a sojourn in the abyss: hypothesis, theory, and established truth in infant head injury. pediatrics 2004; 114:325–6. 37. kemp am, stoodley n, cobley c, coles l, kemp kw. apnoea and brain swelling in non˗accidental head injury. arch dis child 2003; 88:472–6. 38. bonnier c, mesples b, gressens p. animal models of shaken baby syndrome: revisiting the pathophysiology of this devastating injury. pediatr rehabil 2004; 7:165–71. 39. cheng j, howard ic, rennison m. study of an infant brain subjected to periodic motion via a custom experimental apparatus design and finite element modeling. j biomechan 2010; 43:2887–96. the shaken baby syndrome at a regional children’s hospital. trans am ophthalmol soc 1999; 97:545– 81. 22. schloff s, mullaney pb, armstrong dc, simantirakis e, humphreys rp, myseros js, et al. retinal findings in children with intracranial hemorrhage. ophthalmology 2002; 109:1472–6. 23. levin av. ocular manifestations of child abuse. ophthalmol clin n am 1990; 3:249–64. 24. gago lc, wegner rk, capone a jr, williams ga. intraretinal haemorrhage and chronic subdural effusions: glutaric aciduria type 1 can be mistaken for shaking baby syndrome. retina 2003; 23:724–6. 25. minford am, richards em. excluding medical haematological conditions as a cause of bruising in suspected non accidental injury. arch dis child educ pract ed 2010; 95:2–8. 26. barlow k.m, thomson e, johnson d, minns ra. late neurologic and cognitive sequelae of inflicted traumatic brain injury in infancy. pediatrics 2005; 116:e174–85. 27. loh jk, lin cl, kwan al, howng sl. acute subdural hematoma in infancy. surg neurol 2002; 58:218–24. 28. wilkinson ws, han dp, rappley md, owings cl. retinal hemorrhage predicts neurologic injury in the shaken baby syndrome. arch ophthalmol 1989; 107:1472–4. 29. forbes bj, rubin se, margolin e, levin av. evaluation and management of retinal hemorrhages in infants with and without abusive head trauma. j aapos 2010; 14:267–73. 30. berger rp, kochanek pm, pierce mc. biochemical markers of brain injury: could they be used as diagnostic adjuncts in cases of inflicted traumatic brain injury? child abuse negl 2004; 28:739–45. 1department of pediatric oncology, the indus hospital, karachi, pakistan; 2department of pediatrics, dow medical college, dow university of health sciences, karachi, pakistan; 3department of pediatrics, dr. ruth k. m pfau civil hospital, karachi, pakistan *corresponding author’s e-mail: meher59@hotmail.com متالزمة بريسون املرتبطة بقصور الغدة الدرقية والصدمة اإلنتانية اره جمال دِّيقي، م�شاعل بنت علي، َعمَّ �أريبا �إعجاز، ميهر بنت علي، فاطمة �شِ abstract: pierson syndrome is caused by mutations in the laminin β2 gene causing absent β2 laminin, which is a normal component of the basement membranes of the mature glomerulus, structures in the anterior eye and neuromuscular junctions. the mutations manifest as congenital nephrotic syndrome and microcoria which are characteristic ocular features of this disease. these mutations may also result in neurological abnormalities such as hypotonia and psychomotor retardation. we report a two-month old boy who presented to the pediatrics department of dr. ruth k. m. pfau civil hospital, karachi, pakistan, in 2015, with the typical features of microcoria and congenital nephrotic syndrome. the hypocalcaemia, hypoproteinaemia and probable immunocompromised state consequent to nephrotic syndrome resulted in seizures, hypothyroidism and urosepsis. despite being treated aggressively with high dose antibiotics, ionotropic support, angiotensin-converting enzyme inhibitors, thyroxine replacement and nutritional support, the infant died due to significant multiorgan disease including renal failure and septic shock. keywords: pierson syndrome; microcoria and congenital nephrotic syndrome; congenital microcoria; hypothyroidism; septic shock; case report; pakistan. امللخ�ص: حتدث متلزمة بري�شون ب�شبب طفر�ت يف جني المينني بيتا 2 �ملوؤدية �ىل فقد�ن المينني بيتا 2 وهو مكون طبيعي للأغ�شية �لقاعدية َغر �حَلَدَقة للُكَبيبة �لنا�شجة و�ملكونات يف �جلزء �الأمامي للعني و�لو�شلت �لع�شبية �لع�شلية. تظهر هذه �لطفر�ت كمتلزمة كلوية خلقية و�شِ ا �إىل �ختلالت ع�شبية مثل نق�ص �لتوتر �لع�شلي و�لتخلف و�لتي تعترب من �ل�شمات �لب�رصية �ملميزة لهذ� �ملر�ص. قد توؤدي هذه �لطفر�ت �أي�شً �لنف�شي �حلركي. نبلغ هنا عن طفل يبلغ من �لعمر �شهرين َقِدم �إىل ق�شم طب �الأطفال يف م�شت�شفى �لدكتورة روث فاو �ملدين، كر�ت�شي، باك�شتان َغر �حَلَدَقة و�ملتلزمة �لكلوية �خللقية. �أدى نق�ص كال�شيوم وبروتينات �لدم وحالة �ل�شعف �ملحتمل يف عام 2015، ولديه �ل�شفات �ملميزة ل�شِ للمناعة و�لناجتة عن �ملتلزمة �لكلوية �إىل حدوث نوبات �رصع وق�شور يف �لغدة �لدرقية وَنَت يف �لبول. على �لرغم من علج �ملري�ص بقوة عن طريق جرعات عالية من �مل�شاد�ت �حليوية و�لدعم �ملوؤثر يف �لتقل�ص �لع�شلي ومثبطات �الإنزمي �مُلَحوِّل للأجنيوتن�شني وتعوي�ص هرمون �لغدة �لدرقية و�لدعم �لغذ�ئي فقد تويف �لر�شيع ب�شبب �عتلل ج�شيم يف �أع�شاء متعددة مبا يف ذلك �لف�شل �لكلوي و�ل�شدمة �الإنتانية. حالة؛ تقرير �إنتانية؛ �شدمة �لدرقية؛ �لغدة ق�شور �خللقي؛ �حَلَدَقة َغر �شِ خلقية؛ كلوية ومتلزمة �حَلَدَقة َغر �شِ بري�شون؛ متلزمة املفتاحية: الكلمات باك�شتان. pierson syndrome associated with hypothyroidism and septic shock areeba ejaz,1 *meher b. ali,2 fatima siddiqui,2 mashal b. ali,2 ammarah jamal2,3 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e385–389, epub. 21 dec 20 submitted 9 dec 19 revision req. 26 mar 20; revision recd. 25 apr 20 accepted 20 may 20 immunosuppression. the disease generally has a poor prognosis due to renal failure and hence most infants do not survive.5 there have been less than 100 cases of pierson syndrome described in literature so far and the exact prevalence of this syndrome is not yet known.5,6 previously, a case of pierson syndrome in a child born to a pakistani couple living in spain has been reported. however, to the best of the authors’ knowledge, no cases in pakistan have been reported in the literature.7 this report presents the case of an infant with pierson syndrome and hypothyroidism complicated by sepsis. case report a two-month old boy, weighing 3.4 kg, presented to the pediatrics department of dr. ruth k. m. pfau pierson syndrome is a rare disease inherited in an autosomal recessive pattern, often fatal within a few months of life; it is known to mainly affect the eyes and kidneys at infancy.1 those infants that survive are affected by developmental and neurological abnormalities.2,3 this syndrome is caused by homozygous or compound heterozygous mutations on chromosome 3p21 in the laminin β2 (lamb2) gene.4 this causes absent β2 laminin, which is a normal component of the basement membranes of the mature glomerulus, structures in the anterior eye and neuromuscular junctions. kidney involvement presents within three months of life in the form of congenital nephrotic syndrome (ns) which can cause complications such as hypercoagulability, hypothyroidism, growth delay and this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.017 case report https://creativecommons.org/licenses/by-nd/4.0/ pierson syndrome associated with hypothyroidism and septic shock e386 | squ medical journal, november 2020, volume 20, issue 4 civil hospital, karachi, pakistan, in 2015, with a history of fever, seizures and generalised oedema for one month and decreased urine output for one week. the infant would have one to two episodes of generalised tonic-clonic seizures per day without loss of consciousness in between the episodes. later, oedema developed starting from the legs and periorbital area and progressed to the entire body. history of undocumented, low-grade fever was present which occurred on-and-off for one month. no history of haematuria or dysuria was reported. the infant had not achieved any developmental milestones at presentation; social smile was not present and he did not respond to loud voices or to the voice of the mother. the patient was born at home by normal vaginal delivery to a consanguineous couple after an uneventful pregnancy, during which the mother did not receive any antenatal care. he had three other siblings, of whom one brother died at the age of one month, due to seizures. the brother’s seizures were generalised tonic-clonic with loss of consciousness but without fever. the brother was taken to a nearby hospital where he was given an injection to control the seizures; however, the seizures did not stop and he soon died. the parents noticed a similar generalised oedema in the brother but did not seek medical care. further information could not be obtained as medical records of the sibling were not available and thus the underlying cause of the seizures could not be confirmed. upon examination at the time of admission, the patient was afebrile, obtunded with shortness of breath and generalised pitting oedema. length and weight were found to be less than the 3rd centile. occipitofrontal circumference was 35 cm. heart rate and respiratory rate were increased and blood pressure was 99/75 mmhg (>90th centile). peripheries were cold and capillary refill time was delayed. there was mild anaemia. both anterior and posterior fontanelles were wide open. the infant had macroglossia, umbilical hernia and generalised oedema. these findings were suggestive of congenital nephrotic syndrome and hypothyroidism [figure 1]. abdomen was grossly distended and non-tender, with evidence of free fluid. figure 1: photograph of a two-month old boy with pierson syndrome and hypothyroidism showing macro glossia, umbilical hernia and generaliaed oedema. figure 2: photograph of the eye of a two-month old boy with pierson syndrome showing a fixed pupil and nonreactiveness to light (i.e. microcoria). table 1: biochemical investigation findings of a two-month old boy with pierson syndrome at admission biochemical investigation finding normal value haemoglobin level in g/dl 9.0 9.5–13.5 haematocrit level in % 25.9 29–41 mean corpuscle volume in femtolitres 82.2 72.0–82.0 total leucocyte count in ×109/l 24 4.5–11.0 platelet count in ×109/l 319 150–400 c-reactive protein level in mg/dl 108 <0.3 serum calcium level in mg/dl 4.5 8.0–10.7 total liver protein level in g/dl 2.5 5.1–7.3 albumin level in g/dl 0.7 2.8–5.0 globulin level in g/dl 1.8 2.0–3.5 prothrombin time in seconds 22.4 12.2–15.5 activated partial thromboplastin time in seconds 35.6 26.5–35.5 international normalised ratio 1.62 0.8–1.2 spot urinary protein to creatinine ratio 80.3 <0.2 serum cholesterol level in mg/dl 409 50–120 serum triglyceride level in mg/dl 380 20–150 thyroid stimulating hormone level in miu/ml 20.2 0.6–10.1 free t4 level in ng/dl 0.26 0.8–2 free t3 level in ng/dl 0.20 0.24–0.65 iu = international units. areeba ejaz, meher b. ali, fatima siddiqui, mashal b. ali and ammarah jamal case report | e387 the patient’s liver span was 6 cm and gut sounds were audible. on neurological examination, glasgow coma scale (gcs) was 10/15 (eye = 3, verbal = 2 and motor = 5). pupils were fixed, equal in size and non-reactive to light (microcoria) [figure 2]. moro, rooting, sucking and grasping reflexes were weak. on motor examination, power was found to be 3/5 with increased tone and diminished reflexes in all four limbs. on laboratory investigation, complete blood panel showed mild anaemia. total leucocyte count (tlc) was elevated with 44% neutrophils and 53% lymphocytes. platelet count was normal but c-reactive protein was raised. blood urea nitrogen, creatinine, random blood sugar and electrolytes were within normal ranges. serum calcium levels were below normal. arterial blood gasses were suggestive of metabolic acidosis. liver function tests showed decreased levels of total protein, albumin and globulin. prothrombin time, activated partial thromboplastin time and international normalised ratio were all raised. detailed urine report revealed 3+ proteinuria, 3+ granular casts, 2+ leukocytes, 2+ blood and 45 to 50 red blood cells/high power field. spot urinary protein to creatinine ratio was raised. blood cultures were negative but urine culture showed growth of e. coli of more than 100,000 colony-forming unit/ml. serum cholesterol and triglyceride levels were also raised. these findings indicated a diagnosis of congenital ns. thyroid profile showed raised thyroid stimulating hormone and low levels of free t4 and free t3 [table 1]. ultrasound abdomen confirmed gross ascites. both kidneys were of normal size with grade 3 parenchymal changes. chest x-ray was normal. the characteristic features of microcoria and congenital ns helped establish a diagnosis of pierson syndrome. tachycardia, tachypnoea, increased tlc, metabolic acidosis, altered gcs and positive urine culture lead to the diagnosis of urosepsis, for which broad-spectrum antibiotics (amikacin, vancomycin, cefotaxime and cefepime), intravenous (iv) fluids and iv dopamine were started with strict input and output charting. a progressive decrease in renal output was noted and urea and creatinine continued to rise. maintenance fluid was restricted to essential fluid and urinary losses. the infant was diuresed with furosemide and enalapril (angiotensin-converting enzyme [ace] inhibitor) was started for proteinuria along with albumin infusion. calcium was replaced intravenously in the form of calcium gluconate and oral thyroxine was started for hypothyroidism. blood products were then also transfused in the form of packed red cells and fresh frozen plasma. despite being treated aggressively with high dose antibiotics, ionotropic support, ace inhibitors, thyroxine replacement and nutritional support, the infant died due to significant multiorgan disease including renal failure and septic shock. informed consent from the patient’s guardian was obtained for publication purposes. discussion pierson syndrome is named after the scientist who described the first case of congenital nephrotic syndrome associated with microcoria while zenker et al. later confirmed it as a separate disorder involving both kidneys and eyes due to a mutation in lamb2 gene.1,8 the lamb2 gene is needed for the production of β2 laminin and some cases might have a severely reduced production of β2 laminin instead of complete absence, accounting for milder versions of the disease.9 microcoria is the most characteristic ocular feature of pierson syndrome with the pupil being unresponsive to light or mydriatics.1 other features such as flat iris, cataract, retinal degeneration, high myopia, megacornea, retinal detachment and persistent fetal vasculature have also been reported.10 however. these abnormalities may always not be obvious or even present, thus it is imperative to examine the eyes of newborns with kidney problems.1 in the current case, the patient did present with microcoria. other syndromes may involve the kidney, but pierson syndrome specifically causes congenital ns, characterised by proteinuria, hypercholesterolemia and triglyceridaemia. loss of protein causes hypoalbuminemia and fluid retention manifesting as oedema. histologically there is diffuse mesangial sclerosis and crescent formation.2 congenital ns is associated with enlargement of placenta and increased alpha-fetoprotein antenatally.2 in the current case, since the mother delivered the baby at home and did not have any tests done during pregnancy, these factors could not be examined. due to the history of seizures and death, possibly due to a similar case of sepsis in one sibling, two healthy remaining siblings and the parent’s consanguineous marriage, it was assumed that the disease affecting the family was an autosomal recessive disorder. thus, autosomal dominant isolated congenital microcoria was excluded. multiorgan disease, as was present in the current patient, is also not a feature of this disorder.1 autosomal recessive polycystic kidney disease with sepsis, seemed unlikely due to the presence of pierson syndrome's most characteristic feature of microcoria. galloway-mowat syndrome is another autosomal recessive ocular-renal disorder, in which infants have pierson syndrome associated with hypothyroidism and septic shock e388 | squ medical journal, november 2020, volume 20, issue 4 low birth weight, hypotonia and hiatus hernia; 80% of these infants have microcephaly and micrognathia may be severe.1,11 the current patient did not have these features, therefore, galloway-mowat syndrome was excluded. proteinuria can sometimes cause loss of other proteins in the urine leading to further complications. loss of thyroid proteins, causing hypothyroidism can manifest as a low t3, t4 and increased tsh as seen in the current patient.12 thyroxine supplementation should be started in these patients to prevent adverse effects such as lack of brain development.12 eventual kidney failure leads to the early fatality of congenital nephrotic syndrome and only renal transplant has been shown to be effective while corticosteroids are of no value.12 nephrectomy has also been shown to reverse the hypothyroid state thus proving the kidney-related cause.13 in pakistan, nephrectomy in children less than 10 kg is not possible due to lack of advanced techniques. in addition, in the current patient renal transplantation, with the necessary prior administration of immunosuppressants, was impossible due to the ongoing sepsis. loss of immunoglobulins causes an immuno compromised state leading to infections; sepsis is a leading cause of death in children with nephrotic syndrome.13 a prior case of pierson syndrome being complicated by sepsis has been reported in the literature.4 the current patient presented with urosepsis as shown by the urine culture and high white blood cell count, for which he was aggressively managed with antibiotics and ionotropic support. mild anaemia was present, which can be explained by the reduced erythropoietin production and loss of erythropoietin and transferrin in the urine.3,14 similarly, loss of vitamin d-binding protein and albumin (which decreases bound calcium) can cause hypocalcaemia which may contribute to seizures.15 for this, the patient was given iv calcium gluconate. in general, these complications can be reversed by managing the proteinuria. lack of β2 laminin at the neuromuscular junctions affects the development of the infant.15 hypotonia, psychomotor retardation and blindness are the most consistent findings.15 thus, patients who survive infancy may still suffer from these neurological abnormalities. as in the current case, there may be delayed developmental milestones. finally, the current patient had all the features of congenital nephrotic syndrome, which along with microcoria helped to establish the diagnosis of pierson syndrome. biopsy for histopathological analysis was not possible due to the unstable condition of the patient. as pierson syndrome is inherited in an autosomal recessive pattern, it is more likely to be found in consanguineous marriages with multiple children being affected, as was found in the current case. confirmatory testing should be done by genetic analysis; however, due to a lack of adequate resources for mutation analysis at the authors’ institution and limited analysis being done at certain institutes which are too expensive, it was not possible to obtain this significant information. in terms of the outcome of congenital ns, it is fatal within a few years due to renal failure and nephrectomy and renal transplant are the only modalities to save the infant’s life. it is necessary to counsel parents of such patients regarding the limited treatment options for this disease and the importance of lifelong monitoring. ophthalmic and neurological screening for patients of congenital ns should be done, along with regular monitoring of thyroid function tests. consanguineous parents must be warned about the possibility of their offspring being affected by congenital ns and antenatal check-ups for any indication to congenital ns in the foetus must be suggested. the option of genetic diagnosis by analysing the lamb2 gene must also be explained to the parents. conclusion pierson syndrome consisting of microcoria and congenital ns has a poor prognosis due to renal failure. the current patient had the additional complications of hypothyroidism and septic shock, which along with renal failure proved fatal for the infant. references 1. zenker m, tralau t, lennert t, pitz s, mark k, madlon h, et al. congenital nephrosis, mesangial sclerosis, and distinct eye abnormalities with microcoria: an autosomal recessive syndrome. am j med genet a 2004; 130:138–45. https://doi. org/10.1002/ajmg.a.30310. 2. the university of arizona health sciences. nephrotic syndrome. from: https://disorders.eyes.arizona.edu/category/ clinical-features/nephrotic-syndrome accessed: apr 2020. 3. wühl e, kogan j, zurowska a, matejas v, vandevoorde rg, aigner t, et al. neurodevelopmental deficits in pierson (microcoria-congenital nephrosis) syndrome. am j med genet a 2007;143:311–19. https://doi.org/10.1002/ajmg.a.31564. 4. aydin b, ipek ms, ozaltin fa, zenciroğlu a, dilli d, beken s, et al. a novel mutation of laminin β-2 gene in pierson syndrome manifested with nephrotic syndrome in the early neonatal period. genet couns 2013; 24:141–7. 5. beaufils c, farlay d, machuca-gayet i, fassier a, zenker m, freychet c, et al. skeletal impairment in pierson syndrome: is there a role for lamininβ2 in bone physiology? bone 2018; 106:187–93. https://doi.org/10.1016/j.bone.2017.10.015. https://doi.org/10.1002/ajmg.a.30310 https://doi.org/10.1002/ajmg.a.30310 https://doi.org/10.1002/ajmg.a.31564 https://doi.org/10.1016/j.bone.2017.10.015 areeba ejaz, meher b. ali, fatima siddiqui, mashal b. ali and ammarah jamal case report | e389 6. zhu ht, maimaiti m, cao c, luo yf, julaiti d, liang l, et al. a novel homozygous truncating mutation in lamb2 gene in a chinese uyghur patient with severe phenotype pierson syndrome. front med (lausanne) 2019; 6:12. https://doi. org/10.3389/fmed.2019.00012. 7. peña-gonzález l, guerra-garcía p, sánchez-calvín mt, delgado-ledesma f, de alba-romero c. [new genetic muta tion associated with pierson syndrome]. an pediatr (barc) 2016; 85:321–2. https://doi.org/10.1016/j.anpede.2016.01.003. 8. pierson m, cordier j, hervouuet f, rauber g. [an unusual congenital and familial congenital malformative combination involving the eye and kidney]. j genet hum 1963; 12:184–213. https://doi.org/10.1001/jama.1963.03700190169139. 9. zenker m, aigner t, wendler o, tralau t, müntefering h, fenski r, et al. human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. hum mol genet 2004; 13:2625–32. https://doi. org/10.1093/hmg/ddh284. 10. arima m, tsukamoto s, akiyama r, nishiyama k, kohno ri, tachibana t, et al. ocular findings in a case of pierson syndrome with a novel mutation in laminin ß2 gene. j aapos 2018; 22:401–3.e.1. https://doi.org/10.1016/j.jaapos.2018.03.016. 11. mclean rh, kennedy tl, rosoulpour m, ratzan sk, siegel nj, kauschansky a, et al. hypothyroidism in the congenital nephrotic syndrome. j pediatr 1982; 101:72–5. https://doi. org/10.1007/bf00858984. 12. muranjan mn, kher as, nadkarni ub, kamat jr. congenital nephrotic syndrome with clinical hypothyroidism. indian j pediatr 1995; 62:233–5. https://doi.org/10.1007/bf02752333. 13. park sj, shin ji. complications of nephrotic syndrome. korean j pediatr 2011; 54:322–8. https://doi.org/10.3345/ kjp.2011.54.8.322. 14. nithya t, rai bs, khan hu, varghese ad. hypothyroidism & nephrotic syndrome-a cause or effect? karnataka pediatr j 2011; 25:36–7. 15. the university of arizona health sciences. pierson syndrome. http s : / / d i s o rd e r s . e y e s . a r i z o n a . e d u / d i s o rd e r s / p i e r s o n syndrome/ accessed: apr 2020. https://doi.org/10.3389/fmed.2019.00012 https://doi.org/10.3389/fmed.2019.00012 https://doi.org/10.1016/j.anpede.2016.01.003 https://doi.org/10.1001/jama.1963.03700190169139 https://doi.org/10.1093/hmg/ddh284 https://doi.org/10.1093/hmg/ddh284 https://doi.org/10.1016/j.jaapos.2018.03.016 https://doi.org/10.1007/bf00858984 https://doi.org/10.1007/bf00858984 https://doi.org/10.1007/bf02752333 https://doi.org/10.3345/kjp.2011.54.8.322 https://doi.org/10.3345/kjp.2011.54.8.322 1department of dermatology, hospital universitario san cecilio, granada, spain; 2department of dermatology, hospital virgen de las nieves, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com abstract: frontal fibrosing alopecia (ffa) is an emerging disease in western countries. we present the cases of three sisters who were referred simultaneously to the department of dermatology, hospital universitario san cecilio, granada, spain, in 2018. all patients suffered from at least partial frontotemporal hairline recession and eyebrow loss. following trichoscopic examination, the three sisters were diagnosed with ffa. only one of the sisters agreed to be treated; she was prescribed with topical clobetasol propionate solution and minoxidil and achieved disease control at the three-month follow-up. these patients represent a new case of familial ffa wherein three sisters as well as their mother were affected by ffa. a systematic review found a total of 24 cases of familial ffa, of which this report is the 25th. in the majority of families, only females were affected (88%) while in the remainder both males and females (8%) were affected; there was only one family where only males were affected (4%). the relationship between the affected individuals was predominately between sisters (56%) followed by mother and daughter (32%). the median age was 61 years old (range: 14–88 years) and the duration of the disease ranged between 3–360 months. family groups of ffa are an infrequently described phenomenon with unknown prevalence. keywords: alopecia; dermatology; hair diseases; case report; spain. familial frontal fibrosing alopecia report of a case and systematic review of the literature carlos cuenca-barrales,1 *ricardo ruiz-villaverde,1 alejandro molina-leyva2 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e320–323, epub. 21 jun 21 submitted 17 may 20 revision req. 13 jul 20; revision recd. 19 jul 20 accepted 13 aug 20 age of 55. treatment with clobetasol propionate 0,1% solution and minoxidil 5% solution was established and achieved disease control at the scheduled threemonth follow-up visit. the second patient, who was the eldest sister, was a 67-year-old woman who had undergone menopause at the age of 53 and had no medical history of interest. a 10-year alopecia evolution presenting partial loss of eyebrows and slight involvement of frontotemporal hairline was noted with a slow progression [figure 1b]. dermoscopic signs were also consistent with the diagnosis of ffa. she refused any treatment. the third patient, who was the youngest sister, was 59 years-old who underwent menopause at 50. she had a similar scarring alopecia with a threeyear evolution but with a much more inflammatory pattern, accentuated perifollicular erythema, a higher recession of frontotemporal hairline and was overall more aggressive [figure 1c]. similar to her two sisters, her symptoms were in agreement with the diagnosis of ffa. likewise, she rejected any therapeutic approach. all patients provided consent to publish details and photographs of their case. discussion in this article, we presented a case of familial ffa that adds to the body of literature on this condition. a systematic literature review was undertaken to determine the extent of available literature [figure 2]. frontal fibrosing alopecia (ffa) is a type of scarring alopecia described by kossard in 1994.1 since then, the number of publications about this disease has been rising. it has been considered a variant of lichen planopilaris due to histological similarities between the diseases;2 however, others consider it to be an independent disease among scarring alopecias due to the clinical peculiarities of ffa.3–5 new diagnostic criteria have recently facilitated its identification.6 in this case report, we report a case of familial ffa and perform a systematic review of the scientific evidence available in the literature. case reports three sisters were referred simultaneously to the department of dermatology, hospital universitario san cecilio, granada, spain, in 2018. the first patient was a 62-year-old female, who underwent menopause aged 52 and had a medical history of cutaneous lupus and breast cancer. she complained about frontotemporal hairline recession and partial eyebrow loss with a one year evolution [figure 1a]. trichoscopic examination showed erythema and follicular hyperkeratosis [figure 1d]. clinical and dermoscopic findings were consistent with the diagnosis of ffa. the patient claimed that her two sisters both presented with a similar type of alopecia as well as her mother, who died of breast cancer at the this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.025 case report https://creativecommons.org/licenses/by-nd/4.0/ case report | e321 medline® (national library of medicine, bethesda, maryland, usa) and embase (elsevier, amsterdam, netherlands) databases were searched on 11th february 2020 using the term “alopecia and (frontal or fibrosing) and familial”. articles that were published in english, spanish, french or german as well as articles published for at least one year on the databases were included. ffa epidemiological studies were included but narrative reviews were excluded. subsequently, two independent reviewers checked the title and abstract of the articles obtained. the full text of the articles was reviewed as well as the bibliography that supported them to search for sources of additional information. only the articles agreed upon by both reviewers in relation to the inclusion criteria were included in the final analysis. in the case of disagreement, a third reviewer analysed the article. a total of 11 articles were included in this review in which there are a total of 24 cases of familial ffa [figure 2]. the current case represents the 25th and resulted in a total of 59 individual cases [table 1].4,7–16 most affected family members were women (88%) but some families had both men and women (8%) who were affected; only one family presented with only affected males (4%). analysis of the familial relationships showed that the most common relationship was between sisters (56%) followed by mother and daughter (32%) and brother and sister (8%). regarding ethnicity, the majority of families with a known ethnicity were caucasian (83%) followed by hispanic (11%) and black (6%). the median age was 61 years old (range: 14–88 years) and the duration of the disease ranged between 3–360 months. eyebrows were involved in 93% of patients. among the comorbidities, there were autoimmune disorders such as rheumatoid arthritis, vitiligo, hypothyroidism, primary biliary cirrhosis or cutaneous lupus, several cardiovascular risk factors such as diabetes mellitus type 2, dyslipidaemia, high blood pressure or psoriasis, other hair disorders such as lichen planopilaris or alopecia areata, cancers such as colorectal and breast cancer and infectious diseases such as a case of hepatitis due to the hepatitis c virus. it should be noted that this literature review was subject to the limitation that it only included case reports. there is still uncertainty about aetiopathogenesis of ffa. based on the apparent increase in incidence in recent years, ffa has been related to environmental factors such as dioxins and dioxin-like chemicals.7 the importance of hormonal factors has been posed too, due to the widespread prevalence in caucasian postmenopausal women and the high effectiveness of anti-androgens compared with other treatments.5 genetic factors have also been linked to this disease, as family cases reported in the literature to date suggest.4,7–19 finally some authors have stated an autoimmune origin due to the inflammatory infiltrates in the bulb, the similarities to lpp and the association with other autoimmune diseases.17 family groups of ffa are an infrequently described phenomenon, with unknown prevalence among all cases of ffa. from the genetic point of figure 1: photographs of the heads of three sisters. a: a 62-year-old woman with frontotemporal hairline recession and partial eyebrow loss. b: a 67-yearold woman with similar pattern and accentuated eyebrow loss. c: a 59-year-old woman with marked hairline recession and almost total loss of eyebrows. d: trichoscopic examination photograph of the 62-year-old woman showing erythema and follicular hyperkeratosis. figure 2: flowchart showing the process of article selection for a literature review on frontal fibrosing alopecia. carlos cuenca-barrales, ricardo ruiz-villaverde and alejandro molina-leyva table 1: epidemiologic and clinical characteristics of familial cases of ffa reported in the scientific literature. author and year of publication family no. no. and gender relationship age in years ethnicity history of ffa in months eyebrow involvement comorbidities dlova et al.7 (2013) #1 3f sisters 55 61 73 caucasian 12 24 yes yes yes none none none #2 1f 1m sister brother 59 62 caucasian 36 12 yes yes lpp none #3 2f sisters 25 21 hispanic 12 3 yes yes none none #4 3f mother daughter cousin 74 50 44 black 24 12 12 no no yes traction alopecia traction alopecia traction alopecia roche et al.8 (2008) 1f 1m sister brother 75 71 nonspecified 12 8 yes yes none none junqueira ribeiro pereira et al.13 (2010) 2f sisters 57 59 caucasian 12 12 yes yes none oophorectomy (at 32 years-old), colorectal adenocarcinoma (at 54 years-old) and hcv treated with ifn + ribavirin (at 55 years-old) miteva et al.9 (2011) 2f twin sisters 67 caucasian 12 6 yes yes vitiligo vitiligo cranwell and sinclair11 (2017) 2f mother daughter 46 nonspecified 10 non specified yes yes rheumatoid arthritis, aa none chan et al.12 (2014) 2f sisters 49 63 caucasian 18 24–36 yes non-specified none none navarrobelmonte et al.4 (2015) #1 2f mother daughter 75 47 nonspecified non-specified 18 yes yes hypothyroidism psoriasis, hbp, dyslipidaemia #2 2f mother daughter 60 41 nonspecified 24 12 yes yes dm type 2, hbp none #3 2f mother daughter 63 37 nonspecified 24 non-specified yes yes primary biliary cirrhosis none #4 2f mother daughter 62 33 nonspecified non-specified non-specified yes yes none none atarguine et al.10 (2016) 2f twin sisters 14 nonspecified 108 non-specified goitre (one sister) rocha et al.14 (2020) 6f sisters 67 64 62 61 52 51 hispanic 180 144 24 360 24 24 yes yes no yes yes yes dm, systemic arterial hypertension no no allergic rhinitis deep vein thrombosis no porriñobustamante et al.16(2019) #1 2f sisters 59 66 caucasian 30 108 yes yes non-specified non-specified #2 3f mother 1st cousin of mother daughter 78 68 50 caucasian 228 144 36 yes yes yes non-specified non-specified non-specified #3 2m brothers 44 46 caucasian 48 12 yes yes non-specified non-specified #4 2f sisters 39 42 caucasian 72 24 yes yes non-specified non-specified #5 3f sisters 88 72 64 caucasian 24 12 48 yes yes yes non-specified non-specified non-specified #6 2f sisters 53 46 caucasian 96 12 yes yes non-specified non-specified #7 2f sisters 74 72 caucasian 288 240 yes yes non-specified non-specified #8 2f sisters 77 74 caucasian 204 168 yes yes non-specified non-specified #9 2f mother daughter 70 44 caucasian 144 24 yes yes non-specified non-specified current case 3f sisters 62 67 59 caucasian 12 120 36 yes yes yes breast cancer, cutaneous lupus none none f = female; m = male; lpp = lichen planopilaris; hcv = hepatitis c virus; ifn = interferon; aa = alopecia areata; hbp = high blood pressure; dm = diabetes mellitus. familial frontal fibrosing alopecia report of a case and systematic review of the literature e322 | squ medical journal, may 2021, volume 21, issue 2 case report | e323 view, genome-wide association studies in females from a uk cohort (comprising 844 cases and 3,760 controls) and a spanish cohort (consisting of 172 cases and 385 controls) have been related to hla-b*07:02; a genome-wide significant association with ffa was observed at four genomic loci (2p22.2, 6p21.1, 8q24.22 and 15q2.1).20 inheritance mode seems to follow an autosomal dominant pattern with incomplete penetrance which is in line with the current case.21 considering the findings of the present case and available scientific evidence, there are several phenotypic expression patterns of ffa which may be the result of epigenetic modulation or genic interaction mechanisms and give rise to the partial penetrance of the trait. upon this genetic predisposition, some trigger factors may overlap. a decrease in serum oestrogen levels or traumatisms, setting off an inflammatory reaction at the level of the follicular bulge, leading to fibrosis and final loss of the follicular hair may be considered. conclusion the cases of the three sisters highlights the need to carefully evaluate family aggregation patterns when examining patients, since on many occasions, unlike in our case, patients attend consultations alone. international collaboration between researchers is needed in order to perform epidemiological studies with larger sample sizes. references 1. kossard s. postmenopausal frontal fibrosing alopecia. scarring alopecia in a pattern distribution. arch dermatol 1994; 130:770–4. https://doi.org/10.1001/archderm.130.6.770. 2. dlova nc. frontal fibrosing alopecia and lichen planus pigmentosus: is there a link? br j dermatol 2013; 168:439–42. https://doi.org/10.1111/j.1365-2133.2012.11146.x. 3. banka n, mubki t, bunagan mj, mcelwee k, shapiro j. frontal fibrosing alopecia: a retrospective clinical review of 62 patients with treatment outcome and long-term follow-up. int j dermatol 2014; 53:1324–30. https://doi.org/10.1111/ijd.12479. 4. navarro-belmonte mr, navarro-lópez v, ramírez-boscà a, martínez-andrés ma, molina-gil c, gonzález-nebreda m, et al. case series of familial frontal fibrosing alopecia and a review of the literature. j cosmet dermatol 2015; 14:64–9. https://doi. org/10.1111/jocd.12125. 5. vañó-galván s, molina-ruiz am, serrano-falcón c, ariassantiago s, rodrigues-barata ar, garnacho-saucedo g, et al. frontal fibrosing alopecia: a multicenter review of 355 patients. j am acad dermatol 2014; 70:670–8. https://doi.org/10.1016/j. jaad.2013.12.003. 6. vañó-galván s, saceda-corralo d, moreno-arrones óm, camacho-martinez fm. updated diagnostic criteria for frontal fibrosing alopecia. j am acad dermatol 2018; 78:e21–2. https://doi.org/10.1016/j.jaad.2017.08.062. 7. dlova n, goh cl, tosti a. familial frontal fibrosing alopecia. br j dermatol 2013; 168:220–2. https://doi.org/10.1111/j.13652133.2012.11101.x. 8. roche m, walsh my, armstrong dkb. frontal fibrosing alopecia – occurrence in male and female siblings. j am acad dermatol 2008; 58. (suppl. 2):ab91. 9. miteva m, aber c, torres f, tosti a. frontal fibrosing alopecia occurring on scalp vitiligo: report of four cases. br j dermatol 2011; 165:445–7. 10. atarguine h, hocar o, hamdaoui a, akhdari n, amal s. [frontal fibrosing alopecia: report on three pediatric cases]. arch pediatr 2016; 23:832–5. https://doi.org/10.1016/j.arcped.20 16.05.006. 11. cranwell wc, sinclair r. familial frontal fibrosing alopecia treated with dutasteride, minoxidil and artificial hair transplantation. australas j dermatol 2017; 58:e94–6. https:// doi.org/10.1111/ajd.12499. 12. chan dv, kartono f, ziegler r, abdulwahab n, dipaola n, flynn j, et al. absence of hla-dr1 positivity in 2 familial cases of frontal fibrosing alopecia. j am acad dermatol 2014; 71:e208–10. https://doi.org/10.1016/j.jaad.2014.05.064. 13. junqueira ribeiro pereira af, vincenzi c, tosti a. frontal fibrosing alopecia in two sisters. br j dermatol 2010; 162:1154–5. https://doi.org/10.1111/j.1365-2133.2010.09664.x. 14. rocha vb, pires mc, contin la. familial fibrosing frontal alopecia in six sisters. an bras dermatol 2020; 95:125–8. https://doi.org/10.1016/j.abd.2019.02.009. 15. porriño-bustamante ml, garcía-lora e, buendía-eisman a, arias-santiago s. familial frontal fibrosing alopecia in two male families. int j dermatol 2019; 58:e178–80. https://doi. org/10.1111/ijd.14499. 16. porriño-bustamante ml, lópez-nevot má, aneiros-fernández j, garcía-lora e, fernández-pugnaire ma, arias-santiago s. familial frontal fibrosing alopecia: a cross-sectional study of 20 cases from nine families. australas j dermatol 2019; 60:e113–18. https://doi.org/10.1111/ajd.12951. 17. tavakolpour s, mahmoudi h, abedini r, kamyab hesari k, kiani a, daneshpazhooh m. frontal fibrosing alopecia: an update on the hypothesis of pathogenesis and treatment. int j womens dermatol 2019; 5:116–123. https://doi.org/10.1016/j. ijwd.2018.11.003. 18. mahmoudi h, rostami a, tavakolpour s, nili a, teimourpour a, salehi farid a, et al. oral isotretinoin combined with topical clobetasol 0.05% and tacrolimus 0.1% for the treatment of frontal fibrosing alopecia: a randomized controlled trial. j dermatolog treat 2020; 1–7. https://doi.org/10.1080/0954663 4.2020.1750553. 19. missio dm, dias mfrg, trüeb rm. familial cicatricial alopecia: report of familial frontal fibrosing alopecia and fibrosing alopecia in a pattern distribution. int j trichology 2017; 9:130–4. https://doi.org/10.4103/ijt.ijt_59_17. 20. tziotzios c, petridis c, dand n, ainali c, saklatvala jr, pullabhatla v, et al. genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including hla-b*07:02. nat commun 2019; 10:1150. https://doi. org/10.1038/s41467-019-09117-w. 21. tziotzios c, stefanato cm, fenton da, simpson ma, mcgrath ja. frontal fibrosing alopecia: reflections and hypotheses on aetiology and pathogenesis. exp dermatol 2016; 25:847–52. https://doi.org/10.1111/exd.13071. carlos cuenca-barrales, ricardo ruiz-villaverde and alejandro molina-leyva https://doi.org/10.1001/archderm.130.6.770 https://doi.org/10.1111/j.1365-2133.2012.11146.x https://doi.org/10.1111/ijd.12479 https://doi.org/10.1111/jocd.12125 https://doi.org/10.1111/jocd.12125 https://doi.org/10.1016/j.jaad.2013.12.003 https://doi.org/10.1016/j.jaad.2013.12.003 https://doi.org/10.1016/j.jaad.2017.08.062 https://doi.org/10.1111/j.1365-2133.2012.11101.x https://doi.org/10.1111/j.1365-2133.2012.11101.x https://doi.org/10.1016/j.arcped.2016.05.006 https://doi.org/10.1016/j.arcped.2016.05.006 https://doi.org/10.1111/ajd.12499 https://doi.org/10.1111/ajd.12499 https://doi.org/10.1016/j.jaad.2014.05.064 https://doi.org/10.1111/j.1365-2133.2010.09664.x https://doi.org/10.1016/j.abd.2019.02.009 https://doi.org/10.1111/ijd.14499 https://doi.org/10.1111/ijd.14499 https://doi.org/10.1111/ajd.12951 https://doi.org/10.1016/j.ijwd.2018.11.003 https://doi.org/10.1016/j.ijwd.2018.11.003 https://doi.org/10.1080/09546634.2020.1750553 https://doi.org/10.1080/09546634.2020.1750553 https://doi.org/10.4103/ijt.ijt_59_17 https://doi.org/10.1038/s41467-019-09117-w https://doi.org/10.1038/s41467-019-09117-w https://doi.org/10.1111/exd.13071. july 2008.indd molecular anatomic imaging: pet-ct and spectct integrated modality imaging 2nd edition, 2007 sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 237-239 sultan qaboos university© submitted 20th may 2008 this book is a revised edition of clinical molecular anatomic imaging (2003) by the same author. since the publishing of the first edition, the importance of positron emission tomography (pet) and single photon emission tomography (spect) in the clinical arena has evolved achieving a definite place in the realm of clinical investigations of patients. pet is today recognized as the best tumour imaging modality by the scientific community worldwide while spect has almost completely replaced planar imaging in many nuclear medicine investigations. although very sensitive compared to other imaging modalities, pet and spect lack the ability to define anatomical landmarks precisely. this book discusses how this shortfall is currently overcome by integrating pet and spect with computed tomography (ct). the combination with ct anatomical imaging with pet and spect functional/molecular imaging has revolutionised patient investigation. the addition of ct allows more accurate attenuation correction of the photons by overlying tissues and organs. this edition is written in a style that makes it more useful to those in clinical practice rather than those interested in research into molecular imaging. the book is divided into 7 parts which are further subdivided into a total of 68 chapters. j part 1 (chapters 1-13) covers the basic aspects of pet, spect and ct scanning as well as those of pet/ct and spect/ct. it provides a quick review of basic physics of radioactivity, radioactive decay and production of radionuclides as well as basic physics of pet and spect instrumentation, image production and image processing. there are some minor data inaccuracies in this part, e.g. the authors mention that 99mo decays only by emission of beta radiation, however 99mo also decays by gamma emission. also, the authors mention that from 99mo-99mtc generator, the 99mtc is extracted from the alumina column as 99tc ion. it should actually be technetium pertechnetate (99mtco4-). perhaps the authors could have expanded a bit more about the generator which is a source of 85% of our radiopharmaceuticals. the basic physics of pet and spect, is in generally well covered, clear and easy to be understood by the targeted clinicians and residents in-training. the يّ عِ طَ املَقْ وير بالتَّصْ إدماج الصور وسيلة اجلزيئي: التشريحي التصوير األحادي وبالفوتون البوزيترونيّ دارِ بِاإلِصْ ب وسَ َ احملُ جوستاف فون شولتيز تأليف: author: gustav k. von schulthess (and over 70 contributors) publisher: lippincott williams & wilkins isbn: 0-7817-7674-0 orders: http://www.lww.com/product/?978-0-7817-7674-5 b o o k r e v i e w b o o k r e v i e w : m o l e c u l a r a n at o m i c i m a g i n g : p e t c t a n d s p e c tc t i n t e g r at e d m o d a l i t y i m a g i n g 238 section on image co-registration and image rendering is great with good use of good illustrations. the chapters on quantification of pet and imaging are well developed, but would be more useful for researchers rather than clinicians. j part 2 (chapters 14-20) discusses the transition of pet and spect from research to clinical practice. the focus is on the various radiopharmaceuticals used in these investigations and also on clinical protocols. although 18f-fdg is the most commonly used radiopharmaceuticals for pet, the authors cover the use of this and a broader set of other radiopharmaceuticals currently in clinical use, as well as those with strong clinical potential including c-11-labeled radiopharmaceuticals. this section summarises some of the important considerations regarding these radiopharmaceuticals and their desirable properties. part 2 ends with a comprehensive treatment of the latest standards and imaging protocols for pet, pet-ct, spect and spect-ct. j part 3 (chapters 21-27) covers the clinical application of pet and spect in brain diseases. this section covers benign and malignant tumours of the brain, epilepsy, dementia, extrapyramidoldisorders, cerebral infections as well as cerebrovascular disease. using very good illustrations the authors begin by discussing normal brain findings in spect and pet. then the focus is on brain tumours, specifically imaging of astrocytoma, oligodendroglioma and glioblastoma and also their metastases and radiation injury. imaging of cerebral infection with pet using fluorodeoxyglucose (fdg) is well covered in this section, particularly since mri and ct have difficulty in distinguishing between brain abscess and tumours, especially if the tumour is necrotic. an argument of how fdgpet may be helpful in this area is made as well as the use of fdg-pet in distinguishing between toxoplasmosis and lymphoma in hiv patients. the chapter on cerebrovascular disease also includes an interesting section on methodologies for quantitative perfusion imaging. chapter 20 is a good review of the existing types spect-ct hardware. it stresses the importance of quality control (qc). the tabulation of the protocols makes it easy for the reader to find what they need. the authors add a section on patient scheduling that may be useful for the organisation of a new department. j part 4 (chapters 28-32) covers the use of pet and spect investigations for the heart. the emphasis is on coronary artery disease and applications of pet and spect in the diagnosis. of particularly interest in this section is the discussion of flow tracers in spect and pet and also metabolic tracers. chapter 32 discusses integrated spect-ct in cardiac imaging and the use of attenuation correction. j part 5 (chapters 33-57) covers most aspects of body imaging in oncology including head and neck, thyroid, lung, pleura, gastrointestinal, colorectal and anal, breast, kidney, testicular, prostate and bone with very good illustrations. these chapters deal mainly with pet-ct and spect-ct imaging of tumours for staging and therapy monitoring and also radiation therapy planning. regarding pet/ ct, the focus is on18 f-fdg imaging of tumours which is currently the most important application of pet. this section also explains the use of the standardized uptake value (suv) of lesions to differentiate benign from malignant tumours. image artifacts due to technical and physiological problems are relevant to both molecular imaging and anatomical imaging techniques. the resulting artifacts in integrated images can be a problem in interpretation and need to be recognised. they are well covered and illustrated so this section would be helpful for any clinician who wishes to learn more about them. one chapter is reserved for pet and pet-ct applications in the planning of radiation therapy. pet/ct in radiation oncology planning is becoming more popular because it is capable of anatomic imaging and shows a wide variety of biochemical and biologic features of tumours that are known to influence radiation response and hence the potential of remission. the chapter is well organized and again well illustrated. j part 6 (chapters 58-62) is a short section that discusses imaging of inflammation in the body and the use of fdg-pet and spect-ct to detect infection and inflammation in various clinical settings. it includes musculoskeletal problems as well as infection in patients with prostheses and rheumatology disease. b o o k r e v i e w : m o l e c u l a r a n at o m i c i m a g i n g : p e t c t a n d s p e c tc t i n t e g r at e d m o d a l i t y i m a g i n g 239 j part 7 (chapters 63-68) is concerned with miscellaneous and non-standard applications of pet-ct and spect-ct. it includes benign disease conditions, notably thyroid and parathyroid as well as benign bone tumours. there is a short section on the use of spect-ct in the diagnosis of pulmonary thromboembolism. the book ends with a discussion of paediatric applications in a set of separate chapters because of the particularities of investigations in children using ionizing radiation. overall, this is a good textbook of clinical molecular imaging. it discusses well the clinically practical aspects of this modality. its contents are well organised, each chapter starting with an informative abstract of contents. the references are mostly up-to-date, with suggestions for further reading. although the book is fairly comprehensive in molecular imaging with respect to pet and spect, some sections could be improved e.g. the cardiac section could be more comprehensive at least for the nuclear physicians working at cardiac centres. in addition, it would have been good to include a section on optical molecular imaging which is a rapidly evolving clinical imaging modality, as well as a few statements on the newer hybrid imaging tools such as optical-ultrasound mammography and optical-mri tools. the book comes with a cd-rom that contains over 80 full cases that can be studied separately, but which are also referenced in the book making the reading more interactive. residents, radiologists, nuclear physicians and practising clinicians who would like a quick reference on topics such as pet, spect and integrated pet-ct and spect-ct will find this book very useful. i recommend it highly to this group and to students interested in the subject. also it is a good book for basic scientists and their students interested in medical imaging and its relevance. r e v i e w e r hadia bererhi medical physics unit, department of radiology, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: haddiab@squ.edu.om department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: dr.abdullahalalawi@gmail.com a secondary spontaneous pneumothorax in a patient with covid-19 case report *abdullah m. al alawi and zakariya al naamani sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 660–663, epub. 25 nov 21 submitted 30 aug 20 revision req. 12 nov 20; revision recd. 29 nov 20 accepted 23 dec 20 with posterior and basilar predominance, which was associated with significant volume loss of both lungs and traction bronchiectasis [figure 1]. a previous lung function test had demonstrated a restrictive lung disease pattern. on presentation to the ed, the patient appeared to be in respiratory distress; his vitals were as follows: respiratory rate of 23 breath per minute, oxygen saturation of 90% on room air, heart rate of 100 bpm and a normal temperature of 37.2°c and blood pressure of 153/88 mmhg. he had reduced breath sounds in the right lung. other systemic examinations were unremarkable. blood investigations showed normal haemoglobin, lymphocyte count, platelet count and ferritin; elevated results were found for total white blood count, neutro phil count, c-reactive protein, d-dimer and lactate dehydrogenase [table 1]. chest x-ray demonstrated bilateral lung infiltrates and moderate right-sided pneumothorax with a mediastinal shift to the left-side [figure 2]. additionally, there was bilateral reticular shadowing with diffuse ground-glass opacity. because the patient presented with respiratory symptoms, he underwent polymerase chain reaction (pcr) testing for sars-cov-2 using the xpert® xpress sars-cov-2 test of nasal and pharyngeal swabs (cepheid, sunnyvale, california, usa), which was positive for sars cov-2 rna. other investigations, including electrocardiogram, urea and electrolytes, liver function tests, coagulation profiles severe acute respiratory syndrome coronavirus 2 (sars-cov-2), a novel coronavirus, represents an unprecedented global threat, with more than 12.3 million confirmed cases and 556,335 deaths at the time of the writing.1 there have been many trials of therapeutic agents, but none of them have proved to be efficacious to date.2,3 spontaneous pneumothorax is a very rare manifestation of covid-19 and the exact mechanism is not fully understood.4 this article reports the first case of spontaneous pneumothorax in a patient with idiopathic pulmonary fibrosis (ipf) who was admitted with covid-19 pneumonia. the safety of using some of the therapeutic trial agents for treating covid-19 in patients with pneumothorax is not clear. this article explores the possible underlying mechanism of pneumothorax in patients with covid-19. case report a 78-year-old male patient presented to the emergency department (ed) at a tertiary care hospital in muscat, oman, in june 2020 with a one-day history of right chest pain and severe breathlessness. there was no history of fever or cough. the patient was an ex-smoker and was known to have ipf. additionally, he had had two spontaneous pneumothoraces involving the left lung four years prior without a clear precipitating factor. his previous chest computed tomography scan had demonstrated bilateral lung fibrosis and honeycombing this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.046 case report abstract: severe acute respiratory syndrome coronavirus 2 (sars-cov-2), a novel coronavirus, represents an unprecedented global threat. we report a 78-year-old male patient who presented to the emergency department at a tertiary care hospital in muscat, oman, in june 2020 with a one-day history of right chest pain and severe breathlessness. the patient was an ex-smoker and known to have idiopathic pulmonary fibrosis (ipf) with two previous pneumothoraces in the left lung. on presentation, the patient was breathless with an oxygen saturation of 90% on room air. chest x-ray demonstrated bilateral lung infiltrates and right-sided pneumothorax. the patient tested positive for sars cov 2. a chest drain was placed which resulted in good resolution of the pneumothorax. the patient’s condition improved remarkably and he was discharged after 17 days of hospitalisation. to the best of the authors’ knowledge, this was the first case of pneumothorax reported in a patient infected with covid-19 who was known to have underlying ipf. keywords: spontaneous pneumothorax; pulmonary fibrosis; sars coronavirus; oxygen; pleurodesis; covid-19; case report; oman. abdullah m. al alawi and zakariya al naamani case series | 661 and troponin levels were unremarkable. the clinical presentation and laboratory and radiological test results were not suggestive of acute exacerbation of ipf. other differential diagnoses in this clinical setting, including myocardial ischaemia, were excluded. the patient was started on 15 l oxygen via a nonrebreathing mask, enoxaparin (40 mg twice daily), intravenous ceftriaxone (2 gm daily for seven days) and azithromycin (500 mg daily for three days). he had an urgent chest drain insertion and a repeated chest x-ray showed a near-complete expansion of the rigid lung [figure 3a]. in terms of the treatment for covid-19, there were several trials at the treating hospital, including dexamethasone, convalescent plasma and anakinra. the patient consented to receive dexame thasone (6 mg daily for 10 days) and convalescent plasma (one dose) as part of a clinical trial and routine medical care. the patient’s condition continued to improve with gradual oxygen weaning. dexamethasone was discontinued on the 10th day; the patient was off oxygen support on the 14th day, followed by the removal of the chest drain on the 17th day. repeated chest x-ray showed no reoccurrence of pneumothorax [figure 3b]. ideally, pleurodesis should have been performed during admission, but given the recent use of steroids, covid-19 diagnosis and rapid resolution of the pneumothorax, pleurodesis was deferred. the patient remained well at the two-week follow-up visit and a repeated chest x-ray (day 30) showed stable bilateral ipf without evidence of pneumothorax. the patient’s consent was obtained in order to publish this case report and the relevant laboratory and radiological findings. table 1: blood investigations of a 78-year-old male patient with a secondary spontaneous pneumothorax and covid-19 investigation result reference range haemoglobin in g/dl 15.1 11.5–15.5 total white blood count in × 109/l 17.2 2.2–10.0 neutrophil count in × 109/l 14.4 1.0–5.0 lymphocyte count in × 109/l 1.8 1.2–4.0 platelet count in × 109/l 217 150–450 c-reactive protein in mg/l 7 0–5 d-dimer in mg/l 75.2 <0.5 lactate dehydrogenase in u/l 615 135–225 ferritin in µg/l 141 30–400 figure 1: a previous chest computed tomography (done in 2016) of the current patient demonstrating bilateral interstitial lung fibrosis (arrows) with associated honeycombing (arrowhead). figure 2: chest x-ray of the current patient demonstrating right-sided pneumothorax (arrows) with mediastinal shift and bilateral lung shadowing. figure 3: chest x-ray of the current patient showing (a) a right chest drain (arrow) with an expansion of the right lung and (b) showing no reoccurrence of pneumothorax after the removal of the chest drain on day 17. a secondary spontaneous pneumothorax in a patient with covid-19 case report 662 | squ medical journal, november 2021, volume 21, issue 4 discussion spontaneous pneumothorax can complicate pulmonary infections with pneumocystis jirovecii, mycobacteria, fungi or other microorganisms and the incidence varies with the frequency of these diseases in the population.5,6 spontaneous pneumothorax is an unusual compl ication in patients with covid-19; there are very few case reports and the majority of cases occur after the second week of infection.4,7–12 post mortem examination of covid-19 cases demonstrated alveolar exudative inflammation and damage with thickened interalveolar septa, interstitial inflammation and fibrosis and platelet–fibrin thrombi small arterial vessels.13,14 pneumothorax may occur due to the rupture of necrotic lung tissue caused by intense inflammation or ischaemia and the rupture of overdistended alveoli caused by bronchiolar inflammation.15 spontaneous secondary pneumothorax is a potential complication of interstitial lung disease (ild) and it is associated with a poor outcome.16 the current patient had ild and he had had two previous pneumo thoraces in the left lung, suggesting that he had a secondary rather than a primary pneumothorax. it was uncertain whether covid-19 was a coincident or a precipitating factor for pneumothorax. per local guidelines for treating patients with covid-19, the patient received intravenous ceftriaxone and azithromycin. additional treatments were available as a part of ongoing clinical trials at the treating hospital. the patient opted to receive dexamethasone as well as to be enrolled in the convalescent plasma trial. he made a remarkable recovery and was weaned off oxygen within two weeks. the follow-up chest x-ray, after removing the chest drain, showed no reoccurrence of the pneumothorax. pleurodesis was considered but deferred due to several factors, including the rapid resolution of the pneumothorax, the current covid-19 infection and the recent use of steroids that may have slowed the healing process. to the best of the authors’ knowledge, this is the first report to describe a case of spontaneous secondary pneumothorax in a patient with ipf who was treated for covid-19. it highlighted the complexity of decision-making in managing a common disease, i.e. pneumothorax, in the setting of an emerging infection. there are many uncertainties regarding the appropriateness of using specific covid-19 treatments in patients with pneumothorax at this time, especially those who might require pleurodesis. nevertheless, it is believed that the authors adopted a patient-centred approach to treatment that resulted in an excellent outcome. conclusion sars-cov-2 infection may precipitate spontaneous pneumothorax in patients with underlying lung disease. the options for managing sars-cov-2 infection should consider the potential impact of the treatment of other active health issues. additionally, this case illustrated potential uncertainties regarding the management of common conditions coinciding with sars-cov-2 infection. a u t h o r s’ c o n t r i b u t i o n aa conceptualised the work and edited the scientific content. zn drafted the manuscript and prepared the figures. both authors approved the final version of the manuscript. references 1. world health organization. coronavirus disease (covid-19) dashboard. from: https://covid19.who.int accessed: jul 2020. 2. beigel jh, tomashek km, dodd le. remdesivir for the treatment of covid-19 preliminary report. n engl j med 2020; 383:994. https://doi.org/10.1056/nejmc2022236. 3. balkhair a, al-zakwani i, al busaidi m, al-khirbash a, al mubaihsi s, bataher h, et al. anakinra in hospitalized patients with severe covid-19 pneumonia requiring oxygen therapy: results of a prospective, open-label, interventional study. int j infect dis 2021; 103:288–96. https://doi.org/10.1016/j. ijid.2020.11.149. 4. flower l, carter jl, rosales lopez j, henry am. tension pneumothorax in a patient with covid-19. bmj case rep 2020; 13:e235861. https://doi.org/10.1136/bcr-2020-235861. 5. ben saad s, melki b, douik el gharbi l, soraya f, chaouch n, aouina h, et al. [tuberculous pneumothorax: diagnosis and treatment]. rev pneumol clin 2018; 74:81–8. https://doi. org/10.1016/j.pneumo.2017.10.006. 6. she wh, chok ksh, li iws, ma kw, sin sl, dai wc, et al. pneumocystis jirovecii-related spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema in a liver transplant recipient: a case report. bmc infect dis 2019; 19:66. https://doi.org/10.1186/s12879-019-3723-y. 7. lópez vega jm, parra gordo ml, diez tascón a, ossaba vélez s. pneumomediastinum and spontaneous pneumothorax as an extrapulmonary complication of covid-19 disease. emerg radiol 2020;27:727–30. https://doi.org/10.1007/s10140-020-01806-0. 8. spiro je, sisovic s, ockert b, böcker w, siebenbürger g. secondary tension pneumothorax in a covid-19 pneumonia patient: a case report. infection 2020; 48:941–4. https://doi. org/10.1007/s15010-020-01457-w. 9. sun r, liu h, wang x. mediastinal emphysema, giant bulla, and pneumothorax developed during the course of covid-19 pneumonia. korean j radiol 2020; 21:541–4. https://doi. org/10.3348/kjr.2020.0180. abdullah m. al alawi and zakariya al naamani case series | 663 10. ucpinar ba, sahin c, yanc u. spontaneous pneumothorax and subcutaneous emphysema in covid-19 patient: case report. j infect public health 2020; 13:887–9. https://doi.org/10.1016/j. jiph.2020.05.012. 11. wang w, gao r, zheng y, jiang l. covid-19 with spontaneous pneumothorax, pneumomediastinum and subcutaneous emphy sema. j travel med 2020; 27:taaa062. https://doi.org/10.1093/ jtm/taaa062. 12. xiang c, wu g. sars-cov-2 pneumonia with subcutaneous emphysema, mediastinal emphysema, and pneumothorax: a case report. medicine (baltimore) 2020; 99:e20208. https://doi. org/10.1097/md.0000000000020208. 13. carsana l, sonzogni a, nasr a, rossi rs, pellegrinelli a, zerbi p, et al. pulmonary post-mortem findings in a series of covid-19 cases from northern italy: a two-centre descriptive study. lancet infect dis 2020; 20):1135–40. https://doi. org/10.1016/s1473-3099(20)30434-5. 14. schaller t, hirschbühl k, burkhardt k, braun g, trepel m, märkl b, et al. postmortem examination of patients with covid-19. jama 2020; 323:2518–20. https://doi.org/10.1001/ jama.2020.8907. 15. liu k, zeng y, xie p, ye x, xu g, liu j, et al. covid-19 with cystic features on computed tomography: a case report. medicine (baltimore) 2020; 99:e20175. https://doi.org/10.1097/ md.0000000000020175. 16. porcel jm. secondary spontaneous pneumothorax in idiopathic pulmonary fibrosis: grim news. respirology 2018; 23:448–9. https://doi.org/10.1111/resp.13253. to the editor, the review paper by liyam eloul, amaal ambusaidi and samir al-adawi ‘silent epidemic of depression in women in the middle east and north africa region’ published in the april 2009 issue of squmj1 is an interesting discussion of depression in women in the middle east and north africa (mena) region. the authors provided a balanced and well articulated discussion of the factors that may play a role in the development of depression in women such as the higher exposure to postpartum depression, changing roles of women due to modernisation and some local sociocultural practices, not related to islam as a religion. however, it is important to pay attention to the fact that modernisation has not only affected the mental health of women in the mena region. rather, modernisation and changing family life have also influenced women’s mental health in western countries as evidenced by the increased depression rates for women.2,3,4 in addition, social and cultural forces in the region and elsewhere have played a role in the increasing depression rates for men, too. several studies have shown that there is an increased risk of depression in younger cohorts of both men and women.5,2 in addition, the prevalence rates of depression have actually increased for both genders of younger cohorts.2 data showed that they are experiencing an earlier onset of depression, although sex ratios were indistinguishable.2 despite the increase in depression rates, men’s lower reported rates of depression compared to women may not be an accurate estimation of the prevalence of depression among men. therefore, rates of depression for men may be much higher than what is reported in different studies. two important factors may be related to the lower reported depression rates for men.6 the low reported rates of depression may be an indication of the insensitivity of the diagnostic tools utilised to measure depression.7 diagnostic measures focus on the expression of emotion and the identification of the self-inefficiencies in the persons diagnosed with depression, all of which are in strong agreement with the feminine qualities of self-expression, as opposed to men’s who, when depressed, are three times more likely to display inappropriate anger outbursts compared to women.8 these anger outbursts are supposed to be the result of unexpressed emotions.9 another reason for the low reported rates of depression of men appears to be their unwillingness to seek mental health services when needed, especially in mild-moderate depression.10 admitting signs of mental illness is considered to be against the legends of masculinity that place special importance on ignoring symptoms of sickness in the hope that symptoms will go away.11 this is because masculinity requires men to demonstrate to people that they are “tough” and that they exemplify “manhood”.12 that is why future studies have to be extra sensitive when reporting on men’s depression given the complexity of the interaction between the cultural and psychological dimensions of depression. zena al-sharbati department of behavioral medicine, college of medicine & health sciences sultan qaboos university, muscat, sultanate of oman email: zenam@squ.edu.om squ med j, december 2009, vol. 9, iss. 3, pp. 359-360, epub. 19th dec 2009 received 10th oct 09 رد: وباء االكتئاب الصامت لدى املرأة يف منطقة الشرق األوسط و مشال أفريقيا re: silent epidemic of depression in women in the middle east and north africa region letter to editor write effectively a quick course for busy health workers 360 | squ medical journal, december 2009, volume 9, issue 3 references 1. eloul l, ambusaidi a, al-adawi s. silent epidemic of depression in women in the middle east and north africa region. squ med j 2009; 9:5-15. 2. weissman mm, leaf pj, holzer ce. iii, myers jk, tischler gl. the epidemiology of depression: an update on sex differences in rates. j affect disord 1984; 7:179-88. 3. john cl, tepperman l, wilson sj. the futures of the family. new jersey: prentice hall, englewood cliffs, 1995. 4. niemi rg, mueller j, smith tw. trends in public opinion: a compendium of survey data. new york: greenwood press, 1989. 5. simon ge, vonkorff m, ustun tb, gater r, gureje o, sartorius n. is the lifetime risk of depression actually increasing? j clin epidemiol 1995; 48:1109-18. 6. oliffe jl, phillips mj. men, depression and masculinities: a review and recommendations. j mens health 2008; 5:194-202. 7. rutz w, walinder j, von knorring l, rihmer z, pihlgren h. prevention of depression and suicide by education and medication. impact on male suicidality. an update from the gotland study 1997. int j psychiatry clin pract 1997; 1:39-46. 8. brownhill s, wilhem k, barclay l, schmied v. big build: hidden depression in men. aust n z j psychiatry 2005; 39:923-31. 9. winkler d, pjrek e, kasper s. gender-specific symptoms of depression and anger attacks. j mens health gend 2006; 3:19-24. 10. sharp mj, heppner pp. gender role, gender-role conflict, and psychological well-being in men. j couns psychol 1991; 38:323-30. 11. white p, young k, mcteer w. sports, masculinity, and the injured body. in: suso d, gordon f, eds. men’s health and illness: gender, power and the body. thousand oaks, ca: sage publications inc., 1995. pp.158-82. 12. courtenay, wh. college men’s health: an overview and a call to action. j am coll health 1998; 46:279-90. squ med j, december 2009, vol. 9, iss. 3, pp. 279-286, epub. 19th dec 2009 submitted 4th apr 09 revision req. 28th june 09. revision recd. 1st sept 09 accepted 9th sept 09 oral health department, sultan qaboos university hospital, muscat, sultanate of oman. email: abakathir@squ.edu.om عمليات جراحة الفم الصغرى للمرضى املعاجلني بعقار الورفرين دراسة استعادية ملدة مخس سنوات مبستشفى جامعة السلطان قابوس، سلطنة ُعمان عبدالعزيز عبداهلل باكثير امللخص: الهدف: عمليات جراحة الفم الصغرى للمرضى املعاجلني بعقار الورفرين حتمل خطر النزيف بعد اجلراحة. الغرض من هذه الدراسة هو حتليل ووصف الوضع الطبي واجلراحي ملرضى عقار الورفرين الذين خضعوا لعمليات جراحة الفم الصغرى في مستشفى جامعة السلطان قابوس. ممن يستخدمون عقار الورفرين وكان معدل التقييس العاملي لهم الطريقة: ضمت هذه الدراسة االستعادية 124 مريضا (41 ذكرا و 83 أنثى) 3.5≥ قبل خضوعهم لعمليات جراحة الفم بدون وقف العقار حتت التخدير املوضعي خالل فترة 5 سنوات من يناير 2004 إلى ديسمبر 2008. النتائج: خضع 90 مريضا (%72.6) لعمليات خلع أسنان بسيطة، و 26 (%21) خللع جراحي لألسنان، و6 (%4.8) لعمليات خزعة لنسيج فمي لني وحالتني (%1.6) الستئصال جذر السن مع إزالة التكيس. مت عمل اإلجراءات املوضعية لوقف النزيف جلميع املرضى حيث شملت وضع قطن خاص إليقاف النزيف وخياطة اجلرح. تعرض 8 مرضى (%6.5) لنزيف بسيط بعد عمليات جراحة الفم، 5 منهم خضعوا لقلع أسنان جراحي و 3 خللع أسنان بسيط، حيث تطلب عودتهم للمستشفى. مت معاجلة جميع حاالت النزيف بطريقة حتفظية عن طريق إعادة تلفيف و خياطة موقع النزيف بدون احلاجة إلدخال املريض للمستشفى. اخلالصة: ميكن إجراء عمليات جراحة الفم الصغرى للمرضى املعاجلني بعقار الورفرين بأمان دون احلاجة إليقاف العقار عندما يكون معدل التقييس العاملي 3.5≥ قبل العملية مع استخدام الطرق املوضعية املناسبة لوقف النزيف. مفتاح الكلمات: عقار الورفرين، خلع األسنان، جراحة الفم، نزيف ما بعد العملية، املضاعفات. abstract: objectives: minor oral surgery (mos) procedures in warfarinised patients carry the risk of post-operative bleeding. the aim of this study was to conduct a retrospective analysis and to describe the profile of warfarinised patients who underwent mos procedures at sultan qaboos university hospital. methods: a retrospective study of 124 warfarinised patients (41 men and 83 women), who had a pre-operative international normalised ratio (inr) of ≤ 3.5 and underwent different mos procedures under local anaesthesia, without discontinuation of their warfarin therapy, was carried out over a 5-year period from january 2004 to december 2008. results: ninety (72.6%) patients had simple dental extractions, 26 (21%) surgical extractions, 6 (4.8%) soft tissue biopsies and 2 (1.6%) had apicectomies with cyst enucleations. local measures were applied in all patients, which included the use of oxidizing regenerated cellulose haemostatic agent (surgicel) and suturing. a total of eight patients (6.5%), five who had surgical extractions and three who had simple extractions, bled enough post-operatively to require a return to hospital. all cases of post-operative bleeding were managed conservatively by repacking the bleeding site with haemostatic agent and re-suturing without the need for hospital admission. conclusion: minor oral surgery procedures can be safely conducted in warfarinised patients without interruption of warfarin regimen when the pre-operative inr is ≤ 3.5 and appropriate local haemostatic measures are used. keywords: warfarin; tooth extraction; oral surgery; postoperative haemorrhage; complications. minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman abdulaziz a bakathir clinical & basic research advances in knowledge 1. this study adds support to the available literature on the safety of conducting minor oral surgery procedures (mos) in warfarinised patients without interruption of their warfarin therapy. minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 280 | squ medical journal, december 2009, volume 9, issue 3 warfarin, the most commonly prescribed oral anticoagulant, is a vitamin k competitive antagonist that impairs the synthesis of vitamin k-dependent coagulation factors ii, vii, ix, x and endogenous proteins c and s in the liver, resulting in impaired fibrin formation.1,2 warfarin is frequently used to prevent and treat thromboembolism in various recognised clinical conditions such as cardiac arrhythmias, valvular heart diseases and cerebrovascular accidents.2-6 the activity of warfarin is expressed as the international normalised ratio (inr), which is the standard introduced by the world health organization in 1983.7 the inr specifically measures the responsiveness of thromboplastin to a specific warfarin induced defect, and it therefore measures the effect of warfarin and not liver function. it is expressed as a prothrombin ratio obtained by dividing the prothrombin time by the laboratory control prothrombin time.1,2,7 the therapeutic range is the value of inr or degree of anticoagulation that is required to prevent the development of serious thromboembolism and is normally maintained between 2 and 4. the desirable range for the inr depends on the condition being treated, and the risk of bleeding increases as the inr rises.8 published reports have shown an increase in the number of patients attending dental units worldwide who are on warfarin therapy.1,2,5 for many years, controversy has surrounded the correct management of patients on warfarin therapy requiring minor oral surgery (mos) procedures.1,3,6 over the last two decades, various clinical protocols were suggested for managing such patients, which included withdrawal of warfarin, reducing the dose, substitution of heparin for warfarin, and continuation of the normal dose of warfarin.1-6 the risk of intraoperative or post-operative bleeding must be balanced against the risk of thromboembolism in patients whose warfarin is interrupted. several published cases have highlighted the occurrence of serious thromboembolic complications, including death, in patients whose warfarin was withdrawn for dental treatment.3,9-12 in addition, substituting heparin for warfarin often entails hospital admission, which results in an increase in the cost of health care services as well as an increase in patient discomfort.1,2 recently, a considerable body of evidence from research studies has highlighted the relative safety of conducting mos procedures in warfarinised patients at outpatient settings without ceasing or altering their warfarin therapy when the preoperative inr is ≤ 4.2,4-6,13-14 there is no published work in oman on the dental management of patients taking oral anticoagulants. the oral health department of sultan qaboos university hospital (squh) started managing warfarinised patients requiring mos procedures under local anaesthesia without the interruption of warfarin in september 2003. our protocol, as summarised in table 1, states that the pre-operative inr must be ≤ 3.5 and local haemostatic measures are to be used in all patients which is in line with recommended evidence based guidelines.2,4 this retrospective study was conducted with the aim of reporting and describing the profile of all warfarinised patients who underwent mos procedures under local anaesthesia at our outpatient unit over a 5-year period from january 2004 to december 2008. methods all warfarinised patients requiring oral surgery procedures at the oral & maxillofacial unit of the oral health department, squh, are registered in the oral surgery procedures book. a search was conducted to identify all registered cases that underwent mos procedures according to unit protocol and under local anaesthesia without interruption of warfarin at our outpatient setting from january 2004 to december 2008. the patient’s application to patient care 1. medical and dental teams involved in the care of warfarinised patients should be aware of the latest evidence-based recommendations for management of warfarinised patients requiring dental surgery procedures. 2. minor oral surgery (mos) procedures can be safely conducted in warfarinised patients without alteration of warfarin therapy in outpatient settings when the pre-operative international normalised ratio (inr) is ≤ 3.5. 3. mos procedures performed in warfarinised patients carry a low risk of minor post-operative bleeding. 4. local haemostatic measures play an important role in the management of warfarinised patients undergoing mos procedures. abdulaziz a bakathir clinical and basic research | 281 files were retrieved and data collected which included, age and gender, indication for warfarin therapy and the pre-operative inr. the nature of the mos procedure was classified and recorded as either simple extraction; surgical extraction; biopsy or others. surgical extraction was defined as raising a mucoperiosteal flap and removal of bone with a bur. detailed information was also recorded on the operating surgeon; the local haemostatic methods used; preand post-operative antibiotic usage and other post-operative medications. in addition, data were also collected regarding any postoperative bleeding and its time of occurrence, the postoperative inr and the course of management of the post-operative bleeding. prior to the start of the study, ethical approval was obtained from the local research committee. results at our unit, total of 124 warfarinised patients underwent minor oral surgery procedures during the five-year study period without discontinuation of their warfarin therapy. there were 41 (33.1%) male and 83 (66.9%) female subjects with a mean age of 36 years (range 20-86 years). the patients studied were on warfarin therapy for a number of medical conditions as summarised in table 2. a prosthetic heart valve was the most common clinical indication for warfarin therapy, accounting for 62.1% of patients. the oral surgery procedures performed in the study group were conducted by three senior surgeons under local anaesthesia and included simple dental extractions, surgical extractions, soft tissue biopsies and apicectomies with cyst enucleations [table 3]. table 1: protocol for minor oral surgery in warfarinised patients at the oral health department, sultan qaboos university hospital pre-operative assessment inr of ≤ 3.5 obtained on the day of surgery no other coagulopathy no liver disease absence of infection at surgical site patient should not be on aspirin or non-steroidal anti-inflammatory drugs intra-operative management mos procedures: simple dental extraction limited to 1-3 in same quadrant surgical extraction soft tissue biopsy during surgical procedure: atraumatic surgical techniques respect soft tissue and avoid excessive manipulation local haemostatic measures: packing extraction sites with surgicel dressing suturing with resorbable sutures 4.8% tranexamic acid can be given as 10ml mouthwash to be used four times daily for 3-5 days post-operative care verbal and written post-operative instructions to patients: dietary instructions (avoid hot drinks for 24 hrs; soft diet for a few days) limit usage of analgesics to 3 days if possible avoid taking any herbal remedies instructions on how to deal with bleeding at home and where to seek help if bleeding cannot be not stopped at home post-operative medications antibiotics: if required use oral amoxycillin for 3-5 days analgesics: parecetamol compound paracetamol (co-codamol) codiene phosphate follow up appointment in 2 weeks legend: inr = international normalised ratio; mos = minor oral surgery minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 282 | squ medical journal, december 2009, volume 9, issue 3 simple dental extractions of 1-3 teeth accounted for 72.6% of the performed procedures with 149 teeth extracted. the mandibular first and second molars were the most commonly extracted teeth followed by the maxillary second molars. in patients who had surgical extractions, the mandibular third molars were the most commonly removed teeth followed by the upper first premolars. soft tissue procedures were conducted as excisional biopsies of benign tumours and mucous extravasation cysts from the tongue, palate, labial and buccal mucosae. the two cases of apicectomies and cyst enucleations were performed on the upper central incisors. all patients had local anaesthesia in the form of 2% xylocaine with adrenaline 1:80000. infiltrations of local anaesthesia and nerve blocks were used to achieve the required anaesthesia for mos. blind infiltrations involving the floor of the mouth were avoided in all patients. all patients who underwent mos procedures had a pre-operative inr taken on the same day of the procedure. the mean inr of the study group was 2.8 with a range of 2.1-3.5. all patients who had simple and surgical extractions had local haemostatic measures which included the placement of oxidizing regenerated cellulose dressing (surgicel, johnson & johnson) into the extraction sockets and closure with resorbable vicryl sutures. other patients (apicectomy and biopsy patients) had the surgical areas closed with resorbable sutures. seventy-seven patients who had a history of prosthetic heart valves had pre-operative antibiotic prophylaxis against infective endocarditis. all these patients had 3g amoxycillin orally one hour preoperatively according to standardised international guidelines.15-16 twenty patients who had surgical extractions and apicectomies had a 3 day course of post-operative amoxycillin. out of these 20 patients, only one patient also had a pre-operative antibiotic. all patients had a five day course of simple analgesics in the form of paracetamol (n = 60), co-codamol (n = 62) and codeine phosphate (n = 2). all patients were instructed to limit or consider lowering the usage of analgesics after the third day. following mos procedures, all patients were instructed to bite on sterile gauze and were reassessed for immediate post-operative bleeding after 20 minutes before being allowed to leave. both clear verbal and written instructions were given to patients, which included: post-operative instructions; dietary advice; home management of any bleeding and where to seek medical assistance for emergency bleeding. in addition, all patients were given a 2 weeks follow-up appointment. none of the studied patients had any immediate post-operative bleeding. a total of eight patients (6.5%), five who had surgical extractions and 3 had simple extractions, bled post-operatively and had to return to hospital. the bleeding was reported in all these patients to be as continuous oozing from the surgical sites, which was not controlled by local measures at home. all these patients had their inr re-checked with most of them having a higher post-operative inr compared to the pre-operative inr. table 4 shows a summary of patients who presented with post-operative bleeding. all these patients were managed in an outpatient setting and none required hospital admission, as they were all haemodynamically stable with normal vital signs. the management included repacking the bleeding site with surgicel dressing and re-suturing. all patients in the studied group attended the two week review visit. in the eight patients who had postoperative bleeding, the surgical sites had healed adequately and none of these patients reported any new episodes of bleeding from the table 2: indications for warfarin treatment in the study group indication no. of patients (%) cardiac arrhythmias 10 (8.1%) deep vein thrombosis 2 (1.6%) transient ischaemic attack and stroke 19 (15.3%) pulmonary embolism 5 (4%) prosthetic heart valve 77 (62.1%) myocardial infarction 4 (3.2%) others 7 (5.6%) table 3: minor oral surgery procedures conducted in the study group procedure no. of patients( %) simple dental extraction (1-3 teeth) 90 (72.6%) surgical extraction 26 (21%) soft tissue biopsy 6 (4.8%) apicectomy and cyst enucleation 2 (1.6%) abdulaziz a bakathir clinical and basic research | 283 surgical sites. the remaining 116 patients also did not report any episode of bleeding that required any medical intervention and all had satisfactory post-surgical healing. discussion oral surgery is the main oral health care hazard in patients taking warfarin due to the potential risk of bleeding. for many years, controversy has surrounded the correct management of warfarinised patients requiring mos procedures and various clinical protocols have been suggested for managing such patients.1,3,5,6 the traditional management in most dental units, including our unit, entails the discontinuation or reduction of warfarin therapy 2-3 days prior to dental surgery in order to prevent post-surgical haemorrhage.3,12,14 however, this practice may increase the risk of potentially lifethreatening thromboembolic events, especially in high-risk groups such as patients with prosthetic heart valves.2,14 furthermore, there is evidence that thrombosis may actually be more likely to occur due to rebound hypercoagulabilty that may ensue after cessation of warfarin.9,11 to support this, the literature contains several documented cases of serious thromboembolic complications in patients whose warfarin was withdrawn for dental treatment.2,17 in recent years, continuation of warfarin therapy in patients undergoing oral surgery procedures has gained more attention in the scientific literature.2,3,5,6,18 the 4th world workshop in oral medicine recommended that warfarinised patients undergo mos in an outpatients setting when the pre-operative inr is ≤ 3.5.2 published studies have shown the relative safety of conducting mos in warfarinised patients without alteration of the warfarin regimen and recommended the use of local measures to stabilise the clot formation at surgical sites.3-6 these local measures include the use of haemostatic agents such as oxidizing regenerated cellulose (surgicel), fibrin glue and gelatin sponge.6,19-22 conducting the procedure atraumatically and careful closure of the surgical site with adequate resorbable sutures also helps to stabilise the wound and achieve haemostasis. in our unit, surgicel is routinely used as the local haemostatic dressing because it is widely available, easy to handle, inexpensive and does not interfere with healing or bone regeneration. many published studies have demonstrated its use as an effective local agent with comparable efficacy to other agents.3,20,22 furthermore, other published reports also recommend the use of a tranexamic acid mouthwash in the post-operative period of warfarinised patients following mos. tranexamic acid mouthwashes tend to result in a good level of drug concentration in saliva, and thus help to prevent post-operative bleeding due to the continued local anti-fibrinolytic activity.2,19,21 despite the huge table 2: data of patients presenting with post-operative bleeding following oral surgery procedures patient age/sex pre-operative inr procedure pre/post antibiotic use post-operative inr day of presentation 1 55/f 2.8 surgical extraction no 3.5 3 2 39/m 3.5 simple extraction yes 3.8 2 3 48/f 2.4 surgical extraction no 2.3 5 4 40/f 3.2 simple extraction no 3.4 3 5 28/f 2.4 surgical extraction no 2.8 2 6 33/m 2.1 simple extraction no 2.8 4 7 49/m 2.8 surgical extraction yes 3.4 3 8 52/f 3.1 surgical extraction yes 3.7 3 legend: inr = international normalised ratio minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 284 | squ medical journal, december 2009, volume 9, issue 3 body of evidence recommending the continuation of warfarin therapy in patients undergoing mos, linnebur et al.23 identified inconsistencies between teaching practices in us dental schools and medical evidence available for the management of patients taking warfarin with most schools still teaching the practice of altering and/or interrupting warfarin prior to dental surgery. in oman, our unit started treating warfarin patients requiring mos in an outpatient setting in september 2003, according to the protocol summarised in table 1. before this date, there was no existing protocol and most patients were managed after consultation with their treating physician, almost all of whom tended to regard dental treatment, including simple extraction, as invasive and therefore aimed to reduce inr to <2.5, which is currently not in line with international clinical guidelines. as patients who are taking warfarin are increasing in oman, dental and medical teams here need to be aware of the latest evidence-based guidelines, which are available for safe management of this group of patients. with regard to the risk of post-operative bleeding following mos, wahl’s review found little or no difference in terms of blood loss after dental surgery between patients who are anticoagulated and control patients.17 other studies conducted on patients taking warfarin, with inr in the therapeutic range (2-4) versus controls, found little or no difference in the incidence of clinically significant bleeding, even though some had warfarin levels above the present recommended therapeutic levels, and some underwent extensive oral surgery.1 in a series of 2,400 documented dental operations, wahl found only 12 patients experiencing postoperative bleeding that was not controlled by local measures.24 the literature contains no report of patients experiencing serious harm from postoperative bleeding after dental extractions while continuing on warfarin. in our study, none of our patients had any immediate post-operative bleeding and 8 patients (6.8%) had minor post-operative bleeding that required a return to hospital for care. all these patients were managed conservatively by repacking the bleeding site and re-suturing. our finding is in line with other published studies which highlighted that most post-operative bleeding in warfarinised patients tends to be minor in nature and can often be easily managed by simple local measures.3,18,20,25-27 recently published work by malden et al.,28 showed an association between the degree of surgical intervention and the likelihood of anticoagulation being affected and they recommended that the postoperative inr in this group should be monitored carefully. although the finding of our study is in agreement with the finding of malden et al. as most of the patients who bled post-operatively had a much higher post-operative inr when compared with the pre-operative inr, our unit does not recommend routine post-operative inr monitoring following mos unless there is a clear indication. many reports highlighted the potential risk of post-operative bleeding which may result from drug interaction or the use of herbal remedies.1,2,29 many drugs, including non-steroidal analgesics and antibiotics, can interact with warfarin resulting in an alteration in anticoagulation activity and may contribute to an increase in post-operative bleeding.1,29 according to our protocol, routine prescription of post-operative antibiotics is not practised unless there is a clear clinical indication. when a post-operative antibiotic is required, it is limited to oral amoxycillin for 3-5 days. furthermore, our protocol for antibiotic prophylaxis has changed recently in accordance with the newly published clinical guidelines by the national institute for clinical excellence, which ceased recommending routine antibiotic prophylaxis against infective endocarditis for dental procedures.30 in addition, analgesics in form of paracetamol, compound paracetamol (co-codamol) or codeine phosphate are commonly prescribed and our patients are instructed to use them for up to 3 days and not to use other medications including non-steroidal analgaesics. all these measures are aimed to minimise possible interaction with warfarin. furthermore, studies have shown that the use of herbal remedies, which are commonly used in our region, could be a common precipitating cause of post-operative bleeding in warfarinised patient.1-2 to control this potential interaction, all our patients are screened and advised to avoid taking herbal remedies in the preand post-operative period. due to the limitation of the data available in this retrospective study, detailed analysis of the risk of post-operative bleeding was not possible and accordingly our unit is now looking prospectively at risk factors of post-operative bleeding in warfarinised abdulaziz a bakathir clinical and basic research | 285 patients undergoing mos procedures. conclusion based on this retrospective study, our unit protocol for the management of warfarinised patients undergoing mos procedures in an outpatient setting is associated with a low risk of postoperative bleeding and our reported findings are in accordance with the available literature.2,8,27,31-32 furthermore, our study supports and recommends that warfarinised patients can safely undergo mos procedures without alteration of their warfarin therapy when the pre-operative inr is ≤ 3.5. in addition, our study also stresses the importance of local haemostatic measures in preventing as well as managing post-operative bleeding following mos procedures. a c k n o w l e d g e m e n t s the author would like to thank the clinical staff at the oral health department for their support during the period of the study. in addition, the author is also grateful to ms nadia al-ghafri, secretary at the oral health department for her kind assistance in editing the manuscript. conflict of interest the authors report no conflict of interest. references 1. lockhart pb, gibson j, pond sh, leitch j. dental management considerations for the patient with an acquired coagulopathy. part 2: coagulopathies from drugs. br dent j 2003; 195:495-501. 2. aframian dj, lalla rv, pererson de. management of dental patients taking common hemostasis altering medications. oral surg oral med oral pathol oral radiol endod 2007; 103:s45.e1-11. 3. devani p, lavery km, howell cjt. dental extraction in patients on warfarin: is alteration of anticoagulant regime necessary? br j oral & maxillofac surg 1998; 36:107-11. 4. blinder d, manor y, martinowitz u, taicher s. dental extractions in patients maintained on continued oral anticoagulant: comparison of local hemostatic modalities. oral surg oral med oral pathol oral radiol endod 1999; 88:137-40. 5. evans il, sayers ms, gibbons aj, price g, snooks h, sugar aw. can warfarin be continued during dental extractions? results of a randomized controlled trial. br j oral & maxillofac surg 2002; 40:248-52. 6. cannon pd, dharmar vt. minor oral surgery procedures in patients on oral anticoagulants a controlled study. aus dent j 2003; 48:115-8. 7. shinton nk. standardisation of oral anticoagulant treatment. br med j 1983; 287:1000-1. 8. oake n, jennings a, forster aj, fergusson d, doucette s, van walraven c. anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. cmaj 2008; 179:235-44. 9. poller l, thomson j. evidence for “rebound” hypercoagulabilty after stopping anticoagulants. lancet 1964; 2:62-5. 10. harenberg j, haas r, zimmerman r. plasma hypercoagulabilty after termination of oral anticoagulants. thromb res 1983; 29:627-33. 11. mulligan r. response to anticoagulant drug withdrawal. j am dent assoc 1987; 115:435-8. 12. jeske ah, suchko gd. lack of a scientific basis for routine discontinuation of oral anticoagulant therapy for dental treatment. j am dent assoc 2003; 134:1492-7. 13. randall c. surgical management of the primary care dental patient on warfarin. dent update 2005; 32:441-6. 14. webster k, wilde j. management of anticoagulation in patients with prosthetic heart valves undergoing oral and maxillofacial operations. br j oral & maxillofac surg 2000; 38:124-6. 15. ramsdale dr, turner-stokes l. advisory group of the bristish cardiac society clinical practice committee. prophylaxis and treatment of infective endocarditis in adults: a concise guide. clin med 2004; 4:545-50. 16. gould fk, elliott tj, foweraker j, fulford m, perry jd, roberts gj et al. guidelines for the prevention of endocarditis: report of the working party of the british society of antimicrobial chemotherapy. j antimicrob chemother 2006; 57:1035-42. 17. wahl mj. dental surgery in anticoagulated patients. arch inten med 1998; 158:1610-6. 18. malden m. dental procedures can be undertaken without alteration of oral anticoagulant regimen. evid based dent 2005; 6:11. from www.nature.com/ ebd/journal/v6/n1/pdf/6400309a.pdf. accessed march 2009. 19. bal bj, hardee ps. efficacy and cost effectiveness of tranexamic acid mouth rinse for oral surgery in warfarinised patients. br j oral maxillofac surg 2000; 38:390-3. 20. carter g, goss an, lloyd j, tocchetti r. current concepts of the management of dental extractions for patients taking warfarin. aust dent j 2003; 48:8996. 21. carter g, goss an, lloyd j, tocchetti r. tranexamic acid mouthwash versus autologous fibrin glue in minor oral surgery procedures in patients taking warfarin a 5-year retrospective study at sultan qaboos university hospital, sultanate of oman 286 | squ medical journal, december 2009, volume 9, issue 3 patients taking warfarin undergoing dental exactions: a randomized prospective clinical study. j oral & maxillofac surg 2003; 61:1432-5. 22. halfpenny w, fraser js, adlam dm. comparison of 2 hemostatic agents for the prevention of postextraction hemorrhage in patients on anticoagulants. oral surg oral med oral pathol oral radiol endod 2001; 92:257-9. 23. linnebur sa, ellis sl, astroth jd. educational practices regarding anticoagulation and dental procedures in u.s dental schools. j dent educ 2007; 71:296-303. 24. wahl mj. myths of dental surgery in patients receiving anticoagulant therapy. j am dent assoc 2000; 13:77-81. 25. dunn as, turple ag. perioperative management of patients receiving oral anticoagulants: a systematic review. arch intern med 2003; 163:901-8. 26. bailey bmw, fordyce am. complications of dental extractions in patients receiving warfarin anticoagulant therapy a controlled clinical trial. br dent j 1983; 155:308-10. 27. salam s, yusuf h, milosevic a. bleeding after dental extractions in patients taking warfarin. br j oral & maxillofac surg 2007; 45:463-6. 28. malden nj, santini a, mather ci, gardner a. minor oral surgery and interference with anticoagulation in patients taking warfarin: a retrospective study. br j oral & maxillofac surg 2007; 45:645-7. 29. wood gd, deeble t. warfarin: dangers with antibiotics. dental update 1993; 20:350-3. 30. national institute for health and clinical excellence. prophylaxis against infective endocarditis: nice guidance. london: nice, 2008. from http://www. nice.org.uk/guidance/cg64. accessed september 2009 31. van diermen de, aartman ia, baart ja, hoogstraten j, van der waal i. dental management of patients using antithrombotic drugs: critical appraisal of existing guidelines. oral surg oral med oral pathol oral radiol endod 2009; 107:616-24. 32. nematullah a, alabousi a, blanas n, douketis jd, sutherland se. dental surgery for patients on anticoagulant therapy with warfarin: a systematic review and meta-analysis. j cand dent assoc 2009; 75:41. from www.cda-adc.ca/jcda/vol-75/issue-1/41. html. accessed july 2009. 1primary health care, ministry of health, muscat, oman; 2department of family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asmaa_9988@hotmail.com types of primary healthcare emergencies in muscat, oman a retrospective cross-sectional study of five primary care centres amal al mahrouqi,1 raya h. al maqbali,1 faiza al fadhil,1 *asma a. al salmani2 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 572–577, epub. 25 nov 21 submitted 6 jul 20 revision req. 16 sep 20; revision recd. 11 oct 20 accepted 4 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.037 clinical & basic research abstract: objectives: emergencies can occur at any time and be life-threatening or cause permanent damage. accordingly, the management of emergency cases is an integral part of primary healthcare (phc). this study aimed to estimate the proportion and types of emergency cases presented to phc centres in muscat, oman. methods: this retrospective cross-sectional study was conducted from march to august 2016 at five phc centres in the muscat governorate. a total of 800 emergency cases (i.e. those labelled in the health information system as an accident and emergency) of omani patients aged ≥5 years presented during this period. every second case, based on arrival to the registration desk, was selected for analysis. electronic medical records were reviewed to collect data regarding demographic features, presenting complaints, time and season of presentation, management provided and method of transportation if referred to tertiary care. results: the proportion of emergency cases was <2.5% (range: 1–2.5%). the most common type of emergency was musculoskeletal issues/trauma (34.3%) followed by gastroenterological (15.1%) and genitourinary (10.0%) emergencies. most patients were either 21–39 or 5–12 years old (35.0% and 21.6%, respectively). the majority (59.6%) were treated directly at the health centre, while the remaining patients (40.4%) were referred to tertiary care. at referral, only 12.1% were transported by ambulance and the rest via private transport. conclusion: musculoskeletal issues/trauma was the most common type of emergency seen at the selected phc centres in muscat. further research is needed to determine whether phc centres have the capability and resources necessary to appropriately manage emergency cases. keywords: emergencies; primary healthcare; public health; emergency medicine; oman. advances in knowledge musculoskeletal/trauma cases were the most common type of emergency seen at primary healthcare (phc) centres in muscat. a small percentage of emergency cases at phc centres required transportation by ambulance. applications to patient care patients attending the emergency room in phc centres were most commonly referred to tertiary care when they presented with cardiovascular or pharmacological emergencies. most patients who were referred to tertiary care hospitals did not require an ambulance and were able to travel using their own mode of transport. a medical emergency is defined as a sudden acute incident that necessitates urgent and appropriate management in order to treat immediate risks and avoid negative sequelae.1 such an event can occur at any time and be life-threatening or result in permanent damage to the patient; as such, the delivery of appropriate emergency care is integral at all levels of health services, including primary healthcare (phc) settings.1,2 as the first point of contact for medical care in the community, general and family practitioners in phc centres often see patients requiring urgent medical attention.3 however, there is limited information regarding the frequency and characteristics of emergency cases encountered in primary care settings in the gulf. for instance, mahfouz et al.’s study which was conducted in abha, saudi arabia, found that the most common emergencies were trauma, burns and orthopaedic injuries.1 in jeddah, aloufi and bakarman noted that more than 70% of phc physicians had seen more than three cases of acute bronchial asthma in the last 12 months; in addition, frequent cases of renal colic and hypoglycaemia were reported.4 in muscat, oman, there were 1,613,308 outpatient visits to phc centres in 2016; of these, approximately 1,419,666 visits were assigned to general practice clinics, including emergency cases.5 however, the exact nature of emergency cases seen by general practitioners (gps) in phc settings in oman has not yet been explored except in a single study that determined that the rate of injury in phc was 24 cases per 1,000 visits in 2010.6 the healthcare system in oman is divided into primary, secondary and tertiary levels, with the local population receiving free access to public healthcare amal al mahrouqi, raya h. al maqbali, faiza al fadhil and asma a. al salmani clinical and basic research | 573 under the ministry of health.7 at the phc level, there were a total of 108 regional centres in 2016 of which 28 were located in six wilayats (county) in the muscat governorate, the region surrounding the capital city; this comprises nearly 50% of the total population of oman.5,8 these facilities act as the first point-of-care for citizens in designated catchment areas, with an estimated 95% of the population residing ≤5 km away from a phc centre.7 all of these centres share the same structure and resources, use the same health information system software and provide various preventative, curative and rehabilitative primary care services for both acute and chronic illnesses, including standard diabetic, hypertension, antenatal, general and emergency services. each centre is staffed by various types of healthcare professionals including gps, nurses, dentists, laboratory technicians and pharmacists. in 2016, there were approximately 10.8 gps per 10,000 individuals in the population.5 while efforts have been made to launch an appointmentbased system, the majority of phc patients are still seen on a walk-in basis.7 from an economic perspective, it is often difficult to plan for medical emergencies. however, an understanding of the nature and type of emergencies that are most frequently faced by gps in oman may help in allocating sufficient resources and equipment in order to lower the morbidity and mortality rates and ensure an optimum level of care. thus, this study aimed to determine the proportion and types of emergencies presenting to selected primary phc centres in muscat. it is hoped that the outcomes of this study will help healthcare administrators in the delivery of appropriate staff training as well as assist policymakers in formulating an evidence-based policy for the implementation of improved emergency services for patients with acute complaints in oman. methods this retrospective cross-sectional study was conducted over a period of six months from march to august 2016 at selected phc centres in muscat governorate, oman. the target population included omani nationals aged ≥5 years who visited the centres during this period and were labelled as emergency cases in the electronic medical record system based on the decision of the caregivers and receiving triage nurses (this is standard procedure in all phc centres). all younger patients (i.e. <5 years of age), pregnant women and routine cases were excluded. based on a 95% confidence level, an anticipated prevalence of 50% and a design effect of 2.0, the necessary sample size was calculated to be 800 cases. a two-stage cluster sampling strategy was utilised. first, a simple random sample of five centres (clusters) was selected from the 28 phc centres in muscat governorate; all had the same structure and resources and were distributed throughout the region. second, simple random subsampling was employed to select 800 emergency cases within these five centres, wherein every second case was included in the study based on their time of arrival to the registration desk. the number of cases included from each centre was proportional to its size. overall, the sample was distributed as follows: 192 cases (24%) from the al khoud centre in seeb wilayat, 160 cases (20%) from the al khuwair centre in bawsher wilayat, 128 cases (16%) from the muscat centre in muscat wilayat, 200 cases (25%) from the al nahda centre in al amirat wilayat and 120 cases (15%) from the ruwi centre in muttrah wilayat. these five centres were deemed appropriate for inclusion in the study based on published statistics from 2016 detailing the number of general and emergency visits per year.6 subsequently, data were collected from the electronic medical record systems of each centre using a well-designed datasheet. the study included every second emergency case coded as ‘a&e’ (i.e. accident & emergency) based on the opinion of the treating doctors (who are assigned on a daily basis to treat emergencies) and triage nurses. three measures were adopted in this study. first, the demographic features of the patients were determined including age, gender and place of residence. second, the presenting complaints as recorded by the treating physician in each case were noted and categorised according to different body systems (e.g. cardiovascular complaints included ischaemic chest pain, acute heart failure and palpitations). third, the time and season of presentation, type of management provided (if the patient was treated directly at the health centre or referred to tertiary care) and, if necessary, the method of referral of the patients to tertiary care (by private transport or ambulance) were determined. the data were analysed using the statistical package for the social sciences (spss), version 25.0 (ibm corp., armonk, new york, usa). descriptive statistics were computed for all sociodemographic characteristics and items. frequencies and percentages were reported for categorical variables. the proportion of emergency cases was calculated out of the net total of cases recorded during the period (both emergency and non-emergency attendees). this study received ethical approval from the research ethics committee of the ministry of health in oman. in addition, the confidentiality of the information collected was maintained at all times. types of primary healthcare emergencies in muscat, oman a retrospective cross-sectional study of five primary care centres 574 | squ medical journal, november 2021, volume 21, issue 4 results this study included a total of 800 emergency cases that presented to phc centres. the proportions of emergency cases were 1%, 2.5%, 1.6%, 2.3% and 1% at the al khoud, al khuwair, muscat, al nahda and ruwi phc centres, respectively; the overall rate of emergency cases was <2.5%. in terms of frequency, the most common type of emergency was musculoskeletal/trauma-related (n = 274, 34.3%) followed by gastroenterological (n = 121, 15.1%) and genitourinary (n = 80, 10.0%) emergencies. within the musculoskeletal/trauma emergencies, cuts and wounds were most common (n = 159, 58.0%) followed by fractures (n = 27, 9.9%). among the gastrointestinal emergencies, vomiting (n = 59, 48.8%), acute abdomen (n = 32, 26.4%) and gastroenteritis (n = 29, 24.0%) were most frequent, while renal colic (n = 41, 51.3%) and gynaecological emergencies (n = 29; 36.3%) were the most prevalent forms of genitourinary emergencies. in terms of age, adults between 21–39 years (n = 280, 35.0%) and children between 5–12 years (n = 173, 21.6%) most frequently presented to primary care with emergencies [table 1]. musculoskeletal/trauma and gastroenterological emergencies were most common in patients aged 5–12 (61.3% and 16.8%, respectively) and 13–20 years (52.4% and 14.3%, respectively). moreover, those aged 21–39 years most commonly presented with musculoskeletal/trauma (28.9%) and genitourinary (19.3%) emergencies, while cardiovascular (23.5%) and musculoskeletal/ trauma (15.4%) emergencies were most common in patients aged 40–60 years. finally, respiratory (21.1%) and cardiovascular (20.2%) emergencies were most common among those aged 60 years or older. regarding gender distribution, there were 394 (49.3%) male and 406 (50.8%) female patients. male patients most frequently presented with musculoskeletal/trauma (n = 134, 34.0%), gastroenterological (n = 46, 11.7%) and cardiovascular (n = 32, 8.1%) emergencies, while female patients commonly presented with musculoskeletal/trauma (n = 102, 25.1%), gastroenterological (n = 76, 18.7%) and genitourinary (n = 50, 12.3%) emergencies. emergency cases presented at similar rates during both winter and summer months (50.1% and 49.9%, respectively), with musculoskeletal/trauma and gastroenterological table 1: characteristics of emergency cases seen at five selected primary healthcare centres in muscat, oman (n = 800) characteristic n (%) type of emergency cardiovascular 72 (9) respiratory 67 (8.4) gastroenterological 121 (15.1) cns 63 (7.9) endocrinological 51 (6.4) genitourinary 80 (10) musculoskeletal/trauma 274 (34.3) pharmacological 2 (0.3) other 70 (8.8) age in years 5–12 173 (21.6) 13–20 84 (10.5) 21–39 280 (35) 40–60 149 (18.6) >60 114 (14.3) outcome direct management 477 (59.6) immediate referral 272 (34) delayed referral* 51 (6.4) cns = central nervous system. *due to a lack of response to initial treatment. table 2: distribution according to outcomes of different types of emergencies seen at five selected primary health care centres in muscat, oman (n = 800) type of emergency n (%) direct management (n = 477) referral to tertiary care* (n = 323) cardiovascular (n = 72) 22 (30.6) 50 (69.4) respiratory (n = 67) 51 (76.1) 16 (23.9) gastroenterological (n = 121) 84 (69.4) 37 (30.6) cns (n = 63) 34 (53.9) 29 (46.1) endocrinological (n = 51) 38 (74.5) 13 (25.5) genitourinary (n = 80) 42 (52.5) 38 (47.5) musculoskeletal/ trauma (n = 274) 144 (52.6) 130 (47.4) pharmacological (n = 2) 0 (0) 2 (100) other (n = 70) 62 (88.6) 8 (11.4) cns = central nervous system. *either immediately or after a delay following a lack of response to initial treatment. amal al mahrouqi, raya h. al maqbali, faiza al fadhil and asma a. al salmani clinical and basic research | 575 emergencies being most common regardless of season. overall, 44.6% of emergency cases presented on weekday mornings, 45.8% on weekday evenings and 9.6% over the weekend. within the individual health centres, the most common emergencies were musculoskeletal/trauma and gastroenterological at the al khoud (45.8% and 19.3%, respectively), muscat (37.5% and 13.3%, respectively), al khuwair (31.3% and 16.3%, respectively) and al nahdha (27.5% and 14%, respectively) centres. however, at the ruwi centre, the most common type of emergency was musculoskeletal/ trauma (27.5%) followed by cardiovascular (15.8%). in terms of outcome, 477 (59.6%) of the emergency cases were treated directly at the health centre, while 272 (34%) were referred immediately to tertiary care and a further 51 (6.4%) were referred due to a lack of response to initial treatment. upon further analysis, 50 (69.4%), 130 (47.4%) and 29 (46.0%) cases of cardiovascular, musculoskeletal/trauma and central nervous system (cns) emergencies were referred to tertiary care for further management [table 2]. of the 323 cases (40.4%) referred to tertiary care, only 39 (12.1%) were transported by ambulance and the rest by private transport. among those referred to tertiary care, 50 (15.5%) were cardiovascular (i.e. ischaemic chest pain or acute heart failure) and 29 (9%) were cns-related (i.e. seizures, transient ischaemic attacks and syncope) emergencies. respiratory emergencies constituted 16 (5%) of the cases referred to tertiary care (i.e. asthma and chronic obstructive pulmonary disease) while endocrinological (i.e. diabetes), musculoskeletal/trauma (i.e. drowning or electrocution) and gastroenterological (i.e. acute abdomen) emergencies accounted for 13 (4%), 130 (40.2%) and 37 (11.4%) of the referred cases, respectively. discussion the current study described the frequency and characteristics of emergency cases presenting to primary care settings in muscat. overall, the proportion of emergency cases was <2.5% at the five selected health centres. in contrast, the proportion of emergency cases presenting to phc centres in jeddah was 5.2%.4 it should be noted that this rate has been reported to be <3% and 4.6% in norway and the netherlands, respectively.9,10 the lower rate observed in the present study compared to those reported in other research studies could be due to the proximity and easy accessibility of the tertiary hospital in muscat governorate, thereby encouraging more serious or critical cases to present immediately to a tertiary emergency department. alternatively, it is also possible that the studied phc centres had comparatively heavy patient turnovers and that many emergency cases were misregistered as routine outpatient cases. in the current study, musculoskeletal/traumarelated cases were the most common type of emergency, regardless of age. this finding was consistent with previous research. trauma was one of the most common emergencies observed by mahfouz et al. in abha along with burns and orthopaedic emergencies.1 a similar outcome was also found in a study conducted in selangor, malaysia, with the most common emergencies being bronchial asthma, viral fever and trauma/injury.11 in oman, trauma or musculoskeletal emergencies are fairly common, particularly among adolescents and young adults; this is often attributed to the high incidence of road traffic crashes in the country.12 however, in the present study, children constituted the majority of musculoskeletal/ trauma cases. a previous study in oman also found that injuries more predominantly affected children compared to older patients because of their increased physical activity, emotional immaturity and high propensity for risk-taking behaviours.6 overall, the majority of emergency cases presenting to selected phc centres in the current study involved individuals who were either between 21–39 or 5–12 years old. in the former group, there was a high percentage of genitourinary emergencies including gynaecological emergencies and renal colic. after musculoskeletal/trauma, gastroenterological emergencies were most common among children. this is to be expected, as children are generally more prone to trauma, gastroenterological issues and respiratory infections. in contrast, elderly patients made up a comparatively small proportion of emergency cases in the current study. typically, most elderly patients in oman have additional comorbidities and related complications and are, therefore, referred to tertiary care centres where they continue their follow-up; hence, such patients are often under-represented in phc centres. the majority of emergency cases (59.6%) in the current study were treated directly at the phc centres, while the remaining cases (40.4%) were referred to a tertiary hospital. among the referred cases, only 12.1% were transported by ambulance, with the other cases used private transport. while there are policies in place detailing ambulance escort guidelines, most families in oman choose not to avail themselves of ambulance services. this is because most families own two or three cars each; hence, relatives often prefer to transport stable patients themselves. similarly, a study types of primary healthcare emergencies in muscat, oman a retrospective cross-sectional study of five primary care centres 576 | squ medical journal, november 2021, volume 21, issue 4 conducted in selangor found that 40.3% of emergencies were referred to other hospitals, while the others were either advised to attend a follow-up appointment at a clinic (31.5%) or discharged upon recovery (28.2%).11 on the other hand, the rate of hospital referrals was much lower at out-of-hours gp practices in scotland, the netherlands and nottingham, uk (6.8%, 7.5% and 12%, respectively).9,13,14 in the current study, the higher referral rate could be due to the much higher percentage of trauma cases. in australia, johnston et al. found that gps saw a median of eight emergencies per year; of these, the most frequent were cases of acute asthma (72%), psychiatric emergencies (58%) and convulsions (49%); in addition, 95% of gps had seen at least one patient potentially requiring resuscitation in the preceding year.3 another survey conducted in south carolina, usa, found that the average family practice office witnessed 3.8 annual paediatric emergencies.15 in light of the frequency with which emergency cases are presented in these settings, it is crucial that medical personnel working in phc centres have sufficient knowledge and procedural skills as well as access to the necessary equipment and medications to provide optimum emergency care.16 the current study was undertaken to generate evidence to aid decision-making regarding the servicedelivery capabilities of phc centres and determine whether there is a need to incorporate specialised services for emergency cases. the implications of this study are that individuals in oman do present to phc centres with medical emergencies; moreover, just under two-thirds of such cases are treated directly at the phc centres. given the rate of presentation and treatment of emergency cases at phc centres in muscat, additional studies are needed to determine whether these centres have the capability and resources necessary to appropriately manage such cases. emergency cases are often referred to tertiary care because their treatment entails additional observation or specialised knowledge, skills, equipment and medication. previous research indicated that the symptoms most likely to be associated with referral to hospitals include chest pain, shortness of breath and localised abdominal pain.9,17 likewise, the commonest complaint among those referred to tertiary care in the present study was chest pain. this was consistent with the findings reported by other studies.1,13 this is to be expected, as patients with chest pain may need immediate specialist intervention. however, the transfer of care to tertiary care facilities is not always feasible, particularly in light of the acute nature of emergency care. delays in the admission or treatment of emergency cases have a significant impact on patient outcomes besides placing an additional financial burden on the healthcare system by increasing subsequent length of stay and inpatient costs once such patients are eventually admitted.18 unfortunately, many primary care physicians report being unprepared to deal with emergency cases or perform common emergency procedures, such as needle and surgical cricothyrotomies.3,19 a crosssectional study conducted in dammam, saudi arabia, revealed a severe lack of the resources necessary for the provision of emergency care at the phc level; for instance, none of the centres had crucial emergency drugs or equipment, such as tracheostomy sets or cervical collars and only 38.46% were equipped with electrocardiography and x-ray machines.20 moreover, the researchers identified culture-specific factors that could potentially complicate this issue, such as the need for dedicated emergency services in both male and female sections of gender-segregated phc facilities.20 apart from ensuring that appropriate systems, infrastructure and equipment are in place to deal with emergency cases, kalidindi and lacy and kalidindi et al. encouraged primary care personnel to increase their preparedness for emergencies through mock scenarios, in situ simulated training activities and maintaining of basic and advanced life support certifications.21,22 this study was subject to certain limitations. the results may have underestimated the actual number and type of emergencies that attend phc centres, as only those cases specifically designated as emergency visits in the electronic record system were included in the analysis. some cases involving real emergencies might have been incorrectly registered on the system as routine outpatient visits. moreover, another limitation of the study was that the sample size was calculated using a large estimate of 50% prevalence, which was based on the anecdotal experience of phc doctors. additionally, the clustering of data in the analysis was not considered, as the aim of the study was to determine the simple proportion and types of emergencies presenting to phc centres in muscat. furthermore, the study took place over a six-month period that included the summer months (june to august) during which time many individuals choose to leave muscat for their annual holidays. similarly, the holy month of ramadan coincided with july 2016, which may have also affected the results, since many muslims choose to delay medical visits to avoid having to wait and undergo interventions while fasting. it is, therefore, possible that results for the second half of the year would have been different. finally, the current study excluded children under 5 years of age, as they are coded differently within the health information system amal al mahrouqi, raya h. al maqbali, faiza al fadhil and asma a. al salmani clinical and basic research | 577 and emergency cases could not be distinguished. in addition, pregnancy-related emergencies were excluded, as such cases usually present directly to tertiary facilities with antenatal services. conclusion overall, the proportion of emergency cases presenting to primary care centres in muscat, oman, was <2.5%. musculoskeletal/trauma was the most common type of emergency, regardless of demographic or geographical distribution. more than half of the total cases were managed directly at the phc level although cardiovascular cases were usually referred to tertiary care by ambulance. further research is necessary to evaluate the capacity of phc centres to manage these cases. moreover, additional equipment and training are recommended for gps to ensure the provision of appropriate and effective emergency care. c o n f l i c t o f i n t e r e s t the authors report no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n am, rm and ff conceptualised and designed the study. am and rm collected the data. am, rm, ff and as analysed and interpreted the results. am and rm drafted the manuscript. all authors reviewed the results and approved the final version of the manuscript. references 1. mahfouz aa, abdelmoneim i, khan my, daffalla aa, diab mm, el-gamal mn, et al. primary health care emergency services in abha district of southwestern saudi arabia. east mediterr health j 2007; 13:103–12. 2. mahler h. present status of who’s initiative, “health for all by 2000”. annu rev public health 1988; 9:71–7. https://doi. org/10.1146/annurev.pu.09.050188.000443. 3. johnston cl, coulthard mg, schluter pj, dick ml. medical emergencies in general practice in south-east queensland: prev alence and practice preparedness. med j aust 2001; 175:99–103. https://doi.org/10.5694/j.1326-5377.2001.tb143540.x. 4. aloufi ma, bakarman ma. barriers facing primary health care physicians when dealing with emergency cases in jeddah, saudi arabia. glob j health sci 2016; 8:54248. https://doi. org/10.5539/gjhs.v8n8p192. 5. oman ministry of health. annual health report 2016. from: w w w.moh.gov.om/en_us/web/statistics/annual-reports accessed: oct 2020. 6. al-balushi h, al-kalbani a, al-khwaldi t, al-suqri s, almaniri a, alazri m, et al. injuries presented at a primary care setting in oman. oman med j 2012; 27:486–90. https://doi. org/10.5001/omj.2012.116. 7. halim lb, alajmi f, al lamki s. ensuring universal access to primary health care in oman. from: https://improvingphc. org/ensuring-universal-access-primary-health-care-oman accessed: oct 2020. 8. world population review. oman population 2020. from: http s : / / w o r l d p o p u l at i o n r e v i e w. co m / co u nt r i e s / o m a n population accessed: oct 2020. 9. moll van charante ep, van steenwijk-opdam pc, bindels pj. out-of-hours demand for gp care and emergency services: patients’ choices and referrals by general practitioners and ambulance services. bmc fam pract 2007; 8:46. https://doi. org/10.1186/1471-2296-8-46. 10. zakariassen e, hansen eh, hunskaar s. incidence of emergency contacts (red responses) to norwegian emergency primary healthcare services in 2007--a prospective observational study. scand j trauma resusc emerg med 2009; 17:30. https://doi. org/10.1186/1757-7241-17-30. 11. chew bh, than tl, chew ks, jamaludin nk, hassan h. a one month review of the types of medical emergencies and their treatment outcomes at two urban public health clinics. med j malaysia 2012; 67:571–6. 12. bachani am, taber n, mehmood a, hung yw, botchey i, al-kashmiri a, et al. adolescent and young adult injuries in developing economies: a comparative analysis from oman and kenya. ann glob health 2017; 83:791–802. https://doi. org/10.1016/j.aogh.2017.10.030. 13. avery aj, groom l, boot d, earwicker s, carlisle r. what problems do patients present with outside normal general practice surgery hours? a prospective study of the use of general practice and accident and emergency services. j public health med 1999; 21:88–94. https://doi.org/10.1093/pubmed/21.1.88. 14. shipman c, dale j. responding to out-of-hours demand: the extent and nature of urgent need. fam pract 1999; 16:23–7. https://doi.org/10.1093/fampra/16.1.23. 15. mansfield cj, price j, frush ks, dallara j. pediatric emergencies in the office: are family physicians as prepared as pediatricians? j fam pract 2001; 50:757–61. 16. ramanayake rp, ranasingha s, lakmini s. management of emergencies in general practice: role of general practitioners. j family med prim care 2014; 3:305–8. https://doi.org/10.41 03/2249-4863.148089. 17. liddy c, dreise h, gaboury i. frequency of in-office emergencies in primary care. can fam physician 2009; 55:1004–5.e1–4. 18. huang q, thind a, dreyer jf, zaric gs. the impact of delays to admission from the emergency department on inpatient outcomes. bmc emerg med 2010; 10:16. https://doi.org/10.11 86/1471-227x-10-16. 19. somers gt, maxfield n, drinkwater ej. general practitioner preparedness to respond to a medical disaster. part i: skills and equipment. aust fam physician 1999; 28:s3–9. 20. alsaad ssm, abu-grain shs, el-kheir dym. preparedness of dammam primary health care centers to deal with emergency cases. j family community med 2017; 24:181–8. https://doi. org/10.4103/jfcm.jfcm_5_17. 21. kalidindi s, lacy ta. primary care office preparedness for pediatric emergencies. pediatr ann 2018; 47:e93–6. https://doi. org/10.3928/19382359-20180221-01. 22. kalidindi s, kirk m, griffith e. in-situ simulation enhances emergency preparedness in pediatric care practices. cureus 2018; 10:e3389. https://doi.org/10.7759/cureus.3389. املؤمتر اخلليجي األول للتوحد م�سقط, عمان, 24-26 يناير 2020 1st gulf autism conference muscat, oman, 24–26 january 2020 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e237–240, epub. 28 jun 20 https://doi.org/10.18295/squmj.2020.20.02.019 conference abstracts the functioning of aq-10 for initial screening of asd symptoms among residents in the state of qatar *timmermans chantal,1 alhajyaseen wael,1 soliman abdrabo,2 dirix hélène,3 brijs kris,3 brijs tom,3 ross veerle3 1college of engineering, qatar transportation and traffic safety center and 2college of arts and sciences, department of social sciences, qatar university, doha, qatar; 3school for transportation sciences, transportation research institute (imob), hasselt university, hasselt, belgium. *corresponding author’s e-mail: t.chantal@qu.edu.qa objective: prevalence of asd in the state of qatar is very uncertain. therefore, in this pilot study we intended to create understanding of the asd characteristics reported by residents in the state of qatar while making a comparison between males with females. this study also aimed to assess the functionality of the autism quotient questionnaire (aq-10) as initial screening tool in identifying possible residents with suspected asd, improving the referral rate to a specialist for further assessment. methods: the short aq-10 was distributed among students and staff of qatar university and members of the qatari community. results: the total sample includes 214 respondents (126 females, mean age: 28). preliminary results of this pilot study show 5.3% of the respondents scored above the aq10 cut-off point, showing self-reported signs of asd and indicating they require an official diagnostic assessment. conclusion: this referral rate is important to obtain a clearer picture of the current prevalence of asd in the state of qatar because clarification of asd prevalence will help diagnosed residents to get asd-specific support if needed which could improve their quality of life. acknowledgement/funding: this publication was made possible by the nprp award (nprp11s-1228-170143) from the qatar national research fund (a member of qatar foundation). autism screening in oman, knowledge, attitudes and practices of healthcare professionals moza n. al hatmi child health section, ministry of health, muscat, oman. e-mail: dr.alhatmi@gmail.com objectives: the national screening programme for autism and other developmental disorders for all 18-month-old children was launched in september 2016. healthcare professionals are at the first level of care serving such patients in terms of detection and referral to specialised care. this is the first study to assess the trained healthcare professionals’ knowledge, attitudes and to address autism screening practices in oman. methods: in this quantitative study, the link of an online survey (powered by questback) was sent to the mobile phones of 571 healthcare providers. results: a total of 174 responses (response rate: 30%) were obtained from staff nurses (64.4%, n = 112), general practitioners (19.5%, n = 34), paediatricians (10.3%, n = 18), family physicians (2.9%, n = 5), psychiatrists (1.1%, n = 2) and others (1.7%, n = 3) from all 11 governorates of oman. most of the respondents were female (84%, n = 143), young (mean age: 36 ± 6.6 years), working in primary healthcare (91%) and had more than 10 years’ experience (59%). there was a significant knowledge variation among different groups of professionals; paediatricians and gps showed high levels of knowledge. a second important finding suggested no significant relation between professionals’ knowledge levels and their training, practical experience, and the care level they work on. overall good attitudes were noted towards early detection and intervention. an interesting finding was that professionals express satisfaction with their perceived knowledge and self-confidence in autism screening. conclusion: these findings represent a further step towards future studies and improvement of the screening programme. use of floor time in engaging autism: a systematic review divya k. y. college of nursing, sultan qaboos university, muscat, oman. e-mails: divyaky@squ.edu.om and kydivyam@gmail.com objective: floor time is a relationship-based therapy where the parent gets down on the floor with the child to play and interact with the child at their level. this article described the effects of floor time on children with autism and explored the factors influencing the impact of floor time among autistic children and their parents based on a systematic review from identified journals in pubmed, embase, social science citation index and reviews. methods: out of 18,000 studies, 11 studies met the inclusion criteria and were considered for this review. the criteria considered were: the children do not suffer from co-morbid developmental disorders, studies exploring the impact of floor time therapy in autistic children, studies published in english and available for free download from 2014–2019. the search terms used were floor time and autism, dir/floor time and autism, relationship therapy and autism factors influencing floor time in autism. results: the results showed significant improvement in emotional functioning, communication and daily living skills and mothers perceived an improvement in the parent-child interactions. parents who were married, had lower income, severity of the diagnosis and better knowledge of floor time had a better and higher quality parent engagement, which was significantly correlated with better improvement in child development. conclusion: every child with autism is different and every family has its unique make, hence it is important for parents to have the necessary information on various forms of therapies to make informed choices on the type of services their child could receive. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ 1st gulf autism conference e238 | squ medical journal, may 2020, volume 20, issue 2 feeding abnormalities in malaysian children with asd: pilot translation to malay language, internal reliability, and findings utilising the brief autism mealtime behaviour inventory (bambi) questionnaire *norazlin k. nor, azilawati h. m. ghozali, juriza ismail child development center, universiti kebangsaan malaysia medical center, kuala lumpur, malaysia. *corresponding author’s e-mail: norazlinabouzid@yahoo.com objectives: in this study we assessed feeding abnormalities in children with autism spectrum disorder (asd) with the brief autism mealtime behaviour inventory (bambi) questionnaire. methods: for the pilot phase, the bambi questionnaire was translated to malay and back-translated to english and administered to parents of 151 children and adolescents aged 2–18 years at the child development centre (cdc) at the universiti kebangsaan malaysia medical center (ukmmc), diagnosed with asd based on dsm criteria. both questionnaires were tested on 20 bilingual parents and internal reliability was determined. data analysis was carried out using statistical package for social sciences (spss) version 23.0. results: a total of 138 of 151 (91.4%) asd children in the cdc were problematic feeders based on the bambi scoring. of the total sample, 51 (33.7%) children had a limited variety of food, 16 (10.5%) had food refusal and 23 (15.2%) had feeding patterns that showed features of autism. conclusion: in this study, we ascertained using bambi that the majority of asd children in cdc had feeding abnormalities, with up to a third eating a limited variety of food. assessing feeding difficulty may allow improvement in nutrition and care of asd children. the promising benefit of omega-3 for children with autism: diwan clinic experience zainab al mukhaini directorate general of medical services, diwan of royal court, muscat, oman. e-mail: zalmukhini@yahoo.com objectives: omega-3 fatty acid is known to have a positive effect on cognitive function and brain development. autism is a type of neurodevelopmental disorder that affects a person’s communication and functionality including different brain function. literature shows a link between improvement in autism symptoms and supplementation of omega-3 fatty acid. this study aimed to determined the effect of omega-3 fatty acids on autism symptoms in children attending diwan polyclinic, muscat, oman. methods: this was an observational descriptive study (january to october 2019). all children with autism (n = 11, aged 3–9 years, 9 boys and 2 girls), both newly diagnosed and old cases, attend the paediatrics clinic at diwan polyclinic were offered omega-3 on appropriate daily recommended dose. these children were diagnosed with autism at a specialised tertiary governmental hospitals in muscat but continued their follow-up at diwan polyclinic. parents of the included children were advised to continue the rehabilitation sessions and the special educational support in addition to taking omega-3. children were followed-up every 8 weeks. results: eight children started to take omega-3 supplementation, while two refused. all 8 children improved in their hyperactivity, disobedience and concentration. seven (88%) improved in their eye contact, communication, language development, learning ability in both language and simple calculation and in their memory. the younger to start the intervention with omega-3 the better the outcome. conclusion: omega-3 has great potential in helping children with autism. omega-3 supplementation should be used in conjugation with behavioural therapy and rehabilitation and not as a substitute for rehabilitation. understanding the needs of students with autism in higher education settings hanan a. almasoud king saud university, ksa. e-mail: halmasood@ksu.edu.sa objectives: understanding the specific challenges that students with autism face and the services that are appropriate for them remains a challenge for many higher education (he) institutions. this paper reviews the literature regarding the current practices in including students with autism and how their needs are currently met in he settings. methods: research papers and books were searched in electronic databases, such as eric, and in search engines, such as google scholar. sources were also found using the library websites of the university of exeter and king saud university. the primary keywords used in the searches were ‘disability services and he’, ‘inclusion and autism’ and ‘autism and he’. the reviewed materials included publications from journals, such as focus on autism and other developmental disabilities. results: the literature indicates that the adjustment needed for students with autism should reflect their very particular set of needs. conclusion: the role of disability services is also concerned with the broader culture of the university and, in particular, with inclusive practices and how these might be shaped to help integrate students with autism. more research is needed to understand the needs of students with autism and how these needs can be better addressed by disability service providers in he settings. gene expression study of mitochondrial complex i in autism spectrum disorder *arvin haghighatfard,1 ceymi doenyas,2 tannaz r. lori3 1department of genetics, tehran medical sciences branch, islamic azad university, tehran, iran; 2department of psychology, koc university, istanbul, turkey; 3department of biology, ghaemshahr branch, islamic azad university, ghaemshahr, iran. *corresponding author’s e-mail: arvinland@yahoo.com objectives: autism spectrum disorder (asd) is known as a neurodevelopmental disorder with difficulty in social relationships, verbal and non-verbal communication and repetitive and ritualistic behaviours. although genetics is known as the primary cause of autism, it is still not clear which genes and molecular mechanisms are effective in the pathogenesis of this disease. mitochondrial complexes' role in the aetiology of psychiatric disorders, such as schizophrenia, have been reported. the present study aimed to assess the role of mitochondrial complex i and cell bioenergetic pathways in the aetiology and characteristics of asd. methods: mrna levels of all genomic and mitochondrial genes which encode mitochondrial complex i subunits (44 genes) were assessed in blood in 1,594 asd patients and 1,284 non-psychiatric subjects using real-time pcr. three domains of executive functions (working memory, response inhibition and vigilance) were examined using the cambridge neuropsychological test automated battery (cantabexpedio) in all subjects. results: significant expression changes of 7 genes (including ndufs1, ndufv1, ndufb11 and ndufa1) in asd patients were detected in mitochondrial complex i. most of these genes were novel candidate genes for asd. several correlations between mrna levels and severity of symptoms, deficits in attention, working memory, response inhibition and brain activities were found. correlations were found between attention and memory deficiencies and complex i abnormalities. conclusion: the aetiology of asd involves the deregulations of both core and supernumerary subunits of the mitochondrial complex i. abnormal structure, assembly or functions of complex i could result from either upor down-regulation of mrna levels of both core and supernumerary subunits. this abnormal complex i may lead muscat, oman, 24–26 january 2020 conference abstracts | e239 to electron transport chain problems in the prefrontal cortex and neurodegeneration. the identified correlations could lead to better understanding the role of the neuronal bioenergetics system in executive function performances. fragile x syndrome among a cohort of children with developmental delay *watfa al-mamari, abeer al-sayegh, ahmed b idris, saquib jalees, intisar al-hadabi, muna al-jabri, almunther al-mawali, adila al-kindi sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: watfa.almamari@gmail.com objectives: fragile x syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. affected individuals usually have delayed development of speech and language by age 2. most males with fragile x syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. usually, males are more severely affected by this disorder than females. fragile x syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females. fragile x syndrome is inherited in an x-linked dominant pattern. methods: fragile x was one of the tests that was given the priority to be established at the molecular lab due to its important clinical utility in genetic and development medicine (gdm) clinic. currently the test is centralised and offered to all tertiary hospitals in the country. results: two hundred children affected by developmental delay underwent the following test: allele-specific methylation pcr (mpcr) of the cgg trinucleotide repeat within the 5´-untranslated region of the fragile x mental retardation-1(fmr1) gene using the applied x mpcr kit (asuragen). pcr products are sized by capillary electrophoresis. more than 99% of individuals with fragile x syndrome harbour a cgg repeat expansion accompanied by hyper-methylation of the fmr1 promoter region and consequent absence of fmrp protein expression. conclusion: in the cohort, as per clinical standards to investigate affected children with fragile x, 200 affected with developmental delay were included. 2 out of 200 were positive for the pathogenic mutation, which is in keeping with international figures. dance movement therapy: an intervention for children with autism spectrum disorder; integrative review *deepa s. thomas1 and devakirubai jacob2 1department of mch and 2adult health, college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: deepash@squ.edu.om objectives: autism spectrum disorder (asd) is a developmental disorder that exhibits substantial variations in social, communication and behavioural symptoms. although numerous therapies are being implemented as intervention for autism, no particular approach has yet been verified in relieving the vital indicators of asd. creative measure and dance is a useful and practical choice for children with asd. therefore, the purpose of this paper was to present outcomes of an integrative literature review related to dance movement therapy (dmt) and asd in children. methods: the review on dmt for autistic children was conducted by searching electronic records of pubmed, google scholar, medline and cinahl for articles with complete text. the primary search recognised 157 papers published between 2014 and 2019. results: a total of 14 studies were included in this review after applying the exclusion criteria. the main outcomes revealed that dmt does benefit the child by allowing them to work on their behaviour, communication and motor skills in a non-invasive environment. the dmt showed significant progress to several behavioural effects including stereotypic behaviours, social-emotional functioning, cognition and attention. conclusion: there is a high likelihood for further investigations in this area as it is practical and non-invasive and it provides a sociable experience for children diagnosed with asd. while dmt cannot completely treat all symptoms of asd, neither can any single treatment, its benefits do make it a worthwhile complementary to an existing therapy. the role of mentalisation in autism spectrum disorder: explicit and implicit pathways angie cucchi chartered counselling psychologist, regent's university london, regent’s park campus, london, united kingdom. e-mail: cucchia@regents.ac.uk objectives: the proposed presentation reviews the state-of-the-art literature on autism spectrum disorder (asd). children who function on this spectrum possess deficits in social communication and interaction that have traditionally been explained in terms of theory of mind’s (tom) difficulties. however, performances on the tom tests have, at times, been inconsistent with these findings where some children with asd successfully pass these tests, although these results often do not translate into real life situations. this suggests a complexity that does not seem to be fully captured by the literature on the role of the tom in asd. methods: building on this, and in line with asd’s difficulties around understanding others’ internal worlds, recent studies have explored the claim that mentalising might be a useful tool to conceptualise asd presentations and to explain the inconsistencies mentioned above. in fact, mentalising encapsulates the emotional, relational and affective regulation elements that the tom test neglects. results: in keeping with the mentalising dimensions, two pathways to mentalising difficulties in asd have been suggested, an implicit and an explicit one. the implicit system is supposed to be a relatively effortless and fast yet inflexible. the explicit one is believed to be highly flexible, effortful and highly reliant on language and executive functions. it has been suggested that classical false-belief tests rely on the explicit dimension of mentalising whereas in reallife situations, children often rely on implicit mentalising to process social information in the environment. this is a capacity that even children with high-functioning asd difficulties struggle to compensate for. conclusion: in its early conceptualisation, the role of implicit and explicit mentalising in asd ought to be further explored in order to develop adaptive preventative interventions at a systemic level. interaction with roadway environment and infrastructure while driving: experiences of adults with autism dirix hélène,1 *ross veerle,1 brijs kris,1 vermeiren ellen,2 timmermans chantal,3 alhajyaseen wael,3 brijs tom,1 wets geert,1 spooren annemie4,5 1school for transportation sciences, transportation research institute (imob) and 4rehabilitation research centre, uhasselt, agoralaan, diepenbeek, belgium; 2ghent university, master program occupational sciences, faculty of medicine and health sciences, belgium; 3qatar university, qatar transportation and traffic safety center, college of engineering, doha, qatar; 5pxl, centre of expertise in innovation in care, belgium. *corresponding author’s e-mail: veerle.ross@uhasselt.be objectives: this study aimed to (1) determine how drivers with an autism spectrum disorder (asd) experience the use of roadway environment/infrastructure and (2) identify strategies used to cope with environment/infrastructure elements. methods: participants were recruited through convenience and criterion sampling in order to obtain rich case informants. semi-structured interviews identified experiences of asd drivers while interacting with the roadway environment/infrastructure. these were analysed based on a phenomenological hermeneutical approach with participants’ perceptions and experiences being central. results: data saturation was 1st gulf autism conference e240 | squ medical journal, may 2020, volume 20, issue 2 reached when twelve drivers with asd were interviewed (χ = 34.8, 66.7% female). they reported both positive (e.g. calm, feeling safe) and negative (e.g. stress, anger) feelings towards roadway environment/infrastructure. light, sound, chaos, complex situations, etc. are factors that complicate the (1) driving task, (2) observation process and (3) effective application of traffic rules. interviewees reported that driving experience and automation are important to deal with these situations. avoidance, adjustment (e.g. early departure) and use of alternative transport means were mentioned as coping mechanisms. conclusion: roadway environment/infrastructure can have a negative impact on both driving behaviour itself and the subjective experience of the activity by asd drivers. apparently, driving can be an exhausting and stressful daily life activity. future research could focus on novice asd drivers still lacking driving experience to determine how they appraise and cope with roadway infrastructure/environment. acknowledgement/funding: this publication was made possible by the nprp award (nprp11s-1228-170143) from the qatar national research fund (a member of qatar foundation). the statements made herein are solely the responsibility of the authors. a model for applying multiple intelligences theory with autistic children mohamed m. s. ahmed department of sociology and social work, college of arts and social sciences, sultan qaboos university, muscat, oman. e-mail: drmslem@squ.edu.om objectives: autistic children require attention and comprehensive care that is commensurate with the nature of their disability, especially with the development of human thought and scientific and technological progress. therefore, social workers seek to provide the required assistance through using theoretical guidelines that enable them to deal with autism spectrum, including the theory of multiple intelligences. hence, this study aimed to build an applied model for the theory of multiple intelligences with autistic children. methods: this is a descriptive and analytical study using the social survey method utilising the interview guide with experts and specialists. the study was applied at the rehabilitation services center (diagnostic unit), autism department, and center of evaluation and professional rehabilitation for the disabilities, in muscat, ministry of social development during the period of 8th october 2019 to 1st december 2019. results: the results showed the most important roles of the social worker and the steps of the applied model of the theory of multiple intelligences with autistic children. conclusion: the study indicated the multiplicity of concepts, considerations and basic assumptions of the theory of multiple intelligences with autistic children. 1family medicine residency program, oman medical specialty board, muscat, oman; 2department of family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: marwa.alraisi@gmail.com knowledge and attitude regarding cervical cancer and human papillomavirus in oman *marwa al raisi,1 tagharid al yahyai,1 rahma al kindi2 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 493–500, epub. 7 nov 22 submitted 9 feb 21 revisions req. 26 apr, 3 jun & 3 aug 21; revisions recd. 18 may, 7 jul & 27 aug 21 accepted 18 may, 7 jul & 27 aug 21 https://doi.org/10.18295/squmj.9.2021.140 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to assess the knowledge of and attitude toward cervical cancer and human papillomavirus (hpv) among omani women aged 18 years and older. methods: this cross-sectional survey was conducted between september 2019 and february 2020 in primary healthcare facilities throughout oman. a selfadministered questionnaire was distributed to assess women’s knowledge and attitude regarding cervical cancer and hpv. results: a total of 805 women participated in the study (response rate: 89%). two-thirds of the participants had heard about cervical cancer (67.5%) while fewer were aware of hpv (15.8%). approximately one-third of the women identified hpv as a risk factor for developing cervical cancer (38.9%). very few participants knew of hpv vaccines (10.1%). a major source of information regarding both cervical cancer and hpv was social media (33.0%), as compared to healthcare providers (16.9%). despite the poor knowledge, almost half of the participants were open to having their daughters (47.0%) and other schoolgirls (41.2%) vaccinated. conclusion: most participants had poor knowledge of cervical cancer and hpv, even those with a personal or family history of cervical cancer. the main source of knowledge was social media. most participants were open to the idea of offering the hpv vaccine to their daughters and middle school-aged girls. incorporating information about cervical cancer and hpv into school curricula and improving access to trusted medical knowledge through social media may help in enriching the public’s knowledge and, possibly, correcting misinformation and related myths. keywords: papillomavirus vaccines; cervical cancer; surveys and questionnaires; risk factors; communityinstitutional relations; knowledge; attitude; oman. advances in knowledge this study showed that most participants had poor knowledge of cervical cancer and human papillomavirus (hpv). despite this, approximately half were accepting of the hpv vaccine. therefore, healthcare providers and decision-makers should be vigilant and prepare a nationwide awareness programme to enrich the public’s knowledge of cervical cancer, hpv and its implications. to the best of the authors’ knowledge, this is the first study conducted in all the governorates of oman that assesses the knowledge of and attitude towards cervical cancer and hpv among omani women. applications to patient care the findings of this study provide useful information that could form the basis for educational campaigns and initiatives focusing on cervical cancer and the importance of hpv vaccination. this would result in increased utilisation of the screening programme, improved health outcomes and a significant reduction in the incidence of cervical cancer. this survey demonstrates public acceptance of the vaccine; hence, policymakers must initiate urgent plans to integrate the vaccine into the national immunisation schedule. human papillomavirus (hpv) infection has been identified as a precursor to cervical cancer. there are many hpv carcinogenic genotypes, but types 16 and 18 are the most commonly identified in cervical cancer.1,2 in a recent study from oman, the prevalence of hpv was found to be 17.8%, with 22 different types identified, some of which were found to be carcinogenic, thus posing a high risk. the highest prevalence was for the low-risk type 54 (12.3%), followed by the high-risk type 82 (10.77%).3 according to the global cancer observatory (globocan) estimates of 2020, the incidence of cervical cancer was 604,127 (3.1%) worldwide, which ranks it as the seventh most common cancer overall and fourth most common in women.4 the corresponding worldwide mortality is 341,831 (7.7%), which makes cervical cancer rank fourth in cancerrelated mortality in women of all ages.4 in oman, cervical cancer is the fourth most common cancer in women of all ages and the third most common in women aged 15 to 44 years.5,6 approximately 77 new cervical cancer cases are diagnosed annually in oman, with a total of 41 deaths as per the 2019 hpv information centre estimates.6 the hpv vaccine was introduced with different combinations of hpv genotypes. in many countries, the vaccine was approved as a preventative measure against cervical cancer. for the vaccine to provide adequate immunity, it should be administered years before exposure to the virus. this necessitates its use https://creativecommons.org/licenses/by-nd/4.0/ knowledge and attitude regarding cervical cancer and human papillomavirus in oman 494 | squ medical journal, november 2022, volume 22, issue 4 much before the individual becomes sexually active, preferably during prepubertal age.7 many developed countries have integrated the hpv vaccine into their national immunisation programmes.8 among the middle east and north african region, only one country, the united arab emirates, offers the hpv vaccine as a part of their immunisation schedule.9 in oman, the hpv vaccine is not yet included in the expanded national immunization programme and is not systematically provided by the institutes of the ministry of health.10 the incidence of cervical cancer has dropped significantly after the introduction of cervical cancer screening. in the uk, the incidence rates have declined by 24%, and in the usa, cervical cancer has moved from within the top 10 to the 14th place since the introduction of screening.11–14 in a study conducted in sweden, follow-up of more than one million females for more than 10 years showed a substantial reduction in the incidence of cervical cancer, especially among those vaccinated before the age of 17.15 based on a study conducted in 2019, the estimated worldwide incidence of cervical cancer is predicted to be 44.4 million by the year 2069.16 unfortunately, twothirds of the new cases are thought to be from lowto middle-income countries. as per the same study, even if those countries implement hpv vaccine coverage for middle school-aged girls, the number of new cases of cervical cancer will only lower after three to four decades.16 in oman, a previous study in a tertiary hospital reported that women had insufficient knowledge regarding cervical cancer, its risk factors and methods of screening.17 therefore, the present study aimed, first, to assess the knowledge of cervical cancer as well as the knowledge of and attitude towards hpv and its vaccine among omani women throughout oman and, second, to establish a correlation between their knowledge/attitude and sociodemographic factors. assessing women’s knowledge and attitude regarding hpv infection and its consequences will help in assessing the acceptability of introducing a well-structured cervical cancer screening programme. furthermore, assessing the participants’ knowledge and acceptability of the available vaccine will aid the concerned decision-makers in determining whether to add the vaccine to the national immunisation schedule. methods a multi-centric cross-sectional study was carried out in primary health centres across oman from september 2019 to february 2020. oman comprises 11 governorates and the number of health centres varies from one governorate to another. each of these health centres serves the general population with the aim of having one health centre per 10,000 people. health centres provide a single location for primary care teams to work from and deliver primary healthcare needs. these clinics are well developed in terms of the availability of trained and qualified family physicians, appointment systems and a wide range of investigations and medications. a total of 18 health centres were randomly selected from each governorate. this was done by categorising the governorates as either ‘large’ or ‘small’ based on population size. the enrolled health centres were arranged based on the population of the catchment area and the number of outpatient visits, details of which were obtained from the oman health records 2019. of the 11 governorates, seven were categorised as large and four as small. two health centres were randomly selected from the larger governorates and one health centre from the less populated governorates using a simple random sampling method. the number of participants from each centre was then calculated based on the proportion of outpatient visits in that health centre compared to the total number of outpatient visits. the participants were selected randomly using a systematic random sampling method, which chose every second adult female visiting the health centre for any reason (medical or non-medical) during the study period. the target population was omani women aged 18 years and older who were attending the health centre for any service. women who could not read, those who did not speak arabic or english, those with learning difficulties or dementia, acutely sick women who required immediate care or those in a hurry were excluded from the study. based on the anticipated level of knowledge regarding cervical cancer and screening for cervical cancer, the sample size was determined as 50%, with a 5% margin of error, 95% confidence level and 5% two-tailed alpha error. the calculated sample size was 768. in addition, a 4% non-response rate to the survey was anticipated; therefore, a sample size of 800 was considered for the study. the calculation was done using the openepi software (emory university, atlanta, georgia, usa). a structured questionnaire was used for data collection, which had been tested in a previous study in oman.17 the average time taken to fill the questionnaire ranged between 10 and 15 minutes and this was done by face-to-face interview. the study was anonymous, and the participants were assigned a unique code, which was later used for data analysis. the survey consisted of three main parts. the first part concerned the sociodemographic characteristics marwa al raisi, tagharid al yahyai and rahma al kindi clinical and basic research | 495 of the participants including their age, marital status, age at first marriage, number of marriages, total number of children, number of daughters, their level of education and that of their spouses’, employment status, whether their degree was related to healthcare, total monthly income and if their income affected their regular gynaecological reviews. the second part assessed the participants’ cervical cancer risk factors including history of smoking, exercise, use of oral contraceptive methods, history of abortion, history of sexually transmitted infection (sti), history of hpv infection and personal and family history of cervical cancer. moreover, the participants were asked about their immunity status (i.e. whether they or their spouses had a history of hiv infection and whether they were using immunosuppressant medications). the third part assessed knowledge and awareness regarding cervical cancer and hpv. questions included whether the participants had heard of cervical cancer, their source of information and whether they thought it was among the most common cancers leading to death worldwide. they were questioned about their knowledge of the warning signs of cervical cancer, for example, intermenstrual bleeding, persistent low back pain, persistent foul-smelling vaginal discharge, dyspareunia, menorrhagia, persistent diarrhoea, postmenopausal bleeding, persistent pelvic pain, postcoital bleeding, blood in urine or stool and unexplained weight loss. furthermore, the knowledge of factors that affect the chances of developing cervical cancer, including a history of infection with hpv, smoking, weakened immunity of self or spouse, longterm use of contraceptive pills, early marriage before the age of 16 years, having many children (≥3), family history of cervical cancer and, finally, failure to get screened for cervical cancer, were assessed. the last few questions in this part were regarding hpv and its vaccine—whether they had ever heard of this vaccine and whether they generally accepted the provision of the hpv vaccine to middle school-aged girls and, more specifically, to their own daughters. finally, they were asked if their knowledge, awareness and practice regarding cervical cancer and its screening were influenced by the conservative nature of the omani society. to assess the participants’ knowledge, all knowledge-related questions were compiled and a scoring system was created. each correct answer was given one point and the total possible score was 22. the scores were then divided into two categories: not knowledgeable (scores of <12) and knowledgeable (scores of 12–22). data analysis was performed using the statistical package for the social sciences (spss), version 23 (ibm corp, chicago, illinois, usa). descriptive analyses were conducted for sample characteristics. continuous variables were presented as means and standard deviations. categorical variables were reported as frequencies and percentages. pearson’s chi-square (χ2) test was used when appropriate to determine significance. fisher’s exact tests were used for low cell frequencies. a p value of 0.05 or less was considered statistically significant. missing data were not included in the analyses. ethical approval for the study was obtained from the research and ethics committee of the department of planning and studies, ministry of health, oman (moh/csr/18/9478). participation in the study was voluntary and written consent with a statement of confidentiality was obtained from all participants. the purpose and objectives of the research were explained to all participants. privacy, confidentiality and the right to withdraw at any time were assured. results a total of 805 women participated and completed the study (response rate: 89%). most of the participants were in the age group of 21–30 years (38.9%) and 31–40 years (40.6%) [table 1]. more than half of the participants were undergraduates (55.7%). out of the remaining participants, most had secondary school diplomas (38.7%). the participants were almost equally divided between those with employment (46.5%) and those without (53.5%). approximately one-fifth of the participants had degrees related to healthcare (20.6%). only a fifth of the women surveyed were never married (17.0%), while the majority were married, divorced or widowed (83.1%). more than half were married between the ages of 18–25 years (55.9%). only a small number were married before completing 18 years of age (8.0%). the number of children of each participant varied greatly from 1–13, with an average of 2.52 ± 2.44. the number of daughters also varied, with an average of 1.25 ± 1.49, among which 42% did not have any, followed by a quarter who had one daughter (24.3%). almost half of the participants’ husbands had secondary school diplomas (40.7%) followed by undergraduate degrees (37.8%) the participants’ income also varied greatly: 20.2% reported having a low income of less than 500 omani rial (omr) per month, and 20.4% stated having an income of 1,000– 2,500 omr a month. the majority of the participants (78.3%) indicated that their financial status did not affect their visits to the gynaecologist. almost all of the participants were non-smokers (99.5%). around one-third did not exercise (31.9%), while only 69 (8.6%) exercised regularly around 4–5 knowledge and attitude regarding cervical cancer and human papillomavirus in oman 496 | squ medical journal, november 2022, volume 22, issue 4 times a week. most of the women (78.9%) were not using any contraceptive methods. approximately onethird (30.1%) had a history of abortion, with a small proportion having had more than two abortions (6.6%). few (1.1%) had a history of sti and even less (0.5%) had previously been infected with hpv. of all the participants, only six (0.7%) had a history of cervical cancer and 27 (3.4%) had a family history of cervical cancer to their knowledge. few (0.6%) reported having low immunity and only one (0.1%) reported having a husband with low immunity. when questioned regarding their knowledge about cervical cancer, more than two-thirds of the participants (67.5%) reported having heard of cervical cancer. most of them had gained this knowledge from social media (33.0%), followed by their healthcare provider (16.9%), television programmes or advertisements (16.5%), schools or universities (12.9%), family and friends (8.2%) and written media such as magazines and newspapers (8.1%). the majority (60.2%) did not know that cervical cancer is a leading cause of death and only a quarter (26.3%) thought it was. the warning signs of cervical cancer most frequently identified by the participants included spotting between periods (47.3%), vaginal discharge (41.9%), persistent pelvic pain (41.6%) and postmenopausal bleeding (39.0%). in addition, just under half of the participants identified persistent low back pain (47.3%), menorrhagia (38.9%), postcoital bleeding (35.5%), dyspareunia (34.7%) and weight loss (31.1%) as warning signs. however, blood in the stool and urine (26.2%) and diarrhea (12.3%) were seldom identified as warning signs. when questioned regarding factors that increase the chances of developing cervical cancer, most of the participants agreed that the following are risk factors for cervical cancer: immunosuppression (56.9%), having a family history of cervical cancer table 1: knowledge of cervical cancer among omani women (n = 805) character istic n (%) p value† total* poor knowledge knowled geable age group in years 798 (99.1) ≤30 224 (28.1) 143 (17.9) 0.546 >30 254 (31.8) 177 (22.2) qualification 802 (99.6) illiterate 28 (3.5) 17 (2.1) <0.001 secondary 217 (27.1) 93 (11.6) under graduate or higher 236 (29.4) 211 (26.3) degree related to healthcare 804 (99.9) no 420 (52.2) 218 (27.1) <0.001 yes 62 (7.7) 104 (12.9) marital status 802 (99.6) never married 90 (11.2) 46 (5.7) 0.105married\ divorced\ widowed 391 (48.8) 275 (34.3) employment 790 (98.1) no 284 (35.9) 139 (17.6) <0.001 yes 187 (23.7) 180 (22.8) income in omr 632 (78.5) ≤1000 289 (45.7) 144 (22.8) <0.001 >1000 89 (14.1) 110 (17.4) husband’s qualification 662 (82.2) illiterate 52 (7.9) 31 (4.7) 0.410 secondary 186 (28.1) 143 (21.6) under graduate or higher 153 (23.1) 97 (14.7) history of std 805 (100) no 477 (59.3) 319 (39.6) 0.681 yes 6 (0.7) 3 (0.4) history of hpv 805 (100) no 481 (59.8) 320 (39.8) 0.682 yes 2 (0.2) 2 (0.2) history of cervical cancer 805 (100) no 480 (59.6) 319 (39.6) 0.616 yes 3 (0.4) 3 (0.4) family history of cervical cancer 805 (100) no 474 (58.9) 304 (37.8) 0.004 yes 9 (1.1) 18 (2.2) omr = omani rial; std = sexually transmitted disease; hpv = human papillomavirus. *missing data were not included in the statistical analysis. †using chi square test. marwa al raisi, tagharid al yahyai and rahma al kindi clinical and basic research | 497 (53.3%), never being screened for cervical cancer before (49.7%), smoking (48.1%), long-term use of oral contraceptive pills (36.6%) and having a husband with a weakened immune system (34.4%). on the other hand, very few respondents thought that early marriage (17.0%) and having many children (9.3%) played a role in developing cervical cancer. almost half of the respondents (49.7%) did not know whether hpv infection was a risk factor and some (11.4%) thought it was not a risk factor. regarding the knowledge score, 483 (60.0%) participants were categorised as having poor table 2: attitudes of omani women towards administering the human papillomavirus vaccine to their daughters and/or middle school-aged girls character istic acceptability of administering hpv vaccine,n (%)* to daughters p value† to middle school-aged girls p value† no yes no yes age group in years ≤30 43 (43.9) 172 (45.6) 0.817 50 (43.9) 157 (47.4) 0.760 >30 55 (56.1) 206 (54.5) 64 (56.1) 174 (52.6) total 98 378 114 331 qualification illiterate 10 (10.0) 18 (4.8) 0.052 12 (10.4) 15 (4.5) <0.001 secondary 47 (47.0) 133 (35.3) 62 (53.9) 105 (31.6) under graduate or higher 43 (43.0) 226 (59.9) 41 (35.7) 212 (63.9) total 100 377 115 332 degree related to healthcare no 79 (79.0) 287 (76.1) 0.070 98 (85.2) 249 (75.2) 0.036 yes 21 (21.0) 90 (23.9) 17 (14.8) 82 (24.8) total 100 377 115 331 marital status never married 19 (19.2) 62 (16.4) 0.809 22 (19.1) 52 (15.9) 0.682 married/ divorced/ widowed 80 (80.8) 315 (83.6) 93 (80.9) 276 (84.1) total 99 377 115 328 employment no 53 (54.6) 189 (50.3) 0.194 69 (61.6) 157 (47.7) 0.014 yes 44 (45.4) 187 (49.7) 43 (38.4) 172 (52.3) total 97 376 112 329 income in omr ≤1000 omr 56 (70.0) 197 (65.7) 0.333 60 (67.4) 172 (65.4) 0.270 >1000 omr 24 (30.0) 103 (34.3) 29 (32.6) 91 (34.6) total 80 300 89 263 husband’s qualification illiterate 15 (18.8) 33 (10.5) 0.262 18 (18.9) 28 (10.3) 0.284 secondary 38 (47.5) 165 (52.5) 42 (44.2) 140 (51.3) under graduate or higher 27 (33.8) 116 (36.9) 35 (36.8) 105 (38.5) total 80 314 95 273 history of std no 100 (100.0) 371 (98.1) 0.155 115 (100.0) 328 (98.8) 0.455 yes 0 (0.0) 7 (1.9) 0 (0.0) 4 (1.2) total 100 378 115 332 history of hpv no 100 (100.0) 376 (99.5) 0.743 115 (100.0) 330 (99.4) 0.713 yes 0 (0.0) 2 (0.5) 0 (0.0) 2 (0.6) total 100 378 115 332 history of cervical cancer no 99 (99.0) 376 (99.5) 0.796 115 (100.0) 327 (98.5) 0.105 yes 1 (1.0) 2 (0.5) 0 (0.0) 5 (1.5) total 100 378 115 332 family history of cervical cancer no 99 (99.0) 364 (96.3) 0.377 114 (99.1) 317 (95.5) 0.160 yes 1 (1.0) 14 (3.7) 1 (0.9) 15 (4.5) total 100 378 115 332 do you have daughters? no 37 (37.0) 170 (45.0) 0.234 44 (38.3) 148 (44.6) 0.410 yes 63 (63.0) 208 (55.0) 71 (61.7) 184 (55.4) total 100 378 115 332 *“i don’t know”/“not sure responses” were not included in the statistical analysis. †using chi-square test. knowledge and attitude regarding cervical cancer and human papillomavirus in oman 498 | squ medical journal, november 2022, volume 22, issue 4 knowledge, with a score of <12, while 322 (40.0%) were deemed knowledgeable, with a score of ≥12. the knowledge score was significantly associated with the participants’ qualifications (p <0.001) and whether their degree was related to healthcare (p <0.001). most women who were categorised as knowledgeable were undergraduates or had a higher degree (65.7%). considering the relationship between the participants’ field of study, particularly whether it was related to healthcare and their knowledge score, more than half of the participants had poor knowledge (59.9%), with a few being in healthcare-related fields (7.7%). the knowledge score was also significantly associated with employment status (p <0.001), income (p <0.001) and a family history of cervical cancer (p = 0.004). the knowledge score was not significantly associated with the other sociodemographic characteristics or with a previous history of sti, hpv infection or cervical cancer [table 1]. two-thirds of the participants (67.0%) had never heard of hpv. even though only 81 women (10.1%) had heard of the hpv vaccine, 332 (41.2%) were accepting of offering the vaccine to middle schoolaged girls and almost half (47.0%) of the participants agreed that vaccinating their daughters was a good decision. furthermore, 48.3% of the participants admitted that the conservative nature of omani society affected their knowledge of cervical cancer. there was no association between any of the factors and the participants’ acceptance of the provision of the hpv vaccine to their own daughters. however, there was a significant association between the participants’ acceptance of vaccinating school children and their level of education (p <0.001), whether their field of study was related to healthcare (p = 0.036) and their employment status (p = 0.014). on the contrary, there was no association between the participants’ agreement towards vaccination and whether they had daughters [table 2]. discussion even though cervical cancer is the third most common cancer among omani women aged 15–44 years, there is no well-structured national screening programme.5 the unavailability of cervical cancer screening and pap smear testing at the primary healthcare level has led to a lack of knowledge regarding cervical cancer. in the current study, 67.5% of the participants had heard of cervical cancer, which is low compared to a previous similar study in oman where more than 80% of the participants had heard of cervical cancer.17 the main source of information for the participants in the present study was social media (33.0%), followed by healthcare providers (16.9%). this observation is consistent with the findings of studies from other arabic countries such as qatar, hispanic communities in the us and some asian countries including india.18–20 however, these findings are contrary to those of a study conducted in italy among young adult women, which found healthcare providers to be the primary and most trusted source of information.21 this suggests the possibility that national education and awareness programmes are deficient in oman or are not within the reach of the public. social media has become an important platform that can be utilised in educating the public about cervical cancer and the hpv vaccine, especially considering that it is currently one of the fastest and easiest means of delivering information. hence, it could be wisely used by healthcare providers, provided the information is well-prepared and structured. a previous study from oman found that the majority of undergraduates had inadequate knowledge regarding cervical cancer which was found to be 100%, 59.5% and 92.4% for patients, staff and current students, respectively.17 similarly, the present study found that participants demonstrated poor knowledge despite their educational level or employment status, which is indicative of the fact that the public’s overall exposure to cervical cancer awareness, whether through advertisement, their healthcare providers or their schools, is lacking. this highlights the need to utilise different resources to increase awareness of cervical cancer and to focus more on the role of healthcare professionals in delivering the required information, as, being the most reliable of sources, they are uniquely qualified to respond to any enquiry and offer appropriate guidance to the public. in terms of knowledge regarding cervical cancer, the results of the present study were consistent with those of studies done in qatar and kuwait.18,22 people who had better knowledge were mostly those who were undergraduates or those aged 31 years or older. on the other hand, women under 30 years of age, recently married women and uneducated women were found to possess inadequate knowledge. although most of the respondents in the present study were educated, only 40.0% were considered knowledgeable. contrary to the findings of previous studies, even highly educated participants were found to be unaware of cervical cancer in the present study. this could be because the population size in a previous study done in oman was smaller and most of the participants were hospital staff and nursing students who would have previously been exposed to information regarding, if not had patients with, cervical cancer and/or hpv.17 marwa al raisi, tagharid al yahyai and rahma al kindi clinical and basic research | 499 regarding knowledge of hpv and its vaccine, among the participants of the present study, only 15.8% had heard of hpv compared to 34.5% in a study conducted in saudi arabia. in the same study, 29.9% of participating saudi women were aware of the hpv vaccine compared to only 10.1% in the present study.23 both these figures are very low when compared to the 79.1% of participants who knew of the hpv vaccine in a study done in the uk, usa, and australia.24 this calls for a nationwide awareness programme to educate the omani public regarding hpv and its implications. despite the poor knowledge regarding hpv and its vaccine, the population of the present study was found to be accepting of vaccinating middle schoolaged girls, including their own daughters. this could indicate the public’s trust in the health authorities of the country. the acceptability rate of participants towards vaccinating their daughters was 47.1%, which is considered low when compared to 83.7% in thailand, 81.8% in bahrain and 64.3% in saudi arabia.23,25–27 though the acceptance shown towards the hpv vaccine is comparably low, initiatives must be taken to increase acceptability of the vaccine and to make it available for eligible candidates. the strength of the current study lies in the diversity of the respondents. it is the first national study from oman to assess the knowledge and awareness of and attitude towards cervical cancer and hpv. the results of this study can, therefore, be generalised to the entire population. moreover, the response rate was high, likely due to the chosen data collection method (face-to-face interviews), which may have helped to build a stronger rapport with the respondents, allowing for more accurate and complete responses. the limitations of this study include the length of the questionnaire and the fact that the interviews were conducted in the waiting areas of primary healthcare facilities, which can often be crowded. finally, the inclusion of questions referring to the participants’ past experiences and the face-to-face interview setup itself could have inadvertently led to recall or response bias. conclusion most participants had poor knowledge of cervical cancer and hpv. even those with a personal or family history of cervical cancer were not aware of hpv and its role. regardless of this, most participants were open and accepting of the idea of offering the hpv vaccine to middle school-aged girls and even their daughters. community outreach programmes may help in enriching public knowledge and, possibly, correct misinformation and myths regarding cervical cancer and hpv. a u t h o r s’ c o n t r i b u t i o n s mr, ty and rk conceived the presented research idea and conducted the literature review. mr and ty, under the supervision of rk, designed the research methodology. mr and ty were involved in the data collection and date entry. mr, ty and rk analysed and interpreted the results. mr was a major contributor in writing the manuscript in consultation with ty and rk. rk was the research supervisor who guided mr and ty throughout the project. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t we would like to thank dr gauhar rizvi of sultan qaboos university, muscat, oman, and mr sachin jose of oman medical specialty board, muscat, oman, for their invaluable help with the statistics. we would also like to extend our thanks to our research assistants who made it possible to conduct this research project at the national level. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this research has received funding from sultan qaboos university hospital (grant #rf/med/ famco/19/04) references 1. jhingran a, russel ah, seiden mv, duska lr, goodman a, lee sl, et al. cancers of the cervix, vulva, and vagina. in: niederhuber je, armitage jo, doroshow jh, kastan mb, tepper je, eds. clinical oncology, 6th ed. amsterdam, the netherlands: elsevier, 2019. pp. 1468–507. 2. green j, berrington de gonzalez a, sweetland s, beral v, chilvers c, crossley b, et al. risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20-44 years: the uk national case-control study of cervical cancer. br j cancer 2003; 89:2078–86. https://doi.org/10.1038/ sj.bjc.6601296. 3. al-lawati z, khamis fa, al-hamdani a, al-kalbani m, ramadhan fa, al-rawahi tr, et al. prevalence of human papilloma virus in oman: genotypes 82 and 68 are dominating. int j infect dis 2020; 93:22–7. https://doi.org/10.1016/j.ijid.2019.12.038. 4. world health organization. the global health observatory: globacan 2020 cervix uteri. from: https://gco.iarc.fr/ today/data/factsheets/cancers/23-cervix-uteri-fact-sheet.pdf accessed: sep 2021. 5. world health organization. the global health observatory: globacan 2020 oman. from: https://gco.iarc.fr/today/data/ factsheets/populations/512-oman-fact-sheets.pdf accessed: sep 2021. https://doi.org/10.1038/sj.bjc.6601296 https://doi.org/10.1038/sj.bjc.6601296 https://doi.org/10.1016/j.ijid.2019.12.038 knowledge and attitude regarding cervical cancer and human papillomavirus in oman 500 | squ medical journal, november 2022, volume 22, issue 4 6. bruni l, albero g, serrano b, mena m, gómez d, muñoz j, et al. ico/iarc information centre on hpv and cancer (hpv information centre). human papillomavirus and related diseases in oman. summary report 17 june 2019. from: https:// hpvcentre.net/statistics/reports/omn.pdf accessed: sep 2021. 7. güdücü n, gönenç g, i̇şçi h, yiğiter ab, dünder i̇. awareness of human papilloma virus, cervical cancer and hpv vaccine in healthcare workers and students of medical and nursing schools. j clin exp invest 2012; 3:318–25. https://doi.org/10.57 99/ahinjs.01.2012.03.0171. 8. arbyn m, weiderpass e, bruni l, de sanjosé s, saraiya m, ferlay j, et al. estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. lancet glob health 2020; 8:e191–203. https://doi.org/10.1016/s2214-109x(19)30482-6. 9. gamaoun r. knowledge, awareness and acceptability of antihpv vaccine in the arab states of the middle east and north africa region: a systematic review. east mediterr health j 2018; 24:538–48. https://doi.org/10.26719/2018.24.6.538. 10. ministry of health, oman. manual on expanded program on immunisation. from: www.moh.gov.om/documents/27292 8 / 4 0 1 7 9 0 0 / e p i _ m a nu a l . p d f / 7 cd f 4 3 9 3 3 ff 9 3 5 7 5 f 9 1 1 c460ada5831b accessed: sep 2021. 11. cancer research uk. cervical cancer statistics. from: https:// w w w.cancerresearchuk .org/healthprofessional/cancerstatistics/statistics-by-cancer-type/cervical-cancer accessed: oct 2019. 12. peto j, gilham c, fletcher o, matthews fe. the cervical cancer epidemic that screening has prevented in the uk. lancet 2004; 364:249–56. https://doi.org/10.1016/s0140-6736(04)16674-9. 13. siegel r, naishadham d, jemal a. cancer statistics, 2012. ca cancer j clin 2012; 62:10–29. https://doi.org/10.3322/caac.20138. 14. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of inci dence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2018; 68:394–424. https://doi.org/10.3322/ caac.21492. 15. lei j, ploner a, elfström km, wang j, roth a, fang f, et al. hpv vaccination and the risk of invasive cervical cancer. n engl j med 2020; 383:1340–8. https://doi.org/10.1056/nejmoa1917338. 16. simms kt, steinberg j, caruana m, smith ma, lew jb, soerjomataram i, et al. impact of scaled up human papillo mavirus vaccination and cervical screening and the potential for global elimination of cervical cancer in 181 countries, 2020–99: a modelling study. lancet oncol 2019; 20:394–407. https://doi. org/10.1016/s1470-2045(18)30836-2. 17. nasar a, waad a, atheer a, nasra a. awareness of cervical cancer and pap smear testing among omani women. asian pac j cancer prev 2016; 17:4825–30. https://doi.org/10.22034/ apjcp.2016.17.11.4825. 18. al-meer fm, aseel mt, al-khalaf j, al-kuwari mg, ismail mfs. knowledge, attitude and practices regarding cervical cancer and screening among women visiting primary health care in qatar. east mediterr health j 2011; 17:855–61. https://doi.org/10.267 19/2011.17.11.856. 19. ramirez ag, suarez l, laufman l, barroso c, chalela p. hispanic women’s breast and cervical cancer knowledge, attitudes, and screening behaviors. am j health promot 2000; 14:292–300. https://doi.org/10.4278/0890-1171-14.5.292. 20. roy b, tang ts. cervical cancer screening in kolkata, india: beliefs and predictors of cervical cancer screening among women attending a women’s health clinic in kolkata, india. j cancer educ 2008; 23:253–9. https://doi.org/10.1080/08858190802189105. 21. donati s, giambi c, declich s, salmaso s, filia a, ciofi degli atti ml, et al. knowledge, attitude and practice in primary and secondary cervical cancer prevention among young adult italian women. vaccine 2012; 30:2075–82. https://doi.org/10.1016/j.vaccine.20 12.01.057. 22. al sairafi m, mohamed fa. knowledge, attitudes, and practice related to cervical cancer screening among kuwaiti women. med princ pract 2009; 18:35–42. https://doi.org/10.1159/000163044. 23. hussain an, alkhenizan a, mcwalter p, qazi n, alshmassi a, farooqi s, et al. attitudes and perceptions towards hpv vaccin ation among young women in saudi arabia. j family community med 2016; 23:145–50. https://doi.org/10.4103/2230-8229.189107. 24. marlow la, zimet gd, mccaffery kj, ostini r, waller j. knowledge of human papillomavirus (hpv) and hpv vaccination: an international comparison. vaccine 2013; 31:763–9. https:// doi.org/10.1016/j.vaccine.2012.11.083. 25. ling wy, razali sm, ren ck, omar sz. does the success of a school-based hpv vaccine programme depend on teachers’ knowledge and religion? -a survey in a multicultural society. asian pac j cancer prev 2012; 13:4651–4. https://doi.org/10.73 14/apjcp.2012.13.9.4651. 26. moosa k, alsayyad as, quint w, gopala k, deantonio r. an epidemiological study assessing the prevalence of human papillomavirus types in women in the kingdom of bahrain. bmc cancer 2014; 14:905. https://doi.org/10.1186/1471-240714-905. 27. jassim g, obeid a, al nasheet ha. knowledge, attitudes, and practices regarding cervical cancer and screening among women visiting primary health care centres in bahrain. bmc public health 2018; 18:128. https://doi.org/10.1186/s12889-018-5023-7. https://doi.org/10.5799/ahinjs.01.2012.03.0171 https://doi.org/10.5799/ahinjs.01.2012.03.0171 https://doi.org/10.1016/s2214-109x(19)30482-6 https://doi.org/10.26719/2018.24.6.538 https://doi.org/10.1016/s0140-6736(04)16674-9 https://doi.org/10.3322/caac.20138 https://doi.org/10.3322/caac.21492 https://doi.org/10.3322/caac.21492 https://doi.org/10.1056/nejmoa1917338 https://doi.org/10.1016/s1470-2045(18)30836-2 https://doi.org/10.1016/s1470-2045(18)30836-2 https://doi.org/10.22034/apjcp.2016.17.11.4825 https://doi.org/10.22034/apjcp.2016.17.11.4825 https://doi.org/10.26719/2011.17.11.856 https://doi.org/10.26719/2011.17.11.856 https://doi.org/10.4278/0890-1171-14.5.292 https://doi.org/10.1080/08858190802189105. https://doi.org/10.1016/j.vaccine.2012.01.057 https://doi.org/10.1016/j.vaccine.2012.01.057 https://doi.org/10.1159/000163044 https://doi.org/10.4103/2230-8229.189107 https://doi.org/10.1016/j.vaccine.2012.11.083. https://doi.org/10.1016/j.vaccine.2012.11.083. https://doi.org/10.7314/apjcp.2012.13.9.4651 https://doi.org/10.7314/apjcp.2012.13.9.4651 https://doi.org/10.1186/1471-2407-14-905 https://doi.org/10.1186/1471-2407-14-905 https://doi.org/10.1186/s12889-018-5023-7 squ med j, april 2010, vol. 10, iss. 1, pp. 210-214, epub. 19th jun 10 submitted: 19th mar 10 revision req. 04th may 10,. revision recd. 01st jun 10 accepted: 06th jun 10 departments of 1obstetrics and gynaecology, 2radiology & molecular imaging, family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author email: gowrie61@hotmail.com قياس احلوض بالرنني املغناطيسي يف حماولة للوالدة بعد عملية قيصرية سابقة فيدياناثان جويري، راجيف جني ، سيد ريزفي في اخملرج ومؤشر احلوض ألقطار مرجعية قيم لعمل الوالدة نوع حسب املغناطيسي بالرنني احلوض أقطار لقياس الطبقي التصنيف الهدف: امللخص: محاولة الوالدة بعد عملية قيصرية. الطريقة: هذه دراسة استعادية شملت 125 مريضة في مستشفى جامعة السلطان قابوس )عمان(، خضعن لقياس ناِسن، اخملرج احلوض بالرنني املغناطيسي في محاولة للوالدة عن طريق املهبل بعد عملية قيصرية. مت قياس املدخل السهمي، املدخل العرضي، قطر ما بنَيَ السَّ السهمي، واخملرج العرضي لكل املريضات. صنفنا متوسط قياسات األقطار الى طبقات حسب طريقة الوالدة )عن طريق املهبل أو بعملية قيصرية(. متت َّنينْ للجنني ومحيط رأسه عند النساء اللواتي ولدن ناِسن، اخملرج السهمي وبني املحَُونْدَب( وقطر بنَيَ اجلِدارِي مقارنة متوسط مؤشر اخملرج )ناجت جمع أقطار بنَيَ السَّ بالعملية القيصرية أو عن طريق املهبل. النتائج: كل األقطار ما عدا املدخل السهمي كانت أكبر عند النساء اللواتي ولدن عن طريق املهبل مقارنة بالنساء ّي هو)2.05±31.89( سم وهذا اللواتي ولدن بالعملية القيصرية ألي سبب كان. كان متوسط مؤشر اخملرج في مجموعة الوالدة التلقائية في حالة املَيء الِقمِّ أكبر بشكل معتد إحصائيا من متوسط مؤشر اخملرج في حاالت العمليات القيصرية الطارئة واخملتارة، التي كانت )1.85±29.69( سم و)30.62±1.80( سم )31.89+2.05( اخملرج مؤشر اخلالصة: القيصرية. العملية والدات في إحصائيا معتدة بصورة أكبر الرأس محيط متوسط كان التوالي. على سم )اخملرج املحَُونْدَب وبني سم )10.46+0.89( ناِسن السَّ وبنَيَ سم )10.54+1.00( السهمي واخملرج سم )12.56+0.80( العرضي املدخل التالية: واألقطار العرضي( )1.02+10.89( سم حدود فاصلة مفيدة في الوالدة عن طريق املهبل عند مريضاتنا. مفتاح الكلمات: تصوير الرنني املغناطيسي ، قياس احلوض ، قيم طبيعية ، عملية قيصرية ، محيط. abstract: objectives: to stratify the magnetic resonance (mr) pelvimetric diameters according to mode of delivery and establish possible reference values for pelvic diameters and outlet index for trial of labor after a previous caesarean section. methods: this is a retrospective study of 125 patients at sultan qaboos university hospital who underwent mr pelvimetry prior to a trial of vaginal delivery after a previous caesarean section between may 2001 and october 2003. sagittal inlet, transverse inlet, interspinous diameter, sagittal outlet and transverse outlet diameters were measured in all patients. the mean diameters were stratified according to delivery modality (vaginal delivery or caesarean section). the outlet index (sum of interspinous, sagittal outlet and intertuberous diameters), biparietal diameter of the foetus and head circumference were compared in women who delivered by caesarean section or vaginally. results: all the diameters except sagittal inlet, were significantly larger (p < 0.05) in women who delivered normally as compared with those who had a caesarean section for any indication. the mean outlet index in the spontaneous delivery group with vertex presentation 31.89 ± 2.05, was significantly larger than that of the elective and emergency caesarean section, which were 29.69 ± 1.85 & 30.62 ± 1.80 respectively. the mean head circumference was also found to be significantly larger in the caesarean section deliveries. conclusion: an outlet index of 31.89 ± 2.05 and the pelvic diameters, transverse inlet 12.56 ± 0.80cm, sagittal outlet 10.54 ± 1.00 cm, interspinous diameter10.46 ± 0.89cm, and intertuberous diameter (transverse outlet) 10.89 ± 1.02cm are useful cut-off points for vaginal delivery in our population. keywords: mri; pelvimetry; normal values; caesarean section, circumference. magnetic resonance pelvimetry for trial of labour after a previous caesarean section *vaidyanathan gowri,1 rajeev jain,2 syed rizvi3 clinical and basic research advances in knowledge: 1. this is the first study in the middle east to describe magnetic resonance pelvimetry values in this population. 2. the pelvic diameters/outlet index are likely to provide reference values for this population. application to patient care: 1. trial of vaginal delivery after caesarean section has to be encouraged especially in this part of the world where the mean parity is high. the pelvic diameters and the outlet index suggested will help in decision making to choose the appropriate patients for trial of labour after caesarean section. vaidyanathan gowri, rajeev jain, syed rizvi clinical and basic research | 211 radiographic pelvimetry has been in use for most of this century to predict obstetric outcomes, although there is considerable variation in practice and its use is now being criticised mainly due to the high radiation dose involved and the failure to assess the contributions of soft-tissues to outlet obstruction.1 the advent of newer technologies like computerised tomography (ct) and magnetic resonance imaging (mr) scanning has increased interest in this area especially for mr pelvimetry which does not involve ionising radiation.2 antenatal x-ray pelvimetry in women with previous caesarean section could not predict the likelihood of vaginal delivery.3 pelvimetric dimensions by mr imaging were found to be smaller in women undergoing caesarean section or vacuum extraction than they were those in delivering vaginally.4 borell and fernström described an index based on the sum of the transverse diameter of the mid pelvis, the transverse and sagittal diameters of the pelvic outlet, and pelvic contraction was defined as a sum of less than 29.5 cm for assessing pelvic adequacy, as reported by sporri et al.5 a combination of antenatal ultrasound and mr pelvimetry dimensions has been suggested to be useful in predicting cephalopelvic disproportion in nulliparous women.6,7 the cephalopelvic disproportion index compares the smallest pelvic diameter (either the sagittal diameter of the inlet or the transverse diameter of the mid pelvis) with the foetal biparietal diameter (bpd) and indicates how much wider the smallest pelvic diameter is than the biparietal diameter. a positive cephalopelvic disproportion index is present if the pelvic diameter is less than 9 mm wider than the biparietal diameter.8 in view of the desired high parity in this part of the world, and as caesarean section is known to be associated with reduced fertility, efforts are taken to avoid caesarean section as far as possible.9 in this study, the absolute values of all pelvic diameters were compared with antenatal ultrasound for the foetal biparietal diameter near term and a decision for mode of delivery was made. methods this was a retrospective study of 182 patients who underwent mr pelvimetry from may 2001 to october 2003 at sultan qaboos university hospital, muscat, oman, for clinical indications. of the 182 patients, the indication in 125 was a previous caesarean section. the foetus was in vertex presentation in all these 125 women. the indication in the remaining 57 patients was singleton breech presentation. patients with bony pelvic abnormalities, pelvic masses and soft tissue anomalies were excluded. only women with previous caesarean scar were included in the present study. mr pelvimetry was performed with the patient in the supine position on a 1.5 t mri system (siemens, magnetom symphony, erlangen, germany). surface coils were placed over the pelvis and the patient appropriately placed within the gantry. t1 weighted spin-echo sequences were used with the following parameters: tr/te 400/14 ms, fov 330 mm, 6 slices, matrix 512x192, ta 1’46”, to obtain midsagittal, oblique transverse (angulated along the superior border of the symphysis pubis and sacral promontory) and oblique coronal (through the ischial spines and tuberosities) sections of the pelvis. electronic calipers were used to obtain the following measurements: midsagittal section, obstetric conjugate, from the sacral promontory to the top of the symphysis pubis; sagittal outlet, from the lower border of s5 to the bottom of the inner cortex of the symphysis pubis; oblique transverse section, largest transverse diameter of the pelvis; oblique coronal section, interspinous (narrowest) distance between the ischial spines, and the intertuberous (widest) distance between the ischial tuberosities. these five diameters (sagittal inlet, sagittal outlet, transverse inlet, interspinous and intertuberous) were measured in all patients in addition to the sacral configuration and any soft tissue anomalies. the mean of each of the five diameters ± standard deviation was calculated for all 125 patients. the analysis of the data was done retrospectively. the diameters were stratified by mode of delivery in each group separately. the statistical package for the social sciences software, spss version 17, was used for the statistical analysis and a p value of .05 or less was considered as significant. the normality of the study variables was tested using the kolmogorov smirnov test and all the variables were found to follow a normal distribution pattern. pearson’s formula was used to obtain the coefficient of correlation and an independent sample t-test was applied to test the significance of difference between two sample means. an index called outlet index (sum of interspinous, magnetic resonance pelvimetry for trial of labour after a previous caesarean section 212 | squ medical journal, april 2010, volume 10, issue 1 sagittal outlet and intertuberous diameter), as reported by borell and fernström, was calculated and an index of 29.5 was used as a cut off for allowing women with previous caesarean section a trial of labour. in addition, if the least pelvic diameter (sagittal inlet/interspinous diameter) was at least 9 mm wider than the bpd measured near term, the patient was allowed a trial of labour as described by abitbol et al.8 results the mean age and height of the patients was 27.7 ± 5.06 years and 154.60 ± 5.90 cms, respectively. the mean gestation was 37.69 ± 1.19 weeks. mean gravidity was 3 and parity 1.57. the mean values and standard deviations for the observed five diameters for all patients are presented in table 1. significant positive correlation was observed between the sagittal inlet diameter and the height of the women (r = .516, p < .001) there was no significant difference in the sagittal inlet diameter between the spontaneous delivery and caesarean section groups, whereas the other four diameters (transverse inlet, interspinous, sagittal outlet and the intertuberous diameter) were significantly larger in the spontaneous delivery group compared to elective or emergency caesarean sections. the same four diameters were significantly smaller in patients who underwent emergency caesarean section for failure to progress compared with women who delivered vaginally [table 2]. the mean outlet index of patients who had had a caesarean section for failure to progress was significantly smaller than the outlet index of patients who delivered vaginally [table 2]. the mean values for all pelvic diameters and various modes of deliveries is shown in table 3. the mean birth weight of the babies was found to be significantly higher in the elective lower segment caesarean section (lscs) deliveries of the vertex group (3430.0 ± 421.8) compared to emergency lscs (3236.8 ± 512.1) and spontaneous vertex deliveries (3135.1 ± 518.0) (p = 0.019). the mean bpd of the foetal head in the antenatal ultrasound was 9.09 ± 0.39 cm for women who had elective caesarean section, 9.035 ± 0.39 cm for emergency caesarean section and 8.9 ± 0.37 cm for the spontaneous vaginal delivery group. though the mean bpd was not significantly different between table 1: mean diameters for all the patients name of the diameter mean ± sd sagittal inlet 10.92 ± 0.98 cm transverse inlet 12.32 ± 0.89 cm interspinous 10.26 ± 0.98 cm sagittal outlet 10.17 ± 0.86 cm intertuberous diameter 10.45 ± 1.10 cm table 2: comparison of diameters between women who had caesarean section for failure to progress and who delivered vaginally mode of delivery n mean std. deviation p value sagittal inlet lscs, ftp 18 10.6641 0.71956 .074 svd 56 11.0916 1.15938 transverse inlet lscs, ftp 18 12.0706 0.57961 .022 svd 56 12.5620 0.80011 sagittal outlet lscs, ftp 18 10.0211 0.59074 .010 svd 56 10.5380 0.99954 interspinous diameter lscs, ftp 18 9.9722 0.79668 .043 svd 56 10.4589 0.89201 inter tuberous diameter lscs, ftp 18 10.2289 0.86855 .015 svd 56 10.8904 1.01720 outlet index lscs, ftp 18 30.2222 1.37191 .002 svd 56 31.8873 2.05082 legend: lscs = lower segment caesarean section; ftp = failure to progress; svd = spontaneous vertex delivery vaidyanathan gowri, rajeev jain, syed rizvi clinical and basic research | 213 the groups, the bpd in the elective caesarean section group was at least 9 mm more than the smallest pelvic diameter. postnatally, the mean head circumference of the neonate delivered by caesarean section (34.389 ± 1.49 cm) was significantly more than the spontaneous delivery group 33.722 ± 1.43cm (p = 0.019). discussion the standard values for normal or satisfactory pelvic dimensions are based on the work of russell and richards although these values are not universally accepted. one of the problems regarding the role of pelvimetry is that the studies have not always used the same pelvic dimensions or scoring systems to assess pelvic adequacy. x-ray pelvimetry has not been found to be useful in deciding the mode of delivery following a caesarean section.10 in a randomised controlled trial, mr pelvimetry for breech presentation did not help to reduce significantly the overall caesarean section rate, but it did significantly lower the emergency caesarean section rate.11,12 some of the recent reports and studies on mr pelvimetry using fast mri and measurement of foetal biparietal diameter and foetal shoulder measurement appear to offer more advantage over the conventional x-ray pelvimetry.13,14 the evaluation of the soft tissues of the maternal pelvis with least radiation is another advantage of mr pelvimetry. the main drawbacks are the relatively high cost and the limited availability of mr units. the absolute values in the present population are slightly different from the ones reported by keller et al.4 the pelvic diameters in the spontaneous delivery group (with foetuses in vertex presentation) were more than the emergency caesarean section for any indication and these results are likely to be useful for future applications. we did not find the index of 29.5 described by borell and fernström suitable for vaginal delivery as the mean index of women delivering normally was 32. as the caesarean section tends to limit the family size and repeated sections are associated with complications like placenta praevia, vaginal birth after caesarean section has to be given serious consideration in this part of the world. conclusion in conclusion, an outlet index of 32 cm, and the mean values of individual pelvic diameters of women who delivered vaginally, compared with antenatal bpd measurements may serve as useful reference values for allowing a trial of vaginal delivery. references 1. morrison jj, sinnathamby r, hackett g a, tudor j. obstetric pelvimetry in the uk: an appraisal of current practice. br j obstet gynaecol 1995; 102:748–50. 2. wright ar, english pt, cameron h m, wisldon j b. mr pelvimetry a practical alternative. acta radiol 1992; 33:582–7. 3. russell jgb, richards b. a review of pelvimetry data. br j radiol 1971; 44: 780–4. 4. keller tm, rake a, michel sca, selfert b, efe c, treiber k, et al. obstetric mr pelvimetry: reference values and evaluation of inter and intra observer error and intraindividual variability. radiology 2003; table 3: diameters and mode of delivery. mode of delivery sagittal inlet cm (mean ± sd ) transverse inlet cm (mean ± sd) interspinous (mean ± sd) sagittal outlet cm (mean ± sd) intertuberous cm (mean ± sd) lscs elective (41) 10.82 ± 0.78 12.07 ± 1.05 9.90 ± 0.82 9.92 ± 0.92 9.86 ± 1.04 lscs foetal distress (10) 10.78 ± 0.95 12.24 ± 0.90 10.07± 0.47 10.53 ± 1.20 10.73 ± 1.14 lscs, failure to progress (18) 10.66 ± 0.72 12.07 ± 0.58 9.98 ± 0.80 10.02 ± 0.59 10.23 ± 0.87 spontaneous vaginal delivery (56) 11.09 ± 1.16 12.56 ± 0.80 10.46 ± 0.89 10.54 ± 1.00 10.89 ± 1.02 legend: lscs = lower segment caesarean section. magnetic resonance pelvimetry for trial of labour after a previous caesarean section 214 | squ medical journal, april 2010, volume 10, issue 1 227:37–43. 5. spörri s, thoeny hc, raio l, lachat r, vock p, schneider h. mr imaging pelvimetry: a useful adjunct in the treatment of women at risk for dystocia? ajr 2002; 179:137–44. 6. sporri s, hanggi w. pelvimetry by magnetic resonance imaging as a diagnostic tool to evaluate dystocia. obstet gynecol 1997; 89:902–8. 7. bauer m, schulz-wendtland r, de gregorio g, sigmund g. obstetric pelvimetry using nuclear magnetic resonance tomography: clinical experience with 150 patients. geburtshilfe frauenheilkd 1992; 52:322–6. 8. abitbol mm, taylor ub, castillo i, rochelson bl. the cephalopelvic disproportion index: combined fetal sonography and x-ray pelvimetry for early detection of cephalopelvic disproportion. j reprod med 1991; 36:369–73. 9. porter m, bhattacharya s, van teijlingen e, templeton a. for the reproductive outcome following caesarean section (rocs) collaborative group. does caesarean section cause infertility? human reprod 2003; 18:1983–6. 10. pattinson rc. pelvimetry for cephalic presentations. in: neilson jp, crowther ca, hodnett ed, hofmeyr gj, eds. pregnancy childbirth module on the cochrane database of sytematic reviews (updated 2 december 1997). 11. van loon aj, mantingh a, serlier ek, kroon g, mooyaart e, huisjes hj. randomized controlled trial of magnetic resonance pelvimetry in breech presentation at term. lancet 1997; 350:1799–804. 12. walkinshaw s. pelvimetry and breech delivery at term. lancet 1997; 350:1791–2. 13. levine d, edelman rr. fast mri and its application in obstetrics. abdom imaging 1997; 22:589–96. 14. kastler b, gangi a. fetal shoulder measurements with mri. j comput assist tomogr 1993; 17:777– 80. 1departments of ear, nose and throat, oman medical specialty board; 2department of radiology & molecular imaging, sultan qaboos university hospital; 3department of surgery, sultan qaboos university, muscat, oman *corresponding author’s e-mail: doctorkashoob@hotmail.com bilateral chylothorax following total thyroidectomy with neck dissection for papillary thyroid cancer case report *musallam kashoob,1 saleh bawain,2 yahya al badaai3 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 481–484, epub. 29 aug 21 submitted 20 jun 20 revision req. 16 aug 20; revision recd. 15 sep 20 accepted 14 oct 20 went a total thyroidectomy. during the surgery, her thyroid tissue was found adhered to the tracheal wall, with multiple central compartment lymph nodes positive for malignant cells on the frozen section. hence, the surgery was accompanied with bilateral central compartments level vi–vii and left lateral level ii–v neck dissection. cl was encountered during neck dissection and was repaired using surgical clips, prolene 5–0 suture (ethicon inc., somerville, new jersey, usa) and tissue glue. no further leakage was noted, even with positive intrathoracic pressure ventilation pos-repair. the wound was closed after the insertion of two large negative pressure neck drains. the patient was doing well during the immediate post-operative period. the neck drains were removed after ensuring that there was minimal output of less than 10 ml and that the patient was on a fully normal diet. she was discharged two days after surgery. however, on the seventh post-operative day, she presented to the emergency department with shortness of breath and chest tightness. her primary examination showed oxygen saturation of 93%, mild tachypnoea and tachycardia (respiratory rate: 32 breaths/min, heart rate: 112 beats/min). physical examinations revealed a flat neck with a healing incision site and decreased breath sounds bilaterally from the lung bases to the mid-lung fields. imaging demonstrated bilateral moderate pleural effusions with bilateral compressive atelectasis of adjacent lung parenchyma [figure 2]. chylothorax can be classified based on its aetiology, such as traumatic and non-traumatic/idiopathic forms. the most common traumatic cause of chylothorax is chest surgery.1 a rarer yet serious complication is an iatrogenic chyle leak (cl) from a thoracic duct injury during head and neck surgery; this occurs in 0.5–1.4% of thyroidectomies and 2–8% of neck dissections.2–9 bilateral chylothorax is an extremely rare complication that occurs after neck dissection and is potentially life-threatening. in a systematic review by merki et al., the reported incidence of chylothorax after total thyroidectomy and neck dissection was found to be 1.85%.10 we report a case of bilateral chylothorax following total thyroidectomy with central and left lateral neck dissection which was managed conservatively. case report a 35-year-old female patient presented to the emergency department at sultan qaboos university hospital in 2018 with shortness of breath and respiratory distress. previously, the patient, who had no known comorbidities, had been evaluated for a left thyroid nodule during a routine neck ultrasound, which was later proven to be consistent with papillary thyroid cancer by fine needle aspiration cytology. the preoperative ultrasound mapping of her neck and the computed tomography scan of her contrastenhanced head and neck did not reveal any suspicious lymphadenopathy [figure 1]. subsequently, she under this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.018 case report abstract: bilateral chylothorax is a rare condition that occurs after a thyroidectomy and neck dissection, which can lead to severe morbidity and, potentially, death, if not managed properly. we report a rare complication of neck surgery and subsequent bilateral pleural effusion in a 35-year-old female patient who presented at sultan qaboos university hospital in 2018 with shortness of breath and respiratory distress. the bilateral pleural effusion and related symptoms occurred one week after a total thyroidectomy with central and left lateral neck dissection. the patient was managed conservatively and subsequently recovered. keywords: chylothorax; papillary thyroid cancer; thyroidectomy; neck dissection; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ bilateral chylothorax following total thyroidectomy with neck dissection for papillary thyroid cancer case report 482 | squ medical journal, august 2021, volume 21, issue 3 the mentioned conservative measures alone. the chest drains were kept for seven days and the patient did not show any radiological signs of re-accumulation or persistent leakage [figure 3]. the histopathological diagnosis showed a tall cell variant of papillary thyroid carcinoma (tumour size: 2.5 cm) with 11 metastatic lymph nodes out of a total of 88 lymph nodes (largest measuring 1.4 cm). the patient recovered well and received a treatment dose of radio-iodine therapy. the patient provided consent for the publication of this case report. discussion the pathophysiology of bilateral chylothorax is still not fully understood, but there are two proposed mechanisms of injury.10 the first mechanism includes direct injury or incomplete ligation of the duct during surgery, due to variable duct anatomies described earlier.8,11 this first mechanism results in cl into the mediastinum. the second possible mechanism of injury is due to increased retrograde hydrostatic pressure in the thoracic duct, resulting in increased intraluminal pressure. this, combined with negative intrathoracic pressure, causes a secondary rupture within the chest. based on the current patient’s intraoperative and post-operative clinical profile and radiology, it is presumed that the second mechanism is responsible for the bilateral chylothorax in this case. intrathoracic pleural catheters were placed bilaterally, which drained approximately 2.5 litres of chylous fluid from both sides. pleural fluid analysis showed a triglyceride level of 5.7 mmol/l (normal range: 0.0–2.3 mmol/l), which confirmed chylous fluid. the patient was started on a fat-free diet and somatostatin analogue injection (octreotide 100 mcg every 8 hours, subcutaneously) along with chest physiotherapy, intravenous antibiotics and daily monitoring of drain output and electrolytes. chest drains were draining <50 ml on the consecutive follow-up days and a chest x-ray confirmed a marked improvement of the effusions bilaterally after use of figure 2: posterior-anterior chest radiograph of the patient showing bilateral moderate chylothorax with associated atelectasis and post-thyroidectomy surgical clips at the base of the neck. figure 3: postreior-anterior chest x-rays at seven days follow-up showing (a) near-total resolution of the chylothorax post-placement of the bilateral intrathoracic pleural catheters and (b) clear lungs and costophrenic angles. figure 1: contrast-enhancing axial cut computed tomography images of the head and neck of the patient showing (a) a 10 mm hypoattenuating nodule on the left thyroid lobe (arrow) and (b) a 7 mm nodule with a rim of calcification on the right thyroid lobe (arrow). musallam kashoob, saleh bawain and yahya al badaai case report | 483 early diagnosis and appropriate management are essential in order to avoid chylothorax-related morbidity. this can be in the form of either cardiopulmonary compromise or metabolic derangement including loss of proteins, electrolytes, fluid, fat, fat-soluble vitamins and t cell lymphocytes.12 although a comprehensive clinical assessment with imaging may point to the diagnosis of chylothorax, chemical analysis of the pleural fluid is essential for diagnosis. chylothorax is present in 99% of patients with an aspirate triglyceride content of >110 mg/dl (1.24 mmol/l) and a cholesterol content of >200 mg/dl (5.1 mmol/l). moreover, the presence of chylomicrons in the pleural fluid is considered diagnostic.13–15 the pleural aspirate triglyceride content in the patient was 5.7 mmol/l. operating surgeons should have a clear concept of the tortuous anatomy of the thoracic duct to avoid complications. at the level of the upper lumbar spine, the thoracic duct starts as cisterna chyli. it has different anatomical relations when it passes within the abdomen, thoracic cavity, root of the neck and before it terminates. initially, it ascends upward along the abdominal aorta and azygos vein, then through the aortic orifice overlying the vertebral column to enter the thoracic cavity. then, it turns to the left side and continues to pass upwards in the posterior mediastinum to enter the root of the neck. at this level, it passes lateral to the oesophagus, medial to the omohyoid muscle, posterior to the left carotid sheath and anterior to the vertebrae. then, the thoracic duct courses superiorly and laterally before it descends inferiorly to arch over the anterior scalene muscle, phrenic nerve and subclavian artery, before ending within 1 cm from the confluence of the internal jugular vein and subclavian vein.16–18 however, there are anatomical variations of the terminal course of the thoracic duct: in 46% of the cases, it enters the internal jugular vein and in 32% of cases, it enters the junction of the internal jugular and subclavian veins. less commonly, it may enter the subclavian vein in 18% of the cases. although two or three endpoints of thoracic duct terminations have been described, usually it ends as a single duct in about 76% of the cases.8,11 management of chylothorax should be tailored to each case as it varies between conservative approaches, interventional radiological approaches and surgical options. conservative measures include the drainage of the chylothorax in addition to diet modifications in the form of medium-chain triglycerides, a fatfree diet or total parenteral nutrition to reduce chyle production. in addition, certain medications are used such as somatostatin or its analogue or octreotide to reduce chyle production.19,20 however, there is no consensus as to how long these medications should be used. if the quantity of drained chyle is <500 ml/day, spontaneous recovery with conservative measures is more favourable.19 in the current case, conservative treatment was effective in reducing the leak to less than 50 ml/day. depending on the available expertise of each centre, percutaneous lymphangiographyguided cannulation with embolisation of the leakage is another minimally invasive option.21 surgical intervention, including thoracic duct ligation via video-assisted thoracoscopic surgery or open surgery, should be considered if conservative measures fail, drain flow is more than 1 l/day or severe metabolic complications are present. however, there are currently no prospective studies available to compare the efficacy of different approaches. conclusion bilateral chylothorax is a rare and potentially lifethreatening complication, which should be considered in all patients with post-operative dyspnoea occurring after central or left lateral neck dissection. early diagnosis and intervention are crucial for best outcomes. management is tailored according to the clinical scenario, level of expertise available and patient response to the initial treatment. a u t h o r s’ c o n t r i b u t i o n mk drafted the manuscript and performed text data mining. all authors were involved in management of this case and approved the final version of the manuscript. references 1. skandalakis je, skandalakis lj, skandalakis pn. anatomy of the lymphatics. surg oncol clin n am 2007; 16:1–16. https://doi. org/10.1016/j.soc.2006.10.006. 2. lee ys, kim bw, chang hs, park cs. factors predisposing to chyle leakage following thyroid cancer surgery without lateral neck dissection. head neck 2013; 35:1149–52. https://doi. org/10.1002/hed.23104. 3. lorenz k, abuazab m, sekulla c, nguyen-thanh p, brauckhoff m, dralle h. management of lymph fistulas in thyroid surgery. langenbecks arch surg 2010; 395:911–17. https://doi.org/10.1 007/s00423-010-0686-2. 4. roh jl, yoon yh, park ci. chyle leakage in patients undergoing thyroidectomy plus central neck dissection for differentiated papillary thyroid carcinoma. ann surg oncol 2008; 15:2576–80. https://doi.org/10.1245/s10434-008-0017-9. 5. rammal a, zawawi f, varshney r, hier mp, payne rj, mlynarek am. chyle leak: a rare complication post-hemithyroidectomy. case report and review of literature. otolaryngol pol 2014; 68:204–7. https://doi.org/10.1016/j.otpol.2014.03.003. https://doi.org/10.1016/j.soc.2006.10.006 https://doi.org/10.1016/j.soc.2006.10.006 https://doi.org/10.1002/hed.23104 https://doi.org/10.1002/hed.23104 https://doi.org/10.1007/s00423-010-0686-2 https://doi.org/10.1007/s00423-010-0686-2 https://doi.org/10.1245/s10434-008-0017-9 https://doi.org/10.1016/j.otpol.2014.03.003 bilateral chylothorax following total thyroidectomy with neck dissection for papillary thyroid cancer case report 484 | squ medical journal, august 2021, volume 21, issue 3 14. skouras v, kalomenidis i. chylothorax: diagnostic approach. curr opin pulm med 2010; 16:387–93. https://doi.org/10.1097/ mcp.0b013e328338dde2. 15. mcgrath ee, blades z, anderson pb. chylothorax: aetiology, diagnosis and therapeutic options. respir med 2010; 105:1–8. https://doi.org/10.1016/j.rmed.2009.08.010. 16. kwon ss, falk a, mitty ha. thoracic duct injury associated with left internal jugular vein catheterization: anatomic consid erations. j vasc interv radiol 2002; 13:337–9. https://doi.org/10.1 016/s1051-0443(07)61730-8. 17. van pernis pa. variations of the thoracic duct. surgery 1949; 26:806–9. 18. ammar k, tubbs rs, smyth md, wellons jc 3rd, blount jp, salter g, et al. anatomic landmarks for the cervical portion of the thoracic duct. neurosurgery 2003; 53:1385–8. https://doi. org/10.1227/01.neu.0000093826.31666.a5. 19. bender b, murthy v, chamberlain rs. the changing manage ment of chylothorax in the modern era. eur j cardiothorac surg 2016; 49:18–24. https://doi.org/10.1093/ejcts/ezv041. 20. huggins jt. chylothorax and cholesterol pleural effusion. semin respir crit care med 2010; 31:743–50. https://doi.org/10.105 5/s-0030-1269834. 21. van goor at, kröger r, klomp hm, de jong ma, van den brekel mw, balm aj. introduction of lymphangiography and percutaneous embolization of the thoracic duct in a stepwise approach to the management of chylous fistulas. head neck 2007; 29:1017–23. https://doi.org/10.1002/hed.20624. 6. dhiwakar m, nambi gi, ramanikanth tv. drain removal and aspiration to treat low output chylous fistula. eur arch otorhino laryngol 2014; 271:561–5. https://doi.org/10.1007/s00405-0132534-9. 7. nussenbaum b, liu jh, sinard rj. systematic management of chyle fistula: the southwestern experience and review of the literature. otolaryngol head neck surg 2000; 122:31–8. https://doi.org/10.1016/s0194-5998(00)70140-9. 8. langford rj, daudia at, malins tj. a morphological study of the thoracic duct at the jugulo-subclavian junction. j craniomax illofac surg 1999; 27:100–4. https://doi.org/10.1016/s1010-518 2(99)80021-3. 9. crumley rl, smith jd. postoperative chylous fistula prevention and management. laryngoscope 1976; 86:804–13. https://doi. org/10.1288/00005537-197606000-00008. 10. merki v, pichler j, giger r, mantokoudis g. chylothorax in thyroid surgery: a very rare case and systematic review of the literature. j otolaryngol head neck surg 2016; 45:52. https:// doi.org/10.1186/s40463-016-0166-y. 11. phang kl, bowman m, phillips a, windsor j. review of thoracic duct anatomical variations and clinical implications. clin anat 2014; 27:637–44. https://doi.org/10.1002/ca.22337. 12. valentine vg, raffin ta. the management of chylothorax. chest 1992; 102:586–91. https://doi.org/10.1378/chest.102.2.586. 13. staats ba, ellefson rd, budahn ll, dines de, prakash ub, offord k. the lipoprotein profile of chylous and nonchylous pleural effusions. mayo clin proc 1980; 55:700–4. https://doi.org/10.1097/mcp.0b013e328338dde2 https://doi.org/10.1097/mcp.0b013e328338dde2 https://doi.org/10.1016/j.rmed.2009.08.010 https://doi.org/10.1016/s1051-0443(07)61730-8 https://doi.org/10.1016/s1051-0443(07)61730-8 https://doi.org/10.1227/01.neu.0000093826.31666.a5 https://doi.org/10.1227/01.neu.0000093826.31666.a5 https://doi.org/10.1093/ejcts/ezv041 https://doi.org/10.1055/s-0030-1269834 https://doi.org/10.1055/s-0030-1269834 https://doi.org/10.1002/hed.20624 https://doi.org/10.1007/s00405-013-2534-9 https://doi.org/10.1007/s00405-013-2534-9 https://doi.org/10.1016/s0194-5998(00)70140-9 https://doi.org/10.1016/s1010-5182(99)80021-3 https://doi.org/10.1016/s1010-5182(99)80021-3 https://doi.org/10.1288/00005537-197606000-00008 https://doi.org/10.1288/00005537-197606000-00008 https://doi.org/10.1186/s40463-016-0166-y https://doi.org/10.1186/s40463-016-0166-y https://doi.org/10.1002/ca.22337 https://doi.org/10.1378/chest.102.2.586 1department of radiology, oman medical specialty board, muscat, oman; departments of 2radiology and 4ophthalmology, sultan qaboos university hospital, muscat, oman; 3department of radiology, al nahdha hospital, muscat, oman; 5department of ophthalmology, sultan qaboos university, muscat, oman *corresponding author’s e-mail: ath-obaidani@hotmail.com تشوه األوعية الدموية احلجاجية عذاري عبد اهلل العبيدانية، �سمري رانيجا، اأمين احلديدي، بثينة �سبت، عبد اهلل املجيني orbital vascular malformation *athari a. al-obaidani,1 sameer raniga,2 ayman al hadidi,3 buthaina sabt,4 abdullah al-mujaini4,5 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e139–140, epub. 15 mar 21 submitted 10 jun 20 revision req. 11 aug 20; revision recd. 26 aug 20 accepted 16 sep 20 a 56-year-old male patient, known to have hypertension, presented to the sultan qaboos university hospital in 2019 with a six-year history of gradually increasing left eye protrusion associated with reduced vision in the left eye. ophthalmic examination revealed a significant proptosis in the left eye with an inferior displacement of the globe [figure 1]. the best-corrected visual acuity was 6/9 and 6/24 in the right and left eye, respectively. afferent pupillary defect was noted in the left eye, but slit-lamp biomicroscopy was unremarkable on both sides. dilated fundus examination of the left eye showed an elevated optic disc with hazy borders. left eye proptosis secondary to retrobulbar mass was the most likely aetiology and a magnetic resonance imaging (mri) scan was performed. the mri scan showed an oval-shaped retro bulbar intraorbital lesion measuring 3.0 × 2.7 × 3.1 cm (anteroposterior × craniocaudal × transverse) in size, displacing the orbit anteriorly, the optic nerve inferomedially and the superior and lateral rectus muscles peripherally [figure 2]. the lesion showed high signal intensity in t2and isointense signal in t1-weighted images with progressive enhancement starting as a patchy enhancement at the late arterial phase with a complete enhancement of the lesion in the delayed images [figure 3]. findings were consistent with orbital slow-flow vascular malformation which was likely a cavernous malformation. informed consent was obtained from the patient for the publication of these images. comment vascular lesions of the orbits are rare; the various types are charcterised by their growth, histopathology and flow. according to a system proposed by mulliken and glowacki, they are classified as capillary haeman giomas, venous vascular malformations, venous lymphatic malformations, arterial and arteriovenous lesions or neoplasms.1 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.022 interesting medical image figure 1: photograph of the eyes of a 56 year-old male patient showing the left eye protruding outward (proptotic). https://creativecommons.org/licenses/by-nd/4.0/ orbital vascular malformation e140 | squ medical journal, february 2021, volume 21, issue 1 cavernous malformations are the most common orbital lesions in adults and account for 6% of all orbital masses.2 these lesions are slow-growing and often manifest with progressive, painless proptosis. they tend to be septate, well-circumscribed and do not involute.1 these lesions are usually located in the lateral aspect of intraconal retrobulbar space and are rarely found in the conal or extraconal spaces.3 bone remodelling can be seen as well as calcifications. associations with maffucci syndrome and blue rubber bleb nevus syndrome have been reported.1 cavernous malformations have a fibrous pseudocapsule and appear circumscribed on imaging. they usually appear hyperattenuated on computed tomography scan and occasionally contain phleboliths. in addition, they displace adjacent structures without invading them and may cause expansion of the orbital walls. on mri, they appear isointense to the muscle in t1and hyperintense to the muscle in t2-weighted images. in the early arterial phase, they show poor enhancement due to their slow flow nature with progressive accumulation of contrast material in the late phase dynamic and delayed images. the management of these lesions should be individualised and determined by size, location and patient symptoms. conservative management is advised if there are no or minimal symptoms. sclerotherapy with ethanol injection is advised for an extensive facial with orbital/periorbital involvement. other options include surgical excision for localised lesions or surgical resection for more extensive and deep lesions.4 all available measures and their risks and benefits should be discussed with the patient during peri-operative counselling. references 1. smoker wr, gentry lr, yee nk, reede dl, nerad ja. vascular lesions of the orbit: more than meets the eye. radiographics 2008; 28:185–204. https://doi.org/10.1148/rg.281075040. 2. xian j, zhang z, wang z, li j, yang b, chen q, et al. evaluation of mr imaging findings differentiating cavernous haemangiomas from schwannomas in the orbit. eur radiol 2010; 20:2221–8. https://doi.org/10.1007/s00330-010-1774-y. 3. anand r, deria k, sharma p, narula m, garg r. extraconal cavernous hemangioma of orbit: a case report. indian j radiol imaging 2008; 18:310–12. https://doi.org/10.4103/0971-3026.43849. 4. benoiton la, chan k, steiner f, fitzjohn t, tan st. management of orbital and periorbital venous malformation. front surg 2017; 4:27. https://doi.org/10.3389/fsurg.2017.00027. figure 2: multi-sequential multi-planar magnetic resonance images of the head (orbits with intravenous contrast) of a 56-year-old male patient. a & b: axial and coronal t2-weighted images showing an oval-shaped lesion (asterisk) in the retrobulbar intraconal space of the left orbit displacing the glob anteriorly (arrowhead), the optic nerve inferomedially (white arrow) and the superior and lateral rectus muscles (red arrows) peripherally. the lesion shows homogenous intermediate to high signal intensity in t2-weighted images. c: sagittal precontrast t1-weighted image showing that the lesion is isointense to the cerebral cortex (asterisk). figure 3: axial t1-weighted post-intravenous gado linium-enhanced images in the (a) late arterial and (b) delayed phase showing progressive enhancement (solid white arrows). the lesion is almost completly enhanced on the delayed images. https://doi.org/10.1148/rg.281075040 https://doi.org/10.1007/s00330-010-1774-y https://doi.org/10.4103/0971-3026.43849 https://doi.org/10.3389/fsurg.2017.00027 departments of 1urology, 2radiology and 3nephrology, the royal hospital, muscat, oman *corresponding author’s e-mail: kuriangeorge60@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: the recent drop in the mortality rates of emphysematous pyelonephritis, a serious medical condition, is attributable to renal percutaneous drainage (pcd) techniques that have also reduced the necessity for surgery. since the difference in the objectives of the two specific techniques, i.e. pcd and percutaneous nephrostomy (pcn), is often overlooked, this study aimed to highlight the inconsistencies in the use of these two techniques. methods: a retrospective study of 17 patients was conducted over a 10-year period from january 2008 to december 2017 at the royal hospital, muscat, oman. all patients had undergone abdominal computerised tomography. the obtained images were reviewed and categorised based on huang and tseng’s classification. results: from the sample, 13 patients (76%) were categorised as class i and ii, three (17%) as class iiia and one (6%) as class iiib. five patients from the class i and ii categories underwent drainage of the pelvicalyceal system, four by pcn and one by a double-j stent insertion. pcn was performed on all the class iiia and iiib patients. one class iiib patient required pcd for localised gas and fluid collection but later underwent emergency nephrectomy. there were no mortalities. conclusion: the favourable outcome of this study was in keeping with those of the more recent studies. however, despite the present classifications and guidelines, wide variations were reported in the use of percutaneous drains with pcd, ranging from 2.5–91%. the lack of precise guidelines may be a cause of these disparities in clinical management. keywords: renal infection; pyelonephritis; drainage; percutaneous nephrostomy; oman. emphysematous pyelonephritis disparities observed in the use of percutaneous drainage techniques mohammed al-saraf,1 salim al-busaidy,1 *kurian george,1 mohamed elawdy,1 mahmood n.m. al hajriy,2 issa al-salmi3 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 113–116, epub. 28 feb 22 submitted 21 jul 20 revisions req. 22 oct & 29 dec 20; revisions recd. 15 nov 20 & 9 jan 21 accepted 26 jan 21 https://doi.org/10.18295/squmj.4.2021.058 clinical & basic research advances in knowledge recent trends demonstrate a significant decrease in the nephrectomy and mortality rates of emphysematous pyelonephritis (epn). the favourable outcome of this 10-year study with no deaths is in keeping with the recent trends. the use of percutaneous drains is well established as an essential part of the management of epn. however, guidelines do not provide precise details for the deployment of ‘parenchymal’ drainage or percutaneous nephrostomy drainage. application to patient care numerous studies have reported diverse and inconsistent use of ‘parenchymal’ drainage and percutaneous nephrostomy. specific details on the extent of collected parenchymal gas and/or fluid requiring drainage and the appropriate number of drains to use are not defined in existing guidelines and left to the discretion of clinicians. lack of precise guidelines leads to variations in the management of care and uncertainty in clinical and radiological assessments. furthermore, these diverse and inconsistent practices may negatively impact morbidity and mortality rates. emphysematous pyelonephritis (epn) is a serious and often necrotising infection of the kidney that is associated with the presence of gas in the renal parenchyma, collecting system or perinephric tissue. earlier studies have reported high rates of nephrectomy and mortality reaching 50%.1 however, recent studies have highlighted changing trends in the clinical spectrum and reported significantly lower mortality rates of 0–37.5%.2–6 the outcome for the current 10-year-long study on 17 patients in a tertiary hospital reported no deaths and only two nephrectomies. percutaneous drainage (pcd) techniques of the kidney have played a major role in reducing the need for surgery and mortality rates. at the same time, some studies have reported wide variations in clinical management, particularly in the use of the two different percutaneous techniques, i.e. percutaneous nephrostomy (pcn) and pcd of the kidney. however, the difference in the objective of the two techniques is often overlooked. this gap in extant literature may lead to the suboptimal treatment of patients, which affects the clinical outcomes. thus, this study aimed to highlight the inconsistencies in the use of these two techniques, which, to the best of the researchers’ knowledge, has not been documented before. methods a retrospective review of the electronic database was conducted from january 2008 to december 2017 at the royal hospital, muscat, oman. the records of all patients who were admitted with a diagnosis of epn were retrieved and analysed. these records included patients’ demographic data such as age, gender, body mass index (bmi) and the laboratory results (i.e. https://creativecommons.org/licenses/by-nd/4.0/ emphysematous pyelonephritis disparities observed in the use of percutaneous drainage techniques 114 | squ medical journal, february 2022, volume 22, issue 1 full blood count, renal function tests, glycosylated haemoglobin, random blood sugar and blood and urine cultures). all patients routinely underwent abdominal non-contrast computerised tomography (ncct) and contrast-enhanced computerised tomography when not contra-indicated. the obtained images were retrospectively reviewed and categorised based on huang and tseng’s classification.7 the treatment given was recorded, including the initial medical management and the type of drainage procedures performed. to remove the obstruction of the pelvicalyceal system (pcs), pcn was performed or a double-j stent (djs) was inserted, whereas pcd was deployed for the drainage of parenchymal or perinephric gas, with or without fluid collections. any other surgical interventions performed were also noted (i.e. emergency nephrectomy, open drainage or elective operations). the initial medical management consisted of adequate intravenous hydration, broad spectrum antibiotics and glycaemic control. haemo dynamically unstable patients were managed in highdependency care units (hdus) or intensive care units (icus). the period of outpatient follow-up ranged from 12 to 18 months. ethical permission for the study was granted by the scientific research committee of the royal hospital (src#106/2019) results a total of 17 patients were treated for epn over the10year period under consideration for this study. the median patient age was 55 years and the ages ranged from 31 to 82 years. the female patients outnumbered males at a ratio of 12:5 and 13 patients (76%) had a history of diabetes mellitus. these demographics and clinical features were presented at the time of admission [table 1]. regarding symptoms, fever was the most common symptom; four patients presented with severe sepsis associated with unstable vital signs requiring manage ment in an hdu or icu admission. two out of the four non-diabetic patients presented with upper tract urinary calculi—one had an upper ureteric stone and a smaller non-obstructing renal calculus while the other had a stone at the pelviureteric junction (puj); both patients had significant hydronephrosis. the other two table 1: characteristics and clinical features of patients treated for emphysematous pyelonephritis over a 10-year period at the royal hospital, muscat (n = 17) characteristics outcome mean age in years (range) 55 (31–82) male:female 5:12 mean bmi (range) 26.5 (18.5–41) clinical features n loin pain 12 fever 14 septic shock 4 diabetes mellitus 13 urinary obstruction 2 bmi = body mass index. table 2: summarisation of the comparison between the clinical characteristics of emphysematous pyelonephritis patients from the present study and seven other studies author (year) frequency patients class i + ii class iii + iv djs pcn pcd emergency nephrectomy deaths huang and tseng7 (2000) 48 16 32 n/a n/a 41 (13*) 8 9 kangjam et al.9(2015) 8 5 3 0 0 7† 3 3 narlawar et al.10(2004) 11 11 0 n/a n/a 11 (4*) 3 1 sokhal et al.3(2017) 74 45 29 18 n/a 0 4 (2‡) 6 das and pal5(2016) 15 10 5 7 4 0 0 0 sharma et al.6(2013) 14 9 5 3 0 3 (1*) 0 (1‡) 0 sandeep et al.11(2018) 72 n/a n/a 25 0 1 1 2 present study 17 13 4 1 8 1 1 0 djs = double-j stenting ; pcn = percutaneous nephrostomy; pcd = percutaneous drainage; n/a = not available. * number of patients for whom pcd failed. †five patients had one pcd and two had multiple pcd. ‡ number of patients for whom open drainage was performed. mohammed al-saraf, salim al-busaidy, kurian george, mohamed elawdy, mahmood n.m. al hajriy and issa al-salmi clinical and basic research | 115 non-diabetic cases were elderly hypertensive females with a history of chronic renal disease. based on huang and tseng’s classification, 13 patients (76%) were categorised as class i and ii, three patients (17%) as class iiia and one patient (6%) as class iiib [figures 1a and b]. there were no class iv patients. five patients from the class i and ii categories underwent drainage of the pelvicalyceal system—four by pcn and one by djs insertion. pcn was performed on all the class iiia and iiib patients, but only one class iiib patient underwent pcd for localised gas and fluid collection. this patient failed to respond to conservative treatment, which is why an emergency nephrectomy was performed within 72 hours. one of the class iiia patients had elective nephrectomy for a non-functioning kidney with stones. the followup clinic was visited by 12 patients (71%) and all of them were investigated using ncct scans, which, on review, showed clearance of the gas previously seen in the earlier images. there were no mortalities in this study. discussion epn is considered a life-threatening necrotising infection that is common among diabetic individuals, immunocompromised patients and those with obstructive urolithiasis. characteristically, gas is formed and accumulates as part of the infective process. in the present study, 13 of the 17 patients (75%) had uncontrolled diabetes mellitus. it is postulated that four factors are involved in the pathogenesis of epn, namely, gas-forming bacteria, high tissue glucose levels, impaired tissue perfusion and defective immune response.8 the other four non-diabetic patients presented with a deranged renal function—two of them had obstructive uropathy due to a mid-ureteric calculus in one and a puj calculus in another. it is reported that up to 95% of patients with epn have underlying uncontrolled diabetes mellitus, whereas the risk of epn, secondary to obstructive uropathy, is significantly less with a range of 25–40%.8 the classification of epn was based on comput erised tomography (ct) imaging, which is considered the best radiological modality.5 on this basis, wan et al. in 1996 described epn as type 1, a severe form and a milder type 2 form of the disease. huang and tseng later described a more detailed ct classification with sub-categories and four risk factors, namely, thrombocytopenia, acute renal function impairment, altered sensorium and shock. these factors are said to have added value as a guide to selecting the various management options and assisting in the prediction of the prognostic value and outcomes.5,6 the method of performing pcn differs from pcd, in that its purpose is to enter and drain the pcs; however, pcd is not designed to puncture the pcs but to drain parenchymal gas and/or pus. to the best of the researchers’ knowledge, after a careful search of existing literature, no guidelines describing the extent of gas or fluid collections that should be drained, the number of drains to be inserted or the duration of drainage could be found. as stated, all class iii patients in this study underwent pcn and only one of them underwent a pcd procedure. a wide variation in the type and numbers of drainage procedures performed was reported in a series [table 2]. in the first three studies, pcd was performed on combined total of 91% (n = 65) of the patients.7,9,10 approximately 51% of these cases were classified as groups iii and iv. in contrast, only 2.6% of the 192 patients in the other five series underwent pcd insertion, although 22.4% of them were categorised into class iii and class iv.3,5,6,11 there is a wide disparity in the numbers of pcn and djs insertions with some studies reporting no drainage of the pelvicalyceal system.9 this contradicts one of the largest series which reported that a third of their patients underwent djs insertions, without pcn being formed in any of the patients and only one pcd insertion [table 2].11 figure 1: a and b: computerised tomographic scans showing class iiia emphysematous pyelonephritis of the left kidney of a patient, with one stone in the upper ureter and another in the kidney (arrows). emphysematous pyelonephritis disparities observed in the use of percutaneous drainage techniques 116 | squ medical journal, february 2022, volume 22, issue 1 despite the present classifications and guidelines, there is a great difference in the use of pcd and pcn. this may have resulted from surgeons being less conversant with the management of this rare disease, uncertainty in the interpretation of radiological images and lack of clarity in the existing guidelines regarding pcd. furthermore, interventional radiologists may be more familiar and, as such, less hesitant to perform pcn as opposed to pcd. complications of pcd that include bleeding, septic shock and injury to adjacent organs are well documented and might be significant.12 the combined mortality rate of the five studies with only a 2.6% pcd insertion rate was 4.2%. this is in contrast to a 20% mortality rate found in the three studies with a 91% pcd insertion rate.7,9,10 most of these studies are retrospective and demonstrate heterogeneity with some unavailable data, e.g. the extent of the gas/pus drained, the number of pcds per patient and the duration of the drainage, which may be as long as 12 weeks.13 these limitations do not allow for valid comparisons and statistical analyses. although it is not possible to draw conclusions, it is apparent that there is a lack of consistency and standardisation that may affect morbidity and mortality rates. conclusion the favourable outcome of this study is in keeping with the outcomes from recent studies. however, despite the available classifications and guidelines, wide deviations were reported in the usage of the two pcd techniques that ranged from 2.5% to 91%. the lack of more precise guidelines may be a cause of these disparities in clinical management. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n sab conceptualised the work. mas, me and ias collected the data. sab and kg drafted and edited the manuscript. mnmah reviewed the radiological images. all authors approved the final version of the manuscript. references 1. somani bk, nabi g, thorpe p, hussey j, cook j, n’dow j, et al. is percutaneous drainage the new gold standard in the management of emphysematous pyelonephritis? evidence from a systematic review. j urol 2008; 179:1844–9. https://doi. org/10.1016/j.juro.2008.01.019. 2. aboumarzouk om, hughes o, narahari k, coulthard r, kynaston h, chlosta p, et al. emphysematous pyelonephritis: time for a management plan with an evidence-based approach. arab j urol 2014; 12:106–15. https://doi.org/10.1016/j.aju.20 13.09.005. 3. sokhal ak, kumar m, purkait b, jhanwar a, singh k, bansal a, et al. emphysematous pyelonephritis: changing trend of clinical spectrum, pathogenesis, management and outcome. turk j urol 2017; 43:202–9. https://doi.org/10.5152/tud.2016.14227. 4. lu yc, chiang bj, pong yh, chen ch, pu ys, hsueh pr, et al. emphysematous pyelonephritis: clinical characteristics and prognostic factors. int j urol 2014; 21:277–82. https://doi. org/10.1111/iju.12244. 5. das d, pal dk. double j stenting: a rewarding option in the management of emphysematous pyelonephritis. urol ann 2016; 8:261–4. https://doi.org/10.4103/0974-7796.184881. 6. sharma pk, sharma r, vijay mk, tiwari p, goel a, kundu ak. emphysematous pyelonephritis: our experience with conser vative management in 14 cases. urol ann 2013; 5:157–62. https://doi.org/10.4103/0974-7796.115734. 7. huang jj, tseng cc. emphysematous pyelonephritis: clinico radiological classification, management, prognosis, and patho genesis. arch intern med. 2000; 160:797–805. https://doi.org/10.1 001/archinte.160.6.797. 8. ubee ss, mcglynn l, fordham m. emphysematous pyelo nephritis. bju int 2011; 107:1474–8. https://doi.org/10.1111/ j.1464-410x.2010.09660.x. 9. kangjam sm, irom ks, khumallambam is, sinam rs. role of conservative management in emphysematous pyelonephritis a retrospective study. j clin diagn res 2015; 9:pc09–11. https://doi.org/10.7860/jcdr/2015/16763.6795. 10. narlawar rs, raut aa, nagar a, hira p, hanchate v, asrani a. maging features and guided drainage in emphysematous pyelo nephritis: a study of 11 cases. clin radiol 2004; 59:192–7. https://doi.org/10.1016/s0009-9260(03)00295-2. 11. sandeep p, arjun n, prasad m, ramesh dg. a prospective analysis of emphysematous pyelonephritis at a tertiary care centre. j clin urol 2018; 11: 398–402. https://doi.org/10.1177/205141 5817752854. 12. taneja ss. section iii. complications of urologic surgery, 5th ed. philadelphia: elsevier, 2010. 13. pontin ar, barnes rd. current management of emphysematous pyelonephritis. nat rev urol 2009; 6:272–9. https://doi.org/10.1 038/nrurol.2009.51. https://doi.org/10.1016/j.juro.2008.01.019 https://doi.org/10.1016/j.juro.2008.01.019 https://doi.org/10.1016/j.aju.2013.09.005 https://doi.org/10.1016/j.aju.2013.09.005 https://doi.org/10.5152/tud.2016.14227 https://doi.org/10.1111/iju.12244 https://doi.org/10.1111/iju.12244 https://doi.org/10.4103/0974-7796.184881 https://doi.org/10.4103/0974-7796.115734 https://doi.org/10.1001/archinte.160.6.79 https://doi.org/10.1001/archinte.160.6.79 https://doi.org/10.1111/j.1464-410x.2010.09660.x https://doi.org/10.1111/j.1464-410x.2010.09660.x https://doi.org/10.7860/jcdr/2015/16763.6795 https://doi.org/10.1016/s0009-9260(03)00295-2 https://doi.org/10.1177/2051415817752854 https://doi.org/10.1177/2051415817752854 https://doi.org/10.1038/nrurol.2009.51 https://doi.org/10.1038/nrurol.2009.51 association between bioactive molecules in breast milk and type 1 diabetes mellitus *tajudeen yahaya1 and ufuoma shemishere2 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e5–12, epub. 9 mar 20 submitted 28 may 19 revisions req. 1 aug & 2 oct 19; revisions recd. 23 aug & 5 oct 19 accepted 3 nov 19 departments of 1biology and 2biochemistry & molecular biology, federal university birnin kebbi, birnin kebbi, nigeria *corresponding author’s e-mail: yahayatajudeen@gmail.com type 1 diabetes mellitus (t1dm) is a long-term degenerative disease that begins when the body’s defense mechanism starts to destroy its own pancreatic β-cells.1,2 while the exact aetiology of the disease is unknown, several triggers are thought to play a role in disease causation, including genetic, epi genetic and environmental factors. previously, t1dm was thought to affect only children and thus termed juvenile or childhood diabetes mellitus; however, as a result of technological advancements in diagnostic tools, it is now understood that it occurs at any age.1,2 while t1dm affects both genders equally, there are racial disparities in terms of prevalence, with the disease being more common among caucasian americans compared to african americans.3,4 generally, t1dm is considered the most taxing form of diabetes mellitus (dm) and is characterised by severe insulin deficiency and hyperglycaemia.5 early symptoms include increased thirst, appetite and weakness, frequent urination and weight loss.6 uncontrolled hyper glycaemia may subsequently result in multiorgan damage involving the eyes, kidneys, nerves and heart, among other organs.7 unfortunately, there is no cure for the disease yet; as such, affected patients need to self-medicate and take daily doses of insulin for survival.8 although type 2 dm (t2dm) accounts for the majority of the overall economic burden of dm due to its higher prevalence, the economic burden is greater on individual patients with t1dm.9 overall, the prevalence of t1dm is rising steadily, with an annual global increase of over 3%, which is projected to double in the next 20 years.10 for many european and north american countries, the rising incidence of t1dm began around the mid-20th century, coinciding with increased industrialisation.11,12 among other lifestyle modifications, breastfeeding patterns review العالقة بني اجلزيئات النشطة بيولوجًيا يف حليب الثدي وداء السكري من النوع األول تاج الدين يحيا و يوفوما �صمي�صري abstract: the association between breastfeeding and type 1 diabetes mellitus (t1dm) is controversial. however, several recent studies have established a link between these two factors, necessitating a need to review this subject to raise public awareness. current research indicates that breast milk contains a variety of bioactive substances including immunoglobulins, oligosaccharides, insulin, lactoferrin, lysozyme, cytokines, epidermal growth factors, leukocytes, nucleotides, beneficial bacteria and vitamins. such substances strengthen the breastfeeding infant’s immune system, both directly, by increasing gut microbiota diversity and attacking harmful bacteria and proinflammatory molecules, and indirectly, by increasing thymus performance. accordingly, a lack of or inadequate breastfeeding may predispose infants to several autoimmune disorders, including t1dm. nursing mothers and caregivers are therefore advised to follow optimal breastfeeding practices prior to introducing complementary foods. keywords: breastfeeding; type 1 diabetes mellitus; autoimmune diseases; immunoglobulins; oligosaccharides; review literature. امللخ�ص: العالقة بني الر�صاعة الطبيعية وداء ال�صكري من النوع الأول مثرية للجدل. ومع ذلك فقد اأثبتت العديد من الدرا�صات احلديثة احلالية الأبحاث ت�صري العام. الوعي م�صتوى لرفع املو�صوع هذا مراجعة اإىل احلاجة ي�صتدعي مما العاملني هذين بني �صلة وجود قليلة ال�صكريات املناعية، الغلوبولينات ذلك يف مبا بيولوجًيا الن�صطة املواد من متنوعة جمموعة على يحتوي الثدي حليب اأن اإىل التعدد، الأن�صولني، الالكتوفريين، الليزوزمي، ال�صيتوكينات، عوامل منو الب�رشة، كريات الدم البي�صاء، النيوكليوتيدات، البكترييا النافعة والفيتامينات. مثل هذه املواد تقوي اجلهاز املناعي لدى الر�صع املعتمدين على الر�صاعة الطبيعية �صواء ب�صكل مبا�رش وذلك من خالل زيادة تنوع الأحياء املجهرية املعوية ومهاجمة البكترييا ال�صارة واجلزيئات امل�صببة لاللتهاب او ب�صكل غري مبا�رش عن طريق زيادة اأداء الغدة الزعرتية. وفًقا لذلك قد يوؤدي نق�س الر�صاعة الطبيعية اأوعدم كفايتها اإىل تعري�س الر�صع اإىل العديد من ا�صطرابات املناعة الذاتية، مبا يف ذلك داء ال�صكري من النوع الأول. لذلك ُتن�صح الأمهات املر�صعات ومقدمي الرعاية باتباع املمار�صات امُلثلى للر�صاعة الطبيعية قبل اإدخال الأطعمة التكميلية. الكلمات املفتاحية: ر�صاعة طبيعية؛ داء ال�صكري من النوع الأول؛ اأمرا�س املناعة الذاتية؛ غلوبولينات مناعية؛ �صكريات قليلة التعدد؛ مراجعة الأدبيات. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.002 https://creativecommons.org/licenses/by-nd/4.0/ association between bioactive molecules in breast milk and type 1 diabetes mellitus e6 | squ medical journal, february 2020, volume 20, issue 1 changed due to the introduction of infant feeding alternatives such as formula. the loss of immunological function due to inadequate or inappropriate breast feeding habits may contribute to the rising incidence of t1dm. this review therefore aimed to examine the association between t1dm and the immunological function of bioactive molecules in breast milk. association of bioactive molecules with breastfeeding the role of breast milk in the aetiology and prevention of t1dm is controversial, with certain studies showing a protective effect and others reporting predisposing or no effects at all.13–15 in a meta-analysis of 25 studies with 226,508 participants from 12 countries, yan et al. found that breastfeeding resulted in a reduced risk of dm triggers.13 importantly, 17 of these studies indicated a dose-response relationship between breastfeeding duration and a lowered risk of childhood obesity. in another meta-analysis involving 155,392 norwegian and danish children, lund-blix et al. reported that t1dm was related to the early introduction of infant formula, with non-breastfed children having a two-fold increased risk of disease compared to those who were breastfed.14 nevertheless, in a meta-analysis involving 43 observational studies of 9,874 individuals with t1dm, cardwell et al. observed a weak link between exclusive breastfeeding and t1dm.15 many factors, particularly the experimental designs of these studies and variations in breastfeeding patterns in different countries, could be responsible for these inconsistent results. however, studies that report weak or negative effects usually monitor breastfeeding to an imprecise degree, without considering whether breastfeeding is exclusive or complementary. exclusive breastfeeding without vitamin supple mentation may cause vitamin d deficiency in infants, particularly if the mother herself is deficient.16 it may also result in vitamin e deficiency as vitamin e content in breast milk decreases as colostrum matures.17 vitamin e scavenges free radicals, blocking infiltrating toxins and cytokines and protecting cells, including the pan creatic islet cells. deficiencies of both vitamins may play a role in the pathogenesis of t1dm.18,19 giulietti et al. reported the overexpression of pro-inflammatory cytokines, reduced thymus performance and pancreatic islet dysfunction in non-obese diabetic mice kept away from ultraviolet light and fed with a vitamin d-depleted diet.20 in a finnish birth cohort study, hyppönen et al. found that daily supplementation of 200 iu of vitamin d was associated with a lower incidence of t1dm among children.21 in a prospective clinical study of both t1dm and t2dm patients, vitamin e supplementation decreased blood glucose levels and reduced the progression of the disease.22 according to virtanen et al., complementary feeding may yield no effect if this feeding consists of dietary formulas containing certain complex proteins.23 similarly, chia et al. showed that dietary a1 β-casein may affect glucose homeostasis and induce progression to t1dm in non-obese diabetic mice.24 gluten in cereals is also linked with increased t-cell reactivity, with diabetogenic effects in rodents.25 additionally, breastfeeding from containers, which are often coated with preservatives and anti-rust agents such as bisphenol a (bpa), may affect breastfeeding outcomes.26 in a study of new and used baby bottles in iran, bpa levels ranged from 0.49–8.58 μg/l and 0.63–2.47 μg/l, respectively.26 in pregnant rats, bpa doses as low as 0.5 μg/l were found to induce persistent islet insulin hypersecretion for up to one year.27 the duration of breastfeeding and the age at which complementary foods are administered may also deter mine the protective role or otherwise of breast milk on tidm pathogenesis. short-term breastfeeding (<3 months) and the early or late introduction of complementary foods (<4 months and ≥6 months, respectively) are risk factors for t1dm.28 additionally, the introduction of cereals before three months of age may be related to early β-cell autoimmunity.29 furthermore, certain maternal factors and prenatal lifestyle choices such as tobacco smoking, age, mode of birth and psychological stress levels may predispose an infant to t1dm.30–32 these factors may also be linked to breastfeeding outcomes. mechanistic links breast milk has been found to contain various anti pathogenic and anti-inflammatory bioactive molecules, some of which can confer infants with lifelong immunity against many diseases, including t1dm.33 thus, breast milk can be described as a medium through which the maternal defense mechanism trains the immune system of the infant.34 established mechanisms through which breast milk prevents t1dm and other autoimmune diseases are outlined in table 1.33,35–55 r e d u c e d g u t p e r m e a b i l i t y a n d p r i m i n g o f t h e i m m u n e s y s t e m the diversity of the gut microbiota—the composition of which is influenced by various environmental factors such as diet and lifestyle—is important in the aetiology and prevention of t1dm. homeostatically imbalanced microbiota, as characterised by a high preponderance of certain bacteria, increases intestinal permeability, eliciting autoantibodies and causing β-cell auto tajudeen yahaya and ufuoma shemishere review | e7 immunity, the hallmark of t1dm.35 individuals with t1dm have less stable and diverse microbiota comp ared to non-diabetics.36,56 the most frequently reported microbiome imbalance in diabetic individuals is a decreased firmicutes population with a corresponding increase in the bacteroides genus, the opposite of which is usual in non-diabetics.36 in experimental mice, microbiota imbalance was found to decrease tolerance to food antigens and the proportions of regulatory t-cells (tregs) in the intestinal lamina propria, causing intestinal inflammation.37 this results in high intestinal permeability, inducing insulitis or allowing more exogenous antigens into the mucosal immune system. studies of obese and non-obese diabetic mice have observed that this leads to increased cytokine production that may attack and damage pancreatic β-cells.57–59 bacterial metabolites may also attack the pancreatic islet directly. this was shown during a study of mice in which streptomyces-derived toxins impaired glucose tolerance, reducing islet size and β-cell mass at low doses via adenosine triphosphatase inhibition.60 the innate immune system—the body’s first defence mechanism after birth—is weak and lacks important components. in healthy infants, a developing gut microbiome undergoes several stages of maturation in which the ingestion of breast milk is considered the most important factor.61 this is possible because breast milk contains many beneficial bacteria and bioactive molecules. diverse groups of beneficial bacteria in breast milk reduce gut permeability, promote gut microbiota diversity and maturation as well as boost immunological and metabolic function.38 breast milk contains high levels of lactobacillus and bifidobacterium species, which promote the growth of firmicutes bacteria.61,62 firmicutes deficiency has been reported in individuals with t1dm.36,56 bacteroides species are also present in breast milk and increase gut diversity and maturation.61 gut bacteria achieve these functions in vitro by either naturally killing pathogenic bacteria during the competition for food and survival or by producing antimicrobial effects.63,64 insulin is another bioactive molecule found in breast milk; this hormone enhances gut maturation and reduces gut permeability to macromolecules.39 in addition, insulin in breast milk may induce tolerance to blood insulin and prevent t1dm pathogenesis.39 breast milk insulin enhances the diversity of the gut microbiota by boosting the growth of some members of the gammaproteobacteria family and reducing the streptococcaceae population.40 gammaproteobacteria are involved in the maturation of infant gut microbiota, primarily in the first week after birth.41 insulin and leptin, another hormone in breast milk, also influence gut microbiota diversity by suppressing certain microbial metabolic pathways associated with intestinal inflamm ation while promoting beneficial ones.40 oligosaccharides are non-digestible sugars in breast milk that promote the growth of protective bacteria in the colon.33 the non-digestible properties of oligosaccharides allow these molecules to escape the acidic medium of the small intestine into the colon table 1: bioactive molecules in breast milk and their role in type 1 diabetes mellitus risk reduction33,35–55 category molecule potential roles adipokines33,40,43 • leptin • adiponectin • antimicrobial function • immune modulation • increased β-cell function immunoglobulins33,43,45 • iga • igg • antimicrobial function • antiinflammatory function • immune modulation hormones39–41,46,47 • insulin • lactoferrin • lysozyme • caseins • corticosteroids • antiinflammatory function • strengthened immune tolerance • increased thymus performance maternal immune cells51,53,55 • leukocytes • stem cells • cd4+ • mirnas • antimicrobial function • strengthened immunity • increased thymus performance growth factors50–52 • egfs • igf • immune modulation • increased β-cell mass •pancreatic morphogenesis cytokines44,49 • il-1 • il-6 • il-7 • antiinflammatory function • immune modulation • increased thymus size beneficial bacteria35–38 • lactobacillus sp. • bifidobacterium spp. • firmicutes spp. • anti-infectious function • increased gut diversity • strengthened immunity nutrients37,42,48,54 • oligosaccharides • triglycerides • vitamins • minerals • increased gut diversity • anti-microbial function • immune modulation ig = immunoglobulin; cd = cluster of differentiation; mirnas = microri bonucleic acids; egfs = epidermal growth factors; igf = insulin-like growth factor; il = interleukin. association between bioactive molecules in breast milk and type 1 diabetes mellitus e8 | squ medical journal, february 2020, volume 20, issue 1 where they produce short-chain fatty acids.42 these fatty acids enhance the growth of probiotic species, including lactobacillus and bifidobacterium, resulting in a balanced microbiome.43 in an in vitro study, oligo saccharides were found to inhibit and block harmful intestinal microorganisms from binding to their normal targets in the epithelial cells, thus reducing their population.44 oligosaccharides were also reported to confer a protective effect in a murine model of t1dm.65 the administration of oligosaccharides was shown to influence microbiota diversity and produce shortchain fatty acids in non-obese diabetic mice, reversing dm progression.66,67 breast milk also contains large quantities of secretory immunoglobulin (ig) a, which accounts for the majority of the igs in human breast milk.33,43 besides iga, there are four other types of igs in breast milk: ige, igg, igm and igd.45 breast milk secretory iga helps train the immune system of newborns against enteric pathogens acquired through maternal exposure.33,43 breast milk also contains certain bio active substances capable of stimulating iga secretion in infants.43 secretory iga can neutralise infectious agents and reduce the inflammatory effects of other antibodies.68 some children with dm are both iga and igg-deficient.69 lactoferrin, an iron-binding glycoprotein, possesses several anti-infective properties that form part of the innate defense mechanism conferred by mature human breast milk.46 lactoferrin has a high binding affinity for iron, thus limiting its availability to bacteria and other microorganisms.43 in the intestine, lactoferrin may bind to certain receptors, such as toll-like receptors (tlrs) and the cluster of differentiation (cd)14 gene, thereby blocking the attachment of pathogens to the intestinal epithelium.47 in the stomach, lactoferrin combines with pepsin to form lactoferrincin, an antimicrobial agent powerful enough to damage the cell membrane of gram-negative bacteria.70,71 lactoferrin also strengthens neonate immunity by inhibiting tumour necrosis factor-α and interleukin (il)-1β, as well as initiating the maturation of lymphocytes and assisting antioxidation processes.72 adequate levels of lactoferrin have been reported to improve diabetic conditions, while their decline in obese individuals has been linked to insulin resistance.73,74 other molecules present in breast milk include lysozyme, caseins, cytokines, epidermal growth factors (egfs), leukocytes and nucleotides. lysozyme is an antibacterial enzyme that works together with lacto ferrin in the stomach to destroy gram-negative bacteria.75 lysozyme can also degrade bacteria independently by breaking β-glycoside chains in the bacterial cell wall.48 caseins are a family of highly glycosylated proteins; they account for up to 40% of the proteins present in breast milk (mainly β-casein) and functionally boost newborn immunity.43 a minor subunit known as κ-casein mimics a receptor analogue, preventing the attachment of bacteria to the mucosal epithelium.76 cytokines are signalling molecules that mediate, regulate and modulate immune responses, with one example being the anti-inflammatory cytokine il-10.44,49 while many growth factors are present in breast milk, egfs are of particular importance, as these factors aid in the healing and maturation of the intestinal mucosa, nervous system and endocrine system, among others.50 breast milk, particularly colostrum, contains high concentrations of leukocytes, of which approximately 10% are lymphocytes, t-cells, macrophages, neutrophils and antibody-producing b-cells.51 these cells survive passage into the newborn intestines, where they phagocytise microbial pathogens and strengthen the infant’s immune response. triglycerides are also an important component of breast milk. the newborn stomach digests triglycerides using lingual and gastric lipases, releasing free fatty acids and monoglycerides. these two products strengthen the immune system and—through their lytic activities—protect the newborn from various viruses, bacteria and some protozoa, specifically those of the giardia family.52 nucleotides are also present in human breast milk and enhance immune function in infants.53 finally, apart from vitamin d, breast milk contains sufficient quantities of all vitamins essential for normal growth in children.54 enhanced thymus size and function during both the fetal and neonatal periods, the primary function of the thymus is to assist in the development and maturation of t-lymphocytes or t-cells.77 this specific type of white blood cell protects the body from microbial infections and other risks by either controlling immune reactions or directly attacking infected or cancerous cells.77,78 after puberty, the thymus reduces its function and slowly decreases in size until it is replaced by fat at about 75 years of age.77,79 nevertheless, during its active phase, the thymus produces enough t-cells to protect the body from autoimmunity for life.77 due to its role in maintaining a strong neonate defence mechanism, loss of thymus function may be implicated in the pathogenesis of several diseases. for instance, autoimmune-mediated dm begins with the failure of the thymus to develop a normal β-cell self-tolerance.80 dysfunctional thymic activity along with expression of insulin-like growth factor 2 is also suspected in certain cases of insulin resistance.80 one animal study noted the development of autoimmune tajudeen yahaya and ufuoma shemishere review | e9 diseases in mice whose thymuses were removed.81 while scientists are still skeptical about the role of thymus size in its performance, the fact that the organ is largest during childhood when an individual is most prone to immunological threats seems to indicate that increased thymus size is associated with better immunity.77 several factors may influence thymus size and activity, potentially leading to the prevention of autoimmune diseases such as t1dm. some studies show that breast milk may enlarge the thymus gland, either directly via certain components in breast milk or indirectly as a result of the effects of breast milk on infant gut microbiota.82,83 breast milk contains cd4+ t-cells, which are passed into the thymus of the infant where they help train cd8+ t-cells to fight pathogens.55 breast milk also contains maternal cytotoxic t-lymphocytes which pass into the thymus of infants, after which they find their way to the lymphatic tissues in the ileum where they prevent the growth of harmful bacteria.84 microribonucleic acids (mirnas) that regulate post-transcription immune cell activity are also present in breast milk.85 notably, mirna-155 plays a key role in regulating thymus treg and t-helper-2 cell development in humans and animals.86,87 in mice, mirna-449a regulates thymus medullary epithelial cell development.88 certain hormones involved in thymus development are also present in breast milk. among these are corticosteroids, which control thymus epithelial differentiation and the production of thymus corpuscles.89,90 in addition, il-7 is also present in breast milk and regulates thymus size. collinson et al. reported that the children of malnourished mothers have small thymuses, with small thymus size linked with low il-7 levels in maternal breast milk.91 conclusion breast milk contains a wide variety of bioactive sub stances which functionally protect the infant’s immune system from autoimmune disorders by increasing the population of beneficial bacteria in the gut, attacking pathogenic bacteria and pro-inflammatory molecules as well as increasing thymus size and performance. as such, inadequate breastfeeding may predispose an infant to autoimmune diseases, including t1dm. nursing mothers and caregivers are therefore advised to follow optimal breastfeeding practices. for babies unable to be breastfed, perhaps due to maternal death or the risk of vertical disease transmission, the bioactive sub stances mentioned in breast milk can be used to form ulate infant feeding formula for such babies. references 1. kalathi d, james s, zaidi r. diagnosis and management of type 1 diabetes mellitus. clin pharm 2018; 10:1. https://doi.org/10.1 211/cp.2018.20205044. 2. thomas nj, jones se, weedon mn, weedon mn, shields bm, oram ra, et al. frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from uk biobank. lancet diabetes endocrinol 2018; 6:122–9. https://doi.org/10.1016/s2213-8587 (17)30362-5. 3. soltesz g, patterson cc, dahlquist g; eurodiab study group. worldwide childhood type 1 diabetes incidence: what can we learn from epidemiology? pediatr diabetes 2007; 8:6–14. https://doi. org/10.1111/j.1399-5448.2007.00280.x. 4. redondo mj, libman i, cheng p, kollman c, tosur m, gal rl, et al. racial/ethnic minority youth with recent-onset type 1 diabetes have poor prognostic factors. diabetes care 2018; 41:1017–24. https://doi.org/10.2337/dc17-2335. 5. burrack al, martinov t, fife bt. t cell-mediated beta cell destruction: autoimmunity and alloimmunity in the context of type 1 diabetes. front endocrinol (lausanne) 2017; 8:343. https://doi.org/10.3389/fendo.2017.00343. 6. kahanovitz l, sluss pm, russell sj. type 1 diabetes: a clinical perspective. point care 2017; 16:37–40. https://doi.org/10.109 7/poc.0000000000000125. 7. internation diabetes federation. about diabetes: diabetes complications. from: www.idf.org/aboutdiabetes/complicatio ns.html accessed: oct 2019. 8. grose dn, o’brien cl, bongetti ek, corcoran hm, loh mm, ward gm, et al. living with type 1 diabetes and an insulin pump: a qualitative insight. pract diabetes int 2018; 35:2187. https://doi.org/10.1002/pdi.2187. 9. tao b, pietropaolo m, atkinson m, schatz d, taylor d. estim ating the cost of type 1 diabetes in the u.s.: a propensity score matching method. plos one 2010; 5:e11501. https://doi.org/10.1 371/journal.pone.0011501. 10. patterson cc, harjutsalo v, rosenbauer j, nen a, cinek o, skrivarhaug t, et al. trends and cyclical variation in the inc idence of childhood type 1 diabetes in 26 european centres in the 25 year period 1989-2013: a multicentre prospective registration study. diabetologia 2019; 62:408–17. https://doi. org/10.1007/s00125-018-4763-3. 11. harjutsalo v, sjöberg l, tuomilehto j. time trends in the incid ence of type 1 diabetes in finnish children: a cohort study. lancet 2008; 371:1777–82. https://doi.org/10.1016/s0140-6736 (08)60765-5. 12. gale ea. the rise of childhood type 1 diabetes in the 20th century. diabetes 2002; 51:3353–61. https://doi.org/10.2337/ diabetes.51.12.3353. 13. yan j, liu l, zhu y, huang g, wang pp. the association between breastfeeding and childhood obesity: a meta-analysis. bmc public health 2014; 14:1267. https://doi.org/10.1186/1471-245 8-14-1267. 14. lund-blix na, dydensborg sander s, størdal k, nybo andersen am, rønningen ks, joner g, et al. infant feeding and risk of type 1 diabetes in two large scandinavian birth cohorts. diabetes care 2017; 40:920–7. https://doi.org/10.2337/dc17-0016. 15. cardwell cr, stene lc, ludvigsson j, rosenbauer j, cinek o, svensson j, et al. breast-feeding and childhood-onset type 1 diab etes: a pooled analysis of individual participant data from 43 observ ational studies. diabetes care 2012; 35:2215–25. https://doi.org/ 10.2337/dc12-0438. 16. dawodu a, tsang rc. maternal vitamin d status: effect on milk vitamin d content and vitamin d status of breastfeeding infants. adv nutr 2012; 3:353–61. https://doi.org/10.3945/an.1 11.000950. https://doi.org/10.1211/cp.2018.20205044 https://doi.org/10.1211/cp.2018.20205044 https://doi.org/10.1016/s2213-8587%2817%2930362-5 https://doi.org/10.1016/s2213-8587%2817%2930362-5 https://doi.org/10.1111/j.1399-5448.2007.00280.x https://doi.org/10.1111/j.1399-5448.2007.00280.x https://doi.org/10.2337/dc17-2335 https://doi.org/10.3389/fendo.2017.00343 https://doi.org/10.1097/poc.0000000000000125 https://doi.org/10.1097/poc.0000000000000125 https://doi.org/10.1002/pdi.2187 https://doi.org/10.1371/journal.pone.0011501 https://doi.org/10.1371/journal.pone.0011501 https://doi.org/10.1007/s00125-018-4763-3 https://doi.org/10.1007/s00125-018-4763-3 https://doi.org/10.1016/s0140-6736%2808%2960765-5 https://doi.org/10.1016/s0140-6736%2808%2960765-5 https://doi.org/10.2337/diabetes.51.12.3353 https://doi.org/10.2337/diabetes.51.12.3353 https://doi.org/10.1186/1471-2458-14-1267 https://doi.org/10.1186/1471-2458-14-1267 https://doi.org/10.2337/dc17-0016 https://doi.org/10.2337/dc12-0438 https://doi.org/10.2337/dc12-0438 https://doi.org/10.3945/an.111.000950 https://doi.org/10.3945/an.111.000950 association between bioactive molecules in breast milk and type 1 diabetes mellitus e10 | squ medical journal, february 2020, volume 20, issue 1 17. silva al, ribeiro kd, melo lr, bezerra df, de queiroz jl, lima ms, et al. vitamin e in human milk and its relation to the nutritional requirement of the term newborn. rev paul pediatr 2017; 35:158–64. https://doi.org/10.1590/1984-0462/;2 017;35;2;00015. 18. al-agha ae, ahmad ia. association among vitamin d deficiency, type 1 diabetes mellitus and glycemic control. j diabetes metab 2015; 6:1000594. https://doi.org/10.4172/2155-6156.1000594. 19. komisarenko yi, bobryk mi. vitamin d deficiency and immune disorders in combined endocrine pathology. front endocrinol (lausanne) 2018; 9:600. https://doi.org/10.3389/fendo.2018.00600. 20. giulietti a, gysemans c, stoffels k, van etten e, decallonne b, overbergh l, et al. vitamin d deficiency in early life accelerates type 1 diabetes in non-obese diabetic mice. diabetologia 2004; 47:451–62. https://doi.org/10.1007/s00125-004-1329-3. 21. hyppönen e, läärä e, reunanen a, järvelin mr, virtanen sm. intake of vitamin d and risk of type 1 diabetes: a birth-cohort study. lancet 2001; 358:1500–3. https://doi.org/10.1016/s014 0-6736(01)06580-1. 22. baburao jain a, anand jain v. vitamin e, its beneficial role in diabetes mellitus (dm) and its complications. j clin diagn res 2012; 6:1624–8. https://doi.org/10.7860/jcdr/2012/4791.2625. 23. virtanen sm, läärä e, hyppönen e, reijonen h, räsänen l, aro a, et al. cow’s milk consumption, hla-dqb1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes childhood diabetes in finland study group. diabetes 2000; 49:912–17. https://doi.org/10.2337/diabe tes.49.6.912. 24. chia js, mcrae jl, enjapoori ak, lefèvre cm, kukuljan s, dwyer mk. dietary cows’ milk protein a1 beta-casein incr eases the incidence of t1d in nod mice. nutrients 2018; 10:1291. https://doi.org/10.3390/nu10091291. 25. scott fw, rowsell p, wang gs, burghardt k, kolb h, flohé s. oral exposure to diabetes-promoting food or immunomodul ators in neonates alters gut cytokines and diabetes. diabetes 2002; 51:73–8. https://doi.org/10.2337/diabetes.51.1.73. 26. moghadam za, mirlohi m, pourzamani h, malekpour a, amininoor z, merasi mr. exposure assessment of bisphenol a intake from polymeric baby bottles in formula-fed infants aged less than one year. toxicol rep 2015; 2:1273–80. https://doi. org/10.1016/j.toxrep.2015.09.002. 27. manukyana l, dunder l, lind pm, bergsten p, lejonklou mh. developmental exposure to a very low dose of bisphenol a induces persistent islet insulin hypersecretion in fischer 344 rat offspring. environ res 2019; 172:127–36. https://doi.org/10.1 016/j.envres.2019.02.009. 28. frederiksen b, kroehl m, lamb mm, seifert j, barriga k, elisenbarth gs, et al. infant exposures and development of type 1 diabetes mellitus: the diabetes autoimmunity study in the young (daisy). jama pediatr 2013; 167:808–15. https://doi. org/10.1001/jamapediatrics.2013.317. 29. norris jm, barriga k, klingensmith g, hoffman m, eisenbarth gs, erlich ha, et al. timing of initial cereal exposure in infancy and risk of islet autoimmunity. jama 2003; 290:1713–20. https://doi.org/10.1001/jama.290.13.1713. 30. mattsson k, jönsson i, malmqvist e, larsson he, rylander l. maternal smoking during pregnancy and offspring type 1 diab etes mellitus risk: accounting for hla haplotype. eur j epid emiol 2015; 30:231–8. https://doi.org/10.1007/s10654-014-9985-1. 31. rewers m, ludvigsson j. environmental risk factors for type 1 diabetes. lancet 2016; 387:2340–8. https://doi.org/10.1016/ s0140-6736(16)30507-4. 32. chen h, iglesias ma, caruso v, morris mj. maternal cigarette smoke exposure contributes to glucose intolerance and decr eased brain insulin action in mice offspring independent of mat ernal diet. plos one 2011; 6:e27260. https://doi.org/10.1371/ journal.pone.0027260. 33. cacho nt, lawrence rm. innate immunity and breast milk. front immunol 2017; 8:584. https://doi.org/10.3389/fimmu.2 017.00584. 34. field cj. the immunological components of human milk and their effect on immune development in infants. j nutr 2005; 135:1–4. https://doi.org/10.1093/jn/135.1.1. 35. gülden e, wong fs, wen l. the gut microbiota and type 1 diabetes. clin immunol 2015; 159:143–53. https://doi.org/10.1 016/j.clim.2015.05.013. 36. fassatoui m, lopez-siles m, díaz-rizzolo da, jmel h, naouali c, abdessalem g, et al. gut microbiota imbalances in tunisian participants with type 1 and type 2 diabetes mellitus. biosci rep 2019; 39:bsr20182348. https://doi.org/10.1042/bsr20182348. 37. candon s, perez-arroyo a, marquet c, valette f, foray ap, pelletier b, et al. antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes. plos one 2015; 10:e125448. https://doi.org/10.1371/journal.pone.0125448. 38. pannaraj ps, li f, cerini c, bender jm, yang s, rollie a, et al. association between breast milk bacterial communities and establishment and development of the infant gut microbiome. jama pediatr 2017; 171:647–54. https://doi.org/10.1001/jamape diatrics.2017.0378. 39. shehadeh n, shamir r, berant m, etzioni a. insulin in human milk and the prevention of type 1 diabetes. pediatr diabetes 2002; 2:175–7. https://doi.org/10.1034/j.1399-5448.20 01.20406.x. 40. lemas dj, young be, baker pr 2nd, tomczik ac, soderberg tk, hernandez tl, et al. alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome. am j clin nutr 2016; 103:1291–300. https://doi. org/10.3945/ajcn.115.126375. 41. eggesbø m, moen b, peddada s, baird d, rugtveit j, midtvedt t, et al. development of gut microbiota in infants not exposed to medical interventions. apmis 2011; 119:17–35. https://doi. org/10.1111/j.1600-0463.2010.02688.x. 42. triantis v, bode l, van neerven rj. immunological effects of human milk oligosaccharides. front pediatr 2018; 6:190. https://doi.org/10.3389/fped.2018.00190. 43. mehta r, petrova a. biologically active breast milk proteins in association with very preterm delivery and stage of lactation. j perinatol 2011; 31:58–62. https://doi.org/10.1038/jp.2010.68. 44. laucirica dr, triantis v, schoemaker r, estes mk, ramani s. milk oligosaccharides inhibit human rotavirus infectivity in ma104 cells. j nutr 2017; 147:1709–14. https://doi.org/10.3 945/jn.116.246090. 45. mix e, goertsches r, zett uk. immunoglobulins: basic consid erations. j neurol 2006; 253:v9–17. https://doi.org/10.1007/ s00415-006-5002-2. 46. adamkin dh. mother’s milk, feeding strategies, and lactoferrin to prevent necrotizing enterocolitis. jpen j parenter enteral nutr 2012; 36:25s–9s. https://doi.org/10.1177/0148607111420158. 47. sherman mp. lactoferrin and necrotizing enterocolitis. clin perinatol 2013; 40:79–91. https://doi.org/10.1016/j.clp.2012.12.006. 48. lönnerdal b. bioactive proteins in breast milk. j paediatr child health 2013; 49:1–7. https://doi.org/10.1111/jpc.12104. 49. dawod b, marshall sj. cytokines and soluble receptors in breast milk as enhancers of oral tolerance development. front immunol 2019; 10:16. https://doi.org/10.3389/fimmu.2019.00016. 50. khailova l, dvorak k, arganbright km, williams cs, halpern md, dvorak b. changes in hepatic cell junctions structure during experimental necrotizing enterocolitis: effect of egf treatment. pediatr res 2009; 66:140–4. https://doi.org/10.1203/pdr.0b013 e3181aa3198. https://doi.org/10.1590/1984-0462/%3b2017%3b35%3b2%3b00015 https://doi.org/10.1590/1984-0462/%3b2017%3b35%3b2%3b00015 https://doi.org/10.4172/2155-6156.1000594 https://doi.org/10.3389/fendo.2018.00600 https://doi.org/10.1007/s00125-004-1329-3 https://doi.org/10.1016/s0140-6736%2801%2906580-1 https://doi.org/10.1016/s0140-6736%2801%2906580-1 https://doi.org/10.7860/jcdr/2012/4791.2625 https://doi.org/10.2337/diabetes.49.6.912 https://doi.org/10.2337/diabetes.49.6.912 https://doi.org/10.3390/nu10091291 https://doi.org/10.2337/diabetes.51.1.73 https://doi.org/10.1016/j.toxrep.2015.09.002 https://doi.org/10.1016/j.toxrep.2015.09.002 https://doi.org/10.1016/j.envres.2019.02.009 https://doi.org/10.1016/j.envres.2019.02.009 https://doi.org/10.1001/jamapediatrics.2013.317 https://doi.org/10.1001/jamapediatrics.2013.317 https://doi.org/10.1001/jama.290.13.1713 https://doi.org/10.1007/s10654-014-9985-1 https://doi.org/10.1016/s0140-6736%2816%2930507-4 https://doi.org/10.1016/s0140-6736%2816%2930507-4 https://doi.org/10.1371/journal.pone.0027260 https://doi.org/10.1371/journal.pone.0027260 https://doi.org/10.3389/fimmu.2017.00584 https://doi.org/10.3389/fimmu.2017.00584 https://doi.org/10.1093/jn/135.1.1 https://doi.org/10.1016/j.clim.2015.05.013 https://doi.org/10.1016/j.clim.2015.05.013 https://doi.org/10.1042/bsr20182348 https://doi.org/10.1371/journal.pone.0125448 https://doi.org/10.1001/jamapediatrics.2017.0378 https://doi.org/10.1001/jamapediatrics.2017.0378 https://doi.org/10.1034/j.1399-5448.2001.20406.x https://doi.org/10.1034/j.1399-5448.2001.20406.x https://doi.org/10.3945/ajcn.115.126375 https://doi.org/10.3945/ajcn.115.126375 https://doi.org/10.1111/j.1600-0463.2010.02688.x https://doi.org/10.1111/j.1600-0463.2010.02688.x https://doi.org/10.3389/fped.2018.00190 https://doi.org/10.1038/jp.2010.68 https://doi.org/10.3945/jn.116.246090 https://doi.org/10.3945/jn.116.246090 https://doi.org/10.1007/s00415-006-5002-2 https://doi.org/10.1007/s00415-006-5002-2 https://doi.org/10.1177/0148607111420158 https://doi.org/10.1016/j.clp.2012.12.006 https://doi.org/10.1111/jpc.12104 https://doi.org/10.3389/fimmu.2019.00016 https://doi.org/10.1203/pdr.0b013e3181aa3198 https://doi.org/10.1203/pdr.0b013e3181aa3198 tajudeen yahaya and ufuoma shemishere review | e11 51. kimpimäki t, erkkola m, korhonen s, kupila a, virtanen sm, ilonen j, et al. short-term exclusive breastfeeding predisposes young children with increased genetic risk of type 1 diabetes to progressive beta-cell autoimmunity. diabetologia 2001; 44:63–9. https://doi.org/10.1007/s001250051581. 52. newburg ds, walker wa. protection of the neonate by the innate immune system of developing gut and of human milk. pediatr res 2007; 61:2–8. https://doi.org/10.1203/01.pdr.00002 50274.68571.18. 53. pickering lk, granoff dm, erickson jr, masor ml, cordle ct, schaller jp, et al. modulation of the immune system by human milk and infant formula containing nucleotides. pediatrics 1998; 101:242–9. https://doi.org/10.1542/peds.101.2.242. 54. við streym s, højskov cs, møller uk, heickendorff l, vestergaard p, mosekilde l, rejnmark l. vitamin d content in human breast milk: a 9-mo follow-up study. am j clin nutr 2016; 103:107–14. https://doi.org/10.3945/ajcn.115.115105. 55. ghosh mk, nguyen v, muller hk, walker am. maternal milk t cells drive development of transgenerational th1 immunity in offspring thymus. j immunol 2016; 197:2290–6. https://doi. org/10.4049/jimmunol.1502483. 56. giongo a, gano ka, crabb db, mukherjee n, novelo ll, casella g, et al. toward defining the autoimmune microbiome for type 1 diabetes. isme j 2011; 5:82–91. https://doi.org/10.1 038/ismej.2010.92. 57. cani pd, possemiers s, van de wiele t, guiot y, everard a, rottier o, et al. changes in gut microbiota control inflammation in obese mice through a mechanism involving glp-2-driven improvement of gut permeability. gut 2009; 58:1091–103. https://doi.org/10.1136/gut.2008.165886. 58. lee as, gibson dl, zhang y, sham hp, vallance ba, dutz jp. gut barrier disruption by an enteric bacterial pathogen accel erates insulitis in nod mice. diabetologia 2010; 53:741–8. https://doi.org/10.1007/s00125-009-1626-y. 59. maffeis c, martina a, corradi m, quarella s, nori n, torriani s, et al. association between intestinal permeability and faecal microbiota composition in italian children with beta cell auto immunity at risk for type 1 diabetes. diabetes metab res rev 2016; 32:700–9. https://doi.org/10.1002/dmrr.2790. 60. myers ma, hettiarachchi kd, ludeman jp, wilson aj, wilson cr, zimmet pz. dietary microbial toxins and type 1 diabetes. ann n y acad sci 2003; 1005:418–22. https://doi.org/10.1196/ann als.1288.071. 61. soto a, martín v, jiménez e, mader i, rodríguez jm, fernández l. lactobacilli and bifidobacteria in human breast milk: influence of antibiotherapy and other host and clinical factors. j pediatr gastroenterol nutr 2014; 59:78–88. https://doi.org/10.1097/ mpg.0000000000000347. 62. angelakis e, raoult d. the increase of species in the gut flora of newborn broiler chicks and ducks is associated with weight gain. plos one 2010; 5:e10463. https://doi.org/10.1371/journ al.pone.0010463. 63. jara s, sánchez m, vera r, cofré j, castro e. the inhibitory activity of lactobacillus spp. isolated from breast milk on gastro intestinal pathogenic bacteria of nosocomial origin. anaerobe 2011; 17:474–7. https://doi.org/10.1016/j.anaerobe.2011.07.008. 64. lyons a, o’mahony d, o’brien f, macsharry j, sheil b, ceddia m, et al. bacterial strain-specific induction of foxp3+ t regulatory cells is protective in murine allergy models. clin exp allergy 2010; 40:811–19. https://doi.org/10.1111/j.1365-2222.2009.03437.x. 65. xiao l, van’t land b, engen pa, naqib a, green sj, nato a, et al. human milk oligosaccharides protect against the devel opment of autoimmune diabetes in nod-mice. sci rep 2018; 8:3829. https://doi.org/10.1038/s41598-018-22052-y. 66. xiao l, van’t lb, van de worp wr, stahl b, folkerts g, garssen j. early-life nutritional factors and mucosal immunity in the devel opment of autoimmune diabetes. front immunol 2017; 8:1219. https://doi.org/10.3389/fimmu.2017.01219. 67. mariño e, richards jl, mcleod kh, stanley d, yap ya, knight j, et al. gut microbial metabolites limit the frequency of autoimmune t cells and protect against type 1 diabetes. nat immunol 2017; 18:552–62. https://doi.org/10.1038/ni.3713. 68. knip m, veijola r, virtanen s, hyöty h, vaarala o, akerblom hk. environmental triggers and determinants of type 1 diabetes. diabetes 2005; 54:s125–36. https://doi.org/10.2337/ diabetes.54.suppl_2.s125. 69. ali ba, sayed ma, moness hm, mahmoud mm. assessment of serum levels of immunoglobulin a and immunoglobulin g in children newly diagnosed with type 1 diabetes mellitus (t1d). curr pediatr res 2017; 21:627–31. 70. yamauchi k, tomita m, giehl tj, ellison rt 3rd. antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. infect immun 1993; 61:719–28. 71. gifford jl, hunter hn, vogel hj. lactoferricin: a lactoferrinderived peptide with antimicrobial, antiviral, antitumor and immunological properties. cell mol life sci 2005; 62:2588–98. https://doi.org/10.1007/s00018-005-5373-z. 72. legrand d. overview of lactoferrin as a natural immune modulator. j pediatr 2016; 173:s10–15. https://doi.org/10.10 16/j.jpeds.2016.02.071. 73. mohamed wa, schaalan mf. antidiabetic efficacy of lacto ferrin in type 2 diabetic pediatrics: controlling impact on ppar-γ, sirt-1, and tlr4 downstream signaling pathway. diabetol metab syndr 2018; 10:89. https://doi.org/10.1186/s13098-018-0390-x. 74. moreno-navarrete jm, ortega f, moreno m, serrano m, ricart w, fernández-real jm. lactoferrin gene knockdown leads to sim ilar effects to iron chelation in human adipocytes. j cell mol med 2014; 18:391–5. https://doi.org/10.1111/jcmm.12234. 75. lu d, liu s, ding f, wang h, li j, li l, et al. large-scale prod uction of functional human lysozyme from marker-free trans genic cloned cows. sci rep 2016; 6:22947. https://doi.org/10.103 8/srep22947. 76. lönnerdal b. bioactive proteins in human milk: mechanisms of action. j pediatr 2010; 156:s26–30. https://doi.org/10.1016/j. jpeds.2009.11.017. 77. sargis rm. an overview of the thymus: the gland that protects you long after it’s gone. from: www.endocrineweb.com/endo crinology/overview-thymus accessed: oct 2019. 78. world health organization. training for the health sector: immune diseases and children. from: www.who.int/ceh/capa city/immune_diseases.pdf?ua=1 accessed: oct 2019. 79. dietert rr, piepenbrink ms. perinatal immunotoxicity: why adult exposure assessment fails to predict risk. environ health perspect 2006; 114:477–83. https://doi.org/10.1289/ehp.8566. 80. dardenne o, geenen v. thymus dysfunction in the development of type 1 diabetes and endocrine autoimmune diseases. eur endocrinol 2009; 5:24–6. https://doi.org/10.17925/ee.2009.05.00.24. 81. sakaguchi s. naturally arising cd4+ regulatory t cells for immun ologic self-tolerance and negative control of immune responses. annu rev immunol 2004; 22:531–62. https://doi.org/10.1146/ annurev.immunol.21.120601.141122. 82. ngom pt, collinson ac, pido-lopez j, henson sm, prentice am, aspinall r. improved thymic function in exclusively breastfed infants is associated with higher interleukin 7 concentrations in their mothers’ breast milk. am j clin nutr 2004; 80:722–8. https://doi.org/10.1093/ajcn/80.3.722. 83. pannaraj ps, li f, cerini c, bender jm, yang s, rollie a, et al. association between breast milk bacterial communities and establishment and development of the infant gut microbiome. jama pediatr 2017; 171:647–54. https://doi.org/10.1001/jamape diatrics.2017.0378. https://doi.org/10.1007/s001250051581 https://doi.org/10.1203/01.pdr.0000250274.68571.18 https://doi.org/10.1203/01.pdr.0000250274.68571.18 https://doi.org/10.1542/peds.101.2.242 https://doi.org/10.3945/ajcn.115.115105 https://doi.org/10.4049/jimmunol.1502483 https://doi.org/10.4049/jimmunol.1502483 https://doi.org/10.1038/ismej.2010.92 https://doi.org/10.1038/ismej.2010.92 https://doi.org/10.1136/gut.2008.165886 https://doi.org/10.1007/s00125-009-1626-y https://doi.org/10.1002/dmrr.2790 https://doi.org/10.1196/annals.1288.071 https://doi.org/10.1196/annals.1288.071 https://doi.org/10.1097/mpg.0000000000000347 https://doi.org/10.1097/mpg.0000000000000347 https://doi.org/10.1371/journal.pone.0010463 https://doi.org/10.1371/journal.pone.0010463 https://doi.org/10.1016/j.anaerobe.2011.07.008 https://doi.org/10.1111/j.1365-2222.2009.03437.x https://doi.org/10.1038/s41598-018-22052-y https://doi.org/10.3389/fimmu.2017.01219 https://doi.org/10.1038/ni.3713 https://doi.org/10.2337/diabetes.54.suppl_2.s125 https://doi.org/10.2337/diabetes.54.suppl_2.s125 https://doi.org/10.1007/s00018-005-5373-z https://doi.org/10.1016/j.jpeds.2016.02.071 https://doi.org/10.1016/j.jpeds.2016.02.071 https://doi.org/10.1186/s13098-018-0390-x https://doi.org/10.1111/jcmm.12234 https://doi.org/10.1038/srep22947 https://doi.org/10.1038/srep22947 https://doi.org/10.1016/j.jpeds.2009.11.017 https://doi.org/10.1016/j.jpeds.2009.11.017 https://doi.org/10.1289/ehp.8566 https://doi.org/10.17925/ee.2009.05.00.24 https://doi.org/10.1146/annurev.immunol.21.120601.141122 https://doi.org/10.1146/annurev.immunol.21.120601.141122 https://doi.org/10.1093/ajcn/80.3.722 https://doi.org/10.1001/jamapediatrics.2017.0378 https://doi.org/10.1001/jamapediatrics.2017.0378 association between bioactive molecules in breast milk and type 1 diabetes mellitus e12 | squ medical journal, february 2020, volume 20, issue 1 84. cabinian a, sinsimer d, tang m, zumba o, mehta h, toma a, et al. transfer of maternal immune cells by breastfeeding: maternal cytotoxic t lymphocytes present in breast milk localize in the peyer’s patches of the nursed infant. plos one 2016; 11:e0156762. https://doi.org/10.1371/journal.pone.0156762. 85. melnik bc, john sm, schmitz g. milk: an exosomal microrna transmitter promoting thymic regulatory t cell maturation preventing the development of atopy? j transl med 2014; 12:43. https://doi.org/10.1186/1479-5876-12-43. 86. kohlhaas s, garden oa, scudamore c, turner m, okkenhaug k, vigorito e. cutting edge: the foxp3 target mir-155 contributes to the development of regulatory t cells. j immunol 2009; 182:2578–82. https://doi.org/10.4049/jimmunol.0803162. 87. alsaweed m, hartmann pe, geddes dt, kakulas f. micrornas in breastmilk and the lactating breast: potential immunoprotec tors and developmental regulators for the infant and the mother. int j environ res public health 2015; 12:13981–4020. https:// doi.org/10.3390/ijerph121113981. 88. chen p, zhang h, sun x, hu y, jiang w, liu z, et al. microrna449a modulates medullary thymic epithelial cell differentiation. sci rep 2017; 7:15915. https://doi.org/10.1038/s41598-017-16162-2. 89. hale lp, markert ml. corticosteroids regulate epithelial cell differentiation and hassall body formation in the human thymus. j immunol 2004; 172:617–24. https://doi.org/10.4049/ jimmunol.172.1.617. 90. pundir s, wall cr, mitchell cj, thorstensen eb, lai ct, et al. variation of human milk glucocorticoids over 24 hour period. j mammary gland biol neoplasia 2017; 22:85–92. https://doi. org/10.1007/s10911-017-9375-x. 91. collinson ac, moore se, cole tj, prentice am. birth season and environmental influences on patterns of thymic growth in rural gambian infants. acta paediatr 2003; 92:1014–20. https://doi.org/10.1111/j.1651-2227.2003.tb02568.x. https://doi.org/10.1371/journal.pone.0156762 https://doi.org/10.1186/1479-5876-12-43 https://doi.org/10.4049/jimmunol.0803162 https://doi.org/10.3390/ijerph121113981 https://doi.org/10.3390/ijerph121113981 https://doi.org/10.1038/s41598-017-16162-2 https://doi.org/10.4049/jimmunol.172.1.617 https://doi.org/10.4049/jimmunol.172.1.617 https://doi.org/10.1007/s10911-017-9375-x https://doi.org/10.1007/s10911-017-9375-x https://doi.org/10.1111/j.1651-2227.2003.tb02568.x squ med j, may 2011, vol. 11, iss. 2, pp. 179-186, epub. 15th may 11 submitted 14th aug 10 revision req. 13th dec 10, revision recd. 19th jan 11 accepted 8th feb 10 diabetes mellitus is a growing public health concern and a common chronic metabolic disease worldwide.1-4 diabetes mellitus represents a group of metabolic diseases that are characterised by hyperglycaemia due to a total or relative lack of insulin secretion and insulin resistance or both. the metabolic abnormalities involve carbohydrate, protein and fat metabolism. diabetes mellitus affects all age groups, but is more common in adults. the world health organization (who) has recently declared it to be a pandemic.2 its prevalence has increased dramatically over the past few decades and it is expected to triple in the next decade. diabetes mellitus is considered a leading cause of death due to its microvascular and macrovascular complications.5,6 the most common types of diabetes are type 1 (also known as insulin dependent) and type 2 (also known as non-insulin-dependent).7,8 type 2 is the more prevalent type. countries with the highest rates of diabetes in the eastern mediterranean region and the middle east are the united arab emirates, saudi arabia, bahrain, kuwait and oman.9 oman is one of the countries that has a high prevalence of diabetes mellitus, especially type 2 diabetes, and its prevalence is expected to increase in the next twenty years.10,11 various inflammatory diseases and soft tissue pathologies in oral cavities are associated with diabetes mellitus;12-14 however, awareness of these complications is lacking worldwide.15-18 periodontal diseases have been proposed as the sixth most prevalent complication of diabetes mellitus following the other diabetic complications.19 it has been reported as a more frequent oral complication of diabetes compared to other oral manifestations 1department of oral health, sultan qaboos university hospital, muscat, oman; 2department of medicine, college of medicine and health sciences, sultan qaboos university, muscat, oman. *corresponding author email: mmaskari@squ.edu.om ‹à÷]<ª<îü”ä÷]<]å<l^à¬^ñ⁄ê<ö]ü¬_ ì√q]ü⁄<       :مفتاح الكلمات abstract: diabetes mellitus is a chronic disease affecting all age groups. it is one of the leading causes of mortality and morbidity worldwide. many chronic macrovascular and microvascular complications of diabetes have been reported in the literature with few reports about oral complications. this article aims to review and increase the awareness of oral manifestations and complications of diabetes mellitus and to stimulate research on the subject. it treats in depth some of the complications such as periodontal disease, fungal infection and salivary dysfunction while other complications are mentioned briefly. keywords: diabetes mellitus; oral; complications; periodontitis; taste; fungal review oral manifestations and complications of diabetes mellitus a review awatif y. al-maskari,1 *masoud y. al-maskari2, salem al-sudairy1 oral manifestations and complications of diabetes mellitus a review 180 | squ medical journal, may 2011, volume 11, issue 2 such as dry mouth and caries. periodontitis is more frequent and severe in patients with diabetes with poor glycaemic control. early identification and/or management of these oral manifestations may help in the early diagnosis of diabetes and in attaining better glycaemic control.20 therefore, diabetic oral complications need to be identified and included in the ultimate care of diabetes in order to fight this chronic metabolic disease effectively. oral complications and manifestations of diabetes mellitus several soft tissue abnormalities have been reported to be associated with diabetes mellitus in the oral cavity. these complications include periodontal diseases (periodontitis and gingivitis); salivary dysfunction leading to a reduction in salivary flow and changes in saliva composition, and taste dysfunction. oral fungal and bacterial infections have also been reported in patients with diabetes. there are also reports of oral mucosa lesions in the form of stomatitis, geographic tongue, benign migratory glossitis, fissured tongue, traumatic ulcer, lichen planus, lichenoid reaction and angular chelitis.21-25 in addition, delayed mucosal wound healing, mucosal neuro-sensory disorders, dental carries and tooth loss has been reported in patients with diabetes.26 the prevalence and the chance of developing oral mucosal lesions were found to be higher in patients with diabetes compared to healthy controls.27 periodontal diseases pat h o p h y s i o l o g y l o g y o f p e r i o d o n t i t i s periodontitis is one of the most widespread diseases in the world affecting the oral cavity, and is highly prevalent in both developed and developing countries.28 periodontitis is a chronic inflammatory disorder affecting the gingivae and the periodontal tissue initiated by bacteria.29 the micro-flora in the dental plaque that forms daily adjacent to the teeth causes this inflammatory process. eventually, the toxins that are released by the microorganisms in the dental plaque will start the gingival inflammation as a result of failure to remove the dental plaque on a daily basis. a periodontal pocket is formed as a result of the progression of the gingival inflammation causing the gingivae to detach from the tooth surface. this periodontal pocket is filled with bacteria and its toxins. as the disease worsens, the pocket will get deeper carrying the dental plaque until it reaches the alveolar bone that will eventually be destroyed with the periodontal attachment. this process is very common and causes destruction of periodontal tissues, loss of alveolar bone and, finally, tooth loss [figure 1]. there are many factors contributing to this type of inflammation beside the presence of bacteria in dental plaque; a susceptible host is one of them. p e r i o d o n t i t i s a n d d i a b e t e s m e l l i t u s the link between diabetes mellitus and periodontal disease is not well recognised by the medical community. periodontal disease has been reported with increased prevalence and severity in patients with type 1 and type 2 diabetes.30 the mechanism by which hyperglycaemia can induce periodontal destruction is not yet fully understood. however, there are many theories which propose factors such as advanced glycation end products, changes in collagen statue, and altered immune function that causes impaired polymorphonuclear leukocyte function which may facilitate bacterial persistence in the tissue and the accumulation of advanced glycation end products, which results from prolonged and chronic hyperglycaemia and increased secretion of pro-inflammatory cytokines such as tumour necrosis factor-α and prostaglandin e-2.31,32 the increase in collagenase activity together with the reduction in collagen synthesis will adversely influence collagen metabolism. this figure 1. radiographic appearance of diabetic patient with sever periodontal destruction and bone loss. awatif y al-maskari, masoud y al-maskari and salem al-sudairy review | 181 significant reduction in hba1c.50 however, they also recommended that the results need to be viewed with caution due to a lack of strength and limitations in the designs of some of the studies included. periodontitis and diabetes are related to each other therefore further larger studies are required to determine the effect of periodontal treatment on glycaemic control. salivary and taste dysfunction s a l i va r y d y s f u n c t i o n saliva has a major role in maintaining a healthy oral cavity. saliva is produced by major salivary glands (parotid, sub-mandibular and sub-lingual) and numerous minor salivary glands distributed in the oral cavity. salivary dysfunction has been reported in patients with diabetes.51,52 a cross sectional epidemiological study was conducted in 2001 to look at the prevalence of hyposalivation and xerostomia (dry mouth) and to determine the relationship between salivary dysfunction and diabetes complications. this study was conducted in type 1 diabetics and control subjects without diabetes. they found that symptoms of reduced salivary flow rate and xerstomia were more frequently reported by patients with diabetes than the controls, especially by those diabetics who had developed neuropathy.53 other studies conducted in type 2 diabetics also confirmed that xerostomia and hyposalivation were more prevalent in this group of patients.54 it has been shown that poorly controlled type 2 diabetics have a lower stimulated parotid gland flow rate compared to well-controlled patients and patients without diabetes.55 an increase in salivary pathogens was also reported in these patients.56 patients with diabetes usually complain of xerostomia and the need to drink very often (polydypsia and polyuria). the constant dryness of the mouth would irritate the oral soft tissues, which in turn will cause inflammation and pain. patients with diabetes with xerostomia are more predisposed to periodontal infection and tooth decay. the cause of this is not yet fully understood in patients with diabetes, but may be related to polydypsia and polyuria or alternation in the basement membrane of the salivary glands. it is known that diabetes mellitus is associated with would result in compromised wound healing as well as periodontal tissue destruction. recent studies indicate that periodontitis has a bidirectional effect on glycaemic control in patients with diabetes.33 there is a cluster of research studies, which support the hypothesis of periodontitis occurring more frequently in patients with diabetes with poor glycaemic control.33-38 in addition, there is enough evidence to support the hypothesis that poor periodontal conditions could worsen glycaemic control as well. many studies report that diabetes is a risk factor for gingivitis and periodontitis and it is more severe with poor glycaemic control [figure 2].39 the risk of developing periodontitis in patients with diabetes has been reported to be three times higher than the general population.40 numerous risk factors have been reported that make patients with diabetes more susceptible to periodontal disease, especially those with poor oral hygiene, poor metabolic control, longer duration of diabetes and who are smokers.41-43 smoking was identified in many studies as being a major preventable risk factor for periodontal disease and tooth loss in the general population and in patients with diabetes.44-48 the dentist and the physician should play an important role in advising and supporting patients with diabetes regarding smoking cessation. the dentist should be engaged in counselling these patients and referring them to a specialist organisation which deals with smoking cessation.49 several studies showed that the treatment of periodontal disease has an influence on glycaemic control in both type 1 and type 2. a recent metaanalysis of the efficacy of periodontal treatment on glycaemic control in patients with diabetes suggested that such treatment could lead to a figure 2. clinical photograph showing periodontal abscess in poorly controlled diabetic patient. oral manifestations and complications of diabetes mellitus a review 182 | squ medical journal, may 2011, volume 11, issue 2 chronic complications such as neuropathy, microvascular abnormalities and endothelial dysfunction that lead to deterioration of microcirculation and this may play a role in reduction of the salivary flow rate and composition.57,58 sialosis is defined as asymptomatic, non-inflammatory, non-neoplastic, bilateral chronic diffuse swelling mainly affecting the parotid glands. sialosis has been found to be more prevalent in patients with diabetes mellitus.59 ta s t e d y s f u n c t i o n there are many factors that have been implicated in altered taste sensation in the oral cavity. metabolic and endocrine diseases were proposed as causative factors for this disturbance; nevertheless, salivary dysfunction can contribute to altered taste sensation or elevation of detection thresholds.60, 61 taste dysfunction has been reported to occur more frequently in patients with poorly controlled diabetes compared to healthy controls.62 diabetic patients who suffer from neuropathy have a higher taste threshold. taste disturbance has also been reported to lead to poor glycaemic control by inhibiting the ability to maintain a good diet.63 oral infection f u n g a l i n f e c t i o n s oral candidosis is an opportunistic infection frequently caused by candida albicans species. many predisposing factors can lead to this infection; these include smoking, xerostomia and endocrine and metabolic diseases.64 other factors were also implicated such as old age, medications, cushing’s syndrome, malignancies, and the use of dentures.65 oral candidosis has been classified into primary and secondary. primary oral candidosis is subclassified into acute (pseudomembranous and erythematous), chronic (pseudomembranous, erythematous and hyperplastic) and candida associated lesions. pseudomembranace candidosis is also known as oral thrush. it is characterised by the presence of a creamy white patch which, when wiped, reveals underlying erythematous and bleeding oral mucosa. the soft palate is the most commonly affected area followed by the cheek, tongue and gingivae. it could be chronic in immuno-compromised patients.66 erythematous candidosis can present as acute or chronic infection. it is believed to result from the usage of steroid and broad spectrum antibiotics and mainly affects the tongue.66 hyperplastic candidosis is known as candidal leukoplakia. it appears as an irregular whitish raised plaquelike lesion commonly seen in the buccal mucous membrane near the commissures. candida associated lesions include denture induced stomatitis, angular chelitis and median rhomboid glossitis which have mixed bacterial and fungal etiology. denture induced stomatitis is mainly seen in full denture wearers in the underlying surface of the upper denture. angular chelitis is seen in the lip commissures as an erythematous crusting lesion. the lesion has been reported to occur in diabetics with poor glycaemic control. median rhomboid glossitis is seen on the dorsal surface of the tongue as adepopulated erythematous diamond-shaped patch at the midline. the incidence of fungal infections in patients with diabetes mellitus has been recognised for many years.67 candidal infection is reported to be more prevalent in patients with diabetes especially in those patients who smoke, wear dentures, have poor glycaemic control and use steroids and broad spectrum antibiotics.68 in addition, salivary dysfunction in patients with diabetes can also contribute to higher carriage of fungi in this group of patients. it is clear from these studies that both local and systemic predisposing factors might increase candidal carriage rate and hence increase the risk of oral candidal infection in patients with diabetes.69-71 b a c t e r i a l i n f e c t i o n s patients with diabetes are more susceptible to developing oral bacterial infections. they are well known to have an impaired defense mechanism hence considered to be immuno-compromised. diabetics with diabetic complications and poor metabolic control are more prone to spreading and recurrent bacterial infection. several studies have reported that patients with diabetes are more prone to deep neck bacterial infection compared to patient without diabetes.72,73 a fouryear prospective study by rao et al. investigated the severity of maxillofacial space infection of odontogenic origin, the type of micro-organism, the sensitivity of the micro-organisms to awatif y al-maskari, masoud y al-maskari and salem al-sudairy review | 183 especially in type 1 diabetes. in addition, acute hyperglycaemia causes alteration in the immune responsiveness in diabetes mellitus. atrophicerosive oral lesions are more common in patients with diabetes with olp.77 neuro-sensory oral disorder oral dysesthesia or burning mouth syndrome (bms) is a painful condition affecting the oral cavity (palate, tongue, throat and gingivae).78,79 other abnormal oral sensations may co-exist with the burning mouth sensation such as tingling, numbness, dryness or sore mouth at the same time. the exact cause of bms is unknown, but it has been attributed to several conditions such as dry mouth, menopause, candidal infection, diabetes mellitus, cancer therapy, psychological problems and acid reflux. bms is classified into two types: primary idiopathic, and secondary as a result of a systemic process; secondary bms has been reported to occur with diabetes mellitus. it could adversely affect the ability to maintain good oral hygiene in patients with diabetes. diabetic neuropathy could be the underlying cause of bms in patients with diabetes. the nerve damage in diabetic neuropathy has been reported to show an increase in the langerhans cells that are associated with immune disturbance.80, 81 therefore, it is crucial to screen patients who have symptoms of bms for diabetes mellitus. dental caries and tooth loss it is well known that patients with diabetes are susceptible to oral infections that lead to tooth decay and loss.82 salivary secretion dysfunction, periodontal and sensory disorders could increase the likelihood of developing new and recurrent dental caries and tooth loss [figure 3]. the relationship between diabetes and development of dental caries is still unclear. it is well-known that the cleansing and buffering capacity of the saliva is diminished in patients with diabetes mellitus resulting in increased incidence of dental caries, especially in those patients who suffer from xerostomia. antibiotics, and the length of hospital stay of patients with diabetes compared with patients without diabetes. they concluded that the spread of the bacterial infection to the submandibular space was more common in patients and controls and that the second commonest area was the buccal space. streptococcus species was more commonly isolated in both groups. patients with diabetes were found to stay longer in hospital due to more severe infection and required more time to control their blood glucose levels.74 poor oral wound healing poor soft tissue regeneration and delayed osseous healing in patients with diabetes are known complications during oral surgery. therefore, the management and treatment of patients with diabetes undergoing oral surgery is more complex. it was reported that delayed vascularisation, reduced blood flow, a decline in innate immunity, decreased growth factor production, and psychological stress may be involved in the protracted wound healing of the oral cavity mucosa in patients with diabetes.75 non-candidal oral soft tissue lesion oral lesions that are not caused by candidal infection have been reported to occur in patients with diabetes such as fissured tongue, irritation fibroma and traumatic ulcer. these lesions were more prevalent in diabetes compared to the controls.27 altered or delayed wound healing may play a role in traumatic ulcer. oral mucosal disease both lichen planus and recurrent apthous stomatitis have been reported to occur in patients with diabetes.76,77 oral lichen planus (olp) is a skin disorder that produces lesions in the mouth. olp is reported to occur more frequently in patients with type1 diabetes compared to type 2 diabetes.76 the reason for this is that type 1 diabetes is considered an autoimmune disease, and olp has been reported to have an underlying autoimmune mechanism. patients with diabetes are subjected to a prolonged state of chronic immune suppression oral manifestations and complications of diabetes mellitus a review 184 | squ medical journal, may 2011, volume 11, issue 2 conclusion diabetes mellitus is a chronic, non-communicable and endemic disease. type 2 compared to type 1 diabetes mellitus is more prevalent worldwide and increasing, especially in oman. oral manifestations and complications in patients with diabetes mellitus have been recognised and reported recently as a major complication of diabetes mellitus. there is increasing evidence that chronic oral complications in patients with diabetes adversely affect blood glucose control. prevention and management of oral complications, especially periodontal disease, in patients with diabetes is important due to their possible adverse effect on glycaemic control. promotion of a healthy oral cavity in patients with diabetes is paramount. epidemiological and research data on this problem in omani patients with diabetes should be expanded by further studies. there are several clinical implications from this review. these include: 1) a lack of awareness of oral complications among both diabetics and health providers; 2) an understanding of the way diabetes affects oral health is necessary for both clinicians and patients, therefore research in this field should be encouraged; 3) the need for regular follow-up of patients with diabetes mellitus by both dentist and physicians; 4) the major role that dentists should play in recognising the signs and symptoms of diabetes and their oral complications; 5) advice and counselling for diabetic smokers regarding smoking cessation, and 6) vigorous treatment of oral infection either bacterial or fungal in these patients, especially if they have poor glycaemic control. references 1. diabetes—a global threat. lancet 2009; 373:1735. 2. world health organization. global prevalence of diabetes: estimates for the year 2000 and projections for 2030. geneva: world health organization, 2009. 3. mokdad ah, ford es, bowman ba, nelson de, engelgau mm, vinicor f, et al. diabetes trends in the us: 1990 to 1998. diabetes care 2000; 23:1278–83. 4. abegunde do, mathers cd, taghreed a, ortegon m, strong k. the burden and costs of chronic diseases in low-income and middle-income countries. lancet 2007; 370:1929–38. 5. moore pa, zgibor jc, dasanayake ap. diabetes: a growing epidemic of all ages. j am dent assoc 2003; 134:11–15. 6. shelesh j, swarnlata s. type 2 diabetes mellitus – its global prevalence and therapeutic strategies. diabetes metab syndr 2010; 4:48–56. 7. report of the expert committee on the diagnosis and classification of diabetes mellitus. diabetes care 1997; 20:1183–97. 8. report of the expert committee on the diagnosis and classification of diabetes mellitus. diabetes care 2003; 26:s5–20. 9. saadi h, carruthers s. g, nagelkerke n, al-maskari f, afandi b, reed r, et al. prevalence of diabetes mellitus and its complications in a population-based sample in al ain, united arab emirates. diabetes res clin pract 2007; 78:369–377. 10. asfour mg, lambourne a, soliman a, al-behlani s. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: result of the 1991 national survey. diabet med 1995; 12:1122– 5. 11. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954–7. 12. bell g, large d, barclay s. oral health care in diabetes mellitus. dent update 1999; 26:322–30. 13. baldwin e. oral health. lancet 2009; 373:628–9. 14. vernillo at. dental considerations for the treatment of patients with diabetes mellitus. am dent assoc 2003; 134:24–33. 15. yuen hk, wolf bj, bandyopadhyay d, magruder km, salinas cf, london sd. oral health knowledge and behavior among adults with diabetes. diabetes res clin pract 2009; 86:239–46. 16. al habashneh r, khader y, hammad mm, almuradi m. knowledge and awareness about diabetes and periodontal health among jordanians. j diabetes complications 2010; 24:409–414. 17. mirza km, khan a, ali mm, chaudhry s. oral health knowledge, attitude, and practices and sources of information for diabetic patients in lahore, pakistan. diabetes care 2007; 30:3046–7. 18. moore pa, orchard t, guggenheimer j, weyant rj. diabetes and oral health promotion: a survey figure 3. clinical photograph of diabetic patient with poor oral hygiene, showing dental carries and tooth loss. awatif y al-maskari, masoud y al-maskari and salem al-sudairy review | 185 periodontal treatment on glycemic control of diabetic patients: a systemic review and metaanalysis. diabetes care 2008; 33:421–7. 34. pihlstrom bl, michalowicz bs, johnson nw. periodontal diseases. lancet 2005; 366:1809–20. 35. de silva nt, preshaw pm, taylor jj, jayaratne sd, heasman pa, fernando djs. periodontitis: a complication of type 2 diabetes in sri lankans. diabetes res clin pract 2006; 74:209–10. 36. tsai c, hayes c, taylor gw. glycemic control of type 2 diabetes and severe periodontal disease in the us adult population. community dent oral epidemiol 2002; 30:182–92. 37. davies rm, davies gm. periodontal disease and general health. dent update 2005; 32:438–42. 38. taylor jw. periodontal treatment and its effects on glycemic control a review of the evidence. oral surg oral med oral pathol oral radiol endod 1999; 87:311–6. 39. taylor gw, borgnakke ws. periodontal disease: associations with diabetes, glycemic control and complications. oral dis 2008; 14:191–203. 40. ryan me, carnu o, kamer aa. the influence of diabetes on the periodontal tissues. j am dent assoc 2003; 134:34–40. 41. irwin bc, mullally b, ziada h, allen e, byrne pj. periodontics: 2. risk factors and susceptibility in periodontitis. dent update 2007; 34:270–6. 42. katz pp, wirthlin mr, szpunar sm, selby jv, sepe sj, showstack ja. epidemiology and prevention of periodontal disease in individuals with diabetes. diabetes care 1991; 14:375–85. 43. kibayashi m, tanaka m, nishida n, kuboniwa m, kataoka k, nagata h, et al. longitudinal study of the association between smoking as a periodontitis risk and salivary biomarkers related to periodontitis. j periodontol 2007; 78:859–67. 44. calsina g, ramon j-m, echeverrıa j-j. effects of smoking on periodontal tissues. j clin periodontol 2002; 29:771–6. 45. dietrich t, maserejian nn, joshipura kj, krall ea, garcia ri. tobacco use and incidence of tooth loss among us male health professionals. j dent res 2007; 86:373–7. 46. moore pa, orchard t, guggenheimer j, weyant rj. diabetes and oral health promotion: a survey of disease prevention behaviors. j am dent assoc 2000; 131:1333–41. 47. berlin i. smoking-induced metabolic disorders: diabetes metab syndr 2008; 34:307–14. 48. beziaud f, halimi jm, lecomte p, vol s, tichet j. cigarette smoking and diabetes mellitus. diabetes metab 2004; 30:161–6. 49. chestnutt i. tobacco usage: the role of the dental team in smoking cessation. dent update 2010; 37:55–62. 50. darr l, vergnes jn, gourdy p, sixou m. efficacy of periodontal treatment on glycaemic control in diabetic patients: a meta-analysis of interventional of disease prevention behaviors. j am dent assoc 2000; 131:1333–41. 19. löe h. periodontal disease: the sixth complication of diabetes mellitus. diabetes care 1993; 16:329–34. 20. teeuw wj, gerdes vea, loos bg. effect of periodontal treatment on glycemic control of diabetic patients: a systemic review and metaanalysis. diabetes care 2008; 33:421–7. 21. sandberg ge, sundberg he, fjellstrom ca, wikblad kf. type 2 diabetes and oral health: a comparison between diabetic and non-diabetic subjects. diabetes res clin pract 2000; 50:27–34. 22. chomkhakhai u, thanakun s, khovidhunkit s-p, khovidhunkit w, thaweboon s. oral health in thai patients with metabolic syndrome. diabetes metab syndr 2009; 3:192–7. 23. collin hl, niskanen l, uusitupa m, töyry j, collin p, koivisto a-m, et al. oral symptoms and signs in elderly patients with type 2 diabetes mellitus. oral surg oral med oral pathol oral radiol endod 2000; 90:299–305. 24. guggenheimer j, moore pa, rossie k, myers d, mongelluzzo mb, block hm, et al. insulindependent diabetes mellitus and oral soft tissue pathologies: i. prevalence and characteristics of noncandidal lesions. oral surg oral med oral pathol oral radiol endod 2000; 89:563–9. 25. guggenheimer j, moore pa, rossie k, myers d, mongelluzzo mb, block hm, et al. insulindependent diabetes mellitus and oral soft tissue pathologies. ii. prevalence and characteristics of candida and candidal lesions. oral surg oral med oral pathol oral radiol endod 2000; 89:570–6. 26. lamster ib, lalla e, borgnakke ws, taylor gw. the relationship between oral health and diabetes mellitus. j am dent assoc 2008; 139:19–24. 27. saini r, al-maweri sa, saini d, ismail nm, ismail ar. oral mucosal lesions in non oral habit diabetic patients and association of diabetes mellitus with oral precancerous lesions. diabetes res clin pract 2010; 89:320–6. 28. poul ep. priorities for research for oral health in the 21st century the approach of the who global oral health program. community dental health 2005; 22:71–4. 29. kuo l, polson am, kang t. associations between periodontal diseases and systemic diseases: a review of the inter-relationships and interactions with diabetes, respiratory diseases, cardiovascular diseases and osteoporosis. public health 2008; 122:417–33. 30. preshaw pm. periodontal disease and diabetes. j dent 2009; 37:575–7. 31. ritchie cs. mechanistic links between type 2 diabetes and periodontitis. j dent 2009; 37:578–9. 32. moore pa, weyant rj, mongelluzzo mb, myers de, rossie k, guggenheimer j, et al. type 1 diabetes mellitus and oral health: assessment of periodontal disease. j periodontol 1999; 70:409–17. 33. teeuw wj, gerdes vea, loos bg. effect of oral manifestations and complications of diabetes mellitus a review 186 | squ medical journal, may 2011, volume 11, issue 2 studies. diabetes metab 2008; 34:497–506. 51. moore pa, guggenheimer j, etzel kr, weyant rj, orchard t. type 1 diabetes mellitus, xerostomia, and salivary flow rates. oral surg oral med oral pathol oral radiol endod 2001; 92:281–91. 52. lin cc, sun ss, kao a, lee cc. impaired salivary function in patients with noninsulin-dependent diabetes mellitus with xerostomia. j diabetes complications 2002; 16:176–9. 53. sandberg ge, wikblad kf. oral dryness and peripheral neuropathy in subjects with type 2 diabetes. j diabetes complications 2003; 17:192–8. 54. chávez em, borrell ln, taylor jw, ship ja. a longitudinal analysis of salivary flow in control subjects and older adults with type 2 diabetes. oral surg oral med oral pathol oral radiol endod 2001; 91:166–73. 55. chavez em, taylor gw, borrell ln, ship ja. salivary function and glycemic control in older persons with diabetes. oral surg oral med oral pathol oral radiol endod; 89:305–311. 56. khovidhunkit so, suwantuntula t, thaweboon s, mitrirattanakul s, chomkhakhai u, khovidhunkit w. xerostomia, hyposalivation, and oral microbiota in type 2 diabetic patients: a preliminary study. j med assoc thai 2009; 92:1220–8. 57. conner s, iranfour b, mills j. alteration in parotid salivary flow in diabetes mellitus. oral surg oral med oral pathol 1970; 30:55–9. 58. chomkhakhai u, thanakun s, khovidhunkit s-p, khovidhunkit w, thaweboon s. oral health in thai patients with metabolic syndrome. diabetes metab syndr 2009; 3:192–7. 59. scully c, bagán jv, eveson jw, barnard n, turner fm. sialosis: 35 cases of persistent parotid swelling from two countries. br j oral maxillofac surg 2008; 46:468–72. 60. ship ja, chavez em. special senses: disorders of taste and smell. in: silverman s jr, eversole lr, truelove el, eds. essentials of oral medicine. hamilton, london: bc decker inc., 2001. pp. 279– 80. 61. negrato ca, tarzia o. buccal alterations in diabetes mellitus. diabetes metab syndr 2010; 2:3. 62. lalla rv, d’ambrossio ja. dental management considerations for the patient with diabetes mellitus. j am dent assoc 200; 132:1425-32. 63. ship ja. diabetes and oral health: an overview. j am dent assoc 2003; 134:4-10s. 64. mcintyre g. oral candidosis. dent update 2001; 28:132–9. 65. samaranayake lp. host factors and oral candidiasis. in: samaranayake lp, macfarlane tw, eds. oral candidosis, 2nd ed. london: butterworth & co. ltd, 1990. pp. 145–7. 66. akpan a, morgan r. oral candidiasis. postgrad med j 2002; 78 :455-459. 67. lamey pj, darwaza a, fisher bm, samaranayake lp, macfarlane tw, frier bm. secretor status, candidal carriage and candidal infection in patients with diabetes mellitus. j oral pathol 1988; 17:354–7. 68. willis am, coulter wa, fulton cr, hayes rj, bell pm, lamey pj. oral candidal carriage and infection in insulin treated diabetic patients. diabet med 1999; 16:675–9. 69. hill lv, tan mh, pereira lh, embil ja. association of oral candidiasis with diabetic control. j clin pathol 1989; 42:502–5. 70. khosravi ar, yarahmadi s, baiat m, shokri h, pourkabireh m. factors affecting the prevalence of yeasts in the oral cavity of patients with diabetes mellitus. j mycol med 2008; 18:83–8. 71. soysa ns, samaranayake lp, ellepola nb. diabetes mellitus as a contributory factor in oral candidosis. diabet med 2006; 23:455–9. 72. huang tt, tseng fy, liu tc, hsu cj, chen ys. deep neck infection in diabetic patients: comparison of clinical picture and outcomes with nondiabetic patients. otolaryngol head neck surg 2005; 132:943–7. 73. uthkarsh l, shrinath n. diabetic challenge in maxillofacial infection. int j oral maxillofac surg 2007; 36:1040. 74. rao dd, desai a, kulkarni rd, gopalkrishnan k, rao cb. comparison of maxillofacial space infection in diabetic and nondiabetic patients. oral surg oral med oral pathol oral radiol endod 2010; 110:7–12. 75. abiko y, selimovic d. the mechanism of protracted wound healing on oral mucosa in diabetes: review. bosn j basic med sci 2010; 10:186–91. 76. amerikanou cp, markopoulos ak, belazi m, karamitsos d, papanayotou p. prevalence of oral lichen planus in diabetes mellitus according to the type of diabetes. oral dis 1998; 4:37–40. 77. torrente-castells e, figueiredo r, berini-aytés l, gay-escoda c. clinical features of oral lichen planus a retrospective study of 65 cases. med oral patol oral cir bucal 2010; 15:685–90. 78. ada division of communications. burning mouth syndrome. j am dent assoc 2005; 136:1191. 79. scala a, checchi l, montevecchi m, marini i, giamberardino ma. update on burning mouth syndrome: overview and patient management. crit rev oral biol med 2003; 14:275–91. 80. moore pa, guggenheimer j, orchard t. burning mouth syndrome and peripheral neuropathy in patients with type 1 diabetes mellitus. j diabetes complications 2007; 21:397–402. 81. tavakoli m, boulton aj, efron n, malik ra. increased langerhans cell density and corneal nerve damage in diabetic patients: role of immune mechanisms in human diabetic neuropathy. cont lens anterior eye 2010; [epub 2010 sep 16]. 82. collin h-l, uusitupa m, niskanen l, koivisto a-m, markkanen h, meurman jh. caries in patients with non-insulin-dependent diabetes mellitus. oral surg oral med oral pathol oral radiol endod 1998; 85:680–5. departments of 1radiodiagnosis and 2general surgery, all india institute of medical sciences, bhubaneswar, odisha, india *corresponding author’s e-mail: drsudipta.m@gmail.com transmesenteric internal abdominal hernia multi-detector row computed tomography findings *sudipta mohakud,1 suprava naik,1 nerbadyswari deep,1 arshdeep singh,1 tushar s. mishra,2 mithilesh sinha2 sultan qaboos university med j, august 2021, vol. 21, iss.3, pp. 502–503, epub. 29 aug 21 submitted 21 sep 20 accepted 15 dec 20 an 80-year-old female patient presented to the emergency department of the all india institute of medical sciences, bhubaneswar, in 2016 with sub-acute intestinal obstruction features. there was no history of surgery, diabetes, hypertension or previous exposure to tuberculosis. a multidetector row computed tomography (mdct) with an angiography showed a cluster of mild dilated small bowel loops containing air-fluid levels on the right side of the abdomen. engorged and crowded vessels were seen in the pedicle. the vessels converged at the hernia entrance with a twisted vascular pedicle [figures 1a, 1b and 2a]. another case of a 56-year-old female patient, who had undergone a hepaticojejunostomy for a post laparoscopy common bile duct injury six years back, presented to the emergency department of the all india institute of medical sciences, bhubaneswar, in 2017 with features of intestinal obstruction. there was no other significant medical history. mdct angiography showed a cluster of mild dilated small bowel loops in the mid-abdomen without features of bowel ischemia. twisting of the vascular pedicle (whirlpool sign) was suggestive of volvulus [figures 2b and 3]. defect closure with repositioning of the bowel loops and fixation of the mesentery was done surgically with uneventful postoperative recovery in both patients. both patients were doing well during follow-up. consent was obtained from both patients for publication purposes. comment a transmesenteric hernia (tmh) is an uncommon type of an internal hernia that can occur through a congenital or an acquired defect in the mesentery.1 it most commonly presents with intestinal obstruction and is highly prone to volvulus and strangulation. congenital causes account for nearly 8% of all tmhs.2 tmh usually occurs near the origin of mesentery, at the ligament of treitz or close to the ileocecal valve. the defect size ranges from 2–5 cm in diameter.1 the acquired mesenteric rents are mostly secondary to surgery, trauma or inflammation.1 internal hernias are considered dormant as long as they reduce spontaneously. symptoms range from mild digestive complaints, abdominal distension, continuous vague discomfort in the epigastric region, intermittent periumbilical pain, nausea and vomiting to recurrent episodes of intestinal obstruction.3 they become clinically apparent only when there is small bowel obstruction; herniated bowel loops may present as a palpable tender lump.2 non-specific clinical features make the diagnosis challenging but a contrastthis work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.025 interesting medical image figure 1: contrast-enhanced multi-detector row computed tomography images of the abdomen of an 80-year-old female patient with (a) the axial section image showing a sac-like cluster of dilated small bowel loops (within the circle) and (b) an axial maximum intensity projection image showing engorged and crowded vessels in the vascular pedicle (arrow). https://creativecommons.org/licenses/by-nd/4.0/ sudipta mohakud, suprava naik, nerbadyswari deep, arshdeep singh, tushar s. mishra and mithilesh sinha interesting medical image | 503 enhanced mdct scan with angiography is very helpful in diagnosing the condition. the characteristic mdct finding of an internal hernia is a sac-like cluster of dilated small bowel loops.4 the absence of a sac or a surrounding membrane differentiates it from an abdominal cocoon.5 a transition zone can be seen between the proximal dilated small bowel loops and the normal or collapsed distal bowel. the vessels in the vascular pedicle of the herniated bowel loops appear crowded and stretched on a ct angiography. the mesenteric vessels converge at the entrance of the hernial sac, with whirling of the vascular pedicle (whirlpool sign) at the point of the mesenteric twist. in cases of strangulation, bowel ischaemia signs, such as wall thickening and enhancement, pneumatosis and ascites, may be seen.4 identification of the characteristic mdct findings can help in early diagnosis of tmh and rescue the affected bowel loops. a u t h o r s’ c o n t r i b u t i o n sm drafted the manuscript as well as collected the images and patient history. as provided the case diagnosis. tsm and ms performed the clinical and surgical management of the patients and follow-up. all authors edited and reviewed the manuscript. all authors approved the final version of the manuscript. references 1. takeyama n, gokan t, ohgiya y, satoh s, hashizume t, hataya k, et al. ct of internal hernias. radiographics 2005; 25:997–1015. https://doi.org/10.1148/rg.254045035. 2. chaudhary p, rao m, kumar a, khandelwal s, gupta n, arora mp. spontaneous transmesenteric hernia: a rare cause of small bowel obstruction in an adult. clin pract 2013; 3:e6. https://doi. org/10.4081/cp.2013.e6. 3. lanzetta mm, masserelli a, addeo g, cozzi d, maggialetti n, danti g, et al. internal hernias: a difficult diagnostic challenge. review of ct signs and clinical findings. acta biomed 2019; 90:20–37. https://doi.org/10.23750/abm.v90i5-s.8344. 4. blachar a, federle mp, brancatelli g, peterson ms, oliver jh 3rd, li w. radiologist performance in the diagnosis of internal hernia by using specific ct findings with emphasis on transmesenteric hernia. radiology 2001; 221:422–8. https://doi.org/10.1148/rad iol.2212010126. 5. mohakud s, juneja a, lal h. abdominal cocoon: preoperative diagnosis on ct. bmj case rep 2019; 12:e229983. https://doi. org/10.1136/bcr-2019-229983. figure 3: axial maximum intensity projection of the abdomen with angiography of a 56-year-old female patient during contrast-enhanced multi-detector row computed tomography showing twisting of the vascular pedicle (arrow). figure 2: a: axial maximum intensity projection of the abdomen with angiography of an 80-year-old female patient during contrast-enhanced multi-detector row computed tomography showing twisting of the vascular pedicle with engorged vessels (arrow). b: axial section image of the abdomen of a 56-year-old female patient during contrast-enhanced multi-detector row computed tomography showing a cluster of dilated small bowel loops (arrow). https://doi.org/10.1148/rg.254045035 https://doi.org/10.4081/cp.2013.e6 https://doi.org/10.4081/cp.2013.e6 https://doi.org/10.23750/abm.v90i5-s.8344 https://doi.org/10.1148/radiol.2212010126 https://doi.org/10.1148/radiol.2212010126 https://doi.org/10.1136/bcr-2019-229983 https://doi.org/10.1136/bcr-2019-229983 departments of 1orthotics & prosthetics and 6physiotherapy, school of rehabilitation sciences, iran university of medical sciences, tehran, iran; 2undersecretary general for health, treatment and rehabilitation of iranian red crescent society, tehran, iran; 3department of mechanical engineering, sharif university of technology, tehran, iran; 4physical medicine & rehabilitation department, shahid modarres hospital, shahid beheshti university of medical sciences, tehran, iran; 5department of biomechanics, djavad mowafaghian research centre of intelligent neuro-rehabilitation technologies, tehran, iran *corresponding author’s e-mail: hassan_saeedi2@yahoo.co.uk آاثر تقومي الركبة مبفصل ذات درجتني من احلرية على طريقة املشي ومهمة اجللوس إىل الوقوف يف املرضى الذين يعانون من فصال عظمي إنسي يف الركبة �سيامك آقاجاىن ف�ساركي، فرز�م فرهمند، ح�سن �سعيدي، �سيد �أحمد رئيس سادات، �إح�سان عبد اللهي، �أمري �أحمدي، نادر معرويف abstract: objectives: knee bracing as a conservative treatment option for patients with medial knee osteoarthritis (koa) is of great interest to health practitioners and patients alike. optimal orthotic knee joint structure is essential to achieve biomechanical and clinical effectiveness. therefore, this study aimed to identify the effects of a knee orthosis with a new two-degrees-of-freedom (dof) joint design on selected gait parameters and in a sit-to-stand task in patients with mild-to-moderate medial koa. methods: this study was conducted both at the physical medicine and rehabilitation clinic in shahid modarres academic hospital and the biomechanical laboratory of rehabilitation faculty of iran university of medical sciences in tehran, iran from september 2015 to october 2017. the gait performance of 16 patients was assessed without an orthosis, using a common one-dof (dof) knee orthosis and using the same knee orthosis with a two-dof orthotic joint design. the interactive shearing force between limb and brace in the shell area during a sit-to-stand test was also identified. repeated measures analysis of variance was used to analyse the data. results: compared with walking with no orthosis, both orthosis conditions reduced the external knee adduction moment significantly (p ≤0.05). a significant increase between the one-dof and two-dof conditions in terms of walking speed (p = 0.041 and p = 0.009, respectively) and stride length (p = 0.028 and p = 0.038, respectively) was observed. in a sit-to-stand test, wearing the orthosis significantly decreased knee transverse plane range of motion (p ≤0.05). there was a 41.31 ± 8.34 newtons reduction in knee flexion constraint force. conclusion: the two-dof knee orthosis was more comfortable compared to the one-dof knee orthosis during deep knee flexion. otherwise, the onedofand two-dof-braces performed similarly. keywords: knee osteoarthritis; orthosis; braces; gait analysis; rotations; kinematics; kinetics; patient comfort. امللخ�ص: الهدف: يعترب دعم �لركبة للمر�سى �لذين يعانون من ف�سال عظمي �إن�سي يف �لركبة خياًر� عالجًيا حتفظيا ذ�ت �أهمية كبرية لدى �ملمار�سني �ل�سحيني و�ملر�سى على حد �سو�ء. يعترب �لهيكل �لأمثل ملف�سل �لركبة �لتقوميي �رضورًيا لتحقيق �لفعالية �مليكانيكية �حليوية و�ل�رضيرية. لذلك هدفت هذه �لدر��سة �إىل حتديد �آثار تقومي �لركبة مبف�سل جديد ذ�ت درجتني من �حلرية على معايري حمددة للِم�ْسَية ومهمة �جللو�س �ىل �لوقوف يف �ملر�سى �لذين يعانون من ف�سال عظمي �إن�سي خفيف �إىل متو�سط يف �لركبة. الطريقة: �أجريت هذه �لدر��سة يف عيادة �س �لأكادميي يف طهر�ن، �إير�ن من �سبتمرب 2015 �إىل �أكتوبر 2017. مت تقييم �أد�ء العالج الطبيعي و�إعادة �لتاأهيل يف م�ست�سفى �سهيد مود�رٍّ ا بدون جهاز تقومي، وبا�ستخد�م مف�سل �لركبة �لتقوميي �ل�سائع ذ�ت درجة و�حدة من �حلرية و��ستخد�م نف�س جهاز �لتقومي �مل�سي لـ 16 مري�سً مع ت�سميم مف�سلي ذ�ت درجتني من �حلرية. مت حتديد قوة �لق�س �لتفاعلية بني �لطرف و�لدعامة يف منطقة �لهيكل �أثناء �ختبار �جللو�س �إىل �لوقوف. مت ��ستخد�م حتليل �ملقايي�س �ملتكررة للتباين لتحليل �لبيانات. النتائج: باملقارنة مع �مل�سي بدون تقومي، قللت كلتا �حلالتني �لأحادي �لتقوميي �ملف�سل نتائج يف ملحوظة زيادة هناك كان .)p ≤0.05( ملحوظ ب�سكل للركبة �خلارجية �لتقريب حلظة �لتقومييتني و�ملف�سل �لتقوميي �لثنائي من حيث �رضعة �مل�سي )على �لتو�يل، p = 0.009 و p = 0.041( وطول �خلطوة )على �لتو�يل، p = 0.038 و 0.028 = p(. يف �ختبار �جللو�س �إىل �لوقوف، �أدى �رتد�ء �لتقومي �إىل �نخفا�س كبري يف نطاق �حلركة �مل�ستعر�س للركبة )p ≤0.05(. كان هناك �نخفا�س مبقد�ر 8.34 ± 41.31 نيوتن يف �لقوة �ملعيقة لثني �لركبة. اخلال�صة: كانت ُمقومة �لركبة مبف�سل ذ�ت درجتني من �حلرية �أكرث ر�حة مقارنة بجهاز تقومي �لركبة مبف�سل ذ�ت درجة و�حدة من �حلرية �أثناء �لثني �حلاد للركبة. خالف ذلك، كان �أد�ء �لدعامات يف �ملفا�سل �لتقوميية �لأحادية و�لثنائية متماثال. الكلمات املفتاحية: ف�سال عظمي يف �لركبة؛ تقومي؛ دعامات؛ حتليل �مل�سي؛ دور�ت؛ علم �حَلَركات؛ حركيات؛ ر�حة �ملري�س. the effects of knee orthosis with two degrees of freedom joint design on gait and sit-to-stand task in patients with medial knee osteoarthritis siamak aghajani fesharaki,1,2 farzam farahmand,3 *hassan saeedi,1 seyed ahmad raeissadat,4 ehsan abdollahy,5 amir ahmadi,6 nader maroufi6 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e324–331, epub. 21 dec 20 submitted 23 nov 20 revision req. 2 mar 20; revision recd. 22 mar 20 accepted 19 apr 20 advances in knowledge wearing a knee orthosis results in significant improvement in walking parameters in patients with mild-to-moderate medial compartment knee osteoarthritis (koa). this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.008 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ siamak a. fesharaki, farzam farahmand, hassan saeedi, seyed a. raeissadat,ehsan abdollahy, amir ahmadi and nader maroufi clinical and basic research | e325 a major aim of conservative treatment in patients with knee osteoarthritis (koa) is to stop or delay the disease progression.1–3 one of these conservative modalities, knee braces, is so important that studies have addressed its effects.4,5 these braces, regardless of the way they unload the medial compartment of the knee joint or whether they have an orthotic knee joint design, induce a valgus moment to counter the external knee adduction moment (ekam) applied to the knee during walking. numerous studies have shown that knee valgus bracing can decrease ekam and improve overall kinematic and kinetic gait parameters.6–12 although valgus braces have positive effects on knee loading in medial koa patients, they limit the natural motion of the knee joint in all three planes.13–16 patients who wear knee braces report discomfort, poor fit and skin irritation as the main reasons for discontinuing brace use.17 the knee joints in various orthoses are simpler in design and function than anatomic knee joints and may be a reason for these complaints. because the path of motion in orthotic knee joints does not coincide with that of the natural knee, braces tend to piston over the lower leg limb, leading to limited range of motion (rom) in the natural knee with subsequent distal migration of the brace and skin discomfort.18,19 the lack of freedom in transverse plane motion inside orthotic knee joint structures leads brace wearers to feel uncomfortable while walking, sitting and rising from a chair because of the mismatch between the two joints. consequently, the natural movement of the knee joint becomes restricted. in addition, a previous study found that the koa population is prone to torsional misalignment, which is a functional drawback of many knee orthoses.5 the current study is based on a previous study that proposed a new two-degrees-of-freedom (dof) orthotic knee joint design that offers a closer approx imation to the natural knee’s motion.20 the main hypothesis of the current study was that the new orthosis would improve patients’ comfort and perfor mance in walking and sit-to-stand activities. it was necessary, however, to conduct a preliminary study in a small sample size to reveal the new brace’s effect on walking and sit-to-stand activities before starting with a longitudinal study to distinguish its competency in a larger target group. therefore, this study aimed to identify the effects of a custom-molded knee orthosis with a novel knee joint on selected temporospatial parameters, kinetics and kinematics of walking and sit-to-stand task in symptomatic individuals with medial koa. in addition, the study aimed to evaluate the self-assessed comfort of one-dof and two-dof orthoses during level walking and sit-to-stand tasks. methods this study was conducted both at the physical medicine and rehabilitation clinic in shahid modarres academic hospital and the biomechanics laboratory of rehabilitation faculty of iran university of medical sciences in tehran, iran from september 2015 to october 2017. participants were recruited from the patient population seeking non-invasive treatment for koa. individuals who were ≥ 40 years old and had been diagnosed with grade ii or iii medial koa according to the kellgren–lawrence scale were included. those who had a body mass index (bmi) greater than 35 kg/m2, the presence of significant pain (including chronic back pain) or other musculoskeletal disorders (for example, ankle, hip or foot disorders), motor neuron disorders, skin problems making it difficult to wear a brace, were not able to understand and perform tasks or had previously had lower-limb surgery were excluded from the study. the participants visited the biomechanics labor atory twice. in the first session, each patient's lower limb was casted in order to fabricate a customised knee brace. final brace adjustments were made during the second session. the patients were then asked to perform level walking and sit-to-stand activities with the brace set to one-dof or two-dof and without the brace. the order of the two different brace conditions was assigned using a simple randomisation method and the participants had no knowledge of the different orthosis adjustments or what effect to expect. during and immediately after the gait and sit-to-stand analyses, patients were asked to rate the comfort of each brace condition. for integrity, a single researcher was responsible for fitting the knee orthosis to all patients and received training before the study. taking into consideration that as a functional drawback of many knee orthoses with only a single during deep knee flexion, a two-dof knee orthosis is more comfortable compared to a one-dof knee orthosis and this finding merits further investigation. application to patient care: this study highlights the possible benefit of adding a transverse plane rotational movement capability in knee orthoses which would be more comfortable for medial koa patients, especially in sit-to-stand activities where deep flexion is needed. the effects of knee orthosis with two degrees of freedom joint design on gait and sit-to-stand task in patients with medial knee osteoarthritis e326 | squ medical journal, november 2020, volume 20, issue 4 figure 1: photographs showing the marker set adopted with the knee orthosis used for three-dimensional gait analysis. figure 2: photographs showing how the interactive shearing force between the limb and the orthosis in a sit-to-stand task was measured using different instruments. reproduced and modified from figure 1 in aghajani-fesharaki s, farahmand f, saeedi h, abdollahy e. design, implementation and testing of a novel prototype orthotic knee joint with two degrees of freedom in a patient with medial knee osteoarthritis.20 figure 3: photographs showing the knee range of motion testing in the transverse plane in a sit-to-stand test with a knee orthosis. siamak a. fesharaki, farzam farahmand, hassan saeedi, seyed a. raeissadat,ehsan abdollahy, amir ahmadi and nader maroufi clinical and basic research | e327 hinge for oa population in literature which are prone to torsional misalignment5, participants were fitted with a bilateral joint type knee orthosis comprised of a new hinge design with two-dof in the sagittal and transverse planes. this design more closely simulates natural knee joint motion. by unscrewing and detaching the plate, the locked motion in the transverse plane is released and enables the joint to work with two-dof (i.e. flexion, extension and horizontal rotation). knee braces were custom-molded through a cast taken by an experienced orthotist while the patients comfortably sat and semi-flexed their knees to ensure the achievement of maximal correction in a valgus position. kinematics and kinetics were evaluated using a seven-way camera with a motion capturing system (qualisys medical ab, göteborg, sweden) operating at 100 hz and a piezoelectric force plate (kistler instruments ag, winterthur, switzerland) operating at 1,000 hz embedded on a 10-meter walkway. before starting data collection during each session, a dynamic and static system calibration was performed. kinetic and kinematic data synchronisation was obtained using qualisys track manager software (qualisys medical ab).21 in total, 17 retro-reflective markers with 14-mm diameters were attached to each participant’s skin over anterior superior iliac spines, the greater trochanter, the femur (two over the lower and upper lateral third and two over the anterior of the mid-thigh), the knee’s medial and lateral sides, the patella, the tibia (one over the lower lateral third and two over the anterior of the mid-shank), the medial and lateral malleoli, the head of the second metatarsal and the heel. when walking with the knee orthosis, knee markers were attached on the medial and lateral sides of the orthotic knee joint instead [figure 1]. after familiarisation trials, participants walked at a comfortable self-selected speed along the gait laboratory’s walkway. the mean values of three successful trials for each test condition were used for analyses. a trial was considered successful if the participant stepped with the entire foot of the braced side on the force platform. a woltring filter with a frequency of 10 hz was used for data filtering and the time of heel strike was utilised for splitting these data into gait cycle intervals. participants’ lower body anatomy was reconstructed by visual three-dimensional software (c-motion research biomechanics, germantown, maryland, usa) to calculate all angles and movements in lower limb joints. ekam was measured using inverse dynamics and expressed in nm/kg. all technical considerations and instrumentations in this task were based on those utilised in a previous study [figure 2].20 rom in the knee’s transverse plane was also analysed in the sit-tostand test with participants using the one-dof and two-dof braces and without the brace [figure 3]. all the gait analyses were also performed for the sit-tostand task. comfort was assessed on a scale from one (most comfortable) to five (uncomfortable).22 participants walked and completed the sit-to-stand task trials while wearing the orthosis in each of the two brace conditions and provided feedback on their comfort. participants were blinded to adjustments and brace conditions. the statistical calculations were carried out using statistical package for the social sciences (spss), version 22.0 (ibm, corp., armonk, new york, usa). all parameters were expressed as mean ± standard deviation (sd). a shapiro-wilk test was used to confirm normal data distribution. analysis of variance for table 1: kinetic and kinematic parameters during walking and in a sit-to-stand test with a one-degree-of-freedom (dof) knee orthosis, a two-dof knee orthosis and without a knee orthosis variable mean change ± sd* set at onedof set at twodof without orthosis maximum knee flexion during stance 14.68 ± 1.83 15.01 ± 1.90 16.43 ± 2.18 maximum knee extension during stance 5.56 ± 1.38 5.09 ± 1.33 4.04 ± 1.17 maximum knee flexion during swing 45.83 ± 5.21 46.80 ± 4.99† 49.64 ± 5.19 transverse plane rom during walking 4.17 ± 0.56 4.18 ± 0.56 5.49 ± 0.61 transverse plane rom during sit-tostand test 9.05 ± 1.23 10.44 ± 1.19 12.42 ± 1.1 first peak external knee adduction moment in nm/kg 0.568 ± 0.10 0.568 ± 0.09 0.637 ± 0.11 second peak external knee adduction moment in nm/kg 0.607 ± 0.13 0.606 ± 0.13 0.673 ± 0.15 sd = standard deviation; dof = degrees of freedom; rom = range of motion; nm = newton-metre. post hoc comparisons between all test conditions with bonferroni adjusted p values. *significant differences were found for each variable between conditions with out orthosis and orthosis set to one degree of freedom (dof), without orthosis and orthosis set to two-dof and when the orthosis was set to one-dof and two-dof (p ≤0.001 each). †p = 0.002. the effects of knee orthosis with two degrees of freedom joint design on gait and sit-to-stand task in patients with medial knee osteoarthritis e328 | squ medical journal, november 2020, volume 20, issue 4 repeated measures was used to determine differences between the three conditions. a bonferroni correction was performed for post hoc pairwise comparisons. p ≤0.05 was considered statistically significant. ethical approval was obtained from the clinical and research ethics committee of the iran university of medical science on 10th february 2015 (#92-1150-3209). all participants signed an informed consent form before enrolment. results a total of 16 participants (n = 11 women) were included in this study. the majority of the participants were female (68.75%); the mean ± sd age, height, weight and bmi were 56.19 ± 7.61 years, 1.63 ± 0.065 m, 73.75 ± 7.7 kg and 27.96 ± 3.22 kg/m−2, respectively. seven participants had oa grade ii and nine had oa grade iii. wearing the orthosis in both conditions significantly reduced ekam (p ≤0.001 each). however, no significant difference was found between the two orthosis conditions (p >0.05). compared to walking without a knee brace, a significant reduction in knee rom was obtained with both brace conditions (p ≤0.01). there was also significant difference between brace conditions (p ≤0.01) [table 1]. less reduction was found when wearing knee orthosis with two-dof knee joint. no significant gait modification was seen in spatiotemporal parameters; however, speed and stride length were modified when wearing the brace. more specifically, wearing the orthosis in both conditions significantly increased walking speed in the one-dof and two-dof conditions (p = 0.041 and p = 0.009, respectively). additionally, a significant increase in stride length was measured when wearing the orthosis in the one-dof and two-dof conditions (p = 0.028 and p = 0.038, respectively). there were no significant differences between the two brace conditions for any spatiotemporal parameters [table 2]. the sit-to-stand task demonstrated a significant main effect in the knee transverse plane rom (p <0.05). a bonferroni post hoc analysis showed significant differences between all conditions (without orthosis: 12.42 ± 1.1°; with orthosis set at one-dof: 9.05 ± 1.23°; with orthosis set at two-dof: 10.44 ± 1.19°). comparing the two brace conditions, a significantly lower reduction in the transverse plane was found (19% versus 35% decrease; p ≤0.01) when participants wore the knee orthosis with two-dof [table 1]. when the participants performed the sit-to-stand task while wearing the one-dof orthosis, the mounted load cell behind the joint detected a load as high as 41.31 ± 8.34 newtons. when the task was repeated with the joint set to two-dof, the brace was free to mimic more closely the knee joint and, consequently, the knee joint was much more free to flex. under this condition, participants declared more comfort while seated. the rotary part of the orthotic joint in the transverse plane showed a mean displacement of approximately 1.5 cm when measuring the movement of the two sliding components when participants started to sit from a standing position and vice versa. no significant difference was found between walking comfort with orthosis set to one-dof versus table 2: spatiotemporal parameters during walking with orthoses with one degree of freedom (dof), two-dof and without a knee orthosis variable mean ± sd set at onedof set at twodof without orthosis walking speed in metre/second 0.6 ± 0.07* 0.63 ± 0.08† 0.51 ± 0.09 *† stride length in metre 0.94 ± 0.10‡ 0.97 ± 0.11§ 0.84 ± 0.18‡§ cadence in steps/min 76.28 ± 5.69 77.20 ± 5.64 73.78 ± 6.44 sd = standard deviation; dof = degree of freedom; min = minute. post hoc comparisons between all test conditions with bonferroni adjusted p values. *significant difference between conditions without orthosis and orthosis set to one-dof (p = 0.041). †significant difference bet ween conditions without orthosis and orthosis set to two-dof (p = 0.009). ‡significant difference between conditions without orthosis and orthosis set to one-dof (p = 0.028). §significant difference between conditions without orthosis and orthosis set to two-dof (p = 0.038). table 3: patient-reported satisfaction score with brace comfort during walking and sit-to-stand test with one-degreeof-freedom (dof) and two-dof knee orthoses mean ± sd walking sit-to-stand test brace comfort satisfaction* one-dof two-dof one-dof two-dof 2.44 ± 0.51 2.37 ± 0.50 2.37 ± 0.50† 1.44 ± 0.50† sd = standard deviation; dof = degree of freedom * scores ranged from one (most comfortable) to five (uncomfortable). † p ≤0.001 siamak a. fesharaki, farzam farahmand, hassan saeedi, seyed a. raeissadat,ehsan abdollahy, amir ahmadi and nader maroufi clinical and basic research | e329 two-dof. however, during the sit-to-stand test, participants reported significantly greater levels of satisfaction of brace comfort when the orthosis was set to two-dof (p = 0.001). a total of 13 from 16 patients (81.25%) found the knee orthosis with two-dof to be more comfortable than the knee orthosis with onedof (mean satisfaction rate was 1.44 ± 0.51 for twodof versus 2.37 ± 0.50 for one-dof) [table 3]. discussion the knee brace utilised in this study produced a corrective force to the knee joint in the coronal plane, reducing ekam in koa patients. previous studies showed that wearing valgus-inducing knee orthoses can result in a reduction in ekam.8,23,24 although the current study did not aim to compare the effect of wearing a knee orthosis on ekam, the use of the knee orthosis by koa patients as a conservative treatment option reduced the effect of the varus moment applied to the knee during walking. this relatively high reduction in ekam may be due to the type of orthosis used in the study. custom-made knee orthoses appear more effective at inducing the valgus moment as they fit patients’ lower limbs well.4 the current study also found that knee braces increased patients’ gait speeds due to an increase in stride length. one reason for this result may be that when participants wore their orthoses, their knee joints felt stabilised and subsequently increased their confidence during walking. this finding is in agreement with that of a previous study which proposed wearing knee braces in order to improve knee joint function and stability.25 during the stance phase, both knee brace test conditions resulted in greater flexion compared to the no brace condition. during the swing phase, wearing a brace also reduced maximum knee flexion and, as a consequence, the overall knee sagittal plane rom was reduced. this finding mirrors that of previous studies where knee orthoses reduced overall knee rom in the sagittal plane.4,23 it should be noted that there was a significant difference (p ≤0.01) in knee rom between the two brace conditions. the knee orthosis with two-dof resulted in less reduction in knee rom during walking. this observation might be due to the lower limitations of movement around the knee joint with the two-dof brace. additionally, the two-dof brace allows the knee to more closely simulate natural motion in the sagittal and transverse planes. this finding of a lower knee rom with a longer stride length with both orthoses seems to be related to an improvement in the hip joint as an adjacent joint to the knee. stance phase knee pain with instability is typically seen in koa patients and they also generally have less rom of the hip joint during walking.3,26 the increased stride length during walking while the patients wore their knee braces not only may have been a result of amelioration of pain and stability in their knee joint but also due to an increase in their hip joint rom.27 further research focusing on the kinematics of hip and ankle joints will eliminate this ambiguity. in relation to the kinematic changes in knee transverse plane motion with the use of orthosis and their restrictive effects on knee movements have been well documented.21,28,29 the sit-to-stand task demonstrated that when the orthotic knee joint transverse dof was locked (the brace set to the one-dof condition), the mounted load cell behind the joint detected a mean load of as much as 41 newtons. the main reason for this load may be due to a mismatch between the orthotic movement pattern and the anatomic joints. in short, the orthosis forces the knee to follow its simplified motions and prevents the rotary part of the natural knee motion to occur. as a result, an unwanted constraint force (interactive shear force) is also generated between the orthosis and the limb in the contact area. this force is transmitted through sidebars into the orthotic joint and measured by the load cell. as the flexion angle increased, the amount of force increased as well. the maximum amount of force was recorded in the last phase of the seated position when the participants flexed their knee joints to approximately 90º. previous research found that, in case of a mismatch between the kinematics of an orthotic joint and the natural knee, tightening the orthosis will just increase its pistoning force.19 the current study’s results has confirmed this theory; in addition, a high shearing load was also recorded by the load cell. when the task was repeated and the orthotic knee joint transverse dof was released (i.e. two-dof), the orthotic joint was free to mimic more closely the knee joint and, consequently, the knee joint was much more free to flex. the rotary part of the orthotic joint in the transverse plane showed a mean displacement of approximately 1.5 cm when measuring the movement of the two sliding components when participants started to sit from a standing position and vice versa. it is clear that when the knee joint was braced in the two-dof condition with a lower limitation in the path of its motion, the aforementioned force in the contact area between the orthosis and the limb made the rotary parts of the joint displace and allow the knee joint complete the rom. to the researchers’ best knowledge, little research has evaluated the effect of knee orthoses in sit-to-stand tasks. therefore, it should be noted that it is difficult to draw definitive conclusions. the effects of knee orthosis with two degrees of freedom joint design on gait and sit-to-stand task in patients with medial knee osteoarthritis e330 | squ medical journal, november 2020, volume 20, issue 4 the secondary aim of this study was to investigate patients’ comfort levels when walking and in sitto-stand tasks in two orthosis conditions. patients wearing the two-dof knee orthosis expressed more comfort when sitting compared with those wearing the one-dof orthosis, but they did not note differences between these two conditions during level walking. the amount of knee flexion seems to be the main reason for feelings of comfort. in sit-to-stand tests, where deep flexion was needed, the capability of the orthosis with a transverse rotation (i.e. two-dof) made the patients feel more comfortable. comfort, however, was rated immediately after wearing the orthosis for only a short time and it is unclear whether this experience provided a true reflection of brace comfort in everyday life. one limitation of this study, therefore, was that only short tests could be performed (e.g. 10 metres of walking). true comfort levels might become evident only after longer brace use. the researchers, however, believe that the two-dof orthosis might lead to more comfort and better adaptation to daily life based on patients' higher satisfaction with that brace in the laboratory. additionally, because the one-dof condition had a lower degree of indicated comfort in laboratory tests, its effectiveness should be further investigated as patients may not be willing to wear this device regularly. improved proprioception, that can occur after wearing a knee brace, is a factor that can relieve knee pain.30 pagani et al. observed that knee braces offer mechanical stability to the knee, which could contribute to decreased pathological levels of cocontraction of agonists and antagonists often observed in koa patients.30 because the intention of the current study was to evaluate that immediate effects of a two-dof knee orthosis, it was not possible to assess orthosis-related pain levels; this was another limitation of the current study. longitudinal studies should evaluate this new brace over longer periods of time. conclusion this study showed that wearing knee orthoses improved koa patients’ gait parameters. the novel knee orthosis with degrees of freedom in the sagittal and transverse planes offered slightly more comfort when moving from sitting to standing, which could result in better compliance with bracing. furthermore, both knee orthoses unloaded medial compartments, suggesting benefits for patients with medial koa. additionally, patients may experience greater comfort while sitting when using a brace with a two-dof hinge instead of a one-dof hinge. however, the effects of this orthosis on daily wear and long-term compliance needs to be confirmed by further studies. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. van raaij tm, reijman m, brouwer rw, bierma-zeinstra sm, verhaar ja. medial knee osteoarthritis treated by insoles or braces: a randomized trial. clin orthop relat res 2010; 468:1926–32. https://doi.org/10.1007/s11999-010-1274-z. 2. jones rk, nester cj, richards jd, kim wy, johnson ds, jari s, et al. a comparison of the biomechanical effects of valgus knee braces and lateral wedged insoles in patients with knee osteo arthritis. gait posture 2013; 37:368–72. https://doi.org/10.10 16/j.gaitpost.2012.08.002. 3. raja k, dewan n. efficacy of knee braces and foot orthoses in conservative management of knee osteoarthritis: a systematic review. am j phys med rehabil 2011; 90:247–62. https://doi. org/10.1097/phm.0b013e318206386b. 4. hunter d, gross kd, mccree p, li l, hirko k, harvey wf. realignment treatment for medial tibiofemoral osteoarthritis: randomised trial. ann rheum dis 2012; 71:1658–65. https:// doi.org/10.1136/annrheumdis-2011-200728. 5. fantini pagani ch, hinrichs m, brüggemann gp. kinetic and kinematic changes with the use of valgus knee brace and lateral wedge insoles in patients with medial knee osteoarthritis. j orthop res 2012; 30:1125–32. https://doi.org/10.1002/jor.22032. 6. dessery y, belzile el, turmel s, corbeil p. comparison of three knee braces in the treatment of medial knee osteoarthritis. knee 2014; 21:1107–14. https://doi.org/10.1016/j.knee.2014.07.024. 7. schmalz t, knopf e, drewitz h, blumentritt s. analysis of biomechanical effectiveness of valgus-inducing knee brace for osteoarthritis of the knee. j rehabil res dev 2010; 47:419–29. https://doi.org/10.1682/jrrd.2009.05.0067. 8. della croce u, crapanzano f, li l, kasi pk, patritti bl, mancinelli c, et al. a preliminary assessment of a novel pneumatic unloading knee brace on the gait mechanics of patients with knee osteo arthritis. pm r 2013; 5:816–24. https://doi.org/10.1016/j.pmrj.2 013.06.008. 9. johnson aj, starr r, kapadia bh, bhave a, mont ma. gait and clinical improvements with a novel knee brace for knee oa. j knee surg 2013; 26:173–8. https://doi.org/10.1055/s-003 2-1327452. 10. moyer rf, birmingham tb, bryant dm, giffin jr, marriott ka, leitch km. biomechanical effects of valgus knee bracing: a systematic review and meta-analysis. osteoarthritis cartilage 2015; 23:178–88. https://doi.org/10.1016/j.joca.2014.11.018. 11. iijima h, isho t, aoyama t. effects of knee orthoses on walking capacity and biomechanics in patients with knee osteoarthritis: a critical review. oa musculosk med 2014; 2:13. 12. laroche d, morisset c, fortunet c, gremeaux v, maillefert jf, ornetti p. biomechanical effectiveness of a distraction-rotation knee brace in medial knee osteoarthritis: preliminary results. knee 2014; 21:710–16. https://doi.org/10.1016/j.knee.2014.02.015. 13. hanzlíková i, richards j, hébert-losier k, smékal d. the effect of proprioceptive knee bracing on knee stability after anterior cruciate ligament reconstruction. gait posture 2019; 67:242–7. https://doi.org/10.1016/j.gaitpost.2018.10.026. https://doi.org/10.1007/s11999-010-1274-z https://doi.org/10.1016/j.gaitpost.2012.08.002 https://doi.org/10.1016/j.gaitpost.2012.08.002 https://doi.org/10.1097/phm.0b013e318206386b https://doi.org/10.1097/phm.0b013e318206386b https://doi.org/10.1136/annrheumdis-2011-200728 https://doi.org/10.1136/annrheumdis-2011-200728 https://doi.org/10.1002/jor.22032 https://doi.org/10.1016/j.knee.2014.07.024 https://doi.org/10.1682/jrrd.2009.05.0067 https://doi.org/10.1016/j.pmrj.2013.06.008 https://doi.org/10.1016/j.pmrj.2013.06.008 https://doi.org/10.1055/s-0032-1327452 https://doi.org/10.1055/s-0032-1327452 https://doi.org/10.1016/j.joca.2014.11.018 https://doi.org/10.1016/j.knee.2014.02.015 https://doi.org/10.1016/j.gaitpost.2018.10.026 siamak a. fesharaki, farzam farahmand, hassan saeedi, seyed a. raeissadat,ehsan abdollahy, amir ahmadi and nader maroufi clinical and basic research | e331 14. théoret d, lamontagne m. study on three-dimensional kinem atics and electromyography of acl deficient knee subjects wearing a functional knee brace during running. knee surg sports traumatol arthrosc 2006; 14:555–63. https://doi.org/10.1007/ s00167-006-0072-3. 15. singer jc, lamontagne m. the effect of functional knee brace design and hinge misalignment on lower limb joint mechanics. clin biomech (bristol, avon) 2008; 23:52–9. https://doi.org/10.10 16/j.clinbiomech.2007.08.013. 16. hanzlíková i, richards j, tomsa m, chohan a, may k, smékal d, et al. the effect of proprioceptive knee bracing on knee stability during three different sport related movement tasks in healthy subjects and the implications to the management of anterior cruciate ligament (acl) injuries. gait posture 2016; 48:165–70. https://doi.org/10.1016/j.gaitpost.2016.05.011. 17. squyer e, stamper dl, hamilton dt, sabin ja, leopold ss. unloader knee braces for osteoarthritis: do patients actually wear them? clin orthop relat res 2013; 47:1982–91. https:// doi.org/10.1007/s11999-013-2814-0. 18. lew wd, patrnchak cm, lewis jl, schmidt j. a comparison of pistoning forces in orthotic knee joints. orthot prosthet 1982; 36:85–95. 19. lewis gl, lew wd, patrnchak cm, shybut gt. a new concept in orthotics joint design–the northwestern university knee orthosis system. orthot prosthet 1983; 37:15–23. 20. aghajani-fesharaki s, farahmand f, saeedi h, abdollahy e. design, implementation and testing of a novel prototype orthotic knee joint with two degrees of freedom in a patient with medial knee osteoarthritis. sultan qaboos univ med j 2018; 18:524–8. https://doi.org/10.18295/squmj.2018.18.04.016. 21. sinclair jk, vincent h, richards jd. effects of prophylactic knee bracing on knee joint kinetics and kinematics during netball specific movements. phys ther sport 2017; 23:93–8. https:// doi.org/10.1016/j.ptsp.2016.08.005. 22. mauricio e, sliepen m, rosenbaum d. acute effects of different orthotic interventions on knee loading parameters in knee osteoarthritis patients with varus malalignment. knee 2018; 25: 825–33. https://doi.org/10.1016/j.knee.2018.06.017. 23. jones rk, nester cj, richards jd, kim wy, johnson ds, jari s, et al. a comparison of the biomechanical effects of valgus knee braces and lateral wedged insoles in patients with knee osteoarthritis. gait posture 2013; 37:368–72. https://doi.org/10.1 016/j.gaitpost.2012.08.002. 24. fantini pagani ch, potthast w, brüggemann gp. the effect of valgus bracing on the knee adduction moment during gait and running in male subjects with varus alignment. clin biomech (bristol, avon) 2010; 25:70–6. https://doi.org/10.1016/j.clinbiom ech.2009.08.010. 25. ramsey dk, briem k, axe mj. a mechanical theory for the effectiveness of bracing for medial compartment osteoarthritis of the knee. j bone joint surg am 2007; 89:2398–407. https:// doi.org/10.2106/jbjs.f.01136. 26. al-zahrani ks, bakheit am. a study of the gait characteristics of patients with chronic osteoarthritis of the knee. disabil rehabil 2002; 24:275–80. https://doi.org/10.1080/09638280110087098. 27. arazpour m, hutchins sw, bani ma, curran s, aksenov a. the influence of a bespoke unloader knee brace on gait in medial compartment osteoarthritis: a pilot study. prosthet orthot int 2014; 38:379–86. https://doi.org/10.1177/0309364613504780. 28. jalali m, farahmand f, esfandiarpour f, golestanha sa, akbar m, eskandari a, et al. the effect of functional bracing on the arthrokinematics of anterior cruciate ligament injured knees during lunge exercise. gait posture 2018; 63:52–7. https://doi. org/10.1016/j.gaitpost.2018.04.022. 29. kwaees ta, richards j, rawlinson g, charalambous cp, chohan a. can the use of proprioceptive knee braces have implications in the management of osteoarthritic knees: an exploratory study. prosthet orthot int 2019; 43:140–7. https:// doi.org/10.1177/0309364618796852. 30. fantini pagani ch, willwacher s, kleis b, brüggemann gp. influence of a valgus knee brace on muscle activation and co-contraction in patients with medial knee osteoarthritis. j electromyogr kinesiol 2013; 23:490–500. https://doi.org/10.10 16/j.jelekin.2012.10.007. https://doi.org/10.1007/s00167-006-0072-3 https://doi.org/10.1007/s00167-006-0072-3 https://doi.org/10.1016/j.clinbiomech.2007.08.013 https://doi.org/10.1016/j.clinbiomech.2007.08.013 https://doi.org/10.1016/j.gaitpost.2016.05.011 https://doi.org/10.1007/s11999-013-2814-0 https://doi.org/10.1007/s11999-013-2814-0 https://doi.org/10.18295/squmj.2018.18.04.016 https://doi.org/10.1016/j.ptsp.2016.08.005 https://doi.org/10.1016/j.ptsp.2016.08.005 https://doi.org/10.1016/j.knee.2018.06.017 https://doi.org/10.1016/j.gaitpost.2012.08.002 https://doi.org/10.1016/j.gaitpost.2012.08.002 https://doi.org/10.1016/j.clinbiomech.2009.08.010 https://doi.org/10.1016/j.clinbiomech.2009.08.010 https://doi.org/10.2106/jbjs.f.01136 https://doi.org/10.2106/jbjs.f.01136 https://doi.org/10.1080/09638280110087098 https://doi.org/10.1177/0309364613504780 https://doi.org/10.1016/j.gaitpost.2018.04.022 https://doi.org/10.1016/j.gaitpost.2018.04.022 https://doi.org/10.1177/0309364618796852 https://doi.org/10.1177/0309364618796852 https://doi.org/10.1016/j.jelekin.2012.10.007 https://doi.org/10.1016/j.jelekin.2012.10.007 department of paediatric dentistry, mohamed bin rashid university of medicine and health sciences, dubai, united arab emirates *corresponding author’s e-mails: mawlood.kowash@mbru.ac.ae and mkowash@gmail.com تقييم جودة أسئلة اإلختيار من متعدد يف إختبارات الدراسات العليا يف طب أسنان األطفال مولود كوا�س، اإياد ح�شني، منال احللبي abstract: objectives: this study aimed to evaluate the quality of multiple choice question (mcq) items in two postgraduate paediatric dentistry (pd) examinations by determining item writing flaws (iwfs), difficulty index (di) and cognitive level. methods: this study was conducted at mohamed bin rashid university of medicine and health sciences, dubai, uae. virtual platform-based summative versions of the general paediatric medicine (gpm) and prevention of oral diseases (pod) examinations administered during the second semester of the 2017–2018 academic year were used. two pd faculty members independently reviewed each question to assess iwfs, di and cognitive level. results: a total of 185 single best answer mcqs with 4–5 options were analysed. most of the questions (81%) required information recall, with the remainder (19%) requiring higher levels of thinking and data explanation. the most common errors among iwfs were the use of “except” or “not” in the lead-in, tricky or unfocussed stems and opportunities for students to use convergence strategies. there were more iwfs in the gpm than the pod examination, but this was not statistically significant (p = 0.105). the mcqs in the gpm and pod examination were considered easy since the mean dis (89.1% ± 8.9% and 76.5% ± 7.9%, respectively) were more than 70%. conclusion: training is an essential element of adequate mcq writing. a general comprehensive review of all programme’s mcqs is needed to emphasise the importance of avoiding iwfs. a faculty development programme is recommended to improve question-writing skills in order to align examinations with programme learning outcomes and enhance the ability to measure student competency through questions requiring higher level thinking. keywords: examination question; student; educational measurement; discriminant analysis; pediatric dentistry; united arab emirates. امللخ�ص: الهدف: تقييم جودة اأ�شئلة االإختيار من متعدد يف اإختبارين يف برنامج الدرا�شات العليا يف طب اأ�شنان االأطفال من خالل حتديد عيوب كتابة االأ�شئلة وموؤ�رش ال�شعوبة وم�شتوى االإدراك التمييزي لالأ�شئلة. الطريقة: مت عمل هذه الدرا�شة يف جامعة حممد بن را�شد للطب والعلوم ال�شحية يف دبي بدولة االإمارات العربية املتحدة وت�شمنت تقييم جودة اأ�شئلة االإختيار من متعدد الإمتحانني �شابقني يف الف�شل الثاين من ال�شنة الدرا�شية 2017-2018 مت اأدائهما من خالل من�شة االإنرتنت، وذلك يف مادة طب االأطفال العام ومادة الوقاية من اأمرا�س الفم، قام بجمع البيانات اإثنان من اأع�شاء هيئة التدري�س كٌل على حدة عن طريق ت�شجيل العنا�رش املطلوبة )عيوب كتابة االأ�شئلة وموؤ�رش اإجابة وحتمل خيارات 5-4 ذات متعدد من اإختيار �شوؤال 185 عدد حتليل مَت النتائج: �شوؤال. لكل التمييزي( االإدراك وم�شتوى ال�شعوبة �شحيحة واحدة، غالبية االأ�شئلة )%81( كانت من نوع اإ�شرتجاع املعلومات و الباقي )%19( من النوع التحليلي، بالن�شبة حلجم العيوب يف االأ�شئلة املوؤلفة ح�شب ال�شيوع امل�شتنتجة كاالآتي: اإ�شتعمال )ماعدا اأو ال يوجد( يف ال�شوؤال، اإ�شتخدام مفردات خمادعة اأو غري وا�شحة مقارنة الفم اأمرا�س من الوقاية اإختبار يف االأ�شئلة يف العيوب من اأكرب عدد هناك كان عام وب�شكل املقاربة، اإ�شرتاتيجَية واإ�شتخدام باإختبار طب االأطفال العام و لكن الفرق مل يكن كبرياً اإح�شائّيًا .)p = 0.105(حدد م�شتوى �شعوبة االإختبارين بال�شهل ح�شب متو�شط موؤ�رش ال�شعوبة لالأ�شئلة )اأكرث من %70( يف اإمتحان مادتي الوقاية من اأمرا�س الفم وطب االأطفال العام )%89.1 ± %8.9 و %76.5 ± %7.9 على التوايل(. اخلال�صة: التقليل من ن�شبة وجود العيوب يف اأ�شئلة االإختبارات مل�شتوى مقبول يتم من خالل تقييم االإختبارات وتدقيق املحتوى وتدريب الكادر التعليمي يف جمال مهارات و�شع اأ�شئلة االإختبارات، كما نو�شي باإ�شافة االأ�شئلة ذات امل�شتوى االإدراكي العايل لكي تتوافق مع نتائج التعلم املطموحة وتدعم قابلية قيا�س كفاءة الطلبة. الكلمات املفتاحية: اأ�شئلة االأمتحان؛ الطالب؛ قيا�س التعليم؛ التحليل التمييزي؛ طّب اأ�شنان االأطفال؛ االإمارات العربية املتحدة. evaluating the quality of multiple choice question in paediatric dentistry postgraduate examinations *mawlood kowash, iyad hussein, manal al halabi clinical & basic research sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e135–141, epub. 8 sep 19 submitted 3 oct 18 revisions req. 29 oct & 20 dec 18; revisions recd. 19 nov & 27 dec 18 accepted 17 jan 19 advances in knowledge the adequate utilisation of multiple choice questions (mcq) can enhance educational outcomes in dentistry especially in the middle east and gulf cooperative council countries; however, more research and training in mcq creation is needed. various factors may be used to assess mcq items based on their item writing flaws, difficulty index and cognitive level. application to patient care high quality and effective mcq items serve as a well-known and often utilised method for evaluating and assessing students. mcqs can assist dental students in achieving an exceptional dental education. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.009 https://creativecommons.org/licenses/by-nd/4.0/ evaluating the quality of multiple choice question in paediatric dentistry postgraduate examinations e136 | squ medical journal, may 2019, volume 19, issue 2 an examination should evaluate clinicalskills and not merely the ability to recall information.1 in addition to evaluating a student, assessment tools govern the methods chosen by students during their learning process.2 scouller investigated the effect of evaluation methods on students’ learning techniques and found that examinees were generally more likely to adopt a superficial learning style when the evaluation doctrine was based solely on recollection of facts. in comparison, students and trainees were more likely to implement a more in-depth approach to learning if the test questions required higher levels of analytical skills and cognitive abilities.2 several studies have reported that the assessment tool affects examinees’ and trainees’ chosen styles of learning.3–5 multiple choice questions (mcqs) are a wellknown and often utilised method for assessment and are used either individually or in combination with other forms of evaluation and assessment. the advantages of mcqs include their reliability and content validity and their ability to reduce reliance on skills related to writing and self-expression.6 high quality and effective mcqs are suitable for quantifying knowledge and perceptions of a given subject; therefore, this method of examination should be construed as accurately assessing applied practice.6 in addition, for mcqs to be of high quality and effective they must be free of item writing flaws (iwfs).7 single best answer (sba) mcq items were the most common assessment used for evaluation in didactic courses at the hamdan bin mohammed college of dental medicine and mohammed bin rashid university of medicine and health sciences (mbru) in dubai, uae. in addition, recently in dentistry more emphasis has been placed on undergraduate assessments through mcqs.8 therefore, this study aimed to evaluate mcq items’ quality in two postgraduate paediatric dentistry (pd) examinations by determining mcqs’ iwfs, diff iculty index (di) and cognitive levels. methods this study assessed an existing pool of mcqs used in two end-of-semester examinations during the 2017–2018 academic year at mbru. the target courses were pd postgraduate courses in general paediatric medicine (gpm) and the prevention of oral diseases (pod). examinations were accepted as data sources if they contained mcqs of 4–5 items (one single correct option and 3–4 distractors) of sba-type summative questions. some true/false and extended matching questions were excluded. of the four pd faculty who produced the mcq items, two were formally trained in mcq design and assessment by the royal college of surgeons of edinburgh. they independently reviewed each question according to predefined criteria. when debatable questions were encountered, joint faculty agreements were made with the help of a subject expert. the cognitive levels of each question item were analysed using buckwalter’s criteria, which is a revision of bloom’s taxonomy.10,11 each mcq item was assigned to one of three cognitive levels. level one included lower order thinking questions which required recall of information. level two questions tested understanding and interpretation of data. level three included higher order questions which tested the application of knowledge for solving a particular problem. a list of 14 commonly occurring iwf criteria were used to identify iwfs in each question.7,12 the list of iwfs included the use of absolute terms and opportunities for students to use convergence strategy. in using this strategy, students are able to answer the question by recognising that the correct answer includes common elements of other options. the basic structure of an ideal sba was proposed by case and swanson.7 an effective question consists of a stem, which ideally should be a context-rich clin ical case scenario or vignette that encourages the applic ation of knowledge to a clinical situation followed by a lead-in, which states a question or a requirement from a candidate [figure 1]. ideally the lead-in should not include “except” or “not”. the answer options should include one correct answer as well as a number of distractors and be homogenous (e.g. all focusing on diagnosis, investigations, medications or treatment options), plausible, of an appropriate length and uncompl icated. options should avoid the use of “all” or “none of figure 1: anatomy of an effective single best answer question. mawlood kowash, iyad hussein and manal al halabi clinical and basic research | e137 the above” or absolute terms such as “never”. options should also be absent of vague frequency terms such as “often” and “usually” and other iwfs. an example of an easy low-cognitive sba question showing multiple iwfs is presented in figure 2. di is defined as “the proportion of students who answered the item correctly, with the formula for the item-di being p = c/n where, c is the number of students who selected the correct answer and n is the total number of respondents. the prop (proportion) value statistics ranges from 0 to 1”.13,14 the higher the prop value, the simpler the question was. multiplying the prop value by 100 converts di to a proportion. the prop value of the examinees who answered the question correctly could be classified as follows: <30% meant that the item was too difficult; between 30–70% meant that the item was good and acceptable; and a prop value >70% meant that the question was too easy and therefore unacceptable and in need of modification. the di in an examination is defined as a measure of the effectiveness of an item in discriminating between high and low scorers.13 descriptive statistics were used and statistical analysis was carried out using a pairwise t-test using statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). statistical significance was set at p <0.05. the mbru institutional review board approved an exemption as this research did not involve human subjects (mbru-irb-2018-010). results a total of 185 sba mcqs with 4–5 items (one correct option and 3–4 distractors) were analysed. the two pd faculty reviewers initially disagreed on 12 mcq items (6.5%). the iwfs and/or cognitive levels of those questions were determined and agreed upon in a faculty meeting. almost half of the questions (49.7%) had one or more iwfs in both examinations. the pod examination had more iwfs compared to the gpm examination (62.2% versus 37.9%). however, the difference was not statistically significant using a pairwise t-test (p = 0.105). figure 2: example of a poor single best answer question showing multiple item writing flaws and focusing on recall of knowledge. iwfs = item writing flaws. figure 3: distribution of types of item writing flaws in the general paediatric medicine examination in the academic year 2017–2018 at mohamed bin rashid university of medicine and health sciences, dubai, united arab emirates. table 1: distribution of cognitive levels and difficulty index in multiple choice questions from two examinations at mohamed bin rashid university of medicine and health sciences, dubai, united arab emirates (n = 185) examination mean percentage ± sd n (%) difficulty index* cognitive level level one level two gpm† 89.1 ± 8.9 80 (84.2) 15 (15.8) pod‡ 76.5 ± 7.9 70 (77.8) 20 (22.2) total 150 (81.1) 35 (18.9) sd = standard deviation; gpm = general paediatric medicine; pod = prev ention of oral diseases. *statistically significant at p <0.001. †n = 95. ‡n = 90. evaluating the quality of multiple choice question in paediatric dentistry postgraduate examinations e138 | squ medical journal, may 2019, volume 19, issue 2 most mcqs (81.1%) required information recall (level one) while the remaining 18.9% required under standing and interpretation of data (level two). however, there was an absence of higher order thinking questions (level three) to test the application of knowledge. there was a significant difference in the mean dis of gpm and pod mcq items (89.1% ± 8.9% versus 76.5% ± 7.9%; p <0.001) [table 1]. the most common iwfs in the general paediatric medicine [figure 3] and the prevention of oral diseases [figure 4] examinations were as follows respectively: the use of “except” or “not” in the lead-in (17.7% and 13.3%), tricky or unfocussed stems (8.4% and 13.3%) and opportunities for the use of the convergence strategy (3.1% and 12.2%). discussion effective mcqs are considered one of the best assess ment tools available due to their validity, reliability, feasibility, educational impact and acceptability.15 how ever, constructing standard and high-quality peer reviewed mcq items requires training and practice.16 in the current study, the majority of questions (81.1%) tested recollection of isolated facts (level one) and the remainder (18.9%) tested comprehensive pooling of information (level two). none of the mcqs assessed the higher order cognition of applied practice and interpretation (level three). these findings were comparable with other studies which also found a focus on level one questions.17–20 baig et al. evaluated 150 undergraduate pharma cology examination mcqs and found that most quest ions were at cognitive level one (76%) followed by level two (24%), with no questions written at level three.17 tariq et al. found that the majority (60.47%) of the mcqs in an undergraduate pharmacology examination were at level one.18 tarrant and ware evaluated an undergraduate nursing mcq test and determined that >90% of the items were written at a lower cognition level.19 jozefowicz et al. studied the quality of mcqs in three american medical schools and reported an overall low quality of questions, most of which merely sought to assess students’ recollection of basic dental information.20 these studies and the high percentage of mcqs that tested low cognitive abilities in the present study could be attributed to the idea that mcqs were simpler to make, less time consuming and require less knowledge compared to higher order data synthesis items that demand expert input, time and training.7,9 in the current study, the low cognitive levels of the mcqs can be attributed to the collection of examination questions from a recently established dental college with a limited question bank, which were created by various recently appointed faculty with inadequate training in question-writing. the effect of the latter was apparent when comparing the iwfs in the pod with the gpm examination (62.2% versus 37.9%). the newly appointed faculty contributed to constructing mcqs only in the pod test. with proper training and adequate experience and resources, mcqs may be used to test students’ higher cognitive skills.21 for example, dellinges and curtis found that a one-hour mcq training workshop for 24 dental faculty was effective in improving the quality of in-house mcqs when comparing pre-training and post-training mcq-based scores in intervention and non-intervention groups.22 field et al.’s study showed that constructing more challenging mcqs figure 4: distribution of types of item writing flaws in the prevention of oral diseases examination in the academic year 2017–2018 at mohamed bin rashid university of medicine and health sciences, dubai, united arab emirates. mawlood kowash, iyad hussein and manal al halabi clinical and basic research | e139 involving problem-solving (level three) in clinical subjects was considered easier than basic science courses and was superior to other forms of questions.8 in a study examining 50 mcq items, khan and aljarallah reported that 60% of the items addressed the application of knowledge plane, 28% addressed recall of information (level one) but only 6% required interpretation of data (level two).23 in the present study, there were 92 iwfs (49.7%) in both postgraduate pd examinations. it is imperative to assess iwfs in mcqs because violations of accepted mcq item-writing guidelines may affect examinee performance by making the item either easier or more difficult to answer.24 downing evaluated the quality of mcq writing in four tests in the us and found that 46% of the items were classified as iwfs.24 as a result of the iwfs, 10–15% of examinees who were categorised as “failures” would have been categorised as “pass” if flawed questions were excluded.24 tarrant and ware studied the effect of iwfs on nursing examinees’ achievements and reported that iwfs were frequent in high-stakes nursing assessments.19 they did not penalise average examinees; however, high-performing examinees were probably more at risk than average students of being disadvantaged by iwfs.19 the amount of iwfs in the current study may be attributable to an inadequately sized mcq bank in this newly established college or inadequate formal question-writing training for the newly appointed faculty. therefore, it is imperative that test creators reduce iwfs as they negatively affect difficulty and discrimination indices and might lead to a failure in achieving course learning objectives.13,25 the results of the present study showed more iwfs in the pod than the gpm examination (62.2% versus 37.9%); however, this difference was not statistically significant (p = 0.105). the most common iwfs in gpm and pod were the use of “except” or “not” in the lead-in (17.7% and 13.3%), tricky or unfocussed stems (8.4% and 13.3%) and convergence strategy (3.1% and 12.2%), respectively. baig et al. reported a similar pattern of iwfs (46%) in their study; however, the four most frequent iwfs were the use of implausible distracters (30.43%), unfocused stems (27.54%), presenting unnecessary information in the stem (24.64%) or a negative stem (8.7%).17 downing also reported a comparable iwf proportion of 46%.24 khan and aljarallah reported a lower iwf proportion (12%) on a problem-based learning examination.23 in the present study, a higher proportion of iwfs can be interpreted in light of the tarrant and ware study. they stated that “mcqs written at lower cognitive levels are more likely to contain iwfs”.19 tariq et al. found fewer iwfs (28%) and also reported an incr eased proportion of level three questions in 150 pharmacology mcqs;18 baig et al.’s study of the same university determined 46% of the items had iwfs.17 the authors of the aforementioned studies attributed the improvement to the in-house faculty’s continuous medical education. a post-validation item analysis of mcq items should be conducted in order to evaluate correlations between item di, discrimination and distraction effec tiveness to determine whether questions should be reused, modified or discarded.13 the present study eval uated a fairly large sample of mcq items (n = 185) but in a small sample of postgraduate students; therefore, only the di was analysed. the mean di of the pod and gpm (76.5% ± 7.9% and 89.1% ± 8.9%) indicated that the mcq items were easy (prop value >70%), especially in the gpm examination.13,14 in comparison, mukherjee and lahiri reported a better di mean prop value of 61.92% ± 25.1% in medical undergraduates.26 moreover, mehta and mokhasi reported various di scores of which 62% of items were in an acceptable range (prop value 30–70%); 32% were too easy (prop value >70%) and 6% were too difficult (prop value >0.35).27 difficulty and discrimination indices are usually reciprocally related, but their relationship is often considered dome shaped and non-linear.28 this finding suggests that questions with a high di value discriminate poorly and vice-versa, except where the di is either extremely high or low. one possible explanation for the high di in the current sample is that the group consisted of only seven postgraduate residents with a high level of interest in the specialty and the examined topics. in the current study, most mcq items (81%) required knowledge recall (level one). eliminating iwfs and using an examination template can improve cognition levels of mcq test items.25 tarrant et al. challenged this idea and highlighted their belief that mcqs with iwfs were unlikely to alter question cognition.29 cons tructing mcq items at higher cognition planes sub sequently lead to the elimination of iwfs.29 in general, the quality of mcq item writing in the two studied postgraduate pd examinations were comparable to the literature. as a result of this study, standardised question setting workshops were conducted. all future mcq examinations will be subject to rigorous peer review, potentially improving the quality of mcqs by reducing/eliminating iwfs and constr ucting high cognitive level items with average diffi culty and high discrimination. open formal reflection, feedback and training regarding iwfs and mcq analysis with faculty as well as students would help improve evaluating the quality of multiple choice question in paediatric dentistry postgraduate examinations e140 | squ medical journal, may 2019, volume 19, issue 2 learning outcomes. periodic post-examination review of mcq items available in the question bank would identify areas of potential weakness, thus helping to create an ideal item bank. conclusions the most common iwfs in this study were the use of “except” or “not” in the lead-in, tricky or unfocussed stems and opportunities for students to use convergence strategy. most mcqs were level one information recall items. a comprehensive review of the mcq questions for all examinations in the program is needed with emphasis on avoiding iwfs. as a result of this study, a faculty development programme was recommended to improve the faculty’s question writing skills and align examination questions with programme learning outcomes and enhance the ability of the questions to measure the competency of the students through questions that elicit higher order thinking. a c k n o w l e d g e m e n t s the authors would like to thank amar hassan, professor of biostatistics at mohamed bin rashid university of medicine and health sciences, dubai for his help in data analysis. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. drew s. perceptions of what helps learn and develop in education. teaching high educ 2001; 6:309–31. https://doi.org/10.1080/1356 2510120061197. 2. scouller k. the influence of assessment method on students’ learning approaches: multiple-choice question examination versus assignment essay. high educ 1998; 35:453–72. https://doi.org/10.10 23/a:1003196224280. 3. trigwell k, prosser m. improving the quality of student learning: the influence of learning context and student approaches to learning on learning outcomes. high educ 1991; 22:251–66. https://doi.org/10.1 007/bf00132290. 4. biggs j, tang c. teaching for quality learning at university. 4th ed. philadelphia, usa: open university press, 2011. p. 103. 5. reid wa, duvall e, evans p. relationship between assessment res ults and approaches to learning and studying in year two medical students. med educ 2007; 41:754–62. https://doi.org/10.1111/j.136 5-2923.2007.02801.x. 6. abdel-hameed aa, al-faris ea, alorainy ia, al-rukban mo. the criteria and analysis of good multiple choice questions in a health professional setting. saudi med j 2005; 26:1505–10. 7. case s, swanson d. constructing written test questions for the basic and clinical sciences. 3rd ed. philadelphia, usa: national board of medical examiners, 2003. p. 31. 8. field jc, walmsley ad, paganelli c, mcloughlin j, szep s, kavadella a, et al. the graduating european dentist: contemporaneous methods of teaching, learning and assessment in dental undergraduate educ ation. eur j dent educ 2017; 21:28–35. https://doi.org/10.1111/eje.1 2312. 9. tarrant m, ware j. a framework for improving the quality of multiple-choice assessments. nurse educ 2012; 37:98–104. https://doi.org/10.1097/nne.0b013e31825041d0. 10. buckwalter ja, schumacher r, albright jp, cooper rr. use of an educational taxonomy for evaluation of cognitive performance. j med educ 1981; 56:115–21. https://doi.org/10.1097/00001888-198 102000-00006. 11. huitt w. bloom et al.'s taxonomy of the cognitive domain. from: www.edpsycinteractive.org/topics/cognition/bloom.pdf accessed: dec 2018. 12. haladyna tm, downing sm, rodriguez mc. a review of multiplechoice item-writing guidelines for classroom assessment. appl measurement educ 2002; 15:309–33. https://doi.org/10.1207/s1 5324818ame1503_5. 13. sim sm, rasiah ri. relationship between item difficulty and discrimination indices in true/false-type multiple choice questions of a para-clinical multidisciplinary paper. ann acad med singa pore 2006; 35:67–71. 14. kheyami d, jaradat a, al-shibani t, ali fa. item analysis of multiple choice questions at the department of paediatrics, arabian gulf university, manama, bahrain. sultan qaboos univ med j 2018; 18:e68–74. https://doi.org/10.18295/squmj.2018.18.01.011. 15. dascalu cg, enache am, mavru rb, zegan g. computer based mcq assessment for students in dental medicine–adv antages and drawbacks. procedia soc behav sci 2015; 187:22–7. https://doi.org/10.1016/j.sbspro.2015.03.005. 16. botelho mg, lam o, watt rm, leung d, kember d. evaluation of peer-generated mcqs to assess and support learning in a problem-based learning programme. eur j dent educ 2018; 22:e358–63. https://doi.org/10.1111/eje.12304. 17. baig m, ali sk, ali s, huda h. evaluation of multiple choice and short essay question items in basic medical sciences. pak j med sci 2014; 30:3–6. https://doi.org/10.12669/pjms.301.4458. 18. tariq s, tariq s, maqsood s, jawed s, baig m. evaluation of cognitive levels and item writing flaws in medical pharmacology internal assessment examinations. pak j med sci. 2017; 33:866–70. https://doi.org/10.12669/pjms.334.12887. 19. tarrant m, ware j. impact of item-writing flaws in multiplechoice questions on student achievement in high-stakes nursing assessments. med educ 2008; 42:198–206. https://doi.org/10.111 1/j.1365-2923.2007.02957.x. 20. jozefowicz rf, koeppen bm, case s, galbraith r, swanson d, glew rh. the quality of in-house medical school examinations. acad med 2002; 77:156–61. https://doi.org/10.1097/00001888-20 0202000-00016. 21. palmer ej, devitt pg. assessment of higher order cognitive skills in undergraduate education: modified essay or multiple choice quest ions? research paper. bmc med educ 2007; 7:49. https://doi.org/10.1 186/1472-6920-7-49. 22. dellinges ma, curtis da. will a short training session improve multiple-choice item-writing quality by dental school faculty? a pilot study. j dent educ 2017; 81:948–55. https://doi.org/10.21815/ jde.017.047. 23. khan mu, aljarallah bm. evaluation of modified essay questions (meq) and multiple choice questions (mcq) as a tool for assessing the cognitive skills of undergraduate medical students. int j health sci (qassim) 2011; 5:39–43. https://doi.org/10.1080/13562510120061197 https://doi.org/10.1080/13562510120061197 https://doi.org/10.1023/a:1003196224280 https://doi.org/10.1023/a:1003196224280 https://doi.org/10.1007/bf00132290 https://doi.org/10.1007/bf00132290 https://doi.org/10.1111/j.1365-2923.2007.02801.x https://doi.org/10.1111/j.1365-2923.2007.02801.x https://doi.org/10.1111/eje.12312 https://doi.org/10.1111/eje.12312 https://doi.org/10.1097/nne.0b013e31825041d0 https://doi.org/10.1097/00001888-198102000-00006 https://doi.org/10.1097/00001888-198102000-00006 https://doi.org/10.1207/s15324818ame1503_5 https://doi.org/10.1207/s15324818ame1503_5 https://doi.org/10.18295/squmj.2018.18.01.011 https://doi.org/10.1016/j.sbspro.2015.03.005 https://doi.org/10.1111/eje.12304 https://doi.org/10.12669/pjms.301.4458 https://doi.org/10.12669/pjms.334.12887 https://doi.org/10.1111/j.1365-2923.2007.02957.x https://doi.org/10.1111/j.1365-2923.2007.02957.x https://doi.org/10.1097/00001888-200202000-00016 https://doi.org/10.1097/00001888-200202000-00016 https://doi.org/10.1186/1472-6920-7-49 https://doi.org/10.1186/1472-6920-7-49 https://doi.org/10.21815/jde.017.047 https://doi.org/10.21815/jde.017.047 mawlood kowash, iyad hussein and manal al halabi clinical and basic research | e141 24. downing sm. the effects of violating standard item writing principles on tests and students: the consequences of using flawed test items on achievement examinations in medical education. adv health sci educ theory pract 2005; 10:133–43. https://doi. org/10.1007/s10459-004-4019-5. 25. downing sm. twelve steps for effective test development. in: downing sm, haladyna tm, eds. handbook of test development. mahwah, new jersey, usa: lawrence erlbaum associates, inc., 2006. pp. 3–25. 26. mukherjee p, lahiri sk. analysis of multiple choice questions (mcqs): item and test statistics from an assessment in a medical college of kolkata, west bengal. iosr j dental med sci 2015; 14:47–52. https://doi.org/10.9790/0853-141264752. 27. mehta g, mokhasi v. item analysis of multiple choice questions an assessment of the assessment tool. int j health sci res 2014; 4:197–202. 28. menon ar, kannambra pn. item analysis to identify quality multiple choice questions. nat j lab med 2017; 6:mo07–10. https://doi.org/10.7860/njlm/2017/25690:2215. 29. tarrant m, knierim a, hayes sk, ware j. the frequency of item writing flaws in multiple-choice questions used in high stakes nursing assessments. nurse educ today 2006; 26:662–71. https://doi.org/10.1016/j.nedt.2006.07.006. https://doi.org/10.1007/s10459-004-4019-5 https://doi.org/10.1007/s10459-004-4019-5 https://doi.org/10.9790/0853-141264752 https://doi.org/10.7860/njlm/2017/25690:2215 https://doi.org/10.1016/j.nedt.2006.07.006 dengue virus is a mosquito-borne flavivirus and the most prevalent arbovirus in tropical and subtropical regions of the world.1 the 2005 world health assembly resolution wha58.3 on the revision of the international health regulations (ihr) has included dengue as an example of a disease that may constitute a public health emergency of international concern with implications for health security due to disruption and rapid epidemic spread beyond national borders.2 acute abdomen is an uncommon presentation of dengue haemorrhagic fever (dhf). it is important to take dhf into consideration when making a differential diagnosis for patients with acute abdomen, a history of travel to dengue endemic areas and thrombocytopenia. reaching the right diagnosis may help in preventing unnecessary surgical interventions for patients with dhf. case report a 38 year-old sri lankan lady presented with a threeday history of fever associated with abdominal pain, vomiting and diarrhoea. she also gave a history of headache. these symptoms had started on the day she arrived in oman from sri lanka. she denied any history of skin rashes, urinary symptoms or contact with sick people. she had been working in oman for the previous four years and had visited her home country, sri lanka, for four weeks coming back to oman three days prior to admission to hospital. clinical examination showed a sick looking and mildly dehydrated woman. there was no evidence of jaundice, lymphadenopathy or skin rash. she was febrile and hypotensive, but she was not tachypneic or tachycardic. an abdominal examination revealed a generalised abdominal tenderness mainly in the right hypochondrium, but there was no guarding or rigidity. other systemic examinations were unremarkable. initial investigations showed haemoglobin of 14.2 g/dl; haematocrit count of squ med j, may 2011, vol. 11, iss. 2, pp. 265-268, epub. 15th may 11 submitted 18th sept 10 revision req. 11th oct 10, revision recd. 31st oct 10 accepted 24th nov 10 departments of 1microbiology and 2medicine, royal hospital, muscat, oman. *corresponding author email: salabri@gmail.com ïå^£]<‡�f÷]<ö]ü¬`e<ü„øi<ìè àfl÷]<‘flñ÷]<ó∑   38  901 x 22    :مفتاح الكلمات abstract: we describe a case of a 38 year-old sri lankan female who was referred to the surgeon on call with a picture of acute abdomen. she presented with a three-day history of fever, headache, abdominal pain and diarrhoea; however, the physical examination was not consistent with acute abdomen. her platelet count was 22 x109/l. a diagnosis of dengue haemorrhagic fever (dhf) was made and dengue serology was positive. dengue epidemics have been associated with a variety of gastrointestinal symptoms and signs, including acute abdomen. acute abdomen in patients with dhf makes the diagnosis and management challenging. keywords: dengue; haemorrhagic fever; acute abdomen; case report; oman dengue haemorrhagic fever presenting as acute abdomen hanaa al-araimi,1 amal al-jabri,1 arshad mehmoud,2 *seif al-abri2 case report dengue haemorrhagic fever presenting as acute abdomen 266 | squ medical journal, may 2011, volume 11, issue 2 39.9 %; platelet count 22 x109/l; white blood cell count 11.5 x109/l with neutrophils of 2.4 x109/l and lymphocytes of 4.8 x109/l; mildly raised alanine transaminase (alt) of 86 iu/i, and alkaline phosphatase of 184 iu/l. urea and electrolytes, coagulation profile and amylase were normal. an abdominal ultrasonography showed free fluid in the abdomen with a slightly thickened gall bladder wall, but no evidence of gall bladder calculi. the patient was referred to the surgical team with an initial diagnosis of acute cholecystitis. she was kept nil by mouth and was started on intravenous fluids and ceftriaxone injections. on the second day of admission, the patient continued to have severe abdominal pain and a clinically detected guarding abdomen. an urgent computed tomography (ct) scan of the chest and abdomen with oral and intravenous contrast was done. it showed bilateral pleural effusion with right lower lobe collapse and segmental atelectasis, and abdominal and pelvic ascites, but the gall bladder was normal. in view of the ct findings, acute cholecystitis was ruled out and an alternative diagnosis was considered. malaria screening was negative. the blood film revealed very mild leukocytosis with reactive lymphocytes and a mild neutrophil left shift; the platelets were markedly reduced and showed occasional large forms. the features of the blood film were compatible with a viral infection; in view of the recent travel history to a dengue endemic country, dengue haemorrhagic fever (dhf) was suspected. the patient was managed conservatively and made a remarkable improvement clinically with a gradual increase in the platelet count. she was sent home on the fifth day after her admission, symptom free and with a platelet count of 224x109/l. dengue serology was done on admission and was immunoglobulin m (igm) positive; it was repeated two months later and the result was equivocal. polymerase chain reaction (pcr) for dengue virus was requested on admission, but it was not done due to technical reasons in the laboratory. it was, however, done with the repeated serology two months after the initial presentation and was negative. discussion dengue virus infection is the most common cause of arboviral disease in the world. the estimated annual occurrence of dengue fever is 100 million cases of dengue fever with 250,000 cases of dhf, and a mortality rate of 25,000 per year.1 in the last 50 years, the incidence has increased 30fold with geographic expansion to new countries and, in the present decade, from urban to rural settings.3 dengue is endemic in most tropical and subtropical parts of the world. some 1.8 billion (more than 70%) of the populations at risk for dengue worldwide live in member states of the world health organization’s (who) south-east asia and western pacific regions which bear nearly 75% of the current global disease burden due to dengue.2 dengue is transmitted by the mosquito vectors aedes aegypti and aedes albopictus. dengue infection is caused by any of 4 different serotypes of the virus (den-1, den-2, den-3, and den-4). the incubation period is 4–7 days after an infective mosquito bite.4 the recent emergence of dhf in the indian subcontinent has been well documented in sri lanka. the four dengue virus (denv) serotypes have been co-circulating in sri lanka for >30 years. over this period, a new genotype of denv-1 has replaced the old genotype. moreover, new clades of denv-3 genotype iii viruses have replaced older clades. the emergence of new clades of denv-3 in 1989 and 2000 coincided with abrupt increases in the number of reported dengue cases, implicating this serotype in severe epidemics. from 1980 to 1997, most reported dengue cases were in children. recent epidemics have been characterised by many cases in both adults and children. changes in local transmission dynamics and genetic changes in denv-3 are probably responsible for the increasing emergence of severe dengue epidemics in sri lanka.5 there is no published data on dengue fever from oman apart from one case report.6 the clinical manifestations of dengue range from asymptomatic infection, self-limited dengue fever to dhf with shock syndrome. the risk of severe disease is much higher in sequential rather than primary dengue infection.7 the most common symptoms of dengue virus infection are fever, headache, retro-orbital pain, photophobia, backache, severe myalgia and arthralgias. other signs and symptoms include generalised maculopapular rash, lymphadenopathy, positive tourniquet test, petechiae and other haemorrhagic manifestations. the who has set criteria for hanaa al-araimi, amal al-jabri, arshad mehmoud and seif al-abri case report | 267 diagnosing dengue (with or without warning signs) and severe dengue depending on clinical signs and symptoms and laboratory investigations. the criteria for diagnosing probable dengue fever are living in or travel to a dengue endemic area, fever and two of the following criteria: nausea, vomiting, rash, aches, a positive tourniquet test, leukopenia and any warning sign. the warning signs are abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, liver enlargement of >2cm and increase in haematocrit concurrent with a rapid decrease in platelet count. the diagnosis of severe dengue was defined by the who as severe plasma leakage leading to dengue shock syndrome (dss); fluid accumulation with respiratory distress; severe bleeding as evaluated by the clinician, and severe organ involvement (acute liver failure, acute renal failure, encephalopathy, cardiomyopathy), or other unusual manifestations.3 about one-third of patients develop one or more complications that include bleeding, seizures, acute renal failure, and dss. there have been reports of other uncommon clinical complications such as acute hepatitis and hepatic failure,8 unusual neurologic manifestations,9 and acute myocarditis.10 there also have been reports of cases resembling surgical emergencies like acute pancreatitis, acute acalculous cholecystitis,11 acute appendicitis12 and non-specific peritonitis. a retrospective study of patients with dhf and acute abdomen in a dengue epidemic area in southern taiwan found that, of 328 patients with dhf/dss, 14 had acute abdomen. dhf/dss was initially suspected in only 2 of these 14 patients. presumptive diagnoses of acute cholecystitis (6 acalculus and 4 calculus cholecystitis) were made in 10 patients, non-specific peritonitis in three patients, and acute appendicitis in one patient. cholecystectomy, percutaneous transhepatic gall bladder drainage, and appendectomy were performed in three patients. in addition to acute abdomen, these patients had a variety of symptoms and signs such as fever, chills, myalgia, headache, rashes, and petechiae, which were similar to those found in patients with dhf without acute abdomen.4 however, the predominant acute abdomen in these patients was the overwhelming concern and distracted clinicians from the typical clinical manifestations of dengue illness that should have been noticed.13 the treatment of dhf is mainly supportive care. in 2005, wills et al. investigated fluid treatment for vietnamese children with dss.14 with the use of simple clinical monitoring tools, these authors have shown that the administration of ringer’s lactate leads to the same outcome among children with moderate shock as does the administration of colloids.14 guidelines for intravenous fluid therapy of dhf have been developed by the who. for patients with shock, an initial bolus of 5% dextrose in normal saline or ringer's lactate (10 to 20 ml per kg of body weight) infused rapidly is recommended, followed by continuous infusion (10 to 20 ml/ kg per hour) until vital signs and urine output normalise. the infusion rate can then be gradually reduced until it matches plasma fluid losses.3 the symptoms and signs of our patient were mostly similar to those that have been previously described for dengue fever. also the presence of thrombocytopenia, mild derangement of liver enzymes, evidence of plasma leakage (pleural effusion, ascites, hypoalbuminemia and raised haematocrit) and positive igm serology for dengue all supported the diagnosis of dhf. however, the whole clinical picture was masked by acute severe abdominal pain and tenderness. the diagnosis was not made until the patient was referred to the infectious diseases team. this case underlines the need for medical staff to be aware of travel and tropical medicine including geographical epidemiology. conclusion acute abdomen is an uncommon presentation of dhf. it is important to take dengue fever into consideration when making a differential diagnosis on acute abdomen for patients returning from dengue endemic regions. it may help in preventing unnecessary surgical intervention in dhf patients. it is also important for medical personnel to be aware of the epidemiology of tropical diseases. references 1. wilder-smith a, schwartz e. dengue in travelers: n engl j med 2005; 353:924−32. 2. world health organization. revision of the international health regulations. world health dengue haemorrhagic fever presenting as acute abdomen 268 | squ medical journal, may 2011, volume 11, issue 2 assembly resolution wha58.3. geneva: world health organization, 2005. 3. world health organization. dengue guidelines for diagnosis, treatment, prevention and control. geneva: world health organization, 2009. 4. jelinek t. dengue fever in international travelers. clin infect dis 2000; 31:144−7. 5. kanakaratne n, wahala wm, messer wb, tissera ha, shahani a, nihal abeysinghe n, et al. severe dengue epidemics in sri lanka, 2003–2006. emerg infect dis 2009; 15:192−9. 6. mohamed e, mohsin n, al-abri s, obaidani i, jha a, kamble p, et al. acute renal failure in a patient with both dengue fever and leptospirosis. oman med j 2008; 23:101−3. 7. halstead sb. immunological parameters of togavirus disease syndromes. in: schlesinger rw, ed. the togaviruses: biology, structure, replication. new york: academic press, 1980. pp.107−73. 8. mourão mp, de lacerda mv, bastos m, albuquerque bc, alecrim wd. dengue hemorrhagic fever and acute hepatitis: a case report. braz j infect dis 2004; 8:461−4. 9. patey o, ollivaud l, breuil j, lafaix c. unusual neurologic manifestations occurring during dengue fever infection. am j trop med hyg 1993; 48:793−802. 10. salgado dm, eltit jm, mansfield k, panqueba c, castro d, vega mr, et al. heart and skeletal muscle are targets of dengue virus infection. pediatr infect dis j 2009; 28:1140−6. 11. wu kl, changchien cs, moukuo c, chuah sk. dengue fever with acute acalculous. am j trop med hyg 2003; 68: 657−60. 12. kang j, yoon sy. dengue fever mimicking acute appendicitis: a case report. j infect chemother 1993; 41:793−802. 13. khor bs, weiliu j, kitlee i, yang k. dengue hemorrhagic fever patients with acute abdomen: clinical experience of 14 cases. am j trop med hyg 2006; 74:901−4. 14. wills ba, nguyen md, ha tl, dong th, tran tn, le tt, et al. comparison of three fluid solutions for resuscitation in dengue shock syndrome. n engl j med 2005; 353:877−89. optimising wound closure following a fasciotomy a narrative review *mohammed k. alkhalifah and fareed s. h. almutairi sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e192–200, epub. 5 nov 19 submitted 22 nov 18 revisions req. 15 jan & 10 mar 19; revisions recd. 11 feb & 22 mar 19 accepted 15 apr 19 department of surgery, qassim university, qassim, saudi arabia *corresponding author’s e-mail: hamo0ody1333@gmail.com compartment syndrome (cs) is a surgical emergency condition that requires a timely diagnosis to preclude a potentially devastating outcome. it involves an increase in the intracompart mental pressure (icp) due to an imbalance in homeo stasis among the arterial flow, venous pressure and icp.1 cs is caused by vascular obstruction, fracture, injuries (e.g. crush or electrical injuries), excessive use of muscles and/or iatrogenic factors. the affected compartments may involve any muscle surrounded by fascia and are not limited to the axial skeleton; however, it mostly affects the compartments of the legs and, to a lesser extent, the compartments of the shoulders, arms, forearms, hands, thighs and buttocks.2 soft tissue necrosis and permanent disability may occur due to improper management. the gold standard for cs treatment includes a fasciotomy by performing an incision through the skin, fat and muscular fascia in order to reveal the underlying compartment and reduce the established pressure. however, approximately 4–38% of the managed patients will develop unfavourable complications. in addition, failure of early identification of these complications has been associated with a two-fold increase in amputation rates and a four-fold increase in the risk of mortality.3,4 furthermore, 77% and 26% of patients can experience paraesthesia and tethered scars, respectively, which would lead to a significant reduction in quality of life.5,6 therefore, despite the importance of reducing pressure in the muscular compartments, surgical treatment of cs should only be performed after careful consideration of the post operative aspects, such as pressure threshold and the degree of suspicion. however, early management of review توخي اإلغالق األمثل للجرح بعد َبْضع اللفافة مراجعة سرديه حممد خليفة �خلليفة و فريد �صعيد هليل �ملطريي abstract: compartment syndrome is a surgical emergency that could be resolved by a fasciotomy. however, performing substantial skin incisions may lead to life-threatening complications. this narrative review aimed to present the available methods of wound closure and preferential factors for using each technique. viable and noninfected wounds were most often treated by gradual approximation techniques, such as the simple or modified shoelace technique, the prepositioned intracutaneous suture or several commercially-available mechanical devices. in addition, applying negative pressure therapy was found to be feasible, particularly when combined with approx imation techniques. skin grafting was reserved for severely-dehiscent wounds while other non-invasive approaches were considered for other subsets of patients with inadvisable surgical interventions. treatment decision should be made in view of the patient’s condition, ease of application, availability of resources, cost of treatment and aesthetic outcomes. keywords: compartment syndrome; fasciotomy; wound closure techniques; negative-pressure wound therapy. ع �للفافة. غري �أن عمل �ُصقوق كبرية يف �جللد قد يف�صي امللخ�ص: ُمَتاَلِزَمُة �حَليِِّز هي حالة جر�حية طارئة ميكن عالجها عن طريق َب�صْ مل�صاعفات تهدد �حلياة باخلطر. و�لهدف من هذه املراجعة الرسدية هو عر�س �لطرق �ملتوفرة الإغالق �جلرح وعو�مل تف�صيل كل طريقة من تلك �لطرق. وعادة ما تعالج �جلروح �لَعُيو�س وغري �مل�صابة بالعدوى بطرق �ملقاربة �لتدريجية، مثل طريقة رباط �حلذ�ء �لب�صيطة �أو �ملعدلة، �أو طريقة �خلياطة د�خل �جللد �ملعمولة ب�صكل م�صبق، �أو با�صتخد�م �لعديد من �الأدو�ت �مليكانيكية �ملتوفرة جتاريا. وباالإ�صافة لذلك، ُوجد �أنه ميكن تطبيق �لعالج عن طريق �ل�صغط �ل�صلبي، خا�صة عندما يتالزم مع طرق �ملقاربة. �أما �لتطعيم �جللدي فهو مق�صور على حاالت �لتفرز �لوخيم للجروح. وقد يلجاأ لو�صائل غري با�صعة عند �ملر�صى �لذين ال ين�صح بالتدخل �جلر�حي يف حاالتهم. ينبغي �أن يوؤخذ قر�ر نوعية �لعالج بناًء على حالة �ملري�س، و�صهولة �لتطبيق، وتوفر �ملو�رد، وتكلفة �لعالج، و�لنتائج �لَتْجِمْيِلّية. ع �للفافة؛ طرق �إغالق �جلرح؛ عالج �جلرح بال�صغط �ل�صلبي. الكلمات املفتاحية: متالزمة �حليز؛ َب�صْ this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.004 https://creativecommons.org/licenses/by-nd/4.0/ mohammed k. alkhalifah and fareed s. h. almutairi review | e193 fasciotomy wounds is generally not recommended due to potential tissue oedema that may lead to necrosis, infection or recurrence of cs. this may eventually compromise the associated vascular pathology and/ or fracture. hence, fasciotomy performed for both therapeutic and prophylactic purposes should be managed as an open wound during the first 2–3 days followed by a primary closure of the wound.7 all wound closure techniques exploit the inherent viscoelastic and biomechanical properties of the skin.8 a successful wound closure is defined as closure without the need for skin grafting, amputation or death,4 for which there are numerous methods with various outcomes and can represent a challenge in terms of both timing and safety. this narrative review aimed to provide insights into the current techniques and their preferential application in selected groups of patients. the indications, complications, advantages and disadvantages of each procedure have been emphasised to ascertain the best approach to optimise wound closure. skin grafting in patient who underwent fasciotomies, skin grafting has been used for some time due to its safety, low cost and convenient dressing procedures compared to other delayed primary closure techniques.9 splitthickness skin grafting (stsg) is the treatment of choice for early coverage of fasciotomy wounds with persistent oedema and skin retraction. in a recent retrospective cohort study in the usa, stsg was the main surgical indication (40% of patients) for wounds for which primary closure was not possible due to swelling, whereas delayed primary closure techniques were utilised in only 18% of patients.9 stsg was performed if the patient had either remarkable swelling of the lower extremity or open fractures and was more frequently performed on patients with proximal or tibial plateau fractures than patients with midshaft or distal fractures. this technique resulted in a significant reduction in the length of hospital stay (los) compared to other techniques.10 in contrast, a larger retrospective study in the usa found that stsg procedures were associated with longer los compared to either vacuum dressing or dynamic tension-based techniques.11 in general, when applying tension via delayed primary closure is not possible, stsg may be the only available option for managing persistently dehiscent wounds, burns and wounds with a poor and friable edge.7,12 although the cost of stsg procedures increases due to long operative times and supplies required for grafting, this technique may be cost-effective due to shorter los and less frequent additional procedures compared to primary closure techniques. however, the stsg technique does have some limitations. patients might experience pain at the donor site wound with noticeable scarring; this may increase the patient’s morbidity and reduce mobilisation. scarring can also occupy a wide area over the fasciotomy site and could affect the muscular function in the compartment. furthermore, stsg procedures may be associated with cosmetic issues, adhesions between the muscles and tendons and reduced skin sensitivity [table 1].13 negative-pressure therapy since its introduction and development in the late 1990s, vacuum-assisted closure (vac) has been used in order to close a wide variety of wound types and has contributed significantly to the improvement of healing and reduced requirements for reconstructive procedures.14 vac induces tissue microstrain that enhances wound healing by improving angiogenesis and cell division, discards the bacteria-rich exudate from wound edges and removes oedema from the extracellular matrix thereby improving the local blood flow and reducing proinflammatory cytokines.14,15 as a result, healing of the marginalised tissue would be improved and progressive tissue necrosis may be reduced, which is of particular importance in reversing the cs-induced pathological changes. furthermore, vac dressings may have an advantageous role in bridging soft tissues following severe trauma associated with marked tissue loss.16 with this technique, flap coverage may be omitted entirely in selected patients.17 for the management of fasciotomy wounds, vac provides a powerful adjunct to surgical management or it can be utilised on its own. it decreases wound closure time, facilitates wound healing, reduces the time needed for a skin graft and increases the number of patients who can be good candidates for a feasible primary closure.16 in open fasciotomy wounds, vac dressings should be changed every 2–3 days either at bedside or in the operating room for large-sized wounds for better wound visualisation, irrigation and to ultimately maximise the chances of achieving staged primary closure or decreasing the size of skin grafts. yang et al. reviewed the records of 34 vacmanaged patients following leg fasciotomy procedures and found that the average time required for wound closure decreased significantly compared to matched controls (6.7 versus 16.1 days).18 weiland used hyperbaric oxygen in conjunction with vac in order to enhance the reduction of oedema and found that wound closure ranged from 3–18 days in three patients.19 optimising wound closure following a fasciotomy a narrative review e194 | squ medical journal, august 2019, volume 19, issue 3 table 1: summary of studies investigating skin-grafting and dermal approximation techniques for primary wound closure after fasciotomy author and year of study location of study study design indication for fasciotomy type of treatment and sample size material used mean time to primary wound closure in days ± sd type of complication vac technique bussell et al.27 (2018) switzerland retrospective ischaemia, fractures and systemic diseases • vac (n = 19) • temporary synthetic skin replacement (n = 9) • epigard® (biovision gmbh, ilmenau, germany) 9.37 ± 4.67 4.89 ± 2.32 • stsg (n = 1) and wi (n = 1) • none krticka et al.23 (2018) czech republic retrospective fracture • vac (n = 42) • control (n = 21) • sf = 125 mmhg • combined dressing fabric 11 17 • stsg (n = 7), wi (n = 4), osteomyelitis (n = 2) and muscle necrosis (n = 3) • stsg (n = 10), wi (n = 7), osteomyelitis (n = 3) and muscle necrosis (n = 9) lee20 (2016) usa case series complicated wounds • vac (n = 2) • vac with instillation and dwell dime (sf = 125 mmhg) • none saziye et al.17 (2011) switzerland retrospective iri • vac (n = 7) • conservative dressing (n = 8) • sf = 75–125 mmhg • gauze dressings 11 ± 8–13 15 ± 12-20 • stsg (n = 2) • wi (n = 3) weaver et al.10 (2015) usa retrospective fractures and soft tissue injuries • vac (n = 22) • stsg (n = 82) 14.7 12.2 • no information available • no information available zannis et al.16 (2009) usa retrospective fractures and soft tissue injuries • vac (n = 68) • wet-to-dry dressings (n = 74) • sf = 125 mmhg • normal salinesoaked dressings 7.1 9.6 • stsg (n = 29) • stsg (n = 35) shoelace technique branco et al.31 (2016) brazil case report open fracture n = 1 • elastic suture system 7 • none erdös et al.37 (2011) austria case series cs due to fractures and contusion of soft tissues n = 24 • elastic vessel loop with stables and vac 11.9 • stsg (n = 3) lee et al.21 (2014) south korea case series necrotising fasciitis n = 8 • elastic vessel loop with stables and vac 16 • stsg (n = 2) matt et al.11 (2011) usa retrospective fractures and soft tissue injuries n = 24 • elastic vessel loop with stables and vac 16 • stsg (n = 4) and wi (n = 2) murakami et al.36 (2014) japan case report soft tissue injury n = 1 • elastic vessel loop with stables and vac 7 • none saini et al.30 (2018) india prospective fractures and soft tissue injuries n = 19 • silk sutures 8.31 • wi (n = 1) sawant and hallet34 (2001) uk technique description • elastic vessel loop with stables • no information available zorrilla et al.54 (2005) spain retrospective fractures and soft tissue injuries n = 20 • elastic vessel loop with stables 8.8 • none shoelace versus vac technique fowler et al.25 (2012) usa case series fractures and soft tissue injuries • shoelace (n = 49) • vac (n = 7) • elastic vessel loop with stables • vac device (kinetic concepts, inc., san antonio, texas, usa) 19.2 23.7 • stsg (n = 9) and wi (n = 3) • stsg (n = 4) and wi (n = 2) johnson et al.28 (2018) usa rct traumatic injuries • shoelace (n = 5) • vac (n = 9) • elastic vessel loop with stables 7.6 12.9 • no information available • no information available sd = standard deviation; vac = vacuum-assisted closure; stsg = spilt-thickness skin grafting; wi = wound infection; sf = suction force; iri = ischaemia-reperfusion injury; cs = compart ment syndrome; rct = randomised controlled trial. mohammed k. alkhalifah and fareed s. h. almutairi review | e195 another modification of the technique was presented by lee, who used negative-pressure wound therapy with automated wound solutions instillation and dwell time.20 lee found that such a therapy promoted granul ation tissue formation over the bone in a critically-ill and malnourished patient. lee et al. recommended the use of an extended vac therapy for large open fasciotomy wounds in eight patients with necrotising fasciitis, as it led to a significant reduction of wound area compared to the initial presentation without apparent complications.21 kakagia suggested that low suction pressure should be applied to a maximum of 100 mmhg, along with another wound approximation technique in order to avoid wound tissue rigidity owing to overgranulation and the resultant limitation of wound approximation.22 however, the effect of a single vac application may be comparable only to the effect of dressings but not to other wound approximation techniques. compared to traditional dressings, vac therapy has led to a significant acceleration of wound healing and closure in addition to less time required for skin grafting.23 nonetheless, there may be a need for additional stsg in a considerable number of patients, ranging between 20–57%, which increases the overall treatment duration and cost.16,17 in a prospective study, vac therapy was associated with longer treatment durations and an increased demand for stsg with higher costs compared to the shoelace technique.24 in a descriptive case series, fowler et al. found that four out of seven patients who underwent vac-assisted closure required skin grafting; this proportion was significantly higher than in patients managed by vessel loop closure (odds ratio: 5.9, 95% confidence interval: 1.11–31.24; p = 0.04).25 delayed epithelialisation, another vac-related issue, may become evident due to excessive granulation tissue formation that may grow into the dressings, exposing the wound to inflammation and infection.24,26 in a recent retrospective study in children who underwent a lower extremity fasciotomy, vac treatment was compared with a temporary synthetic skin replacement therapy and was associated with longer times to wound closure (9.4 versus 4.9 days) and more prolonged los (16.2 versus 9.9 days).27 vac-assisted wound closure was also prolonged compared to wounds closed by the shoelace technique, as demonstrated in multiple studies [table 1].24,25,28 dermal apposition techniques several techniques have been described for gradual approximation of wound edges. these techniques are frequently performed, such as daily bedside suture tightening, which leads to a gradual increase in skin length and reduction in the force required to maintain that length. therefore, primary wound closure is possible and can be achieved after 7–15 days.24 gradual approx imation can be achieved by multiple techniques such as using sutures, static tension devices and mechanical devices. table 1 (contd.): summary of studies investigating skin-grafting and dermal approximation techniques for primary wound closure after fasciotomy kakagia et al.24 (2014) greece rct fractures and soft tissue injuries in the leg • shoelace (n = 25) • vac (n = 25) • silastic vessel loop with stables • sf = 125 mmhg 15.1 ± 3.8 19.1 ± 6.1 • wi (n = 4) • stsg (n = 6) and wi (n = 6) suture technique chiverton and redden40 (2000) uk case series fracture of the lower limb n = 6 • prepositioned intracutaneous suture • broken suture (n = 1) dahners55 (2003) usa technique description • running nearnear-far-far suture • none janzing and broos39 (2001) belgium case series n = 5 • prepositioned intracutaneous suture 9 ± 3.5 • second operation (n = 2). traction under anaesthesia because of pain in one patient and another patient required additional sutures van der velde and hudson56 (2005) south africa prospective n = 11 • bootlace nylon suture and vac 7.5 • skin necrosis (n = 1), broken suture (n = 1) and vacuum leak (n = 1) static tension strips technique harrah et al.42 (2000) usa technique description iri n = 6 • plaster strips • none weissman et al.43 (2015) israel case series n = 4 • plaster strips 21 • hypertrophic scar (n = 1) sd = standard deviation; vac = vacuum-assisted closure; stsg = spilt-thickness skin grafting; wi = wound infection; sf = suction force; iri = ischaemia-reperfusion injury; cs = compart ment syndrome; rct = randomised controlled trial. optimising wound closure following a fasciotomy a narrative review e196 | squ medical journal, august 2019, volume 19, issue 3 g r a d u a l s u t u r e a p p r o x i m at i o n t e c h n i q u e s the shoelace technique was first described in 1986 and employs vessel loops, which are threaded in a criss cross manner 48 hours after a fasciotomy;29 subsequently, skin staples are used to secure the wound edges with regular loop-tightening every 48 hours [table 1]. intra venous analgaesia may be required during tightening sessions due to the associated pain. ultimately, suturing of wound edges is performed, resulting in acceptable aesthetic outcomes and high wound closure rates.25 simple silk-suturing may be performed in a shoelace pattern following fracture-related fasciotomies which may be sufficient for wound closure without complic ations as shown in a series of 19 patients.30 while the shoelace technique is safe, inexpensive and minimally interferes with mobility, it lacks adeq uate strength to close large wound gaps. in areas of high tension such as point-loading sites, the staples may be dislodged.24 as a result, several variations of the shoelace technique have been proposed. branco et al. used an elastic wire instead of vessel loops in a patient following tibial fracture-related cs; wound closure was successful within seven days.31 eid and elsoufy used a shoelace apparatus consisting of one or two paediatric urinary catheters as well as skin staples without encountering major complications in a series of 17 patients with fracture-related cs.32 galois et al. used wide drainage tubes containing sutures to increase the contact area between the muscles and sutures and prevent muscular injury.33 the drains were placed in contact with the muscles and were regularly tightened over the skin.33 sawant and hallett secured the ends of vessel loops using a paper-clip instead of securing them with endstaples and knots.34 this modification prevents pain and discomfort induced by tying and manipulation of the end-staples. in addition, based on the results from eight emergency fasciotomies, zenke et al. recommended the use of both vac treatment and the shoelace tech nique to reduce the need of stsg and provide better aesthetic outcomes.35 such a combination was helpful in wound approximation in patients with severe softtissue injuries or abdominal injuries and could shorten the total treatment time compared to when each technique is used individually. murakami et al. used the vessel loop technique in addition to vac treatment in a patient with cs after an ischaemia-reperfusion injury; wound closure was achieved within one week without complications.36 however, it should be noted that treatment costs would increase with the inclusion of vac treatment and even more so if stsg is required.11,37 this might be of considerable importance in a milieu of limited healthcare expenditures and austerity. riedl et al. first described an alternative approach for wound approximation, where a subcuticular suture was placed directly following fasciotomy without applying tension.38 within 3–5 days, progressive traction was applied and the patients were usually not required to undergo a secondary operation. using this prepositioned intracutaneous suture technique, janzing and broos found that it provided excellent skin apposition within nine days of regular surgical wounds in five patients (100%) with acute limb cs; however, its efficiency may be questionable in traumatic wounds with irregular edges.39 the subcuticular suture technique may be associated with inflammation around sutures and might lead to suture tears during closure attempts and subsequent suture replacement.39,40 s tat i c t e n s i o n s t r i p s gradual closure of fasciotomy wounds can also be attained by applying non-invasive techniques relying on repeated application of plaster strips on the second day post-surgery. this method was initially reported by mbubaegbu and stallard who used two longitudinal strips on both sides of the wound with application of connecting (bridging) strips in an outpatient setting.41 new longitudinaland cross-strips should be added every 2–3 weeks until full wound closure is achieved. when using this method, surgeons should monitor the development of granulation tissue, which may inhibit wound closure. similarly, harrah et al. placed 1.2 cm wide plaster strips in the same manner following application of a tincture of benzoin to decrease the risk of blistering and epidermal shearing.42 however, this technique may not be feasible on large wounds where more tension on the strips is required as they may not withstand the tension of the protruding muscles. moreover, the resulting scar due to tension may not be aesthetically acceptable, except for small fasciotomy wounds. weissman et al. applied the same method in a paediatric population and showed that wound closure was achieved in 15–26 days without major complications; they suggested that this is an appropriate technique for patients for whom surgical interventions are inadvisable.43 d y n a m i c m e c h a n i c a l d e v i c e s a n d i n n o vat i v e t o o l s there are many innovative mechanical devices and techniques that focus on dermal approximation to achieve wound closure [table 2]. commercially-avail able devices exploit skin-stretching properties and mechanical creep; however, their typical role on the mohammed k. alkhalifah and fareed s. h. almutairi review | e197 biological creep seems to be less effective. for example, sure-closure (medchem products inc, woburn, massachusetts, usa) employs frequent intraoperative tightening of the wound edges using two hooked, u-shaped arms; this process is interspersed with a 10 minute period of loosening the mechanical device.44 the silver bullet wound closure device (boehringer laboratories, norristown, pennsylvania, usa) is another mechanical device that relies on rotating an internal cylinder to tighten pre-inserted sutures that have passed from one wound side to the opposite edge.45 however, the use of some of these mechanical devices has been restricted to distinct medical centres due to increased experience with these sophisticated procedures. moreover, the use of such devices may be criticised due to the need for multiple applications of the technique, limited availability, lack of effective treatment for large wounds and the increased risk of skin necrosis and bulkiness.46 due to the potential costs of using these devices, they are generally limited to middleor high-income countries such as usa, canada and belgium.39,45,47 for example, the costs of wound closure using the sure-closure (medchem products inc) and silver bullet wound closure table 2: a summary of case series that employed dermal approximation techniques using dynamic mechanical devices/tools author and year of study device name number of patients treatment duration in days advantages disadvantages complication expensive device barnea et al.57 (2006) wisebands device 16 1–15 providing a feedback control to safeguard when excessive skin tension is applied expensive and not readily available sepsis (n = 1), pain (n = 1) and scar (n = 1) janzing and broos39 (2001) marburger system 5 9 materials needed for intracutaneous sutures are readily available expensive skin necrosis (n = 2) and skin grafting (n = 2) medina et al.45 (2008) silver bullet wound closure device 8 5–10 simple and efficacious daily tightening, numbness and tenderness of the scar pain (n = 2), scar (n = 3) and numbness (n = 2) ozyurtlu et al.58 (2014) v-loc wound closure device using barbed sutures 5 8.6 knotted sutures to prevent wound pulling back, faster tightening procedure and use of absorbable sutures rupture or lockups of the sutures necrosis (n = 1) taylor et al.47 (2003) anchors 5 6–14 equal distribution of tension forces expensive and not readily available none inexpensive device eid and elsoufy32 (2012) paediatric urinary catheters and staples 17 average of 4.2 tightening sessions readily available and inexpensive point-loading skin necrosis (n = 5) govaert and van helden59 (2010) ty-raps 13 4–23 stiff and very strong not readily available skin grafting (n = 1) kenny et al.46 (2018) rubber bands 17 no information available readily available and used for large wounds more than one application may be needed and qualitative assessment of the required tension skin grafting (n = 1) mittal et al.49 (2018) dermotaxis 25 12 easy to use and no point-loading k-wire cut-out skin grafting (n = 2) pasha et al.60 (2012) pasha device 9 5-8 simple, cheap and user friendly not readily available wi (n = 1) ravinder et al.48 (2018) dermotaxis using ravinder et al’s skin traction 100 8–15 can be used in wounds with exposed bones k-wire cut-out skin grafting (n = 12) rijal et al.50 (2011) circular rubber bands plus longitudinal gauzes 3 8 inexpensive and provides evenly distributed pointloading rubber band breakage and not suitable for active bleeders none suliman and aizaz51 (2008) plastic bands 5 4–12 simple, inexpensive and readily available risk of infection hypertrophic scar (n = 1) and wi (n = 1) walker et al.61 (2012) a silicon sheet fixed with a running prolene suture 69 11.9 safe, painless, provides constant wound control and easily removed risk of infection stsg (n = 17) wi = wound infection; stsg = spilt-thickness skin grafting. optimising wound closure following a fasciotomy a narrative review e198 | squ medical journal, august 2019, volume 19, issue 3 devices (boehringer laboratories) are $300–$500 and $575 usd, respectively.45,47 mechanical devices should only be used with sufficient clinical experience as the benefits of these devices may be questionable compared to other simple and approved techniques such as the shoelace or simple suture techniques. on the other hand, several innovative approaches have been developed to provide simple and inexpensive solutions to close fasciotomy wounds. ravinder et al.’s dermotaxis approach is a skin traction method involving two kirschner wires which are connected by a specific compression device and are passed through the margins of the wound; subsequently, tightening is performed every 12 hours in a total of 5–7 tightening sessions.48 the overall cost of such a method was estimated to be $5 usd per patient.49 recently, kenny et al. developed a rubber band-based technique that costs <$1 usd for each application consisting of applying the rubber bands across the length of the wound or leaving the wound centre open according to the clinical condition with subsequent wound coverage with a dressing.46 vac therapy can also be utilised with such techniques in cases of large-gapping wounds. rijal et al. developed another technique based on tying circular rubber bands to the marginal staples in a luggage-tag tying manner in addition to placing longitudinal layers of gauzes on the muscles to absorb fluid or discharge.50 suliman and aizaz described a simple approach for wound closure using plastic bands which were originally used to bind electric cables (22 bands cost $1 usd).51 nonetheless, the use of these simple tools, including other dermato-traction techniques, may not be preferable in patients with atrophic, infected, doubtfully-viable or friable skin. however, stsg can be a better solution to maximise the cost-effectiveness of treatment. non-invasive wound closureoptimising approach l i m b e l e vat i o n bengezi and vo recommended limb elevation to decrease the amount of time taken for oedema resolution and be able to perform a primary wound closure.52 this approach depends on the rigorous enforcement of patients to keep the affected limb elevated on either an intravenous pole or at least five pillows with frequent checking for the laxity of the surrounding skin for optimal wound closure. this method is simple, has minimal costs and provides superior cosmetic outcomes. however, it may not be suitable for large or severely-affected wounds. h e a l i n g b y s e c o n d a r y i n t e n t i o n healing by using skin contraction for gradual fasciotomy wound approximation is possible and would decrease overall cost of treatment.53 however, wound closure only occurs after an average of 3–4 months and requires the patient to change their dressings 1–3 times during this period. in addition, complete normalisation of the scar conformation may take up to four years. other limitations of this method include an increased risk of infection and muscular necrosis as well as significant delay implied in rehabilitation. although healing by secondary intention has been abandoned in current surgical practice, it may be used in cases where delayed primary wound closure has failed or in associated wound-dehiscence circumstances.22,53 conclusion both the amount of time taken to intervene and the fasciotomy technique that is used are crucial for optimal wound closure and may be more impactful than the type of wound closure technique itself. the current repertoire of methods of fasciotomy closure seems to be promising and additional methods are emerging. generally, there is no preferred method for treatment, however, suture-based dermal approximation techniques are most widely used. in the instance of resource availability in developed countries, the outcomes of these techniques could be optimised by concurrent application of negative-pressure therapy. surgeons should be aware of the advantages and limitations of each technique, in addition to the cost of treatment in low-income countries. finally, non-invasive methods, such as the use of tension-inducing adhesive strips and limb elevation, may be considered for patients for whom surgical interventions are inadvisable. references 1. forsh da, wolinsky pr. compartment syndrome. in: smith wr, sthel pf, eds. management of musculoskeletal injuries in the trauma patient. new york, usa: springer, 2014. pp 225–42. 2. saber a. compartment syndromes. j acute dis 2014; 3:169–77. https://doi.org/10.1016/s2221-6189(14)60040-8. 3. ojike ni, roberts cs, giannoudis pv. compartment syndrome of the thigh: a systematic review. injury 2010; 41:133–6. https://doi.org/10.1016/j.injury.2009.03.016. 4. jauregui jj, yarmis sj, tsai j, onuoha ko, illical e, paulino cb. fasciotomy closure techniques. j orthop surg (hong kong) 2017; 25:2309499016684724. https://doi.org/10.1177/23094990 16684724. 5. donaldson j, haddad b, khan ws. the pathophysiology, diagnosis and current management of acute compartment syndrome. open orthop j 2014; 8:185–93. https://doi.org/10.2174/18743 25001408010185. https://doi.org/10.1016/s2221-6189%2814%2960040-8 https://doi.org/10.1016/j.injury.2009.03.016 https://doi.org/10.1177/2309499016684724 https://doi.org/10.1177/2309499016684724 https://doi.org/10.2174/1874325001408010185 https://doi.org/10.2174/1874325001408010185 mohammed k. alkhalifah and fareed s. h. almutairi review | e199 6. han f, daruwalla zj, shen l, kumar vp. a prospective study of surgical outcomes and quality of life in severe foot trauma and associated compartment syndrome after fasciotomy. j foot ankle surg 2015; 54:417–23. https://doi.org/10.1053/j.jfas.201 4.09.015. 7. potter mbk, freedman lba, shuler ms. fasciotomy wound management and closure. tech orthop 2014; 29:180–4. https://doi.org/10.1097/bto.0000000000000109. 8. hussain s, limthongkul b, humphreys t. the biomechanical properties of the skin. dermatol surg 2013; 39:193–203. https://doi.org/10.1111/dsu.12095. 9. ganske i, wall j. skin grafts. in: meara jg, mcclain cd, mooney dp, rogers jr so, eds. global surgery and anesthesia manual: providing care in resource-limited settings. boca raton, usa: crc press, 2014. pp. 419. 10. weaver mj, owen tm, morgan jh, harris mb. delayed primary closure of fasciotomy incisions in the lower leg: do we need to change our strategy? j orthop trauma 2015; 29:308–11. https://doi.org/10.1097/bot.0000000000000278. 11. matt se, johnson ls, shupp jw, kheirbek t, sava ja. management of fasciotomy wounds--does the dressing matter? am surg 2011; 77:1656–60. 12. rai a, khalil s, batra p, gupta sk, bhattacharya s, dubey nk, et al. electrical injuries in urban children in new delhi. pediatr emerg care 2013; 29:342–5. https://doi.org/10.1097/ pec.0b013e3182852f71. 13. hazani r, whitney r, wilhelmi bj. optimizing aesthetic results in skin grafting. am surg 2012; 78:151–4. 14. blonska-staniec mk, barczak ae, garus a, balchanowski n, miszczuk jp. the use vacuum therapy in wound healing after fasciotomy in compartment syndrome — case report and literature review. acta angiologica 2016; 22:158–63. https://doi.org/10.5603/aa.2016.0015. 15. morykwas mj, howell h, bleyer aj, molnar ja, argenta lc. the effect of externally applied subatmospheric pressure on serum myoglobin levels after a prolonged crush/ischemia injury. j trauma 2002; 53:537–40. https://doi.org/10.1097/00005373200209000-00023. 16. zannis j, angobaldo j, marks m, defranzo a, david l, molnar j, et al. comparison of fasciotomy wound closures using trad itional dressing changes and the vacuum-assisted closure device. ann plast surg 2009; 62:407–9. https://doi.org/10.1097/sap.0 b013e3181881b29. 17. saziye k, mustafa c, ilker u, afksendyios k. comparison of vacuum-assisted closure device and conservative treatment for fasciotomy wound healing in ischaemia-reperfusion syndrome: preliminary results. int wound j 2011; 8:229–36. https://doi. org/10.1111/j.1742-481x.2011.00773.x. 18. yang cc, chang ds, webb lx. vacuum-assisted closure for fasciotomy wounds following compartment syndrome of the leg. j surg orthop adv 2006; 15:19–23. 19. weiland de. fasciotomy closure using simultaneous vacuumassisted closure and hyperbaric oxygen. am surg 2007; 73:261–6. 20. lee p. treating fasciotomy wounds with negative pressure wound therapy with instillation and dwell time (npwti-d). cureus 2016; 8:e852. https://doi.org/10.7759/cureus.852. 21. lee jy, jung h, kwon h, jung sn. extended negative pressure wound therapy-assisted dermatotraction for the closure of large open fasciotomy wounds in necrotizing fasciitis patients. world j emerg surg 2014; 9:29. https://doi.org/10.1186/17497922-9-29. 22. kakagia d. how to close a limb fasciotomy wound: an over view of current techniques. int j low extrem wounds 2015; 14:268–76. https://doi.org/10.1177/1534734614550310. 23. krticka m, ira d, bilik a, rotschein p, svancara j. fasciotomy closure using negative pressure wound therapy in lower leg compartment syndrome. bratisl lek listy 2016; 117:710–14. https://doi.org/10.4149/bll_2016_136. 24. kakagia d, karadimas ej, drosos g, ververidis a, trypsiannis g, verettas d. wound closure of leg fasciotomy: comparison of vacuum-assisted closure versus shoelace technique. a randomised study. injury 2014; 45:890–3. https://doi.org/10.1016/j.injury.20 12.02.002. 25. fowler jr, kleiner mt, das r, gaughan jp, rehman s. assisted closure of fasciotomy wounds: a descriptive series and caution in patients with vascular injury. bone joint res 2012; 1:31–5. https://doi.org/10.1302/2046-3758.13.2000022. 26. saeed mu, kennedy dj. a retained sponge is a complication of vacuum-assisted closure therapy. int j low extrem wounds 2007; 6:153–4. https://doi.org/10.1177/1534734607305597. 27. bussell hr, aufdenblatten ca, gruenenfelder c, altermatt s, tharakan sj. comparison of lower extremity fasciotomy wound closure techniques in children: vacuum-assisted closure device versus temporary synthetic skin replacement. eur j trauma emerg surg 2018. https://doi.org/10.1007/s00068-018-0985-9. 28. johnson ls, chaar m, ball cg, perez s, nicholas jm, wyrzykowski ad, et al. management of extremity fasciotomy sites prospective randomized evaluation of two techniques. am j surg 2018; 216:736–9. https://doi.org/10.1016/j.amjs urg.2018.07.033. 29. cohn bt, shall j, berkowitz m. forearm fasciotomy for acute compartment syndrome: a new technique for delayed primary closure. orthopedics 1986; 9:1243–6. 30. saini ra, sharma d, shah n. shoe lace technique, a simple and less expensive method for fasciotomy wound closure following compartment syndrome. int j orthop sci 2018; 4:445–9. https://doi.org/10.22271/ortho.2018.v4.i1g.64. 31. branco ps, cardoso junior m, rotbande i, ciraudo ja, silva cr, leal pc. elastic suture (shoelace technique) for fasciotomy closure after treatment of compartmental syndrome associated to tibial fracture. rev bras ortop 2016; 52:103–6. https://doi. org/10.1016/j.rboe.2016.11.004. 32. eid a, elsoufy m. shoelace wound closure for the management of fracture-related fasciotomy wounds. isrn orthop 2012; 2012:528382. https://doi.org/10.5402/2012/528382. 33. galois l, pauchot j, pfeffer f, kermarrec i, traversari r, mainard d, et al. modified shoelace technique for delayed primary closure of the thigh after acute compartment syndrome. acta orthop belg 2002; 68:63–7. 34. sawant mr, hallett jp. the paper-clip modification to the vessel loop 'shoelace' technique for delayed primary closure of fasciotomies. injury 2001; 32:619–20. https://doi.org/10.1016/ s0020-1383(01)00035-3. 35. zenke y, inokuchi k, okada h, ooae k, matsui k, sakai a. useful technique using negative pressure wound therapy on postoperative lower leg open wounds with compartment syndrome. injury extra 2014; 45:83–7. https://doi.org/10.1016/j. injury.2014.07.015. 36. murakami m, morikage n, samura m, yamashita o, suehiro k, hamano k. shoelace technique plus vacuum-assisted closure in leg fasciotomy. anz j surg 2014; 84:795. https://doi.org/10. 1111/ans.12662. 37. erdös j, dlaska c, szatmary p, humenberger m, vécsei v, hajdu s. acute compartment syndrome in children: a case series in 24 patients and review of the literature. int orthop 2011; 35:569–75. https://doi.org/10.1007/s00264-010-1016-6. 38. riedl s, werner j, göhring u, meeder pj. [the pre-positioned intracutaneous suture--a method for treatment of soft tissue defects after fascia splitting in acute compartment syndrome]. chirurg 1994; 65:1052–5. https://doi.org/10.1053/j.jfas.2014.09.015 https://doi.org/10.1053/j.jfas.2014.09.015 https://doi.org/10.1097/bto.0000000000000109 https://doi.org/10.1111/dsu.12095 https://doi.org/10.1097/bot.0000000000000278 https://doi.org/10.1097/pec.0b013e3182852f71 https://doi.org/10.1097/pec.0b013e3182852f71 https://doi.org/10.5603/aa.2016.0015 https://doi.org/10.1097/00005373-200209000-00023 https://doi.org/10.1097/00005373-200209000-00023 https://doi.org/10.1097/sap.0b013e3181881b29 https://doi.org/10.1097/sap.0b013e3181881b29 https://doi.org/10.1111/j.1742-481x.2011.00773.x https://doi.org/10.1111/j.1742-481x.2011.00773.x https://doi.org/10.7759/cureus.852 https://doi.org/10.1186/1749-7922-9-29 https://doi.org/10.1186/1749-7922-9-29 https://doi.org/10.1177/1534734614550310 https://doi.org/10.4149/bll_2016_136 https://doi.org/10.1016/j.injury.2012.02.002 https://doi.org/10.1016/j.injury.2012.02.002 https://doi.org/10.1302/2046-3758.13.2000022 https://doi.org/10.1177/1534734607305597 https://doi.org/10.1007/s00068-018-0985-9 https://doi.org/10.1016/j.amjsurg.2018.07.033 https://doi.org/10.1016/j.amjsurg.2018.07.033 https://doi.org/10.22271/ortho.2018.v4.i1g.64 https://doi.org/10.1016/j.rboe.2016.11.004 https://doi.org/10.1016/j.rboe.2016.11.004 https://doi.org/10.5402/2012/528382 https://doi.org/10.1016/s0020-1383%2801%2900035-3 https://doi.org/10.1016/s0020-1383%2801%2900035-3 https://doi.org/10.1016/j.injury.2014.07.015 https://doi.org/10.1016/j.injury.2014.07.015 https://doi.org/10.1111/ans.12662 https://doi.org/10.1111/ans.12662 https://doi.org/10.1007/s00264-010-1016-6 optimising wound closure following a fasciotomy a narrative review e200 | squ medical journal, august 2019, volume 19, issue 3 39. janzing hm, broos pl. dermatotraction: an effective technique for the closure of fasciotomy wounds: a preliminary report of fifteen patients. j orthop trauma 2001; 15:438–41. https://doi. org/10.1097/00005131-200108000-00010. 40. chiverton n, redden jf. a new technique for delayed primary closure of fasciotomy wounds. injury 2000; 31:21–4. https:// doi.org/10.1016/s0020-1383(99)00193-x. 41. mbubaegbu ce, stallard mc. a method of fasciotomy wound closure. injury 1996; 27:613–15. https://doi.org/10.1016/s002 0-1383(96)00111-8. 42. harrah j, gates r, carl j, harrah jd. a simpler, less expensive technique for delayed primary closure of fasciotomies. am j surg 2000; 180:55–7. https://doi.org/10.1016/s0002-9610(00)0 0409-8. 43. weissman o, goldman n, stavrou d, barzilai l, grabov nardini g, farber n, et al. adhesive skin closure technique for closure of fasciotomy wounds in pediatric patients: a case series. wounds 2015; 27:118–222. 44. hirshowitz b, lindenbaum e, har-shai y. a skin-stretching device for the harnessing of the viscoelastic properties of skin. plast reconstr surg 1993; 92:260–70. https://doi.org/10.1 097/00006534-199308000-00010. 45. medina c, spears j, mitra a. the use of an innovative device for wound closure after upper extremity fasciotomy. hand (n y) 2008; 3:146–51. https://doi.org/10.1007/s11552-007-9082-y. 46. kenny em, egro fm, russavage jm, spiess am, acartürk to. primary closure of wide fasciotomy and surgical wounds using rubber band-assisted external tissue expansion: a simple, safe, and cost-effective technique. ann plast surg 2018; 81:344–52. https://doi.org/10.1097/sap.0000000000001506. 47. taylor rc, reitsma bj, sarazin s, bell mg. early results using a dynamic method for delayed primary closure of fasciotomy wounds. j am coll surg 2003; 197:872–8. https://doi.org/10.1 016/s1072-7515(03)00646-x. 48. ravinder s, gill hs, walia jps, brar bs, nagra ts. management of skin loss by dermotaxis. j bone joint surg br 2018; 90-b. 49. mittal n, bohat r, virk js, mittal p. dermotaxis v/s loop suture technique for closure of fasciotomy wounds: a study of 50 cases. strategies trauma limb reconstr 2018; 13:35–41. https://doi.org/10.1007/s11751-017-0299-1. 50. rijal l, nepal p, adhikari a, regmi s. luggage tag tie technique for delayed primary closure of fasciotomy wounds. eur j orthop surg traumatol 2011; 21:449–52. https://doi.org/10.1007/s0059 0-010-0729-y. 51. suliman mt, aizaz s. closing fasciotomy wounds using plastic bands: an alternative simple and cheap method. ann vasc surg 2008; 22:697–700. https://doi.org/10.1016/j.avsg.2008.05.001. 52. bengezi o, vo a. elevation as a treatment for fasciotomy wound closure. can j plast surg 2013; 21:192–4. https://doi.org/10.11 77/229255031302100303. 53. boxer l, buchman s. an alternative method for closure of fasciotomy wounds: healing by secondary intention. internet j plast surg 2002; 1:2. 54. zorrilla p, marín a, gómez la, salido ja. shoelace technique for gradual closure of fasciotomy wounds. j trauma 2005; 59:1515–17. https://doi.org/10.1097/01.ta.0000199242.24511.30. 55. dahners le. the running near-near-far-far stitch for closure of fasciotomies and other large wounds. orthopedics 2003; 26:383–4. 56. van der velde m, hudson da. vader (vacuum-assisted dermal recruitment): a new method of wound closure. ann plast surg 2005; 55:660–4. https://doi.org/10.1097/01.sap.00001871 81.59748.19. 57. barnea y, gur e, amir a, leshem d, zaretski a, miller e, et al. delayed primary closure of fasciotomy wounds with wisebands, a skinand soft tissue-stretch device. injury 2006; 37:561–6. https://doi.org/10.1016/j.injury.2006.02.056. 58. ozyurtlu m, altınkaya s, baltu y, ozgenel gy. a new, simple technique for gradual primary closure of fasciotomy wounds. ulus travma acil cerrahi derg 2014; 20:194–8. https://doi. org/10.5505/tjtes.2014.54077. 59. govaert ga, van helden s. ty-raps in trauma: a novel closing technique of extremity fasciotomy wounds. j trauma 2010; 69:972–5. https://doi.org/10.1097/ta.0b013e3181f2d9d3. 60. pasha if, qureshi ma, arshad rm, tahir ub, akram m, awais sm. delayed primary closure of open double fasciotomy wounds at leg with "pasha device" a novel method. ann king edw med univ 2012; 18:168–73. 61. walker t, gruler m, ziemer g, bail dh. the use of a silicon sheet for gradual wound closure after fasciotomy. j vasc surg 2012; 55:1826–8. https://doi.org/10.1016/j.jvs.2011.12.009. https://doi.org/10.1097/00005131-200108000-00010 https://doi.org/10.1097/00005131-200108000-00010 https://doi.org/10.1016/s0020-1383%2899%2900193-x https://doi.org/10.1016/s0020-1383%2899%2900193-x https://doi.org/10.1016/s0020-1383%2896%2900111-8 https://doi.org/10.1016/s0020-1383%2896%2900111-8 https://doi.org/10.1016/s0002-9610%2800%2900409-8 https://doi.org/10.1016/s0002-9610%2800%2900409-8 https://doi.org/10.1097/00006534-199308000-00010 https://doi.org/10.1097/00006534-199308000-00010 https://doi.org/10.1007/s11552-007-9082-y https://doi.org/10.1097/sap.0000000000001506 https://doi.org/10.1016/s1072-7515%2803%2900646-x https://doi.org/10.1016/s1072-7515%2803%2900646-x https://doi.org/10.1007/s11751-017-0299-1 https://doi.org/10.1007/s00590-010-0729-y https://doi.org/10.1007/s00590-010-0729-y https://doi.org/10.1016/j.avsg.2008.05.001 https://doi.org/10.1177/229255031302100303 https://doi.org/10.1177/229255031302100303 https://doi.org/10.1097/01.ta.0000199242.24511.30 https://doi.org/10.1097/01.sap.0000187181.59748.19 https://doi.org/10.1097/01.sap.0000187181.59748.19 https://doi.org/10.1016/j.injury.2006.02.056 https://doi.org/10.5505/tjtes.2014.54077 https://doi.org/10.5505/tjtes.2014.54077 https://doi.org/10.1097/ta.0b013e3181f2d9d3 https://doi.org/10.1016/j.jvs.2011.12.009 july 2008.indd sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 241-242 sultan qaboos university© received 21st april 2008 acy re: continuity of care literature review and implications to the editor, we read the paper “continuity of care literature review and implications” by alazri m et al. with interest,1 and were gratified to find that it supported most of our personal biases regarding the benefits of continuity of care, in particular page 201, column 2, paragraph 3, lines 1-3, “in type 2 diabetes, relational and longitudinal continuity could decrease diabetes related complications and improve the quality of life” [reference 53]2 exactly what we would expect from a strong, supportive, caring environment! it was only when we got to the follow-on, page 201, column 2 and paragraph 3, lines 3-5 that some disquiet set in when we read,“…however, another study showed that longitudinal continuity was associated with more diabetic complications” [reference 52]3. perhaps, we reflected, the primary health care team in this study might have delayed appropriate referral for eye, renal or other complications, a problem that might be associated with the lack of proper secondary/tertiary diabetes support services. however, page 201, paragraph 6, lines 7-9, goes on to state “in diabetes, longitudinal continuity has been associated with worsening diabetic control and increased risk of complications” [reference 53]2. this appeared to be in direct conflict with the earlier citation of reference 531. on review of the references, it appears that reference 522 is unrelated to diabetes; the paper by love and colleagues deals only with asthma in adults. reference 532 by hanninen et al. addresses the benefits of continuity of care in diabetes. apart from its virtues, these authors also found that good continuity of care was associated with less satisfactory glucose control (hb a(1c) 8.9 +/2.0 (+/sd) vs. 8.3 +/2.0, p=0.04). otherwise, we could not find any other evidence that continuity of care is bad for diabetic complications. it would be speculative to consider that a difference of hb a(1c) of 0.6 percent, that was barely statistically significant in that study, is equivalent to “increased risk of complications.” in a recent comprehensive analysis of diabetic outcomes in northern europe, wandell3 supports the concept that good continuity of care in diabetics was associated with better health related quality of life. we would be grateful if you shared our concerns with dr. alazri and his co-authors. some clarification would be gratefully appreciated. george carruthers and hussain saadi, department of internal medicine and office of the dean, faculty of medicine & health sciences, uae university, al ain, uae r e fe r e n c e s 1. continuity of care literature review and implications. squ med j 2007 7:197-206. 2. [reference 53] hanninen j, takala j, keinanen-kiukaanniemi s. good continuity of care may improve quality of life in type 2 diabetes. diabetes res clin pract 2001; 51:21-27. l e t t e r t o t h e e d i t o r g e o r g e c a r r u t h e r s a n d h u s s a i n s a a d i 242 2. [reference 52] love mm, mainous ag, talbert jc, hager gl. continuity of care and the physician-patient relationship: the importance of continuity for adult patients with asthma. j fam pract 2000; 49:998-1004. 3. wandell pe. quality of life of patients with diabetes mellitus. an overview of research in primary health care in the nordic countries. scand j prim health care 2005; 23:68-74. a u t h o r ’ s r e s p o n s e thank you for the comments of prof. carruthers, dean of medicine at uae university, and his colleague about our paper published in the squmj, continuity of care literature review and implications.1 our response to his comments is as follows: • we agree with dr. carruthers regarding reference no. 52 which is not related to diabetes, but to asthma and it came to the reference list by mistake. the correct reference for the study, which showed that longitudinal continuity has been associated with worsening diabetic control and increased risk of complications, is: overland j, yue dk, mira m. continuity of care in diabetes: to whom does it matter?2 however, this study used data derived from patients referred by general practitioners to a diabetic clinic in a teaching hospital in australia, thus, there is a possibility of sampling bias, as patients who do not have longitudinal continuity may have less chances to be referred. furthermore, some of those patients might have developed already diabetes-related complications, thus, they have been referred to the hospital. • reference no. 52 has been corrected and now relates to diabetes.2 • paragraph 6, lines 7-9, states “in diabetes, longitudinal continuity has been associated with worsening diabetic control and increased risk of complications.” the reference to this statement should be no. 52 (corrected) and not no. 53 in the article. • i agree with dr carruthers that in the hanninen et al study3 good continuity of care was associated with less satisfactory glucose control (hb a(1c) 8.9 +/2.0 (+/sd) vs. 8.3 +/2.0, p = 0.04) which could have a significant effect on the long term outcomes. in fact, the explanation for the poor glycaemic control has not been explored in this study, but an assumption is made that patients would like to be treated for diabetes with their usual gp who accepts less strict glucose control and concentrates more on achieving better well-being. overall, i would like to thank dr. carruthers for his valuable comments. mohammed alazri department of family medicine and public health college of medicine and health sciences sultan qaboos university r e fe r e n c e s 1. continuity of care literature review and implications. squ med j 2007 7:197-206. 2. overland j, yue dk, mira m. continuity of care in diabetes: to whom does it matter? diabetes res clin pract 2001; 52:5561. 3. hanninen j, takala j, keinanen-kiukaanniemi s. good continuity of care may improve quality of life in type 2 diabetes. diabetes res clin pract 2001; 51:21-27. department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com contact vitiligo following allergic contact dermatitis *ricardo ruiz-villaverde and francisco j. navarro-triviño sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 152–153, epub. 28 feb 22 submitted 19 jan 21 revision req. 19 jan 21; revision recd. 5 apr 21 accepted 21 apr 21 a 45-year-old male patient who was a construction worker, with no personal history of psoriasis, atopic dermatitis or vitiligo, was referred to the contact eczema department of a tertiary care hospital in granada, spain with chronic hand eczema and skin depigmentation over a period of 12 months. regarding the primary eczema, skin depigmentation appeared a few months later. the patient reported the use of rubber gloves for many years. he had noticed itching and mild erythema over both hands. currently, he wears nitrile gloves at work. physical examination showed symmetric erythematous-squamous, hyperkeratotic and fissured plaques on both hands and ventral aspect of wrists [figures 1a and 1b]. skin depigmentation areas showed irregular edges [figure 1c]. wood’s lamp examination accentuated that the depigmentation areas overlapped the eczema without vitiligo pattern [figure 2]. no other anatomical sites were involved. blood test results showed no significant alterations including tests from autoimmune thyroiditis, celiac disease and pernicious anaemia. patch tests were performed with the european comprehensive baseline series (chemotechnique diagnostics, vellinge, sweden), rubber additives series (chemotechnique diagnostics) and hydroquinone monobenzylether 1% pet (shoe series; chemotechnique diagnosis). the results were interpreted according to the criteria of the international contact dermatitis research group. patch tests were read on day two and day four. the patient showed a strong positive patch test reaction to mercaptobenzothiazole (mbt). the patch test was performed with a piece of glove that the patient previously used which showed a positive reaction on day two and day four. orthokeratotic epidermis of slightly reduced thickness with a conserved ridge pattern with hypopigmentation as well as a marked decrease in the number of melanocytes was observed in the histological examination [figure 3a]. melan-a, s100 and hmb-45 staining were absent from the depigmented lesions [figure 3b]. at three and six months follow-up, a slight depigmentation of the area where mbt was tested was observed. contact vitiligo following allergic contact dermatitis caused by mbt was diagnosed. treatment with uvb-narrowband phototherapy was indicated. almost complete improvement of eczema and depigmented areas was observed after at the six-month follow-up. comment contact vitiligo is the term used to describe an acquired form of skin depigmentation caused by certain chemicals, mainly phenolic/catecholic this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.078 interesting medical image figure 1: photographs of the hands of a 45-year-old male patient showing (a) hyperkeratotic and fissured eczema on the back of both hands with skin depigmentation, (b) depigmentation on the ventral side of both wrists and (c) depigmentation of well-defined edges on the back of the hand. https://creativecommons.org/licenses/by-nd/4.0/ ricardo ruiz-villaverde and francisco j. navarro-triviño interesting medical image | 153 derivatives.1 the terms contact leukoderma (cl) and contact vitiligo (cv), which have different meanings, may be confused in the literature. cl is the term used to describe depigmentation that develops after contact with chemicals or allergens, which may or may not be accompanied by allergic contact dermatitis. for a diagnosis of cl, the patient must fulfil the following criteria: history of repeated exposure to depigmenting agent, must show numerous acquired confetti or pea-sized macules and the affected areas should correspond to the sites of chemical exposure. on the other hand, cv is an acquired leukoderma that occurs as a result of repeated topical or systemic exposure to a variety of chemicals, mainly alkyl phenols and catechols, regardless of the form of skin involvement.2 ju et al. reported a case of contact vitiligo caused by ippd.3 while cl is not frequent, and is clinically and histologically similar to vitiligo, it is sometimes confused with the latter. the first case was reported in 1939 and was caused by monobenzyl ether of hydroquinone in rubber gloves.4 phenols and catechol derivatives are mainly responsible due to their direct toxic effect on melanocytes.5 hydroquinone (monomethyl ether or monobenzyl ether), p-toluene diamine, monobenzone, azo dyes, aldehydes, epoxy resins, metals, dental acrylics, isopropanol or rotigotine, among others, have also been reported to lead to the development of contact leukoderma.6,7 mbt is used for natural and other rubber products as an accelerator, retarder and peptiser. this allergen can be found in items such as gloves, shoes, clothing, condoms, medical devices and adhesives. a u t h o r s’ c o n t r i b u t i o n rr-v and fjn-t contributed equally to the design, drafting and critical review of the manuscript. both authors approve the final version of the manuscript. references 1. boissy re, manga p. on the etiology of contact/occupational vitiligo. pigment cell res 2004; 17:208–14. https://doi.org/10.1 111/j.1600-0749.2004.00130.x. 2. harris je. chemical-induced vitiligo. dermatol clin 2017; 35:151–61. https://doi.org/10.1016/j.det.2016.11.006. 3. ju hj, lee jh, kim gm, park cj, bae jm. contact vitiligo induced by rubber ear loops from a disposable sanitary mask. eur j dermatol 2018; 28:690–1. https://doi.org/10.1684/ejd.2 018.3350. 4. oliver ea, schwartz l, warren lh. occupational leukoderma: preliminary report. jama 1939; 113:927–8. https://doi. org/10.1001/jama.1939.72800350003010a. 5. bonamonte d, vestita m, romita p, filoni a, foti c, angelini g. chemical leukoderma. dermatitis 2016; 27:90–9. https://doi. org/10.1097/der.0000000000000167. 6. sinha s, sardana k. contact leukoderma following irritant contact dermatitis to an isopropanol-based hand rub: a consequence of rigorous hand hygiene. contact dermatitis 2021; 84:346–8. https://doi.org/10.1111/cod.13743. 7. takeuchi a, egawa g, nomura t, kabashima k. contact leuko derma induced by rotigotine transdermal patch (neupro®). eur j dermatol 2019; 29:215–17. https://doi.org/10.1684/ejd.20 19.3500. figure 3: a: haematoxylin and eosin staining showing orthokeratotic epidermis of slightly reduced thickness with a conserved ridge pattern with hypopigmentation. b: immunostaining s100 protein at x3 magnification showing few melanocytes at both edges of the lesion. figure 2: wood´s lamp examination photographs of the hands of a 45-year-old male patient showing enhancement of depigmented skin and no achromic areas, as is seen in vitiligo. https://doi.org/10.1 111/j.1600-0749.2004.00130.x https://doi.org/10.1 111/j.1600-0749.2004.00130.x https://doi.org/10.1016/j.det.2016.11.006 https://doi.org/10.1684/ejd.2018.3350 https://doi.org/10.1684/ejd.2018.3350 https://doi.org/10.1001/jama.1939.72800350003010 https://doi.org/10.1001/jama.1939.72800350003010 https://doi.org/10.1097/der.0000000000000167 https://doi.org/10.1097/der.0000000000000167 https://doi.org/10.1111/cod.13743 https://doi.org/10.1684/ejd.2019.3500 https://doi.org/10.1684/ejd.2019.3500 1department of oral and maxillofacial surgery, oman medical specialty board, muscat, oman; departments of 2dental & maxillofacial surgery and 4haematology, sultan qaboos university hospital, muscat, oman; 3department of oral and maxillofacial surgery, al-nahda hospital, muscat, oman *corresponding author’s e-mail: khamisalhasani@squ.edu.om تعديل يف القطع العظمي لوفور 1 ورأب الذقن لعالج تشوه سين وجهي حاد حلالة مصابة أبنيميا البحر املتوسط الكربى تقرير حالة مع مراجعة أدبية خمي�س حممد احل�شني، عبدالعزيز عبداهلل باكثري، اأحمد خمي�س الها�شمي، بدر الرواحي، عبداهلل البكري abstract: β-thalassaemia major is an autosomal recessive form of haemoglobinopathy that is characterised by complete lack of production of the β-chains resulting in multiple complications that include severe anaemia, failure to thrive and skeletal abnormalities. facial deformities induced by β-thalassaemia major are rare and are very challenging to treat from a surgical point of view. we report a 33-year-old female patient with β-thalassaemia major who presented to the dental & maxillofacial surgery department, sultan qaboos university hospital, muscat, oman, in 2017 with gross dentofacial skeletal deformity contributing to her psychosocial issues. the facial deformity was corrected surgically by excision of the enlarged maxilla, modified le fort i osteotomy and advancement genioplasty. this case highlights the pre-operative preparation, surgical management, encountered complications and treatment outcome within 24 months of follow-up. keywords: beta-thalassaemia; thalassaemia major; cooley's anemia; le fort osteotomy; genioplasty; dentofacial deformities; case report; oman. امللخ�ص: اأنيميا البحر املتو�شط الكربى هي �شكل �شبغي ج�شدي متنحي من اعتالل الهيموغلوبني والذي يتميز بنق�س كامل يف اإنتاج �شال�شل بيتا مما يوؤدي اإىل م�شاعفات متعددة ت�شمل فقر الدم ال�شديد، والف�شل يف النمو وت�شوهات الهيكل العظمي. ت�شوهات الوجه الناجمة عن اأنيميا البحر املتو�شط الكربى تعترب نادرة وي�شعب عالجها من الناحية اجلراحية. نعر�س هنا حالة مري�شة تبلغ من العمر 33 عاًما م�شابة باأنيميا البحر املتو�شط الكربى والتي تقدمت اإىل ق�شم الأ�شنان وجراحة الوجه والفكني مب�شت�شفى جامعة ال�شلطان قابو�س، م�شقط، عمان، يف عام 2017 مع ت�شوه هيكلي عظمي ج�شيم يف الوجه والأ�شنان والذي اأ�شهم يف م�شاكلها النف�شية والجتماعية. مت ت�شحيح ت�شوه الوجه جراحًيا عن طريق ا�شتئ�شال الفك العلوي املت�شخم، ت�شحيح الفك بتعديل يف القطع العظمي لوفور ا1 وراأب الذقن بالتقدمي. ت�شلط هذه احلالة ال�شوء على التح�شري قبل اجلراحة والإدارة اجلراحية وامل�شاعفات التي مت مواجهتها ونتائج العالج خالل فرتة 24 �شهًرا من املتابعة. الكلمات املفتاحية: اأنيميا البحر املتو�شط الكربى ؛ فقر الدم كويل؛ قطع عظم لوفور؛ راأب الذقن؛ ت�شوهات الأ�شنان والوجه؛ تقرير حالة؛ ُعمان. modified le fort i osteotomy and genioplasty for management of severe dentofacial deformity in β-thalassaemia major case report and review of the literature *khamis m. al hasani,1 abdulaziz a. bakathir,2 ahmed k. al-hashmi,3 badar al rawahi,4 abdullah albakri1 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e362–367, epub. 5 oct 20 submitted 5 feb 20 revision req. 2 apr 20; revision recd. 29 apr 20 accepted 21 may 20 myocardial diseases, skeletal abnormalities and other complications.4–7 skeletal changes are common features in β-thalassaemia major patients, and in the craniofacial region these include bossing of the skull, prominent malar eminences giving the typical mongoloid facial appearance and maxillary hypertrophy.1,2,5,6 as a consequence of inadequate erythropoiesis, hypertrophy of erythroid marrow tissue especially at medullary sites lead to the typical craniofacial deformities that are usually seen in poorly transfused individuals.3,6,7 β-thalassaemia has been reported as the most common autosomal recessive mutational disorder of haemoglobin (hb) synthesis, which is characterised by reduction or absent synthesis of the β-globin chains of the hb tetramer.1 cooley and lee reported the first thalassaemia case in 1925 presenting with severe anaemia, splenomegaly and characteristic skeletal abnormalities.1,2 β-thalassaemia is classified according to the mutation in the β-globin genes as thalassaemia minor, intermedia and major subtypes.3 clinically, β-thalassaemia major patients present with chronic severe anaemia, failure to thrive, hepatosplenomegaly, this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.018 case report https://creativecommons.org/licenses/by-nd/4.0/ khamis m. al hasani, abdulaziz a. bakathir, ahmed k. al-hashmi, badar al rawahi and abdullah albakri case report | 363 surgical management of the facial deformity in β-thalassaemia major patients is challenging. various surgical treatment options have been advocated particularly for the surgical correction of the enlarged maxilla, however, most are published as case reports with some controversies on the complexity of these procedures.8–10 we report a rare case of severe dentofacial deformity in a β-thalassemia major patient who underwent surgical correction with a successful and stable outcome. case report a 33-year-old female patient with β-thalassaemia major was referred to the dental & maxillofacial surgery department, sultan qaboos university hospital, muscat, oman, in 2017 for evaluation and management of her dentofacial deformity. the patient’s chief complaints were related to her poor aesthetics, malocclusion and excessive upper jaw enlargement. the patient was diagnosed with β-thalassaemia major at the age of two years and was also known to have diabetes mellitus, coagulopathy and moderate liver iron over-load. moreover, she had no history of splenectomy or platelet dysfunction and her medical treatment included regular monthly blood transfusions, metformin and oral iron-chelating agents, which were recently changed to intravenous deferoxamine to improve her iron over-load status. clinical examination showed pallor of the skin and oral mucosa, prominent left maxilla, incompetent lips with excessive tooth show at rest. intraorally, there was an excessive vertical expansion of the left maxilla resulting in an occlusal cant. there was also malocclusion with dental crowding and a noticeable increased overjet [figure 1]. radiographic imaging showed poor maxillary bone density with obliteration of the maxillary sinuses and gross left maxillary bone enlargement especially in the premolar and molar regions [figures 1 and 2]. a lateral cephalogram showed severe proclination of the upper and lower anterior teeth and moderate retrogenia. the patient requested surgical correction of her dentofacial deformity. surgical options including conventional orthodontic-orthognathic treatment, modified le fort i osteotomy and genioplasty with excision of the enlarged maxillary mass were explained to the patient. the patient understood the due risks and complications. she chose the modified maxillary osteotomy and genioplasty without pre-surgical orthodontics. the patient’s pre-operative investigations showed a haemoglobin level of 9 g/dl, deranged coagulation with increased activated partial thromboplastin time and fibrinogen as well as reduction factor ix and xii levels. pre-operatively, a haematologist was consulted and the recommended blood transfusion raised the patient’s hb level to 11.4 g/dl and transfused fresh frozen plasma (ffp) was arranged to correct the coagulopathy status. under nasotracheal intubation and antibiotic prophylaxis with second-generation cephalosporin, figure 1: pre-operative clinical photographs and radiographic images of a 33-year-old female patient with β-thalassaemia showing (a) frontal and (b) lateral views showing lip incompetence, excessive teeth showing and maxillary enlargement. orthopantogram showing (c) left maxillary enlargement with obliteration of the maxillary sinuses and over-eruption of left maxillary teeth. lateral cephalogram showing (d) severe proclination of the upper and lower anterior teeth, increased overjet and moderate retrogenia. modified le fort i osteotomy and genioplasty for management of severe dentofacial deformity in β-thalassaemia major case report and review of the literature 364 | squ medical journal, august 2020, volume 20, issue 3 bilateral full crevicular incisions were performed to expose the maxilla, which revealed a lack of bony cortex with presence of very loose honeycombed medullary bone overlying the expanded maxilla. the hypertrophied bone of the left maxilla was excised together with extractions of maxillary posterior teeth 18, 17, 27 and 28. at the extraction sites, bilateral vertical osteotomies were performed which were linked by bilateral horizontal osteotomies 5 mm above the apices of the remaining teeth (modified le fort i osteotomy without involving the pterygoid plates or the nasal floor). an additional horizontal osteotomy was performed above the initial horizontal osteotomy bilaterally to facilitate maxillary impaction, by removing a wedge of bone between the two horizontal osteotomies. the maxilla, as a single segmental unit, was then mobilised and impacted 6 mm on the right side and 4 mm on the left side and was set back by 4 mm. fixation was then accomplished using five 2.0 mm bone plates and screws with good stability. following the closure of the maxillary surgical area, a conventional 6 mm advancement genioplasty was performed uneventfully [figure 3]. intra-operatively, persistent oozing from the hyperplastic maxilla was encountered throughout the procedure, which resulted in dropping of the hb level to 7 g/dl, requiring multiple blood and ffp transfusions. the combination of using absorbable haemostatic agent (surgicel®, ethicon, hamburg, germany) packing, tranexamic acid, stable maxillary fixation and soft tissue closure resulted in good control of the intra-operative bleeding. post-operatively, the patient developed moderate facial oedema, mild maxillary oozing but had no signs of surgical infection. local measures consisting of oral packing and tranexamic acid rinses were utilised to control the post-operative ooze. further postoperative drop of hb required an additional two units of blood transfusion. two weeks post-operatively, the patient’s general condition improved with resolution of the facial oedema and adequate healing of the surgical sites with satisfactory occlusion, acceptable tooth show at rest and a good facial profile. at 24 months follow-up, the patient was pleased with the surgical outcome and clinical assessment revealed satisfactory facial profile and stable occlusion with no evidence of significant surgical relapse [figure 4]. the patient’s verbal consent was obtained to use her clinical images for educational and publication purposes; this was documented in the patient’s medical file. figure 3: intra-operative surgical photographs of a 33-year-old female patient with β-thalassaemia showing the intraoral view showing a hypertrophied left maxillary bony mass, excised hypertrophied left maxillary mass and fixation and stabilisation of modified le fort osteotomy with multiple mini-plates. figure 2: pre-operative cone beam computed tomography of the head of a 33-year-old female patient with β-thalassaemia showing (a) 3-dimensional reconstruction scan showing extensive left maxillary mass with lack of bony cortex. coronal (b) and axial (c) cuts demonstrating left maxillary medullary expansion with overlapping downward overgrowth of the left maxilla and obliteration of the maxillary sinuses. khamis m. al hasani, abdulaziz a. bakathir, ahmed k. al-hashmi, badar al rawahi and abdullah albakri case report | 365 discussion β-thalassaemia major, also known as cooley’s anaemia and transfusion-dependent thalassaemia, is a hereditary form of severe anaemia that is commonly prevalent among natives of the mediterranean and middle eastern and asian countries.3 in recent years, the life expectancy of β-thalassaemia major patients has improved dramatically as reported in different countries, nevertheless, serious disease-related complications are still common and pose a direct impact on the quality of life and increases patient morbidity and mortality.11–13 β-thalassaemia major patients are well known to have skeletal changes, particularly orofacial deformity and the prevalence and severity of such deformity coincides with the degree of ineffective erythropoiesis and extra-medullary haematopoiesis.6,14 the typical features of the facial deformity manifest clinically as frontal bossing, obliteration of the nasal sinuses, depression of the nasal bridge, protrusion of zygoma and expansion of the maxilla giving rise to a chipmunk-like appearance or rodent-like face and dental malocclusion.14 the pathogenesis of such skeletal changes are related to the hyperplasia and hypertrophy of the marrow erythroid under influence of the hyperactivity of the red marrow that leads to expansion of the medullary cavities and thinning of the cortical structures resulting in an overall loss of bone density, which is commonly seen in the maxilla.6,14,15 the facial changes are more pronounced as haematopoiesis continues in the cranium compared to other sites in the body. the mandible undergoes less changes than the maxilla and usually results in a retrognathic facial appearance.6,9,14,16 the dentition appears displaced as a consequence of the maxillary expansion and accordingly, results in dental malocclusion and functional difficulties during eating, swallowing and speech.9 iron over-load is a common complication in β-thalassaemia major patients.1,3,10,17,18 it occurs due to the ineffective erythropoiesis and/or transfusion iron over-load. ineffective erythropoiesis promotes an increase of the intestinal iron uptake that has an influence over iron balance regulation. in addition, iron also has the potential to precipitate within the parenchyma of the heart and liver and eventually leads to haemochromatosis. growth impairment, cirrhosis, hepatosplenomegaly, endocrine and metabolic abnormalities and cardiac complications are the main sequelae of haemochromatosis.3,10,13,17–19 oral iron chelating agents are widely used in β-thalassaemia major patients to prevent iron over-load.1,3,10,17,18 evidence suggests that iron chelation therapy can arrest the progression of endocrine abnormalities and liver and heart complications.18 however, patients’ compliance with oral therapy is often reported to be poor.17,18,20 in non-compliant patients with evidence figure 4: post-operative (24 months) clinical photographs and radiographic images of a 33-year-old female patient with β-thalassaemia showing the (a) frontal and (b) lateral views showing a pleased patient with satisfactory facial profile. intra-oral view showing (c) stable occlusion with symmetrical and harmonised maxillary buccal buttress. orthopantogram showing (d) stable occlusion with plates used for mandibular and maxillary osteotomy procedure and (e) a lateral cephalogram showing satisfactory chin position and lateral profile. modified le fort i osteotomy and genioplasty for management of severe dentofacial deformity in β-thalassaemia major case report and review of the literature 366 | squ medical journal, august 2020, volume 20, issue 3 of iron over-load, intravenous deferoxamine is indicated with a good outcome despite the high cost of treatment.17,18 in the current case, the patient was placed on intensive intravenous deferoxamine for over a year prior to surgery to correct the iron overload status. despite the improved iron status, the existence of coagulopathy and diabetes as previous complications of iron over-load were major surgical challenges. there are a limited number of case reports on the surgical correction of β-thalassaemia-induced facial deformity.8–10 there are few published reports addressing facial deformity in this group which included cases of thalassaemia intermedia.3,8,9,16 the suggested treatment includes surgical reduction of the enlarged maxillary bone and/or surgical jaw correction with or without associated orthodontic treatment.8–10,16 re-contouring the enlarged maxillary bone was a highly suggested treatment option, however, most reports were based on thalassaemia intermedia cases.1,5,8 mortazavi and khojasteh reported performing surgical re-contouring of the enlarged maxilla with dental clearance of maxillary teeth to facilitate the insertion of dental prosthesis thus, correcting the skeletal and dental deformities.8 the most commonly reported surgical form of management of the β-thalassaemia-induced facial deformity is surgical re-contouring along with either segmental osteotomy or a le fort i osteotomy.8–10,16,21,22 segmental osteotomy is more frequently used for vertical and sagittal repositioning of the premaxilla in the inter-canine area after extraction of the bilateral canines or first premolars to produce a reasonable occlusal relationship and facial harmony.8,23 le fort i osteotomy is less frequently reported in the literature compared to segmental osteotomy and purposely used for superior and posterior repositioning of the enlarged maxilla.8,10,22 in earlier reports, there was a preference for carrying out the surgical procedures in two-stages rather than a single-stage, owing to the potential increased risk of bleeding and surgical complications during a single long procedure.8,10,16,21 currently, the tendency is to perform both procedures of recontouring and segmental or le fort i osteotomies jointly.8,16 in the current case, the decision of surgical treatment was determined based on the patient’s choice, haematological status and the potential complications of the treatment. hence, a singlestage modified le fort i osteotomy (large one-unit segmental osteotomy), resection of enlarged maxilla and conventional genioplasty were performed. the midface is a well-known highly vascularised area and in patients presenting with β-thalassaemiainduced deformity, this region is further characterised by expansion and very porous cancellous bone, thus, during the surgical procedure, excessive bleeding is expected from mucosal and bone tissues.8,10,22 there are no guidelines or consensus for optimal peri-operative hb level prior to surgery for β-thalassaemia major patients, however, transfusion should be considered in patients with low hb levels.8,10,24 published work has shown that in operated cases of β-thalassaemiainduced facial deformity between 1969 and 2004, at least 2 units of blood were required as a pre-operative measure.8,10 furthermore, blood transfusion was also recommended in the intraand post-operative stages depending on the nature of bleeding and the hb levels.4,8–10,16,22,24 pre-operatively, following an assessment by the haematologist, the current patient’s hb level was raised to 11.4 g/dl and ffp was transfused to correct the coagulopathy status. intra-operatively, multiple measures were employed to minimise bleeding during the maxillary procedure including hypotensive anaesthesia, sub-periosteal gingival dissection and the application of local measures of oxidised regenerated cellulose packing impregnated with tranexamic acid. in addition, performing a less invasive modified le fort i osteotomy instead of the conventional le fort i osteotomy, which requires pterygomaxillary disjuncture plates, also contributed in minimising the intra-operative bleeding. despite all these measures, continuous bleeding from the porous maxilla was encountered intra-operatively and accordingly four units of blood were transfused. bleeding from the surgical site further reduced following fixation of the maxilla and soft tissue closure. post-operatively, bleeding from the surgical site and haematoma formation are the most commonly reported complications that need blood transfusion and haematoma evacuation, respectively.8,10 the current patient had a drop in hb level, which required the transfusion of a further two units of blood. the encountered pre-, intraand post-operative findings and their management are in line with other published reports.8–10,16 the facial surgical correction had a positive impact on the patient’s social and psychological status which is in line with the literature.7,8,10,17,22 a successful outcome of the dentofacial deformity correction in β-thalassaemia patients is dependent on understanding the medical status of the patient, coordinating with the haematologist and anaesthesiologist, good surgical planning and preventing complications.8 the presented case had a satisfactory and stable outcome in terms of aesthetics and occlusion at 24 months follow-up. khamis m. al hasani, abdulaziz a. bakathir, ahmed k. al-hashmi, badar al rawahi and abdullah albakri case report | 367 conclusion maxillary jaw deformity in β-thalassaemia major patients is rare and is very challenging surgically. careful case selection, assessment, pre-operative planning and surgical management are important to avoid complications and to achieve the required surgical outcome. references 1. olivieri nf. the beta-thalassemias. n engl j med 1999; 341:99–109. https://doi.org/10.1056/nejm199907083410207. 2. cao a, galanello r. beta-thalassemia. genet med 2010; 12:61–76. https://doi.org/10.1097/gim.0b013e3181cd68ed. 3. javid, b, said-al-naief n. craniofacial manifestations of β-thalassemia major. oral surg oral med oral pathol oral radiol 2015; 119:e33–40. https://doi.org/10.1016/j. oooo.2014.08.020. 4. poyton hg, davey kw. thalassemia: changes visible in radiographs used in dentistry. oral surg oral med oral pathol oral radiol 1968; 25:564–76. https://doi.org/10.1016/00304220(68)90301-0. 5. taher a, isma’eel h, cappellini md. thalassemia intermedia: revisited. blood cells mol dis 2006; 37:12–20. https://doi. org/10.1016/j.bcmd.2006.04.005. 6. ficarra g, hansen ls, beckstead jh, stoddard el, erickson rt. thalassemia diagnosed through facial distortion. int j oral maxillofac surg 1987; 16:227–31. https://doi.org/10.1016/ s0901-5027(87)80136-4. 7. gharaibeh h, barqawi ma, al-awamreh k, al bashtawy m. clinical burdens of β-thalassemia major in affected children. j pediatr hematol oncol 2018; 40:182–7. https://doi.org/10.10 97/mph.0000000000001104. 8. mortazavi sh, khojasteh a. superior repositioning of the maxilla in thalassemia-induced facial deformity: report of 3 cases and a review of the literature. j oral maxillofac surg 2007; 65:1023–31. https://doi.org/10.1016/j.joms.2006.06.305. 9. park n, lazow s, berger j. β-thalassemia: medical and surgical considerations in managing facial deformities: case report and review of the literature. j oral maxillofac surg 2012; 70:e284–9. https://doi.org/10.1016/j.joms.2011.11.027. 10. drew sj, sachs sa. management of the thalassemia-induced skeletal facial deformity: case reports and review of the literature. j oral maxillofac surg 1997; 55:1331–9. https://doi. org/10.1016/s0278-2391(97)90197-x. 11. borgna-pignatti c, cappellini md, de stefano p, del vecchio gc, forni gl, gamberini mr. et al. survival and complications in thalassemia. ann n y acad sci 2005; 1054:40–7. https://doi. org/10.1196/annals.1345.006. 12. rachmilewitz ea, giardina pj. how i treat thalassemia. blood 2011; 118:3479–88. https://doi.org/10.1182/blood-20 10-08-300335. 13. cappellini md, motta i, musallam km, taher at. redefining thalassemia as a hypercoagulable state. ann n y acad sci 2010; 1202:231–6. https://doi.org/10.1111/j.1749-6632.2010.05548.x. 14. singh a, varma s. β-thalassemia intermedia masquerading as β-thalassemia major. bmj case rep 2014; 2014:bcr2014207637. https://doi.org/10.1136/bcr-2014-207637. 15. baker dh. roentgen manifestations cooley's anemia. ann n y acad sci 1964; 119:641–61. https://doi.org/10.1111/j.1749-66 32.1965.tb54064.x. 16. bouguila j, besbes g, khochtali h. skeletal facial deformity in patients with β thalassemia major: report of one tunisian case and a review of the literature. int j pediatr otorhinolaryngol 2015; 79:1955–8. https://doi.org/10.1016/j.ijporl.2015.08.037. 17. rund d, rachmilewitz e. beta-thalassemia. n engl j med 2005; 353:1135–46. https://doi.org/10.1056/nejmra050436. 18. farmaki k, tzoumari i, pappa c, chouliaras g, berdoukas v. normalisation of total body iron load with very intensive comb ined chelation reverses cardiac and endocrine complications of thalassaemia major. br j haematol 2010; 148:466–75. https:// doi.org/10.1111/j.1365-2141.2009.07970.x. 19. musallam km, cappellini md, daar s, karimi m, el-beshlawy a, graziadei g, et al. serum ferritin level and morbidity risk in transfusion-independent patients with β-thalassemia intermedia: the orient study. haematologica 2014; 99:e218–21. https://doi.org/10.3324/haematol.2013.097220. 20. farmaki k, angelopiulos n, anagnostopoulos g, gotsis e, rombopoulos g, tolis g. effect of enhanced iron chelation therapy on glucose metabolism in patients with betathalassaemia major. br j haematol 2006; 134:438–44. https:// doi.org/10.1111/j.1365-2141.2006.06203.x. 21. silling g, moss sj. cooley’s anemia--orthodontic and surgical treatment. am j orthod 1978; 74:444–9. https://doi. org/10.1016/0002-9416(78)90067-2. 22. weel f, jackson it, crookendale wa, mcmichan j. a case of thalassaemia major with gross dental and jaw deformities. br j oral maxillofac surg 1987; 25:348–52. https://doi. org/10.1016/0266-4356(87)90076-3. 23. naini fb, gill ds. orthognathic surgery: principles, planning and practice. 1st ed. london, uk: john wiley & sons, inc., 2017. 24. staikou c, stavroulakis e, karmaniolou i. a narrative review of peri-operative management of patients with thalassaemia. anaesthesia 2014; 69:494–510. https://doi.org/10.1111/anae.12591. https://doi.org/10.1056/nejm199907083410207 https://doi.org/10.1097/gim.0b013e3181cd68ed https://doi.org/10.1016/j.oooo.2014.08.020 https://doi.org/10.1016/j.oooo.2014.08.020 https://doi.org/10.1016/0030-4220%2868%2990301-0 https://doi.org/10.1016/0030-4220%2868%2990301-0 https://doi.org/10.1016/j.bcmd.2006.04.005 https://doi.org/10.1016/j.bcmd.2006.04.005 https://doi.org/10.1016/s0901-5027%2887%2980136-4 https://doi.org/10.1016/s0901-5027%2887%2980136-4 https://doi.org/10.1097/mph.0000000000001104 https://doi.org/10.1097/mph.0000000000001104 https://doi.org/10.1016/j.joms.2006.06.305 https://doi.org/10.1016/j.joms.2011.11.027 https://doi.org/10.1016/s0278-2391%2897%2990197-x https://doi.org/10.1016/s0278-2391%2897%2990197-x https://doi.org/10.1196/annals.1345.006 https://doi.org/10.1196/annals.1345.006 https://doi.org/10.1182/blood-2010-08-300335 https://doi.org/10.1182/blood-2010-08-300335 https://doi.org/10.1111/j.1749-6632.2010.05548.x https://doi.org/10.1136/bcr-2014-207637 https://doi.org/10.1111/j.1749-6632.1965.tb54064.x https://doi.org/10.1111/j.1749-6632.1965.tb54064.x https://doi.org/10.1016/j.ijporl.2015.08.037 https://doi.org/10.1056/nejmra050436 https://doi.org/10.1111/j.1365-2141.2009.07970.x https://doi.org/10.1111/j.1365-2141.2009.07970.x https://doi.org/10.3324/haematol.2013.097220 https://doi.org/10.1111/j.1365-2141.2006.06203.x https://doi.org/10.1111/j.1365-2141.2006.06203.x https://doi.org/10.1016/0002-9416%2878%2990067-2 https://doi.org/10.1016/0002-9416%2878%2990067-2 https://doi.org/10.1016/0266-4356%2887%2990076-3 https://doi.org/10.1016/0266-4356%2887%2990076-3 https://doi.org/10.1111/anae.12591 squ med j, february 2011, vol. 11, iss. 1, pp. 69-76, epub. 12th feb 11 submitted 28th feb 10 revision req. 19th may 10, revision recd. 25th jun 10 accepted 25th aug 10 departments of 1chemical pathology, and 2haematology, directorate of laboratory medicine and pathology, royal hospital, muscat, oman. *corresponding author email: drsharef@live.com xèç3÷]<gèe^fi_ê<l^fèf �”÷]<ãò^æá÷<ìë2j~π]<l˜˜ç÷] ô2”÷]<^è€èâ¯n÷]<óïü⁄<çfl¬<ìëá◊ �”÷]< ·^€ �¬<ìfl�◊â<h<ífi^�◊ä÷]<óàéjäπ^e<ìè√�œ⁄<ìâ]öå    إ   302008 –  ± 1632 15 15      3.42 ± 21.23     2   6 > 90 > 2 1.73 90 <   %1 < 2.5 > 10 22 < 2% 6.7 % 23.3 0.85 <% % 76.7 23 0.95 < 0.95 0.85 % 3.3 1.0 <  < 1.5% 96.7 29 1.5 1.0 % 80 24 1.4  (r = 0.904, p < 0.001)       :مفتاح الكلمات abstract: objectives: there are limited data concerning the assessment of renal function in beta-thalassaemia major, with no study of such involvement in omani patients. the objective of this study was to establish the pattern of renal glomerular and tubular function using traditional and specific laboratory tests in patients with beta-thalassaemia major. methods: this cross-sectional study, from january–july 2008, included 30 patients of the thalassaemia clinic at the royal hospital, oman, with transfusion-dependent homozygous beta-thalassaemia major. they included 15 males and 15 females, aged 16-32 years with mean ± standard deviation of 21.23 ± 3.42 years. the medical records were reviewed and renal function states assessed as follows: serum creatinine, estimated glomerular filtration rate (egfr); urea; phosphate, fractional excretion of filtered sodium (fena); urine albumin: creatinine index; urine ß2-microglobulin:creatinine index; tubular reabsorption of phosphate (trp), and tubular maximum phosphate reabsorption (tmp)/gfr. results: all patients had egfr >90 ml/min/1.73m2; serum creatinine <90 µmol/l; serum urea <6.0 mmol/l, and urine albumin:creatinine <2.5 mg/mmol. only 2 (6.7%) patients had fena >1% and 3 (10.0%) patients had urine ß2-microglobulin: creatinine >22 µg/mmol. all patients had trp >0.85, of whom seven (23.3%) patients had values within the range of 0.85-0.95 and 23 (76.7%) had values xèç3÷]<gèe^fi_ê<l^fèf �”÷]<ãò^æá÷<ìë2j~π]<l˜˜ç÷]xèç3÷]<gèe^fi_ê<l^fèf �”÷]<ãò^æá÷<ìë2j~π]<l˜˜ç÷] indicators of renal glomerular and tubular functions in patients with beta-thalassaemia major a cross sectional study at the royal hospital, oman *waad-allah s mula-abed,1 huda s al-hashmi,1 muhanna n al-muslahi2 clinical & basic research indicators of renal glomerular and tubular functions in patietns with beta-thalassaemia major a cross sectional study at the royal hospital, oman 70 | squ medical journal, february 2011, volume 11, issue 1 haemoglobinopathies are a common medical problem worldwide including in oman.1 a recent prospective neonatal screening programme in two major cities of oman, which included consecutive cord blood samples from a total of 7,837 neonates, revealed that the overall incidence of alpha-thalassaemia (alpha-thal) was 48.5%. beta-globin-related abnormalities accounted for 9.5% of the samples (4.8% sickle cell trait, 2.6% beta-thalassaemia trait, 0.9% haemoglobin (hb) e trait, 0.8% hb d trait, 0.08% hb c trait, 0.3% sickle cell disease and 0.08% homozygous beta-thalassaemia).2 also, data from an earlier community-based survey of the most common genetic blood disorders among omani children reported a prevalence rate of 2% for betathalassaemia trait, 0.07% for beta-thalassaemia major, 6% for sickle cell trait and 0.2% for sickle cell disease.3 comparable data has also been reported from gulf cooperation council states and other neighbouring countries.4,5,6,7 beta-thalassaemia major is an inherited monogenic disorder that was first described in 1925 by cooley and lee.8 it is caused by a mutation at the ß-globin gene locus resulting in persistence of α-globin chain that is precipitated within the erythroid precursors in the bone marrow associated with severe dyserythropoeitic anaemia.9 the combination of early diagnosis, improvement in monitoring complications and advances in supportive therapy has enabled patients with thalassaemia major to have improved life expectancy.10 the cornerstone of management is life-long blood transfusion with frequent iron chelation therapy to minimise the deleterious effect of chronic iron deposition and its accumulation in tissues.9 despite this, these patients are prone to long-term organ dysfunction particularly the cardiovascular, hepato-biliary, endocrine and skeletal systems.11 the renal system, particularly the kidneys, is an important functional unit that is exposed to the pathophysiological changes as well as the burden of iron deposition and chelation therapy in beta-thalassaemia. however, it appears that there is limited data available concerning renal involvement in this disease, and no such data is available for patients with beta-thalassaemia in oman. the objective of this study was to evaluate the degree of renal dysfunction, both glomerular and tubular, using traditional and specific laboratory tests of renal function in adult omani patients with transfusion-dependent homozygous betathalassaemia major at the royal hospital, oman. advances in knowledge 1. the cornerstone in the management of patients with beta-thalassaemia major is life-long blood transfusion with frequent iron chelation therapy. despite this, these patients are prone to long-term organ dysfunction particularly in their cardiovascular, hepato-biliary, endocrine and skeletal systems. the renal system, particularly the kidneys, also undergoes pathophysiological changes and may be affected by the burden of iron and the chelation therapy. this is the first study of the assessment of laboratory-based renal function tests in patients with beta-thalassaemia major in oman. 2. glomerular tests are usually within the reference ranges, while alteration in certain tubular tests (such as raised trp and tmp/gfr) may reflect an upward trend in serum phosphate and, as a consequence, in increasing renal phosphate reabsorption. otherwise, renal function appeared to be well preserved with no overt renal disease. application to patient care 1. this study helps health care professionals to select and interpret renal function tests in patients with beta-thalassaemia major using glomerular indicators (egfr, serum creatinine, urine microalbumin) and tubular indicators (fena, ß2-microglobulinuria, trp and tmp/gfr). >0.95. also, all patients had tmp/gfr >1.0 mmol/l, of whom only one (3.3%) patient had tmp/gfr of 1.0–1.5, and 29 (96.7%) patients had tmp/gfr >1.5 mmol/l. finally, 24 (80%) patients had serum phosphate >1.4 mmol/l. linear regression revealed a highly significant correlation between serum phosphate and tmp/gfr (r = 0.904, p < 0.001). conclusion: renal function, glomerular and tubular, appears to be well preserved in beta-thalassaemia major. almost all renal function indicators were within the recommended ranges. raised tmp/gfr and trp were noted in the majority of patients, reflecting an up-trend in serum phosphate and therefore increasing renal phosphate reabsorption. keywords: beta-thalassaemia; glomerular; tubular; renal function; oman waad-allah s mula-abed, huda s al-hashmi and muhanna n al-muslahi clinical and basic research | 71 methods this cross-sectional study was conducted during a six months period (1 january to 31 july 2008) and covered adult omani patients with transfusiondependent homozygous beta-thalassaemia major registered with the thalassaemia clinic at the royal hospital, oman. this is one of a number of thalassaemia clinics in oman which together deal patients with this disease. the study included 30 patients (15 male, 15 female), aged 16–32 years who were seen at the clinic at 3 monthly intervals. the diagnosis of homozygous thalassaemia was based on the characteristic haematological criteria (peripheral blood evaluation and haemoglobinopathy screening) at presentation or screening from the early years of life. the study protocol was a naturalistic observation, an integral part of routine clinical procedure through reviewing the medical records of these thalassaemic patients from the hospital computer records including the haematologists’ clinical review as well as results of laboratory investigations. the clinical haematologists are regularly consulted on the management of these patients which includes supervision of blood transfusion and chelation therapy, as well as monitoring of organ dysfunction due to predicted iron deposition in tissues. the patients had been regularly transfused every three weeks since the early years of life with packed red blood cells, and were regularly taking iron chelators such as desferrioxamine (40 mg/kg body weight) as subcutaneous infusions 5 days per week, and deferiprone (75 mg/kg body weight) tablets daily. for the laboratory investigations, blood samples were collected in the fasting state, and early morning urine specimens were provided from all the patients during their visits to the clinic. in addition to complete blood count and serum ferritin, different biochemical function profiles are regularly done to screen for any possible dysfunction. evaluation of renal function is usually performed, together with other core function profile tests. the biochemical tests included: serum creatinine, and creatinine-based estimated glomerular filtration rate (egfr); urea; phosphate as well as fractional excretion of filtered sodium (fena); urine albumin: creatinine index (for microalbuminuria); urine ß2-microglobulin: creatinine index (for ß2-microglobulinuria); tubular reabsorption of phosphate (trp), and tubular maximum phosphate reabsorption/gfr (tmp/gfr). all these parameters were measured in the clinical biochemistry laboratory at the royal hospital. creatinine was analysed by kinetic jaffe reaction; urea and sodium by ion-selective electrodes; phosphate by molybdenum blue, and albumin by the immunoturbidemetric method (all from synchron lx20, beckman coulter, inc, ca, usa), and ß2-microglobulin by chemiluminescent microparticle immunoassay method on axsym (abbott, usa).12 urinary ratios of microalbumin and ß2-microglobulin in relation to urine creatinine, as well as fena were calculated.12 the egfr was calculated by the modification of diet in renal disease (mdrd) equation13 and trp as well as tmp/gfr were calculated as recommended by payne.14 the reference ranges for the concerned biochemical parameters were as follows: serum creatinine (female 40–90 µmol/l; male 50–100 µmol/l); egfr (>90 ml/min/1.73m2); serum urea (3.0–6.0 mmol/l); serum phosphate (0.7-1.4 mmol/l); fena (<1%); urine albumin: creatinine ratio (female < 3.5 mg/mmol, male < 2.5 mg/mmol); urine ß2 microglobulin: creatinine ratio (<22 µg/mmol); trp (0.85–0.95), and tmp/gfr (1.0–1.5 mmol/l). the results were analysed and numerical data presented as mean ± standard deviation (sd) and range. anova (analysis of variance) was used to compare the differences in the means of results between the different groups. pearson’s correlation coefficient was also used to compare between certain parameters where appropriate, which include serum phosphate and tmp/gfr. the statistical significance was assigned at p < 0.05.15 results thirty homozygous ß-thalassaemia patients (15 male, 15 female), aged 16-32 years, mean 21.23 years, sd of ± 3.42, were evaluated in this study. the recommended cut-off for the studied renal function tests include: egfr >90 ml/ min/1.73m2; serum creatinine <90 µmol/l (in females) and <100 µmol (in males); serum urea <6.0 mmol/l; serum phosphate <1.40 mmol/; fena <1.0 %; urine albumin: creatinine <3.5 mg/mmol (in females) and <2.5 mg/mmol (in males); urine ß2micglobulin: creatinine indicators of renal glomerular and tubular functions in patietns with beta-thalassaemia major a cross sectional study at the royal hospital, oman 72 | squ medical journal, february 2011, volume 11, issue 1 <22 µg/mmol; trp 0.85–0.95, and tmp/gfr 1.0–1.5 mmol/l. the results of the renal function tests, glomerular and tubular, are shown in table 1. for egfr, and due to the possible effect of imprecision and analytical bias in creatinine assays at concentrations within the reference range, it has been recommended to report egfr values higher than 90 ml/min/1.73m2 as >90 ml/min/1.73m2 with no numerical value.16 hence, statistical data was not applied for egfr results when calculated egfr >90 ml/min/1.73m2. all thirty patients had egfr >90 ml/min/1.73m2; serum creatinine <90 µmol/l (all group median 43, range 23–73 µmol/l); serum urea <6.0 mmol/l (median 3.3, range 1.3–5.6 mmol/l), and urine albumin: creatinine <2.5 mg/mmol (median 0.50, range 0.1–1.7 mg/mmol). only two (6.7%) patients had fena >1% (median 0.30, range 0.06–1.35%), and three (10%) patients had urine ß2-microglobulin: creatinine >22 µg/mmol (median 7.1, range 1.14– 60.4 µg/mmol). concerning renal phosphate handling, all patients had trp >0.85 (all group median 0.97, range 0.91–0.99), and tmp/gfr >1.0 mmol/l (median 2.01, range 1.15–4.48 mmol/l). further characterisation of the results revealed that seven (23.3%) patients had trp within the recommended reference range of 0.85–0.95 and 23 (76.7%) patients had values >0.95, with no patient having trp <0.85. for tmp/gfr, only one (3.3%) patient had tmp/gfr within the reference range of 1.0– 1.5 mmol/l, and 29 (96.7%) patients had raised tmp/gfr >1.5 mmol/l; 13 (43.3%) patients had values 1.51–2.00 mmol/l, nine (30%) had values 2.01–2.50 mmol/l, five (16.7%) had values 2.5–3.0 mmol/l and two (6.7%) had values >3.0 mmol/l; no patient had tmp/gfr <1.0 mmol/l. also, six (20%) and 24 (80%) patients had serum phosphate ≤1.4 and >1.4 mmol/l respectively (median 1.66, range 1.10–3.14 mmol/l). a linear regression analysis revealed a highly significant correlation between serum phosphate and tmp/gfr (r = 0.904, p <0.001), [figure 1]. in order to compare the parameters of phosphate handling, the results were also assessed in relation to the endocrine complications that were previously reported and reviewed in these patients.17 the patients were grouped as those with ≥ one endocrinopathy, n = 22; hypogonadism alone, n = 12; hypogonadism with diabetes mellitus, n = 7; with primary hypoparathyroidism, n = 1; with hypoparathyroidism and diabetes mellitus, n = 1; and with hypoparathyroidism and hypothyroidism, n = 1, and those with no endocrinopathy, n = 8. a significant difference (p <0.005) was noted in tmp/gfr (2.456 ± 0.69 versus 1.818 ± 0.255 mmol/l) and in serum table 1: indicators of renal glomerular and tubular function tests in 30 patients with homozygous beta-thalassaemia. parameter mean ± sd of results no. and (%) of patients normal values abnormal values* abnormal values normal values egfr (ml/min/1.73m2) > 90 30 (100%) 0 (0.0%) serum creatinine (µmol/l) 44.4 ± 10 30 (100%) 0 (0.0%) serum urea (mmol/l) 3.4 ± 1.0 30 (100%) 0 (0.0%) serum phosphate (mmol/l) 1.33 ± 0.12 1.91 ± 0.39 6 (20%) 24 (80) urine albumin: creatinine (mg/mmol) 0.69 ± 0.5 30 (100%) 0 (0.0%) fena (%) ** 0.35 ± 0.22 1.24 ± 0.14 28 (93.5%) 2 (6.7%) urine ß2.micglobulin: creatinine (µg/mmol) ** 7.1 ± 4.9 39.3 ± 18.3 27 (90.0%) 3 (10.0%) trp *** 0.96 ± 0.02 30 (100%) 0 (0.0 %) tmp/gfr *** (mmol/l) 2.28 ± 0.646 30 (100%) 0 (0.0 %) notes * all patients marked as (-) had values within the reference ranges with no patient exceeded the cut-off for the renal function test ** only 2 patients had high results for fena and 3 patients had high results for urine, b2.microglobulin: creatinine; statistical data are not presented as the number is low ***abnormal values indicate high values for all parameters, except for trp and tmp/gfr which are indicated by low values legend: egfr = estimated glomerular filtration rate; fena = fractional excretion of filtered sodium; trp = tubular reabsorption of phosphate; tmp/ gfr = tubular maximum phosphate reabsorption/glomerular filtration rate. waad-allah s mula-abed, huda s al-hashmi and muhanna n al-muslahi clinical and basic research | 73 phosphate (1.928 ± 0.42 versus 1.46 ± 0.18 mmol/l); however, no significant difference was noted in trp (0.962 ± 0.021 versus 0.960 ± 0.025) in patients with and without endocrinopathy respectively. the three patients with primary hypoparathyroidism had the highest tmp/gfr values (4.48, 3.36, and 2.32 mmol/l). no significant difference was noted in serum ferritin between these two groups (6480 ± 3418.6 versus 5647 ± 3663 µg/l). discussion patients with beta-thalassaemia major are prone to metabolic complications, including different organ dysfunction which can occur as single or multiple involvements. although the actual mechanism is not definitive, the most likely explanation is related to anaemia and iron overload, in addition to lipid peroxidation, oxidative stress and free radical release.18 in this study, all 30 beta-thalassaemia major patients had normal glomerular renal function tests as indicated by their normal levels of egfr >90 ml/min/1.73m2; serum creatinine <90 µmol/l; serum urea <6.0 mmol/l and urine albumin: creatinine <2.5 mg/mmol. despite the increased iron deposition and the consequence of its possible oxidative stress on the renal parenchyma of these patients, many workers have also reported normal serum creatinine and creatinine clearance in patients with beta-thalassaemia major.19,20 the absence of microalbuminuria in our patients is another reflector of intact renal glomerular function. microalbuminuria is an early indicator of nephropathy in patients at risk of developing kidney involvement, such as those with underlying chronic diseases including diabetes mellitus, hypertension or cardiovascular disease.21 in this study, almost all patients also had normal tubular renal function tests. this is indicated by the normal levels of fena and urine ß2-microglobulin: creatinine, with only two (6.7%) patients having slightly raised fena >1% and three (10%) patients with raised urine ß2-microglobulin: creatinine >22 µg/mmol; serum ß2-microglobulin was not measured in these three patients. also, no patient had trp <0.85 or tmp/gfr <1.0 mmol/l, which exclude the possibility of a renal tubular phosphate leak. hence, all our patients had normal renal indicators for handling microalbumin and phosphate, with the vast majority of them having normal renal indicators for handling sodium and ß2-microglobulin. these are amongst the important tubular functions tests, which have almost excluded a significant impairment in tubular renal function in our patients’ series. gosling reported an estimate that when there is complete failure of renal tubular absorption, there will be an approximately 1,800-fold normal increase in ß2microglobulin loss and 20-fold normal increase in urine albumin loss.22 in comparison with other studies, aldudak et al. reported no significant figure 1: correlation between serum phosphate and tubular maximum phosphate reabsorption/glomerular filtration rate (tmp/gfr) in 30 homozygous beta-thalassaemia major patients. indicators of renal glomerular and tubular functions in patietns with beta-thalassaemia major a cross sectional study at the royal hospital, oman 74 | squ medical journal, february 2011, volume 11, issue 1 difference in creatinine clearance and fena between thalassaemics and healthy controls.23 kalman et al. also reported no significant difference in many tubular function indicators that include fractional excretion of sodium, magnesium, uric acid as well as calcium, protein, glucose, urine ß-2.microglobulin, n-acetyl-ß-dglucosaminidase (nag) levels and trp in children with beta-thalassaemia major and thalassaemia intermedia.24 however, there are reports by other researchers who observed impairment in renal function when using other sensitive renal tubular function tests. smolkin et al.25 reported normal creatinine clearance, fena and trp; however, urine nag excretion was significantly raised in beta-thalassaemics, as also reported by aldudak et al. 23 and sumboonnnanonda et al.26, who observed increase in both urinary nag and malondialdehyde (mda) excretion. mda is an indicator of lipid peroxidation.27 hence anaemia and increased oxidative stress, possibly iron induced, may play a role in precipitating some degree of tubular dysfunction, which may be mild, and so can not be detected when using other tubular function indicators. in our study, 96.7% patients had tmp/gfr of >1.5 mmol/l and 76.7% patients had trp values >0.95, indicating enhanced renal tubular phosphate reabsorption. this may be due to the raised phosphate level, due to the accelerated turnover of erythrocytes from the excess haemolysis in betathalassaemia. this is supported by the observation that 80% of our thalassaemics had raised serum phosphate and the significant correlation (r = 0.904) observed between serum phosphate and tmp/gfr levels. this compares with other studies where some researchers revealed no change24,26 while others observed some degree of altered trp.23 however, no data is available in the literature for comparing tmp/gfr as a renal tubular index in beta-thalassaemic patients, although this test is more representative of renal tubular handling of phosphate than trp alone, but there is limited awareness about its importance.14 also, in this study significantly higher mean tmp/gfr and serum phosphate values were observed in beta-thalassaemics with endocrinopathies compared with those with no endocrinopathy. hypogonadism, the most frequent endocrine disorder that was observed in 22 (73.3%) thalassaemics in our series, appears to be the most likely underlying aetiology.17 the upward trend in tmp/gfr in these patients may be due to the decline in sex hormones (estrogens in women and androgens in men) as a consequence of impaired gonadal function resulting in a decline in the stimulating effect of sex hormones on calcitonin secretion, and accelerated bone resorption through inhibiting the formation of osteoclasts.28 multiple pathways have been described for the inhibitory effect of estrogens and androgens on osteoclasts with calcitonin receptors and sex hormones have been demonstrated at multiple steps in the osteoclast lineage.29,30 dundar et al. reported low calcitonin, osteocalcin, gonadal steroids, and pituitary hormones with high phosphate and n. telopeptide in beta-thalassaemic patients.31 in addition, other hormone deficiencies, such as parathyroid, thyroid and insulin, which are known to influence calcitonin secretion and skeletal protection as well as direct iron toxicity on osteoblasts, also contribute to the pathogenesis of altered bone metabolism in betathalassaemia.32 the highest tmp/gfr values in our patients were observed in three beta-thalassaemics who had primary hypoparathyroidism in addition to hypogonadism. while the main function of the parathyroid hormone (pth) is calcium homeostasis, it is also an important determinant of phosphate reabsorption, with tmp/gfr being increased in hypoparathyroidism and decreased in hyperparathyroidism.33 normal or raised tmp/gfr may offer an advantage, as low values are associated with hypercalciuria, nephrocalcinosis and tubular proteinuria. this is presumably a result of direct tubular dysfunction, although it is controversial and may be difficult to prove.34,35,36 however, regardless of the underlying mechanism, in patients with renal tubular dysfunction whether due to the effect of metabolites, drugs or toxins, the response of low tmp/gfr to therapy may assist in monitoring these patients. conclusion renal function, glomerular as well as tubular, appears to be well preserved in beta-thalassaemic adult patients. in this study, almost all renal indicators that include egfr, serum creatinine and urea as well as fena, urine microalbumin, and ß2-microglobulin were within the recommended waad-allah s mula-abed, huda s al-hashmi and muhanna n al-muslahi clinical and basic research | 75 reference ranges. raised trp and tmp/gfr values were noted in the majority of thalassaemics, studied reflecting an upward trend in serum phosphate and its consequence in increasing renal reabsorption of phosphate. despite the impairment in certain laboratory-based renal tubular indicators in some patients, especially those reported in the reviewed literature, these beta-thalassaemics had no overt renal disease, and so it remains questionable whether such functional abnormalities would have any long-term effect. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. rajab ag, patton ma, modell b. study of hemoglobinopathies in oman through a national register. saudi med j 2000; 21:1168–72. 2. alkindi s, al zadjali s, al madhani a, daar s, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. 3. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 4. al-siliman a. prevalence of beta-thalassarmia trait in premarital screening in al-hassa, saudi arabia. ann saudi med 2006; 26:14–6. 5. mohammed am, al-hilli f, nadkarni kv, bhagwat gp, bapat jp. hemoglobinopathies and glucose-6phosphate dehydrogenase deficiency in hospital births in bahrain. ann saudi med 1992; 12:536–9. 6. miller cj, dunn ev, berg b, abdouni sf. a hematological survey of preschool children of the united arab emirates. saudi med j 2003; 24:609–13. 7. karimi m, jamalian n, yarmohammadi h, askarnejad a, afrasiabi a, hashemi a. premarital screening for beta-thalassaemia in southern iran: options for improving the programme. j med screen 2007; 14:62–6. 8. cooley tb, lee p. a series of cases of splenomegaly in children with anemia and peculiar changes. trans am pediatr soc 1925; 37:29–30. 9. thein sl. beta-thalassaemia. baillieres clin haematol 1998; 11:91–126. 10. olivieri nf, nathan dg, macmillan jh, wayne as, liu pp, mcgee a, et al. survival in medically treated patients with homozygous beta-thalassaemia. n engl j med 1994; 331:574–8. 11. britton rs, ramm ga, olynyk j, singh r, o’neill r, bacon br. pathophysiology of iron toxicity. adv exp med biol 1994; 356:239–53. 12. burtis ca, ashwood er, bruns de, eds. tietz textbook of clinical chemistry and molecular diagnostics. 14th ed. st. louis, missouri: elsevier saunders, 2006. 13. levey as, greene t, kusek jw, beck gl. a simplified equation to predict glomerular filtration rate from serum creatinine. j am soc nephrol 2000; 11:a0828. 14. payne rb. renal tubular reabsorption (tmp/gfr): indications and interpretation. ann clin biochem 1998; 35:201–6. 15. hill ab, hill id. bradford hill’s principles of medical statistics. 12th ed. london: hodder arnold, 1991. 16. lamb ej, tomson crv, roderick pj. estimating kidney function in adults using formulae. ann clin biochem 2005; 42:321–45. 17. mula-abed wa, al-hashmi hs, almuslahi mn, almuslahi hn, allamki ma. prevalence of endocrinopathies in patients with beta-thalassaemia major: a cross-sectional study in oman. oman med j 2008; 23:257–62. 18. walter pb, macklin ea, porter j, evans p, kwiatkowski jl, neufeld ej, et al. inflammation and oxidantstress in beta-thalassemia patients treated with iron chelators desferasirox (icl670) or desferoxamine: an ancillary study of the novartis cicl670a0107 trial. haematologica 2008; 93:817–25. 19. ong-ajyooth l, malasit p, ong-ajyooth s, fucharoen s, pootrakul p, vasuvattkul s, et al. renal function in adult beta-thalassemia/hb e disease. nephron 1998; 78:156–61. 20. kotopodis kp, elisaf ms, pappas ha, theodorou jc, milionis hj, bourantas kl, et al. renal abnormalities in patients with sickle cell beta-thalassemia. j nephrol 1997; 10:163–7. 21. hillege hl, fidler v, diercks gf, van gilst wh, de zeeuw d, van veldhuisen dj, et al. urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. circulation 2002; 106:1777–82. 22. gosling p. proteinuria. in: marshall wj, bangert sk, eds. clinical biochemistry: metabolic and clinical aspects. 2nd ed., new york: elsevier, 2008: pp. 156– 73. 23. aldudak b, karabay bayazit a, noyan a, ozel a, anarat a, sasmaz i, et al. renal function in pediatric patients with beta-thalassemia major. pediatr nephrol 2000; 15:109–12. 24. kalman s, atay aa, sakallioglu o, ozgurtas t, gok f, kurt i, et al. renal tubular function in children with beta-thalassemia minor. nephrology 2005; 10:427–9. 25. smolkin v, halevy r, levin c, mines m, sakran w, ilia k, et al. renal function in children with betathalassemia major and thalassemia intermedia. pediatr nephrol 2008; 23:1847–51. indicators of renal glomerular and tubular functions in patietns with beta-thalassaemia major a cross sectional study at the royal hospital, oman 76 | squ medical journal, february 2011, volume 11, issue 1 26. sumboonnanonda a, malasit p, tanphaichitr vs, ong-ajyooth s, sunthornchart s, pattanakakitsakul s, et al. renal tubular function in beta-thalassemia. pediatr nephrol 1998; 12:280–3. 27. del rio d, stewart aj, pellergini n. a review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. nutr metab cardiovasc dis 2005; 15:316–28. 28. mundy gr. factors regulating bone resorbing and bone forming cells. in: mundy gr, ed. bone remodeling and its disorders. 2nd ed. london: martin dunitz, 1999. pp. 45–82. 29. hofbauer lc, khosla s, dunstan cr, lacey dl, spelsberg tc, riggs bl. estrogens stimulate gene expression and protein production of osteoprotegerin in human osteoblastic cells. endocrinology 1999; 140:4367–70. 30. abu eo, horner a, kusec v, triffitt jt, compston je. the localization of androgen receptors in human bone. j clin endocrinol metab 1997; 82:3493–7. 31. dundar u, kupesiz a, ozdern s, gilgil e, tuncer t, yesilipek a, et al. bone metabolism and mineral density in patients with beta-thalassemia major. saudi med j 2007; 28:1525–9. 32. voskaridou e, terpos e. pathogenesis and management of osteoporosis in thalassemia. pediatr endocrinol rev 2008; 6:86–93. 33. shaw nj, wheeldon j, brocklebank jt. indices of intact serum parathyroid hormone and renal excretion of calcium, phosphate, and magnesium. arch dis child 1990; 65:1208–11. 34. wikstrom b, backman u, danielson bg, fellstrom b, johansson g, ljunghall s, et al. phosphate metabolism in renal stone formers. (ii): relation to renal tubular functions and calcium metabolism. scand j urol nephrol 1981; 61:ii:1–26. 35. jaeger p, portmann l, ginalski jm, jacquet af, temler e, burckhardt p. tubulopathy in nephrolithiasis: conseque rather than cause. kidney int 1986; 29:563–71. 36. alpern rj, sakhaee k. does hyperphosphaturia underlie hypercalciuria? lancet 1997; 349:518–9. 1family medicine, primary care, ministry of health, muscat, oman; 2department of family medicine and public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drameena88@gmail.com internet addiction and depression among postgraduate residents a cross-sectional survey *ameena m. al mukhaini,1 fakhriya a. al houqani,1 rahma m. al kindi2 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 408–415, epub. 29 aug 21 submitted 13 may 20 revision req. 6 jul 20; revision recd. 29 jul 20 accepted 22 sep 20 https://doi.org/10.18295/squmj.4.2021.008 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. the advent of the internet has caused major changes in the way individuals entertain themselves and interact with each other, with a myriad of social networking sites, such as facebook (facebook inc., menlo park, california, usa), whatsapp (facebook inc.), instagram (facebook inc.), snapchat (snap inc., santa monica, california, usa) and twitter (twitter inc., san francisco, california, usa) becoming increasingly popular.1,2 in the usa, research has shown that 82–89% of adults aged 18–49 years old use different social networking sites, with 52% of users reporting accessing several platforms in 2016 compared to 42% in the previous year, resulting in an unexpected annual increase of almost 10%.3 in saudi arabia, 42.4% of participants in a study admitted to spending more than four hours a day on social networking sites, with 60.9% believing that life was boring without such sites and 50.6% checking their social media accounts as soon as they woke up.4 in oman, a previous study involving university students revealed various degrees of social media addiction according to different criteria.5 based on a set of criteria proposed by lemmens et al., 14.2% of the surveyed students were addicted to facebook, 47.2% were addicted to youtube (google llc, san bruno, california, usa) and 33.3% were addicted to twitter, although these percentages dropped to 6.3%, 13.8% and 12.8% respectively when criteria suggested by andreassen et al. were applied.5–7 nevertheless, high rates of social media usage and increasing exposure to social networking sites have led to concerns over whether excessive use of social media should be considered a distinct form of behavioural addiction.8 while social media addiction is not currently acknowledged in either the diagnostic and statistical manual of mental disorders (dsm), fifth edition, or abstract: objectives: this study aimed to estimate the prevalence of social media usage and internet addiction among oman medical specialty board (omsb) residents and to determine associations between internet addiction, sociodemographic characteristics and symptoms of depression. methods: this cross-sectional study took place between january and march 2017. all 499 residents enrolled in omsb training programmes during the 2016–2017 academic year were targeted. a self-administered questionnaire was distributed to collect information concerning sociodemographic characteristics. in addition, the patient health questionnaire-9 and internet addiction test were used to screen for depression and internet addiction, respectively. results: a total of 399 residents participated in the study (response rate: 80%). overall, 115 residents (28.8%) had varying degrees of depression and 149 (37.3%) were addicted to the internet; moreover, among those addicted, 54 (36.2%) had depression. while no significant associations were observed between internet addiction and sociodemographic characteristics, the association between internet addiction and depression was statistically significant (p = 0.012). conclusion: internet addiction was clearly detected among many omsb residents, with a significant association observed between internet addiction and depression. although a causal link between these two variables cannot be established as depression is multifactorial in origin, the disadvantages and harmful effects of excessive internet and social media usage need to be addressed. further research on the consequences of internet addiction and its effect on quality of life and academic achievement is recommended. keywords: internet; social media; social networking; addictive behaviors; depression; medical students; oman. advances in knowledge this study found a significant relationship between internet addiction and depression among oman medical specialty board (omsb) residents. however, further research is warranted to elaborate on this association and to identify associated risk factors. application to patient care although a causal link between internet addiction and depression cannot be established, as depression is multifactorial in origin, these findings should be disseminated to healthcare professionals to prompt early detection of these conditions and ensure the provision of appropriate support and treatment. furthermore, public health education regarding these issues is necessary to mitigate any negative effects on the quality of life and academic performance of affected individuals. https://creativecommons.org/licenses/by-nd/4.0/ ameena m. al mukhaini, fakhriya al houqani and rahma al kindi clinical and basic research | 409 the international classification of disease (icd), 11th edition, the term is becoming more frequent following observations of its increasing impact.9,10 as such, some researchers have suggested that social media addiction constitutes an ‘excessive use of social networking sites and the failure to control it which seriously harms a human’s life’.4 in contrast, others have defined internet addiction as ‘a psychological dependence on the internet characterised by (a) an increasing investment of resources on internet-related activities, (b) unpleasant feelings such as anxiety, depression, and emptiness when offline, (c) an increasing tolerance to the effect of being online, and (d) denial of the problematic behaviors’.11 however, caution is warranted before defining internet addiction as a disorder, particularly as the diagnosis relies primarily on self-reported symptoms rather than direct clinical examination, with varying cut-off rates being utilised in the existing literature.8 addictive online behaviours represent an important public health problem and have been linked to numerous adverse health outcomes, including increased levels of physical inactivity, vision and musculoskeletal problems, sleep deprivation and impaired psychosocial development and functioning.12 in particular, various studies worldwide have reported a positive association between internet addiction and depression.13–17 moreover, multiple systematic reviews have shown that the prevalence of depression is greater among medical residents than in the general population; in one meta-analysis of 54 studies from around the world, the overall pooled prevalence of depression among medical residents was 28.8%, with a 15.8% increase in depressive symptoms during the first year of training regardless of choice of specialty or location of training.18–21 as such, the main objectives of this study were to quantify the prevalence of social media usage and internet addiction among oman medical specialty board (omsb) residents and to determine associations with sociodemographic characteristics and depression. methods this cross-sectional study was carried out over a three-month period from january to march 2017 at the omsb, the only recognised postgraduate medical training centre in oman. all residents enrolled in omsb training programmes during the 2016–2017 academic year were targeted. overall, a total of 609 residents were registered under 18 different training programmes during the study period; however, 110 were excluded due to prolonged absence/leave or because they were studying abroad. as such, the remaining 499 residents based in oman and currently undergoing residency training were recruited for participation in the study. a self-administered questionnaire was distributed to all residents during various mandatory release days and workshops organised by the omsb. the question naire was divided into four sections. the first section collected sociodemographic information, including age, gender, marital status, living circumstances, average monthly income, chosen specialty, residency level, sleeping and exercise habits and history of smoking, alcohol and drug use. the second section explored online behaviours and practices, including method of access, duration of use, average daily time spent online and commonly accessed social networking sites. the third and fourth sections comprised the nine-item patient healthcare questionnaire (phq9) and the 20-item internet addiction test (iat) to screen for signs and symptoms of depression and internet addiction, respectively.22,23 overall, the survey took approximately 20 minutes to complete. researchers were available on site to support residents in completing the questionnaire. in order to maintain privacy and avoid peer influence, respondents were asked not to discuss questions with each other. the phq-9 is a self-administered version of the primary care evaluation of mental disorders diagnostic instrument, which is used to screen for common mental disorders in primary care.22 it is a reliable and valid tool used for screening and monitoring depression of varying degrees of severity. the phq-9 has been studied in many different settings and populations and has been compared favourably to longer clinician-administered instruments.22,24 the tool assesses nine items, including loss of interest/ pleasure, low mood/hopelessness, sleeping difficulties, loss of energy, changes in appetite, feelings of guilt/ worthlessness, difficulties concentrating, feelings of being slow/restlessness and the presence of suicidal thoughts. the total score for each participant is then calculated, with participants considered to have depression if their phq-9 scores were ≥5, with the severity of depressive symptoms classified as either minimal (scores of <5 points), mild (scores of 5–9), moderate (scores of 10–14), moderately severe (scores of 15–19) or severe (scores of ≥20).22 based on the dsm-iv criteria for pathological gambling and alcoholism, the iat is a popular psychological tool used to determine an individual’s degree of addiction to the internet and the impact of this addiction on their daily activities, social life, productivity, sleeping patterns and feelings.23 the iat includes 20 items rated on a five-point likert scale from 1 (signifying ‘not at all’) to 5 (signifying internet addiction and depression among postgraduate residents a cross-sectional survey 410 | squ medical journal, august 2021, volume 21, issue 3 ‘always’). the overall score is then calculated and the degree of addiction is classified as either mild (scores of 20–49, representing the average online user with full control over their usage), moderate (scores of 50– 79, suggesting excessive usage resulting in occasional or frequent difficulties) or severe (scores of 80–100, indicating that the level of internet usage is a direct cause of substantial problems or difficulties).23 data entry and analysis were performed using epidata software (epidata association, odense, denmark) and the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa), respectively. descriptive statistics were calculated for sociodemographic characteristics. for categorical variables, frequencies and percentages were reported, while means and standard deviations were reported for continuous variables. associations between independent and outcome variables were estimated using pearson’s chi-squared (χ2) test (or fisher’s exact test for cells <5). a multivariate binary logistic regression analysis was applied to identify independent predictors of internet addiction. the level of two-tailed significance was set at p ≤0.050. ethical approval for this study was granted by the omsb research ethics committee (#1582/2/5/2017). written informed consent was received from all participants prior to completion of the questionnaire. all participants were informed about the objectives of the study, the voluntary and confidential nature of participation and their right to withdraw from the study at any time. results a total of 399 residents submitted completed question naires (response rate: 80%). of these, 241 (60.4%) were female and 158 (39.6%) were male. the mean age was 29.15 ± 1.95 years old (range: 25–31 years). overall, 287 residents (71.9%) were married, 111 (27.8%) were single and one (0.2%) was divorced. more than half (n = 236; 59.1%) were in medical specialties, while 119 (29.8%) were in surgical specialties and 45 (11.3%) were in diagnostic specialties. most of the residents (n = 267; 66.9%) lived with their families; the rest either lived with friends (n = 73; 18.3%), alone (n = 48; 12%) or did not respond to the question (n = 11; 2.8%). onethird (n = 133; 33.3%) took part in regular exercise and the average sleep duration was 6.63 ± 1.44 hours per day. participants were almost equally divided between senior (n = 200; 50.1%) and junior (n = 199; 49.9%) resident levels. only three residents (0.8%) were smokers and none admitted to a history of alcohol or drug consumption. average monthly income ranged from 1,200–2,000 omani rials. the vast majority of participants (n = 391; 98%) reported using smart phones to access social networking sites. other methods of access included tablets (n = 181; 45.4%), laptops (n = 148; 37.1%) and desktop computers (n = 27; 6.8%). the average total lifetime duration of social media usage was 7.65 ± 2.89 years, while the average duration per day was 3.20 ± 2.43 hours. the most popular social networking site was whatsapp (n = 388; 97.2%), followed by instagram (n = 255; 63.9%), youtube (n = 187; 46.9%), facebook (n = 135; 33.8%), twitter (n = 127; 31.8%) and snapchat (n = 117; 29.3%). participants were asked at what times they usually accessed social media sites, with the option of giving multiple responses. a total of 253 residents (63.4%) accessed social media after working hours, while 58 (14.5%) accessed these sites during working hours. moreover, 44 residents (11%) accessed these sites almost all the time, while 193 (48.4%) accessed these sites before bedtime. the most frequently used network for accessing social networking sites was wireless (n = 163; 40.9%), followed by cellular data (n = 110, 27.6%), with 126 residents (31.6%) utilising both. table 1 presents the prevalence of depression and its varying degrees of severity according to selected sociodemographic characteristics. the mean total phq-9 score was 3.60 ± 3.95. overall, 115 residents (28.8%) had some form of depression (i.e., phq-9 scores of ≥5); of these, 36 (31.3%) were male and 79 (68.7%) were female. among those who were depressed, 105 (91.3%) had mild-to-moderate depression, while 10 (8.7%) had moderately-severe to severe depression. table 2 shows the prevalence of internet addiction and its varying degrees of severity according to selected sociodemographic characteristics. the mean total iat score was 28.17 ± 11.72. a total of 149 residents (37.3%) were addicted (i.e., iat scores of ≥31); of these, 65 (43.6%) were male and 84 (56.4%) were female. among those who were addicted, 132 (88.6%) were mildly addicted, 16 (10.7%) were moderately addicted and only one (0.7%) was severely addicted. there was no significant association between internet addiction and various demographic characteristics such as age, gender, marital status, choice of specialty, level of residency, living circumstances and sleeping and exercise patterns (p >0.050 each) [table 3]. however, there was a statistically significant positive association between internet addiction and depression (p = 0.012) [table 4]. out of the 149 residents who were addicted, 54 (36.2%) had some form of depression. in terms of addiction severity, 43 (32.6%) of those mildly addicted, 10 (62.5%) of those moderately addicted and the one resident (100%) who was severely addicted had depression. a ameena m. al mukhaini, fakhriya al houqani and rahma al kindi clinical and basic research | 411 table 1: prevalence of depression* by severity according to sociodemographic characteristics among oman medical specialty board residents (n = 399) characteristic depression severity† n (%) minimal mild moderate moderately severe/severe total gender male 122 (77.2) 26 (16.5) 5 (3.2) 5 (3.2) 158 (39.6) female 162 (67.2) 59 (24.5) 15 (6.2) 5 (2.1) 241 (60.4) marital status single 75 (68.2) 27 (24.5) 5 (4.5) 3 (2.7) 111 (27.8) married 206 (72.3) 57 (20) 15 (5.3) 7 (2.5) 287 (71.9) divorced 0 (0) 1 (100) 0 (0) 0 (0) 1 (0.2) choice of specialty medical 169 (71.9) 47 (20) 12 (5.1) 7 (3) 235 (58.9) surgical 79 (66.4) 33 (27.7) 5 (4.2) 2 (1.7) 119 (29.8) diagnostic 36 (80) 5 (11.1) 3 (6.7) 1 (2.2) 45 (11.3) residency level junior (r1–r2) 153 (76.9) 34 (17.1) 5 (2.5) 7 (3.5) 199 (49.9) senior (r3–r6) 131 (65.5) 51 (25.5) 15 (7.5) 3 (1.5) 200 (50.1) *assessed using the self-administered nine-item patient healthcare questionnaire.22 †depression severity was classified as either minimal (scores of <5), mild (scores of 5–9), moderate (scores of 10–14) or moderately severe/severe (scores of ≥15). table 2: prevalence of internet addiction* by severity according to sociodemographic characteristics among oman medical specialty board residents (n = 399) characteristic addiction severity† n (%) normal mild moderate severe total gender male 93 (58.9) 60 (38) 4 (2.5) 1 (0.6) 158 (39.6) female 157 (65.1) 72 (29.9) 12 (5) 0 (0) 241 (60.4) marital status single 67 (60.9) 36 (32.7) 7 (6.4) 0 (0) 111 (27.8) married 180 (63.2) 96 (33.7) 8 (2.8) 1 (0.4) 287 (71.9) divorced 1 (100) 0 (0) 0 (0) 0 (0) 1 (0.2) choice of specialty medical 145 (61.7) 74 (31.5) 15 (6.4) 1 (0.4) 235 (58.9) surgical 77 (64.7) 41 (34.5) 1 (0.8) 0 (0) 119 (29.8) diagnostic 28 (62.2) 17 (37.8) 0 (0) 0 (0) 45 (11.3) residency level junior (r1–r2) 127 (63.8) 65 (32.7) 7 (3.5) 0 (0) 199 (49.9) senior (r3–r6) 123 (61.5) 67 (33.5) 9 (4.5) 1 (0.5) 200 (50.1) *assessed using the self-administered 20-item internet addiction test.23 †addiction severity was classified as either normal (scores of ≤30), mild (scores of 31–49), moderate (scores of 50–79) or severe (scores of 80–100s). internet addiction and depression among postgraduate residents a cross-sectional survey 412 | squ medical journal, august 2021, volume 21, issue 3 multivariate analysis revealed that the number of years of social media usage was positively associated with the likelihood of internet addiction (odds ratio [or]: 1.095, 95% confidence interval [ci]: 1.016–1.181; p = 0.018). in addition, residents with easy access to social networking sites at any time were almost twice as likely to become addicted (or: 1.972, 95% ci: 1.027–3.786; p = 0.041) [table 5]. discussion existing research supports the theory that excessive use of the internet and social media constitutes a distinct form of behavioural addiction, with this behaviour being linked to symptoms typically associated with substance use disorders, such as social anxiety and depressive symptoms.13–15 overuse of the internet has been classified alternatively as an impulse control disorder, an obsessive-compulsive disorder or as a type of behavioural addiction akin to video game addiction or gambling.8 however, few studies have investigated the most appropriate instrument for measuring social media addiction, although those affected clearly show various signs of behavioural addiction such as tolerance, withdrawal, conflict, salience, relapse and mood changes.3,25,26 varying rates of social media usage have been reported among postgraduate residents. moubarak et al. reported that up to 73% of french medical residents and fellows had active facebook profiles.27 according to irfan et al., 95.4% of family physicians and family medicine residents in saudi arabia felt compelled to check their social media accounts at least once a day, with 51% checking them up to four times or more daily.28 another study of family medicine residents and family physicians found that residents used social media more frequently compared to senior physicians (90.2% versus 70.2%), with half of the residents visiting social networking sites on a daily basis.29 while the overall prevalence of internet addiction varies widely based on different study designs, assess ment criteria and sampling methods, the prevalence table 4: association between internet addiction* and depression† among oman medical specialty board residents (n = 399) internet addiction depression p value n (%) no yes no 190 (75.7) 61 (24.3) 0.012 yes 95 (63.8) 54 (36.2) *assessed using the self-administered 20-item internet addiction test.23 †assessed using the self-administered nine-item patient healthcare questionnaire.22 table 5: independent risk factors for internet addiction among oman medical specialty board residents (n = 399) variable b coefficient p value adjusted or (95% ci) total duration of social media usage in years 0.091 0.018 1.095 (1.016–1.181) average duration of daily social media usage in hours 0.082 0.070 1.085 (0.993–1.185) easy access to social media at any time 0.679 0.041 1.972 (1.027–3.786) or = odds ratio; ci = confidence interval. table 3: association between internet addiction* and sociodemographic characteristic among oman medical specialty board residents (n = 399) characteristic n (%) p value no yes age, mean ± sd 29.04 ± 1.92 29.33 ± 1.99 0.145 gender male 94 (59.5) 64 (40.5) 0.291 female 157 (65.1) 84 (34.9) marital status single 67 (60.9) 43 (39.1) 0.575 married 180 (63.2) 105 (36.8) divorced 1 (100) 0 (0) choice of specialty medical 146 (61.9) 90 (38.1) 0.869 surgical 77 (64.7) 42 (35.3) diagnostic 28 (62.2) 17 (37.8) residency level junior (r1–r2) 128 (64.0) 72 (36.0) 0.679 senior (r3–r6) 123 (61.5) 77 (38.5) living circumstances family 166 (62.2) 101 (37.8) 0.595 friends 50 (68.5) 23 (31.5) alone 28 (58.3) 20 (41.7) others 3 (50.0) 3 (50.0) regular exercise no 161 (61.9) 99 (38.1) 0.659 yes 86 (64.7) 47 (35.3) sleep duration 6.64 ± 1.34 6.60 ± 1.60 0.769 *assessed using the self-administered 20-item internet addiction test.23 ameena m. al mukhaini, fakhriya al houqani and rahma al kindi clinical and basic research | 413 in the general population is estimated to be approximately 2%.8 in the current study, just over onethird (37.3%) of the omsb residents were considered to have some form of internet addiction, although the majority of cases were mild (88.6%), with 10.7% moderately addicted and 0.7% severely addicted. similar findings have been reported in north india, in which 54% of medical residents were mildly addicted to the internet, 8.24% were moderately addicted and there were no cases of severe addiction.30 however, a study of junior doctors (including both postgraduate students and in-house surgeons) at a teaching hospital in southwestern india found the prevalence of moderate internet addiction to be only 13%, with no cases of severe addiction.31 in addition, neither of these studies noted an association between internet addiction and gender.30,31 a recent meta-analysis found the global prevalence of internet addiction among medical students to be 30.1%; in addition, gender did not account for the high heterogeneity in prevalence rates.32 in contrast, previous research has indicated that internet addiction does follow a gender predilection, although reported findings are often contradictory. irfan et al. observed a high level of social media usage for personal purposes among male residents and physicians; however, female physicians were statistically more likely to use social media sites for professional purposes.28 other studies have shown that addictive social media behaviours are more dominant among women.25,33 a large national survey in norway reported that women had significantly higher scores when assessing addiction using the bergen social media addiction scale.26 another large study of university students also found that there was a high positive correlation between being female and being addicted to social media.3 these differences in results could be attributed to various factors, including variable sample sizes, diverse research methodologies and differing measurement tools as well as cultural variations in internet access, behaviours and practices. the present study identified a significant positive relationship between internet addiction and the total duration of social media use, with individuals who had used social media for a greater number of years being more likely to be addicted to it. moreover, there was a strong association between internet addiction and the average number of hours spent on social networking sites per day. these findings support the definition of addiction suggested by the iat, wherein internet addiction is linked to an average internet usage of 39 hours per week.23 the current study also identified several specific social networking sites as being most frequently used by omsb residents, including whatsapp, instagram and youtube. in contrast, irfan et al. reported that youtube (68.2%) and facebook (45.5%) were the most frequently used social media sites among family medicine residents and physicians in saudi arabia, with the median duration of use during a working day being 120 minutes.28 such findings correspond to the fact that the internet has become an integral part of most people’s lives and highlights the need for early and continuous educational initiatives that can be integrated into the curriculum at a young age to identify and prevent internet addiction.34 this is composed of a wide variety of interventions aimed at reducing the incidence of the addiction and its disabilities, or slowing the progression and exacerbation, with health promotion serving as a component of prevention, examples of which includes student education and awareness raising, self-control training programmes and improving self-esteem and teachers and parents training. therefore, there is a need to develop reliable, cost-effective and evidencebased health promotion prevention programmes for internet addiction. the current study revealed a significant assoc iation between internet addiction and depression, with addiction associated with depressive symptoms. a significant association was similarly noted between internet addiction and psychological distress among junior doctors in southwestern india.31 moreover, grover et al. reported that internet addiction was associated with a higher level of depressive symptoms, perceived stress and burnout among medical residents in north india.30 the relationship between these two variables could be because individuals who are heavily engaged with different social networking sites often neglect other, more constructive aspects of their lives, potentially contributing to depression. indeed, people who are very involved in online activities often demonstrate less face-to-face social interaction, decreased levels of physical activity and poor sleeping habits, all of which are conducive to the development of depressive symptoms.35,36 on the other hand, those experiencing depressive symptoms may equally be more prone to becoming addicted to the internet.37 it is apparent that the association between internet addiction and depressive symptoms is bidirectional in nature, with both conditions influencing and contributing to an increase in the other.38 however, additional research is warranted to further elaborate on this association using a more complex longitudinal study design. previous research indicates that the rate of depression is higher among both medical students and postgraduate residents in comparison to their ageand gender-matched peers.19,20 as such, further research is internet addiction and depression among postgraduate residents a cross-sectional survey 414 | squ medical journal, august 2021, volume 21, issue 3 recommended to compare overall rates of depression among postgraduate medical residents in oman with those of an age-matched cohort in another profession to assess possible causes of depression in this specific group and determine whether omsb residents are at a greater likelihood of demonstrating depressive symptoms compared to their counterparts in different occupations or fields of study. this is particularly important as high rates of depression among medical residents have been linked to increased rates of medication errors, career dissatisfaction and suicide.20 in the meantime, measures should be implemented to counteract the apparently high rate of depressive symptoms among omsb residents, such as therapeutic counselling, stress management seminars and peer-led support groups.20 there are several limitations to this study that need to be addressed. although the version of the iat used in this study is one of the most commonly used tools, a newer, updated version is available, which may deliver more accurate results; moreover, the iat scores were not verified by psychiatric assessment to confirm whether the residents were truly addicted. in addition, the data gathered in this study were collected using selfreported tools, potentially resulting in recall bias and the underreporting of relevant symptoms. moreover, the study was conducted on a small sample of medical residents; as such, the results cannot be generalised to the entire population of oman. this limitation can be overcome in future studies by involving a larger sample comprising of other population groups. finally, even though the data is from 2017, the findings are still relevant and an important addition to the existing literature, as it forms a baseline for further research and possible future interventions. notably, the findings of this study do not support a causal link between internet addiction and depression due to the complex aetiology of the latter condition. for instance, the contribution of other factors that can lead to depression was not evaluated (i.e., chronic diseases, major life events, anxiety and comorbid personality disorders); in addition, while the phq-9 is a well-known and validated screening tool, it cannot be used alone for diagnosing depression.22 moreover, it was not confirmed whether any of the omsb residents, particularly those with moderate-to-severe depression, were currently taking any antidepressants, a factor that could have affected the results. finally, the reported internet addiction might be overestimated as the questionnaire used in the study did not distinguish between different reasons for social media use, such as workor academic-related activities. conclusion both depression and internet addiction were clearly detected among omsb residents. in particular, the study found that the longer the total duration of social media usage and average number of hours spent daily on social networking sites, the more likely participants were to become addicted. although a causal link between these factors cannot be established, health education initiatives are recommended to address the potential harmful effects and disadvantages of excessive internet usage. moreover, further research on the consequences of internet addiction and its effect on the quality of life and academic performance is needed. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n am, fh, and rk conceived the presented research idea and went through literature review. am and fh, under the supervision of rk, designed the research methodology and the questionnaire format. am and fh were involved in data collection and date entry. am, fh and rk analysed and interpreted the results. am was a major contributor in writing the manuscript in consultation with fh and rk. rk was the research supervisor who guided am and fh throughout the project. all authors read and approved the final version of the manuscript. references 1. allen ka, ryan t, gray dl, mcinerney dm, waters l. social media use and social connectedness in adolescents: the positives and the potential pitfalls. educ develop psychol 2014; 31:18–31. https://doi.org/10.1017/edp.2014.2. 2. ryan t, chester a, reece j, xenos s. the uses and abuses of facebook: a review of facebook addiction. j behav addict 2014; 3:133–48. https://doi.org/10.1556/jba.3.2014.016. 3. hawi ns, samaha m. the relations among social media addiction, self-esteem, and life satisfaction in university students. soc sci comput rev 2017; 35:576–86. https://doi.org/10.1177/089443 9316660340. 4. khormi sm, ageel ma, otayf sy, al-shafai ha, majrashi sm, hakami nm. addiction to social media among students at jazan university. int j acad sci res 2016; 4:176–80. 5. masters k. social networking addiction among health sciences students in oman. sultan qaboos univ med j 2015; 15:e357–63. https://doi.org/10.18295/squmj.2015.15.03.009. https://doi.org/10.1017/edp.2014.2 https://doi.org/10.1556/jba.3.2014.016 https://doi.org/10.1177/0894439316660340 https://doi.org/10.1177/0894439316660340 https://doi.org/10.18295/squmj.2015.15.03.009. ameena m. al mukhaini, fakhriya al houqani and rahma al kindi clinical and basic research | 415 6. lemmens js, valkenburg pm, peter j. development and valid ation of a game addiction scale for adolescents. media psych 2009; 12:77–95. https://doi.org/10.1080/15213260802669458. 7. andreassen cs, torsheim t, brunborg gs, palleson s. develop ment of a facebook addiction scale. psychol rep 2012; 110:501–17. https://doi.org/10.2466/02.09.18.pr0.110.2.501-517. 8. poli r. internet addiction update: diagnostic criteria, assessment and prevalence. neuropsychiatry (london) 2017; 7:04–08. https://doi.org/10.4172/neuropsychiatry.1000171. 9. american psychiatric association. diagnostic and statistical manual of mental disorders, 5th ed. washington d.c., usa: american psychiatric association publishing, 2013. https://doi. org/10.1176/appi.books.9780890425596. 10. world health organization. icd-11: international class ification of diseases 11th revision the global standard for diagnostic health information. from: https://icd.who.int/en accessed: jul 2020. 11. kandell jj. internet addiction on campus: the vulnerability of college students. cyberpsychol behav 1998; 1:11–17. https:// doi.org/10.1089/cpb.1998.1.11. 12. world health organization. public health implications of excessive use of the internet, computers, smartphones and similar electronic devices: meeting report. from: https://apps.who.int/iris/rest/ bitstreams/826746/retrieve accessed: jul 2020. 13. bányai f, zsila á, király o, maraz a, elekes z, griffiths md, et al. problematic social media use: results from a large-scale nationally representative adolescent sample. plos one 2017; 12:e0169839. https://doi.org/10.1371/journal.pone.0169839. 14. van rooij aj, ferguson cj, van de mheen d, schoenmakers tm. time to abandon internet addiction? predicting problematic internet, game, and social media use from psychosocial well-being and application use. clin neuropsychiatry 2017; 14:113–21. 15. pontes hm. investigating the differential effects of social net working site addiction and internet gaming disorder on psychol ogical health. j behav addict 2017; 6:601–10. https://doi.org/1 0.1556/2006.6.2017.075. 16. shensa a, escobar-viera cg, sidani je, bowman nd, marshal mp, primack ba. problematic social media use and depressive symp toms among u.s. young adults: a nationally-representative study. soc sci med 2017; 182:150–7. https://doi.org/10.1016/j.socsci med.2017.03.061. 17. saikia am, das j, barman p, bharali md. internet addiction and its relationships with depression, anxiety, and stress in urban adolescents of kamrup district, assam. j family community med 2019; 26:108–12. https://doi.org/10.4103/jfcm.jfcm_93_18. 18. mata d, ramoa m, bansal n, khan r, guille c, di angelantonio e, et al. prevalence of depression and depressive symptoms among resident physicians: a systematic review and meta-analysis. jama 2015; 314:2373–83. https://doi.org/10.1001/jama.2015.15845. 19. dyrbye ln, thomas mr, shanafelt td. systematic review of depression, anxiety, and other indicators of psychological distress among us and canadian medical students. acad med 2006; 81:354–73. https://doi.org/10.1097/00001888-200604000-00009. 20. joules n, williams dm, thompson aw. depression in resident physicians: a systematic review. open j depress 2014; 3:89–100. https://doi.org/10.4236/ojd.2014.33013. 21. vargas-cáceres s, mantilla mf, ortega g, bruguera e, casas m, ramos-quiroga ja, et al. dual diagnosis among medical residents: a systematic review. adicciones 2020; 0:1253. https://doi.org/1 0.20882/adicciones.1253. 22. kroenke k, spitzer rl, williams jb. the phq-9: validity of a brief depression severity measure. j gen intern med 2001; 16:606–13. https://doi.org/10.1046/j.1525-1497.2001.016009606.x. 23. young ks. psychology of computer use: xl addictive use of the internet: a case that breaks the stereotype. psychol rep 1996; 79:899–902. https://doi.org/10.2466/pr0.1996.79.3.899. 24. becker s, al zaid k, al faris e. screening for somatization and depression in saudi arabia: a validation study of the phq in primary care. int j psychiatry med 2002; 32:271–83. https://doi. org/10.2190/xtdd-8l18-p9e0-jyrv. 25. andreassen cs. online social network site addiction: a compr ehensive review. curr addict rep 2015; 2:175–84. https://doi. org/10.1007/s40429-015-0056-9. 26. andreassen cs, pallesen s, griffiths md. the relationship between addictive use of social media, narcissism, and selfesteem: findings from a large national survey. addict behav 2017; 64:287–93. https://doi.org/10.1016/j.addbeh.2016.03.006. 27. moubarak g, guiot a, benhamou y, benhamou a, hariri s. facebook activity of residents and fellows and its impact on the doctor-patient relationship. j med ethics 2011; 37:101–4. https://doi.org/10.1136/jme.2010.036293. 28. irfan ks, farhana i, eiad af, nassr am, al mohammed aq, maya n, et al. family physicians' utility of social media: a survey comparison among family medicine residents and physicians. afr health sci 2018; 18:817–27. https://doi.org/10.4314/ahs.v18i3.41. 29. klee d, covey c, zhong l. social media beliefs and usage among family medicine residents and practicing family physicians. fam med 2015; 47:222–6. 30. grover s, sahoo s, bhalla a, avasthi a. problematic internet use and its correlates among resident doctors of a tertiary care hospital of north india: a cross-sectional study. asian j psychiatr 2019; 39:42–7. https://doi.org/10.1016/j.ajp.2018.11.018. 31. prakash s. internet addiction among junior doctors: a crosssectional study. indian j psychol med 2017; 39:422–5. https:// doi.org/10.4103/0253-7176.211746. 32. zhang mwb, lim rbc, lee c, ho rcm. prevalence of internet addiction in medical students: a meta-analysis. acad psychiatry 2018; 42:88–93. https://doi.org/10.1007/s40596-017-0794-1. 33. griffiths md, kuss dj, demetrovics z. social networking addiction: an overview of preliminary findings. in: rosenberg kp, feder lc, eds. behavioral addictions: criteria, evidence, and treatment. london, uk: academic press, 2014. pp. 119–41. https://doi.org/10.1016/b978-0-12-407724-9.00006-9. 34. throuvala ma, griffiths md, rennoldson m, kuss dj. school based prevention for adolescent internet addiction: prevention is the key. a systematic literature review. curr neuropharmacol. 2019;17(6):507-525. doi: 10.2174/1570159x1666618081315380 6.pmid: 30101714; pmcid: pmc6712298. 35. choi k, son h, park m, han j, kim k, lee b, et al. internet over use and excessive daytime sleepiness in adolescents. psychiatry clin neurosci 2009; 63:455–62. https://doi.org/10.1111/j.14401819.2009.01925.x. 36. moreno ma, jelenchick la, koff r, eickhoff jc, goniu n, davis a, et al. associations between internet use and fitness among college students: an experience sampling approach. j interact sci 2013; 1:4. https://doi.org/10.1186/2194-0827-1-4. 37. lin ly, sidani je, shensa a, radovic a, miller e, colditz jb, et al. association between social media use and depression among u.s. young adults. depress anxiety 2016; 33:323–31. https:// doi.org/10.1002/da.22466. 38. seabrook em, kern ml, rickard ns. social networking sites, depression, and anxiety: a systematic review. jmir ment health 2016; 3:e50. https://doi.org/10.2196/mental.5842. https://doi.org/10.1080/15213260802669458 https://doi.org/10.2466/02.09.18.pr0.110.2.501-517 https://doi.org/10.4172/neuropsychiatry.1000171 https://doi.org/10.1176/appi.books.9780890425596 https://doi.org/10.1176/appi.books.9780890425596 https://doi.org/10.1089/cpb.1998.1.11 https://doi.org/10.1089/cpb.1998.1.11 https://doi.org/10.1371/journal.pone.0169839 https://doi.org/10.1556/2006.6.2017.075 https://doi.org/10.1556/2006.6.2017.075 https://doi.org/10.1016/j.socscimed.2017.03.061 https://doi.org/10.1016/j.socscimed.2017.03.061 https://doi.org/10.4103/jfcm.jfcm_93_18 https://doi.org/10.1001/jama.2015.15845 https://doi.org/10.1097/00001888-200604000-00009 https://doi.org/10.4236/ojd.2014.33013 https://doi.org/10.20882/adicciones.1253 https://doi.org/10.20882/adicciones.1253 https://doi.org/10.1046/j.1525-1497.2001.016009606.x https://doi.org/10.2466/pr0.1996.79.3.899 https://doi.org/10.2190/xtdd-8l18-p9e0-jyrv https://doi.org/10.2190/xtdd-8l18-p9e0-jyrv https://doi.org/10.1007/s40429-015-0056-9 https://doi.org/10.1007/s40429-015-0056-9 https://doi.org/10.1016/j.addbeh.2016.03.006 https://doi.org/10.1136/jme.2010.036293 https://doi.org/10.4314/ahs.v18i3.41 https://doi.org/10.1016/j.ajp.2018.11.018 https://doi.org/10.4103/0253-7176.211746 https://doi.org/10.4103/0253-7176.211746 https://doi.org/10.1007/s40596-017-0794-1 https://doi.org/10.1016/b978-0-12-407724-9.00006-9 https://doi.org/10.1111/j.1440-1819.2009.01925.x https://doi.org/10.1111/j.1440-1819.2009.01925.x https://doi.org/10.1186/2194-0827-1-4 https://doi.org/10.1002/da.22466 https://doi.org/10.1002/da.22466 https://doi.org/10.2196/mental.5842 departments of 1child health and 2surgery, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: alsineidiksk@hotmail.com abstract: cor triatriatum sinistrum (cts) is a rare congenital cardiac anomaly characterised by an abnormal septum within the left atrium impairing blood flow to the left ventricle. we report the case of a two-month-old male infant who presented with symptoms of heart failure since the age of two weeks. he was admitted to a local hospital and was managed with antibiotics because of the impression of pneumonia. due to persistent unresolved tachypnoea and tachycardia, he was referred to sultan qaboos university hospital, muscat, oman, in 2019 for cardiac evaluation which confirmed a diagnosis of isolated cts with severe stenosis and pulmonary hypertension. he underwent an urgent surgical excision of the membrane with uneventful recovery. keywords: cor triatriatum sinistrum; congenital heart disease; pulmonary hypertension; heart failure; case report; oman. cor triatriatum sinistrum a rare disease with a common presentation al rumitha al sabri,1 niranjan joshi,1 hamood al kindi,2 *khalfan s. al senaidi1 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e324–326, epub. 21 jun 21 submitted 15 jun 20 accepted 11 aug 20 was no history of cyanosis or choking while feeding. there were no maternal illnesses and the pregnancy was uneventful. the antenatal detailed anatomy ultrasound scan was reported as normal. he was born at term by caesarean section for maternal indication (previous two caesarean sections). on examination, he looked emaciated with no obvious dysmorphic features had a weight of 3.4 kg (<3rd centile) and a length of 57 cm (<25th centile). his respiratory rate was 48 breaths/min and he had a heart rate of 150 beats/min, blood pressure of 99/53 mmhg and oxygen saturation of 100% in room air. cardiovascular examination showed a normal s1 and loud s2 with a soft ejection systolic murmur in the left upper sternal border. his abdomen was soft with the liver 2 cm below the right costal margin. there were no abnormalities detected in the basic blood workup. cxr showed cardiomegaly with upturned cardiac apex indicating right ventricular hypertrophy with features of pulmonary venous congestion [figure 1]. ecg showed sinus rhythm with right axis deviation and right ventricular hypertrophy with strain pattern [figure 2]. echocardiogram showed situs solitus with levocardia. a double chambered left atrium was seen separated by a thick membrane with a restrictive opening of 2 mm to the lower atrial chamber with severe stenosis with peak gradient (pg) of 30 mmhg and a mean of 15 mmhg [figure 3]. there was a mild tricuspid valve regurgitation with pg of 80 mmhg consistent with severe pulmonary hypertension. a small patent foramen ovale was seen with restrictive flow with pg of 22 mmhg and a mean of 14 mmhg. the right atrium and right ventricle were dilated with flattened interventricular septum. the mitral valve cor triatriatum sinistrum (cts) is a rare congenital cardiac anomaly characterised by an abnormal septum within the left atrium impairing blood flow to the left ventricle. it can be isolated or associated with other congenital heart anomalies and commonly diagnosed in early childhood.1 diagnosis is suspected by findings of cardiomegaly and pulmonary oedema on chest radiograph (cxr) and right axis deviation and right ventricular hypertrophy on electrocardiogram (ecg). however, a detailed echocardiogram is required for confirmation and ruling out associated lesions. this report describes a two-month-old infant who presented with heart failure symptoms since the age of two weeks and was diagnosed with cts by echocardiogram. he underwent an urgent surgical intervention with an uneventful recovery. case report a two-month old male infant was referred to sultan qaboos university hospital, muscat, oman, in 2019 with a five-day history of fever, cough and shortness of breath. there was a history of interrupted feeding and sweating since the age of two weeks. he was not thriving well with a presenting weight of 3.4 kg (birth weight: 3 kg). he received a course of intravenous antibiotics in the local hospital due to the diagnosis of a possible chest infection. he was referred for a cardiac evaluation because of persistent tachypnoea, tachycardia and mild cardiomegaly on chest radiograph. there was a history of two previous similar presentations but he was managed as an outpatient with nebulisation and oral antibiotics without much improvement. there this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.026 case report https://creativecommons.org/licenses/by-nd/4.0/ case report | e325 appeared normal with mild mitral valve regurgitation. all pulmonary veins drained to the upper left atrial chamber with no stenosis. there was no right or left outflow tract obstruction. the left atrial appendage opening was seen below the membrane. the aortic arch was normal with no patent ductus arteriosus or coarctation of aorta. systolic cardiac function was normal. the findings were consistent with cts and therefore, the patient was referred for surgical repair. pre-operative transoesophageal echocardiogram (tee) confirmed the cts diagnosis and showed a well demarcated cts with good-sized left atrial appendage below the level of the transverse membranous partition with small fenestration to the lower chamber with severe restrictive flow. intraoperatively, the membrane was visualised and resected fully and the interatrial communication was closed. he was successfully extubated on the second day and weaned off oxygen support in three days with 100% oxygen saturation. he was discharged home on a small dose of diuretics. on last follow-up five months later, he was asymptomatic, off diuretics, tolerating feeds and gaining weight with no distress. repeat echocardiogram showed laminar flow across the left atrium with normalisation of pulmonary artery pressure. discussion cor triatriatum is a rare congenital cardiac anomaly characterised by an abnormal septum within the atrium impairing blood flow to the ventricles. it can be isolated or associated with other congenital heart anomalies and is commonly diagnosed in early childhood.1 it was first described in 1868 by church and accounts for 0.1% of all congenital cardiac anomalies.2 when it involves the left atrium it is called cts and it rarely involves the right atrium (called cor triatriatum dexter).3 in a paediatric population, approximately 77% of cases are associated with congenital cardiac anomalies commonly atrial septal defects (asd) and anomalous pulmonary venous return.4 other rare major associated congenital cardiac lesions include tetralogy of fallot, double outlet right ventricle and coarctation of the aorta. the pathogenesis of cts is unknown but different theories have been suggested. the most popular theory is the entrapment theory introduced by van praagh and corsini.5 this theory suggested that cor triatriatum results from entrapment of the left atrial ostium of the common pulmonary vein by tissue of the right horn of the sinus venosus from which septum primum develops, leading to failure of incorporation of the common pulmonary vein into the left atrium during the fifth embryonic week. however, no single theory explains the different presentation and wide spectrum of cts. yet, multiple classifications of cts based on the completeness of the membrane and presence of associated anomalies have been proposed.3 recent animal studies demonstrated that mutations in the hyaluronidase 2 (hyal2) gene contribute to the development of cts.6 hyal2 is involved in different cellular processes and tissue morphogenesis and is required for endothelial-to-mesenchymal transition for proper development of the endocardial cushion in normal heart development.6 al kindi et al. recently found that hyal2 was expressed in human cts membranes that were resected during surgical repair.7 therefore, hyal2 deficiency may not explain the pathogenesis of cts membrane in humans. future studies are needed to evaluate the complex mechanisms involved and the embryological basis of this disease. in isolated cts, the presentation depends on the size of the communication between the upper and lower atrial chambers and the size of the interatrial communication.4 as seen in the current case, patients figure 1: 12-leads electrocardiogram of a two-monthold male infant with cor triatriatum sinistrum showing sinus rhythm with right axis deviation and right ventricular hypertrophy with strain pattern. figure 2: chest radiography of a two-month-old male infant with cor triatriatum sinistrum showing features of pulmonary venous congestion and right ventricular hypertrophy. al rumitha al sabri, niranjan joshi, hamood al kindi and khalfan s. al senaidi presenting in infancy with symptoms are mostly those with small openings in the membrane or with no asd. cts usually presents with symptoms mimicking mitral stenosis and supra mitral ring including commonly tachypnoea, recurrent respiratory infections and failure to thrive.4 a rise in the atrial pressure and pulmonary congestion leads to dyspnoea.4 the risk of death is over 75% if untreated.2 other common differential diagnoses for cts clinical presentation include obstructed anomalous pulmonary venous drainage and congenital heart disease with left to right shunts such as ventricular septal defects and patent ductus arteriosus. investigations for the diagnosis and follow-up of cts include ecg, which can be normal or show evidence of right ventricular hypertrophy and right axis deviation, and cxr which may show cardiomegaly with pulmonary venous congestion or pulmonary oedema. echocardiogram is a non-invasive and diagnostic procedure that can accurately show the membrane and any associated anomalies. furthermore, cxr is usually performed to assess the cardiac size and to exclude other possible secondary causes for the patient’s symptoms. tee is usually done pre-operatively to better visualise the membrane and ensure that it is completely excised post-operatively. it is also especially valuable to differentiate cts from the supra-valvular mitral ring, the latter being located below the left atrial appendage. surgical management is the optimal choice for symptomatic patients. the presence of obstructive symptoms at any age requires surgical intervention and the severity of presenting symptoms determines the urgency of surgery. the outcome is usually excellent but can be variable depending on the complete excision of the membrane and the associated anomalies.8 conclusion stenotic simple cts is a rare congenital heart disease with a favourable prognosis if diagnosed early and managed promptly. for clinicians, it is important to have a high index of suspicion to recognise its common clinical presentation which mimics the presentation of other more common diseases. as shown in the current case, prompt diagnosis and management can lead to an excellent outcome. references 1. jha ak, makhija n. cor triatriatum: a review. semin cardio thorac vasc anesth 2017; 21:178–85. https://doi.org/10.1177/1 089253216680495. 2. brown j, hanish si. cor triatriatum sinister, atresia of the common pulmonary vein, pulmonary vein stenosis, and cor triatriatum dexter. in: mavroudis c, backer c, eds. pediatric cardiac surgery. philadelphia, pennsylvania, usa: mosby, 2003. pp. 625–33. 3. nassar pn, hamdan rh. cor triatriatum sinistrum: classif ication and imaging modalities. eur j cardiovasc med 2011; 1:84–7. https://doi.org/10.5083/ejcm.20424884.21. 4. humpl t, reineker k, manlhiot c, dipchand ai, coles jg, mccrindle bw. cor triatriatum sinistrum in childhood. a single institution's experience. can j cardiol 2010; 26:371–6. https://doi.org/10.1016/s0828-282x(10)70418-9. 5. van praagh r, corsini i. cor triatriatum: pathologic anatomy and a consideration of morphogenesis based on 13 postmortem cases and a study of normal development of the pulmonary vein and atrial septum in 83 human embryos. am heart j 1969; 78:379–405. https://doi.org/10.1016/0002-8703(69)90046-5. 6. marei wf, salavati m, fouladi-nashta aa. critical role of hyaluronidase-2 during preimplantation embryo development. mol hum reprod 2013; 19:590–9. https://doi.org/10.1093/ molehr/gat032. 7. al kindi hn, shehata m, ibrahim am, roshdy m, simry w, aguib y, et al. cor triatriatum sinister (divided left atrium): histopathologic features and clinical management. ann thorac surg 2020; 110:1380–6. https://doi.org/10.1016/j. athoracsur.2020.01.025. 8. van son ja, danielson gk, schaff hv, puga fj, seward jb, hagler dj, et al. cor triatriatum: diagnosis, operative approach, and late results. mayo clin proc 1993; 68:854–9. https://doi. org/10.1016/s0025-6196(12)60693-4. figure 3: (a) four chamber and (b) parasternal long axis echocardiographic views showing the divided left atrium into upper (1) and lower (2) chambers by the membrane (blue arrow). note the dilated hypertrophied right ventricle and the very small restricted opening in the membrane (red arrow). ra = right atrium; rv = right ventricle; lv = left ventricle; mv = mitral valve. airway and anaesthetic challenges in a child with bronchus suis and superimposed double aortic arch a case report e326 | squ medical journal, february 2021, volume 21, issue 1 https://doi.org/10.1177/1089253216680495 https://doi.org/10.1177/1089253216680495 https://doi.org/10.5083/ejcm.20424884.21 https://doi.org/10.1016/s0828-282x%2810%2970418-9 https://doi.org/10.1016/0002-8703%2869%2990046-5 https://doi.org/10.1093/molehr/gat032 https://doi.org/10.1093/molehr/gat032 https://doi.org/10.1016/j.athoracsur.2020.01.025 https://doi.org/10.1016/j.athoracsur.2020.01.025 https://doi.org/10.1016/s0025-6196%2812%2960693-4 https://doi.org/10.1016/s0025-6196%2812%2960693-4 clinical & basic research squ med j, april 2010, vol. 10, iss. 1, pp. 74-79, epub. 17th apr 10 submitted 14th april 09 revision req. 17th oct 09, revisions recd. 31st oct 09 and 7th feb 10 accepted 22rd feb 10 1department of physical education, college of education, sultan qaboos university, muscat, oman; 2fitness first, amman, jordan *to whom correspondence should be addressed. email: hakilani@squ.edu.om َّة املُثلى لرتكيب اجلسم املثالي معايري الِقياساِت الَبَشِري املتعلق باللياقة هاشم كيالني، عاصم أبو عيشة اخلال�صة: الهدف: هناك ثالثة اأهداف لهذه الدرا�صة: عمل معادالت لرتكيب اجل�شم املثايل املتعلق باللياقة ال�شتعماله من ِقَبل البالغني الراغبني باحل�ش�ل على تركيب اجل�شم املثايل املتعلق باللياقة، التنب�ؤ مبحيط الع�شلة الرئي�شية املتناظر، وح�شاب الن�شبة املئ�ية املثالية لُدْهن اجل�شم مع ال�زن املثايل للج�شم باالعتماد على من�شب كتلة اجل�شم. الطريقة: مت اختيار 24 ريا�شيا، ط�ل قاماتهم بني 166190 �شم واأعمارهم املفرط«. اجل�شم فئة « اللياقة تناف�س اأجل من للياقة العاملي لالحتاد املح�رة املعايري ا�شتعملت جلنة راأي على بناء �شنة، 24 – 20 بني ة ال�شائعة وتركيب اجل�شم للمتغريات امل�صتقلة : وزن اجل�شم، ط�ل الطرف العل�ي، ط�ل الطرف ال�شفلي، ط�ل الفخذ، ط�ل اخذت الِقيا�شاِت الَب�رَسِيَّ وال�رك واخل�رس والفخذ الكتف من كل حميط املعتمدة التالية: وللمتغريات املع�شم، حميط ال�شاق، ط�ل ال�شاعد، ط�ل الكتف، عر�س الذراع، وال�شدر والع�شلة ذات الراأ�شني وال�شاعد وال�شاق والرقبة. مت قيا�س ثخن طية اجللد يف ثالث مناطق بفرجار هاربيندين لقيا�س الن�شبة املئ�ية لدهن اجل�شم. النتائج: ت�ؤ�رس النتائج اىل وج�د ترابط تنب�ؤي بني املتغريات امل�شتقلة الرئي�شية وقيا�شات حميط اجل�شم. كان مت��شط املدى الذي املثايل: اجل�شم وزن الإيجاد ا�شتعملت التي اجل�شم كتلة من�شب معادلة .%6.6 – 5.6 اجل�شم لدهن املثالية املئ�ية الن�شبة اليجاد ا�شتخدم التنب�ؤ. كانت اأكرث املتغريات امل�شتقلة القابلة للتنب�ؤ حميط معادالت ال�شتقاق املت�شاعد املتعدد التح�ف ا�شتعمل .h2 × 23.77 ± 2se املع�شم والط�ل. مفتاح الكلمات: تركيب اجل�شم، القيا�شات الب�رسية، مترين املقاومة. abstract: objectives: the three aims of this study were to establish equations for ideal body composition related fitness to be used by adults willing to gain optimum body composition related fitness; to predict the possible symmetrical major muscle circumference, and to compute the ideal body fat percentage (bfp) with ideal body weight (ibw) based on the body mass index (bmi). methods: twenty-four athletes were intentionally selected, with heights of 166–190 cm and aged 20–42 years, according to a judging committee that used modified international fitness federation criteria for the mr. fitness competition “super body category”. common anthropometric and body composition measurements were taken for the following independent variables: body height, upper limb length, lower limb length, thigh length, arm length, shoulder width, forearm length, shank length, and wrist girth; and for the following dependent variables: circumferences of shoulder, thigh, waist, hip, chest, biceps, forearm, shank, and neck. skin fold thickness was measured at three sites by a harpenden caliper to calculate bfp. results: the findings indicate that there was a predictive correlation between major independent variables and body circumferences. the mean range used to find out the ideal bfp percentage which was 5.6–6.7 %. the bmi equation used to find the ibw was h2 × 23.77 ± 2 se. stepwise multiple regressions were also used to derive predictive equations. the most predictive independent variables were wrist girth and height. conclusion: it is suggested that the above equations, the ideal bfp percentage and the ibw be used as criteria in training sessions to achieve ideal body composition related fitness. keywords: body composition; anthropometric; resistance training; optimum anthropometric criteria for ideal body composition related fitness *hashem kilani,1 and asem abu-eisheh2 clinical & basic research advances in knowledge 1. this is the first study that establishes prediction equations to achieve ideal body composition related fitness. 2. the results of this study will help novices in developing their own resistance training programme based on the equations. application to patient care 1. in order to maintain good health status, patients need to follow a regular physical activity regime based on this study’s equations. 2. patients with posture abnormality may apply these prediction formulas to achieve body alignment and correct posture through a rehabilitation program. hashem kilani, and asem abu-eisheh clinical and basic research | 75 fitness club participants have different goals when they plan to workout. some people would like to reduce weight, others to increase cardiovascular endurance, and the rest would like to develop muscle mass. for the first two groups, sufficient standards and criteria exist for the design and monitoring of an appropriate physical training programme that would lead to beneficial changes in body composition, such as reductions in body fat and increases in cardiovascular fitness. the third group, bodybuilders, compete on the size, definition, symmetry and shape of their muscular body composition. the ideal body composition related fitness represents the actual lean body mass symmetry combined with a low fat percentage that leads to a high level of health-related fitness. however, before aiming to achieve ideal body composition related fitness, people need to follow a well-balanced diet with a regular physical activity regime early in their lives in order to maintain a good health status. not only is regular physical activity essential for normal growth and development, but physical activity habits established early in life tend to carry over into adulthood.1,2 although activities that enhance cardiorespiratory fitness are generally recommended for all, research increasingly suggests that resistance training can offer unique benefits for children, adolescents, and for patients having osteoporosis, diabetics, arthritis and most non-communicable diseases, especially when appropriately prescribed and supervised.3,4,5 physical fitness requirements for body builders have recently evolved away from only developing bulky muscle. physical fitness is a term that is used interchangeably with cardiorespiratory fitness, musculoskeletal fitness and health related physical fitness. recently, resistance training and weight training with cardio drills were developed to allow people to achieve multiple physical fitness objectives. thus, the relationship between cardio and muscular functioning is enhanced by virtue of multiple intervention training leading to a healthier life style.5 the american college of sport medicine (acsm) recommends that young adults, who have no medical problems that may limit their acceptable level of activity, should engage in moderate intensity aerobic exercise for a minimum of 30 minutes at least 5 days a week. in addition to the recommendations for aerobic exercise, the guidelines also specify that healthy adults should engage in moderate resistance (strength) training at least twice per week and should aim to work all of the major muscle groups.6 the available evidence suggests that muscular strength and power also prevent the risk of cardiovascular mortality, independent of cardiovascular fitness, and their development might be considered as prophylaxis for non-communicable diseases.7,8 in the context of promoting muscular strength and power, the international body fitness federation (inbf), the non-profit amateur affiliate of the world national bodybuilding federation (wnbf), organises the mr. fit body contest where health fitness and body symmetry are demonstrated by contestants executing certain manoeuvres.9 planning, predicting, and monitoring changes in body symmetry and health fitness are critical for this calibre of bodybuilders. anthropometrically based prediction equations designed to detect body composition changes, have not been rigorously tested in athletes. several reports have commented on the inadequacy of various skin-fold-thickness equations to predict changes in body composition, whether modest10,11 or large.12,13,14 most previous studies predicted bmi or body fat percentages from either anthropometric measures only, or with other correlation methods to body segment circumferences. to date, standard or predictive equations that would assess the relationship between body parts and the symmetrical composition of the desired ideal body composition are not available for practical application. the purpose of this study is to establish equations for ideal body composition related fitness that can be used by adults wanting to gain optimum body composition related fitness to predict the possible symmetrical major muscle circumference, and to compute the ideal body fat percentage (bfp) with ideal body weight (ibw) based on the body mass index (bmi). in this 3. using the equations from this study, weight reduction can be achieved through resistance training that would optimise body composition and fitness level. 4. the knowledge obtained from this study will encourage young people to initiate an active life style early in their lives thus preventing the occurrence of non-communicable diseases. optimum anthropometric criteria for ideal body composition related fitness 76 | squ medical journal, april 2010, volume 10, issue 1 context, the following questions were raised: 1) what is the ideal fat percentage for optimum body composition? 2) what is the ideal body weight for optimum body composition? 3) which are the most predictive variables derived from this study? methods twenty-four jordanian male athletes participated in this study. they were 20–42 years old and their height ranged between 166 and 190 cm. they were selected from a total of 84 athletes from 91 clubs by a judging committee using modified international fitness federation criteria for the mr. fit body contest. the “super body” category was used as the standard for the ideal bodies for this study. they reported to have been drug-free for the previous seven years. although, the sample size is not large, it was sufficient for the classical statistics used in this analysis as shown in the tables. the statistical package for the social sciences (spss) software, version 15, was used for statistical analysis. all participants gave informed consent to participate in the study. common anthropometric and body composition measurements were taken for the following independent variables: body height (bh), upper limb length (ull), lower limb length (lll), thigh length (tl), arm length (al), shoulder width (sw), forearm length (fl), shank length (sl), and table 1: descriptive statistics for the subjects’ variables. mean max value min value sd m se the confidence interval 95% of the sample variables minimum–maximum age (yr) 25.79 42 20 4.83 25.00 0.99 23.75–27.83 height (cm) 175.02 190 166 6.32 173.25 1.29 172.35–177.69 weight (kg) 73.50 88.7 64.8 6.21 72.85 1.27 70.87–76.12 bmi 23.78 24.8 22 0.62 23.80 0.13 23.51–24.04 fat % 6.17 9 4 1.33 6.00 0.27 5.60–6.73 neck circum (cm) 39.69 44 37 1.78 39.75 0.36 38.94–40.44 chest circum (cm) 101.81 110 96 3.57 102.0 0.73 100.31–103.32 waist circum (cm) 78.23 84 72 3.23 78.50 0.66 76.87–79.59 hip circum (cm) 91.63 99 85 3.36 91.00 0.69 90.21–93.04 shoulder circum (cm) 119.96 129 111 4.90 119.0 1.00 117.89–122.03 arm circum (cm) 35.04 38.5 32 1.76 35.00 0.36 34.30–35.78 forearm (cm) 29.77 32 28 1.29 30.00 0.26 29.22–30.32 thigh circum (cm) 55.54 62 52 2.60 55.00 0.53 54.44–56.64 shank circum (cm) 36.08 39 31 1.97 36.25 0.40 35.25–36.92 arm length (cm) 33.02 38 30 1.93 33.00 0.39 32.21–33.83 shank length (cm) 42.65 48.5 38.5 2.51 42.00 0.51 41.59–43.71 wrist girth (cm) 17.61 19 17 0.63 17.50 0.13 17.34–17.87 upper extremity length (cm) 80.98 89 76 2.77 81.25 0.57 79.81–82.15 upper extremity length (cm) 94.02 103 85 4.64 95.00 0.95 92.06–95.98 forearm length (cm) 28.17 30 25 1.38 28.50 0.28 27.58–28.75 thigh length (cm) 43.40 48 38 2.80 44.00 0.57 42.21–44.58 shoulder width (cm) 37.77 43 34 2.01 37.75 0.41 36.92–38.62 legend: se = standard error; sd = standard deviation; hashem kilani, and asem abu-eisheh clinical and basic research | 77 wrist girth (wrg); and the following dependent variables: circumferences of shoulder (sh), thigh (t), waist (w), hip (h), chest (ch), biceps (bi), forearm (f), shank (s), and neck (nk). skin fold thickness was measured at three sites with a harpenden caliper to ascertain the subject’s body fat percentage (bfp). based on a previous pilot study and other research, all measures were reliable and valid. results the descriptive anthropometric statistics mean, median, standard deviation, and minimum and maximum values for the 24 participants are presented in table 1. the 95% confidence interval for each variable is also shown in the table. values falling beyond this confidence interval were assumed as outliers. with respect to the first and second research questions, table 1 illustrates 95% confidence interval for the ideal fat percentage and the ideal body weight for the optimum body composition. the formula applied to determine bmi, which uses the bw over square height in metres, can be applied inversely to predict the ideal body weight using either the mean or the values falling within the 95% confidence interval. thus, the acceptable values used to find out the ideal bfp %, which are between 5.6 and 6.7%, can be used to determine the (ibw) which is = h2 × 23.77 ± 2se. table 2 also showed that the highest significant coefficient correlation was between shoulder circumference and total body height. in addition, shoulder circumference was the dependent variable that significantly correlated with all independent variables except wrist girth. in order to determine the best prediction equation for each dependent variable, an analysis was conducted using spss software which uses several independent variables and one dependent variable. stepwise multiple linear regressions were used. in addition, regression variance analysis was used to explore the explanation power for the predicted equations. wrist girth was the independent variable most often derived as a predictor whether in isolation or combined with other independent variables. the total body height came next as shown in table 3. the following predictive equations were derived from the statistical manipulation: 1. neck circumference = -3.882 + 0.349 (ull) + 0.868 (wrg) 2. shoulder circumference = -6.221 + 0.943 (bh) + 1.031 (tl) – 0.889 (lll) table 2: coefficient of correlation between independent and dependent variables height arm length shank length wrist girth upper extremity length lower extremity length forearm length thigh length shoulder width variables 0.676*0.468*0.556*0.545*0.678*0.518*0.270.300.20neck circum 0.570*0.260.586*0.240.260.619*0.455*0.457*0.32chest circum 0.722*0.547*0.648*0.200.495*0.690*0.420*0.250.36waist circum 0.774*0.723*0.656*0.360.563*0.715*0.320.230.423*hip circum 0.781*0.430*0.745*0.370.616*0.697*0.512*0.688*0.521*shoulder circum 0.390.130.390.260.330.330.390.414*0.19arm circum 0.511*0.390.496*0.563*0.290.520*0.491*0.310.31forearm circum 0.513*0.230.438*0.010.340.500*0.270.618*0.27thigh circum 0.437*0.380.411*0.534*0.200.474*0.360.380.17shank circum legend: * = p value at 0.05 optimum anthropometric criteria for ideal body composition related fitness 78 | squ medical journal, april 2010, volume 10, issue 1 3. chest circumference = 57.083 + 0.476 (lll) 4. waist circumference = 25.772 + 0.459 (bh) – 1.581 (wrg) 5. hip circumference = 34.212 + 0.425 (bh) – 0.442 (tl) + 0.881 (al) 1.528 (wrg) 6. biceps circumference = 23.776 + 0.26 (tl) 7. forearm circumference = 9.406 + 1.157 (wrg) 8. thigh circumference = 30.632 + 0.574 (tl) 9. shank circumference = 6.666 + 1.671 (wrg) discussion since the statistical analyses were run for variable values falling within the 95% confidence interval, the above equations would apply for a sample of men aged between 24 and 28 years, height between 172 and 178 cm, and body fat percentages between 5.6 and 6.7%. the ideal homogenous weight can be predicted using the formula of bmi inversely which is h2 × 23.77 ± 2se. this equation offers an advantage over other methods such as measures of bmi or weight, body composition, and fat distribution in assessing body composition related fitness.13 body weight is not a suitable measure for assessing ideal body composition related fitness because an increase in weight due to an increase in fat-free mass (ffm) can be misinterpreted as an increase in body fatness. bmi measure can not be valid for all people; hence, we should be cautious when this index is applied to the extremes of physical types such as elite athletes, the physical frail, pregnant women, and children.15 direct measures of percentage body fat and ffm are currently impractical for widespread use in screening for general health and fitness standards. indirect or clinical methods usually rely on estimation of body composition from easily measured variables such as circumferences or skinfold thicknesses and use of prediction equations. fridel et al. suggest that anthropometry can provide better estimates of fatness than body mass index, but it is still relatively insensitive to short-term alterations in body composition.10 in order to identify changes correctly and to provide positive and correct feedback, it is necessary to be able to assess progress without the use of expensive equipment or technically complex procedures. kilani indicated that on average, fat percentages are 12 to 15% and 18 to 22% for males and females respectively. for most elite athletes, these percentages are lower and might reach 3% for bodybuilders.15 three percent is the lowest level of essential body fat needed for males to survive without hazardous health problems. fat loss is well represented by a simple decrease in the abdominal girth measurement, even for the leanest men.10 not surprisingly, the circumference equation that includes the wrist girth and height length instead of arm and thigh lengths proved to be the most reliable to follow as shown in table 2. using all nine equations before enrolling into an exercise programme will lead to an optimisation of the symmetry of body segment circumferences and an ideal body weight and body fat percentage related health status. in addition, the above equations can also be used for non-athletes, including patients, when they want to exercise in a scientific manner. in general, if patients have posture abnormalities, they may table 3: summary of stepwise regression analyses for significant variables predicting selected dependent variables dependent variable to predict significant prediction variables coeff. of regr. standard error neck circumference constant -3.882 8.939 upper extremity length 0.349 0.106 wrist girth 0.868 0.468 waist circumference constant 25.772 14.233 height 0.459 0.087 wrist girth -1.581 0.876 hip circumference constant 34.212 11.286 height 0.425 0.087 thigh length -0.422 0.153 arm length 0.881 0.267 wrist girth -1.528 0.716 shank circumference constant 6.666 9.943 wrist girth 1.671 0.564 forearm circumference constant 9.406 6.379 wrist girth 1.157 0.362 hashem kilani, and asem abu-eisheh clinical and basic research | 79 apply these formulae to achieve body alignment and correct posture. if obesity is the major health problem, weight reduction can be achieved through resistance training that would optimise body composition and fitness level.16 the use of the previous equations can also be prescribed to patients in rehabilitation programmes. finally, young people need to work out based on these equations to achieve fitness and to prevent non-communicable diseases since the effective application of the equations works as prophylaxis for patients with arthritis, obesity, diabetes, and hypertension. conclusion this analysis provides a thorough study of multiple anthropometric and body composition measures and their association with ideal body shape related fitness in a population highly involved in achieving muscle symmetry outcomes. the study has identified the equations for the most predictive criteria in order to achieve ideal body shape related fitness. a training programme can therefore be planned based on the initial anthropometric measurements and then predict the homogeneity of muscle bulk, definitions, and shape with fairly accurate efficiency and effectiveness. the above equations can be used to predict ideal bfp % and ibw as criteria in the training sessions to achieve ideal body composition. however, further research is still needed to confirm the validity of implementing the above predictive formulas for any active person initiating a training programme. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. raitakari ot, porkka kv, taimela s, telama r, räsänen l, viikari js. effects of persistent physical activity and inactivity on coronary risk factors in children and young adults: the cardiovascular risk in young finns study. am j epidemiol 1994; 40:195– 205. 2. telama r, yang x, viikari j, välimäki i, wanne o, raitakari o. physical activity from childhood to adulthood: a 21 year tracking study. am j prev med 2005; 28:267–73. 3. blimkie c. resistance training during preadolescence: issues and controversies. sports med 1993; 15:389– 407. 4. guy j, micheli l. strength training for children and adolescents. j am acad orthop surg. 2001; 9:29– 36. 5. american college of sports medicine. scam’s guidelines for exercise testing and prescription. philadelphia: lippincott, williams & wilkins, 2000. pp. 143–7. 6. american college of sports medicine and the american heart association physical activity and public health. updated recommendation for adults for physical acitivity and public health. circulation 2007; 116:1081–93. 7. ball k, cleland vj, timperio af, salmon j, crawford da. socioeconomic position and children’s physical activity and sedentary behaviors: longitudinal findings from the clan study. j phys act health 2009; 6:289–98. 8. katzmarzyk pt, craig cl. musculoskeletal fitness and risk of mortality. med sci sports exerc 2000; 34:740–4. 9. gaines rp. comparison of anthropometric measures of competitive bodybuilders to judges’ scores & a comparison of judges’ scores. phd thesis, virginia polytechnic institute & state university, usa, 2001. 10. friedl ke, moore rj, martinez-lopez le, vogel ja, askew ew, marchitelli lj, et al. lower limits of body fat in healthy active men. j appl physiol 1994; 77:933–40. 11. wilmore jh, girandola rn, moody dl.validity of skinfold and circumference assessment for predicting alterations in body composition. j appl physiol 1970; 29:313–7. 12. zwiren l, skinner js, buskirk er. use of body density and various skinfold equations for estimating small reductions in body fatness. j sports med 1973; 13:213–8. 13. scherf j, franklin ba, lucas cp, stevenson d, rubenfire m. validity of skinfold thickness measures of formerly obese adults. am j clin nutr 1986; 43:128–35. 14. king ma, katch fi. changes in body density, fatfolds and girths at 2.3 kg increments of weight loss. hum biol 1986; 58:709–18. 15. kilani h. physiology of physical effort. amman: haneen publisher, 2006. pp. 360–90. 16. kilani, h. the effect of aerobic versus anaerobic exercises on weight reduction. proceedings of obesity in the arab world, third arab conference for obesity and physical activity, manamah, bahrain, 2010. pp.136–51. pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials *mohammad z. asha1 and sundos f. h. khalil2 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e291–304, epub. 22 dec 19 submitted 25 apr 19 revision req. 2 jul 19; revision recd. 10 jul 19 accepted 26 jul 19 1department of internal medicine, dr mohamad amine zbeib polyclinic, doha, qatar; 2department of pharmacology, university of jordan, doha, qatar *corresponding author’s e-mail: drmohammadasha@gmail.com gastrointestinal neuropathies in patients with diabetes represent vital aspects of the chronic course of the disease. they may include oesophageal dysmotility, gastroparesis, small bowel dysmotility or diarrhoea and fecal incontinence.1 more precisely, reduced gastric emptying (ge) has been frequently reported in diabetic patients having gastro intestinal autonomic neuropathy.2 delayed ge was first reported by boas in 1925, which was subsequently termed gastroparesis diabeticorum by kassender in 1958.3,4 a symptom entailing contractile, functional, sensory and electrical dysfunction of the stomach was then identified and described as diabetic gastroparesis (dg).5 this can be perceived as chronic delayed ge associated with nausea, vomiting, postprandial fullness, weight loss, anorexia and abdominal pain without evidence of mechanical obstruction. furthermore, dg patients usually have poor quality of life and poor glycaemic control; in addition, the disease imposes a significant financial burden on healthcare systems.6 the prevalence of dg varies in the literature; in general, the risk of gastroparesis is higher in patients with type 1 diabetes mellitus (t1dm) compared to type 2 diabetes mellitus (t2dm). dg disease prevalence in t1dm was found to be 4.8% based on diabetes registries while tertiary medical centres have reported a prevalence of up to 64%.7–9 in t2dm, dg is reported in 10.8–30% of patients.10,11 gender differences were review النـُُهج الدوائية لعالج َخَزل املعدة السَُّكرِي مراجعة منهجية للتجارب السريرية العشوائية حممد زكي ع�صا و �صند�ض فالح ح�صني خليل abstract: pharmacological interventions of diabetic gastroparesis (dg) constitute an essential element of a patient’s management. this article aimed to systematically review the available pharmacological approaches of dg, including their efficacy and safety. a total of 24 randomised clinical trials (rcts) that investigated the efficacy and/or safety of medications targeting dg symptoms were identified using several online databases. their results revealed that metoclopramide was the only approved drug for accelerating gastric emptying and improving disease symptoms. however, this medication may have several adverse effects on the cardiovascular and nervous systems, which might be resolved with a new intranasal preparation. acceptable alternatives are oral domperidone for patients without cardiovascular risk factors or intravenous erythromycin for hospitalised patients. preliminary data indicated that relamorelin and prucalopride are novel candidates that have proven to be effective and safe. future rcts should be conducted based on unified guidelines using universal diagnostic modalities to reveal reliable and comprehensive outcomes. keywords: gastroparesis; diabetes mellitus; diabetes complications; randomized controlled trial; metoclo pramide; domperidone; relamorelin. َكري عن�رسا اأ�صا�صيا لعالج املري�ض. تهدف هذه املقالة اإىل مراجعة منتظمة للُنُهج امللخ�ص: ت�صكل التدخالت الدوائية يف َخَزل املعدة ال�صُّ َكري، مبا يف ذلك فعاليتها و�صالمتها. مت حتديد ما جمموعه 24 جتربة �رسيرية ع�صوائية والتي الدوائية املتوافرة لعالج َخَزل املعدة ال�صُّ َكري با�صتخدام العديد من قواعد البيانات عرب النرتنت. مت التحقق من فعالية و�صالمة الأدوية التي ت�صتهدف اأعرا�ض َخَزل املعدة ال�صُّ اأظهرت نتائج هذه التجارب اأن امليتوكلوبراميد كان الدواء الوحيد املعتمد لت�رسيع التفريغ امَلِعِدي وحت�صني اأعرا�ض املر�ض. ومع ذلك ، قد يكون لهذا الدواء العديد من الآثار اجلانبية على اجلهاز القلبي الوعائي واجلهاز الع�صبي، والتي ميكن التغلب عليها عن طريق م�صتح�رس جديد ي�صتخدم عرب الأنف. البدائل املقبولة هما الدومبرييدون عن طريق الفم للمر�صى الذين لي�ض لديهم عوامل خطر قلبية وعائية اأو الإريرثومي�صني عن طريق احلقن الوريدي للمر�صى املنومني يف امل�صت�صفى. اأ�صارت البيانات الأولية اإىل اأن الريالموريلني والربوكالوبريد على بناًء م�صتقبلية ع�صوائية �رسيرية جتارب اإجراء ينبغي ا�صتعمالها. و�صالمة فعاليتها ثبتت التي اجلديدة املر�صحة الأدوية من هي مبادئ توجيهية موحدة با�صتخدام طرائق ت�صخي�صية عامة للك�صف عن نتائج موثوقة و�صاملة. َكِري؛ جتربة ع�صوائية ُمراقبة؛ ميتوكلوبراميد؛ دومبرييدون؛ ريالموريلني. َكِري؛ م�صاعفات ال�صُّ َكري؛ داء ال�صُّ الكلمات املفتاحية: َخَزل املعدة ال�صُّ this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.004 https://creativecommons.org/licenses/by-nd/4.0/ pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials e292 | squ medical journal, november 2019, volume 19, issue 4 observed in several publications where females had higher prevalence rates than males.8,10,12 poorlycontrolled diabetes, higher glycosylated haemoglobin (hba1c), long duration of diabetes and the presence of comorbidities have been consistently reported as independent risk factors of dg.8,10 similarly, in an epidemiological study involving 8,657 individuals in australia, patients with poor glycaemic control had increased prevalence of upper and lower gastro intestinal symptoms.12 additionally, the probability of developing dg symptoms increased with advanced age, with a mean age of onset at approximately 34 years.5 the diagnosis of dg may remain elusive until the development of complications. to avoid this delay, a precise medical history of the timing of symptoms (i.e. vomiting and satiety) in relation to meals, diet history, symptom progression and diabetes control should be carefully assessed. severity of dg symptoms is evaluated using the gastroparesis cardinal symptom index (gcsi), which can be utilised to rate changes in symptoms in clinical studies either by the patient or the physician on a scale ranging from zero (no symptoms) to six (very severe symptoms).13 furthermore, gastric obstruction can be excluded using abdominal radiography, computed tomography and magnetic resonance imaging scans. consequently, a dg diagnosis is confirmed by means of three main diagnostic tests. the first method is gastric emptying scintigraphy (ges), which is a noninvasive method employing a radio-labelled solid meal (mostly using 99mtc-sulfur) followed by scanning the stomach at one, two and four hours after the meal.14 the second method is the stable isotope breath test (gastric emptying breath test [gebt]). after ingestion of meals with 13c-labelled substrates, such as octanoic acid and spirulina platensis, the isotope is absorbed in the small intestine and metabolised to 13carbon dioxide and exhaled through the lungs. finally, a recent diagnostic modality is a swallowed wireless motility capsule wherein a specialised sensor is used to measure pressure, temperature and ph.15 ge in patients with dg is challenging in terms of treatment. this is particularly evident because optimum glycaemic control should be achieved in poorlycontrolled diabetic patients. dietary modifications, such as replacing solid food with a soft and liquid diet, are required. several pharmacologic options are available although the efficacy and safety of these medications vary. usually, patients with mild to moderate symptoms are managed by prokinetics and antiemetics. however, disease burden in patients experiencing severe symptoms is difficult to manage. therefore, it is necessary to determine the most appropriate therapeutic options bearing in mind the prevention of potential gastrointestinal complications in dg patients including gastroesophageal reflux disease, bacterial and fungal infections of the gastrointestinal tract and intestinal dysmotility. in this context, this article aimed to systematically review the available approaches for the pharmacotherapy of dg, including their efficacy and safety and emphasising their roles in patients with different disease severities. methods based on the guidelines provided by the preferred reporting items for systematic reviews and metaanalyses statement, this systematic review was cond ucted on investigated medications of diabetic patients with dg.16 in the context of dg, a medication’s efficacy targets the severity of symptoms and/or ge while safety deals with the reported adverse events (aes) in the groups under investigation. medline® (national library of medicine, bethesda, maryland, usa), embase (elsevier, amsterdam, netherlands), cochrane library (wiley, hoboken, new jersey, usa) and google scholar (google llc, menlo park, california, usa) databases were used to search for randomised clinical trials (rcts) that assessed the efficacy and/or safety of medications used for the management of dg. although the last search was performed until april 2019, there was no time limit set for the included trials. the search strategy used specific keywords based on a patient/problem, intervention, comparison and outcome strategy, utilising relevant subject headings and boolean operators. these databases were searched with the terms “diabetes” or “diabetic”, “gastroparesis” or a combination of the two, “prokinetics” or “prokinetic”, “metoclopramide” or “domperidone” or “erythromycin” or “cisapride” or “bethanecol” or “tegaserod”, “motilin agonist” or “ghrelin agonist” or “5-ht4 agonist” (5-hydroxy tryptamine receptor 4) and “antiemetic” or “phenothiazine” or “serotonin 5-ht3 receptor antagonist” or “anti histamine”. only rcts with the following charact eristics were included in this review: (1) dg had to be diagnosed based on the exclusion of gastrointestinal obstruction; (2) studies should have allocated at least two groups for comparing the outcomes of a single medication versus placebo or another medication; (3) the allocated patients may be adults or children with t1dm or t2dm; (4) the study should be published in a peer-reviewed journal and written in english; (5) the primary outcomes of the rct should include changes in the scores of the severity of symptoms (as indicated by the gcsi scale, visual analogue scores, etc.) in addition to changes in ge (assessed by ultrasound, ges, gebt or the swallowed wireless motility capsule); (6) all changes should have been initially measured at mohammad z. asha and sundos f. h. khalil review | e293 baseline and reassessed during the course of the study after the administration of medication(s); (7) the aes should have been assessed in patients in accordance with the physical examination or patient self-reported data; and (8) changes in ge as retrieved from gebt may be reported as gastric half-emptying time (t½). studies recruiting a population or subpopulation of healthy individuals or presenting comorbidities with serious conditions rather than diabetes were excluded. additionally, studies were ineligible if they were nonrandomised prospective investigations, retrospective studies, narrative reviews, systematic reviews and meta analyses. finally, a comprehensive search for on-going clinical trials for each medication in clinicaltrials.gov (https://clinicaltrials.gov/) was performed. a medic ation was considered novel when its relevant phase 2 rct was published in 2010 or later. two authors independently screened the titles and abstracts obtained by the database search process. additionally, the reference lists of the identified rcts were screened for additional eligible studies. the obtained publications were uploaded to endnote, version x7 (clarivate analytics, philadelphia, usa) and all duplicate publications were omitted. decisions regarding the included studies were approached via consensus and any disagreement was resolved via discussion. all data were extracted into a specifically-designed excel spreadsheet, version 2016 (microsoft inc., redmond, washington, usa), that included: 1) study data (name of the first author, year of publication, study design, study duration and country); 2) patients’ data (gender, total sample size, age, type of diabetes, glycaemic indicators [e.g. hba1c] and baseline parameters used to confirm dg symptoms); 3) study groups and inter ventions (medication(s) used and/or placebo, dosage and methods and duration of administration); 4) the efficacy of medication(s) (changes in severity scores and/or ge in relation to other groups and baseline values when appropriate); and 5) the safety of medication(s) (reported aes following drug administration). the methodological quality of the included rcts was assessed using the cochrane’s risk of bias tool.17 the domains assessed in each trial included perform ance bias, selection bias, detection bias, attrition bias and other biases. the results of the assessment process were either reported as “low risk”, “high risk” or “unclear”. trials were labelled “unclear” when no data were available in the rct about the domain under investigation. all data were entered and graphically presented using revman, version 5.3 (cochrane, london, england). results a total of 854 publications were initially obtained in the specified databases by using the relevant keywords. four studies were additionally identified from google search (google llc). following the removal of 18 duplicate publications, the titles and abstracts of 840 studies were screened and 809 were excluded. the full-text versions of the remaining 31 articles were thoroughly checked for eligibility. nonetheless, seven articles were excluded due to the inclusion of healthy individuals, inclusion of patients with idiopathic gastroparesis, inclusion of patients with diabetes but without signs/symptoms of gastroparesis or a separate trial which included a population subset of an already included study.18–24 finally, a total of 24 rcts were included in this qualitative review [figure 1]. a total of 2,309 patients, of which the majority (65.22%) were female, were included in all studies which were published between 1982 and 2017. only one rct recruited paediatric patients; adults were included in the remaining investigations.25 studies were conducted in european countries, at multiple sites in europe and the usa or only in the usa.25–33 patients were diagnosed with t1dm exclusively in nine studies,25,30,31,34–39 only t2dm in one study and both types in the remaining trials [table 1].40 figure 2 shows the summary of risk of bias assessment. random sequence generation was generated by a computer software in eight trials and an inter active voice response system was used in four trials.27,29–33,38,40–44 since the method of randomisation figure 1: a flowchart of the search process used to identify randomised clinical trials investigating the efficacy and/or safety of medications targeting diabetic gastroparesis symptoms (n = 24). pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials e294 | squ medical journal, november 2019, volume 19, issue 4 table 1: summary of the included randomised clinical trials investigating the efficacy and/or safety of medications targeting diabetic gastroparesis symptoms21,25–45,59,66 author and year of study study duration country gender age in years diabetic indicators gastroparesis indicators male female total barton et al.66 (2014) 4 weeks usa 32 47 79 18–60 n/a • gcsi-dd score: 1.68 ± 0.38; ge was confirmed by 13c-gebt at baseline braden et al.30 (2002) 12 months germany 5 14 19 56–72 hba1c: 7.1–8.2% • gebt t½ >170 min camilleri et al.42 (2017) 3 months usa 148 245 393 20–76 hba1c: 5.2–11.0% • dg symptom severity daily e-diaries (to report vomiting frequency, ge and other symptom scores) desautels et al.59 (1995) na usa 10 0 10 26–70 hba1c: 6.7–12.9% • history of previous ges ejskjaer et al.28 (2009) 10 months denmark 5 5 10 46–56 hba1c: 9.5 ± 2.2 % • gcsi scores: 3.0 ± 0.9 (moderate to severe dg); ≥29% retention 4 hours following a radio-labelled solid meal. • gastric t½ above the normal limits for both breath test and scintigraphy ejskjaer et al.29 (2010) 17 months denmark 25 51 76 18–80 hba1c: 6.6–10.9% • gcsi scores: 3.4-4 (moderate to severe dg) • gastric t½ above the normal limits for both breath test and scintigraphy ejskjaer et al.32 (2013) 13 months 18 centres in different countries 32 60 92 20–70 hba1c: 6.5–10.2% • gcsi-dd score: 3.3 ± 0.8 (moderate-to-severe dg) • gmbt t½ ≥150 min erbas et al.26 (1993) 9 weeks turkey 4 9 13 19–68 self-reported treatment by an oral diabetic agent and/or insulin • a specific questionnaire for dg symptoms (patients were graded as experiencing severe symptoms) • objective documentation of delayed ge by a radionuclide solid meal franzese et al.25 (2002) 8 weeks italy 14 14 28 6–16.9 insulin dependence for a mean of 5 years • n/a hellström et al.39 (2016) 4 weeks usa 5 5 10 18–70 n/a • a positive history of at least 3 months of dg symptoms lehmann et al.31 (2003) 7 months switzerland 4 4 8 28–63 hba1c: 8.0 ± 1.3% • n/a lembo et al.41 (2016) 14 months usa 67 137 204 18–75 hba1c: ≤11% • gcsi-dd score ≥2.6 • gastric t½ ≥79 min by 13c-gebt mccallum et al.35 (1983) 3 weeks usa 16 28 44 21–67 insulin dependence for 12.6 years • patients’ self-reported data (mean dg symptoms 2.5 years) mccallum et al.21 (2007) 12 weeks usa 139 253 392 18–70 hba1c: 7.7 ± 1.7% • composite tss score: 2.38 ± 0.69 mccallum et al.43 (2013) 22 months usa 56 145 201 42–66 hba1c: 7.8 ± 1.5% • gcsi score: 3.4 ± 0.7 (moderate to severe dg) • the michigan neuropathy screening instrument score: 5 ± 2.6 (mild neuropathy) • gastric t½ above the normal limits for both breath test and scintigraphy murray et al.27 (2005) n/a uk 5 5 10 36–63 hba1c: ≤11% • patients were recruited based on the presence of bloat plus two gastrointestinal symptoms as predictors of dg parkman et al.33 (2014) 6 weeks usa (in 6 centres) 41 48 89 18–82 n/a • mean tss score range: 21.3–23.4 (indicating moderate to severe symptoms) • all symptoms were reported except nausea at baseline parkman et al.44 (2015) 4 weeks usa 83 202 285 18–75 self-reported treat ment by an oral diabetic agent and/or insulin • gcsi-dd score: 2.74 ± 0.48 patterson et al.37 (1999) 4 weeks usa 33 62 95 19–69 n/a • tss scale ricci et al.36 (1985) 6 weeks usa 6 7 13 24–73 insulin dependence for 12.5 years • objective documentation of delayed ge by a radio nuclide solid meal shin et al.38 (2013) 6 months usa 2 8 10 31–65 hba1c: ≤11.3% • gcsi-dd score: 1.66 ± 0.38 • gastric t½: 4.9 ± 1.3 by 13c-gebt • baseline composite nvfp score: 1.73 ± 0.39 shin et al.40 (2013) 3 months usa 0 10 10 36–60 hba1c: 7.2 ± 0.4% • gcsi-dd score: 1.32 ± 0.21 silvers et al.45 (1998) 4 weeks usa 66 142 208 19–76 n/a • tss scale of five symptoms (≥8 out of 15, indicating moderate to severe dg) snape et al.34 (1982) 6 weeks usa 5 5 10 21–49 insulin dependence for 16.2 ± 2.4 years • a specific questionnaire for dg symptoms • objective documentation of delayed ge by a radionuclide solid meal n/a = not available; gcsi-dd = the gastroparesis cardinal symptom index-daily diary; ge = gastric emptying; 13c-gebt = 13c-spirulina gastric emptying breath test; t½ = half-emptying time; hba1c = glyco sylated haemoglobin; dg = diabetic gastroparesis; min = minutes; ges = gastric emptying scintigraphy; gmbt = gastric motility breath test; tss = total symptom score; nvfp = nausea, vomiting, fullness, and pain. mohammad z. asha and sundos f. h. khalil review | e295 was inexplicitly mentioned in the remaining rcts, they were assessed as “unclear”. participants’ allocation was concealed from the investigators in ten trials, while selection bias was apparent in one trial, owing to the randomisation using an incomplete block method.29,32,35,36,38–44 the method of concealment was unclear in the remaining trials. both performance and detection biases were evident in a trial conducted by silvers et al. since the investigators were not blinded to the patients receiving the intervention.45 intentionto-treat analysis was performed in eight trials in order to investigate the efficacy of interventions following withdrawal of a number of participants.33,37,39,41,43–46 patients’ withdrawal had not affected the comparability between groups as explored by statistical analyses in the remaining trials [table 2]. t r a d i t i o n a l m e d i c at i o n s dopamine d2 receptor antagonists metoclopramide has dual actions on the brainstem and peripheral nerves as a dopamine d2 receptor antagonist and serotonin (i.e. 5-ht4) receptor agonist. the main effects on the gastrointestinal tract are exerted by increasing antral contraction by releasing acetylcholine from enteric neurons.47 in dg patients, early trials indicated significant improvements in the scores of nausea, fullness and bloating after three weeks of metoclopramide oral administration as compared to the placebo.35,36 in addition, ge improved significantly and consistently in all trials of oral regimens assessed by ges.34–36 therefore, it was the sole drug approved by the food and drug administration (fda) for the treatment of dg. rather than oral administration, in terms of improving gcsi scores, more recent rcts have shown superior efficacy of nasal spray preparations.33,44 however, some aes were reported in other trials, particularly in comparative ones which were conducted for more than four weeks.26,33,37 these aes include anxiety, depression, somnolence, headache and leg cramps. furthermore, there are some concerns about the development of tardive dyskinesia with the chronic use of metoclopramide.48 diabetes itself may be independently associated with the risk of tardive dyskinesia.49 therefore, this medication received a ‘black box warning’ from the fda. collectively, recomm endations indicate the use of metoclopramide for no longer than 12 weeks.50 therefore, alternative medications with high efficacy and safety have been studied. domperidone is another dopamine d2 receptor antagonist which is effective against nausea and vomiting with a better safety profile than metoclopramide. patterson et al. showed that domperidone was associated with less frequent central aes compared to metoclopramide.37 similarly, dom peridone ameliorated nausea and early satiety compared to placebo in adults and cisapride in children with dg.25,45 it can be initially administered three times daily at a dose of 10 mg, which is increased to 20 mg at bedtime. early prospective investigations conducted almost three decades ago revealed that dg symptoms improved significantly after six months or one year of treatment.51,52 additionally, it improved the quality of life of patients in a subsequent retrospective analysis.53 however, domperidone may be associated with a risk of cardiac arrhythmia and may cause qt prolongation.54 therefore, recommendations based on a moderate level of evidence indicate performing a baseline electro cardiogram and a cessation of treatment if the corrected qt is more than 470 and 450 ms in males and females, respectively. moreover, a follow-up electrocardiogram along the course of treatment is advised.55 ghrelin and ghrelin receptor agonists early studies have shown favourable implications of ghrelin in the treatment of gastroparesis as it modulates energy homeostasis and gastrointestinal motility.27 this was evident in ten patients with dg using a test meal of rice pudding where ghrelin infusion caused a significant increase in ge independent of cardiovagal tone.27 however, the therapeutic effects of ghrelin were limited by its relative plasma instability and short half-life.56 thus, several synthetic ghrelin analogues were investigated for their clinical potential. tzp-101 (i.e. ulimorelin) is a macrocyclic ghrelin receptor analogue which has been investigated in patients with dg in a phase 1 trial in denmark.28 tzp-101 figure 2: a summary of risk of bias assessment for the included randomised clinical trials (n = 24). pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials e296 | squ medical journal, november 2019, volume 19, issue 4 table 2: the outcomes of randomised clinical trials investigating traditional and novel medications for the treatment of diabetic gastroparesis21,25–45,59,66 author and year of study study groups and int efficacy on gastroparesis symptoms efficacy on ge safety dopamine d2 receptor antagonist snape et al.34 (1982) • metoclopramide (10 mg orally, four times per day) • placebo (two 3-week treatment int with a 1-week washout period before cross-over) • no significant changes observed in abdominal pain or bloating • using ges, a 24% increase in ge rate (p <0.01) was reported 3 weeks after treatment versus 5% increase in placebo • n/a mccallum et al.35 (1983) • metoclopramide (10 mg orally, four times per day) • placebo (for 3 weeks) • a significant improvement of fullness and nausea (p <0.05) in the int versus placebo (assessed using grading diary sheets) • ge improved in the int group comp ared to baseline values (p <0.05, assessed by ges scintigraphy) but not to placebo • restlessness, amenorrhea, headache, constipation and leg cramps were noted in the metoclopramide group ricci et al.36 (1985) • metoclopramide (10 mg orally, four times per day) • placebo • significant improvement of fullness, bloating, nausea and anorexia when comp ared to placebo (p <0.05) • no significant correlation between changes in symptoms and ge improvement • ge improved significantly (isotope retention was 91% at baseline and 78.6% after metoclopramide admin istration) • mild symptoms ignore, such as sedation, headache and mild hand tremors were noted in metoclopramidereceiving patients parkman et al.33 (2014) • metoclopramide (10 mg orally, four times per day; n = 18) • metoclopramide (10 mg nasal spray, four times per day; n = 35) • metoclopramide (20 mg nasal spray, four times per day; n = 36) • using tss scores, cfb was significantly improved in the 20 mg nasal spray group compared to the oral group (p = 0.026) • n/a • three subjects discontinued the study due to severe restlessness, severe drowsiness and mild headache. • nausea was more frequently reported in the oral group parkman et al.44 (2015) • metoclopramide (10 mg nasal spray, four times per day; n = 95) • metoclopramide (14 mg nasal spray, four times per day; n = 95) • placebo (n = 95) • gsdd scores did not improve signific antly in the int groups as compared to placebo • severity scores improved significantly only in women for both int groups as compared to placebo (p = 0.02 each) • n/a • aes were mild to moderate. they were more frequent in the 14 mg (8.4%, incl uding headache, dizziness, diarrhoea, cholelithiasis, vomiting and nausea) rather than the 10 mg group (nausea, myoclonus, and memory impairment) patterson et al.37 (1999) the following regimens were given for 4 weeks: • metoclopramide (one 10 mg tablet plus one placebo tablet were taken four times per day) • domperidone (two 10 mg tablets were taken four times per day) • no significant differences between groups in improving symptoms (improved by 41.1% with domperidone and 38.9% with metoclopramide) • n/a • somnolence, anxiety, akathisia and depr ession were significantly more severe in the metoclopramide group after 2 and 4 weeks of treatment (p <0.001) • severe cns events accounted for treatment discontinuation in four patients and one patient in the metoclopramide and domper idone groups, respectively silvers et al.45 (1998) • domperidone 20 mg (four times per day; n = 105) • placebo (n = 103) • significant improvements were noted in the domperidone group for total symptoms (p = 0.011), nausea (p = 0.024) and early satiety (p = 0.004) compared to placebo • n/a • no significant differences between both groups in the tolerability profile • headache, diarrhoea, abdominal pain, rhinitis and sinusitis were most commonly reported among patients franzese et al.25 (2002) • domperidone (0.9 mg/kg three times per day; n = 14) • cisapride (0.8 mg/kg three times per day; n = 14) • significant improvements in the tss in both groups (p <0.001 each) compared to baseline • ultrasonography revealed significant short ening of ge time in the domperidone group compared to baseline (p <0.01). • no remarkable differences were noted in the cisapride group • n/a erbas et al.26 (1993) the following regimens were given for 3 weeks, then 3 weeks washout and 3 weeks cross-over: • metoclopramide (10 mg orally, three times per day) • erythromycin (250 mg orally, three times per day) • the total score of gastrointestinal symptoms significantly improved after erythromycin (0–5) compared to postmetoclopramide therapy (0–11; p <0.05) • gastric t½ improved significantly in both int groups at 60 and 90 min after meal • two patients reported sedation, leg cramps and weakness, while one patient reported drowsiness and palpitation with use of metoclopramide ghrelin receptor agonist murray et al.27 (2005) • the patients received either ghrelin (5 pmol/kg/min) or saline on two different occasions • no significant differences between ghrelin and saline in the incidence of bloating, nausea and hunger during infusion as assessed by vas • significant improvement of ge (from 30% to 43%) as assessed by ultrasound • n/a ejskjaer et al.28 (2009) • a cross-over administration of diff erent doses of tzp-101 infusions (80, 160, 320, or 600 g/kg) • placebo • no significant differences between the int and placebo groups in the intensity of post-meal symptoms and postprandial fullness • gastric t½ (20%; p = 0.043) and latency times were significantly reduced compared to placebo • no differences in aes between tzp101 and placebo group ejskjaer et al.29 (2010) • a 4-day consecutive regimen of intra venous infusion of ulimorelin at a dosage of: 20μg/kg (n = 8); 40μg/kg (n = 17); 80μg/kg (n = 13); 160μg/kg (n = 6); 320μg/kg (n = 6); 600μg/kg (n = 7); • placebo (n = 19) • in the group receiving ulimorelin 80 μg/ kg, the severity of gcsi loss of appetite and vomiting scores was significantly improved (p = 0.034 and 0.006, respectively) • the post-prandial fullness domain of the gsa score was significantly improved compared to placebo • no difference in gastric t½ among groups • the frequency and severity of aes were comparable between the int and placebo group ejskjaer et al.32 (2013) • the following regimens were given once daily (oral capsules before break fast) for 28 days: tzp-102 10 mg (n = 22); tzp-102 20 mg (n = 21); tzp-102 40 mg (n = 23); placebo (n = 26) • all doses (combined) caused a significant decline of the gsci total score compared to placebo • no significant differences in gmbt t½ between int groups and the placebo group • no correlation between gmbt t½ and the gsci score at baseline or at 28 days • no differences in aes between the tzp-102 and placebo groups int = interventions; ge = gastric emptying; ges = gastric emptying scintigraphy; na = not available; tss = total symptom score; cfb = change from baseline; cns = central nervous system; min = min utes; vas = visual analogue score; aes = adverse events; gcsi = gastroparesis cardinal symptom index; gsa = gastroparesis symptom assessment; gmbt = gastric motility breath test; gsdd = gastroparesis symptom daily diary; cfb = change from baseline; gebt = gastric emptying breath test; sc = subcutaneous; dd = daily diary; nvfp = nausea, vomiting, fullness and pain. mohammad z. asha and sundos f. h. khalil review | e297 infusion (given at 80, 160, 320, or 600 μg/kg in a crossover manner) caused 20% reduction in gastric t½ of solids compared to a placebo; however, no apparent effects were noted on postprandial symptoms.28 a phase 2 trial conducted by the same team revealed that the infusion of 80 μg/kg tzp-101 caused a significant reduction in severity of several symptoms including vomiting, loss of appetite and reduction of the gcsi scores (25% versus 8% among patients allocated to placebo), although no differences were reported in gastric t½.29 table 2 (contd.): the outcomes of randomised clinical trials investigating traditional and novel medications for the treatment of diabetic gastroparesis21,25–45,59,66 author and year of study study groups and int efficacy on gastroparesis symptoms efficacy on ge safety mccallum et al.43 (2013) • the following regimens were given once per day (oral capsules) for 12 weeks: tzp-102 10 mg (n = 69); tzp102 20 mg (n = 66); placebo (n = 66) • gsdd improved significantly in all groups, but no difference was reported versus placebo (cfb: -1.1 versus 0.98 for int groups and placebo groups) • no statistical difference in cfb of gebt among all groups • aes occurred in 57%, 58% and 67% in the 10 mg, 20 mg and placebo groups, respectively without remarkable differences shin et al.38 (2013) • relamorelin 100 μg sc once per day (n = 5) • patients crossed over with a 7-day washout period • placebo (n = 5) • relamorelin significantly reduced gcsidd (p = 0.041) and nvfp (p = 0.041) scores compared to placebo • ge was significantly accelerated in eight patients relative to the placebo (p = 0.005) • no serious aes were reported • only hunger was almost significant with relamorelin use (p = 0.063) shin et al.40 (2013) • a single dose of relamorelin 100 μg sc (n = 5) • patients crossed-over with a 7-day washout period • placebo (n = 5) • since it was a single-dose study, it was not powered to investigate dg • gcsi scores were similar in both groups. • gastric t½ of solids, but not liquids, reduced by relamorelin versus placebo (p = 0.011) • significant effects were noted also in ge at 2 and 4 hours (with percent differ ences of 48% and 19%, respectively) • relamorelin led to a large ge acceleration lembo et al.41 (2016) • relamorelin 10 μg once per day (n = 67) • relamorelin 10 μg twice per day (n = 68) • placebo (n = 69) • the twice-daily regimen reduced vomiting severity and frequency by 60% compared to placebo, while it had no effects on abdominal pain and satiety • significant improvement of ge (p <0.03) with twice-daily regimen • in the int group ≥5% of patients experienced headache and worsening of glycaemic control camilleri et al.42 (2017) • the following sc injections were given twice per day: relamorelin 100 μg (n = 82); relamorelin 30 μg (n = 109); relamorelin 10 μg (n = 98); placebo (n = 104) • relamorelin reduced the frequency of vomiting by 75% compared to baseline, but not compared to placebo • different doses of relamorelin decreased all composite symptoms of dg compared to placebo (p <0.05) • ge was significantly accelerated in the 10 and 30 μg groups by 12% (p <0.05) compared to placebo after 12 weeks • in the int group, 14.5% of patients experienced dose-related deteriorations of glycaemic control; this was resolved by drug dosage adjustments motilin receptor agonist desautels et al.59 (1995) • erythromycin base 250 mg • erythromycin base 1000 mg • placebo • n/a • significant improvements of ge were reported between erythromycin groups and placebo (p = 0.0007) • no differences were present between erythromycin 250 and 1000 mg groups • diarrhea was reported in one patient in the erythromycin 1000 mg group mccallum et al.21 (2007) • the following regimens were given for 12 weeks twice per day: mitemcinal 5 mg (n = 131); mitemcinal 10 mg (n = 130); placebo (n = 131) • no significant effects were noted over 12 weeks among groups • in a subset of the population under study (those having 75% positive weekly responses), mitemcinal 10 mg produced a significant imp rovement in total symptoms during the study period (p <0.05) compared to placebo • n/a • severe aes were reported in 18.8%, 15.9% and 20.0% of patients in the placebo, mitemcinal 5 mg, and mitemcinal 10 mg groups, respectively • there were non-significant differences among groups barton et al.66 (2014) • the following regimens were given once per day for 4 weeks: camicinal 10 mg (n = 18); camicinal 50 mg (n = 18); cami cinal 125 mg (n = 22); placebo (n = 21) • the most significant improvements occ urred at 2–4 weeks for fullness and satiety for 10 mg (53%) and 50 mg (65%) groups • no or little effect was reported for the highest dose • gebt t½ decreased significantly with increasing dose (p <0.05) as assessed by swallowed wireless motility capsule • there were similar frequencies of aes among different groups (urinary tract and gastrointestinal symptoms) hellström et al.39 (2016) • each patient participated in three single oral int (out of four int) with a 7-day washout period in-between. the groups were: camicinal 50 mg; camicinal 125 mg; placebo • no symptomatic improvement was observed • gebt t½ decreased by 65% (p <0.05) by 125 mg camicinal compared to placebo • there was a non-significant trend of reduced gebt t½ with 25 and 50 mg doses • a dose-response relationship was apparent • headache, vomiting and decreased blood glucose were reported in a similar frequency in all groups 5-ht4 receptor agonist braden et al.30 (2002) • given thrice per day: cisapride 10 mg (n = 9); placebo (n = 10) • n/a • gebt t½ decreased significantly in the int group after 12 months compared to baseline (p = 0.03); the placebo group showed no changes from baseline • no effects were noted on glucose control in both groups • n/a lehmann et al.31 (2003) • the following treatments were given for 3 months, then 4 weeks washout and 3 months cross-over: cisapride 20 mg twice per day; placebo • n/a • ge improved significantly at 120 min in the int group (p = 0.025), while gastric t½ did not differ between the int and placebo groups (p = 0.09) • no apparent improvements in glycaemic control • no serious ae • patients with prolonged qtc were excluded at the initial recruitment phase int = interventions; ge = gastric emptying; ges = gastric emptying scintigraphy; na = not available; tss = total symptom score; cfb = change from baseline; cns = central nervous system; min = min utes; vas = visual analogue score; aes = adverse events; gcsi = gastroparesis cardinal symptom index; gsa = gastroparesis symptom assessment; gmbt = gastric motility breath test; gsdd = gastroparesis symptom daily diary; cfb = change from baseline; gebt = gastric emptying breath test; sc = subcutaneous; dd = daily diary; nvfp = nausea, vomiting, fullness and pain. pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials e298 | squ medical journal, november 2019, volume 19, issue 4 consequently, tzp-102 was developed as an oral preparation. a phase 2a trial was performed in 2013 to assess the impact of a 28-day tzp-102 regimen for doses ranging between 10 and 40 mg versus a placebo. ejskjaer et al. found that all doses (combined) significantly alleviated dg symptoms, but with no remarkable effects on ge indices.32 similarly, a phase 2b trial, which administered tzp-102-cl-g003 and tzp-102-cl-g004 for 12 weeks, emphasised the lack of improving effects on the gastroparesis symptom daily diary scores as well as ge analysis compared to a placebo.43 in addition, the investigations of tzp-102cl-g004 were terminated at an early stage due to lack of efficacy in dg patients. motilin receptor agonists erythromycin has been well-established for its prokinetic action since its introduction six decades ago.57 its motilin agonistic action promotes peristaltic movement and enhances ge through the induction of phase iii contractions of the migrating motor complex. thus, it increases gastric antral contraction. early studies revealed that acute intravenous and chronic oral administration for four weeks led to a significant reduction in the total symptom score in dg patients, which may be superior to the effect of metoclopramide.26,58 desautels et al. reported significant ge acceleration via a single dose of 250 mg with no apparent side effects in diabetic patients.59 however, subsequent studies have shown that erythromycin was associated with tachyphylaxis, whereby its prokinetic effect may be lost after 48 hours of treatment.60 in addition, its venous administration may be associated with serious aes such as ventricular arrhythmia and can interact with other medications due to inhibition of cytochrome p450 c3a4.61,62 additional medications without antibiotic activities and avoiding the previously-mentioned aes need to be developed. mitemcinal is another motilin agonist which has been tested in a 12-week double-blind rct.46 although there was evidence of ge improvements in patients with non-delayed ge, the results showed no significant differences in the symptoms of dg. 5-hydroxytryptamine receptor 4 agonists cisapride is a traditional non-selective 5-ht4 receptor agonist which causes increased muscular contraction through cholinergic pathways. two rcts have shown that the chronic use of this medication (for at least seven months) reduces ge time in patients with dg with no remarkable effects on their glycaemic control.30,31 however, both trials excluded patients with prolonged qtc at the initial recruitment. given that cisapride administration can activate the human ether-a-gogo-related gene (herg) potassium channels and may consequently lead to qt prolongation, ventricular arrhythmias and syncope, it has been withdrawn from the market in several countries.63 similarly, the use of tegaserod (another 5-ht4 agonist) has been suspended since 2007 owing to its association with ischaemic cardiovascular events.64 novel and investigational medications ghrelin and ghrelin receptor agonists rm-131 (i.e. relamorelin), the most recently invest igated member of the ghrelin analogue family, has provided promising outcomes. initially, shin et al. tested the efficacy of subcutaneous injections of rm131 in 10 patients with t1dm in a double-blind, table 3: ongoing clinical trials which investigate candidate medications for diabetic gastroparesis candidate drug mechanism of action disease intervention clinicaltrials. gov identifier prucalopride (resotran™ [janssen pharmaceutica, beerse, belgium]) 5-ht4 agonist dg 2 × 2 mg tablets of prucalopride or placebo given once daily for 28 days nct02031081 velusetrag (td-5108) 5-ht4 agonist dg and ig velusetrag 5, 15, 30 mg capsules once daily versus placebo for 12 weeks nct02267525 rq-00000010 5-ht4 agonist gastroparesis the intervention will be given once daily at doses of either 10, 50, 100 μg orally for 2 weeks versus placebo nct02838797 tak-906 dopamine d2 receptor antagonist dg and ig tak-906 5, 25, and 100 mg capsules versus placebo for 9 days nct03268941 sitagliptin (mk-0431075) dpp-4 inhibitor dg 100 mg sitagliptin once daily for 2 days versus placebo nct02324010 vly-686 (tradipitant) neurokinin 1 antagonist gastroparesis vly-686 oral capsule once daily for 4 weeks versus placebo nct02970968 relamorelin (rm-131) selective ghrelin receptor agonist dg relamorelin 10 μg sc injection twice daily for 12 weeks versus placebo relamorelin 10 μg sc injection twice daily for 52 weeks versus placebo nct03285308 nct03383146 5-ht4 = 5-hydroxytryptamine receptor 4; dg = diabetic gastroparesis; ig = idiopathic gastroparesis; dpp-4 = dipeptidyl peptidase-4; sc = subcutaneous. mohammad z. asha and sundos f. h. khalil review | e299 cross-over, placebo-controlled rct and assessed the symptoms of dg using the gcsi score and ge using scintigraphy.38 results revealed that gastric t½ was significantly accelerated at one and two hours after meals compared to a placebo along with significant improvements in the average symptoms scores. similar results were reported by shin et al. in an rct cond ucted among female patients with t2dm.40 more recent data from placebo-controlled rcts indicated that subcutaneous injection of rm-131 twice daily had the most remarkable impact on reducing the frequency and severity of dg symptoms besides ge acceleration.41,42 additionally, these regimens were safe and well-tolerated in all trials. phase 3 clinical trials are on-going concerning this novel medication [table 3]. motilin receptor agonists camicinal (i.e. gsk962040) is a novel small-molecule motilin agonist which causes ge acceleration in healthy individuals.65 the pharmacokinetic characteristics of camicinal in the latter populations were similar to those in patients with t1dm, causing a significant reduction of gastric t½ (65% improvement) following a single dose of up to 125 mg compared to a placebo (52 versus 147 minutes; p <0.05) despite a lack of remarkable symptomatic improvements.39 however, in a double-blind, phase 2 rct, barton et al. found a significant amelioration of fullness and early satiety after camicinal administration (10 and 50 mg) for four weeks.66 5-hydroxytryptamine receptor 4 agonists there are multiple on-going investigations concerning new 5-ht4 receptor agonists that exert beneficial outcomes on the gastrointestinal tract without prom inent aes on cardiac muscle. however, these trials are either performed on patients with idiopathic gastro paresis or their outcomes have not been published yet. revexepride is a specific agonist that has been tested in an rct on diabetic and non-diabetic patients with gastroparesis.22 there were no significant improvements in gcsi scores, ge or quality of life of patients allocated to the intervention group versus a placebo.22 prucalopride is a selective 5-ht4 agonist which significantly reduced gebt t½ compared to a placebo (p <0.050) as well as gsci scores of bloating/ distension (p <0.001), nausea/vomiting (p = 0.010) and fullness (p <0.001) when it was given at a dose of 2 mg once a day for four weeks.67 a phase 2 trial in dg patients was completed with no reported results so far [table 3]. likewise, velusetrag, which has been proven for its ge-accelerating effects in patients with constipation, is being investigated in patients with gastroparesis. discussion dg is a relatively common complication among diabetic patients. nevertheless, there is no consensus on the optimal management approach. hence, several medications have been tested to relieve the symptoms in individuals with an established health burden. the current article aimed to review the best level of evidence, namely rcts, which tested the efficacy and safety of medications targeting dg. results showed multiple safety concerns of the currently used drugs. while metoclopramide is the only fda-approved drug, other traditional drugs have been withdrawn from the markets of several countries owing to risky complications, mostly cardiovascular, in diabetic patients. current efforts are aimed at developing novel medic ations and/or new safe preparations of traditional drugs. metoclopramide can interfere with emesis through its action on the central nervous system and increase gut motility via its prokinetic effect. due to the risk of aes such as tardive dyskinesia, it has been traditionally prescribed at the lowest effective dose for short periods of time. the novel intranasal preparation is seemingly more practical due to the intolerability of oral medications in dg patients with severe nausea and vomiting. for those who are unable to use metoclopramide, domperidone has recently been granted fda’s expanded access investigational new drug application in adults with gastroparesis.68 this drug should be prescribed to manage severe symptoms in patients whom the potential benefits of the medication may justify its potential risks. although the impact on the central nervous system is not apparent, domperidone still has cardiovascular risks owing to its tendency of causing a prolonged qtc interval. seemingly, intravenous erythromycin is warranted in hospitalised patients who need intra venous therapy as they are continually monitored for any aes.69 recent trials showed promising effects of the novel ghrelin receptor agonist relamorelin, the motilin receptor agonist camicinal and the 5-ht4 agonist prucalopride. subcutaneous relamorelin has been effective and safe in healthy individuals and in dg patients has been shown to accelerate ge and induce antral contraction.42,70 the most effective doses are 10 and 20 µg while the on-going rcts use the smaller dose to assess its efficacy in managing gastroparesis symptoms. camicinal can be considered an attractive candidate for the treatment of dg as it showed ge acceleration in a dose-dependent manner in healthy and diabetic patients at a minimum dose of 125 mg.39,71 owing to small sample sizes and its administration at a pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials e300 | squ medical journal, november 2019, volume 19, issue 4 single dose, the conducted rcts failed to demonstrate significant effects on dg symptoms. as such, further trials are warranted giving due consideration to using multiple-dose regimens and recruiting larger samples. prucalopride is approved in many countries for the treatment of chronic constipation and its preliminary favourable actions on patients with gastroparesis may be attributable to its high affinity to 5-ht4 receptors with no effects on herg channels.67,72 the efficacy of prokinetics in diabetic patients may be affected by other factors which can decrease ge. for instance, the patient’s diabetologist should be consulted regarding the use of glp-1 analogues such as liraglutide and exenatide as well as incretin-based drugs (e.g. pramlintide) as they may interfere with ge.73,74 furthermore, while there is no confirmative evidence of the relationship between long-term improved glycaemic control, the symptoms of dg and the rates of ge, studies have shown that acute hyperglycaemia can slow ge in diabetic patients.75,76 it is worth noting that a diet rich in both fibre and fat can delay ge. as such, the main essence of dietary interventions should be consuming small and frequent meals which are low in fat and fibre.50,77 additionally, a recent rct has indicated the significance of small-particle size diets in reducing the severity of key symptoms of dg including postprandial fullness, nausea/vomiting and bloating.78 ethnic-based differences in disease presentation have been reported in a retrospective analysis of adult patients in the national institutes of health gastroparesis consortium registries, where non-hispanic blacks with dg had more severe symptoms (nausea/vomiting) and more frequent hospitalisation rates compared to non-hispanic whites.79 the increased severity of dg symptoms in non-whites was also reported in other cross-sectional studies.80,81 additionally, hispanics were more likely to develop gastroparesis secondary to diabetes than non-hispanic whites who experienced idiopathic gastroparesis.79 therefore, domperidone treatment and peripherally inserted catheters were less used in hispanics compared to non-hispanic whites. nonetheless, the therapeutic effects based on racial differences were not exclusively investigated in rcts. studies employing a large proportion of white patients of caucasian heritage (>80%) showed acceptable efficacy and safety outcomes after using ulimorelin, relamorelin and domperidone.29,41,45 the use of antiemetics predominantly focuses on symptomatic management. antihistamines (i.e. prome thazine) and phenothiazines (i.e. prochlorperazine) are frequently prescribed, yet they may interact with the prokinetics particularly if the medications are metabolised through the cyp450 pathway. serotonin 5-ht3 receptor antagonists, such as ondansetron and dolasetron, may be used in emergency settings when other therapies fail to relieve nausea; little is known about their efficacy in gastroparesis secondary to diabetes.82 moreover, patients with profound nausea and vomiting may benefit from synthetic cannabinoids, including dronabinol and nabinol, although they showed variable pharmacokinetic profiles.83 they may be associated with a risk of hyperemesis on withdrawal and were not previously tested in dg patients.84 recently, aprepitant, a neurokinin 1 (nk-1) receptor antagonist, has shown encouraging outcomes. while it was originally used for managing chemotherapyinduced nausea and vomiting, a 4-week, double-blind multicentre trial revealed that aprepitant ameliorated the severity of nausea, vomiting and all gcsi symptoms in patients with all-cause gastroparesis.85,86 moreover, fountoulakis et al. found that this medication was effective in the long-term management of severe symptoms in two cases of dg refractory to treatment with first-line medications.87 currently, the efficacy of a 4-week regimen of tradipitant, another nk-1 receptor antagonist, is being investigated to manage gastroparesis. this review provides an updated overview of the currently used medications and their therapeutic effects on patients with gastroparesis secondary to diabetes in rcts. other systematic reviews have summarised pharmacological and other management approaches to dg, such as nutritional support, glycaemic management, surgical techniques, intrapyloric botulinum toxin injection and gastric electrical stimulation. however, the current review was subject to some limitations. the impact of antiemetics was not assessed due to a lack of relevant rcts. furthermore, the design of included rcts might have impacted the results. for example, there were conflicting outcomes between phase 2a and phase 2b studies of tzp-102 which included variations in breath test methods (a 6-hour 13c-octanoate test and a 3-hour 13c-spirulina platensis test, respectively).32,43 therefore, unified guide lines should be implemented and carefully employed for future trials. the fda has provided several recommendations regarding this aspect, which include conducting double-blind, placebo-controlled trials with a 2-week screening period, a 12-week treatment period and an at least 2-week withdrawal period.88 rcts of longer durations should be performed for at least 12 months. importantly, patients with diabetic and idiopathic gastroparesis should be studied in separate trials. finally, efficacy assessment should primarily be based on the signs and symptoms of gastroparesis. mohammad z. asha and sundos f. h. khalil review | e301 conclusion there is a significant unmet need for patients with dg who require effective medications to manage their symptoms with optimal levels of safety. patients with mild to moderate symptoms are traditionally managed with metoclopramide or domperidone taking into consideration their cardiovascular consequences. in an endeavour to develop novel drugs, relamorelin, camicinal and prucalopride have shown the best outcomes; however, further investigations are required prior to approval for use in a healthcare setting. future trials should be conducted based on unified guidelines such as those implemented by the fda in order to enable comprehensive and reliable assessment of their outcomes. references 1. kempler p, várkonyi t, körei ae, horváth vj. gastrointestinal autonomic neuropathy in diabetes: the unattended borderline between diabetology and gastroenterology. diabetologia 2016; 59:401–3. https://doi.org/10.1007/s00125-015-3826-y. 2. izbéki f, rosztóczy a, várkonyi t, wittmann t. the clinical picture, diagnosis and therapy of gastrointestinal autonomic neuropathy. in: kempler p, várkonyi t, eds. neuropathies. a global clinical guide. budapest, hungary: zaf ír press-mona lib kft, 2012. pp. 131–50. 3. boas i. [diseases of the stomach]. 9th ed. leipzig, germany: georg thieme, 1925. 4. kassander p. asymptomatic gastric retention in diabetics (gastro paresis diabeticorum). ann intern med 1958; 48:797–812. https://doi.org/10.7326/0003-4819-48-4-797. 5. krishnasamy s, abell tl. diabetic gastroparesis: principles and current trends in management. diabetes ther 2018; 9:1–42. https://doi.org/10.1007/s13300-018-0454-9. 6. lacy be, crowell md, mathis c, bauer d, heinberg lj. gastro paresis: quality of life and health care utilization. j clin gastro enterol 2018; 52:20–4. https://doi.org/10.1097/mcg.0000000 000000728. 7. aleppo g, calhoun p, foster nc, maahs dm, shah vn, miller km, et al. reported gastroparesis in adults with type 1 dia betes (t1d) from the t1d exchange clinic registry. j diabetes complications 2017; 31:1669–73. https://doi.org/10.1016/j.jdi comp.2017.08.014. 8. bharucha ae. epidemiology and natural history of gastroparesis. gastroenterol clin north am 2015; 44:9–19. https://doi.org/10.1016/j.gtc.2014.11.002. 9. alipour z, khatib f, tabib sm, javadi h, jafari e, aghaghazvini l, et al. assessment of the prevalence of diabetic gastroparesis and validation of gastric emptying scintigraphy for diagnosis. mol imaging radionucl ther 2017; 26:17–23. https://doi.org/10.42 74/mirt.61587. 10. almogbel ra, alhussan fa, alnasser sa, algeffari ma. prevalence and risk factors of gastroparesis-related symptoms among patients with type 2 diabetes. int j health sci (qassim) 2016; 10:397–404. https://doi.org/10.12816/0048734. 11. horowitz m, harding pe, maddox af, wishart jm, akkermans lm, chatterton be, et al. gastric and oesophageal emptying in pat ients with type 2 (non-insulin-dependent) diabetes mellitus. diab etologia 1989; 32:151–9. https://doi.org/10.1007/bf00265086. 12. bytzer p, talley nj, leemon m, young lj, jones mp, horowitz m. prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. arch intern med 2001; 161:1989–96. https://doi.org/10.1001/archinte.161.16.1989. 13. revicki da, rentz am, dubois d, kahrilas p, stanghellini v, talley nj, et al. gastroparesis cardinal symptom index (gcsi): development and validation of a patient reported assessment of severity of gastroparesis symptoms. qual life res 2004; 13:833–44. https://doi.org/10.1023/b:qure.0000021689.86296.e4. 14. abell tl, camilleri m, donohoe k, hasler wl, lin hc, maurer ah, et al. consensus recommendations for gastric emptying scintigraphy: a joint report of the american neurogastroenterology and motility society and the society of nuclear medicine. am j gastroenterol 2008; 103:753–63. https://doi.org/10.1111/j.1572-0241.2007.01636.x. 15. farmer ad, scott sm, hobson ar. gastrointestinal motility revisited: the wireless motility capsule. united european gastroenterol j 2013; 1:413–21. https://doi.org/10.1177/20506 40613510161. 16. moher d, liberati a, tetzlaff j, altman dg; prisma group. preferred reporting items for systematic reviews and metaanalyses: the prisma statement. plos med 2009; 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097. 17. higgins jp, altman dg, gøtzsche pc, jüni p, moher d, oxman ad, et al. the cochrane collaboration's tool for assessing risk of bias in randomised trials. bmj 2011; 343:d5928. https://doi.org/10.1136/bmj.d5928. 18. dumitrascu dl, weinbeck m. domperidone versus meto clopramide in the treatment of diabetic gastroparesis. am j gastroenterol 2000; 95:316–17. https://doi.org/10.1111/j.15720241.2000.01721.x. 19. heer m, müller-duysing w, benes i, weitzel m, pirovino m, altorfer j, et al. diabetic gastroparesis: treatment with domperidone--a double-blind, placebo-controlled trial. dig estion 1983; 27:214–17. https://doi.org/10.1159/000198955. 20. richards rd, valenzuela ga, davenport kg, fisher kl, mccallum rw. objective and subjective results of a randomized, double-blind, placebo-controlled trial using cisapride to treat gastroparesis. dig dis sci 1993; 38:811–16. https://doi.org/10.1007/bf01295905. 21. mccallum rw, cynshi o; investigative team. clinical trial: effect of mitemcinal (a motilin agonist) on gastric emptying in patients with gastroparesis a randomized, multicentre, placebo-controlled study. aliment pharmacol ther 2007; 26:1121–30. https://doi.org/10.1111/j.1365-2036.2007.03461.x. 22. tack j, rotondo a, meulemans a, thielemans l, cools m. randomized clinical trial: a controlled pilot trial of the 5-ht4 receptor agonist revexepride in patients with symptoms suggestive of gastroparesis. neurogastroenterol motil 2016; 28:487–97. https://doi.org/10.1111/nmo.12736. 23. stacher g, schernthaner g, francesconi m, kopp hp, bergmann h, stacher-janotta g, et al. cisapride versus placebo for 8 weeks on glycemic control and gastric emptying in insulindependent diabetes: a double blind cross-over trial. j clin endocrinol metab 1999; 84:2357–62. https://doi.org/10.1210/ jcem.84.7.5859. 24. wo jm, ejskjaer n, hellström pm, malik ra, pezzullo jc, shaughnessy l, et al. randomised clinical trial: ghrelin agonist tzp-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data. aliment pharmacol ther 2011; 33:679–88. https://doi.org/10.1111/ j.1365-2036.2010.04567.x. 25. franzese a, borrelli o, corrado g, rea p, di nardo g, grandinetti al, et al. domperidone is more effective than cisapride in children with diabetic gastroparesis. aliment pharmacol ther 2002; 16:951–7. https://doi.org/10.1046/j.13 65-2036.2002.01240.x. https://doi.org/10.1007/s00125-015-3826-y https://doi.org/10.7326/0003-4819-48-4-797 https://doi.org/10.1007/s13300-018-0454-9 https://doi.org/10.1097/mcg.0000000000000728 https://doi.org/10.1097/mcg.0000000000000728 https://doi.org/10.1016/j.jdiacomp.2017.08.014 https://doi.org/10.1016/j.jdiacomp.2017.08.014 https://doi.org/10.1016/j.gtc.2014.11.002 https://doi.org/10.4274/mirt.61587 https://doi.org/10.4274/mirt.61587 https://doi.org/10.12816/0048734 https://doi.org/10.1007/bf00265086 https://doi.org/10.1001/archinte.161.16.1989 https://doi.org/10.1023/b:qure.0000021689.86296.e4 https://doi.org/10.1111/j.1572-0241.2007.01636.x https://doi.org/10.1177/2050640613510161 https://doi.org/10.1177/2050640613510161 https://doi.org/10.1371/journal.pmed.1000097 https://doi.org/10.1136/bmj.d5928 https://doi.org/10.1111/j.1572-0241.2000.01721.x https://doi.org/10.1111/j.1572-0241.2000.01721.x https://doi.org/10.1159/000198955 https://doi.org/10.1007/bf01295905 https://doi.org/10.1111/j.1365-2036.2007.03461.x https://doi.org/10.1111/nmo.12736 https://doi.org/10.1210/jcem.84.7.5859 https://doi.org/10.1210/jcem.84.7.5859 https://doi.org/10.1111/j.1365-2036.2010.04567.x https://doi.org/10.1111/j.1365-2036.2010.04567.x https://doi.org/10.1046/j.1365-2036.2002.01240.x https://doi.org/10.1046/j.1365-2036.2002.01240.x pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials e302 | squ medical journal, november 2019, volume 19, issue 4 26. erbas t, varoglu e, erbas b, tastekin g, akalin s. comparison of metoclopramide and erythromycin in the treatment of diabetic gastroparesis. diabetes care 1993; 16:1511–14. https://doi.org/10.2337/diacare.16.11.1511. 27. murray cd, martin nm, patterson m, taylor sa, ghatei ma, kamm ma, et al. ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. gut 2005; 54:1693–8. https://doi.org/10.1136/gut.2005.069088. 28. ejskjaer n, vestergaard et, hellström pm, gormsen lc, madsbad s, madsen jl, et al. ghrelin receptor agonist (tzp101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. aliment pharmacol ther 2009; 29:1179–87. https://doi.org/10.1111/j.1365-2036.2009.03986.x. 29. ejskjaer n, dimcevski g, wo j, hellström pm, gormsen lc, sarosiek i, et al. safety and efficacy of ghrelin agonist tzp-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study. neurogastroenterol motil 2010; 22:1069–e281. https://doi.org/10.1111/j.1365-298 2.2010.01519.x. 30. braden b, enghofer m, schaub m, usadel kh, caspary wf, lembcke b. long-term cisapride treatment improves diabetic gastroparesis but not glycaemic control. aliment pharmacol ther 2002; 16:1341–6. https://doi.org/10.1046/j.1365-2036.20 02.01257.x. 31. lehmann r, honegger ra, feinle c, fried m, spinas ga, schwizer w. glucose control is not improved by accelerating gastric emptying in patients with type 1 diabetes mellitus and gastroparesis. a pilot study with cisapride as a model drug. exp clin endocrinol diabetes 2003; 111:255–61. https://doi. org/10.1055/s-2003-41283. 32. ejskjaer n, wo jm, esfandyari t, mazen jamal m, dimcevski g, tarnow l, et al. a phase 2a, randomized, double-blind 28day study of tzp-102 a ghrelin receptor agonist for diabetic gastroparesis. neurogastroenterol motil 2013; 25:e140–50. https://doi.org/10.1111/nmo.12064. 33. parkman hp, carlson mr, gonyer d. metoclopramide nasal spray is effective in symptoms of gastroparesis in diabetics compared to conventional oral tablet. neurogastroenterol motil 2014; 26:521–8. https://doi.org/10.1111/nmo.12296. 34. snape wj jr, battle wm, schwartz ss, braunstein sn, goldstein ha, alavi a. metoclopramide to treat gastroparesis due to diabetes mellitus: a double-blind, controlled trial. ann intern med 1982; 96:444–6. https://doi.org/10.7326/0003-481 9-96-4-444. 35. mccallum rw, ricci da, rakatansky h, behar j, rhodes jb, salen g, et al. a multicenter placebo-controlled clinical trial of oral metoclopramide in diabetic gastroparesis. diabetes care 1983; 6:463–7. https://doi.org/10.2337/diacare.6.5.463. 36. ricci da, saltzman mb, meyer c, callachan c, mccallum rw. effect of metoclopramide in diabetic gastroparesis. j clin gastroenterol 1985; 7:25–32. https://doi.org/10.1097/00004836198502000-00003. 37. patterson d, abell t, rothstein r, koch k, barnett j. a double blind multicenter comparison of domperidone and meto clopramide in the treatment of diabetic patients with symp toms of gastroparesis. am j gastroenterol 1999; 94:1230–4. https://doi.org/10.1111/j.1572-0241.1999.00456.x. 38. shin a, camilleri m, busciglio i, burton d, smith sa, vella a, et al. the ghrelin agonist rm-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus. clin gastroenterol hepatol 2013; 11:1453–9.e4. https://doi.org/10.1016/j.cgh.2013.04.019. 39. hellström pm, tack j, johnson lv, hacquoil k, barton me, richards db, et al. the pharmacodynamics, safety and pharma cokinetics of single doses of the motilin agonist, camicinal, in type 1 diabetes mellitus with slow gastric emptying. br j pharmacol 2016; 173:1768–77. https://doi.org/10.1111/bph.13475. 40. shin a, camilleri m, busciglio i, burton d, stoner e, noonan p, et al. randomized controlled phase ib study of ghrelin agonist, rm-131, in type 2 diabetic women with delayed gastric emptying: pharmacokinetics and pharmacodynamics. diabetes care 2013; 36:41–8. https://doi.org/10.2337/dc12-1128. 41. lembo a, camilleri m, mccallum r, sastre r, breton c, spence s, et al. relamorelin reduces vomiting frequency and severity and accelerates gastric emptying in adults with diabetic gastroparesis. gastroenterology 2016; 151:87–96.e6. https://doi.org/10.1053/j.gastro.2016.03.038. 42. camilleri m, mccallum rw, tack j, spence sc, gottesdiener k, fiedorek ft. efficacy and safety of relamorelin in diabetics with symptoms of gastroparesis: a randomized, placebo-controlled study. gastroenterology 2017; 153:1240–50.e2. https://doi.org/1 0.1053/j.gastro.2017.07.035. 43. mccallum rw, lembo a, esfandyari t, bhandari br, ejskjaer n, cosentino c, et al. phase 2b, randomized, double-blind 12week studies of tzp-102, a ghrelin receptor agonist for diabetic gastroparesis. neurogastroenterol motil 2013; 25:e705–17. https://doi.org/10.1111/nmo.12184. 44. parkman hp, carlson mr, gonyer d. metoclopramide nasal spray reduces symptoms of gastroparesis in women, but not men, with diabetes: results of a phase 2b randomized study. clin gastro enterol hepatol 2015; 13:1256–63.e1. https://doi.org/10.1016/j. cgh.2014.12.030. 45. silvers d, kipnes m, broadstone v, patterson d, quigley em, mccallum r, et al. domperidone in the management of symptoms of diabetic gastroparesis: efficacy, tolerability, and quality-of-life outcomes in a multicenter controlled trial. dom usa-5 study group. clin ther 1998; 20:438–53. https://doi.org/10.1 016/s0149-2918(98)80054-4. 46. mccallum rw, cynshi o; us investigative team. efficacy of mitemcinal, a motilin agonist, on gastrointestinal symptoms in patients with symptoms suggesting diabetic gastropathy: a randomized, multi-center, placebo-controlled trial. aliment pharmacol ther 2007; 26:107–16. https://doi.org/10.1111/j.13 65-2036.2007.03346.x. 47. sanger gj, furness jb. ghrelin and motilin receptors as drug targets for gastrointestinal disorders. nat rev gastroenterol hepatol 2016; 13:38–48. https://doi.org/10.1038/nrgastro.2015.163. 48. lata pf, pigarelli dl. chronic metoclopramide therapy for diabetic gastroparesis. ann pharmacother 2003; 37:122–6. https://doi.org/10.1345/aph.1c118. 49. solmi m, pigato g, kane jm, correll cu. clinical risk factors for the development of tardive dyskinesia. j neurol sci 2018; 389:21–7. https://doi.org/10.1016/j.jns.2018.02.012. 50. camilleri m. novel diet, drugs, and gastric interventions for gastroparesis. clin gastroenterol hepatol 2016; 14:1072–80. https://doi.org/10.1016/j.cgh.2015.12.033. 51. koch kl, stern rm, stewart wr, vasey mw. gastric emptying and gastric myoelectrical activity in patients with diabetic gastroparesis: effect of long-term domperidone treatment. am j gastroenterol 1989; 84:1069–75. 52. silvers d, kipnes m, broadstone v, patterson d, quigley em, mccallum r, et al. domperidone in the management of symp toms of diabetic gastroparesis: efficacy, tolerability, and qualityof-life outcomes in a multicenter controlled trial. dom-usa 5 study group. clin ther 1998; 20:438–53. https://doi.org/10.10 16/s0149-2918(98)80054-4. 53. soykan i, sarosiek i, mccallum rw. the effect of chronic oral domperidone therapy on gastrointestinal symptoms, gastric emptying, and quality of life in patients with gastroparesis. am j gastroenterol 1997; 92:976–80. 54. morris ad, chen j, lau e, poh j. domperidone-associated qt interval prolongation in non-oncologic pediatric patients: a review of the literature. can j hosp pharm 2016; 69:224–30. https://doi.org/10.4212/cjhp.v69i3.1560. https://doi.org/10.2337/diacare.16.11.1511 https://doi.org/10.1136/gut.2005.069088 https://doi.org/10.1111/j.1365-2036.2009.03986.x https://doi.org/10.1111/j.1365-2982.2010.01519.x https://doi.org/10.1111/j.1365-2982.2010.01519.x https://doi.org/10.1046/j.1365-2036.2002.01257.x https://doi.org/10.1046/j.1365-2036.2002.01257.x https://doi.org/10.1055/s-2003-41283 https://doi.org/10.1055/s-2003-41283 https://doi.org/10.1111/nmo.12064 https://doi.org/10.1111/nmo.12296 https://doi.org/10.7326/0003-4819-96-4-444 https://doi.org/10.7326/0003-4819-96-4-444 https://doi.org/10.2337/diacare.6.5.463 https://doi.org/10.1097/00004836-198502000-00003 https://doi.org/10.1097/00004836-198502000-00003 https://doi.org/10.1111/j.1572-0241.1999.00456.x https://doi.org/10.1016/j.cgh.2013.04.019 https://doi.org/10.1111/bph.13475 https://doi.org/10.2337/dc12-1128 https://doi.org/10.1053/j.gastro.2016.03.038 https://doi.org/10.1053/j.gastro.2017.07.035 https://doi.org/10.1053/j.gastro.2017.07.035 https://doi.org/10.1111/nmo.12184 https://doi.org/10.1016/j.cgh.2014.12.030 https://doi.org/10.1016/j.cgh.2014.12.030 https://doi.org/10.1016/s0149-2918%2898%2980054-4 https://doi.org/10.1016/s0149-2918%2898%2980054-4 https://doi.org/10.1111/j.1365-2036.2007.03346.x https://doi.org/10.1111/j.1365-2036.2007.03346.x https://doi.org/10.1038/nrgastro.2015.163 https://doi.org/10.1345/aph.1c118 https://doi.org/10.1016/j.jns.2018.02.012 https://doi.org/10.1016/j.cgh.2015.12.033 https://doi.org/10.1016/s0149-2918%2898%2980054-4 https://doi.org/10.1016/s0149-2918%2898%2980054-4 https://doi.org/10.4212/cjhp.v69i3.1560 mohammad z. asha and sundos f. h. khalil review | e303 55. camilleri m, parkman hp, shafi ma, abell tl, gerson l; american college of gastroenterology. clinical guideline: management of gastroparesis. am j gastroenterol 2013; 108:18–37. https://doi.org/10.1038/ajg.2012.373. 56. mosińska p, zatorski h, storr m, fichna j. future treatment of constipation-associated disorders: role of relamorelin and other ghrelin receptor agonists. j neurogastroenterol motil 2017; 23:171–9. https://doi.org/10.5056/jnm16183. 57. frazee la, mauro ls. erythromycin in the treatment of diabetic gastroparesis. am j ther 1994; 1:287–95. https://doi.org/10.10 97/00045391-199412000-00008. 58. richards rd, davenport k, mccallum rw. the treatment of idiopathic and diabetic gastroparesis with acute intravenous and chronic oral erythromycin. am j gastroenterol 1993; 88:203–7. 59. desautels sg, hutson wr, christian pe, moore jg, datz fl. gastric emptying response to variable oral erythromycin dosing in diabetic gastroparesis. dig dis sci 1995; 40:141–6. https://doi.org/10.1007/bf02063957. 60. berne jd, norwood sh, mcauley ce, vallina vl, villareal d, weston j, et al. erythromycin reduces delayed gastric emptying in critically ill trauma patients: a randomized, controlled trial. j trauma 2002; 53:422–5. https://doi.org/10.1097/00005373200209000-00004. 61. albert rk, schuller jl; copd clinical research network. macro lide antibiotics and the risk of cardiac arrhythmias. am j respir crit care med 2014; 189:1173–80. https://doi.org/10.1164/ rccm.201402-0385ci. 62. akiyoshi t, ito m, murase s, miyazaki m, guengerich fp, nakamura k, et al. mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome p450 3a4 genetic variants. drug metab pharmacokinet 2013; 28:411–15. https://doi.org/10.2133/dmpk.dmpk-12-rg-134. 63. lewis k, alqahtani z, mcintyre l, almenawer s, alshamsi f, rhodes a, et al. the efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials. crit care 2016; 20:259. https://doi.org/10.1186/s13054-016-1441-z. 64. loughlin j, quinn s, rivero e, wong j, huang j, kralstein j, et al. tegaserod and the risk of cardiovascular ischemic events: an observational cohort study. j cardiovasc pharmacol ther 2010; 15:151–7. https://doi.org/10.1177/1074248409360357. 65. hobson r, farmer ad, dewit oe, o'donnell m, hacquoil k, robertson d, et al. the effects of camicinal, a novel motilin agonist, on gastro-esophageal function in healthy humans-a randomized placebo controlled trial. neurogastroenterol motil 2015; 27:1629–37. https://doi.org/10.1111/nmo.12663. 66. barton me, otiker t, johnson lv, robertson dc, dobbins rl, parkman hp, et al. 70 a randomized, double-blind, placebocontrolled phase ii study (mot114479) to evaluate the safety and efficacy and dose response of 28 days of orally administered camicinal, a motilin receptor agonist, in diabetics with gastro paresis. gastroenterology 2014; 146:s–20. 67. carbone f, rotondo a, andrews cn, holvoet l, van oudenhove l, vanuytsel t, et al. 1077 a controlled cross-over trial shows benefit of prucalopride for symptom control and gastric emptying enhancement in idiopathic gastroparesis. gastroenterology 2016; 150:s213–4. 68. u.s. food & drug administration. how to request domp eridone for expanded access use. from: www.fda.gov/dru gs/developmentapprovalprocess/howdrugsaredevelopedanda pproved/approvalapplications/investigationalnewdruginda pplication/ucm368736.htm accessed: jul 2019. 69. kumar m, chapman a, javed s, alam u, malik ra, azmi s. the investigation and treatment of diabetic gastroparesis. clin ther 2018; 40:850–61. https://doi.org/10.1016/j.clinthe ra.2018.04.012. 70. nelson ad, camilleri m, acosta a, busciglio i, linker nord s, boldingh a, et al. effects of ghrelin receptor agonist, relam orelin, on gastric motor functions and satiation in healthy volun teers. neurogastroenterol motil 2016; 28:1705–13. https://doi. org/10.1111/nmo.12870. 71. deloose e, depoortere i, de hoon j, van hecken a, dewit oe, vasist johnson ls, et al. manometric evaluation of the mot ilin receptor agonist camicinal (gsk962040) in humans. neuro gastroenterol motil 2018; 30:e13173. https://doi.org/10.1111/ nmo.13173. 72. sajid ms, hebbar m, baig mk, li a, philipose z. use of prucalopride for chronic constipation: a systematic review and meta-analysis of published randomized, controlled trials. j neurogastroenterol motil 2016; 22:412–22. https://doi. org/10.5056/jnm16004. 73. phillips lk, deane am, jones kl, rayner ck, horowitz m. gastric emptying and glycaemia in health and diabetes mellitus. nat rev endocrinol 2015; 11:112–28. https://doi.org/10.1038/ nrendo.2014.202. 74. marathe cs, rayner ck, jones kl, horowitz m. relationships between gastric emptying, postprandial glycemia, and incretin hormones. diabetes care 2013; 36:1396–405. https://doi.org/10.2 337/dc12-1609. 75. halland m, bharucha ae. relationship between control of glycemia and gastric emptying disturbances in diabetes mellitus. clin gastroenterol hepatol 2016; 14:929–36. https:// doi.org/10.1016/j.cgh.2015.11.021. 76. fraser rj, horowitz m, maddox af, harding pe, chatterton be, dent j. hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. diabetologia 1990; 33:675–80. https://doi.org/10.1007/bf00400569. 77. homko cj, duffy f, friedenberg fk, boden g, parkman hp. effect of dietary fat and food consistency on gastroparesis symptoms in patients with gastroparesis. neurogastroenterol motil 2015; 27:501–8. https://doi.org/10.1111/nmo.12519. 78. olausson ea, störsrud s, grundin h, isaksson m, attvall s, simrén m. a small particle size diet reduces upper gastro intestinal symptoms in patients with diabetic gastroparesis: a randomized controlled trial. am j gastroenterol 2014; 109:375–85. https://doi.org/10.1038/ajg.2013.453. 79. parkman hp, yamada g, van natta ml, yates k, hasler wl, sarosiek i, et al. ethnic, racial, and sex differences in etiology, symptoms, treatment, and symptom outcomes of patients with gastroparesis. clin gastroenterol hepatol 2019; 17:1489–99.e8. https://doi.org/10.1016/j.cgh.2018.10.050. 80. parkman hp, hallinan ek, hasler wl, farrugia g, koch kl, calles j, et al. nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis. neurogas troenterol motil 2016; 28:1902–14. https://doi.org/10.1111/ nmo.12893. 81. friedenberg fk, kowalczyk m, parkman hp. the influence of race on symptom severity and quality of life in gastroparesis. j clin gastroenterol 2013; 47:757–61. https://doi.org/10.1097/ mcg.0b013e3182819aae. 82. barrett tw, dipersio dm, jenkins ca, jack m, mccoin ns, storrow ab, et al. a randomized, placebo-controlled trial of ondansetron, metoclopramide, and promethazine in adults. am j emerg med 2011; 29:247–55. https://doi.org/10.1016/j. ajem.2009.09.028. 83. badowski me. a review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and phar macodynamics. cancer chemother pharmacol 2017; 80:441–9. https://doi.org/10.1007/s00280-017-3387-5. 84. richards jr, gordon bk, danielson ar, moulin ak. pharma cologic treatment of cannabinoid hyperemesis syndrome: a systematic review. pharmacotherapy 2017; 37:725–34. https://doi.org/10.1002/phar.1931. https://doi.org/10.1038/ajg.2012.373 https://doi.org/10.5056/jnm16183 https://doi.org/10.1097/00045391-199412000-00008 https://doi.org/10.1097/00045391-199412000-00008 https://doi.org/10.1007/bf02063957 https://doi.org/10.1097/00005373-200209000-00004 https://doi.org/10.1097/00005373-200209000-00004 https://doi.org/10.1164/rccm.201402-0385ci https://doi.org/10.1164/rccm.201402-0385ci https://doi.org/10.2133/dmpk.dmpk-12-rg-134 https://doi.org/10.1186/s13054-016-1441-z https://doi.org/10.1177/1074248409360357 https://doi.org/10.1111/nmo.12663 https://doi.org/10.1016/j.clinthera.2018.04.012 https://doi.org/10.1016/j.clinthera.2018.04.012 https://doi.org/10.1111/nmo.12870 https://doi.org/10.1111/nmo.12870 https://doi.org/10.1111/nmo.13173 https://doi.org/10.1111/nmo.13173 https://doi.org/10.5056/jnm16004 https://doi.org/10.5056/jnm16004 https://doi.org/10.1038/nrendo.2014.202 https://doi.org/10.1038/nrendo.2014.202 https://doi.org/10.2337/dc12-1609 https://doi.org/10.2337/dc12-1609 https://doi.org/10.1016/j.cgh.2015.11.021 https://doi.org/10.1016/j.cgh.2015.11.021 https://doi.org/10.1007/bf00400569 https://doi.org/10.1111/nmo.12519 https://doi.org/10.1038/ajg.2013.453 https://doi.org/10.1016/j.cgh.2018.10.050 https://doi.org/10.1111/nmo.12893 https://doi.org/10.1111/nmo.12893 https://doi.org/10.1097/mcg.0b013e3182819aae https://doi.org/10.1097/mcg.0b013e3182819aae https://doi.org/10.1016/j.ajem.2009.09.028 https://doi.org/10.1016/j.ajem.2009.09.028 https://doi.org/10.1007/s00280-017-3387-5 https://doi.org/10.1002/phar.1931 pharmacological approaches to diabetic gastroparesis a systematic review of randomised clinical trials e304 | squ medical journal, november 2019, volume 19, issue 4 85. zhang y, yang y, zhang z, fang w, kang s, luo y, et al. neurokinin-1 receptor antagonist-based triple regimens in preventing chemotherapy-induced nausea and vomiting: a network meta-analysis. j natl cancer inst 2017; 109. https://doi.org/10.1093/jnci/djw217. 86. pasricha pj, yates kp, sarosiek i, mccallum rw, abell tl, koch kl, et al. aprepitant has mixed effects on nausea and reduces other symptoms in patients with gastroparesis and related disorders. gastroenterology 2018; 154:65–76.e11. https://doi.org/10.1053/j.gastro.2017.08.033. 87. fountoulakis n, dunn j, thomas s, karalliedde j. successful management of refractory diabetic gastroparesis with longterm aprepitant treatment. diabet med 2017; 34:1483–6. https://doi.org/10.1111/dme.13413. 88. us food & drug administration. gastroparesis: clinical evaluation of drugs for treatment. from: www.fda.gov/down loads/drugs/guidancecomplianceregulator yinformation/ guidances/ucm455645.pdf accessed: jul 2019. https://doi.org/10.1093/jnci/djw217 https://doi.org/10.1053/j.gastro.2017.08.033 https://doi.org/10.1111/dme.13413 1department of ophthalmology, universidad autónoma de bucaramanga, bucaramanga, santander, colombia; 2department of ophthalmology, centro oftalmológico virgilio galvis, floridablanca, santander, colombia; 3department of ophthalmology, universidad industrial de santander, bucaramanga, santander, colombia *corresponding author’s e-mail: alejandrotello@gmail.com حتدمية جسيمة بعد بضع القزحية بالليزر يف مريض يتناول عالج ثنائي من مضادات تكتل الصفيحات الدموية )األسربين باألضافة اىل التيكاجريلور( تقرير حالة ومراجعة لألدبيات فريجيليو غالفي�ض، األيخاندرو تيللو، ني�ستور كارينو، والرت �سان�سيز، غابرييل فريدريك، نيكول�ض بالنكو abstract: massive hyphaema presentation after a laser iridotomy is very rare. we report a 63-year-old man with ischaemic heart disease on dual antiplatelet therapy (aspirin plus ticagrelor) who was diagnosed as a primary angle-closure suspect and was to undergo a neodymium-doped yttrium aluminium garnet laser iridotomy at centro oftalmológico virgilio galvis, floridablanca, colombia in 2016. while performing the iridotomy in the left eye, active bleeding occurred that finally filled approximately 75% of the anterior chamber. intraocular pressure (iop) increased to 62 mmhg. mannitol and a topical dorzolamide/timolol were used to control the increase in iop. the hyphaema slowly resolved over the following week without sequelae. this case revealed that massive hyphaema can complicate laser iridotomy in patients on dual antiplatelet therapy, although this is rare. therefore, if patients are taking aspirin and ticagrelor, it would be advisable to stop the second medication if possible. in addition, sequential application of photocoagulation and photodisruption lasers might diminish the risk of significant bleeding. keywords: iridectomy; nd-yag laser; hyphema; platelet aggregation inhibitors; angle-closure glaucoma; ocular hypertension; case report; columbia. امللخ�ص: ح�سول حتدمية ج�سيمة بعد ب�سع القزحية بالليزر هو امر نادر جًدا. نعر�ض هنا حالة رجل يبلغ من العمر 63 عاًما م�ساب مبر�ض نق�ض تروية القلب ويتلقى عالج ثنائي من م�سادات تكتل ال�سفيحات الدموية )الأ�سربين بالإ�سافة اإىل التيكاجريلور( والذي مت ت�سخي�سه كم�ستبه م�ساب بزرق اإن�سداد الزاوية الأويل وخ�سع لعملية ب�سع القزحية بالليزر العقيقي الذي ي�ستخدم اإيرتيوم الألومنيوم املن�سط بالنيودمييوم وذلك يف مركز فريجيليو غالفي�ض لطب العيون، فلوريدابالنكا ، كولومبيا يف عام 2016. اأثناء اإجراء عملية ب�سع القزحية يف العني الي�رسى، حدث نزيف ن�سط مالأ حوايل %75 من الغرفة الأمامية للعني. وزاد ال�سغط داخل العني اإىل 62 مم زئبق. مت ا�ستخدام مانيتول ودورزولميد/تيمولول مو�سعيا لل�سيطرة على زيادة ال�سغط داخل العني. وزال نزيف العني يف الأ�سبوع التايل دون م�ساعفات. ك�سفت هذه احلالة اأن التحدمية اجل�سيمة ميكن اأن حتدث كم�ساعفة لعملية ب�سع القزحية بالليزر يف املر�سى الذين يتلقون عالج ثنائي من م�سادات تكتل ال�سفيحات الدموية، رغم اأن هذا الأمر نادر احلدوث. بناء على ذلك اإذا كان املر�سى يتناولون الأ�سربين و التيكاجريلور من امل�ستح�سن اإيقاف العالج الثاين اإن اأمكن ذلك. بالإ�سافة اإىل ذلك ، ال�ستخدام املتتايل لليزر التخثري ال�سوئي وليزر التفتيت ال�سوئي قد يقلل من خطر حدوث نزيف حاد. حالة؛ تقرير العني؛ �سغط ارتفاع الزاوية؛ اإن�سداد زرق الدموية؛ ال�سفيحات تكتل مثبطات حتدمية؛ nd-yag؛ ليزر القزحية؛ ب�سع املفتاحية: الكلمات كولومبيا. massive hyphaema following laser iridotomy in a patient on dual antiplatelet therapy (aspirin plus ticagrelor) case report and literature review virgilio galvis,1,2 *alejandro tello,1,2 néstor i. carreño,1,2 walter a. sánchez,1 gabriel a. frederick,1 nicolás a. blanco3 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e63–67, epub. 30 may 19 submitted 31 jul 18 revision req. 7 oct 18; revision recd. 4 nov 18 accepted 22 nov 18 anticoagulant agents, the number of such patients req uiring a laser iridotomy while concomitantly being on antiplatelet therapy is increasing. case report a 63-year-old male patient with ischaemic heart disease, in whom a prophylactic laser iridotomy had been indic ated, presented to centro oftalmológico virgilio galvis, floridablanca, colombia in 2016. at that time, he was taking two antiplatelet agents, ticagrelor and aspirin. initially, a neodymium-doped yttrium aluminium garnet significant hyphaema as a complication of laser iridotomy has rarely been reported.1–4 massive hyphaema may cause secondary acute elevation of intraocular pressure (iop) and corneal blood staining which may lead to serious visual morb idity. laser iridotomy is a common procedure since curr ently it is performed prophylactically on most patients with narrow anterior chamber angles; the prevalence of this condition in adults varies according to race, from 0.7% in brazil to 10% in china.5–7 given the wide use of antiplatelet drugs in preventing thrombotic diseases and the increased frequency of patients taking this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.012 case report https://creativecommons.org/licenses/by-nd/4.0/ massive hyphaema following laser iridotomy in a patient on dual antiplatelet therapy (aspirin plus ticagrelor) case report and literature review e64 | squ medical journal, february 2019, volume 19, issue 1 (nd:yag) laser iridotomy (visulas® yag iii, carl zeiss meditec ag, jena, germany) was performed in the right eye (four laser shots each containing 6 mj of power). a small amount of bleeding was noted but was stopped under digital pressure on the abraham lens [figure 1a]. when performing the second shot in the left eye, however, the iridotomy site started to bleed and the blood flow did not stop despite applying digital pressure. over the subsequent ten minutes a hyphaema formed, filling approximately 75% of the anterior chamber and the iop increased to 62 mmhg [figure 1b]. given the patient’s medical history of ischaemic heart disease, he was sent to the emergency department. internal medicine advised to give an intravenous injection of mannitol (2 g/kg) over one hour and to discontinue the antiplatelet therapy. topical treatment was started with prednisolone acetate (1%) four times a day and dorzolamide/timolol twice a day. by the next day, iop had decreased to 14 mmhg. by the fourth day postprocedure, the blood clot filled approximately 25% of the anterior chamber. following the evaluation by the cardiologist, the patient resumed antiplatelet therapy. ten days after the iridotomy attempt, the anterior chamber of the left eye was free of blood and iop was 18 mmhg. the iridotomy site in that eye was not patent [figure 1c]. two months later, after the patient’s cardiol ogist had temporarily suspended antiplatelet therapy, a new iridotomy was performed in the patient’s left eye without complications. this session used a sequential application of a yellow 577 nm laser (pascal streamline 577, topcon medical systems inc., oakland, new jersey, usa) in order to photocoagulate the tissue and an nd:yag laser was used to create the perforation (vis ulas® yag iii) [figure 2]. at the last check-up visit two years later, the iridotomy was open and iop was 15 mmhg [figure 3]. discussion preventative laser iridotomies are currently performed in most patients with narrow anterior chamber angles; the prevalence of this condition in adults varies from 0.7–10% depending on race.7–10 in addition, given the growing frequency of patients taking antiplatelet or anticoagulant agents, the number of patients requiring a laser iridotomy is increasing. both photocoagulating (argon laser: 514 nm or nd:yag frequency-doubled laser: 532 nm) and photodisrupting lasers (nd:yag: 1064 nm) have been used to perform laser iridotomies; the use of the latter has become more common in the past three decades. bleeding at the iridotomy site that stops under digital pressure on the abraham lens has figure 1: a: photograph of the right eye of a 63-year-old male patient during a laser iridotomy showing mild bleeding from the iridotomy site. b: photograph of the left eye showing massive hyphaema occupying approximately 75% of the anterior chamber. c: photograph of the left eye ten days after the iridotomy attempt showing resolved hyphaema and non-patent iridotomy site (arrow). figure 2: a: photograph of the iris stroma of the left eye of a 63-year-old male patient after focal photocoagulation with a yellow 577 nm laser during the second iridotomy procedure two months after hyphaema was resolved. some tissue contraction (red circle) was observed. b: completed iridotomy using a laser neodymium-doped yttrium aluminum garnet 1064 nm laser (red circle). no bleeding was evident. figure 3: photograph of the left eye of a 63-year-old male patient two years after a successful iridotomy procedure that was still patent and had an intraocular pressure of 15 mmhg. virgilio galvis, alejandro tello, néstor i. carreño, walter a. sánchez, gabriel a. frederick and nicolás a. blanco case report | e65 been reported in a wide range of cases, from 3% to approximately 50%.2,8–14 however, massive hyphaema has been rarely reported as a complication of nd:yag laser iridotomies in patients with uveitis or rubeosis and in some patients without apparent risk factors.1,2,4 bleeding seems to be less frequent with photocoagul ating lasers because of the thermal coagulation effect. however, at least one case of significant hyphaema following peripheral iridotomy using an argon laser has been reported.3 the sequential use of two different types of laser—photocoagulating and photodisruptive— has also been reported to diminish the risk of bleeding.13,14 antithrombotic medications are widely used to prevent both arterial or venous thromboembolisms, which can cause cerebrovascular or cardiovascular disease (e.g. myocardial infarction, ischaemic stroke and peripheral arterial disease leading to limb gangrene) usually related to arterial thrombosis or deep vein throm bosis that can result in pulmonary embolism.15 aspirin is the most commonly used antiplatelet medication which inhibits platelet cyclo-oxygenase-1 therefore blocking the synthesis of thromboxane a2. another family of antiplatelet medications are the adenosine diphosphate (p2y12) receptor inhibitors, including thienopyridines (e.g. clopidogrel and prasugrel) and the newer class of cyclopentyl triazolopyrimidines (e.g. ticagrelor).15–18 newer antiplatelet agents, like ticagrelor, are freq uently used in addition to aspirin in order to reduce the rate of major adverse cardiovascular events in patients with ischaemic heart disease. this approach has been advantageous in terms of preventing thrombotic and major adverse cardiovascular events in high-risk patients. however, these combined therapies are associated with increased risk of bleeding.16,19–21 in the platelet inhibition and patient outcomes trial, ticagrelor was compared with clopidogrel, both in addition to aspirin, revealing a similar association with total major bleeding. neverthe less, ticagrelor exhibited higher and more consistent levels of inhibition of platelet aggregation across the dosing interval than clopidogrel and also a higher risk of both minor and major non-cardiac surgery related bleeding rates as well as during non-coronary artery-bypassgrafting.15,17,18,21 based on the results of a prospective controlled trial, golan et al. suggested that there was no indication for discontinuing antiplatelet or anticoagulant treatment before an nd:yag laser iridotomy.12 however, golan et al.’s study only included patients taking either aspirin, warfarin sodium or clopidogrel, with no patients on a dual antiplatelet therapy. none of the patients experienced massive hyphaema, yet the incidence of minor bleeding from the iridotomy site was comparable with and without the antiplatelet therapy (34.6% in both groups).12 how ever, there were five cases (4.8%) of grade two bleeding —defined by the authors as not controlled by light pressure on the lens but no macroscopic hyphaema— in the group of patients treated while taking antiplatelet agents, and only one case (1%) in the group of patients treated two weeks after discontinuing the medication. although golan et al. found this difference to be not statistically significant (p = 0.14); however, calculations made by the current authors based on the data publ ished by golan et al. and using a one-tailed z score to compare the two population proportions, revealed the results to be significant (p = 0.046). in 2012, the evidence-based clinical practice guide lines of the american college of chest physicians adv ised that interrupting aspirin before non-cardiac surgeries may be reasonable for patients at low risk of cardio vascular events due to the low benefit-to-risk ratio of continuing it perioperatively.22 on the other hand, in patients at moderate-to-high risk of perioperative adverse cardiovascular events, it may be preferable to continue the aspirin perioperatively. with regard to dual antiplatelet therapy in patients who require a coronary artery bypass graft, the guide lines indicated that perioperative continuation of dual antiplatelet therapy has been related to an increased risk of bleeding. however, it was not clear whether there was a similarly increased risk for serious bleeding with perioperative continuation of dual antiplatelet therapy in patients having non-cardiac surgery and procedures.22 kong and khan stated that although dual antiplatelet therapy increases the likelihood of bleeding in ophth almic procedures, this complication is generally less significant than major adverse cardiac events in patients with coronary stents. therefore, they advised that anti platelet therapy should be continued in patients with coronary stents undergoing eye surgery.23 based on the joint consensus of several european and asiatic scientific societies, thachil advised stopping the second agent in dual antiplatelet therapy if the bleeding risk of a non-cardiac procedure was low.24 similarly in a recent multidisciplinary consensus from spain, vivas et al. concluded that in patients receiving dual antiplatelet therapy and scheduled for an elective procedure, the first step should be to consider postponing the procedure if the patient has a moderate-to-high risk of thrombosis until the risk is lower. once the risk is low, they recommend maintaining aspirin, unless contraindicated (e.g. in neuro surgery) and withdrawing the second antiplatelet agent. if the thrombotic risk remains high, the decision to stop dual antiplatelet therapy will depend on the bleeding risk associated with the procedure. if the bleeding risk is low, they do not suggest stopping dual antiplatelet therapy but cases of moderate-to-severe risk of bleeding are more controversial and they advocate evaluating patients on a case-by-case basis within a multi-disciplinary team.25 massive hyphaema following laser iridotomy in a patient on dual antiplatelet therapy (aspirin plus ticagrelor) case report and literature review e66 | squ medical journal, february 2019, volume 19, issue 1 although the current patient was hypertensive and diabetic, he did not have renal failure. there were no signs of diabetic retinopathy and the iris did not show rubeosis. it is therefore difficult to state that a comorbidity could have played a role in the hyphaema development. on the other hand, suspicion that the origin of the haemorrhage had not been the iris was rejected since when performing a laser iridotomy, the risk of causing a lesion to other vascularised intraocular structures such as the ciliary body, has never been reported and is almost non-existent since a space separates the iris from more posterior structures and the laser energy acts focally. however, in view of the current case, it is important to note that there was no significant bleeding in the first eye treated in the patient and it is therefore not possible to establish a direct link between the dual antiplatelet therapy and massive bleeding during the peripheral iridotomy. conclusion massive hyphaema is a very rare complication foll owing nd:yag laser iridotomy, which may occur in patients on dual antiplatelet therapy, as shown in the current case. the bleeding risk with a laser iridotomy is low; however, to avoid this potentially vision-threat ening complication in patients on dual antiplatelet therapy, it is suggested to consult with an internist/ cardiologist in order to evaluate the option of tempor arily discontinuing the two or at least the second antico agulant, while continuing aspirin, for patients with low thrombotic risk. in patients with a high risk of throm bosis, a case-by-case analysis should be undertaken with a cardiologist where the risk of bleeding during the proc edure is weighed against the risk of developing a cardio vascular thrombotic event. in addition, as sequential use of photocoagulating and photodisrupting lasers has been shown to have a lower risk of iris bleeding, this approach would be preferable in these patients. however, these recommendations are based on the limited evidence of this case report. references 1. drake mv. neodymium:yag laser iridotomy. surv ophthalmol 1987; 32:171–7. https://doi.org/10.1016/0039-6257(87)90092-0. 2. snyder wb, vaiser a, hutton wl. laser iridectomy. trans sect ophthalmol am acad ophthalmol otolaryngol 1975; 79:op381–6. 3. hodes bl, bentivegna jf, weyer nj. hyphema complicating laser iridotomy. arch ophthalmol 1982; 100:924–5. https://doi.org/10.10 01/archopht.1982.01030030932005. 4. gilbert cm, robin al, pollack ip. iridotomy using the q-switched neodymium (nd):yag laser. ophthalmology 1984; 91:1123. https://doi.org/10.1016/s0161-6420(84)34181-1. 5. sheth hg, goel r, jain s. uk national survey of prophylactic yag iridotomy. eye (lond) 2005; 19:981–4. https://doi.org/10. 1038/sj.eye.6701696. 6. sakata k, sakata lm, sakata vm, santini c, hopker lm, bernardes r, et al. prevalence of glaucoma in a south brazilian population: projeto glaucoma. invest ophthalmol vis sci 2007; 48:4974–9. https://doi.org/10.1167/iovs.07-0342. 7. foster pj, johnson gj. glaucoma in china: how big is the prob lem? br j ophthalmol 2001; 85:1277–82. https://doi.org/10.11 36/bjo.85.11.1277. 8. del priore lv, robin al, pollack ip. neodymium: yag and argon laser iridotomy. long-term follow-up in a prospective, randomized clinical trial. ophthalmology 1988; 95:1207–11. https://doi.org/10.1016/s0161-6420(88)33039-3. 9. liebmann jm, ritch r. laser surgery for angle closure glau coma. semin ophthalmol 2002; 17:84–91. https://doi.org/10.10 76/soph.17.2.84.14720. 10. kam jp, zepeda em, ding l, wen jc. resident-performed laser peripheral iridotomy in primary angle closure, primary angle closure suspects, and primary angle closure glaucoma. clin ophthalmol 2017; 11:1871–6. https://doi.org/10.2147/opth. s148467. 11. waisbourd m, shafa a, delvadia r, sembhi h, molineaux j, henderer j, et al. bilateral same-day laser peripheral iridotomy in the philadelphia glaucoma detection and treatment project. j glaucoma 2016; 25:e821–5. https://doi.org/10.1097/ ijg.0000000000000409. 12. golan s, levkovitch-verbin h, shemesh g, kurtz s. anterior chamber bleeding after laser peripheral iridotomy. jama oph thalmol 2013; 131:626–9. https://doi.org/10.1001/jamaoph thal mol.2013.1642. 13. zborwski-gutman l, rosner m, blumenthal m, naveh n. sequential use of argon and nd:yag lasers to produce an iridotomy--a pilot study. metab pediatr syst ophthalmol (1985) 1988; 11:58–60. 14. ho t, fan r. sequential argon-yag laser iridotomies in dark irides. br j ophthalmol 1992; 76:329–31. https://doi.org/10.11 36/bjo.76.6.329. 15. jaffer ih, weitz ji. antithrombotic drugs. in: hoffman r, benz ej, silberstein le, heslop h, weitz ji, anastasi j, eds. hematology, basic principles and practice. 7th ed. amsterdam, netherlands: elsevier, 2018. pp. 2168–87. 16. mega jl, simon t. pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. lancet 2015; 386:281–91. https://doi.org/10.1016/s0140-6736 (15)60243-4. 17. franchi f, angiolillo dj. novel antiplatelet agents in acute cor onary syndrome. nat rev cardiol 2015; 12:30–47. https://doi.org/10. 1038/nrcardio.2014.156. 18. wiviott sd, steg pg. clinical evidence for oral antiplatelet therapy in acute coronary syndromes. lancet 2015; 386:292–302. https://doi.org/10.1016/s0140-6736(15)60213-6. 19. squizzato a, bellesini m, takeda a, middeldorp s, donadini mp. clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. cochrane database syst rev 2017; 12:cd005158. https://doi.org/10.1002/14651858.cd005158.pub4. 20. degrauwe s, pilgrim t, aminian a, noble s, meier p, iglesias jf. dual antiplatelet therapy for secondary prevention of coronary artery disease. open heart 2017; 4:e000651. https://doi.org/10.11 36/openhrt-2017-000651. https://doi.org/10.1016/0039-6257%2887%2990092-0 https://doi.org/10.1001/archopht.1982.01030030932005 https://doi.org/10.1001/archopht.1982.01030030932005 https://doi.org/10.1016/s0161-6420%2884%2934181-1 https://doi.org/10.1038/sj.eye.6701696 https://doi.org/10.1038/sj.eye.6701696 https://doi.org/10.1167/iovs.07-0342 https://doi.org/10.1136/bjo.85.11.1277 https://doi.org/10.1136/bjo.85.11.1277 https://doi.org/10.1016/s0161-6420%2888%2933039-3 https://doi.org/10.1076/soph.17.2.84.14720 https://doi.org/10.1076/soph.17.2.84.14720 https://doi.org/10.2147/opth.s148467 https://doi.org/10.2147/opth.s148467 https://doi.org/10.1097/ijg.0000000000000409 https://doi.org/10.1097/ijg.0000000000000409 https://doi.org/10.1001/jamaophthalmol.2013.1642 https://doi.org/10.1001/jamaophthalmol.2013.1642 https://doi.org/10.1136/bjo.76.6.329 https://doi.org/10.1136/bjo.76.6.329 https://doi.org/10.1016/s0140-6736%2815%2960243-4 https://doi.org/10.1016/s0140-6736%2815%2960243-4 https://doi.org/10.1038/nrcardio.2014.156 https://doi.org/10.1038/nrcardio.2014.156 https://doi.org/10.1016/s0140-6736%2815%2960213-6 https://doi.org/10.1002/14651858.cd005158.pub4 https://doi.org/10.1136/openhrt-2017-000651 https://doi.org/10.1136/openhrt-2017-000651 virgilio galvis, alejandro tello, néstor i. carreño, walter a. sánchez, gabriel a. frederick and nicolás a. blanco case report | e67 21. becker rc, bassand jp, budaj a, wojdyla dm, james sk, cornel jh, et al. bleeding complications with the p2y12 receptor anta gonists clopidogrel and ticagrelor in the platelet inhibition and patient outcomes (plato) trial. eur heart j 2011; 32:2933–44. https://doi.org/10.1093/eurheartj/ehr422. 22. douketis jd, spyropoulos ac, spencer fa, mayr m, jaffer ak, eckman mh, et al. perioperative management of antithromb otic therapy: antithrombotic therapy and prevention of throm bosis, 9th ed: american college of chest physicians evidencebased clinical practice guidelines. chest 2012; 141:e326s–50s. https://doi.org/10.1378/chest.11-2298. 23. kong kl, khan j. ophthalmic patients on antithrombotic drugs: a review and guide to perioperative management. br j oph thalmol 2015; 99:1025–30. https://doi.org/10.1136/bjophthalm ol-2014-306036. 24. thachil j. antiplatelet therapy a summary for the general phy sicians. clin med (lond) 2016; 16:152–60. https://doi.org/10.78 61/clinmedicine.16-2-152. 25. vivas d, roldán i, ferrandis r, marín f, roldán v, tello-montoliu a, et al. perioperative and periprocedural management of antith rombotic therapy: consensus document of sec, sedar, seacv, sectcv, aec, secpre, sepd, sego, sehh, seth, semer gen, semfyc, semg, semicyuc, semi, semes, separ, sen ec, seo, sepa, servei, secot and aeu. rev esp cardiol (engl ed) 2018; 71:553–64. https://doi.org/10.1016/j.rec.2018.01.029. https://doi.org/10.1093/eurheartj/ehr422 https://doi.org/10.1378/chest.11-2298 https://doi.org/10.1136/bjophthalmol-2014-306036 https://doi.org/10.1136/bjophthalmol-2014-306036 https://doi.org/10.7861/clinmedicine.16-2-152 https://doi.org/10.7861/clinmedicine.16-2-152 https://doi.org/10.1016/j.rec.2018.01.029 lamk mohamed al lamki has served as the editor-in-chief of sultan qaboos university medical journal (squmj) for the last 14 years. when he took the helm of the journal, he embarked on dual mandates. the first was to ‘unclog’ the existing infrastructure to deliver timely and quality issues of squmj. he first set out to acquire an office as the ‘home’ of squmj and the staff responsible for managing it. under his stewardship, the office was set up, so the team was recruited. squmj thus blossomed to offer a venue for capacity-building among the cadre of young aspirants for careers in the field. such undertaking diverges from the common wisdom of the means and know-how that only major publishing houses have to establish a journal with a stellar reputation. as there is no ‘degree’ that qualifies one to work in the journal office, through trial and error, the skills of the team in the office slowly but surely leapt and bound with efficiency; hence squmj began publishing four issues per year. to celebrate the newly established rhythm, the journal simultaneously underwent a metamorphosis. it was renamed from “sultan qaboos university journal for scientific research medical sciences” to “sultan qaboos university medical journal”. the change of identity coincided with the new momentum, namely, to fulfil al-lamki’s second mandate, that is, squmj to become the window to the world of medical research from oman and other emerging economies. to increase the visibility of this window, squmj embarked to be featured in international bibliographic databases. in the world of the southnorth divide, it is often an insurmountable task for a journal from emerging economies or the global south to be indexed in international databases.1,2 al lamki’s tenacity prevailed as squmj was indexed in pubmed.3 to date, squmj continues to receive submissions from all corners of the world. al-lamki’s persistence owed its beginning to his interesting biography. his exposure to diverse environments during his upbringing seems to have resulted in some very positive qualities, such as flexibility and adaptability. he spent his childhood in the sultanate of zanzibar and studied medicine at the royal college of surgeons, dublin, ireland. as a physician, he had roamed many landscapes— including toronto (canada), new york (usa), abu dhabi (united arab emirates)—before switching his academic hat when he moved to texas, usa, where he was endowed with a tenured professorship at the university of texas-houston medical school and adjunct professor at the baylor college of medicine. in 2004, he came to oman and served many roles including the role of editor-in-chief of squmj. as a torchbearer of such exemplary tenacity, i see the challenge and opportunity on the horizon as i take the baton from al-lamki. the next challenge is to secure an impact factor for squmj. another aspiration is to keep pace with the fast-shifting sands of the world of publication and concurrently keeping the journal abreast with international best practices within the background of diminishing resources and challenges posed by so-called predatory journals and other amorphous research and publication malpractice. even amid the perceived challenges on the horizon, the inspiration and motivation of allamki will remain our navigational tool. my mantra is that squmj, like knowledge and education, should develop further and not return to its original dimension. this echoes the statement of the late his majesty sultan qaboos, of which the journal bears it name: “knowledge is renewable, and we have to add something new to world knowledge”.4 professor lamk mohamed al-lamki, on behalf of the squmj’s board of trustees–academic publications board, my colleagues in the journal’s office, our esteemed associated editors and international advisory board, as well as many authors and readers across the world, i would like to express our sincere appreciation to you for your unstinting dedication to the service and the growth of squmj, and very best wishes for your welldeserved retirement. editor-in-chief, sultan qaboos university medical journal, muscat, oman author’s e-mail: adawi@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. lamk mohamed al lamki md, frcpc, facr, facnm editor-in-chief 2006-2020 samir al-adawi message from the editor-in-chief sultan qaboos university med j, aug 2021, vol. 21, iss. 3, pp. 339–340, epub. 29 aug 21 https://doi.org/10.18295/squmj.8.2021.123 https://creativecommons.org/licenses/by-nd/4.0/ lamk mohamed al lamki md, frcpc, facr, facnm editor-in-chief 2006-2020 340 | squ medical journal, august 2021, volume 21, issue 3 references 1. confraria h, godinho mm, wang l. determinants of citation impact: a comparative analysis of the global south versus the global north. res policy 2017; 46:265–79. 2. el rassi r, meho li, nahlawi a, salameh js, bazarbachi a, akl ea. medical research productivity in the arab countries: 2007-2016 bibliometric analysis. j glob health 2018; 8:020411. https://doi.org/10.7189/jogh.08.020411. 3. al-busaidi is. medline® indexing of the sultan qaboos univ ersity medical journal: a great leap forward for biomedical research and publishing in the gulf region. sultan qaboos univ med j 2017; 17:e123–4. https://doi.org/10.18295/squmj.2016.17. 01.025. 4. highlights from the speech of his majesty sultan qaboos bin said during his visit to sultan qaboos university on may 2nd, 2000. from: https://www.squ.edu.om/about/hmvisits accessed: jul 2021. https://doi.org/10.7189/jogh.08.020411 https://doi.org/10.18295/squmj.2016.17.01.025 https://doi.org/10.18295/squmj.2016.17.01.025 re: the bacillus calmette-guerin (bcg) vaccine is it a better choice for the treatment of viral warts? sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e141–142, epub. 15 mar 21 submitted 11 oct 20 accepted 6 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.023 letter to the editor رد: لقاح ُعَصيَّة كامليت-غريان هل هو خيار أمثل لعالج الثآليل الفريوسية؟ dear editor, i read the distinguished study by al-yassen et al. published in the august 2020 issue of squmj.1 this study compared the effectiveness of the intradermal bacillus calmette-guérin (bcg) vaccine with the topical salicylic acid (sa) in treating viral warts among a cohort of iraqi patients. they found that bcg vaccine was more effective compared to topical sa in the treatment of viral warts with the best response observed in treating genital warts, followed by flat warts; plantar warts showed the least response to this therapy.1 they concluded that the bcg vaccine could be regarded as an alternative therapy with a simple and cheap implementation in the clinical field.1 the precise diagnosis of tuberculosis (tb) is an essential step in tb control and prevention program worldwide, particularly in the developing countries. in iraq, tb is a worrying health problem. the available data indicates that iraq is among seven of the countries of the eastern mediterranean region with a high tb burden; iraq accounts for 3% of the total number of cases.2 there are an estimated 20,000 tb cases in iraq and the number of estimated deaths due to tb is more than 4,000 annually.2 tuberculin skin test (tst) is applied widely to assess bcg vaccine efficacy and screen latent tb infection. studies have demonstrated that tst interpretation is affected by the antecedent bcg vaccine exposure.3–5 i assume that implementing intradermal bcg vaccine immunotherapy in treating viral warts could ultimately curtail employing tst in the diagnostic panel of tb in suspected patients. hence, weighing the benefit-risk ratio of this new treatment modality must be exercised before finally recommending it in the clinical setting in high tb burden countries, including iraq. conducting additional clinical and immunological studies on that aspect is imperative. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al-yassen aq, al-maliki sk, al-asadi jn. the bacillus calmette-guérin (bcg) vaccine: is it a better choice for the treatment of viral warts? sultan qaboos univ med j 2020; 20:e330–6. https://doi.org/10.18295/squmj.2020.20.03.013. 2. world health organization. iraq. from: http://www.emro.who.int/irq/programmes/tuberculosis.html accessed: oct 2020. 3. yildirim c, küçük ai, ongüt g, oğünç d, colak d, mutlu g. [evaluation of tuberculin reactivity in different age groups with and without bcg vaccination]. mikrobiyol bul 2009; 43:27–35. 4. subramani r, datta m, swaminathan s. does effect of bcg vaccine decrease with time since vaccination and increase tuberculin skin test reaction? indian j tuberc 2015; 62:226–9. https://doi.org/10.1016/j.ijtb.2015.08.002. 5. mancuso jd, mody rm, olsen ch, harrison lh, santosham m, aronson ne. the long-term effect of bacille calmette-guérin vaccination on tuberculin skin testing: a 55-year follow-up study. chest 2017; 152:282–94. https://doi.org/10.1016/j.chest.2017.01.001. response from the authors dear reader, after reading the above letter to the editor, we would like to clarify some points. first, many studies previously done in countries such as india (where over 2.4 million tb patients were reported in 2019 with an incidence rate https://creativecommons.org/licenses/by-nd/4.0/ https://doi.org/10.18295/squmj.2020.20.03.013 https://doi.org/10.1016/j.ijtb.2015.08.002 https://doi.org/10.1016/j.chest.2017.01.001 re: the bacillus calmette-guerin (bcg) vaccine is it a better choice for the treatment of viral warts? e142 | squ medical journal, february 2021, volume 21, issue 1 of 19.9/100,000) recommend and support the efficacy and safety of bcg in treatment of viral warts.1,2 second, the world health organization report referenced above was released in 2014.3 recent data about the extent of tb in iraq according to the annual report of the iraqi ministry of health in 2019, states that the number of new cases registered in iraq was 6,663 with an incidence rate of 17/100,000.4 third, traditionally, the tuberculin tst has been used as the standard for the identification of prior exposure to mycobacterium tuberculosis. however, the specificity of a positive test is less than optimal.5 four, it was reported that in subjects without active tb, immunisation with bcg increases the possibility of a positive tuberculin skin test, but the effect of bcg on the mantoux test was less after 10–15 years of vaccination.6,7 in addition, bcg vaccination was not an important cause of false-positive mantoux test results, except in populations with a low prevalence of active tb.8 finally, there is evidence suggesting that bcg revaccination in adolescence confers protection against tb meningitis.9 in the united kingdom, boosting healthy previously vaccinated adults was found to be well tolerated and improved purified protein derivative-specific cluster of differentiation 4+ t-cell responses.10 despite the importance of what has been mentioned above and irrespective of the extent of tb in iraq or elsewhere, tb is an important health problem and the benefit/risk of the bcg vaccine should be evaluated before its use. moreover, the interpretation of the skin test needs to take into consideration the individual clinical context and evaluation of other risk factors for infection. a cut-off measurement of skin indurations of >15 mm is more likely to be the result of tb infection rather than previous bcg vaccination.8 asaad q. al yassen, shukrya k. al maliki, *jasim n. al asadi department of family & community medicine, college of medicine, university of basrah, basrah, iraq *corresponding author’s e-mails: jnk5511@yahoo.com and jasim.naeem@gmail.com references 1. central tb division, ministry of health and family welfare. india tb report 2020. from: https://tbcindia.gov.in/showfile.php?lid=3538 accessed: oct 2020. 2. jaisinghani ak, dey vk, suresh ms, saxena a. bacillus calmette-guerin immunotherapy for recurrent multiple warts: an open-label uncontrolled study. indian j dermatol. 2019; 64:164. https://doi.org/10.4103/ijd.ijd_558_16. 3. world health organization. iraq. from: http://www.emro.who.int/irq/programmes/tuberculosis.html accessed: oct 2020. 4. ministry of health/environment, republic of iraq. annual statistical report, 2019. from: https://moh.gov.iq/upload/upfile/ar/1349.pdf accessed: oct 2020. 5. regatieri a, abdelwahed y, perez mt, bush lm. testing for tuberculosis: the roles of tuberculin skin tests and interferon gamma release assays. lab med 2011; 42:11–16. https://doi.org/10.1309/lmu57kyinz6wjtit. 6. farhat m, greenaway c, pai m, menzies d. false-positive tuberculin skin tests: what is the absolute effect of bcg and non-tuberculous mycobacteria? int j tuberc lung dis 2006; 10:1192–204. 7. wang l, turner mo, elwood rk, schulzer m, fitzgerald jm. a meta-analysis of the effect of bacille calmette guérin vaccination on tuberculin skin test measurements. thorax 2002; 57:804–9. https://doi.org/10.1136/thorax.57.9.804. 8. araujo z, de waard jh, de larrea cf, borges r, convit j. the effect of bacille calmette-guérin vaccine on tuberculin reactivity in indigenous children from communities with high prevalence of tuberculosis. vaccine 2008; 26:5575–81. https://doi.org/10.1016/j.vaccine.2008.08.006. 9. rodrigues lc, diwan vk, wheeler jg. protective effect of bcg against tuberculous meningitis and miliary tuberculosis: a meta-analysis. int j epidemiol 1993; 22:1154–8. https://doi.org/10.1093/ije/22.6.1154. 10. whelan kt, pathan aa, sander cr, fletcher ha, poulton i, alder nc, et al. safety and immunogenicity of boosting bcg vaccinated subjects with bcg: comparison with boosting with a new tb vaccine, mva85a. plos one 2009; 4:e5934. https://doi.org/10.1371/journal. pone.0005934. https://doi.org/10.4103/ijd.ijd_558_16 https://doi.org/10.1309/lmu57kyinz6wjtit https://doi.org/10.1136/thorax.57.9.804 https://doi.org/10.1016/j.vaccine.2008.08.006 https://doi.org/10.1093/ije/22.6.1154 https://doi.org/10.1371/journal.pone.0005934 https://doi.org/10.1371/journal.pone.0005934 abstract: objectives: bone failure due to avascular necrosis (avn) is a complex pathological phenomenon. analysis of molecular changes in the bone matrix may help to shed light on the disease process and guide management. this study aimed to explore changes in bone quality and structural damage caused by sickle cell disease (scd)induced avn using raman spectroscopy. methods: a total of 10 necrotic femoral heads were obtained from seven scd patients who underwent total hip replacements. the femoral heads were cut in half and scanned using raman spectroscopy in correlation with preoperative magnetic resonance imaging to identify necrotic and healthy control areas. subsequently, samples were examined to determine changes in bone mineralisation, crystallinity, carbonate content, collagen cross-linking and mineral and collagen fibril orientation. results: significant changes were observed in bone mineral content, mineral-to-organic content and collagen fibril orientation in necrotic compared to control areas (p ≤0.050). conclusion: the necrotic samples displayed severe structural damage and loss of mineral and organic contents. similar raman signals have been reported in other metabolic bone diseases such as osteoporosis, thereby potentially supporting the use of medical treatment in avn to promote bone quality. keywords: sickle cell disease; osteonecrosis; femur head necrosis; bone mineralization; bone density; bone remodeling; extracellular matrix; raman spectroscopy. analysis of bone microarchitectural changes and structural damage in sickle cell disease-induced avascular necrosis using raman spectroscopy is there potential for medical management? *ahmed al-ghaithi,1 john husband,2 sultan al-maskari1 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e297–301, epub. 21 jun 21 submitted 15 apr 20 revision req. 9 jun 20; revision recd. 1 jul 20 accepted 21 jul 20 1department of surgery, sultan qaboos university hospital, muscat, oman; 2department of chemistry, college of science, sultan qaboos university, muscat, oman *corresponding author’s e-mail: dr.alghaithi@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.020 clinical & basic research advances in knowledge this study found that sickle cell disease-induced avascular necrosis (avn) in femoral head samples resulted in significant alterations in bone mineral type and content as well as disruption of the orientation and cross-linking of collagen fibrils in the extracellular matrix. these ultrastructural changes were similar to those previously reported in other metabolic diseases, including animal models of osteoporosis, and may therefore explain the sporadic success of bisphosphonates in the treatment of early-stage avn. application to patient care these findings appear to support the use of medical therapy in patients with early-stage avn, thereby helping to prevent further bone deterioration or even potentially improving bone quality. the pathogenesis of avascular necrosis (avn) is complex and may arise due to multiple aetiological factors.1 bone is a metabolically active organ composed of cells, the extracellular matrix and inorganic molecules. overall, 90% of the organic matrix is composed of type i collagen with small amounts of non-collagenous proteins, whereas calcium and phosphate are the main inorganic mineral components.1 three types of cells are involved in bone remodelling: osteoclasts, osteoblasts and osteocytes. osteoclasts are responsible for the resorption of defective bone, while osteoblasts are responsible for the deposition and mineralisation of the new matrix.1 however, disruption of the dynamic bone remodelling process can lead to the production of abnormal bone. in particular, chronic circulatory failure can disrupt this physiological balance and induce structural matrix damage.2 in patients with sickle cell disease (scd), avn can potentially result in joint incongruity and physical dysfunction, eventually requiring prosthetic joint replacement surgery.3 however, the process through which circulatory failure eventually leads to the collapse of the femoral head is still not yet fully understood. since most affected patients are young, there is an urgent need to save the femoral head in the early stages of the disease, prior to joint collapse.3 as a result, less invasive treatment modalities have been proposed including bisphosphonates, teriparatide, vasodilators and anticoagulants.4 in particular, alendronate has been effective in the treatment of adult early-stage femoral head avn.5–7 vasoactive agents can improve blood flow in the terminal vessels, resulting in improved clinical and radiological outcomes.8 similarly, anticoagulants have also been shown to improve blood flow in underlying https://creativecommons.org/licenses/by-nd/4.0/ coagulopathy disorders.9,10 this may indicate the importance of the inhibition of platelet aggregation, while measuring pathological progression may lead to a better understanding of the effectiveness of medical therapy in treating femoral head avn in the early stages. raman spectroscopy is a powerful spectroscopic tool which can be utilised to examine bone samples at the ultrastructural and molecular level based on the inelastic scattering of light by vibrating molecules. recent research has illustrated the effectiveness of raman spectroscopy in evaluating bone quality by providing data regarding mineral-to-matrix ratios, mineral crystallinity, carbonate content, collagen cross-linking and mineral and collagen fibril depolarisation.11 the objective of this study was to examine molecular structural changes using raman spectroscopy in necrotic compared to normal bone samples from patients with scd-induced avn. methods a total of 10 femoral heads were collected from seven scd patients undergoing total hip arthroplasties for stage 5 or 6 femoral head avn according to the steinberg classification system.12 the femoral heads were stored under aseptic conditions at −20°c until processing. each sample was cut into two halves and preoperative magnetic resonance imaging was used to identify necrotic and healthy control areas [figure 1]. raman spectroscopy results for both necrotic and normal control areas of the femoral heads were recorded and compared at 400–2,000 cm−1.11 each sample was scanned using a raman spectrometer (i-raman® ex portable raman spectrometer, b&w tek inc., newark, delaware usa) with excitation from a laser diode operating at 1,064 nm. corresponding spectroscopy software (b&w tek inc.) was used to analyse the obtained bone spectra. the spectra were baselined and averaged to improve the signal-to-noise ratio. the identification of key raman bands was performed manually. each sample was assessed for degree of bone mineralisation, mineral crystallinity, carbonate content, collagen cross-linking and mineral and collagen fibril orientation. ratios of mineral content and mineral-toorganic matrix content were generated for analytical purposes. the volume of bone mineral content was assessed by comparing phosphate and carbonate bands at 958 and 1,070 cm−1, respectively, relative to that of the amide band at 1,656 cm−1. bone mineral crystallinity was studied by comparing the carbonate band at 1,070 cm−1 to the phosphate band at 958 cm−1. this ratio corresponds to the extent of carbonate substitution for carbonate in bone mineral crystals and is inversely related to bone remodelling.1 collagen represents the organic scaffold providing the tensile and viscoelastic properties of bone. the collagen cross-linking ratio was examined by comparing the shift in the amide i band from 1,660 to 1,684 cm−1. all data were entered into the statistical package for the social sciences (spss), version 22 (ibm corp., chicago, illinois, usa). means and standard figure 1: a: photograph of the bisected femoral head of a patient with sickle cell disease-induced avascular necrosis showing necrosis in the subchondral area (arrow). b: preoperative magnetic resonance imaging showing the same necrotic area as a hypointense signal (arrowhead). figure 2: graphs comparing the acquired raman spectra of (a) normal bone and (b) bone collected from femoral heads affected by sickle cell disease-induced avascular necrosis (n = 10). the normal bone shows peaks at 958 cm−1 for phosphate, 1,070 cm−1 for carbonate, 1,660 cm−1 for amide i and 1,684 cm−1 for amide ii. it demonstrates the overall drop in spectra of necrotised bone. analysis of bone microarchitectural changes and structural damage in sickle cell disease-induced avascular necrosis using raman spectroscopy is there potential for medical management? e298 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e299 deviations were examined using a student’s t-test and analysis of variance. the level of statistical significance was set at p ≤0.050. this study was approved by the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (squ-ec1039114). written informed consent was obtained from all patients prior to surgery. consent of the patient was obtained for publication of figure 1. results of the seven patients with scd included in the study, five (71.4%) were female and three (42.9%) underwent figure 3: charts showing the average acquired raman spectra from bone samples collected from femoral heads affected by sickle cell disease-induced avascular necrosis (n = 10). in comparison to healthy control areas, the necrotic areas showed (a) an increased carbonate-to-phosphate ratio, indicating a difference in bone crystallinity and transformation to a brittle matrix, (b & c) reduced phosphate-to-amide and carbonate-to-amide ratios, indicating a reduction in mineral relative to organic material, and (d) a reduced collagen crosslinking ratio, indicating increased collagen cross-linkage disruption. avn = avascular necrosis. table 1: average ratios of matrix and minerals based on acquired raman spectra from bone samples collected from femoral heads affected by sickle cell disease-induced avascular necrosis (n = 10) sample carbonate at 1,070 cm−1 to phosphate at 958 cm−1 carbonate at 1,070 cm−1 to amide i at 1,660 cm−1 phosphate at 958 cm−1 to amide i at 1,660 cm−1 amide i at 1,660 cm−1 to amide ii at 1,684 cm−1 avn control avn control avn control avn control 1 0.58 0.30 1.92 8.74 1.11 2.64 0.92 0.83 2 0.78 0.43 1.67 2.57 1.30 1.09 0.91 1.06 3 0.93 0.43 1.39 3.88 1.29 1.67 0.96 1.08 4 0.88 0.42 1.47 3.96 1.29 1.67 1.03 1.27 5 0.80 0.29 1.92 2.31 1.53 0.67 0.81 1.44 6 0.98 0.20 1.33 1.89 1.30 0.38 1.03 1.04 7 0.87 0.43 1.64 3.88 1.43 1.67 1.54 1.08 8 0.85 0.22 1.29 9.54 1.10 2.09 0.90 1.34 9 0.58 0.49 2.15 4.06 1.24 2.00 0.99 1.87 10 0.55 0.27 2.03 15.84 1.11 4.22 0.84 1.04 average 0.78 ± 0.32 0.35 ± 0.05 1.68 ± 0.44 5.68 ± 1.39 1.14 ± 0.09 1.81 ± 0.34 0.99 ± 0.65 1.21 ± 0.31 avn = atraumatic avascular necrosis. ahmed al-ghaithi, john husband and sultan al-maskari a staged bilateral arthroplasty. the average age was 25 years (range: 22–32 years). overall, avn resulted in a drop in bone quality as measured by the mineral-tomatrix ratio, mineral crystallinity, carbonate content, collagen cross-linking ratio and orientation of the mineral and collagen fibrils. figure 2 shows the average collected spectra of necrotic compared to healthy bone, along with the band assignment. there was a significant decrease in both phosphate-to-amide ratio (p = 0.01; mean ratio of 1.14 ± 0.09 from necrotic areas and 1.81 ± 0.34 from healthy area) and carbonate-to-amide ratio (p = 0.02; mean ratio of 1.68 ± 0.44 from necrotic areas and 5.68 ± 1.39 from healthy area) observed for necrotic compared to control areas, indicating a drop in mineral volume. in addition, there was a significant drop in the carbonate-to-phosphate ratio for the necrotic compared to control areas (p = 0.008; mean ratio of 1.14 ± 0.09 from necrotic areas and 1.81 ± 0.34 from healthy area) and significant shift from amide signal at 1,660 cm−1 to amide at 1,684 cm−1 (mean ratio of 0.99 ± 0.65 from necrotic areas and 1.21 ± 0.31 from healthy area) [table 1]. figure 3 demonstrates the drop of the overall mineral-to-matrix ratios in the necrotic compared to the control. discussion the current study aimed to examine molecular structural changes in necrotic compared to normal bone samples from patients with scd-induced avn using raman spectroscopy. the results indicated that scdinduced avn resulted in severe structural damage to the bone and a loss of mineral and organic contents, with necrotic areas showing a significant loss in bone quality and protein formation compared with the healthy control areas. these changes in bone quality were apparent even at an advanced stage of disease. these results are consistent with the concept of bone remodelling disruption due to circulatory failure, in which the bone loses its ability to remodel due to disturbances in bone tissue vascularity.13 low levels of oxygen and nutrition disrupt the physiological bone remodelling process, leading to the production of low-quality bone. in addition, the shift of collagen spectra from 1,660 to 1,684 cm−1 suggests the disruption of collagen cross-linking, which would lead to the deformation of the fibril scaffold, loss of tensile strength and eventually bone collapse. silva et al. reported similar findings in a senescence-accelerated mouse prone 6 model of osteoporosis due to reduced collagen content and collagen-to-mineral ratios.14 bone mineralisation is the process by which mineral crystals are deposited in the organic bone matrix, providing structural strength; however, any alterations to this process can result in the bone having poor biomechanical properties.1 raman spectrometry can determine the degree of bone mineralisation by measuring different ratios including the mineralto-matrix ratio, carbonate-to-phosphate ratio and degree of mineral crystallinity.11 the latter variable is attributed to the altered bone remodelling process which transforms the normal bone into a more brittle tissue susceptible to fragility fractures. in the present study, the results indicated a significant reduction of mineral-to-matrix ratios in necrotic compared to control areas, as represented by the ratios of phosphate at 958 cm−1 or carbonate at 1,070 cm−1 relative to that for collagen amide i at 1,656 cm−1. moreover, there was a significant increase in the carbonate-to-phosphate ratio in the necrotic compared to control areas, with the ratio increasing with reduced remodelling. acquired raman signals from the necrotic bone samples were comparable to those reported from other bone pathologies known to respond to antiresorptive therapy such as osteoporosis.15,16 for example, a study of cancellous bone collected from the lumbar spine of female cadavers indicated a reduced mineral-to-matrix ratio in those with osteoporosis.15 similarly, shen et al. observed a decrease in the mineral-to-matrix ratios of rats with spinal cord injury-induced osteoporosis, a finding attributed to hormonal changes.16 in avn, the rationale behind the use of medical therapy such as bisphosphonates is that bone collapse may be prevented during the repair phase by the inhibition or slowing down of resorptive activity.17 using raman spectroscopy, various studies have shown that the response of osteoporotic bone to antiresorptive agents leads to improved mineral and matrix ratios.18,19 burket et al. found that the femurs of osteoporotic sheep treated with antiresorptive agents demonstrated improved parameters in terms of carbonate substitution, crystallinity and collagen.18 anabolic agents such as teriparatide, a form of parathyroid hormone 1-34, have also been shown to have a positive in vivo time-dependent effect on bone mineral and matrix quality.19 in line with previous research, the findings of the present study suggest that raman spectroscopy may be useful in studying the effect of these agents in animal or even human models. however, further work is advocated, especially in the early stages of disease, in order to better understand the disease process and help develop timely therapeutic strategies. analysis of bone microarchitectural changes and structural damage in sickle cell disease-induced avascular necrosis using raman spectroscopy is there potential for medical management? e300 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e301 conclusion the current study found that necrotic areas of bone collected from the femoral heads of scd patients with avn demonstrated abnormal structural features compared to normal bone, thereby indicating poorer mechanical properties. however, acquired raman signals from these necrotic areas were similar to those reported in other metabolic diseases found to respond well to medical treatment such as osteoporosis. such findings appear to support the use of medical therapy in the early stages of avn, as well as highlight the utility of raman spectroscopy in studying the physiological bone remodelling process. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the research council, oman, through the 2016 individual innovation competition scheme. references 1. clarke b. normal bone anatomy and physiology. clin j am soc nephrol 2008; 3:s131–9. https://doi.org/10.2215/cjn.04151206. 2. boettcher wg, bonfiglio m, hamilton hh, sheets rf, smith k. non-traumatic necrosis of the femoral head: i. relation of altered hemostasis to etiology. j bone joint surg am 1970; 52:312–21. https://doi.org/10.2106/00004623-197052020-00012. 3. vaishya r, agarwal ak, edomwonyi eo, vijay v. musculo skeletal manifestations of sickle cell disease: a review. cureus 2015; 7:e358. https://doi.org/10.7759/cureus.358. 4. marker dr, seyler tm, mcgrath ms, delanois re, ulrich sd, mont ma. treatment of early stage osteonecrosis of the femoral head. j bone joint surg am 2008; 90:175–87. https://doi.org/10.2 106/jbjs.h.00671. 5. agarwala s, jain d, joshi vr, sule a. efficacy of alendronate, a bisphosphonate, in the treatment of avn of the hip: a prospective open-label study. rheumatology (oxford) 2005; 44:352–9. https://doi.org/10.1093/rheumatology/keh481. 6. lai ka, shen wj, yang cy, shao cj, hsu jt, lin rm. the use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis: a randomized clinical study. j bone joint surg am 2005; 87:2155–9. https:// doi.org/10.2106/jbjs.d.02959. 7. luo rb, lin t, zhong hm, yan sg, wang ja. evidence for using alendronate to treat adult avascular necrosis of the femoral head: a systematic review. med sci monit 2014; 20:2439–47. https://doi.org/10.12659/msm.891123. 8. jäger m, tillmann fp, thornhill ts, mahmoudi m, blondin d, hetzel gr, et al. rationale for prostaglandin i2 in bone marrow oedema: from theory to application. arthritis res ther 2008; 10:r120. https://doi.org/10.1186/ar2526. 9. glueck cj, freiberg ra, sieve l, wang p. enoxaparin prevents progression of stages i and ii osteonecrosis of the hip. clin orthop relat res 2005; 435:164–70. https://doi.org/10.1097/01. blo.0000157539.67567.03. 10. johnson aj, mont ma, tsao ak, jones lc. treatment of femoral head osteonecrosis in the united states: 16-year analysis of the nationwide inpatient sample. clin orthop relat res 2014; 472:617–23. https://doi.org/10.1007/s11999-013-3220-3. 11. morris md, mandair gs. raman assessment of bone quality. clin orthop relat res 2011; 469:2160–9. https://doi.org/10.10 07/s11999-010-1692-y. 12. steinberg me, steinberg dr. classification systems for osteonecrosis: an overview. orthop clin north am 2004; 35:273–83. https://doi.org/10.1016/j.ocl.2004.02.005. 13. parfitt am, mundy gr, roodman gd, hughes de, boyce bf. a new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. j bone miner res 1996; 11:150–9. https://doi.org/10.1002/jbmr.5650110203. 14. silva mj, brodt md, wopenka b, thomopoulos s, williams d, wassen mh, et al. decreased collagen organization and content are associated with reduced strength of demineralized and intact bone in the samp6 mouse. j bone miner res 2006; 21:78–88. https://doi.org/10.1359/jbmr.050909. 15. kim g, cole jh, boskey al, baker sp, van der meulen mc. reduced tissue-level stiffness and mineralization in osteoporotic cancellous bone. calcif tissue int 2014; 95:125–31. https://doi. org/10.1007/s00223-014-9873-4. 16. shen j, fan l, yang j, shen ag, hu jm. a longitudinal raman microspectroscopic study of osteoporosis induced by spinal cord injury. osteoporos int 2010; 21:81–7. https://doi.org/10.10 07/s00198-009-0949-3. 17. young ml, little dg, kim hk. evidence for using bisphos phonate to treat legg-calvé-perthes disease. clin orthop relat res 2012; 470:2462–75. https://doi.org/10.1007/s11999-011-2240-0. 18. burket jc, brooks dj, macleay jm, baker sp, boskey al, van der meulen mch. variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment. bone 2013; 52:326–36. https:// doi.org/10.1016/j.bone.2012.10.018. 19. pettway gj, schneider a, koh aj, widjaja e, morris md, meganck ja, et al. anabolic actions of pth (1-34): use of a novel tissue engineering model to investigate temporal effects on bone. bone 2005; 36:959–70. https://doi.org/10.1016/j. bone.2005.02.015. ahmed al-ghaithi, john husband and sultan al-maskari https://doi.org/10.2215/cjn.04151206 https://doi.org/10.2106/00004623-197052020-00012 https://doi.org/10.7759/cureus.358 https://doi.org/10.2106/jbjs.h.00671 https://doi.org/10.2106/jbjs.h.00671 https://doi.org/10.1093/rheumatology/keh481 https://doi.org/10.2106/jbjs.d.02959 https://doi.org/10.2106/jbjs.d.02959 https://doi.org/10.12659/msm.891123 https://doi.org/10.1186/ar2526 https://doi.org/10.1097/01.blo.0000157539.67567.03 https://doi.org/10.1097/01.blo.0000157539.67567.03 https://doi.org/10.1007/s11999-013-3220-3 v v https://doi.org/10.1016/j.ocl.2004.02.005 https://doi.org/10.1002/jbmr.5650110203 https://doi.org/10.1359/jbmr.050909 https://doi.org/10.1007/s00223-014-9873-4 https://doi.org/10.1007/s00223-014-9873-4 https://doi.org/10.1007/s00198-009-0949-3 https://doi.org/10.1007/s00198-009-0949-3 https://doi.org/10.1007/s11999-011-2240-0 https://doi.org/10.1016/j.bone.2012.10.018 https://doi.org/10.1016/j.bone.2012.10.018 https://doi.org/10.1016/j.bone.2005.02.015 https://doi.org/10.1016/j.bone.2005.02.015 disasters and crises are disruptive to the structures and functions of communities. however, the challenges they present also bring opportunities for learning and changing at both individual and organisational levels. healthcare systems owe much of their developments and advancements to crisis situations. hence, healthcare organisations need to pay attention to these opportunities for thriving— and not just surviving—amid the chaos of adversities. thriving through and within crises requires systems to be antifragile. taleb coined the term “antifragility” to describe systems that “benefit from shocks” and “thrive and grow when exposed to volatility, randomness, disorder, and stressors and love adventure, risk, and uncertainty”.1 taleb advances the notion that “by grasping the mech anisms of antifragility we can build a systematic and broad guide to non-predictive decision making under uncertainty in business, politics, medicine, and life in general”.1 in other words, antifragile systems need to be built and designed so they not only survive during a crisis but thrive through it. the current global outbreak of covid-19 presents exceptional challenges that can serve as an opportunity for healthcare systems to thrive and boost their anti fragility as the pandemic continues to spread and evolve over time. this makes the current time a valuable chance for healthcare systems to develop their organisational skills proactively in tandem with the development of the crisis itself. this opportunity to thrive, however, should not be taken for granted. instead, healthcare systems and organisations need to be prepared, guided and directed towards this thriving learning mode during the crisis. unfortunately, many healthcare systems are ill-prepared for pandemic crisis management and are not prepared at all for the opportunity to thrive under such circumstances. in 2019, both the global preparedness monitoring board and the global health security index reported a global lack of preparedness for health emergencies worldwide.2,3 during a pandemic, health systems are typically absorbed in managing the chaos that ensues and these systems find themselves exhausted afterwards. hence, they may lose a great opportunity to thrive amid the chaos of a crisis. it is the responsibility of healthcare leaders to guide their systems through the transition of surviving the crisis to thriving in it. healthcare organisational skills much like individuals, organisations have mechanisms and skills that allow them to survive and thrive. living organisms might survive with the provision of minimal requirements for living such as breathing, eating and drinking. however, these organisms need more proactive efforts for thriving and growing. each living organism has its own mechanisms for surviving and thriving. similarly, organisations and systems can survive with the provision of their basic requirements but thriving requires planned proactive efforts that best suit the organisation. there are two types of organisational skills used during crises: specific and generic.4 on the one hand, specific skills are needed to manage a particular crisis, such as the development of management protocols and measures to manage the outbreak of covid-19. hence, specific skills can be viewed as the ‘survival skills’ necessary to allow the system to continue functioning despite the crisis. on the other hand, generic skills are necessary for the organisation to carry out its functions and duties to achieve its goals and are usually applied to routine duties. these generic skills are also the platform for applying specific skills during a crisis. generic skills include aspects such as department of emergency medicine, ibri hospital, ministry of health, ibri, oman *author’s e-mail: dralazri@yahoo.com الصالبة وسط أزمة كوفيد-19 جعل أنظمة الرعاية الصحية تزدهر من خالل املهارات التنظيمية الشاملة نا�رص حماد العزري antifragility amid the covid-19 crisis making healthcare systems thrive through generic organisational skills nasser hammad al-azri editorial sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e241–244, epub. 5 oct 20 submitted 8 mar 20 revision req. 20 apr 20; revision recd. 11 may 20 accepted 13 may 20 https://doi.org/10.18295/squmj.2020.20.03.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ antifragility amid the covid-19 crisis making healthcare systems thrive through generic organisational skills e242 | squ medical journal, august 2020, volume 20, issue 3 leadership, teamwork and communication, and they can enhance the antifragility of the system. although generic organisational skills are not specific to a single type of crisis, they are critical for initiating, building and maintaining specific organisa tional capabilities before as well as during a crisis. more over, because they are applicable to routine duties, generic skills remain relevant after the crisis. if these skills are well developed, they can help an organisation thrive well beyond the crisis, adding to the system’s reservoir of antifragility mechanisms. much of the current literature concerning covid-19 management is focused on the specific organisational skills needed to control the outbreak. however, little is being said about generic organisational skills as the basis of specific skills and how they should be realised. hence, the focus of this article is on crisis management through the lens of five critical generic organisational skills that give healthcare systems an opportunity to grow and thrive amid the covid-19 pandemic. developing antifragility through generic skills vuca is a military term used to describe situations characterised by volatility, uncertainty, complexity and ambiguity.5 disasters and crises are deemed to have a vuca nature. in the disruptive crisis environment of vuca, some systems become fragile and breakdown under pressure, while others remain robust and, relatively, indifferent to change. yet, there are systems that take the opportunity of the disaster to grow and develop their antifragility amid the crisis. many systems choose to adapt and survive, but antifragile ones evolve, grow and thrive, becoming more resilient in the future.6 the following discussion briefly presents an example of five generic organisational skills that give healthcare systems a chance to boost their antifragility in a vuca environment like the current covid-19 crisis. these skills include leadership, teamwork, comm unication, system design and learning and feedback. leadership leadership is a cornerstone for any system or organisation. the whole activity of a system revolves around the leadership style manifested in that system. leadership is not an individual task but rather a mindset that diffuses throughout the organisation. almost all other organisational skills, whether specific or generic, are dependent in their execution on organ isational leadership, and crisis management relies heavily on leadership.7 leadership is essential to build capacity and mitigate risks during pandemics.2 the covid-19 outbreak has shown that leaders need to act now.8 in particular, vuca environments, like the covid-19 pandemic, require unique leadership characteristics. lawrence suggests a set of leadership characteristics known as vuca prime to be used in vuca environments;5 these characteristics include vision, understanding, clarity and agility. to be properly prepared, leaders need to have developed these traits well ahead of a vuca situation. this is achieved through practice and applying the correct type of leadership styles to daily/routine situations prior to a crisis. teamwork how systems and organisations perform is defined by the integrative activities of their actors. teams are the backbone of healthcare systems and teamwork is a rate-limiting factor for organisational outcomes. the execution of healthcare activities cannot be achieved without coordinated teamwork. however, a crisis is a hard test for teams as it stretches the systems’ needs beyond the normal capacity of the system. teams in healthcare systems are the source of power in the system. in fact, there is sufficient evidence that teamwork is more important than technical prowess for preventing and mitigating a major crisis or disaster in high-risk fields such as healthcare.9 unfortunately, it is not uncommon during a crisis for some managers to strip teams of their professional autonomy and ability to cooperate with others through the piling up of structures such as procedures and formal rules.10 as systems are stretched beyond their means during a crisis, more gaps appear at critical times, and the organisational capacity for patching and stitching that prevails during routine work is no longer sufficient. undoubtedly, teamwork has been proved essential to address concerns related to the covid-19 pandemic,11 and systems cannot succeed in managing the crisis without good teamwork. a crisis is a time for teamwork; leaders must equip their organisations with this invaluable skill. communication a single, reliable tool during a crisis has always been communication. over several decades, communication has been recognised as a key element for successful crisis management.12 moreover, poor communication has been repeatedly associated with crisis management failure.13 the joint commission in the united states asserts that “the success or failure of an eop [emergency nasser hammad al-azri editorial | e243 operations plan] is often determined by timely access to communication that ensures the flow of critical information”.14 the covid-19 crisis has shown how effective communication is serving as a key factor in managing the pandemic through proper flow of information, handling uncertainty and fear and promoting behavioural changes in the community.15 however, leaders must realise that this critical, key element cannot be developed overnight, especially during a crisis. instead, commun ication requires time and proactive efforts well in advance of the crisis in order to establish itself in the system. a crisis provides a live test for the quality of established communication strategies within an organisation. nevertheless, it is also a lesson for future planning. system design it is a fundamental concept in biology and physiology that the structure of a system determines its functions.16 using a medical analogy, one might think of the system’s structure as the anatomy and the system’s processes and functions as the physiology. for any system to serve specific outcomes, it is not enough to adjust the physiological functions through enforcing new or modified processes, policies, protocols and standards of the system unless the anatomical structure of the system is fit for the intended purpose. as has been shown during the covid-19 crisis, many healthcare systems failed as their anatomy was not made to meet the physiological adaptations needed during a crisis. a system that is not structurally designed to meet the challenges of crisis management will not be able to cope with the stressors resulting from required functional changes during a disaster. although it might be late to review and modify a system’s design during an emergency status, how the system responds to the challenges offers invaluable insight into how the anatomical structure of the system might present a constraint to its processes and functionality. this insight should inform a better, future system design— one that takes into account the needs that may arise during crisis management, and beyond. learning and feedback social systems, such as healthcare, are informationbonded. they change their behaviour in response to information flow within the system.17 hence, understanding the centrality of learning and feedback in such systems is massive as it provides the means for the system to adapt to a changing external, as well as internal, environment. the quality of embedded learning and feedback functionality within a system determines, to a large extent, the quality of change in response to a dynamic environment. the vuca nature of reality during any crisis precludes the ability to forecast much of the changes and prepare for them in advance. in such a dynamic and constantly unfolding environment, meadows once said: “we can’t control systems or figure them out. but we can dance with them!”.18 responding within such a dynamic environment requires consciously planned and continuously monitored learning and feedback loops that allow the system to self-organise its behaviour as it emerges within the crisis. the way forward disasters and crises disrupt the ‘normal’ activities of systems and organisations. however, amid this disruption, crises also offer organisations the potential to grow and thrive. the current covid-19 pandemic is a good example of such a potential. as much as healthcare systems focus on their specific organisational skills to mitigate the effects of the crisis, one must also pay attention to the generic organisational skills through which they can develop and improve. by focusing on both specific and generic organisational skills, systems will not only survive through the crisis but will also grow and thrive towards antifragility. antifragility and thriving are, therefore, a reflection of how much we have invested in our generic organisational skills through leadership, teamwork, communication, system’s design, and learning and feedback. systems will, almost always, output during a crisis whatever inputted in them at routine times. references 1. taleb nn. antifragile: how to live in a world we don’t understand. london, uk: allen lane, 2012. 2. global preparedness monitoring board. a world at risk. from: https://apps.who.int/gpmb/assets/annual_report/gpmb_ annualreport_2019.pdf accessed: may 2020. 3. global health security index. global health security index october 2019. from: www.ghsindex.org/wp-content/ uploads/2020/04/2019-global-health-security-index.pdf accessed: may 2020. 4. friedman ml. everyday crisis management. 1st ed. naperville, illinois, usa: first decision press, 2002. 5. lawrence, k. developing leaders in a vuca environment. from: www.emergingrnleader.com/wp-content/uploads/2013/02/ developing-leaders-in-a-vuca-environment.pdf accessed: may 2020. 6. alhir, ss. the anti-fragility edge: antifragility in practice. london, uk: lid publishing, 2017. 7. hawley a, matheson j. making sense of disaster medicine: a hands-on guide for medics. 1st ed. boca raton, florida, usa: crc press, 2010. antifragility amid the covid-19 crisis making healthcare systems thrive through generic organisational skills e244 | squ medical journal, august 2020, volume 20, issue 3 8. fraher, al. thinking through crisis: improving teamwork and leadership in high-risk fields. 1st ed. cambridge, uk: cambridge university press, 2011. 9. gates b. responding to covid-19 a once-in-a-century pandemic? n engl j med 2020; 382:1677–9. https://doi.org/10.1056/nejm p2003762. 10. morieux y, tollman p. six simple rules: how to manage compl exity without getting complicated. boston, massachusetts, usa: harvard business review press, 2014. 11. ling l, joynt gm, lipman j, constantin jm, joannes-boyau o. covid-19: a critical care perspective informed by lessons learnt from other viral epidemics. anaesth crit care pain med 2020; 39:163–6. https://doi.org/10.1016/j.accpm.2020.02.002. 12. garnett jl, kouzmin a. communicating throughout katrina: competing and complementary conceptual lenses on crisis communication. public adm rev 2007; 67: 171–88. https://doi. org/10.1111/j.1540-6210.2007.00826.x. 13. cheng ss. crisis communication failure: a case study of typhoon morakot. asian soc sci 2013; 9:18–32. https://doi.org/10.5539/ ass.v9n3p18. 14. the joint commission, joint commission resources. emer gency management in health care: an all-hazards approach. 2nd ed. illinois, usa: joint commission resources, 2012. 15. finset a, bosworth h, butow p, gulbrandsen p, hulsman rl, pieterse ah, et al. effective health communication a key factor in fighting the covid-19 pandemic. patient educ couns 2020; 103:873–6. https://doi.org/10.1016/j.pec.2020.03.027. 16. heulitt mj. structure determines function. j pediatr intensive care 2013; 2:1–3. https://doi.org/10.3233/pic-13041. 17. gharajedaghi j. systems thinking: managing chaos and complexity: a platform for designing business architecture. 3rd ed. burlington, massachusetts, usa: morgan kaufmann, 2011. 18. meadows dh. thinking in systems: a primer. hartford, vermont, usa: chelsea green publishing, 2008. https://doi.org/10.1056/nejmp2003762 https://doi.org/10.1056/nejmp2003762 https://doi.org/10.1016/j.accpm.2020.02.002 https://doi.org/10.1111/j.1540-6210.2007.00826.x https://doi.org/10.1111/j.1540-6210.2007.00826.x https://doi.org/10.5539/ass.v9n3p18 https://doi.org/10.5539/ass.v9n3p18 https://doi.org/10.1016/j.pec.2020.03.027 https://doi.org/10.3233/pic-13041 نتائج احلملة الوطنية للتوعية بسرطان الرأس والعنق وفحصه يف سلطنة ُعمان زينة الذهلية، �صاملة حممد ال�صيبانية، في�صل الكلباين، جميل حيدر abstract: objectives: the prognosis of head and neck cancer (hnc) depends substantially on disease stage at the time of diagnosis. unfortunately, the majority of hnc patients present at relatively late stages. in oman, a national screening campaign was conducted to increase public awareness of hnc and encourage early detection. this study aimed to report the outcomes of that campaign. methods: the campaign took the form of biannual events conducted at a tertiary care centre and in public malls in muscat, oman from april 2015 to july 2019. data were collected from participants using the head and neck cancer alliance screening form. otolaryngologists and oral maxillofacial surgeons performed a thorough physical evaluation of the head and neck region. results: of the 1,500 individuals visiting the hospital and malls during the campaign events, a total of 509 agreed to undergo screening (response rate: 33.9%). of these, 12.8% had positive screening results and 5.9% required further evaluation. however, none of the cases with suspicious findings were found to be malignant after a thorough evaluation. overall, 16.9% of the participants were aware of the early signs of hnc; in addition, 5.5% knew how to perform an oral self-examination. conclusion: screening is a simple and safe method for the prevention and early detection of hnc. mass screening and public awareness programmes may help to reduce the burden of this disease in oman. keywords: head and neck cancer; early detection of cancer; mass screening; knowledge; health risk behaviors; oman. غالبية �ص ُي�َصخَّ احلظ ل�صوء الت�صخي�ص. وقت املر�ص مرحلة على كبري ب�صكل والعنق الراأ�ص �رسطان ت�صخي�ص يعتمد الهدف: امللخ�ص: مر�صى �رسطان الراأ�ص والعنق يف مراحل متاأخرة ن�صبًيا. مت اإجراء حملة فح�ص وطنية يف ُعمان لزيادة الوعي العام ب�رسطان الراأ�ص والعنق وت�صجيع الك�صف املبكر. هدفت هذه الدرا�صة اإىل الإبالغ عن نتائج تلك احلملة. الطريقة: اأُجريت احلملة ب�صكل ن�صف �صنوي يف مركز رعاية ثالثية ومراكز جتارية عامة يف م�صقط، ُعمان من اأبريل 2015 اإىل يوليو 2019. مت جمع البيانات من امل�صاركني با�صتخدام منوذج فح�ص احتاد �رسطان الراأ�ص والعنق. قام اأطباء جراحة الأنف والأذن واحلنجرة وجراحة الوجه والفكني واأطباء الأنف والأذن واحلنجرة باإجراء تقييم �صامل ملنطقة الراأ�ص والعنق. النتائج: وافق 509 �صخ�ص من بني 1500 �صخ�ص ممن قاموا بزيارة امل�صت�صفى واملراكز التجارية خالل فعاليات احلملة على اخل�صوع للفح�ص )معدل ال�صتجابة: %33.9(. من بني هوؤلء ح�صل %12.8 على نتائج فح�ص اإيجابية و احتاج 5.9% منهم اإىل مزيد من التقييم. ورغم ذلك مل تكن اأي من احلالت ذات النتائج امل�صبوهة خبيثة بعد اجراء تقييم �صامل. ب�صكل عام كان 16.9% من امل�صاركني على علم بالعالمات املبكرة ل�رسطان الراأ�ص والعنق؛ بالإ�صافة اإىل ذلك عرف %5.5 منهم كيفية اإجراء فح�ص فموي ذاتي. اخلال�صة: الفح�ص هو طريقة ب�صيطة واآمنة للوقاية والك�صف املبكر عن �رسطان الراأ�ص والعنق. قد ت�صاعد برامج امل�صح ال�صامل والتوعية العامة على تخفيف َوْطاأَة هذا املر�ص يف �صلطنة ُعمان. الكلمات املفتاحية: �رسطان الراأ�ص والعنق؛ الك�صف املبكر عن ال�رسطان؛ امل�صح ال�صامل؛ املعرفة؛ �صلوكيات املخاطر ال�صحية؛ �صلطنة ُعمان. outcomes of the national head and neck cancer awareness and screening campaign in oman zaina al-dhahli,1 *salma m. al-sheibani,2 faisal al-kalbani,2 jamil hyder2 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e173–178, epub. 28 jun 20 submitted 24 jun 19 revision req. 2 sep 19; revision recd. 14 nov 19 accepted 18 dec 19 advances in knowledge this study describes outcomes from the first national head and neck cancer (hnc) screening campaign conducted in oman and establishes baseline data for the omani population. in addition, this study assessed the level of awareness among the general population with regards to early hnc symptoms and signs. application to patient care this study assessed the prevalence of hnc risk factors in the omani population. such information is of paramount importance for otolaryngologists and other physicians in the country. the campaign emphasised the importance of self-examination among participants; such methods may help hnc cases be diagnosed at an earlier stage, thereby improving patient prognosis and reducing the burden on the local healthcare system. 1department of ear, nose & throat, oman medical specialty board, muscat, oman; 2department of ear, nose & throat, al-nahdha hospital, muscat, oman *corresponding author’s e-mail: salsheibani@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.007 clinical & basic research head and neck cancer (hnc) is the sixth most common cancer globally and includes cancers of the upper aerodigestive tract (i.e. the oral cavity, oropharynx, nasopharynx and larynx), the nasal and paranasal sinuses and the salivary glands.1,2 worldwide, there are 550,000 new hnc cases diagnosed per year.1 in muscat, the capital city of oman, the incidence of hnc was 4.3 cases per https://creativecommons.org/licenses/by-nd/4.0/ outcomes of the national head and neck cancer awareness and screening campaign in oman e174 | squ medical journal, may 2020, volume 20, issue 2 100,000 individuals in 2014.3 overall, the prognosis of hnc depends upon the time of onset and the type and staging of the disease at presentation. the average five-year survival rate is 80% for early hnc; however, this decreases to 30% if regional or distant metastasis is present.4,5 it was observed by the authors that patients with hnc, particularly those with cancers of the oral cavity, usually presented at an advanced stage. generally, the management of advanced stage hnc is complex, costly and results in poor outcomes, with many resources wasted on molecular studies that are non-reproducible and not applicable to the majority of patients.6 underlying factors exacerbating the late presentation of cases include a lack of awareness regarding the signs, symptoms and risk factors for hnc within the general community as well as inadequate preventative and early detection measures on the part of healthcare providers.7 in contrast, screening programmes are comp aratively cheaper and have been shown to play a key role in ensuring the early detection of affected patients worldwide.4,8–12 moreover, because such programmes can detect cancerous or pre-cancerous lesions in the early stages, thus allowing a more timely management, they indirectly help to improve treatment outcomes and survival rates.13,14 in addition, these programmes serve to increase awareness of cancer symptoms among the general population.13,15 in 2005, the world health organization recommended that preventative programmes be implemented to combat the huge number of neglected patients with oral cancer.16 this study aimed to report the outcomes of the first hnc awareness and screening campaign conducted in oman. methods a national hnc screening and awareness campaign was conducted by the departments of ear, nose & throat (ent) and head & neck surgery at al-nahdha hospital in muscat, oman. the campaign took the form of biannual events conducted in the months of april and july over a five-year period. the april event, known as oral head and neck cancer awareness day, was conducted on an annual basis from 2015 until 2019, while the july event was conducted yearly from 2016 to 2018 in recognition of world head and neck cancer day. each event was conducted at both al-nahdha hospital and several public malls in muscat in order to target patients and their relatives attending outpatient clinics as well as members of the general population. individuals who were under 10 years old and those who had a recent history of infections (i.e. upper respiratory tract infections) or who were undergoing chemoradiation for any type of malignancy were excluded from the screening. data were collected using the head and neck cancer alliance screening form.17 this questionnaire provided data regarding the participants’ demographic characteristics, health behaviours (i.e. smoking status and alcohol consumption), family or personal history of hnc, current symptoms and level of awareness regarding hnc symptoms and signs. subsequently, each participant underwent a thorough physical examination by trained otolaryngologists and oral maxillofacial surgeons, focusing on the skin of the head and neck, ears, nose, oral cavity, oropharynx, larynx and salivary and thyroid glands. a rigid nasal endoscope and fibreoptic laryngoscope was also utilised to examine non-visualised areas in the nose, nasopharynx, oropharynx and larynx.18 participants with positive findings were subsequently given a follow-up appointment at the head and neck clinic at al-nahdha hospital or at another related clinic for further evaluation. those who were found to have suspicious lesions were followed up at outpatient clinics, with the results of the clinical assessment obtained from their medical records. in terms of education awareness, participants were provided with printed leaflets regarding the risk factors and symptoms of head hnc as well as audio-visual materials on how to perform a selfexamination of the head and neck area. furthermore, heath educators and volunteers from the oman table 1: symptoms identified during a five-year biannual national head and neck cancer screening campaign cond ucted in oman (n = 509) symptom n (%) 95% ci voice changes 43 (8.4) 6.2–11.2 sore throat 65 (12.8) 10–16 mouth sore 26 (5.1) 3.4–7.4 bleeding 39 (7.7) 5.5–10.3 lump in throat 8 (1.6) 0.7–3.1 tooth or gum problems 107 (21) 17.6–24.8 earache 46 (9) 6.7–11.9 difficulty swallowing 16 (3.1) 1.8–5.1 growth in neck 13 (2.6) 1.4–4.3 swelling in the head and/or neck 25 (4.9) 3.2–7.2 dental problems 29 (5.7) 3.8–8.1 red or white patches in the mouth 23 (4.5) 2.9–6.7 ci = confidence interval. zaina al-dhahli, salma m. al-sheibani, faisal al-kalbani and jamil hyder clinical and basic research | e175 anti-tobacco society provided counselling services for interested participants. this included education regarding health risk behaviours such as diet, exercise, smoking and alcohol consumption. data regarding the participants’ demographic characteristics, screening results and follow-up clinical assessment results underwent statistical analysis using the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). the biannual campaign was approved by the hospital administration as part of its community outreach services. moreover, this study received ethical approval from the research & ethics committee at al-nahdha hospital. verbal consent was obtained from all subjects prior to screening. results a total of 1,500 individuals attended either the alnahdha hospital as outpatients or visited malls during the course of campaign events conducted over a fiveyear period. of these, 509 agreed to undergo hnc screening (response rate: 33.9%). there were 321 males (63.1%) and 188 females (36.9%), resulting in a maleto-female ratio of 1.7:1. the mean age was 37 ± 11.5 years old (range: 11–76 years). overall, 55 participants (10.8%) were current tobacco users at the time of screening, of which 46 (83.6%) reported smoking cigarettes and 27 (49.1%) smoked both cigarettes and pipes. a total of 46 individuals (9%) were ex-smokers and 13 (2.6%) consumed alcohol. in terms of medical history, 82 participants (16.1%) reported a family history of hnc, while three (0.6%) had been previously treated for skin cancer. during screening, the most common hnc symptoms observed were tooth or gum problems (21%), followed by a sore throat (12.8%) [table 1]. a total of 65 participants (12.8%) had positive exam ination findings, with 30 (5.9%) requiring further eval uation; among those requiring further evaluation, a total of 33 suspicious lesions were recorded [table 2]. among the patients with suspicious lesions, there was an almost equal distribution among males and females (53.3% versus 46.7%) and smokers and ex-smokers (16.7% versus 13.3%) [table 3]. of the 30 cases requiring further evaluation, 17 (56.7%) presented for follow-up at a clinic. all cases were found to be negative for malignancy after a thorough evaluation. one participant had a lesion in the oral cavity that was excised, which histopathology subsequently revealed to be a squamous papilloma. six participants with thyroid swelling underwent fineneedle aspiration cytology and ultrasonography; all were revealed to be benign lesions. three participants were referred to the dermatology department for skin lesions. two participants had cervical lymphadenopathy and underwent appropriate investigations at another table 2: anatomical site of suspicious lesions among cases requiring further evaluation identified during a five-year biannual national head and neck cancer screening campaign conducted in oman (n = 30) site* n (%) skin 3 (10) ears 4 (13.3) nose 3 (10) oral cavity 7 (23.3) oropharynx 0 (0) larynx 4 (13.3) salivary glands 2 (6.7) thyroid gland 5 (16.7) neck 5 (16.7) *the percentages do not add up to 100% as some patients had multiple suspicious lesions. table 3: characteristics of cases with suspicious lesions identified during a five-year biannual national head and neck cancer screening campaign conducted in oman (n = 509) characteristic n (%) cases with suspicious lesions (n = 30) total gender female 14 (46.7) 188 (36.9) male 16 (53.3) 321 (63.1) age in years <45 20 (66.7) 376 (73.9) ≥45 10 (33.3) 133 (26.1) smoking status smoker 5 (16.7) 55 (10.8) ex-smoker 4 (13.3) 46 (9) non-smoker 21 (70) 408 (80.2) alcohol consumption yes 1 (3.3) 13 (2.6) no 29 (96.7) 496 (97.4) family history of hnc yes 6 (20) 82 (16.1) no 24 (80) 427 (83.9) hnc = head and neck cancer. outcomes of the national head and neck cancer awareness and screening campaign in oman e176 | squ medical journal, may 2020, volume 20, issue 2 hospital. one participant had a palpable level ii cervical lymph node which improved following a course of antibiotics. one participant had a hard palate lesion which disappeared upon follow-up. two participants had submandibular gland swellings and underwent sialendoscopies revealing ductal stenosis. one part icipant had pre-existing lung cancer that had been treated with radiotherapy; the screening identified an oral cavity lesion that was diagnosed as osteoradio necrosis and treated with debridement. in terms of awareness, 86 participants (16.9%) were aware of early signs of hnc compared to 423 participants (83.1%) who were not aware. in addition, 5.5% knew how to perform an oral self-examination. the majority of the participants (90.6%) reported an interest in volunteering to raise awareness of hnc. discussion up to 40,000 deaths from oral cancer can be prev ented in high-risk individuals as a result of visual screening.19,20 moreover, most hnc cases are prev entable, with the two major risk factors being tobacco and alcohol consumption which account for approx imately 75% of cases, with the effects of these risk factors being compounded in combination.21,22 gen erally, patients with hnc present with a variety of symptoms depend on the site of lesion. however, early recognition of these symptoms and timely diagnosis and management greatly reduces the burden of this disease on the healthcare system.21,23–25 this study reported outcomes of the first national screening campaign conducted in oman to screen for and establish the level of awareness of hnc signs and symptoms among the general public. in total, 509 participants were screened over a five-year period and underwent complete head and neck examinations. of these, 22.4% constituted a high-risk population (i.e. smokers, ex-smokers and alcohol consumers). a small proportion (5.9%) of the participants required further evaluation and were given follow-up appointments. these findings were similar to those reported from other screening programmes. in the usa, dwojak et al. found that 8% of native americans in south dakota had positive hnc screening results.10 similarly, nunn et al. reported that 5.7% of bangladeshi participants who received positive screening results in the uk were referred for further investigation.26 the majority of participants (56.7%) with positive findings and required further evaluation in the present study attended their scheduled appointments. this rate of compliance was much higher in comparison to other screening programmes. frenández garotte et al. and o’sullivan et al. reported follow-up compliance rates of <30% and 33%, respectively.13,15 it is likely that these findings indicate that the omani campaign was successful in increasing awareness of hnc and the importance of its early detection.27 an interesting finding of the present study was that none of the participants in the screening campaign were found to have malignant disease. however, the reported detection rate for premalignant or malignant conditions during screening programmes is <3%.4,23,28,29 furthermore, participants in the current study were self-selected and most were not at particularly high risk of developing hnc; this may explain why there were no positive findings during the campaign. indeed, previous studies have suggested that hnc screening programmes are more effective if they target populations who are at high risk.15,23 shuman et.al. reported the outcomes of a screening campaign in which the many participants were smokers and alcohol consumers; a total of 47% had abnormal findings and 5% had suspicious lesions.23 during a screening campaign of residents at alcohol addiction treatment centres, o’sullivan et.al. reported the prevalence of mucosal abnormalities to be 29% with 84 mucosal abnormalities/symptoms detected in 61 out of 220 subjects.15 the researchers concluded that oral cancer screening is an efficient and effective way of detecting potentially malignant lesions in highrisk individuals.15 based on the findings of the current study, the level of knowledge among the omani general population regarding the risk factors and signs and symptoms of hnc was low. only 16.9% of the participants were aware of early signs of hnc, with 83.1% having never heard of hnc at all. alarmingly, a similar lack of knowledge among both laypeople and healthcare personnel has been previously reported.26 in the present study, only 5.5% knew how to perform a self-examination of the oral cavity and head and neck region. nevertheless, by the end of the campaign, the participants reported an increase in their awareness of hnc risk factors, symptoms and signs. moreover, they had also learned an easy self-examination technique which they could practice on themselves and others and were strongly encouraged to share this information with their family and friends. this study had several strengths. first, the screening was performed by trained otolaryngologists and oral maxillofacial surgeons. second, the screening included a complete examination of the head and neck region and was not limited to the oral cavity as in other campaigns.30 third, a rigid nasal endoscope and fibreoptic laryngoscope was utilised to examine non-visualised areas.18 finally, the majority of the participants with positive findings were followed-up zaina al-dhahli, salma m. al-sheibani, faisal al-kalbani and jamil hyder clinical and basic research | e177 and evaluated at outpatient clinics after screening. on the other hand, the campaign was limited to muscat and the results cannot be generalised to other areas of oman. it is possible that people in other cities and rural areas would not demonstrate a similar level of awareness of hnc or its early symptoms and signs. in future, the national screening campaign will be extended to cover other regions of the country and will target high-risk populations to improve detection and awareness of this disease. conclusion this study describes the outcomes of the first national hnc screening campaign conducted in oman, establishing baseline data for the omani population. awareness and screening campaigns for hnc are a cost-effective, simple and non-invasive strategy to encourage early detection and increase community awareness of the disease and its related risk factors. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin 2005; 55:74–108. https://doi.org/10.33 22/canjclin.55.2.74. 2. head and neck cancer alliance. what are cancers of the head and neck? from: www.headandneck.org/types/ accessed: nov 2019. 3. oman ministry of health. cancer incidence in oman: 2015. from: https://oca.om/wp-content/uploads/2019/01/cancerincidence-in-oman-2015.pdf accessed: nov 2019. 4. gogarty ds, shuman a, o’sullivan em, sheahan p, kinsella j, timon c, et al. conceiving a national head and neck cancer screening programme. j laryngol otol 2016; 130:8–14. https://doi.org/10.1017/s0022215115003084. 5. jackson cr, shuman ag, hogikyan nd. a critical review of head and neck cancer screening. eur j clin med oncol 2011; 3:33–41. 6. mignogna md, fedele s, ruoppo e, lo russo l. the role of molecular techniques in preventing oral cancer and improving its poor prognosis: an illusion? j oral pathol med 2002; 31:246–8. https://doi.org/10.1034/j.1600-0714.2002.310411.x. 7. mignogna md, fedele s, lo russo l, ruoppo e, lo muzio l. oral and pharyngeal cancer: lack of prevention and early detection by health care providers. eur j cancer prev 2001; 10:381–3. https://doi.org/10.1097/00008469-200108000-00014. 8. hapner er, wise jc. results of a large-scale head and neck cancer screening of an at-risk population. j voice 2011; 25:480–3. https://doi.org/10.1016/j.jvoice.2009.12.004. 9. nakamura h. biosensors: monitoring human health for the sdgs sustainable development goals. biomed j sci tech res 2018; 9:6953–6. https://doi.org/10.26717/bjstr.2018.09.001761. 10. dwojak s, deschler d, sargent m, emerick k, guadagnolo ba, petereit d. knowledge and screening of head and neck cancer among american indians in south dakota. am j public health 2015; 105:1155–60. https://doi.org/10.2105/ajph.2014.302177. 11. nagao t, warnakulasuriya s. annual screening for oral cancer detection. cancer detect prev 2003; 27:333–7. https://doi.org/1 0.1016/s0361-090x(03)00101-6. 12. mathew b, sankaranarayanan r, sunilkumar kb, kuruvila b, pisani p, nair mk. reproducibility and validity of oral visual inspection by trained health workers in the detection of oral precancer and cancer. br j cancer 1997; 76:390–4. https://doi. org/10.1038/bjc.1997.396. 13. frenández garrote l, sankaranarayanan r, lence anta jj, rodriguez salvá a, maxwell parkin d. an evaluation of the oral cancer control program in cuba. epidemiology 1995; 6:428–31. https://doi.org/10.1097/00001648-199507000-00019. 14. brocklehurst p, kujan o, glenny am, oliver r, sloan p, ogden g, et al. screening programmes for the early detection and prevention of oral cancer. cochrane database syst rev 2010; 11:cd004150. https://doi.org/10.1002/14651858.cd004150.pub3. 15. o’sullivan em. prevalence of oral mucosal abnormalities in addiction treatment centre residents in southern ireland. oral oncol 2011; 47:395–9. https://doi.org/10.1016/j.oraloncology.20 11.03.003. 16. petersen pe. strengthening the prevention of oral cancer: the who perspective. community dent oral epidemiol 2005; 33:397–9. https://doi.org/10.1111/j.1600-0528.2005.00251.x. 17. head and neck cancer alliance. screening form. from: www.tmh. org/~/media/files/cancer/screeningform.pdf accessed: nov 2019. 18. patton ll. the effectiveness of community-based visual screening and utility of adjunctive diagnostic aids in the early detection of oral cancer. oral oncol 2003; 39:708–23. https://doi.org/10.10 16/s1368-8375(03)00083-6. 19. downer mc, moles dr, palmer s, speight pm. a systematic review of measures of effectiveness in screening for oral cancer and precancer. oral oncol 2006; 42:551–60. https://doi.org/10.10 16/j.oraloncology.2005.08.006. 20. mignogna md, fedele s. oral cancer screening: 5 minutes to save a life. lancet 2005; 365:1905–6. https://doi.org/10.1016/ s0140-6736(05)66635-4. 21. sankaranarayanan r, ramadas k, thara s, muwong r, thomas g, anju g, et al. long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in kerala, india. oral oncol 2013; 49:314–21. https://doi.org/10.1016/j. oraloncology.2012.11.004. 22. kowalski lp, franco el, torloni h, fava as, de andrade sobrinho j, ramos g, et al. lateness of diagnosis of oral and oropharyngeal carcinoma: factors related to the tumour, the patient and health professionals. eur j cancer b oral oncol 1994; 30b:167–73. https://doi.org/10.1016/0964-1955(94)90086-8. 23. shuman ag, entezami p, chernin as, wallace ne, taylor jm, hogikyan nd. demographics and efficacy of head and neck cancer screening. otolaryngol head neck surg 2010; 143:353–60. https://doi.org/10.1016/j.otohns.2010.05.029. 24. mehanna h, paleri v, west cm, nutting c. head and neck cancer--part 1: epidemiology, presentation, and prevention. bmj 2010; 341:c4684. https://doi.org/10.1136/bmj.c4684. 25. national institute for health and care excellence. improving outcomes in head and neck cancers: cancer service guideline [csg6]. from: http://guidance.nice.org.uk/csghn/guidance/pdf/ english accessed: nov 2019. 26. nunn h, lalli a, fortune f, croucher r. oral cancer screening in the bangladeshi community of tower hamlets: a social model. br j cancer 2009; 101:s68–72. https://doi.org/10.1038/ sj.bjc.6605394. https://doi.org/10.3322/canjclin.55.2.74 https://doi.org/10.3322/canjclin.55.2.74 https://doi.org/10.1017/s0022215115003084 https://doi.org/10.1034/j.1600-0714.2002.310411.x https://doi.org/10.1097/00008469-200108000-00014 https://doi.org/10.1016/j.jvoice.2009.12.004 https://doi.org/10.26717/bjstr.2018.09.001761 https://doi.org/10.2105/ajph.2014.302177 https://doi.org/10.1016/s0361-090x%2803%2900101-6 https://doi.org/10.1016/s0361-090x%2803%2900101-6 https://doi.org/10.1038/bjc.1997.396 https://doi.org/10.1038/bjc.1997.396 https://doi.org/10.1097/00001648-199507000-00019 https://doi.org/10.1002/14651858.cd004150.pub3 https://doi.org/10.1016/j.oraloncology.2011.03.003 https://doi.org/10.1016/j.oraloncology.2011.03.003 https://doi.org/10.1111/j.1600-0528.2005.00251.x https://doi.org/10.1016/s1368-8375%2803%2900083-6 https://doi.org/10.1016/s1368-8375%2803%2900083-6 https://doi.org/10.1016/j.oraloncology.2005.08.006 https://doi.org/10.1016/j.oraloncology.2005.08.006 https://doi.org/10.1016/s0140-6736%2805%2966635-4 https://doi.org/10.1016/s0140-6736%2805%2966635-4 https://doi.org/10.1016/j.oraloncology.2012.11.004 https://doi.org/10.1016/j.oraloncology.2012.11.004 https://doi.org/10.1016/0964-1955%2894%2990086-8 https://doi.org/10.1016/j.otohns.2010.05.029 https://doi.org/10.1136/bmj.c4684 https://doi.org/10.1038/sj.bjc.6605394 https://doi.org/10.1038/sj.bjc.6605394 outcomes of the national head and neck cancer awareness and screening campaign in oman e178 | squ medical journal, may 2020, volume 20, issue 2 27. conway di, hashibe m, boffetta p; inhance consortium, wunsch-filho v, muscat j, la vecchia c, et al. enhancing epidem iologic research on head and neck cancer: inhance the international head and neck cancer epidemiology consortium. oral oncol 2009; 45:743–6. https://doi.org/10.1016/j.oralonco logy.2009.02.007. 28. hawkins rj, wang ee, leake jl. preventive health care, 1999 update: prevention of oral cancer mortality. the canadian task force on preventive health care. j can dent assoc 1999; 65:617. 29. mishra gs, bhatt sh. novel program of using village health workers in early detection and awareness of head and neck cancers: audit of a community screening program. indian j otolaryngol head neck surg 2017; 69:488–93. https://doi. org/10.1007/s12070-017-1231-1. 30. paleri v, staines k, sloan p, douglas a, wilson j. evaluation of oral ulceration in primary care. bmj 2010; 340:c2639. https://doi.org/10.1136/bmj.c2639. https://doi.org/10.1016/j.oraloncology.2009.02.007 https://doi.org/10.1016/j.oraloncology.2009.02.007 https://doi.org/10.1007/s12070-017-1231-1 https://doi.org/10.1007/s12070-017-1231-1 https://doi.org/10.1136/bmj.c2639 1student research committee, department of midwifery, school of nursing and midwifery, mashhad university of medical sciences, mashhad, iran; 2student research committee, torbat heydariyeh university of medical sciences, torbat heydariyeh, iran; 3department of midwifery, neyshabur university of medical sciences, neyshabur, iran *corresponding author’s e-mail: azmoudehe@gmail.com the relationship between menstrual patterns and menstrual attitude dimensions among women of reproductive age cross-sectional survey mona larki,1 azadeh salavati,2 *elham azmoude3 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 241–246, epub. 26 may 22 submitted 31 aug 20 revisions req. 9 nov & 30 dec 20 & 7 feb 21; revisions recd. 7 dec 20 & 13 jan & 11 feb 21 accepted 3 mar 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.7.2021.079 clinical & basic research abstract: objectives: women’s attitudes towards menstruation play a critical role in shaping their bodies and psychosocial integrity. menstruation is affected by certain bio-psychosocial factors, necessitating an in-depth understanding of the phenomenon to cope better with the consequent difficulties. this study aimed to investigate the relationship between menstrual patterns and menstrual attitude dimensions in women of reproductive-age. methods: an observational cross-sectional study was conducted between january and december 2019 on women referred to various urban health centres of torbat heydariyeh, iran. the menstrual attitudes questionnaire and verbal multidimensional scoring systems were used to collect the required data. the features of the menstrual cycle were also recorded. results: a total of 164 women (response rate: 96.74%) were included in this study. women with dysmenorrhea perceived menstruation as a more debilitating, bothersome and predictable event and they were less likely to deny any menstrual effect (p = 0.001). the results also revealed that subjective menstrual blood loss was associated with higher levels of perceiving menstruation as a natural (p = 0.008), bothersome (p = 0.026) and anticipatory event (p = 0.021) and reporting less denial of any menstrual effect (p = 0.001). moreover, women rated menstruation as a more bothersome event with an increase in the duration of menstrual bleeding (p = 0.014). there was no significant relationship between the other features of the menstrual cycle and menstrual dimensions (p >0.05). conclusion: the findings of this study suggest that women’s attitudes towards menstruation were associated with menstrual pain, duration of the menstrual cycle and subjective volume of menstrual flow. these factors could be used to modify women’s attitudes towards the natural phenomenon of menstruation. keywords: attitude; menstruation; dysmenorrhea; menarche; menorrhagia. advances in knowledge this study identified the biomedical factors related to women’s attitudes towards menstruation, including the features of the menstrual cycle. women who experienced menstrual pain and had a longer duration of and heavier menstrual flow perceived menstruation as a more negative event. application to patient care health policy-makers should be aware of the potential factors that influence menstrual attitudes so as to promote more favourable attitudes towards this phenomenon across different populations. given that negative attitudes and beliefs about menstruation can affect women’s health, it is necessary for specialists to design and implement effective biomedical and behavioural interventions for girls and women at risk. women suffering from dysmenorrhea and women with a longer duration of and heavier menstrual flow should be the focus of intervention strategies such as menstrual education to promote positive attitudes towards menstruation. menstruation, as an inevitable biological event, is a significant sign of puberty and the onset of reproductive capability.1–3 this phenomenon, especially its first occurrence, is one of the unique experiences faced by women during their reproductive period.4 challenges encountered during menstruation affect women and their role in the community.3 in addition, several studies have indicated that women’s attitudes towards menstruation have a critical effect on how they perceive their bodies.5 attitude towards menstruation (atm) is a complex concept influenced by the cultural environment in which it is formed. this psychosocial event has significant effects on women’s physical and psychological health and well-being.6 several factors may be involved in the formation of atm, including menstrual characteristics, personal awareness and experiences, cultural values, religious beliefs and community environment.7–8 while some women exhibit positive behaviours and https://creativecommons.org/licenses/by-nd/4.0/ the relationship between menstrual patterns and menstrual attitude dimensions among women of reproductive age cross-sectional survey 242 | squ medical journal, may 2022, volume 22, issue 2 feelings towards menstruation, others may perceive menstruation as a negative, shameful, debilitating and destructive event.1,9 studying awareness about menstrual beliefs and their cultural origins is essential for understanding how women respond to this phenomenon.10 a few studies have reported the relationship between atm and the emergence of menstrual symptoms. a survey among female students documented a negative correlation between atm and the severity of premenstrual symptoms.11 in contrast, another study on adolescent girls revealed no significant correlation between the severity of menstrual symptoms and atm.12 given that the women’s atm implicitly reflects their life experiences and since few studies have been conducted in iran to address this issue, further research in this field is imperative.13 thus, this study aimed to detect the relationship between menstrual patterns and menstrual attitude dimensions among women of reproductive-age. methods for this cross-sectional study conducted between january and december 2019, 170 women of reproductive-age referred to the urban health centres in torbat heydariyeh, khorasan razavi, iran were selected using the convenience sampling method. given that the ideal sample size in correlational studies is 5–10 persons per studied variable, the minimum expected sample size was set as 130. after considering a 30% non-response rate, the final sample size was found to be 170 women. healthy reproductive women aged 18–35 years were included in this study. pregnant or breastfeeding women, those with a history of diseases such as gynaecological cancers and definitive psychiatric disorders such as bipolar disorder or depression and those undergoing hormonal therapy were excluded. socio-demographic and menstrual questionnaires were used to collect the required data, including age, level of education, employment status, monthly household income, age at menarche, the duration and volume of bleeding, dysmenorrhea, type of dysmenorrhea, the regularity of the current menstrual cycle and pain management. the menstrual attitudes questionnaire (maq) contains 33 items addressing five distinct attitudinal dimensions: menstruation as a debilitating (the most negative item), bothersome (less harmful) or natural (the most positive item) event, the denial of any menstrual effect and the prediction of the onset of menstruation. the items were scored based on a seven-point likert scale (strongly disagree = 1 to strongly agree = 7), with a higher score indicating a higher level of the concerned dimension. this scale was developed and validated by brooks-gunn and ruble who reported a cronbach’s alpha coefficient of 0.95– 0.97 for the subscales.14 the reliability and validity of the farsi version of the maq have been confirmed in several previous studies.8,13 the internal consistency of the questionnaire was also confirmed in the present study using the cronbach’s alpha coefficient (ranging from 0.75–0.94 for the five subscales). permission was obtained for the use of this questionnaire from the authors prior to the study. the verbal multidimensional scoring (vms) system, previously developed and validated by andersch and milsom, was also used to assess women’s perception of the severity of menstrual pain and its effect on their daily activities.15 the items were scored using a four-point likert scale ranging from no symptoms to severe symptoms (i.e. none = 1, mild = 2, moderate = 3 and severe = 4). in this study, the content validity of this questionnaire was confirmed by an expert panel, while the internal consistency was supported by the test-retest procedure. the findings were in agreement with those of other studies conducted in iran.16,17 in this study, a pictorial blood loss assessment chart was used to assess the respondents’ menstrual blood volume over the three months preceding the administration of the questionnaire. this chart is considered one of the most useful and reliable measures to assess menstrual bleeding. it was table 1: socio-demographic data of women referred to various urban health centres of torbat heydariyeh, iran (n = 164) variables n (%) or mean ± sd age in years 27.78 ± 6.59 parity 1.13 ± 1.16 menarche age in years 12.71 ± 1.63 education primary school 21 (12.8%) high school 85 (51.8%) college or university 58 (35.4%) employment housewives 125 (76.2%) employed 39 (23.8%) monthly household income less than average 14 (8.5%) average* 136 (82.9%) more than average 14 (8.5%) sd = standard deviation. *average income = 30,000,000–40,000,000 iranian rials. mona larki, azadeh salavati and elham azmoude clinical and basic research | 243 table 2: differences in menstrual attitude dimensions based on the menstrual attitudes questionnaire among women with different menstrual pattern characteristics referred to various urban health centres of torbat heydariyeh, iran (n = 164) menstrual variables menstruation as a debilitating event menstruation as a bothersome event menstruation as a natural event anticipation and prediction of the onset of menstruation denial of any effect of menstruation mean rank p value mean rank p value mean rank p value mean rank p value mean rank p value dysmenorrhea yes 115.18 0.001* 114.32 0.001* 79.06 0.176 114.01 0.001* 42.51 0.001* no 67.33 67.73 89.84 67.87 101.07 dysmenorrhea type primary 27.00 0.664 26.49 0.991 29.04 0.027* 23.83 0.018* 26.00 0.664 secondary 24.83 26.54 18.04 35.42 28.17 menstrual pain severity based on vms absent 67.63 0.001* 67.23 0.001* 78.63 0.260 69.13 0.001* 100.59 0.001*mild 106.83 104.33 88.27 108.42 50.15 moderate 125.23 129.29 94.15 117.21 33.04 heavy menstrual bleeding† yes 83.57 0.607 81.73 0.954 89.11 0.057 77.76 0.266 81.76 0.948 no 79.76 81.31 75.10 85.95 81.28 perceived severity of menstrual bleeding amount scant 67.10 0.082 61.87 0.026* 69.82 0.008* 72.43 0.021* 113.95 0.001*normal 82.52 85.21 76.90 76.87 81.82 heavy 91.52 90.23 99.07 97.58 65.11 pain medication during menstruation yes 29.31 0.164 27.83 0.507 28.26 0.383 25.57 0.641 23.37 0.121 no 23.46 25.06 24.60 27.50 29.88 menstrual cycle regularity yes 78.26 0.379 80.93 0.744 83.59 0.820 81.89 0.899 89.14 0.168 no 85.01 83.43 81.85 82.86 78.57 vms = verbal multidimensional scoring. *correlation is significant at p <0.05. †based on the higham chart.18 table 3: the relationship between menstrual attitude dimensions (based on the menstrual attitudes questionnaire) and menstrual pattern characteristics among women referred to various urban health centres of torbat heydariyeh, iran (n = 164) menstrual variables menstruation as a debilitating event menstruation as a bothersome event menstruation as a natural event anticipation and prediction of the onset of menstruation denial of any effect of menstruation menarche age in years r =-0.054 r = 0.047 r = 0.067 r = -0.084 r = -0.025 p = 0.494 p = 0.552 p = 0.396 p = 0.286 p = 0.752 the number of days with associated pain r = 0.234 r = 0.187 r = 0.241 r = -0.078 r = -0.190 p = 0.095 p = 0.184 p = 0.086 p = 0.583 p = 0.176 days of blood loss per cycle r = -0.122 r = 0.192 r = -0.104 r = -0.083 r = 0.036 p = 0.120 p = 0.014* p = 0.185 p = 0.291 p = 0.648 duration of menstrual cycle in days r = -0.012 r = -0.062 r = 0.048 r = -0.118 r = 0.037 p = 0.876 p = 0.428 p = 0.541 p = 0.132 p = 0.640 *correlation is significant at p <0.05. the relationship between menstrual patterns and menstrual attitude dimensions among women of reproductive age cross-sectional survey 244 | squ medical journal, may 2022, volume 22, issue 2 developed and validated by higham et al.18 this chart measures the volume of menstrual bleeding based on the number of pads or tampons used and the degree to which they are stained. loss of blood exceeding 80 cc was considered as heavy menstrual bleeding (hmb). the validity and reliability of the farsi version of the chart have already been confirmed in iran.19 the required data were collected by two researchers. all women referred to the concerned healthcare centres were invited to participate in the study. the self-administered questionnaires were distributed when the women were waiting for their health consultation. on average it took them 20 minutes to complete the questionnaires. the data was analysed using the statistical package for social sciences (spss) software, version 16.0 (ibm corp., armonk, new york, usa). the kolmogorov-smirnov test was used to verify the normality of the quantitative variables. the dependent variables were all menstrual attitude dimensions. the mann-whitney u test and the wilcoxon rank test were used to compare the atm of women with different characteristics. moreover, correlations were calculated using the spearman rank coefficient. in all the analyses, p <0.05 was set as the level of significance. this research was approved by the ethics committee of torbat heydariyeh university of medical sciences (code: ir.thums.rec.1396.16). all the participants were informed about the research objectives and procedures and they participated in this study voluntarily. they were also assured about the confidentiality of their personal information. all the participants gave verbal and written consent before completing the questionnaires. results after the exclusion of six incomplete questionnaires, 164 women were included (response rate: 96.47%) in this study. the mean age of the participants was 27.78 ± 6.59 years, almost half of whom (n = 85, 51.8%) had a high school education and 35.4% (n = 58) had a college or university education. furthermore, most participants (n = 125, 76.2%) were housewives, and their families’ monthly incomes were within the average range (n = 136, 82.9%) [table 1]. the participants reported that they had started menstruating at an average age of 12.71 ± 1.63 years (range: 10–17 years). furthermore, the mean duration of bleeding and length of the menstrual cycle were 6.41 ± 1.75 days (range: 2–10 days) and 28.10 ± 4.05 days (range: 20–40 days), respectively. overall, 62.8% of women (n = 103) reported a regular menstrual pattern. results showed that 31.7% of participants (n = 52) had dysmenorrhoea, among which 76.92% (n = 40) suffered from primary dysmenorrhoea and 23.07% (n = 12) had secondary dysmenorrhoea. however, most of the participants (n = 134, 81.7%) reported taking no medicine for menstrual pain. the proportional mean scores of all maq subscales were as follows: predictive = 3.77 ± 0.89, debilitating = 4.07 ± 1.25, bothersome = 3.68 ± 1.42, natural = 5.24 ± 1.01 and the denial of menstrual effect = 4.30 ± 1.33. women with menstrual pain mostly perceived menstruation as a bothersome and debilitating event compared to women without dysmenorrhea. these women described menstruation as significantly more predictable and they were also significantly less likely to deny the menstrual effects (p <0.05). similar relation ships were also observed between the menstrual attitude dimensions and severity of menstrual pain based on vms. furthermore, women with primary dysmenorrhea perceived menstruation as a more natural event compared to women with secondary dysmenorrhea. moreover, the women considered menstruation as a more natural, bothersome and anticipatory event with increased subjective menstrual volume. in this regard, women with lesser volumes of menstrual blood were found to be more likely to deny any effect of menstruation. in contrast, no significant difference was observed between the menstrual attitudes of women with and without hmb when considering the higham chart as a more objective measurement criterion [table 2]. according to the result of spearman’s test, the mean score of menstruation as a bothersome event was related to the number of bleeding days per cycle [table 3]. discussion the present study aimed to investigate the relationship between menstrual cycle patterns and menstrual attitude dimensions. according to the findings, women with cyclic menstrual pain perceived menstruation as a debilitating and bothersome event compared to women without such pain. consistent results were reported using the vms scale. it was noted that women’s atm became more negative with an increase in the intensity of pain reported. the results were consistent with the findings of previous studies.20–21 in india, omidvar et al. reported that women in the dysmenorrhoea group experienced menstruation as a debilitating and disturbing mona larki, azadeh salavati and elham azmoude clinical and basic research | 245 phenomenon more frequently than women in the nondysmenorrhoea group.21 dysmenorrhoea, as the most common menstrual complaint, tends to contribute to negative menstrual attitudes among girls.22 the present study indicated that women with primary dysmenorrhoea perceived menstruation as a natural event compared to women with secondary dysmenorrhoea. unlike primary dysmenorrhoea, secondary dysmenorrhoea is caused by underlying pelvic diseases;23 therefore, pathological factors may lead to the belief that menstruation is not a natural phenomenon among these women. no difference was observed between the attitude dimensions among participants with and without hmb upon the measurement of menstrual blood volume using higham’s objective criteria. nevertheless, when the menstrual volume was measured subjectively, the results showed that women with higher blood volumes considered menstruation more bothersome, natural and predictable. moreover, the effects of menstruation on their lives were also denied less frequently. this may be attributed to the differences in women’s opinions about the volume of menstrual bleeding. in this regard, morrison concluded that women with severe menstrual bleeding were more likely to consider menstruation as a curse, while those with lesser bleeding generally regarded menstruation as a natural phenomenon.7 many women have little or no information about normal and abnormal menstruation.24 the differences in self-rated bleeding may be caused by the individual variability in perceiving bleeding and the lack of a universally-accepted method to describe hmb. future research can examine population-specific patterns of menstruation to determine expected, acceptable and abnormal notions.25 the perception of menstruation as a bothersome event was also correlated with the number of bleeding days per cycle. the present study noted a non-significant correlation between the regularity of menstruation, the length of the menstrual cycle and the number of bleeding days and attitude dimensions. in contrast, a study reported that an irregular menstrual cycle was a factor that contributed to the increase in mental stress levels.26 this difference in results may be caused by methodological differences and variations in the study population. the current research revealed no significant association between menarche age and the menstrual attitude dimensions. contrary to the findings of the present research, a survey conducted in china found that those who experienced menstruation at a younger age reported more menstrual pain and discomfort.27 tiwari et al. noted a correlation between the level of preparedness and menarche age.28 they reported a sense of guilt, shame, apprehension and anxiety if a girl was unprepared in the event of early-onset menstruation. such inconsistency might have been observed because most of the females in the present study reported a normal menarche age. the present study has several limitations. first, the cross-sectional method limits the conclusions that can be drawn; however, a longitudinal study may provide a clear understanding of the correlation between the variables. second, the participants were selected from one city in khorasan razavi. more comprehensive studies that include women from the other regions of iran are required. the data in this study were collected from self-report questionnaires, which may pose some potential errors. another limitation pertains to the retrospective nature of the study. further qualitative studies should address the beliefs about menstruation among women with different menstrual patterns. this type of research can lead to the better identification of factors contributing to atm. the detection of factors leading to negative and positive attitudes is necessary to design effective interventions that modify negative attitudes and foster positive attitudes towards menstruation, thereby enabling women to experience womanhood more positively. conclusion the present study’s findings provide a preliminary exploratory ground to examine the factors contributing to atm in iran. it was concluded that menstrual pain and menstrual bleeding volume and duration are associated with women’s atm. negative beliefs about menstruation may have a significantly negative effect on women and girls; hence, these factors could be used to modify their attitudes towards this natural phenomenon. this study highlighted the need to focus on creating strategies to help women and girls eradicate negative atms and exploring ways of improving attitudes when experiencing dysmenorrhea and long and heavy menstruation. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by torbat heydariyeh university of medical sciences, torbat heydariyeh, iran. a u t h o r s’ c o n t r i b u t i o n ea and ml conceptualised and designed the study. as performed the data collection. ea and ml analysed the relationship between menstrual patterns and menstrual attitude dimensions among women of reproductive age cross-sectional survey 246 | squ medical journal, may 2022, volume 22, issue 2 the data. ml and as drafted the manuscript, while ea revised the manuscript. all authors approved the final version of the manuscript. references 1. aflaq f, jami h. experiences and attitudes related to menstruation among female students. pak j psychol res 2012; 27:201–24. 2. marván ml, chrisler jc. menarcheal timing, memories of menarche, and later attitudes toward menstruation. cogent psychol 2018; 5:1–12. https://doi.org/10.1080/23311908.2018. 1525840. 3. kwak y, kim y, baek ka. prevalence of irregular menstruation according to socioeconomic status: a population-based nation wide cross-sectional study. plos one 2019; 14:1–12. https://doi. org/10.1371/journal.pone.0214071. 4. lawal am, idemudia es, balogun sk. menstrual attitude dimensions, anxiety and body esteem in adolescent girls. psychol health med 2020; 25:418–25. https://doi.org/10.1080/13548506.2019.1640885. 5. sveinsdóttir h. menstruation, objectification and health-related quality of life: a questionnaire study. j clin nurs 2018; 27:e503–13. https://doi.org/10.1111/jocn.14049. 6. sommer m, hirsch js, nathanson c, parker rg. comfortably, safely, and without shame: defining menstrual hygiene manage ment as a public health issue. am j public health 2015; 105:1302–11. https://doi.org/10.2105/ajph.2014.302525. 7. morrison la, larkspur l, calibuso mj, brown s. women’s attitudes about menstruation and associated health and behavioral characteristics. am j health behav 2010; 34:90–100. https://doi.org/10.5993/ajhb.34.1.11. 8. ghiasi a, keramat a, mollaahmadi l. the relationship between attitudes toward menstruation and perimenstrual symptoms among female students of shahroud university of medical sciences, northeast iran. shiraz e med j 2018; 19:1–7. https:// doi.org/10.5812/semj.65714. 9. fehintola fo, fehintola ao, aremu ao, idowu a, ogunlaja oa, ogunlaja ip. assessment of knowledge, attitude and practice about menstruation and menstrual hygiene among secondary high school girls in ogbomoso, oyo state, nigeria. int j reprod contracept obstet gynecol 2017; 6:1726–32. https://doi. org/10.18203/2320-1770.ijrcog20171932. 10. firat mz, kulakaç ö, öncel s, akcan a. menstrual attitude questionnaire: confirmatory and exploratory factor analysis with turkish samples. j adv nurs 2009; 65:652–6. https://doi. org/10.1111/j.1365-2648.2008.04919.x. 11. chang y-t, chen y-c. study of menstrual attitudes and distress| among postmenarcheal female students in hualien county. j nurs res 2009; 17:20–9. https://doi.org/10.1097/jnr.0b013 e3181999d25. 12. wong lp. attitudes toward menstruation, menstrual-related symptoms, and premenstrual syndrome among adolescent girls: a rural school-based survey. women health 2011; 51:340–64. https://doi.org/10.1080/03630242.2011.574792. 13. mohamadirizi s, kordi m, shakeri mt. the relationship bet ween perimenstrual symptoms and menstrual attitude in high school girls in mashhad city in years 2011-2012. iran j obstetrics, gynecol and infertil 2012; 15:25–31. 14. brooks-gunn j, ruble dn. men’s and women’s attitudes and beliefs about the menstrual cycle. sex roles 1986; 14:287–99. https://doi.org/10.1007/bf00287580. 15. andersch b, milsom i. an epidemiologic study of young women with dysmenorrhea. am j obstet gynecol 1982; 144:655–60. https://doi.org/10.1016/0002-9378(82)90433-1. 16. firouzi m, zahedifard t, salari p, mazlom sr. comparing the pattern of primary dysmenorrhea before and after childbirth. journal of midwifery and reproductive health 2019; 7:1514–21. https://doi.org/10.22038/jmrh.2018.8966.1081. 17. taherpour m, momeni m, kazemi a, ranjkesh f, salimi h, shakiba m. the effects of dry cupping on primary dysmenorrhea: a randomized clinical trial. nurs and midwifery stud 2018; 7:151–6. https://doi.org/10.4103/nms.nms_4_17. 18. higham jm, o'brien pm, shaw rw. assessment of menstrual blood loss using a pictorial chart. br j obstet gynaecol 1990; 97:734–9. https://doi.org/10.1111/j.1471-0528.1990.tb16249.x. 19. ziba mazari, azita goshtazebi, somayeh mookhah, fatemeh saki. the menorrhagia questionnaire (mq): translation and validation study of the iranian version. payesh 2012; 11:83–8. 20. guvenc g, kilic a, akyuz a, ustunsoz a. premenstrual syndrome and attitudes toward menstruation in a sample of nursing students. j psychosom obstet gynaecol 2012; 33:106–11. https://doi.org /10.3109/0167482x.2012.685906. 21. omidvar s, salmalian h, begum k. the relationship between dysmenorrhea and menstrual attitudes among adolescent and young females in urban area, south india. world journal of medical sciences 2015; 12:56–61. https://doi.org/10.5829/ idosi.wjms.2015.12.1.94. 22. park s. a study on middle school girls’ menstrual symptoms, attitudes, and coping behaviors related menstruation [masters thesis]. kwangju: chonnam university 2006. https://doi.org/10.1 2799/jkachn.2013.24.3.264. 23. chen cx, draucker cb, carpenter js. what women say about their dysmenorrhea: a qualitative thematic analysis. bmc womens health 2018; 18:47. https://doi.org/10.1186/s12905-018-0538-8. 24. zegeye dt, megabiaw b, mulu a. age at menarche and the menstrual pattern of secondary school adolescents in northwest ethiopia. bmc womens health 2009; 9:29. https://doi.org/10.11 86/1472-6874-9-29. 25. nooh am. menstrual disorders among zagazig university students, zagazig, egypt. middle east fertil soc j 2015; 20:198–203. https://doi.org/10.1016/j.mefs.2014.08.002. 26. barron ml, flick lh, cook ca, homan sm, campbell c. assoc iations between psychiatric disorders and menstrual cycle charact eristics. arch psychiatr nurs 2008; 22:254–65. https://doi. org/10.1016/j.apnu.2007.11.001. 27. tang cs-k, yeung dy, lee am. a comparison of premenarcheal expectations and postmenarcheal experiences in chinese early adolescents. j early adolesc 2004; 24:180–95. https://doi.org/10.1 177/0272431603262669. 28. tiwari h, oza u, tiwari r. knowledge, attitudes and beliefs about menarche of adolescent girls in anand district, gujarat. east mediterr health j 2006; 12:428–33. https://doi.org/10.1080/23311908.2018.1525840 https://doi.org/10.1080/23311908.2018.1525840 https://doi.org/10.1371/journal.pone.0214071 https://doi.org/10.1371/journal.pone.0214071 https://doi.org/10.1080/13548506.2019.1640885 https://doi.org/10.1111/jocn.14049 https://doi.org/10.2105/ajph.2014.302525 https://doi.org/10.5993/ajhb.34.1.11 https://doi.org/10.5812/semj.65714 https://doi.org/10.5812/semj.65714 https://doi.org/10.18203/2320-1770.ijrcog20171932 https://doi.org/10.18203/2320-1770.ijrcog20171932 https://doi.org/10.1111/j.1365-2648.2008.04919.x https://doi.org/10.1111/j.1365-2648.2008.04919.x https://doi.org/10.1097/jnr.0b013e3181999d25 https://doi.org/10.1097/jnr.0b013e3181999d25 https://doi.org/10.1080/03630242.2011.574792 https://doi.org/10.1007/bf00287580 https://doi.org/10.1016/0002-9378(82)90433-1 https://doi.org/10.22038/jmrh.2018.8966.1081 https://doi.org/10.4103/nms.nms_4_17 https://doi.org/10.1111/j.1471-0528.1990.tb16249.x https://doi.org/10.3109/0167482x.2012.685906 https://doi.org/10.3109/0167482x.2012.685906 https://doi.org/10.5829/idosi.wjms.2015.12.1.94 https://doi.org/10.5829/idosi.wjms.2015.12.1.94 https://doi.org/10.1 2799/jkachn.2013.24.3.264 https://doi.org/10.1 2799/jkachn.2013.24.3.264 https://doi.org/10.1186/s12905-018-0538-8 https://doi.org/10.1186/1472-6874-9-29 https://doi.org/10.1186/1472-6874-9-29 https://doi.org/10.1016/j.mefs.2014.08.002 https://doi.org/10.1016/j.apnu.2007.11.001 https://doi.org/10.1016/j.apnu.2007.11.001 https://doi.org/10.1177/0272431603262669 https://doi.org/10.1177/0272431603262669 squ med j, february 2011, vol. 11, iss. 1, pp. 115-118, epub. 12th feb 11 submitted 3rd jun 10 revision req. 22nd jun 10, revision recd. 19th jul 10 accepted 19th sept 10 a fistula is an abnormal pathological pathway between two anatomic spaces or a pathway that leads from an internal cavity or organ to the surface of the body. a sinus tract is an abnormal channel that originates or ends in one opening. an odontogenic cutaneous fistula is a pathologic communication between the cutaneous surface of the face and the oral cavity. in the literature, the terms fistulas and sinuses are often used interchangeably. a cutaneous fistula of dental origin is a rare entity,1 but well documented in medical, dental and dermatological literature.2,3 as the lesion develops, it is usually not thought to be of dental origin and the patient seeks treatment from a dermatologist, a family physician or a general surgeon, often undergoing multiple antibiotic regimens, surgical excisions and biopsies. it has been estimated that half of the patients with odontogenic cutaneous fistulas are submitted to multiple dermatological surgical operations and long-term antibiotic therapy before the correct diagnosis is established.4 delay in diagnosis adds to the chronicity of the lesion and sometime leads to cosmetic deformities secondary to cutaneous scarring. an odontogenic cutaneous fistula usually arises as a sequel to bacterial invasion of the dental pulp through a breach in the enamel and the dentine by a carious lesion, trauma, or other causes.3,5 if treatment is not initiated at this stage, the pulp becomes necrotic and infection spreads beyond the confines of the tooth into the peri-radicular area resulting in apical periodontitis that subsequently dissects along the path of least resistance and erupts through the skin.4 once diagnosed, the treatment is simple and effective, consisting of removal of the infected pulp tissue and filling of the root canal with biocompatible material resulting in minimal scarring of skin. c a s e o n e d e s c r i p t i o n a 25 year-old man with no known co-morbidity presented to the family medicine clinic of sultan qaboos university hospital (squh), oman, for the evaluation of a chronically draining, dimpled, crusted small nodule on his right cheek. the lesion departments of 1family medicine and public health and 2oral health, sultan qaboos university hospital, muscat, oman. *corresponding author email: nafisa77@squ.edu.om îç◊¢]<; ��ä÷]<öáâ^fl÷] ∞j÷^u<üëüœi     :مفتاح الكلمات abstract: odontogenic cutaneous fistula or sinus is an uncommon, but well documented condition, which is often initially misdiagnosed as a sole cutaneous lesion and inappropriately treated. the misdiagnosis as a skin infection often results in inappropriate management. we here present two cases of odontogenic cutaneous fistula that were seen after being treated unnecessarily with antibiotics. keywords: odontogenic; cutaneous fistula; case report; oman odontogenic cutaneous fistula report of two cases *nafisa samir,1 abdulaziz al-mahrezi,1 salim al-sudairy2 case report odontogenic cutaneous fistula report of two cases 116 | squ medical journal, february 2011, volume 11, issue 1 was initially diagnosed as a superficial skin infection and was treated for several months with a number of systemic and topical antibiotics which provided only temporary relief. physical examination revealed a small retracted skin lesion on lower part of right cheek of about 5 mm in diameter. the skin opening of the lesion was crusted, but with minimal swelling. gentle pressure on the surrounding tissue elicited a scanty non-purulent bloody discharge on the surface. there was also a cord-like palpable tract extending from the cutaneous lesion to the oral cavity inside. intra-oral examinations showed poor oral hygiene and dental caries in the right lower premolar and first permanent molar (teeth nos. 45 and 46). the patient was referred to an oral and maxillofacial surgeon. his orthopantomogram (opg) demonstrated well defined radiolucency around the apex of teeth 45 and 46 [figure 1]. c a s e t w o d e s c r i p t i o n an 18 year-old male student was referred from the squh surgery department to an oral and maxillofacial surgeon in the oral health department regarding a chronic, but painless, draining lesion on the left side of the cheek. like the first case, this patient had also been treated for several months with antibiotics. on examination, there was a crusted skin lesion of about 0.8 cm in diameter on left side of the face [figure 2]. again, non-purulent discharge was expressed on pressing the surrounding skin. intra-oral examination showed poor oral hygiene and caries in the lower left second premolar (tooth no. 35) and lower left first permanent molar (tooth no. 36). his opg also showed radiolucency at the apex of teeth numbers 35 and 36 [figure 3]. c a s e s o n e a n d t w o – t r e at m e n t the intra-operative findings for both patients showed a fluid-filled cyst around diseased teeth with a draining tract extending from the cyst to the outside skin. both patients were booked for surgery under general anaesthesia (ga), as not only was the extraction of diseased teeth required, but also the excision and repair of the skin lesions. to excise the fistula, first an elliptical incision was made on the skin layer only. in this way, the facial nerve was protected as it lies in the deeper fascia. then the dissection was made below the skin until the fistula tract was reached. the dissection was continued through the muscle until the intraoral origin of the tract was reached. the affected teeth were removed and the cystic lesion and granulation tissue were completely enucleated. the incision site was irrigated and closed in layers (muscles and oral mucosa with 3.0 vicryl suture and skin with 4.0 nylon suture). the elliptical shape of the incision has the effect of minimising post-surgical scar formation as compared to the disfiguring scar which may result if the lesion is left to heal on its own by granulation. both patients were followed up postoperatively and both showed significant improvement [figure 4]. figure 1: orthopantomogram of patient 1. arrows indicate radiolucency around the apex of right lower second premolar and first permanent molar. figure 2: photograph of patient 2. arrow indicates odontogenic cutaneous fistula and retracted skin. nafisa samir, abdulaziz al-mahrezi and salim al-sudairy case report | 117 discussion the clinical cases of odontogenic cutaneous lesions described in this study had been previously misdiagnosed and managed inappropriately. the cutaneous fistula of dental origin is an uncommon, but well documented, condition in the literature. diagnosis is challenging for many reasons. this can be due to the fact that these lesions do not always arise in close proximity to the underlying dental infection and only about half of patients ever recall having had toothache.6 a clinician’s high index of suspicion can lead to early and correct diagnosis. a thorough history taking and intraoral examination are critical for making the appropriate diagnosis and may spare the patient much unnecessary treatment. in suspected cases, early consultation with a dentist is of great importance in providing appropriate differential diagnosis and clinical care.2 the classic lesion is an erythematous, smooth, symmetrical nodule, 1–20 mm in diameter with or without drainage. the chronic lesion often leads to retraction of skin secondary to scarring. a cord like tract can be felt attached to the underlying bony structure. many of above mentioned typical findings were present in the two cases described in this report. patients may experience intermittent remission of the symptoms. intraoral examination may reveal dental caries or restorations and periodontal disease, but the examiner should keep in mind that even the tooth involved can appear normal.7 the initial working diagnosis is confirmed by radiographs and pulp vitality tests, diseased teeth responding negatively to the latter. in the clinical cases described here, the radiographs clearly revealed obvious periapical radiolucencies which are associated with diseased teeth. as far as definitive treatment is concerned, root canal therapy or surgical extraction is the treatment of choice.7,8 usually, no systemic antibiotics need to be prescribed as the lesion is a localised entity, but they should be considered in patients with diabetes, immunosuppression, or signs of systemic infection.4 most authors believe that once the primary cause is removed the cutaneous lesion heals without treatment, usually resolving in 1 to 2 weeks. the residual scarring can be surgically revised if it is cosmetically unappealing for the patient.4 delay in the treatment of dental infections can sometimes lead to the infection spreading to fascial spaces in the orofacial area or deep in the head and neck (peripharyngeal space infections). in addition, odontogenic infections may cause osteomyelitis of the jaw or systemic illness. many patients seek evaluation from several physicians before an accurate diagnosis is made. it has been estimated that half of all patients undergo multiple surgeries and trials of antibiotics before definitive diagnosis.4 this emphasises the importance of communication between medical sub-specialists and dentists in the evaluation of patients with head and neck lesions. figure 3: orthopantomogram of patient 2. arrows indicate radiolucency around the apex of the left lower second premolar and first permanent molar. figure 4: postoperative photograph of patient 2. arrow indicates scarring after surgery. odontogenic cutaneous fistula report of two cases 118 | squ medical journal, february 2011, volume 11, issue 1 conclusion these cases highlight the fact that dental aetiology should be considered as a part of a differential diagnosis for any orofacial skin lesions. it also serves to underline the importance of communication between medical subspecialties. although many non-odontogenic disorders may also produce an extra-oral fistula, the opinion of a dentist in cases of a cutaneous sinus tract is of great importance in providing appropriate clinical care. endodontic treatment or dental extraction may eliminate the infection and lead to resolution of the lesion and prevent unnecessary ineffective antibiotic therapy and/or surgical intervention. these cases would also suggest that dentists may need to educate their medical colleagues and medical students on the importance of oral examination and role of the dentist in the management of oro-facial infections references 1. cioffi ga, terezhalmy gt, parlette hl. cutaneous sinus tract: an odontogenic etiology. j am acad dermatol 1986; 14:94. 2. yasui h, yamaguchi m, ichimiya m, yoshikawa y, hamamoto y, muto m. a case of cutaneous odontogenic sinus. j dermatol 2005; 32:852–5. 3. mittal n, gupta p. management of extra oral sinus cases: a clinical dilemma. j endod 2004; 30:541–7. 4. cantatore jl, klein pa, lieblich lm. cutaneous dental sinus tract, a common misdiagnosis: a case report and review of the literature. cutis 2002; 70:264–7. 5. stoll hl, solomon ha. cutaneous sinuses of dental origin. jama 1963; 184:120–4. 6. winstock d. four cases of external facial sinuses of dental origin. proc r soc med 1959; 52:749–51. 7. ong st, ngeow wc. medial mental sinus in twins. dent update 1999; 26:163–5. 8. swift jq, gulden ws. antibiotic therapy: managing odontogenic infections. dent clin n am 2002; 46:623–33. 1national genetic center and departments of 2pediatric allergy & clinical immunology and 4histopathology, royal hospital, muscat, oman; 3division of pediatric stem cell transplantation & regenerative medicine, stanford university, stanford, usa; 5department of biosciences & nutrition, karolinska university hospital, stockholm, sweden *corresponding author e-mail: nishahamz@yahoo.co.uk a novel spink5 gene mutation associated with netherton syndrome in an omani patient *nishath hamza,1 nashat al sukaiti,2 khwater a.m. ahmed,2 rosa romano,3 uday a. gokhale,4 qiang pan-hammarström5 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 652–656, epub. 25 nov 21 submitted 1 sep 20 revision req. 18 oct 20; revision recd. 16 nov 20 accepted 3 dec 20 in muscat, oman at 34 days of age. he was born to consanguineous parents and was affected with generalised erythematous desquamative skin rash from birth. at four months of age, the patient had normal igg, iga and igm levels. moreover, repeated immunepanel testing indicated normal complement c3, c4 and total haemolytic complement levels. in addition, he had a normal lymphocyte count, mildly elevated eosinophil and normal ige, which later rose to >1000 iu/l on follow-up [table 1]. immunophenotyping indicated 27% of human leukocyte antigen (hla)-dr isotype positive cells within the lymphocyte subset and the patient was reactive for antibody-specific response to hepatitis b vaccine. the patient suffered recurrent infections from the age of one month, which increased in frequency and worsened in severity over time. cultures from his blood, ears, cerebrospinal fluid and eyes showed colonisation by methicillin-resistant staphylococcus aureus. until the age of two years, he required peripheral red blood cell transfusion six times. at 27 months of age, the patient displayed failure to thrive, global developmental delay, severe anaemia and food allergy, indicated by high immunocap and radioallergosorbent test values of cow’s milk and wheat [table 1]. an older deceased male sibling had also presented with a skin condition similar to the index patient. this sibling was born by spontaneous vaginal delivery at home and was rushed to the nearest hospital with delay in crying, cyanosis and distress. he was intubated and ventilated for approximately four weeks in the new-born intensive care unit (nicu), where he was diagnosed by a dermatologist to have non-bullous netherton syndrome (ns) is defined asan autosomal recessive primary immunodeficiency, which is characterised by a sub stantial skin barrier defect leading to ichthyosis being present at birth with erythroderma, which subsequently evolves into ichthyosis linearis circumflexa.1 ns is caused by mutations in the serine peptidase inhibitor kazal type 5 (spink5) gene, which encodes the serine protease inhibitor lymphoepithelial kazal-type inhibitor 1 (lekti) protein. ns patients exhibit severe atopic diathesis and a predisposition to allergies, asthma and eczema, with hypereosinophilia, elevated serum immunoglobulin (ig)e and trichorrhexis invaginata (hair-shaft abnormality which leads to bamboo-like hair).2 owing to its dermatological manifestations, ns is often misdiagnosed as severe atopic dermatitis or hyper-ige syndrome.3,4 in ns patients, early genetic testing and diagnosis can prove critical to the provision of correct clinical management and decreased mortality. to date, more than 80 ns-associated pathogenic mutations in the spink5 gene have been reported worldwide.5 while there have been reports of ns patients from the middle east, to the best of the authors’ knowledge, only one ns-related mutation has been reported so far among the arab population.6 the current case report presents the case of a novel nsassociated mutation in an omani-arab patient with a family history of multiple affected individuals. case report the index patient was a male infant born in 2014, who presented to a paediatric immunology clinic this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.047 case report abstract: netherton syndrome (ns) is an autosomal recessive primary immunodeficiency. it is characterised by substantial skin barrier defects and is often misdiagnosed as severe atopic dermatitis or hyper-immunoglobulin e syndrome. although more than 80 ns-associated pathogenic mutations in the serine peptidase inhibitor kazal type 5 (spink5) gene have been reported worldwide, only one has been reported in the arab population to date. we report the case of a novel association between the c.1887+1g>a mutation in the spink5 gene and ns in an omani-arab patient born in 2014 who was managed at a paediatric immunology clinic in muscat, oman. accurate genetic diagnosis facilitated tailored clinical management of the index patient and enabled the provision of genetic counselling and offering of future reproductive options to the individuals related to the index patient. keywords: netherton syndrome; primary immunodeficiency disease; serine peptidase inhibitor kazal type 5; congenital ichthyosiform erythroderma; genetics; case report; oman. nishath hamza, nashat al sukaiti, khwater a. m. ahmed, rosa romano, uday a. gokhale and qiang pan-hammarström case report | 653 congenital ichthyosiform erythroderma. during his stay in the nicu, he developed sepsis with coagulasenegative staphylococci and candida. by 70 days of age, the sibling had rapidly developed septic shock and died while he was admitted. upon probing further, the parents of the index patient revealed a history of infant deaths of the index patient’s paternal cousins, who had died of sepsis before the age of one and had received diagnoses of atopic dermatitis [figure 1]. given this family history and the propensity for recurrent infections, the index patient was suspected of having a primary immunodeficiency. later, hair biopsy and histopathology evaluations of the index patient at five months of age using haemotoxylin showed psoriasiform acanthosis spongiosis and mild lymphocytic exocytosis with occasional dyskeratotic cells, which indicated a clinical diagnosis of ns [figure 2]. whole exome sequencing (wes) of the index patient’s dna in 2016 revealed a homozygous mutation c.1887+1g>a (nm_001127699.2; hg19:chr5:147492498) in intron 20 of the spink5 gene associated with autosomal-recessive ns. this mutation affects the highly conserved consensus donor splice site at the exon 20-intron 20 junction. this variant is present in the dbsnp database (rs1042707088; national center for biotechnology information, bethesda, maryland, usa) and was detected only twice in heterozygous form within a human longevity project from 2016 but was never associated with any clinical presentation. sanger sequencing technique further validated the wes result and confirmed the segregation of the c.1887+1g>a mutation in heterozygous form in each parent. the c.1887+1g>a variant was initially classified as a variant of uncertain significance (vus) due to the lack of population frequency data or functional evidence. however, the ever-increasing figure 1: family pedigree of the index patient. a sibling of the index patient (red arrow) was affected and had previously died of sepsis. two paternal cousins who presented with features similar to the index patient also died of sepsis before the age of one year. figure 2: haemotoxylin and eosin stain of a skin biopsy of the index patient at ×10 magnification showing psoriasiform acanthosis spongiosis, mild lymphocytic exocytosis with occasional dyskeratotic cells. table 1: immunological investigations of the index patient parameter result reference range investigations at the age of four months lymphocyte count in × 109/l total lymphocytes in × 109/l 7.91 3.6–8.8 t-cells (cd3+) in × 109/l 5.19 2.3–6.5 b-cells (cd19+) in × 109/l 1.32 0.5–1.5 t-helper cells (cd3+/cd4+) in × 109/l 2.63 1.7–4.6 t-cytotoxic cells (cd3+/ cd8+) in × 109/l 1.46 0.7–3.5 cd4:cd8 ratio in × 109/l 1.79 1.2–3.5 t-helper cd4+ count in cells/ul 2,630 eosinophils in percentage 2.6 0.1–0.8 serum ig ige in iu/l 193 0–15 igg in g/l 6.0 2.05–9.5 iga in g/l 0.89 0.08–0.91 igm in g/l 0.58 0.17–1.5 serum complement levels c3 in mg/l 968 820–1,850 c4 in mg/l 283 150–530 ch50 in % 71 70–140 investigations at the age of two years serum ige in iu/l 1526 0–60 allergy testing for specific ige* cow’s milk in ku/l 20.60 wheat in ku/l 9.25 cd = cluster of differentiation; ig = immunoglobulin; ch50 = total haemolytic complement. *a result of >0.1 ku/l indicates sensitisation to the tested allergen. a novel spink5 gene mutation associated with netherton syndrome in an omani patient 654 | squ medical journal, november 2021, volume 21, issue 4 volume of exome sequencing data compiled since 2016 at the two laboratories participating in this study and the absence of this variant in online population databases enabled the authors to ascertain that this mutation was indeed rare and novel with respect to ns. moreover, an unaffected sibling of the index patient born in 2020 was also screened and found to carry only normal spink5 alleles [figure 3a]. the potential impact of the c.1887+1g>a mutation was further analysed using the in silico human splicing finder (hsf) suite (genomnis) which evaluates a candidate’s splice site mutations using both the hsf matrix and the maxentscan matrix (burge lab, massachusetts institute of technology, massachusetts, usa).8,9 both matrices predicted the c.1887+1g>a mutation observed in the index patient to ‘probably affect splicing’ [figure 3b]. interestingly, another mutation, c.1888-1g>a (hg19:chr5:147493924), affecting the same intron 20 at the opposite end (i.e. the acceptor splice site at the intron 20-exon 21 junction) had already been reported as being pathogenic in ns patients.9,10 it was observed that the previously reported c.1888−1g>a mutation and the c.1887+1g>a mutation reported here scored 3.83 and 3.85, respectively, on measurements of evolutionary conservation by two algorithms— phastcons and phylop—from the phylogenetic analysis with space/time models (phast) package (cold spring harbor laboratory, new york, usa) generated using the bioinformatic tools in the university of california santa cruz comparative genomics alignment pipeline.11 this indicated that both mutations (separated by >1.4 kbp) were located at equally and highly conserved splice sites at opposite ends of intron 20 of the spink5 coding sequence. given all of the above evidence, the c.1887+1g>a mutation was hence re-classified as ‘pathogenic’ and predicted to result in aberrant lekti protein expression in homozygous patients. an accurate genetic diagnosis enabled a tailored clinical strategy whereby intravenous (iv) ig therapy (0.4 g/kg/month) was administered and led to decreased inflammation and itching of the skin; it also led to thicker hair with reduced hair-shaft breakage and a healthier scalp. at the time of the last clinical follow-up, the index patient was at 33 months of age. his skin condition had vastly improved, albeit with some generalised persistent redness. while he still suffered from developmental delay, he had started to reach milestones such as being able to sit without support. figure 3: outputs showing evidence for pathogenicity of the c.1888+1g>a mutation. a: family segregation analysis using sanger sequencing data of the exon 20-intron 20 junction shows the c.1888+1g>a mutation as homozygous in the index patient (asterisk) and as heterozygous (r indicates g/a transition) in the parents of the index patient. the unaffected sibling of the index patient does not carry the mutated allele. b: results from the in silico analysis using the human splicing finder suite (genomnis) indicates that the c.1888+1g>a mutation probably affects splicing at the exon 20-intron 20 junction. nishath hamza, nashat al sukaiti, khwater a. m. ahmed, rosa romano, uday a. gokhale and qiang pan-hammarström case report | 655 informed consent for testing and publication of anonymised data was collected from all patients/ guardians involved in this study; appropriate ethical standards were employed in all procedures. discussion this case report presents a novel ns-associated c.1887+1g>a mutation in the spink5 gene. although this mutation was observed in the index patient in 2016, it was initially classified as a vus. however, with access to growing data from subsequent exome sequencing studies over the past years, it is evident that the c.1887+1g>a mutation was indeed rare and likely to be pathogenic in association with ns in the index patient. given that more than 50% of marriages in oman are reported to be consanguineous unions, the prospect of this being a founder mutation cannot be ignored.12 hence, the detection of novel variants in rare disorders such as ns facilitates a targeted screening approach for quicker diagnosis in future cases. spink5 gene mutations can result in lekt1 deficiency. lekti has been shown to inhibit several members of the serine protease family such as kallikrein related peptidase (klk)5, klk7 and klk14 as well as trypsin, plasmin, subtilisin a, cathepsin g and human neutrophil elastase.13 unhindered functioning of these serine proteases can trigger a cascade of events, whereby increased proteolysis destroys the stratum corneum integrity, affects lipid barrier maintenance and exacerbates desquamation of the epidermis.13 these effects conceivably compromise the antimicrobial-barrier function of the skin in ns patients, thereby leading to colonisation of lesional and non-lesional skin by s. aureus—a presentation reported in both the index patient and his deceased sibling. unearthing the genetic aetiology of the index patient’s symptoms was crucial in providing correct clinical management and likely helped avoid the severe complications observed in the index patient’s older sibling and deceased paternal cousins. while there are multiple treatment modalities targeting skin manifestations and immune defects, symptomatic treatment with allergy control medication, moisturisers, steroid creams and antibiotics has limited effect on ns patients. however, ivig replacement therapy has been reported to be quite effective in ns patients as was seen in the current patient.14 retrospective evaluation of the case histories of the previously deceased paternal cousins of the index patient indicated that they had likely been affected with ns as well. this was unsurprising as all the affected offspring were born of consanguineous unions. therefore, mutation carrier screening was offered to other individuals within the extended family, especially to provide pre-marital counselling for unmarried heterozygous carriers who intended to seek consanguineous unions. the family members with previously deceased offspring were also counselled to educate them about alternative reproductive options to avoid the recurrence of affected offspring. in oman, prenatal genetic screening combined with assisted reproduction is usually offered as a safe and culturally acceptable option to such affected families. conclusion ns is a rare and severe disease, which can be lifethreatening in infants without accurate diagnosis and tailored management. genetic diagnosis of ns patients can have significant implications for their correct and effective clinical management using ivig, which helps in reduction of infections as well as ameliorates skin and hair anomalies. moreover, genetic testing for patients with rare diseases such as ns also facilitates the provision of genetic counselling and selection of future reproductive options provided to affected families, particularly in societies that are highly consanguineous and opposed to abortion. a u t h o r s’ c o n t r i b u t i o n nh organised the study, analysed the data and drafted the manuscript. ns provided clinical supervision, while ns and ka collected clinical data and reviewed the manuscript. rr and ug analysed the patient data. qph reviewed the data and manuscript. all authors approved the final version of the manuscript. references 1. sun jd, linden kg. netherton syndrome: a case report and review of the literature. int j dermatol 2006; 45:693–7. https:// doi.org/10.1111/j.1365-4632.2005.02637.x. 2. hannula-jouppi k, laasanen sl, ilander m, furio l, tuomiranta m, marttila r, et al. intrafamily and interfamilial phenotype variation and immature immunity in patients with netherton syndrome and finnish spink5 founder mutation. jama dermatol 2016; 152:435–42. https://doi.org/10.1001/jamader matol.2015.5827. 3. leung akc, barankin b, leong kf. an 8-year-old child with delayed diagnosis of netherton syndrome. case rep pediatr 2018; 2018:9434916. https://doi.org/10.1155/2018/9434916. 4. özyurt k, atasoy m, ertaş r, ulaş y, akkuş mr, kiraz a, et al. netherton syndrome previously misdiagnosed as hyper ige syndrome caused by a probable mutation in spink5 c. turk j pediatr 2019; 61:604–7. https://doi.org/10.24953/ turkjped.2019.04.020. a novel spink5 gene mutation associated with netherton syndrome in an omani patient 656 | squ medical journal, november 2021, volume 21, issue 4 5. sarri ca, roussaki-schulze a, vasilopoulos y, zafiriou e, patsatsi a, stamatis c, et al. netherton syndrome: a genotypephenotype review. mol diagn ther 2017; 21:137–52. https:// doi.org/10.1007/s40291-016-0243-y. 6. nevet mj, indelman m, ben-ari j, bergman r. a case of netherton syndrome with intestinal atresia, a novel spink5 mutation, and a fatal course. int j dermatol 2017; 56:1055–7. https://doi.org/10.1111/ijd.13730. 7. desmet fo, hamroun d, lalande m, collod-béroud g, claustres m, béroud c. human splicing finder: an online bioinformatics tool to predict splicing signals. nucleic acids res 2009; 37:e67. https://doi.org/10.1093/nar/gkp215. 8. yeo g, burge cb. maximum entropy modeling of short sequence motifs with applications to rna splicing signals. j comput biol 2004; 11:377–94. https://doi.org/10.1089/1066527041410418. 9. chavanas s, bodemer c, rochat a, hamel-teillac d, ali m, irvine ad, et al. mutations in spink5, encoding a serine protease inhibitor, cause netherton syndrome. nat genet 2000; 25:141–2. https://doi.org/10.1038/75977. 10. descargues p, deraison c, prost c, fraitag s, mazereeuwhautier j, d’alessio m, et al. corneodesmosomal cadherins are preferential targets of stratum corneum trypsinand chymotrypsin-like hyperactivity in netherton syndrome. j invest dermatol 2006; 126:1622–32. https://doi.org/10.1038/ sj.jid.5700284. 11. kent wj, sugnet cw, furey ts, roskin km, pringle th, zahler am, et al. the human genome browser at ucsc. genome res 2002; 12:996–1006. https://doi.org/10.1101/gr.229102. 12. rajab a, hamza n, al harasi s, al lawati f, gibbons u, al alawi i, et al. repository of mutations from oman: the entry point to a national mutation database. f1000res 2015; 4:891. https://doi.org/10.12688/f1000research.6938.1. 13. furio l, hovnanian a. netherton syndrome: defective kallikrein inhibition in the skin leads to skin inflammation and allergy. biol chem 2014; 395:945–58. https://doi.org/10.1515/ hsz-2014-0137. 14. renner ed, hartl d, rylaarsdam s, young ml, monacoshawver l, kleiner g, et al. comèl-netherton syndrome defined as primary immunodeficiency. j allergy clin immunol 2009; 124:536–43. https://doi.org/10.1016/j.jaci.2009.06.009. department of surgery, jawaharlal institute of postgraduate medical education and research, pondicherry, india *corresponding author’s e-mail: drvikramkate@gmail.com acute gastric dilatation leading to ischemic necrosis a rare complication following sigmoid volvulus balakrishnan gurushankari, sathasivam sureshkumar, amaranathan anandhi, b. s. rajesh, debasis naik, kumar saurabh, *vikram kate sultan qaboos university med j, august 2021, vol. 21, iss.3, pp. 504–506, epub. 29 aug 21 submitted 26 sep 20 revision req. 30 nov 20; revision recd. 7 dec 20 accepted 23 dec 20 a 25-year-old male patient presented to the emergency room (er) at the jawaharlal institute of postgraduate medical education and research, pondicherry, india, in 2019 with complaints of abdominal pain, distension, vomiting and non-passage of flatus and faeces for two days. the patient had no history of previous surgery, any toxin ingestion or any other congenital abnormalities. on general physical examination, the patient was tachycardic, dehydrated and the systemic examination was unremarkable. on abdominal examination, diffuse tenderness and no guarding with normal bowel movements were recorded. digital rectal examination revealed an empty rectum with free rectal mucosa. an x-ray of the abdomen revealed a hugely dilated sigmoid colon. contrast-enhanced computed tomography (cect) of the abdomen revealed a massively dilated sigmoid colon with a whirl sign, suggestive of sigmoid volvulus. the patient was taken up for emergency laparotomy, as endoscopic decompression facilities were not available. intraoperatively, the sigmoid colon was found to be extensively dilated; it was twisted around 270 degrees anti-clockwise, with no gangrene or perforation [figures 1a and 1b]. resection of the redundant sigmoid colon was performed after detorsion followed by an end-to-end anastomosis, with the fashioning of a diverting loop ileostomy. on post-operative day (pod) 1, when the stoma started functioning and bowel sounds returned, the nasogastric tube was removed and the patient was started on oral liquids. on pod 2, the patient developed tachycardia due to dehydration, which was corrected with intravenous fluids. the abdomen was soft and non-distended and the stoma was functioning. on pod 3, persistent tachycardia, multiple febrile spikes and decreased urine output were noted. furthermore, the patient developed tachypnoea, hypotension, abdominal distension and non-functioning stoma. a nasogastric tube was reinserted, which drained around this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.026 interesting medical image figure 1: radiological and intra-operative images of sigmoid volvulus of a 25-year-old male patient presenting to the er at the jawaharlal institute of postgraduate medical education and research, pondicherry, india, in 2019. a: contrastenhanced computer tomography of the abdomen showing sigmoid volvulus (solid arrow) compressing the stomach (red arrow). b: intraoperative image showing dilated sigmoid volvulus. https://creativecommons.org/licenses/by-nd/4.0/ balakrishnan gurushankari, sathasivam sureshkumar, amaranathan anandhi, b. s. rajesh, debasis naik, kumar saurabh and vikram kate interesting medical image | 505 4 l of bilious fluid instantaneously. the patient’s electrolytes were within normal limits, but the total leukocyte count was elevated to 20,000 cells per mm3. arterial blood gas results showed a ph of 7.28, po2 of 58 mmhg, pco2 of 21 mmhg, hco3 of 15meq/l and spo2 of 82%. the patient was intubated and put on a mechanical ventilator. inotropes were started and antibiotics were changed from intravenous ceftriaxone 1 g twice daily with metronidazole 500 mg thrice daily to 2 g of intravenous meropenem twice a day based on blood and exudate culture sensitivity. the patient was not put on any intravenous opioids post-operatively. an x-ray of the abdomen revealed a hugely dilated stomach with few dilated bowel loops [figure 2a]. re-exploration revealed a healthy anastomotic site at the previous sigmoidectomy site. around 100 ml of turbid fluid was present in the abdominal cavity. the stomach was dilated, with gangrenous patches of 4 × 5 cm on both the anterior and posterior walls of the stomach. subtotal gastrectomy with gastrojejunostomy was performed [figure 2b]. it can be hypothesised that the hugely dilated sigmoid volvulus could have led to gastric volvulus either by some tamponade effect or displacement of the stomach, which might have further led to gastric ischemia and necrosis. post-operatively, the patient was not extubated in the light of severe acidosis and high inotropic support. the patient was shifted to the surgical intensive care unit (icu), where over a few hours, his acidosis worsened, ionotropic support increased and urine output dropped to nil. however, despite our best resuscitation, the patient could not be salvaged and succumbed to septic shock on pod 5 of sigmoid volvulus resection. due to logistical reasons, a post-mortem could not be carried out. the postoperative biopsy reports of the sigmoid volvulus and gastrectomy specimen were unremarkable; while the former was descriptive, the latter showed gangrene. comment acute gastric dilatation (agd) is a rare condition that can lead to life-threatening complications such as ischemic necrosis, perforation and hemorrhage.1 however, it is rare for this condition to lead to gastric necrosis. although agd is reported most commonly in patients with psychogenic polyphagia and eating disorders, it is also found to occur in association with other conditions.2,3 there are very few reports in the literature on gastric necrosis in association with bowel obstruction.4 the mortality rate is as high as 80% in delayed interventions.1 thus, early radiological imaging and surgical intervention can reduce the mortality rate. to the best of the researchers’ knowledge, gastric necrosis associated with agd following sigmoid volvulus has not been reported before and this is the first time the interesting medical images of agd following sigmoid volvulus leading to a disastrous complication of gastric necrosis are being presented. a u t h o r s’ c o n t r i b u t i o n vk was involved in the conceptualization and validation of the manuscript. vk, ss and aa were involved in supervision of the work. bg, bsr, dn and ks contributed to the collection of data and drafting the manuscript. bg, ss and aa contributed manuscript editing. all authors approved the final version of the manuscript. figure 2: radiological and intra-operative images of acute gastric dilatation and gastric necrosis in a 25-year-old male patient presented to the er at the jawaharlal institute of postgraduate medical education and research, pondicherry, india, in 2019. a: plain abdominal radiograph showing extensively dilated stomach. b: gastrectomy specimen showing impending perforation. acute gastric dilatation leading to ischemic necrosis a rare complication following sigmoid volvulus 506 | squ medical journal, august 2021, volume 21, issue 3 references 1. koyazounda a, le baron jc, abed n, daussy d, lafarie m, pinsard m. gastric necrosis caused by acute gastric dilatation. total gastrectomy. recovery. j chir visc 1985; 122:403–7. 2. turan m, sen m, canbay e, karadayi k, yildiz e. gastric necrosis and perforation caused by acute gastric dilatation: report of a case. surg today 2003; 33:302–4. https://doi. org/10.1007/s005950300068. 3. bortul m, scaramucci m, tonello c, spivach a, liguori g. gastric wall necrosis from organo-axial volvulus as a late complication of laparoscopic gastric banding. obes surg 2004; 14:285–7. https://doi.org/10.1381/096089204322857726. 4. powell jl, payne j, meyer cl, moncla pr. gastric necrosis assoc iated with acute gastric dilatation and small bowel obstruction. gynecol oncol 2003; 90:200–3. https://doi.org/10.1016/s00908258(03)00204-x. https://doi.org/10.1007/s005950300068 https://doi.org/10.1007/s005950300068 https://doi.org/10.1381/096089204322857726 https://doi.org/10.1016/s0090-8258(03)00204-x https://doi.org/10.1016/s0090-8258(03)00204-x submitted 29 dec 22 revision req. 12 feb 23; revision recd. 15 mar 23 accepted 5 apr 23 online-first: may 2023 doi: https://doi.org/10.18295/squmj.5.2023.030 knowledge and awareness of emergency medical physicians on the management of traumatic dental avulsion at sultan qaboos university hospital *sara al barkhati1 and ali al mullahi2 1college of medicine and health science, sultan qaboos university, muscat, oman; 2department of dental and maxillofacial surgery, sultan qaboos university hospital, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: s125886@student.squ.edu.om abstract objective: this study aimed to assess the level of knowledge regarding traumatic dental avulsion management among emergency physicians at sultan qaboos university hospital (squh), muscat, oman. methods: a cross-sectional survey-based observational study conducted among emergency physicians at squh from august 2021 to october 2021. data were collected through a standardized and validated questionnaire. fisher’s exact and mann-whitney u tests were used to analyze the data. results: eighteen completed questionnaire forms were received, yielding a response rate of 72%. the data revealed that 66.7% of participants had prior knowledge of avulsion management, and 50% had received education on dental trauma. however, 83% of participants did not feel comfortable replanting an avulsed tooth themselves. with regard knowledge level, 45% of the participating physicians demonstrated low knowledge, 22% had moderate knowledge, and 33% showed high knowledge. thus, 94% of participants were interested in acquiring information about avulsion management. conclusion: the level of knowledge was significantly associated with receiving dental education and higher clinical grade. as a result, it is crucial to include information about avulsion and its management in both medical undergraduate and post-graduate curricula. mailto:s125886@student.squ.edu.om keywords: avulsion; replantation emergency; knowledge; dental education; first aid. advances in knowledge: • to the best of the authors’ knowledge, this is the first study to assess avulsion management knowledge among emergency medicine physicians in oman. • this study demonstrated knowledge deficiency in managing traumatic dental avulsion among emergency physicians. application to patient care: • more than 50% of the emergency physicians came across dental avulsion cases in the emergency room. these cases need immediate management by these physicians for favourable long-term survival of the tooth. • dental avulsion and its management need to be integrated into the medical undergraduate and emergency medicine post-graduate programs to graduate physicians with higher knowledge of managing avulsion. introduction the most common injuries among maxillofacial injuries are the traumatic dental injuries.1 traumatic dental avulsion (tda) is considered the most complex and severe injury among all traumatic dental injuries.2 it is the total dislodge of the tooth from the socket.3 the prevalence of avulsion among all traumatic dental injuries is 0.5% to 16%.4 furthermore, it is the most common type of traumatic dental injury seen in emergency departments (ed).5 it is well documented that avulsion is more among the age group between seven to nine years.6 that is attributed to the lesser degree of alveolar bone mineralization and low resilience of the periodontal ligament (pdl).7 moreover, avulsion occurs more frequently in children due to falls at home, sporting activities and fights.7 management of traumatic dental avulsion the prognosis of dental avulsion depends highly on immediate management provided at the injury site.8 therefore, immediate replantation of the permanent avulsed tooth is appropriate first-aid management.4 if the replantation is delayed, using a suitable storage medium till replantation can help maintain the pdl cells’ vitality,9 which is essential factor affecting the long-term survival of replanted avulsed teeth.10 additionally, to increase the possibility of sound healing, the reinserted tooth needs to be splinted to other teeth for 2 weeks. finally, to reassure adequate healing and avoid complications, further reviews and assessments should be carried out regularly.11 at emergency room, full-time dentists are not available.12 hence, emergency physicians should determine the type of dental injury and the tooth involved and to provide immediate management for avulsion. many studies have assessed avulsion management knowledge among physicians.4– 6,9,13 however, in oman, no data were reported on the level of knowledge on avulsion management among emergency physicians. a study from pakistan revealed that most (97.1%) of the included medical physicians had poor knowledge of avulsion management.9 furthermore, it showed that only 3% of medical doctors suggested immediate replantation of avulsed permanent teeth, and 8.6% correctly identified the suitable storage medium.9 another study reported that none of the medical physicians had high knowledge of tooth avulsion, although 73.3% (22/30) had low knowledge.6 in addition, this study found that 96.6% of the physicians had not received dental education. however, there are few studies have reported that most physicians (64%) knew the nature of avulsion, whereas 33% misdiagnosed the avulsion as displacement or fracture of the tooth.13 additionally, a study from the united states of america (usa) demonstrated that 89% of the physicians identified the appropriate avulsion management. furthermore, most participants (80%) in this study received training on avulsion management during their dental courses.5 the findings from previous studies revealed that physicians who received education on avulsion management during their medical training had better knowledge of the management of avulsion than those who did not.4-6,9,13 methods study setting and design the present study is a cross-sectional survey-based observational study that was conducted in the emergency department (ed) in sultan qaboos university hospital (squh), a tertiary health care hospital in muscat government, sultanate of oman, from 25th august to 25th october 2021. study subjects the inclusion and excluding criteria this study included all physicians working at the ed in squh and willing to participate in the study. clinical attachment trainees and doctors from other medical and surgical specialities attending the ed at squh were excluded. sample size calculation our sample size was calculated to be 78 participants with a 99% confidence level using a mathematical formula based on the study that assessed the first-aid knowledge of avulsion.9 n= (z2 p(1-p))/d2, where n= sample size, z= statistic corresponding to the level of confidence, p= expected prevalence and d= precision (corresponding to effect size). in this study z= 2.58, p= 3, 0.03, d= 0.05 and the sample size= 78. ethical considerations this study was conducted after receiving ethical approval (squ-ec-487-2021) from the medical research and ethics committee (mrec) at the college of medicine and health science (comhs) at sultan qaboos university on 26th july 2021 (#2542). data collection the instrument used in our study for collecting the data was a standardized and validated questionnaire adopted from a study by bahammam, 2018 after taking the author’s consent.12 there were 20 close-ended (multiple-choice) english questions divided into three parts. part i (6 questions) contained demographic questions. part ii (8 questions) for assessing the knowledge of avulsion management. finally, part iii (6 questions) for evaluating the attitudes toward receiving more information. e-mail addresses were provided in the survey for any inquiries from the participants. the questionnaire surveys were distributed among all emergency physicians at squh using two ways; link to the e-survey (google forms ®) was e-mailed to emergency physicians and distributed through social media professional groups . in addition, paper forms were handed out personally with the help of the squh cooperative. this study used electronic forms initially due to the covid-19 precaution measures. also, it will be easier to analyze and reduce paper waste. however, paper forms were used due to the low number of respondents electronically. consent to participate in the study was taken from each subject by mentioning that in the survey form. this form contained a description of the study, its aim, and how it would be conducted. in addition, it informed the participants that anyone could exit the survey without a penalty, and the information provided would be used only for the study. data analysis after collecting the data through a questionnaire survey, it was analyzed using the (spss®) (v.27). a standardized scoring method was used to measure each physician’s actual levels of avulsion management knowledge this method was adopted from abu-dawoud et al., 2007.6 a score of eight points was calculated for each participant by using eight questions from the questionnaire form. the interpretation of the score of each physician was as follow: score=8–6; high level of knowledge, score=5–3; moderate level of knowledge and score=2-0; low level of knowledge. finally, all participants' overall knowledge level was determined to find the association between categorized variables, and fisher's exact test was done. additionally, the mann-whitney u test compared the means of continuous variables. moreover, descriptive statistics were presented as mean, median, range and standard deviation for continuous variables. additionally, categorized variables are presented as frequency and percentages. as well as suitable tables and graphs were used to present the findings. results questionnaire administration out of 25 emergency physicians in squh, 18 (72%) had completed the questionnaire form, and more than half (55.6%) had completed the forms electronically. demographic descriptions the study cohort comprised 18 emergency physicians ranging from 25 to 52 years old. as shown in table 1, the female-to-male ratio was 1.25 (1:0.8) among these physicians. almost all the study population contained an equal number of different clinical grades, with fewer consultants (16.7%). in addition, most of the participants (77.8%) graduated from oman. further details on the demographic data are described in table 1. previous dental avulsion’ management knowledge and experiences the avulsion knowledge was variable among the emergency physicians. 59% of the participants came across avulsion cases. table 2 demonstrates that 66.7% of the emergency physicians had prior avulsion knowledge, and sources of this knowledge were variable. half of the emergency physicians had received dental trauma education. furthermore, 55.6% of emergency physicians considered medical books the primary source of knowledge. on the other hand, undergraduate and post-graduate dental education were the primary sources of knowledge for 33.4% of the participants. the fisher’s exact test found a significant association (p-value=0.029) between the reported level of information and previous dental courses. factors determining the knowledge of dental avulsion management many factors can determine the actual level of knowledge of avulsion management, as shown in figure 1. more than 60% of all participants had determined the correct ways of managing the avulsion, including the correct suitable media, the correct way of holding the avulsed tooth and replanting the clean tooth. on the other hand, only 39% determined the suitable way of replanting the dirty avulsed teeth. moreover, only 17% of the emergency physicians could replant the avulsed tooth themselves. measured level of avulsion management’s knowledge among the emergency physicians, 45% had low-level knowledge of avulsion management (0-2 correct answers), 22% had a moderate level of knowledge (3-5 correct answers), and 33% had a high knowledge level (6-8 correct answers). fisher’s exact test showed a significant association between the measured level of knowledge and knowing that the replantation of the avulsed tooth is essential (p-value=0.007) (table 3). to find the association between the level of avulsion management knowledge and different characteristics, fisher’s exact test was applied. it showed that the level of knowledge is significantly associated with higher clinical grade (p-value <0.05). while 87.5% of specialists to senior consultants had high knowledge, only 30% of the rest had high knowledge. however, other characteristics are not significantly associated with avulsion management knowledge (table 4). in comparing the physicians’ age means in two groups of the level of avulsion management knowledge, a significant difference (p-value=0.032) in means between the two age groups was shown by the mann-whitney u test. older physicians have a higher level of avulsion management knowledge than younger physicians. the attitude of the physicians toward avulsion management 72% of the physicians indicated that their level of avulsion information is inadequate. consequently, most of them (94%) were interested in improving their knowledge. therefore, all participants were united in the opinion of the importance of learning about avulsion. discussion in recent years, the number of avulsion cases in emergency departments (eds) has been increasing,5 and several studies have evaluated emergency physicians' knowledge of avulsion management.5,6,9,11,13 however, to the best of our knowledge, such data has not been available for emergency physicians in the sultanate of oman. therefore, the overall aim of this study was to assess avulsion management knowledge among ed physicians at sultan qaboos university hospital (squh), a single center in oman. it should be noted that logistical barriers and the recent unstable circumstances caused by covid-19 affected the flexibility in researching other medical centers in the country. therefore, this study only included emergency physicians at squh, which limited the study's population and affected the results. consequently, many findings in this study cannot be generalized .the response rate was higher (72%) than previous studies conducted at eds, which varied between 40-60%.7,9 this higher response rate can be attributed to the two methods of distributing the questionnaire forms, online and paper forms. a higher response rate (81.33%) was achieved by a study in the kingdom of saudi arabia,12 which included physicians from eight hospitals. more than half (66.7%) of the participants in our study had prior knowledge of avulsion management, whereas a previous study6 reported only 16.7% of physicians had information on managing avulsion. the difference between our findings and the previous study can be attributed to the age of the studied populations. our study contained more senior clinicians who graduated between 1994-2021, whereas the other study included a limited range of young physicians who graduated between 2000 and 2004. numerous sources are available to improve the knowledge of avulsion management. half (50%) of the participants in our study received undergraduate and post-graduate dental courses, whereas previous studies reported that only 3%-6% of physicians had dental education.6 these findings in our study could be attributed to the undergraduate oral health course in the md curriculum at the college of medicine and health science (comhs). furthermore, the fisher's exact test revealed that the level of knowledge is significantly associated with previous dental education, which agrees with the results reported by another study.5 the study was conducted to evaluate the level of physicians' knowledge in avulsion management and focused on the key factors that determine avulsion management, based on the international association of dental traumatology (iadt) guidelines.8 the findings of the study showed that holding an avulsed tooth by the crown is the appropriate way to save the pdl, and 78% of emergency physicians had adequate knowledge of this fact. this finding is consistent with the results of a study by jyothi et al., where 72.8% of the participants correctly identified the appropriate method of holding an avulsed tooth.14 the need for immediate replantation was identified by 72% of physicians, but only 17% were confident enough to replant it themselves. when it comes to managing a dirty avulsed tooth, only 39% of physicians correctly identified the way to clean it with a stream of saline before replantation. in contrast to our study, a study conducted in ksa showed that a higher percentage of physicians, 79.5%, agreed to replant an avulsed tooth, and 48.4% were confident in doing so themselves.12 the study population in bahammam, 2018, which had a higher percentage of older physicians, also showed a greater ability to replant avulsed teeth themselves. although there was no difference in the age range between our study and the ksa study,12 the ksa study had 12 physicians over the age of 50, while our study had only one. saving an avulsed tooth in an appropriate storage medium is crucial for preserving the vitality of the periodontal ligament (pdl) and enhancing the tooth's long-term survival since replantation may be delayed. therefore, knowledge of the appropriate storage medium is a fundamental factor in determining the physician's avulsion management expertise. the study found that 61% of physicians chose saline as the appropriate storage medium, which is readily available in the ed compared to other recommended media. physicians in our study demonstrated better knowledge of the suitable storage media than those in a study conducted in pakistan, where only 8.6% of physicians were aware of the appropriate storage medium.9 this better understanding could be attributed to our participants receiving more dental courses and information. the study found that only 33.3% of the ed physicians demonstrated a high level of knowledge, and 22.2% showed moderate knowledge of avulsion management. these findings are generally higher than those of previous studies from neighbouring countries, which ranged between 1012%. 1,6,9 the age factor may explain the difference, as our study included older participants compared to those in previous studies. however, our results significantly differed from a study conducted in the usa, which found that 89% of physicians were able to identify appropriate avulsion management. this difference can be attributed to the training on avulsion management during dental courses, which most participants (80%) in the us study had received.5 furthermore, 44.4% of physicians in our study had insufficient knowledge, which is higher than the findings of a previous study by abu-dawoud et al. in 2007, where only 26.6% had insufficient knowledge of avulsion management.6 our study identified that the level of knowledge can be improved by enhancing education. however, the junior clerkship phase of the medical degree to md program at squ does not include avulsion management in the oral health rotation. our study also found a significant association between the measured level of knowledge and the understanding that the avulsed tooth needed to be replanted (p-value=0.007). improving knowledge on this topic is critical for emergency physicians to provide appropriate care for patients with avulsion. overall, only 33.3% of ed physicians showed a high level of knowledge, while 22.2% showed moderate knowledge, and 44.4% had insufficient knowledge. the study found that the level of knowledge of avulsion management was significantly associated with higher clinical grade and older age physicians. however, no significant association was found with the number of years of experience. the study also found that all physicians agreed on the importance of avulsion management knowledge, and 94% were interested in increasing their knowledge. conclusion avulsion management needs to be integrated into medical programs to graduate physicians with higher knowledge to manage avulsion. emergency physicians also need to improve their knowledge to have better outcomes of avulsion management. conflicts of interest the authors declare no conflict of interests. funding no funding was received for this study. authors’ contribution sab and aam designed the study. sab reviewed the literature, collected and analyzed the data. sab and aam drafted the manuscript. aam supervised the work. both authors approved the final version of the manuscript. references 1. raoof m, vakilian a, kakoei s, manochehrifar h, mohammadalizadeh s. should medical students be educated about dental trauma emergency management? a study of physicians and dentists in kerman province, iran. j dent educ. 2013;77(4):494–501. doi: 10.1002/j.0022-0337.2013.77.4.tb05495.x 2. holan g, shmueli y. knowledge of physicians in hospital emergency rooms in israel on their role in cases of avulsion of permanent incisors. int j paediatr dent. 2003;13(1):13–9. doi: 10.1046/j.1365-263x.2003.00414.x 3. westphalen vpd, martins wd, deonizio mda, da silva neto ux, da cunha cb, fariniuk lf. knowledge of general practitioners dentists about the emergency management of dental avulsion in curitiba, brazil. dental traumatology. 2007;23(1):6–8. doi: 10.1111/j.16009657.2005.00392.x 4. çalışkan s, delikan e, kızılaslan s, özbek ö. knowledge of dental avulsion among emergency physicians: a survey study. the journal of pediatric research. 2021;8(1):62–8. doi: 10.4274/jpr.galenos.2020.98705 5. needleman hl, stucenski k, forbes pw, chen q, stack am. massachusetts emergency departments’ resources and physicians’ knowledge of management of traumatic dental injuries. dental traumatology. 2013;29(4):272–9. doi: 10.1111/j.1600-9657.2012.01170.x 6. abu-dawoud m, al-enezi b, andersson l. knowledge of emergency management of avulsed teeth among young physicians and dentists. dental traumatology. 2007;23(6):348–55. doi: 10.1111/j.1600-9657.2006.00477.x 7. ulusoy at, önder h, çetin b, kaya ş. knowledge of medical hospital emergency physicians about the first-aid management of traumatic tooth avulsion. int j paediatr dent. 2012;22(3):211–6. doi: 10.1111/j.1365-263x.2011.01178.x 8. fouad af, abbott p v., tsilingaridis g, cohenca n, lauridsen e, bourguignon c, et al. international association of dental traumatology guidelines for the management of traumatic dental injuries: 2. avulsion of permanent teeth. dental traumatology. 2020;36(4):331–42. doi: 10.1111/edt.12573 9. qazi sr, nasir ks. first-aid knowledge about tooth avulsion among dentists, doctors and lay people. dental traumatology. 2009;25(3):295–9. doi: 10.1111/j.1600-9657.2009.00782.x 10. subhashraj k. awareness of management of dental trauma among medical professionals in pondicherry, india. dental traumatology. 2009;25(1):92–4. doi: 10.1111/j.16009657.2008.00714.x 11. cagetti mg, marcoli pa, berengo m, cascone p, cordone l, defabianis p, et al. italian guidelines for the prevention and management of dental trauma in children. ital j pediatr. 2019;45(1):1–14. doi: 10.1186/s13052-019-0734-7 12. bahammam la. knowledge and attitude of emergency physician about the emergency management of tooth avulsion. bmc oral health. 2018;18(1):1–9. doi: 10.1186/s12903-0180515-5 13. venkataramana m, pratap k, padma tm, kalyan vs, bhargava a, varma lsc. knowledge and attitude of medical professionals towards emergency management of avulsed tooth in a teaching medical hospital, khammam town, south india. journal of indian association of public health dentistry. 2015;13(2):183. doi: 10.4103/2319-5932.159062 14. jyothi kn, venugopal p, nanda s, shah mk. knowledge and attitude of medical doctors towards emergency management of avulsed tooth-a cross sectional survey. j dent sci res. 2015;2:156–67. doi: 10.1186/s12903-018-0515-5 https://doi.org/10.1186%2fs12903-018-0515-5 table 1: general and demographic characteristics of the participants table 2: prevalence and associations of education, knowledge and its sources among participants with the reported level of information on avulsion management * fisher’s exact test characteristics study population (n=18) age (year) mean ± sd (range) 36 ± 7 (25-52) gender (n,%) male female 8 (44.4%) 10 (55.6%) experience (n,%) ≤ 15 years > 15 years 9 (50.0%) 9 (50.0%) country of graduation (n,%) oman others 14 (77.8%) 4 (22.2%) clinical grade (n,%) house officer senior house officer resident specialist senior specialist consultant senior consultant 5 (27.8%) 5 (27.8%) 5 (27.8%) 3 (16.7%) questions and answers frequency (n,%) the reported level of avulsion management information p-value* adequate information inadequate information have you received dental trauma education? yes no 9 (50%) 9 (50%) 5 (55.6%) 0 4 (44.4%) 9 (100%) 0.029 do you have prior avulsion management knowledge? yes no 12 (66.7%) 6 (33.3%) 5 (41.7%) 0 7 (58.3%) 6 (100%) 0.114 what is the better source of information? medical books education courses undergraduate dental education courses post-graduate dental education courses others 10 (55.6%) 3 (16.7%) 3 (16.7%) 2 (11.1%) 4 (40%) 0 1 (33.3%) 0 6 (60%) 3 (100%) 2 (66.7%) 2 (100%) 0.522 table 3: the association of factors affecting level of knowledge of avulsion management with the measured level of knowledge factors affecting the level of avulsion management knowledge measured level of avulsion managemnt knowledge p-value* high-moderate knowledge low knowledge correct suitable media 8 (72.7%) 3 (27.3%) 0.145 the correct way of replanting the dirty avulsed tooth 4 (57.1%) 3 (42.9%) 1.000 replanting the permanent avulsed tooth 10 (76.9%) 3 (23.1%) 0.007 the correct way of holding the tooth 9 (64.3%) 5 (35.7%) 0.275 * fisher’s exact test table 4: comparison and association of the measured avulsion management knowledge with different characteristics characteristic level of knowledge p-value high-moderate low gender (n, %) male female 5(62.5%) 5(50%) 3(37.5%) 5(50%) 0.664* age (years) (n) mean(sd) median 41(6.8) 39 32(6.4) 29 0.032** clinical-grade (n, %) house officer residinet specialist senior consultant 3(30%) 7(87.5%) 7(70%) 1(12.5%) 0.025* country of graduation (n, %) oman others 8(57.1%) 2(50%) 6(42.9%) 2(50%) 1.000* years of experience (n, %) ≤ 15 years >15 years 8(50%) 2(100%) 8(50%) 0 0.477* * fisher’s exact test ** mann-whitney u test figure 1: awareness of factors determining correct ways of management of avulsion as per participating physicians 0% 20% 40% 60% 80% 100% 120% holding avulsed tooth replantation of permanent avulsed tooth replantation of dirty avulsed tooth suitable storage media correct ways incorrect ways re: the effect of change in posture on spirometry in patients with obstructive sleep apnoea syndrome sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e114–115, epub. 9 mar 20 submitted 30 dec 19 accepted 12 feb 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.019 letter to the editor رد: تأثري تغري وضعية اجلسد على قياس التنفس عند مرضى متالزمة انقطاع النفس االنسدادي النومي dear editor, i read with great interest the original study by al lawati et al. published in the november 2019 issue of squmj.1 among a cohort of omani obstructive sleep apnoea syndrome patients, the authors nicely compared spirometry parameters between obese and non-obese patients when patients changed position from sitting to supine.1 they found a significant difference in the forced expiratory volume in 1 second/forced vital capacity (fvc) in obese and non-obese patients when changing position (p = 0.03). moreover, there was a significant gender difference in fvc percentages (p <0.05) whereby male patients had a decreased fvc compared to females. considering the remaining spirometry elements, there was no significant difference with patients’ change of position.1 i assume that the study’s results must be taken cautiously as, in addition to the limitations addressed by the authors, there is an additional relevant methodological limitation. the evaluation of lung function in a given population is usually done by examination of the absolute values of various spirometry components, comparing them with the predicted values and ultimately, checking the shape of the resultant curves. this requires the employment of populationspecific reference values.2 normal pulmonary function is controlled by genetic, physiological, environmental, psychological, nutritional, socioeconomic and racial determinants.2 consequently, many population-specific reference values of spirometry have been formulated to be used in clinical settings and research institutions.3,4 interestingly, omani population-specific prediction equations for reference values of spirometry have already been established.5 however, the authors did not clearly state which reference values they used in their study methodology to analyse the readings of various spirometry parameters. consequently, this may bring into question the results of the study. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. al lawati r, al abri ma, kuppuswamy b, al-kharousi a, alatbi a, rizvi s, et al. the effect of change in posture on spirometry in patients with obstructive sleep apnoea syndrome. sultan qaboos univ med j 2019; 19:e310–15. 2. rivero-yeverino d. [spirometry: basic concepts]. rev alerg mex 2019; 66:76–84. https://doi.org/10.29262/ram.v66i1.536. 3. rufino r, costa ch, lopes aj, maiworm ai, maynard k, silva lm, et al. spirometry reference values in the brazilian population. braz j med biol res 2017; 50:e5700. https://doi.org/10.1590/1414-431x20175700. 4. fawibe ae, odeigah lo, saka mj. reference equations for spirometric indices from a sample of the general adult population in nigeria. bmc pulm med 2017; 17:48. https://doi.org/10.1186/s12890-017-0390-x. 5. al-rawas oa, baddar s, al-maniri aa, balaji j, jayakrishnan b, al-riyami bm. normal spirometric reference values for omani adults. lung 2009; 187:245–51. https://doi.org/10.1007/s00408-009-9148-4. response from the authors dear reader, thank you for your interest and we very much appreciate your comments on our recently published original study.1 we would like to highlight that this is the first study to explore the changes in spirometry parameters when changing from sitting to supine position in patients with moderate and severe obstructive sleep apnoea syndrome https://creativecommons.org/licenses/by-nd/4.0/ https://doi.org/10.29262/ram.v66i1.536 https://doi.org/10.1590/1414-431x20175700 https://doi.org/10.1186/s12890-017-0390-x https://doi.org/10.1007/s00408-009-9148-4 mahmood d. al-mendalawi letter to the editor | e115 (osas). while earlier studies have examined spirometry characteristics in osas patients, there has been no mention of posture changes.2,3 other studies used different methodologies and most measured spirometry only in one position.3 however, we used both the absolute values and the percentages of each parameter of spirometry when comparing obese and non-obese osas patients as well as age and gender differences. the study aimed to analyse the changes resulting from a change in posture; it was not intended to compare osas patients with healthy subjects and therefore local reference values were not used in the study. the novel results from our study showed that obesity plays a major role in spirometry changes while changing posture rather than osas; this could lead to the development of obesity hypoventilation in obese osas patients.4 additionally, international standards of spirometry indices were used as a reference only.5 while local reference values have already been determined in healthy subjects, there are no reference values for osas patients.6 as you mentioned, we stated in the limitations of the study that osas patients were not compared with non-osas subjects. finally, our results showed that obesity has a significant impact on spirometry while changing position; gender and age do not have an effect in osas patients only.1,7 *mohammed al-abri,1 redha al-lawati,2 mohan dikshit3 1department of clinical physiology, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2oman medical specialty board, muscat, oman; 3formerly department of physiology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: malabri@squ.edu.om references 1. al lawati r, al abri ma, kuppuswamy b, al-kharousi a, alatbi a, rizvi s, et al. the effect of change in posture on spirometry in patients with obstructive sleep apnoea syndrome. sultan qaboos univ med j 2019; 19:e310–15. 2. shepard jw jr, burger cd. nasal and oral flow-volume loops in normal subjects and patients with obstructive sleep apnea. am rev respir dis 1990; 142:1288–93. https://doi.org/10.1164/ajrccm/142.6_pt_1.1288. 3. shore et, millman rp. abnormalities in the flow-volume loop in obstructive sleep apnoea sitting and supine. thorax 1984; 39:775–9. https://doi.org/10.1136/thx.39.10.775. 4. littleton sw, tulaimat a. the effects of obesity on lung volumes and oxygenation. respir med 2017; 124:15–20. https://doi.org/10.1016/j. rmed.2017.01.004. 5. miller mr, hankinson j, brusasco v, burgos f, casaburi r, coates a, et al. standardisation of spirometry. eur respir j 2005; 26:319–38. https://doi.org/10.1183/09031936.05.00034805. 6. al-rawas oa, baddar s, al-maniri aa, balaji j, jayakrishnan b, al-riyami bm. normal spirometric reference values for omani adults. lung 2009; 187:245–51. https://doi.org/10.1007/s00408-009-9148-4. 7. littleton sw. impact of obesity on respiratory function. respirology 2012; 17:43–9. https://doi.org/10.1111/j.1440-1843.2011.02096.x. https://doi.org/10.1136/thx.39.10.775 https://doi.org/10.1016/j.rmed.2017.01.004 https://doi.org/10.1016/j.rmed.2017.01.004 https://doi.org/10.1183/09031936.05.00034805 https://doi.org/10.1007/s00408-009-9148-4 https://doi.org/10.1111/j.1440-1843.2011.02096.x emerging and novel therapies for keloids a compendious review hamed memariani, *mojtaba memariani, hamideh moravvej, mohammad shahidi-dadras sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e22–33, epub. 15 mar 21 submitted 20 may 20 revision req. 29 jun 20; revision recd. 27 jul 20 accepted 13 aug 20 skin research center, shahid beheshti university of medical sciences, tehran, iran *corresponding author’s e-mail: memaryani@gmail.com keloids are fibroproliferative scars that undergo aggressive dermal growth expanding beyond the borders of the original injury and do not regress spontaneously.1,2 keloids often form within a year of injury, tend to persist over time and are among the most perplexing challenges facing physicians.3 keloids can arise from burns, deep dermal injury, post-elective surgery or trauma and can result in deformity and even restricted joint mobility.4 homo sapiens is the only species that develops keloids.5 the recorded history of keloids dates back to 3,000 bce, where egyptian surgical techniques were described on the smith papyrus.6,7 rooted in african folklore, the ancient yoruba people of western nigeria recorded features of the keloid diathesis and depicted them in sculptures of the 10th century ad.8 the term keloid stems from the greek cheloide which is derived from chele, meaning crab claw, and was initially coined by alibert in 1816 because the lesions resemble crayfish legs penetrating the skin.6 keloids are equally prevalent in both genders, with the greatest incidence in the second decade of life.9 it seems that some genetic predispositions can affect the occurrence rate of keloid scarring. in this context, individuals with darker skin tones are more prone to keloid development than fairer-skinned individuals.10 keloids are described as the fifth most frequent skin disease among black adults in the united kingdom.11 the incidence of keloid scarring in highrisk populations including african, hispanic and asian people is approximately 5% to 16%.12 review العالجات املستجدة واحلديثة للُجَدرَات مراجعة موجزة حامد معامرياين، جمتبى معمرياين، حميدة مرّوج، حممد شهيدي-دادرس abstract: keloids are abnormal fibroproliferative scars with aggressive dermal growth expanding beyond the borders of the original injury. different therapeutic modalities, such as corticosteroids, surgical excision, topical silicone gel sheeting, laser therapy, cryotherapy, photodynamic therapy and radiotherapy, have been used to treat keloids; however, none of these modalities has proven completely effective. recently, researchers have devised several promising anti-keloid therapies including anti-hypertensive pharmaceuticals, calcineurin inhibitors, electrical stimulation, mesenchymal stem cell therapy, microneedle physical contact and ribonucleic acid-based therapies. the present review summarises emerging and novel treatments for keloids. pubmed® (national library of medicine, bethesda, maryland, usa), embase (elsevier, amsterdam, netherlands) and web of science (clarivate analytics, philadelphia, pennsylvania, usa) were searched for relevant literature published between january 1987 to june 2020. a total of 118 articles were included in this review. a deeper understanding of the molecular mechanisms underlying keloid scarring pathogenesis would open further avenues for developing innovative treatments. keywords: keloid; treatment; fibroblast; scar; dermatology. امللخ�ص: اجُلَدَرات هي ندوب ليفية تكاثرية غري طبيعية حتدث مع منو جلدي عنيف ميتد ملا بعد حدود الإ�سابة الأ�سلية. وت�ستخدم و�سائل عالجية متعددة لعالج اجُلَدَرات منها الكورتيكو�ستريودات، والإزالة اجلراحية، وامل�سح بهالم ال�سيلكون، والعالج بالليزر، واملعاجلة بالربد، والعالج املقتوي بال�سوء، واملعاجلة بالأ�سعة. غري اأن كل هذه الو�سائل العالجية مل تثبت عالجا ناجعا ب�سورة تامة. و�سمم الباحثون موؤخرا عالجات واعدة للُجَدَرات ت�سمل اأدوية �سغط الدم املرتفع، وم�سادات كال�سينورين، والتنبيه الكهربائي، والعالج باخلاليا اجلذعية املتعلقة باللحمة املتو�سطة، والت�سال اجل�سدي باإبرة جمهرية، والعالج با�ستخدام مواد تعتمد على احلام�ص النووي الريبوزي. وتلخ�ص هذه املراجعة pubmed بع�ص العالجات امل�ستجدة واحلديثة للُجَدَرات ذات ال�سلة واملذكورة يف الفرتة بني يناير 1987م ويناير 2020م يف بومبيد )مكتبة الطب القومية، بيثيثدا، ماري لجن، الوليات املتحدة الأمريكية(، و embase )�رشكة ال�سيفري، اأم�سرتدام، هولندا(، و�سبكة العلوم )web of science( من �رشكة كالريفيت اناليتك�ص، فيالديلفيا، بن�سلفانيا، الوليات املتحدة الأمريكية. و�سملت هذه املراجعة 118 ورقة. �سيتيح فهم اأعمق لالآليات اجلزئية لإِْمرا�ص الندوب يف اجُلَدَرات فتح م�سارات اأبعد نحو تطوير عالجات مبتكرة لهذا املر�ص. الكلمات املفتاحية: ُجَدَرة؛ عالج؛ اأرومة ليفية؛ ندبة؛ طب اجللد. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.004 https://creativecommons.org/licenses/by-nd/4.0/ hamed memariani, mojtaba memariani, hamideh moravvej and mohammad shahidi-dadras review | e23 various therapeutic modalities have been described for keloid treatment. conventional treatment options include silicone gel sheeting, compressive therapy, intralesional steroids, topical mitomycin c, intralesional or topical 5-fluorouracil (5-fu), surgical excision, cryotherapy, radiotherapy, laser therapy and photo dynamic therapy, etc.13,14 nevertheless, no single effective therapeutic regimen has been hailed as the gold standard, mainly owing to the high recurrence rates of keloids and a dearth of extensive research evaluating available treatments.9 in recent decades, advances in understanding molecular mechanisms of diseases have led to a new era of drug design and development. this compendious review aims to summarise emerging and novel anti-keloid therapies. due to the scope of this review and space constraints, however, conventional therapies are not discussed herein; interested readers should seek out reviews provided by others.1,15,16 also available within this article are grades of recommendations and levels of evidence, which have been established for each therapy according to the national institute for health and clinical excellence guidelines [tables 1–3].17 a schematic overview of possible anti-keloid mechanisms of action with regard to emerging and novel treatments is also presented [figure 1]. table 1: strength of recommendation and level of evidence for anti-keloid therapies17 treatment strength of recommendation level of evidence anti-hypertensive pharmaceuticals b 1+ botulinum toxin a a 1++ calcineurin inhibitors d 3 doxorubicin d (gpp) 4 electrical stimulation d 2+ microneedle physical contact c 2+ extracorporeal shockwave therapy c 2+ fat grafting c 2+ stem cell therapy d (gpp) 4 imidazoquinolines d 3 interferons b 1++ tamoxifen d 3 rna-based therapies d (gpp) 4 gpp = good practice point. table 2: strength of recommendation for anti-keloid therapies17 grade evidence a • at least one meta-analysis, systematic review or rct rated as 1++, and directly applicable to the target of population, or • a systematic review of rcts or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results • evidence drawn from a nice technology appraisal b • a body of evidence including studies rated as 2++, directly applicable to the target population and demonstrating overall consistency of results, or • extrapolated evidence from studies rated as 1++ or 1+ c • a body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results, or • extrapolated evidence from studies rated as 2++ d • evidence level 3 or 4, or • extrapolated evidence from studies rated as 2+, or • formal consensus d (gpp) •a gpp is a recommendation for best practice based on the experience of the guideline development group rct = randomised controlled trial; nice = national institute for health and clinical excellence; gpp = good practice point. table 3: level of evidence for anti-keloid therapies17 level of evidence type of evidence 1++ • high-quality meta-analyses, systematic reviews of rcts, or rct with a very low risk of bias 1+ • well-conducted meta-analysis, systematic review of rcts or rct with a low risk of bias 1• meta-analysis, systematic review of rct or rct with a high/low risk of bias 2++ • high-quality systematic review of casecontrol or cohort studies • high-quality case-control or cohort study with a very low risk of confounding, bias or chance with a high probability that the relationship is causal 2+ • well-conducted case-control or cohort studies with a low risk of confounding, bias or chance with a moderate probability that the relationship is causal 2• case-control or cohort study with a high risk of confounding, bias or chance with a significant risk that the relationship is not causal 3 • non-analytical studies (for example, case reports, case series) 4 • expert opinion, formal consensus rct = randomised controlled trial. emerging and novel therapies for keloids a compendious review e24 | squ medical journal, february 2021, volume 21, issue 1 methods pubmed® (national library of medicine, bethesda, maryland, usa), embase (elsevier, amsterdam, netherlands) and web of science (clarivate analytics, philadelphia, pennsylvania, usa) databases were searched for articles published from january 1987 to june 2020. the following terms were used: ‘keloid’ and ‘treatments’ or ‘therapies’ or ‘antihypertensive pharmaceuticals’ or ‘botulinum toxin a’ or ‘calcineurin inhibitors’ or ‘doxorubicin’ or ‘electrical stimulation’ or ‘microneedle physical contact’ or ‘extracorporeal shockwave therapy’ or ‘fat grafting’ or ‘mesenchymal stem cell therapy’ or ‘imidazoquinolines’ or ‘interferons’ or ‘tamoxifen’ or ‘rna-based therapies’. reference lists of selected articles, other related studies and review articles were also examined. the inclusion criteria comprised all articles referring to different methods of treatment for keloids in the english language literature. following an initial screening of 5,351 titles and abstracts, 167 potentially relevant articles were retrieved for full-text review. of these potentially relevant articles, 49 were excluded as they failed to meet the inclusion criteria. a total of 118 articles were selected for final inclusion in this review. e m e r g i n g a n d n o v e l t r e at m e n t s anti-hypertensive pharmaceuticals angiotensin-converting enzyme (ace) is a peptidyl dipeptide hydrolase which converts angiotensin i to angiotensin ii. this enzyme is involved in both blood pressure regulation and fibrous remodeling.18,19 given that severe keloids seem to be associated with hypertension, ace inhibition should be considered as a potential treatment against keloids.20,21 angiotensin ii elevates the level of transforming growth factor beta (tgf-β) and plays a prominent role in collagen biosynthesis and wound healing.22,23 for instance, an ace-inhibitor lisinopril weakened in vitro proliferation of mouse nih 3t3 fibroblasts and collagen expression by suppressing phosphorylation of smad2/3 and tak1.24 in rats with acute dermal wounds, scars treated with ramipril (an ace-inhibitor) were narrower compared to the control groups, which had their wounds treated with water; the treated wounds also exhibited augmented neovascularisation and reepithelialisation.24 interestingly, complete recovery from keloid scars was reported in a 54-year-old female patient following daily oral administration of the ace-inhibitor enalapril (10 mg).25 in a second case, satisfactory results were reported in a 70-year-old figure 1: possible mechanisms of action for emerging and novel treatments of keloids. 1 = anti-hypertensive pharmaceuticals; 2 = botulinum toxin a; 3 = calcineurin inhibitors; 4 = doxorubicin; 5 = electrical stimulation; 6 = microneedle physical contact; 7 = extracorporeal shockwave therapy; 8 = fat grafting; 9 = stem cell therapy; 10 = imidazoquinolines; 11 = interferons; 12 = tamo xifen; 13 = rna-based therapies; tgf-β = transforming growth factor beta; α-sma= alpha-smooth muscle actin; ecm = extracellular matrix; igf = insulin-like growth factor; ifn-α = interferon-alpha. hamed memariani, mojtaba memariani, hamideh moravvej and mohammad shahidi-dadras review | e25 female diabetic patient who received the same dose of enalapril.25 uzun et al. showed that oral administration of enalapril following dermal injury reduced formation of hypertrophic scars in rabbit ear wounding models.26 moreover, six weeks of twice-daily application of captopril cream (5%) in an 18-year-old female patient lessened not only the height of scar but also the redness and itchiness, without cutaneous and systemic side effects.23 one study evaluated the efficacy of losartan (an angiotensin ii receptor blocker) on hypertrophic scars and keloids.22 in this study, 5% losartan ointment twice a day for three months resulted in a significant reduction in vascularity and pliability compared to patients receiving a placebo (p <0.05). no allergic or hypotensive symptoms were observed in patients who underwent the ointment treatment.22 verapamil is a member of the phenylalkylamine family, which is a class of calcium antagonists. it is capable of blocking both l-type and t-type calcium channels, thereby lowering blood pressure.27 verapamil triggers synthesis of procollagenase in keloids and normal human cultured fibroblasts, causing reduced production of fibrous tissue. for example, an intralesional injection of verapamil (2.5 mg/ml) led to a decrement in pliability, vascularity, height and width of scars after three weeks of treatment.28 a doubleblind randomised controlled trial (rct) revealed that intralesional verapamil injections (2.5 mg/ml) at monthly intervals (four doses) in half of the wounds were safe but not as effective as a similar regimen (10 mg/ml) of triamcinolone (tac) for prevention of keloid scar recurrence following excision removal.29 it has been suggested that increasing the dose or frequency of injections would improve treatment outcomes when verapamil is exploited as an adjunct to surgical excision.29 in a recent retrospective study, combination of verapamil and intralesional tac led to a pronounced improvement of keloid scars with a long-lasting result.30 lawrence also demonstrated that intralesional verapamil hydrochloride after earlobe surgical keloid excision had a 52% cure rate in 31 african-american patients.31 similarly, one study revealed that keloidectomy with core fillet flap and intralesional verapamil injection is a reliable and cost-effective method in the treatment of earlobe keloids with a low rate of recurrence.32 overall, keloid recurrence rates for verapamil have been found to range from 1.4–48%.29 botulinum toxin a botulinum toxin, a potent neurotoxin produced by clostridium botulinum, has a wide range of applications in medicine including the united states food and drug administration (fda)-approved treatments for strabismus, blepharospasm, hemifacial spasm, cervical dystonia, axillary hyperhidrosis, chronic migraine, neurogenic detrusor overactivity and for cosmetic use.33 with regard to keloids, intralesional injection of the toxin abates scar proliferation by reducing muscle tension during wound healing, halting fibroblast cell cycles in the non-proliferative stage and modulating tgf-β1 expression.34,35 patients have also reported higher satisfaction rates and improvements in erythema, pain, pliability and itching.36,37 a prospective, uncontrolled study revealed that intralesional injections of botulinum toxin a (70–140 units per session every three months) into keloids resulted in peripheral regression and lesion flattening without recurrence after one year.38 this finding is in line with an rct in which intralesional administration of botulinum toxin a (5 iu/cm3 every eight weeks) caused significant decrements in both the volume and height of keloid lesions (p <0.01 each) as well as substantial softening of the lesions compared to baseline.39 by contrast, another study found that intralesional botulinum toxin a (70–140 speywood units per session every two months) did not lead to regression of keloid tissue; neither cell proliferation nor metabolism of keloid fibroblasts were influenced by botulinum toxin a.35 in a double-blinded study, botulinum toxin a was not superior to corticosteroids for preventing earlobe or sternal keloid recurrence at oneand three-month follow-up.40 however, the advantage of using botulinum toxin a is that it is a single injection compared to steroid therapy which requires monthly injections.40 a recent study demonstrated adjuvant properties of botulinum toxin in treating keloids.41 in this context, intralesional tac plus botulinum toxin a led to significant symptomatic improvement of pain and pruritus in comparison to intralesional tac alone (p <0.001). likewise, botulinum toxin a in combination with surgery was also successful in treating postotoplasty keloids in 16 patients.42 a systematic review and meta-analysis of 15 rcts also revealed that injection of intralesional botulinum toxin a was more effective in treating keloids than injecting intralesional corticosteroid or a placebo.43 although intralesional injection of the toxin has shown satisfactory results in patients with keloids, further large-scale studies with comparative designs and long-term follow-up are warranted to delineate the value of this therapy in keloid management protocols.44 calcineurin inhibitors the cyclic depsipeptide tacrolimus (fk-506) produced by streptomyces tsukubaensis inhibits calcineurin complex with fk-binding proteins.45 as a potent emerging and novel therapies for keloids a compendious review e26 | squ medical journal, february 2021, volume 21, issue 1 immunosuppressor, tacrolimus has been applied widely to prevent organ rejection and treat autoimmune diseases as well as skin disorders including atopic dermatitis, keloids, erosive mucosal lichen planus, psoriasis and pyoderma gangrenosum.46–48 tacrolimus interdicts keloidal fibroblast proliferation, migration and collagen production. additionally, it inhibits tgf-β/smad signalling pathways in keloid fibroblasts through down-regulation of tgf-β receptors.49 expression of glioma-associated oncogene 1 (gli1) has been shown to be elevated in keloids. because tacrolimus is able to inhibit signalling from the gli1, kim et al. suggested that tacrolimus may have antikeloid properties.50 another study demonstrated the beneficial effects of topical tacrolimus ointment in preventing hypertrophic scars in rabbit models.51 in an open-label pilot study, the majority of patients exhibited a decrement in induration, erythema, pruritus and tenderness after topical application of tacrolimus ointment (0.1%) twice a day for 12 weeks, yet no statistically significant benefits as a therapeutic agent were observed.52 another study showed the preventive role of topical tacrolimus against keloids in 25 patients after surgery.53 nevertheless, further clinical investigations involving topical tacrolimus are warranted for delineating its efficacy in keloid treatment. sirolimus (rapamycin) is a cyclic depsipeptide produced by streptomyces hygroscopius; it has antifungal, immunosuppressive and anti-tumour/antiproliferative properties that have been ascribed to sirolimus.45,54 this medication hampers the mammalian target of rapamycin (mtor), a serine/threonine kinase that regulates both metabolic processes and translation rates. levels of total endogenous mtor have been reported to be increased in keloids.55 it is worth noting that mtor regulates the expression of collagen type i in human dermal fibroblasts.56 when applied to cultured normal and keloidal fibroblasts, sirolimus down-regulated the expression of cytoplasmic proliferating cell nuclear antigen, cyclin d1, collagen fibronectin and alpha-smooth muscle actin (α-sma) in a doseand time-dependent manner, indicating the anti-proliferative effects and therapeutic potential of sirolimus in keloid treatment.55 inhibition of extracellular matrix (ecm) deposition, prevention of platelet-derived growth factor-induced collagen synthesis and reduction in over-expression of collagen i and iii in keloid fibroblasts are other functions of sirolimus.57 doxorubicin doxorubicin, which was first extracted from streptomyces peucetius, is an anthracycline antibiotic with a dna intercalating property that is routinely exploited in cancer chemotherapy.58,59 poor wound healing as a consequence of impaired collagen biosynthesis has been acknowledged as an adverse effect associated with doxorubicin administration, suggesting the potential role of this medication in treating hypertrophic scars and keloids.60 doxorubicin has been demonstrated to decrease fibroblast proliferation in vitro.61 it inhibits enzymes prolyl 4-hydroxylase and prolidase in human skin fibroblast cultures, thereby reducing collagen synthesis.60,61 no published trials regarding the anti-keloidal effects of doxorubicin are available in the literature, warranting further studies to evaluate its efficacy in keloid treatment.62 electrical stimulation electrical stimulation (es) has been used to treat abnormal scars in the past.63 a novel device called fenzian system, which produces degenerate waves, was developed recently and shows promise in curing keloids and hypertrophic scars.64 for instance, in a study conducted by ud-din et al., the effectiveness of the fenzian system on symptomatic raised dermal scars was assessed in 18 patients using full-field laser perfusion imaging to evaluate changes in dermal blood flow.65 a significant reduction in pain scores (p = 0.007) and pruritus scores (p = 0.002) was observed over one month. the researchers also found that symptoms in patients with long-standing sternal scars needed more time to diminish compared to patients with scars in less stress-prone anatomical locations such as the breast or abdomen.65 perry et al. showed that the fenzian system successfully reduced pain, itching and scar scores (p <0.05) in 30 patients with 140 scars, most of which were keloids and hypertrophic scars on the sternum, breast and shoulder girdle.63 it seems that suppression of excessive collagen i formation is a major mechanism behind the anti-keloid properties of es.63 another investigation revealed that the cytotoxic effects of photodynamic therapy on keloid fibroblasts can be enhanced significantly (p <0.05) when combined with degenerate electrical waveform stimulation.66 in one study, combining the local treatment of mature scars with low-intensity electromagnetic and electric stimulation with negative pressure exhibited a satisfactory synergic effect on scar collagen and elastic fibre remodelling in 20 patients.67 nevertheless, further large-scale controlled studies are needed to elucidate the overall efficacy of es. microneedle physical contact microneedles have been studied by many researchers over the past decade primarily for transdermal drug delivery. in contrast to conventional needles that are hamed memariani, mojtaba memariani, hamideh moravvej and mohammad shahidi-dadras review | e27 at least 1 mm in width or have even larger dimensions, microneedle devices consist of needles with sizes expressed in microns. microneedles are able to penetrate the stratum corneum without contacting the nerves in the dermis. various types of microneedles, such as solid, coated, dissolving and hollow forms, exist. on the whole, these devices cause less pain, infection and injury compared with conventional injections.68 in a controlled clinical trial, tan et al. found that once-daily application of dissolving tac-embedded microneedle patches markedly diminished the volume of keloids on the chest, arms and shoulders.69 similarly, yeo et al. tested fda-approved liquid crystalline polymer-based microneedles to determine its ability to inhibit keloid fibroblast proliferation.70 after a 12hour treatment, the non-viable proportion of keloid fibroblasts in cell cultures increased to 83.8 ± 11.96%. they also showed that microneedle treatment in rabbit ear hypertrophic scar models prevented dermis tissue thickening in 83.33% (n = 15) of wounds.70 in the same study, the microneedle patch was evaluated on a patient suffering from a single post-surgical hypertrophic scar on the dorsum region; after treatment, the patient’s redness, pruritus and chronic inflammation reduced.70 the efficiency of a microneedle patch comprising polyethylene glycol diacrylate and encapsulating 5-fu for transdermal delivery has been examined in its use with keloids. the microneedle patch effectively abolished keloid fibroblast proliferation in a cell culture. although soluble 5-fu delivery was able to reduce keloid fibroblast proliferation (6.9 ± 3.6-fold expansion), the extent of inhibition was even higher when microneedle-assisted delivery was applied (2.0 ± 0.4-fold expansion; p <0.05).71 surprisingly, even drug-free microneedles induced an inhibitory effect, with an approximately 10-fold reduction in cell viability compared to controls.71 a preliminary analysis of cell morphology demonstrated that keloid fibroblasts treated with blank microneedles decreased in size and had higher nucleus-to-cytoplasm ratios, while the non-treated keloid fibroblasts were flat and spindle-shaped. however, the mechanism of this unexpected phenomenon in which the physical presence of microneedles inhibits the proliferation of keloid fibroblasts remains unclear.71 transdermal delivery of antimicrobial peptides using microneedle stamping devices or drug-loaded microneedle patches has recently been proposed as a new strategy for treating keloids and hypertrophic scars.72,73 future studies should involve clinical subjects to validate the efficiency and safety of microneedle drug delivery systems for treating keloids. extracorporeal shockwave therapy extracorporeal shockwave therapy (eswt) was first introduced in 1982 for urinary stone lithotripsy.74 in recent decades, the success of eswt in addressing urinary stones has made it a first-line, cost-effective, non-invasive treatment. eswt has also been used to treat musculoskeletal maladies including plantar fasciitis and chronic lateral epicondylitis.75 multiple lines of evidence exist in the literature regarding eswt’s effectiveness in enhancing healing in patients with acute and chronic wounds and diabetic foot ulcers.76,77 a few studies have evaluated eswt for treating post-burn, hypertrophic and keloid scars.78–80 in one study, 17 patients with burn scars on their extremities underwent eswt sessions once a week for six weeks. the visual analogue scale (vas) was used to quantify pruritus and pain, while the vancouver scar scale (vss) was used to evaluate scar appearance. both vas and vss scores were significantly diminished after treatment and during follow-ups (p <0.001).78 another study assessed the effects of eswt used twice a week for six weeks on 16 patients with post-burn scar contractures, hypertrophic scars and keloids.79 the scars were located on patients’ extremities, their faces or mentosternal regions or on their trunks. the study found that the scars appeared more pliable and colour mismatch was lessened after the first session. at the end of the treatment, all of the scars had more acceptable appearances.79 wang et al. also compared the efficiency of eswt and intralesional steroid injection with tac in treating keloid scars.80 the eswt group received three eswt treatments in six weeks whereas the steroid group received three intralesional tac injections in six weeks. both groups demonstrated substantial improvements in keloid appearance with less discolouration, greater flattening, a softer consistency and greater elasticity. moreover, the eswt group displayed comparable functional outcomes and a remarkable reduction in collagen fibres as well as increasing matrix metalloproteinase-13 degrading enzyme levels compared to the intralesional steroid injection group.80 the exact mechanism underlying the observed beneficial effects of eswt remains unknown. when primary dermal fibroblasts derived from human postburn hypertrophic scars were exposed to shockwave pulses, tgf-β1, α-sma, collagen-i, fibronectin and twist1 levels were significantly reduced, while expression of e-cadherin was increased.81 it was suggested that suppressed epithelial-mesenchymal transition might be responsible for the antiscarring effects of eswt.81 the acoustic waves also emerging and novel therapies for keloids a compendious review e28 | squ medical journal, february 2021, volume 21, issue 1 mechanically disrupt tissue by cavitation.78 indeed, shock waves yield microscopic injuries in scar tissue and disintegrate collagen fibres which results in scar remodelling. two mechanisms for eswt have been explained: (1) shock waves affect pain receptor physiology and (2) these waves generate micro-trauma and release cytokines, promoting tissue repair.78 fat grafting autologous fat grafting (i.e. lipotransfer) for patients with keloids has been exemplified in several studies.82–84 in three clinical cases, fat injection at the dermalhypodermal junction in hemifacial hypertrophic scars and keloids led to substantial improvement in skin texture, softness, thickness and elasticity after a six-month follow-up period.82 another study also demonstrated that autologous fat grafting in 18 patients with post-burn hypertrophic scars and keloids improved texture, colour, softness, thickness and elasticity of the treated skin.83 new collagen deposition, dermal hyperplasia and neoangiogenesis were also evident based on histological evaluation.83 the procedure causes less fibrosis, pain reduction and more flexibility in areas of scar contraction. it seems that transfer of adipose tissue-derived stem cells (adscs) into wounds plays a key role in inhibiting keloid fibroblast proliferation and ecm formation.84 stem cell therapy the possible mechanisms underlying mesenchymal stem cell (msc) therapy are modulation and prevention of inflammatory processes as well as antifibrosis effects by reducing collagen production while enhancing normal angiogenetic activity.36 various delivery methods, including systemic injection, local injection at the site of wound, intradermal or subcutaneously and engineered msc-seeded tissue scaffolds have been used.85 for instance, zhang et al. demonstrated that intralesional injection of adscs decreased hypertrophic scarring in rabbits by reducing the gene expression of collagen type i, α-sma and collagen deposition.86 in another study, adscconditioned medium (adsc-cm) not only decreased the expression of collagen type i and iii and α-sma but also suppressed collagen deposition and scar formation through the inhibition of the p38/mitogenactivated protein kinase (mapk) signalling pathway in hypertrophic scar-derived fibroblasts in vitro.87 in a recent study, adsc-cm has been reported to attenuate the gene expression of plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinases 1 (timp-1) and collagen type i in keloid fibroblasts.88 notably, 24-hour incubation of keloid fibroblasts with adsc-cm significantly inhibited cell proliferation in the g2/m phase compared to the control group (p <0.05). adsc-cm was also capable of reducing invasive abilities of keloid fibroblasts in vitro.88 furthermore, bone marrow-derived stem cellsconditioned medium (bmsc-cm) has been shown to inhibit cell proliferation and migration of hypertrophic scar and keloid fibroblasts.89 at both transcriptional and translational levels, bmsc-cm reduced expression of profibrotic genes in hypertrophic scar and keloid fibroblasts.89 additionally, this novel strategy has been investigated in several fibrotic diseases such as myocardial infarctions, renal fibrosis, and liver cirrhosis. although promising, msc therapy requires further in vivo studies in order to apply these results to clinical practice.36 imidazoquinolines imidazoquinolines, including imiquimod and resiquimod, are toll-like receptors 7 and 8 agonists with potent immune modulator activities. resiquimod is up to 100-fold more potent in vitro and in vivo than imiquimod.90 they stimulate production of interferon-alpha (ifn-α) at the site of application, which intensifies collagen breakdown. imiquimod 5% cream is approved for the treatment of genital warts, superficial basal cell carcinoma and actinic keratosis.91 imiquimod can be applied post-surgery using different treatment regimens, starting on the night of surgery with daily treatments or two weeks after the operation on alternate nights for eight weeks.92–94 in a pilot study, post-surgical use of imiquimod 5% cream was effective in treating earlobe keloids without recurrence after 12 months’ follow-up.95 in addition, alleviation of symptoms such as pruritus and pain within the first post-operative month was reported in all patients.95 likewise, berman et al. showed the effectiveness of imiquimod 5% cream in preventing recurrence of earlobe keloids after excision.96 in their study, four patients with a total of eight large pedunculated earlobe keloids were successfully treated with debulking by tangential shave excision followed by daily application of imiquimod 5% cream for six weeks.96 in another study, post-surgical use of imiquimod 5% cream in 35 patients with keloids indicated a recurrence rate of 28.6%.93 however, a high recurrence rate (88.9%) was reported in one study in which nine patients with trunk keloids underwent surgery followed by daily application of imiquimod 5% cream for eight weeks.97 the imiquimod-poly(2-(2methoxyethoxy)ethyl methacrylate) hydrogel dressing has also been shown to inhibit the proliferation of keloid fibroblasts in vitro.98 interferons interferons are potent cytokines that possess antiproliferative, anti-fibrotic and anti-viral effects. they hamed memariani, mojtaba memariani, hamideh moravvej and mohammad shahidi-dadras review | e29 are extensively employed in a variety of maladies including condylomata accuminata, basal cell carcinoma, high risk melanoma, kaposi’s sarcoma and viral hepatitis. all interferon isoforms—especially inf-α2b and inf-γ—have been shown to attenuate collagen synthesis together with fibroblast proliferation and to induce tgf-β1 down-regulation.36,99,100 some evidence showed that inf-γ enhances myofibroblast apoptosis and prevents its differentiation, whereas inf-α2b inhibits wound contraction in vitro.101,102 nonetheless, some clinical trials have revealed contrasting results.103–105 for this reason, more rcts should be performed to enrich existing data. complications of therapy with interferon injection are flu-like symptoms, fever, headaches, fatigue and myalgia.36,99 in berman and flores’ study, post-operative injections of inf-α2b in keloids (80% were earlobe keloids) resulted in a lower recurrence rate (18.7%) compared to adjuvant post-operative tac injections (58.4%).106 when combined with intralesional tac, inf-α2b caused a significant decrease in keloid volume (86.6%; p = 0.002) and depth (81.6%; p = 0.005).107 the majority of these scars were located on the chest, shoulders, upper arms and back. no keloid recurrence was reported.107 tamoxifen tamoxifen is a synthetic non-steroidal anti-estrogen which has been exploited extensively in both chemoprevention and breast cancer treatment.108 tamoxifen modifies rna transcription, hinders keloidal fibroblast proliferation, influences the cell cycle in the g-phase and suppresses insulin-like growth factor production.109,110 one study showed that tamoxifen dose-dependently waned the expression of tgf-β1 in keloid fibroblast cultures.111 moreover, it was capable of impeding lattice contraction in a dose and time-dependent manner in vitro.110 additionally, topical application of a 2% tamoxifen ointment on third-degree burns in rats augmented angiogenesis and decreased fibrotic tissue thickness.112 in pasquetti et al.’s study, topical application of 0.1% tamoxifen citrate on keloids or hypertrophic scars located on the sternum, shoulders, abdomen and upper limbs had satisfactory results with a substantial decrement in lesion height, width and length.113 soares-lopes et al. found that the intralesional administration of tamoxifen in 13 patients with keloids resulted in a significant reduction in collagen fibres and fibroblasts (p <0.0001).114 rna-based therapies rna interference (rnai) is a biological process for gene-specific rna degradation. it is mediated by small interfering rnas (sirnas).115 during the past few years, several attempts have been made to inhibit gene expression by sirnas in keloid fibroblasts. for example, sirna targeting timp-1/-2 resulted in degradation of collagen type i in keloid fibroblasts.116 in shin et al.’s study, heat shock protein 70 knockdown using sirnas caused a marked decrement in collagen production in keloid fibroblasts compared to controls.117 furthermore, transfection of keloid fibroblasts with sirna targeting the human winglessrelated mouse mammary tumour virus integration site 2 led to considerably slower growth and a substantial delay in cell doubling time.118 these studies show that rna-based therapies hold potential for treating keloids. conclusion although a plethora of therapeutic options are now available for keloids, they still remain an ongoing clinical challenge for both patients and clinicians. given the complex process of keloid formation, a deeper understanding of the molecular mechanisms that drive development and recurrence of keloids would open further avenues for developing innovative treatments. several promising therapeutic approaches, such as the use of mesenchymal stem cells, autologous fat grafting, microneedle physical contact and rnabased therapies, are currently underway. nevertheless, there is still a great need for high-quality rcts with sufficient sample sizes. a u t h o r s’ c o n t r i b u t i o n s all authors contributed equally for writing and revision of this manuscript. the authors reviewed and approved the final submitted manuscript. references 1. mari w, alsabri sg, tabal n, younes s, sherif a, simman r. novel insights on understanding of keloid scar: article review. j am coll clin wound spec 2016; 7:1–7. https://doi.org/10.10 16/j.jccw.2016.10.001. 2. chodon t, sugihara t, igawa hh, funayama e, furukawa h. keloid-derived fibroblasts are refractory to fas-mediated apop tosis and neutralization of autocrine transforming growth factor beta1 can abrogate this resistance. am j pathol 2000; 157:1661–9. https://doi.org/10.1016/s0002-9440(10)64803-1. 3. porter jp. treatment of the keloid: what is new? otolaryngol clin north am 2002; 35:207–20. https://doi.org/10.1016/s003 0-6665(03)00103-8. 4. bran gm, goessler ur, hormann k, riedel f, sadick h. keloids: current concepts of pathogenesis (review). int j mol med 2009; 24:283–93. https://doi.org/10.3892/ijmm_00000231. 5. marttala j, andrews jp, rosenbloom j, uitto j. keloids: animal models and pathologic equivalents to study tissue fibrosis. matrix biol 2016; 51:47–54. https://doi.org/10.1016/j.matbio.2016.01.014. https://doi.org/10.1016/j.jccw.2016.10.001 https://doi.org/10.1016/j.jccw.2016.10.001 https://doi.org/10.1016/s0002-9440%2810%2964803-1 https://doi.org/10.1016/s0030-6665%2803%2900103-8 https://doi.org/10.1016/s0030-6665%2803%2900103-8 https://doi.org/10.3892/ijmm_00000231 https://doi.org/10.1016/j.matbio.2016.01.014 emerging and novel therapies for keloids a compendious review e30 | squ medical journal, february 2021, volume 21, issue 1 6. berman b, bieley hc. adjunct therapies to surgical management of keloids. dermatol surg 1996; 22:126–30. https://doi.org/10.11 11/j.1524-4725.1996.tb00493.x. 7. cheng et, nowak kc, koch rj. effect of blended carbon dioxide and erbium: yag laser energy on preauricular and ear lobule keloid fibroblast secretion of growth factors: a serumfree study. arch facial plast surg 2001; 3:252–7. https://doi. org/10.1001/archfaci.3.4.252. 8. murray jc, pollack sv, pinnell sr. keloids: a review. j am acad dermatol 1981; 4:461–70. https://doi.org/10.1016/s01909622(81)70048-3. 9. ghazawi fm, zargham r, gilardino ms, sasseville d, jafarian f. insights into the pathophysiology of hypertrophic scars and keloids: how do they differ? adv skin wound care 2018; 31:582–95. https://doi.org/10.1097/01.asw.0000527576.27489.0f. 10. glass da 2nd. current understanding of the genetic causes of keloid formation. j investig dermatol symp proc 2017; 18:s50–3. https://doi.org/10.1016/j.jisp.2016.10.024. 11. child fj, fuller lc, higgins em, du vivier aw. a study of the spectrum of skin disease occurring in a black population in south-east london. br j dermatol 1999; 141:512–17. https://doi.org/10.1046/j.1365-2133.1999.03047.x. 12. jones cd, guiot l, samy m, gorman m, tehrani h. the use of chemotherapeutics for the treatment of keloid scars. dermatol reports 2015; 7:5880. https://doi.org/10.4081/dr.2015.5880. 13. lee yi, kim j, yang ce, hong jw, lee wj, lee jh. combined therapeutic strategies for keloid treatment. dermatol surg 2019; 45:802–10. https://doi.org/10.1097/dss.0000000000001695. 14. moravvej h, memariani m, memariani h. quercetin: a potential treatment for keloids. sultan qaboos univ med j 2019; 19:e372–3. https://doi.org/10.18295/squmj.2019.19.04.015. 15. mafong ea, ashinoff r. treatment of hypertrophic scars and keloids: a review. aesthetic surg j 2000; 20:114–21. https://doi. org/10.1067/maj.2000.106649. 16. betarbet u, blalock tw. keloids: a review of etiology, prevention, and treatment. j clin aesthet dermatol 2020; 13:33–43. 17. national institute for health and clinical excellence (nice). from: http://www.nice.org.uk/ accessed: jul 2020. 18. stewart j, glass 2nd da. plasma angiotensin-converting enzyme levels in patients with keloids and/or hypertension. wounds 2018; 30:e71–2. 19. morihara k, takai s, takenaka h, sakaguchi m, okamoto y, morihara t, et al. cutaneous tissue angiotensin-converting enzyme may participate in pathologic scar formation in human skin. j am acad dermatol 2006; 54:251–7. https://doi.org/10.1016/j. jaad.2005.09.027. 20. ogawa r, arima j, ono s, hyakusoku h. case rep ort total management of a severe case of systemic keloids associated with high blood pressure (hypertension): clinical symptoms of keloids may be aggravated by hypertension. eplasty 2013; 13:e25. 21. niazi f, hooshyar sh, hedayatyanfard k, ziai sa, doroodgar f, niazi s, et al. detection of angiotensin ii and at1 receptor concentrations in keloid and hypertrophic scar. j clin aesthet dermatol 2018; 11:36–9. 22. hedayatyanfard k, ziai sa, niazi f, habibi i, habibi b, moravvej h. losartan ointment relieves hypertrophic scars and keloid: a pilot study. wound repair regen 2018; 26:340–3. https://doi. org/10.1111/wrr.12648. 23. ardekani gs, aghaei s, nemati mh, handjani f, kasraee b. treatment of a postburn keloid scar with topical captopril: report of the first case. plast reconstr surg 2009; 123:112e–3. https://doi.org/10.1097/prs.0b013e31819a34db. 24. fang qq, wang xf, zhao wy, ding sl, shi bh, xia y, et al. angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical tgfβ1 pathways. sci rep 2018; 8:3332. https://doi.org/10.1038/s41598-018-21600-w. 25. iannello s, milazzo p, bordonaro f, belfiore f. low-dose enalapril in the treatment of surgical cutaneous hypertrophic scar and keloid--two case reports and literature review. medgenmed 2006; 8:60. 26. uzun h, bitik o, hekimoğlu r, atilla p, kayikçioğlu au. angio tensin-converting enzyme inhibitor enalapril reduces formation of hypertrophic scars in a rabbit ear wounding model. plast reconstr surg 2013; 132:e361–71. https://doi.org/10.1097/prs.0 b013e31829acf0a. 27. bergson p, lipkind g, lee sp, duban me, hanck da. verapamil block of t-type calcium channels. mol pharmacol 2011; 79:411–19. https://doi.org/10.1124/mol.110.069492. 28. margaret shanthi fx, ernest k, dhanraj p. comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids. indian j dermatol venereol leprol 2008; 74:343–8. https://doi.org/10.4103/03786323.42899. 29. danielsen pl, rea sm, wood fm, fear mw, viola hm, hool lc, et al. verapamil is less effective than triamcinolone for prevention of keloid scar recurrence after excision in a randomized controlled trial. acta derm venereol 2016; 96:774–8. https://doi.org/10.2340/00015555-2384. 30. kant sb, van den kerckhove e, colla c, tuinder s, van der hulst rrwj, piatkowski de grzymala aa. a new treatment of hypertrophic and keloid scars with combined triamcinolone and verapamil: a retrospective study. eur j plast surg 2018; 41:69–80. https://doi.org/10.1007/s00238-017-1322-y. 31. lawrence wt. treatment of earlobe keloids with surgery plus adjuvant intralesional verapamil and pressure earrings. ann plast surg 1996; 37:167–9. https://doi.org/10.1097/00000637199608000-00008. 32. el-kamel mf, selim mk, alghobary mf. keloidectomy with core fillet flap and intralesional verapamil injection for recurrent earlobe keloids. indian j dermatol venereol leprol 2016; 82:659–65. https://doi.org/10.4103/0378-6323.187084. 33. chen s. clinical uses of botulinum neurotoxins: current indications, limitations and future developments. toxins (basel) 2012; 4:913–39. https://doi.org/10.3390/toxins4100913. 34. austin e, koo e, jagdeo j. the cellular response of keloids and hypertrophic scars to botulinum toxin a: a comprehensive literature review. dermatol surg 2018; 44:149–57. https://doi. org/10.1097/dss.0000000000001360. 35. gauglitz gg, bureik d, dombrowski y, pavicic t, ruzicka t, schauber j. botulinum toxin a for the treatment of keloids. skin pharmacol physiol 2012; 25:313–18. https://doi.org/10.1159/000342125. 36. lee hj, jang yj. recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids. int j mol sci 2018; 19:711. https://doi.org/10.3390/ijms19030711. 37. viera mh, amini s, valins w, berman b. innovative therapies in the treatment of keloids and hypertrophic scars. j clin aesthet dermatol 2010; 3:20–6. 38. zhibo x, miaobo z. intralesional botulinum toxin type a injection as a new treatment measure for keloids. plast reconstr surg 2009; 124:e275–7. https://doi.org/10.1097/prs.0b013e3181b98ee7. 39. shaarawy e, hegazy ra, abdel hay rm. intralesional botulinum toxin type a equally effective and better tolerated than intra lesional steroid in the treatment of keloids: a randomized controlled trial. j cosmet dermatol 2015; 14:161–6. https://doi. org/10.1111/jocd.12134. 40. pruksapong c, yingtaweesittikul s, burusapat c. efficacy of botulinum toxin a in preventing recurrence keloids: double blinded randomized controlled trial study: intraindividual subject. j med assoc thai 2017; 100:280–6. 41. rasaii s, sohrabian n, gianfaldoni s, hadibarhaghtalab m, pazyar n, bakhshaeekia a, et al. intralesional triamcinolone alone or in combination with botulinium toxin a is ineffective for the treatment of formed keloid scar: a double blind controlled pilot study. dermatol ther 2019; 32:e12781. https://doi.org/10.1111/dth.12781. https://doi.org/10.1111/j.1524-4725.1996.tb00493.x https://doi.org/10.1111/j.1524-4725.1996.tb00493.x https://doi.org/10.1001/archfaci.3.4.252 https://doi.org/10.1001/archfaci.3.4.252 https://doi.org/10.1016/s0190-9622%2881%2970048-3 https://doi.org/10.1016/s0190-9622%2881%2970048-3 https://doi.org/10.1097/01.asw.0000527576.27489.0f https://doi.org/10.1016/j.jisp.2016.10.024 https://doi.org/10.1046/j.1365-2133.1999.03047.x https://doi.org/10.4081/dr.2015.5880 https://doi.org/10.1097/dss.0000000000001695 https://doi.org/10.18295/squmj.2019.19.04.015 https://doi.org/10.1067/maj.2000.106649 https://doi.org/10.1067/maj.2000.106649 https://doi.org/10.1016/j.jaad.2005.09.027 https://doi.org/10.1016/j.jaad.2005.09.027 https://doi.org/10.1111/wrr.12648 https://doi.org/10.1111/wrr.12648 https://doi.org/10.1097/prs.0b013e31819a34db https://doi.org/10.1097/prs.0b013e31829acf0a https://doi.org/10.1097/prs.0b013e31829acf0a https://doi.org/10.1124/mol.110.069492 https://doi.org/10.4103/0378-6323.42899 https://doi.org/10.4103/0378-6323.42899 https://doi.org/10.2340/00015555-2384 https://doi.org/10.1007/s00238-017-1322-y https://doi.org/10.1097/00000637-199608000-00008 https://doi.org/10.1097/00000637-199608000-00008 https://doi.org/10.4103/0378-6323.187084 https://doi.org/10.3390/toxins4100913 https://doi.org/10.1097/dss.0000000000001360 https://doi.org/10.1097/dss.0000000000001360 https://doi.org/10.1159/000342125 https://doi.org/10.3390/ijms19030711 https://doi.org/10.1097/prs.0b013e3181b98ee7 https://doi.org/10.1111/jocd.12134 https://doi.org/10.1111/jocd.12134 https://doi.org/10.1111/dth.12781 hamed memariani, mojtaba memariani, hamideh moravvej and mohammad shahidi-dadras review | e31 42. batifol d, de boutray m, galmiche s, finiels pj, jammet p. treatment of keloid scars by botulinum toxin. j ear nose throat disord 2017; 2:1024. 43. bi m, sun p, li d, dong z, chen z. intralesional injection of botulinum toxin type a compared with intralesional injection of corticosteroid for the treatment of hypertrophic scar and keloid: a systematic review and meta-analysis. med sci monit 2019; 25:2950–8. https://doi.org/10.12659/msm.916305. 44. sohrabi c, goutos i. the use of botulinum toxin in keloid scar management: a literature review. scars burn heal 2020; 6:2059513120926628. https://doi.org/10.1177/2059513120926628. 45. thell k, hellinger r, schabbauer g, gruber cw. immuno suppressive peptides and their therapeutic applications. drug discov today 2014; 19:645–53. https://doi.org/10.1016/j.drudis.2013.12.002. 46. viera mh, vivas ac, berman b. update on keloid manage ment: clinical and basic science advances. adv wound care (new rochelle) 2012; 1:200–6. https://doi.org/10.1089/wound.2011.0313. 47. kelly ap. medical and surgical therapies for keloids. dermatol ther 2004; 17:212–18. https://doi.org/10.1111/j.1396-0296.200 4.04022.x. 48. nasr is. topical tacrolimus in dermatology. clin exp dermatol 2000; 25:250–4. https://doi.org/10.1046/j.1365-2230.2000.00628.x. 49. wu cs, wu ph, fang ah, lan cc. fk506 inhibits the enhancing effects of transforming growth factor (tgf)β1 on collagen expression and tgf-β/smad signalling in keloid fibroblasts: implication for new therapeutic approach. br j dermatol 2012; 167:532–41. https://doi.org/10.1111/j.1365-2133.2012.11023.x. 50. kim a, dicarlo j, cohen c, mccall c, johnson d, mcalpine b, et al. are keloids really "gli-loids"?: high-level expression of gli1 oncogene in keloids. j am acad dermatol 2001; 45:707–11. https://doi.org/10.1067/mjd.2001.117736. 51. menezes mcs, vasconcellos ls, nunes cb, alberti lr. evaluation of the use of tacrolimus ointment for the prevention of hyper trophic scars in experimental model. an bras dermatol 2019; 94:164–71. https://doi.org/10.1590/abd1806-4841.20197490. 52. berman b, poochareon v, villa am. an open-label pilot study to evaluate the safety and tolerability of tacrolimus ointment 0.1% for the treatment of keloids. cos derm 2005; 18:399–404. 53. borzykh ya. the efficacy of topical tacrolimus in complex treat ment of keloids. 2014; 15:50–2. https://doi.org/10.22141/16081706.1.15.2014.81264. 54. sehgal sn. sirolimus: its discovery, biological properties, and mechanism of action. transplant proc 2003; 35:s7–14. https://doi.org/10.1016/s0041-1345(03)00211-2. 55. ong ct, khoo yt, mukhopadhyay a, do dv, lim ij, aalami o, et al. mtor as a potential therapeutic target for treatment of keloids and excessive scars. exp dermatol 2007; 16:394-404. https://doi.org/10.1111/j.1600-0625.2007.00550.x. 56. shegogue d, trojanowska m. mammalian target of rapamycin positively regulates collagen type i production via a phos phatidylinositol 3-kinase-independent pathway. j biol chem 2004; 279:23166–75. https://doi.org/10.1074/jbc.m401238200. 57. park j, ha h, ahn hj, kang sw, kim ys, seo jy, et al. sirolimus inhibits platelet-derived growth factor-induced collagen synthesis in rat vascular smooth muscle cells. transplant proc 2005; 37:3459–62. https://doi.org/10.1016/j.transproceed.2005.09.066. 58. thorn cf, oshiro c, marsh s, hernandez-boussard t, mcleod h, klein te, et al. doxorubicin pathways: pharmacodynamics and adverse effects. pharmacogenet genomics 2011; 21:440–6. https://doi.org/10.1097/fpc.0b013e32833ffb56. 59. tacar o, sriamornsak p, dass cr. doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. j pharm pharmacol 2013; 65:157–70. https://doi. org/10.1111/j.2042-7158.2012.01567.x. 60. muszyńska a, pałka j, wołczyński s. doxorubicin-induced inhib ition of prolidase activity in human skin fibroblasts and its implic ation to impaired collagen biosynthesis. pol j pharmacol 1998; 50:151–7. 61. sasaki t, holeyfield kc, uitto j. doxorubicin-induced inhibition of prolyl hydroxylation during collagen biosynthesis in human skin fibroblast cultures. relevance to impaired wound healing. j clin invest 1987; 80:1735–41. https://doi.org/10.1172/jci113265. 62. berman b, maderal a, raphael b. keloids and hypertrophic scars: pathophysiology, classification, and treatment. dermatol surg 2017; 43:s3–18. https://doi.org/10.1097/dss.0000000000000819. 63. perry d, colthurst j, giddings p, mcgrouther da, morris j, bayat a. treatment of symptomatic abnormal skin scars with electrical stimulation. j wound care 2010; 19:447–53. https://doi.org/10.1 2968/jowc.2010.19.10.79092. 64. ud-din s, bayat a. electrical stimulation and cutaneous wound healing: a review of clinical evidence. healthcare (basel) 2014; 2:445–67. https://doi.org/10.3390/healthcare2040445. 65. ud-din s, giddings dip p, colthurst j, whiteside s, morris j, bayat a. significant reduction of symptoms of scarring with electrical stimulation: evaluated with subjective and objective assessment tools in a prospective noncontrolled case series. wounds 2013; 25:212–24. 66. sebastian a, allan e, allan d, colthurst j, bayat a. addition of novel degenerate electrical waveform stimulation with photo dynamic therapy significantly enhances its cytotoxic effect in keloid fibroblasts: first report of a potential combination therapy. j dermatol sci 2011; 64:174–84. https://doi.org/10.10 16/j.jdermsci.2011.08.012. 67. nicoletti g, perugini p, bellino s, capra p, malovini a, jaber o, et al. scar remodeling with the association of monopolar capacitive radiofrequency, electric stimulation, and negative pressure. photomed laser surg 2017; 35:246–58. https://doi.org/10.1089/pho.2016.4180. 68. waghule t, singhvi g, dubey sk, pandey mm, gupta g, singh m, et al. microneedles: a smart approach and increasing potential for transdermal drug delivery system. biomed pharmacother 2019; 109:1249–58. https://doi.org/10.1016/j.biopha.2018.10.078. 69. tan cwx, tan wd, srivastava r, yow ap, wong dwk, tey hl. dissolving triamcinolone-embedded microneedles for the treat ment of keloids: a single-blinded intra-individual controlled clinical trial. dermatol ther (heidelb) 2019; 9:601–11. https:// doi.org/10.1007/s13555-019-00316-3. 70. yeo dc, balmayor er, schantz jt, xu cj. microneedle physical contact as a therapeutic for abnormal scars. eur j med res 2017; 22:28. https://doi.org/10.1186/s40001-017-0269-6. 71. xue p, yeo dcl, chuah yj, tey hl, kang y, xu cj. drugeluting microneedles for self-administered treatment of keloids. technology 2014; 2:144–52. https://doi.org/10.1142/s2339547 814500137. 72. marasca c, ruggiero a, marasca d, megna m, fabbrocini g. skin needling in combination with antimicrobial peptides for the treatment of keloids: a novel perspective proposal and approach for skin scars. dermatology 2020; 236:601–2. https:// doi.org/10.1159/000507927. 73. moravvej h, memariani m, memariani h, robati rm, gheisari m. can antimicrobial peptides be repurposed as a novel therapy for keloids? dermatology 2020; 20:1–3. https://doi.org/10.11 59/000506831. 74. reilly jm, bluman e, tenforde as. effect of shockwave treat ment for management of upper and lower extremity musculo skeletal conditions: a narrative review. pm&r 2018; 10:1385–403. https://doi.org/10.1016/j.pmrj.2018.05.007. 75. romeo p, lavanga v, pagani d, sansone v. extracorporeal shock wave therapy in musculoskeletal disorders: a review. med princ pract 2014; 23:7–13. https://doi.org/10.1159/000355472. 76. zhang l, weng c, zhao z, fu x. extracorporeal shock wave therapy for chronic wounds: a systematic review and metaanalysis of randomized controlled trials. wound repair regen 2017; 25:697–706. https://doi.org/10.1111/wrr.12566. 77. hitchman lh, totty jp, raza a, cai p, smith ge, carradice d, et al. extracorporeal shockwave therapy for diabetic foot ulcers: a systematic review and meta-analysis. ann vasc surg 2019; 56:330–9. https://doi.org/10.1016/j.avsg.2018.10.013. https://doi.org/10.12659/msm.916305 https://doi.org/10.1177/2059513120926628 https://doi.org/10.1016/j.drudis.2013.12.002 https://doi.org/10.1089/wound.2011.0313 https://doi.org/10.1111/j.1396-0296.2004.04022.x https://doi.org/10.1111/j.1396-0296.2004.04022.x https://doi.org/10.1046/j.1365-2230.2000.00628.x https://doi.org/10.1111/j.1365-2133.2012.11023.x https://doi.org/10.1067/mjd.2001.117736 https://doi.org/10.1590/abd1806-4841.20197490 https://doi.org/10.22141/1608-1706.1.15.2014.81264 https://doi.org/10.22141/1608-1706.1.15.2014.81264 https://doi.org/10.1016/s0041-1345%2803%2900211-2 https://doi.org/10.1111/j.1600-0625.2007.00550.x https://doi.org/10.1074/jbc.m401238200 https://doi.org/10.1016/j.transproceed.2005.09.066 https://doi.org/10.1097/fpc.0b013e32833ffb56 https://doi.org/10.1111/j.2042-7158.2012.01567.x https://doi.org/10.1111/j.2042-7158.2012.01567.x https://doi.org/10.1172/jci113265 https://doi.org/10.1097/dss.0000000000000819 https://doi.org/10.12968/jowc.2010.19.10.79092 https://doi.org/10.12968/jowc.2010.19.10.79092 https://doi.org/10.3390/healthcare2040445 https://doi.org/10.1016/j.jdermsci.2011.08.012 https://doi.org/10.1016/j.jdermsci.2011.08.012 https://doi.org/10.1089/pho.2016.4180 https://doi.org/10.1016/j.biopha.2018.10.078 https://doi.org/10.1007/s13555-019-00316-3 https://doi.org/10.1007/s13555-019-00316-3 https://doi.org/10.1186/s40001-017-0269-6 https://doi.org/10.1142/s2339547814500137 https://doi.org/10.1142/s2339547814500137 https://doi.org/10.1159/000507927 https://doi.org/10.1159/000507927 https://doi.org/10.1159/000506831 https://doi.org/10.1159/000506831 https://doi.org/10.1016/j.pmrj.2018.05.007 https://doi.org/10.1159/000355472 https://doi.org/10.1111/wrr.12566 https://doi.org/10.1016/j.avsg.2018.10.013 emerging and novel therapies for keloids a compendious review e32 | squ medical journal, february 2021, volume 21, issue 1 78. taheri p, khosrawi s, mazaheri m, parsa ma, mokhtarian a. effect of extracorporeal shock wave therapy on improving burn scar in patients with burnt extremities in isfahan, iran. j res med sci 2018; 23:81. https://doi.org/10.4103/jrms.jrms_681_17. 79. fioramonti p, cigna e, onesti mg, fino p, fallico n, scuderi n. extracorporeal shock wave therapy for the management of burn scars. dermatol surg 2012; 38:778–82. https://doi.org/10.1111/ j.1524-4725.2012.02355.x. 80. wang cj, ko jy, chou wy, cheng jh, kuo yr. extracorporeal shockwave therapy for treatment of keloid scars. wound repair regen 2018; 26:69–76. https://doi.org/10.1111/wrr.12610. 81. cui hs, hong ar, kim jb, yu jh, cho ys, joo sy, et al. extra corporeal shock wave therapy alters the expression of fibrosis related molecules in fibroblast derived from human hypertrophic scar. int j mol sci 2018; 19:124. https://doi.org/10.3390/ijms19010124. 82. klinger m, marazzi m, vigo d, torre m. fat injection for cases of severe burn outcomes: a new perspective of scar remodeling and reduction. aesthetic plast surg 2008; 32:465–9. https://doi. org/10.1007/s00266-008-9122-1. 83. brongo s, nicoletti gf, la padula s, mele cm, d'andrea f. use of lipofilling for the treatment of severe burn outcomes. plast reconstr surg 2012; 130:e374–6. https://doi.org/10.1097/ prs.0b013e3182590387. 84. silva vz, albacete a neto, horácio gs, andrade ga, procópio ld, coltro ps, et al. evidences of autologous fat grafting for the treat ment of keloids and hypertrophic scars. rev assoc med bras (1992) 2016; 62:862–6. https://doi.org/10.1590/1806-9282.62.09.862. 85. seo bf, jung sn. the immunomodulatory effects of mesenchymal stem cells in prevention or treatment of excessive scars. stem cells int 2016; 2016:6937976. https://doi.org/10.1155/2016/6937976. 86. zhang q, liu ln, yong q, deng jc, cao wg. intralesional injection of adipose-derived stem cells reduces hypertrophic scarring in a rabbit ear model. stem cell res ther 2015; 6:145. https://doi.org/10.1186/s13287-015-0133-y. 87. li y, zhang w, gao j, liu j, wang h, li j, et al. adipose tissuederived stem cells suppress hypertrophic scar fibrosis via the p38/mapk signaling pathway. stem cell res ther 2016; 7:102. https://doi.org/10.1186/s13287-016-0356-6. 88. wang x, ma y, gao z, yang j. human adipose-derived stem cells inhibit bioactivity of keloid fibroblasts. stem cell res ther 2018; 9:40. https://doi.org/10.1186/s13287-018-0786-4. 89. fang f, huang rl, zheng y, liu m, huo r. bone marrow derived mesenchymal stem cells inhibit the proliferative and profibrotic phenotype of hypertrophic scar fibroblasts and keloid fibroblasts through paracrine signaling. j dermatol sci 2016; 83:95–105. https://doi.org/10.1016/j.jdermsci.2016.03.003. 90. craft n, birnbaum r, quanquin n, erfe mcb, quant c, haskell j, et al. topical resiquimod protects against visceral infection with leishmania infantum chagasi in mice. clin vaccine immunol 2014; 21:1314–22. https://doi.org/10.1128/cvi.00338-14. 91. del rosso jq. the use of topical imiquimod for the treatment of actinic keratosis: a status report. cutis 2005; 76:241–8. 92. berman b, kaufman j. pilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids. j am acad dermatol 2002; 47:s209–11. https://doi.org/10.1067/ mjd.2002.126585. 93. chuangsuwanich a, gunjittisomram s. the efficacy of 5% imiquimod cream in the prevention of recurrence of excised keloids. j med assoc thai 2007; 90:1363–7. 94. martín-garcía rf. imiquimod: an effective alternative for the treatment of invasive cutaneous squamous cell carcinoma. dermatol surg 2005; 31:371–4. https://doi.org/10.1111/j.1524-47 25.2005.31093. 95. stashower me. successful treatment of earlobe keloids with imiquimod after tangential shave excision. dermatol surg 2006; 32:380–6. https://doi.org/10.1111/j.1524-4725.2006.32077.x. 96. berman b, harrison-balestra c, perez oa, viera m, villa a, zell d, et al. treatment of keloid scars post-shave excision with imiquimod 5% cream: a prospective, double-blind, placebocontrolled pilot study. j drugs dermatol 2009; 8:455–8. 97. cação fm, tanaka v, messina mc. failure of imiquimod 5% cream to prevent recurrence of surgically excised trunk keloids. dermatol surg 2009; 35:629–33. https://doi.org/10.1111/j.152 4-4725.2009.01101.x. 98. lin wc, liou sh, kotsuchibashi y. development and character isation of the imiquimod poly(2-(2-methoxyethoxy)ethyl metha crylate) hydrogel dressing for keloid therapy. polymers (basel) 2017; 9:579. https://doi.org/10.3390/polym9110579. 99. wolfram d, tzankov a, pülzl p, piza-katzer h. hypertrophic scars and keloids--a review of their pathophysiology, risk factors, and therapeutic management. dermatol surg 2009; 35:171–81. https://doi.org/10.1111/j.1524-4725.2008.34406.x. 100. shridharani sm, magarakis m, manson pn, singh nk, basdag b, rosson gd. the emerging role of antineoplastic agents in the treatment of keloids and hypertrophic scars: a review. ann plast surg 2010; 64:355–61. https://doi.org/10.1097/sap.0b013e3181afaab0. 101. yokozeki m, baba y, shimokawa h, moriyama k, kuroda t. interferon-gamma inhibits the myofibroblastic phenotype of rat palatal fibroblasts induced by transforming growth factor-beta1 in vitro. febs lett 1999; 442:61–4. https://doi.org/10.1016/ s0014-5793(98)01626-3. 102. nedelec b, shen yj, ghahary a, scott pg, tredget ee. the effect of interferon alpha 2b on the expression of cytoskeletal proteins in an in vitro model of wound contraction. j lab clin med 1995; 126:474–84. 103. espinassouze f, heid e, grosshans e. [treatment of keloid by intralesional injections of interferon alfa-2b]. ann dermatol venereol 1993; 120:629–30. 104. wong tw, chiu hc, yip km. intralesional interferon alpha-2b has no effect in the treatment of keloids. br j dermatol 1994; 130:683–5. https://doi.org/10.1111/j.1365-2133.1994.tb13125.x. 105. al-khawajah mm. failure of interferon-alpha 2b in the treatment of mature keloids. int j dermatol 1996; 35:515–17. https://doi.org/10.1111/j.1365-4362.1996.tb01671.x. 106. berman b, flores f. recurrence rates of excised keloids treated with postoperative triamcinolone acetonide injections or interferon alfa-2b injections. j am acad dermatol 1997; 37:755–7. https://doi.org/10.1016/s0190-9622(97)70113-0. 107. lee jh, kim se, lee ay. effects of interferon-alpha2b on keloid treatment with triamcinolone acetonide intralesional injection. int j dermatol 2008; 47:183–6. https://doi.org/10.1111/j.13654632.2008.03426.x. 108. shagufta, ahmad i. tamoxifen a pioneering drug: an update on the therapeutic potential of tamoxifen derivatives. eur j med chem 2018; 143:515–31. https://doi.org/10.1016/j.ejmech.2017.11.056. 109. mancoll js, zhao j, mccauley rl, phillips lg. the inhibitory effect of tamoxifen on keloid fibroblasts. surg forum 1996; 47:718–20. 110. hu d, hughes ma, cherry gw. topical tamoxifen--a potential therapeutic regime in treating excessive dermal scarring? br j plast surg 1998; 51:462–9. https://doi.org/10.1054/bjps.1997.0100. 111. mikulec aa, hanasono mm, lum j, kadleck jm, kita m, koch rj. effect of tamoxifen on transforming growth factor beta1 production by keloid and fetal fibroblasts. arch facial plast surg 2001; 3:111–14. https://doi.org/10.1001/archfaci.3.2.111. 112. mehrvarz s, ebrahimi a, sahraei h, bagheri mh, fazili s, manoochehry s, et al. effects of topical tamoxifen on wound healing of burned skin in rats. arch plast surg 2017; 44:378–83. https://doi.org/10.5999/aps.2017.44.5.378. 113. pasquetti af, mota wn, dos santos mr, de farias brito hl. uso do tamoxifeno no tratamento de queloides e cicatrizes hipertroficas. bjps 2010; 25:372–8. https://doi.org/10.4103/jrms.jrms_681_17 https://doi.org/10.1111/j.1524-4725.2012.02355.x https://doi.org/10.1111/j.1524-4725.2012.02355.x https://doi.org/10.1111/wrr.12610 https://doi.org/10.3390/ijms19010124 https://doi.org/10.1007/s00266-008-9122-1 https://doi.org/10.1007/s00266-008-9122-1 https://doi.org/10.1097/prs.0b013e3182590387 https://doi.org/10.1097/prs.0b013e3182590387 https://doi.org/10.1590/1806-9282.62.09.862 https://doi.org/10.1155/2016/6937976 https://doi.org/10.1186/s13287-015-0133-y https://doi.org/10.1186/s13287-016-0356-6 https://doi.org/10.1186/s13287-018-0786-4 https://doi.org/10.1016/j.jdermsci.2016.03.003 https://doi.org/10.1128/cvi.00338-14 https://doi.org/10.1067/mjd.2002.126585 https://doi.org/10.1067/mjd.2002.126585 https://doi.org/10.1111/j.1524-4725.2005.31093 https://doi.org/10.1111/j.1524-4725.2005.31093 https://doi.org/10.1111/j.1524-4725.2006.32077.x https://doi.org/10.1111/j.1524-4725.2009.01101.x https://doi.org/10.1111/j.1524-4725.2009.01101.x https://doi.org/10.3390/polym9110579 https://doi.org/10.1111/j.1524-4725.2008.34406.x https://doi.org/10.1097/sap.0b013e3181afaab0 https://doi.org/10.1016/s0014-5793%2898%2901626-3 https://doi.org/10.1016/s0014-5793%2898%2901626-3 https://doi.org/10.1111/j.1365-2133.1994.tb13125.x https://doi.org/10.1111/j.1365-4362.1996.tb01671.x https://doi.org/10.1016/s0190-9622%2897%2970113-0 https://doi.org/10.1111/j.1365-4632.2008.03426.x https://doi.org/10.1111/j.1365-4632.2008.03426.x https://doi.org/10.1016/j.ejmech.2017.11.056 https://doi.org/10.1054/bjps.1997.0100 https://doi.org/10.1001/archfaci.3.2.111 https://doi.org/10.5999/aps.2017.44.5.378 hamed memariani, mojtaba memariani, hamideh moravvej and mohammad shahidi-dadras review | e33 114. soares-lopes lr, soares-lopes im, filho ll, alencar ap, da silva bb. morphological and morphometric analysis of the effects of intralesional tamoxifen on keloids. exp biol med (maywood) 2017; 242:926–9. https://doi.org/10.1177/1535370217700524. 115. wang z, gao z, shi y, sun y, lin z, jiang h, et al. inhibition of smad3 expression decreases collagen synthesis in keloid disease fibroblasts. j plast reconstr aesthet surg 2007; 60:1193–9. https://doi.org/10.1016/j.bjps.2006.05.007. 116. aoki m, miyake k, ogawa r, dohi t, akaishi s, hyakusoku h, et al. sirna knockdown of tissue inhibitor of metalloproteinase-1 in keloid fibroblasts leads to degradation of collagen type i. j invest dermatol 2014; 134:818–26. https://doi.org/10.1038/ jid.2013.396. 117. shin ju, lee wj, tran tn, jung i, lee jh. hsp70 knockdown by sirna decreased collagen production in keloid fibroblasts. yonsei med j 2015; 56:1619–26. https://doi.org/10.3349/ ymj.2015.56.6.1619. 118. cai y, yang w, pan m, wang c, wu w, zhu s. wnt2 knock down by rnai inhibits the proliferation of in vitro-cultured human keloid fibroblasts. medicine (baltimore) 2018; 97:e12167. https://doi.org/10.1097/md.0000000000012167. https://doi.org/10.1177/1535370217700524 https://doi.org/10.1016/j.bjps.2006.05.007 https://doi.org/10.1038/jid.2013.396 https://doi.org/10.1038/jid.2013.396 https://doi.org/10.3349/ymj.2015.56.6.1619 https://doi.org/10.3349/ymj.2015.56.6.1619 https://doi.org/10.1097/md.0000000000012167 clinical & basic research squ med j, december 2010, vol. 10, iss. 3, pp. 361-369, epub. 14th nov 10 submitted 27th feb 10 revision req. 7th july 10, revision recd. 15th july 10 accepted 19th sept 10 1al-salaam hospital, mosul city, iraq; 2department of pharmacology, mosul college of medicine, university of mosul, mosul city, iraq *corresponding author email: imadpharma@yahoo.com <çëç£]<<ôájä⁄ê<<ti<í◊¬^àj÷]<∞iê2÷]<hçä“`j◊÷<<ïå^ñπ]<ì÷^£] îáòü÷]<·öçj÷]<óïü⁄<ª عماد عبد اجلبار ذنون، ضياء احمد طه      150 75  275 400         abstract: objectives: the objective of this study was to evaluate the influence of acute pulmonary tuberculosis and the effect of drug therapy on markers of oxidative stress (malondialdehyde [mda] and total antioxidant status [tas]), c-reactive protein (crp) and iron body status indices. methods: forty patients with active pulmonary tuberculosis from the advisory clinic for chest and respiratory diseases in mosul city, iraq,were included in this study, with fifty healthy age and sex matched subjects as controls. assessment of serum concentrations of mda, tas, crp, serum iron, total iron binding capacity, transferring saturation percent and ferritin were done for both patients and controls. after two months of therapy with a daily dose of isoniazid 75 mg, rifampicin 150mg, pyraziamide 400 mg, and ethambutol 275 mg, the same parameters were reassessed for the patients. results: after two months of therapy, there was a significant reduction in the levels of mda, crp, and ferritin, with a significant increase in the tas, serum iron, and transferring saturation percentage with an insignificant effect on the total iron binding capacity in comparison with the patients’ pre-therapy values. conclusion: active pulmonary tuberculosis is associated with oxidative stress; the increase in the levels of crp indicated that pulmonary tuberculosis is associated with an inflammatory response. the initial two months therapy led to significant improvement in oxidative stress and suppression of inflammatory responses. newly diagnosed cases of pulmonary tuberculosis often had chronic anaemia of inflammation, but this therapy resulted in a significant correction of such anaemia. keywords: pulmonary tuberculosis; oxidant/antioxidant status; c-reactive protein; iron status antioxidant status, c-reactive protein and iron status in patients with pulmonary tuberculosis dhia a taha1 and *imad a-j thanoon2 clinical & basic research advances in knowledge 1. newly diagnosed cases of pulmonary tuberculosis are associated with oxidative stress as indicated by enhanced lipid peroxidation (reflected in the malondialehyde level) and reduced total antioxidant status. 2. they are also associated with an intense inflammatory response as indicated by increase levels of acute phase protein c-reactive protein. antioxidant status, c-reactive protein and iron status in patients with pulmonary tuberculosis 362 | squ medical journal, december 2010, volume 10, issue 3 mycobacteria are capable of inducing reactive oxygen species production by activating both mononuclear and polymorphonuclear phagocytes that may possess antimicrobial activity. the enhanced level of free radical production, although designed to combat the invader, has the potential to damage the host; however, host tissue damage is limited by the concurrent enhancement of the antioxidant defences of the host.1 in tuberculosis (tb) patients, there are also some reports of poor antioxidants defence that may expose to oxidative host tissue damage.2,3 c-reactive protein (crp), an acute phase protein, is synthesised by hepatocytes in response to proinflammatory cytokines in particular il-6.4 crp has been reported to be significantly elevated in patients with active tuberculosis (tb), normalising over time on therapy, thereby correlating with clinical response.5,6 the physiological roles of crp are numerous, one of the critical functions being its importance in host defense. in the presence of calcium, crp specifically binds to polysaccharides such as phosphocholine moieties present on the cell surface of many pathogenic microbes.7 crp binding activates the classical complement pathway and initiates opsonization, phagocytosis, and lyses of invading cells. crp can also augment cell mediated cytotoxicity i.e. amplify the immune response.7 iron has a crucial role in tb infection. on the one hand, it influences both the innate and acquired immune response, and it is required for bacterial replication.8 indeed, iron levels can be a determining factor during infection because overload in human and mice results in exacerbation of the disease.9 the concentration in serum of iron and the iron-binding protein, transferrin, varies markedly in different pathological and physiological conditions. both concentrations (with transferrin being expressed as total iron-binding capacity) with or without serum ferritin are used in identifying various types of anaemia.10 both iron deficiency and anaemia of chronic inflammation may coexist in patients with pulmonary tuberculosis. chronic anaemia of inflammation has several features in common with iron deficiency anaemia, thus confusing the aetiological diagnosis. low serum iron and transferrin saturation percentages, characteristic laboratory findings of iron-deficiency anaemia, are also seen in chronic inflammatory anaemia.11 it is, therefore, difficult to establish the exact mechanism of associated anaemia in pulmonary tuberculosis patients by the routine investigations for diagnosis of anaemia. the aims of this study were to assess the influence of an initial two months of treatment on serum levels of lipid peroxidation products: malondialdehyde (mda), total antioxidant status (tas), crp, and indices of iron body status (serum iron, total iron binding capacity (tibc), transferrin saturation percentage, and serum ferritin) in patients with active pulmonary tb in comparison to controls. methods patients included in this study, which was undertaken from december 2007 to april 2008, were obtained from advisory clinic for chest and respiratory diseases in mosul city, iraq. the analytical work was performed in the department of pharmacology, college of medicine, at the university of mosul. approval was obtained from ethical committees of the main health centre in ninevah, mosul-city, and the college of medicine of the university of mosul, iraq. eligibility for entry into the study included typical symptoms of pulmonary tb: fibrocavitary lung infiltrate on chest radiograph and at least one sputum specimen staining positive with ziehl-neelsen for acid-fast bacilli. all patients included in the study were non-smokers and had no history of drug usage (including vitamins, iron, or antibiotics) at the time of initial assessment. they also had no history of blood transfusion in the previous 6 months and no recent history of blood loss. additional criteria for females included neither being pregnant nor lactating, nor 3. newly diagnosed cases of pulmonary tuberculosis often had chronic anaemia of inflammation, although the possibility of iron deficiency anaemia cannot be ruled out. application to patient care 1. initial therapy with antituberculosis drugs is very important to suppress oxidative stress, acute inflammation and chronic anaemia of inflammation in patients with active pulmonary tuberculosis. dhia a taha and imad a-j thanoon clinical and basic research | 363 menstruating at the time of blood collection. patients with a history of previous treatment for tuberculosis were not included in order to exclude those with previous lung fibrosis or infection with multidrugresistant tuberculosis. also, patients were excluded who had co-existing lung pathology, defined as a history of previous respiratory disease or clinical or radiological evidence of lung pathology other than tuberculosis, cardiac disease or metabolic problems including chronic liver disease, renal failure or diabetes mellitus. out of 48 patients interviewed and examined, only forty patients with active tb (29 males, 11 females, age range from 19-70 years), with a mean age of 39.95 ± 13.46 years consented to participate in this study. they were followed up for two months after receiving the initial course of antituberculosis drugs described below. fifty apparently healthy volunteers (36 males and 14 females, age range from 18–70 years), with a mean age of 43.88 ± 14.26 years, and with no previous history of tuberculosis, were recruited as controls to establish the normal values for mda, tas, crp, serum iron, total iron binding capacity, transferrin saturation percentage, and serum ferritin. after diagnosis, patients with pulmonary tuberculosis were treated according to the standard protocol at the advisory clinic. patients were given 4 tablets of rimstar®, a fixed-dose tablet containing 4 anti-tuberculosis drugs (isoniazid (inh) 75 mg, rifampicin 150 mg, pyraziamide 400 mg, ethambutol 275 mg) to be swallowed daily before breakfast for the initial two months. approximately 10 ml of venous blood was drawn using disposable plastic syringes from tuberculosis patients prior to initiation of antituberculosis treatment, and again at the end of the two month intensive phase of treatment, and transferred immediately into disposable plain tubes. the serum was separated after centrifugation of the blood and kept frozen at –20 oc to be analysed. blood samples from the healthy control subjects were collected and processed in the same way. serum mda levels were estimated using a thiobarbituric acid (tba) assay,12 and tas according to the method described by miller et al.,13 using a randox tas kit (randox laboratories ltd., antrim, uk). crp was determined semi-quantitatively by slide agglutination using a crp latex kit (chemelex, spain). serum iron was measured colorimetrically (direct method)14 using a ferene assay kit (biolabo reagents, france). tibc was measured using a ref 92308 assay kit (biolabo reagents, france). transferrin saturation percentage was calculated according to the following formula15: transferrin saturation % = serum iron concentration x 100 tibc finally, serum ferritin was measured, using the elfa technique (enzyme linked fluorescent assay), with vidas instrument, and a ferritin kit (both from bio merieux, france). the data of the study, subjected to statistical analysis, were expressed as mean ± standard deviation (sd). statistical comparisons were performed using the student’s t-test. the fisher-freeman-halton test was used to compare the results of crp of tuberculosis patients with the controls. the paired wilcoxon z-test was used to compare the results of crp in tuberculosis patients before and after therapy. linear regression analysis and pearson correlation coefficients(r), were performed to determine the relationships between different parameters. analysis of variance was performed for determining the relationships between crp and other parameters. a p-value of <0.05 was considered to be statistically significant. table 1: concentrations of malondialdehyde, total antioxidant status and iron body status indices in healthy controls and patients with pulmonary tuberculosis before and after therapy parameters control (n = 50) tb cases (n = 40) before therapy after therapy mda (µmol/l) 1.24 ± 0.17 3.18 ± 0.58*** 2.82 ± 0.60*** §§§ tas (mmol/l) 1.86 ± 0.30 1.06 ± 0.12*** 1.27 ± 0.11*** §§§ iron (µg/dl) 99.12 ± 27.5 55.73 ± 16.78*** 76.95 ± 2 8.29*** §§§ tibc (µg/dl) 397.1 ± 68.5 394.8 ± 148.7 376.7 ± 136.0 transferrin saturation % 25.58 ± 8.4 15.89 ± 7.0*** 21.37 ± 8.7* §§§ ferritin (ng/ ml) 183.1 ± 65.6 441.76 ± 319.4*** 185.64 ± 129.1 §§§ note: results are expressed as mean ± sd legend: mda = malondialdehyde; *** significant difference from control at p <0.001; tas = total antioxidant status; §§§ significant difference from before at p <0.001; tibc = serum iron, total iron binding capacity; * = significant difference from control at p <0.05. antioxidant status, c-reactive protein and iron status in patients with pulmonary tuberculosis 364 | squ medical journal, december 2010, volume 10, issue 3 results the serum levels of mda, tas, iron, total iron binding capacity, transferrin saturation percent, ferritin and crp from healthy subjects and patients with pulmonary tb before and after two months of therapy are shown in tables 1 and 2. the serum levels of mda were significantly higher (p <0.001) and tas were significantly lower (p <0.001) in patients with pulmonary tb before starting therapy in comparison with the control group. after two months of therapy, there was a highly significant reduction (p <0.001) in the serum mda with a highly significant increase (p <0.001) in the serum tas from initial pre-treatment levels. both serum iron and transferrin saturation percentages were significantly lower (p <0.001), and serum ferritin concentration was significantly higher (p <0.001) in patients with pulmonary tb before starting therapy in comparison with the control subjects. however, tibc showed insignificant differences compared to the control values. after two months therapy, there was highly significant elevation in the levels of serum iron (p <0.001) and transferrin saturation percentage (p <0.001) and a highly significant reduction in ferritin levels (p <0.001); however, tibc showed insignificant differences after therapy. as shown in table 2, the serum levels of crp were significantly higher (p <0.001) in patients with pulmonary tb before starting therapy in comparison with the control group and, after two months therapy, there was a highly significant reduction (p <0.001) in crp levels. regarding correlations between different biochemical parameters, figures 1, 2 and 3 show the relationships between mda, tas and serum ferritin in patients with pulmonary tb (before and after therapy) and in the control group. there was a highly significant negative correlation (r = -0.852; p <0.001) between serum mda and tas, a highly significant positive correlation (r = 0.348; p <0.001) between serum ferritin and mda and a highly significant negative correlation (r = -0.345; p <0.001) between serum ferritin and tas in patients with pulmonary tb (before and after therapy) and in the control group. tables 3, 4 and 5 show the relationships between crp, mda, tas and serum ferritin in patients with pulmonary tb (before and after therapy) and table 2: comparison of c-reactive protein (crp) concentrations between healthy controls and patients with pulmonary tuberculosis before and after therapy crp mg/l control (n = 50) before drug (n = 40) after drug (n = 40) no. % no. % no. % <6 39 78.0 0 0.0 12 30.0 6 9 18.0 6 15.0 19 47.5 12 2 4.0 11 27.5 7 17.5 24 0 0.0 10 25.0 2 5.0 48 0 0.0 4 10.0 0 0.0 96 0 0.0 9 22.5 0 0.0 p-value versus control <0.001 <0.001 y = -0.3499x + 2.2448 r = -0.852 p<0.001 0 0.5 1 1.5 2 2.5 3 0 1 2 3 4 5 mda (µmol/l) ta s (m m ol /l) before drug after drug control figure 1: relationship between mda and tas in the studied cases and control. legend: mda = malondialdehyde; tas = total antioxidant status dhia a taha and imad a-j thanoon clinical and basic research | 365 in the control group. there was a highly significant correlation between crp and mda, between crp and tas and between crp and serum ferritin in patients with pulmonary tb (before and after therapy) and in the control group. discussion in the present study, it was observed that the serum mda levels were significantly high and the antioxidant status was significantly low in newly diagnosed patients with pulmonary tb as compared to healthy controls. it was also observed that the administration of antimicrobial agents to such patients for a period of 2 months was associated with a significant reduction in mda concentrations and a significant increase in total antioxidant status. although considerable improvement was noted in these parameters, still there were significant differences from the control values. our finding of enhanced lipid peroxidation product and reduced tas provides evidence for the presence of oxidative stress in newly diagnosed patients with active pulmonary tuberculosis. furthermore, the decrease in levels of mda, with a concomitant increase in tas after two month of therapy seen in our study, may indicate a good response to therapy. plit et al. found that even after 6 months of successful chemotherapy, pulmonary tb is still associated with increased levels of circulating lipid peroxides and low plasma concentrations of vitamin e.3 these findings are in line with our results of significant differences in mda concentrations and tas between patients after two months of therapy and the control group which indicate that oxidative stress were ongoing even after two months of y = 0.0015x + 1.9244 r = 0.348 p<0.001 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 0 200 400 600 800 1000 1200 1400 ferritin (ng/ml) m d a (µ m ol /l) be fore drug afte r drug control figure 2: relationship between ferritin and mda in the studied cases and control. legend: mda = malondialdehyde y = -0.0006x + 1.594 r = 0.345 p<0.001 0 0.5 1 1.5 2 2.5 3 0 200 400 600 800 1000 1200 1400 ferritin (ng/ml) ta s (m m ol /l) before drug after drug control figure 3: relationship between ferritin and total antioxidant status in the studied cases and control legend: tas = total antioxidant status antioxidant status, c-reactive protein and iron status in patients with pulmonary tuberculosis 366 | squ medical journal, december 2010, volume 10, issue 3 chemotherapy. in an attempt to kill mycobacteria, host cells (namely macrophages, neutrophils and monocytes) generate huge amounts of reactive oxygen species (ros).16 one of the manifestations of these reactive species is lipid peroxidation. these high levels of reactive species are often cytotoxic and may cause host tissue damage such as lung fibrosis and lung dysfunction in patients with pulmonary tb if antioxidant defences of the host are deficient.17 malnutrition is more common in patients with pulmonary tb than in the healthy subjects, and could possibly explain the low levels of antioxidant potential. furthermore, patients with tuberculosis are unable to produce a sufficient amount of antioxidant to cope with their increased oxidative stress.18 in the present study, tas was measured instead of determining individual antioxidant enzymes and molecules. low levels of tas were observed in pulmonary tb. this might be due to malnutrition or exhaustion in an attempt to neutralise the heavy load of free radical in these patients. this study showed a highly significant negative correlation between serum mda levels and tas in patients with pulmonary tb (before and after therapy) and in the control group. this suggests increased utilisation by reactive oxygen species as an important contributing factor to the lower concentrations of antioxidants in tuberculosis patients.18,19 in fact, the combination of malnutrition (leading to decreased “supplementation” of antioxidants) and enhanced ros generation (leading to increased utilisation of these compounds) may represent a pathogenic loop that results in markedly enhanced oxidative stress during tuberculosis infection.18,19 this study also showed that the crp concentrations in newly diagnosed patients were significantly higher than those of healthy controls and that the administration of anti-tuberculosis drug therapy for an initial two months was associated with a significant reduction in serum levels. crp has been reported to be significantly elevated in patients with active tb, normalising over weeks on therapy, thereby correlating with clinical response.5,6 higher crp concentrations have also been associated with more severe tuberculosis tb and poor prognosis.20 this observation is supported by reports that patients with more severe lung dysfunction, as evidenced by lung cavitation, had significantly higher crp levels than patients without cavitation.21 mycobacterium tuberculosis and its components have been shown to stimulate mononuclear phagocytes in vitro to release il-6, which are regarded as inflammatory mediators. il-6 is known to induce hepatic acute phase reactants (including crp). several clinical and laboratory findings support the significant relation between il-6 and crp.22 bekker et al. suggested that the decrease in crp concentration in patients treated for pulmonary tuberculosis is paralleled by a similar reduction in plasma cytokines such as il-6, the principal cytokine that induces crp synthesis, and that the fall in serum crp concentration during treatment of pulmonary tuberculosis might be correlated with the resolution of the systemic inflammatory process.23 in the present study, the serum iron levels and transferrin saturation percentage were observed to be significantly lower in patients with active pulmonary tuberculosis before starting therapy in comparison with the controls. this study also demonstrated that after therapy the serum levels of both parameters showed significant elevation. although considerable improvements were reported in these parameters, still there were highly significant differences in serum iron levels and mildly significant differences in transferrin table 3: relationship between c-reactive protein (crp) and malondialdehyde (mda) in the studied cases and control group crp n mda, mean ±sd p value <6 51 1.56 ±0.70 <0.001 6 34 2.51 ±0.88 12 20 2.72 ±0.78 24 12 3.30 ±0.46 48 4 3.00 ±0.12 96 9 3.44 ±0.65 table 4: relationship between c-reactive protein (crp) and total antioxidant status (tas) in the studied cases and control. crp n tas, mean ±sd p value <6 51 1.74 ±0.37 <0.001 6 34 1.36 ±0.33 12 20 1.25 ±0.27 24 12 1.10 ±0.10 48 4 1.00 ±0.08 96 9 1.01 ±0.11 dhia a taha and imad a-j thanoon clinical and basic research | 367 saturation percentages after two months of therapy in comparison to control values. kassu et al. found that the concentrations of iron were significantly lower in the serum of patients with pulmonary tb in comparison with the control group, with no significant differences at the end of the intensive phase of chemotherapy.24 although these are in agreement with our findings of lower pre-treatment serum iron levels in patients in comparison to the healthy controls, they disagree with our finding of a significant increase in serum iron levels after therapy. the hypoferraemia in tb patients may be induced by the shift of iron from a transferrin-bound available state to a ferritin-incorporated storage state.24 the condition may have evolved as a cytokine-mediated defence against microbial pathogens, effectively withholding iron from microbes, which incidentally also deprives erythroid precursors of their iron supply.25 gobin and horwitz suggested that mycobacteria acquire their iron from the host’s own transferrin/ ferritin iron binding proteins, and they achieve this by releasing a type of iron-capturing siderophore called an exochelin. this, in turn, transfers and donates the iron back to the mycobactins which exist in the cell walls of the mycobacteria.26 baynes et al. suggested that patients with pulmonary tuberculosis are often anaemic due to restriction of available iron by the host.5 this restriction occurs as a major component of the host natural immunity and is characterised by the induction of an acute phase response that limits the amount of circulating iron, primarily accomplished by iron sequestration. the sequestration of iron by the host also limits iron-induced cellular damage to the host itself through binding by serum proteins such as transferrin, ferritin and lactoferrin. overall, an attempt is made by the host to induce an iron deficiency upon the pathogen.27 the low serum iron levels seen in this study may also be attributed to low levels of dietary iron intake, low socioeconomic status and blood loss by haemoptysis. values of tibc are usually high in iron deficiency anaemia and low in inflammatory anaemia.28 the tibc reflects transferrin, the protein to which virtually all iron in the blood is bound.29 in this study, we assessed tibc as an indirect measurement of serum transferrin concentrations, and found no significant differences in tibc between patients with pulmonary tb before and at the end of intensive phase of therapy and control subjects. al-omar and oluboyede reported low initial (pre-treatment) tibc levels in patients with pulmonary tuberculosis.30 also, devi et al. reported low tibc concentrations in patients with pulmonary tuberculosis, and they attributed their findings to an acute phase response since transferrin is a negative acute phase protein and serum levels may be decreased in inflammatory conditions.11 our results also showed a significantly higher serum ferritin concentration in tuberculosis patients before starting therapy in comparison with healthy controls. there was also a significant reduction in the serum levels at the end of the intensive phase of chemotherapy. ferritin concentration in blood is considered to be a specific indicator of body iron stores;31 however, the concentration can rise following an inflammatory response, irrespective of iron status. some reports indicated that ferritin synthesis is stimulated in pulmonary tuberculosis as a consequence of the inflammatory process.32 al-omar and oluboyede attributed the rise in serum ferritin levels in their study to two factors: first, increased production by monocytes and macrophages, monocytosis having been observed in pulmonary tb; second, serum ferritin is an acute phase protein that increases in inflammatory conditions.30 in favour of this conclusion, we found a positive correlation between serum ferritin and crp. the raised ferritin levels seen in our patients point more towards the possibility of anaemia of inflammation, although an association with iron deficiency anaemia cannot be completely ruled out. in patients with anaemia of chronic inflammation, there appear to be a defect in the freeing of iron from macrophages, the loading of iron onto plasma transferrin, or both. reticuloendothelial iron is plentiful in bone marrow macrophages, but this iron is not available to erythroid precursors.33 this study showed that after two months of therapy there were significant corrections in serum table 5: relationship between c-reactive protein (crp) and ferritin in the studied cases and control group crp n ferritin, mean ±sd p value <6 51 142.18 ±88.00 <0.001 6 34 94.37 ±97.43 12 20 203.24 ±189.68 24 12 419.09 ±425.85 48 4 561.07 ±323.15 96 9 653.39 ±281.07 antioxidant status, c-reactive protein and iron status in patients with pulmonary tuberculosis 368 | squ medical journal, december 2010, volume 10, issue 3 iron levels, transferrin saturation percent and serum ferritin despite the fact that our patients received no iron supplementation. these observations give rise to the possibility that the anaemia in our patients is of chronic inflammation rather than iron deficiency anaemia; however, the possibility of iron deficiency anaemia cannot be ruled out, since the only effective treatment for anaemia of chronic inflammation is correction of the underlying disorder. both crp and ferritin have been reported to reflect the extent of oxidative stress and inflammation in individual patients and may be useful markers of disease activity and mortality risk.34 in the present study, we have investigated the relationship between markers of oxidative stress and markers of inflammation in tb patients and in healthy controls. subjects with higher serum ferritin and crp concentrations, indicative of greater inflammatory response in such individuals, also had higher serum mda levels and lower tas than those with lower serum ferritin and crp concentrations. this picture was observed in the figures which showed that both serum crp and ferritin levels were positively correlated with lipid peroxidation product and negatively correlated with tas. nguyen-khoa et al. conducted a study to investigate the role of inflammation in exacerbating oxidative stress in haemodialysis patients, and they found that plasma crp levels were correlated positively with plasma levels of lipid peroxidation products, and negatively with plasma α-tocopherol and albumin levels.35 they suggested that inflammatory processes induce an increase production of ros which lead to the consumption of fat-soluble antioxidants and subsequently to the generation of lipid peroxidation products. they also found that the increase in plasma ferritin levels observed in haemodialysis patients was not associated with an increase in the level of lipid and protein oxidative stress markers. ferritin expression is modulated by a variety of conditions associated with oxidative stress that act either directly on gene expression or indirectly via the modification of iron responsive elements activity. superoxide anions produced during oxidative stress can mobilise iron from ferritin and this may augment the intensity of oxidative stress by catalysing the production of highly toxic hydroxyl radicals by fenton and haber-weiss reactions.36 conclusion this study concluded that pulmonary tuberculosis is associated with oxidative stress as indicated by enhanced lipid peroxidation products (mda) and reduced total antioxidant status and that the administration of anti-tuberculosis treatments for the initial two months (intensive phase) reduces the serum mda level, elevates tas and decreases oxidative stress. the increased levels of acute phase proteins (crp and serum ferritin) indicate that pulmonary tb is associated with an inflammatory response and that the administration of treatment for the initial two months brings about suppression of the inflammatory response with significant reduction in these proteins. this study also concluded that newly diagnosed patients with pulmonary tb often had anaemia of chronic inflammation as shown by disturbances in iron body status indices, although the possibility of iron deficiency anaemia cannot be ruled out, and that therapy resulted in a significant correction of such anaemia. conflict of interest the authors reported no conflict of interest. references 1. madebo t. clinical and operational challenges in the control of tuberculosis in south ethiopia. thesis. centre for international health, university of bergen, norway, 2003. 2. jack cl, jackson mj, hind cr. circulating markers of free radical activity in patients with pulmonary tuberculosis. tuber lung dis 1994; 75:132–7. 3. plit ml, theron aj, fickl h, van rensburg ce, pendel s, anderson r. influence of antimicrobial chemotherapy and smoking status on the plasma concentrations of vitamin c, vitamin e, beta carotene, acute phase reactants, iron and lipid peroxides in patients with pulmonary tuberculosis. int j tuberc lung dis 1998; 2:590–6. 4. ribeiro ma. levels of c-reactive protein in serum samples from healthy children and adults in são paulo, brazil. braz j med biol res 1997; 30:1055–9. 5. baynes rd, flex h, bothwell th, bezwoda wr, macphail ap, alkinson p, et al. haematological and iron related measurements in active pulmonary tuberculosis. scand j haematol 1986; 36:280–7. 6. peresi e. cytokines and acute-phase serum proteins as markers of inflammatory regression during pulmonary tuberculosis treatment. j venom anim toxins incl trop dis 2008; 14:190. 7. reeves g. abnormal laboratory results c-reactive dhia a taha and imad a-j thanoon clinical and basic research | 369 protein. aust prescr 2007; 30:74–6. 8. rodriguez gm. control of iron metabolism in mycobacterium tuberculosis. trends microbiol 2006; 14:320–7. 9. gangaidzo it, moyo vm, mvundura e, aggrey g, murphree nl, khumalo h. association of pulmonary tuberculosis with increased dietary iron. j infect dis 2001; 184:936–9. 10. peter f, wang s. serum iron and total iron-binding capacity compared with serum ferritin in assessment of iron deficiency. clin chem 1981; 27:276–9. 11. devi u, rao cm, srivastava vk, rath pk, das bs. effect of iron supplementation on mild to moderate anemia in pulmonary tuberculosis. brit j nutr 2003; 90:541–50. 12. buege ja, aust sd. thiobarbuturic acid assay. methods enzymol 1978; 52: 306–7. 13. miller nj, rice-evans c, davies mj, gopinathan v, milner a. a novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. clin sci 1993; 84:407–12. 14. douglas j h, reid gr, smith fe, thompson sl. ferene: a new spectrophotometric reagent for iron. can j chem 1984; 62:721–4. 15. al-buhairan am, oluboyede oa. determination of serum iron, total iron binding capacity and serum ferritin in healthy saudi adults. ann saudi med 2001; 21:100–3. 16. kaur k, kishan j, bedi gk, ahi rs. oxidants stress and antioxidants in pulmonary tuberculosis. chest 2005; 128:397s. 17. kwiatkowska s, piasecka g, zieba m, piotrowski w, nowak d. increased serum concentrations of conjugated dienes and malondialdehyde in patients with pulmonary tuberculosis. respir med 1999; 93:272–6. 18. reddy yn, murthy sv, krishna dr, prabhakar mc. role of free radicals and antioxidants in tuberculosis patients. indian j tuberc 2004; 51:213–8. 19. madebo t, lindtjørn b, aukrust p, berge rk. circulating antioxidants and lipid peroxidation products in untreated tuberculosis patients in ethiopia. am j clin nutr 2003; 78:117–22. 20. scott gm, murphy pg, gemidjioglu me. predicting deterioration of treated tuberculosis by corticosteroid reserve and c-reactive protein. j infect 1990; 21:61–9. 21. de beer fc, nel ae, gie rp, donald pr, strachan af. serum amyloid a protein and c-reactive protein levels in pulmonary tuberculosis: relationship to amyloidosis. thorax 1984; 39:196–200. 22. ünsal e, aksaray s, köksal d, sipit t. potential role of interleukin-6 in reactive thrombocytosis and acute phase response in pulmonary tuberculosis. postgrad med j 2005; 81:604–7. 23. bekker lg, maartens g, steyn l, kaplan g. selective increase in plasma tumor necrosis factor alpha and concomitant clinical deterioration after initiating therapy in patients with severe tuberculosis. j infect dis 1998; 178:580–4. 24. kassu a, yabutani t, mahmud zh, mohammad a, nguyen n, huong bt, et al. alteration in serum levels of trace elements in tuberculosis and hiv infections. europ j clin nutr 2006; 60:580–6. 25. jurado ri. iron, infection, and anemia of inflammation. clin infect dis 1997; 25:888–95. 26. gobin j, horwitz ma. exochelins of mycobacterium tuberculosis remove iron from human iron binding proteins and donate iron to mycobactrins in the m. tuberculosis cell wall. j exp med 1996; 183:1527–32. 27. mcdermid jm, prentice am. iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and nrampi (slciiai) on hostpathogen interactions in tuberculosis and hiv. clin sci 2006; 110:503–24. 28. punnonen k, irjala k, rajamaki a. iron deficiency anemia is associated with high concentrations of transferrin receptors in serum. clin chem 1994; 40:774–6. 29. wish jb. assessing iron status: beyond serum ferritin and transferrin saturation. clin j am soc nephrol 2006; 1:s4–8. 30. al-omar ia, oluboyede ao. serum ferritin and other iron parameters in patients with pulmonary tuberculosis. saudi med j 2002; 23:244–6. 31. lammi-keefe cj, lickteig es, ahluwalia n, haley nr. day-to-day variation in iron status indexes is similar for most measures in elderly women with and without rheumatoid arthritis. j am diet assoc 1996; 96:247–51. 32. wessels g, schaaf hs, beyers n, gie rp, nel e, donald pr. haematological abnormalities in children with tuberculosis. j trop pediatr 1999; 45:307–10. 33. andrews nc. disorders of iron metabolism. n engl j med 2000; 34:364. 34. huang hh, yan hc, han cl, yu fc, kao wy, chen wt. association of in vitro oxidative stress, serum ferritin concentration and c-reactive protein in febrile emergency room patients. clin invest med 2005; 28:48–54. 35. nguyen-khoa t, massy za, de bandt jp. oxidative stress and haemodialysis: role of inflammation and duration of dialysis treatment. nephrol dial transplant 2001; 16:335–40. 36. rehma a. assessment of nonhaem ferrous iron and glutathione redox ratio as markers of pathogenecity of oxidative stress in different clinical groups. thesis. department of biochemistry, university of tartu, estonia, 2004. 1department of neurology, bangur institute of neurosciences, institute of post-graduate medical education & research and seth sukhlal karnani memorial hospital, kolkata, india; departments of 2radiology and 3internal medicine, r g kar medical college, kolkata, india *corresponding author’s e-mail:chandraatanu123@gmail.com metronidazole induced neurotoxicity a clinico-radiological diagnosis amlan k. datta,1 uddalak chakraborty,1 adreesh mukherjee,1 arpan dutta,1 sudeshna malakar,2 *atanu chandra3 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 149–151, epub. 28 feb 22 submitted 10 dec 20 revisions req. 29 dec 20 & 14 mar 21; revisions recd. 3 jan & 21 mar 21 accepted 18 apr 21 a 44-year-old male patient presented to a tertiary care hospital in kolkata, india in 2019 with a history of subacute onset ataxia, dysarthria and episodes of generalised tonic-clonic seizures for two weeks. he had a history of prolonged intake of over-the-counter metronidazole tablets for irritable bowel syndrome. he did not have a history of hypertension or diabetes. neurological examination revealed bilateral gaze-evoked nystagmus and positive cerebellar signs. basic laboratory parameters were within normal limits. in magnetic resonance imaging scans of the brain, the splenium of corpus callosum showed evidence of diffusion restriction as well as hyperintensity on fluid attenuation inversion recovery (flair) scans [figures 1a and b]. there were also symmetrical areas of hyperintensity involving bilateral lentiform nucleus and dentate nucleus of cerebellum [figures 1c and d]. cerebrospinal fluid (csf) study was noncontributory with absent oligoclonal bands (ocb). vasculitis and infectious profiles were negative. nutritional, paraneoplastic and autoimmune causes of cerebellar ataxia were ruled out by relevant investigations [table 1]. serum thiamine was not performed due to logistic issues. the patient was advised to discontinue metronidazole and upon follow-up six months later, most of his symptoms had resolved. repeat brain imaging after one year revealed complete resolution of previous abnormalities [figure 2]. an informed written consent was obtained from the patient after full explanation regarding the use of his images for publication purposes for academic interest. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.080 interesting medical image figure 1: magnetic resonance imaging scans of the brain of a 44-year-old male patient showing (a) the splenium of corpus callosum with evidence of diffusion restriction (arrow) and (b) hyperintensity (arrow) on fluid attenuation inversion recovery scans. scans also showed (c) symmetrical areas of hyperintensity involving bilateral lentiform nucleus (arrow) and (d) dentate nucleus of cerebellum (arrow). https://creativecommons.org/licenses/by-nd/4.0/ metronidazole induced neurotoxicity a clinico-radiological diagnosis 150 | squ medical journal, february 2022, volume 22, issue 1 the patient did not have any objection regarding use of his images which may reveal his identity and gave permission to use them. comment metronidazole is a nitroimidazole derived synthetic antibiotic; it is mainly used in the treatment of various anaerobic bacterial infections and protozoal infections, such as intestinal amoebiasis, giardiasis and trichomoniasis.1 mechanisms of neurotoxicity have not been properly elucidated. however, rao and mason proposed that free radical mediated damage may be the mechanism for neurotoxicity caused by nitroheterocyclic drugs such as metronidazole.2 other proposed mechanisms include rna-binding by metronidazole and its derivatives causing inhibition of protein synthesis.3 peripheral neuropathy, optic neuropathy and encephalopathy are reported adverse effects occurring with prolonged usage.metronidazoleinduced central and peripheral neurotoxicity is poten tially debilitating.3 characteristic imaging findings include bilateral, symmetric t2/flair hyperintensities of dentate nulcei, dorsal aspect of pons and medulla and genu and splenium of corpus callosum.4 the current patient exhibited most of these radiological findings with additional involvement of basal ganglia. primary central nervous system (cns)demyelinating diseases such as multiple sclerosis and acute demyelinating encephalomyelitis can mimic these findings. however, the temporal profile, absence of ocb in csf and reversibility of imaging findings were uncharacteristic of a demyelinating aetiology. wernicke’s encephalopathy is the closest radio logical differential of metronidazole-induced encepha lopathy (mie). as opposed to mie, involvement of mammillary body and diencephalon are hallmark features of wernicke’s encephalopathy.4 brainstem lesions in mie may mimic those of central pontine myelinolysis (cpm), with or without extra-pontine myelinolysis. however, brainstem lesions in cpm typically show restriction on diffusion weighted images.5 causes of focal t2 splenial hyperintensities are myriad and include encephalitis, marchiafava-bignami syndrome, extra-pontine myelinolysis, demyelinating lesions including drugs and toxic encephalopathies.4 normal plasma folate and serum vitamin b12 level, electrolytes level, thyroid function tests and csf studies effect ively excluded metabolic and infectious causes in the current patient. concurrence of symmetric radiol ogical findings with affection of deep cerebellar nuclei, history of preceding drug intake and resolution of symptoms following drug cessation, established the diagnosis in this case. figure 2: magnetic resonance imaging scans of the brain of a 44-year-old male patient showing (a) axial diffusion weighted image with no restriction in splenium of corpus callosum and (b) axial t2 fluid attenuation inversion recovery sequence showing resolution of hyperintensities in dentate nucleus of cerebellum. table 1: relevant biochemical results of the current patient parameter result normal range blood investigations haemoglobin in g/l 128 120–160 erythrocyte sedimentation rate (1st hour) in mm 27 <30 fasting blood sugar in mg/dl 101 75–110 anti-nuclear antibody negative serum vitamin b12 in pg/ml 442 190–950 plasma folate in ng/ml 11 2–20 serum t4 in mcg/dl 7.7 5.10–14.10 thyroid stimulating hormone in miu/l 2.9 0.27–4.20 serum calcium in mg/dl 9.7 9–11 cerebrospinal fluid investigations white blood cell count in microl 4; all were lymphocytes glucose in mg/dl 75 44–100 protein in mg/dl 36 15–45 adenosine deaminase level in u/l 4.2 0–9 oligoclonal bands absent amlan k. datta, uddalak chakraborty, adreesh mukherjee, arpan dutta, sudeshna malakar and atanu chandra interesting medical image | 151 this case highlights a severe adverse effect of metronidazole, a commonly prescribed antibiotic, on the cns. albeit rare, awareness about its association is important among general practitioners since the toxicity is reversible on discontinuation of the medication. a u t h o r s’ c o n t r i b u t i o n akd and uc contributed to conception and initial drafting of manuscript and were involved in the direct care of the patient. uc and sm helped with the collection of the images and relevant laboratory investigations necessary for the treatment as well as documentation of the case. am and ad supervised the entire procedure of preparing the manuscript as well as supervised the treatment. akd, uc and ac helped in the preparation of the manuscript, relevant revision and editing. all authors are in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. all authors approved the final version of the manuscript. references 1. hernández ceruelos a, romero-quezada lc, ruvalcaba ledezma jc, lópez contreras l. therapeutic uses of metro nidazole and its side effects: an update. eur rev med pharmacol sci 2019; 23:397–401. https://doi.org/10.26355/eurrev_20190 1_16788. 2. rao dn, mason rp. generation of nitro radical anions of some 5-nitrofurans, 2and 5-nitroimidazoles by norepinephrine, dopamine, and serotonin. a possible mechanism for neuro toxicity caused by nitroheterocyclic drugs. j biol chem 1987; 262:11731–6. https://doi.org/10.1016/s0021-9258(18)60872-5. 3. daneman n, cheng y, gomes t, guan j, mamdani mm, saxena fe, et al. metronidazole-associated neurologic events: a nested-case control study. clin infect dis 2021; 72:2095–100. https://doi.org/10.1093/cid/ciaa395. 4. kim e, na dg, kim ey, kim jh, son kr, chang kh. mr imaging of metronidazole-induced encephalopathy: lesion distribution and diffusion-weighted imaging findings. ajnr am j neuroradiol 2007; 28:1652–8. https://doi.org/10.3174/ajnr.a0655. 5. cramer sc, stegbauer kc, schneider a, mukai j, maravilla kr. decreased diffusion in central pontine myelinolysis. ajnr am j neuroradiol 2001; 22:1476–9. https://doi.org/10.26355/eurrev_20190 1_16788 https://doi.org/10.26355/eurrev_20190 1_16788 https://doi.org/10.1016/s0021-9258(18)60872-5 https://doi.org/10.1093/cid/ciaa395 https://doi.org/10.3174/ajnr.a0655 1department of medicine, sultan qaboos university, muscat, oman; departments of 2radiology & molecular imaging and 3pathology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: ikramburney@hotmail.com complete response to sorafenib in locally recurrent unresectable aggressive fibromatosis *ikram a. burney,1 anupam k. kakaria,2 suad al-jahdhami3 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e327–328, epub. 21 jun 21 submitted 6 jul 20 revision req. 21 oct 20; revision recd. 8 nov 20 accepted 8 dec 20 a 48-year-old female patient presented with a 5 cm mass in the left supra-clavicular fossa of 12-months duration, progressively increasing in size. a biopsy revealed a spindle cell neoplasm arranged in long fascicles, positive for b-catenin and focally positive for smooth muscle actin [figure 1]. a diagnosis of aggressive fibromatosis was established. the mass was surgically excised, the resection margin was positive and the diagnosis was consistent with aggressive fibromatosis. the mass recurred within three months of resection and the patient presented to the clinic with a 7 × 5 cm lobulated, hyper-attenuated soft tissue mass at the left posterior cervical region extending to the infraclavicular region abutting the muscles. there were no co-morbidities and the performance status on the who scale was 1. the patient was commenced on celecoxib. an mri demonstrated a locally advanced disease [figures 2a, b and c]. due to the increasing pain and a lack of clinical response over three months while on celecoxib, the patient was commenced on a multi-tyrosine kinase inhibitor, sorafenib, at a standard dose of 400 mg twice daily. within two weeks after starting sorafenib, the patient developed a generalised rash with itching, aches and pains, fatigue, blisters over the sole of the left foot and diarrhea. the patient had then stopped using sorafenib. full blood count, renal, liver and thyroid function tests remained within the normal limits. three weeks later, after the rash and the blister had settled, the patient has commenced again on sorafenib at a reduced dose of 200 mg twice daily. the patient developed grade iii hand-foot syndrome as the mass clinically decreased in size. the frequency of sorafenib was reduced to once daily and the patient maintained this treatment for a total of 11 months. a follow-up mri revealed a complete radiological response [figures 2d, e and f]. she was then referred for adjuvant radiotherapy. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.027 interesting medical image figure 1: (a) hematoxylin & eosin (h&e) stained section of the supra-clavicular mass in a 48-year-old female patient at x200 magnification showing a bland spindle cell neoplasm consisting of sweeping intersecting fascicles, set in variable loose-to-dense fibrocollagenous stroma; (b) beta-catenin immunohistochemical stain at x600 magnification showing positive nuclear staining in tumour cells (arrows); (c) smooth muscle actin immunohistochemical stain at x400 magnification positive in tumour cells (arrow). https://creativecommons.org/licenses/by-nd/4.0/ comment aggressive fibromatosis, also known as desmoid tumour, is a rare, locally aggressive neoplasm commonly arising from the abdominal wall’s connective tissue, mesentery, and the neurovascular bundle of extremities. the vast majority of cases are sporadic and 5-16% are associated with germline mutations in the adenomatous polyposis coli (apc) gene.1 details of presenting features, etiopathogenesis, molecular cytogenetics and treatment have been recently reviewed.1,2 complete surgical excision remains the standard treatment, yet local recurrence risk is high and is reported to be up to 40%. if excised incompletely, the tumours are known to recur rapidly. several agents have been shown to have modest activity.1 due to the tumour’s rarity, the data are derived from a case series and retrospective analysis.1,2 recently, a prospective randomised trial compared sorafenib to a placebo.3 out of the 49 patients, the objective response rate (orr) was 33% with only one complete response in the sorafenib group, compared to an orr of 20% in the placebo group. the median time to objective response was 9.6 and 13.3 months in the sorafenib and the placebo groups, respectively. the 2-year progression-free survival was 81% and 36%, respectively (hazard ratio 0.13; 0.05–0.31). we report a complete response to an abbreviated sorafenib dose in a patient with locally advanced, unresectable aggressive fibromatosis. reference 1. ganeshan dm, amini b, nikolaidis p, assing m, vikram r. current update on desmoids fibromatosis. j computer assist tomogr 2019; 43:29–38. https://doi.org/10.1097/rct.00000 00000000790. 2. garcia-ortega dy, martin-tellez ks, cuellar-hubbe m, martínez-said h, álvarez-cano a, brener-chaoul m, et al. desmoid-type firbromatosis. cancers (basel) 2020; 12:1851. https://doi.org/10.3390/cancers12071851. 3. gounder mm, mahoney mr, van tine ba, ravi v, attia s, deshpande ha, et al. sorafenib for advanced and refractory desmoids tumors. n eng j med 2018; 379:2417–28. https://doi. org/10.1056/nejmoa1805052. figure 2: (a) coronal short-ti inversion recovery (stir) images, (b) axial stir image at c7-t1 level and (c) axial fatsaturated contrast-enhanced t1 weighted image at c7-t1 level of a 48-year-old female patient before commencing sorafenib treatment showing a t2 hyperintense enhancing lesion in the left posterior supra-clavicular and the suprascapular regions and an ipsilateral cervical lymph node (marked with arrows). (d) coronal stir image, (e) axial stir image at c7-t1 level and (f) axial fat-saturated contrast-enhanced t1 weighted image at c7-t1 level 11 months after treatment with sorafenib showing no residual disease. complete response to sorafenib in locally recurrent unresectable aggressive fibromatosis e328 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1097/rct.0000000000000790 https://doi.org/10.1097/rct.0000000000000790 https://doi.org/10.3390/cancers12071851 https://doi.org/10.1056/nejmoa1805052 https://doi.org/10.1056/nejmoa1805052 1department of community medicine, gulf university, ajman, uae; 2department of community medicine, karnataka institute of medical sciences, hubballi, india; 3department of paediatrics, new york university, new york, usa *corresponding author’s e-mail: rizbsk@gmail.com predictors of nicotine dependence among adult male midwakh and cigarette smokers shatha al sharbatti,1 *rizwana b. shaikh,2 jayadevan sreedharan,1 jayakumary muttappallymyalil,1 michael weizman3 clinical & basic research sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 212–217, epub. 26 may 22 submitted 20 aug 20 revisions req. 22 oct & 16 dec 20; revisions recd. 23 nov 20 & 1 jan 21 accepted 7 feb 21 https://doi.org/10.18295/squmj.4.2021.064 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: midwakh is a popular form of smoking in the middle east. this study aimed to assess the predictors of nicotine dependence among cigarette or midwakh smokers in the united arab emirates (uae). methods: this cross-sectional study was conducted from september to december 2015 in ajman, uae. a convenience sampling strategy was implemented to recruit adult male smokers aged ≥18 years who exclusively smoked either cigarettes or midwakh. a validated self-administered questionnaire was used to collect data from the participants, with nicotine dependence assessed using the modified fagerström test for nicotine dependence. in addition, the levels of salivary cotinine and exhaled breath carbon monoxide (co) were measured. results: of the 88 adult male smokers included in the study, 40 (45.5%) were cigarette smokers and 48 (54.5%) smoked midwakh. the majority of participants were 26–35 years of age (48.9%), followed by 18–25 years (30.7%) and >35 years (20.5%). midwakh use was associated with more than a three-fold increase in the risk of moderate-to-high nicotine dependence compared to cigarette smoking. moreover, for each unit increase in co level, there was a 10% increase in the risk of nicotine dependency. there was also a significant association between nicotine dependence level and depth of inhalation (p = 0.023). conclusion: type of smoking and co level were found to be significant predictors of nicotine dependence among adult male smokers. in particular, greater dependency was observed among midwakh smokers than cigarette smokers. keywords: tobacco use; cigarette smoking; addictive behaviours; nicotine; risk assessment; carbon monoxide; cotinine; united arab emirates. advances in knowledge the use of midwakh was associated with more than a three-fold increase in the risk of nicotine dependence compared to cigarette smoking. there was a significant association between depth of inhalation and nicotine dependence. to the best of the authors’ knowledge, this is the first study to assess nicotine dependence in relation to midwakh smoking. application in patient care the findings of this study highlight the importance of assessing forms of tobacco consumption other than cigarette and waterpipe smoking when eliciting a patient’s smoking history, particularly because midwakh smoking is rapidly gaining popularity in the middle east. healthcare practitioners should be aware of the high risk of nicotine dependency among midwakh smokers when recommending smoking cessation strategies. tobacco use is responsible for the deaths of an estimated eight million people worldwide each year and is one of the main risk factors for cancer and lung and cardiovascular diseases.1,2 moreover, tobacco use adversely affects the heart, lungs, kidneys, bones, teeth, gums, blood vessels and reproductive and immune systems.3 evidence suggests that there is a twoto three-fold increase in mortality among middle-aged smokers compared to non-smokers of the same age group, leading to a lifespan reduction of approximately 10 years.4 in 2017, the world health organization estimated the current prevalence of tobacco smoking among adults in the united arab emirates (uae) to be 9%, rising to 15% among males alone.5 despite being aware of its adverse effects, many individuals continue using tobacco due to the presence of and interactions between highly addictive ingredients within these products.6 in particular, nicotine—the main psychoactive compound in tobacco—is respon sible for reinforcing smoking and tobacco use behaviours, thus establishing and maintaining dependency.6,7 the modified fagerström test for nicotine dependence (mftnd) is a tool for determining an individual’s degree of physical addiction to nicotine as well as indicators for prescribing tobacco cessation medic ations.8,9 in turn, a widely used biomarker of tobacco smoke exposure is cotinine, a primary metabolite of nicotine that has a longer half-life (9–16 hours) than nicotine (approximately two hours), allowing for the assessment of tobacco exposure occurring more than eight hours beforehand.10 in the uae, smoking is an important public health problem. midwakh is a common form of smoking in https://creativecommons.org/licenses/by-nd/4.0/ shatha al sharbatti, rizwana b. shaikh, jayadevan sreedharan, jayakumary muttappallymyalil and michael weizman clinical and basic research | 213 this region; it involves a small pipe called midwakh which is filled with dokha, a blend of shredded tobacco leaves and herbs [figure 1].11 a previous study identified midwakh to be the second most frequent form of smoking after cigarettes, accounting for 15% of all tobacco smokers in the uae.12 notably, this type of smoking appears to have high addictive potential; a study of high-school students in dubai found that 23.4% regularly smoked midwakh on a daily or weekly basis.13 furthermore, a recently published report showed no significant differences in the median breath carbon monoxide (co) and salivary cotinine levels between cigarette and midwakh smokers, although mahboub et al. concluded that the nicotine level in dokha is higher than in other types of tobacco products, including cigarettes, chewing tobacco, snuff tobacco and electronic cigarettes.14,15 limited data is available regarding the predictors of nicotine dependence in the uae and the relationship between midwakh smoking and nicotine dependence. therefore, this study aimed to assess the predictors of nicotine dependence among cigarette and midwakh smokers in the uae. methods this cross-sectional survey study was conducted between september and december 2015 in ajman, uae, and included adult males aged ≥18 years who exclusively smoked either cigarettes or midwakh. poly-smokers and those who smoked any other form of tobacco such as beedis, cigars, pipes, kretecks or e-cigarettes were excluded from the study. a convenience sampling strategy was used to recruit healthy participants from among university students and workers at different work sites in ajman. details regarding the enrolment of participants in the study have been published elsewhere.14 a validated, pilot-tested and self-administered questionnaire was used to collect data from the part icipants, including their sociodemographic profile, method/depth of inhalation (i.e. the volume of each ‘puff ’) and age when they first started smoking. nicotine dependence was assessed using the mftnd instrument.8 the mftnd is a valid and reliable tool that consists of six questions and a total score ranging from zero to 10. in particular, one of the items seeks to determine the timing of a smoker’s first cigarette of the day; this is an important predictor of dependence because the short half-life of nicotine is responsible for the discomfort and craving often experienced by smokers as soon as they awaken.8 another item assesses the number of cigarettes smoked per day, a face-valid measure of dependence and a significant predictor of smoking habits.8 the remaining items assess other behavioural aspects of nicotine addiction including the difficulty to refrain from smoking when required (i.e. due to illness or in locations where such behaviours are forbidden) and increased frequency of smoking in the morning.8 levels of nicotine dependence were considered to be moderate-to-high when mftnd scores were ≥4 and low when mftnd scores were <4. for the purposes of the current study, the number of individual smoking sessions for midwakh smokers was deemed equivalent to the number of cigarettes, as cigarettes contain approximately 0.5–0.9 g of tobacco, similar to the amount used per session of midwakh smoking (~0.5 g).11,14 in addition, salivary cotinine and exhaled breath co levels were assessed. salivary cotinine testing was conducted using rapid test strips (nicalert™ strips, craig medical distribution inc., california, usa) based on a semi-quantitative immunochromatographic assay that uses monoclonal antibody-coated gold particles and a series of avidity traps.16 salivary samples were obtained using the funnel device and collection container provided, with participants asked to spit into the funnel until the collection container was filled at least halfway. the rapid test device was subsequently laid on a flat, dry surface with the numbered levels facing up. the collection container was squeezed until approximately eight drops from the inverted saliva tube fell directly onto the white padded end of the strip. after 20–30 minutes, the level at which the colour change stopped was observed and scored to obtain the test results. the levels on the strip and the cotinine equivalent were as follows: level 0 was 1–10 ng/ml, level 1 was 10–30 ng/ml, level 2 was 30–100 ng/ml, level 3 was 100–200 ng/ml, level 4 was 200–500 mg/ml, level 5 was 500–2000 ng/ml and level 6 was 2000 + ng/ml. salivary cotinine levels 2 and above (>30 ng/ml) were considered to indicate tobacco users; a salivary cotinine level of 0 (1–10 ng/ ml) was considered to indicate non-users of tobacco. exhaled co levels were measured using a portable co monitor (pico+ smokerlyzer®, covita llc, new jersey, usa) that measures breath co levels in parts per million (ppm) based on the conversion of co to carbon dioxide over a catalytically active electrode.17 monitoring was performed within eight hours of smoking with the subjects asked to exhale completely, inhale fully and then hold their breath for 15 seconds. the participants were then requested to exhale slowly and fully into the portable co monitor so that samples of alveolar air could be collected; each subject repeated this process twice. the average of the two co measurements were used for the analysis. predictors of nicotine dependence among adult male midwakh and cigarette smokers 214 | squ medical journal, may 2022, volume 22, issue 2 statistical analysis was performed using the statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa). a t-test was performed to identify differences between the mean co and salivary cotinine levels among midwakh and cigarette smokers, while associations were determined using a chi-squared test. binary and multiple logistic regression analyses were performed to identify predictors of nicotine dependence based on the calculation of adjusted odds ratio (aor) and 95% confidence interval (ci) values. a p value <0.050 was considered statistically significant. written informed consent was obtained from each participant prior to their enrolment in the study. ethical approval for this study was obtained from the research and ethics committees of the gulf medical university in ajman and new york university in abu dhabi (nyuadphrc-pilot2014-rshaikh35000). results a total of 88 adult males were included in the study, of which 40 (45.5%) were cigarette smokers and 48 (54.4%) were midwakh smokers. in terms of age distribution, 27 participants (30.7%) were 18–25 years old, 43 (48.9%) were 26–35 years old and 18 (20.5%) were >35 years old. the majority were of arab ethnicity (60.2%), were employed (69.3%) and had attained an education level of graduate or higher (56.8%). in terms of smoking behaviours, most participants had started smoking before the age of 20 years (56.8%); moreover, 42% usually inhaled deeply when smoking. a significant association was found between nicotine dependence and ethnicity, with moderateto-high nicotine dependence being significantly more frequent among arab participants than those of other ethnicities (75.5% versus 48.6%; p = 0.010). in addition, table 1: associations between nicotine dependence and selected variables among adult male midwakh and cigarette smokers in ajman, united arab emirates (n = 88) variable n (%) p value total moderate/high dependence low dependence age in years 0.441 18–25 27 (30.7) 19 (70.4) 8 (29.6) 26–35 43 (48.9) 25 (58.1) 18 (41.9) >35 18 (20.5) 13 (72.2) 5 (27.8) type of smoker 0.080 cigarette 40 (45.5) 22 (55.0) 18 (45.0) midwakh 48 (54.5) 35 (72.9) 13 (27.1) ethnicity 0.010 arab 53 (60.2) 40 (75.5) 13 (24.5) non-arab 35 (39.8) 17 (48.6) 18 (51.4) occupation 0.089 student 27 (30.7) 21 (77.8) 6 (22.2) employed 61 (69.3) 36 (59) 25 (41) education level 0.467 less than graduate level 38 (43.2) 23 (60.5) 15 (39.5) graduate level or higher 50 (56.8) 34 (68) 16 (32) age at smoking onset in years 0.467 <20 50 (56.8) 34 (68) 16 (32) ≥20 38 (43.2) 23 (60.5) 15 (39.5) depth of inhalation 0.023 not deep 51 (58) 28 (54.9) 23 (45.1) deep 37 (42) 29 (78.4) 8 (21.6) shatha al sharbatti, rizwana b. shaikh, jayadevan sreedharan, jayakumary muttappallymyalil and michael weizman clinical and basic research | 215 there was a significant association between nicotine dependence and depth of inhalation, with higher levels of dependency noted among smokers accustomed to inhaling deeply compared to their counterparts (78.4% versus 54.9%; p = 0.023) [table 1]. mean age at smoking onset was lower for smokers with moderate-to-high dependence than those with low dependence; however, this finding was not statistically significant (18.4 ± 4.7 versus 19.7 ± 3.5 years; p = 0.209). in contrast, mean co level was significantly higher in people with moderate-to-high dependence than those with low dependence (22.0 ± 12.2 versus 14.2 ± 5.2 ppm; p = 0.001). in addition, mean salivary cotinine level was significantly higher in smokers with moderate-to-high dependence compared to those with low dependence (3.8 ± 1.8 versus 2.8 ± 1.9; p = 0.018) [table 2]. of the six variables included in the simple binary logistic regression analysis, ethnicity and overall age were not significant and were, therefore, not included in the multiple binary logistic regression analysis. of the remaining variables, midwakh use significantly increased the risk of moderate-to-high nicotine dependence by a factor of 3.3 compared to cigarettes (aor = 3.3, 95% ci: 1.1–10.1; p = 0.034). in addition, the risk of nicotine dependence was almost twice as high among smokers who inhaled deeply compared to those who did not inhale deeply; however, this predictor was not statistically significant (aor = 1.9, 95% ci: 0.6–5.8; p = 0.251). finally, a one unit increase in co level significantly increased the risk of nicotine dependence by 10% (aor = 1.1, 95% ci: 1.0–1.2; p = 0.025) [table 3]. discussion nicotine dependence is a significant barrier to successful smoking cessation.18 in the current study, midwakh smoking was associated with more than a three-fold increase in the risk of moderate-to-high nicotine dependence in a cohort of adult males who exclusively smoke either midwakh or cigarettes in the uae. to the best of the authors’ knowledge, this is the first study to assess nicotine dependence in relation figure 1: photograph of a midwakh pipe with dokha tobacco. table 2: predictors of nicotine dependence according to level of dependence among adult male midwakh and cig arette smokers in ajman, united arab emirates (n = 88) predictor mean ± sd p value moderate/ high dependence low dependence age at smoking onset in years 18.4 ± 4.7 19.7 ± 3.5 0.209 co level in ppm 22.0 ± 12.2 14.2 ± 5.2 0.001 salivary cotinine level* 3.8 ± 1.8 2.8 ± 1.9 0.018 age in years 29.0 ± 6.8 29.6 ± 5.8 0.673 sd = standard deviation; co = carbon monoxide. *cotinine equivalent in ng/ml is given in the methods. table 3: logistic regression analysis to determine predictors of nicotine dependence among adult male midwakh and cigarette smokers in ajman, united arab emirates (n = 88) predictor* cor (95% ci) p value aor (95% ci) p value type of smoking 0.082 0.034 midwakh 2.2 (0.9–5.4) 3.3 (1.1– 10.1) cigarette 1 1 depth of inhalation 0.026 0.251 deep 3.0 (1.1–7.8) 1.9 (0.6– 5.8) not deep 1 1 ethnicity 0.011 arab 3.3 (1.3–8.1) non-arab 1 age 1.4 (-3.5–2.3) 0.669 co level 1.1 (1.1– 1.2) 0.002 1.1 (1.0– 1.2) 0.025 salivary cotinine level 1.3 (1.1– 1.7) 0.021 1.1 (0.8– 1.6) 0.431 cor = crude odds ratio; ci = confidence interval; aor = adjusted odds ratio; co = carbon monoxide. *the model predicted 30.6% of the variability in nicotine dependence (r2 = 0.306). predictors of nicotine dependence among adult male midwakh and cigarette smokers 216 | squ medical journal, may 2022, volume 22, issue 2 to midwakh smoking. aden et al. stated that the nicotine content of dokha tobacco is higher than that of cigarettes;19 this may explain the higher dependence associated with midwakh smoking in the present study. these findings are concerning as midwakh smoking is rapidly increasing, particularly among young people living in the middle eastern region; moreover, this type of smoking is likely to grow in popularity as a result of marketing efforts, with dokha products being advertised to potential consumers as “the future of tobacco”.12 in light of these findings, there is an urgent need for the aggressive implementation and enforcement of strict regulations on dokha tobacco products as well as public health education campaigns to raise awareness of the risks associated with midwakh smoking among potential users. in contrast, neither overall age nor age at smoking onset were found to be significantly associated with dependence level in the current study. various researchers have suggested that the age at which an individual starts smoking cigarettes is related to their subsequent smoking behaviours.20–22 in the current study, a higher proportion of participants who had started smoking during adolescence demonstrated a moderate-to-high dependence compared to those who had started at 20 years of age or later; however, this finding was not statistically significant. similarly, ethnicity was not found to be a significant predictor of nicotine dependence in the current study’s multiple regression analysis. evidence related to the role of ethnicity in nicotine dependence is inconsistent in the literature as well. duncan et al. found that the effect of ethnicity on nicotine dependence was significant only when the onset of dependence occurred at <18 years of age and not when the dependence developed later in life.23 however, luo et al. concluded that nicotine dependence occurred with a lower number of cigarettes per day among african american respondents compared to caucasian americans.24 furthermore, a longitudinal study by brook et al. highlighted the importance of various psychosocial and environmental factors when comparing the nicotine dependence of different ethnic groups.25 level of breath co was found to be a significant predictor of nicotine dependence in the present study, with a one unit increase in co level associated with a 10% increase in the risk of moderate to high nicotine dependence. this finding is in agreement with a study from tunisia, in which the rate of expired co was found to be a significant determinant of tobacco dependence (or = 1.059).26 other researchers have also noted significant correlations between exhaled breath co level and number of cigarettes smoked over the preceding 24-hour period as well as the amount of time since the last cigarette was smoked.21 while each unit increase in salivary cotinine level resulted in a 10% increase in the risk of moderate-tohigh nicotine dependence in the current study, this association was not statistically significant. similar results have been reported by asha and dhanya among tobacco chewers in india.27 with regards to depth of inhalation (i.e. the volume of each ‘puff ’), the risk of nicotine dependence in the present study was almost twice as high among smokers who inhaled deeply compared to those who did not. these findings are in line with the results reported by moolchan et al. indicating a relationship between puffing behaviour and the rate of nicotine metabolism and dependence.22 this study was limited by various factors, including the small sample size and recruitment of solely male participants; due to this, the findings cannot be generalised. further research in this area is recommended to incorporate larger and more diverse samples. nevertheless, to the best of the authors’ knowledge, this is the first study to assess nicotine dependence among midwakh smokers compared to cigarette smokers. these findings provide important insights into a growing public health concern. conclusion the type of smoking and co levels were significant determinants of nicotine dependence among a cohort of adult male smokers in the uae. in particular, midwakh smoking was associated with a more than a three-fold increase in the risk of moderate-tohigh nicotine dependence compared to cigarette smoking. furthermore, for each unit increase in the level of breath co, there was a 10% increase in the risk of moderate-to-high nicotine dependence. these findings highlight the need for public health education measures that can increase awareness of the risk of nicotine dependency among midwakh smokers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this work was supported by the new york university, abu dhabi, uae (grant number: nyuadphrcpilot2014-rshaikh35000). a u t h o r s’ c o n t r i b u t i o n rbs conceptualised the idea of the study. sas, rbs and mw designed the study. js and jm collected and shatha al sharbatti, rizwana b. shaikh, jayadevan sreedharan, jayakumary muttappallymyalil and michael weizman clinical and basic research | 217 analysed the data. sas drafted the manuscript. rbs and mw revised the manuscript. all authors approved the final version of the manuscript. references 1. world health organization. tobacco: key facts. from: https://www. who.int/news-room/fact-sheets/detail/tobacco accessed: jan 2021. 2. world health organization. tobacco free initiative (tfi): health effects of smoking among young people. from: https://www. who.int/health-topics/tobacco#tab=tab_1 accessed: jan 2021. 3. centers for disease control and prevention. health effects of cigarette smoking. from: www.cdc.gov/tobacco/data_statistics/ fact_sheets/health_effects/effects_cig_smoking/ accessed: jan 2021. 4. jha p, peto r. global effects of smoking, of quitting, and of taxing tobacco. n engl j med 2014; 370:60–8. https://doi. org/10.1056/nejmra1308383. 5. world health organization. tobacco free initiative (tfi): who report on the global tobacco epidemic, 2017. from: https:// c d n . w h o . i n t / m e d i a / d o c s / d e f a u l t s o u r c e / n c d s / n c d s u r v e i l l a n c e / d a t a r e p o r t i n g / u n i t e d a r a b e m i r a t e s / u a e n a t i o n a l h e a l t h s u r v e y r e p o r t 2 0 1 7 2 0 1 8 . pdf?sfvrsn=86b8b1d9_1&download=true accessed: jan 2021. 6. medscape. nicotine addiction: practice essentials. from: http:// emedicine.medscape.com/article/287555-overview accessed: jan 2021. 7. rupprecht le, smith tt, schassburger rl, buffalari dm, sved af, donny ec. behavioral mechanisms underlying nicotine reinforcement. curr top behav neurosci 2015; 24:19–53. https://doi. org/10.1007/978-3-319-13482-6_2. 8. heatherton tf, kozlowski lt, frecker rc, fagerström ko. the fagerström test for nicotine dependence: a revision of the fager ström tolerance questionnaire. br j addict 1991; 86:1119–27. https://doi.org/10.1111/j.1360-0443.1991.tb01879.x. 9. rustin ta. assessing nicotine dependence. am fam physician 2000; 62:579–84. 10. srnt subcommittee on biochemical verification. biochemical verification of tobacco use and cessation. nicotine tob res 2002; 4:149–59. https://doi.org/10.1080/14622200210123581. 11. al-houqani m, ali r, hajat c. tobacco smoking using midwakh is an emerging health problem--evidence from a large crosssectional survey in the united arab emirates. plos one 2012; 7:e39189. https://doi.org/10.1371/journal.pone.0039189. 12. vupputuri s, hajat c, al-houqani m, osman o, sreedharan j, ali r, et al. midwakh/dokha tobacco use in the middle east: much to learn. tob control 2016; 25:236–41. https://doi. org/10.1136/tobaccocontrol-2013-051530. 13. crookes a, wolff k. prevalence of the tobacco product dokha among high school students in dubai. subst use misuse 2014; 49:1349–52. https://doi.org/10.3109/10826084.2014.901388. 14. shaikh rb, sreedharan j, al sharbatti s, muttappallymyalil j, lee l, weitzman m. salivary cotinine concentration and carbon monoxide levels in young adults smoking midwakh in comparison with cigarette smokers. tob control 2019; 28:141–5. https:// doi.org/10.1136/tobaccocontrol-2017-054202. 15. mahboub b, mohammad ab, nahlé a, vats m, al assaf o, alzarooni h. analytical determination of nicotine and tar levels in various dokha and shisha tobacco products. j anal toxicol 2018; 42:496–502. https://doi.org/10.1093/jat/bky029. 16. craig medical distribution inc. nicalert saliva nicotine test. from: http://craigmedical.com/nicotine_saliva_tests.htm accessed: jan 2021. 17. covita llc. smokerlyzer® breath co test results. from: https:// www.covita.net/wp-content/uploads/smokerlyzer-resultshandout.pdf accessed: jan 2021. 18. tan l, tang q, hao w. nicotine dependence and smoking cessation. zhong nan da xue bao yi xue ban 2009; 34:1049–57. 19. aden b, karrar s, shafey o, al hosni f. cigarette, water-pipe, and medwakh smoking prevalence among applicants to abu dhabi’s pre-marital screening program, 2011. int j prev med 2013; 4:1290–5. 20. klein h, sterk ce, elifson kw. initial smoking experiences and cur rent smoking behaviors and perceptions among current smokers. j addict 2013; 2013:491797. https://doi.org/10.1155/2013/491797. 21. low ec, ong mc, tan m. breath carbon monoxide as an indication of smoking habit in the military setting. singapore med j 2004; 45:578–82. 22. moolchan et, parzynski cs, jaszyna-gasior m, collins cc, leff mk, zimmerman dl. a link between adolescent nicotine metabolism and smoking topography. cancer epidemiol biomarkers prev 2009; 18:1578–83. https://doi.org/10.1158/1055-9965.epi-08-0592. 23. duncan ae, lessov-schlaggar cn, sartor ce, bucholz kk. differences in time to onset of smoking and nicotine dependence by race/ethnicity in a midwestern sample of adolescents and young adults from a high risk family study. drug alcohol depend 2012; 125:140–5. https://doi.org/10.1016/j.drugalcde p.2012.04.003. 24. luo z, alvarado gf, hatsukami dk, johnson eo, bierut lj, breslau n. race differences in nicotine dependence in the collab orative genetic study of nicotine dependence (cogend). nicotine tob res 2008; 10:1223–30. https://doi.org/10.1080/1 4622200802163266. 25. brook js, brook dw, zhang c. psychosocial predictors of nico tine dependence in black and puerto rican adults: a longitud inal study. nicotine tob res 2008; 10:959–67. https://doi.org/10.10 80/14622200802092515. 26. sriha belguith a, bouanene i, elmhamdi s, ben salah a, harizi c, ben salem k, et al. [nicotine dependance and carbon monoxide intoxication among adult smokers]. tunis med 2015; 93:231–6. 27. asha v, dhanya m. immunochromatographic assessment of salivary cotinine and its correlation with nicotine dependence in tobacco chewers. j cancer prev 2015; 20:159–63. https://doi. org/10.15430/jcp.2015.20.2.159. https://doi.org/10.1056/nejmra1308383 https://doi.org/10.1056/nejmra1308383 https://doi.org/10.1007/978-3-319-13482-6_2 https://doi.org/10.1007/978-3-319-13482-6_2 https://doi.org/10.1111/j.1360-0443.1991.tb01879.x https://doi.org/10.1080/14622200210123581 https://doi.org/10.1371/journal.pone.0039189 https://doi.org/10.1136/tobaccocontrol-2013-051530 https://doi.org/10.1136/tobaccocontrol-2013-051530 https://doi.org/10.3109/10826084.2014.901388 https://doi.org/10.1136/tobaccocontrol-2017-054202 https://doi.org/10.1136/tobaccocontrol-2017-054202 https://doi.org/10.1093/jat/bky029 https://doi.org/10.1155/2013/491797 https://doi.org/10.1158/1055-9965.epi-08-0592 https://doi.org/10.1016/j.drugalcdep.2012.04.003 https://doi.org/10.1016/j.drugalcdep.2012.04.003 https://doi.org/10.1080/14622200802163266 https://doi.org/10.1080/14622200802163266 https://doi.org/10.1080/14622200802092515 https://doi.org/10.1080/14622200802092515 https://doi.org/10.15430/jcp.2015.20.2.159 https://doi.org/10.15430/jcp.2015.20.2.159 clinical & basic research squ med j, december 2009, vol. 9, iss. 3, pp. 287-295, epub. 19th dec 2009 submitted 3rd july 2009 revision req. 4th oct 09, revision recd. 10th nov 09 accepted 14th nov 09 وجهات نظر املرضى حول الرعاية املستمرة يف أربعة مراكز للرعاية الصحية األولية يف حواضر سلطنة ُعمان محمد العزري، شيام جنجولي امللخص: الهدف: يعتبر استمرار الرعاية الطبية عند نفس الطبيب/الطبيبة ذا قيمة أساسية في الرعاية األولية وعامل حاسم في نوعية الرعاية ، ومع هذا تبقى هذه االستمرارية بالتعامل مهملة في الدول العربية ومنها ُعمان. تهدف الدراسة إلى معرفة آراء املرضى حول ذلك املوضوع في عمان. الطريقة: اختيرت أربعة مراكز صحية أولية من منطقتني حضريتني في عمان بني يونيو وأغسطس سنة 2008. مت استبيان البالغني من املرضى وهم بانتظار دورهم للقاء الطبيب في املركز الصحي األولي. النتائج: مت إكمال 319 استبيانا (%71) من املرضى املشاركني. كان مدى العمر بني 18 الى 70 سنة. معظم املرضى 223 (%70 ) يعتقدون أن مراجعة نفس الطبيب مهم جدا لهم ، وشعر 232 (%73 ) منهم حصلوا على عناية أفضل عند مراجعتهم نفس الطبيب. فضل (225 %71) استمرار العالج عند نفس الطبيب في حالة مشاكل شخصية أو عائلية أو اجتماعية . كان حظ النساء أقل من الرجال في استمرارية مراجعة نفس الطبيب (p = 0.018) . كما وجدنا أن استمرارية العالج عند نفس الطبيب تزداد بازدياد عدد الزيارات الطبية (p = 0.030) بزيادة العمر يزداد تفضيل استمرار املراجعة عند نفس الطبيب (p = 0.020) ، وكذلك في حالة األمراض املزمنة الطبيب وتعليمات بنصائح أكثر يلتزمون الطبيب نفس عند العالج استمرار يفضلون والذين مزمنة بأمراض املصابون املرضى . (p = 0.001) مقارنة باآلخرين (p = 0.027) . اخلالصة: املرضى العمانيون يعتقدون أن استمرار العالج عند نفس الطبيب عامل مهم في الرعاية الصحية األولية . على ادارة الرعاية الصحية األخذ بنظر االعتبار تفضيل االستمرار عند نفس الطبيب واتخاذ االجراءات الالزمة لدعم ذلك. من الضروري عمل دراسة تشمل عددا أكبر من املرضى من عدة مراكز صحية أولية في ُعمان . مفتاح الكلمات: استمرار الرعاية عند نقس الطبيب ،رعاية أولية ، ُعمان. abstract: objectives: interpersonal continuity of care (consulting the same physician) is widely regarded as a core value of primary care and a crucial component of quality of care. nonetheless, interpersonal continuity as experienced by patients remains a neglected topic in arab countries including oman. the aim of this study was to explore how patients view interpersonal continuity of care in the primary care setting in oman. methods: four primary health centres (phcs) were selected from two urban cities in oman. in the period june to august 2008, adult patients were surveyed by questionnaire at their phc while waiting to see their primary care physicians (pcps). results: we interviewed 319 (71%) of enrolled participants. their ages ranged from 18-70 years. the majority of patients (223 70%) thought interpersonal continuity was very important for them; 232 (73%) patients felt that they obtained better care with interpersonal continuity. 225 (71%) patients preferred interpersonal continuity if they had personal, family or social problems. nonetheless, compared to male patients, female patients had less chance to maintain interpersonal continuity (p = 0.018). interpersonal continuity increased as the number of consultations increased (p = 0.030). preference for interpersonal continuity was associated with increasing age (p = 0.020) and with the presence of chronic illnesses (p = 0.001). patients with chronic illnesses, who reported more preference for interpersonal continuity, were also found to be more compliant with medications and committed to carrying out recommended advice compared to patients without such illnesses (p = 0.027). conclusion: omani patients perceived interpersonal continuity as an important aspect of primary care. health planners should note patients’ preference for interpersonal continuity and take visible measures to support it. a larger study is needed to survey more of the phcs of oman. keywords: interpersonal continuity; primary care; oman. patients’ views of interpersonal continuity of care in four primary health care centres of urban oman *mohammed al-azri m1 and shyam s ganguly2 clinical & basic research 1department of family medicine & public health, sultan qaboos university hospital, muscat, sultanate of oman; 2department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman. *to whom correspondence should be addressed. email: mhalazri@squ.edu.om. advances in knowledge 1. this is the first study conducted in oman to explore patients’ views of interpersonal continuity of care (seeing/consulting the same primary care physician) in primary care in oman. 2. the results of this study help to identify that patients in primary care prefer interpersonal continuity. patients’ views of interpersonal continuity of care in four primary health care centres of urban oman 288 | squ medical journal, december 2009, volume 9, issue 3 continuity of care has been regarded as one of the core values of primary care and as being fundamental to the work of the family physician.1,2 interpersonal continuity has been defined as care provided by the same physician most of the time with an ongoing therapeutic relationship between the patient and their usual physician being developed and maintained.3 several other types of continuity are also proposed in the literature including team, informational, management, cross-boundary and geographic.4 throughout the world, good quality primary care improves health outcomes for the population.5 as an element of primary care, interpersonal continuity has been evaluated for the extent to which it impacts on health care outcomes such as prevention or reduction of physical, mental, and social disabilities, increased patient satisfaction, trust and reduced aggregate health care spending.6 it has been shown that if there is trust between the patients and their usual physicians, patients are more likely to adhere to the recommended treatment.7 oman is a fast developing country located on the south-eastern tip of the arabian peninsula with total population of 2.75 million in 2007 of which 1.9 million were omani.8 in that year, only 3.7% of omani were over 60 years of age and 36% under 15 years of age.8 the primary health care services in oman are funded by the government, through the ministry of health (moh), for all omanis and non-omanis working in the government sector. since its inception in 1970, the moh has gradually expanded health care services to all regions of oman through a network of primary health centres (phcs) providing high quality services easily accessible to everyone in the country.9 primary health care has been considered as the first portal of entry to all levels of health care services. if required, primary care physicians (pcps) refer their patients to secondary and tertiary care hospitals for specialist care. in 2001, oman was ranked by the world health orgazination (who) as first in the world in relation to the efficient utilisation of health services mainly due to the effectiveness of phc services.10 despite the fact that availability, accessibility, continuity and comprehensiveness of care were considered when establishing primary health care services in oman,9 patients are still accustomed to consult any pcp on a “first come first served basis”. nonetheless, since april 2008, an appointment system has been approved and implemented in all phcs in the governorate of muscat, the capital city of oman.11 one of the aims of the system is to improve interpersonal continuity, but interpersonal continuity may be interrupted as patients can still consult different pcps in the same health centre. this might result in patients being given conflicting advice which could affect outcomes of care and hence the quality of services. thus, pcps are faced with a challenge to provide good quality services, including interpersonal continuity. to our knowledge, there are no previous studies conducted in arabic countries, including oman, to explore patients’ views of interpersonal continuity of care. the aim of this study was, therefore, to explore patients’ view of interpersonal continuity of care in the primary care setting in oman. methods this study was approved by the medical ethics research committee of the college of medicine & health sciences (com&hs) at sultan qaboos university (squ). a survey questionnaire was developed using models from the literature,1 but modified to accommodate the omani context of primary health care. the description of the survey questionnaire contents can be found in table 1. the questions were formulated as statements with which the patient could agree or disagree. patients application to patient care 1. improving interpersonal continuity by allowing and encouraging patients to see the same health care professional must be a priority for any future health care plan in oman. 2. modifying the appointment system by allowing patients to see the same primary care physician will improve interpersonal continuity and hence quality of care in primary care in oman. 3. interpersonal continuity must be given higher priority for elderly patients and those with chronic conditions (diabetes mellitus, hypertension, asthma, etc.) 4. active measures should be considered to obtain periodic feedback from patients in primary care. mohammed al-azri m and shyam s ganguly clinical and basic research | 289 were asked to rank their responses on the following scale between “strongly agree”, “somewhat agree”, “hard to decide”, “somewhat disagree” and “strongly disagree”. the questionnaire was translated into arabic and then retranslated into english to ensure that the meaning had been maintained. a pilot study of 20 patients was carried out in one of the selected health centres to test the suitability of the questionnaire and highlight any problems that could occur during the implementation of the study. three medical students of the com&hs of squ were chosen to conduct this study and were trained to perform face-to-face survey interviews. to assure data quality, students were supervised by the principal author during the pilot phase. two phcs were selected from each of the two main cities in oman: the capital city muscat and sohar, which is located in the al batinah region of oman, 240kms north-west of muscat. the selection of cities and phcs was based on convenience for medical students to collect data in a specific timeframe. the characteristics of the selected phcs are outlined in table 2. all arabic speaking patients aged 18 years and above attending their phcs were invited to participate in the study and the purpose of the study was explained to them. patients who agreed to participate were asked to sign a consent form and to fill in the questionnaire if they were literate. for illiterate patients, questionnaires were administered by the medical students. non-arabic speakers, table 1: description of patient survey contents section number areas of assessment examples of assessment 1 socio-demographic characteristics of the patient age, gender, marital status, education level, history of common chronic illnesses, name of the phc, duration of registration with the phc, etc. 2 patient’s perception and knowledge of interpersonal continuity 1. whether it is important to consult the same or different pcp at every visit 2. when it would be important to consult the same or different pcp 3. the preference between easy access by consulting any pcp or waiting to consult the same pcp 4. the importance of building a good relationship with the same pcp 5. the feelings experienced when consulting the same pcp compared with other pcps 6. whether the medical record is sufficient for continuity compared with consulting the same pcp 3 implication of interpersonal continuity and how interpersonal continuity links to outcomes of care 1. whether the patient has had the chance to consult the same pcp at every visit or they had to wait a long time 2. whether the patient will obtain better care by consulting the same pcp 3. did the patient’s condition improve and did he/she feel more comfortable and at ease when consulting the same pcp compared to consulting different pcps? 4. is the usual pcp involved with the patient in making decision? 5. is the usual pcp knowledgeable about the patient's personal, psychosocial and medical background? 6. is the usual pcp considering psychosocial aspects when making decisions? 7. are patients becoming more committed to recommended regimens when consulting the same pcp compared to other doctors, etc? legend: phc = primary health centres; pcp = primary care physician table 2: characteristics of the selected primary health centres (phcs) location muscat sohar name of phc a b c d number of registered patients 38,900 50,600 45,978 42,147 number of recruited patients 87 129 60 43 number of working doctors 15 10 13 11 patients’ views of interpersonal continuity of care in four primary health care centres of urban oman 290 | squ medical journal, december 2009, volume 9, issue 3 children, and emergency cases were excluded from the study. patients were assured of the confidentiality of the data and that their responses would not affect their future management by their pcps. nonparticipants were ask to complete an anonymous demographic information form which included questions on age and gender. data collection was carried out while the patients waiting to consult their pcps. the study was conducted in the period june to august 2008. data management and analysis were done as follows: proportions, mean, median and other distribution measures were estimated for the variables included in the questionnaire. a score on interpersonal continuity of care was generated from the questionnaire and correlated with all demographic variables using both bivariate and multivariate analyses. both descriptive and analytical statistics were generated using statistical package for the social sciences (spss), version 16. in questions with matrix responses, some groups had few responses. therefore, all of the responses were collapsed to three points by combining “strongly agree” and “somewhat agree” into a single code; “strongly disagree” and “somewhat disagree” were similarly combined. frequency tables were created for each variable. cross-tabulations were run where appropriate. chi-square tests were used to test statistical significance between independent variables (age, sex, presence of chronic illnesses) and dependent variables (patients’ responses). p-values <0.05 were used to indicate statistically significant associations. results a total of 319 patients participated from the 450 invited (response rate = 71%). two hundred and sixteen patients (68%) were recruited from muscat (phcs a and b) and 103 (32%) were recruited from sohar (phcs c and d). the socio-demographic characteristics of the participants compared with non-participants are highlighted in table 3. two hundred and twenty nine patients (72%) thought that it was important to see the same pcp at every visit to the phc and 241 patients (76%) identified the importance of interpersonal continuity in order gradually to build up a good relationship with the pcp. indeed, 249 patients (78%) recognised that better care can be obtained by consulting the same pcp; this became more important if they had psychosocial problems (n = 248, 77%) or any chronic illnesses (n = 211, 66%) such as diabetes, asthma or hypertension. nevertheless 122 patients (38%) had had the chance to consult their preferred pcp over the past two years. ninety eight patients (31%) stated that their table 3: characteristics of participants compared with non-participants variables participants (n = 319) non-participants (n = 131) age range (year) 18-70 18-67 mean (year) 38 34 median (year) 33 29 standard deviation (±sd) 9.3 9.5 gender male 92 (29%) 30 (23%) female 227 (71%) 101(77%) education illiterate 61(19%) 32 (24%) completed primary school 120 (38%) 42 (32%) completed secondary school 102 (32%) 47 (36%) completed university or postgraduate education. 36 (11%) 10 (8%) mohammed al-azri m and shyam s ganguly clinical and basic research | 291 medical record is sufficient to provide continuity in the absence of their pcp and 303 patients (95%) thought that there should be a link between primary and secondary health care services to manage their health problems more effectively. female patients were more in agreement with the statement that they had less chance to see the same pcp compared to male patients. they thought that they received less personal care and it was less important for them to build-up relationships with a specific pcp [table 4]. a significant association was found between patients’ ages and their responses. as patients’ ages increased both their desire to maintain interpersonal continuity with the same pcp (p = 0.02) and to build-up a relationship with the same pcp increased (p = 0.03) [table 5]. there was significant agreement between patients with chronic illnesses (diabetes, hypertension, asthma) and without chronic illnesses. patients who reported suffering from any chronic illnesses preferred to consult the same pcp (p = 0.001); they felt improvement of their conditions when consulting the same pcp (p = 0.043); they were more willing to comply with recommended medications and advice (p = 0.027); they were more satisfied with the quality of services provided at their health care centres ((p = 0.017) and they thought that there should be link between their phc and the hospital to mange their chronic illnesses (p = 0.024) [table 6]. further analysis of the data showed a significant association between patients who reported suffering from hypertension and diabetes compared to those without hypertension and diabetes. patients who suffered from hypertension thought that their doctors were more understanding of their problems (p = 0.012); they received more personal attention (p = 0.001) and personal care (p = 0.032) [table 7]. patients who suffered from diabetes thought that their usual pcps were more aware of their personal and family background (p = 0.002) [table 8]. discussion in this study, we have explored patients' views of interpersonal continuity of care, an importan subject for comprehensive health care delivery in the phc set up. to our knowledge there have been no similar previous studies conducted in arabian countries including oman. the results from this study show for the first time that the majority of patients in primary care settings in oman valued interpersonal continuity in order to obtain better care, particularly if they were old, suffering from chronic diseases such as diabetes, asthma, hypertension, or if they encountered psychosocial problems. nevertheless, female patients had table 4: agreement according to gender item gender p-value male (n = 92) female (n = 227) total (n = 319) have always had the chance to see the same doctor 40 (43.5%) 72 (31.7%) 112 (35.1%) 0.018 receiving better care by seeing the same doctor 77 (83.7%) 162 (71.4%) 239 (74.9%) 0.033 important to build-up relationships over time with the same doctor 76 (82.6%) 156 (68.4%) 232 (73.0%) <0.00 table 5: agreement according to age groups item age groups p-value< 30 (n = 224) 31-50 (n = 81) > 50 (n = 10) total (n = 315) important to see the same doctor 128 (58.2%) 54 (67.0%) 7 (70.0%) 189 (60.6%) 0.024 important to build-up relationship with the same doctor over the time 157(70.4%) 60 (75.0%) 10 (100.0%) 227 (72.5%) 0.025 patients’ views of interpersonal continuity of care in four primary health care centres of urban oman 292 | squ medical journal, december 2009, volume 9, issue 3 less chance to develop interpersonal continuity compared to male patients. we also found that patients who reported more interpersonal continuity also reported more beneficial outcomes such as satisfaction with the services provided, improvement of their conditions and compliance with the recommended medication and advice. in this study, we found that 72% of the patients perceived that it is important for them to consult the same pcp when visiting phc. a study in usa found that nearly two thirds of patients in phc preferred having one doctor to take care of them;12 another study, also conducted in the usa, reported that over 90% of respondents thought it was very important to have the same pcp to take care of them over time.13 indeed, when there is interpersonal continuity, patients usually feel they know the doctor and experience trust, satisfaction and good quality of care.14 interpersonal continuity implies empathy and personal responsibility from the doctor as well as commitment by both the patient and the doctor.15 despite most patients’ ambitions of interpersonal continuity in this study, only 38% of them had had the chance to consult their preferred pcp over the previous two years; hence, interpersonal continuity was difficult to achieve for some patients who wanted it. the health care system at different phcs in oman seems not to support interpersonal table 6: agreement according to presence of chronic illnesses (diabetes mellitus, hypertension, asthma) item total respondents for each item(n) total patients with above illnesses (n) agreement among patients with above illnesses n (%) total patients without above illnesses (n) agreement among patients without above illnesses n (%) p-value important to see the same doctor 290 62 46 (74.2) 228 148 (64.9) 0.001 improvement if the same doctor is seen 290 61 43 (70.5) 229 123 (53.7) 0.043 comply with medications / follow advice if the same doctor is seen 286 58 33 (56.9) 228 104 (45.6) 0.027 health centre provides high quality care 288 60 32 (53.3) 228 76 (33.3) 0.017 there should be a link between my health centre and hospital 287 60 50 (83.3) 227 214 (94.3) 0.024 table 7: additional agreement of hypertensive patients item total respondents for each item (n) total patients with hypertension (n) agreement among patients with hypertension n (%) total patients without hypertension (n) agreement among patients without hypertension n (%) p-value understanding of the usual doctor 309 24 22 (91.7) 285 189 (66.3) 0.012 attention of the usual doctor 313 29 28 (96.6) 284 204 (71.8) 0.001 personal care of the usual doctor 313 29 25 (86.2) 284 181 (63.7) 0.032 mohammed al-azri m and shyam s ganguly clinical and basic research | 293 continuity; patients are not allotted to the same pcp when registered and doctors work in shifts which decreases their availability to patients. the catchments area populations of both muscat and sohar are large; each pcp looks after approximately 3,800 patients which could affect their availability to each patient and therefore interfere with providing adequate interpersonal continuity. indeed, in other countries, some large phcs have become more like small hospitals with the increases in the numbers of staff, multidisciplinary teams, and specialist clinics.16,17 thus, as the primary care organisation becomes more complex and the system impedes patients’ access to their usual pcp, personal patient-doctor relationships and interpersonal continuity may decline.18,19 nevertheless, an appointment system for consulting a pcp has been introduced recently in all phcs of the capital area, muscat.11 thus, patients can now select an appointment with a chosen pcp, with whom they feel comfortable and whom they trust so that could promote interpersonal continuity in the future. the reason for the low rate of interpersonal continuity amongst female patients in our study compared to male patients in our study is not clear. a study conducted in brazil, on the contrary, showed that being a female patient was associated with high achievement of interpersonal continuity.20 more research is therefore needed to confirm our current findings. in our study, older patients and those who suffered from psychosocial or chronic physical illnesses (diabetes, hypertension, asthma) were more in favour of interpersonal continuity than younger patients or patients without such conditions. it has been found that older patients feel unsafe if they are not seeing their usual pcp.21 patients with minor problems tend to prioritise speedy access to care over interpersonal continuity.22 indeed, in previous studies, interpersonal continuity has been more valued by patients with chronic and psychological problems compared with acute or minor illnesses.23,22 patient with chronic and psychosocial illnesses could consult the same physician frequently which could increase satisfaction, trust and confidence.24,25 in addition, patients who exhibited satisfaction, trust and confidence were more likely to have had a longer relationship with their providers and hence to believe more in the importance of interpersonal continuity.26,27 our study has the followings limitations. first, the study was conducted in four phcs out of 165 phcs of the moh in oman which were selected because of their convenience to medical students carrying out the survey. hence, results might not be representative of the whole omani adult population and outcomes cannot be extrapolated to the entire primary health system in oman. indeed, this limitation becomes more significant when we take into account the fact that approximately 50% of the omani population is less than 18 years of age and we did not include in our study the parents of children visiting phcs. nevertheless, we believe that patients attending these phcs are not very different from omani patients in other regions of the country. therefore, a valid extrapolation of our results to other omani populations may be feasible. second, there were more female patients recruited than male; this might be attributable to the fact that the study was conducted in the morning when more male patients are at work. this may have introduced some bias towards female opinions. third, although the questionnaire has been adapted from literature, the validity and reliability of the questionnaire still needs to be scrutinised. fourth, we cannot guarantee that that most patients who were recruited for the study attended their phcs repeatedly and therefore that they could evaluate interpersonal continuity reliably. finally, although the medical students table 8: additional agreement of diabetic patients item total respondents for each item (n) total patients with diabetes (n) agreement among patients with diabetes n (%) total patients without diabetes (n) agreement among patients without diabetes n (%) p-value awareness of the usual doctor of personal and family background 309 9 8 (90) 300 110 (37) 0.002 patients’ views of interpersonal continuity of care in four primary health care centres of urban oman 294 | squ medical journal, december 2009, volume 9, issue 3 were taught to be non-judgmental when collecting data from illiterate patients, we cannot guarantee that their behaviour had no effect on the study outcomes. taking into account the effect of interpersonal continuity on improving the quality of care, the moh in oman could consider strategies to promote interpersonal continuity. the expansion of the appointment system for patients to consult their pcps outside the capital city (muscat) could enhance interpersonal continuity. patients could then book an appointment with a specific trusted doctor. indeed, service providers should take steps to help patients to obtain primary care services from doctors they prefer, particularly from someone whom they know and trust. nevertheless, future strategies of the moh in oman could propose that patients should be registered with a specific pcp at their phcs which could maximize the opportunities for the development of interpersonal continuity. finally, female patients may have less chance to experience interpersonal continuity than male patients; however, another study is needed to find out why female patients had less chance for interpersonal continuity. conclusion this study showed for the first time that the majority of patients in primary health care in oman value interpersonal continuity and they want to consult someone whom they know; this tendency becomes more significant if they are old or have chronic illnesses, such as diabetes, hypertension, asthma or psychosocial illnesses. acknowledgments the authors thank the following medical students of sultan qaboos university who helped in data collection: fatema al-lawatiya, reem al-farsi, and fatema al-kendi. the authors also thank dr thord theodorsson, department of family medicine and public health, sultan qaboos university hospital who helped in revising the manuscript. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. references 1. alazri m, heywood p, neal r, leese b. continuity of care literature review and implications. squ med j 2007; 7:31-40. 2. al-azri m. continuity of care and quality of care inseparable twins. oman med j 2008; 23:147. 3. saultz jw. defining and measuring interpersonal continuity of care. ann fam med 2003; 1:134-43. 4. haggerty jl, reid rj, freeman gk, starfield bh, adair ce, mckendry r. continuity of care: a multidisciplinary review. bmj 2003; 327:1219-21. 5. starfield b. is primary care essential? lancet 1994; 344:1129-33. 6. cabana md, jee sh. does continuity of care improve patient outcomes? j fam pract 2004; 53:974-80. 7. safran dg, taira da, rogers wh, kosinski m, ware je, tarlov ar. linking primary care performance to outcomes of care. j fam pract 1998; 47:213-20. 8. ministry of health. annual health report 2007. muscat: director general of planning, ministry of health. from http://www.moh.gov.om/stat/ ch01y07.pdf. accessed october 2009. 9. ministry of health. phc mission and policy 7th five year plan (2006-2010). 2006. muscat: ministry of health, oman. from http://www.primarycareoman. com/phc_policy.aspx. accessed june 2009. 10. evans db, tandon a, murray cj, lauer ja. comparative efficiency of national health systems: cross national econometric analysis. bmj 2001; 323:307-10. 11. director of health affairs, director general of health services. protocol for appointment systems at primary health care. governorate of muscat, 3rd ed. muscat: ministry of health, oman, 2008. 12. lewis cl, wickstrom gc, kolar mm, keyserling tc, bognar ba, dupre ct, et al. patient preferences for care by general internists and specialists in the ambulatory setting. j gen intern med 2000; 15:7583. 13. pereira ag, pearson sd. patient attitudes toward continuity of care. arch intern med 2003; 163:90912. 14. tarrant c, colman am, stokes t. past experience, shadow of the future, and patient trust: a crosssectional survey. br j gen pract 2008; 58:780-3. 15. baker r, boulton m, windridge k, tarrant c, bankart j, freeman gk. interpersonal continuity of care: a cross-sectional survey of primary care patients’ preferences and their experiences. br j gen pract 2007; 57:283-9. 16. freeman g, hjortdahl p. what future for continuity of care in general practice? bmj 1997; 314:1870-3. 17. stokes t, tarrant c, mainous ag, iii, schers h, freeman g, baker r. continuity of care: is the mohammed al-azri m and shyam s ganguly clinical and basic research | 295 personal doctor still important? a survey of general practitioners and family physicians in england and wales, the united states, and the netherlands. ann fam med 2005; 3:353-9. 18. baker r, streatfield j. what type of general practice do patients prefer? exploration of practice characteristics influencing patient satisfaction. br j gen pract 1995; 45:654-9. 19. baker r. will the future gp remain a personal doctor? br j gen pract 1997; 47:831-3. 20. filho r, artur l, fassa ag, paniz vmv. factors associated with interpersonal continuity of care: a population-based study. cad saْde pْblica 2008; 24:915-25. 21. pandhi n, schumacher j, flynn ke, smith m. patients’ perceptions of safety if interpersonal continuity of care were to be disrupted. health expect 2008; 11:400-8. 22. kearley ke, freeman gk, heath a. an exploration of the value of the personal doctor-patient relationship in general practice. br j gen pract 2001; 51:712-8. 23. alazri mh, neal rd, heywood p, leese b. patients’ experiences of continuity in the care of type 2 diabetes: a focus group study in primary care. br j gen pract 2006; 56:488-95. 24. gore j, ogden j. developing, validating and consolidating the doctor-patient relationship: the patients’ views of a dynamic process. br j gen pract 1998; 48:1391-4. 25. tarrant c, stokes t, baker r. factors associated with patients’ trust in their general practitioner: a crosssectional survey. br j gen pract 2003; 53:798-800. 26. mainous ag iii, baker r, love mm, gray dp, gill jm. continuity of care and trust in one’s physician: evidence from primary care in the united states and the united kingdom. fam med 2001; 33:22-7. 27. hjortdahl p, laerum e. continuity of care in general practice: effect on patient satisfaction. bmj 1992; 304:1287-90. squ med j, may 2011, vol. 11, iss. 2, pp. 269-272, epub. 15th may 11 submitted 29th aug 10 revision req. 5th oct 10, revision recd. 17th oct 10 accepted 9th mar 11 leishmaniases are a group of zoonotic diseases caused by a haemoflagellate protozoan of the genus leishmania. the parasites are present in the macrophages of a wide variety of vertebrates. they are transmitted to man from the animal reservoir through the bite of female sand flies of the phlebotomus species.1 there are several species of leishmania that can infect human and result in a spectrum of diseases known as leishmaniasis.2 depending on the mode of presentation there are three main types: cutaneous leishmaniasis, which is often self-limiting, mucosal leishmaniasis and visceral leishmaniasis.3 visceral leishmaniasis affects mainly the mononuclear phagocytic system of the bone marrow, liver and spleen1 and is caused mainly by leishmania donovani and leishmania infantum species.2 it shows a wide geographical spread in more than 88 countries all over the world.4 clinically, typical cases of visceral leishmaniasis are found primarily in children.4 it's features include fever, anaemia, hepatosplenomegaly, adenomegaly, hypergammaglobulinaemia, and pancytopenia, but it can also manifest itself atypically, mostly in patients infected with hiv and geriatric immunocompetent patients.5 the definitive diagnosis of visceral leishmaniasis is achieved by identification of the organism in a bone marrow biopsy. the characteristic leishmania amastigotes are round to ovoid in shape and can be identified after routine haematoxylindepartment of pathology, nineveh medical college, university of mosul, iraq. *corresponding author email: nazar3nhn@yahoo.com <h^í⁄<òëü⁄<ôç÷<îáé£]<^èfi^€éè◊÷]<]ç÷<<ïöå^fi<ì÷^u l^èeå_<ì√q]ü⁄<ƒ⁄<hgäj”π]<ì¬^flπ]<ìœfi<åê4àe          :مفتاح الكلمات abstract: visceral leishmaniasis is a disease caused by a haemoflagellate protozoan of the genus leishmania. it has a wide geographical spread. classic cases are found primarily in children and present with typical features that include fever, anaemia, hepatosplenomegaly, hypergammaglobulinaemia, and pancytopenia. the diagnosis is usually achieved by bone marrow smears, culture and serology; however, it can manifest itself atypically, mostly in patients infected with hiv and geriatric immunocompetent patients. we report an unusual case of visceral leishmaniasis diagnosed in a 27 year-old hiv-infected male who presented with abdominal discomfort and diarrhoea of four weeks duration associated with nausea and vomiting, but with no typical symptoms or signs of visceral leishmaniasis. the diagnosis was established through the identification of the leishmania organism in duodenal and colonic biopsies and confirmed by subsequent bone marrow smears. keywords: visceral leishmaniasis; hiv; duodenal biopsy; case report; iraq visceral leishmaniasis with an unusual presentation in an hiv positive patient nazar m.t. jawhar case report visceral leishmaniasis with an unusual presentation in hiv positive patient 270 | squ medical journal, may 2011, volume 11, issue 2 eosin or giemsa staining.4,6 other diagnostic tools include isolation of promastigotes by novymcneal-nicolle (nnn) culture2,4 and serological tests to detect antileishmanial antibodies, but the latter have low sensitivity.3,4 histopathological identification of leishmania organisms in tissue sections is quite easy and very sensitive;4 however, the diagnosis of leishmaniasis in paraffin sections may be difficult in some conditions, such as when the parasites are present in unusual sites which is frequently observed in visceral leishmaniasis that develops in immunocompromised patients.2,7 this is a presentation of an unusual case of visceral leishamniasis diagnosed in an hiv-infected patient, with atypical clinical features, who was unexpectedly diagnosed through the identification of the leishmania organism in an unusual site. case report the patient was a 27 year-old yemeni male, diagnosed with hiv infection 8 years previously, who presented with abdominal discomfort and diarrhoea of four weeks duration associated with nausea and vomiting, but no fever or anorexia. the diarrhoea (5–6 times a day) was watery and accompanied by mucus, but with no blood. on physical examination, the patient was conscious, oriented, afebrile and not pale. his vital signs were stable. his chest was clear and abdominal examination showed mild subumbilical tenderness, but no abdominal mass or organ enlargement was detected. no lymphadenopathy was present. the patient was not receiving any antiretroviral therapy. laboratory investigations showed leukocytes 10.88x103/µl, 83% neutrophils, 8.4% lymphocytes and 8.4% monocytes. the haemoglobin level was 136 g/l, erythrocytes sedimentation rate 16 mm/ hour. urine examination showed mild proteinuria and his serum creatinine was mildly elevated at 2.1 mg/dl. stool samples were negative for cryptosporidium and clostridium difficile toxin and repeated stool culture revealed no pathogens. his cd4 cell count was 210 cells/mm3. an abdominal ultrasound showed no abnormalities. an upper git endoscopy showed normal oesophageal and gastric mucosa; however, the mucosa of the second part of the duodenum showed congestion with a peculiar whitish nodular appearance [figure 1]. a colonoscopy showed normal colonic mucosa. multiple biopsies were taken from the oesophagus, stomach, duodenum and colon for histopathological examination to exclude microscopic lesions and opportunistic infections. the histopathological examination demonstrated widening of the duodenal villi with infiltration of duodenal and rectal mucosa by a large number of macrophages filled with intracytoplasmic leishmania amastigote parasites (donovan bodies) [figure 2]. gastric and oesophageal biopsies showed no significant pathologic changes. the case was diagnosed as visceral leishmaniasis. subsequent bone marrow aspirate (showing leishman– donovan bodies) confirmed the diagnosis [figure 3]. the patient was treated with sodium stibogluconate (20 mg/kg/day), but he was lost to follow-up after 1 week of therapy. figure 1: upper git endoscopy revealing whitish nodular appearance of the duodenal mucosa. figure 2: duodenal biopsy showing many macrophages with abundant intracytoplasmic leishmaniae. nazar m.t. jawhar case report | 271 discussion although it affects mainly immunocompetent individuals, leishmania is considered an opportunistic pathogen in immunosuppressed patients particularly those with aids.8,9 on the other hand, hiv infection increases the risk of developing visceral leishmaniasis by 100–1,000 times in endemic areas.10 in fact, some studies showed that visceral leishmaniasis is the fourth most common opportunistic parasitic disease in hiv-positive individuals after pneumocystosis, toxoplasmosis, and cryptosporidiosis.4,10,11 indeed, both hiv and leishmaniasis result in a cumulative deficiency of the cellular immune response since both agents damage similar immune resources thus promoting chronicity and, when untreated, result in death.6,10 the first case of leishmania/hiv coinfections was diagnosed in 198512 and almost all cases of leishmania co-infection with hiv have been described in patients with hiv-1.13 according to data from the world health organization, hivleishmania co-infection is widely distributed.14 the most common areas are southern european countries (like spain), and brazil, india, bangladesh and nepal.1,10 the real impact of hiv-leishmania co-infection is probably underestimated owing to constraints in the surveillance and reporting of cases. the majority of leishmaniasis cases in hivpositive patients appear in the advanced stages of the disease. in about 80% of patients, the number of cd4 lymphocytes is less than 200/mm3 while in c. 20 % of patient.1,4,15 in the current case, the number was low (210 cells/mm3). leishmaniasis has different characteristics in patients with aids compared with immunocompetent patients.8 classic visceral leishmaniasis in immunocompetent individuals is found primarily in children, but in recent years an increasing number of adult cases have been observed mostly in hiv patients.4,5,15–17 in the latter, the location is more likely to be atypical such as gastrointestinal tract, larynx, lungs, kidneys, pancreas and testes.5,6 organomegaly, which is one of the typical clinical features of classical visceral leishmaniasis in immunocompotent individuals, is usually absent in hiv positive adults3 as in our case. also cytopenia is more frequent in immunosuppressed individuals along with negative serology and higher relapse rate after therapy. 5,6,8,10 the gastrointestinal involvement and overt malabasorption in visceral leishmaniasis is reported more freqently in those with concomitant hiv infection.3,5,8,18–20 lesions have been seen from the oesophagus to the rectum;6 however, the duodenum is the most common site.5 the exact pathogenesis of the diarrhoea and malabsorption is not clear, but it has been suggested that these symptoms in enteropathic visceral lesihsmaniasis may be a combination of the mechanical occlusion of the mucosa by parasites, bacterial overgrowth, partial villous atrophy, competition between the host and the parasite for nutrients, altered motility, bile salt deconjugation and lymphatic blockade.3 endoscopic examination of these patients is usually performed because of diarrhoea and epigastralgia. the findings are variable and may be unremarkable,6,18,21 showing non-specific inflammation,5,22 or an atrophic mucosal pattern.8 in the current case, the mucosa of the second part of the duodenum showed congestion with a peculiar whitish nodular appearance, a rare and unusual finding also reported by others.1 the colonoscopy showed a normal colonic mucosal pattern. histopathological examination of intestinal (duodenal and colonic) biopsies shows intact architecture and abundant macrophages with intracytoplasmic leishmania amastigotes (donovan bodies).5,6,19,22 some cases may show duodenal villous atrophy.3,22 conclusion in conclusion, clinicians should be alert about the figure 3: bone marrow aspirate smear revealing intracytoplasmic leishmaniae. visceral leishmaniasis with an unusual presentation in hiv positive patient 272 | squ medical journal, may 2011, volume 11, issue 2 possibility of leishmaniasis in hiv positive patients presenting with diarrhoea, particularly in patients from endemic areas. also pathologists should pay attention to the possible finding of leishmania amastigotes in biopsies from intestinal mucosa in hiv infected patients. references 1. del olmo martínez l, aller de la fuente r, velayos jiménez b, fernández salazar l. gonzález hernández jm. visceral leishmaniasis diagnosed by duodenal biopsy. gastroenterol hepatol 2009; 101:439–51. 2. hofman v, borusset p, mougneau e, marty p, lamat l, antoine jc, et al. immunostaining of visceral leishmaniasis caused by leishmania infantum using monoclonal antibody (19-11) to the leishmania homologue of receptors for activated c-kinase. am j clin pathol 2003; 120:567–74. 3. hicks l, kant p, tay ph, vincini v, schuster h, rotimi o, et al. visceral leishmaniasis presenting with intestinal failure: a case report and literature review. eur j gastroenterol hepatol 2009; 21:117– 22. 4. alvar j, canavate c, gutierrez-solar b, jiménez m, laguna f, lópez-vélez r, et al. leishmania and human immunodeficiency virus co-infection: the first 10 years. clin microbiol rev 1997; 10:298–319. 5. alvarez-nebreda ml, alvarez-fernández e, rada s, brañas f, marañón e, vidán mt, et al. unusual duodenal presentation of leishmaniasis. j clin pathol 2005; 58:1321–2. 6. kostiuk o, levi i, krieger m, assouline-dayan y, barshack. intestinal leishmaniasis in a patient with aids. isr med assoc j 2006; 8:714–15. 7. albrecht h, sobottka i, emminger c. visceral leishmaniasis emerging as an important opportunistic infection in hiv infected persons living in areas nonendemic for leishmania donovani. arch pathol lab med 1996; 120:189–98. 8. ellul p, piscopo t, vassallo m. visceral leishmaniasis diagnosed on duodenal biopsy. clin gastroenterol hepatol 2007; 5:a26. 9. mcbride mo, fisher m, skinner cj, golden r, main j. an unusual gastrointestinal presentation of leishmaniasis. scand j infect dis 1995; 27:297–8. 10. paredes r, munoz j, diaz i, domingo p, gurgui m, clotet b. leishmaniasis in hiv infection. j postgrad med 2003; 49:39–49. 11. montalban c, calleja jl, erice a, laguna f, clotet b, podzamczer d, et al. co-operative group for the study of leishmaniasis in aids. visceral leishmaniasis in patients infected with human immunodeficiency virus. j infect 1990; 21:261–70. 12. de la loma a, alvar j, martı´nez e, bla´zquez j, alcala´ a, na´jera r. leishmaniasis or aids? trans r soc trop med hyg 1985; 79:421–2. 13. sacramento r, horta a, vasconcelos o, coelho h, granato c, rocha a. leishmaniasis visceral en enfermo infectado por vih-2. rev clin esp 1995; 195:591–92. 14. world health organization. leishmania/hiv co-infection. epidemiological analysis of 692 retrospective cases. wkly epidemiol rec 1997; 72:49–54. 15. moreno-camacho a, lópez-vélez r, muñoz sanz a, labarga-echevarría p. intestinal parasitic infections and leishmaniasis in patients with hiv infection. enferm infecc microbiol clin 1998; 1:52–60. 16. bel haj salah m, mekni a, khanfir m, bellil k, benhaha-bellil s, chelly i, et al. unusual presentation of visceral leishmaniasis in an immunocompetent patient. med mal infect 2006; 36:167–9. 17. alvar, j. leishmaniasis and aids co-infection. the spanish example. parasitol today 1994; 10:160–3. 18. baba cs, makharia gk, mathur p, ray r, gupta sd, samantaray jc. chronic diarrhoea and malabsorption caused by leishmania donavani. indian j gastroenterol 2006; 25:309–10. 19. zimmer, g, guillou l, gauthier t, iten a, saraga ep. digestive leishmaniasis in acquired immunodeficiency syndrome: a light and electron microscopic study of two cases. mod pathol 1996; 9:966–9. 20. hofman v, marty p, perrin c, saint-paul mc, le fichoux y, michiels jf, et al. the histological spectrum of visceral leishmaniasis caused by leishmania infantum mon-1 in acquired immune deficiency syndrome. hum pathol 2000; 31:75–84. 21. alonso mj, muñoz e, picazo a, abad mm, gómez f, roldán m, et al. duodenal leishmaniasis diagnosed by biopsy in two hiv-positive patients. pathol res pract 1997; 193:43–50. 22. laguna f, garcía-samaniego j, soriano v, valencia e, redondo c, alonso mj, et al. gastrointestinal leishmaniasis in human immunodeficiency virusinfected patients: report of five cases and review. clin infect dis 1994; 19:48–53. re: thyroid dysfunction in children with idiopathic nephrotic syndrome attending a paediatric hospital in qazvin, iran sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e332, epub. 21 jun 21 submitted 6 jan 21 revision req. 16 feb 21; revision recd. 28 feb 21 accepted 9 mar 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.030 letter to the editor dear editor, i read with interest the case-control study by saffari et al. published in the november 2020 issue of squmj.1 among a cohort of iranian children, saffari et al. compared thyroid hormone levels between patients with nephrotic syndrome (ns) and healthy controls as well as between patients with ns in the active stage of the disease and those in remission. they found that increased thyroid-stimulating hormone (tsh) levels were more common in patients with ns in comparison with controls (34.2% versus 10.8%; p = 0.001). a significantly lower number of patients with active disease were euthyroid in comparison with those in remission (51% versus 95.8%; p = 0.001). furthermore, 9.5% of patients in the active and no patient in the remission stage had abnormal free thyroxine levels (p <0.001), while 14.3% and 0% had highly increased tsh levels, respectively (p = 0.002).1 in patients with ns, the rates of subclinical hypothyroidism (34.7%) and overt hypothyroidism (14.3%) were significantly higher compared to controls (4.2%; 0% respectively; p = 0.001). based on the reported prevalence of subclinical (34.7%) and even overt hypothyroidism (14.3%), saffari et al. recommended that thyroid screening tests might be needed for patients with ns.1 they also mentioned two study limitations, namely small sample size and short follow-up period that did not allow adequate detection of hypothyroid subsidence in cases of subclinical hypothyroidism. it is worth mentioning that the correct evaluation of thyroid health status is centred on the use of suitable reference intervals (ri) of the thyroid function tests (tft) to evaluate the readings of different components of tft. there are certain determinants of ri of tft for a particular population that must be taken into consideration such as age, gender, body mass index and genetic variants.2 iran is among the pioneer countries that have already formulated their own ri of tft to be utilised in researche centres and clinical fields.3 instead of using a local standard, saffari et al. mentioned in the study methodology that they referred to the foreign ri of tft to define subclinical hypothyroidism and hypothyroidism.4,5 accordingly, this limitation might question the accuracy of the study results and recommendation. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. saffari f, ahadi s, dalirani r, esfandiar n, yazdi z, arad b. thyroid dysfunction in children with idiopathic nephrotic syndrome attending a paediatric hospital in qazvin, iran. sultan qaboos univ med j 2020;20:e332–8. https://doi.org/10.18295/squmj.2020.20.04.009. 2. chaker l, korevaar ti, medici m, uitterlinden ag, hofman a, dehghan a, et al. thyroid function characteristics and determinants: the rotterdam study. thyroid 2016;26:1195–204. https://doi.org/ 10.1089/thy.2016.0133. 3. mansourian ar, ahmadi ar, saifi a, bakhshandehnosrat s. the children reference range of thyroid hormones in northern iran. pak j biol sci 2010;13:862–5. https://doi.org/10.3923/pjbs.2010.862.865. 4. crisafulli g, aversa t, zirilli g, pajno gb, corica d, de luca f, et al. subclinical hypothyroidism in children: when a replacement hormonal treatment might be advisable. front endocrinol (lausanne) 2019; 10:109. https://doi.org/10.3389/fendo.2019.00109. 5. ito s, kano k, ando t, ichimura t. thyroid function in children with nephrotic syndrome. pediatr nephrol 1994; 8:412–15. https://doi. org/10.1007%2fbf00856516. e332 | squ medical journal, may 2021, volume 21, issue 2 https://creativecommons.org/licenses/by-nd/4.0/ https://doi.org/10.18295/squmj.2020.20.04.009 https://doi.org/%2010.1089/thy.2016.0133 https://doi.org/10.3923/pjbs.2010.862.865 https://doi.org/10.3389/fendo.2019.00109 https://doi.org/10.1007%252fbf00856516 https://doi.org/10.1007%252fbf00856516 12nd orthopaedic department, general hospital of thessaloniki ‘papageorgiou’, thessaloniki, greece; 2school of medicine, aristotle university of thessaloniki, thessaloniki, greece *corresponding author’s e-mail: vasiliadis.av@gmail.com mid-term radiological and functional outcomes of bicondylar tibial plateau fractures managed with open reduction and internal fixation using dual plates *angelo v. vasiliadis,1,2 frideriki poutoglidou,1 dimitrios metaxiotis,1 anastasios mpeletsiotis1 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 51–57, epub. 28 feb 22 submitted 20 jul 20 revision req. 28 sep 20; revision recd. 28 oct 20 accepted 9 dec 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.059 clinical & basic research abstract: objectives: this study aimed to evaluate the mid-term radiological and functional outcome of tibial plateau fractures treated by plating. methods: this study was conducted at the general hospital of thessaloniki ‘papageorgiou’, thessaloniki, greece. patients with schatzker type v and vi tibial plateau fractures who were managed with open reduction and internal fixation using dual plates between january 2011 and december 2018 were included in this retrospective study. the functional evaluation of the patients was carried out with the visual analogue scale (vas), the health-related quality of life status was measured using the short form-36 and the dimensions of pain, stiffness and function were assessed using the western ontario and mcmaster universities arthritis index. for the radiological outcome evaluation, the modified rasmussen criteria were used. results: fifty-seven patients (30 male and 27 female) were included in the study with a mean follow-up of 50.88 months. there were 23 schatzker type v and 34 type vi fractures. the majority of patients (86%) had a good to excellent radiological outcome. the mean vas score was 1.65 for all the patients. the functional outcome was excellent in the majority of the patients. among them, 5.3% (n = 3) suffered wound infection and all wounds healed after different treatments. all patients returned to their pre-injury activities of daily living and employment status, while 53% of the patients returned to sporting activities. conclusion: the findings support previous literature which has demonstrated that bicondylar tibial plateau fractures can provide good-to-excellent radiological and functional outcomes if they are treated with open reduction and internal fixation with dual plating. keywords: tibial; fracture; classification; surgical procedure; plating. advances in knowledge the findings of the present study show that bicondylar tibial plateau fractures treated operatively with open reduction and internal fixation (orif) with dual plates had good-to-excellent mid-term radiological (modified rasmussen criteria) and functional (short form-36 and western ontario and mcmaster universities arthritis index) outcomes at mid-term follow-up. there were no statistically significant differences between the early (≤48 hours) and delayed time to surgery with respect to superficial and deep wound infection. application to patient care early surgical intervention for bicondylar tibial plateau fractures may be the key to successful treatment and improved functional outcomes. tibial plateau fractures comprise approximately 2% of all fractures and tend to have a bimodal age distribution. males in the fourth decade of their life are more likely to sustain these types of injuries due to high-energy trauma. meanwhile, tibial plateau fractures are usually a result of lowenergy trauma in females around the age of 70.1 these injuries are often associated with soft tissue damage such as vasculature, nerves, ligaments and meniscus.2 schatzker proposed a classification system based on the two-dimensional radiological features, dividing tibial plateau fractures into six types, from type i to vi.3 as a supplement to the schatzker classification, in 2010, luo et al. introduced the three-column classification based on computed tomography scan images and three-dimensional reconstruction, thereby increasing the ability to identify the posteromedial fragment.4 these types of fractures, which pose a challenge even to a senior orthopaedic surgeon, still yield unsatisfactory results despite appropriate surgical treatment due to their complexity and the associated soft tissue disruption.2,3 the objective of tibial plateau operative treatment is to obtain a stable osteosynthesis and to enable early mobilisation of the knee joint. various techniques have been proposed over the last few decades, each one with its own merits and demerits. open reduction and internal fixation (orif) with various types of plates and screws remains the gold standard. alternatively, circular external fixation with limited internal https://creativecommons.org/licenses/by-nd/4.0/ mid-term radiological and functional outcomes of bicondylar tibial plateau fractures managed with open reduction and internal fixation using dual plates 52 | squ medical journal, february 2022, volume 22, issue 1 fixation (hybrid fixator) and arthroscopically assisted percutaneous reduction and internal fixation have been reported for the treatment of tibial plateau fractures.5–7 despite the plethora of techniques, malalignment and secondary osteoarthritis are common complications encountered after surgery for complex tibial plateau fractures. this study aimed to evaluate the mid-term radiological and functional outcome of tibial plateau fractures managed with orif using dual plates. methods this retrospective study was conducted at the general hospital of thessaloniki ‘papageorgiou’, thessaloniki, greece. all patients admitted with the diagnosis of bicondylar tibial plateau fractures over a period of eight years, from january 2011 to december 2018, were included in the study. only patients with schatzker type v and vi managed with dual plating were included. the data were extracted from hospital records and outpatient department notes. the exclusion criteria were: 1) patients with bilateral fractures; 2) patients with ipsilateral femoral fractures (floating knee) or other lower limb fractures; 3) open tibial fractures; and 4) severe head injury with neurological deficits. the fractures were graded preoperatively using schatzker’s classification system of tibial plateau fractures by routine anterior posterior and lateral radiographs of the knee. a computed tomography and a threedimensional reconstruction was also performed to evaluate the fractures’ morphology and severity according to the three-column classification [figure 1].4 according to this classification, patients were categorised as: i) lateral and medial column; ii) lateral and posterior column; iii) medial and posterior column; and iv) lateral, medial and posterior column. a magnetic resonance imaging (mri) was performed on each patient in order to determine ligament and meniscal injuries. all patients had their limb elevated and immobilised with an above knee cast. if oedema was present and development of haemorrhagic fracture blisters occurred, surgery was delayed until soft tissue recovery, as evidenced by reduction of the swelling and appearance of skin lines and ‘wrinkle’ signs. all patients underwent orif of the fracture through an anterolateral approach for fixation of the lateral column, an anteromedial approach for fixation of the medial column and a posteromedial approach for fixation of the posteromedial column. no temporary knee-spanning external fixation or bony skeletal traction was required preoperatively. the fractures were manipulated and fixed with plates under fluoroscopic guidance in order to assist and assess the reduction. the metaphyseal void was filled with allogenic bone grafts to support reduction and to promote fracture healing in depressed and comminuted fractures patterns. all patients in this study were contacted and a last follow-up evaluation was scheduled, during which radiographs of the knee were obtained in the anteroposterior and lateral views to assess the articular depression, the condylar widening, the varus/valgus angulation and any evidence of posttraumatic degenerative changes [figure 2]. regarding functional outcome, the pain was assessed using the visual analogue scale (vas), the health-related quality of life status was measured using the short form36 (sf-36) and the dimensions of pain, stiffness and function were assessed using the western ontario and mcmaster universities arthritis index (womac). the radiological outcome was assessed using modified rasmussen criteria for radiological assessment. range of motion (rom) was measured using a standard goniometer. finally, all complications were documented during the last follow-up. the statistical analysis was conducted with jamovi software version 1.1.9.8 continuous variables were given as mean and standard deviation, while nominal variables were expressed as number of cases. the shapiro-wilk test was used to determine whether data were normally distributed. continuous variables were analysed using the independent samples t-test or the mann-whitney u-test. categorical variables were analysed using pearson’s chi-square test or fisher’s exact test. a p-value of <0.05 was considered to be statistically significant. this study was examined and approved by the institutional review board at the general hospital of thessaloniki ‘papageorgiou’, thessaloniki, greece (56805.2020). informed consent for medical photographs was obtained from the patients. results a total of 57 patients were included in the study. all patients in the present study underwent surgery at a mean interval of 3.09 days (range = 1–9 days). the mean duration of hospitalisation was 8.19 days ranging from 6–13 days. a follow-up ranging from 26–78 months (mean = 50.88 ± 16.56 months) showed that all fractures were healed [table 1]. at the final follow-up, none of the patients reported knee instability while the mean rom was 119.35 ± 4.84 degrees (range = 110– 125 degrees) for type v and 110 ± 10.3 degrees (range = 90–125 degrees) for type vi fractures [table 2]. reatment complications were rare, involving two cases of superficial wound infection (one male and one angelo v. vasiliadis, frideriki poutoglidou, dimitrios metaxiotis and anastasios mpeletsiotis clinical and basic research | 53 female patient with a body mass index of >30 kg/m2), which responded well to non-operative treatment, including local wound care and initial administration of intravenous antibiotics followed by oral antibiotics. one patient, an 86-year-old female with a body mass index of >30 kg/m2, developed deep tissue infection that required surgical intervention with a full-thickness skin flap and intravenous antibiotics administration; the infection was completely resolved. comparison of early (≤48 hours) and delayed time to surgery with respect to superficial and deep infection rate showed no statistically significant difference (p = 0.565). none of the patients developed compartment syndrome. forty-nine patients (86%) had returned to their pre-injury occupation and activities of daily living, while eight (14%) patients reduced or modified table 1: patients’ characteristics of schatzker type v and vi tibial plateau fracture (n = 57) n (%) total (n = 57) type v (n = 23) type vi (n = 34) p value demographic age in years 52.44 ±16.21 51.35 ± 17.85 53.18 ± 15.22 0.680 males 30 (53%) 6 (26%) 24 (71%) < 0.001 mechanism of injury 0.356 road traffic accidents 30 (52.6%) 12 (52%) 18 (53%) fall 23 (40.4%) 11 (48%) 12 (35%) sport 2 (3.5%) 2 (6%) other 2 (3.5%) 2 (6%) time to surgery in days 3.09 ± 2.2 2.96 ± 2.16 3.18 ± 2.25 0.726 early (≤48 hours) 30 13 17 0.629 delayed (>48 hours) 27 10 17 hospitalisation in days 8.19 ± 2.16 8.04 ± 1.99 8.29 ± 2.29 0.778 follow-up in months 50.88 ± 16.56 49.75 ± 15.03 51.65 ± 17.69 0.673 related fractures 0.19 no fractures 39 (68.5%) 17 (74%) 22 (54%) fibula 12 (21%) 4 (17%) 8 (24%) radius 2 (3.5%) 2 (6%) clavicle 2 (3.5%) 2 (6%) rib 2 (3.5%) 2 (9%) ligament injuries < 0.05 no injuries 49 (86%) 23 (100%) 26 (76%) anterior cruciate ligament 6 (11%) 6 (18%) patella tendon 2 (3%) 2 (6%) meniscal injuries 6 (11%) 2 (9%) 4 (12%) return to work/activities of daily living 0.549 yes 49 (86%) 19 (83%) 30 (88%) part-time 8 (14%) 4 (17%) 4 (12%) return to sports* 0.228 yes 2 (11%) 2 (22%) no 9 (47%) 3 (33%) 6 (60%) part-time 8 (42%) 4 (45%) 4 (40%) *n = 19 (reporting sports status pre-injury). mid-term radiological and functional outcomes of bicondylar tibial plateau fractures managed with open reduction and internal fixation using dual plates 54 | squ medical journal, february 2022, volume 22, issue 1 their working status. out of 57 patients, 19 reported a sport status before injury, while approximately 67% and 40% returned to sport activity after surgical treatment for schatzker type v and type vi fractures, respectively [table 1]. at the final follow-up, the mean vas score was 1.39 (range = 0–2) for type v and 1.82 (range = 1–3) for type vi fractures, the sf-36 was 90.65 ± 4.07 (range = 85–95) for type v and 87.35 ± 4.31 (range = 80–95) for type vi fractures and the womac was 21.64 ± 7.14 (range = 10.9–29.8) and 25.26 ± 5.24 (range = 14.9–34.5). radiological results were classified in four categories as per modified rasmussen criteria. of the 57 cases, 14 patients (24.6%) had excellent results, 35 patients (61.4%) had good, seven patients (12.3%) had fair, while only one (1.7%) had poor results [table 2]. table 2: functional and radiological outcomes of tibial plateau fractures (n = 57) total (n = 57) schatzker classification p value type v (n = 23) type vi (n = 34) vas 1.65 ± 0.67 1.39 ± 0.66 1.82 ± 0.63 <0.05 sf-36 88.68 ± 4.48 90.65 ± 4.07 87.35 ± 4.31 <0.05 womac 23.80 ± 6.28 21.64 ± 7.14 25.26 ± 5.24 0.108 rasmussen* 0.865 excellent 14 6 8 good 35 14 21 fair 7 3 4 poor 1 1 rom in degrees 113.77 ± 9.65 119.35 ± 4.84 110 ± 10.3 <0.001 vas = visual analogue scale; sf-36 = short-form 36 health survey; womac = western ontario and mcmaster universities arthritis index; rom = range of motion. *rasmussen assessment criteria for radiological outcome. figure 1: all the fractures were classified preoperatively with the three-column classification system using twodimensional and three-dimensional (3d) computed tomography images. figure 2: plain radiograph (a) of left tibia showing the bicondylar tibial fracture and metaphyseal involvement (schatzker type vi). plain radiographs (b, c) taken at the final follow-up showing the anatomic reduction. figure 3: radiological outcomes of tibial plateau fractures according to the column specific plating. l-mc : lateral-medial column; l-pc : lateral-posterior column; l-m-pc : lateral-medial-posterior column; e = excellent; g = good; f = fair; p = poor. angelo v. vasiliadis, frideriki poutoglidou, dimitrios metaxiotis and anastasios mpeletsiotis clinical and basic research | 55 radiological outcomes according to the column specific plating are shown in figure 3. statistical analysis showed that there was a significant difference between the schatzker type v and type vi fractures in vas and sf-36 (p <0.05), while there was no significant difference on the womac and modified rasmussen criteria (p = 0.108 and p = 0.865, respectively) [table 2]. finally, all the patients were evaluated at the followup for the rom, the extension lag, the flexion deficit and the malalignment [figure 4]. discussion tibial plateau fractures are among the most complex injuries and remain a challenge even for the most experienced orthopaedic trauma surgeons. in order to maintain normal knee joint anatomy and function and accordingly, to ensure the maximal possible rom, the treatment should be focused on the restoration of joint stability, the alignment and the intraarticular congruity.2 orif is the gold standard for the management of bicondylar tibial plateau fractures, despite the high rates of compartment syndrome, infection and wound necrosis being reported following placement of dual plating.1–3,9 the earlier reports of internal fixation with double plating by prasad et al. and pun et al. had shown zero cases of deep tissue infection and only one case with superficial wound infection which healed after hardware removal.10,11 jagdev et al. reported a postoperative superficial infection in 8.69% of the patients treated with dual plates.3 orif with double plates in schatzker type v and type vi fractures had also shown high rates of infections ranging between 11% and 18%.12–15 in the current study, the overall infection rate was 5.3%, which is lower than the one reported in the current literature. it should be noted that the infections in our study were observed only in obese patients. furthermore, the incidence of compartment syndrome reported in the literature in bicondylar tibial plateau fractures treated with dual plating ranges from 0–13%.1,10,13,15 in the current study, no patient developed compartment syndrome. previous studies have demonstrated that the status of the soft tissue envelope at the time of injury and its dissection during surgery has a major impact on the final outcome.3,16 ellsworth et al. have shown that early surgical fixation, within 48 hours of lateral plateau fractures (schatzker type i to iii), can be performed safely and is not associated with a significant increase in the infection or the complication rates.17 however, this study found no statistically significant difference in the overall complication and infection rate between fractures (schatzker type v and vi) treated within 48 hours from the admission and those treated later. this suggests that even complex tibial plateau fractures can be treated immediately with an appropriate preoperative treatment plan. in addition, surgical delay could result in prolonged postoperative hospitalisation and increased overall cost to the healthcare system. numerous surgical fixation methods—such as a conventional dual-plate, a hybrid external fixator and/or less invasive stabilizing system—have been proposed for the treatment of complex tibial plateau fractures.7 pun et al. reported a series of 21 bicondylar tibial plateau fractures treated with dual plating or with the ilizarov fixator. the mean rom was 128.09 degrees (range = 90–145 degrees).11 jagdev et al. also reported a series of 26 patients with schatzker type v and type vi fractures using conventional dual plating. the mean rom was 123.4 degrees, while five patients had a functional extension lag of less than 10 degrees.3 christiano et al. demonstrated a mean rom of 121 degrees following orif of bicondylar tibial plateau fractures.15 the results of the current study (type v = 119.35 degrees; type vi = 110 degrees) seem to be quite similar to functional results reported by christiano et al.15 the possible explanations for the differences in the rom may be due to: i) the surgical technique; ii) the postoperative initiation of physical therapy; and iii) the exact time of the final follow-up. in 2017, mengi et al. conducted a retrospective study in 38 patients with type c1 to c3 tibial plateau fractures treated with single (n = 23) or double plating figure 4: functional pictures showed good flexion without extension lag (a, b), no varus/valgus mal alignment (c) and patient’s ability to cross their legs while sitting (d). mid-term radiological and functional outcomes of bicondylar tibial plateau fractures managed with open reduction and internal fixation using dual plates 56 | squ medical journal, february 2022, volume 22, issue 1 (n = 15) and followed up for at least 12 months.18 clinical outcomes were assessed by the knee injury and osteoarthritis outcome score and sf-36 and showed better scores when a single plate was applied relative to a double plate fixation. pun et al. evaluated clinical and radiological outcomes of 21 patients with schatzker type v and vi tibial plateau fractures treated with double plates who were followed up for a mean period of 2.5 years.11 in that study, the womac questionnaire was used. the authors reported overall satisfactory results without, however, reporting differences between the two treatment groups. the current study also demonstrated favourable clinical outcomes (womac and sf-36) following double plating in both groups, while scores in patients with schatzker type v fractures were found to be statistically significant compared with patients with schatzker type vi fractures. the current results are similar to a retrospective study conducted in india.3 in that study, the oxford knee score was greater in patients with schatzker type v fractures treated with dual plating. furthermore, hasan et al., in a biomechanical comparative study, suggested that thinner (3.5 mm) locking plates are likely viable alternatives to 4.5 mm locking plats and may be associated with less soft-tissue irritation and future wound healing complications.19 soft tissue damage in fractures around the knee joint, limb malalignment and delayed mobilisation are associated with joint instability and may be implicated in the pathogenesis of degenerative knee joint disease.2 parkkinen et al. reported that the articular congruity and restoration of the mechanical axis seem to have a role in prevention of post-traumatic osteoarthritis.20 nevertheless, in a sample of 73 patients, they confirmed that in the mid-term follow-up these factors do not appear to be detrimental to the functional outcomes. the age of the patient at the time of injury seems to be a significant prognostic indicator and correlated negatively with the functional outcomes.3,10 in longterm follow-up studies, articular incongruities are well tolerated; conversely, the stability of the knee joint is crucial for the final outcome.2,20,21 in the current study, the rasmussen criteria was used for radiological assessment and a good-to-excellent outcome was achieved in the majority of patients (86%), which is comparable to other, similar series treated with dual plating.12,22,23 according to the same rating system, yao et al. reported a quite lower radiological result of 77% good-to-excellent patients after dual buttress plates fixation.22 in a series of 34 patients with tibial plateau fracture type v and vi, rohra et al. reported a result of 94% good-to-excellent satisfaction rate after plating with dual plates.23 consequently, we suggest that the dual buttress plating technique could achieve favourable fracture reduction and satisfactory clinical outcome. tibial plateau fractures are high-energy injuries, commonly associated with ligament, tendon or meniscus injuries, with an overall incidence reported between 12.3% and 35.2%.2,10,11,24,25 the degree of widening of the tibial plateau has been proposed to be a possible predictor of concomitant soft tissue injury.10,11 stevens et al. reported an incidence of ligament injuries in 24% of the cases of type i to iii and 33% in type iv to vi tibial plateau fractures.24 yu et al. reported an anterior cruciate ligament injury in 11.1% of the patients with type v and vi of tibial plateau fractures.25 they had also noticed a high incidence of meniscus injury (35.2%) in their study. in the current study, 21.5% had soft tissue injuries including ligaments, tendons and meniscus. this marked variation in the incidence of soft tissue injuries reported in the literature may be due to the variety of the methods employed for the diagnosis of these injuries, such as mri or clinical examination.2,10,25 conclusion despite the relatively small sample size, this study aligns with the results of the current literature. although technically demanding, orif of bicondylar tibial plateau fractures with dual plates is the most stable mechanical construct. the good-to-excellent mid-term radiological (modified rasmussen criteria) and functional outcomes (sf-36 and womac) support the fact that dual plating of bicondylar tibial plateau fracture is the optimal treatment option. the potential postoperative complications associated with open reduction, such as wound infection and compartment syndrome, can be prevented and/or minimised by general practices including timing of surgical intervention, meticulous soft tissue dissection and suture placement. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n avv and dm conceptualised and designed the study. avv performed the data collection. avv and fp analyzed the data. avv and fp drafted the manuscript, while dm and am revised the manuscript. all authors approved the final version of the manuscript. angelo v. vasiliadis, frideriki poutoglidou, dimitrios metaxiotis and anastasios mpeletsiotis clinical and basic research | 57 references 1. wenger d, petersson k, rogmark c. patient-related outcomes after proximal tibial fractures. int orthop 2018; 42:2925–31. https://doi.org/10.1007/s00264-018-3920-0. 2. khatri k, lakhotia d, sharma v, kiran kumar gn, sharma g, farooque k. functional evaluation in high energy (schatzker type v and type vi) tibial plateau fractures treated by open reduction and internal fixation. int sch res notices 2014; 2014:589538. https://doi.org/10.1155/2014/589538. 3. jagdev ss, kumar pathak s, salunke a, maheshwari p, ughareja p, shah s. functional outcome of schatzker type v and vi tibial plateau fractures managed with open reduction internal fixation using dual plates. int j res orthop 2017; 3:961–5. https://doi. org/10.18203/issn.2455-4510.intjresorthop20173215. 4. luo cf, sun h, zhang b, zeng bf. three-column fixation for complex tibial plateau fractures. j orthop trauma 2010; 24:683–92. https://doi.org/10.1097/bot.0b013e3181d436f3. 5. lee kw, yang js, hwang jy, kim kj, choy ws. arthroscopic assessment of cartilage healing status after treatment of tibial plateau fracture. indian j orthop 2019; 53:257–62. https://doi. org/10.4103/ortho.ijortho_190_17. 6. chouhan dk, saini uc, rajnish rk, prakash m. complex bicondylar tibial plateau fractures with reversed tibial slope – our experience with a fracture-specific correction strategy. trauma case rep 2020; 25:100256. https://doi.org/10.1016/j. tcr.2019.100256. 7. ryu sm, yang hs, shon oj. staged treatment of bicondylar tibial plateau fracture (schatzker type v or vi) using temporary external fixator: correlation between clinical and radiological outcomes. knee surg relat res 2018; 30:261–8. https://doi. org/10.5792/ksrr.17.008. 8. the jamovi project (2021). jamovi (version 1.6) [computer software]. from: https://www.jamovi.org accessed: oct 2020. 9. prat-fabregat s, camacho-carrasco p. treatment strategy for tibial plateau fractures: and update. effort open reviews 2016; 1:225–32. https://doi.org/10.1302/2058-5241.1.000031. 10. thiruvengita prasad g, suresh kumar t, krishna kumar r, murthy gk, sundaram n. functional outcome of schatzker type v and vi tibial plateau fractures treated with dual plates. indian j orthop 2013; 47:188–94. https://doi.org/10.4103/00195413.108915. 11. pun tb, krishnamoorthy vp, poonnoose pm, oommen at, korula rj. outcome of schatzker type v and vi tibial plateau fractures. indian j orthop 2014; 48:35–41. https://doi.org/10.41 03/0019-5413.125490. 12. zhai q, hu c, lup c. multi-plate reconstruction for severe bicondylar tibial plateau fractures of young adults. int orthop 2014; 38:1031–5. https://doi.org/10.4103/0019-5413.125490. 13. dall’oca c, maluta t, lavini f, bondi m, micheloni gm, bartolozzi p. tibial plateau fractures: compared outcomes between arif and orif. strategies trauma limb reconstr 2012; 7:163–75. https://doi.org/10.1007/s11751-012-0148-1. 14. ozkaya u, sancar parmaksizoglou a. dual locked plating of unstable bicondylar tibial plateau fractures. injury 2015; 46:s9–13. https://doi.org/10.1016/j.injury.2015.05.025. 15. christiano av, pean ca, kugelman dn, konda sr, egol ka. function and knee range of motion plateau six months following lateral tibial plateau fractures. j knee surg 2020; 33:481–5. https://doi.org/10.1055/s-0039-1678676. 16. tang x, liu l, tu c-q, yang t-f, wang g-l, fang y, et al. timing of internal fixation and effect on schatzker iv-vi tibial plateau fractures. chin j traumatol 2012; 15:81–5. 17. ellsworth hs, dubin jr, shaw cm, alongi sm, cil a. immediate versus delayed operative treatment of low-energy tibial plateau fractures. curr orthop pract 2016; 27:351–4. https://doi.org/10.1097/bco.0000000000000390. 18. menghi a, mazzitelli g, marzetti e, barberio f, d’angelo e, maccauro g. complex tibial plateau fractures: a retrospective study and proposal of treatment algorithm. injury 2017; 48:s1–6. https://doi.org/10.1016/s0020-1383(17)30649–6. 19. hasan s, ayalon ob, yoon rs, sood a, militano u, cavanaugh m, liporace fa. a biomechanical comparison between locked 3.5-mm plates and 4.5-mm plates for the treatment of simple bicondylar tibial plateau fractures: is bigger necessarily better? j orthop traumatol 2014; 15:123–9. https://doi.org/10.1007/s10195-01 3-0275-6. 20. parkkinen m, madanat r, mustonen a, koskinen sk, paavola m, lindahl j. factors predicting the development of early osteo arthritis following lateral tibial plateau fractures: mid-term clinical and radiographic outcomes of 73 operatively treated patients. scand j surg 2014; 103:256–62. https://doi.org/10.11 77/1457496914520854. 21. marsh jl, buckwalter j, gelberman r, dirschl d, olson s, brown t, et al. articular fractures: does an anatomic reduction really change the result? j bone joint surg amer 2002; 84:1259–71. https://doi.org/10.2106/00004623-200207000-00026. 22. yao y, lv h, zan j, li j, zhu n, jing j. functional outcomes of bicondylar tibial plateau fractures treated with dual buttress plates and risk factors: a case series. injury 2014; 45:1980–4. https://doi.org/10.1016/j.injury.2014.10.004. 23. rohra n, singh suri h, gangrade k. functional and radiological outcome of schatzker type v and vi tibial plateau fracture treatment with dual plates with minimum 3 years follow-up: a prospective study. j clin diagn res 2016; 10:rc05–rc10. https://doi.org/10.7860/jcdr/2016/18732.7855. 24. stevens dg, beharry p, mckee md, waddell jp, schemitsch eh. the long-term functional outcome of operative treated tibial plateau fractures. j orthop trauma 2001; 15:312–20. https:// doi.org/10.1097/00005131-200106000-00002. 25. yu z, zheng l, zhang y, li j, ma b. functional and radiological evaluations of high-energy tibial plateau fractures treated with double-buttress plate fixation. eur j med res 2009; 14:200–5. https://doi.org/10.1186/2047-783x-14-5-200. https://doi.org/10.1007/s00264-018-3920-0 https://doi.org/10.1155/2014/589538 https://doi.org/10.18203/issn.2455-4510.intjresorthop20173215 https://doi.org/10.18203/issn.2455-4510.intjresorthop20173215 https://doi.org/10.1097/bot.0b013e3181d436f3 https://doi.org/10.1016/j.tcr.2019.100256 https://doi.org/10.1016/j.tcr.2019.100256 https://doi.org/10.5792/ksrr.17.008 https://doi.org/10.5792/ksrr.17.008 https://doi.org/10.1302/2058-5241.1.000031 https://doi.org/10.4103/0019-5413.108915 https://doi.org/10.4103/0019-5413.108915 https://doi.org/10.4103/0019-5413.125490 https://doi.org/10.4103/0019-5413.125490 https://doi.org/10.4103/0019-5413.125490 https://doi.org/10.1007/s11751-012-0148-1. https://doi.org/10.1016/j.injury.2015.05.025 https://doi.org/10.1055/s-0039-1678676 https://doi.org/10.1097/bco.0000000000000390 https://doi.org/10.1016/s0020-1383(17)30649–6 https://doi.org/10.1007/s10195-013-0275-6 https://doi.org/10.1007/s10195-013-0275-6 https://doi.org/10.1177/1457496914520854 https://doi.org/10.1177/1457496914520854 https://doi.org/10.2106/00004623-200207000-00026 https://doi.org/10.1016/j.injury.2014.10.004 https://doi.org/10.7860/jcdr/2016/18732.7855 https://doi.org/10.1097/00005131-200106000-00002 https://doi.org/10.1097/00005131-200106000-00002 http://v squ med j, august 2011, vol. 11, iss. 3, pp. 328-337, epub. 15th aug 11 invited article submitted 12th nov 10 revision req. 10th apr 11, revision recd. 10th may 11 accepted 24th may 11 a common argument heard in health care planning and health policy reform debates is that the government should stay out of health care and let the market allocate resources efficiently. it is further argued that government rules and regulations applied in health care markets interfere with proper resource allocation resulting in inefficiency.1 the argument further states that without government interference, the "invisible hand" of the market would allocate resources optimally leading to economic efficiency in health care. although interesting, this argument is based on the assumption that health care meets all necessary conditions for an ideal perfect/free market. unfortunately, this assumption is never articulated explicitly therefore the argument is not fully explored, understood or challenged. it is important to explore fully the argument, the assumptions made about the free market, and the conditions necessary for the "invisible hand" to allocate resources efficiently.2 a market that meets all necessary conditions for efficient resource allocation is an ideal in economic theory, but a rarity in the real world. markets do fail because necessary conditions for perfect/free markets are rarely met in any industry and least of all in health care.3 when the necessary conditions of the ideal free market are not met, there can be market failures some of which are not easily corrected by the market and therefore require interventions from outside the market. another important issue that is also rarely articulated is whether free markets are a desirable feature of a health care system. this issue cannot be easily addressed through economic theory. it is an issue that requires a closer examination of the philosophy behind the foundation of the health care system in any country. it requires an examination of the culture and beliefs of the country about health 1university of oklahoma health sciences center, okalhoma city, usa; 2college of public health, university of oklahoma health sciences center, okalhoma city, usa. *corresponding author email: ala@ou.edu ìè÷^nπ]<—áä÷]ê<ìèví÷]<ìë^¬ü÷]<—áâ<∞e<^⁄<l^œêüà÷]         :الكلمات مفتاح  abstract: a common argument in the health policy debate is that market forces allocate resources efficiently in health care, and that government intervention distorts such allocation. rarely do those making such claims state explicitly that the market they refer to is an ideal in economic theory which can only exist under very strict conditions. this paper explores the strict conditions necessary for that ideal market in the context of health care as a means of examining the claim that market forces do allocate resources efficiently in health care. keywords: health economics; ideal market; market structure; market failure; perfect competition; market forces; supply/demand; equity; economic efficiency review health care market deviations from the ideal market ari mwachofi1 and *assaf f. al-assaf2 ari mwachofi and assaf f. al-assaf review | 329 and health care. is health care a commodity to be bought and sold for profit, or is it a basic human right that should be accessible to all citizens? s o m e b a s i c e c o n o m i c s c o n c e p t s a n d d e f i n i t i o n s for the sake of clarity and simplicity, it is necessary to define some basic economic terms and concepts. efficiency is central to economic theory because human beings have unlimited wants but limited resources with which to meet those wants. given the limited resources, human beings constantly make decisions that require tradeoffs. for example, a working person earning $200 per week has many wants that might require more than the earnings. because of the limited earnings, the individual has to prioritise in order to meet the most important wants, or the wants that provide the highest level of satisfaction. for each want met, there are several unmet wants (the trade-offs). the term efficiency means that resources are being used where they provide the highest value. efficiency in consumption means that consumers use resources where they get the highest satisfaction level. for producers of goods and services, being efficient means they produce at the lowest possible average cost. the term market refers to a situation where buyers (consumers) and sellers (producers) interact (directly or through intermediaries) to trade goods and services. it is a situation where forces of demand and supply interact to determine prices of goods and services being exchanged. therefore, a market includes mechanism for: determining prices and quantities of the traded item, communicating information about prices, and for the distribution of the goods and services. supply is the total amount of a product (good or service) that producers (sellers) are willing and able to sell at a specified price. demand is the total amount of a good or service that consumers are willing and able to purchase at a given price. market forces of supply and demand represent the aggregate influence of self-interested buyers and sellers on prices and quantities of goods and services offered in a market. demand arises from consumers' push to get as much satisfaction as possible (utility maximisation) given their income limits, so it is a reflection of the value that consumers associate with the goods or services. supply arises from producers’ effort to maximise their profits. it reflects the costs of production. driven by self-interest, consumers will try to pay the lowest prices possible while producers try to sell at the highest price possible. this process results in an equilibrium where the quantity demanded is equal to quantity supplied at which point the equilibrium price and equilibrium quantity are determined.4 under ideal conditions, production of goods or services is efficient (meaning that it is done at the lowest possible per unit cost). consumption is also efficient—meaning that consumers are getting the best value for their money by combining goods and services in a manner that attains them the highest possible satisfaction (maximum utility) given their limited income. in other words, there is no waste in production or in consumption. this is the condition is described by economists as pareto optimality or social efficiency. under pareto optimality everyone is at their highest possible welfare level given the resources they own. this occurs automatically only under ideal market conditions that facilitate the "invisible hand's" efficient resource allocation.2 however, in the real world, ideal market conditions are rarely met. consequently, there are market failures, meaning that the market fails to allocate resources efficiently, there is waste in production (average production cost is not at its lowest level), or in consumption (individual consumers are not attaining the value for their money), and pareto optimality is not attained which means that there is resource waste and social welfare is less than optimal.3 h e a lt h c a r e m a r k e t s health care has several interdependent markets such as: education, manpower, institutional, pharmaceutical and others. the education market determines how many doctors, nurses and other professionals are trained every year and therefore how many such professionals are available to provide services. in this market, prices can be viewed in terms of tuition and other costs to the individual seeking training to be a physician, a nurse or other professional. manpower markets determine labour prices (salaries and wages) paid to professionals. institutional markets determine prices for hospital stays, or stays in nursing homes. in the pharmaceutical markets, prices of medications are determined. one can identify many other markets in health care. because of the nature of the product for sale and the structure of health care markets health care market deviations from the ideal market 330 | squ medical journal, august 2011, volume 11, issue 3 power in the market. the ideal economic structure is perfect competition which has the following characteristics: many sellers (firms) and many buyers and each one individually too small to affect price levels so they are all price-takers not price-setters; homogeneous products such that buyers are unable to discern any difference between products sold by different sellers/firms; firms can enter and exit the market freely without restriction from regulations or costs so that new suppliers can enter the market to increase competition, or be forced to leave the market if they are inefficient; perfect knowledge/ information about prices, and technology so that consumers and firms can access such information at zero cost, and no externalities (spill-over effects, e.g. smoking affects non-smokers) in production and consumption. these characteristics define an ideal market structure that might not exist in its pure form in real life, but has normative value and provides an understanding of how equilibrium prices and quantities are determined by market forces. economists can demonstrate mathematically (first fundamental theorem of welfare economics)3 that perfect competition leads to pareto optimality. consumers get the "best bang for their buck" and producers produce at the lowest per unit cost. inefficient producers are weeded out (go out of business because they make heavy losses) so that only the efficient producers survive, i.e. survival of the efficient. if the conditions of this market are not met, the market is unable to attain efficiency. for example, if there are barriers to entry or exit, new producers cannot get into the industry to increase competition. prices and costs of production remain high and inefficient producers stay in business because they are protected from having to compete with more efficient producers. with higher prices, consumers do not get the best value for their money. there is inefficiency in production and in consumption. perfect competition attains efficiency because producers compete and increase production, which lowers the prices that consumers pay. lower prices force producers to be efficient (produce at lower average costs) so as to make a profit. those unable to cut their production costs experience losses and eventually have to go out of business. inefficient producers have higher average costs and most of these markets do not meet the ideal perfect market conditions that facilitate efficient resource allocation. i d e a l m a r k e t c o n d i t i o n s – w i t h r e f e r e n c e t o h e a lt h c a r e several conditions facilitate the efficient workings of the market leading to efficient resource allocation. the main set of conditions can be viewed in terms of market structure. other conditions include: marketability of all goods and services; demand certainty, i.e. the demand that is regular and predictable; supply certainty, i.e. the known or predictable quality of the product; avoidable risks; the customer's ability to test the product before consumption; information symmetry (between buyers and sellers); no price discrimination (charging consumers different prices for the same product), and that all suppliers in the market have a profit motive.5 other implied conditions are: consumers have sufficient information to make good choices; consumers can accurately predict the results of their consumption decisions; individuals are rational; a person is the best judge of his/her own welfare; there are no externalities; consumer tastes are predetermined; supply and demand are independently predetermined; firms do not have monopoly power; there are no increasing returns to scale, and others.6 we will examine some of these conditions in the context of health care: m a r k e t s t r u c t u r e the structure of the market in which the firm is operating has a significant effect on efficiency. market structure is defined by: the number and size of the firms in the market; the ease with which firms may enter and exit the market; the degree to which firms' products are differentiated; and the information available to both buyers and sellers regarding prices and product characteristics. market structure characteristics determine competition which ranges from perfect competition where there are many small sellers and many buyers, a homogenous product and everyone is a price-taker, to a pure monopoly where there is only one supplier or a monopsony, a market with only one buyer. between these extremes there are other structures such as monopolistic competition (many buyers and many sellers with a differentiated product) and oligopoly with a few sellers varying in size and ari mwachofi and assaf f. al-assaf review | 331 therefore they incur heavy losses and are forced to shut down production. only efficient producers survive in the market—survival of the efficient again. thus, perfect competition automatically weeds out inefficiency and improves consumer welfare through lower prices. lower prices enhance consumers’ purchasing power so that they are able to meet more wants with their limited resources/ income, thus gaining more "value for their money".7 the structure of markets in health care is not competitive. there are barriers to entry and exit. some barriers come from professional licensing, long and expensive training and expensive investment requirements (e.g. hospitals are expensive to build). the barriers might protect inefficient producers from being weeded out so that efficient resource allocation does not occur automatically. there might be a few hospitals in a city (oligopoly) or only one hospital in a rural location (monopoly) and a drug company with a patent is a monopoly with the power to set prices. other conditions of perfect competition are contravened in health care: product homogeneity— the services of one physician are not identical to those of another; rather than perfect information, there is information asymmetry which can be a serious source of market failures as demonstrated later (see information asymmetry below). price discrimination is common in health care (consumers pay different prices for the same service depending on their incomes or bargaining power). obviously, health care markets do not meet the conditions of perfect competition. in health care, there are firms that have market power and are able to move and set prices. for example, a rural community that has only one hospital is essentially a monopoly within that geographic area. such a hospital is not facing serious competition so it will be able to set prices high enough to suit its revenue needs. more importantly, it does not have to be efficient in production because it is not necessarily going to be driven out of the market by more efficient producers. another example is a pharmaceutical company that has a patent on a drug. the company is a monopoly by virtue of the fact that no other company can legally produce and sell that drug until the patent runs out. for the duration of the patent the drug company is a monopolist. it is a price-setter for that particular drug, it can earn high profits and it will not have to be efficient in production because it is not facing any competition. because of the structure of health care markets, producers are not forced to be efficient. the market does not punish inefficiency as would be the case under perfect competition. there are other market structures that lead to sub-optimal resource allocation because some agents have enough power to set prices by shifting demand or supply. for example, if there are only a few large sellers in the market (oligopoly) the sellers have enough market power to set prices and the market fails to allocate resources efficiently. a good example of oligopolies is in the us health insurance industry which is dominated by a few large companies. in some local areas, there might be only one company which essentially means that they are monopolies. thus the condition that everyone in the market is a price taker is contravened in health care and that does lead to market failures. p r o d u c t m a r k e ta b i l i t y health care as a product or service is not consumed because it provides a consumer with satisfaction (it might even be unpleasant or painful), but because the individual wants to retain good health. the demand for health care is derived from an individual’s wish to regain good health. the qualities of the product (health) make it difficult for markets to meet the ideal market conditions. health is not a marketable product, that is, it cannot be exchanged between consumers. since demand for health care is derived from the demand for health, the nonmarketability of health reduces the power of market forces (demand and supply) to determine prices and quantities. consequently the ability of the market to determine resource allocation is greatly reduced. i n f o r m at i o n a s y m m e t r y there are several information asymmetries in health care, but we will examine two: between the doctor and the patient, and between the consumer and the health insurance company. doctors (suppliers) know more about illness and treatments than their patients. patients depend on the doctor to act in their best interest, but there is a conflict of interest because the doctor is selling a service to the patient. the doctor is in a position to determine demand for the service (acting on behalf of the patient, presumably for the patient's welfare) and the doctor is also the supplier of the services. in health care market deviations from the ideal market 332 | squ medical journal, august 2011, volume 11, issue 3 universal coverage, i.e. everyone buys coverage so that insurance companies have a pooled risk which on the average is lower than the risk from covering only the very ill. the other solution is screening and experience rating that allows insurance companies to change different premiums according to risk levels.13 studies indicate huge welfare losses due to adverse selection.14 m o r a l h a z a r d individuals covered by insurance tend to use more health care and they might not take necessary precautions to stay healthy because they know they have insurance coverage. this leads to inefficient use of resources. insurance companies try to correct this by employing gate-keepers who monitor and restrict health care access and by charging copayments and deductibles. unfortunately, these are applied to everyone including those not overusing services, which make these solutions inefficient. i n t e r d e p e n d e n t d e m a n d a n d s u p p ly d e t e r m i n at i o n an increase in demand for health care (e.g. due to an influx of population, or an epidemic) can lead to higher prices for such care. the increase in prices might result in the physician supplying less hours of work. for example, if a physician wants to earn $100,000 per year, he may usually earn that much by seeing 100 patients a week. if the price for services goes up, he might be able to earn that income by seeing only 80 patients a week. he/she will then be able to hit the target income by supplying less hours of work—thus seeing fewer patients and spending more of his/her time on leisure. this situation results in the famous "backward bending" labor supply curve. thus supply and demand in health care are not determined independently leading to market failures. c o n s u m e r r at i o n a l i t y a n d a b i l i t y t o m a k e t h e b e s t j u d g m e n t s a b o u t t h e i r w e l fa r e consumers seeking care are not always in a position to make the best judgment about their welfare even if they have the ability and freedom to do so. for one, they lack necessary information about their illness or the effective treatment. moreover, there are some situations of extreme stress making it impossible for the individual consumer to make the this case demand and supply are jointly determined by the same individual at the same time which can result in market failure. for example, if the doctor is driven by the profit motive, or is seeking higher income, the doctor might order more services than necessary (e.g. if he/she owns a laboratory or imaging equipment). this market failure is termed “supplier induced demand”. there are several studies that indicate evidence of supplierinduced demand in health care. in a japanese study, izumida, urushi and nakinishi found that increases in the number of physicians per capita significantly increased use of inpatient services and outpatient services.8 this implies that when more doctors moved into an area they had to share the patients so they increased demand for their services in each encounter by inducing demand from the patients under their care. another japanese study examined whether more frequent use of percutaneous transluminal coronary angioplasty (ptca) for patients with acute myocardial infarction (ami) in japan is driven by physicians’ self-interest or by patient behaviour.9 after controlling for a patient’s detailed characteristics, they found that increases were significantly related to physician-initiated expenditures and the effect is higher for high-tech treatments. this finding is supported by findings of an american study that found similar market failure in large metropolitan areas.10 similarly a study of ambulatory care in france found strong support for the existence of physician induced demand in the french system.11 information asymmetry between individuals purchasing health insurance and the insurance company results in two market failures termed adverse selection and moral hazard. a d v e r s e s e l e c t i o n individuals in poor health have a greater incentive to purchase health insurance than those in good health. individuals in poor health make greater utilisation of health care than the healthy, leading to higher payouts by the insurance company. to avoid incurring losses, insurance companies might raise premiums. higher premiums will further discourage healthy individuals from purchasing health insurance so that only the very ill buy insurance leading to losses by insurance companies and eventually this might mean the demise of a market.12 this market failure can be corrected by ari mwachofi and assaf f. al-assaf review | 333 judgment (e.g. someone in a car accident, passed out on the roadside). furthermore, consumers cannot accurately predict the results of consuming health care. when visiting a doctor for a particular condition, the consumer is not able to predict accurately what the results of the visit will be, even if they have been through similar circumstances before. a treatment regimen that worked previously might not work the same way. economists consider an individual to be rational if they made consistent and transitive decisions. "consistent" means that when faced with the same conditions they make the same decisions every time. "transitive" is used in the mathematical logic sense that, in a relation between three elements, if it holds between the first and second, and it also holds between the second and third, it must necessarily hold between the first and third. for example, an individual is offered three choices a, b, and c. if they prefer choice a over b and they also prefer choice b over c then they must prefer choice a over c. economists would consider an individual rational if they decided/acted in this manner. however there are numerous findings of consumers acting irrationally.15 this is why we all ask ourselves the question “what was i thinking?” after realising that we acted irrationally. thus there is evidence that consumers do not always act rationally thus the condition is not met in health care. e x t e r n a l i t i e s externalities are spill-over effects of consumption or production. positive externalities occur when the actions of one individual result in a spill-over that improves the well being of another individual and negative externalities impose a cost on another individual. smoking is an example of a negative consumption externality because one individual's consumption (smoking) affects other people's health negatively (effects of second-hand smoke). an example of a positive externality is immunisation. if some individuals are immunised they provide "herd immunity" in the sense that they do not get the illness therefore they do not pass it on to others. their immunisation provides a benefit to others—a positive externality. with the presence of externalities, individual production or consumption decisions are not optimal because they are made without consideration of all costs or benefits. often, spillover effects are not included in decision-making because they are not visible to the producer or consumer. in the case of a negative externality, the external spill-over costs are not included and in the case of positive externality, the spill-over benefits are excluded. therefore, the consumption or production level selected is not optimal or efficient. in cases of positive externality, the production or consumption level is below the optimal while with negative externalities the level is higher than optimal. therefore externalities lead to inefficiency and so to market failures. the market is usually not able to correct inefficiencies arising from externalities. to correct failure due to externalities, the consumer or producer has to consider both the private and the external (spill-over) costs or benefits. such considerations in the decision-making process would result in production or consumption at optimal levels. one method of making the producer or consumer consider total benefits or costs in production is to provide subsidies in case of positive externalities, or taxes in the situation of negative externality. the subsidy makes the external benefit part of the private benefits that the consumer or producer will consider in decision-making so as to arrive at optimal production/consumption quantities. the tax serves to make the producer aware of the extra costs that they impose on society so that they can arrive at optimal quantities in their decision-making. thus taxes or subsidies might eliminate the effects of externalities and lead to efficient allocation of resources. however, these usually require government action. the way taxes are used (allocated and distributed) has an effect on societal welfare. furthermore, there are issues of measurement and arriving at the correct amount of tax or subsidy that will lead to efficiency. p r e d e t e r m i n e d c o n s u m e r ta s t e s another implied condition is that consumer tastes are already determined at the time the consumer enters the market. this condition is not met in health care and consumer tastes are malleable. for example, consumers in the usa might demand newer, more expensive technologies rather than older ones that are equally effective, but less expensive. such demands lead to unnecessary increases in health care costs—an inefficient use of resources (market failure). health care market deviations from the ideal market 334 | squ medical journal, august 2011, volume 11, issue 3 profits. under perfect competition, they are driven to be efficient, not only by the profit motive, but also by the need to stay in business. in doing so they use resources efficiently thus improving social welfare; however, in health care not all firms are profit driven. for example, in the usa and in other countries, there are hospitals that are not for profit, but provide a necessary service. in fact, of the 5,162 hospitals in the usa in 2008, only 1,072 were for profit (20.8% of the total). this implies that the majority of the hospitals are driven by other goals than profit.16 empirical evidence suggests that doctors might be motivated by a "target income"17 not necessarily by profit. they might also be motivated by the satisfaction they get from seeing their patients recover. thus the profit motive is not always the dominating factor in health care. this implies that health care firms are not necessarily driven to be efficient in production as other firms aiming to make a profit under stiff competition. in the usa, a large number of nursing homes are for profit and so is the health care product market (pharmaceuticals and equipment). therefore the us health care industry is not all profit driven but has for-profit enclaves. this would imply that the profit motive condition is also contravened in health care. firms do not always strive for efficiency. in the usa, there are disparities in health status and access to care. minority populations (african americans, american indians, hispanics and others) experience poor health status and poorer effective access to health care than the majority white population.18 moreover, there are geographic disparities (lower access in rural than in urban areas) and socioeconomic disparities with the poor having worse health than the rich. there are also gender disparities with women experiencing worse health care access than men although they have longer life expectancies. there is therefore an unequal distribution of health and health care that is not approved by society. some of the reasons for the unequal distribution are economic while others might be historical. the minority health disparities seem to be experienced by other countries as well such as the uk,19 india, australia and others. disparities might not be corrected by the market. r e t u r n s t o s c a l e increasing returns to scale refer to production situations with large fixed costs so that as the scale of production increases the average (per unit) cost of production decreases. this is true in industries that require expensive machinery to operate and, once the machinery is in place, the extra costs of production are not as high as the initial costs of setting up such machinery. in health care, there are increasing returns to scale. for example a hospital or imaging centre might cost a lot to build and equip, but once it is in operation the more services it provides the smaller the per unit costs of providing each unit of service. the existence of economies of scale leads to market power because large firms have lower average costs and are able to survive in the market and to make profits. this also means that the large firms are more efficient than the smaller ones. if there are economies of scale, it would make sense to ensure that the industry has a few larger firms producing at low per unit costs rather than many little ones producing at higher per unit costs. this might happen naturally (survival of the most efficient) because larger producers experience lower average costs and are less likely to make a loss than small firms producing at high average costs. if there are infinite economies of scale, the most efficient production might need only one firm—a situation termed natural monopoly. this situation gives the one or few firms a great deal of market power which can be used to set prices at very high levels (reducing consumer purchasing power and welfare), produce poor quality services, or practice price discrimination (segmenting the market and charging consumers different prices for the same good or service). this situation can lead to a transfer of income from consumers to the powerful producer, and therefore, a decrease in consumer welfare. the bottom line then is that this condition (no economies of scale) is contravened in health care leading to non-competitive market structures and to monopoly pricing and lower consumer welfare—market failures. p r o f i t m o t i v e according to economic theory, the objective of a producer is to make as much profit as possible (profit maximisation). producers who seek to maximise profits are forced to be efficient because they need to reduce production costs so as to increase their ari mwachofi and assaf f. al-assaf review | 335 i n t e r v e n t i o n s t o r e d u c e e f f e c t s o f m a r k e t fa i l u r e consistent with economic theory, markets respond to failures by developing structures that fill the gaps resulting from such failures.3 examples of such structures in the us include: independent physicians, cost-based reimbursement for hospitals and managed care.20 to some degree, health insurance is a structure that covers market failure due to large unavoidable risks of illness. market structures are not always successful in closing such gaps. they might even create other inefficiencies as is the case of health insurance (adverse selection, moral hazard and stinting) governments can and do intervene in markets to correct market failure. the intervention might come in the form of taxes, subsidies, regulations and providing services directly. in us health care there are subsidies for older people, or people with disabilities and for children. support for direct supply of services is that governments can provide more of the merit goods or services with positive externalities that markets tend to underproduce; they can provide services in industries with economies of scale and ensure that minimum standards are met and there is greater equality in distribution of goods or services. however, government intervention is not always successful in correcting market failure. there are government failures due to reasons such as: poor information about the type and size of services needed to correct the failure; political exigency focusing on short term effects (e.g. in an election year) rather the long run goals; administrative costs and bureaucracy; inefficiency because there are no incentives to be efficient; multiplicity of conflicting objectives in government, and changes in government policy as a result of the political business cycle. discussion and conclusion obviously, health care markets do not function like the ideal economic market. these markets do not meet all necessary or sufficient conditions for the ideal economic market. therefore, there are numerous market failures and inefficiencies due to such failures. moreover, the distribution of health and health care is not at a desired level. as a consequence, there have to be interventions in these markets to close gaps and improve efficiency. however, issues of economic efficiency, market structure, and whether the government has any role in the health care of its citizens can be a cause of bitter and divisive political debates (e.g. 2010 us health policy reforms). such debates tend to use economic theory without full disclosure of the assumptions made about the market. this is particularly true of arguments that support the market economy blindly without due consideration for market failures and their impact on economic efficiency and social welfare. the result is statements that sound true to a non-economist, but are totally false given that the wrong assumption has been made. there is evidence that government control in health care can have desirable results in the form of better and equitable access to care and good health outcomes. some of the more successful health care systems are government controlled with little influence from the market and others are very tightly regulated. a good example of a government controlled health care system is the cuban system. it is built on a strong primary care foundation. it provides comprehensive health care to all its residents with nobody falling between the cracks.21 despite cuba being a poor country, it attains health outcomes that are comparable and sometime better than those of rich economies such as the usa. for example, cuba enjoys higher vaccination rates (99.9%); an excellent ability to control and quell epidemics effectively; high life expectancies (78–84 years), and low infant mortality rates. despite being under a trade embargo, cuba has developed a unique methods of treating illnesses such as parkinson's disease, retinitis pigmentosa, multiple sclerosis and other neurological disorders. it exports medical products such as vaccines. consequently, cuba attracts about 20,000 health tourists annually.22 cuba sends doctors to provide services all over the world and trains doctors from other countries through a programme of international giving and support. one fundamental difference between the cuban system and market-based systems is the philosophy on which the system is built. the philosophical question for any health care system is, "should health care be traded for profit?" a question that relates back to an even more fundamental question, "should health be treated as a human right or as a commodity that can be traded health care market deviations from the ideal market 336 | squ medical journal, august 2011, volume 11, issue 3 forces alone. for example, if health and health care equity are desirable features, there might be need for government intervention because these qualities are not easily attained through the market. government involvement in health care is often necessary because there are many market failures in health care and the market is not always able to correct such failures. it is even more important for smaller countries to determine and explicitly state the philosophical foundations of their health care systems. the reason for this is that smaller countries might have economies that are more open and therefore more vulnerable to economic changes than other countries/economies. furthermore, their citizens might be dependent on accessing care from other countries, or at the very least they might depend on getting health care manpower from other economies. these conditions might cause the small country to "import" inefficiencies from other economies that are a result of market failures or even government failures. for example in oman, the health care system might use care providers from outside the nation. this might make their system more vulnerable to inefficiencies from outside oman. however, the example of cuba indicates that a small economy can avoid the inefficiencies of other economies by being clear about what the fundamental purpose of their health care system is and then building it to attain the stated purpose. another example is thailand that reformed its health care system in 2001 with a clear purpose of attaining universal health care. with this aim, the country built a health care system supported by an insurance system and an electronic data storage and access system that improved efficiency and increased access for the poor.24 references 1. the heritage foundation. government intervention in health care increases costs. from: http://blog. heritage.org/?p=45329(2010) accessed: apr 2011. 2. smith a. an inquiry into the nature and causes of the wealth of nations. chicago: university of chicago press, 1976 (originally published in 1904 by methuen & co, ltd.). 3. greenwald b, stiglitz je. externalities in economies with imperfect information and incomplete markets. quart j econ 1986; 101:229–64. 4. barr n. economics of the welfare state. new york: for profit?" the cuban system is built on the belief that health care is a human right that should be accessible to all. based on this belief, the system is set up to make sure that health care is accessible to all cubans. the fundamental philosophy governing the health care system in any country is reflected in the kind of system that is in place to provide care. if a country treats health and access to care as a basic human right for its citizens, then the question of profit maximisation would be a non-issue. the health care system would have a different objective function with a slightly different focus. efficiency in health care markets would be judged by a different standard because then the objective function of the health care system would be different from a typical economics objective function. the structure of the health care system and its distribution patterns and channels would also be different and would reflect the system's basic philosophy about health and health care. efficiency in health care does not always lend itself to market forces because health care takes on properties of merit goods. consumption of such goods is desirable because the social benefits exceed the private benefits, i.e. there are positive externalities. like education, health can be viewed as capital stock or human capital. according to grossman, each individual is endowed with a stock of health which depreciates over time, but the individual has the ability to increase this stock through healthy behaviour such as good diet, accessing health care and preventive measures.23 the stock of health is a merit good because an individual's health has an effect on the rest of society. a healthy population provides a productive labour force that builds a country's economy. an individual sees the benefits of being healthy, but might not necessarily see the benefits of his/her good health to the rest of society, i.e. the private benefits of good health are less than the societal benefits. so an individual's decision about the optimal level of their health might be less than optimal considering the larger societal benefits. this is also true of education and that is why the governments play a big role in it. if merit goods are left to the private sector—or the market, there is under-consumption (e.g. vaccination) and therefore, inefficiency. moreover, other desirable features in a country might not be attainable through market ari mwachofi and assaf f. al-assaf review | 337 oxford university press, 2004. 5. arrow kj. uncertainty and the welfare economics of medical care. am econ rev, 1963; 53:941–73. 6. rice t, unruh l. the economics of heath reconsidered. 3rd ed. chicago: health administration press, 2009. 7. frank r. microeconomics and behavior. 9th ed. new york: mcgraw-hill, 2009. 8. izumida n, urushi h, nakanishi s. an empirical study of the physician-induced demand hypothesis —the cost function approach to medical expenditure of the elderly. japan rev soc policy 1999; 8:11–25. 9. noguchi h, shimizutani s, masuda y. physicianinduced demand for treatments for heart attack patients in japan: evidence from the tokai acute myocardial study (tamis). econ soc res instit (esri) discussion paper series 2005;no.147. 10. cromwell j, mitchell jb. physician-induced demand for surgery. j health econ 1986; 5:293–313. 11. delattre e, dormont b. fixed fees and physicianinduced demand: a panel data study on french physicians. health econ 2003; 12:741–54. 12. akerlof ga. the market for "lemons": quality uncertainty and the market mechanism. quart j econ 1970; 84:488–500. 13. manning wg, newhouse jp, duan n, keeler eb, benjamin b, liebowitz a, et al. health insurance and the demand for medical care evidence from a randomized experiment. rand health insur series rep 1988; r-3476-hhs. 14. cutler dm, zeckhauser rj. the anatomy of health insurance. in: culyer aj, newhouse jp, eds. handbook of health economics vol. 1, part 2, 2000. pp. 1093–139. 15. ariely d. predictably irrational. the hidden forces that shape our decisions. london: harper collins, 2010. 16. us agency for healthcare research and quality. national estimates on characteristics of various types of hospitals from the hcup nationwide inpatient sample, 2010. from: http://hcupnet.ahrq. gov/hcupnet.jsp accessed: jun 2010. 17. fuchs vr. the supply of surgeons and the demand for operations. j hum res 1978; 13:35–56. 18. smedley bd, stith ay, nelson ar. unequal treatment: confronting racial and ethnic disparities in health care. washington dc: institute of medicine, national academies press, 2003. 19. parry j, judge k. tackling the wider determinants of health disparities in england: a model for evaluating the new deal for communities regeneration initiative. am j public health 2005; 95:626–8. 20. dranove, d, satterthwaite ma. the industrial organization of health care markets. in: culyer aj newhouse jp, eds. handbook of health economics vol. 1, part 2, 2000. pp. 1093–139. 21. anderson m, mother r. cuban health care system. social medicine portal. from: http://www. socialmedicine.org/2008/05/18/latin-americansocial-medicine/the-cuban-health-care-system/ 2008. accessed: may 2011. 22. drain pk, huffman sa, pirtle se, chan k. caring for the world: a guidebook to global health opportunities. toronto: university of toronto press, 2009. 23. grossman m. on the concept of health capital and the demand for health. jpe 1972; 80:223–55. 24. hughes d, leethongdee s. universal coverage in the land of smiles: lessons from thailand's 30 baht health reforms. health affairs 2007; 26:999–1. directorate general of health services, ministry of health, 1al-dhakhiliya region, al-hamra and 2al-dhahira region, ibri, oman; 3department of family medicine & public health, sultan qaboos university, muscat, oman *corresponding author’s e-mail: abdulaziz@squ.edu.om. إدراك املرضى ملهارات التواصل واملهارات السريرية ألطباء الرعاية الصحية األولية يف سلطنة عمان نهى الكندية، �شارة الوائلية، �شاجني جاجو، عبدالعزيز حممود املحرزي abstract: objectives: as a large proportion of patients are seen in primary healthcare (phc) centres, it is important to explore patients’ perceptions of communication and clinical skills of phc physicians. in oman, phc is provided by both trained family physicians (fps) and general practitioners (gps). methods: this crosssectional study was conducted at 12 phc centres in muscat governorate, oman between november 2014 and august 2015. adult omani patients’ perceptions of omani and other arabic-speaking doctors were examined using an arabic translation of a validated self-administered questionnaire. results: a total of 626 patients completed the questionnaire (response rate: 100%). the patients’ responses were significantly more positive towards fps compared to gps on whether the doctor provided reassurance (p = 0.03), took a complete medical history (p = 0.03) and gave the patient the opportunity of a follow-up with the same doctor (p = 0.01). conclusion: certain skills in communication and clinical aspects of fps were favourably viewed by patients compared to gps. keywords: patient satisfaction; physicians, primary health care; communication; clinical competence; quality of health care; oman. امللخ�ص: الهدف: نظرا ملعاينة ن�شبة كبرية من املر�شى يف مراكز الرعاية ال�شحية االأولية، فمن املهم ا�شتك�شاف اإدراك املر�شى ملهارات التوا�شل واملهارات ال�رشيرية الأطباء الرعاية ال�شحية االأولية. يتم توفري الرعاية ال�شحية االأولية يف عمان بوا�شطة اأطباء االأ�رشة املدربني واأطباء العموم. الطريقة: اأجريت هذه الدرا�شة امل�شتعر�شة يف عدد 12 مركز من مراكز الرعاية ال�شحية االأولية يف حمافظة م�شقط بني نوفمرب 2014 واأغ�شط�س 2015. متت درا�شة اإدراك املر�شى العمانيني البالغني ملهارات التوا�شل واملهارات ال�رشيرية لالأطباء العمانيني وغريهم من االأطباء الناطقني بالعربية باإ�شتخدام ترجمة عربية الإ�شتبيان معتمد مت تعبئته ذاتًيا. النتائج: قام ما جمموعه 626 مري�شا بتعبئة االإ�شتبيان )مبعدل اإ�شتجابة: %100(. كانت اإجابات املر�شى اأكرث اإيجابية ب�شكل ملحوظ جتاه اأطباء االأ�رشة مقارنة مع اأطباء العموم حول ما اإذا كان الطبيب قادرا على اإعادة الطماأنينة )p = 0.03(، واأخذ تاريخ طبي كامل )p = 0.03( واإعطاء املري�س فر�شة ملتابعة العالج مع نف�س الطبيب االأ�رشة طب الأطباء ال�رشيري والفح�س التوا�شل جمال يف املهارات بع�س اإىل اأكرث اإيجابي ب�شكل املر�شى ينظر )p = 0.01(. اخلال�صة: املدربني باملقارنة مع نظرائهم من اأطباء العموم. الكلمات املفتاحية: ر�شا املر�شى؛ االأطباء، الرعاية ال�شحية االأولية؛ التوا�شل؛ الكفاءة ال�رشيرية؛ جودة الرعاية ال�شحية؛ عمان. patients’ perceptions of communication and clinical skills of primary healthcare physicians in oman nuha al-kindi,1 sara al-waili,2 sanjay jaju,3 *abdulaziz m. al mahrezi3 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e148–152, epub. 8 sep 19 submitted 2 mar 19 revision req. 7 apr 19; revision recd. 7 may 19 accepted 2 jun 19 primary healthcare (phc) plays a fundamental role in establishing strong healthcare systems.1 in addition, studies have confirmed the value of phc in making healthcare systems more cost-effective.2 patients’ perceptions are widely used as an indicator for assessing the performance of healthcare systems and has been frequently utilised by policymakers for corrective measures to improve healthcare services.3,4 various studies have addressed patients’ opinions, perceptions or satisfaction about quality in phc and in general, demonstrated positive perceptions and satis faction towards phc physicians.3–6 in arab countries, several studies have focused on major aspects of phc such as accessibility to care, communication skills and technical competencies; they found an overall good level of patient satisfaction.7–10 albalushi et al.’s study was conducted in muscat, oman, in 2009 and focused on the major domains of care such as “accessibility to service, continuity of care, humaneness of staff, and effectiveness of services” and indicated an overall good level of satisfaction with phc services.11 however, they reported dissatisfaction with the level of continuity of care.11 an earlier study in the rural al dhahira governorate showed a positive association between patients’ perceived health status and satisfaction with quality of care.12 another study conducted by al-mandhary et al. in al batinah region this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.011 brief communication https://creativecommons.org/licenses/by-nd/4.0/ nuha al-kindi, sara al-waili, sanjay jaju and abdulaziz m. al mahrezi brief communication | e149 showed an adequate level of acceptance to omani doctors.13 their study assessed participants’ acceptance of the communication skills of their omani doctor, care to the patient, absence of a language barrier, competence level, preference to be seen by a doctor of the same gender, embarrassment from seeing an omani doctor, qualifications, experience, knowledge and skills of the omani doctor and trust in the omani doctor.13 in oman, phc is provided by two types of prac titioners: 1) trained family physicians (fps) who have undergone a structured four-year residency training in family medicine; and 2) general practitioners (gps) who did not undergo any structured postgraduate training or have higher qualifications in other disciplines of med icine except family medicine. the majority of prac titioners who work in phc in oman are gps. this study aimed to explore the perceptions of patients on the communication and clinical skills of arabic-speaking phc physicians and to identify any differences in the perceptions towards fps and gps. methods this cross-sectional study was carried out between november 2014 and august 2015 at 12 phc centres located in al seeb (n = 8) and bowsher (n = 4) wilayats in muscat governorate, oman. there are 27 phc centres in muscat governorate distributed in six wilayats. al seeb and bowsher wilayats were selected because they have the largest population and highest number of total daily visits compared to other wilayats in muscat governorate. the total number of visits to these two wilayats represented approximately 57% of the total daily visits in muscat governorate.14 a sample size of 610 patients was calculated using nmaster, version 2.0 (department of biostatistics, christian medical college, india) assuming a 70% positive perception, 80% power and 95% confidence level. the sample size was equally divided among the 12 studied phc centres. all omani patients who were ≥18 years of age were included in this study. patients who were illiterate or had impaired cognitive abilities were excluded. data were collected through a self-administered questionnaire which consisted of two parts. the first part included socio-demographic information of the patients (age, gender and educational level), information about the visit (time and day of the week [workday or weekend]), first visit or follow-up, frequency of visits with the same treating doctor and their self-perceived health status (‘good’ or ‘not good’). the second part consisted of an arabic translation of a validated 22-item scale created by haddad et al.15 the scale was translated from english to arabic following the standard procedure of forward-and-backward translation. this validated scale covers three main domains; doctor’s communication skills, clinical skills and result or outcome of care. the cronbach’s alpha coefficients of the arabic version ranged from 0.86–0.92 for the three domains. during the pilot study, patients were requested to complete questions under the domain of ‘outcome of care’ 1−3 weeks after the day of consultation. despite several reminders, none of the participants responded. hence, the researchers decided to omit the ‘outcome of care’ table 1: characteristics of patients who completed the questionnaire on primary healthcare (phc) physicians’ communication and clinical skills in 12 phc centres in muscat governorate, oman (n = 626) characteristic n (%) gender male 158 (25.2) female 468 (74.8) age group in years 18–30 403 (64.4) 31–40 171 (27.3) 41–50 46 (7.3) 51–60 6 (1) education level elementary 13 (2.1) preparatory 28 (4.5) secondary 268 (42.8) college/higher 317 (50.6) perceived health status* good 538 (86.5) not good 84 (13.5) *a total of 622 responded to this item. table 2: characteristics of the primary healthcare physicians treating patients who were evaluated in the study (n = 125) characteristic n (%) male female total nationality gp fp gp fp omani 9 (69.2) 4 (100) 67 (85.9) 30 (100) 110 (88) non-omani 4 (30.8) 0 (0) 11 (14.1) 0 (0) 15 (12) total 13 (10.4) 4 (3.2) 78 (62.4) 30 (24) 125 (100) gp = general practitioner; fp = family physician. patients’ perceptions of communication and clinical skills of primary healthcare physicians in oman e150 | squ medical journal, may 2019, volume 19, issue 2 part of the questionnaire in the current study and to include only the first two domains. the questionnaire was distributed by the main investigators with the help of healthcare assistants/ medical orderlies working in the participating phc centres. questionnaires were distributed to eligible patients who were seen by doctors who spoke arabic. questionnaires were given to patients after the consult ation and upon completion were collected on the same day. the name of the physician was recorded by the healthcare assistant after the completion of the questionnaire and the details of the physician (gender, nationality, fp or gp and total years of experience) were later separately collected from the medical officer in charge of the phc centre. data collection were done during different times of the day and on both workdays and weekends. a five-point likert scale was used to classify responses as ‘strongly agree’, ‘agree’, ‘neutral’, ‘disagree’ or ‘strongly disagree’. the responses were then recategorised as ‘agree’, ‘neutral’ and ‘disagree’ for the purpose of analysis. the characteristics of the respondents along with the gender and nationality of their treating physicians were expressed as proportions. the patient responses to the communication skills and clinical skills of their treating doctors were tested individually for any stat istical association within the sub-groups of the specialty of their treating phc physician using a chi-square test. statistical package for the social sciences (spss), version 20 (ibm corp., armonk, new york, usa) was used for data entry and analysis. a p value of <0.05 was considered statistically significant. table 3: percentage of ‘agree’ responses by patients regarding communication and clinical skills items comparing general practitioners versus family physicians at primary healthcare centres in muscat governorate, oman (n = 616) item number questionnaire domains and items percentage of ‘agree’ responses* p value† gp fp communication skills of doctors 1 the doctor received me in a good manner (polite, kind and set me at ease). 91.7 96.7 >0.05 2 the doctor showed me respect regardless of my age, i expect to be treated as a person and not as a number. 92.3 95.8 >0.05 3 the doctor reassured me. 87.7 95.8 0.03 4 the doctor respected my privacy during the physical examination. 93.1 95.0 >0.05 5 the doctor listened to me and encouraged me to express my problems. 89.5 91.7 >0.05 clinical skills of doctors 1 the doctor took my complete medical history (previous illnesses, personal problems and family history). 72.4 82.5 0.03 2 the doctor was skilled in making the physical examination more comfortable. 84.1 85.0 >0.05 3 the doctor explained my health problem clearly and completely (cause, seriousness and progress). 79.2 80.8 >0.05 4 the doctor involved me in decisions concerning tests and treatments. 74.0 78.3 >0.05 5 the doctor explained the tests and radiological findings clearly and completely (the process, and the test results). 80.2 85.8 >0.05 6 the time spent waiting to obtain test results was appropriate. 66.5 69.2 >0.05 7 the tests and examinations prescribed by the doctor were appropriate. 56.3 60.0 >0.05 8 i think the doctor made the correct diagnosis. 77.8 82.5 >0.05 9 the doctor explained the chosen treatment clearly and completely (process, effects and complications). 78.8 87.5 >0.05 10 the time spent in consultation with the doctor was appropriate. 82.7 88.3 >0.05 11 the doctors have given me the chance to see them for follow-up. 73.0 85.8 0.01 12 in general, the doctor’s care was good. 88.5 88.3 >0.05 gp = general practitioner; fp = family physician. *a total of 496 patients responded for general practitioners and 120 patients for family physicians. †using chi-square test. nuha al-kindi, sara al-waili, sanjay jaju and abdulaziz m. al mahrezi brief communication | e151 a written informed consent was obtained from all the participants and enrolment in the study was voluntary. the ethical approval for the study was obtained from the research and ethics committee of the ministry of health, oman (mh/dghs/dpt/877/2014). results a total of 626 participants completed the questionnaire (response rate: 100%). the majority of participants were ≤40 years of age (91.7%), had at least a secondary level education (93.5%), were female (74.8%) and reported their perceived health status to be good (85.9%) [table 1]. a total of 125 phc physicians working in the included centres were evaluated in this study. the majority of physicians were gps (72.8%), had omani nationality (88%) and were female (86.4%). the femaleto-male ratio among gps was 6:1 while among fps it was 7.5:1 [table 2]. overall, patient responses were positive for most of the items regardless of whether the patient had seen a gp or a fp. however, fps received better responses for almost all items but without reaching a level of statistical significance. patients gave the lowest resp onses for the “time spent waiting to obtain test results was appropriate” and “the tests and exams prescribed by the doctor were appropriate in my opinion” items. the patients’ responses towards fps were signif icantly more positive compared to gps on whether the doctor had reassured the patient (p = 0.03), had taken the complete medical history (p = 0.03) and whether the doctor permitted the patient to follow-up with them (p = 0.01) [table 3]. discussion the current study has shown an overall good level of patient satisfaction with the performance of phc phys icians working in muscat governorate. these results are consistent with previous studies in terms of high levels of satisfaction with similar data.3,5,6 patients’ perceived certain communication and clinical skills as significantly more positive in the fps sub-group compared to the gps; this may be attributed to better training as fps in oman undergo a four-year structured residency training program prior to receiving their qualification, unlike gps who usually have no post graduate training. a study from thailand found similar higher patient satisfaction with fps compared to gps in the dimension of communication skills.16 effective doctor-patient communication is one of the most important aspects of medical care and has been associated with a better doctor-patient relationship and positive health outcomes.17 reassurance and relief of anxiety from illness plays a major role in physical and psychological well-being of the patient and should be considered as one of the initial management goals of phc physicians.18 however, the current study has some limitations. no other study using the same scale utilised in the present study could be identified. thus, it was not possible to compare these findings with other studies. this study was conducted in urban muscat, which is different from other regions in oman in terms of setting, patient characteristics and composition of phc physicians which might affect the generalisability of the findings to other parts of oman. conclusion the findings of this study should reassure policymakers about the positive levels of patients’ perceptions regarding the communication and clinical skills of phc physicians in muscat, oman. overall, locally trained fps possessed some key aspects necessary for the delivery of better healthcare. in addition, completion of training in a family medicine residency programme appears to result in acquiring better communication skills. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references: 1. shi l. the impact of primary care: a focused review. scientifica (cairo) 2012; 2012:432892. https://doi.org/10.6064/2012/432892. 2. papp r, borbas i, dobos e, bredehorst m, jaruseviciene l, vehko t, et al. perceptions of quality in primary health care: perspectives of patients and professionals based on focus group discussions. bmc fam pract 2014; 15:128. https://doi.org/10.1186/1471-229 6-15-128. 3. sánchez-piedra ca, prado-galbarro fj, garcía-pérez s, santamera as. factors associated with patient satisfaction with primary care in europe: results from the euprimecare project. qual prim care 2014; 22:147–55. https://doi.org/10.7175/fe.v15i 4.979. 4. raftopoulos v. assessment of users’ expectations, perceived quality and satisfaction with primary care in greece. int j caring sci 2010; 3:110–21. 5. the physicians foundation. consumer attitudes toward family/ primary care physicians and the u.s. healthcare system. from: h t t p s : / / p h y s i c i a n s f o u n d a t i o n . o r g / w p c o n t e n t / u p l o a ds/2018/01/physicians_foundation_consumer_omnibus_ survey.pdf accessed: may 2019. 6. singh h, haqq ed, mustapha n. patients’ perception and satisfaction with health care professionals at primary care facilities in trinidad and tobago. bull world health organ 1999; 77:356–60. https://doi.org/10.6064/2012/432892 https://doi.org/10.1186/1471-2296-15-128 https://doi.org/10.1186/1471-2296-15-128 https://doi.org/10.7175/fe.v15i4.979 https://doi.org/10.7175/fe.v15i4.979 patients’ perceptions of communication and clinical skills of primary healthcare physicians in oman e152 | squ medical journal, may 2019, volume 19, issue 2 7. alotaibi m, alazemi t, alazemi f, bakir y. patient satisfaction with primary health-care services in kuwait. int j nurs pract 2015; 21:249–57. https://doi.org/10.1111/ijn.12257. 8. mohamed ey, sami w, alotaibi a, alfarag a, almutairi a, alanzi f. patients’ satisfaction with primary health care centers’ services, majmaah, kingdom of saudi of saudi arabia. int j health sci (qassim) 2015; 9:163–70. https://doi.org/10.12816/0 024113. 9. hemadeh r, hammoud r, kdouh o, jaber t, ammar l. patient satisfaction with primary healthcare services in lebanon. int j health plann manage 2019; 34:e423–35. https://doi.org/10.10 02/hpm.2659. 10. bawakid k, rashid oa, mandoura n, usman shah hb, ahmed wa, ibrahim a. patients’ satisfaction regarding family physician’s consultation in primary healthcare centers of ministry of health, jeddah. j family med prim care 2017; 6:819–23. https://doi.org/10.4103/jfmpc.jfmpc_170_17. 11. albalushi rm, sohrabi mr, kolahi aa. clients’ satisfaction with primary health care in muscat. int j prev med 2012; 3:713–17. 12. al-mandhari as, hassan aa, haran d. association between perceived health status and satisfaction with quality of care: evidence from users of primary health care in oman. fam pract 2004; 21:519–27. https://doi.org/10.1093/fampra/cmh508. 13. al-mandhary a, al-zakwani i, afifi m. primary health care consumers’ acceptance, trust and gender preferences towards omani doctors. oman med j 2007; 22:51–6. 14. ministry of health, sultanate of oman. annual health report 2015. from: https://www.moh.gov.om/en_us/web/statistics /-/20-27 accessed: may 2019. 15. haddad s, potvin l, roberge d, pineault r, remondin m. patient perception of quality following a visit to a doctor in a pri mary care unit. fam pract 2000; 17:21–9. https://doi.org/10.10 93/fampra/17.1.21. 16. jaturapatporn d, dellow a. does family medicine training in thailand affect patient satisfaction with primary care doctors? bmc fam pract 2007; 8:14. https://doi.org/10.1186/1471-22968-14. 17. ha jf, longnecker n. doctor-patient communication: a review. ochsner j 2010; 10:38–43. 18. traeger ac, hübscher m, henschke n, moseley gl, lee h, mcauley jh. effect of primary care-based education on reassur ance in patients with acute low back pain: systematic review and meta-analysis. jama intern med 2015; 175:733–43. https://doi.org/10.1001/jamainternmed.2015.0217. https://doi.org/10.1111/ijn.12257 https://doi.org/10.12816/0024113 https://doi.org/10.12816/0024113 https://doi.org/10.1002/hpm.2659 https://doi.org/10.1002/hpm.2659 https://doi.org/10.4103/jfmpc.jfmpc_170_17 https://doi.org/10.1093/fampra/cmh508 https://doi.org/10.1093/fampra/17.1.21 https://doi.org/10.1093/fampra/17.1.21 https://doi.org/10.1186/1471-2296-8-14 https://doi.org/10.1186/1471-2296-8-14 https://doi.org/10.1001/jamainternmed.2015.0217 1department of radiology, oman medical specialty board, muscat, oman; departments of 2radiology, 3histopathology, 4surgery and 5pathology, the royal hospital, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com ساركوما ليفية جلدية حدبية ُتاكي اورام الثدي األولية تقرير حالة واستعراض االدبيات العلمية لسمات التصوير التشخيصي عبري الفار�شية، عزا الربا�شدية، �شامية ال�شاحلية، نا�رص الرحبي، �شامل الرحبي، حممد املسقري، زينب املنجية، را�شد العمريي abstract: dermatofibrosarcoma protuberans (dfsp) is a rare, slow-growing mesenchymal neoplasm of the dermis and subcutaneous tissues that has a lowto intermediate-grade malignancy. dfsp commonly involves the trunk and extremities, and very rarely the breast skin, mimicking a primary breast neoplasm with few reported cases in the literature. we report a 35-year old female patient who was referred to the royal hospital, muscat, oman in 2017, with a two-year history of a slow growing left breast lump. assessment of the breasts with mammography revealed a lobulated lesion in the left-upper-inner quadrant with neither microcalcification nor architectural distortion, mimicking a benign lesion. however, on ultrasound, the lesion had suspicious features with increased vascularity and hence, it was categorised as breast imaging reporting and data system (birad) iv. the patient underwent left breast wide local excision and the histopathological diagnosis was dermatofibrosarcoma protuberans. keywords: breast; dermatofibrosarcoma protuberans; ultrasonography; oman. امللخ�ص: ال�شاركوما الليفية اجللدية احلدبية هي ورم نادر وبطيء النمو من اورام اللُّْحَمُة املتو�شطة والتي ت�شيب الأدمة والأن�شجة حتت اجللد، وتعترب ورمَا خبيثَا منخف�ض اإىل متو�شط الدرجة. عادة ما تظهر ال�شاركوما الليفية اجللدية احلدبية يف اجلذع والأطراف، ويف حالت نادرة جدا قد ت�شيب اجللد الذي يغطي الثدي حماكيًة اأورام الثدي الولية مع عدد قليل من احلالت املبلغ عنها يف الأدبيات. نعر�ض هنا حالة لمراأة تبلغ من العمر 35 عاًما مت حتويلها اإىل امل�شت�شفى ال�شلطاين يف م�شقط، �شلطنة ُعمان عام 2017، لديها كتلة بطيئة النمو يف الثدي الي�رص ملدة �شة يف الربع الإْن�ِشّي العلوي للثدي الي�رص بدون وجود عامني. وقد ك�شف تقييم الثدي با�شتخدام ت�شوير الثدي ال�شعاعي عن وجود اآفة ُمَف�شَّ تكل�ض جمهري اأو ت�شوه يف البناء الن�شيجي حماكيَة اآفة حميدة، يف حني اأظهر ا�شتخدام جهاز املوجات فوق ال�شوتية �شمات مريبة للآفة مع زيادة يف الوعية الدموية وبالتايل مت ت�شنيف الورم على انه من الفئة 4 ح�شب نظام الإبلغ عن ت�شوير الثدي والبيانات. خ�شعت املري�شة ل�شتئ�شال مو�شعي وا�شع للثدي الأي�رص وجاء الت�شخي�ض املر�شي الن�شيجي على �شكل �شاركوما ليفية جلدية حدبية. الكلمات املفتاحية: ثدي؛ ال�شاركوما ليفية جلدية حدبية؛ ت�شوير باملوجات فوق ال�شوتية؛ �شلطنة ُعمان. dermatofibrosarcoma protuberans mimicking primary breast neoplasm a case report and literature review abeer al-farsi,1 aza al-brashdi,1 samyia al-salhi,2 nasser al-rahbi,3 salim al-rahbi,4 mohammed al-masqari,5 zainab al-manji,3 *rashid s. al-umairi2 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e368–371, epub. 5 oct 20 submitted 4 feb 20 revision req. 15 mar 20; revision recd. 30 mar 20 accepted 30 apr 20 having imaging findings. in the current case, we report the mammographic and ultrasonographic findings of a breast skin dfsp in a 35-year-old female patient and performed a review of the literature. case report a 35-year-old female patient was referred from a local hospital to the breast surgery outpatient clinic in the royal hospital, muscat, oman, in 2017, with a twoyear history of a slow growing nodular lesion over the left breast [figure 1]. there was no associated nipple discharge and no family history of breast cancer. on physical examination, there was a nodular pinkish skin lesion over the upper-inner quadrant dermatofibrosarcoma protuberans (dfsp) is a rare, slow-growing soft tissue sarcoma that commonly affects young to middle aged adults.1 it has intermediateto lowgrade malignancy with a high propensity for local infiltration as well as having a high local recurrence rate after excision.2 dfsp most commonly involves the trunk, followed by the extremities, and the head and neck area.3 however, dfsp very rarely involves the breast, mimicking primary breast tumour.1,2,4,5 awareness of this rare entity and its typical imaging features is crucial to avoid the misdiagnosis of dfsp with a benign breast lesion and to suggest a preoperative diagnosis. however, reports of imaging features have been scarce in the literature compared to histopathological features, with few reported cases this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.019 case report https://creativecommons.org/licenses/by-nd/4.0/ abeer al-farsi, aza al-brashdi, samyia al-salhi, nasser al-rahbi, salim al-rahbi, mohammed al-masqari, zainab al-manji and rashid s. al-umairi case report | e369 of the left breast, which was mobile and non-tender, measuring 3 × 3 cm. there was a mobile single left axillary lymph node. the nipple and areola looked normal. on mammography, there was a lobulated mass in the upper-inner quadrant of the left breast measuring 3 × 2 cm [figure 2]. there was neither associated microcalcification nor architectural distortion. bilateral axillary lymph nodes were seen but demonstrated benign imaging features. left breast ultrasound was performed during the same sitting and revealed a subcutaneous lobulated mass measuring 3 × 1.4 cm. on colour doppler, the lesion showed increased vascularity [figure 3]. based on the ultrasound findings, the lesion was categorised as breast imagingreporting and data system (birad) iv. clinical examination and imaging findings were suggestive of dfsp. therefore, the patient underwent left breast wide local excision with an attempt at a 2 cm gross margin. histologic examination showed a hypercellular spindle cell lesion, largely located in the dermis, with irregular subcutaneous infiltration; however, there was no infiltration of the breast parenchyma. the cells were monotonous with occasional mitosis and a storiform pattern of arrangement. immunohistochemically, the spindle cells were diffusely positive for cluster of differentiation (cd)34 and negative for pan cytokeratin ae1/ae3 [figures 4 and 5]. these findings were consistent with dfsp. the patient has been under regular close follow-up for three years with breast ultrasonography surveillance every six months and has remained disease-free. consent for publication of the present clinical details and/or clinical images was obtained from the patient. discussion dfsp is a rare sarcoma of the dermis and subcutaneous tissue that has an estimated incidence of 0.8–5 cases per one million per year and accounts for less than 6% of all sarcomas. it usually affects patients aged between 20–50 years.6 dfsp has an intermediateto low-grade malignancy with a high predilection for local invasion. although rare, distant metastasis, especially in the lungs and lymph nodes, has been reported.7,8 dfsp has a high propensity for local recurrence following inadequate surgical excision. moreover, poorly treated lesions can lead to differentiation into highergrade sarcoma with a higher recurrence rate.9 dfsp commonly occurs on the trunk (50–60%), followed by the limbs (25%) and the head and neck area (10–15%). involvement of the breast by dfsp is extremely rare, with only a few cases reported in the literature.6,9 figure 1: photograph of the left breast of a 35-year-old female patient showing a nodular pinkish skin lesion over the upper-inner quadrant measuring 3 × 3 cm. figure 3: colour doppler ultrasound image of the left breast of a 35-year-old female patient showing a wellcircumscribed lobulated subcutaneous mass measuring 3 × 1.4 cm with increased vascularity. figure 2: a mammogram of a 35-year-old female patient with dermatofibrosarcoma protuberans of left breast. mediolateral oblique (a) and craniocaudal (b) showing a lobulated, smoothly marginated mass in the upper-inner quadrant of the left breast. dermatofibrosarcoma protuberans mimicking primary breast neoplasm a case report and literature review e370 | squ medical journal, august 2020, volume 20, issue 3 clinically, dfsp usually appears as an irregular reddish-brown to bluish superficial nodule and the diagnosis might be suggested from the appearance.6,8,10 however, dfsp can present as a subcutaneous nodule known as subcutaneous dfsp and when it involves the breast it can be confused with a primary breast lesion.11 the current patient had a superficial nodular pinkish nodule. histologically, dfsp is composed of monomorphous spindle-shaped cells arranged in a storiform pattern with scattered mitosis and mild nuclear pleomorphism on a background of fibrous stroma and infiltration of surrounding subcutaneous fat. immunohistochemically, the tumour is diffusely and strongly cd34 positive and negative for cytokeratins, smooth muscle actin (sma), desmin and s100.2,12 dermatofibroma is one of the main differential diagnoses for dfsp. unlike dfsp, tumoural cells in dermatofibroma do not show a prominent storiform pattern, increased mitotic activity nor positive immune histochemical reactivity for cd34. dermatofibroma is a tumour of the dermis, whereas dfsp frequently infiltrates the subcutaneous adipose tissue.13 bednar tumour is the pigmented variant of dfsp and has similar morphologic properties as dfsp. however, bednar tumour has melanin containing dendritic cells.13 another differential diagnosis is malignant fibrous histiocytoma (mfh). marked nuclear pleomorphism, increased mitotic activity and necrosis are detected in mfh and tumour cells are negative for cd34.14 the current case was differentiated from leiomyoma and leiomyosarcoma by immunohistochemical positivity for cd34 and negativity for sma, along with its morphological characteristics. on mammography, breast dfsp appears as a skinbased or intra-mammary located well-circumscribed oval-shaped lesion with no microcalcification nor speculation. these mammography findings are not specific and hence, breast dfsp can mimic a benign breast lesion such as fibroadenoma, sebaceous cyst or an abscess.1,4,5,9,15 in the current case, the mammography findings were consistent with findings reported in the literature with a skin-based well-defined lesion with no microcalcification nor architectural distortion, mimicking a sebaceous cyst. ultrasonographically, breast dfsp appears as a skin-based or subcutaneous, well-circumscribed hypoechoic lesion with mild lobulation and increased vascularity on colour doppler. increased vascularity can be used to differentiate dfsp from benign breast lesions that usually appear as well-circumscribed lesions such as sebaceous cysts and liver abscesses. another useful ultrasonographic finding that can help to distinguish dfsp is the presence of a peripheral hyperechoic rim in the subcutaneous tissue that represents a mixture of tumour cells and fibrous tissue infiltrating the subcutaneous fat.1,2,4,5,9,11 on magnetic resonance imaging (mri), dsfp has no specific features and appears as a well-defined nodule or mass that is t1 isointense to the muscle and shows homogenous or heterogenous enhancement on post-contrast examination. however, owing to its high spatial resolution and high tissue characterisation, mri is very helpful in delineation of tumour extent and evaluating the anatomical relation of the tumour to adjacent structures.2,3,9 due to its infiltrative behaviour, dfsp tends to extend beyond the clinical margin. this explains the high local recurrence rate of 20–50% following local excision and justifies the current recommendation of a wide local excision with a 2–3 cm resection margin.2,6,10 radiation therapy can be used in inoperable and metastatic cases. it is estimated that about 80–90% of dfsp tumours have a fusion gene that results in continuous activation of the platelet-derived growth factor-β (pdgf-β) signalling pathway. therefore, molecular targeted therapy inhibiting pdgf-β is an effective option for inoperable and metastatic dfsp. multikinase inhibitor imatinib is the first agent to be approved for systemic treatment of dfsp and has figure 4: histopathologic findings of the left breast lesion in a 35-year-old female patient. a: hematoxylin and eosin (h&e) stain at x40 magnification. the tumour was hypercellular and composed of spindle cells arranged in a storiform pattern. b: h&e stain at x200 magnification showing that the tumour was infiltrating the subcutaneous tissue. figure 5: histopathologic findings of the left breast lesion in a 35-year-old female patient. a: hematoxylin and eosin stain at x400 magnification demonstrating storiform arrangement of short spindle cells and mitotic figures. b: the tumor cells show positive immune histochemical reactivity for cd34. abeer al-farsi, aza al-brashdi, samyia al-salhi, nasser al-rahbi, salim al-rahbi, mohammed al-masqari, zainab al-manji and rashid s. al-umairi case report | e371 shown objective response rates of approximately 50% in clinical trials.16 imatinib treatment has been also used for metastatic dfsp.17 long-term follow-up requires strict monitoring every 6–12 months with ultrasound and tissue biopsy in cases of suspected recurrence. the 10-year survival rate is >99%.18 conclusion breast skin dfsp is a rare entity that can mimic a primary breast tumour. awareness of this rare lesion and its typical imaging features will help to avoid the misdiagnosis of dfsp with a benign breast lesion and suggest a pre-operative diagnosis. references 1. maji s, paul mj, sen s. dermatofibrosarcoma protuberans of the breast: a rare entity. indian j surg oncol 2018; 9:351–4 https://doi.org/10.1007/s13193-017-0684-8. 2. lee s-j, mahoney mc, shaughnessy e. dermatofibrosarcoma protuberans of the breast: imaging features and review of the literature. ajr am j roentgenol 2009; 193:w64–9. https://doi. org/10.2214/ajr.08.2141. 3. zhang l, liu qy, cao y, zhong js, zhang wd. dermatofibrosarcoma protuberans: computed tomography and magnetic resonance imaging findings. medicine (baltimore) 2015; 94:e1001. https://doi.org/10.1097/md.0000000000001001. 4. sin fn, wong kw. dermatofibrosarcoma protuberans of the breast: a case report. clin imaging 2011; 35:398–400. https:// doi.org/10.1016/j.clinimag.2011.04.004. 5. pohlodek k, mečiarová i, grossmann p, kinkor z. dermatofibrosarcoma protuberans of the breast: a case report. oncol lett 2017; 14:993–8. https://doi.org/10.3892/ ol.2017.6206. 6. paramythiotis d, stavrou g, panagiotou d, petrakis g, michalopoulos a. dermatofibrosarcoma protuberans: a case report and review of the literature. hippokratia 2016; 20:80–3. 7. lal p, sharma r, mohan h, sekhon ms. dermatofibrosarcoma protuberans metastasizing to lymph nodes: a case report and review of literature. j surg oncol 1999; 72:178–80. https:// doi.org/10.1002/(sici)1096-9098(199911)72:3<178::aidjso12>3.0.co;2-7. 8. kahn lb, saxe n, gordon w. dermatofibrosarcoma protuberans with lymph node and pulmonary metastases. arch dermatol 1978; 114:599–601. 9. bae sh, lee jy. imaging features of breast dermatofibrosarcoma protuberans in various modalities including fdg-pet ct. iranian j radiol 2016; 13:e33916. https://doi.org/10.5812/ iranjradiol.33916. 10. dubay d, cimmino v, lowe l, johnson tm, sondak vk. low recurrence rate after surgery for dermatofibrosarcoma protuberans: a multidisciplinary approach from a single institution. cancer 2004; 100:1008–16. https://doi.org/10.1002/ cncr.20051. 11. bulliard c, murali r, chang ly, brennan me, french j. subcutaneous dermatofibrosarcoma protuberans in skin of the breast: may mimic a primary breast lesion. pathology 2007; 39:446–8. https://doi.org/10.1080/00313020701444523. 12. haycox cl, odland pb, olbricht sm, piepkorn m. immuno histochemical characterization of dermatofibrosarcoma protu berans with practical applications for diagnosis and treatment. j am acad dermatol 1997; 37:438–44. https://doi.org/10.1016/ s0190-9622(97)70146-4. 13. özcan tb, hacıhasanoğlu e, nazlı ma, aksoy ş, leblebici c, talu ck. a rare breast tumor: dermatofibrosarcoma protu berans. j breast health 2016; 12:44–6. https://doi.org/10.5152/ tjbh.2015.2680. 14. djilas-ivanovic d, prvulovic n, bogdanovic-stojanovic d, vicko f, sveljo o, ivkovic-kapicl t. dermatofibrosarcoma protuberans of the breast: mammographic, ultrasound, mri and mrs features. arch gynecol obstet 2009; 280:827–30. https://doi.org/10.1007/s00404-009-1004-5. 15. bouhani m, fertani y, zemni i, adouni o, bouida a, chargui r, et al. dermatofibrosarcoma protuberans of the breast in man: an extremely rare entity with a review of the literature. j investig med high impact case rep 2019; 7:2324709619875634. https:// doi.org/10.1177/2324709619875634. 16. ugurel s, kortmann rd, mohr p, mentzel t, garbe c, breuninger h, et al. s1 guidelines for dermatofibrosarcoma protuberans (dfsp) update 2018. j dtsch dermatol ges 2019; 17:663–8. https://doi.org/10.1111/ddg.13849. 17. navarrete-dechent c, mori s, barker ca, dickson ma, nehal ks. imatinib treatment for locally advanced or metastatic derma tofibrosarcoma protuberans: a systematic review. jama dermatol 2019; 155:361–9. https://doi.org/10.1001/jamaderm atol.2018.4940. 18. chan t-c, wu c-j, jeng s-f. dermatofibrosarcoma protuberans: a 10-year experience. formosan j surg 2015; 48:10–6. https://doi.org/10.1016/j.fjs.2014.06.004. https://doi.org/10.1007/s13193-017-0684-8 https://doi.org/10.2214/ajr.08.2141 https://doi.org/10.2214/ajr.08.2141 https://doi.org/10.1097/md.0000000000001001 https://doi.org/10.1016/j.clinimag.2011.04.004 https://doi.org/10.1016/j.clinimag.2011.04.004 https://doi.org/10.3892/ol.2017.6206 https://doi.org/10.3892/ol.2017.6206 https://doi.org/10.1002/%28sici%291096-9098%28199911%2972:3%3c178::aid-jso12%3e3.0.co%3b2-7 https://doi.org/10.1002/%28sici%291096-9098%28199911%2972:3%3c178::aid-jso12%3e3.0.co%3b2-7 https://doi.org/10.1002/%28sici%291096-9098%28199911%2972:3%3c178::aid-jso12%3e3.0.co%3b2-7 https://doi.org/10.5812/iranjradiol.33916 https://doi.org/10.5812/iranjradiol.33916 https://doi.org/10.1002/cncr.20051 https://doi.org/10.1002/cncr.20051 https://doi.org/10.1080/00313020701444523 https://doi.org/10.1016/s0190-9622%2897%2970146-4 https://doi.org/10.1016/s0190-9622%2897%2970146-4 https://doi.org/10.5152/tjbh.2015.2680 https://doi.org/10.5152/tjbh.2015.2680 https://doi.org/10.1007/s00404-009-1004-5 https://doi.org/10.1177/2324709619875634 https://doi.org/10.1177/2324709619875634 https://doi.org/10.1111/ddg.13849 https://doi.org/10.1001/jamadermatol.2018.4940 https://doi.org/10.1001/jamadermatol.2018.4940 https://doi.org/10.1016/j.fjs.2014.06.004 public health education through the lens of social media implications in the covid-19 era sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e143–145, epub. 15 mar 21 submitted 4 jun 20 revision req. 22 jul 20; revision recd. 3 aug 20 accepted 3 sep 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.024 letter to the editor التثقيف الصحي العام من خالل عدسة وسائل التواصل االجتماعي التداعيات يف زمن كوفيد -19 dear editor, covid-19 has been at the centre of a devastating 21st century pandemic, claiming over 600,000 lives as of august 1st, 2020.1 with a limited supply of vaccines against covid-19, protective measures remain key for slowing down its spread. since the start of the pandemic, protective measures have been implemented on a worldwide level. implementation of such measures necessitates awareness of the public. raising public awareness requires powerful and impactful messages, displayed on widely viewed communication platforms for rapid dissemination of accurate information. for many, social media have been the primary sources of information and insight into the covid-19 pandemic.2 while the landscapes of social media do harbour trustworthy material from reliable sources, rumours or misinformation have often propagated faster and on larger scales.2–4 in these times of crises, rumours running rampant can often escalate anxiety and fear among the public, leading to a state of information overload or cyberchondria, which ultimately results in wrongful and harmful practices.4,5 for instance, claims in march 2020 by the previous president of the united states, donald trump, regarding his own personal intake of hydroxychloroquine for prevention of covid-19 lead to a sharp increase in both hydroxychloroquine and chloroquine prescriptions in the united states.6 ultimately, this has led to several reports of drug overdose in people that took the drug without medical supervision.4–6 while the world struggles to control the virus, reduction of misinformation and rumours is vital in the management of this pandemic. an impactful way to combat misinformation is through strong and influential presence of medical professionals on social media. although increasing in prevalence, the collective social media presence of medical professionals has been lacking.7 a recent report concluded that only 43% of healthcare practitioners who own social media accounts would utilise them for educational purposes, with the probability significantly decreasing in those ≥40 years old.8 additionally, in a survey encompassing more than 4,000 physicians, more than 90% of physicians reported the use of social media for personal activities. however, only 65% reported use of such platforms for professional purposes.9,10 the shortage of sound and influential professional voices on social media has created a significant void that was deepened by the public thirst for knowledge and filled with misconceptions and false information. it is time for medical professionals to embrace social media's formidable influence and put it to good use. the traditional methods of spreading public awareness via intermediaries such as television channels, locally organised public events and others have limited reach. they are usually time, cost and space prohibitive at the time of a pandemic. on the other hand, through social media's digitalised platforms, medical professionals can reach hundreds, if not tens of thousands of people, with just a few clicks and at little to no cost.11 social media's value extends beyond combating misinformation to fueling public learning of vital medical concepts during covid-19. such concepts include principles in vaccine development, experimental drug treatments and others. explaining and rationalising complex medical ideas in simple terms can lift the haze of ambiguity. ambiguity, during times of uncertainty, generates fear, reluctance and ultimately avoidance. through a self-developed professional social media presence that hosts over 100,000 users, i have constructed numerous self-made visuals and videos that have illustrated various medical concepts before and during this pandemic.12 through the simple yet compounded usage of ‘‘emojis’’, i have developed constructs on principles of antiviral development and vaccinations against viruses [figures 1 and 2].13,14 these constructs received a broad https://creativecommons.org/licenses/by-nd/4.0/ public health education through the lens of social media implications in the covid-19 era e144 | squ medical journal, february 2021, volume 21, issue 1 public appraisal, registering over 135,000 views in one month.13,14 while many physicians have adopted similar professional digital platforms for health education, the utilisation of simplistic yet expressive and elaborative emoji-constructed health demonstrations has not been done before the same extent expressed in this letter by the author. the adaptation of common everyday humanistic activities (i.e. unlocking of doors with keys, invasion of foreign territories) and utilising such activities to illustrate and mirror complex medical principles is both creative and extremely engaging.12 more importantly, these constructions can be done with the simple tools located in any smartphone without any prior knowledge of sophisticated digital design software. the combination of simple language, brief but robust statements, entertaining visuals and drawing resemblances to everyday life have made these simple illustrations incredibly impactful. in this instance, a picture was worth a thousand words. it is worth noting here that the latter demonstrations in figures 1 and 2 were originally posted in arabic, targeting the arabic-speaking population and were subsequently adapted and translated for the present paper. from my years of experience building my health education platform, the extent of public education for arabic speaking nations has been lacking. it often does not meet the public’s demand for updated health information. additionally, pre-existing methods and tools for education lack the element of simplicity and public engagement. the designs and posts illustrated in this letter and many others have served to bridge the gap in these critical educational healthcare delivery domains.15 social media is here to stay. moreover, without a clear direction in the form of robust medical professional presence on social media, public health education, particularly in the arab world, will suffer. we ought not to fear from engaging in the online world of social media. instead, we should embrace it and plan to engage in it strategically and thoughtfully. here, i present a condensed list of recommendations for building an educational social media presence. first, start by creating a public, visible profile on one social media platform. second, pick medical themes relevant to your speciality or time of posting. then, explain the themes and concepts in simple terms, preferably drawing examples from everyday life. seek feedback from viewers and colleagues on areas to figure 1: visual illustration, as it appeared on social media on march 13th, 2020, showing the structure of covid-19, its mechanism of human cell invasion, replication and release from human cells.13 figure 2: visual illustration, as posted on social media on march 19th, 2020, explaining the principles in development of vaccines against viruses.14 khawla f. ali letter to editor | e145 improve (visuals, sound effects, selection of topics, or even presentation style). finally, always be cognizant of your professional presence and maintain the same ethical standards exercised during in-person dealings. it must also be emphasised here that building a widely viewed platform is no easy task; it takes grit, time and resilience. nevertheless, the impact could be remarkable. khawla f. ali royal college of surgeons in ireland medical university of bahrain, adliya, bahrain e-mail: khawlafouad@hotmail.com references 1. world health organization coronavirus disease (covid-2019) situation reports. from: www.who.int/emergencies/diseases/novelcoronavirus-2019/situation-reports accessed: aug 2020. 2. armitage l, lawson bk, whelan me, newhouse n. paying special consideration to the digital sharing of information during the covid-19 pandemic and beyond. bjgp open 2020; 4:bjgpopen20x101072. https://doi.org/10.3399/bjgpopen20x101072. 3. llewellyn s. covid-19: how to be careful with trust and expertise on social media. bmj 2020; 368:m1160. https://doi.org/10.1136/bmj. m1160. 4. tasnim s, hossain mm, mazumder h. impact of rumors and misinformation on covid-19 in social media. j prev med public health 2020; 53:171–4. https://doi.org/10.3961/jpmph.20.094. 5. farooq a, laato s, islam akmn. impact of online information on self-isolation intention during the covid-19 pandemic: crosssectional study. j med internet res 2020; 22:e19128. https://doi.org/10.2196/19128. 6. goodman j, giles c. coronavirus and hydroxychloroquine: what do we know? from: https://www.bbc.com/news/51980731 accessed: aug 2020. 7. ventola cl. social media and health care professionals: benefits, risks, and best practices. p t 2014; 39:491–520. 8. pizzuti ag, patel kh, mccreary ek, heil e, bland cm, chinaeke e, et al. healthcare practitioners' views of social media as an educational resource. plos one 2020; 15:e0228372. https://doi.org/10.1371/journal.pone.0228372. 9. m. modahl, l. tompsett, t. moorhead. doctors, patients and social media. from: www.quantiamd.com/q-qcp/doctorspatientsocialmedia. pdf accessed: feb 2021. 10. ventola cl. social media and health care professionals: benefits, risks, and best practices. p t. 2014; 39:491–520. 11. lake h, bermingham f, johnson g, tabner a. mitigating the psychological impact of covid-19 on healthcare workers: a digital learning package. int j environ res public health 2020; 17:e2997. https://doi.org/10.3390/ijerph17092997. 12. ali kf. instagram. from: www.instagram.com/dr.khawla.fuad.ali accessed: aug 2020. 13. ali kf. instagram. from: www.instagram.com/p/b9q4szoh8kw/ accessed: aug 2020. 14. ali kf. instagram. from: www.instagram.com/p/b96snfuhvql/ accessed: aug 2020. 15. elkhayat h, amin mt, thabet ag. patterns of use of social media in cardiothoracic surgery; surgeons' prospective. j egypt soc cardiothorac surg 2018; 26:231–6. https://doi.org/10.1016/j.jescts.2018.07.003. https://doi.org/10.3399/bjgpopen20x101072 https://doi.org/10.1136/bmj.m1160 https://doi.org/10.1136/bmj.m1160 https://doi.org/10.3961/jpmph.20.094 https://doi.org/10.2196/19128 https://doi.org/10.1371/journal.pone.0228372 https://doi.org/10.3390/ijerph17092997 https://doi.org/10.1016/j.jescts.2018.07.003 a 7-year-old boy from south india presented with recurrent left motor seizure with secondary generalisation. the computed tomography scan of his brain [figure 1] demonstrated a solitary enhancing cystic lesion with eccentric mural nodule (scolex) in the right frontal region. based on the epidemiological profile (he came from an endemic area), as well squ med j, february 2011, vol. 11, iss. 1, pp. 119-121, epub. 12th feb 11 submitted 30th jun 10 revision req. 26th jul 10, revision recd. 7th aug 10 accepted 29th sept 10 department of medicine, sultan qaboos university hospital, muscat oman; former affiliation: department of neurology, sri venkateswara institute of medical sciences (svims), tirupati, india. email: rnandagopal@yahoo.com …^⁄ç÷]<ª<<ìf� fiñ̌�⁄<ìä̌è”÷<çèuê< � �9èf̌ �u< �›ö̌ê̌  solitary cerebral cysticercus granuloma ramachandiran nandhagopal interesting medical image figure 1: cranial computerised tomography scan demonstrating a single solitary enhancing right frontal cystic lesion (arrow) with eccentric mural nodule-scolex (asterix in the inset) and perilesional oedema. solitary cerebral cysticercus granuloma 120 | squ medical journal, february 2011, volume 11, issue 1 as the clinical and imaging findings,1 a diagnosis of solitary cerebral cysticercus granuloma was made. he was treated with a short course of anticysticercal treatment (albendazole), prednisolone (after excluding spinal and ocular cysticercosis) and phenytoin. follow-up imaging at 6 months revealed significant improvement. solitary cysticercal cysts are an important cause of symptomatic seizure in endemic areas. other clinical manifestations include headache and focal neurological deficits. in the natural history of neurocysticercosis, the following stages of evolution of parenchymal larval cysts can be observed on neuroimaging: viable cyst, granulomatous cysticercosis and disappearance of cyst with or without residual calcification.2 in the viable cyst stage, the cyst wall is not visible on imaging and the cyst demonstrates little or no perilesional oedema. ring-like or nodular areas of enhancement with prominent perilesional oedema mark the phase of granulomatous cysticercosis. the image shown here demonstrates the granulomatous cysticercosis as a ring-enhancing lesion with scolex and peri-lesional oedema. ultimately, the remnant of the cyst is either not visible on the imaging or observed as calcified lesion(s). medical treatment for viable or granulomatous cysticercosis includes antihelminthic medication, standard anticonvulsants for seizures and symptomatic medication such as anti inflammatory drugs such as steroids. antiparasitic therapy for solitary cysticercus granuloma is shrouded in controversy for the following reasons: 1) solitary cysticercus granuloma may resolve spontaneously without antihelminthic treatment; 2) the parasite cannot grow and develop further in the cerebral parenchymal location, and 3) antihelminthic treatment kills the parasite that can potentially cause neurological complications such as a transient increase in seizure frequency, headaches, and raised intracranial pressure. the latter complication is observed especially in patients with multiple cysticercus granulomata. the arguments for cysticidal therapy include rapid disappearance of cyst(s) and the possibility of less residual calcification.2 albendazole in a dose of 15 mg/kg/day divided into two doses is the antihelminthic drug widely employed. the duration of treatment was 1 month in older studies,3 but this has been reduced to 15 days and even 1 week in later studies.4,5 it is usually administered along with corticosteroids to prevent the neurological complications associated with the degeneration and death of the parasite as mentioned above. a recent cochrane database systematic review found evidence for a reduction both in the number of viable lesions and in seizure frequency in those patients with non-viable cysts on albendazole therapy.6 the other available antihelminthic drug is praziquantel, usually given in dose of 50 mg/kg/ day for 2 weeks. a single day course of praziquantel has also been employed.7 surgery is usually reserved for extraparenchymal neurocysticercosis such as an intraventricular cyst, spinal cysticercosis causing spinal cord compression, for hydrocephalus, or for ophthalmic cysticercosis.8 in general, the seizure outcome in solitary cerebral cysticercosis is good in view of the symptomatic nature of the seizure. the optimal duration of anticonvulsant prophylaxis has not been finally decided. some authors favour anticonvulsant prophylaxis for 6 months and repeat the neuroimaging scan (by ct or magnetic resonance imaging) to look for resolution of the lesion with a view to tapering anticonvulsants in patients who are fit free,8 while others have continued anticonvulsant therapy for 2 years.9 patients with residual calcification may be at risk of recurrent seizures. the image is mainly presented here to highlight the characteristic appearance of cysticercus lesion termed 'hole with a dot’;1 the hole represents the cysticercus ring lesion itself and the dot the scolex. for physicians in non-endemic regions such as oman, awareness of this imaging characteristic aids in the recognition of cerebral cysticercosis in patients who originate from or have travelled to endemic areas. references 1. del brutto oh, rajshekhar v, white ac jr, tsang vc, nash te, takayanagui om, et al. proposed diagnostic criteria for neurocysticercosis. neurology 2001; 57:177–83. 2. garcia hh, evans ca, nash te, takayanagui om, white ac jr, botero d, et al. current consensus guidelines for treatment of neurocysticercosis. clin microbiol rev 2002; 15:747–56. 3. agapejev s, meira da, barraviera b, machado jm, pereira pc, mendes rp, et al. ramachandiran nandhagopal interesting medical image | 121121 | squ medical journal, february 2011, volume 11, issue 1 neurocysticercosis: treatment with albendazole and dextrochloropheniramine (preliminary report). rev inst med trop sao paulo 1988; 30:387–9. 4. garcia hh, gilman rh, horton j, martinez m, herrera g, altamirano j, et al. albendazole therapy for neurocysticercosis: a prospective double-blind trial comparing 7 versus 14 days of treatment. cysticercosis working group in peru. neurology 1997; 48:1421–7. 5. thussu a, chattopadhyay a, sawhney im, khandelwal n. albendazole therapy for single small enhancing ct lesions (ssectl) in the brain in epilepsy. j neurol neurosurg psychiatry 2008; 79:272–5. 6. abba k, ramaratnam s, ranganathan ln. anthelmintics for people with neurocysticercosis. cochrane database syst rev 2010; 3:cd000215. 7. pretell ej, garcia hh, custodio n, padilla c, alvarado m, gilman rh, et al. short regimen of praziquantel in the treatment of single brain enhancing lesions. clin neurol neurosurg 2000; 102:215-8. 8. sinha s, sharma bs. neurocysticercosis: a review of current status and management. j clin neurosci 2009; 16:867-76. 9. de souza a, thennarasu k, yeshraj g, kovoor jm, nalini a. randomized controlled trial of albendazole in new onset epilepsy and mri confirmed solitary cerebral cysticercal lesion: effect on long-term seizure outcome. j neurol sci 2009; 276:108-14. departments of 1pulmonary medicine and 2pathology, all india institute of medical sciences, bhopal, india *corresponding author’s e-mail: aqeelturabi09@gmail.com askin’s tumour massive tumour with minimal symptoms *aqeel hussain,1 alkesh k. khurana,1 abhishek goyal,1 deepti joshi2 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 664–665, epub. 25 nov 21 submitted 3 sep 20 revision req. 12 nov 20; revision recd. 7 dec 20 accepted 24 jan 21 a 33-year-old female patient presented to a tertiary care hospital bhopal, india, in 2019 with complaints of left-sided chest discomfort for four months and progressively increasing shortness of breath for one month. the patient developed hoarseness of voice, chest pain and dysphagia one week before presenting to this hospital. the chest x-ray revealed a large homogenous opacity in the left hemithorax with tracheal and cardiac deviation to the right side [figure 1a]. a contrast enhanced computed tomography of the thorax revealed a single large heterogeneously enhancing soft tissue mass lesion occupying the entire left hemithorax, measuring 27 × 14.6 × 15.5 cm [figure 1b]. the lesion had caused a significant mass effect in the form of a gross contralateral mediastinal shift, inferior displacement of the diaphragm, anterior displacement of the spleen, encasement and obliteration of the left pulmonary artery and abutment and displacement of the left subclavian artery, arch of aorta and descending aorta without any luminal narrowing. no obvious bony lytic or sclerotic lesion was noted. an ultrasonography-guided fine needle aspiration cytology of the lesion revealed a malignant round cell tumour, potentially qualifying as a primitive neuroectodermal tumour (pnet). a biopsy of the lesion revealed malignant round cell tumour [figure 2a]. immunohistochemistry of the lesion was positive for cluster of differentiation (cd)99 [figure 2b]. the lymphoid markers—wilms’ tumour 1 gene and epithelial membrane antigen—were negative. apart from cd99 positivity, the characteristic site and morphology of the tumour supported the diagnosis of pnet. no blasts were observed on peripheral blood and bone marrow examination, excluding the possibility of lymphoblastic malignancy. there was also no sign of desmoplasia in the tumour stroma thereby excluding the diagnosis of a desmoplastic small round cell tumour. the patient was started on chemotherapy with a vac-ie (vincristine, adriamycin, cyclophosphamide followed by ifosfamide and etoposide) regimen on the advice of a multidisciplinary team. serum lactate dehydrogenase (ldh) level was at 904 u/l. a bone marrow aspiration and biopsy done for staging purposes revealed hyper cellular marrow with erythroid hyperplasia and mild megalobastosis with no evidence of marrow infiltration by tumour cells. the patient’s performance status as per the eastern cooperative oncology group scale was 3/5. she received her first cycle of chemotherapy as per protocol and supportive treatment in the form of feeding through a nasogastric tube, analgesics and hydration. on the fourth day post-chemotherapy, the patient developed hypoxemic respiratory failure which was managed with supplemental oxygen and antibiotics. however, her condition worsened over the next few days with the patient succumbing to respiratory failure. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.048 interesting medical image figure 1: a: chest radiography showing the left hemithorax (whiteout) and gross contralateral shifting of mediastinal structures and b: computerised tomography of the thorax (mediastinal window) at level t-5 showing a huge mass lesion virtually replacing the left lung and gross contralateral shifting of mediastinum in a 33-years-old female patient with askin’s tumour. the mass lesion also shows various necrotic areas interspersed in between. aqeel hussain, alkesh k. khurana, abhishek goyal and deepti joshi interesting medical image | 665 consent was obtained from the patient’s husband to utilise her case record and images for publication purposes. comment pnet of the thoracopulmonary region, also referred to as askin’s tumour, was first described in 1979 by askin et al. and is a very rare entity.1 developing from the soft tissues of the chest wall, particularly in the paravertebral region, the clinical symptoms include painful chest wall mass and other associated symptoms such as dyspnoea, cough, weight loss and regional lymphadenopathy. a chest wall soft-tissue density mass, sometimes associated with rib erosion and/or pleural effusion, is the most commonly found radiographic manifestation. it may only produce vague discomfort occasionally, thereby delaying the diagnosis to a very advanced stage.2 the differential diagnosis of such a large unilateral soft tissue density includes ewing’s sarcoma, rhabdomyosarcoma, neuroblastoma and ganglioneuroblastoma.2,3 to the best of the authors’ knowledge, the current case of askin’s tumour is the largest tumour reported in existing literature (27 × 14.6 × 15.5cm) compared to the previously reported maximum of 15 × 22.5 cm.4 the largest tumour in a case series of 20 patients reported by askin et al. had a maximum diameter of 14 cm.1 the maximum size of askin’s tumour in a series of 11 patients reported by zhang et al. was 12.5 cm and was 13.7 cm in another series reported by xia et al.3,5 the relatively stable vitals at admission and lack of rib erosion and pleural effusion, for a mass of this size, were quite unique to this case. the histopathology of askin’s tumour typically reveals undifferentiated sarcomatous tissue of small round cells with scant eosinophilic cytoplasm, high nuclear-cytoplasmic ratio, small single nucleoli and a high mitotic rate.6 immunohistochemistry is generally positive for cd99 and neuron specific enolase. presently, the diagnosis of askin’s tumour is based on oncogenetic practices that look for chromosomal translocations (t [11;22][q24; q12]) and/ or their fusion transcripts. this mutation is also seen in ewing’s sarcoma.6 the prognosis of this tumour remains poor due to local recurrence and distant metastasis, usually to the lungs and skeletal system.3 the factors determining prognosis include size of the primary tumour, ldh levels, distant metastasis and performance score of the patient.4 these factors predicted a poor prognosis in our patient who died shortly after starting chemotherapy. a u t h o r s’ c o n t r i b u t i o n ah, akk and ag were involved in patient management. ah and akk performed the literature review. ah drafted the manuscript, while akk, ag and dj edited the manuscript. dj performed the laboratory diagnosis. all authors approved the final version of the manuscript. references 1. askin fb, rosai j, sibley rk, dehner lp, mcalister wh. malignant small cell tumour of the thoracopulmonary region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis. cancer 1979; 43:2438–51. https://doi.org/10.1002/1097-0142(197906)43:6<2438::aidcncr2820430640>3.0.co;2-9. 2. sabati jm, franquet t, parellada ja, monill jm, oliva e. malignant neuroectodermal tumour of the chest wall (askin tumour): ct and mr findings in eight patients. clin radiol 1994; 49:634–8. https://doi.org/10.1016/s0009-9260(05)81882-3. 3. xia t, guan y, chen y, li j. askin tumor: ct and fdg-pet/ ct imaging findings and follow-up. medicine (baltimore). 2014; 93:e42. https://doi.org/10.1097/md.0000000000000042. 4. dou x, yan h, wang r. treatment of an askin tumor: a case report and review of the literature. oncol lett 2013; 6:985–9. https://doi.org/10.3892/ol.2013.1488. 5. zhang ke, lu r, zhang p, shen s, li x. askin's tumor: 11 cases and a review of the literature. oncol lett 2016; 11:253–6. https://doi.org/10.3892/ol.2015.3902. 6. desai ss, jambhekar na. pathology of ewing's sarcoma/pnet: current opinion and emerging concepts. indian j orthop 2010; 44:363–8. https://doi.org/10.4103/0019-5413.69304. figure 2: ultrasonography-guided biopsy showing a hypercellular tumour lying in sheets composed of small, round, hyperchromatic tumour cells with scant cytoplasm in a 33-year-old female patient with askin’s tumour. a: haematoxylin and eosin stain at ×200 magnification showing tumour cells that are seen encircling lumen forming rosettes at certain places. b: immunostaining with cluster of differentiation 99 at ×200 magnification showing tumour cells displaying strong membranous positivity. attention deficit hyperactivity disorder (adhd) is the most common neuropsychiatric disorder encountered in children and adolescents, whether in the community or in the clinic. it can be mild, moderate or severe. the prevalence rate of adhd in oman is 5.1% in schoolgirls and 7.8% in schoolboys, which are comparable to the rates found in other studies.1,2,3,4 boys are affected more than girls in a ratio of 3−4:1. the three main symptoms of adhd are: attention problems, hyperactivity and impulsivity, occurring in variable proportions, giving rise to three main subgroups: mainly inattentive (20%), mainly hyperactive-impulsive (12%) and the combined subgroup (68%).5,6 in addition, adhd children have low self-esteem, emotional instability and squ med j, april 2010, vol. 10, iss. 1, pp. 84-88, epub. 17th apr 10 submitted 13th oct 09 revision req. 8th dec 09, revision recd. 6th jan 10 accepted 6th jan 10 departments of 1behavioral medicine and 4radiology college of medicine and health sciences, sultan qaboos university, muscat, oman; departments of 2behavioral medicine and 3child health, sultan qaboos university hospital, muscat, oman * to whom correspondence should be addressed. email: marwan@squ.edu.om. عرض نادر الضطراب نقص االنتباه/فرط النشاط توصية النتباه أكرب! مروان ال�رسبتي، را�شد الزيدي، رحمة النعماين، اآمنة الفطي�شي، راجيف جني امللخ�ص: ندرج هنا حالة طفلة عمانية عمرها سبع سنوات تُعاني من التصلب احلدبي واضطراب نقص االنتباه/ فرط النشاط مع اضطراب الهوس في مستشفى جامعة السلطان قابوس. في السنة األخيرة كانت تُعاني من فرط النشاط والعدوانية والثرثرة واألرق والسلوك اخلطر ونقص االنتباه وسرعة التشتت ونوبات الصرع. بدأت هذه األعراض ببطء لكنها كانت تزداد مبرور الوقت . في املركز الصحي (قبل مراجعة مستشفى اجلامعة) أعطيت لها أربعة أدوية دون إجراء الفحوص الضرورية الالزمة، وقد ساءت حالة الطفلة بعد العالج. في مستشفى اجلامعة كانت تُظهر فرطا في النشاط مع سلوك متهور، وُسرور بالغ غير ُمبرّر وتطاير األفكار، والكالم واللعب مع الذات، كما أن ثقتها بنفسها كانت عالية. أظهر الفحص الطبي السريري وجود عدة بقع ناقصة امليالنني في مختلف مناطق اجلسم وكذلك وجود َلْطَخٌة َحرْشاء في أسفل الظهر. في تخطيط الدماغ كان هناك كهربائية زائدة في مختلف املناطق بينما ظهر في تصوير الدماغ وجود تكلسات في فصيه . بقية الفحوصات كانت طبيعية. أعطيت عقار الفالبرويت ومن ثم امليثايل فينيديت حيث استقرت حالتها. الهدف من إدراج هذه احلالة ليست فقط ألنها حالة مراضة مرافقة نادرة احلصول، بل لتذكير زمالئنا األطباء الشباب بأن يكونوا أكثر يقظة ومتعنا في فحص وعالج األطفال الذين يعانون من أعراض عصبية نفسية من أجل الوصول إلى تشخيص وعالج صحيحني. مفتاح الكلمات: اضطراب نقص االنتباه/فرط النشاط، التصلب احلدبي، االضطراب ثنائي القطبية، األطفال، الهوس، الفحص السريري، الفحوصات، تقرير حالة، ُعمان. abstract: we report the case of a 7 year-old omani girl with tuberous sclerosis (ts), attention deficit hyperactivity disorder (adhd) and bipolar disorder (bd), at sultan qaboos university hospital (squh), oman. for a year she had been suffering from hyperactivity, aggression, over talkativeness, insomnia, risk-taking behaviour, distractibility, poor attention and seizures. this clinical picture evolved slowly, but was progressive in nature. before the consultation at her local health centre, she was given four drugs without being properly investigated; she continued to deteriorate. in squh, she showed hyperactive-impulsive behaviour, elation, flight of ideas, preoccupation with self and high self-confidence. the physical examination revealed multiple hypomelanotic patches all over the body and a shagreen patch at the sacral area. the electroencephalogram showed generalised epileptic discharges, while brain imaging showed multiple parenchymal calcified foci in both cerebral hemispheres. other investigations were normal. she was given valproate, and then a psychostimulant, methylphenidate, that controlled her state. our aim in reporting this case is not only because it is unique, given its rare comorbidity (adhd, ts and bd), but also to remind our junior colleagues to be alert to the possibility of an underlying neuropathology when performing clinical examinations and investigations of children presenting with neuropsychiatric symptoms. keywords: attention deficit hyperactivity disorder; tuberous sclerosis; bipolar disorder; children; mania; physical examination; investigation; case report; oman. a rare presentation of attention deficit/hyperactivity disorder a recommendation to be more alert! *marwan al-sharbati,1 rashid al-zaidi,2 rahma al-naamani,2 amna al-futaisi,3 rajeev jain4 case report marwan al-sharbati, rashid al-zaidi, rahma al-namaani, amna al-futaisi and rajeev jain case report | 85 poor memory. often the age of onset is 3 years of age; however, symptoms must appear during the first seven years of life, and should persist at least for six months, to fulfill the diagnostic criteria. the disorder may continue even after adolescence in about half of the cases.7 many family studies suggest that genes play a large role in causation, possibly through polygenetic inheritance. like many other psychiatric illnesses, adhd probably results from an interaction between both genetic and environmental factors such as: cigarette smoking, alcohol, malnutrition, and infection during pregnancy; hypoxia and brain injuries during labor.8,9 also, exposure to a high level of lead is linked to adhd.10 other rare causes of adhd are single gene disorders (phenylketonurea, galactosemia), neurofibromatosis, tuberous sclerosis, etc. adhd is usually associated with comorbid disorders such as: oppositional defiant and conduct disorders, anxiety, depression, autism, mental retardation, sleep disorder, dyslexia and bipolar disorder. adhd should be differentiated from a long list of other disorders (some of which may be found in association with adhd) such as: petit mal epilepsy, severe iron deficiency anaemia, hyperand hypothyroidism, adjustment disorders, child abuse, sleep disorders, drug abuse, lead poisoning, emotional disorders, developmental speech and language disorders, post-traumatic stress disorder, bipolar disorder, and hearing impairment. if not diagnosed and treated early, the consequences of adhd will be alarming, not only for the person him/herself, but also for the family and the community. these include: school failure, smoking, drug abuse, alcoholism, road traffic accidents, domestic injuries, family problems, juvenile delinquency, occupational difficulties, etc.3,11,12 the treatment of adhd is multimodal, including special education, psychotherapy and psycho-pharmacotherapy. the prognosis of adhd depends on many factors including the severity of the condition, early diagnosis and treatment, comorbid conditions (especially mental retardation), and the availability of a supportive environment at school and at home. case report a 7 year-old omani girl was referred by a local polyclinic to the child and adolescent psychiatry clinic at sultan qaboos university hospital (squh), oman. the information giver was the patient’s father. the main complaints were: hyperactivity, aggression and insomnia during the previous year. also, both parents had noticed that, during the same period, the patient had become over talkative (sometimes making irrelevant remarks), distractible with poor attention and concentration, and had exhibited risk-taking behaviour. her symptoms had started gradually, but were progressive in nature. because of her aggressive and risk-taking behavior she had stopped going to school. a few months before the consultation, the patient had figure 1: non-contrast computed tomography scan showing the largest parenchymal calcified focus in right frontal subcortical region. figure 2: non-contrast computed tomography scan showing multiple subependymal calcified foci noted in both lateral ventricles. a rare presentation of attention deficit/hyperactivity disorder a recommendation to be more alert! 86 | squ medical journal, april 2010, volume 10, issue 1 started to have tonic-clonic seizures lasting for about 3 minutes, mostly during the night with uprolling of the eyes, loss of consciousness, frothing in the mouth, and urination. the convulsions had gradually became more frequent (twice a week), occurring both during the day and night. she looked happy, talking and playing with herself most of the time, showing high self confidence. although the patient had gained bladder control at an early age, she then became incontinent. her appetite had also diminished. there was no history of fever, head trauma or child abuse. regarding her sleep pattern, she was going to sleep very late (around 1−2 a.m.) with initial insomnia, sleep interruptions and early wakening (at 5−6 a.m.); she did not sleep during the day. several months previously, her family had taken her to a local polyclinic (psychiatry outpatient department), and without being investigated she was given the following treatment: haloperidol 1.5 mg, procyclidine 5 mg and phenobarbitone 30 mg all three drugs once a day and carbamazepine 100 mg twice daily. the patient did not improve on that treatment, on the contrary, her symptoms worsened over the time. her medical and psychiatric histories were uneventful. there was no consanguinity between parents, and no family history of mental disorders. she was the last of 7 siblings (from both parents). the pregnancy and delivery were normal; her birth weight was 2.9 kg. her development was normal. she was described before her illness as a playful, sociable and intelligent girl. the mental state examination showed a well-dressed, highly hyperactive, impulsive, easily distractible, inattentive, over-familiar child. her speech was of a high rate and volume with flights of ideas. she maintained eye contact. her mood looked high with some irritability. she had high self-esteem with evident self-confidence. her recent memory was disturbed, while her intelligence seemed to be normal. her weight was 19 kg and height was 113 cm (both at 10th percentile). there were multiple hypomelanotic patches all over the body and a shagreen patch at the sacral area. the physical examination (including neurological) was normal. the computed tomography (ct) and magnetic resonance imaging (mri) brain scan showed multiple parenchymal calcified foci in both cerebral hemispheres. the largest one was in the right frontal subcortical region and there were multiple subependymal calcified foci noted in both lateral ventricles, which often suggest tuberous sclerosis (ts) [figures 1, 2 and 3]. the blood investigations were normal. the electroencephalogram (eeg) showed generalised epileptic discharges. she was referred to the neurology section of the child health department for further investigations and for medications to control her seizures. in addition, systemic investigations were done: an echocardiography, a chest x-ray and abdominal ultrasonography, all of which were normal. the fits were controlled with sodium valproate (175 mg twice daily), while the hyperactivity was controlled by methylphenidate (slow release) 20 mg once a day. a diagnosis of tuberous sclerosis, complicated by adhd and hypomania, was made. a significant change was reported by the parents during followup visits in her hyperactivity, inattention and insomnia. she became less talkative, less elated and was seizure-free over follow-up visits. discussion this case represents the commonest neuropsychiatric disorder in child psychiatry, adhd, which is characterised by disruptive behaviour and disturbed cognitive functions starting in early life. after doing the appropriate clinical assessment and investigations, we found that adhd was caused by a rare disease, ts. this is a multi-system-genetic disease, resulting in multiple benign tumours affecting different organs, with a prevalence of 1/6,000 newborns. ts is distributed figure 3: multiple parenchymal calcified foci in both cerebral hemispheres . marwan al-sharbati, rashid al-zaidi, rahma al-namaani, amna al-futaisi and rajeev jain case report | 87 equally between the two sexes and is caused by mutations of one or two genes: ts1, ch 9 (produces hamartin) and ts2, ch 16 (produces tuberin). these proteins act as tumour growth suppressors. ts can be transmitted either by autosomal dominance inheritance or by spontaneous mutation. treatment is directed to control symptoms as there is no cure for ts. the use of adequate doses of valproate controlled the epilepsy in this case, while methylphenidate controlled the hyperactive-impulsive behavior. in addition to the adhd and ts, this patient showed symptoms and signs of bipolar disorder (mania) as manifested by marked elation, over talkativeness, flight of ideas, high self-confidence and noticeable irritability. such an association of these conditions is very rare, reported only in two cases in medical literature.13,14 bipolar disorder (bd) in children was previously thought to be an uncommon occurrence, although cases have been diagnosed since the 1970s. it was a matter of debate until few years ago, when psychiatrists start to diagnose and treat such cases with more frequency, possibly due to doctors’ increased awareness of the condition.15 the majority of the bd cases in children (> 90%) is associated with adhd, while only a minority of adhd cases (< 20%) suffer from comorbid bd.16 early diagnosis and treatment of bd is of high importance to alleviate the devastating outcome of the disorder, which might end in suicide in many cases. in this case, valproate acted as an anti-epileptic and a mood stabiliser while the symptoms of adhd were treated by methylphenidate. this case had been treated at the local health centre by active psychotropic drugs without being fully investigated. it is not surprising that the patient did not improve; on the contrary, her state worsened. we emphasise the importance of appropriate physical examination and proper investigations in medical practice, and stress the necessity of excluding organic causes before commencing any treatment. conclusion this case may be the third one in the world presenting with a rare association of ts, adhd and bd appearing at an early age. we strongly underline the importance of performing a careful clinical examination and proper investigations, which are of crucial importance for sound diagnosis and treatment. a c k n o w l e d g m e n t this case was presented on 11th february 2009 in the squ clinical-pathological conference series (scraps) as: “be more reflective!” references 1. al-sharbati m, al-adawi s, ganguly s, al-lawatiya s, al-mshefri f. hyperactivity in a sample of omani schoolboys. j atten disord 2008; 12:264−9. 2. al-sharbati m, adawi sa, al-hussaini aa, lawati sa, martin r. adhd in omani schoolgirls. j am acad child adolesc psychiatry 2004; 43:132−3. 3. al-sharbati mm, al-hussaini aa, antony sx. profile of child and adolescent psychiatry in oman. saudi med j 2003; 24:391−5. 4. polanczyk g, de lima ms, horta bl, biederman j, rohde la. the worldwide prevalence of adhd: a systematic review and metaregression analysis. am j psychiatry 2007; 164:942−48. 5. al-sharbati m. attention deficit/hyperactivity disorder in omani youth. a paper presented at international congress of world psychiatric association, florence, italy, november 2004. 6. american psychiatric association. diagnostic and statistical manual of mental disorders. 4th ed. washington, dc: american psychiatric press, 2000. 7. elia j, ambrosini pj, rapoport jl. treatment of attention-deficit-hyperactivity disorder. n engl j med 1999; 340:780–8. 8. linnet km, dalsgaard s, obel c, wisborg k, henriksen tb, rodriguez a, et al. maternal lifestyle factors in pregnancy risk of attention-deficit/ hyperactivity disorder and associated behaviors: review of the current evidence. am j psychiatry 2003; 160:1028−40. 9. mick e, biederman j, faraone sv, sayer j, kleinman s. case-control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. j am acad child adolesc psychiatry 2002; 41:378−85. 10. braun j, kahn rs, froehlich t, auinger p, lanphear bp. exposures to environmental toxicants and attention-deficit/hyperactivity disorder in u.s. children. environ health perspect 2006; 114:1904−9. 11. discala c, lescohier i, barthel m, li g. injuries to children with attention deficit hyperactivity disorder. pediatrics 1998; 102:1415−21. 12. barkley ra, murphy kr, kwasnik d. motor vehicle driving competencies and risks in teens and young adults with attention deficit hyperactivity disorder. pediatrics 1996; 98:1089−95. 13. khanna r, borde m. mania in a 5-year-old child with a rare presentation of attention deficit/hyperactivity disorder a recommendation to be more alert! 88 | squ medical journal, april 2010, volume 10, issue 1 tuberous sclerosis. br j psychiatry 1989; 155:117−19. 14. vk chopra, y cintury, vk sinha. bipolar disorder associated with tuberous sclerosis: chance association or aetiological relationship? indian j psychiatry 2006; 48:66−8. 15. biederman j, mick e, faraone sv, van patten s, burback m, wozniak j. a prospective follow up study of pediatric bipolar disorder in boys with attention deficit/hyperactivity disorder. j affect disord 2004; 82:s17−23. 16. wozniak j, biederman j, kiely k, ablon js, faraone sv, mundy e, et al. mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. j am acad child adolesc psychiatry 1995; 34:867−76. 1oral & maxillofacial surgery residency program, oman medical specialty board, muscat, oman; 2dental and maxillofacial surgery department, al-nahdha hospital, muscat, oman; 3dental and maxillofacial surgery department, sultan qaboos university hospital, muscat, oman; 4plastic and reconstructive surgery department, khoula hospital, muscat, oman; 5oral and maxillofacial surgery, oman dental college, muscat, oman *corresponding author’s email: albakri122@gmail.com the impact of traffic law enforcement regulations on the incidence and severity of maxillofacial injuries *abdullah albakri,1 ahmed al-hashmi,2 abdulaziz bakathir,3 shikhan al hashmi,4 said al rashdi,2 khamis al hasani,1 mohammed al ismaily5 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 479–485, epub. 7 nov 22 submitted 14 apr 21 revisions req. 2 jun & 12 jun 21; revisions recd. 28 jun & 25 aug 21 accepted 9 sep 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.129 clinical & basic research abstract: objectives: this study aimed to assess the effectiveness of the new traffic law enforcement regulations (tlers) on the incidence and severity of maxillofacial injuries in oman, as road traffic accidents (rtas) are the main cause of facial injuries in oman. methods: a retrospective longitudinal analytic study was conducted at three tertiary care hospitals in muscat, oman. all patients with rta-related maxillofacial injuries during a five-year period from january 2005 to december 2009 (before the new tlers) and the five-year period from january 2015 to december 2019 (after the new tlers) were included in the study. results: a total of 1,127 patients were included in the study. of these, 646 (57.3%) patients sustained rta-related maxillofacial injuries before the implementation of the new tlers compared to 481 (42.7%) after the introduction of tlers. no significant gender-based difference was found between the two study periods. the incidence of injury before the implementation of the new tlers was 22.7 per 100,000 population, which then reduced significantly to 11 per 100,000 after the tlers were implemented. overall, the mean facial injury severity score reduced significantly, from 3.2 to 2.3, after the implementation of the new tlers. conclusions: the findings of this study indicate that the newly introduced tlers have resulted in a reduction in the incidence and severity of rta-related maxillofacial injuries. continuous improvement and reinforcement of tlers will further help reduce the burden of these injuries to society in general and health services in particular. keywords: law enforcement; traffic accidents; maxillofacial injuries; injury severity score; oman. advances in knowledge this is the first omani study that highlights the effectiveness of the new traffic law enforcement regulations in reducing the incidence and severity of road traffic accident (rta)-related maxillofacial injuries in oman. the findings of this study would be of interest to other countries, which may adopt the omani approach to reducing the incidence and severity of rta-related maxillofacial injuries. application to patient care the results of this study will help stakeholders and decision-makers to assess, review and improve current and future road safety strategies. the impact of human awareness and behavioural change is important in relation to road safety, and further studies need to focus on this area. as part of ensuring the effective implementation of traffic law enforcement regulations, the role of law enforcement in ensuring behavioural change and thus improving road safety should be considered. globally, road traffic accidents (rtas)are ranked as the 11th most common cause of death and the ninth most common cause of disabilities. in addition, the world health organization (who) has reported that more than 3,000 people die and 30,000 were injured or disabled every day because of rtas.1,2 in 2010, the institute for health metrics and evaluation reported that rtas were the main cause of death in oman.3 over the past five decades, oman has experienced significant economical and sub-structural development, which has been accompanied by an exponential increase in its population, as well as the total number of vehicles.4 rtas have a great impact and result in multiple challenges that hinder the progressive development of the country and consume human, financial and health resources.1–3,5 governmental bodies, including the royal oman police (rop), ministry of transport, ministry of information and local municipalities, have been playing important roles in controlling and reducing the number and severity of these accidents by utilising information and communication technologies as well as by introducing different measures such as speed cameras, fines, penalty points and constructing safer highways (unpublished date).6 the maxillofacial region has prominent and mobile structures; thus, it is at risk of being injured during rtas. such injuries are serious and can cause https://creativecommons.org/licenses/by-nd/4.0/ the impact of traffic law enforcement regulations on the incidence and severity of maxillofacial injuries 480 | squ medical journal, november 2022, volume 22, issue 4 severe blood loss, airway obstruction, facial deformity and, occasionally, death.3,5,7 studies have reported a marked reduction in the number and severity of maxillofacial injuries as an outcome of increased awareness within society as well as the amplification of traffic law enforcement regulations (tlers).5,7,8 in oman, the implementation of the new tlers, new road network and monitoring technologies have resulted in major improvements and upgrades, especially in the period between the end of 2009 and early 2014.6 assessing the impact of these measures and regulations on the incidence and severity of maxillofacial injuries is crucial to establishing their effectiveness and to marking the need for their continuous improvements. therefore, this study was conducted to assess the incidence and severity of rta-related maxillofacial injuries before and after the introduction of the new tlers in oman. methods this retrospective longitudinal analytic study was carried out at three tertiary care hospitals: alnahdha hospital, khoula hospital and sultan qaboos university hospital (squh), muscat, oman. these are the three main hospitals in oman managing craniomaxillofacial injuries. the target patients were divided into two periods: first, before the introduction of the new tlers (january 2005 to december 2009) and, second, after the introduction of tlers (january 2015 to december 2019). data were retrieved from two electronic healthcare systems (alshifa 3 plus, ministry of health, for al-nahdha hospital and khoula hospital and trakcare® 2018, unified healthcare system, intersystems corporation, for squh). data for the period before 2006 were gathered from the trauma log books that were used to manually record maxillofacial injuries before the start of the electronic healthcare systems. all patient files with a history of rtas were reviewed. the study inclusion criteria included all patients who presented to the three aforementioned hospitals with the diagnosis of maxillofacial injury as a conseq uence of rta during the study periods. study variables included gender, age, year of injury and diagnosis of the maxillofacial injury. all fractures were categorised according to the location: upper face (frontal bone and skull), mid-face (malar, maxillary, nasal bones and naso-orbito-ethmoid) and lower face (mandible). the injury was classified as an isolated injury when only one facial bone was involved and combined when it involved more than one facial bone. the facial injury severity score (fiss) was chosen to assess the severity of the injury. this index was first created by bagheri et al. and has subsequently been used in multiple studies.9 the fiss system categorises facial bones into three anatomical regions (upper face, mid-face and mandible) and each fracture line occurring in these areas is given an injury score according to the location, displacement and severity of the injury. facial lacerations are also recorded as part of the fiss and the final score is calculated as the sum of each anatomical area sub-scores. furthermore, the severity of the facial injury was categorised based on the fiss as mild (1–3), moderate (4–7) and severe (8–15), according to alasseri et al.10 a data collection sheet was designed using microsoft excel, version 2019 (microsoft corp., redmond, washington, usa) to collect the study data and statistical analysis was conducted using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). descriptive statistics were used for the study variables and the data were expressed in terms of number, percentage, mean and standard deviation. chi-squared tests were used for significance analysis between the study variables and the periods before and after the implementation of the new tlers p=0.001 . a statistically significant result was set at p <0.05. before the commencement of the study, ethical approval was obtained from the respective research and ethics committees: the research and ethical review & approval committee at the centre of studies & research (moh/csr/20/16596), the research and ethics committee at al-nahdha hospital (moh/ anh/rc/22/20) and the medical research ethics committee at sultan qaboos university (mrec #2319). results a total of 5,444 patients with maxillofacial injuries were identified during the two study periods, of whom 1,127 met the study inclusion criteria of having sustained rta-related maxillofacial injuries [figure 1]. the mean age was 30.8 years for the first period (2005–2009) and 27.8 years for the second period (2015–2019), with the difference being statistically significant (p <0.01). the maxillofacial injuries were more prevalent among men compared to women (78.6% versus 21.4%); however, in relation to the gender of those who sustained injuries, the difference between the two study periods was not statistically significant (p = 0.213) [table 1]. the overall incidence of maxillofacial injuries per 100,000 population during the first and second periods was 22.7 and 11, respectively, indicating a significant abdullah albakri, ahmed al-hashmi, abdulaziz bakathir, shikhan al hashmi, said al rashdi, khamis al hasani and mohammed al ismaily clinical and basic research | 481 reduction in these injuries after the implementation of the new tlers (p = 0.001). the majority of the encountered maxillofacial injuries were isolated fractures, accounting for 72.8% and 94% before and after the introduction of tlers, respectively. furthermore, these isolated fractures demonstrated an increase of 21.2% during the second period under study. on the contrary, combined injuries exhibited a significant decrease from 27.2% to 6%. this difference in the combined and isolated types of injuries between the two periods was statistically significant with a p value of <0.001 [table 1]. considering the location of the fractures, in both the study periods, an overall increase was observed in the occurrence of mid-facial fractures, while a reduction was noted in the number of upper and table 1: characteristics and demographic data of the study population (n = 1,127) variables n (%) p value 2005–2009 2015–2019 total rta-related maxillofacial injuries among the total injuries* 646 (19.5) 481 (22.6) 1,127 (20.7) gender male 516 (79.9) 369 (76.7) 885 (78.5) 0.213female 130 (20.1) 112 (23.3) 242 (21.5) total 646 (57.3) 481 (42.7) 1,127 (100) age in years mean 30.8 27.8 29.9 0.0001minimum 1 2 1 maximum 83 63 83 diagnosis fracture of malar and maxillary bones 121 (18.7) 151 (31.4) 272 (24.1) 0.0001 fracture of mandible 247 (38.2) 175 (36.4) 422 (37.4) fracture of nasal bones 112 (17.3) 93 (19.3) 205 (18.2) noe fracture 14 (2.2) 30 (6.2) 44 (3.9) fracture of frontal bone 152 (23.5) 32 (6.7) 184 (16.3) location of injury upper face 152 (23.5) 30 (6.3) 182 (16.2) 0.0001mid-face 247 (38.2) 276 (57.4) 523 (46.4) lower face 247 (38.2) 175 (36.4) 422 (37.4) injury type isolated 470 (72.8) 452 (94.0) 922 (81.8) 0.0001 combined 176 (27.2) 29 (6.0) 205 (18.2) rta = road traffic accident; noe = naso-orbito-ethmoid. *calculated out of the total rta-related injuries from each study period. table 2: comparison of facial injury severity scores before and after the implementation of the new traffic law enforcement regulations in relation to age and gender (n = 1,127) variable n mean age ± sd p value mean fiss score ± sd p value year 2005–2009 646 30.9 ± 13.3 0.0001 3.22 ± 2.15 0.0001 2015–2019 481 27.8 ± 12.5 2.31 ± 1.71 gender male 885 29.4 ± 12.7 0.312 2.87 ± 2.01 0.237 female 242 30.4 ± 14.2 2.69 ± 2.09 sd = standard deviation; fiss = facial injury severity score. the impact of traffic law enforcement regulations on the incidence and severity of maxillofacial injuries 482 | squ medical journal, november 2022, volume 22, issue 4 lower facial fractures. mandibular fracture was the most frequently encountered diagnosis, accounting for 37.4%, with naso-orbito-ethmoid fracture being the least encountered (4%) in both the study periods [table 1]. although the mean fiss score before the introduction of the new tlers was mild at 3.22 ± 2.15, this further reduced to 2.31 ± 1.71 after the introduction of the new tlers. this reduction in the mean scores between the two periods was statistically significant (p <0.001). there was no statistically significant difference in the mean fiss scores between the genders (p = 0.237) [table 2]. the overall fiss categorisation was higher for mild injuries and low for severe injuries, accounting for 68.5% and 2.7%, respectively. however, there was a statistically significant decrease in the percentage of moderate and severe injuries after the introduction of the tlers (p <0.001) [figure 2 and table 3]. discussion oman is the second-largest country in land area and third in population size among the gulf cooperation council (gcc) countries.11 the income from oil revenue, coupled with guided government policies in development, has moved oman to a prestigious position in several aspects and it was ranked the most ‘improved nation’ in the world in terms of development during the past five decades.3,12 this rapid development was associated with a corresponding rapid rise in population and infrastructure, leading to a remarkable increase in the number of drivers and registered vehicles. the population in oman increased from 2.8 million in 2009 to 4.6 million by the end of 2019. similarly, the number of registered vehicles and drivers increased from 840,000 cars and 84,000 registered drivers at the end of 2009 to 1.7 million cars and 1.5 million drivers by the end of 2019.11,13–15 over the past 10 years, through multiple governmental bodies, including the rop, the omani government has worked to further improve and enhance the road network and safety (unpublished data).6,14 a national road safety committee was created in 2011 and october 18th was announced as the annual day of traffic safety. furthermore, traffic safety symposia have been held annually since 2011, which also feature traffic safety competitions focusing on school audiences. major media and reporting campaigns have been conducted over the years, promoting and focusing on road safety issues. all table 3: facial injury severity score before and after the implementation of the new traffic law enforcement regulations year gender n (%) total p value mild* moderate* severe* 2005–2009 male 310 (60.1) 189 (36.6) 17 (3.3) 516 (100) 0.0001female 76 (58.5) 49 (37.7) 5 (3.8) 130 (100) total 386 (59.8) 238 (36.8) 22 (3.4) 646 (100) 2015–2019 male 289 (78.3) 75 (20.3) 5 (1.4) 369 (100) 0.0001female 97 (87.4) 12 (10.8) 2 (1.8) 111 (100) total 386 (80.4) 87 (18.1) 7 (1.5) 480 (100) total 772 (68.6) 325 (28.9) 29 (2.6) 1,127 (100) 0.0001 *facial injury severity scores: mild (1–3), moderate (4–7) and severe (8–15). figure 1: road traffic accident-related maxillofacial injuries before and after the implementation of the new traffic law enforcement regulations (n = 1,127). figure 2: facial injury severity score group categor isation before and after the implementation of the new traffic law enforcement regulations (n = 1,127). abdullah albakri, ahmed al-hashmi, abdulaziz bakathir, shikhan al hashmi, said al rashdi, khamis al hasani and mohammed al ismaily clinical and basic research | 483 media platforms have been utilised to this end, with the specific objectives of increasing awareness within the society, delivering educational programmes and encouraging behavioural changes in relation to road safety.6 furthermore, the rop annually participate in and conduct activities as part of the gcc traffic week; these activities focus on raising public awareness and educating the public on issues related to road safety.6,16 furthermore, the scientific research council of oman has allocated annual road safety research funds and facilitated a liaison and consultancy agreement with the british research and transportation centre to enhance traffic safety.6 aligning with the move towards better road safety in oman, the new tlers were reintroduced gradually from late 2009 to early 2014. these regulations were equally applied and strictly reinforced across oman. the tlers included strict traffic law regulations and penalties, road and speed monitoring technologies and other initiatives— including traffic rehabilitations and regular traffic awareness campaigns (unpublished data).6,14,15 the present study, which addresses the impact of the new tlers on maxillofacial injuries, was conducted five years after the implementation of the new regulations that aim to enhance public awareness and ensure the proper adoption and implementation of traffic laws. this is the first study in oman and the second in the gcc countries to assess the impact of tlers on maxillofacial injuries. the present study looked at two five-year periods—one before and another after the introduction of the new tlers. hence, it was unique in covering a longer period before and after the implementation of tlers when compared to the study by alasseri et al.10 the result of this study showed that the incidence of rta-related maxillofacial injuries dropped from 22.7 to 11 per 100,000 people after the introduction of the new tlers. this finding is consistent with those of other published works, indicating that more stringent traffic law regulations result in a significant reduction in rtas and related injuries.8,10,17–20 the present study showed a male predominance in rta-related maxillofacial injuries during both the study periods (mean = 78.6%). this finding is similar to previously published regional and international studies that reported that men are more commonly involved in rta and account for up to 80% of these injuries.9,10,18–20 such high prevalence was attributed to the fact that men, being more empowered in society and engaged in more outdoor activities, were more likely to be involved in reckless driving compared to female drivers.10,20 furthermore, in the present study, the mean age of the involved patients was 29.9 years, which is consistent with the findings of published studies, indicating that this age group is associated with increased self-dependence, high activity and social interactions, which may increase their susceptibility to reckless driving and more road usage.9,10,17–20 regarding the location of the injury, published data from saudi arabia reported that most maxillofacial injuries were in the lower face, with no reported occurrence in the upper face during both study periods—before and after the implementation of the saher law enforcement system.10 the present findings are in contrast to the study by alasseri et al., in that before the implementation of tlers, lower face and mid-face injuries had an equal occurrence, while after the adoption of tlers, mid-face injuries were predominant, followed by lower face. this study also reports the occurrence of upper face injuries before and after the implementation of tlers, with a statistically significant reduction in the occurrence of upper face injuries during the second study period. this important finding is in line with other published studies.17–21 considering the injury location based on the international classification of diseases diagnosis, the mandible was the most commonly involved maxillofacial bone during both study periods, a finding that supported other published scientific data.9,10,17,20,21 assessing the severity of trauma is an important tool in estimating the risks of injury, predicting survival probability and outcome, planning for emergency and definitive treatment, predicting health costs and determining hospital length of stay (los).10,21,22 for this purpose, many trauma severity scoring systems have been proposed and adopted over the past few decades.21 the abbreviated injury scale, the injury severity score (iss) and the trauma and injury severity score (triss) were among the first trauma severity scoring systems adopted in the 1970s and 1980s and have since undergone various revisions and updates.23–26 in 1997, osler et al. revised the iss system and proposed the new injury severity score (niss), which eliminated the shortcomings of iss and made it more simple and accurate to record.27 the main drawback of these trauma systems is that they were primarily designed to assess general trauma and, in particular, survival but not disability, prognostic outcome, cost of treatment or los.10,21 proper assessment of the severity of maxillofacial trauma requires accurate recording of the injury type, location, functional abnormalities and disability implications.9,10,22,23 to address this area of trauma, newer severity scoring systems were introduced, including the maxillofacial injury severity score (mfiss), introduced by zhang et al. in 2006; the facial injury severity score (fiss) introduced by bagheri et al. in 2006; and the miss introduced by shi et al. the impact of traffic law enforcement regulations on the incidence and severity of maxillofacial injuries 484 | squ medical journal, november 2022, volume 22, issue 4 in 2008.9,23,28 recently published work by chen et al. comparing four different maxillofacial trauma severity scoring systems showed that the mfiss was a better scoring system. it has also proved to be a reliable system in assessing trauma severity, treatment plan, prognosis prediction and outcome and in assisting epidemiological and clinical studies on maxillofacial trauma.22 however, the mfiss has multiple inherent deficiencies, which also exist within the other severity systems, including an inability to accurately record the severity of mid-face fractures and functional impairments.22,23 the mfiss is also a more complex system and demands multiple data entries compared to the fiss. accordingly, for this study, the fiss was used to evaluate trauma severity preand postimplementation of the new tlers, without the need for analysing the outcome, prognosis or treatment needs. furthermore, the fiss is a simple system to use, as it requires far less data entry in comparison to the mfiss and miss systems and has been validated as a reliable system for recording maxillofacial trauma severity.6,7,21 the fiss is a simple maxillofacial severity scoring scale that was designed and introduced by bagheri et al. in 2006 for maxillofacial trauma research purposes and has since been used in multiple international studies to record maxillofacial trauma severity.9,10,22 the current study showed that there was a statistically significant reduction in fiss score from 3.2 to 2.3 after the implementation of the new tlers, which contradicts the findings of alasseri et al., wherein the mean fiss changed from 3.2 to 3.5 after the introduction of the saher system.10 although their sample size was small, alasseri et al. showed that a reduction in the fiss injury subtype scores and a reduction in the overall incidence of rta-related maxillofacial injuries from 58.9% to 41.4% occurred after the implementation of the new traffic regulations in saudi arabia.10 the present study findings are in line with previously published studies that highlight the overall benefits of the enforcement and adoption of strict traffic law regulations in reducing the incidence of rta-related trauma.7,8,10,17–20 many developed countries, including countries in north america and europe, have succeeded in reducing the incidence of rtas from over 30% to 3–8% over a few decades by investing in human education, research and strict traffic regulations.7,8,16,20,29,30 previously published data from different gcc countries reported that 51–63% of the maxillofacial injuries are rta-related, which indicates that it is the major aetiological factor in these injuries. these reports have identified the need for collaborative work to reduce this relatively high incidence and have recommended adopting multiple measures that focus on improving public awareness, education, road network and safety and more strict traffic regulations.16,17,20,31 the present study has demonstrated the benefits of adopting the new tlers that have led to a significant reduction in the incidence of rta-related maxillofacial injuries in oman from 53% and 63% before introducing the new tlers, as reported by bakathir et al. and al-hashmi et al. in 2008, to 19.5% and 22.6% after the introduction of the tlers.16,31 furthermore, the significant increase in isolated maxillofacial fractures and the significant decrease in combined injuries are indicative of oman’s achievement and success in the implementation and reinforcement of tlers. this retrospective analysis had a few limitations and inherent drawbacks, including missing and limited sources of data and failure to record other associated injuries that would serve as an additional measure of the severity of the injury. this national study is not fully comprehensive, as it lacks data from other smaller maxillofacial surgery units, such as the armed forces hospital and the three regional hospitals in sohar, salalah and ibri that have started managing maxillofacial trauma since 2016. further studies incorporating detailed maxillofacial trauma assessment, treatment, outcome, cost and los will be important in assessing the impact of rta-related maxillofacial injuries on the healthcare system in oman. conclusion the new omani tlers were effective in reducing the incidence and severity of rta-related maxillofacial injuries. however, additional work is required for the continued improvement and reinforcement of tlers, which can further reduce the incidence and burden of rta-related injuries in oman. the findings of this study should help all stakeholders assess and review current and future road safety strategies. the role of human awareness and behaviour is important in relation to road safety and further studies need to focus on this area. a u t h o r s’ c o n t r i b u t i o n ah, ab and aa conceptualised and designed the study. aa obtained ethical approval for the study. ah, ab and sh supervised the work. aa, kh and sr collected the data. aa and ab drafted the manuscript. mi edited the manuscript. all authors approved the final version of the manuscript. abdullah albakri, ahmed al-hashmi, abdulaziz bakathir, shikhan al hashmi, said al rashdi, khamis al hasani and mohammed al ismaily clinical and basic research | 485 a c k n o w l e d g e m e n t the authors would like to thank prof mohammed alismaili from oman dental college for proofreading the manuscript and captain bader mohammed salim al-shuaili and captain saif sultan mohammed aladawi for providing data from the rop. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. world health organization. world report on road traffic injury prevention: summary. geneva: world health organization, 2004. wa 275. 2. world health organization. the global burden of disease: 2004 update. geneva, switzerland: world health organization, 2004. w 74. 3. halasa ya, monasta l, montico m, naidoo ks, ronfani l, salomon ja, et al. gbd 2010 country results: a global public good. lancet 2013; 381:965–70. https://doi.org/10.1016/s01406736(13)60283-4. 4. national center for statistics and information. statistical year book, issue 39. 2011. 5. kheirallah m, almeshaly h. epidemiological analysis of mandibular fractures in ksa. from: https://www.researchgate. net/publication/303389924 accessed: aug 2021. 6. traffic safety institute. annual report. muscat, oman. 7. alqahtani f, bishaw k, jaber m. analysis of the pattern of maxillo facial injuries in saudi arabia: a systematic review. saudi dent j 2020; 32:61–7. https://doi.org/10.1016/j.sdentj.2019.08.008. 8. andersson l. road traffic accidents a cause of death and trauma. dent traumatol 2011; 27:1. https://doi.org/10.1111/j.1600-96 57.2010.00965.x. 9. bagheri sc, dierks ej, kademani d, holmgren e, bell rb, hommer l, et al. application of a facial injury severity scale in craniomaxillofacial trauma. j oral maxillofac surg 2006; 64:408–14. https://doi.org/10.1016/j.joms.2005.11.013. 10. alasseri n, almanea rs, algarni ms, alajmi ss, jeleudan ws, alsaeed mi. effect of law enforcement system (saher) on maxillo facial injuries caused by road traffic accidents in riyadh. saudi j oral sci 2019; 6:88–95. https://doi.org/10.4103/sjos.sjoralsci_3_18. 11. gulf cooperation council countries statistical atlas 2019. from: https://docplayer.ae/200703034-gulf-cooperation-coun c i l c o u n t r i e s s t a t i s t i c a l a t l a s 2 0 1 9 % d 8 % a 7 % d 8 % a 3 % d 9 % 8 4 % d 8 % b 7 % d 9 % 8 4 % d 8 % b 3 % d 8 % a 7 % d 8 % a 5 % d 9 % 8 4 % d 8 % a d % d 8 % b 5 % d 8 % a 7 % d 8 % a 6 % d 9 % 8 a % d 9 % 8 4 % d 8 % a f % d 9 % 8 8 % d 9 % 8 4 % d 9 % 8 5 % d 8 % a c % d 9 % 8 4 % d 8 % b 3 % d 8 % a 7 % d 9 % 8 4 % d 8 % a a % d 8 % b 9 % d 8 % a 7 % d 9 % 8 8 % d 9 % 8 6 % d 9 % 8 4 % d 8 % a f % d 9 % 8 8 % d 9 % 8 4 % d 8 % a 7 % d 9 % 8 4 % d 8 % a e % d 9 % 8 4 % d 9 % 8 a % d 8 % ac% d 8 % a 7 % d 9 % 8 4 % d 8 % b 9 % d 8 % b 1 % d 8 % a 8 % d 9 % 8 a % d 8 % a 9 2 0 1 9 % d 9 % 8 5 1 . h t m l accessed: aug 2021. 12. united nations. human development report: five arab countries among top leaders in long-term development gains. e7-1–7-3. 13. national center for statistics and information. statistical year book, issue 48. august 2020. 14. royal oman police. statistical year book, version 34. 2018. 15. royal oman police. traffic statistics. 2010. 16. al-hashmi ak, al-ismaily mi, goss an. a comparative study of the etiology of adult mandibular fractures in the sultanate of oman and south australia. saudi med j 2008; 29:1828–30. 17. al-khateeb t, abdullah fm. craniomaxillofacial injuries in the united arab emirates: a retrospective study. j oral maxillofac surg 2007; 65:1094–101. https://doi.org/10.1016/j.joms.2006.0 9.013. 18. agnihotri a, galfat d, agnihotri d. incidence and pattern of maxillofacial trauma due to road traffic accidents: a prospective study. j maxillofac oral surg 2014; 13:184–8. https://doi.org/10.1 007/s12663-013-0502-y. 19. srinivasan p, sanjay. road traffic accidents under the influence of alcohol causing maxillofacial trauma: one year retrospective study. indian j multidiscip dent 2014; 4:911–5. 20. alhammad z, nusair y, alotaibi s, ababtain r, alsulami s, aljumah g. a cross-sectional study of the prevalence and severity of maxillo facial fractures resulting from motor vehicle accidents in riyadh, saudi arabia. saudi dent j 2020; 32:314–20. https://doi.org/10.10 16/j.sdentj.2019.09.009. 21. xiao-dong l, qiu-xu w, wei-xian l. epidemiological pattern of maxillofacial fractures in northern china. medicine (baltimore) 2020; 99:e19299. https://doi.org/10.1097/md.0000000000019299. 22. chen c, zhang y, jin-gang an, he y, gong x. comparative study of four maxillofacial trauma scoring systems and expert score. j oral maxillofac surg 2014; 72:2212–20. https://doi. org/10.1016/j.joms.2014.04.035. 23. zhang j, zhang y, el-maaytah m, ma l, liu l, zhou ld. maxillofacial injury severity score: proposal of a new scoring system. int j oral maxillofac surg 2006; 35:109–14. https://doi. org/10.1016/j.ijom.2005.06.019. 24. association for the advancement of automotive medicine. the abbreviated injury scale. from: https://www.aaam.org/ abbreviated-injury-scale-ais/ accessed: aug 2021. 25. baker sp, o’neill b, haddon wj, long wb. the injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. j trauma 1974; 14:187–96. 26. boyd cr, tolson ma, copes ws. evaluating trauma care: the triss method. trauma score and the injury severity score. j trauma 1987; 27:370–8. 27. osler t, baker sp, long w. a modification of the injury severity score that both improves accuracy and simplifies scoring. j trauma 1997; 43:922–5. https://doi.org/10.1097/00005373-199712000-00009. 28. shi z, zhou s, feng x, li s, liu y, bo b, et al. the design and implementation of chinese maxillofacial trauma registry, analysis and injury severity score system. j trauma 2008; 64:1024–33. https://doi.org/10.1097/ta.0b013e31809fea9b. 29. bocchialini g, castellani a. facial trauma: a retrospective study of 1262 patients. ann maxillofac surg 2019; 9:135–9. https://doi.org/10.4103/ams.ams_51_19. 30. ramalingam s. role of maxillofacial trauma scoring systems in determining the economic burden to maxillofacial trauma patients in india. j int oral health 2015; 7:38–43. 31. bakathir aa, margasahayam mv, al-ismaily mi. removal of bone plates in patients with maxillofacial trauma: a retrospective study. oral surg oral med oral pathol oral radiol endod 2008; 105:e32–7. https://doi.org/10.1016/j.tripleo.2008.01.006. https://doi.org/10.1016/j.sdentj.2019.08.008 https://doi.org/10.1111/j.1600-9657.2010.00965.x https://doi.org/10.1111/j.1600-9657.2010.00965.x https://doi.org/10.1016/j.joms.2005.11.013. https://doi.org/10.4103/sjos.sjoralsci_3_18 https://doi.org/10.1016/j.joms.2006.09.013 https://doi.org/10.1016/j.joms.2006.09.013 https://doi.org/10.1007/s12663-013-0502-y https://doi.org/10.1007/s12663-013-0502-y https://doi.org/10.1016/j.sdentj.2019.09.009 https://doi.org/10.1016/j.sdentj.2019.09.009 https://doi.org/10.1097/md.0000000000019299 https://doi.org/10.1016/j.joms.2014.04.035. https://doi.org/10.1016/j.joms.2014.04.035. https://doi.org/10.1016/j.ijom.2005.06.019 https://doi.org/10.1016/j.ijom.2005.06.019 https://doi.org/10.1097/00005373-199712000-00009 https://doi.org/10.1097/ta.0b013e31809fea9b https://doi.org/10.4103/ams.ams_51_19 https://doi.org/10.1016/j.tripleo.2008.01.006 departments of 1medicine and 2cardiology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com احلقن املباشر ملواضع التخثر داخل شراين اتجي أمين مرتهل و مسدود بكميات غزيرة من اخلثرة التاجية يف مريض مصاب ابحتشاء قليب حاد حامت اللواتي، حفيظ الهادي، �سونيل كومار نادار abstract: managing a high intracoronary (ic) thrombus burden is a major challenge in patients with ectatic coronary arteries who present with an st-elevation myocardial infarction (stemi). we report a 45-year-old male patient who presented to the department of medicine, sultan qaboos university hospital, muscat, oman, in 2017 with an inferior stemi. coronary angiography revealed ectatic coronary arteries with an occluded right coronary artery (rca). the rca had a massive thrombus burden that did not resolve with aspiration thrombectomy or balloon angioplasty. subsequently, ic thrombolysis was administered resulting in significant reperfusion. during the course of his treatment, the patient suffered from intracranial bleeding as a complication; however, he recovered completely with no residual neurological sequelae. this case report demonstrates that ic thrombolysis is a valid option in patients with a massive thrombus burden in the setting of a stemi, albeit with an increased risk of major bleeding. keywords: ectasia; mechanical thrombolysis; myocardial infarction; case report; oman. امللخ�ص: تعترب معاجلة وتفتيت كميات هائلة من اخلرثة التاجية اأحد التحديات الكبرية التي تعوق عالج مري�ض القلب امل�ساب باحت�ساء قلبي حاد وخ�سو�سا يف �رشايني تاجية متو�سعة ومرتهلة. نعر�ض هنا حالة ملري�ض يف �سن اخلام�سة والأربعني من عمره تلقى عالجه يف 2017 مب�ست�سفى جامعة ال�سلطان قابو�ض لنوبة قلبية مفاجئة من جراء ان�سداد كامل وحاد يف ال�رشيان التاجي الرئي�سي الأمين. ك�سف ت�سوير الأ�سعة عن طريق ق�سطرة القلب ترهال ومتددا ملحوظا غري طبيعي يف ال�رشيان التاجي الأمين مع وجود خرثة تاجية �سخمه مل ت�ستجب ملحاولت ا�ستئ�سالها بال�سفط التداخلي او تفتيتها بالبالون. مت عالج احلالة بنجاح عن طريق احلقن املبا�رش ملوا�سع اخلرثة يف ال�رشيان املن�سد، الأمر الذي اأدى اىل حتلل اخلرثة وا�سرتجاع تروية الدم اىل اجلزء املتاأثر من ع�سلة القلب. لالأ�سف اأ�سيب املري�ض بنزيف دماغي موؤقت و تعافى منه ب�سكل كامل بدون اأي اآثار متبقية. يو�سح هذا التقرير اأن احلقن املبا�رش ملوا�سع التخرث يف ال�رشايني التاجية خيار بديل فعال يف عالج حالت احت�ساء ع�سلة القلب احلادة والتي ي�ستع�سي عالجها بالأ�ساليب العتيادية ب�سبب �سخامة اخلرثة امل�سببة للنوبة القلبية. الكلمات املفتاحية: تو�سع ال�رشايني؛ حتليل اخلرثة امليكانيكي؛ احت�ساء ع�سلة القلب؛ تقرير حالة؛ ُعمان. use of intracoronary thrombolysis for huge thrombus burden in an ectatic right coronary artery hatim al-lawati,1 hafidh alhadi,1 *sunil k. nadar2 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e390–393, epub. 21 dec 20 submitted 19 mar 20 revision req. 11 may 20; revision recd. 9 jun 20 accepted 24 jun 20 intracoronary (ic) lysis is an option that is not considered often either due to lack of clear practice protocols or a high perceived bleeding risk.2 in addition, the 2017 european guidelines on management of stemi do not clearly state how these patients should be managed besides the usual procedures, such as aspiration thrombectomy and balloon angioplasty.5 in this report, we present a case of an occluded ectatic right coronary artery (rca) presenting as a stemi which was successfully treated with ic fibrinolysis. case report a 45-year-old male patient presented to the department of medicine, sultan qaboos university hospital, muscat, oman, in 2017 with a central chest coronary artery ectasia is a relatively uncommon abnormality with a reported incidence of around 0.3–5.3% of patients undergoing coronary angiography.1 due to the abnormal flow dynamics, these vessels are prone to thrombus formation and occlusion presenting as an acute st-elevation myocardial infarction (stemi). the management of these patients is often challenging due to the high thrombus burden, with the use of various available modalities such as manual thrombus aspiration often being inadequate.2 presence of a large amount of thrombus has been shown to be associated with poor long-term prognosis and is also often associated with complications such as stent thrombosis, no reflow phenomenon and distal embolisation.3,4 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.018 case report https://creativecommons.org/licenses/by-nd/4.0/ hatim al-lawati, hafidh alhadi and sunil k. nadar case report | e391 pain lasting for two hours. he was not known to be diabetic or hypertensive. on examination, he was in pain with a blood pressure of 140/80 mmhg and heart rate of 80 beats per minute, which was regular. his electrocardiogram (ecg) showed st-segment elevation in the inferior leads. he was immediately transferred for primary percutaneous coronary intervention (pci). his angiogram showed that all the coronary arteries were ectatic. the rca was occluded at the junction of the proximal and mid-third with a heavy thrombus burden [figure 1]. a balance middle weight universal ii wire (cordis ltd, santa clara, california, usa) easily passed into the distal vessel. after predilatations were performed, manual thrombus aspiration was performed with an export™ aspiration catheter (medtronic ltd, minneapolis, minnesota, usa) as per standard protocol. the thrombus was only slightly resolved, requiring further aspirations directly through the guide catheter deeply engaged in the vessel and also through a guideliner™ (teleflex ltd, morrisville, usa) passed deep into the vessel. a bolus dose of weight-adjusted ic eptifibatide was also administered. at the end of the procedure, there was significant, although not complete, thrombus resolution with thrombolysis in myocardial infarction (timi) grade two flow into the distal vessel [figure 2]. the st-segment elevation in the patient’s ecg had resolved and he was free of chest pain. at this point, it was decided to stop the procedure and start intravenous eptifibatide infusion with the intention to check again with another angiogram after 48 hours. however, the next day the patient developed chest pain with st-segment elevation in the inferior leads once again. the patient underwent an emergency coronary angiogram where the rca was found to be occluded again, but in a more proximal location to the previous occlusion [figure 3a]. further aspiration was performed, but with no significant reduction in the thrombus burden. therefore, it was decided to administer ic fibrinolysis. this was done using alteplase in aliquots of 5 mg over 10 minutes. this was given four times (total dose of 20 mg at 10 minute intervals) due to incomplete resolution of the thrombus. a spider fx device (medtronic ltd) was used to prevent distal embolisation during thrombolysis. at the end of the procedure, there was timi grade three flow in the rca [figure 3b]. the patient was then started on eptifibatide and heparin infusion. he remained well from a cardiac point of view with no further chest pains and normalisation of the ecg changes; however, he developed ataxia 24 hours figure 1: initial angiogram of a 45-year-old male patient who presented to sultan qaboos university hospital, muscat, oman showing (a) an occluded right coronary artery and (b) ectatic left corony artaries. figure 2: the right coronary artery of a 45-year-old male patient at the end of the first aspirations procedure. figure 3: the right coronary artery of a 45-year-old male patient at the (a) beginning and (b) end of the second aspirations procedure. use of intracoronary thrombolysis for huge thrombus burden in an ectatic right coronary artery e392 | squ medical journal, november 2020, volume 20, issue 4 later. a head computed tomography (ct) revealed a small intracerebellar bleed secondary to an existing previously undiagnosed arterio-venous malformation. the eptifibatide and heparin infusions were stopped but he was continued on dual antiplatelet agents. he subsequently had a full neurological recovery. at three months, he remained free of chest pain with no new ecg abnormalities and no neurological deficits. he was not willing to undergo another coronary angiogram but instead underwent a cardiac ct which showed that the rca remained widely patent. discussion percutaneous management of acute coronary occlusion presenting as an acute stemi focuses on restoration of normal flow in the infarct-related epicardial artery. in addition, the operator also aims to restore coronary perfusion at the microcirculatory level using a combination of mechanical measures (e.g. aspiration thrombectomy) and pharmacological agents (e.g. glycoprotein [gp] iib/iiia inhibitors). impaired coronary flow results in reperfusion injury and microvascular impairment which leads to arrhythmias, irreversible myocardial damage and permanent ventricular contractile dysfunction, heart failure and increased mortality.6,7 thrombus management is the cornerstone of pci in acute stemi. the level of thrombus burden predicts slow-flow, no-reflow phenomenon, which is a predictor of poor outcome.4 the presence of a large amount of thrombus is also associated with a higher incidence of stent thrombosis and reinfarctions. the thrombus may also embolise distally and obstruct the microcirculation, impairing tissue perfusion which may manifest as incomplete resolution of the st-segment on the ecg or persistent wall motion abnormalities on the echocardiogram.4 therefore, many strategies have been described to tackle the problem of large ic thrombus.2 the thrombus can be disrupted with local balloon dilatation or treated with thrombectomy devices such as aspiration catheters or mechanical rheolytic thrombectomy.8 injectable antiplatelets, such as gp iib/iiia inhibitors, are also used to help reduce thrombus burden and prevent complications. thrombectomy may be performed using standard aspiration catheters such as the export™ (medtronic ltd), diver™ (invatec, thurgau, switzerland) or pronto® (vascular solutions inc., maple grove, minnesota, usa) catheters, which are advanced into the vessel and manual aspiration with a syringe is performed. specialised thrombectomy devices such as the angiojet™ (medrad inc., warrendale, pennsylvania, usa), x-sizer™ (covidien, dublin, ireland) systems are motorised devices that can also be used in situations with high thrombus burden.9 these latter devices, although more successful in aspirating thrombus are cumbersome to use and are associated with more complications and have fallen out of favour by the interventionalists. although routine thrombectomy is discouraged due to an unacceptably high risk of cerebral embolism and disabling strokes, it is still performed if there is a high level of thrombus present in the infarct related artery.10 massive thrombus burden is not uncommon and is encountered in nearly 16–17% of acute coronary syndromes (acs) undergoing coronary angiography.10 they are also unlikely to respond to conventional thrombus dissolution strategies whether mechanical (thrombus aspiration) or potent anticoagulant and antiplatelet agents, with studies showing persistent significant amount of thrombus in 8% of patients despite employing various measures to resolve it.11 systemic fibrinolysis is recommended in the management of acute stemi where facilities for primary pci are limited.5 however, the evidence for its use via the ic route for the treatment of large ic thrombus is not clear. the most commonly used agent for this indication is alteplase or tenecteplase (tnk). streptokinase (one of the first thrombolytic agents to be used in stemi) is not used routinely anymore due to various side effects and the availability of more potent and fibrin-specific agents. alteplase is administered in a 5–10 mg aliquots given ic over five minutes.11 this allows for a more controlled delivery of the agent locally, especially in a patient heavily pretreated with antiplatelet agents, anticoagulation and gp iib/iiia inhibitors. kelly et al. studied 34 patients treated with ic thrombolysis for various indications (22 for acute stemi, four for rescue pci, six for non-stemi and two for in situ thrombosis during elective pci).12 they found that ic administration of tenecteplase was proven to be both safe and effective with clot dissolution documented in 91% of treated patients. ic thrombolysis has also been shown to improve measures of microvascular function including coronary flow reserve, microvascular resistance, collateral flow, diastolic deceleration time as well as corrected timi frame count.13 boscarelli et al. showed that low dose ic thrombolysis is both safe and effective in restoring epicardial flow and myocardial reperfusion.11 jayagopal basha recently published a series of nine cases where ic tenecteplase was used successfully in patients with very high thrombus burden.14 in the series, tnk was given ic at one fifth the systemic dose hatim al-lawati, hafidh alhadi and sunil k. nadar case report | e393 and the remaining four fifths were given systemically along with intravenous unfractionated heparin. all the patients had prompt and complete st resolution and improvement in their timi myocardial blush grade with no patients having any significant bleeding. the delivery of thrombolytics before thromb ectomy in patients with stemi undergoing primary pci (dissolution) randomised trial compared ic urokinase with ic saline control group prior to aspiration thrombectomy in patients with large thrombus.15 this trial showed that patients with ic thrombolytic upfront had better angiographic findings (higher rate of timi3 flow and higher myocardial blush grade) as well as a significantly lower major adverse cardiovascular event rate at six months— driven mainly by a lower rate of rehospitalisation for heart failure. there was no increase in bleeding. although the sample size was small (n = 102), it does suggest that ic thrombolysis may be useful. in the current patient, the first attempt at percutaneous revascularisation with manual aspiration thrombectomy and balloon angioplasty resulted in modest restoration of epicardial flow to the distal vessel. however, two days later, the vessel had reoccluded and had no improvement with aspiration. therefore, ic thrombolysis was performed. using thrombolytic therapy, major bleeding is a not an uncommon complication. due to an underlying previously undiagnosed arteriovenous malformation, the current patient developed intracranial bleed that was precipitated by the gp iib/iiia inhibitor infusion and heparin infusion. fortunately, the patient recovered completely with no neurological sequelae. therefore, efforts to open an infarct related artery with large thrombus burden should be done with caution as it exposes the patient to a higher risk of severe potentially fatal bleeding complications, including intracranial haemorrhage. conclusion occluded ectatic coronary vessels often present a therapeutic dilemma due to the huge thrombus burden that does not respond well to routine management. ic thrombolysis is a viable option in these patients with good resolution of thrombus but with a higher risk of major bleeding. references 1. pursnani a, jacobs je, saremi f, levisman j, makaryus an, capunay c, et al. coronary cta assessment of coronary anomalies. j cardiovasc comput tomogr 2012; 6:48–59. https://doi.org/1 0.1016/j.jcct.2011.06.009. 2. tsang m, jolly s interventional strategies in thrombus mana gement for st elevation myocardial infarction. interv cardiol 2015; 10:35–8. https://doi.org/10.15420/icr.2015.10.1.35. 3. vecchio s, varani e, chechi t, balducelli m, vecchi g, aquilina m, et al. coronary thrombus in patients undergoing primary pci for stemi: prognostic significance and management. world j cardiol 2014; 6:381–92. https://doi.org/10.4330/wjc.v6.i6.381. 4. sianos g, papafaklis mi, serruys pw. angiographic thrombus burden classification in patients with st-segment elevation myocardial infarction treated with percutaneous coronary intervention. j invasive cardiol 2010; 22:6b–144b. 5. ibanez b, james s, agewall s, antunes mj, bucciarelli-ducci c, bueno h, et al. the task force for the management of acute myocardial infarction in patients presenting with st segment elevation of the european society of cardiology (esc). the 2017 esc guidelines for the management of acute myocardial infarction in patients presenting with st segment elevation, eur heart j 2018; 39:119–77. https://doi.org/10.1093/eurheartj/ ehx393. 6. moens al, claeys mj, timmermans jp, vrints cj. myocardial ischemia/reperfusion injury, a clinical view on a complex pathophysiological process. int j cardiol 2005; 100:179–90 https://doi.org/10.1016/j.ijcard.2004.04.013. 7. resnic fs, wainstein m, lee mk, behrendt d, wainstein rv, ohno-machado l, et al. no-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention. am heart j 2003; 145:42–6. https://doi. org/10.1067/mhj.2003.36. 8. fröbert o, lagerqvist b, olivercrona gk, omerovic e, gudnason t, maeng m, et al. thrombus aspiration during stsegment elevation myocardial infarction. n engl j med 2013; 369:1587–97. https://doi.org/10.1056/nejmoa1308789. 9. rathod ks, hamshere sm, choudhury tr, jones da, mathur a use of thrombectomy devices in primary percutaneous interventions for st-elevation myocardial infarctionan update. interv cardiol 2014; 9:102–7. 10. de luca g, navarese ep, suryapranata h. a meta-analysis overview of thrombectomy during primary angioplasty. int j cardiol 2013; 166:606–12. https://doi.org/10.1016/j.ijcard.2 011.11.102. 11. boscarelli d, vaquerizo b, miranda-guardiola f, arzamendi d, tizon h, sierra g, et al. intracoronary thrombolysis in patients with st-segment elevation myocardial infarction presenting with massive intraluminal thrombus and failed aspiration. eur heart j: acute cardiovasc care 2014; 1:1–8. https://doi. org/10.1177/2048872614527008. 12. kelly rv, crouch e, krumnacher h, cohen mg, stouffer ga. safety of adjunctive intracoronary thrombolytic therapy during complex percutaneous coronary intervention: initial experience with intracoronary tenecteplase. catheter cardiovasc interv 2005; 66:327–32. https://doi.org/10.1002/ccd.20521. 13. sezer m, oflaz h, goren t, okçular i, umman b, nisanci y, et al. intracoronary streptokinase after primary percutaneous coronary intervention. n engl j med 2007; 356:1823–34. https://doi.org/10.1056/nejmoa054374. 14. jayagopal basha m. intracoronary tenectaplae in stemi with massive thrombus. indian heart j 2018; 70:446–9. https://doi. org/10.1016/j.ihj.2017.08.016. 15. greco c, pelliccia f, tanzilli g, tinti md, salenzi p, cicerchia c, et al. usefulness of local delivery of thrombolytics before thrombectomy in patients with st-segment elevation myo cardial infarction undergoing primary percutaneous coronary intervention (the delivery of thrombolytics before thrombectomy in patients with st-segment elevation myocardial infarction und ergoing primary percutaneous coronary intervention [dissol ution] randomized trial). am j cardiol 2013;112:630–5. https://doi.org/10.1016/j.amjcard.2013.04.036. https://doi.org/10.1016/j.jcct.2011.06.009 https://doi.org/10.1016/j.jcct.2011.06.009 https://doi.org/10.15420/icr.2015.10.1.35 https://doi.org/10.4330/wjc.v6.i6.381 https://doi.org/10.1093/eurheartj/ehx393 https://doi.org/10.1093/eurheartj/ehx393 https://doi.org/10.1016/j.ijcard.2004.04.013 https://doi.org/10.1067/mhj.2003.36 https://doi.org/10.1067/mhj.2003.36 https://doi.org/10.1056/nejmoa1308789 https://doi.org/10.1016/j.ijcard.2011.11.102 https://doi.org/10.1016/j.ijcard.2011.11.102 https://doi.org/10.1177/2048872614527008 https://doi.org/10.1177/2048872614527008 https://doi.org/10.1002/ccd.20521 https://doi.org/10.1056/nejmoa054374 https://doi.org/10.1016/j.ihj.2017.08.016 https://doi.org/10.1016/j.ihj.2017.08.016 https://doi.org/10.1016/j.amjcard.2013.04.036 squ med j, february 2011, vol. 11, iss. 1, pp. 77-82, epub. 12th feb 11 submitted 15th jun 10 revision req. 18th jul 10, revision recd. 26th jul 10 accepted 11th aug 10 1department of medical microbiology, faculty of medicine & health sciences, sana’a university, yemen; 2department of medical microbiology, faculty of medicine & health sciences, taiz university, yemen; 3department of medical microbiology, faculty of medical sciences, university of sciences & technology, sana'a, yemen. *corresponding author email: shmahe@yemen.net.ye <ìe^rjâ˜]ê<íò^f÷]<íâê4à÷]<çf”÷]<h^„j÷]<çï<‹è√�j÷]<ìè�«i <^√flë<ìflëç≤<ïüç^√÷]<‡â<k†<ÿ^àõ˜]<çfl¬<‰÷<ìè¬^flπ] d‡€è÷]e    840                      %44 %56504   %69.9 504 276%66.8%72.1  10           %54.8 %45.2504228  109 %63.6 53    abstract: objectives: the study was undertaken, first, to determine the coverage rate of hepatitis b (hb) vaccine and second to evaluate the immune response to hb vaccine among children under 10 years old by measuring the level of circulating anti-hb surface antigen (anti-hbs) antibodies after immunisation with three doses. methods: first, 840 children were randomly selected from 4 randomly selected sites in sana'a city to study the coverage rate of the vaccine; of these, 504 children vaccinated against hbv prior to the study, were tested (56% males and 44% females). sera were tested for anti-hbs antibodies by elisa quantitative technique. each individual’s data was collected in a pre-designed questionnaire including: vaccination date, sex, and age at the time of the study. results: the coverage rate of hbv vaccine was only 69.9%, being slightly higher among male children (72.1%) than female children (66.8%). a total of 276 (54.8%) of the 504 children responded to the vaccine with anti-hbs antibody level ≥ 10 miu/ml, while 228 (45.2%) of the 504 children had non-protective anti-hbs antibodies levels (<10iu/ml). children of ages 3–5 years had the highest protective rate (63.6%), and the lowest protective rate was in the 9–10 years age group. conclusion: this study revealed a low coverage rate of hbv vaccine and a low protective rate against hbv infection. a considerable proportion of vaccinated children should be considered for either revaccination or booster doses. there is also the need to complete hbv vaccine coverage among the child population in san’a, yemen. keywords: hepatitis b; vaccine; children; yemen; sana'a hepatitis b vaccine coverage and the immune response in children under ten years old in sana’a, yemen *hassan a al-shamahy,1 samira h hanash,2 iqbal a rabbad,3 nameem m al-madhaji,1 samarih m naser1 clinical & basic research advances in knowledge 1. there is a low coverage rate of hepatitis b (hb) vaccine in sana’a, yemen (70% of children) as well as a low protective rate against hb infection. this is despite the existence of an official vaccine supply since 2000. hepatitis b vaccine coverage and the immune response in children under ten years old in sana’a, yemen 78 | squ medical journal, february 2011, volume 11, issue 1 hepatitis b (hb) is a human disease caused by a virus that attacks the liver. the hepatitis b virus (hbv) can cause lifelong infection, cirrhosis of the liver, liver cancer, liver failure and death.1 hb infection is one of the world’s most common and serious infectious diseases. it is estimated that more than one third of the world’s population has been infected with hbv.2 about 5% of the population are chronic carriers of hbv, and nearly 25% of all carriers develop serious liver diseases such as chronic hepatitis, cirrhosis and primary heptocellular carcinoma (hcc).3 hbv infection causes more than one million deaths every year.4 for long-term protection against hbv, there are two types of vaccines: plasma-derived hb surface antigen (hbsag) vaccine, and yeast-derived hbsag vaccine.5 hb immunisation, using either type of vaccine, has been shown to eliminate hbv transmission and prevent hbv-related chronic liver disease.6 hbv vaccine can be routinely given to children and individuals at risk, along with other commonly used vaccines in a variety of schedules that results in excellent immunogenicity and do not interfere with the immunogenicity of other vaccines.7 the sero-conversion rate for vaccination is influenced by a number of factors, the most important ones being age and sex. rates in excess of 95% are seen in young women, whereas the rate may drop to 80% in older men. immunosuppressed patients, smokers, and obese individuals show even lower rates.8 according to the yemeni national infectious viral hepatitis control programme, yemen was recognised as hbv-endemic area.9 in 1998, the world health organization (who) recommended the inclusion of hb vaccine in the national immunisation programme of yemen, particularly among neonates, where vertical transmission is common, regardless of the prevalence of hbsag. in sana’a city, the hb antigen carrier rate is classified as intermediate, rather than high. the incidence of acute hbv has declined dramatically in the past decade since the start of the vaccination programme, especially among young people, although it may still take several decades until the effect of vaccination is translated into reduced transmission and morbidity.10 the aims of this study were first to determine the coverage rate of hbv among children and second to evaluate the immune response to hbv vaccine among vaccinated children with the three doses of hbv vaccine by measuring the level of circulating anti-hb surface antibodies. methods this cross sectional study was carried out from january to march 2010. the study proposal was approved by the department of medical microbiology, faculty of medicine & health sciences, sana’a university, yemen. first, 840 children, aged <1–10 years, (470 males and 370 females) were randomly selected by a systematic random sampling of every fifth child attending randomly selected health centres or from the lists of randomly selected primary schools in sana’a city. the histories of all 540 children who had received three doses of hbv vaccine were investigated. a total of 81.9% of them had received yeast-derived vaccine and 18.1% plasma-derived vaccin; 62.2% of the children had been vaccinated at a dose interval of 0, 1, 2 months and 37.8% at a dose interval of 0, 1, 6 months the immune response to the hbv vaccine of these 504 vaccinated children was then evaluated. a consent form was completed by the parents for each participant. a full history was taken from each individual studied and the findings recorded in a pre-designed questionnaire. the data collected included name, age at the time of the study, sex, residence, and vaccination date according to the last dose of hbv vaccine, number of doses, intervals between the three doses and type of vaccine. a full history of vaccinations against other diseases was also taken. four millilitres of whole blood were collected from each subject. then the sera were separated and frozen at -20 °c until tested. anti-hbs antibodies were determined by an enzymelinked immunosorbent assay (elisa) using a application to patient care 1. health care centres need to pay more attention to boosting hb vaccine coverage among children. 2. the role of vaccine in hb protection is fundamentally important as hb is endemic in sana’a. hassan a al-shamahy, samira h hanash, iqbal a rabbad, nameem m al-madhaji and samarih m naser clinical and basic research | 79 commercially available kit (biokit, s.a., barcelona, spain). bio-elisa anti-hb is a direct immunoenzymatic method of the “sandwich” type in which the samples to be analysed are incubated in wells of micro-plate that are coated with highly purified hb antigens. in order to differentiate naturally occurring immunity to hbv infection, total anti-hb core antibodies were measured; all individuals with antihb core antibody positive were excluded from the evaluation of hbv vaccine group. the data and results were analysed by using epi-info version 6, centers for disease control (cdc, atlanta, ga, usa). results the coverage rate of hbv vaccine was only 69.9%, slightly higher among male children (72.1%) than females (66.8%) [table 1]. table 2 shows the immune response to hbv vaccine by quantifying anti-hb antibody levels among males and females. a total of 276 (54.8%) of the 504 children responded to the vaccine with antihbs antibody levels ≥10 miu/ml, while 228 (45.2%) had non-protective anti-hbs antibodies level (<10 iu/ml). the average protective rate in both sexes was 54.8%, but higher among males (57.4%) than females (51.4%). there was no statistically significant variation between both sexes. table 3 shows the protective rate among different age groups, the rate being higher in younger compared to older age groups. children aged 3–5 years had the highest protective rate (63.6%); the lowest protective rate was in the 9–10 year old age group (32.4%) [table 3]. table 4 shows the protection by yearly intervals after primary immunisation against hbv. children immunised one year or less prior to the study had a higher protective rate (66.7%), than those immunised 4 years prior (44.2%). in this study, different hbv-markers were obtained from the whole 504 group of vaccinated children. it was found that the frequency of hbsag positivity among these children was 1.8%. table 1: the coverage rate of hepatitis b vaccine (hbv) among randomly selected male and female children under ten years old in sana’a, yemen status male (n = 470) female (n =370) total (n =840) x2 p value no. % no. % no. % vaccinated for hbv 339 72.1 247 66.8 586 69.9 2.83 0.09non-vaccinated for hbv total 131 470 27.9 56 123 370 33.2 44 254 810 30.2 100 table 2: the immune response to hepatitis b vaccine by quantifying anti-hbs antibody levels and protective and nonprotective levels among males and females antibody levels male % female % total % χ2 p value* non-responders (<10 miu/ml) 120 42.6 108 48.6 228 54.1 1.8 0.17 low-responders (10–100 miu/ml ) 87 30.9 45 20.3 132 26.2 7.2 0.007 adequate responders (>100–1000 miu/ml ) 45 16 45 20.3 90 17.6 1.6 0.2 high-responders (>1000 miu/ml ) 30 10.6 24 10.8 54 10.7 0.0 0.95 immune response protective anti-hbs non-protective antihbs 162 120 57.4 42.6 114 108 51.4 48.6 276 228 54.8 45.2 1.9 0.17 notes: * χ2≥ 3.84, p <0.05 (significant); protective anti-hbs ≥10 miu/ml; non-protective anti-hbs <10 miu/ml. hepatitis b vaccine coverage and the immune response in children under ten years old in sana’a, yemen 80 | squ medical journal, february 2011, volume 11, issue 1 discussion since the 1980s, there has been an increasing body of information on viral hepatitis in yemen, which is a major public health problem affecting thousands of people throughout the country.10 viral hepatitis is a major cause of morbidity and mortality in humans in yemen, both from acute infection and its chronic sequelae which include hepatitis b and hepatitis c infection, chronic hepatitis cirrhosis and primary liver cancer.11 the endemic rate of hepatitis b virus infection is considered high in yemen, where the prevalence of the positive (hbsag) ranges from 8–20%, and up to 50% of the general population have serological evidence of previous hbv infection.12 yemen introduced a universal immunisation programme against hbv for infants and high risk groups in early 2000, but feed-back on the coverage rate of vaccination and its efficacy in the community have been ignored for a long period. in addition, there has been inadequate information on the prevalence and risk determinants of viral hepatitis as well as on vaccination coverage rate among children in yemen. this study was carried out in response to this information gap. one of the aims of this study was to determine the coverage rate of hbv vaccine among children. the study findings showed that the vaccination coverage rate was 69.9%. this result is lower than findings in other hbv endemic countries, where hbv vaccine coverage rates among children range from 90–98%.13-15 also the study findings showed that only 54.8% of all vaccinated individuals were regarded as protected (≥10 miu/ml), and that the protective rate of hbs antibody was higher in males (57.4%), than in females (51.3%). different findings were reported elsewhere among children, where a high protective anti-hb response rate was found among vaccinated children (97.4%), and the rate for females was also higher than that for males.16,17 this difference in the findings could be attributed to a different response in the primary course of vaccination, different age groups, to the different degrees of exposure to natural boosters, or to differences in nutritional status and socioeconomic factors, race factors, or the type of vaccines used.18 concerning the rest of the study group, 45.2% developed a low antibody level (<10 miu/ml), indicating a poor anti-hbs response after receiving table 3: immune response among vaccinated children in different age groups age groups protected non-protected x2 p value no. % no. % 1–2 years (n = 72) 39 54.2 33 45.8 0.01 0.91 3–5years (n = 165) 105 63.6 60 36.4 7.8 0.005 6–8years (n = 165) 99 60 66 40 2.7 0.09 9–10 years (n = 102) 33 32.4 69 67.6 25.9 0.0000004 total 276 54.8 228 45.2 notes: protected (anti-hbs ≥10 miu/ml); non-protected (anti-hbs <10 miu/ml). table 4: protected and non-protected vaccinated individuals according to period since vaccination year intervals protected (n = 276) non-protected (n = 228) x2 p value no. % no. % 1 year or less prior to study (n = 72) 48 66.7 24 33.3 4.8 0.02 2 years prior to study (n = 125) 78 62.4 47 37.6 3.9 0.04 3 years prior to study (n = 119) 69 57.9 50 42.1 0.65 0.41 4 years prior to study (n = 86) 38 44.2 48 55.8 4.7 0.03 5 years or more prior to study (n = 102) 48 47.1 54 52.9 3.1 0.08 total no. = 504 notes: protected ≥10 miu/ml; non protected <10 miu/ml. hassan a al-shamahy, samira h hanash, iqbal a rabbad, nameem m al-madhaji and samarih m naser clinical and basic research | 81 a full course of vaccine, as shown in table 2. it can be deduced from this finding either that these vaccinated individuals were hypo-responsive to the immunisation and that their antibodies may have waned rapidly over time, or that the vaccine was of poor quality. even in these instances, loss of antibodies does not necessarily imply loss of protection.19 considering that anti-hbs may disappear in a substantial proportion of vaccinees after initially successful vaccination, a booster dose of vaccine, following the administration of the primary course, is recommended by most national bodies. however, the results of long-term follow-up studies, together with assessment of the role of immunological memory among vaccinees, now call into question the necessity of providing booster doses following successful course of primary immunisation.19 other studies showed that protection is still maintained among vaccinees, even in hbv-endemic countries, despite waning or undetectable anti-hbs levels.20-23 in this study, different hbv-markers were obtained from all the vaccinated children studied. however, due to the lack of serological data, either before or after vaccination, it was impossible to conclude whether these children were already infected at the time of vaccination or had been infected subsequently. in the present study, it was found that the frequency of hbsag positivity among the whole group of children was 1.8%, which was lower than the rate of the non-vaccinated children (2.8%) in sana’a city in 2001.11 this indicates the efficacy of hbv vaccine in preventing chronic carriage of infection. in a long-term follow-up study (over c. 16 years) on hb vaccine immune efficacy in china, the positive rate of hbsag for children born after the introduction of the immunisation programme was much lower than those of the background group before vaccination.24,25 also our result were similar to that found in egypt among children, where hbsag positivity was 0.8% in vaccinated children compared to 2.2% for nonvaccinated children.26 no clinically overt hepatitis has been reported so far among the studied vaccinated individuals. this was similar to findings reported elsewhere.27,28 host factors, such as age, may influence the immune response to the vaccine.29 increasing age was shown to be correlated with a decreasing level of protection rate [table 3]. the response rate of anti-hbs declined from 63.6% in the 3–5 years age group to 32.4% in the 9–10 years age group. similar findings were reported from saudi arabia, showing that being in the >10 years age group correlated with a decreasing protection rate.27 in another study conducted in european countries, the main age for children who had non-protected levels against hbv was 9.5 years, while the main age for those who responded and had protected levels of antibodies was 5.7 years.30 in this study, there was a difference in protection rate at the various annual intervals (1–5 years) since vaccination [table 4]. zhou et al. reported that protective levels of antibodies decrease with time;25 however, they can remain sufficient in healthy individuals for at least 10 years after primary immunisation.31 conclusion this study revealed a low coverage rate of hbv vaccine, and a low protective rate against hbv infection. a considerable proportion of vaccinated children should be considered for either revaccination or booster doses due to a nonexistent, inadequate, or low response. an effort to complete hbv vaccine coverage to 100% among the yemeni child population is recommended, especially among newborns. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. centers for disease control (cdc). updated u.s. public health service guidelines for the management of occupational exposures to hbv, hcv and hiv and recommendations for post exposure prophylaxis. morbid mortal wkly rep mmwr 2001; 50:1−54. 2. hepatitis b vaccine. from: www.who.int/ vaccines/ en/ hepatitisb.shtml. accessed: may 2010. 3. hyams kc. risks of chronicity following acute hepatitis b virus infection: a review. clin infect dis 1995; 20:992−1000. 4. robinson ws. hepatitis b viruses. general features (human). in: webster rg, granoff a, eds. encyclopedia of virology, london: academic press ltd, 1994. pp. 54−69. 5. burton grw, engelkirk pg. microbiology for the health sciences. 6th ed. philadelphia: williams & hepatitis b vaccine coverage and the immune response in children under ten years old in sana’a, yemen 82 | squ medical journal, february 2011, volume 11, issue 1 wilkins, 2000. p. 3. 6. lavanchy d. hepatitis b virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. j viral hepat 2004; 11:97−107. 7. giammanco g, li volti s, mauro l, bilancia gg, salemi i, barone p, et al. immune response of simultaneous administration of a recombinant dna hepatitis b vaccine and multiple compulsory vaccines in infancy. vaccine 1991; 9:747−50. 8. richman dd, whitely rj, hayden fg. clinical virology. 2nd ed. washington dc: asm press, 2001. pp. 623−43. 9. al-zaggar l. report of the yemen national infectious viral hepatitis control programme. no. 43/97. ministry of public health, republic of yemen, 1999. p.1. 10. al-shamahy h. prevalence of hepatitis b surface antigen and risk factors of hbv infection in samples of healthy mothers and their infants in sana’a, yemen. ann saudi med 2000; 20:464−7. 11. al-shamahy ha, rabbad ia, al-hababy a. hepatitis b virus serum markers among pregnant women in sana’a, yemen. ann saudi med 2003; 23:87−9. 12. scott da, burans jp, al-ouzeib hd, arunkumar bk, al-fadeel m, nigad yr, et al. a sero-epidemiology survey of viral hepatitis in the yemen arab republic. trans roy soc trop med hyg 1990; 84:82−4. 13. centers for disease control (cdc). a comprehensive immunization strategy to eliminate transmission of hepatitis b virus infection in the united states: recommendations of the advisory committee on immunization practices (acip). part ii: immunization of adults. morbid mortal wkly rep mmwr 2006; 55:16. 14. centers for disease control (cdc). implementation of newborn hepatitis b vaccination worldwide, 2006. mmwr morb mortal wkly rep 2008; 57:1249–52. 15. costa am, l ‚italien g, nita me, araujo es. costeffectiveness of entecavir versus lamivudine for the suppression of viral replication in chronic hepatitis b patients in brazil. braz j infect dis 2008; 12:368−73. 16. goldstein st, zhou f, hadler sc, bell bp, mast ee, margolis hs. a mathematical model to estimate global hepatitis b disease burden and vaccination impact. int j epidemiol 2005; 34:1329−39. 17. guo y, hui cy. pilot-scale production and quality control of multiepitope hepatitis b virus dna vaccine. nan fang yi ke da xue xue bao 2009; 29:118−20. 18. greengold b, nyamathi a, kominski g, wiley d, lewis ma, hodge f, et al. cost-effectiveness analysis of behavioral interventions to improve vaccination compliance in homeless adults. vaccine 2009; 27:718−25. 19. lake jr. do we really need long-term hepatitis b hyperimmune globulin? what are the alternatives? liver transpl 2008; 14:s23−6. 20. liu sl, dong y, zhang l, li mw,wo je, lu lw, et al. influence of hbv gene heterogeneity on the failure of immunisation with hbv vaccines in eastern china. arch virol 2009; 154:437–43. 21. lee pi, lee cy, huang mh, chang mh. long term efficacy of recombinant hepatitis b vaccine and risk of infection in infants borne to mothers with hepatitis b e antigen. pediatrics 1995; 126:716−21. 22. lunn er, hoggarth bj, cook wj. prolonged hepatitis b surface antigenemia after vaccination. pediatrics 2000; 105:e81. 23. ayerbe mc, pe’rez-rivilla a, icovahb group. assessment of long-term efficacy of hepatitis b vaccine. eur j epidemiol 2001; 17:151−6. 24. zhou jj, wu ws, sun cm, dai hq, zhou n, liu cb. long-term evaluation of immune efficacy among newborns 16 years after hbv vaccination. zhongguo ji hua mian yi (chinese j vaccines & immuniz) 2003; 9:129−33. 25. zhou yh, wu c, zhuang h. vaccination against hepatitis b: the chinese experience. chin med j (engl) 2009; 122:98–102. 26. reda a, arafa am, youssry aa, wandan eh, ab de ati m, daebees h. epidemiologic evaluation of the immunity against hepatitis b in alexandria, egypt. eur j epidemiol 2003; 18:1007−11. 27. madani ta. trend in incidence of hepatitis b virus infection during a decade of universal childhood hepatitis b vaccination in saudi arabia. trans r soc trop med hyg 2007; 101:278−83. 28. manzini p, girotto m, borsotti r, giachino o, guaschino r, lanteri m, et al. italian blood donors with anti-hbc and occult hepatitis b virus infection. haematologica 2007; 92:1664−70. 29. shepard cw, simard ep, finelli l, fiore ae, bell bp. hepatitis b virus infection: epidemiology and vaccination. epidemiol rev 2006; 28:112−25. 30. nardone a, anastassopoulou cg, theeten h, kriz b, davidkin i, thierfelder w, et al. a comparison of hepatitis b seroepidemiology in ten european countries. epidemiol infect 2008; 23:1−9. 31. floreani a, baldo v, cristofoletti m, renzulli g, valeri a, zanetti c, et al. long-term persistence of anti-hbs after vaccination against hbv: an 18 year experience in health care workers. vaccine 2004; 22:607−10. 1department of surgery, al-shifa general hospital, basrah, iraq; 2department of surgery, al-zubair general hospital, basrah, iraq *corresponding author’s e-mail: sadiqalsaidi222@yahoo.com استئصال الغدة الدرقية باملنظار عن طريق دهليز الفم سلسلة أول عشر حاالت يف العراق �سادق غالب كاظم، �رسمد مانع حب�ض، علي ح�سني جا�سم abstract: transoral endoscopic thyroidectomy was first described as an experimental sublingual approach. this approach was modified to a vestibular approach to avoid complications. in this report, we describe the results of the first ten cases of a transoral endoscopic thyroidectomy via vestibular approach (toetva) performed in iraq. all operations were performed at al shifa general hospital, basrah, iraq, in 2017 using three laparoscopic ports inserted at the oral vestibule. one out of ten patients underwent a near total thyroidectomy, the remaining cases underwent thyroid lobectomies. the average operative time was 113.5 minutes and the average duration of hospital stay was 41.9 hours. one case of mild cervical emphysema and one case of temporary mental nerve palsy were reported but both were treated conservatively without permanent sequelae. in conclusion, toetva is a safe, feasible procedure with an excellent cosmetic outcome when the patients are selected carefully. keywords: thyroidectomy; endoscopy; mouth; robotics; case reports; iraq. كطريقة الل�سان حتت جراحة اأ�سلوب باإ�ستخدام الفم طريق عن باملنظار الدرقية الغدة ا�ستئ�سال عملية اأول و�سف البدء مت امللخ�ص: جتريبية. ثم مت بعد ذلك تعديلها من خالل الدخول عن طريق دهليز الفم خلف ال�سفة ال�سفلى تفاديا للم�ساعفات. ون�سف يف هذه ال�سل�سلة نتائج اأول ع�رس حالت ل�ستئ�سال الغدة الدرقية باملنظار عن طريق دهليز الفم مت اإجرائها يف العراق. اأُجريت جميع العمليات يف م�ست�سفى ال�سفاء العام يف مدينة الب�رسة جنوب العراق عام 2017م، با�ستخدام ثالث منافذ عن طريق املنظار، اأدخلت عرب دهليز الفم. واأجريت لواحد من بني املر�سى الع�رسة عملية ا�ستئ�سال �سبه كلية للغدة الدرقية، بينما اأجريت للمر�سى الآخرين عمليات ا�ستئ�سال ف�ض واحد فقط من الغدة الدرقية. وا�ستغرقت كل عملية 113.5 دقيقة يف املتو�سط، بينما بلغ معدل فرتة رقود املري�ض يف امل�ست�سفى 41.9 �ساعة. ومت ت�سجيل حالة واحدة نفاخ عنقي ب�سيط، وحالة اأخرى ل�سلل موؤقت للع�سب الذقني. وُعوجلت كلتا احلالتني حتفظيا دون حدوث اأي م�ساعفات دائمة. نخل�ض اإىل اأن ا�ستئ�سال الغدة الدرقية باملنظار عن طريق دهليز الفم هي طريقة اآمنة وممكنة وذات نتائج جتميلية ممتازة عندما يتم اختيار املر�سى املنا�سبني بعناية. العراق. حالت؛ تقارير الروبوتات؛ الفم؛ التنظري؛ الدرقية؛ الغدة ا�ستئ�سال املفتاحية: الكلمات transoral endoscopic thyroidectomy via vestibular approach a series of the first ten cases in iraq *sadq g. kadem,1 sarmad m. habash,1 ali h. jasim2 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e68–72, epub. 30 may 19 submitted 13 aug 18 revisions req. 24 sep & 7 nov 18; revisions recd. 17 oct & 9 nov 18 accepted 29 nov 18 witzel et al. first described transoral endoscopic thyroidectomy as an experimental sublingual approach in 2007.1 karakas et al. evaluated this approach in a series of patients for transoral parathyroid surgery and suggested that while it is feasible, it is poorly accepted by patients and it has a high complication rate.2 in 2012, nakajo et al. changed the site of the port entry from sublingual to vestibular and reported that one patient had recurrent laryngeal nerve palsy as a complication of this approach.3 in 2015, anuwong reported the first large cohort of 60 patients that had been operated on using transoral endoscopic thyroidectomy via vestibular approach (toetva) with no permanent complications. the vest ibular approach was modified by changing the positions of the vestibular ports to a high and more lateral area in the vestibule near the angle of the mouth.4 navarra et al. described the patient selection crit eria for surgeons who are less experienced with the toetva procedure.5 these include: (1) strong motiv ation for scar-free surgery; (2) young and healthy patients able to tolerate the relatively long procedure; (3) a single benign thyroid nodule with a size of approximately 3 cm that is not posteriorly located so that it is easy to handle and endoscopically dissect; and (4) males with laryngeal prominence and obese patients with short necks should be avoided because surgeons need more experience due to the difficulty of the dissection. the authors also stipulated that a right-handed surgeon should start by operating on right-sided thyroid nodules because the left lobectomy is more challenging for a right-handed surgeon. in this report, we describe the results of the first ten cases of toetva performed in iraq. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.013 case report https://creativecommons.org/licenses/by-nd/4.0/ sadq g. kadem, sarmad m. habash and ali h. jasim case report | e69 exceeding 4 cm in the largest dimension on preoperative ultrasound—to allow for easy endoscopic dissection and extraction through the vestibular wound; and (4) preferably, patients with right-sided pathology since the surgeon was right-handed. all male patients, patients with thyroiditis or hyperthyroidism, obese patients, patients with short necks, those with a history of neck irradiation or previous neck surgery and patients with mouth sores and infections were excluded. all patients were asked to gargle with chlorhexi dine mouthwash three times a day for three days prior to surgery. the patients were admitted to the hospital one day pre-surgery for routine investigations and prep aration for general anaesthesia. a flexible fibre-optic laryn goscopy was performed to confirm normal recurrent laryngeal nerve function. the surgical approach followed the operative steps described by anuwong.4 during induction of general anaesthesia with endotracheal intubation through the mouth, the patient received intravenous prophylactic antibiotics, either amoxicillin (1 g) or clindamycin (900 mg) in cases of an allergy to penicillin. the steps in the surgical procedure are shown in figure 1. following washing of the oral cavity with diluted povidone iodine and normal saline, a 10 mm transverse vestibular incision was made in the midline and extended in depth up to the mandible symphysis using an ultrasonic energy device sonicbeat, usg 400 (olympus, tokyo, japan) to dissect and divide the tissue and blood vessels [figure 1a]. using a verse needle, sub-platysmal hydrodissection with approximately 20 ml of normal saline with adrenaline (500 ml normal saline + 1 ml adrenaline) was performed in three axes (central, right and left) [figure 1b]. blunt dissection of the sub-platysmal plane with a blunt dilator was performed in the same three axes as the hydrodissection [figure 1c]. a 10 mm central trocar for the camera was placed through the vestibular incision and insufflation was performed up to 5–6 mmhg with carbon dioxide [figure 1d]. two additional 5 mm trocars were placed under direct vision through two 5 mm vertical incisions case report all operations were conducted at al shifa general hospital, basrah, iraq in 2017. all surgeons had at least ten years’ experience in open thyroid surgery and in general laparoscopic surgery. the inclusion criteria was as follows: (1) female patients that are young and healthy with strong motivation for scar-free surgery; (2) patients with a benign solitary thyroid nodule with the largest dimension between 2–4 cm; (3) patients with a benign multinodular goitre where each thyroid lobe not figure 1: photographs of the surgical procedure steps. a: transverse vestibular incision (10 mm) was made in the midline and extended to the mandible symphysis. b: sub-platysmal hydrodissection was performed on three axes. c: blunt dissection of the sub-platysmal plane with a blunt dilator on the same three axes as the hydrodissection. d: a 10 mm central trocar for the camera was placed through the vestibular incision and carbon dioxide insufflation was done. e: two additional 5 mm trocars were placed through vertical incisions in the most lateral aspects of either side of the vestibule nearest to the edges of the mouth. table 1: demographics of ten patients who underwent trans oral endoscopic thyroidectomy via vestibular approach at al shifa general hospital, basrah, iraq case age in years bmi in kg/m2 pre-operative ultrasound findings preoperative cytology findings largest dimension of thyroid nodule or lobe in cm 1 25 20 bilateral multi nodular right lobe left lobe 3.6 3.4 cystic colloid nodules 2 28 23 right solitary nodule 3.2 adenomatoid nodule 3 24 22 right solitary nodule 2.8 adenomatoid nodule 4 30 25 right solitary nodule 3.0 adenomatoid nodule 5 36 20 right solitary nodule 2.2 adenomatoid nodule 6 27 24 right solitary nodule 3.4 adenomatoid nodule 7 33 26 right solitary nodule 2.6 adenomatoid nodule 8 40 23 right solitary nodule 2.0 adenomatoid nodule 9 29 25 right solitary nodule 3.3 adenomatoid nodule 10 31 21 right solitary nodule 2.1 adenomatoid nodule average 30.3 22.9 2.87 bmi = body mass index. transoral endoscopic thyroidectomy via vestibular approach a series of the first ten cases in iraq e70 | squ medical journal, february 2019, volume 19, issue 1 in the most lateral aspects of either side of the vestibule nearest to the edges of the mouth [figure 1e]. using hanging sutures passing through the skin, the strap muscles were retracted laterally. the thyroid isthmus was dissected and transected. all thyroid blood vessels were divided as close to the thyroid as possible. intra operative neuromonitoring for the recurrent laryngeal nerve is not practised in al shifa general hospital’s surgical department and, therefore, anatomical land marks were used to identify and preserve this nerve. all parathyroid glands were identified and preserved. the specimen was removed using an endobag via the 10 mm vestibular incision and sent for histopathology analysis. if indicated, the same procedure was repeated on the left thyroid lobe. a redivac drain was inserted through the skin to drain the surgical field. closure of the peri tracheal fascia was performed using absorbable sutures and the vestibular wounds were closed in two layers with absorbable sutures. during removal of the endo tracheal tube, the vocal cords were re-examined with flexible fibre-optic laryngoscopy to confirm normal function of the recurrent laryngeal nerve. intravenous antibiotics were continued until the patients were discharged from hospital. the drain was removed when the amount of post-operative drainage was less than 30 ml per day. the patients were dis charged from hospital once the drain was removed, vital signs were within normal range, the patient could manage an oral diet and had been given instructions to continue oral antibiotics and mouthwash for one week. patients were re-examined at the end of the first post-operative week at which time flexible fibre-optic laryngoscopy was again performed to evaluate vocal cord function. subsequently, patients were re-examined after two, four and eight weeks. at the end of the follow-up period, the patients were asked whether they were satisfied with the results of this procedure and whether they would advise other patients to have the same procedure. figure 2: photographs of the first patient in this report showing (a) her preoperative state and (b) one week post-transoral endoscopic thyroidectomy via vestibular approach with (c) complete healing of the vestibular wound. table 2: summary of intraoperative and post-operative outcomes and complications of ten patients who underwent transoral endoscopic thyroidectomy via vestibular approach at al shifa general hospital, basrah, iraq case* type of thyroid surgery operative time in minutes duration of drain removal in hours amount of drainage in ml duration of hospital stay in hours final pathology complication 1 near total lobectomy 150 26 25 47 bccd cervical emphysema 2 lobectomy 125 24 20 38 bca temporary mental nerve palsy 3 lobectomy 123 24 18 40 bca none 4 lobectomy 120 24 20 43 bca none 5 lobectomy 112 24 15 45 bca none 6 lobectomy 110 24 20 44 bca none 7 lobectomy 112 24 22 40 bca none 8 lobectomy 98 24 23 33 bca none 9 lobectomy 95 24 20 43 bca none 10 lobectomy 90 24 17 46 bca none average 113.5 24.2 20 41.9 bccd = benign colloid cystic degeneration; bca = benign colloid adenoma. *inadvertent parathyroid removal was not observed in any of the cases. sadq g. kadem, sarmad m. habash and ali h. jasim case report | e71 also recorded. this finding is consistent with the results by razavi et al. who evaluated a series of 30 toetva patients, which concluded that the learning curve for toetva plateaus at 11 cases.9 they reported a signif icant reduction in the operative time over the first 11 cases after which the operative time remained steady with no significant changes. this is significantly shorter than the published learning curve for other remote access thyroidectomy and robotic thyroidectomy which is 20–50 cases.10–12 in this report, the surgeons were still inexper ienced with this procedure and expected a high rate of post-operative haematoma. therefore, a drain was used routinely as a precaution in all ten cases. in all cases, the drain was removed after a minimum of 24 hours with an average drainage volume of 20 ml. the patients were discharged from hospital with an average stay of 41.9 hours. this differed from anuwong who reported the use of a drain only after total thyroidectomy with toetva with an average drainage volume of 74.76 ml and an average duration of drain removal and hospital stay of approximately 72 hours.4 this report focused on the feasibility and safety of the toetva technique rather than the evaluation of post-operative pain. the post-operative score of toetva has been previously reported to be lower than that of open thyroidectomy.13 another study found a difference in the profile pain scores between toetva and open thyroidectomy.14 pain scores in the mental and vestibular area were higher in toetva while pain scores in the neck area were higher in open thyroidectomy. patients had similar post-operative pain after toetva and open thyroidectomy on the fifth and seventh days and a similar post-operative stay in hospital (1.5 versus 1.6 days).14 with regard to the benefits of toetva in comp arison to other remote access, robotic or open thyroi dectomy approaches, the published literature demonstr ated that toetva provides clear magnification of the operative field. this allows the surgeon to view the operative field in the craniocaudal direction, therefore permitting an approach to both thyroid lobes and ident ification of the recurrent laryngeal nerve early, near its insertion, which is the most constant part of the nerve.15–17 in addition, toetva is associated with less post-opera tive pain and only requires conventional laparoscopic instruments.15–17 the only recorded complications in the current cases were one case of mild cervical emphysema that resolved completely within 24 hours and another case showing symptoms of temporary mental nerve injury that resolved completely within four weeks. there were no reported cases of conversion to open thyroidectomy or mortality. the absence of other complications may ten cases of toetva were successfully performed during the time-period without conversion to open thyroi dectomy. the results of the ten cases are summarised in tables 1 and 2. at the end of the follow-up period, all patients were satisfied with the excellent cosmetic results and stated that they would advise other patients to have the same surgery [figure 2]. this report received approval of the local ethics committee. informed consent was obtained from all patients and they were informed of the novel nature of this procedure and the associated risks that included the possibility of converting the toetva to an open thyroidectomy. discussion all included patients were young and healthy females with a strong motivation for scar-free surgery. most (90%) had right-sided benign solitary thyroid nodules with the largest dimension ranging between 2–3.6 cm. based on the 2015 american thyroid association guide lines, some of these selected nodules can be observed safely without surgery.6 since the current patients were not overweight and had anteriorly located nodules that are easily visible, they preferred the removal of these nodules with the scar-free toetva procedure for cos metic reasons. the selection criteria of the current patients were consistent with the criteria described by navarra et al. for novice toetva surgeons and to some degree, followed the early selection criteria described by anuwong.4,5 in a review by razavi et al.’s, all authors concluded that the primary indication for performing toetva is the patient’s motivation to avoid neck scarring.7 other indications identified include having a thyroid diameter ≤10 cm and a dominant nodule size ≤6 cm, when benign or indeterminate, or a thyroid diameter ≤2 cm, when malignancy is suspected or a well-differentiated thyroid cancer is confirmed. the recommended contraindic ations were having a history of neck surgery or neck irradiation, being unfit for general anaesthesia, showing evidence of uncontrolled hyperthyroidism, lymph node metastasis, extra-thyroidal extension, substernal thyroidal extension and presence of oral abscesses. patients with thyroiditis and those with a high body mass index were considered relative contraindications. in the current cases, an average operative time of 113.5 minutes was recorded. this result was comparable to the first results by anuwong that reported an average operative time of 115.5 minutes.4 it was also comparable to the current literature on toetva that reports an average operative time of 115.4 minutes for subtotal thyroidectomy and 136.6 minutes for total thyroidectomy.8 a gradually decreasing operative time that reached 90 minutes in the tenth and last case was transoral endoscopic thyroidectomy via vestibular approach a series of the first ten cases in iraq e72 | squ medical journal, february 2019, volume 19, issue 1 be due to the small number of patients and to the careful selection of patients in this report. camenzuli et al. published a systematic review of 16 studies on toetva with a total number of 785 patients.8 the over all reported complications were temporary recurrent transient post-operative hypocalcaemia (7.4%), laryn geal nerve palsy (4.3%), seroma (2.8%), temporary mental nerve palsy (2.3%), conversion to open thyroidectomy (1.3%), subcutaneous emphysema (0.8%), deep-seated neck infections (0.6%), mediastinal emphysema (0.1%), and operative site haematoma (0.1%). conclusion toetva is a safe and feasible procedure with an excellent cosmetic outcome. however, patients should be carefully selected especially during the surgeon’s learning curve to avoid complications. at present, it is a relatively time-consuming procedure and, therefore, candidate patients with a strong motivation for scarfree surgery are recommended. references 1. witzel k, von rahden bh, kaminski c, stein hj. transoral access for endoscopic thyroid resection. surg endosc 2008; 22:1871–5. https://doi.org/10.1007/s00464-007-9734-6. 2. karakas e, steinfeldt t, gockel a, mangalo a, sesterhenn a, bartsch dk. transoral parathyroid surgery--a new alternative or nonsense? langenbecks arch surg 2014; 399:741–5. https://doi.org/10. 1007/s00423-014-1187-5. 3. nakajo a, arima h, hirata m, mizoguchi t, kijima y, mori s, et al. trans-oral video-assisted neck surgery (tovans). a new transoral technique of endoscopic thyroidectomy with gasless premandible approach. surg endosc 2013; 27:1105–10. https://doi.org/10.1007/s00464-012-2588-6. 4. anuwong a. transoral endoscopic thyroidectomy vestibular approach: a series of the first 60 human cases. world j surg 2016; 40:491–7. https://doi.org/10.1007/s00268-015-3320-1. 5. navarra g, bartolo v, rizzo ag, marullo m, cancellieri a, catalfamo a, et al. preand post-operative patient care for trans oral thyroidectomy. ann thyroid 2018; 3:3. https://doi.org/10.21 037/aot.2018.01.01. 6. haugen br, alexander ek, bible kc, doherty gm, mandel sj, nikiforov ye, et al. 2015 american thyroid association manage ment guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the american thyroid associ ation guidelines task force on thyroid nodules and differen tiated thyroid cancer. thyroid 2016; 26:1–133. https://doi.org/10. 1089/thy.2015.0020. 7. razavi cr, russell jo. indications and contraindications to trans oral thyroidectomy. ann thyroid 2017; 2:12. https://doi.org/10. 21037/aot.2017.10.01. 8. camenzuli c, shembri wismayer p, calleja agius j. transoral endoscopic thyroidectomy: a systematic review of the practice so far. jsls 2018; 22:e2018.00026. https://doi.org/10.4293/jsls. 2018.00026. 9. razavi cr, vasiliou e, tufano rp, russell jo. learning curve for transoral endoscopic thyroid lobectomy. otolaryngol head neck surg 2018; 159:625–9. https://doi.org/10.1177/01945998 18795881. 10. lee j, yun jh, nam kh, soh ey, chung wy. the learning curve for robotic thyroidectomy: a multicenter study. ann surg oncol 2011; 18:226–32. https://doi.org/10.1245/s10434-0101220-z. 11. yang j, wang c, li j, yang w, cao g, wong hm, et al. complete endoscopic thyroidectomy via oral vestibular approach versus areola approach for treatment of thyroid diseases. j laparoendos adv surg tech a 2015; 25:470–6. https://doi.org/10.1089/lap.20 15.0026. 12. park jh, lee j, hakim na, kim hy, kang sw, jeong jj, et al. robotic thyroidectomy learning curve for beginning surgeons with little or no experience of endoscopic surgery. head neck 2015; 37:1705–11. https://doi.org/10.1002/hed.23824. 13. anuwong a. post-operative pain control protocol for transoral endoscopic thyroidectomy vestibular approach (toetva): reply. gland surg 2017; 6:422–3. https://doi.org/10.21037/gs. 2017.06.02. 14. dionigi g, lavazza m, pappalado v, inversini d, wu cw, liu x, et al. op35 -transoral endoscopic thyroidectomy ves tibular approach (toetva) or open thyroidectomy: a pros pective randomised trial to compare length of stay and postop erative pain. from: https://thyroidworldcongress.com/presen tation/op35-transoral-endoscopic-thyroidectomy-vestibularapproach-toetva-or-open-thyroidectomy-a-prospectiver a n d o m i s e d t r i a l t o c o m p a r e l e n g t h o f s t a y a n d postoperative-pain/ accessed: nov 2018. 15. russell jo, clark j, noureldine si, anuwong a, al khadem mg, yub kim h, et al. transoral thyroidectomy and parathyroidec tomy a north american series of robotic and endoscopic trans oral approaches to the central neck. oral oncol 2017; 71:75–80. https://doi.org/10.1016/j.oraloncology.2017.06.001. 16. jitpratoom p, ketwong k, sasanakietkul t, anuwong a. trans oral endoscopic thyroidectomy vestibular approach (toetva) for graves’ disease: a comparison of surgical results with open thyroidectomy. gland surg 2016; 5:546–52. https://doi.org/10.21 037/gs.2016.11.04. 17. anuwong a, kim hy, dionigi g. transoral endoscopic thyroid ectomy using vestibular approach: updates and evidences. gland surg 2017; 6:277–84. https://doi.org/10.21037/gs.2017.03.16. https://doi.org/10.1007/s00464-007-9734-6 https://doi.org/10.1007/s00423-014-1187-5 https://doi.org/10.1007/s00423-014-1187-5 https://doi.org/10.1007/s00464-012-2588-6 https://doi.org/10.1007/s00268-015-3320-1 https://doi.org/10.21037/aot.2018.01.01 https://doi.org/10.21037/aot.2018.01.01 https://doi.org/10.1089/thy.2015.0020 https://doi.org/10.1089/thy.2015.0020 https://doi.org/10.21037/aot.2017.10.01 https://doi.org/10.21037/aot.2017.10.01 https://doi.org/10.4293/jsls.2018.00026 https://doi.org/10.4293/jsls.2018.00026 https://doi.org/10.1177/0194599818795881 https://doi.org/10.1177/0194599818795881 https://doi.org/10.1245/s10434-010-1220-z https://doi.org/10.1245/s10434-010-1220-z https://doi.org/10.1089/lap.2015.0026 https://doi.org/10.1089/lap.2015.0026 https://doi.org/10.1002/hed.23824 https://doi.org/10.21037/gs.2017.06.02 https://doi.org/10.21037/gs.2017.06.02 https://doi.org/10.1016/j.oraloncology.2017.06.001 https://doi.org/10.21037/gs.2016.11.04 https://doi.org/10.21037/gs.2016.11.04 https://doi.org/10.21037/gs.2017.03.16 departments of 1dermatology and 2pathology, hospital clínic de barcelona, barcelona, spain *corresponding author’s e-mail: alamon@clinic.cat erythema multiforme when targets lead to diagnosis *francesc alamon-reig,1 natalia castrejón,2 xavier bosch-amate1 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 666–667, epub. 25 nov 21 submitted 10 nov 20 revision req. 19 jan 21; revision recd. 25 jan 21 accepted 10 feb 21 a 40-year-old colombian female patient, allergic to non-steroidal anti-inflammatory drugs and with no other relevant medical history, attended the emergency department at a tertiary care hospital of barcelona, spain in 2020, due to a 4-day mucocutaneous eruption without associated fever. she had presented with a similar self-resolving symptoms two years prior, which was diagnosed as chickenpox. she did not take any medication and denied having had a herpes outbreak or had any other infections in the previous few weeks. on examination, she presented with multiple targetoid erythematous-violaceous circular plaques on the thorax, arms and back of the hands, some with a central vesicle [figure 1]. the oro-genital mucosa showed painful haemorrhagic crusts and erosions [figure 2]. erythema multiforme (em) was suspected clinically. a skin biopsy was performed and treatment was started with a tapered dosage of prednisone, topical methylprednisolone (1 mg/g) and ebastine (10 mg/12 hours). the biopsy showed vacuolar degeneration of the basal layer of the epidermis and spongiosis with isolated colloid bodies corresponding to an interface dermatitis. direct immunofluorescence showed fibrinogen deposits within the basement membrane and immunoglobulin (ig)g, iga, igm and fraction c3 within the intraepidermal colloid bodies. both results supported the diagnosis of em. after two weeks, the lesions resolved, leaving residual hyperpigmentation. the patient in this manuscript has given written informed consent for publication purposes of their case details. comment em is a sudden-onset hypersensitivity reaction which usually resolves within 2–4 weeks. it usually manifests in young individuals with target-like concentric erythematous-bullous skin lesions, predominantly affecting acral and facial areas. these lesions typically measure less than 3 cm in diameter, have a regular this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.027 interesting medical image figure 1: photograph of the hands of a 40-year-old female patient showing classic lesions of erythema multiforme manifesting a targetoid appearance with quasi-vesiculation, distributed on the dorsal aspects of both hands. francesc alamon-reig, natalia castrejón and xavier bosch-amate interesting medical image | 667 round shape with a central dusky zone and two concentric outer rings. em targetoid lesions are often palpable and should be distinguished from the atypical ‘targets’ that can be seen in stevens-johnson syndrome (sjs) or toxic epidermal necrolysis (ten), which are round, asymmetric, non-palpable lesions with only two zones and a poorly defined border.1 the em spectrum has been classified into major and minor forms, the latter associated with mild or absent mucosal affection and acral location of the skin lesions. severe mucosal involvement is characteristic of major em and usually consists in vesiculobullous lesions which rapidly develop into painful erosions that can give rise to serohaemorrhagic crusts. general symptoms such as fever, asthenia and arthralgias usually precede and accompany the skin lesions. infections trigger a significant percentage of cases, the most common being herpes simplex virus and mycoplasma pneumoniae. the administration of drugs such as sulfonamides, non-steroidal antiinflammatory drugs and penicillines, account for less than 10% of cases.2 em requires differentiation from sjs/ten as these conditions can be life threatening. many other conditions can display targetoid vesiculobullous lesions or mucosal involvement and could be mistaken for em, including urticaria, fixed drug eruptions, bullous pemphigoid, paraneoplastic pemphigus or rowell syndrome.2 a skin biopsy could be helpful to distinguish these entities from em. possible findings on direct immunofluorescence include granular deposition of c3 and igm at the dermo-epidermal junction. however, direct immunofluorescence is usually non-specific in em and its purpose is to exclude other similar conditions.3 mild disease can be managed in most patients with topical steroids, analgesic agents and anti histamines. when identified, treatment of any under lying infection should be instituted. patients with severe em may require systemic steroids.4 it is important to differentiate em from other erythematous-bullous pathologies, with typical targetlike lesions, a key diagnostic clue.5 a u t h o r s’ c o n t r i b u t i o n fa-r conceptualised and designed the work and drafted the manuscript. nc performed the histopathological analysis and interpretation. xb-a collected the data. nc and xb-a critically revised the manuscript. all authors approved the final version of the manuscript. references 1. schwartz ra, mcdonough ph, lee bw. toxic epidermal necrolysis: part i. introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopatho genesis. j am acad dermatol 2013; 69:173.e1–13. https://doi. org/10.1016/j.jaad.2013.05.003. 2. samim f, auluck a, zed c, williams pm. erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment. dent clin north am 2013; 57:583–96. https://doi. org/10.1016/j.cden.2013.07.001. 3. sokumbi o, wetter da. clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. int j dermatol 2012; 51:889–902. https://doi. org/10.1111/j.1365-4632.2011.05348.x. 4. trayes kp, love g, studdiford js. erythema multiforme: recognition and management. am fam physician 2019; 100:82–8. 5. rizo-potau d, marti-marti i, fustà-novell x. erythema multiforme. med clin (barc) 2021; 156:533. https://doi. org/10.1016/j.medcli.2020.04.063. figure 2: photograph of the face of a 40-year-old female patient showing erosions and thick haemorrhagic crusting of the vermilion lips and the perioral region. children growth research center, qazvin university of medical sciences, qazvin, iran *corresponding author’s e-mail: banafsheh.arad@gmail.com ضعف الغدة الدرقية لدى األطفال املصابني ابملتالزمة الكلوية جمهولة السبب يف مستشفى األطفال يف قزوين، إيران فاطمة �شفاري، �شامية اأهدي، ر�شا دالرياين، ن�رسين ا�شفنديار، زهرة يزدي، بانف�شة عراد abstract: objectives: nephrotic syndrome is a glomerular disease characterised by a loss of albumin and high-molecular-weight proteins such as thyroxine-binding globulin and thyroid hormones, potentially resulting in subclinical or even overt hypothyroidism. this study aimed to compare thyroid hormone levels between nephrotic children and healthy controls as well as between nephrotic children in the active phase of the disease and those in remission. methods: this case-control study was conducted between march 2016 and 2018 at a paediatric hospital in qazvin, iran. a total of 73 nephrotic children comprised the case group—including 49 with active disease and 24 in remission—while the control group included 74 healthy children. thyroid function was assessed according to levels of thyroid-stimulating hormone (tsh), free triiodothyronine (t3), free thyroxine (t4), total t4, total t3 and anti-thyroid peroxidase. results: all of the controls had normal total t4 levels. elevated tsh levels were more frequent in nephrotic children compared to controls (34.2% versus 10.8%; p = 0.001). a significantly lower number of patients with active disease were euthyroid compared to those in remission (51% versus 95.8%; p = 0.001). moreover, 7 (9.5%) of patients in the active and no patient in remission phase had abnormal total t4 levels (p <0.001), while 14.3% and 0% had highly elevated tsh levels (p = 0.002). conclusion: due to the prevalence of subclinical and even overt hypothyroidism, thyroid screening tests may be required for nephrotic children. however, further research is needed to confirm these findings. keywords: nephrotic syndrome; children; albuminuria; proteinuria; hypothyroidism; iran. اجلزيئي الوزن عالية والربوتينات الألبومني بفقدان يتميز اجللومرييولت ي�شيب مر�ض هي التنفرزالكلوية متالزمة الهدف: امللخ�ص: مثل اجللوبيولني املرتبط بهرمون الغدة الدرقية وهرمونات الغدة الدرقية، مما قد يوؤدي اإىل ق�شور الغدة الدرقية حتت الإكلينيكي اأو حتى واملجموعه التنفرزالكلوية مبتالزمة امل�شابني الأطفال بني الدرقية الغدة هرمون م�شتويات مقارنة اإىل الدرا�شة هذه هدفت ال�رسيح. ال�شابطه من الأ�شحاء وكذلك بني الأطفال امل�شابني مبتالزمة التنفرزالكلوية يف املرحلة الن�شطة من املر�ض واأولئك الذين هم يف �شكون. الطريقة: اأجريت هذه الدرا�شة بني مار�ض 2016 و 2018 يف م�شت�شفى لالأطفال يف قزوين، اإيران. كان هناك اإجمايل 73 طفاًل من امل�شابني مبتالزمة التنفرزالكلوية-مبا يف ذلك 49 م�شاًبا مبر�ض ن�شط و 24 يف حالة �شكون-بينما �شمت املجموعة ال�شابطة 74 طفاًل يتمتعون ب�شحة جيدة. مت تقييم وظيفة الغدة الدرقية وفًقا مل�شتويات الهرمون املنبه للغدة الدرقية )tsh(، ثالثي يودوثريونني احلر )t3(، هرمون الغدة الدرقية )t4(، اإجمايل t4، اإجمايل t3 و البريوك�شيديزات امل�شاده للغدة الدرقية. النتائج: اأظهرت الدرا�شة اأن جميع اأفراداملجموعة �شيوًعا اأكرث املرتفعة الدرقية للغدة املنبه الهرمون م�شتويات كانت الدرقية. الغدة هورمون من طبيعية م�شتويات لديهم كان ال�شابطة يف الأطفال املر�شى مقارنًة باملجموعة ال�شابطة %34.2 مقابل p >0.001 10.8% عالوة على ذلك، فاإن %51 من الأطفال املر�شى يف املرحلة الن�شطة و %95.8 من الأطفال املر�شى يف حالة ال�شكون كانت لديهم م�شتويات طبيعية من هورمون الغدة الدرقية )p = 0.001(. يف املقابل، كان لدى %9.5 و %0 من املر�شى يف مرحلتي الن�شاط وال�شكون، على التوايل، م�شتويات اإجمالية غري طبيعية من هورمون الغدة الدرقية )p >0.001(، بينما كان لدى %14.3 و %0 م�شتويات مرتفعة للغاية من الهرمون املنبه للغدة. اخلال�صة: نظًرا لنت�شار ق�شور الغدة الدرقية حتت الإكلينيكي وحتى ال�رسيح يف الأطفال امل�شابني مبتالزمة التنفرزالكلوية، فقد تكون اختبارات فح�ض الغدة الدرقية مطلوبة لديهم. ومع ذلك، هناك حاجة اإىل مزيد من البحث لتاأكيد هذه النتائج. الكلمات املفتاحية: متالزمة التنفر الكلوية؛ الأطفال؛ بيلة الألبومني؛ بيلة الربوتينات؛ ق�شور الغدة الدرقية؛ اإيران. thyroid dysfunction in children with idiopathic nephrotic syndrome attending a paediatric hospital in qazvin, iran fatemeh saffari, samieh ahadi, reza dalirani, nasrin esfandiar, zohreh yazdi, *banafsheh arad sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e332–338, epub. 21 dec 20 submitted 5 oct 20 revisions req. 2 dec 19 & 11 mar 20; revisions recd. 25 jan & 8 apr 20 accepted 31 may 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.009 clinical & basic research advances in knowledge this study found that the most common thyroid disorder among children with active nephrotic syndrome was subclinical hypothyroidism, a feature closely related to hypercholesterolaemia and hypoalbuminaemia . moreover, nephrotic syndrome mostly affected levels of thyroid-stimulating hormone and total thyroxine levels, with no impact on free and total triiodothyronine levels. https://creativecommons.org/licenses/by-nd/4.0/ fatemeh saffari, samieh ahadi, reza dalirani, nasrin esfandiar, zohreh yazdi and banafsheh arad clinical and basic research | e333 idiopathic nephrotic syndrome (ins) is acommon paediatric glomerular disease characterised by symptoms of severe proteinuria—as defined by a urinary protein-to-creatinine ratio of >2 in the first morning sample or a rate of >40 mg/ m²/hour over 24 hours—hypoalbuminaemia (<2.5 g/ dl), oedema and serum cholesterol (>250 mg/dl).1,2 moreover, recent studies have shown that nephrotic children may develop thyroid hormone dysfunction as the result of the urinary excretion of thyroidbinding globulin, transthyretin and thyroid hormones; however, the exact prevalence of thyroid disorders in this population has not yet been defined as thyroid tests are not conducted on a routine basis.3 thyroid function disorders can lead to changes in fluid homeostasis and electrolytes; for instance, hypothyroidism decreases glomerular sodium filtration, thereby affecting urine osmolality.4 approximately 4–10% of the general population is affected by subclinical hypothyroidism.5 in particular, nephrotic children with low thyroid reserves may develop subclinical hypothyroidism which, without thyroxine (t4) replacement therapy, will likely progress to overt hypothyroidism.6 hence, the need for t4 replacement therapy in patients with hypothyroidism is increased in the presence of nephrotic syndrome.7 thyroid hormonal therapy in children with subclinical hypothyroidism and short stature has been shown to improve growth velocity, especially in prepubertal groups, although other researchers have reported contradictory findings.8,9 in addition, treatment for hypothyroidism has been observed to improve renal function.10 in light of the aforementioned evidence, the aim of this study was to compare levels of thyroid hormones between nephrotic children and healthy controls, as well as between nephrotic children in the active phase of the disease and those in remission. methods this case-control study was carried out between march 2016 and march 2018 at a children’s hospital in qazvin, iran. the case group consisted of children aged 1–12 years with nephrotic syndrome who were being examined in the nephrology department or outpatient clinic of the hospital during the study period. in addition, a control group was recruited consisting of healthy children without any metabolic or infectious diseases who were admitted to the hospital for elective surgery during the same timeframe. the necessary sample size for the case group was determined to be 70 nephrotic children based on a two-sided confidence level (1-alpha) equal to 0.95 and at 80% power.11 sampling continued in succession until this target was met. as such, the final cohort consisted of 73 nephrotic children in the case group, including 49 with active disease and 24 in remission, and 74 healthy children in the control group. nephrotic children in the case group were deemed to have ins if they met the following parameters: (1) a urinary protein-to-creatinine ratio of >2 in the first morning sample or a rate of >40 mg/m²/hour over 24 hours; (2) a serum albumin level of <2.5 g/dl; (3) oedema; and (4) a serum cholesterol level of >250 mg/ dl. children with congenital nephrotic syndrome, nephrotic syndrome secondary to infection, metabolic or other disorders and those with acute or chronic renal failure were excluded. blood samples were taken from all the children to measure their serum levels of albumin, cholesterol, free t4, free triiodothyronine (t3), total t4, total t3, thyroid-stimulating hormone (tsh) and anti-thyroid peroxidase (tpo). in the control group, these tests were performed on initial blood samples requested for elective surgery. in the case group, these tests were performed for all nephrotic patients regardless of whether they were in the active phase of the disease or in remission. the personnel who analysed the samples were not aware of whether the samples originated from patients or controls. laboratory tests for thyroid hormones were performed using an enzyme-linked immunosorbent assay (pishsaz teb, eliza kit, model 50104475, 481 cpc, iran). in addition, an endpoint assay (pars azmun co, 3311 isic, iran) was used to determine levels of albumin and cholesterol oxidase. urine samples were collected and the proportion of protein to random urinary creatinine was measured, with ratios of >2 considered to indicate nephrotic-range proteinuria. children with elevated serum tsh levels (5−10 miu/l) and normal free t4 levels (i.e. within the reference range) were considered to have subclinical hypothyroidism.12 hypothyroidism was considered as high tsh levels (>10 miu/l) with normal thyroid hormone levels that require levothyroxine replacement therapy, or high tsh levels with decreased total t3 and t4 and/or free t3 and t4 [table 1].13 application to patient care this study highlighted the importance of measuring levels of thyroid hormones in children with nephrotic syndrome in order to determine the prevalence of subclinical or overt hypothyroidism in this population. thyroid dysfunction in children with idiopathic nephrotic syndrome attending a paediatric hospital in qazvin, iran e334 | squ medical journal, november 2020, volume 20, issue 4 initially, none of the nephrotic patients under went kidney biopsies due to the absence of gross haema turia, hypertension, renal insufficiency or hypocompl ementemia and were instead treated with daily pred nisolone therapy.14 however, four did not respond to treatment following eight weeks of prednisolone therapy; these cases were diagnosed with steroidresistant nephrotic syndrome and subsequently under went diagnostic kidney biopsies. two patients had focal and segmental glomerulonephritis, one had lupus nephritis and one had mesangioprolifrative glomerul onephritis. data were analysed using the statistical package for the social sciences (spss), version 18.0 (ibm corp., armonk, new york, usa). continuous variables were presented using means and standard deviations while categorical variables were expressed in frequencies and percentages. either a chi-squared test or fisher’s exact test (for variables with <5 data points) was used to compare the prevalence of thyroid function abnormalities between two groups (i.e. between patients and controls or between patients with active disease and those in remission). in addition, a kolmogorov-smirnov test was used to determine the distribution of numerical data. comparisons between three groups (i.e. nephrotic children categorised into three groups according to tsh level) were carried out using a kruskal-wallis test, while comparisons between two groups (i.e. between patients with active disease and those in remission) were carried out using a mann-whitney u test. a p value of <0.050 was considered statistically significant. this study was approved by the ethics committee of the research department at the qazvin university of medical sciences (ir.qums.rec.1395.269). in addition, written informed consent was provided on behalf of the children by their parents or legal guardians. results the mean age of the nephrotic children was 5.2 ± 3 years and 41 (56.2%) were male. the mean age of control group was 5.4 ± 3.4 and 32 (43.2%) were male. overall, there was a significantly higher proportion of nephrotic children with low total t4 levels compared to the control group (9.5% versus 0%; p <0.001). moreover, a significantly higher number of nephrotic children had elevated tsh levels compared to the control group (34.2% versus 10.8%; p = 0.001). no significant differences were noted between the nephrotic children and healthy controls for any other thyroid hormone abnormalities [table 2]. thyroid test results were subsequently compared between nephrotic patients with active disease and those in remission. a total of 7 (9.5%) and no patients in the active and remission phases, respectively, table 1: criteria used to define thyroid function categories in the current study category hormone levels total t3* total t4† free t3‡ free t4§ tsh¶ euthyroidism normal normal normal normal normal hypothyroidism\\ low low low low high subclinical hypothyroidism normal normal normal normal high t3 = triiodothyronine; t4 = thyroxine; tsh = thyroid-stimulating hormone. *normal ranges for children aged 1–6 years and 7–12 years are 0.92–2.48 ng/ml and 0.93–2.30 ng/ml, respectively. †normal ranges for children aged 1–6 years and 7–12 years are 5.95–14.7 μg/dl and 5.99–13.80 μg/dl, respectively. ‡normal ranges for children aged 1–6 years and 7–12 years are 2.41–5.50 pg/ml and 2.53–5.22 pg/ml, respectively. §normal ranges for children aged 1–6 years and 7–12 years are 0.96–1.77 ng/dl and 0.97–1.67 ng/dl, respectively. ¶normal ranges for children aged 1–6 years and 7–12 years are 0.70–5.97 miu/l and 0.60–4.84 miu/l, respectively. \\high tsh levels (>10 miu/l) and normal levels of thyroid hormones was also considered hypothyroidism. table 2: frequency of thyroid hormone abnormalities among nephrotic children and healthy controls (n = 147) abnormality n (%) p value* nephrotic children (n = 73) control group (n = 74) decreased total t3† 18 (24.7) 17 (23) 0.848 decreased total t4‡ 7 (9.5) 0 (0) <0.001 decreased free t3§ 11 (15.1) 6 (8.1) 0.208 decreased free t4¶ 9 (12.3) 5 (6.8) 0.276 increased tsh// 25 (34.2) 8 (10.8) 0.001 increased antitpo** 2 (2.7) 3 (4.1) >0.999 t3 = triiodothyronine; t4 = thyroxine; tsh = thyroid-stimulating hormone; tpo = thyroid peroxidase. *calculated using a chi-squared test or fisher’s exact test for variables with <5 data points. †normal ranges for children aged 1–6 years and 7–12 years are 0.92–2.48 ng/ml and 0.93–2.30 ng/ml, respectively. ‡normal ranges for children aged 1–6 years and 7–12 years are 5.95–14.7 μg/dl and 5.99–13.80 μg/dl, respectively. §normal ranges for children aged 1–6 years and 7–12 years are 2.41–5.50 pg/ml and 2.53–5.22 pg/ml, respectively. ¶normal ranges for children aged 1–6 years and 7–12 years are 0.96–1.77 ng/dl and 0.97–1.67 ng/dl, respectively. //normal ranges for children aged 1–6 years and 7–12 years are 0.70–5.97 miu/l and 0.60–4.84 miu/l, respectively. **normal range for children aged 1–12 years is <2 iu/ml. fatemeh saffari, samieh ahadi, reza dalirani, nasrin esfandiar, zohreh yazdi and banafsheh arad clinical and basic research | e335 had abnormal total t4 levels (p <0.001). moreover, 24 (49%) patients with active disease had slightly elevated tsh levels (>5 miu/l) in comparison to one (4.2%) patient in remission (p <0.001), while highly elevated tsh levels (>10 miu/l) were observed in seven (14.3%) patients with active disease and none of the patients in remission (p = 0.002). there were no significant differences in other thyroid hormone abnormalities between the two groups. significantly higher mean tsh levels (p <0.001) and significantly lower mean total t4 (p <0.001) and free t4 levels (p = 0.002) were observed among patients with active disease in comparison to those in remission [table 3]. a significantly lower number of patients with active disease had euthyroidism compared to those in remission (51% versus 95.8%; p = 0.001). however, significantly higher rates of subclinical hypothyroidism (34.7% versus 4.2%; p = 0.001) and hypothyroidism (14.3% versus 0%; p = 0.001) were noted in patients with active disease [table 4]. predictive factors for highly elevated tsh levels (>10 miu/l) included hypoalbuminaemia (p = 0.004) and hypercholesterolaemia (p <0.001) [table 5]. although the prevalence of highly elevated tsh levels (>10 miu/l) was higher in female children, this difference was not statistically significant (p = 0.117). discussion this study aimed to compare thyroid hormone levels between nephrotic children and healthy controls as well as between nephrotic children in the active phase of the disease and those in remission. while the case and control groups did not differ significantly in terms of levels of total t3, free t3, free t4 and antitpo, a significantly higher proportion of nephrotic patients demonstrated abnormal total t4 and tsh levels compared to the healthy controls. fonseca et table 3: mean levels of thyroid hormones according to disease phase among nephrotic children (n = 73) hormone mean level ± sd p value* active phase (n = 49) remission phase (n = 24) total t3 in ng/ml† 1.82 ± 0.53 2.41 ± 0.53 0.009 total t4 in μg/dl‡ 4.83 ± 1.70 7.93 ± 1.80 <0.001 free t3 in pg/ml§ 3.91 ± 1.10 3.70 ± 0.85 0.557 free t4 in ng/dl¶ 9.60 ± 2.54 12.30 ± 2.80 0.002 tsh in miu/l// 7.12 ± 7.90 2.70 ± 1.71 <0.001 anti-tpo in iu/ml** 0.73 ± 2.30 0.33 ± 0.41 0.737 t3 = triiodothyronine; t4 = thyroxine; tsh = thyroid-stimulating hormone; tpo = thyroid peroxidase. *calculated using a mann-whitney u test. †normal ranges for children aged 1–6 years and 7–12 years are 0.92–2.48 ng/ml and 0.93–2.30 ng/ml, respectively. ‡normal ranges for children aged 1–6 years and 7–12 years are 5.95–14.7 μg/dl and 5.99–13.80 μg/dl, respectively. §normal ranges for children aged 1–6 years and 7–12 years are 2.41–5.50 pg/ml and 2.53–5.22 pg/ml, respectively. ¶normal ranges for children aged 1–6 years and 7–12 years are 0.96–1.77 ng/dl and 0.97–1.67 ng/dl, respectively. //normal ranges for children aged 1–6 years and 7–12 years are 0.70–5.97 miu/l and 0.60–4.84 miu/l, respectively. **normal range for children aged 1–12 years is <2 iu/ml. table 4: thyroid function according to disease phase among nephrotic children (n = 73) category n (%) p value* active phase (n = 49) remission phase (n = 24) euthyroidism† 25 (51) 23 (95.8) 0.001 hypothyroidism‡ 7 (14.3) 0 (0) 0.001 subclinical hypothyroidism§ 17 (34.7) 1 (4.2) 0.001 t3 = triiodothyronine; t4 = thyroxine. *calculated using a chi-squared test or fisher’s exact test for variables with <5 data points. †defined as normal levels of all thyroid hormones. ‡defined as high levels of thyroid stimulating hormone (tsh; 5−10 miu/l) and low levels of total t3 and total t4 and/or low levels of free t3 and free t4, as well as highly elevated tsh levels (>10 miu/l) with normal levels of thyroid hormones. §defined as high levels of tsh (5−10 miu/l) and normal levels of total t3, total t4, free t3 and free t4. table 5: mean levels of thyroid-stimulating hormone, albumin, triglycerides, cholesterol and urine protein/creatinine level according to age group among nephrotic children (n = 73) parameter mean level ± sd p value† tsh of 0–5 miu/l* (n = 46) tsh of 5–10 miu/l* (n = 20) tsh of >10 miu/l* (n = 7) albumin level in g/l‡ 3.00 ± 0.95 2.58 ± 0.72 1.92 ± 0.33 0.004 tg level in mg/dl§ 265.84 ± 206.71 292.15 ± 193.49 320.28 ± 321.02 0.439 cholesterol level in mg/dl¶ 263.76 ± 152.62 304.14 ± 107.03 450.70 ± 141.16 <0.001 upr/cr ratio in mg/mg// 18.52 ± 38.21 25.37 ± 40.77 19.65 ± 18.67 0.250 sd = standard deviation; tsh = thyroid-stimulating hormone; iu = international unit; tg = triglycerides; upr = urinary protein; cr = creatinine. *normal ranges for children aged 1–6 years and 7–12 years are 0.70–5.97 miu/l and 0.60–4.84 miu/l, respectively. †calculated using a kruskalwallis test. ‡hypoalbuminaemia was defined as <2.5 g/l. §hypertriglyceridaemia was defined as <75 mg/dl and <90 mg/dl for children aged 0–9 and 10–19 years, respectively. ¶hypercholesterolaemia was defined as >250 mg/dl. //nephrosis was defined as >2 mg/mg. thyroid dysfunction in children with idiopathic nephrotic syndrome attending a paediatric hospital in qazvin, iran e336 | squ medical journal, november 2020, volume 20, issue 4 al. reported significantly lower free t4 and free t3 levels in nephrotic patients for whom high urinary t4 levels were detected.15 while the current study did note significantly lower free t4 levels among nephrotic children in the active phase of the disease, no significant differences were observed with regards to free t3 levels between nephrotic patients with active disease and those in remission. ito et al. found that children with nephrotic syndrome had lower serum t3 and t4 levels in the active phase of the disease compared to the remission phase; moreover, mean free t4 and free t3 concentrations were lower in untreated nephrotic patients.13 the researchers also observed that most nephrotic children had normal tsh values, with a negative correlation between serum albumin and tsh levels.13 in contrast, the prevalence of subclinical hypothyroidism (as defined by high levels of tsh alone) was higher among nephrotic children in the present study, although there was a significant association noted between hypoalbuminaemia and highly elevated serum tsh levels. hajizadeh et al. reported that 34.7% of children with active nephrotic syndrome had high tsh levels; this rate was close to that observed in the present study (46.9%).11 furthermore, the mean tsh level among untreated nephrotic children was 11.65 ± 6.71 miu/l (range: 4.31–34.40 miu/l).11 this is comparable to the mean tsh level of nephrotic patients with active disease in the current study (7.12 ± 7.90 miu/l). finally, the researchers noted a relationship between tsh levels and the severity of proteinuria, hypoalbuminaemia and hypertriglyceridaemia.11 in the present study, while both hypoalbuminaemia and hypercholesterolaemia were significantly associated with serum tsh levels, there was no association with proteinuria or hypertriglyceridaemia. much like the present study, ebadi et al. reported that children with nephrotic syndrome had low t4 and high tsh levels; however, the researchers also observed low t3 levels, a finding not observed in the current study.16 afroz et al. described significantly higher tsh levels in children with nephrotic syndrome (mean: 9.11 ± 6.36 miu/l), with a negative correlation with serum albumin levels, but normal total t4 levels.17 guo et al. indicated that nephrotic children had lower serum albumin levels and higher tsh levels; overall, elevated tsh levels were detected in 44.51% of nephrotic children, a lower percentage compared to that noted in the current study (34.2%).18 bona et al. observed significant associations between highly elevated tsh levels (>10 miu/l) and initial tsh levels of >7.5 miu/l as well as the female gender, but not with age.19 while female children in the present study did more frequently demonstrate highly elevated tsh levels (>10 miu/l) compared to males, this difference was not statistically significant. in children diagnosed with nephrotic syndrome, the loss of binding proteins through urine (such as thyroxine-binding proteins, albumin and thyroid hormones) can result in a decrease in serum levels of thyroid hormones and an increase in tsh levels as a compensatory mechanism.18 previous research has also confirmed differences in thyroid profiles in nephrotic patients.20 the urinary loss of total t3, total t4 and thyroid-binding globulin occurs during the proteinuric phase of nephrotic syndrome and subsequently reverts during the remission phase.13 in addition, high levels of thyroid hormones bind to plasma proteins that cross the glomerular barrier and are briefly reabsorbed by proximal tubule. the free t4 with two iodine atoms in phenolic ring are mainly reabsorbed by the tubules, while free t3 with one iodine atom in phenolic ring is mostly secreted.15,21 a portion of nephrotic patients can manifest with euthyroid sick syndrome, a condition characterised by low total t3 and total t4 levels and increased reverse t3 levels, but normal-to-low tsh levels.13 this syndrome results from a decrease in the activity of type 1 5’-deiodinase, the hepatic enzyme that deiodinates t4 to the biologically active t3.22 in some patients, the expression of tsh in the pituitary gland is inhibited by the prolonged use of glucocorticoids, oxidative activation and psychological stress, thus resulting in normal or even low tsh levels.23 in the current study, significantly lower free t4 and total t4 levels were observed in the active phase of nephrotic syndrome in comparison with the remission phase; however, there was no difference in free t3 and total t3 levels. in an assessment of thyroid hormones among outpatients, legakis et al. revealed that t3 and tsh levels were practically independent, while t4 and tsh levels had a significant negative correlation; moreover, there was a positive correlation between t3 and t4 levels that became more pronounced with age.24 these correlations could explain the normal t3 levels noted in the present study compared to other reports.13,15,16 subclinical hypothyroidism is less common in children and adolescents than in adults.25 indeed, the progression of this condition to overt hypothyroidism has been reported in 0–12.5 % of cases.26 predictors for this include serum tsh level above 7.5 miu/l and female gender, however age was not significant predictor.19 however, it can prove difficult to distinguish between euthyroid patients and those with mild or overt thyroid disease.5 thyroid disorders impact fluid haemostasis, electrolyte levels, glomerular fatemeh saffari, samieh ahadi, reza dalirani, nasrin esfandiar, zohreh yazdi and banafsheh arad clinical and basic research | e337 filtration rate and urine osmolality, thereby leading to fluid retention.4,27 moreover, patients with subclinical hypothyroidism (i.e. highly elevated tsh levels of >10 miu/l) have an increased risk of cardiovascular morbidity and mortality compared to patients with lower serum tsh levels due to high serum cholesterol levels and other cardiac risk factors.28 as such, thyroid hormone assessment is strongly recommended for nephrotic patients with elevated serum cholesterol levels. the present study was subject to certain limitations including the small sample size and short follow-up period which did not permit adequate detection of hypothyroid abatement in cases of subclinical hypothyroidism. the authors therefore recommend further studies be conducted incorporating a longer follow-up period in order to determine whether there is a need for treatment in nephrotic children with subclinical hypothyroidism. conclusion few studies have sought to assess the prevalence of subclinical and overt hypothyroidism in the presence of ins. this study conducted comparative thyroid hormone assessments for both nephrotic children and healthy controls, as well as for nephrotic children in the active phase of the disease and those in remission. while it remains unclear whether subclinical hypothyroidism influences the natural history and prognosis of nephrotic syndrome, the findings of this study underline the importance of conducting thyroid function tests in nephrotic children with prolonged and severe urinary protein loss. a c k n o w l e d g e m e n t s the preliminary version of this research was submitted as part of a phd thesis in the field of paediatrics to the school of medicine, qazvin university of medical sciences, in 2016. the authors wish to thank the parents and their children for their participation in the study as well as the staff of the center for clinical research at qazvin children’s hospital for their help in preparing this manuscript for publication. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this research was funded with the aid of a grant (28/20/13577) from the research department of the qazvin university of medical sciences. references 1. uwaezuoke sn. steroid-sensitive nephrotic syndrome in children: triggers of relapse and evolving hypotheses on pathogenesis. ital j pediatr 2015; 41:19. https://doi.org/10.1186/ s13052-015-0123-9. 2. lombel rm, gipson ds, hodson em. treatment of steroidsensitive nephrotic syndrome: new guidelines from kdigo. pediatr nephrol 2013; 28:415–26. https://doi.org/10.1007/s004 67-012-2310-x. 3. iglesias p, díez jj. thyroid dysfunction and kidney disease. eur j endocrinol 2009; 160:503–15. https://doi.org/10.1530/eje-080837. 4. gilles r, den heijer m, ross ah, sweep fc, hermus ar, wetzels jf. thyroid function in patients with proteinuria. neth j med 2008; 66:483–5. https://doi.org/10.1530/eje-08-0837. 5. mcdermott mt, ridgway ec. subclinical hypothyroidism is mild thyroid failure and should be treated. j clin endo crinol metab 2001; 86:4585–90. https://doi.org/10.1210/jcem.86.1 0.7959. 6. di mario f, pofi r, gigante a, rivoli l, rosato e, isidori am, et al. hypothyroidism and nephrotic syndrome: why, when and how to treat. curr vasc pharmacol 2017; 15:398–403. https://doi.or g/10.2174/1570161115999170207114706. 7. junglee na, scanlon mf, rees da. increasing thyroxine requirements in primary hypothyroidism: don’t forget the urinalysis! j postgrad med 2006; 52:201–3. 8. cetinkaya e, aslan at, vidinlisan s, ocal g. height improve ment by l-thyroxine treatment in subclinical hypothyroidism. pediatr int 2003; 45:534–7. https://doi.org/10.1046/j.1442200x.2003.01786.x. 9. rapa a, monzani a, moia s, vivenza d, bellone s, petri a, et al. subclinical hypothyroidism in children and adolescents: a wide range of clinical, biochemical, and genetic factors involved. j clin endocrinol metab 2009; 94:2414–20. https:// doi.org/10.1210/jc.2009-0375. 10. den hollander jg, wulkan rw, mantel mj, berghout a. correlation between severity of thyroid dysfunction and renal function. clin endocrinol (oxf ) 2005; 62:423–7. https://doi. org/10.1111/j.1365-2265.2005.02236.x. 11. hajizadeh n, marashi sm, nabavizadeh b, elhami e, mohammadi t, nobandegani nm, et al. examine of thyroid function in pediatric nephrotic syndrome: tehran-iran. int j pediatr 2015; 3:59–65. https://doi.org/10.22038/ijp.2015.4051. 12. crisafulli g, aversa t, zirilli g, pajno gb, corica d, de luca f, et al. subclinical hypothyroidism in children: when a replacement hormonal treatment might be advisable. front endocrinol (lausanne) 2019; 10:109. https://doi.org/10.3389/ fendo.2019.00109. 13. ito s, kano k, ando t, ichimura t. thyroid function in children with nephrotic syndrome. pediatr nephrol 1994; 8:412–15. https://doi.org/10.1007/bf00856516. 14. kliegman rm, st. geme j. nelson textbook of pediatrics. 21st ed. amsterdam, netherlands: elsevier, 2019. p. 2757. 15. fonseca v, thomas m, katrak a, sweny p, moorhead jf. can urinary thyroid hormone loss cause hypothyroidism? lancet 1991; 338:475–6. https://doi.org/10.1016/0140-6736 (91)90546-2. 16. ebadi a, shirali s, daneghian s, saki s. evaluating the thyroid function in pediatric nephrotic syndrome: a study conducted in ahvaz, iran. int j pharm res allied sci 2016; 5:82–5. 17. afroz s, khan ah, roy dk. thyroid function in children with nephrotic syndrome. mymensingh med j 2011; 20:407–11. 18. guo qy, zhu qj, liu yf, zhang hj, ding y, zhai ws, et al. steroids combined with levothyroxine to treat children with idiopathic nephrotic syndrome: a retrospective singlecenter study. pediatr nephrol 2014; 29:1033–8. https://doi. org/10.1007/s00467-013-2727-x. https://doi.org/10.1186/s13052-015-0123-9 https://doi.org/10.1186/s13052-015-0123-9 https://doi.org/10.1007/s00467-012-2310-x https://doi.org/10.1007/s00467-012-2310-x https://doi.org/10.1530/eje-08-0837 https://doi.org/10.1530/eje-08-0837 https://doi.org/10.1530/eje-08-0837 https://doi.org/10.1210/jcem.86.10.7959 https://doi.org/10.1210/jcem.86.10.7959 https://doi.org/10.2174/1570161115999170207114706 https://doi.org/10.2174/1570161115999170207114706 https://doi.org/10.1046/j.1442-200x.2003.01786.x https://doi.org/10.1046/j.1442-200x.2003.01786.x https://doi.org/10.1210/jc.2009-0375 https://doi.org/10.1210/jc.2009-0375 https://doi.org/10.1111/j.1365-2265.2005.02236.x https://doi.org/10.1111/j.1365-2265.2005.02236.x https://doi.org/10.22038/ijp.2015.4051 https://doi.org/10.3389/fendo.2019.00109 https://doi.org/10.3389/fendo.2019.00109 https://doi.org/10.1007/bf00856516 https://doi.org/10.1016/0140-6736%20%2891%2990546-2 https://doi.org/10.1007/s00467-013-2727-x https://doi.org/10.1007/s00467-013-2727-x thyroid dysfunction in children with idiopathic nephrotic syndrome attending a paediatric hospital in qazvin, iran e338 | squ medical journal, november 2020, volume 20, issue 4 19. bona g, prodam f, monzani a. subclinical hypothyroidism in children: natural history and when to treat. j clin res pediatr endocrinol 2013; 5:23–8. https://doi.org/10.4274/jcrpe.851. 20. dagan a, cleper r, krause i, blumenthal d, davidovits m. hypothyroidism in children with steroid-resistant nephrotic syndrome. nephrol dial transplant 2012; 27:2171–5. https:// doi.org/10.1093/ndt/gfr665. 21. faber j, siersbaek-nielsen k, kirkegaard c. renal handling of thyroxine, 3,5,3'and 3,3',5'-triiodothyronine, 3,3'and 3',5' diiodothyronine in man. acta endocrinol (copenh) 1987; 115:144–8. https://doi.org/10.1530/acta.0.1150144. 22. liu h, yan w, xu g. thyroid hormone replacement for nephrotic syndrome patients with euthyroid sick syndrome: a meta-analysis. ren fail 2014; 36:1360–5. https://doi.org/10.310 9/0886022x.2014.949559. 23. warner mh, beckett gj. mechanisms behind the non-thyroidal illness syndrome: an update. j endocrinol 2010; 205:1–13. https://doi.org/10.1677/joe-09-0412. 24. legakis i, manousaki m, detsi s, nikita d. thyroid function and prevalence of anti-thyroperoxidase (tpo) and antithyroglobulin (tg) antibodies in outpatients hospital setting in an area with sufficient iodine intake: influences of age and sex. acta med iran 2013; 51:25–34. 25. wasniewska m, salerno m, cassio a, corrias a, aversa t, zirilli g, et al. prospective evaluation of the natural course of idiopathic subclinical hypothyroidism in childhood and adolescence. eur j endocrinol 2009; 160:417–21. https://doi. org/10.1530/eje-08-0625. 26. radetti g, gottardi e, bona g, corrias a, salardi s, loche s, et al. the natural history of euthyroid hashimoto's thyroiditis in children. j pediatr 2006; 149:827–32. https://doi.org/10.1530/ eje-08-0625oi.org/10.1530/eje-08-0625. 27. chonchol m, lippi g, salvagno g, zoppini g, muggeo m, targher g. prevalence of subclinical hypothyroidism in patients with chronic kidney disease. clin j am soc nephrol 2008; 3:1296–300. https://doi.org/10.2215/cjn.00800208. 28. rodondi n, den elzen wp, bauer dc, cappola ar, razvi s, walsh jp, et al. subclinical hypothyroidism and the risk of coronary heart disease and mortality. jama 2010; 304:1365–74. https://doi.org/10.1001/jama.2010.1361. https://doi.org/10.4274/jcrpe.851 https://doi.org/10.1093/ndt/gfr665 https://doi.org/10.1093/ndt/gfr665 https://doi.org/10.1530/acta.0.1150144 https://doi.org/10.3109/0886022x.2014.949559 https://doi.org/10.3109/0886022x.2014.949559 https://doi.org/10.1677/joe-09-0412 https://doi.org/10.1530/eje-08-0625 https://doi.org/10.1530/eje-08-0625 https://doi.org/10.1530/eje-08-0625oi.org/10.1530/eje-08-0625 https://doi.org/10.1530/eje-08-0625oi.org/10.1530/eje-08-0625 https://doi.org/10.2215/cjn.00800208 https://doi.org/10.1001/jama.2010.1361 squ med j, may 2011, vol. 11, iss. 2, pp. 187-195, epub. 15th may 11 submitted 23rd oct 10 revision req. 12th jan 11, revision recd. 13th feb 11 accepted 15th feb 11 the sultanate of oman is a muslim arab country located in the southeastern arabian peninsula. the strategic position of oman, particularly as a marine centre connecting the arabian peninsula with the indian subcontinent and east africa, contributed largely to creating the dynamic cultural hub which characterises the country. for many people in oman, the year 1970, when the current sultan took power, marked the leap of oman into a nation state and the move towards modernisation. the health care sector has been one of the essential priorities in the evolving state.1 looking today at the public, state-wide biomedical health care system, the presence and evolution of biomedicine over the last two centuries could be easily overlooked by future generations. as even the seemingly minor traces of history do contribute to shaping and explaining current health care policies in the country,2 and because of significant rising challenges to the existing system in oman,3,4 the need to look back at the roots of current practice and identify historical learning points seems more imperative than ever. few papers have attempted to address, even in brief, some of the aspects related to the history of medicine in oman. the college of medicine medical department, petroleum development oman, muscat, oman. *corresponding author email: dralazri@gmail.com s{{{�÷^√�è�÷ê<xjàè÷<hãé”jäè÷<ÿ̌ �âö �_ <·^€ �¬<ª<îáè£]<g�÷]<öá�i<�ëö^i îå¯èπ]<üé¬<ƒâ^j÷]<·üœ÷]<ª               :مفتاح الكلمات abstract: during the past four decades, oman has transformed into a modern state with remarkable changes in all fields, including public health and the provision of medical services. little attention has been paid so far to the history of the development of biomedicine in oman. a history of healing practices, just like clinical patient histories, helps to diagnose problems, plan interventions and predict their future within a dynamic context. this study is the first to explore the beginnings and evolution of biomedicine in oman during the 19th century, categorising it into three eras: from the casual system offered by occasional visiting biomedical practitioners to the more organised, but limited, british military hospital and, finally, to public missionary medical care toward the end of the 19th century. the study concludes by recommending further focus on medical humanities, including the history of medicine, as a contributing factor to improve and sustain the art and practice of medicine within the existing omani health care system. keywords: oman; history of medicine; mission and missionaries; colonialism special contribution s{{{�÷^√�è�÷ê<xjàè÷<hãé”jäè÷<ÿ̌ �âö �_s{{{�÷^√�è�÷ê<xjàè÷<hãé”jäè÷<ÿ̌ �âö �_ sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century nasser hammad al-azri sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century 188 | squ medical journal, may 2011, volume 11, issue 2 at sultan qaboos university took an interesting initiative in the dean's prize essay in the history of medicine for medical students which existed for several years during the 1990s. the award-winning essays touched on various aspects related to the history of medicine in general although often with a focus on oman. essays such as folk medicine in oman through the eyes of traditional healers, the early history of modern medicine in oman and the history of medicine in relation to medical education in oman could form the seed for a deeper insight on the subject.5,6,7 unfortunately, such initial efforts have neither been nurtured further nor sustained. alas, there are at present no organised or sustainable efforts to study the historical development of the system of medical practice in relation to health and health care in the country. the aim of this paper, therefore, is to trace the introduction and evolution of biomedicine in oman during the 19th century in relation to internal and external factors. it is an attempt to ignite interest in the medical humanities in general, and to break new grounds for investigation and research on the history of medicine by relating it further to health and health care in the country. as such, the article is expected to generate more questions and open more new doors for enquiry than it may present ready-made answers on the subject. methods this study, to the best of the author’s knowledge, is the first to investigate and document in detail the very beginning and development of biomedicine in oman in the 19th century. labelling medical and healing practices poses always a dilemma of terminology and definitions, particularly when it comes to western medicine and its counterparts in other cultures.8,9 the term “biomedicine” is used in this paper specifically to connote biological medicine which is based on a positivist approach,10,11,12 so as to differentiate it from other forms of local medical practices that were present in the community. since writing a global history of biomedicine in oman is virtually impossible, this study has to be limited in time to the 19th century and in content to the evolution of biomedicine. the introduction of biomedicine in oman corresponded largely with the increased western involvement and intrusion into the region during late 18th and the 19th centuries. the pattern almost parallels the development of western imperialism through the stages of exploration and discoveries, military and economic interests and religious imperialism. investigating such a historical issue is hindered by the lack of documentation for this period. moreover, socio-political events and internal conflicts were the topics of interest for local historians, but they rarely documented the health status of the general population, or healing practices in the community. in studying history, there are usually three types of source materials.13 primary sources include all materials produced at the time of an event by people with direct knowledge of it. secondary sources are those that discuss, analyse or review primary sources. tertiary sources are usually collections that organise data from secondary sources. this study utilised primary sources from travelogues written by visitors to oman during the period under study. it also utilised the information contained in the administration reports sent by the british naval resident surgeon in muscat to headquarters. american mission reports contributed as well to the documentation of medical practice in the country starting from the 1890s onwards. the study would have not been complete without referring to the few local resources that addressed health-related aspects of omanis. in addition, secondary sources were also consulted and used to augment this study. why study the history of medicine? medical humanities, including the history of medicine, are as essential to medicine as basic sciences are. medicine is an art and a science,14,15 and both aspects therefore should be considered whether one is dealing with an individual patient or with a medical system. just like the vital importance of patient history in the clinical context, the history of medicine attempts to place people, institutions and events in the broader context in which they happened, lived or interacted.16 among other functions, it questions the past in order to provide answers to current or expected problems of health and health care. being rather a dynamic social organism and not simply a mechanical structure, a health care system should be understood, evaluated and enhanced within its context and locale. medical nasser hammad al-azri special contribution | 189 humanities are essential for a practice that is suffering proliferating ethical dilemmas, frequent patient-carer miscommunication and increasing customer dissatisfaction despite skyrocketing costs. it can operate, as well, as a countermeasure against the “dehumanizing atmosphere that technology brings to medicine”.17 in addition, humanities may also contribute positively to medical education and practice in an age of crisis.18,19 medical humanities could also improve the art of medical practice and guide the rethinking of current health policies. although it is thought commonly to deal with the past, studying history is about affecting the future course of events differently from what already happened or is happening.20,21 this makes the link between history and policy unambiguous, and as rosenberg stated:22 “policy is always history”. as such, history is indispensable for health systems in order to understand current public health challenges and affect, directly or indirectly, related future policies.23,24 in brief, the history of medicine can be a compass showing where health care was, where it stands now and in which future direction it should be steered. brief history of oman during 19 th century throughout history, oman has remained an independent land, apart from short periods when mainly coastal areas were under persian and, later, portuguese control. toward the end of the 18th century, omani dominion had expanded beyond the south eastern arabian peninsula eastwards to the coast of baluchistan in the indian subcontinent and westwards to the shores of mozambique. by the 19th century, its influence extended across the gulf, persia, asia, and east africa. this was the epoch of the “omani empire”. the 19th century had also witnessed the struggle between western powers to gain a foothold in the area as part of their imperial expansion. as a consequence of rising western interests and competition in the region, the east india company established a british political agency in oman. this was moved in 1843 to zanzibar when the capital was shifted there earlier under sultan said. in 1861, the british residency was re-established by re-appointing a european political officer at muscat.25 this was an important landmark for the institutionalisation of biomedicine in oman as the nucleus of an organised biomedical practice was soon established by the british army. although the omani empire had receded since the mid-19th century to occupy its original lands in the arabian peninsula, oman continued to influence and be influenced by the external competing forces in the region, especially following the discovery of oil in the gulf. biomedicine in oman: the early days the rise of biomedicine and its first contact with people in arabia coincided with the rising tide of western colonialism and evangelisation in the region. soldiers, missionaries, administrators and capitalists became almost simultaneously interested in arabia. these different “invaders” attempted to enlighten the people they encountered, albeit by different means and for different reasons, but commonly toward “civilisation”.26,27,28 doctors and nurses had diverse motivations for working away from home including economic, practical, social, professional and religious reasons; nevertheless, “they were all culturally determined”.29 wendell phillips portrays this civilising mission as he describes the work of dr. krause in the desert of oman: “[h]ere is one of the wildest, least known areas of the world, a primitive badawi lies in the sand extremely ill. then, without warning, one of america’s leading medical specialists drops down as from heaven to serve his most grateful patient”.30 they were simply missionaries of a new culture, a new way of life and a new weltanschauung. moreover, invading forces used medicine as a tool for penetration into arabia, making the connection between biomedicine and these forces unavoidable. as an instrument used by various groups of politicians, armies and missionaries, and practised by professionals and non-professionals to gain entry into the region including oman, biomedicine could be considered as a trojan horse of arabia. major ross “believed that in the coming (20th) century the success of imperialism would depend largely upon success with the microscope”.31 members of the royal family and rich people who had more contact with the westerners were more ready to welcome and adopt the biomedical approach to healing as they had access to it.32 gradually, however, several sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century 190 | squ medical journal, may 2011, volume 11, issue 2 pushing and pulling factors contributed to the incorporation of biomedicine in the local omani community as a mode of healing practice. pushing factors external pushing factors probably preceded the internal pulling ones. politicians, discoverers, investors and missionaries guarded by military troops all used, or abused, biomedicine to fulfil their agenda in this region as they had in other parts of the world such as china, india and africa. as will be noted later in the discussion, physicians were used to bargain for political and military advantages. they also helped the newcomers to cope with the harsh, “unhealthy” environment of their new “settlements”. biomedicine was, initially at least, more of a condition for survival of the foreigners in the country than a requirement for the locals. toward the end of the 19th century, with increasing wealth and urban growth, new social hierarchies and influential relationships were being shaped by the imperial powers in the region. medicine served a dual role for both the local elite and the invaders. it was a means for the elite to strengthen their relationships with the military powers and to prove their devotion in order to protect their interests in the region. as noted by ghubash et al., “pro-british personalities played a substantial part in motivating britain to introduce medical services into the region. that was their natural role, taking into consideration the status they enjoyed at that time”.33 on the other hand, medicine was utilised as a tool for those military powers to gain the confidence and satisfaction of the rulers and local people. pulling factors pushing factors, no matter how forceful they could be, would not have exerted the required influence without a significant accompanying change in the social milieu. pulling, or internal, factors calling for biomedicine to be part of local culture were related mostly to the pushing factors. the need was partly created by the new epidemics, illnesses and injuries shipped in by soldiers, merchants and missionaries. ibn-ruzaiq, a prominent omani historian who died in 1857, described the cholera epidemic in 1821 as an ‘unusual plague’,34 leading to an assumption that cholera was probably not a known disease in this country until that date. this is consistent with various historical data that linked the 1821 omani cholera epidemic with british troops sent from india to aid the sultan against a local rebellion.35,36 the industrial revolution and its surge of scientific discoveries had been associated with a new set of illnesses and injuries. the introduction of guns, for example, led to injuries previously unknown to locals. as peter j. zwemer noted, a man was brought over 600 km from abu-thabi (abu-dhabi, uae, today) to the british military hospital in muscat because of a gunshot wound, and a bullet was extracted successfully by the attending surgeon.37 major surgery, in its modern practice, was indeed an incredible treatment modality for a population that largely used herbal medicines and other simple “surgical” procedures such as tajbeer (bone-setting) and wasm (cauterisation or branding). in addition, and as happened in other cultures,38 the perceived inability of local healers to cope with new epidemics and types of illnesses and injuries paved the road for biomedicine to claim its effectiveness among the locals. people even copied new healing practices from others, probably with the hope of combating the ‘new plagues’. the omani princess sayyida salma, in her memoirs published first in 1886, noted that some superstitious practices were unknown to omanis until they mixed with people in the african part of their empire.32 probably she was referring to the zar cult which has been used to treat spirit possession victims. this is consistent with other sources that refer the origin of this practice to africa,39,40,41 and might explain earlier observations that this cult flourished in coastal rather than interior areas of oman.42 biomedicine was being accepted as a mode of healing practice to combat the new illnesses, but never as the sole one. evolution of biomedicine in oman biomedicine in oman can be traced back to the late 18th century. the development can be categorised into three eras, distinctive in their characteristics, but yet having limited time overlap: 1. first era (sent to explore): the era of casual nasser hammad al-azri special contribution | 191 medical practice by physician and non-physician explorers extended for the first six decades of 19th century. 2. second era (sent to conquer): the era of organised military medicine services extended from the seventh decade of 19th century and beyond. 3. third era (sent to heal): the era of missionary medicine extended from the 1890s onward. these eras represent more topical than chronologic stages of biomedicine in oman. the labelling of the eras reflects the general dominant trend of western powers in the region rather than individual practitioners’ objectives. the first and second eras correspond closely to phase 1 (exploration phase) and phase 2 (colonial phase) in the basalla model for explanation of the spread of western sciences to non-western dominions.43 sent to explore the last decade of 18th century witnessed a peak in the strife between the british and the french. sayyid sultan, the ruler of muscat, had at that time a french military surgeon in his service.44 this prompted the british in 1799 to suggest sending assistant surgeon a. h. bogle as a personal physician to the sultan if the later agreed to exclude the french, and their physician, from muscat. the sultan did, and dr. bogle became the first british political agent in muscat.25 dr. bogle, who died in less than a year, was then succeeded by captain david seton of the bombay army. biomedicine has entered oman on military ships as a door opener for the colonials and the doctor was the bait! one of the earliest encounters during the early 19th century was with the italian traveller, vincinzo maurizi, known to local people in the region as shaik mansur. he was appointed as the sultan’s physician in 1809, shortly after his arrival in oman.45 in addition to this position, he also had his own private medical practice, which he described as being ‘very extensive’. nevertheless, he described the suspicions raised by some people regarding his claim of being a physician and how luck helped him overcome it! apart from casual stories of patients he successfully treated, he did not elaborate much on the population health status, common illnesses, or medical and healing practices. not surprisingly, this era coincided with western geographical exploration and is the most difficult to track as biomedical practice was not yet organised. most of the information is in the writings of travellers who visited the country, or in the political history records. a few journals also referred to some biomedical practitioners in oman, but mainly for their contribution to geographic explorations rather than their medical practice. many military surgeons visited and toured the country, such as dr. w. s. w. ruschenberger of the united states navy,46 dr. hulton, and john henry carter of the british navy.47,48,49 their accounts on the culture, geology, and topography of oman reflect the trend of western explorers in asia and africa at that time, but contain no elaborate medical reports. the british navy in muscat had medical staff to care for its employees and also the royal family. grant is probably referring to this in his statement: ‘the british residency started medical work in muscat in 1800, and maintained a medical staff throughout the century’.50 bosch also asserted that a medical officer was maintained at that time by the british residency as ‘port quarantine officer’.51 the proposition that the quarantine officer was maintained throughout 19th century cannot be substantiated since the regulations were not present till 1867. in addition, the british political agency had been shifted to zanzibar from 1843 until 1861, and it was represented in muscat by an illiterate jew during that period.25 thus, it is hard to assume that any organised biomedical practice was undertaken by british residency medical staff during the first half of the century. nevertheless, this was the exploratory era when such visits probably had an impact on the elite society, in particular, and prepared it for the “new medicine” to come. sent to conquer during the 19th century, western commercial interests in oman developed into political as well as military affairs. although the arabian gulf was never formally a part of the british empire, it is acknowledged that the gulf was indeed british.52 the british government of india was the only foreign government that could maintain a permanent mission in muscat throughout the second half of the 19th century.53 the re-establishment of the sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century 192 | squ medical journal, may 2011, volume 11, issue 2 british residency in muscat in 1861 was a driving force to provide other supporting services for the permanent troops, including medical facilities. in fact, this was the first time biomedical services were institutionalised in oman, and probably in the arabian peninsula. a hospital was maintained within the agency compound and was run by a surgeon major from the indian medical services. the sultan had donated a building that was suitable for the hospital and its dispensary.37 the doctor during this period assumed multiple roles. doctors not only treated their fellow soldiers, but they were also pioneers in reporting on local flowers and species, documenting socio-cultural practices and informing headquarters about political and military issues. the regular administration reports that were sent by the resident surgeon to the headquarters in india documented, among other things, the health of the population at that time. surgeon major mr. apothecary gaspar de rozario was appointed as the british political agent in 1866. rozario wrote an account of muscat, which included a two-page briefing on the prevailing diseases, mainly small pox, measles and whooping cough.54 he had also documented the malaria and cholera epidemics in the summer of 1865. rozario asserted that vaccination was started for the people of muscat after nine years of "haranguing and illustration". although this report was not dated, it could be assumed that it was written around 1875, i.e. 9 years after appointment of rozario in oman. surgeon major a. s. g. jayakar succeeded rozario in muscat and is probably better known to zoologists than to physicians as he identified three important omani species that now carry his name: tahr (hermitragus jayakari), fakhakh (agama jayakari), and the small boa (eryx jayakari).53 he seemed to have travelled extensively throughout oman during the 21 years that he spent in the country before his retirement in 1900. jayakar deserves the credit for the first comprehensive biomedical report on oman, entitled, medical topography of muscat.55 this 14-page account offered valuable information on the geology, climate, water supply, food, sanitation, streets and population of muscat. it also included a detailed description of the prevailing diseases and related health issues in the country. interestingly, jayakar noted the very uncommon prevalence of organic diseases of the heart and large blood vessels and the rare occurrence of kidney and bladder diseases, dysentery, rheumatism and brain diseases. on the other hand, malaria was the prevailing disease in the region, and cases of consumption (tuberculosis) were common. according to him, bronchitis, dyspepsia, haemorrhoids, ulcers, and eye and skin diseases were also common in the region. the 19th century witnessed a remarkable increase in the frequency of epidemics in the country. much of the burden of these epidemics could be attributed to poor sanitation, unavailability of clean water, and the ‘harsh’ climate of the country as described by many western travellers. nevertheless, the contribution of population movement to and from their new dominions in asia and africa, combined with increased use of the muscat port by military and trading ships, cannot be overlooked. following the first cholera epidemic in oman in 1821, a second outbreak took place in 1864, and a third in 1899. although jayakar reported that that “plague” had never been known to prevail in oman, a breakout of plague was indeed reported in mutrah, the twin city of muscat, in 1899–1900.56 marching troops, cruising steamers, ambitious explorers and locals moving to and from their new dominions in africa were advancing faster than controlling health measures in the country. as noticed above, despite the fact that many epidemics were related directly or indirectly to imperial activities in the region, there was neglect of the health of the general population in favour of a focus on health of the troops, western travellers and the elite. for example, 'maskat quarantine regulations' were issued in 1867 for british subjects and british-protected subjects who entered oman.56 this may not be surprising since “[t]he first priority of imperial medicine prior to the first world war was to keep soldiers and officials functioning in unhealthy environments”.57 however, this era paved the road for the next when missionaries came to a country which was suffering from diseases and epidemics both contributed to and neglected by their fellow countrymen. sent to heal toward the end of the 19th century, evangelical missionary activities were flourishing in arabia. oman was a strategic area to the missionary nasser hammad al-azri special contribution | 193 enterprise, just as it was for the foreign political and military powers. general f. t. haig of the british army suggested oman, bahrain, and the najd region in saudi arabia as profitable places for establishing permanent missionary stations.58 missionaries realised early on that it would be futile to start out with empty hands on the adventure of “healing souls”. healing bodies with biomedicine, tried already in some other areas such as china and africa with success, could pave the way toward “god” in arabia as well, or so it was thought. despite the fact that the muslim people of the region did not consent to any evangelisation, medical missionaries were still of particular importance as they were the key to the people and area. the arabian (american) mission started its work in oman in 1893. it was customary for nonmedical missionaries to practice medicine and dispense drugs to people in the region during their tours, just as earlier explorers did. samuel zwemer, for example, was known to do this, and he used it as a door-opener during his tours in arabia, including oman.59,60 in 1896, the first recorded exploratory visit by a medical missionary to oman was made by dr. worrall.61 although missionaries frequented the country with their ‘medicine chests’ during the 1890s, it was not until 1904 that a medical clinic was started in mutrah, the port area of muscat, and run by mrs. james cantine. female medical practitioners were of particular importance to the missionary enterprise in the region and they were awarded a central role in arabia. in fact, women’s medical services were among the most effective agents of cultural change in the region.62 sayyida salma, who converted to christianity, called particularly for female physicians, as ‘there is a great opening here for christian charity, that would bear fruit a hundredfold, without any great obstacles in the way’.33 it seemed that "oman and all arabia offer untold opportunities for the [missionary] medical profession".63 at the turn of the 19th century, the arab gulf region was sandwiched between the tight military grip of the british army on one side and the soft, “humanitarian” services of the american missionaries on the other. in contrast with the already existing british military hospital, missionary medical services were primarily public and sought to serve otherwise impenetrable parts of the country. medical missionaries, just as in other parts of the world, blended in with the people as no other “foreigners” did. they lived their life, ate their food and shared their joys and sorrows. their work included not only conquering the diseases of the poor, but also civilising the “heathen” with their western cultural values.64,65,66 as etherington has noted: “although missions and the official empire were quite different operations, they play related parts in a larger drama—the spread of modernisation, globalisation, and western cultural hegemony”.57 until the end of the 19th century, biomedical work was restricted mostly to the muscat area although missionaries also started exploratory visits to the batinah.67 their activities expanded in the 20th century to include the interior of oman, an area that had remained largely unreached by other foreigners. medical missions with two operating hospitals were the active force in omani biomedical practice until a national health care system was established in the 1970s. agenda for future research the history of the evolution of biomedicine in oman is intriguing and raises many questions that could form an agenda for future research on the topic. the nature of the interaction between state power, western powers in the region, biomedicine, culture and traditional healing practices in oman, and factors that affected such interactions, is a virgin area for investigation. missionary medicine and missionaries in oman and arab gulf is another almost untouched topic despite a wealth of primary sources. in addition, it would also be worth investigating social milieu changes in relation to health and healing practices, particularly following the establishment of missionary medical centres. such studies should address these issues and relate them to the then health and healing practices, as well as probing possible implications for the currrent health system. conclusion the introduction and evolution of biomedicine in oman, which began in the 19th century, is a fascinating topic. what started out as casual exploratory visits further crystallised into a sent to explore, conquer and heal history of the evolution of biomedicine in oman during the 19th century 194 | squ medical journal, may 2011, volume 11, issue 2 permanent british military hospital that served mainly military staff and the elite, but occasionally the poor as well. the last decade of the 19th century witnessed the growing interest of american missionaries in the country, who were particularly influential in opening doors for not only the evangelising enterprise in the community, but for foreign intrusion in general. the history of changes in biomedicine and health in oman is an interesting subject that needs more attention from local scholars and researchers. humanities, in general, are still a subject which is lacking, or thought to be auxiliary, in the medical scene of most developing countries. literature, history, philosophy, ethics and religion should be addressed in medical education not as a supplementary, but as a core subject. in addition, focused research and practice in these disciplines should be encouraged in order to explore and assess their contribution to current and future health and health care in oman. a c k n o w l e d g e m e n t s the author is grateful to prof. musbah tanira, department of pharmacology & clinical pharmacy, and dr. abdullah al-muniri, department of family medicine & public health of the college of medicine & health sciences at sultan qaboos university for their invaluable comments on earlier versions of this manuscript. references 1. alshishtawy mm. four decades of progress: evolution of the health system in oman. squ med j 2010; 10:12−22. 2. hill ag, muyeed az, al-lawati ja, eds. the mortality and health transitions in oman: patterns and processes. muscat: who regional office for the eastern mediterranean and unicef, oman, 2000. p. 11. 3. abri sm, west dj jr, spinelli rj. managing overutilization, quality of care, and sustainable health care outcomes in oman. health care manag 2006; 25:348−55. 4. al dhawi aa, west dj jr, spinelli rj, gompf ta. the challenge of sustaining health care in oman. health care manag 2007; 26:19−30. 5. al hinai n. folk medicine in oman through the eyes of traditional healers. essay, sultan qaboos university college of medicine. al khod: sultan qaboos university press, 1994. 6. al-kharusi l. the early history of modern medicine in oman. essay, sultan qaboos university college of medicine. al khod: sultan qaboos university press, 1995. 7. al-maini m. the history of medicine in relation to medical education in oman. essay, sultan qaboos university college of medicine. al khod: sultan qaboos university press, 1996. 8. foster gm. disease etiologies in non-western medical systems. am anthropol 1976; 78:773−82. 9. press i. problems in the definition and classification of medical systems. soc sci med 1980; 14:45−57. 10. baronov d. biomedicine: an ontological dissection. theor med bioeth 2008; 29:235–54. 11. gaines ad, davis-floyd r. biomedicine. in: ember cr, ember m, eds. encyclopedia of medical anthropology: health and illness in world cultures. new york: kluwer academic, 2000. vol. i, pp. 95−109. 12. gillett g. clinical medicine and the quest for certainty. soc sci med 2004; 58:727−38. 13. joy rjt, smith dc. on writing medical history. ann diagnos pathol 1997; 1:130−7. 14. malterud k. the art and science of clinical knowledge: evidence beyond measures and numbers. lancet 2001; 358:397−400. 15. saunders j. the practice of clinical medicine as an art and as a science. med humanities 2000; 26:18−22. 16. lynaugh je. common working ground. in: mortimer b, mcgann s, eds. new directions in the history of nursing: international perspectives. oxford: routledge, 2005. pp. 194−202. 17. mcclure lw. who needs history? acad med 1995; 70:461–2. 18. acuña le. don’t cry for us argentineans: two decades of teaching medical humanities. med humanities 2000; 26:66−70. 19. grant vj. making room for medical humanities. med humanities 2002; 28:45−8. 20. brandt am. from analysis to advocacy: crossing boundaries as a historian of health policy. in: huisman f, warner jh, eds. locating medical history: the stories and their meanings. baltimore: johns hopkins university press, 2006. pp. 460−84. 21. southgate b. history: what and why? london: taylor and francis e-library, 2003. 22. rosenberg ce. anticipated consequences: historians, history, and health policy. in: stevens ra, rosenberg ce, burns lr, eds. history and health policy in the united states: putting the past back in. new brunswick: rutgers university press, 2006. pp. 13−31. 23. berridge v. thinking in time: does health policy needs history as evidence? lancet 2010; 375:798−9. 24. coovadin h, jewkes r, barron p, sanders d, mcintyre d. the health and health system of south africa: historical roots of current public health challenges. lancet 2009; 374:817−34. 25. lorimer jg. gazetteer of the persian gulf, oman and central arabia. london: archive editions, 1986. nasser hammad al-azri special contribution | 195 26. niezen r. healing and conversion: medical evangelism in james bay cree society. ethnohist 1997; 44:463−91. 27. nkomazana f. livingstone’s ideas of christianity, commerce and civilization. botswana j afr stud 1998; 12:44−57. 28. manshardt c. what will succeed religious imperialism? j religion 1932; 12:526−43. 29. crozier a. practising colonial medicine: the colonial medical services in british east africa. london: i.b. tauris, 2007. 30. philips w. unknown oman. london: longmans, 1966. 31. the malaria expedition to west africa. science 1900; 11:36−37. 32. ruete e. memoirs of an arabian princess from zanzibar. new york: markus wiener publishing, 1989. 33. ghubash ro, lutah ms, tanira mo. a study on the dawn of modern health services in the united arab emirates. emirates med j 1998; 16:191−8. 34. ibn ruzaiq h. al-fat'h al-mubeen fi seerat a'ssadah albusaidyeen. muscat: ministry of national heritage and culture, 1983. 35. bollet aj. plagues and poxes: the impact of human history on epidemic disease. 2nd ed. new york: demos medical publishing, 2004. 36. hays jn. epidemics and pandemics: their impacts on human history. california: abc-clio, 2005. 37. zwemer pj. quarterly field report of the arabian mission: july–september, 1897. in: neglected arabia: the arabian mission field reports quarterly letters. london: archive editions, 1988. pp. 8−10. 38. young tk. health care and cultural change: the indian experience in the central subarctic. toronto: university of toronto press, 1988. 39. al-adawi sh, martin rg, al-salmi a, ghassani h. zar: group distress and healing. ment health relig cult 2001; 4:47−61. 40. khalifa ab. african influence on culture and music in dubai. int soc sci 2006; 58:227−35. 41. natvig r. oromos, slaves and the zar spirits: a contribution to the history of the zar cult. int j african hist stud 1987; 20:669−89. 42. thomas b. alarms and excursions in arabia. 1st ed. indianapolis: the bobbs-merrill company, 1931. 43. basalla g. the spread of western science. science 1967; 156:611−22. 44. al-qasmi sm. omani-french relations 1715-1900. exeter: forest row; 1996. 45. maurizi v. history of seyd said, sultan of muscat. 2nd ed. new york: the oleander press, 1984. 46. ruschenberger wsw. narrative of a voyage round the world, during the years 1835, 36, and 37: including a narrative of an embassy to the sultan of muscat and the king of siam, vol.1. london: r. bentley, 1838. 47. buist g. the curia muria islands. proc royal geog soc london 1859−1860; 4:50−8. 48. carter hj. the ruins of el balad. j royal geol soc london 1846; 16:187−99. 49. thomas b. among some unknown tribes of south arabia. j royal anthropol inst gb & irl 1929; 59:97−111. 50. grant cs, al-kindy n. surgery in oman. arch surg. 2005; 140:21−5. 51. bosch d, bosch e. the doctor and the teacher: oman 1955-1970, memoirs of dr. donald and eloise bosch. muscat: apex publishing, 2000. 52. onley j. the arabian frontier of the british raj: merchants, rulers, and the british in the nineteenth century gulf. oxford: oxford university press, 2007. 53. bailey r. records of oman 1867-1947: why, how and wherefore? asian aff 1990; 2:131−43. 54. rozario g. an account of muscat. in: bailey r, ed. records of oman 1867–1947. london: archive editions. p. 233−43. 55. jayakar asg. medical topography of muscat. in: the persian gulf administration reports 1873-1947. london: archive editions; 1986. p. 96–109. 56. sanitary matters in maskat, 1899-1904. in: the persian gulf precis. london: archive editions, 1986. vol. iii, pp. 142−3. 57. etherington n, ed. missions and empire. oxford: oxford university press, 2005. 58. al-sayegh f. american missionaries in the uae region in the twentieth century. mid east stud 1996; 32:120−39. 59. bosch dt. the american mission hospitals in oman: 1893-1974, 81 years. muscat, oman, 2002. 60. wilson jc. the apostle to islam: the legacy of samuel zwemer. int j frontier miss 1996; 13:163−8. 61. worrall hrl. quarterly field report of the arabian mission: medical report oct-dec 1896. in: neglected arabia: the arabian mission field reports quarterly letters. london: archive editions, 1988. pp. 5−6. 62. al-sayegh f. american women missionaries in the gulf: agents for cultural change. islam christ musl rels 1998; 9:339−56. 63. van peuresm gd. village evangelization in oman. muslim wld 1919; 10:68−71. 64. aguwa jc. mission, colonialism, and the supplanting of african religions and medical practices. in: korieh cj, njoku rc, eds. missions, states, and european expansion in africa. new york: routledge 2007, pp. 127−45. 65. chahrour m. ‘a civilizing mission’? austrian medicine and the reform of medical structures in the ottoman empire, 1838–1850. stud hist philos sci 2007; 38c:687−705. 66. twells a. the civilizing mission and the english middle class, 1792−1850: the ‘heathen’ at home and overseas. hampshire: palgrave-macmillan, 2009. p. 41a. 67. neglected arabia: the arabian mission field reports, quarterly letters. london: archive editions, 1988. vol. i. departments of 1medicine and 3surgery, sultan qaboos university hospital, muscat, oman; 2department of radiation oncology, shifa cancer center, islamabad, pakistan; 4department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: bhagia1@yahoo.com نتائج مرضى سرطان الثدي الثالثي السليب غري املنتشر يف عمان جتربة مركز واحد �صيام كومار، حممد فروخ، خالد �لبيماين، عادل �لعجمي، �إكر�م برين، من�صور �ملنذري abstract: objectives: triple-negative breast cancer (tnbc) is one of the most aggressive and heterogeneous variants of breast cancer. however, little is known regarding the prevalence and outcome of this entity in the middle east. this study aimed to evaluate the outcomes of tnbc patients at a university hospital in oman. methods: this retrospective study took place at the sultan qaboos university hospital, muscat, oman, in may 2017. all patients diagnosed with non-metastatic tnbc between december 2000 and december 2015 were included. the patients’ electronic medical records were reviewed to identify their clinical and pathological characteristics as well as survival outcomes. results: a total of 79 patients were diagnosed with non-metastatic tnbc during the study period. the median age was 46 years, with approximately one-third of patients (31.6%) under 40 years of age. almost half had an advanced tumour size (49.4%) or node-positive disease (48.1%) at presentation and only 16.6% demonstrated a complete pathological response (pcr) to neoadjuvant chemotherapy. the median survival for all patients was not reached within the study period; however, the median overall survival for stage iii patients was 44.6 months. the five-year overall survival for all patients was 64%, increasing to 100% and 72% for patients with stage i and ii, respectively, and dropping to 47% for those with stage iii disease. conclusion: the findings of this study indicate that the majority of women with tnbc in oman present at an advanced stage; moreover, such women have low rates of pcr to neoadjuvant chemotherapy and poor five-year survival. keywords: breast cancer; triple-negative breast cancer; neoadjuvant therapy; survival; patient outcome assessment; oman. امللخ�ص: الهدف: �رصطان �لثدي �لثالثي �ل�صلبي هو �أحد �أكرث �أنو�ع �رصطان �لثدي عدو�نية وعدم جتان�صية. ومع ذلك ، ال ُيعرف �لكثري عن مدى �نت�صار ونتائج هذ� �ل�رصطان يف �ل�رصق �الأو�صط. تهدف هذه �لدر��صة �إىل تقييم نتائج عالج مر�صى �رصطان �لثدي �لثالثي �ل�صلبي يف م�صت�صفى جامعي يف عمان. الطريقة: �أجريت هذه �لدر��صة �ملرجتعة يف م�صت�صفى جامعة �ل�صلطان قابو�س، م�صقط، عمان، يف مايو 2017. مت ح�رص جميع �ملر�صى �لذين مت ت�صخي�صهم من �رصطان �لثدي �لثالثي �ل�صلبي غري �ملنت�رص بني دي�صمرب 2000 ودي�صمرب 2015. متت مر�جعة �ل�صجالت �لطبية �الإلكرتونية للمر�صى لتحديد خ�صائ�صهم �ل�رصيرية و�ملر�صية وكذلك نتائج �لبقاء على قيد �حلياة. النتائج: خالل فرتة ما وكان �صنة، �ملر�صى 46 عمر متو�صط كان �ملنت�رص. غري �ل�صلبي �لثالثي �لثدي ب�رصطان مري�صا جمموعه 79 ما ت�صخي�س مت �لدر��صة يقرب من ثلث �ملر�صى )%31.6( حتت �صن 40 �صنة. كان �ملر�س متقدم وكبري �حلجم عند ما يقرب من ن�صف �ملر�س )%49.4( ووجدت �إ�صابة �لعقد�لليمفاوية يف )%48.1(. كذلك �أظهرت �لنتائج �أن فقط %16.6 ح�صلو� على ��صتجابة جمهرية كاملة للعالج �لكيميائي. خالل �حلياة قيد على للبقاء �لعام �ملتو�صط كان ذلك، ومع �ملر�صى؛ جلميع �حلياة قيد على �لبقاء متو�صط �إىل �لو�صول يتم مل �لدر��صة فرتة �يل ز�دت لكنها و 64% �ملر�صى جلميع �صنو�ت خم�س ملدة �حلياة قيد على �لبقاء ن�صبة كانت �صهر�و 44.6 هو �لثالثة �ملرحلة ملر�صى %100 للمر�صى من �ملرحلة �الأوىل و %72 ملر�صى �ملرحلة�لثانية، وتر�جعت ن�صب متو�صط �لبقاء�إىل %47 بالن�صبة الأولئك �لذين يعانون من مر�س �ملرحلة �لثالثة. اخلال�صة: ت�صري نتائج هذه �لدر��صة �إىل �أن غالبية �ملر�صى �مل�صابني ب�رصطان �لثدي �لثالثي �ل�صلبي يف عمان يتم ت�صيخ�صهم يف مرحلة متقدمة؛ عالوة على ذلك، فاإن هوؤالء �لن�صاء لديهم معدالت منخف�صةلالإ�صتجابة �ملجهرية �لكاملة للعالج �لكيميائي و ن�صب منخف�صة للبقاء على قيد �حلياة ملدة خم�س �صنو�ت. الكلمات املفتاحية: �رصطان �لثدي؛ �رصطان �لثدي �لثالثي �ل�صلبي؛ �لعالج �لكيميائي؛ ن�صب �لبقاء؛ تقييم نتائج �ملري�س؛ عمان. outcomes of women with non-metastatic triple-negative breast cancer in oman a single-centre experience *shiyam kumar,1 muhammad furrukh,2 khalid al-baimani,1 adil al-ajmi,3 ikram a. burney,1 mansour s. al-moundhri4 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e209–216, epub. 5 nov 19 submitted 26 nov 18 revision req. 23 jan 19; revision recd. 11 feb 19 accepted 22 mar 19 advances in knowledge to the best of the authors’ knowledge, this study is the first in oman to report the clinical presentation, pathological features and outcomes of women diagnosed with triple-negative breast cancer (tnbc). these findings may serve as a reference point for future research on this subject. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.006 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ outcomes of women with non-metastatic triple-negative breast cancer in oman a single-centre experience e210 | squ medical journal, august 2019, volume 19, issue 3 breast cancer is a heterogeneous disease, with variable outcomes based on individual clinical, pathological, molecular and ethnic features.1–4 distinct molecular subtypes of breast cancer and differences in progenitor cells also play a role in disease presentation and prognosis.5 triple-negative breast cancer (tnbc) is a form of breast cancer charact erised by a lack of expression of oestrogen, progesterone and human epidermal growth factor receptor 2 (her2)/ neu receptors, with the diagnosis confirmed by immuno histochemistry and/or other tests such as fluorescence in situ hybridisation.2,6–9 approximately 10–20% of women with breast cancer in western countries have tnbc.1,6 this variant is considered one of the most aggressive forms of breast cancer, usually presenting at an early age and high grade. it has distinct pathological and molecular markers and variable outcomes as well as an ethnic predilection.2,7–10 in general, tnbc cases have poorer outcomes in comparison to other subtypes of breast cancer, despite advances in breast cancer treatment.2,6–9 in oman, government-funded healthcare is prov ided free of charge to all nationals across the country via a well-established network of primary and secondary health services which are linked with tertiary care hospitals.11 much like the rest of the world, breast cancer is the most common type of cancer among females in oman; while patients usually present at a younger age and more advanced stage, survival rates are similar to those reported in developed countries.4,12 although there is extensive literature available regarding the outcomes of tnbc cases in western countries, few studies have been conducted on this topic in the middle east. therefore, this study aimed to describe the outcomes of women diagnosed with tnbc and treated at a university hospital in oman over a 15-year period. methods this retrospective non-interventional study included all tnbc patients diagnosed and treated at the medical oncology unit of sultan qaboos university hospital (squh), muscat, oman, between december 2000 and december 2015. electronic patient records were reviewed from 2006 onwards, as prior to that the hospital utilised a paper-based record system. patients who were diagnosed earlier than this period and were still alive and being followed-up by the medical oncology unit, were also included in the analysis. a database was compiled of the patients’ clinical and pathological characteristics as well as survival outcomes—including age; gender; clinical stage acc ording to the american joint committee on cancer tumor-node-metastasis (tnm) staging system; final histological subtype, tumour size and grade; ki67 score; lymph node status; number of lymph nodes retrieved; oestrogen, progesterone and her2/neu receptor status; surgical and systemic treatment offered; and survival status (i.e. dead or alive) at the time of data collection in may 2017.13 all information was retrieved from medical charts as well as radiological and pathological reports. all tissue samples (including those of patients who were diagnosed externally) were reviewed by a pathology team for verification purposes. data analysis was performed using the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). kaplan-meier curves were used to calculate both relapse-free survival (rfs), measured from diagnosis to the date of documented relapse, and overall survival (os), measured from the date of diagnosis to the date of death or last follow-up. a log-rank test was used for the univariate analysis, while the cox regression method was applied for the multivariate analysis. a p value of <0.05 was considered statistically significant. this study received ethical approval from the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos univ ersity (mrec # 1047). results a total of 79 female patients were diagnosed with nonmetastatic tnbc during the study period. the median age was 46 years (range: 19–74 years old), with 31.6% under 40 years old at the time of diagnosis. in total, 73 patients (92.4%) were omani nationals, while the remaining six were from egypt (2.5%), pakistan (2.5%), south africa (1.3%) or india (1.3%). the majority of patients were premenopausal (65.8%), had one or more comorbidities (53.2%) and an above-normal body mass index (65.8%). moreover, nearly half had an advanced tumour size of >5 cm, invading the skin or chest wall (49.4%) or node-positive disease (48.1%) at presentation [table 1]. application to patient care this study will help clinicians in oman to evaluate responses to treatment and survival rates according to disease stage among tnbc patients. local data may also help health decision-makers to form future policies on patient awareness and tnbc prevention in oman. shiyam kumar, muhammad furrukh, khalid al-baimani, adil al-ajmi, ikram a. burney and mansour s. al-moundhri clinical and basic research | e211 the median pathological tumour size was 4 cm (range: 0–13 cm). the median number of recovered lymph nodes was three (range: 1–14), with a median of one involved lymph node (range: 0–33). almost all of the patients had infiltrative ductal carcinomas (97.5%). the vast majority of tumours were poorly differentiated (i.e. pathological grade of iii; 77.2%) and had a ki67 proliferation index of >20% (74.7%). in total, 35 women (44.3%) had a mastectomy and 37 (46.8%) had breast conservation surgeries. seven women (8.9%) did not undergo surgery, either due to patient refusal (3.8%), disease progression despite neoadjuvant chemotherapy (nac; 3.8%) or for an unknown reason (1.3%) [table 2]. the surgical margins were negative in 39 patients (49.4%), with margins of <1 mm in four cases (5.1%), 1–5 mm in eight cases (10.1%), 5–10 mm in four cases (5.1%) and >10 mm in 23 cases (19.1%). no information regarding surgical margins was available for the remaining 40 patients (50.6%). the majority of patients (92.4%) received some type of chemotherapy, with six women (7.6%) refusing treatment. overall, nac therapy was administered to 36 patients (45.6%), while 37 (46.8%) received adjuvant chemotherapy. a total of 59 patients (74.7%) were treated with anthracyclines followed by taxanes, while five (6.3%) were also treated with platinumbased combination chemotherapy and of those only one patient achieved complete pathological response (pcr). paclitaxel was administered weekly or thrice weekly, while the two most fit patients were treated with a combination of doxorubicin, docetaxel and cyclophosphamide (tac). dose dense doxorubicin and cyclophosphamide (ac) followed by dose dense paclitaxel is not practiced currently at squh. the median number of chemotherapy cycles administered was eight (range: 2–8 and 4–8 cycles for patients receiving adjuvant and nac regimens, respectively). the main side-effects of first-line treat ment were weakness and fatigue (7.6%), febrile neutro paenia (6.3%) and non-neutropaenic fever (5.1%). of the 36 patients who were treated with nac, most (69.4%) received a standard regimen of four cycles of ac, followed by four cycles of docetaxel. only six patients (16.6%) demonstrated pcr to treatment for both primary and nodal disease, while nine patients (11.4%) demonstrated a complete response in their recovered lymph nodes which signif icantly affected the relapse-free survival (rfs) on uni variate log rank analysis (p = 0.029). there were 35 cases (44.3%) of disease relapse. of the patients who relapsed, 20 (57.1%) underwent another biopsy, of which three were diagnosed with hormone-positive disease and were treated with hormonal therapy. overall, 45.7% of patients who relapsed were treated with chemotherapy alone, 5.7% underwent radiotherapy alone and 5.7% were treated with surgery alone, while table 1: clinical characteristics of women with nonmetastatic triple-negative breast cancer at the sultan qaboos university hospital, muscat, oman (n = 79) characteristic n (%) age in years <40 25 (31.6) 40–60 46 (58.2) >60 8 (10.1) median (range) 46 (19–74) menstrual status premenopausal 52 (65.8) menopausal 27 (34.2) family history of breast cancer yes 5 (6.3) no 66 (83.5) unknown 8 (10.1) affected side left 38 (48.1) right 41 (51.9) clinical tumour size tx 1 (1.3) t1 6 (7.6) t2 33 (41.8) t3 23 (29.1) t4 15 (19) inflammatory breast cancer 1 (1.3) clinical node status n0 41 (51.9) n1 26 (32.9) n2 11 (13.9) n3 1 (1.3) clinical stage at presentation i 5 (6.3) ii 41 (51.9) iii 33 (41.8) tx = tumour size could not be ascertained; t1 = tumour of ≤2 cm; t2 = tumour of 2.1–5 cm; t3 = tumour of >5 cm; t4 = tumour of any size invading the chest wall, breast skin (ulceration or macroscopic nodules) or inflammatory carcinoma; n0 = absence of nodal involvement; n1 = metastasis to the ipsilateral axillary lymph nodes that are mobile; n2 = metastasis to the ipsilateral axillary lymph nodes that are fixed; n3 = metastasis to the ipsilateral infra-clavicular lymph nodes with or without axillary lymph nodes. outcomes of women with non-metastatic triple-negative breast cancer in oman a single-centre experience e212 | squ medical journal, august 2019, volume 19, issue 3 the remaining 42.8% of patients were treated with combined treatment modalities. out of 29 patients, 13 (44.8%) received a salvage regimen of gemcitabine and carboplatin for a median of one cycle (range: 0–9 cycles). growth factors were prescribed in 38 cases (48.1%) as a form of primary or secondary prophylaxis. none of the patients dev eloped treatment-related cardiomyopathy or secondary cancers during the follow-up period. following chemo therapy and surgery, radiation was administered to 59 patients (74.7%). at the time of their first local relapse, radiotherapy was incorporated as part of treatment for nine patients (25.7%). radiotherapy was administered to five other patients at different intervals as a sub sequent line of treatment for recurrent progressive disease. the median follow-up period was 43 months (range: 0–205 months). by the end of the study period, 44 patients (55.7%) were in remission, 25 (31.6%) had died, four (5.1%) were alive and undergoing active treatment, one (1.3%) was alive and on best supportive care and five (6.3%) were lost to follow-up. overall, the vast majority of deaths (96%) were due to breast cancer, with only one death (1.3%) occurring due to other causes. the median rfs was 18 months (range: 5–77 months) [figure 1], with no recurrence noted among stage i patients, while median rfs for stage ii and iii disease was 27 and 15 months, respectively. the median os was not reached during the study period [figure 2a]. the median os for stage iii patients was 44.6 months. overall, the five-year os rate was 64%; according to disease stage, five-year survival rates were 100%, 72% and 47% for patients with stage i, ii and iii disease, respectively [figure 2b]. according to a univariate log-rank analysis, a number of factors were found to significantly affect rfs, including age, a positive family history of breast cancer, affected side (i.e. right versus left breast), clinical figure 1: kaplan-meier survival curve showing relapsefree survival among women with non-metastatic triplenegative breast cancer at the sultan qaboos university hospital, muscat, oman (n = 79). table 2: surgical and pathological characteristics of women with non-metastatic triple-negative breast cancer at the sultan qaboos university hospital, muscat, oman (n = 79) characteristic n (%) type of surgery modified radical mastectomy 31 (39.2) bcs and alnd 23 (29.1) bcs and sln 14 (17.7) skin-sparing mastectomy and alnd 3 (3.8) simple mastectomy and sln 1 (1.3) none 7 (8.9) pathological type infiltrating ductal carcinoma 77 (97.5) infiltrating lobular carcinoma 1 (1.3) micropapillary carcinoma 1 (1.3) pathological tumour size t0 8 (10.1) t1 17 (21.5) t2 31 (39.2) t3 12 (15.2) t4 5 (6.3) unknown 6 (7.6) pathological node status n0 37 (46.8) nmic 1 (1.3) n1 17 (21.5) n2 10 (12.7) n3 7 (8.9) unknown 7 (8.9) pathological stage pcr to chemotherapy 6 (7.6) i 9 (11.4) ii 37 (46.8) iii 20 (25.3) unknown 7 (8.9) pathological grade i 2 (2.5) ii 12 (15.2) iii 61 (77.2) unknown 4 (5.1) lymphovascular invasion no 38 (48.1) yes 24 (30.4) unknown 17 (21.5) ki67 score <20% 2 (2.5) >20% 59 (74.7) unknown 18 (22.8) bcs = breast conservation surgery; alnd = axillary lymph node dissection; sln = sen tinel lymph node biopsy; t0 = main tumour could not be found; t1 = tumour of ≤2 cm; t2 = tumour of 2.1–5 cm; t3 = tumour of >5 cm; t4 = tumour of any size with invasion or adherence to pectoralis muscle, skin ulceration, skin oedema and inflamm atory carcinoma; n0 = absence of nodal involvement; nmic = node micrometastases; n1 = metastasis to 1–3 ipsilateral axillary lymph nodes; n2= metastasis to 4 –9 ipsi lateral axillary lymph nodes; n3= metastasis to ≥10 axillary lymph nodes, infraclav icular lymph nodes; pcr = complete pathological response. shiyam kumar, muhammad furrukh, khalid al-baimani, adil al-ajmi, ikram a. burney and mansour s. al-moundhri clinical and basic research | e213 tumour size, pathological tumour size, pathological node status, ki67 score, number of first-line chemo therapy cycles and response to nac (p <0.05 each). furthermore, os was significantly affected by type of surgery, pathological tumour size and lymphovascular invasion (p <0.05 each) [table 3]. however, during a multivariate cox regression analysis, none of the aforementioned factors were found to be significant in regards to rfs; only pathological tumour size was found to significantly affect os. discussion in oman, tnbc accounts for 18.8% of all female breast cancers.4 however, to the best of the authors’ knowledge, no previous studies have reported the out comes of clinical or pathological features of tnbc cases. in the current study, the median age at presentation was 46 years, which is similar to that reported by other researchers in oman as well as other parts of the world.1,3,14–16 however, the percentage of patients figure 2: kaplan-meier survival curves showing (a) overall survival (os) and (b) five-year os according to disease stage among women with non-metastatic triple-negative breast cancer at the sultan qaboos university hospital, muscat, oman (n = 79). table 3: univariate analysis of factors affecting median relapse-free and overall survival among women with non-meta static triple-negative breast cancer at the sultan qaboos university hospital, muscat, oman (n = 79) variable rfs os median (95% ci) p value median (95% ci)* p value age† 3.7 (10.6–25.3) <0.001 family history of breast cancer 16 (12.6–19.3) 0.043 affected side 30 (22.8–37.1) 0.016 clinical tumour size 27 (18.4–35.5) <0.001 clinical lymph node status 18 (10.6–25.3) 0.174 clinical stage at diagnosis 27 (17.4–36.5) 0.167 type of surgery 11 (6.4–15.5) 0.084 20 (7.2–32.7) <0.001 pathological tumour size 34 (19.5–48.4) <0.001 61 (35–86.9) 0.002 surgical margins 32 (13.9–50) 0.463 pathological node status 18 (12.3–23.6) 0.038 lymphovascular invasion 15 (0–33.9) 0.515 52 (25.4–78.5) 0.041 ki67 score† 17 (10.7–23.2) <0.001 chemotherapy regimen 17 (7.9–26) 0.781 number of chemotherapy cycles 15 (12.4–17.5) <0.001 response to nac 17 (13.7–20.2) <0.001 adjuvant radiotherapy 26 (12.7–39.2) 0.133 rfs = relapse-free survival; os = overall survival; ci = confidence interval; nac = neoadjuvant chemotherapy. *95% ci values for many variables were not available due to a lack of median events. †continuous variable. outcomes of women with non-metastatic triple-negative breast cancer in oman a single-centre experience e214 | squ medical journal, august 2019, volume 19, issue 3 in oman with stage i disease at presentation (6.3%) was considerably lower than reports from the rest of the world, even in comparison to the low percentage of african american women presenting with stage i disease in the usa.10,17 this may be a regional trend as only 3.9% and 10.8% of women from india and pakistan, respectively, have been reported to have stage i disease at presentation.3,18 worldwide, tumour size and lymph node status remain significant prognostic factors in tnbc cases, despite the availability of numerous molecular markers, and are an integral part of the american joint committee on cancer tnm staging system.13 clinically, almost half of the patients in the current cohort presented with an advanced tumour size (t3 or t4), nodepositive disease and grade iii disease. bonsang-kitzis et al. reported similar results in france.14 furthermore, the current study found a significant correlation between tumour size and positive lymph node status, with both factors prognostic for rfs and os. nevertheless, although it has been suggested that tumour size may predict lymph node involvement, this may not necessarily be the case; in contrast to hormone-positive breast cancer, the proliferation rate of tnbc cells is high and there is a high probability of lymph node involvement, independent of tumour size.19 foulkes et al. found no correlation between tumour size and positive lymph node status among carriers of the breast cancer (brca) 1 gene, although there was a highly significant correlation between these variables among brca2 carriers and both brca1 and brca2 non-carriers.20 overall, pcr to treatment (i.e. the absence of residual disease in the primary site as well in the recovered lymph nodes) is an important endpoint when determining nac treatment efficacy for advanced stage non-metastatic breast cancer; moreover, this variable has been associated with improved diseasefree survival (dfs) and os.14 in the present study, the post-nac pcr rate was significantly lower in comp arison to those reported from western countries, despite the use of similar chemotherapy agents (i.e. anthracyclines and taxanes).14,21–23 this may be due to the fact that most patients in the current study presented at an advanced stage; in comparison to a report from france, 93.7% versus 26% of patients presented at grades i or ii.14 moreover, 14.9% of patients from the usa had t3 tumours at presentation, while 29.1% and 19% of patients had t3 and t4 tumours, respectively, before starting nac.21 other factors contributing to this difference in findings could be the small sample size of the present cohort or biological differences in disease subtype.24 in the current study, clinical and pathological tumour size and pathological lymph node status significantly affected rfs for all patients; however, for patients who were treated with nac, only pathological lymph node status was associated significantly with rfs (p = 0.029). this finding contradicts those previously reported by bonsang-kitzis et al. in which post-nac residual disease in the primary site as well as the axillary lymph nodes was associated with poor dfs and post-nac pcr in primary disease was associated with improved os.14 generally, anthracyclines and taxanes (either in sequence or combination) in conventional or dosedense fashion are considered the standard of care internationally for breast cancer patients in either an adjuvant or neoadjuvant setting.22,25 chemotherapy alone remains the proven option for tnbc patients as hormonal agents or anti-her2-directed therapy cannot be administered.26 the majority of patients in the present study were treated with four cycles of ac, followed by four cycles of docetaxel. other prescribed regimens included paclitaxel (on a weekly as well as thrice weekly basis), carboplatin along with docetaxel after ac and tac. however, none of the patients were treated on a dose-dense schedule. while the use of platinum compounds has resulted in significantly improved pcr rates, especially among tnbc patients harbouring brca1 mutations in a neoadjuvant setting, this treatment is not yet routinely used.6,26 only five out of 36 patients in the present study received carboplatin in neoadjuvant setting; of these, only one (13.9%) achieved pcr. in light of lower response rates to conventional chemotherapeutic agents, there is increasing interest in newer treatment modalities. poly (adenosine diphos phate-ribose) polymerase inhibitors are an option for brca mutation-associated cancers, including tnbc.26 recently, a phase iii trial showed improved efficacy among patients with brca germline-mutant metastatic breast cancer.27 a phase ii trial of metastatic tnbc patients found that pembrolizumab as a single agent had an overall response rate of only 5%; in contrast, immune-modulating agents such as checkpoint inhibitors have shown significantly better results in combination with chemotherapy.26,28 another phase ii trial investigating pembrolizumab combined with anthracyclines and taxanes in a neoadjuvant setting showed remarkable pcr rates of up to 71.4% in patients with tnbc.29 generally, os rates are poorer among tnbc patients in comparison to those with other breast cancer subtypes.1,7,9,21,25,26 in the usa, the five-year os rate is 64–80% among patients with tnbc; this is higher shiyam kumar, muhammad furrukh, khalid al-baimani, adil al-ajmi, ikram a. burney and mansour s. al-moundhri clinical and basic research | e215 than that reported in the current cohort (63%).1,21,30 surprisingly, higher rfs and os rates have been reported among patients with tnbc from india and pakistan as well.3,18 despite access to standard treatment modalities, one possible reason for the lower survival rate in the current study may be ethnic differences which can affect breast cancer-related outcomes.1,17 stage by stage, the five-year os rate for the present cohort was better in comparison to that of african american women, but worse than that of caucasian and south asian women.1,3,17,18 various molecular subtypes of tnbc (i.e. basal-like [bl]1, bl2, mesenchymal and luminal androgen receptor subtypes) have also shown different responses to treatment and associated outcomes.6,7,9,26 as such, it is possible that patients in oman have a divergent molecular subtype of tnbc resulting in more aggressive disease behaviour and poor survival. while it is difficult to generalise the results of this cohort to the entire country, such trends have been reported previously.4,12 the retrospective nature of the study, the small sample size and that the analysis was spread over a long period of time are the main limitations of this study. despite these limitations, this study provides valid data regarding presentation stage, treatment offered and outcome of omani patients and also discuss the possibilities of poorer associated outcomes. this study also can serve as a scaffolding for future studies in tnbc which should also assess the molecular signatures of different subtypes of breast cancer in arab women and the differences in outcome. conclusion the current study found that women with tnbc in oman presented at a younger age in comparison to western countries. in addition, almost half of the patients presented with large tumours of high grades as well as early lymph node metastasis. moreover, pcr after completion of nac was rare and the os rate was poor. this is likely due to the fact that patients presented at a more advanced stage. in addition, ethnic and biological differences in terms of molecular tnbc subtypes may also play a role. further molecular studies are recommended to confirm this hypothesis. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bauer kr, brown m, cress rd, parise ca, caggiano v. descr iptive analysis of estrogen receptor (er)-negative, progesterone receptor (pr)-negative, and her2-negative invasive breast cancer, the so-called triple-negative phenotype: a populationbased study from the california cancer registry. cancer 2007; 109:1721–8. https://doi.org/10.1002/cncr.22618. 2. brewster am, chavez-macgregor m, brown p. epidemiology, biology, and treatment of triple-negative breast cancer in women of african ancestry. lancet oncol 2014; 15:e625–34. https://doi.org/10.1016/s1470-2045(14)70364-x. 3. gogia a, raina v, deo sv, shukla nk, mohanti bk. triplenegative breast cancer: an institutional analysis. indian j cancer 2014; 51:163–6. https://doi.org/10.4103/0019-509x.138275. 4. kumar s, burney ia, al-ajmi a, al-moundhri ms. changing trends of breast cancer survival in sultanate of oman. j oncol 2011; 2011:316243. https://doi.org/10.1155/2011/316243. 5. prat a, perou cm. mammary development meets cancer genomics. nat med 2009; 15:842–4. https://doi.org/10.1038/ nm0809-842. 6. carey l, winer e, viale g, cameron d, gianni l. triplenegative breast cancer: disease entity or title of convenience? nat rev clin oncol 2010; 7:683–92. https://doi.org/10.1038/ nrclinonc.2010.154. 7. kandil d, khan a. triple negative breast carcinoma: the good, the bad and the ugly. diagn histopathol (oxf ) 2012; 18:210–16. https://doi.org/10.1016/j.mpdhp.2012.02.001. 8. carey la. directed therapy of subtypes of triple-negative breast cancer. oncologist 2011; 16:71–8. https://doi.org/10.1634/the oncologist.2011-s1-71. 9. foulkes wd, smith ie, reis-filho js. triple-negative breast cancer. n engl j med 2010; 363:1938–48. https://doi.org/10.1 056/nejmra1001389. 10. trivers kf, lund mj, porter pl, liff jm, flagg ew, coates rj, et al. the epidemiology of triple-negative breast cancer, including race. cancer causes control 2009; 20:1071–82. https://doi. org/10.1007/s10552-009-9331-1. 11. world health organization regional health systems observatory. health system profile: oman. from: http:// apps.who.int/medicinedocs/documents/s17304e/s17304e.pdf accessed: feb 2019. 12. al-moundhri m, al-bahrani b, pervez i, ganguly ss, nirmala v, al-madhani a, et al. the outcome of treatment of breast cancer in a developing country--oman. breast 2004; 13:139–45. https://doi.org/10.1016/j.breast.2003.10.001. 13. american joint commitee on cancer. what is cancer staging? from: www.cancerstaging.org/references-tools/pages/what-is cancer-staging.aspx accessed: feb 2019. 14. bonsang-kitzis h, chaltier l, belin l, savignoni a, rouzier r, sablin mp, et al. beyond axillary lymph node metastasis, bmi and menopausal status are prognostic determinants for triplenegative breast cancer treated by neoadjuvant chemotherapy. plos one 2015; 10:e0144359. https://doi.org/10.1371/journal. pone.0144359. 15. mehdi i, monem ea, al bahrani bj, al kharusi s, nada am, al lawati j, et al. age at diagnosis of female breast cancer in oman: issues and implications. south asian j cancer 2014; 3:101–6. https://doi.org/10.4103/2278-330x.130442. 16. rahman m, ahsan a, begum f, rahman k. epidemiology, risk factors and tumor profiles of breast cancer in bangladeshi underprivileged women. gulf j oncolog 2015; 1:34–42. 17. field ts, buist ds, doubeni c, enger s, fouayzi h, hart g, et al. disparities and survival among breast cancer patients. j natl cancer inst monogr 2005:88–95. https://doi.org/10.1093/ jncimonographs/lgi044. https://doi.org/10.1002/cncr.22618 https://doi.org/10.1016/s1470-2045%2814%2970364-x https://doi.org/10.4103/0019-509x.138275 https://doi.org/10.1155/2011/316243 https://doi.org/10.1038/nm0809-842 https://doi.org/10.1038/nm0809-842 https://doi.org/10.1038/nrclinonc.2010.154 https://doi.org/10.1038/nrclinonc.2010.154 https://doi.org/10.1016/j.mpdhp.2012.02.001 https://doi.org/10.1634/theoncologist.2011-s1-71 https://doi.org/10.1634/theoncologist.2011-s1-71 https://doi.org/10.1056/nejmra1001389 https://doi.org/10.1056/nejmra1001389 https://doi.org/10.1007/s10552-009-9331-1 https://doi.org/10.1007/s10552-009-9331-1 https://doi.org/10.1016/j.breast.2003.10.001 https://doi.org/10.1371/journal.pone.0144359 https://doi.org/10.1371/journal.pone.0144359 https://doi.org/10.4103/2278-330x.130442 https://doi.org/10.1093/jncimonographs/lgi044 https://doi.org/10.1093/jncimonographs/lgi044 outcomes of women with non-metastatic triple-negative breast cancer in oman a single-centre experience e216 | squ medical journal, august 2019, volume 19, issue 3 18. bhatti ab, khan ai, siddiqui n, muzaffar n, syed aa, shah ma, et al. outcomes of triple-negative versus non-triple-negative breast cancers managed with breast-conserving therapy. asian pac j cancer prev 2014; 15:2577–81. https://doi.org/10.7314/ apjcp.2014.15.6.2577. 19. foulkes wd, reis-filho js, narod sa. tumor size and survival in breast cancer--a reappraisal. nat rev clin oncol 2010; 7:348–53. https://doi.org/10.1038/nrclinonc.2010.39. 20. foulkes wd, metcalfe k, hanna w, lynch ht, ghadirian p, tung n, et al. disruption of the expected positive correlation between breast tumor size and lymph node status in brca1related breast carcinoma. cancer 2003; 98:1569–77. https://doi. org/10.1002/cncr.11688. 21. liedtke c, mazouni c, hess kr, andré f, tordai a, mejia ja, et al. response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. j clin oncol 2008; 26:1275–81. https://doi.org/10.1200/jco.2007.14.4147. 22. von minckwitz g, martin m. neoadjuvant treatments for triple-negative breast cancer (tnbc). ann oncol 2012; 23:vi35–9. https://doi.org/10.1093/annonc/mds193. 23. von minckwitz g, untch m, blohmer ju, costa sd, eidtmann h, fasching pa, et al. definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. j clin oncol 2012; 30:1796–804. https://doi.org/10.1200/ jco.2011.38.8595. 24. rouzier r, perou cm, symmans wf, ibrahim n, cristofanilli m, anderson k, et al. breast cancer molecular subtypes respond differently to preoperative chemotherapy. clin cancer res 2005; 11:5678–85. https://doi.org/10.1158/1078-0432.ccr-04-2421. 25. mustacchi g, de laurentiis m. the role of taxanes in triplenegative breast cancer: literature review. drug des devel ther 2015; 9:4303–18. https://doi.org/10.2147/dddt.s86105. 26. mayer ia, dent r, tan t, savas p, loi s. novel targeted agents and immunotherapy in breast cancer. am soc clin oncol educ book 2017; 37:65–75. https://doi.org/10.14694/edbk_175631. 27. robson m, im sa, senkus e, xu b, domchek sm, masuda n, et al. olaparib for metastatic breast cancer in patients with a germline brca mutation. n engl j med 2017; 377:523–33. https://doi.org/10.1056/nejmoa1706450. 28. adams s, schmid p, rugo hs, winer ep, loirat d, awada a, et al. phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mtnbc): keynote-086 cohort a. j clin oncol 2017; 35:s1008. https://doi.org/10.1200/jco.2017.35.15_suppl.1008. 29. nanda r, liu mc, yau c, asare s, hylton n, veer lv, et al. pembrolizumab plus standard neoadjuvant therapy for highrisk breast cancer (bc): results from i-spy 2. j clin oncol 2017; 35:s506. https://doi.org/10.1200/jco.2017.35.15_suppl.506. 30. haffty bg, yang q, reiss m, kearney t, higgins sa, weidhaas j, et al. locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. j clin oncol 2006; 24:5652–7. https://doi.org/10.1200/ jco.2006.06.5664. https://doi.org/10.7314/apjcp.2014.15.6.2577 https://doi.org/10.7314/apjcp.2014.15.6.2577 https://doi.org/10.1038/nrclinonc.2010.39 https://doi.org/10.1002/cncr.11688 https://doi.org/10.1002/cncr.11688 https://doi.org/10.1200/jco.2007.14.4147 https://doi.org/10.1093/annonc/mds193 https://doi.org/10.1200/jco.2011.38.8595 https://doi.org/10.1200/jco.2011.38.8595 https://doi.org/10.1158/1078-0432.ccr-04-2421 https://doi.org/10.2147/dddt.s86105 https://doi.org/10.14694/edbk_175631 https://doi.org/10.1056/nejmoa1706450 https://doi.org/10.1200/jco.2017.35.15_suppl.1008 https://doi.org/10.1200/jco.2017.35.15_suppl.506 https://doi.org/10.1200/jco.2006.06.5664 https://doi.org/10.1200/jco.2006.06.5664 1school of nursing and midwifery, sabzevar university of medical sciences, sabzevar, iran; 2student research committee, school of nursing and midwifery, iran university of medical sciences, tehran, iran; 3zahedan university of medical sciences, zahedan, iran; 4faculty of allied medical sciences, zabol university of medical sciences, zabol, iran; 5student research committee, school of nursing and midwifery, zabol university of medical sciences, zabol, iran *corresponding author’s e-mail: pahlevan1377@gmail.com the effect of happiness training on psychological well-being in patients with thalassaemia major a quasi-experimental study mohammad s. sargolzaei,1 milad g. shirsavar,2 jasem allahyari,3 ali bazi,4 *abolghasem p. nasirabady5 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 370–375, epub. 25 aug 22 submitted 16 mar 21 revisions req. 3 may & 21 jun 21; revisions recd. 6 jun & 3 jul 21 accepted 14 jul 21 https://doi.org/10.18295/squmj.8.2021.109 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. thalassaemia is a common inherited haematological disease.1 thalassaemia major (tm) is characterised by either the lack of or reduced production of globin chains.2 around 200,000 tm patients are currently seeking treatment worldwide.3 the prevalence of tm is particularly high in the central asia, middle east, india, southern china, mediterranean countries and central africa.4 iran is also among the countries with a high prevalence of tm, with more than 26,000 registered patients.5 the chronic nature of thalassaemia affects different aspects of patients’ lives, including physical and social activities, familial relationships, educational performance, leisure activities and communication with other people. furthermore, there is an increased risk of psychological problems such as anxiety and depression in these patients.6,7 the psychosocial problems experienced by these patients can severely affect their psychological well-being, quality of life and, finally, the disease’s course.8 psychological well-being reflects the desired psychological performance and refers to the exper ienced quality of life. people with psychological wellbeing are satisfied with their health and success, improving their quality of lives.9 psychological wellbeing includes dimensions such as self-acceptance, positive relationships with others, independence, environmental dominance, having a purpose in life and personal growth.10 the ryff model is one of the most prominent models in the psychological wellbeing field, which considers psychological well-being as an attempt to grow, progress and accomplish one’s potential capabilities.11 ghorbani et al. reported that patients with thalassaemia had low levels of psychological well-being.12 among the factors that seem to be effective in controlling and coping with chronic diseases are happiness and cheerfulness.13 happiness is a necessary element for a better quality of life and is considered by the world health organization (who) as an abstract: objectives: this study aimed to determine the effects of happiness training on the psychological well-being of thalassaemia major (tm) patients. tm is a chronic haematological disease that can have profound effects on patients’ mental health and psychological well-being. methods: this quasi-experimental study with a pre/post-test design was performed on 52 patients with tm attending the thalassaemia care centre of imam khomeini hospital in zabol city, iran, from august to december 2020. the patients were randomly categorised into experimental and control groups. in the experimental group, happiness training was performed in eight sessions, each for 60 minutes. the control group received routine care. the data collection tool employed was the ryff ’s scale of psychological well-being. data were analysed by spss 16 using descriptive (mean ± standard deviation) and inferential (paired and independent t-test) statistics. results: regarding the psychological well-being score at the pre-test stage, there was no statistically significant difference between the intervention (74.92 ± 6.36) and control (74.57 ± 5.83) groups (p = 0.83). after the intervention, however, a statistically significant difference was observed between the two groups in terms of psychological well-being (p <0.001). additionally, a statistically significant difference was seen one comparing the psychological well-being score between the preand post-intervention phases in the experimental (p = 0.01) but not control (p = 0.12) group. conclusion: the results of this study showed that happiness training improved tm patients’ psychological well-being. therefore, this type of training can be used as an appropriate educational strategy to improve the psychological well-being in these patients. keywords: happiness; education; mental health; thalassemia; iran. advances in knowledge according to the results of this study, happiness training may improve the psychological well-being of tm patients. application to patient care happiness training, as an easy, accessible and safe method, can improve patients’ psychological well-being and, thus, the quality of patient care. https://creativecommons.org/licenses/by-nd/4.0/ mohammad s. sargolzaei, milad g. shirsavar, jasem allahyari, ali bazi and abolghasem p. nasirabady clinical and basic research | 371 important and vital component of mental health and a part of the overall concept of health.14 one of the ways to increase happiness is to train it through the fordyce happiness programme. fordyce describes happiness as a positive thrill or a feeling that is characterised with satisfaction and well-being. fordyce employed an educational approach which included both cognitive and behavioural aspects. in the cognitive dimension, the role of specific thoughts and behaviours in creating happiness is deeply discussed. in the behavioural dimension, a variety of techniques and solutions resulting from cognitive and behavioural therapies are indicated.15 research supports the fact that psychological well-being leads to better lifestyle choices, such as avoiding fatty foods and drug abuse and helps cope with conflicts or negative emotions without perpetrating drug abuse or self-destructive behaviours. on the other hand, the likelihood of such negative health-related behaviours increases in those exposed to stress or psychological distress.16 moreover, psychological distress can have direct negative effects on certain immunological responses and increase the release of cytokines, thus facilitating chronic inflammatory responses that, in turn, promote depression or anxiety disorders.17 in a study, sobhani et al. reported a positive relationship between happiness and psychological well-being.18 multiple studies have shown that cognitive behavioural training through the fordyce happiness programme significantly increases happiness and quality of life.19,20 in the study of fayazi et al., they noted that the fordyce happiness programme improved psychological well-being in people with physical and skeletal disabilities.21 moreover, ekrami et al. concluded that happiness training affected the psychological well-being and positive and negative emotions of housewives.22 although advances in therapeutic approaches have improved tm patients’ longevity and quality of lives, studies on mental health status indicate a relatively high prevalence of psychological problems in these patients, impairing their psychological wellbeing. considering the important role of education in improving and reducing tm patients’ psychological problems, the aim of the present study was to determine the effect of happiness training on the psychological well-being of tm patients. methods this quasi-experimental study was conducted with a pre/post-test design from august to december 2020. the study population included tm patients who were referred to the thalassaemia care centre of imam khomeini hospital of zabol city, iran. sampling was performed in a continuous mode. the patients were randomly divided into the intervention and control groups using the table of random numbers. inclusion criteria were definite diagnosis of tm, age above 12 years, having no cognitive problems or physical disability and willingness to participate in the study. missing one of the training sessions, unwillingness to continue participation and the patient’s death were regarded as exclusion criteria. considering a confidence interval of 95%, power of 80%, the means of psychological well-being scores reported by ghazavi et al. and finally regarding the possibility of a ratio of sample loss, sample size was determined as 26 subjects per group giving a total sample size of 52.23 the data collection tool included the ryff ’s scale of psychological well-being (rspwb). demographic data including age, gender, marital status, occupation, education, economic status, parents’ consanguineous marriage, number of blood transfusions per month and having other affected family members were recorded as well. in this study, a short 18-question version of this scale with six subscales (three statements per subscale) was used. in iran, khanjani et al. translated the scale and assessed its psychometrics.24 the subscales included self-acceptance (items 2, 8 and 10), positive communication with others (items 3, 11 and 13), independence (items 9, 12 and 16), having a purpose in life (items 5, 14 and 15), personal growth (items 7, 17 and 18) and environmental dominance (items 1, 4 and 6). the score of each subscale ranged from 3 to 18. the participants responded to the questions on a 6-point scale from complete disagreement (score 1) to complete agreement (score 6). the total score of psychological well-being was calculated by summing up the scores of the subscales (ranging from 18 to 108, a higher score indicating a better psychological well-being).11 the internal consistency of the 18item scale was assessed, showing the cronbach’s alpha coefficients of 94% for the whole questionnaire and 63–89% for the subscales.21 van dierendonck confirmed the reliability of this questionnaire with the cronbach’s alpha of 90%.25 in the present study, by calculating a cronbach’s alpha coefficient of 77%, the reliability of the questionnaire was also approved. patients attending the care centre were then recruited for the study. after an introductory explanations were provided, written consent was obtained and patients were allocated into their study groups, rspwb was completed by the patients at the effect of happiness training on psychological well-being in patients with thalassaemia major a quasi-experimental study 372 | squ medical journal, august 2022, volume 22, issue 3 the pre-test stage. to avoid sharing of information between the two groups, first the control group and then the experimental group was studied. happiness training based on the cognitivebehavioural fordyce happiness training protocol was performed for the experimental group in eight sessions of 60 minutes (once a week) in groups of five to six people.26 these programmes covered the following topics in each session: session one: after introducing and acquainting the members with each other, explanations were provided about the protocol (i.e. the number and time of sessions). the importance of happiness in life was highlighted by presenting some evidence in this regard. the technique of how to be more active was taught to the patients. at the end of this session, feedback was taken from the participants. session two: the techniques of boosting social communications and increasing intimacy were explained. session three: the technique of increasing creativity was discussed. session four: it was explained how to have better planning and organisation. session five: discussions were presented about how to cope with and stop thinking about worries and concerns. session six: this session focused on how to have lower expectations and be oneself. session seven: the techniques of developing positive thinking, being optimistic and living in the present. session eight: expressing emotions and appreciating the value of happiness. the content of the programme was presented by lectures along with questions and answers and expressing the participants’ experiences. in each session, a 15-minute rest period was given. no intervention was performed for the control group. for the post-test, the questionnaire was completed by the members of both groups one month after training. after this, the training booklet was provided to the control group as well. data analysis was performed in spss software, version 16, (ibm corporation, armonk, new york, usa) using descriptive (mean ± standard deviation) and inferential (chi-squared, fisher’s exact test and independent and paired samples student t-test) statistics. one-way ancova was used to adjust postintervention well-being score for the effects of the preintervention score and age covariates. the statistical significance level was considered at p <0.05. after approval by the ethics committee of iran university of medical sciences, tehran, iran, (ir. iums.rec.1398.815) and receiving a referral letter, imam khomeini hospital in zabol, iran, was contacted and permission to conduct the study was acquired from the hospital’s authorities. results the mean age of the participants in the study was 20.52 ± 6.04 years old (p = 0.40). overall, 42.3% and 53.8% of patients in the experimental and control groups, respectively, were <18 years old. there were no significant differences between the two groups regarding demographic and disease-related variables (p >0.05) [table 1]. table 1: the distribution of demographic variables of patients with thalassaemia major in the control and experimental groups (n = 52) variables n (%) p value experimental (n = 26) control (n = 26) age in years 0.40* <18 11 (42.3) 14 (53.8) >18 15 (57.7) 12 (46.2) gender 0.57* male 15 (57.7) 13 (50) female 11 (42.3) 13 (50) marital status 1* single 24 (92.3) 24 (92.3) married 2 (7.7) 2 (7.7) education 0.69* illiterate 3 (11.5) 1 (3.8) lower than diploma 16 (61.5) 17(65.4) diploma and higher 7 (26.9) 8 (30.8) occupation 0.94* selfemployment 6 (23.1) 5 (19.2) unemployed 7 (26.9) 6 (23.1) housewife 3 (11.5) 4 (15.4) student 10 (38.5) 11 (42.3) economic status 0.09* poor 9 (34.6) 5 (19.2) moderate 11 (42.3) 9 (34.6) good 6 (23.1) 12 (46.1) number of transfusions per month 0.94* 1 5 (19.2) 6 (23.1) 2 18 (69.2) 17 (65.4) 3 3 (11.5) 3 (11.5) parents’ consanguineous marriage 0.53* yes 18 (69.2) 20 (76.9) no 8 (30.8) 6 (23.1) having another affected family member 0.56† yes 11 (42.3) 8 (30.8) no 15 (57.7) 18 (69.2) *calculated using the chi-squared test. †calculated using fisher’s exact test. mohammad s. sargolzaei, milad g. shirsavar, jasem allahyari, ali bazi and abolghasem p. nasirabady clinical and basic research | 373 there was no statistically significant difference between the two groups comparing the psychological well-being score at the pre-test stage (p = 0.83). however, a statistically significant difference in the psychological well-being score was observed between the experimental and control groups after the training (p <0.001). furthermore, a statistically significant difference was observed comparing the preand post-test psychological well-being scores in the experimental (p = 0.01), but not the control group (p = 0.12) [table 2]. considering psychological wellbeing subscales before and after the intervention, statistically significant differences were noticed in the self-acceptance, positive communications with others, purposefulness, personal growth and dominance dimensions in both groups (p <0.05 each). however, there was no statistically significant difference regarding the independence dimension in both groups (p = 0.54) [table 3]. discussion the present study was conducted to assess the effect of a happiness training programme on the psychological well-being of patients with tm. data analysis showed a significant difference comparing the mean psychological well-being scores between the experimental and control groups after the happiness training intervention. the results of the current study also showed the positive effects of happiness training on the dimensions of self-acceptance, positive communications with others, purposefulness, personal growth and environmental dominance, as well as the total psychological well-being score of patients with tm. on the other hand, the impact of this training programme on the independence dimension was not statistically significant. these findings were consistent with the results of a study by babaei et al., who showed that stress management and resilience training improved the table 3: the scores of psychological well-being dimensions in the experimental and control groups before and after happiness training dimension mean ± sd p value* before intervention after intervention self-acceptance experimental 13.53 ± 1.98 14.53 ± 1.63 0.06 control 12.57 ± 2.51 11.50 ± 2.21 0.14 p value† 0.13 <0.001 positive communication with others experimental 12.30 ± 2.09 13.65 ± 2.93 0.08 control 11.88 ± 2.43 11.57 ± 2.35 0.62 p value† 0.5 0.007 independence experimental 12.34 ± 1.46 12 ± 2.28 0.001 control 11.76 ± 1.81 11.65 ± 1.76 0.88 p value† 0.21 0.54 purposefulness experimental 10.73 ± 2.70 10.26 ± 2.16 0.42 control 11.50 ± 1.65 11.84 ± 2.64 0.5 p value† 0.22 0.02 personal growth experimental 12.73± 1.3 14.73 ± 1.84 <0.001 control 13.80 ±1.52 12.11 ± 2.55 0.002 p value† 0.009 <0.001 environmental dominance experimental 13.26 ± 2.64 15.42 ± 2.23 0.007 control 13.03 ± 2.19 12.53 ± 2.38 0.47 p value† 0.73 <0.001 sd = standard deviation. *calculated using the paired samples student t-test; †calculated using the independent samples student t-test. table 2: the psychological well-being score in the experimental and control groups before and after happiness training group mean ± sd p value† pre-intervention post-intervention* mean difference experimental 74.92 ± 6.36 80.7 ± 6.47 5.69 ± 10.47 0.01 control 74.57 ± 5.83 71.13 ± 8.32 3.34 ± 10.77 0.12 p value§ 0.83 <0.001 0.003 sd = standard deviation. *one-way ancova was used to adjusted for age and pre-intervention well-being score; †calculated using the paired samples student t-test; §calculated using the independent samples student t-test. the effect of happiness training on psychological well-being in patients with thalassaemia major a quasi-experimental study 374 | squ medical journal, august 2022, volume 22, issue 3 psychological well-being of tm patients.27 dustkafi et al. assessed the effectiveness of positive psychotherapy training on the psychological well-being of women with lung cancer and showed that this training programme improved the psychological well-being of these patients.28 furthermore, khayeri et al. showed that happiness training improved depression, stress, anxiety and fatigue in patients with multiple sclerosis.29 according to another study by samadzadeh et al., happiness training improved the quality of lives of the cancer patients undergoing haemodialysis.20 the effectiveness of happiness training on the psychological well-being of patients with tm can be explained by a number of reasons or mechanisms. happiness training and rational thinking can help patients understand their problems and then learn strategies to cope with and adapt to these problems. this, in turn, increases their self-esteem and psychological well-being. from the perspectives of the people who feel happier in life, unpleasant experiences and problems are valuable and meaningful. additionally, these people believe that they have appropriate resources to deal with problems and the ability to use these resources to manage stressful situations.30 in this regard, hoseini abdkhodaei reported that the fordyce happiness training programme increased the feeling of happiness and psychological consistency in diabetic patients.31 happiness training, by influencing personal thoughts, beliefs and feelings, would free people from norms and social pressures and improve personal growth (through learning) and self-acceptance (via creating a positive attitude towards oneself and the past history).32 patients with tm, due to the nature of their disease, are exposed to several physical and psychological problems.33 because happiness training based on the fordyce approach has a cognitivebehavioural aspect, it can help these patients to first identify their uncomfortable thoughts and behaviours and then employ cognitive-behavioural management programmes to change the situation. in addition, focusing on life’s negative aspects and persistent emotional unhappiness can have destructive effects on the body’s physiological system and disrupt the immune system functionality.21 limitations of the present study included the limited space used for the training and the fact that the study was conducted in a single centre. in addition, continuous sampling, which is a non-random method, may compromise the generalisability of the results. another limitation of this study was the simultaneous measurement of the psychological well-being of adolescents and adults; therefore, it is suggested to examine these age groups separately in future studies. considering the positive impact of happiness training on the psychological well-being of tm patients, it is recommended that care centres and supportive associations pay special attention to the important role of psychological interventions and counselling sessions in improving tm patients’ psychological wellbeing. furthermore, these patients should be more frequently provided with exciting and entertaining programmes. conclusion according to the results of the present study, it seems that happiness training can improve tm patients’ psychological well-being. considering that this type of training is safe and accessible to patients and their families and is easy to be implemented, it is recommended that psychologists, nurses and mental health specialists and officials use this strategy to improve the psychological well-being of these patients. a u t h o r s’ c o n t r i b u t i o n mss and apn conceptualised and designed the study as well as the sampling process. mss, apn, ab and mgs drafted the manuscript. ja and ab analysed the data. mgs provided critical revision of the manuscript. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t s we would like to thank the esteemed authorities of imam khomeini hospital of zabol, the members of the thalassaemia supporting association of the hospital and all the patients who contributed to this study. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this was the result of a research project approved by the student research committee of iran university of medical sciences (code: 15683) and was financially supported by the university. references 1. ismail dk, el-tagui mh, hussein za, eid ma, aly sm. evaluation of health-related quality of life and muscular strength in children with beta thalassemia major. ejmhg 2018; 19:353–7. https://doi.org/10.1016/j.ejmhg.2018.04.005. 2. al-khabori m, daar s, al-busafi sa, al-dhuhli h, alumairi aa, hassan m, et al. noninvasive assessment and risk factors of liver fibrosis in patients with thalassemia major using shear wave elastography. hematology 2019; 24:183–8. https://doi.or g/10.1080/10245332.2018.1540518. https://doi.org/10.1016/j.ejmhg.2018.04.005 https://doi.org/10.1080/10245332.2018.1540518 https://doi.org/10.1080/10245332.2018.1540518 mohammad s. sargolzaei, milad g. shirsavar, jasem allahyari, ali bazi and abolghasem p. nasirabady clinical and basic research | 375 3. sargolzaei ms, jahantigh f, allahyari j. interventions to improve quality of life in patients with major thalassemia: a systematic review. payesh 2020; 19:723–33. https://doi.org/10.29252/ payesh.19.6.723. 4. azami m, parizad n, sayehmiri k. prevalence of hypothyroidism, hypoparathyroidism and the frequency of regular chelation therapy in patients with thalassemia major in iran: a systematic review and meta-analysis study. iran j ped hematol oncol 2016; 6:261–76. 5. mashayekhi f, jozdani rh, chamak mn, mehni s. caregiver burden and social support in mothers with β-thalassemia children. glob j health sci 2016; 8:206–12. https://doi. org/10.5539/gjhs.v8n12p206. 6. mevada st, al saadoon m, zachariah m, al rawas ah, wali y impact of burden of thalassemia major on health-related quality of life in omani children. j pediatr hematol oncol 2016; 38:384–8. https://doi.org/10.1097/mph.0000000000000565. 7. yengil e, acipayam c, kokacya mh, kurhan f, oktay g, ozer c. anxiety, depression and quality of life in patients with beta thalassemia major and their caregivers. int j clin exp med 2014; 7:2165–72. 8. seyedtabaee r, rahmatinejad p, etemad a. the role of coping strategies and cognitive emotion regulation in well-being of patients with cancer. j inflamm dis 2017; 21:41–9. 9. huynh t, torquati jc. examining connection to nature and mindfulness at promoting psychological well-being. j environ psychol 2019; 66:101370. https://doi.org/10.1016/j. jenvp.2019.101370. 10. cho j, martin p, margrett j, macdonald m, poon lw. the relationship between physical health and psychological wellbeing among oldest-old adults. j aging res 2011; 2011:605041. https://doi.org/10.4061/2011/605041. 11. ryff cd, keyes cl. the structure of psychological well-being revisited. j pers soc psychol 1995; 69:719–27. https://doi. org/10.1037//0022-3514.69.4.719. 12. ghorbani a, rahimi p, khalili ma, ebrahimi m. prediction of psychological well-being based on islamic lifestyle and coping strategies in patients with major thalassemia in tehran. brain 2018; 9:17–24. 13. kamthan s, sharma s, bansal r, pant b, saxena p, chansoria s, et al. happiness among second year mbbs students and its correlates using oxford happiness questionnaire. j oral biol craniofac res 2019; 9:190–2. https://doi.org/10.1016/j. jobcr.2018.06.003. 14. oliveira pinto sm, alves caldeira berenguer sm, martins jc. cancer, health literacy, and happiness: perspectives from patients under chemotherapy. nurs res pract 2013; 2013:291767. https://doi.org/10.1155/2013/291767. 15. fordyce mw. a review of research on the happiness measures: a sixty second index of happiness and mental health. soc indic res 1988; 20:355–81. https://doi.org/10.1007/bf00302333. 16. sapranaviciute-zabazlajeva l, luksiene d, virviciute d, bobak m, tomasiunas a. link between healthy lifestyle and psychological well-being in lithuanian adults aged 45–72: a cross-sectional study. bmj open 2017; 7:e014240. https://doi: 10.1136/bmjopen-2016-014240. 17. marshall gd jr. the adverse effects of psychological stress on immunoregulatory balance: applications to human inflammatory diseases. immunol allergy clin north am 2011; 31:133–40. https://doi: 10.1016/j.iac.2010.09.013. 18. sobhani z, amini m, hosseini sv, khazraei s, khazraei h. self-efficacy, happiness and psychological well-being after sleeve gastrectomy. world j surg 2020; 44:4193–6. https://doi. org/10.1007/s00268-020-05761-2. 19. nazari m, basiri f, kaveh mh, ghaem h. investigating the effect of fordyce happiness cognitive-behavioral training on perceived stress and happiness in pregnant females: applying the self-efficacy theory. iran red crescent med j 2018; 20:e59284. https://doi.org/10.5812/ircmj.59284. 20. samadzadeh m, shahbazzadegan b, abbasi m. study of fordyce happiness model effectiveness on quality of life in patients undergo dialysis and patients who suffering from cancer. procedia soc behav sci 2013; 83:644–9. https://doi. org/10.1016/j.sbspro.2013.06.122. 21. fayazi m, ayadi n, sadri e, kasirloo y. the effectiveness of cognitive-behavioral fordyce happiness training on psychological well-being and experienced stress women with physicalmotor disabilities. rooyesh 2019; 8:17–24. 22. ekrami r. the effectiveness of group-based happiness training on psychological well-being and positive and negative affects of housewives. j woman family stud 2014; 6:21–35. 23. ghazavi z, mardany z, pahlavanzadeh s. effect of happiness educational program of fordyce on the level of nurses’ happiness. jhc 2017; 19:117–24. 24. khanjani m, shahidi s, fathabadi j, mazaheri ma, shokri o. factor structure and psychometric properties of the ryff ’s scale of psychological well-being, short form (18-item) among male and female students. jtbcp 2014; 9:27–36. 25. van dierendonck d. the construct validity of ryff ’s scales of psychological well-being and its extension with spiritual well-being. pers individ dif 2004; 36:629–43. https://doi. org/10.1016/s0191-8869(03)00122-3. 26. fordyce mw. development of a program to increase personal happiness. j couns psychol 1977; 24:511–21. https://doi. org/10.1037/0022-0167.24.6.511. 27. babaei mr, askarizadeh g, towhidi a. the effectiveness of stress management and resilience training (smart) on psychological well-being in patients with thalassemia major. pcnm. 2019; 8:8–15. https://doi.org/10.29252/pcnm.8.4.8. 28. dustkafi h, heidari h, davoodi h, zare bahramabadi m. comparison of the effectiveness of group counseling by gestalt therapy and positive psychology approach on psychological well-being in woman with lung cancer. qom univ med sci j 2019; 13:80–90. https://doi.org/10.29252/qums.13.9.80. 29. khayeri f, rabiei l, shamsalinia a, masoudi r. effect of fordyce happiness model on depression, stress, anxiety, and fatigue in patients with multiple sclerosis. complement ther clin pract 2016; 25:130–5. https://doi.org/10.1016/j.ctcp.2016.09.009. 30. mikaeili n, rahimzadegan s. the effect of cognitive-behavioral fordyce happiness training on fatigue perception and sense of coherence in diabetic patients type 2. rooyesh 2020; 9:61–70. 31. hoseini m, abdkhodaei ms. effects of cognitive-behavioral fordyce happiness training on sense of coherence in patients with type 2 diabetes. neyshabur univ med sci 2017; 4:1–10. 32. yaghoobi a, nesai moghadam b. the effect of positive psychology intervention on the psychological well-being of adolescents. ijpcp 2019; 25:14–25. https://doi.org/10.32598/ ijpcp.25.1.14. 33. shamsi a, amiri f, ebadi a, ghaderi m. the effect of partnership care model on mental health of patients with thalassemia major. depress res treat 2017; 2017:3685402. https://doi.org/10.1155/2017/3685402. https://doi.org/10.29252/payesh.19.6.723 https://doi.org/10.29252/payesh.19.6.723 https://doi.org/10.5539/gjhs.v8n12p206 https://doi.org/10.5539/gjhs.v8n12p206 https://doi.org/10.1097/mph.0000000000000565 https://doi.org/10.1016/j.jenvp.2019.101370 https://doi.org/10.1016/j.jenvp.2019.101370 https://doi.org/10.4061/2011/605041 https://doi.org/10.1037//0022-3514.69.4.719 https://doi.org/10.1037//0022-3514.69.4.719 https://doi.org/10.1016/j.jobcr.2018.06.003 https://doi.org/10.1016/j.jobcr.2018.06.003 https://doi.org/10.1155/2013/291767 https://doi.org/10.1007/bf00302333 https://doi: 10.1136/bmjopen-2016-014240 https://doi: 10.1136/bmjopen-2016-014240 https://doi: 10.1016/j.iac.2010.09.013 https://doi.org/10.1007/s00268-020-05761-2 https://doi.org/10.1007/s00268-020-05761-2 https://doi.org/10.5812/ircmj.59284 https://doi.org/10.1016/j.sbspro.2013.06.122 https://doi.org/10.1016/j.sbspro.2013.06.122 https://doi.org/10.1016/s0191-8869(03)00122-3 https://doi.org/10.1016/s0191-8869(03)00122-3 https://doi.org/10.1037/0022-0167.24.6.511 https://doi.org/10.1037/0022-0167.24.6.511 https://doi.org/10.29252/pcnm.8.4.8 https://doi.org/10.29252/qums.13.9.80 https://doi.org/10.1016/j.ctcp.2016.09.009 https://doi.org/10.32598/ijpcp.25.1.14 https://doi.org/10.32598/ijpcp.25.1.14 https://doi.org/10.1155/2017/3685402 squ med j, may 2011, vol. 11, iss. 2, pp. 273-275, epub. 15th may 11 submitted 10th oct 10 revision req. 14th dec 10, revision recd. 8th jan11 accepted 15th feb11 patient positioning for surgical procedures has long been associated with intraoperative complications; this is especially true for surgery in the prone position. reported complications resulting from the prone position are usually related to neurovascular injuries, eyes and ears. other reported complications are related to loss of airway, monitors and catheters or to venous air embolisms.1,2 ventilatory and haemodynamic changes have also been reported in the prone position,3 as well as pressure necrosis of the skin.4 to the author’s knowledge lip necrosis has not been reported before in english medical literature as a complication of the prone position. case report a 16 year-old female, a known case of right thoracic scoliosis (idiopathic type) was admitted to the orthopedic department at college of medicine, king saud university, riyadh, saudi arabia, for elective surgical correction and spinal fusion for the scoliotic curve. during the procedure, the patient was placed in a prone position as is usual for posterior surgical correction in scoliosis surgeries. during the operation, gel pads were placed under the chest and another one against both iliac crests with a pillow under both feet to relax the knees which were also supported by separate gel pads. the face was supported with a gel pad too, but it was placed on the operating table not on a horseshoe head support. the endotracheal tube was fixed and maintained by tape over an airway protector to protect the lips and teeth as well as the tongue. the procedure was done under the continuous control of the motor evoked potential and sensory evoked potential. these give stimulation through the cortex and transmit the signals through the spinal cord for certain muscles to contract in upper limb as well as the lower limbs. in this way, the status of spinal cord conductivity and affection during the corrective surgery of scoliosis is checked. the time taken for the procedure was four hours. after the extubation we noticed that the patient had a swelling in the left side of the lower lip. there was no wound on the lips. the eyes, cheeks, chin, ears, and other bony prominent areas were not affected. after discussing the case thoroughly orthopedic department, college of medicine, king saud university, riyadh, saudi arabia. *corresponding author email: alsiddiky@hotmail.com ãfl¢]<ìu]üq<ª<h^f”fi˜]<ìè√ïá÷<ìà¬^ñ€“<ìàé÷]<üˇ™̌           61            :مفتاح الكلمات abstract: during the prone positioning of patients for scoliosis surgery, bony prominences should be protected to avoid pressure necrosis and the face should be carefully positioned to protect the eyes and ears, etc. the author reports a lower lip necrosis in a 16 year-old female as a complication of improper prone positioning during scoliosis surgery. the condition was treated successfully with an advancement flap. keywords: lip; necrosis; scoliosis; complication; case report; saudi arabia lip necrosis as a complication of a prone position in scoliosis surgery abdulmonem alsiddiky case report lip necrosis as a complication of a prone position in scoliosis surgery 274 | squ medical journal, may 2011, volume 11, issue 2 with the anaesthetist, we thought that the cause of this problem was a direct pressure from the endotracheal tube which was pushed against the lip by the gel pad support for the face. the swelling in the lower lip was observed for few days without any spontaneous improvement. six days later, an area of the swollen lower lip became black and necrotic [figures 1 and 2]. the patient was seen by the plastic surgeon who continued the observation and dressings for the necrotic part of the lower lip for ten more days, but no improvement was noticed. the plastic surgeon therefore then decided to take the patient for advancement lip flap surgery of the lower lip. this was done successfully fifteen days after the original surgery. the dressing for the lip and the flap were changed daily. the patient was followed up by the plastic surgeon in his clinic. three months later, the patient had recovered well with complete healing of the lower lip with a very minimal scar [figure 3a & 3b]. discussion pressure necrosis of the skin is a well-known complication for patients who undergo lengthy surgical procedures under general anaesthesia. the condition occurs more frequently in patients undergoing surgical procedures in the prone position.5,6 it is crucial that both the surgeon and the anaesthetist are aware of the risks and the need for careful positioning of the face, eyes, ears, breasts, genitalia, and other dependent areas to prevent pressure sores or skin necrosis.7,8 other areas that also need care include the iliac crests, the chin, eyelids, the nose, and the tongue.9,10 the case reported here had a lower lip necrosis secondary to direct pressure of the endotracheal tube which had been pushed by the gel pad against the lower lip as a result of improper head positioning. previously, a horse shoe (c-shape) head support which has free space around the lower part of the face was routinely used. with this device there would not be any risk of pressure around the mouth and lower part of the face. it was not used in this case because of the anesthetist’s preference for the use of a gel pad. this unfortunate complication is rare and could be avoided by following the strict precautions of prone head positioning and the use of the proper devices as well as continuous checkups by the attending anaesthetist. many devices have been described to be used to protect the face during prone position other than the well known horse shoe head support. in 2007, mollmann et al. described a foam-cushion face mask and a see-through operating table as a new setup for face protection and increase safety in the prone position.11 no previous case of direct pressure necrosis of the lip has been reported secondary to prone positioning. however, lip injury has been reported in a single case due to allergic contact dermatitis to the face, including the lips of a patient, who had become sensitised to the material of the flexible polyurethane foam applied to support the face during surgery.12 figure 1: swelling of the lower lip. figure 2: area of necrosis of the lower lip (black arrow). abdulmonem alsiddiky case report | 275 conclusion in conclusion, lip necrosis can occur if the head of the patient is improperly positioned for scoliosis surgery. both the anaesthetist and the surgeon should work together to create proper positioning for the patient during the surgical procedure and always use the appropriate equipment for the patient’s safety. the author recommends the use of a horse shoe head support in all cases undergoing surgery in the prone position and in scoliosis corrective surgeries in particular. a c k n o w l e d g m e n t s i would like to thank prof. mohammed zamzam, professor of orthopedics at king saud university, riyadh and dr. mohammed albarrag, orthopedic consultant at king fahad hospital, riyadh for reviewing this report. references 1. cucchiara rf, faust rj. patient positioning. in: miller rd ed. anesthesia. 5th ed. new york: churchill livingstone, 2000. pp. 1017–32. 2. anderton jm. the prone position for the surgical patient: a historical review of the principles and hazards. br j anaesth 1991; 67:452–63. 3. yokoyama m, ueda w, hirakawa m, yamamoto h. hemodynamic effect of the prone position during anesthesia. acta anaesthesiol scand 1991; 35:741–4. 4. edgcombe h, carter1 k, yarrow s. anaesthesia in the prone position. br j anaesth 2008; 100: 165–83. 5. jain v, bithal pk, rath gp. pressure sore on malar prominences by horseshoe headrest in prone position. anaesth intensive care 2007; 35:304–5. 6. moore dc, edmunds lh. prone position frame. surgery 1950; 27:276–9. 7. ray cd. new kneeling attachment and cushioned face rest for spinal surgery. neurosurgery 1987; 20:266–9. 8. roth s, tung a, ksiazek s. visual loss in a pronepositioned spine surgery patient with the head on a foam headrest and goggles covering the eyes: an old complication with a new mechanism. anesth analg 2007; 104:1185–7. 9. smith rh. one solution to the problem of the prone position for surgical procedures. anesth analg 1974; 53:221–4. 10. weis k. threatening necrosis of the tip of the tongue during long-term anaesthesia in the prone position. der anaesthetist 1964; 13:241. 11. mollmann m, henning m, liljenqvist u, wenk m. a foam-cushion face mask and a see-through operation table: a new set-up for face protection and increased safety in prone position. br j anaesth 2007; 99:597−8. 12. jericho bg, skaria gp. contact dermatitis after the use of the prone positioner. anesthesia analgesia 2003; 97:1706−8. figure 3a and 3b: two views for the lip three months after plastic surgery. travel health (th) is a specific medical discipline designed to prevent and manage illnesses associated with international travel. th is usually delivered through primary healthcare (phc) with support from specialised units and central public health authorities. there is an ever-increasing number of international travellers often visiting dest inations with new health risks not known at home. every effort should be made to protect these travellers against health risks, such as malaria or yellow fever, at their destinations. international travel reached 1.4 billion travellers in 2019.1 as international travel is increasing in popularity, so too is the risk of associated disease outbreak. known culprits are megacities with high population density, centralised food production, an ageing population and an increasing number of immunocompromised people.2 concurrently, travellers and migrants may carry with them infections from the countries they visited or moved from and the receiving country must ensure that these infections do not pose a risk to the resident population. risk of spreading infections by travellers from one country to another is regulated through the international health regulations of the world health organization (who).3 oman is a culturally diverse country and has a heterogeneous population of around 4.6 million people. of these, approximately 2.7 million (58.8%) are omani nationals and 1.9 million (41.2%) are expatriates.4 omanis, as is the global trend, are travelling across borders more than ever before. throughout history, oman and tanzania and particularly zanzibar, remain intricately connected locations. east africa has always been a common travel destination for omanis and this rise in popularity in international travel is making it even more so; in fact, direct flights from muscat to zanzibar have resulted in strengthened trade links. other common ports of call are mecca, saudi arabia, where many omanis travel for hajj and umrah, and south asia, particularly india, bangladesh and pakistan, home to the large migrant expatriate population who live and work in oman.5 in addition, many omanis go for medical tourism especially to thailand and india. oman's ministry of health (moh) is in the process of establishing a th service at a national level; this is part of meeting the needs for national health security, meeting the requirements and preparedness for epidemics and the commitment of the government to reach univ ersal health coverage. oman has a sophisticated and well-organised phc system that offers care at no cost to citizens. the system is poised to provide pre-th care to omanis looking to travel internationally.5 in this editorial, we will discuss the needs of the population and how the moh will expand its services to address these requirements. protecting travellers in oman the purpose of the th service is to establish and integrate pre-th services into phc in oman’s public and private healthcare facilities. the th service shall ensure that phc physicians and nurses are equipped with up-to-date information of public health threats abroad and of imported infectious diseases into oman. although a pre-th service is already well established for hajj travellers, it still needs to be expanded and made accessible to all travellers. the existing pre-th service includes a sustained supply of relevant vaccines and drugs, especially for malaria chemoprophylaxis. a recent review of severe malaria cases imported into oman underline the need 1directorate general of disease surveillance and control and 2primary health care, ministry of health, oman; 3world health organization, regional office for the eastern mediterranean, cairo, egypt *corresponding author’s e-mail: salabri@gmail.com األمهية املستقبلية للصحة املتعلقة ابلسفر يف الشرق األوسط فرصة سلطنة ُعمان لتعزيز خدماهتا �سيف العربي، �سعيد اللمكي، ا�سكيلد بيرت�سن، اأحمد املنظري the future importance of travel health in the middle east oman’s opportunity to enhance its services *seif al-abri,1 said al-lamki,2 eskild petersen,1 ahmed al-mandhari3 editorial sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e121–124, epub. 28 jun 20 submitted 23 nov 19 revision req. 28 jan 20; revision recd. 8 apr 20 accepted 6 may 20 https://doi.org/10.18295/squmj.2020.20.02.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ the future importance of travel health in the middle east oman’s opportunity to enhance its services e122 | squ medical journal, may 2020, volume 20, issue 2 for prophylaxis as only 1 in 13 of these cases had taken preventive measures.6 the th service will be supported by the “travax” decision support computer system (glasgow, uk, https://www.travax.nhs.uk/) maintained by public health scotland, providing on-line up-todate information. one study found that only 22.5% of residents of oman departing from muscat international airport had received pre-travel advice, only 6.9% had taken any pre-travel preventive measures like a prescription for malaria chemoprophylaxis or immunisations and only 38.2% had th-insurance coverage.7 another study among primary care physicians found that 58.3% had given a pre-travel consultation during the month prior to travel and 79.6% had given a post-travel consultation, concluding that th does currently occur in phc.8 to people looking forward to a trip abroad, the expanded th service will provide statistics on the use of vaccines and malaria prophylaxis and disseminate information on side effects from vaccines and malaria prophylaxis that may arise. travellers will also receive counselling on non-communicable diseases and some recommendations in case they are travelling for medical tourism. protecting the country infections travel with people. to ensure rapid diagnosis, treatment and notification, any illness acquired abroad that may be of national public health concerns must be dealt with swiftly and systematically. the th service will strengthen the existing surv eillance of infectious diseases in the country by ensuring early diagnosis and providing adequate treatment of infections acquired outside of the country at all levels of healthcare and in both public and private facilities. phc facilities will receive information on imported infectious diseases into oman via the existing weekly bulletin published by the directorate general of disease surveillance and control. this ensures that surveillance of imported infections prevent public health events and are in accordance with the international health regul ations of the who. post-travel surveillance in travellers and migrants can be difficult; better access to expert consultations on illness in travellers and migrants is needed. we propose to establish a “fever service”—a hotline for public and private th clinics and hospitals in oman providing access to specialised physicians and nurses functioning as nodal centres for comprehensive preand post-travel advice. the model is the “imported fever service” established in the uk where patients difficult to diagnose at their local health centre or hospital can be discussed with specialists.9 a recent review of imported infections in oman from 1999 to 2013 found that approximately 8% of notifiable infections in oman were travel related. in addition, 78 cases of dengue fever, 80 cases of measles and 2 cases of polio were all imported. of the imported infections, 73% came from asia, 23% from middle eastern countries and 4% from africa.10 the outbreak of dengue fever in muscat, oman, in 2018 to 2019 due to travel illustrate how an imported disease can cause an outbreak.11 reintroduction of malaria is a continued risk with between 900 and 1,500 travel-related cases diagnosed every year. a few limited local ‘first generation’ malaria outbreaks have occurred, the largest in mabela, muscat governorate in 2015 with more than 50 cases. however, the outbreak was effectively controlled within two months.12 a case of imported cholera resulted in a secondary case after delayed diagnosis.13 the dengue and malaria outbreaks were identified through the routine surveillance of infectious diseases in the country. the dengue outbreak was able to happen because the vector, aedes aegypti, has become established in muscat; this illustrates how ecological factors related to vector characteristics can allow new pathogens to be introduced by travellers.14 surveillance also needs to include multi-drug resistant bacteria. considerable work has been done between the gulf cooperation council countries and it is well established that resistant bacteria is spread between countries via travellers whether they are asympt omatic carriers or arrive with a presenting infection.15–17 a case of colistin-resistant escherichia coli isolated in oman, where the plasmid carrying the gene coding for colistin resistance could be traced to china, illustrates the international spread of multidrug-resistant bacteria.18 indeed, it has been suggested that travellers from countries with a high level of multidrug-resistant gram-negative bacteria should be screened.19 addressing the expatriate population travel-related infection in oman is primarily imported by migrant expatriates who are responsible for a stagg ering and unfortunate 86% of travel-related infections.8 this places the experience of expatriates of utmost importance and an issue that needs addressing. most people relocating to oman for work come from south asia and since the primary risk factor for travel-related illness transmission is visiting family and friends, this puts this group at high risk of importing infections such as malaria.5 though healthcare services are provided free of charge for citizens, expatriates have limited access to the system yet are able to access an enhanced level seif al-abri, said al-lamki, eskild petersen and ahmed al-mandhari editorial | e123 of th. accessing this service is helpful in two-fold, it improves the health of the migrant working population while reducing the risk of disease transmission to the country at large.5 now is the time to target the residents of oman who need the services most. the opportunity is present and the need is paramount. currently, clinical care is provided at no cost to expatriates who have pre-existing communicable diseases such as malaria and tuberculosis. the challenge remains to remove barriers to access and decrease/eliminate the cost to deliver pre-th care that includes vaccination and treatment of communicable diseases for expatriates. regarding malaria specifically, there is an increasing concern about asymptomatic malaria and its impact on countries, such as oman, which are free of the disease yet where the anopheles mosquitos that transmit malaria exist. in reaction to this and other travel-related illness concerns, the moh is working with the private health sector to set up private th clinics poised for access by expatriates to receive an enhanced level of th care thereby improving their personal health status and reducing the risk to the indigenous population of oman. international collaboration oman participates in geosentinel, an international disease surveillance network established by the inter national society for travel medicine, collecting data on illness in returning travellers. geosentinel’s aim is spotting new trends in the worldwide movement of disease.20–22 oman will be an active participant in the geosentinel collaboration and will benefit from pre publication access to information on new international disease trends and access to an international network of highly experienced th specialists and public health experts. governance the th service will be executed by phc centres under the supervision and guidance of the moh. regular meetings between the directorate general of disease surveillance and control, directorate general of phc, and directorate general of health services will ensure continuous adjustment according to the needs of the traveller, the phc services and public health surv eillance. the moh will continuously evaluate public and private healthcare services and publish statistics of the activities. the moh will also ensure that the necessary vaccines and drugs such as malaria chemoprophylaxis are available. evaluation of training workshops will be implemented and it will be ensured that training opportunities are matched with the development of the service. oman is prepared for enhanced preand postth services to tackle travel-related illnesses which threaten the health of the country’s population. oman’s geographical position in the middle east and its melting pot culture pose three risk factors for travel-acquired illness: (1) pilgrimages for hajj and umrah; (2) strong bonds with east africa; and (3) a large population of migrant expatriates from south asia. however, oman is well prepared and positioned to meet these challenge because of the country’s state-of-the-art public health laboratory and diagnostic resource facilities, broad access to a well-operating phc system, and sophisticated electronic health records and notification system that operates throughout all moh health centres.5 the future of travel medicine is at a proverbial crossroads and the move to seize the opportunity to enhance these services in oman will be of great benefit to both expatriates and nationals. references 1. world tourism organization. international tourism highlights, 2019 edition. from: https://www2.unwto.org/publication/inter national-tourism-highlights-2019-edition accessed: apr 2020. 2. petersen e, petrosillo n, koopmans m, escmid emerging infections task force expert panel. emerging infections-an increasingly important topic: review by the emerging infections task force. clin microbiol infect 2018; 24:369–75. https://doi. org/10.1016/j.cmi.2017.10.035. 3. world health organization. international health regulations. 2nd edition. geneva, 2005. from: https://www.who.int/ihr/pub lications/9789241596664/en/ accessed: apr 2020. 4. national centre for statistics & information. from: https:// ncsi.gov.om/pages/ncsi.aspx accessed: apr 2020. 5. schlagenhauf p, jones me. travel medicine in oman--chances and challenges. travel med infect dis 2015; 13:351–2. https://doi.org/10.1016/j.tmaid.2015.09.009. 6. al farsi f, chandwani j, mahdi as, petersen e. severe imported malaria in an intensive care unit: a case series. idcases 2019; 17:e00544. https://doi.org/10.1016/j.idcr.2019.e00544. 7. al-abri ss, abdel-hady dm, al-abaidani is. knowledge, atti tudes, and practices regarding travel health among muscat international airport travelers in oman: identifying the gaps and addressing the challenges. j epidemiol glob health 2016; 6:67–75. https://doi.org/10.1016/j.jegh.2016.02.003. 8. kurup pj, al abri ss, al ajmi f, khamis ha, singh j. knowledge, attitude and practice of travel medicine among primary care physicians in oman: the need for intervention. east mediterr health j 2019; 25:40–6. https://doi.org/10.26719/ emhj.18.027. 9. imported fever service (ifs). from: https://www.gov.uk/gui dance/imported-fever-service-ifs. accessed: apr 2020. 10. al-abri ss, abdel-hady dm, al mahrooqi ss, al-kindi hs, al-jardani ak, al-abaidani is. epidemiology of travel-assoc iated infections in oman 1999-2013: a retrospective analysis. travel med infect dis 2015; 13:388–93. https://doi.org/10.10 16/j.tmaid.2015.08.006. https://doi.org/10.1016/j.cmi.2017.10.035 https://doi.org/10.1016/j.cmi.2017.10.035 https://doi.org/10.1016/j.tmaid.2015.09.009 https://doi.org/10.1016/j.idcr.2019.e00544 https://doi.org/10.1016/j.jegh.2016.02.003 https://doi.org/10.26719/emhj.18.027 https://doi.org/10.26719/emhj.18.027 https://doi.org/10.1016/j.tmaid.2015.08.006 https://doi.org/10.1016/j.tmaid.2015.08.006 the future importance of travel health in the middle east oman’s opportunity to enhance its services e124 | squ medical journal, may 2020, volume 20, issue 2 11. al-abri ss, kurup pj, al manji a, al kindi h, al wahaibi a, al jardani a, et al. control of the 2018-2019 dengue fever out break in oman: a country previously without local transmission. int j infect dis 2019; 90: 97–103. https://doi.org/10.1016/j. ijid.2019.10.017. 12. simon b, sow f, al mukhaini sk, al-abri s, ali oam, bonnot g, et al. an outbreak of locally acquired plasmodium vivax mal aria among migrant workers in oman. parasite 2017; 24:5. https://doi.org/10.1051/parasite/2017028. 13. al mayahi z, al-shaqsi n, elmutashi ha, al-dhoyani a, al hattali a, salim k, et al. two cases of cholera o1 in south batinah, oman, april 2019: lessons learned. epidemiol health 2019; 41:e2019033. https://doi.org/10.4178/epih.e2019033. 14. kilpatrick am, randolph se. drivers, dynamics, and control of emerging vector-borne zoonotic diseases. lancet 2012; 380:1946–55. https://doi.org/10.1016/s0140-6736(12)61151-9. 15. sonnevend á, ghazawi aa, hashmey r, jamal w, rotimi vo, shibl am, et al. characterization of carbapenem-resistant enterobacteriaceae with high rate of autochthonous trans mission in the arabian peninsula. plos one 2015; 10:e0131372. https://doi.org/10.1371/journal.pone.0131372. 16. balkhy hh, assiri am, mousa ha, al-abri ss, al-katheeri h, alansari h, et al. the strategic plan for combating antimicrobial resistance in gulf cooperation council states. j infect public health 2016; 9:375–85. https://doi.org/10.1016/j.jiph.2016.03.003. 17. pál t, ghazawi a, darwish d, villa l, carattoli a, hashmey r, et al. characterization of ndm-7 carbapenemase-producing escherichia coli isolates in the arabian peninsula. microb drug resist 2017; 23:871–8. https://doi.org/10.1089/mdr.2016.0216. 18. mohsin j, pál t, petersen je, darwish d, ghazawi a, ashraf t, et al. plasmid-mediated colistin resistance gene mcr-1 in an escherichia coli st10 bloodstream isolate in the sultanate of oman. microb drug resist 2018; 24:278–82. https://doi. org/10.1089/mdr.2017.0131. 19. petersen e, mohsin j. should travelers be screened for multidrug resistant (mdr) bacteria after visiting high risk areas such as india? travel med infect dis 2016; 14:591–4. https://doi. org/10.1016/j.tmaid.2016.11.014. 20. angelo km, libman m, caumes e, hamer dh, kain kc, leder k, et al. malaria after international travel: a geosentinel analysis, 2003-2016. malar j 2017; 16:293. https://doi.org/10.1 186/s12936-017-1936-3. 21. angelo km, libman m, gautret p, barnett e, grobusch mp, hagmann shf, et al. the rise in travel-associated measles infections-geosentinel, 2015-2019. j travel med 2019; 26:taz046. https://doi.org/10.1093/jtm/taz046. 22. gautret p, angelo km, asgeirsson h, lalloo dg, shaw m, schwartz e, et al. rabies post-exposure prophylaxis started during or after travel: a geosentinel analysis. plos negl trop dis 2018; 12:e0006951. https://doi.org/10.1371/journal.pntd.0006951. https://doi.org/10.1016/j.ijid.2019.10.017 https://doi.org/10.1016/j.ijid.2019.10.017 https://doi.org/10.1051/parasite/2017028 https://doi.org/10.4178/epih.e2019033 https://doi.org/10.1016/s0140-6736%2812%2961151-9 https://doi.org/10.1371/journal.pone.0131372 https://doi.org/10.1016/j.jiph.2016.03.003 https://doi.org/10.1089/mdr.2016.0216 https://doi.org/10.1089/mdr.2017.0131 https://doi.org/10.1089/mdr.2017.0131 https://doi.org/10.1016/j.tmaid.2016.11.014 https://doi.org/10.1016/j.tmaid.2016.11.014 https://doi.org/10.1186/s12936-017-1936-3 https://doi.org/10.1186/s12936-017-1936-3 https://doi.org/10.1093/jtm/taz046 https://doi.org/10.1371/journal.pntd.0006951 use of noninvasive ventilation and high-flow nasal cannulae therapy for infants and children with acute respiratory distress outside of paediatric intensive care a review article *khaloud s. almukhaini,1 najwa m. al-rahbi2 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e245–250, epub. 5 oct 20 submitted 20 jan 20 revision req. 26 mar 20; revision recd. 24 apr 20 accepted 6 may 20 1department of child health, royal hospital, muscat, oman; 2department of child health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: kholoud_saeed@hotmail.com non-in va si ve ventil ation (ni v ) is defined as the administration of positive airway pressure through an interface to avoid creating an invasive artificial airway through the trachea.1,2 it comprises various techniques, including continuous positive airway pressure (cpap) and bilevel positive airway pressure. over the last decade, the use of niv has significantly increased in the paediatric population.3–5 in general, niv holds several advantages over invasive mechanical ventilation and is associated with improved pulmonary gas exchange.1,2 moreover, the physiological effects of niv reduce respiratory distress in children presenting with acute respiratory failure.6 high-flow nasal cannulae therapy (hfnct) refers to the delivery of a humidified oxygen and gas mixture at flow rates that equal or exceed the patient’s inspiratory flow.7 at higher flow rates, this technique can generate positive end-expiratory press ure, although the amount of pressure generated is not predictable.7–9 in addition, hfnct has effects on gas conditioning, thereby reducing energy needs, and is associated with anatomical dead space washout, improving oxygenation and reducing carbon dioxide.7 review استخدام التهوية الغري جراحية والعالج ابلقنيات األنفية ذات التدفق العايل لعالج املواليد واألطفال املصابني بضائقة تنفسية حادة خارج العناية املركزة لألطفال مراجعة أدبية خلود �سعيد املخينية، جنوى مرهون الرحبية abstract: noninvasive ventilation (niv) and high-flow nasal cannulae therapy (hfnct) are first-line methods of treatment for children presenting with acute respiratory distress, with paediatric intensive care units (picus) providing an ideal environment for subsequent treatment monitoring. however, the availability of step-down units, where niv and hfnct can be safely utilised, has reduced the need for such patients to be admitted to picus, thereby leading to the better overall utilisation of critical care resources. in addition, niv and hfnct can also be used during transport instead of invasive ventilation, thus avoiding the complications associated with the latter approach. this review article examines the safety and applicability of these respiratory support approaches outside of paediatric intensive care as well as various factors associated with treatment success or failure. keywords: critical care; children; pediatric intensive care units; noninvasive ventilation; nasal cannulae; transportation of patients. امللخ�ص: ُتعترب التهوية غري البا�سعه والعلج بالقنيات الأنفية عالية التدفق من اأ�ساليب العلج الأول للأطفال الذين يعانون من �سائقة تنف�سية حادة، حيث توفر وحدات العناية املركزة للأطفال بيئة مثالية ملراقبة العلج لحقا. غري اأن توافر وحدات العناية املتو�سطة حيث ميكن ا�ستخدام التهوية غري البا�سعه والعلج بالقنيات الأنفية عالية التدفق باأمان قد قلل من احلاجة اإىل قبول هوؤلء املر�سى يف وحدات العناية املركزة للأطفال، مما يوؤدي اإىل ال�ستخدام الكلي الأف�سل ملوارد الرعاية احلرجة. بالإ�سافة اىل ذلك فاإن ا�ستخدام هذه التقنيات التنف�سية اأثناء نقل املر�سى بدل من التهوية البا�سعة �ساهم يف جتنب امل�ساعفات املرتبطة بالنهج الأخري. يتناول هذا املقال الأ�ستعرا�سي �سلمة واإمكانية تطبيق اأ�ساليب الدعم التنف�سي هذه خارج العناية املركزة للأطفال بالإ�سافة اإىل العوامل املختلفة املرتبطة بنجاح هذا العلج اأو ف�سله. الكلمات املفتاحية: رعاية حرجة؛ اأطفال؛ وحدات العناية املركزة للأطفال؛ تهوية غري با�سعة. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.002 https://creativecommons.org/licenses/by-nd/4.0/ use of noninvasive ventilation and high-flow nasal cannulae therapy for infants and children with acute respiratory distress outside of paediatric intensive care a review article e246 | squ medical journal, august 2020, volume 20, issue 3 overall, both niv and hfnct are superior to invasive ventilation as these methods reduce the risk of infection, need for sedation and treatment costs associated with the latter approach.1,10 safety and efficacy in respiratory diseases variable success rates have been reported in different paediatric diseases following niv. for instance, fav ourable results have been observed with primary respiratory diseases including bronchiolitis, asthma and pneumonia.4,5 however, niv has resulted in lower success rates among children diagnosed with acute respiratory distress syndrome (ards).5 in addition, patients presenting with multi-organ failure have reportedly demonstrated worse outcomes with niv.5 similarly, hfnct is widely used to treat infants and children presenting with acute respiratory distress and has been successful for various respiratory diseases including pneumonia, asthma and obstructive sleep apnoea.8,11 according to kawaguchi et al., hfnct significantly decreased the need for intubation in a cohort of patients with mixed respiratory diseases (38% versus 63%; p <0.001).11 other research has also shown a decrease in intubation rates following hfnct among infants with severe bronchiolitis (5–9%).12–14 nevertheless, a randomised controlled trial (rct) comparing hfnct to nasal cpap demonstrated that the latter method required less escalation of respiratory support and was associated with earlier improvement in respiratory distress among a cohort of young infants with acute viral bronchiolitis.14 application outside of paediatric intensive care traditionally, niv and hfnct were reserved for use in intensive care environments in order to closely monitor the development of any technical issues or complications and assess the need for further treatment.15 however, in recent years, both the number of critically ill patients and that of patients requiring readmission to intensive care units (icus) has increased.16–19 these additional demands on limited intensive care resources have encouraged the application of noninvasive respiratory support methods in non-icu settings including paediatric wards, emergency rooms (ers) and during transport. moreover, the implementation of high-dependency or step-down units with the necessary resources to safely deliver and monitor respiratory support has also assisted in reducing the need for icu admission.20 e m e r g e n c y r o o m s a n d g e n e r a l wa r d s over the past few years, the use of niv and hfnct has increased in paediatric wards and ers.21–23 this is because both methods reduce the need for invasive ventilation thereby lowering requirements for escal ation to paediatric icus (picus).2,24 in a recent survey conducted across several european countries, 15.5% and 20% of participating picus reported niv usage in wards and ers, respectively.25 moreover, recent reports from france and finland indicate that hfnct is increasingly utilised in paediatric wards in hospitals without icus with no major adverse events, with hfnct usage outside of the icu ranging from 53.3–86.5%.26,27 table 1 summarises the characteristics and outcomes of various studies evaluating the use of niv and hfnct in paediatric ers and general wards.21–24,28,29 franklin et al. conducted a large multicentre rct evaluating the use of hfnct versus low-flow oxygen in 1,472 infants with bronchiolitis managed in a general paediatric ward.24 the trial noted that fewer infants in the hfnct group required escalation to intensive care compared to those treated with low-flow oxygen (12% versus 23%; p <0.001). moreover, 61% of patients in the low-flow oxygen group required hfnct as a rescue treatment, subsequently avoiding the need for transfer to the picu.24 davison et al. described the successful application of hfnct in an institution without an on-site-picu; however, the researchers advised strict observation and treatment monitoring and recommended that infants without clinical improvement within 60–90 minutes of treatment be immediately transferred to a picu.21 various factors have been associated with hfnct failure in general wards and ers. in a large retrospective study of 231 paediatric patients treated outside of an icu, betters et al. identified underlying cardiac disease and increased fraction of inspired oxygen requirements to be risk factors for hfnct failure.30 however, the researchers also observed that non-responders generally underwent a shorter duration of treatment with hfnct compared to responders (median duration: 5.5 versus 28 hours).30 the use of a treatment protocol to guide the application of hfnct may help to reduce duration of hospital stay and treatment costs as well as faster weaning.27,31 in the er, patients with increased work of breathing at presentation, high initial partial pressure of carbon dioxide measurements and ph values of <7.3 were reportedly more likely to fail hfnct treatment.28,29 moreover, patients who required intubation were more likely to have features of impending respiratory khaloud s. almukhaini and najwa m. al-rahbi review | e247 failure at their initial assessment.28 in contrast, certain respiratory conditions such as bronchiolitis have been associated with hfnct success.28,30 d u r i n g t r a n s p o r t the popularity of noninvasive respiratory approaches during transport has also increased in recent years. the european survey reported that 36.4% of participating picus used niv during paediatric transport.25 a summary of previous research evaluating the use of niv and hfnct during paediatric transport is presented in table 2.32–38 unfortunately, all of the studies evaluating niv and hfnct outcomes during transport were observational in nature. therefore, there is a need for rcts comparing outcomes with hfnct to those of cpap and other modes of niv during paediatric and neonatal transport. schlapbach et al. compared outcomes following hfnct during transport with that of a historical cohort transferred prior to the introduction of hfnct.32 overall, 49% of patients in the pre-hfnct era were intubated during transport compared to 35% in the period following hfnct introduction (p <0.001). similarly, niv utilisation also decreased following the introduction of hfnct (7% versus 2%).32 in total, 33% of the patients received hfnct during transport in the latter era, with no significant adverse events noted, including the need for intubation or cardiopulmonary resuscitation.32 abraham et al. also confirmed the safety of hfnct usage during transfer in a retrospective study of 114 infants, although 23% subsequently required escalation of respiratory support following transfer.33 table 1: summary of selected studies evaluating the use of noninvasive ventilation and high-flow nasal cannulae therapy in paediatric emergency rooms and general wards21–24,28,29 author and year of study study design mode of respiratory support study setting sample outcome franklin et al.24 (2018) rct low-flow oxygen versus hfnct paediatric ers and general wards at 17 hospitals 1,472 infants aged <12 months with bronchiolitis • fewer infants in the hfnct group required transfer to the picu compared to those in the low-flow oxygen group (12% versus 23%). • overall, 61% of infants in the low-flow oxygen group required rescue treatments involving hfnct. davison et al.21 (2017) retrospective study hfnct non-tertiary er and paediatric wards 61 infants and children aged 1–23 months with suspected bronchiolitis • two-thirds of the patients underwent hfnct in paediatric wards with no adverse effects. • only 13% of patients required transfer to an off-site picu. ballestero et al.22 (2018) prospective randomised pilot study low-flow oxygen versus hfnct tertiary paediatric er 62 children aged 1–14 years with refractory asthma and respiratory failure • hfnct was superior to low-flow oxygen in improving respiratory distress within two hours of treatment. vitaliti et al.23 (2013) retrospective study niv paediatric er children presenting with respiratory distress • niv led to improvements in wob and pulmonary gas exchange. • in addition, niv reduced the need for picu transfer. kelly et al.28 (2013) retrospective study hfnct er 498 children with bronchiolitis, pneumonia or asthma • the majority of patients were treated successfully with hfnct, with only 8% requiring intubation. • most cases of hfnct failure demonstrated features of impending respiratory failure at triage stage. long et al.29 (2016) prospective observational study hfnct er 71 patients • the majority of patients improved following hfnct, with only 39% requiring escalation of respiratory support. rct = randomised controlled trial ; hfnct = high-flow nasal cannulae therapy; er = emergency room; picu = paediatric intensive care unit ; niv = noninvasive ventilation; wob = work of breathing. use of noninvasive ventilation and high-flow nasal cannulae therapy for infants and children with acute respiratory distress outside of paediatric intensive care a review article e248 | squ medical journal, august 2020, volume 20, issue 3 boyle et al. concluded that hfnct was a safe option for transporting neonates, provided that the neonate was stable for 24 hours pre-transfer and certain pre-requisites were met concerning age, weight and flow at the time of transfer.39 moreover, the researchers noted that hfnct usage was associated table 2: summary of selected research evaluating the use of noninvasive ventilation and high-flow nasal cannulae therapy during paediatric transport32–38 author and year of study study design mode of respiratory support sample outcome schlapbach et al.32 (2014) retrospective study invasive ventilation, niv or hfnct 793 infants aged ≤2 years • the frequency of both invasive ventilation (49% versus 35%) and niv (7% versus 2%) decreased following the introduction of hfnct. • overall, 33% of infants underwent hfnct during transport. • no adverse effects were noted among those who underwent hfnct during transport. abraham et al.33 (2019) retrospective study hfnct 114 infants, of which 50% had bronchiolitis • no adverse events were observed during transport. • the method of respiratory support was changed to niv (cpap) before transport in 3% of patients. • post-transport, 23% of patients required escalation of respiratory support. fleming et al.34 (2012) retrospective study niv (cpap) 54 infants with suspected bronchiolitis • no adverse events were noted during transport. • however, 10% required intubation within 24 hours of transport. resnick and sokol35 (2010) retrospective study niv (cpap) 369 neonates aged ≥32 gestational weeks with acute respiratory distress • during the two-year study period, cpap use increased from 33% to 59%. • overall, 13% of the neonates required intubation within 24 hours of transport, likely due to higher initial oxygen requirements. • there was no significant morbidity or mortality. baird et al.36 (2009) retrospective study niv (cpap and bpap) 25 children and teenagers aged ≤18 years • overall, 64% and 36% of patients were transported on cpap and bpap, respectively. • no adverse events were observed during transport. • however, 35% of patients required intubation within 84 hours of transport. millán et al.37 (2017) prospective observational study invasive ventilation, niv (cpap) or ocn 288 children aged ≤17 months with acute respiratory failure, of which 58% had bronchiolitis • overall, 19%, 37% and 44% of patients were transported on invasive ventilation, cpap and ocn, respectively. • minor adverse events (i.e. intolerance to the interface) were observed in 3% of patients. • one patient required intubation during transport. cheema et al.38 (2018) systematic review niv (cpap) and hfnct 858 neonates and children • the rate of minor adverse events was 1–4%. • only 0.4% of patients required intubation or escalation of support during transfer. • overall, 10% needed intubation within 24 hours of transfer. • the odds of intubation within 24 hours were higher for patients on cpap compared to those on hfnct. niv = noninvasive ventilation; hfnct = high-flow nasal cannulae therapy; cpap = continuous positive airway pressure; bpap = bilevel positive airway pressure; ocn = oxygen cannula/nebulisation. khaloud s. almukhaini and najwa m. al-rahbi review | e249 with increased comfort for patients, as well as a reduction in the need to change the mode of respiratory support for the purposes of patient stabilisation before transfer.39 similarly, a large prospective study of 288 children with acute respiratory failure found that stabilisation occurred more rapidly with niv compared to invasive ventilation (median time: 48 versus 83 minutes; p <0.001).36 other research has also shown that niv and hfnct usage during transport is safe and feasible and reduces the need for invasive ventilation.34,35 cheema et al. noted that the rate of adverse events was low (1–4%) in a systematic review of eight observational studies evaluating niv and hfnct usage during paediatric transport.38 observed side-effects included apnoea and the need for cardiopulmonary resuscitation or bag mask ventilation. however, only 0.4% required intubation or escalation of respiratory support during transport, although 10% required intubation within 24 hours of transfer.38 regardless of mode of respiratory support, spec ialised retrieval teams are essential to the safe transfer of patients. in an observational study of paediatric transfers over a six-month period, barry and ralston reported that patient retrieval by non-specialised teams was linked with complications during transfer.40 in addition, researchers have noted certain clinical contraindications for transporting children on niv.36,37 an early study assessing the safety of niv during transport reported no adverse events; however, this approach was not considered for children diagnosed with shock, cardiopulmonary arrest or trauma to the head and neck.36 according to millán et al., this respiratory support approach should be considered only in the presence of a well-trained transport team.37 the authors also recommended the application of strict inclusion and exclusion criteria when selecting patients. for example, the researchers considered niv usage during transport to be unsuitable for children with a diagnosis of ards and those requiring high niv settings or demonstrating a lack of clinical response to niv.37 conclusion according to the available literature, the application of hfnct or niv respiratory approaches in nonintensive care environments seems to be safe and feasible, provided that continuous monitoring and specialised staff are available. in addition, institutional protocols for the early evaluation of children with acute respiratory distress may be useful to determine the necessity for further escalation of therapy or picu transfer. references 1. antonelli m, conti g, rocco m, bufi m, de blasi ra, vivino g, et al. a comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. n engl j med 1998; 339:429–35. https://doi. org/10.1056/nejm199808133390703. 2. yañez lj, yunge m, emilfork m, lapadula m, alcántara a, fernández c, et al. a prospective, randomized, controlled trial of noninvasive ventilation in pediatric acute respiratory failure. pediatr crit care med 2008; 9:484–9. https://doi.org/10.1097/ pcc.0b013e318184989f. 3. ganu ss, gautam a, wilkins b, egan j. increase in use of non-invasive ventilation for infants with severe bronchiolitis is associated with decline in intubation rates over a decade. intensive care med 2012; 38:1177–83. https://doi.org/10.1007/ s00134-012-2566-4. 4. wolfler a, calderini e, iannella e, conti g, biban p, dolcini a, et al. evolution of noninvasive mechanical ventilation use: a cohort study among italian picus. pediatr crit care med 2015; 16:418–27. https://doi.org/10.1097/pcc.0000000000000387. 5. essouri s, chevret l, durand p, haas v, fauroux b, devictor d. noninvasive positive pressure ventilation: five years of exp erience in a pediatric intensive care unit. pediatr crit care med 2006; 7:329–34. https://doi.org/10.1097/01.pcc.00002250 89.21176.0b. 6. essouri s, durand p, chevret l, haas v, perot c, clement a, et al. physiological effects of noninvasive positive ventilation during acute moderate hypercapnic respiratory insufficiency in children. intensive care med 2008; 34:2248–55. https://doi. org/10.1007/s00134-008-1202-9. 7. milési c, boubal m, jacquot a, baleine j, durand s, odena mp, et al. high-flow nasal cannula: recommendations for daily practice in pediatrics. ann intensive care 2014; 4:29. https://doi.org/10.11 86/s13613-014-0029-5. 8. mikalsen ib, davis p, øymar k. high flow nasal cannula in children: a literature review. scand j trauma resusc emerg med 2016; 24:93. https://doi.org/10.1186/s13049-016-0278-4. 9. lee jh, rehder kj, williford l, cheifetz im, turner da. use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of the literature. intensive care med 2013; 39:247–57. https://doi.org/10.1007/s00134-012-2743-5. 10. essouri s, laurent m, chevret l, durand p, ecochard e, gajdos v, et al. improved clinical and economic outcomes in severe bron chiolitis with pre-emptive ncpap ventilator strategy. intensive care med 2014; 40:84–91. https://doi.org/10.1007/s00134-013-3129-z. 11. kawaguchi a, yasui y, decaen a, garros d. the clinical impact of heated humidified high-flow nasal cannula on pediatric respiratory distress. pediatr crit care med 2017; 18:112–19. https://doi.org/10.1097/pcc.0000000000000985. 12. mckiernan c, chua lc, visintainer pf, allen h. high flow nasal cannulae therapy in infants with bronchiolitis. j pediatr 2010; 156:634–8. https://doi.org/10.1016/j.jpeds.2009.10.039. 13. schibler a, pham tm, dunster kr, foster k, barlow a, gibbons k, et al. reduced intubation rates for infants after introduction of high-flow nasal prong oxygen delivery. intensive care med 2011; 37:847–52. https://doi.org/10.1007/s00134-011-2177-5. 14. milési c, essouri s, pouyau r, liet jm, afanetti m, portefaix a, et al. high flow nasal cannula (hfnc) versus nasal continuous positive airway pressure (ncpap) for the initial respiratory man agement of acute viral bronchiolitis in young infants: a multi center randomized controlled trial (tramontane study). int ensive care med 2017; 43:209–16. https://doi.org/10.1007/s00 134-016-4617-8. 15. cabrini l, moizo e, nicelli e, licini g, turi s, landoni g, et al. noninvasive ventilation outside the intensive care unit from the patient point of view: a pilot study. respir care 2012; 57:704–9. https://doi.org/10.4187/respcare.01474. https://doi.org/10.1056/nejm199808133390703 https://doi.org/10.1056/nejm199808133390703 https://doi.org/10.1097/pcc.0b013e318184989f https://doi.org/10.1097/pcc.0b013e318184989f https://doi.org/10.1007/s00134-012-2566-4 https://doi.org/10.1007/s00134-012-2566-4 https://doi.org/10.1097/pcc.0000000000000387 https://doi.org/10.1097/01.pcc.0000225089.21176.0b https://doi.org/10.1097/01.pcc.0000225089.21176.0b https://doi.org/10.1007/s00134-008-1202-9 https://doi.org/10.1007/s00134-008-1202-9 https://doi.org/10.1186/s13613-014-0029-5 https://doi.org/10.1186/s13613-014-0029-5 https://doi.org/10.1186/s13049-016-0278-4 https://doi.org/10.1007/s00134-012-2743-5 https://doi.org/10.1007/s00134-013-3129-z https://doi.org/10.1097/pcc.0000000000000985 https://doi.org/10.1016/j.jpeds.2009.10.039 https://doi.org/10.1007/s00134-011-2177-5 https://doi.org/10.1007/s00134-016-4617-8 https://doi.org/10.1007/s00134-016-4617-8 https://doi.org/10.4187/respcare.01474 use of noninvasive ventilation and high-flow nasal cannulae therapy for infants and children with acute respiratory distress outside of paediatric intensive care a review article e250 | squ medical journal, august 2020, volume 20, issue 3 16. randolph ag, gonzales ca, cortellini l, yeh ts. growth of pediatric intensive care units in the united states from 1995 to 2001. j pediatr 2004; 144:792–8. https://doi.org/10.1016/j. jpeds.2004.03.019. 17. yoon js, jhang wk, choi yh, lee b, kim yh, cho hj, et al. current status of pediatric critical care in korea: results of 2015 national survey. j korean med sci 2018; 33:e308. https://doi.org/10.3346/jkms.2018.33.e308. 18. khanal a, sharma a, basnet s. current state of pediatric intensive care and high dependency care in nepal. pediatr crit care med 2016; 17:1032–40. https://doi.org/10.1097/ pcc.0000000000000938. 19. choong k, fraser d, al-harbi s, borham a, cameron j, cameron s, et al. functional recovery in critically ill children, the “weecover” multicenter study. pediatr crit care med 2018; 19:145–54. https://doi.org/10.1097/pcc.0000000000001421. 20. scala r. respiratory high-dependency care units for the burden of acute respiratory failure. eur j intern med 2012; 23:302–8. https://doi.org/10.1016/j.ejim.2011.11.002. 21. davison m, watson m, wockner l, kinnear f. paediatric high flow nasal cannula therapy in children with bronchiolitis: a retro spective safety and efficacy study in a nontertiary environment. emerg med australas 2017; 29:198–203. https://doi.org/10.11 11/1742-6723.12741. 22. ballestero y, de pedro j, portillo n, martinez-mugica o, aranaarri e, benito j. pilot clinical trial of high-flow oxygen therapy in children with asthma in the emergency service. j pediatr 2018; 194:204–10.e3. https://doi.org/10.1016/j.jpeds.2017.10.075. 23. vitaliti g, wenzel a, bellia f, pavone p, falsaperla r. noninvasive ventilation in pediatric emergency care: a literature review and description of our experience. expert rev respir med 2013; 7:545–52. https://doi.org/10.1586/17476348.2013.816570. 24. franklin d, babl fe, schlapbach lj, oakley e, craig s, neutze j, et al. a randomized trial of high-flow oxygen therapy in infants with bronchiolitis. n engl j med 2018; 378:1121–31. https://doi.org/10.1056/nejmoa1714855. 25. mayordomo-colunga j, pons-òdena m, medina a, rey c, milesi c, kallio m, et al. non-invasive ventilation practices in children across europe. pediatr pulmonol 2018; 53:1107–14. https://doi.org/10.1002/ppul.23988. 26. panciatici m, fabre c, tardieu s, sauvaget e, dequin m, stremier-le bel n, et al. use of high-flow nasal cannula in infants with viral bronchiolitis outside pediatric intensive care units. eur j pediatr 2019; 178:1479–84. https://doi.org/10.1007/ s00431-019-03434-4. 27. sokuri p, heikkilä p, korppi m. national high-flow nasal cannula and bronchiolitis survey highlights need for further research and evidence-based guidelines. acta pediatr 2017; 106:1998–2003. https://doi.org/10.1111/apa.13964. 28. kelly gs, simon hk, sturm jj. high-flow nasal cannula use in children with respiratory distress in the emergency department: predicting the need for subsequent intubation. pediatr emerg care 2013; 29:888–92. https://doi.org/10.1097/ pec.0b013e31829e7f2f. 29. long e, babl fe, duke t. is there a role for humidified heated highflow nasal cannula therapy in paediatric emergency departments? emerg med j 2016; 33:386–9. https://doi.org/10.1136/emerm ed-2015-204914. 30. betters ka, gillespie se, miller j, kotzbauer d, hebbar kb. high flow nasal cannula use outside of the icu: factors associated with failure. pediatr pulmonol 2017; 52:806–12. https://doi.org/10.1002/ppul.23626. 31. riese j, fierce j, riese a, alverson bk. effect of a hospital-wide high-flow nasal cannula protocol on clinical outcomes and resource utilization of bronchiolitis patients admitted to the picu. hosp pediatr 2015; 5:613–18. https://doi.org/10.1542/ hpeds.2014-0220. 32. schlapbach lj, schaefer j, brady am, mayfield s, schibler a. high-flow nasal cannula (hfnc) support in interhospital transport of critically ill children. intensive care med 2014; 40:592–9. https://doi.org/10.1007/s00134-014-3226-7. 33. abraham v, manley bj, owen ls, stewart mj, davis pg, roberts ct. nasal high-flow during neonatal and infant transport in victoria, australia. acta paediatr 2019; 108:768–9. https://doi.org/10.1111/apa.14650. 34. fleming pf, richards s, waterman k, davis pg, kamlin co, soko j, et al. use of continuous positive airway pressure during stabilisation and retrieval of infants with suspected bronchiolitis. j paediatr child health 2012; 48:1071–5. https://doi.org/10.11 11/j.1440-1754.2012.02468.x. 35. resnick s, sokol j. impact of introducing binasal continuous pos itive airway pressure for acute respiratory distress in newborns during retrieval: experience from western australia. j paediatr child health 2010; 46:754–9. https://doi.org/10.1111/j.14401754.2010.01834.x. 36. baird js, spiegelman jb, prianti r, frudak s, schleien cl. noninvasive ventilation during pediatric interhospital ground transport. prehosp emerg care 2009; 13:198–202. https://doi. org/10.1080/10903120802706112. 37. millán n, alejandre c, martinez-planas a, cartig j, esteban e, pons-òdena m. noninvasive respiratory support during pediatric ground transport: implementation of a safe and feasible proce dure. respir care 2017; 62:558–65. https://doi.org/10.4187/resp care.05253. 38. cheema b, welzel t, rossouw b. noninvasive ventilation during pediatric and neonatal critical care transport: a systematic re view. pediatr crit care med 2018; 20:9–18. https://doi.org/10.10 97/pcc.0000000000001781. 39. boyle ma, dhar a, broster s. introducing high-flow nasal cannula to the neonatal transport environment. acta paediatr 2017; 106:1363. https://doi.org/10.1111/apa.13910. 40. barry pw, ralston c. adverse events occurring during inter hospital transfer of the critically ill. arch dis child 1994; 71:8–11. https://doi.org/10.1136/adc.71.1.8. https://doi.org/10.1016/j.jpeds.2004.03.019 https://doi.org/10.1016/j.jpeds.2004.03.019 https://doi.org/10.3346/jkms.2018.33.e308 https://doi.org/10.1097/pcc.0000000000000938 https://doi.org/10.1097/pcc.0000000000000938 https://doi.org/10.1097/pcc.0000000000001421 https://doi.org/10.1016/j.ejim.2011.11.002 https://doi.org/10.1111/1742-6723.12741 https://doi.org/10.1111/1742-6723.12741 https://doi.org/10.1016/j.jpeds.2017.10.075 https://doi.org/10.1586/17476348.2013.816570 https://doi.org/10.1056/nejmoa1714855 https://doi.org/10.1002/ppul.23988 https://doi.org/10.1007/s00431-019-03434-4 https://doi.org/10.1007/s00431-019-03434-4 https://doi.org/10.1111/apa.13964 https://doi.org/10.1097/pec.0b013e31829e7f2f https://doi.org/10.1097/pec.0b013e31829e7f2f https://doi.org/10.1136/emermed-2015-204914 https://doi.org/10.1136/emermed-2015-204914 https://doi.org/10.1002/ppul.23626 https://doi.org/10.1542/hpeds.2014-0220 https://doi.org/10.1542/hpeds.2014-0220 https://doi.org/10.1007/s00134-014-3226-7 https://doi.org/10.1111/apa.14650 https://doi.org/10.1111/j.1440-1754.2012.02468.x https://doi.org/10.1111/j.1440-1754.2012.02468.x https://doi.org/10.1111/j.1440-1754.2010.01834.x https://doi.org/10.1111/j.1440-1754.2010.01834.x https://doi.org/10.1080/10903120802706112 https://doi.org/10.1080/10903120802706112 https://doi.org/10.4187/respcare.05253 https://doi.org/10.4187/respcare.05253 https://doi.org/10.1097/pcc.0000000000001781 https://doi.org/10.1097/pcc.0000000000001781 https://doi.org/10.1111/apa.13910 https://doi.org/10.1136/adc.71.1.8 1department of child health, sultan qaboos university hospital, muscat, oman; 2department of child and adolescent psychiatry, al-massarah hospital, muscat, oman; 3pediatric department, royal hospital, muscat, oman; 4department of woman and child health, 5directorate general of primary health care, ministry of health, muscat, oman; 6department of statistics, college of science, sultan qaboos university, muscat, oman *corresponding author’s e-mail: ahmed30411@gmail.com إعادة النظر يف معدل إنتشار إضطراب طيف التوحد بني األطفال العمانيني دراسة متعددة املراكز وطفة املعمرية، اأحمد بابكر اإدري�ض، �صمر دقاق، منى ال�صكيلي، زوينة احلارثية، اأ�صيه النعمانية، فاطمة الهنائية، ثاقب جلي�ض، موزة احلامتية، حممد النجاري، م.مظهر الإ�صالم abstract: objectives: this study aimed to provide an updated estimate of the prevalence of autism spectrum disorder (asd) among omani children. methods: this retrospective descriptive study was conducted from december 2011 to december 2018. data were retrieved from the three main autism diagnostic centres in oman: sultan qaboos university hospital, royal hospital and al-massarah hospital. the asd diagnosis was made by experienced clinicians based on the fifth edition of the diagnostic and statistical manual of mental disorders (dsm-5). the overall population prevalence estimates per 10,000 children aged 0–14 years old in oman were calculated using the denominator of the mid-period population data. results: a total of 1,705 asd cases were identified with the majority of cases being male (78.1%). the overall prevalence rate of asd was estimated at 20.35 per 10,000 children (95% confidence interval: 19.39–21.32) between 2012–2018. boys were found to have a 3.4-fold higher prevalence of asd than girls (31.23/10,000 versus 9.07/10,000). regionally, the majority of cases were found in the capital, muscat, where the highest prevalence was 36.51 cases per 10,000 children. conclusion: the prevalence of asd among omani children is 15-fold higher than estimates from 2011. this increase can be attributed to improvements in diagnostic services, increased awareness of asd, better screening programmes and changes in diagnostic criteria. in addition, this increase in prevalence suggests a need for a registry of developmental disabilities and more extensive diagnostic and rehabilitation services in oman. keywords: autism spectrum disorder; epidemiology; prevalence; oman. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل اعادة تقدير ملعدل انت�صار اإ�صطراب طيف التوحد بني الأطفال العمانيني. الطريقة: اأجريت درا�صة و�صفية اإ�صرتجاعية يف الفرتة ما بني دي�صمرب 2011 حتي دي�صمرب 2018. مت جمعا لبيانات من ثالثة مراكز رئي�صية لت�صخي�ض اإ�صطراب طيف التوحد يف عمان، و هم م�صت�صفى جامعة ال�صلطان قابو�ض، امل�صت�صفى ال�صلطاين و م�صت�صفى امل�رسة. مت ت�صخي�ض اإ�صطراب طيف التوحد بوا�صطة اأطباء ذوي خربة مرتكزين على الإ�صدار اخلام�ض من الدليل الت�صخي�صي والإح�صائي لال�صطرابات العقلية )dsm-5(. مت تقدير املعدل الإجمايل لإنت�صار ال�صكان لكل 10,000 طفل الذي ترتاوح اأعمارهم بني 14–0 عاًما با�صتخدام املقام يف بيانات منت�صف الفرتة لعدد �صكان ُعمان. النتائج: مت ت�صجيل 1,705 حالة اإ�صابة با�صطراب طيف التوحد الذي كان اأكرث �صيوعا بني الذكور )78.1(. يقدر معدل النت�صار الإجمايل لإ�صطراب طيف التوحد ب 20.35 لكل 10,000 طفل. )%95 جمال الثقة: 19.39-21.32( بني 2012-2018. كان معدل اإنت�صارطيف التوحد اأعلى بني الذكور ب 3.4 �صعف عن الإناث )31.23/10,000 مقابل 9.07/10,000(. كان اأعلى معدل انت�صار للحالت يف العا�صمة م�صقط و هو 36.51 حالة لكل 10,000 طفل. اخلال�صة: معدل اإنت�صار اإ�صطراب طيف التوحد بني الأطفال العمانيني اأعلى بخم�صة ع�رس �صعًفا من تقديرات عام 2011. ميكن اأن تعزى هذه الزيادة اإىل التح�صن يف اخلدمات الت�صخي�صة، وتغيري معايريالت�صخي�ض و برامج ك�صف مبكر اأف�صل. ت�صري الزيادة يف درجة الوعي و اأنت�صار اإ�صطراب طيف التوحد اإىل احلاجة اإىل وجود �صجل لالإعاقات النمائية وخدمات ت�صخي�ض وتاأهيل اأكرث �صموًل يف ُعمان. الكلمات املفتاحية: اإ�صطراب طيف التوحد؛ علم الأوبئة؛ معدل انت�صار؛ �صلطنة عمان. revisiting the prevalence of autism spectrum disorder among omani children a multicentre study watfa al-mamri,1 *ahmed b. idris,1 samar dakak,2 muna al-shekaili,2 zuwaina al-harthi,3 asia m. alnaamani,4 fatma i. alhinai,5 saquib jalees,1 moza al hatmi,4 mohamed a. el-naggari,1 m. mazharul islam6 clinical & basic research sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e305–309, epub. 22 dec 19 submitted 26 feb 19 revisions req. 21 mar & 7 may 19; revisions recd. 27 mar & 13 may 19 accepted 30 may 19 https://doi.org/10.18295/squmj.2019.19.04.005 advances in knowledge the prevalence of autism spectrum disorder among omani children aged 0–14 years increased almost 15-fold from 2011 estimates. application to patient care this study’s findings indicate that a registry of developmental disabilities is needed and that diagnostic and rehabilitation services in oman should be expanded. revisiting the prevalence of autism spectrum disorder among omani children a multicentre study e306 | squ medical journal, november 2019, volume 19, issue 4 autism spectrum disorder (asd) is a neurodevelopmental disorder that is characterised by deficits in social communication and interaction as well as restricted repetitive patterns of behaviour, interests and activities.1 although asd is usually diagnosed after the age of three years, parental concerns commonly appear between the first and second years of life. subtle characteristics are thought to be present even in infancy and include decreased social responsiveness, lack of empathy, absence of gestures, decreased pretend play and lack of attention to others.2 the gold standard tools for asd diagnosis are based on behavioural observations that require the input of a clinician who is experienced in the diagnosis and treatment of asd.1 the diagnostic criteria for asd have been revised periodically, reflecting advances in research, practice and knowledge in this growing field. the diagnostic and statistical manual of mental disorders fifth edition’s (dsm-5) diagnostic criteria improve the specificity of the asd diagnosis at the expense of sensitivity.3 in the past, asd was thought to be a rare condition. recently, the prevalence of asd diagnoses have increased worldwide from approximately 0.0002–0.0006% of all individuals prior to the 1990s to current estimates of up to 2.6%.4–6 globally, the median asd prevalence is estimated to be 62 per 10,000.6 some explanations for the increase in the observed prevalence of asd include the development of better identification and screening methods, changes in diagnostic criteria, increased awareness among parents and clinicians, changes in the availability of services and in risk factors or aetiological causes.7,8 based on available data, publications have reported that the prevalence of asd ranges from 1.4 to 29 per 10,000 children among arab gulf countries.9,10 these prevalence estimates differ from the asd prevalence rate estimated by the centres for disease control and prevention which reports that 1 in 59 children in the usa are affected.11 a south korean study found a higher prevalence rate of asd (about 1 in 38 children) than in arab gulf countries, which suggests that better screening methods may lead to substantially higher estimates of asd’s global prevalence in the future.12 broadening the dsm-5’s diagnostic criteria may play a role in differences in prevalence estimates as most publications from arab gulf countries are based on the dsm-4 criteria.13–15 however, the similar sociocultural factors and underdiagnosis of cases might be a comm onality amongst arab gulf countries, including oman. the prevalence of asd in the omani population was estimated to be 1.4 per 10,000 children in 2011, which could most likely be an underestimation of the actual number of asd cases.13 since the developmental paediatric services in oman are still in their infancy, underdiagnosis and under-reporting still place major constraints on estimations of asd’s true prevalence.13,16 accurate prevalence estimates are essential for planning policy and service needs and identifying potential risk factors for asd. the increase in asd prevalence world wide has raised concern among national governments and international agencies to take action in terms of advocacy and policy, research and service devel opment.17,18 therefore, this study aimed to examine the prevalence of asd among omani children in view of increasing awareness and developing better diagnostic services and broader diagnostic criteria. methods this retrospective descriptive study was conducted between december 2011 and december 2018. data were retrieved from the three main autism diagnostic centres in oman: sultan qaboos university (squ) hospital, royal hospital and al-massarah hospital. these three autism diagnostic centres are the only formal sources of diagnosing and recording asd in oman among the target population; thus, these three centres were likely to capture most of the diagnosed asd cases in the country. fulfilment of dsm-5 criteria formed the basis of the asd diagnoses. the identified subjects were reviewed thoroughly to ensure the absence of repetition, since different hospitals in oman do not share electronic records. the target population consisted of all children below 14 years old who had been referred to a main diagnostic centre and formally diagnosed with asd. demographic data included age, gender and region/governorate of residence. in addition, the age at diagnosis was also recorded. clinical inform ation was obtained from the medical records at each study site. as this study used retrospective data collected over seven years, period prevalence rates at national and subnational levels were used to reflect the proportion of patients with a particular disease or attribute at any time during the study’s timeframe. period prevalence rates were calculated using a mid-period population aged 0–14 years as the denominator, which corresponds to the mid-year population of the year 2015 from a previously published report on oman population stat istics by the national centre for statistical information.19 a chi-square test was used to compare groups. a p value of less than 0.05 was considered statistically significant. ethical approval was obtained from the medical research & ethics committee of the college of medicine & health sciences, squ and the centre of studies and research, research committee, ministry of health, oman in january 2017 (mrec #1726; unique identification code #5820, respectively). watfa al-mamri, ahmed b. idris, samar dakak, muna al-shekaili, zuwaina al-harthi, asia m. alnaamani, fatma i. alhinai, saquib jalees, moza al hatmi, mohamed a. el-naggari and m. mazharul islam clinical and basic research | e307 results a total of 1,705 cases of asd were identified during the study period out of a mid-interval population of 837,655 children aged 0–14 years old. most patients were below five years old (62%) and predominantly male (78.1%; p <0.001). the mean age of children with asd was 4.8 ± 2.4 years. more than one-third (37.3%) of the asd cases were recorded in muscat governorate, followed by al-batinah north governorate (15.7%). the fewest cases were recorded in the musandam and al-wusta governorates (0.2% and 0.3%). this distribution of asd cases is somewhat consistent with the distribution of the targeted population across oman [table 1]. the overall estimate of the prevalence of asd in oman was found to be 20.35 per 10,000 children (95% confidence interval [ci]: 19.39–21.32). males had a significantly higher (3.6-fold higher) prevalence of asd than females (31.23/10,000 versus 9.07/10,000; p <0.001) [table 1]. this finding was true for all age groups [figure 1]. the prevalence of diagnosed asd cases showed an association with age. it was higher among children under five years old (30.34/10,000) compared to children aged 5–9 years old (20.2/10,000) and children aged 10–14 years old (4.52/10,000). the prevalence of asd was found to vary significantly across oman’s administrative regions, with the majority of cases found in the capital, muscat, where the preval ence was 36.51 cases per 10,000 children (95% ci: 33.68–39.34). the prevalence in al-batinah north, being the second more populous region, was sign ificantly lower (16.14/10,000; 95% ci: 14.21–18.07). however, outside of muscat, the prevalence was highest in ash-sharqiyah south (20.65/10,000; 95% ci: 17.22–24.08) and lowest in musandam (4.27/10,000; 95% ci: 0.09–8.45) [table 1]. discussion the prevalence of asd among omani children increased almost 15-fold since 2011 estimates.13 this finding could be attributed to an increase in the autism detection rate among the omani population rather than a real environmental increment. another factor table 1: distribution of children aged 0–14 years with autism spec trum disorder (asd) and estimated prevalence of asd in oman (n = 1,705) characteristic n (%) mid-year population estimated prevalence/ 10,000 children (95% ci) p value* gender male 1,332 (78.1) 426,450 31.23 (29.56–32.91) <0.001 female 373 (21.9) 411,205 9.07 (8.15–9.99) age in years 0–4 1,057 (62) 348,419 30.34 (28.51–32.16) <0.0015–9 550 (32.3) 272,309 20.2 (18.51–21.88) 10–14 98 (5.7) 216,927 4.52 (3.62–5.41) mean age in years ± sd 4.8 ± 2.4 region/governorate muscat 636 (37.3) 174,198 36.51 (33.68–39.34) <0.001 dofar 64 (3.8) 70,222 9.11 (6.88–11.35) musandam 4 (0.2) 9,373 4.27 (0.09–8.45) al-buraymi 12 (0.7) 18,416 6.52 (2.83–10.2) ad-dakhliyah 231 (13.5) 115,140 20.06 (17.48–22.65) al-batinah north 267 (15.7) 165,423 16.14 (14.21–18.07) al-batinah south 182 (10.7) 100,311 18.14 (15.51–20.78) ash-sharqiyah north 119 (7) 58,244 20.43 (16.76–24.1) ash-sharqiyah south 139 (8.2) 67,307 20.65 (17.22–24.08) adh-dhahirah 46 (2.7) 50,873 9.04 (6.43–11.65) al-wusta 5 (0.3) 8,148 6.14 (0.76–11.51) total 1,705 (100) 837,655 20.35 (19.39–21.32) ci = confidence interval; sd = standard deviation. *using chi-square test. figure 1: estimated prevalence of autism spectrum disorder among the current study cohort classified by age and gender (n = 1,705). revisiting the prevalence of autism spectrum disorder among omani children a multicentre study e308 | squ medical journal, november 2019, volume 19, issue 4 that could contribute to this increase is the launch of the national screening programme for autism and other developmental disorders in early 2017. although the programme has not reached its full potential yet, the collateral outcomes of awareness and media interest could have played a role. although no published data are available for comparison, unpublished data from squ estimated the prevalence by the end of 2015 to reach 8.5 cases per 10,000 children.20 increasing comm unity awareness plays a major role in detecting asd within the general population. it has been reported that family members are the first to notice and report children’s milestones.21 although knowledge about autism in omani school-teachers in mainstream schools has been described as low, it can be assumed that their awareness of asd, like awareness in the general population, has improved in the last decade mostly due to media and increasing diagnostic facilities and governmental interests.22 moreover, the increasing prevalence of asd has been attributed to diagnostic substitution as the increment in the autism diagnosis has been accompanied by a decrease in labelling intellectual disability.23 the gender distribution found in the current study is comparable with international autism data.6,11,12 the vast majority of patients had a presenting age below four years old, which is in agreement with published studies on autism.24–26 the paucity of cases diagnosed in the older age group may be affected by the degree of the severity of the cases that were detected and referred from peripheral facilities. coo et al. attributed similar findings to the possibility that mild-to-moderate cases were mixed in mainstream schools and special needs classes and, in these settings, were misclassified as intellectually disabled or as having learning difficulties rather than asd.23 asd is not limited by geographical or political boundaries unless it is linked to hidden genetic or environmental factors; hence, the differences in the prevalence of asd among governorates may be due to an inconsistency in referral policies and accessibility to services.27,28 the findings of a relatively higher prev alence of asd in muscat and ash-sharqiyah regions highlight the importance of determining why these regions have a higher prevalence of asd and develop region-specific approaches. the current study’s estimation of the prevalence was based on a hospital-based sample; thus, a major limitation may arise from the fact that many undiagn osed cases were not included in this cohort, leading to an underestimation of the true prevalence. conclusion the prevalence of asd among omani children is estimated to be 20.35 per 10,000 children. the prev alence of asd among omani children is 15-fold greater than estimates from 2011. this rise can be attributed to improvements in the detection rate due to increasing awareness and screening programmes, better diagnostic services and changing diagnostic criteria. a registry of developmental disabilities should be established and diagnostic and rehabilitation services should be expanded. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references: 1. american psychiatric association. autism spectrum disorder. in: diagnostic and statistical manual of mental disorders, 5th ed. washington, dc: american psychiatric association, 2013. p. 50. 2. sigman m, dijamco a, gratier m, rozga a. early detection of core deficits in autism. ment retard dev disabil res rev 2004; 10:221–33. https://doi.org/10.1002/mrdd.20046. 3. mcpartland jc, reichow b, volkmar fr. sensitivity and specificity of proposed dsm-5 diagnostic criteria for autism spectrum disorder. j am acad child adolesc psychiatry 2012; 51:368–83. https://doi.org/10.1016/j.jaac.2012.01.007. 4. fombonne e. epidemiology of pervasive developmental disorders. pediatr res 2009; 65:591–8. https://doi.org/10.1203/ pdr.0b013e31819e7203. 5. rice ce, rosanoff m, dawson g, durkin ms, croen la, singer a, et al. evaluating changes in the prevalence of the autism spectrum disorders (asds). public health rev 2012; 34:1–22. https://doi.org/10.1007/bf03391685. 6. elsabbagh m, divan g, koh yj, kim ys, kauchali s, marcín c, et al. global prevalence of autism and other pervasive develop mental disorders. autism res 2012; 5:160–79. https://doi.org/10.1 002/aur.239. 7. king m, bearman p. diagnostic change and the increased prevalence of autism. int j epidemiol 2009; 38:1224–34. https://doi.org/10.1093/ije/dyp261. 8. hansen sn, schendel de, parner et. explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices. jama pediatr 2015; 169:56–62. https://doi.org/10.1001/ jamapediatrics.2014.1893. 9. salhia ho, al-nasser la, taher ls, al-khathaami am, el-metwally aa. systemic review of the epidemiology of autism in arab gulf countries. neurosciences (riyadh) 2014; 19:291–6. 10. almandil nb, alkuroud dn, abdulazeez s, alsulaiman a, elaissari a, borgio jf. environmental and genetic factors in autism spectrum disorders: special emphasis on data from arabian studies. int j environ res public health 2019; 16:e658. https://doi.org/10.3390/ijerph16040658. https://doi.org/10.1111/dme.13413 https://doi.org/10.1111/dme.13413 https://doi.org/10.1111/dme.13413 https://doi.org/10.1111/dme.13413 https://doi.org/10.1007/bf03391685 https://doi.org/10.1002/aur.239 https://doi.org/10.1002/aur.239 https://doi.org/10.1093/ije/dyp261 https://doi.org/10.1001/jamapediatrics.2014.1893 https://doi.org/10.1001/jamapediatrics.2014.1893 https://doi.org/10.3390/ijerph16040658 watfa al-mamri, ahmed b. idris, samar dakak, muna al-shekaili, zuwaina al-harthi, asia m. alnaamani, fatma i. alhinai, saquib jalees, moza al hatmi, mohamed a. el-naggari and m. mazharul islam clinical and basic research | e309 11. baio j, wiggins l, christensen dl, maenner mj, daniels j, warren z, et al. prevalence of autism spectrum disorder among children aged 8 years autism and developmental disabilities monitoring network, 11 sites, united states, 2014. mmwr surveill summ 2018; 67:1–23. https://doi.org/10.15585/mmwr. ss6706a1. 12. kim ys, leventhal bl, koh yj, fombonne e, laska e, lim ec, et al. prevalence of autism spectrum disorders in a total popul ation sample. am j psychiatry 2011; 168:904–12. https://doi. org/10.1176/appi.ajp.2011.10101532. 13. al-farsi ym, al-sharbati mm, al-farsi oa, al-shafaee ms, brooks dr, waly mi. brief report: prevalence of autistic spectrum disorders in the sultanate of oman. j autism dev disord 2011; 41:821–5. https://doi.org/10.1007/s10803-010-1094-8. 14. al-salehi s, al-hifthy e, ghaziuddin m. autism in saudi arabia: presentation, clinical correlates and comorbidity. transcult psychiatry 2009; 46:340–7. https://doi.org/10.1177/1363461509 105823. 15. eapen v, mabrouk a, zoubeidi t, yunis f. prevalence of pervasive developmental disorders in preschool children in the uae. j trop pediatr 2007; 53:202–5. https://doi.org/10.1093/ tropej/fml091. 16. ouhtit a, al-farsi y, al-sharbati m, waly m, gupta i, al-farsi o, et al. underlying factors behind the low prevalence of autism spectrum disorders in oman: sociocultural perspective. sultan qaboos univ med j 2015; 15:e213–17. 17. munir km, lavelle ta, helm dt, thompson d, prestt j, azeem mw. autism: a global framework for action. from: www.wish.org.qa/wp-content/uploads/2018/01/impj4495_ wish_autism_report_web.pdf accessed: may 2019. 18. dunlop aw, mcgregor e, marwick h, ravet j, robinson a, rydzewska e, et al. action on autism research in scotland: an advanced international multidisciplinary, multi-agency research seminar series held between november 2013 and november 2014. from: https://strathprints.strath.ac.uk/59541/1/dunlop_ etal_2016_action_on_autism_research_in_scotland.pdf accessed: may 2019. 19. national center for statistics and information. sultanate of oman. from: www.ncsi.gov.om accessed: may 2019. 20. al-mamari w, idris ab, al-jabri m, abdelsattar a, al-hinai f, al-hatmi m, et al. a turning point for paediatric developmental services in oman: establishment of a national autism screening programme. sultan qaboos univ med j 2017; 17:e125–6. https://doi.org/10.18295/squmj.2016.17.01.026. 21. wetherby am, brosnan-maddox s, peace v, newton l. valid ation of the infant-toddler checklist as a broadband screener for autism spectrum disorders from 9 to 24 months of age. autism 2008; 12:487–511. https://doi.org/10.1177/1362361308094501. 22. al-sharbati m, al-farsi ym, ouhtit a, waly mi, al-shafaee m, al-farsi o, et al. awareness about autism among school teachers in oman: a cross-sectional study. autism 2015; 19:6–13. https://doi.org/10.1177/1362361313508025. 23. coo h, ouellette-kuntz h, lloyd je, kasmara l, holden jj, lewis me. trends in autism prevalence: diagnostic substitution revisited. j autism dev disord 2008; 38:1036–46. https://doi. org/10.1007/s10803-007-0478-x. 24. autism and developmental disabilities monitoring network surveillance year 2002 principal investigators, centers for disease control and prevention. prevalence of autism spectrum disorders -autism and developmental disabilities monitoring network, 14 sites, united states, 2002. mmwr surveill summ 2007; 56:12–28. 25. wiggins ld, baio j, rice c. examination of the time between first evaluation and first autism spectrum diagnosis in a population-based sample. j dev behav pediatr 2006; 27:s79–87. 26. ouellette-kuntz hm, coo h, lam m, yu ct, breitenbach mm, hennessey pe, et al. age at diagnosis of autism spectrum disorders in four regions of canada. can j public health 2009; 100:268–73. https://doi.org/10.1097/00004703-200604002-00005. 27. hallmayer j, cleveland s, torres a, phillips j, cohen b, torigoe t, et al. genetic heritability and shared environ mental factors among twin pairs with autism. arch gen psych iatry 2011; 68:1095–102. https://doi.org/10.1001/archgenpsy chiatry.2011.76. 28. kinney d, miller a, crowley d, huang e, gerber e. autism prevalence following prenatal exposure to hurricanes and tropical storms in louisiana. j autism dev disord 2008; 38:481–8. https://doi.org/10.1007/s10803-007-0414-0. https://doi.org/10.15585/mmwr.ss6706a1 https://doi.org/10.15585/mmwr.ss6706a1 https://doi.org/10.1176/appi.ajp.2011.10101532 https://doi.org/10.1176/appi.ajp.2011.10101532 https://doi.org/10.1007/s10803-010-1094-8 https://doi.org/10.1177/1363461509105823 https://doi.org/10.1177/1363461509105823 https://doi.org/10.1093/tropej/fml091 https://doi.org/10.1093/tropej/fml091 https://doi.org/10.18295/squmj.2016.17.01.026 https://doi.org/10.1177/1362361308094501 https://doi.org/10.1177/1362361313508025 https://doi.org/10.1007/s10803-007-0478-x https://doi.org/10.1007/s10803-007-0478-x https://doi.org/10.1097/00004703-200604002-00005 https://doi.org/10.1001/archgenpsychiatry.2011.76 https://doi.org/10.1001/archgenpsychiatry.2011.76 https://doi.org/10.1007/s10803-007-0414-0 a 52 year-old right-handed man, from south india, presented with left hemiparesis of one day duration. he had vascular risk factors such as hypertension, ethanol consumption and cigarette smoking. there was no family history of left handedness. neurologically, he demonstrated left faciobrachial (muscle power: grade 0–1/5), crural weakness (grade 3–4/5), global aphasia, left hemisensory impairment and left hemianopsia, with a national institute of health (nih) stroke scale score of 19. the cardiac evaluation did not disclose valvular lesion/vegetation, mural thrombus, or significant ischaemic lesion. the computed tomography (ct) scan of his brain [figure 1a] showed recent infarction in the distribution of the right middle cerebral artery, but there were no additional left hemispheric infarcts (also confirmed subsequently squ med j, february 2011, vol. 11, iss. 1, pp. 122-123, epub. 12th feb 11 submitted 30th jun 10 accepted 29th sept 10 department of medicine, sultan qaboos university hospital, muscat oman; former affiliation: department of neurology, sri venkateswara institute of medical sciences (svims), tirupati, india. *corresponding author email: rnandagopal@yahoo.com ‡µ_<ì~ç<ª<ìfäj”⁄<ìf÷^íj⁄<ìäfu  acquired crossed aphasia in a dextral ramachandiran nandhagopal interesting medical image figure 1: a: cranial computed tomography scan obtained on the day of the stroke demonstrates ill-defined hypodensity (arrow pointing to the low signal) in the right fronto-parieto-temporal region, corona radiate and capsulo-ganglionic area consistent with a recent infarct in the distribution of right middle cerebral artery. b: the lesion is well delineated with a density similar to that of cerebrospinal fluid (arrow) along with dilatation of ipsilateral ventricle in the scan performed 7 months after the event indicating chronic infarction. note the absence of an additional lesion in the left hemisphere in both figures a and b. by a diffusion weighted magnetic resonance imaging scan). as he presented beyond the time window for thrombolytic therapy, he was treated with an antiplatelet drug, statins, antihypertensive medication, speech therapy and physiotherapy. a repeat computed tomography ct brain scan [figure 1b], performed 7 months later, demonstrated a chronic infarction in the same location with no additional left hemispheric lesion. athough his left hemiparesis had significantly improved (arm power: grade 3–4/5), his global aphasia continued to pose significant problem for verbal communication over the subsequent years. crossed aphasia (ca) refers to a language (symbolic communication with words) disorder resulting from a unilateral right hemispheric lesion in dextrals (right-handers).1-3 ca is rare with an estimated prevalence of 0.4–3.5% of all aphasic syndromes.2 in right handers, language function is often lateralised to the left hemisphere. atypical cerebral dominance for language in our patient accounted for the right hemispheric stroke-related aphasia that was persistent and functionally disabling. the pattern of his clinical course suggested complete lateralisation of language to his right hemisphere. apart from ischaemic strokes, other aetiologies include aneurysmal subarchnoid haemorrhage, multiple sclerosis, direct cortical stimulation, migraine with aura and focal dementia.4-8 references 1. alexander mp, fischette mr, fischer rs. crossed aphasias can be mirror image or anomalous. case reports, review and hypothesis. brain 1989; 112:953– 73. 2. dewarrat gm, annoni jm, fornari e, carota a, bogousslavsky j, maeder p. acute aphasia after right hemisphere stroke. j neurol 2009; 256:1461–7. 3. marien p, engelborghs s, vignolo la, de deyn pp. the many faces of crossed aphasia in dextrals: report of nine cases and review of the literature. eur j neurol 2001; 8:643–58. 4. demirkiran m, ozeren a, sonmezler a, bozdemir h. crossed aphasia in multiple sclerosis. mult scler 2006; 12:116–9. 5. martins ip. crossed aphasia during migraine aura: transcallosal spreading depression? j neurol neurosurg psychiatr 2007; 78:544–5. 6. oishi m, suzuki k, sasaki o, nakazato s, kitazawa k, takao t, et al. crossed aphasia elicited by direct cortical stimulation. neurology 2006; 67:1306–7. 7. repetto c, manenti r, cotelli m, calabria m, zanetti o, borroni b, et al. right hemisphere involvement in non-fluent primary progressive aphasia. behav neurol 2007; 18:239–43. 8. seckin h, yigitkanli k, kapucu o, bavbek m. crossed wernicke's aphasia after aneurysmal subarachnoid hemorrhage: a case report. turk neurosurg 2009; 19:77–81. ramachandiran nandhagopal interesting medical image | 123 departments of 1obstetrics & gynaecology and 2radiology, royal hospital, muscat, oman *corresponding author’s e-mail: santhosh.jayasree@yahoo.com spontaneous haemoperitoneum in pregnancy with placenta percreta in bicornuate uterus with successful pregnancy outcome a case study *jayasree santhosh,1 latha v. kharka,1 atheel kamona,2 sumaiya saif al amri1 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 291–294, epub. 26 may 22 submitted 17 nov 20 revision req. 21 jan 21; revision recd. 16 feb 21 accepted 16 mar 21 (ctg) was normal. abdominal ultrasound scan (uss) revealed free fluid suggestive of haemoperitoneum and a large right adnexal haematoma. foetal status remained normal. images were discussed with the radiologist and scar dehiscence was ruled out both clinically and radiologically. there was no obvious inflammatory mass or bowel thickening and the appendix and right kidney looked normal. she was given a blood transfusion and supportive care. on abdominal magnetic resonance imaging (mri), the haematoma was found to extend from the right iliac fossa to the uterine fundus [figures 1 and 2]. abdominal computed tomography (ct) angiography was done as suggested by the consultant surgeon to exclude ongoing haemorrhage. the patient also preferred to proceed with imaging rather than with laparotomy to avoid possible preterm delivery. as there was no active bleeding, she was conservatively managed. she remained stable and became asymptomatic. followup uss showed that the haematoma was resolving and that there was a marked reduction in free fluid. she was discharged from the hospital with a plan for weekly review with serial growth scans and ctg. at 36 weeks of gestation, she underwent elective lscs for breech presentation and delivered a baby weighing 3.2 kg with good apgar. her uterus was found to be partially bicornuate with a shallow external indentation or groove. this had not been documented in her previous caesarean section notes. the placenta intr aperitone al haemorrhage during pregnancy or postpartum (up to 42 days) without any history of trauma is termed spontaneous haemoperitoneum in pregnancy (ship).1 this is a rare condition which can cause significant morbidity and mortality for the mother and neonate.2 we present a patient with ship who was conservatively managed and delivered at 36 weeks by caesarean section. the uterus was found to be bicornuate with a placenta percreta at the junction of the horns with possible bleeding from the serosal surface. case report a 27-year-old female patient at 31 weeks of gestation (gravida 2 para 1) with history of previous lower segment caesarean section (lscs), was referred from a regional hospital to a tertiary care hospital in muscat, oman, in 2019 for acute abdominal pain. at the regional hospital, she had presented with complaints of right iliac fossa pain. emergency laparoscopy was planned with a provisional diagnosis of acute appendicitis. however, she refused surgery and hence was referred. she had no significant previous medical illness. on examination, she was found to be pale, tachycardic and tachypnoeic but afebrile. her haemoglobin had dropped to 8 g/dl from 10 g/dl over a period of eight hours. her inflammatory markers were found to be normal and cardiotocography this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.102 case report abstract: intraperitoneal haemorrhage during pregnancy or postpartum without any history of trauma (spontaneous haemoperitoneum in pregnancy [ship]) is a rare condition, causing significant morbidity and mortality for the mother and the neonate. we report a 27-year-old female patient with ship at 31 weeks of gestation who was referred to a tertiary care hospital in muscat, oman, in 2019, with right iliac fossa pain, pallor and tachycardia. radiological investigations revealed intraperitoneal bleeding and a right adnexal haematoma. she was managed conservatively with blood transfusion and supportive care. at 36 weeks of gestation, lower segment caesarean section was done and a live baby with good apgar score was delivered. pre-operatively, she was found to have a bicornuate uterus, placenta percreta at the junction of the horns and a right adnexal haematoma. this case highlights the significance of thorough evaluation of acute abdominal pain in pregnancy in avoiding unnecessary surgical intervention and iatrogenic prematurity. keywords: abdominal pain; caesarean section; hemoperitoneum; placenta accreta; pregnancy; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ spontaneous haemoperitoneum in pregnancy with placenta percreta in bicornuate uterus with successful pregnancy outcome a case study 292 | squ medical journal, may 2022, volume 22, issue 2 was found attached to the bridging area between the two horns of the uterus. the delivery of the placenta revealed a myometrial defect covered only by vascular serosa at the junction of the two horns [figure 3]. as the placenta was infiltrating the serosa, it was assumed to be a case of focal percreta. the previous caesarean scar was found to be intact. the serosa was opened and the uterine defect was closed in layers. the organised necrotic haematoma adherent to the right adnexal region was removed [figure 4]. ovaries and appendix looked normal. the patient had an uneventful post-operative recovery and was discharged on day four. histopathology report showed that the haematoma was surrounded by fibroblastic reaction. a follow-up uss done one year later was found to be normal. patient consent was obtained for clinical photography and publication of this case report. discussion acute abdominal pain in pregnancy is a diagnostic and therapeutic challenge. many times the diagnosis is in favour of more common conditions such as appendicitis. the current patient presented with right iliac fossa pain, tachycardia, abdominal tenderness and guarding. however, absence of fever, normal inflammatory markers and a significant drop in haemoglobin was suggestive of intra-abdominal bleeding; this was confirmed by radiological investigations. figure 1: axial t2 weighted abdominal magnetic resonance image of a 27-year-old pregnant female patient showing the placenta (yellow arrow) and a welldefined haematoma (white arrows) in the right parauterine region, inseparable from the uterine wall (red arrow). figure 3: intraoperative photograph during the lower segment caesarean section of the current patient showing bicornuate uterus with defect in the junction of uterine horns. figure 2: coronal t2 weighted abdominal magnetic resonance image of a 27-year-old pregnant female patient showing the placenta (yellow arrow), fetus (blue arrow) and a well-defined haematoma (white arrows) in the right para-uterine region, inseparable from the uterine wall (red arrow). figure 4: intraoperative photograph during the lower segment caesarean section of the current patient showing organised right adnexal haematoma. jayasree santhosh, latha v. kharka, atheel kamona and sumaiya saif al amri case report | 293 according to a literature review including case reports by xu et al., pregnancy-related causes of ship are antepartum rupture of uterus, rupture of rudimentary horn, placenta percreta, scar rupture and ruptured corpus luteum of pregnancy.2 causes unrelated to pregnancy are variceal bleed from the surface of uterus, rupture of ovarian vein, venous bleed from the surface of sub-serous myoma, bleeding from endometriotic deposits and rupture of splenic or renal vein. however, the pathogenesis is unclear. parauterine veins and superficial veins of the uterus, when complicated by endometriosis, can result in bleeding with trivial trauma. this is more so in pregnancy when venous pressure increases due to compression from gravid uterus. patients present with abdominal pain, nausea, vomiting, pallor, tachycardia, tachypnoea and hypotension. clinical examination and radiological investigations have limitations during pregnancy. lier et al. have done a systematic review and meta-analysis describing 59 cases of ship.1 in the majority of cases, ship occurred in the third trimester of pregnancy and presented with acute abdominal pain, hypovolaemic shock, low haemoglobin and in some cases, foetal distress. imaging confirmed free peritoneal fluid in 62.7% cases. at the time of surgery, 91.1% patients were found to have active bleeding which originated from ruptured uteroovarian vessels (56.8%), endometriotic implants (21.6%), haemorrhagic nodules of decidualised cells (2.0%) or a combination (19.6%). median amount of haemoperitoneum was 1600 ml. of the 76.3% women who underwent surgical interventions during pregnancy, 15.6% reported a successful continuation of pregnancy with recurrence rate of 8.5%. there was one maternal death. perinatal mortality was reported to be 26.9%. they concluded that ship is a very serious complication of pregnancy, highly associated with adverse pregnancy outcomes and particularly relevant to women with endometriosis. as there are no preventive measures, early recognition of ship plays a crucial role in improving pregnancy outcome. after reviewing a case series by lier et al., van den bosch published a mini-commentary where he states that in any woman presenting with acute abdominal pain, hypotension and/or foetal distress in the second or third trimester of pregnancy, an abdominal ultrasound examination is to be performed immediately, not only to exclude obstetric causes, but also to look for intra-abdominal free fluid.3 in the absence of obstetric causes and other causes of massive abdominal bleeding such as splenic rupture, ship should be considered and prompt multidisciplinary intervention is to be started. in their case series, lier et al. advocates median laparotomy to obtain optimal access to all abdominal compartments.4 if the foetus is viable, a caesarean section may be needed to reduce the uterine size for thorough assessment of the posterior uterine wall and posterior compartment. the bleeding point(s) are to be repaired by suturing and/or the use of haemostatic agents. hysterectomy was not required for any patient in their case series. they conclude that timely diagnosis and prompt surgical intervention provides excellent prognosis for both mother and foetus. according to xu et al., once ship is diagnosed, exploratory laparotomy is to be performed.2 whether lscs is performed at the same time should be based on the conditions of operation and foetus. however, brossens et al. suggests that in preterm cases where the bleeding points are successfully handled, there is a place for conservative management till term.5 recently, markou and fysekidis suggested that in the absence of hypovolaemic shock or fetal distress, expectant management could be considered.6 the possibility that recovery can be complicated by the development of infected haematomas or recurrence of ship needs to be taken into account. however, successful surgical intervention does not rule out the recurrence of ship.7 the current patient remained stable despite the para-uterine haematoma and haemoperitoneum diagnosed by uss and mri. she received blood transfusion, antibiotics and analgesics. foetal status also remained stable. a ct angiography of the abdomen, taken after weighing the risks and benefits of imaging studies and obtaining consent, revealed no ongoing haemorrhage.8 hence, she was conservatively managed. during lscs, the current patient was found to have a bicornuate uterus with placenta percreta at the junction of the two horns. the uterine anomaly and placenta percreta were not diagnosed in the antenatal period as the uterine indentation was shallow, the placenta percreta was focal, the uterine cavity was distended with the pregnancy and the right-sided haematoma became the main focus of attention on acute presentation. the incidence of bicornuate uterus in a fertile population ranges from 0.1–0.6%. it is believed to account for 20% of uterine anomalies.9 bicornuate uterus (american fertility society class iv) forms when the mullerian ducts fuse incompletely at the level of the uterine fundus. the depth of the groove and the length of the uterine septum depends on the degree of fusion.10 bicornuate uterus is associated with placenta accreta spectrum (pas) disorders. the failure of normal decidualisation in the uterine area corresponding to the defect of the endometriummyometrial interface leads to the development of spontaneous haemoperitoneum in pregnancy with placenta percreta in bicornuate uterus with successful pregnancy outcome a case study 294 | squ medical journal, may 2022, volume 22, issue 2 references 1. lier mci, malik rf, ket jcf, lambalk cb, brosens ia, mijatovic v. spontaneous hemoperitoneum in pregnancy (ship) and endometriosis a systematic review of the recent literature. eur j obstet gynecol reprod biol 2017; 219:57–65. https://doi. org/10.1016/j.ejogrb.2017.10.012. 2. xu y, zhou y, xie j, yin x, zhang x. intraperitoneal hemorrhage during pregnancy and parturition: case reports and literature review. medicine (baltimore) 2019; 98:e16300. https://doi. org/10.1097/md.0000000000016300. 3. van den bosch t. spontaneous haemoperitoneum in pregnancy (ship): take-home messages. bjog 2017; 124:313. https://doi. org/10.1111/1471-0528.14443. 4. lier m, malik rf, van waesberghe j, maas jw, van rumpt-van de geest da, coppus sf, et al. spontaneous haemoperitoneum in pregnancy and endometriosis: a case series. bjog 2017; 124:306–12. https://doi.org/10.1111/1471-0528.14371. 5. brosens ia, fusi l, brosens jj. endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. fertil steril 2009; 92:1243–5. https://doi.org/10.1016/j.fertnstert.2009.03.091. 6. markou ga, fysekidis m. spontaneous hemoperitoneum during pregnancy. is there any place for a wait and see approach in the absence of maternal hypovolemic shock or fetal distress? eur j obstet gynecol reprod biol 2018; 225:260–1. https://doi. org/10.1016/j.ejogrb.2018.04.004. 7. maya et, srofenyoh ek, buntugu ka, lamptey m. idiopathic spontaneous haemoperitoneum in the third trimester of pregnancy. ghana med j 2012; 46:258–60. 8. committee opinion no. 723: guidelines for diagnostic imaging during pregnancy and lactation. obstet gynecol 2017; 130:e210–16. https://doi.org/10.1097/aog.0000000000002355. 9. attaran m, gidwani gp. chapter 9 congenital and developmental anomalies. 2007 15 may 2009. in: sokol ai, sokol er. general gynecology. maryland heights: mosby, 2007. pp. 205–23. 10. amesse ls, pfaff-amesse t. mullerian duct anomalies. from: https://emedicine.medscape.com/article/273534-overview accessed: feb 21. 11. jauniaux e, ayres-de-campos d, langhoff-roos j, fox ka, collins s; figo placenta accreta diagnosis and management expert consensus panel. figo classification for the clinical diagnosis of placenta accreta spectrum disorders. int j gynaecol obstet 2019; 146:20–4. https://doi.org/10.1002/ijgo.12761. trophoblastic tissue deep within the myometrium and thus results in pas disorders.11 in the current patient, the origin of haemoperitoneum may have been from bleeding from subserosal vessels of the uterus at the junction of the horns where the placenta was adherent. later it may have resulted in the organised haematoma in the right para-uterine region. conclusion pregnant patients presenting with acute abdominal pain should be evaluated thoroughly before contemplating surgical procedure or delivery. to an extent, this can avoid surgical morbidity and iatrogenic prematurity. spontaneous intraperitoneal haemorrhage in pregnancy is a rare but lifethreatening disease. in cases of endometriosis, assisted reproductive techniques, uterine anomalies and fibroids complicating pregnancy, ship is to be ruled out in patients presenting with acute abdominal pain. foetal outcome depends on gestational age, hypovolaemia of the mother, the rapidity of diagnosis and aggressive management. a u t h o r s’ c o n t r i b u t i o n js and sa clinically managed the case. ak provided the radiology data. js drafted the manuscript. lk, ak and sa critically reviewed the manuscript. all authors approved the final version of the manuscript. https://doi.org/10.1016/j.ejogrb.2017.10.012 https://doi.org/10.1016/j.ejogrb.2017.10.012 https://doi.org/10.1097/md.0000000000016300 https://doi.org/10.1097/md.0000000000016300 https://doi.org/10.1111/1471-0528.14443 https://doi.org/10.1111/1471-0528.14443 https://doi.org/10.1111/1471-0528.14371 https://doi.org/10.1016/j.fertnstert.2009.03.091 https://doi.org/10.1016/j.ejogrb.2018.04.004 https://doi.org/10.1016/j.ejogrb.2018.04.004 https://doi.org/10.1097/aog.0000000000002355 https://doi.org/10.1002/ijgo.12761 department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com أورام قرنية شوكية طفحية يف وشم أمحر لورا ليناري�س غونزالي�س، ترييزا رودينا�س-هريانز، مارينا جالفيز-مورينو، ريكاردو رويز فيالفريدي eruptive keratoacanthomas in a red tattoo laura linares-gonzalez, teresa ródenas-herranz, marina galvez-moreno, *ricardo ruiz-villaverde sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e372–373, epub. 5 oct 20 submitted 4 feb 20 revision req. 15 mar 20; revision recd. 30 mar 20 accepted 30 apr 20 a 65-ye ar-old female patient with extensive body tattoos and no medical history of interest, presented at the outpatient dermatological clinic, university hospital san cecilio, granada, spain, with a two-week history of several rapidly growing crusted nodules on the red tattoo ink that had been done one month prior [figure 1]. on clinical examination, several well-demarcated, skin-coloured hyperkeratotic nodules with central ulcerations and crateriform surfaces, ranging in size between 0.4–2 cm on the right leg were discovered. no other lesions could be observed. haematoxylin and eosin examination and cultures for bacteria, fungi and atypical mycobacteria were made from samples taken by cutaneous biopsy. histological examination showed findings compatible with eruptive keratoacanthomas (ka) and an intense chronic histiocytic dermatitis in response to the exogenous pigments in the underlying dermis [figure 2]. after one week, some of the lesions had resolved spontaneously and the largest lesion was treated with intralesional methotrexate 15 mg/dl every other week, which resulted in a mild decrease in size. a complete removal of the lesion was performed, with no recurrence after 12-months of follow-up. comment ka is a relatively common keratinising squamous neoplasm that only rarely progresses to metastatic carcinoma, in spite of its initial rapid growth. this this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.020 interesting medical image figure 1: hyperkeratotic nodules appearing on the red ink of a tattoo on the leg of a 65-year-old female patient. https://creativecommons.org/licenses/by-nd/4.0/ laura linares-gonzalez, teresa ródenas-herranz, marina galvez-moreno and ricardo ruiz-villaverde interesting medical image | e373 lesion usually presents as a solitary dome-shaped, skincoloured nodule with a central keratinous core, most commonly on sun-exposed skin areas of middle-aged or elderly people. involution may occur spontaneously after a few months.1 eruptive ka has been rarely described in the literature. although its origin remains uncertain, several factors have been associated with the development of these lesions, including ultraviolet light exposure, genetic background, carcinogens, immunosuppression, viruses and various types of skin trauma.2 kluger and koljonen reported 50 cases of skin cancers on tattoos, 23 of which were squamous carcinoma or ka; in a case-series of 8 patients with 11 tattoo associated ka, 82% of the cases occurred in red tattoo ink, which is well known to be the most reactive of ink colours.2 this is possibly related to the inflammatory nature of its specific components. the physiopathology of ka formation remains unclear. it has been postulated that ka develops as a result of hypersensitivity to the ink or due to trauma or viral infection from the tattooing process. another theory postulates that the ink itself may possess carcinogenic properties.3 the composition of tattoo inks has not been properly regulated and some components have been classified by the international agency for research on cancer as possibly carcinogenic to humans (e.g. mercury, cobalt salts and carbon black) or carcinogenic to humans (e.g. cadmium).2 on the other hand, some authors consider ka formation to be a reactive response rather than a neoplastic condition. junqueira et al. hypothesised that the skin tries to eliminate the ink like a foreign body by the development of granulomas.4 differential diagnosis of ka arising within tattoos may include mycobacterial or fungal infections, foreign body reactions, pseudolymphomatous reactions or sarcoidosis. histological examination should always be performed, which is considered the gold standard to confirm the diagnosis and rule out squamous cell carcinoma. multiple treatment modalities have been suggested for ka. while spontaneous regression has been described; in fact, several small nodules resolved spontaneously in our case. for lesions not resolving on their own, surgical modalities may be considered as the first-line treatments. this includes shave excision, curettage, cautery and surgical excision; other options include intralesional therapy with steroids, methotrexate, 5-fluorouracil (5-fu) or bleomycin and topical agents, such as imiquimod or 5-fu. systemic modalities include steroids, methotrexate or retinoids. acitretin, a metabolite of etretinate that inhibits the growth of keratinocytes, used in a dose of 25 mg daily is the preferred treatment for recalcitrant lesions and for patients in whom surgery or radiation therapy can cause aesthetic defects.5 finally, ablative therapies such as radiation therapy, laser therapy, cryotherapy or photodynamic therapy may be useful, especially for small lesions.6 references 1. rinker mh, fenske na, scalf la, glass lf. histologic variants of squamous cell carcinoma of the skin. cancer control 2001; 8:354–63. https://doi.org/10.1177/107327480100800409. 2. kluger n, koljonen v. tattoos, inks, and cancer. lancet oncol 2012; 13:e161–8. https://doi.org/10.1016/s1470-2045 (11)70340-0. 3. muñoz borrás d. allergic reactions to tattoo inks: a new diagnostic challenge. las reacciones alérgicas frente a las tintas de los tatuajes, un nuevo reto diagnóstico. actas dermosifiliogr 2018; 109:100. https://doi.org/10.1016/j.ad.2017.10.010. 4. junqueira al, wanat ka, farah rs. squamous neoplasms arising within tattoos: clinical presentation, histopathology and management. clin exp dermatol 2017; 42:601–6. https:// doi.org/10.1111/ced.13183. 5. gon a dos s, minelli l, meissner mcg. keratoacanthoma in a tattoo. dermatol online j 2009; 15:9. 6. alloo a, garibyan l, leboeuf n, lin g, werchniak a, hodi fs jr, et al. photodynamic therapy for multiple eruptive keratoacanthomas associated with vemurafenib treatment for metastatic melanoma. arch dermatol 2012; 148:363–6. https:// doi.org/10.1001/archdermatol.2011.3080. figure 2: a: haematosilin and eosin stain at x10 maginification showing proliferation of atypical keratinocytes with crateriform appearance and central corneal material. b: haematosilin and eosin stained dermis at x20 maginification showing intense mixed inflammatory infiltrate predominantly histiocytic and subcutaneous cellular tissue with abundant exogenous pigment. https://doi.org/10.1177/107327480100800409 https://doi.org/10.1016/s1470-2045%2811%2970340-0 https://doi.org/10.1016/s1470-2045%2811%2970340-0 https://doi.org/10.1016/j.ad.2017.10.010 https://doi.org/10.1111/ced.13183 https://doi.org/10.1111/ced.13183 https://doi.org/10.1001/archdermatol.2011.3080 https://doi.org/10.1001/archdermatol.2011.3080 1 submitted 8 nov 22 1 revision req. 22 jan 23; revision recd. 2 mar 23 2 accepted 4 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.029 5 6 incidence of optic neuritis among omani patients with multiple sclerosis 7 at the sultan qaboos university hospital, muscat, oman 8 fatma alkharusi,1 buthaina sabt,2 *abdullah s. al-mujaini3 9 10 3department of ophthalmology, 1college of medicine and health sciences, sultan qaboos 11 university, muscat, oman; 2department of ophthalmology, sultan qaboos university 12 hospital, sultan qaboos university, muscat, oman 13 *corresponding author’s e-mail: abdullah.almujaini@gmail.com 14 15 abstract 16 objectives: multiple sclerosis (ms) is a chronic, multifaceted, heterogeneous autoimmune 17 disease, with optic neuritis (on) being a common early manifestation. this study aimed to 18 estimate the incidence of on among omani patients with ms. methods: this retrospective 19 cross-sectional study included all omani patients diagnosed with ms at the sultan qaboos 20 university hospital, muscat, oman, between january 1991 and december 2019. data were 21 collected from the neurology registry and electronic medical records. the data was analysed 22 descriptively using univariant and multivariant statistical techniques. results: of the 185 23 patients diagnosed with ms during the study period, 170 were included in the analysis. the 24 male-to-female ratio was 1:3 and the mean age was 28 years. the incidence of on in the 25 population was 28.8%, with 83.7% of on patients presenting with relapse-remitting ms 26 (rrms). overall, 28.6% presented with on as an initial manifestation of ms, while 42.8% 27 developed on at a later stage. most patients (49.4%) were from higher-latitude regions of 28 oman, like muscat and al batinah. conclusion: the incidence of both ms and on 29 increased over the study period. while the overall incidence was low in comparison with 30 western data, it was similar to rates reported elsewhere in the arabian peninsula. overall, 31 on was the most common manifestation of ms in the cohort, with younger female patients 32 mailto:abdullah.almujaini@gmail.com 2 more frequently presenting with both ms and on. there was a significant association 33 between the rrms subtype and on presentation. 34 keywords: demyelinating diseases; optic neuritis; multiple sclerosis; multiple sclerosis, 35 relapsing-remitting; incidence; epidemiology; oman. 36 37 advances in knowledge 38 the overall incidence of optic neuritis (on) among patients diagnosed with multiple 39 sclerosis (ms) at a tertiary hospital in oman over a 29-year period was 28.8%. while 40 this is lower than rates reported elsewhere around the globe, it remains in line with 41 findings reported by other arabian gulf countries. 42 moreover, the incidence of both ms and on was found to increase over time, 43 particularly over the past decade, likely as a result of the application of more stringent 44 diagnostic criteria. in particular, younger female patients were more likely to present 45 with both ms and on and there was a significant association between the relapse-46 remitting ms subtype and on presentation. 47 the number of cases originating from the muscat and al batinah regions of oman 48 supports the hypothesis that latitude affects ms incidence. 49 50 application to patient care 51 as the findings show that on is a common early manifestation of ms in omani 52 patients, ophthalmologists and family physicians should ensure that they refer patients 53 presenting with symptoms of vision loss for neurological assessment, especially 54 young female patients who are at greater risk of developing both on and ms. 55 moreover, in light of the fact that the incidence of both ms and on increased 56 considerably over the study period, there is a need for enhanced suspicion of ms in 57 the differential diagnosis process. moreover, a national ms-specific registry should 58 be established to more accurately monitor the number of cases recorded every year. 59 60 introduction 61 multiple sclerosis (ms) is a chronic, multifaceted, complicated, and heterogeneous 62 autoimmune disease which results in central nervous system inflammation, demyelination, 63 gliosis, and axonal degeneration.1 neurological deficits are common due to interrupted 64 communication between neurons in the brain and spinal cord as a result of the demyelination 65 process. clinically, ms takes a variety of forms which can be distinguished through disease 66 3 activity and patterns of relapse and remission.1 according to current international 67 classifications, four ms subtypes are recognised: relapsing-remitting ms (rrms), primary 68 progressive ms, secondary progressive ms (spms), and progressive-relapsing ms.2 the 69 primary cause of ms is still unknown, although both environmental and genetic factors are 70 believed to play a role. the epidemiology of ms varies according to demographic 71 characteristics and latitude, a well-established risk factor; in addition, ethnicity/race has also 72 been found to influence the global distribution of ms.3 73 74 optic neuritis (on) is an acute, inflammatory, demyelinating disease of the optic nerve 75 resulting from an autoimmune process, characterised by unilateral, painful, and rapid loss of 76 vision.4,5 typically, on is recognised as an early clinical manifestation of ms in 20% of 77 patients, but this condition can occur over the course of the disease in up to 50% of all ms 78 patients.6 in particular, female patients between 18–45 years of age have an increased 79 tendency to develop on in comparison to other ms patients.7 this study aimed to estimate 80 the incidence of on among omani patients diagnosed with ms at a tertiary hospital over a 81 29-year period and compare the findings to internationally published data. 82 83 methods 84 this retrospective cross-sectional study was conducted at the sultan qaboos university 85 hospital (squh), a tertiary hospital in muscat, oman, from january 1991 until december 86 2019. this study included all omani patients seen at squh with confirmed ms diagnoses 87 according to the 2017 mcdonald diagnostic criteria.8 patients without confirmed ms 88 diagnoses were excluded from the study. data were collected from the squh neuro-89 ophthalmology clinic registry, the patients’ electronic medical records, and the hospital 90 information system database. 91 92 electronic medical records were established at squh in 2006; as such, the data of patients 93 diagnosed with ms prior to 2006 were retrieved from the hospital’s neurology clinic registry, 94 while data from 2006 onwards were collected from the patients’ electronic medical records 95 (trakcare®, intersystems corp., cambridge, massachusetts, usa). various information 96 was recorded, including sociodemographic characteristics (i.e., age, gender, and location of 97 residence), year of diagnosis, subtype of ms, and the presence of on. in addition, additional 98 data were collected and reported for patients with on, including age at presentation, number 99 of attacks during follow-up period, and progression of the disease. patients were contacted 100 4 directly to confirm their location of residence in order to estimate the geographic distribution 101 of the disease. 102 103 collected data were analysed using the statistical package for the social sciences (spss), 104 version 23 (ibm corp., armonk, new york, usa). ethical approval for this study was 105 obtained from the medical research & ethics committee of the college of medicine & 106 health sciences at sultan qaboos university. further authorisation was obtained from the 107 relevant hospital authorities to access the patients’ electronic medical records and the hospital 108 information system database. 109 110 results 111 a total of 185 patients were diagnosed with ms at squh between january 1991 and 112 december 2019; of these, 15 patients (8.1%) were excluded due to diagnostic uncertainty, 113 resulting in a 170 patients (85.4%) being included in the analysis. overall, 59 (34.7%) were 114 male and 111 (65.3%) were female, with a male-to-female ratio of 1:3 and a mean age of 28 115 years. the youngest patient began showing signs of ms at the age of 9 years, whereas the 116 eldest was 60 years old. in terms of subtype, most patients had rrms (n = 135; 79.4%), 117 followed by clinically isolated syndrome (cis; n = 21; 12.4%), and spms (n = 14; 8.2%). 118 other ms subtypes were not detected or diagnosed during the study period. 119 120 of the 135 patients with rrms, 50 were male (37%) and 85 were female (63%), while there 121 were six male (28.6%) and 15 female (71.4%) patients with cis, and three male (21.4%) and 122 11 female (78.6%) patients with spms [figure 1a]. the association between gender and ms 123 subtype was not significant (p >0.050). the first documented case of ms in the neurology 124 registry was recorded in 1991. subsequently, the number of ms diagnoses per year began to 125 increase, particularly from 2010 onwards. the greatest number of cases per year was 126 recorded in 2016 (n = 23), comprising six male (26.1%) and 17 female (73.9%) patients 127 [figure 1b]. 128 129 in terms of geographic distribution, the majority of ms patients originated from muscat (n = 130 48; 28.2%) [figure 1c], with 16 male (33.3%) and 32 female (66,7%) patients, followed by 131 al batinah (n = 36; 21.2%), with seven male (19.4%) and 29 female (80.6%) patients. the 132 region with the fewest cases was ad dhakhiliyah (n = 16; 9.4%), of which six patients 133 (37.5%) were male and 10 (62.5%) were female. no cases were reported from three 134 5 governorates of oman (musandam, al buraimi, and al wusta) [table 1]. the association 135 between disease incidence and areas of high latitude was not significant (p >0.050). 136 137 over the 29-year study period, 49 ms patients developed on, resulting in an incidence of 138 28.8%; of these, 11 patients (22.5%) were male and 38 (77.5%) were female [figure 2a]. 139 the first case of on at squh appeared in the registry in 2004, with the number of diagnoses 140 per year increasing considerably from 2012 onwards. the highest number of cases was 141 reported in 2016 for male patients (n = 2) and 2017 for female patients (n = 7) [figure 2b]. 142 overall, 28.6% of patients with both ms and on presented with on as an initial presentation 143 of ms, while 42.8% developed on over the course of the disease [table 2]. the association 144 between gender and the development of on was not significant (p = 0.050); however, there 145 was a significant association with ms subtype (p <0.050), with the majority of on cases 146 occurring in patients with the rrms subtype (83.7%) [table 3]. 147 148 discussion 149 the incidence of on among ms patients at squh over the 29-year study period was 28.8%, 150 lower than rates reported elsewhere around the world. according to a prospective study 151 conducted in india, the incidence of on among ms patients was 70% (n = 20/30).9 another 152 study reported an incidence of 50% at a tertiary care unit in turkey, with on often reported 153 as an initial presenting feature of ms.10 the low incidence rate of on noted in the current 154 study could be due to several reasons, including methodological differences in sample size 155 and study design, as well as genetic variations between different populations. 156 157 however, it is also possible that this finding is due to the generally low incidence of ms in 158 oman, given the previously reported prevalence rate of 4 in 100,000 individuals.11 other 159 arabian gulf countries have reported similarly low rates of ms, although there are 160 methodological concerns to such studies which may hinder definitive conclusions as to 161 regional prevalence.12 a more recent study indicated that the rate of ms in oman may be 162 much higher than previously believed, with a crude estimated prevalence of 15.9 per 100,000 163 individuals, designating the country as a medium-risk zone.13 164 165 in the present study, the incidence of both ms and on at squh was found to increase 166 considerably over time, beginning from 2010–2012 onwards. this increase over the past 167 decade may be due to the application of the mcdonald criteria to support the diagnosis of 168 6 suspected cases of ms at squh, resulting in fewer cases going undiagnosed.8in the present 169 study, on represented the first clinical manifestation of ms in 28.6% of patients who 170 developed on. this finding is in parallel with other research conducted elsewhere around the 171 globe. in bosnia and herzegovina, 10 out of 89 ms patients (11.2%) demonstrated clinical 172 signs of on as the first sign of disease, a finding which was statistically significant compared 173 to other disease manifestations (p = 0.01).7 in addition, a previous review of the literature 174 suggested that on is the initial presentation in approximately 20% of ms patients.14 175 176 overall, 79.4% of ms patients in the present study had the rrms subtype, while the 177 remaining 12.4% and 8.2% of patients had cis and spms, respectively. a retrospective 178 study conducted in the united arab emirates (uae) reported a comparable distribution of 179 these subtypes among emirati ms patients (77.8%, 12.3%, and 8.2%, respectively).15 180 moreover, there was a significant association between the rrms subtype and on 181 presentation in the current omani cohort, with 83.7% of patients with both on and ms 182 having the rrms subtype; this result was found to be slightly higher in comparison to other 183 research reporting that 70% of ms patients with on demonstrated relapsing-remitting 184 disease activity.16 in addition, female patients were found to be more frequently diagnosed 185 with ms compared to male patients in the present study, at a ratio of 1.9. the gender ratio of 186 ms cases varies depending on country and region, with higher ratios of 2.6 and 3.0 reported 187 in the usa and east asia, respectively.17 in turn, the female preponderance of ms is lower in 188 arabian gulf countries, with ratios of 1.8 and 1.3 reported in kuwait and saudi arabia, 189 respectively.17,18 in the present study, 34.2% of female patients with ms developed on 190 compared to 18.6% of male patients, with a female-to-male ratio of 3.5. the female 191 predominance of on is well-established in the existing literature at a ratio of 3 or higher.19 192 193 in the present study, the mean age of the enrolled population was 28 years, with similar mean 194 ages observed for both males and females at 29 and 28 years, respectively. corresponding 195 findings have been reported from iran (mean age: 25 years), while ms patients in the uae 196 are reportedly somewhat older (mean age: 34 years).15,20 in turn, the mean age of on patients 197 in the current research was found to be 26 years, with a mean age of 24 and 27 years for male 198 and female patients, respectively. overall, the majority of on patients (59.2%) were between 199 21–30 years of age. this finding was lower in comparison with data originating from hong 200 kong showing the mean age of on patients to be 40 years; however, 90% of ms patients 201 presenting with on in bosnia and herzegovina were between 18–30 years of age.7,21 such 202 7 results suggest that the demographic epidemiology for ms-associated on may be similar to 203 that of ms in general. 204 205 latitude is a well-established factor affecting the incidence of both ms and on; for instance, 206 previous research has indicated that the incidence of ms in argentina is six times higher than 207 that recorded in ecuador.22 it is therefore unsurprising that oman, a country located in the 208 east mediterranean region, should demonstrate a lower incidence of ms compared with 209 western countries of higher latitude.23 moreover, according to the geographical distribution 210 of patients in the present study, certain regions of oman at higher latitudes (i.e., muscat and 211 al batinah) accounted for the greatest number of patients, with fewer cases originating from 212 lower-latitude regions like dhofar, ash sharqiyah, ad dhakhiliyah, ad dhahirah, and al 213 wusta. 214 215 nonetheless, the association between latitude and disease incidence was not statistically 216 significant in the present study, which may be due to several reasons. first, no cases were 217 reported from the highest-latitude areas in oman (musandam and al buraimi). second, such 218 associations are difficult to ascertain in a single country that does not span a considerable 219 latitude or longitude. finally, as the capital city of oman, muscat is home to a large 220 proportion of the national population, followed by the surrounding region of al batinah, 221 which may account for the large number of cases from these areas. however, it was found 222 that male patients more frequently originated from areas of lower latitude like dhofar 223 compared with other governorates. the idea that the gender ratio in ms may vary with 224 changes in latitude might be another possible explanation for these findings.24 225 226 interpretation of the findings of this study is contingent upon certain limitations. 227 generalisation of the results is difficult as the study was conducted using a retrospective 228 cross-sectional design and was limited to a single institution. while squh is a tertiary care 229 institution which accepts referrals from all over the country, the catchment area remains 230 limited; moreover, the presence of other tertiary institutions in muscat which might also 231 receive ms and on patients prohibits generalisation of the incidence of these conditions to 232 the whole of oman. in addition, as a partially heritable disease, genetic factors play a 233 considerable role in the epidemiology and incidence of ms. unfortunately, data concerning 234 such genetic factors were missing for the majority of patients in the present study. further 235 8 prospective research is therefore recommended to counteract these limitations using a larger 236 sample size. 237 238 conclusion 239 over the 29-year study period, the incidence of on among ms patients at squh was low 240 (28.8%), a rate in keeping with other arabian gulf countries. nonetheless, on remained the 241 most common early manifestation of ms among the enrolled patients, with almost one-third 242 of ms patients presenting initially with on as their first symptom. moreover, the incidence 243 of both ms and on appeared to increase over time, particularly over the last decade, 244 supporting the need for further research on this topic. finally, more ms cases were reported 245 from higher-latitude areas of oman, a result in line with previous research supporting latitude 246 as a well-established risk factor for ms. 247 further research is needed that can focus on more in-depth analysis such as comparing the 248 difference between the initial presentation (on versus other ms) and gender, governorate 249 and year and whether sub-types (rrms vs other sub-types) are significantly different by 250 gender, governorate and year. 251 252 authors’ contribution 253 am designed the study. fk and bs collected the data. fk performed the statistical analysis. 254 fk and bs drafted the manuscript. am critically reviewed and revised the manuscript. all 255 authors approved the final version of the manuscript. 256 257 conflict of interest 258 the authors declare no conflicts of interest. 259 260 funding 261 no funding was received for this study. 262 263 references 264 1. sutherland jm, tyrer jh, eadie mj. the prevalence of multiple sclerosis in australia. 265 brain 1962; 85:149–64. https://doi.org/10.1093/brain/85.1.149. 266 2. annapurna a, kumar vk, rao pmm, rao ks, rajasekhar j. multiple sclerosis: the 267 disease and its treatment. indian j pharmacol 2002; 34:3–15. 268 3. brownlee wj, hardy ta, fazekas f, miller dh. diagnosis of multiple sclerosis: 269 9 progress and challenges. lancet 2017; 389:1336–46. https://doi.org/10.1016/s0140-270 6736(16)30959-x. 271 4. pau d, al zubidi n, yalamanchili s, plant gt, lee ag. optic neuritis. eye (lond) 272 2011; 25:833–42. https://doi.org/10.1038/eye.2011.81. 273 5. helmut w, martin s. [diagnosis and therapy of optic neuritis]. dtsch arztebl int 2015; 274 112:616–26. https://doi.org/10.3238/arztebl.2015.0616. 275 6. pagnotta p. the most/common eye manifestation in multiple sclerosis: optic neuritis. 276 insight 2016; 41:5–8. 277 7. halilovic ea, alimanovic i, suljic e, al hassan n. optic neuritis as first clinical 278 manifestations the multiple sclerosis. mater sociomed 2014; 26:246–8. 279 https://doi.org/10.5455/msm.2014.246-2481. 280 8. thompson aj, banwell bl, barkhof f, carroll wm, coetzee t, comi g, et al. 281 diagnosis of multiple sclerosis: 2017 revisions of the mcdonald criteria. lancet 282 neurol 2018; 17:162–73. https://doi.org/10.1016/s1474-4422(17)30470-2. 283 9. singh s, sharma r, gurunadh vs, shankar s. oct based evaluation of retinal 284 changes in multiple sclerosis. int j res med sci 2017; 5:4117. 285 https://doi.org/10.18203/2320-6012.ijrms20173994. 286 10. kale n. optic neuritis as an early sign of multiple sclerosis. eye brain 2016; 8:195–287 202. https://doi.org/10.2147/eb.s54131. 288 11. tharakan jj, chand rp, jacob pc. multiple sclerosis in oman. neurosciences 289 (riyadh) 2005; 10:223–5. 290 12. al-hashel j, besterman ad, wolfson c. the prevalence of multiple sclerosis in the 291 middle east. neuroepidemiology 2008; 31:129–37. 292 https://doi.org/10.1159/000151514. 293 13. l-senani m, al-salti a, nandhagopal r, al-zakwani i, alkhabouri j, elyas me, et al. 294 epidemiology of multiple sclerosis in the sultanate of oman: a hospital based study. 295 mult scler relat disord 2021; 53:103034. 296 https://doi.org/10.1016/j.msard.2021.103034. 297 14. abou zeid n, bhatti mt. acute inflammatory demyelinating optic neuritis: evidence-298 based visual and neurological considerations. neurologist 2008; 14:207–23. 299 https://doi.org/10.1097/nrl.0b013e31816f27fe. 300 15. schiess n, huether k, fatafta t, fitzgerald kc, calabresi pa, blair i, et al. how 301 global ms prevalence is changing: a retrospective chart review in the united arab 302 emirates. mult scler relat disord 2016; 9:73–9. 303 10 https://doi.org/10.1016/j.msard.2016.07.005. 304 16. toosy at, mason df, miller dh. optic neuritis. lancet neurol 2014; 13:83–99. 305 https://doi.org/10.1016/s1474-4422(13)70259-x. 306 17. mohammed ema. multiple sclerosis is prominent in the gulf states: review. 307 pathogenesis (amst) 2016; 3:19–38. https://doi.org/10.1016/j.pathog.2016.04.001. 308 18. daif ak, al-rajeh s, awada a, al bunyan m, ogunniyi a, abduljabar m, et al. 309 pattern of presentation of multiple sclerosis in saudi arabia: analysis based on 310 clinical and paraclinical features. eur neurol 1998; 39:182–6. 311 https://doi.org/10.1159/000007931. 312 19. balcer lj. clinical practice: optic neuritis. n engl j med 2006; 354:1273–80. 313 https://doi.org/10.1056/nejmcp053247. 314 20. etemadifar m, sajjadi s, nasr z, firoozeei ts, abtahi sh, akbari m, et al. 315 epidemiology of multiple sclerosis in iran: a systematic review. eur neurol 2013; 316 70:356–63. https://doi.org/10.1159/000355140. 317 21. choy bnk, ng alk, lai jsm. clinical characteristics of optic neuritis in hong kong 318 population: 10-year review. int ophthalmol 2018; 38:557–64. 319 https://doi.org/10.1007/s10792-017-0491-9. 320 22. evans c, beland sg, kulaga s, wolfson c, kingwell e, marriott j, et al. incidence 321 and prevalence of multiple sclerosis in the americas: a systematic review. 322 neuroepidemiology 2013; 40:195–210. https://doi.org/10.1159/000342779. 323 23. pugliatti m, sotgiu s, rosati g. the worldwide prevalence of multiple sclerosis. clin 324 neurol neurosurg 2002; 104:182–91. https://doi.org/10.1016/s0303-8467(02)00036-7. 325 24. trojano m, lucchese g, graziano g, taylor bv, simpson s jr, lepore v, et al. 326 geographical variations in sex ratio trends over time in multiple sclerosis. plos one 327 2012; 7:e48078. https://doi.org/10.1371/journal.pone.0048078. 328 11 329 330 331 332 333 figure 1: distribution of multiple sclerosis (ms) cases according to gender by (a) subtype, 334 (b) over time at the sultan qaboos university hospital, muscat, oman, from 1991–2019 (n = 335 170) and (c) among governorates. 336 0% 20% 40% 60% 80% 100% rrms cis spms males females figure 1a figure 1b figure 1c dhofar al wusta musandam al buraimi al batinah ash sharqiyah adh dhahirah ad dakhiliyah 12 spms = secondary progressive multiple sclerosis; cis = clinically isolated syndrome; rrms 337 = relapse-remitting multiple sclerosis. 338 339 340 341 342 343 344 figure 2: distribution of combined optic neuritis and multiple sclerosis cases by (a) gender 345 and (b) over time at the sultan qaboos university hospital, muscat, oman, from 2004–2019 346 (n = 49). 347 on = optic neuritis. 348 349 350 351 71.2% 77.5% 22.5% 28.8% figure 2a figure 2b 13 table 1: regional distribution of multiple sclerosis cases according to gender at the sultan 352 qaboos university hospital, muscat, oman, from 1991–2019 (n = 170) 353 governorate gender, n (%) male female total muscat 16 (33.3) 32 (66.7) 48 (28.2) al batinah (north and south) 7 (19.4) 29 (80.6) 36 (21.2) dhofar 12 (48) 13 (52) 25 (14.7) ash sharqiyah (north and south) 8 (33.3) 16 (66.7) 24 (14.1) ad dhahirah 10 (47.6) 11 (52.4) 21 (12.4) ad dhakhiliyah 6 (37.5) 10 (62.5) 16 (9.4) musandam 0 (0) 0 (0) 0 (0) al buraimi 0 (0) 0 (0) 0 (0) al wusta 0 (0) 0 (0) 0 (0) total 59 (34.7) 111 (65.3) 170 (100) 354 table 2: initial presentation of combined optic neuritis and multiple sclerosis cases by gender 355 at the sultan qaboos university hospital, muscat, oman, from 1991–2019 (n = 49) 356 gender initial presentation, n (%) on other ms manifestations both total male 2 (18.2) 3 (27.4) 6 (54.5) 11 (22.4) female 12 (31.6) 18 (47.4) 8 (21.1) 38 (77.6) total 14 (28.6) 21 (42.8) 14 (28.6) 49 (100) on = optic neuritis; ms = multiple sclerosis. 357 358 table 3: incidence of combined optic neuritis and multiple sclerosis (ms) cases according to 359 gender and ms subtype at the sultan qaboos university hospital, muscat, oman, from 2004–360 2019 (n = 49) 361 ms = multiple sclerosis; rrms = relapse-remitting multiple sclerosis; cis = clinically 362 isolated syndrome; spms = secondary progressive multiple sclerosis. 363 364 gender ms subtype, n (%) rrms cis spms total male 10 (90.9) 1 (9.1) 0 (0) 11 (22.4) female 31 (81.6) 4 (10.5) 3 (7.9) 38 (77.6) total 41 (83.7) 5 (10.2) 3 (6.1) 49 (100) department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author email: mansoursallam@yahoo.com squ med j, december 2010, vol. 10, iss. 3, pp. 370-376, epub. 14th nov 10 submitted 29th march 10 revision req. 21st june 10, revision recd. 14th july 10 accepted 24th august 10 <ôç⁄<ó◊¬<›ç÷]<º«ï<l]]üœ<ÿèräi<∞e<ìfiö^œ⁄<ìâ]öå <ª<ìëüëüä÷]<<ï]üœ÷]ê<ì¬^â<‡ëüé¬ê<ƒeö_ ›ç÷]<<º«ï<≈^àiö]<<<t¯¬ê<<ïöá�}<‹ëáœi      104 12009 2007 4         32 %51.9 41.1 ± 8.6 %10.6  %3.34%27.9%18.2    %4.46 73124 82134 %29.8%22.1  p 0.043      abstract: objectives: blood pressure (bp) measurements taken in a physician’s clinic do not represent readings throughout the day. ambulatory blood pressure monitoring (abpm) overcomes this problem by providing multiple readings with minimal interference with the patient’s daily activities. the purpose of our study was to evaluate the value of abpm in risk assessment and management of hypertension compared to office measurements. methods: a total of 104 consecutive hypertensive patients were retrospectively studied from january 2007 to december 2009. the following data were gathered: 1) clinic bp measurements; 2) routine blood test results; 3) electrocardiography, echocardiography, and 4) 24-hour abpm. results: the mean age of patients was 41.1 ± 8.6 years and 51.9% of them male. indications for abpm were: suspected “white coat” hypertension (10.6%), de novo hypertension (18.2%), resistant hypertension (27.9%) and others (43.3%). mean daytime and nighttime bp were 134/82 and 124/73 mmhg respectively. a non-dipping pattern was reported in 64.4%. echocardiographic evidence of left ventricular hypertrophy (lvh) and diastolic dysfunction (lvdd) was encountered in 22.1% and 29.8% respectively. abpm parameters were significantly correlated with lvdd (p = 0.043). patients with proved “white coat” hypertension did not receive antihypertensive therapy. conclusion: twenty-four hour abpm is an important yet underused tool for proper risk stratification of treated hypertensive patients. the non-dipping profile is associated with a higher incidence of diastolic dysfunction. our collective results revealed the superiority of abpm over office bp measurement. keywords: hypertension; blood pressure monitoring, ambulatory; hypertrophy; left ventricular; ventricular dysfunction, left. comparative study of ambulatory blood pressure monitoring and clinic blood pressure measurement in the risk assessment and management of hypertension hatem farhan, mona al-hasani, mohamed misbah and *mansour sallam clinical & basic research hatem farhan, mona al-hasani, mohamed misbah and mansour sallam clinical and basic research | 371 over the past three decades, the accuracy of using the conventional sphygmomanometer to measure blood pressure (bp) has been questioned, and efforts have been made to improve measurements with automated devices.1 ambulatory blood pressure monitoring (abpm) is being increasingly recommended for routine clinical practice. it may be particularly useful in evaluating the patient with variable bp readings in the office, or the patient with wide discrepancies between bp readings at home and in the physician’s office (i.e. “white coat” hypertension). abpm and, in particular, nocturnal bp readings, may also provide prognostic data.2,3 this has focused attention on methods of measurement that provide profiles of bp rather than rely on isolated measurements made under circumstances that may influence bp.4 early clinical uses of abpm were limited in identifying patients with white-coat hypertension; however, abpm has evolved into a useful modality for stratifying cardiovascular risk and guiding therapeutic decisions. left ventricular hypertrophy (lvh) is an important predictor of cardiovascular morbidity and mortality.5 the prevalent circadian pattern in both normotensive and hypertensive individuals is characterised by a marked decrease of systolic and diastolic bp during the night (dippers), but there is a noticeable fraction of subjects who exhibit a diminished nocturnal decline in bp (non-dippers).6 many clinical studies with non-invasive abpm have shown that some cardiovascular complications of hypertension, namely lvh, tend to be more frequent in patients in whom bp does not fall, or falls only minimally at night and who consequently, suffer a prolonged exposure to high bp levels over 24 hours.7,8 the purpose of our study was to evaluate the value of 24-hour abpm in the risk assessment and management of hypertension compared to the traditional office measurements. methods this retrospective study included 104 existing or newly diagnosed essential hypertensive patients attending the out-patient cardiology clinic at sultan qaboos university hospital, oman, from january 2007 to december 2009. only records of patients with at least three readings showing diastolic bp ≥ 90 mmhg and/or systolic bp ≥ 140 mmhg, or established hypertensive patients who were currently on treatment were included. all patients had to have undergone the following procedures: 1) detailed history taking, general and cardiovascular examination including repeated clinic bp measurements; 2) blood sampling for routine chemistry examinations; 3) 12-leads electrocardiography, transthoracic echocardiography, and 4) 24-hour abpm. patients with congestive heart failure, previous myocardial infarction, significant cardiac valve diseases, or poor echocardiography window were excluded. bp was measured from both of the patient’s arms in the hospital’s out-patient clinic by a dedicated nurse using a well calibrated automated bp machine (datascope: trio, china, 2005), and after the patient had rested for 5 minutes in the sitting position. the higher reading was recorded. twenty-four-hour abpm was carried out on the arm with the higher reading using a (24/48 hour bp recorder, (br-102 plus, schiller, switzerland, 2006). the device was set to obtain bp readings at 30 minutes interval during the daytime and at 60 minutes interval during night-time according to the patient’s lifestyle. daytime and nighttime were individually predetermined depending upon the individual patient’s awake and sleep times; for example, if a patient normally woke at 6 am and went to sleep at 10 pm, his or her daytime recordings were taken from 6 am to 10 pm and nighttime ones from 10 pm to 6 am. the patients were instructed to continue with their usual daily activities, but to advances in knowledge 1. the present study sheds light on the important role of 24-hour ambulatory blood pressure monitoring (abpm) in the management and risk stratification of hypertensive patients. 2. it draws attention to the advantages of this procedure and compares our results with studies in the available literature. application to the patient care 1. in patients with treated hypertension, a higher ambulatory systolic or diastolic bp predicts adverse cardiovascular events. 2. abpm provides useful information for determining which patients have isolated office hypertension and in guiding drug regimen modification. comparative study between ambulatory blood pressure monitoring and clinic blood pressure measurement in the risk assessment and management of hypertension 372 | squ medical journal, december 2010, volume 10, issue 3 remain still at measurement times. the recording was then analysed to obtain 24-hour daytime and night-time average systolic blood pressure (sbp), diastolic blood pressure (dbp) and heart rates. only sbp was used to assess dipping. two-dimensional, m-mode, and doppler echocardiographic examinations were performed using the commercially available instruments (acuson sequoia 265, usa, 2003 and geving med system v, norway, 2000). end-diastolic and endsystolic left ventricular internal diameter (lvidd and lvids); interventricular septum thickness (ivst); posterior wall thickness (pwt); ejection fraction (ef) and fractional shortening (fs) were calculated from two-dimensionally guided m-mode tracing. left ventricular filling to evaluate diastolic function was assessed by recording mitral flow and the ratio of the early to late flow velocity peaks (e/a ratio) was assessed. a ‘non-dipping bp profile’ is defined as a nocturnal systolic bp fall of less than 10% compared to daytime values.6,9 left ventricular hypertrophy is defined as increased left ventricular mass as assessed by 2d guided m-mode echocardiographic examination of interventricular septum and posterior wall thickness in diastole equal to more than 1.2 cm.10 left ventricular diastolic dysfunction is defined as abnormality in the left ventricle’s filling during diastole as assessed by the utility of mitral annulus doppler flow velocity with reversed e/a ratio.11 there is no consensus definition of borderline hypertension; however, some studies in the literature have defined borderline htn as “prehypertension” described as systolic bp 135139 mmhg and/or diastolic bp 85-89 mmhg.12 the term “white coat” hypertension is applied to patients with office readings that average more than 140/90 mmhg and reliable out of office readings that average less than 140/90 mmhg.4 resistant hypertension is defined in the 2008 american heart association scientific statement as bp that remains above goal in spite of concurrent use of three antihypertensive agents of different classes. thus, patients whose bp is controlled with four or more medications should be considered to have resistant hypertension.13 orthostatic hypotension is defined as at least a 20 mmhg fall in systolic pressure and or 10 mmhg fall in diastolic pressure after quiet standing for 2 minutes.14 episodic (paroxysmal) htn with symptoms is defined as an abrupt elevation of bp that is documented by a clinician or home bp monitor associated with abrupt onset of distressful physical symptoms, such as headache or palpitation.15 statistical analyses were carried out using the statistical package for the social sciences (spss), version 15, (spss inc., chicago, il). continuous data were expressed as mean value ± standard deviation (sd) and categorical data as percentages. continuous variables were compared using the student’s paired t-test. categorical data were compared using chi-square (x2) analysis. data were first identified in a univariate fashion with linear regression analysis for continuous variables and x2 test for dichotomous variables. a p value of 0.05 or less was considered statistically significant. results the demographic and clinical characteristics of the study population are reported in table 1. the table 1: baseline clinical characteristics of the study population parameter result age in years ± standard deviation 41.1 ± 8.6 male gender % 51.9 dyslipidemia % 21.2 diabetes mellitus % 13.4 renal impairment % 6.7 obstructive sleep apnea %? 1.9 cerebrovascular accident % 3.8 hypertension duration/years 4.7 ± 6.03 office systolic blood pressure mmhg 146.9 ± 22.7 office diastolic blood pressure mmhg 86.6 ± 13.7 mean office heart rate beats per minute 63.0 ± 24.1 table 2: indications of ambulatory blood pressure monitoring indication % suspected “white coat” htn 10.6 recent onset htn 18.2 resistant htn 27.9 borderline htn 16.3 orthostatic hypotension 7.7 episodic htn with symptoms 19.3 legend: htn = hypertension hatem farhan, mona al-hasani, mohamed misbah and mansour sallam clinical and basic research | 373 mean age of the patients was 41.1 ± 8.6 years, with slightly more males than females (51.9%). mean office sbp and dbp were 146.9 ± 22.7 and 86.6 ± 13.7 mmhg respectively. hypertension duration was reported as 4.7 ± 6.03 years; however, we declare that in our database we could not find the exact duration of hypertension for all patients. table 2 illustrates our indications of abpm. table 3 illustrates abpm parameters. from this latter table, it is clear that, only 35.6% of patients showed a fall in sbp/dbp > 10% during nighttime compared to daytime measurements and were categorised as dippers, while the remaining 64.4% showed a fall ≤ 10% and were categorised as non-dippers. there were significant differences between systolic and diastolic bp measured at the office and the mean 24-hour systolic and diastolic bp measured by abpm with p = 0.0001. table 4 depicts the electrocardiogram (ecg) and echocardiographic findings. lvh was reported in 6.7% of analysed ecg readings; however, it was remarkably higher, 22.1% of the study population, when measured by echocardiography. left ventricular diastolic dysfunction was noted in 29.8% of our patients. as to circadian bp variation and cardiac structure and function, when the echocardiographic data were analysed in a categorical way as a presence or absence of lvh, the prevalence of lvh was similar in dippers and non-dippers (p = 0.09). a significant correlation was found between left ventricular diastolic dysfunction and mean systolic and diastolic daytime bp (p < 0.043). discussion the purpose of our present study was to observe whether or not 24-hour abpm improved the risk assessment and management of hypertensive patients. by its unique 24-hour bp evaluation outside the medical field, abpm was considered to be an effective tool to assess the average bp over the day in addition to circadian variation. many prospective studies have reported that such measurements give a better prediction of clinical outcomes compared to conventional clinic measurements. currently, it is the only tool available to exclude the well known phenomenon of “white coat” hypertension and has a role in assessing apparent drug-resistant hypertension, hypertension in pregnancy, during symptomatic episodes of hypotension or hypertension, and in monitoring adequacy of bp control in patients at high risk of cardiovascular disease.2-4 according to circadian variation in bp, abpm allows stratification into “dipper” or “non-dipper” status. in our study, we found 64.4% of patients were non-dippers. as many studies have related target organ damage to the non-dipping phenomenon,6 we intended to optimise the bp of those patients, especially diabetics. the interesting finding was that 16.6% of the non-dippers were found to have a normal ambulatory blood pressure (abp) profile. there is as yet no consensus about the proper management strategy for non-dippers with a table 3: ambulatory blood pressure monitoring (abpm) parameters parameter mmhg mean 24 hour sbp 131.2±14.8 mean 24 hour dbp 79.5 ±9.3 mean daytime sbp 133.9 ± 15.3 mean daytime dbp 81.7 ± 9.7 mean nighttime sbp 123.6 ± 14.7 mean night-time dbp 73.4 ± 9.4 mean dipping % 8.2 ± 4.8 dipper % 35.6 note: many abpm parameters have been proposed. this table illustrates some of those commonly used. from this table, it is clear that, only 35.6% of patients could be considered as dippers. legend: sbp = systolic blood pressure; dbp = diastolic blood pressure table 4: baseline electrocardiogram and echocardiography findings parameter result ecg-lvh % 6.7 echo-lvh % 22.1 lvedd/mm 48.3 ± 5.3 lvesd/mm 29.6 ± 4.8 ivst/mm 10.9 ± 1.7 pwt/mm 10.3 ± 1.6 ef % 68.1 ± 6.7 fs % 38.3 ± 5.8 lv diastolic dysfunction % 29.8 legend: ecg = electrocardiography; lvh = left ventricular hypertrophy; echo = echocardiography; lvedd/mm = left ventricular end diastolic diameter; lvesd = left ventricular end systolic diameter; ivst = interventricular septal thickness; pwt = posterior wall thickness; ef = ejection fraction; fs = fractional shortening ; lv= left ventricular. comparative study between ambulatory blood pressure monitoring and clinic blood pressure measurement in the risk assessment and management of hypertension 374 | squ medical journal, december 2010, volume 10, issue 3 normal bp profile. we assume that the non-dipping group with a normal abpm profile may be highly susceptible for future persistent hypertension requiring shorter-term follow-up by office and abpm measurements [figure 1a-d]. the association between diurnal bp profile and target organ damage remains controversial.7,16 our data are in agreement with several studies which failed to detect significant differences between dipper and non-dipper hypertensive patients and lvh assessed by either ecg or echocardiography.17,18 despite this, there was a trend towards increased incidence of lvh in the non-dipper group (p = 0.09). the reduced nocturnal fall in bp was found in the majority of our study population (64.4%), and appeared particularly high in the group with resistant and refractory hypertension. contradictory to the nonsignificant correlation between lvh and abpm, left ventricular diastolic function was found to be closely related to ambulatory, rather than clinic bp measurements, the mean nocturnal diastolic bp being a powerful marker of lv filling impairment (p = 0.043). this was in agreement with other studies which have addressed this issue.19,20 “white coat” hypertension was suspected in 10.6% of our study population (as they were not receiving any antihypertensive drug). one third of those patients had a normal abp profile; many of them described attacks of dull aching internal discomfort just before attending the hospital and others described palpitation and flushing. most of these patients had an elevated last bp reading before disconnecting the machine thus constituting the typical presentation of office hypertension. this is consistent with reports by many authors who found figure 1a figure 1b figure 1c figure 1d figure 1: example graph from ambulatory blood pressure monitoring (abpm) report of 62-year old male diabetic and hypertensive patient with normal average active, resting and total 24-hour blood pressure readings. it shows the association between non-dipper status [1a & 1b] and the echocardiographic evidence of left ventricular hypertrophy [1c] and diastolic dysfunction [1d]. despite his office blood pressure measures being persistently high, the abpm noticeably showed a “white coat” effect. hatem farhan, mona al-hasani, mohamed misbah and mansour sallam clinical and basic research | 375 that the incidence of this condition ranges from 1548%.21 this phenomenon can only be detected by abpm and reported by some patients who have the facility of self-monitoring. actually, most of those patients had either emotional or physical stress or a family history of hypertension. a high proportion of patients with borderline hypertension may actually exhibit “white coat” hypertension which exaggerates bp measurement immediately before arriving at the clinic. measurements obtained by means of abpm can provide additional information for risk stratification in patients with borderline elevations in bp. resistant hypertension is defined as the inability to reach a target bp lower than 140/90 mmhg despite 3 or more drug regimens in correct dosages. a total of 29% of our patients fulfilled this criterion. interestingly, abpm identified that 42% of them had controlled bp. there are many limitations of the current study. the sample size was relatively small for a retrospective study; however, many studies with larger samples have shown similar results.2 these data represent the acute outcome; however, our aim was to highlight the value of abpm over traditional office bp measurements. our study is still ongoing as we have subsequently added more patients and increased the range of indications and the follow-up duration. conclusion ambulatory bp monitoring is an established and robust technology, but an underused tool in hypertension management and risk assessment either before or after drug treatments. further prospective studies in selected group of patients are indicated. c o n f l i c t o f i n t e r e s t the auhtors reported no conflict if interest. references 1. o’brien e, mee f, tan ks, atkins n, o’malley k. training and assessment of observers for blood pressure measurement in hypertension research. j hum hypertens 1991; 5:7–10. 2. gosse p, coulon p. ambulatory or home measurement of blood pressure? j clin hypertens (greenwich) 2009; 11:234–7. 3. pickering tg, miller nh, ogedegbe g, krakoff lr, artinian nt, goff d. call to action on use and reimbursement for home blood pressure monitoring: executive summary: a joint scientific statement from the american heart association, american society of hypertension, and preventive cardiovascular nurses association. hypertension 2008; 23:299– 323. 4. mcgrath bp. ambulatory blood pressure monitoring and white coat hypertension: saving costs. med j aust 2002; 176:571–2. 5. sullivan jm, vander zwaag r, el-zeky f, ramanathan kb, mirvis dm. left ventricular hypertrophy: effect on survival. j am coll cardiol 1993; 22:508–13. 6. boggia j, li y, thijs l, hansen tw, kikuya m, björklund-bodegård k, et al. prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. lancet 2007; 370:1219–29. 7. dolan e, stanton a, thijs l, hinedi k, atkins n, mcclory s, et al. superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the dublin outcome study. hypertension 2005; 46:156–61. 8. white wb. relating cardiovascular risk to outof-office blood pressure and the importance of controlling blood pressure 24 hours a day. am j med 2008; 121:2–7. 9. shimada k, kawamoto a, matsubayashi k, nishinaga m, kimura s, ozawa t. diurnal blood pressure variations and silent cerebrovascular damage in elderly patients with hypertension. j hypertens 1992; 10:875–8. 10. reichek n. standardization in the measurement of left ventricular wall mass. m-mode echocardiography. hypertension 1987; 9:ii-27–9. 11. goyal d, macfadyen r, watson r, lip gyh. ambulatory blood pressure monitoring in heart failure: a systematic review. eur j heart fail 2005; 7:149–56. 12. hsia j, margolis kl, eaton cb. prehypertension and cardiovascular disease risk in the women’s health initiative. circulation 2007; 115:855–60. 13. calhoun da, jones d, textor s, goff dc, murphy tp, toto rd, et al. resistant hypertension: diagnosis, evaluation, and treatment. a scientific statement from the american heart association professional education committee of the council for high blood pressure research. hypertension 2008; 5:1403–19. 14. kaufmann h. consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. clin auton res 1996; 6:125–6. 15. mann sj. severe paroxysmal hypertension. an autonomic syndrome and its relationship to repressed emotions. psychosomatics 1996; 37:444– 50. 16. clement dl, de buyzere ml, de bacquer da, de comparative study between ambulatory blood pressure monitoring and clinic blood pressure measurement in the risk assessment and management of hypertension 376 | squ medical journal, december 2010, volume 10, issue 3 leeuw pw, duprez da, fagard rh, et al. prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. n engl j med 2003; 348:2407–15. 17. schulze kl, liederwald k, meyer-sabellek m, van gemmeren d, lenz t, gotzen r. relationship between ambulatory blood pressure, forearm vascular resistance and left ventricular mass in hypertensive and normotensive subjects. am j hypertens 1993; 6:786–93. 18. cuspidi c, lonati l, sampieri l, macca g, valagussa l, zaro t, et al. impact of nocturnal fall in blood pressure on early cardiovascular changes in essential hypertension. j hypertens 1999; 17:1339–44. 19. galderisi m, petrocelli a, alfieri a, garofalo m, de divitiis o. impact of ambulatory blood pressure on left ventricular diastolic dysfunction in uncomplicated arterial systemic hypertension. am j cardiol 1996; 77:597–601. 20. andersen nh, poulsen sh, poulsen pl, knudsen st, helleberg k, hansen kw, et al. left ventricular dysfunction in hypertensive patients with type 2 diabetes mellitus. diabet med 2005; 22:1218–25. 21. fagard, rh, cornelissen, va. incidence of cardiovascular events in white-coat masked and sustained hypertension versus true normotension: a meta-analysis. j hypertens 2007; 25:2193–8. departments of 1family medicine & 3woman and child health, directorate general of primary health care, ministry of health, muscat, oman; 2department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 4research section & 6department of strategy and planning, oman medical specialty board, muscat, oman; 5severnside integrated urgent care service, bristol, uk. *corresponding author’s e-mail: drmaysa@squ.edu.om أتثري إكتئاب ما قبل الوالدة على نتائج احلمل وحدوث إكتئاب ما بعد الوالدة دراسة استقصائية أترابية للنساء العمانيات عائ�سة الرواحية، ماي�سة حمد الكيومية، ريا الكميانية، اإميان اللواتية، �ساثيا مورثي، روبن ديفيد�سون، عبد اهلل املنريي، حممد العزري abstract: objectives: this study aimed to identify the relationship between antenatal depression and pregnancy outcomes, including the risk of developing postpartum depression in oman. methods: this follow-up prospective longitudinal cohort study included pregnant women attending primary healthcare institutions in muscat, oman from january to november 2014. the edinburgh postnatal depression scale (epds) was used to screen for antenatal and postnatal depression. pregnant omani women with a gestational age ≥32 weeks attending 12 local health centres for antenatal care in muscat were invited to participate. recruited women were followed-up at 6–8 weeks after delivery. the following pregnancy outcomes were assessed: mode of delivery (normal or caesarean section [cs]), gestational age at delivery (preterm or fullterm), baby’s birth weight and development of postnatal depression. results: a total of 959 women participated in this study (response rate: 97.3%). in total, 233 women (24.4%) had antenatal depression with a score of ≥13 on the epds. of the 592 participants (61.7%) who attended postnatal clinics at 6–8 weeks post-delivery, 126 (21.3%) were positive for postnatal depression. logistic multivariate regression analysis showed that antenatal depression was associated with increased risk of cs (odds ratio [or] = 1.79; 95% confidence interval [ci]: 1.20–2.66) and postnatal depression (or = 8.63; 95% ci: 5.56–13.39). conclusion: screening women for antenatal depression and providing appropriate management may reduce adverse pregnancy outcomes and the risk of developing postnatal depression. keywords: depression; postnatal depression; women health services; maternal health services; pregnancy; primary health care; oman. امللخ�ص: الهدف: هدفت هذه الدرا�سة لتحديد العالقة بني اإكتئاب ما قبل الولدة ونتائج احلمل، مبا يف ذلك خطر الإ�سابة باإكتئاب ما بعد الولدة يف �سلطنة ُعمان. الطريقة: �سملت هذه الدرا�سة امُلتاِبعة ال�ستق�سائية الطولية الأترابية الن�ساء احلوامل الالتي يرتددن على موؤ�س�سات الرعاية ال�سحية الأولية يف م�سقط، �سلطنة ُعمان من يناير اإىل نوفمرب 2014. مت ا�ستخدام مقيا�س اإدنربه لإكتئاب ما بعد الولدة للك�سف عن اإكتئاب ما قبل الولدة وما بعدها. متت دعوة الن�ساء الُعمانيات احلوامل الالتي يبلغ عمر حملهن 32≥ اأ�سبوًعا ويرتددن على 12 مركًزا �سحًيا حملًيا للرعاية ال�سابقة للولدة يف م�سقط للم�ساركة يف هذه الدرا�سة. كما متت متابعة الن�ساء املتطوعات عند 8-6 اأ�سابيع بعد الولدة. مت تقييم نتائج احلمل التالية: طريقة الولدة )طبيعية اأو قي�سية( وعمر احلمل عند الولدة )حمل ُمْبَت�َس اأو كامل املدة( و وزن الطفل عند الولدة وحدوث اإكتئاب ما بعد الولدة. النتائج: �سارك ما جمموعه 959 امراأة يف هذه الدرا�سة )معدل ال�ستجابة: %97.3(. يف املجموع كان لدى 233 امراأة )%24.4( اإكتئاب ما قبل الولدة مبجموع نقاط 13≥ على مقيا�س اإدنربه لالكتئاب ما بعد الولدة، مما يوؤكد وجود الكتئاب. من بني 592 م�ساركة )%61.7( ممن ترددن على عيادات ما بعد الولدة عند 8-6 اأ�سابيع بعد الولدة كانت نتائج 126 م�ساركة )%21.3( اإيجابًية بالن�سبة لإكتئاب ما بعد الولدة. اأظهر حتليل النحدار اللوج�ستي متعدد املتغريات اأن الإكتئاب ماقبل الولدة ارتبط بزيادة خطر الولدة القي�سية )ن�سبة الأرجحية = 1.79؛ %95 من جمال الثقة: 2.66–1.20( والإ�سابة باإكتئاب ما بعد الولدة )ن�سبة الأرجحية = 8.63؛ %95 من جمال الثقة: 13.39–5.56(. اخلال�صة: فح�س الن�ساء للك�سف عن اإكتئاب ما قبل الولدة وتوفري العالج املالئم قد يقلل من نتائج احلمل ال�سلبية وخطر الإ�سابة باكتئاب ما بعد الولدة. الكلمات املفتاحية: الإكتئاب؛ اإكتئاب ما بعد الولدة؛ خدمات �سحة املراأة؛ خدمات �سحة الأم؛ احلمل؛ الرعاية ال�سحية الأولية؛ �سلطنة ُعمان. the effect of antepartum depression on the outcomes of pregnancy and development of postpartum depression a prospective cohort study of omani women aisha al rawahi,1 *maisa h. al kiyumi,2 raya al kimyani,3 iman al-lawati,1 sathiya murthi,4 robin davidson,5 abdullah al maniri,6 mohammed al azri2 clinical & basic research sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e179–186, epub. 28 jun 20 submitted 25 sep 19 revision req. 19 nov 19 revision recd. 28 nov 19 accepted 19 jan 20 https://doi.org/10.18295/squmj.2020.20.02.008 advances in knowledge this cohort study was the first conducted in oman to examine the relationship between antenatal depression and pregnancy outcomes, including the development of postnatal depression. understanding the relationship between antepartum and postpartum depression should help identify women who are at greater risk of developing postpartum depression, resulting in early detection and treatment. identifying the effects of antenatal depression on the outcomes of pregnancy, such as birth weight and mode of delivery, should help health practitioners understand the relationship of such associations. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ the effect of antepartum depression on the outcomes of pregnancy and development of postpartum depression a prospective cohort study of omani women e180 | squ medical journal, may 2020, volume 20, issue 2 application to patient care a screening programme for pregnant women should be considered at the primary care level. women found to be depressed during pregnancy might be offered treatment, including referrals to psychology or psychiatry outpatient clinics depending on the severity of depression, resulting in the attenuation of the detrimental effects of depression by early detection and treatment. women with antepartum depression should be followed-up during the postnatal period and rescreened as screening all women during the postpartum period might not always be feasible. women with adverse pregnancy outcomes might have had antenatal depression. thus, targeting women by screening for antenatal depression and treating or referring them for further care may help reduce pregnancy-related complications and improve maternal and infant well-being. antenatal depression is considered a major cause of disability among women worldwide, particularly in low-income countries; both antenatal and postnatal depression are associated with detrimental effects on child development.1,2 several risk factors for antenatal depression have been reported, including low socioeconomic status and educational level, a lack or unavailability of social support, experiencing physical violence from a spouse, poor partner relationships, alcohol abuse and a history of psychiatric morbidities such as depression, anxiety and stress.3–5 a recent study conducted in oman revealed that unplanned pregnancy and marital conflicts were significant predictors of antenatal depression.6 antenatal depression is frequently undetected by doctors and therefore left untreated, which may lead to adverse effects on both mother and baby.7 for the mother, antenatal depression increases the risk of preeclampsia, caesarean section (cs), assisted vaginal delivery, epidural analgaesia use during delivery, suicidal ideation and the development of postnatal depression.8,9 for the baby, antenatal depression has been found to increase the risk of spontaneous preterm delivery, low birth weight (lbw), intensive neonatal care admission and sudden death.8 in addition, babies of women with antenatal depression are more at risk of receiving suboptimal care from their mothers after birth and during their growth.10 antenatal depression has been reported as the strongest predictor of postnatal depression.3 several consequences are associated with postnatal depression including marital conflict, self-harm, suicidal thoughts and the development of depressive symptoms in fathers.11 indeed, it has been found that children of mothers who had postnatal depression were more likely to have impairment of cognitive and emotional functioning, receive less psychological care and suffer neglect and experience a disturbance in the ability to breastfeed.12 thus, it has been suggested that early detection and treatment of maternal depression could have a positive impact on preventing offspring depression, especially during adulthood.13 currently, in oman the risk for depression is not included as part of routine antenatal or postnatal screening or assessments. oman is an arabian gulf country with an estimated population of 4.6 million, of which 2.5 million are omani and 2.1 million are expatriates.14 almost one-third of omanis (35%) are below 15 years old, and only 3.5% of the population are above 65 years old.14 in oman, primary health centres are the portal to accessing secondary and tertiary healthcare services. primary healthcare facilities are funded by the government and all omanis and nonomanis who are sponsored by the government have access to these services at all levels. private institutions providing healthcare services are also present. standard antenatal care services are provided in local health centres (lhcs) as soon as a woman becomes pregnant. each pregnant woman is issued an antenatal ‘green card’ that includes personal details, medical history, family history, details of previous pregnancies and the results of routine antenatal investigations. the card also includes information about the current pregnancy, including type and time of delivery and baby’s birth weight and apgar score. women with low-risk pregnancies make six antenatal visits to lhcs during their pregnancy. pregnancies rated as high-risk are referred through specific protocols to secondary or tertiary hospitals and receive care appropriate to their condition. women usually deliver in local secondary or tertiary hospitals and are followed-up in their lhcs at 6–8 weeks for postnatal care.15 during their postnatal visit, women are examined and investigated medically as required and counselled regarding birth spacing. antenatal and postnatal clinics are mainly staffed by female general practitioners with the help of a specialised nurse. to the best of the authors’ knowledge, no prev iously published cohort-based studies on antenatal and postnatal depression have been undertaken in oman. therefore, this study aimed to identify the relationship between antenatal depression and pregnancy outcomes, including the development of postnatal depression, in oman. methods this prospective longitudinal cohort study included pregnant women attending primary healthcare instit utions from january to november 2014 in muscat, aisha al rawahi, maisa h. al kiyumi, raya al kimyani, iman al-lawati, sathiya murthi, robin davidson, abdullah al maniri and mohammed al azri clinical and basic research | e181 oman. this study is an extension of a previous study that assessed the prevalence and risks of antenatal depression among omani women attending primary healthcare centres.6 women who had medical conditions such as gestational diabetes (gdm), hypertension, pregnancy-induced hypertension or who were receiving treatment for depression were excluded as were nonomani women.6 in total, 12 out of 32 lhcs in muscat were randomly selected to conduct the current study. three nurses from each lhc were trained on how to administer the questionnaire to women and to collect data on pregnancy outcomes. all pregnant omani women at a gestational age of ≤32 weeks who attended their lhcs for routine antenatal care visits were ident ified and invited by nurses to participate in the study.6 sample size was calculated based on a presumed prevalence rate of 20%, 95% confidence interval (ci) and an error rate of 2%. the required sample size was 1,000. the arabic version of the self-administered edinburgh postnatal depression scale (epds) was used as a screening tool to identify both antenatal and postnatal depression in the current study. this validated, reliable questionnaire comprises 10 questions where each question is scored from 0–3 for a total score ranging from 0–30. a score of ≤13 is indicative of probable antenatal or postnatal depression.3,16 the arabic version of the epds was validated and used in a study conducted in an arabic-speaking country.3 permission to use the arabic version of the epds was obtained from the corresponding author. this questionnaire was administered twice, once during the antenatal visit and again during a postnatal follow-up appointment. social, demographic and medical characteristics of women were recorded in a separate section and were attached to the epds questionnaire. these characteristics include age, education level, occupation, gestational age, gravidity and whether the pregnancy was planned or not. the recruited women were followed-up post natally at 6–8 weeks and were given the epds quest ionnaire to complete for a second time. women who did not attend the postnatal visit were reminded to do so via telephone.6 the pregnancy outcomes were collected 6–8 weeks after delivery during the routine postnatal visit, with data collected from the ‘green card’ and the birth register available in the lhcs. the collected data included type of delivery (i.e. normal vaginal delivery or cs), gestational age at time of delivery and baby’s birth weight. preterm birth was defined as delivery at <37 weeks of gestation. birth weight of less than 2.5 kg was table 1: baseline sociodemographic and antenatal and post natal characteristics of pregnant omani women (n = 959) characteristic* n (%) age in years (n = 957) <24 261 (27.3) 25–30 451 (47.1) >30 245 (25.6) occupation (n = 959) housewife 609 (63.5) employed 350 (36.5) highest level of education (n = 957) basic education 519 (54.2) university & higher education 438 (45.8) planned pregnancy (n = 958) yes 560 (58.5) no 398 (41.5) gravidity (n = 959) primigravida (1 pregnancy) 373 (38.9) multigravida (2–4 pregnancies) 465 (48.5) grand multigravida (5+ pregnancies) 121 (12.6) gestational age in weeks (n = 959) 32–34 399 (41.6) 35–37 376 (39.2) >37 184 (19.2) history of miscarriage (n = 959) yes 170 (17.7) no 789 (82.3) antenatal depression (n = 959) depressed 233 (24.3) not depressed 726 (75.7) gestational age at delivery in weeks (n = 953) <37 59 (6.2) ≤37 894 (93.8) type of delivery (n = 953) normal vaginal delivery 822 (86.3) cs 131 (13.7) type of cs (n = 131) emergency 108 (82.4) elective 23 (17.6) birth weight of infant in kg (n = 952) <2.5 64 (6.7) ≤2.5 888 (93.3) postnatal depression† (n = 592) depressed 126 (21.3) not depressed 466 (78.7) cs = caesarean section; kg = kilogram. *as the current study is a continuation of a previous study, some data are the same.6 the total of each variable corresponds to the number of respondents for each question. †a score of ≥13 on the edinburgh postnatal depression scale was indicative of probable antenatal or postnatal depression. the effect of antepartum depression on the outcomes of pregnancy and development of postpartum depression a prospective cohort study of omani women e182 | squ medical journal, may 2020, volume 20, issue 2 defined as lbw. women who delivered at ≤37 weeks of gestation were categorised as having had a full-term delivery.17,18 a pilot study was conducted with the first 50 women to assess the clarity of the questions as well as the reliability of the arabic version of the epds. the participants included in the pilot study were included in the final analysis of the current study. a cronbach's alpha was calculated to test the reliability of the epds and it was found to be 0.766. statistical analysis was conducted using statistical package for social sciences (spss), version 23 (ibm corp., armonk, new york, usa). descriptive analysis for sociodemographic variables and participants’ resp onses were recorded. relationships between antenatal depression, pregnancy outcomes and postnatal depr ession were assessed using a chi-squared test. a p value of <0.05 was considered statistically significant. multivariate regression analysis was conducted to attenuate the effects of possible confounding factors. on multivariate regression analysis, the independent variables included gravidity (primigravida) and ante natal depression with cs delivery as the dependent variable. a second regression analysis was done for postnatal depression development (the dependent variable) and antenatal depression, with mother’s age and unplanned pregnancy as the independent variables. all participants provided informed consent and were given a form to read that explained the purpose of the study. this study was approved by the medical research and ethics committee (mrec) of the college of medicine and health sciences at sultan qaboos university, muscat, oman (mrec #572). results a total of 959 pregnant women were included in this study (response rate: 97.3%). the ages of participants ages ranged from 17–43 years with a mean of 27 ± 4.79 years. the majority of participants were housewives (63.5%) and the remaining participants (36.5%) were employed. regarding gravidity, 48.5% were multigravida (2–4 pregnancies), 38.9% were primigravida and 12.6% were grand multigravida (5+ pregnancies). most women (58.4%) were at ≤35 weeks of gestation and the remaining participants (41.6%) were between 32–34 weeks. more than 40% of participants reported that their pregnancy had been unplanned [table 1]. the majority of participants (93.2%) delivered at or after 37 weeks of gestation. most (86.3%) had normal vaginal deliveries and the remainder (13.7%) had a cs. of the cs deliveries, 82.4% were due to emergencies (i.e. non-progression of labour and/or fetal distress) and 17.6% were elective. in the majority of women (93.3%), babies’ birth weights were 2.5 kg or more [table 1]. the epds scores ranged from 0–23, with a mean score of 9 ± 4.785. of the 959 participants, 233 (24.4%) had scores that suggested antenatal depression at a cut point of ≤13. more than half of participants (61.7%) attended a postnatal follow-up at 6–8 weeks. of these partic ipants, 126 (21.3%) had epds scores suggestive of postnatal depression using a cut point of ≤13, of which, 58.7% had also had antenatal depression [table 2]. a total of 367 (38.3%) women were lost to follow-up as they did not attend postnatal follow-ups. of these, 94 (25.6%) had antenatal depression, which might have affected the results. however, such a percentage is not sufficiently high to substantially affect the outcome of this study. a bivariate analysis revealed that depression during pregnancy was significantly associated with cs delivery (p = 0.004) and developing postnatal depression (p <0.001). no significant associations were found between antenatal depression and lbw or preterm labour (p = 0.177 and 0.300, respectively) [table 2]. gravidity (primigravida) and antenatal depression were found to be significantly associated with cs delivery (p <0.001 and 0.034, respectively). furthermore, table 2: associations between antenatal depression and outcomes of pregnancy and postnatal depression among pregnant omani women (n = 959) variables n (%) p value antenatal depression* depressed (n = 233) not depressed (n = 726) birth weight of infant in kg 0.177 <2.5 20 (8.6) 44 (6.1) ≤2.5 213 (91.4) 682 (93.9) gestational age at delivery in weeks 0.300 <37 11 (4.7) 48 (6.6) ≤37 222 (95.3) 678 (93.4) type of delivery 0.004† normal vaginal delivery 188 (80.7) 640 (88.2) cs 45 (19.3) 86 (11.8) postnatal depression‡ <0.001† depressed (n = 126) 74 (58.7) 52 (41.3) not depressed (n = 466) 66 (14.2) 400 (85.8) cs = caesarean section. * as the current study is a continuation of a previous study, some data are the same.6 the total of each variable corresponds to the number of respondents for each question. †statistically significant at p ≤0.05. ‡a score of ≥13 on the edinburgh postnatal depression scale was indicative of probable antenatal or postnatal depression. aisha al rawahi, maisa h. al kiyumi, raya al kimyani, iman al-lawati, sathiya murthi, robin davidson, abdullah al maniri and mohammed al azri clinical and basic research | e183 table 3: associations between baseline variables and mode of delivery and postnatal depression among pregnant omani women (n = 959) variables n (%) mode of delivery* postnatal depression† nvd (n = 822) cs (n = 131) p value depressed (n = 126) not depressed (n = 466) p value age in years <24 233(28.3) 29 (22.1) 0.190 45 (35.7) 124 (26.6) 0.033‡ 25–30 378 (46.0) 71 (54.2) 59 (46.8) 213 (45.7) >30 211 (25.7) 31 (23.7) 22 (17.5) 129 (27.7) history of miscarriage yes 145 (17.6) 23 (17.6) 0.982 108 (85.7) 382 (82.0) 0.355 no 677 (82.4) 108 (82.4) 18 (14.3) 84 (18.0) gravidity primigravida (1 pregnancy) 300 (36.5) 72 (55.0) <0.001‡ 50 (39.7) 187 (40.1) 0.400 multigravida (2–4 pregnancies) 412 (50.1) 50 (38.2) 64 (50.8) 215 (46.1) grand multigravida (5+ pregnancies) 110 (13.4) 9 (6.9) 12 (9.5) 64 (13.7) highest level of education basic education 446 (54.3) 73 (55.7) 0.756 73 (57.9) 245 (52.6) 0.314 university & higher education 376 (45.7) 58 (44.3) 53 (42.1) 221 (47.4) occupation housewife 518 (63.0) 85 (64.9) 0.680 85 (67.5) 311 (66.7) 0.915 employed 304 (37.0) 46 (35.1) 41 (32.5) 155 (33.3) history of depression yes 8 (1.0) 1 (0.8) 0.818 2 (1.6) 3 (0.6) 0.289 no 814 (99.0) 130 (99.2) 124 (98.4) 463 (99.4) family history of depression yes 18 (2.2) 0 (0.0) 0.087 4 (3.2) 6 (1.3) 0.232 no 804 (97.8) 131 (100.0) 122 (96.8) 460 (98.7) planned pregnancy yes 478 (58.2) 80 (61.1) 0.529 63 (50.0) 285 (61.2) 0.025‡ no 344 (41.8) 51 (38.9) 63 (50.0) 181 (38.8) antenatal depression depressed 153 (18.6) 35 (26.7 0.034‡ 52 (41.3) 400 (85.8) <0.001‡ not depressed 669 (81.4) 96 (73.3) 74 (58.7) 66 (14.2) nvd = normal vaginal delivery; cs = caesarean section; epds = edinburgh postnatal depression scale. *the total corresponds to the number of respondents for the question. †a score of ≥13 on the edinburgh postnatal depression scale was indicative of probable antenatal or postnatal depression. a total of 367 participants were lost to follow-up. ‡statistically significant at p ≤0.05. the effect of antepartum depression on the outcomes of pregnancy and development of postpartum depression a prospective cohort study of omani women e184 | squ medical journal, may 2020, volume 20, issue 2 antenatal depression, mother’s age and unplanned pregnancies were deemed significant predictors of post natal depression development (p <0.001, 0.033 and 0.025, respectively) [table 3]. the multivariate regression analysis revealed that women who had antenatal depression were 1.79 times more likely to undergo cs delivery (95% ci: 1.20–2.66) and 8.63 times more likely to develop postpartum depression (95% ci: 5.56–13.39) [table 4]. discussion to the best of the author’s knowledge, this study is the first in oman to explore the association between antenatal depression and the outcomes of pregnancy, including postnatal depression development. it showed that antenatal depression is significantly associated with cs delivery and development of postnatal depression. however, effects of antenatal depression on gestational age at delivery and baby’s birth weight were not significant. this study found an antenatal depression prev alence among omani women of 24.3% which was determined using a cut point of ≤13 on the epds.6 this prevalence is similar to that of women in brazil (24.3%) but is higher than what has been reported in other arabic-speaking countries such as jordan (19%) and morocco (19.2%).3,5,19 the prevalence of antenatal depression in oman is higher than rates found in bangladesh (18%), australia (16.9%), italy (14.9%) and turkey (21.6%).20–23 the finding of a significant association between antenatal depression and cs delivery is consistent with other studies.24,25 the reason for the increased risk of cs in omani women with antenatal depression is unclear. however, women who experience antenatal depression may have greater anxiety and fear of childbirth leading to a lower pain threshold and increased demand for epidural analgaesia and incidence of cs.8 furthermore, it has been found that psychological distress can impair uterine contractility leading to prolonged labour, failure to progress and eventually fetal distress, all of which could increase cs risk.26,27 the current study revealed that omani women who had antenatal depression were at a greater risk of developing postnatal depression than women without antenatal depression. similar results were reported in a study from the usa which showed that women who reported poor mental health at antenatal period were found to be 11 times as likely to develop poor mental health at postnatal period.28 in another study, 23% of women with postnatal depression reported that symptoms of depression had started during pregnancy.29 it was also found that women who had experienced postnatal depression have an increased risk of suffering from further episodes of postnatal depression following subsequent deliveries.30 the current study found that antenatal depression had no effect on birth weight or gestational age at delivery (i.e. preterm birth), which was both consistent and inconsistent with previous studies.31–33 the reasons for these contradictory studies are most likely related to differences in study design, type of antenatal depression measurement tool used, the influence of confounders such as ethnicity, smoking and substance abuse and previous obstetric complications such as lbw or preterm labour.31 the absence of a positive association between antenatal depression and preterm birth might be related to the fact that in this study women were recruited from 32 weeks of gestation onward, resulting in an artificially low number of women in the study who had had preterm births. this study was subjected to some limitations. first, the screening tool for depression was self-reported, resulting in a possible overor underestimating of the true prevalence of depression. moreover, choosing a cut-off value of ≤13 to diagnose antenatal and postnatal depression was based on a jordanian study as no previous validation study was conducted in oman.3 second, while epds is a valid and reliable screening tool for probable depression, it should be followed by more objective assessments to confirm the presence of depression. this study lacked such an objective assess ment. third, other confounding obstetric variables such as previous history of lbw and cs were not included in the current analysis and may have affected the findings. this study also did not identify the proportion of women with antenatal depression who developed obstetric and labour complications such as pre-eclampsia or obstructed labour, both of which might have had an impact on the mode of delivery. fourth, this study did not determine whether women diagnosed with antenatal depression, based on the epds, had sought treatment from healthcare services. moreover, types of treatment (e.g. cognitive behavioural therapy, medic ations or referral to a psychiatrist) those women might table 4: logistic regression analysis of the effects of ante natal depression on birth outcomes and development of postnatal depression (n = 959) variables or 95% ci p value cs* 1.79 1.20–2.66 0.004† postnatal depression‡ 8.63 5.56–13.39 <0.001† or = odds ratio; ci = confidence interval; cs = caesarean section. *independent variables include gravidity and antenatal depression. †stat istically significant at p ≤0.05. ‡ independent variables include mother’s age, unplanned pregnancy and antenatal depression. aisha al rawahi, maisa h. al kiyumi, raya al kimyani, iman al-lawati, sathiya murthi, robin davidson, abdullah al maniri and mohammed al azri clinical and basic research | e185 have received were not identified. fifth, recruiting pregnant women at 32 weeks or more gestation might have resulted in the exclusion of women who delivered earlier, affecting the study’s results. finally, although telephone calls were used to remind women about the 6–8-week postnatal epds questionnaire, 38.3% of the women were lost to follow-up. conclusion this study showed that antenatal depression has detrimental effects on both the mother and baby’s health and is associated with several adverse outcomes in women, including the risk of postnatal depression. screening women for the presence of antenatal depression and managing them appropriately may help reduce pregnancy and delivery complications. while no positive relationships were found between antenatal depression and a baby’s gestational age or birth weight, additional research is needed to investigate this finding further. a c k n o w l e d g e m e n t the authors would like to thank the participants in this study and the nurses from local health centres for their great help in data collection. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the college of medicine and health sciences, sultan qaboos university, muscat, oman. references 1. world health organization, department of mental health and substance abuse. maternal mental health and child health and development in low and middle income countries. from: www.who.int/mental_health/prevention/suicide/mmh_jan08_ meeting_report.pdf accessed: nov 2019. 2. underwood l, waldie k, d'souza s, peterson er, morton s. a review of longitudinal studies on antenatal and postnatal depression. arch womens ment healt 2016; 19:711–20. https://doi.org/10.10 07/s00737-016-0629-1. 3. mohammad ki, gamble j, creedy dk. prevalence and factors associated with the development of antenatal and post natal depression among jordanian women. midwifery 2011; 27:e238–45. https://doi.org/10.1016/j.midw.2010.10.008. 4. milgrom j, gemmill aw, bilszta jl, hayes b, barnett b, brooks j, et al. antenatal risk factors for postnatal depression: a large prospective study. j affect disord 2008; 108:147–57. https://doi.org/10.1016/j.jad.2007.10.014. 5. melo ef jr, cecatti jg, pacagnella rc, leite df, vulcani de, makuch my. the prevalence of perinatal depression and its associated factors in two different settings in brazil. j affect disord 2012; 136:1204–8. https://doi.org/10.1016/j.jad.2011.11.023. 6. al-azri m, al-lawati i, al-kamyani r, al-kiyumi m, al-rawahi a, davidson r, et al. prevalence and risk factors of antenatal depression among omani women in a primary care setting: crosssectional study. sultan qaboos univ med j 2016; 16:e35–41. https://doi.org/10.18295/squmj.2016.16.01.007. 7. moses-kolko el, roth ek. antepartum and postpartum depression: healthy mom, healthy baby. j am med womens assoc (1972) 2004; 59:181–91. 8. chung tk, lau tk, yip as, chiu hf, lee dt. antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. psychosom med 2001; 63:830–4. https://doi.org/10.1097/00006842-200109000-00017. 9. melville jl, gavin a, guo y, fan my, katon wj. depressive disorders during pregnancy: prevalence and risk factors in a large urban sample. obstet gynecol 2010; 116:1064–70. https://doi.org/10.1097/aog.0b013e3181f60b0a. 10. larsson c, sydsjö g, josefsson a. health, sociodemographic data, and pregnancy outcome in women with antepartum depressive symptoms. obstet gynecol 2004; 104:459–66. https://doi.org/10.1097/01.aog.0000136087.46864.e4. 11. fihrer i, mcmahon ca, taylor aj. the impact of postnatal and concurrent maternal depression on child behaviour during the early school years. j affect disord 2009; 119:116–23. https://doi.org/10.1016/j.jad.2009.03.001. 12. o'connor tg, heron j, glover v; alspac study team. antenatal anxiety predicts child behavioral/emotional problems indep endently of postnatal depression. j am acad child adolesc psychiatry 2002; 41:1470–7. https://doi.org/10.1097/00004583200212000-00019. 13. pearson rm, evans j, kounali d, lewis g, heron j, ramchandani pg, et al. maternal depression during pregnancy and the postnatal period: risks and possible mechanisms for offspring depression at age 18 years. jama psychiatry 2013; 70:1312–19. https://doi. org/10.1001/jamapsychiatry.2013.2163. 14. national center for statistics and information. 2018 statistical year book. from: ncsi.gov.om/elibrary/librarycontentdoc/ bar_statistical%20year%20book%202018_a8b32d59-cdc94987-ba29-1e7ce78d5cca.pdf accessed: nov 2019. 15. oman ministry of health. pregnancy & childbirth management guidelines. a guide for nurses, midwives and doctors. from: w w w.moh.gov.om/documents/272928/3240138/pregnan cy+%26+childbirth+guideline+level+2.pdf/01d4c976-83bb7a9d-12c4-9ed7d8a53041 accessed: nov 2019. 16. heron j, o'connor tg, evans j, golding j, glover v; alspac study team. the course of anxiety and depression through pre gnancy and the postpartum in a community sample. j affect disord 2004; 80:65–73. https://doi.org/10.1016/j.jad.2003.08.004. 17. niemi m, falkenberg t, petzold m, chuc nt, patel v. symptoms of antenatal common mental disorders, preterm birth and low birthweight: a prospective cohort study in a semi-rural district of vietnam. trop med int health 2013; 18:687–95. https://doi. org/10.1111/tmi.12101. 18. straub h, adams m, kim jj, silver rk. antenatal depressive symptoms increase the likelihood of preterm birth. am j obstet gynecol 2012; 207:329.e1–4. https://doi.org/10.1016/j. ajog.2012.06.033. 19. alami km, kadri n, berrada s. prevalence and psychosocial correlates of depressed mood during pregnancy and after childbirth in a moroccan sample. arch womens ment health 2006; 9:343–6. https://doi.org/10.1007/s00737-006-0154-8. 20. nasreen he, kabir zn, forsell y, edhborg m. low birth weight in offspring of women with depressive and anxiety symptoms during pregnancy: results from a population based study in bangladesh. bmc pub health 2010; 10:515. https://doi. org/10.1186/1471-2458-10-515. 21. leigh b, milgrom j. risk factors for antenatal depression, postnatal depression and parenting stress. bmc psychiatry 2008; 8:24. https://doi.org/10.1186/1471-244x-8-24. https://doi.org/10.1007/s00737-016-0629-1 https://doi.org/10.1007/s00737-016-0629-1 https://doi.org/10.1016/j.midw.2010.10.008 https://doi.org/10.1016/j.jad.2007.10.014 https://doi.org/10.1016/j.jad.2011.11.023 https://doi.org/10.18295/squmj.2016.16.01.007 https://doi.org/10.1097/00006842-200109000-00017 https://doi.org/10.1097/aog.0b013e3181f60b0a https://doi.org/10.1097/01.aog.0000136087.46864.e4 https://doi.org/10.1016/j.jad.2009.03.001 https://doi.org/10.1097/00004583-200212000-00019 https://doi.org/10.1097/00004583-200212000-00019 https://doi.org/10.1001/jamapsychiatry.2013.2163 https://doi.org/10.1001/jamapsychiatry.2013.2163 https://doi.org/10.1016/j.jad.2003.08.004 https://doi.org/10.1111/tmi.12101 https://doi.org/10.1111/tmi.12101 https://doi.org/10.1016/j.ajog.2012.06.033 https://doi.org/10.1016/j.ajog.2012.06.033 https://doi.org/10.1007/s00737-006-0154-8 https://doi.org/10.1186/1471-2458-10-515 https://doi.org/10.1186/1471-2458-10-515 https://doi.org/10.1186/1471-244x-8-24 the effect of antepartum depression on the outcomes of pregnancy and development of postpartum depression a prospective cohort study of omani women e186 | squ medical journal, may 2020, volume 20, issue 2 22. agostini f, neri e, salvatori p, dellabartola s, bozicevic l, monti f. antenatal depressive symptoms associated with specific life events and sources of social support among italian women. matern child health j 2015; 19:1131–41. https://doi. org/10.1007/s10995-014-1613-x. 23. gulseren l, erol a, gulseren s, kuey l, kilic b, ergor g. from antepartum to postpartum: a prospective study on the prevalence of peripartum depression in a semiurban turkish community. j reprod med 2006; 51:955–60. 24. chung tk, lau tk, yip as, chiu hf, lee dt. antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. psychosom med 2001; 63:830–4. https://doi.org/10.1097/00006842-200109000-00017. 25. bayrampour h, salmon c, vinturache a, tough s. effect of depressive and anxiety symptoms during pregnancy on risk of obstetric interventions. j obstet gynaecol res 2015; 41:1040–8. https://doi.org/10.1111/jog.12683. 26. kuo sy, chen sr, tzeng yl. depression and anxiety trajectories among women who undergo an elective cesarean section. plos one 2014; 9:e86653. https://doi.org/10.1371/journal.pone.0086653. 27. teixeira jm, fisk nm, glover v. association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort-based study. bmj 1999; 318:153–7. https://doi.org/10.11 36/bmj.318.7177.153. 28. witt wp, wisk le, cheng er, hampton jm, creswell pd, hagen ew, et al. poor prepregnancy and antepartum mental health predicts postpartum mental health problems among us women: a nationally representative population-based study. womens health issues 2011; 21:304–13. https://doi.org/10.10 16/j.whi.2011.01.002. 29. watson jp, elliott sa, rugg aj, brough di. psychiatric disorder in pregnancy and the first postnatal year. br j psychiatry 1984; 144:453–62. https://doi.org/10.1192/bjp.144.5.453. 30. robertson e, grace s, wallington t, stewart de. antenatal risk factors for postpartum depression: a synthesis of recent liter ature. gen hosp psychiatry 2004; 26:289–95. https://doi.org/10.10 16/j.genhosppsych.2004.02.006. 31. grote nk, bridge ja, gavin ar, melville jl, iyengar s, katon wj. a meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. arch gen psychiatry 2010; 67:1012–24. https://doi. org/10.1001/archgenpsychiatry.2010.111. 32. andersson l, sundström-poromaa i, wulff m, aström m, bixo m. neonatal outcome following maternal antenatal depression and anxiety: a population-based study. am j epidemiol 2004; 159:872–81. https://doi.org/10.1093/aje/kwh122. 33. rahman a, bunn j, lovel h, creed f. association between antenatal depression and low birthweight in a developing country. acta psychiatr scand 2007; 115:481–6. https://doi. org/10.3389/fpsyt.2014.00175. https://doi.org/10.1007/s10995-014-1613-x https://doi.org/10.1007/s10995-014-1613-x https://doi.org/10.1097/00006842-200109000-00017 https://doi.org/10.1111/jog.12683 https://doi.org/10.1371/journal.pone.0086653 https://doi.org/10.1136/bmj.318.7177.153 https://doi.org/10.1136/bmj.318.7177.153 https://doi.org/10.1016/j.whi.2011.01.002 https://doi.org/10.1016/j.whi.2011.01.002 https://doi.org/10.1192/bjp.144.5.453 https://doi.org/10.1016/j.genhosppsych.2004.02.006 https://doi.org/10.1016/j.genhosppsych.2004.02.006 https://doi.org/10.1001/archgenpsychiatry.2010.111 https://doi.org/10.1001/archgenpsychiatry.2010.111 https://doi.org/10.1093/aje/kwh122 https://doi.org/10.3389/fpsyt.2014.00175 https://doi.org/10.3389/fpsyt.2014.00175 department of orthopaedics, lady hardinge medical college, new delhi, india *corresponding author’s e-mail: draminarang@gmail.com treatment of cleft foot deformity using fish mouth incision and suture-button in paediatric foot a case report *amit narang, ayanjit chattopadhyay, amit sharma, sumit gupta sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 288–290, epub. 26 may 22 submitted 11 nov 20 revisions req. 24 jan & 4 mar 21; revisions recd. 18 feb & 11 mar 21 accepted 16 mar 21 horizontal lying metacarpal on the left cleft hand [figures 1 and 2]. there was no history of any such deformity in other family members. the indication of surgery for this patient was mainly cosmetic and due to her inability to wear shoes on her right foot. a cleft closure surgery was planned for the right foot using a fish mouth incision and suture-button and fibre-wire technique to bring the two metatarsals closer together. a fish mouth incision was used in the cleft and after carefully preserving the digital vessels and nerves in the cleft, excess fatty tissue was removed. three drill holes to accommodate 1.0 mm k-wires were made in the transverse plane at 3–5 mm distance in the second and third metatarsal bones to be able to insert the fibre-wire into the bone. two 4 mm endobuttons were used to loop the fibre-wire, while one endobutton was stationary on a metatarsal; the fibre-wires were pulled gently through the other button to achieve closure of the gap [figure 3]. on complete closure of the skin, the foot was aesthetically acceptable with closure of the cleft. sterile dressing was used until suture removal (i.e. two weeks post-surgery). the patient was followedup until one and a half years post-operatively with satisfactory outcome as per her parents and normal fitting footwear [figure 4]. a full written informed consent was obtained from the parents of the patient for treatment as well as for using the patient’s data and pictures for publication purposes. dysplastic cleft feet are commonly seen as a main feature of the ectrodactyly-ectodermal dysplasia-clefting syndrome. it is usually characterised by the absence of the median rays of the feet, sparing the first and the fifth ray and can range from complete absence of the metatarsal to presence of a rudimentary metatarsal bone. due to its characteristic appearance, it has been called ‘the lobster claw’. associated cleft hand and syndactyly in the feet and hands are other common features seen in affected children.1,2 the principal indications for surgery in affected children are cosmetic appearance and a better functional foot for footwear. this article reports a case where the deformity was managed surgically using a suture-button system and cleft closure using fish mouth incision. case report a one-year-old female child presented to the paediatric orthopaedic clinic at a medical college in new delhi, india, in 2018 with complaints of abnormal looking hands and feet. on complete examination, there was right-side cleft foot with four toes and syndactyly of the first and second toes. the left foot had five toes without cleft but there was syndactyly of the second to fifth toes. the patient also had a bilateral cleft hand with four digits on the left hand and three digits on the right hand. radiographic examination revealed a complete absence of the third metatarsal bone in the right foot and six metacarpal bones with one this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.097 case report abstract: cleft foot is a congenital anomaly characterised by absence of the metatarsal bones and phalanges. it is commonly seen in children with ectrodactyly-ectodermal dysplasia-clefting syndrome ranging from a median cleft up to the mid metatarsals to a deep cleft up to the tarsal bones. surgical treatment in the form of cleft closure, excision of the rudimentary metatarsal bone and cross k-wire fixation of metatarsal bones have been tried for the management of such cases. we report a one-year-old child who presented to the paediatric orthopaedic clinic at a medical college in new delhi, india, in 2018 with type iii cleft foot with four metatarsals. the patient was treated with a suture-button system using three transverse tunnels in the second and third metatarsal bones in order to bring them closer together. a satisfactory outcome was achieved with normal fitting footwear. keywords: podiatry; congenital abnormality; pediatrics; case report; india. https://creativecommons.org/licenses/by-nd/4.0/ amit narang, ayanjit chattopadhyay, amit sharma and sumit gupta case report | 289 discussion cleft foot is a rare anomaly which is usually syndromic and associated with other spectrum of deformities such as cleft lip and cleft palate, etc.3 clinical presentation can vary from an absence of toes to a deep cleft with absence of metatarsals. blauth and borisch’s radiographic classification is commonly used to classify the deformity. according to this classification, the current patient was a type iii with four metatarsal bones.4 in addition, abraham et al.’s classification was used to classify the deformity clinically; the patient was type i clinically with the cleft almost crossing the mid-metatarsal level.5 the indications for surgery in these patients are an improved foot shape for footwear and a better cosmetic appearance. treatment should be devised as per the patient’s demand and the magnitude of the deformity. the various techniques used for such repairs are simple cleft closure with z-plasty, application of double pedicled flap, cross k-wire fixation of the metatarsal bones to prevent splaying in the post-operative period and removing the horizontal metatarsal in order to bring the other metatarsals closer and decrease the width of the foot.6–8 all the authors in the literature have emphasised the need for reconstruction of intermetatarsal ligament to prevent failure of correction. insertion of a silicone block has been used in cases with two or three ray deficiencies to fill the gap.6 some authors have used the ilizarov apparatus for correction of cleft foot at an adult age, but this can’t be used in children owing to the cartilaginous nature of foot bones.9 the suture-button mechanism is used to bring the two metatarsals closer and is a recent modality being tried in these patients with the purpose of restoration of the intermetatarsal ligament function. although there are risks with this technique, such as splintering of the metatarsal while tunnel drilling and tunnel blow-out during the tightening of the suture, if done carefully, it is an excellent technique to decrease the intermetatarsal space; it protects the cleft repair and restores the function of the intermetatarsal ligament. it is also thought to maintain the alignment of the metatarsal bones during growth so that they do not divert.10 instead of using a single large drill hole to pass the fibre-wire, in the current patient three figure 2: x-ray images of the limbs of a one-year-old female child. a: anteroposterior view of the left cleft hand. b: anteroposterior view of both feet showing right cleft foot. c: immediate post-operative x-ray of the right foot d: post-operative x-ray of the right foot at 18-month-follow-up. figure 3: illustration showing the sequence of sutures passing through metatarsal holes. figure 1: photographs of the right foot of a one-year-old female child. a: clinical photograph showing cleft foot. b & c: intraoperative photographs showing suture-button loop being passed through the metatarsal tunnels. d: post-procedure photograph showing closure of the cleft. treatment of cleft foot deformity using fish mouth incision and suture-button in paediatric foot a case report 290 | squ medical journal, may 2022, volume 22, issue 2 transverse drill holes of 1 mm diameter were used so as to decrease the chances of iatrogenic fracture and suture cut-out in such a young child. it should be noted that the shorter duration of follow-up can be considered as a limitation of this report considering the chance of recurrence of deformity at a later age. conclusion cleft foot is a complex deformity with poor cosmesis and the treatment procedure should be chosen judiciously to obtain a good cosmetic and functional result for the patient. cleft closure combined with a suture-button technique is a relatively new approach and is effective in protecting the soft tissue closure by decreasing the inter-metatarsal gap, keeping in mind the possibility of iatrogenic metatarsal fracture and suture cut-out. a u t h o r s’ c o n t r i b u t i o n ac collected the data and provided the pictures. as and sg followed-up the case. an drafted the manuscript. an, as and sg revised the manuscript. all authors approved the final version of the manuscript. references 1. penchaszadeh vb, de negrotti tc. ectrodactyly-ectodermal dysplasia-clefting (eec) syndrome: dominant inheritance and variable expression. j med genet 1976; 13:281–4. https://doi. org/10.1136/jmg.13.4.281. 2. mason wh. congenital cleft foot deformity (split foot or lobster claw). j am podiatr med assoc 1991; 81:575–9. https:// doi.org/10.7547/87507315-81-11-575. 3. sharma ak, sarin yk. congenital cleft foot (lobster claw): an unusual association with ano-rectal malformation. indian pediatr 1992; 29:1295–7. 4. blauth w, borisch nc. cleft feet. proposals for a new classif ication based on roentgenographic morphology. clin orthop relat res 1990; 258:41–8. https://doi.org/10.1097/00003086199009000-00007. 5. abraham e, waxman b, shirali s, durkin m. congenital cleftfoot deformity treatment. j pediatr orthop 1999; 19:404–10. https://doi.org/10.1097/01241398-199905000-00023. 6. ergün ss, öztürk k. surgical treatment of cleft foot using double opposing z-plasty. j 1st faculty med 2007; 70:44–6. 7. onizuka t. surgical correction of lobster-claw feet. plast reconstr surg 1976; 57:98–102. https://doi.org/10.1097/00006 534-197601000-00024. 8. tani y, ikuta y, ishida o. surgical treatment of the cleft foot. plast reconstr surg 2000; 105:1997–2002. https://doi.org/10.10 97/00006534-200005000-00013. 9. leonchuk ss, neretin as, blanchard aj. cleft foot: a case report and review of literature. world j orthop 2020; 11:129–36. https://doi.org/10.5312/wjo.v11.i2.129. 10. talusan pg, telles c, perez jl, reach js jr. treatment of cleft foot deformity with a suture-button construct in the pediatric foot: a case report. foot ankle int 2013; 34:1299–304. https:// doi.org/10.1177/1071100713487184. figure 4: photographs of the feet at 18 months of follow-up with footwear. https://doi.org/10.1136/jmg.13.4.281 https://doi.org/10.1136/jmg.13.4.281 https://doi.org/10.7547/87507315-81-11-575 https://doi.org/10.7547/87507315-81-11-575 https://doi.org/10.1097/00003086-199009000-00007 https://doi.org/10.1097/00003086-199009000-00007 https://doi.org/10.1097/01241398-199905000-00023 https://doi.org/10.1097/00006534-197601000-00024 https://doi.org/10.1097/00006534-197601000-00024 https://doi.org/10.1097/00006534-200005000-00013 https://doi.org/10.1097/00006534-200005000-00013 https://doi.org/10.5312/wjo.v11.i2.129 https://doi.org/10.1177/1071100713487184 https://doi.org/10.1177/1071100713487184 squ med j, april 2010, vol. 10, iss. 1, pp. 89-93, epub. 17th apr 10 submitted 27th sept 09 revision req. 24th nov 09, revision recd. 24th dec 09 accepted 27th dec 09 incidence of congenital malformations is three to four times more common in infants of diabetic mothers than in the general population. these include neural tube defects, anomalies of the heart, urogenital system, skeleton and alimentary tract, and the caudal regression syndrome (crs). caudal regression syndrome is characterised by variable lumbosacrococcygeal or sacrococcygeal agenesis. it is accompanied by symmetrical multiple musculoskeletal anomalies of the pelvis and legs in babies of mothers with diabetes mellitus;1 however, genetic predisposition and vascular hypoperfusion have been suggested as other causal factors.2 agenesis of the corpus callosum and holoprosencephaly has also been described as a component of diabetic embryopathy.3 a rare combination of all these three conditions in an infant of a diabetic mother is reported here. case report a baby boy was born at 38 weeks gestation to a 28 year-old, gravida 6, mother of a non-consanguineous marriage. her previous five babies were normal. she was diagnosed to have hodgkin’s lymphoma in 2005 and was in remission at the time of this report. when diagnosed with lymphoma, she was also detected to have diabetes and has been on insulin since that time. the glycaemic control of the mother was poor in the first trimester with a high level of haemoglobin a1c (hba1c) of 11.6% at 8 weeks of gestation. the control improved subsequently departments of 1child health and 2obstetrics and gynecology, sultan qaboos university hospital, muscat, oman *to whom correspondence should be addressed. e mail: lalitha_krishnan@hotmail.com متالزمة النكوص الذيلي مع نقص التكّون اجلزئي للجسم م الدماغ الفصي اجلزئي الثفين وِانِْدَماُج ُمَقدَّ تقرير حالة هالل اله�شامي، ماريا باتاكالن، مرمي ماثي�، الليثا كر�شنان امللخ�ص: متالزمة النكوص الذيلي حالة جنينية نادرة احلدوث في احلمل املصاحب بداء السكري . وعلى الرغم من أن اآللية الدقبقة حلدوث هذه احلالة غير معروفة، لكن ارتفاع سكر الدم أثناء تكوين اجلنني يبدو هو املسؤول . ومن جهة اخرى فقد مت وصف متالزمة النكوص الذيلي وعدم التكون للجسم الثفني واندماج مقدم الدماغ الفصي اجلزئي بصورة منفردة ألجنة األمهات املصابات بسكر احلمل. وعلى حد علمنا فإن اجلمع بني كل هذه احلاالت مع بعضها لم يتم اإلبالغ عنها حلد اآلن. ََّفِنيُّ، تقرير حالة، ُعمان. مفتاح الكلمات: داء السكر في احلمل، متالزمة النكوص الذيلي، اِنِْدَماُج ُمَقدَِّم الدِّماغ، اجلِْسُم الث abstract: caudal regression syndrome is a rare fetal condition of diabetic pregnancy. although the exact mechanism is not known, hyperglycaemia during embryogenesis seems to act as a teratogen. independently, caudal regression syndrome (crs), agenesis of the corpus callosum (acc) and partial lobar holoprosencephaly (hpe) have been reported in infants of diabetic mothers. to our knowledge, a combination of all these three conditions has not been reported so far. keywords: diabetes in pregnancy; caudal regression syndrome; holoprosencephaly; corpus callosum; case report; oman. caudal regression syndrome with partial agenesis of the corpus callosum and partial lobar holoprosencephaly case report hilal al hashami,1 maria f bataclan,1 mariam mathew,2 *lalitha krishnan1 case report caudal regression syndrome with partial agenesis of the corpus callosum and partial lobar holoprosencephaly case report 90 | squ medical journal, april 2010, volume 10, issue 1 with a drop in hba1c to 9.5% at 20 weeks and 6.5% at 32 weeks, (the recommended value during pregnancy is <6%). an antenatal scan of the fetus at 24 weeks showed abrupt termination of the lumbar spine with bilateral club feet and bilaterally dilated lateral ventricles with absent septum pellucidum [figures 1a and 1b]. the baby was born by elective cesarean section for breech presentation at 38 weeks gestation. his apgar score was 8 at one minute and 9 at 5 minutes. the birth weight was 3610 g (90th percentile for gestational age [ga]); his head circumference 36 (90th percentile for ga). physical examination of the lower limbs showed muscle wasting below the hips. there were dimples on the lateral aspect of both thighs overlying the greater trochanters and also over the bony prominence in the lower spine. the hips were flexed and adducted with fixed hyperextension of the knees. the femoral bones assumed a v-shaped position [figures 2a and 2b]. dribbling of urine was noticed on the second day of birth with a poor urine stream. the anus was patulous. the baby had transient tachypnea requiring nasal continuous positive airway pressure. the neonatal period was otherwise uneventful. his skeletal survey showed sacral agenesis with iliolumbar articulation (type iii) and a narrow pelvis [figures 3a and 3b]. a magnetic resonance imaging (mri) scan of the brain showed partial agenesis of the corpus callosum involving the anterior body, genu and rostrum. the t2 weighted image also showed an absence of the septum pellucidum along with partial lobar holoprosencephaly involving the posterior hemispheres [figures 4a and 4b]. an mri figure 1a : antenatal ultrasound scan of the fetus at 24 weeks showing abrupt termination of the lumbar spine (arrow) figure 1b. bilaterally dilated lateral ventricles with absent septum pellucidum (arrows) figure 2a : sacral dimples typical of caudal regression syndrome (block arrows) figure 2b. v-shaped position of lower limbs and patulous anus al hashami hilal, maria flordeliz bataclan, mariam mathew and lalitha krishnan case report | 91 scan of the spine showed complete sacral agenesis, a tethered cord, and an intramedullary cyst in the lower part of spinal cord [figure 5]. his abdominal ultrasound (us) and cardiac echocardiogram were normal. the orthopaedic follow-up showed a progressive enlargement of the intramedullary cyst which required excision at 6 months of age. the renal tract was normal with no infections or vesicoureteric reflux until the time of this report, but the anus has remained patulous. his weight at 9 months follow-up was 10.1 kg and his head circumference 46 cm. except for the effect of the lower limb anomaly the developmental milestones have been normal. discussion prospective and retrospective cohort studies have demonstrated an increased risk of congenital figure 2a : x-ray showing sacral agenesis with iliolumbar articulation type iii figure 2b: x-ray showing narrow pelvis anterior posterior view figure 4a : magnetic resonance imaging brain scan, sagittal view, showing anterior partial agenesis of corpus callosum figure 4b. coronal view showing absence of septum pellucidum with partial lobar holoprosencephaly caudal regression syndrome with partial agenesis of the corpus callosum and partial lobar holoprosencephaly case report 92 | squ medical journal, april 2010, volume 10, issue 1 abnormalities with pre-existing diabetes. experimental studies suggest that hyperglycaemia is the major teratogen in diabetic pregnancies, but other diabetes-related factors may also affect fetal outcomes.4 the teratogenic insult in diabetic embryopathy occurs between the third and seventh week of gestation at the initiation of organogenesis.5 miller et al.6 found no major anomalies if the hba1c was less than 6.9%, and significantly lower incidence if the hba1c was less than 8.5% in the first trimester. our patient had an hba1c of 11.6% in the first trimester. the main differential diagnosis of crs would be sirenomelia. the relationship between crs and sirenomelia is still debated with many researchers considering the latter to be a severe form of crs.7 the presence of renal and anal agenesis, fused lower limbs and a large single umbilical artery distinguish sirenomelia from crs. maternal diabetes is associated with increased risk of other congenital central nervous system (cns) malformations in the offspring. holoprosencephaly (hpe) is a complex human brain malformation resulting from incomplete cleavage of the prosencephalon into right and left hemispheres, occurring between the 18th and the 28th day of gestation. the rostral neuropore closes at 24 days of gestation. holoprosencephaly occurs due to rostral mesodermal dysfunction. at 74 days of gestation, axons cross through the dorsal region of the commissural plaque and start forming the corpus callosum. at 115 days of gestation, the corpus callosum reaches its adult form.8 many phenotypic variants of hpe exist with partial or complete agenesis of the corpus callosum.9 our patient had hyperglycaemia in the first trimester and this may explain the presence of both partial lobar hpe and partial agenesis of corpus callosum. some researchers have been successful in prenatal diagnosis in the first trimester based on a short crown rump length.10 the crown rump length was reported to be normal in our patient at 10 weeks of gestation. on the 24 weeks scan, abrupt termination of the lumbar spine was noted. in crs, the mental functions are often normal and these children only need neurologic and orthopaedic support for the lower limbs and control of bowel and bladder. morbidity and mortality is often due to a neurogenic bladder resulting in renal failure. association of crs with partial agenesis of the corpus callosum and partial lobar holoprosencephaly, as in our case, may result in additional neurological problems although at age 9 months this child appeared neurologically normal. the incidence of all forms of diabetes is increasing among the omani population. in a study in the dhahira region of north-western oman, 12.2% of stillbirths were among diabetic mothers.11 many omani multigravida have several normal babies before developing pregestational and gestational diabetes. because of a previous good obstetric history, they often come late in pregnancy for their first antenatal visit, thus losing out on an opportunity for early diagnosis of hyperglycaemia and anomalies. conclusion diabetes in pregnancy, whether insulin or noninsulin dependant, can be associated with multiple malformations in the fetus. recognition of women with, and at risk of, diabetes is important as optimal glycaemic control in the periconceptional period may reduce the risk of embryopathy. in these mothers, early antenatal us may help in identifying this devastating disorder so that appropriate counselling can be offered. a c k n o w l e d g e m e n t the authors would like to thank dr ranjan william, figure 5: magnetic resonance imaging scan of the spine showed complete sacral agenesis, tethered cord, and intramedullary cyst (arrow) in the lower part of spinal cord al hashami hilal, maria flordeliz bataclan, mariam mathew and lalitha krishnan case report | 93 assistant professor, department of radiology & molecular imaging, college of medicine and health sciences, sultan qaboos university, for help with the images for this article. references 1. kalter h. case reports of malformations associated with maternal diabetes: history and critique. clin genet 1993; 43:174−9. 2. hentschel j, stierkorb e, schneider g, goedde s, siemer s, gortner l. caudal regression sequence: vascular origin? j perinatol 2006; 26:445−7. 3. cohen mm, shiota k. teratogenesis of holoprosencephaly. am j med genet 2002; 109:1−15. 4. allen vm, armson ba, wilson rd, allen vm, blight c, gagnon a, et al. teratogenicity associated with pre-existing and gestational diabetes. j obstet gynaecol can 2007; 29:927−44. 5. mills jl, baker l, goldman as. malformations in infants of diabetic mothers occur before the seventh gestational week. implications for treatment. diabetes 1979; 28:292−3. 6. miller e, hare jw, cloherty jp, dunn pj, gleason re, soeldner js, et al. elevated maternal hemoglobin a1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. n engl j med 1981; 304:1331−4. 7 valenzano m, paoletti r, rossi a, farinini d, garlaschi g, fulcheri e. sirenomelia. pathological features, antenatal ultrasonographic clues, and a review of current embryogenic theories. hum reprod update 1999; 5:82−6. 8. alfonso i, papazian o, sinisterra s. cerebral malformation in the newborn: holoprosencephaly and agenesis of the corpus callosum. rev neurol 2003; 36:179−84. 9. dubourg c, bendavid c, pasquier l, henry c, odent s, david v. holoprosencephaly. orphanet j rare dis 2007; 2:2−8. 10. chen cp, chen cy, lin cy, shaw sw, wang w, tzen cy. prenatal diagnosis of concomitant lobar holoprosencephaly and caudal regression syndrome associated with maternal diabetes. prenat diagn 2005; 25:264−6. 11. profile of fetal deaths in dhahira region, oman. from: http://www.omjournal.org/originalarticles/ f u l l te x t / 2 0 0 8 0 1 / p r o fi l e % 2 0 o f % 2 0 f e t a l % 2 0 deaths%20in%20dhahira%20region,%20oman. html accessed february 2010. 1national oncology centre, royal hospital, muscat, oman; 2department of pathology, khoula hospital, muscat, oman; 3department of pathology, university of california, san francisco, united states; 4department of education & training, royal hospital, muscat, oman *corresponding author’s e-mail: abeer_albattashi@hotmail.com ورم خميخي ظهاري عصيب ذو درجة عالية مع تغيري جني bcor عند طفل عمره مخس سنوات تقرير حالة عبري البطا�شية، زهرة احلجرية، اآري بريي، حنينة الكندية، اإبراهيم الغيثي abstract: new groups of high-grade neuroepithelial tumours (hgnet) have emerged from the reclassification of central nervous system (cns) embryonal tumours that have recognised cns hgnet with bcor alteration (cns hgnet-bcor). we report a two-year, nine-month-old omani boy who presented to the royal hospital, muscat, oman, in 2015 with subacute head tilting and neck pain. a well-defined cerebellar lesion was found and he was treated with standard chemoradiotherapy. after a relapse at the age of five years, molecular testing revealed a bcor alteration. he was treated with further surgery and high-dose chemotherapy; unfortunately, he relapsed and died three years after he was diagnosed. keywords: neuroepithelial tumor; glioblastoma; human bcor protein; embryonal tumors; case report; oman. امللخ�ص: ظهرت جمموعات جديدة من االأورام الظهارية الع�شبية عالية الدرجة )hgnet( من خالل اإعادة ت�شنيف االأورام اجلينية للجهاز الع�شبي املركزي )cns( وت�شمل hgnet cns مع حتول يف جني bcor ويرمز له بـ bcor-hgnet cns ككيان قائم بذاته. ن�شتعر�س هنا حالة اول طفل عماين )عمره عامني وت�شعة اأ�شهر( م�شاب بـ bcor-hgnet cns، والذي مت ت�شخي�شه �شابًقا على اأنه ورم اأرومي دبقي. قدم هذا املري�س اإىل امل�شت�شفى ال�شلطاين، م�شقط، عمان يف عام 2015 باآفة خميخية وا�شحة املعامل وعولج بالعالج الكيميائي واال�شعاعي. وبعد انتكا�شة املري�س يف عمر اخلم�س �شنوات، ك�شفت االختبارات اجلزيئية عن تغري يف جني bcor ومت عالجه بعملية جراحية اخرى وجرعة عالية من العالج الكيميائي. ل�شوء احلظ، انتك�س املري�س مرة اخرى وتويف بعد ثالث �شنوات من ت�شخي�س حالته. الكلمات املفتاحية: ورم ظهاري ع�شبي؛ ورم اأرومي دبقي؛ بروتني bcor الب�رشي؛ اأورام جنينية؛ تقرير حالة؛ عمان. a cerebellar high-grade neuroepithelial tumour with bcor alteration in a five-year-old child a case report *abeer al-battashi,1 zahra al hajri,2 arie perry,3 hunaina al-kindi,2 ibrahim al-ghaithi4 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e153–156, epub. 8 sep 19 submitted 13 oct 18 revision req. 13 jan 19; revision recd. 12 feb 19 accepted 7 mar 19 system primitive neuroectodermal tumours (pnets) using a dna methylation technique and transcriptomic profiling.1 very few cases have been described in the literature within this unique genetic landscape.1,3,4 this report describes the first omani patient with bcor alteration in a cns high-grade neuroepithelial tumour (hgnet). case report a two-year, nine-month-old boy presented in 2015 to the royal hospital, muscat, oman, with subacute head tilting and neck pain. in addition, he had a mild headache but no vomiting or altered sensorium. there was no significant personal or family history of tumours or malignancies. clinically, he had a left side trochlear nerve palsy, resulting from high intracranial pressure and brainstem compression on the trochlear nucleus with no other focal neurological signs and no cerebellar signs. a magnetic resonance imaging (mri) scan rev managing children with central nervous system (cns) tumours is challenging as most data have been extrapolated from adult studies.1 therefore, different diagnostic and thera peutic modalities have been implemented to tackle this challenge. molecular testing using next-generation genome sequencing (ngs) has aided researchers in understanding the different behaviours and outcomes of tumours that are grouped by histopathology. in 2016, the world health organization (who) reclassified certain brain tumours according to their biology, for example, medulloblastoma and ependymoma.2 further reclassification is being studied for other categories as tumours can be biologically distinct from each other, which delineates unique and separate tumour entities. this might aid in tailoring new treatment approaches to improve the survival of children affected by such tumours. in 2016, strum et al. described new brain tumour entities by reclassifying a group of central nervous this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.012 case report https://creativecommons.org/licenses/by-nd/4.0/ a cerebellar high-grade neuroepithelial tumour with bcor alteration in a five-year-old child a case report e154 | squ medical journal, may 2019, volume 19, issue 2 ealed a right-sided cerebellar mass (5.5 × 5.6 cm). it was well-defined, predominantly solid with some cystic components, hyperintense in t2 and hypointense in t1 with a mild diffusion restriction [figures 1a and b]. the mass caused compression of the fourth ventricle with resultant hydrocephalus and a degree of tonsillar herniation. magnetic resonance spectroscopy (mrs) showed a reduction in n-acetylaspartate and a high choline peak with a lactate/lipid doublet that was indicative of a very aggressive tumour [figure 1c]. there was no evidence of metastasis in the cerebral hemispheres, the spine or cerebrospinal fluid. these findings could be due to many aggressive infratentorial lesions, such as anaplastic ependymoma, high grade glioma, medulloblastoma and atypical teratoid rhabdoid tumour. the patient underwent a gross total excision within a few days of his presentation using an occipital craniotomy approach. intra-operatively, the tumour was very vascular. no residual tumour tissue was observed on the post-operative mri scan. pathology showed a well-circumscribed, highly cellular neoplasm composed of moderately pleomorphic cells with irregular nuclei and vesicular chromatin, arranged mostly in sheet-like to fascicular architectural patterns [figure 2a]. in many areas, the tumour cells formed perivascular collections suggestive of pseudorosettes. palisading necrosis and collections of apoptotic nuclei (apoptotic lakes) were also present and mitoses were abundant [figures 2b and c]. microvascular proliferation was not identified. immuno histochemistry showed negative stains for glial fibrillary acidic protein, synaptophysin, and oligodendrocyte tran scription factor 2. the neuronal nuclei were focally positive for epithelial membrane antigen testing which demonstrated occasional cytoplasmic to paranuclear dot-like staining and the neurofilament protein staining had patchy positivity [figure 3]. the tumour retained ini1 in the nuclei. the patient was stable post-operatively and was started on bridging systemic chemotherapy, as he was less than three years of age at the time. the chemo therapy consisted of four cycles of vincristine, cyclo phosphamide, cisplatin and etoposide. he was then ini tiated on chemoradiotherapy, during which he received focal radiotherapy in the form of intensity modulated radiotherapy at a total dose of 54 gy in 30 fractions with concurrent temozolamide at a dose of 75 mg/m2. he was then started on maintenance temozolamide at a dose of 200 mg/m2; one year after presentation, he completed the twelve cycles uneventfully. his post-radiotherapy mri scan and his followup scans showed that he was in remission with no residual tumour tissue or recurrence. in 2017, at the age of five years and two months—exactly one year after the completion of treatment—a surveillance scan detected a local recurrence in the primary tumour bed in the right cerebellum (figures 2b and 4a). he underwent another gross total excision of the tumour with post-operative scans showing no residual tumour figure 1: magnetic resonance imaging scans of the head of a five-year-old boy showing a cerebellar primary tumour that is (a) hypointense on t1 and (b) hyperintense on t2 with both solid and cystic components. magnetic resonance spectroscopy showed (c) a choline peak with low n-acetylaspartate and a lactate/lipid doublet. figure 2: haematoxylin and eosin stains (a) at x20 showing a highly cellular neoplasm (arrow) (b) at x100 magnification showing tumour cells arranged in a spongioblastic pattern and palisading necrosis with apoptotic lakes (arrows) and (c) at x400 magnification showing numerous mitotic figures. abeer al-battashi, zahra al hajri, arie perry, hunaina al-kindi and ibrahim al-ghaithi case report | e155 tissue. the histological features of the specimen were identical those of the specimen examined in 2015. next-generation sequencing (ngs) of the tumour was done using the university of california, san francisco 500 next-generation sequencing cancer gene test that has the ability to analyse 479 cancer genes. it uses capture-based ngs by analysing genomic dna from both tumour as well as normal cells. target enrichment was performed by hybrid capture using custom oligonucleotides. it demonstrated an internal tandem duplication within exon 15 of the bcor gene (this begins at codon p.v17141, which is an insertion of 30 amino acids). additional alterations were telomerase reverse transcriptase (tert) amplification and smarca2 mutation. other alterations, such as idh1, idh2, histone 3, mycn, or pdgfra were not demonstrated. the tert and smarca2 alterations have not been previously reported within the cnshgnet-bcor entity. the patient was restarted on temozolamide with the addition of bevacizumab (an antiangiogenic agent which inhibits the vascular endothelial growth factor). he received a total of six courses and remained well. subsequently, he received four tandem autologous bone marrow transplants at the age of five years, six months based on the paediatric cns embryonal tumour protocol. he presented with an extensive local relapse two months after transplantation. he developed severe obstructive hydrocephalus and reduced level of consciousness and was treated palliatively. he died three years after his initial presentation. verbal consent was obtained from the patient’s parents for the publication of this case report. discussion a cluster of cns pnets, also known as embryonal tumours were regrouped into the following four molec ular sub-categories by strum et al. in 2016: cns neuro blastoma with foxr2 activation, cns ewing sarcoma family tumour with cic alteration, cns high-grade neuroepithelial tumour with mn1 alteration and cns hgnet-bcor.1 there are very few reports of cnshgnet-bcor in the literature. this patient exhibited a common location for these tumours, which is within the cerebellum. however, these tumours can arise any where within the supratentorium or posterior fossa.1,3,4 this tumour has been rarely described as disseminating beyond the neuroaxis. there have been cases that described bone metastasis and subcutaneous nodule seeding.3,4 hgnet-bcor was described after reviewing a variety of tumours, including medulloblastoma, epen dymoma and high-grade glioma.1 despite the different initial histological diagnosis, these tumours share pathol ogical features including proliferation of uniform round or ovoid cells with fine chromatin and a rich arborising capillary network. other characteristics may include stellate-, vacuolatedor spindle cell-cytomorphology, myxoid stromal changes and perivascular pseudoro settes.3 radiologically, hgnet-bcor share features with other high-grade lesions including increased enhance ment and diffusion restriction, as seen in the current patient. they can be solid, cystic or both and have features of a highly malignant lesion on mrs [figure 1c]. the current patient had similar features to other patients described in the literature, with the mass being welldemarcated, hypointense on t1 and hyperintense on t2 [figures 1a & b and 4a & b).1,2 the signal intensity in the present patient was fairly homogenous with a significant cystic component. figure 3: immunohistochemistry of the tumour cells of a five-year-old boy. (a) epithelial membrane antigen staining showing cytoplasmic to paranuclear dot-like staining and (b) sporadically positive neurofilament. figure 4: magnetic resonance imaging scans of the head of a five-year-old boy showing the tumour at recurrence in the same primary site (arrows) with the same features as the primary tumour, as there is a well-circumscribed lesion that is (a) hypointense on t1 and (b) hyperintense on t2. a cerebellar high-grade neuroepithelial tumour with bcor alteration in a five-year-old child a case report e156 | squ medical journal, may 2019, volume 19, issue 2 different treatments have been attempted for hgnet-bcor. these included the use of multi-agents (cisplatin, etoposide and cyclophosphamide), bevaci zumab, the use of intrathecal chemotherapy (metho trexate and topotecan) and autologous stem cell trans plants.4 yoshida et al. reported two patients who received autologous stem cell transplants and were both alive at the time of publication.4 in terms of local control, a total surgical excision is highly recommended and most patients received either focal radiotherapy or craniospinal radiotherapy with the majority receiving the former.3,4 in general, this tumour has a poor outcome and a tendency for relapse.3,4 conclusion the diagnostic approach to cns tumours is evolving into sophisticated molecular profiling, which aids researchers in understanding the differences in behaviour between tumours that fall into the same histological classification and, therefore, their prog nosis and different therapeutic approaches. the new who classification might reclassify these new entities into different categories. as the number of cns hgnet-bcor cases is very limited in the literature, more pathological, clinical and biological testing is required to understand this new entity. references 1. strum d, orr ba, toprak uh, hovestadt v, jones dtw, capper d, et al. new brain tumor entities emerge from molecular classifi cation of cns-pnets. cell 2016; 164:1060–72. https://doi.org/10.1 016/j.cell.2016.01.015. 2. louis dn, perry a, reifenberger g, von deimling a, figarellabranger d, cavenee wk, et al. the 2016 world health organization classification of tumors of the central nervous system: a summary. acta neuropathol 2016; 131:803–20. https://doi.org/10.1007/s00401-016-1545-1. 3. appay r, macagno n, padovani l, korshunov a, kool m, andré n, et al. hgnet-bcor tumors of the cerebellum: clinicopathologic and molecular characterization of 3 cases. am j surg pathol 2017; 41:1254–60. https://doi.org/10.1097/ pas.0000000000000866. 4. yoshida y, nobusawa s, nakata s, nakada m, arakawa y, mineharu y, et al. cns high-grade neuroepithelial tumor with bcor internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. brain pathol 2018; 28:710–20. https://doi.org/10.1111/bpa.12585. https://doi.org/10.1016/j.cell.2016.01.015 https://doi.org/10.1016/j.cell.2016.01.015 https://doi.org/10.1007/s00401-016-1545-1 https://doi.org/10.1097/pas.0000000000000866 https://doi.org/10.1097/pas.0000000000000866 https://doi.org/10.1111/bpa.12585 efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome a systematic review and meta-analysis *mohammad z. asha1 and sundos f. h. khalil2 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e13–24, epub. 9 mar 20 submitted 25 jun 19 revision req. 8 aug 19; revision recd. 11 aug 19 accepted 12 sep 19 1department of internal medicine, dr mohamad amine zbeib polyclinic, doha, qatar; 2department of pharmacology, university of jordan, amman, jordan *corresponding author’s e-mail: drmohammadasha@gmail.com irritable bowel syndrome (ibs) is a disorderwhich manifests as a set of chronic gastrointestinal (gi) symptoms and changes in bowel habits in the absence of evident structural and biochemical abnorm alities.1,2 overall, ibs is the most commonly diagnosed gi disorder with a global prevalence of 10–15% and is more frequent among individuals aged <50 years old.3,4 altered bowel habits are the most commonly reported clinical feature, with the syndrome predominantly associated with constipation (ibs-c), diarrhoea (ibs-d) or a mixture of both conditions (ibs-m).1 in addition, patients with ibs often experience abdominal pain, which can be provoked by emotional stress or eating and is usually alleviated by the passing of stool.1,2 a diagnosis of ibs is confirmed according to the latest version of the rome criteria based on the clinical experience and consensus of a committee of multinational experts.2,5–7 the role of radiological imaging in the diagnosis of ibs is still limited to those patients with ‘red flag’ symptoms, such as rectal bleeding, iron-deficiency anaemia and weight loss, in order to exclude other underlying diseases.8 however, a recent study indicated that diffusion-weight imaging can accurately assess disease activity among patients with crohn’s disease, a gi condition with similar symptoms to ibs.9 despite extensive research, the typical mechanistic pathways of ibs have not yet been clearly elucidated. it review فعالية وسالمة الربوبيوتيك والربيبايوتك والسينوبيوتيك يف عالج متالزمة القولون املتهيج مراجعة منهجية والتحليل البعدي حممد زكي ع�صا و �صند�س فالح ح�صني خليل abstract: treatments that target alterations in gut microbiota may be beneficial for patients with irritable bowel syndrome (ibs). a systematic review and meta-analysis was conducted of randomised clinical trials (rcts) evaluating the efficacy and safety of probiotics, prebiotics and synbiotics. factors considered in the analysis included global ibs symptoms and/or abdominal pain, secondary symptoms and the frequency of adverse events. a total of 33 rcts involving 4,321 patients were identified. overall, probiotics significantly improved global ibs symptoms compared to placebos (standardised mean difference = −0.32, 95% confidence interval: −0.48 to −0.15; p <0.001), with significant heterogeneity between studies (i2 = 72%; p <0.001). this remained apparent in both singleand multi-strain probiotic interventions as well as synbiotic formulations. however, evidence regarding prebiotics was scarce. there were no significant inter-group differences in terms of the frequency of adverse events. future rcts should address methodological limitations, including short follow-up periods and patient adherence. keywords: irritable bowel syndrome; gastrointestinal microbiome; dietary supplements; probiotics; prebiotics; synbiotics; meta-analysis; systematic review. امللخ�ص: قد تكون العالجات التي ت�صتهدف التغيريات يف ميكروبات الأمعاء مفيدة للمر�صى الذين يعانون من متالزمة القولون املتهيج. اأجريت هذه املراجعة املنهجية والتحليل البعدي للتجارب ال�رشيرية الع�صوائية وذلك لتقييم فعالية و�صالمة الربوبيوتيك والربيبايوتيك وال�صينوبيوتيك. و�صملت العوامل التي مت النظر فيها يف التحليل اأعرا�س القولون املتهيج ال�صامل و/اأو اأمل يف البطن والأعرا�س الثانوية ح�صنت وعموما، مري�صا. 4,321 على �صملت التي الع�صوائية ال�رشيرية التجارب من 33 جمموعه ما حتديد مت ال�صلبية. الأحداث وتكرار الثقة٪: فا�صل 95% ،-0.32 = موحد متو�صط )فرق الغفل مع مقارنة ال�صامل املتهيج القولون اأعرا�س من ملحوظ ب�صكل الربوبيوتيك تدخالت من كل يف وا�صحا هذا ظل .)i2 = 72% p؛ >0.001( الدرا�صات بني كبري جتان�س عدم مع ،)p >0.001 0.15-؛ اإىل -0.48 الربوبيوتيك الأحادية ومتعددة ال�صاللت وكذلك يف تركيبات ال�صينوبيوتيك. ومع ذلك، فاإن الأدلة املتعلقة بالربيبايوتك كانت نادرة. مل تكن هناك اختالفات كبرية بني املجموعات من حيث تواتر الأحداث ال�صلبية. ينبغي اأن تعالج التجارب ال�رشيرية الع�صوائية يف امل�صتقبل القيود املنهجية، مبا يف ذلك فرتات املتابعة الق�صرية والتزام املري�س. الكلمات املفتاحية: متالزمة القولون املتهيج؛ ميكروبيوم اجلهاز اله�صمي؛ املكمالت الغذائية؛ الربوبيوتيك؛ الربيبايوتك�س؛ ال�صينوبيوتيك؛ التحليل البعدي؛ مراجعة منهجية. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.003 https://creativecommons.org/licenses/by-nd/4.0/ efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome a systematic review and meta-analysis e14 | squ medical journal, february 2020, volume 20, issue 1 has been postulated that enteric infections, immuno modulation, visceral hypersensitivity and an imbalance in neurotransmitters may all play a role in the devel opment of ibs.10–12 importantly, alterations in the gut microbiota can induce changes in gut motility, permea bility, food processing and visceral perception which eventually leads to the occurrence of ibs-related symptoms.13,14 multiple studies have shown that ibs patients experience bacterial overgrowth in the small intestine or altered gi microbes.15–18 a recent metaanalysis observed that patients with ibs (particularly ibs-d) have significantly reduced gi colonies of bifidobacterium, lactobacillus and faecalibacterium prausnitzii bacteria compared to healthy individuals.19 furthermore, the link between gi microbial disruption and ibs is corroborated by the fact that 10–53% of patients are diagnosed with ibs following a gi infection.20 such findings have opened a new avenue of treatment to control ibs symptoms, namely the manipulation of gut microbiota. potential therapies to modulate the microbial composition of the gi envir onment include dietary supplements incorporating prebiotics, probiotics or synbiotics. prebiotics are non digestible dietary compounds that stimulate the growth and activity of specific bacterial populations, while probiotics are live microorganisms that can be supple mented in adequate amounts to induce therapeutic benefits.21 synbiotics, the combination of both prebiotics and probiotics, can provide beneficial effects to the host and improve the viability of its constituents.22 nevertheless, the effects of such therapeutic approaches in the treatment of ibs are questionable, particularly with regards to using single or several variations or combinations of probiotics and prebiotics. therefore, a comprehensive evaluation of the efficacy and safety of prebiotics, probiotics and synbiotics in the manage ment of patients with ibs is necessary. methods all procedures were conducted according to the standards of the preferred reporting items for syst ematic reviews and meta-analyses.23 only prospective randomised clinical trials (rcts) published in englishlanguage peer-reviewed journals between 2000 and 2019 that compared the effects of prebiotics, probiotics and synbiotics on adult ibs patients (aged ≥18 years) were included in the analysis. trials including children or patients with other gi disorders were excluded. the diagnosis of ibs was confirmed according to any version of the rome criteria in order to ensure minimal heterogeneity if other diagnostic criteria or basic physician opinions were used initially.2,5–7 in order to be eligible for inclusion, the rcts had to involve the administration of at least one of three therapeutic interventions (prebiotics, probiotics and/ or synbiotics) to a specific cohort of ibs patients and compare outcomes with another group receiving a placebo. the minimum sample size was 50 patients. trials using probiotics could include either single or multi-strain preparations. if a trial incorporated multiple intervention groups with different doses, the group with the highest dose was included in the analysis in order to avoid any overlap that might result from multiple analyses of placebo outcomes. trials employing a cross-over design were excluded.24 in addition, narrative reviews, case reports, conference proceedings, retrospective studies and systematic reviews were excluded. the primary outcomes of the meta-analysis included the efficacy of the therapeutic interventions on global ibs symptoms and/or abdominal pain. these outcomes were presented as continuous variables in terms of mean differences in scores at the end of the follow-up period. additionally, secondary outcomes included the effects of the interventions on the scores of other symptoms (i.e. bloating/distension, flatulence and urgency), along with impact on quality of life (qol). in terms of safety, the reported frequencies of adverse events at the end of the follow-up period were analysed. a comprehensive literature search was performed of various databases, including medline® (national library of medicine, bethesda, maryland, usa), embase (elsevier, amsterdam, the netherlands) cochrane library (cochrane, london, uk) and google scholar (google llc, mountain view, california, usa). the search was conducted in june 2019 using the following keywords combined as appropriate using boolean operators (e.g. “or” and “and”): “irritable bowel syndrome”, “irritable bowel”, “probiotic”, “bacillus”, “bifidobacterium”, “lacto bacillus”, “streptococcus”, “enterococcus”, “propioni bacterium”, “saccharomyces”, “clostridium”, “synbiotic”, “prebiotic”, “fructooligosaccharide”, “inulin”, “randomized/ randomised” and “trial”. two researchers independently screened the titles and abstracts of identified articles to determine their eligibility for inclusion in the analysis. the reference lists of the articles were also screened for any additional publications. any disagreements concerning eligibility were discussed until a consensus was reached. information concerning all eligible articles was uploaded to a ref erence management software (endnote, version x7, clarivate analytics, philadelphia, pennsylvania, usa) to check for any potential duplication. subsequently, all non-full-text articles were excluded from the final analysis. mohammad z. asha and sundos f. h. khalil review | e15 an initial literature search revealed a total of 3,478 publications across the databases, of which 30 were duplicates. in addition, seven eligible articles were identified from reference lists. after the exclusion of 3,408 irrelevant publications, a total of 47 full-text rcts were assessed for eligibility. during the assessment, 14 trials were excluded for various reasons, including having <50 patients in both groups, presenting outcomes in an uninterpretable manner, employing a 2 × 2 factorial design with changes in diet, investigating qol as the primary outcome without focusing on ibs symptoms, adding simethicone to the intervention or for not being written in english. ultimately, a total of 33 rcts were included in the final analysis [figure 1]. information concerning each of these rcts was recorded in an excel spreadsheet, version 2016 (microsoft corp., redmond, washington, usa). the name of the first author, year of publication, country, study duration and sample size of the study was recorded as well as the gender distribution of the patients and the number of patients allocated to the study groups. regarding disease-specific data, the distribution of ibs subtypes, version of rome criteria utilised and data collection instrument was noted. in terms of interventionrelated data, the type of intervention (i.e. prebiotic, probiotic or synbiotic), use of singleor multi-strain probiotics and the dosage and form of the intervention was documented, as well as outcome data with regards to scores for global ibs symptoms, abdominal pain, bloating/distension, flatulence, urgency and qol and the frequency of adverse events at the end of the follow-up period. each trial underwent quality assessment using the cochrane risk of bias tool which assesses processes of random sequence generation and blinding of out comes, participant/personnel data and intervention allocation, among other measurements of bias.25 the results were presented graphically using revman software, version 5.3 (cochrane), with each domain interpreted as being either low-risk, high-risk or unclear. with regards to statistical analysis, continuous variables (i.e. symptom and qol scores) were presented as standardised mean differences (smds) with 95% conf idence intervals (cis), while dichotomous variables (i.e. frequencies of adverse events) were expressed as relative risks (rrs) with 95% cis. overall effects were analysed using z-statistics. inter-study heterogeneity was assessed using the i2 test, with a random effect model applied in the event of significant heterogeneity (i2 ≥50%). a subgroup analysis was performed based on the sample size, type of therapeutic intervention and the version of rome criteria utilised. a p value of <0.05 was considered statistically significant. results the general characteristics of the rcts are outlined in table 1.26–58 all of the rcts were published between 2000 and 2018, with the duration of the intervention ranging between 2–24 weeks. overall, there were a total of 4,321 patients with ibs, of which 59.5% were female.26–58 in terms of ibs subtypes, six rcts included patients with ibs-d, one with ibs-c and one with both ibs-d and ibs-m.26–33 the remaining trials included patients with all subtypes.34–58 with regards to location, the majority of the trials were conducted in europe (n = 18) followed by asia (n = 13).26–33,36–58 the remaining two rcts were based in south africa and the usa, respectively.34,35 the rome i criteria were used for diagnosis in two trials, while the rome ii criteria were used in 11 trials.32–34,40–49 the rest of the trials utilised the rome iii criteria.26–31,35–39,50–58 in terms of intervention, three trials investigated prebiotics (partially-hydrolysed guar gum and fructooligosaccharides) and three investigated synbiotics.38,40,42,50,51 the remaining 27 rcts evaluated probiotics.26–37,39,41,43,44,46–49,52–58 just over half of the probiotic trials contained multiple bacterial strains (n = 14).29–32,35,37,44,47–49,52–54 the other 13 trials cont ained single strains, comprising of lactobacillus, bifi figure 1: flow chart showing the search process used to identify articles included in this study’s systematic review and meta-analysis. efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome a systematic review and meta-analysis e16 | squ medical journal, february 2020, volume 20, issue 1 table 1: summary of randomised clinical trials assessing the efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome26–58 author and year of study country study duration in weeks sample size (male/female) mean age in years ± sd group allocation diagnostic criteria ibs subtypes intervention strain or type of intervention dosage and form of intervention azpiroz et al.51 (2017) spain 4 79 (48/31) i: 41.0 ± 11.1 p: 42.4 ± 10.6 i: 41 p: 38 rome iii all prebiotic foo twice daily in powder sachets niv et al.50 (2016) israel 12 108 (37/71) i: 46.2 ± 19.2 p: 40.8 ± 15.6 i: 49 p: 59 rome iii all prebiotic phgg once daily in powder sachets olesen et al.42 (2000) denmark 12 63 (11/52) i: 45.1 ± 13.1 p: 45.1 ± 13.1 i: 30 p: 32 rome i all prebiotic foo once daily in powder sachets abbas et al.27 (2014) pakistan 6 72 (53/19) i: 37.7 ± 11.6 p: 33.0 ± 12.0 i: 37 p: 35 rome iii ibs-d probiotic ss s. boulardii once daily in syrup amirimani et al.39 (2013) iran 4 92 (36/56) i: 44.9 ± 13.0 p: 37.7 ± 10.5 i: 41 p: 31 rome iii all probiotic ss l. reuteri once daily begtrup et al.54 (2013) denmark 24 131 (97/34) i: 31.6 ± 10.1 p: 29.4 ± 8.6 i: 54 p: 44 rome iii all probiotic ms l. paracasei, l. acidophilus and b. lactis twice daily in capsules choi et al.33 (2011) korea 4 74 (37/37) i: 40.2 ± 13.1 p: 40.6 ± 12.9 i: 34 p: 33 rome ii ibs-d and ibs-m probiotic ss s. boulardii twice daily in capsules drouaultholowacz et al.44 (2008) france 4 100 (24/76) i: 47.0 ± 14.0 p: 44.0 ± 14.0 i: 48 p: 52 rome ii all probiotic ms b. longum, l. acidophilus, lactococcus lactis and streptococcus thermophilus once daily in powder sachets ducrotté et al.36 (2012) india 4 214 (151/63) i: 36.5 ± 12.1 p: 38.4 ± 13.1 i: 108 p: 106 rome iii all probiotic ss l. plantarum once daily in capsules guglielmetti et al.56 (2011) italy 4 122 (40/82) i: 36.7 ± 12.4 p: 40.9 ± 12.8 i: 60 p: 62 rome iii all probiotic ss b. bifidum once daily in capsules guyonnet et al.32 (2007) france 6 267 (199/68) i: 49.4 ± 11.4 p: 49.2 ± 11.4 i: 135 p: 132 rome ii ibs-c probiotic ms b. animalis, s. thermophilus and l. delbrueckii twice daily in yoghurt hod et al.29 (2017) israel 8 107 (0/107) i: 29.0 ± 4.0 p: 30.0 ± 6.0 i: 54 p: 53 rome iii ibs-d probiotic ms l. rhamnosus, l. paracasei, l. plantarum, l. acidophilus, l. bulgaricus, l. lactis, b. bifidum, b. longum, b. breve, b. infantis and s. thermophilus twice daily in capsules ishaque et al.31 (2018) bangladesh 16 360 (281/79) i: 32.2 ± 10.1 p: 31.7 ± 9.7 i: 181 p: 179 rome iii ibs-d probiotic ms bacillus subtilis, b. bifidum, b. breve, b. infantis, b. longum, l. acidophilus, l. delbrueckii, l. casei, l. plantarum, l. rhamnosus, l. helveticus, l. salivarius, l. lactis and s. thermophilus twice daily in capsules jafari et al.37 (2014) iran 4 108 (43/65) i: 36.6 ± 12.1 p: 36.8 ± 11.0 i: 54 p: 54 rome iii all probiotic ms b. animalis, l. acidophilus, l. delbrueckii and s. thermophilus twice daily in capsules kajander et al.49 (2008) finland 20 86 (6/80) i: 50.0 ± 13.0 p: 46.0 ± 13.0 i: 43 p: 43 rome ii all probiotic ms l. rhamnosus, propionibacterium freudenreichii and b. animalis once daily in a milk product ki cha et al.30 (2012) korea 10 50 (26/24) i: 37.9± 12.4 p: 40.3± 11.2 i: 25 p: 25 rome iii ibs-d probiotic ms l. acidophilus, l. plantarum, l. rhamnosus, b. breve, b. lactis, b. longum and s. thermophilus once daily in capsules lyra et al.55 (2016) finland 12 262 (64/198) i: 47.2 ± 12.5 p: 49.4 ± 12.9 i: 131 p: 131 rome iii all probiotic ss l. acidophilus once daily in powder nobaek et al.41 (2000) sweden 4 51 (15/36) i: 51.0 ± 22.0 p: 46.0 ± 19.0 i: 25 p: 26 rome i all probiotic ss l. plantarum once daily in a rosehip drink pineton de chambrun et al.57 (2015) france 8 179 (25/154) i: 42.5 ± 12.5 p: 45.4 ± 14 i: 86 p: 93 rome iii all probiotic ss s. cerevisiae once daily in capsules preston et al.35 (2018) usa 12 113 (45/68) i: 40.6 ± 13.4 p: 39.9 ± 14.0 i: 76 p: 37 rome iii all probiotic ms l. acidophilus and l. rhamnosus twice daily in capsules roberts et al.52 (2013) uk 4 179 (30/149) i: 44.7 ± 11.9 p: 43.7 ± 12.8 i: 88 p: 91 rome iii all probiotic ms b. lactis, s. thermophilus and l. delbrueckii twice daily in a milk product shin et al.28 (2018) korea 8 51 (22/29) i: 35.0 ± 5.0 p: 38.0 ± 8.0 i: 24 p: 27 rome iii ibs-d probiotic ss l. gasseri twice daily in capsules sd = standard deviation; ibs = irritable bowel syndrome; i = intervention group; p = placebo group; foo = fructooligosaccharides; phgg = partially hydrolysed guar gum; d = diarrhoea; ss = single-strain; s. = saccharomyces; l. = lactobacillus; ms = multi-strain; b = bifidobacterium; m = mixed condition; c = constipation. mohammad z. asha and sundos f. h. khalil review | e17 dobacterium and saccharomyces species as well as clostridium butyricum.26–28,33,34,36,39,41,43,55–58 only one of the rcts was single-blinded.39 the remaining trials employed a double-blinded design.26–38,40–58 the method of randomisation was not explicitly mentioned in five trials (15.2%); this was therefore categorised as an unclear risk in the risk of bias assessment under the random sequence generation domain.32,35,41,43,46 block randomisation and a random allocation table was used in 12 rcts each.26,28–40,43,45,47–52,54–58 computer-based or online randomisation so ftware was used in four trials.27,31,34,53 for all studies, the primary outcome analysis was based on the intention-to-treat paradigm, apart from two studies investigating probiotic products and one study investigating a synbiotic intervention.31,39,40 the efficacy results of the interventions versus a placebo were presented in 17 probiotic trials involving 2,431 patients for probiotics and three prebiotic trials involving 250 patients, while none of the synbiotic trials investigated effects on global symptoms scores.26,30–35,41–43,46,48–54,56,58 the pooled outcomes of the probiotic rcts indicated significant improvements in global symptoms scores (smd = −0.32, 95% ci: −0.48 to −0.15; p <0.001). however, significant heterogeneity was observed between studies (i2 = 72%; p <0.001). this improvement remained significant with probiotics containing multi-strains (smd = −0.23, 95% ci: −0.44 to −0.02; p = 0.030) and those using species of bifido bacterium (smd = −0.77, 95% ci: −1.00 to −0.53; p <0.001) and clostridium (smd = −0.34, 95% ci: −0.62 to −0.06; p = 0.020) [table 2]. additionally, probiotics significantly improved global ibs symptom scores in studies with a sample size of <150 patients (smd = −0.31, 95% ci: −0.52 to −0.10; p = 0.004) and >150 patients (smd = −0.32, 95% ci: −0.57 to −0.06; p <0.001) as well as studies utilising rome i (smd = −1.17, 95% ci: −1.76 to −0.57; p <0.001), rome ii (smd = −0.29, 95% ci: −0.53 to −0.05; p = 0.020) and rome iii (smd = −0.28, 95% ci: −0.50 to −0.06; p = 0.010) diagnostic criteria. as for prebiotics, there was no significant effect on ibs symptoms using a random effects model (smd = 0.59, 95% ci: −0.01 to 1.19; p = 0.050). this lack of significance was also apparent in the subgroup analyses. abdominal pain scores were assessed in 29 rcts, including 25 probiotics, one prebiotic and three synbiotic trials.26–33,36–41,43–50,52–58 in a pooled analysis, there were no significant differences concerning abdominal pain scores with probiotics as compared to a placebo (smd = −0.18, 95% ci: −0.43 to 0.07; p = 0.150) with significant heterogeneity between studies (i2 = 92%; p <0.001). however, abdominal pain scores were reduced table 1 (cont’d): summary of randomised clinical trials assessing the efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome26–58 simrén et al.47 (2010) sweden 8 74 (52/22) i: 42.0 ± 15.0 p: 44.0 ± 16.0 i: 37 p: 37 rome ii all probiotic ms l. paracasei, l. acidophilus and b. lactis once daily in fermented milk sisson et al.53 (2014) uk 12 186 (129/57) i: 39.6 ± 10.5 p: 36.8 ± 10.8 i: 124 p: 62 rome iii all probiotic ms l. rhamnosus, l. plantarum, l. acidophilus and enterococcus faecium once daily in syrup søndergaard et al.48 (2011) denmark 8 52 (13/39) i: 53.9 ± 14.0 p: 48.5 ± 13.7 i: 27 p: 25 rome ii all probiotic ms l. paracasei, l. acidophilus and b. lactis once daily in fermented milk spiller et al.58 (2016) uk 12 379 (62/317) i: 45.3 ± 15.7 p: 45.4 ± 14.1 i: 192 p: 187 rome iii all probiotic ss s. cerevisiae twice daily in capsules stevenson et al.34 (2014) south africa 8 81 (2/79) i: 48.1 ± 13.5 p: 47.3 ± 12.1 i: 54 p: 27 rome ii all probiotic ss l. plantarum once daily in capsules sun et al.26 (2018) china 4 200 (116/84) i: 43.0 ± 12.5 p: 44.9 ± 13.0 i: 105 p: 95 rome iii ibs-d probiotic ss clostridium butyricum thrice daily in capsules whorwell et al.43 (2006) uk 4 182 (0/182) i: 41.8 ± 1.1 p: 42.4 ± 1.1 i: 90 p: 92 rome ii all probiotic ss b. infantis once daily in capsules williams et al.46 (2009) uk 8 52 (7/45) i: 40.0 ± 12.0 p: 38.0 ± 11.0 i: 28 p: 24 rome ii all probiotic ms l. acidophilus, b. lactis and b. bifidum once daily in capsules cappello et al.45 (2013) italy 4 62 (21/41) i: 36.6 ± 2.2 p: 40.8 ± 2.2 i: 32 p: 32 rome ii all synbiotic l. plantarum, l. rhamnosus, l. gasseri, l. acidophilus, l. salivarius, l. sporogenes, b. infantis, b. longum, s. termophilus and inulin twice daily in powder sachets rogha et al.38 (2014) iran 12 56 (12/44) i: 42.6 ± 12.8 p: 37.7 ± 12.4 i: 23 p: 33 rome iii all synbiotic b. coagulans and foo once daily in tablets shavakhi et al.40 (2014) iran 2 129 (44/85) i: 36.1 ± 7.9 p: 36.4 ± 10.5 i: 66 p: 63 rome ii all synbiotic l. casei, l. rhamnosus, l. acidophilus, l. delbrueckii ssp. bulgaricus, b. breve, b. longum, s. thermophilus and foo twice daily in capsules sd = standard deviation; ibs = irritable bowel syndrome; i = intervention group; p = placebo group; foo = fructooligosaccharides; phgg = partially hydrolysed guar gum; d = diarrhoea; ss = single-strain; s. = saccharomyces; l. = lactobacillus; ms = multi-strain; b = bifidobacterium; m = mixed condition; c = constipation. efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome a systematic review and meta-analysis e18 | squ medical journal, february 2020, volume 20, issue 1 sd = st an da rd d ev ia tio n; iv = in ve rs e v ar ia nc e; d f = d eg re es o f f re ed om ; c i = c on fid en ce in te rv al . *h et er og en ei ty : t au ² = 0 .0 7; c hi ² = 2 8. 40 , d f = 9 (p = 0 .0 00 8) ; i ² = 6 8% . o ve ra ll eff ec t: z = 2 .1 5 (p = 0 .0 30 ). † h et er og en ei ty : t au ² = 0 .0 0; c hi ² = 0 .0 0, d f = 1 (p = 0 .9 5) ; i ² = 0 % . o ve ra ll eff ec t: z = 1 .1 4 (p = 0 .2 50 ). ‡ h et er og en ei ty : t au ² = 0. 00 ; c hi ² = 0 .2 2, d f = 1 (p = 0 .6 40 ); i² = 0% ; o ve ra ll eff ec t: z = 6 .4 4 (p < 0. 00 00 1) . § h et er og en ei ty : n ot a pp lic ab le . o ve ra ll eff ec t: z = 2 .3 7 (p = 0 .0 20 ). ¶ h et er og en ei ty : t au ² = 0 .5 8; c hi ² = 8 .7 6, d f = 1 (p = 0 .0 03 ); i² = 89 % . o ve ra ll eff ec t: z = 1 .0 2 (p = 0 .3 10 ). \\ h et er og en ei ty : t au ² = 0 .0 8; c hi ² = 5 6. 97 , d f = 1 6 (p < 0. 00 00 1) ; i ² = 7 2% . o ve ra ll eff ec t: z = 3 .8 1 (p = 0 .0 00 1) . s ub gr ou p di ffe re nc es : c hi ² = 2 0. 02 , d f = 4 (p = 0 .0 00 5) , i ² = 8 0. 0% . ta bl e 2: f or es t p lo t s ho w in g th e eff ec ts o f p ro bi ot ic s on g lo ba l s ym pt om s co re s in r an do m is ed c lin ic al tr ia ls o f p at ie nt s w it h ir ri ta bl e bo w el s yn dr om e2 6, 30 – 35 ,4 1, 43 ,4 6, 48 ,4 9, 52 – 54 ,5 6, 58 mohammad z. asha and sundos f. h. khalil review | e19 sd = st an da rd d ev ia tio n; iv = in ve rs e v ar ia nc e; df = d eg re es of fr ee do m ; c i = co nfi de nc e i nt er va l. *h et er og en eit y: ta u² = 0 .2 8; c hi ² = 1 21 .6 8, d f = 1 3 (p < 0. 00 00 1) ; i² = 8 9% . o ve ra ll e ffe ct : z = 0 .2 3 (p = 0 .8 20 ). † h et er og en eit y: ta u² = 0 .0 6; c hi ² = 9 .4 8, d f = 3 (p = 0. 02 0) ; i² = 6 8% . o ve ra ll e ffe ct : z = 0 .4 0 (p = 0 .6 90 ). ‡ h et er og en eit y: ta u² = 5 .4 7; c hi ² = 1 39 .3 5, d f = 1 (p < 0. 00 00 1) ; i² = 9 9% . o ve ra ll e ffe ct : z = 0 .3 4 (p = 0 .7 40 ). § h et er og en eit y: n ot a pp lic ab le . o ve ra ll e ffe ct : z = 1 .8 0 (p = 0 .0 70 ). ¶ h et er og en eit y: ta u² = 0 .4 3; c hi ² = 4 9. 12 , d f = 4 (p < 0. 00 00 1) ; i² = 9 2% . o ve ra ll e ffe ct : z = 2 .2 6 (p = 0 .0 20 ). \\ h et er og en eit y: ta u² = 0 .3 8; c hi ² = 3 32 .3 2, d f = 2 5 (p < 0. 00 00 1) ; i² = 9 2% . o ve ra ll e ffe ct : z = 1 .4 3 (p = 0 .1 50 ). s ub gr ou p di ffe re nc es : c hi ² = 6 .2 2, d f = 4 (p = 0 .1 80 ), i ² = 3 5. 7% . ta bl e 3: f or es t p lo t s ho w in g th e eff ec ts o f p ro bi ot ic s on a bd om in al p ai n sc or es in r an do m is ed c lin ic al tr ia ls o f p at ie nt s w it h ir ri ta bl e bo w el s yn dr om e2 6– 33 ,3 6, 37 ,3 9, 41 ,4 3, 44 ,4 6– 50 ,5 2– 58 efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome a systematic review and meta-analysis e20 | squ medical journal, february 2020, volume 20, issue 1 significantly with probiotics containing lactobacillus species (smd = −0.71, 95% ci: −1.33 to −0.10; p = 0.020) and when the rome i criteria were utilised (smd = −1.65, 95% ci: −2.29 to −1.00; p <0.001) [table 3]. the one prebiotic rct assessing abdominal pain scores compared partially-hydrolysed guar gum to a placebo.47 no significant improvement was observed in abdominal pain (smd = 0.69, 95% ci: −0.28 to 1.36; p = 0.810). however, different combinations of probiotics and prebiotics in the synbiotic rcts resulted in significant abdominal pain amelioration compared to a placebo (smd = −4.27, 95% ci: −7.73 to −0.80; p = 0.020); in addition, the difference remained significant in trials employing the rome iii diagnostic criteria (smd = −11.24, 95% ci: −13.46 to −9.01; p <0.001). regarding other ibs symptoms, the pooled effects of the probiotic trials showed no significant improve ments in bloating and urgency scores. however, there was a trend of flatulence alleviation, with the effects nearing statistical significance (smd = −0.68, 95% ci: −1.38 to 0.01; p = 0.050). furthermore, a subgroup analysis revealed promising outcomes for distinct symptoms with certain single-strain probiotics. specif ically, probiotics containing saccharomyces improved bloating (smd = −0.20, 95% ci: −0.37 to −0.03; p = 0.020), while those containing lactobacillus improved flatulence (smd = −1.84, 95% ci: −2.43 to −1.25; p <0.001) and those containing bifidobacterium improved urgency (smd = −0.55, 95% ci: −0.85 to −0.26; p <0.001) in several rcts.27,33,41,43,58 in one trial, a synbiotic inter vention incorporating inulin and several probiotic strains significantly improved scores for both flatulence (smd = −1.84, 95% ci: −2.43 to −1.25; p <0.001) and urgency (smd = −0.70, 95% ci: −1.21 to −0.20; p = 0.006).45 in general, the use of probiotics did not significantly improve qol scores, except in two trials involving lactobacillus strains (smd = 0.57, 95% ci: 0.21 to 0.94; p = 0.020).28,34 similarly, most of the prebiotic and synbiotic interventions did not affect qol, although one prebiotic trial noted improvements following a 12-week regimen of partially-hydrolysed guar gum.50 as for the frequency of adverse events, a pooled risk analysis revealed no significant differences between patients receiving different types of interventions and those receiving a placebo (rr = 1.17, 95% ci: 0.98 to 1.40; p = 0.080; i2 = 0%). discussion while various pharmalogical treatments are available to alleviate the symptoms of ibs, such as tricyclic anti depressants, antispasmodics and selective serotonin reuptake inhibitors, non-pharmalogical options are needed in order to improve efficacy of treatment and mitigate the risk of adverse events.59 probiotics, pre biotics and synbiotics are potentially promising appr oaches of altering gut microbiota and alleviating symptoms of functional bowel disorders. the current article presents a systematic review and meta-analysis of recent rcts evaluating the efficacy and safety of probiotics, prebiotics and synbiotics in the context of ibs. the findings of the present analysis indicate that probiotics had the most robust effect on improving global ibs symptoms, particularly those containing multi-strains and bifidobacterium species. additionally, lactobacillus-containing probiotic products helped to significantly reduce specific symptoms (i.e. abdominal pain and flatulence) and improve the qol of patients. intriguingly, when probiotics were combined with prebiotics in synbiotic formulations, they also exhibited beneficial effects on urgency, abdominal pain and flatulence. probiotics have significant effects on the integrity of the gi epithelium, which is maintained via tight junction (tj) proteins. zyrek et al. observed that pro biotics containing the escherichia coli strain nissle 1917 promoted the expression and redistribution of the zo-2 protein to cellular contact sites in order to ultimately stabilise tj proteins and preserve cellular morphology.60 another species, l. plantarum, utilised in various rcts as a component of singleand multistrain probiotic formulations, stimulates the expression of important tj proteins (zo-1, zo-2, cingulin and occludin), leading to a remarkable enhancement in intestinal barrier functionality.29–31,34,36,41,45,53 these regulatory mechanisms eventually stabilise gi functions against pathogenic bacteria and limit the development of increased intestinal permeability, a factor likely involved in the pathogenesis of ibs.61 bowel movement, another relevant target for ibs patients, could also be regulated via probiotic-cont aining products. in a recent meta-analysis of rcts involving patients with constipation, miller et al. found that probiotics containing lactobacillus or bifido bacterium species increased stool frequency and reduced intestinal transit time.62 in the present analysis, lactobacillus-containing products resulted in signif icant pain reduction, which may have contributed to qol improvement. indeed, lactobacillus species are often reported as beneficial for abdominal pain in functional gi disorders.63,64 although the exact mechanism of pain in ibs is as yet unclear, it is possible this symptom is mediated via persistent low-grade intestinal inflammation and changes in the quantity of gut microbiota.65 overall, the act of altering the gut microbiota via the administration of probiotics seems to yield beneficial results for general ibs symptoms. this mohammad z. asha and sundos f. h. khalil review | e21 could be further supported by the use of synbiotics; in the present analysis, this type of intervention resulted in significant improvements in abdominal pain, urgency and flatulence. the synbiotics were primarily composed of the most common probiotic strains (lactobacillus and bifidobacterium).40,45 on the other hand, the benefits of prebiotics (e.g. fruct ooligosaccharides and partially-hydrolysed guar gum) seem to be less apparent.42,50,51 indeed, the role of prebiotics in alleviating ibs symptoms is controversial since most of them are fermentable oligosaccharides, disaccharides, monosaccharides and polyols. such compounds, including fructans and fructose, are poorly absorbed in the small intestine and undergo fermentation, exacerbating ibs symptoms.66,67 in terms of methodologies, the rcts included in the current analysis were of moderate-to-high quality, with the majority employing a double-blind design. moreover, a rigorous search strategy was used based on several keyword combinations in order to identify the most relevant studies. minimal limits for sample sizes and methodological considerations were based on previous recommendations so that the findings would be reliable.24 importantly, despite variations in the version used and the lack of trials utilising the latest criteria (rome iv), all trials employed a unified diagnostic tool. previous systematic reviews and meta-analyses have confirmed the effectiveness and safety of probiotics for ibs patients.66 however, such analyses have failed to provide reliable recommendations regarding specific bacterial strains. in the present analysis, lactobacillus and bifidobacterium species resulted in significant benefits; these strains are therefore recommended by the authors. supporting evidence exists, indicating that alterations in these species have been previously reported in ibs patients.68–70 moreover, unlike other recently-published meta-analyses on this topic, the current article presents insight into the effect of synbiotics, showing that this type of intervention results in a significant ameliorating effect on ibs symptoms.71,72 in addition, to the best of the authors’ knowledge, this is the first meta-analysis to assess the effects of these formulations on qol. nonetheless, the present analysis was not without limitations. the majority of the rcts included in the analysis assessed adherence to regimens qualitatively via verbal questioning. in addition, while patients were instructed to maintain their usual dietary patterns, no formal dietary assessment was performed; as such, the confounding effect of nutritional variables was not taken into consideration. moreover, although it is the authors’ belief that the duration of interventions should be greater than four weeks, 13 trials (39.4%) did not meet this threshold.26,33,36,37,39–41,43–45,51,52,56 therefore, longer follow-up periods are warranted in future studies. furthermore, the effects of probiotics on specific subgroups of patients are unclear; for instance, the impact on those with ibs-d is conflicting, while little is known about the outcomes on patients with other ibs subtypes.26–31 hence, future trials incorporating specific ibs subtypes are recommended. another important limitation of the present meta analysis was the failure to determine the exact sources of heterogeneity between studies. the authors suggest that consistent methodological designs, such as unified symptomatic assessment scores, should be used in future studies on this topic. moreover, it is vital to highlight the low number of prebiotic studies identified in this review, since this limitation may interfere with the interpretation of pertinent outcomes. finally, in terms of safety outcomes, it was difficult to determine whether repeatedly-reported side-effects (such as abdominal pain, diarrhoea, nausea, flatulence and heartburn) were due to the interventions or the disease itself because of symptom overlap. therefore, the exact relationship between the interventions and such symptoms was unclear. conclusion the findings of this systematic review and metaanalysis indicate that probiotics and synbiotics have the potential to alleviate global ibs symptoms. more specifically, products containing lactobacillus species significantly reduced abdominal pain and flatulence scores and improved qol, while urgency and other general symptoms were alleviated by bifidobacteriumcontaining formulations. therefore, preparations cont aining multi-strains of these bacterial species might be beneficial. however, there was significant inter-study heterogeneity, which warrants cautious interpretation of these findings. future studies on this topic should employ longer follow-up periods, unify symptomatic assessment scores, monitor dietary patterns and clin ically assess patient adherence to the interventions. references 1. koloski na, talley nj. irritable bowel syndrome. in: goldman mb, troisi r, rexrode km, eds. women and health, 2nd ed. cambridge, massachusetts, usa: academic press, 2012. pp. 1353–66. 2. drossman da, richter je, talley n, thompson g, corazziari e, whitehead w. the functional gastrointestinal disorders: diagnosis, pathophysiology and treatment a multinational consensus. new york, usa: little, brown and co., 1994. 3. defrees dn, bailey j. irritable bowel syndrome: epidemiology, pathophysiology, diagnosis, and treatment. prim care 2017; 44:655–71. https://doi.org/10.1016/j.pop.2017.07.009. https://doi.org/10.1016/j.pop.2017.07.009 efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome a systematic review and meta-analysis e22 | squ medical journal, february 2020, volume 20, issue 1 4. lovell rm, ford ac. global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. clin gastroenterol hepatol 2012; 10:712–21.e4. https://doi.org/10.1016/j.cgh.2012.02.029. 5. drossman da, corazziari e, talley n, thompson w, whitehead w. rome ii: the functional gastrointestinal disorders, 2nd ed. mclean, virginia, usa: degnon associates inc., 2000. 6. drossman da, corazziari e, delvaux m, eds. rome iii: the functional gastrointestinal disorders, 3rd ed. mclean, virginia, usa: degnon associates inc., 2006. 7. drossman da, chang l, chey wd, kellow j, tack j, whitehead we, eds. rome iv: functional gastrointestinal disorders disorders of gut-brain interaction, 4th ed. raleigh, north carolina, usa: rome foundation, 2016. 8. kavanagh rg, o’grady j, carey bw, o’connor oj, maher mm. review of the role of abdominal imaging in irritable bowel syndrome. world j radiol 2018; 10:143–9. https://doi.org/10.43 29/wjr.v10.i11.143. 9. abd-el khalek abd-alrazek a, fahmy dm. diagnostic value of diffusion-weighted imaging and apparent diffusion coefficient in assessment of the activity of crohn disease: 1.5 or 3 t. j comput assist tomogr 2018; 42:688–96. https://doi.org/10.1097/rct.00 00000000000754. 10. o’malley d. immunomodulation of enteric neural function in irritable bowel syndrome. world journal of gastroenterology: wjg. 2015 jun 28; 21(24):7362. 11. halvorson ha, schlett cd, riddle ms. postinfectious irritable bowel syndrome—a meta-analysis. american journal of gastro enterology. 2006 aug 1; 101(8):1894-9. 12. chong pp, chin vk, looi cy, wong wf, madhavan p, yong vc. the microbiome and irritable bowel syndrome–a review on the pathophysiology, current research and future therapy. frontiers in microbiology. 2019; 10:1136. 13. ringel y, ringel-kulka t. the intestinal microbiota and irrit able bowel syndrome. j clin gastroenterol 2015; 49:s56–9. https://doi.org/10.1097/mcg.0000000000000418. 14. könig j, wells j, cani pd, garcía-ródenas cl, macdonald t, mercenier a, et al. human intestinal barrier function in health and disease. clin transl gastroenterol 2016; 7:e196. https://doi. org/10.1038/ctg.2016.54. 15. giamarellos-bourboulis ej, pyleris e, barbatzas c, pistiki a, pimentel m. small intestinal bacterial overgrowth is assoc iated with irritable bowel syndrome and is independent of proton pump inhibitor usage. bmc gastroenterol 2016; 16:67. https://doi.org/10.1186/s12876-016-0484-6. 16. ghoshal uc, shukla r, ghoshal u, gwee ka, ng sc, quigley em. the gut microbiota and irritable bowel syndrome: friend or foe? int j inflam 2012; 2012:151085. https://doi.org/10.1155/20 12/151085. 17. shimura s, ishimura n, mikami h, okimoto e, uno g, tamagawa y, et al. small intestinal bacterial overgrowth in patients with refractory functional gastrointestinal disorders. j neurogastro enterol motil 2016; 22:60–8. https://doi.org/10.5056/jnm15116. 18. pyleris e, giamarellos-bourboulis ej, tzivras d, koussoulas v, barbatzas c, pimentel m. the prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. dig dis sci 2012; 57:1321–9. https://doi.org/10.1007/s10620-012-2033-7. 19. liu hn, wu h, chen yz, chen yj, shen xz, liu tt. altered molecular signature of intestinal microbiota in irritable bowel syndrome patients compared with healthy controls: a systematic review and meta-analysis. dig liver dis 2017; 49:331–7. https:// doi.org/10.1016/j.dld.2017.01.142. 20. klem f, wadhwa a, prokop lj, sundt wj, farrugia g, camilleri m, et al. prevalence, risk factors, and outcomes of irritable bowel syndrome after infectious enteritis: a systematic review and meta analysis. gastroenterology 2017; 152:1042–54.e1. https://doi.org/ 10.1053/j.gastro.2016.12.039. 21. floch mh. probiotics and prebiotics. gastroenterol hepatol (n y) 2014; 10:680–1. 22. pandey kr, naik sr, vakil bv. probiotics, prebiotics and synbioticsa review. j food sci technol 2015; 52:7577–87. https://doi.org/10.1007/s13197-015-1921-1. 23. moher d, liberati a, tetzlaff j, altman dg; prisma group. preferred reporting items for systematic reviews and metaanalyses: the prisma statement. plos med 2009; 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097. 24. mazurak n, broelz e, storr m, enck p. probiotic therapy of the irritable bowel syndrome: why is the evidence still poor and what can be done about it? j neurogastroenterol motil 2015; 21:471–85. https://doi.org/10.5056/jnm15071. 25. higgins jp, altman dg, gøtzsche pc, jüni p, moher d, oxman ad, et al. the cochrane collaboration’s tool for assessing risk of bias in randomised trials. bmj 2011; 343:d5928. https://doi.org/10.1 136/bmj.d5928. 26. sun yy, li m, li yy, li lx, zhai wz, wang p, et al. the effect of clostridium butyricum on symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. sci rep 2018; 8:2964. https://doi.org/10.1038/s41598-018-21241-z. 27. abbas z, yakoob j, jafri w, ahmad z, azam z, usman mw, et al. cytokine and clinical response to saccharomyces boulardii therapy in diarrhea-dominant irritable bowel syndrome: a rand omized trial. eur j gastroenterol hepatol 2014; 26:630–9. https://doi.org/10.1097/meg.0000000000000094. 28. shin sp, choi ym, kim wh, hong sp, park jm, kim j, et al. a double blind, placebo-controlled, randomized clinical trial that breast milk derived-lactobacillus gasseri bnr17 mitigated diarrhea-dominant irritable bowel syndrome. j clin biochem nutr 2018; 62:179–86. https://doi.org/10.3164/jcbn.17-73. 29. hod k, sperber ad, ron y, boaz m, dickman r, berliner s, et al. a double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant ibs. neuro gastroenterol motil 2017; 29. https://doi.org/10.1111/nmo.13037. 30. ki cha b, mun jung s, hwan choi c, song id, woong lee h, joon kim h, et al. the effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo controlled trial. j clin gastroenterol 2012; 46:220–7. https:// doi.org/10.1097/mcg.0b013e31823712b1. 31. ishaque sm, khosruzzaman sm, ahmed ds, sah mp. a rand omized placebo-controlled clinical trial of a multi-strain pro biotic formulation (bio-kult®) in the management of diarrheapredominant irritable bowel syndrome. bmc gastroenterol 2018; 18:71. https://doi.org/10.1186/s12876-018-0788-9. 32. guyonnet d, chassany o, ducrotte p, picard c, mouret m, mercier ch, et al. effect of a fermented milk containing bifi dobacterium animalis dn-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, double-blind, cont rolled trial. aliment pharmacol ther 2007; 26:475–86. https:// doi.org/10.1111/j.1365-2036.2007.03362.x. 33. choi ch, jo sy, park hj, chang sk, byeon js, myung sj. a randomized, double-blind, placebo-controlled multicenter trial of saccharomyces boulardii in irritable bowel syndrome: effect on quality of life. j clin gastroenterol 2011; 45:679–83. https:// doi.org/10.1097/mcg.0b013e318204593e. 34. stevenson c, blaauw r, fredericks e, visser j, roux s. rand omized clinical trial: effect of lactobacillus plantarum 299 v on symptoms of irritable bowel syndrome. nutrition 2014; 30:1151–7. https://doi.org/10.1016/j.nut.2014.02.010. https://doi.org/10.1016/j.cgh.2012.02.029 https://doi.org/10.4329/wjr.v10.i11.143 https://doi.org/10.4329/wjr.v10.i11.143 https://doi.org/10.1097/rct.0000000000000754 https://doi.org/10.1097/rct.0000000000000754 https://doi.org/10.1097/mcg.0000000000000418 https://doi.org/10.1038/ctg.2016.54 https://doi.org/10.1038/ctg.2016.54 https://doi.org/10.1186/s12876-016-0484-6 https://doi.org/10.1155/2012/151085 https://doi.org/10.1155/2012/151085 https://doi.org/10.5056/jnm15116 https://doi.org/10.1007/s10620-012-2033-7 https://doi.org/10.1016/j.dld.2017.01.142 https://doi.org/10.1016/j.dld.2017.01.142 https://doi.org/10.1053/j.gastro.2016.12.039 https://doi.org/10.1053/j.gastro.2016.12.039 https://doi.org/10.1007/s13197-015-1921-1 https://doi.org/10.1371/journal.pmed.1000097 https://doi.org/10.5056/jnm15071 https://doi.org/10.1136/bmj.d5928 https://doi.org/10.1136/bmj.d5928 https://doi.org/10.1038/s41598-018-21241-z https://doi.org/10.1097/meg.0000000000000094 https://doi.org/10.3164/jcbn.17-73 https://doi.org/10.1111/nmo.13037 https://doi.org/10.1097/mcg.0b013e31823712b1 https://doi.org/10.1097/mcg.0b013e31823712b1 https://doi.org/10.1186/s12876-018-0788-9 https://doi.org/10.1111/j.1365-2036.2007.03362.x https://doi.org/10.1111/j.1365-2036.2007.03362.x https://doi.org/10.1097/mcg.0b013e318204593e https://doi.org/10.1097/mcg.0b013e318204593e https://doi.org/10.1016/j.nut.2014.02.010 mohammad z. asha and sundos f. h. khalil review | e23 35. preston k, krumian r, hattner j, de montigny d, stewart m, gaddam s. lactobacillus acidophilus cl1285, lactobacillus casei lbc80r and lactobacillus rhamnosus clr2 improve quality-of-life and ibs symptoms: a double-blind, randomised, placebo-controlled study. benef microbes 2018; 9:697–706. https://doi.org/10.3920/bm2017.0105. 36. ducrotté p, sawant p, jayanthi v. clinical trial: lactobacillus plantarum 299v (dsm 9843) improves symptoms of irritable bowel syndrome. world j gastroenterol 2012; 18:4012–18. https://doi.org/10.3748/wjg.v18.i30.4012. 37. jafari e, vahedi h, merat s, momtahen s, riahi a. therapeutic effects, tolerability and safety of a multi-strain probiotic in iranian adults with irritable bowel syndrome and bloating. arch iran med 2014; 17:466–70. 38. rogha m, esfahani mz, zargarzadeh ah. the efficacy of a synbiotic containing bacillus coagulans in treatment of irritable bowel syndrome: a randomized placebo-controlled trial. gastro enterol hepatol bed bench 2014; 7:156–63. 39. amirimani b, nikfam s, albaji m, vahedi s, nasseri-moghaddam s, sharafkhah m, et al. probiotic vs. placebo in irritable bowel syndrome: a randomized controlled trial. middle east j dig dis 2013; 5:98–102. 40. shavakhi a, minakari m, farzamnia s, peykar ms, taghipour g, tayebi a, et al. the effects of multi-strain probiotic compound on symptoms and quality-of-life in patients with irritable bowel syndrome: a randomized placebo-controlled trial. adv biomed res 2014; 3:140. https://doi.org/10.4103/2277-9175.135157. 41. nobaek s, johansson ml, molin g, ahrné s, jeppsson b. alter ation of intestinal microflora is associated with reduction in abdo minal bloating and pain in patients with irritable bowel syndrome. am j gastroenterol 2000; 95:1231–8. https://doi.org/10.1111/ j.1572-0241.2000.02015.x. 42. olesen m, gudmand-hoyer e. efficacy, safety, and tolerability of fructooligosaccharides in the treatment of irritable bowel syndrome. am j clin nutr 2000; 72:1570–5. https://doi.org/10. 1093/ajcn/72.6.1570. 43. whorwell pj, altringer l, morel j, bond y, charbonneau d, o’mahony l, et al. efficacy of an encapsulated probiotic bifidobacterium infantis 35624 in women with irritable bowel syndrome. am j gastroenterol 2006; 101:1581–90. https://doi. org/10.1111/j.1572-0241.2006.00734.x. 44. drouault-holowacz s, bieuvelet s, burckel a, cazaubiel m, dray x, marteau p. a double blind randomized controlled trial of a probiotic combination in 100 patients with irritable bowel syndrome. gastroenterol clin biol 2008; 32:147–52. https://doi.org/10.1016/j.gcb.2007.06.001. 45. cappello c, tremolaterra f, pascariello a, ciacci c, iovino p. a randomised clinical trial (rct) of a symbiotic mixture in patients with irritable bowel syndrome (ibs): effects on symptoms, colonic transit and quality of life. int j colorectal dis 2013; 28:349–58. https://doi.org/10.1007/s00384-012-1552-1. 46. williams ea, stimpson j, wang d, plummer s, garaiova i, barker me, et al. clinical trial: a multistrain probiotic preparation significantly reduces symptoms of irritable bowel syndrome in a double-blind placebo-controlled study. aliment pharmacol ther 2009; 29:97–103. https://doi.org/10.1111/j.13 65-2036.2008.03848.x. 47. simrén m, ohman l, olsson j, svensson u, ohlson k, posserud i, et al. clinical trial: the effects of a fermented milk containing three probiotic bacteria in patients with irritable bowel syndrome a randomized, double-blind, controlled study. ali ment pharmacol ther 2010; 31:218–27. https://doi.org/10.11 11/j.1365-2036.2009.04183.x. 48. søndergaard b, olsson j, ohlson k, svensson u, bytzer p, ekesbo r. effects of probiotic fermented milk on symptoms and intestinal flora in patients with irritable bowel syndrome: a randomized, placebo-controlled trial. scand j gastroenterol 2011; 46:663–72. https://doi.org/10.3109/00365521.2011.565066. 49. kajander k, myllyluoma e, rajilić-stojanović m, kyrönpalo s, rasmussen m, järvenpää s, et al. clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota. aliment pharmacol ther 2008; 27:48–57. https://doi.org/10.1111/j.136 5-2036.2007.03542.x. 50. niv e, halak a, tiommny e, yanai h, strul h, naftali t, et al. randomized clinical study: partially hydrolyzed guar gum (phgg) versus placebo in the treatment of patients with irritable bowel syndrome. nutr metab (lond) 2016; 13:10. https://doi.org/10.1186/s12986-016-0070-5. 51. azpiroz f, dubray c, bernalier-donadille a, cardot jm, accarino a, serra j, et al. effects of scfos on the composition of fecal microbiota and anxiety in patients with irritable bowel syndrome: a randomized, double blind, placebo controlled study. neurogastroenterol motil 2017; 29. https://doi.org/10.11 11/nmo.12911. 52. roberts lm, mccahon d, holder r, wilson s, hobbs fd. a randomised controlled trial of a probiotic ‘functional food’ in the management of irritable bowel syndrome. bmc gastroenterol 2013; 13:45. https://doi.org/10.1186/1471-230x-13-45. 53. sisson g, ayis s, sherwood ra, bjarnason i. randomised clin ical trial: a liquid multi-strain probiotic vs. placebo in the irritable bowel syndrome--a 12 week double-blind study. aliment pharmacol ther 2014; 40:51–62. https://doi.org/10.1111/apt.12787. 54. begtrup lm, de muckadell ob, kjeldsen j, christensen rd, jarbøl de. long-term treatment with probiotics in primary care patients with irritable bowel syndrome--a randomised, double-blind, placebo controlled trial. scand j gastroenterol 2013; 48:1127–35. https://doi.org/10.3109/00365521.2013.825314. 55. lyra a, hillilä m, huttunen t, männikkö s, taalikka m, tennilä j, et al. irritable bowel syndrome symptom severity improves equally with probiotic and placebo. world j gastroenterol 2016; 22:10631–42. https://doi.org/10.3748/wjg.v22.i48.10631. 56. guglielmetti s, mora d, gschwender m, popp k. randomised clinical trial: bifidobacterium bifidum mimbb75 significantly alleviates irritable bowel syndrome and improves quality of life--a double-blind, placebo-controlled study. aliment pharmacol ther 2011; 33:1123–32. https://doi.org/10.1111/j.13652036.2011.04633.x. 57. pineton de chambrun g, neut c, chau a, cazaubiel m, pelerin f, justen p, et al. a randomized clinical trial of saccharomyces cere visiae versus placebo in the irritable bowel syndrome. dig liver dis 2015; 47:119–24. https://doi.org/10.1016/j.dld.2014.11.007. 58. spiller r, pélerin f, cayzeele decherf a, maudet c, housez b, cazaubiel m, et al. randomized double blind placebo-contr olled trial of saccharomyces cerevisiae cncm i-3856 in irritable bowel syndrome: improvement in abdominal pain and bloating in those with predominant constipation. united european gastro enterol j 2016; 4:353–62. https://doi.org/10.1177/2050640615602571. 59. munjal a, dedania b, cash b. update on pharmacotherapy for irritable bowel syndrome. curr gastroenterol rep 2019; 21:25. https://doi.org/10.1007/s11894-019-0692-7. 60. zyrek aa, cichon c, helms s, enders c, sonnenborn u, schmidt ma. molecular mechanisms underlying the probiotic effects of escherichia coli nissle 1917 involve zo-2 and pkc zeta redistribution resulting in tight junction and epithelial barrier repair. cell microbiol 2007; 9:804–16. https://doi.org/10.1 111/j.1462-5822.2006.00836.x. 61. slyepchenko a, maes m, jacka fn, köhler ca, barichello t, mcintyre rs, et al. gut microbiota, bacterial translocation, and interactions with diet: pathophysiological links between major depressive disorder and non-communicable medical comorbidities. psychother psychosom 2017; 86:31–46. https:// doi.org/10.1159/000448957. 62. miller le, ouwehand ac, ibarra a. effects of probioticcontaining products on stool frequency and intestinal transit in constipated adults: systematic review and meta-analysis of randomized controlled trials. ann gastroenterol 2017; 30:629–39. https://doi.org/10.20524/aog.2017.0192. https://doi.org/10.3920/bm2017.0105 https://doi.org/10.3748/wjg.v18.i30.4012 https://doi.org/10.4103/2277-9175.135157 https://doi.org/10.1111/j.1572-0241.2000.02015.x https://doi.org/10.1111/j.1572-0241.2000.02015.x https://doi.org/10.1093/ajcn/72.6.1570 https://doi.org/10.1093/ajcn/72.6.1570 https://doi.org/10.1111/j.1572-0241.2006.00734.x https://doi.org/10.1111/j.1572-0241.2006.00734.x https://doi.org/10.1016/j.gcb.2007.06.001 https://doi.org/10.1007/s00384-012-1552-1 https://doi.org/10.1111/j.1365-2036.2008.03848.x https://doi.org/10.1111/j.1365-2036.2008.03848.x https://doi.org/10.1111/j.1365-2036.2009.04183.x https://doi.org/10.1111/j.1365-2036.2009.04183.x https://doi.org/10.3109/00365521.2011.565066 https://doi.org/10.1111/j.1365-2036.2007.03542.x https://doi.org/10.1111/j.1365-2036.2007.03542.x https://doi.org/10.1186/s12986-016-0070-5 https://doi.org/10.1111/nmo.12911 https://doi.org/10.1111/nmo.12911 https://doi.org/10.1186/1471-230x-13-45 https://doi.org/10.1111/apt.12787 https://doi.org/10.3109/00365521.2013.825314 https://doi.org/10.3748/wjg.v22.i48.10631 https://doi.org/10.1111/j.1365-2036.2011.04633.x https://doi.org/10.1111/j.1365-2036.2011.04633.x https://doi.org/10.1016/j.dld.2014.11.007 https://doi.org/10.1177/2050640615602571 https://doi.org/10.1007/s11894-019-0692-7 https://doi.org/10.1111/j.1462-5822.2006.00836.x https://doi.org/10.1111/j.1462-5822.2006.00836.x https://doi.org/10.1159/000448957 https://doi.org/10.1159/000448957 https://doi.org/10.20524/aog.2017.0192 efficacy and safety of probiotics, prebiotics and synbiotics in the treatment of irritable bowel syndrome a systematic review and meta-analysis e24 | squ medical journal, february 2020, volume 20, issue 1 63. horvath a, dziechciarz p, szajewska h. meta-analysis: lacto bacillus rhamnosus gg for abdominal pain-related functional gastrointestinal disorders in childhood. aliment pharmacol ther 2011; 33:1302–10. https://doi.org/10.1111/j.1365-2036.2011.04665.x. 64. jadrešin o, hojsak i, mišak z, kekez aj, trbojević t, ivković l, et al. lactobacillus reuteri dsm 17938 in the treatment of functional abdominal pain in children: rct study. j pediatr gastroenterol nutr 2017; 64:925–9. https://doi.org/10.1097/ mpg.0000000000001478. 65. chichlowski m, rudolph c. visceral pain and gastrointestinal microbiome. j neurogastroenterol motil 2015; 21:172–81. https://doi.org/10.5056/jnm15025. 66. ooi sl, correa d, pak sc. probiotics, prebiotics, and low fodmap diet for irritable bowel syndrome what is the current evidence? complement ther med 2019; 43:73–80. https://doi.org/10.1016/j.ctim.2019.01.010. 67. yan yl, hu y, gänzle mg. prebiotics, fodmaps and dietary fiber — conflicting concepts in development of functional food products? curr opin food sci 2018; 20:30–7. https://doi. org/10.1016/j.cofs.2018.02.009. 68. lacy be. hot topics in primary care: role of the microbiome in disease implications for treatment of irritable bowel syndrome. j fam pract 2017; 66:s40–5. 69. principi n, cozzali r, farinelli e, brusaferro a, esposito s. gut dysbiosis and irritable bowel syndrome: the potential role of probiotics. j infect 2018; 76:111–20. https://doi.org/10.1016/j. jinf.2017.12.013. 70. menees s, chey w. the gut microbiome and irritable bowel syndrome. f1000res 2018; 7:f1000. https://doi.org/10.12688/ f1000research.14592.1. 71. ford ac, quigley em, lacy be, lembo aj, saito ya, schiller lr, et al. efficacy of prebiotics, probiotics, and synbiotics in irri table bowel syndrome and chronic idiopathic constipation: syst ematic review and meta-analysis. am j gastroenterol 2014; 109:1547–61. https://doi.org/10.1038/ajg.2014.202. 72. ford ac, harris la, lacy be, quigley em, moayyedi p. syst ematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel synd rome. aliment pharmacol ther 2018; 48:1044–60. https://doi. org/10.1111/apt.15001. https://doi.org/10.1111/j.1365-2036.2011.04665.x https://doi.org/10.1097/mpg.0000000000001478 https://doi.org/10.1097/mpg.0000000000001478 https://doi.org/10.5056/jnm15025 https://doi.org/10.1016/j.ctim.2019.01.010 https://doi.org/10.1016/j.cofs.2018.02.009 https://doi.org/10.1016/j.cofs.2018.02.009 https://doi.org/10.1016/j.jinf.2017.12.013 https://doi.org/10.1016/j.jinf.2017.12.013 https://doi.org/10.12688/f1000research.14592.1 https://doi.org/10.12688/f1000research.14592.1 https://doi.org/10.1038/ajg.2014.202 https://doi.org/10.1111/apt.15001 https://doi.org/10.1111/apt.15001 squ med j, august 2011, vol. 11, iss. 3, pp. 338-342, epub. 15th aug 11 submitted 12th jan 11 accepted 5th apr 11 acute coronary syndrome (acs) is a clinical syndrome characterised by unstable angina (ua), st-segment elevation myocardial infarction (stemi) and non–stemi. in the majority of cases, the primary mechanism of acs is either erosion or rupture of an atherosclerotic plaque resulting in intracoronary thrombus formation leading to either subtotal or total occlusion of a major coronary artery. acs is the most common cause of cardiovascular mortality and morbidity in western countries. international guidelines with recommendations for diagnosis and treatment have been developed based on randomised clinical trials.1,2 however, data from international registries like the national registry of myocardial infarction from the usa3 and the global registry of acute coronary events (grace),4 report a lack of association between guideline recommendations and actual clinical practice. similar to these registries, the gulf heart association initiated a registry called gulf registry of acute coronary events (gulf race). this registry was developed to determine the characteristics and management of acs in the gulf countries including oman.5 registry data is extremely important because the information is derived from unselected populations of patients reflecting "real-life" practice as well as including patients who are frequently left out of clinical trials, such as the elderly or female patients. additionally, registries allow an assessment of the acceptance and practice of new treatments by the medical community. gulf race is the largest multinational prospective acs registry from the middle east with 1department of cardiology, royal hospital, muscat, oman; 2department of pharmacology & clinical pharmacy, college of medicine & health sciences, sultan qaboos university, muscat, oman, and 3gulf health research, muscat, oman. *corresponding author email: prashanthp_69@yahoo.co.in <‡⁄<sò^jfi<v·^€ �¬<ª<ïå^£]<íq^j÷]<·^ëüé÷]<ì⁄á¯j⁄ ïå^£]<íq^j÷]<·^ëüé÷]<p]çu˜<írè◊§]<ÿrä÷]           :مفتاح الكلمات abstract: acute coronary syndrome (acs) is the most common cause of cardiovascular mortality and morbidity in western countries. international guidelines for diagnosis and treatment have been developed based on randomised clinical trials. however, data from international registries report a lack of association between guideline recommendations and actual clinical practice. similarly, the gulf heart association initiated a registry called gulf registry of acute coronary events (gulf race). this registry was developed to determine the characteristics and management of acs in the gulf countries including oman. here, we report on the results of the various gulf race registry studies from oman and compare our results with the main gulf race data as well as other international registries. keywords: acute coronary syndrome; oman sounding board acute coronary syndrome in oman results from the gulf registry of acute coronary events *prashanth panduranga,1kadhim sulaiman,1 ibrahim al-zakwani2,3 sounding board | 339 prashanth panduranga, kadhim sulaiman, ibrahim al-zakwani more than 8,000 patients with a final diagnosis of acs admitted in the periods 8 may to 6 june 2006 and 29 january to 29 june 2007. it provides a unique opportunity to study acs management in this part of the world. as part of the gulf race study, the data from oman on 1,579 patients from 14 hospitals (including two hospitals with catheterisation facilities) have thrown light on the characteristics, management, and in-hospital outcomes of acs patients in oman. this registry determined the epidemiology of acs including risk factors, clinical presentation, accuracy of ecg (electrocardiogram) interpretation, validation of risk models like the grace risk score, and in-hospital management, including utilisation of medications and invasive procedures. this registry also determined whether the evidence-based guideline recommendations are being applied, along with in-hospital outcomes and mortality in patients with acs. table 1 shows the baseline characteristics of acs patients from oman. with a mean age of 59 years, acs patients from oman are younger than those in western countries whose mean age is about 65 years.4 the majority of patients were omani citizens (84%) and were male (61%). in the grace registry, women consisted of 34% of the patients whereas in oman they formed 39% of acs patients.4 among the risk factors, hypertension was the commonest risk factor (53%) followed by diabetes (37%) and hyperlipidaemia (35%). smoking (17%), a family history of coronary artery disease (cad) and obesity were not found to be high in acs patients from oman. in the grace ukbelgian study, hypertension was recorded in 46% of patients, diabetes in 16% and smoking in 30% of the patients.6 in the main gulf race registry, diabetes and smoking prevalence were high at 40% and 38%, respectively.5 this high prevalence of diabetes among acs patients from oman and other gulf countries is an alarming trend as it is well known that diabetic acs patients have poor hospital outcomes. this was reported in a recent gulf race analysis from oman.7 when adjusted for age and gender, diabetes status was an independent risk factor of in-hospital mortality in acs patients (adjusted odds ratio [or] 1.68; 95% confidence interval [ci] 1.02–2.77; p = 0.042).7 moreover, the burden of diabetes mellitus in gulf countries is the highest among all world regions (13–18% versus the 6–7% global prevalence) and according to the international diabetic federation it will double by 2030.8 furthermore, in another analysis of gulf race data from oman, it was seen that non-diabetic acs patients presenting with hyperglycaemia of >11 mmol/l were found to have a higher mortality rate when compared to euglycaemic patients (13.1% versus 1.52%; p <0.001).9 this indicates that diabetes mellitus remains undiagnosed in many patients in oman. table 1: baseline clinical characteristics of patients with acute coronary syndrome from oman characteristic n = 1,579 age + sd age, mean ± sd, years 58 ± 13 body mass index, mean ± sd, kg/m2 27 ± 5 (n, %) male gender 971 (61) omani citizen 1326 (84) diabetes mellitus 581 (37) hypertension 838 (53) hyperlipidaemia 550 (35) current smoker 278 (17) family history of cad 121 (7.6) prior angina 757 (48) past mi 285 (18) past pci 118 (7.5) past cabg 108 (6.8) aspirin use 751 (47) copd 77 (4.8) stroke 55 (3.4) dialysis 26 (1.6) pvd 34 (2.1) ischemic chest pain 1154 (73) atypical chest pain 109 (6.9) dyspnoea 216 (14) unstable angina 795 (50) non-stemi 381 (24) stemi 393 (25) lbbb mi 10 (0.6) legend: ns = non-significant; sd = standard deviation; cad = coronary artery disease; mi = myocardial infarction; pci = percutaneous coronary intervention; cabg = coronary artery bypass surgery; copd = chronic obstructive pulmonary disease; pvd = peripheral vascular disease; stemi = st-elevation myocardial infarction; lbbb = left bundle branch block. all values are n (%) unless specified otherwise. 340 | squ medical journal, august 2011, volume 11, issue 3 acute coronary syndrome in oman results from the gulf registry of acute coronary events hence, measures to prevent and control diabetes as well as diagnose it early are very important in oman. even though hyperlipidaemia was found in 34% of acs patients in a recent analysis of gulf race patients from oman, metabolic syndrome was found to be present in 66% of patients who had higher rates of heart failure (odds ratio (or): 1.37; 95% confidence interval (ci): 1.03–1.81; p = 0 .028) and mortality (or: 4.42; 95% ci: 1.25–15.5; p = 0.020) when compared to non-metabolic syndrome patients.10 among acs patients from oman, prior angina was seen in 48% of patients, with prior myocardial infarction (mi) in 18%, prior percutaneous coronary intervention (pci), or coronary artery bypass graft surgery (cabg) in 7.5% and 6.8%, respectively, and prior stroke in 3.4% of patients. the prevalence of prior angina is similar to the grace uk-belgian study where it was found in 47% of the patients, but prior mi, prior pci, prior cabg, and previous stroke were higher in oman than in the grace population at 28%, 17%, 11% and 8% respectively.6 of the 1,579 acs patients from oman, 50% had a final diagnosis of ua, 25% had stemi, and 24% had non-stemi. among the types of acs, investigators of the grace registry reported that ua was the most frequent cause of hospital admission (38%), followed by 30% stemi, and 25% non-stemi patients.4 the occurrence of ua is higher in patients in oman, which indicates that picking up these patients for an early invasive strategy will prevent future cardiac events. figures 1 and 2 show the in-hospital management of acs patients in oman. the frequent use of inhospital evidence-based pharmacologic therapies, such as aspirin (98%), anticoagulation (84%), statins 0 10 20 30 40 50 60 70 80 90 100 asa 98 25 84 0.5 62 68 85 11 clo hep in-hospital management gp bb ace/arb sta cag per cen tag e o f pa tien ts figure 1: in-hospital management of patients with acute coronary syndrome from oman. legend: asa = aspirin; clo = clopidogrel; hep = heparin (includes low molecular weight heparin); gp = glycoprotein iib/iiia inhibitors; bb = betablockers; ace = angiotensin-converting enzyme inhibitors; arb = angiotensin ii receptor blockers; sta = statins; cag = coronary angiography. figure 2: missed opportunities for thrombolysis in patients with acute coronary syndrome from oman. sounding board | 341 prashanth panduranga, kadhim sulaiman, ibrahim al-zakwani (85%), and thrombolytic therapy (91%) is similar to the grace and crusade (can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the acc/aha guidelines) registries.4,11,12 the use of beta-blockers (62%) is low in oman compared to nearly 80% use in these registries as well as in the main gulf race registry, but angiotensinconverting enzyme inhibitors (acei)/angiotensin ii receptor blockers (arb) (68%) use is similar to these registry reports. this variation in the use of guideline-recommended medications may be related to patient or physician characteristics, as well as hospital type and national variations.11,12 in one of the grace analyses, which may be true for oman as well, high-risk features (e.g. heart failure, older age) were related to failure to use beta-blockers, but being at a teaching hospital and care by a cardiologist were associated with better use of these drugs.13 some drugs with proven benefits were used less often, such as clopidogrel (25%) and glycoprotein iib/iiia receptor inhibitors (0.25%), probably due to the non-availability of these medications in most of the hospitals in oman. among stemi patients, 26% had delayed presentation of >12 hours which is similar to the grace study;11 however, 91% of the eligible patients were thrombolysed which is consistent with guideline recommendations. coronary angiography was utilised in only 11% of the patients which is mostly due to the existence of only two invasive catheterisation facility hospitals in oman. however, in a recent gulf race analysis14 overall utilisation of catheterisation in acs patients from all gulf countries was very low (20%) when compared to 66% usage rate in the grace registry.11 other than the unavailability of catheterisation facilities, a second important reason for the low rate was the avoidance of catheterisation in high risk acs patients among gulf cardiologists. low risk acs patients were more often catheterised than intermediate or high risk patients.11 this "treatment-risk paradox" has been proposed as one of the reasons why less or no mortality benefit was seen in some acs registries when compared with randomised trials. table 2 shows the in-hospital outcomes of acs patients from oman. most of the outcomes were comparable to the grace registry except for the high prevalence of heart failure (25%) among omani acs patients which is nearly twice that of the grace registry. the reason could be the high prevalence of diabetic acs patients in oman. in-hospital mortality of 4.3% is low compared to 10.8% in the grace registry. in another analysis of acs patients from oman, women experienced more recurrent ischaemia and heart failure, but had similar in-hospital mortality (4.6% versus 4.3%) even after adjusting for age (p = 0.500).15 in conclusion, acs patients in oman, compared to other countries, are younger with higher rates of diabetes and heart failure, but lower overall in-hospital mortality. there is evidence of good adherence to most of the evidence-based medications, except for the use of catheterisation. there is a need to explore ways to increase the overall rate of in-hospital cardiac catheterisation as well as to provide other evidence-based medications in oman and prescribe them to patients who would benefit most. in addition, there is a need to diagnose and control diabetes effectively. awareness of these findings from oman may help the medical community adhere more strictly to the national and international guidelines. references 1. american college of cardiology. cardiosource. fro m : http : / / w w w. a cc . o rg / qu a l i t y a n d s c i e n ce / clinical/statements.htm. accessed: sep 2009. 2. european society of cardiology. esc guidelines. from: http://www.escardio.org/guidelines-surveys/ esc-guidelines/pages/guidelineslist.aspx accessed: sep 2009. 3. rogers wj, canto jg, lambrew ct, tiefenbrunn aj, kinkaid b, shoultz da, et al. temporal trends in the treatment of over 1,5 million patients with myocardial infarction in the us from 1990 through 1999: the national registry of myocardial infarction table 2: in-hospital outcome in patients (n,[%]) presenting with acute coronary syndrome from oman characteristic n = 1,579 recurrent ischaemia 150 (9.4) re-infarction 38 (2.4) congestive heart failure 403 (25) ventilation 82 (5) cardiogenic shock 89 (5.6) major bleed 16 (1) stroke 16 (1) mortality 69(4.3) 342 | squ medical journal, august 2011, volume 11, issue 3 acute coronary syndrome in oman results from the gulf registry of acute coronary events 1, 2 and 3. j am coll cardiol 2000; 36:2056–63. 4. steg pg, goldeberg rj, gore jm, fox ka, eagle ka, flather md, et al. baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the global registry of acute coronary events (grace). am j cardiol 2002; 90:358–63. 5. zubaid m, rashed wa, al-khaja n, almahmeed w, al-lawati j, sulaiman k, et al. clinical presentation and outcomes of acute coronary syndromes in the gulf registry of acute coronary events (gulf race). saudi med j 2008; 29:251–5. 6. fox ka, carruthers kf, dunbar dr, graham c, manning jr, de raedt h, et al. underestimated and under-recognized: the late consequences of acute coronary syndrome (grace uk-belgian study). eur heart j 2010; 31:2755–64. 7. panduranga p, sulaiman kj, al-zakwani is, al-lawati ja. characteristics, management, and in-hospital outcomes of diabetic acute coronary syndrome patients in oman. saudi med j 2010; 31:520–4. 8. idf diabetes atlas, 4th ed., 2009. from: http://www. diabetesatlas.org/content/diabetes-and-impairedglucose-tolerance accessed: mar 2010. 9. panduranga p, sulaiman k, al-zakwani i. relationship between admitting (non-fasting) blood glucose and in-hospital mortality stratified by diabetes mellitus among acute coronary syndrome patients in oman. heart views 2011; 12:12–17. 10. al-rasadi k, sulaiman k, panduranga p, al-zakwani k. prevalence, characteristics, and in-hospital outcomes of metabolic syndrome among acute coronary syndrome patients from oman. angiology 2011; 62:381–9. 11. goodman sg, huang w, yan at, budaj a, kennelly bm, gore jm, et al. expanded global registry of acute coronary events (grace 2) investigators. the expanded global registry of acute coronary events: baseline characteristics, management practices, and hospital outcomes of patients with acute coronary syndromes. am heart j 2009; 158:193–201. 12. mehta rh, roe mt, chen ay, lytle bl, pollack cv jnr, brindis rg, et al. recent trends in the care of patients with non–st-segment elevation acute coronary syndromes: insights from the crusade initiative. arch intern med 2006; 166:2027–34. 13. granger cb, steg pg, peterson e, lópez-sendón j, van de werf f, kline-rogers e, et al. grace investigators. medication performance measures and mortality following acute coronary syndromes. am j med 2005; 118:858–65. 14. panduranga p, sulaiman k, al-zakwani i, zubaid m, rashed w, al-mahmeed w, et al. utilization and determinants of in-hospital cardiac catheterization in patients with acute coronary syndrome from the middle east. angiology 2010; 61:744–50. 15. panduranga p, sulaiman k, al-zakwani i. genderrelated differences in the presentation, management, and outcomes among patients with acute coronary syndrome from oman. j saudi heart assoc 2011; 23:17–22. 1department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 2department of family medicine, ministry of health and 3department of family medicine & public health, sultan qaboos university, muscat, oman *corresponding author’s e-mail: drshs@squ.edu.om depression in urban omani adults with type 2 diabetes a cross-sectional study *sanaa h. alsumry,1 tharaya al ghelani,2 sanjay jaju3 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 45–50, epub. 28 feb 22 submitted 7 sep 20 revision req. 15 oct 20; revision recd. 12 nov 20 accepted 3 dec 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.065 clinical & basic research depression is a mental health disorder which commonly manifests as symptoms of low mood or sadness, loss of interest and pleasure in normal activities or surroundings, decreased energy, feelings of guilt or low self-esteem, sleep or appetite disturbances and difficulties concentrating.1 this public health problem is a significant contributor to the global burden of diseases; according to the world health organization (who), an estimated 264 million people worldwide are affected by depression.1,2 in 2011, results from the world mental health survey indicated that approximately one in 20 people had experienced a depressive episode in the previous year.1 indeed, depression has been identified as the third leading cause of disease burden and years lost due to disability worldwide.2 diabetes mellitus is a chronic metabolic disorder which represents the fourth leading cause of disability globally.2 estimates from the who indicate that 422 million adults were affected by diabetes in 2014, with the global age-standardised prevalence of this disease rising from 4.7% in 1980 to 8.5% in 2014.3 moreover, both diabetes and diabetes-related complications have a tremendous financial impact, particularly in lowand middle-income countries, both in terms of direct and indirect medical costs and premature mortality as well as productivity loss and labour market effects.3,4 while patients with type 2 diabetes mellitus (t2dm) have a 24% increased risk of depression compared to nondiabetic individuals, the mechanisms underlying this relationship are still unclear.5,6 in particular, depressive symptoms in diabetic individuals have been associated with worsened glycaemic control, an increased prevalence of diabetes-related complications, increased functional disability, lower adherence to antidiabetic medications, higher health-related costs and increased mortality.7–12 the overall prevalence of depression among people with t2dm has been reported to be 27%; moreover, in a meta-analysis of 42 studies comprising 21,351 adults, the prevalence of abstract: objectives: this study aimed to identify the prevalence of clinically significant depression among adult omani patients with type 2 diabetes mellitus (t2dm) and explore potential associations with sociodemographic and clinical variables in this population. methods: this descriptive cross-sectional study was conducted between august 2018 and september 2019 and included 427 omani t2dm patients from 12 randomly selected government health centres in muscat, oman. an arabic version of the validated patient health questionnaire-9 was administered to the participants via face-to-face interviews to determine the prevalence of depression. results: a total of 111 t2dm patients (response rate: 100%) had depression (26%). the presence of a personal history of depression was the only variable significantly associated with depression (p <0.001). other sociodemographic and clinical factors including age, gender, duration of diabetes, glycated haemoglobin level, mode of diabetes treatment or the presence of diabetes-related complications such as cardiac complications, renal impairment, retinopathy, neuropathy and erectile dysfunction, were not associated with depression, (p >0.050 each). conclusion: this study revealed a high prevalence of depression among urban omani adults with t2dm and a personal history of depression, which was found to be significantly associated with depression. therefore, early screening for depressive symptoms is necessary to improve the quality of life of diabetic patients in this region. keywords: depression; type 2 diabetes mellitus; prevalence; public health; primary healthcare; oman. advances in knowledge depression was found to be common among urban omani adults with type 2 diabetes mellitus. moreover, a personal history of depression was the only factor found to be significantly associated with depression in the studied cohort. application to patient care in light of these findings, early detection and intervention tools should be implemented in diabetic clinics in oman in order to help counteract the high prevalence of depression among diabetic individuals and improve their quality of life. https://creativecommons.org/licenses/by-nd/4.0/ depression in urban omani adults with type 2 diabetes a cross-sectional study 46 | squ medical journal, february 2022, volume 22, issue 1 major depression in people with diabetes was 11.4%, while the prevalence of clinically significant depressive symptoms was 31%.13 over the last few decades, the burden of diabetes has risen dramatically in oman (i.e., from 8.3% in 1991 to 11.6% in 2000).14 alarmingly, the number of individuals living with diabetes in oman is predicted to further increase by 174% from 128,769 in 2015 to 352,156 in 2050.15 depression among those with diabetes would most likely lead to poor adherence to medical treatment, thus further increasing the economic burden of this disease. a previous study showed the overall prevalence of depression to be 8.1% among urban omani adults attending primary healthcare clinics in muscat for various reasons; however, while the study highlighted the co-existence of depression with chronic physical illnesses, it failed to show a clear association due to the limited number of subjects with chronic diseases (p = 0.19).16 a meta-analysis revealed depression to be a significant comorbidity among a cohort of arab women with t2dm, including omanis.17 to the best of the authors’ knowledge, no studies have yet been conducted in oman to identify the prevalence of depression among omani diabetic patients. hence, this study aimed to determine the prevalence of depression among a population of omani adults with t2dm attending randomly selected governmental diabetic clinics in an urban region. additionally, this study aimed to identify associations between depression and sociodemographic and clinical variables in order to inform the development and implementation of early detection and intervention tools so as to improve the quality of life of this group. as the ministry of health in oman provides free treatment to all citizens, the care of diabetes-related complications represents an increasing financial burden. it is, therefore, imperative to conduct local studies for the benefit of policy-planners to further strengthen measures to tackle the rising impact of non-communicable diseases. methods this descriptive cross-sectional study was conducted from august 2018 to september 2019 at a random selection of 12 out of 30 governmental primary healthcare centres in the muscat governorate, oman. all patients with t2dm attending the diabetes clinics of these health centres during the aforementioned period were included. however, patients with major mental illnesses and those who were deaf and mute, currently taking antidepressants, pregnant or less than six months postpartum were excluded from the study. the necessary sample size was calculated to be 384 for a single proportion using nmaster software, version 2.0 (department of biostatistics, christian medical college, vellore, india), based on a documented depression prevalence rate of approximately 50% and at a confidence level of 95% and relative precision of 5%.18 however, in order to account for a presumed non-response rate of 10%, the desired sample size was set at 422. data were collected from the patients at the selected health centres during face-to-face interviews performed by several trained research assistants. a previously translated arabic version of the patient health questionnaire (phq)-9 was used to assess the prevalence of depression.19 the original phq-9 is a valid and reliable tool for depression screening which focuses on nine specific symptoms and signs of depression based on criteria proposed by the fifth edition of the diagnostic and statistical manual of mental disorders, including loss of interest/ pleasure, low mood/hopelessness, sleeping difficulty, loss of energy, changes in appetite, feelings of guilt/ worthlessness, difficulty concentrating, feelings of being slow/restless and suicidal ideation.20 in-line with previous research, a cut-off score of ≥10 was considered to indicate the presence of a depressive disorder.21 the information provided by the patients during the face-face interviews was subsequently verified with their medical records and medication lists using the standard electronic healthcare software used in oman. data were analysed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). as appropriate, chisquared or fisher’s exact tests were used to compare differences in proportion between groups. a univariate analysis was performed to determine associations between depression and various sociodemographic and clinical variables. all statistical tests were twosided. a p value of <0.05 was considered statistically significant. ethical approval for this study was obtained from the regional research committee of the directorate general of planning and studies at the ministry of health in muscat (mh-dgsp-14/2018). the purpose of the study was explained beforehand to the patients, all of whom provided written informed consent prior to participation. results a total of 427 patients (response rate: 100%) with type 2 diabetes mellitus (t2dm) were included in the study. according to their total phq-9 scores, 111 sanaa h. alsumry, tharaya al ghelani and sanjay jaju clinical and basic research | 47 patients (26%) were found to have depression, while 316 (74%) were not depressed. among those who were depressed, 55 (49.5%) were male and 56 (50.4%) were female, whereas 152 (48.1%) were male and 164 (51.9%) were female in the non-depressed group [figure 1]. depression was most prevalent among those aged 30–40 years and least prevalent among those aged 51–60 years (36.2% versus 21.3%). however, the presence of a personal history of depression was the only variable significantly associated with depression (p <0.001). no significant associations were observed between other sociodemographic characteristics and depression, including gender (p = 0.79) or age (p = 0.056) [table 1]. in terms of clinical characteristics, the rate of depression was highest among patients who had had diabetes for more than 10 years (27.5%). however, the difference between the two groups was not statistically significant (p = 0.54). depression was also not significantly associated with diabetes control as measured by the glycated haemoglobin (hba1c) level (p = 0.06). similarly, no significant associations were noted between depression and other clinical factors, such as the presence of various diabetes-related complications, body mass index or mode of antihyperglycaemic treatment [table 2]. discussion depression can be reliably diagnosed and treated in primary care settings, with standard treatment consisting of basic psychological support combined with antidepressant medications or psychotherapy, such as cognitive behavioural therapy, interpersonal psychotherapy or problem-solving treatment.22 however, many primary care patients presenting with multiple disorders including depression often go undiagnosed; moreover, even if depression is recognised, treatment is usually prioritised for other diseases.23 results from the world health survey table 1: prevalence of depression according to demographic characteristics among urban omani adults with type 2 diabetes from muscat governorate, oman (n = 427) characteristic total n (%) p value depressed (n = 111) not depressed (n = 316) age in years 0.056 30–40 47 17 (36.2) 30 (63.8) 41–50 89 29 (32.6) 60 (67.4) 51–60 127 27 (21.3) 100 (78.7) >60 164 38 (23.2) 126 (76.8) gender 0.79 male 207 55 (26.6) 152 (73.4) female 220 56 (25.5) 164 (74.5) education level 0.92 illiterate 181 44 (24.3) 137 (75.7) primary 98 26 (26.5) 72 (73.5) secondary 93 26 (28.0) 67 (72.0) university and above 55 15 (27.3) 40 (72.7) marital status 0.64 single 19 9 (47.4) 10 (52.6) married 311 75 (24.1) 236 (75.9) divorced 23 9 (39.1) 14 (60.9) widowed 74 18 (24.3) 56 (75.7) presence of parental consanguinity 0.14 none 261 76 (29.1) 185 (70.9) first-degree 119 27 (22.7) 92 (77.3) second-degree 47 8 (17.0) 39 (83.0) employment status 0.72 employed fulltime 94 25 (26.6) 69 (73.4) employed part-time 27 10 (37.0) 17 (63.0) unemployed 9 3 (33.3) 6 (66.7) business owner 17 4 (23.5) 13 (76.5) housewife 173 40 (23.1) 133 (76.9) retired 107 29 (27.1) 78 (72.9) personal history of depression 0.00 yes 51 33 (64.7) 18 (35.3) no 376 78 (20.7) 298 (79.3) family history of depression 0.57 yes 39 17 (43.6) 22 (56.4) no 388 94 (24.2) 294 (75.8) family history of major disability or illness 0.05 yes 64 29 (45.3) 35 (54.7) no 363 82 (22.6) 281 (77.4) regular physical activity 0.098 yes 162 42 (25.9) 120 (74.1) no 265 69 (26.0) 196 (73.9) smoking status 0.11 smoker 35 13 (37.1) 22 (62.9) non-smoker 392 98 (25.0) 294 (75.0) figure 1: chart showing the prevalence and severity of depression according to gender among urban omani adults with type 2 diabetes from muscat governorate, oman (n = 427). depression in urban omani adults with type 2 diabetes a cross-sectional study 48 | squ medical journal, february 2022, volume 22, issue 1 confirmed that depression had a stronger negative influence on health status compared to other chronic diseases; as such, the timely diagnosis and treatment of depressive disorders is imperative.24 the current study found the rate of depression to be 26% among adult omani patients with t2dm attending urban primary health centres. other studies conducted in the gulf cooperation council (gcc) region have reported similar findings. for instance, nasser et al. reported a comparable rate (33%) among primary care diabetic patients in bahrain.25 alzahrani et al. observed the rate of depression to be 33.8% among 450 patients with t2dm attending primary health centres in western saudi arabia, with similar findings reported in central saudi arabia (34.8%).26,27 alarmingly, the prevalence of depression in the present study was more than twice that noted among other urban omani adults attending primary health clinics (26% versus 8.1%).16 a meta-analysis also revealed an increased prevalence of depression among diabetic patients compared to the general population (31% versus 11%).13 however, much higher prevalence rates of depression have been reported among other diabetic populations in gcc countries. for instance, in eastern saudi arabia, the prevalence of depression among individuals with t2dm was 49.6%, with depression significantly associated with gender, marital status and diabetes-related complications.18 in addition, a study conducted in southern saudi arabia reported 37.6% of those with t2dm to be depressed, a finding which was also significantly associated with complications.28 in contrast, in the united arab emirates (uae), sulaiman et al. found the prevalence of depression or anxiety to be only 12.5% among t2dm patients attending diabetes clinics at primary care centres or hospitals in sharjah; however, this study utilised the kessler psychological distress scale rather than the phq-9 tool to assess mental health status.29 the differing prevalence rates of depression could be explained by variations in study methods and sample characteristics. in the current study, various sociodemographic factors—including age, gender, educational level, marital status, monthly income and a family history of major illness—were not found to have a significant influence on the rate of depression. albasheer et al. reported similar findings in saudi arabia.28 no significant associations between depression and clinical variables such as diabetes duration were observed in the present study. this is consistent with results reported by studies from eastern and southern saudi arabia.19,28 this could be attributed to cultural, religious and ethnic differences. the current study also showed no significant associations with diabetes control (as represented by hba1c values) or with diabetic microand macro-vascular complications. similar findings were noted by albasheer et al. in southern saudi arabia.28 in contrast, sulaiman et al. found the presence of ocular, vascular and neurological diabetes-related complications such as diabetic retinopathy, glaucoma and diabetic foot disease to be significantly associated with psychological symptoms of depression and anxiety among t2dm patients in the uae.29 comparable findings were also reported table 2: prevalence of depression according to clinical characteristics among urban omani adults with type 2 diabetes (n = 427) characteristic total n (%) p value depressed (n = 111) not depressed (n = 316) duration of dm in years 0.54 <1 31 6 (19.4) 25 (80.6) 1–5 134 35 (26.1) 99 (73.9) 6–10 102 26 (25.5) 76 (74.5) >10 160 44 (27.5) 116 (72.5) hba1c in % 0.06 ≤7 182 43 (23.6) 139 (76.4) 7.1–8.9 149 34 (22.8) 115 (77.2) ≥9 96 34 (35.4) 62 (64.6) body mass index in kg/m2 0.35 ≤25 99 25 (25.3) 74 (74.7) 26–29 136 30 (22.1) 106 (77.9) ≥30 192 56 (29.2) 136 (70.8) mode of dm treatment 0.24 oral 314 76 (24.2) 238 (75.8) injection 39 10 (25.6) 29 (74.4) oral plus injection 74 25 (33.8) 49 (66.2) complications* diabetic foot 14 4 (28.6) 10 (71.4) 0.81 cardiac or vascular 61 17 (27.9) 44 (72.1) 0.72 renal impairment 73 21 (28.8) 52 (71.2) 0.61 neuropathy 22 7 (31.8) 15 (68.2) 0.52 retinopathy 105 28 (26.7) 77 (73.3) 0.86 dm = diabetes mellitus; hba1c = glycated haemoglobin. *some participants had no complications while others had more than one complication. sanaa h. alsumry, tharaya al ghelani and sanjay jaju clinical and basic research | 49 by other researchers.28 this could be explained by the difference in study settings, as primary care centres usually ensure continuity of care and provide specialised diabetes-related services. this level of medical support could help patients adapt more easily to disease complications, thereby potentially lessening the likelihood of depression. overall, the presence of a personal history of depression was the only variable significantly associated with depression in the current study. this could point to an effect of inherited genes on the development of depression. however, no significant associations were noted for other potential genetic factors, such as the presence or absence of consanguinity or a family history of depression. as such, further research is required to confirm these findings. in the meantime, early pointof-care screening is recommended to evaluate the occurrence of depressive symptoms among diabetic individuals in oman in order to improve the quality of life of this patient group. in terms of limitations, the present study was conducted in a single governorate of oman, thereby hindering generalisation of the results. further studies involving additional patients attending primary health clinics in other parts of the country are necessary. moreover, the phq-9 questionnaire used in the study was not the latest version of this tool; nevertheless, this version was used in order to compare findings with previous studies available in the existing literature. additionally, as a multivariate regression analysis was not conducted, the study could only identify associations between variables and potential confounders could not be ruled out. in addition, while the information provided by the patients during the face-to-face interviews was corroborated with their medical records, it is possible that the findings were subject to self-reporting bias. finally, all of the subjects consisted of diagnosed t2dm cases with health issues of sufficient severity to involve seeking treatment at a clinic. additional studies may be necessary to determine whether depression is similarly high among undiagnosed diabetics in the general population or among those with less severe or overt symptoms. despite these limitations, this study is the first in the country to identify the prevalence of depression among omani diabetic patients. this information would be of use in the development and implementation of early detection and intervention tools to help counteract the high prevalence of depression in this group. conclusion in primary care settings, depression among patients with type 2 diabetes mellitus (t2dm) often goes unnoticed and, therefore, untreated. this study revealed a fairly high prevalence of depression among a cohort of urban omani adults with t2dm, with a personal history of depression found to be the only variable significantly associated with depression in this group. accordingly, early screening for depressive symptoms is highly recommended in order to improve the quality of life of these patients. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the deanship of research at sultan qaboos university (budget id: ih25051905). a c k n o w l e d g e m e n t s the authors extend their sincere gratitude to the patients who participated in this study as well as the research assistants for their help in conducting the interviews and collecting data. a u t h o r s’ c o n t r i b u t i o n shs performed the literature review. shs and tg collected the data. sj analysed the results. shs drafted the manuscript. all authors approved the final version of the manuscript. references 1. world health organization. depression: a global public health concern. from: www.who.int/mental_health/management/depr ession/who_paper_depression_wfmh_2012.pdf accessed: aug 2020. 2. global burden of disease collaborators. global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017. lancet 2018; 392:1789–858. https://doi. org/10.1016/s0140-6736(18)32279-7. 3. world health organization. global report on diabetes. from: h t t p s : / / a p p s . w h o . i n t / i r i s / b i t s t r e a m / h a n d l e / 1 0 6 6 5 / 2 0 4871/9789241565257_eng.pdf accessed: oct 2020. 4. seuring t, archangelidi o, suhrcke m. the economic costs of type 2 diabetes: a global systematic review. pharmacoeconomics 2015; 33:811–31. https://doi.org/10.1007/s40273-015-0268-9. 5. nouwen a, winkley k, twisk j, lloyd ce, peyrot m, ismail k, et al. type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. diabetologia 2010; 53:2480–6. https://doi.org/10.1007/s00125-010-1874-x. 6. al-shookri a, khor gl, chan ym, loke sc, al-maskari m. effectiveness of medical nutrition treatment delivered by dietitians on glycaemic outcomes and lipid profiles of arab, omani patients with type 2 diabetes. diabet med 2012; 29:236–44. https://doi.org/10.1111/j.1464-5491.2011.03405.x. 7. lustman pj, anderson rj, freedland ke, de groot m, carney rm, clouse re. depression and poor glycemic control: a meta-analytic review of the literature. diabetes care 2000; 23:934–42. https://doi.org/10.2337/diacare.23.7.934. https://doi.org/10.1016/s0140-6736(18)32279-7 https://doi.org/10.1016/s0140-6736(18)32279-7 https://doi.org/10.1007/s40273-015-0268-9 https://doi.org/10.1007/s00125-010-1874-x https://doi.org/10.1111/j.1464-5491.2011.03405.x https://doi.org/10.2337/diacare.23.7.934 depression in urban omani adults with type 2 diabetes a cross-sectional study 50 | squ medical journal, february 2022, volume 22, issue 1 8. de groot m, anderson r, freedland ke, clouse re, lustman pj. association of depression and diabetes complications: a meta-analysis. psychosom med 2001; 63:619–30. https://doi. org/10.1097/00006842-200107000-00015. 9. egede le, zheng d, simpson k. comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. diabetes care 2002; 25:464–70. https://doi.org/10.2337/diacare.25.3.464. 10. zhang x, norris sl, gregg ew, cheng yj, beckles g, kahn hs. depressive symptoms and mortality among persons with and without diabetes. am j epidemiol 2005; 161:652–60. https:// doi.org/10.1093/aje/kwi089. 11. egede le. diabetes, major depression, and functional disability among u.s. adults. diabetes care 2004; 27:421–8. https://doi. org/10.2337/diacare.27.2.421. 12. ciechanowski ps, katon wj, russo je. depression and diabetes: impact of depressive symptoms on adherence, function, and costs. arch intern med 2000; 160:3278–85. https://doi. org/10.1001/archinte.160.21.3278. 13. anderson rj, freedland ke, clouse re, lustman pj. the prevalence of comorbid depression in adults with diabetes: a meta-analysis. diabetes care 2001; 24:1069–78. https://doi. org/10.2337/diacare.24.6.1069. 14. al-shookri a, khor gl, chan ym, loke sc, al-maskari m. type 2 diabetes in the sultanate of oman. malays j nutr 2011; 17:129–41. 15. al-lawati ja, panduranga p, al-shaikh ha, morsi m, mohsin n, khandekar rb, et al. epidemiology of diabetes mellitus in oman: results from two decades of research. sultan qaboos univ med j 2015; 15:e226–33. 16. al-salmani a, juma t, al-noobi a, al-farsi y, jaafar n, almamari k, et al. characterization of depression among patients at urban primary healthcare centers in oman. int j psychiatry med 2015; 49:1–18. https://doi.org/10.2190/pm.49.1.a. 17. hawamdeh s, dator wl, abunab hy. prevalence of depression among arab women with type 2 diabetes: a systematic review and meta-analysis. health 2016; 8:650–7. https://doi.org/10.42 36/health.2016.87068. 18. el mahalli aa. prevalence and predictors of depression among type 2 diabetes mellitus outpatients in eastern province, saudi arabia. int j health sci (qassim) 2015; 9:121–7. https://doi. org/10.12816/0024105. 19. multicultural mental health resources centre. phq-9 arabic for israel. from: www.multiculturalmentalhealth.ca/wp-conten t/uploads/2013/11/phq9_arabic-for-israel.pdf accessed: oct 2020. 20. kroenke k, spitzer rl, williams jb. the phq-9: validity of a brief depression severity measure. j gen intern med 2001; 16:606–13. https://doi.org/10.1046/j.1525-1497.2001.016009606.x. 21. hermanns n, kulzer b, krichbaum m, kubiak t, haak t. how to screen for depression and emotional problems in patients with diabetes: comparison of screening characteristics of depression questionnaires, measurement of diabetes-specific emotional problems and standard clinical assessment. diabet ologia 2006; 49:469–77. https://doi.org/10.1007/s00125-005-0094-2. 22. world health organization, world organization of national colleges, academies and academic associations of general practitioners/family physicians. integrating mental health into primary care: a global perspective. from: www.who. int/mental_health/resources/mentalhealth_phc_2008.pdf accessed: apr 2020. 23. cassano p, fava m. depression and public health: an overview. j psychosom res 2002; 53:849–57. https://doi.org/10.1016/ s0022-3999(02)00304-5. 24. moussavi s, chatterji s, verdes e, tandon a, patel v, ustun b. depression, chronic diseases, and decrements in health: results from the world health surveys. lancet 2007; 370:851–8. https://doi.org/10.1016/s0140-6736(07)61415-9. 25. nasser j, habib f, hasan m, khalil n. prevalence of depression among people with diabetes attending diabetes clinics at primary health settings. bahrain med bull 2009; 31. 26. alzahrani a, alghamdi a, alqarni t, alshareef r, alzahrani a. prevalence and predictors of depression, anxiety, and stress symptoms among patients with type ii diabetes attending primary healthcare centers in the western region of saudi arabia: a cross-sectional study. int j ment health syst 2019; 13:48. https://doi.org/10.1186/s13033-019-0307-6. 27. al-mohaimeed aa. prevalence and factors associated with anxiety and depression among type 2 diabetes in qassim: a descriptive cross-sectional study. j taibah univ med sci 2017; 12:430–6. https://doi.org/10.1016/j.jtumed.2017.04.002. 28. albasheer ob, mahfouz ms, solan y, khan da, muqri ma, almutairi ha, et al. depression and related risk factors among patients with type 2 diabetes mellitus, jazan area, ksa: a crosssectional study. diabetes metab syndr 2018; 12:117–21. https:// doi.org/10.1016/j.dsx.2017.09.014. 29. sulaiman n, hamdan a, tamim h, mahmood da, young d. the prevalence and correlates of depression and anxiety in a sample of diabetic patients in sharjah, united arab emirates. bmc fam pract 2010; 11:80. https://doi.org/10.1186/1471-2296-11-80. https://doi.org/10.1097/00006842-200107000-00015 https://doi.org/10.1097/00006842-200107000-00015 https://doi.org/10.2337/diacare.25.3.464 https://doi.org/10.1093/aje/kwi089 https://doi.org/10.1093/aje/kwi089 https://doi.org/10.2337/diacare.27.2.421 https://doi.org/10.2337/diacare.27.2.421 https://doi.org/10.1001/archinte.160.21.3278 https://doi.org/10.1001/archinte.160.21.3278 https://doi.org/10.2337/diacare.24.6.1069 https://doi.org/10.2337/diacare.24.6.1069 https://doi.org/10.2190/pm.49.1.a https://doi.org/10.4236/health.2016.87068 https://doi.org/10.4236/health.2016.87068 https://doi.org/10.12816/0024105 https://doi.org/10.12816/0024105 https://doi.org/10.1046/j.1525-1497.2001.016009606.x https://doi.org/10.1007/s00125-005-0094-2 https://doi.org/10.1016/s0022-3999(02)00304-5 https://doi.org/10.1016/s0022-3999(02)00304-5 https://doi.org/10.1016/s0140-6736(07)61415-9 https://doi.org/10.1186/s13033-019-0307-6 https://doi.org/10.1016/j.jtumed.2017.04.002 https://doi.org/10.1016/j.dsx.2017.09.014 https://doi.org/10.1016/j.dsx.2017.09.014 https://doi.org/10.1186/1471-2296-11-80 1department of cardiovascular surgery, tehran university of medical sciences, tehran, iran; 2department of cardiovascular surgery, shahrekord university of medical sciences, shahrekord, iran *corresponding author’s e-mail: behshakerian@yahoo.com رتج األذين األمين يف امرأة ابلغة مع إحصار احلزمية اليسرى بهنام �ساكريان وحممد ح�سني مانديغار abstract: right atrial diverticulum is a very rare anomaly. it is an outpouching arising from the right atrial free wall. clinical presentations vary widely but some cases are associated with supraventricular tachycardia and atrial flutter/fibrillation. the incidence/prevalence of this anomaly is not available because only a few cases have been reported. we report a 38-year-old female patient who presented to the heart clinic, tehran, iran in 2019 with a history of dyspnea and chest pain. electrocardiography revealed left bundle branch block. following a magnetic resonance imaging study, the patient was diagnosed with a right atrial diverticulum. she underwent surgical resection of the diverticulum. the post-operative course was uneventful and no recurrence of the arrhythmia was detected during the six months of follow-up. to the best of the authors’ knowledge, this combination has not been described in the literature. keywords: right atrium; diverticulum; left bundle branch block; case report; iran. يُّب َخاِرِجي ين�ساأ من اجلدار احلر للأُذين الأمين. تتفاوت الأعرا�ض ال�رسيرية تفاوتا كبريا امللخ�ص: رجت الأُذين الأمين هو �سذوذ نادر جًدا. هو َتَ ولكن ترتبط بع�ض احلالت بت�سارع القلب فوق البطيني والرفرفة الأذينية/الرجفان الأذيني. معدل حدوث/انت�سار هذا ال�سذوذ غري معروف لأنه ل يتم الإبلغ ال عن حالت قليلة فقط. نعر�ض هنا حالة مري�سة تبلغ من العمر 38 عاًما َقِدَمت اإىل عيادة القلب، طهران، اإيران يف عام 2019 ولديها تاريخ من �سيق التنف�ض واأمل يف ال�سدر. ك�سف تخطيط كهربية القلب عن اإِْح�سار احُلَزمَية الُي�رسى. مت ت�سخي�ض املري�سة برجت اأذيني اأمين بعد درا�سة الت�سوير بالرنني املغناطي�سي. خ�سعت لعملية ا�ستئ�سال جراحي للرجت وكانت مرحلة ما بعد اجلراحة خالية من امل�ساعفات ومل يتم الك�سف عن اأي تكرار ل�سطراب �رسبات القلب خلل الأ�سهر ال�ستة من املتابعة. على حد علم املوؤلفني مل يتم و�سف هذه التوليفة يف الأدبيات. الكلمات املفتاحية: اأذين اأمين؛ رجت؛ اإح�سار احلزمية الي�رسى؛ تقرير حالة؛ اإيران. right atrial diverticulum in an adult woman with left bundle branch block *behnam shakerian1,2 and mohammad h. mandegar1 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e394–396, epub. 21 dec 20 submitted 15 apr 20 revision req. 11 may 20; revision recd. 8 jun 20 accepted 24 jun 20 months before presenting to the hospital. she had no significant history or family history. cardiovascular system examination did not reveal any murmurs. electrocardiography (ecg) showed sinus rhythm with lbbb [figure 1]. all laboratory tests were within normal limits. transthoracic echocardiography showed an echolucent space around the ra approximately 2 × 3 cm in size that was connected to the ra [figure 2]. contrast echocardiography was suggestive of an ra diverticulum. the tricuspid valve was normal without significant annular dilation. no stenosis or abnormal displacement of the tricuspid valve leaflets was detected and no significant regurgitation of the tricuspid valve was found. no other cardiac anomalies were found. the left ventricle ejection fraction was 55%. cardiac magnetic resonance imaging (mri) showed a 25.2 × 16.5 × 35 mm pouch in the inferior wall of the ra [figure 3]. the pericardium was visualised without any abnormality. the diverticulum caused no haemodynamic effects. the patient was evaluated by a cardiac team and single right atrial (ra) diverticulum, a rare congenital anomaly, is a saccular structure that protrudes from an otherwise normal ra.1 most of the diverticula originate from the atrial free wall. the aetiology of this anomaly is not yet clearly understood. the size of the diverticulum is variable. this case report describes a patient with a rare atrial diverticulum and left bundle branch block (lbbb) who underwent surgery successfully. the presence of (lbbb) has not been reported in the english literature to date. case report a 38-year-old female patient presented to the heart clinic, tehran, iran in 2019 with a history of palpitation, dyspnoea on exertion and recurrent chest pain accompanied by three episodes of syncope that occurred two years prior to presentation. she received imipramine for depression but the symptoms did not improve. therefore, she discontinued it six this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.019 case report https://creativecommons.org/licenses/by-nd/4.0/ behnam shakerian and mohammad h. mandegar case report | e395 due to arrhythmias (lbbb), high risk of thrombus formation and the risk of progression, the patient was scheduled for surgery. through a median sternotomy, cardiopulmonary bypass was established with aortic and bicaval cannulation. the diverticulum was visible, arising from the free wall of the ra, discrete from the caval veins, coronary sinus and tricuspid valve. intraoperative findings were consistent with the features of a diverticulum [figures 4a & b]. there was no thrombus in the diverticulum. resection of the diverticulum was done and cryoablation of the diverticulum neck was performed successfully. the ra was reconstructed by direct sutures. histologic examination revealed a thin wall with areas of fibrosis covered by cuboidal cells without muscular tissue suggestive of an atrial diverticulum [figure 4c]. the postoperative course was uneventful and sinus rhythm was maintained. she was discharged on the sixth postoperative day. after discharge, she remained asymptomatic with no arrhythmias. the patient was still asymptomatic six months after the operation. discussion ra diverticulum is a very rare congenital anomaly with an unclear aetiology. bailey described the excision of a right atrial diverticulum for the first time in 1953.2 ra diverticulum is a structure that protrudes from the ra free wall but does not include all layers of the atrial wall.3 a diverticulum can be detected at any time between fetal and adult life and the size varies with the largest being reported at 13 × 8.9 × 13.8 cm.4 this anomaly is usually asymptomatic, but it can be associated with atrial arrhythmia, chest pain, peripheral oedema, shortness of breath, fatigue and jugular engorgement. the incidence of arrhythmia and the clinical outcome of the patients have not been reported to date. arrhythmia may be caused by abnormal impulses generated within the diverticular wall. supraventricular arrhythmia has been reported in patients, which is associated with a high risk of morbidity and mortality due to cardiac dysfunction and increased risk of stroke and heart failure.5,6 the current patient did not have any supraventricular arrhythmias but she did have lbbb on ecg. while antidepressant agents can cause cardiac arrhythmias, this was not considered for the current patient as she had stopped taking imipramine six months before presenting to the hospital. lbbb is usually associated with coronary artery disease, hypertension and cardiomyopathy. lbbb is usually pathological and is rare in young individuals.7 in case of cardiac arrhythmia, structural anomalies of the atrium should be suspected. lbbb can progress to complete heart block. the reason for arrhythmia was not clear in the patient but the authors believe that it was caused by structural disorientation of the conduction system, which may allow ample electrical communication figure 1: electrocardiogram of a 38-year-old female patient showing left bundle branch block. figure 3: cardiac magnetic resonance image of a 38-year-old female patient showing the finding of a right atrial diverticulum (white arrow). figure 2: echocardiography of a 38-year-old female patient showing a right atrial diverticulum. right atrial diverticulum in an adult woman with left bundle branch block e396 | squ medical journal, november 2020, volume 20, issue 4 between the atrium and ventricle without a welldefined accessory pathway. this is supported by the fact that a normal sinus rhythm resumed when the diverticulum was removed. the slow flow in the diverticulum is likely to predispose a patient to clot formation and pulmonary embolisation. the incidence of sudden death is approximately 6%.8 a right atrial diverticulum is usually diagnosed by echocardiography but computed tomography and mri imaging are also used. differential diagnosis includes ebstein’s anomaly, aneurysms, pericardial cysts and mediastinal tumours. although the optimal treatment of this rare anomaly is not clear, surgical excision is the therapy of choice and indicated in arrhythmia, thromboembolism, progressive ra dilatation and compressive symptoms; therapeutic outcomes are good. other options include resection of the diverticulum with an endoscopic linear cutter through a limited right thoracotomy, but this device is not available in the authors’ centre. transcatheter ablation through the whole diverticulum is crucial for the successful treatment of arrhythmia. due to a wide connection between the ra diverticulum and right ventricle, transcatheter ablation may not be complete, which may result in recurrence. conclusion a combination of ra diverticulum and lbbb has not been reported in the literature to date as was presented in the current case. surgical excision of the diverticulum removes the substrate and cures the conduction abnormality. patients do not usually experience the recurrence of conduction abnormality after excision of the diverticulum. references 1. borgohain s, malik l, prasad s, gupta a, grover v, gupta vk. case of single right atrial diverticulum and review of etiology and management. asian cardiovasc thorac ann 2013; 21:592–5. https://doi.org/10.1177/0218492312458787. 2. bailey cp. surgery of the heart. philadelphia, pa, usa: lea & febiger, 1955. pp. 413. 3. chockalingam a, alagesan r, gnanavelu g, dorairajan s, subrananiam t. right atrial aneurysm in adults--report of three cases and review of literature. echocardiography 2004; 21:639–43. https://doi.org/10.1111/j.0742-2822.2004.03156.x. 4. yuan g, yan bp, hu j, wang s, sun jp. compressive giant right atrial diverticulum. eur heart j cardiovasc imaging 2016; 17:1065. https://doi.org/10.1093/ehjci/jew113. 5. hagens ve, ranchor av, van sonderen e, bosker ha, kamp o, tijssen jg, et al. effect of rate or rhythm control on quality of life in persistent atrial fibrillation. results from the rate control versus electrical cardioversion (race) study. j am coll cardiol 2004; 43:241–7. https://doi.org/10.1016/j. jacc.2003.08.037. 6. van gelder ic, hagens ve, bosker ha, kingma jh, kamp o, kingma t, et al. a comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. n engl j med 2002; 347:1834–40. https://doi.org/10.1056/ nejmoa021375. 7. sinha a, shelter ub, pinchani m, sayyed aa, sintia nk. the enigma of intermittent left bundle branch block: a case report. pravara med rev 2013; 5:32–4. 8. binder tm, rosenhek r, frank h, gwechenberger m, maurer g, baumgartner h. congenital malformations of the right atrium and the coronary sinus: an analysis based on 103 cases reported in the literature and two additional cases. chest 2000; 117:1740–8. https://doi.org/10.1378/chest.117.6.1740. figure 4: a & b: intraoperative view of the heart of a 38-year-old female patient showing a right atrial (ra) diverticulum (white arrow). c: haematoxylin and eosin stain at x100 magnification of the ra diverticulum showing a thin wall with areas of fibrosis covered by cuboidal cells without muscular tissue. https://doi.org/10.1177/0218492312458787 https://doi.org/10.1111/j.0742-2822.2004.03156.x https://doi.org/10.1093/ehjci/jew113 https://doi.org/10.1016/j.jacc.2003.08.037 https://doi.org/10.1016/j.jacc.2003.08.037 https://doi.org/10.1056/nejmoa021375 https://doi.org/10.1056/nejmoa021375 https://doi.org/10.1378/chest.117.6.1740 submitted 25 dec 22 1 revisions req. 7 feb & 23 mar 23; revisions recd. 2 mar & 4 apr 23 2 accepted 11 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.031 5 6 direct and moderating effects of work environment and structural 7 empowerment on job stress and job satisfaction among nurses in the 8 sultanate of oman 9 raeda abualrub,1 *sulaiman d. al sabei,2 omar al-rawajfah,3,4 10 leodoro j. labrague,5 ikram a. burney6 11 12 1community and mental health nursing department, faculty of nursing, jordan university of 13 science and technology, irbid, jordan; 2fundamentals and administration department, college 14 of nursing, sultan qaboos university, muscat, oman; 3adult and critical care department, 15 college of nursing, sultan qaboos university, muscat, oman; 4college of nursing, al al-bayt 16 university, jordan; 5health systems & adult health nursing department, loyola university 17 chicago, usa; 6sultan qaboos comprehensive cancer center, muscat, oman. 18 *corresponding author’s e-mail: alsabei@squ.edu.om 19 20 abstract 21 objective: this paper seeks to explore the relationships between nurses’ work environment, job 22 stress, and job satisfaction, as well as the moderating effects of work environment and 23 empowerment on the job stress–job satisfaction relationship. methods: a descriptive 24 correlational design was utilized. the study encompassed a convenience sample of 1,796 25 hospital nurses from the 11 governorates in oman. a self-report questionnaire that included a set 26 of instruments was used to collect data. results: the results showed that nurses who perceived 27 higher levels of job stress reported lower levels of satisfaction and empowerment, and perceived 28 their work environment as less favorable and supportive. the findings only confirmed the direct 29 effects of work environment and empowerment on satisfaction; there was no support for indirect 30 or moderating effects. the hierarchical regression model showed that 46.5% of the variation in 31 the level of job satisfaction was explained by the study variables. conclusion: the results of this 32 study demonstrate the importance of implementing strategies that empower staff, provide a 33 supportive and positive work environment, and tackle job stress to enhance levels of job 34 satisfaction. 35 keywords: work environment; empowerment; job stress; job satisfaction; nurses; oman. 36 37 advances in knowledge: 38 • the findings of the study supported the negative correlations between job stress and job 39 satisfaction, job stress and work environment, and job stress and empowerment. 40 • the findings support the positive direct effects of work environment as well as 41 empowerment on job stress and job satisfaction; while the indirect or moderating effects 42 of work environment and empowerment on job stress-job satisfaction relationship were 43 not supported among nurses working in oman. 44 • background variables, job stress, work environment, and empowerment explained 46.5% 45 of the variation in the level of job satisfaction among nurses working in oman. 46 • the results support the existing evidence on the importance of adopting and 47 implementing strategies that tackle job stress and promote a supportive work 48 environment as well. 49 50 application to patient care: 51 • auditing healthcare services, implementing programs to lean process of tests and 52 procedures execution, and investing in subacute health services and home-based care 53 programs are essential steps to improve early discharges and minimize inappropriate 54 hospital stay. 55 • identifying modifiable factors that can enhance satisfaction among nurses working in 56 oman can help improve the quality of care provided to patients as well. 57 58 59 60 61 introduction 62 working in healthcare is stressful and can be physically and emotionally demanding.1 the work 63 environment can either support or hinder workers’ health and performance. therefore, promoting 64 a healthy work environment has become a focus of healthcare organizations worldwide. 65 66 research evidence has shown a strong association between supportive work environment and 67 nurse outcomes: including enhanced quality of patient care, lower levels of job stress, fewer 68 adverse events, higher levels of job satisfaction, reduced levels of intention to leave, and higher 69 levels of willingness to engage in leadership roles.2–7 70 71 in contrast, unhealthy work environments can lead to negative staff outcomes, such as higher levels 72 of job stress and lower levels of job satisfaction. evidence has shown that unhealthy work 73 environments lead to decreased productivity, increased turnover rates, and increased healthcare 74 costs by billions of dollars annually.8 working in unhealthy work environment can negatively 75 impact patient safety and quality outcomes.6 exploring the work environment and its underpinning 76 variables is therefore paramount in healthcare institutions. 77 78 one such variable is the concept of empowerment, which is well researched among nurses. the 79 structural empowerment model 9 based on kanter’s theory10 stands out among the various 80 models in the nursing context. according to kanter,10 the characteristics of the work 81 environment determine work behaviors and attitudes, regardless of personal characteristics. 82 thus, when the workplace is characterized by a supportive work environment that provides the 83 "necessary power" to meet job demands, nurses feel empowered. mounting evidence has 84 demonstrated a strong positive relationship between structural empowerment and job 85 satisfaction.11,12 a meta-analysis of 59 studies showed that higher levels of job satisfaction 86 among hospital nurses are associated with a positive work environment, an increased level of 87 structural empowerment, and a decreased level of job stress.13 88 89 nursing is regarded as a stressful profession.14 psychological risks at work, such as job stress, 90 conflicts, and excessive workloads, have become one of the challenges of the 21st century due to 91 their negative impact on staff and organizational outcomes.15 job stress and strain have been 92 associated with the physical and mental health and well-being of employees.1 increased levels of 93 job stressors are significantly correlated with burnout and decreased levels of empowerment.16 94 95 exploring job satisfaction and its associated variables has been of great interest to nurse 96 researchers around the globe. to date, several variables that have mediating or moderating 97 effects on job satisfaction have been identified by researchers.13 despite the abundance of 98 research on job stress and satisfaction, there has been a relative lack of studies that focus on the 99 association between empowerment and job stress and their impact on job satisfaction among 100 nurses. to the author’s knowledge, no study worldwide has investigated specifically the 101 moderating effects of work environment and empowerment on the job stress–job satisfaction 102 relationship. however, studies in western countries have investigated these concepts with 103 different aims. evidence of the impact of the nurse work environment on nurses’ outcomes in the 104 sultanate of oman is scant. thus, this study was conducted to explore the direct and moderating 105 effects of work environment and structured empowerment on job stress and job satisfaction 106 among nurses in the sultanate of oman. 107 108 methods 109 study design 110 a descriptive correlational design was used to answer research objectives. 111 112 setting and sampling procedure 113 a convenience sampling method was used to recruit nurses who had at least one year of 114 experience and at least a diploma degree. the required participants were recruited conveniently 115 from a proportional stratified clustered sample of hospitals from the 11 governorates of oman. 116 hospitals were stratified based on two dimensions: type (private vs. public hospitals) and 117 location (based on the 11 governorates in the country). public hospitals included both those 118 under the ministry of health and those not under the ministry of health. the population of 119 governorates in the sultanate is geographically diverse. for that reason, some governorates have 120 only one public hospital. for governorates that have more than one public and/or more than one 121 private hospitals, hospitals were selected using convenience approach. for example, in muscat, 122 where there are several public and private hospitals, hospitals were selected based on their 123 convenient accessibility. 124 125 population and sample size 126 the sample size in the present study was 1,796 registered nurses. the sample size was based on 127 the calculated total accessible population size of nurses working in oman which was 11,096 at 128 the time of the survey.17according to yamane’s standardized formula for calculating sample size 129 from the defined population,18 the estimated sample size was 386 nurses. however, 130 given that the sample was drawn from 11 governorates in the sultanate, applying these 131 calculations will mostly result in unrepresentative sample. therefore, the researchers decided to 132 sample at least 10% of the accessible population to produce representative results. a total of 133 2000 nurses were recruited from across the 11 governorates. the use of this method is supported 134 in the literature.6,19 135 136 data collection procedure and ethical considerations 137 approvals from the institutional review boards of the affiliated university, the ministry of health, 138 and the targeted private hospitals were granted before the study commenced. the purpose and 139 significance of the study were explained to the nurse administrators and participants. nurses 140 were invited to participate by research assistants during different shifts. participants were 141 provided with a package that contained information about the purpose and significance of the 142 study, as well the study instruments [the nursing work index (pes–nwi), the conditions of 143 work effectiveness questionnaire–ii (cwq–ii), one question to assess job satisfaction: “how 144 satisfied are you with your current job?”, and the perceived stress scale], and a return envelope. 145 the english version of all instruments was used as there were expatriate nurses among the 146 sample. participants were asked to drop the completed surveys in a locked box in their manager’s 147 office. participants were assured that their responses would remain confidential and would be 148 reported in aggregate form. 149 150 instruments 151 nursing practice environment was measured using the 31-item practice environment scale of the 152 nursing work index (pes–nwi).20 the pes–nwi consists of 31 items and 5 subscales: nurse 153 participation in hospital affairs; nursing foundation for quality care; nurse manager ability, 154 leadership, and support of nurses; staffing and resource adequacy; and collegial nurse–physician 155 relations. items are rated on a four-point likert scale ranging from 1 (strongly disagree) to 4 for 156 (strongly agree). a score below an average of 2.5 for the scale or its subscales represents 157 disagreement, while a score of an average higher than 2.5 represents agreement that the scale or 158 the subscale items are present in the current practice environment. the scale was reported to be 159 reliable and valid in previous studies.6,20 in the present study, the alpha coefficient was 0.94. 160 161 structural empowerment was evaluated using the conditions of work effectiveness 162 questionnaire–ii (cwq–ii).21 the cwq–ii is a 12-item likert scale ranging from 1 for none to 163 5 for a lot. it measures four dimensions of empowerment: information, access to opportunity, 164 support, and resources. the reliability and validity of the scale have been well established 165 (cronbach’s alpha = 0.82 for the composite score).21 166 167 job satisfaction was assessed using a single question: “how satisfied are you with your current 168 job?”. responses range from 1 for very dissatisfied to 4 for very satisfied. this measure has been 169 widely used in international health services studies.22,23 it has also been selected over other 170 measures of job satisfaction to overcome the overlap with the satisfaction components of the 171 pes–nwi. 172 173 job stress was measured using the four-item perceived stress scale.24 respondents are asked to 174 indicate their agreement with each item on a 5-point likert scale from 0 for never to 4 for very 175 often. 176 177 a demographic form was used to collect information on participants’ age, gender, level of 178 education, nationality, years of work experience, marital status, place of work, and position. 179 180 data analysis 181 spss version 22 was used for analysis. descriptive statistics were utilized to analyze 182 participants’ characteristics. pearson's correlation coefficient was used to examine the 183 relationships between the study variables. hierarchical regression analysis was used to examine 184 the moderating effects of work environment and empowerment on the job stress–job satisfaction 185 relationship and the variance in job satisfaction explained by the study variables. variables with 186 more than 10% missing data were excluded from the final analysis. a p value of 0.05 was set as 187 the cutoff for significance; however, the exact p values whether higher or lower than 0.05 were 188 reported for all statistical tests. 189 190 results 191 characteristics of the sample 192 a total of 1,796 registered nurses working in omani hospitals participated in the study. the 193 mean age of the participants was 34 years (sd = 6.9); with a range from 20 to 61 years. the 194 majority of them were females (n = 1,546; 87.2%), married (n = 1,388; 79.4%), and worked as 195 staff nurses (n = 912; 76.8%). more than 50% of the participants were expatriates (n = 1,030; 196 58.5%) who worked full-time (n = 1,560; 91.9%) in governmental (n = 1,750; 97.4%) and non-197 teaching hospitals (n = 983; 54.7%). the mean value for nurses’ experience in their current unit 198 was 7.3 years (sd = 5.1). around 42% of the participants had a bachelor’s degree (n = 731; 199 41.9%). more than a third of the participants (n = 253; 37.6%) worked day shifts in different 200 units, such as medical–surgical (n = 601; 35.2%) and critical care (n = 509; 29.9%). background 201 variables were analyzed and reported separately for omani and expatriate nurses. table 1 202 presents the data regarding participants’ background variables. 203 204 variables of the study 205 the results showed that the participants of the present study perceived a low level of job stress 206 (m = 1.7; sd = .59 on a scale from 0 to 4); and above a moderate level of job satisfaction (m = 207 2.9; sd = .76 on a scale from 1 to 4). the results also showed that participants perceived their 208 work environment as positive (m = 2.8; sd = .90 on a scale from1 to 4). all five subscales of the 209 work environment scale were perceived positively. the subscale that received the highest rating 210 was “foundations for quality care (m = 3, sd = 0.47). on the other hand, “staffing and 211 resources adequacy” was perceived as the lowest among the subscales (m = 2.7, sd = 0.62). 212 further, the participants perceived above moderate level of empowerment (m = 3.5; sd =.71 on 213 a scale from 1 to 5). the subscale “access to opportunity” was rated by participants as the 214 highest (m = 3.7, sd = .90), followed by “access to information” (m = 3.5, sd = .92) and 215 “access to support” (m = 3.5; sd = .92). “access to resources” was rated as the lowest (m = 216 3.2, sd =.86). table 2 presents data about means and standard deviations of the study variables. 217 218 further analysis showed that expatriate nurses perceived (1) lower levels of job stress in 219 comparison with their counterparts (expatriate nurses: m = 1.7; omani nurses: 1.9; p =.001); (2) 220 their work environment more positively than omani nurses (expatriate nurses: m=2.9; omani 221 nurses: 2.7; p = .001); (3) and higher levels of structural empowerment than omani nurses 222 (expatriate nurses: m = 3.6; omani nurses: 3.2; p = .001); and higher levels of job satisfaction 223 in comparison with their counterparts (omani nurses) (expatriate nurses: m = 3.1; omani 224 nurses: m = 2.6; p = .001). table 3 presents data about difference between omani and expatriate 225 nurses concerning study variables. 226 227 moreover, analysis was done to examine if the levels of job stress, work environment, 228 empowerment and job satisfaction vary according to the education degree of participants and the 229 type of hospital. the results showed that a significant difference was only found for the stress 230 level; wherein nurses who had diploma degree perceived higher levels of stress than nurses with 231 bachelor degree (t = 2.5, p = .01). for the type of hospital, the results showed that significant 232 differences were only found for the work environment and empowerment; wherein nurses who 233 worked in private hospitals perceived higher levels of empowerment (t= -3.4, p<.001) and 234 perceived their work environment more positive (t = -5.1, p < .001 than nurse who work in 235 governmental hospitals. 236 237 relationships between study variables 238 the results showed that there was a significant negative correlation between job stress and job 239 satisfaction (r = -.32, p < 0.001); that is, nurses who perceived having more job stress had lower 240 perceptions of job satisfaction. job stress was also negatively correlated with work environment 241 (r = -.19, p < 0.001) and empowerment (r = -.19, p < 0.001); that is, nurses with higher levels of 242 job stress perceived lower levels of empowerment and a less supportive work environment. 243 regarding the relationships between work environment, job satisfaction, and empowerment, the 244 results showed significant positive correlations between work environment and job satisfaction (r 245 = .31, p < 0.001), and between work environment and empowerment (r = .47, p < 0.001). that is, 246 nurses who perceived their work environment as supportive reported higher levels of job 247 satisfaction and empowerment. furthermore, empowerment was positively correlated with job 248 satisfaction (r = .18, p < 0.001). that is, nurses who felt more empowered were more satisfied at 249 work. table 4 presents data about correlations for work environment, empowerment, job stress, 250 and job satisfaction. 251 252 hierarchical regression analysis was utilized to investigate the moderating effects of work 253 environment and empowerment on the job stress–job satisfaction relationship. table 5 presents a 254 summary of the hierarchical regression analysis. in the first step, the demographic and work-255 related variables (age, experience in the current unit, nationality, gender, marital status, level of 256 education, work unit, type of hospital, work status, shift worked) were entered to control for their 257 effects on the dependent variable (job satisfaction). these variables explained 31% of the 258 variation (r2) in job satisfaction (cumulative r2 = 31%). 259 260 in the second step, job stress was entered in the regression model. it showed that job stress 261 explained an additional 13% of the variation in job satisfaction (r2 change = 13%, cumulative r2 262 = 44%, p < 0.01). this step showed that the relationship between job stress and job satisfaction 263 was negative (r = -.39, p < 0.001). 264 265 in the third step, work environment was added to the regression model. work environment 266 explained another 2% of the variation in job satisfaction (r2 change = 2%, cumulative r2 = 46%, 267 p < 0.01). this increase in r2 was statistically significant, which demonstrated that the 268 perception of a positive work environment enhanced the level of job satisfaction (r = 0.16, p < 269 0.001). 270 271 in the fourth step, the empowerment variable was added to the model. it showed only a 0.003 272 addition to the cumulative r2 (46.3%), which did not reach the level of significance. 273 274 in the fifth step, the product or multiplicative term of work environment and job stress was added 275 to the model to explore the moderating effect of work environment on the job stress–job 276 satisfaction relationship. this step showed only a 0.002 addition to the cumulative r2 (46.5%), 277 which was insignificant. this indicated that the interaction between job stress and work 278 environment had no moderating effect on the job stress–job satisfaction relationship. 279 280 in the sixth step, the product of empowerment and job stress was added to the model to explore the 281 moderating effect of empowerment on the job stress–job satisfaction relationship. this step showed 282 no addition to the cumulative r2 (46.5%). this indicated that the interaction between job stress and 283 empowerment had no moderating effect on the job stress–job satisfaction relationship. 284 285 discussion 286 the findings of the study indicated that participants of the study reported a low level of stress. 287 however, omani nurses reported higher levels of job stress in comparison to their counterparts 288 (expatriate nurses). this might be related to the fact that expatriate nurses are older and had more 289 years of experience than omani nurses. this is an indication that omani nurses are more junior, 290 with less experience at work, which might have implication on their management of stressful 291 situations. 292 293 research evidence had showed that as age and years of experience of staff increased, their job stress 294 levels decreased as well.22,23 the results also showed that a higher percentage of omani nurses 295 (62.5%) had diploma degrees in comparison to expatriate nurses (51.8%); this might also have 296 contributed to the higher levels of stress among omani nurses as the results of the present study 297 revealed that participants with diploma degrees reported higher levels of stress comparing to those 298 with bachelor degrees. the results also showed that participants of the study reported above average 299 level of job satisfaction and empowerment and perceived their work environment as positive. 300 however, the results showed that omani nurses reported lower levels of job satisfaction and 301 empowerment and perceived their work environment as less positive in comparison with expatriate 302 nurses. this could be related to the fact that omani nurses reported higher stress levels than their 303 counterparts, which in turn lead to dissatisfactions and poor perceptions of their work environment as 304 was showed in the present study and in previous literature.1,13,16,22 305 306 further, the results also showed that a higher percentage of omani nurses (99.9%) worked in 307 governmental hospitals in comparison to expatriate nurses (95.9%); this might also have contributed 308 to the lower levels of empowerment and the less positive perceptions of work environment among 309 omani nurses as the results of the present study revealed that participants who worked in private 310 hospitals reported higher levels of empowerment and perceived their work environment more 311 positive comparing to those working in governmental hospitals. 312 313 the findings of the study supported the negative correlation between job stress and job satisfaction 314 and added to the research evidence on this issue.13 increased stress levels affect the mental well-being 315 of nurses and lead to job dissatisfaction. there is a vicious circle between job stress and job 316 satisfaction where higher stress levels enhance job dissatisfaction which in turn increase stress 317 levels.22 the results also indicated significant negative relationships between job stress and work 318 environment and empowerment. that is, nurses who perceived higher levels of job stress perceived 319 their work environment as less positive. stressed nurses usually do not participate in hospital 320 affairs, do not focus on their collegial relationships and perceived resources in their organizations 321 to be inadequate; thus they perceived their work environment as less supportive. this result is 322 congruent with the findings of previous studies. 1,16,24 furthermore, nurses who perceived higher 323 levels of job stress reported lower levels of empowerment. this result confirms the findings reported 324 by other researchers11,13,16 and adds an omani cultural perspective to the international evidence in the 325 literature. 326 327 nurses in the present study rated the characteristics of their work environment concerning the 328 participation in hospital affairs, staffing and resources adequacy, adequate access to support form 329 colleagues and perceptions of manager leadership abilities above the moderate level. however, it 330 is worth noting they rated staffing and resources adequacy as a dimension of their work 331 environment as well as access to resources as a dimension of structural empowerment as the 332 lowest among other dimensions. evidence from research showed that better perceptions of work 333 environment characteristics can lead to reduced stress levels and enhanced empowering levels of 334 staff.25,26 335 336 moreover, the results showed that nurses who perceived their work environment as supportive 337 reported higher levels of job satisfaction. this result is consistent with the results of other 338 previous studies.1,25,27 staff experiences at work and how they perceive their work environment 339 affects their personal well-being as well as their levels of job satisfaction. a positive work 340 environment was also associated with higher levels of empowerment. this result is congruent 341 with the findings of a previous study.26 such results highlight the important role of nurse 342 administrators in creating a work environment that values and promotes the empowerment of 343 nurses. 344 345 concerning the moderating effects of empowerment and work environment on the job stress–job 346 satisfaction relationship, the results showed that there was no moderating or indirect effect of 347 either work environment or empowerment on the relationship between job stress and job 348 satisfaction. the results of the present study provided evidence only for the direct effect of work 349 environment and empowerment on the level of job satisfaction. nonetheless, the results highlight 350 the importance of providing a supportive work environment and empowering all employees, not 351 only highly stressed ones. the regression model that included background variables (31%), job 352 stress (13%), work environment (2%), empowerment (0.04%), the product of stress and work 353 environment (0.02%), and the product of stress and empowerment (0%) explained 46.5% of the 354 total variation in job satisfaction. this percentage signifies the importance of the variables of job 355 stress, work environment and empowerment in the prediction of the level of job satisfaction. 356 357 concerning the limitations of the study, the subjective measurement of the study variables might 358 have created reporting bias. furthermore, the convenience sampling method might have limited 359 the generalizability of the results. however, the latter was enhanced by the fact that the study 360 utilized a national sample from different governorates of oman. 361 362 implications and recommendations 363 the findings of the study emphasize the importance of implementing strategies to create a 364 positive work environment. the perceptions of omani nurses about their work environment need 365 to be checked frequently. it is recommended to take suggestions from nurses themselves to 366 improve the work environment. the explanatory regression model points to the significance of 367 managing stress and providing a supportive work environment to enhance nurses' job 368 satisfaction. experienced nurses’ opinions need to be considered when developing strategies 369 regarding their job satisfaction and work environment. nurse managers should also help their 370 staff manage their stress by implementing stress management programs. another area of specific 371 concern for nurses working in oman was that the adequacy of staffing and resources. the issue 372 of nurse staffing is a global concern in health care organizations. it is imperative for nurse 373 managers to advocate for adequate staffing and resources in their units since these factors impact 374 both nurses' and their patients' outcomes. they need to create an organizational culture that 375 embraces a supportive work environment and empowers nurses through providing adequate 376 resources, support, teamwork, and cooperation. 377 378 conclusion 379 the findings of the present study provided evidence only for the direct effects of work 380 environment and empowerment on job satisfaction with no support for the indirect or moderating 381 effects. the results also showed that nurses, working in oman, who had higher levels of job 382 stress perceived lower levels of job satisfaction and empowerment and a less supportive work 383 environment. further, nurses who perceived their work environment as supportive reported 384 higher levels of job satisfaction and empowerment. therefore, nurse administrators need to adopt 385 and implement strategies that tackle job stress, empower staff, and promote a supportive work 386 environment for nurses working in oman. 387 388 acknowledgment 389 the authors would like to acknowledge and thank all nurses who contributed to this study. 390 391 conflicts of interest 392 the authors declare no conflict of interests. 393 394 funding 395 this work was supported by sultan qaboos university (rf/con/facn/19/01); and the 396 research council, sultanate of oman (rc/rg-con/facn/18/01). 397 398 author contributions 399 raa, sds and oa-r conceptualized the study. oa-r designed the methodology and supervised 400 the work. raa performed the formal analysis and provided the visualization. raa, sds, ljl 401 and iab drafted, reviewed and edited the manuscript. all authors approved the final version of 402 the manuscript. 403 404 references 405 1. donley j. the impact of work environment on job satisfaction: pre-covid research to 406 inform the future. nurse lead. 2021;19(6):585-589. doi:10.1016/j.mnl.2021.08.009 407 2. driscoll a, grant mj, carroll d, dalton, s, deaton, c, jones, i, et al. the effect of nurse-408 to-patient ratios on nurse-sensitive patient outcomes in acute specialist units: a systematic review 409 and meta-analysis. eur j cardiovasc nurs. 2018;17(1):6-22. doi:10.1177/1474515117721561 410 3. olds dm, aiken lh, cimiotti jp, lake et. association of nurse work environment and 411 safety climate on patient mortality: a cross-sectional study. int j nurs stud. 2017;74:155-161. 412 doi:10.1016/j.ijnurstu.2017.06.004 413 4. albashayreh a, al sabei sd, al-rawajfah om, al-awaisi h. healthy work 414 environments are critical for nurse job satisfaction: implications for oman. int nurs rev. 415 published online 2019:389-395. doi:10.1111/inr.12529 416 5. al sabei sd, ross am, lee cs. factors influencing nurses’ willingness to lead. j nurs 417 manag. 2019;27(2):278-285. doi:10.1111/jonm.12698 418 6. al sabei sd, abualrub r, labrague lj, burney ia, al-rawajfah o. the impact of 419 perceived nurses’ work environment, teamness, and staffing levels on nurse-reported adverse 420 patient events in oman. nurs forum. 2021;56(4):897-904. doi:https://doi.org/10.1111/nuf.12639 421 7. falguera cc, santos jaad los, galabay jr, firmo, c, tsaras, k, rosales, r, et al. 422 relationship between nurse practice environment and work outcomes: a survey study in the 423 philippines. int j nurs pract. 2021;27(1):e12873. doi:10.1111/ijn.12873 424 8. ulrich b, barden c, cassidy l, varn-davis n. critical care nurse work environments 425 2018: findings and implications. crit care nurse. 2019;39(2):67-84. doi:10.4037/ccn2019605 426 9. laschinger hks, finegan j, shamian j, wilk p. impact of structural and psychological 427 empowerment on job strain in nursing work settings: expanding kanter’s model. j nurs adm. 428 2001;31(5):260-272. doi:10.1097/00005110-200105000-00006 429 10. kanter rm. men and women of the corporation: new edition. basic books; 2008. from 430 scholar.google.com/scholar_lookup?hl=en&publication_year=1993&author=r.m.+kanter&title431 =men+and+women+of+the+corporation. accessed april 2021. 432 11. orgambídez a, almeida h. exploring the link between structural empowerment and job 433 satisfaction through the mediating effect of role stress: a cross-sectional questionnaire study. int 434 j nurs stud. 2020;109:103672. doi:10.1016/j.ijnurstu.2020.103672 435 12. choi s, kim m. effects of structural empowerment and professional governance on 436 autonomy and job satisfaction of the korean nurses. j nurs manag. 2019;27(8):1664-1672. 437 doi:10.1111/jonm.12855 438 13. lu h, zhao y, while a. job satisfaction among hospital nurses: a literature review. int j 439 nurs stud. 2019;94:21-31. doi:10.1016/j.ijnurstu.2019.01.011 440 14. al maqbali m, al sinani m, al-lenjawi b. prevalence of stress, depression, anxiety and 441 sleep disturbance among nurses during the covid-19 pandemic: a systematic review and meta-442 analysis. j psychosom res. 2021;141:110343. doi:10.1016/j.jpsychores.2020.110343 443 15. european agency for safety and health at work. european survey of enterprises on new 444 and emerging risks esener oshwiki. 2022. from: www. 445 oshwiki.eu/wiki/european_survey_of_enterprises_on_new_and_emerging_risks_-_esener. 446 accessed december 2022. 447 16. al sabei sd, al-rawajfah o, abualrub r, labrague lj, burney ia. nurses’ job 448 burnout and its association with work environment, empowerment and psychological stress 449 during covid-19 pandemic. int j nurs pract. 2022;28(5):e13077. doi:10.1111/ijn.13077 450 17. ministry of health. annual health reports . published 2019. from: 451 www.moh.gov.om/en/web/statistics/annual-reports. accessed april 2021. 452 18. yamane t. statistics: an introductory analysis. 2nd ed. harper and row; 1967. 453 19. labrague lj, ds, sabei a, abualrub, r., burney, i, al rawajfah, o, et al. authentic 454 leadership, nurse‐assessed adverse patient events and quality of care: the mediating role of 455 nurses’ safety actions. j nurs manag. 2021;29(7):2152-2162. doi:10.1111/jonm.13356 456 20. lake et. development of the practice environment scale of the nursing work index. res 457 nurs heal. 2002;25(3):176-188. doi:10.1002/nur.10032 458 21. laschinger hks, finegan j, shamian j, wilk p. impact of structural and psychological 459 empowerment on job strain in nursing work settings: expanding kanter’s model. j nurs adm. 460 2001;31(5):260-272. doi:10.1097/00005110-200105000-00006 461 22. al sabei sd, labrague lj, al-rawajfah o, abualrub r, burney ia, jayapal sk. 462 relationship between interprofessional teamwork and nurses’ intent to leave work: the 463 mediating role of job satisfaction and burnout. nurs forum. 2022;57(4):568-576. 464 doi:10.1111/nuf.12706 465 23. labrague l, de los santos jaa, falguera cc, nwafor, c, galabay, j, rosales, r, et al. 466 predictors of nurses’ turnover intention at one and five years’ time. int nurs rev. 467 2020;67(2):191-198. doi:10.1111/inr.12581 468 24. cohen s, kamarck t, mermelstein r. perceived stress scale4 item. j health soc 469 behav. 1983;4:385-396. 470 25. nantsupawat a, kunaviktikul w, nantsupawat r, wichaikhum oa, thienthong h, 471 poghosyan l. effects of nurse work environment on job dissatisfaction, burnout, intention to 472 leave. int nurs rev. 2017;64(1):91-98. doi:10.1111/inr.12342 473 26. albashayreh a, al-rawajfah om, al-awaisi h, karkada s, al sabei sd. psychometric 474 properties of an arabic version of the patient satisfaction with nursing care quality 475 questionnaire. j nurs res. 2019;27(1):1-9. doi:10.1097/jnr.0000000000000273 476 27. al sabei sd, labrague lj, miner ar, karkada, s, albashayreh, a, al masroori, f, et al. 477 nursing work environment, turnover intention, job burnout, and quality of care: the 478 moderating role of job satisfaction. j nurs scholarsh. 2020;52(1):95-104. 479 doi:10.1111/jnu.12528 480 28. mamdouh elkholy s, ebrahim aly el dahshan m, hassan abd el mageed h. authentic 481 leadership and its relation to structural empowerment and work environment among nurses. 482 am j nurs sci. 2020;9(3):136-144. doi:10.11648/j.ajns.20200903.21 483 27. albashayreh a, al-rawajfah om, al-awaisi h, karkada s, al sabei sd. psychometric 484 properties of an arabic version of the patient satisfaction with nursing care quality 485 questionnaire. j nurs res. 2019;27(1). doi:10.1097/jnr.0000000000000273 486 487 table 1: background variables of participants (n = 1796) 488 characteristic total (n= 855) age (years)-median (iqr) 64 (44-75) female-no (%) 401(46.9%) male -no (%) 454 (53.1%) the average length of hospital stays (days)-median (iqr) 5 (3-9) total hospitalisation days (n) 6785.4 admissions with appropriate date of discharge no (%) 583 (68.2%) admissions included inappropriate hospitalization days -no (%) 272 (31.9%) total number of inappropriate hospitalization days (days) 674 mortalityno (%) 29 (3.4%) note. the sample of some variables do not add to the total sample due to missing data 489 490 table 2: means and standard deviation (sd) of study variables (n = 1796) 491 variable (scale and subscales) mean (sd) job stress job satisfaction work environment participation in hospital affairs foundations for quality of care manager ability, leadership and support staffing and resource adequacy collegial nurse–physician relations structural empowerment access to opportunity access to resources access to information access to support 1.7 (.59) 2.9 (.76) 2.8 (.40) 2.8 (.55) 3 (.47) 2.9 (.54) 2.7 (.62) 2.9 (.54) 3.5 (.71) 3.7 (.90) 3.2 (.86) 3.5 (.92) 3.5 (.90) 492 493 table 3: the differences between omani and expatriate nurses concerning study variables (n = 494 1796) 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 variable mean (sd) t-test p value job stress omani nurses 1.9(.54) 10.4 .001 expatriate nurses 1.7(.59) work environment omani nurses 2.7(.41) -11.2 .001 expatriate nurses 2.9(.40) structural empowerment omani nurses 3.2(.72) -11.8 .001 expatriate nurses 3.6(.65) job satisfaction omani nurses 2.6(.84) -12.2 .001 expatriate nurses 3.1(.65) table 4: pearson correlations for work environment, empowerment, job stress, and job 512 satisfaction (n = 1796) 513 work environment empowerment job stress job satisfaction work environment 1 empowerment 0.47** 1 job stress -0.19** -0.19** 1 job satisfaction 0.31** 0.18** -0.32** 1 note. ** correlation is signifcant at p < 0.01 514 515 table 5: hierarchical regression for job satisfaction as a dependent variable (n=1796) 516 step variables r2 cum. r2 change std ß t value p 1 background variables 0.31 0.31 2 job stress 0.44 0.13 -0.39 -9.5 <0.001 3 work environment 0.46 0.02 0.16 3.9 <0.001 4 empowerment 0.463 0.003 -0.002 -.05 0.96 5 stress * work environment 0.465 0.002 0.31 1.1 0.26 6 stress * empowerment 0.465 0.00 0.14 .67 0.50 517 518 final model = r2 = 0.465 (adjusted r2 = 0.44), f(16,392) = 21.31, p < 0.001. 519 std b, the standardized b coefficient; r2 cum. = r2 cumulative. 520 cancer is one of the leading causes of mortality worldwide and was responsible for an estimated 9.6 million deaths in 2018, with the majority (70%) occurring in lowand middleincome countries (lmics).1 furthermore, cancer survival tends to be poor in lmics, most likely due to delays in cancer diagnosis, limited access to resources and a lack of national cancer screening programmes.2 as such, the number of cancer-related deaths can be reduced if patients are diagnosed and treated early.1 delay in cancer diagnosis can occur at any point along the diagnostic spectrum, from the first observation of symptoms to the start of treatment and are typically categorised within one of the three time intervals: patient, primary care and secondary care intervals [figure 1].3 in march 2020, the world health organization (who) declared that the coronavirus disease 2019 (covid-19) virus had become a global health problem; accordingly, most countries developed specific policy responses to decrease the number of infections and slow the transmission of the virus, including the implementation of national lockdowns and social distancing guidelines.4 the intention behind these measures was to ‘flatten the curve’ of the infection and to minimise the impact of the pandemic on national healthcare services and resources.5 however, a recent study conducted in the uk predicted that the disruption of routine health services and other aspects of the covid-19 pandemic would lead to a substantial increase in the frequency of avoidable deaths by 7.9–9.6% among patients with breast, colorectal, oesophageal and lung cancers as a result of diagnostic delays, resulting in a total of 59,204–63,229 additional lives lost in a year.6 in response to the pandemic, routine or nonurgent appointments in primary care settings were cancelled in many countries, including lmics, and cancer screening services were suspended so as to limit gatherings of multiple individuals and decrease the risk of exposing patients and staff to possible sources of infection.7 moreover, hospital resources were diverted to accommodate patients with severe illness due to covid-19; as such, many essential cancer diagnostic procedures such as radiology and endoscopic procedures were suspended or continued operating solely in an extremely limited capacity.8 elective surgeries for those already diagnosed with cancer were deferred indefinitely, while only urgent surgeries were permitted, often resulting in severe psychological distress to the affected patients and caregivers.9 services in the primary care sector were restructured to implement mandatory covid-19 triaging, screening, swab-taking and quarantine or isolation procedures, with staff training implemented to ensure the appropriate referral and management of symptomatic and asymptomatic patients.10 although these measures were undoubtedly necessary, such changes have had a profound effect on existing essential cancer services, leading to further delays in cancer diagnosis and worsening patient outcomes, including their survival rate.11 in some countries, the rate of referral for potential cancer cases has decreased by 80% or more, even for patients in whom cancer is highly likely and who would normally be directed into urgent two-weekwait referral pathways.12 in april 2020, the number of urgent referrals of cancer patients by primary care physicians in scotland and england decreased by more than 70% compared to the average rate over the preceding three years.13 instead, the only way in which patients can currently present to doctors with possible cancer symptoms is through emergency departments. however, even emergency visits were found to have dropped by nearly 33% in march 2020, compared to the previous year, in the uk; moreover, while certain types of cancer (e.g. lung and colorectal) can manifest at an early stage with alarming symptoms (i.e. coughing up blood or blood in the stool), which would trigger a visit to the emergency department, other types of cancer (e.g. breast and prostate) are less likely to be associated with such complications.10,13 as a result, researchers have calculated that approximately 2,000 fewer diagnoses of cancer are currently being made per week in the uk.13 furthermore, it has been found that patients who are diagnosed with cancer department of family medicine & public health, college of medicine & health, sultan qaboos university, oman author’s e-mail: mhalazri@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. delay in cancer diagnosis during the era of the coronavirus disease 2019 pandemic learning lessons mohammed h. al-azri editorial sultan qaboos university med j, aug 2021, vol. 21, iss. 3, pp. 341–343, epub. 29 aug 21 submitted 14 oct 20 revision req. 4 jan 21; revision recd. 11 jan 21 accepted 20 jan 20 https://doi.org/10.18295/squmj.4.2021.028 https://creativecommons.org/licenses/by-nd/4.0/ delay in cancer diagnosis during the era of the coronavirus disease 2019 pandemic learning lessons 342 | squ medical journal, august 2021, volume 21, issue 3 after initially presenting to an emergency department demonstrate poorer outcomes and lower survival rates compared to those with other routes of presentation, such as primary care settings.14 attitudes and help-seeking behaviours on the part of patients have also changed substantially during the covid-19 pandemic in response to physical and social distancing measures introduced by politicians and healthcare authorities to slow or limit the transmission of infection.15 many patients are reluctant to consult a doctor in primary care because of the anxiety over acquiring or transmitting the covid-19 infection and concerns about wasting the doctor’s time for non-covid-19-related symptoms.16 in addition, some patients may be discouraged from seeking medical help as they believe that being diagnosed with cancer might place them at a higher risk of developing serious complications if they were subsequently infected by covid-19. unfortunately, this fear is justified given that covid-19-related mortality appears to be higher among cancer patients compared to those without cancer (6% versus 2%), likely due to immunocompromise resulting both from the disease itself as well as its various treatment modalities such as surgery, radiation and chemotherapy.17 various measures have been implemented in order to limit the risk of transmission of covid-19 while still delivering and facilitating health-related services. in many countries, face-to-face consultations with primary care doctors are being reserved for patients with urgent concerns, while consultations for non-urgent issues are being conducted virtually through online and telehealth technologies.18 however, not all patients in lmics have the necessary access to, familiarity with or knowledge of such technologies to make appropriate use of telemedicine services.19 indeed, even in developed countries, patients from low socioeconomic backgrounds are much less likely to arrange and utilise online telehealth consultations, further compounding the ongoing socioeconomic divide in delays in cancer diagnosis.20 furthermore, the unavoidable drawbacks associated with virtual consultations can increase the chance of a missed cancer diagnosis as the result of the inability of the consulting doctor to conduct physical examinations.21 a substantial increase in the number of avoidable cancer deaths globally is, therefore, to be expected as a result of diagnostic delays due to the covid-19 pandemic. furthermore, it is anticipated that the health systems of many countries, particularly lmics, will be severely strained in the coming months and possibly years due to the foreseeable influx of patients presenting with advanced-stage cancer as a result of current diagnostic delays. as such, the ongoing impact of this outbreak on cancer services requires careful forethought and analysis so that negative outcomes can be minimised as much as possible. as the first anniversary of the official declaration of the covid-19 global pandemic approached, healthcare authorities and policy-makers should consider taking certain steps to mitigate cancer delays and deal with the coming influx of patients presenting with advanced-stage cancer. first, the public should be reassured of their safety and the importance of seeking early medical help for possible cancer symptoms, even during the pandemic. traditional and social media campaigns along with interviews with healthcare professionals and politicians should be conducted to reassure the public of their safety when attending healthcare facilities and to encourage participation in cancer screening programmes to help overcome potential barriers to medical help-seeking caused by the covid-19 pandemic.15,22 second, cancer diagnostic and treatment services such as surgery and endoscopy must be made accessible and available while adhering to strict infection prevention and control policies, for instance, by stressing the importance of hand hygiene, use of personal protective equipment, the implementation of aseptic ‘no-touch’ techniques for all invasive procedures and routine environmental cleaning and waste management as well as respiratory hygiene and cough etiquette. third, the capacity of current cancer services and resources—including diagnostic procedures, radiology and elective surgeries—should be increased to meet the extra demand that will ensue from the growing backlog of undiagnosed and untreated cancer patients. nonetheless, this will be a major challenge in many lmics where national healthcare systems are already stretched to nearly full capacity under normal circumstances.2,20 figure 1: diagram showing key time points and diagnostic intervals between observation of the first symptom of cancer until the start of treatment. reproduced from coxon d, campbell c, walter fm, scott se, neal rd, vedsted p, et al. the aarhus statement on cancer diagnostic research: turning recommendations into new survey instruments.3 mohammed h. al-azri editorial | 343 references 1. world health organization. cancer. from: www.who.int/ news-room/fact-sheets/detail/cancer accessed: jan 2021. 2. shah sc, kayamba v, peek rm jr, heimburger d. cancer control in lowand middle-income countries: is it time to consider screening? j glob oncol 2019; 5:1–8. https://doi. org/10.1200/jgo.18.00200. 3. coxon d, campbell c, walter fm, scott se, neal rd, vedsted p, et al. the aarhus statement on cancer diagnostic research: turning recommendations into new survey instruments. bmc health serv res 2018; 18:677. https://doi.org/10.1186/s12913018-3476-0. 4. world health organization. who director-general’s opening remarks at the media briefing on covid-19: 27 july 2020. from: www.who.int/dg/speeches/detail/who-director-generals-opening-remarks-at-the-media-briefing-on-covid-19---27july-2020 accessed: jan 2021. 5. uk government. covid-19: guidance for health professionals. from: www.gov.uk/government/collections/wuhan-novel-coro navirus accessed: jan 2021. 6. maringe c, spicer j, morris m, purushotham a, nolte e, sullivan r, et al. the impact of the covid-19 pandemic on cancer deaths due to delays in diagnosis in england, uk: a national, population-based, modelling study. lancet oncol 2020; 21:1023–34. https://doi.org/10.1016/s1470-2045(20)303 88-0. 7. chudasama yv, gillies cl, zaccardi f, coles b, davies mj, seidu s, et al. impact of covid-19 on routine care for chronic diseases: a global survey of views from healthcare prof essionals. diabetes metab syndr 2020; 14:965–7. https://doi. org/10.1016/j.dsx.2020.06.042. 8. cooley l, linn jf. developing countries can respond to covid-19 in ways that are swift, at scale, and successful. from: www.brookings.edu/blog/future-development/2020/06/04/ developing-countries-can-respond-to-covid-19-in-ways-thatare-swift-at-scale-and-successful/ accessed: jan 2021. 9. canadian cancer survivor network. the devastating effect on cancer care of cancelling elective surgeries during the pandemic. from: https://survivornet.ca/news/the-devastatingeffect-on-cancer-care-of-cancelling-elective-surgeries-duringthe-pandemic/ accessed: jan 2021. 10. lash rs, bell jf, reed sc, poghosyan h, rodgers j, kim kk, et al. a systematic review of emergency department use among cancer patients. cancer nurs 2017; 40:135–44. https://doi. org/10.1097/ncc.0000000000000360. 11. al-azri mh. delay in cancer diagnosis: causes and possible solutions. oman med j 2016; 31:325–6. https://doi.org/10.5001/ omj.2016.65. 12. bodkin h. cancer referrals down by 80 per cent in some areas as coronavirus fears keep patients from hospitals. from: www. telegraph.co.uk/news/2020/04/15/cancer-referrals-80-per-centareas-coronavirus-fears-keep-patients/ accessed: jan 2021. 13. richards m, anderson m, carter p, ebert bl, mossialos e. the impact of the covid-19 pandemic on cancer care. nat cancer 2020; 1:565–7. https://doi.org/10.1038/s43018-020-0074-y. 14. king-okoye m, arber a, faithfull s. routes to diagnosis for men with prostate cancer: men’s cultural beliefs about how changes to their bodies and symptoms influence help-seeking actions a narrative review of the literature. eur j oncol nurs 2017; 30:48–58. https://doi.org/10.1016/j.ejon.2017.06.005. 15. kennedy m. u.k. prime minister tells brits they must stay home, threatens fines. from: www.npr.org/sections/coronavirus-liveupdates/2020/03/23/820335870/u-k-prime-minister-tells-britsto-stay-home-threatens-fines accessed: jan 2021. 16. dinmohamed ag, visser o, verhoeven rh, louwman mw, van nederveen fh, willems sm, et al. fewer cancer diagnoses during the covid-19 epidemic in the netherlands. lancet oncol 2020; 21:750–1. https://doi.org/10.1016/s1470-2045(20) 30265-5. 17. tsamakis k, gavriatopoulou m, schizas d, stravodimou a, mougkou a, tsiptsios d, et al. oncology during the covid-19 pandemic: challenges, dilemmas and the psychosocial impact on cancer patients. oncol lett 2020; 20:441–7. https://doi. org/10.3892/ol.2020.11599. 18. lynn community health center. health center to cancel some appointments, increase screening in response to corona virus. from: www.lchcnet.org/health-center-cancel-some-appo intments-increase-screening-response-coronavirus accessed: jan 2021. 19. world health organization. e-health in lowand middleincome countries: findings from the center for health market innovations. from: www.who.int/bulletin/volumes/9 0/5/11-099820/en/ accessed: jan 2021. 20. rivera-franco mm, leon-rodriguez e. delays in breast cancer detection and treatment in developing countries. breast cancer (auckl) 2018; 12:1178223417752677. https://doi.org/10.1177/1 178223417752677. 21. jones d, neal rd, duffy sr, scott se, whitaker kl, brain k. impact of the covid-19 pandemic on the symptomatic diagnosis of cancer: the view from primary care. lancet oncol 2020; 21:748–50. https://doi.org/10.1016/s1470-2045(20)30242-4. 22. hamilton w, walter fm, rubin g, neal rd. improving early diagnosis of symptomatic cancer. nat rev clin oncol 2016; 13:740–9. https://doi.org/10.1038/nrclinonc.2016.109. https://doi.org/10.1200/jgo.18.00200 https://doi.org/10.1200/jgo.18.00200 https://doi.org/10.1186/s12913-018-3476-0 https://doi.org/10.1186/s12913-018-3476-0 https://doi.org/10.1016/s1470-2045(20)30388-0 https://doi.org/10.1016/s1470-2045(20)30388-0 https://doi.org/10.1016/j.dsx.2020.06.042 https://doi.org/10.1016/j.dsx.2020.06.042 https://doi.org/10.1097/ncc.0000000000000360 https://doi.org/10.1097/ncc.0000000000000360 https://doi.org/10.5001/omj.2016.65 https://doi.org/10.5001/omj.2016.65 https://doi.org/10.1038/s43018-020-0074-y https://doi.org/10.1016/j.ejon.2017.06.005 https://doi.org/10.1016/s1470-2045(20)30265-5 https://doi.org/10.1016/s1470-2045(20)30265-5 https://doi.org/10.3892/ol.2020.11599 https://doi.org/10.3892/ol.2020.11599 https://doi.org/10.1177/1178223417752677 https://doi.org/10.1177/1178223417752677 https://doi.org/10.1016/s1470-2045(20)30242-4 https://doi.org/10.1038/nrclinonc.2016.109 1department of public health, ministry of heath, riyadh, saudi arabia; 2department of global health, rollins school of public health, emory university, atlanta, georgia, usa; 3tobacco control program, ministry of health, riyadh, saudi arabia *corresponding author’s e-mail: yumnalnimr@gmail.com العوامل املؤثرة يف بدء التدخني واإلقالع عنه لدى النساء السعوديات الالئي يرتددن على عيادات اإلقالع عن التدخني مُين اآل منر، غادة فرحات، علي الوادعي abstract: objectives: smoking is one of the most adaptable risk behaviours associated with increased mortality rates, yet over one billion individuals worldwide are smokers. this study aimed to examine self-reported reasons for starting and quitting smoking among women attending smoking cessation clinics in saudi arabia. methods: this cross-sectional study took place between january 2014 and january 2017 in saudi arabia using previously collected data. a survey was distributed to 3,000 female smokers attending smoking cessation programmes in 18 clinics from different regions in saudi arabia to determine self-reported reasons for smoking initiation and willingness/ unwillingness to quit. results: a total of 2,190 women participated in the study (response rate = 73%). overall, the most common reason for starting to smoke was friends (31.1%), while the predominant reason for willingness to quit was health concerns (45.5%). the most frequent reason for being unwilling to quit smoking was a fear of mood changes (28%). conclusion: most saudi women are socially-driven to start smoking, while the most common reason for quitting is health concerns. the latter finding is promising in that it shows that smokers are gaining awareness of the adverse effects of smoking. keywords: tobacco smoking; smoking cessation; health risk behaviors; lifestyle risk reduction; primary health care; saudi arabia. امللخ�ص: الهدف: يعد التدخني اأحد اأكرث ال�صلوكيات اخلطرة القابلة للتكييف واملرتبطة بارتفاع معدلت الوفيات، ورغم ذلك يوجد اأكرث من مليار مدخن حول العامل. هدفت هذه الدرا�صة لبحث الأ�صباب امُلَبلغ عنها ذاتيا لبدء التدخني والتوقف عنه بني الن�صاء الالئي يرتددن على عيادات الإقالع عن التدخني يف اململكة العربية ال�صعودية. الطريقة: اأجريت هذه الدرا�صة امل�صتعر�صة بني يناير 2014 ويناير 2017 يف اململكة العربية ال�صعودية با�صتخدام بيانات مت جمعها م�صبقا. مت توزيع ا�صتبيان على 3,000 من الن�صاء املدخنات الالئي يح�رشن برامج الإقالع عن التدخني يف 18 عيادة من مناطق خمتلفة يف اململكة العربية ال�صعودية لتحديد الأ�صباب امُلَبلغ عنها ذاتيا لبدء التدخني وكذلك اأ�صباب الرغبة اأو عدم الرغبة يف التوقف عن التدخني. النتائج: �صارك ما جمموعه 2,190 امراأة يف الدرا�صة )معدل ال�صتجابة = %73(. ب�صكل عام كان الأ�صدقاء ال�صبب الأكرث �صيوًعا لبدء التدخني )%31.1(، يف حني كان ال�صبب ال�صائد للرغبة يف التوقف عن التدخني هو املخاوف ال�صحية )%45.5(. كان ال�صبب الأكرث تواترا لعدم الرغبة يف الإقالع عن التدخني هو اخلوف من تقلبات املزاج )%28(. اخلال�صة: الدافع الأجتماعي هو �صبب بدء التدخني لدى معظم الن�صاء ال�صعوديات، يف حني اأن ال�صبب الأكرث �صيوًعا لرتك التدخني هو املخاوف ال�صحية. وتعترب هذه النتيجة الأخرية واعدة حيث اأنها تك�صف اكت�صاب املدخنني للوعي باآثار التدخني ال�صلبية. الكلمات املفتاحية: تدخني التبغ؛ الإقالع عن التدخني؛ �صلوكيات تعر�س ال�صحة للخطر؛ تقليل خماطر منط العي�س؛ الرعاية ال�صحية الولية؛ اململكة العربية ال�صعودية. factors affecting smoking initiation and cessation among saudi women attending smoking cessation clinics *yumn m. al-nimr,1 ghada farhat,2 ali alwadey3 brief communication sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e95–99, epub. 9 mar 20 submitted 15 jan 19 revisions req. 23 jan, 3 mar & 5 may 19; revisions recd. 28 jan, 1 apr & 16 jun 19 accepted 24 jul 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.014 tobacco smoking is a major public health problem worldwide, leading to various health problems including lung cancer, respiratory disorders (i.e. chronic obstructive pulmonary disease), eye-related diseases and arthritis.1,2 moreover, smoking not only harms smokers, but also those around them with second-hand smoke exposure responsible for over 600,000 deaths annually.3 for women, smoking during pregnancy may lead to antenatal and postpartum complications, as well as an increased risk of infants of low birth weight and who are small-for-gestational age (sga).4–6 cigarettes are composed of various substances, such as nicotine and tar, which can cause pregnancy-related diabetes, hypertension and intrauterine growth restriction, conditions significantly associated with sga infants.5,6 for many pregnant women, such adverse health effects contribute to reasons for smoking cessation once they realise that they are pregnant.7,8 as part of the national smoking cessation programme (nscp), clinics offering free standardised smoking cessation support have been established in https://creativecommons.org/licenses/by-nd/4.0/ factors affecting smoking initiation and cessation among saudi women attending smoking cessation clinics e96 | squ medical journal, february 2020, volume 20, issue 1 various regions of saudi arabia, with a wide range of services available including cognitive behavioural therapy, nicotine replacement therapy (nrt) and nonnrt treatment, among others.9 nevertheless, there is a shortage of information concerning the characteristics of female saudi smokers, particularly with regards to factors that would aid smoking cessation efforts. as such, this study aimed to describe the characteristics of female saudi smokers and their self-reported reasons for starting to smoke and willingness/unwillingness to quit smoking. methods this cross-sectional study took place between january 2014 and january 2017. previously collected data from 18 clinics offering smoking cessation programmes which are located in various regions of saudi arabia were analysed. a total of 3,000 saudi females attending these clinics for the first time were invited to participate in the study. self-administered english, with arabic translation, questionnaires were used to gather data from the participants, including sociodemographic characteristics (i.e. age, education level and monthly income), the participant’s weight and height, previous attempts to quit smoking and the presence of any other smokers at home, as well as self-reported reasons for smoking initiation and willingness/unwillingness to quit smoking. the latter part of the survey consisted of 18 questions, including six potential reasons for smoking initiation (i.e. friends who smoke, family members who smoke, social imitation, stress, advertising and other), six reasons for being willing to quit smoking (i.e. health, to save money, religious beliefs, familial pressure, wanting to live a better life and other) and six reasons for being unwilling to quit smoking (i.e. cost of treatment, fear of mood changes, peer pressure, fear of failure, previous failure when attempting to quit and other). participants were required to choose responses on a five-point likert scale ranging from ‘strongly disagree’ to ‘strongly agree’ for each question. body mass index (bmi) was calculated from self reported weight and height, with participants categ orised as underweight, normal weight or overweight. data concerning the participants’ age, bmi category, location of clinic, education level, monthly income, presence of another smoker at home and previous attempts to quit smoking were presented in percentages and frequencies. in terms of reasons for smoking initiation, cessation and unwillingness to quit, results were presented as the frequency and percentage of respondents answering ‘strongly agree’, along with 95% confidence intervals (cis) due to a large proportion of missing data for each variable. approval to use the data presented in this study was obtained from the supervisor general of the nscp in riyadh, saudi arabia. all participants gave written informed consent prior to their participation in the study. the women were informed that all participation was voluntary and that they could withdraw from the study at any time. in addition, they were reassured that their contributions were anonymous and confidential. results overall, 2,190 women took part in the study (response rate = 73%). of these, 40.9% were ≤30 years old and 50.5% attended clinics in either jeddah or makkah (24.4% and 26.1%, respectively). only 12% were overweight. in terms of education level, 21% had a bachelor’s degree and 19.6% had a high school diploma. over a quarter (26.3%) reported having no income. most women (67.4%) reported the presence of another smoker at home [table 1]. the most common reason for starting to smoke was friends who smoke (31.1%, 95% ci: 29.2–33.1), followed by family members who smoke (8.3%, 95% ci: 7.2–9.5). overall, 42.3% (95% ci: 40.3–44.4) of the participants reported being influenced by social factors. this finding emerged after aggregating responses to three reasons (having a family member who smokes, having a friend who smokes, and social imitation). however, there were missing data for 55.5% of the part icipants regarding evidence that they were influenced to smoke by their friends; there were also missing data for other variables [table 2]. in terms of willingness to quit smoking, the most common reason cited was health concerns (45.5%, 95% ci: 43.4–47.6), followed by familial pressure (20.4%, 95% ci: 18.7–22.1) and religious beliefs (18.1%, 95% ci: 16.5–19.8). finally, 14.7% (95% ci: 13.3–16.3) and 14.3% (95% ci: 12.9–15.9) of the participants reported that their willingness to quit was in order to save money and have a better life, respectively. there were missing data for 54.3% of participants who were willing to quit smoking due to health concerns; in addition, there were missing data for other variables [table 3]. some of the women indicated that they were unwilling to quit smoking. reasons for this included a fear of mood changes (28%, 95% ci: 26.1–29.9), peer pressure (18.5%, 95% ci: 16.9–20.2), cost of treatment (13.2%, 95% ci: 11.9–14.7), fear of failure (11.2%, 95% ci: 9.9–12.6) and failure after previous attempt(s) to quit (7.8%, 95% ci: 6.7–9). however, data were missing yumn m. al-nimr, ghada farhat and ali alwadey brief communication | e97 for 86.8% of participants concerning unwillingness to quit smoking due to fear of mood changes; there were missing data for other variables as well [table 4]. discussion in the current study, the majority of saudi women attending smoking cessation clinics were ≤40 years old. other studies have noted that most women start table 1: demographic characteristics of women attending smoking cessation clinics in saudi arabia (n = 2,190) characteristic n (%) age in years 10–15 181 (8.3) 16–20 110 (5) 21–25 283 (12.9) 26–30 322 (14.7) 31–35 267 (12.2) 36–40 76 (3.5) 41–45 149 (6.8) 46–50 53 (2.4) 51–55 142 (6.5) 56–60 184 (8.4) >60 423 (19.3) location of clinic al-madinah 69 (3.2) eastern region 44 (2) jeddah 535 (24.4) jizan 45 (2.1) makkah 572 (26.1) northern borders 153 (7) riyadh 37 (1.7) central region 461 (21.1) taif 228 (10.4) other* 46 (2.1) education level illiterate 58 (2.6) primary school 83 (3.8) middle school 142 (6.5) high school 429 (19.6) diploma 120 (5.5) bachelor’s degree 459 (21) master’s degree 18 (0.8) doctorate 6 (0.3) other 168 (7.7) unknown 707 (32.3) monthly income in saudi riyals none 577 (26.3) <3,000 206 (9.4) 3,000–5,999 264 (12.1) 6,000–10,000 174 (7.9) >10,000 93 (4.2) unknown 876 (40) presence of other smokers at home yes 1,475 (67.4) no 715 (32.6) body mass index category underweight 350 (16) normal weight 733 (33.5) overweight 262 (12) unknown 845 (38.6) previous attempts at quitting yes 575 (26.3) no 1,615 (73.7) *including nine clinics with ≤20 participants each located in al-bahah, al-jawf, al-qassim, qurrayat, aseer, bisha, hafar al-batin, najran and tabuk. table 2: reasons for smoking initiation among women att ending smoking cessation clinics in saudi arabia (n = 2,190) reason* n (%) 95% ci strongly agree missing data friends who smoke 682 (31.1) 1,216 (55.5) 29.2–33.1 family members who smoke 181 (8.3) 1,705 (77.9) 7.2–9.5 stress 125 (5.7) 1,840 (84) 4.8–6.8 social imitation 64 (2.9) 1,815 (82.9) 2.7–3.7 advertising 22 (1) 2,002 (91.4) 0.6–1.5 other 71 (3.2) 2,093 (95.6) 2.5–4.1 ci = confidence interval. *percentages do not add up to 100% as the rem aining participants chose responses ranging from ‘agree’ to ‘strongly disagree’. table 3: reasons for willingness to quit smoking among women attending smoking cessation clinics in saudi arabia (n = 2,190) reason* n (%) 95% ci strongly agree missing data health concerns 996 (45.5) 1,190 (54.3) 43.4–47.6 familial pressure 446 (20.4) 1,740 (79.5) 18.7–22.1 religious beliefs 397 (18.1) 1,789 (81.7) 16.5–19.8 to save money 323 (14.7) 1,863 (85.1) 13.3–16.3 to have a better life 314 (14.3) 1,872 (85.5) 12.9–15.9 other 30 (1.4) 2,156 (98.4) 0.9–2 ci = confidence interval. *percentages do not add up to 100% as the rem aining participants chose responses ranging from ‘agree’ to ‘strongly disagree’. table 4: reasons for unwillingness to quit smoking among women attending smoking cessation clinics in saudi arabia (n = 2,190) reason* n (%) 95% ci strongly agree missing data fear of mood changes 613 (28) 1,900 (86.8) 26.1–29.9 peer pressure 405 (18.5) 1,785 (81.5) 16.9–20.2 cost of treatment 290 (13.2) 1,900 (86.8) 11.9–14.7 fear of failure 245 (11.2) 1,945 (88.8) 9.9–12.6 failed previous attempt(s) 170 (7.8) 2,020 (92.2) 6.7–9 other 65 (3) 2,125 (97) 2.3–3.8 ci = confidence interval. *percentages do not add up to 100% as the rem aining participants chose responses ranging from ‘agree’ to ‘strongly disagree’. factors affecting smoking initiation and cessation among saudi women attending smoking cessation clinics e98 | squ medical journal, february 2020, volume 20, issue 1 smoking in their early 20s.10–12 this often occurs while attending college or university, perhaps as a result of being surrounded by peers who believe that smoking is fashionable.13–16 importantly, the present study noted that peer pressure, especially from friends, was the main reason that women started smoking. research indicates that most young adult smokers lack critical information regarding the adverse health effects of tobacco smoking.17 nevertheless, even with knowledge of the associated risks, friendship plays a crucial role in smoking behaviours among young adult females.14 a study involving young women attending a college in dammam, saudi arabia, similarly observed that their introduction to smoking was due to seeing this behaviour reflected in someone they knew.18 as such, it is imperative that anti-smoking strategies be integrated into higher educational institutions in saudi arabia in order to reach a greater number of young adults. the majority of women in the current study expressed a willingness to quit smoking, with the most common reason being health concerns. this is encouraging as it indicates that most saudi women attending smoking cessation programmes are aware of the adverse effects of tobacco smoking on their health. the ministry of health in saudi arabia has already initiated efforts to incorporate health messages on cigarette packaging to ensure consumers are aware of the consequences of smoking.19,20 however, while health was reported to be the most important reason to quit smoking among saudi women in the present study, it was not possible to discern which precise health concern most encouraged these women to consider quitting. smoking cessation programmes are among the most cost-effective and successful strategies for helping people to quit smoking.20 in saudi arabia, compr ehensive tobacco control measures, including bans on smoking in public places and high taxation on tobacco products, have also contributed to high cessation rates in the general population.9 based on the findings of the present study, smoking dependence clinics should be established on the campuses of saudi arabian colleges and tobacco smoking cessation programmes integrated into the curricula. in addition, the authors recommend that the nscp integrate referral to cessation clinics into routine clinical care. the strengths of this study include the large sample size which was nationally representative, covering all regions of saudi arabia, and the use of a uniform data collection method via a standardised questionnaire. however, there were a number of limitations. there were many missing values which were not categorised, making it difficult to discern between ‘true’ missing values and inapplicable answers; indeed, in terms of reasons for smoking initiation and cessation, some answer choices had missing values for more than 90% of the sample. as such, certain variables could not be properly analysed and the results should be taken in light of this limitation. another limitation was the exclusion of other important reasons for willingness to stop smoking such as pregnancy. while this reason might have been subsumed under the health concerns category, it would have been interesting to study the influence of this variable independently. in addition, the findings may have been affected by recall bias, particularly with regards to reasons for smoking initiation if the participant had been smoking for a number of years. other variables, such as age, should have been collected on a continuous scale; however, as age was not stratified beyond this level of detail in the original questionnaire, it was not possible to determine if there were younger respondents. conclusion social factors are the primary reasons for smoking initiation among the studied sample of women in saudi arabia while health concerns were the main reason for smoking cessation, followed by familial pressure, religion, saving money and having a better life. additional on-campus smoking cessation clinics should be introduced at colleges in saudi arabia in order to target younger smokers. furthermore, the authors recommend that referral to cessation clinics be integrated into routine clinical care. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bonnie rj, stratton k, kwan ly, eds. the effects of tobacco use on health. in: public health implications of raising the minimum age of legal access to tobacco products. washington dc, usa: national academies press, 2015. https://doi.org/10.17226/18997. 2. el-zaatari zm, chami ha, zaatari gs. health effects associated with waterpipe smoking. tob control 2015; 24:i31–43. https://doi.org/10.1136/tobaccocontrol-2014-051908. 3. oberg m, jaakkola ms, woodward a, peruga a, prüss-ustün a. worldwide burden of disease from exposure to secondhand smoke: a retrospective analysis of data from 192 countries. lancet 2011; 377:139–46. https://doi.org/10.1016/s01406736(10)61388-8. https://doi.org/10.17226/18997 https://doi.org/10.1136/tobaccocontrol-2014-051908 https://doi.org/10.1016/s0140-6736%2810%2961388-8 https://doi.org/10.1016/s0140-6736%2810%2961388-8 yumn m. al-nimr, ghada farhat and ali alwadey brief communication | e99 4. chiolero a, bovet p, paccaud f. association between maternal smoking and low birth weight in switzerland: the eden study. swiss med wkly 2005; 135:525–30. https://doi.org/2005/35/ smw-11122. 5. ko tj, tsai ly, chu lc, yeh sj, leung c, chen cy, et al. parental smoking during pregnancy and its association with low birth weight, small for gestational age, and preterm birth offspring: a birth cohort study. pediatr neonatol 2014; 55:20–7. https://doi.org/10.1016/j.pedneo.2013.05.005. 6. reeves s, bernstein i. effects of maternal tobacco-smoke exposure on fetal growth and neonatal size. expert rev obstet gynecol 2008; 3:719–30. https://doi.org/10.1586/1747 4108.3.6.719. 7. kataoka mc, carvalheira ap, ferrari ap, malta mb, de barros leite carvalhaes ma, de lima parada cm. smoking during pregnancy and harm reduction in birth weight: a crosssectional study. bmc pregnancy childbirth 2018; 18:67. https://doi.org/10.1186/s12884-018-1694-4. 8. levis dm, stone-wiggins b, o’hegarty m, tong vt, polen kn, cassell ch, et al. women’s perspectives on smoking and pregnancy and graphic warning labels. am j health behav 2014; 38:755–64. https://doi.org/10.5993/ajhb.38.5.13. 9. moradi-lakeh m, el bcheraoui c, tuffaha m, daoud f, al saeedi m, basulaiman m, et al. tobacco consumption in the kingdom of saudi arabia, 2013: findings from a national survey. bmc public health 2015; 15:611. https://doi.org/10.1186/s12889015-1902-3. 10. al-mohrej oa, al-shirian sd, altraif si, tamim hm, fakhoury hma. what encourages saudis to quit smoking? j health spec 2016; 4:146–50. https://doi.org/10.4103/1658-600x.179825. 11. koura mr, al-dossary af, bahnassy aa. smoking pattern among female college students in dammam, saudi arabia. j family community med 2011; 18:63–8. https://doi.org/10.410 3/2230-8229.83370. 12. chezhian c, murthy s, prasad s, kasav jb, mohan sk, sharma s, et al. exploring factors that influence smoking initiation and cessation among current smokers. j clin diagn res 2015; 9:lc08–12. https://doi.org/10.7860/jcdr/2015/12047.5917. 13. anjum ms, srikanth mk, reddy pp, monica m, rao ky, sheetal a. reasons for smoking among the teenagers of age 14–17 years in vikarabad town: a cross-sectional study. j indian assoc public health dent 2016; 14:80–3. https://doi. org/10.4103/2319-5932.178733. 14. wray rj, jupka k, berman s, zellin s, vijaykumar s. young adults’ perceptions about established and emerging tobacco products: results from eight focus groups. nicotine tob res 2012; 14:184–90. https://doi.org/10.1093/ntr/ntr168. 15. pepper jk, reiter pl, mcree al, cameron ld, gilkey mb, brewer nt. adolescent males’ awareness of and willingness to try electronic cigarettes. j adolesc health 2013; 52:144–50. https://doi.org/10.1016/j.jadohealth.2012.09.014. 16. saari aj, kentala j, mattila kj. the smoking habit of a close friend or family member--how deep is the impact? a crosssectional study. bmj open 2014; 4:e003218. https://doi.org/10.1 136/bmjopen-2013-003218. 17. glenn nm, lapalme j, mccready g, frohlich kl. young adults’ experiences of neighbourhood smoking-related norms and practices: a qualitative study exploring place-based social inequalities in smoking. soc sci med 2017; 189:17–24. https://doi.org/10.1016/j.socscimed.2017.07.021. 18. ansari k, farooqi fa. comparison and prevalence of smoking among saudi females from different departments of the college of applied medical sciences in dammam. int j health sci (qassim) 2017; 11:56–62. 19. hiilamo h, crosbie e, glantz sa. the evolution of health warning labels on cigarette packs: the role of precedents, and tobacco industry strategies to block diffusion. tob control 2014; 23:e2. https://doi.org/10.1136/tobaccocontrol-2012-050541. 20. world health organization. (2017). who report on the global tobacco epidemic, 2017: monitoring tobacco use and prevention policies. from: https://who.int/tobacco/global_ report/2017/en/ accessed: jun 2019. https://doi.org/2005/35/smw-11122 https://doi.org/2005/35/smw-11122 https://doi.org/10.1016/j.pedneo.2013.05.005 https://doi.org/10.1586/17474108.3.6.719 https://doi.org/10.1586/17474108.3.6.719 https://doi.org/10.1186/s12884-018-1694-4 https://doi.org/10.5993/ajhb.38.5.13 https://doi.org/10.1186/s12889-015-1902-3 https://doi.org/10.1186/s12889-015-1902-3 https://doi.org/10.4103/1658-600x.179825 https://doi.org/10.4103/2230-8229.83370 https://doi.org/10.4103/2230-8229.83370 https://doi.org/10.7860/jcdr/2015/12047.5917 https://doi.org/10.4103/2319-5932.178733 https://doi.org/10.4103/2319-5932.178733 https://doi.org/10.1093/ntr/ntr168 https://doi.org/10.1016/j.jadohealth.2012.09.014 https://doi.org/10.1136/bmjopen-2013-003218 https://doi.org/10.1136/bmjopen-2013-003218 https://doi.org/10.1016/j.socscimed.2017.07.021 https://doi.org/10.1136/tobaccocontrol-2012-050541 departments of 1biochemistry, 2allied health sciences and 3medicine, college of medicine and health sciences, 4department of chemistry, college of science, sultan qaboos university; 5center of excellence in marine biotechnology, sultan qaboos university, muscat, oman *corresponding author’s e-mail: ikramburney@hotmail.com hymenialdisine is cytotoxic against cisplatin-sensitive but not against cisplatin-resistant cell lines nada abdullah,1 najwa al balushi,1 syed i. hasan,4 shadia al bahlani,2 sergey dobretsov,5 yahya tamimi,1 *ikram a. burney3 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 632–634, epub. 25 nov 21 submitted 12 sep 20 revision req. 11 oct 20; revision recd. 28 oct 20 accepted 8 nov 20 hymenialdisine (boc science, new york, usa) was dissolved in dimethyl sulfoxide (sigma-aldrich, burlington, massachusetts, usa) to create a stock solution of 3085.2 μm. cisplatin solution (1 mg/ ml; mylan s.a.s, saint priest, france) was obtained at a concentration of 3333.2 μm. cisplatin-sensitive (a2780s) and cisplatin-resistant (a2780cp) ovarian cancer cell lines. the cell lines were seeded in a 96-well plate, cultured in dulbecco’s modified eagle’s medium (dmem/f12) and maintained as has been described earlier.7 the anti-cancer effects of hymenialdisine and cisplatin were assessed by treating cells with different concentrations of hymenialdisine (100–300 μg/ml) or cisplatin (10–70 μm) over a 24-hour period. cell viability was determined using the alamarblue® assay (invitrogen, waltham, usa) and following the manufacturer’s protocol. briefly, the cells were stained after trypsinisation by trypan blue and counted. approximately 20,000 cells were grown to confluence in a complete growth medium (dmem/f12 + 10% fetal bovine serum). then, cells were exposed to different concentrations of hymenialdisine and cisplatin in serum-free media. alamarblue® (invitrogen) was added to the cells in an amount equal to 10% of the final volume in the well 24 hours after the treatment. three hours later, the absorbance was measured at 570 and 600 nm using thermo multiskan spectrum spectrophotometer (thermo fisher scientific, epithelial ovarian cancer (eoc) is one of the most common gynaecological cancers and a leading cause of cancer-related deaths.1 combination chemotherapy consisting of cisplatin and paclitaxel has been the standard of care; however, the vast majority of patients develop resistance, especially to the platinum drug.2,3 the five-year survival remains dismally low at 15–25%, and therefore, new compounds are needed to achieve better disease control and survival.4 in the previous study by dobretsov et al., hymenialdisine was observed to have potent cytotoxic activity against the michigan cancer foundation-7 breast cancer cell line.5 hymenialdisine is a marine alkaloid consisting of a pyrrole-ring fused to an azepine that was first isolated from the marine sponges acanthella sp. and axinella sp. in 1982.6 it has been shown to be a potent inhibitor of a number of kinases and proteins that regulate membrane transport, gene expression, cellular proliferation and apoptosis. this study investigated the cytotoxic effect of hymenialdisine in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines to determine whether the compound would be effective against ovarian cancer cells. methods this study was conducted at sultan qaboos university, muscat, oman between august and november, 2019. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.049 brief communication abstract: objectives: new compounds are needed to overcome the resistance to commonly used cytotoxic chemotherapy for epithelial ovarian cancer. marine sponges are a rich source of diverse chemical compounds and hymenialdisine has been found to have antiproliferative effects. this study aimed to investigate the cytotoxic effect of hymenialdisine in cisplatin-sensitive and cisplatin resistant ovarian cancer cell lines. methods: this study took place at sultan qaboos university, muscat, oman between august and november, 2019. the anti-cancer effects of hymenialdisine or cisplatin were assessed using treating cells with different concentrations of hymenialdisine and cisplatin. cell viability was determined using the alamarblue® assay. results: the half-maximal inhibitory concentration (ic50) of cisplatin was estimated at 31.4 μm for a2780s and 76.9 μm for a2780cp, whereas the ic50 of hymenialdisine was evaluated at 146.8 μm for a2780s cells. despite the higher concentrations of hymenialdisine (up to 300 μm), ic50 could not be determined for the a2780cp cell line. conclusion: when compared to cisplatin, hymenialdisine was less toxic against both a2780s and a2780cp ovarian cancer cell lines. keywords: gynecologic neoplasm; ovarian cancer; cisplatin; hymenialdisine; oman. nada abdullah, najwa al balushi, syed i. hasan, shadia al bahlani, sergey dobretsov, yahya tamimi and ikram a. burney brief communication | 633 waltham, usa). one-way analysis of variance, followed by tukey’s post-hoc test, was used to determine whether there was any difference. p <0.05 was considered statistically significant. half-maximal inhibitory concentration (ic50) was obtained using graphpad prism, version 8.0.2 (graphpad software inc, san diego, california, usa) and microsoft office excel, version 2016 (microsoft corp., redmond, washington, usa). results were expressed as mean ± standard deviation. this study was approved by the institutional medical research committee. results a2780cp was 2.5 times more resistant when treated with cisplatin compared to a2780s cancer cell lines. the viability of cells was reduced to <50% at a concentration of 300 μm of hymenialdisine, whereas no significant reduction in the viability of a2780cp was detected despite increasing the concentration of hymenialdisine to 300 μm. the ic50 of cisplatin was estimated at 31.4 μm for a2780s and 76.9 μm for a2780cp, whereas the ic50 of hymenialdisine was evaluated at 146.8 μm for a2780s cells. despite the higher concentrations of hymenialdisine used (300 μg/ ml), ic50 could not be calculated for the a2780cp cell line. all results are from three independent experiments for a2780s (p <0.0001) and a2780cp (p <0.0005) [figure 1]. discussion the current study found that, when compared to cisplatin, hymenialdisine was less toxic against both a2780s and a2780cp ovarian cancer cell lines. these results are different from our previous study, where hymenialdisine demonstrated portent cytotoxic action against the michigan cancer foundation (mcf)-7 breast cancer cell line (ic50 at <100 μg/ml).5 several kinase inhibitors such as hymenialdisine have strong selectivity not only for specific kinase subtypes but also for cancer cells. hymenialdisine in the micromolar range was shown to have antiproliferative effects against human tumor cell lines, exerting its antiproliferative activity through the inhibition of cyclin-dependent kinase (cdk)-1/cyclin-b, cdk-2/ cyclin-a, mitogen-activated protein kinase-1, casein kinase 1, protein serine/threonine kinases cdk5, cdk-2/cyclin e, glycogen synthase kinase 3 and creatine kinase 1.8,9 these kinases and transcription factors are vital for processes such as cellular proliferation, gene expression and apoptosis. on the other hand, several other enzymes are only modestly inhibited by hymenialdisine, such as 3’ 5’-cyclic adenosine monophosphate-dependent protein kinase, insulin receptor tyrosine kinase, c-src tyrosine kinase and c-abl tyrosine kinase.10 the results of the current study clearly demonstrated the different responses of cisplatinsensitive and cisplatin resistant cell lines to cisplatin. the resistant cell line was at least 2.5 times more resistant compared to the sensitive cell line. the mechanisms of cisplatin resistance include the activity of general efflux mechanisms, post-translational modification, a defect in the mismatch repair pathway due to the silencing of the human mutl homolog 1 gene and expression of small non-coding rnas.11–13 however, the reason for resistance against hymenialdisine remains speculative. one possible explanation is the differential expression of 11 mirnas in cisplatin-resistant cells, which have targets in the transforming growth factor-b and mitogen-activated protein kinase (mapk) signalling pathways.14 the activation of mapk due to phosphorylation can lead to either cell proliferation or apoptosis. aldisine figure 1: a: viability percentage for a2780s in the presence of different concentrations of cisplatin (ic50 at 31.4 µm) and hymenialdisine (ic50 at 146.6 µm. b: viability percentage for a2780cp in the presence of different concentrations of cisplatin (ic50 at 76.9 µm) and hymenialdisine (ic50 was not reached at 300 µm). hymenialdisine is cytotoxic against cisplatin-sensitive but not against cisplatin-resistant cell lines 634 | squ medical journal, november 2021, volume 21, issue 4 alkaloids, including hymenialdisine, which act through the inhibition of mapk-1, may inhibit apoptosis and promote cell proliferation because of the differential expression of mirnas in the cisplatin-resistant cells.9 alternatively, hymenialdisine may exert its anti-proliferative activity through the inhibition of membrane transport, cell proliferation and/or differentiation. the mechanisms through which drugs such as cisplatin and hymenialdisine interact need to be studied further. conclusion while the results of this study showed the inhibitory effect of hymenialdisine against cisplatin sensitive cell lines, the effect against the cisplatin-resistant cell lines was not pronounced. this could have been either due to a similar mechanism of toxicity between cisplatin and hymenialdisine or due to hitherto unexplained mechanisms. therefore, the study of the mechanism of action of hymenialdisine would be useful if the compound were to be used in combination with cytotoxic chemotherapy or used to overcome drug resistance. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by his majesty’s trust fund grant (sr/med/mede/17/01). a c k n o w l e d g e m e n t we thank prof benjamin tsang for providing a2780s and a2780cp cell lines. a u t h o r s’ c o n t r i b u t i o n na and nb carried out the experiments in the laboratory; sih, sb, sd, yt and ib wee involved in designing of the experiments and in writing and reviewing the manuscript. all authors approved the final version of the manuscript. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2018; 68:394–424. https://doi. org/10.3322/caac.21492. 2. mcguire wp 3rd, markman m. primary ovarian cancer chemotherapy: current standards of care. br j cancer 2003; 89:s3–8. https://doi.org/10.1038/sj.bjc.6601494. 3. markman m. combination versus sequential cytotoxic chemotherapy in recurrent ovarian cancer: time for an evidence-based comparison. gynecol oncol 2010; 118:6–7. https://doi.org/10.1016/j.ygyno.2010.03.017. 4. peres lc, cushing-haugen kl, köbel m, harris hr, berchuck a, rossing ma, et al. invasive epithelial ovarian cancer survival by histotype and disease stage. j natl cancer inst 2019; 111:60–8. https://doi.org/10.1093/jnci/djy071. 5. dobretsov s, tamimi y, al-kindi ma, burney i. screening for anti-cancer compounds in marine organisms in oman. sultan qaboos univ med j 2016; 16:168–74. https://doi.org/10.18295/ squmj.2016.16.02.006. 6. mattia ca mazzarella l, puliti r. 4-(2-amino-4-oxo-2imidazolin-5-ylidene)-2-bromo-4, 5, 6, 7-tetrahydropyrrolo [2, 3-c] azepin-8-one methanol solvate: a new bromo compound from the sponge acanthella aurantiaca. acta cryst 1982; 38:2513–15. https://doi.org/10.1107/s0567740882009236. 7. al bahlani s, fraser m, wong ay, sayan bs, bergeron r, melino g, et al. p73 regulates cisplatin-induced apoptosis via a calcium/calpain-dependent mechanism. oncogene 2011; 30:4219–30. https://doi.org/10.1038/onc.2011.134. 8. meijer l, thunnissen am, white aw, garnier m, nikolic m, tsai lh, et al. inhibition of cyclin-dependent kinases, gsk3beta and ck1 by hymenialdisine, a marine sponge constituent. chem biol 2000; 7:51–63. https://doi.org/10.1016/s10745521(00)00063-6. 9. tasdemir d, mallon r, greenstein m, feldberg lr, kim sc, collins k, et al. aldisine alkaloids from the philippine sponge stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (mek-1). j med chem 2002; 45:529–32. https://doi.org/10.1021/jm0102856. 10. alex aw, carpenter n, lottin jr, mcclelland ra, nicholson ri. synthesis and evaluation of novel anti-proliferative pyrroloazepinone and indoloazepinone oximes derived from the marine natural product hymenialdisine. eur j med chem 2012; 56:246–53. https://doi.org/10.1016/j.ejmech.2012.08.022. 11. zhu k, fukasawa i, fujinoki m, furuno m, inaba f, yamazaki t, et al. profiling of proteins associated with cisplatin resistance in ovarian cancer cells. int j gynecol cancer 2005; 15:747–54. https://doi.org/10.1111/j.1525-1438.2005.00247.x. 12. yang h, kong w, he l, zhao j-j, o'donnell jd, wang j, et al. microrna expression profiling in human ovarian cancer: mir-214 induces cell survival and cisplatin resistance by targeting pten. cancer res 2008; 68:425–33. https://doi. org/10.1158/0008-5472.can-07-2488. 13. brown r, hirst gl, gallagher wm, mcilwrath aj, margison gp, van der zee ag, et al. hmlh1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. oncogene 1997; 15:45–52. https://doi. org/10.1038/sj.onc.1201167. 14. kumar s, kumar a, shah pp, rai sn, panguluri sk, kakar ss. microrna signature of cis-platin resistant vs. cis-platin sensitive ovarian cancer cell lines. j ovarian res 2011; 4:17. https://doi.org/10.1186/1757-2215-4-17. departments of 1paediatrics and 2paediatric surgery, pandit bhagwat dayal sharma post graduate institute of medical sciences, rohtak, haryana, india *corresponding author’s e-mail: jasbir2001@gmail.com التشوه العمالق لألوعية الدموية يف يد رضيع جا�صرب �صينغ، كمال رتان، بونام دالل giant vascular malformation in an infant’s hand *jasbir singh1, kamal n. rattan2, poonam dalal1 a 40-day-old infant weighing 3.5 kg was referred to the department of paediatric surgery at pandit bhagwat dayal sharma post graduate institute of medical sciences, rohtak, haryana, india, in 2016 with swelling of the left hand since birth. the swelling was soft, oval and approximately 9 × 7 cm in size starting from the base of the hand proximally and extending up to the distal interphalangeal joints [figure 1]. the size of swelling had progressively increased since birth. due to the large size of the swelling, movement of the wrist joint was restricted and the hand was grossly deformed. an x-ray of the lesion revealed a soft tissue swelling with multiple calcifications. absolute platelet count and coagulation profile were within normal ranges; abdominal ultrasound and chest x-ray were unremarkable. with the differential diagnosis of giant vascular malformation, infantile haemangioma and tufted angioma involving proximal part of all fingers, palmer and dorsal surface of the hand, further interventions were planned. however, the parents chose to discharge the infant against medical advice. comment the diagnosis of vascular lesions such as infantile haemangioma, kaposiform haemangioendothelioma (khe), tufted angioma (ta) and vascular malform ations are usually established by clinical features, radio-imaging and immunohistochemical markers.1 benign vascular neoplasm khe has a wider age of presentation then infantile haemangioma. similarly, ta presents in infants, children or young adults and are usually located on the neck or the upper part of the thorax. both, khe and ta have glucose transporter protein isoform (glut1) negative endothelial cells and sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e262–263, epub. 5 nov 19 submitted 6 mar 19 revisions req. 15 apr & 30 may 19; revisions recd. 2 may & 9 jun 19 accepted 30 jun 19 figure 1: photographs of the hand of a 40-day-old infant showing the (a) palmer and (b) dorsal aspect of a haemangioma. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.015 interesting medical image https://creativecommons.org/licenses/by-nd/4.0/ jasbir singh, kamal n. rattan and poonam dalal interesting medical image | e263 may be associated with thrombocytopaenia. vascular malformations are congenital lesions that sometimes become apparent later in life and do not involute spontaneously. haemangiomas are the most common benign soft tissue tumours in infants, found in 4–10% with higher female preponderance.2 haemangiomas are seen most commonly in the craniofacial region (60%), followed by the trunk (25%) and extremities (15%). immunohistochemical markers such as glut1 can be useful for differentiating haemangiomas from other vascular lesions.3 after a rapidly proliferative phase during the early infantile period, most uncomplicated lesions undergo spontaneous slow involution and an active non-intervention approach may be preferred.4 however, some children require further intervention due to associated complications. therapeutic interventions are based on the location, size of haemangioma, age of the patient, presence of complications and experts’ and parents’ preferences. beta-blockers (e.g. oral propranolol) haveshown promising results in uncomplicated haeman giomas; however, detailed cardiovascular and respiratory evaluation is required before initiating these drugs.5 oral propranolol therapy is usually given for 6–12 months depending on the size and location of the lesion. in recent years, the use of corticosteroids to treat haemangiomas has decreased and is only used when beta-blockers are contraindicated.4 other medications such as vincristine, interferon-α and imiquimod may be useful but are rarely used due to their serious side effects. recently, the common antifungal agent itraco nazole has been found to be useful in the treatment of infantile haemangioma by inhibiting proliferation and promoting apoptosis of infantile primary haeman gioma endothelial cells.6 in addition to pharmacological treatment, laser therapy and surgical interventions are alternative treatment options. although pulsed-dye laser treat ment has debatable efficacy, they may be used on superficial lesions.7 excisional surgery may be under taken when the haemangioma causes visual or sub glottic obstruction, bleeding or recurrent ulceration as well as slow involution or failure of pharmacological treatment.5 references 1. perman mj, castelo-soccio l, jen m. differential diagnosis of infantile hemangiomas. pediatr ann 2012; 41:e160–6. https://doi.org/10.3928/00904481-20120727-09. 2. lowe lh, marchant tc, rivard dc, scherbel aj. vascular malformations: classification and terminology the radiologist needs to know. semin roentgenol 2012; 47:106–17. https://doi. org/10.1053/j.ro.2011.11.002. 3. darrow dh, greene ak, mancini aj, nopper aj. diagnosis and management of infantile hemangioma: executive summary. pediatrics 2015; 136:786–91. https://doi.org/10.1542/peds.201 5-2482. 4. sethuraman g, yenamandra vk, gupta v. management of infantile hemangiomas: current trends. j cutan aesthet surg 2014; 7:75–85. https://doi.org/10.4103/0974-2077.138324. 5. sepulveda a, buchanan ep. vascular tumors. semin plast surg 2014; 28:49–57. https://doi.org/10.1055/s-0034-1376260. 6. chen s, zhuang k, sun k, yang q, ran x, xu x, et al. itraconazole induces regression of infantile hemangioma via down regulation of the platelet-derived growth factor-d/pi3k/ akt/mtorpathway. j invest dermatol 2019; 139:1574–82. https://doi.org/10.1016/j.jid.2018.12.028. 7. stier mf, glick sa, hirsch rj. laser treatment of pediatric vascular lesion: port wine stains and hemangiomas. j am acad dermatol 2008; 58:261–85. https://doi.org/10.1016/j.jaad.200 7.10.492. https://doi.org/10.3928/00904481-20120727-09 https://doi.org/10.1053/j.ro.2011.11.002 https://doi.org/10.1053/j.ro.2011.11.002 https://doi.org/10.1542/peds.2015-2482 https://doi.org/10.1542/peds.2015-2482 https://doi.org/10.4103/0974-2077.138324 https://doi.org/10.1055/s-0034-1376260 https://doi.org/10.1016/j.jid.2018.12.028 https://doi.org/10.1016/j.jaad.2007.10.492 https://doi.org/10.1016/j.jaad.2007.10.492 clinical & basic research squ med j, december 2009, vol. 9, iss. 3, pp. , epub submitted 19th september 09 revision req. 28th oct 09 revision recd. 1st nov 09 accepted 4th nov 09 1oral health department, sultan qaboos university hospital, muscat, sultanate of oman; 2biotechnology and craniofacial section, glasgow university dental school, uk; 3infection and immunity section, glasgow university dental school, uk. *to whom correspondence should be addressed. email: abakathir@squ.edu.om العوامل املؤدية إىل انتشار التهابات األسنان دراسة استباقية ارتيادية عبدالعزيز عبداهلل باكثير، خورشيد ف. موس، أشرف فوزي أيوب، جيرمي باج متعددة استباقية بدراسة القيام مت والوجه. الفم منطقة في خطورة االلتهابات أكثر من السنية االلتهابات يعد انتشار امللخص: الهدف: املراكز في مقاطعة غرب اسكوتالندا للتحقق من دور العوامل االجتماعية والبدنية واجلرثومية في حصول وانتشار التهابات األسنان. الطريقة: مت دراسة 25 مريضا مصابا بالتهابات األسنان الشديدة خالل فترة 6 أشهر. عند دخول املستشفى شمل التقييم الطبي األولي ارتفاع درجة حرارة اجلرثومية العينات أخذ للمرضى. مت والطبية واالجتماعية السكانية البيانات جمع . مت احلياتية الكيماوية والفحوصات الدم وفحوصات اجلسم لدراسة اجلراثيم املسببة باإلضافة إلى تسجيل الطريقة الطبية املستخدمة في عالج االلتهابات لكل مريض. النتائج: معظم االلتهابات كانت لها عالقة باألسنان أو بجذور األسنان.كان %80 من املرضى من املدخنني و %72 منهم كانوا من سكان أحياء فقيرة. خمسة مرضى كانوا يتعاطون اخملدرات عن طريق الوريد، وأربعة مرضى مدمنون على الكحول، وستة مرضى مصابون بأمراض بدنية واثنان معرضان لسوء التغذية . ارتفاع مستوى سبب إزالة بدون سابقا احليوي املضاد استخدام سوء االلتهاب. شدة لتقييم مفيدا مؤشرا كان املستشفى دخول (ج) عند املتفاعل البروتني االلتهاب كان شائعا في هذه الدراسة. تشير نتائج زراعة جراثيم االلتهابات إلى عدة جراثيم الهوائية خاصة العقديات الال هوائية والبريتوفيلال واملغزلية. . اخلالصة: انتشار االلتهابات السنية ال يزال شائعا وأظهرت الدراسة االرتيادية احلالية إلى وجود عالقة وثيقة مع حالة الفقر االجتماعي والتدخني. زيادة التحقق من دور سوء التغذية في انتشار االلتهابات السنية سيكون مستحبا. الوصف اجلزيئي للجراثيم املسببة اللتهابات األسنان سيساعد على إيضاح فيما إذا كانت العوامل البكتيرية لها دور في حتويل خراج االسنان املوضعي إلى التهابات منتشرة و خطيرة. مفتاح الكلمات: التهاب األسنان، اجلراثيم الالهوائية، مضاعفات. abstract: objectives: spreading odontogenic infections (soi) are the commonest type of serious infections encountered in the orofacial region. a prospective multi-centre study was conducted in the west of scotland to investigate the contributing role of social, systemic and microbial factors in the pathogenesis of soi. methods: twenty-five patients with severe odontogenic infections were recruited over a period of six months. at admission, clinical assessment included temperature rise, haematological and biochemical investigations. demographic data, social and past medical histories were obtained. microbiology samples were collected to identify causative microorganisms and the clinical management of each infection was recorded. results: most infections were associated with teeth or roots. eighty percent of the patients were tobacco smokers and 72% came from deprived areas. five patients were intravenous drug users, four admitted chronic alcohol abuse, six had underlying systemic disorders and two were at high risk of malnutrition. a raised c-reactive protein at admission was a useful indicator of the severity of infection. inappropriate prior antibiotic treatment in the absence of surgical drainage was common. microbiology results showed a predominance of strict anaerobes, notably anaerobic streptococci, prevotella and fusobacterium species. conclusion: sois remain surprisingly common and our present pilot study showed a particular association with social deprivation and tobacco smoking. further elucidation of the role of malnutrition in soi would be of interest. molecular characterisation of the microflora associated with soi may help to highlight whether bacterial factors play a role in converting a localised dentoalveolar abscess into a serious, spreading odontogenic infection. key words: dental focal infection; anaerobic bacteria; complications. factors contributing to the spread of odontogenic infections a prospective pilot study *abdulaziz a bakathir,1 khursheed f moos,2 ashraf f ayoub,2 jeremy bagg3 clinical & basic research advances in knowledge 1. the study shows that spreading odontogenic infection (soi) has a particular association with social deprivation and tobacco smoking. 2. molecular characterisation of the associated microflora may help to determine the pathogenicity of the microorganisms involved in soi. 3. the study stimulates the need to conduct futher studies into the role of social and systemic factors in the pathogenesis of soi. abdulaziz a bakathir, khursheed f moos,ashraf f ayoub and jeremy bagg clinical and basic research | 297 spreading odontogenic infections (soi) are the commonest type of serious orofacial infection encountered by oral and maxillofacial surgeons.1-3 although the incidence of these infections has decreased over the past few decades, they do still occur and expeditious early management is required to prevent or minimise the development of potentially serious complications such as airway obstruction.2,4,5 there have been relatively few studies of the factors contributing to the spread of odontogenic infections, but local, systemic and social factors are believed to play a role.2,5,6 while there is a considerable understanding of the influence of local factors, such as the anatomic location of teeth and the surrounding facial planes,2, 5 there is limited literature on the contribution of other factors such as poverty, deprivation, smoking and substance abuse, which may all play contributory roles in the development and severity of such infections. furthermore, there is also a limited literature on the role of systemic factors in the spread of odontogenic infections. in 1992, helfrick and kelly6 proposed 13 risk factors, which were associated with increased potential for complications in odontogenic infections. among these factors was the presence of co-existing major systemic disease that puts the patient into an american society of anesthesiologists (asa) classification of ii, iii or iv. in addition, systemic conditions that interfere with normal healing processes and haemostasis were highlighted as risk factors, including diabetes mellitus, bleeding dyscrasias, steroid therapy, immune suppression and malnutrition. it is also recognised that patients with pre-existing medical conditions often suffer from more serious soi and have an increased length of hospital stay.7-9 published data describing the microbiology of soi, highlight their polymicrobial nature,10-12 which is similar to localised dentoalveolar infection. however, a higher incidence of fusobacterium and bacteroides species has been reported in spreading infections.10 there is also a higher prevalence of streptococcus milleri (now classified as the anginosus group of oral streptococci) in severe odontogenic infections.10, 13 the combination of streptococci milleri and fusobacterium species has also been reported in life-threatening soi, highlighting the important concept of bacterial synergism.10, 14, 15 to date, we are unaware of any published work that has looked prospectively at factors which contribute to soi. addressing such factors could be of great importance in the prevention and management of these infections. to address this gap in our knowledge, a prospective pilot study was devised to investigate the role of social factors (such as deprivation, smoking, alcohol and drug abuse), systemic factors (including malnutrition and underlying systemic disease) and the microbiological flora in the pathogenesis of soi. methods this prospective multi-centre pilot study was conducted in the west of scotland oral & maxillofacial service centres, united kingdom. patients presenting with soi at the above centres for treatment, from february to july 2003, were included in this study. the hospitals involved were glasgow dental hospital & school, canniesburn hospital, victoria infirmary, western infirmary, glasgow royal infirmary, crosshouse district general hospital, monkland’s district general hospital and yorkhill royal hospital for sick children. ethical approval was obtained from the respective research ethics committees in the participating hospitals. patients with soi which involved one or more fascial spaces were enrolled. patients requiring treatment under local or general anaesthesia were eligible for inclusion. all patients gave informed consent before enrolment into the study. at admission, demographic data were collected for each patient together with social and past medical histories. the deprivation category for each was obtained by utilising the postcode area application to patient care 1. raised c-reactive protein level at admission was a useful indicator of the severity of soi compared to white cell counts. 2. the microbiology of soi is mixed in nature with a predominance of strict anaerobes. 3. the management of soi includes: airway monitoring, surgical draining with removal of causative agent and administration of empirical antibiotics. factors contributing to the spread of odontogenic infections a prospective pilot study 298 | squ medical journal, december 2009, volume 9, issue 3 of the patient and the carstairs scores for scottish postcode sectors from the 1991 census.16 category 1 refers to the most affluent and category 7 to the most deprived areas. a full history of the current complaint was collected, including duration and any recent treatment. alcohol intake was measured in units per week. acceptable limits were as 21 units/week for males and 14 units/week for females. smoking history was quantified by pack per year (py), quantified as “number of cigarettes x number of smoking years/20”. the temperature on admission was recorded for all patients. the source of infection was identified, together with the facial spaces involved. trismus was recorded on a four point scale from none to severe (< 10mm), and pain was assessed by each patient using a visual analogue scale. venous blood was collected from each patient for a full blood count, haematinics (vitamin b12, folate and ferritin), serum proteins (albumin, prealbumin, transferring globulins and total proteins), random blood glucose, liver function test, and c-reactive protein (crp). the weight in kilogrammes and height in metres were recorded in order to calculate the body mass index (bmi). the risk of protein energy malnutrition was assessed by means of the simple nutritional screening tool (snst), which utilises the body mass index (bmi) and serum albumin level to provide a score of 0-4 [table 1].17 individuals with a score of 2-4 are categorized as at high risk for protein energy malnutrition. during the surgical management of the infection, a note was taken of whether an emergency airway was needed, of the method of drainage and any antibiotics prescribed. in addition, pus samples were obtained for microbiological investigations. a note was taken of whether antibiotics had been administered prior to sample collection. before sampling, the oral mucosa was disinfected with 0.2% chlorhexidine gluconate solution (corsody1, smithkline beecham healthcare, uk) and the skin was disinfected with a 10% alcoholic solution of povidone-iodine (betadine, seton, england). sampling was accomplished either intra-orally through intact oral mucosa or extra-orally through intact skin, using a sterile, disposable 5ml syringe (plastipak™, becton dickinson, spain) through a gauge-21 needle (microlance, becton dickinson, spain). in cases where no pus could be aspirated, sampling of sero-sanguinous fluid was undertaken using a sterile transport swab (probact, technical service consultants ltd, uk). a direct gram-stained smear was prepared from each aspirate. each specimen was then inoculated onto columbia blood agar for incubation in 5% co2 at 37°c and onto fastidious anaerobe agar (bioconnections, wetherby, uk) with 7.5% horse blood for anaerobic incubation at 37°c. plates were incubated for 48 hours and purity plates prepared of each morphological colony type. isolates were identified according to standard laboratory techniques and antimicrobial drug susceptibilities determined by the stokes method. results of the 25 patients who participated, 16 (64%) were male. the age range of the study patients was 8-57 years (mean 28.7 years), of whom 36% were in the 21-30 year age group. thirteen patients (52%) were categorised in the deprivation category 7 and a further 10 patients (40%) divided equally between deprivation categories 5 and 6. one patient was in each of the deprivation categories 1 and 2. twenty patients (80%) were active smokers. the mean py for smokers was 17.2 with a range from 0.5 to 80 py. of the 16 male patients, 11 were smokers; all of the table 1: simple nutritional screening tool risk factors 1 point 2 points score bmi adult (< 64 yrs of age) 17-18.4 <17 elderly (> 65 yrs of age) 21-23.9 <21 albumin 28-35g/l <28g/l total score of tool 0 1 point = low risk of pem total score 2 4 points = high risk of pem legend: bmi = body mass index; pem = protein energy malnutrition abdulaziz a bakathir, khursheed f moos,ashraf f ayoub and jeremy bagg clinical and basic research | 299 female patients smoked. the mean py for females was 19.5 and for males were 15.1, but the difference was not statistically significant. seven patients (28%) reported no alcohol intake. fourteen of the remaining 18 patients reported alcohol intake within acceptable limits. four patients (16%) consumed more than 25 units of alcohol per week. five patients (20%), of whom three were male, gave a history of previous or current recreational intravenous drug use (ivdu). all these five patients were also active smokers. six patients (24%) suffered from an underlying medical condition. one had drugcontrolled diabetes mellitus; one was hypertensive and taking atenolol; two were asthmatic controlled with prednisolone, becotide 100 and ventolin and two had iron deficiency anaemia. according to the snst, two patients were at high risk of protein energy malnutrition, with snst scores of 3. all of the patients presented with pain and swelling. most (92%) also had fever and trismus. sixteen (64%) patients had dysphagia and three (12%) were suffering respiratory distress. twentytwo (88%) patients had a combination of hard and fluctuant areas of swelling, cellulites and a discharging sinus. the mean duration of infection was 3 days (range 1-10 days). previous episodes of infection were reported by 48% of the patients. eight patients (32%) gave no recent history of antibiotic use. seventeen patients (68%) were on oral antibiotics at admission. these had been prescribed by a general medical practitioner in 13 cases (77%) and by a general dental practitioner in four cases (23%). amoxicillin, both singly and in combination with metronidazole, was the most commonly prescribed antibiotic [table 2]. each case of soi was categorised by the fascial space or spaces involved, as described by laskin.5 in 14 patients, multiple fascial spaces (up to a maximum of 5) were involved. the buccal space was the most commonly involved fascial space (96%), followed by the submandibular space (68%) [table 3]. the most common source of infection was carious teeth and roots (88% of cases). in two patients, the infection was post-extraction, one after surgical removal of a wisdom tooth and the other following multiple extractions of grossly carious deciduous molars. the source of infection was an impacted wisdom tooth in one elderly patient. the mandibular posterior teeth were the most common source of infection (64%), particularly the first and second molars, followed by the upper anterior teeth (16%). all patients were managed by incision and drainage, removal of the source of infection and antibiotics. twenty-two patients were managed as in-patients and the remaining three as out-patients. all patients underwent surgical drainage within 24 hours of initial presentation. five of the in-patients and three outpatients were managed under local anaesthesia (la). seventeen in-patients received surgical drainage under general anaesthesia (ga), three of whom required further surgical drainage, two under la and one patient, with diabetes mellitus, requiring a second ga to establish adequate drainage. all patients received a combination of two antibiotics. those treated as in-patients received intravenous antibiotics. metronidazole was prescribed to all 25 patients. the choice of second antibiotic was variable. cefuroxime (10 cases) and augmentin (6 cases) were the most commonly prescribed agents. two patients received benzyl penicillin, four amoxicillin and one flucloxacillin. erythromycin was used in two cases for patients who were allergic to penicillin, although two patients who received cefuroxime were also allergic to penicillin. four patients (16%) required airway control. three of these patients had a compromised airway with difficulty breathing at admission; one had an extensive swelling with a potential risk of airway obstruction. as a secure method of airway control, three patients had a tracheostomy under general anaesthesia and one had an endotracheal intubation over a period of four days. the mean period of hospitalisation for the 22 in-patients was 4.2 days (range 1-16 days). investigations at admission revealed that twenty-three patients (92%) had pyrexia (> 37°c) table 2: type of antibiotic prescribed to patients (n = 17) prior to admission antibiotic used number (%) amoxycillin 5 (29.4%) erythromycin 4 (23.5%) penicillin 2 (11.8%) metronidazole 1 (5.9%) amoxycillin and metronidazole 4 (23.5%) penicillin and metronidazole 1 (5.9%) factors contributing to the spread of odontogenic infections a prospective pilot study 300 | squ medical journal, december 2009, volume 9, issue 3 on admission. the mean temperature was 37.9°c (range 37.2-39°c). haematological investigations found that the range of white cell counts (wbc) was 7.9 20.9 x 10/l (mean 13.2 x 10/l). the mean haemoglobin (hb) level was 13.5g/l (range 10.1 16.6g/l), and within the normal range for age and sex in all but five patients. two of these patients had an associated low serum ferritin indicative of iron deficiency anaemia. no patients demonstrated reduced vitamin b12 or folate levels. biochemical investigations revealed that the level of crp was raised in all patients (mean 126.9 mg/l; range of 20-393 mg/l). the mean crp level was higher in females (154.3 mg/l) than males (115.5 mg/l), but the difference was not found to be statistically significant. liver function tests were normal in 24 patients. one patient, who reported high alcohol consumption, demonstrated raised serum aspartate aminotransferase (ast) and serum alanine aminotransferase (alt) liver enzymes levels. microbiology samples from 13 patients were processed at the specialist oral microbiology diagnostic laboratory at glasgow dental hospital (gdh). the remaining 12 samples were processed in the general medical microbiology laboratories at three of the other hospitals participating in the study. due to variation in the standard operating and reporting procedures of the four laboratories, results could not be compared directly. for this reason, microbiology data are only presented for the 13 specimens that were processed in the specialist oral microbiology laboratory. one of the 13 samples provided no growth. this patient had been taking antibiotics for more than five days. of the remaining 12 samples, three yielded growth of anaerobes only and nine were mixtures of aerobic and anaerobic bacteria. table 4 shows the bacteria isolated from the 12 remaining samples. the ratio of anaerobes to aerobes/facultative anaerobes was 2:1. among the aerobes/facultative anaerobes, microorganisms from the anginosus group of streptococci were the most commonly isolated organisms, accounting for six isolates (35.5%). anaerobic bacteria, notably anaerobic streptococci, prevotella, and fusobacterium species were the most frequently isolated obligate anaerobes. the average number of bacterial species per sample was 4.3. antibiotic sensitivity tests showed that erythromycin resistance was encountered in three patients with five resistant microorganisms (streptococcus constellatus, two prevotella species, fusobacterium nucleatum and haemophilus parainfluenzae). penicillin resistance was also encountered in two patients with three different microorganisms, two strains of bacteroides species and one strain of fusobacterium species. a cefuroxime-resistant bacteroides species was encountered in one patient [table 4]. metronidazole was active against all isolates of strict anaerobes. discussion the spread of odontogenic infections through fascial spaces can result in significant morbidity and risk of mortality if clinical management is inappropriate.1,4 an understanding of the infection process, risk factors and the microbiology of these infections is of importance if effective clinical protocols are to be developed. the predominance of male patients with soi identified in this study has been reported by others,3,18 although this predominance has been less marked in other series.10,12 we identified a broad range of ages of patients, from 8 to 57 years (mean 28.8 years), with 36% of patients in the 21-30 year group. this finding compares well with other studies.8, 12, 14 har-el et al., in a retrospective study of 110 patients with deep neck abscesses, reported a high incidence of infections in socially deprived patients.9 in the present pilot study, we used the carstairs scores for scottish postcode sectors (cssps) to assess the deprivation category and table 3: frequency of involvement of fascial spaces in soi (25 patients) spaces frequency (%) buccal 24 (96%) submandibular 17 (68%) submasseteric 9 (36%) sublingual 7 (28%) lateral pharyngeal (parapharyngeal) 4 (16%) submental 3 (12%) canine 2 (8%) pterygomandibular 1 (4%) retropharyngeal 1 (4%) abdulaziz a bakathir, khursheed f moos,ashraf f ayoub and jeremy bagg clinical and basic research | 301 thereby the socio-economic status of our patients. the cssps has been widely used as a method of recording the deprivation category for many epidemiological studies, including the scottish boards dental epidemiological programme.16 based on this system we observed a high incidence (72%) of soi among patients living in deprived areas (deprivation categories 6 and 7). there is evidence in the literature supporting the role of smoking in the pathogenesis of periodontal disease.2 in the present study there was a high prevalence of smokers among those with soi. it is unclear whether this is an indirect reflection of health neglect or a more subtle influence of tobacco smoking on immune responses to odontogenic infection. this area is worthy of future study. a few case studies have reported soi in ivdu.2,3,19 five patients (20%) with soi in the present study were ivdu, four of whom were on a methadone programme. methadone, which is widely used in the united kingdom for patients undergoing rehabilitation from opioids addiction, is frequently delivered orally in the form of a sugarcontaining syrup. this high sugar content can result in the development of rampant caries in patients with poor oral hygiene.20 four patients were categorised as alcohol users, with an average intake of >25 units/ week. none had clinical symptoms of liver disease, although one had elevated liver enzymes levels. six patients (24%) had an underlying systemic disease. the association between underlying medical conditions or immunosuppressive treatments, such as diabetes mellitus and steroid therapy, and the risk of soi is well documented.2, 6, 9, 19 the association between nutritional deficiencies and immune deficiency is also recognised.21 however, to our knowledge there have been no studies of malnutrition in relation to soi. in the light of the high level of deprivation for many of the patients in this study, the role of nutritional status is worthy of examination. detailed assessment of nutritional status for the patients recruited in this study proved difficult. initial attempts involved making a number of measurements, tests and completion of a detailed dietary questionnaire, all of which were logistically very difficult with acutely ill patients. instead, the simple nutritional screening tool was used, which required only height, weight and serum albumin estimation. two patients were identified by this method to be at high risk of protein energy malnutrition. this preliminary finding suggests that a carefully constructed and controlled study of nutritional factors in soi would be worthwhile. at initial presentation, the mean duration of table 4: bacteria cultured at glasgow dental hospital from 12 pus samples of spreading odontogenic infections bacteria isolated no. of times isolated aerobes/facultative anaerobes streptococcus anginosus 5 streptococcus constellatus 1 streptococcus oralis 2 streptococcus parasanguis 1 streptococcus mitis 1 streptococcus sanguis 1 streptococcus sobrinus 1 streptococcus salivarius 1 haemophilus parainfluenzae 2 actinomyces naeslundii 1 eikenella corrodens 1 total aerobes/facultative anaerobes 17 anaerobes anaerobic streptococci 8 fusobacterium nucleatum 2 fusobacterium species (unspecific) 4 prevotella intermedia 2 prevotella oralis 2 prevotella loeschii 1 prevotella buccae 2 prevotella melaninogenica 1 prevotella dentocola 1 bacteroides ureolyticus 1 bacteroides capillosus 1 bacteroides species (unspecific) 2 veillonella species 4 propionibacterium propionicum 1 propionibacterium acne 1 bifidobacterium species 1 total anaerobes 34 total bacteria isolated 51 factors contributing to the spread of odontogenic infections a prospective pilot study 302 | squ medical journal, december 2009, volume 9, issue 3 symptoms for our sample of patients was 3 days, ranging from 1-10 days. krishnan et al., in a review of 50 maxillofacial infections, stated that most of their patients had presented with symptoms of at least one week in duration.22 ylijoki et al. reported that dental pathology caused by carious or periodontally involved teeth was the commonest cause of soi, accounting for 74% in a sample of 100 patients.19 post-extraction was the second most common cause (15%) followed by pericoronitis related to impacted third molars (9%), and infected dental cysts (2%). our findings are in agreement with this and other studies.19,22 our finding that the molars were the most commonly involved teeth in soi also accords with previously published studies.6,8,12,23 odontogenic infections usually spread from the structures supporting the teeth along the path of least resistance to involve the potential fascial spaces of the head and neck.5 in the current study, we observed that the offending teeth showed an obvious relationship to the adjacent anatomical spaces involved in the infection. the buccal space was the most frequently involved space (96%), followed by the submandibular space (68%) and the submasseteric space (36%). this finding contradicts earlier reports that the submandibular space is the most frequently involved in soi.10,22 while our study identified a different order of the frequency of involvement of fascial spaces, we found a much higher proportion of submandibular and buccal space infections than previously reported.8, 19 many published reports have indicated that most patients with soi were on antibiotics at admission.6,7,14,22 furthermore, ylijoki et al.19 observed that 55% of a sample of 100 patients with soi had received antibiotics prior to hospitalisation, most commonly a combination of penicillin and metronidazole. our results were similar, but with a much higher observed percentage of antibiotic use on admission (68%) than previously reported.7,10,19 these antibiotics were prescribed by general medical practitioners for 77% of patients and by general dental practitioners for 23% of patients. this observation highlights the willingness of patients with soi to visit their medical rather than dental practitioner, and the inappropriate use of antibiotics in primary care for the management of odontogenic infection, as opposed to establishing adequate surgical drainage. it is widely accepted that antimicrobial agents should not be considered as a substitute for surgical intervention in the management of soi.1-3,5 the protocol of the west of scotland oral & maxillofacial services for the management of soi consists of both early surgical and medical intervention, in agreement with other published protocols.12, 23 however, there was no clear antibiotic prescribing protocol within these surgical units for the management of soi. all the patients received metronidazole in combination with another antibiotic, of which cefuroxime was the most frequently prescribed (40%), followed by augmentin (24%) and amoxicillin (16%). this pattern of antimicrobial use reflects the polymicrobial nature of soi, which typically includes the anaerobic bacteria.1, 22 at admission, an elevated temperature was observed in 23 (92%) patients, with a mean temperature of 37.9°c, ranging from 37.2 to 39°c. many others have reported fever on admission7,12,23 an expected finding in patients with infections of the severity described in these studies. various haematological and biochemical tests were undertaken to provide a comprehensive clinical assessment of the patients. traditionally, the white blood cell count, erythrocyte sedimentation rate and admission temperature have been used to monitor the progress of infectious diseases.7 however, the wbc may react slowly to bacterial infections.24 in our study, the mean wbc was 13.2 x 09 /l with a range between 7.9 20.9 x 109 /l, similar to earlier studies.7,12,4,19 clearly the wbc at admission is normal or only slightly raised in many patients with soi. heimdahl et al.14 concluded that the wbc is of minor importance when judging the severity of orofacial infections, a view that the present study would support. the wbc is perhaps more useful in assessing a patient’s response to therapy. levels of crp are widely used to aid the diagnosis and to monitor many infections such as pneumonia, septic arthritis and acute meningitis.19 however, crp levels in odontogenic infections have not been widely studied. boucher et al. reported that high crp values were associated with acute dental abscesses.25 ylijoki et al. suggested that crp levels may be useful in the clinical assessment of patients with soi.19 in their prospective study of 100 patients with soi, they reported a mean crp level of 140.2mg/l in the patients who required critical care, compared to 76.7mg/l in non-critical care patients following surgical treatment of soi. abdulaziz a bakathir, khursheed f moos,ashraf f ayoub and jeremy bagg clinical and basic research | 303 furthermore, the eight patients who needed reoperation to establish further drainage of the infection had a mean crp level of 147.9 mg/l. the crp levels in all patients had fallen to near normal (10mg/l) by the time of discharge from hospital care. in our own study, the mean crp level was 126.9mg/l, ranging from 20 to 393mg/l. the three patients who required repeat incision and drainage had a mean crp level of 256 mg/l. on this basis, the crp level rises faster than wbc in soi, in agreement with published reports.19, 24, 25 the detailed microbiology resulst based on thirteen samples, indicated a predominance of anaerobic microorganisms over aerobic/facultative anaerobes, in line with other reports.3,10,14 the average number of bacterial species per sample was 4.3, similar to earlier reports.10,15 among the isolated aerobic/facultative anaerobic microorganisms, the anginosus group of oral streptococci was the most frequently isolated, with a total of six isolates (35.3%). this finding is similar to that reported in other studies and in published case reports of patients with soi.2,4,10,11,15,26,27 with regard to the anaerobic bacteria, prevotella and anaerobic streptococci species were the most common isolates, followed by fusobacterium and bacteroides species. this finding, despite the relatively small size of the sample, correlates well with that of heimdahl et al.,10 who reported a significantly higher frequency of bacteroides and fusobacterium species among patients with soi compared to localised infections. however, these microbiology data are all derived from traditional culture techniques. recent work on endodontic infections and dentoalveolar abscesses, utilising molecular biological techniques, has shown the presence of a wide range of fastidious and non-cultivable species.28 recently published work from from glasgow university dental school, utilising molecular techniques has identified a far more diverse microflora in soi with predominance of prevotella species.29 it is likely that such species may play a role in soi and, indeed, may be responsible for the aggressive nature of these infections. further work is required to examine in more detail the pathogenicity of microorganisms involved in soi and the associated host responses. with regard to antibiotic resistance, our experience, despite the observed resistance of some strains of bacteria to the antibiotics used, including penicillin, erythromycin and cefuroxime, shows that the use of a combination of antimicrobial agents, especially including metronidazole along with early surgical drainage, was associated with a complete and uneventful cure of the majority of studied patients except three patients who required second procedures to establish further drainage without the need to change the course of antibiotics. this observation was similar to the published work by labriola30 and kuriyama31 who reported that most patients were clinically well by the time antibiotic resistance was discovered. conclusion spreading odontogenic infections remain surprisingly common. in the present study, they showed a particular association with social deprivation and tobacco smoking and were typically caused by carious teeth or roots. a raised crp at admission was a useful indicator of the severity of infection. the microflora associated with soi was very similar to that reported for dentoalveolar abscesses, namely mixed infections with an anaerobic component. inappropriate prior treatment with an antibiotic in the absence of surgical drainage was common. additional work to elucidate the role of malnutrition in soi would be of interest. furthermore, molecular characterisation of the microflora associated with soi may help to highlight whether bacterial factors play a role in converting a localised dentoalveolar abscess into a serious, spreading odontogenic infection. a c k n o w l e d g e m e n t s the authors would like to thank all the participating patients, consultants, specialist registrars and senior house officers at the west of scotland oral & maxillofacial surgery units and staff of the oral microbiology department at glasgow dental hospital for their kind support throughout the period of the study. this paper was presented at the 17th international conference on oral & maxillofacial surgery in vienna, austria, on 2nd september 2005. c o n f l i c t o f i n t e r e s t the authors report no conflict of interest. factors contributing to the spread of odontogenic infections a prospective pilot study 304 | squ medical journal, december 2009, volume 9, issue 3 references 1. flynn tr. surgical management of orofacial infections. oral & maxillofac surg clin north am 2000; 8:77-100. 2. topazian rg, goldberg mh. oral and maxillofacial infections, 3rd ed. philadelphia: wb saunders, 1994. ch. 6. 3. bridgeman a, wiesenfeld d, hellyar a, sheldon w. major maxillofacial infections: an evaluation of 107 cases. austral dent j 1995; 40:281-8. 4. green aw, flower ea, new ne. mortality associated with odontogenic infection. br dent j 2001; 190:52930. 5. laskin dm. anatomic considerations in diagnosis and treatment of odontogenic infections. j am dent assoc 1964; 69:308-16. 6. helfrick j k, kelly jf. parameters of care for oral and maxillofacial surgery. a guide for practice, monitoring and evaluation. j oral maxillofac surg 1992; 50:1-174. 7. dodson tb, perrott dh, kaban lb. paediatric maxillofacial infections: a retrospective study of 113 patients. j oral maxillofac surg 1989; 47:327-30. 8. haug rh, hoffman mj, indresano at. an epidemiologic and anatomic survey of odontogenic infections. j oral maxillofac surg 1991; 49:976-80. 9. har-el g, aroesty jh, shaha a, lucente fe. changing trends in deep neck abscess. a retrospective study of 110 patients. oral surg oral pathol oral med 1994; 77:446-50. 10. heimdahl a, von konow l, satoh t, nord ce. clinical appearance of orofacial infections of odontogenic origin in relation to microbiological findings. j clin microbiol 1985; 22:299-302. 11. molina jm, leport c. clinical and bacterial features of infections caused by streptococcus milleri. scand j infect dis 1991; 23:659-66. 12. storoe w, haug rh, lillich tt. the changing face of odontogenic infections. j oral maxillofac surg 2001; 59:739-48. 13. whiley ra, beighton d. current classification of oral streptococci. oral microbiol immunol 1998; 13:195216. 14. heimdahl a, nord ce. orofacial infections of odontogenic origin. scand j infect dis 1983; 39:8691. 15. von konow l. nord ce, nordenram a. anaerobic bacteria in dentoalveolar infections. int j oral surg 1981; 10:313-22. 16. mcloone p. carstairs scores for scottish postcode sectors from the 1991 census. glasgow: public health research unit, university of glasgow, 1997. 17. laporte m, villalon l, payette h. simple nutrition screening tools for healthcare facilities: development and validity assessment. canad j diet prac & res 2001; 62:26-34. 18. kannangara dw, thadepalli h, mcquirter ji. bacteriology and treatment of dental infections. oral surg oral path oral med 1980; 50:103-9. 19. ylijoki s. suronen r, jousimies-somer h, meurman jh, lindqvist c. differences between patients with or without the need for intensive care due to severe odontogenic infections. j oral maxillofac surg 2001; 59:867-72. 20. meaney pj. methadone and caries. austral dent j 1997; 42:138-41. 21. lesourd bm. nutrition and immunity in the elderly: modification of immune responses with nutritional treatments. am j clin nutr 1997; 66:s478-84. 22. krishnan v, johnson jv, helfrick jf. management of maxillofacial infections: a review of 50 cases. j oral maxillofac surg 1993; 51:868-73. 23. sethi ds, stanley re. deep neck abscesses changing trends. j laryngol otol 1994; 108:138-43. 24. unkila-kallio l. kallio mj, peltola h. the usefulness of c-reactive protein levels in the identification of concurrent septic arthritis in children who have acute hematogenous osteomyelitis. j bone surg br 1994; 76:848-53. 25. boucher ne, hanharan jj, kihara fy. occurrence of c-reactive protein in oral diseases. j dent res 1976; 46:624-7. 26. cousin gcs. potentially fatal oro-facial infections: five cautionary tales. j roy coll surg edin 2002; 47:585-6. 27. al-qamachi lh, aga h, mcmahon j, leanord a, hammersley n. microbiology of odontogenic infections in deep neck spaces: a retrospective study. br j oral maxillofac surg 2009. article in press. doi: 10.1016/j.bjoms.2008.12.007. 28. rolph hj, lennon a, riggio m, saunders wp, mackenzie d, coldero l, bagg j. molecular identification of microorganisms from endodontic infection. j clin microbiol 2001; 39:3282-9. 29. riggio mp, aga h, murray ca, jackson ms, lennon a, hammersley n, bagg j. identification of bacteria associated with spreading odontogenic infections by 16s rrna gene sequencing. oral surg oral med oral pathol oral radiol endod 2007; 103:610-7. 30. labriola jd, mascaro j, alpert b. the microbiologic flora of orofacial abscesses. j oral maxillofac surg 1983; 41:71-14. 31. kuriyama t, karasawa t, nakagawa k, saiki y, yamamoto e, nakamura s. bacteriologic features and antimicrobial susceptibility in isolates from orofacial odontogenic infections. oral surg oral med oral pathol oral radiol endod 2000; 90:600-8. 1department of oral pathology & microbiology, institute of dental sciences, siksha ‘o’ anusandhan deemed to be university, bhubaneswar, odisha, india; 2department of management, school of commerce & management, central university of rajasthan, ajmer, india *corresponding author’s e-mail: swagatikapanda@soa.ac.in إحتمالية االستدالل ابلتغريات اجملهرية لغشاء الفم املخاطي للتنبؤ عن مرحلة ما بعد الوفاة جاغاناث باترو، �سواجاتيكا باندا، نيتا موهانتي، اأوما �سانكار مي�رشا abstract: objectives: the post-mortem interval (pmi) refers to the amount of time elapsed between death and discovery of the body. this study aimed to evaluate light microscopic cellular changes in the oral mucosa and identify the potential of this method for predicting pmi. methods: this prospective study was conducted between july 2016 and january 2018 at the institute of dental sciences, siksha ‘o’ anusandhan university, bhubaneswar, india. a total of 150 post-mortem (including 75 gingival and 75 buccal mucosa samples) and 40 ante-mortem (including 20 gingival and 20 buccal mucosa samples) tissue samples were compared using haematoxylin and eosin, periodic acid-schiff (pas) and van gieson stains. microscopic changes in the epithelium and connective tissue were categorised according to pmi stage as early (<12.5 hours since death), intermediate (12.5–20.5 hours since death) or late (>20.5 hours since death). results: most epithelial cellular changes occurred early, except for arc-shaped nuclei and epithelial shredding which were intermediate and late changes, respectively. however, microscopic changes in the connective tissue were only observable at ≥12.5 hours. there was a progressive decrease in intensity in van gieson stains and an increase in intensity in pas stains as pmi increased. several microscopic features were found to be significant predictors of pmi including epithelial homogenisation, cytoplasmic vacuolation, nuclear degeneration, arc-shaped nuclei, chromatin clumping, red blood cell clumping and lysis, melanin incontinency, myofibril degeneration, salivary gland acini degeneration and epithelial connective tissue separation (p <0.050 each). conclusion: these findings indicate that microscopic evaluation of the oral mucosa may be helpful for pmi prediction. keywords: post-mortem changes; light microscopy; oral mucosa; epithelial cells; lamina propria; salivary glands; histocytochemistry; periodic acid-schiff reaction; india. امللخ�ص: الهدف: ت�سري فرتة ما بعد الوفاة )pmi( اإىل مقدار الوقت املنق�سي بني املوت واكت�ساف اجل�سد. هدفت هذه الدرا�سة اإىل تقييم الدرا�سة هذه اأجريت الطريقة: .pmi مبوؤ�رش للتنبوؤ الطريقة هذه اإمكانات وحتديد للفم املخاطي الغ�ساء يف املجهرية اخللوية التغريات امل�ستقبلية بني يوليو 2016 ودي�سمرب 2018 يف معهد علوم طب الأ�سنان، جامعة �سيك�سا 'o' اأنو�ساندان، بوبان�سوار، الهند. متت مقارنة جمموعه تتكون من 150 عينة بعد الوفاة )ت�سمل 75 عينة من اللثة و 75 عينة من الغ�ساء املخاطي ال�سدق( و 40 عينة من الأن�سجة من الأحياء )مبا يف ذلك 20 عينة من اللثة و 20 عينة من الغ�ساء املخاطي ال�سدق( با�ستخدام الهيماتوك�سيلني واإيو�سني، و�سبغةحم�ض �سيف الدوري )pas( و�سبغة فان جي�سون. مت ت�سنيف التغريات امليكرو�سكوبية يف الن�سيج الظهاري والن�سيج ال�سام وفًقا ملرحلة ما بعد الوفاة اإىل مرحلة مبكرة )اأقل من 12.5 �ساعة منذ الوفاة(، متو�سطة )20.5-12.5 �ساعة منذ الوفاة(، ومتاأخرة )20.5> �ساعة منذ الوفاة(. النتائج: تغريات �سّكال اللذين الظهاري والتقطع قو�ض �سكل على النوى با�ستثناء املبكرة، املرحلة يف الظهارية اخللوية التغريات معظم حدثت متو�سطة ومتاأخرة على التوايل. ومع ذلك، كانت التغيريات املجهرية يف الن�سيج ال�سام ملحوظة فقط عند-12.5 �ساعة. كان هناك انخفا�ض امليزات من العديد على العثور مت الوفاة. بعد ما فرتة تزايد مع pas �سبغة كثافة يف وزيادة جي�سون فان �سبغ كثافة يف تدريجي �سكل على والنواة النووي، والتنك�ض ال�سيتوبالزمي، والتفريغ الظهاري، التجان�ض ذلك يف مبا الوفاة بعد ما بفرتة تنبًئا التي املجهرية قو�ض، وتكتل الكروماتني، وتكتل خاليا الدم احلمراء وحتللها، و�سل�ض امليالنني، وتنك�ض اللييفات الع�سلية، وتنك�ض الغدة اللعابية، وتف�سخ الأن�سجة الطالئية )p >0.050 لكل منها(. اخلال�صة: ت�سري هذه النتائج اإىل اأن التقييم املجهري للغ�ساء املخاطي للفم قد يكون مفيًدا كموؤ�رش للتنبوؤ عن فرتة ما بعد الوفاة. كيمياء اللعابية؛ الغدد القاعدي؛ الغ�ساء الظهارية؛ اخلاليا للفم املخاطي الغ�ساء ال�سوئي؛ املجهر الوفاة؛ بعد ما تغيريات املفتاحية: الكلمات الأن�سجة؛ تفاعل حم�ض �سيف الدوري؛ الهند. the potential of light microscopic features of the oral mucosa in predicting post-mortem interval jagganath patro,1 *swagatika panda,1 neeta mohanty,1 uma s. mishra2 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e34–41, epub. 15 mar 21 submitted 25 mar 20 revisions req. 18 may & 13 jul 20; revisions recd. 21 jun & 20 jul 20 accepted 13 aug 20 https://doi.org/10.18295/squmj.2021.21.01.005 clinical & basic research advances in knowledge the findings of the study not only emphasise the potential of light microscopy in the estimation of post-mortem interval, but also highlight the importance of special stains other than haematoxylin and eosin as a complementary tool in forensic investigation. to the best of the authors’ knowledge, this study is the first of its kind to depict the sequential, temporal, cellular and architectural histological features of the oral mucosa after death in a large sample using two distinct kinds of mucosal samples and three staining techniques. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ jagganath patro, swagatika panda, neeta mohanty and uma s. mishra clinical and basic research | e35 application to patient care estimation of time since death is an important forensic tool in identifying human remains and determining possible causes of death, thereby indirectly influencing patient care. thanatology refers to the philosophical and scientific study of various aspects of death including the forensic examination of bodily changes which take place at death and during the post-mortem period. while dozens of methods are currently used to determine the amount of time elapsed between death and discovery of the body—a period known as the post-mortem interval (pmi)— there is nevertheless still demand for more reliable and precise techniques.1 currently, many approaches to pmi estimation focus on observable and measurable changes to the body after death such as autolysis, algor mortis, rigor mortis, livor mortis and the digestive status of the stomach contents.1,2 following death, many physical and chemical changes begin to take place and continue until the body eventually decomposes. at the onset of death, respiration ceases and cell glycolysis begins, leading to the production of lactic acid followed by a drop in the ph of the cellular contents.3 eventually, cellular metabolism comes to an end and the subsequent predominance of lytic enzymes results in autolysis. the cell membranes disintegrate and a reduction in adenosine triphosphate levels causes loss of the cellular architecture and fatty acids.3 cell swelling occurs due to a decrease in energy level; subsequently, the cells progressively detach from one another in a process known as necrosis. the reduction in cellular energy causes disruption of the mitochondrial electron transport system and leads to fermentation, resulting in the formation of anaerobic lactic acid from pyruvic acid.3 utilising light microscopy, cells are perceived as dead after they have undergone a series of specific morphological changes which occur as a result of two distinct cellular processes: (1) apoptosis, a programmed and orderly form of cell death and (2) necrosis, a disorderly and unpredictable form of cell death. necrotic cells show an increased eosinophilia. nucleus of the epithelial cells may undergo changes like karyolysis, pyknosis and karyorrhexis.4 post-mortem cellular changes have been proven to reliably estimate pmi in several organs including the liver, kidney, pancreas and heart.5,6 as in other tissues, autolytic enzymes are released by the oral mucosal cells after death, resulting in abnormal morphology. therefore, researchers have explored the possibility of identifying time since death via microscopic examination of the oral mucosa.7 degenerative post-mortem changes to the epithelium and connective tissue in the oral mucosa may demonstrate specific patterns that could prove useful to determine pmi; however, few studies have sought to evaluate post-mortem cellular changes in the oral tissues including the gingiva, salivary glands and dental pulp.7–14 moreover, inadequacies in terms of sample size and standardised methodology have often precluded confirmation of this approach. therefore, the current study aimed to investigate post-mortem light microscopic cellular changes in the oral tissues with the objective of estimating their potential for pmi prediction. methods this prospective study took place over an 18-month period between july 2016 and january 2018 at the institute of dental sciences, siksha ‘o’ anusandhan university, bhubaneswar, odisha, india, in collaboration with two government medical colleges in odisha. oral mucosa samples were collected from the bodies of recently deceased individuals aged 18–45 years old. in each case, information was obtained concerning cause of death, age, gender, time and date of death and time spent outside or in a natural environment since death. the bodies of individuals with a history of chronic generalised periodontitis, neoplastic growth or communicable disease were excluded, as were those of pregnant females, victims with facial burns and those who had been preserved after death. the bodies were placed in a dry environment with adequate light and kept at room temperature. oral tissues were collected under the direct supervision of a forensic medicine and toxicology specialist. the gingival and buccal mucosa were accessed using basic diagnostic instruments including a mouth mirror, a no. 5 interproximal explorer, a pair of tweezers and a pair of toothed forceps. samples were collected using a round punch knife of 6 mm in diameter, a no. 15 bard-parker® stainless steel blade (aspen surgical corp., caledonia, michigan, usa) and a langenbeck retractor to retract the buccal mucosa. a total of 150 mucosa samples of approximately 6 × 8 × 5 mm in size were collected, comprising both gingival (n = 75) and buccal (n = 75) samples. in addition, 40 antemortem samples of keratinised (n = 20) and non-keratinised (n = 20) oral mucosa were collected from living patients of the same age group admitted for surgical procedures the potential of light microscopic features of the oral mucosa in predicting post-mortem interval e36 | squ medical journal, february 2021, volume 21, issue 1 such as gingivectomy, surgical impaction and biopsies of reactive lesions. the excised tissues were fixed in 10% buffered formalin. subsequently, formalin-fixed paraffinembedded (ffpe) blocks were prepared for both post-mortem and antemortem samples. the ffpe blocks were sectioned into slides of 4 µm in thickness and stained with routine haematoxylin and eosin (h&e) stain. in addition, 21 slides were stained with van gieson stain (hi-media laboratories pvt. ltd., einhausen, germany) and 15 slides were stained with periodic acid-schiff (pas) stain (hi-media laboratories pvt. ltd.) to determine changes in the intensity of collagen/reticulin fibres and basement membranes/mucous acini, respectively, with time since death. stained tissue sections were viewed under a light microscope to evaluate epithelial and connective tissue changes. these changes were categorised according to pmi stage as either early (<12.5 hours since death), intermediate (12.5–20.5 hours since death) or late (>20.5 hours since death). epithelial changes included cytoplasmic vacuolation, changes to the cellular outline, homogenisation, changes to the nuclear outline, nuclear degeneration, nuclear vacuolation, arc-shaped nuclei, chromatin clumping and epithelial shredding (i.e. separation of layers of the epithelium). connective tissue changes to the lamina table 1: light microscopic cellular changes according to time since death in oral mucosa samples (n = 150) type of tissue pmi stage* early intermediate late epithelium • cytoplasmic vacuolation (bm and gm) • homogenisation (bm and gm) • nuclear degeneration (bm and gm) • chromatin clumping (bm and gm) • arc-shaped nuclei (gm) • arc-shaped nuclei (bm) • epithelial shredding (bm) connective tissue • collagen lysis (bm) • melanin incontinency (bm and gm) • loss of epithelial connective tissue interface (bm) • myofibril degeneration (bm) • mucous acini degeneration (bm) • rbc clumping (bm and gm) • collagen lysis (gm) pmi = post-mortem interval; bm = buccal mucosa; gm = gingival mucosa; rbc = red blood cell. *pmi stage was categorised as early (<12.5 hours since death), intermediate (12.5–20.5 hours since death) or late (>20.5 hours since death). table 2: predictive potential of selected light microscopic cellular features to estimate post-mortem interval in oral mucosa samples* from recently deceased individuals (n = 75) type of tissue feature frequency according to pmi stage†, n (%) p value early (n = 25) intermediate (n = 28) late (n = 22) epithelium gm homogenisation 10 (40) 24 (86) 19 (86) 0.011 bm nuclear degeneration 18 (72) 26 (93) 21 (95) 0.021 gm cytoplasmic vacuolation 17 (68) 25 (89) 20 (91) 0.012 bm chromatin clumping 14 (56) 24 (86) 19 (86) 0.029 bm arc-shaped nuclei 6 (24) 19 (68) 13 (59) 0.038 lamina propria bm clumping and lysis of rbcs 6 (24) 10 (36) 13 (59) 0.049 gm clumping and lysis of rbcs 2 (8) 8 (29) 9 (41) 0.010 gm collagen lysis 4 (16) 7 (25) 13 (59) <0.001 bm myofibril degeneration 2 (8) 8 (29) 6 (27) 0.003 bm melanin incontinency 7 (28) 15 (54) 17 (77) 0.017 bm epithelial connective tissue separation 0 (0) 6 (21) 4 (18) 0.028 salivary gland bm mucous acini degeneration 9 (36) 15 (54) 16 (73) 0.013 pmi = post-mortem interval; bm = buccal mucosa; gm = gingival mucosa; rbcs = red blood cells. *including one sample each of bm and gm. †pmi stage was categorised as early (<12.5 hours since death), intermediate (12.5–20.5 hours since death) or late (>20.5 hours since death). jagganath patro, swagatika panda, neeta mohanty and uma s. mishra clinical and basic research | e37 propria included collagen lysis, fibroblast vacuolation, inflammation, homogenisation, clumping and lysis of the red blood cells (rbcs) and melanin incontinency. in addition, the buccal submucosa was examined for degeneration of the myofibrils and salivary glands. the interface between the epithelium and connective tissue was also studied. changes in the intensity of van gieson stains in the collagen fibres as well as that of pas stains in the basement membrane and mucous acini were recorded via consensus. the same slide was evaluated consecutively by three different pathologists and interpreted subjectively as being either of mild, moderate or severe intensity. data were entered into an excel spreadsheet, version 2013 (microsoft corp., redmond, washington, usa), and analysed using the statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa). the antemortem and postmortem samples were compared for the frequency of microscopic changes in the epithelium, lamina propria and submucosa. early, intermediate and late changes in post-mortem samples were identified depending upon a minimum frequency of >40% of specific microscopic features at each pmi stage. logistic regression analysis was conducted to determine the predictive efficiency of these parameters in the estimation of time since death. changes in staining intensity of the collagen fibres, mucous acini and basement membrane for special stains were evaluated with respect to changes in pmi using analysis of variance. ethical approval for this study was obtained from the institutional ethical committee of the institute of dental sciences, siksha ‘o’ anusandhan university (#dmr/ims-3h/soa/180053). written consent was obtained from the next of kin of the deceased individuals. figure 1:haematoxylin and eosin stains at 10x magnification of post-mortem samples of oral mucosa epithelial cells showing (a) arc-shaped nuclei (arrow), (b) epithelial homogenisation (arrow), (c) nuclear degeneration (arrow) and (d) cytoplasmic vacuolation (arrow). these cellular and architectural microscopic changes were found to be significant predictors of post-mortem interval. figure 2: haematoxylin and eosin stain at 10x magnification of post-mortem samples of oral mucosa connective tissue cells showing (a) epithelial connective tissue separation (arrow), (b) clumping (arrow) and lysis (arrowhead) of the red blood cells, (c) myofibril degeneration (arrow), (d) collagen lysis (arrow), (e) melanin incontinency (arrow) and (f) degeneration of the mucous acini (arrow). these cellular and architectural microscopic changes were found to be significant predictors of post-mortem interval. the potential of light microscopic features of the oral mucosa in predicting post-mortem interval e38 | squ medical journal, february 2021, volume 21, issue 1 results a total of 150 oral mucosa samples comprising 75 gingival and 75 buccal mucosa samples were obtained from 75 deceased individuals. of these, 51 (68%) were male and 24 (32%) were female. the most common cause of death was road traffic accidents (n = 37; 49%), followed by poisoning (n = 19; 25%), hypoxia (n = 15; 20%) and cardiac arrhythmia (n = 1; 1%). the reason for death in the remaining three patients was unknown. in terms of pmi stage, 25 (33%) individuals had died <12.5 hours previously, 28 (37%) had died between 12.5–20.5 hours previously and 22 (29%) had died >20.5 hours previously. in the epithelial cells, early microscopic changes seen within 12.5 hours of death included epithelial homogenisation, cytoplasmic vacuolation, nuclear degen eration and chromatin clumping with a progressive increase in the frequency of these features in the intermediate and late stages. arc-shaped nuclei and epithelial shredding were intermediate and late changes, respectively. interestingly, microscopic features of the connective tissue such as melanin incontinency and mucous acini degeneration were observed in the intermediate stage, whereas rbc clumping and lysis and collagen lysis were late changes. epithelial connective tissue separation and myofibril degen eration were observed in <40% of the cell population at all three pmi stages. in addition, inflammatory cells in the connective tissue stroma were observed in very few post-mortem tissues. time-specific microscopic changes according to pmi stage are summarised in table 1. the appearance of these features in the epithelium and connective tissue are shown in figures 1 and 2, respectively. none of these architectural or cytological abnormalities were identified in the antemortem specimens. in the buccal mucosa samples, a logistic regression analysis indicated that epithelial features such as nuclear degeneration, arc-shaped nuclei and chromatin clumping along with connective tissue features such as rbc clumping and lysis, melanin incontinency, degeneration of the myofibrils and salivary gland acini and epithelial connective tissue separation were significant predictors of pmi (p <0.050 each). in turn, epithelial homogenisation, changes to the nuclear outline, nuclear vacuolation in the epithelial cells and collagen lysis and rbc clumping and lysis in connective tissue cells were significant predictors of pmi in the gingival samples (p <0.050 each) [table 2]. there was a progressive decrease in staining intensity of collagen fibres in van gieson stains [figure 3]. the intensity of van gieson stains in collagen fibres was found to be a significant predictor of time since death in both buccal mucosa and gingival samples (p = 0.029). while there was no progressive change in pas staining intensity in the basement membranes of either buccal mucosa or gingival samples as pmi increased, pas staining intensity in salivary gland acini increased significantly with pmi (p = 0.021) [figure 4]. discussion the current study was conducted on post-mortem samples of otherwise healthy buccal and gingival mucosae collected at three different intervals of time since death. the first objective was to identify figure 3: van gieson stains at 10x magnification showing the (a) mild, (b) moderate and (c) severe decrease in staining intensity of collagen fibres in post-mortem samples of the oral mucosa as the post-mortem interval increased. figure 4: periodic acid-schiff stains at 10x magnification showing the (a) mild, (b) moderate and (c) severe increase in staining intensity of mucous acini in post-mortem samples of the oral mucosa as the post-mortem interval increased. jagganath patro, swagatika panda, neeta mohanty and uma s. mishra clinical and basic research | e39 differences between antemortem and post-mortem samples of oral mucosa among adults of similar age groups, while the secondary objective was to evaluate early, intermediate and late microscopic changes in oral tissues according to pmi stage. finally, the study sought to determine the potential of these microscopic features in predicting time since death using both routine and special staining techniques. with regards to the first objective, various degen erative microscopic features in the epithelium and connective tissue of the oral mucosa were observed in post-mortem samples, but not in antemortem samples. in particular, cytoplasmic vacuolation, epithelial homo genisation, nuclear degeneration and chromatin clumping were early changes in both the buccal and gingival mucosa. however, while arc-shaped nuclei were seen at <12.5 hours since death in the gingival mucosa, this feature was only seen at ≥12.5 hours in the buccal mucosa. similarly, melanin incontinency was the only microscopic change observed in both the buccal and gingival mucosa at ≥12.5 hours, whereas collagen lysis, degeneration of the myofibrils and salivary gland acini and epithelial connective tissue separation were seen at this stage only in the buccal mucosa. these findings support those of previous research conducted by pradeep et al. and yadav et al.7,15 in addition, the present study also focused on additional features such as arc-shaped nuclei as an early change in the gingiva and as an intermediate change in the buccal mucosa. the identification of epithelial shredding as a late microscopic change in the buccal mucosa is in agreement with results reported by yadav et al. in the gingival and labial mucosa.8,15 microscopic changes in the connective tissue such as rbc clumping and lysis in both types of mucosae and collagen lysis in the gingiva occurred at >20.5 hours. the latter finding supports previous research by yadav et al. indicating that collagen disruption becomes increasingly apparent over time.8,15 however, yadav et al. reported no abnormalities in the rbcs, a finding which contradicts that of the present study.7 the logistic regression analysis indicated that certain microscopic features in the epithelium— including homogenisation and cytoplasmic vacuolation in the gingiva and nuclear degeneration, arc-shaped nuclei and chromatin clumping in the buccal mucosa— were significant predictors of pmi. similarly, conn ective tissue features of rbc clumping and lysis, melanin incontinency, degeneration of the myofibrils and salivary gland acini and epithelial connective tissue separation in the buccal mucosa and rbc clumping and lysis and collagen lysis in the gingiva were significant pmi predictors. while the role of melanin incontinency in estimating pmi has been evidenced in the skin, no previous study had yet explored its potential in the oral mucosa.16 several connective tissue stains are currently used in forensic pathology practice to order to identify the nature of death.17,18 however, to the best of the authors’ knowledge, no other studies have sought to determine their role in predicting pmi. the current study found that, with an increase in time elapsed since death, there was a significant progressive decrease in the staining intensity of collagen fibres using van gieson stains, whereas there was a significant progressive increase in the staining intensity of salivary gland acini using pas stains. therefore, either of these two staining techniques may be useful in the estimation of pmi. the van gieson stain is a simple stain which tints collagen red and other tissues yellow and is often used for the differential demonstration of collagen. varying shades of red are produced depending on the density of the collagen fibres. a progressive decrease in stain intensity can be attributed to collagen lysis, a feature observed in both the intermediate and late pmi stages; alternatively, this may be due to a decrease in the thickness of the submucosa or lamina propria.15,19 in a previous study, mahalakshmi et al. evaluated histological changes in gingival tissue based on an evaluation of unfixed antemortem tissues alone.9 yadav et al. also studied post-mortem changes in oral mucosa without comparison with antemortem mucosa.15 in comparison, other researchers have compared antemortem and post-mortem mucosal samples to determine post-mortem cellular changes.7,8,10,16 three studies have been conducted to associate changes in salivary gland oral mucosa with time since death.11,12,20 based on evaluations of the cellular changes in antemortem and post-mortem mucosa, gururaj suggested that the decomposition process begins in the initial 24 hours, while pradeep et al. concluded that the decomposition process at the cellular level begins within 10 hours of death.7,21 yadav et al. investigated 10 antemortem mucosa samples to determine nuclear and cytoplasmic changes at various time intervals and proposed the usefulness of histological changes in the oral mucosa for estimating pmi.8 in a recent study, muthukrishnan et al. described early and late postmortem changes in five antemortem and five postmortem gingival samples.10 due to sample size limitations, none of the aforementioned studies were able to provide statistical confirmation of the usefulness of light microscopic cellular changes in the oral mucosa as a method of predicting time since death.9–11,15,20,21 moreover, several studies either evaluated post-mortem cellular changes in the gingiva alone or in the labial mucosa.7,8,15 no studies have yet sought to assess the role of these the potential of light microscopic features of the oral mucosa in predicting post-mortem interval e40 | squ medical journal, february 2021, volume 21, issue 1 changes in the buccal mucosa. indeed, the present study is the first to establish the usefulness of this approach in both the gingiva and buccal mucosa, which are distinct types of oral mucosal tissues which are different from both an anatomical and structural perspective. for instance, the mean thickness of the epithelium in the buccal mucosa and gingiva are 294 ± 68 µm and 239 ± 57 µm, respectively.22 in addition, the thickness of the connective tissue also differs in these two zones as submucosa is absent in the gingiva, but present in the buccal mucosa. as such, characterisation of the role of the oral mucosa in identifying pmi requires the individual evaluation of different mucosal regions. this study is subject to certain limitations, such as the absence of quantifying the cellular and nuclear changes to establish any association with pmi and observing the post-mortem cellular and nuclear changes in different environments. these factors would have led to further accuracy in determining pmi. however, the strengths of this study lie in the inclusion of a large sample size, the evaluation of two different kinds of oral mucosa tissue—including the buccal mucosa—and examination of the role of microscopic features in routine h&e stains as well as special stains such as van gieson and pas. based on these findings, further research is recommended to determine the point in time after death at which microscopic changes cease. in addition, advanced histological techniques, such as immunohistochemistry and electron microscopy, should also be investigated as other potential methods of determining post-mortem changes in the oral tissues. conclusion several microscopic features of the gingiva and buccal mucosa were found to be significant predictors of pmi including epithelial homogenisation, cytoplasmic vacuolation, nuclear degeneration, arc-shaped nuclei, chromatin clumping, rbc clumping and lysis, melanin incontinency, myofibril degeneration, salivary gland acini degeneration and epithelial connective tissue separation. in addition, there was a progressive decrease and increase in staining intensity with the use of van gieson and pas stains, respectively. to the best of the authors’ knowledge, this study is the first of its kind to identify light microscopic features in two distinct kinds of oral mucosae using two special staining techniques in addition to conventional h&e staining. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. buchan mj, anderson gs. time since death: a review of the current status of methods used in the later post-mortem interval. can soc forensic sci 2001; 34:1–22. https://doi.org/10.1080/00 085030.2001.10757514. 2. wang q, lin hc, xu jr, huang p, wang zy. current research and prospects on post-mortem interval estimation. fa yi xue za zhi 2018; 34:459–67. https://doi.org/10.12116/j.issn.10045619.2018.05.002. 3. milroy cm. forensic taphonomy: the post-mortem fate of human remains. bmj 1999; 319:458. https://doi.org/10.1136/ bmj.319.7207.458. 4. kumar v, cotran rs, robbins sl. textbook of basic pathology, 5th ed. elsevier, india, 1992, p 22–5. 5. mel’nikov iul. [post-mortem changes in the liver as a criterion for the establishment of the time of death (experimental study)]. sud med ekspert 1969; 12:20–3. 6. tomita y, nihira m, ohno y, sato s. [histological study of early post-mortem changes in various organs: comparison of the paraffin embedding method and the epoxy resin embedding method]. nihon hoigaku zasshi 1999; 53:207–17. 7. pradeep gl, uma k, sharada p, prakash n. histological assessment of cellular changes in gingival epithelium in antemortem and post-mortem specimens. j forensic dent sci 2009; 1:61–5. https://doi.org/10.4103/0974-2948.60375. 8. yadav ab, angadi pv, kale ad, yadav sk. histological assessment of cellular changes in post-mortem gingival specimens for estimation of time since death. j forensic odontostomatol 2015; 33:19–26. 9. mahalakshmi v, gururaj n, sathya r, sabarinath tr, sivapatha sundharam b, kalaiselvan s. assessment of histological changes in antemortem gingival tissues fixed at various time intervals: a method of estimation of post-mortem interval. j forensic dent sci 2016; 8:114. https://doi.org/10.4103/0975-1475.186373. 10. muthukrishnan s, narasimhan m, paranthaman sk, hari t, viswanathan p, rajan st. estimation of time since death based on light microscopic, electron microscopic, and electrolyte analysis in the gingival tissue. j forensic dent sci 2018; 10:34–9. https://doi.org/10.4103/jfo.jfds_36_17. 11. azevedo-alanis lr, tolentino ede s, de assis gf, cestari tm, lara vs, damante jh. acinar autolysis and mucous extra vasation in human sublingual glands: a microscopic postmortem study. j appl oral sci 2015; 23:459–66. https://doi. org/10.1590/1678-775720150139. 12. agarwal s, chaudhary m, gawande m, gupta p. documentation of post-mortem changes in salivary gland architecture and staining characteristics. j forensic dent sci 2016; 8:113. https:// doi.org/10.4103/0975-1475.186360. 13. poór vs, lukács d, nagy t, rácz e, sipos k. the rate of rna degradation in human dental pulp reveals post-mortem interval. int j legal med 2016; 130:615–19. https://doi.org/10.1007/ s00414-015-1295-y. 14. carrasco pa, brizuela ci, rodriguez ia, muñoz s, godoy me, inostroza c. histological transformations of the dental pulp as possible indicator of post mortem interval: a pilot study. forensic sci int 2017; 279:251–7. https://doi.org/10.1016/j. forsciint.2017.09.001. 15. yadav a, angadi pv, hallikerimath s, kale a, shetty a. applic ability of histologic post-mortem changes of labial mucosa in estimation of time of death – a preliminary study. aust j forensic sci 2012; 44:343–52. https://doi.org/10.1080/0045061 8.2012.674977. https://doi.org/10.1080/00085030.2001.10757514 https://doi.org/10.1080/00085030.2001.10757514 https://doi.org/10.12116/j.issn.1004-5619.2018.05.002 https://doi.org/10.12116/j.issn.1004-5619.2018.05.002 https://doi.org/10.1136/bmj.319.7207.458 https://doi.org/10.1136/bmj.319.7207.458 https://doi.org/10.4103/0974-2948.60375 https://doi.org/10.4103/0975-1475.186373 https://doi.org/10.4103/jfo.jfds_36_17 https://doi.org/10.1590/1678-775720150139 https://doi.org/10.1590/1678-775720150139 https://doi.org/10.4103/0975-1475.186360 https://doi.org/10.4103/0975-1475.186360 https://doi.org/10.1007/s00414-015-1295-y https://doi.org/10.1007/s00414-015-1295-y https://doi.org/10.1016/j.forsciint.2017.09.001 https://doi.org/10.1016/j.forsciint.2017.09.001 https://doi.org/10.1080/00450618.2012.674977 https://doi.org/10.1080/00450618.2012.674977 jagganath patro, swagatika panda, neeta mohanty and uma s. mishra clinical and basic research | e41 16. bardale rv, tumram nk, dixit pg, deshmukh ay. evaluation of histologic changes of the skin in post-mortem period. am j forensic med pathol 2012; 33:357–61. https://doi.org/10.1097/ paf.0b013e31822c8f21. 17. lau g, lai sh. forensic histopathology. in: tsokos m (ed). forensic pathology reviews, volume 5. totowa, new jersey, usa: humana press, 2008. pp. 239–65. https://doi.org/10.1007/9 78-1-59745-110-9_13. 18. parai jl, milroy cm. the utility and scope of forensic histo pathology. acad forensic pathol 2018; 8:426–51. https://doi. org/10.1177/1925362118797602. 19. nahar n, ara s, zohora f, siddika d, yesmin t. histological study on thickness of different layers of the gallbladder: a postmortem study. bangladesh j anat 2011; 9:41–4. https://doi. org/10.3329/bja.v9i1.8147. 20. takeda y. oncocytic hyperplasia in the human minor salivary glands: a post-mortem study. virchows arch a pathol anat histopathol 1993; 423:105–9. https://doi.org/10.1007/bf01606584. 21. gururaj ns, sivapathasundharam b. post mortem findings in the gingiva assessed by histology and exfoliative cytology. j oral maxillofac pathol 2004; 8:18–21. 22. prestin s, rothschild si, betz cs, kraft m. measurement of epithelial thickness within the oral cavity using optical coherence tomography. head neck 2012; 34:1777–81. https://doi.org/10.10 02/hed.22007. https://doi.org/10.1097/paf.0b013e31822c8f21 https://doi.org/10.1097/paf.0b013e31822c8f21 https://doi.org/10.1007/978-1-59745-110-9_13 https://doi.org/10.1007/978-1-59745-110-9_13 https://doi.org/10.1177/1925362118797602 https://doi.org/10.1177/1925362118797602 https://doi.org/10.3329/bja.v9i1.8147 https://doi.org/10.3329/bja.v9i1.8147 https://doi.org/10.1007/bf01606584 https://doi.org/10.1002/hed.22007 https://doi.org/10.1002/hed.22007 squ med j, may 2011, vol. 11, iss. 2, pp. 276-279, epub. 15th may 11 submitted 1st dec 10 revision req. 12th jan 11, revision recd. 17th jan 11 accepted 15th feb 11 orbital exenteration is a radical procedure consisting of removal of the orbital contents, including orbital fat, conjunctival sac, globe, and a part or whole of the eyelids1. orbital defects are injurious to a person’s self-concept and sense of body image. treatment should be provided as soon as possible to raise morale and ease the mind of the afflicted person. orbital prostheses are made of silicone elastomers, acrylic resin, or a combination of these.2 most maxillofacial elastomers perform well initially, but deterioration, associated with either degradation of mechanical properties or changes in appearance, commonly occurs subsequently.3-8 this deterioration limits the service life of extraoral prostheses, and refabrication of these prostheses is time consuming, labour intensive, and costly. moreover, extraoral prostheses are exposed to mucosa and skin secretions; subsequently, multilayer biofilm formation can occur on the silicone surfaces. problems such as black stains on the surface of prostheses, offensive odours, and tissue infection can arise from microbial colonisation.9 karakoca et al. reported a mean life span of 14.5 to 14.7 months for a patient’s first and second implant-retained extraoral prostheses, respectively. the primary reasons for making a new prosthesis were discoloration, tear of the prosthesis, and mechanical failures of the acrylic resin substructure or retentive elements.10 jebreil reported that adhesive-retained orbital prostheses last for 6–9 months and need to be refabricated subsequently.11 problems with silicone orbital prosthesis can be avoided by reconstructing the upper and lower eyelids surgically and then rehabilitating with custom-made ocular prostheses. this clinical report describes the management of a patient with an orbital defect by a department of prosthodontics, government dental college and research institute, bangalore 560002, india. *corresponding author email: dr_poojagarg@yahoo.com ‰�i^ëá̌ǰ� �¶< �p^n �j �q]<ç√e<<t^r£̌]<^fle<ïå^¬c <í¬^flí÷]<s„fl÷]ê<ìu]ü¢]<ÿ^€√jâ^e<              :مفتاح الكلمات abstract: reconstruction of an exenterated orbit remains a challenge. orbital prostheses are nowadays are made of silicone elastomers. a major limitation with silicone orbital prostheses is their relatively short life span. this case report describes the treatment of a patient with an exenterated orbit using a combined surgical and prosthetic approach. the upper and lower eyelids were reconstructed surgically using a deltopectoral flap. a sectional eye prosthesis was made and placed in the modified bottle-neck shaped defect to restore the patient’s appearance and confidence. keywords: exenteration; ocular prosthesis; maxillofacial prosthesis; psychology; silicone elastomers; case report; india reconstruction of exenterated orbit using combined surgical and prosthetic approach d r prithviraj, anish gupta, sumit khare, *pooja garg, malesh pujari case report d r prithviraj, anish gupta, sumit khare, pooja garg and malesh pujari case report | 277 combined surgical and prosthetic approach. case report a 24 year-old woman, who had undergone a right orbital exenteration for orbital meningioma, presented to the department of prosthodontics and implantology, at the government dental college and research institute (gdcri), bangalore, india, for rehabilitation of an orbital defect [figure 1]. it was decided to reconstruct the eyelids surgically in collaboration with the department of plastic surgery, victoria hospital, bangalore. a deltopectoral flap from the second and third intercostal region was raised and then rotated into the exenterated orbit and sutured to the free skin margins. after 3 weeks, the pedicle was separated from the intercostal region. four weeks later the flap was divided to construct the upper and lower eyelids. after 6 months, the patient presented to the department with reconstructed upper and lower eyelids [figure 2]. although plastic surgery resulted in marked improvement, yet the resultant eyelids were thick, tense, and scarred. moreover, the modified orbital defect was bottle-neck shaped. the palpebral aperture was 15 mm whereas the cavity inside was approximately 32 mm; hence, it was virtually impossible to fabricate a single piece eye prosthesis. this necessitated a unique treatment modality for the rehabilitation of the modified exenterated orbit. separate impressions were made of the superior and inferior surfaces of the defect using irreversible hydrocolloid material (hydrogum, zhermack spa, italy). after that, irreversible hydrocolloid was injected directly into the remaining socket using an ocular impression tray. multiple parts of the impression were assembled outside to pour a twopiece dental stone cast. three pieces of wax template were fabricated to be assembled in a specific spatial configuration in the reconstructed orbit and processed using heat cure acrylic (trevalon, india). a notch was made in the middle piece for orientation of the fourth piece. after placing the multiple pieces of eye prosthesis in the modified orbit, an impression for the fourth piece was made according to the allen and webster technique.12 the irreversible hydrocolloid material was injected into the remaining socket through the attached hollow stem of the impression tray. using this impression and a small plastic tumbler, an irreversible hydrocolloid mould was prepared, which was cut using a sharp blade to remove the impression. the mould space was subsequently filled with molten inlay wax. once the wax was hard, it was removed from the mould, and the external surface was smoothed for a try-in on the patient’s face. the wax form and its corneal prominence were modified wherever necessary to duplicate the shape of the natural eye. after a try-in the wax template was processed using white acrylic. the acrylic shell was removed and trimmed for about 1–2mm on the external surface. during iris orientation patient was asked to gaze straight ahead. the distance from the pupil of the normal eye to the midline was used in establishing the horizontal position of the prosthetic pupil’s centre. its vertical position was determined by the canthus relationships. marked coordinates of the pupil were used to circumscribe the diameter of the iris. iris and scleral painting were carried out using acrylic colors and mono-poly. as the palpebral aperture of the reconstructed eyelids was larger than that of the natural eye, it was camouflaged during scleral painting. subsequently, using the same plaster mould, the eye shell was packed with figure 1: orbital defect following exenteration figure 2: reconstructed upper and lower eyelids reconstruction of exenterated orbit using combined surgical and prosthetic approach 278 | squ medical journal, may 2011, volume 11, issue 2 transparent acrylic to give a natural appearance. later, it was removed from the mould, trimmed, finished and polished. the prosthesis was placed into the ocular defect and critically evaluated [figure 3]. spectacles were used to camouflage the scarred tissue [figure 4]. at the time of writing, the prosthesis had been in service for 9 months without complications. discussion this case report describes the treatment of a patient with exenterated orbit using a combined surgical and prosthetic approach. upper and lower eyelids were reconstructed surgically using a deltopectoral flap from the second and third intercostal region to avoid the fabrication of a silicone prosthesis. silicones have been used for over 50 years in the field of maxillofacial prosthetics, with desirable material properties including flexibility, biocompatibility, ability to accept intrinsic and extrinsic colorants, chemical and physical inertness and mouldability.9,13 a major limitation with silicone orbital prostheses is their relatively short life span (on average 1.5 to 2 years). the main reasons for the refabrication of orbital prostheses are discoloration, problems with the attachment of the acrylic resin clip carrier to the silicone, rupture or deterioration of the silicone material and a poor fit. moreover, meticulous hygiene is mandatory to prevent periimplant problems, including inflammation of the skin in the implant retained orbital prosthesis.14 the resultant eyelids were thick, tense, and scarred and the modified orbital defect was bottle-neck shaped. a sectional eye prosthesis was fabricated to overcome this limitation. the impression was made with irreversible hydrocolloid which helped in retrievability of the impression from undercut area. heat cure polymethyl methacrylate was used for fabrication of the prosthesis which has better biocompatibility.4 multiple pieces of eye prosthesis were fabricated to be assembled in a specific spatial configuration in the reconstructed exenterated orbit. the prosthesis, although static, helped restore the patient’s appearance and confidence. in the absence of recurrent orbital meningioma, this prosthesis can be a definitive treatment for the patient. conclusion reconstruction of the exenterated orbit remains a challenge. patients in this situation can be treated by reconstructing the upper and lower eyelids surgically and then rehabilitation with custommade ocular prostheses. a c k n o w l e d g e m e n t the authors would like to thank the patient for granting consent for her case and photographs to be published. references 1. perman ki, baylis hi. evisceration, enucleation and exenteration. otolaryngol clin north am 1988; 21:171–82. 2. kurunmaki h, kantola r, hatamleh mm, watts dc, vallittu pk. a fiber-reinforced composite prosthesis restoring a lateral midfacial defect:a clinical report. j prosthet dent 2008; 100:348–52. 3. han y, kiat-amnuay s, powers jm, zhao y. effect of nano-oxide concentration on the mechanical properties of a maxillofacial silicone elastomer. j prosthet dent 2008; 100:465–73. 4. dootz er, koran a 3rd, craig rg. physical properties of three maxillofacial materials as a function of accelerated aging. j prosthet dent 1994; 71:379–83. figure 3: multiple unit eye prosthesis placed in reconstructed exenterated orbit figure 4: spectacles used to camouflage the scarred tissue d r prithviraj, anish gupta, sumit khare, pooja garg and malesh pujari case report | 279 5. haug sp, moore bk, andres cj. color stability and colorant effect on maxillofacial elastomers. part ii: weathering effect on physical properties. j prosthet dent 1999; 81:423–30. 6. frangou mj, polyzois gl, tarantili pa, andreopoulos ag. bonding of silicone extraoral elastomers to acrylic resin: the effect of primer composition. eur j prosthodont restor dent 2003; 11:115–8. 7. lemon jc, chambers ms, jacobsen ml, powers jm. color stability of facial prostheses. j prosthet dent 1995; 74:613–8. 8. polyzois gl, tarantili pa, frangou mj, andreopoulos ag. physical properties of a silicone prosthetic elastomer stored in simulated skin secretions. j prosthet dent 2000; 83:572–7. 9. kiat-amnuay s, johnston da, powers jm, jacob rf. color stability of dry earth pigmented maxillofacial silicone a-2186 subjected to microwave energy exposure. j prosthodont 2005; 14:91–6. 10. karakoca s, aydin c, yilmaz h, bal bt. retrospective study of treatment outcomes with implant-retained extraoral prostheses: survival rates and prosthetic complications. j prosthet dent 2010; 103:118–126. 11. jebreil k. acceptability of orbital prostheses. j prosthet dent 1980; 43:82–5. 12. allen l, webster he. modified impression method of artificial eye fitting. am j ophthalmol 1969; 67:189. 13. jani rm, schaaf ng. an evaluation of facial prostheses. j prosthet dent 1978; 39:546–50. 14. anita v, raghoebar gm, oort rp, vissink a. fate of implant-retained craniofacial prostheses: life span and aftercare. int j oral maxillofac implants 2008; 23:89–98. departments of 1obstetrics & gynaecology, 2pathology and 3clinical immunology, jawaharlal institute of postgraduate medical education & research, pondicherry, india *corresponding author’s e-mail: keepan_r@yahoo.com تسمم احلمل املبكر مع بيلة بروتينية كلوية كمظهر مبدئي اللتهاب الكلية الذئيب تقرير ثالث حاالت فينيتا اأودوبا، اأني�ض كيبانا�رسيل، نرياجا فيجايان، ديباداَتا با�سو، فري �سينج نيجي abstract: early onset pre-eclampsia (pre-eclampsia at less than 34 gestational weeks) is a severe form of preeclampsia; in addition, some women may also develop nephrotic range proteinuria. de novo diagnosis of lupus nephritis (ln) in pregnancy is challenging as it may present with features similar to commonly occurring preeclampsia. we report three cases of early onset pre-eclampsia with nephrotic range proteinuria and subsequent diagnosis of ln at the women and children hospital attached to jawaharlal institute of postgraduate medical education and research, puducherry, india, between 2014 and 2017. these cases highlights the need for further evaluation of the association between nephrotic-range proteinuria and early onset pre-eclampsia. the index of suspicion for underlying ln of these type of cases should be high. earlier detection of ln will prompt better management that can avert or delay shortand long-term morbidity. keywords: lupus nephritis; pre-eclampsia; nephrotic syndrome; proteinuria; case reports; india. قد ، ذلك جانب اىل احلمل. ت�سمم من حاد �سكل هو احلمل( من 34 ال�سبوع قبل احلمل املبكرة )ت�سمم البداية ذو احلمل ت�سمم امللخ�ص: ا. الت�سخي�ض اجلديد للتهاب الكلية الذئبي اأثناءاحلمل يعترب حتديا لأنه قد يظهر ت�ساب بع�ض هوؤلء الن�سوة ببيلة بروتينية كلوية اأي�سً ب�سفات مماثلة لت�سمم احلمل الأكرث �سيوعا. نورد هنا ثالث حالت من ت�سمم احلمل املبكر م�سحوبة ببيلة بروتينية كلوية والتي �سخ�ست لحقا كالتهاب كلية ذئبي يف م�ست�سفى الن�ساء والأطفال امللحق مبعهد جواهرلل للدرا�سات العليا يف التعليم الطبي والبحث، بودوت�سريي ، الهند بني الأعوام 2014 و 2017. ت�سلط هذه ال�سل�سلة من احلالت ال�سوء على احلاجة اإىل مزيد من التقييم للعالقة بني البيلة الربوتينية الكلوية وبني ت�سمم احلمل املبكر. يجب اأن يكون موؤ�رس ال�سك بوجود �سمني للتهاب الكلية الذئبي يف مثل هذا النوع من احلالت عاليا. ان الك�سف املبكر عن التهاب الكلية الذئبي �سوف يدفع اإىل رعاية اأف�سل ميكن معها جتنب اأو تاأخري الإعتاللت ذات الآجال الق�سرية والطويلة. الكلمات املفتاحية: التهاب الكلية الذئبي؛ ت�سمم احلمل؛ متالزمة كلوية؛ بيلة بروتينية؛ تقارير حالة؛ الهند. early onset pre-eclampsia with nephrotic range proteinuria as the initial manifestation of lupus nephritis report of three cases vinita udupa,1 *anish keepanasseril,1 neeraja vijayan,1 debadatta basu,2 vir singh negi3 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e73–76, epub. 30 may 19 submitted 23 oct 18 revision req. 12 dec 18; revision recd. 3 jan 19 accepted 31 jan 19 pre-eclampsia is characterised by abnormal placentation and endothelial dysfunction secondary to an imbalance of angiogenic factors occurring early in pregnancy. early onset pre-eclampsia that develops before 34 gestational weeks represents a severe form of the hypertensive disorders during preg nancy. the presence of significant proteinuria is regarded as one of the diagnostic criteria distinguishing pre eclampsia from gestational hypertension.1 systemic lupus erythematosus (sle) is a multi-systemic autoimmune disorder affecting mostly women of child-bearing age. nearly two-thirds of the women affected have lupus nephritis (ln) and usually have nephrotic-range protein uria (>3.5 g/day) with active urinary sediments.2,3 preeclampsia occurs in 10–15% of pregnant women with sle and is more frequent in those with ln (20–40%).4,5 women with sle are reported to have an increased risk of early onset pre-eclampsia. owing to the similar presentation of pre-eclampsia and ln, it is possible to overestimate this risk due to misclassification of cases.4 nephrotic-range proteinuria complicates 0.32% of pregnancies, of which pre-eclampsia contributes to 0.19%.6,7 in women with ln where nephrotic-range proteinuria is a criterion for diagnosis, differentiating new-onset sle or ln in pregnancy from pre-eclampsia remains a challenge. these cases should be met with a high index of suspicion and require further evaluation with autoantibody screening and a possible renal biopsy for diagnosis.8 we report three female patients who presented with early onset pre-eclampsia and nephrotic range proteinuria and were subsequently diagnosed with ln. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.014 case report https://creativecommons.org/licenses/by-nd/4.0/ early onset pre-eclampsia with nephrotic range proteinuria as the initial manifestation of lupus nephritis report of three cases e74 | squ medical journal, february 2019, volume 19, issue 1 case reports all three cases presented at women and children hosp ital attached to jawaharlal institute of postgraduate med ical education and research, puducherry, india, between 2014−2017 with early onset of pre-eclampsia between 26 and 30 gestational weeks. all cases had nephroticrange proteinuria and hypoalbuminaemia. urinary sedi ments or haematuria were not noted and ultrasound examination showed normal sized kidneys at present ation. none had any clinical symptoms suggestive of any connective tissue disorders. on evaluation, all patients were found to be antinuclear antibody (ana) positive with low complement levels (c3 and c4). during the antenatal period, all patients were monitored for blood pressure, urine output, renal function and fetal monit oring with ultrasound biometry and non-stress tests [table 1]. labour and delivery details were gathered for the three cases [table 2]. all information was retrieved from medical records without collecting any identifying details, therefore, ethical approval was not sought. however, all patients signed written informed consent forms. case one a 26-year-old primigravida woman at 26 gestational weeks presented to the emergency obstetric services in 2014 with a maximum blood pressure of 160/100 mmhg and spot urine protein of 3+; thus, she was diagnosed with early onset pre-eclampsia. she was started on nifedipine 10 mg three times per day. her laboratory tests revealed raised serum creatinine (1.7 mg/dl) and 24 hour urinary protein of 3,540 mg/day. in view of her rapidly worsening renal function (highest serum creatinine level was 3.4 mg/dl) and nephrotic-range proteinuria, a renal biopsy was performed at 28 gesta tional weeks which revealed class-iv ln. she was ana positive and was started on prednisolone (60 mg/day) and hydroxychloroquine (200 mg/day). at the time of delivery, her creatinine levels dropped to 1.4 mg/dl. labour was induced at 34 gestational weeks in view of the severe early onset pre-eclampsia. she delivered a baby boy weighing 2,100 g with an apgar score of 9 at 5 minutes. her post-partum blood pressure returned to normal by the tenth day and her serum creatinine level at discharge was 1.1 mg/dl. case two a 30-year-old woman with three previous abortions was referred, to the emergency services in 2015, at 30 gestational weeks with early onset pre-eclampsia. she had a blood pressure of 150/90 mmhg and spot urine protein of 4+ on admission and was on nifedipine 30 mg/day. she was started on prednisolone 40 mg/day in view of suspected ln based on positive ana and dsdna results. her blood pressure remained normal and her creatinine levels were stable (1.2–1.4 mg/dl). she was induced at 33 gestational weeks with prosta glandin e2 gel and delivered a baby girl weighing 1,900 g with an apgar score of 9 at 5 minutes. her blood pressure table 1: summary of three cases with early onset preeclampsia and lupus nephritis characteristics case 1 case 2 case 3 age in years 26 30 31 parity index g1 g4, a3 g2, pl1 gestational age at presentation in weeks 26 30 29 24 hour urinary protein in mg/ day 3,540 4,020 3,800 serum albumin in mg/dl 2.1 1.9 2.3 highest serum creatinine in mg/dl 3.4 1.9 2.1 platelet count in × 105/mm3 2.05 2.53 2.37 other obstetric complication none none iugr antibody profile ana positive ana and dsdna positive ana and dsdna positive timing of renal biopsy antenatal (28 gestational weeks) postnatal postnatal renal biopsy finding class-iv ln class-iv–v ln class-iv ln treatment received hcq and prednisolone hcq and prednisolone hcq and prednisolone g = gravida; a = abortion; pl = preterm and living; iugr = intrauterine growth restriction; ana = antinuclear antibody; dsdna = double stranded dna; ln = lupus nephritis; hcq = hydroxychloroquine. table 2: labour and delivery details of three cases with early onset pre-eclampsia and lupus nephritis variable case 1 case 2 case 3 gestational age at delivery in weeks* 34 33 31 neonatal outcome live born live born stillborn birth weight in g 2,100 1,900 980 apgar score at 5 minutes 9 9 neonatal complications low birth weight low birth weight and nicu admission nicu = neonatal intensive care unit. *all labour was induced and mode of delivery was vaginal. vinita udupa, anish keepanasseril, neeraja vijayan, debadatta basu and vir singh negi case report | e75 those with active lupus and ln.13,14 due to a multi system involvement similar to lupus, pre-eclampsia might represent the initial manifestation of an autoimmune disorder. studies have found that pregnant women with sle have worse manifestations than pregnant women without sle and due to the hormonal changes and the increase in cytokines during pregnancy this disease may only be diagnosed for the first time during pregnancy.9,10 most women with new-onset sle are found to have a lower frequency of common symptoms suggestive of lupus at presentation, such as fever, arthritis, arthralgia, alopecia, oral ulcers and/or hypocomplementaemia, compared to those diagnosed in a non-pregnant state.2,3 thrombocytopaenia is reported to occur in 10–40% of cases of new-onset lupus but in all present cases platelet counts were normal.5 however, more women have nephrotic syndrome when diagnosed during pregnancy making it difficult to differentiate from pre-eclampsia, which complicates pregnancy.2,5 indications for a renal biopsy in pregnant women include unexplained rapidly progressive renal failure and symptomatic nephrotic syndrome; it may also be used as a guide in managing patients with ln.15 as there is a risk of maternal-fetal morbidity, any procedure is usually deferred until the post-partum period, unless it requires management before delivery. the risk of various complications following a renal biopsy is higher during pregnancy compared to the post-partum period (7% versus 1%).16 the presence of a gravid uterus makes it difficult for patients to lie prone so alternative positions, such as sitting upright or lying in the lateral decubitus position, may be preferred.15,16 in the current case report, due to rapidly deteriorating renal function, a biopsy was performed at 28 gestational weeks in one case, whereas it was deferred until delivery in the other two. miyamoto et al. found eight out of 11 patients diagnosed with new-onset sle during pregnancy had pre-eclampsia upon initial presentation, while three dev eloped pre-eclampsia after sle was diagnosed.3 all cases except one, who developed sle post-partum, had preeclampsia detected in the third trimester of pregnancy. termination of pregnancy for treating pre-eclampsia resulted in premature births in six out of seven cases. renal haemodynamic changes along with the hormonal changes of pregnancy may accelerate the decline in renal function and worsen hypertension and proteinuria, as was seen in the current case report. unless the index of suspicion is high, this can be misinterpreted as worsening pre-eclampsia resulting in iatrogenic premature birth, especially if no prenatal or early preg nancy reports of normal renal function are available. zao et al.’s study on new-onset sle in pregnancy observed that two-thirds (68.8%) of the patients diagn was controlled with nifedipine 30 mg/day. in view of positive autoantibody screening, raised creatinine levels (1.9 mg/dl) and nephrotic-range proteinuria, a renal biopsy was done in the postnatal period which was reported as class-iv and -v ln. her creatinine level at discharge on the fourteenth postnatal day was 1.1 mg/dl. at discharge, she was on prednisolone, hydroxychloro quine and nifedipine (60, 200 and 30 mg/day, respectively). case three a 31-year-old multiparous woman with chronic hyper tension was admitted to the antenatal wards in 2016, at 29 gestational weeks for evaluation of superimposed pre-eclampsia. she was on alpha-methyldopa 250 mg three times a day and to control her high blood pressure, nifedipine 10 mg three times a day was added. invest igations revealed normal liver function, serum creatinine (1.22 mg/dl), platelet count (2.05 × 105/mm3) and a normal peripheral smear. her 24-hour urine protein excretion was 3,800 mg/day. at 30 gestational weeks and 6 days she developed nausea and vomiting and had a blood pressure of 190/110 mmhg. after consulting a neonatologist, a caesarean section was ruled out due to the neonate’s growth restriction and prematurity. labour was induced with misoprostol (prostaglandin e1) and resulted in intrapartum stillbirth. her autoanti body screen was positive and in view of nephroticrange proteinuria with persistent renal dysfunction (serum creatinine levels: 1.8–2.1 mg/dl), a renal biopsy was performed in the postnatal period which revealed class-iv ln. discussion pregnancy leads to changes in the immune system and hormonal profile to promote immune tolerance to sustain pregnancy. diagnosis of new onset sle presenting as ln during pregnancy is challenging as it simulates the commonly occurring pre-eclampsia during this period. presence of medical disorders, especially those associated with autoimmune pathology or vasculopathy are consid ered risk factors of pre-eclampsia; recent studies have reported similarities in pathogenesis of pre-eclampsia and sle.9–11 the elevated levels of interferon-α found in sle have anti-angiogenic and anti-proliferative properties that lead to endothelial cell dysfunction mimicking the endothelial-milieu as in pre-eclamptic women.12 similar to pre-eclampsia, angiogenic factors like vasc ular endothelial growth factor and placental growth factor decrease and levels of anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 increase in early onset pre-eclampsia with nephrotic range proteinuria as the initial manifestation of lupus nephritis report of three cases e76 | squ medical journal, february 2019, volume 19, issue 1 osed in pregnancy had ln; this was a much higher rate than among those who were not pregnant.2 women who developed ln had nephrotic-range proteinuria and low serum albumin levels compared to non-pregnant control cases with sle.2 all three of the current patients who presented with pre-eclampsia had nephroticrange proteinuria and serum hypoalbuminaemia. all current patients had autoantibodies present and under went a renal biopsy according to the american college of rheumatology guidelines, two cases during the post natal period and one case during the antenatal period, confirming the diagnosis of ln.8 conclusion the index of suspicion of underlying ln should be high upon presentation of early-onset pre-eclampsia with nephrotic-range proteinuria and hypoalbuminaemia. autoantibody screening should be performed and if positive, a renal biopsy may be considered. early detection of ln would lead to better management that can avert or delay shortand long-term morbidity. references 1. american college of obstetricians and gynecologists; task force on hypertension in pregnancy. hypertension in pregnancy. report of the american college of obstetricians and gyne cologists’ task force on hypertension in pregnancy. obstet gynecol 2013; 122:1122–31. https://doi.org/10.1097/01.aog.00 00437382.03963.88. 2. zhao c, zhao j, huang y, wang z, wang h, zhang h, et al. new-onset systemic lupus erythematosus during pregnancy. clin rheumatol 2013; 32:815–22. https://doi.org/10.1007/s100 67-013-2180-z. 3. miyamoto t, hoshino t, hayashi n, oyama r, okunomiya a, kitamura s, et al. preeclampsia as a manifestation of new-on set systemic lupus erythematosus during pregnancy: a case-based literature review. ajp rep 2016; 6:e62–7. https://doi.org/10.10 55/s-0035-1566245. 4. simard jf, arkema ev, nguyen c, svenungsson e, wikström ak, palmsten k, et al. early-onset preeclampsia in lupus pregnancy. paediatr perinat epidemiol 2017; 31:29–36. https://doi.org/10.11 11/ppe.12332. 5. stanhope tj, white wm, moder kg, smyth a, garovic vd. obstetric nephrology: lupus and lupus nephritis in pregnancy. clin j am soc nephrol 2012; 7:2089–99. https://doi.org/10.22 15/cjn.12441211. 6. côté am, sauvé n. the management challenges of nonpreeclampsia-related nephrotic syndrome in pregnancy. obstet med 2011; 4:133–9. https://doi.org/10.1258/om.2011.110001. 7. brown ra, kemp gj, walkinshaw sa, howse m. pregnancies complicated by preeclampsia and non-preeclampsia-related nephrotic range proteinuria. obstet med 2013; 6:159–64. https://doi.org/10.1177/1753495x13498382. 8. hahn bh, mcmahon ma, wilkinson a, wallace wd, daikh di, fitzgerald jd, et al. american college of rheumatology guide lines for screening, treatment, and management of lupus nephritis. arthritis care res (hoboken) 2012; 64:797–808. https://doi.org/1 0.1002/acr.21664. 9. doria a, ghirardello a, iaccarino l, zampieri s, punzi l, tarricone e, et al. pregnancy, cytokines, and disease activity in systemic lupus erythematosus. arthritis rheum 2004; 51:989–95. https://doi.org/1 0.1002/art.20837. 10. cudihy d, lee rv. the pathophysiology of pre-eclampsia: current clinical concepts. j obstet gynaecol 2009; 29:576–82. https://doi.org/10.1080/01443610903061751. 11. nanjundan p, bagga r, kalra jk, thakur js, raveendran a. risk factors for early onset severe pre-eclampsia and eclampsia among north indian women. j obstet gynaecol 2011; 31:384–9. https://doi.org/10.3109/01443615.2011.566389. 12. andrade d, kim m, blanco lp, karumanchi sa, koo gc, redecha p, et al. interferon-α and angiogenic dysregulation in pregnant lupus patients who develop preeclampsia. arthritis rheumatol 2015; 67:977–87. https://doi.org/10.1002/art.39029. 13. rhee js, young bc, rana s. angiogenic factors and renal disease in pregnancy. case rep obstet gynecol 2011; 2011:281391. https://doi.org/10.1155/2011/281391. 14. de jesus gr, de jesus nr, levy ra, klumb em. the use of angiogenic and antiangiogenic factors in the differential diag nosis of pre-eclampsia, antiphospholipid syndrome nephropathy and lupus nephritis. lupus 2014; 23:1299–301. https://doi.org/10. 1177/0961203314529172. 15. almaani s, meara a, rovin bh. update on lupus nephritis. clin j am soc nephrol 2017; 12:825–35. https://doi.org/10.2215/ cjn.05780616. 16. piccoli gb, daidola g, attini r, parisi s, fassio f, naretto c, et al. kidney biopsy in pregnancy: evidence for counselling? a syste matic narrative review. bjog 2013; 120:412–27. https://doi.org/10. 1111/1471-0528.12111. https://doi.org/10.1097/01.aog.0000437382.03963.88 https://doi.org/10.1097/01.aog.0000437382.03963.88 https://doi.org/10.1007/s10067-013-2180-z https://doi.org/10.1007/s10067-013-2180-z https://doi.org/10.1055/s-0035-1566245 https://doi.org/10.1055/s-0035-1566245 https://doi.org/10.1111/ppe.12332 https://doi.org/10.1111/ppe.12332 https://doi.org/10.2215/cjn.12441211 https://doi.org/10.2215/cjn.12441211 https://doi.org/10.1258/om.2011.110001 https://doi.org/10.1177/1753495x13498382 https://doi.org/10.1002/acr.21664 https://doi.org/10.1002/acr.21664 https://doi.org/10.1002/art.20837 https://doi.org/10.1002/art.20837 https://doi.org/10.1080/01443610903061751 https://doi.org/10.3109/01443615.2011.566389 https://doi.org/10.1002/art.39029 https://doi.org/10.1155/2011/281391 https://doi.org/10.1177/0961203314529172 https://doi.org/10.1177/0961203314529172 https://doi.org/10.2215/cjn.05780616 https://doi.org/10.2215/cjn.05780616 https://doi.org/10.1111/1471-0528.12111 https://doi.org/10.1111/1471-0528.12111 departments of 1cardiac anesthesia and 3cardiothoracic surgery, national heart center, royal hospital, muscat, oman; 2anesthesia residency training program, oman medical specialty board, muscat, oman *corresponding author’s e-mail: madanmaddali@gmail.com anaesthetic management of pulmonary metastasectomy in a patient infected with novel corona virus sars-cov-2 mohammed j. al-naabi,1 *madan m. maddali,1 karima r.s. al aliyani,2 ahmed al-balushi3 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 578–582, epub. 7 nov 22 submitted 28 mar 21 revisions req. 31 may & 27 jul 21; revisions recd. 4 jul & 29 jul 21 accepted 15 aug 21 tomography/computed tomography imaging revealed an interval progression of the pulmonary metastases [figure 1]. a left lung metastasectomy as a semi-emergency was planned as the metastatic nodule in the left lower lobe was rapidly increasing in size and was in close proximity to the pulmonary artery. at the time, the covid-19 pandemic was at its peak and a preoperative rrt-pcr test as a screening investigation was done despite the patient being asymptomatic. surgery was deferred as sars-cov-2 rna was detected. after four weeks, the patient’s rrt-pcr test was still positive. however, it was decided to proceed with the surgery as the cycle threshold (ct) value was 43, above the cut off value of 34.2,3 the cross-linked d-dimer assay xdp value was normal at 0.1 mg/l (normal range: <0.5 mg/l). a quantitative covid-19 antibody test (anti-sars-cov-2 s) done one day before surgery was negative (<0.400 iu/ml). the cardiopulmonary reserve assessed by a 6-minute walk test was acceptable (500 m). the room air arterial blood gas analysis results were within the normal range (ph = 7.4, partial pressure of carbon dioxide [pco2] = 40 mmhg, partial pressure of oxygen [po2] = 88 mmhg, oxygen saturation = 96%, bicarbonate [hco3] = 24 mmol/l, sodium [na+] = 138 mmol/l, potassium [k+] = 4.2 mmol/l, lactate = 1 mmol/l); vital parameters were also normal (blood pressure = 140/88 mmhg, heart rate = 78/min). the patient could hold his breath for more than 10 seconds and he was using an incentive spirometer regularly. the chest x-ray displayed multiple nodular opacities related to the emergence of the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), named the covid-19 pandemic, has resulted in the prioritising of individual patients for thoracic surgeries in order to conserve resources.1 droplets, contact and natural aerosols cause the spread of sars-cov-2. thoracic anaesthesia for thoracic surgical procedures in patients infected with sars-cov-2 gain special attention as many inherent procedures involved are a major source of aerosol generation and may contribute to the speared of the virus. this case report describes the successful anaesthesia management of an elderly patient who tested positive twice for real-time reverse transcription–polymerase chain reaction (rrt-pcr) and needed a pulmonary metastasectomy as a semiemergency. this report highlights the rationale behind the decision for surgery and the precautions taken for reducing aerosol generation during the various stages of anaesthesia. to the best of the authors’ knowledge, this is the first case report from oman describing the practical aspects of anaesthetic management of a thoracic surgical procedure in a patient with covid-19. case report a 76-year-old-male patient presented to a tertiary care hospital in muscat, oman, 2020, with bilateral pulmonary metastasis one year after having surgical excision of an adenocarcinoma of the sigmoid colon (pt4an1b). the 18f-fluorocholine positron emission this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.137 case report abstract: prioritisation of individual patients for thoracic surgeries gained importance during the current covid-19 pandemic to ensure optimal utilisation of resources. we report a 76-year-old-male patient who presented to a tertiary care hospital in muscat, oman, 2020, with bilateral pulmonary metastasis. the patient underwent an urgent pulmonary metastasectomy with successful anaesthesia management in an elderly patient despite him testing positive for covid-19 twice via real-time reverse transcription–polymerase chain reaction. at the 3-month follow-up some pulmonary abnormalities persisted but the patient was recovering well. this report discusses the rationale to perform surgery in this case and highlights the precautions taken for reducing aerosol generation during the various stages of anaesthesia. keywords: covid-19; coronavirus infections; one-lung ventilation; personal protective equipment; aerosols; thoracic surgical procedures; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ mohammed j. al-naabi, madan m. maddali, karima r.s. al aliyani and ahmed al-balushi case report | 579 the underlying malignancy. there were no ground glass opacities or evidence of consolidation suggestive of a covid-19 involvement of the lungs [figure 2]. after obtaining informed consent for the surgical procedure, the patient was shifted to the operation room. all personnel involved, donned personal protective equipment (ppe). the positive-pressure system and air conditioning in the operating room was turned off. after preoxygenation with oxygen through a tight-fitting face mask for three minutes, general anaesthesia was administered under standard american society of anesthesiologists monitoring protocol. the patient’s trachea was intubated with a 37 fr double lumen tube (dlt) with the help of a video laryngoscope. the dlt was positioned and the placement was confirmed by fibreoptic bronchoscopy (fob) with the patient being apnoeic. the tracheal and bronchial cuffs of the dlt were inflated immediately to avoid leakage of aerosol. high-efficiency particulate air (hepa) filters were applied between the disposable anaesthesia face mask and the breathing circuit, on the inspiratory and expiratory limbs of the breathing circuit, between the dlt catheter mount and the breathing circuit and on the bronchial lumen of the dlt that would be in communication with the operative non-dependent lung adding up to a total of five hepa filters. a pressure-controlled mode of mechanical ventilation was initiated with a fraction of inspired oxygen (fio2) of 0.7 and a positive end expiratory pressure of 5 cmh2o. pressure limit was adjusted to achieve 6 ml/kg/min tidal volume monitoring the end tidal carbon dioxide. general anaesthesia was maintained with infusions of dexmedetomidine (0.6 mcg/kg/hr), cisatracurium, fentanyl and sevoflurane (0.6 to 1 mac). one lung ventilation was achieved without any episode of hypoxaemia. left parenchymal sparing metastasectomy with anatomical figure 3: flowchart showing the stages of patient management and the zones in the operating room. rt-pcr = reverse transcription–polymerase chain reaction; ct = cycle threshold; ppe = personal protective equipment; fio2 = fraction of inspired oxygen; peep = positive end expiratory pressure; icu = intensive care unit. figure 1: 18f-fluorocholine positron emission tomo graphy/computed tomography imaging of the lungs of a 76-year-old-male patient showing metastatic nodules in the (a) left and (b) right lungs (circles). figure 2: chest radiograph of a 76-year-old-male patient in the anteroposterior view showing the lung fields with no signs of opacities or consolidation suggestive of covid-19 infection of the lungs. anaesthetic management of pulmonary metastasectomy in a patient infected with novel corona virus sars-cov-2 580 | squ medical journal, november 2022, volume 22, issue 4 segmentectomy was performed and six metastatic masses were removed. on completion of the procedure, aspiration of secretions was performed via a closed system from the non-dependent of the lung, followed by an alveolar recruitment maneuver of the collapsed lung and initiation of both lung ventilation. the wound was closed in layers; the surgery took approximately 95 minutes. one intercostal drain was inserted that was connected to an argyle™ thora-seal™ iii chest drain system (cardinal health, dublin, ireland). synchronised intermittent mandatory ventilation mode was initiated on return of spontaneous breathing. this was changed to pressure support mode (10 cmh2o) and the neuromuscular blockade was reversed. the cough reflex was inhibited with dexmedetomidine infusion and a bolus of lidocaine injection (1 mg/kg). all anaesthetic agents were stopped once surgical dressing was completed. fio2 of 100% was administered for two minutes and the patient’s trachea was extubated. oxygen was administered through nasal prongs and a surgical face mask was applied to the patient’s face. an arterial blood gas analysis was done (ph = 7.39, paco2 = 37 mmhg, po2 = 90 mmhg, oxygen saturation = 99%, hco3 = 22 mmol/l, na+ = 136 mmol/l, k+ = 3.2 mmol/l, lactate = 1.9 mmol/l). after confirmation of uncompromised spontaneous breathing, the patient was transferred to the intensive care unit (icu). the intercostal drain was removed after 48 hours postoperatively and the patient was discharged home on the seventh day after surgery. the patient’s flow diagram shows the stages of management of the patient as well as the zones in the operating room [figure 3]. a computed tomography (ct) scan done at the 3-month follow-up reported diffuse bronchial wall thickening with patent central tracheobronchial tree. there was mild para-septal emphysema with bi-apical scarring. the left apical region displayed cicatrisation and atelectasis. institutional ethical committee approval [src#cr22/2020] and informed consent from the patient were obtained for publishing this report. discussion this report describes the successful anaesthetic management of an elderly patient who had a positive rrt-pcr test and needed urgent pulmonary metastasectomy. the recommendation for timing the surgery in patients with sars-cov-2 infection has changed recently. at the time the current patient was operated on, the recommendation was that once sars-cov-2 infection was diagnosed, surgery was to be postponed for at least 7–14 days from the end of symptoms and should be followed by a negative test result.4,5 recent evidence suggests that surgery should be delayed by seven weeks.6 however, a positive rrt-pcr assay result alone may not be as important as the ct value. the ct threshold value is the number of amplification cycles needed to yield a positive fluorescent signal in a rrtpcr test and is a surrogate marker for the viral load. ct levels are inversely proportional to the amount of target nucleic acid in the sample. at the time of surgery for the current patient, data suggested 34 cycles as the cut-off value for determining on sarscov-2 infectivity.2 a patient may not be infectious if ct values are ≥35.3 viral droplets are the principal cause of the spread of covid-19 infection.4 many anaesthetic procedures result in aerosol generation of viral particles that may pose a risk for the medical team taking care of covid-19 positive patients. stress on minimising aerosol generation during the various stages of anaesthesia is the primary difference in anaesthetising a covid-19 negative patient for thoracic surgery compared to those who test positive for covid-19. the european association of cardiothoracic anaesthesiology thoracic subspecialty committee published updated recommendations for the management of thoracic anaesthesia patients with suspected or confirmed covid-19 infection.4 the recommendations emphasise achieving successful airway management without compromising the health of the treating team. guidelines are also available for triaging patients with thoracic malignancies based on the trajectory and the impact of covid-19 cases on each institution.1 notwithstanding a rapidly escalating covid-19 trajectory with many hospital admissions and resources constraint, the current patient underwent early surgery. during preoperative evaluation of suspected covid-19 patients, rrt-pcr testing and when its unavailable, chest ct needs to be done.5 there might be covid-19–related blood test anomalies such as elevated values of c-reactive protein, erythrocyte sedimentation rate and d-dimer levels.5 covid-19 patients may exhibit chest radiography abnormalities as well.5 the current patient tested positive for covid-19 on rrt-pcr on two occasions with a ct of >35 the second time. as the metastatic lesions were rapidly increasing in size with the possibility of infiltration into pulmonary vasculature, the decision to operate was made. tracheal intubation is to be performed electively using rapid sequence induction with complete neuromuscular paralysis after preoxygenation in mohammed j. al-naabi, madan m. maddali, karima r.s. al aliyani and ahmed al-balushi case report | 581 an ‘isolated’ negative pressure room with >12 air changes/minute.4 in the current patient, as a negative pressure operating room was not available, the tracheal intubation was done in an operating room after switching off the positive pressure with the doors closed. the operating room area was separated into red, white and yellow zones.4 in the red zone (i.e. the operating room), there were two staff members donned with full ppe during the tracheal intubation that was performed by a senior anaesthesiologist with the assistance of a nurse. the yellow zone was the induction room that was attached to the operating room and separated by a glass partition where an anaesthesiologist with full ppe was available in case assistance was required as suggested by şentürk et al.4 an observer from the institutional infection control team was present in the white zone that was outside the dedicated operating room. the ppe donned by the team comprised of hair covers, two n95 face masks each, face shield, long sleeve fluid-resistant gown, double gloves and overshoes as prescribed.4 according to the european guidelines, lung separation with a bronchial blocker maybe the preferred mode in covid-19 patients undergoing thoracic surgery.4 this technique mandates the use of an fob guidance. simultaneously, many other international societies recommend consideration of dlts in lieu of bronchial blockers for patients who do not have a known or suspected difficult airway with the placement of an antiviral filter on the open non-ventilated lumen of the dlt.7,8 a dlt may be positioned without the help of fob guidance based on auscultation and may be a better choice of lung isolation in covid-19 postive patients. in the current patient, an initial attempt was made to place a dlt without the help of fob guidance. as this initial attempt failed, it necessitated the need for fob for accurate placement of the dlt during the second attempt. this was done maintaining the patient apnoeic status. the management guidelines suggested by şentürk et al. for the conduct of one lung ventilation in patients with covid-19 were used in the current case.4 the placement of hepa filters in the anaesthesia circuit, management of ventilation parameters, alveolar recruitment techniques prior to resumption of both lung ventilation after achieving one lung ventilation, use of closed system for aspiration of secretions, cough suppression at the time of tracheal extubation were in accordance with these guidelines.4 nasal prongs for oxygen supplementation were inserted in the patient with the application of a surgical face mask over the prongs. observation of the patient during the immediate post-extubation period was done in the operating room and once the anaesthesiologist was convinced of the cardio-pulmonary stability of the patient, the patient was shifted to an isolation room in the icu for further management. attention was paid towards the possibility of virus transmission via the chest drainage unit. following the metastasectomy, no air leak was detected during the process of recruitment and expansion of the lung that was operated on. the intercostal drain was connected to a chest drain unit that was a closed system which had three chambers: a collection chamber for pleural fluid/ chest drain output, a water-seal chamber that acted as a one-way valve and a suction control chamber set to negative pressure of 5 cmh2o. the outlet port of the third chamber was connected to the wall-mounted suction to scavenge the exhaust from any ongoing air leak or air displaced by pleural drainage in the operating room and in the icu. during transport to the icu, the outlet port was kept sealed. in order to reduce the possibility of disease transmission, it has been suggested to attach a hepa filter to the port of the drainage system that is open to the environment.9 based on prior experience of management of patients during the middle east respiratory syndrome-cov outbreak and the available literature, guidelines for anaesthesia management of thoracic surgery in patients with suspected/confirmed covid-19 were recently published by the saudi anesthesia society.10 these guidelines address the general regulations, organisation, preparations and lung isolation/separation in different types of patients during a covid-19 outbreak.10 many of these were adopted in the current patient’s management. conclusion case selection for thoracic surgeries during the current covid-19 pandemic must be based on multidisciplinary discussion; the timing of surgery may be dictated by the patients underlying pathology. the perioperative anaesthetic management poses an important challenge as many events that are necessary for the conduct of anaesthesia in these patients are a major source of aerosol generation and may contribute to the spread of the infection. therefore, the primary objective of the conduct of thoracic anaesthesia in covid-19 positive patients is to minimise aerosol generation at all stages. a u t h o r s’ c o n t r i b u t i o n mmm conceptualised the work and was involved in acquisition of the images and drafted the manuscript. mjn, mmm, krsa and ab were involved in the interpretation of the data. mjn was responsible anaesthetic management of pulmonary metastasectomy in a patient infected with novel corona virus sars-cov-2 582 | squ medical journal, november 2022, volume 22, issue 4 for the provision of the anaesthesia details. ab was responsible for the provision of the operation data. krsa collected the data. all authors approved the final version of the manuscript. references 1 thoracic surgery outcomes research network, inc, antonoff m, backhus l, boffa dj, broderick sr, brown lm, et al. covid-19 guidance for triage of operations for thoracic malignancies: a consensus statement from thoracic surgery outcomes research network. ann thorac surg 2020; 110:692–6. https://doi.org/10.10 16/j.jtcvs.2020.03.061. 2. engelmann i, alidjinou ek, ogiez j, pagneux q, miloudi s, benhalima i, et al. preanalytical issues and cycle threshold values in sars-cov-2 real-time rt-pcr testing: should test results include these? acs omega 2021; 6:6528–36. https://doi. org/10.1021/acsomega.1c00166. 3. zacharioudakis im, prasad pj, zervou fn, basu a, inglima k, weisenberg sa, et al. association of sars-cov-2 genomic load with outcomes in patients with covid-19. ann am thorac soc 2021; 18:900–3. https://doi.org/10.1513/annalsat s.202008-931rl. 4. şentürk m, el tahan mr, szegedi ll, marczin n, karzai w, shelley b, at al. thoracic anesthesia of patients with suspected or confirmed 2019 novel coronavirus infection: preliminary recommendations for airway management by the european association of cardiothoracic anaesthesiology thoracic subspecialty committee. j cardiothorac vasc anesth 2020; 34:2315–27. https://doi.org/10.1053/j.jvca.2020.03.059. 5. fiorelli s, menna c, piccioni f, ibrahim m, rendina ea, rocco m, et al. the cutting edge of thoracic anesthesia during the coronavirus disease 2019 (covid-19) outbreak. j cardio thorac vasc anesth 2020; 34:3203–10. https://doi.org/10.1053/j. jvca.2020.05.042. 6. covidsurg collaborative; globalsurg collaborative. timing of surgery following sars-cov-2 infection: an international prospective cohort study. anaesthesia 2021; 76:748–58. https:// doi.org/10.1111/anae.15458. 7. shaylor r, verenkin v, matot i. anesthesia for patients under going anesthesia for elective thoracic surgery during the covid-19 pandemic: a consensus statement from the israeli society of anesthesiologists. j cardiothorac vasc anesth 2020; 34:3211–17. https://doi.org/10.1053/j.jvca.2020.07.049. 8. thornton m, reid d, shelley b, steven m. management of the airway and lung isolation for thoracic surgery during the covid-19 pandemic: recommendations for clinical practice endorsed by the association for cardiothoracic anaesthesia and critical care and the society for cardiothoracic surgery in great britain and ireland. anaesthesia 2020; 75:1509–16. https://doi.org/10.1111/anae.15112. 9. ghoniem a, abdellateef a, osman ai, elsayed hh, elkhayat h, adel w. a tentative guide for thoracic surgeons during covid 19 pandemic. cardiothorac surg 2020; 28:16. https://doi.org/1 0.1186/s43057-020-00026-z. 10. eldawlatly a, el tahan mr, abdulmomen a, kattan m, ahmad ae. anesthesia management of thoracic surgery in a patient with suspected/confirmed covid-19: interim saudi anesthesia society guidelines. saudi j anaesth 2020; 14:383–6. https://doi. org/10.4103/sja.sja_252_20. https://doi.org/10.1016/j.jtcvs.2020.03.061 https://doi.org/10.1016/j.jtcvs.2020.03.061 https://doi.org/10.1021/acsomega.1c00166 https://doi.org/10.1021/acsomega.1c00166 https://doi.org/10.1513/annalsats.202008-931rl https://doi.org/10.1513/annalsats.202008-931rl https://doi.org/10.1053/j.jvca.2020.03.059 https://doi.org/10.1053/j.jvca.2020.05.042 https://doi.org/10.1053/j.jvca.2020.05.042 https://doi.org/10.1111/anae.15458 https://doi.org/10.1111/anae.15458 https://doi.org/10.1053/j.jvca.2020.07.049 https://doi.org/10.1111/anae.15112 https://doi.org/1 0.1186/s43057-020-00026-z https://doi.org/1 0.1186/s43057-020-00026-z https://doi.org/10.4103/sja.sja_252_20 https://doi.org/10.4103/sja.sja_252_20 december 2007 vol 8 after meeting.indd osteopoikilosis spotted bone s s suresh sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 265-266 sultan qaboos university© submitted 31st may 2007 accepted 2nd september 2007 i n t e r e s t i n g m e d i c a l i m a g e العظم املنقط ظام العِ لُ تَبَكُّ سوريش اس. اس. د. department of orthopaedics, ibri regional hospital, p. o. box 46, ibri 516, sultanate of oman to whom correspondence should be addressed. email: dr.s.s.suresh@gmail.com symptomatology. her skeletal survey was normal. a diagnosis of osteopoikilosis was made. osteopoikilosis, or spotted bone, is a rare autosomal dominant bone disorder of unknown pathology seen incidentally on x-rays.1,2 it was initially described by albers-schonberg and ledoux-lebard and associates in the year 1915.3 it is usually detected as an incidental finding in x-rays taken for other conditions. there are multiple small (2-10 mm) well circumscribed round or oval areas of increased bone density widely distributed in periarticular areas.4 the distribution is symmetrical. it develops in childhood and persists throughout life. there is predilection for the epiphysis and metaphysis of the long tubular bones, carpus, tarsus, pelvis and scapula.4 lesions of the spine, skull, ribs and scapula are rare. it should be differentiated from osteoblastic bone metastasis, osteopathia striata, melorheostosis and tuberous sclerosis. the oval lesions of osteopoikilosis are often oriented with their long axis parallel to the shafts of tubular bones.2 it is usually asymptomatic, but in 15-20% of patients there may be slight articular pain and joint effusions.3 in approximately 25 % of cases whitish fibrocollagenous infiltrations (buschke-ollendorf syndrome) are found.3 histopathological study reveals a picture similar to bone islands, with focal condensations of compact lamellar bone with the spongiosa. bone scans are normal.the recognition of this condition by plain radiograph makes other expensive investigations unnecessary.5 a 21 year old girl presented at the orthopaedic clinic of ibri regional hospital, oman, with history of vague pain of the left wrist. the x-rays of the wrist showed multiple small osteosclerotic lesions. her blood investigations were normal ruling out systemic disease. her esr (erythrocyte sedimentation rate) was normal. she had no other figure 1: x-ray image of patients left hand s s s u r e s h 266 c o n c l u s i o n osteopoikilosis should be included in the differential diagnosis of sclerotic bone lesions and, if diagnosed, has not much clinical significance. r e f e r e n c e s 1. handa r, gulati ms. osteopoikilosis. j indian rheumatol assoc 2003; 11:59. 2. benli it, skalin s, boysan e etal. epidemiological, clinical and radiological aspects of osteopoikilosis. j bone joint surg 1992; 74:504-506. 3. tunc e, savas s. osteopoikilosis: report of a familial case. tr j med science 1999; 29:701-704. 4. knot r, sikarwar js, gupta rp, shrama gl. osteopoikilosis: a case report. ind j radiol imag 2005; 15:453-454. 5. tander b, cengiz k, diren b, canturk f. a case of osteopoikilosis mimicking metastasis on mri study. turk j phy med rehab 2006; 52:85-87. squ med j, february 2011, vol. 11, iss. 1, pp. 124-126, epub. 12th feb 11 submitted 22nd oct 2010 this article is based on an interview with the parents of the child conducted in august 2010 by theo poulton, a year 12 student at the british school muscat, on placement at sultan qaboos university hospital. it was edited by dr prakash mandhan, his supervisor and the neonatal surgeon in charge of the patient. “having children is not only a blessing, but also a joy for parents and grandparents” said mrs. a. her son ah, now an eight month-old boy, has spent almost 90% of his life in sultan qaboos university hospital (squh). ah and his twin brother were to be the couple’s first children so, naturally, they were very excited as they awaited the birth of their sons. however, this excitement was dampened when they learnt that their son, ah, would need an operation. ah was born at squh in january 2010 and since then has undergone three major and several minor operations. he was born prematurely as the second twin; this meant that he not only weighed less than a normal newborn, but was also more susceptible to infections. any procedures he underwent would be higher risk to him compared to a full-term baby. when he was 12 days-old and in the incubator in the neonatal intensive care unit (nicu), the nurse noted that his abdomen was enlarged and soon green coloured bile started pouring from his mouth. a quick assessment by doctors in the nicu together with x-ray and blood test findings suggested that he had an intestinal infection. the neonatal surgeon on duty was called and ah immediately underwent an emergency operation to save his intestine. “when the neonatal surgeon told us about ah’s condition, the necessity of urgent operation and the expected outcome, we were very worried and prayed to almighty god to save his life” said ah’s parents. “i was so worried because as it was such a big operation for such a small baby (1.4 kg). i wondered, how can surgeon operate on such a small baby?”, added ah’s mother. while the senior neonatal surgeon, two senior anaesthetists and a couple of senior nurses were trying hard to save ah’s life, his parents and family members were praying and waiting for news about the baby. nearly 95% of his small intestine was seriously infected and the germs had already affected his whole body. the neonatal surgeon had to remove his dead small intestine and then tried to save some of other affected parts of intestine in order to give ah a chance to live and grow unaided. after the operation, ah was given very strong antibiotics and full intensive care support to give him a chance to fight against the deadly infection. unfortunately, within 48 hours, he deteriorated further and needed a second operation. during this procedure, all except the first ten centimetres of the small intestine was found to be dead. it was a very hard decision for the surgeons to make, as well as for the parents, but since this was the only option to save his life, his entire dead small intestine was removed in the hope that once he was cured of the infection, he could be offered other alternatives. this left ah with only a very small percentage of the 250 cms of intestine of an average full-term newborn. “i remember, my wife was shocked after she had this news about 1the british school, muscat, oman; 2department of surgery, sultan qaboos university hospital, muscat, oman. *corresponding author email: kidsurg@squ.edu.om ^fl‚<ÿí†<·_<ÿ⁄`fi çëçé÷]<îçè÷á÷]<ïç√π]<h^„j÷]<gœ]á¬<çï<ì“ü√⁄  patient's viewpoint hope happens here battle with the consequences of severe neonatal gut infection theo poulton1 and *prakash mandhan2 theo poulton and prakash mandhan patient's viewpoint | 125 ah and so was i, but since we had no other option and we wanted him to survive, we made this hard decision. it helped to hear that there would be some options afterwards for ah to get an intestine” said ah’s father, an employee in a private company. despite this second operation, ah’s health was not good in the following few days. his father said, “we feared that we were very close to losing him, but we had great confidence in the doctors in squh and also hope from almighty god that he would be alright”. he also said, “it was through our hope and the efforts of the surgeons, doctors and nurses that he survived and within a week he was a different boy.” during this difficult period, ah’s father said that they had great moral support from family and friends. ah’s mother agreed and added, “the most important thing was that my husband was there for me and that everyone in the unit was trying his/her best for our son”. she continued, “when we looked at our twin sons in the neonatal unit, we always felt more protective of ah due to his condition. “i used to look at him, touch and cuddle him for hours to give him loads of support and love as he was my very tiny and cute baby,” said ah’s mother. due to the shortness of his small intestine, ah was now dependent on intravenous (iv) total parenteral nutrition for his supply of basic nutrients with the paediatric gastroenterologist taking over this special care. after a few weeks, it was time for the surgeon to restore ah’s intestine so that he could be started on oral feeds. “based on our previous experience, this time we were more confident and less worried about the operation since we had great trust in ah’s surgeon, who had already operated on him twice”, ah’s father commented. “we had more hope now that ah would be able to have some feed and grow like his brother”. ah’s third operation successfully rejoined his 10 cm of small intestine to his large intestine and also made a temporary hole in his stomach for supplementary feeds.. “ah could be started on small feeds ten days after his third operation and we were very excited on that day” said his parents. “when i saw the nurse giving him his first feed, i was thrilled”, said ah’s mother. “i was imagining joyfully that soon i would be able to feed him myself ”. after a few days, his feed was increased slowly and he was also removed from the incubator as he was improving and looking well. time flew by. at eight months-old, ah now weighs 5.0 kg and receives nutrition from iv drips as well as from the tube into his stomach. “although, he does have very minor problems with the tube in his stomach and with the central line for his iv feeding (which is very close to his heart), overall he is doing well”, said ah’s mother. by august 2010, ah had had four operations and his parents had more hope for his future health. ah has spent most of his life in squ hospital, his mother almost constantly with him. she is a teacher, but unable to fulfil her professional commitments due to ah’s condition. her husband has been a great support and they share the care of ah and his twin brother at hospital and home. ah’s mother said that although the care in the ward was good, she sometimes felt frustrated at not being given all the details about her son’s condition, “i like to know everything about my baby and his condition. maybe more junior staff are not used to being asked about every little thing. it’s not only the doctor’s decision. as his mother, i would like to be involved in his care plan”. she felt that the consultants did understand her feelings and did provide the information she wanted. her husband agreed, saying, “for us, we would like to make the decisions. if they decide to operate on him and we are not convinced, then we will say no. i remember, when the surgeon said ah needed one more operation (to connect ah’s small and large intestines). he explained the risks and benefits. it took us some time to decide, but finally we agreed with him. i think it is better to make the decisions yourself rather than leaving it to others”. as for the overall care and support given to ah at squh, ah’s mother said, “i feel it is really very good especially from the consultants, such as the paediatric surgeon, the paediatric gastroenterologist, the neonatologist and the paediatrician”. it has been a great experience for us to see what a great team of doctors and nurses we have here. everyone at different levels has been very helpful and supportive to us. the hospital administration has also been very cooperative for the supply of consumables, iv feeding and medicine for our son”. ah is now at home on iv nutrition, but regularly comes to squh for evaluation. the hope is that ah can have an intestine transplant, using part of the small intestine from his twin brother or a parent, so that he can have a chance to grow and survive without iv nutrition. one of the major disadvantages of iv nutrition is that it affects the hope happens here battle with the consequences of severe neonatal gut infection 126 | squ medical journal, february 2011, volume 11, issue 1 liver functions and can eventually cause liver failure, and the need for a liver transplant. up to now, there have been quite a few intestinal and liver transplants in children all over the world and the results are very encouraging. however, this treatment modality still needs more development before it becomes safe and easily available. “since there is no facility for intestine and liver transplant in oman, we have been in touch with transplant teams in europe and america for our son”, said ah’s parents. “the doctors from europe have asked us to send the medical reports and soon, inshallah, we will go and see a transplant team in order to get an opinion for ah. “i have done a lot of research and reading on the internet about intestine and liver transplant”, said ah’s mother. “although, i am not very comfortable with the final results, i have gradually become quite convinced about the need for it. earlier, i was totally against the proposition when the consultants first suggested it. it is going to be a huge burden on both of us financially as well as socially as we are the only earning members in the family. finally, we are a bit concerned about the care ah will need after the transplant. it is going to be very tough and hard on both of us to travel to europe for post-transplant care hence we hope that transplant doctors in europe will make a team with our surgeons and gastroenterologists in squh, so that we can get very similar care right here in squh. i have seen the hard work of our doctors and nurses in squh and we have a lot of confidence in all of them. we only wish this transplant could happen as soon as possible so that our son can have a more normal life”, concluded ah’s mother. department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com آثليل التنني لورا ليناري�س غونزالي�س، فران�سي�سكو نافارو تريفينيو، ريكاردو رويز فيالفريدي dragon warts laura linares-gonzalez, francisco navarro-triviño, *ricardo ruiz-villaverde sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e397–398, epub. 21 dec 20 submitted 27 jan 20 revision req. 27 apr 20; revision recd. 28 apr 20 accepted 20 may 20 a 31-year-old male patient with a personal history of type-1 diabetes presented to the dermatological outpatient clinic in hospital universitario san cecilio, granada, spain in january 2020, with asymptomatic, multiple, skin-colored papules of different sizes within a black tattoo on his abdomen [figure 1]. the tattoo was done 15 years ago and the lesions developed one year after on the lines of the tattoo and remained exclusively confined to it. however, the patient did not seek medical attention for the papules on his tattoo. dermatoscopy showed skin-coloured homogeneous papilomatous papules; laboratory investigations were within normal limits [figure 2]. complimentary tests such as blood cell count test, general biochemistry, autoantibodies, angiotensin converting enzyme, erythrocyte sedimentation rate, c-reactive protein complement, immunoglobulins, urinalysis were within normal limits. the histological findings were consistent with verruca vulgaris. patient consent was obtained for publication of the images. comment as tattooing has spread worldwide, the number of medical consultations regarding its side effects has increased. although the most common reactions to tattoos are inflammatory reactions, a variety of infectious diseases including bacterial and viral infections has also been described.1 the first formal report of in a tattoo dates back to 1884.2 most reports seem to be confined to certain colours used multicoloured tattoos, with a clear preference for black ink.3 in the current case, the distribution of warts over the black ink along with the this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.020 interesting medical image figure 1: skin-coloured papules on a black tattoo of the abdomen of a 31-year-old male patient who presented to the dermatological outpatient clinic in hospital universitario san cecilio, granada, spain. https://creativecommons.org/licenses/by-nd/4.0/ dragon warts e398 | squ medical journal, november 2020, volume 20, issue 4 surrounding normal skin raised suspicion regarding the localisation of the warts. in the current case, the source of infection was difficult to determine. however, it has been proposed that it was the result of contaminated ink or other contaminated materials or instruments, implantation of viral particles present in the saliva of the tattoo artist during the procedure or autoinoculation of the patient’s own wart by tattooing through virally contaminated skin.4 another possibility is that the infection was already present before tattooing. an interesting theory suggests that virus replication might have been activated by mechanical impairment of the skin barrier. in most cases, lesions could be observed several months or years after tattooing.5 the longest latency period between tattooing and the manifestations of human papillomavirus (hpv) infection was 10 years. this suggests that the immune system is able to control the infection and that the development of cutaneous viral warts could depend on a local persistent dysregulation of the skin immune system. in addition, delayed activation of hpv and induction of warts in a tattoo has also been described after sunlight exposure implying that hpv can be triggered by external stressors.5 another explanation to this phenomena is that the tattooed area becomes an immunocompromised district. an immunocompromised district is a site which is particularly susceptible to subsequent outbreaks of opportunistic infections, tumours and immune disorders confined to the district itself.6,7 a simple physical examination will easily suggest the correct diagnosis in most cases. however, dermatoscopy is a useful adjuntive tool when clinical diagnosis is not clear or if histological images are inconclusive or not available. references 1. messahel a, musgrove b. infective complications of tattooing and skin piercing. j infect public health 2009; 2:7–13. https:// doi.org/10.1016/j.jiph.2009.01.006. 2. fox, tc. warts occurring on tattooed lines. j cutan vener dis 1884; 2:216. 3. baxter sy, deck dh. tattoo-acquired verrucae plana. am fam physician 1993; 47: 732. 4. ragland hp, hubbell c, stewart kr, nesbitt lt. verruca vulgaris inoculated during tattoo placement. int j dermatol 1994; 33:796–7. https://doi.org/10.1111/j.1365-4362.1994.tb00998.x. 5. wanat ka, tyring s, rady p, kovarik cl. human papillomavirus type 27 associated with multiple verruca within a tattoo: report of a case and review of the literature. int j derm 2014; 53:882–4. https://doi.org/10.1111/j.1365-4632.2012.05644.x. 6. ruocco v, brunetti g, puca rv, ruocco e. the immuno compromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. j eur acad dermatol venereol 2009; 23:1364–73. https://doi.org/10.1111/ j.1468-3083.2009.03345.x. 7. ruocco v, ruocco e, piccolo v, brunetti g, guerrera lp, wolf r. the immunocompromised district in dermatology: a unifying pathogenic view of the regional immune dysregulation. clin dermatol 2014; 32:569–76. https://doi.org/10.1016/j. clindermatol.2014.04.004. figure 2: dermatoscopy at x10 magnification showing skin-coloured homogeneous papilomatous papules on the black tattoo of a 31-year-old male patient. https://doi.org/10.1016/j.jiph.2009.01.006 https://doi.org/10.1016/j.jiph.2009.01.006 https://doi.org/10.1111/j.1365-4362.1994.tb00998.x https://doi.org/10.1111/j.1365-4632.2012.05644.x https://doi.org/10.1111/j.1468-3083.2009.03345.x https://doi.org/10.1111/j.1468-3083.2009.03345.x https://doi.org/10.1016/j.clindermatol.2014.04.004 https://doi.org/10.1016/j.clindermatol.2014.04.004 squ med j, may 2011, vol. 11, iss. 2, pp. 196-200, epub. 15th may 11 invited article submitted 2nd apr 11 revision req. 20th apr 11, revision recd. 23rd apr 11 accepted 24th apr 11 only a small amount of vitamin d comes from dietary sources, e.g. fish and meat,1 while most of it is known to be made by the body as a natural by-product of the skin's exposure to sunlight.2 in the early 1900s, the discovery of the link between rickets and vitamin d deficiency helped to ensure that exposure to the ultraviolet b (uvb) fraction of sunlight became popular as a preventative medical intervention.3 uvb rays enter the epidermis and release energy that changes a pre-existing cholesterol metabolite to previtamin d3, which is then slowly converted nonenzymatically to vitamin d3 (cholecalciferol). vitamin d3, bound to a specific vitamin d binding protein (dbp), is then transported to the liver, where it is enzymatically hydroxylated to 25-hydroxyvitamin d (calcifidiol or 25(oh)d). although 25(oh)d is only weakly biologically active, its circulating level furnishes a good index of the bioavailability of vitamin d because it has a long serum half-life (2 weeks).4 then, 25(oh)d, bound to dbp, is transported to the kidney and other organs, where it is hydroxylated at the 1 position to produce 1,25(oh)2d, the most biologically active form of vitamin d.4 from our point of view, sun education started to emphasise the importance of protection from harmful ultraviolet rays (uvr), especially after office of h.e. the undersecretary of planning, ministry of health, muscat, oman. *corresponding author email: drmoness@gmail.com ïüç^fπ]<ã€é÷]<ì√ç˘<öü√jfi<˜<ê_<öü√jfi ·^€ �¬<ª<dåe<∞⁄^jè <ìœfi    3"2004"            25:مفتاح الكلمات abstract: only small amounts of vitamin d come from dietary sources as it is mainly synthesised in the skin from the ultraviolet b (uvb) fraction of sunlight if the person is sufficiently exposed to direct sunlight. vitamin d deficiency has been well documented in oman. the "2004 oman national micronutrients survey" and other recent studies revealed that vitamin d3 stores are low among healthy omani females of childbearing age and pregnant women. this situation is confusing as oman is known to be one of the sunniest countries in the world. however, it is known that most omani women are well covered and for various reasons avoid sun exposure. the article addresses a question about the balance that should be maintained between excessive sun exposure that leads to an increased risk of skin cancer, and healthy exposure that provides sufficient ultraviolet radiation (uvr) to maintain adequate vitamin d levels. in order to avoid vitamin d deficiency, sun exposure or protection messages must be tailored according to different situations, in recognition of the complex combination of personal, cultural and social factors that affect vitamin d synthesis in the skin. keywords: vitamin d deficiency, 25-hydroxyvitamin d, sunlight, ultraviolet rays, skin cancer, oman sounding board to be or not to be exposed to direct sunlight vitamin d deficiency in oman moeness m. alshishtawy moeness m. alshishtawy sounding board | 197 the strong involvement of the united nations (un) in work to understand the health effects of uvr exposure. this was established at the un conference on environment and development in 1992. the trigger for that was the recognition that the ozone layer was being depleted and that the risk of diseases resulting from excessive exposure to uvr, particularly skin cancers, would probably increase.5 several studies have demonstrated that exposure to environmental levels of uvr alters the activity and distribution of some of the cells responsible for triggering immune responses in humans. consequently, sun exposure may enhance the risk of infection with viral, bacterial, parasitic or fungal infections, which has been demonstrated in a variety of animal models.6 the known health effects of uvr include also photokeratitis and photoconjunctivitis. moreover, sun exposure, in particular exposure to uvb, appears to be a major risk factor for cataract development.7 regarding skin, exposure to uvr is considered to be a major aetiological factor for its three common forms: basal cell carcinoma (bcc), squamous cell carcinoma (scc) and malignant melanoma (mm). non-melanoma skin cancers, bcc and scc, are most frequent on parts of the body that are commonly exposed to the sun such as ears, face, neck and forearms. this implies that longterm, repeated uvr exposure is a major causative factor. moreover, there is a clear relationship, in some countries, between an increasing incidence of non-melanoma skin cancers and decreasing latitude, i.e. higher uvr levels.6 on the other hand, the causes of malignant melanoma (mm) are not fully understood. however, several epidemiological studies support a positive association with a history of sunburn, particularly sunburn at an early age. tumour development may be linked to high, intermittent exposure to solar uvr,6 such as at weekends or on holiday.7 the higher incidence of malignant melanoma in indoor workers compared to outdoor workers supports that notion.7 studies show also that malignant melanoma risk is higher in people with a history of non-melanoma skin cancers and of solar keratoses, both of which are indicators of cumulative uv exposure.6 in assessing how much sun exposure is needed for adequate vitamin d production, one should be aware that there is a threshold level of uvb required to induce vitamin d production.8 however, the exact dose of uvr exposure for optimal vitamin d levels is not known, particularly as the required uvr dose will be influenced by host factors. whole body exposure in a bathing suit to one minimum erythemal dose (med) of uvr is equivalent to ingesting 10,000 international units of vitamin d.9 med is defined as the uvr exposure that will produce a just perceptible erythema 8–24 hours after irradiation of the skin. the med is specific to each individual and varies with the source of uvr, the tanning capacity and any adaptation from previous exposures.10 a low level of casual sun exposure, even during summer, will result in only very small amounts of endogenous vitamin d3 production.11 the effects of sunlight exposure on vitamin d3 synthesis are also decreased by the use of sunscreens and in individuals with darker skin pigmentation12 because of the presence of high concentrations of melanin in the stratum corneum that severely inhibits vitamin d3 production.10 in addition to that, concentrations of 25(oh)d in blood serum—the best clinical index of vitamin d status—decline with age due to declining intake, decreased sun exposure and, perhaps most importantly, less efficient skin synthesis of vitamin d3.13 thus, for a person with moderately fair skin, exposure of face, hands and arms for 6–7 minutes at 10:00 or 14:00 in summer (or 9–12 minutes in winter) in northern australia (latitude 17° south), should produce around 1,000 iu of vitamin d, an amount sufficient to maintain vitamin d concentrations in the normal range. the equivalent exposure required at a higher latitude such as tasmania (41–43° south) is 7–9 minutes in summer, but 40–47 minutes in winter.14 however, some argument remains over the range of concentrations of vitamin d in blood that should be considered ‘normal’. currently, 50 nmol/l is accepted as the lower limit of sufficiency,5 although a study from finland, suggested 80 nmol/l as the minimum level in blood able to prevent physiological changes associated with vitamin d insufficiency.15 although a low prevalence should be expected, studies carried out in the last two decades show a high prevalence of vitamin d deficiency in many tropical countries,16 including oman. in 2004, the ministry of health (moh), oman, in collaboration with the centers for disease control and prevention (cdc), the world health organization (who) and the united nations international children's to be or not to be exposed to direct sunlight vitamin d deficiency in oman 198 | squ medical journal, may 2011, volume 11, issue 2 emergency fund (unicef) conducted a crosssectional household-based survey of micronutrient status using the sophisticated technique of highperformance liquid chromatography (hplc) in the moh central public health laboratory to analyse vitamin d and other micronutrients in serum samples from 832 households. the survey clusters were selected using the pps (proportional to population size) sampling methodology.17 a subsample of 298 non-pregnant women of child bearing age was analysed for serum 25(oh)d. alarmingly 21.4% of the women included in the survey were found to be vitamin d deficient (<27.0 nmol/l).17 almost half of the women (47%) tested had serum 25(oh)d levels below 37.5 nmol/l, while only 10% of the women had levels above 75 nmol/l.18 a more recent study by al-kindi in 201016 investigated serum 25(oh)d levels among 41 apparently healthy omani women of childbearing age. all the women had a 25(oh)d level <50 nmol/l as the cut-off for deficiency. another study conducted by al kalbani et al. in 201019 investigated the vitamin d status of pregnant omanis by measuring their circulating 25(oh)d levels. in that study, blood samples were obtained from a cohort of 103 consecutive healthy pregnant omanis on their first antenatal visit to the hospital. the study revealed that vitamin d deficiency ([25(oh)d] <25 nmol/l) was present in 34 cases (33%), ‘at risk’ levels ([25(oh)d] = 25–50 nmol/l) were found in 67 cases (65%); two cases (1.9%) had values between 50 and 75 nmol/l, and not one case was found in the optimal range (25(oh)d >75 nmol/l). the results confirmed that vitamin d3 stores are low in omani females of reproductive age. the findings of the study were found by al kalbani and her colleagues to be similar to those reported earlier in saudi arabia and recently in the uae and qatar.20,21,22 these recent studies conducted in oman give a warning that subclinical vitamin d deficiency may be prevalent amongst omani women and indicate the need for vitamin d replacement especially during pregnancy and lactation.16,19 this situation is surprising as oman is known to be one of the sunniest countries in the world and its people are thus expected to have adequate sun exposure. this unexpected situation may be attributed to social and cultural factors16 as the conservative dress of omani women, especially those who wear the veil, blocks exposure to sunlight. added to that, the reduction in outdoor leisure time that has accompanied urbanisation in oman and the rise in office-based work has lead to an increased lack of sunlight exposure. females, particularly those who are sensitive to the sun's uv rays, are more concerned about their appearance and health. they are unwilling to get dark-coloured skin or sunburn, and so avoid being exposed directly or indirectly to sunlight. so, the boundaries between the risks and the benefits of uvr are unclear and the question therefore arises: “what is the balance between healthy sun exposure that provides sufficient uvr to maintain adequate vitamin d levels in blood serum, and excessive exposure that leads to an increased risk of skin cancer?” unfortunately, public health campaigns aiming to decrease the incidence of skin cancer urged people to limit exposure to ultraviolet light, which is important for maintenance of vitamin d levels, especially in at-risk groups such as those who are elderly, who suffer from malabsorption or who have dark skin (particularly if they wear a veil).23 it is important also to mention that the guidelines for decreasing exposure included directives from the american academy of pediatrics (aap) that infants younger than 6 months should be kept out of direct sunlight, children’s activities that minimise sunlight exposure should be selected, and protective clothing as well as sunscreens should be used.24 accordingly, one consequence of avoiding possibly harmful sun exposure could be a reduced amount of physical activity, especially when school, work and rec-reational activities are usually scheduled outdoors between 10:00 and 16:00. sun protection messages may, thus, inadvertently increase health risks related to physical inactivity such as obesity and cardiovascular disease.23 all these irritatingly contradictory relationships make it very difficult to determine what the adequate sunshine exposure time is for any given person. the message to protect against excessive uvr exposure was seen to be correct in countries with abundant sunshine and populated by fair-skinned inhabitants. even for populations that remain in the physical environments for which they are evolutionarily suited, marked changes in the social environment now predispose people to diseases associated with underor over-exposure to uvr. similarly, in populations that have moved from their traditional habitats, problems of both excess sun exposure and moeness m. alshishtawy sounding board | 199 vitamin d insufficiency are clearly evident.5 the first national cancer council to recognise the importance of balance in recommendations about sun exposure was the cancer council australia in its 2005 position statement "risks and benefits of sun exposure".23 the statement did provide sufficient guidance on optimum levels of exposure.5 however, the correct answers to several questions are still under debate: “what is the optimal level of vitamin d?”, “what is the amount of uvr needed to maintain an adequate vitamin d level?”, and “what is the optimal age-appropriate uvr dose?” the conclusion is that increased uvr exposure is known to have harmful health consequences; however, uvr exposure also has some beneficial effects, especially in relation to vitamin d production. therefore, a ‘one message fits all’ approach is not appropriate. sun exposure or protection messages may need to be shaped to different situations, in recognition of the complex combination of host factors, e.g. age, sex, race, skin pigmentation, and sun-seeking or sun-avoidance practices. this matrix of considerations becomes even more complex when a diversity of cultural and social environments are taken into account. added to that, the lack of clear guidelines may lead to inappropriate personal solar exposure. the substantial challenge for health workers is to translate their knowledge into readily comprehensible public health messages and, subsequently, to take account of the accretion of upcoming evidence-based information. references 1. norris jm. can the sunshine vitamin shed light on type 1 diabetes? lancet 2001; 358:1476–8. 2. webb ar, kline lw, holick mf. influence of season and latitude on the cutaneous synthesis of vitamin d3: exposure to winter sunlight in boston and edmonton will not promote vitamin d3 synthesis in human skin. j clin endocrinol metab 67:337–8; 1988. 3. carpenter k, zhao d. forgotten mysteries in the early history of vitamin d. j nutr 1999; 129:923–7. 4. cunningham j, anderson dc, manson jp. metabolic bone disease and mineral metabolism. in: souhami rl, moxham j, eds. textbook of medicine, 3rd ed. new york: churchill livingstone, 1997. p. 779. 5. lucas rm, repacholi mh, mcmichael aj. is the current public health message on uv exposure correct? bull world health org 2006, 84:6. 6. world health organization. health effects of uv radiation. from: http://www.who.int/uv/health/uv_ health2/en/index3.html. accessed: february 2011. 7. world health organization. ultraviolet radiation and the intersun programme: the known health effects of uv. from: http://www.who.int/uv/ faq/uvhealtfac/en/index5.html accessed: february 2011. 8. matsuoka ly, wortsman j, haddad jg, hollis bw. in vivo threshold for cutaneous synthesis of vitamin d3. j lab c1in med 1989; 114:301–5. 9. mcmichael aj, lucas r, ponsonby al, edwards sj. stratospheric ozone depletion: ultraviolet radiation and health. from: http://www.who.int/ globalchange/publications/climatechangechap8.pdf. accessed: february 2011. 10. vecchia p, hietanen m, stuck be, van deventer e, niu s. protecting workers from ultraviolet radiation. geneva: international commission on non-ionizing radiation protection in collaboration with international labour organization & world health organization, 2007. 11. hollis bw. circulating 25-hydroxyvitamin d levels indicative of vitamin d sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin d. j nutr 2005; 135:317–22. 12. fuller ke, casparian jm. vitamin d: balancing cutaneous and systemic considerations. south med j 2001; 94:58–64. 13. world health organization. keep fit for life: meeting the nutritional needs of older persons. geneva: world health organization and tufts university school of nutrition and policy, 2002. 14. working group of the australian and new zealand bone and mineral society, endocrine society of australia and osteoporosis australia. vitamin d and adult bone health in australia and new zealand: a position statement. med j aust 2005; 182:281–5. 15. lamberg-allardt cj, outila ta, karkkainen mu, rita hj, valsta lm. vitamin d deficiency and bone health in healthy adults in finland: could this be a concern in other parts of europe? j bone miner res 2001; 16:2066–73. 16. al-kindi mk. vitamin d status in healthy omani women of childbearing age: study of female staff at the royal hospital, muscat, oman. squ med j 2011; 11:56–61. 17. ministry of health, oman. micronutrients testing, community health & disease surveillance newsletter, 2008; 17:12–13. 18. alasfoor d, kaur m, al kiyumi s, al busaidy s, suleiman aj, ruth l, parvanta i. vitamin d deficiency: a public health problem in oman. from: http://www.micronutrientforum.org/meeting2009/ pdfs/poster%20presentations/3_thursday/dkb/ th66_kaur.pdf. accessed: april 2010. 19. al kalbani m, elshafie o, rawahi m, al mamari a, to be or not to be exposed to direct sunlight vitamin d deficiency in oman 200 | squ medical journal, may 2011, volume 11, issue 2 al zakwani a, woodhouse n. vitamin d status in pregnant omanis: a disturbingly high proportion of patients with low vitamin d stores. squ med j 2011; 11:52–5. 20. woodhouse ny, norton w. low vitamin d levels in saudi arabians. king faisal spec hosp med j 1982; 2:127–31. quoted in: al kalbani m, elshafie o, rawahi m, al mamari a, al zakwani i, woodhouse n. vitamin d status in pregnant omanis: a disturbingly high proportion of patients with low vitamin d stores. squ med j 2011; 11:52–5. 21. saadi hf, nagelkerke n, benedict s, qazaq hs, zilahi e, mohamadiyeh mk, et al. predictors and relationships of serum 25 hydroxyvitamin d concentration with bone turnover markers, bone mineral density and vitamin d receptor genotype in emirati women. bone 2006; 39:1136–43. epub 2006 june 30. quoted in: al kalbani m, elshafie o, rawahi m, al mamari a, al zakwani i, woodhouse n. vitamin d status in pregnant omanis: a disturbingly high proportion of patients with low vitamin d stores. squ med j 2011; 11:52–5. 22. saadi hf, dawodu a, afandi bo, zayed r, benedict s, nagelkerke n. efficacy of daily and monthly high dose calciferol in vitamin d deficient nulliparous and lactating women. am j clin nutr 2007; 85:1565–71. quoted in: al kalbani m, elshafie o, rawahi m, al mamari a, al zakwani i, woodhouse n. vitamin d status in pregnant omanis: a disturbingly high proportion of patients with low vitamin d stores. squ med j 2011; 11:52–5. 23. the cancer council australia. risks and benefits of sun exposure: position statement, 2005. from: http:// www.cancer.org .au/documents/risks_benefits_ sun_exposure_mar05.pdf. accessed: march 2010. 24. american academy of pediatrics, committee on environmental health. ultraviolet light: a hazard to children. pediatrics 1999; 104:328–33. department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: edwinmay2013@gmail.com طرق التعامل مع احلاالت الطارئة جلراحة االوعية الدموية أثناء جائحة كوفيد-19 يف املستشفى مرجعي يف ُعمان اإدوين �ستيفن, �سارة العدوي, اإبراهيم عبدالهادي, حنان املعويل, خليفة الوهيبي abstract: objectives: this study aimed to discuss the different challenges faced while managing emergency vascular surgery cases during the covid-19 pandemic and how these challenges were overcome. methods: this study details 14 emergency cases that were managed during a period of one month from mid-march to mid-april at sultan qaboos university hospital, muscat, oman. the cases included acute limb ischaemia, critical limb ischaemia, type b dissection of the thoracic aorta, thoraco-abdominal aneurysm, critical internal carotid artery stenosis, trauma, infected arteriovenous forearm loop graft and thrombosed arteriovenous fistulas. results: only one patient was confirmed to have covid-19. five were negative for covid-19 while the remaining eight were not tested. various strategies on how the vascular surgical team accommodated changes in hospital protocols and nationwide lockdown are discussed in detail. conclusions: with the judicious use of personal protective equipment and consumable surgical and endovascular devices, communication with support services and other hospitals and implementation of triage protocols, it was possible to manage vascular surgery emergencies effectively. keywords: covid-19; vascular surgery; emergencies; oman. الطارئة احلاالت مع التعامل يف الدموية االوعية جراحة فريق واجهها التي التحديات ملناق�سة الدرا�سة هذه هدفت الهدف: امللخ�ص: جلراحة االوعية الدموية اأثناء جائحة كوفيد 19 و كيف مت التغلب عليها. املنهجية: �سملت هذه الدرا�سة 14 حالة طارئة مت التعامل معها خالل منت�سف �سهر مار�س اىل ابريل �سنة 2020 يف م�ست�سفى جامعة ال�سلطان قابو�س ‘م�سقط‘ �سلطنة عمان. ت�سمنت هذه احلاالت حاالت النوع من االورطي ال�رشياين االن�سالخ حاالت و احلرجة االطراف تروية نق�س حاالت و ال�سفلية االطراف �رشايني يف احلادة اجللطات جتلط و االلتهابات حاالت كذلك و احلوادث حاالت و ال�سباتي لل�رشيان ال�سديد الت�سيق حاالت و االورطي ال�رشياين التمدد حاالت و ب خم�س هناك .19 كوفيد بفريو�س م�ساب انه على ت�سخي�سه مت واحد مري�س يوجد الكلى. النتائج: لغ�سيل الوريدية ال�رشيانية الو�سالت ا�ستخدام طرق الدرا�سة هذه بينت لها. الفح�س اجراء يتم مل حاالت ثمانية هناك كانت بينما بالفريو�س. اال�سابة فيها يثبت مل حاالت و امل�ست�سفى بروتوكول يف امل�ساحب التغيري لتالئم احلاالت هذه مع للتعامل الدموية االوعية جراحة لفريق املختلفة اال�سرتاتيجيات ملعدات ال�سحيح باال�ستخدام اخلامتة: الوقت. ذلك يف امل�ستجد كورونا فريو�س مع للتعامل العليا اللجنة قرارات ح�سب االغالق نظام تطبيق و االخرى امل�ست�سفيات مع اجليد التوا�سل و الدموية االوعية جراحة اجهزة و اجلراحية واالجهزة ال�سخ�سية للحماية ال�سالمه بروتوكول الفرز وت�سنيف االولويات مت التعامل مع احلاالت الطارئة جلراحة االوعية الدموية بكفاءة اأثناء اجلائحة. الكلمات املفتاحية: كوفيد-19؛ جراحة االوعية الدموية؛ احلاالت الطارئة؛ ُعامن. managing vascular surgery emergencies and referrals during the covid-19 pandemic at a tertiary centre in oman *edwin stephen, sara s. h. al-adawi, ibrahim abdelhady, hanan al mawali, khalifa al-wahaibi sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e116–119, epub. 15 mar 21 submitted 24 jun 20 revision req. 9 aug 20;revisions recd. 30 aug 20 accepted 16 sep 20 https://doi.org/10.18295/squmj.2021.21.01.016 brief communication this work is licensed under a creative commons attribution-noderivatives 4.0 international license. on the 24 th of february 2020 the first two cases of covid-19 were confirmed in oman. in an effort to curtail the spread of the pandemic and ‘flatten the curve’, the international borders were shut in mid-march for non-residents and a staged lockdown between governorates was enforced from the beginning of april 2020. all patients presenting to the sultan qaboos university hospital (squh), muscat, oman, were subject to a questionnaire regarding symptoms suggestive of a covid-19 infection and polymerase chain reaction testing was done accordingly. this article discusses how the vascular surgical team effectively managed the vascular emergency referrals during the transition period from a non-covid-19 time to a time of covid-19-based restrictions and protocols. methods for the purpose of this study, only emergency cases referred to the vascular surgical team at squh between the period of 17th of march to 16th of april 2020 were included. a total of 14 emergency https://creativecommons.org/licenses/by-nd/4.0/ edwin stephen, sara s. h. al-adawi, ibrahim abdelhady, hanan al mawali and khalifa al-wahaibi brief communication | e117 table 1: details of emergency surgeries and referrals at sultan qaboos university hospital from mid-march to midapril 2020 emergency presentation characteristic pcr covid-19 testing results diagnosis/management age in years gender ihr comorbidity covid-19 status symptom acute limb ischaemia 77 f no dm, htn and dlp cough for two weeks and no fever negative femoral embolectomy 43 m no esrd, dm and htn sepsis and cxr suspect negative popliteal and tibial embolectomy 28 f no sickle cell disease sepsis and cxr suspect negative rutherford grade 3 bilateral hand and forefeet on maximum inotropic support given anticoagulation medication 95 f no dm, htn and chf shortness of breath and cxr suspect negative cold forefoot and pain pta pulse ++ cta pta is only run off bmt 43 m no trisomy 21 shortness of breath and fever negative brachial embolectomy critical limb ischaemia 59 m yes dm, htn, ckd stage 1, non-healing left foot wound and rest pain asymptomatic not done diabetic foot sfa + pta angioplasty telephonic follow-up 69 f no ckd stage 4, dm, htn and gangrenous second and third toes asymptomatic not done sfa angioplasty + stenting and pta angioplasty amputation of gangrenous toes type b dissection 65 f no htn, dm and chest and back pain asymptomatic not done no mal-perfusion medical management for blood pressure control in the cardiac icu outpatient follow-up thoracoabdominal aneurysm 96 f no anaemia, dm, htn and history of falling sepsis not done poor functional status bmt critical ica stenosis 75 f yes stroke, dm and htn asymptomatic not done telephonic consult right hemiparesis left ica 75% stenosis on duplex bmt and cta trauma 22 m no open fracture of tibia and fractured pelvis and femur asymptomatic not done left internal iliac artery embolisation ex-fix femur and tibia infected av forearm loop graft 74 f no esrd on dialysis, dm and htn sepsis and cxr suspect negative graft explanted thrombosed av fistula 54 f yes esrd on dialysis shortness of breath, fever, cough and required niv positive dialysed via a quinton line at the local hospital 52 m no esrd, dm and htn asymptomatic not done thrombosed av fistula with cellulitis in arm catheter directed thrombolysis and iv antibiotics ihr = interhospital referral; pcr = polymerase chain reaction; f = female; dm = diabetes mellitus; htn = hypertension; dlp = dyslipidaemia; m = male; esrd = end stage renal disease; cxr = chest x-ray; chf = congestive heart failure; pta = posterior tibial artery; cta = computed tomography angio graphy; ckd = chronic kidney disease; sfa = superficial femoral artery; icu = intensive care unit; bmt = best medical therapy; ica = internal carotid artery; av = arteriovenous; niv = non-invasive ventilation; iv = intravenous. managing vascular surgery emergencies and referrals during the covid-19 pandemic at a tertiary centre in oman e118 | squ medical journal, february 2021, volume 21, issue 1 surgeries and referrals were included [table 1]. the usual case volume before the pandemic was around 40–50 patients per month for elective surgical and endovascular procedures. ethical approval was obtained from the institutional research ethics committee (mrec #2143) results of the 14 cases, one was confirmed to be positive for covid-19, requiring respiratory support with noninvasive ventilation. five patients tested negative, one of whom was being managed as a potentially positive covid-19 case until the second test revealed a negative result. the remaining eight cases did not meet the criteria set for covid-19 testing. discussion squh is one of two centres in oman with endovascular and vascular surgical services in the capital city of muscat. elective surgical procedures were stopped from the 15th of march 2020, with priority given to patients with malignancies and emergency cases. for example, two patients were scheduled for elective aneurysm repairs (a thoracic endovascular aortic repair and a fenestrated endovascular aortic repair) were postponed as they were in the geriatric age group with multiple comorbidities, until such a time that the pandemic was deemed to be under control. interventional procedures (cardiac and interventional radiology) were carried out in the hybrid catheterisation laboratory. squh like other hospitals around the globe, experienced a shortage in personal protective equip ment (ppe). healthcare professionals underwent a series of training sessions in donning, doffing and care of ppe. if the covid-19 test results were expected within one hour and a patient was likely to need intervention, assessment was performed by the consultant on call, thereby reducing the use of ppe. anaesthetists, radiologists, technicians, nurses and porters were willing to expedite results of invest igations, perform medical imaging and transfer the suspected covid-19 patients in order to minimise exposure time despite intentional and planned reduction in staffing. this reduction was periodically assessed by the administration to ensure that patient care wasn’t affected. inpatient transfers were limited between hospitals by facilitating visit(s) by the consultant vascular surgeons to hospitals, within the governorate of muscat. for patients requiring a transfer, they were permitted to cross the police check-points establishing during lockdown with a referral letter from their primary hospital. telemedicine was put to good use between doctors in the periphery who sought the opinion of the surgical team at squh. despite the above systems being in place, one of the included patients with a diabetic foot that required dressings preferred to remain as an inpatient to avoid travel between governorates. however, there were also patients with concerns who were encouraged to visit the clinic but preferred to delay their visit due to the fear of contracting the virus in hospital. in order to reduce the inter-hospital referrals, telephonic consultation was utilised to communicate with doctors in peripheral hospitals and with patients. there were four to five consultations per day which mainly involved patients with arteriovenous fistularelated concerns, critical limb ischaemia and diabetic foot infections. blood is an important resource that became scarce during the covid-19 pandemic. donors were reluctant to go to the blood donation centres for fear of contracting the virus. in a patient who presented with trauma massive a blood transfusion was required; the relatives of the patient had to be actively encouraged to donate blood and re-assured that precautions were in place to minimise person-to-person contact. disposable hardware for endovascular procedures that are normally shipped from abroad were limited due to the initial closure of airand seaports. there was discussion about reuse of endovascular hardware. these were put in abeyance until standard operating procedures and ethical approvals were in place. meanwhile, cases that required endovascular interventions were kept on-hold unless emergent. the result was postponement of all elective vascular cases that included aortic aneurysms, thoracic outlet syndrome, varicose veins, arteriovenous fistula creation and fistulogram/fistuloplasty. triage protocols, as suggested by the society of vascular surgery (svs) and the national health service (nhs), have been helpful to squh in triaging patient care.1,2 the impact of the covid-19 pandemic on the vascular surgery service at squh is comparable to that on other surgical specialties at squh and elsewhere.3 conclusion during the covid pandemic, challenges faced in managing vascular surgical cases and referrals were overcome effectively at squh. these included the judicious use of ppe, better communication in the midst of limited support service staff and reducing edwin stephen, sara s. h. al-adawi, ibrahim abdelhady, hanan al mawali and khalifa al-wahaibi brief communication | e119 inter-hospital transfer of in-patients. protocols such as those published by the svs and the nhs have helped the surgical team of squh triage its patients better. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this pilot study. references 1. society of vascular surgery. vascular surgery triage by tier class. from: https://vascular.org/news-advocacy/covid-19-resources accessed: aug 2020. 2. american college of surgeons. covid-19 guidelines for triage of vascular surgery patients. from: https://www.facs. org/covid-19/clinical-guidance/elective-case/vascular-surgery accessed: aug 2020. 3. hemingway jf, singh n, starnes bw. emerging practice patterns in vascular surgery during the covid-19 pandemic. j vasc surg 2020; 72:396–402. https://doi.org/10.1016/j.jvs.20 20.04.492. https://doi.org/10.1016/j.jvs.2020.04.492 https://doi.org/10.1016/j.jvs.2020.04.492 safe return to exercise after covid-19 infection *angelo v. vasiliadis1 and vasiliki boka2 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 373–377, epub. 29 aug 21 submitted 30 dec 20 revision req. 28 feb 21; revision recd. 25 mar 21 accepted 2 may 21 12nd department of orthopaedic surgery, general hospital of thessaloniki “papageorgiou”, thessaloniki, greece; 2school of dentistry, aristotle university of thessaloniki, thessaloniki, greece *corresponding author’s e-mail: vasiliadis.av@gmail.com in december 2019, the world he alth organization (who) was informed about cases of pneumonia detected in the city of wuhan in china. by the first week of january 2020, the presence of a novel coronavirus which became known as covid-19 was officially announced by chinese authorities. approximately 10 days into the month of march 2020, the who declared the covid-19 outbreak as a global pandemic.1 in less than a year, the covid-19 pandemic emerged as a worldwide health issue with over 40 million documented cases and 1.1 million deaths worldwide.2 as the war against this pandemic continues, the world of sports faces the most significant health battle it has ever faced in modern history. although athletes – fulfilling the following three criteria: (i) intent of the exercise, (ii) participation in sport events and (iii) registration in a sports federation are not considered to be at higher risk of covid-19 infection, they may still be at risk of acquiring a covid-19 infection.3,4 as expected, a significant number of athletes have been affected by covid-19 infection or have been in close contact with somebody who has tested positive.5,6 athletes need to follow the infection prevention strategies suggested for the general population including self-isolation for the entire symptomatic period to curtail the spread of the coronavirus and protect themselves, their families and their communities.6 the public health recommendations such as the universal closure of stadiums, gymnasiums and fitness centres and the need for quarantine or self-isolation (for a period of two weeks) of athletes who tested positive are fundamental.6,7 these recommendations are aimed at curtailing the spread of the disease and protect individuals and their communities. however, they also led to the disruption of many regular life activities, including physical activity in general and sports in particular. these drastic lifestyle changes resulting from self-isolation and physical inactivity have increased the risk of negative, acute and, possibly, long-term consequences for the athletes’ health.7,8 there are concerns that the said lack of exercise routines and engagement in sports activities may have a serious impact on the immune system and the physical and mental health of athletes, leading also to the exacerbation of pre-existing diseases or development of new diseases.7 t h e p r o b l e m physical inactivity, defined as the lack of sufficient daily physical activity, and disruption of exercise routines may increase susceptibility to infections, whether being an athlete or not, due to dysfunction or deficiency of components of the immune system and also increase the overall risk of developing additional comorbidities over time.7 moreover, the reduction of physical activity may negatively impact an athlete’s physical fitness due to the loss of skeletal muscle mass and a concomitant decline in muscle strength.9,10 the negative metabolic effects of physical inactivity have been previously described.7,9 for instance, low levels of ambulatory activity for two weeks (a reduction in the number of daily steps from 10,000 to 1,000) may initiate or contribute to metabolic alterations, including reduced peripheral insulin sensitivity, impaired lipid profile and increased deposition of visceral fat.8,11 the decrease in the physical activity of a covid-19-positive athlete during self-isolation has been documented. each athlete responds and recovers differently and may face difficulties as they return to special contribution this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.124 abstract: covid-19 has been posing a significant challenge to the athletic community. a wide spectrum of clinical features was reported in athletes with confirmed covid-19 infection having mild to severe symptoms requiring hospitalisation and intensive medical care. possibly, a lack of exercise may negatively impact the immune system, leading to an increased susceptibility to infection and comorbidities. determining safe return to exercise after covid-19 infection is a challenge for sports physicians. a gradual return to exercise under the guidance of a specialised medical team to achieve the pre-infection fitness level is of utmost importance. individualised exercise programmes must be initiated at low intensity which could be gradually made more rigorous based on the pertinent metabolic equivalent. thus, there is a clear need for clinical recommendations before athletes may return to exercise after covid-19 infection. keywords: covid-19; coronavirus; exercise; athletes; return to sports. https://creativecommons.org/licenses/by-nd/4.0/ safe return to exercise after covid-19 infection 374 | squ medical journal, august 2021, volume 21, issue 3 activities of daily living and exercise.7 it is, therefore, critical to guide an athlete diagnosed with covid-19 for their safe return to exercise. g e n e r a l r e c o m m e n d at i o n s f o r at h l e t e s w i t h c o v i d-19 in this regard, a panel of international experts has classified athletes who have been diagnosed with covid-19 infection into five different groups as follows: (i) asymptomatic; (ii) those with mild symptoms; (iii) those with moderate symptoms; (iv) those with severe symptoms without mechanical ventilation; and (v) those with severe symptoms with mechanical ventilation and/or myocardial injury.5,6,8 they have also provided specific recommendations for each group on how to safely return to exercise.5,6,8 while a majority of the athletes with covid-19 infection either remain asymptomatic or experience mild symptoms, a comprehensive clinical evaluation is recommended before they return to exercise. specifically, two-weeks of self-isolation and rest from exercise followed by a gradual return to exercise under figure 1: covid-19 return-to-exercise algorithm for athletes. mri = magnetic resonance imaging ; ct = computed tomography; mets = metabolic equivalents. angelo v. vasiliadis and vasiliki boka special contribution | 375 the guidance of a medical team have been proposed for asymptomatic athletes who have tested positive for covid-19 [figure 1]. athletes who experience mild symptoms but do not require hospitalisation are recommended two additional weeks of social distancing, followed by an evaluation of their situation based on blood tests (c-reactive protein, brain natriuretic peptide and troponin) and 12-lead electrocardiogram and echocardiography, if clinically indicated. a gradual return to exercise under the guidance of a medical team has also been recommended for this group [figure 1].5,8,12 a more complex investigation protocol is recommended for athletes with moderate to severe symptoms who needed hospitalisation. those who were hospitalised with respiratory symptoms and myocardial injury are advised to undergo a compre hensive and multidisciplinary evaluation before they return to exercise [figure 1].5,6,8,12 ideally, this individual assessment should be done by a team comprising a sports physician, a sports cardiologist, a specialised pulmonologist and a professional athletic trainer.5,6 barker-davies et al. recommended an extensive exercise-abstinence period of three to six months in patients with confirmed myocarditis and that the adjustment of this period of rest should be based on the clinical severity and duration of the underlying disease.13 verwoert et al. emphasised the need for a comprehensive rehabilitation plan including intensive monitoring for cardiac complications and a complete cardiovascular evaluation before return to exercise and sports.6 overall, close monitoring of hospitalised athletes with covid-19-related respiratory symptoms is warranted. it is also recommended that those with severe respiratory symptoms be monitored by a specialised pulmonologist even as they gradually return to exercise in keeping with how their recovery progresses.8 e x e r c i s e a n d v i r a l i n f e c t i o n s almost all viral infections induce the recruitment and activation of inflammatory cells, such as macrophages and neutrophils, which release a wide range of molecules (cytokines, metalloproteinases and components of the oxygen burst) that have been associated with tissue damage or dysfunction.14 a good balance between protective immunity and inflammatory response facilitates both viral clearance and resolution of infection. exercise acts as a modulator of the immune system, stimulating cellular immunity while reducing the risk of developing systemic inflammatory processes.15 various studies have suggested that exercise is directly related to decreased mortality that may be caused by pneumonia and influenza, improvements in the cardiorespiratory function and metabolic profile, including those concerning triglycerides, cholesterol, fasting plasma glucose, blood pressure and waist circumference.7,9–11,16 the additional potential benefits of exercise, especially exercise of low-to-moderate intensity, includes a reduction in respiratory infection rate and improved recovery rate following a viral infection.16 apart from the positive effects of exercise on the overall cardiorespiratory and metabolic function, it has also been shown to alleviate various mental health issues as it reduces anxiety and depression while improving self-esteem and cognitive function.16 recent studies have also shown that exercise relieves symptoms such as low self-esteem and mitigates negative effects of self-isolation during quarantine.15,16 endogenous opioids such as endorphins play a significant role in the integration of hormonal and metabolic responses to exercise and are associated with euphoria, which has been shown to significantly increase after running or swimming.7 improving covid-19 infected patients’ general health condition (physiological and psychological status) can facilitate their ability to carry out necessary activities of daily living and enable their return to work.16 as athletes of all levels return to exercise after a viral infection, special consideration should be given to the intensity and volume of exercise. for those who have been recovering from a covid-19 infection, returning to exercise can be a challenge. in this context, return to exercise should be guided by clinical symptoms and symptomatic patients should be encouraged to follow a low-intensity exercise programme during the selfisolation after 72 hours of resolution of symptoms. this programme can be adjusted as per the available equipment such as a stationary bike and/or a treadmill or even include resistance exercises.8,17 high-intensity exercise should be avoided as it is associated with an increased risk of upper respiratory tract infection and figure 2: j-shaped curve of the relationship between the exercise volume and intensity and risk of viral infection. safe return to exercise after covid-19 infection 376 | squ medical journal, august 2021, volume 21, issue 3 significant complications and can even lead to sudden cardiac arrest.7,10,18 previous studies show that low-tomoderate exercise improves immune function, while high-intensity exercise depresses the immune system and increases susceptibility to infection [figure 2].7,10 it is important to note that the combination of high and low-intensity training is an important component for advanced athletes to elicit improvements in their aerobic capacity and achieve optimal performance when they exercise.19 a key concern for athletes is determining the optimal time before they can return to practicing and/or high-intensity exercise training following an infection. returning to high-intensity exercise training while the body is still experiencing a systemic infection with persistent cough, fever and dyspnoea is strongly associated with a significant risk of major complications such as myocarditis.20 covid-19-positive athletes should opt for a gradual return to exercise after the resolution of symptoms to achieve their pre-infection fitness level.7,8 while data related to the return to exercise after covid-19 are limited, low-intensity exercise for one week is recommended before engaging in more strenuous and/or rigorous types of exercise. due to the long period of physical inactivity (of at least two weeks of rest without exercising), those recovering from an infection may be at an increased risk of injury.8 to avoid such injuries, barker-davies et al. recommend three metabolic equivalents (mets) for a period of two to three weeks.13 physical activity is classified as low-intensity (<3 mets), moderate-intensity (3–6 mets) and high-intensity (>6 mets).21,22 exercising on a treadmill (walking velocity of 3.2 km/h), stationary bike (<50 watts) and/or resistance exercise with light weights are equivalents of 3 mets and, hence, are possible options for starting an exercise programme.22 an exercise programme should be initiated at a low intensity which could be gradually made more rigorous [figure 1].21,22 an otherwise healthy athlete, infected with covid-19, who underwent a self-limiting infection after being asymptomatic for seven days may return to exercise at 50% of normal intensity and volume.8 it should be noted that the current recommendations for physical activity in healthy individuals specify at least 150 minutes per week (30 minutes per day for five days) of moderate-intensity exercise or 75 minutes per week (25 minutes per day for three days) of vigorousintensity exercise or a combination of moderate and vigorous-intensity exercise.21 it is important to note that any applied exercise programme must be individualised according to the severity of the disease, and sometimes even a gradual return to exercise may take months. many athletes are reporting covid-19-related symptoms after resolution of the infection, especially during high-intensity exercise.7,20 these may include the runner who experiences persistent fatigue and the swimmer who reports ongoing respiratory symptoms (cough and dyspnoea).8 it is important to note that exercise should be discontinued and a sports physician consulted in cases where symptoms such as fever, dyspnoea, cough, tachycardia and extreme fatigue are manifested as they may be associated with the recurrence or reactivation of the covid-19 infection.23 additionally, it must be emphasised that initiating exercise at regular intensity and volume before complete recovery can increase the risk of serious injuries and/or illnesses.7 a potentially increased risk for illness in periods of high-intensity exercise is predominantly a concern for non-competitive, recreational athletes.19 it is expected that most will fully recover following a progressive individualised exercise programme.6,7 conclusion the covid-19 infection is a global pandemic which affects all segments of the population to varying degrees, ranging from a few days of mild symptoms to myocardial injury, respiratory distress and death; athletes are not exempt from the threat of this infection. healthcare professionals are faced with unprecedented challenges concerning the covid-19 infection and the complications related to it. it is critical, therefore, to track and evaluate the rapidly evolving scientific landscape of returning safely to exercise after the covid-19 infection. the development of elemental recommendations about the safe return of athletes to exercise is warranted. a u t h o r s’ c o n t r i b u t i o n avv and vb conceptualised and designed the data. both authors were involved in drafting the manuscript. both authors approve the final version of the manuscript. references 1. cucinotta d, vanelli m. who declares covid-19 a pandemic. acta biomed 2020; 91:157–60. https://doi.org/10.23750/abm. v91i1.9397. 2. jacobs jjl. persistent sars-2 infections contribute to long covid-19. med hypotheses 2021; 149:110538. https://doi. org/10.1016/j.mehy.2021.110538. 3. araújo cg, scharhag j. athlete: a working definition for medical and health sciences research. scand j med sci sports 2016; 26:4–7. https://doi.org/10.1111/sms.12632. https://doi.org/10.23750/abm.v91i1.9397 https://doi.org/10.23750/abm.v91i1.9397 https://doi.org/10.1016/j.mehy.2021.110538 https://doi.org/10.1016/j.mehy.2021.110538 https://doi.org/10.1111/sms.12632 angelo v. vasiliadis and vasiliki boka special contribution | 377 4. yanguas x, dominguez d, ferrer e, florit d, mourtabib y, rodas g. returning to sport during the covid-19 pandemic: the sports physicians’ role. apunts sports med 2020; 55:49–51. https://doi.org/10.1016/j.apunsm.2020.06.001. 5. löllgen h, bachl n, papadopouloou t, shafik a, holloway g, vonbank k, et al. infographic. clinical recommendations for return to play during the covid-19 pandemic. br j sports med 2020; 55:344–5. https://doi.org/10.1136/bjsports-2020-102985. 6. verwoert gc, de vries st, bijsterveld n, willems ar, vd borgh r, jongman jk, et al. return to sports after covid-19: a position paper from the dutch sports cardiology section of the netherlands society of cardiology. neth heart j 2020; 28:391–5. https://doi.org/10.1007/s12471-020-01469-z. 7. woods ja, hutchinson nt, powers sk, roberts wo, gomezcabrera mc, radak z, et al. the covid-19 pandemic and physical activity. sports med health sci 2020; 2:55–64. https:// doi.org/10.1016/j.smhs.2020.05.006. 8. metzl jd, mcelheny k, robinson jn, scott da, sutton km, toresdahl bg. considerations for return to exercise following mild-to-moderate covid-19 in the recreational athlete. hss j 2020; 16:1–6. https://doi.org/10.1007/s11420-020-09777-1. 9. booth fw, roberts ck, laye mj. lack of exercise is a major cause of chronic diseases. compr physiol 2012; 2:1143–211. https://doi.org/10.1002/cphy.c110025. 10. gentil p, de lira cab, souza d, jimenez a, mayo x, de fátima pinho lins gryschek al, et al. resistance training safety during and after the sars-cov-2 outbreak: practical recommendations. biomed res int 2020; 2020:3292916. https:// doi.org/10.1155/2020/3292916. 11. krogh-madsen r, thyfault jp, broholm c, hartvig mortensen o, olsen rh, mounier r, et al. a 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity. j appl physiol (1985) 2010; 108:1034–40. https://doi.org/10.1152/japplphysio l.00977.2009. 12. phelan d, kim jh, chung eh. a game plan for the resumption of sport and exercise after coronavirus disease 2019 (covid-19) infection. jama cardiol 2020; 5:1085–6. https:// doi.org/10.1001/jamacardio.2020.2136. 13. barker-davies rm, o’sullivan o, senaratne kpp, baker p, cranley m, dharm-datta s, et al. the stanford hall consensus statement for post-covid-19 rehabilitation. br j sports med 2020; 54:949–59. https://doi.org/10.1136/bjsports-2020-102596. 14. rouse bt, sehrawat s. immunity and immunopathology to viruses: what decides the outcome? nat rev immunol 2010; 10:514–26. https://doi.org/10.1038/nri2802. 15. lega s, naviglio s, volpi s, tommasini a. recent insight into sars-cov2 immunopathology and rationale for potential treatment and preventive strategies in covid-19. vaccines (basel) 2020; 8:224. https://doi.org/10.3390/vaccines8020224. 16. da silveira mp, da silva fagundes kk, bizuti mr, starck é, rossi rc, de resende e silva dt. physical exercise as a tool to help the immune system against covid-19: an integrative review of the current literature. clin exp med 2021; 21:15–28. https://doi.org/10.1007/s10238-020-00650-3. 17. toresdahl bg, asif im. coronavirus disease 2019 (covid-19): considerations for the competitive athlete. sports health 2020; 12:221–4. https://doi.org/10.1177/1941738120918876. 18. baggish al, levine bd. icarus and sports after covid 19: too close to the sun? circulation 2020; 142:615–17. https://doi. org/10.1161/circulationaha.120.048335. 19. hull jh, loosemore m, schwellnus m. respiratory health in athletes: facing the covid-19 challenge. lancet respir med 2020; 8:557–8. https://doi.org/10.1016/s2213-2600(20)30175-2. 20. wilson mg, hull jh, rogers j, pollock n, dodd m, haines j, et al. cardiorespiratory considerations for return-to-play in elite athletes after covid-19 infection: a practical guide for sport and exercise medicine physicians. br j sports med 2020; 54:1157–61. https://doi.org/10.1136/bjsports-2020-102710. 21. gonzález k, fuentes j, márquez jl. physical inactivity, sedentary behavior and chronic diseases. korean j fam med 2017; 38:111–15. https://doi.org/10.4082/kjfm.2017.38.3.111. 22. pate rr, pratt m, blair sn, haskell wl, macera ca, bouchard c, et al. physical activity and public health. a recommendation from the centers for disease control and prevention and the american college of sports medicine. jama 1995; 273:402–7. https://doi.org/10.1001/jama.273.5.402. 23. gousseff m, penot p, gallay l, batisse d, benech n, bouiller k, et al. clinical recurrences of covid-19 symptoms after reco very: viral relapse, reinfection or inflammatory rebound? j infect 2020; 81:816–46. https://doi.org/10.1016/j.jinf.2020.06.073. https://doi.org/10.1016/j.apunsm.2020.06.001 https://doi.org/10.1136/bjsports-2020-102985 https://doi.org/10.1007/s12471-020-01469-z https://doi.org/10.1016/j.smhs.2020.05.006 https://doi.org/10.1016/j.smhs.2020.05.006 https://doi.org/10.1007/s11420-020-09777-1 https://doi.org/10.1002/cphy.c110025 https://doi.org/10.1155/2020/3292916 https://doi.org/10.1155/2020/3292916 https://doi.org/10.1152/japplphysiol.00977.2009 https://doi.org/10.1152/japplphysiol.00977.2009 https://doi.org/10.1001/jamacardio.2020.2136 https://doi.org/10.1001/jamacardio.2020.2136 https://doi.org/10.1136/bjsports-2020-102596 https://doi.org/10.1038/nri2802 https://doi.org/10.3390/vaccines8020224 https://doi.org/10.1007/s10238-020-00650-3 https://doi.org/10.1177/1941738120918876 https://doi.org/10.1161/circulationaha.120.048335 https://doi.org/10.1161/circulationaha.120.048335 https://doi.org/10.1016/s2213-2600(20)30175-2 https://doi.org/10.1136/bjsports-2020-102710 https://doi.org/10.4082/kjfm.2017.38.3.111 https://doi.org/10.1001/jama.273.5.402 https://doi.org/10.1016/j.jinf.2020.06.073 1department of medicine, sultan qaboos university hospital, muscat, oman; 2oman medical specialty board, muscat, oman *corresponding author’s e-mail: dr.abdullahalalawi@gmail.com elevated peripheral blood eosinophils during acute exacerbation of chronic obstructive pulmonary disease prevalence and clinical significance maitha al sibani,1,2 *abdullah al alawi,1,2 jamal al aghbari1,2 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 339–342, epub. 25 aug 22 submitted 9 mar 21 revisions req. 29 apr & 2 jun 21; revisions recd. 30 apr & 7 jun 21 accepted 29 jun 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.099 clinical & basic research abstract: objectives: this study aimed to evaluate the prevalence and clinical significance of elevated peripheral blood eosinophil (pbe) counts in hospitalised patients with acute exacerbation of chronic obstructive pulmonary disease (aecopd) in oman. an elevated pbe count during aecopd is a potential predictor of treatment responsiveness and future exacerbation risk. methods: this single-centre retrospective study included all patients with aecopd who were admitted to sultan qaboos university hospital, muscat, oman, between january 2017 and july 2019. the patients were classified as having eosinophilic or non-eosinophilic aecopd based on blood eosinophil counts. an elevated eosinophil count was defined as a blood eosinophil count >0.3 × 109 cells/l on admission. the length of hospital stay, use of oral and inhaled steroids, number of readmissions in a year and use of mechanical ventilation on admission were compared between the eosinophilic and non-eosinophilic aecopd groups. results: of the 102 patients included in the study, 42.2% had eosinophilic aecopd. the eosinophilic aecopd group had a reduced length of hospital stay (p = 0.02) but an increased risk of readmission in a year (p = 0.04). most patients in both groups were treated with inhaled and oral steroids. the need for mechanical ventilation did not differ between the groups. conclusion: eosinophilia is highly prevalent in patients with aecopd and is associated with a reduced length of hospital stay but an increased risk of readmission in a year. it can be used as a surrogate marker to predict the health outcomes of patients with aecopd and select treatment options. keywords: chronic obstructive pulmonary disease; eosinophils; steroids; length of stay; hospital readmission; oman. advances in knowledge eosinophilia is highly prevalent in patients with acute exacerbation of chronic obstructive pulmonary disease (copd). eosinophilic exacerbation of copd is associated with a reduced length of hospital stay but an increased risk of readmission in a year. application to patient care peripheral blood eosinophil (pbe) count can be used as a surrogate marker to predict treatment response. pbe count can be used to guide the treatment choices for patients with chronic obstructive pulmonary disease. chronic obstructive pulmonary disease (copd) is characterised by irreversible airflow limitation. patients with copd suffer from exacerbation, reduced quality of life and increased morbidity and mortality.1–3 acute exacerbation of chronic obstructive pulmonary disease (aecopd) is mainly associated with neutrophilic inflammation; however, predominant eosinophilic airway inflammation has been reported in a subset of patients with copd.4–6 up to 40% of patients with copd have an eosinophilic phenotype of copd, defined as peripheral blood eosinophil (pbe) counts ≥2%.4 several studies have demonstrated that patients with elevated pbe counts are at an increased risk of frequent exacerbations but show a good response to steroid therapy.1,4 evidence suggests that circulating eosinophils can be recruited to the lungs and can increase inflammation by the actions of cytokines, immunoregulatory cells and other proinflammatory mediators.7 accordingly, pbe count has been suggested to be useful as a surrogate marker to direct the use of oral steroid therapy in patients with aecopd and as a predictor of future exacerbation and disease stability.6 the data assessing the role of pbe on mortality outcomes are inconsistent.8,9 overall, the role of pbes in the clinical manifestation of copd remains highly debatable.10,11 no prior study has been conducted in the middle east to assess the prevalence and clinical significance of eosinophilia during aecopd. the present study aimed to evaluate the prevalence and clinical significance of elevated pbe counts in hospitalised patients with aecopd. methods this retrospective cohort study was conducted between january 2017 and july 2019 at sultan qaboos university hospital (squh), muscat, oman, a https://creativecommons.org/licenses/by-nd/4.0/ elevated peripheral blood eosinophils during acute exacerbation of chronic obstructive pulmonary disease prevalence and clinical significance 340 | squ medical journal, august 2022, volume 22, issue 3 500-bed multi-speciality tertiary hospital providing health care for muscat and al-batinah governorates’ residents. it is also considered a major referral centre for many specialities that provide high-quality care for patients referred from the entire country of oman.12 all patients with aecopd admitted to squh during the study period were included in the study. the global initiative for chronic obstructive lung disease (gold) criteria was used to ascertain copd diagnosis for all included patients.13 additionally, when there was more than one lung function test, the study considered the most recent lung function test before the index hospitalisation. the data were collected from electronic patient records using a standardised electronic data collection sheet. the patients were classified as having eosinophilic or non-eosinophilic aecopd based on their blood eosinophil counts. an elevated eosinophil count was defined as a blood eosinophil count greater than 0.3 × 109 cells/l at the time of admission. furthermore, the length of hospital stay, use of oral and inhaled steroids, number of readmissions in a year and use of mechanical ventilation on admission were compared between the eosinophilic and non-eosinophilic aecopd groups. categorical variables were reported as numbers and percentages, while continuous variables were expressed as means ± standard deviations for normally distributed data and as medians and interquartile ranges for non-normally distributed data. continuous variables between the groups were compared using student’s t-test for normally distributed data and wilcoxon’s rank-sum test for non-normally distributed data. fisher’s exact test was used to assess the association between categorical variables (given the small sample size). a two-sided p value <0.05 was considered statistically significant. statistical calculations were performed using stata, version 16.1 (statacorp., college station, texas, usa). the study was approved by the medical research ethics committee of the college of medicine and health sciences of sultan qaboos university (squec/037/19 mrec). results a search of the hospital database revealed 128 patients with aecopd who were hospitalised during the study period. overall, 23 patients were found to be asthmatic, while three patients were lost to followup. thus, 102 patients were included in the study. the mean age of the patients was 72.9 ± 10.9 years, and 79.4% of the patients were male. a total of 93.1% of the patients had a history of smoking (current or exsmoker). both groups exhibited a severely reduced forced expiratory volume in one second (fev1; 43.8 ± 17.8%). in total, 42.2% of the patients had eosinophilic aecopd. patients with non-eosinophilic aecopd stayed in the hospital for a longer duration than those with eosinophilic aecopd (p = 0.02). patients with eosinophilic aecopd had a significantly higher table 1: characteristics, treatment options and outcomes of patients with eosinophilic and non-eosinophilic chronic obstructive pulmonary disease exacerbation admitted to a tertiary care hospital in muscat, oman (n = 102) characteristic n (%) p value total normal eosinophil count (n = 59) high eosinophil count (n = 43) mean age in years ± sd 72.9 ± 10.9 73.0 ± 12.3 72.4 ± 8.8 0.17 male 81 (79.4) 50 (84.8) 31 (72.1) 0.10 smoking 95 (93.1) 56 (94.9) 39 (90.7) 0.40 median eosinophil count on admission in cells × 109/l (iqr) 0.3 (0.0–0.6) 0.1 (0–0.2) 0.6 (0.5–1.2) <0.001 mean fev1 in % ± sd 43.8 ± 17.8 44.3 ± 17.2 43.1 ± 18.7 0.52 treatment oral steroids 94 (92.2) 55 (93.2) 39 (90.7) 0.72 inhaled steroids 80 (78.4) 44 (74.6) 36 (83.7) 0.33 need for mechanical ventilation 47 (46.1) 30 (50.9) 17 (39.5) 0.32 outcome median length of hospital stay in days (iqr) 4 (3–7) 5 (4–7) 4 (6–3) 0.02 median eosinophil count on discharge in cells × 109/l (iqr) 0.1 (0.0–0.3) 0.1 (0–0.3) 0.2 (0.0–0.5) 0.43 median readmission in a year (iqr) 0 (0–2) 0 (0–1) 1 (0–3) 0.04 *mean ± standard deviation. †number of patients (%). ‡median (iqr). §forced expiratory volume in one second. maitha al sibani, abdullah al alawi and jamal al aghbari clinical and basic research | 341 number of readmissions in a year than those with non-eosinophilic aecopd (p = 0.04). most patients in both groups received systemic steroids (92.2%) and were on inhaled steroids (78.4%) before admission. there was no significant difference in the need for mechanical ventilation between the groups (p = 0.32). moreover, the eosinophil counts just before discharge did not differ significantly between the groups (p = 0.43) [table 1]. discussion to the best of the authors’ knowledge, the present study is the first to assess the prevalence and clinical significance of eosinophilia in hospitalised copd patients in the middle east, where a majority of the patients are of arab ethnicity. the study findings indicate that patients with eosinophilic aecopd had a reduced length of hospital stay but were at an increased risk of readmission in a year. the prevalence of eosinophilic aecopd ranged from 10–37% in previous studies.14–16 these differences in the prevalence of eosinophilia during aecopd could be explained by the difference in patients’ ethnicity, use of corticosteroids before admission and difference in cut-off values used to define eosinophilia.1,17–19 when defining eosinophilic copd, the most commonly used cut-off value is 2%, which corresponds to 150 cells/μl.1 however, the absolute eosinophil count might be more accurate because the white blood cell count can differ significantly for various reasons. in the present study, a cut-off value greater than 300 cells/μl was used to define eosinophilic aecopd and this has been validated in previous studies.1,7,17,20,21 the prevalence of eosinophilic aecopd in the current cohort was 42.2%, which is higher than most of the previously reported values. this higher prevalence of eosinophilic aecopd could be related to the high prevalence of smoking in this cohort. in patients with copd and under certain circumstances, pbes are recruited to the lungs, prompting cascades of inflammatory responses, including secretion of chemokines, cytokines and cytotoxic granular products.22 most patients in both groups were treated with inhaled and oral steroids; however, patients with elevated pbe counts showed a better response, as evidenced by a reduced length of hospital stay (p = 0.02). this could be explained by the anti-inflammatory role of corticosteroids in patients with eosinophilic aecopd. notably, the study’s finding regarding the reduced length of hospital stay for eosinophilic aecopd patients is in line with previous studies.17,23 about 40% of patients with eosinophilic aecopd required mechanical ventilation compared to 50.9% of patients with non-eosinophilic aecopd. this disparity may be attributed to the poor response of non-eosinophilic aecopd to corticosteroids. furthermore, studies have demonstrated that non-eosinophilic aecopd is strongly associated with infections and worse outcomes, which may be explained by the higher need for mechanical ventilation.22 no significant differences in age, gender, fev1 and smoking status between the groups were found in this study. additionally, just before discharge from the hospital, the eosinophil count did not differ significantly between the eosinophilic and noneosinophilic aecopd patients. this finding could be attributed to the high percentage of patients who were treated with steroids in both groups. moreover, this finding may provide insight into using oral and inhaled steroids in patients with aecopd based on the eosinophil count and, thus, help avoid risks associated with the indiscriminate use of steroids in such patients.24 additionally, no difference in the need for mechanical ventilation between the groups was noted (p = 0.32). furthermore, in the present study, the mortality outcome was not assessed because of the small sample size; however, studies have suggested that eosinophilic aecopd is associated with a lower inpatient mortality rate, but the data are conflicting.8,9,23 conversely, patients with eosinophilic aecopd had an increased number of readmissions in a year (p = 0.04), which is in line with previous findings.18,23 it is noteworthy that, to the best of the authors’ knowledge, this study was the first to assess the prevalence of eosinophilia in patients of arab ethnicity. ultimately, the results confirmed that eosinophil count could be used as a surrogate marker to predict the treatment response and risk of readmission in inpatients with aecopd. this finding supports the 2020 gold recommendation regarding the role of pbe in guiding the treatment choice for patients with copd.10 the present study has several limitations. first, it was a single-centre retrospective study. second, the inpatient mortality rate in the groups could not be assessed because of the small sample size. third, the study included hospitalised patients with aecopd; however, it did not include patients with mild and moderate exacerbations who were managed in the outpatient setting. finally, potential confounders including heart failure, ischaemic heart disease and hypertension, were not considered. elevated peripheral blood eosinophils during acute exacerbation of chronic obstructive pulmonary disease prevalence and clinical significance 342 | squ medical journal, august 2022, volume 22, issue 3 conclusion eosinophilia is highly prevalent in hospitalised patients with aecopd. it is associated with a reduced length of hospital stay and an increased risk of readmission in a year. additionally, the eosinophil count can be used as a surrogate marker to predict the health outcomes of patients with aecopd and select treatment options, including corticosteroid use. a u t h o r s’ c o n t r i b u t i o n ms, aa and ja contributed to the research design. ms collected the data. ms and aa analysed the data and handled manuscript writing. aa and ja revised the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. yun jh, lamb a, chase r, singh d, parker mm, saferali a, et al. blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease. j allergy clin immunol 2018; 141:2037–47.e10. https://org/doi. org/10.1016/j.jaci.2018.04.010. 2. tashiro h, kurihara y, takahashi k, sadamatsu h, haraguchi t, tajiri r, et al. clinical features of japanese patients with exacer bations of chronic obstructive pulmonary disease. bmc pulm med 2020; 20:318. https://doi,org/10.1186/s12890-020-01362-w. 3. lopez-campos jl, tan w, soriano jb. global burden of copd. respirology 2016; 21:14–23. https://doi.org/10.1111/resp.12660. 4. pavord id, chanez p, criner gj, kerstjens ham, korn s, lugogo n, et al. mepolizumab for eosinophilic chronic obstructive pulmo nary disease. n engl j med 2017; 377:1613–29. https://doi. org/10.1056/nejmoa1708208. 5. couillard s, larivée p, courteau j, vanasse a. eosinophils in copd exacerbations are associated with increased readmissions. chest 2017; 151:366–73. https://doi.org/10.1016/j.chest.2016.10.003. 6. singh d, kolsum u, brightling ce, locantore n, agusti a, talsinger r, et al. eosinophilic inflammation in copd: prevalence and clinical characteristics. eur respir j 2014; 44:1697–700. https://doi.org/10.1183/09031936.00162414. 7. david b, bafadhel m, koenderman l, de soyza a. eosinophilic inflammation in copd: from an inflammatory marker to a treatable trait. thorax 2020; 76:188–95. https://doi. org/10.1136/thoraxjnl-2020-215167. 8. prudente r, ferrari r, mesquita cb, machado lhs, franco eat, godoy i, et al. peripheral blood eosinophils and nine years mortality in copd patients. int j chron obstruct pulmon dis 2021; 16:979–85. https://doi.org/10.2147/copd.s265275. 9. zhang y, liang lr, zhang s, lu y, chen yy, shi hz, et al. blood eosinophilia and its stability in hospitalized copd exacerbations are associated with lower risk of all-cause mortality. int j chron obstruct pulmon dis 2020; 15:1123–34. https://doi.org/10.2147/copd.s245056. 10. contoli m, morandi l, di marco f, carone m. a perspective for chronic obstructive pulmonary disease (copd) management: six key clinical questions to improve disease treatment. expert opin pharmacother 2020; 22:427–37. https://doi.org/10.1080/ 14656566.2020.1828352. 11. oshagbemi oa, franssen fme, braeken dcw, henskens y, wouters efm, maitland-van der zee ah, et al. blood eosinophilia, use of inhaled corticosteroids, and risk of copd exacerbations and mortality. pharmacoepidemiol drug saf 2018; 27:1191–99. https://doi.org/10.1002/pds.4655. 12. al-maliky gr, al-ward mm, taqi a, balkhair a, al-zakwani i. evaluation of antibiotic prescribing for adult inpatients at sultan qaboos university hospital, sultanate of oman. eur j hosp pharm 2018; 25:195–9. https://doi.org/10.1136/ejhpha rm-2016-001146. 13. global initiative for chronic obstructive lung disease (gold). 2020. 2020 global strategy for prevention, diagnosis and management of copd. from: https://goldcopd.org/goldreports/ accessed: jun 2021. 14. bafadhel m, davies l, calverley pma, aaron sd, brightling ce, pavord id. blood eosinophil guided prednisolone therapy for exacerbations of copd: a further analysis. eur respir j 2014; 44:789–91. https://doi.org/10.1183/09031936.00062614. 15. duman d, aksoy e, agca mc, kocak nd, ozmen i, akturk ua, et al. the utility of inflammatory markers to predict readmissions and mortality in copd cases with or without eosinophilia. int j chron obstruct pulmon dis 2015; 10:2469–78. https://doi. org/10.2147/copd.s90330. 16. zeiger rs, tran tn, butler rk, schatz m, li q, khatry db, et al. relationship of blood eosinophil count to exacerbations in chronic obstructive pulmonary disease. j allergy clin immunol pract 2018; 6:944–54.e5. https://doi.org/10.1016/j. jaip.2017.10.004. 17. ho j, he w, chan mtv, tse g, liu t, wong sh, et al. eosinophilia and clinical outcome of chronic obstructive pulmonary disease: a meta-analysis. sci rep 2017; 7:13451. https://doi.org/10.1038/s41598-017-13745-x. 18. chan mc, yeung yc, yu elm, yu wc. blood eosinophil and risk of exacerbation in chronic obstructive pulmonary disease patients: a retrospective cohort analysis. int j chron obstruct pulmon dis 2020; 15:2869–77. https://doi.org/10.2147/copd. s268018. 19. lonergan m, dicker aj, crichton ml, keir hr, van dyke mk, mullerova h, et al. blood neutrophil counts are associated with exacerbation frequency and mortality in copd. respir res 2020; 21:166. https://doi.org/10.1186/s12931-020-01436-7. 20. calverley pma, tetzlaff k, vogelmeier c, fabbri lm, magnussen h, wouters efm, et al. eosinophilia, frequent exacerbations, and steroid response in chronic obstructive pulmonary disease. am j respir crit care med 2017; 196:1219–21. https://doi.org/10.11 64/rccm.201612-2525le. 21. wade rc, wells jm. point: are eosinophils useful for the management of copd? yes. chest 2020; 157:1073–75. https:// doi.org/10.1016/j.chest.2019.12.043. 22. david b, bafadhel m, koenderman l, de soyza a. eosinophilic inflammation in copd: from an inflammatory marker to a treatable trait. thorax 2021; 76:188–95. https://doi.org/10.1136/ thoraxjnl-2020-215167. 23. you y, shi gc. blood eosinophils and clinical outcome of acute exacerbations of chronic obstructive pulmonary disease: a systematic review and meta-analysis. respiration 2020; 100:228–37. https://doi.org/10.1159/000510516. 24. saito z, yoshida m, kojima a, tamura k, hasegawa t, kuwano k. benefits and risks of inhaled corticosteroid treatment in patients with chronic obstructive pulmonary disease classified by blood eosinophil counts. lung 2020; 198:925–31. https://doi.org/10.1007/ s00408-020-00397-4. https://org/doi.org/10.1016/j.jaci.2018.04.010 https://org/doi.org/10.1016/j.jaci.2018.04.010 https://doi,org/10.1186/s12890-020-01362-w https://doi.org/10.1111/resp.12660 https://doi.org/10.1056/nejmoa1708208 https://doi.org/10.1056/nejmoa1708208 https://doi.org/10.1016/j.chest.2016.10.003 https://doi.org/10.1183/09031936.00162414 https://doi.org/10.1136/thoraxjnl-2020-215167 https://doi.org/10.1136/thoraxjnl-2020-215167 https://doi.org/10.2147/copd.s265275 https://doi.org/10.2147/copd.s245056 https://doi.org/10.1080/14656566.2020.1828352 https://doi.org/10.1080/14656566.2020.1828352 https://doi.org/10.1002/pds.4655 https://doi.org/10.1136/ejhpharm-2016-001146 https://doi.org/10.1136/ejhpharm-2016-001146 https://doi.org/10.1183/09031936.00062614 https://doi.org/10.2147/copd.s90330 https://doi.org/10.2147/copd.s90330 https://doi.org/10.1016/j.jaip.2017.10.004 https://doi.org/10.1016/j.jaip.2017.10.004 https://doi.org/10.1038/s41598-017-13745-x https://doi.org/10.2147/copd.s268018 https://doi.org/10.2147/copd.s268018 https://doi.org/10.1186/s12931-020-01436-7 https://doi.org/10.1164/rccm.201612-2525le https://doi.org/10.1164/rccm.201612-2525le https://doi.org/10.1016/j.chest.2019.12.043 https://doi.org/10.1016/j.chest.2019.12.043 https://doi.org/10.1136/thoraxjnl-2020-215167 https://doi.org/10.1136/thoraxjnl-2020-215167 https://doi.org/10.1159/000510516 https://doi.org/10.1007/s00408-020-00397-4. https://doi.org/10.1007/s00408-020-00397-4. faiha specialized diabetes, endocrine and metabolism center, basrah health directorate, 1alzahraa college of medicine and 2college of medicine, university of basrah, basrah, iraq *corresponding author’s e-mail: ammar.almomin75@gmail.com serum glucose measurement after five to six hours is comparable to eight hours fasting in ramadan *ammar m.s. almomin,1 samih a. odhaib,2 mahmood t. altemimi,2 hussein a. nwayyir,2 ibrahim h. hussein,2 haider a.y. alidrisi,2 nassar t.y. alibrahim,2 abbas a. mansour2 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 123–128, epub. 28 feb 22 submitted 23 oct 20 revision req. 10 dec 20; revision recd. 6 jan 21 accepted 30 jan 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.084 clinical & basic research abstract: objectives: this study aimed to evaluate whether a shorter fasting duration of five to six hours can be used as an alternative to the usually recommended eight hours for fasting glucose measurement. methods: this one-month observational, cross-sectional study was conducted during ramadan (may to june) 2019. it included those attending faiha specialized diabetes, endocrine and metabolism center, basrah, iraq; all individuals ate a pre-dawn meal (suhoor) followed by a complete fast for many hours. two fasting serum glucose (fsg) venous samples were taken; the first was taken five to six hours and the second eight hours after the pre-dawn meal. participants were divided into two groups: individuals with type 2 diabetes mellitus (t2dm) and those with a normal glucose level. t2dm patients were further subdivided into three groups: those without treatment, those on oral antidiabetic drugs (oad) and those using insulin and oad. results: a total of 200 individuals participated in this study. there was no significant difference found between the mean fsg levels in the first and second samples for those without t2dm (104.5 ± 21.4 mg/dl versus 104.8 ± 12.6 mg/dl; p = 0.80) as well as those with t2dm (235.0 ± 107.0 mg/dl versus 230.0 ± 105.0 mg/dl; p = 0.20). untreated t2dm patients had non-significant fsg readings for the two samples (194.0 ± 151.5 mg/dl versus 193.9 ± 128.9 mg/dl; p = 0.90). patients on insulin and oad showed a similar pattern of fsg (268.0 ± 111.0 mg/dl versus 269.0 ± 114.0 mg/dl). however, the two fsg samples were found to be significantly different among patients on oad (220.0 ± 78.0 mg/dl versus 207.0 ± 77.0 mg/dl; p = 0.01). conclusion: the fasting duration of five to six hours can give a comparable measurement of fsg as that obtained after eight hours. keywords: glucose; fasting; duration of therapy; diabetes mellitus; iraq. advances in knowledge fasting five to six hours showed comparable serum glucose measurements to fasting eight hours. application to patient care shortening the duration of fasting will reduce the waiting time to obtain a valid sample after the last meal. most benefits would be for those who have a limited time for medical services. disruption in the typical cyclical pattern of glucose tolerance is the hallmark of type 2 diabetes mellitus (t2dm). thus, underst anding the normal control of glucose metabolism hour-by-hour is critical to achieve optimal diabetes care. the current recommendations emphasise the standardised measurement of fasting plasma glucose (fpg) after overnight fasting for at least eight hours to assess the magnitude of basal glucose abnormalities.1–5 however, the discordance with other diagnostic tests and uncertainty regarding the duration of fasting reported by some individuals raises a doubt about the applicability of the current diagnostic criteria for diagnosing diabetes mellitus (dm).6,7 although plasma is devoid of red and white blood cells, they still contain platelets, which consume glucose over time. on the other hand, the serum is free from any cells and hence, would be suitable for determining blood glucose level, especially when there is a time delay in the measurement. if assayed immediately, blood glucose measured in fluoride plasma correlated linearly with blood glucose in the serum; the serum value is lower than the corresponding fluoride plasma value by 1.15%.8 as this may not be physiologically relevant, serum may be used as an alternative for blood glucose determination with an error rate of 1.15%.8 despite wide variations in glucose flux in feeding and fasting states, blood glucose is maintained in a narrow range; late-night meals can interrupt healthy sleep and usually affects glucose control in patients with dm. however, the circadian rhythm of cortisol is robust and minimally affected.4,9,10 this study aimed to evaluate whether a shorter fasting duration of five to six hours can substitute the standard glucose measurement after eight hours. https://creativecommons.org/licenses/by-nd/4.0/ serum glucose measurement after five to six hours is comparable to eight hours fasting in ramadan 124 | squ medical journal, february 2022, volume 22, issue 1 methods a one-month observational, cross-sectional study was conducted during the month of ramadan (may to june) in 2019. this study included individuals with different demographic characteristics attending faiha specialized diabetes, endocrine and metabolism center (fdemc) in basrah, iraq. all individuals shared the standard behaviour of eating a pre-dawn meal, also known as suhoor, at approximately 3 am followed by a complete fast (null by mouth) for many hours. two fasting serum glucose (fsg) samples were collected from each participant, the first sample was taken five to six hours and the second eight hours after the pre-dawn meal. the exclusion criteria were as follows: non-fasting or incomplete fasting state; patients with type 1 dm; fasting without a prior pre-dawn meal; individuals who did not have a real pre-dawn meal (i.e. continued to eat frequent small meals until fasting time); and night-shift workers. the participants were divided into two groups: individuals with t2dm and individuals without t2dm. individuals with t2dm were subdivided according to the modality of treatment into patients on only oral antidiabetic (oad) medications, patients on insulin and oad and patients with no treatment. demographic characteristics, such as gender, age and body mass index (bmi), the timing of meals, fasting pattern and the type of treatment for t2dm patients were collected. after ensuring a fasting state for five to six hours, a venous blood sample of 2–3 ml was collected in a plain test tube. the samples were immediately transferred to the laboratory and were allowed to be clotted then centrifuged prior to the estimation of fsg by (cobas, integra 400 plus, roche company, switzerland). this procedure was repeated after eight hours of fasting for each individual. data were entered and matched using microsoft excel (microsoft corp., redmond, washington, usa); subsequently, the different variables were analysed using statistical package for the social sciences (spss), version 23.0 (ibm corp., chicago, illinois, usa). the study used mean ± standard deviation or frequency for data expression. a paired t-test was used to compare the difference between the mean fsg readings in the two samples. a p value of <0.05 was considered statistically significant. the study was designed to show the efficacy of fasting for only five to six hours to attain a valid fasting glucose measurement compared to the standard eight-hour fasting. if the mean difference between the two samples was less than 6 mg/dl, they would be considered equivalent on the assumption that variation within this limited range would unlikely affect medical decisions in clinical practice. all participants were given a detailed explanation of the study and written consent was obtained from each participant before the day of the examination. the fdemc ethical committee approved the study. results a total of 200 individuals were included in this study. participants had a mean age of 45.6 ± 14.4 years and the majority were male (n = 113, 56.5%). there were 115 participants (57.5%) had t2dm, which were further subdivided according to the type of treatment into individuals on oad (n = 54, 47.0%), individuals on insulin and oad (n = 45, 39.1%) and individuals not on any medication for t2dm (n = 16, 13.9%) [table 1]. the mean fsg after five to six hours for nont2dm individuals was 104.5 ± 21.4 mg/dl (5.79 ± 1.18 mmol/l) compared to the eight-hour sample which was 104.8 ± 12.6 mg/dl (5.82 ± 0.70 mmol/l); the mean difference was insignificant at -0.2 ± 15.9 mg/ dl (0.01 ± 0.88 mmol/l; p = 0.80). while for t2dm patients, the mean fsg was 235.0 ± 107.0 mg/dl (13.04 ± 5.94 mmol/l) after five to six hours and 230.0 ± 105.0 mg/dl (12.77 ± 5.83 mmol/l) after eight hours of fasting, with a mean insignificant difference of 5.6 ± 45.6 mg/ dl (0.31 ± 2.53 mmol/l; p = 0.20). according to the type of therapy for t2dm, the mean fsg values for untreated patients were 194.0 ± 151.5 mg/dl (10.77 ± 8.41 mmol/l) after five to six hours of fasting and table 1: characteristics of the study’s participants (n = 200) characteristic n (%) mean age in years 45.6 ± 14.4 mean bmi ± sd 31.3 ± 6.4 gender male 113 (56.5) female 87 (43.5) diabetic condition non-t2dm 85 (42.5) t2dm 115 (57.5) type of therapy for t2dm patients (n = 115) no therapy 16 (13.9) oad 54 (47.0) insulin with oad 45 (39.1) sd = standard deviation; bmi = body mass index; t2dm = type 2 diabetes mellitus; oad = oral antidiabetic medications. ammar m.s. almomin, samih a. odhaib, mahmood t. altemimi, hussein a. nwayyir, ibrahim h. hussein, haider a.y. alidrisi, nassar t.y. alibrahim and abbas a. mansour clinical and basic research | 125 193.9 ± 128.9 mg/dl (10.76 ± 7.15 mmol/l) after eight hours (p = 0.90). among t2dm patients on oad, the fsg mean values were 220.0 ± 78.0 mg/dl (12.21 ± 4.33 mmol/l) after five to six hours and 207.0 ± 77.0 mg/dl (11.49 ± 4.27 mmol/l) after eight hours of fasting with a mean significant difference of 13.1 ± 37.8 mg/dl (0.73 ± 2.10 mmol/l; p = 0.01). for patients on insulin with oad, the fsg mean values were 268.0 ± 111.0 mg/dl (14.87 ± 6.16 mmol/l) and 269.0 ± 114.0 mg/dl (14.93 ± 6.33 mmol/l) at five to six hours and after eight hours of fasting, respectively, with a mean insignificant difference of -1.4 ± 54.7 mg/dl (0.08 ± 3.04 mmol/l; p = 0.80) [table 2 and figure 1]. discussion overnight fpg measurement is a core component of glycaemic regulation in t2dm and related disorders. however, there is no singular definition of a fasting state; the world health organization recommends an 8–14 hours of fasting while the american diabetes association defines fasting as no caloric consumption for at least eight hours.2,3 in the current study, the mean fsg value after five or six hours was similar to the value obtained after eight hours as the difference being less than 6 mg/dl which seems practically irrelevant. moebus et al. measured the hourly decrease in fpg since the last nightly meal in healthy individuals. they found a non-significant decrease (0.16–0.43 mg/ dl) for each additional fasting hour.4 unexpectedly, they found that three hours of fasting is sufficient to give a comparable fpg reading similar to that obtained after eight hours.4 these results were ascertained by the british regional heart study.11 glucose homeostasis is never constant.12 the human body can maintain normal blood glucose levels by modifying insulin response to stimulate glucose disposal under the tightly-controlled circadian pattern.13,14 however, the relative contribution of the circadian versus the behavioural cycle is unclear.15 generally, the endogenous hormonal control of glucose homeostasis precedes the influential role of the suprachiasmatic nucleus (scn), which occurs later throughout the day.16 table 2: comparison of fasting serum glucose measurements between five to six hours and eight hours of fasting parameters mean fasting serum glucose in mg/dl ± sd 95% ci for the mean difference t p value 5–6 hours 8 hours difference diabetic condition non-t2dm 104.5 ± 21.4 104.8 ± 12.6 -0.2 ± 15.9 -0.37–3.1 -0.1 0.80 t2dm 235.0 ± 107.0 230.0 ± 105.0 5.6 ± 45.6 -2.8–14.0 1.3 0.20 type of therapy for t2dm patients no therapy 194.0 ± 151.5 193.9 ± 128.9 0.06 ± 40.1 -21.3–0.9 0.006 0.90 oad 220.0 ± 78.0 207.0 ± 77.0 13.1 ± 37.8 2.8–23.4 2.5 0.01 insulin with oad 268.0 ± 111.0 269.0 ± 114.0 -1.4 ± 54.7 -17.8–15.0 -0.1 0.80 sd = standard deviation; ci = confidence interval; t2dm = type 2 diabetes mellitus; oad = oral antidiabetic medications. figure 1: boxplots of serum glucose measurements after five to six hours and eight hours fasting among the study’s participants. oad = oral antidiabetic medications; t2dm = type 2 diabetes mellitus. serum glucose measurement after five to six hours is comparable to eight hours fasting in ramadan 126 | squ medical journal, february 2022, volume 22, issue 1 the fpg and plasma insulin maintain a nadir overnight in healthy individuals, with a modest, transient elevation in insulin secretion rate (isr) at pre-dawn to restrain endogenous glucose production (egp) and prevent hyperglycaemia.17,18 the increased insulin requirement at dawn had been attributed to either increased insulin clearance that may increase almost 2-fold or decreased insulin action and hepatic insulin resistance.19 morris et al. showed insignificant changes in fpg, insulin, isr and growth hormone (gh) after five and eight hours of overnight fasting.15 healthy humans have a time-of-day variation in glucose tolerance with highest in the early hours of the day and a trough at night;20 however, patients with diabetes show marked fluctuations.4,13 in the current study, which was conducted during the early daytime hours, individuals without diabetes had fsg readings in the normal upper range after eight hours of fasting. the fsg readings did not show a significant difference between the 5–6 hour and 8-hour samples, which matches the cycle of internal glucose metabolism.20 on the other hand, patients with t2dm had fasting hyperglycaemia according to diagnostic guidelines.2,3 the ‘dawn phenomenon’ could explain the early morning hyperglycaemia in t2dm patients. this event had been observed in patients with diabetes, and even in some individuals without diabetes, where glucose concentration peaks before the onset of daily activity.7,16,19 when plasma glucose is high before the start of an activity, humans seem to be more glucose-tolerant, with a preserved glucose homeostasis during the day.16 nocturnal elevations in gh and early morning incr eases in cortisol secretion may contribute to this phenomenon by stimulating egp through gluconeo genesis and glycogenolysis.21–24 van cauter et al. evaluated individuals for glucose and insulin responses after they consumed two low caloric mixed meals in the morning and evening. they found no difference in fpg levels between five and eight hours, while cortisol level peaked after five hours and increased slightly more than that after eight hours; however, the difference is insignificant. van cauter et al. suggest the possible contribution of cortisol in carbohydrate tolerance, given the failure of insulin secretion to increase in proportion to changes in post-meal glucose responses.25 the changes in cortisol concentration occurred following changes in egp for the control group, while for patients with diabetes, egp increased three hours before a rise in cortisol. moreover, the later decline in cortisol does not accompany the fall in egp and this might be due to defective scn activity in patients with diabetes and/or nonlinear personal behaviour.23,25 many studies found that individuals without diabetes have a steady state in terms of glucose utilisation, insulin concentration, egp and glucagon, while those with diabetes exhibit a slight increase in glucose utilisation after fasting for eight hours compared to five hours which reflects the rise in the egp during that time.19,23,26 a danish study explained the non-linear inverse relationship between insulin sensitivity and glucagon response and described high fasting glucagon level versus lower insulin sensitivity and inadequate glucagon suppression after meals.27 monnier et al. found that oad does not adeq uately control the prebreakfast hyperglycaemia that occurs between 6 am and 8 am particularly in the presence of dawn phenomenon , even when they are given in combination. sulphonylureas increases the risk of developing afternoon or evening hypoglycaemia after dose adjustment to counteract the early morning hyperglycemia.28,29 oral incretin-based therapies may improve blood glucose in the postprandial but not during the fasting period.30 on the contrary, the evening administration of basal insulin is effective in abolishing the ‘dawn phenomenon’ by restraining egp and lipolysis.17 the present study shows no significant difference in the first and second fsg readings in patients with diabetes, as well as in individuals without diabetes. the only exception was for those with t2dm using only oad, who showed a significant difference between the two fasting readings. there are several limitations to this study. first, this study could not determine whether the fsg changes after fasting for five to six and eight hours reflected the effect of the duration of prior fasting or real circadian modulation. second, the quality and patterns of night sleep that impact fsg levels were not assessed. third, this study did not determine the precise timing and amount of last caloric intake, as this was self-reported and, therefore, subject to error and potential bias. although, approximate recordings of the timing of food intake were collected, it was not possible to identify which ingestions were considered by the participants as meals. fourth, the exercise effect was not estimated. lastly, the responses of the counter-regulatory hormones and melatonin during and after six and eight hours of fasting were not measured; this may be a potential topic to be explored in future research. ammar m.s. almomin, samih a. odhaib, mahmood t. altemimi, hussein a. nwayyir, ibrahim h. hussein, haider a.y. alidrisi, nassar t.y. alibrahim and abbas a. mansour clinical and basic research | 127 conclusion there was no significant difference in fsg after five to six and eight hours fasting in individuals with or without t2dm. the minimal fasting duration to assess fsg can be shortened to five to six hours and there is no need to fast an extra two to three hours. this study’s findings support the recommendation of standardisation of fasting duration as it is essential in clinical studies that deal with glycaemic control. further studies are needed to evaluate the appropriate timing and duration of fasting in non-ramadan fasters, as well as the evaluation of the effect of sleep quality and the circadian rhythm on the glycaemic pattern. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n amsa designed the study. mta, han and ihh planned and supervised the work. aam was the project director. all authors collected the data. haya and ntya performed the computational framework and analysed the data. sao drafted the manuscript. all authors reviewed and edited the manuscript. all authors approved the final version of the manuscript. references 1. sitasuwan t, lertwattanarak r. prediction of type 2 diabetes mellitus using fasting plasma glucose and hba1c levels among individuals with impaired fasting plasma glucose: a crosssectional study in thailand. bmj open 2020; 10:e041269. https://doi.org/10.1136/bmjopen-2020-041269. 2. american diabetes association. 2. classification and diagnosis of diabetes: standards of medical care in diabetes-2021. diab etes care 2021; 44:s15–33. https://doi.org/10.2337/dc21-s002. 3. world health organization. classification of diabetes mellitus. from: https://apps.who.int/iris/handle/10665/325182 accessed: jan 21. 4. moebus s, göres l, lösch c, jöckel kh. impact of time since last caloric intake on blood glucose levels. eur j epidemiol 2011; 26:719–28. https://doi.org/10.1007/s10654-011-9608-z. 5. li y, teng d, shi x, qin g, qin y, quan h, et al. prevalence of diabetes recorded in mainland china using 2018 diagnostic criteria from the american diabetes association: national cross sectional study. bmj 2020; 369:m997. https://doi.org/10.1136/ bmj.m997. 6. tucker la. limited agreement between classifications of diabetes and prediabetes resulting from the ogtt, hemoglobin a1c, and fasting glucose tests in 7412 u.s. adults. j clin med 2020; 9:2207. https://doi.org/10.3390/jcm9072207. 7. bolli gb, gerich je. the “dawn phenomenon”--a common occurrence in both non-insulin-dependent and insulin-depen dent diabetes mellitus. n engl j med 1984; 310:746–50. https:// doi.org/10.1056/nejm198403223101203. 8. frank ea, shubha mc, d'souza cj. blood glucose determina tion: plasma or serum? j clin lab anal 2012; 26:317–20. https:// doi.org/10.1002/jcla.21524. 9. steiger a. sleep and the hypothalamo-pituitary-adrenocortical system. sleep med rev 2002; 6:125–38. https://doi.org/10.1053/ smrv.2001.0159. 10. jerjes wk, cleare aj, peters tj, taylor nf. circadian rhythm of urinary steroid metabolites. ann clin biochem 2006; 43:287–94. https://doi.org/10.1258/000456306777695564. 11. emberson jr, whincup ph, walker m, thomas m, alberti kg. biochemical measures in a population-based study: effect of fasting duration and time of day. ann clin biochem 2002; 39:493–501. https://doi.org/10.1258/000456302320314511. 12. radziuk j, pye s. production and metabolic clearance of glucose under basal conditions in type ii (non-insulin-dependent) diabetes mellitus. diabetologia 2001; 44:983–91. https://doi.org/1 0.1007/s001250100589. 13. stumvoll m, tataranni pa, stefan n, vozarova b, bogardus c. glucose allostasis. diabetes 2003; 52:903–9. https://doi.org/10.2 337/diabetes.52.4.903. 14. base sa, fang mz, rustgi v, zarbl h, androulakis ip. at the interface of lifestyle, behavior, and circadian rhythms: metabolic implications. front nutr 2019; 6:132. https://doi.org/10.3389/ fnut.2019.00132. 15. morris cj, yang jn, garcia ji, myers s, bozzi i, wang w, et al. endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. proc natl acad sci u s a 2015; 112:e2225–34. https://doi.org/10.1073/ pnas.1418955112. 16. la fleur se, kalsbeek a, wortel j, fekkes ml, buijs rm. a daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. diabetes 2001; 50:1237–43. https://doi.org/10.2337/ diabetes.50.6.1237. 17. sharma a, varghese rt, shah m, man cd, cobelli c, rizza ra, et al. impaired insulin action is associated with increased gluca gon concentrations in nondiabetic humans. j clin endocrinol metab 2018; 103:314–19. https://doi.org/10.1210/jc.2017-01197. 18. porcellati f, lucidi p, bolli gb, fanelli cg. thirty years of research on the dawn phenomenon: lessons to optimize blood glucose control in diabetes. diabetes care 2013; 36:3860–2. https://doi.org/10.2337/dc13-2088. 19. arslanian s, ohki y, becker dj, drash al. demonstration of a dawn phenomenon in normal adolescents. horm res 1990; 34:27–32. https://doi.org/10.1159/000181791. 20. saad a, dalla man c, nandy dk, levine ja, bharucha ae, rizza ra, et al. diurnal pattern to insulin secretion and insulin action in healthy individuals. diabetes 2012; 61:2691–700. https://doi.org/10.2337/db11-1478. 21. campbell pj, bolli gb, cryer pe, gerich je. pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. n engl j med 1985; 312:1473–9. https://doi.org/10.10 56/nejm198506063122302. 22. trümper bg, reschke k, molling j. circadian variation of insulin requirement in insulin dependent diabetes mellitus the relationship between circadian change in insulin demand and diurnal patterns of growth hormone, cortisol and glucagon during euglycemia. horm metab res 1995; 27:141–7. https:// doi.org/10.1055/s-2007-979926. 23. radziuk j, pye s. diurnal rhythm in endogenous glucose prod uction is a major contributor to fasting hyperglycaemia in type 2 diabetes. suprachiasmatic deficit or limit cycle behaviour? diabetologia 2006; 49:1619–28. https://doi.org/10.1007/s0012 5-006-0273-9. https://doi.org/10.1136/bmjopen-2020-041269 https://doi.org/10.2337/dc21-s002 https://doi.org/10.1007/s10654-011-9608-z https://doi.org/10.1136/bmj.m997 https://doi.org/10.1136/bmj.m997 https://doi.org/10.3390/jcm9072207 https://doi.org/10.1056/nejm198403223101203 https://doi.org/10.1056/nejm198403223101203 https://doi.org/10.1002/jcla.21524 https://doi.org/10.1002/jcla.21524 https://doi.org/10.1053/smrv.2001.0159 https://doi.org/10.1053/smrv.2001.0159 https://doi.org/10.1258/000456306777695564 https://doi.org/10.1258/000456302320314511 https://doi.org/10.1007/s001250100589 https://doi.org/10.1007/s001250100589 https://doi.org/10.2337/diabetes.52.4.903 https://doi.org/10.2337/diabetes.52.4.903 https://doi.org/10.3389/fnut.2019.00132 https://doi.org/10.3389/fnut.2019.00132 https://doi.org/10.1073/pnas.1418955112 https://doi.org/10.1073/pnas.1418955112 https://doi.org/10.2337/diabetes.50.6.1237 https://doi.org/10.2337/diabetes.50.6.1237 https://doi.org/10.1210/jc.2017-01197 https://doi.org/10.2337/dc13-2088 https://doi.org/10.1159/000181791 https://doi.org/10.2337/db11-1478 https://doi.org/10.1056/nejm198506063122302 https://doi.org/10.1056/nejm198506063122302 https://doi.org/10.1055/s-2007-979926 https://doi.org/10.1055/s-2007-979926 https://doi.org/10.1007/s00125-006-0273-9 https://doi.org/10.1007/s00125-006-0273-9 serum glucose measurement after five to six hours is comparable to eight hours fasting in ramadan 128 | squ medical journal, february 2022, volume 22, issue 1 24. lin hv, accili d. hormonal regulation of hepatic glucose production in health and disease. cell metab 2011; 14:9–19. https://doi.org/10.1016/j.cmet.2011.06.003. 25. van cauter e, shapiro et, tillil h, polonsky ks. circadian modulation of glucose and insulin responses to meals: relationship to cortisol rhythm. am j physiol 1992; 262:e467–75. https://doi.org/10.1152/ajpendo.1992.262.4.e467. 26. defronzo ra. pathogenesis of type 2 diabetes mellitus. med clin north am 2004; 88:787–835, ix. https://doi.org/10.1016/j. mcna.2004.04.013. 27. færch k, vistisen d, pacini g, torekov ss, johansen nb, witte dr, et al. insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation. diabetes 2016; 65:3473–81. https://doi.org/10.2337/db16-0240. 28. monnier l, colette c, dejager s, owens d. magnitude of the dawn phenomenon and its impact on the overall glucose exposure in type 2 diabetes: is this of concern? diabetes care. 2013; 36:4057–62. https://doi.org/10.2337/dc12-2127. 29. monnier l, colette c, dunseath gj, owens dr. the loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. diabetes care 2007; 30:263–9. https://doi.org/10.2337/dc06-1612. 30. inzucchi se, bergenstal rm, buse jb, diamant m, ferrannini e, nauck m, et al. management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the american diabetes association (ada) and the european association for the study of diabetes (easd). diabetes care 2012; 35:1364–79. https://doi.org/10.2337/dc12-0413. https://doi.org/10.1016/j.cmet.2011.06.003 https://doi.org/10.1152/ajpendo.1992.262.4.e467 https://doi.org/10.1016/j.mcna.2004.04.013 https://doi.org/10.1016/j.mcna.2004.04.013 https://doi.org/10.2337/db16-0240 https://doi.org/10.2337/dc12-2127 https://doi.org/10.2337/dc06-1612 https://doi.org/10.2337/dc12-0413 1 1 submitted 25 dec 22 1 revision req. 8 feb 23; revision recd. 9 mar 23 2 accepted 19 apr 23 3 online-first: june 2023 4 doi: https://doi.org/10.18295/squmj.6.2023.040 5 6 caregiving preparedness and caregiver burden in omani family caregivers for 7 patients with acquired brain injury 8 hema roslin,1 *joshua k. muliira,2 eilean r. lazarus,1 devakirubai jacob,1 9 warda al-habsi,3 fatma al-musallami3 10 11 1department of adult health & critical care, college of nursing, sultan qaboos university, 12 muscat, oman; 2school of nursing, ball state university, muncie, usa; 3directorate general of 13 khoula hospital, ministry of health, muscat, oman. 14 *corresponding author’s e-mail: joshua.muliira@bsu.edu 15 16 abstract 17 objective: to explore the caregiving preparedness and burden among omani family caregivers 18 (fcs) of patients with acquired brain injury (abi). methods: a prospective observational design 19 was used to collect data from 119 fcs and their patients at the time of discharge from the hospital 20 and 16 weeks post-discharge during follow up-care in the neurology clinic. the questionnaire 21 comprised the zarit burden index, the preparedness for caregiving scale, the sf-12 general health 22 survey, and a patient symptom scale. results: fcs were predominantly female (55.5%), and their 23 mean age was 38.27 ± 9.11 years. most patients had moderate to severe abi (95.8%) due to stroke 24 (56.3%) and trauma (30.3%). the most common patient symptoms were loss of muscle strength, 25 speech problems, mood problems, memory loss, and change in behavior. most fcs had a low 26 caregiving preparedness (58%) at discharge, and 19.1% had a high level of caregiving burden at 16 27 weeks post-discharge. the length of time post-injury (p < 0.01), symptom severity (p < 0.01), and 28 the fcs’ physical and mental health status (p < 0.01) were significant predictors of caregiving 29 preparedness. the predictors of caregiver burden were caregiver preparedness (p < 0.01), symptom 30 about:blank 2 2 severity (p < 0.01), and caregivers’ mental health (p = 0.028). conclusion: omani fcs of patients 31 with abi commence the caregiver role with inadequate preparation, and shortly a significant number 32 suffer a high caregiving burden. interventions focusing on the caregiver’s health and training in 33 symptom management may enhance the outcomes of fcs and patients. 34 keywords: acquired brain injury; caregiving; caregiving preparedness; caregiver burden; family 35 caregivers; rehabilitation; traumatic brain injury; oman. 36 37 advances in knowledge 38 • this is the first study to explore caregiving preparedness and caregiver burden in fcs 39 of abi patients in oman. 40 • the findings show that patients with abi are discharged from the acute care setting to 41 home when they are still physically dependent and with a high symptom burden. 42 • the fcs assume the caregiver role in a state of low caregiving preparedness. 43 • in a period of 16 weeks post-discharge, up to 19 % of the fcs report a high level of 44 caregiver burden, despite initiating care in a state of good physical and mental health. 45 46 application to patient care 47 • the findings indicate a gap in neurorehabilitation care for abi patients in oman and 48 the need for caregiver support programs to augment their efficacy and caregiving 49 preparedness before resuming the caregiver role. 50 • discharge planning for patients with abi needs to be augmented with programs to 51 educate, train, and support the fcs to gain confidence in managing the patient’s symptoms, 52 general care, and personal health while at home. 53 • the uptake of caregiver burden in a short period of time post-discharge has 54 significant implications for the caregiver and abi patient outcomes, and system-wide 55 interventions such as home health services may help to address the gaps. 56 57 introduction 58 acquired brain injury (abi) is recognized as a major contributor to the global burden of disability, 59 death, and lifelong sequelae.1 abi includes any injury to the brain that is not congenital, 60 degenerative, hereditary, or caused by the birth process but resulting from traumatic and non-61 3 3 traumatic causes. the non-traumatic causes include stroke, infection, and tumors, while traumatic 62 brain injury occurs due to an external force such as falls, traffic accidents, or violence injuring the 63 brain with or without penetration of the skull.2 abi leads to physical, physiological, cognitive, 64 behavioral, social, and economic difficulties with ramifications for the patient and their families.1 65 many individuals affected by abi experience functional limitations necessitating long-term care and 66 support.3 in countries with less established healthcare systems, rehabilitation care is limited, and the 67 support and care needed by patients with abi are mainly provided at home by family members.4 68 69 the world health organization estimates that 60% of the abi burden is due to road traffic accidents 70 (rta)5 and predicts that by 2030, rta will be the 7th leading cause of death worldwide.6 oman, a 71 country where the current study was conducted, has a high rate of rta.7 oman is rated 4th among 72 the arabian gulf co-operation nations and 57th worldwide for rta injuries and deaths.5-7 stroke is 73 another major cause of abi in oman and is associated with a 25.4% and 30% cumulative mortality 74 rate at 12 months and 24 months, respectively.8 the key factors fueling the high rates of abi in 75 oman include the high incidence of hypertension, diabetes mellitus, dyslipidemia, obesity, sedentary 76 lifestyles, and the aging population.8 approximately 41.4% of omani stroke patients remain 77 physically dependent after the acute phase, and 59% remain with a modified rankin scale for 78 neurologic disability of greater than two (2) after discharge from the hospital.8 79 80 due to the lack of robust neuro-rehabilitation and home care services in oman, patients affected by 81 abi and related sequelae are directly discharged home (after acute hospital care), and the family 82 members assume the caregiving role. the family member who takes on the primary responsibility of 83 providing physical, emotional, and financial support to the abi patient while at home is referred to 84 as the family caregiver (fc).9 in oman, there are currently no support systems for the fc. the fc 85 assumes the caregiver role without any formal assistance from the healthcare system. in other 86 studies, the lack of support is reported to be associated with low preparedness and high caregiver 87 burden among family caregivers (fcs) of patients with abi.10 on the other hand, education 88 programs for fcs have been found to improve caregiver preparedness and well-being.11 89 90 the caregiver role requires tolerance and commitment to meet the abi patient’s needs related to 91 personal hygiene, dressing, nutrition, communication, emotional support, mobility, and safety, 92 4 4 especially in those with minimal physical capabilities.12 therefore, the fcs play a vital role in the 93 recovery, rehabilitation, and community re-integration of a patient with abi.13 thus, the lack of 94 support for fcs can negatively impact the abi patient. additionally, the demands of caregiving 95 increase the tendency of self-neglect among fcs, which worsens as the abi patients’ home care 96 needs become prolonged and arduous.14 subsequently, the fcs may become some kind of hidden 97 patients themselves.15 98 99 studies from other countries show that the caregiving burden from abi patients is relatively higher 100 compared to patients with other conditions.10 caregiving burden is a multidimensional phenomenon, 101 with physical, psychological, financial, and social isolation ambits.1 the fcs also have a burden of 102 inadequate information about future patient outcomes.16 one of the moderators of caregiver burden 103 is the level of preparedness for the caregiver role. caregiving preparedness is the caregiver’s 104 perceived ability to meet the care needs of the patient and the ability to arrange for the patient and 105 handle emergent situations.17 the fc may feel unprepared for the role due to personal factors and 106 lack of skills.18 the fact that most abi occurs unexpectedly allows no time for most fcs to learn 107 new skills or adjust to the new roles.10 108 109 caregivers with high caregiving preparedness tend to experience low caregiver burden, marginal 110 strain, and mood disturbances and have better self-care.17 a high caregiving preparedness is 111 associated with low hospital readmissions and accelerated abi patient recovery.17 despite the 112 contribution of fcs towards the rehabilitation and recovery of abi patients, no studies have focused 113 on their preparedness, caregiver burden, or health outcomes in oman. the current study explored the 114 caregiver burden and preparedness of fcs of patients with abi in oman. the study results will be 115 used to plan a home-based nurse-led program to support abi patients and their fcs. 116 117 methods 118 a prospective observational design was used to follow fcs of patients with abi for a period of 16 119 weeks post-discharge (april 2019december 2021) from the acute care hospital. the fcs and 120 patients were recruited at the time of discharge from the neuro-critical care unit (30 beds) and 121 neurology ward at khoula hospital in oman. the patients were individuals of age ≥ 18 years and 122 5 5 admitted with a confirmed diagnosis of any type of abi. in order to be included in the study, the 123 abi patient had to be able to state their names, positively identify family members, and a 124 125 modified rankin scale for neurologic disability of at least +1. the fc was the family member 126 (relative) responsible for providing day-to-day care at home for the abi patient after discharge from 127 the hospital. the fcs were included if they were identified by the patient as the main person who 128 will be responsible for the care of the patient once discharged from the hospital; omani by 129 nationality; age ≥18 years; able to speak and understand arabic or english; live in the same 130 household as the abi patient; and able to provide written consent. 131 132 a purposive sampling approach was used to identify abi patients and their fcs. a total of 119 133 patients with abi and their fcs were recruited in the study at the time of discharge from the 134 hospital. an interview questionnaire was used to collect data from the fcs. the questionnaire was 135 comprised of the sf-12 healthy survey (sf-12), the preparedness for caregiving scale (pcs), the 136 abridged arabic version of the zarit burden inventory (azbi), and the abi symptom severity scale. 137 the fcs’ general health was measured using the sf-12. the physical and mental health scores range 138 from 0 to 100, where zero indicates the lowest level of health and 100 indicates the highest level of 139 health. the internal consistency and test-retest reliabilities of the sf-12 range from 0.67 to 0.82.19 140 141 the fcs’ preparedness for caregiving was measured with the pcs.20 the pcs (8 items) assesses 142 how well the fc is prepared for the demands of caregiving.20 the responses are rated on a 5-point 143 likert scale ranging from 0 (not at all prepared) to 4 (very well prepared). item scores are summed 144 to generate a total score (ranging from 0 to 32), and high scores indicate a high level of 145 preparedness. the pcs cronbach’s alpha in the current study was 0.98, and this is consistent with 146 the range of 0.88 to 0.95 reported in other studies.20 the caregiving burden incurred while caring for 147 the patient with abi was measured using the azbi. the azbi has 12 items with a five-point 148 response likert scale (total scores range from 0 to 48).21 high scores indicate a high caregiving 149 burden. in this study, the azbi cronbach’s alpha was 0.90, whereas other studies reported alpha’s 150 ranging from 0.74 to 0.81.21 151 152 6 6 the abi patient symptom severity score was used to assess the presence and severity of symptoms 153 commonly associated with abi. the symptoms assessed are summarized in table 2. the severity of 154 the symptom was rated on a scale developed by the investigators, ranging from 1 to 5 (1= no 155 difficulty, 3 = mild difficulty, 4 = moderate difficulty, and 5 = severe difficulty). a total score was 156 computed by generating the sum of all items (symptom burden). the cronbach’s alpha of the 157 symptom severity scale was 0.88. 158 159 the study was approved by the research committee of the hospital, the ministry of health in oman, 160 and the investigators’ institutions. the participants received explanations of the study procedures 161 and signed the consent form before data collection. the investigators approached the charge nurses 162 of units that admit patients with abi to identify those scheduled for discharge. the nurses notified 163 the study research assistant (a nurse) of the discharge time and when a family member could take the 164 patient home. the research assistant screened the family member for eligibility before collecting 165 data about the patient and caregiver characteristics, fc preparedness for caregiving, and health status 166 at discharge. 167 168 the fcs were also informed that additional data about the caregiving burden would be collected 169 during the patient’s neurology clinic follow-up appointment at 16 weeks. the patients with abi 170 return to the neurology clinic for follow-up care at least every two months. the caregiving burden 171 data were collected during the 2nd follow-up appointment (at 16 weeks) because this span of time 172 ensured adequate experience and familiarity with the caregiving role and demands. of the 119 173 participants recruited in the study, 105 (fcs and abi patients) showed up for the 2nd appointment at 174 16 weeks (see figure 1). the remaining 14 fcs did not show up because the patient died before the 175 2nd follow-up appointment. 176 177 data were analyzed using statistical package for the social sciences (spss), version 23 (ibm 178 corp., armonk, new york, usa). descriptive statistics were used to summarize sample 179 characteristics, patient symptoms, fcs’ health status, caregiving preparedness, and caregiver burden. 180 pearson’s correlations were used to determine the factors associated with caregiving preparedness 181 and caregiver burden. multiple linear regression analyses (stepwise method) were conducted to 182 7 7 establish the predictors of caregiving preparedness and burden. multicollinearity was tested using 183 the variance inflation factor and tolerance. a p-value of less than 0.05 was statistically significant. 184 185 results 186 the mean age of fc was 38.27 ± 9.114 years, and the majority were female (55.5%), the parent 187 (36.1%) or child (38.7%) of the patient and had no help at home with the caregiving responsibilities 188 (95.8%) (see table 1). most patients were male (57.1%), with a diagnosis of stroke (56.3%), and had 189 a glasgow coma scale (gcs) score equivalent to moderate or severe injury at the time of admission 190 (95.8%) and mild injury at the time of discharge (86.6%). the mean gcs scores at the time of 191 admission and discharge were 8.43 ± 2.381 (severe injury status) and 14.25 (mild injury status), 192 respectively. 193 194 at the time of discharge from the hospital, all the abi patients had at least seven symptoms (see 195 table 2). the most common and severe symptoms were inability to live independently (4.92 ± 0.44), 196 loss of muscle strength, paralysis, limited physical mobility or poor coordination (4.68 ± 0.68), 197 change in speech or difficulty in being understood (4.45 ± 1.10), mood problems (4.27 ± 1.09), loss 198 of memory and concentration (4.25 ± 1.24), and behavior problems (4.08 ± 1.14). the mean 199 symptom score of the patients was 38.14 ± 7.42 out of 45 possible points. most patients (94.1%) had 200 a very high symptom burden (total score ≥ 24) at the time of discharge. 201 202 overall the fcs reported good physical (m= 79.24 ± 24.08) and mental health (m= 63.31 ± 15.0), 203 low caregiving preparedness (m= 17.52 ± 9.29), and low caregiver burden (m= 16.98 ± 8.76) (see 204 table 3). at the time of discharge, the majority of fcs were in good physical (83.2%) and mental 205 health (90.8%) but had low caregiving preparedness (58%). after 16 weeks of caregiving, 19.1% of 206 the fcs had a high caregiver burden. the factors associated with caregiving preparedness and 207 caregiver burden are presented in table 4. 208 209 the results from multiple regression analysis to determine predictors of caregiving preparedness and 210 burden are summarized in table 5. the final model explained a statistically significant amount of 211 variance in caregiving preparedness, f (4, 113) = 29.81, p < 0.01, r2 = 0.513, r2adjusted = 0.496. the 212 length of time since the injury occurred (p < 0.01), symptom severity score (p < 0.01), fcs’ physical 213 8 8 health (p < 0.01), and fcs’ mental health (p < 0.01) at the time of discharge were significant 214 predictors of caregiving preparedness. the four factors explain 49.6% of the variance in caregiving 215 preparedness. 216 217 the level of caregiving preparedness (p < 0.01), symptom severity score (p < 0.01), and the fcs’ 218 mental health status (p = 0.028) at the time of discharge were significant predictors of caregiver 219 burden. the final model explained a statistically significant amount of variance in caregiving 220 burden, f (3, 100) = 20.57, p < 0.01, r2 = 0.382, r2adjusted = 0.363. the three factors explained 36.3% 221 of the variance in caregiver burden. a 0.4-point increase in preparedness was associated with a one-222 point decrease in the caregiving burden. a 0.1-point increase in the fcs’ mental health status was 223 associated with a 1-point decrease in the caregiver burden. and a 0.3-point increase in the patient’s 224 overall symptom severity was associated with a 1-point increase in caregiver burden. 225 226 discussion 227 to our knowledge, this is the first study to explore caregiving preparedness and caregiver burden in 228 omani fcs of patients with abi. the findings show that many abi patients are discharged home 229 when they are still physically dependent and with a high symptom burden. and the fcs assume the 230 caregiver role in a state of low caregiving preparedness. it is therefore not surprising that in a period 231 of 16 weeks post-discharge, up to 19.1% of the fcs report high levels of caregiver burden, despite 232 initiating care in a state of good physical and mental health. the above findings indicate a gap in 233 neurorehabilitation care for abi patients in oman and the need for fc support programs to augment 234 their efficacy and preparedness before resuming the caregiver role. 235 236 the uptake in caregiver burden in a short period of time post-discharge has significant implications 237 for the abi patient’s outcomes, such as symptom management, recovery, hospital re-admission, 238 survival, and the fcs’ health and well-being. these should be investigated in future studies. 239 considering the absence of structured rehabilitation programs, there is a need for structured pre-240 discharge interventions to educate, support, and prepare the fcs for the caregiver role. other studies 241 show that structured caregiver education and training programs increase preparedness, decreased 242 caregiver burden, and lead to better outcomes for the abi patient.22 strategies like peer mentoring 243 9 9 and peer support groups can also improve fcs’ preparedness, mental health, and ability to handle 244 caregiving stress.3 245 246 in other countries, patients with abi and their families have identified specific needs during the 247 transition from acute care to home.23 these include patient and family education, discharge 248 preparation, information about the patient’s recovery roadmap, linking pre-discharge care with post-249 discharge resources, and others.23 the provision of the above supportive measures empowers the 250 fcs to approach care for abi patients in a better way and with a high degree of resilience. 251 252 the majority of abi patients in our study had at least seven symptoms at the time of discharge, and 253 this is similar to the findings of other studies.24,25 in other studies, the abi patients had reduced 254 symptoms after six months.24,25 in our study, symptom severity was assessed at the time of discharge 255 from acute care. this highlights the need for longitudinal studies to evaluate the trajectory of abi 256 patient symptoms over time and the impact of the symptom burden on omani fcs. a few studies 257 recommend that reassuring the patients that the symptoms are manageable with proper treatment and 258 regular exercise during the period of rehabilitation is a good approach.24,25 unfortunately, in oman, 259 access to post-hospital rehabilitation is intermittent or not accessible. 260 261 the predictors of caregiving preparedness were the length of time since the occurrence of the injury, 262 symptom severity score, and fcs’ physical and mental health status. the four factors highlight the 263 importance of preparing fcs in symptom management and personal health promotion and coping. 264 this can be achieved during the time when the abi patient is in acute care and residential 265 rehabilitation. the predictors inform us that interventions that help the fcs to gain confidence in 266 managing the abi patient’s symptoms, fcs’ personal health promotion, home health care services, 267 and additional time in rehabilitation may enhance the caregiver’s preparedness. 268 269 up to 19.1% of the fcs reported severe caregiver burden at 16 weeks post-discharge, and the 270 predictors of caregiver burden were the level of caregiving preparedness, symptom severity score, 271 and the fcs’ mental health status at the time of discharge. this rate of burden is closely similar to 272 that reported by other studies.23,26 a study of fcs of stroke survivors conducted in texas reported 273 that 17% had moderate to severe caregiver burden, and the burden was associated with moderate to 274 10 10 severe functional disability.27 other studies show that a high level of caregiving burden is associated 275 with abi patients’ brain injury severity, low ability to perform activities of daily living,11,28 presence 276 of tracheostomy tube, and speech or swallowing disorders.1,3,12 277 278 our study, like others, supports the observation that it takes time for the fcs to attain adequate 279 preparedness or readiness to care for the abi patient at home.10,29,30 therefore, supportive 280 interventions and deliberate training for fcs are needed in order to shorten the time and reduce the 281 challenges faced in the process of achieving preparedness. the fcs experience better health status 282 when they receive support, teaching, home health care services, and orientation to caring for abi 283 patients at home.1,13,14 the current study was observational that could not implement the above 284 interventions. therefore, we recommend interventional studies tailored to oman culture to address 285 the unmet needs of fcs while caring for abi patients at home. 286 287 the study had limitations that need to be considered when interpreting its results, and these include a 288 small sample, limited follow-up period (16 weeks), limited data about patient symptoms, and 289 participant recruitment from a single site. additionally, the sample was comprised of abi patients 290 who had a high severity of deficits, which could have skewed the caregiver burden. moreover, 291 family caregivers tend to minimize their personal health problems in an effort to emphasize the 292 primacy of the care and needs of the patient they are responsible for. 293 294 conclusion 295 the fcs of abi patients in oman commence the caregiver role when they are in good health, but 296 with inadequate preparation, and shortly a large number experience a high caregiving burden. the 297 abi patients are discharged from acute care when they still have multiple severe symptoms 298 associated with abi, and this situation escalates the caregiver burden. the process of in-hospital 299 care for abi patients should be augmented with interventions to enhance the fcs’ caregiving 300 preparedness in order to enhance the outcomes of both the caregiver and the patient. additionally, 301 the healthcare system needs to be augmented with neurorehabilitation services as a way of 302 improving patient outcomes and reducing the fc’s burden. 303 304 authors’ contribution 305 11 11 jkm, hr, and dj conceptualized and planned the study. hr, wa, fa, and dj collected the data 306 and carried out measurements. jkm, hr, and dj supervised the study and acquired the funding. 307 jkm and erl analyzed and interpreted the data. jkm, hr, and erl wrote the draft manuscript 308 with critical feedback and help from dj, wa, and fa. all authors were involved in the study 309 investigation, discussed the results, and approved the final version of the manuscript 310 311 312 acknowledgments: the authors convey thanks to the administrators and healthcare providers at 313 khoula hospital for their cooperation during data collection. 314 315 conflict of interest 316 the authors declare no conflicts of interest. 317 318 funding: the study was funded by the sultan qaboos university internal grant 319 ig/con/ahcc/19/03. 320 321 references 322 1. tezel n, umay e, çakcı a. factors affecting the caregiver burden following traumatic brain 323 injury. gulhane med j 2021; 63(3):186-92. https://doi.org/10.4274/gulhane.galenos.2021.1460 324 2. de geus eq, milders mv, van horn je, jonker fa, fassaert t, hutten jc, et al. acquired brain 325 injury and interventions in the offender population: a systematic review. front psychiatry 2021; 326 12:658328. https://doi.org/10.3389/fpsyt.2021.658328 327 3. jones m, holley c, jacobs m, batchelor r, mangin a. effects of peer mentoring for caregivers 328 of patients with acquired brain injury: a preliminary investigation of efficacy. arch rehabil 329 res clin transl 2021; 3(3):100149. https://doi.org/10.1016/j.arrct.2021.100149 330 4. mehmood a, allen ka, al-maniri a, al-kashmiri a, al-yazidi m, hyder aa. 2017. trauma 331 care in oman: a call for action. surgery 2017; 162(6): s107-s116. 332 https://doi.org/10.1016/j.surg.2017.01.028 333 5. world health organization (2022). injuries, traffic. from http://www.emro.who.int/health-334 topics/injuries-traffic/index.html accessed: sept 2022 335 https://doi.org/10.4274/gulhane.galenos.2021.1460 https://doi.org/10.3389/fpsyt.2021.658328 https://doi.org/10.1016/j.arrct.2021.100149 https://doi.org/10.1016/j.surg.2017.01.028 http://www.emro.who.int/health-topics/injuries-traffic/index.html http://www.emro.who.int/health-topics/injuries-traffic/index.html 12 12 6. dunne j, quiñones-ossa ga, still eg, suarez mn, gonzález-soto ja, vera ds, rubiano am. 336 the epidemiology of traumatic brain injury due to traffic accidents in latin america: a narrative 337 review. j neurosci rural pract 2020;11(02):287-90. https://doi.org/10.1055/s-0040-1709363 338 7. chitme hr, al-kashmiri a, al-thehli hm, al-qanoobi mj, al-mushefri mm, venuvgopal j. 339 impact of medical conditions and medications on road traffic safety. oman med j 2018; 340 33(4):316. https://doi.org/10.5001/omj.2018.58 341 8. al alawi am, al busaidi i, al shibli e, al-senaidi ar, al manwari s, al busaidi i, et al. 342 health outcomes after acute ischemic stroke: retrospective and survival analysis from oman. 343 ann saudi med 2022; 42(4): 269-75. https://doi.org/10.5144/0256-4947.2022.269 344 9. annisa f. burden of family caregiver. belitung nurs j 2016; 2(1):10-8. 345 https://doi.org/10.33546/bnj.7 346 10. lieshout k, oates j, baker a, unsworth ca, cameron id, schmidt j, lannin na. burden and 347 preparedness amongst informal caregivers of adults with moderate to severe traumatic brain 348 injury. int j environ res public health 2020; 17(17):6386. 349 https://doi.org/10.3390/ijerph17176386 350 11. carnahan jl, judge ks, daggy jk, slaven je, coleman n, fortier el, et al. supporting 351 caregivers of veterans with alzheimer’s disease and traumatic brain injury: study protocol for a 352 randomized controlled trial. trials 2020; 21(1):1-1. https://doi.org/10.1186/s13063-020-4199-1 353 12. azman a, jali na, singh ps, abdullah jm, ibrahim h. family roles, challenges and needs in 354 caring for traumatic brain injury (tbi) family members: a systematic review. j health res 2020; 355 34(6):495-504. https://doi.org/10.1108/jhr-07-2019-0138 356 13. cameron ji. family caregiving research: reflecting on the past to inform the future. j spinal 357 cord med 2021; 44(sup1): s19-22. https://doi.org/10.1080/10790268.2021.1970883 358 14. devi y, khan s, rana p, dhandapani m, ghai s, gopichandran l, et al. cognitive, behavioral, 359 and functional impairments among traumatic brain injury survivors: impact on caregiver burden. 360 j neurosci rural pract 2020;11(04):629-35. https://doi.org/10.1055/s-0040-1716777 361 15. steppacher i, kissler j. a problem shared is a problem halved? comparing burdens arising for 362 family caregivers of patients with disorders of consciousness in institutionalized versus at home 363 care. bmc psychol 2018: 6(1):1-3. https://doi.org/10.1186/s40359-018-0272-x 364 16. broodryk m, pretorius c. initial experiences of family caregivers of survivors of a traumatic 365 brain injury. afri j disabil 2015; 4(1):1-7. https://doi.org/10.4102/ajod.v4i1.165 366 https://doi.org/10.1055/s-0040-1709363 https://doi.org/10.5001/omj.2018.58 https://doi.org/10.5144/0256-4947.2022.269 https://doi.org/10.33546/bnj.7 https://doi.org/10.3390/ijerph17176386 https://doi.org/10.1186/s13063-020-4199-1 https://doi.org/10.1108/jhr-07-2019-0138 https://doi.org/10.1080/10790268.2021.1970883 https://doi.org/10.1055/s-0040-1716777 https://doi.org/10.1186/s40359-018-0272-x https://doi.org/ http://dx.doi.org/10.4102/ajod.v4i1.165 13 13 17. pucciarelli g, savini s, byun e, simeone s, barbaranelli c, vela rj, et al. psychometric 367 properties of the caregiver preparedness scale in caregivers of stroke survivors. heart lung 368 2014; 43(6):555-60. https://doi.org/10.1016/j.hrtlng.2014.08.004 369 18. garcia‐rudolph a, sauri j, garcia‐molina a, cegarra b, opisso e, tormos jm, et al. the 370 impact of coronavirus disease 2019 on emotional and behavioral stress of informal family 371 caregivers of individuals with stroke or traumatic brain injury at chronic phase living in a 372 mediterranean setting. brain behav 2022;12(1): e2440. https://doi.org/10.1002/brb3.2440 373 19. lam et, lam cl, fong dy, huang ww. is the sf‐12 version 2 health survey a valid and 374 equivalent substitute for the sf‐36 version 2 health survey for the chinese? j eval clin pract 375 2013; 19(1):200-8. https://doi.org/10.1111/j.1365-2753.2011.01800.x 376 20. henriksson a, andershed b, benzein e, årestedt k. adaptation and psychometric evaluation of 377 the preparedness for caregiving scale, caregiver competence scale and rewards of caregiving 378 scale in a sample of swedish family members of patients with life-threatening illness. palliat 379 med 2012; 26(7):930-8. https://doi.org/10.1177/02692163114199 380 21. bachner yg. preliminary assessment of the psychometric properties of the abridged arabic 381 version of the zarit burden interview among caregivers of cancer patients. eur j oncol nurs 382 2013;17(5):657-60. https://doi.org/10.1016/j.ejon.2013.06.005 383 22. driscoll r, fitzpatrick l, karsten j, scott s, winters e. care partner carryover day: a 384 formalized training program to improve care partner preparedness for patients with acquired 385 brain injury prior to discharge home. arch phys med rehabil 2021;102(10):e52. 386 https://doi.org/10.1016/j.apmr.2021.07.620 387 23. oyesanya to, loflin c, harris g, bettger jp “just tell me in a simple way”: a qualitative study 388 on opportunities to improve the transition from acute hospital care to home from the perspectives 389 of patients with traumatic brain injury, families, and providers. clin rehabil 2021; 35(7):1056-390 72. https://doi.org/10.1177/0269215520988679 391 24. levin hs, temkin nr, barber j, nelson ld, robertson c, brennan j, et al. association of sex 392 and age with mild traumatic brain injury–related symptoms: a track-tbi study. jama netw 393 open 2021; 4(4): e213046. https://doi.org/10.1001/jamanetworkopen.2021.3046 394 25. machamer j, temkin n, dikmen s, nelson ld, barber j, hwang p, et al. symptom frequency 395 and persistence in the first year after traumatic brain injury: a track-tbi study. j 396 neurotrauma 2022; 39(5-6):358-70. https://doi.org/10.1089/neu.2021.0348 397 https://doi.org/10.1016/j.hrtlng.2014.08.004 https://doi.org/10.1002/brb3.2440 https://doi.org/10.1111/j.1365-2753.2011.01800.x https://doi.org/10.1177/0269216311419987 https://doi.org/10.1016/j.ejon.2013.06.005 https://doi.org/10.1016/j.apmr.2021.07.620 https://doi.org/10.1177/0269215520988679 https://doi.org/10.1001/jamanetworkopen.2021.3046 https://doi.org/10.1089/neu.2021.0348 14 14 26. shankar j, nicholas d, mrazik m, waugh e, tan s, zulla r, et al. transition from pediatric to 398 adult services: challenges for family caregivers of young adults with traumatic brain injury. sage 399 open 2018; 8(4):2158244018807954. https://doi.org/10.1177/2158244018807954 400 27. achilike s, beauchamp je, cron sg, okpala m, payen ss, baldridge l, et al. caregiver burden 401 and associated factors among informal caregivers of stroke survivors. j neurosci nurs 2020; 402 52(6):277-83. https://doi.org/10.1097/jnn.0000000000000552 403 28. elsheikh ma, moriyama m, rahman mm, kako m, el-monshed ah, zoromba m, et al. 404 protocol: effect of a tailored multidimensional intervention on the care burden among family 405 caregivers of stroke survivors: study protocol for a randomized controlled trial. bmj open 406 2020;10(12): e041637. https://doi.org/10.1136/bmjopen-2020-041637 407 29. walker j, schlebusch l, gaede b. support for family members who are caregivers to relatives 408 with acquired brain injury. j mind medical sci 2021; 8(1):76-85. 409 https://doi.org/10.22543/7674.81.p7685 410 30. anderson mi, daher m, simpson gk. a predictive model of resilience among family caregivers 411 supporting relatives with traumatic brain injury (tbi): a structural equation modelling approach. 412 neuropsychol rehabil 2020; 30(10):1925-46. https://doi.org/10.1080/09602011.2019.1620787 413 414 https://doi.org/10.1177/2158244018807954 https://doi.org/10.1097/jnn.0000000000000552 https://doi.org/10.1136%2fbmjopen-2020-041637 https://doi.org/10.22543/7674.81.p7685 https://doi.org/10.1080/09602011.2019.1620787 15 15 figure 1. flow chart 119 patients and family caregivers were recruited at the time of discharge from hospital no data collection. 14 patients died before the first appointment 105 patients and family caregivers showed up for the follow-up appointment at 16 weeks post-discharge caregiving preparedness and patient symptom data collected from 119 caregiver burden data were collected from 105 family caregivers 415 416 16 16 table 1: characteristics of the family caregivers and patients 417 characteristic fcs (n=119) patients (n=119) f (%) f (%) gender male female 55 (44.5) 66 (55.5) 68 (57.1) 51 (42.9) age in years 18-38 39-59 60-80 ≥ 81 66 (55.5) 50 (42) 3 (2.5) - 18 (15.1) 22 (18.5) 59 (49.5) 20 (16.8) marital status single married separated/divorced/widowed 22 (18.5) 93 (78.2) 4 (3.4) 12 (10.1) 71 (59.7) 36 (30.3) level of education ≤ high school associate degree/diploma ≥ bachelor’s degree 90 (75.6) 7 (5.9) 22 (18.4) 114 (95.8) 1 (0.8) 4 (3.1) employment status full-time part-time unemployed 68 (57.1) 9 (7.6) 42 (35.3) 44 (37) 6 (5) 69 (58) relationship to patient parent spouse child sibling legal guardian 43 (36.1) 13 (10.9) 46 (38.7) 14 (11.8) 3 (2.5) - - - - - has other family members who need care no yes 114 (95.8) 5 (4.2) - - cause of injury or patient diagnosis trauma (mva and assault) aneurysm stroke - - - 36 (30.3) 16 (13.4) 67 (56.3) length of time since the injury occurred (days) 1 – 180 181 – 360 ≥ 361 - - - 66 (55.5) 6 (5) 47 (39.5) glasgow coma scale on admission 13 15 (mild) 9 12 (moderate) 8 (severe) - - - 5 (4.2) 62 (52.1) 52 (43.7) glasgow coma scale at the time of discharge 13 15 (mild) 12 (moderate) - - 103 (86.6) 16 (13.4) mva, motor vehicle accident, fcs, family caregivers 418 419 420 421 17 17 table 2: symptom profile of acquired brain injury patients at the time of discharge 422 symptom severity rating m ± sd no difficulty mild difficulty moderate difficulty severe difficulty % % % % ability to live independently 0.8 0.8 3.4 95 4.92 ± 0.44 loss of muscle strength, paralysis, limited physical mobility, or poor coordination 1.7 1.7 21.8 73.9 4.68 ± 0.68 change in speech or difficulty being understood 6.7 7.6 12.6 73.1 4.45 ± 1.10 mood problems (including depression, anxiety, denial, and frequent change in emotion) 5.9 13.4 22.7 58 4.27 ± 1.09 loss of memory and concentration 9.2 16.9 16 63 4.25 ± 1.24 changes in behavior, aggression, anger, impulsiveness, and others 6.7 20.2 24.4 48.7 4.08 ± 1.14 insomnia 10.9 20.2 22.7 46.2 3.93 ± 1.29 blurred or loss of vision 16.8 10.9 26.9 45.4 3.84 ± 1.44 loss of hearing or ringing in the ears 21 13.4 22.7 42.9 3.66 ± 1.54 423 table 3: family caregivers’ quality of life, caregiving preparedness, and caregiving burden 424 variable level % median mean sd se sf-12 physical component summary (n= 119) poor (≤ 50) 16.8 91.67 79.24 24.08 2.21 good (≥ 51) 83.2 sf-12 mental component summary (n =119) poor (≤ 42) 9.2 65 63.31 15 1.38 good (≥ 43) 90.8 caregiving preparedness (n=119) low (≤ 19) 58 16 17.52 9.29 0.85 high (≥ 20) 42 caregiving burden (n= 105) low (≤ 24) 81.9 18 16.98 8.76 0.85 high (≥ 25) 19.1 sd, standard deviation; se, standard error of the mean 425 426 18 18 table 4: factors associated with caregiving preparedness and burden (n= 105) 427 factor caregiving preparedness caregiving burden r p-value r p-value caregiving preparedness at the time of discharge from the hospital 0.545 < 0.01** fc mental health status at the time of patient discharge -0.267 < 0.01** -0.315 < 0.01** fc physical health status at the time of patient discharge -0.249 0.006** 0.045 0.65 glasgow’s coma score at the time of discharge from the hospital 0.156 0.090 -0.227 0.020* symptom severity score at the time of discharge from the hospital -0381 < 0.01** 0.427 < 0.01** length of time since patient injury (in days) 0.609 < 0.01** -0.431 < 0.01** **correlation is significant at the 0.01 level (2-tailed); *correlation is significant at the 0.05 428 level (2-tailed); r = pearson’s correlation; fc = family caregiver 429 430 table 5: predictors of caregiving preparedness and caregiver burden 431 dependent variable factor unstandardized coefficient t p-value 95% ci β se caregiving preparedness constant 23.59 4.45 5.30 < 0.01 14.76 – 32.41 length of time since patient injury (in days) 0.01 0.00 5.99 < 0.01 0.0 – 0.01 symptom severity score -0.28 0.09 -3.35 < 0.01 0.45 – -0.12 fc physical health status -0.13 0.03 -4.11 < 0.01 -0.20 – -0.07 fc mental health status -0.20 0.05 -3.82 < 0.01 0.10 – 0.30 caregiver burden constant 18.996 5.174 3.67 < 0.01 8.73 – 29.24 caregiving preparedness -0.37 0.08 -4.48 < 0.01 -0.53 – -0.21 symptom severity score 0.30 0.10 3.06 < 0.01 0.11 – 0.49 fc mental health status -0.10 0.05 -2.22 0.028 -0.19 – -0.11 ci, confidence interval; se, standard error; fc, family caregiver 432 department of dermatology, hospital clínic de barcelona, barcelona, spain *corresponding author’s e-mail: fusta@clinic.cat الفتق العضلي عرب اجلاهية التشخيص بواسطة املوجات فوق الصوتية الديناميكية كز�فييه فو�صتا نوفيل، د�نييل مورجادو كار��صكو، بيالر �إير�نزو، بري�صيال جيافيدوين transfascial muscular hernias diagnosis by dynamic ultrasonography *xavier fustà-novell, daniel morgado-carrasco, pilar iranzo, priscila giavedoni a 28-year-old male patient presented tothe department of dermatology of the hospital clínic de barcelona, barcelona, spain, in 2018 with a seven-year history of skin-coloured soft nodules on the anterior and lateral sides of the legs that appeared when standing and disappeared with pressure release [figure 1]. the lesions were asymptomatic but became painful after hours of standing or during physical exercise. the patient had performed weightlifting in the past and denied any previous trauma in the areas where the nodules appeared. a skin biopsy and a muscu loskeletal magnetic resonance imaging (mri) scan, performed at another institution, reported no pathol ogical findings. an ultrasonographic examination with an 18-mhz probe (mylab™ class c, esaote, genoa, italy) of the lateral side of the left leg at rest was performed with no pathological findings [figure 2a]. the exam ination was repeated with the patient in a standing position, revealing thinning and partial discontinuity of the fascial layer resulting in muscular protrusion to the subcutaneous tissue [figure 2b]. these findings were evident due to the increase in muscle pressure while standing. furthermore, in the doppler mode, blood vessels going through the muscle fascia at the sites of muscular protrusions were observed [figure 2c]. the patient was diagnosed with transfascial muscular hernias of the lower extremities. he was conservatively managed and the lesions had not progressed at the one-year follow-up. sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e264–266, epub. 5 nov 19 submitted 23 apr 19 revision req. 12 jun 19; revision recd. 25 jun 19 accepted 21 jul 19 figure 1: photograph of the left leg of a 28-year-old male patient showing subcutaneous nodules on the anterior and lateral sides appearing in a standing position (arrows). this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.016 interesting medical image https://creativecommons.org/licenses/by-nd/4.0/ xavier fustà-novell, daniel morgado-carrasco, pilar iranzo and priscila giavedoni interesting medical image | e265 comment muscular hernias are frequently found during trauma tology and orthopaedic consultations, yet they are still unknown by many physicians from other medical specialties. few cases have been reported of this entity, resulting in misdiagnosis and unnecessary diagnostic tests.1,2 a fascia is a band of connective tissue beneath the skin that attaches, stabilises and separates muscles and other internal organs. there are three main types of fascia: 1) the superficial fascia which is located in the subcutaneous tissue and blending with the reticular layer of the dermis; 2) the deep fascia which interpenetrates and surrounds muscles, bones, nerves and blood vessels; and 3) the visceral fascia which wraps around internal organs. in this article, the terms “fascial layer” and “muscle fascia” refer to the deep fascia that surrounds the muscle. muscular hernias are focal protrusions of muscle tissue through fascial defects.1 these defects can be due to a congenital defect of the muscle fascia or an acquired lesion, usually secondary to trauma.2 the legs, particularly the tibialis anterior muscle, are most frequently affected.3 the typical clinical presentation consists of young athletic males who present with subcutaneous soft nodules in the legs that appear with muscle contraction (when standing or during physical exercise) and disappear when muscles relax.1,3 although the lesions are asymptomatic, they may cause discomfort or become painful with physical exercise.3 it is not uncommon for these patients to be referred to a dermatologist, raising the differential diagnosis with vascular malformations, haematomas or soft tissue tumours.3 ultrasound scans are used in the diagnosis of many musculoskeletal diseases and can be a valid alternative to mri scans, which are the gold standard for most of these entities.4 ultrasound investigations are fast, safe, painless, well-tolerated, widely accessible and less expensive than other methods; in addition, patients are not exposed to ionising radiation. on the other hand, this technique has some limitations. ultrasonography is highly operator-dependent whereby adequate training in obtaining and interpreting the images is essential.4 however, transfascial muscular hernias can be easily diagnosed and confirmed with ultrasonography. a dynamic study will show a discontinuity in the muscle fascia resulting in a muscular protrusion that will become more evident with muscular contraction.5 in doppler mode, vessels penetrating the fascia at the site of the hernia can be visualised. although many cases of transfascial muscular hernias have been reported in the literature, cases in which mri scans have been falsely negative are scarce. the present case highlights that these lesions can go completely unnoticed in any imaging technique if a dynamic study is not performed with the patient standing.5 figure 2: a: ultrasound image of the lateral side of the left leg of a 28-year-old mjale patient in a sitting position with no pathological findings showing the epidermis (yellow asterisks), dermis (blue line), subcutaneous tissue (yellow line) and muscle fascia (green asterisks). b: ultrasound image of the same patient in a standing position showing a disruption in the integrity of the fascia (red arrows), resulting in a muscular herniation through the fascial plane (red asterisks). the normal muscle fascia can be seen beyond the hernia (green asterisks). c: doppler mode ultrasound image of the same patient in a standing position showing blood vessels (red asterisk) going through the fascial plane at the sites of muscular herniation. red arrows indicate the margins of the hernia. transfascial muscular hernias diagnosis by dynamic ultrasonography e266 | squ medical journal, august 2019, volume 19, issue 3 treatment of asymptomatic hernias is not necessary. for painful lesions or for cosmetic reasons, surgical treatment may be considered. longitudinal fasciotomy is the most frequently used surgical technique.3 simple fascial repair is not recommended due to the risk of developing compartment syndrome.1 in the current case, the patient was diagnosed with transfascial muscular hernias by using a dynamic ultrasound study; this diagnosis could not be confirmed even after an mri scan or histopathological studies. physicians should be familiar with this entity to avoid invasive and unnecessary tests, such as in the current case. references 1. alfageme f, morales v, garcía c, miguelez ap, domínguez e, segurado a. transfascial muscular hernia: an unusual cause for a “hide and seek” subcutaneous nodule. dermatol online j 2011; 17:4. 2. kim m, hong sp, hwang sm, park h, ahn sk. tibialis anterior muscle herniation developed after trauma. int j dermatol 2008; 47:845–7. https://doi.org/10.1111/j.1365-4632.2008.03640.x. 3. sigüenza-sanz m, alfageme-roldán f, salgüero-fernández i, roustan-gullón g. the utility of ultrasound in the diagnosis of muscle hernias in the dermatology clinic. actas dermosifiliogr 2018; 109:842–4. https://doi.org/10.1016/j.ad.2017.11.010. 4. razek aa, al mahdy al belasy f, ahmed wm, haggag ma. assessment of articular disc displacement of temporomandi bular joint with ultrasound. j ultrasound 2015; 18:159–63. https://doi.org/10.1007/s40477-014-0133-2. 5. çarli ab, turgut h, bozkurt y. choosing the right imaging method in muscle hernias: musculoskeletal ultrasonography. j sports sci 2015; 33:1919–21. https://doi.org/10.1080/02640414.201 5.1017735. https://doi.org/10.1111/j.1365-4632.2008.03640.x https://doi.org/10.1016/j.ad.2017.11.010 https://doi.org/10.1007/s40477-014-0133-2 https://doi.org/10.1080/02640414.2015.1017735 https://doi.org/10.1080/02640414.2015.1017735 تأثري تغري وضعية اجلسد على قياس التنفس عند مرضى متالزمة انقطاع النفس االنسدادي النومي ر�صا اللواتي، حممد عبداهلل العربي، بالجي كوبو�صوامي، اأمرية اخلرو�صية، اليقظان العتبي، �صيد رزيف، موهان ديك�صيت abstract: objectives: obstructive sleep apnoea syndrome (osas) is a growing health concern as it is associated with serious comorbidities. osas is mainly related to obesity, age, gender and a narrowed upper airway is commonly seen in patients with osas. this study aimed to compare spirometry parameters between obese osas patients and non-obese osas patients when patients moved from sitting to supine. methods: this cross-sectional study was conducted at sultan qaboos university hospital, muscat, oman, between december 2009 and december 2010. patients with severe osas and who were osas treatment naïve were recruited. spirometry was performed in all patients in sitting and supine positions to assess forced vital capacity (fvc), forced expiratory volume in the first second (fev1), fev1/fvc, forced expiratory flow (fef) 50%, fef 25–75%, maximum forced inspiratory flow and expiratory reserve volume. the mean difference in spirometry parameters between patients in sitting and supine positions was calculated. results: a total of 27 osas patients (19 males and 8 females) were included in this study. there was a significant difference in fev1/fvc in obese and non-obese patients when changing position (p = 0.03). in addition, there was a significant change between male and female patients’ fvc percentages (p <0.05). male patients with osas had reduced fvc compared to females. there was no significant difference in the remaining spirometry parameters with patients’ change of position. conclusion: a supine position may cause lower airway obstruction in obese patients with osas. the reduced fvc in males possibly contributes to the high prevalence of osas in men compared to women. keywords: obstructive sleep apnea; obesity; gender; spirometry; posture; oman. خطرية. م�صاحبة باأمرا�ض لإرتباطها املتزايدة ال�صحية امل�صاكل من النومي الن�صدادي النف�ض انقطاع متالزمة ُتعد الهدف: امللخ�ص: مر�صى عند ال�صائعة الأعرا�ض من العلوي الهوائي املجرى ت�صيق ويعد واجلن�ض، والعمر، بال�صمنة، اأ�صا�صي ب�صكل املتالزمة هذه ترتبط هذه املتالزمة. هدفت هذه الدرا�صة اإىل مقارنة معايري قيا�ض التنف�ض عند مر�صى هذه املتالزمة الذين يعانون من ال�صمنة املفرطة مبر�صى املتالزمة الذين ل يعانون من ال�صمنة املفرطة وذلك اثناء انتقال املري�ض من اجللو�ض اإىل ال�صتلقاء. الطريقة: اأجريت هذه الدرا�صة املقطعية يف م�صت�صفى جامعة ال�صلطان قابو�ض، م�صقط، �صلطنة عمان بني دي�صمرب 2009 ودي�صمرب 2010. متت درا�صة مر�صى متالزمة انقطاع النف�ض الن�صدادي النومي من النوع احلاد والذين مل يبدوؤوا العالج بعد. مت قيا�ض التنف�ض لدى جميع املر�صى يف و�صعيتي اجللو�ض وال�صتلقاء لتقييم ال�صعة احليوية الق�رسية، احلجم الزفريي الق�رسي خالل الثانية الأوىل ، احلجم الزفريي الق�رسي خالل الثانية الأوىل/ال�صعة احليوية الق�رسية، التدفق الزفريي الق�رسي %50، التدفق الزفريي الق�رسي %75–25، التدفق ال�صهيقي الق�رسي الأق�صى، واحلجم الأحتياطي الزفريي. مت ح�صاب متو�صط الفرق يف معايري قيا�ض التنف�ض عند املر�صى يف و�صعيتي اجللو�ض وال�صتلقاء. النتائج: �صملت هذه الدرا�صة ماجمموعه خالل الق�رسي الزفري حجم يف كبري اختالف هناك كان اإناث(. و8 ذكور 19( النومي الن�صدادي النف�ض انقطاع متالزمة مر�صى من 27 تغيري عند املفرطة ال�صمنة من يعانون ل والذين املفرطة ال�صمنة من يعانون الذين املر�صى بني الق�رسية احليوية الأوىل/ال�صعة الثانية الو�صعية )p = 0.03(. بالإ�صافة اإىل ذلك، كان هناك تغيري كبرييف الن�صب املئوية لل�صعة احليوية الق�رسية بني املر�صى الذكور والإناث )p >0.05(. كانت ال�صعة احليوية الق�رسية منخف�صة عند مر�صى املتالزمة الذكور مقارنة بالإناث. مل يكن هناك اختالف كبري يف بقية معايري قيا�ض التنف�ض عند تغري و�صعية املر�صى. اخلال�صة: قد يت�صبب و�صع ال�صتلقاء يف ان�صداد جمرى الهواء ال�صفلي عند مر�صى متالزمة انت�صار معدل ارتفاع يف الق�رسية احليوية ال�صعة انخفا�ض ي�صاهم املفرطة. ال�صمنة من يعانون الذين النومي الن�صدادي النف�ض انقطاع متالزمة انقطاع النف�ض الن�صدادي النومي عند الذكور مقارنة بالن�صاء. الكلمات املفتاحية: انقطاع النف�ض الن�صدادي النومي؛ ال�صمنة؛ اجلن�ض؛ معايري قيا�ض التنف�ض؛ و�صعية؛ ُعمان. the effect of change in posture on spirometry in patients with obstructive sleep apnoea syndrome redha al lawati,1 *mohammed a. al abri,2 balaji kuppuswamy,2 amira al-kharousi,2 al yaqdhan al-atbi,1 syed rizvi,3 mohan dikshit4 clinical & basic research sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e310–315, epub. 22 dec 19 submitted 24 feb 19 revision req. 27 mar 19; revision recd. 18 may 19 accepted 23 jun 19 advances in knowledge changing from a sitting to a supine position might affect the upper airway, possibly explaining the symptoms seen in patients with obstructive sleep apnoea syndrome such as snoring, snorting, apnoea episodes and early morning headaches. obesity could cause lower airway obstruction in addition to upper airway occlusion during sleep. https://doi.org/10.18295/squmj.2019.19.04.006 1oman medical specialty board, muscat, oman; departments of 2clinical physiology and 3family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 4formerly department of physiology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: malabri@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ redha al lawati, mohammed a. al abri, balaji kuppuswamy, amira al-kharousi, al yaqdhan al-atbi, syed rizvi and mohan dikshit clinical and basic research | e311 obstructive sleep apnoea syndrome (osas) is a growing health concern as it has been associated with a number of serious comorbidities particularly of the cardiovascular system.1,2 sleep apnoea is defined as the cessation of airflow for a period of 10 seconds or more (apnoea) or diminished airflow accompanied by either ≥3% oxygen desaturation or awakening from sleep.3 osas is mainly related to obesity, which is defined as a body mass index (bmi) of more than 30 kg/m2.4 as the prevalence of obesity has increased, there has been a parallel increase in the prevalence of osas.5 the pathophysiology of osas is complex and not completely understood, particularly for non-obese osas patients. a narrowed upper airway is commonly seen in patients with osas and may be attributed to other factors such as fat deposition in the neck or abnormal bony morphology of the upper airway.6 such defects may lead to functional impairment of the upper airway dilating muscles and alter airway diameter and transmural pressures. even in non-obese subjects, the upper airway’s diameter reduces in the supine posture.7 this deficit is likely to be exaggerated in patients with osas, particularly while the individual is supine due to the effect of gravity. spirometry and flow-volume loops have been used to detect the presence of airway obstruction in patients with osas.8–11 evidence suggests that overweight/obesity may also affect lung function in non-asthmatic subjects.11,12 the underlying mechanisms of these observations have not been adequately studied but it is believed to result from a complex interaction between mechanical and metabolic factors. for example, obesity affects the respiratory system by increasing the deposition of adipose tissue in the upper respiratory tract. these tissues start to produce adipokines, which are inflamm atory substances, such as interleukin (il)-1, il-6 and tumour necrosis factor-α. these inflammatory substances stimulate mucus secretion and may cause broncho spasms, leading to small airway obstructions.12 to the best of the authors’ knowledge, this is the first study to use spirometry to assess the effect of change when moving from sitting to supine in patients with osas. the majority of previous studies focused on spirometry parameters in the erect position, yet none consider changes occurring in a supine position. the hypothesis of the current study was that obese osas patients are more prone to develop lower airway obstruction compared to non-obese patients while changing position. in addition, this study examined the effect of age and gender on the degree of lower airway obstruction in osas patients while changing positions. methods this cross-sectional study was conducted at sultan qaboos university hospital (squh), muscat, oman, between december 2009 and december 2010. new patients who were over the age of 18 years and had been diagnosed with severe osas (apnoea-hypopnoea index >30) after one night of level-one polysomno graphy as per the standard criteria of the american academy of sleep medicine were included in this study.13 all patients were osas treatment naïve and were nonasthmatic, non-smokers and free of chronic obstructive pulmonary disease and other cardiopulmonary diseases. participants were not taking medication which may affect spirometry indices such as non-selective betablockers. the patients reported to the pulmonary function testing laboratory, squh, between 10:00 and 11:00 am to avoid time-related variation in spirometry parameters and had been asked to refrain from consuming caffeinated drinks on the day of the test. height and weight were measured at the time of arrival and bmi was calculated for all subjects. subjects with a bmi of 18.5–25 were considered nonobese, while those with a bmi of 25–30 were classified as overweight; obese subjects were classed as having a bmi >30.4 participants were then split into two groups: obese (bmi >30) and non-obese (bmi = 18.5–30). the spirometry device used (cpfs/d usb™ spirometer, mgc diagnostics, saint paul, minnesota, usa) measures and calculates forced expiratory volume in the first second (fev1), forced vital capacity (fvc), fev1/fvc and flow-volume curve parameters, forced expiratory flow (25–75% and at 50%; fef), maximum forced inspiratory flow (fifmax) and expiratory reserve volume (erv) percentage. the spirometer used the software breezesuite, version 8.5 (medical graphics corporation, st. paul, minnesota, usa). a three-litre calibration syringe was used to provide the calibration signal. room temperature, relative humidity and barometric pressure were entered into the spirometer prior to starting the procedure. application to patient care obese male patients with osas are at risk of having lower airway obstruction, possibly worsening their nocturnal symptoms. a change from a sitting to a supine position may cause lower airway obstruction in obese male patients with osas. the effect of change in posture on spirometry in patients with obstructive sleep apnoea syndrome e312 | squ medical journal, november 2019, volume 19, issue 4 the device reported all values at body temperature and pressure saturated with water vapour. spirometry was performed based on the standards and guidelines of the american thoracic society.14 the subjects breathed 5–6 times at tidal volume and then breathed in maximally and breathed out maximally to residual volume. the procedure was done while patients were supine and while they were sitting. a new pneumotach and nose clip were used for each patient to avoid contamination through saliva or body fluids. all participants performed the slow vital capacity (svc) and fvc manoeuvers thrice while sitting and thrice while supine. three minutes were given between each fvc trial. the best effort in each posture was included for the analysis. the data were analysed using statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa). normality of the parameters under study was checked using a kolmogorov-smirnov one sample test; if the distribution pattern was normal, then an independent samples t-test was used to evaluate the significance of the difference between the means of the two groups. if the distribution pattern was not normal, then the non-parametric mannwhitney-u test was used to determine the equality of the two groups. a p value of ≤0.05 was considered statistically significant. changes in spirometry parameters were calculated using the following formula: the mean difference in change of position from sitting and supine positions was compared based on bmi, age and gender. informed consent was obtained from all partic ipants and the study was explained. participants could withdraw from the study at any time. the study was approved by the medical research & ethics committee of the college of medicine & health sciences, squh (mrec #488). results a total of 27 osas patients were included in this study, the majority of which were male (70.4%). the mean male patient age was 40.32 ± 9.68 years, the mean male bmi was 32.11 ± 4.83 kg/m2 and the mean male apnoea/hypopnoea index was 49.01 ± 23.78. the mean female patient age was 47.63 ± 7.21 years, the mean female bmi was 37.26 ± 4.55 kg/m2 and the mean female apnoea/hypopnoea index was 53.05 ± 18.31. there was a significant difference in bmi (p = 0.02) but not age (p = 0.07) or apnoea/hypopnoea index (p = 0.67) between table 1: comparison of mean spirometry parameters between obese and non-obese obstructive sleep apnoea syndrome patients while changing from a sitting to supine position (n = 27) spirometry parameter in percentage mean ± sd p value non-obese (n = 9) obese (n = 18) fvc 6.42 ± 4.7 3.95 ± 2.85 0.100 fev1 5.87 ± 3.43 5.48 ± 2.7 0.750 fev1/fvc -0.81 ± 1.88 1.58 ± 1.72 0.030 fef 25–75% 20.54 ± 11.61 21.03 ± 9.09 0.910 fef 50% 13.35 ± 13.27 13.86 ± 11.08 0.920 fifmax 11.8 ± 24.11 5.65 ± 12.36 0.489 erv 26.79 ± 48.23 25.68 ± 49.03 0.956 sd = standard deviation; fvc = forced vital capacity; fev1 = forced expirator y volume in the first second ; fef = forced expirator y flow; fifmax = maximum forced inspiratory flow; erv = expiratory reserve volume. table 2: comparison of absolute values of spirometry parameters between obese and non-obese obstructive sleep apnoea syndrome patients in sitting and supine positions (n = 27) spirometry parameter in litre (position) mean ± sd p value non-obese (n = 9) obese (n = 18) fvc (sitting) 3.424 ± 0.817 3.187 ± 1.165 0.590 fvc (supine) 3.214 ± 0.839 3.058 ± 1.113 0.714 fev1 (sitting) 2.883 ± 0.700 2.710 ± 0.899 0.618 fev1 (supine) 2.718 ± 0.690 2.562 ± 0.855 0.640 fev1/fvc (sitting) 84.111 ± 4.755 86.222 ± 4.697 0.283 fev1/fvc in % (supine) 84.778 ± 4.755 84.833 ± 4.274 0.976 fef 25–75% (sitting) 3.361 ± 1.042 3.322 ± 1.028 0.927 fef 25–75% (supine) 2.677 ± 0.914 2.629 ± 0.882 0.897 fef 50% (sitting) 4.144 ± 1.199 4.189 ± 1.235 0.932 fef 50% (supine) 3.574 ± 1.095 3.597 ± 1.191 0.963 fifmax (sitting) 4.933 ± 1.772 4.605 ± 1.742 0.650 fifmax (supine) 4.162 ± 1.444 4.314 ± 1.544 0.807 erv (sitting) 0.664 ± 0.312 0.545 ± 0.408 0.448 erv (supine) 0.419 ± 0.251 0.359 ± 0.319 0.627 sd = standard deviation; fvc = forced vital capacity; fev1 = forced expirator y volume in the first second ; fef = forced expirator y flow; fifmax = maximum forced inspiratory flow; erv = expiratory reserve volume. mean percentage = [(sitting-supine)/sitting)*100 redha al lawati, mohammed a. al abri, balaji kuppuswamy, amira al-kharousi, al yaqdhan al-atbi, syed rizvi and mohan dikshit clinical and basic research | e313 the genders. the mean patient age was 41.82 ± 9.69 years and mean bmi was 33.68 ± 5.44 kg/m2. there was no significant difference in fvc or fev1 between non-obese and obese osas patients in sitting and supine positions or when changing posture from a sitting to a supine position. however, there was a significant difference in the change of fev1/fvc between obese and non-obese subjects (-0.81% versus 1.58%; p = 0.030). there was no significant difference table 4: comparison of mean spirometry parameters between patients less than and more than 40 years old when changing from sitting to supine position (n = 27) spirometry parameter in percentage mean ± sd p value ≤40 years (n = 11) >40 years (n = 16) fvc 5.35 ± 4.50 4.37 ± 3.09 0.504 fev1 6.44 ± 3.22 5.04 ± 2.62 0.225 fev1/fvc 1.04 ± 2.15 0.60 ± 2.09 0.600 fef 25–75% 22.02 ± 10.04 20.06 ± 9.84 0.619 fef 50% 12.94 ± 10.94 14.27 ± 12.29 0.778 fifmax 6.51 ± 12.16 8.51 ± 19.95 0.770 erv 34.90 ± 26.58 19.96 ± 58.29 0.378 sd = standard deviation; fvc = forced vital capacity; fev1 = forced expirator y volume in the first second ; fef = forced expirator y flow; fifmax = maximum forced inspiratory flow; erv = expiratory reserve volume. table 3: comparison of absolute values of spirometry parameters between patients less than and more than 40 years old when changing from sitting to supine position (n = 27) spirometry parameter in litre (position) mean ± sd p value ≤40 years (n = 11) >40 years (n = 16) fvc (sitting) 3.916 ± 0.947 2.819 ± 0.892 0.005 fvc (supine) 3.716 ± 0.965 2.694 ± 0.845 0.007 fev1 (sitting) 3.340 ± 0.710 2.374 ± 0.670 0.001 fev1 (supine) 3.133 ± 0.715 2.258 ± 0.647 0.003 fev1/fvc in % (sitting) 85.909 ± 4.437 85.250 ± 5.053 0.730 fev1/fvc in % (supine) 85.000 ± 4.450 84.688 ± 4.438 0.859 fef 25–75% (sitting) 4.065 ± 1.022 2.833 ± 0.650 0.001 fef 25–75% (supine) 3.191 ± 0.981 2.269 ± 0.564 0.005 fef 50% (sitting) 4.751 ± 1.083 3.753 ± 1.132 0.033 fef 50% (supine) 4.154 ± 1.209 3.176 ± 0.919 0.028 fifmax (sitting) 5.015 ± 1.438 4.508 ± 1.915 0.464 fifmax (supine) 4.729 ± 1.451 3.944 ± 1.466 0.182 erv (sitting) 0.805 ± 0.380 0.434 ± 0.300 0.009 erv (supine) 0.548 ± 0.350 0.263 ± 0.182 0.026 sd = standard deviation; fvc = forced vital capacity; fev1 = forced e xpirator y volume in the first second ; fef = forced e xpirator y f low; fifmax = maximum forced inspiratory flow; erv = expiratory reserve volume. table 6: comparison of mean spirometry parameters between male and female obstructive sleep apnoea synd rome patients when changing from a sitting to supine position (n = 27) spirometry parameter in percentage mean ± sd p value male (n = 19) female (n = 8) fvc 5.66 ± 3.65 2.66 ± 2.95 0.050 fev1 6.03 ± 2.93 4.61 ± 2.74 0.254 fev1/fvc 0.32 ± 2.21 1.87 ± 1.63 0.077 fef 25–75% 20.99 ± 9.78 20.553 ± 10.43 0.917 fef 50% 13.66 ± 11.07 13.79 ± 13.31 0.979 fifmax 10.66 ± 18.32 0.652 ± 11.13 0.166 erv 30.22 ± 52.31 16.14 ± 36.07 0.496 sd = standard deviation; fvc = forced vital capacity; fev1 = forced expirator y volume in the first second ; fef = forced expirator y flow; fifmax = maximum forced inspiratory flow; erv = expiratory reserve volume. table 5: comparison of absolute values of spirometry para meters between male and female obstructive sleep apnoea syndrome patients in sitting and supine positions (n = 27) spirometry parameter in litre (position) mean ± sd p value male (n = 19) female (n = 8) fvc (sitting) 3.689 ± 0.915 2.261 ± 0.562 <0.001 fvc (supine) 3.490 ± 0.918 2.209 ± 0.588 0.001 fev1 (sitting) 3.096 ± 0.724 1.988 ± 0.460 0.001 fev1 (supine) 2.915 ± 0.710 1.900 ± 0.463 0.001 fev1/fvc in % (sitting) 84.316 ± 4.820 88.375 ± 3.204 0.039 fev1/fvc in % (supine) 84.000 ± 4.333 86.750 ± 3.204 0.137 fef 25–75% (sitting) 3.585 ± 1.077 2.743 ± 0.510 0.046 fef 25–75% (supine) 2.836 ± 0.924 2.191 ± 0.562 0.080 fef 50% (sitting) 4.528 ± 1.207 3.380 ± 0.750 0.021 fef 50% (supine) 3.912 ± 1.197 2.864 ± 0.541 0.027 fifmax (sitting) 5.232 ± 1.725 3.486 ± 0.975 0.013 fifmax (supine) 4.595 ± 1.530 3.476 ± 1.080 0.073 erv (sitting) 0.733 ± 0.349 0.232 ± 0.107 <0.001 erv (supine) 0.456 ± 0.314 0.195 ± 0.119 0.004 sd = standard deviation; fvc = forced vital capacity; fev1 = forced expirator y volume in the first second ; fef = forced expirator y flow; fifmax = maximum forced inspiratory flow; erv = expiratory reserve volume. the effect of change in posture on spirometry in patients with obstructive sleep apnoea syndrome e314 | squ medical journal, november 2019, volume 19, issue 4 in the remaining parameters with change of posture or with absolute values [tables 1 and 2]. there was a significant difference between the patients who were ≤40 years old and >40 years old in all absolute values of the spirometry parameters in sitting and supine positions (p <0.05) except fev1/ fvc and fifmax (p >0.05). there was no significant difference between the two groups when changing posture in any of the spirometry parameters (p >0.05) [tables 3 and 4]. there was a significant difference between gender in all absolute values of the spirometry parameters (p <0.05) except fev1/fvc in the supine position, fef 25–75% in the supine position and fifmax in a supine position (p >0.05). there was a significant difference between male and female participants in the change of fvc while changing position from a sitting to supine (5.66 ± 3.65 versus 2.66 ± 2.95; p = 0.050). other parameters did not show any significant differences between genders with change of position [tables 5 and 6]. discussion spirometry and flow-volume loops are simple, commonly used tests in patients with respiratory diseases. this study aimed to examine the effect of a change of position on the reactivity of airways in osas patients with different risk factors such as obesity, age and gender. no significant difference was found in fev1/fvc when changing from sitting to supine positions between obese and non-obese osas patients. this finding can be attributed to a greater reduction of fvc in obese subjects. nevertheless, no significant difference was found between the two groups with absolute values of spirometry parameters in either position. this finding would support the initial assumption that obesity may predispose individuals with osas to an obstructive airway pattern when moving from a sitting to supine position. this may be due to the limited mobility of the diaphragm and chest wall when in a supine position.15 the current study contradicts hoffstein et al.’s findings that sleep apnoea is unrelated to pulmonary function measured during wakefulness.16 however, hoffstein et al. studied a larger cohort compared to the current sample size and measured the spirometry parameters in one position only while the current study examined the difference resulting from a change in position.16 in the current study, a significant difference was found in absolute values for most of the spirometry parameters in both positions when comparing osas patients who were less than or more than 40 years old. this finding may be attributed to the effect of age on lung functions. however, no significant changes were found in the mean differences of those parameters between the two groups. previous studies have indicated, that with age, all spirometry parameters decrease which could be attributed to a decrease in elastic recoil and stiffening of the chest wall.17 this decline, however, mostly occurs after the age of 60 according to medbø and melbye.18 other explanations for this finding could be that aging does not cause lower airway obstruction while changing position. further studies are required to confirm this phenomenon. an additional risk factor for osas is being male.19 in the current study there was a weak significant difference of the percentage decrease in fvc when comparing male and female patients with no significant increase in fev1/fvc. males have been found to be more prone to develop severe osas due to anatomical factors and impaired ventilatory control during sleep.19 in addition, men have a greater abdominal fat distrib ution than women, which may explain less frequent fvc and fev1.15 when comparing osas patients in different positions, significant differences were found between different factors. campbell et al. compared osas patients and patients with brief upper airway dys function (buad) with normal subjects and found no difference in flow-volume curve indices.20 however, they eliminated the confounders of obesity and age which were the main variables under comparison in the current study. nevertheless, campbell et al.’s study measured the flow-volume curve in different positions as did the current study. campbell et al.’s main aim was to predict osas and buad from changes in flowvolume curve which differs from the current study which examines the relationship between changes in spirometry parameters and changes in posture in patients with severe osas. the current study has limitations. a major limit ation is the study’s small sample size which might have affected the statistical reliability of the comparisons. additionally, osas patients were not compared with non-osas subjects. however, it is extremely difficult to find obese subjects without osas. obesity was measured in only one way and should have been measured by different means such as waist/hip ratio and neck circumference in order to determine whether the patient is truly obese. for example, patients with high muscle mass can have a high bmi but not be obese. while the current study examined the spirometry indices of patients with osas in two positions, adding a standing position in future studies would add more value to this type of examination. redha al lawati, mohammed a. al abri, balaji kuppuswamy, amira al-kharousi, al yaqdhan al-atbi, syed rizvi and mohan dikshit clinical and basic research | e315 conclusion a supine position may increase lower airway obstr uction in obese patients with osas. however, in patients with osas, age and, to a lesser extent, gender did not have a large impact on spirometry parameters while changing between sitting and supine positions. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. young t, finn l. epidemiological insights into the public health burden of sleep disordered breathing: sex differences in survival among sleep clinic patients. thorax 1998; 53:s16–19. https://doi.org/10.1136/thx.53.2008.s16. 2. kuniyoshi fh, pusalavidyasagar s, singh p, somers vk. cardiovascular consequences of obstructive sleep apnoea. indian j med res 2010; 131:196–205. 3. guilleminault c, tilkian a, dement wc. the sleep apnea syndr omes. annu rev med 1976; 27:465–84. https://doi.org/10.1146/ annurev.me.27.020176.002341. 4. guyton a, hall j. obesity. in: guyton ac, hall je, eds. text book of medical physiology. 11th ed. philadelphia: elsevier saunders, 2006. pp. 872–3. 5. tintinger gr, pretorius l, labadarios d. obstructive sleep apnoea and obesity. south afr j clin nutr 2011; 24:174–7. https://doi.org/10.1080/16070658.2011.11734384. 6. deegan pc, mcnicholas wt. pathophysiology of obstructive sleep apnoea. eur respir j 1995; 8:1161–78. https://doi.org/10.11 83/09031936.95.08071161. 7. hudgel dw. mechanisms of obstructive sleep apnea. chest 1992; 101:541–9. https://doi.org/10.1378/chest.101.2.541. 8. jan ma, marshall i, douglas nj. effect of posture on upper airway dimensions in normal human. am j respir crit care med 1994; 149:145–8. https://doi.org/10.1164/ajrccm.149.1.81 11573. 9. haponik ef, bleecker er, allen rp, smith pl, kaplan j. abnormal inspiratory flow-volume curves in patients with sleep-disordered breathing. am rev respir dis 1981; 124:571–4. 10. owens gr, murphy dm. spirometric diagnosis of upper airway obstruction. arch intern med 1983; 143:1331–4. https://doi. org/10.1001/archinte.1983.00350070047008. 11. shore et, millman rp. abnormalities in the flow-volume loop in obstructive sleep apnoea sitting and supine. thorax 1984; 39:775–9. https://doi.org/10.1136/thx.39.10.775. 12. mccoy ek, thomas jl, sowell rs, george c, finch ck, tolley ea, et al. an evaluation of peak expiratory flow monitoring: a comparison of sitting versus standing measurements. j am board fam med 2010; 23:166–70. https://doi.org/10.3122/ jabfm.2010.02.090120. 13. kapur vk, auckley dh, chowdhuri s, kuhlmann dc, mehra r, ramar k, et al. clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an american academy of sleep medicine clinical practice guideline. j clin sleep med 2017; 13:479–504. https://doi.org/10.5664/jcsm.6506. 14. aggarwal an, agarwal r. the new ats/ers guidelines for assessing the spirometric severity of restrictive lung disease differ from previous standards. respirology 2007; 12:759–62. https://doi.org/10.1111/j.1440-1843.2007.01117.x. 15. melo lc, silva ma, calles ac. obesity and lung function: a systematic review. einstein (sao paulo) 2014; 12:120–5. https://doi.org/10.1590/s1679-45082014rw2691. 16. hoffstein v, oliver z. pulmonary function and sleep apnea. sleep breath 2003; 7:159–65. https://doi.org/10.1007/s11325003-0159-8. 17. hassel e, stensvold d, halvorsen t, wisløff u, langhammer a, steinshamn s. association between pulmonary function and peak oxygen uptake in elderly: the generation 100 study. respir res 2015; 16:156. https://doi.org/10.1186/s12931-015-0317-0. 18. medbø a, melbye h. lung function testing in the elderly--can we still use fev1/fvc<70% as a criterion of copd? respir med 2007; 101:1097–105. https://doi.org/10.1016/j.rmed.2006.11.019. 19. joosten sa, khoo jk, edwards ba, landry sa, naughton mt, dixon jb, et al. improvement in obstructive sleep apnea with weight loss is dependent on body position during sleep. sleep 2017; 40. https://doi.org/10.1093/sleep/zsx047. 20. campbell ah, guy pa, rochford pd, worsnop cj, pierce rj. flow-volume curve changes in patients with obstructive sleep apnoea and brief upper airway dysfunction. respirology 2000; 5:11–18. https://doi.org/10.1046/j.1440-1843.2000.00220.x. https://doi.org/10.1136/thx.53.2008.s16 https://doi.org/10.1146/annurev.me.27.020176.002341 https://doi.org/10.1146/annurev.me.27.020176.002341 https://doi.org/10.1080/16070658.2011.11734384 https://doi.org/10.1183/09031936.95.08071161 https://doi.org/10.1183/09031936.95.08071161 https://doi.org/10.1378/chest.101.2.541 https://doi.org/10.1164/ajrccm.149.1.8111573 https://doi.org/10.1164/ajrccm.149.1.8111573 https://doi.org/10.1001/archinte.1983.00350070047008 https://doi.org/10.1001/archinte.1983.00350070047008 https://doi.org/10.1136/thx.39.10.775 https://doi.org/10.3122/jabfm.2010.02.090120 https://doi.org/10.3122/jabfm.2010.02.090120 https://doi.org/10.5664/jcsm.6506 https://doi.org/10.1111/j.1440-1843.2007.01117.x https://doi.org/10.1590/s1679-45082014rw2691 https://doi.org/10.1007/s11325-003-0159-8 https://doi.org/10.1007/s11325-003-0159-8 https://doi.org/10.1186/s12931-015-0317-0 https://doi.org/10.1016/j.rmed.2006.11.019 https://doi.org/10.1093/sleep/zsx047 https://doi.org/10.1046/j.1440-1843.2000.00220.x departments of 1obstetrics & gynaecology and 2anesthesiology & critical care, jawaharlal institute of postgraduate medical education and research, puducherry, india *corresponding author’s e-mail: dr.niveditajha@gmail.com a rare type of uterine rupture following over-the-counter use of misoprostol in second trimester abortion *nivedita jha,1 haritha sagili,1 jyotsna sharma,1 ajay k. jha2 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 657–659, epub. 25 nov 21 submitted 25 sep 20 revision req. 10 nov 20; revision recd. 15 nov 20 accepted 8 dec 20 and curettage to treat heavy vaginal bleeding one day prior to presentation at the hospital. her vaginal bleeding did not subside and she could have developed iatrogenic uterine perforation after dilatation and curettage. at admission, she was drowsy, extremely pale and afebrile. her vitals included a pulse rate of 130/min, systemic blood pressure of 90/60 mmhg and respiratory rate of 28 breaths per minute. the remaining cardiovascular, respiratory and central nervous system findings were unremarkable. abdominal examination revealed a diffuse tenderness and a well retracted uterus deviated towards the rightside of the abdomen. during speculum examination, a continuous fresh blood trickling was noted along with cervical tears at the 2 o’clock and 6 o’clock positions extending until the posterior fornix. furthermore, the cervix appeared uneffaced and os patulous. both fornices were boggy and tender; a transverse rent was noted in the posterior fornix through which the posterior wall of the uterus was felt. a bedside pelvic ultrasound scan revealed a post-abortal uterus with an empty cavity and a moderate amount of free fluid in the abdomen. resuscitation was performed under guided haemodynamic monitoring and an immediate exploratory laparotomy was planned under general anaesthesia. intraoperatively, 500ml of haemoperitoneum was noted with large clots in the pelvic cavity. there was a full-length scar rupture with the rent extending posteriorly. the posterior aspect of the uterus was avulsed completely above the level of the internal os and termination of pregnancy in the first and second trimesters in patients with prior uterine scarring is challenging.1 misoprostol is a commonly used drug for induction of abortion even in unsupervised clinical settings.2 however, its dosing regimen has remained controversial.3,4 over-the-counter use of misoprostol has resulted in documented or undocumented incidents of varying grades of uterine rupture. uterine rupture is a surgical emergency that requires immediate care to avoid life-threatening medical, surgical and psychological consequences.4 in the current case, a patient with a previous caesarean scar experienced a unique type of uterine rupture which developed after over-thecounter use of misoprostol to induce second trimester abortion. case report a 24-year-old g3p1l1a1 (pregnant woman who had had a full-term delivery and one abortion and also had one living child) presented at the emergency department of a tertiary care hospital in puducherry, india, in 2020 with haemorrhagic shock. she had taken an unknown dosage of misoprostol (unsupervised) to induce abortion at the 16th week of gestation. she had undergone a caesarean delivery two years before the current pregnancy. she self-administered an unknown dosage of misoprostol through the vaginal route at four-hour intervals. she noticed expulsion of the products of conception after two hours of the last dose of misoprostol. a local physician performed dilatation this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.050 case report abstract: the use of misoprostol in the second trimester by a woman with a uterine scar may lead to severe contractions and uterine rupture. we report a 24-year-old pregnant female patient who presented at the emergency department at a tertiary care hospital in puducherry, india, in 2020 with haemorrhagic shock. she was at 16 weeks of gestation and had taken over the counter misoprostol for inducing an abortion. a quick initial resuscitation and urgent laparotomy were performed. an irreparable circumferentially avulsed uterus suspended only by round ligaments was noted. haemostasis required internal artery ligation and immediate total hysterectomy. the patient was doing well upon follow-up six months after the surgery. proper and supervised use of misoprostol in the appropriate dosage can avoid life-threatening consequences of uterine rupture. keywords: uterine rupture; misoprostol; induced abortion; hysterectomy; case report; india. a rare type of uterine rupture following over-the-counter use of misoprostol in second trimester abortion 658 | squ medical journal, november 2021, volume 21, issue 4 it was suspended only by the round ligament bilaterally; it appeared like a bucket handle tear [figure 1]. the patient remained haemodynamically unstable and circumferential rent repair did not seem possible. there was a broad ligament haematoma of 5 × 5 cm on the left-side. the left uterine artery appeared avulsed and could not be traced. bladder integrity was normal and there was no evidence of haematuria. total abdominal hysterectomy along with left internal artery ligation was performed to achieve haemostasis. the patient was successfully resuscitated and extubated inside the operation theatre. her postoperative investigations were unremarkable. the patient’s clinical condition improved completely and she was discharged from the hospital on the seventh postoperative day. the patient was doing well when she was last contacted nearly six months after her surgery. the patient provided written informed consent for publication of the anonymised data during her first follow-up. discussion an unknown dose of misoprostol followed by dilatation and curettage in a previously scarred uterus could have led to uterine rupture in the current patient. uterine rupture is primarily a clinical diagnosis, and hence, prompt surgical management is critical. risk factors for uterine rupture include a previous uterine scar, short interpregnancy interval, multiparity, uterotonic drugs and obstructed labour.5 additionally, the incidence of uterine rupture has been noted to be higher in scarred compared to unscarred uteri (0.28% versus 0.04%).1 a patient’s survival after uterine rupture depends on the time interval between the rupture and the intervention and urgent referral to a tertiary care centre. rent repair is the key to treatment and internal iliac artery ligation is a lifesaving procedure in cases of uncontrolled obstetric haemorrhage. however, hysterectomy should not be delayed if the bleeding is intractable or the uterine rupture is irreparable. second trimester pregnancy termination using misoprostol in an appropriate dosage in supervised settings for women with cesarean scar is safe and it has been associated with uterine rupture in only 0.3–0.4% of cases.1,6,7 a retrospective report did not observe uterine rupture after misoprostol induction for the termination of second trimester pregnancy in a scarred uterus.8 in the current patient, a characteristic bucket handle type uterine rupture was noted as was also reported by abubekar et al.9 an unyielding cervix with misoprostol-induced strong uterine contractions in a scarred uterus may predispose to this type of uterine rupture.10 in addition, unsupervised vigorous dilatation and curettage could have either led to iatrogenic uterine perforation or further aggravated the tear induced by misoprostol. conclusion unsupervised over-the-counter use of misoprostol in a scarred uterus to induce second trimester abortion can have catastrophic consequences. dilatation and curettage should be avoided before ruling out uterine rupture. an early referral to a higher centre may prevent severe maternal morbidity and mortality. a u t h o r s’ c o n t r i b u t i o n nj, hs, js and akj conceptualised and designed the work as well as extracted the data. nj, js and akj interpreted the results. js performed the statistical figure 1: photographs of the uterus of a 24-year-old female patient following over-the-counter use of misoprostol for abortion induction. a: anterior view of the uterus circumferentially avulsed at the level of the internal os. b: lateral view showing the avulsed uterus. c: avulsed uterus suspended only through round ligaments. nivedita jha, haritha sagili, jyotsna sharma and ajay k. jha case report | 659 analysis. all authors contributed to the drafting and approved the final version of the manuscript. references 1. goyal v. uterine rupture in second-trimester misoprostolinduced abortion after cesarean delivery: a systematic review. obstet gynecol 2009; 113:1117–23. https://doi.org/10.1097/ aog.0b013e31819dbfe2. 2. varras m, akrivis ch. misoprostol for second trimester abortion in women with prior uterine incisions. clin exp obstet gynecol 2010; 37:10–12. 3. borgatta l, kapp n; society of family planning. clinical guidelines. labor induction abortion in the second trimester. contraception 2011; 84:4–18. https://doi.org/10.1016/j.contrac eption.2011.02.005. 4. datta s, minocha s. how much misoprostol is safe? first reported case of second trimester uterine rupture after a single low dose. j obstet gynaecol 2016; 36:549–51. https://doi.org/1 0.3109/01443615.2015.1072808. 5. murphy dj. uterine rupture. curr opin obstet gynecol 2006; 18:135–40. https://doi.org/10.1097/01.gco.0000192989.45589.57. 6. berghella v, airoldi j, o'neill am, einhorn k, hoffman m. misoprostol for second trimester pregnancy termination in women with prior caesarean: a systematic review. bjog 2009; 116:1151–7. https://doi.org/10.1111/j.1471-0528.2009.02190.x. 7. daskalakis gj, mesogitis sa, papantoniou ne, moulopoulos gg, papapanagiotou aa, antsaklis aj. misoprostol for second trimester pregnancy termination in women with prior caesarean section. bjog 2005; 112:97–9. https://doi. org/10.1111/j.1471-0528.2004.00285.x. 8. fawzy m, abdel-hady el-s. midtrimester abortion using vaginal misoprostol for women with three or more prior cesarean deliveries. int j gynaecol obstet 2010; 110:50–2. https://doi.org/10.1016/j.ijgo.2010.02.008. 9. abubeker fa, fessehaye a, feyssa md, prager s. bucket-handle uterine rupture during second-trimester medication abortion, a rare form of rupture of the lower uterine segment and vaginal fornix: a case report. contracept x 2020; 2:100025. https://doi. org/10.1016/j.conx.2020.100025. 10. nayki u, taner ce, mizrak t, nayki c, derin g. uterine rupture during second trimester abortion with misoprostol. fetal diagn ther 2005; 20:469–71. https://doi.org/10.1159/000087115. clinical & basic research squ med j, february 2011, vol. 11, iss. 1, pp. 83-94, epub. 12th feb 11 submitted 19th jun 10 revision req. 27th sept 10, revisions recd. 1st nov 10 accepted 7th nov 10 1department of biochemistry, college of medicine and health sciences, sultan qaboos university, muscat, oman; 2department of biochemistry, sultan qaboos university hospital, muscat, oman. *corresponding author email: yaj@squ.edu.om (in silico)<téá€fle<ün~j÷]<l^√fi^⁄<çë^jfèe<‹è€íi <viia<ün~j÷]<ÿ⁄^¬<çï<< منال العامري٬ خالد الرصادي٬ رياض بيومي٬ ياجنافالكا بانيرجي    viiain silicoin silico proline bracket  –tco�ee viiaviia viia viia     in silicoviia:مفتاح الكلمات abstract: objectives: the coagulation cascade initiated during vascular injury prevents bleeding. unwanted clot formation is however detrimental and requires the use of anticoagulants for prophylaxis and treatment. anticoagulants targeting a specific step or an enzyme in the clotting process are most preferred as they minimise disadvantageous side-effects. a principal step in the discovery of novel anticoagulants encompasses the in silico design of potential leads. this study depicts the in silico design of peptide anticoagulants targeting coagulation factor viia. methods: applying the proline bracket rule and using various bioinformatics tools: the basic alignment search tool (blast) of national center for biotechnology information; the t-coffee module provided by european molecular biology laboratory-european bioinformatics institute, and several modules available on the expasy server, we designed five bivalent chimeric anticoagulants targeting factor viia, using factor viia inhibitors – hemextin a from hemachatus haemachatus (african ringhals cobra) venom and factor viia exosite-inhibitor peptide as templates. six peptides were derived from hemextin a, which were concomitantly fused with factor viia exosite-inhibitor peptide intermediated by a polyalanine spacer, and analysed for structural stability using the swiss-model software developed at the swiss institute of bioinformatics and weblab viewerpro (version 4.2). results: twelve chimeric peptides were obtained; only five exhibited stable structures in silico. conclusion: the five peptides obtained are probable anticoagulant leads that should be further evaluated using suitable in vitro and in vivo assays. further, this study shows how simple web-based modules can be used for the rational design of probable leads targeting specific physiological molecular targets. keywords: anticoagulant; factor viia; in silico drug design in silico design of novel anticoagulant peptides targeting blood coagulation factor viia manal s q al-amri,1 khalid alrasadi,2 riad bayoumi,1 *yajnavalka banerjee1 clinical & basic research advances in knowledge 1. five potential bivalent chimeric peptide inhibitors of coagulation factor viia have been designed, which should be assessed using in vitro and in vivo assays. in silico design of novel anticoagulant peptides targeting blood coagulation factor viia 84 | squ medical journal, february 2011, volume 11, issue 1 blood coagulation is a physiological response to vascular injury in which zymogens of serine proteases present in the plasma milieu are sequentially activated culminating in the formation of the fibrin clot.1-3 coagulation factor viia (fviia), along with cofactor tissue-factor (tf), act as the prima ballerinas to initiate the coagulation cascade.4-6 the extrinsic pathway is responsible for initiating the clotting process whereas the intrinsic pathway propagates the process of coagulation. a comprehensive description of both these pathways is summarised in figure 1. although coagulation reactions are pivotal for appropriate homeostasis, unwanted clot formation can mediate debilitating affects leading to thrombosis and associated disorders. anticoagulants are pivotal for the prevention and treatment of thromboembolic disorders, and ~0.7% of the western population receives oral anticoagulant treatment.7 coumarins and heparin are the most well known clinically used anticoagulants. coumarins inhibit the activity of all vitamin k-dependent proteins, including procoagulants (thrombin, fxa, fixa, and fviia) and anticoagulants (activated protein c and protein s). heparin mediates its anticoagulant activity by enhancing the inhibition of thrombin and fxa by antithrombin iii.8,9 the non-specific mode of action of these anticoagulants accounts for their therapeutic limitations in maintaining a balance between thrombosis and haemostasis. these limitations have provided the impetus for the development of new anticoagulants that target specific coagulation enzymes or a particular step in the clotting process.10,11 because of its relatively low concentrations in blood (10 nm) and its pivotal role in the initiation of the coagulation reactions,12 fvii/fviia is an attractive drug target for the development of novel and specific anticoagulant agents. so far, only two proteins that specifically inhibit the tf-fviia complex have been evaluated in clinical trials, viz. tissue factor pathway inhibitor (tfpi) and nematode anticoagulant peptide c2 (napc2). tfpi is an endogenous inhibitor of this complex, whereas napc2 is an exogenous inhibitor isolated from canine hookworm (ancylostoma caninum).13-15 of these, only napc2 has future viability as a probable anticoagulant lead. in a phase ii study, napc2 showed promise in preventing venous thromboembolism after elective knee replacement surgery.16,17 because of the lack of natural inhibitors that specifically interfere with fviia activity, a number of artificial inhibitors have been designed and developed. they include proteins that block the association of tf and fviia, such as antibodies against tf and fviia, tfaa (a tf mutant with reduced cofactor function for fx), ffr-viia (inactivated form of fviia with 5-fold higher affinity for tf compared with native fviia), and peptides derived from tf and fviia.18-22 in addition, two series of peptide exosite inhibitors were selected from phage display libraries for their ability to bind to the tf-fviia complex.18,19 they bind to two distinct exosites on the serine protease domain of fviia and exhibit steric and allosteric inhibition.21although both peptide classes are potent and selective inhibitors of the tf-fviia complex, they fail to inhibit 100% activity even at saturating concentrations. this is overcome either by the fusion of the two peptides,22 or by using a protease switch with substrate phage.20 a number of synthetic compounds have also been designed as active-site inhibitors of fviia as well as the tffviia complex.23,24 a number of naphthylamidines have recently been reported to have fviia inhibitory activity. they were synthesised by the coupling of amidinobenzaldehyde analogs to a polystyrene resin. however, apart from inhibiting fviia activity, these synthetic compounds nonspecifically inhibit the activity of other blood coagulation serine proteases.25 in the past, we reported the identification and 2. depiction of a scheme to design rationally peptide based drugs using simple web-based software tools application to patient care 1. the designed peptides, if viable in clinical trials, will provide the clinical community with an arsenal of anticoagulants targeting clot initiation thereby helping in the treatment and prophylaxis of thromboembolic and associated disorders. 2. the study has translational significance since it provides a simple and viable strategy to design peptide based drugs targeting different diseases/disorders. manal s q al-amri, khalid alrasadi, riad bayoumi and yajnavalka banerjee clinical and basic research | 85 in-depth characterisation of a novel fviia inhibitor, christened hemextin ab complex, from the venom of the african ringhals cobra.26-29 this synergistic anticoagulant complex consists of two proteins, hemextin a (ha) and hemextin b (hb), both of which belong to the three-finger family of snake venom proteins [figure 2]. of the two subunits, ha individually possesses anticoagulant activity whereas hb is inactive. unlike napc2, ha of hemextin ab complex does not use coagulation factor xa as a scaffold for fviia inhibitory activity positing a very unusual mechanism of anticoagulation.29 thus ha provides us with a novel and intriguing anticoagulant lead that can be further developed into an anticoagulant. in this study, we report the design of a short chimeric anticoagulant mimetic (with probable fviia inhibitory function) using peptides derived from ha (by applying the proline bracket rule) and fusing them with an already characterised peptide fviia-exosite inhibitor,20 using simple webbased bioinformatics. only five of the 12 designed peptides exhibited structural stability and warrant assessment with regards to anticoagulant activity. this study therefore not only provided a foundation in the quest for the rational design of anticoagulants figure 1: the current model of the blood coagulation cascade. there are two blood coagulation pathways, the contact activation or “intrinsic” pathway and the primary or “extrinsic” pathway. these multicomponent processes are illustrated as enzymes, inhibitors, zymogens, or complexes. the contact activation pathway has no known bleeding cause associated with it; thus, this pathway is considered accessory to haemostasis. on injury to the vessel wall, tissue factor, the cofactor for the extrinsic tenase complex, is exposed to circulating fviia and forms the extrinsic tenase. fix and fx are converted to their serine proteases fixa and fxa, which then form the intrinsic tenase and the prothrombinase complexes with their cofactors, respectively. the combined actions of the intrinsic and extrinsic tenase and the prothrombinase complexes lead to an explosive burst of the key enzyme thrombin (iia). in addition to its multiple procoagulant roles, thrombin also can act in an anticoagulant capacity when combined with the cofactor thrombomodulin in the protein case complex. the product of the protein case reaction, activated protein c (apc), inactivates the cofactors fva (cofactor for fxa) and fviiia (cofactor for fixa). the cleaved species, fvai and fviiiai, no longer support the respective procoagulant activities. once thrombin is generated through procoagulant mechanisms, thrombin cleaves fibrinogen (releasing fibrinopeptides a and b [fpa and fpb]) and activates fxiii to form a cross-linked fibrin clot. thrombin–thrombomodulin also activates a thrombin activate-able fibrinolysis inhibitor that slows fibrin degradation by plasmin. the procoagulant response is downregulated at various stages by the stoichiometric inhibitors, tissue factor pathway inhibitor (tfpi) and antithrombin iii (at-iii). tfpi serves to attenuate the activity of the extrinsic tenase trigger of coagulation. at-iii directly inhibits thrombin, fixa, and fxa. the accessory pathway provides an alternate route for the generation of fixa. thrombin has also been shown to activate fxi. the fibrin clot is eventually degraded by plasmin yielding soluble fibrin peptides. in silico design of novel anticoagulant peptides targeting blood coagulation factor viia 86 | squ medical journal, february 2011, volume 11, issue 1 specifically targeting fviia, but also depicted a scheme that can be utilised in the rational design of drug leads using web-based bioinformatics. methods the complete sequence of ha protein had been determined earlier using edman degradation protein chemistry, and is depicted below (using the single letter amino acid code): l kc h n k lv pf l s k t c p e g k n l c y k m t m l k m p k i p i k r g c t d a c p k s s l lv k v v c c n k d k c n . the sequence of the 26-mer fviia-exosite inhibitor peptide was obtained from the literature,22 and is as follows: eewevlcwtwetcergegveelwewr. the various software employed in this study are freely available on the internet and do not require special access to any paid database or server. most of these modules are windows based, however some operate at an optimum on a linux platform. sequence alignment involving ha involved a detailed search of homologous sequences from the national center for biotechnology information protein database,30,31following which the basic alignment search tool (blast)32-34 was employed. the sequence alignment of ha was carried out by looking at the position of the cys residues using the online t-coffee module provided by the european molecular biology laboratoryeuropean bioinformatics institute.35 in order to look at the various specifics of the amino acid sequence, appropriate modules available on the expasy server were used.36 in order to model figure 2: analysis of primary structure of ha. 1) comparison of amino acid sequence of hemextin a with other sequences of the three-finger toxin family. the conserved cysteine residues are indicated in black. the four conserved disulfide linkages and the segments contributing to the three loops are outlined. comparison were made with the following sequences: cytotoxin 1, cytotoxin 2, toxin 9b, weak toxin cm-1b, weak toxin cm-1c, toxin ii, toxin iv are from hemachatus haemachatus (african ringhals cobra); carditoxin γ from naja nigricollis (black spitting cobra); carditoxin a3 from naja atra (taiwan cobra); fasciculin from dendroaspis angusticeps; mambin from dendroaspis jamesoni; calciseptin from dendrosaspis polylepsis; muscarinic toxin 2 from d. angusticeps; erabutoxin b from laticauda semifasciata. 2) three-dimensional structural similarity among three-finger toxins from snake venoms a) erabutoxin a (1qkd); b) α-bungarotoxin (2abx); c) cardiotoxin v4 (1cdt); d) κ-bungarotoxin (1kba); e) candoxin (1jgk); f) fasciculin 2 (1fas); g) muscarinic toxin mt-2 (1ff4; r menez et al., pers. comm., 2002); (h) fs2 toxin (1tfs). note all these ‘sibling’ toxins share a similar structural fold; three β-sheeted ‘fingers’ start from the core. these β-sheeted loops are numbered right to left as loop i, ii and iii, respectively. however, these toxins differ from each other in their biological activities. manal s q al-amri, khalid alrasadi, riad bayoumi and yajnavalka banerjee clinical and basic research | 87 the three-dimensional structures of the ha and chimeric peptides, the sequences of the proteins were submitted to the swiss-model developed by the protein structure bioinformatics group at the swiss institute of bioinformatics (sib) and the biozentrum at the university of basel.37 the raw data obtained were then analysed using the weblab viewerpro (version 4.2) (accelrys, inc. san diego, ca, usa). the surface charge distribution of the modeled as well solved structures obtained from the protein data bank were analysed using the molecular graphics laboratory tools (mglt) package obtained from the scripps research institute (tsri) molecular modeling server (tsri, la jolla, ca, usa) the python molecular viewer (pmv) of the mglt package was used predominantly in this study.38,39 results our finding on the alignment of ha, was that ha belongs to the three-finger family of snake venom proteins [figure 2a] and not to the family of snake venom serine protease inhibitors which are kunitz type inhibitors with a very different cys bonding pattern. proteins belonging to this group exhibit a characteristic β-sheet structure [figure 2b]. in order to design short peptides rationally from ha, we used the proline bracket rule.40,41 in this rule, unique physicochemical properties of proline, the most commonly found imino acid in proteins, are used for the prediction of active sites. the distinct properties of proline residues are due to the bulky pyrrolidine ring and the lack of protons important for hydrogen bond formation in the α-helix and β sheet. proline residues are the common structural elements found in the flanking segments of protein-protein interaction sites and they enhance the protein-protein interactions. the proline residues most likely reduce the number of possible conformations due to their ability to constrain the conformation of the neighbouring residues. the short segments of 3-7 residues flanked by proline residues have been identified as the potential protein-protein interaction sites directly from the amino acid sequence of the protein. a case in point is that incorporation of proline residues on either or both sides of the interaction site of an antiplatelet peptide (peptide that prevents platelet aggregation), iargdmna, enhances the antiplatelet activity to approximately the same extent (1.5to 2.5-fold). the incorporation of proline residues on both sides enhances the activity by 7to 13-fold. this enhancement of the biological activity of the peptide is probably due to a reduction in the number of possible conformations of the peptide, without introducing the rigidity that would accompany cyclization.40 therefore we hypothesised that proline residues will be present on the flanking regions of the probable interaction/ active sites. based on this premise, we designed the six short peptides from ha [figure 3]. we also kept two amino residues beside each proline residue on each side to provide structural stability to the figure 3: peptides derived from ha. six short peptides were derived from ha using the proline bracket rule. we kept two amino acids on the flanking region of each proline residue in order to provide structural stability to the peptide. in silico design of novel anticoagulant peptides targeting blood coagulation factor viia 88 | squ medical journal, february 2011, volume 11, issue 1 designed peptide. for the modelling of the ha 3d-structure, the sequence alignment showed that ha has conserved cys residues with other members of the threefinger toxin (3-ftx) family, which indicated that ha is a 3-ftx. earlier studies involving circular dichroism spectroscopy also have supported this finding.26 in order to confirm further that ha has a similar architecture to three-finger proteins, we modelled the ha. as observed in figure 4 a, it has a characteristic fold of a three-finger toxin, with anti-parallel β-sheets. further, we mapped the surface charge distribution of ha using pymol molecular viewer (pmv) [figure 4b]. ha shows a predominance of blue or positively charged patches, from which it can be concluded that ha is a basic protein and therefore will have a higher propensity of binding to negatively charged regions on its corresponding target molecule. this observation was further confirmed by the calculating the theoretical pi for ha, which was found to be 9.34, confirming that the protein is of basic nature. in order to predict the binding sites of ha on fviia, the structure of fviia was modelled using the x-ray crystallographic structure of tf-fviia as a template (pdb id 1dan).42 as shown in figure 5, fviia consists of two chains, the heavy and the light chains. the heavy chain consists of the protease domain of the enzyme, whereas the light chain consists of two epidermal growth-factor-like domains and a γ-carboxyglutamic acid domain. ha does not bind to the light chain of fviia (data not shown) and therefore its binding site is located on the heavy chain. the heavy chain of fviia consists of a patch of negatively charged residues (highlighted in yellow in figure 5) and ha, being predominantly basic in nature, will have its binding/interaction site localised to this acidic patch. therefore, peptides derived from ha are supposedly going to bind to this acidic or negatively charged patch on fviia. as to the design of chimeric peptides, since peptides derived from ha will bind to the acidic patch on the fviia molecule, we fused these ha derived peptides with another peptide that binds to the basic patch on the heavy chain. this peptide has already been characterised with regards to the structure-function details of the peptide.20,21 the binding site of the peptide on the fviia heavy chain is shown in figure 6 a and was determined using x-ray crystallography (pdb id 1jbu). the peptide is inherently highly acidic in nature and binds to a predominantly positively charged region on the fviia heavy chain, as shown in the surface potential plot in figure 6 b. ha derived peptides were fused with this fviia exosite-inhibitory peptide. a spacer consisting of polyalanine residues was introduced between the ha derived and fviia exosite-inhibitory peptides in order to maintain figure 4: modeled three dimensional structure of ha. a) the ribbon representation of the three-dimensional structure of ha (red). the amino acid residues are represented in line model with their corresponding one letter code. note: ha exhibits a characteristic three-finger structure and is predominantly β-sheeted like other members of the three-finger family(figure 2b). b) surface potential calculation of ha using pymol molecular viewer. ha is predominantly basic as revealed by the scale on top of the figure (blue represents positively charged patches where as red represents negatively charged patches). manal s q al-amri, khalid alrasadi, riad bayoumi and yajnavalka banerjee clinical and basic research | 89 the distance between the acidic and the basic patches. the designed chimeric peptides are shown in table 1. the structural stability of the chimeras was assessed by modelling their structure in a way similar to that used for ha. only five of the 12 chimeric proteins were found to be structurally stable [figure 7a-e], whereas the 3d-structure modelling of the other peptides failed, thus indicating their structural instability. discussion in the present study, we designed bivalent anticoagulant peptides targeting coagulation fviia, the clotting factor responsible for the initiation of the clotting reactions, employing simple web-based bioinformatics. for our study, we used two different proteins as templates: ha, a fviia inhibitor isolated and characterised from the venom of hemachatus haemachatus (african ringhals cobra), and factor viia exosite-inhibitor peptide which is a synthetic peptide identified in phage-display libraries. the complete sequence alignment of ha revealed that it belongs to the three-finger family of snake venom proteins. this family of proteins is found only in the venoms of elapids (cobras, kraits and mambas) and hydrophids (sea snakes) and not those of vipers and crotalids (rattlesnakes). they contain four or five disulphide bridges, of which four are conserved in all members. accordingly, all proteins of this family show a similar pattern of protein folding: three β-stranded loops extending from a central core containing the four conserved disulphide bridges [figure 2]. despite the overall similarity in structure, these polypeptides differ from each other in their biological activities. however, because of their well folded and compact structure, proteins belonging to this family are attractive as drug leads (if the parent protein is pharmacologically active) or are used as molecular scaffolds in the peptide based drug design.43 for our study one of the principal reasons for choosing ha was its well-folded and compact structure. the idea of designing a bivalent inhibitor for a coagulation serine protease was first successfully implemented in case of thrombin, where two peptides acetyl-(d)f-p-r-p-q-s-hn-d-g-d-f-e-e-i-p-e-e-y-l-q (binding to the catalytic active site) and (d)f-p-r-p-g-g-g-g-ng-d-f-e-e-i-p-e-e-y-l (binding to the exosite of thrombin) were covalently linked, and the resultant peptide mimicked the activity of hirudin and had higher inhibitory potency than the individual figure 5: modeled three dimensional structure of fviia. fviia consists of heavy and light chains. the model was obtained from the solved structure of the tf-fviia complex (pdb id 1dan). the negatively charged cluster on the fviia molecule localized on the heavy chain is highlighted in yellow. in silico design of novel anticoagulant peptides targeting blood coagulation factor viia 90 | squ medical journal, february 2011, volume 11, issue 1 peptides.44 some bivalent peptides, although having weak binding properties, have been derived from the activation sequences of thrombin-activated receptors, also referred to as protease-activated receptors (pars). these peptides carry the ldpr sequence and binding motifs targeting the fibrinogen-recognition exosite of thrombin.45,46 the essence of designing such inhibitors is to use peptides which are structurally stable and do not have overlapping binding sites. in our study, we targeted coagulation fviia, since this serine protease is responsible for the initiation of the clotting cascade. therefore, inhibiting the activity of this protein will inhibit the cascade in its initial stages. also the levels of this protein in blood is low in comparison to some of the other coagulation serine proteases, necessitating the use of low levels of the designed anticoagulant, a key factor involved in the success of any drug. based on the surface charge calculations [figure 4 b], it is pertinent that ha is a basic protein and therefore peptides derived from it will bind to predominantly negatively charged regions on its target molecule. also, previous studies have shown that ha is a specific inhibitor of fviia.29 based on this premise we identified the regions of fviia which have a high density of negatively charged clusters. such clusters exist in both the heavy and light chains of the fviia molecule. however, these clusters in the light chain are not accessible to ha since they are involved in co-factor (tf binding) as revealed in the crystallographic structure solved by banner et al.42 and later confirmed by us (data not shown). therefore, we localised the negatively charged cluster on the heavy chain of the protein using the solved structure of tf--fviia (pdb id 1dan) as the model [figure 5, highlighted in yellow]. in order to derive peptides from ha we used the proline bracket rule [figure 3] (see above with regards to the details). in our next step, we needed to select an fviia-inhibitory peptide whose binding site will not overlap with ha derived peptides. after a literature search we found a peptide ( e e w e v l c w t w e tc e r g e g v e e lw e w r ) which is predominantly negatively charged (pi = 3.98) as the ideal candidate to be used for the design of the chimera. firstly, because of its inherent acidic nature, it will be involved in binding to a patch of residues which are positively charged and secondly [figure 6 a and b], the presence of a disulfide bond in the peptide guarantees its having a well defined fold. since ha derived peptides are positively charged and might interact with the fviia-inhibitory peptide, we introduced a spacer of nine alanine residues in between them. the designed chimeras were then assessed for structural stability using the appropriate tools mentioned in the methods section. only five of the designed 12 chimeras were found to be structurally viable figure 6: binding site of the fviia-inhibitory peptide on fviia molecule. a) the ribbon representation of the fviia heavy chain molecule (blue) in complex with the fviia-inhibitory peptide (green) b) surface charge distribution of the heavy chain and the inhibitory peptide. note that the inhibitory peptide is negatively charged binding to a positively charged region on the fviia molecule keeping the ha binding site on fviia molecule free. manal s q al-amri, khalid alrasadi, riad bayoumi and yajnavalka banerjee clinical and basic research | 91 [figure 7 a-e]. one of the intriguing highlights of the study was that the designed structurally viable peptides had the positively and negatively charged residues separated as in observed in figure 7. also, we designed various combination of chimeras where the ha derived peptides were placed at the amino-terminal as well as the carboxyterminal ends. switching of ends was found to affect the stability of the designed chimera. as shown in table 1, for combination 3, the presence of the fviia-inhibitory peptide on the carboxy-terminal end leads to structural instability of the designed chimera, whereas its presence on the aminoterminal does not affect its structural viability. these putative bivalent anticoagulants still need to be evaluated in various in vitro and in vivo assays before they can be assessed in clinical trials. one of the advantages of the current strategy is that it can be successfully applied without the involvement of large financial commitment by researchers with limited knowledge of bioinformatics. however, the designed chimeric anticoagulant, although structurally viable, might lose its activity since the fold it attains might not favour its binding to its specific interaction sites. conclusion table: 1. designed chimeric peptides and result of structural modeling hemextin a (peptide) terminal link chimera (ha p + lazarus p) structure analysis 1. alvpflsktapeg blvpflsktapeg cooh terminal nh2 terminal lvpflsktapeg + eewevlcwtwetcergegveeelwewr eewevlcwtwetcergegveeelwewr + lvpflsktapeg no recognisable fold was obtained no recognisable fold was obtained 2. atcpegknlcykmtmlkmpki btcpegknlcykmtmlkmpki cooh terminal nh2 terminal tcpegknlcykmtmlkmpki + eewevlcwtwetcergegveeelwewr eewevlcwtwetcergegveeelwewr + tcpegknlcykmtmlkmpki no recognisable fold was obtained no recognisable fold was obtained 3. akipikrgctdacpks bkipikrgctdacpks cooh terminal nh2 terminal kipikrgctdacpks + eewevlcwtwetcergegveeelwewr eewevlcwtwetcergegveeelwewr + kipikrgctdacpks no recognisable fold was obtained distinct fold was observe wafter modeling 4. atcpegknlcykmtmlkmckipik btcpegknlcykmtmlkmckipik cooh terminal nh2terminal tcpegknlcykmtmlkmckipik + eewevlcwtwetcergegveeelwewr eewevlcwtwetcergegveeelwewr + tcpegknlcykmtmlkmckipik distinct fold was observe wafter modeling distinct fold was observe wafter modeling 5. alvpflsktccegknlcykmtmlkmpki blvpflsktccegknlcykmtmlkmpki cooh terminal nh2 terminal lvpflsktccegknlcykmtmlkmpki + eewevlcwtwe tcergegveeelwewr eewevlcwtwetcergegveeelwewr + lvpflsktccegknlcykmtmlkmpki distinct fold was observe wafter modeling distinct fold was observe wafter modeling 6. akmpkicikrgctdacpks bkmpkicikrgctdacpks cooh terminal nh2 terminal kmpkicikrgctdacpks + eewevlcwtwetcergegveeelwewr eewevlcwtwetcergegveeelwewr + kmpkicikrgctdacpks no recognisable fold was obtained no recognisable fold was obtained notes: + denotes the nine alanine spacer; ha p denotes the peptide fragment derived from hemextin a; lazarus p denotes the peptide designed at genentech ca, usa by dr bob lazarus and his colleagues. in silico design of novel anticoagulant peptides targeting blood coagulation factor viia 92 | squ medical journal, february 2011, volume 11, issue 1 in summary, we designed bivalent inhibitors for fviia using simple bioinformatics. the five structurally viable inhibitors will be assessed for functional potency using appropriate in vitro and in vivo assays/experiments in the near future. although a great deal of effort was involved in the analysis of data and literature search during the study, it was relatively inexpensive since all the tools used were freely available on the internet. further, a similar strategy can be used for designing peptide based drugs for other physiological target molecules. thus this study introduces a novel paradigm in strategy design for drug-leads. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. references 1. davie ew. introduction to clotting in blood plasma. methods enzymol. 1981; 80:c153–6. 2. davie ew, fujikawa k, kisiel w. the coagulation cascade: initiation, maintenance, and regulation. biochemistry 1991; 30:10363–70. 3. davie ew. biochemical and molecular aspects of the coagulation cascade. thromb haemost 1995; 74:1–6. 4. breitenstein a, tanner fc, luscher tf. tissue factor and cardiovascular disease: quo vadis? circ j 2010; 74:3–12. 5. mackman n. the many faces of tissue factor. j thromb haemost 2009; 7:s136–9. 6. butenas s, orfeo t, mann kg. tissue factor in coagulation: which? where? when? arterioscler thromb vasc biol 2009; 29:1989–96. 7. melnikova i. the anticoagulants market. nat rev drug discov 2009; 8:353–4. 8. wittkowsky ak. warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. semin vasc med 2003; 3:221– 30. 9. hirsh j. heparin. n engl j med 1991; 324:1565–74. 10. hirsh j. oral anticoagulant drugs. n engl j med 1991; 324:1865–75. 11. trujillo tc. emerging anticoagulants for venous thromboembolism prevention. am j health syst pharm 2010; 67:s17–25. 12 butenas s, brummel ke, branda rf, paradis sg, mann kg. mechanism of factor viia-dependent coagulation in hemophilia blood. blood 2002; 99:923–30. 13. lorenzet r, donati mb. blood clotting activation, angiogenesis and tumor metastasis: any role for tfpi? thromb haemost 2002; 87:928–9. 14. lee ay, vlasuk gp. recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor viia/tissue factor. j intern med 2003; 254:313–21. 15. vlasuk gp, rote we. inhibition of factor viia/tissue figure 7: structure of the five viable chimeric peptides. a-e) the ribbon representation of the three-dimensional structure of five designed viable chimera along with their surface charge distribution. a) peptide 3 in table 1; b) and c) are peptide 4 in table 1; d) and e) are peptide 5 in table 1. blue represent positively charged regions and red negatively charged regions respectively.. manal s q al-amri, khalid alrasadi, riad bayoumi and yajnavalka banerjee clinical and basic research | 93 factor with nematode anticoagulant protein c2: from unique mechanism to a promising new clinical anticoagulant. trends cardiovasc med 2002;12:325– 31. 16. fluture a, giugliano gr, giugliano rp. recombinant nematode anticoagulant protein c2 in non-st segment elevation acute coronary syndrome and beyond. future cardiol 2007; 3:365–75. 17. giugliano rp, wiviott sd, stone ph, simon di, schweiger mj, bouchard a, et al. recombinant nematode anticoagulant protein c2 in patients with non-st-segment elevation acute coronary syndrome: the anthem-timi-32 trial. j am coll cardiol 2007; 49:2398–407. 18. dennis ms, eigenbrot c, skelton nj ultsch mh, santell l, dwyer ma, et al. peptide exosite inhibitors of factor viia as anticoagulants. nature 2000; 404:465–70. 19. dennis ms, roberge m, quan c, lazarus ra. selection and characterization of a new class of peptide exosite inhibitors of coagulation factor viia. biochemistry 2001; 40:9513–21. 20. maun hr, eigenbrot c, lazarus ra. engineering exosite peptides for complete inhibition of factor viia using a protease switch with substrate phage. j biol chem 2003; 278:21823–30. 21. roberge m, santell l, dennis ms, eigenbrot c, dwyer ma, lazarus ra, et al. a novel exosite on coagulation factor viia and its molecular interactions with a new class of peptide inhibitors. biochemistry 2001; 40:9522–31. 22. roberge m, peek m, kirchhofer d, dennis ms, lazarus ra. fusion of two distinct peptide exosite inhibitors of factor viia. biochem j 2002; 363:387– 93. 23. uchiba m, okajima k, abe h, okabe h, takatsuki k. effect of nafamostat mesilate, a synthetic protease inhibitor, on tissue factor-factor viia complex activity. thromb res 1994;74:155–61. 24. lazarus ra, olivero ag, eigenbrot c, kirchhofer d. inhibitors of tissue factor. factor viia for anticoagulant therapy. curr med chem 2004;11:2275–90. 25. buckman bo, chou yl, mccarrick m, liang a, lentz d, mohan r, et al. solid-phase synthesis of naphthylamidines as factor viia/tissue factor inhibitors. bioorg med chem lett 2005; 1 5:2249–52. 26. banerjee y, lakshminarayanan r, vivekanandan s, anand gs, valiyaveettil s, kini rm. biophysical characterization of anticoagulant hemextin ab complex from the venom of snake hemachatus haemachatus. biophys j 2007; 93:3963– 76. 27. banerjee y, kumar s, jobichen c, kini rm. crystallization and preliminary x-ray diffraction analysis of hemextin a: a unique anticoagulant protein from hemachatus haemachatus venom. acta crystallogr sect f struct biol cryst commun 2007; 63:701–3. 28. banerjee y, mizuguchi j, iwanaga s, kini rm. hemextin ab complex--a snake venom anticoagulant protein complex that inhibits factor viia activity. pathophysiol haemost thromb 2005; 34:184–7. 29. banerjee y, mizuguchi j, iwanaga s, kini rm. hemextin ab complex, a unique anticoagulant protein complex from hemachatus haemachatus (african ringhals cobra) venom that inhibits clot initiation and factor viia activity. j biol chem 2005; 280:42601–11. 30. baxevanis ad. searching the ncbi databases using entrez. curr protoc bioinformatics 2006; ch.1:unit 3.1. 31. ji l, barrett t, ayanbule o, troup db, rudnev d, muertter rn, et al. ncbi peptidome: a new repository for mass spectrometry proteomics data. nucleic acids res 2010; 38:d731–5. 32. altschul sf, gish w, miller w, myers ew, lipman dj. basic local alignment search tool. j mol biol 1990; 215:403–10. 33. madden tl, tatusov rl, zhang j. applications of network blast server. methods enzymol 1996; 266:131–41. 34. altschul sf, madden tl, schaffer aa, zhang j, zhang z, miller w, et al. gapped blast and psiblast: a new generation of protein database search programs. nucleic acids res 1997; 25:3389–402. 35. notredame c, higgins dg, heringa j. t-coffee: a novel method for fast and accurate multiple sequence alignment. j mol biol 2000; 302:205–17. 36. gasteiger e, gattiker a, hoogland c, ivanyi i, appel rd, bairoch a. expasy: the proteomics server for in-depth protein knowledge and analysis. nucleic acids res 2003; 31:3784–8. 37. arnold k, bordoli l, kopp j, schwede t. the swissmodel workspace: a web-based environment for protein structure homology modelling. bioinformatics 2006; 22:195–201. 38. armano g, manconi a. prodama: an open source python library to generate protein structure datasets. bmc res notes 2009; 2:202. 39. fufezan c, specht m. p3d--python module for structural bioinformatics. bmc bioinformatics 2009; 10:258. 40. kini rm, evans hj. a novel approach to the design of potent bioactive peptides by incorporation of proline brackets: antiplatelet effects of arg-gly-asp peptides. febs lett 1995; 375:15–17. 41. kini rm, evans hj. prediction of potential proteinprotein interaction sites from amino acid sequence. identification of a fibrin polymerization site. febs lett 1996; 385:81–6. 42. banner dw, d‘arcy a, chene c, winkler fk, guha in silico design of novel anticoagulant peptides targeting blood coagulation factor viia 94 | squ medical journal, february 2011, volume 11, issue 1 a, konigsberg wh, et al. the crystal structure of the complex of blood coagulation factor viia with soluble tissue factor. nature 1996; 380:41–6. 43. menez a. functional architectures of animal toxins: a clue to drug design? toxicon 1998; 36:1557–72. 44. weitz ji, buller hr. direct thrombin inhibitors in acute coronary syndromes: present and future. circulation 2002; 105:1004–11. 45. liu lw, vu tk, esmon ct, coughlin sr. the region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity. j biol chem 1991; 266:16977–80. 46. mathews ii, padmanabhan kp, ganesh v, tulinsky a, ishii m, chen j, et al. crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes. biochemistry 1994; 33:3266–79. sickle cell haemoglobinopathy is the third most common genetic blood disorder in oman.1 the genetic background of the omani population is heterogeneous and hence there are several haplotypes including african (e.g. benin, bantu) and the arab-indian resulting in different disease severity ranging from very mild to very severe.2 in our population, there are some other factors that can modify the course of the disease like co-inheritance of alpha thalassemia that is highly prevalent in the omani population (amounting to about 50%) and is believed to be associated with development of avascular necrosis (avn) of the hip.3 avn of the femoral head is a common complication in patients with sickle cell disease (scd), and collapse of the femoral head occurs in 90% of the patients within five years of the diagnosis of osteonecrosis.4 in our hospital, we follow more than 500 children with scd and 32 of them have developed avn over the last 10 years. we have tried several treatment modalities, starting from early childhood, to improve or prevent progression of the disease in these patients. for milder grades of the disease, steinberg stages i, ii & iiia (15 cases), we practice conservative measures such as non-weight bearing exercises using crutches, and physiotherapy including anti-gravity muscle strengthening exercises and a non-joint loading range of motion exercises. for more severe forms of the disease (17 cases), many of our patients (11) have undergone surgical intervention either locally or abroad and came back to us for follow-up. following published reports of some success, we used concentrated autologous bone marrow injection in 4 cases, with 3 failures and improvement of the hip in one child [table 1]. in many of our patients (13/32), the disease has progressed to warrant hip replacement which is a major surgery. since these patients are young, they may need to undergo revision 3 to 4 times in their life. we tried to address the reasons for the poor outcome in our children and we found that they do not use the crutches supplied and are not very compliant with the pre and postoperative physiotherapy rehabilitation programme. despite the seriousness of the problem and its life long effect on the patient's life with increasing pain, decreasing mobility, increasing liability to overweight, psychological stress and catastrophic economic impact on the patient, avn in paediatric scd patients has been inadequately addressed in the literature with only 19 papers cited in pubmed. in addition, there is no consensus in the literature on the best treatment options for the paediatric scd patient with femoral head avn. though strong evidence is lacking, hydroxurea, despite squ med j, february 2011, vol. 11, iss. 1, pp. 127-128, epub. 12th feb 11 submitted 16th oct 10 revision req. 13th dec 10, revision recd. 4th jan 11 accepted 10th jan 11 <ª<í◊rflπ]<›ç÷]<üœ <öü⁄<ª<’öá÷]<ª<ìè¬ê˘]<›]ç√fi]ü™ ·^€ �¬ [›^ø√÷]<≈^™<≈öá<üë2j÷<íà”ë<^≤<ï4�}<ÿ‚  avascular necrosis of the hip in sickle cell disease in oman is it serious enough to warrant bone marrow transplantation? *yasser wali1 and sultan almaskari2 letter to editor 1department of child health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of surgery, sultan qaboos university hospital, muscat, oman. *corresponding author email: yasser_wali@hotmail.com avascular necrosis of the hip in sickle cell disease in oman is it serious enough to warrant bone marrow transplantation? 128 | squ medical journal, february 2011, volume 11, issue 1 its very positive effects on many aspects of scd, has been implicated as a possible precipitator of avn as it increases haemoglobin level in these patients.5 nowadays, more indications are evolving for bone marrow transplantation (bmt) in scd. however, the major problem for experts is to identify which patients require bmt earlier in life before the development of serious and life long complications. the management of scd–avn, in our experience and in this part of the world,6 has been frustrating and associated in most instances with progression or recurrence of the disease. however, in oman, we have many extended families with high rates of consanguinity thus increasing the possibility of human leukocyte antigen (hla) matched sibling donors. the cost of an hla matched transplant is much less in our setup (us $45,000–50,000) than in western countries. since scd vasculopathy is the main factor for developing cerebrovascular accidents (cva)7 and avn,8 it is plausible to speculate that bmt will be useful in avn as in the case of cva. we believe that avn of the hip is a severe complication of scd that warrants haematology experts considering it among the indications for bmt. references 1. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 2. al-lamki z, wali ya, wasifuddin ms, zacharia m, shakeel a, rafique b. natural history of sickle hemoglobinopathy in omani children. int j pediatr hematol oncol 2000; 7:101–7. 3. adekile ad, gupta r, yacoub f, sinan t, al-bloushi m, haider mz. avascular necrosis of the hip in children with sickle cell disease and high hb f: magnetic resonance imaging findings and influence of alpha-thalassemia trait. acta haematol 2001; 105:27–31. 4. neumayr ld, aguilar c, earles an, jergesen he, haberkern cm, kammen bf, et al. national osteonecrosis trial in sickle cell anemia study group. physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. results of a multicenter study at a mean of three years after treatment. j bone joint surg am 2006; 88:2573–82. 5. sidani ca, ballourah w, el dassouki m, muwakkit s, dabbous i, dahoui h. venous sinus thrombosis leading to stroke in a patient with sickle cell disease on hydroxyurea and high hemoglobin levels: treatment with thrombolysis. am j hematol 2008; 83:8–20. 6. akinyoola al, adediran ia, asaleye cm. avascular necrosis of the femoral head in sickle cell disease in nigeria: a retrospective study. niger postgrad med j 2007; 14:217–20. 7. hillery ca, panepinto ja. pathophysiology of stroke in sickle cell disease. microcirculation 2004; 11:195–208. 8. smith ja. bone disorders in sickle cell disease. hematol oncol clin north am dec 1996; 10:1345–56. table 1: outcome of different surgical interventions to treat sickle cell disease children with avascular necrosis of the hip in oman intervention no. of patients result autologous bone marrow injection 4 1 success, 3 failures (progression) core decompression 4 1 success, 3 failures (progression to collapse) vascularised bone graft 2 1 success, 1 failure (non union) non-vascularised bone graft 1 failure (progression to collapse) femoral osteotomy 1 success pelvic osteotomy 1 failure (progression to collapse) hip joint fusion 1 failure (non-union) distraction arthrodiatasis 1 failure (regional osteoporosis/collapse) اإلدارة الذاتية ملرض السكري والعوامل املرتبطة هبا بني الُعمانيني البالغني املصابني مبرض السكري من النوع األول رجاء احل�رضمية، عمر الرواجفة، جو�شوا موليريا abstract: objectives: this study aimed to assess and explore factors affecting diabetes self-management (dsm) among omani adults with type one diabetes mellitus (t1dm). methods: this cross-sectional study was conducted from may to november 2018. convenience sampling was used to recruit participants from three referral hospitals in oman. data were collected using the diabetes self-management questionnaire, empowerment scale (short form), medical outcome study social support scale, diabetes knowledge test and glycosylated haemoglobin test results. linear multiple regression analysis was used to explore possible predictors of dsm. results: a total of 210 people participated in the study (response rate: 87.5%). the majority of participants were female (70.5%) with a mean age of 26.82 ± 8.25 years. the mean score for dsm was 6.8 ± 1.4, which represents 68% of the total maximum score. more than one-third (36.2%) of the participants had poor glycaemic control. the predictors of high levels of dsm were being employed (p = 0.049), earning a low monthly income of less than 300 omani rials (p = 0.014), having other chronic diseases (p = 0.029), a high diabetes self-efficacy (dse; p = 0.003) and high social support (ss; p = 0.006). conclusion: according to the findings of this study, omanis with t1dm have suboptimal dsm levels. factors such as diabetes knowledge, dse and ss are modifiable factors that can be targeted by interventions from different healthcare professionals to enhance dsm. keywords: diabetes mellitus; type 1 diabetes mellitus; self-management; adult; oman. البالغني الُعمانيني بني عليها املوؤثرة العوامل ي وتق�شِّ ال�شكري ملر�ض الذاتية الإدارة تقييم اإىل الدرا�شة هذه هدفت الهدف: امللخ�ص: امل�شابني بالنوع الأول من مر�ض ال�شكري. الطريقة: اأجريت هذه الدرا�شة املقطعية يف الفرتة من مايو اإىل نوفمرب 2018. مت ا�شتخدام تقنية اأخذ العينات املالئمة لتعيني امل�شاركني يف هذه الدرا�شة من ثالثة م�شت�شفيات مرجعية يف ُعمان. مت جمع البيانات با�شتخدام ا�شتبيان الإدارة الذاتية ملر�ض ال�شكري ومقيا�ض التمكني )منوذج ق�شري( ومقيا�ض الدعم الجتماعي لدرا�شة النتائج الطبية واإختباراملعرفة مبر�ض ي العوامل املوؤثرة على الإدراة الذاتية ملر�ض ال�شكري ونتائج اختبار الهيموجلوبني ال�ُشَكري. مت ا�شتخدام حتليل اإنحدار خطي متعدد لتق�شِّ ال�شكري. النتائج: �شارك يف الدرا�شة 210 �شخ�شا )معدل الإ�شتجابة %87.5(. كانت غالبية امل�شاركني من الإناث )%70.5( مبتو�شط عمر 8.25 ± 26.82 �شنوات. كان متو�شط نقاط الإدراة الذاتية ملر�ض ال�شكري 1.4 ± 6.8 والتي متثل %68 من جمموع احلد الأق�شى للنقاط. كان اأكرث من ثلث امل�شاركني )%36.2( يعانون من �شعف التحكم بن�شبة ال�شكر يف الدم. من العوامل املنبئة مب�شتويات عالية من الإدراة الذاتية ملر�ض ال�شكري هي كون ال�شخ�ض موظفا)p = 0.049( وجني دخل �شهري منخف�ض اأقل من 300 ريال ُعماين )p = 0.014( والإ�شابة باأمرا�ض مزمنة اأخرى )p = 0.029( واإرتفاع الكفاءة الذاتية ملر�ض ال�شكري )p = 0.003( والدعم الجتماعي الكبري )p = 0.006(. اخلال�صة: وفقا لنتائج هذه الدرا�شة لدى العمانيني البالغني امل�شابني مبر�ض ال�شكري من النوع الأول اإدارة ذاتية ملر�ض ال�شكري دون امل�شتويات الأمثل. عوامل مثل املعرفة مبر�ض ال�شكري والكفاءة الذاتية ملر�ض ال�شكري والدعم الإجتماعي هي عوامل قابلة للتغيري وميكن ا�شتهدافها من خالل التدخالت من خمتلف املتخ�ش�شني يف الرعاية ال�شحية لتعزيز الإدراة الذاتية ملر�ض ال�شكري. الكلمات املفتاحية: مر�ض ال�شكري؛ مر�ض ال�شكري من النوع الأول؛ الإدارة الذاتية؛ البالغني؛ ُعمان. diabetes self-management and the associated factors among adult omanis with type 1 diabetes *rajaa al-hadhrami,1 omar al-rawajfah,2 joshua muliira3 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e339–345, epub. 21 dec 20 submitted 28 aug 19 revision req. 3 mar 20; revision recd. 9 apr 20 accepted 5 may 20 1department of emergency medicine, sultan qaboos university hospital, muscat, oman; 2college of nursing, sultan qaboos university, muscat, oman; 3willisknighton healthcare system, shreveport, louisiana, usa *corresponding author’s e-mail: rajaa@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.010 clinical & basic research advances in knowledge this study assesses diabetes self-management (dsm) level among adult omanis with type 1 diabetes mellitus (t1dm) and evaluates the factors influencing dsm. good glycaemic control (hba1c) among adult omanis with t1dm was significantly associated with higher dsm. diabetes knowledge, self-efficacy, social supports are key factors that influence dsm of adult with t1dm. application of patient care there is a need to assess, improve and evaluate dsm and associated factors during diabetes visits. healthcare providers who are directly involved in managing diabetes must consider culturally sensitive programmes to enhance the dsm among diabetic omanis. https://creativecommons.org/licenses/by-nd/4.0/ diabetes self-management and the associated factors among adult omanis with type 1 diabetes e340 | squ medical journal, november 2020, volume 20, issue 4 diabetes mellitus (dm) is one of the most common non-communicable diseases among adults globally, and its prevalence continues to increase.1 in 2017, the worldwide prevalence was reported at approximately 424.9 million people for those aged 20–79 years and is projected to increase to 629 million by 2045.2 in 2017, oman’s ministry of health reported the incidence of dm as 225 cases per 10,000 for men and 484 cases per 10,000 for women in the omani population.3 due to the impact dm has on all body systems, it increases the risk of developing life-threatening problems and is therefore the leading cause of cardiovascular disease, blindness, and kidney failure.4 the percentage of omanis who had retinopathy, micro-albuminuria, amputation and nephropathy was approximately 14%, 27%, 47.3%, and 42.5%, respectively.5–8 dm was the fourth leading cause of early death and the third leading cause of disability in oman in 2010.9 diabetes self-management (dsm) is an essential step to controlling or ameliorating the associated impact of and complications from dm. dsm is critical to effective management of both type one (t1) dm and type two (t2) dm. research shows that dsm results in improved patient quality of life (qol), reduces the incidence of complications and promotes glycaemic control.4,10 the potential improvements to qol are the rationale for considering dsm a cornerstone in dm care and management.11 dsm requires the affected person to be actively involved in performing a set of daily planned activities that are essential to managing the disease including eating a healthy diet, getting regular physical exercise, monitoring blood glucose levels, seeking preventive healthcare or medical treatment and using prescribed treatments.12,13 people affected by dm, therefore, must be equipped with adequate knowledge and have a clear understanding of each aspect of dsm because all of dsm’s components are essential for daily living.11 few studies have explored dsm among diabetic omanis and to the best of the authors’ knowledge, no study has focused on patients with t1dm.4,14 moreover, limited information is available on the factors that may affect dsm among omanis with t1dm. therefore, this study aimed to assess the levels of dsm among omani adults with t1dm. furthermore, this study aimed to explore the factors that may affect dsm among omani adults with t1dm. method this cross-sectional, descriptive study was conducted from may to november 2018. a convenience sample was recruited from the diabetic clinics at sultan qaboos university hospital, royal hospital and nizwa hospital located in muscat and nizwa, oman, respectively. the main variables measured were dsm, diabetic self-efficacy (dse), social support (ss), diabetes knowledge (dk), glycosylated haemoglobin control (hba1c) levels and socio-demographic characteristics. all omani adults with t1dm who came to receive follow-up care at the dm clinics were approached by a researcher during their visit. patients with a t1dm diagnosis and were 18 years and above (data confirmed using patients’ electronic records) were included in this study. all patients who had previously been diagnosed with mental or cognitive problems were excluded. the english versions of all standardised tools used in this study were translated into arabic following a standard procedure of translation and back translation. the final arabic versions of the instruments were validated for content, clarity and readability by two bilingual nurse researchers. the diabetes self-management questionnaire, which consists of 27 items with a four-point likert scale, was used to assess dsm levels. the original english version of the tool was reported to be reliable with a cronbach’s alpha of 0.84.15 total dsm scores were categorised as good (8–10), poor (4–7) or very poor (<4).4 in the current study, the reliability cronbach's alpha of the arabic version was 0.83. dse was assessed using the diabetes empowerment scale—short form which consists of eight items with a five-point likert scale.16 the original english version has a reliability cronbach's alpha of 0.84 and the arabic version in the current study was found to have the same reliability.10 the medical outcome study social support survey (mos-ss) was used to assess participants’ ss. the survey consists of 19 items with a five-point likert scale. the reliability cronbach's alpha of the original english version was above 0.91 and, in the current study, the cronbach's alpha for the arabic version was 0.94.17 dk was assessed using the diabetes knowledge test (dkt) which consists of 23 multiple choice items and is appropriate for patients on insulin treatment.16 the reliability cronbach's alpha of the original english version was 0.77, and was found to be 0.63 for the arabic version; scores were categorised as low (1–11), moderate (12–18) or high (19–23).18,19 patients latest hba1c in percentage results were obtained via electronic patient records to determine level of glycaemic control. hba1c result was categorised into good glycaemic control (hba1c <7%), medium glycaemic control (hba1c 7–9%) and poor glycaemic control (hba1c >9%). rajaa al-hadhrami, omar al-rawajfah and joshua muliira clinical and basic research | e341 the standardised yamane’s formula was used to estimate the sample size needed for this study: where n is the population size and e is the alpha level. based on the number of patients recorded in the study’s settings, the accessible population was estimated to be approximately 700 patients. the required sample size, therefore, was calculated as 254 participants. a confidence level of 95% and error margin of 5% was adequate to achieve a minimum power of 80%. data were analysed using statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa). frequencies, means ± standard deviation and percentile quartiles were used to describe the study sample as well as the outcome variables. pearson’s correlation and t-test were used to determine the relationship between dsm and dse, ss and dk scores and participants’ glycaemic control based on hba1c values. a multiple linear regression analysis was conducted to examine the potential predictors of dsm. variables initially entered into the model were age, gender, marital status, level of education, employment status, income, period of dm diagnosis, number of hospital admissions in the last year, the presence of other chronic disease and levels of dk, ss and dse. the “enter selection” method was used to exclude variables that were not significant. multicollinearity was tested using variance inflation factor and tolerance; the variables included demographic characteristics, period of dm diagnosis, admission during the last 12 months, the presence of other chronic diseases and levels of dk, ss and dse. variable or data sheets missing more than 10% of their data were excluded from the final analysis. this study was approved by the research and ethics committees of all participating hospitals as well as by the principal investigators’ affiliated university (moh/csr/18/8997, mrec 1664). all participants received a clear, detailed explanation of the study procedures and their rights before being enrolled in the study. additionally, participants voluntarily signed an informed consent form prior to data collection. result a total of 240 individuals who met the eligibility criteria were approached. however, four participants were excluded because they had been diagnosed with mental retardation, 26 refused to participate and four did not complete the questionnaires. therefore, the final sample size was 210 participants (response rate: 87.5%). the majority of participants were female (70.5%) and unemployed (64.8%). the mean age was 26.82 ± 8.25 years and the majority (65.2%) were 18– 28 years old. about half of the participants were single (52.8%), living in muscat governorate (49.0%) and had a secondary school education or lower (51.4%). most of the participants (69.0%) had had a dm diagnosis for more than five years (range: 5.1–32.0 years) and had not been admitted to hospital in the last 12 months (71.4%). the majority of the participants had a family history of dm (74.8%) but had no history of other chronic diseases (77.1%). in addition, most (36.2%) had poor glycaemic control [table 1]. the dsm mean score was compared across different sociodemographic characteristics. the mean dsm of participants who reported having other chronic diseases along with their dm was higher (7.2 ± 1.1) than in those without other chronic diseases (6.7 ± 1.4; p = 0.02). the dsm mean scores were also higher among participants who had more than one family member working as a healthcare professional (7.5 ± 1.3) compared to participants who had just one family member working in healthcare (6.5 ± 1.4; p = 0.03) or who did not have any family members in healthcare (6.8 ± 1.3; p <0.01). furthermore, dsm levels were statistically significant across hba1c categories; the dsm mean score for participants with good glycaemic control (7.2 ± 1.3) was higher compared to those with poor glycaemic control (6.5 ± 1.4; p = 0.02). there were no statistically significant differences in mean dsm across other sociodemographic characteristics [table 1]. the mean dsm score across the sample was 6.8 ± 1.4, which is 68% of the dsm scale’s total maximum score of 10. the mean dse score was 27.6 ± 4.5, which is 69% of the dse scale’s total maximum score of 40. the mean score for ss was 53.0 ± 15.7, which is 53% of the mos-ss maximum score of 95. the mean score on the dkt was 16.0 ± 3.2, which is 69.6% of the dkt’s maximum score of 23. of the total number of participants, 53 (25.2%) scored ≤14 on dk. finally, participants’ mean glycaemic control value was 8.6 ± 2.5 [table 2]. a statistically significant positive correlation was found between participants’ dsm and dse (r = 0.265; p <0.01), ss (r = 0.268; p <0.01), dk (r = 0.151; p <0.05) and glycaemic control values (r = −0.190; p <0.01) [table 3]. finally, a model testing multicollinearity was statistically significant with five predictors of dsm (f[13,196] = 3.857; p <0.001) with an r² of 0.20 and an adjusted r² of 0.15 with no evidence of multicollinearity within the variables in the model. the results suggest that after controlling other variables in the model, participants who were employed had n = n/1+n (e) 2 [equation 1] diabetes self-management and the associated factors among adult omanis with type 1 diabetes e342 | squ medical journal, november 2020, volume 20, issue 4 table 1: characteristics of patients with type one diabetes mellitus in oman (n = 210) variable n (%) mean dsm value ± sd p value gender male 62 (29.5) 6.5 ± 1.3 0.07 female 148 (70.5) 6.9 ± 1.4 employment status employed 74 (35.2) 6.7 (1.4) 0.06 unemployed 136 (64.8) 7.1 (1.4) age in years 18–28 137 (65.2) 6.7 ± 1.4 0.40 29–39 52 (24.8) 7.0 ± 1.4 40–48 21 (10) 6.8 ± 1.3 marital status single 111 (52.8) 6.7 ± 1.4 0.20 married 97 (46.2) 7.0 ± 1.3 widowed 2 (1.0) 6.9 ± 1.2 level of education secondary or less 108 (51.4) 6.8 ± 1.4 0.90 diploma or higher 102 (48.6) 6.8 ± 1.4 monthly income in omr <300 30 (14.3) 7.0 ± 1.3 0.41 300–1000 122 (58.1) 6.8 ± 1.3 >1000 58 (27.6) 6.6 ± 1.5 time since dm diagnosis in years 0–3 39 (18.6) 6.6 ± 1.5 0.90 3.1–5 26 (12.4) 6.8 ± 1.4 5.1–32.0 145 (69.0) 6.9 ± 1.4 reason for hospital admission in the last 12 months no admission 150 (71.4) 6.9 ± 1.4 0.72 hyperglycaemia 42 (20.0) 6.7 ± 1.3 hypoglycaemia 6 (2.9) 6.3 ± 1.6 other 12 (5.7) 6.9 ± 1.1 other chronic diseases no 162 (77.1) 6.7 ± 1.4 0.02 yes 48 (22.9) 7.2 ± 1.1 dm complication none 143 (68.1) 6.8 ± 1.4 0.8 vision 52 (24.8) 7.0 ± 1.3 kidney 4 (1.9) 6.8 ± 0.7 other 11 (5.2) 6.6 ± 0.9 family member with dm no 53 (25.2) 6.7 ± 1.6 0.70 yes 157 (74.8) 6.8 ± 1.3 family member(s) who are healthcare professionals none 126 (60.0) 6.8 ± 1.3 <0.01 one 58 (27.6) 6.5 ± 1.4 more than one 26 (12.4) 7.5 ± 1.3 glycaemic control* good (<7%) 64 (30.5) 7.2 ± 1.3 0.02 medium (7–9%) 70 (33.3) 6.8 ± 1.3 poor (>9%) 76 (36.2) 6.5 ± 1.4 dsm = diabetes self-management; sd = standard deviation; omr = omani riyal, dm = diabetes mellitus. *glycaemic control as a measurement of percentage glycosylated haemoglobin. table 2: descriptive statistics of participants’ levels of diabetes self-management, self-efficacy, social support, diabetes knowledge and glycaemic control (n = 210) variable mean ± sd q1 median q3 dsm 6.8 ± 1.4 6.0 6.9 7.7 dse 27.6 ± 4.5 25.5 28.5 30.5 ss 53.0 ± 15.7 45.8 57.0 66.0 dk 16.0 ± 3.2 14.0 16.0 18.0 glycaemic control* 8.6 ± 2.5 6.5 8.2 9.9 sd = standard deviation; q1= 25th percentile; median = 50th percentile; q3= 75th percentile; dsm = diabetes self-management; dse = diabetes self-efficacy; ss = social support; dk = diabetes knowledge. *glycaemic control as a measurement of percentage glycosylated haemoglobin. table 3: pearson’s correlation between diabetes self-management and other continuous variables variable dsm dse ss dk glycaemic control‡ dsm dse 0.265* ss 0.268* 0.319* dk 0.151† 0.187* 0.179* glycaemic control‡ −0.190* −0.086 0.039 −0.153† dsm = diabetes self-management; dse = diabetes self-efficacy; ss = social support; dk = diabetes knowledge; hba1c = glycosylated haemoglobin. *pearson correlation significant at p <0.01; †pearson correlation significant at p <0.05; ‡glycaemic control as a measurement of percentage glycosylated haemoglobin. rajaa al-hadhrami, omar al-rawajfah and joshua muliira clinical and basic research | e343 significantly higher dsm compared with those who were unemployed (b = 0.166; p = 0.049). participants with incomes of more than 1,000 omani rial per month demonstrated lower dsm compared to those with middle or low incomes (b = −0.254; p = 0.014). furthermore, participants with other chronic diseases demonstrated significantly higher dsm (b = 0.145; p = 0.029) after controlling for other variables. participants with high ss also demonstrated significantly higher dsm (b = 0.192; p = 0.006) compared to those with lower levels of ss after controlling for other variables. lastly, participants with high dse demonstrated significantly higher dsm (b = 0.209; p = 0.003) after controlling for other variables [table 4]. discussion the goal of dsm is to achieve optimal glycaemic control, hence preventing or delaying the onset of dm complications and improving qol.20 this study’s findings suggest that a significant number of omanis with t1dm may have suboptimal levels of dsm. although no previous studies have been done among omanis with t1dm, previous studies of omanis with t2dm reported similar findings.4,20 for example, alrahbi found a mean dsm score of 174.5 ± 22.4 (out of a possible score of 240) among omanis with t2dm, representing 73% of the maximum possible dsm score.20 similarly, elliot et al. reported that, in a sample of 309 omanis with t2dm, the dsm and education mean score was 5.0 ± 2.3 out of 10.4 the findings from the current study and previous studies suggest that the issue of dsm for both t1dm and t2dm patients in oman needs more attention because dsm in oman continues to be suboptimal across potentially large swaths of the country’s population. the current study suggests that omanis with t1dm who have been diagnosed with other chronic diseases have higher levels of dsm than those without other chronic disease. this may be due to individuals with dm who are affected by other chronic diseases become afraid of the progression or worsening of their condition and become more aware of the required lifestyle modifications. broadbent et al. reported that having one or more diseases significantly influenced the individual’s lifestyle and improved behavioural changes.21 furthermore, a study by abubakari et al. showed that diabetic individuals with kidney problem perceived greater consequences and threats as well as greater understanding and adherence to diabetes management than those without kidney disease.22 in addition, diabetic individuals with other chronic diseases will have more follow-up in diabetes as well as other speciality clinics, which means those patients will be closely monitoring and enforcing their selfmanagement behaviours.23 the literature shows that individuals with dm and other chronic illnesses tend to pursue more follow-up in dm clinics and other specialty clinics; healthcare professionals must pay closer attention to their monitoring and selfmanagement behaviours.23 the current study also revealed a positive significant relationship between dsm and dse, ss and dk. participants with higher dse were more likely to have optimal dsm. this finding is congruent with those of other studies which have shown that diabetics with high dse are more likely to optimise dsm.22,24–27 table 4: multiple linear regression analysis for various potential predictor of diabetes self-management variables* unstandardised coefficients standardised beta p value beta se (constant) 4.685 0.890 <0.001 age 0.000 0.016 -0.003 0.979 gender 0.354 0.202 0.117 0.082 marital status 0.133 0.255 0.048 0.602 level of education 0.145 0.195 0.053 0.522 employment status 0.476 0.241 0.166 0.049† middle income −0.366 0.277 −0.132 0.188 high income −0.780 0.315 −0.254 0.014† time since dm diagnosis 0.014 0.017 0.062 0.419 admission to hospital in last 12 months 0.010 0.203 0.003 0.963 other chronic diseases 0.475 0.216 0.145 0.029† dk 0.058 0.030 0.135 0.056 ss 0.489 0.175 0.192 0.006† dse 0.063 0.021 0.209 0.003† se = standard error; dm = diabetes mellitus; dk = diabetes knowledge; ss = social support; dse = diabetes self-efficacy. *gender = male versus female; marital status = married versus single; employment status = employed versus unemployed; level of education = secondary or less versus diploma or higher; middle income = monthly income of 301–1000 omani rial (omr); high income = monthly income of >1000 omr ; chronic disease = no versus yes; †statistically significant predictors of dsm at p <0.05. diabetes self-management and the associated factors among adult omanis with type 1 diabetes e344 | squ medical journal, november 2020, volume 20, issue 4 self-efficacy is a cognitive concept that reflects an individual’s propensity and motivation to activate, perform and persist in performing certain behaviours even in the event of difficulties.28 the relationship between dsm and self-efficacy is reciprocal. a previous study revealed that people with dm who adhere to dsm activities become more confident in performing the required activities, leading to better glycaemic control.29 the results of the current study also suggest that participants with high ss have better dsm; similar findings have been reported among omanis with t2dm.14 this finding is not surprising as other studies have shown that involving partners, friends and couples in a person’s dm care is associated with better dsm.30–32 a previous study of omanis with t2dm reported that they received various forms of support and assistance from family members and relatives including help with daily dm management, reminders about glucose monitoring and medications and companionship on walks.20 the current findings show that participants with higher levels of dk report higher dsm. effective selfmanagement requires people with dm to be equipped with the relevant knowledge and skills to enable them to perform required daily self-care such as blood glucose monitoring, exercise, diet and medication preparation and administration.11,31 a previous study of omanis with t2dm found that participants who received dm education had greater knowledge of dm and a higher dsm score; in addition, they had higher compliance levels with glycaemic control activities than those who did not receive the same education.4 the results from the current study indicate that employed participants had better dsm compared to unemployed participants. similar results have been reported among omanis with t2dm.14 alrahbi explained that employed omanis have higher levels of education which mediates dsm behaviours.14 this explanation is also valid for the current study as 66% of the employed participants had higher educational levels compared to 39% of unemployed participants. this study also found monthly income to be a significant predictor of dsm. interestingly, after controlling for other variables, high monthly income was associated with lower levels of dsm compared to individuals with low incomes. this finding was inconsistent with a previous study which found higher income to be associated with better dsm.13 in the omani context, higher incomes may increase the chance and frequency of eating in public restaurants including fast food chains and participating in leisure activities that may negatively affect dsm behaviours. finally, the present study found that dse and ss were both significant predictors of dsm. these findings were similar to those of other studies.22,33 although the current study can be considered a pioneering study of omani adults with t1dm, it was subject to certain limitations. for example, this study utilised a cross-sectional design and participants had a wide range of time since their t1dm diagnosis (range: 1–48.0 years). studying dsm using a longitudinal approach could lead to a better understanding of how dsm develops and evolves as the disease progresses. although the participants from the current study were from different regions in oman and most likely were representative of the omani population, sampling bias could have occurred because some of the sample subgroups were not equally distributed. future studies, therefore, should take into consideration the fact that comparisons of dsm across different subgroups were made in the current study but the subgroups were likely not equally distributed; selection bias at the subgroup level may exist and may have affected the results. finally, although this study utilised the clinical marker hba1c as an outcome indicator of dsm, this study was unable to link hba1c with dm complications. future research should consider the association of dsm and shortand long-term complications. conclusion this study explored dsm as a critical aspect of dm care and found that omanis with t1dm have suboptimal dsm levels. this study provides insight to clinicians, researchers and healthcare educators about factors that are associated with dsm among omanis with t1dm. modifiable factors such as dk, dse and ss should be targeted by interventions from different healthcare professionals to enhance dsm. awareness of such factors is likely to improve patient care and offer further direction for future dm research in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. international diabetes federation. idf diabetes atlas ninth edition. from: https://www.diabetesatlas.org/upload/ resources/2019/idf_atlas_9th_edition_2019.pdf accessed: apr 2020. rajaa al-hadhrami, omar al-rawajfah and joshua muliira clinical and basic research | e345 2. cho nh, shaw je, karuranga s, huang y, da rocha fernandes jd, ohlrogge aw, et al. idf diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. diabetes res clin pract 2018; 138:271–81. https://doi.org/10.1016/j. diabres.2018.02.023. 3. ministry of health. annual health report 2017-chapter nine: morbidity and mortality. from: https://www.moh.gov.om/en/ web/statistics/annual-reports accessed: apr 2020. 4. elliott ja, abdulhadi nn, al-maniri aa, al-shafaee ma, wahlström r. diabetes self-management and education of people living with diabetes: a survey in primary health care in muscat oman. plos one 2013; 8:e57400. https://doi. org/10.1371/journal.pone.0057400. 5. khandekar r, al lawatii j, mohammed aj, al raisi a. diabetic retinopathy in oman: a hospital-based study. br j ophthalmol. 2003; 87:1061–4. https://doi.org/10.1136/bjo.87.9.1061. 6. al-futaisi a, al-zakwani i, almahrezi a, al-hajri r, al-hashmi l, al-muniri a, farooqui m. prevalence and predictors of micro albuminuria in patients with type 2 diabetes mellitus: a crosssectional observational study in oman. diabetes res clin pract. 2006; 72:212–5. https://doi.org/10.1016/j.diabres.2005.10.001. 7. al-busaidi is, abdulhadi nn, coppell kj. care of patients with diabetic foot disease in oman. sultan qaboos univ med j 2016; 16:e270–6. https://doi.org/10.18295/squmj.2016.16.03.002. 8. alrawahi, a. h., rizvi, s. g., al-riyami, d., & al-anqoodi, z. prevalence and risk factors of diabetic nephropathy in omani type 2 diabetics in al-dakhiliyah region. oman med j 2012; 27:212–16. https://doi.org/10.5001/omj.2012.48. 9. institute for health metrics and evaluation gbd profile: oman. from: www.healthdata.org/sites/default/files/files/ country_profile/gbd/ihme_gbd_country_report_oman.pdf accessed: apr 2020. 10. anderson rm, fitzgerald jt, gruppen ld, funnell mm, oh ms. the diabetes empowerment scale-short form (des-sf). dia betes care 2003; 26:1641–2. https://doi.org/10.2337/diacare.26. 5.1641-a. 11. lorig kr, holman h. self-management education: history, definition, outcomes, and mechanisms. ann behav med 2003; 26:1–7. https://doi.org/10.1207/s15324796abm2601_01. 12. funnell mm, anderson rm. empowerment and self-management of diabetes. clin diabetes 2004; 22:123–7. https://doi. org/10.2337/diaclin.22.3.123. 13. grant s. physical and social environmental predictors of diabetes self managment in african americans: the mediating effects of individual level psychosocial factors. ph.d. thesis, 2007, howard university, washington d.c., usa. pp. 12–131. 14. alrahbi h. diabetes self managment (dsm ) in omani with type 2 diabetes. int j nurs sci 2014; 1:352–9. https://doi. org/10.1016/j.ijnss.2014.09.002. 15. schmitt a, gahr a, hermanns n, kulzer b, huber j, haak t. the diabetes selfmanagement questionnaire (dsmq): devel opment and evaluation of an instrument to assess diabetes selfcare activities associated with glycaemic control. health qual life outcomes 2013; 11:138. https://doi.org/10.1186/1477-75 25-11-138. 16. michigan diabetes research center. tools for health professionals. from: http://diabetesresearch.med.umich.edu/ tools_surveyinstruments.php accessed: apr 2020. 17. sherbourne cd, stewart al. the mos social support survey. soc sci med 1991; 32:705–14. https://doi.org/10.1016/02779536(91)90150-b. 18. fitzgerald jt, funnell mm, anderson rm, nwankwo r, stansfield rb, piatt ga. validation of the revised brief diabetes knowledge test (dkt2). diabetes educ 2016; 42:178–87. https://doi.org/10.1177/0145721715624968. 19. zowgar am, siddiqui mi, alattas km. level of diabetes knowledge among adult patients with diabetes using diabetes knowledge test. saudi med j 2018; 39:161–8. https://doi. org/10.15537/smj.2017.2.21343. 20. alrahbi h. diabetes self managment (dsm ) in omani with type 2 diabetes. phd thesis, 2013, villanova university, pennsylvania, usa. pp. 10–117 21. broadbent e, ellis cj, thomas j, gamble g, petrie kj. further development of an illness perception intervention for myocardial infarction patients: a randomized controlled trial. j psychosom res 2009; 67:17–23. https://doi.org/10.1016/j. jpsychores.2008.12.001. 22. abubakari ar, cousins r, thomas c, sharma d, naderali ek. sociodemographic and clinical predictors of self-management among people with poorly controlled type 1 and type 2 diabetes: the role of illness perceptions and self-efficacy. j diabetes res 2016; 2016:6708164. https://doi.org/10.1155/2016/6708164. 23. chew bh, khoo em, chia yc. social support and glycemic control in adult patients with type 2 diabetes mellitus. asia pac j public health 2015; 27:np166–73. https://doi. org/10.1177/1010539511431300. 24. fisher l, hessler d, masharani u, strycker l. impact of base line patient characteristics on interventions to reduce diabetes distress: the role of personal conscientiousness and diabetes self efficacy. diabet med 2014; 31:739–46. https://doi.org/10.1111/ dme.12403. 25. law gu, walsh j, queralt v, nouwen a. adolescent and parent diabetes distress in type 1 diabetes: the role of self-efficacy, perceived consequences, family responsibility and adolescentparent discrepancies. j psychosom res 2013; 74:334–9. https:// doi.org/10.1016/j.jpsychores.2012.12.009. 26. nouwen a, urquhart law g, hussain s, mcgovern s, napier h. comparison of the role of self-efficacy and illness repres entations in relation to dietary self-care and diabetes distress in adolescents with type 1 diabetes. psychol health 2009; 24:1071–84. https://doi.org/10.1080/08870440802254597. 27. walker rj, smalls bl, hernandez-tejada ma, campbell ja, egede le. effect of diabetes self-efficacy on glycemic control, medication adherence, self-care behaviors, and quality of life in a predominantly low-income, minority population. ethn dis 2014; 24:349–55. 28. bandura a. self-efficacy: toward a unifying theory of behavioral change. psychol rev 1977; 84:191–215. https://doi. org/10.1037/0033-295x.84.2.191. 29. daly jm, hartz aj, xu y, levy bt, james pa, merchant m, et al. an assessment of attitudes, behaviours and outcomes of patients with type 2 diabetes. j am board fam med 2009; 22:280–90. https://doi.org/10.3122/jabfm.2009.03.080114. 30. trief p, jiang y, beck r, huckfeldt pj, knight t, miller km, et al. adults with type 1 diabetes: partner relationships and outcomes. j health psychol 2017; 22:446–56. https://doi. org/10.1177/1359105315605654. 31. hermanns n, kulzer b, ehrmann d, bergis-jurgan n, haak t. the effect of a diabetes education programme (primas) for people with type 1 diabetes: results of a randomized trial. diabetes res clin pract 2013; 102:149–57. https://doi. org/10.1016/j.diabres.2013.10.009. 32. trief p, sandberg jg, ploutz-snyder r, brittain r, cibula d, scales k, et al. promoting couples collaboration in type 2 diabetes: the diabetes support project pilot data. fam syst health 2011; 29:253–61. https://doi.org/10.1037/a0024564. 33. keyvanara m, hosseini sm, emami p. social support and diabetes control: a study among patients admitted to specialized clinic of dr. gharazi hospital in isfahan. med arh 2012; 66:24–7. https://doi.org/10.5455/medarh.2012.66.24-27. https://doi.org/10.1016/j.diabres.2018.02.023 https://doi.org/10.1016/j.diabres.2018.02.023 https://doi.org/10.1371/journal.pone.0057400 https://doi.org/10.1371/journal.pone.0057400 https://doi.org/10.1136/bjo.87.9.1061 https://doi.org/10.1016/j.diabres.2005.10.001 https://doi.org/10.5001/omj.2012.48 https://doi.org/10.2337/diacare.26.5.1641-a https://doi.org/10.2337/diacare.26.5.1641-a %20https://doi.org/10.1207/s15324796abm2601_01 https://doi.org/10.2337/diaclin.22.3.123 https://doi.org/10.2337/diaclin.22.3.123 https://doi.org/10.1016/j.ijnss.2014.09.002 https://doi.org/10.1016/j.ijnss.2014.09.002 https://doi.org/10.1186/1477-7525-11-138 https://doi.org/10.1186/1477-7525-11-138 https://doi.org/10.1016/0277-9536%2891%2990150-b https://doi.org/10.1016/0277-9536%2891%2990150-b https://doi.org/10.1177/0145721715624968 https://doi.org/10.15537/smj.2017.2.21343 https://doi.org/10.15537/smj.2017.2.21343 https://doi.org/10.1016/j.jpsychores.2008.12.001 https://doi.org/10.1016/j.jpsychores.2008.12.001 https://doi.org/10.1155/2016/6708164 https://doi.org/10.1177/1010539511431300 https://doi.org/10.1177/1010539511431300 https://doi.org/10.1111/dme.12403 https://doi.org/10.1111/dme.12403 https://doi.org/10.1016/j.jpsychores.2012.12.009 https://doi.org/10.1016/j.jpsychores.2012.12.009 https://doi.org/10.1080/08870440802254597 https://doi.org/10.1037/0033-295x.84.2.191 https://doi.org/10.1037/0033-295x.84.2.191 https://doi.org/10.3122/jabfm.2009.03.080114 https://doi.org/10.1177/1359105315605654 https://doi.org/10.1177/1359105315605654 https://doi.org/10.1016/j.diabres.2013.10.009 https://doi.org/10.1016/j.diabres.2013.10.009 https://doi.org/10.1037/a0024564 https://doi.org/10.5455/medarh.2012.66.24-27 1department of dermatology, bahla hospital, bahla, oman; 2dermatology program, oman medical specialty board, muscat, oman; 3department of pathology, khoula hospital, muscat, oman; 4department of dermatology, al nahdha hospital, muscat, oman *corresponding author’s e-mail: mhhh1414@gmail.com التهاب اجللد الورمي احلبييب حول الفم يف شخص بالغ تقرير حالة مع مراجعة املعت�صم الق�صابي، خالد البو�صعيدي، كوثر البكو�س، عبلة الإ�صماعيلية abstract: granulomatous periorificial dermatitis (gpd) is a benign, self-limiting eruption that is considered a clinical variant of periorificial dermatitis, also known as perioral dermatitis. it presents primarily in prepubertal children as monomorphic scaly papules over perioral, paranasal and periorbital areas of the face with rare occurrence in adults. we report a 36-year-old omani male patient who presented to the dermatology clinic at bahla polyclinic, bahla, oman, in 2018 with a papular eruption over his face for the previous six months. based on clinical and histopathological findings the patient was diagnosed with gpd with sarcoid-like histology. he was treated effectively with oral doxycycline and topical metronidazole. this report provides a review of the literature on gpd and summarises all reported cases in adults to date. keywords: perioral dermatitis; dermatitis; granulomas; case report; oman. امللخ�ص: التهاب اجللد الورمي احلبيبي حول الفوهة هو مر�س حميد ي�صفى تلقائيا ويعترب اأحد الأ�صكال ال�رشيرية لداء التهاب اجللد حول الفوهة والذي يعرف اأي�صا بالتهاب اجللد حول الفم. ي�صيب غالبا الأطفال ما قبل �صن البلوغ ويظهر على �صكل حبوب مت�صابهة عليها طبقة من الق�صور يف مناطق حول الفم والأنف والعني بالوجه مع ندرة حدوثه يف البالغني. نعر�س هنا حالة لذكر عماين عمره 36 �صنة قدم اإىل عيادة اجللد مبجمع بهالء ال�صحي، عمان، يف عام 2018 وهو يعاين من ثوران حطاطي يف الوجه منذ �صتة اأ�صهر. بناء على النتائج ال�رشيرية و فح�س الهي�صتوباثولوجيا مت ت�صخي�صه مبر�س التهاب اجللد الورمي احلبيبي حول الفوهة مع تغريات �صبيهه بال�صاركويد ن�صيجيًا. مت عالج املري�س بنجاح باإ�صتخدام عقار الدوك�صي �صيكلني عن طريق الفم ومرهم ميرتونيدازول. يقدم هذا التقرير مراجعة لالأدبيات املتعلقة بالتهاب اجللد الورمي احلبيبي حول الفوهة ويلخ�س جميع احلالت املبلغ عنها يف البالغني حتى الآن. الكلمات املفتاحية: التهاب اجللد حول الفم؛ التهاب اجللد؛ اأورام حبيبية روماتزمية؛ تقرير حالة؛ عمان. granulomatous periorificial dermatitis in an adult a case report with review of literature *al-mutasim al-qassabi,1 khalid al-busaidi,2 kaouthar al baccouche,3 abla al ismaili4 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e100–103, epub. 9 mar 20 submitted 7 aug 19 revisions req. 25 sep & 14 oct 19; revisions recd. 29 sep & 16 oct 19 accepted 31 oct 19 case report a 36-year-old omani male patient presented to the dermatology clinic at bahla polyclinic, bahla, oman, in 2018 with a papular eruption over his face for the previous six months. he reported no itching, burning sensation or facial redness. he had no known comorbidities and denied a history of fever, shortness of breath or other systemic complaints. in addition, he denied having used any topical or oral medications prior to the eruption. there was no recent history of travel and no abnormal environmental exposure. he was prescribed topical mometasone cream for two months and tacrolimus (0.1%) ointment for three months with partial response and recurrence once the treatment was discontinued. following the reoccurrence of the papular eruption, examination showed monomorphic scaly erythematous papules localised to the perioral, paranasal and peri orbital areas of the face [figure 1]. the vermilion border granulomatous periorificial dermatitis (gpd), also known as childhood granulomatous periorificial dermatitis (cgpd), is an uncommon, benign inflammatory skin disease that affects primarily dark-skinned prepubertal children; few cases have been reported in adults.1–5 it is characterised by a monomorphic, skin-coloured to yellow-brown or red papular eruption around the mouth, nose and eyes that usually heals with no scarring. however, extra-facial lesions have been reported.6 gpd shares many similarities with granulomatous rosacea (gr) and cutaneous sarcoidosis. some authors consider it a variant of gr, while others suggest that it may be a variant of sarcoidosis.7,8 this case report describes a rare case of gpd in an adult with sarcoidlike histology that was successfully treated with oral doxycycline and topical metronidazole. in addition, this report discusses controversies and distinguishing features of gpd from gr and sarcoidosis as well as a review of literature of all reported cases of gpd in adults. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.015 case report https://creativecommons.org/licenses/by-nd/4.0/ al-mutasim al-qassabi, khalid al-busaidi, kaouthar al baccouche and abla al ismaili case report | e101 was involved. there was no facial erythema or telan giectasia. there were no other skin lesions and other orifices were not involved. the rest of the physical examination was unremarkable. the differential diagnoses included periorificial dermatitis, gr, cutaneous sarcoi dosis and lupus miliaris disseminatus faciei (lmdf). laboratory investigations, including angiotensin converting enzyme (ace) levels, were normal. the chest x-ray was also normal. a punch biopsy was taken from the area with erythematous papules and sent for histo logical investigation. histopathological examination of an erythem atous papule showed non-caseating naked granulomas containing histiocytes, multinucleated giant cell of langhans type and focally surrounded lymphocytes [figure 2]. periadnexal and perivascular lymphocytic infiltrate was also present. stains for fungi (i.e. periodic acid–schiff ) and acid-fast bacilli (i.e. ziehl-neelsen and wade-fite) were negative. as a result of the clinical and histopathological findings, the patient was diagnosed with gpd. the patient was treated with oral doxycycline (100 mg) once daily and topical metronidazole cream twice daily. he showed marked improvement after six weeks with complete resolution of the lesions without scarring after 12 weeks, after which treatments were stopped [figure 3]. he had no recurrence on follow-up visits after three and six months. the patient gave consent for his images and clinical information to be reported in a journal. the authors explained that while the patient’s name would not be published, complete anonymity could not be guaranteed. discussion gpd is a well-recognised entity that affects commonly dark-skinned prepubertal children. while topical steroids are considered to be the most important and frequently reported pathogenic factor, other reported factors include cosmetic products, physical factors and microorganisms.1,8–11 gpd is a controversial disease as it shares many similarities with other granulomatous disorders such as gr and cutaneous sarcoidosis. gdp is distinguished from cutaneous sarcoidosis by the absence of systemic involvement and a self-limiting nature. antony et al. reported a case of gpd that could be a variant of sarcoidosis with raised ace levels and a chronic nature.8 gr usually shows similar histology to gpd but it mainly affects the central face and may show classic signs of telangiectasia, oedema and erythema.7 lmdf is distinguishable from gpd as it has a tendency to affect periorbital areas only, a presence of caseation on histology and resolution with scarring. misago et al. reported a case of cgpd with similar features to lmdf suggesting that the term ‘facial idiopathic granulomas with regressive evolution’ should include both cgpd and lmdf.12 since gpd sometimes presents with eczematous features, seborrheic dermatitis is also an accepted differential diagnosis, but the latter usually involves other areas such as the eyebrows and scalp with a dramatic response to topical steroids and different histologic features without granulomas. dermatoscopy may show additional features that aid in diagnosis.13 table 1 summarises the differential diagnoses with figure 1: photographs of the face of a 36-year-old male showing monomorphic erythematous scaly papules localised to (a) periorbital, (b) paranasal and perioral areas with involvement of vermilion border. figure 3: photographs of the face of a 36-year-old male showing complete resolution after 12 weeks of treatment with oral doxycycline and metronidazole cream. figure 2: haematoxylin and eosin stains at (a) x10 mag nification showing non-caseating granulomatous inflamm ation with some naked granulomas and (b) at x40 mag nification showing surrounding lymphocytic infiltrate. granulomatous periorificial dermatitis in an adult a case report with review of literature e102 | squ medical journal, february 2020, volume 20, issue 1 clinical and dermoscopic features of granulomatous papules on the face. gpd has a self-limiting nature, therefore treatment is not necessary. however, many topical and systemic treatments have been reported to hasten clearance.1,2,6,7,11,18 topical treatments include metronidazole, erythromycin or pimecrolimus.1,6,11 systemic treatments mainly include tetracycline antibiotics such as tetracycline and doxy cycline; oral erythromycin and clarithromycin are also effective.2,7,18 to date, there are a total of six reported cases of gpd in adults [table 2].1–5 the present case is the only case in a male. in two cases, the lesions were erythematous plaques and the remainder had erythematous papules as in the present case. all cases showed dermal noncaseating granulomas upon histopathological exam ination. one case was treated with oral isotretinoin while the others were treated with oral antibiotics. all cases showed complete resolution without recurrence. table 1: differential diagnosis of granulomatous papules on the face11,13–17 disease typical patient characteristics clinical features main dermoscopic features histopathological findings prognosis gpd • prepubertal children • rarely seen in adults • monomorphic, skin-coloured to yellowbrown or red papules confined to the periorificial areas of the face • not described • dermal noncaseating granulomas • spontaneous resolution without scarring gr • middle-aged women • yellow-brown or pink papules on the cheeks, periorbital or perioral skin • blushing, erythema or telangiectasia, may be seen • linear reddish or purple vessels arranged in a polygonal network (vascular polygons) • epithelioid granulomas adjacent to hair follicles • caseation in 10% of the cases • chronic nature cutaneous sarcoidosis • any age and gender • non-inflammatory facial papules and nodules with systemic symptoms such as fatigue, weight loss, joint pain and pulmonary symptoms • structure-less, orangish areas and well-focused linear or branching vessels • naked, non-caseating granulomatous infiltration • chronic nature lmdf • young adults • reddish-yellow or yellowish-brown papules on the central face and eyelids • follicular keratotic plugs and vascular structures • caseating granulomas • spontaneous resolution with scarring gpd = granulomatous periorificial dermatitis; gr = granulomatous rosacea; lmdf = lupus miliaris disseminatus faciei. table 2: summary of reported cases of granulomatous periorificial dermatitis in adults1–5 author and year of publication age in years gender clinical presentation histopathological findings treatment (duration) chintagunta et al.1 (2018) 34 female well-defined erythematous to pigmented plaques associated with scaling involving the perioral, paranasal and glabella granulomatous inflammation in the dermis composed of lymphocytes, histiocytes, epitheliod cells and multinucleated giant cells oral doxycycline 100 mg od + pimecrolimus 1% cream bid (3 months) vincenzi et al.2 (2000) 19 female numerous, flesh-coloured micropapular lesions involving the perioral and peri nasal areas associated with a mild diffuse erythema and slight vesiculation numerous well-formed granulomas containing occasional multinucl eated giant cells in the dermis oral clarithromycin 250 mg od (6 weeks) then 125 mg od (8 weeks) vincenzi et al.2 (2000) 25 female numerous red micropapules involving the nasal folds and the perioral regions perifollicular non-caseating epithe lioid cell granulomas in the dermis with some multinucleated giant cells and a variable number of lymph ocytes and histiocytes in perivas cular and perifollicular areas oral clarithromycin 250 mg od (10 days) then 250 mg on alternate days (20 days) tambe et al.3 (2018) 30 female multiple erythematous, scaly papules and plaques on the supra orbital, peri orbital, perioral and perinasal area perifollicular and perivascular granu lomatous inflammatory infiltrate composed of lymphocytes, epithe lioid cells and giant cells oral isotretinoin 20 mg od + metronidazole cream (3 weeks) li et al.4 (2006) 28 female pink to normal skin-coloured, discrete and coalescing papules ranging from 1–3 mm in diameter over the face, nape and bilateral forearms dermal granuloma formation around hair follicles, composed of lympho cytes, epithelioid histiocytes and occasional multinucleated giant cells oral doxycycline 100 mg od + topical metronidazole gel (2 months) loai and huang5 (2015) 24 female multiple, discrete, red to brown papules on erythematous base on the perioral and periocular areas granulomatous infiltration composed of lymphocytes, histiocytes, epithe lioid cells and multinucleated giant cells, without caseation in the dermis oral minocycline 50 mg bid + tacrolimus ointment 0.03% bid (50 days) present case 36 male monomorphic scaly erythematous papules localised to the perioral, paranasal and periorbital areas of the face non-caseating naked granulomas containing histiocytes, multinucl eated giant cell of langhans type and focally surrounded lymphocytes oral doxycycline 100 mg od + metronidazole cream (3 months) od = once daily; bid = twice daily. al-mutasim al-qassabi, khalid al-busaidi, kaouthar al baccouche and abla al ismaili case report | e103 conclusion gpd is a well-recognised entity that may affect adults and should be differentiated from gr, cutaneous sarcoidosis and other granulomatous disorders of the face by clinicopathological correlation to minimise systemic treatment use. references 1. chintagunta s, manchala s, arakkal g. granulomatous peri orificial dermatitis in an adult: a rare case report. j dr ntr univ health sci 2018; 7:143–6. https://doi.org/10.4103/22778632.233845. 2. vincenzi c, parente g, tosti a. perioral granulomatous dermatitis: two cases treated with clarithromycin. j dermatolog treat 2000; 11:57–61. https://doi.org/10.1080/09546630050517702. 3. tambe s, jerajani h, pund p. granulomatous periorificial dermatitis effectively managed with oral isotretinoin. indian dermatol online j 2018; 9:68–70. https://doi.org/10.4103/idoj. idoj_129_17. 4. li yw, chuan mt, hu sl. granulomatous periorificial dermatitis in a young woman. dermatol sinica 2006; 24:38–41. https://doi.org/10.29784/ds.200603.0006. 5. loai s, huang c. childhood granulomatous perioral dermatitis with good responses to minocycline and topical tacrolimus, extraordinary significance. austin j dermatol 2015; 2:1034. 6. urbatsch aj, frieden i, williams ml, elewski be, mancini aj, paller as. extrafacial and generalized granulomatous periorificial dermatitis. arch dermatol 2002; 138:1354–8. https://doi.org/10.1 001/archderm.138.10.1354. 7. lucas cr, korman nj, gilliam ac. granulomatous periorif icial dermatitis: a variant of granulomatous rosacea in children? j cutan med surg 2009; 13:115–18. https://doi.org/10.2310/77 50.2008.07088. 8. antony fc, buckley da, russell-jones r. childhood granulo matous periorificial dermatitis in an asian girl--a variant of sarcoid? clin exp dermatol 2002; 27:275–6. https://doi.org/10.1 046/j.1365-2230.2002.01019.x. 9. zalaudek i, di stefani a, ferrara g, argenziano g. childhood granulomatous periorificial dermatitis: a controversial disease. j dtsch dermatol ges 2005; 3:252–5. https://doi.org/10.1111/ j.1610-0387.2005.05009.x. 10. hatanaka m, kanekura t. case of childhood granuloma tous periorificial dermatitis. j dermatol 2018; 45:e256–7. https://doi.org/10.1111/1346-8138.14296. 11. lee gl, zirwas mj. granulomatous rosacea and periorificial dermatitis: controversies and review of management and treat ment. dermatol clin 2015; 33:447–55. https://doi.org/10.1016/j. det.2015.03.009. 12. misago n, nakafusa j, narisawa y. childhood granulomatous periorificial dermatitis: lupus miliaris disseminatus faciei in children? j eur acad dermatol venereol 2005; 19:470–3. https://doi.org/10.1111/j.1468-3083.2004.01178.x. 13. errichetti e, stinco g. dermatoscopy of granulomatous disorders. dermatol clin 2018; 36:369–75. https://doi.org/10.1016/j.det.2 018.05.004. 14. khokhar o, khachemoune a. a case of granulomatous rosacea: sorting granulomatous rosacea from other granulomatous diseases that affect the face. dermatol online j 2004; 10:6. 15. elder d, elenitsas r, johnson bl, murphy gf. lever's histopathology of the skin. 9th ed. philadelphia, pennsylvania, usa: lippincott williams and wilkins, 2005. p. 469. 16. ayhan e, alabalik u, avci y. dermoscopic evaluation of two patients with lupus miliaris disseminatus faciei. clin exp dermatol 2014; 39:500–2. https://doi.org/10.1111/ced.12331. 17. toda-brito h, aranha jmp, tavares es. lupus miliaris dissemin atus faciei. an bras dermatol 2017; 92:851–3. https://doi.org/10.1 590/abd1806-4841.20174534. 18. choi yl, lee kj, cho hj, kim ws, lee jh, yang jm, et al. case of childhood granulomatous periorificial dermatitis in a korean boy treated by oral erythromycin. j dermatol 2006; 33:806–8. https://doi.org/10.1111/j.1346-8138.2006.00183.x. https://doi.org/10.4103/2277-8632.233845 https://doi.org/10.4103/2277-8632.233845 https://doi.org/10.1080/09546630050517702 https://doi.org/10.4103/idoj.idoj_129_17 https://doi.org/10.4103/idoj.idoj_129_17 https://doi.org/10.29784/ds.200603.0006 https://doi.org/10.1001/archderm.138.10.1354 https://doi.org/10.1001/archderm.138.10.1354 https://doi.org/10.2310/7750.2008.07088 https://doi.org/10.2310/7750.2008.07088 https://doi.org/10.1046/j.1365-2230.2002.01019.x https://doi.org/10.1046/j.1365-2230.2002.01019.x https://doi.org/10.1111/j.1610-0387.2005.05009.x https://doi.org/10.1111/j.1610-0387.2005.05009.x https://doi.org/10.1111/1346-8138.14296 https://doi.org/10.1016/j.det.2015.03.009 https://doi.org/10.1016/j.det.2015.03.009 https://doi.org/10.1111/j.1468-3083.2004.01178.x https://doi.org/10.1016/j.det.2018.05.004 https://doi.org/10.1016/j.det.2018.05.004 https://doi.org/10.1111/ced.12331 https://doi.org/10.1590/abd1806-4841.20174534 https://doi.org/10.1590/abd1806-4841.20174534 https://doi.org/10.1111/j.1346-8138.2006.00183.x 1department of dermatology, hospital de poniente, el ejido, spain; 2department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com دور عقار التوفاسيتينيب يف عالج داء الثعلبة الكلي كارلو�ض هرنانديز مونتويا و ريكاردو رويز-فيالفريدي the role of tofacitinib in the management of alopecia totalis carlos hernandez-montoya1 and *ricardo ruiz-villaverde2 a 37-year-old caucasian female patientwas referred to the dermatology unit of the hospital de poniente, el ejido, spain, in 2017 with alopecia totalis (at). the at had occurred over the past five months and was classified as grade iv (75–100% hair loss) severity alopecia tool index (salt) [figure 1]. no nail changes were found prior to treatment. previous failure of topical treatments (high potency corticosteroids, diphenylcyclopropenone and minoxidil 5%), infiltration of intralesional corticosteroids (triamci nolone acetonide/mepivacaine 2% at 2 ml/month for six months) and dexamethasone minipulses (0.1 mg/kg twice a week for six months) was reported. there was no personal or family history of alopecia areata. following approval of the hospital’s pharmaceutical committee, treatment with tofacitinib 5 mg/12 hours was prescribed five months after the last unsuccessful treatment (dexa methasone minipulses). complete blood count, liver and kidney function tests, electrolytes, thyroid function, sero logy tests for hepatitis b and c, hiv and tuberculin skin test were within normal ranges. a 40% regrowth of the hair of the scalp was observed at three months [figure 2]. at six months, the patient’s remaining hair loss was equivalent to salt i (less than 25% total hair loss) with a substantial improvement of her quality of life as recored on the dermatology quality of life index from 25 to 3 [figure 3]. routine biochemical tests, such as hepatic and kidney function tests and lipid profile showed no anomalies during the course of the treatment. the patient is currently continuing treatment with no side effects reported for the previous 10 months. comment tofacitinib is an inhibitor of janus kinase-3 and is approved by the food and drug administration for the treatment of rheumatoid arthritis (ra). craiglow and king first observed the effectiveness of tofacitinib in the treatment of alopecia areata.1 subsequently, retros pective studies with more than 90 patients and clinical trials using the dosage approved for ra evaluated its shortand medium-term effectiveness.2 alopecia areata is considered an autoimmune disease with a 1.7% incid ence rate. scalp biopsy will not help in determining the cause of alopecia in such patients. sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e77–78, epub. 30 may 19 submitted 30 oct 18 revision req. 13 dec 18; revision recd. 16 dec 18 accepted 3 jan 19 figure 1: photographs of the scalp of a 37-year-old female patient showing alopecia totalis, which is an advanced form of alopecia areata. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.015 interesting medical image https://creativecommons.org/licenses/by-nd/4.0/ the role of tofacitinib in the management of alopecia totalis e78 | squ medical journal, february 2019, volume 19, issue 1 treatment with tofacitinib may be adapted according to previously reported cases.3 frequent side effects include grade i and ii infections, transaminitis and temp orary cholesterol elevations. nevertheless, doses greater than 10 mg twice a day may be associated with an increased risk of serious infections and malignancies.2 the salt score will be imperative to determine the severity and monitor the response to treatments, using either the original salt i or salt ii (determined by adding the percentage of hair loss in various areas of the scalp). analysis of gene expression can be crucial to identify non-responders and slow responders and adjust the treatment in a timely manner. further research to determine protocols of use, monotherapy and combined therapy and monitoring the side effects of alopecia areata are required. unfortunately, the discontinuation of tofacitinib can cause relapse of the alopecia.3 references 1. craiglow bg, king ba. tofacitinib for the treatment of alopecia areata in preadolescent children. j am acad dermatol 2019; 80:568−70. https://doi.org/10.1016/j.jaad.2018.08.041. 2. iorizzo m, tosti a. emerging drugs for alopecia areata: jak inhi bitors. expert opin emerg drugs. 2018; 23:77−81. https://doi.org/10. 1080/14728214.2018.1444750. 3. kostovic k, gulin sj, mokos zb, ceovic r. tofacitinib, an oral janus kinase inhibitor: perspectives in dermatology. curr med chem 2017; 24:1158−67. https://doi.org/10.2174/18744672106 66170113104503. figure 2: photographs of the scalp of a 37-year-old female patient after three months of treatment with tofacitinib. figure 3: photographs of the scalp of a 37-year-old female patient after six months of treatment with tofacitinib. https://doi.org/10.1016/j.jaad.2018.08.041 https://doi.org/10.1080/14728214.2018.1444750 https://doi.org/10.1080/14728214.2018.1444750 https://doi.org/10.2174/1874467210666170113104503 https://doi.org/10.2174/1874467210666170113104503 1department of radiology & molecular imaging, sultan qaboos university hospital, muscat, oman; departments of 2histopathology, 3radiology and 4medicine, royal hospital, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com الورم الرئوي احلبييب الزجاجي تقرير حالتني امني كمونة، فاطمة اللواتية، اثيل كمونة، نا�رش البو�شعيدي، يعقوب املحروقي، �شقر الطائي، نبيل اللواتي، را�شد بن �شيف العمريي abstract: pulmonary hyalinising granuloma (phg) is a rare fibrosclerosing inflammatory lung condition of unknown aetiology. it is characterised by solitary or multiple pulmonary nodules that are usually found incidentally while imaging the chest for other reasons. we report two cases of histologically proven phg diagnosed at the royal hospital, muscat, oman. the first case was a 71-year-old male patient who presented in 2010 with a dry cough, weight loss and bilateral pulmonary nodules. the second case was a 58-year-old male patient who presented in 2012 and was found to have incidental bilateral pulmonary nodules on chest x-ray. both patients were started on prednisolone and on follow-up the phg nodules remained stable. although there is no definitive treatment, phg generally has an excellent prognosis. keywords: granuloma; x-ray computed tomography; multiple pulmonary nodules; lung; case report; oman. امللخ�ص: الورم الرئوي احلبيبي الزجاجي هو نوع نادر من التهابات الرئة املت�شفة بالتليف والتحجر والذي ال يعرف م�شببه حتى االآن. يتميز الورم الرئوي احلبيبي الزجاجي بوجود عقدة رئوية وحيدة اأو بوجود جمموعة من العقد الرئوية والتي عادة ما يتم اكت�شافها عن ت�شخي�شهما اإثبات مت والتي الزجاجي احلبيبي الرئوي للورم حالتني هنا نعر�س اأخرى. الأ�شباب ال�شدر ت�شوير اأثناء ال�شدفة طريق يف امل�شت�شفى ال�شلطاين، م�شقط، �شلطنة عمان عن طرق درا�شة االأن�شجة من العينات املاأخوذة من العقد الرئوية. كانت احلالة االأوىل يف عام يف الثانية احلالة وكانت رئوية. عقد لديه ووجد الوزن يف وفقدان �شعال من يعاين كان عاما العمر 71 من يبلغ لرجل عام 2010 باإ�شتخدام املري�شني عالج مت واليمنى. الي�رشى الرئتني يف عقد عدة بال�شدفة لديه وجد والذي عاما 58 العمر من يبلغ لرجل 2012 الربيدنيزولون. خالل املتابعة ظلت بقية العقد الروية ثابتة يف احلجم من دون تغري. تبقى توقعات �شري املر�س ممتازة على الرغم من عدم وجود عالج اأكيد للورم الرئوي احلبيبي الزجاجي. عمان. حالة؛ تقرير رئة؛ متعددة؛ رئوية عقيدات مقطعية؛ �شينية اأ�شعة حبيبي؛ ورم املفتاحية: الكلمات pulmonary hyalinising granuloma a report of two cases ameen kamona,1 fatma al lawati,2 atheel kamona,3 nasser al busaidi,4 yaqoob al mahrooqi,4 saqar al-tai,3 nabil al lawati,4 *rashid s. al-umairi3 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e157–160, epub. 8 sep 19 submitted 2 jan 18 revision req. 13 mar 19; revision recd. 25 mar 19 accepted 18 apr 19 pulmonary hyalinising granuloma (phg) is a rare fibrosclerosing inflammatory lung disease which was first reported by benfield et al. in 1962 and then characterised by engleman et al. in 1977.1,2 patients with phg might have non-specific mild symptoms or be asymptomatic. the presence of phg is usually discovered incidentally by chest x-ray or computed tomography (ct) scan performed for other reasons.3 phg is characterised by either unilateral or bilateral multiple pulmonary nodules which consist of extracellular, eosinophilic hyaline lamellae, surrounded by a collection of plasma cells, lymphocytes and histio cytes.2–5 although an exaggerated immune response to the antigenic stimuli by infection or autoimmune processes has been proposed as an aetiology, the exact pathophysiology of phg remains unknown.3 on imaging, phg presents as solitary or multiple pulmonary nodules that can mimic other more common pulmonary disorders, such as neoplastic and granulo matous conditions.3 to the best of the authors’ knowledge, these are the first cases of phg reported in oman. case one a 71-year-old male patient was referred to the royal hospital, muscat, oman, in 2010 for the further work-up of lung lesions found on a chest ct scan. he had diabetes and hypertension and complained of a six-month history of dry cough associated with weight loss. there was no history of smoking, haemoptysis, anorexia or fever. on physical examination, there were bilateral palpable supraclavicular lymph nodes, but an otherwise unremarkable systemic examination. lab oratory tests were normal, including complete blood count, renal function test, liver function test, rheumatoid factor and antinuclear antibody. chest x-ray showed bilateral pulmonary nodules and further evaluation this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.013 case report https://creativecommons.org/licenses/by-nd/4.0/ pulmonary hyalinising granuloma a report of two cases e158 | squ medical journal, may 2019, volume 19, issue 2 however, the patient developed prostate cancer after three years following the diagnosis of phg. case two a 58-year-old male patient with a known history of paraparesis due to myelopathy since 2009 presented to the neurology clinic at the royal hospital, in 2012 with a history of painless haematuria, significant weight loss and generalised abdominal pain. the patient had no history of smoking. physical examination was normal except for rhonchi on the left lung and stable neuro logical deficits. urine analysis was positive for blood, leukocytes and protein. other laboratory tests were normal, including complete blood count and renal and liver function tests. abdominal ultrasound showed diffuse bladder wall thickening and trabeculation with a moderate right hydroureteronephrosis; no renal calculi were detected. the patient was treated as having a urinary tract infection; however, his chest x-ray showed bilateral multiple pulmonary nodules and masses [figure 3]. ct scans of the abdomen, chest and pelvis were perf ormed for further work-up and showed multiple pul monary nodules and masses, some of which were calcified [figure 4]. there were also multiple enlarged mediastinal lymph nodes and some had evidence of calcification with no identifiable primary source. based on the ct findings, radiological differential diagnoses included lymphoma and metastasis from an unknown primary and histopathological correlation was recomm ended. bone scan showed no evidence of bone metastasis. both the afb test and tb culture were negative. bronchoscopy was performed and bal was negative for malignant cells as well as for afb. the tb culture from the bronchial lavage was also negative. pulmonary nodules were further evaluated with a ctguided lung biopsy and the histopathological report was inconclusive. subsequently, a right thoracoscopic with a chest ct scan revealed bilateral pulmonary nodules and masses associated with nodular inter lobular septal thickening, along with extensive bilateral hilar and mediastinal lymphadenopathy. some pulmonary nodules showed central calcification [figure 1]. there was a small right-sided pleural effusion. findings from the chest ct scan were suggestive of a metastatic process from an unknown primary source. f-18-fluor deoxyglucose positron emission tomography/ct (fdg pet/ct) was performed; however, no extrathoracic lesion could be seen. the decision was made to obtain a tissue sample from the lung nodules. bronchoscopy was performed and bronchoalv eolar lavage (bal) was tested. findings were negative for malignant cells and acid-fast bacilli (afb). the tuberculosis (tb) culture from bronchial lavage was also negative. subsequently, ct-guided biopsy of the pulmonary nodule was performed. microscopic exam ination of the obtained tissue sample using haemat oxylin and eosin stain showed a thick relatively acellular eosinophilic collagen bundle with lamellar arrangement that formed a storiform pattern [figure 2]. the congo red stain for amyloid was negative. histopathological findings were consistent with phg. the patient was started on prednisolone 30 mg for two months and then 5 mg for another ten months. the phg nodules remained stable on follow-up; figure 2: haematoxylin and eosin stains of a pulmonary hyalinising granuloma nodule tissue sample obtained from a 71-year-old male patient (case one). a: lung core biopsy at x5 magnification showing fascicles of collagen. b: lung wedge biopsy at x2 magnification showing keloid-like collagen surrounded by a rim of lymphocytes. figure 1: high resolution computed tomography scans of the chest of a 71-year-old male patient (case one) in (a) axial and (b) coronal views showing bilateral pulmonary nodules (black and red arrows) and central calcification in the right upper lobe nodule (red arrow). ameen kamona, fatma al lawati, atheel kamona, nasser al busaidi, yaqoob al mahrooqi, saqar al-tai, nabil al lawati and rashid s. al-umairi case report | e159 lung biopsy and nodular excision were performed. histopathological findings of the excised tissue were consistent with phg. the patient was counselled about the benign nature of the diagnosis and treated with prednisolone, initially 30 mg for three months and then gradually decreased over another three months. the patient was followed-up for five years and the pulmonary nodules remained stable. however, the patient developed hodgkin’s lymphoma five years following the diagnosis of phg. discussion phg is a rare benign pulmonary disorder that is characterised by single or multiple pulmonary nodules. it is more predominant in males, with a mean age of 44.6 years (range: 15–83 years) at presentation.3 patients with phg can present with mild and non-specific symptoms such as cough, fever, fatigue, dyspnoea and pleuritic chest pain. however, up to 25% of patients might be completely asymptomatic, with the pulmonary lesions detected incidentally while imaging the chest for other reasons. in the current cases, the first patient had a history of cough for six months associated with weight loss, while the second patient had pulmonary figure 3: coronal chest x-ray of a 58-year-old male patient (case two) showing bilateral pulmonary nodules and masses (black arrows), predominantly in the right lung. figure 4: high resolution computed tomography scans of the chest of a 58-year-old male patient (case two) in (a) axial and (b) coronal views showing bilateral pulmonary nodules (black and red arrows) and central calcification in the right upper lobe nodule (red arrow). nodules that were detected incidentally while the patient was being evaluated for abdominal complaints. although the cause of phg is unknown, it has been associated with infection and autoimmune and neoplastic disorders.3,4,6–12 lhote et al. reported a series of five phg cases and reviewed 135 cases in the literature; they found that 19 cases were associated with infectious causes, of which tb was the most common infection. in the same study, 17 cases were associated with auto-immune disease and an association with mediastinal and retroperitoneal fibrosis was found in 19 and 12 cases, respectively.3 therefore, it has been proposed that phg might be caused by an abnormal immune response to all of the above conditions. chapman et al. reported a case of phg and found elevated serum immunoglobulin (ig)g4 and tissue igg4-postive plasma cell in the phg and concluded that phg is part of igg4 related-sclerosing disease.12 in the current cases, neither of the patients were tested for igg4 level. in lhote et al.’s study, phg was found to be associated with solid tumours in six cases, including breast paget’s disease, lung adenocarcinoma, menin gioma, anaplastic astrocytoma, thyroid carcinoma and basocellular carcinoma.3 ren et al. reported an association between phg and lymphoma.13 the current patients had developed two different malignant tumours on follow-up: the first patient developed prostate cancer, while the second developed hodgkin’s lymphoma. this suggests a possible association between phg and the future development of malignancies, which needs to be further explored. on chest x-ray and ct, phg is characterised by solitary or, more often, multiple randomly distributed, unilateral or bilateral pulmonary nodules and/or masses without preferential distribution. the phg nodules are usually well-defined and homogeneous, ranging in size from several millimetres to 5 cm in diameter, with an average diameter of 2 cm. they can calcify but rarely cavitate. up to 60% of phg lesions show increased metabolic activity using fdg-pet/ct.3–12,14–16 radiological findings in phg can mimic other nodular pulmonary disorders such as neoplastic and granulomatous processes; hence, radiological differ ential diagnosis should include sarcoidosis, rheumatoid nodules, wegener’s granulomatosis, tb and amyloi dosis, as well as primary or metastatic tumours of the lung.3,9,10,12,15 therefore, histopathological examination is required to diagnose phg and differentiate it from other nodular pulmonary disorders. in the present two cases, the radiological findings of both patients are similar to those reported in the literature, with bilateral randomly distributed pulmonary nodules, some of which showed calcification. both pulmonary hyalinising granuloma a report of two cases e160 | squ medical journal, may 2019, volume 19, issue 2 2. engleman p, liebow aa, gmelich j, friedman pj. pulmonary hyalinizing granuloma. am rev respir dis 1977; 115:997–1008. 3. lhote r, haroche j, duron l, girard n, lafourcade mp, martin m, et al. pulmonary hyalinizing granuloma: a multicenter study of 5 new cases and review of the 135 cases of the literature. immunol res 2017; 65:375–85. https://doi.org/10.1007/s12026-0 16-8852-4. 4. uçvet a1, tözüm h, gürsoy s, gülle aa, yaldiz s, aydoğdu dinç z. [pulmonary hyalinizing granuloma mimicking pulmonary carcinoma]. tuberk toraks 2006; 54:71–4. 5. shinohara t, kaneko t, miyazawa n, nakatani y, nishiyama h, shoji a, et al. pulmonary hyalinizing granuloma with laryngeal and subcutaneous involvement: report of a case successfully treated with glucocorticoids. intern med 2004; 43:69–73. 6. ussavarungsi k, khoor a, jolles hi, mira-avendano i. a 40-year old woman with multiple pulmonary nodules. pulmonary hyali nizing granuloma. chest 2014; 146:e198–203. https://doi.org/10.1 378/chest.14-0796. 7. lien ct, yang cj, yang sf, chou sh, huang ms. pulmonary hyalinizing granuloma mimicking multiple lung metastases: report of fluorodeoxyglucose positron emission findings. j tho rac imaging 2010; 25:w36–9. https://doi.org/10.1097/rti.0b01 3e3181a4bb41. 8. kaneta t, saito a, akiyama t, takahashi y, takahashi r, kudou k. [a case of pulmonary hyalinizing granuloma with high-grade uptake on fdg-pet mimicking metastatic lung cancer]. nihon kokyuki gakkai zasshi 2009; 47:953–9. 9. düzgün n, kurtipek e, esme h, eren karanis mi̇, tolu i̇. pulmo nary hyalinizing granuloma mimicking metastatic lung cancer. case rep pulmonol 2015; 2015:610417. https://doi.org/10.1155/2 015/610417. 10. colen rr, nagle ja, wittram c. radiologic-pathologic confe rence of the massachusetts general hospital. pulmonary hyali nizing granuloma. ajr am j roentgenol 2007; 188:w15–16. https://doi.org/10.2214/ajr.06.0380. 11. coleman c, nassar a, mccomb b. pulmonary hyalinizing granuloma associated with idiopathic thrombocytopenic pur pura. j clin imaging sci 2014; 4:8. https://doi.org/10.4103/21567514.127835. 12. chapman em, gown a, mazziotta r, churg a. pulmonary hyalinizing granuloma with associated elevation in serum and tissue igg4 occurring in a patient with a history of sarcoidosis. am j surg pathol 2012; 36:774–8. https://doi.org/10.1097/pas.0 b013e318248713d. 13. ren y, raitz en, lee kr, pingleton sk, tawfik o. pulmonary small lymphocytic lymphoma (mucosa-associated lymphoid tis sue type) associated with pulmonary hyalinizing granuloma. chest 2001; 120:1027−30. https://doi.org/10.1378/chest.120.3.1027. 14. satti mb, batouk aa, abdelaziz mm, ahmad mf, abdelaal ma. pulmonary hyalinizing granuloma. bilateral pulmonary nodules associated with chronic idiopathic thrombocytopenic purpura. saudi med j 2005; 26:1459–63. 15. lvovsky d, rosman j, iliescu me. pulmonary hyalinizing granuloma (phg) presenting as bilateral dense apical masses. chest 2004; 126:950s. https://doi.org/10.1378/chest.126.4_mee tingabstracts.950s. 16. atagi s, sakatani m, akira m, yamamoto s, ueda e. pulmo nary hyalinizing granuloma with castleman's disease. intern med 1994; 33:689–91. https://doi.org/10.2169/internalmedici ne.33.689. patients had mediastinal lymphadenopathy, with some lymph nodes in the second patient showing central calcification. microscopically, phg lesions are composed of a concentric dense network of hyalinised collagen that is centred in the perivascular lymphoplasmacytic infiltrate located in the centre of phg lesions.3,6,8–10,12,16 the prognosis for patients with phg is generally excellent. on follow-up, phg shows a variable course with some nodules changing size and some remaining stable. multiple lesions usually show a more rapid growth rate compared to single lesions.3,12 there is no definitive treatment for phg. although radiological and symptomatic improvement or even successful resolution of the nodules with the administration of glucocorticoids has been reported, the effect of corticosteroids remains unclear.3,5 surgical resection in patients with a solitary phg nodule has been reported as a cure.3,4,12 the current two patients received oral prednisolone; however, the nodules remained stable in size on follow-up chest ct scan. conclusion phg is a rare fibrosclerosing inflammatory pulmonary disease that can mimic other nodular pulmonary disorders such as neoplastic and granulomatous processes; therefore, it should be included in the differential diagnosis of pulmonary nodules or masses. few reported cases of pgh in the literature developed extra-pulmonary malignancy on follow-up, however, this was the case for both current patients. there is a possible association between phg and the future development of malignancy, which needs to be further explored and should warrant close follow-up of patients with proven phg. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. benfield jr, harrison rw, moulder pv, lyon es, graff pw. bilateral nodular pulmonary granulomas and retroperitoneal fibrosis. simulated metastatic malignant neoplasm and spont aneous remission of ureteral obstruction. jama 1962; 182:579–81. https://doi.org/10.1001/jama.1962.03050440071021e. https://doi.org/10.1007/s12026-016-8852-4 https://doi.org/10.1007/s12026-016-8852-4 https://doi.org/10.1378/chest.14-0796 https://doi.org/10.1378/chest.14-0796 https://doi.org/10.1097/rti.0b013e3181a4bb41 https://doi.org/10.1097/rti.0b013e3181a4bb41 https://doi.org/10.1155/2015/610417 https://doi.org/10.1155/2015/610417 https://doi.org/10.2214/ajr.06.0380 https://doi.org/10.4103/2156-7514.127835 https://doi.org/10.4103/2156-7514.127835 https://doi.org/10.1097/pas.0b013e318248713d https://doi.org/10.1097/pas.0b013e318248713d https://doi.org/10.1378/chest.120.3.1027 https://doi.org/10.1378/chest.126.4_meetingabstracts.950s https://doi.org/10.1378/chest.126.4_meetingabstracts.950s https://doi.org/10.2169/internalmedicine.33.689 https://doi.org/10.2169/internalmedicine.33.689 https://doi.org/10.1001/jama.1962.03050440071021e in the era of social media is it time to establish a code of online ethical conduct for healthcare professionals? amal a. al-balushi sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e25–28, epub. 9 mar 20 submitted 24 jul 19 revision req. 17 sep 19; revision recd. 30 oct 19 accepted 3 dec 19 muscat directorate of general health services, ministry of health, muscat, oman e-mail: amel.albulushi@gmail.com the use of social media has significantlyreduced personal privacy of individuals.1 healthcare professionals are no exception as they often use social media as a marketing tool for their services, a way to provide health education, for research or as a socialisation tool.2 use of social media by professionals carries some risk as shared posts can be permanent.3 since the personal life of a healthcare professional can affect his or her professional life, a number of countries have developed guidelines for the use of social media by healthcare professionals.4,5 to date, there are no guidelines in oman for the use of social media by healthcare professionals. when healthcare professionals and patients interact on social media, it is often initiated by patients.6 while discussions regarding medical issues in online forums do have considerable educational value, such interactions may carry a risk of misconduct. a study done in the usa showed that the most common forms of online-professionalism violations included inappropriate communications with patients—specif ically internet prescribing, misrepresentation of credentials and sexual misconduct.7 the medical profession deals with the health and lives of people and has traditionally been respected and trusted by the public. this positive view is essential sounding board يف عصر وسائل التواصل االجتماعي هل حان الوقت لوضع مدونة للسلوك األخالقي الستخدام اإلنرتنت للعاملني يف جمال الرعاية الصحية؟ اأمل اأحمد البلو�صية abstract: social media is becoming an invasive part of the lives of many professionals including those in the healthcare field. one of the countless implications of such an invasion is how the healthcare professional’s engagement with social media affects the traditional doctor-patient relationship. the online presence of professionals should be carefully self-monitored as it affects the individual’s reputation and society’s perception of their profession. therefore, the contents of public and personal accounts must differ according to their purpose. in the public eye, conflicts of interest must be declared and scientifically-based medical advice should be clearly differentiated from experience-based advice, personal opinions or commercial advertisements. online doctorpatient relationships risk the privacy of patients as well as the personal privacy of the healthcare professional. personal accounts created for friends and family should be kept separate from public accounts created for educational, professional or commercial purposes. published educational material should be clearly differentiated from commercial material so that it is easier for the public to make an informed decision. this paper proposes a code of online ethical conduct to be implemented in oman. keywords: codes of ethics; social media; health personnel; privacy; confidentiality; conflict of interest; physician-patient relations; oman. الرعاية جمال يف العاملني ذلك يف مبا املهنيني من العديد حياة من يتجزاأ ل جزًءا الجتماعي التوا�صل و�صائل اأ�صبحت امللخ�ص: ال�صحية. من الآثار التي ل ح�رش لها يف هذا املجال هو تاأثري و�صائل الجتماعي على العالقة التقليدية بني الطبيب واملري�س. يجب اأن تتوافر املراقبه الذاتية للعاملني يف املجال ال�صحي عند م�صاركتهم يف و�صائل التوا�صل الجتماعي بعناية فائقة ملا له من تاأثري على النا�س، عامة نظر يف لأهدافها. وفًقا وال�صخ�صية العامة احل�صابات حمتويات تختلف اأن يجب للمهنه. املجتمع وت�صور الأفراد �صمعة اخلربة على القائمة وامل�صورة العلم على القائمة الطبية امل�صورة بني وا�صح ب�صكل التمييز ويجب امل�صالح ت�صارب عن الإعالن يجب اأو الآراء ال�صخ�صية اأو الإعالنات التجارية. العالقات بني الطبيب واملري�س عرب و�صائل التوا�صل الجتماعي تهدد خ�صو�صية املر�صى منف�صلة والعائلة لالأ�صدقاء اإن�صاوؤها يتم التي ال�صخ�صية احل�صابات تظل اأن يجب ال�صحيني. للعاملني ال�صخ�صية اخل�صو�صية وكذلك عن احل�صابات العامة التي يتم اإن�صاوؤها لأغرا�س تعليمية اأو مهنية اأو جتارية. يجب متييز املواد التعليمية املن�صورة بو�صوح عن املواد التجارية حتى ي�صهل على اجلمهور اتخاذ قرار م�صتنري. لذلك تقرتح هذه الورقة طرح مدونة لل�صلوك الأخالقي يف ا�صتخدام الإنرتنت يف هذا املجال ليتم تنفيذها يف عمان. الكلمات املفتاحية: مدونات ال�صلوك الأخالقي؛ و�صائل التوا�صل الجتماعي؛ موظفو ال�صحة؛ اخل�صو�صية؛ ال�رشية؛ ت�صارب امل�صالح؛ العالقات بني الطبيب واملري�س؛ �صلطنة عمان. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.004 https://creativecommons.org/licenses/by-nd/4.0/ in the era of social media is it time to establish a code of online ethical conduct for healthcare professionals? e26 | squ medical journal, february 2020, volume 20, issue 1 as patient compliance and prognosis are dependent on such trust. healthcare professionals have significant influence over their patients which should not be misused for their personal benefit. engaging with a patient online can affect the doctor-patient relationship and may lead to personal or even romantic relationships.8 online professional image the image and behaviour of healthcare professionals outside of work should be a personal matter. however, their public image outside of work—online or other wise—becomes a professional matter as it represents their profession. society expects that its healthcare professionals be role models that can be emulated, that are healthy and fit, free from addictions, not prone to extramarital affairs and generally free from behavioural issues. it is likely that patients might have less faith in a healthcare professional’s abilities when they are not capable of solving their own problems. as a result of the long-term and easy availability to an online personality and by the nature of their profession, healthcare professionals have an inherent influence on society and are therefore obliged to lead by example. this responsibility is inherent to the medical profession, as well as any other professions which can influence people’s opinions, ideas, thoughts and behaviours. the medical profession requires some commit ment that extends to the private lives of those working within it, as the public scrutinise these professional’s online behaviour. the medical profession has an influence on society in terms of what is healthy and not healthy regarding products, practices and lifestyles. people expect healthcare professionals and providers to adhere to the advice that they give. describing patients or colleagues in a negative light in online forums affects current and future doctor patient relationships.9 social media should be used positively to promote health and to set an example of online professional behaviour.10 the online image of healthcare professionals may provoke an unconscious judgment which may affect the belief in the profession and hence adherence to any proposed treatment plans. the online image can also affect the professional’s reputation as well as the reputation of the profession itself.3,7 medical schools should begin by teaching medical students about the consequences of poor online behaviour.10 while senior healthcare professionals usually concentrate on formal teaching and training activities, they may forget that informal teaching is continuously occurring through the behaviours they model. therefore, senior healthcare professionals should actively act as role models for junior healthcare professionals.11 additionally, inappropriate comments or photographs of compromising behaviour on social media forums can not only tarnish the image of the professional but also have an impact on their affiliated institution’s reputation.12 furthermore, online posts are difficult to delete if they are shared and become permanent, thereby staining a medical professional’s record.3,13 social networking, confidentiality and conflicts of interest social networking is a very useful way of communicating with the public. healthcare professionals can use social media positively to follow and support their patients and to increase awareness and educate the public about health-related issues.14,15 however, the public needs to be aware of the high possibility of misinformation on social media channels.15 online information may only be partially accurate and not fully represent an individual’s case.16 even factual information can cause confusion or unnecessary anxiety; for example, an individual with iron-deficiency anaemia may think that they have cancer upon reading ‘fatigue’ as a symptom of cancer. fake accounts, which present false credentials or profiles that pose as someone they are not by using a real doctor’s name, are harmful as they disseminate inaccurate information which can harm patients’ health and affect public trust in the profession. moreover, society needs to learn how to differentiate between opinion, advertisement, experience-based advice and scientific evidence-based advice. social media can violate one’s privacy and can be used to violate other’s privacy and confidentiality.2 professional social media accounts should not be used to share details of one’s personal life with the public. while healthcare professionals should certainly not live in isolation, it is recommended that personal accounts not be shared with the public. if the account is made accessible to the public, content on personal accounts should be carefully curated. alternatively, a professional can have two accounts, one personal and private and another professional and public. the user name of personal accounts should not include a prof essional title such as ‘dr’ or professional credentials. it is advisable to set the privacy settings to ‘high’ on personal accounts.3 however, one should still be cautious with content in general as privacy cannot be guaranteed. a healthcare professional should not post anything unless they would be comfortable if that content went public.16 doctors and healthcare providers can ethically use social media to communicate with colleagues, for public education, to advertise their services or to pro amal a. al balushi sounding board | e27 mote products that they think would be beneficial.2 however, it would be unethical to promote a specific pharmaceutical product or company. healthcare pro viders are supposed to promote the health of the public; however, it is assumed that promoting specific products is more about the promotion of personal wealth. this also applies to healthcare professionals who run their own businesses in the pharmaceutical or cosmetic industry. medical advice must be distinguished from marketing by full disclosure. whereas in classic print media, advertorials in magazines stated in small print that they were selling something, in this new era of social media, this type of disclosure is often overlooked. moreover, healthcare professionals need to disclose any conflicts of interests when marketing a product. if such a disclosure is not made, a conflict of interest might arise as marketing could be mistaken for medical advice. ultimately, disclosure alone may not be sufficient and any conflict of interest should be avoided by healthcare professionals not engaging in marketing in the first place. regarding confidentiality, using social media channels to share patient cases might harm the patient and expose their identity.9 publicly sharing photos of patients for educational or marketing purposes or with other professionals for consultations is unethical as it jeopardises the patient’s confidentiality and privacy unless written consent is provided by the patient; this is regardless of whether the photograph contains identifying information or not.17 not adhering to such guidelines have resulted in some healthcare professionals losing their practicing license and/or career.17 written consent in such cases is of vital import ance to protect the patient’s privacy and the physician from liability as such photographs are difficult to remove by the non-consenting patient once published online and shared.17 accessing patient information online poses another issue for healthcare providers. psychiatrists can use social media profiles of their patients to gain additional collateral history as some patients cannot provide a reliable history.18 neurol ogists or intensive care unit professionals can also use social media to find the profiles of trauma or comatose patients. although such use could aid in diagnosis, it should not be done without the patient’s or next of kin’s consent. therapeutic doctor-patient relationship accepting requests from patients to connect online may risk the integrity of the therapeutic relationship.9,19 it can also risk exposing personal information about the physician that would not be revealed in a regular doctor-patient relationship.9 therefore, it is advisable not to accept online requests from patients on any social media platform as this might lead to power imbalances in the therapeutic relationship. the physician can discuss why accepting such communications is unethical and can affect the therapeutic relationship with the patient during an appointment.19 on one hand, some patients might feel more at ease consulting a general practitioner online.20 on the other hand, the physical examination, which is an important part of the medical consultation, cannot be done online and therefore online consult ation is considered an unacceptable clinical practice.20 in addition, the source and eligibility of the person providing medical recommendations via social media can be difficult to verify.21 furthermore, such advice or recommendation did not undergo a peer-review process.22 because of these reasons, online advice should be given and received with caution. conclusion the use of social media networks by medical prof essionals and its associated ethical dilemmas necess itates its regulation. social media use by healthcare professionals can have implications on the doctor-patient relationship, public trust in the profession as well as possible litigation. each individual should take respons ibility and accountability for their posts on social media platforms. if a medical professional would like to have a personal account, then they should not be identifiable as a medical professional in that account. in addition, it is advisable to act modestly even in personal accounts. accounts created for medical purposes, for example, to educate the public, raise awareness about health-related issues or advertise for a licensed private practice, should provide clear medical identification. furthermore, such public accounts should be managed carefully and the material posted should be presented appropriately. interactions with patients are discouraged and should never take place via personal accounts. healthcare workers should be taught and encouraged to act professionally; it is fellow professionals that should establish a norm regarding online behaviour that others may then follow. establishing a code of online ethical conduct in oman would help to draw a line between professional and non-professional online behaviour. references 1. senthil kumar n, saravanakumar k, deepa k. on privacy and security in social media – a comprehensive study. procedia comput sci 2016; 78:114–19. https://doi.org/10.1016/j. procs.2016.02.019. 2. milton cl. ethics and social media. nurs sci q 2014; 27:283–5. https://doi.org/10.1177/0894318414546417. https://doi.org/10.1016/j.procs.2016.02.019 https://doi.org/10.1016/j.procs.2016.02.019 https://doi.org/10.1177/0894318414546417 in the era of social media is it time to establish a code of online ethical conduct for healthcare professionals? e28 | squ medical journal, february 2020, volume 20, issue 1 3. rouprêt m, morgan tm, bostrom pj, cooperberg mr, kutikov a, linton kd, et al. european association of urology (@uroweb) recommendations on the appropriate use of social media. eur urol 2014; 66:628–32. https://doi.org/10.1016/j.eururo.2014.06.046. 4. federation of state medical boards. social media and elec tronic communications. from: http://www.fsmb.org/siteassets /advocacy/policies/social-media-and-electronic-commun ications.pdf accessed: oct 2019. 5. british medical association. social media guidance for doctors. from: https://www.bma.org.uk/advice/employment/ethics/soc ial-media-guidance-for-doctors accessed: oct 2019. 6. bosslet gt, torke am, hickman se, terry cl, helft, pr. the patient-doctor relationship and online social networks: results of a national survey. j gen intern med 2011; 26:1168–74. https://doi.org/10.1007/s11606-011-1761-2. 7. greysen sr, chretien kc, kind t, young a, gross cp. physician violations of online professionalism and disciplinary actions: a national survey of state medical boards. jama 2012; 307:1141–2. https://doi.org/10.1001/jama.2012.330. 8. guseh js 2nd, brendel rw, brendel dh. medical professionalism in the age of online social networking. j med ethics 2009; 35:584–6. https://doi.org/10.1136/jme.2009.029231. 9. gabbard go, kassaw ka, perez-garcia g. professional bound aries in the era of the internet. acad psychiatry 2011; 35:168–74. https://doi.org/10.1176/appi.ap.35.3.168. 10. greysen rs, kind t, chretien kc. online professionalism and the mirror of social media. j gen intern med 2010; 25:1227–9. https://doi.org/10.1007/s11606-010-1447-1. 11. paice e, heard s, moss f. how important are role models in making good doctors? bmj 2002; 325:707–10. https://doi.org/10.1136/ bmj.325.7366.707. 12. farnan jm, paro ja, higa jt, reddy st, humphrey hj, arora vm. commentary: the relationship status of digital media and prof essionalism: it’s complicated. acad med 2009; 84:1479–81. https://doi.org/10.1097/acm.0b013e3181bb17af. 13. landman mp, shelton j, kauffmann rm, dattilo jb. guide lines for maintaining a professional compass in the era of social networking. j surg educ 2010; 67:381–6. https://doi.org/10.10 16/j.jsurg.2010.07.006. 14. korda h, itani z. harnessing social media for health promotion and behavior change. health promot pract 2013; 14:15–23. https://doi.org/10.1177/1524839911405850. 15. elkhayat h, amin mt, thabet ag. patterns of use of social media in cardiothoracic surgery; surgeons’ prospective. j egypt soc cardiothorac surg 2018; 26:231–6. https://doi.org/10.101 6/j.jescts.2018.07.003. 16. terrasse m, gorin m, sisti d. social media, e-health, and medical ethics. hastings cent rep 2019; 49:24–33. https://doi. org/10.1002/hast.975. 17. palacios-gonzález c. the ethics of clinical photography and social media. med health care philos 2015; 18:63–70. https:// doi.org/10.1007/s11019-014-9580-y. 18. appelbaum ps, kopelman a. social media's challenges for psychiatry. world psychiatry 2014; 13:21–3. https://doi.org/10.10 02/wps.20085. 19. chretien kc, kind t. social media and clinical care: ethical, professional, and social implications. circulation 2013; 127:1413–21. https://doi.org/10.1161/circulationaha.112.128017. 20. derse ar, miller te. net effect: professional and ethical chall enges of medicine online. camb q healthc ethics 2018; 17:453–64. https://doi.org/10.1017/s0963180108080572. 21. lagu t, kaufman ej, asch da, armstrong k. content of weblogs written by health professionals. j gen intern med 2008; 23:1642–6. https://doi.org/10.1007/s11606-008-0726-6. 22. taubert m. social media in palliative medicine research: jump into the cool water. bmj support palliat care 2018; 8:292–3. https://doi.org/10.1136/bmjspcare-2018-001620. https://doi.org/10.1016/j.eururo.2014.06.046 https://doi.org/10.1007/s11606-011-1761-2 https://doi.org/10.1001/jama.2012.330 https://doi.org/10.1136/jme.2009.029231 https://doi.org/10.1176/appi.ap.35.3.168 https://doi.org/10.1007/s11606-010-1447-1 https://doi.org/10.1136/bmj.325.7366.707 https://doi.org/10.1136/bmj.325.7366.707 https://doi.org/10.1097/acm.0b013e3181bb17af https://doi.org/10.1016/j.jsurg.2010.07.006 https://doi.org/10.1016/j.jsurg.2010.07.006 https://doi.org/10.1177/1524839911405850 https://doi.org/10.1016/j.jescts.2018.07.003 https://doi.org/10.1016/j.jescts.2018.07.003 https://doi.org/10.1002/hast.975 https://doi.org/10.1002/hast.975 https://doi.org/10.1007/s11019-014-9580-y https://doi.org/10.1007/s11019-014-9580-y https://doi.org/10.1002/wps.20085 https://doi.org/10.1002/wps.20085 https://doi.org/10.1161/circulationaha.112.128017 https://doi.org/10.1017/s0963180108080572 https://doi.org/10.1007/s11606-008-0726-6 https://doi.org/10.1136/bmjspcare-2018-001620 departments of 1radiology, 2pathology and 3medicine, the royal hospital, muscat, oman; 4department of radiology, oman medical specialty board, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com cardiac involvement in eosinophilic granulomatosis with polyangiitis (churg-strauss disease) the role of cardiovascular magnetic resonance *rashid s. al umairi,1 khalid al manei,4 fatma al lawati,2 yaqoob al mahrouqi,3 farida al balushi3 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 644–647, epub. 25 nov 21 submitted 7 jul 20 revisions req. 19 aug & 27 oct 20; revisions recd. 4 oct & 9 nov 20 accepted 18 nov 20 a history of fever and cough lasting for two months. on chest auscultation, bilateral scattered rhonchi were detected. other systemic examinations were unremarkable. his chest x-ray showed bilateral upper lung airspace opacification suggestive of an acute infective process [figure 1]. complete blood count (cbc) showed eosinophilia with a value of 4.7 × 109/l (normal range: 0.1–0.5 × 109/l). sputum examination was negative for acid-fast bacilli and there was no growth in the sputum culture. further assessment with a chest ct scan revealed bilateral upper lobe airspace opacities associated with nodular interlobular septal thickening, predominantly with peripheral subpleural distribution. the patient was treated with amoxiclav (1,200 mg three times/day for seven days) but his symptoms did not improve. a repeat chest hrct scan showed stable lung findings [figure 2a]. subsequently, the patient was referred to the chest clinic at a tertiary hospital in 2019 for further management. when the patient was seen, he was still complaining of cough but did not have a fever. his vital signs were stable (temperature = 35.5°c, heart rate = 84 beats per minute, respiratory rate = 20 breaths per minute and blood pressure = 125/68 mmhg). his cbc revealed normal haemoglobin (12.9 g/dl, normal range: 11.5– 15.5 g/d) and white cell count (6.5 × 109/l, normal range: 2.2–10.5 × 109/l); however, the eosinophilic count was high (2.1 × 109/l, normal range: 0.1–0.5 × 109/l). other blood investigations were as follows: urea was 4.8 mmol/l (normal range: 2.5–6.7 mmol/l), eosinophilic granulomatosis with polyangiitis (egpa), historically known as churg-strauss disease, is an uncommon necrotising vasculitis of smallto medium-sized vessels that can involve multiple organs, including the paranasal sinuses, lungs, heart, nervous system, kidneys and gastrointestinal tract.1–3 cardiac involvement in egpa is seen in approximately 45–62% of patients and can present as eosinophilic myocarditis, coronary vasculitis, congestive heart failure, pericarditis or valvular disease.4 cardiovascular magnetic resonance (cmr) is a non-invasive diagnostic tool that can be used to detect cardiac involvement in egpa. typically, myocardial involvement in egpa manifests as subendocardial and midmyocardial late gadolinium enhancement.4 herein, we present a case of histologically confirmed egpa with characteristic findings on chest high-resolution computed tomography (hrct) and cmr. in addition, the role of cardiac magnetic resonance imaging (mri) in the assessment of cardiac involvement in patients with egpa is discussed. to the best of the authors’ knowledge, this is the first case of egpa with cardiac involvement detected by mri to be reported in oman. case report a 39-year-old male patient with a known history of asthma for 24 years and a nasal polypectomy several years earlier presented to a local hospital in 2019 with this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.038 case report abstract: eosinophilic granulomatosis with polyangiitis (egpa), previously known as churg-strauss disease, is a rare vasculitis that affects smallto medium-sized vessels and has a propensity to involve the heart. patients with cardiac involvement have a poor prognosis and usually require immunosuppressive treatment along with corticosteroids. cardiovascular magnetic resonance (cmr) is a non-invasive diagnostic tool for detecting cardiac involvement and guiding the management plan. we report a 39-year-old male patient with a known history of bronchial asthma who was referred to the chest clinic at a tertiary hospital in 2019 for further assessment of persistent lung parenchymal changes on chest computed tomography. given the clinical context of the patient and the radiological findings, egpa was suspected and confirmed with a lung biopsy. cmr was performed for further assessment, which confirmed cardiac involvement. the patient was started on prednisolone and azathioprine and showed significant radiological and clinical improvement. keywords: eosinophilic granulomatous vasculitis; vasculitis; eosinophils; vascular diseases; anti-neutrophil cytoplasmic antibody-associated vasculitis; case report; oman. rashid s. al umairi, khalid al manei, fatma al lawati, yaqoob al mahrouqi and farida al balushi case report | 645 were not reactive and the protein creatine ratio in urine was 5.2 mg/mmol/l (normal value: <20 mg/ mmol/l). a repeated chest hrct scan at our hospital, performed two months after the initial hrct scan, showed improvement in the previously observed airspace opacities; however, new airspace opacities had developed [figure 2b]. given the patient’s clinical history of asthma, in addition to the blood eosinophilia and migratory chest ct findings, egpa was suspected and a lung biopsy was performed. the tissue biopsy examination confirmed the diagnosis of egpa [figure 3]. the patient was assessed for potential cardiac involvement; his electrocardiogram and echocardiogram were unremarkable. his cmr scan showed normal biventricular function and volume, a left ventricle ejection fraction of 66% and right ventricle ejection fraction of 64%. however, patchy areas of midmyocardium lge were detected, which confirmed cardiac involvement in egpa [figure 4]. egfr was >90 ml/min/1.73 m2 (normal range: >90 ml/min/1.73 m2), serum c-reactive protein was 78 mg/l (normal value is <5 mg/l), immunoglobulin e was 122 iu/ml (normal range: 0–100 iu/ml), pand c-antineutrophil cytoplasmic antibodies (anca) figure 1: chest x-ray of a 39-year-old male patient showing bilateral upper lung zone airspace opacities (arrows). figure 3: haematoxylin and eosin stains at (a) ×20 magnification showing smalland medium-sized blood vessels with intramural eosinophil infiltrate (arrow) and at (b) ×40 magnification showing a non-caseating granuloma with infiltration by eosinophils (arrow). figure 2: chest high-resolution computed tomography axial views of a 39-year-old male patient showing (a) bilateral ground glass and airspace opacity (black arrow) associated with interlobular septal thickening (red arrow) and (b) two months post-initial scan showing improvement of the previously seen airspace opacities and new airspace opacities (black arrow). figure 4: late gadolinium enhancement short-axis (a) oblique and (b) 4-chamber views showing patchy midmyocardium enhancement (arrow). cardiac involvement in eosinophilic granulomatosis with polyangiitis (churg-strauss disease) the role of cardiovascular magnetic resonance 646 | squ medical journal, november 2021, volume 21, issue 4 as part of the assessment for egpa, the patient was tested for anca and his results were negative. the patient was started on prednisolone (5 mg once daily) and azathioprine (150 mg once daily) for nine months. the patient remained on regular follow-up every three months and the patient’s symptoms improved significantly, with normalisation of inflammatory markers and a decrease in c-reactive protein from 78 mg/l to 1 mg/l (normal value: <5 mg/l). his eosinophilic count was observed to have reduced from 2.1 × 109/l to 0.7 × 109/l (normal range: 0.1–0.5 × 109/l). a repeat chest x-ray performed one month after starting treatment showed complete resolution of the lung abnormalities. consent to publish the present clinical details and clinical images was obtained from the patient. discussion eosinophilic granulomatosis with polyangiitis is a rare, systemic disease that was first described by churg and strauss in 1951.1 it has an annual incidence of approximately 0.9 to 2.4 per million individuals, with no difference in distribution between males and females. the median age of onset is usually between 49 and 59 years. approximately 40–60% of patients with egpa are anca-positive; therefore, egpa is classified as anca-associated vasculitis.3 the diagnosis of egpa is widely based on the presence of four of the six criteria proposed by the american college of rheumatology in 1990: peripheral eosinophilia (10% on differential leukocyte count); (2) paranasal sinus abnormality; asthma; (4) migrating pulmonary opacities; (5) mononeuritis multiplex or polyneuropathy; and (6) biopsy evidence of extravascular eosinophils.2,5,6 the current patient fulfilled five of these criteria: asthma, peripheral eosinophilia, nasal polyps, migratory pulmonary opacities and a lung biopsy showing eosinophilic infiltration. there are three distinct phases of egpa: the prodromal period, consisting of asthma and rhinitis and may last for several years; (2) the eosinophilic phase; and the vasculitis phase.7 cardiac involvement in egpa varies widely in the literature, ranging from 16–92%, and it has been associated with increased morbidity and mortality.8,9 egpa with cardiac involvement is more frequently encountered in patients who are anca-negative, and patients can present with acute myocarditis, coronary vasculitis, congestive heart failure, pericarditis and valvular disease.9 cardiac magnetic resonance is a non-ionising imaging modality that has emerged as a non invasive tool for the assessment of structural and functional cardiac abnormalities.10 cmr is a useful non-invasive diagnostic tool that can be used to detect cardiac involvement in egpa. it has been shown that cmr has a sensitivity of 88% and specificity of 72% for detecting cardiac involvement in egpa.11 the most common cmr findings of cardiac involvement are subendocardial lge and left ventricle dilatation with decreased left ventricular systolic function. midmyocardium lge is less commonly seen, indicating that myocardial necrosis in acute setting and fibrosis is related to myocardial damage.12 native t1 and t2 are promising mapping techniques that can be used to detect myocardial fibrosis related to egpa. greulich et al. showed that patients with anca associated vasculitis, including egpa, had higher values for native t1, ecv and t2 compared to controls, irrespective of the presence of lge.13 cardiac mri can also be used to follow-up patients with cardiomyopathy related to egpa. dunogué et al. used cmr to follow-up 15 patients with egpa who showed evidence of cardiac involvement on baseline cmr and received treatment. he reported an improvement in seven patients and stabilisation or worsening in the remaining eight patients.14 cardiac mri has certain drawbacks including high cost, limited availability, long examination duration and the need for the patient to repeatedly hold their breath. the characteristic findings of egpa in the chest hrct, seen in up to 90% of patients, includes bilateral predominantly peripheral subpleural consolidation and airspace opacities. other findings include bronchial wall thickening and dilation along with peribronchial ground-glass nodules.15 the current patient had characteristic chest hrct with bilateral predominantly peripheral ground-glass opacities associated with interlobular septal thickening which were migratory. the five-factor score scale is a widely used prognostic tool for egpa and consists of five characteristics: age >65 years; (2) renal impairment (proteinuria >1 g/24 h or creatinine > 140 μmol/l); cardiac involvement; (4) severe gastrointestinal symptoms; and (5) central nervous system manifestations. patients are considered to have a good prognosis if they have a score of zero; they are classified as having a poor prognosis if they score ≥1 point.16 corticosteroids are classically used for the treatment of patients with a good prognosis, with the addition of immunosuppressive medication, usually rashid s. al umairi, khalid al manei, fatma al lawati, yaqoob al mahrouqi and farida al balushi case report | 647 5. lanham jg, elkon kb, pusey cd, hughes gr. systemic vasculitis with asthma and eosinophilia: a clinical approach to the churg-strauss syndrome. medicine (baltimore) 1984; 63:65–81. https://doi.org/10.1097/00005792-198403000-00001. 6. masi at, hunder gg, lie jt, michel ba, bloch da, arend wp, et al. the american college of rheumatology 1990 criteria for the classification of churg-strauss syndrome (allergic granulomatosis and angiitis). arthritis rheum 1990; 33:1094–100. https://doi.org/10.1002/art.1780330806. 7. greco a, rizzo mi, de virgilio a, gallo a, fusconi m, ruoppolo g, et al. churg-strauss syndrome. autoimmun rev 2015; 14:341–8. https://doi.org/10.1016/j.autrev.2014.12.004. 8. szczeklik w, miszalski-jamka t. cardiac involvement in eosinophilic granulomatosis with polyangitis (churg strauss) (rcd code: i-3a.7a). j rare cardiovasc dis 2014; 1:91–5. https://doi.org/10.20418/jrcd.vol1no3.56. 9. dalia t, parashar s, patel nv, gautam a, dai h, bormann s. eosinophilic myocarditis demonstrated using cardiac magnetic resonance imaging in a patient with eosinophilic granulomatosis with polyangiitis (churg-strauss disease). cureus 2018; 10:e2792. https://doi.org/10.7759/cureus.2792. 10. rajiah p, tandon a, greil gf, abbara s. update on the role of cardiac magnetic resonance imaging in congenital heart disease. curr treat options cardiovasc med 2017; 19:2. https://doi.org/10.1007/s11936-017-0504-z. 11. eyler ae, ahmad fa, jahangir e. magnetic resonance imaging of the cardiac manifestations of churg-strauss. jrsm open 2014; 5:2054270414525370. https://doi.org/10.1177/205 4270414525370. 12. marmursztejn j, vignaux o, cohen p, guilpain p, pagnoux c, gouya h, et al. impact of cardiac magnetic resonance imaging for assessment of churg-strauss syndrome: a cross-sectional study in 20 patients. clin exp rheumatol 2009; 27:s70–6. 13. greulich s, mayr a, kitterer d, latus j, henes j, steubing h, et al. t1 and t2 mapping for evaluation of myocardial involvement in patients with anca-associated vasculitides. j cardiovasc magn reson 2017; 19:6. https://doi.org/10.1186/ s12968-016-0315-5. 14. dunogué b, terrier b, cohen p, marmursztejn j, legmann p, mouthon l, et al. impact of cardiac magnetic resonance imaging on eosinophilic granulomatosis with polyangiitis outcomes: a long-term retrospective study on 42 patients. autoimmun rev 2015; 14:774–80. https://doi.org/10.1016/j. autrev.2015.04.013. 15. silva ci, müller nl, fujimoto k, johkoh t, ajzen sa, churg a. churg-strauss syndrome: high resolution ct and pathologic findings. j thorac imaging 2005; 20:74–80. https://doi. org/10.1097/01.rti.0000155268.00125.de. 16. groh m, pagnoux c, baldini c, bel e, bottero p, cottin v, et al. eosinophilic granulomatosis with polyangiitis (churg-strauss) (egpa) consensus task force recommendations for evaluation and management. eur j intern med 2015; 26:545–53. https:// doi.org/10.1016/j.ejim.2015.04.022. cyclophosphamide, for patients with a poor prognosis. the current patient had cardiac involvement and was, therefore, considered to have a poor prognosis.16 therefore, azathioprine was prescribed in addition to the corticosteroid. conclusion eosinophilic granulomatosis with polyangiitis is a rare, necrotising vasculitis that has the propensity to involve the heart, leading to increased mortality and morbidity. cmr is a useful tool not only for the assessment of cardiac involvement in egpa patients but also for stratifying patients according to the risk and guiding their therapy. a u t h o r s’ c o n t r i b u t i o n rsu is responsible for the majority of the work. ku collected the clinical information and wrote the initial manuscript. fl provided the histopathology results and the manuscript was send to be reviewed by her before final submission ym and fb were the treating physicians and the manuscript was send to them to review before submission. all authors approved the final version of the manuscript. references 1. churg j, strauss l. allergic granulomatosis, allergic angiitis, and periarteritis nodosa. am j pathol 1951; 27:277-301. 2. jennette jc, falk rj, bacon pa, basu n, cid mc, ferrario f, et al. 2012 revised international chapel hill consensus conference nomenclature of vasculitides. arthritis rheum 2013; 65:1–11. https://doi.org/10.1002/art.37715. 3. gioffredi a, maritati f, oliva e, buzio c. eosinophilic granulomatosis with polyangiitis: an overview. front immunol 2014; 5:549. https://doi.org/10.3389/fimmu.2014.00549. 4. yune s, choi dc, lee bj, lee jy, jeon es, kim sm, et al. detecting cardiac involvement with magnetic resonance in patients with active eosinophilic granulomatosis with polyangiitis. int j cardiovasc imaging 2016; 32s1:155–62. https://doi.org/10.1007/s10554-016-0843-y. departments of 1medicine and 2internal medicine, r g kar medical college, kolkata, india; 3department of internal medicine, midnapore medical college, midnapore, india *corresponding author’s e-mail:chandraatanu123@gmail.com عيون الراكون يف الداء النشواين اأتانو �ساندرا، �سواروب كانتا �ساها، اأوداالك ت�ساكرابورتي، بارثا �ساراثي كارماكار، جوتام بي�سوا�س، اأريرتا كومار راي، �سوكانتا دوتا raccoon eyes in amyloidosis *atanu chandra,1 swarup k. saha,2 uddalak chakraborty,2 partha s. karmakar,2 goutam biswas,2 aritra k. ray,2 sukanta dutta3 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e399–400, epub. 21 dec 20 submitted 7 may 20 revision req. 29 jun 20; revision recd. 7 jul 20 accepted 29 jul 20 a 62-year-old male patient was admittedto the department of internal medicine, rg kar medical college, kolkata, india, in 2018 with a history of gradually progressive shortness of breath on exertion for four months. he also complained of swelling of lower limbs, dry cough, weight loss and painless blackish discolouration of the eyelids. he did not have a history of hypertension or diabetes. there was also no history of trauma to the face or the head. physical examination showed periorbital hyperpigmentation with skin folds (‘raccoon eyes’) and macroglossia [figure 1]. there was bilateral pitting pedal oedema, elevated jugular venous pressure, diminished breath sound with a dull note on percussion in the lower zone of right lung suggestive of congestive cardiac failure with right-sided pleural effusion. further evaluation of effusion with a thoracocentesis revealed a pleural effusion that was transudative in nature (pleural fluid protein = 0.3 g/dl, lactate dehydrogenase = 28 u/l, white cell count = 18/mm3). urine studies revealed nephrotic range proteinuria (24-hour urine collection demonstrated excretion of 5.4 grams of protein). antinuclear antibody and infectious screening were negative. echocardiography showed concentric left ventricular hypertrophy and a sparkly appearance of myocardium with increased echogenicity [figure 2a]. strain echocardiography showed a cherry-on-top appearance [figure 2b]. abdominal fat pad biopsy was done and congo red stain was positive [figure 3]. serum protein electrophoresis showed a monoclonal spike of 3.66 g/dl in the gamma fraction; urine electrophoresis was positive for bence-jones protein. kappa free lightchains (flc) were elevated at 1,020 mg/l (normal range: 3.3–19.4 mg/l) with an elevated kappa/lambda flc ratio of 56.6 (normal range: 0.26–1.75). in light this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.021 interesting medical image figure 1: photographs of the face of a 62-year-old male patient with amyloidosis showing (a) bilateral periorbital hyperpigmentations with skin folds (‘raccoon eyes’) and (b) macroglossia. https://creativecommons.org/licenses/by-nd/4.0/ raccoon eyes in amyloidosis e400 | squ medical journal, november 2020, volume 20, issue 4 of the clinical and immunohistological findings, a diagnosis of amyloid light chain (al) amyloidosis was made. the patient was treated conservatively with diuretics and angiotensin converting enzyme inhibitors. his therapy was initially planned to be in the form of bortezomib, linalidomide and prednisolone. however, he was unfortunately lost to follow-up. an informed written consent was obtained from the patient after full explanation regarding the publication of his images for academic interest. the patient did not have any objection regarding the use of his images which may reveal his identity and gave due permission to use them. comment amyloidosis consists of a group of disorders characterised by the extracellular deposition of insoluble protein polymers in different tissues and organs.1 al amyloidosis, also known as primary systemic amyloidosis, is frequently caused by a clonal expansion of plasma cells that secrete a monoclonal immunoglobulin light chain depositing as amyloid fibrils in tissues. there is deposition of amyloid in different organs such as the kidney, gastrointestinal tract, autonomic nervous system and the heart.2 early bruising, particularly around the eyes which is also known as ‘raccoon eyes’, is pathognomonic of this clonal plasma cell proliferative disorder. other possible causes of ‘raccoon eyes’ are trauma and malignancies such as neuroblastoma and lymphoma. ‘raccoon eyes’ occurs due to increased vascular fragility propagated by accumulation of amyloid fibrils.3,4 kidneys are the most frequently involved organ and are seen in 70–80% of the patients followed by the heart (50–60%).1 macroglossia, a pathognomonic sign of this disorder, is seen in only 10% of patients.1 ‘raccoon eyes’ is another uncommon but highly characteristic sign of al amyloidosis. although, ‘raccoon eyes’ are a very well-known manifestation of amyloidosis, the constellation of all these characteristic findings as were displayed by the current patient has been rarely reported in the literature. due to non-specific symptoms, diagnosis is often delayed until symptoms referable to a specific organ develop. as amyloidosis is a progressive disease often with fatal consequences, early and precise diagnosis is needed to prevent further organ damage. clinicians should acquaint themselves with these specific clinical signs and with the importance of systemic evaluation to avoid delay in diagnosis. references 1. berk jl, sanchorawala v. amyloidosis. in: jameson jl, fauci a, kasper d, hauser s, longo d, loscalzo j. harrison’s principles of internal medicine. 20thed.new york, new york, usa: mcgraw-hill education, 2018. pp. 803–9. 2. merlini g, seldin dc, gertz ma. amyloidosis: pathogenesis and new therapeutic options. j clin oncol 2011;29:1924–33. https://doi.org/10.1200/jco.2010.32.2271. 3. passosrda h, pereira a, neto ac, ribeiro af, kutner j, hamerschlak n,et al. clinical image: bilateral black eyes (raccoon's eyes) in al amyloidosis. arthritis rheum 2006;54:3724. https://doi.org/10.1002/art.22184. 4. pereira vg, jacinto m, santos j, de abreu tt. periorbital purpura (raccoon's eyes). bmj case rep 2014;2014:bcr2013201407. https://doi.org/10.1136/bcr-2013-201407. figure 2: echocardiography of a 62-year-old male patient showing (a) concentric left ventricular hypertrophy and sparkly appearance of myocardium with increased echogenicity and (b) strain echocardiography showing cherry-on-top appearance. figure 3: positive congored stain at x100 magnification showing abdominal fat pad biopsy indicative of the presence of amyloid fibrils. https://doi.org/10.1200/jco.2010.32.2271 https://doi.org/10.1002/art.22184 https://doi.org/10.1136/bcr-2013-201407 1bone and joint diseases research center, department of physical medicine and rehabilitation, 2shiraz geriatric research center and departments of 4rheumatology and 5urology, shiraz university of medical sciences, shiraz, iran; 3urology research center, al-thora general hospital, department of urology, ibb university of medical science, ibb, yemen; 6department of biostatics and epidemiology, babol university of medical science, babol, iran *corresponding author’s e-mail: farporh@gmail.com is there any sympathetic skin response abnormality in raynaud phenomenon? mohammad r. emad,1 *hamid r. farpour,1,2 faisal ahmed,3 masoumeh tayebi,1 mohammadali nazarinia,2,4 mohammad r. askarpour,5 hossein-ali nikbakht6 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 274–279, epub. 26 may 22 submitted 7 sep 20 revisions req. 12 nov 20 & 7 feb 21; revisions recd. 2 dec 20 & 16 feb 21 accepted 23 feb 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.066 clinical & basic research abstract: objectives: this study aimed to evaluate sympathetic skin response (ssr) among patients with raynaud phenomenon (rp). ssr is a technique for assessment of the damage of peripheral neuropathies and the disorders of the sympathetic system. methods: between january 2015 and december 2018, approximately 20 patients with rp and 20 healthy subjects (control group) were recruited from patients referred to the outpatient clinics of shiraz university of medical sciences, shiraz, iran. all participants were clinically examined and the ssr was evaluated using a standard protocol. ssr is abnormal when the latency is prolonged and/or the amplitude is reduced. results: the rp group consisted of 19 women (95%) and one male (5%); three patients (15%) had primary raynaud’s phenomenon (prp) and 17 patients (85%) had secondary raynaud’s phenomenon. the control group consisted of 16 women (80%) and four males (20%). the mean age of the rp group and control subjects was 43.1 ± 9 and 36.7 ± 8.6 years, respectively. the ssr to the electrical stimulus was absent in three patients with prp. the total median nerve mean latencies in the upper limb were 1.90 ± 0.57 and 1.19 ± 0.52 seconds for the rp group and control groups, respectively (p <0.001). these findings revealed significantly prolonged ssr latencies in the rp group, while the mean amplitude showed no significant differences in both groups (p = 0.756). conclusion: absence or prolonged latency of ssr was associated with the disorders of the unmyelinated axons in the sympathetic system. the findings of the present study suggested the disorders of unmyelinated axons in raynaud’s phenomenon. keywords: raynaud disease; autonomic nervous system; electrodiagnosis; sympathetic fibers; nerve conduction; iran. advances in knowledge it is expected that this study, conducted in iran, will increase both individual and physicians’ awareness of raynaud’s phenomenon (rp). the absence or prolonged latency of the sympathetic skin response was associated with disorders of unmyelinated axons in the sympathetic system such as rp. application to patient care the sympathetic skin response test is recommended to be used for evaluating the sympathetic status and symptoms in patients with rp. raynaud phenomenon (rp) is a condition in which a sequence of pallor, cyanosis and redness manifest when one is exposed to cold weather or stress. this condition can be painful and lead to recurrent vasospasms in the digits.1,2 there are two types of rps: primary raynaud’s phenomenon (prp) and secondary raynaud’s phenomenon (srp). the criteria of prp includes a symmetric presentation of this phenomenon without tissue necrosis, ulceration or gangrene after secondary causes are ruled out.3 srp occurs in association with underlying diseases, including neurological disorders and mixed connective tissue disorders.3 sympatholytic drugs and reduction of emotional stress are useful in rp treatments; it has been suggested that autonomic nervous system (ans) dysfunctions may lead to rp.1 to evaluate a patient presenting with rp, a physician should obtain the required laboratory data and imaging after acquiring the patient’s medical history and completing their physical examination. these assessments are essential tools in the broader evaluation of rp symptoms.4 to manage the phenomenon, patients should consider lifestyle modification, keep the affected areas warm and stop taking vasoconstricting drugs such as nicotine. hughes et al. reported that only 16% of the participants with rp stated that at least one current medication had been effective to prevent or control rp attacks.5 sympathetic skin response (ssr) is evaluated using a simple and non-invasive test that reveals an interaction between the surrounding epidermal tissue and sweat glands.6 because it is a multisynaptic reflex, its waveform amplitude and latency are variable. ssr evaluation involves recording the electrical stimulus of a peripheral nerve from the surface electrodes attached to the hands and feet in order to study the neural activity of type c unmyelinated fibres. it is a reliable indicator of the sudomotor sympathetic https://creativecommons.org/licenses/by-nd/4.0/ mohammad r. emad, hamid r. farpour, faisal ahmed, masoumeh tayebi, mohammadali nazarinia, mohammad r. askarpour and hossein-ali nikbakht clinical and basic research | 275 function, used to evaluate patients with somatic and autonomic neuropathies.6,7 most of the recent studies have assessed the large myelinated fibres and not measured the thin myelinated or unmyelinated fibres including the sympathetic fibres within the peripheral nerve.8 there are few studies that evaluate the ans effect electrophysiologically in patients with rp. this study evaluates the ssr in patients with rp to assess the sympathetic dysfunction found in such patients. methods the present study included 20 patients with prp and srp in the period between january 2015 and december 2018. the patients were recruited from those referred to the outpatient clinics of physical medicine & rehabilitation and rheumatology departments of shiraz university of medical sciences, shiraz, iran. the control group included 20 healthy participants who did not consume any medication affecting the ans. written informed consent was taken from all participants to be enrolled in the present study. patients included in this study were those who had been diagnosed with prp and srp according to previously published criteria and had definite sensitivity to cold with the classic colour sequence triad in their hands.9 patients were selected at least six months after the onset of the symptoms and were recruited from among those referred to the outpatient clinics of the physical medicine and rehabilitation and rheumatology departments of the university. patients were excluded if they had been diagnosed with endocrine diseases such as diabetes mellitus, thyroid diseases and metabolic diseases. patients with scars, ulcers or gangrene of the fingers, neurological disorders, other mixed connective tissue diseases, a history of cancer or any type of peripheral neuropathy were excluded as well. furthermore, patients were also excluded if they used drugs that are known to affect the ans (e.g. tricyclic antidepressants, clonidine, ergotamine and serotonin-receptor agonists, ß-blockers or oral contraceptives). at first, general clinical and neurological exam inations were performed for all subjects in a half dark and silent room with a temperature of 23–26 °c and a humidity between 30–35%.10 ssrs with an intensity between 15–25 ma were used to assess the sympathetic activity in 20 patients with rp and 20 controls. the skin temperature was kept above 32 °c in all patients. one electromyographic apparatus, the medelec synergy electromyograph (carefusion corp., san diego, california) was used for all patients and the control group by the same physiatrist.10 a sweep speed of 500 ms/div, sensitivity of 200–1000 mv/div and filtering of 0.5 khz were used.11 the subjects were conscious, silent and fixed in a supine position to diminish movement artifacts. before performing the test, the procedure was explained to all the participants. for the median nerve ssr, the active electrode was attached to the base of the second finger in the palmar surface and the reference electrode was placed in the dorsal aspect of the hand. stimulating electrodes were placed on the wrist area between the palmaris longus and flexor carpi radialis tendons. a ground electrode was located proximal to the active electrode with respect to the cathode’s location [figures 1 and 2].10 to record the ssr, the authors used the minimum stimulation intensity which was needed and increased it in the subsequent stimulation. the stimuli were given at irregular intervals of more than 65 seconds to avoid considerable habituation. latencies and amplitudes of the waves were measured. the latency of ssr was measured in seconds from the stimulation artifact onset to the onset of the first deflection from the baseline; the amplitude was measured in µv from peak to peak (i.e. the peak of the first deflection to that of the next one). three recordings were performed for each limb and the average responses were used for analysis.12 an absent response was considered an abnormal test. median and tibial nerve compound muscle action potential (cmap) and median and sural sensory nerve action potential (snap) were done for all subjects for assessment of any peripheral neuropathy (e.g. carpal tunnel syndrome). only the reproducible responses with no movement artifacts were chosen for analysis.13 statistical package for the social sciences (spss), version 18 (ibm corp., chicago, illinois, usa) was used to analyse the data. arithmetic mean and standard deviation of the data were determined using a t-test and mann whitney’s u test. the chi-square test was utilised to compare the responses from the rp and control groups. p values less than 0.05 were considered significant. this study was approved by the ethics committee of shiraz university of medical sciences (ir.sums. rec. 1387.s4254). results the present study consisted of 20 rp patients, 19 (95%) of whom were females. the patients’ mean age was 43.1 ± 9 years. the control group consisted of 16 females (80%) and four males (20%). the mean age of the control group subjects was 36.7 ± 8.6 years. no underlying diseases were found in three patients (15%) is there any sympathetic skin response abnormality in raynaud phenomenon? 276 | squ medical journal, may 2022, volume 22, issue 2 with prp. however, the remaining 17 patients (85%) with srp had a history of underlying diseases such as systemic sclerosis (n = 14; 70%) and rheumatoid arthritis (ra; n = 3; 15%). all of the prp patients had abnormal sympathetic ssr latency and amplitude tests (100%). the mean latencies for ssr of the right and left median nerves lasted 1.86 ± 0.55 and 1.79 ± 0.49 seconds in the rp group and 1.11 ± 0.50 and 1.21 ± 0.65 seconds in the control group, respectively. the total median nerves mean latencies in the upper limb was 1.90 ± 0.57 and 1.19 ± 0.52 seconds for the rp and control groups, respectively. comparisons in both groups demonstrated significant differences for ssr mean latencies (p <0.001). however, the comparison of ssr mean amplitudes in both groups did not show a significant difference (p = 0.756) [table 1]. all individuals had normal median and tibial nerve cmap and median and sural snap. any peripheral neuropathy such as carpal tunnel syndrome or peripheral polyneuropathy was excluded. discussion the present study aimed to investigate electrophysiologic alterations of the sympathetic figure 1: photograph showing the sites at which sympathetic skin response from the median nerve were recorded using an electromyograph. sites included an active electrode on the hand (a), a reference electrode on the dorsal aspect of the hand (b), a stimulating electrode for the median nerve on the wrist (c) and a ground electrode on the forearm (d). figure 2: photograph of the sympathetic skin response waveform showing onset latency in seconds (range: 0–1), peak to peak amplitude in microvolts (range: 2–3) and the total duration of the sympathetic skin response in seconds (range: 1–4). table 1: comparison of parameters of the sympathetic skin response between the raynaud’s phenomenon (rp) and control groups (nrp = 20; nc = 20) parameters rp group (mean± sd) control group (mean± sd) p value latency in seconds right median nerve 1.86 ± 0.55 1.11 ± 0.50 *<0.001 left median nerve 1.79 ± 0.49 1.21 ± 0.65 *<0.002 upper limbs 1.90 ± 0.57 1.19 ± 0.52 *<0.001 amplitude in mv right median nerve 1.14 ± 0.89 0.93 ± 0.48 0.358 left median nerve 0.85 ± 0.5 1.01 ± 0.50 0.318 upper limbs 0.94 ± 0.7 1.00 ± 0.50 0.756 rp = raynaud's phenomenon; mv = millivolts; sd = standard deviation. *p value of <0.05 was considered significant. mohammad r. emad, hamid r. farpour, faisal ahmed, masoumeh tayebi, mohammadali nazarinia, mohammad r. askarpour and hossein-ali nikbakht clinical and basic research | 277 nervous system in rp patients. there are some conditions associated with abnormal ssr such as lesions of the peripheral nerves as well as those of the nerve roots (diabetic neuropathy, familial amyloid neuropathy, alcoholic neuropathy, lepromatous neuropathy).8 additionally, abnormality of ssr was observed in carpal tunnel syndrome and complex regional pain syndrome.7,14 measures have been taken to utilise the ssr in the diagnosis of sympathetic damage in some rheumatologic disorders such as scleroderma, sjogren’s syndrome, ra, fibromyalgia, chronic fatigue syndrome and rp and in urologic diseases such as chronic prostatitis.11,15–17 to the best of the authors’ knowledge, the literature lacks adequate data regarding ans evaluation in patients with rp. neurological changes in rp are doubtful. when used clinically, ssr has many limitations. latency and amplitude of the signal response are different in a single individual and even more diverse when studying a population. adding the habituation phenomenon to letters makes it challenging to calculate normal ssr parameters.18,19 one study on the clinical use of ssr reported lower amplitude response in the contralateral side than the side of common peripheral nerve stimulation.19 this might happen due to greater excitation dispersion of the afferents arc. when studying the role of sympathetic fibres in mononeuropathies, one can bypass the obtaining absolute reference values dilemma using the unaffected side as an internal control by comparing the parameters between the two sides. thus, the ratio of values between the two side values can be calculated.18,19 based on previous studies, to identify the abnormal response in the amplitude and latency of ssr, the present study made a comparison between patients and normal individuals. the results of the present study showed that prp patients showed abnormal ssr latency and amplitude, which was similar to a previous study carried out by mondelli et al.20 the authors reported sympathetic dysfunction in prp. while they stimulated the ulnar nerve in the upper limb, the authors of this study stimulated the median nerve that has more sympathetic fibres and found a significant delay in ssr latency in the patients with prp.20 additionally, instead of ssr amplitude, this study measured the area due to good accuracy of values for total sympathetic excitability of the nerve. according to a study carried out by charkoudian, the sympathetic nervous system, via both peripheral (local) and central system mechanisms, plays a critical role in the pathogenesis of prp and srp.21 pancera et al. investigated the sympathetic hyperactivity in systemic sclerosis and prp.15 subjects with prp had normal heart rate changeability and more activity of sympathetic fibres. in another study, prp was compared with srp in systemic sclerosis. both groups showed a decrease in calcitonin gene-related peptide, endothelium–1 flare and a prostaglandin production value of 9.5. these findings indicate that there is a general vascular hyperactivity in these conditions that probably reflect a primary vascular disorder.22 in a study on 20 patients with srp, gosk-bierska et al. noted a significantly low ssr amplitude and long latency in their palms and soles.23 in patients with srp, no relationship was found between ssr and microangiopathy; this confirmed that these two processes occur independently in patients with srp. the authors concluded that normal peripheral nerve function with impaired ans suggested the central origin of srp. abnormal ssr habituation might also result from the central mechanism.23 gledhill et al. showed ans dysfunction in nine srp patients with cardiovascular autonomic dysfunction.24 the heart rate response to deep breathing—valsalva and standing— were measured before and after triiodothyronine administration. the amplitude was decreased in three patients, and mild slowing of conduction velocity in six patients (less than 20%) was observed. test results showed considerable improvement of ans function after administration of triiodothyronine.24 using median nerve stimulation, badry et al. compared the ssr in 21 patients with systemic sclerosis (ssc) and 39 patients with ra to ssr in 60 healthy participants.25 they found increased latency and reduced amplitude in ssc and ra patients. the ssr of ssc patients was significantly prolonged in latency and showed reduced amplitude when compared to ra patients. additionally, six ssc patients had increased ssr latency without manifestations of polyneuropathy. the authors concluded that patients with ssc and ra suffered from ans dysfunction with more effects being seen in ssc patients.25 saba and sultan evaluated the ans changes in ra patients. the ssr amplitude decreased and latency was prolonged in ra patients compared to the control group. additionally, there were no statistically significant differences between the patients with different disease activity of ra and functional disability of ra, ssr latency and amplitude.26 another study of ssr in 30 ra patients showed that ssr was abnormal in six patients.27 the authors did not include amplitude as a diagnostic criterion as it was too variable even within the same patient. they found frequent abnormalities in ssr in patients with ra regardless of whether or not there was a clinical symptom of ans.27 is there any sympathetic skin response abnormality in raynaud phenomenon? 278 | squ medical journal, may 2022, volume 22, issue 2 the findings of the present study are in line with those of previous studies; there was no significant abnormality in ssr amplitude between the patients and controls. most studies did not consider amplitude as a valid measure of normality versus abnormality.20,27 there was also no relationship between the type of ssr abnormality and intensity of autonomic impairment. in one study on reflex sympathetic dystrophy, the mean amplitude and onset latency of ssr in the involved limb was greater and shorter than that of the uninvolved limb.7 these findings support the crucial role of ans dysfunction in rp.28 overall, in the present study, the individuals in the rp group presented with abnormal ssr in regards to the mean latency, suggesting a significant difference between the groups in skin innervation. in pathophysiology, lack of ssr represents the failure of the polysynaptic system in propagating impulses to the end organs. increased latency in ssr may originate from milder neuropathic damage or from loss of thicker axons, changes in cholinergic fibres and/or sweat glands and synaptic transmission interruption through central processing.23 since there was no evidence of afferent somatic fibres or central nervous system or sweat gland diseases in the present study, it is suggested that the source of ssr latency abnormalities might be the sympathetic efferent nerves. notably, prp is more common in women than men; thus, many published studies failed to match gender in the control and case groups.20 by matching gender between the case and control groups, the authors of this study have tried to control for this bias. performing the ssr test in rheumatology patients helps detect autonomic disorders early, thus enabling the patient to receive the appropriate treatment for potential complications (for example, cardiovascular or skin disorders such as dry skin or excessive sweating or, alternatively, neurological disorders such as dizziness and imbalance).27 it could also be beneficial in regulating the drugs that affect the autonomic system in rp patients. furthermore, using the ssr test for better management of underlying autonomous system-related symptoms helps the patient in controlling rp symptoms optimally.20 ans dysfunction is one of the aetiological factors linked to the development of microvascular manifestations of ra and ssc, which may play a role in developing the pain symptoms associated with these diseases.7 this study had some limitations including a small sample size (n = 20). this was also just an observational report which would require validation with randomised criteria and a larger sample size. moreover, some patients with srp use anti-hypertensive drugs and the authors could not discontinue the medication for the patient group. it is possible that medications could alter the ssr since the test is very sensitive and requires complete relaxation during the examination. hence, there is a need to implement certain specific techniques in order to account for such confounding variables and enhance patient cooperation. the authors recommend further studies with a larger sample size and clinical trials to better evaluate ssr parameters. conclusion absence or prolonged latency of sympathetic skin response was associated with unmyelinated axon disorders in the sympathetic system. the findings of the present study confirm the role of the disorders of unmyelinated axons and sympathetic nervous system in rp. a c k n o w l e d g e m e n t s the authors would like to thank the research consultation center (rcc) of shiraz university of medical sciences for their invaluable assistance in analysing the data. the authors would also like to thank the center for development of clinical research of nemazee hospital and dr. nasrin shokrpour for editorial assistance. this study is a part of the thesis of masoumeh gerami tayebi (grant no: 4254). c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n ma and hf conceptualised the work. ma supervised the work. mt and hf prepared the proposal and collected the data. fa and mn analysed and interpreted the data. ma drafted the manuscript. fa and hn reviewed and edited the drafted manuscript. hf collected, labelled and formatted the images. all authors approved the final version of the work. references 1. bakst r, merola jf, franks ag jr, sanchez m. raynaud’s pheno menon: pathogenesis and management. j am acad dermatol 2008; 59:633–53. https://doi.org/10.1016/j.jaad.2008.06.004. 2. mallipeddi r, mathias cj. raynaud’s phenomenon after sympa thetic denervation in patients with primary autonomic failure: questionnaire survey. bmj 1998; 316:438–9. https://doi.org/10.1 136/bmj.316.7129.438. https://doi.org/10.1016/j.jaad.2008.06.004 https://doi.org/10.1136/bmj.316.7129.438 https://doi.org/10.1136/bmj.316.7129.438 mohammad r. emad, hamid r. farpour, faisal ahmed, masoumeh tayebi, mohammadali nazarinia, mohammad r. askarpour and hossein-ali nikbakht clinical and basic research | 279 3. wigley fm. clinical practice. raynaud’s phenomenon. n engl j med 2002; 347:1001–8. https://doi.org/10.1056/nejmcp013013. 4. pauling jd, hughes m, pope je. raynaud’s phenomenon-an update on diagnosis, classification and management. clin rheumatol 2019; 38:3317–30. https://doi/org/10.1007/s10067-019-04745-5. 5. hughes m, snapir a, wilkinson j, snapir d, wigley fm, herrick al. prediction and impact of attacks of raynaud’s phenomenon, as judged by patient perception. rheumatology (oxford) 2015; 54:1443–7. https://doi.org/10.1093/rheumatology/kev002. 6. shahani bt, halperin jj, boulu p, cohen j. sympathetic skin response--a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. j neurol neurosurg psychiatry 1984; 47:536–42. https://doi.org/10.1136/jnnp.47.5.536. 7. kim hj, yang he, kim dh, park yg. predictive value of sympa thetic skin response in diagnosing complex regional pain syndrome: a case-control study. ann rehabil med 2015; 39:116–21. https://doi.org/10.5535/arm.2015.39.1.116. 8. kucera p, goldenberg z, kurca e. sympathetic skin response: review of the method and its clinical use. bratisl lek listy 2004; 105:108–16. 9. leroy ec, medsger ta, jr. raynaud’s phenomenon: a proposal for classification. clin exp rheumatol 1992; 10:485–8. 10. emmer a, mangalo s, kornhuber me. augmentation of the sympathetic skin response after electrical train stimuli. front neurol 2012; 3:152. https://doi.org/10.3389/fneur.2012.00152. 11. ozkan o, yildiz m, arslan e, yildiz s, bilgin s, akkus s, et al. a study on the effects of sympathetic skin response parameters in diagnosis of fibromyalgia using artificial neural networks. j med syst 2016; 40:54. https://doi.org/10.1007/s10916-015-0406-0. 12. el-badawy ma, el mikkawy dm. sympathetic dysfunction in patients with chronic low back pain and failed back surgery syndrome. clin j pain 2016; 32:226–31. https://doi.org/10.1097/ ajp.0000000000000250. 13. emad r, zafarghasempour m, roshanzamir s. sympathetic skin response in incomplete spinal cord injury with urinary incon tinence. ann indian acad neurol 2013; 16:234. https://doi. org/10.4103/0972-2327.112479. 14. cevik b, kurt s, aksoy d, solmaz v. sympathetic skin response and boston questionnaire in carpal tunnel syndrome. neuro physiology 2016; 48:191–6. https://doi.org/10.1007/s11062-016-9588-4. 15. pancera p, sansone s, presciuttini b, montagna l, cerù s, lunardi c, et al. autonomic nervous system dysfunction in sclerodermic and primary raynaud’s phenomenon. clin sci (lond) 1999; 96:49–57. https://doi.org/10.1042/cs0960049. 16. dumitru d, zwarts mj. special nerve conduction techniques. in: dumitru d, amato a, zwarts m, eds. electro diagnostic medicine. 2nd ed. philadelphia: hanley & belfus, 2001. pp. 249. 17. eslahi a, farpour h, hosseini a, ahmed f, chowdhury u, nikbakht ha. evaluation of the sympathetic skin response in men with chronic prostatitis: a case-control study. res rep urol 2020; 12:239–45. https://doi.org/10.2147/rru.s253101. 18. bayrak ao, tilki he, coşkun m. sympathetic skin response and axon count in carpal tunnel syndrome. j clin neurophysiol 2007; 24:70–5. https://doi.org/10.1097/01.wnp.0000239107.10424.fa. 19. mondelli m, aretini a, ballerini m, vecchiarelli b, rossi a. sympathetic skin response. glabella stimulation may be more useful than peripheral nerve stimulation in clinical practice. auton neurosci 2011; 164:101–4. https://doi.org/10.1016/j.aut neu.2011.07.002. 20. mondelli m, de stefano r, rossi s, aretini a, romano c. sym pathetic skin response in primary raynaud’s phenomenon. clin auton res 2009; 19:355–62. https://doi.org/10.1007/s10286-009 0021-6. 21. charkoudian n. skin blood flow in adult human thermoregulation: how it works, when it does not, and why. mayo clin proc 2003; 78:603–12. https://doi.org/10.4065/78.5.603. 22. sulli a, soldano s, pizzorni c, montagna p, secchi me, villaggio b, et al. raynaud’s phenomenon and plasma endothelin: correlations with capillaroscopic patterns in systemic sclerosis. j rheumatol 2009; 36:1235–9. https://doi.org/10.3899/jrheum.081030. 23. gosk-bierska i, misterska-skóra m, wasilewska m, bilińska m, gosk j, adamiec r, et al. analysis of peripheral nerve and auto nomic nervous system function and the stage of microangiopathy in patients with secondary raynaud’s phenomenon in the course of connective tissue diseases. adv clin exp med 2018; 27:1587–92. https://doi.org/10.17219/acem/75618. 24. gledhill rf, dessein ph, van der merwe ca. treatment of raynaud’s phenomenon with triiodothyronine corrects co-existent autonomic dysfunction: preliminary findings. postgrad med j 1992; 68:263–7. https://doi.org/10.1136/pgmj.68.798.263. 25. badry r, gamal rm, hassanien mm, el hamed ma, hammam n, el fawal bm. sympathetic skin response in patients with systemic sclerosis and rheumatoid arthritis. egypt j neurol psychiatr neuro surg 2018; 54:38. https://doi.org/10.1186/s41983-018-0044-9. 26. saba e, sultan h. autonomic nervous system changes associated with rheumatoid arthritis: clinical and electrophysiological study. egypt rheumatol 2014; 36:157–63. https://doi.org/10.1016/j. ejr.2014.03.002. 27. tan j, akin s, beyazova m, sepici v, tan e. sympathetic skin response and r-r interval variation in rheumatoid arthritis. two simple tests for the assessment of autonomic function. am j phys med rehabil 1993; 72:196–203. https://doi.org/10.1097 /00002060-199308000-00005. 28. vetrugno r, liguori r, cortelli p, montagna p. sympathetic skin response: basic mechanisms and clinical applications. clin auton res 2003; 13:256–70. https://doi.org/10.1007/s10286003-0107-5. https://doi.org/10.1056/nejmcp013013 https://doi/org/10.1007/s10067-019-04745-5 https://doi.org/10.1093/rheumatology/kev002 https://doi.org/10.1136/jnnp.47.5.536 https://doi.org/10.5535/arm.2015.39.1.116 https://doi.org/10.3389/fneur.2012.00152 https://doi.org/10.1007/s10916-015-0406-0 https://doi.org/10.1097/ajp.0000000000000250 https://doi.org/10.1097/ajp.0000000000000250 https://doi.org/10.4103/0972-2327.112479 https://doi.org/10.4103/0972-2327.112479 https://doi.org/10.1007/s11062-016-9588-4 https://doi.org/10.1042/cs0960049 https://doi.org/10.2147/rru.s253101 https://doi.org/10.1097/01.wnp.0000239107.10424.fa https://doi.org/10.1016/j.autneu.2011.07.002 https://doi.org/10.1016/j.autneu.2011.07.002 https://doi.org/10.1007/s10286-009-0021-6 https://doi.org/10.1007/s10286-009-0021-6 https://doi.org/10.4065/78.5.603 https://doi.org/10.3899/jrheum.081030 https://doi.org/10.17219/acem/75618 https://doi.org/10.1136/pgmj.68.798.263 https://doi.org/10.1186/s41983-018-0044-9 https://doi.org/10.1016/j.ejr.2014.03.002 https://doi.org/10.1016/j.ejr.2014.03.002 https://doi.org/10.1097/00002060-199308000-00005 https://doi.org/10.1097/00002060-199308000-00005 https://doi.org/10.1007/s10286-003-0107-5 https://doi.org/10.1007/s10286-003-0107-5 departments of 1family medicine & public health, 2community & mental health, 3fundamentals & administration and 4maternal & child health, sultan qaboos university, muscat, oman; 5department of child health, royal hospital, muscat, oman *corresponding author’s e-mail: rkindi@squ.edu.om مدى وعي طالب املدارس الثانوية وموقفهم اجتاه برنامج الفحص ما قبل الزواج يف مسقط، ُعمان رحمة حممد �لكندية، �صار��صو�ثي كانيكانتي، جان�صي ناتار�جان، لينا �صاكمان، زينب �لعزرية، نيفني �إبر�هيم �لكلبانية abstract: objectives: this study aimed to explore high school students’ awareness and attitude towards premarital screening (pms). methods: this cross-sectional study was conducted in 10 public high schools in muscat, oman from may to july 2016. a three-part self-administered questionnaire was used to collect data from grade 12 students. the first part focused on respondents’ sociodemographic characteristics, while the second part dealt with awareness of the national pms programme and the third part explored attitudes towards the national pms programme. results: a total of 1,541 participants (response rate: 91.1%) completed the questionnaire. most participants (78.1%) were aware of the availability of the pms programme and their main source of information was family and friends (34.3%). the majority of students (87.4%) believed that pms is important and most students (87.2%) indicated that they would undergo pms. over half of the students (55.3%) agreed that pms should be mandatory before marriage and approximately one-third (38.3%) were in favour of having laws and regulations to prevent consanguineous marriages. females were significantly more in favour of making pms mandatory (p = 0.002) and enforcing pms laws (p = 0.010) compared to males. conclusion: most respondents had good levels of knowledge about the pms programme and half thought it is important to be tested. however, some students were not in favour of pms. increasing awareness about oman’s pms programme is important and motivating students could contribute significantly to increasing the utilisation of the pms programme and to limiting genetic blood disorders. keywords: awareness; knowledge; attitude; secondary school; students; premarital examinations; genetic carrier screening; oman. امللخ�ص: الهدف: تهدف هذه �لدر��صة �إىل ��صتك�صاف مدى وعي طالب �ملد�ر�س �لثانوية وموقفهم من �لفح�س ما قبل �لزو�ج. �لطريقة: �أجريت هذه �لدر��صة �ملقطعية يف ع�رص مد�ر�س ثانوية حكومية يف م�صقط، ُعمان يف �لفرتة من مايو �إىل يوليو 2016. مت ��صتخد�م ��صتبيان مكون و�ل�صكانية �الأول على �خل�صائ�س �الجتماعية �لثاين ع�رص. ركز �جلزء �لبيانات من طالب �ل�صف ذ�تيا جلمع ثالثة �أجز�ء يتم تعبئته من للم�صتجيبني، يف حني تناول �جلزء �لثاين مدى �لوعي بالربنامج �لوطني للفح�س ما قبل �لزو�ج و�جلزء �لثالث ��صتك�صف موقفهم اجتاه �لربنامج �لوطني للفح�س ما قبل �لزو�ج. النتائج: �أكمل ما جمموعه 1,541 م�صارًكا )معدل �لرد: %91.1( �ال�صتبيان. كان معظم �مل�صاركني )%78.1( على در�ية بتوفر برنامج �لفح�س ما قبل �لزو�ج، وكان م�صدر �ملعلومات �لرئي�صي هو �لعائلة و�الأ�صدقاء )%34.3(. يعتقد غالبية �لطالب )%87.4( �أن �لفح�س ما قبل �لزو�ج مهم، و�أ�صار معظمهم )%87.2( �إىل �أنهم �صيخ�صعون للفح�س. و�إتفق �أكرث من ن�صف �لطالب )55.3%( على �أن �لفح�س يجب �أن يكون �إلز�ميا قبل �لزو�ج، وكان ما يقارب �لثلث )%38.3( موؤيدين لو�صع �لقو�نني و�للو�ئح ملنع زو�ج �الأقارب. .)p = 0.010( وفر�س قو�نني تلزم بالفح�س ماقبل �لزو�ج )p = 0.002( وعند مقارنتهن بالذكور كانت �الإناث �أكرث تاأييد� جلعله �إلز�ميا �ملهم من �أنه ن�صفهم و�عتقد �لزو�ج قبل ما �لفح�س برنامج حول �ملعرفة من جيدة م�صتويات �مل�صتجيبني معظم لدى كان اخلال�صة: �جر�ئه. ومع ذلك كان بع�س �لطالب غري موؤيدين للفح�س ما قبل �لزو�ج. ُتعد زيادة �لوعي بربنامج ُعمان للفح�س ما قبل �لزو�ج �أمًر� مهًما وقد ي�صاهم حتفيز �لطالب بازدياد ملمو�س يف ��صتخد�م برنامج �لفح�س ما قبل �لزو�ج و�حلد من ��صطر�بات �لدم �لور�ثية. الكلمات املفتاحية: وعي؛ معرفة؛ موقف؛ مدر�صة ثانوية؛ طالب؛ فح�س ما قبل �لزو�ج؛ فح�س �لناقل �لور�ثي؛ ُعمان. awareness and attitude towards the premarital screening programme among high school students in muscat, oman *rahma m. al-kindi,1 saraswathi kannekanti,2 jansi natarajan,3 lina shakman,4 zeinab al-azri,4 naifain i. al-kalbani5 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e217–224, epub. 5 nov 19 submitted 9 jan 19 revisions req. 29 jan, 25 feb & 27 mar 19; revisions recd. 2 feb, 12 mar & 8 apr 19 accepted 10 apr 19 advances in knowledge this study found that high school students are willing to follow premarital screening (pms) policies, suggesting support for modifying laws around pms. this study suggests recommendations to improve pms utilisation and efficacy in oman. application to patient care pms should be promoted through a health education campaign that stresses the availability of the programme and its importance in decreasing the burden of genetic blood disorders. healthcare providers should encourage the target population to take advantage of pms. students and young adults should be motivated to utilise pms services. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.007 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ awareness and attitude towards the premarital screening programme among high school students in muscat, oman e218 | squ medical journal, august 2019, volume 19, issue 3 genetic blood disorders are common in the arab world and are responsible for major physical and mental disabilities.1 according to the world health organization, 28% of deaths in children below five years of age in oman are due to inherited blood disorders.2 the most common inherited blood disorders are glucose-6-phosphate dehydrogenase (g6pd) deficiency, thalassaemia and sickle cell anaemia.3 g6pd enzyme deficiency had the highest prevalence in the 2003 genetic blood disorders survey in oman, with 25% of males and 10% of females affected. in the same survey, the prevalence of the sickle cell trait was 6% and the beta-thalassaemia trait was 2%, while the prevalence of sickle cell disease was 0.2% and homozygous betathalassaemia was 0.07%. oman has an annual increase of 120 cases of sickle cell disease and 18–20 cases of the beta-thalassaemia trait.4 consanguinity is very common in oman as embedded beliefs, customs and traditions reinforce high rates of consanguinity. in total, 39% of omanis are married to their first cousins; oman ranks among the top seven arab countries in terms of consanguinity rates.5,6 consanguineous marriages can result in increased expression of autosomal recessive disorders.7 these hereditary blood disorders are a major concern to the ministry of health (moh) as they represent a considerable economic burden on the healthcare system. in response to the high prevalence of these disorders, the moh initiated the premarital screening (pms) and counselling programme in 2001 as a cost-effective preventative measure to reduce the incidence of inherited blood disorders. this programme involves clinical assessment and blood investigations for g6pd enzyme activity and haemoglobin electro phoresis to screen for genetic blood disorders. rel evant health education and genetic counselling are important pillars of this programme.8 currently, the pms programme is not mandatory in oman and is provided on a voluntary and individual basis. although the pms programme was introduced in oman in 2001, its utilisation remains low.8,9 according to 2014 moh statistics, oman’s estimated level of pms programme utilisation is 10%.9 however, several other screening programmes in gulf cooperation council (gcc) and mediterranean countries have been very effective. in iran, the incidence of thalassaemia has been reduced by 70% and in lebanon the incidence was comparably decreased by 75% as a result of pms programmes.10,11 despite introducing pms in most gcc countries, only bahrain has had a 60% reduction in the incidence of thalassaemia, which could be due to its laws that prevent marriage in cases of positive screening tests.12 oman might benefit equally by legally stopping marriages in cases of positive screening test results. many studies have been conducted in oman addressing pms awareness. a study among university students revealed that 79% of participants were aware of the availability of oman’s pms programme; the vast majority of participants (92%) acknowledged its importance and agreed to undergo the screening.13 another study among adults attending primary health care centres found that 89.3% of participants were aware of the pms programme, of which 84.5% believed that premarital counselling is necessary.14 both studies showed that approximately half of the participants were in favour of making pms mandatory. studies in the region have revealed a lack of knowledge of premarital testing.13–18 informal interviews with high school teachers and school nurses have confirmed the infrequency of in-school instruction around oman’s pms programme. furthermore, high school students may not have enough knowledge about genetic disorders to realise the potential of pms in reducing such disorders. therefore, it is important that this group be empowered with knowledge intended to ultimately reduce the incidence of inherited blood disorders. hence, this study aimed to explore the current knowledge and attitudes towards oman’s pms programme among high school students with the intention of influencing methods of effective implementation of such an important pro gramme. methods this cross-sectional study was conducted at 10 public high schools in al-seeb area of muscat governorate from may to july 2016. these schools had approx imately 2,100 grade 12 students distributed among 70 classes. students were excluded if they were absent from school during the study period, refused to participate or had learning difficulties that made the independent completion of the questionnaire difficult. a validated, pre-tested and well-structured quest ionnaire with closed-ended questions on pms was used to collect data. this questionnaire had been used in a previous study and permission was obtained from the authors to use the tool with minimal modifications to questions associated with demographic information.13 the questionnaire was divided into three parts: part one focused on participants’ sociodemographic charact eristics (gender, age, parents’ consanguinity and personal and family histories of existing inherited blood disorders); part two explored students’ knowledge and awareness of pms (its availability in oman, sources of information about pms, components of the screening, who can be tested and which diseases it targets); and part three rahma m. al-kindi, saraswathi kannekanti, jansi natarajan, lina shakman, zeinab al-azri and naifain i. al-kalbani clinical and basic research | e219 questioned the respondents’ attitudes towards oman’s pms programme. this study was conducted during school hours and the arabic version of the questionnaire was distr ibuted to all participants by trained research assistants. the researchers explained the aims of the study to each class and were available to assist with any inquiries. each class required approximately 20 minutes to com plete the questionnaire which was followed by a brief introduction on oman’s pms programme. statistical package for social sciences (spss), version 23 (ibm, corp., armonk, new york, usa) was used for data entry and analysis. all participants who indicated ‘did not know’ for a question were excluded from the analysis of that variable. students with missing data were excluded from the statistical analysis for some variables. descriptive statistics were used to describe the sample’s characteristics and frequencies and percentages were reported for categorical variables. pearson’s chi-squared test or fisher’s exact test for cells less than five were used to test significance when appropriate. a p value of ≤0.05 was considered statistically significant. participation was voluntary and written informed consent was obtained prior to data collection. all participants were informed about their right to withdraw from the study at any time and their anonymity and confidentiality were assured and emphasised. ethical approval for the study was granted by the college of nursing medical research and the ethics committee, sultan qaboos university, muscat, oman, in march 2015. official permission to distribute the questionnaires was obtained from the directorate general of education muscat region, ministry of education, oman. results a total of 1,541 students completed the questionnaire (response rate: 91.1%). all respondents were unmarried, the majority were omani (96%) and male (55.4%). the mean age was 17.7 ± 0.8 years (range: 16–20 years) [table 1]. a personal history and a family history of hereditary diseases were reported by 8.2% and 28.8% of respondents, respectively. more than one-third of the participants (39.6%) reported that their parents were related where some indicated that their parents were first (25%) or second (14.6%) cousins. the rest of the respondents reported distant or no familial relationship between their parents. most students (78.1%) were aware of the avail ability of the pms programme in oman. the main source of information about the pms programme were family and friends (34.4%) followed by school subjects (30.3%), media and newspaper reports (18.5%) and healthcare services and school nurses (16.8%). the vast majority of students (92.8%) knew that the screening test should involve both partners. some students (40.2%) knew that the pms programme includes blood tests and physical examinations while others thought it only includes blood tests (33.4%). the majority of participants (59.8%) thought that the pms programme targets genetic blood disorders as well as sexually transmitted diseases (stds); however, some thought that it tests only genetic blood disorders (17.8%) or only stds (9.7%) [table 2]. the majority of students (87.4%) thought that carrying out pms is important and a similar number of students (87.2%) agreed to undergo the pms tests. the respondents’ reasons for agreeing to pms testing were to prevent transmission of diseases to their offspring (73.4%), ensure that their partner is healthy (43.6%), protect themselves from diseases (25.3%) and confirm their fitness for marriage (19.1%). table 1: characteristics of high school students who partic ipated in this study (n = 1,541) characteristic n (%) p value total male (n = 853) female (n = 688) personal history of hereditary disease yes 126 (8.2) 58 (6.8) 68 (9.9) 0.047 no 1,204 (78.1) 671 (78.7) 533 (77.5) don’t know 211 (13.7) 124 (14.5) 87 (12.6) family history of hereditary disease yes 444 (28.8) 187 (21.9) 257 (37.4) <0.001no 717 (46.5) 472 (55.3) 245 (35.6) don’t know 380 (24.7) 194 (22.7) 186 (27) consanguineous relationship between parents yes 626 (40.6) 379 (44.4) 247 (35.9) <0.001no 790 (51.3) 388 (45.5) 402 (58.4) don’t know 125 (8.1) 86 (10.1) 39 (5.7) type of relationship between parents first-degree cousins 386 (25) 229 (62.1) 157 (64.9) 0.535 second-degree cousins 225 (14.6) 140 (37.9) 85 (36.1) distant or no familial relationship 930 (60.4) 484 (56.7) 446 (64.8) awareness and attitude towards the premarital screening programme among high school students in muscat, oman e220 | squ medical journal, august 2019, volume 19, issue 3 in contrast, only 139 students (9%) thought that it is unimportant to undergo pms and 125 students (8.1%) were not in favour of carrying out pms. of those who disagreed with pms, 58 students (46.4%) did not want to interfere with god’s will, were afraid that the screening results would not be in favour of their partner selection (32%), feared social stigma (19.2%) and family refusal to continue the marriage (16.8%). a minority were concerned that positive screening results would prevent continuation of the marriage or cause personal insult (15.2% each) [table 3]. most students (87.9%) agreed that the most appropriate time to undergo pms would be before marriage. some thought that the appropriate time would be during high school (8.8%) or after marriage (3.4%). over one-third of the students (36.6%) would proceed with marriage despite positive pms test results as they believe in god’s will and some (28.2%) would make a decision based on the probability of disease. a smaller number of students indicated that they would not know what to do (17.4%), while others would either end the engagement (10%), proceed with marriage for emotional reasons (6.6%) or proceed because of family pressure (1.2%) [table 3]. over half of the students (55.3%) wanted pms to be mandatory before marriage while 26.5% were neutral and 18.2% disagreed with making pms mandatory. more than one-third of the students (38.3%) agreed that there should be laws and regulations to stop marriage in cases of positive pms results, while the rest of the students were either neutral (33%) or disagreed (28.7%) [table 3]. statistical analysis to determine associations bet ween students’ sociodemographic characteristics and attitudes towards pms showed a significant association between students’ attitudes towards pms and their gender, if their parents were related and a positive family history of hereditary diseases. significantly more female students thought that carrying out pms is important (p = 0.016) and were in favour of making pms mandatory before marriage (p = 0.002) compared to male students. females were also more likely to support the creation of laws and regulations to stop marriages in case of positive pms tests (p = 0.010). students whose parents were related were significantly more in support of making pms manadatory before marriage (p = 0.018) and creating laws and regulations to stop marriages in case of positive pms results (p = 0.020). participants with a family history of heredi tary blood disorders were signficantly more likely to see pms as important (p = 0.001); however, they were table 2: knowledge of high school students about oman’s premarital screening programme (n = 1,541) knowledge item n (%) p value total male (n = 853) female (n = 688) is a pms programme available in oman? yes 1,204 (78.1) 627 (73.5) 577 (83.9) 0.002no 58 (3.8) 43 (5.0) 15 (2.2) don’t know* 279 (18.1) 183 (21.5) 96 (14.0) source of information about pms programme (n = 1,200)† family and friends 413 (34.4) 213 (34.1) 200 (34.7) 0.180 school subjects 364 (30.3) 175 (28) 189 (32.8) media and newspapers 222 (18.5) 126 (20.2) 96 (16.7) healthcare services and school healthcare nurse 201 (16.8) 110 (17.6) 91 (15.8) who should be screened males 43 (2.8) 35 (4.1) 8 (1.2) <0.001females 68 (4.4) 51 (6) 17 (2.5) both 1,430 (92.8) 767 (89.9) 663 (96.4) components of pms physical examination 50 (3.2) 39 (4.6) 11 (1.6) <0.001 blood tests 515 (33.4) 251 (29.4) 264 (38.4) both physical examination and blood tests 620 (40.2) 336 (39.4) 284 (41.3) don’t know* 356 (23.1) 227 (26.6) 129 (18.8) disorders targeted by pms genetic disorders 275 (17.8) 144 (16.9) 131 (19) 0.004 sexually transmitted diseases 149 (9.7) 96 (11.3) 53 (7.7) both 922 (59.8) 489 (57.3) 433 (62.9) don’t know* 195 (12.7) 124 (14.5) 71 (10.3) pms = premarital screening. *not included in the statistical analysis. †missing data were not included in the statistical analysis. rahma m. al-kindi, saraswathi kannekanti, jansi natarajan, lina shakman, zeinab al-azri and naifain i. al-kalbani clinical and basic research | e221 table 3: attitudes of high school students towards oman’s premarital screening programme (n = 1,541) attitudes n (%) p value total male (n = 853) female (n = 688) is pms important? yes 1,347 (87.4) 723 (84.8) 624 (90.7) 0.016no 139 (9) 90 (10.6) 49 (7.1) don’t know 55 (3.6) 40 (4.7) 15 (2.2) would you agree to undergo pms? yes 1,344 (87.2) 727 (85.2) 617 (89.7) 0.032no 125 (8.1) 78 (9.1) 47 (6.8) don’t know 72 (4.7) 48 (5.6) 24 (3.5) reasons for agreeing to undergo pms* to prevent transmission of diseases to my offspring 801 (73.4) 421 (69.1) 380 (78.8) <0.001 to ensure that my partner is healthy 476 (43.6) 298 (48.9) 178 (36.9) <0.001 to prevent transmission of diseases to me 276 (25.3) 137 (22.5) 139 (28.8) 0.020 to ensure fitness for marriage 208 (19.1) 119 (19.5) 89 (18.5) 0.710 reasons for disagreement with pms* i don't want to interfere with god’s will 58 (46.4) 38 (49.4) 20 (41.7) 0.561 afraid that the test results will not be in favour of my marital choice 40 (32) 21 (27.3) 19 (39.6) 0.190 leads to social stigma 24 (19.2) 15 (19.5) 9 (18.8) 1.000 family will refuse continuation of marriage 21 (16.8) 10 (13) 11 (22.9) 0.213 afraid that the positive results will prevent continuation of marriage 19 (15.2) 15 (19.5) 4 (8.3) 0.161 such test results are an insult to me 19 (15.2) 9 (11.7) 10 (20.8) 0.241 most appropriate timing of pms during high school 135 (8.8) 94 (11) 41 (6) <0.001before marriage 1,354 (87.9) 716 (83.9) 638 (92.7) after marriage 52 (3.4) 43 (5) 9 (1.3) response to pms if you were told that your children could be affected continue with engagement and marriage because i believe in god 564 (36.6) 366 (42.9) 198 (28.8) <0.001 decision will depend on the probability of getting the disease 435 (28.2) 209 (24.5) 226 (32.8) cancel/discontinue the engagement 154 (10) 62 (7.3) 92 (13.4) proceed with marriage due to emotional reasons 102 (6.6) 59 (6.9) 43 (6.3) proceed with marriage due to family pressure 18 (1.2) 13 (1.5) 5 (0.7) i wouldn’t know what to do 268 (17.4) 144 (16.9) 124 (18) level of agreement with making pms mandatory agree 852 (55.3) 438 (51.3) 414 (60.2) 0.010neutral 408 (26.5) 245 (28.7) 163 (23.7) disagree 281 (18.2) 170 (19.9) 111 (16.1) level of agreement with putting laws and regulations in place to stop marriages in case of positive pms results agree 590 (38.3) 302 (35.4) 288 (41.9) 0.003neutral 509 (33) 283 (33.2) 226 (32.8) disagree 442 (28.7) 268 (31.4) 174 (25.3) pms = premarital screening. *percentages do not add up to 100% as participants could choose multiple responses. awareness and attitude towards the premarital screening programme among high school students in muscat, oman e222 | squ medical journal, august 2019, volume 19, issue 3 not signficantly more likely to approve of either making pms mandatory (p = 0.732) or having laws and regul ations to stop marriages in case of positive pms results (p = 0.336) [table 4]. discussion oman’s pms programme is offered free of charge to all omani couples planning to get married. however, the programme is not popular and its utilisation is low.8,9 various factors contribute to this low utilisation, such as lack of public awareness and failure to make the programme legally mandatory. in addition, the role of healthcare teams in cases of positive pms results is ambiguous. implementing clear policies and guidelines with a comprehensive description of the roles of all stakeholders will eventually strengthen the prog ramme. clear roles and explicit policies in combination with legal reinforcement have been reported in bahrain and cyprus and have successfully contributed to red ucing the incidence of inherited blood disorders.12,19 the current study showed that most students were aware of the availability of the pms programme in oman. however, their knowledge about what the programme includes and what diseases it targets was insufficient. more than half of the participants believed that pms targets both genetic blood disorders and stds and less than 20% knew that it tests for genetic blood disorders only. these findings are fairly similar to other studies conducted in oman and the arab world.13,14,16,20,21 factors contributing to this finding include age, lack of information in school curricula as well as insufficient information from school health programmes and primary healthcare facilities. with lack of guidance from healthcare officials, students indicated obtaining most of their knowledge from families, friends, media and newspaper reports. unfor tunately, healthcare service providers and school nurses were only the fourth most important source of inform ation on pms, which is similar to the findings of alfarsi et al.’s study.14 therefore, the role of healthcare providers in raising awareness through health educ ation and disseminating information about pms is an essential one. the vast majority of participants appreciated the importance of pms and favoured pms testing. this was based on their desire to prevent transmission of disease to their offspring and revealed that the partic ipants had a good understanding of the preventative role of pms. this finding is similar to those reported in other arab countries.13,14,16,20,21 on the other hand, a few participants were not willing to undergo pms screening as they did not want to interfere with god’s will. in addition, they indicated that they were afraid that the screening results may not be in favour of their choices or may lead to social stigma. many studies in the arab world have reported similar results, indicating a lack of knowledge and students’ misunderstanding table 4: high school students’ attitudes towards premarital screening by sociodemographic characteristics (n = 1,541) variables* agreed that carrying out pms is important agreed with making pms mandatory agreed with putting laws and regulations in place to stop marriage in case of positive pms results n (%) p value n (%) p value n (%) p value participants who agreed with variable 1,347 (87.4) 852 (55.3) 590 (38.3) gender male 723 (88.9) 0.016 438 (51.3) 0.002 302 (35.4) 0.010 female 624 (92.7) 414 (60.2) 288 (41.9) consanguineous parents yes 551 (92.4) 0.245 357 (57) 0.018 266 (42.5) 0.020 no 697 (90.5) 435 (55.1) 284 (35.9) personal history of hereditary disease yes 111 (94.9) 0.127 74 (58.7) 0.391 41 (32.5) 0.113 no 1,051 (90.1) 671 (55.7) 488 (40.5) family history of hereditary disease yes 405 (94.2) 0.001 257 (57.9) 0.732 164 (36.9) 0.336 no 604 (87.7) 399 (55.6) 296 (41.3) *missing data were not included in the statistical analysis. rahma m. al-kindi, saraswathi kannekanti, jansi natarajan, lina shakman, zeinab al-azri and naifain i. al-kalbani clinical and basic research | e223 of the importance of pms.13,14,21,22 therefore, misinter pretation of religious beliefs necessitates the involve ment of religious leaders in future awareness campaigns. most students agreed that the most appropriate time to carry out pms is before marriage. however, it was alarming that more than one-third of the partic ipants indicated that they would proceed with marriage in spite of positive pms results due to religious beliefs, emotional reasons or family pressure. approximately one-quarter reported that their decision would be based on the probability of transmitting the disease to their children, indicating that students consider pms as an adjunct and not an essential step to completing the marriage process. more than half of the participants agreed that pms screening should be mandatory and more than onethird were in favour of laws and regulations to prevent marriage in case of positive pms results. this finding is similar to other studies conducted in oman, yet lower than results from saudi arabia where 85% agreed that pms should be mandatory and 63% favoured developing legal restrictions on marriage in case of positive pms results.13,14,21 traditionally, the decision to marry in oman is not limited to the couple’s choice alone; familial influence plays a major role in whether a couple weds. therefore, creating a legal basis on which to prevent marriages may conflict with traditional customs. consequently, massive campaigns and legal support would be required to improve compliance with healthcare team recommendations, especially in individuals with a family history of genetic disorders. the current study was the first to explore knowl edge and attitudes about oman’s pms programme among local high school students. however, this study did have various limitations. it was conducted in only one governorate and the results may not be generalised to other regions of the country. despite the fact that pms was explained and clarified before distributing the questionnaires, it is possible that the information was not comprehended. furthermore, it is possible that some of the participants may have been influenced by their peers while completing the questionnaires. the questionnaire used in the study did not evaluate the participants’ previous personal experience with the pms programme, which is an important variable that could have altered the findings. in addition, the current study included only younger members of the community whereas other studies have evaluated the awareness and attitudes of older individuals. a large-scale community-based study which includes all omani governorates and various age groups would overcome some of these limitations. conclusion this study showed that high school students from al seeb area in muscat governorate have good knowledge of the availability of the pms programme and a positive attitude towards the programme but lacked knowledge about the diseases it targets. although the majority of respondents agreed that they would undergo pms, only half indicated that pms should be mandatory before marriage and just one-third agreed on the importance of laws and regulations to stop marriage in case of positive pms test results. these findings highlight the need to increase students’ awareness of and improve their knowledge and attitudes towards oman’s pms programme. it is of utmost importance that healthcare services embed a well-structured health-related prog ramme within a schools’ curricula. a school-based programme should go hand-in-hand with a community based health education programme. various means of communication can be utilised to circulate important information among the target population. such efforts might focus on disseminating information through mass media, for example through popular and readily available social media platforms. awareness campaigns should extend to the community and involve family members and friends. religious leaders and lawmakers are also important contributors and can help to increase compliance and utilisation of the pms programme. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g this project was funded by an internal grant from the college of nursing at sultan qaboos university, muscat, oman (project code: ig/con/cmhd/16/01). references 1. teebi as. genetic disorders among arab populations, 2nd ed. new york, usa: springer, 2010. p. 7–8. 2. world health organization. world health statistics 2013. from: www.who.int/gho/publications/world_health_statistics/ en_whs2013_full.pdf accessed: apr 2019. 3. world health organization. community control of genetic and congenital disorders. regional office for the eastern medit erranean: world health organization. from: http://apps.who. int/ir is/bit stre am/handle/10665/119571/dsa21.p df?s e q uence=1&isallowed=y accessed: apr 2019. 4. al-riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j trop pediatr 2003; 49:i1–20. 5. hamamy ha. oman: a model for the integration of community genetic services into primary health. from: h t t p : / / p d f s . s e m a n t i c s c h o l a r. o r g / 5 0 e 2 / 1 a f d b 1 d b 7 6 a ddc78f5a73e1db98b044607ef.pdf accessed: may 2019. awareness and attitude towards the premarital screening programme among high school students in muscat, oman e224 | squ medical journal, august 2019, volume 19, issue 3 6. islam m. m. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571–94. https://doi.org/10.1017/s0021932012000016. 7. hamamy h, antonarakis se, cavalli-sforza ll, temtamy s, romeo g, kate lp, et al. consanguineous marriages, pearls and perils: geneva international consanguinity workshop report. genet med 2011; 13:841–7. https://doi.org/10.1097/ gim.0b013e318217477f. 8. oman ministry of health. premarital testing and counseling guidelines, 1st ed. department of women and child health, directorate general of primary health care. muscat, oman: ministry of health, 2018. p. 8–12. 9. united nation fund for population activities (unfpa). preconception care mission, oman. gulf cooperation council. from: https://countryoffice.unfpa.org/gcc/2014/06/24/10005/ preconception_care_mission_oman/ accessed: apr 2019. 10. karimi m, jamalian n, yarmohammadi h, askarnejad a, afrasiabi a, hashemi a. pre-marital screening for beta-thal assaemia in southern iran: options for improving the prog ramme. j med screen 2007; 14:62–6. https://doi.org/10.1258/09 6914107781261882. 11. saffi m, howard n. exploring the effectiveness of mandatory premarital screening and genetic counselling programs for β-thalassaemia in the middle east: a scoping review. public health genomics 2015; 18:193–203. https://doi.org/10.1159/0 00430837. 12. al arrayed s. campaign to control genetic blood diseases in bahrain. community genet 2005; 8:52–5. https://doi.org/10.1 159/000083340. 13. al kindi r., al rujaibi s, al kendi m. knowledge and attitude of university students towards premarital screening program. oman med j 2012; 27:291–6. https://doi.org/10.5001/omj.20 12.72. 14. al-farsi oa, al-farsi ym, gupta i., ouhtit a, al-farsi ks, al-adawi s. a study on knowledge, attitude, and practice towards premarital carrier screening among adults attending primary healthcare centers in a region in oman. bmc public health 2014; 14:380. https://doi.org/10.1186/1471-2458-14-380. 15. abdel-meguid n, zaki ms, hammad sa. premarital genetic investigations: effect of genetic counselling. east mediterr health j 2000; 6:652–60. 16. eshra dk, dorgham ls, el-sherbini af. knowledge and attitudes towards premarital counselling and examination. j egypt public health assoc 1989; 64:1–15. 17. gharaibeh h, mater fk. young syrian adults’ knowledge, per ception and attitudes to premarital testing. int nurs rev 2009; 56:450–5. https://doi.org/10.1111/j.1466-7657.2009.00736.x. 18. alkhaldi sm, khatatbeh mm, berggren ve, taha ha. knowl edge and attitudes toward mandatory premarital screening among university students in north jordan. hemoglobin 2016; 40:1–7. https://doi.org/10.3109/03630269.2015.1135159. 19. bozkurt g. results from the north cyprus thalassemia prev ention program. hemoglobin 2007; 31:257–64. https://doi. org/10.1080/03630260701297204. 20. al-aama jy, al-nabulsi bk, alyousef ma, asiri na, al-blewi sm. knowledge regarding the national premarital screening pro gram among university students in western saudi arabia. saudi med j 2008; 29:1649–53. 21. al-kahtani nh. acceptance of premarital health counseling in riyadh city, 1417h. j family community med 2000; 7:27–34. 22. al-khaldi ym, al-sharif ai, sadiq aa, ziady hh. attitudes to premarital counseling among students of abha health sciences college. saudi med j 2002; 23:986–90. https://doi.org/10.1017/s0021932012000016 https://doi.org/10.1097/gim.0b013e318217477f https://doi.org/10.1097/gim.0b013e318217477f https://doi.org/10.1258/096914107781261882 https://doi.org/10.1258/096914107781261882 https://doi.org/10.1159/000430837 https://doi.org/10.1159/000430837 https://doi.org/10.1159/000083340 https://doi.org/10.1159/000083340 https://doi.org/10.5001/omj.2012.72 https://doi.org/10.5001/omj.2012.72 https://doi.org/10.1186/1471-2458-14-380 https://doi.org/10.1111/j.1466-7657.2009.00736.x https://doi.org/10.3109/03630269.2015.1135159 https://doi.org/10.1080/03630260701297204 https://doi.org/10.1080/03630260701297204 asymptomatic hypercalcaemia is a common metabolic derangement, usually detected incidentally on routine biochemical screening. the most common aetiologies are primary hyperparathyroidism and cancer. primary hyperparathyroidism is usually mild and asymptomatic. only a few patients with primary hyperparathyroidism develop severe hypercalcaemia with serum calcium concentrations above 3.5mmol/l and evidence of end-organ involvement, such as bone or kidney. in contrast, a severe hyperparathyroid state is usually present in parathyroid carcinoma. we present a case of severe primary hyperparathyroidism and then discuss in what circumstances it should be treated as parathyroid carcinoma as well as review the evidence for what action clinicians should take when faced with such a dilemma. case report a 44 year-old male with a 4 year history of renal calculi, but no other chronic illness, was admitted to the urology service at mubarak al-kabeer teaching hospital, jabriya, kuwait with an impacted urethral stone. he was a naval officer working outdoors, on a normal diet with no symptoms of malabsorption, no neck masses on clinical exam and no cervical lymphadenopathy. he had normal renal and liver functions. he was found to be severely squ med j, april 2010, vol. 10, iss. 1, pp. 94-100, epub. 17th apr 10 submitted 5th jun 2009 revision req. 4th oct 09, revisions recd. 9 nov. and 18 jan 09 accepted 23rd jan 10 departments of 1medicine, 2radiology and 3surgery, mubarak al-kabeer teaching hospital, jabriya, kuwait and 4school of population health, university of queensland, brisbane, australia to whom correspondence should be addressed. email: goldlife203@hotmail.com َريِقيَّة َريِقيَّة الشديد مقابل سرطانة الغدة الدُّ فرط نشاط الُغَدُد الدُّ معضلة سريرية مرمي الف�شلي، �شهيل دوي، ت�ما�س متكال، با�شل ال�شميط امللخ�ص: الت�جد معطيات �رسيرية اأو خمتربية تتيح ت�شخي�س �رسطانة الغدد الدريقية قبل اجلراحة، ولكن نادرا ما ت�جد نتيجة نهائية تفرق ما بني ال�رم احلميد واخلبيث، ن�شتعر�س هنا حالة فرط ن�شاط الغدد الدريقية واملعرو�س على �شكل ارتفاع اأويل �شديد لهرم�ن الغدد الدريقية ويف م�شت�ى الكال�شي�م يف امل�شل وكذلك يف م�شاعفاتها. كما نناق�س هذه احلالة على �ش�ء مراجعة االأدبيات. �شدة ارتفاع هرم�ن الغدد الدريقية وكذلك التغريات الكيمائية االأخرى، وم�شاعفاتها على الهيكل العظمي والكلى وكتلة الرقبة يجب اأن تنبه الطبيب املخت�س الإحتمال االإ�شابة ب�رسطانة الغدة الدريقية. تعترب العملية اجلراحية هي العالج ال�حيد الفعال ل�رسطانة الغدة الدريقية، والتي يجب اأن جترى يف حالة وج�د اأدنى �شك. مفتاح الكلمات: فرط ن�شاط الغدد الدريقية، �رسطانة الغدد الدريقية، جراحة ، م�شاعفات، عالج. abstract: no clinical or laboratory data allow a preoperative diagnosis of parathyroid carcinoma and only occasionally does a definitive finding differentiate an adenoma from a carcinoma. we present a case of primary hyperparathyroidism presenting with severe elevation of parathyroid hormone and serum calcium as well as complications. we go on to discuss the case in the light of a literature review. the severity of the elevation of the parathyroid hormone, other biochemical alterations, the presence of skeletal and renal complications and of a neck mass should alert the clinician to a possible parathyroid carcinoma. radical surgery is the only effective therapy for parathyroid carcinoma, and should always be performed if a preoperative suspicion is entertained. keywords: hyperparathyroidism; parathyroid carcinoma; surgery; complications; treatment; case report; kuwait severe hyperparathyroidism versus parathyroid carcinoma a clinical dilemma mariam al-fadhli,1 *suhail a r doi,1,4 thomas muttikkal,2 basel al-sumait3 case report mariam al-fadhli, suhail a r doi, thomas muttikkal and basel al-sumait case report | 95 hypercalcaemic (corrected calcium 3.4 mmol/l) and subsequent investigations revealed severe hyperparathyroidism (intact parathyroid hormone (ipth) 84 pmol/l (normal range 2.2–7.1 pmol/l) and alkaline phosphatase (alp) 1200 iu/l (normal range 26–88 iu/l). hypercalcaemia was controlled with saline diuresis, calcitonin (200 units twice daily subcutaneous) and pamidronate (initially a 60 mg infusion followed by 30 mg 10 days later), but despite these intensive measures, there was only a transient drop in serum calcium down to a nadir of 2.7 mmol/l corrected, after which it slowly began to rise again. although, on evaluation, he had vitamin d deficiency: 25-hydroxy (oh) vitamin d was 22 nmol/l (low < 30 nmol/l; insufficient 30–80 nmol/l; normal > 80 nmol/l), his bone mineral density (bmd) t-scores were normal at anteriorposterior (ap) spine and femoral neck suggesting that this state of severe hyperparathyroidism was not long-standing. given the previous data and the severity of the hyperparathyroidism plus raised alp and the presence of radiological evidence of metabolic bone disease, it was suspected that he might have parathyroid carcinoma (ptc) which could have evolved from a state of preceding mild primary hyperparathyroidism (accounting for renal calculi over the preceding 4 years). his normal bmd, in retrospect, was attributed to a possibility of recent ptc transformation. localisation studies confirmed the presence of a large tumour posterior to the trachea and just above the superior pole of the right thyroid lobe by both sestamibi scanning and a computed tomography (ct) scan of his neck [figures 1 and 2], but was missed by ultrasound (us) in view of its ectopic location. the ct scan also showed the presence of three large (1cm) lymph nodes in the upper jugular group close to the tumour. he was booked for radical excision (based only on clinical suspicion of ptc) and had this done about 2 weeks after being reviewed by the endocrine team, with central and paratracheal lymph node dissection and right hemithyroidectomy. the three enlarged superior jugular lymph nodes were removed and sent for frozen section that showed no evidence of metastases from the possible parathyroid tumour. this was confirmed by the final pathology report. as expected, he went into hungry bone syndrome post surgery and was managed on parenteral calcium for the first 72 hours. there were no surgical complications and he had complete surgical recovery. he was placed subsequently on alfacalcidol 0.25 mcg twice a day and calcium (sandoz) 1 gm thrice daily. histopathology revealed no morphologic features of ptc within the tumour and there was no capsular or vascular invasion. immumohistochemical studies revealed 5% ki67 protein positivity and a weakly positive b-cell leukaemia/lymphoma 2 (bcl2). he is doing well figure 1a: pre-contrast and post-contrast axial images showing soft tissue density lesion (parathyroid carcinoma) with intense enhancement. figure 1b: the lesion (arrow) is indenting the posterior aspect of pharynx and shows preserved fat planes. severe hyperparathyroidism versus parathyroid carcinoma a clinical dilemma 96 | squ medical journal, april 2010, volume 10, issue 1 post surgery and is currently normocalcaemic. fourteen months after surgery, he had a traumatic fracture of the right neck of his femur. a repeat ipth was 3.3 pmol/l, calcium 2.6 mmol/l, albumin 32 g/l and bmd revealed normal t-scores. this was thus not attributed to a recurrence of his underlying disease. discussion ptc is often misdiagnosed preoperatively as primary hyperparathyroidism secondary to parathyroid adenoma or hyperplasia. the clinician’s suspicion of malignancy should be aroused in the presence of severe hyperparathyroidism and such suspicion is the most valuable tool in planning surgery thereby optimising the outcome. although such clinical and laboratory findings may suggest carcinoma,1 these findings are non-specific and there are no obvious clinical or biochemical markers that can clearly differentiate patients with carcinoma from adenomas. an important clue is very high serum calcium, although this is not diagnostic. calcium levels above 3.5 mmol/l are common in contrast to the typical elevation of 0.25 to 0.5 mmol/l above normal seen in benign primary hyperparathyroidism.2 a majority of patients with subsequently proved ptc have been shown to have a calcium level in excess of 3.8 mmol/l, and indeed 12% of patients present with hypercalcaemic crisis.3 alkaline phosphatase is also more commonly elevated in patients with ptc, this finding is thought to result from the higher incidence of bone degradation in this population.4 another clue is a severely elevated parathyroid hormone (pth) levels in patients with subsequently proven ptc. levels up to 12 times those in normal subjects are the norm in these patients, whereas pth levels approximately two times normal are the more common presentation in primary hyperparathyroidism.4 occasionally, values as high as 75-fold may occur.5 this is in contrast to benign adenomas where no correlation exists between clinical variables and preoperative biochemical markers of calcium homeostasis and adenoma weight or volume.6 the most commonly affected organ systems in patients with primary hyperparathyroidism are the renal and skeletal systems.7 benign hyperparathyroidism is reported to cause renal impairment (nephrolithiasis, nephrocalcinosis, impaired glomerular filtration) in fewer than 20% of patients. in contrast, wynne et al. reported a 56% prevalence of nephrolithiasis and an 84% prevalence of renal insufficiency in ptc.8 radiological hyperparathyroid skeletal features such as osteitis fibrosa cystica, subperiosteal erosion and ‘salt and pepper ‘ skull, are more commonly observed in ptc (39-91%);5 less than 10% of patients with benign disease have these features. patients with ptc are also at higher risk for developing complications in other organ systems (severe pancreatitis, peptic ulcer disease and anaemia) than patients with primary hyperparathyroidism.5,9 although none of these findings is specific to the diagnosis of ptc, they should alert the surgeon to the possibility of it. in addition to severe hyperparathyroidism, careful neck examination may reveal the presence of a palpable firm lump within the neck which has been reported in approximately half of patients with ptc, but in less than 10% of patients with benign primary hyperparathyroidism.2,9 paralysis of the recurrent laryngeal nerve is also a sign of late invasive ptc, but is noted to be rare.9 at the time of presentation 15-20% of patients with cancer have lymph node metastasis and up to one-third have distant metastasis, usually to lung or bone.3,10,11 despite the easy access to the tumour in ptc, the use of fine needle aspiration in suspected cases is not recommended for several reasons. first, the diagnosis of ptc can be extremely difficult figure 2: post-contrast sagittal reformat showing the extent of the lesion (arrow). mariam al-fadhli, suhail a r doi, thomas muttikkal and basel al-sumait case report | 97 cytologically and, further, sampling errors may lead to significant false negative results. second, by violating the fibrous capsule, there is a risk of seeding of parathyroid tissue. it is noteworthy that one case report of cutaneous seeding of a lesion subsequently proved to be ptc followed a fine needle aspiration which itself showed no cellular atypia.12 while not being specific for malignancy, sestamibi scanning is also an excellent modality to detect the presence of local and distant metastasis.13 us of the neck is the most useful initial method for localisation of parathyroid glands. distinguishing features of ptc, noted on the us, include a depthwidth ratio greater than 1 in 94% of cases in contrast to 5% of patients with adenoma. the us scan may also indicate the lobulated appearance and inhomogeneous echogenicity often associated with ptc.14 our patient had an ectopic tumour (hence missed on ultrasonography), being in one of the four most common ectopic locations which are: retrotracheal adenoma, mediastinal adenoma, intrathyroid, and carotid sheath adenoma. finally, bone mineral density scans have been used to detect significant skeletal abnormalities and, when correlated with grossly abnormal laboratory values (calcium, pth and alkaline phosphatase), have been found helpful in distinguishing patients with ptc from those with adenoma.4 normalisation of hypercalcaemia prior to surgery is essential for patients with ptc to prevent possible renal failure and cardiac arrest. adequate rehydration with intravenous normal saline increases renal calcium excretion. the additional use of frusemide or other loop diuretics promotes sodium and calcium diuresis. bisphosphonates inhibit bone resorption and have become the main line treatment for lowering severe hypercalcaemia. intravenous pamidronate is commonly used and produces a striking, but transient, fall in serum calcium. routine blood tests and adequate renal function must be checked prior to surgery. in patients with persistent hypercalcaemia and those with unresectable tumours, medical treatment aimed at reducing calcium levels has been implemented. also the use of octreotide can inhibit parathyroid hormone secretion from some ptcs. conservative treatment with saline and loop diuretics is typically not sufficient, and more aggressive medical therapy is required.5 medications that have been used with some success include pamidronate (bisphosphonates),15 mithramycin,16 calcitonin17 and cinacalcet.18 surgery is currently the only effective treatment for ptc. the diagnosis of ptc should be suspected in patients with primary hyperparathyroidism if at the time of neck exploration a large white or grey adherent mass is seen (the majority of them weigh in between 2 and 10 gm).8 this is in contradistinction to benign parathyroid neoplasias, which tend to be soft, flattish, and red-brown in colour.9 frozen section often provides results of little value as microscopic infiltration of tumours can be missed. en bloc resection of the ptc, avoiding capsular rupture with widely adjacent tissue, is the treatment of choice.10 this usually involves a large collar incision with ipsilateral thyroid lobectomy and excision of paratracheal alveolar tissue, lymph nodes and thymic tongue. sacrifice of the recurrent laryngeal nerve may be required if involved. although cervical lymph node metastasis occurs in less than 20% of cases, most authors recommend routine dissection of the tracheo-oesophageal groove.10 surgery offers the patient the best chance of a cure. unfortunately, the diagnosis of ptc is often made following pathologic review, but if carcinoma is suspected based on laboratory values and intraopreoperative findings are consistent with ptc, en bloc resection should be completed at the time of initial surgery, before definitive pathologic assessment.5,19 controversy exists as to whether the patient without obvious tumour extension should be taken back to the operating room for thyroidectomy, isthmusectomy and excision of paratracheal and central neck nodes after the diagnosis of ptc is obtained from the pathology report. if preoperative diagnosis of ptc is suspected, we advocate preemptive radical surgery with en bloc resection of the tumour, together with ipsilateral thyroid lobe, paratracheal and central lymph node dissection and adjacent structures (only if involved) avoiding any capsular rupture of the mass. this represents the gold standard of surgical treatment of patients.20 regular postoperative calcium levels must be monitored after resection as calcium levels may fall rapidly due to the ‘hungry bone syndrome’ where high levels of parathyroid hormone have depleted bone stores of calcium. intravenous calcium as well as oral calcium and vitamin d may be required for a variable amount of time. after the operation, all patients require careful long-term monitoring. severe hyperparathyroidism versus parathyroid carcinoma a clinical dilemma 98 | squ medical journal, april 2010, volume 10, issue 1 in the early postoperative period, symptomatic hypocalcaemia may occur secondary to redeposition of calcium into the bones (hungry bone syndrome);21 this requires treatment with intravenous calcium and we usually start immediately post surgery with a continuous infusion starting at 0.5 mg/kg/h of elemental calcium. supplemental calcium and calcitriol must be prescribed to maintain calcium at the lower limit of the normal range.5 once the suppressed parathyroid glands recover and adequate bone deposition has taken place, the requirement for supplemental calcium and calcitriol will drop and eventually these agents can be stopped. thereafter, serum calcium and pth levels should be monitored every 3 months. although the post-operative diagnosis of ptc relies often on histological examination, the histological criteria for this diagnosis are not definitive. several authors have suggested that criteria for pathologic diagnosis of ptc should include the presence of a fibrous capsule, fibrous trabeculae, trabecular or rosette-like cellular architecture, presence of mitotic figures and presence of capsular or vascular invasion.22 however, other authors have pointed out that mitotic activity can occasionally be seen in adenoma and hyperplastic glands. mckeown et al. have noted that the presence of cellular pleomorphism and atypia per se are not reliable indicators of malignancy, and mitotic activity in parenchymal cells must be distinguished from mitotic activity in endothelial cells.23 others have suggested that spindle cells and coagulation necrosis on standard slides may suggest ptc with a poorer prognosis. however, in the absence of pathognomonic diagnostic criteria, a definitive pathological diagnosis of ptc may not be possible, especially in its less aggressive forms.23 nonetheless, diagnostic accuracy should be improved by recognition of the constellation of macroscopic and microscopic features in combination with multidisciplinary correlation. with immunohistochemical staining, several cellular proteins have been found to occur more commonly in specimens of ptc than in the parathyroid adenoma.22 ki-67 has been found in about 11%, (range 3-65%) of patients with ptc in contrast to 2% of those with a parathyroid adenoma.22,24 the retinoblastoma (rb) protein has been found to be present in most patients with parathyroid adenoma and to be significantly reduced or entirely absent in various studies in patients with ptc.22 stojadinovic et al. tested several molecular phenotypes and found that 76% of patients with a parathyroid adenoma and no patients with carcinoma had the phenotype “p27(+) bcl-2(+) ki-67(-) mdm2(+)”.22 although these immunohistochemical markers have shown potential to discriminate between benign and malignant parathyroid disease, probably only vascular invasion that correlates with tumour recurrence and metastases should be considered useful in confirming malignancy.20 recurrence of tumours can be monitored by calcium and parathyroid hormone levels. most recurrences occur 2-3 years after the initial operation, but this period is variable and a prolonged disease-free interval of as long as 23 years has been reported in the literature.5,11 this emphasises the importance of long-term follow-up of patients who have had a parathyroidectomy for malignant disease. a short disease free interval is associated with poor prognosis. recurrent disease presents with rising levels of serum calcium and pth. rarely, a patient may present with a severe hypercalcaemic crisis. parathyroid carcinoma metastasises through both lymphatic and haematogenous routes. the regional lymph nodes are common sites of metastatic disease (30%) and distant metastases most frequently involve the lungs and bones, followed by the liver and other visceral organs. cervical recurrences are frequently palpable in patients. modified radical neck dissection has not been reported to improve survival and is associated with higher operative complications.11 therefore modified radical neck dissection may only be indicated in patients with cervical lymph node metastasis, local invasion or with local recurrence.11 the lung is the most common site of distant metastasis, followed by the bones and the liver. for localised distant metastasis, multiple, aggressive surgical resection is recommended by most authors as it reduces tumour bulk, thereby reducing the serum calcium and parathyroid hormone levels. when hypercalcaemia is refractory to surgical resection, medical treatment is required. radiation therapy has been described in the literature with limited data and conflicting results.8 data from treatment groups receiving adjuvant radiation therapy following surgical excision, where margins were positive, have shown evidence of possible improvement in preventing recurrence of disease. limited data exist regarding mariam al-fadhli, suhail a r doi, thomas muttikkal and basel al-sumait case report | 99 primary treatment with radiation therapy, but there may be a role for adjuvant radiotherapy as it may provide a survival benefit.25 data are also limited for the treatment of ptc with chemotherapy. conclusion there are no clinical or laboratory data which allow a preoperative diagnosis of parathyroid carcinoma and only occasionally does a definitive histopathologic finding differentiate an adenoma from a carcinoma. we have argued that this sort of presentation should alert the clinician to the presence of a possible parathyroid carcinoma. this should then lead to radical surgery since this is the only effective therapy for parathyroid carcinoma, and it should always be performed if a preoperative suspicion is entertained. finally, at the time of publication of this report, our patient had been followed for 2 years, and had a normal calcium, ipth and bmd. he did have a fracture neck of femur that occurred on minimal trauma, but there is no evidence to suggest a recurrence of his disease at this point. it can be argued that this could be a case of primary hyperparathyroidism complicated by vitamin d deficiency, and this is probably true even though there were no features of severe vitamin d deficiency (other than vitamin d levels) including a normal skeletal status. while the vitamin d deficiency may be aetiologic in the pathogenesis of such a severely hyperparathyroid state, our focus nevertheless is not on why the hyperparathyroidism was so severe. rather the focus here is that such severe hyperparathyroidism is also seen in parathyroid carcinoma and as such we should have a high index of suspicion for parathyroid carcinoma whenever we are faced with this severity of hyperparathyroidism, as it is the more serious condition and should not be missed. conversely, parathyroid carcinoma is extremely uncommon and thus, if there is a clear vitamin d deficiency clinically and biochemically with tertiary hyperparathyroidism and hypercalcaemia, the likelihood of carcinoma is extremely low and need not be considered further. – references 1. robert jh, trombetti a, garcia a, pache jc, herrmann f, spiliopoulos a, et al. primary hyperparathyroidism: can parathyroid carcinoma be anticipated on clinical and biochemical grounds? report of nine cases and review of the literature. ann surg oncol 2005; 12:526–32. 2. fernandez–ranvier gg, khanafshar e, jensen k, zarnegar r, lee j, kebebew e, et al. parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis? cancer 2007; 110:255–64. 3. kebebew e, clark oh. parathyroid adenoma, hyperplasia, and carcinoma: localization, technical details of primary neck exploration, and treatment of hypercalcemic crisis. surg oncol clin n am 1998; 7:721–48. 4. chen q, kaji h, nomura r, sowa h, yamauchi m, tsukamoto t, et al. trial to predict malignancy of affected parathyroid glands in primary hyperparathyroidism. endocr j 2003; 50:527 –34. 5. shane e. clinical review 122: parathyroid carcinoma. j clin endocrinol metab 2001; 86:485–93. 6. randhawa ps, mace ad, nouraei sa, stearns mp. primary hyperparathyroidism: do perioperative biochemical variables correlate with parathyroid adenoma weight or volume? clin otolaryngol 2007; 32:179–84. 7. rao sr, shaha ar, singh b, rinaldo a, ferlito a. management of cancer of the parathyroid. acta otolaryngol 2002; 122:448–52. 8. wynne ag, van heerden j, carney ja, fitzpatrick la. parathyroid carcinoma: clinical and pathologic features in 43 patients. bull sch med univ md 1992; 71:197–205. 9. fujimoto y, obara t. how to recognize and treat parathyroid carcinoma. surg clin north am 1987; 67:343–57. 10. obara t, fujimoto y. diagnosis and treatment of patients with parathyroid carcinoma: an update and review. world j surg 1991; 15:738–44. 11. kebebew e. parathyroid carcinoma. curr treat options oncol 2001; 2:347–54. 12. spinelli c, bonadio ag, berti p, materazzi g, miccoli p. cutaneous spreading of parathyroid carcinoma after fine needle aspiration cytology. j endocrinol invest 2000; 23:255–7. 13. al–sobhi s, ashari lh, ingemansson s. detection of metastatic parathyroid carcinoma with tc-99m sestamibi imaging. clin nucl med 1999; 24:21–3. 14. hara h, igarashi a, yano y, yashiro t, ueno e, aiyoshi y, et al. ultrasonographic features of parathyroid carcinoma. endocr j 2001; 48:213–7. 15. newrick pg, braatvedt gd, webb aj, sheffield e, corrall rj. prolonged remission of hypercalcaemia due to parathyroid carcinoma with pamidronate. postgrad med j 1994; 70:231–2. 16. singer fr, neer rm, murray tm, keutmann ht, deftos lj, potts jt jr. mithramycin treatment of intractable hypercalcemia due to parathyroid severe hyperparathyroidism versus parathyroid carcinoma a clinical dilemma 100 | squ medical journal, april 2010, volume 10, issue 1 carcinoma. n engl j med 1970; 283:634–6. 17. bhansali a, kataria rn, dutta p, saha mm, singh p, dash rj. parathyroid carcinoma: difficult management options. indian j cancer 2002; 39:119– 22. 18. silverberg sj, rubin mr, faiman c, peacock m, shoback dm, smallridge rc, et al. cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. j clin endocrinol metab 2007; 92:3803–08. 19. fujimoto y, obara t, ito y, kanazawa k, aiyoshi y, nobori m. surgical treatment of ten cases of parathyroid carcinoma: importance of an initial en bloc tumor resection. world j surg 1984; 8:392–400. 20. lumachi f, basso sm, basso u. parathyroid cancer: etiology, clinical presentation and treatment. anticancer res 2006; 26:4803–7. 21. brasier ar, nussbaum sr. hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery. am j med 1988; 84:654– 60. 22. stojadinovic a, hoos a, nissan a, dudas me, cordon-cardo c, shaha ar, et al. parathyroid neoplasms: clinical, histopathological, and tissue microarray-based molecular analysis. hum pathol 2003; 34:54–64. 23. mckeown pp, mcgarity wc, sewell cw. carcinoma of the parathyroid gland: is it overdiagnosed? a report of three cases. am j surg 1984; 147:292–8. 24. lumachi f, ermani m, marino f, iacobone m, baldessin m, cappuzzo g, et al. pcna-lii, ki-67 immunostaining, p53 activity and histopathological variables in predicting the clinical outcome in patients with parathyroid carcinoma. anticancer res 2006; 26:1305–8. 25. rawat n, khetan n, williams dw, baxter jn. parathyroid carcinoma. br j surg 2005; 92:1345–53. squ med j, may 2011, vol. 11, iss. 2, pp. 280-283, epub. 15th may 11 submitted 2nd oct 10 revision req. 22nd nov 10, revision recd. 1st jan & 19th feb 11 accepted 2nd mar 11 parvovirus, a single stranded dna virus with tropism for the erythroid progenitor cells1 is known to cause lytic destruction of the proerythroblasts leading to a mild anaemia in the immunocompetent person.2 it is the only known member of the parvoviridae family to be pathogenic to humans.3 infections occur worldwide and especially in the spring and winter months. it is so common in the northern european community that by the age of 50 years about 80% of this population will have been infected.4 although it is believed that the virus infects only erythroid progenitors, the viral capsid antigen has been demonstrated inside giant granulocytes in the bone marrow in patients with pancytopenia following bone marrow 1department of hematology & blood transfusion, royal hospital, muscat, oman; 2department of nephrology, sohar hospital, oman. *corresponding author email: preeni@omantel.net.om <ôêç√÷]<gfäe<si^fl÷]<gäj”π]<]ü€£]<l^ëü”÷]<s �äfľ�i<�›ç̌¬̌ ìè◊”÷]<≈öá<ç√e<d19<íee<ï4«í÷]<ìâê4à÷^e                     19 19      19                        19          19         abstract: we report a young omani male who developed severe and persistent anaemia after a kidney transplantation while being on immunosuppression therapy, standard practice to prevent rejection of the transplanted kidney. his bone marrow aspirate showed the classic morphological changes of pure red cell aplasia (prca), induced by parvovirus b19 infection which is the presence of giant proerythroblasts with viral inclusions. the virus was also demonstrated by polymerase chain reaction in the blood along with igm antibodies to parvovirus b19. he responded dramatically to high dose immunoglobulin with a normalisation of his haemoglobin level in two weeks and remained normal until seven months later. parvovirus b19 induced prca can be cured. this aetiology must be kept in mind especially when a chronic anaemia, refractory to treatment, is accompanied by a reticulocytopenia. the latter reflects the lysis of the proerythroblasts, preventing maturation of the erythroid cells causing anaemia. early recognition and prompt treatment spares the patient unnecessary exposure to blood transfusions, erythropoietin and renal disease caused by the virus. prca secondary to parvovirus b19 infection following kidney transplantation is reported in the literature, but not in the omani population. to the best of our knowledge, this is the first such report in oman. keywords: red cell aplasia, pure; human parvovirus b19; kidney transplantation; immunosuppuression; case report; oman acquired pure red cell aplasia caused by parvovirus b19 infection following a renal transplant arundathi kurukulasuriya,1 amal a. hamed,1 muhanna al-muslahi,1 asaid ibrahim2 case report arundathi kurukulasuriya, amal a. hamed, muhanna al-muslahi and asaid ibrahim case report | 281 transplantation.5 viral growth can also be maintained in fetal liver cell cultures.2 in children, parvovirus b19 infection causes a transient anaemia associated with an erythematous rash called the fifth disease or erythema infectiosum. occasionally, in immunocompetent adults, a symmetric polyarthropathy mimicking rheumatoid arthritis occurs.3 the tropism to erythroid progenitors in the bone marrow is well known to cause a transient aplastic crisis (tac) in individuals with an underlying haemolytic anaemia and hydrops fetalis in intrauterine infections.6 in immunocompromised patients, the inability to generate an immune response leads to a state of persistent anaemia, reticulocytopenia caused by lytic destruction of proerythroblasts giving rise to an acquired pure red cell aplasia (prca). following allogeneic stem cell transplants (asct), this infection is known to occur most commonly in the first year post transplant as the immune suppression is at a maximum during this period.7-11 the standard treatment for these patients is intravenous (iv) gammaglobulin (ivig). this replaces the neutralising antibodies which the patient does not possess; however, it is unknown whether the virus is always eliminated completely by this treatment. case report an omani man aged 30 had end stage renal disease caused by pyelonephritis of the right kidney. he was on haemodialysis for three years following which figure 1: bone marrow smear showing two giant proeythroblasts. one intact with intranuclear eosinophilic inclusion body like nucleoli. arrow points to ‘dog ear’ cytoplasmic projections. adjacent is a denuded nucleus of a giant proerythroblast. (x 1000). he had a kidney transplant from a live donor. he had a course of antilymphocyte globulin (alg), commenced intraoperatively and was on tacrolimus, mycophenolate mofetil and prednisolone as a means of immunosuppression. no information was available regarding the donor’s parvovirus status as the transplant was done in another country. three months later he was referred to our clinic for investigation of tiredness on exertion and anaemia with a haemoglobin of 5 g/dl. on presentation, his renal and liver functions were normal. he was afebrile, cheerful and, apart from being very pale, was clinically well. he received a transfusion of two units of packed red blood cells. despite this his anaemia persisted at an hb of 6.9 g/dl. the doses of immunosupressive drugs (tacrolimus and mycophenolate mofetil) were reduced. other laboratory investigations were as follows; red cell count 2.93 x 109/l (4.5–6.6); white blood cells 4.0 x 109/l (4–11); platelets 353 x 109/l; absolute reticulocyte count3 x109/l (5–200); haptoglobin level 1817 mg/l (360 – 1950mg/l); lactate dehydrogenase level 322 (95– 190 iu/l); folate level 30.7 (4.8–30.5 nmol/l), vitamin b12 – 130 (139–651 pmol/l); iron profile – normal; direct and indirect antibody tests no antibodies detected; antibodies for parvovirus b19 – positive; igm antibodies and polymerase chain reaction (pcr) parvovirus positive. figure 1 shows the bone marrow aspirate, figure 2 shows bone marrow trephine biopsy with giant proerythroblast with a megakaryocyte at the left hand end of the, and figure 3 positive glycophorin stain for giant figure 2: trephine biopsy. arrow points to three giant proerythroblasts with a megakaryocyte at the left hand end of the row ( x1000). acquired pure red cell aplasia caused by parvovirus b19 infection following a renal transplant 282 | squ medical journal, may 2011, volume 11, issue 2 proerythroblasts. the above investigations show the absence of an aetiology of haemolytic anaemia (immune mediated and non immune), iron deficiency, vitamin b12 or folate deficiency for the anaemia in this patient. the persisting anaemia, with a reticulocytopenia, no evidence of myelodysplasia, haemolysis, nutritional deficiency, the morphological evidence of parvovirus b19 infection, of gigantoblasts containing viral inclusion bodies and the absence of late normoblasts in the bone marrow confirmed the diagnosis of parvo virus b19 by morphology. positive staining of giant proerythroblasts with the glycophorin stain, established the large cells as being erythroid in nature. further confirmation was made by the presence of the anti parvovirus b19 immunoglobulin m (igm) and positive polymerase chain reaction (pcr) for a high load of parvovirus b19. the cornerstone of treatment for this disease is passive transfusion of ivig to enrich the humoral immunity of the patient supported with packed red blood cell transfusions. in the immune competent host, 0.4g/kg/day of ivig is given for 3 days. in the immunocompromised host, prolonged treatment with ivig reduces the viral levels to undetectable levels by repeated pcr. a higher dose of 1g/kg/day is used for 5 days in these patients and when necessary for a longer period. patients generally respond after two weeks of treatment. some patients may require more than one course of immunoglobulin therapy and some may benefit from alteration of their immunosuppressive therapy.12-16 other immunomodulatory approaches such as rituximab, steroids, (alg), cyclophosphamide, and methotrexate have also been used in chronic prca. this is especially the case if it present as the primary haematological disorder, with no obvious cause, or in association with other disease ssuch as lymphorproliferative disorders, connective tissue diseases, thymoma, solid tumours, pregnancy, or following bone marrow transplantation, but rarely in patients with parvovirus b19 infection.15 our patient was treated with 1g of ivig /kg / day for 5 days and packed red blood cells. his haemoglobin levels recovered in two weeks. he was completely well with a normal complete blood count (cbc) seven months later, at time of writing. discussion in immunocompetent persons with normal red cell life spans, parvovirus b19 infections cause a 5–10 day erythropoietic aplasia, but do not cause significant anaemia as their red cell life span is 120 days.6 however, in patients with haemolytic anaemias whose red cell life spans are shortened, for example 15 days in hereditary spherocytosis, a transient decompensated erythropoiesis leads to a severe anaemia.6 in immunocompromised patients, such as our patient, the infection can persist leading to chronic anaemia. congenital immunodeficient states, human immunodeficiency virus (hiv) infections, post organ transplants, lymphoproliferative disorders are some of the other known immunodeficient states associated with prca caused by parvo virus b19. the diagnosis rests on the presence of a persistent anaemia, with normal other blood cell counts, a reticulocytopenia, giant proerythroblasts (gigantoproerythroblasts) with prominent eosinophilic viral inclusions in the bone marrow, serum anti parvoviral igm/igg and positive pcr for parvoviral dna. the neutralising antibodies are able to clear the infection usually by 5th to 10th day of infection. it is proposed that with the rising titres the virus is cleared and the giant proerythroblasts are replaced by regenerating erythroid cells.6 parvoviridae are difficult to culture, but can be grown from the bone marrow. in the immunocompromised host, parvoviral antibodies maybe difficult to demonstrate,6 although the presence of anti parvo viral igg makes persistent infection improbable. in figure 3: trephine biopsy glycophorin stain giant proerythroblasts staining positive (x1000). arundathi kurukulasuriya, amal a. hamed, muhanna al-muslahi and asaid ibrahim case report | 283 prca caused by other aetiological causes like thymoma, large granular lymphocytic leukaemia, systemic lupus erythematosus and rheumatoid arthritis, giagantoproerythroblasts are not seen. parvoviral infections are also associated with glomerulonephritis and a nephrotic syndrome such as protein-losing kidney disease. conclusion in isolated persistent anaemia in immunocompromised adults, accompanied by a reticulocytopenia and no other aetiological evidence for the anaemia, a parvovirus b19 induced prca should be excluded, particularly as there is no vaccine for protecting those at risk. references 1. brown ke, anderson sm, young ns. erythrocyte p antigen: cellular receptor for b10 parvo virus. science 1993; 262:114−17. 2. forea av, lonescu dn, melhem mf. parvovirus b19 infection in the immunocompromised host. arch pathol lab med 2007; 131:799−804. 3. hayes-lattin b, seipei j, gatter k, heinrich mc, mariarz t. pure red cell aplasia associated with parvovirus b19 infection occurring late after allogeneic bone marrow transplantation. american j hematol 2004; 75:142−5. 4. heegaard ed, brown ke. human parvovirus b19. clin microbiol rev 2002; 15:485−505. 5. kobayashi s, maruta a, yamamoto t, katayama n, higuichi r, sakano y, et al. human parvovirus b19 capsid antigen in granulocytes in parvovirus b19 induced pancytopenia after bone marrow transplantation. acta haematol 1998; 100:195−9. 6. fisch p, handgretinger r, schaefer he. pure red cell aplasia. br j haematol 2000; 111:1010−22. 7. weiland ht, salimans mm, fibbe we, kluein pm, cohen bj. prolonged parvovirus b19 infection with severe anaemia in a bone marrow transplant patient. br j haematol 1989; 71:300. 8. solano c, juan o, giemno c, garcia-conde j. engraftment failure associated with peripheral blood stem cell transplantation, after b19 parvovirus infection. blood 1996; 88:1515−17. 9. azzi a, fanci r, ciappi s, zakrezewska k, bosi a. human parvovirus b19 infection in bone marrow transplantation patients. am j hematol 1993; 44:207−9. 10. broliden k, parvovirus b19 infection in pediatric solid organ and bone marrow transplantation. pediatr transplant 2001; 5:320−30. 11. frickhofen n, arnold r, hertenstein b, weisneth m, young ns. parvovirus b19 infection and bone marrow transplantation. ann hematol 1992; 64:121−4. 12. waldman m, kopp jb. parvovirus-b19-associated complications in renal transplant recipients. nat clin pract nephrol 2007; 3:540−50. 13. choi sh, chang sp, won jc, lee js, chi hs, yang ws, et al. a case of persistent anemia in a renal transplant recipient: association with parvovirus b19 infection. j infect dis 2002; 34:71−5. 14. wong ty, chan pk, leung cb, szeto cc, tam js, li pk. parvovirus b19 infection causing red cell aplasia in renal transplantation on tacrolimus. am j kidney dis 1999; 34:1132−6. 15. geetha d, zachary jb, baldado hm, kronz jd, kraus es. pure red cell aplasia caused by parvovirus b19 infection in solid organ transplant recipients: a case report and review of literature. clin transplant 2000; 14:586−91. 16. sawada k, fujishima n, hirokawa m. acquired pure red cell aplasia: updated review of treatment. br j haematol 2008; 142:505−14. إستفادة الطالب من دمج شهادة البكالوريوس يف العلوم الصحية مع برانمج دكتور يف الطب يف جامعة السلطان قابوس حممد ر�سيد بولع�سل، اإكرام برين، نادية الوردية، عمر حبال، عمر الروا�س abstract: objectives: after completing the pre-clinical phase of a doctor of medicine (md) curriculum, undergraduate medical students may choose to add a bachelor of science (bsc) degree in health sciences to their md degree. limited data exists on the motives behind students’ decisions to undertake such intercalated degrees. hence, this study aimed to identify the factors that influence students in making this choice. methods: undergraduate students who chose the research-based academic track of the intercalated phase of the bsc programme at the college of medicine and health sciences, sultan qaboos university, muscat, oman, between 2014–2018 were enrolled. a standardised and validated self-explanatory questionnaire examining motivations to join the intercalated phase was administered to all students in the first week of enrolment. results: over a five-year period, out of 557 eligible students, 18 (3%) were enrolled in the intercalated phase and all completed the questionnaire. the mean age was 22 ± 1.5 years and the majority (83%) were female. out of the 18 students, 10 (55%) had taken the university’s foundation programme. a total of 45% of students chose to intercalate out of their own interest, regardless of career ambitions. the main reasons to intercalate were an opportunity to enhance research experience, alignment with long-term career goals and a chance to publish in indexed journals. conclusion: despite the benefits of obtaining an additional degree, a relatively small proportion of md students were attracted to the intercalated phase. a better presentation of the bsc degree is needed to help students make a more informed decision. keywords: medical education; undergraduate medical education; career choice; curriculum; oman. درجة اإ�سافة الطالب بع�س يختار قد الطب، يف دكتور برنامج من ال�رسيرية قبل ما املرحلة متطلبات اإكمال بعد الهدف: امللخ�ص: من القليل هناك باالنرتكليتد. املرحلة هذه وت�سمى الطب يف دكتور وهي اأال االأ�سا�سية �سهادتهم اإىل ال�سحية العلوم يف البكالوريو�س املعلومات حول العوامل التي تدفع هوؤالء الطالب اإىل اتخاذ هذا القرار، لذلك فاإن هذه الدرا�سة تهدف اإىل التعريف باأهم العوامل التي توؤثر البحث م�سار بدرا�سة قاموا الذين الطلبة جميع اختيار مت لقد انرتكليتد. الطريقة: مرحلة اإىل باالإن�سمام الطالب يتخذه الذي القرار على العلمي من مرحلة انرتكليتد للح�سول على �سهادة البكالورو�س يف العلوم ال�سحية اإ�سافة اإىل �سهادة دكتور يف الطب من العام 2014 اإىل العام 2018 يف كلية الطب والعلوم ال�سحية، جامعة ال�سلطان قابو�س، م�سقط، عمان لالإن�سمام اإىل هذه الدرا�سة. وقد مت توزيع ا�ستبيان لبحث العوامل التي دفعت هوؤالء الطلبة الختيار مرحلة االنرتكليتد يف اأول اأ�سبوع من االإن�سمام اإىل املرحلة. النتائج: خالل اخلم�س �سنوات املا�سية، اأ�ستوفى قرابة 557 طالب �رسوط االإلتحاق مبرحلة انرتكليتد. من بني هوؤالء الطلبة، 18 طالب )%3( قاموا فعليًا باالإن�سمام اإىل مرحلة االنرتكليتد، كما اأنهم اأجابوا على اأ�سئلة اال�ستبيان. اإن متو�سط العمر لهوؤالء الطبة كان 1.5 ± 22 �سنوات، و الغالبية العظمى كانت من االإناث )%83(. من بني هوؤالء الثمانية ع�رس طالبًا، 10 طالب )%55( التحقوا بالربنامج التاأ�سي�سي يف اجلامعة يف �سنتهم االأوىل. كان هناك قرابة %45 من الطالب اختاروا االإن�سمام اإىل مرحلة االنرتكليتد ب�سبب اهتمامهم اخلا�س، بغ�س النظر عن التوجه الوظيفي لهم. اإن احل�سول على الفر�سة لتطوير اخلربة البحثية ون�رس البحوث يف جمالت طبية معروفة كانت من االأ�سباب ال�سائعة التي اأدت اإىل االإن�سمام اخلال�صة: الطالب. لهوؤالء الوظيفي للتوجه املدى بعيدة االأهداف مع انرتكليتد مرحلة متطلبات توافق اإىل باالإ�سافة انرتكليتد، ملرحلة االنرتكليتد. مرحلة اإىل لالإن�سمام الدافع ميلكون كانو الطب طلبة من قليل عدد اأن اإاّل اأخرى، �سهادة على احل�سول اإيجابية اإىل بالرغم قد تكون امل�ساهمة يف تطوير الو�سف الدرا�سي ل�سهادة البكالوريو�س يف العلوم ال�سحية من االأمور التي �ست�ساعد الطلبة يف اتخاذ قرار االإن�سمام اإىل مرحلة انرتكليتد. الكلمات املفتاحية: التعليم الطبي؛ التعليم الطبي اجلامعي؛ اختيار املهنة؛ الربنامج؛ عمان. students’ perceived benefits of integrating a bsc in health sciences within a medical degree at sultan qaboos university *mohamed-rachid boulassel,1,2 ikram burney,3 nadia al-wardy,4 omar habbal,5 omar al-rawas6 clinical & basic research sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e187–193, epub. 28 jun 20 submitted 9 jul 19 revision req. 30 jul 19; revision recd. 29 sep 19 accepted 14 nov 19 advances in knowledge to the best of the authors’ knowledge, this study was the first conducted at sultan qaboos university (squ) to identify the reasons influencing medical undergraduate students’ decisions to undertake the intercalated phase of the doctor of medicine curriculum. medical undergraduate students who joined the intercalated phase throughout the five-year study period demonstrated maturity and autonomy in their thinking. they undertook the bachelor of science (bsc) degree with a deep interest in medical research and future academic positions. https://doi.org/10.18295/squmj.2020.20.02.009 departments of 1allied health sciences, 2haematology, 4biocehmistry, 5human & clinical anatomy and 6medicine, sultan qaboos university, muscat, oman; 3department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: boulassel@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ students' perceived benefits of integrating a bsc in health sciences within a medical degree at sultan qaboos university e188 | squ medical journal, may 2020, volume 20, issue 2 intercalated degrees may be undertaken as part of medical undergraduate coursework. these degrees are endowed with several advantages as they allow students to spend a year focusing on areas they particularly enjoy while they obtain an additional degree as well as skills. pursuing an intercalated degree may also provide a competitive edge when individuals apply for programmes after graduation. pursuing an intercalated degree can support students in enlarging their professional networks and making new friends. such a degree also allows students to take a year off from the busy life of medical school. additionally, medical schools, health systems and society get more well-rounded graduates who are well-versed in research skills, innovative thinking and other related areas. however, there are some disadvantages to an intercalated degree, including an extra year at the undergraduate level and additional costs.1–3 several medical schools offer the intercalated degree as an option. at sultan qaboos university (squ), muscat, oman, the doctor of medicine (md) degree progr amme has evolved to meet the varying needs of the public and align with the increasing demands of healthcare services. indeed, the md programme was redesigned and restructured with the end goal of shifting the curriculum from a traditional discipline-based model to an outcome-based integrated curriculum that fosters independent learning and critical thinking. the new md curriculum was launched in 2008 at squ’s college of medicine and health sciences (comhs) with an annual intake of 130 students which included 65 males and 65 females.4 to be admitted into the md programme, a minimum b+ grade point average (gpa) in the three out of four science subjects, namely biology, chemistry, mathematics and physics, is required. currently, all medical students are of omani origin and the programme is provided free of cost. the curriculum consists of three phases. phase i comprises college requirements and college and university electives and a minimum focused gpa of 2.5 is required to progress to the next phase. phase ii consists of integrated system courses, integrated modules offering opportunities for early clinical exposure and student projects spanning three semesters to introduce students to research. a cumulative gpa of ≥2.5 is required at this stage to progress to phase iii which is the clinical clerkship phase. it is at this juncture that students might opt to intercalate in order to obtain a bachelor of science (bsc) in health sciences. the minimum time to complete the md degree is six years and the maximum allowed time is nine years. the intercalated year of study runs two parallel tracks—the hospital management/hands-on track (track 1) and the research track (track 2). track 1 is limited to students who do not achieve a gpa of 2.5; they graduate from the comhs with a bsc degree in health sciences after successful completion of taught courses and hands-on practice. track 2 is offered to students who achieve a gpa ≥2.5. unlike many other medical schools where this form of intercalated year is offered to a limited number of students, such as the top 10–20%, squ offers this track to all students who achieve the required gpa. students take some taught courses but spend most of their time learning research methods, carrying out a research project and finally submit a written thesis. on completion of the intercalated phase, track 2 students enter the clinical phase iii of the md programme for an additional three years. when completed, students are awarded two degrees—the bsc in health sciences and the md. although some studies report that intercalated degrees may add value to undergraduate programmes, other studies have found no effect of taking an intercalated degree on academic performance among medical students.2,5–9 these conflicting results highlight the need to conduct more studies to assess whether taking an integrated degree would affect medical students’ academic performance. according to the social cognitive career theory, three main elements—self-efficacy beliefs, outcome expectations and personal goals—influence a student’s decision-making around career choices; hence, these elements may play a role in choosing whether to do an intercalated degree.10 early studies have shown that a balance between career prospects and financial challenges is the main driving force for undergraduate students when deciding whether to take an intercalated degree.1,3 however, it should be emphasised that these findings may not be applicable to other medical schools, including squ, as omani students pay no tuition or fees. in addition, the decision to intercalate could be influenced by several other factors such as cultural background, educational system and application to patient care the intercalated bsc degree at squ resulted in developing a ‘cluster’ of medical undergraduate students who may become clinicianacademicians capable of taking scientific discovery to the bedside to enhance patient care. promoting an intercalated phase is an essential step to help attract more students to applying for a bsc degree and foster the development of medical scientists in oman. mohamed-rachid boulassel, ikram burney, nadia al-wardy, omar habbal and omar al-rawas clinical and basic research | e189 geographical variations.1,9 thus, factors influencing choosing an intercalated degree within one country may differ from the factors in other countries even though the general features of the md programmes may be similar. identifying these influential factors is crucial not only to help students make an informed decision about joining the degree but also to improving teaching outcomes in general. therefore, in order to attract more students to the intercalated phase, especially those who are genuinely interested, stakeholders need to identify the factors influencing this decision-making. to date, no studies have examined the motives influencing students’ decisions to undertake an intercalated degree at squ's comhs. hence, this exploratory study aimed to identify motives influencing undergraduate medical students’ decisions to pursue a bsc as an intercalated degree. methods this study included undergraduate medical students who had opted to take track 2 of the intercalated phase between 2014–2018 at squ’s comhs. in the first week of enrolment, students were invited to complete a standardised and validated self-explanatory questionnaire adapted from a previous study which examined the motivations to join intercalated medical programmes.1 to suit the squ’s intercalated degree, minor modifications were made by adding demographic items, including the participants’ md programme paths and place of residence. these added items did not affect the main content of the questionnaire. the questionnaire was administered in english and handed personally to all participants and completed manually. the paper questionnaires were then collected and data were recorded in microsoft excel, version 13.0 (microsoft corp., redmond, washington, usa). the questionnaire consisted of ten items. the first four questions asked for demographic information including gender, age, marital status and omani governorate of residence. the next three questions were related to md programme entry, decisionmaking around choosing the intercalated phase and career ambitions. students were asked to select the benefits of doing the intercalated bsc degree from a list of 14 reasons and could select more than one benefit. finally, students were asked if they thought that the intercalated degree could improve their thinking and reasoning skills as well as their academic performance, using three open-ended questions. graphpad prism software, version 5.0 (graphpad software, san diego, california, usa) was used to analyse the data. percentage, mean, standard deviation and bar graphs were used to illustrate the data. comparisons were made using a chi-square test with a p value less than 0.05 considered statistically significant. students were informed that the questionnaire was completely anonymous and participation was entirely voluntary. this study was approved by the medical research ethics committee (mrec #1883) at squ. results over the five-year study period, a total of 607 students were enrolled in phase ii of the md degree. among these, 50 students were not eligible to enter the clinical phase iii of the md programme and were advised to take track 1 and graduate with a bsc degree in health sciences. the remaining students (n = 557) achieved a gpa ≥2.5 and were eligible to progress to the clinical phase iii. of this total, 18 students (3%) decided to take the intercalated degree and all completed the questionnaire. their gpas at the end of phase ii ranged from 2.8–3.4. the mean age of the study cohort was 22 ± 1.5 years (range: 21–26 years). of the participants, 15 (83%) were female and all students, except one, were unmarried (95%). the students were from different parts of oman including muscat governorate, which was the most common (39%), followed by ad-dakhiliyah (32%), ad-dhahirah (11%), al-batinah (7%), ash-sharqiyah (6%) and al-buraymi (5%). the number of students who took the foundation programme was higher, but not statistically significant when compared to students who joined the md programme directly (55% versus 45%; p = 0.45). more than a third of the students (33%) indicated that they were influenced by family members to take the intercalated phase. while 45% of students said they were interested in the bsc degree on their own and that no one influenced their decision to take the intercalated phase, 22% of students indicated that others had influenced their decision to undertake the intercalated phase. almost 39% of students said they did not know what their career path would be. similar proportions of students were aiming for an academic position or a hospital-based career (33% and 28%, respectively) [figure 1]. all students agreed that the intercalated phase would provide experience in research. students agreed that new skills would be learnt (78%), their knowledge would be broadened (78%) and that they might be able to publish (83%). interestingly, 78% of students indicated that the intercalated phase would students' perceived benefits of integrating a bsc in health sciences within a medical degree at sultan qaboos university e190 | squ medical journal, may 2020, volume 20, issue 2 figure 1: characteristics of students according to doctor of medicine programme entry, decision to intercalate and career ambitions (n = 18). md = doctor of medicine. figure 2: motivating reasons for choosing to intercalate among medical students (n = 18). md = doctor of medicine. be enjoyable and 72% agreed that it would improve their learning habits for future studies. similarly, 89% of students agreed that it would improve their longterm career prospects and 44% thought it would help them to get a job in the future. importantly, only 11% of students were motivated by an extra summer holiday [figure 2]. the stated reasons were further studied in relation to the demographic information, md entry path, degree choice and career ambitions. as the study included only three male students (17%), and almost all were aged less than 23 years old and single, it was not possible to evaluate the effects of age and gender on the reasons for undertaking the intercalated phase. however, students who joined the md programme directly were more likely to select “a chance to get a publication” as a reason for joining the programme, although this finding was not statistically significant (p = 0.06). regarding other reasons, no statistically significant differences were found between students who joined the md programme directly and those who took the foundation programme before starting the md degree. similarly, no statistically significant differences were observed in any reason according to the decision to intercalate and career ambitions. to the open-ended question: “do you feel that taking the intercalated phase will improve your thinking and reasoning skills?” all students answered affirmatively. a female student (22 years old) replied with: “yes, i will learn how to critically appraise articles and apply them to clinical practices”. another female student (23 years old) recognised that she would improve by “solving problems of research question by improving interpretation skills”. a female student (23 years old) indicated that “by building a research hypothesis and developing literature review and research skills” she would advance her thinking skills. a male student (24 years old) stated that the intercalated degree would help him “to think critically and analyse the problems and make appropriate solutions by mohamed-rachid boulassel, ikram burney, nadia al-wardy, omar habbal and omar al-rawas clinical and basic research | e191 identifying strategies and models”. a female student (23 years old) suggested that the degree would help her “by widening the way of thinking during the discussion of different topics”. to the question: “do you feel that taking the intercalated phase will improve your academic performance?”, 44% of students indicated a belief that it would not improve their academic outcomes when returning to the md programme, while 56% stated the opposite. some students provided explanations for their answers; a female student (23 years old) stated that the degree would make her “more comfortable to read and understand articles and update my sources during my clinical studies”. the benefit of greater learning was also expected to translate into a competitive edge in terms of knowledge as a female student (23 years old) said: “i’ll be more knowledgeable on specific subjects than my colleagues”. enhanced skills were also acknowledged, for example two female students said: “it will add a value to my performance in clinical years” and it could “give me a boost how i could perform good in clinical topics” (22 and 23 years old, respectively). among the students who joined the intercalated phase, five students (three females and two males) chose not to continue to the md programme and left squ for personal reasons, having earned a bsc degree in health sciences. discussion little is known about factors that influence an undergraduate medical student’s decision to choose to intercalate a bsc in health sciences within an md degree at squ. to the best of the researchers’ knowledge, this study was the first to address this issue since the first cohort of students who received the new md curriculum in 2008. intercalating an additional degree within the primary md programme was considered a key step in the new curriculum, aiming to generate interest among undergraduate medical students in becoming clinician-scientists, thereby opting for future academic careers. available data indicate that only a small percentage (3%) joined the intercalated phase. it is uncertain, however, whether this small number reflects the students' lack of interest or a more global change in students’ perceptions about the potential advantages of joining this phase. hence, it is important to examine the reasoning behind students’ decisions in future studies. the current findings also suggested that a signif icant proportion of students decided to undertake the bsc degree due to personal interest. this observation is encouraging as it suggests motivation among students to pursue this degree with dedication. it could be also attributed to their genuine interest in or positive experience with phase ii research exposure. however, this study also revealed that the preference to intercalate was influenced by family for some students. this social pressure may have forced some students to undertake the bsc degree who had neither an interest in research nor the desire to improve their career prospects. interestingly, these data showed that more female students joined the intercalated phase compared to male students, with a female-to-male ratio of 5:1, although an equal number of female and male students were admitted each year into the md programme. this finding may suggest that female students were more likely to be interested in research than male students. another possible explanation is that female students outperform their male counterparts across all colleges at squ and therefore have more self-belief.11 it could also be argued that an increasing number of male students take the foundation programme compared to female students. an intercalated degree would lengthen the already lengthy md programme and may decrease their interest in obtaining an intercalated degree. most students in the current study choose to be academicians or have hospital-based careers. this result is consistent with earlier observations demonstrating that intercalated degrees resulted in greater interest in academic careers and hospital medical specialties. evered et al. reported that intercalating students were more likely to enter academic careers, and this research training and experience substantially influenced their future career development.12 similarly, nguyen-van-tam et al. reported that students taking intercalated degrees showed greater interest in medical research careers and their research at this level strongly influenced the subsequent choice of specialty.13 likewise, goldacre et al. noted that students who undertook intercalated degrees were more likely to choose hospital medical specialties compared to those who did not pursue such a degree.14 collectively, these observations indicate that intercalated degrees appear to develop a ‘cluster’ of undergraduate medical students who most likely become clinician-academicians capable of taking scientific discovery to the bedside. this study revealed that the main reasons for intercalating were to gain experience in research and improve long-term career goals. using a similar survey questionnaire, agha and howell found that the most common reasons for undergraduate students to intercalate were to improve their long-term students' perceived benefits of integrating a bsc in health sciences within a medical degree at sultan qaboos university e192 | squ medical journal, may 2020, volume 20, issue 2 career prospects and knowledge base.1 the current results are consistent with those findings, although the total number of respondents and demographic characteristics of the study populations were different. the third most common reason for intercalating in the current study was a chance to publish, although it was one of the least important reasons among students in agha and howell’s study.1 this finding could be partially explained by the structure of the intercalated degree. in fact, in some universities, such as squ, the degree is optional while in other universities the degree is compulsory for all students.3,15 another possible explanation could be that squ’s students recognised the benefits of having an additional qualification and associated research experiences. additionally, they recognised that having a publication might positively impact their future academic careers. another reason to intercalate was the perceived advantage of getting a job in the future. in fact, in many countries, intercalated degrees could help students gain points in the ranking system when applying for their first jobs as doctors.5 surprisingly, this reason was chosen by less than half of the students in this study, suggesting a weak association between intercalating and future job competition in omani settings. the most suitable time to proceed with the intercalated phase is while the student has no family responsibilities. in addition, it is less likely that students who join the intercalated phase will change their major or drop-out. however, this study revealed that more than a quarter of students who chose the intercalated phase left the md programme. this number is high when compared to agha and howell’s study, where approximately 6% of students dropped out after intercalating.1 it should be noted that the current students were relatively young and unmarried and 60% joined the md programme directly without taking the university’s foundation programme. further investigation is required, including in-depth interviews, to ensure a greater precision of determining the reasons behind their decisions to leave the md programme. although a major strength of this study was collecting data via standardised and validated selfexplanatory measures, there were some limitations. the sample size was relatively small, which may impact the study findings. however, these results reflected the ongoing intercalated phase at squ since its establishment in 2008. repeating this survey in the coming years will reveal whether more students have joined the intercalated phase. another limitation of the current study is that unrecognised confounders may affect a student’s decision to intercalate, especially personal difficulties, psychological stress and parental support. therefore, when repeating this survey, in-depth interviews should be included to better understand the effects of other factors that have not been considered in this study. conclusion the findings of this study provide evidence that students who took the intercalated phase at squ are more interested in research and want to pursue an academic career. it also shows that the intercalated bsc degree in health sciences forecasts the development of future clinician-scientists who are better prepared for future academic positions. hence, further active steps should be taken to explain to the medical undergraduate students the benefits associated with the intercalated phase and help them make informed decisions about intercalating a bsc within a md degree. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s we are grateful to all students who joined the intercalated phase. we are also thankful to all tutors involved in the bsc heath sciences from squ, squ hospital and the college of nursing. references 1. agha r, howell s. intercalated bsc degrees – why do students do them? clin teacher 2005; 2:72–6. https://doi.org/10.1111/ j.1743-498x.2005.00059.x. 2. mahesan n, crichton s, sewell h, howell s. the effect of an intercalated bsc on subsequent academic performance. bmc med educ 2011; 11:76. https://doi.org/10.1186/1472-6920-11-76. 3. nicholson ja, cleland j, lemon j, galley hf. why medical students choose not to carry out an intercalated bsc: a questionnaire study. bmc med educ 2010; 10:25. https://doi. org/10.1186/1472-6920-10-25. 4. albarwani s, al-saadoon m, al-rawas o, al-yaarubi s, al-abri r, al-lamki l, et al. reflections on the academic accreditation of the md programme of the college of medicine & health sciences, sultan qaboos university, oman. sultan qaboos univ med j 2014; 14:e7–e11. 5. agha r, fowler a, whitehurst k, rajmohan s, gundogan b, koshy k. why apply for an intercalated research degree? int j surg oncol (ny) 2017; 2:e27. https://doi.org/10.1097/ij9.0000 000000000027. 6. jones m, hutt p, eastwood s, singh s. impact of an intercalated bsc on medical student performance and careers: a beme systematic review: beme guide no. 28. med teach 2013; 35:e1493–510. https://doi.org/10.3109/0142159x.2013.806983. 7. tait n, marshall t. is an intercalated bsc degree associated with higher marks in examinations during the clinical years? med educ 1995; 29:216–19. https://doi.org/10.1111/j.1365-29 23.1995.tb02833.x. https://doi.org/10.1111/j.1743-498x.2005.00059.x https://doi.org/10.1111/j.1743-498x.2005.00059.x https://doi.org/10.1186/1472-6920-11-76 https://doi.org/10.1186/1472-6920-10-25 https://doi.org/10.1186/1472-6920-10-25 https://doi.org/10.1097/ij9.0000000000000027 https://doi.org/10.1097/ij9.0000000000000027 https://doi.org/10.3109/0142159x.2013.806983 https://doi.org/10.1111/j.1365-2923.1995.tb02833.x https://doi.org/10.1111/j.1365-2923.1995.tb02833.x mohamed-rachid boulassel, ikram burney, nadia al-wardy, omar habbal and omar al-rawas clinical and basic research | e193 8. howman m, jones m. does undertaking an intercalated bsc influence first clinical year exam results at a london medical school? bmc med educ 2011; 11:6. https://doi.org/10.1186/14 72-6920-11-6. 9. mcmanus ic, richards p, winder bc. intercalated degrees, lear ning styles, and career preferences: prospective longitudinal study of uk medical students. bmj 1999; 319:542–6. https://doi.org/10.1 136/bmj.319.7209.542. 10. lent rw, brown sd, hackett g. toward a unifying social cognitive theory of career and academic interest, choice, and performance. j vocat behav 1994; 45:79–122. 11. osman met. as females outperform male students. from: w w w.s qu.e du.om/por t als/33/public ation/hor i zon/258. pdf?ver=2014-04-27-094846-593. accessed: sep 2019. 12. evered dc, anderson j, griggs p, wakeford r. the correlates of research success. br med j (clin res ed) 1987; 295:241–6. https://doi.org/10.1136/bmj.295.6592.241. 13. nguyen-van-tam js, logan rf, logan sa, mindell js. what happens to medical students who complete an honours year in public health and epidemiology? med educ 2001; 35:134–6. https://doi.org/10.1046/j.1365-2923.2001.00774.x. 14. goldacre mj, davidson jm, lambert tw. career preferences of graduate and non-graduate entrants to medical schools in the uk. med educ 2007; 41:349–61. https://doi.org/10.1111/ j.1365-2929.2007.02706.x. 15. collins jp, farish s, mccalman js, mccoll gj. a mandatory intercalated degree programme: revitalising and enhancing academic and evidence-based medicine. med teach 2010; 32:e541–6. https://doi.org/10.3109/0142159x.2010.528807. https://doi.org/10.1186/1472-6920-11-6 https://doi.org/10.1186/1472-6920-11-6 https://doi.org/10.1136/bmj.319.7209.542 https://doi.org/10.1136/bmj.319.7209.542 https://doi.org/10.1136/bmj.295.6592.241 https://doi.org/10.1046/j.1365-2923.2001.00774.x https://doi.org/10.1111/j.1365-2929.2007.02706.x https://doi.org/10.1111/j.1365-2929.2007.02706.x https://doi.org/10.3109/0142159x.2010.528807 sustainable clinical academic training pathways a framework for implementation in oman *ibrahim s. al-busaidi1 and rashid a. al-mandhari2 sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e251–259, epub. 5 oct 20 submitted 26 aug 19 revisions req. 12 nov 19 & 2 feb 20; revisions recd. 31 dec 19 & 11 feb 20 accepted 9 mar 20 1department of medicine, christchurch hospital, christchurch school of medicine, university of otago, christchurch, new zealand; 2dunedin hospital, southern district health board, dunedin, new zealand *corresponding author’s e-mail: ibra.3sk@gmail.com continuous medical research is essential for the generation of new knowledge and the development of high-quality and evidencebased clinical practice.1 also known as clinicianscientists, clinical academics are medical doctors who have received further training in basic science or clinical research. by virtue of their combined experience in patient care and research, these professionals play a pivotal role in converting biomedical research into practical applications to clinical care.1,2 however, global reports point towards a gradual decline in the clinical academic workforce, for instance in north america, the uk, europe, new zealand and australia.2–6 in many cases, clinicians are disinclined to pursue training in order to establish careers as clinical academics due to a lack of research training pathways, appropriate mentorship and funding.6,7 the importance of developing sustainable clinical academic training pathways has been recognised since the mid-20th century.1,2 in the usa, the gradual decline in the clinical academic workforce prompted the establishment of programmes combining research training with medical education.8 since then, other countries have similarly introduced different types of programmes in order to bridge this gap in the workforce.9–13 however, while many countries have made efforts to understand and address this trend, issues related to the clinical academic workforce in oman have remained largely unexplored. published articles on the subject are scarce and there is as yet no consolidated source of information available to describe omani clinical academic training pathways and their outcomes. as such, the purpose of this paper was to ignite interest in clinical academic training programmes among governmental agencies, educators and students in oman. this article sheds light on existing pathways around the world which provide research training opportunities alongside clinical training. it also explores the status of these pathways and concludes review مسارات التدريب األكادميي السريري املستدامة إطار عمل للتنفيذ يف عمان اإبراهيم �شالح البو�شعيدي ورا�شد عبد اهلل املنذري abstract: clinical academics—medical doctors with additional training in basic science or clinical research— play a pivotal role in translating biomedical research into practical bedside applications. however, international studies suggest that the proportion of clinical academics relative to the medical workforce is dwindling worldwide. although efforts to reverse this trend are ongoing in many countries, there is little perceptible dialogue concerning these issues in oman. this article explores the current status of clinical academic training pathways worldwide, concluding with a framework for the implementation of a dual-degree medical-research training programme in oman in order to stimulate and develop a sustainable national clinical academic workforce. keywords: training programs; undergraduate medical education; graduate medical education; internship and residency; medical students; research; oman. دوًرا ال�رسيرية البحوث اأو الأ�شا�شية العلوم يف اإ�شايف تدريب على احلا�شلون الأطباء من الإكلينيكيون الأكادمييون يلعب امللخ�ص: مقارنة ال�رسيحة هذه ن�شبة اأن اإىل الدولية الدرا�شات ت�شري ذلك، ومع �رسيرية. عملية تطبيقات اإىل الطبية البحوث حتويل يف حمورًيا ببقية القوى الطبية العاملة يف تناق�ص م�شتمر يف جميع اأنحاء العامل. وعلى الرغم من اجلهود املبذولة لت�شحيح هذا امل�شار يف العديد من البلدان حول العامل، اإل اأن هناك القليل من احلوار امللمو�ص ب�شاأن هذه الق�شايا يف ُعمان. ت�شتطلع هذه املقالة اإىل و�شف الو�شع احلايل مل�شارات التدريب الأكادميي ال�رسيري يف جميع اأنحاء العامل، وتختتم بعر�ص اإطار عمل لتنفيذ برنامج تدريب طبي بحثي مزدوج يف ُعمان من اأجل حتفيز وتطوير قوى وطنية اأكادميية �رسيرية م�شتدامة. الكلمات املفتاحية: الربامج التدريبية؛ التعليم الطبي يف املرحلة اجلامعية؛ التعليم الطبي؛ املعاودة والإقامة يف الطب؛ طالب الطب؛ بحث؛ عمان. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.003 https://creativecommons.org/licenses/by-nd/4.0/ sustainable clinical academic training pathways a framework for implementation in oman e252 | squ medical journal, august 2020, volume 20, issue 3 with a suggested framework for the development of a sustainable clinical academic workforce in oman. global clinical academic training programmes an examination of the structure and outcomes of the main training pathways offered across the globe is an important initial step to developing a successful research training programme in oman, as it can help to identify potential barriers or obstacles prior to implementation. examples of various training path ways available globally are presented in table 1.9,14–19 d u a l m e d i c a l-d o c t o r o f p h i l o s o p h y p r o g r a m m e s a dual medical-doctor of philosophy (phd) prog ramme is a structured pathway which offers students the opportunity to combine their medical training (i.e. a doctor of medicine [md] degree) with a research-based degree (i.e. a phd).9–12,20 in 1956, the case western reserve university school of medicine in the usa introduced the first combined md-phd programme, with the md considered a postgraduate degree in the usa.21 since then, the number of dual md-phd programmes has continued to increase; according to a recent estimate, they are offered in 85% of medical schools across the usa.20 this pathway has also rapidly grown in popularity elsewhere around the globe, with programmes established in both developed and developing countries including canada, the uk, europe, australia, new zealand and south africa.9–13 although they share the common objective of producing independent researchers, dual-degree progr ammes often vary in terms of curriculum design, admission model (i.e. undergraduate versus postgrad uate entry), selection criteria, funding sources (i.e. government versus private bodies/universities) and graduation requirements. they are typically offered to a highly selective group of motivated and academically exceptional students and span 6–10 years, with the phd portion of the programme sandwiched between the preclinical and clinical years.9–12,20 overall, a dual medical-phd programme is the most well-established and successful pathway for prod ucing a sustainable and productive clinical academic workforce.10,20 previous studies indicate that most dualdegree medical-phd graduates continue to pursue further training in research, secure academic posts and obtain research grants following graduation.10,20,22 in addition, according to a report by the national institutes of health in the usa, these graduates were more successful in obtaining competitive research grants compared to those holding single degrees or either degree alone.14 despite their success, combined medical-phd programmes have faced various setbacks. in a study of 24 dual md-phd programmes, brass et al. observed that the level of interest in intercalated research degrees among medical students was decreasing with time, with an average attrition rate of 10%; moreover, between 1965–2007, more research-oriented residency choices like internal medicine, neurology, pathology and paediatrics declined in popularity.22 suggested barriers to entering and/or completing a dual-degree md-phd programme include the lengthy training period, poor mentorship and a lack of funding.20,22,23 c l i n i c i a n i n v e s t i g at o r p r o g r a m m e s in canada, the first clinical investigator programme (cip) was developed in 1995.17,24 unlike the mdphd pathway, cips are aimed at the postgraduate/ resident level and comprise a minimum of two years of condensed and structured research training courses.24 although initially both non-degree and graduate degree options were provided, only graduate degree options have been offered since 2008, leading to a master’s degree at minimum, with a phd degree also available.24 table 1: examples of global clinical academic research training programmes9,14–19 type of pathway example duration intercalated/concurrent medicalresearch degrees • md-phd programmes backed by the national institute of health in the usa14 • the clinician-scientist track in australia15 • the md-mph programme at the university of north carolina at chapel hill in the usa16 • the mb chb-bmedsc(hons) programme at the university of auckland and university of otago in new zealand9 1–3 years postgraduate/residency-level tracks • the clinician investigator programme in canada17 2–3 years phd-to-medical degree programmes • the phd-to-md programme at the university of miami in the usa18 2–3 years formal extracurricular opportunities •the summer studentship programme at the university of otago in new zealand19 10 weeks md = doctor of medicine; phd = doctor of philosophy; mph = master of public health; bmedsc(hons) = bachelor of medical sciences with honours. ibrahim s. al-busaidi and rashid a. al-mandhari review | e253 residents may select from three different cip pathways to integrate their postgraduate medical training. the continuous pathway provides uninterr upted intensive research training during a minimum of 24 months.24 in the distributive pathway—offered only to outstanding residents with prior research experience—postgraduate first-year residents gain entry to both residency training and the cip. finally, the fractionated pathway involves at least 24 months of research, of which 12 months can be undertaken in three-month blocks during clinical training with the addition of one year of continuous research training.24 in general, cips have been successful in attracting canadian residents seeking academic or researchfocused careers.17,24,25 residents enrolled in these programmes have benefited from multiple funding sources including universities, hospitals, the canadian ministry of health, granting agencies and private funding foundations resulting in consistently low dropout rates.17,24 statistics show that cip residents publish an average of six peer-reviewed publications during their residency training, with approximately two-thirds (67%) attaining academic positions following graduation.17,24 nevertheless, cips are subject to similar challenges as those faced by md-phd programmes in the usa.22,24,25 moreover, governmental funding for canadian clinical academic training programmes was recently cut due to budgetary constraints.26 this move has been met by much astonishment and protest within the medical education community, both in canada and worldwide.10,26,27 t h e c l i n i c i a n-s c i e n t i s t t r a c k the clinician-scientist track (cst) in australia was developed by the university of queensland in 2010 to address the decline in medical students pursuing intercalated medical/research degrees.15 unlike strict intercalated programmes, the cst provides the opportunity for outstanding students to enrol in a parttime master’s or phd degree that is either concurrent or intercalated with their medical degree. funding is provided by the australian government, along with a scholarship from the university of queensland’s graduate school.15 the cst programme offers three separate training pathways, all of which culminate in a dual degree.15 the concurrent md-master’s pathway gives students the option of completing a research-focused master’s degree on a part-time basis while continuing their md training without disruption. in the intercalated md-master’s pathway, students undertake one year of full-time research after the second year of their md course, with the master’s degree subsequently being completed on a part-time basis. finally, with the intercalated md-phd pathway, students interrupt their four-year md training after the second year for two full-time years of phd research, before finalising their phd research projects during the remainder of their md programme.15 overall, the cst training pathway has been received with great enthusiasm by the students enrolled at the university of queensland.15 as of 2018, a total of 96 students had been enrolled in the pathway in the eight years since its inception, of which 36 had completed a dual md-phd degree, with 28% transferring from the master’s to the phd track; moreover, the overall attrition rate was 14%, similar to those reported in other pathways.15,20,22 furthermore, cst students reportedly published 159 journal papers and 112 conference abstracts between 2010 and 2016, with an average of 2.24 papers and 1.58 conference abstracts per student.15 d o c t o r o f p h i l o s o p h y-t od o c t o r o f m e d i c i n e p r o g r a m m e s in the usa and canada, phd-to-md programmes offer phd holders the opportunity to take an accelerated twoor three-year md degree.28 despite initial concern, no significant discrepancies have been observed in the clinical performance of graduates of expedited three-year degrees compared to those of the usual four-year medical training programmes.28 in fact, an evaluation of the two-year phd-to-md programme at the university of miami in the usa found that the truncated training course was successful in producing accomplished clinical academics.18 d o c t o r o f m e d i c i n e-m a s t e r o f p u b l i c h e a lt h p r o g r a m m e s in the usa, the first formal md-master of public health (mph) programme was developed at the university of north carolina at chapel hill to address the lack of mph degrees among medical graduates.16 in the early 1990s, md-mph programmes were offered in 25% of american medical schools; this subsequently increased to 60% by 2013.29 various programmes were developed, most of which combine clinical training with research in public health-related topics over a five-year period.16 since then, the dual-degree md-mph progr amme has gained traction in other developed and devel oping countries.30,31 according to a national cohort study conducted in the usa, graduates of md-mph programmes were reportedly not at a disadvantage in terms of student debt and were more likely to pursue primary care specialties (e.g. family medicine) and obtain appointments at academic centres.29 sustainable clinical academic training pathways a framework for implementation in oman e254 | squ medical journal, august 2020, volume 20, issue 3 b a c h e l o r o f m e d i c a l s c i e n c e w i t h h o n o u r s a bachelor of medical science with honours (bmedsc [hons]) is an intercalated research degree in new zealand in which students interrupt their regular medical training (i.e. a bachelor of medicine and bachelor of surgery [mbchb] degree) to undertake a one-year full-time supervised research project.9 academically outstanding students also have the opportunity to subsequently transfer to a phd degree. this typically involves one additional year of full-time research incorporated between the preclinical and clinical years (i.e. two years of full-time research).9 according to recent studies, approximately one-third (33%) of theses written by bmedsc(hons) graduates were found to result in peer-reviewed journal publications.32,33 however, while students generally report a high degree of satisfaction with this type of programme, a number of barriers exist including poor supervision, increased debt and delayed graduation.34 s u m m e r r e s e a r c h s t u d e n t s h i p s studentships are a popular form of short-term supervised research experiences available to medical students in several countries.9,19,35 typically, students spend between 8–16 weeks of their summer vacation working on a research project.9,19,35 short-term research projects provide students with a chance to meaningfully contribute to the mainstream medical literature, with research showing that approximately one-third of studentships result in subsequent peerreviewed publications.19,36 o t h e r pat h way s other than the aforementioned medical dual-degree research programmes, a number of alternative training pathways are also available, such as md-juris doctor, md-master of business administration, mdmaster of mass communication and md-master of advanced study in health informatics programmes, among others.37,38 framework for implementation in oman c u r r e n t s i t u at i o n from the beginning of the reign of the former ruler sultan qaboos bin said in 1970, oman has invested greatly in health services and medical research, as evidenced by successful efforts over the last two decades to control the burden of communicable and preventable diseases.39 in addition, the number of medical schools, academic centres and funding bodies has increased dramatically.39–41 in 1991, the ministry of health established the centre of studies and research (csr), previously known as the directorate of research and studies, in order to support research development in oman.39,41 the csr is responsible for advising researchers, reviewing and approving research proposals, setting health research priorities and holding research training workshops.39 other initiatives include the creation of research funding bodies (e.g. the research council) as well as postgraduate or higher academic qualification programmes in biomedical fields.39,40 in 2006, the oman medical speciality board (omsb), a national body accredited by the accreditation council for graduate medical education-international, was established to oversee graduate medical education in the country.42 all omsb residency programmes include a structured research module and residents are expected to complete a research project from design to dissemination.43 these factors indicate that oman has an infrastructure suitable for the development of future generations of researchers. unfortunately, recent reports indicate that oman is not living up to its potential in terms of the quality and quantity of its medical research.44,45 al-maawali et al. reported promising trends in biomedical research in the gulf cooperative council (gcc) region between 1970 and 2010; however, oman was found to have the lowest research output after the results were normalised for population size.45 moreover, oman has the second lowest hirsch index (an indicator of research productivity and impact) in medicine among all gcc countries and ranks 11th among middle eastern countries and 81st globally in terms of medical research output.46 according to a recent study, only 15% of primary healthcare professionals in oman reported participating in clinical research, with poor mentorship, time constraints, funding and a lack of training and statistical support being the main barriers.47 similarly, less than one-quarter (8–22.1%) of research performed by omsb residents has been found to result in peer-reviewed publications.43,48 the health vision 2050 initiative of the ministry of health aspires for oman to be “a regional leader and a research hub of international standards”, with collaboration between local and international academic institutions recognised as a key factor in strengthening the country’s research capacity.39 however, although this mission acknowledges that establishing a career path for research-oriented professionals is an important factor in improving research quality and quantity, to the best of the authors’ knowledge, no well-defined research training pathways have as yet been established in oman. ibrahim s. al-busaidi and rashid a. al-mandhari review | e255 current medical programmes currently, there are two medical schools in oman, namely the college of medicine and health sciences at sultan qaboos university (comhs-squ) and the college of medicine and health sciences at the national university of science & technology (comhs-nu), formerly known as the oman medical college.49–52 however, neither medical school currently offers an intercalated medicine-research degree (e.g. a dual md-master’s or md-phd degree).50,52 squ was established in 1986, with the comhs forming one of its five constituent colleges; however, it was not until 2013 that the md programme was fully accredited.49 the current md programme at comhssqu is a six-year undergraduate degree divided into three phases.50,51 phase i involves two semesters of various basic sciences and university-mandated cour ses (i.e. courses’ requirements set by the university, regardless of choice of degree) over a one-year period. subsequently, phase ii incorporates clinical sciences, medical informatics, research teaching and experience and early medical contact over two years, while phase iii consists of clinical clerkships and pre-internship experience which take place over three years.50,51 the primary objective of comhs-squ is to provide students with a supportive environment that encourages research participation.50 this is evident with in the structure of the newly accredited md progr amme; in phase ii, students take part in a module entitled “research project module” which spans three semesters and is dedicated to teaching research methods, design, ethics, critical appraisal, biostatistics and diss emination. moreover, as part of this module, students are required to conduct a complete research study (either clinical or laboratory-based), from initial data collection and analysis to the dissemination of their findings via written reports and oral presentations.50 historically, comhs-squ required all md candidates to undertake a four-year bachelor of science in health sciences (bsc[hs]) degree as a prerequisite to a three-year md degree, resulting in a seven-year undertaking.50 however, the current sixyear curriculum gives students the option of obtaining a bsc(hs) degree by taking part in an additional year (an intercalated phase) between phases ii and iii.50,51 currently, the postgraduate research degrees offered to both md and non-md graduates at comhs-squ include a master of biomedical sciences (offered since 2001 with six scholarships available annually) and a phd (offered since 2009 with two scholarships available annually).50 in contrast, comhs-nu offers a six-year under graduate md programme that consists of one year of pre-medical courses, three years of pre-clinical courses and two years of clinical courses.52 in the third year of the pre-clinical phase, students are required to complete two research-related courses entitled “research metho dology and project” and “epidemiology, public health and biostatistics”. however, comhs-nu does not offer any postgraduate degrees at present.52 e x p e r i e n c e o f o m a n i s t u d e n t s w i t h c l i n i c a l a c a d e m i c t r a i n i n g pat h way s a b r o a d it is instructive to reflect on the experience of omani medical graduates who have explored clinical academic training pathways abroad. since 2004, the ministry of higher education has provided scholarships for omani students to pursue undergraduate medical training (i.e. a mbchb programme) at the university of otago and university of auckland in new zealand (verbal communication, dr hussain al-lawati). in new zealand, medical degree programmes are similar to those in oman, in that they last six years and consist of both pre-clinical and clinical phases. however, the mbchb degree at the university of otago is structured somewhat differently.53 to begin with, students at the university of otago take part in a one-year phase entitled “health sciences first year”, a competitive one-year course that determines admission to second year courses.53 subsequently, they undergo a two-year phase known as “early learning in medicine” involving a variety of pre-clinical courses including research education. the final three-year phase is titled “advanced learning in medicine” and involves two years of clinical courses followed by one year as a trainee intern.53 the trainee internship is an apprenticeship-type course that comprises four 12week stages, of which three are research, hospital and community-based attachments and the remaining stage is a medical elective attachment.53 in addition, unlike the md programmes offered in oman, the mbchb programme at the university of otago considers applications from candidates in the following three categories: health sciences first year completionists (i.e. those who have successfully completed the competitive one-year phase), domestic graduates (i.e. those who have received a bachelor’s degree from another university in new zealand) and others (i.e. domestic students who have completed a master’s or doctoral degree in new zealand or those with health-related professional experience in a relevant field).53 in new zealand, intercalated mbchb-research programmes offer students the opportunity to combine their medical training with a full-time research-based degree.9,32–34 currently, two intercalated research degrees are offered: a bmedsc(hons) degree, a one-year full sustainable clinical academic training pathways a framework for implementation in oman e256 | squ medical journal, august 2020, volume 20, issue 3 time supervised thesis-based degree completed after the third year of the mbchb course or a phd degree, an eight-year degree offered to academically out standing students.9 the former intercalated degree (i.e. mb chb-bmedsc(hons) is a seven-year course, while the latter requires a minimum of two years of dedicated research training in addition to the sixyear mbchb course. phd-related work can also be completed during the summer holidays and a threemonth elective period as part of the final year (i.e. during the trainee internship) of the mbchb course. for both bmedsc(hons) and phd degrees, candidates are required to submit a thesis.9 as of december 2018, 31 omani medical students have graduated with mbchb degrees from medical schools in new zealand (verbal communication, ms. val farmer). of these, eight (25.8%) were enrolled in intercalated research degrees, of which seven took part in bmedsc(hons) programmes and one a phd degree [table 2]. while it is still too early to determine the long-term academic success of these graduates (i.e. whether they will go on to complete higher academic degrees or obtain university faculty positions), most of the dual-degree graduates have continued to be involved in research following graduation. a literature search of the pubmed® database (national library of medicine, bethesda, maryland, usa) in august 2019 indicated that five of the graduates (62.5%) had authored at least one peer-reviewed publication after graduation, with 75 publications in total (range: 1–33 publications each; median time since graduation: 3.7 years). i m p l e m e n t i n g a d u a l m e d i c a lr e s e a r c h p r o g r a m m e in light of the relatively high uptake of dual medicalresearch degrees by omani students in new zealand and their continued involvement in research after graduation, it seems likely that a similar research training programme might be of interest to medical students in oman. however, given that formal pathways to integrate research and medical training are lacking, omani medical students interested in a clinical academic career are currently obligated to pursue stand-alone postgraduate degrees after graduating from medical school. unfortunately, this involves putting specialty training on hold and spending upwards of 2–6 years away from clinical practice, an approach that is unappealing to most medical students.9,33 as evidenced earlier, a dual-degree md-phd programme is the most popular, coordinated and well-established type of research training pathway.10,20 although other degree programmes exist in oman, there is an absence of programmes combining clinical training and research. with this in mind, the following framework is proposed for the development of an intercalated dual-degree md-research programme at omani medical schools. the programme should be offered to academically outstanding students interested in combining clinical practice and research. the intercalated research degree would include either a master’s (involving one year of full-time research) and/or a phd (comprising three years of full-time research). as a result, the suggested pathway would take between 7–9 years to complete [figure 1]. table 2: details of omani students who have completed a research intercalated degree during medical undergraduate training in new zealand (n = 31) gender n (%) total university of otago university of auckland mbchb (n = 15) bmedsc(hons)/phd (n = 6/1) mbchb (n = 16) bmedsc(hons) (n = 1) male 9 (60) 5 (71.4) 5 (31.3) 1 (100) 14 (45.2) female 6 (40) 2 (28.6) 11 (68.8) 0 (0) 17 (54.8) mbchb = bachelor of medicine and bachelor of surgery; bmedsc(hons) = bachelor of medical sciences with honours; phd = doctor of philosophy. figure 1: proposed framework for the integration of research training into medical education in oman. p = phase; inter = internship; phd = doctor of philosophy. ibrahim s. al-busaidi and rashid a. al-mandhari review | e257 it is hoped that this framework will help to develop and maintain the clinical academic workforce in oman by attracting medical students committed to a career in both medicine and research. possible barriers to implementing this programme are likely to be similar to those reported in other training pathways, such as dwindling interest in research among medical students, a high attrition rate, lack of availability of research infrastructure, lack of time among mentors/supervisors and inadequate funding.10,17,20,23,33 therefore, sufficient intellectual, financial and administrative support is crucial for the success of this programme. several initiatives are required prior to the implementation of this framework. to begin with, studies should be undertaken to evaluate omani medical students’ interest in, attitudes towards and perceived barriers to a combined medical-research training programme. secondly, it remains to be determined whether the omsb has the capacity and resources necessary to provide research supervision and mentorship for dual-degree candidates. thirdly, the perspective of policymakers at both comhssqu and comhs-nu should be elicited, particularly as comhs-squ already offers medical students the option of intercalating a bsc(hs) degree with the sixyear md programme.47,48 nevertheless, it would be beneficial if an additional one-year supervised thesisbased research degree were to be offered to qualified medical students. finally, it is imperative that sufficient funding be secured to support the implementation of a clinical academic training programme in oman. conclusion parallel with the current md programmes available, the establishment of an optional intercalated research degree programme in oman would be invaluable to enhance the development of a sustainable and productive national clinical academic workforce. hopefully, the framework described in this article will be of use in facilitating this initiative and sparking discussion on this important topic. the authors sincerely welcome any input from interested parties both in oman and across the globe, from deans of medical schools to residency programme directors, university faculty members, clinical teachers, physicians, fellows, residents, trainees and medical students. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this research. references 1. arias i. training basic scientists to bridge the gap between basic science and its application to human disease. n engl j med 1989; 321:972–4. https://doi.org/10.1056/nejm198910053211412. 2. ley tj, rosenberg le. the physician-scientist career pipeline in 2005: build it, and they will come. jama 2005; 294:1343–51. https://doi.org/10.1001/jama.294.11.1343. 3. fitzpatrick s. a survey of staffing levels of medical clinical academics in uk medical schools as at 31 july 2012: a report by the medical schools council. from: www.medschools.ac.uk/ media/1248/2012-staffing-levels-of-medical-clinical-academicsin-uk-medical-schools-2012-data.pdf accessed: feb 2020. 4. sheridan dj. reversing the decline of academic medicine in europe. lancet 2006; 367:1698–701. https://doi.org/10.1016/ s0140-6736(06)68739-4. 5. windsor j, garrod t, talley nj, tebbutt c, churchill j, farmer e, et al. the clinical academic workforce in australia and new zealand: report on the second binational summit to implement a sustainable training pathway. intern med j 2017; 47:394–9. https://doi.org/10.1111/imj.13356. 6. lander b, hanley ge, atkinson-grosjean j. clinician-scientists in canada: barriers to career entry and progress. plos one 2010; 5:e13168. https://doi.org/10.1371/journal.pone.0013168. 7. milewicz dm, lorenz rg, dermody ts, brass lf. rescuing the physician-scientist workforce: the time for action is now. j clin invest 2015; 125:3742–7. https://doi.org/10.1172/jci84170. 8. mark al, kelch rp. clinician scientist training program: a pro posal for training medical students in clinical research. j investig med 2001; 49:486–90. https://doi.org/10.2310/6650.2001.33624. 9. al-busaidi is, wells ci. stimulating the clinical academics of tomorrow: a survey of research opportunities for medical students in new zealand. n z med j 2017; 130:80–8. 10. skinnider ma, squair jw, twa dd, ji jx, kuzyk a, wang x, et al. characteristics and outcomes of canadian md/phd program graduates: a cross-sectional survey. cmaj open 2017; 5:e308–14. https://doi.org/10.9778/cmajo.20160152. 11. barnett-vanes a, ho g, cox tm. clinician-scientist mb/phd training in the uk: a nationwide survey of medical school policy. bmj open 2015; 5:e009852. https://doi.org/10.1136/ bmjopen-2015-009852. 12. power bd, white aj, sefton aj. research within a medical degree: the combined mb bs-phd program at the university of sydney. med j aust 2003; 179:614–16. https://doi.org/10.5694/j.1 326-5377.2003.tb05719.x. 13. katz aa, futter m, mayosi bm. the intercalated bsc (med) honours/mb chb and integrated mb chb/phd tracks at the university of cape town: models for a national medical student research training programme. s afr med j 2014; 104:111–13. https://doi.org/10.7196/samj.7639. 14. national institutes of health. physician-scientist workforce (psw) report 2014: effects of early career nih programs on physician-scientists with a medical degree. from: https:// report.nih.gov/workforce/psw/index.aspx accessed: feb 2020. 15. eley ds. the clinician-scientist track: an approach addressing australia’s need for a pathway to train its future clinical academic workforce. bmc med educ 2018; 18:227. https://doi. org/10.1186/s12909-018-1337-5. 16. harris r, kinsinger ls, tolleson-rinehart s, viera aj, dent g. the md-mph program at the university of north carolina at chapel hill. acad med 2008; 83:371–7. https://doi.org/10.1097/ acm.0b013e318166a848. https://doi.org/10.1056/nejm198910053211412 https://doi.org/10.1001/jama.294.11.1343 https://doi.org/10.1016/s0140-6736%2806%2968739-4 https://doi.org/10.1016/s0140-6736%2806%2968739-4 https://doi.org/10.1111/imj.13356 https://doi.org/10.1371/journal.pone.0013168 https://doi.org/10.1172/jci84170 https://doi.org/10.2310/6650.2001.33624 https://doi.org/10.9778/cmajo.20160152 https://doi.org/10.1136/bmjopen-2015-009852 https://doi.org/10.1136/bmjopen-2015-009852 https://doi.org/10.5694/j.1326-5377.2003.tb05719.x https://doi.org/10.5694/j.1326-5377.2003.tb05719.x https://doi.org/10.7196/samj.7639 https://doi.org/10.1186/s12909-018-1337-5 https://doi.org/10.1186/s12909-018-1337-5 https://doi.org/10.1097/acm.0b013e318166a848 https://doi.org/10.1097/acm.0b013e318166a848 sustainable clinical academic training pathways a framework for implementation in oman e258 | squ medical journal, august 2020, volume 20, issue 3 17. hayward cp, danoff d, kennedy m, lee ac, brzezina s, bond u. clinician investigator training in canada: a review. clin invest med 2011; 34:e192. https://doi.org/10.25011/cim. v34i4.15360. 18. koniaris lg, cheung mc, garrison g, awad wm jr, zimmers ta. perspective: phd scientists completing medical school in two years looking at the miami phd-to-md program alumni twenty years later. acad med 2010; 85:687–91. https://doi. org/10.1097/acm.0b013e3181d296da. 19. alamri y, currie w, magner k, al-busaidi is, wilkinson tj, beckert l. publication rates of, and attitudes toward, summer research projects: 10-year experience from a single institution in new zealand. adv med educ pract 2019; 10:263–71. https:// doi.org/10.2147/amep.s198789. 20. jeffe db, andriole da, wathington hd, tai rh. educational outcomes for students enrolled in md-phd programs at medical school matriculation, 1995-2000: a national cohort study. acad med 2014; 89:84–93. https://doi.org/10.1097/ acm.0000000000000071. 21. case western reserve university school of medicine. medical scientist training program: the original md/phd. from: https://case.edu/medicine/admissions-programs/md-phdprogram/ accessed: feb 2020. 22. brass lf, akabas mh, burnley ld, engman dm, wiley ca, andersen os. are md-phd programs meeting their goals? an analysis of career choices made by graduates of 24 md-phd programs. acad med 2010; 85:692–701. https://doi.org/10.1097/ acm.0b013e3181d3ca17. 23. kersbergen cj, bowen cj, dykema ag, koretzky mo, tang o, beach mc. student perceptions of m.d.-ph.d. programs: a qualitative identification of barriers facing prospective m.d.ph.d. applicants. teach learn med 2020; 32:1-10. 24. canadian federation of medical students. supporting clinicianscientist training in canada. from: www.cfms.org/files/ position-papers/2016_supporting%20clinician-scientist%20 training%20in%20canada.pdf accessed: feb 2020. 25. ballios bg, rosenblum nd. challenges facing physician scientist trainees: a survey of trainees in canada’s largest undergraduate and postgraduate programs in a single centre. clin invest med 2014; 37:e268–83. https://doi.org/10.25011/ cim.v37i5.22008. 26. twa dd, squair jw, skinnider ma, ji jx. the canadian clinician-scientist training program must be reinstated. j clin invest 2015; 125:4317–19. https://doi.org/10.1172/jci85194. 27. zhou te, savage pa, eisenberg mj. canadian md-ph.d. programs produce impactful physician-scientists: the mcgill experience. j biomed educ 2016; 2016:3836467. https://doi. org/10.1155/2016/3836467. 28. raymond jr sr, kerschner je, hueston wj, maurana ca. the merits and challenges of three-year medical school curricula: time for an evidence-based discussion. acad med 2015; 90:1318–23. https://doi.org/10.1097/acm.0000000000000862. 29. andriole da, jeffe db, tai rh. characteristics and career intentions of md-mph program graduates: a national cohort study. public health rep 2016; 131:637–49. https://doi. org/10.1177/0033354916662224. 30. rowson m, smith a, hughes r, johnson o, maini a, martin s, et al. the evolution of global health teaching in undergraduate medical curricula. global health 2012; 8:35. https://doi. org/10.1186/1744-8603-8-35. 31. manavi s, nedjat s, pasalar p, majdzadeh r. what motivates talented medical students to study simultaneously at master of public health (mph)? iran j public health 2013; 42:402–9. 32. al-busaidi is, alamri y. publication rates and characteristics of undergraduate medical theses in new zealand. nz med j 2016; 129:46–51. 33. al-busaidi is, alamri y, wilkinson tj. successful publication by medical students in new zealand: the role of clinical versus academic supervisors. n z med j 2017; 130:9–12. 34. park sj, liang mm, sherwin tt, mcghee cn. completing an intercalated research degree during medical undergraduate training: barriers, benefits and postgraduate career profiles. n z med j 2010; 123:24–33. 35. patel s, walsh cm, udell ja. exploring medically-related canadian summer student research programs: a national cross-sectional survey study. bmc med educ 2019; 19:140. https://doi.org/10.1186/s12909-019-1577-z. 36. wells ci, wallace hb, mclaughlin sj, alexander hc, shelling an. rate and predictors of publication by medical and health science summer research students: a 14-year analysis from auckland, new zealand. mededpublish 2016; 5:43. https://doi. org/10.15694/mep.2016.000129. 37. mayo clinic and arizona state university. dual degrees. from: https://mayo.asu.edu/dualdegrees accessed: feb 2020. 38. stanford medicine. dual-degree programs. from: http://med. stanford.edu/education/dual-degree-programs.html accessed: feb 2020. 39. al mawali ah, al qasmi am, al sabahi sm, idikula j, abd elaty ma, morsi m, et al. oman vision 2050 for health research: a strat egic plan for the future based on the past and present exper ience. oman med j 2017; 32:86–96. https://doi.org/10.5001/ omj.2017.18. 40. al-shukaili a, al-maniri a. writing a research proposal to the research council of oman. oman med j 2017; 32:180–8. https://doi.org/10.5001/omj.2017.35. 41. united nations educational, scientific and cultural organisation cairo office. ethics and law in biomedicine and genetics: an overview of national regulations in the arab states. cairo, egypt: united nations education, 2011. p. 38. 42. oman medical specialty board. resident manual. from: www.omsb.org/file_publications/files_2016081409265 0801_491c9cb8-60ce-404f-97bc-bf1312b458be.pdf accessed: feb 2020. 43. al-busaidi is, al-shaqsi sz, al alawi ak, al-sinani s, al-kashmiri a. characteristics, trends, and factors associated with publication among residents of oman medical specialty board programs. j grad med educ 2019; 11:104–9. https://doi. org/10.4300/jgme-d-19-00259. 44. rohra dk, azam si. quantitative and qualitative analysis of pubmed-indexed biomedical publications in oman from years 2005-2009. oman med j 2011; 26:160–5. https://doi. org/10.5001/omj.2011.39. 45. al-maawali a, al busadi a, al-adawi s. biomedical publica tions profile and trends in gulf cooperation council countries. sultan qaboos univ med j 2012; 12:41–7. https://doi.org/10.12 816/0003086. 46. scimago journal & country rank. country rankings: middle east. from: www.scimagojr.com/countryrank.php?area=2700& region=middle%20east&order=h&ord=desc accessed: feb 2020. 47. jahan f, al maqbali a, siddiqui ma, al zadjali nm. attitude and barrier towards research amongst health care professionals working in primary care service of oman. j health educ res dev 2015; 3:1000144. https://doi.org/10.4172/2380-5439.1000144. 48. al-busaidi is, dupo ju. rate and predictors of publication of resident abstracts presented at oman medical specialty board scientific meetings. sultan qaboos univ med j 2018; 18:e501–6. https://doi.org/10.18295/squmj.2018.18.04.012. 49. albarwani s, al-saadoon m, al-rawas o, al-yaarubi s, al-abri r, al-lamki l, et al. accrediting the md programme in sultan qaboos university: process, earned benefits, and lessons learned. health prof educ 2015; 1:50–7. https://doi. org//10.1016/j.hpe.2015.11.011. https://doi.org/10.25011/cim.v34i4.15360 https://doi.org/10.25011/cim.v34i4.15360 https://doi.org/10.1097/acm.0b013e3181d296da https://doi.org/10.1097/acm.0b013e3181d296da https://doi.org/10.2147/amep.s198789 https://doi.org/10.2147/amep.s198789 https://doi.org/10.1097/acm.0000000000000071 https://doi.org/10.1097/acm.0000000000000071 https://doi.org/10.1097/acm.0b013e3181d3ca17 https://doi.org/10.1097/acm.0b013e3181d3ca17 https://doi.org/10.25011/cim.v37i5.22008 https://doi.org/10.25011/cim.v37i5.22008 https://doi.org/10.1172/jci85194 https://doi.org/10.1155/2016/3836467 https://doi.org/10.1155/2016/3836467 https://doi.org/10.1097/acm.0000000000000862 https://doi.org/10.1177/0033354916662224 https://doi.org/10.1177/0033354916662224 https://doi.org/10.1186/1744-8603-8-35 https://doi.org/10.1186/1744-8603-8-35 https://doi.org/10.1186/s12909-019-1577-z https://doi.org/10.15694/mep.2016.000129 https://doi.org/10.15694/mep.2016.000129 https://doi.org/10.5001/omj.2017.18 https://doi.org/10.5001/omj.2017.18 https://doi.org/10.5001/omj.2017.35 https://doi.org/10.4300/jgme-d-19-00259 https://doi.org/10.4300/jgme-d-19-00259 https://doi.org/10.5001/omj.2011.39 https://doi.org/10.5001/omj.2011.39 https://doi.org/10.12816/0003086 https://doi.org/10.12816/0003086 https://doi.org/10.4172/2380-5439.1000144 https://doi.org/10.18295/squmj.2018.18.04.012 https://doi.org//10.1016/j.hpe.2015.11.011 https://doi.org//10.1016/j.hpe.2015.11.011 ibrahim s. al-busaidi and rashid a. al-mandhari review | e259 50. sultan qaboos university college of medicine and health sciences. md programme self study. from: http://web.squ.edu. om/med/accreditation/selfstudy2012_2013.pdf accessed: feb 2020. 51. burney ia. the curriculum at the college of medicine and health sciences, sultan qaboos university. from: www.squ. edu.om/portals/6/orientation%20_ikram.pptx accessed: feb 2020. 52. national university of science and technology college of medicine and health sciences. about college of medicine. from: www.nu.edu.om/cm/deptcontent.aspx?id=304 accessed: feb 2020. 53. university of otago. the otago medical degree: bachelor of medicine and bachelor of surgery (mb chb) programme information. from: www.otago.ac.nz/medicine/about/program me-structure/index.html accessed: feb 2020. december 2007 vol 8 after meeting.indd abstract iodine deficiency disorders (idd) are one of the biggest worldwide public health problem of today. their effect is hidden and profoundly affects the quality of human life. iodine deficiency occurs when the soil is poor in iodine, causing a low concentration in food products and insufficient iodine intake in the population. when iodine requirements are not met, the thyroid may no longer be able to synthesize sufficient amounts of thyroid hormone. the resulting low-level of thyroid hormones in the blood is the principal factor responsible for the series of functional and developmental abnormalities, collectively referred to as idd. iodine deficiency is a significant cause of mental developmental problems in children, including implications on reproductive functions and lowering of iq levels in school-aged children. the consequence of iodine deficiency during pregnancy is impaired synthesis of thyroid hormones by the mother and the foetus. an insufficient supply of thyroid hormones to the developing brain may result in mental retardation. brain damage and irreversible mental retardation are the most important disorders induced by iodine deficiency. daily consumption of salt fortified with iodine is a proven effective strategy for prevention of idd. keywords: iodine; cretinism; mental retardation. health consequences of iodine deficiency umesh kapil department of public health, oman medical college, sohar campus, sohar, sultanate of oman email: umeshkapil@yahoo.com اليود لنقص الصحية العواقب كابل اوميش يؤثر لكنه ، مخفيا يكون تأثيرها أن ولو الوقت احلالي. العالم في ــية في الرئيس العامة الصحة ــاكل مش من نقص اليود اضطرابات امللخص: تعتبر وهذا ، الزراعية في املنتجات اليود بنقص يتسبب والذي العنصر بذلك فقر التربة نتيجة اليود يحصل نقص كبير. ــكل بش ــان اإلنس حياة نوعية على الكافية الكمية إنتاج الغدة الدرقية ــتطيع تس ال ، من املطلوب أقل اليود كمية تكون وعندما . الناس يتناولها التي اليود كمية قلة إلى يؤدي بدوره نقص ويعتبر . اليود نقص تعرف باضطرابات والتطورية الوظيفية االضطرابات من سلسلة حصول عن ــؤوال مس يكون ــني والذي الثايروكس هرمون من انخفاض أن كما في ذكاء الطفل. تدنيا ــبب ويس ــلية التناس الوظائف على يؤثر وكذلك ، األطفال الذهني عند التطور ــاكل ــيا ملش رئيس ــببا اليود س تلف إن . العقلي التخلف إلى يؤدي اجلنني دماغ في الهرمون وقلة وجود ، واجلنني عند أالم الدرقية الغدة هرمون إنتاج في خلال أثناء احلمل يسبب اليود على اليود يعتبر يحتوي الذي امللح ــاول تن أن ثبت . نقص اليود عن الناجتة االضطرابات أهم من يعتبران للعالج ــل القاب غير العقلي ــف والتخل ــاغ الدم . اليود نقص اضطرابات حصول ملنع وسيلة فعالة عقلي. تخلف ، قدامة ، : اليود الكلمات مفتاح sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 267-272 sultan qaboos university© submitted 16th july 2007 accepted 12th september 2007 iodine is a trace element essential for the synthesis of thyroid hormones, triodothyronine (t3) and thyroxine (t4). these hormones regulate the metabolic pattern of most cells and play a vital role in the process of early growth and development of most organs, especially the brain. in humans, the early development of the brain occurs during foetal and early postnatal life.1 inadequate intake of iodine leads to insufficient production of these hormones, which adversely affect the muscle, heart, liver, kidney and the developing brain. this results in the disease states collectively known as iodine deficiency disorders (idd). m a g n i t u d e o f i d d iodine deficiency disorders are known to be a significant public health problem in 118 countries. at least 1,572 million people worldwide are estimated to be at risk of idd i.e. those who live in areas where iodine deficiency is prevalent (total goiter rates above 5%), and at least 655 million of these are considered to be affected by goiter.1, 2 most of these are in developing countries in africa, asia, and latin america, but large parts of europe are also vulnerable.4 c o n t i n u i n g m e d i c a l e d u c a t i o n u m e s h k a p i l 268 p h y s i o l o g i c a l f u n c t i o n s o f i o d i n e iodine is an essential dietary element which is required for the synthesis of the thyroid hormones, thyroxine (t4) and triiodothyronine (t3). the t4 and t3, which are iodinated molecules of the essential amino acid tyrosine, regulate cellular oxidation and hence affect calorigenesis, thermoregulation, and intermediary metabolism. these hormones are necessary for protein synthesis. they also promote nitrogen retention, glycogenolysis, intestinal absorption of glucose and galactose, as well as lipolysis, and the uptake of glucose by adipocytes.5 the healthy human body contains 15-20 mg of iodine, of which about 70-80% is present in the thyroid gland. in a day, 60 µg of circulating iodine needs to be trapped by the thyroid for the adequate supply of t3 and t4. to extract this amount of iodine from the circulation, the thyroid daily clears several hundred litres of plasma of its iodine. this work can increase several times over in severely iodine deficient environments. to cope with this increased workload, the thyroid enlarges in size, under the influence of the thyroid stimulating hormone (tsh), secreted from the pituitary gland. this compensatory mechanism, triggered by the hypothalamus to increase tsh secretion from the pituitary, causes remarkable enlargement of the thyroid gland (goiter).6 an inadequate dietary intake of iodine leads to insufficient production of thyroid hormones, which affects many parts of the body, particularly muscle, heart, liver, kidney and the developing brain. inadequate hormone production adversely affects these tissues, resulting in the disease states known collectively as iodine deficiency disorders, or idd. dietary iodine deficiency stimulates tsh secretion, which results in thyroid hypertrophy. the enlargement of the thyroid gland due to dietary iodine deficiency is called endemic goiter. iodine intakes consistently lower than 50 µg /day usually result in goiter. severe and prolonged iodine deficiency, may lead to a deficient supply of thyroid hormones. this condition is referred to as hypothyroidism.5 e t i o l o g y o f i d d iodine is one of the essential elements required for normal human growth and development. its daily per capita requirement is 150 micrograms [table 1]. soils from mountain ranges, such as the himalayas, alps, and andes and from areas with frequent flooding, are particularly likely to be iodine deficient. the problem is aggravated by accelerated deforestation and soil erosion. the food grown in iodine deficient regions can never provide enough iodine to the population and live-stock living there. unlike nutrients such as iron, calcium or vitamins, iodine does not occur naturally in specific foods; rather, it is present in the soil and is ingested through foods grown on that soil. iodine deficiency results when there is lack of iodine on the earth’s crust. living on the sea coast does not guarantee iodine sufficiency and significant pockets of iodine deficiency have been reported from costal regions in different parts of the world.7 iodine deficiency thus results mainly from geological rather than social and economic conditions. it cannot be eliminated by changing dietary habits or by eating specific kinds of foods grown in the same area. besides nutritional iodine deficiency, a variety of other environmental, socio-cultural and economic factors operate to aggravate iodine deficiency and related thyroid dysfunctions. these include poverty related protein-energy malnutrition, ingestion of goitrogens through unusual diets (particularly by the poor), bacteriologically contaminated drinking water, as well as bulky, high residue diets, which interfere with the intestinal absorption of iodine.8 several environmental and genetic factors interfere with the processes of thyroxin synthesis leading to goiter formation. the genetic factors, which are rare, mainly affect the enzymes involved in thyroxin synthesis. environmental factors are amongst the most common factors that interfere in thyroxin synthesis and lead to goiter formation. the most important environmental factors are (i) environmental iodine deficiency and (ii) goitrogens. the most frequent cause of goiter in india and other countries is environmental iodine deficiency. however, there is emerging evidence in different countries of world that goitrogens may play a secondary role in several endemic foci. goitrogens are chemical substances that occur primarily in plant food. they can occasionally be present in contaminated drinking water. goitrogens interfere in thyroxin synthesis by inhibiting the enzymes involved in the synthesis of thyroxin. there is also evidence to show that intensive cropping, resulting in large scale removal of biomass from the soil, as well as widespread use of alkaline fertilizers, rapidly deplete the soil of its iodine content. since h e a lt h c o n s e q u e n c e s o f i o d i n e d e f i c i e n c y t h e s i t uat i o n i n o m a n 269 both intensive cropping and use of alkaline fertilizers are widely practiced in almost all developing the countries, it is not surprising that nutritional iodine deficiency and endemic goiter are seen wherever they are looked for in these regions.5 the relationship between dietary iodine intake and severity of idd is shown in table 2. m e t a b o l i s m o f i o d i n e i n t h e t h y r o i d iodine enters the body in the form of iodate or iodide in the water we drink or food we eat; the iodate is converted to iodide in the stomach. the thyroid gland traps and concentrates iodide and uses it in the synthesis and storage of thyroid hormones [figure 1]. the minimum daily iodine intake needed to maintain normal thyroid function in adults is about 150µg/dl. iodide is rapidly absorbed from the gastrointestinal tract and distributed to extracellular fluids. but the concentration of iodide in the extracellular fluid is usually low because of the rapid uptake by the thyroid gland and renal clearance. it is estimated that 75% of the iodide taken into the body each day enters the thyroid by active transport. about two-thirds of that is used in hormone synthesis, with the remaining amount released back into the extra cellular fluid. the thyroid gland contains the body’s largest pool of iodide, about 8 to 10 mg. most of this iodide is associated with thyroglobulin, a thyroid hormone precursor and a source of hormone and iodinated tyrosines. the thyroid produces thyroxine (t4) and triiodothyronine (t3). iodine is an essential component of both t3 and t4. these hormones regulate the rate of metabolism and affect physical and mental growth and the rate of function of many other systems in the body. the thyroid is controlled by the hypothalamus and the pituitary gland. the production of thyroxine and triiodothyronine is regulated by the thyroid-stimulating hormone (tsh), released by the anterior pituitary. tsh production is suppressed when the t4 levels are high, and vice versa. the tsh production itself is modulated by the thyrotropin-releasing hormone (trh), which is produced by the hypothalamus. s o u r c e s o f d i e t a r y i o d i n e about 90% of iodine intake is obtained from food consumed and the remainder from water. iodine is available in traces in water, food and common salts. it is very low in the foods grown at high altitudes. iodine found in sea-water is 0.2 mg per litre. sea weeds and spongy shells are rich in iodine. the iodine content of common food items is given in table 3. rich sources are sea fish, green vegetables and leaves like spinach grown on iodine rich soil. common sources are milk, meat, and cereals. common salt fortified with small quantities of sodium or potassium iodate is now compulsorily made available in the market as iodized salt to check goiter. certain vegetables like cabbage, cauliflower and radish contain glucosinolates (thiogluosides) which are potential goitrogens. eating too much of these foods inhibits the availability of iodine to the body from the food and thus leads to the development of goiter. t h e d a i l y r e f e r e n c e i n t a k e s o f i o d i n e h e a lth c o n se q ue n c e s o f i o d i n e d e fi c i e n c y iodine deficiency remains the single greatest cause of preventable brain damage and mental retardation worldwide. eliminating iodine deficiency is recognized as one of the most achievable of the goals that the 1990 world summit for children set for the year 2000. the most important biological role played by thyroxin is in the early foetal stage of life. it ensures the growth, differentiation and maturation of different organs of the body, and particularly the brain. iodine deficiency has been identified as the world’s major cause of preventable mental retardation. its severity can vary from mild intellectual blunting to frank cretinism, a condition that includes gross mental retardation, deafmutism, short stature and various other defects. in areas of severe iodine deficiency, the majority of individuals risk some degree of mental impairment. the damage to the developing brain results in individuals poorly equipped to fight disease, learn, work effectively, or reproduce satisfactorily. the spectrum of disorders caused due to iodine deficiency affects all the stages of life, from foetus to adult age [table 3].9 if pregnant women’s diets do not contain adequate iodine, the foetus cannot produce enough thyroxin and foetal growth is retarded. hypothyroid foetuses often perish in the womb and many infants die within a week of birth. the current data on the embryology of the brain suggest that the critical time for the effect of iodine deficiency is mid the second trimester i.e. 1418 weeks of pregnancy. at this time, neurons of the u m e s h k a p i l 270 cerebral cortex and basal ganglia are formed. it is also the time of formation of the cochlea (10-18 weeks), which is also severely effected in endemic cretinism. a deficit in iodine or thyroid hormones occurring during this critical period of life results in the slowing down of the metabolic activities of all the cells of the foetus and irreversible alterations in the development of brain. the growth and differentiation of the central nervous system are closely related to the presence of iodine and thyroid hormones. hypothyroidism may lead to cellular hypoplasia and reduced dendritic ramification gemmules and interneuronal connections. hypothyroid children are intellectually subnormal and may also suffer physical impairment. they lack the aptitudes of normal children of similar age, and are often incapable of completing school. studies have documented that in areas with an incidence of mild to moderate idd, iqs of school children are, on average, 10 –12 points below those of children living in areas where there is no iodine deficiency.10 e n d e mi c c r e ti n i sm endemic cretinism is the extreme clinical manifestation of severe hypothyroidism during foetal, neonatal and childhood stages of development. it is characterised by severe and irreversible mental retardation, short stature, deaf-mutism, spastic dysplegia and squints. in early eighties, in many seriously endemic tarai districts of north india, an average prevalence of 1-2% of cretinism was seen. the situation has improved significantly with the supply of iodized salt and cretins are no longer born. cretinism seen in severe endemic areas is predominantly of two types (a) neurological cretinism, where the neurological manifestations of thyroxin deficiency early in life, i.e. hypothyroidism, were confined to the in-utero or neonatal stages. (b) myxedematous cretinism, where besides having mental retardation, sufferers also have myxoedema and dwarfism. this variant of cretinism is presumably because of continuing hypothyroidism through all phases of life. c r e ti n o i d s besides the few children who manifest as cretins in an endemic goiter area, a large number of individuals with lesser degrees of mental retardation, speech and hearing defects, psychomotor retardation, as well as gait defects may be seen. such individuals are foetus abortions stillbirths congenital anomalies increased perinatal mortality increased infant mortality neurological cretinism mental deficiency deaf-mutism spastic diplegia squint myxedematous cretinism mental deficiency dwarfism psychomotor defects neonate neonatal goiter neonatal hypothyroidism child and adolescent goiter juvenile hypothyroidism impaired mental function retarded physical development adult goiter with complications hypothyroidism impaired mental function table 2: the spectrum of iodine deficiency disorders7 life stage iodine mcg infants 0-6 months 110 7-12 months 130 children 1-8 years 90 males 9-13 years 120 14-70 years 150 > 70 years 150 females 9-13 years 120 14-18 years 150 19-70 years 150 > 70 years 150 pregnancy < 18 50 years 220 lactation < 18 years 290 19-30 years 290 31-50 years 290 table 1: the daily reference intakes (dri) for iodine h e a lt h c o n s e q u e n c e s o f i o d i n e d e f i c i e n c y t h e s i t uat i o n i n o m a n 271 known as cretinoids. the prevalence of cretinoids in severely endemic regions may be ten-fold greater or more than fully manifested cretins.11 oth e r s y n d r ome s d ue to f o e ta l i o d i n e d e fi c i e n c y there is preliminary scientific evidence suggesting that severe iodine deficiency can lead to foetal wastage such as abortion, still births and congenital abnormalities; however, hard evidence available in this regard is limited.5 n e o n ata l a n d c h i l d h o o d h y p oth y r o i d i sm studies have documented that more than 30% of the goitrous subjects in endemic areas are functionally decompensated and hypothyroid despite the `adaptive’ enlargement of the thyroid. research studies on screening the cord blood of over 20,000 newborns discovered that one out of every 10 newborns from the tarai regions of uttar pradesh were hypothyroid at birth.12 a d ult h y p oth y r o i d i sm a large number of goitrous adults in an endemic region can have varying degrees of hypothyroidism leading to a variety of clinical symptomatologies and complications related to hypo-metabolic states. this symptomatology can seriously hamper human energy and work capacity with resultant erosion of the economic productivity of endemic regions.12 s i t u a t i o n o f i d d i n o m a n a n d t h e g u l f a study conducted in oman which included 3,061 school children in the 9-12 years age group revealed that 10% of the population showed signs of goiter grades 1a, 1b and 2. cases of grade 3 were not seen, and 88.1% of the children did not show goiter.13 a study conducted amongst 2,996 children in bahrain aged 8-11.99 years during 1993-94 , revealed that the total prevalence of goiter was 10 % (9.6 % grade i and 0.4 % grade ii ), the median urinary iodine excretion levels was 91 µg per liter.14 another national study in oman conducted in 2004 amongst non-pregnant women (sample size 338, age group 1549.99 years) revealed that the median urinary iodine excretion levels was 223 µg per liter.15 s i t u a t i o n o f i o d i z a t i o n o f s a l t i n o m a n presently, there is no national programme for the control of iodine deficiency disorders in oman; however, since 1995, there has been legislation/royal decree, for universal salt iodization in the country. the percentage of households consuming iodized salt was 61% as per the moh/unicef survey in 1998.16 c o n c l u s i o n today, iodine deficiency is claimed to be the world’s single most significant preventable cause of brain damage and mental retardation. the detrimental effect of iodine deficiency on the mental and physical development of children as well as on the productivity of adults has been recognized. the neurological sequelae of iodine deficiency are mediated by thyroid hormone deficiency. all the basic processes of neurogenesis: cellular proliferation, differentiation, migration and selective cell death are impaired during the major period of brain growth. in oman, for the prevention of idd, there is a need to undertake regular cyclic surveys, every 3 5 years, to assess the urinary iodine excretion amongst the school age children along with the level of iodization in salt consumed by them. this data can provide the current status of iodine nutriture and status of universal salt iodization in the country. also, there is a need to enforce strictly the decree of universal iodization of salt in the country so that the population can have acnutritional status daily iodine intake (µg) associated with cretinism 20 or less associated with goiter 20 50 marginal 50 100 normal 100 300 more than normal 300 and above table 4: relationship between iodine intake and iddfood iodine (µg) salt, iodized, 1 teaspoonful 400 haddock, 75g 104 145 bread, regular process, 1 slice 35 cheese, cottage, 2% fat, 1/2 cup 26 71 shrimp, 75g 21 37 egg, 1 18 26 cheese, cheddar, 30g 5 23 ground beef, 75g, cooked 8 table 3: iodine content of food u m e s h k a p i l 272 cess only to iodized salt. r e f e r e n c e s 1. bernal j, nunez j. thyroid hormone action and brain development. trends endocrinol metab 2000; 133:390398. 2. http://www.who.int/reproductive-health/docs/iodine_ deficiency.pdf, accessed july 2007. 3. http://www.nihfw.org/ndc-nihfw/html/programmes/ nationaliodinedeficiency.htm, accessed july 2007. 4. assessment of iodine deficiency disorders and monitoring their elimination in: a guide for programme managers, 2nd ed. who press geneva, 2001. iccidd/ uncf/who. p. 7-9. 5. hetzel bs. sos for a billion the nature and magnitude of iodine deficiency disorders. in: hetzel bs and pandav cv, eds. sos for a billion the conquest of iodine deficiency disorders. 2nd ed. new delhi: oxford university press, 1997. p. 1-29. 6. stanbury jb. the iodine deficiency disorders: introduction and general aspects. in: hetzel bs, dunn jt and stanbury jb, eds. the prevention and control of iodine deficiency disorders. amsterdam: elsevier science publishers, 1987. p. 35-48. 7. indicators for assessing iodine deficiency disorders and their control through salt iodization. in: world health organization, geneva, who press, 1994. whounicef-iccidd. p.12-16. 8. dunn jt. endemic goitre and cretinism. an updated on iodine status. j pediatr endocrinol metab 2001; 14:14691473. 9. markou k, georgopolous n, kyriazopoulou v, vagenakis ga. iodine induced hypothyroidism. thyroid 2001; 11:501-507. 10. delange fm, fisher da. thyroid hormone and iodine requirements in man during brain development. in: stannbury jb, delange f, dunn jt and pandav cs, eds. iodine in pregnancy. delhi:oxford university press, 1998. p. 1-27. 11. who. iodine. in: trace elements in human nutrition and health. geneva:macmillan, 1996. p. 49-71. 12. kochupillai n, godbole mm, pandav cs, karmarkar mg and ahuja mms. neonatal thyroid status in iodine deficient environments of the subhimalayan region. indian j med res 1984; 80:293-299. 13. ministry of health(oman),who, unicef, sultan qaboos university. sultanate of oman national study on prevalence of iodine deficiency disorders (idd). muscat: ministry of health, 1994. 14. moosa k, abdul wahab awm, al-sayyad j and baig bzh. national study on the prevalence of iodine deficiency disorders among schoolchildren 8-12 years of age in bahrain. east mediterr health j 2001; 7:609-616. 15. vitamin and mineral nutrition information system (vmnis), who global database on iodine deficiency, who press, geneva: world health organisation, 2006. 16. monitoring of universal salt iodization: a collaborative project of moh/unicef. ministry of health, muscat, 1998. c m e q u i z 1. what are the three sociocultural and ecological factors that aggravate iodine deficiency in a population? i) ............................................................................. ii) ............................................................................. iii) ............................................................................. 2. mention some clinical conditions that are induced by iodine deficiency. i) ............................................................................. ii) ............................................................................. iii) ............................................................................. 3. what are physiological mechanisms behind the clinical observation that, in spite of severe iodine deficiency in certain individuals, they have no signs or symptoms of goiter or cretinism? i) ............................................................................. ii) ............................................................................. iii) ............................................................................. 4. what is the duration of transient neonatal hypothyroidism in relation to the severity of iodine deficiency and what factors determine the persistence of hypothyroids in the postnatal period? i) ............................................................................. ii) ............................................................................. iii) ............................................................................. 5. what are therapeutic strategies for the different iodine deficiency disorders? i) ............................................................................. ii) ............................................................................. iii) ............................................................................. department of pathology, the university of jordan, amman, jordan *corresponding author’s e-mail: tnaladily@ju.edu.jo follicular lymphoma rich in warthin-finkeldey cells *tariq aladily and nadwa bustami sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 668–669, epub. 25 nov 21 submitted 11 nov 20 revision req. 7 jan 21; revision recd. 14 jan 21 accepted 9 feb 21 a 70-year old male patient presented to a tertiary care hospital in amman, jordan, in 2020 complaining of generalised lymph adenopathy in the neck, axilla and groin. there were no b symptoms, focal signs of infection or palpable spleen. serologic tests for viral hepatitis and hiv were negative and the serum lactate dehydrogenase level was normal. the patient underwent excisional biopsy of cervical lymph nodes. microscopic examination revealed effacement of the architecture by myriads of variable-sized follicles. the follicles were crowded, lacked the normal polarisation pattern and the presence of tingible-body macrophages and showed permeation of the lymph node capsule. the inter-follicular area was expanded by small cleaved lymphocytes. the follicles were composed of numerous centrocytes and a moderate amount of centroblasts [figure 1]. an immunohisto chemical study showed the follicles were positive for cluster of differentiation (cd)20, paired box (pax)5, b-cell lymphoma (bcl)2, bcl6 and cd10. cd21 highlighted irregular follicular dendritic cell (fdc) meshwork inside the follicles. the overall features were diagnostic of grade-ii follicular lymphoma. it should be noted that most of the neoplastic follicles exhibited one or more warthin-finkeldey cells (wfc). on low-power microscopic view, they appeared as dark, hyperchromatic cells, mainly located at the periphery of follicles and occasionally in the centre. the number of nuclei ranged from three to as many as 16. the nuclei were round, larger than lymphocytes and exhibited vesicular chromatin and a small central nucleolus. they were arranged in grapeor chain-like patterns. careful examination of pax5 immunohistochemical staining showed a negative nuclear reaction in these cells [figure 2]. comment wfc is a type of multinucleated giant cell that arises in lymphoid tissues in certain conditions. it was first described by dr a. warthin and dr w. finkeldey in 1931 after examining tonsils removed from children with measles.1,2 more studies revealed wfcs appearing in lymph nodes and even the appendix of measles patients, creating a strong relationship between them.3 however, later reports identified wfcs in various benign and malignant lymph node diseases such as hiv-lymphadenopathy, kimura disease and neoplastic lymphoid proliferations such as hodgkin lymphoma as well as b and t-cell lymphomas.4 wfc is characterised by a large size and numerous nuclei arranged in a grape-like cluster; the number of nuclei can be in the dozens. the cytoplasm and cell membrane are indistinct by light microscopy. the cells are mainly located in germinal centres, but can appear in interfollicular areas as well. the origin of wfcs remained enigmatic for decades, until it was recently found via immunohistochemistry that they express this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.051 interesting medical image figure 1: haematolxylin and eosin stains at (a) ×200 magnification (low-power view; inset at ×1,000 magnification) and (b & c) ×600 magnification (high-power views) showing neoplastic follicles that are predominantly composed of small cleaved cells and lack tingible-body macrophages, characteristic of follicular lymphoma. the presence of peripherally and centrally located warthin-finkeldey cells should be noted (black circles). tariq aladily and nadwa bustami interesting medical image | 669 fdc markers.5 while the pathogenesis of its formation is uncertain, it is hypothesised to result from the fusion of fdcs.5 this case brings to light the possible appearance of wfcs in follicular lymphoma which, to the best of the authors’ knowledge, has not been previously described. this is an important massage to the community of pathologists as the presence of a follicular lesion in a lymph node with numerous wfcs does not indicate, by default, a reactive viral disease. a u t h o r s’ c o n t r i b u t i o n ta conceptualised the work and established the diagnosis of the case. nb provided the image, conducted the literature review and drafted the manuscript. both authors approved the final version of the manuscript. references 1. warthin as. occurrence of numerous large giant cells in the tonsils and pharyngeal mucosa in the prodromal stage of measles. arch pathol 1931; 11:864–74. 2. finkeldey w. ueber riesenzellbefunde in den guamenmandeln, zugleich ein beitrag zur histopathologie der mandelveranderungen im maserninkubationsstadium. vichows arch pathol anat 1931; 281:323-9. 3. whalen tv, klos jr, kovalcik pj, cross gh. measles and appendicitis. am surg 1980; 46(7):412-3. 4. delsol g, pradere m, voigt jj, nespoulous m, gorguet b, marty c, et al. warthin-finkeldey-like cells in benign and malignant lymphoid proliferations. histopathology 1982; 6:451–65. https://doi.org/10.1111/j.1365-2559.1982.tb02742.x. 5. orenstein jm. the warthin-kinkeldey-type giant cell in hiv infection, what is it? ultrastruct pathol 1998; 22:293–303. https://doi.org/10.3109/01913129809103350. figure 2: a: cluster of differentiation (cd)21 immunohistochemical stain at ×200 magnification showing follicular dendritic cells in the neoplastic follicle and the membranous positivity in warthin-finkeldey cell (wfc; inset at ×600 magnification). b: pax5 immunohistochemical stain at ×200 magnification showing a positive result in the nuclear pattern in neoplastic lymphocytes but a negative result in wfcs (inset at ×400 magnification). c: cd3 immunohistochemical stain at ×400 magnification highlighting reactive t-lymphocytes but a negative result in wfcs. black circles indicate the wfc. squ med j, december 2009, vol. 9, iss. 3, pp. 305-310, epub. 19th dec 2009 submitted 19th may 2009 revision req. 4th oct 09. revision recd. 28th oct 09 accepted 31st oct 09 departments of 1hematology and 2biochemistry, baqai medical university, karachi, pakistan. *to whom correspondence should be addressed. email: staytune1@hotmail.com حتري مخسة أنواع من طفرات ثاالسيميا ) ب( يف باكستان محمد عثمان، معني الدين معني الدين، روبينة غاني، ساديا عثمان »حزام في للمرض انتشار أعلى العالم. في انتشارا السائد األحادي املورث اضطرابات أكثر من (ثاالسيميا) املتوسط األبيض البحر دم فقر الهدف: امللخص: وباكستان األقصى الشرق من اجلنوبية واألجزاء الهندية القارة وشبه األوسط الشرق مناطق وبعض املتوسط األبيض البحر منطقة يشمل الثاالسيميا« الذي معهد في الدراسة وجنوب شرق آسيا. نهدف هذه الدراسة إلى اكتشاف التشوهات اجلزيئية الشائعة ملتالزمة الثاالسيميا (ب) في باكستان. الطريقة: أجريت الدم بجامعة باكي الطبية (كرانسي/باكستان) من أغسطس 2005 إلى نوفمبر 2007. أخذت عينات الدم من (400) مريضا مصابا بالثاالسيميا الكبرى (ب) من مراكز نقل الدم واخملتبرات التشخيصية في مختلف مناطق كراتشي ميثلون األجناس اخلمسة الكبيرة: البنجابي ، الباثان ،السندي ، البلوشي واألوردو. مت حتليل كل العينات للطفرات الشائعة اخلمسة باستعمال تقنية سلسلة انزمي البوليميريز. النتائج: أظهرت النتائج خمسة طفرات شائعة وهي .هذه تشمل (%90) من كل مورثات الثاالسيميا (ب) في باكستان. كان مورث ال}ivs 1-5(grc){ األكثر شيوعا عند الباكستانيني حيث مثل (%44) عند كل األجناس الرئيسية . اخلالصة: ستساعد نتائج هذه الدراسة على تأسيس برنامج واسع النطاق لتشخيص حاالت املرض خالل احلمل في الباكستان. مفتاح الكلمات: ثاالسيميا (ب)، طفرات ، شعب باكستان، أثناء احلمل. abstract: objectives: thalassemia is one of the most common autosomal single-gene disorder worldwide. the highest prevalence of the disease is in the “thalassemia belt” which includes the mediterranean region, parts of the middle east, the indian subcontinent, the southern parts of the far east, pakistan and south-east asia. this study aimed to detect the common molecular abnormalities of the beta thalassemia syndrome in pakistan. methods: the study was conducted at the institute of hematology, baqai medical university, karachi, pakistan from august 2004 to november 2007. blood samples of patients with beta thalassemia major (n = 400) were collected from hospital transfusion centres and diagnostic laboratories in different districts of karachi representing five major ethnic groups including punjabi, pathan, sindhi, baluchi and urdu speaking. all the samples were analysed for five common mutations by using the polymerase chain reaction technique arms (amplification of refractory mutation system). results: the data revealed five common mutations including ivs 1-5(gc), fr 41/42(-cttt), fr 8/9 (+g), ivs 1-1 and del 619. these accounted for 90% of the total beta thalassemia genes in pakistan. the ivs 1-5(gc) was found to be the most common beta thalassemia gene in the pakistani population with a frequency of 44.4% present in all major ethnic groups. conclusion: the results of this study will be helpful in the establishment of a large scale prenatal diagnosis programme in pakistan. keywords: beta thalassemia; mutations; pakistani population; prenatal diagnosis. screening of five common beta thalassemia mutations in the pakistani population a basis for prenatal diagnosis *muhammad usman,1 moinuddin moinuddin,1 rubina ghani,2 sadia usman1 clinical & basic research advances in knowledge 1. this study shows that in the pakistani population only five mutations are common and these account for 90% of beta thalassemia genes. application to patients care 1. this study could help in establishing an economical and cost effective large scale prenatal diagnosis programme in pakistan by focusing on a limited number of mutations since the heterogeneity and complexity of the molecular abnormalities of the beta thalassemia syndrome make antenatal diagnosis difficult and expensive. 2. this study will be useful to stop the propagation of the beta thalassemia gene in the homozygous form that causes transfusion dependent beta thalassemia. screening of five common beta thalassemia mutations in the pakistani population a basis for prenatal diagnosis 306 | squ medical journal, december 2009, volume 9, issue 3 thalassemia is the most common genetic disorder world wide.1,2 more than 200 causative molecular defects have been described to date in the beta-globin gene causing beta thalassemia.3,4,5 these are not uniformly distributed, but have geographic specificity, and each ethnic group has a few common mutations and a variable number of rare ones. immigration plays a major role in both the distribution and the extent of mutation variations across the globe.6,7 beta thalassemia usually results from mutations that affect transcription, translation, or ribonucleic acid (rna) stability.8, 9,10 thalassemia is a serious public health problem, demanding the use of a preventive program with newborn screening in specific areas. to date, the highly heterogeneous distribution of molecular defects in the beta-globin gene has hampered the development of a flexible strategy that allows rapid analysis of mutations.7 thalassemia occurs with a particularly high frequency in a broad belt extending from the mediterranean basin through the middle east, indian subcontinent, burma to south east asia. 9,11,12,13, during the last 8-10 years, the amplification refractory mutation system (arms) and restriction fraction length polymorphisms (rflp) were the principal techniques used for the diagnosis of beta thalassemia.14 however, pakistan, with a multiethnic population of around 160 million, represents a vast spectrum of beta thalassemia mutations. we report the application of the arms procedure for the detection of five common mutations in five major ethnic groups and its advantages in prenatal diagnosis of beta thalassemia. methods the blood samples from patients with beta thalassemia major (n = 400) were collected in ethylenediaminetetraacetic acid (edta). the patients included in this study were all transfusion dependent and had been diagnosed earlier in life as beta thalassemia major with the help of basic haematological parameters, peripheral blood morphology and haemoglobin electrophoresis. among the 400 beta thalassemia major patients 250 were males and 150 were females with a mean age of 13.5 years. all samples were tested by the modified method of amplification of refractory mutation system (arms)14,15 for the five commonest mutations previously reported in population of the sub-continent.16,17,18 the five mutated primer sequences which were used during this study were ivsi-1 (g→t), ivsi-5 (g→c), del 619, fr 41-42(ttct) and fr 8-9 (+g). for the isolation of dna, the blood samples were collected in edta and dna was extracted from whole blood by following the kit protocol, using the gentra pure gene kit (minneapolis, minnesota, usa). the arms technique was used to characterise and screen the mutations as follows. after dna extraction, polymerase chain reaction (pcr) reactions were set up in two separate tubes for each sample. the mutant primers, namely ivs 1-1(g→t), ivs 1-5 (g→c), fr 41/42(-tctt), fr 8/9(+g) and del 619 at the 3’ end of the gene were distributed in two separate tubes according to their base pairs. the amplification with primers a and b served as internal controls in all the pcr reaction mixtures giving rise to 861bp fragments. a total of 20μl final pcr reaction volume was used to measure the pcr condition. the reaction volume was composed of 0.5 micrograms of the dna template, 10 pmol of each of the five primers (2 control primers, and 1 mutant arms primer for the reaction), 2.5 unit taq dna polymerase, and 0.2 mm of each deoxyribonucleotide triphosphate (dntp) in a solution of 10 mm tris-hc1, 50mm kcl and 1.2mm mgcl2, (promega, usa). the thermal cycling regimen consisted of 25 cycles; denaturation 94oc for 1 minute, primer annealing at 65oc for 1 minute and extension at 72oc for 1.5 minute with the final extension at 72oc for 3 minutes. the electrophoresis condition was measured as follows. fifteen microlitres of the pcr products were removed and mixed with 3 μl of a loading buffer and then loaded on a 2% agarose gel. the gel was set at 100 volts for 1 hour and then stained with ethidium bromide. after staining, the bands became visible under ultraviolet (uv) light. the different mutations were characterised with 100bp or 50 bp dna ladders. approval for this study was obtained from the ethical committee of baqai medical university. muhammad usman, moinuddin moinuddin, rubina ghani and sadia usman clinical and basic research | 307 results in this study, we used arms for the detection of beta-thalassemia mutations, which is one of the most commonly used techniques for diagnosis of this disease. the analyses were carried out on 800 alleles by arms technique for the detection of five common mutations ivs-1 nt 5 (g→c), ivs-1 nt 1(g→t), fr 41/42 (tctt), fr 8/9 (+g) and del 619. a total of sample of 400 homozygous beta thalassemia patients was analysed and among 800 beta thalassemia genes, 720 were identified with five common mutations [table 1 and figures 1a and 1b]. this study confirmed the presence of these five common mutations were: ivs 1-5(g→c), fr 41/42 (-cttt), fr 8/9 (+g), ivs 1-1 and del 619 comprising 90% of the total beta thalassemia genes in the pakistani population [table 1 and figures 1a and 1b]. molecular analysis in this study revealed that ivs1-5 (g→c) was the most common beta thalassemic gene that was present in all major ethnic groups of pakistan. this mutation comprised around 44.4% of the total beta thalassemia genes in pakistan with a frequency of 48.6% in punjabis, 47.3% in pathans, 36.5% in sindhis, 36.8% in baluchis and 61.6% in the urdu speaking population. its prevalence in the urdu speaking population is very high compared to the other four ethnic groups. fr 41/42c (-ttct) was the second most common beta thalassemia gene in this study; it comprised 17.5% of the total beta thalassemia gene with a frequency of 24% in punjabis, 28.4% in pathans, 13% in sindhis, 27.4% in baluchis and 12.5% in the urdu speaking population. the third most common beta thalassemia gene observed during this study was fr 8/9 (+g). it comprised 14.6% of the total beta thalassemia gene in the pakistani population with frequency of 17.1% in punjabis, 18.9% in pathans, 34.8% in sindhis, 7.4% in baluchis and 9.2% in the urdu speaking population. screening of the five common mutations of the beta thalassemia syndrome revealed ivs-1-1 (g→t) as the fourth most common mutation in the pakistani population. this accounted for 7.5% of total beta thalassemic genes in pakistan with frequency 6.8% in punjabis, 3.1% in pathans, 4.3% in sindhis, 21% in baluchis and 8.3% in the urdu speaking population. these data revealed that the prevalence of ivs 1-1 (g→t) is high in the baluchi population of pakistan. del 619 was identified as the fifth commonest beta thalassemia gene in this study. it comprised 6% of the total beta thalassemia genes in our population with a frequency of 3.4% in punjabis, 2.1% in pathans, 11.3% in sindhis, 7.4% in baluchis and 8.3% in the urdu speaking population. in the urdu speaking group, the del 619 mutation was present at high frequency in the gujurati and memon communities. discussion pakistan has a population of around 160 million people. the annual rate of population growth is 3% and almost 40% of the population is below 15 years of age.16,20 there are five major ethnic groups: sindhi, urdu speaking, punjabi, baluchi and pathan. the carrier frequency of beta thalassemia is estimated at around 6% in pakistani population.17 the results of the molecular analysis of the beta thalassemia table 1: five commonest beta thalassemia mutations among the five main ethnic groups in pakistan mutation punjabi pathan sindhi baluchi urdu speaking all ivs-1-5 (g-c) 85 (48.6%) 45 (47.3%) 42 (36.5%) 35 (36.8%) 148 (61.6%) 355 (44.4%) fr-8/9 (+g) 30 (17.1%) 18 (18.9%) 40 (34.8%) 07 (7.4%) 22 (9.2%) 117 (14.6%) fr-41/42 (-ttct) 42 (24%) 27 (28.4%) 15 (13%) 26 (27.4%) 30 (12.5%) 140 (17.5%) ivs-1-1 (g-t) 12 (6.8%) 03 (3.1%) 05 (4.3%) 20 (21%) 20 (8.3%) 60 (7.5%) del 619 06 (3.4%) 02 (2.1%) 13 (11.3%) 07 (7.4%) 20 (8.3%) 48 (0.6%) total 175 95 115 95 240 720 (90%) screening of five common beta thalassemia mutations in the pakistani population a basis for prenatal diagnosis 308 | squ medical journal, december 2009, volume 9, issue 3 syndrome in these five major ethnic groups revealed five common mutations, which comprised 90% of the total beta thalassemia genes in the pakistani population. these mutations included ivs-1-5 (g→c), fr 8/9 (+g), fr 41/42 (-ttct), ivs-1-1 (g→t) and del 619. although the five common beta thalassemia mutations reported during this study have already been detected and reported in pakistani population by ahmed et al. in 1996,20 the most important difference between the previous study and the present one is that this study detected the frequency of these five common mutations. the data of this study reveal that the frequency of these five mutations is 90% in the pakistani population while it was reported at around 82% in the previous study. in the light of present study, it is quite clear that these five mutations play a major role in propagation of the beta thalassemia gene in pakistan as they comprised around 90% of the total beta thalassemia genes in this region. results of this study showed the strong need for a large scale prevention program based on ante-natal diagnosis by pcr. the spectrum of beta thalassemia mutations that was identified in the indian population also showed the same five common mutations ivs-1-5 (g→c), fr 8/9 (+g), fr 41/42 (-ttct), ivs-1-1 (g→t) and del 619. these accounted for 93.6% of the total beta thalassemia genes in the indian population.17 another exclusive study of molecular genetics of beta thalassemia in the indian population also showed the same five common mutations i.e. ivs1-5 (g→c), fr 8/9 (+g), fr 41/42 (-ttct), ivs-1-1 (g→t) and del 619 that accounted for 91.8% of the total beta thalassemia genes. these mutations were frequently encountered in various regions of india 1 2 3 4 5 6 7 8 9 10 11 m 50bp control 861 bp fr 8/9 215 bp fr 41/42 439 bp ivs 1-1 281 bp ivs 1-5 285 bp del 619 242 bp figure 1a: the analysis of dna sample with mutation primer ivs 1-5, frame 41/42 ivs 1-1 and frame 8/9lane 1,2 and 3 are ivs 1-5; lane 4,5 and 6 are fr 41/42; lane 7 shows normal control band ; lane 8 is del 619, lane 9 and 10 is ivs 1-1 and lane 10 and 11 shows fr 8/9. 1 2 3 4 5 6 7 8 9 m 100bp control 861 bp ivs 1-5 285 bp ivs 1-1 281 bp figure 1b: the analysis of dna sample with mutation primer ivs 1-5 and ivs 1-1 lane 1, 2, 3 and 4 are ivs 1-1; lane5 and 9 are ivs 1-5. muhammad usman, moinuddin moinuddin, rubina ghani and sadia usman clinical and basic research | 309 including southern, eastern and northern states.18 similar patterns of molecular genetics of beta thalassemia syndromes in the pakistani and indian populations may have two basic causes. first, pakistan and india was one state for several hundred years before partition in august 1947. therefore cross-population and inter-linkage marriages were common. second, there was large scale migration from india to pakistan and from pakistan to india during the indo-pak partition in 1947. the spectrum of molecular genetics of the beta thalassemia syndrome in pakistan and india also shows the influence of genetic distribution of beta thalassemia from the mediterranean region. the exact cause of the influence of mediterranean region in indian and pakistani people is unknown; geographical migration and a history of invasions of the subcontinent favour the influence across the borders.19 studies of the molecular spectrum of beta thalassemia syndrome in the uae (united arab emirates) revealed that ivs-1-5 (g→c) was the most frequent mutation in the uae population.21, 22 a study of the molecular spectrum of beta thalassemia in arab populations (jordan, egypt, syria, lebanon, yemen and saudi arabia) revealed that the most frequent mutations were ivs-1-5 (g→c), ivs-ii-1 (g→a), ivs-1-1, fr 8/9, fr 41/42, cd 15, cd 16, cap +1 (a-c), ivs-1-110, ivs-1-3’ end (-25 bp) and ivs-1-6.23 the close similarity in molecular genetics of the beta thalassemia syndrome in the arab and pakistani populations is likely to have arisen because of the influence of trading and invasions of sindh and pakistani punjab by arabs. conclusion this research will help in the establishment of a large-scale prevention programme based on fetal diagnosis (prenatal) of beta thalassemia by dna analysis (pcr) in the pakistani population. references 1. quek l, thein sl. molecular therapies in beta thalassemia. br j haematol 2007; 3:353-65. 2. pan hf, long gf, li q, feng yn, lei zy, wei hw, et al. current status of thalassemia in minority population in guangxi, china. clin genet 2007; 5:419-26. 3. najmabadi h, teimourian s, khatibi t, neishabury m, pourfarzad f, jalil-nejad s, et al. amplification refractory mutation system (arms) and reverse hybridization in the detection of beta-thalassemia mutations. arch iran med 2001; 4:165-70. 4. weatherall dj, clegg jb. the biology of the thalassemias. in: weatherall dj, clegg jb, eds. the thalassemia syndromes. 4th ed. oxford: blackwell science ltd., 2001. pp.121-284. 5. huisman th, carver mf. the ßand -thalassemia repository. hemoglobin 1998; 22:169-95. 6. al-ali ak, al-ateeq s, imamwerdi bw, al-sowayan s, al-madan m, al-muhanna f, et al. molecular bases of beta-thalassemia in the eastern province of saudi arabia. j biomed biotechnol 2005; 4:322-5. 7. najmabadi h, karimi-nejad r, sahebjan s, pourfarzad f, teimourian s, sahebjam f, et al. the ß-thalassemia mutation spectrum in iranian population. hemoglobin 2001; 3:285-96. 8. foglieni b, cremonesi l, travi m, ravani a, giambona a, rosatelli mc, et al. beta-thalassemia microelectronic chip: a fast and accurate method for mutation detection. clini chem 2004; 50:73-9. 9. verma ic, kleanthous m, saxena r, fucharoen s, winichagoon p, raizuddin s, et al. multicenter study of the molecular basis of thalassemia intermedia in different ethnic populations. hemoglobin 2007; 4:439-52. 10. baig sm, azhar a, hassan h, baig jm, aslam m, ud din ma, et al. prenatal diagnosis of beta-thalassemia in southern punjab, pakistan. prenat diagn 2006; 10:903-5. 11. old jm, varawalla ny, weatherall dj. rapid detection and prenatal diagnosis of beta-thalassemia: studies in indian and cypriot populations in uk. lancet 1990; 336: 834-7. 12. kulozik ae, kar bc, serjeant gr, serjeant be, weatherall dj. the molecular basis of alpha thalassemia in india. its interaction with the sickle cell gene. blood 1988; 2:467-72. 13. derakhshandeh-peykar p, akhavan-niaki h, tamaddoni a, ghawidel-parsa s, naieni kh, rahmani m, et al. distribution of beta-thalassemia mutations in northern province of iran. hemoglobin 2007; 3:351-6. 14. lee gr, forester j, lukens j, paraskovas f, greer jp, rodgers gm, eds. wintrobe’s clinic hematology, vol. 1. 10th ed. baltimore: lippincott, williams and wilkins, 1999. 15. newton cr, graham a, heptinstall le, powell sj, summers c, kalsheker n, et al analysis of any point mutation in dna. the amplification refractory mutation system (arms). nucleic acids res 1989; 7:2503-16. 16. ahmed s, petrou m, saleem m. molecular genetics screening of five common beta thalassemia mutations in the pakistani population a basis for prenatal diagnosis 310 | squ medical journal, december 2009, volume 9, issue 3 of beta thalassaemia in pakistan: a basis for prenatal diagnosis. br j haematol 1996; 3:476-82. 17. varawalla ny, old jm, sarkar r, venkatesan r, weatherall, dj. the spectrum of beta-thalassaemia mutations on the indian subcontinent: the basis for prenatal diagnosis. br j haematol 1991; 2:242-7. 18. verma ic, saxena r, thomas e, jain pk regional distribution of beta-thalassemia mutations in india. hum genet 1997; 1:109-13. 19. usman m, moinuddin m, usman s. cap+1 mutation; an unsuspected cause of beta thalassemia transmission in pakistan. turk j haematol (accepted september 01, 2009). 20. ahmed s, saleem m, sultana n, raashid y, waqar a, anwar m, et al prenatal diagnosis of betathalassaemia in pakistan: experience in a muslim country. prenat diagn 2000; 5:378-83. 21. el-kalla s, mathews ar. molecular characterization of beta thalassemia in the united arab emirates. hemoglobin 1993; 4:355-62. 22. de leo r, deidda g, novelletto a, el-kalla s, mathews ar, felicetti l. analysis of beta-thalassemia mutations in the united arab emirates provides evidence for recurrent origin of the ivsi nt 5 (g-c) mutation. hum mutat 1995; 4:327-8. 23. el-hazmi ma, al-swailem ar, warsy as. molecular defects in beta thalassaemias in the population of saudi arabia. hum hered 1995; 5:278-85. o n l i n e s u b m i s s i o n ! you can now submit your manuscript online on the squmj website www.squ.edu.om/squmj note: please make sure that you register only once for all your manuscripts 1department of general surgery, oman medical specialty board, muscat, oman; 2department of vascular surgery, mcgill university, montreal, canada; department of 3vascular surgery and 4radiology, sultan qaboos university hospital, muscat, oman; department of 5radiology and 6vascular surgery, the royal hospital, muscat, oman *corresponding author’s e-mail: sara93916@gmail.com إصاابت رضحية كليلة مزمنة يف األهبر الصدري تقرير عن ثالث حاالت من ُعمان �سارة العدوية، احمد نعيم، ابراهيم عبد الهادي، را�سد ال�سكيتي، حممود الهاجري، ادوين �ستيفن، �سليمان ال�سام�سي، خليفة الوهيبي abstract: blunt thoracic aortic injuries are potentially lethal. those who survive may form an organised haematoma in the periadventitial space resulting in a pseudoaneurysm, which may be identified incidentally decades later. while the role of thoracic endovascular aortic repair (tevar) in acute settings has been established, its role in chronic cases is yet to be defined. we report three cases that were diagnosed incidentally six, nine and 18 years after the injury. two were managed by tevar while the third declined intervention and is on annual followup. patients with asymptomatic and stable pseudoaneurysms of the descending thoracic aorta should be offered surveillance versus tevar because the risk of rupture is not negligible, whilst taking into account the patient’s level of physical activity. these three cases highlight the importance of early diagnosis of aortic injuries in blunt trauma and its grading. keywords: thoracic aortic aneurysm; endovascular procedures; false aneurysm; nonpenetrating wounds; traffic accidents; oman. امللخ�ص: تكمن خطورة اإ�سابات ال�رشيان الأورطي ال�سدري يف اإمكانية اإف�سائها اإىل الوفاة. ويتكون عادًة ورم دموي منظم يف املنطقة املحيطة بالإ�سابة يوؤدي اإىل متدد �رشياين ُيكت�سف بال�سدفة بعد فرتة طويلة من الزمن. وعلى الرغم من اأهمية دور عملية اإ�سالح متدد الأوعية الدموية يف الإ�سابات احلادة٬ اإل اأن دورها يف الإ�سابات املزمنة غري وا�سح. نقدم هنا تقريراَ عن ثالثة حالت مت ت�سخي�سها بال�سدفة بعد انق�ساء فرتة ترتاوح بني 6، 9 و 18 عاًما من الإ�سابة. مت عالج حالتني جراحيَا٬ بينما رف�ض املري�ض الثالث التدخل اجلراحي وتتم متابعته �سنويَا. يجب اأن يخ�سع املر�سى للمراقبة الدورية بعد الت�سخي�ض بتمدد �رشياين يف ظل خلوهم من الأعرا�ض٬ مع و�سع التدخل اجلراحي كخياٍر مهم ب�سبب خطر حدوث مزق اأورطي. كما يجب مراعاة م�ستوى الن�ساط البدين للمري�ض عند اإختيار اخلطة العالجية. يهدف هذا البحث اإىل ت�سليط ال�سوء على اأهمية الت�سخي�ض املبكر لإ�سابات ال�رشيان الأورطي ال�سدري املزمنة. الكلمات املفتاحية: متدد الأوعية الدموية لل�رشيان الأورطي؛ عمليات الأوعية الدموية؛ متدد الأوعية الدموية؛ اجلروح؛ احلوادث، حركة املرور؛ ُعمان. chronic blunt traumatic thoracic aortic injuries report of three cases from oman *sara s.h. al-adawi,1 ahmed naiem,2 ibrahim abdelhady,3 rashid al-sukaiti,4 mahmood al-hajeri,5 edwin stephen,3 sulaiman al-shamsi,6 khalifa al-wahaibi3 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e120–123, epub. 15 mar 21 submitted 26 feb 20 revision req. 21 apr 20; revision recd. 3 jun 20 accepted 5 jul 20 a widened mediastinum on a chest x-ray performed for a routine health screening for his promotion as an army officer. he denied any chest pain, hoarseness of voice, shortness of breath or other symptoms. the patient had a history of a motor vehicle collision (mvc) 18 years prior to presentation when he had undergone a laparotomy and splenectomy. following these surgeries, he carried on regular official and recreational activities in the army with no restrictions. he had no family history suggestive of connective tissue disorder. a subsequent computed tomography angiography (cta) revealed a 3.8 cm pseudoaneurysm at the proximal descending thoracic aorta at the origin of the left subclavian artery with partial calcification [figure 1]. having discussed the risks and benefits of endovascular intervention, a thoracic endovascular aortic repair (tevar) was performed using a 30 × 100 mm zenith alpha™ thoracic endovascular graft blunt thoracic aortic injuries (btai) are potentially fatal. those with lesser degrees of injury may survive with a haematoma formation in the periadventitial space followed by subsequent pseudoaneurysm formation. with the advent of better radiological imaging, cases have emerged where individuals survive the initial injury and live with a pseudoaneurysm for decades until its incidental discovery on imaging. the management of such cases has not been clearly established as it is underreported. we report three cases of chronic pseudoaneurysms detected six, nine and 18 years after the initial injury. case one in 2015, a 37-year-old male patient was referred to sultan qaboos university hospital (squh) with findings of this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.017 case report https://creativecommons.org/licenses/by-nd/4.0/ sara s.h. al-adawi, ahmed naiem, ibrahim abdelhady, rashid al-sukaiti, mahmood al-hajeri, edwin stephen, sulaiman al-shamsi and khalifa al-wahaibi case report | e121 (cook medical, bloomington, indiana, usa) through a femoral cutdown. he has been under annual follow up with cta. in 2018, a linear intra-stent thrombus was seen [figure 2]. he was started on rivaroxaban 15 mg twice daily for three weeks, followed by 20 mg once daily for nine weeks. repeat cta in 2019 showed no progression of the thrombus, so he was switched to clopidogrel 75 mg once daily. his latest cta in january 2020 showed no thrombus progression and no complications related to the stent-graft. he will be continued on antiplatelet therapy as long as there is evidence of thrombus on annual imaging. meanwhile, he continues his army activities with a reduction in physical intensity and contact sport. case two in january 2017, a 37-year-old mother of four pres ented at squh and underwent a ct imaging of the abdomen for peritonitis. she was diagnosed with an acutely inflamed appendix and an incidental finding of a 7.5 cm right-sided diaphragmatic defect containing a herniated right lobe of the liver. a ct chest scan was performed to assess the diaphragmatic hernia further. it revealed a saccular pseudoaneurysm at the aortic isthmus, measuring 3 × 3 cm, that was distal to the left subclavian artery by 1.5 cm and with a curvilinear wall calcification [figure 3]. her history revealed an mvc nine years prior. she had occasional stabbing chest pain and tenderness over the left chest wall, which was managed with analgesics; otherwise, she lived an active lifestyle and had two of her children after the mvc. following a discussion, she underwent a successful tevar through a femoral cutdown using a 28 × 100 mm valiant™ thoracic stent graft with the captivia™ delivery system (medtronic, minneapolis, minnesota, usa) under fluoroscopic guidance. she has been on aspirin 75 mg once daily and under annual follow-up since. her latest cta in november 2019 showed the stent-graft in place and no endoleak or instent thrombus. case three in may 2019, a 29-year-old male patient was referred to squh with an incidental finding of a pseudo aneurysm of the descending thoracic aorta [figure 4]. the patient denied any symptoms, had normal blood pressure readings and his examination was unrem arkable. he was working with the military and regularly figure 1: 3d reconstructed image of (a) anterior and (b) posterior view of an incidentally detected pseudoaneurysm of the descending thoracic aorta in a 37-year-old male patient, 18 years after initial trauma. figure 3: (a) computed tomography scan showing an incidentally detected saccular pseudoaneurysm at the aortic isthmus, and (b) right diaphragmatic hernia containing the right lobe of the liver in a 37-year-old female patient, nine years after initial trauma. figure 2: a linear intra-stent thrombus in a 37-year-old male patient seen on computed tomography angio graphy after thoracic endovascular aortic repair. figure 4: 3d reconstructed image of (a) anterior and (b) posterior view of an incidentally detected pseudoaneurysm of the descending thoracic aorta in a 29-year-old male patient, six years after initial trauma. chronic blunt traumatic thoracic aortic injuries report of three cases from oman e122 | squ medical journal, february 2021, volume 21, issue 1 participating in intense physical activity. his history was significant for an mvc six years prior. after exploring all options and its associated risks and benefits, the patient opted to decline any intervention. he was given a follow-up appointment and instructions to report back if he developed any symptoms such as chest pain, inter-scapular pain, hoarseness of voice, dysphagia, dyspnoea or haemoptysis. discussion we report three cases of pseudoaneurysms diagnosed incidentally on imaging several years after the initial trauma. all were young, otherwise healthy members of society. two were regularly performing strenuous physical activities associated with their job as military personnel. the third was a female of childbearing age who had two pregnancies between the time of trauma until the pseudoaneurysm diagnosis. btai can be classified into four grades: grade 1 signifies intimal tear; grade 2 is an intramural haema toma; grade 3 is a pseudoaneurysm; and grade 4 is the free rupture of the aorta.1 the presence of shock, higher injury severity scores and concomitant brain injury are associated with a poor outcome from btai.2 the society of vascular surgery and eastern assoc iation for the surgery of trauma recommend endo vascular repair over open surgery, given the reduced rates of complications in the acute setting for grade 2–4 injuries. grade 1 injuries may be managed nonoperatively, but newer studies have emerged to suggest further that non-operative management for grade 2 injuries may also be acceptable.3–6 late complications of conservative treatment of aortic injuries include dissection, free rupture and pseudoaneurysms.7 chronic pseudoaneurysms have been reported to develop years after the injury.7–9 in the current patients, these pseudoaneurysms were incidentally discovered several years after the trauma. still, they could have led to free rupture when exposed to increased intra-abdominal and thoracic pressure during military exercise or labour. there has been documented success of tevar in chronic traumatic pseudoaneurysms of the thoracic aorta.10,11 this is not free of complications including endoleak, stroke, paraplegia, intra-graft thrombus and mortality.5,10,12,13 left subclavian artery coverage requiring carotid-subclavian bypass or use of fenes trated or chimney grafts must also be considered.13 while there are continuous improvements in profile and structure of stent-grafts, only time will tell whether the newer stent-grafts would have decreased re-intervention rates than their predecessors. non-operative management could be considered if the pseudoaneurysm remains stable in size, asymp tomatic, densely calcified and with no connective tissue disease history. literature in this regard is limited to earlier experience in this field.14 the role of open surgical therapy in acute and chronic cases cannot be ruled out. however, it is associated with higher morbidity and is reserved for those patients who are unsuitable for tevar. literature is limited to case reports concerning open repair.15 in the current report, the risks of free rupture versus complications of tevar were weighed. considering their lifestyles, all three patients were offered tevar. one patient developed intra-stent thrombus, which was managed with anticoagulant therapy. the second patient did not have any compl ications after tevar. the third patient refused intervention, so he was offered regular follow-up to ensure adequate blood pressure control with a ct angiogram every two years, followed by a yearly transoesophageal echocardiogram.16 conclusion chronic, stable and a calcified wall are features that might support successful non-operative management of pseudoaneurysms formed after btai. nonoperative management of btai should only be offered with imaging surveillance and regular follow-up. the level of physical activity and its impact on exertional arterial pressure changes should be considered in decision-making. references 1. azizzadeh a, keyhani k, miller 3rd cc, coogan sm, safi hj, estrera al. blunt traumatic aortic injury: initial experience with endovascular repair. j vasc surg 2009; 49:1403–8. https:// doi.org/10.1016/j.jvs.2009.02.234. 2. lin c-c, liu k-s, chen h-w, huang y-k, chu j-j, tsai f-c, et al. blunt aortic injury: risk factors and impact of surgical approaches. surg today 2016; 46:188–96. https://doi.org/10.10 07/s00595-015-1152-0. 3. lee wa, matsumura js, mitchell rs, farber ma, greenberg rk, azizzadeh a, et al. endovascular repair of traumatic thoracic aortic injury: clinical practice guidelines of the society for vascular surgery. j vasc surg 2011; 53:187–92. https://doi. org/10.1016/j.jvs.2010.08.027. 4. fox n, schwartz d, salazar jh, haut er, dahm p, black jh, et al. evaluation and management of blunt traumatic aortic injury: a practice management guideline from the eastern association for the surgery of trauma. j trauma nurs 2015; 22:99–110. https://doi.org/10.1097/jtn.0000000000000118. 5. soong tk, wee ijy, tseng fs, syn n, choong amtl. a syst ematic review and meta-regression analysis of non-operative manage ment of blunt traumatic thoracic aortic injury in 2897 patients. j vasc surg 2019; 3:941–53.e13. https://doi.org/10.1016/j.jvs.20 18.12.045. https://doi.org/10.1016/j.jvs.2009.02.234 https://doi.org/10.1016/j.jvs.2009.02.234 https://doi.org/10.1007/s00595-015-1152-0 https://doi.org/10.1007/s00595-015-1152-0 https://doi.org/10.1016/j.jvs.2010.08.027 https://doi.org/10.1016/j.jvs.2010.08.027 https://doi.org/10.1097/jtn.0000000000000118 https://doi.org/10.1016/j.jvs.2018.12.045 https://doi.org/10.1016/j.jvs.2018.12.045 sara s.h. al-adawi, ahmed naiem, ibrahim abdelhady, rashid al-sukaiti, mahmood al-hajeri, edwin stephen, sulaiman al-shamsi and khalifa al-wahaibi case report | e123 6. sandhu hk, leonard sd, perlick a, saqib nu, miller 3rd cc, charlton-ouw km, et al. determinants and outcomes of nonoperative management for blunt traumatic aortic injuries. j vasc surg 2018; 2:389–98. https://doi.org/10.1016/j.jvs.2017.07.111. 7. mosquera vx, marini m, lopez-perez jm, muñiz-garcia j, herrera jm, cao i, et al. role of conservative management in traumatic aortic injury: comparison of long-term results of conservative, surgical, and endovascular treatment. j thorac cardiovasc surg 2011; 3:614–21. https://doi.org/10.1016/j. jtcvs.2010.10.044. 8. rabin j, dubose j, sliker cw, o’connor jv, scalea tm, griffith bp. parameters for successful non-operative management of trau matic aortic injury. j thorac cardiovasc surg 2014; 1:143–9. https://doi.org/10.1016/j.jtcvs.2013.08.053. 9. finkelmeier ba, mentzer jr rm, kaiser dl, tegtmeyer cj, nolan sp. chronic traumatic thoracic aneurysm. influence of operative treatment on natural history: an analysis of reported cases, 1950-1980. j thorac cardiovasc surg 1982; 84:257–66. 10. szostek mm, jakuczun w, alagbari a, pogorzelski r, szostek m, osęka m, et al. chronic traumatic thoracic aortic aneurysmsresults of endovascular treatment. fourteen-year single-center experience. int angiol 2015; 34:506–13. 11. fattori r, napoli g, lovato l, russo v, pacini d, pierangeli a, et al. indications for, timing of, and results of catheter-based treatment of traumatic injury to the aorta. ajr am j roentgenol 2002; 179:603–9. https://doi.org/10.2214/ajr.179.3.1790603. 12. abdoli s, ham sw, wilcox ag, fleischman f, lam l. sympt omatic intragraft thrombus following endovascular repair of blunt thoracic aortic injury. ann vasc surg 2017; 42:305.e7–12. https://doi.org/10.1016/j.avsg.2016.12.007. 13. dubose jj, leake ss, brenner m, pasley j, o’callaghan t, luoowen x, et al. contemporary management and outcomes of blunt thoracic aortic injury: a multicenter retrospective study. j trauma acute care surg 2015; 78:360–9. https://doi.org/10.10 97/ta.0000000000000521. 14. katsumata t, shinfeld a, westaby s. operation for chronic traumatic aortic aneurysm: when and how? ann thorac surg 1998; 66:774–8. https://doi.org/10.1016/s0003-4975(98)00519-0. 15. miller s, kumar p, van den bosch r, khanafer a. chronic thoracic aortic aneurysm presenting 29 years following trauma. case rep surg 2015; 2015:470917. https://doi.org/10.1155/2015/470917. 16. hiratzka lf, bakris gl, beckman ja, bersin rm, carr vf, casey de, et al. 2010 accf/aha/aats/acr/asa/ sca/scai/sir/sts/svm guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the american college of cardiology foundation/ american heart association task force on practice guidelines, american association for thoracic surgery, american college of radiology, american stroke association, society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, society of interventional radiology, society of thoracic surgeons, and society for vascular medicine. circulation 2010; 121:266–369. https://doi. org/10.1161/cir.0b013e3181d4739e. https://doi.org/10.1016/j.jvs.2017.07.111 https://doi.org/10.1016/j.jtcvs.2010.10.044 https://doi.org/10.1016/j.jtcvs.2010.10.044 https://doi.org/10.1016/j.jtcvs.2013.08.053 https://doi.org/10.2214/ajr.179.3.1790603 https://doi.org/10.1016/j.avsg.2016.12.007 https://doi.org/10.1097/ta.0000000000000521 https://doi.org/10.1097/ta.0000000000000521 https://doi.org/10.1016/s0003-4975%2898%2900519-0 https://doi.org/10.1155/2015/470917 https://doi.org/10.1161/cir.0b013e3181d4739e https://doi.org/10.1161/cir.0b013e3181d4739e departments of 1nutrition & food technology and 3pharmacy, an-najah national university, nablus, palestine; 2department of healthy and therapeutic nutrition, palestine polytechnic university, hebron, palestine *corresponding author’s e-mail: m.altamimi@najah.edu knowledge, attitudes and practices related to dietary supplements among a group of palestinian pharmacists *mohammad altamimi,1 may hamdan,2 manal badrasawi,1 saad allahham3 clinical & basic research sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 613–620, epub. 25 nov 21 submitted 9 apr 20 revisions req. 14 jul & 9 sep 20; revisions recd. 16 aug & 24 sep 20 accepted 7 oct 20 https://doi.org/10.18295/squmj.4.2021.029 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: the use of dietary supplements (ds) has increased, but due to a lack of related regulations, the prescription of ds depends on pharmacists’ knowledge. hence, this study aimed to evaluate the knowledge, attitudes and practices (kap) related to ds among community-based pharmacists. methods: this study followed a crosssectional design targeting community pharmacists in west bank, palestine between september and december 2019. selected participants filled a self-administered questionnaire regarding their kap related to ds. the questionnaire contained 15 items: five questions on knowledge, seven on practices and three on attitudes. results: at a 90% response rate, 56.2% of the representative sample was female. the participants’ experience was distributed almost equally across the categories of 0–5, 5–10 and over 10 years. additionally, a majority of the participants were the responsible pharmacist and/or the pharmacy owner. overall, the participants showed a moderate level of knowledge about ds with a mean score of 3.68 ± 1.1 out of 5; the correct answers ranged from 3.6% to 75.3% of the surveyed participants. the practices with the highest frequencies were as follows: taking ds sometimes (79.9%), taking supplements from wellknown brands (56.2%), giving supplements to any patient (55.7%), selling supplements according to the participants’ knowledge (74.2%) and providing advice about supplements (73.2%). the questions about the pharmacists’ attitudes towards ds market regulation revealed that more than half (52%) of the participants believed that it was suitable. the association between knowledge score and practices was highly significant (p <0.001). conclusion: the study revealed that participants had moderate knowledge about ds. additionally, knowledge and practices were highly connected. keywords: dietary supplements; pharmacists; knowledge; attitude; general practice; curriculum. advances in knowledge to the authors’ knowledge, this is the first study in palestine to highlight the knowledge, attitudes and practices (kap) related to dietary supplements (ds) amongst pharmacists. the study evaluated the knowledge and practices of the pharmacists, which was revealed to be moderate. the study helped to identify the gap in the kap of pharmacists as frontline healthcare providers and suggested solutions to bridge such a gap. application to patient care addressing such a gap in the knowledge, attitudes and practices of pharmacists will positively improve the service provided to patients who use ds. theoretically, dietary supplements (ds) are seen as isolated and highly concentrated forms of nutrients and other substances such as herbs and botanicals, sport and weight-loss supplements and meal replacements.1,2 they are consumed in the form of pills, capsules, powders or liquids that are designed to be taken in doses supplementing a diet. ds were conventionally used to compensate for a low-nutrient diet or, at least, provide an easier way to stay healthy.1 in developed countries, the number of adults using multivitamins or mineral supplements is increasing (more than 60% of adults), especially in the age group of over 60 years.1 it was estimated that in 2018, $30.7 billion was spent on vitamins and nutritional supplements in the usa alone.3,4 another study showed that approximately one-third of the adolescents included in the study were using supplements; almost half of them were taking them on a daily basis.3 almost half of the population of the uk was also reported to be using ds.4 moreover, parents who use supplements are more likely to use them for their infants and toddlers (age 4–24 months). briefel et al. estimated that the prevalence of ds use was 19% among infants.2 research has shown that several factors have led individuals to take ds: maintaining health and wellbeing, providing the body with nutrients that are deficient in the food and improving cognitive and physical performance.5,6 a positive belief regarding ds is common among individuals in these categories. for example, the following views were expressed by many ds users: ‘the best i can do for myself ’, ‘help me to be knowledge, attitudes and practices related to dietary supplements among a group of palestinian pharmacists 614 | squ medical journal, november 2021, volume 21, issue 4 healthy’ and ‘the easy way to stay healthy’.7 it is critical to mention here that ds intake is associated with other factors such as gender, age, level of education, socioeconomic status, place of residence and ethnicity.5,6 previous studies have demonstrated that ds can help in reducing micronutrient deficiencies.1 however, more recent studies have revealed a prevalence of overconsumption [exceeding the tolerable upper intake level (ul)] of minerals/vitamins as a result of ds intake in the general population as well as among individuals of specific nutrition and health status, e.g. athletes, adolescents and obese individuals.1,3 therefore, the increasing rate of ds consumption is not necessarily proportionate to the population’s needs and the level of over-dosing amongst the wider population remains high.7 blumberg et al. noticed that multivitamin/multimineral use at any frequency was linked to a lower prevalence of inadequacy (p <0.01) for 15 out of the 17 nutrients examined.8 furthermore, there has been an increased prevalence of intakes greater than the ul for nutrients especially when the supplements provide the recommended daily requirement or above.9 similarly, it was reported that regular users of ds are people who are concerned about their health.4 such people are found to have higher intakes of fruits and vegetables than non-users, which may make those people prone to overconsumption of minerals/ vitamins and toxicity.10 it is also worth mentioning that ds intake can be regulated personally without the supervision of healthcare professionals (e.g. nutritionist, dietitian and general practitioner).6 in the middle east, micronutrient deficiencies are becoming a public concern, particularly amongst children and women of childbearing age.11,12 one-third of the population, in this particular area, are iron and iodine-deficient; 50% of the people are dyslipidaemic, and 65% are overweight or obese.13 despite various recommendations indicating the importance of a well-balanced diet with fruits and vegetables to meet the micronutrient and fibre requirements, the achievement of such a goal is relatively low. the long-term consequences can be dysfunctionality in the cellular system and chronic diseases.10 using multivitamins can also be associated with a decrease in the risk of chronic disease, as shown by some studies.4,14,15 therefore, it is expected that more people in the middle east are going to use ds. in many countries, ds use is not subject to specific regulations and they can be sold over the counter.16 it is well-known that ds, primarily herbal, may interact with other prescribed drugs.17 however, it was reported that in the usa, individuals who have been prescribed drugs for chronic diseases also take ds.16 this emphasises the fact that pharmacists’ knowledge and practices regarding ds are crucial. as ds are widely sold in community pharmacies, pharmacists have the opportunity to provide ds users with advice and discuss different choices. however, due to no or insufficient knowledge, whether such conversations happen between the pharmacist and consumer is doubtful. studies have highlighted that community pharmacists have poor knowledge of dietary and herbal supplements.17–19 however, pharmacists seem to insist on contributing to a patient’s requirements of the ds.5 reportedly, community pharmacists appear to rarely use reliable references that were part of the pharmacy curriculum.5,14 pharmacists serving the frontline of the healthcare practitioners are required to be equipped with knowledge about ds alongside possible drug interactions. they are also required to provide their patients with an unbiased, evidence-based opinion about the healthy use of ds.19 it was reported that in countries such as palestine, qatar, kuwait, jordan and iran, ds are one of the most recommended complementary alternative medicines suggested by pharmacists.19–22 in the palestinian context, for example, ds are taken by around 12% of polypharmacy patients who simultaneously take other medications.23 therefore, the risk of a pharmacokinetic or pharmacodynamic interaction between drugs and ds is high amongst this group.15 such interaction is a huge concern, especially with certain ds that contain pharmaceutical contaminants.5 therefore, as many studies have highlighted, there is an urgent need for pharmacists to accrue proper knowledge of ds and, more importantly, offer better professional medical advice and guidance to patients.24,25 the available literature revealed that there is a paucity of research in the field, specifically on the level of knowledge. ds-related practices of community pharmacists in palestine requires further exploration. therefore, this study aimed to evaluate the knowledge, attitudes and practices (kap) concerning ds and create a link between knowledge and practices among community pharmacists in the west bank, palestine. methods a cross-sectional survey was conducted between september and december 2019 in the northern and southern districts of the west bank, palestine; jenin, tubas, nablus and tulkarem in the north and hebron in the south. the included pharmacies were either public or non-governmental. the number of samples mohammad altamimi, may hamdan, manal badrasawi and saad allahham clinical and basic research | 615 and distribution was based on the latest information published by the ministry of health,26 particularly in the northern districts, jenin and tubas have 148, nablus and salfit have 201 and tulkarem and qalqilia have 136, while in the southern district, hebron has 244 community pharmacies. it was reported that the total number of licensed community pharmacies in the west bank is about 1,101 by the year 2020.26 a total of 252 questionnaires were distributed. 227 completed questionnaires were returned, yielding a 90% response rate. the rest of the questionnaires either had missing data or had not been filled in properly. the following percentages of coverage were achieved: 100 questionnaires from the northern districts (representing 20.6% of pharmacies in that area) and 127 questionnaires from the southern districts (representing 52% of pharmacies in that area). the questionnaire, comprising of two parts, was adopted from the literature with modifications to suit the aim of the study. the first part was about personal and sociodemographic information, including gender, age, residency, work position, experience, marital status and health status, while the second part was about knowledge, attitudes and practices. the knowledge part of this section consisted of five questions: ‘do you understand the term ds?’; ‘can you identify the type of ds?’; ‘can you define ds?’; ‘what is your source of knowledge about ds?’; and ‘what is your knowledge about the treatment of nutrient deficiency?’ the seven questions regarding practices included those on taking ds, giving ds, recommending ds, who ds should be prescribed to and who should prescribe ds. in the attitudes part of this section, there were three questions, including those regarding the following: the reason a person took ds, whether pharmacists were qualified to prescribe ds and regulations of ds. for scoring, the following scale was used, where a correct answer in the knowledge and practices sections was given one point, while an incorrect answer was given zero points. the knowledge scale ranged from 0 to 5 (poor knowledge was 0–2, medium knowledge was 3 and knowledgeable was 4–5), and for practices it ranged from 0 to 7 (poor practice was < 3, satisfactory practice was 4–5 and good practice was 6–7). the views on the ds market were used to measure the attitudes of the participants. the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa) was used to analyse the collected data; the selection of statistical tests according to variables types was done following field’s work.27 the reliability test for the knowledge items showed that cronbach’s alpha was 0.71, while for practice items, it was 0.65, revealing acceptable reliability. the normality test was done for nutritional knowledge scores using the kolmogorov simonov test. descriptive statistics, including the means and standard deviations, were used along with the interval data of the continuous dependent and independent variables and the percentages were used with the categorical variables. an independent t-test and oneway anova tests were conducted to examine the relationship between the sociodemographic variables, the practices variables and the total score of the knowledge items at p <0.05. this study was approved by the institutional review board at an-najah national university and was assigned the number 12. direct verbal consent was provided by each subject before filling the questionnaire and participation was completely voluntary without any monetary or non-monetary incentives. no names of participants were mentioned during data extraction and the raw data were solely used for research and not shared with a third party. results the total number of pharmacists who joined the study was 227; only 194 participants were included in the final analysis as 33 participants were excluded due to missing data. table 1 shows the demographic characteristics of the study participants (presented as frequencies and percentages). the difference in the number of male and female participants was small (56.2% female and 43.8% male) and 67.1% of the participants were married. a majority of the participants were living in cities (76.3%). with regard to work position, 54.1% were employed as ‘responsible pharmacists’. experience wise, 37.1% of the participants had less than 5 years of experience, 29.4% had 5–10 years of experience and 33.5% had more than 10 years of experience. table 2 shows participants’ knowledge about ds. overall, participants indicated a moderate level of knowledge regarding ds; the mean score was 3.68 ±1.1. the range of the correct answers was from 3.6% (as in item 5) to 75.3% (as in item 2). table 3 shows the participants’ practices and attitudes towards using supplements (presented as frequencies and percentages). the major practices with a high frequency were as follows: taking supplements sometimes (79.9%), taking supplements from well-known brands (56.2%), giving supplements to any patient (55.7%), selling supplements according to their knowledge (74.2%) and providing advice about supplements (73.2%). the questions about the pharmacists’ attitudes towards the prescription, recommendation and regulation of the ds market knowledge, attitudes and practices related to dietary supplements among a group of palestinian pharmacists 616 | squ medical journal, november 2021, volume 21, issue 4 table 3: practices and attitudes of pharmacists with regard to dietary supplements in the west bank, palestine (n = 194) item answers n (%) i take ds never 21 (10.8) sometimes* 155 (79.9) often† 18 (9.3) i take ds if the brand is familiar, well known or trusted 109 (56.2) the price is reasonable, it is within my budget or it is free 32 (16.5) the ingredients are high in concentration 53 (27.3) usually, i give ds to any customer who buys them 36 (18.6) any patient who requires them 108 (55.7) anyone referred by a physician 50 (25.8) i sell ds according to availability: whatever i have in my pharmacy 35 (18) my knowledge about the quality of product, source, etc. 144 (74.2) price of the product 15 (7.7) if a patient asks for advice about ds, i redirect them to the physician 20 (10.3) redirect them to the nutritionist 32 (16.5) provide advice based on what i know 142 (73.2) ds should be prescribed by anyone, with no restriction 8 (4.1) specialised persons 161 (83) pharmacists only 25 (12.9) i recommend the use of ds to everyone 34 (17.5) persons who need them 158 (81.4) no one 2 (1) in palestine, the regulations on exporting and importing ds, etc., are suitable 102 (52.6) very restrictive 45 (23.2) very flexible 47 (24.2) ds = dietary supplements. *less than 3 times a month; †once to twice a week. table 1: sociodemographic characteristics of pharmacists from the west bank, palestine (n = 194) variable n percentage gender male 85 43.8 female 109 56.2 age (in years) 23–28 113 58.2 29–33 3 1.5 34–39 33 17.0 >40 45 23.2 marital status married 49 25.3 married with children 81 41.8 single 64 33.0 other 0 0.0 area of residence city 148 76.3 village/ camps 46 23.7 work position responsible pharmacist 105 54.1 assistant pharmacist 32 16.5 pharmacy owner 57 29.4 years of experience less than 5 72 37.1 5–10 57 29.4 more than 10 65 33.5 chronic disease no 179 92.3 yes 15 7.7 table 2: knowledge of pharmacists with regard to dietary supplements in the west bank, palestine (n = 194) item # item correct answer n (%) wrong answer n (%) 1 understanding the meaning of the term ds 65(33.5) 129 (66.5) 2 identifying the type of ds 146 (75.3) 48 (24.7) 3 definition of ds 51 (26.3) 143 (73.7) 4 source of knowledge about ds* 117 (60.3) 77 (39.7) 5 methods of treating nutrient deficiency 7 (3.6) 187 (96.4) ds = dietary supplement. *this item was assessed according to the reliability of the sources. mohammad altamimi, may hamdan, manal badrasawi and saad allahham clinical and basic research | 617 showed that more than half (52%) of the participants believed that it was suitable as a majority of them believed that ds should be prescribed by a specialist (83%), recommended to people who need them (81.4%) and regulated by the law as it is now (52.6%). table 4 presents the relationship between the knowledge score and the sociodemographic variables. the results revealed no significant relationship between the knowledge score and the other variables, which was indicated by no significant differences between the means of the defined groups. the relationship between the level of knowledge and the attitudes and practices regarding ds use is presented in table 5. the results revealed a significantly higher knowledge score among those who take the supplements depending on ds price, a patient’s need for supplements or a patient’s reliance on a nutritionist referral to use the supplements. meanwhile, a significantly lower score of knowledge was found among pharmacists who take the supplements according to the concentration of nutrients (3.2 vs 4.5) or reported that they provided supplements for any patients that required them. table 5: relationship between the level of knowledge and the practices and attitudes of pharmacists with regard to dietary supplements in the west bank, palestine (n = 194) item mean ± sd p value i take ds never 3.7 ± 1.3 0.789sometimes 3.7 ± 1.1 often 3.5 ± 1.3 i take ds if the brand is familiar, well known or trusted 3.7 ± 1.0 0.0001* the price is reasonable, it is within my budget or it is free 4.5 ± 1.1 the ingredients are high in concentration 3.2 ± 1.1 usually, i give ds to any customer who buys them 2.75 ± 1.2 0.0001*any patient who requires them 4.1 ± 0.9 anyone referred by a physician 3.4 ± 0.9 i sell ds according to availability: whatever i have in my pharmacy 3.0 ± 1.4 0.0001*my knowledge about the quality of product, source, etc. 3.9 ± 1 price of the product 3.4 ± 1.1 if a patient asks for advice about ds, i redirect them to the physician 3.3 ± 1.1 0.0001*redirect them to the nutritionist 4.9 ± 1.1 provide advice based on what i know 3.5 ± 0.9 ds should be prescribed by anyone, with no restriction 2.2 ± 1.3 0.0001*specialised persons 3.9 ± 1.0 pharmacists only 2.9 ± 1.0 i recom mend the use of ds to everyone 2.6 ± 1.0 0.0001*persons who need them 3.9 ± 1.0 no one 2.0 ± 1.4 in palestine, the regula tions on exp orting and importing ds, etc., are suitable 3.7 ± 1.1 0.745 very restrictive 3.7 ± 1.5 very flexible 3.6 ± 1.0 ds = dietary supplements. * p-value calculated using chi-square test. table 4: relationship between knowledge score and various sociodemographic variables of pharmacists with regard to dietary supplements in the west bank, palestine (n = 194) variable mean sd p value gender male 3.68 1.1 0.939* female 3.67 1.1 age (in years) 23–28 3.69 1.01 0.499† 29–33 3.67 2.1 34–39 3.42 1.3 more than 40 3.8 1.2 marital status married 3.53 1.2 0.589† married with children 3.73 1.3 single 3.7 0.9 area of residence city 3.66 1.1 0.839* village/camps 3.8 1.6 work position responsible pharmacist 3.62 1.2 0.14†assistant pharmacist 4.03 1.2 pharmacy owner 3.58 0.9 years of experience less than 5 3.75 0.9 0.567†5–10 years 3.72 1.2 more than 10 3.55 1.3 presence of chronic disease no 3.64 1.1 0.318*yes 4 0.9 *not significant using independent sample t-test; †not significant using one-way anova test. knowledge, attitudes and practices related to dietary supplements among a group of palestinian pharmacists 618 | squ medical journal, november 2021, volume 21, issue 4 discussion incorporation of healthy eating habits with sufficient nourishment as part of a busy modern lifestyle is not a simple task. due to increasing awareness among individuals about wellbeing and counteracting sicknesses, the utilisation of ds has become widespread. different research investigations have shown that awareness about nutrition is expanding among both the all-inclusive community and special groups such as athletes, individuals experiencing malignancy treatment, healthcare professionals and students.28,29 recently, community pharmacists’ knowledge of ds was reported to be relatively poor despite a professional responsibility to provide advice about ds to the public.22 researchers found that 33.3% of ethiopian pharmacists had poor knowledge about ds, while in other studies, the lack of knowledge ranged between 40–60%.25 generally speaking, pharmacies, which are considered to be a significant cornerstone of the health framework, are in the right position to counsel clients with evidence-based data about ds. pharmacists in the palestinian community enjoy high social status. being a pharmacist is considered to be one of the well-paid professions. pharmacy programs are also highly selective and students are required to enrol in a comprehensive range of courses on pathology, pharmacognosy and ethics in pharmacology. standardisation of students’ knowledge about a specific topic by modifying or updating the curriculum is included as part of the university mission. this study aimed to shed light on one of the essential topics representing the overlap between pharmacy and nutrition, i.e. ds. given the results, it seems that the current situation is not in the best interest of consumers and there is a gap that needs to be filled through further action from policymakers either at the university level or the pharmacist syndicate level. the current research covered the northern and southern districts of the west bank with 227 participants representing 24% of the community pharmacies. concerning the knowledge of pharmacists about ds, this study found that one-third of the pharmacists understood the meaning of the term ds. meanwhile, 75.3% of them showed correct knowledge about the types of ds. however, only 26.3% of the pharmacists correctly defined the meaning of the term ds and less than 5% of them knew about the methods of treating nutrient deficiency. a previous study conducted in palestine showed that pharmacists’ knowledge of complementary alternative medicine (cam) was ‘fair to average’, while their ability to answer patients’ questions about cam was ‘inadequate’.19 in a study conducted in saudi arabia, almost half of the participating pharmacists agreed on the importance of receiving more training and continuing education pertaining to herbal products.18 a finding from another study suggested that a majority of pharmacists exhibited poor professional practice with regard to ds despite having adequate knowledge and a positive attitude towards ds.25 hence, a suggestion was made to emphasise teaching or training community pharmacists on how to critically evaluate the use, efficacy and safety of standard ds. mehralian et al. conducted a similar survey in tehran and found that 62% of the participating pharmacists had weak knowledge of ds.22 these results highlighted the need to increase the awareness among the pharmacists about ds. moreover, another study revealed that people rely on pharmacists’ knowledge about ds and pharmacists are in a good position to provide patients with evidence-based information about ds, 30 however, their knowledge has to be improved to enable them to perform such a task adequately. on the other hand, the current findings showed that a little more than 10% of the pharmacists never took ds, less than 10% of them took supplements often and the rest took supplements only sometimes. this indicated that at some capacity, pharmacists were convinced that ds could help and support wellbeing. such results were in accordance with other findings of several studies where almost half of the participants were found to consume ds.30–35 moreover, howard et al. found that participants who personally took ds and recommended ds were twice the number of pharmacists who did not take ds personally and recommended ds to patients.28 in the current study, differences in knowledge scores were not significant between participants who took supplements and those who did not. the main drive for the high scoring participants who took supplements was the price (p <0.0001). another study conducted by shraim et al. revealed that adequate knowledge is positively linked with pharmacist’s level of study with a master’s degree reported having a higher knowledge score than pharmacists with a bachelor’s degree.19 in the same context, another study by alsayari et al. concluded that pharmacists have good knowledge about some dietary supplements (herbal medicines) although their experience ranged from 1–20 years.18 furthermore, pharmacists aged between 20 and 29 years were found to have a higher knowledge score than older pharmacists. in the current study, a majority of the sample were adults between 23 and 28 years of age, indicating that they had 0–5 years of experience. the aforementioned results may explain the moderate scores achieved by the participants. mohammad altamimi, may hamdan, manal badrasawi and saad allahham clinical and basic research | 619 in the current study, 74.3% of the pharmacists prescribed ds to any customer or patient who asked for them. at the same time, only 25.3% of the pharmacists sold supplements to patients on the advice of a physician. knowledge played a great role in such a decision as high-scoring pharmacists sold ds according to their knowledge about the product quality, not due to price or availability (p <0.000). this reflected the ethical responsibilities of pharmacists, which entails offering advice based on scientific and verified information. moreover, the findings showed that 26.8% of the pharmacists tended to redirect patients to physicians or nutritionists, while around 74.2% of the pharmacists provided advice to patients according to their knowledge. pharmacists whose knowledge scores were higher preferred to redirect patients to nutritionists or physicians rather than taking the responsibility of giving advice. such a result emphasised the initial statement of this study about the necessity of increasing pharmacists’ awareness and knowledge related to ds. medhat et al. explored similar trends, where 59.2% of the pharmacists considered that supplements should be dispensed according to the nutritionist’s or physician’s prescription.36 meanwhile, 69.3% of the pharmacists considered that supplements could be sold in the pharmacy under the pharmacist’s supervision.36 finally, approximately half of the pharmacists from the current study considered the palestinian regulations for exporting and importing ds suitable. meanwhile, 22.7% of the pharmacists considered the palestinian regulations in this regard very restrictive, while a similar portion (23.7%) of the pharmacists considered these regulations very flexible. knowledge scores related to ds were similar among pharmacists with different attitudes towards the regulations, meaning that knowledge was not a significant player in taking such a decision. the study has certain limitations with regard to sampling and design. first, as a cross-sectional study, there may be a bias from responders and data collectors. however, the sample was made as representative as possible. secondly, the interpretation of relationships between the outcomes and the prevalence of kap was not found to be easily generalisable. conclusion the current study showed that a majority of the participants scored moderately in terms of knowledge related to ds. the low level of knowledge is likely to affect their practices in taking or giving ds. however, it was observed that this level of knowledge has no relationship with their attitude towards ds regulations. this emphasised the need to promote a specific culture that actively supports knowledge enhancement and awareness raising about ds among pharmacists. in return, this can significantly improve their decisions and the advice they give to consumers and help them make scientific evidence-based decisions systemically without the influence of other business-driven factors such as prices, brands or the availability of products. it is also recommended that community pharmacists incorporate learning about cam into their continued professional development. such learning can be a step in the right direction wherein knowledge and practices would not only be about herbal medicine but also ds. a c k n o w l e d g e m e n t the authors would like to thank everyone who contributed to this study, especially by distributing, filling and collecting the questionnaires. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n ma contributed in the concept and design, mh in writing the manuscript discussion and proving final draft, mb data analysis and interpretation and sa writing and proving final draft. references 1. weeden a, remig v, holcomb ca, herald tj, baybutt rc. vitamin and mineral supplements have a nutritionally significant impact on micronutrient intakes of older adults attending senior centers. j nutr elder 2010;29:41–54. https:// doi.org/10.1080/01639366.2010.480897. 2. briefel r, hanson c, fox mk, novak t, ziegler p. feeding infants and toddlers study: do vitamin and mineral supplements contribute to nutrient adequacy or excess among us infants and toddlers? j am diet assoc 2006; 106:52.e1– e15. https:// doi.org/10.1016/j.jada.2005.09.041. 3. stang j, story mt, harnack l, neumark-sztainer d. relationships between vitamin and mineral supplement use, dietary intake, and dietary adequacy among adolescents. j am diet assoc 2000; 100:905–10. https://doi.org/10.1016/s00028223(00)00262-5. 4. mason p. one is okay, more is better? pharmacological aspects and safe limits of nutritional supplements. proc nutr soc india 2007; 66:493–507. https://doi.org/10.1017/ s0029665107005812. 5. axon dr, vanova j, edel c, slack m. dietary supplement use, knowledge, and perceptions among student pharmacists. am j pharm educ 2017; 81:1–12. https://doi.org/10.5688/ajpe81592. knowledge, attitudes and practices related to dietary supplements among a group of palestinian pharmacists 620 | squ medical journal, november 2021, volume 21, issue 4 6. balzo vd, vitiello v, germani a, donini lm, poggiogalle e, pinto a. a cross sectional survey on dietary supplements consumption among italian teenagers. plos one 2014; 9:1–6. https://doi.org/10.1371/journal.pone.0100508. 7. lentjes ma. the balance between food and dietary supplements in the general population. proc nutr soc 2019; 78:97–109. https://doi.org/10.1017/s0029665118002525. 8. blumberg jb, frei bb, fulgoni vl, weaver cm, zeisel sh. impact of frequency of multi-vitamin/multi-mineral supplement intake on nutritional adequacy and nutrient deficiencies in us adults. nutrients 2017; 9:849. https://doi. org/10.3390/nu9080849. 9. murphy sp, white kk, park sy, sharma s. multivitaminmultimineral supplements' effect on total nutrient intake. am j clin nutr 2007; 85:280s–4s. https://doi.org/10.1093/ ajcn/85.1.280s. 10. harrison ra, holt d, pattison dj, elton pj. are those in need taking dietary supplements? a survey of 21 923 adults. br j nutr 2004; 91:617–23. https://doi.org/10.1079/bjn20031076. 11. khatib la, obeid o, sibai a-m, batal m, adra n, hwalla n. folate deficiency is associated with nutritional anaemia in lebanese women of childbearing age. public health nutr 2006; 9:921–7. https://doi.org/10.1017/phn2005921. 12. bagchi k. iron deficiency anaemia--an old enemy. east mediterr health j 2004; 10:754–60. 13. hwalla n, al dhaheri as, radwan h, alfawaz ha, fouda ma, al-daghri nm, et al. the prevalence of micronutrient deficiencies and inadequacies in the middle east and approaches to interventions. nutrients 2017; 9:229. 14. huang hy, caballero b, chang s, alberg aj, semba rd, schneyer c, et al. multivitamin/mineral supplements and prevention of chronic disease: executive summary. am j clin nutr 2007; 85:265s–8s. https://doi.org/10.1093/ajcn/85.1.265s. 15. parian a, limketkai bn. dietary supplement therapies for inflammatory bowel disease: crohn’s disease and ulcerative colitis. curr pharm des 2016; 22:180–8. https://doi.org/10.21 74/1381612822666151112145033. 16. asher gn, corbett ah, hawke rl. common herbal dietary supplement-drug interactions. am fam physician 2017; 96:101–7. 17. amadi cn, mgbahurike aa. selected food/herb-drug interactions: mechanisms and clinical relevance. am j ther 2018; 25:e423–e33. https://doi.org/10.1097/mjt.0000000000000705. 18. alsayari a, almghaslah d, khaled a, annadurai s, alkhairy ma, alqahtani ha, et al. community pharmacists' knowledge, attitudes, and practice of herbal medicines in asir region, kingdom of saudi arabia. evid based complement alternat med. 2018; 2018:1568139. https://doi. org/10.1155/2018/1568139. 19. shraim ny, shawahna r, sorady ma, aiesh bm, alashqar gs, jitan ri, et al. community pharmacist’ knowledge, practices and beliefs about complementary and alternative medicine in palestine: a cross-sectional study. bmc complement altern med 2017; 17:429. https://doi.org/10.1186/s12906-017-1940-8. 20. awaisu a, kheir n, ibrahim mim, el-hajj m, hazi h, khudair n, et al. knowledge, attitudes, and practices of community pharmacists on generic medicines in qatar. int j clin pharm 2014; 36:394–404. https://doi.org/10.1007/s11096-013-9909-2. 21. shilbayeh sa. exploring knowledge and attitudes towards counselling about vitamin supplements in jordanian community pharmacies. pharm pract 2011; 9:242. https://doi. org/10.4321/s1886-36552011000400010. 22. mehralian g, yousefi n, hashemian f, maleksabet h. knowledge, attitude and practice of pharmacists regarding dietary supplements: a community pharmacy-based survey in tehran. iran j pharm res 2014; 13:1457. 23. zyoud s, abd-alhafez a, hussein a, abu-shehab i, al-jabi s, sweileh w. patterns of use of medications, herbal products and nutritional supplements and polypharmacy associating factors in palestinian geriatric patients. eur geriatr med 2014; 5:188–94. https://doi.org/10.1016/j.eurger.2013.11.004. 24. shields km, mcqueen ce, bryant pj. natural product education in schools of pharmacy in the united states. am j pharm edu 2003; 67:43–8. https://doi.org/10.5688/aj670110. 25. emiru yk, belay yb, bizuneh gk, tegegn hg. community pharmacists' knowledge, attitude, and professional practice behaviors towards dietary supplements: results from multicenter survey in ethiopia. nutr diet suppl 2019; 11:59–68. https://doi.org/10.2147/nds.s222114. 26. ministry of health, health annual report, palestine 2020. 2021. from: https://www.unrwa.org/2020unrwahealthannu alreport accessed: sept 2020. 27. field a. discovering statistics using spss (introducing statistical methods series) 3rd ed. thousand oaks, california, usa: sage publications inc; 2009. 28. howard n, tsourounis c, kapusnik-uner j. dietary supplement survey of pharmacists: personal and professional practices. j altern complement med 2001; 7:667–80. https:// doi.org/10.1089/10755530152755225. 29. sasanfar b, toorang f, nemati s, djazayery a, zendehdel k. development and validation of a knowledge, attitude, and practice questionnaire on nutrition-related cancer prevention for iranian women. j res med sci 2019; 24:87. https://doi. org/10.4103/jrms.jrms_777_18. 30. kwan d, hirschkorn k, boon h. us and canadian pharmacists' attitudes, knowledge, and professional practice behaviors toward dietary supplements: a systematic review. bmc complement altern med 2006; 6:31. https://doi.org/10.1186/1472-6882-6-31. 31. holick mf, biancuzzo rm, chen tc, klein ek, young a, bibuld d, et al. vitamin d2 is as effective as vitamin d3 in maintaining circulating concentrations of 25-hydroxyvitamin d. j clin endocrinol metab 2008; 93:677–81. https://doi. org/10.1210/jc.2007-2308. 32. sharma a, adiga s. knowledge, attitude and practices related to dietary supplements and micronutrients in health sciences students. j clin diagn res 2014; 8:hc10–hc13. https://doi. org/10.7860/jcdr/2014/9329.4683. 33. woodside jv, mccall d, mcgartland c, young is. micronutrients: dietary intake v. supplement use. proc nutr soc india 2005; 64:543–53. https://doi.org/10.1079/pns2005464. 34. teng cl, tey kk, lim ph, cheng sf, nordin ms, ng cm, et al. dietary supplements: usage and opinions among health sciences students. int e-j sci med edu 2008; 2:30–2. 35. spencer eh, bendich a, frank e. vitamin and mineral supplement use among us medical students: a longitudinal study. j am diet assoc 2006; 106:1975–83. https://doi. org/10.1016/j.jada.2006.09.003. 36. medhat m, sabry n, ashoush n. knowledge, attitude and practice of community pharmacists towards nutrition counseling. int j clin pharm 2020; 42:1456–68. https://doi. org/10.1007/s11096-020-01106-0. departments of 1dermatology and 2pathology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com احلزاز املسطح يف راحة اليد وباطن القدم تشخيص جيب أخذه بعني اإلعتبار ريكاردو رويز-فيالفريدي، بياتريز رويدا فيالفرانكا، مارينا رويز غالفيز مورينو palmoplantar lichen planus a diagnosis to keep in mind *ricardo ruiz-villaverde,1 beatriz rueda-villafranca,2 marina ruiz galvez-moreno1 a 29-year-old caucasian female patient was referred to the dermatology outpatient clinic of hospital universitario san cecilio, granada, spain in 2018 with a pruriginous palmo plantar eruption over the previous five months that had not improved with the application of high-potency topical corticosteroids. she had no personal or family history of skin diseases. recently, she denied the use of any medications. dermatological examination revealed the presence of a well-defined diffuse erythema on the palm of the hands that spared the fingertips and bilateral violaceous polygonal papules on the dorsum aspect of the hands [figures 1a & b]. on the soles of her feet, well-defined erythematous patches sparing the plantar arch were observed [figure 1c]. no involvement of other skin areas or mucosa was noted. laboratory tests including complete blood count, general biochemistry, venereal research laboratory tests, hepatitis b and c and hiv serology showed normal results. in addition, an allergic contact dermatitis patch test was negative. histolopathologic examination of a lesion on the dorsum of the right hand revealed orthokeratotic hyper keratosis, irregular acanthosis, vacuolar degeneration of the basal layer and band-like lymphocytic infiltration on the papillary dermis [figure 2]. therefore, the patient was diagnosed with palmo plantar lichen planus (pplp). treatment with isotretinoin was proposed at a dose of 0.5 mg/kg/day with a sub stantial improvement three months later. at present, the patient remains asymptomatic with periodic consult ations. psoralen and ultraviolet a (puva) therapy for localised disease was refused by the patient for her inability to attend due to work-related reasons. comment pplp is an uncommon entity of low prevalence on the clinical spectrum of lichen planus with an incidence rate of 12.9–26%.1 this disease has a male predilection and the average age of onset of 38 years with a range of 9–72 years.2 the absence of the typical polygonal violaceous papules, which were found on the dorsal aspect of both hands of the current patient, is not unusual; on the palms, the fingertips are usually spared.3,4 in general, of localised lichen planus cases become generalised with sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e79–80, epub. 30 may 19 submitted 6 nov 18 revision req. 9 dec 18; revision recd. 11 dec 18 accepted 3 jan 19 figure 1: photographs of the hands and feet of a 29-year-old female patient showing well-defined diffuse erythema (arrows) on both (a) palms and (b) dorsum sparing the fingertips and (c) well-defined erythematous patches sparing the plantar arch on both soles. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.01.016 interesting medical image https://creativecommons.org/licenses/by-nd/4.0/ palmoplantar lichen planus a diagnosis to keep in mind e80 | squ medical journal, february 2019, volume 19, issue 1 the average time of evolution estimated to be between 1–4 months.5 five clinical types of pplp have been described, namely eczematous, lichenoid, punctate keratotic, ulcer ative and psoriasiform, which is the most frequent.1 there are isolated cases that have described the presence of vesicles, petechiae or umbilicated papules.4 histolo pathological studies are crucial to diagnose pplp. the pathological characteristics of pplp are shared with those of classic lichen planus. the thickness of the stratum lucidum of palms and soles has its clinical meaning in the absence of the characteristic wickham's striae.5 differ ential diagnosis should include psoriasis, hyperkeratotic eczema, diffuse keratoderma, keratosis punctata, lichen nitidus, granuloma annulare and secondary syphilis among others.4 a variable response to treatments, including reti noids, puva therapy, corticosteroids, methotrexate, cyclo sporine and enoxaparin sodium, has been reported.4–6 it is necessary to establish a therapeutic protocol that assesses the risks and benefits of each patient. references 1. sinha s, sarkar r, garg vk. palmoplantar lesions of lichen planus. indian j dermatol 2018; 63:57−61. https://doi.org/10.4103/ijd. ijd_161_17. 2. gutte r, khopkar u. predominant palmoplantar lichen planus: a diagnostic challenge. indian j dermatol 2014; 59:343−7. https://doi.org/10.4103/0019-5154.135477. 3. burillo-martínez s, tous-romero f, rodríguez-peralto jl, postigo-llorente c. palmoplantar lichen planus: the spectrum of clinical manifestations in a single patient. actas dermo sifiliogr 2017; 108:790−2. https://doi.org/10.1016/j.ad.2017.01.019. 4. solak b, kara ro, kosem m. palmoplantar lichen planus successfully treated with acitretin. bmj case rep 2015; 2015:bcr 2015211115. https://doi.org/10.1136/bcr-2015-211115. 5. kim mj, choi m, na sy, lee jh, cho s. two cases of palmo plantar lichen planus with various clinical features. j dermatol 2010; 37:985−9. https://doi.org/10.1111/j.1346-8138.2010.00936.x. 6. rieder e, hale cs, meehan sa, leger m. palmoplantar lichen planus. dermatol online j 2014; 20:13030/qt1vn9s55z. figure 2: haematoxylin and eosin stain at (a) x2 magnification showing orthokeratotic hyperkeratosis (arrowhead), irregular acanthosis and vacuolar degeneration of the basal layer (*) and at (b) x20 magnification showing the degeneration of the basal layer (arrow) and band-like lymphocytic infiltration on the papillary dermis. https://doi.org/10.4103/ijd.ijd_161_17 https://doi.org/10.4103/ijd.ijd_161_17 https://doi.org/10.4103/0019-5154.135477 https://doi.org/10.1016/j.ad.2017.01.019 https://doi.org/10.1136/bcr-2015-211115 https://doi.org/10.1111/j.1346-8138.2010.00936.x العدوى ذات الصلة بالقسطرة الوريدية يف املرضى ذوي احلاالت احلرجة central venous catheter-related infection in critically ill patients dear editor, we read with great interest recent studies about infections related to central venous catheter (cvc) and associated risk factors in critically ill postoperative patients evaluated in iran, oman and egypt.1–4 beigmohammadi evaluated 66 iranian patients who were in the intensive care unit (icu) following cancer surgery.1 he reported 23 simple cvcs without antimicrobials and 43 cvcs impregnated with antimicrobial agents—with 28 impregnated internally and 15 impregnated internally and externally.1 the jugular (51.5%) and subclavian (48.5%) veins were the sites for insertion of the catheters. cvc-related infection was confirmed by positive cultures of blood samples from the catheters. a total of 22.7% of cases had positive blood cultures and 9.1% had catheter-related bloodstream infections; therefore, there were 5.8 infections per 1,000 catheter-days for cvcs.1 there were no significant differences between simple and impregnated cvcs with respect to catheter tip colonisation, as well as in relation to the prevention of bloodstream infections.1 hamid et al. evaluated the early and late complications of 204 doublelumen cuffed tunnelled cvcs placed in 161 patients in a tertiary healthcare centre in oman.2 the jugular (90.6%) and femoral (9.4%) veins were the sites for insertion of the catheters and infections were detected in 29 catheters (22%) in 22 patients. staphylococcus aureus (55.2%), acinetobacter and pseudomonas (20.6% each) were the main infectious agents. a total of 18 (62.1%) cases had a haematogenous origin, four (13.8%) were exit site infections, and seven (24.1%) were both. most infected catheters had to be removed and few infections improved with antibiotics.2 khalil and azqul’s prospective study in egypt included 111 cardiac patients with cvcs. they found 11 (9.9%) cases of infection by the following agents: coagulase negative staphylococci, acinetobacter, alcaligenes faecalis, enterobacter and klebsiella. the compliance of health workers to cvc care recommendations played a role in the presence of infections.3 al-hadi and sallam discussed additional complications of fractured cvcs lodged in the heart or in the pulmonary artery that may cause thrombosis, perforation, endocarditis or sepsis.4 they reported three patients: 1) a 45-year-old male patient with chronic renal failure under haemodialysis with a fractured catheter lodged in the right pulmonary artery; 2) a 55-year-old female patient with chronic renal failure under haemodialysis and a fractured catheter lodged in the left pulmonary artery; and 3) a 62-year-old male patient who had acute myocardial infarction and heart failure one month prior to his admission and a broken catheter in the right atrium. however, the short time from the catheter rupture to its retrieval avoided the occurrence of infection.4 falcão pedrosa costa et al. reported a 40-year-old brazilian female patient who had endocarditis from burkholderia cepacia associated with an intra-cardiac fragment of a peripherally inserted central catheter utilised a long time prior during postpartum septic shock treated in an icu.5 although this infectious agent is not common in hospitalised patients, it may occur in immunocompromised individuals. the unsuspected foreign body, infected after immunosuppression for renal transplant, was incidentally found via routine investigation of infective foci in a renal transplant patient. the authors highlighted the importance of monitoring the heart for infections in haemodialytic patients and end-stage renal disease as well as the risks of blood infection by peripherally inserted cvcs utilised in the icu.5 fragments of cvcs may cause embolisms, arrhythmias or cardiac perforation.5 the articles discussed herein emphasised that critically ill patients with cancer and end-stage renal disease are immunocompromised and more prone to severe infections.1,2,5,6 the main risk factors include ageing, haemodialysis, chemotherapy and the type of fluid infusion.1,2,5 particular attention should be given to unspecific clinical manifestations and the growing number of gramnegative bacteria which often pose diagnostic challenges and may potentiate the mortality rate.1,3,5 acinetobacter, burkholderia, klebsiella and enterobacter are microorganisms frequently identified among these groups of patients and their resistance to antibiotics is elevated.1–3,5 the two main concerns of such infections are the increasing mortality rate, which is up to 35%, and increasing hospital costs.6 the infection routes begin at the tip and the sultan qaboos university med j, august 2019, vol. 19, iss. 1, pp. e267–268, epub. 5 nov 19 submitted 6 may 19 revision req. 17 jun 19; revision recd. 20 jun 19 accepted 7 jul 19 https://doi.org/10.18295/squmj.2019.19.03.017 letter to the editor this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ central venous catheter-related infection in critically ill patients e268 | squ medical journal, august 2019, volume 19, issue 3 internal lumen of the cvcs; therefore, routine prevention should involve better personnel training and more rigid procedures of sterilisation.1,3 frasca et al. summarised the following main measures to reduce colonisation at the skin insertion site or the infusion line: 1) accurately following the protocols; 2) involvement of qualified personnel in catheter changing and care; 3) use of biomaterials that inhibit microorganism growth and adhesion; 4) good hand hygiene; 5) use of an alcoholic formulation of chlorhexidine for skin disinfection and manipulation of the vascular line; 6) choice of the subclavian vein route for insertion of cvcs using full-barrier care; and 7) removal of unnecessary catheters.6 the duration of catheterisation and the frequent catheter hub access have a large impact on the risks of colonisation in catheter-related infections, with migration of agents along the lumen of the catheter.6 further research is needed to optimise the prevention and reduce the rate of cvc-related infections in immunocompromised hosts who are managed in an icu environment.1,2 this letter aimed to enhance the suspicion index of non-specialised healthcare workers about a scarcely reported entity which may evolve unsuspectedly and has a poor patient outcome. *vitorino m. dos santos1 and lister a. m. dos santos2 1department of internal medicine, armed forces hospital and catholic university, brasília, brazil, 2department of general and oncologic surgery, state workers hospital, são paulo, brazil *corresponding author’s e-mail: vitorinomodesto@gmail.com references 1. beigmohammadi mt. incidence of central venous catheter-related infection and risk factors in critically ill post-operative cancer patients: a randomized prospective cohort study. arch crit care med 2016; 1:e7732. https://doi.org/10.17795/accm-7732. 2. hamid rs, kakaria ak, khan sa, mohammed s, al-sukaiti r, al-riyami d, et al. safety and complications of double-lumen tunnelled cuffed central venous dialysis catheters: clinical and radiological perspective from a tertiary centre in oman. sultan qaboos univ med j 2015; 15:e501–6. https://doi.org/10.18295/squmj.2015.15.04.010. 3. khalil gm, azqul mm. risk factors and microbial profile of central venous catheter related blood stream infection in medical cardiac care units, national heart institute, egypt. egypt heart j 2018; 70:361–4. https://doi.org/10.1016/j.ehj.2018.07.001. 4. al-hadi h, sallam m. retrieval of dislodged central venous pressure catheters: early experience with three case presentations. sultan qaboos univ med j 2009; 9:175–9. 5. falcão pedrosa costa a, castelo branco cavalcanti f, modesto dos santos v. endocarditis due to burkholderia cepacia and an intracardiac foreign body in a renal transplant patient. rev port cardiol 2014; 33:117.e1–4. https://doi.org/10.1016/j.repc.2013.09.012. 6. frasca d, dahyot-fizelier c, mimoz o. prevention of central venous catheter-related infection in the intensive care unit. crit care 2010; 14:212. https://doi.org/10.1186/cc8853. https://doi.org/10.17795/accm-7732 https://doi.org/10.18295/squmj.2015.15.04.010 https://doi.org/10.1016/j.ehj.2018.07.001 https://doi.org/10.1016/j.repc.2013.09.012 https://doi.org/10.1186/cc8853 1armed forces medical college, pune, maharashtra; 2command hospital pune, maharashtra, india; 3sapthagiri institute of medical science and research centre, bengaluru, karnataka, india *corresponding author’s e-mail: rohitaggy@gmail.com magnetic resonance imagery findings in androgen insensitivity a case series indrani mukhopadhyay,1 *rohit aggarwal,2 deepti mutreja,1 sujit maheswari3 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 472–476, epub. 29 aug 21 submitted 10 jun 20 revision req. 20 aug 20; revision recd. 9 sep 20 accepted 14 oct 20 case one a 16-year-old female patient presented at command hospital, bangalore, india, in 2013 with primary amenorrhea. the patient’s clinical and usg findings can be found in table 1. tanner staging was used for thelarche and pubarche [table 2].6 magnetic resonance imaging of the pelvis revealed vagina measuring 5 cm in length and a gartner’s duct cyst was seen in the posterior vaginal wall [figure 1a]. bilateral testes were seen along the lateral pelvic walls, measuring 19 × 14 × 35 mm and 25 × 16 × 37 mm [anteroposterior (ap) × transverse (tr) × craniocaudal (cc)] on the right and left sides, respectively. there were multiple welldefined hypointense nodules on t2-weighted imaging (t2wi) seen within these structures, bilaterally suggestive of sertoli cell adenomas [figure 1b]. the uterus and cervix were not visualised. further, penile structure or phallus was not identified by the mri. a diagnosis of complete ais was given. the patient underwent laparoscopic gonadectomy and histopathology of specimen revealed stroma separating lobules of seminiferous tubules, consisting of only sertoli cells. no spermatogonia/spermatocytes were seen. the interstitium showed leydig cell hyperplasia. the hypointense nodules seen on mri corresponded to sertoli cell adenomas [figure 1c]. the pubertal stage is crucial for a female individual during which there is a sequential development of secondary sexual characteristics. aberrations in the phenotype during this stage need to be treated early so that the female individual is clinically and psychosocially able to lead a normal life. one such condition involving discordance between the genotype and phenotype in pubertal development is the androgen insensitivity syndrome (ais).1 ais is an inherited x-linked recessive disorder, first described by morris,1 in which there is an inability of the organs concerned to respond to androgens due to a lack or defect of the androgen receptor (ar). it is associated with müllerian regression and the presence of testes along its path of descent. in the complete form of this disorder, the individuals are genetically male but phenotypically and psychologically female.2 in such cases, early detection of the gonads and their removal is imperative to prevent the malignant transformation of gonads.3 ultrasonography (usg), being the primary modality for localisation of gonads, can miss the intraabdominal gonads. however, magnetic resonance imaging (mri) provides a comprehensive imaging for both localisation and characterisation of gonads.4,5 existing literature on the abovementioned roles of mri in these patients is limited. in this case series, three such cases of ais are presented, showcasing mri as a ‘one-stop shop’ for visualising the spectrum of ais and its possible complications. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.012 case series abstract: androgen insensitivity syndrome (ais) is a sex-development disorder resulting from mutations in the androgen receptor. in its complete form, patients are genetically male but phenotypically female, presenting with primary amenorrhea. we report three cases of ais highlighting the multifaceted role of magnetic resonance imaging (mri) for presurgical planning by evaluating location and type of gonads and detecting complications. all patients presented at the gynaecology out-patient department of command hospital, bangalore, india, between 2013–2016 with primary amenorrhea and mri accurately localised testes in all; one patient had bilateral inguinal testes; two had intraabdominal testes. intraabdominal testes were not localised on ultrasonography. mri also depicted sertoli cell adenomas and wolffian duct remnants. mri provides comprehensive imaging before surgical treatment and can, thus, be considered a ‘one-stop shop’ for ais imaging. all patients underwent laparoscopic gonadectomy which is the standard of care, with preoperative counselling about fertility. postoperatively, they were started on oestrogen therapy. keywords: amenorrhea; androgen insensitivity syndrome; magnetic resonance imaging; case report; india. https://creativecommons.org/licenses/by-nd/4.0/ indrani mukhopadhyay, rohit aggarwal, deepti mutreja and sujit maheswari case series | 473 case two a 15-year-old female patient presented at command hospital, bangalore, india, in 2016 with primary amenorrhea. the patient’s clinical and usg findings table 1: clinical details, hormonal levels and ultrasonography findings of three patients with androgen insensitivity syndrome presenting at gynaecology out patient department of command hospital, bangalore, india variable/ finding case i case ii case iii age (in years) 16 15 23 symptom primary amenorrhoea primary amenorrhoea primary amenorrhoea thelarche tanners iii tanners iii tanners v pubarche tanners ii tanners ii tanners iii labia welldeveloped illdeveloped welldeveloped* vagina blind, welldeveloped vagina blind, short vagina blind, short vagina male secondary sexual characters nil short phallus nil serum testosterone (ng/dl) (normal: 20–80 ng/dl)† 342 1044 654 serum lh (iu/l) (normal: 5–20 iu/l)‡ 24.7 18 22.09 serum fsh (iu/l) (normal: 5–20 iu/l)‡ 7.14 5.2 4.94 karyotyping 46,xy 46,xy 46,xy transabdominal ultrasonography absent uterus, gonads not located absent uterus, gonads in nguinal canal absent uterus, gonads not located *both labia and clitoris; †taylor et al.18; ‡ taylor et al19 figure 1: a: a multiplanar t2 weighted magnetic resonance image (sagittal view) showing absent uterus and presence of a vagina (star) and hyperintense gartner’s duct cyst (arrow); b: multiplanar t2 weighted magnetic resonance image (coronal view) showing bilateral testes (stars) with well-defined hypointense sertoli cell adenomas (right arrows); and c: haematoxylin and eosin histopathological stain of the intraabdominal testes at 100x magnification showing sertoli cell adenoma (star) of a 16-year-old female patient with primary amenorrhea. figure 3: t2-weighted magnetic resonance image showing axial views of the (a) bilateral testes (four point star) and (b) seminal vesicles (left arrow) and (c) a haematoxylin and eosin histopathological stain of abdominal testes at 400x magnification showing seminiferous tubules lined by sertoli cells (red arrows) with surrounding stroma showing leydig cell hyperplasia (white arrows) of a 23-year-old female patient with primary amenorrhea. figure 2: a: a multiplanar t2-weighted magnetic resonance image (coronal view) depicting bilateral inguinal testes with paratesticular cysts (left arrow) and corpora cavernosa (star); b: multiplanar t2-weighted magnetic resonance image (axial view) showing bilateral inguinal testes (arrows) and seminal vesicles (star); and c: haematoxylin and eosin histopathological stain at 400x magnification showing seminiferous tubules with thickened hyalinised walls (white arrow) lined with immature sertoli cells (red arrow) of a 15-year-old female patient with primary amenorrhea. table 2: tanner staging for thelarche and pubarche in patients with androgen insensitivity syndrome stage/ region breast pubic hair stage one elevation of papilla only no pubic hair stage two elevation of breast and papilla as small mound, increased areola diameter sparse, long, pigmented hair, primarily on labia majora stage three further enlargement without separation of breast and areola dark, coarse, curled hair sparsely distributed over mons stage four secondary mound of areola and papilla above the breast adult-type hair, abundant but limited to the mons stage five recession of areola to contour of the breast adult-type hair, extending onto the medial thigh magnetic resonance imagery findings in androgen insensitivity a case series 474 | squ medical journal, august 2021, volume 21, issue 3 can be found in table 1. tanner staging was used for thelarche and pubarche [table 2].6 mri imaging of the pelvis showed bilateral undescended small testes (measuring 2.5 cm on the right side and 2.3 cm on the left side) in the distal inguinal canal. no focal lesions were seen within the testes. there were paratesticular cysts seen bilaterally [figure 2a]. a small penile shaft with corpora cavernosa and bilateral seminal vesicles were also seen along with rudimentary vagina [figure 2b]. the uterus and bilateral ovaries were not visualised. these findings were suggestive of incomplete ais. the patient underwent laparoscopic bilateral inguinal gonadectomy and histopathology of the specimen revealed decreased size of seminiferous tubules with thickened tubular walls and foci of hyalinisation. there was loss of germ cells in the tubules with immature sertoli cells. moreover, there was leydig cell hyperplasia and no atypia or dysplasia was seen [figure 2c]. case three a 23-year-old female patient presented at command hospital, bangalore, india, in 2016 with primary amenorrhea. the patient’s clinical and usg findings can be found in table 1. tanner staging was used for thelarche and pubarche [table 2].6 the mri showed bilateral intraabdominal testes. on the right side, the gonad anterior to the external iliac vessels was seen near a deep inguinal ring measuring 9.3 × 16.4 × 29 mm (ap × tr × cc). on the left side, the gonad posterior to the external iliac vessels was seen measuring 19 × 9.8 × 23 mm (ap × tr × cc) [figure 3a]. bilateral seminal vesicles were observed [figure 3b]. the penile structure or phallus was not identified on mri. these mri findings were consistent with complete ais. the patient underwent laparoscopic gonadectomy and histopathology revealed semini ferous tubules lined by sertoli cells with 50% showing luminal formation and leydig cell hyperplasia. no spermatocytes or matured spermatids were seen [figure 3c]. it is to be noted that written consent has been obtained from all three patients for the use of their clinical and radiological data while maintaining strict confidentiality about patient identity. discussion morris coined the term ‘testicular feminisation syndrome’, now known as ais, in 1953 after his study on 82 patients.1 complete ais constitutes males with female phenotype who are raised as females. partial ais reflects a phenotype with varying degrees of masculinisation of the external genitalia due to variation in the levels of response to androgen.2 the incidence of ais has been variably reported and based on molecular proof of diagnosis, one study in denmark has reported it to be from one in 40,800 to one in 99,000.7 in complete ais, there is mutation of the ar gene located on the long arm of the x chromosome and it follows x-linked recessive inheritance.8 approximately 40% of the patients with ais may have no family history of mutations of the ar gene.9 the ar in ais is unresponsive to androgen action and androgens are converted into oestrogens with action of aromatase. this leads to development of female secondary sexual characteristics. the secretion of the müllerian-inhibiting substance (mis) by the testes results in the absence of the müllerian system and hence, the uterus and fallopian tubes are not developed.10 low prenatal androgenic effect in ais also results in inadequate testicular descent. the testes develop on the anteromedial surface of the mesonephros in the urogenital ridge and are anchored in position by the cranial suspensory ligament (csl) cranially and gubernaculum caudally during the transabdominal stage at 10–15 weeks.10 the descent of the testis in the groin is achieved by testicular enlargement and gubernacular swelling reaction.10 subsequently, csl regression occurs under the influence of androgens. both of these factors facilitate the migration of testes through the inguinal canal. the inguinoscrotal phase at 25–35 weeks’ gestation is androgen-dependent and consists of the passage of the testes from the internal inguinal ring down into the scrotum.10 testicular descent can get arrested at either of the two stages in ais. clinical presentation of incomplete ais can vary from phenotypic females with mild virilisation to under-virilised males presenting with ambiguous genitalia.11 these patients have variable development of the wolffian duct system. complete ais presents with female secondary sexual characteristics such as well-developed breasts, scanty pubic or axillary hair with shortened vagina and no evidence of male characteristics. incomplete ais patients may have normal breasts and sparse pubic and axillary hair, with some abnormal form of male external genitalia. in the above series, cases one and three showed no virilisation and a well-formed vagina, whereas case two showed partial virilisation with the phallus. instead of ovaries, all the three cases showed undescended testes. for genetic diagnosis of ais, karyotyping is usually the first step and it reveals a 46, xy state as was seen in all of the above cases. the most definitive indrani mukhopadhyay, rohit aggarwal, deepti mutreja and sujit maheswari case series | 475 way for diagnosis is to look for the ar gene mutation by molecular genetic tests; however, facilities for these tests are not readily available and hence not routinely done.11 hormonal assays in these patients reveal normal to mildly elevated serum gonadotropins with normal to high androgen levels.12 it must be noted that hormonal assays are non-specific as a diagnostic tool as far as ais is concerned. in the above series, mildly elevated male levels of serum testosterone and normal or mildly increased gonadotropins were detected [table 1]. imaging plays a vital role in locating and characterising the gonads.4 although ultrasonography (usg) is usually the first imaging ordered, operator/ equipment dependence, interference with bowel gas on transabdominal approach, requirement of transvaginal/transperineal approach and inherently smaller gonads in ais are some of the reasons for low gonadal detection rates on usg. these are better with mri, as it has better soft tissue contrast and multiplanar capability.4 exact localisation of gonads is valuable to decide the surgical approach. nakhal et al. have reported bilateral intraabdominal testes in 62% patients (n = 15) and at least one inguinal testes in 37% patients (n = 9).5 it must be noted that two of the cases reported in this article (case one and case three) had bilateral intraabdominal testes and case two had bilateral inguinal testes. the potential risk of malignancy in these gonads has been reported to be 0.8–30% in complete ais13,14 and up to 50% in partial ais.15 mri can detect heterogeneity of these gonads which may represent neoplastic changes. well-defined hypointense nodules on t2wi represent sertoli cell adenomas which occur in up to 83% of testes.5 detection of these on usg has not been reported in the literature till date. although sertoli cell adenomas are usually considered benign, nakhal et al. found one out of 10 patients to have premalignant intratubular germ cell neoplasm which could not be detected on mri.5 paratesticular cysts appearing homogenously hyperintense on t2wi have been reported in up to 96% of testes and case two also showed these cysts. mri also helps in ruling out other differential diagnosis of mayer-rokitansky-küster-hauser syndrome and müllerian duct anomalies wherein ovaries are. wolffian duct remnants including vas deferens and epididymis have been reported in the literature; however, presence of seminal vesicles, as seen in two of the above cases, has not been reported.15 the morphology of external genitalia including length of the vagina and thickness/length of the phallus are essential for gender-assignment surgical planning in partial ais.12 secaf et al. have defined objectively the criterion for diagnosing phallus/clitoral hypertrophy on mri.16 these measurements can be accurately recorded on mri. due to highly variable rates of malignancies in these patients, many patients prefer to retain their gonads till late adolescence or even adulthood.17 there is a felt need for monitoring these patients for in situ or invasive neoplasm. although micro-rna-based and single-nucleotide-polymorphism-based tests have shown some promise, their clinical use is still not in vogue.17 until a reliable screening tool is developed, mri may be used to detect neoplastic changes in these testes, although mri cannot detect in situ tumour.5,17 gonadectomy done at puberty may prevent occurrence of germ cell tumours in the abnormally placed gonads.3 laparoscopic gonadectomy was performed in all of the cases reported in as part of this article. the histological correlation of these gonads revealed maturation arrest without any dysplastic changes. the patients were extensively counselled preoperatively about their future fertility prospects and were started on oestrogen therapy. conclusion in ais, imaging should be done to evaluate the internal genitalia. usg continues to remain the primary modality for evaluation as it is inexpensive and easily accessible. however, usg can miss detection of these gonads. magnetic resonance imaging (mri) appears to be a ‘one stop shop’ for visualising the spectrum of ais including its possible complications. it plays a key role in decision-making for management by gonadectomy or gender-assignment surgery. finally, mri may be used as a screening tool for detection of neoplastic changes in patients of ais who retain their gonads into late adolescence or adulthood, although it cannot detect in situ neoplasm. a u t h o r s’ c o n t r i b u t i o n im contributed to the conception and design of the report. ra and sm were involved in acquisition of the data. ra and dm contributed to the analysis and interpretation of the data. im and sm drafted the initial version of the manuscript. im and ra revised the manuscript. all authors approved the final version of the manuscript. references 1. morris jm. the syndrome of testicular feminization in male pseudohermaphrodites. am j obst gynec 1953; 65:1192–211. https://doi.org/10.1016/0002-9378(53)90359-7. https://doi.org/10.1016/0002-9378(53)90359-7 magnetic resonance imagery findings in androgen insensitivity a case series 476 | squ medical journal, august 2021, volume 21, issue 3 2. hughes ia, davies jd, bunch ti, pasterski v, mastroyanno poulou k, dougall jm. androgen insensitivity syndrome. lancet 2012; 380:1419–28. https://doi.org/10.1016/s0140-6736(12)60071-3. 3. döhnert u, wünsch l, hiort o. gonadectomy in complete androgen insensitivity syndrome: why and when? sex dev 2017; 11:171–4. https://doi.org/10.1159/000478082. 4. khan s, craig lb. a review of radiologic imaging in patients with androgen insensitivity. j genit syst disor 2013; s1. https:// doi.org/10.4172/2325-9728.s1-003. 5. nakhal rs, craggs mh, freeman a, kirkham a, conway gs, arora r, et al. evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. radiology 2013; 268:153–60. https://doi.org/10.1148/radiol.13 121068. 6. taylor hs, pal l, seli e. normal and abnormal growth and pubertal development. in: speroff ’s clinical gynecologic endocrinology and infertility, 9th ed. philadelphia: wolters kluwer, 2020. pp. 321. 7. boehmer alm, brinkmann o, bruggenwirth h, assendelft cv, otten bj, verleun-mooijman mc, et al. genotype versus pheno type in families with androgen insensitivity syndrome. j clin endocrinol metab 2001; 86:4151–60. https://doi.org/10.1210/ jcem.86.9.7825. 8. chauhan p, rani a, singh sk, rai ak. complete androgen insensitivity syndrome due to mutations in the dna-binding domain of the human androgen receptor gene. sex dev 2018; 12:269–74. https://doi.org/10.1159/000492261. 9. touzon ms, garrido np, marino r, ramirez p, costanzo m, guercio g, et al. androgen insensitivity syndrome: clinical phenotype and molecular analysis in a single tertiary center cohort. j clin res pediatr endocrinol 2019; 11:24–33. https:// doi.org/10.4274/jcrpe.galenos.2018.2018.0185. 10. hutson jm, southwell br, li r, lie g, ismail k, harisis g, et al. the regulation of testicular descent and the effects of cryptorchidism. endocr rev 2013 oct; 34:725–52. https://doi. org/10.1210/er.2012-1089. 11. raza j, zaidi sz, warne gl. management of disorders of sex development with a focus on development of the child and adolescent through the pubertal years. best prac res clin endocrinol metab 2019; 33:1–14. https://doi.org/10.1016/j. beem.2019.101297. 12. lee pa, nordenström a, houk cp, ahmed sf, auchus r, baratz a, et al. global disorders of sex development update since 2006: perceptions, approach and care. horm res paediatr 2016; 85:158–80. https://doi.org/10.1159/000442975. 13. cools m, drop sl, wolffenbuttel kp, oosterhuis jw, looijenga lh. germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. endocr rev 2006; 27:468–84. https://doi. org/10.1210/er.2006-0005. 14. huang h, wang c, tian q. gonadal tumour risk in 292 phenotypic female patients with disorders of sex development containing y chromosome or y-derived sequence. clin endocrinol (oxf ) 2017; 86:621–7. https://doi.org/10.1111/cen.13255. 15. kathrins m, kolon tf. malignancy in disorders of sex development. transl androl urol 2016; 5:794–98. https://doi. org/10.21037/tau.2016.08.09. 16. secaf e, hricak h, gooding ca, ho vw, gorczyca dp, ringertz h, et al. role of mri in the evaluation of ambiguous genitalia. pediatr radiol 1994; 24:231–5. https://doi.org/10.1007/bf02015441. 17. cools m, looijenga l. update on the pathophysiology and risk factors for the development of malignant testicular germ cell tumors in complete androgen insensitivity syndrome. sex dev 2017; 11:175–81. https://doi.org/10.1159/000477921. 18. taylor hs, pal l, seli e. hirsuitism. in: speroff ’s clinical gynecologic endocrinology and infertility, 9th ed. philadelphia: wolters kluwer, 2020. p. 452. 19. taylor hs, pal l, seli e. amenorrhea. in: speroff ’s clinical gynecologic endocrinology and infertility, 9th ed. philadelphia: wolters kluwer, 2020. p. 349. https://doi.org/10.1016/s0140-6736(12)60071-3 https://doi.org/10.1159/000478082 https://doi.org/10.4172/2325-9728.s1-003 https://doi.org/10.4172/2325-9728.s1-003 https://doi.org/10.1148/radiol.13121068 https://doi.org/10.1148/radiol.13121068 https://doi.org/10.1210/jcem.86.9.7825 https://doi.org/10.1210/jcem.86.9.7825 https://doi.org/10.1159/000492261 https://doi.org/10.4274/jcrpe.galenos.2018.2018.0185 https://doi.org/10.4274/jcrpe.galenos.2018.2018.0185 https://doi.org/10.1210/er.2012-1089 https://doi.org/10.1210/er.2012-1089 https://doi.org/10.1016/j.beem.2019.101297 https://doi.org/10.1016/j.beem.2019.101297 https://doi.org/10.1159/000442975 https://doi.org/10.1210/er.2006-0005 https://doi.org/10.1210/er.2006-0005 https://doi.org/10.1111/cen.13255 https://doi.org/10.21037/tau.2016.08.09 https://doi.org/10.21037/tau.2016.08.09 https://doi.org/10.1007/bf02015441 https://doi.org/10.1159/000477921 squ med j, may 2011, vol. 11, iss. 2, pp. 201-206, epub. 15th may 11 submitted 9th aug 10 revision req. 27th sept 10, revision recd. 5th feb 11 accepted 1st mar health care professionals are dedicated individuals who require minimal direction and supervision to perform their duties. they are professionals in that they are bound to their code of ethics and their fiduciary responsibility to perform well and render quality services to their clients. it is believed that health care providers are the type of professionals that embody such beliefs and behaviour. these professionals are seldom found committing intentional mistakes or causing harm to their clients or their environment, but errors do occur in health care and “unacceptable” behaviour occasionally happens as well. for this reason, one has to question these practices and wonder why such highly regarded individuals who are extremely dedicated to their profession, clients and profession still commit errors. some of these individuals also raise such questions as “what’s in it for me?” to do this or that and have been increasingly asking, “why do i need to continue to work hard?” especially if there is no system of appreciation. one cause of the problem could be that there is a system that punishes errors, but no system to reward productivity. pay-for-performance one of the performance incentives models being used in the usa is pay-for-performance (p4p). this is a model that was initiated to improve measures of quality and efficiency, and eliminate excessive cost. it provides a financial incentive that allows payers and providers to link economic incentives and operational quality outcomes. the underlying assumption is that p4p will improve, motivate, and enhance providers to pursue aggressively and college of public health, university of oklahoma health sciences center, oklahoma city, ok 73104, usa. *corresponding author email: ala@ou.edu; asaad.abduljawad@gmail.com íví÷]ê<9�÷]<ÿ^.]<ª<ÿñ _<]å˘<<ïàà-]<ÿ⁄]á√÷]         :  abstract: incentives for better performance in health care have several modes and methods. they are designed to motivate and encourage people to perform well and improve their outcomes. they may include monetary or non-monetary incentives and may be applied to consumers, individual providers or institutions. one such model is the pay-for-performance system. in this system, beneficiaries are compared with one another based on a set of performance indicators and those that achieve a high level of performance are rewarded financially. this system is meant to recognise and primarily to reward high performers. its goal is to encourage beneficiaries to strive for better performance. this system has been applied in several countries and for several recipients and settings. early indications show that this system has had mixed effects on performance. keywords: pay for performance; pi; healthcare quality; incentives; health care; rewards and recognition; professional performance; tqm sounding board incentives for better performance in health care *asaad abduljawad and assaf f. al-assaf 202 | squ medical journal, may 2011, volume 11, issue 2 incentives for better performance in health care ultimately achieve the quality performance targets thus decreasing the number of medical errors with less malpractice events.1 in 2005, 75% of american companies and employers paid part of their employees’ salaries by a p4p method.2 payment systems have been known traditionally to reward and pay health care providers for the quantity of their services rather than their quality. on the other hand, health care providers were still able to increase their incomes by providing quality service, but only as part of a payment for performance incentives system. in 2004, the uk’s national health service (nhs) began a system of p4p, where 8,000 general practitioners and family physicians agreed to increases in their incomes based on 146 quality indicators. a study showed that british health care providers have increased their average income by $40,000 by adhering to the p4p system.3 therefore, incentives in any form combined with other methods to improve performance may prove successful to change provider behaviour. rewarding employees is becoming the norm in most successful organisations in the usa and worldwide. a recognised employee is a loyal employee and a loyal employee is a dedicated employee. a dedicated employee will perform at a higher level, but when dedication is not recognised it causes employees to lose their enthusiasm. those unrecognised employees will gradually lose morale as well as their desire to work for improvement and innovation. it behoves an organization to recognise its employees often and continuously. however, recognition without sincerity may not have the same effect and in some cases, may even backfire. for example, saying thank you to employees who help a facility provide quality service can go a long way when facility managers are sincere. it is believed that a happy employee is one who innovates and competes with others to be the best. dedicated employees impact their organisations positively. on the other hand, a struggling organisation generally has a minimum number of dedicated employees. dedication is critical for sustainability and continuous success. without dedicated employees, organisations will not do well. having a rewards and recognition programme in place lets valued employees know that their contributions are important and their efforts are appreciated. not only will the employees appreciate it, but clients may appreciate it as well. when employees are happy and satisfied with their work, their attitude will be reflected in the services they provide. when managers “go the extra mile” to keep the employees happy and treat team members well, employees will often go the extra mile to ensure clients are happy. treating people well is reflective of how employees expect others to treat them. again with p4p, physician reimbursements will be partly dependent on patient outcomes, and it is widely assumed that a doctor can only do so much. in a study reported in the new england journal of medicine in 2003, patients only received 55% of the care they were supposed to get regardless of whether it was preventive, acute or chronic care.4 p4p is intended improve this situation. another study found that hospitals participating in a p4p programme had modestly superior outcome measures compared to those who did not participate in such incentive programmes.5 although monetary rewards are important, recognition is even more important for professionals. high performing employees expect to be recognised, but do not necessarily expect to be rewarded. sometimes a small token of appreciation may go a long way towards motivating dedicated employees. in fact, recognising employees (sincerely, often and on a timely basis) will improve retention and have a major and positive impact on attracting new staff. employees want to be appreciated, valued and recognised and not all are motivated by money alone.6 nelson suggests that, “the best praise is done soon, specifically, sincerely, personally, positively, and proactively.”7 when employees feel valued, they are more satisfied and happier at work, and in turn will provide better service to patients. putting an employee rewards and recognition programme in place does not have to be difficult or costly. there are many ways to show the team that their efforts are appreciated, not only for large accomplishments, but also for the smaller daily ones. incentives of all forms have two main goals: 1) to motivate the employee to perform or continue to perform better and 2) to have a long lasting effect on their performance. motivations coming from any type of incentive should spur the recipients to meet these two goals by sparking an interest and a change in behaviour in the recipient and having a lasting effect on that individual’s desire to perform better. to achieve this, most researchers and experienced sounding board | 203 asaad abduljawad and assaf f. al-assaf organisations try to customise rewards based on employees’ preferences and expectations. rewards may have different effects on different individuals depending on their education, culture and status in the organisation. therefore trying different rewards and motivational methods may be necessary to engage employees more and to stimulate them to improve their performance. on the other hand, w. edwards deming, a leading quality management scholar and consultant, taught and demonstrated that motivation efforts are a form of tampering because they try to make improvements to individual components of what is largely a common cause (or routine system) variation. he argued that the overall performance of a unit was much more a function of the quality of materials, process design and management, quality specifications and machine performance—in other words, the “system.” deming went on to demonstrate that the result of an improvement strategy based on trying to lift the performance of each worker one-at-a-time would not be system improvement; rather, it would simply be an increased variation in performance. he encouraged management to find ways to lift the performance of the whole system.8,9 putting together an incentive programme is, nonetheless, a great step toward improving employee morale and encouraging productivity. if employees are happy and motivated, it follows that clients will be happier and will reap the benefits as well. saying thank you to everyone for a job well done is important. incentives can be either monetary or nonmonetary. monetary incentives include: p4p, cash, non-cash gift cards, certificates, merchandise, travel and experiential rewards. these and other such incentives have a varying impact on performance and behaviour.10 examples of nonmonetary incentives include: payroll or premium contributions, flexible work hours, health savings or reimbursement accounts, training, or even paid sabbaticals. also, plaques, thank you letters, recognition certificates, stickers, and t-shirts with a logo are used. other no-cost or low-cost awards include:11 presentation of a certificate of appreciation for a job well done at a staff meeting; nomination of department employee of the month; allowing employees to take classes and improve skills; sending a handwritten note of thanks for the completion of a challenging task; sending flowers to an employee’s family thanking them for sharing their loved one with the organisation during the preparation of an important project; making time to stop and chat with your employees; bringing treats for the office; encouraging participation in organisation’s activities; sending an employee to a conference, and development of a flexible work schedule.12 payment-for-performance for health care providers p4p programmes are designed to measure employees’ performance accurately while aligning pay such that it rises and falls in accordance with variations in performance. the use of p4p comes from a simple desire to motivate employees towards more constructive behaviour.13 p4p is an emerging movement in health insurance (initially in britain and usa). providers (and in some instances consumers) under this arrangement are rewarded for meeting pre-established targets for delivery of (or increased use) of health care services. this is a fundamental change from the fee for service payment system. the p4p or “value-based purchasing,” model rewards physicians, hospitals, medical groups, and other health care providers for meeting certain performance measures for quality and efficiency. disincentives, such as eliminating payments for negative consequences of care (medical errors) or increased costs, have also been proposed. in developed nations, the rapidly ageing population and rising health care costs have recently brought p4p to the forefront of health policy discussions. pilot studies underway in several large health care systems have shown modest improvements in specific outcomes and increased efficiency, but no cost savings because of the added administrative requirements. statements by professional medical societies generally support incentive programmes to increase the quality of health care, but express concern with the validity of quality indicators, patient and physician autonomy and privacy, and increased administrative burdens.14 in the united states, the centers for medicare and medicaid services (cms), in an attempt to reform payment to providers for services rendered, designed and implemented a basic p4p system; one for hospitals and one for doctors’ offices. 204 | squ medical journal, may 2011, volume 11, issue 2 incentives for better performance in health care based on the commonest and most effective and evidence-based clinical practice guidelines of high volume medical conditions, cms designed and implemented a programme to reward high performers. for hospitals, cms identified some 20 plus process and outcome indicators related to three medical conditions: congestive heart failure, acute myocardial infarction and community acquired pneumonia. hospitals were asked to volunteer in the programme by submitting their performance against those indicators to be ranked with other hospitals in the national database of these indicators. the high performing hospitals in the top 4% would receive a bonus on top of their reimbursements for maintaining a high level of performance. a similar system was designed for physician offices, but this one was based on medical conditions most frequently seen in an outpatient setting namely, diabetes, asthma, hypertension, back ache, etc. again a number of indicators were identified and those doctor’s offices who volunteered to submit their measurements of performance against those indicators were entered in the national database and ranked against the performance of their peers. high performers will be rewarded with an annual bonus as a percentage of their reimbursement amount. the cms programmme is in its early stages and has already experienced some challenges related to design, communication and impact on performance. common design challenges include: difficulties in measuring performance; setting payouts at the correct level; managing factors outside the control of individuals being paid for performance; discomfort that managers and peers have with rating employees differentially; limited funding for payouts; resistance to adjusting payout levels as technology or market conditions change; avoiding perceptions of unfairness, and quality of implementation.15 communication challenges stem from the difficulties about how the programme works and what is required to achieve rewards. additionally, there is little evidence so far that there is a marked impact on performance in general of those enrolled in the programme compared to those who are not. in fact, providers (hospitals and physicians) can easily manipulate the system by concentrating their performance improvement interventions on the specific indicators which will make their “focused” performance look good, but ignoring other indicators or medical conditions not included in the programme. in addition, the cost of designing, maintaining and evaluating the system is another burden that needs attention and perhaps a re-design. pay-for-performance for health care clients yet the p4p system has led to marked improvement in outcomes in several other locations and projects. the bolse familia, a results-based financing for health project in brazil, provides small monetary incentives for poor and very poor families on condition that they use certain health care services. several health indicators showed marked improvements in these families: 1) decrease in income inequity and poverty levels by 81%; 2) decrease in child mortality, and 3) improvements in maternal health.16 monetary incentives for consumers have been introduced not just in brazil, but in a number of countries world-wide. the common factor between these projects was improving performance or enhancing behavioural change through incentives (primarily monetary). these practices showed a positive impact on health care outcomes and health indices. it was noticed that even small monetary incentives in certain populations (low or very low income families) had a positive impact on the health indices of these families’ mothers and children. according to the center for global development, these projects were so successful that the number of families wishing to participate increased dramatically from the first year of these programmes.17 as part of the millennium development goals, in a project in 2006, conditional cash transfer (family stipends) was provided (us $26–55 per month/family) to more than 11 million families (or 46 million individuals) in latin america.18 once again, marked and tangible improvements were recorded in child health related to weight, vaccinations, school attendance, and nutrition. similar results were noted in other conditional cash transfers projects in such countries as guatemala and nicaragua (combining demand and supply side incentives), haiti (performance incentives model), afghanistan, (paying ngos for performance in post-conflict settings), rwanda (performance sounding board | 205 asaad abduljawad and assaf f. al-assaf based financing in the public sector) and several latin american countries and world-wide to offer incentives for tb diagnosis and treatment.19–21 two models were implemented in these projects: one targeted primarily to providers to increase the demand for health care services and another targeted at consumers to increase their use of health care and related services. in the all projects, workers reported that to ensure success of these projects the following characteristics should be present: 1) designed in collaborative manner; 2) development of realistic goals; 3) development of indicators that are smart (specific, measurable, achievable, realistic, and timely); 4) tailoring of incentives (types and amounts) according to the target population; 5) putting in place a system to monitor and validate performance, and 6) development and execution of contracts. pay-for-performance outside the health sector outside the health sector, national and international companies have been using performance based incentives for their employees for a long time. for example, conoco-philips has long offered what they call a viable cash incentives programs (vcip) to their employees based on the performance of the organisation, i.e. a share in the business success.22 employees are rewarded for advancing company objectives and are accountable to their performance outcomes. other practices elsewhere include the rewarding of employees in terms of monetary incentives or discounts for their participation in health enhancing programmes (exercise, dieting, smoking cessation, alcohol and drug abuse awareness programmes etc.) insurance companies on the other hand also use monetary incentives to encourage their consumers to live and practice a healthy life style.23,24 conclusion an incentive programme represents a substantial investment for most organisations. receiving a sufficient return on that investment requires the full participation of the programme participants. incentive programmes are based upon the concept that effort increases as people perceive themselves progressing towards their goal. therefore programmes should offer participants a variety of products and services based on their unique interests and diverse needs. successful programmes need to develop their reward methods carefully to keep participants eager to approach a new goal once they have achieved a reward.25 there is often a poor level of incentives given to providers. unless incentives are worthwhile, providers may not be interested or encouraged to participate. incentives have to be based on a sound system of performance measurements that is both comprehensive and valid. measures have to be reliable, valid and clear while comparisons between provider performances based on these measures should be risk adjusted and unbiased. these conditions are almost impossible to achieve in the current system of performance.26,27 p4p and similar incentives programmes are a major improvement in the right direction. providers must be accountable. performance must be measured and levels must be ranked and compared with one another. basing reimbursements of providers on quantity should be changed and payment based on performance should be encouraged.28 workers in general (even the most dedicated) thrive on constant encouragement, effective rewards and suitable recognition. rewards tend to motivate people to do more and to do it better or continue to do it better. without rewards, workers tend to lose interest in excelling and innovating. if not properly recognised, they will lose their enthusiasm for perfection and that will in turn diminish their morale and happiness. it is documented that unhappy employees are less productive, but worse still they will negatively affect the satisfaction of their clients. there are many types of incentive programmes and a variety of options within each type. not all incentives are applicable to all organisations and not all successful programmes will be successful in all organisations. for these programmes to be effective they must be customised, well-focused and suitable to the organisation’s culture and setting. references 1. adsit d, chingos p. paying for performance: a guide to compensation management, 2nd ed. hoboken, nj: wiley & co., 2003. p. 416. 2. rosenthal m, frank r, li z, epstein a. early 206 | squ medical journal, may 2011, volume 11, issue 2 incentives for better performance in health care experience with pay-for-performance: from concept to practice. jama 2005; 294:1788–93. 3. doran t, fullwood c, gravelle h, reeves d, kontopantelis, hiroeh e, roland m. pay-forperformance programs in family practices in the united kingdom. new engl j med 2006; 355:375–84. 4. mcglynn e, asch sm, adams j, nelson de, bland s, powell-griner e, et al. the quality of health care delivered to adults in the united states. new engl j med 2003; 348:2635–45. 5. lindenauer pk, remus d, roman s, roothberg mb, benjamin em, ma a, et al. public reporting and pay for performance in hospital quality improvement. new engl j med 2007; 356:486–96. 6. al-assaf a, akgun s. practical guide on healthcare quality. 2nd ed. ankara: ena group, 2009. 7. nelson b. 1001 ways to reward employees: 100s of new ways to praise! 2nd ed. new york: workman publishing company, 2005. 8. coombs a. a caution on reward programs, in queue (2008). from: http://www.nationalcallcenters. org accessed: may 2010. 9. adsit d. the futility of call center coaching. from: http://www.isixsigma.com/library accessed: may 2010. 10. hrh global resources center from: http://www. hrhresourcecenter.org/ accessed: may 2010. 11. cal tech. rewarding and recognizing employees. from: www.caltech.edu accessed: may 2010. 12. beith, a, eicher r, weil d. do performance-based incentives improve tb detection and treatment completion? from: http://www.cgdev.org. http:// w w w. c g d e v. o rg / fi l e s / 1 3 5 4 4 _ fi l e _ t b _ fi n a l . p d f accessed: march 2011. 13. cannon, m. pay-for-performance pay: new developments and issues. peabody college of vanderbilt university, 2009. from: www. performanceincentives.org accessed: may 2010. 14. performance based incentives network project. from: http://www.cgdev.org/section/initiatives/_active/ ghprn/workinggroups/performance accessed: may 2010. 15. rosenthal mb, dudley ra. pay-for-performance: will the latest payment trend improve care? jama 2007; 292:740–4. 16. lindert k. brazil: bolsa familia program: scalingup cash transfers for the poor. mfdr principles in action: sourcebook on emerging good practices. washington dc: world bank, 2005. 17. eichler r. can "pay for performance" increase utilization by the poor and improve the quality of health services? washington dc: center for global development, 2009. 18 world bank project appraisal document: brazil bolsa familia project. report no. 28544-br washington dc: world bank, may 25, 2004. 19. glassman a, todd j, gaarder m. demand-side incentives for better health for the poor: conditional cash transfer programs in latin american and the caribbean, 2008. from: http://www.cgdev.org/ content/publications accessed: may 2010. 20. eichler r, auxila p, antoine u, desmangles b. going to scale with performance-based payment: six years of results in haiti, 2009. from: www.cgdev.org/ content/publications accessed: may 2010. 21. beith a, eicher r, weil d. do performance-based incentives improve tb detection and treatment completion? from: http://www.cgdev.org accessed: may 2010. 22. results based financing in health, 2010. from: http://www.rbfhealth.org/rbfhealth accessed: may 2010. 23. lester h, schmittdiel j, selby j, fireman b, campbell s, lee j, et al. impact of removing financial incentives from clinical quality indicators. bmj 2010; 340:1898. 24. regalia f, castro l. demand-and supply-side incentives in the nicaraguan red de protección social, 2008. from: http://www.cgdev.org/content/ publications accessed: may 2010. 25. willis-shattuck m, bidwell p, thomas s,wyness l, blaauw d, ditlopo p. motivation and retention of health professionals in developing countries: a systematic review. bmc health serv res 2008; 8:247. 26. locke r, srinivasan m. attitudes toward payfor-performance initiatives among primary care osteopathic physicians in small group practices”. j am osteopath assoc 2008; 108:21–24. 27. casalino l, alexander c, jin l, konetzka rt. general internists’ views on pay-for-performance and public reporting of quality scores: a national survey. health affairs 2007; 26:492–9. 28. rosenthal mb, dudley r a. pay-for-performance: will the latest payment trend improve care? j am med assoc 2007; 292:740–4. a 22 year-old man from south india presented with migraine with aura and depression. neurologically, he demonstrated cognitive impairment, pseudobulbar affect and bilateral pyramidal signs. the magnetic resonance imaging (mri) scan of his brain [figure 1] showed increased flair and t2 signals in the bilateral anterior temporal and frontal white matter, basal ganglia and external capsule. the clinical features and the mri finding of bilateral white matter lesions in the anterior temporal pole and external capsule, in the absence of hypertension and optic nerve and spinal cord lesions, were diagnostic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil).1-3 squ med j, may 2011, vol. 11, iss. 2, pp. 284-285, epub. 15th may 11 submitted 3rd jul 10 accepted 21st sept 10 department of medicine, sultan qaboos university hospital, muscat, oman; former affiliation: department of neurology, sri venkateswara institute of medical sciences, tirupati, andhra pradesh, india. *correspondning author email: rnandagopal@yahoo.com <l]^éju]<ƒ⁄<ïçò^ä÷]<ìëçä¢]<ìè«fí÷]<ìè∆^⁄ç÷]<∞ë]üé÷]<ÿ¯j¬] <^ñèf÷]<ìœ�flπ]ê<ïüéœ÷]<ÿ¯j¬]ê<ïüéœ÷]<k†  cadasil cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ramachandiran nandhagopal interesting medical image figure 1: magnetic resonance imaging (mri) scan of brain demonstrating increased signal in a) flair image of the white matter in the anterior temporal region, b) frontal region, and c) t2 weighted image of the external capsule and basal ganglia. ramachandiran nandhagopal interesting medical image | 285 cadasil is a rare inherited neurological disorder that clinically manifests with migraine with aura, depression, stroke-like episodes before the age of 60 years, cognitive impairment and behavioral disturbances.1-4 the characteristic lesions, which can be seen on an mri scan, involve white matter of temporal pole and external capsule1-3 and the lesion load is often highest in the frontal white matter.1-3 although a positive family history might provide diagnostic support, it is not required in making the diagnosis.4 cadasil is associated with notch 3 gene mutation and de novo mutation accounts for the sporadic cases;4 however, genetic analysis was not available in our centre in india where the patient was seen. brain mri scanning aids in the diagnosis of cadasil in young subjects with a phenotypic manifestation of migraine with aura, depression, stroke and cognitive disturbance, but lacking conventional vascular risk factors such as hypertension, diabetes mellitus, hyperlipidaemia, obesity, smoking and alcohol consumption. the characteristic lesion distribution differentiates these cases from acquired white matter conditions such as multiple sclerosis. references 1. dichgans m, filippi m, bruning r, iannucci g, berchtenbreiter c, minicucci l, et al. quantitative mri in cadasil: correlation with disability and cognitive performance. neurology 1999; 52:1361-7. 2. opherk c, peters n, herzog j, luedtke r, dichgans m. long-term prognosis and causes of death in cadasil: a retrospective study in 411 patients. brain 2004; 127:2533-9. 3. o’sullivan m, jarosz jm, martin rj, deasy n, powell jf, markus hs. mri hyperintensities of the temporal lobe and external capsule in patients with cadasil. neurology 2001; 56:628-34. 4. joutel a, dodick dd, parisi je, cecillon m, tournierlasserve e, bousser mg. de novo mutation in the notch3 gene causing cadasil. ann neurol 2000; 47:388-91. re: maxillary artery pseudoaneurysm as a complication of maxillofacial injuries report of three cases and literature review sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e401–403, epub. 21 dec 20 submitted 19 may 20 accepted 16 aug 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.022 letter to the editor رد: متدد كاذب للشراين الفكي العلوي كإحدى مضاعفات إصاابت الوجه والفكني تقرير ثالث حاالت مع مراجعة أدبية dear editor, we read with interest the case report by al saadi et al. published in november 2019 issue of squmj and would like to commend the authors for their efforts in highlighting three examples of maxillary artery pseudoaneurysm.1 as indicated in their article it is a rare but devastating complication that could occur from maxillofacial trauma or its management. however, there were some points that we would like to discuss when attempting to understand the relationship between maxillofacial trauma and pseudoaneurysms of the vascular supply in the head and neck. there is usually a dilemma of what actually causes the pseudoaneurysm in the first place in the setting of maxillofacial trauma that undergoes a surgical intervention. is it the initial injury or the surgery? it is difficult to definitively delineate the exact cause without pre-operative vascular imaging assessment such as a computed tomography-angiogram (cta) or a conventional angiogram. in other words, in order to assume that the initial injury caused the pseudoaneurysm rather than manipulation during surgery, a detailed pre-operative vascular assessment is required. in the cases presented in the article, there is no evidence of pre-operative imaging provided for any of the cases and therefore pre-existing vascular injury cannot be excluded. therefore, one cannot assume that the subsequent development of pseudoaneurysm is secondary to the initial injury. it could also be iatrogenic and caused by surgical manipulation or at least masked by the surgery itself. surgical manipulation during maxillofacial trauma management could cause vascular injury by impacting sharp bony edges or excessive traction of already traumatised vessels. therefore, surgical intervention is a known and reported cause of vascular injury in maxillofacial trauma.2,3 some might argue that case two had evidence of mature arterio-venous fistula (avf) during their digital subtraction angiography assessment which accounts for the chronicity of the pseudoaneurysm and therefore likely formed from the time of injury. however, acute arteriovenous fistulas has been reported in the literature and could be caused by surgical manipulation that usually leads to vessel trauma and haemorrhage.4–6 the question remains whether it even matters what caused the pseudoaneurysm, whether it is the initial trauma or the surgical trauma. we would argue that it is critical to be specific about the cause of rare but potentially devastating complications. understanding the root cause could lead to improvement in surgical techniques in order to design safe approaches. for example, investigating high risk cases with vascular imaging prior to operative management would guide surgical management and potentially avoid devastating complications. in the case of subacute bilateral displaced condylar fractures, cta is arguably indicated. if a pseudoaneurysm is detected, then neoadjuvant endovascular intervention to address the pseudoaneurysm is warranted prior to embarking on a surgical intervention; this may avert a potential complication. furthermore, it is important to highlight any rare but potentially devastating complications during the consent discussion with the patient particularly in high risk situations where surgical manipulation could traumatise an otherwise asymptomatic pseudoaneurysm. moreover, for the legal protection of healthcare providers, the severity of the injury and its associated complications should be delineated to avoid litigation arising from a complication that occurs from the trauma rather than the surgery. the article would have been strongly supplemented if the authors had provided some pre-operative vascular assessment. while we appreciate that not all cases might have pre-operative vascular assessment, the fact that case two had a previous avf and embolisation procedure suggests that a pre-surgical vascular imaging could have been done and possibly the maxillary pseudoaneurysm would have been identified and managed appropriately with endovascular intervention. https://creativecommons.org/licenses/by-nd/4.0/ re: maxillary artery pseudoaneurysm as a complication of maxillofacial injuries report of three cases and literature review e402 | squ medical journal, november 2020, volume 20, issue 4 we advocate for vascular imaging to be considered as an initial step if there is high clinical suspension for possible vascular injury based on mechanism of trauma or other identified injuries such as basal skull and cranial fractures, high condylar, midfacial, pan facial fractures and associated vascular injuries.2,7 we do recognise that this approach might not be practical in cases of acute life threatening haemorrhage, however, most facial and cranial fractures can be treated sub-acutely once life-threatening issues have been adequately addressed. therefore, preoperative vascular imaging in the form of a cta is appropriately indicated in all patients with severe blunt facial and neck trauma. there is growing literature in the field of trauma that indicates that blunt neck and facial trauma is associated with high rate of vascular injuries such as vertebral artery dissection and cta are indicated.8,9 in summary, it is difficult to assess the exact cause of symptomatic vascular pseudoaneurysm in maxillofacial trauma especially if vascular imaging is not conducted pre-operatively. it is possible that the initial trauma or the surgery could cause the pseudoaneurysm and delineating the exact cause is critical. it is also likely that surgical manipulation could cause an otherwise asymptomatic vascular injury to develop into a devastating haemorrhaging pseudoaneurysm. hence, we recommend considering vascular imaging such as cta or conventional angiogram in high risk patients. *sultan al shaqsi1 and yarab al-bulushi2 1department of plastic and reconstructive surgery, university of toronto, toronto, canada; 2department of radiology, mcgill university, montreal, canada corresponding author’s e-mail: drsultanalshaqsi@gmail.com references 1. al-saadi nj, bakathir a, al-mashaikhi a, al-hashmi a, al-habsi a, al-azri f. maxillary artery pseudoaneurysm as a complication of maxillofacial injuries: report of three cases and literature review. sultan qaboos univ med j 2019; 19:e364-8. https://doi.org/10.18295/ squmj.2019.19.04.013. 2. khanna s, dagum ab. a critical review of the literature and an evidence-based approach for life-threatening hemorrhage in maxillofacial surgery. ann plast surg 2012; 69:474–8. https://doi.org/10.1097/sap.0b013e31824a2171. 3. hacein-bey l, blazun jm, jackson rf. carotid artery pseudoaneurysm after orthognathic surgery causing lower cranial nerve palsies: endovascular repair. j oral maxillofac surg 2013; 71:1948–55. https://doi.org/10.1016/j.joms.2013.07.001. 4. long x, cheng y, li x, li h, hu s. arteriovenous fistula after mandibular condylar fracture. j oral maxillofac surg 2004; 62:1557–8. https:// doi.org/10.1016/j.joms.2004.01.028. 5. goffinet l, laure b, tayeb t, amado d, herbreteau d, arbeille p, et al. an arteriovenous fistula of the maxillary artery as a complication of le fort i osteotomy. j craniomaxillofac surg 2010; 38:251–4. https://doi.org/10.1016/j.jcms.2009.07.002. 6. miekisiak g, mis m, sandler a, druszcz a. iatrogenic arteriovenous fistula of the superficial temporal artery. oral maxillofac surg 2008; 12:219–21. https://doi.org/10.1007/s10006-008-0133-5. 7. gassner r, tuli t, hächl o, rudisch a, ulmer h. cranio-maxillofacial trauma: a 10 year review of 9,543 cases with 21,067 injuries. j craniomaxillofac surg 2003; 31:51–61. https://doi.org/10.1016/s1010-5182(02)00168-3. 8. bayarogullari h, acipayam m, akbay e, atci n, davran r, cevik c. pseudoaneurysm of the carotid arterial system. j craniofac surg 2014; 25:e314–16. https://doi.org/10.1097/scs.0000000000000578. 9. laitt rd, lewis tt, bradshaw jr. blunt carotid arterial trauma. clin radiol 1996; 51:117–22. https://doi.org/10.1016/s0009-9260(96)80268-6. response from the authors dear reader, we appreciate the interest in our article describing maxillary artery pseudoaneurysm as a complication of maxillofacial injuries.1 our primary goal was to emphasise the importance of keeping a high level of suspicion should an intra-operative brisk bleeding be encountered while operating in the field of this artery in an otherwise asymptomatic trauma patient. the clinical presentation, diagnosis and management of this complication were highlighted with a brief literature review in an attempt to provide more information on the topic including the relationship between trauma and pseudoaneurysm formation.1 we agree that there could be a dilemma in the exact cause of the pseudoaneurysm. nonetheless, as the formation of pseudoaneurysm usually takes time and as all our presented cases were sent for cta and embolisation immediately after the operation, the pseudoaneurysm is more likely to have formed at the time of trauma rather than during surgery; the surgical manipulation is more likely to have caused the disruption of the pseudoaneurysm https://doi.org/10.18295/squmj.2019.19.04.013 https://doi.org/10.18295/squmj.2019.19.04.013 https://doi.org/10.1097/sap.0b013e31824a2171 https://doi.org/10.1016/j.joms.2013.07.001 %20https://doi.org/10.1016/j.joms.2004.01.028 %20https://doi.org/10.1016/j.joms.2004.01.028 https://doi.org/10.1016/j.jcms.2009.07.002 https://doi.org/10.1007/s10006-008-0133-5 https://doi.org/10.1016/s1010-5182%2802%2900168-3 https://doi.org/10.1097/scs.0000000000000578 https://doi.org/10.1016/s0009-9260%2896%2980268-6 sultan al shaqsi and yarab al-bulushi letter to editor | e403 and bleeding.1 however, this can not be proven unless pre-operative imaging is done. in our second reported case, the avf was diagnosed and managed immediately after trauma before any surgical intervention, thus the avf could not have been iatrogenic. as it was correctly mentioned, this complication is rare. on the other hand, maxillofacial injures are common.1,2 moreover, condylar process fracture is one of the most common mandibular fractures and could represent up to 50% of all mandibular fractures with low reported vascular complications even with surgical management.2–4 it is clear that maxillary pseudoaneurysms are problematic if they rupture leading to bleeding and further complications. otherwise, the location of the maxillary artery may tamponade the pseudoaneurysm initially, while spontaneous thrombosis of 90% of the aneurysmal sac naturally occurs in 5–90 days, even in larger vessels such as the femoral artery.1,5 thus, the risk of exposing such cases to cta versus the benefit of detecting this rare finding is a highly arguable indication; not only does cta pose an additional high radiation dose with other potential complications, it also poses an additional burden on the healthcare system. in our institutions pre-operative cta is a routine protocol for trauma patients who are symptomatic or highly suspected of having a vascular injury. as all our presented cases were asymptomatic and were scheduled for elective surgery there was no clear indication for a pre-operative vascular assessment. in addition, as these complications are rare or uncommon, a unified protocol is not possible to be applied to all cases; a situation-based decision is more appropriate. moreover, a high-risk consent is usually a case-based decision depending on the severity of the injury. in conclusion, maxillary artery pseudoaneurysm is a rare complication of maxillofacial trauma. vascular assessment with cta should only be performed when clinically indicated. surgeon awareness of the possibility of such an unusual complication while operating, in an otherwise asymptomatic patient, is crucial for successful management. noor al saadi department of plastic, reconstructive and craniofacial surgery, khawla hospital, muscat, sultanate of oman author’s e-mail: dr.noorjabbar@ymail.com references 1. al-saadi nj, bakathir a, al-mashaikhi a, al-hashmi a, al-habsi a, al-azri f. maxillary artery pseudoaneurysm as a complication of maxillofacial injuries: report of three cases and literature review. sultan qaboos univ med j 2019; 19:e364-8. https://doi.org/10.18295/ squmj.2019.19.04.013. 2. zachariades n, mezitis m, mourouzis c, papadakis d, spanou a. fractures of the mandibular condyle: a review of 466 cases. literature review, reflections on treatment and proposals. j craniomaxillofac surg 2006; 34:421–32. https://doi.org/10.1016/j.jcms.2006.07.854. 3. kyzas p, saeed a, tabbenor o. the treatment of mandibular condyle fractures: a meta-analysis. j craniomaxillofac surg 2012; 40:e438–52. https://doi.org/10.1016/j.jcms.2012.03.002. 4. al kindi st, bakathir a, al azri f, al wahaibi k. dissecting aneurysm of the internal carotid artery as a complication of facial bone trauma. oman med j 2019; 34:520–3. https://doi.org/10.5001/omj.2019.12. 5. cameron jl, cameron am. current surgical therapy. 12th ed. amsterdam, netherlands: elsevier, 2016. https://doi.org/10.18295/squmj.2019.19.04.013 https://doi.org/10.18295/squmj.2019.19.04.013 https://doi.org/10.1016/j.jcms.2006.07.854 https://doi.org/10.1016/j.jcms.2012.03.002 https://doi.org/10.5001/omj.2019.12 التغيريات يف الكفاءة الذاتية والدعم االجتماعي بعد تدخل لزايدة النشاط البدين بني البالغني املصابني بداء السكري من النوع الثاين يف ُعمان movediabetes متابعة ملدة 12 شهرًا لتجربة ثمرة �سعيد �لغافرية، �سعود �حلارثي، يحيى �لفار�سي، �أجنيال كريجي، �إيلني بانرمان، �آين �أندر�سون abstract: objectives: this study aimed to describe changes in self-efficacy (se) and social support (ss) 12 months after the movediabetes trial, an intervention designed to increase physical activity (pa) among adults with type 2 diabetes mellitus in oman. methods: the original movediabetes trial was conducted between april 2016 and june 2017 in muscat, oman. the intervention group (ig) received personalised pa consultations, pedometers and monthly messages using a web-based application, while the comparison group received usual care. self-reported se and ss from family and friends were assessed using validated psychosocial scales. results: of the 232 original participants in the trial, a total of 174 completed the 12 months follow-up study period (response rate: 75%). however, based on intention-to-treat analysis with several imputation procedures for missing data at 3 and/or 12 months, there was a significant increase in se scores in the ig (+10.3, 95% confidence interval [ci]: 7.1–13.5; p <0.001); however, the correlation with pa levels was weak (+4.2, 95% ci: 2.7–5.7; p <0.001). higher se scores were noted in those without comorbidities (+12.2, 95% ci: 6.8–17.6; p <0.001) and with high income levels (+9.7, 95% ci: 5.2–14.2; p <0.001). additionally, ss scores increased significantly among those in the ig who received support from friends (+2.3, 95% ci: 1.1–3.7; p <0.001), but not family (+1.2, 95% ci: −0.4–2.8; p = 0.110). the reliability of the scales was acceptable for se and ss from family, but poor for ss from friends (cronbach’s alpha coefficients = 0.82, 0.82 and 0.40, respectively). conclusion: the pa intervention was associated with positive changes in se and ss from friends. however, further tools for assessing psychosocial influences on pa are needed in arab countries. keywords: physical activity; type 2 diabetes mellitus; self-management; health behaviors; social support, selfefficacy; primary healthcare; oman. movediabetes امللخ�ص: الهدف: هدفت هذه �لدر��سة �إىل و�سف �لتغيري�ت يف �لكفاءة �لذ�تية و�لدعم �الجتماعي بعد 12 �سهًر� من جتربة جتربة �أجريت الطريقة: ُعمان. يف �لثاين �لنوع من �ل�سكري بد�ء �مل�سابني �لبالغني بني �لبدين �لن�ساط لزيادة م�سمم تدخل وهو ، movediabetes �الأ�سلية بني �أبريل 2016 ويونيو 2017 يف م�سقط، ُعمان. تلقت جمموعة �لتدخل م�سور�ت �سخ�سية ب�ساأن �لن�ساط �لبدين مت �ملعهودة. �لرعاية �ملقارنة جمموعة تلقت بينما �ملعلومات، �سبكة على معتمد تطبيق با�ستخد�م �سهرية ور�سائل �خلطو�ت وعد�د�ت تقييم �لكفاءة �لذ�تية و�لدعم �الجتماعي �ملبلغ عنهما ذ�تًيا من ِقَبل �لعائلة و�الأ�سدقاء با�ستخد�م مقايي�س نف�سية �جتماعية مت �لتحقق من �سحتها. النتائج: �أكمل ما جمموعه 174 من �أ�سل 232 م�سارًكا فرتة 12 �سهر� من �لدر��سة �ملتعلقة باملتابعة )معدل �ال�ستجابة: 75%(. ومع ذلك و��ستناًد� �إىل حتليل نية �ملعاجلة، وبعد �إجر�ء عدد من ح�سابات �لبيانات �ملفقودة عند �ل�سهرين 3 و12، كانت هناك زيادة كبرية م�ستويات مع �الرتباط �أن 10.3+(؛ بالرغم ،95% �لثقة :فا�سل 1.7–13.5 p؛ >0.001( �لتدخل جمموعة لدى �لذ�تية �لكفاءة درجات يف p؛ >0.001( م�ساحبة �أمر��س لديهم لي�س �لذين �أولئك يف �أعلى ذ�تية كفاءة درجات لوحظت .)p >0.001( �سعيفا كان �لبدين �لن�ساط باالإ�سافة .)+9.7 ،95% �لثقة :فا�سل 5.2–14.2 p؛ >0.001( �ملرتفعة �لدخل م�ستويات ومع 12.2+(؛ ،95% �لثقة :فا�سل 6.8–17.6 �إىل ذلك، ز�دت درجات �لدعم �الجتماعي ب�سكل ملحوظ بني �أفر�د جمموعة �لتدخل �لذين تلقو� دعًما من �الأ�سدقاء )p >0.001؛ 3.7–1.1 �ملقايي�س موثوقية كانت .)+1.2 ،95% �لثقة :فا�سل -0.423–2.8 p؛ = 0.110( �لعائلة ِقَبل من لي�س ولكن ،)2.3 ،95% �لثقة :فا�سل مقبولة بالن�سبة لتقييم �لكفاءة �لذ�تية و�لدعم �الجتماعي من ِقَبل �لعائلة، ولكنها �سعيفة بالن�سبة للدعم �الجتماعي من طرف �الأ�سدقاء )على �لتو�يل 0.400 و0.820، 0.820 = معامالت كرونباخ �ألفا(. اخلال�صة: �رتبط تدخل �لن�ساط �لبدين بتغيري�ت �إيجابية يف �لكفاءة �لذ�تية و�لدعم �الجتماعي من ِقَبل �الأ�سدقاء. ومع ذلك، هناك حاجة �إىل مزيد من �الأدو�ت لتقييم �لتاأثري�ت �لنف�سية و�الجتماعية على �لن�ساط �لبدين يف �لبلد�ن �لعربية. الكلمات املفتاحية: ن�ساط بدين؛ د�ء �ل�سكري من �لنوع �لثاين؛ �إد�رة ذ�تية؛ �سلوكيات �سحية؛ دعم �جتماعي؛ كفاءة ذ�تية؛ رعاية �سحية �أولية؛ ُعمان. changes in self-efficacy and social support after an intervention to increase physical activity among adults with type 2 diabetes in oman a 12-month follow-up of the movediabetes trial *thamra s. al-ghafri,1 saud al-harthi,2 yahya al-farsi,3 angela m. craigie,4 elaine bannerman,5 annie s. anderson4 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e42–49, epub. 15 mar 21 submitted 16 mar 20 revision req. 23 apr 20; revision recd. 21 may 20 accepted 10 jun 20 1department of planning, directorate general of planning & studies, ministry of health, muscat, oman; 2department of medicine, al nahdha hospital, muscat, oman; 3department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 4centre for public health nutrition research, university of dundee, dundee, uk; 5global academy of agriculture & food security, royal (dick) school of veterinary studies, university of edinburgh, edinburgh, uk *corresponding author’s e-mail: thamra74@yahoo.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.006 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ thamra s. al-ghafri, saud al-harthi, yahya al-farsi, angela m. craigie, elaine bannerman and annie s. anderson clinical and basic research | e43 physical activity (pa) has been recognised as a cornerstone in the management of type 2 diabetes mellitus (t2dm); however, many individuals with t2dm fail to achieve the recommended target of at least 150 minutes/week of moderate to vigorous exercise.1 in muscat, oman, a cluster randomised controlled trial known as the movediabetes trial was conducted over one year between 2016 and 2017.2 a structured intervention was designed to increase pa levels among adults with t2dm in oman incorporating face-to-face personalised pa consult ations, pedometers and monthly messages using a web based application.2 the movediabetes intervention was structured according to three complementary theoretical models, including the stages of change model, health belief model and social cognitive theory.3,4 in addition, behaviour change techniques (bcts) were incorporated to facilitate the translation and application of the theories into practice; in particular, these techniques were drawn from tudor-locke and lute’s explanation of the effectiveness of pedometers and constructs of the theoretical models included within the coventry, aberdeen and london-refined taxonomy.5,6 the final bcts in the trial (i.e. goal setting, action planning, self-monitoring of behaviour, barrier identification, instructions on how to perform a behaviour, use of follow-up prompts and social support [ss]) have been previously identified as effective approaches to increases in pa.7–10 specifically, self-efficacy (se) and lack of social support (ss), particularly for females, have been identified as important barriers to the performance of pa.11–17 therefore, the objective of the present study was to present additional follow-up findings from the movediabetes trial.2 this study sought to examine changes in factors influencing pa levels 12 months after the original movediabetes trial with regards to: (1) associations between changes in pa levels with se and ss; (2) changes in se and ss according to various sociodemographic factors (i.e. gender, age, education level, income level and employment status); and (3) the validity and internal consistency of the psychosocial measurement tools used to assess se and ss. methods the original movediabetes trial was performed between april 2016 and june 2017 in muscat, oman.2 a total of eight primary health centres were randomly selected to deliver either the intervention (n = 4) or provide usual care (n = 4).2,3 the primary outcome was to assess the effectiveness of a multicomponent interv ention on changes in pa levels (primary outcome), as well as changes in weight, body mass index (bmi), glycated haemoglobin (hba1c) level, blood pressure and lipid profile (secondary outcomes).2 eligible participants included adults aged 18–60 years with t2dm and no contraindications to pa who were deemed by trained project officers (pos) to be inactive based on results from the scottish physical activity screening questionnaire.2,3,18 four pos were recruited from doctors and nurses who worked at diabetes clinics at each of the selected health centres. participants in the intervention group (ig) received personalised pa consultations, a pedometer (digiwalker™ sw-200, yamax, bridgnorth, shropshire, uk) to measure weekly step counts and monthly messages using a web-based application (whatsapp messenger®, facebook inc., menlo park, california, usa).2 the consultations lasted a maximum of 20 minutes and were delivered by trained pos on three separate occasions at 0 (baseline), 4 and 8 weeks. participants in the ig received monthly standardised motivational messages and participated in a whatsapp messenger® group (facebook inc.) with the pos from their respective health centres to facilitate the reporting of their step counts and receive support during the intervention period. the content of the motivational messages was designed to coincide with international occasions to promote pa.2 the pos initiated and facilitated the group conversations, received feedback from the participants and monitored the group dynamics. a multicomponent interview-based questionnaire was developed to elicit sociodemographic data (i.e. age, gender, marital status, education level and income), metabolic parameters (i.e. weight and bmi) and cardiovascular biomarkers (i.e. blood pressure, hba1c level and lipid profile).2 self-reported pa levels advances in knowledge this study’s findings help address the existing gap in the literature regarding behavioural interventions to promote physical activity (pa) in arab settings. the study found that the movediabetes intervention to increase pa levels among adults with type 2 diabetes mellitus in oman resulted in significant positive changes in self-efficacy and social support from friends. application to patient care this study provides evidence to support the applicability of behavioural interventions tailored to individual needs within local clinical settings. as such, the integration of behavioural counselling techniques in primary healthcare is recommended. changes in self-efficacy and social support after an intervention to increase physical activity among adults with type 2 diabetes in oman a 12-month follow-up of the movediabetes trial e44 | squ medical journal, february 2021, volume 21, issue 1 across work, travel and leisure domains were estimated via face-to-face interviews using the 13-item global physical activity questionnaire.19,20 self-estimated pa levels were expressed as metabolic equivalent of task (met), defined as the ratio of a person’s working metabolic rate relative to their resting metabolic rate and equivalent to an energy consumption of 1 kcal/kg/ hour. target levels for biochemical variables in t2dm patients were defined according to the guidelines of the ministry of health in oman.21 subequently, two questionnaires were used to explore the participants’ perceptions of se and ss for pa at baseline and 12 months. the original english-language tools were translated into arabic using the forward-backwards translation techniques recommended by the world health organization.22 the 12-item se scale used in the study was based on the exercise self-efficacy (ese) scale.23 the ese has been shown to be reliable after being translated to multiple other languages.24–26 in addition, a previous study conducted in jordan found that the modified ese demonstrated high validity and internal consistency for use in an arabic-speaking population, based on factor analysis and internal consistency reliability tests.27 the main interest in the current study was to examine se related to the ability to perform pa in the face of previously identified barriers to pa.17 as such, two questions in the ese scale were modified to highlight these barriers, namely: “how confident are you that you can engage in physical activity when you do not have access to pa resources?” and “how confident are you to overcome lack of social support that could be an obstacle to performing pa?”. participants were asked to rate each item in the final 12-item arabic questionnaire from 0 (no confidence) to 10 (complete confidence) according to their perceived current ability to perform 150 minutes of moderate to vigorous pa per week. the total possible score ranged from 0–120, with higher scores indicating greater self-confidence. a modified version of a previously reported scale by sallis and hovell was used to assess perceived levels of ss.28 the scale involves a series of 13 questions to determine participants’ perceptions of the level of ss received from family and friends. for the current study, modifications were made to counteract potentially gender-sensitive issues.17,29 these modifications were deemed necessary as females in arab countries often face certain cultural norms and social expectations which may impact pa, especially in terms of perceived safety, security and modesty.30 therefore, the first two questions were extended to determine whether they “asked someone to accompany me to perform pa” and whether family or friends “offered to drive me to the nearest pa facility”. additionally, the penultimate question was changed to determine whether they received “support to select appropriate pa clothing”. each item of the scale was asked twice to determine levels of support from family and friends independently. each item was scored from 0 (no support) to 5 (maximum support). the total score ranged from 0–65, with higher scores indicative of greater levels of support. the psychosocial scales were piloted on 50 random adults selected from the patient appointment list at a diabetes clinic in one of the primary health centres. due to the complexity of the terminology used in the scales, a statistician advised that sampling continue until a clear common understanding was reached; thus, the sampling continued for five days. initial construct validity was performed using factor analysis.31 for the se scale, factor loading—for which a desirable magnitude for item-factor relationships was ≥0.3—was significant for three components, namely confidence to: (1) engage in pa (5 items); (2) follow pa instructions (4 items); and (3) make time for pa (3 items). this was used to structure the final version of the se scale. no specific pattern was observed from the factor analysis for items in the ss scale. both the se and ss scales had acceptable internal consistency (cronbach’s alpha coefficients = 0.65 and 0.70, respectively).32 the statistical methods used in the original movediabetes trial have been described elsewhere.2 in summary, frequency tables and t-tests were used to describe the study population and compare differences between the groups at baseline. for the current study, scores for the se and ss scales were compared using descriptive statistics. additionally, an independent samples t-test was used to compare summed scores between the groups at baseline. generalised linear modelling (glm) was performed to calculate inter-group differences in summed scores. differences in scores according to selected sociodemographic characteristics were also explored using glm. spearman’s correlation test was used to identify associations between changes in se and ss scores with changes in reported pa levels.2 the level of statistical significance was set at <0.050. an intentionto-treat analysis was performed according to the last value carried forward imputation for missing data at 3 and/or 12 months and a mean imputation procedure was done where baseline data was missing. factor analysis was carried out to identify components that would explain a minimum of 10% of the data variance. item loadings of >0.3 were identified via principal components analysis with oblique rotation. ethical approval was obtained from the national research and ethical review and approve committee in oman ministry of health and reciprocally approved thamra s. al-ghafri, saud al-harthi, yahya al-farsi, angela m. craigie, elaine bannerman and annie s. anderson clinical and basic research | e45 in the university of dundee. in addition to providing informed consent, individuals were given the right to withdraw consent for participation in any aspect of this trial at any time without affecting their routine diabetes care. all participants were advised to report any serious adverse events occurring throughout the trial as they would immediately be referred by the pos to their general practitioner.2 results a detailed description of the sociodemographic, anthropometric and physiological characteristics of the sample has been reported elsewhere, including a flowchart describing the participants’ progress.2 out of the 232 participants who agreed to take part in the study, a total of 227 completed baseline measurements and 174 completed the final 12-month measurements (response rates: 97.8% and 75%, respectively). analysis was performed utilising intent-to-treat analysis where all 232 participants were included in the analysis.2 at baseline, more than half of the participants were female (64.5% and 54.1% in the ig and comparison group [cg], respectively).2 the mean age was 44.2 ± 8.1 years (median of 43 and 45 years in the ig and cg, respectively). the majority of the cohort were married (79.3%), had completed secondary education (50.9%) and were employed (58.2%).2 there were significantly more married individuals in the cg than the ig (85.5% versus 73.8%; p = 0.031). however, fewer employed individuals in the cg compared to the ig (50% versus 65.6%; p = 0.022).2 the mean bmi was 33.8 ± 7.9 kg/m2 in the ig and 33.1 ± 8.7 kg/ m2 in the cg. the mean duration of t2dm was 5.8 ± 3.7 years, with many subjects presenting with comorbidities, including hypertension (45.3%), hyperlipidaemia (35.6%) or both (15%).2 while mean systolic blood pressure (sbp) levels were within target levels in both groups, they were significantly higher in the ig compared to the cg (83.2 ± 9.4 mmhg versus 78.7 ± 14.4 mmhg; p = 0.003). average total and low-density lipoprotein (ldl) cholesterol levels in both groups were higher than target levels.2 however, high-density lipoprotein and triglyceride levels were within target limits. levels of hba1c were >7% in both groups (71% and 58% in the ig and cg, respectively).2 there were no significant differences between groups in terms of bmi, sbp, hba1c levels and lipid profile at baseline. at 12 months, the mean change in pa was +631.3 met/minute/week (95% confidence interval [ci]: 369.4–893.2 met/minute/week) in the ig compared table 1: changes in self-efficacy* at baseline and 12 months later according to group allocation† among adults with type 2 diabetes mellitus in oman (n = 232) component mean sum se score‡ ± sd inter-group md§ (95% ci) p value intervention group (n =122) comparison group (n = 110) baseline 12 months md baseline 12 months md engagement with pa 11.8 ± 5.0 19.3 ± 5.3 7.6 ± 6.7 11.0 ± 2.6 14.4 ± 2.9 3.4 ± 4.3 +4.2 (2.7–5.7) <0.001 following instructions 11.8 ± 2.4 14.8 ± 6.2 3.0 ± 6.3 11.4 ± 2.2 11.7 ± 4.0 0.2 ± 5.0 +2.9 (1.4–4.4) <0.001 managing time 8.9 ± 2.4 11.6 ± 5.5 2.8 ± 6.6 9.2 ± 2.1 8.8 ± 3.7 −0.4 ± 2.1 +3.2 (1.7–4.6) <0.001 total 32.4 ± 5.9 45.7 ± 13.8 13.3 ± 13.7 31.8 ± 4.3 34.8 ± 8.7 3.0 ± 10.9 +10.3 (7.1–13.5) <0.001 se = self-efficacy; sd = standard deviation; md = mean difference from baseline; ci = confidence interval; pa = physical activity. *self-assessed using a 12-item se scale based on the exercise self-efficacy scale.23 †the intervention group received personalised pa consultations, pedometers and monthly messages using a web-based application while the comparison group received usual care. ‡total sum scores ranged from 0–120, with higher scores indicating greater levels of confidence. §inter-group differences in sum scores were calculated using generalised linear modelling. figure 1: box plot chart showing total sum self-efficacy* scores at baseline and 12 months later, according to group allocation among adults with type 2 diabetes mellitus in oman (n = 232). the intervention group (n = 122) received personalised pa consultations, pedometers and monthly messages using a web-based application while the comparison group (n = 110) received usual care. *self-assessed using a 12-item se scale based on the exercise selfefficacy scale.23 total sum scores ranged from 0–120, with higher scores indicating greater levels of confidence. changes in self-efficacy and social support after an intervention to increase physical activity among adults with type 2 diabetes in oman a 12-month follow-up of the movediabetes trial e46 | squ medical journal, february 2021, volume 21, issue 1 to +183.2 met/minute/week (95% ci: 83.3–283.0 met/minute/week in the cg, with a significant intergroup difference (+447.4 met/minute/week; 95% ci: 150.7–744.1 met/minute/week; p <0.001).2 overall, total se sum scores were found to have increased at 12 months from baseline. summed scores for items assessing levels of confidence to engage with pa, follow pa instructions and manage time increased from 2,631 ± 11.34 to 3,938 ± 16.97, from 2,720 ± 11.72 to 3,080 ± 13.28 and from 2,096 ± 9.03 to 2,387 ± 10.29, respectively. there was a higher contribution of questions related to engagement with pa (5 items) to overall se score compared to other categories of items. notably, mean total se scores were comparable at baseline for both the ig and cg (32.4 ± 5.9; 95% ci: 31.1–33.5 versus 31.8 ± 4.3; 95% ci: 31.0–32.8; p = 0.581) [figure 1]. however, a univariate analysis using glm showed a significant increase at 12 months in mean se scores for the ig compared to the cg (+10.3, 95% ci: 7.1–13.5; p <0.001) [table 1]. multivariate analysis indicated that participants in the ig without comorbidities had a significantly greater increase in total se sum scores compared to ig participants with comorbidities (+12.2, 95% ci: 6.8–17.6; p <0.001). similarly, individuals with higher income levels in the ig also demonstrated significantly higher total se sum scores compared to those with lower income levels (+9.7, 95% ci: 5.2–14.2; p <0.001). gender was the only variable found to influence total se sum scores in the cg, with males having a significantly greater change in sum score between baseline and 12 months compared to females (+4.2, 95% ci: 0.5–7.9; p = 0.021). there was a positive but weak association between changes in total se sum scores and reported changes in pa levels within the ig only (r = 0.4; p <0.001). exploratory factor analysis at both baseline and 12 months indicated that all 12 items in the se scale were suitable for the study population. according to the categorisation utilised during the piloting phase, three components were identified at baseline and 12 months: confidence to engage with pa, follow pa instructions and manage time. inter-item correlations ranged from −0.1 to 0.9 at baseline and −0.2 to 0.8 at 12 months. the highest inter-item correlation at baseline was noted between items 2 and 4 (“how confident are you that you can engage in pa when you are in a bad mood?” and “how confident are you that you can engage in pa during bad weather?”; r = 0.9). a high correlation was also identified between items 2 and 3 (“how confident are you that you can engage in pa when you are in a bad mood?” and “how confident are you that you can engage in pa when you feel you do not have time?”; r = 0.7). similarly, at 12 months, high inter-item correlations were noted between items 6 and 7 (“how confident are you that you can follow pa directions from an instructor?” and “how confident are you that you can pace yourself during the activity to avoid overexertion?”; r = 0.8) and between items 7 and 10 (“how confident are you that you can pace yourself during the activity to avoid overexertion?” and “how confident are you to arrange your schedule to perform pa regularly no matter what?”; r = 0.8). at baseline and 12 months, cronbach’s alpha coefficient values for the se scale were 0.79 and 0.82, respectively, indicating reasonable-to-good internal consistency in this population. total ss sum scores were also found to have increased at 12 months from baseline from 2,804 ± 12.1 to 3,279 ± 14.1 for ss from family and from 2,162 ± 9.3 to 2,543 ± 10.9 for ss from friends. overall, scores for perceived ss from family were higher than those for ss from friends in both groups. there was a difference in changes in score in the ig compared to the cg, although this difference was only significant for ss from friends (+2.3, 95% ci: 1.1–3.7; p <0.001) [table 2]. however, changes in total ss scores for either family or friends at 12 months from baseline were not significantly associated with changes in reported pa levels (p = 0.232). a factor analysis of the family version of the ss scale indicated that six factors with eigenvalues of >1.0 significantly explained the maximum variance in data table 2: changes in social support from family and friends* at baseline and 12 months later according to group alloc ation† among adults with type 2 diabetes mellitus in oman (n = 232) component mean sum ss score‡ ± sd inter-group md§ (95% ci) p value intervention group (n =122) comparison group (n = 110) baseline 12 months md baseline 12 months md family ss 13.5 ± 4.5 16.1 ± 4.5 +2.6 ± 6.4 10.5 ± 3.5 12.0 ± 5.3 +1.4 ± 6.3 +1.2 (−0.4–2.8) 0.101 friends ss 9.5 ± 2.8 12.2 ± 5.1 +2.7 ± 6.0 9.2 ± 3.1 9.6 ± 3.0 +0.4 ± 4.2 +2.3 (1.1–3.7) <0.001 ss = social support; sd = standard deviation; md = mean difference from baseline; ci = confidence interval. *self-assessed using a modified version of 13-item scale by sallis et al.28 †the intervention group received personalised pa consultations, pedometers and monthly messages using a web-based application while the comparison group received usual care. ‡total sum scores ranged from 0–65, with higher scores indicating greater levels of support. §inter-group differences in sum scores were calculated using generalised linear modelling. thamra s. al-ghafri, saud al-harthi, yahya al-farsi, angela m. craigie, elaine bannerman and annie s. anderson clinical and basic research | e47 at baseline and 12 months. inter-item correlations ranged from −0.1 to 0.4 at baseline and from −0.2 to 0.7 at 12 months. however, no values of >0.7 were identified, indicating no significant interaction between responses to the different items in the scale. cronbach’s alpha coefficient values for this subscale were 0.60 and 0.82 at baseline and 12 months, respectively, indicating good internal consistency. at 12 months, all items in the friends version of the ss scale were retained in the factor analysis, apart from items 3 and 4 (“gave me helpful reminders to exercise” and “gave me encouragement to stick with my exercise programme”). seven and five factors were identified at baseline and 12 months, respectively. inter-item correlations ranged from −0.01 to 0.5 at baseline and from −0.08 to 0.6 at 12 months. no values of >0.70 were identified. at baseline and 12 months, cronbach’s alpha coefficient values for the friends ss subscale were 0.20 and 0.40, respectively, indicating poor internal consistency in this population. discussion the results from the current study showed that the movediabetes intervention resulted in improvements in se among participants of both the ig and cg groups at 12 months from baseline, with the increase being significantly greater in the ig. similar findings have been reported in other research.27 moreover, this increase was positively, albeit weakly, associated with changes in pa levels. defined as the ability to meet activity goals despite barriers, se has been reported to be a strong predictor for performing and adhering to pa goals in various populations, including adults with t2dm.33 despite the weak correlation between se sum scores and perceived pa levels in the present study, it is reasonable to conclude that the results support the utilisation of this pa intervention in adults with t2dm. however, objective pa measurement would be required to validate the findings, especially in arabicspeaking countries where pa data are limited. in the current study, improvements in se at 12 months within the ig were greater among those without comorbidities and among those who had higher incomes. the first finding may be due to such individuals being in better health, which is likely to enhance one’s self-confidence and ability to perform more intense pa.9 in turn, higher income may be associated with enhanced opportunities for pa, including the ability to purchase or access additional resources, such as pedometers, watches, treadmills, gym memberships or clothing, thereby potentially facilitating positive behavioural changes.34 in addition, as in other studies, being male was associated with a greater improvement in se in the cg.35 this suggests that gender-specific approaches may be needed to improve se among females.17 such approaches could offer additional support for women living in arab countries to enable them to meet sociocultural and religious expectations related to wearing appropriate clothing and ensuring their safety while exercising in a hot climate.17,29,30 in the current study, the personalised pa consultations were designed to include specific seenhancing techniques, namely goal setting, action planning, self-monitoring of behaviour, barrier identification, instructions on how to perform a behaviour, use of follow-up prompts and ss.3 the results showed that questions related to engagement with pa (5 items) contributed more to the overall se score compared to other categories. further exploration may be useful to ensure that the strategies that resulted in high pa engagement are maintained; in contrast, other less influential se components related to following pa instructions and managing time may need to be modified or addressed to determine why they do not contribute to overall se with regards to pa. several studies have highlighted the importance of ss in initiating and/or maintaining pa-related behavioural changes.14,36,37 in the current study, participants in the ig were encouraged to attend their personalised pa consultations with a family member or a friend.3 while there was a significant difference in changes in ss from friends in the ig compared to the cg, changes in family ss were not significantly different between the groups. this may not be surprising given the strong cultural importance placed on family in the arab and muslim world.38,39 this is reinforced by the fact that the majority of the overall study population were married, potentially indicating that the majority already received adequate levels of ss from family.39 despite evidence of the positive effect of peer support in lifestyle modification interventions, more information is needed regarding the methods, strategies and expected outcomes when using technology to promote pa across subpopulations.40 there was no significant association between changes in reported pa levels and perceived support from either family or friends in the current study. in contrast, findings from the literature have indicated that ss has positive effects on pa levels.14 despite using a web-based messaging application, reasons for the lack of association between pa levels and ss in the present study require further evaluation. to the best of the authors’ knowledge, the current study is one of very few to investigate the psychometric changes in self-efficacy and social support after an intervention to increase physical activity among adults with type 2 diabetes in oman a 12-month follow-up of the movediabetes trial e48 | squ medical journal, february 2021, volume 21, issue 1 properties of arabic versions of psychosocial pa scales among adults with t2dm. based on cronbach’s alpha coefficients, the internal consistency of the scales for se and ss from family was deemed to be acceptable, suggesting that these scales are reliable for use in arabic-speaking t2dm patients. however, the internal consistency of the scale assessing ss from friends was weak. this could be explained by the complexity of the terminology used in the questions, especially after being translated from english to arabic. furthermore, the structure of the ss scale may have been confusing to the participants as they had to answer the same question twice for family and friends independently. future research on this topic should, therefore, consider introducing the scale for family and friends separately. this study was subject to certain limitations. notably, the sample size was not powered to detect differences in the psychosocial scales. in addition, data were collected at baseline and 12-month followup only. future studies may consider utilising a larger sample size and performing additional rounds of data collection on multiple occasions throughout the study period. despite these limitations, this study’s findings add valuable information to the limited literature pertaining to psychosocial scales that measure pa in arabic-speaking populations. further research is recommended to validate these scales in a larger cohort. conclusion this study presented follow-up results regarding changes in se and ss 12 months after the movediabetes trial, an intervention designed to increase pa levels among adults with t2dm in oman. although significant and positive changes were observed in se and ss from friends within the ig compared to the cg, only se improvements were significantly associated with changes in pa levels. in addition, measurement of the internal consistency for these psychosocial tools indicated that these scales were acceptable for use in arabic-speaking patients with t2dm. however, further studies are needed to identify more robust tools to measure pa psychosocial influences in arab countries. a c k n o w l e d g e m e n t s the data generated from this study are available from the corresponding author upon reasonable request and approval from the ministry of health in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded jointly by the research council and ministry of health in muscat, oman, as part of a phd grant offered to the corresponding author (grant number: grsp/moh/15/002). references 1. heath gw, parra dc, sarmiento ol, andersen lb, owen n, goenka s, et al. evidence-based intervention in physical activity: lessons from around the world. lancet 2012; 380: 272–81. https://doi.org/10.1016/s0140-6736(12)60816-2. 2. alghafri ts, alharthi sm, al-farsi y, alrawahi ah, bannerman e, craigie am, et al. ‘movediabetes’: a cluster randomised controlled trial to increase physical activity in adults with type 2 diabetes in primary health in oman. bmj open diabetes res care 2018; 6:e000605. https://doi.org/10.1136/bmjdrc-2018-000605. 3. alghafri ts, alharthi sm, al-farsi ym, craigie am, mcleod m, anderson as. study protocol for “movediabetes”: a trial to promote physical activity for adults with type 2 diabetes in primary health care in oman. bmc public health 2017; 17:28. https://doi.org/10.1186/s12889-016-3990-0. 4. avery l, charman sj, taylor l, flynn d, mosely k, speight j, et al. systematic development of a theory-informed multifaceted behavioural intervention to increase physical activity of adults with type 2 diabetes in routine primary care: movement as medicine for type 2 diabetes. implement sci 2016; 11:99. https://doi.org/10.1186/s13012-016-0459-6. 5. tudor-locke c, lutes l. why do pedometers work? a reflection upon the factors related to successfully increasing physical activity. sports med 2009; 39:981–93. https://doi.org/10.2165/1 1319600-000000000-00000. 6. michie s, ashford s, sniehotta ff, dombrowski su, bishop a, french dp. a refined taxonomy of behaviour change techniques to help people change their physical activity and healthy eating behaviours: the calo-re taxonomy. psychol health 2011; 26:1479–98. https://doi.org/10.1080/08870446.2010.540664. 7. cradock ka, ólaighin g, finucane fm, gainforth hl, quinlan lr, ginis ka. behaviour change techniques targeting both diet and physical activity in type 2 diabetes: a systematic review and meta-analysis. int j behav nutr phys act 2017; 14:18. https:// doi.org/10.1186/s12966-016-0436-0. 8. avery l, flynn d, van wersch a, sniehotta ff, trenell mi. changing physical activity behavior in type 2 diabetes: a systematic review and meta-analysis of behavioral interventions. diabetes care 2012; 35:2681–9. https://doi.org/10.2337/dc11-2452. 9. williams sl, french dp. what are the most effective intervention techniques for changing physical activity self-efficacy and physical activity behaviour--and are they the same? health educ res 2011; 26:308–22. https://doi.org/10.1093/her/cyr005. 10. greaves cj, sheppard ke, abraham c, hardeman w, roden m, evans ph, et al. systematic review of reviews of intervention components associated with increased effectiveness in dietary and physical activity interventions. bmc public health 2011; 11:119. https://doi.org/10.1186/1471-2458-11-119. 11. gleeson-kreig jm. self-monitoring of physical activity: effects on self-efficacy and behavior in people with type 2 diabetes. diabetes educ 2006; 32:69–77. https://doi.org/10.1177/014572 1705284285. 12. mcauley e. self-efficacy and the maintenance of exercise participation in older adults. j behav med 1993; 16:103–13. https://doi.org/10.1007/bf00844757. 13. oman rf, king ac. predicting the adoption and maintenance of exercise participation using self-efficacy and previous exercise participation rates. am j health promot 1998; 12:154–61. https://doi.org/10.4278/0890-1171-12.3.154. https://doi.org/10.1016/s0140-6736%2812%2960816-2 https://doi.org/10.1136/bmjdrc-2018-000605 https://doi.org/10.1186/s12889-016-3990-0 https://doi.org/10.1186/s13012-016-0459-6 https://doi.org/10.2165/11319600-000000000-00000 https://doi.org/10.2165/11319600-000000000-00000 https://doi.org/10.1080/08870446.2010.540664 https://doi.org/10.1186/s12966-016-0436-0 https://doi.org/10.1186/s12966-016-0436-0 https://doi.org/10.2337/dc11-2452 https://doi.org/10.1093/her/cyr005 https://doi.org/10.1186/1471-2458-11-119 https://doi.org/10.1177/0145721705284285 https://doi.org/10.1177/0145721705284285 https://doi.org/10.1007/bf00844757 https://doi.org/10.4278/0890-1171-12.3.154 thamra s. al-ghafri, saud al-harthi, yahya al-farsi, angela m. craigie, elaine bannerman and annie s. anderson clinical and basic research | e49 14. smith gl, banting l, eime r, o’sullivan g, van uffelen jg. the association between social support and physical activity in older adults: a systematic review. int j behav nutr phys act 2017; 14:56. https://doi.org/10.1186/s12966-017-0509-8. 15. trost sg, owen n, bauman ae, sallis jf, brown w. correlates of adults’ participation in physical activity: review and update. med sci sports exerc 2002; 34:1996–2001. https://doi.org/10.10 97/00005768-200212000-00020. 16. sallis jf, hovell mf. determinants of exercise behavior. exerc sport sci rev 1990; 18:307–30. https://doi.org/10.1249/000 03677-199001000-00014. 17. alghafri t, alharthi sm, al farsi ym, bannerman e, craigie am, anderson as. perceived barriers to leisure time physical activity in adults with type 2 diabetes attending primary healthcare in oman: a cross-sectional survey. bmj open 2017; 7:e016946. https://doi.org/10.1136/bmjopen-2017-016946. 18. physical activity and health alliance. scottish physical activity screening question (scot-pasq). from: www.paha.org.uk/ resource/scottish-physical-activity-screening-question-scotpasq accessed: may 2020. 19. bull fc, maslin ts, armstrong t. global physical activity quest ionnaire (gpaq): nine country reliability and validity study. j phys act health 2009; 6:790–804. https://doi.org/10.1123/ jpah.6.6.790. 20. world health organization. global physical activity quest ionnaire (gpaq): analysis guide. from: www.who.int/ncds/ sur veillance/steps/resources/gpaq_analysis_guide.pdf accessed: may 2020. 21. oman ministry of health. diabetes mellitus management guidelines: 3rd edition 2015. from: www.moh.gov.om/docum e n t s / 2 7 2 9 2 8 / 1 3 1 4 7 6 3 / d i a b e t e s + m e l l i t u s + m a n a g e m e n t + g u i d e l i n e s + 3 r d + e d i t i o n + + + 2 0 1 5 % 2 8 1 % 2 9 . p d f / bafeceed-1a79-4e78-9166-9afee4ad3bf9 accessed: may 2020. 22. world health organization. management of substance abuse: process of translation and adaptation of instruments. from: www.who.int/substance_abuse/research_tools/translation/en/ accessed: may 2020. 23. bandura a. self-efficacy: the exercise of control. new york, usa: worth publishers ltd., 1997. 24. van der heijden mm, pouwer f, pop vj. psychometric properties of the exercise self-efficacy scale in dutch primary care patients with type 2 diabetes mellitus. int j behav med 2014; 21:394–401. https://doi.org/10.1007/s12529-013-9308-z. 25. shin y, jang h, pender nj. psychometric evaluation of the exercise self-efficacy scale among korean adults with chronic diseases. res nurs health 2001; 24:68–76. https://doi.org/10.1002/1098240x(200102)24:1<68::aid-nur1008>3.0.co;2-c. 26. noroozi a, ghofranipour f, heydarnia ar, nabipour i, tahmasebi r, tavafian ss. the iranian version of the exercise self-efficacy scale (eses): factor structure, internal consistency and construct validity. health educ j 2010; 70:21–31. https://doi.org/10.11 77/0017896910374547. 27. darawad mw, hamdan-mansour am, khalil aa, arabiat d, samarkandi oa, alhussami m. exercise self-efficacy scale: validation of the arabic version among jordanians with chronic diseases. clin nurs res 2016; 27:890–906. https://doi. org/10.1177/1054773816683504. 28. sallis jf, grossman rm, pinski rb, patterson tl, nader pr. the development of scales to measure social support for diet and exercise behaviors. prev med 1987; 16:825–36. https://doi. org/10.1016/0091-7435(87)90022-3. 29. alghafri ts, alharthi sm, al-balushi s, al-farsi y, al-busaidi z, bannerman e, et al. health professionals’ perceptions about physical activity promotion in diabetes care within primary health care settings in oman. heliyon 2018; 3:e00495. https:// doi.org/10.1016/j.heliyon.2017.e00495. 30. donnelly tt, al suwaidi j, al enazi nr, idris z, albulushi am, yassin k, et al. qatari women living with cardiovascular diseases: challenges and opportunities to engage in healthy lifestyles. health care women int 2012; 33:1114–34. https:// doi.org/10.1080/07399332.2012.712172. 31. henson rk, roberts jk. use of exploratory factor analysis in published research: common errors and some comment on improved practice. educ psychol meas 2006; 66:393–416. https://doi.org/10.1177/0013164405282485. 32. dunn tj, baguley t, brunsden v. from alpha to omega: a practical solution to the pervasive problem of internal consistency estimation. br j psychol 2014; 105:399–412. https://doi.org/10.1111/bjop.12046. 33. resnick b, palmer mh, jenkins ls, spellbring am. path analysis of efficacy expectations and exercise behaviour in older adults. j adv nurs 2000; 31:1309–15. https://doi.org/10.1046/j.13652648.2000.01463.x. 34. kari jt, pehkonen j, hirvensalo m, yang x, hutri-kähönen n, raitakari ot, et al. income and physical activity among adults: evidence from self-reported and pedometer-based physical activity measurements. plos one 2015; 10:e0135651. https:// doi.org/10.1371/journal.pone.0135651. 35. heiss v, petosa r. correlates of physical activity among adults with type 2 diabetes: a systematic literature review. am j health educ 2014; 45:278–87. https://doi.org/10.1080/193250 37.2014.933139. 36. rosenstock im, strecher vj, becker mh. social learning theory and the health belief model. health educ q 1988; 15:175–83. https://doi.org/10.1177/109019818801500203. 37. gristwood j. applying the health belief model to physical activity engagement among older adults. illuminare 2011; 9:59–71. 38. crescent of care nursing model. family in arab culture. from: www. crescentofcare.com/family-in-arab-culture accessed: may 2020. 39. benjamin k, donnelly tt. barriers and facilitators influencing the physical activity of arabic adults: a literature review. avicenna 2013; 2013:8. https://doi.org/10.5339/avi.2013.8. 40. ginis ka, nigg cr, smith al. peer-delivered physical activity interventions: an overlooked opportunity for physical activity promotion. transl behav med 2013; 3:434–43. https://doi. org/10.1007/s13142-013-0215-2. https://doi.org/10.1186/s12966-017-0509-8 https://doi.org/10.1097/00005768-200212000-00020 https://doi.org/10.1097/00005768-200212000-00020 https://doi.org/10.1249/00003677-199001000-00014 https://doi.org/10.1249/00003677-199001000-00014 https://doi.org/10.1136/bmjopen-2017-016946 https://doi.org/10.1123/jpah.6.6.790 https://doi.org/10.1123/jpah.6.6.790 https://doi.org/10.1007/s12529-013-9308-z https://doi.org/10.1002/1098-240x%28200102%2924:1%3c68::aid-nur1008%3e3.0.co%3b2-c https://doi.org/10.1002/1098-240x%28200102%2924:1%3c68::aid-nur1008%3e3.0.co%3b2-c https://doi.org/10.1177/0017896910374547 https://doi.org/10.1177/0017896910374547 https://doi.org/10.1177/1054773816683504 https://doi.org/10.1177/1054773816683504 https://doi.org/10.1016/0091-7435%2887%2990022-3 https://doi.org/10.1016/0091-7435%2887%2990022-3 https://doi.org/10.1016/j.heliyon.2017.e00495 https://doi.org/10.1016/j.heliyon.2017.e00495 https://doi.org/10.1080/07399332.2012.712172 https://doi.org/10.1080/07399332.2012.712172 https://doi.org/10.1177/0013164405282485 https://doi.org/10.1111/bjop.12046 https://doi.org/10.1046/j.1365-2648.2000.01463.x https://doi.org/10.1046/j.1365-2648.2000.01463.x https://doi.org/10.1371/journal.pone.0135651 https://doi.org/10.1371/journal.pone.0135651 https://doi.org/10.1080/19325037.2014.933139 https://doi.org/10.1080/19325037.2014.933139 https://doi.org/10.1177/109019818801500203 https://doi.org/10.5339/avi.2013.8 https://doi.org/10.1007/s13142-013-0215-2 https://doi.org/10.1007/s13142-013-0215-2 departments of 1medicine and 3community medicine, hawler medical university, erbil, iraq; 2nanakali hospital for blood diseases and oncology, erbil, iraq *corresponding author’s e-mail: mah_kawa@yahoo.com evaluation of ruxolitinib versus best available therapy in treating primary myelofibrosis *kawa m. hasan,1,2 ahmed y. elmeshhadany,1,2 nazar p. shabila3 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 393–399, epub. 25 aug 22 submitted 17 mar 21 revisions req. 7 jun & 25 jul 21; revisions recd. 27 jun & 7 aug 21 accepted 11 aug 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.110 clinical & basic research abstract: objectives: this study aimed to evaluate the effectiveness of ruxolitinib and compare it with the best available therapy in patients with primary myelofibrosis. ruxolitinib is a janus kinase inhibitor that is approved for the treatment of myelofibrosis. the therapeutic protocol has changed after the introduction of ruxolitinib. methods: in this retrospective study, 72 patients with primary myelofibrosis were scrutinised from january 2012 to january 2018 at nanakali hemato-oncology teaching centre in erbil, iraqi kurdistan. the patients were divided into two cohorts: 26 of them were treated with ruxolitinib and 46 received the best available therapy. the patients’ characteristics, their response to the treatment and the outcomes were evaluated. the efficacy of the treatment in both groups was compared. results: most patients (n = 46; 63.9%) were in the high and intermediate-2 risk groups according to the international prognostic scoring system. at the time of diagnosis, no noticeable differences in the clinical characteristics and laboratory data were observed among the ruxolitinib and best available treatment groups. ruxolitinib was found to be effective in reducing the size of the spleen and improving the overall survival rate when compared to the best available treatment group (p <0.001 and p = 0.008, respectively). the patients’ performance status had a significant effect on the overall survival in both treatment groups (p = 0.003). conclusion: ruxolitinib appears to have a significant role in reducing the spleen size and potentially affect the survival outcomes in patients with myelofibrosis. keywords: ruxolitinib; myelofibrosis; splenomegaly; janus kinase inhibitor; iraq. advances in knowledge treatment with ruxolitinib plays a significant role in reducing the spleen size in myelofibrosis (mf) patients compared to treatment with the best available options. the overall survival is improved with ruxolitinib. the performance status of mf patients significantly affected their overall survival. application to patient care treating myelofibrosis patients with ruxolitinib has the potential to improve the clinical course of this disease. myelofibrosis (mf) is a myeloproliferative neoplasm that is characterised by somatic mutation of the haematopoietic stem cells, which leads to overactive signalling through the janus kinase-signal transducer and act ivator of transcription (jak-stat) pathway as the central pathogenic mechanism.1 mf could be primary, secondary to polycythaemia vera (post-pv mf) or essential thrombocythemia (post-et mf).2 the principal genetic drivers in most mf patients are the janus kinase 2 (jak2), mpl proto-oncogene, thrombopoietin receptor (mpl) and calreticulin (calr) mutations that contribute to the pathophysiology of the disease; additionally, almost half of the patients carry a mutation in the jak2 gene (jak2 v617f).3,4 the characteristic clinical features of mf are constitutional symptoms such as fatigue, bone pain, weight loss and a hypercatabolic state. mf is also associated with cytopaenia (especially progressive anaemia), splenomegaly, bone marrow fibrosis, leukoerythroblastosis in the peripheral blood, poor quality of life and shortened survival.4,5 patients with mf are categorised into different risk groups based on the presence of the following five adverse prognostic factors at the time of diagnosis: (i) age >65 years; (ii) haemoglobin (hb) <10 g/dl; (iii) white blood cell (wbc) count >25 × 109/l; (iv) blood blasts ≥1%; and (v) constitutional symptoms. depending on the number of these adverse risk factors, mf patients are grouped into one of four groups according to the international prognostic scoring system (ipss) or dynamic ipss (dipss): low risk, intermediate risk-1, intermediate risk-2 and high risk.6 the estimated median survival of patients after primary mf diagnosis ranges from 2.25 to 11.25 years, depending on the risk level.6 although the therapeutic outlines have been changed after the introduction of ruxolitinib as a janus kinase (jak) inhibitor, allogeneic stem cell transplantation (allo-sct) remains the only curative therapy; however, allo-sct is applicable for a minority of patients. the other forms of conventional treatments include using erythropoiesis-stimulating agents, immunomodulatory agents or androgen https://creativecommons.org/licenses/by-nd/4.0/ evaluation of ruxolitinib versus best available therapy in treating primary myelofibrosis 394 | squ medical journal, august 2022, volume 22, issue 3 to treat anaemia in asymptomatic patients using hydroxyurea as a cytoreductive drug for splenomegaly and constitutional symptoms and employing splenic radiation and splenectomy.7 however, all of these means of conventional therapies remain palliative and aim to improve the patients’ quality of life. ruxolitinib was approved for the first time in november 2011 in the united states for the treatment of intermediate or high-risk mf patients. in europe, it was approved for treating splenomegaly and mfrelated symptoms.8 the initial ruxolitinib approval was based on the results of two clinical trials, comfort-i and comfort-ii.9,10 although ruxolitinib exerts a dramatic therapeutic effect, it seems to be temporary as symptoms rapidly return with the splenic size increasing soon after the drug is stopped or its dose reduced.11 in this context, this study aimed to compare the effectiveness of ruxolitinib to the other best available treatment (bat) options in mf patients. methods in this study, patients with primary mf were retrospectively analysed. the patients were diagnosed and treated at nanakali hemato-oncology teaching centre in erbil, iraqi kurdistan, from january 2012 to january 2018. clinical and laboratory data were retrieved from the patients’ hospital records. the diagnosis and staging of mf were based on world health organization criteria.6,12 the complete blood picture with circulating blast cell percentage and serum lactate dehydrogenase (ldh), recorded both at the baseline and after 24 weeks of follow-up, was checked. all patients underwent bone marrow biopsies for the assessment of the grade of fibrosis. spleen size was measured by ultrasound at the time of presentation and 24 weeks after treatment for all patients. the patients were analysed only for jak2 mutation while the mpl and calr mutations were not analysed due to lack of facilities. the eastern cooperative oncology group performance status (ecog-ps) was determined for the included patients. the ipss category was determined based on the presence of the previously mentioned adverse prognostic factors at the time of presentation. patients with incomplete data or no proper follow-up were excluded from this study. the recruited patients were divided into two groups according to the type of treatment they received: the ruxolitinib group included 26 patients treated with ruxolitinib and the other group included the remaining 46 patients who received the bat including danazol, hydroxyurea and blood transfusion. table 1: characteristics of patients with primary myelo fibrosis at the time of diagnosis (n = 72) characteristic n (%) p value* ruxolitinib bat mean age in years 58.1 ± 12.03 60.7 ± 12.61 0.400 gender 0.723 male (n = 38) 13 (34.2) 25 (65.8) female (n = 34) 13 (38.2) 21 (61.8) median time of follow-up in months 55.2 36 ipss 0.390 high risk 11 (42.3) 15 (57.7) intermediate-2 6 (30.0) 14 (70.0) intermediate-1 7 (46.7) 8 (53.3) low risk 2 (18.2) 9 (81.8) ecog-ps score 0.900 0 2 (40.0) 3 (60.0) 1 13 (38.2) 21 (61.8) 2 11 (33.3) 22 (66.7) 3 0 (0.0) 0 (0.0) parameter mean hb in g/dl ± sd 10.5 ± 2.21 9.1 ± 2.16 0.17 mean wbcs in × 109/l ± sd 18.9 ± 13.89 10.7 ± 8.12 0.002 mean platelets in × 109/l ± sd 263.0 ± 128.9 229.2 ± 234.9 0.501 mean peripheral blasts in % ± sd 2.0 ± 2.85 1.2 ± 2.11 0.177 mean ldh in u/l ± sd 1125.4 ± 618.6 909.7 ± 560.8 0.135 grade of marrow fibrosis 0.570 0 3 (50.0) 3 (50.0) 1 11 (44.0) 14 (56.0) 2 8 (29.6) 19 (70.4) 3 4 (28.6) 10 (71.4) mean spleen volume in cm3 ± sd 934.3 ± 423.3 764.4 ± 388.6 0.092 constitutional symptoms 0.225 yes 20 (40.8) 29 (59.2) no 6 (26.1) 17 (73.9) bat = best available therapy; ipss = international prognostic scoring system; ecog-ps = eastern cooperative oncology group performance status; hb = haemoglobin; sd = standard deviation; wbc = white blood cell; ldh = lactate dehydrogenase. *p ≤0.05 was considered statistically significant. kawa m. hasan, ahmed y. elmeshhadany and nazar p. shabila clinical and basic research | 395 the starting dose of ruxolitinib depended on the baseline platelet count. patients with a platelet count of 100–200 × 109/l were given 15 mg twice daily and those with a platelet count >200 × 109/l received 20 mg twice daily. the dose was adjusted for lack of efficacy or excess toxicity as specified in the comfort-i study.9 follow-up was done on a weekly basis in the first month, then every other week for the next two months and monthly thereafter. a clinical and haematological evaluation was conducted at each follow-up visit and an abdominal sonogram was performed monthly. common side effects were haematological (mild anaemia or thrombocytopaenia) while non-haematological side effects (dizziness, headache, fatigue and bloating) were mild and necessitated dose modification. the response to treatment and the outcome of the disease were recorded. progression-free survival (pfs) and overall survival (os) were estimated. in this regard, pfs is the time from treatment initiation until disease progression or worsening while os is the duration of patient survival from the time of treatment initiation; os is a universally accepted direct measure of clinical benefit. statistical package for the social sciences (spss), version 22.0 (ibm, armonk, ny, usa), was used for data analysis. the chi-squared test of association was used to compare proportions. paired sample t-test was used to compare the mean hb, platelets, ldh levels and spleen size of the patients in both the groups before and after treatment. the five-year os and pfs estimates were calculated using the life table method and cox multivariate analysis was performed to detect the risk factors that affected os and pfs. the kaplan– meier method was used to plot the survival curves. p ≤0.05 was considered statistically significant. this study was approved by the scientific and ethical committees of the college of medicine, hawler medical university in erbil, iraq (no.md 305). results the records of a total of 72 patients were retrospectively examined for this study. the mean age of the studied patients was 59.7 ± 12.4 years. males constituted 52.8% of the sample population and the male-tofemale ratio was 1.1:1. the median time of follow-up was 43 months, with the follow-up time ranging from 15 to 98 months. the majority of the patients in both treatment groups combined (n = 46, 63.9%) were in the high and the intermediate-2 risk ipss groups and the ecog-ps was one and two in 67 patients (93.1%) in total. statistical analysis demonstrated no significant differences between the two groups regarding baseline clinical and laboratory characteristics except for the wbc count which was significantly higher in the ruxolitinib group (p = 0.002). constitutional symptoms were present in 49 (68.1%) patients in total (from both groups), but no significant difference was present between the two (p = 0.225) [table 1]. concerning the efficacy of treatment, mf patients who received ruxolitinib had a significant regression in spleen volume compared to patients in the bat group (p <0.001). the remaining parameters of hb, wbc and platelet levels did not show any significant differences. the mean ldh level reduced following ruxolitinib administration; however, the difference was not statistically significant when compared to the bat group (p = 0.125) [table 2]. the five-year os and the pfs rates among mf patients were 41% and 67%, respectively. the os rate of the ruxolitinib group was significantly higher than that of the bat group (53% versus 26%; p = 0.008) [table 3, figure 1]. similarly, the pfs rate was higher in the ruxolitinib group; however, it did not reach a statistically significant level (p = 0.073) [table 3, figure 2]. the ipss significantly affected both os and pfs in the bat cohort (p = 0.004 and p = 0.001, respectively) but not in the ruxolitinib cohort. the os rate related table 2: comparison of the efficacy of treatment across two groups of patients (treated using either ruxolitinib or the best available therapy) with primary myelofibrosis parameter ruxolitinib bat p value before treatment after treatment before treatment after treatment mean hb in g/dl ± sd 10.5 ± 2.21 9.5 ± 3.04 9.1 ± 2.16 9.4 ± 2.64 0.097 mean wbc in × 109/l ± sd 18.9 ± 13.89 17.6 ± 15.49 10.7 ± 8.12 15.0 ± 17.32 0.136 mean platelets in × 109/l ± sd 263.0 ± 128.9 192.1 ± 117.75 229.2 ± 234.9 364.7 ± 917.65 0.303 mean ldh in u/l ± sd 1125.4 ± 618.6 1058.2 ± 585.80 909.7 ± 560.8 998.4 ± 501.62 0.125 mean spleen volume in cm3 ± sd 934.3 ± 423.3 616.7 ± 384.58 764.4 ± 388.6 894.0 ± 563.29 < 0.001 bat = best available therapy; hb = haemoglobin; sd = standard deviation; ldh = lactate dehydrogenase. *p ≤0.05 was considered statistically significant. evaluation of ruxolitinib versus best available therapy in treating primary myelofibrosis 396 | squ medical journal, august 2022, volume 22, issue 3 significantly to the ecog-ps in both groups. no significant correlation was found between survival rates and the means of wbc, platelet and ldh levels and spleen volume in both groups. the percentage of peripheral blast cells significantly affected the pfs in both cohorts (p = 0.013 and p = 0.004, respectively) and the os in the bat cohort only (p = 0.001). the mean hb level had a significant effect on os in the bat group only (p = 0.018) [table 4]. the cox multivariate analysis of the prognostic factors demonstrated that only the type of treatment had a significant association with the os (hazard ratio = 9.16, 95% ci: 2.81–29.86), while the age of the patients, type of the treatment, hb level, platelet count and high risk as per the ipss were significantly associated with pfs [table 5]. discussion ruxolitinib is a jak inhibitor that has been approved for the treatment of patients with mf. in particular, the food and drug administration (fda) has approved it for intermediate and high-risk mf patients whereas the european medicines agency (ema) has approved it for the treatment of splenomegaly and/or constitutional symptoms, irrespective of the patient’s risk group.8 the median age of the primary mf patients was 60 years and males constituted 53% of the included sample. it is noteworthy that according to the literature, mf in many other parts of the world occurs later in life.9,13,14 the majority of the patients in this study were in the intermediate-2 and high-risk groups and most of their ecog-ps scores were one and two. two-thirds of the patients had constitutional symptoms at the time of diagnosis, a finding that is in alignment with previous studies.6,15 the analysis revealed that ruxolitinib has a significant effect on the regression of the spleen size after 24 weeks of follow-up. conversely, the mean spleen size increased after treatment in the bat cohort and these data are comparable to many other studies.9,10,11,16,17 needless to say, a reduction in the size of the spleen will alleviate the patients’ abdominal complaints and will, hence, improve the patients’ quality of life. furthermore, a study found that a reduction in spleen size following ruxolitinib administration is correlated with higher survival.15 however, the findings of this study could not note such a correlation among the patients, probably due to the small sample size. on the other hand, patients who received treatment with ruxolitinib experienced anaemia and a greater reduction in platelet and wbc count compared to those who received the bat; however, the reduction in the haematological parameters did not reach a statistically significant level. these findings were expected and are attributed to the mechanism of table 3: survival rates (overall survival and progressionfree survival) across two groups of patients (treated using either ruxolitinib or the best available therapy) with primary myelofibrosis type of treatment os in % ( 95% ci) p value pfs in % ( 95% ci) p value ruxolitinib 53 (33.8–72.2) 0.008 79 (63.3–94.7) 0.073 bat 26 (13.3–38.7) 55 (40.6–69.4) os = overall survival; ci = confidence interval; pfs = progression-free survival; bat = best available therapy. *p ≤0.05 was considered statistically significant. figure 1: kaplan-meier cumulative survival curve showing the overall survival rates in relation to the type of treatment among a group of patients with primary myelofibrosis. figure 2: kaplan-meier cumulative survival curve showing the progression-free survival rates in relation to the type of treatment among a group of patients with primary myelofibrosis. kawa m. hasan, ahmed y. elmeshhadany and nazar p. shabila clinical and basic research | 397 action of ruxolitinib. similar observations have been made in many other reports.4,10,18 a very high ldh level is well known as being an independent predictor of shorter os and leukaemiafree survival in primary mf.19 in the current study, no significant correlation between the ldh level and survival rates was observed; however, the mean serum ldh level was elevated in the bat cohort, while it was only slightly (not statistically significant) reduced after ruxolitinib administration. this finding aligned with another study conducted in taiwan, which reported that none of the mf patients had normalised ldh levels after treatment with ruxolitinib.20 table 4: the effect of clinical parameters on the overall survival and progression-free survival rates across two groups of patients (treated using either ruxolitinib or the best available therapy) with primary myelofibrosis parameter ruxolitinib bat os in % p value pfs in % p value os in % p value pfs in % p value age 0.328 0.872 0.090 0.228 <60 years 67 79 44 42 ≥60 years 42 78 16 62 gender 0.166 0.340 0.727 0.337 male 74 71 28 46 female 38 89 22 67 ipss 0.395 0.121 0.004 0.001 high risk 27 55 7 25 intermediate-2 61 100 26 100 intermediate-1 57 100 0 87 low risk 100 100 75 58 ecog-ps 0.003 0.140 0.003 0.125 0 50 100 100 50 1 92 89 37 72 2 11 58 6 56 mean hb in g/dl 0.670 0.068 0.018 0.127 <10 47 64 20 63 ≥10 62 100 37 55 mean wbc in × 109/l 0.780 0.521 0.548 0.980 ≤11 55 88 25 68 >11 55 73 32 53 mean platelets in × 109/l 0.143 0.760 0.666 0.544 <100 0 100 30 61 ≥100 56 79 24 49 mean peripheral blasts in % 0.407 0.013 0.001 0.004 = 0 64 100 42 69 ≥1 36 54 7 34 mean ldh in u/l 0.688 0.413 0.077 0.431 ≤450 75 100 75 75 >450 51 76 21 51 mean spleen volume in cm3 0.262 0.526 0.115 0.349 ≤324 33 100 100 100 >324 56 78 22 54 bat = best available therapy; os = overall survival; pfs = progression-free survival; ipss = international prognostic scoring system; ecog-ps = eastern cooperative oncology group performance status; hb = haemoglobin; wbc = white blood cell; ldh = lactate dehydrogenase. evaluation of ruxolitinib versus best available therapy in treating primary myelofibrosis 398 | squ medical journal, august 2022, volume 22, issue 3 furthermore, the findings of this study demonstr ated that ruxolitinib could affect the survival outcomes, as indicated by the improved os and pfs of the ruxolitinib group of mf patients. many clinical studies using data from the comfort studies have reported similar results.11,21,22 on the other hand, tefferi et al. did not find any survival advantage for ruxolitinib and they related this discrepancy in ruxolitinib’s effect on the survival state to lack of biological evidence (the attainment of remission or reversal of bone marrow fibrosis) and lack of a molecular or cytogenetic response.8,23 additionally, this study found that some of the patients’ characteristics affected the survival rate for mf. the ecog-ps had an impact on the os among both therapeutic groups and this is in line with other studies on the effect of ecog on survival state in mf.24,25 cox multivariate analysis demonstrated that the age of patients, high risk as per the ipss and some of the lab findings (hb level and platelet count) also affected pfs. the age of the patient and hb level are well-known risk factors from the widely used prognostic scores as per the ipss and dipss.6 additionally, a low platelet count is a poor prognostic factor in mf as shown in other studies and the dipssplus classification.26,27 this study is not without limitations. one of the limitations was the relatively small sample which was also retrospectively analysed. additionally, genetic testing was limited to the jak2 mutation analysis. conclusion the findings of the current study revealed that treatment of mf with ruxolitinib has a significant impact on reducing splenic size; in return, this will improve the quality of life and the survival outcomes in patients with myelofibrosis. therefore, the treatment of mf with ruxolitinib has the potential to improve the clinical course of this disease. a u t h o r s’ c o n t r i b u t i o n s kmh and aye collected the data. nps performed the statistical analysis. kmh drafted the manuscript. all authors approved the final version of the manuscript. f u n d i n g no funding was received for this study. c o n f l i c t s o f i n t e r e s t the authors declare no conflicts of interest. references 1. rampal r, al-shahrour f, abdel-wahab o, patel jp, brunel jp, mermel ch, et al. integrated genomic analysis illustrates the central role of jak–stat pathway activation in myeloproliferative neoplasm pathogenesis. blood 2014; 123:e123–33. https://doi. org/10.1182/blood-2014-02-554634. table 5: cox analysis of prognostic factors for survival among patients with primary myelofibrosis factor os pfs p value hazard ratio (95% ci) p value hazard ratio (95% ci) age 0.187 0.97 (0.94–1.01) 0.008 0.85 (0.75–0.96) gender male 1 1 female 0.352 1.50 (0.64–3.52) 0.185 0.24 (0.03–1.96) ruxolitinib 1 1 bat 0.000 9.16 (2.81–29.86) 0.047 13.88 (1.04–185.96) hb level 0.144 0.81 (0.61–1.07) 0.016 0.34 (0.14–0.82) wbc 0.288 1.02 (0.98–1.07) 0.677 0.98 (0.91–1.06) platelet 0.127 1.00 (1.00–1.00) 0.023 1.01 (1.00–1.01) blasts 0.223 1.12 (0.93–1.35) 0.687 0.93 (0.65–1.33) ldh 0.434 1.00 (1.00–1.00) 0.073 1.00 (1.00–1.00) spleen 0.142 1.00 (1.00–1.00) 0.301 1.00 (1.00–1.00) ipss low 1 1 inter mediate-1 0.207 3.43 (0.51–23.23) 0.602 0.36 (0.01–16.98) inter mediate-2 0.237 3.18 (0.47–21.58) high 0.152 5.18 (0.55–49.13) 0.046 93.30 (1.09–7,979.77) ecog-ps 0 1 1 1 0.315 0.26 (0.02–3.54) 0.237 0.09 (0.00–4.84) 2 0.834 1.33 (0.09–19.28) 0.665 0.38 (0.00–31.68) os = overall survival; pfs = progression-free survival; ci = confidence interval; bat = best available therapy; hb = haemoglobin; wbc = white blood cell; ldh = lactate dehydrogenase; ipss = international prognostic scoring system; ecog-ps = eastern cooperative oncology group performance status https://doi.org/10.1182/blood-2014-02-554634 https://doi.org/10.1182/blood-2014-02-554634 kawa m. hasan, ahmed y. elmeshhadany and nazar p. shabila clinical and basic research | 399 2. mesa ra, verstovsek s, cervantes f, barosi g, reilly jt, dupriez b, et al. primary myelofibrosis (pmf), post polycythemia vera myelofibrosis (post-pv mf), post essential thrombocythemia myelofibrosis (post-et mf), blast phase pmf (pmf-bp): consensus on terminology by the international working group for myelofibrosis research and treatment (iwg-mrt). leuk res 2007; 31:737–40. https://doi.org/10.1016/j.leukres.2006.12.002. 3. klampfl t, gisslinger h, harutyunyan as, nivarthi h, rumi e, milosevic jd, et al. somatic mutations of calreticulin in myeloproliferative neoplasms. n engl j med 2013; 369:2379–90. https://doi.org/10.1056/nejmoa1311347. 4. verstovsek s, kantarjian h, mesa ra, pardanani ad, cortesfranco j, thomas da, et al. safety and efficacy of incb018424, a jak1 and jak2 inhibitor, in myelofibrosis. n engl j med 2010; 363:1117–27. https://doi.org/10.1056/nejmoa1002028. 5. tefferi a. myelofibrosis with myeloid metaplasia. n engl j med 2000; 342:1255–65. https://doi.org/10.1056/nejm2000 04273421706. 6. cervantes f, dupriez b, pereira a, passamonti f, reilly jt, morra e, et al. new prognostic scoring system for primary myelofibrosis based on a study of the international working group for myelofibrosis research and treatment. blood 2009; 113:2895–901. https://doi.org/10.1182/blood-2008-07-170449. 7. cervantes f. how i treat myelofibrosis. blood 2014; 124:2635–42. https://doi.org/10.1182/blood-2014-07-575373. 8. cervantes f, pereira a. does ruxolitinib prolong the survival of patients with myelofibrosis? blood 2017; 129:832–7. https:// doi.org/10.1182/blood-2016-11-731604. 9. verstovsek s, mesa ra, gotlib j, levy rs, gupta v, dipersio jf, et al. a double-blind placebo-controlled trial of ruxolitinib for myelofibrosis. n engl j med 2012; 366:799–807. https://doi. org/10.1056/nejmoa1110557. 10. harrison c, kiladjian j-j, al-ali hk, gisslinger h, waltzman r, stalbovskaya v, et al. jak inhibition with ruxolitinib versus best available therapy for myelofibrosis. n engl j med 2012; 366:787–98. https://doi.org/10.1056/nejmoa1110556. 11. bryan jc, verstovsek s. overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib. cancer chemother pharmacol 2016; 77:1125–42. https://doi. org/10.1007/s00280-016-3012-z. 12. arber da, orazi a, hasserjian r, thiele j, borowitz mj, le beau mm, et al. the 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. blood 2016; 127:2391–405. https://doi.org/10.1182/ blood-2016-03-643544. 13. iurlo a, cattaneo d. treatment of myelofibrosis: old and new strategies. clin med insights blood disord 2017; 10:1–10. https://doi.org/10.1177/1179545x17695233. 14. benites bd, lima csc, lorand-metze i, delamain mt, oliveira gb, de almeida d, et al. primary myelofibrosis: risk stratification by ipss identifies patients with poor clinical outcome. clinics (sao paulo) 2013; 68:339–43. https://doi. org/10.6061/clinics/2013(03)oa09. 15. takenaka k, shimoda k, akashi k. recent advances in the diag nosis and management of primary myelofibrosis. korean j intern med 2018; 33:679–90. https://doi.org/10.3904/kjim.2018.033. 16. kantarjian hm, silver rt, komrokji rs, mesa ra, tacke r, harrison cn. ruxolitinib for myelofibrosis—an update of its clinical effects. clin lymphoma myeloma leuk 2013; 13:638–45. https://10.1016/j.clml.2013.09.006. 17. verstovsek s, mesa ra, gotlib j, gupta v, dipersio j, catalano j, et al. long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, doubleblind, placebo-controlled, phase 3 comfort-i trial. j hematol oncol 2017; 10:55. https://10.1186/s13045-017-0417-z. 18. shi jg, chen x, mcgee rf, landman rr, emm t, lo y, et al. the pharmacokinetics, pharmacodynamics, and safety of orally dosed incb018424 phosphate in healthy volunteers. j clin pharmacol 2011; 51:1644–54. https://doi.org/10.1177/ 0091270010389469. 19. shah s, mudireddy m, hanson ca, ketterling r, gangat n, pardanani a, et al. marked elevation of serum lactate dehydro genase in primary myelofibrosis: clinical and prognostic correl ates. blood cancer j 2017; 7:657. https://doi.org/10.1038/ s41408-017-0024-9. 20. chen y-y, huang c-e, lee k-d, chen c-c. clinical efficacy and safety of ruxolitinib in the management of myelofibrosis: a single institution experience in taiwan. hematology 2016; 21:3–9. https://doi.org/10.1179/1607845415y.0000000036. 21. verstovsek s, kantarjian hm, estrov z, cortes je, thomas da, kadia t, et al. long-term outcomes of 107 patients with mye lofibrosis receiving jak1/jak2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. blood 2012; 120:1202–9. https://doi.org/10.1182/blood-2012-02-414631. 22. schain f, vago e, song c, he j, lewing j, löfgren c, et al. survival outcomes in myelofibrosis patients treated with ruxo litinib: a population-based cohort study in sweden and norway. eur j haematol 2019; 103:614–19. https://doi.org/10.1111/ ejh.13330. 23. tefferi a, litzow mr, pardanani a. long-term outcome of treatment with ruxolitinib in myelofibrosis. n engl j med 2011; 365:1455–7. https://doi.org/10.1056/nejmc1109555. 24. newberry kj, naqvi k, nguyen kt, cardenas-turanzas m, tanaka mf, pierce s, et al. comorbidities predict worse prognosis in patients with primary myelofibrosis. cancer 2014; 120:2996–3002. https://doi.org/10.1002/cncr.28857. 25. bartoszko j, panzarella t, mcnamara cj, lau a, schimmer ad, schuh ac, et al. distribution and impact of comorbidities on survival and leukemic transformation in myeloproliferative neoplasm-associated myelofibrosis: a retrospective cohort study. clin lymphoma myeloma leuk 2017; 17:774–81. https:// doi.org/10.1016/j.clml.2017.06.031. 26. tam cs, kantarjian h, cortes j, lynn a, pierce s, zhou l, et al. dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. j clin oncol 2009; 27:5587–93. https://10.1200/jco.2009.22.8833. 27. gangat n, caramazza d, vaidya r, george g, begna k, schwager s, et al. dipss plus: a refined dynamic international prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. j clin oncol 2011; 29:392–7. https://doi.org/10.1200/jco.2010.32.2446. https://doi.org/10.1016/j.leukres.2006.12.002 https://doi.org/10.1056/nejmoa1311347 https://doi.org/10.1056/nejmoa1002028 https://doi.org/10.1056/nejm200004273421706 https://doi.org/10.1056/nejm200004273421706 https://doi.org/10.1182/blood-2008-07-170449 https://doi.org/10.1182/blood-2014-07-575373 https://doi.org/10.1182/blood-2016-11-731604 https://doi.org/10.1182/blood-2016-11-731604 https://doi.org/10.1056/nejmoa1110557 https://doi.org/10.1056/nejmoa1110557 https://doi.org/10.1056/nejmoa1110556 https://doi.org/10.1007/s00280-016-3012-z https://doi.org/10.1007/s00280-016-3012-z https://doi.org/10.1182/blood-2016-03-643544 https://doi.org/10.1182/blood-2016-03-643544 https://doi.org/10.1177/1179545x17695233 https://doi.org/10.6061/clinics/2013(03)oa09. https://doi.org/10.6061/clinics/2013(03)oa09. https://doi.org/10.3904/kjim.2018.033 https://10.1016/j.clml.2013.09.006 https://10.1186/s13045-017-0417-z https://doi.org/10.1177/0091270010389469 https://doi.org/10.1177/0091270010389469 https://doi.org/10.1038/s41408-017-0024-9 https://doi.org/10.1038/s41408-017-0024-9 https://doi.org/10.1179/1607845415y.0000000036 https://doi.org/10.1182/blood-2012-02-414631 https://doi.org/10.1111/ejh.13330 https://doi.org/10.1111/ejh.13330 https://doi.org/10.1056/nejmc1109555 https://doi.org/10.1002/cncr.28857 https://doi.org/10.1016/j.clml.2017.06.031 https://doi.org/10.1016/j.clml.2017.06.031 https://10.1200/jco.2009.22.8833 https://doi.org/10.1200/jco.2010.32.2446 department of surgery, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mails: alkindi2001@gmail.com and adil.h.alkindi@gmail.com giant intrathoracic lipoma mohammad s. siddiqi, *adil h. al kindi, malyar al marhoon, abdulmageed salem sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 670–672, epub. 25 nov 21 submitted 23 dec 20 revision req. 3 feb 21; revision recd. 17 feb 21 accepted 9 mar 21 most lipomas are slow-growing soft tissue tumours that rarely reach 2 cm in size. those reaching more than five cm are called giant lipomas and are an exceedingly rare entity.1 the following is a description of a case of a large intrathoracic lipoma compressing the right lung managed by complete excision through a median sternotomy. a 27-year-old female patient presented to the obstetrics department of a tertiary care hospital in muscat, oman, in 2019 with abdominal pain. an abdominal x-ray revealed a space-occupying lesion on the right side of the chest above the diaphragm as an incidental finding. the patient was referred to the cardiothoracic surgery department for assessment and management. a computed tomography scan showed an anterior mediastinal mass extending into the right thoracic cavity [figure 1]. magnetic resonance imaging showed a large fat density lesion in the right hemithorax that appeared inseparable from the thymus [figure 2]. the mass was exposed through median sterno tomy given that the tumour was arising from the anterior mediastinum. following sternotomy, the large mass was seen arising from the thymic area and extending into the right pleural cavity above the diaphragm and compressing the right lower lobe of the lung. the tumour grossly appeared as a light-yellow coloured, soft, encapsulated mass with a smooth surface [figure 3]. it was attached by its pedicle to the thymus, adjacent to the right phrenic nerve. removed en-bloc along with the thymus gland, the tumour weighed 2.32 kg and measured 38 × 26 × 15 cm in dimensions. a histopathology of the specimen confirmed the diagnosis of benign thymolipoma [figure 4]. the post-operative period was uneventful and the patient was discharged after four days. consent was obtained from the patient for the publication of the case and associated images. comment lipomas are benign mesenchymal tumors.2 although they are predominantly found originating in the subcutaneous tissues of the body, they can rarely originate in the intrathoracic cavity in the mediastinum or intrapulmonary areas. intrathoracic lipoma has two variants: an hourglass or dumbbell-shaped tumour that originates in the subcutaneous tissue and enters through the intercostal space or thoracic inlet into the thoracic cavity while the other is purely intrathoracic.3 the current case belongs to the second category as the tumour was situated entirely within the chest cavity. mediastinal lipomas commonly originate within the anterior mediastinum and constitute 1.6–2.3% of all primary mediastinal tumors.2 thymolipoma is a this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.052 interesting medical image a b figure 1: computed tomography scans showing (a) coronal and (b) axial views of a huge and well-defined intrathoracic mass in a 27-year-old female. mohammad s. siddiqi, adil h. al kindi, malyar al marhoon and abdulmageed salem interesting medical image | 671 benign variant of this type and accounts for 2–9% of all thymic neoplasms.4 microscopic examination typically shows exuberant lymphoid nodular hyperplasia with thymomatous differentiation, as is seen in the current case. liposarcoma was reported to constitute 9% of all anterior mediastinal malignancies in a case series by burt et al.5 these lipomas are slow-growing and patients generally remain asymptomatic until the lipoma grows to a large size and starts producing compressive symptoms. the symptoms of dyspnoea and dysphagia are due to pressure effects on the trachea and oesophagus, respectively.5 these lipomas are found incidentally during radiological examination in the majority of cases. computed tomography provides a confirmed diagnosis when it shows a homogeneous fatty attenuation (−50 to −150 hounsfield units) forming an obtuse angle with the chest wall and compressing the adjacent structures.6 the density may vary because lipomas often contain fibrous elements.6 in the current case, the mass appeared to be benign as it was well-encapsulated with well-circumscribed margins. malignant lesions tend to invade the surrounding structures and are symptomatic. on imaging, they produce non-homogenous enhancing density with variable fat and soft tissue density, along with an invasion of surrounding structures.7 the current recommendations include complete excision whenever feasible because it is difficult to differentiate a lipoma from liposarcoma preoperatively and, albeit low risk, they may undergo malignant transformation. the approach depends on the site and the size of the mass. median sternotomy, or thoracotomy, appears to be the best procedure for total resection of these large masses. video-assisted thoracoscopy can be used in small, uncomplicated and adhesion-free tumours. the local recurrence of these tumours is uncommon and has been reported to be less than 5%.8 the overall prognosis after complete resection is excellent. a u t h o r s’ c o n t r i b u t i o n mss drafted the manuscript and aak edited the manuscript. mam performed the literature review. ams formatted the images. all authors approved the final version of the manuscript. figure 2: magnetic resonance imaging scan showing (a) coronal and (b) axial views of a large fat density lesion at the thymic level appearing inseparable from the thymus in the right hemithorax of a 27-year-old female. figure 3: photograph of a mediastinal mass with an attachment to the thymus in the anterior mediastinum following dissection in a 27-year-old female. figure 4: haematoxylin and eosin stain at ×400 magnification of a mediastinal mass showing islands of unremarkable thymic tissue within a mature adipose tissue of a 27-year-old female patient. giant intrathoracic lipoma 672 | squ medical journal, november 2021, volume 21, issue 4 references 1. cribb gl, cool wp, ford dj, mangham dc. giant lipomatous tumours of the hand and forearm. j hand surg br 2005; 30:509–12. https://doi.org/10.1016/j.jhsb.2005.05.002. 2. politis j, funahashi a, gehlsen ja, decock d, stengel bf, choi h: intrathoracic lipomas: report of three cases and review of the literature with emphasis on endobronchial lipoma. j thorac cardiovasc surg 1979, 77:550–6. https://doi.org/10.1016/s002 2-5223(19)38260-1. 3. keeley jl, vana aj: collective reviews: lipomas of the mediastinum: 1940– 1955. int abstr surg 1955; 103:313–22. 4. gaerte sc, meyer ca, winer-muram ht, traver rd, conces dj: fat-containing lesions of the chest. radiographics 2002; 22:61–78. https://doi.org/10.1148/radiographics.22.suppl_1.g02oc08s61. 5. burt m, ihde jk, hajdu si, smith jw, bains ms, downey r, et al. primary sarcomas of the mediastinum: results of therapy. j thorac cardiovasc surg 1998; 115:671–80. https://doi. org/10.1016/s0022-5223(98)70333-2. 6. buxton rc, tan cs, khane nm, cuasay ns, shor mj, spigos dg. atypical transmural thoracic lipoma: ct diagnosis. j comput assist tomogr 1988, 12:196–8. https://doi. org/10.1097/00004728-198803000-00002. 7. shahrzad m, le tsm, silva m, bankier aa, eisenberg rl. anterior mediastinal masses. ajr am j roentgenol 2014; 203:w128–38. https://doi.org/10.2214/ajr.13.11998. 8. sakurai h, kaji m, yamazaki k, suemasu k: intrathoracic lipomas: their clinicopathological behaviors are not as straightforward as expected. ann thorac surg 2008; 86:261–5. https://doi.org/10.1016/j.athoracsur.2008.03.052. 1department of anatomy, katuri medical college & hospital, guntur, andhra pradesh, india; 2department of anatomy, all india institute of medical sciences, mangalagiri, andhra pradesh, india *corresponding author’s e-mail: snandha@gmail.com دراسة ُجثّية للشقوق الطِّحالية واألْطِحلة ثنائية الفصوص �ساجنيثا اأروموجام وناندا كومار �سوبيا abstract: objectives: anatomical knowledge regarding the external morphology of the spleen is essential for surgical intervention and radiological diagnosis. a characteristic feature of the spleen is the presence of splenic notches at the superior border; however, such notches rarely extend deep enough to be considered fissures or to separate the spleen into multiple lobes. to date, there are very few cadaveric reports of splenic fissures. this study aimed to examine the anatomy and morphological structure of spleens collected from cadavers in order to identify the prevalence and clinical significance of splenic notches, fissures and lobation. methods: this study was conducted at the department of anatomy, katuri medical college and hospital, guntur, andhra pradesh, india. a total of 50 spleens were collected from cadavers over a period of seven years from 2012–2019 and examined to determine the presence of splenic notches or fissures. results: of the 50 spleens, 40% had notches at the superior border, 10% had notches at the inferior border and 50% had no notches at either border. fissures were present in five spleens (10%); of these, three showed incomplete fissures and the remaining two had complete fissures that divided the spleen into two lobes. conclusion: the findings of this study provide valuable information regarding the anatomy and prevalence of splenic fissures and bilobed spleens. a bilobed spleen is a rare congenital malformation which should be considered distinct from other known splenic anomalies. the presence of splenic fissures in bilobed spleens can serve as a guide for surgeons during conservatory splenectomy procedures. keywords: anatomic variation; spleen; anatomy and histology; abnormalities; congenital abnormalities; splenectomy; india. حال اأ�سا�سية للتدخل اجلراحي والت�سخي�ص الإ�سعاعي. ال�سمة املميزة املعرفة الت�رشيحية املتعلقة بال�سكل اخلارجي للطِّ الهدف: امللخ�ص: َلٌم ِطحالية على احلافة العلوية؛ غري انه نادًرا ما متتد هذه الثَُّلم بعمق كاٍف لعتبارها �سقوًقا اأولف�سل الطحال اإىل ف�سو�ص حال هي وجود ثُّ للطِّ حالية. هدفت هذه الدرا�سة اإىل فح�ص الت�رشيح والبنية ال�سكلية متعددة. اىل يومنا هذا هناك عدد قليل جًدا من التقارير اجلثثية عن ال�سقوق الطِّ حايل واأهميتها ال�رشيرية. الطريقة: �ص الطِّ حالية والَتَف�سُّ للأْطِحلة التي مت جمعها من اجلثث من اأجل التعرف على مدى انت�سار الثَُّلم وال�سقوق الطِّ اأجريت هذه الدرا�سة يف ق�سم الت�رشيح بكلية وم�ست�سفى كاتوري الطبي، جونتور، اأندرا برادي�ص، الهند. مت جمع ما جمموعه 50 ِطحاًل من جثث َلما عند حالية. النتائج: من بني 50 ِطحاًل، %40 كان لديها ثُّ على مدى �سبع �سنوات من 2019-2012 وفح�سها لتحديد وجود الثَُّلم اأو ال�سقوق الطِّ َلٌم عند اأي من احلواف. كانت ال�سقوق موجودة يف خم�سة َلما عند احلافة ال�سفلية و %50 منها لي�ص لديها ثُّ احلافة العلوية و %10 منها لديها ثُّ حال اإىل ف�سني. اخلال�صة: توفر نتائج اأْطِحلة )%10(. اأظهر ثلثة منها �سقوًقا غري مكتملة وكان لدى الثنان املتبقيان �سقوقا كاملة ق�سمت الطِّ حال ثنائي الف�سو�ص هو ت�سوه حالية والأْطِحلة ثنائية الف�سو�ص. الطِّ هذه الدرا�سة معلومات قيمة فيما يتعلق بت�رشيح ومدى انت�سار ال�سقوق الطِّ حال يف الأْطِحلة ثنائية الف�سو�ص قد ي�ستخدم كمر�سد حال املعروفة الأخرى. وجود �سقوق الطِّ ِخلقي نادر يجب اعتباره متميًزا عن ت�سوهات الطِّ حال التحفظية. للجراحني اأثناء عمليات ا�ستئ�سال الطِّ حال؛ الهند. الكلمات املفتاحية: الختلف الت�رشيحي؛ ِطحال؛ علم الت�رشيح وعلم الأن�سجة؛ ت�سوهات؛ ت�سوهات ِخْلقّية؛ ا�ستئ�سال الطِّ a cadaveric study of splenic fissures and bilobed spleen sangeetha arumugam1 and *nandha k. subbiah2 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e346–351, epub. 21 dec 20 submitted 13 nov 19 revisions req. 25 dec 19 & 2 mar 20; revisions recd. 19 jan & 22 mar 20 accepted 8 apr 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.011 clinical & basic research advances in knowledge the present study provides a complete anatomical description of splenic fissures and bilobed spleens collected over a seven-year period. bilobed spleen is a rare congenital malformation which should be considered distinct from other known congenital defects of the spleen. application to patient care these findings will help radiologists to differentiate bilobed spleens from other adjacent solid masses. moreover, splenic fissures represent avascular planes which can act as a guide for surgeons performing conservatory splenectomies following injury. the spleen is the largest lymphoid organ and is located in the left upper quadrant of the abdomen.1,2 among adults, the spleen is wedge shaped, approximately 3 × 12 × 7 cm in dimension and 150 g in weight and has a smooth serosal surface. the organ has two surfaces, the visceral and parietal surfaces, and three borders known as the superior, inferior and intermediate borders.1,2 in certain cases, https://creativecommons.org/licenses/by-nd/4.0/ sangeetha arumugam and nandha k. subbiah clinical and basic research | e347 the superior border can have between 2−4 notches which arise during embryological development.1–4 in contrast, notches do not typically occur on the intermediate or inferior borders.2 splenic notches along the superior border are often used as a clinical guide to palpate an enlarged spleen.3 however, in some variant spleens, the notches extend as fissures on both the costal and visceral surfaces, dividing the spleen into two or more lobes.5 moreover, the presence of notches along the inferior border can lead to complications in defining the borders of the spleen and adjacent structures such as the stomach and kidneys. in some cases, fluid can accumulate in splenic fissures due to their depth and be misdiagnosed as lacerations during radiological investigations.6 blunt trauma of the abdomen most often involves the spleen and leads to intraabdominal complications such as haemorrhage and peritonitis. although a complete splenectomy is the treatment of choice for splenic injuries, modern protocols advocate for a partial splenectomy in less severe cases with a view to preventing postoperative complications.2 from this perspective, it is imperative that radiologists and surgeons understand the complete anatomy of the spleen—including the splenic artery, ligaments, segments and lobes—and its position relative to other surrounding structures.7 however, few cadaveric reports have been published describing splenic fissures and bilobed spleens. hence, the present study was performed to identify and assess the clinical significance of splenic notches, fissures and lobation among spleens collected from cadavers over a sevenyear period. methods the present study was conducted with specimens collected between december 2012 and march 2019 at the department of anatomy of the katuri medical college and hospital in guntur, andhra pradesh, india. a total of 50 spleens were collected from cadavers of unknown medical history over the study period. the spleens were removed during routine dissection of the abdominal region by cutting the splenic vessels near the hilum and carefully detaching the organ from the peritoneum. following removal, the spleens were preserved in 10% formalin. each spleen was carefully examined to determine the presence of splenic notches, fissures and lobation. spleens possessing abnormal notches, fissures and more than one lobe were photographed. the data were tabulated and subjected to further analysis using an excel spreadsheet, version 2016 (microsoft corp., redmond, washington, usa). subsequently, findings were compared with those from previously reported studies in the literature. this study received ethical approval from the college ethics committee of the katuri medical college and hospital. all cadavers included in the study were unclaimed bodies issued by governmental tertiary care hospitals for use in teaching and research. results of the 50 spleens, 20 (40%) had notches at the superior border and five (10%) at the inferior border, while the remaining 25 spleens (50%) had no notches at either border. fissures were observed in five spleens (10%). among those with splenic notches, the number of notches varied from 2–4 at the superior border and 1–2 at the inferior border. fissures were classified as either complete or incomplete based on the depth and extent of the opening. complete and incomplete fissures were observed in two (4%) and three (6%) spleens, respectively. in one spleen with a complete fissure, the cleft extended from the superior to the inferior border of the diaphragmatic surface, divided it into two lobes (bilobed spleen) [figure 1a]; moreover, each lobe had a separate hilum, as shown on the visceral surface [figure 1b]. in another spleen, two notches were observed at the inferior border on the diaphragmatic surface [figures 2a and b], one of which extended as a fissure from the inferior border to the hilum, dividing the spleen into two lobes that were visible only on the visceral surface [figures 2c and d]. in the remaining three spleens, incomplete fissures of approximately 3−4 cm in length were visible on the diaphragmatic and visceral surfaces, extending to a depth of approximately figure 1: photographs of the (a) diaphragmatic and (b) visceral surfaces of a cadaveric spleen with a complete fissure dividing the spleen into two lobes (i.e. a bilobed spleen). l = lobe; h = hilum. a cadaveric study of splenic fissures and bilobed spleen e348 | squ medical journal, november 2020, volume 20, issue 4 0.5−1 cm without lobation [figure 3a–c]. a repres entative spleen with no fissures or notches at either border is shown in figure 3d for comparative purposes. discussion in humans, the spleen begins to develop during the fourth week of gestation during mesenchymal condensation in the dorsal mesogastrium of the lesser figure 2: photographs of the (a & b) diaphragmatic and (c & d) visceral surfaces of cadaveric spleens with notches (arrows) on the inferior border. using a hook retractor, the notches were found to extend in the form of a fissure from the inferior border to the hilum. h = hilum. figure 3: photographs of the diaphragmatic surface of cadaveric spleens with incomplete fissures showing the fissures (arrows) extending from either the (a) superior border or (b & c) inferior border to the diaphragmatic surface and a (d) normal spleen without any notches or fissures. figure 4: a: schematic of a bilobed spleen with separate hila and polar artery branches. b: model of a bilobed spleen showing the avascular plane between the two lobes. table 1: literature review of studies assessing the topic of spleen segmentation20–24 author and year of publication number of segments redmond et al.24 (1989) 2 gutierrez cubillos20 (1969) 2–4 gupta et al.21 (1976) 2−4 mikhail et al.22 (1979) 5 voboril23 (1982) 6 present study (2020) 2 sangeetha arumugam and nandha k. subbiah clinical and basic research | e349 sac. later, these mesenchymal cells differentiate to form lobules which subsequently fuse together to form a lymphatic organ, the spleen.3,4 the fusion of multiple lobules leads to the formation of notches on the superior border of the spleen.8,9 while the fetal spleen is typically lobulated, the majority of these lobules disappear before birth; however, some can persist and be seen at the hilum as an accessory spleen. accessory spleens are one of the most frequent congenital splenic anomalies and are sometimes located on the upper pole of the kidney, thereby leading to misdiagnosis as a renal mass or tumour.10 splenomegaly is a symptom of various haematol ogical, immunological and infectious diseases. clin ically, enlarged spleen is identified during palpation due to the presence of notches on its superior border.3 radiologically, splenic notches also help to differentiate the spleen from other viscera in the left hypochondriac region.10 humans typically possesses 4−5 notches along the superior border of the spleen, with the presence of a greater number of notches indicating its embryological persistence.1,3 however, as reported by gandhi et al., some variant spleens can possess as many as seven notches on the superior border.11 in the present study, the maximum number of notches on the superior border was four. previous studies have shown variations in the percentage of spleens possessing notches along the superior border (50–98%).2,5,8,10 however, in the present study, the prevalence of splenic notches was much lower (40%). skandalakis et al. reported that splenic notches indicate the entrance of multiple arteries to the organ; as such, special care should be taken to ligate these arteries during surgical procedures involving the spleen.2 the presence of notches along the inferior border is a rare occurrence, with previous studies reporting the incidence of this feature to be very low (4–8%).8,12 in the current study, five spleens (10%) possessed notches on the inferior border; in fact, in one case, two notches were seen on the inferior border, one of which extended as a fissure up to the hilum, dividing the spleen into two lobes on the visceral surface with a single hilum. this abnormal fissure could result from a developmental defect during fusion of the splenic lobules or due to the compression effect of adjacent organs.8 such fissures may mimic a splenic tear or laceration in cases of abdominal trauma, potentially leading to diagnostic pitfalls. no notches were visible on either border among the remaining spleens in the current study (50%). the absence of notches has no clinical relevance; from an embryological perspective, this simply suggests the complete fusion of the splenic lobules during fetal development.4 splenic fissures are notches that extend to a depth of 2–3 cm and can be seen on both the diaphragmatic and visceral surfaces of the spleen.8,13 the occurrence of deep fissures on the diaphragmatic surface is uncommon.8,13 in the present study, only one spleen showed a complete fissure extending from the superior to the inferior border of the diaphragmatic surface, dividing the spleen into two lobes. similarly, das et al. observed this feature in only 2% of cases.8 nayak et al. reported a case in which a bilobed spleen was divided by a single fissure on the costal/diaphragmatic surface, with the presence of multiple hila.14 it would seem that the occurrence of a complete fissure dividing the spleen into two lobes is very rare.15 ultrasonography and computed tomography (ct)—the modalities most commonly used for imaging the spleen—typically show a homogenous pattern.16 however, bilobed spleens may show a mottled heterogeneous enhancement pattern (i.e. a zebra-like pattern) during arterial-phase ct due to variable blood flow rates through the sinuses of the red pulp.17 this is a significant finding which can help to distinguish normal and bilobed spleens. furthermore, bilobed spleens should be differentiated from a wide variety of other congenital splenic anomalies such as accessory spleens, splenunculi and other adjacent solid masses. the medial lobe of a bilobed spleen is most often misdiagnosed as a solid mass arising from the gastric fundus, left adrenal gland, upper pole of the left kidney or the body or tail of the pancreas; moreover, it often displaces the left kidney to a lower position.9 hence, clinicians should be aware of the possibility of fissures dividing the spleen into two lobes, in addition to other congenital anomalies, in order to successfully differentiate bilobed spleens from the adjacent viscera. the existence of splenic notches has long raised questions regarding segmentation of the spleen. in 1870, researchers observed that the human spleen consists of segments divided by fibrous septa, similar to that seen in animals such as cats, dogs and horses.18 subsequently, in 1956, braithwaite and adams injected radiopaque media into the spleens or tributaries of the portal venous system of rats which confirmed that the spleen consists of distinct segments, each of which has its own dedicated arterial supply and venous drainage.19 despite multiple studies on this topic, there is as yet no consensus regarding the precise number of spleen segments in humans [table 1].20–24 both gutierrez cubillos and gupta et al. reported the presence of 2−4 segments, while mikhail et al. revealed up to five individual lobes.20–22 voboril found as many as 10 distinct segments with a mean of six.23 using a combination of gross dissection, casting and a cadaveric study of splenic fissures and bilobed spleen e350 | squ medical journal, november 2020, volume 20, issue 4 radiological methods, redmond et al. claimed that the spleen had three segments, consisting of one central segment and one at each pole.24 anatomical knowledge regarding splenic vasculature is vital during surgeries involving the spleen. in general, splenic vessels do not anastomose, resulting in several vascular segments separated by avascular planes.25 during splenic lobectomies or segmentectomies, the first step involves the ligation of vessels in the injured lobe or segment.26,27 in the current study, the bilobed spleen had a single fissure resulting in two lobes, both of which were equal in size and of a similar shape. the splenic artery arises almost invariably from the coeliac axis along with the left gastric and hepatic arteries.1 in contrast, the authors hypothesise that bilobed spleens have two polar branches arising from the splenic artery, with the single fissure representing the avascular plane of division [figure 4]. these avascular planes between segments can be used to minimise blood loss during subtotal splenectomies.28 moreover, splenic fissures in bilobed spleens can serve as a guide to assist surgeons in the ligation of vessels during partial splenectomies. conclusion in cases of blunt abdominal trauma, knowledge of the complete morphology and anatomy of abdominal organs such as the liver, spleen, pancreas and kidneys is vital. the present study describes the incidence of notches, fissures and lobation in spleens collected from cadavers over a seven-year period. gross variations in the presence of notches and fissures were observed on both the visceral and diaphragmatic surfaces and extending to various depths, sometimes dividing the spleen into two separate lobes. bilobed spleens are one of the rarest types of congenital splenic anomalies. these findings are valuable for distinguishing splenic variations from other visceral abnormalities in abdominal imaging and during conservatory splenectomies. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. standring s, ed. gray’s anatomy: the anatomical basis of clinical practice, 39th ed. london, uk: churchill livingstone, 2005. pp. 1239–44. 2. skandalakis je. skandalaki’s surgical anatomy: the embryologic and anatomic basis of modern surgery. nicosia, cyprus: broken hill publishers ltd., 2004. pp. 1231–77. 3. moore kl, persaud tv. the developing human: clinically oriented embryology, 6th ed. philadelphia, pennsylvania, usa: saunders, 1998. pp. 271–302. 4. larsen wj, ed. human embryology, 2nd ed. philadelphia, pennsylvania, usa: saunders, 1997. pp. 229–59. 5. nayak bs, somayaji sn, soumya kv. a study on the variations of size, shape and external features of the spleen in south indian population. int j morphol 2011; 29:675–77. https://doi. org/10.4067/s0717-95022011000300001. 6. dodds wj, taylor aj, erickson sj, stewart et, lawson tl. radiologic imaging of splenic anomalies. ajr am j roentgenol 1990; 155:805–10. https://doi.org/10.2214/ajr.155.4.2119113. 7. zarzaur bl, rozycki gs. an update on nonoperative manage ment of the spleen in adults. trauma surg acute care open 2017; 2: e000075. https://doi.org/10.1136/tsaco-2017-000075. 8. das s, abd latiff a, suhaimi fh, ghazalli h, othman f. anomalous splenic notches: a cadaveric study with clinical importance. bratisl lek listy 2008; 109:513–16. 9. gayer g, hertz m, strauss s, zissin r. congenital anomalies of the spleen. semin ultrasound ct mr 2006; 27:358–69. https:// doi.org/10.1053/j.sult.2006.06.002. 10. ungör b, malas ma, sulak o, albay s. development of spleen during the fetal period. surg radiol anat 2007; 29:543–50. https://doi.org/10.1007/s00276-007-0240-2. 11. gandhi kr, chavan sk, oommen sa. spleen with multiple notches: a rare anatomical variant with its clinical significance. int j stud res 2013; 3:24–5. https://doi.org/10.4103/22307095.113829. 12. parsons fg. notches and fissures of the spleen. j anat physiol 1901; 35:416–27. 13. nayak sb, kumar v, kumar n, jetti r. unusual fissure on the diaphragmatic surface of the spleen: a case report. int j anat var 2012; 5:96–8. 14. nayak sb, shetty p, deepthinath r, sirasanagandla sr, shetty sd. a lobulated spleen with multiple fissures and hila. j clin diagn res 2014; 8:ad01–2. https://doi.org/10.7860/ jcdr/2014/8996.4774. 15. yildiz ae, ariyurek mo, karcaaltincaba m. splenic anomalies of shape, size, and location: pictorial essay. scientificworldjournal 2013; 2013:321810. https://doi.org/10.1155/2013/321810. 16. vancauwenberghe t, snoeckx a, vanbeckevoort d, dymarkowski s, vanhoenacker fm. imaging of the spleen: what the clinician needs to know. singapore med j 2015; 56:133–44. https://doi.org/10.11622/smedj.2015040. 17. ali hm. bilobed spleen: an extremely rare imaging finding. bjr case rep 2017; 3:20170021. https://doi.org/10.1259/ bjrcr.20170021. 18. kyber e. über die milz des menschen und einiger säugetiere [concerning the spleen of humans and some other mammals]. arch mikrosk anat 1870; 6: 540–80. 19. braithwaite jl, adams dj. vascular compartments in the rat spleen. nature 1956; 178:1178–9. https://doi.org/10.1038/1781178a0. 20. gutierrez cubillos c. segmentación esplénica [splenic segmentation]. rev esp enferm apar dig 1969; 29:341–50. 21. gupta cd, gupta sc, arora ak, singh pj. vascular segments in the human spleen. j anat 1976; 121:613–16. 22. mikhail y, kamel r, nawar nn, rafla mf. observations on the mode of termination and parenchymal distribution of the splenic artery with evidence of splenic lobation and segmentation. j anat 1979; 128:253–8. https://doi.org/10.4067/s0717-95022011000300001 https://doi.org/10.4067/s0717-95022011000300001 https://doi.org/10.2214/ajr.155.4.2119113 https://doi.org/10.1136/tsaco-2017-000075 https://doi.org/10.1053/j.sult.2006.06.002 https://doi.org/10.1053/j.sult.2006.06.002 https://doi.org/10.1007/s00276-007-0240-2 https://doi.org/10.4103/2230-7095.113829 https://doi.org/10.4103/2230-7095.113829 https://doi.org/10.7860/jcdr/2014/8996.4774 https://doi.org/10.7860/jcdr/2014/8996.4774 https://doi.org/10.1155/2013/321810 https://doi.org/10.11622/smedj.2015040 https://doi.org/10.1259/bjrcr.20170021 https://doi.org/10.1259/bjrcr.20170021 https://doi.org/10.1038/1781178a0 sangeetha arumugam and nandha k. subbiah clinical and basic research | e351 23. voboril z. on the question of segmentation of the human spleen. folia morphol (praha) 1982; 30:295–314. 24. redmond hp, redmond jm, rooney bp, duignan jp, bouchierhayes dj. surgical anatomy of the human spleen. br j surg 1989; 76:198–201. https://doi.org/10.1002/bjs.1800760230. 25. garcía-porrero ja, lemes a. arterial segmentation and subsegmentation in the human spleen. acta anat (basel) 1988; 131:276–83. https://doi.org/10.1159/000146529. 26. liu dl, xia s, xu w, ye q, gao y, qian j. anatomy of vasculature of 850 spleen specimens and its application in partial splenectomy. surgery 1996; 119:27–33. https://doi. org/10.1016/s0039-6060(96)80209-1. 27. vanhoenacker fm, op de beeck b, de schepper am, salgado r, snoeckx a, parizel pm. vascular disease of the spleen. semin ultrasound ct mr 2007; 28:35–51. https://doi.org/10.1053/j. sult.2006.10.006. 28. uy ppd, francisco dm, trivedi a, o’loughlin m, wu gy. vascular diseases of the spleen: a review. j clin transl hepatol 2017; 5:152–64. https://doi.org/10.14218/jcth.2016.00062. https://doi.org/10.1002/bjs.1800760230 https://doi.org/10.1159/000146529 https://doi.org/10.1016/s0039-6060%2896%2980209-1 https://doi.org/10.1016/s0039-6060%2896%2980209-1 https://doi.org/10.1053/j.sult.2006.10.006 https://doi.org/10.1053/j.sult.2006.10.006 https://doi.org/10.14218/jcth.2016.00062 squ med j, april 2010, vol. 10, iss. 1, pp. 101-105, epub. 17th apr 10 submitted 17th june 09 revision req. 23rd nov 09 revision recd. 30th dec 09 accepted 23rd jan 10 in differentiated thyroid cancer (dtc), metastases occur outside the neck in up to 15% of patients and less than 3% of these are in bone.1,2 their early detection is made possible by measurement of serum thyroglobulin (tg) and by whole body scanning (wbs) using i-131. thyroglobulin is synthesised by all thyroid tissue except anaplastic cancers and, when detected after all non-malignant tissue has been destroyed, indicates the presence of residual dtc. thyroid stimulating hormone receptors (tsh-r) are present on most but not all dtc metastases. if present, tg levels usually increase when the patient is hypothyroid, off thyroxine (t4) with elevated endogenous thyroid stimulating hormone (tsh) levels, or after injections of recombinant human tsh (rhtsh) with the patient euthyroid on t4 replacement.3 for those patients without a tg response to tsh and those who do not take up i-1314, other treatments must be employed as indicated, for example, additional surgery, external radiotherapy, embolisation, etc.5 treatment guidelines for dtc include total thyroidectomy and removal of any nodal metastases followed by an ablation dose of i-131 4–6 weeks later when tsh levels are elevated.6 this first dose destroys residual normal tissue and may localise any metastatic disease.7 after a further 6 months an i-131 wbs is carried out after withholding t4 or using rhtsh. if the wbs is positive, a further ablation dose is given and the process repeated, when indicated, at 6 monthly intervals until there is no further i-131 uptake. thyroglobulin measurements are more sensitive than wbs for detecting metastases; however, up to 6% of patients departments of medicine,1 nuclear medicine,2 pathology,3 sultan qaboos university hospital, muscat, oman; 4department of medicine, college of medicine & health science sultan qaboos university, muscat, oman. *to whom correspondence should be addressed. email: omayma0@hotmail.com انتشار سرطان الغدة الدرقية املتمايز يف عظام مريضة شفاء كامل بعد استئصال الغدة الدرقية وعالجها بأربع جرعات من اليود املشع اأميمة ال�شفيع، �شامر ح�شني، عائ�شة احلمداين، هادية بريرحي، نيك�ال�س وودهاو�س سرطانية نقائل ثمانية لديها كان شابة مريضة هذه العظام. في الدرقيةاملتمايز الغدة سرطان انتشار حالة في عادة شاف عالج يوجد ال امللخ�ص: منعزلة في العظام بعد ثالث سنوات من االستئصال الكامل للغدة الدرقية. وبعد إعطاء أربع جرعات من اليود املشع اختفى السرطان من الناحية السريرية والكيمياوية احلياتية ملدة خمس سنوات. امللفت للنظر في هذه احلالة هو الرفض املستمر للزوج الستعمال مانع للحمل له أو لزوجته، وهذا ما سبب تأخير العالج ألكثر من ست سنوات، متكنت املريضة أثناءها من والدة وإرضاع أربعة أطفال يتمتعون بصحة جيدة. مفتاح الكلمات: سرطان الغدة الدرقية املتمايز، استئصال الغدة الدرقية،العالج باليود املشع، نقائل، عظم، تقرير حالة، ُعمان. abstract: multiple bone metastases from a differentiated thyroid cancer are usually incurable. we report the case of a young omani woman who presented with 8 discrete skeletal lesions three years after a total thyroidectomy. following four ablation doses of i-131 she has remained in clinical and biochemical remission for over five years. an extraordinary aspect of this case was the persistent refusal of her husband to use contraception either for himself or his wife. this resulted in her treatment being delayed for more than 6 years during which time the patient delivered and breastfed four additional healthy babies. keywords: differentiated thyroid cancer; thyroidectomy; resolution of bone metastases; i-131 ablation. multiple bone metastases in a patient with differentiated thyroid cancer (dtc) complete resolution following thyroidectomy and four ablation doses of i-131 *omayma t elshafie,1 samir hussein,2 aisha al-hamdani,3 haddia bererhi,2 nicholas jy woodhouse4 case report multiple bone metastases in a patient with differentiated thyroid cancer (dtc) complete resolution following thyroidectomy and four ablation doses of i-131 102 | squ medical journal, april 2010, volume 10, issue 1 may have functioning metastases when serum tg and tg antibody levels are unmeasurable.8 in this paper, we present details of a young patient who developed multiple bone metastases and whose treatment, both surgical and isotopic, was delayed by multiple pregnancies, the husband refusing contraception for his wife or for himself. in spite of this, and following surgery and four ablation doses of i-131, the patient has remained in clinical and biochemical remission for more than five years. case report the patient aged 20, a mother of four children, presented, in 1996, to another hospital in oman with a large multinodular goitre. surgery was advised, but delayed until 1999 because of two further pregnancies. after a total thyroidectomy, the histology confirmed a follicular variant of papillary thyroid carcinoma with capsular and vascular invasion [figures 1 & 2] without lymph node involvement. she was then referred to sultan qaboos university hospital, oman, for i-131 ablation. her clinical examination at that time and thyroid function tests were normal with an undetectable tg level on t4 replacement. she was admitted one month later, having stopped t4, at which time the tg level was 39 ng/ml. unfortunately, treatment had to be postponed as she was again pregnant (for the seventh time). abortion was offered, but refused, and, as a result of the families’ insistence on breast feeding, her first ablation dose was delayed for an additional 2 years until july 2001. the tg had now risen to 513 ng/ml off t4, and the post i-131 ablation whole body scan (wbs) revealed uptake in the thyroid bed and extensive metastases involving the skull, dorsal and lumbar spine, pelvis, right hip, right humerus, sternum and ribs [figure 3]. these were not visible on a routine skeletal survey. additional i-131 ablation doses were planned every 4–6 months and the family was again advised to use contraception until the patient’s treatment was complete. this advice was ignored. the second ablation dose was given 6 months later in january 2002. with the patient off t4, the tg had now decreased to 164 ng/ml, but the wbs still revealed extensive asymptomatic metastases, but without any uptake in the neck. a further pregnancy (number 8) delayed the third ablation for another two years until november 2004. at this time, however, the tg was only 2 ng/ml off t4 and the wbs had become negative. she received a fourth ablation dose in march 2006 although the tg was undetectable off t4 figure 1: papillary carcinoma showing nuclear overlap, cleaving and grooves (arrows) omayma t elshafie, samir hussein, aisha al-hamdani, haddia bererhi and nicholas jy woodhouse case report | 103 and the wbs remained negative. pregnancy number 9 was uneventful and her tg levels have remained undetectable on t4 for more than 6 years [figure 4]. thyroglobulin antibodies were undetectable throughout. lactation was discontinued 3 months before the first and third ablation doses of i-131. the patient was not lactating before the second and fourth doses. each time, ablation doses were given after stopping t4 for one month. the tsh levels were >100 on each occasion. discussion patients with dtc have a 10-year survival rate of 80–95%. this drops to 40% when distant metastases are present and to less than 21% when these are in bone.9 bone metastases are from mainly follicular or less well differentiated tumours and 80% occur within the axial skeleton, which contains a large number of stored growth factors.10 tumour cell products inhibit osteoprotegerin production thus permitting increased interaction of the receptor activator of nuclear factor kappa beta (rank) and its circulating ligand (rank-l). this results in excessive bone resorption with release of transforming growth factor beta (tgf-β), platelet derived growth factor (pdgf) and insulin like growth factor (igf), amongst others, which stimulate further tumour growth.11 remission rates for single lesions may be as high as 54%, but this falls to less than 3% with multiple bone metastases and usually occurs in those patients figure 2: papillary carcinoma showing vascular and capsular invasion figures 3a-d: i-131 post ablations scans: bone metastases are obvious in scans a and b, but are no longer visible in scans c and d. multiple bone metastases in a patient with differentiated thyroid cancer (dtc) complete resolution following thyroidectomy and four ablation doses of i-131 104 | squ medical journal, april 2010, volume 10, issue 1 under 45 years of age with a small tumour burden and normal appearing skeletal x-rays,12 this was the case in our patient whose metastases developed 18 months after the delayed thyroid surgery. the i-131 ablation doses were widely spaced due to her intervening pregnancies. rising outpatient tg levels and i-131 wbss confirmed the presence of multiple metastases which were confined to the skeleton, but not visible on routine skeletal surveys. our patient’s situation was most unusual as contraception was refused throughout. however, the prevailing view is that pregnancy has no major influence on the prognosis of dtc.13 nonetheless, the resultant delays and the effects of her pregnancies undoubtedly encouraged the development of the metastatic disease. in spite of this, her tg level was undetectable at the time of her fourth admission. nevertheless, we elected to give another ablation dose in an attempt to destroy any microscopic foci of residual disease or functioning metastases that may be present when tg and tg antibody levels are negative.8 at this point, the wbs was negative and the tg levels have remained undetectable since then. conclusion inspite of all the delays in this patient's treatment, it appears that her dtc with multiple bone metastases has been cured. references 1. schlumberger m, pacini f. distant metastases. in: schlumberger m, pacini f. eds. thyroid tumours. paris: editions nucleon, 1997. pp 167–189. 2. hoie j, stenwig ae, kullman g, lindegaard m. distant metastases in papillary thyroid cancer: a review of 91 patients. cancer 1998; 61:1–6. 3. mazzaferri el, kloos rt. using recombinant human tsh in the management of differentiated thyroid cancer: current strategies and future directions. thyroid 2000; 10:767–78. 4. mazzaferrie el, robbins rj, spencer ca, braverman le, pacini f, wartofsky l, et al. a consensus report of the role of serum thyroglobulin as a monitoring method for low risk patients with papillary thyroid cancer. j clin endocrinol metab 2003; 88:1433–41. 5. muresan mm, olivier p, leclere j, sirueaux f, brunand l, klein m, et al. bone metastases from differentiated thyroid carcinoma. endoc relat cancer 2008; 15:37–49. 6. pacini f, schlumber m, dralle h, elisei r, smit jw, wiersinga w. european consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. eur j endocrinol 2006; 154:787–803. 7. doi sar, woodhouse njy, thalib l, onitilo a. 7 p p p 8 9 98 0 100 200 300 400 500 99 00 01 02 03 04 05 10 b i-131 i-131 on t4 off t4 th yr og lo bu lin n g/ m l year figure 4: serial thyroglobulin levels on (o) and off (•) thyroxine (t4). the patient received 4 ablation doses of i-131; 2.26, 8.9, 7.6 and 4.94 gbq respectively after which the thryoglobulin levels had fallen from 540 to < 1.0 ng/ml when hypothyroid off t4. p. 7, 8, 9 refers to the number of pregnancies. omayma t elshafie, samir hussein, aisha al-hamdani, haddia bererhi and nicholas jy woodhouse case report | 105 ablation of the thyroid remnant and i-131 dose in differentiated thyroid cancer: a meta-analysis revisited. clin med res 2007; 5:87–90. 8. park e-k, chung j-k, lim ii h, park dj, lee ds, lee mc, et al. recurrent/metastatic thyroid carcinomas false negative for serum thyroglobulin but positive by posttherapy 1-131 whole body scans. eur j nucl med mol imaging 2009; 36:172–9. 9. beierwaltes wh, nishiyama rh, thompson nw, copp je, kubo a. survival time and cure in papillary and follicular thyroid carcinoma with distant metastases: statistics following university of michigan therapy. j nucl med 1982; 23:561–8. 10. wexler ja, shauetts j. thyroid and bone. endocrinol metab clin north am 2007; 36:673–705. 11. roodman gd. mechanism of bone metastases. n engl j med 2004; 350:1655–64. 12. slumberger m, challeton c, de vathaire f, travagli jp, gardet p, lumbroso jd, et al. radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinomas. j nucl med 1996; 37:598–605. 13. amdur rj, mazzaferri el. management of differentiated thyroid cancer during pregnancy. in: amdur rj, mazzaferri el, eds. essentials of thyroid cancer management. new york: springer us, 2005. pp. 347–51. 1 1 submitted 14 feb 23 1 revision req. 21 mar 23; revision recd. 5 apr 23 2 accepted 3 may 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.032 5 6 7 challenges and strategies for providing effective antenatal education 8 services in oman’s public healthcare system 9 perspectives of service providers and pregnant women 10 maha y.k. aldughaishi,1 *vidya seshan,2 gerald a. matua3 11 12 1labor ward, sultan qaboos university hospital, muscat, oman; departments of 2maternal & 13 child health and 3fundamentals & administration, college of nursing, sultan qaboos 14 university, muscat, oman. 15 *corresponding author’s e-mail: vidya69@squ.edu.om 16 17 abstract 18 objectives: globally, maternal mortality is considered a critical healthcare issue because 19 statistics consistently show that many avoidable deaths and injuries occur during pregnancy and 20 childbirth. the aim of this research was to explore the challenges to quality antenatal education 21 from the perspective of both the service providers and the pregnant women. methods: this 22 qualitative study was carried out on 30 participants who were selected using purposive sampling 23 technique. data was collected through in-depth interviews and field notes and analyzed manually 24 using thematic analysis. results: the service providers identified their challenges as lack of 25 consultation room and designated space for health education, work overload, time constraints, 26 under-staffing, lack of educational materials, language barriers, lack of authority and negative 27 attitude. the pregnant women identified lack of focus on women’s needs, superficial antenatal 28 education, overcrowding, lack of educational facilities, use of medical jargon and unprofessional 29 staff attitude towards women as key barriers to quality service. the remedies included improved 30 staffing levels, designated space for antenatal education, expanded educational activities, 31 2 2 continuing education for caregivers, establishing midwife-led units, focused antenatal education 32 and improved communication between providers and the users. conclusion: based on the 33 results, both health care service providers and pregnant women experienced significant barriers 34 that hindered them from providing and accessing quality antenatal education services 35 respectively. therefore, policymakers, health planners and hospital administrators should remove 36 these barriers and integrate some of the recommendations to promote better health outcomes. 37 keywords: antenatal education; challenges; strategies; health care providers; pregnant 38 women; oman. 39 40 advances in knowledge 41 • this study helped to explore the challenges faced by health care providers and pregnant 42 women while providing and receiving antenatal education. identifying this will help to 43 design cost effective corrective strategies to lower maternal and fetal healthcare costs. 44 • the study revealed the existence of disparity in adherence to moh national guidelines 45 regarding antenatal education. this finding implies the need for wider dissemination of the 46 guidelines to streamline the provision of recommended antenatal education services across 47 all the healthcare setting in oman. 48 application to patient care 49 • pregnant women trust and value the information provided by healthcare providers. 50 healthcare providers should provide adequate, consistent, and comprehensive antenatal 51 education for pregnant women in every antenatal visit. this ensures better understanding 52 of vital information by pregnant women, resulting in positive maternal and fetal outcomes. 53 54 introduction 55 globally, maternal mortality has been considered a critical healthcare issue because statistics 56 consistently show that avoidable deaths and injury occur during pregnancy and childbirth.1 as 57 further evidence of the extent of this problem, (world health organization) who, (united nations 58 international children’s emergency fund) unicef, (united nations population fund) unfpa, 59 world bank group and the united nations population division reported in their study that in 2017 60 alone, up to 295,000 women died during pregnancy until delivery across the world.2 these deaths 61 have been attributed to preventable complications, and would be stopped if women have access to 62 3 3 relatively basic maternal health education services to recognize the danger signs and act 63 accordingly.3,4 64 65 several studies suggest that low levels of awareness of danger signs of pregnancy and delivery 66 contribute to high maternal mortality ratios globally.5 to address these challenges, the united 67 nation through the sustainable development goal (sdg 3) directed member countries to improve 68 maternal health through working to reduce maternal mortality rate (mmr) to less than 70 per 69 100,000 live births by 2030.6,7,8 70 71 in oman, like other developing countries, there have been both positive and negative changes in 72 significant health indicators like the infant mortality rate (imr), low birth weight (lbw), and 73 poor breastfeeding practices. for instance, in 2016, the infant mortality rate was 5.3 per 1,000 live 74 births; in 2020, it increased to 7.6, and in 2021 further increased to 8.1 (moh, 2021).9 there was 75 an increase in the number of low birth weight (lbw) babies, from 11.3% in 2019 to 12% in 2021 76 (moh, 2021).9 similarly, in 2019, maternal mortality rate (mmr) was 14.1 (per 100.000 live 77 births), and the unwelcoming increase in 2020 to 29.4 and 42.5 in 2021.9 such gaps indicate the 78 existence of challenges in the system. 79 80 another significant maternal health indicator is that in the last five years, the number of pregnant 81 women attending the antenatal clinic in the first trimester reduced nearly by 10,000 from 2016 to 82 2019.10 these statistics indicate the existence of significant problems occurring during the 83 antenatal period and emphasize the need to understand the contributing factors to devise corrective 84 strategies to reduce maternal and infant mortality and morbidity rate especially in developing 85 countries.11 an important ingredient in addressing the gaps in antenatal care is the central role 86 played by healthcare workers, who provide the necessary information to make pregnancy and 87 childbirth a positive experience for the fetus, the pregnant women and her family. 88 89 whereas the ministry of health in oman, has made impressive steps to build a robust health 90 infrastructure across the country, promoting greater access in health care delivery to ensure that 91 all pregnant women receive quality healthcare services during antenatal visits, however some 92 challenges continue to hamper this success.12. in order to succeed in their mission of addressing 93 4 4 the healthcare needs of pregnant women, providers of antenatal education services must build 94 professional relationships, exchange information and involve the women in decision-making.13.14 95 96 this research reports the challenges experienced by healthcare providers and pregnant women 97 while delivering and receiving antenatal education services including some remedial strategies. 98 99 methodology 100 research design 101 the study utilized a generic qualitative research approach using semi-structured in-depth 102 interviews guided by open-ended questions. generic qualitative research approach is guided by 103 the naturalistic paradigm and utilizes different principles and practices from various qualitative 104 traditions and theories. the naturalistic framework was chosen because it allows the researcher to 105 explore poorly understood phenomena by generating rich data directly from concerned individuals 106 to make logical conclusions.16 this research approach resulted in a deeper understanding of the 107 challenges experienced by healthcare providers that negatively impacted their service provision. 108 study setting 109 this study was conducted in 9 outpatient antenatal clinics located in the public health centers of 110 muscat governorate, oman. these outpatient antenatal clinics provide health care services to both 111 low and high-risk pregnant women. 112 113 study sample and sampling method 114 a purposive non-probability sampling technique was used to identify participants who had 115 experience working in these units. these were health care providers who educated pregnant 116 women and pregnant women who received the antenatal education. 117 118 the healthcare providers included doctors, midwives, nurses, and health educators (both omani 119 and non-omani) who had worked in the antenatal clinics for a minimum of 12 months. the 120 pregnant women had to be attending antenatal care services in one of the institutions, had to be 121 over 30 weeks of gestation, aged above 18 years, omani and willing to participate in oneon-one 122 in depth interview with the research team. 123 124 5 5 the number of participants, both providers and users of the antenatal education services was 125 determined by the stage at which data saturation was reached.15 in this study, data saturation 126 occurred after a total of 17 healthcare providers and 13 pregnant women were interviewed.16,17. 127 128 ethical considerations 129 the researchers obtained ethical clearance and study approval from the relevant institutions and 130 the ministry of health. each participant was asked to sign an informed consent form after 131 determining that they had understood the nature and purpose of the study. prior to the data 132 collection, all the participants were informed that they had the right to withdraw from the study at 133 any stage either from individual questions or from the entire study without any consequences. the 134 anonymity of participants and confidentiality of their data were upheld and preserved. each 135 interview was conducted individually in a private and quiet room in the respective clinics. to 136 ensure anonymity, codes were used instead of names and digital copies of the interview data were 137 kept under password protection, with access only to the research team. in addition, the physical 138 copies of the interview data are carefully stored in an office and will be destroyed after 3 years. 139 140 data collection 141 the research data was generated using a semi-structured in-depth interview guide up to the point 142 of data saturation, resulting in a total of 30 participants.15 the participants were informed that the 143 interview sessions would last between 45 to 60 minutes or until such time that the participants 144 answered all the questions. the researcher started the interview with casual conversation to set the 145 stage for the participants to be ready for the interview. the questions were developed by the 146 research team and validated by both subject and research experts. the open-ended questions were 147 aimed at their personal experiences, including their thoughts, feelings, views, and perspectives 148 regarding antenatal service, both as a provider and user. to get more detailed information, follow-149 up questions were asked to encourage the participants to explain more by using probes and silence. 150 151 13 pregnant women participated in the study aged between 23 to 39 years. all of them were 152 educated. the interview guide for the key informants consists of 7major questions with some 153 probing questions. the researcher used communication skills that enabled her to interact 154 sensitively with each participant during the interview by asking, maintaining proper eye contact, 155 6 6 listening attentively, observing, showing respect and interest in what they were saying, and asking 156 prop questions when needed. these strategies encouraged and motivated the participants to express 157 themselves more and control the flow of the interview. the researcher found no difficulty 158 communicating with all participants. 159 160 sample questions: 161 for service providers 162 • what specific education do you give to prepare the women for a safe pregnancy? 163 • what challenges do you experience in providing antenatal education? 164 probe question: 165 166 • what barriers hinder you from being an effective antenatal educator? 167 • how do these barriers affect your role as an antenatal educator? 168 • which strategies would be useful in mitigating these barriers? 169 170 for pregnant women 171 • what challenges did you face during antenatal education sessions? 172 • what specific actions would help to resolve each challenge? 173 174 probe question: 175 • tell me if you had all your questions answered, if not? what went wrong? 176 • tell me more about the other barriers or challenges that you encountered? 177 • from your point of view, what strategies would be useful in mitigating these barriers? 178 179 the researchers ensured that the study had rigor by meeting the gold standard articulated by 180 lincoln and guba (1985) consisting of five critical elements of credibility, dependability, 181 transferability, trustworthiness, and confirmability.18 to ensure data quality, all the 30 in depth 182 interviews were digitally audio-recorded and transcribed verbatim to preserve the data integrity. 183 184 data analysis 185 7 7 data analysis occurred concurrently with data collection. the researchers analyzed the data set 186 manually using the thematic analysis framework through the process of reflexive ‘immersion and 187 crystallization’.19. the “immersion” phase started off with each researcher by reading and 188 rereading and examining portions of the data in detail, followed by suspending the process of 189 examining or reading the research data to reflect on the analysis experience. this phase then led 190 to the second, “crystallization phase”, which is characterized by the researchers identifying and 191 refining the themes. this two-step sequential data analysis process creates rich, trustworthy, 192 sensitive, and insightful research findings, hence its popularity among qualitative researchers.20 193 194 results 195 demographic characteristics 196 a total of 30 participants voluntarily participated in the study, 17 healthcare providers (doctors 5, 197 midwives 5, nurses 5, and health educators 2) and 13 pregnant women. the healthcare providers 198 had between 5 and 20 years of clinical experience in antenatal clinics. the pregnant women 199 were aged between 23-39 years; were 30 to 37 weeks of gestation and had between 1 to 6 children. 200 all the pregnant women had either primary, secondary or college level education, with 9 formally 201 employed while 4 were housewives. 202 203 part 1 achallenges experienced by service providers 204 lack of consultation room 205 the first challenge reported is the lack of a separate room for performing individual assessments 206 of pregnant women. several healthcare workers reported the shared examination rooms as a major 207 challenge noting that it negatively affected the pregnant women’s ability to discuss sensitive issues 208 of concern with their healthcare providers, fearing they might be overheard by others: 209 “the patient doesn't feel comfortable…she might have a lot to discuss with her care 210 providers. but privacy issues are compromised here…” (hcp-dr#1). 211 “there is no privacy… we are seeing and talking with the women in the same room where 212 another doctor is seeing another woman” (hcp-mw#1). 213 214 lack of designated space for health education 215 8 8 a second challenge that hindered provision of quality antenatal education services is the lack of 216 designated and private space for providing education: 217 “we do not have room to separate pregnant women and provide education session for 218 them” (hcp-mw#4) 219 “we need a proper place …. unfortunately, we have one office, and 2 colleagues share the 220 same office…women don’t feel comfortable ….” (hcp-edu#1) 221 “the room is really not suitable… sometimes because of disturbance i will forget to 222 provide education to the women. i cannot close the door, when i close it, the other patient 223 keeps knocking the door, so i decided to leave the door open” (hcp-sn#3) 224 225 work overload 226 another significant challenge is increased work overload due to high patient numbers and multiple 227 responsibilities: 228 “we have a lot of patients… this is an issue that prevents us from providing the optimal 229 type of care in general…” (hcp-dr#1) 230 “also, the patient list is long causing you to rush” (hcp-sn#4) 231 “.... the clinic is very busy and there's more workload…we are seeing overbooked cases. 232 …with this, of course is difficult to provide elaborative education to the women” (hcp-233 dr#5) 234 235 in relation to multiple assignments, the providers reported being assigned multiple tasks, which 236 hindered them from providing effective education: 237 “usually,as a doctor we are doing multiple tasks, we are the one collecting blood for 238 investigation, doing ultrasound scan, and talking to the patient and giving advice…a lot of 239 things we are doing… we are in a rush” (hcp-dr#1) 240 “a lot of documentation, which consumes the time we register in the system, in the book 241 and the green card, etc. i feel if there was less registration [documentation] i might get 242 time so i can provide education…” (hcp-sn#5) 243 “my role here is to give education to all patients in the health centre including school 244 students, and those with chronic diseases, not just pregnant women” (hcp-edu#2) 245 246 9 9 lack of time 247 the lack of time was another obstacle faced in providing antenatal education to pregnant women: 248 “no time for education, we really need time and honestly i feel that the women need a lot 249 of education as part of their care, lack of time is the biggest challenge….” (hcp-sn#5) 250 “...for proper counseling she [patient] needs at least 30 minutes along with examining her 251 and documenting the care, we are seeing lots of patients per day, so we don’t have much 252 time for education and counseling” (hcp-dr#4) 253 “no time to talk to them or to educate them but we give tips and if she has any question, 254 we’ll try to answer them but as a routine to teach them, no time to stay with the patient 255 explaining to her about her condition” (hcp-mw#4) 256 257 under-staffing 258 another major challenge experienced by healthcare providers is the shortage of staff in the 259 antenatal clinics: 260 “we are only 2 staff in the clinic, we have a lot of things to do, but we try our best... we see 261 what they [ pregnant women] know and what they don’t know and based on that we give 262 the [missing] education…” (hcp-sn#1) 263 “the problem is we have one doctor, and she has to finish 14 patients …, that is why there’s 264 no time to sit and give time for patient education.” (hcp-sn#3) 265 266 another aspect of the staff shortage reported was the non-availability of a midwife in these 267 antenatal clinics. 268 “i don’t have a midwife here... she could help somehow if we work together, and i guess 269 she can help a lot in this part as well” (hcp-dr#5) 270 “we do not have a midwife in our institution and me as a nurse i did not have any 271 [midwifery]course …except[from] my experience working in an anc clinic. i learn things 272 from daily work and self-learning…” (hcp-sn#4) 273 274 lack of educational materials 275 the non-availability of teaching resources and materials was also cited as these participants noted: 276 10 10 “we are not provided with the educational resources and materials such as recorded 277 videos to provide the education, only we are depending on the leaflets and we try to give 278 education when they ask us…” (hcp-mw#5) 279 “we do not have leaflets for all educational topics, that is why we sometimes ask them to 280 read more on the internet…” (hcp-sn#3) 281 282 lack of authority and recognition 283 in addition to other barriers, several midwives particularly emphasized the persistent challenge of 284 disempowerment by the healthcare system in relation to their limited prescribed scope of practice 285 in the antenatal clinics: 286 “i feel the midwife has the capability to provide antenatal education 287 comprehensively if she was given the support [read permission] to do that by the 288 necessary authorities” (hcp-mw#1) 289 “i am here as a general nurse not as a midwife, although my certificate is in 290 midwifery... in the clinic my responsibility is just to inform the doctors. ...we are 291 not authorized to give education regarding complications of pregnancy. (hcp-292 mw#4) 293 294 identifying valuable educational sessions 295 an important challenge experienced by health workers is reluctance of some women to 296 focus on the available health education opportunities. this challenge was reported mainly 297 as reluctance of some pregnant women to planned educational sessions as herein reported: 298 “…[some pregnant women]…are not interested, and they don’t ask… even if we tell 299 something they will not show the interest to learn or to know” (hcp-dr#4) 300 “also some women who have previous experience, for example with diabetes, will 301 tell that i already know what to eat and what to do from my previous experience... 302 she will not come even if the services are available. i wish the women take it 303 seriously...” (hcp-edu#1) 304 305 11 11 this meant that the health care professional had to shoulder the additional burden of 306 constantly finding out the desired educational needs of the women. this resulted in an 307 additional workload for hcp’s. 308 309 part 1bchallenges experienced by pregnant women 310 lack of focus on women’ actual needs and superficial education 311 a major challenge experienced by pregnant women in this study was that lack of focus of antenatal 312 education on the actual needs of pregnant women: 313 “every pregnant woman should receive education …even me when i will come for 314 my second pregnancy, i believe i might need education in many things, each 315 pregnancy is unique, it should not be treated as she knows from her previous 316 experience” (p.w#1) 317 “unfortunately, she explained without details… the patient comes out of the 318 [antenatal] clinic with questions in her mind. as that was my first childbirth, that 319 situation caused me fear and phobia…” (p.w#4) 320 321 in addition, some women felt that the healthcare providers gave them answers that did not 322 address their needs. they perceived this as providing them with superficial education: 323 “we see that the pregnant woman is not aware of the problem and the doctor gives 324 her superficial information about treatment and the risks and consequences. the 325 medical staff must ask and discuss the problems and symptoms with the pregnant 326 woman in [more] detail” (p.w#7) 327 “we also need those [hcps] to focus more on educating us about childbirth, the 328 postpartum stage and how to deal with a nursing baby” (p.w#9) 329 “we wish the medical staff would pay more attention to education… they only pay 330 attention to routine examinations of pregnant women…” (p.w#12) 331 “they are not focusing on educating the pregnant women. if the pregnant woman 332 is educated and aware of these topics, she would be able to deal with every symptom 333 and problem that happens with her” (p.w#13) 334 335 overcrowding in the antenatal clinic 336 12 12 another hindrance is the large number of patients resulting in overcrowding in the clinics: 337 “another big problem is the overcrowded clinic and the large number of pregnant women 338 who visit the clinic. sometimes i find six patients with me in the same room to do blood 339 pressure examinations. so, you find the nurse is trying to finish off the patients and just 340 leave”. (p.w#4) 341 342 in further agreement, another participant reiterated that: 343 “the problem in the institution is the limited number of employees. every day, they receive 344 from 20-30 pregnant women. this is difficult … [and] over the health workers’ capacity. 345 they cannot make lectures or provide [quality] antenatal educational services for all the 346 women here” (p.w#5) 347 348 lack of educational resources 349 another persistent challenge mentioned by most pregnant women is the lack of resources required 350 for effective teaching sessions: 351 “we need more educational services… the medical staff is only depending on leaflets...they are 352 not using a variety of methods... how can they guarantee pregnant women will read these leaflets 353 to get the information? (p.w#11) 354 355 use of medical jargons 356 this use of unfamiliar language during sessions limited women's understanding of the content: 357 “among the challenges i face as a pregnant woman is the medical staff's use of terms that 358 i do not understand. although i’m a nurse, there are some terms i do not understand 359 especially that i do not work in maternity department” (p.w#7) 360 361 part 2 astrategies to improve antenatal education services 362 the providers suggested the following strategies to improve antenatal education services: 363 staffing the antenatal clinic with midwives 364 some providers recommended staffing antenatal clinics with midwives as a strategy to help 365 improve the provision of antenatal educational services: 366 13 13 “...we should also have specialized staff mainly midwives so that they can give more, since 367 they are more familiar with these topics that need to be discussed with pregnant women, 368 and they can give better services” (hcp-sn#1) 369 370 “[it is] very important to have a midwife...she will help to make my life easy. she knows 371 what to do without coming back to me. a midwife is very important to be available in each 372 health center…” (hcp-dr#1) 373 “if we have a midwife, she can help a lot… she can do abdominal palpation, checking the 374 foetal heart rate, providing health education, if she is available, i feel the burden will be 375 divided and the workload will be divided between us…” (hcp-dr#2) 376 “the midwife will help a lot…and she will be more interested to prepare the women for 377 delivery and even she can explain to the doctors here about the management of different 378 stages of labour” (hcp-dr#3) 379 380 designated space for antenatal education 381 another recommendation is having a designated room provided to the clients: 382 “we need a proper place to educate mothers because education is an essential part of 383 antenatal care” (hcp-mw#3) 384 “one of the solutions is to provide room for counseling” (hcp-edu#2) 385 386 improving staffing levels 387 some healthcare providers further recommended increasing the number of clinical staff: 388 “if we increase the number of staff will help to improve the quality of our service” (hcp389 dr#5) 390 “if they can give enough staff that will help a lot in this area” (hcp-ns#1) 391 “they need to provide more educators to the [antenatal] clinics” (hcp-edu#1) 392 393 expansion of educational activities and methods 394 expanding and ensuring diversity in the educational activities and methods is another strategy 395 to improve provision of educational service to the users: 396 14 14 “we [currently use] leaflets and posters. …[but] we need various educational materials, 397 such as figurine and manikins…to explain and deliver the information clearly…, the 398 illustrations attract more attention” (hcp-edu#2) 399 “maybe we can make audio-visual aids will really help to attract especially the new 400 generation of the young and even the multigravida mothers” (hcp-dr#5) 401 “put a schedule for nurses to prepare a topic for the pregnant women, and we can 402 cooperate with other healthcare providers like physiotherapist, dietitian to provide 403 teaching session for the pregnant women, it will be fair enough for the pregnant women to 404 provide them with schedule with different educational classes” (hcp-mw#4) 405 406 in terms of the scheduled teaching sessions, a midwife recommended that: 407 “i think we should schedule teaching session for pregnant women at least weekly” (hcp-408 mw#1) 409 410 continuing professional development programs 411 participants also suggested continuing professional development through courses and workshops: 412 “[we] need courses related to antenatal education because there are many methods, we 413 can learn to provide better services… and if the educator is trained then more topics can 414 be included in education… it will be perfect” (hcp-mw#2) 415 “...workshops are needed and training for the staff to improve because not all are familiar 416 with the educational topics… sometime new staff need somebody to follow with…., the idea 417 of training will be good for us to learn, refresh and update our knowledge…” (hcp-sn#4) 418 “providing training courses for the physician, nurses and educators especially about the 419 topics related labour and birth, exercises contraceptive…etc , will be very helpful to 420 improve” (hcp-dr#5) 421 422 dedicated staff for antenatal education 423 an important strategy suggested by a midwife to improve the provision of ane services involves 424 hiring a dedicated staff for provision of education. 425 “i will suggest assigning a staff, whose role is to educate the women only, that really will 426 help a lot …even a simple advice you will give it might stick with her [pw] mind and it will 427 15 15 help to change a lot of behaviours. as a midwife we try our best to benefit the women with 428 the information we gained from midwifery program… education should be something 429 regularly provided to the women in all aspect of care for the pregnant women and s… not 430 wait for the complication to occur to provide the education”. (hcp-mw#5) 431 432 provision of hotline for urgent clarification 433 an innovative strategy suggested is providing a hotline for pregnant women to enable them call 434 and inquire about key questions that need to be answered instantly by healthcare providers: 435 “...they need a hotline to answer inquiries… i believe some of the questions might not come 436 during the visit; when she will go home some questions might arise and then she wonders 437 what to do…” (hcp-mw#2) 438 439 establishment of midwife-led care units 440 another recommendation is the establishment of midwifery-led care units across the country: 441 “in the midwife-led clinic we have sufficient time to discuss and provide individualized 442 care… the women will be seen by the same midwife, so it helps in strengthening the trust 443 relationship… also, she will feel more comfortable to discuss and express [herself] rather 444 than be seen by different providers during each visit…” (hcp-mw#2) 445 446 mass education through social media 447 the use of social media to pass educational messages was also recommended to be used since 448 social media is widely accepted by many people as this participant affirms: 449 “like in tv, structured education can be displayed in tv so people can see and follow 450 because i feel through social media the idea of [antenatal] education will be more accepted 451 by people” (hcp-sn#4) 452 453 part 2 brecommendations from pregnant women 454 the pregnant women suggested the following ways to improve antenatal education services: 455 focused antenatal education 456 the women suggest the need for focused and regular antenatal education throughout pregnancy: 457 16 16 “the pregnant woman should get education before going through the experience of 458 childbirth… she might go too late…, also they should focus more on the proper method of 459 pushing while giving birth….” (p.w#10) 460 “they need to give us information about childbirth and the child. in the first trimester, they 461 are supposed to give us information about the correct meals, medicine, exercises, and 462 positions of sleeping and the movement of the pregnant woman for safe pregnancy”. 463 (p.w#9) 464 “the staff in antenatal clinic should give pregnant women at the beginning of their 465 pregnancy a lecture on how to deal with the symptoms of pregnancy and the 466 complications that they may be exposed to,…we need more focus from the medical staff 467 … educate them about pregnancy…as a very sensitive and important stage” (p.w#4) 468 “they [hcps] are supposed to tell us that at the first stage of pregnancy, avoid this type 469 of food, and in the second stage, certain types that you avoid or take…also they should 470 educate us about the movement and physical activity in the pregnancy either as routine or 471 daily, especially if the pregnant women have problems during pregnancy” (p.w#8) 472 473 innovative educational activities 474 some pregnant women suggested introduction of various educational activities in the clinics: 475 “we do not need only routine visits and check-ups; we need education about all related 476 care. i suggest conducting educational lectures… and to discuss the experiences of other 477 mothers. also the available posters and brochures should be reviewed and updated … 478 (p.w#2) 479 “make a group and give education, and sometime in same group some women might have 480 the experience so other women will benefit from each other’s experience” (p.w#3) 481 “we also wish there to have an awareness video for the pregnant woman to benefit from 482 and to understand and comprehend the information more” (p.w#7) 483 484 dedicated staff for antenatal education 485 in addition, some pregnant women recommended hiring a dedicated staff: 486 “it would be beneficial if we have a specialist nurse in the health institution for the 487 antenatal educational services” (p.w#13) 488 17 17 “i feel the nurses are busy., so better employ somebody to provide the teaching and 489 education…, so this person will listen to the woman, answer all her questions, reassure her 490 and make her feel supported…” (p.w#1) 491 “i belief that a nurse or a specialist in antenatal educational services must provide the 492 pregnant women with all information needed” (p.w#2) 493 494 provide a dedicated space for education 495 similar to providers, the users also suggested a dedicated office for education and counseling: 496 “an education office can be set up for pregnant women. this will result in more caring, 497 … they will open their hearts to express their feelings, needs and inquiries. this will help 498 to answer questions in their mind …” (p.w#2) 499 500 improved communication 501 another recommendation to improve antenatal services is minimizing the use of medical jargon: 502 “the first thing is to make sure that the pregnant woman understands all that the doctor 503 says to her, so they need to avoid using difficult terms” (p.w#7). 504 505 discussion 506 the study identified many factors that negatively impacted the provision and receiving of antenatal 507 education services in the selected health facilities in oman. these findings are comparable to those 508 of previous studies conducted in oman by al maqbali (2018) who found that pregnant women 509 appeared disempowered and seemed to lack control over the care they received.14 as a result the 510 women felt that their needs were not satisfied since a significant discrepancy existed between what 511 they expected and needed and the actual care and information they received during antenatal visits. 512 513 similarly, in iran, javanmardi, et al., (2019) in a study on the challenges women experience to 514 access health information during pregnancy, found that there was insufficient interaction between 515 women and healthcare providers. in addition, there was also failure to access various information 516 resources from the health facilities.21 the authors recommended that policymakers and health 517 planners should remove the barriers that interfere with delivery of quality health information 518 during pregnancy. a study conducted in addis ababa in ethiopia on antenatal care and health 519 18 18 education also identified similar challenges. the challenges included but were not limited to the 520 shortage of staff, lack of time, lack of training, negative staff attitude, negative cultural beliefs and 521 practices, and lack of incentives for providers. as reported in the current study, these barriers 522 hindered effective antenatal education service provision in the selected health facilities.5 523 524 in terms of how these challenges might be mitigated, both healthcare providers and pregnant 525 women provided some suggestions about who, where, when and how to improve the current 526 antenatal education services. the rationale for these strategies is that when such gaps are 527 addressed, they result in improved antenatal education services, which in turn creates positive 528 impact on obstetrical outcomes, such as reducing low-birthweight, prematurity and promoting 529 exclusive breastfeeding among other positive outcomes for baby, mother and family.22,23 530 531 the most prominent suggestions from both groups included the need for proper designated space 532 for antenatal education, dedicated staff for antenatal education, innovative educational activities 533 and facilities and provision of tailor-made training for healthcare providers. these 534 recommendations are consistent with those documented in woldeyohannes and modiba’s (2020) 535 study in ethiopia which advocated for ongoing education for healthcare givers, assignment of 536 dedicated staff to provide antenatal education services, and reducing the patient numbers per day.5 537 538 another recommendation that has received attention in previous studies is the midwife-led 539 antenatal clinics. a classical cochrane collaborative study found that pregnant women who 540 received prenatal, intrapartum, and postnatal care primarily from a midwife were less likely to 541 deliver prematurely while requiring fewer medical interventions, compared with women cared for 542 by obstetricians or family physicians.24 the study found that midwife-led care resulted in fewer 543 epidurals, fewer episiotomies, lower odds of premature delivery and greater odds of spontaneous 544 vaginal birth and overall better pregnancy experience. this finding is consistent with who (2016), 545 icm (2018) and nice (2019) recommendation, which state that midwife-led care is the safest 546 approach of care for healthy pregnant women, who have no immediate danger signs.25,26,27 547 548 in addition, several other studies argue that midwife-led-care is associated with increased 549 empowerment and confidence in the pregnant women's ability to give birth without the need for 550 19 19 medical and obstetric intervention. according to international confederation of midwives (icm) 551 (2018), a midwife-ledcare means that the midwife is the lead health-care professional who is 552 responsible for the planning, organizing and delivering of care to a woman from the initial booking 553 of antenatal care until the postpartum period.26 the women in these studies also reported 554 developing the ability to recognize the danger signs in pregnancy, which helped them to abstain 555 from risky behaviors and reduced complications associated with pregnancy and childbirth resulting 556 in positive outcomes.28,29 in recent times, this model has received further support in 2020 with the 557 world health organization advocating for investment in such midwifery models of care to provide 558 high-certainty and evidence-based care. this strategy would improve maternity care by integrating 559 such care into existing healthcare systems, thereby helping to transform maternal health globally.30 560 561 moreover, these proposed strategies align with the antenatal care recommendations stated by 562 queensland health, australia (2018), which requires antenatal education to equip pregnant women 563 with balanced information, including information about pregnancy, birth and possible 564 complexities and transition to the postnatal period. in addition, the strategy recommends a 565 dedicated health educator who should be adequately trained and prepared to provide antenatal 566 education based on the principle of adult learning (queensland health, 2018).31 further, in ireland, 567 the national women, and infant health program (2020) states that providers of antenatal education 568 should be supported with the most up to date educational materials. this support should include 569 innovative audio-visual aids to provide evidence-based information to the parents. besides, these 570 providers should be granted protected time to engage in continuous professional development 571 programs to improve their skills and understanding of adult learning, group facilitation, and 572 evidence-based practice among others. the program further recommends conducting the antenatal 573 education in a safe, clean and well-equipped physical environment to enhance each pregnant 574 woman's active participation so as to adequately meet their learning needs. 575 576 conclusion 577 the study identified that healthcare providers and pregnant women experienced many challenges 578 while providing and receiving antenatal education services. as a result of the barriers, significant 579 deficiencies exist in the quality and quantity of antenatal education services provided to pregnant 580 women related to pregnancy, labor and birth, postpartum and newborn care. the findings also 581 20 20 clearly indicate that these antenatal educational services are not provided uniformly and adequately 582 to all pregnant women. as a remedy, it is recommended that there should be designated spaces, 583 dedicated staff, innovative educational activities, and creation of awareness about the actual scope 584 of midwifery practice among healthcare providers and the public. finally it is also recommended 585 that midwife-led antenatal clinics should be established to provide comprehensive maternity 586 services in line with the current recommendation of the world health organization. 587 588 conflicts of interest 589 the authors declare no conflict of interests. 590 591 funding 592 no funding was received for this study. 593 594 authors’ contribution 595 myka conceptualized the idea, involved in data collection. vs and gam contributed to the 596 design and analysis and drafting of the manuscript. vs and gam supervised the study. all 597 authors approved the final version of the manuscript. 598 599 acknowledgement 600 the authors are grateful to all the participants, the health care providers, and pregnant women 601 for their participation in the study. 602 603 references 604 1. world health organization (2021). new global targets to prevent maternal deaths. 605 https://www.who.int/news/item/05-10-2021-new-global-targets-to-prevent-maternal-deaths. 606 2. who, unicef, unfpa, world bank group and the united nations population division. 607 maternal mortality: levels and trends 2000 to 2017. geneva: 2019. 608 (https://www.who.int/reproductivehealth/publications/maternalmortality-2000-2017/en/). 609 3. ahmad d, mohanty i, hazra a, niyonsenga t. (2021). the knowledge of danger signs of 610 obstetric complications among women in rural india: evaluating an integrated microfinance 611 21 21 and health literacy program. bmc pregnancy childbirth 2021; 21:79. 612 doi: https://10.1186/s12884-021-03563-5. 613 4. feroz a, perveen s, aftab w. role of mhealth applications for improving antenatal and 614 postnatal care in low and middle income countries: a systematic review. bmc health services 615 research 2017; 17:1704. https://doi.org/10.1186/s12913-017-2664-7. 616 5. wulandaria rd, laksonob ad. (2020). education as predictor of the knowledge of pregnancy 617 danger signs in rural indonesia. international journal of innovation, creativity and change 618 2020; 13:1-10.10371051. 619 6. kruk me, chukwuma a, mbaruku g, leslie hh. (2017). variation in quality of primary-care 620 services in kenya, malawi, namibia, rwanda, senegal, uganda and the united republic of 621 tanzania. bulletin of the world health organization 2017; 95:6-408. 622 https://dx.doi.org/10.2471%2fblt.16.175869. 623 7. ononokpono dn, baffour b, richardson a. (2020) mapping maternal healthcare access in 624 selected west african countries. etude de la population africaine 2020; 34 :1-5082-5105. 625 https://dx.doi.org/10.11564/34-1-1495. 626 8. united nations sustainable development goal 3: ensure healthy lives and promote well-being 627 for all at all ages. newyork: 2022. https://www.un.org/sustainabledevelopment/health/ 628 9. ministry of health (2021). annual health report https://www.moh.gov.om/en/web/statistics/-629 /-2-10 630 10. ministry of health (2019). annual health report. 631 https://www.moh.gov.om/en/web/statistics/annual-reports . 632 11. karlsen s, say l, souza jp. et al. the relationship between maternal education and mortality 633 among women giving birth in health care institutions: analysis of the cross sectional who 634 global survey on maternal and perinatal health. bmc public health 2011; 11:606. 635 https://doi.org/10.1186/1471-2458-11-606. 636 12. halim lb, alajmi f, & al lamki s. (2018). ensuring universal access to primary health care 637 in oman 2018. primary health care performance 638 initiative.https://improvingphc.org/ensuring-universal-access-primary-health-care-oman . 639 13. dong k, jameel b, gagliardi ar. (2022). how is patient-centred care conceptualized in 640 obstetrical health? comparison of themes from concept analyses in obstetrical healthand 641 patient-centred care. health expect 2022; 25:3-823-839. doi: 10.1111/hex.13434. 642 https://doi.org/10.1186%2fs12884-021-03563-5 https://doi.org/10.1186/s12913-017-2664-7 https://dx.doi.org/10.2471%2fblt.16.175869 https://dx.doi.org/10.2471%2fblt.16.175869 https://doi.org/10.11564/34-1-1495 https://www.un.org/sustainabledevelopment/health/ https://www.moh.gov.om/en/web/statistics/annual-reports https://www.moh.gov.om/en/web/statistics/annual-reports https://improvingphc.org/ensuring-universal-access-primary-health-care-oman 22 22 14. al maqbali f. (2018). navigating antenatal care in oman: a grounded theory of women's 643 and healthcare professionals' experiences. phd thesis, 2019, the university of manchester, 644 uk. proquest dissertations publishing, 27775318. 645 15. etikan i, musa sa, alkassim rs. comparison of convenience sampling and purposive 646 sampling. american journal of theoretical and applied statistics 2016; 5:1-1-4. doi: 647 10.11648/j.ajtas.20160501.11 648 16. bradshaw, c., atkinson, s., & doody, o. (2017). employing a qualitative description approach 649 in health care research. global qualitative nursing research, 4, 2333393617742282. 650 https://doi.org/10.1177%2f2333393617742282 651 17. moser a & korstjens i. 2018. series: practical guidance to qualitative research. part 3: 652 sampling, data collection and analysis. eur j gen pract 2018; 24:1-9-18. doi: 653 10.1080/13814788.2017.1375091. 654 18. lincoln y. guba eg. (1985). naturalistic inquiry. newbury park, ca: sage 655 19. borkan jm. (2021). immersion–crystallization: a valuable analytic tool for healthcare 656 research. family practice 2021; 39: 785–789. https://doi.org/10.1093/fampra/cmab158. 657 20. nowell, l. s., norris, j. m., white, d. e., & moules, n. j. (2017). thematic analysis: 658 striving to meet the trustworthiness criteria. international journal of qualitative methods, 659 16(1), 1609406917733847. 660 661 21. javanmardi m, noroozi m, mostafavi f, ashrafi-rizi h (2019). challenges to access health 662 information during pregnancy in iran: a qualitative study from the perspective of pregnant 663 women, midwives and obstetricians. reproductive health 2019;16:1-1-7. 664 https://doi.org/10.1186/s12978-019-0789-3. 665 22. silva epd, lima rtd, osorio mm. (2016). impact of educational strategies in low-risk 666 prenatal care: systematic review of randomized clinical trials. ciência & saúde coletiva 667 2016;21:2935-2948. https://doi.org/10.1590/1413-81232015219.01602015. 668 23. maastrup r, rom al, walloee s, sandfeld hb, kronborg h. improved exclusive 669 breastfeeding rates in preterm infants after a neonatal nurse training program focusing on six 670 breastfeeding-supportive clinical practices. plos one 2021; 16:2671 e0245273. https://doi.org/10.1371/journal.pone.0245273. 672 about:blank https://doi.org/10.1093/fampra/cmab158 about:blank about:blank about:blank https://doi.org/10.1590/1413-81232015219.01602015 https://doi.org/10.1371/journal.pone.0245273 23 23 24. potera c. evidence supports midwife-led care models: fewer premature births, epidurals, and 673 episiotomies; greater patient satisfaction. am j nurs 2013;113:11-15. doi: 674 10.1097/01.naj.0000437097.53361.dd. pmid: 24149253. 675 25. world health organization. standards for improving quality of maternal and new born care in 676 health facilities 2016. retrieve from 677 https://apps.who.int/iris/bitstream/handle/10665/249155/9789241511216-per.pdf. 678 26. international confederation of midwives. philosophy and model of midwifery care 2018. 679 https://www.internationalmidwives.org/assets/files/definitionsfiles/eng-philosophy-and-680 model-of-midwifery681 27. national institute for national and care excellent. antenatal care for uncomplicated 682 pregnancies. clinical guideline 2020. https://www.nice.org.uk/terms-and-conditions#notice683 of rights. 684 28. voon, s. t., lay, j. t. s., san, w. t. w., shorey, s., & lin, s. k. s. (2017). comparison of 685 midwife-led care and obstetrician-led care on maternal and neonatal outcomes in singapore: 686 a retrospective cohort study. midwifery, 53, 71-687 79.https://doi.org/10.1016/j.midw.2017.07.010 688 689 29. sandall, j., soltani, h., gates, s., shennan, a., & devane, d. (2016). midwife‐led continuity 690 models versus other models of care for childbearing women. cochrane database of 691 systematic reviews, (4).https://doi.org/10.1002/14651858.cd004667.pub5 692 30. edmonds jk, ivanof j, & kafulafula u. midwife led units: transforming maternity care 693 globally. annals of global health 2020; 86:1. https://dx.doi.org/10.5334%2faogh.2794 694 31. the queensland health. (2018). recommendations for antenatal education content, 695 development and delivery. https://clinicalexcellence.qld.gov.au/priority-areas/service-696 improvement/maternity-service-improvement. 697 https://apps.who.int/iris/bitstream/handle/10665/249155/9789241511216-per.pdf https://doi.org/10.1016/j.midw.2017.07.010 https://doi.org/10.1002/14651858.cd004667.pub5 https://dx.doi.org/10.5334%2faogh.2794 https://clinicalexcellence.qld.gov.au/priority-areas/service-improvement/maternity-service-improvement https://clinicalexcellence.qld.gov.au/priority-areas/service-improvement/maternity-service-improvement املؤمتر األول لعلم احلياء الطيب يف ُعمان 26-27 فرباير 2020 first biomedical science conference in oman 26–27 february 2020 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e146–159, epub. 15 mar 21 https://doi.org/10.18295/squmj.2021.21.01.025 conference abstracts the effect of ionising radiation in cell lines of the oral cavity and prostate cancer tânia estrada,1 maria a. cipriano,2 maria f. silva,1,2 ana m. abrantes,3,4 maria f. botelho,3,4 diana martins,1,5 paulo teixeira,1,2,4 *fernando mendes1,3,4 1politécnico de coimbra, estesc, departamento de ciências biomédicas laboratoriais, estesc, coimbra, portugal; 2pathology department, coimbra hospital and universitary centre, coimbra, portugal; 3cnc.ibili consortium/center for innovative biomedicine and biotechnology (cibb), university of coimbra, coimbra, portugal; 4biophysics institute, coimbra institute for clinical and biomedical research (icbr) area of environment genetics and oncobiology (cimago), faculty of medicine, university of coimbra, coimbra, portugal; 5i3s, instituto de investigação e inovação em saúde, universidade do porto, porto, portugal. *corresponding author’s e-mail: fjmendes@netcabo.pt objectives: this study aimed to examine the effect of ionising radiation (ir) in apoptosis, using cell lines of epidermoid carcinoma of the oral cavity (ecoc) and prostate cancer (pc) with mutated or inactive p53 and associate it to the mismatch repair (mmr) system. methods: the study was performed in bicr 10 ecoc and lncap pc cell lines previously exposed to ir (0–6 gy). p53 expression, mmr protein and apoptotic markers were analysed using immuno-cytochemistry. in order to evaluate the cell morphology, maygrünwald giemsa staining was performed. results: our results suggest a decrease in proliferation associated with a higher radiation dose in both cell lines. the expression of caspase3 and bad increased significantly after ir exposure in a dose-dependent manner. an increase in msh2 and msh6 expression in bicr10 and lncap cell lines was observed, respectively, without statistical significance. a significant positive correlation between caspase 3 and msh2 protein expression in both cell lines and between msh2 and pms2 in bicr 10 cell line was observed. conclusion: in both cell lines, our results suggest that the mmr system actively participates in apoptosis induction in response to ir in a p53-independent pathway. moreover, it seems to suggest that mmr-dependent apoptosis occurs through the intrinsic pathway and does not result from the participation of the mutlα and mutsα. the challenges faced in the education of biomedical science curriculum joanna andrew institute of biomedical science, london, united kingdom. e-mail: joanna.andrew@york.nhs.uk the biomedical science curriculum presents a number of educational and professional challenges. this talk will examine how these challenges can be overcome to ensure that biomedical science graduates are fit for the future workplace. it will use the quality assurance agency subject benchmark statement and curriculum frameworks as reference points. it will discuss the curriculum's depth and breadth, different assessment strategies, the challenges of delivering practical classes, and supporting projects. in addition, it will look at the value of practitioners in delivering discipline-specific aspects. from an employer and professional aspect, the challenges of new technology and the changing landscape of pathology will be examined and discussed. the role of biomedical laboratory scientists in health professions anne l. berndt swedish association of health professionals, stockholm, sweden. e-mail: anne.lindgren@vardforbundet.se biomedical laboratory scientists (bls) play essential roles in various settings, from laboratories and clinics providing health and medical care services, to pharmaceutical and academic research laboratories. technology is changing rapidly and a healthcare revolution is underway to meet the challenges of an ageing population, an increase in chronic diseases and spiralling costs. tomorrow’s patients are well informed, expect choices and high-quality personalised care. to keep pace with these changes, bls must evolve to participate in, stay on top of and often lead the rapidly changing technologies and new ways of providing healthcare. in addition to core competencies, a strong professional identity developed through ethical reflection and strong core values can support the professionals. ifbls works to stimulate discussion and raise awareness among the practitioners to ensure that the bls will continue to bring unique knowledge, competencies and skills to a wide variety of fields, from being person-centred healthcare partner to biotechnology research, meeting the changing needs of the 21st century. updates in the medical sciences profession fernando mendes politécnico de coimbra, estesc, departamento de ciências biomédicas laboratoriais, estesc, coimbra, portugal. e-mail: fjmendes@netcabo.pt biomedical sciences (bms) have evolved significantly over the last years due to unprecedented knowledge increase and technology development. from the fundamental areas (such as haematology, blood banking, clinical biochemistry, microbiology, immunohistochemistry, cytopathology and public health) to a molecular era (such as molecular biology, proteomics and all omics, genetic profiles, among others), bms are now fully available for diagnosis, treatment and monitoring of diseases. with a rapid translation from research to bench, the conjunction of science and technology allowed bms to be one of the fastest and most adaptive professions worldwide. the miniaturisation of equipment, point-of-care testing, online connection, wearable devices, higher patient levels of literacy, the integration of big-data, virtualisation (health 4.0), all contributes to higher knowledge demands this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ 26–27 february 2020 conference abstracts | e147 at education levels for the future biomedical scientists and their continuous professional development and access to post-graduate education. regarding patient safety, these health professionals have to fulfil determined minimum standards and rules to enter the regulated profession. the future will bring new challenges for biomedical scientists including being recognised as a full diagnostic partner capable of getting out of the laboratory and actively contributing to clinical decisions, improving the health service and the output for the patient. in the near future, all biomedical scientists with the right level of knowledge, skills and competencies should be able to become laboratory directors. the challenges ahead for this profession are vast, but biomedical sciences' future can only be bright. oral presentations genomic and expression analyses define muc17 and pcnx1 as predictors of chemotherapy response in breast cancer *waleed s. al amri,1,2 lisa m. allinson,1 diana e. baxter,1 sandra m. bell,1 andrew m. hanby,1,3 stacey j. jones,4 abeer m. shaaban,5 lucy f. stead,1 eldo t. verghese,3 thomas a. hughes1 1school of medicine, university of leeds, leeds, uk; 2department of histopathology and cytopathology, the royal hospital, muscat, oman; 3department of histopathology, st. james’s university hospital, leeds, uk; 4department of breast surgery, leeds teaching hospitals nhs trust, leeds, uk; 5histopathology and cancer sciences, queen elizabeth hospital birmingham and university of birmingham, birmingham, uk. *corresponding author’s e-mail: waleed0401@gmail.com objectives: poorer prognosis breast cancers are treated with cytotoxic chemotherapy, but predictive markers are not currently available. treatment failure (recurrence) is relatively common. we aimed to identify predictive markers and resistance pathways. the hypothesis was that tumour cells remaining after neoadjuvant chemotherapy (nac) contain somatic variants causing therapy resistance, while variants present pre-nac but lost post-nac cause sensitivity. methods: whole exome sequencing was performed on matched preand post-nac cancer cells (isolated by laser microdissection) (n = 6). somatic variants selected for/against by nac were identified. candidates were screened in vitro using knockdowns. expression was tested for predictive value in cohorts of chemotherapy-treated breast cancers (n = 53 and n = 303). results: somatic variant diversity was reduced after therapy (p <0.05). muc17 variants were identified in three tumours and were selected against by nac, while pcnx1 variants were identified in two tumours and were selected for by nac. in vitro knockdown of muc17 or pcnx1 were associated with increased or decreased chemotherapy sensitivity respectively (p <0.05). kaplan-meier analyses revealed that low muc17 expression was significantly associated with longer survival after chemotherapy, while low pcnx1 was significantly associated with reduced survival. conclusion: therapy-driven selection of somatic variants allows identification of chemotherapy response genes. muc17 and pcnx1 are mediators of chemotherapy response. β-caryophyllene induces apoptosis and inhibits angiogenesis in human colorectal cancer xenografts in vivo saad s. dahham departments of science, rustaq college of education, ministry of higher education, muscat, oman. e-mail: saad.dahham.rus@cas.edu.om objectives: β-caryophyllene (β-c), bicyclic sesquiterpene, is one of the major terpenes found in several essential oil plants. previously, we have reported the anticancer properties of β-c by employing a series of in vitro antitumour-promoting assays using colorectal cancer cells. β-c is the lead compound of a relatively new class of vascular disrupting agents that target existing tumour blood vessels. in this regard, the present study was designed to investigate the anti-tumour activity of β-c against xenograft tumour models (ectopic and orthotopic) of human colorectal cancer and the associated mechanisms by which it inhibits angiogenesis and induces apoptosis. methods: the effect of β-c on apoptotic morphological changes of colorectal cancer hct-116 was investigated using human antibody apoptotic array and transmission electron microscopy (tem). on the other hand, an orthotopically implanted human colorectal cancer cells (hct-116) into xenograft nude mice model were used to investigate the effects of β-c on tumour growth; the tumour volume was determined by fluorescence molecular tomography. results: results of human antibody apoptotic array study demonstrated that β-c downregulates the cell survival proteins survivin, hsps and xiap and at the same time upregulates the pro-apoptosis marker p21. β-c was also strongly antiangiogenic by inhibiting endothelial cell migration, tube formation, sprouting of rat aorta microvessels and suppressing the vascular endothelial growth factor. in the tumour xenograft model, β-c showed a remarkable reduction in all treated animals’ tumour size, in a dose-dependent manner. tumour histology revealed a clear reduction of the density of vascularisation. conclusion: overall, it can be concluded that β-c exhibits strong inhibitory activity against colorectal tumour growth through a mechanism that appears to involve apoptosis induction and angiogenesis suppression. sigma2 receptor/pgrmc1 is a potential modulator of epidermal growth factor receptor expression in human gastric cancer cell line *noor al-foudhili and ikhlas ahmed department of pharmacology and clinical pharmacy, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: noormohd.1994.nm@gmail.com objectives: s2r/pgrmc1 is essential for tumour formation, invasion and metastasis, and is upregulated in different types of tumours including gastric cancer. s2r/pgrmc1 increases the expression of epidermal growth factor receptor (egfr) in breast cancer cell lines, indicating that s2r/pgrmc1 may play a role in the stabilisation trafficking of egfr to the cell surface. this study aimed to determine whether s2r/pgrmc1 can be used as an alternative targeted therapy for gastric cancer through egfr, which was achieved by studying the extent to which s2r/pgrmc1 affect egfr expression on gastric cell lines. methods: this study was carried out between july 2016 and march 2017 at the pharmacology laboratory of the sultan qaboos university in muscat, oman. in the present study, we have treated gastric cancer cell line (ags) with increased concentration of s2r/pgrmc1 inhibitor (ag-205) and the samples were analysed for viability and protein expression of egfr and s2r/pgrmc1. results: s2r/pgrmc1 inhibition reduced gastric cell line viability significantly (p <0.05). s2r/pgrmc1 and egfr levels decreased significantly with the treatment. first biomedical science conference in oman sultan qaboos university conference hall e148 | squ medical journal, february 2021, volume 21, issue 1 conclusion: the results demonstrate that s2r/pgrmc1 is a potential therapeutic target for gastric cancer and can solve many problems associated with targeting egfr. boswellic acid sensitises gastric cancer cells to cisplatin-induced apoptosis via p53-mediated pathway *safiya al-kharusi,1 shadia al-bahlani,1 ikram burney,2 buthaina al-dhahli,1 fakhra al-kharousi,1 amani al-kalbani,1 ikhlas ahmed,3 mansour al mandhari2 departments of 1allied health sciences, 2medicine and 3pharmacology & clinical pharmacy, college of medicine and health sciences, sultan qaboos university, muscat, oman. corresponding author’s e-mail: safiya.alkharusi1@gmail.com objectives: gastric cancer (gc) is the fourth most common cancer worldwide and the fifth in oman. although cisdiamminedichloridoplatinum (cddp) is an effective chemotherapeutic agent for treating gc, most cases develop resistance against it. such resistance occurs when cddp fails to induce apoptosis by either activating pro(i.e. p53) or inhibiting antiapoptotic (i.e. akt and nfkb) proteins. cddp-resistance is a multifactorial process that can be partially overcome by additional agents with anticancer properties, one of which is akba (acetyl-keto-beta boswellic acid) has shown promising anticancer effects in certain types of cancer. however, its role in enhancing cddp-induced apoptosis in gastric cancer and the underlying molecular mechanisms has not been studied. therefore, this study aimed to examine the effectiveness of akba on p53-mediated, cddpinduced apoptosis in gc cells. methods: ags and nci-n87 gastric cancer cells were treated with different cddp concentrations (0, 50, 100 µm) and akba (0, 25, 50, 100 µm). apoptosis and expression of p53, akt and nfkb proteins were assessed using flow cytometry and western blot, respectively, while the role of p53 was determined by inhibiting its function through sirna. results: in nci-n87 cells, both cddp and akba significantly induced apoptosis in a dose-dependent manner (p = 0.004 and p <0.001 at 50 µm, respectively). decreased akt and nfkb expression with loss of p53 expression. in ags cells, a similar effect of both drugs was seen in apoptosis induction and akt and nfkb expression except for p53 protein, which was increased. p53 down-regulation affected apoptosis induction by both drugs, suggesting its role in their mechanisms’ of action. conclusion: altogether, our findings suggested, for the first time, that akba enhances gc cell sensitivity to cddp-induced apoptosis via a p53-mediated pathway. characterisation of congenital von willebrand disease types by von willebrand factor multimer analysis in oman *karima al falahi,1 anil pathare,1 margerate cunningham2 1department of haematology, sultan qaboos university hospital, muscat, oman; 2institute of pharmacy and biomedical sciences, university of strathclyde, scotland. *corresponding author’s e-mail: karima@squ.edu.om objectives: von willebrand disease (vwd) is the most common inherited bleeding disorder. it is caused by quantitative (type 1 and type 3) or qualitative (type 2) defects of von willebrand factor (vwf). the study aimed to perform the vwf multimeric analysis on known diagnosed omani vwd patients and subclassify them into appropriate types. methods: in this study, a cohort of 40 historically diagnosed and classified vwd patients at sultan qaboos university hospital was investigated by vwf multimer analysis using sodium dodecyl sulphate agarose gel electrophoresis and capillary blotting. the phenotyping test results and the clinical history of the patients were used to assist the classification process. results: overall, vwf multimer analysis results matched in 38 out of 40 cases of historically diagnosed vwd patients. of which, 11 cases (type 1) showed normal multimer structure to a mild reduction in the intensity of the multimer bands. multimer analysis of type 2 vwd showed abnormal multimers in six cases and normal multimers in 14 cases. the total absence of all multimers was observed in seven cases (type 3). the analysis of vwf multimer was not informative in two cases of studied vwd. conclusion: the analysis of vwf multimers was successfully used to classify vwd types and flagged potential misdiagnosis of some type 1 and one type 2 vwd that require followup investigations. the vwf multimeric assay helped classify the different vwd cohort subtypes with the incorporation of clinical history and quantitative laboratory tests. national registry of red blood cell phenotypes for the blood donors in oman: what is next? *zainab al-arimi,1 raya al-muhaidhri,1 hawraa al-lawati,1 shathya al-khan,1 maisoon al-subhi,1 samya ahmed,1 khalid al-habsi,1 fatma al-bulushi2 1departments of blood banks services, ministry of health, muscat, oman; 2oman medical specialty board, muscat, oman. *corresponding author’s e-mail: alfannah05@yahoo.com objectives: this study aimed to determine the characteristics of red blood cell (rbc) antigen phenotypes among the blood donors in oman and create a centralised rbc donor phenotype registry. this registry helps improve the transfusion management and outcome of many sickle cell disease (scd) patients by providing a phenotype matched rbc. methods: a total of 610 blood donors attending the department of the blood banks services were randomly included from january 2018 to july 2019 and were tested by id-gel column techniques for abo/rhesus (rh) (d) and the other blood group antigens. results: the most common abo blood group was group o with a frequency of (51.5%) followed by group a, group b and lastly group ab. the majority of the blood donors are rhd positive, representing 89%. r1r is the most common among the rh phenotype (32.6%), whereas r2r2 is the least (2.5%). kell system (k-k+ 92.1%, k+k0.5%), kidd (jk(a+b+) 49 %, jk(a-b+) 16.4%. mns (mss 23.3%, ns 0.2%). fy(a-b-) 71.8%, fy(a+b+) 5.9%. le(a-b+) 64%, le(a+b+) 0.5%. lu(a-b+) 97%, lu(a-b-) 0.3%. conclusion: blood donor rbc phenotype registry is crucial to ensure phenotype-matched blood to multi-transfused patients, including scd. this study also showed the differences in the rbc antigens among blood donors in oman compared to other ethnic groups. building up a national database of phenotyped rbc is ongoing, labour-intensive and requires continuous updating to ensure blood availability for all patients, including patients who need support with rare blood types. 26–27 february 2020 conference abstracts | e149 comparative analysis between the manual gel card and automated technique for abo and rh grouping *jalila al-sheryani,1 ali al-marhoobi,1 saif al-hosni,2 ishaq al-omairi,2 sabah al-mahroqi,2 mohmaed-rachid boulassel1 departments of 1allied health sciences and 2hematology, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: aljloo989@gmail.com objectives: the abo and rhesus (rh) groups are the most important systems in blood transfusion. different methods are used to assess the abo and rh groups, including the manual gel card and the automated ih-1000 instrument. this study aimed to assess the agreements between the manual gel card method and the automated ih-1000 technique for assessing abo and rh blood groups using routine blood samples. methods: this cross-sectional study performed at sultan qaboos university hospital from september to november 2018. all blood samples received at the blood bank unit for abo and rh typing were tested by the manual gel card and the automated ih-1000 methods. in addition, some blood samples were tested for antibody screening. the clinical information for each participant was taken from the squh database. chi-square test was used to compare the data. results: a total of 1,419 samples were screened for abo and rh groups using both methods. among these samples, 143 cases were also tested for antibody screening. the mean age of the study population was 30 ± 16 years and 51.6% were female. no statistically significant differences were found between the two methods for abo and rh typing (p = 0.99). however, five cases (0.35%) showed discrepancies in abo typing. similarly, discrepancies were observed in 18 cases (12.5%) for antibody screening. conclusion: overall, a good-to-excellent agreement was evidenced between the manual gel card and ih-1000 automated instrument methods, but some discrepancies were also noticed. socs3 gene is not epigenetically silenced by cpg methylation in gastric cancer *fatima al-kindi,1 atika al-saqri,1 yahya tamimi,1 mansour al-moundhri2 departments of 1biochemistry and 2medicine, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: f.alkindi92@gmail.com objectives: gastric cancer is a life-threatening disease considered the fifth most diagnosed cancer and the third cause-related death. a complex heterogeneity characterises it with no early specific signs and symptoms associated with its onset and progression. suppressor of cytokine signalling (socs) family is an essential negative regulator of the cytokine signalling mediated by the jak/ stat pathway. loss of socs3 expression was reported in gastric cancer, suggesting its tumour suppressor role. this study aimed to identify the methylation status of the socs3 gene using patients’ tissues and a large cohort of gc tcga database. methods: in this study, we analysed 44 patient’s tissues using gene panel exome sequencing along with a larger cohort of 118 patients found on tcga public databases to examine the question of whether the socs3 gene was silenced by methylation mechanism(s). kaplan mayer curve was used to examine the effect of socs3 methylated and unmethylated cases on survival. results: thirteen out of forty-four (29.5%) patients showed methylation suggesting gastric cancer's epigenetic role. the cancer genome atlas database (tcga; nci) was used to validate the hypothesis that socs3 expression is silenced by cpg methylation. a negative correlation (r = −0.82) was found between socs3 expression and the methylation status estimated by β-values. moreover, moderate methylation (β <0.4) and high methylation (β >0.4) did not affect free survival. conclusion: silencing the socs3 gene is likely to be regulated by other mechanisms such as mirna and lncrna rather than methylation. reliability of carbapenem inactivation method and modified carbapenem inactivation method for detection of oxa48 and ndm-1 *dhoha ben khalid,1 hiba sami,2 zaima al jabri,1 munawer al-quraini,1 fatima khan,2 anuradha singh,2 nusrat zafar,2 badriya al adawi,1 meher rizvi1 1department of microbiology & immunology, sultan qaboos university, muscat, oman; 2department of microbiology, aligarh muslim university, aligarh, india. *corresponding author’s e-mail: rizvimeher@squ.edu.om objectives: two phenotypic tests, carbapenem inactivation method and modified carbapenem inactivation method, were recently developed to rapidly detect carbapenemase-producing gram-negative bacilli. in this study, we compared the ability of carbapenem inactivation method (cim) and modified cim (mcim) to differentiate between carbapenemase producers and nonproducers among carbapenem-resistant bacteria. methods: fifty-six carbapenem-resistant organisms (28 each from oman and india) were identified in various clinical samples. identification of the isolates and antimicrobial susceptibility testing was performed as per standard guidelines. genotyping of all strains was performed. cim, mcim and modified hodge test were performed. results: in oman, most isolates were klebsiella pneumoniae and expressed oxa-48 genotype. in india, the majority of the isolates were escherichia coli and they expressed ndm-1 genotype. modified hodge test was positive in all the oxa-48 producers and 57% of the ndm-1 isolates. the sensitivity of cim in detecting 0xa-48 and ndm-1 carbapenemases were 10% and 89%, respectively. on the other hand, mcim detected 56% and 57% of 0xa-48 and ndm-1 carbapenemases, respectively. conclusion: cim and mcim are simple, cheap and easy to perform tests. cim gave excellent results with ndm1 strains while was relatively poor in predicting oxa-48. detection of oxa-48 improved to 57% when mcim was used while ndm1 detection was relatively poor. the two methods’ sensitivity appears to vary in different genotypes of carbapenemases and further evaluation is needed. determination of the prevalence of methicillin-resistant-staphylococcus aureus in sultan qaboos university hospital healthcare workers *loai al-wahaibi,1 rajaa al-sudairi,1 abdullah balkhair,2 huda al-owaisi,3 mohamed mabruk1 1department of allied health sciences, sultan qaboos university, muscat, oman; 2department of medicine, infectious diseases unit, sultan qaboos university hospital, muscat, oman; 3department of nursing affairs, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: loaioct1994@gmail.com objectives: this study aimed to detect the prevalence of methicillin-resistant staphylococcus aureus (mrsa) in nasal carriage among healthcare workers in the sultan qaboos university hospital (squh) and determine the risk factors possible transmission of mrsa. methods: a total of 200 nasal swab samples were collected from the healthcare workers at squh from october 2018 to first biomedical science conference in oman sultan qaboos university conference hall e150 | squ medical journal, february 2021, volume 21, issue 1 january 2019. data on risk factors for mrsa colonisation were also collected. results: forty-one of the 200 screened healthcare workers (20.5%) were found to have nasal carriage of s. aureus, of which 63.4% were methicillin-sensitive and 36.6% were methicillinresistant. mrsa was isolated from 15 of the 200 screened healthcare workers giving a prevalence rate of nasal colonisation with mrsa of 7.5%. we found no association between healthcare worker mrsa nasal colonisation and age, gender, speciality, hand hygiene practices, skin condition, previous mrsa infection or previous exposure to antibiotics. conclusion: according to this study, the prevalence of mrsa nasal colonisation in screened healthcare workers at squh was 7.5%. this finding is concerning and calls for large scale prevalence studies to determine the true prevalence and guide preventive strategies, including universal and periodic healthcare worker screening. whole-genome sequencing of clinical isolates of staphylococcus epidermidis identifies copper efflux transporters of the arginine catabolic mobile element and the copper and mercury resistance *zaaima al-jabri,1 amal al-hinai,1 atika al-bimani,1 ammar al-shabibi,2 zahra al-shabibi,3 meher rizvi1 1department of microbiology & immunology, 2college of medicine, sultan qaboos university, muscat, oman; 3oman animal & plant genetic resources center, muscat, oman. *corresponding author’s e-mail: zaeema@squ.edu.om objectives: two mobile genetic elements (mges) namely the arginine catabolic mobile element (acme) and the copper and mercury resistance (comer) were shown to enhance the fitness by facilitating the survival of methicillin-resistant staphylococcus aureus (mrsa) within the host macrophages. these elements have been closely associated with staphylococcal chromosomal complex (sccmec). this study aimed to analyse copper efflux transporters and antimicrobial resistance-conferring genes carried by or on mges in s. epidermidis; the reservoir for resistance determinans, utilising whole-genome sequencing (wgs). methods: acme and comer and mlst were investigated by analysing wgs of 24 s. epidermidis isolates recovered from bacteremic patients from squh using blast and artemis bioinformatics tools. antimicrobial resistance genes were identified through card online tool. hospital-adapted lineages were studied using whole-genome phylogenetic single nucleotide polymorphism tree. results: sccmec was identified by sccmecfinder tool in most isolates, mainly type iv (n = 8, st-2). high variability in acme subtypes was observed in s. epidermidis isolates with type i being the most prevalent (n = 16), type ii (n = 2), type iii (n = 1), type iv (n = 1) and type v (n = 4). by contrast, comer elements were very similar to copper efflux transporters copb, mco and copa/copz from core chromosome identified in most isolates. copr (two strains), and an additional copy of (copa/copz) in 17 strains were associated with copper resistance in s. epidermidis. disc diffusion assay showed reduced susceptibility to copper in most strains, but none were hyper-resistant. conclusion: this study has shed light on wgs contribution to analysing antimicrobial and metal resistance determinants. investigating the role of sphingosine kinase in leishmaniasis badriya al-balushi strathclyde institute of pharmacy and biomedical sciences, strathclyde university, glasgow, scotland. author’s e-mail: badriyab@squ.edu.om objectives: sphingosine-1-phosphate (s1p1) receptor expression in activated t cells in vivo is downregulated by receptor internalisation and degradation. this study aimed to determine the effect of fty720 and its analogues on the expression of s1p1 receptors on the t cells in vitro. additionally, activating t lymphocytes using ova technique and studying the effect of fty720 on activated cd4+ t cells in vitro. a new approach has been studied, in which cell line expressing s1p1 was used to analyse the influence of the novel compounds in s1p1 receptor expression and localisation. methods: the effect of fty720 on s1p1 level on t cells from otii mice in vivo was investigated by flow cytometry. a cell line expressing a stable amount of s1p1 was used to examine the effect of fty720 and fty720 analogues in the expression level of the receptor by western blot. results: increasing the incubation time of t cells pulsed with ova antigen more than 24 hours increases the expression of the s1p1 receptor. fty720 did not suppress s1p1 in treated t cells. fty720 treated cell line showed decreased expression of s1p1 receptor. among the analogues used, compound a showed a remarkable effect in s1p1 protein as several fragments were formed in the treated cell. fragment formation was suppressed by a proteasomal inhibitor. conclusion: the two compounds and fty720 affected the amount of s1p1 receptor and those compounds can be used for in vivo study to investigate their role in inhibiting the egress of t cells in inflammation and infection. assessment of estrogen receptor, progesterone receptor and human epider mal growth factor receptor 2 immunohistochemistry of breast cancer fineneedle aspiration cell blocks *hajer m. al-badi,1 noha m. al-masrouri,1 nasar y. al-wahaibi,1 shadia s. al-sinawi,2 najat al-dairi2 1department of allied health sciences, sultan qaboos university, muscat, oman; 2department of pathology, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: halbadi@squ.edu.om objectives: this study aimed to evaluate the expression of estrogen receptor (er), progesterone receptor (pr) and human epidermal growth factor receptor 2 (her2) immunohistochemistry in the fine needle aspiration (fna) cell block (cb) of breast cancer (bc) and correlate the finding with surgical tissue block (tb). methods: immunohistochemistry was performed in 48 fna cbs diagnosed with bc from 2007 to 2016 at sultan qaboos university hospital. the results were scored and compared with previously made tb results. sensitivity, specificity, positive predictive value, and negative predictive value were measured. cohen’s kappa (κ) test was used to calculate the degree of agreement between the two methods. results: er results showed 67.7% sensitivity, 94.1% specificity, 95.5% ppv and a moderate agreement (κ = 0.588). pr results showed 50% sensitivity, 90% specificity, 87.5% ppv and a fair agreement (κ = 0.368). her2 results showed 58.3% sensitivity, 100% specificity, 100% ppv and a moderate agreement (κ = 0.539). conclusion: the results of this study confirm the wide variations that occur between immunohistochemistry in cb and tb. compared with other studies, low sensitivity and high specificity rates for er, pr and her2 in fna cb were reported. more studies are needed. 26–27 february 2020 conference abstracts | e151 expression of programmed death-ligand 1 in breast carcinoma with correlation to molecular subtypes and clinicopathological parameters in patients following at sultan qaboos university hospital *malika al-dighaishi and asem shalaby 1department of pathology, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: u106490@student.squ.edu.om objectives: breast cancer (bc) is the most common cancer among omani women. programmed death ligand 1 (pd-l1) protect tumour cells form anti-tumour immunity and promote tumour proliferation. this study aimed to investigate the pd-l1 expression in breast cancer cases presented to sultan qaboos university hospital and correlate it with the molecular subtypes, different clinicopathological parameters and clinical outcome. methods: we studied pd-l1 expression in 55 breast carcinoma specimens collected from 2010 to 2016 using immunohistochemistry (ihc) on tissue microarray (tma) with the use of commercial antipdl1 antibody. the expression was evaluated according to the intensity of the staining in the tumour cells. chi-square and log-rank tests were used to determine the correlation of pd-l1 expression with the molecular subtypes, clinicopathological parameters and clinical outcomes. results: twenty-seven out of 55 cases (51.9%) showed membranous pd-l1 expression ranging from mild (n = 17) to moderate expression (n = 10). pd-l1 was associated with a positive family history (p = 0.023) and high cellular marker of proliferation ki-67% (p = 0.04) but was not correlated with clinicopathological parameters, receptor status and molecular subtypes. pd-l1 was associated with better relapse-free survival (rfs) in the overall population (p = 0.028) but was not correlated with overall survival (os; p = 0.131). conclusion: the high positivity rate of pd-l1 may support immunotherapy in the treatment of breast carcinomas. in addition, pd-l1 may be considered as a potential marker for prognosis. further validation with a larger sample of the population and the use of different antibody types is warranted. evaluation of a protective effect of aqueous thymus extract against diclofenac sodium-induced hepatocytotoxicity in mal syrian hamster mohamed morra department of science, rustaq college of education, rustaq, oman. e-mail: mdmorra.rus@cas.edu.om objectives: this study aimed to evaluate the protective effect of aqueous extract of thymus leaves against diclofenac sodiuminduced hepatocytotoxicity. methods: 32 mal hamsters were used and equally divided into four groups. group 1 was the control, while group 2 received an oral thymus extract dose (300 mg/kg.b.w) orally daily for five weeks. groups 3 received diclofenac sodium (6mg/kg.b.w) three times/week also for five weeks. group 4 received a dose of diclofenac sodium combined with a thymus extract dose in the same concentrations. blood was taken from each animal and stored until biochemical study. then, hamsters were sacrificed, autopsied, and liver tissue samples were prepared for histopathology assessment. results: biochemical study showed a significant increase in the levels of alt, ast enzymes, bilirubin, uric acid, and urea (p <0.001) while albumin level decreased (p <0.001) in the blood serum of group 3 compared to the control and group 2. a significant decrease in all the precedent biochemical parameters (p <0.001) and elevation of albumin have been recorded in the blood serum of group 4. histopathological study revealed strong indices of injury mediated by diclofenac sodium, especially congestion of liver cells, dilation of the hepatic portal and central veins, cell nucleus disappearance and inflammatory cells infiltration. these indices were greatly ameliorated and activation of liver cells division was recorded in the liver of 4th group animals. conclusion: the present results suggest that aqueous extract of thymus leaves could be a potent natural herbal product provide a promising hepatoprotective effect against hepatotoxicity induced by diclofenac sodium. neoadjuvant chemotherapy in vitro models reveal an increase in her-2 and neuropilin-1 proteins conferring drug resistance *sirin a. adham and noura al-zeheimi department of biology, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: sadham@squ.edu.om objectives: locally advanced breast cancer patients usually receive third-generation neoadjuvant chemotherapy (nac). although nac treatment improved overall survival, patients’ response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. we aimed to identify the molecular changes attributed to nac resistance attempting to find new therapeutic targets in different breast cancer subtypes. methods: we mimicked nac treatment used in clinical practice and generated resistant cell lines in an in vitro model. the resistant cells were generated by consequent treatment with four cycles of adriamycin/cyclophosphamide (4×ac) followed by an additional four cycles of paclitaxel (4×ac + 4×pac). results: our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. ac and paclitaxel resistant mdamb-231 cells activated nrp1/tnc/integrin β3/fak/nf-κbp65 axis and displayed a decrease in breast cancer resistant protein (bcrp/abcb2). in turn, resistant mcf7 cells to ac (4×ac), induced her-2 expression which converted mcf7 subtype from being a luminal a to luminal b-her-2 type, upregulated nrp-1, er-α, and egfr and activated pi3k/akt/nf-κbp65 survival axis. unlike mda-mb-231 cells, mcf7 cells upregulated bcrp/abcg2 in response to paclitaxel resistance. co-immunoprecipitation demonstrated a novel interaction between her-2 and nrp-1 which drives the resistance features. conclusion: nac induced a concurrent increase in nrp-1 and her-2 expression, enhancing breast cancer drug resistance. this translational study suggests that anti-nrp-1 might be useful for treating triple-negative breast cancer and might increase the efficacy of herceptin in treating resistant luminal a overexpressing her-2 as a result of nac. design, synthesis and biological evaluation of some new 2-pyridylquinazoline derivatives *ahmad f. eweas1 and qasem m.a. abdallah2,3 1department of science, rustaq college of education, rustaq, oman; 2medicinal chemistry department, national research center, dokki, cairo, egypt; 3department of pharmacology & biomedical sciences, faculty of pharmacy and medical sciences, university of petra, amman, jordan. *corresponding author’s e-mail: eweas1@gmail.com objectives: 2-pyridyl [3h]-quinazolin-4-one derivatives fused or substituted with different oxygen or nitrogen heterocycle first biomedical science conference in oman sultan qaboos university conference hall e152 | squ medical journal, february 2021, volume 21, issue 1 moieties as potential anti-tumour and antimicrobial agents were prepared, characterised and biologically screened synthesise. a novel series of 6-bromo quinazolin-4[3h]-ones linked or fused to other heterocyclic moieties such as pyrazolone, triazole, tetrazole ring systems are evaluated for their antimicrobial and antiproliferative activity in this study. methods: the synthesis process started from 5-bromo-2-[pyridin-4-ylcarbonyl]amino]benzoic acid 1 which was converted to the crucial building block 3 via two alternative procedures. compound 3 underwent halogenation reaction pocl3 and pcl5 to afford compound 4. various cyclisation reactions were applied to compound 4 to afford the novel compounds 5a,b-10. the newly prepared compounds underwent antimicrobial screening as well as cytotoxicity evaluation against five different cell lines. results: only compound 9 was found to possess selective activity against staphylococcus aureus. this gram-positive selective activity may be due to the selective targeting of 9 to the thick cell wall of gram-positive bacteria. moreover, a toxicological assessment of compound 9 revealed no human cytotoxicity on tested normal and cancer cell lines. therefore, 9 may serve as a good candidate for further development studies by structure modification in order to optimise its potency. conclusion: a new series of 2-pyridyl [3h]-quinazolin-4-one derivatives incorporated into diverse n and o heterocyclic moieties as potential antimicrobial agents were synthesised, characterised and screened for their antimicrobial and cytotoxic activity. among all new compounds, only compound 9 was found to process selective antibacterial activity against gram-positive bacteria s. aureus (iz = 26 mm, mic = 256 µg/ml). development of prolactin receptor antagonists *gunnar norstedt,1 a. al-kharusi,1 t. gräslund,2 s. yu2 1department of biochemistry, sultan qaboos university, muscat, oman; 2school of biotechnology, kth royal institute of technology, stockholm, sweden. *corresponding author’s e-mail: gnorstedt@squ.edu.om objectives: prolactin (prl) consists of 200 amino acids and binds to a membrane-bound prl receptor. a role for prl in breast, prostate and ovarian cancer is suspected since this growth-promoting hormone can be produced by cancer cells and that the prl receptor is frequently overexpressed. a specific feature of the prl receptor is that it is rapidly internalised into cells once it has bound prl. due to the suspected cancer relevance of prl, we have developed antagonists for the prl receptor and have also initiated attempts to link such antagonists to low molecular weight anticancer drugs. the design, manufacture and bioactivity of these new prl receptor antagonist are described. methods: plasmid constructs were made for using an e. coli expression system to produce a variant of prl with antagonistic activity. this variant has four amino acid substitution that converts the agonist into an antagonist. the recombinant proteins were tested in biacore assays and cultured cells. the prl receptor antagonist was further conjugated to dm1, an anticancer compound, using the so-called sortase system. prl receptor binding of the produced compounds was tested using biacore assays and biological activity was tested in cultured cells by analysing stat5 phosphorylation. results: systems for recombinant prl receptor antagonist production can be established in e. coli. the sortase system is an efficient method to achieve site-specific drug conjugation. the recombinant prl receptor antagonists bind the prl receptor with equal or higher affinity compared to native prl. prl is known to activate stat5 in cultured cells and our results indicated that prl receptor antagonists could block this activity. conclusion: the first steps to produce prl receptor antagonists have been taken, which allows for further investigations on the role of prl in cancer. extracellular vesicles mediate development of renal cysts *fahad zadjali,1,2 prashant kumar,2 ying yao,2 john bissler2 1departments of biochemistry, sultan qaboos university, muscat, oman; 2department of pediatrics, university of tennessee health science center, usa. *corresponding author’s e-mail: fahadz@squ.edu.om objectives: patients with tuberous sclerosis complex (tsc) experience disease because of developmental and cell growth control abnormalities. the disease can manifest as solid tumours in the kidney, called angiomyolipoma or renal cancer, or fluid-filled lesions called cysts. this latter lesion can be as aggressive and even more devastating than the solid tumours. mechanism of cyst development in tsc is not known. methods: various models were used to study cyst fluid from tsc2 deletion in principal cells (aqp2cretsc2 mice), tsc2 deleted cell lines and patients with tsc-renal cysts. results: we found, unlike the solid tumours, the cysts do not have a significant burden of cells that have experienced additional mutations, but rather the cysts are composed of genetically healthy cells that are ‘instructed to do bad things’ by a very small population of genetically mutant cells. we have discovered that these instructions, or communication, between the genetically mutant or ‘sick’ cells and genetically normal cells occur through structures called extracellular vesicles (evs). evs isolated from principle cells and patient’s cysts fluid had a mean diameter of 300–400 nm. evs form tsc2-null cells had a ph buffering effect. tsc2 deletion in cells showed increased mtorc1 activity and increased evs synthesis and release. recipient cells had higher mtorc1 activity when treated with evs or evsprotein/rna from tsc2-null cells. these data suggest that disease phenotype is conveyed via evs from mutant cells to normal cells. mice with tsc2 deletion in principal cells (aqp2cretsc2 mice) develop renal cyst(s) with age and urine evs characteristics are similar to above. aged aqp2cretsc2 mice develop renal cell carcinoma, which implicates chronic phenotype spreading via evs in cellular re-programming. conclusion: extracellular vesicles provide a novel mechanism of developing renal cysts in tsc and may mediate cellular programming into renal cell carcinoma. effects of mobile phone electromagnetic field on the living cells: an in vivo study *najam siddiqi,1 nasser a. nizwani,1 asem shalaby,2 yahya tamimi,3 fatima al-ghafri,2 mohammad al-kindi,2 abdul rahman al-nabhani,2 zoya shaikh3 departments of 1anatomy & biochemistry, national university of science and technology, muscat, oman; departments of 2pathology and 3biochemistry, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: najamsiddiqi@nu.edu.om objectives: this study aimed to examine the effects of electromagnetic waves emitted by mobile phone on gross morphology of the developing chick embryo and the organelles in the liver and heart tissues. methods: forty zero-day fertilised eggs of gallus domesticus were randomly divided into control and experimental groups and placed in an egg incubator. the experimental group was exposed to electromagnetic waves by placing a mobile phone inside the incubator and calling it from outside according to a planned schedule. the control group had no such exposure. embryos were euthanised at day 10 and day 15. gross morphology, histology, em, hsp 70, mrna was studied in liver and heart tissues. results: mortality was higher in the exposed group. cutaneous haemorrhages limb deformities were apparent. liver revealed fatty change, increase the number of degenerated and 26–27 february 2020 conference abstracts | e153 deformed mitochondria and fat-filled vacuoles. cardiac muscle also revealed a marked increase in the number of elongated and degenerated mitochondria. a significant increase in hsp 70 mrna in the experiment group was seen. in the control group, no such abnormities were seen. conclusion: the electromagnetic field has caused morphological and intracellular damage to liver and heart in developing chick embryo. a non-invasive microwave-based sensing system for water accumulation abnormality detection in lungs *mohammed m. bait-suwailam, omar al-busaidi, ahmed al-shahimi, mohammed al-shizawi, muhanna al-qanuni, abdulrahman matar, and moosa al-balushi department of electrical & computer engineering, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: msuwailem@squ.edu.om objectives: lungs play an important role in the respiratory system for breathing. deficiencies in lung operations result due to accumulation of fluid inside the lungs, which is considered a sign of a medical abnormality, for instance heart failure. current diagnosis techniques are time consuming and relatively unable to monitor, detect or even provide accurate assessment of water accumulation in lungs in terms of water accumulation percentage and related degree of illness. as such, developing low cost mechanism for water accumulation in lungs will provide an alternative yet rapid and accurate enough diagnosis tool for critical conditioned patients. methods: electromagnetic detection mechanism using microwaves is well suited for detecting watery fluid accumulation in the lungs. this is because accumulated water in the lungs has high dielectric constant concentration compared to normal lungs. in this work, we developed a low-cost non-invasive microwave detection system for water accumulation in smallscale lungs. two low-profile microwave sensors were placed in a front-to-back scenario to capture the amount of electromagnetic field strength as a transfer power strength. this power detector can easily map the amount of power to a reasonable voltage level that then can be processed and displayed in an lcd unit. this study was carried out in a capstone design project in a controlled laboratory room at the department of electrical and computer engineering at sultan qaboos university. results: experimental trials were conducted by changing lungs status through loading it with salty water in different percentages. the detection status was correct in all scenarios. in future work, we aim to integrate the system with more sophisticated algorithms that will provide both qualitative and quantitative measures. conclusion: in this abstract, a microwave-based non-invasive detection system was developed for water accumulation abnormality detection in the lungs. different water accumulation percentages in lungs were detected from all performed scenarios in this study, with correct status display as either normal or abnormal lungs. in the second phase of this research work, the developed detection system shall be integrated with more additional sensing units including capturing heart rate, ensuring accuracy of reading the percentage of water accumulation within the lungs and integrating textile sensors within an easy to carry washable belt. the application of herzberg’s two-factor theory of motivation to job satisfaction in clinical laboratories in omani hospitals samira al-rawahi department of pathology, sultan qaboos university hospital, muscat, oman. e-mail: samiraalrawahi4@gmail.com objectives: job satisfaction is an important condition for staff retention in most healthcare organisations. as a concept, job satisfaction is linked to motivation theory. herzberg’s two-factor theory of motivation is used in this study to explore what motivational elements are associated with job satisfaction among medical laboratory professionals (mlps) in oman. methods: a qualitative methodology was adopted and focus group discussions (fgds) were used for data collection. the fgds were conducted in the three main hospitals in oman: the royal, al nahdha and khoula hospitals. participants included senior and junior staff classified as mlps. the study was undertaken in 2017 and the data were analysed by directed content analysis. results: the mlps identified the following factors that influenced their job satisfaction: health and safety, recognition and appreciation, salary and promotion, organisational policies, professional training and relationships with coworkers and leaders. applying herzberg’s theory, participants showed a low motivation level in their jobs. conclusion: the job dissatisfaction reported by the participants in each of the three hospitals resulted from the absence of factors that lead to satisfaction. such factors, referred to as hygiene factors in herzberg’s theory, must be present for this group of health professionals to experience job satisfaction; therefore, hospital managers need to address these factors or actively incorporate satisfiers that increase motivation and improve job satisfaction. poster presentations evaluating ordering blood smear criteria in haematology laboratory at sultan qaboos university hospital *muna al-maskari1 and sara al-habsi2 1departments of allied health sciences and 2haematology, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: munam@squ.edu.om objectives: this study aimed to evaluate existing blood smear ordering criteria used at sultan qaboos university hospital (squh) and obtain the optimal cut-off percentage of immature granulocyte (ig) that should be applied. methods: an evaluation study was conducted to evaluate the current cut-off percentage of ig used by the sysmexxn9000 analyser. a total of 118 blood samples were selected randomly within 24 hours of collection from the laboratory. blood smears were performed, stained using romanwsky stain and stored. the wbc differential was performed manually using a manual cell counter. for data analysis, bland and altman's analysis was used to see the agreement between the two different methods and deciding the optimum cut-off percentage by observing the tendency of the data. results: the agreement interval was found using the following equation: 1.96 sd ± mean equal (−0.042, 0.024). at a cut-off (mean) = 3%, the bias was toward the sysmex ig%. at a cut-off between 4–6%, ig sysmex ig% > manual ig%. outliers for number of patients differed so that sysmex measured much more ig than manual at a cut-off of nearly 5% and more. however, at a cut-off between 3–7%, sysmex measured ig% much less than manual. conclusion: ordering blood smear criteria at the squh is based on an ig = 10% cut-off point. however, according to the results obtained from this research, using 10% as a cut-off leads to loss of cases. therefore, ordering criteria cut-off should be set to 3% ig. first biomedical science conference in oman sultan qaboos university conference hall e154 | squ medical journal, february 2021, volume 21, issue 1 assessing proand anti-coagulant pathways in early-onset preeclampsia *amani al-zadjali,1 karl egan,2 fionnuala ní áinl2 1department of haematology, sultan qaboos university hospital, muscat, oman; 2conway institute of bimolecular and biomedical research, university of dublin, dublin, ireland. *corresponding author’s e-mail: alzadjalia-11@hotmail.com objectives: this study aimed to characterise coagulation in patients with early-onset preeclampsia (eop) and to elucidate the underlying mechanism. methods: patients with eop (n = 26), normal pregnant controls (pc; n = 21) and non-pregnant controls (n = 16) were recruited at the rotunda hospital, dublin, ireland. blood samples were collected into vacutainers containing sodium citrate (contact or intrinsic coagulation pathway not inhibited) or sodium citrate plus corn trypsin inhibitor (contact pathway inhibited) as an anticoagulant. platelet poor plasma was prepared and coagulation was assessed using calibrated automated thrombography and measurement of d-dimer, thrombin-antithrombin iii (tat) and tissue factor pathway inhibitor (tfpi) levels. results: compared to pc, eop patients had comparable tissue factor pathway-dependent thrombin generation profiles when the contact pathway was not inhibited. in contrast, eop patients were characterised by impaired thrombin generation compared to pregnant controls when the contact pathway was inhibited. this impaired thrombin generation was most apparent in patients with severe eop. furthermore, eop patients had increased sensitivity to activated protein c (apc) anticoagulant activity and endogenously generated apc compared with pc. d-dimer and tat levels were not elevated in eop patients than pc, suggesting that the impaired thrombin generation was not due to an in vivo coagulopathy and the consumption of clotting factors. however, tfpi levels were elevated in eop patients, most significantly in severe cases. inhibition of tfpi corrected the impaired thrombin generation profile in preeclampsia patients, suggesting that elevated tfpi levels were responsible for this observation. conclusion: thrombin generation is reduced in patients with eop owing to elevated tfpi levels. this may explain the reduced vte risk seen in association with preeclampsia patients compared to other inflammatory disorders. anti-d alloimmunisation in rhd+ sickle cell disease patient *zainab a. al fana, raya al-muhaidri, hawra al-lawati, mazin al-belushi department of blood banks services, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: al_fannah05@yahoo.com a 28-year-old woman with scd was admitted with a history of multiple transfusions and was known to have multiple antibodies with anti-e, anti-c and anti-kell antibodies. the blood bank investigations showed that the blood group was o rhd + and confirmed the already known antibodies with anti-c, anti-e and anti kell specificities. however, there were additional reactions observed suspicious of anti-d detected by the enzyme method only. the direct antiglobulin test (dat) was negative. we report a case of scd found to have anti-d despite being serologically strong rhd+. full sequencing of the rhd for the patient revealed that the patient harboured a partial d allele dau-3 which harboured two mutations v279 and t379m. given these findings, the transfusion recommendation was to give antigen-negative for d, c, e and kell and cross-match compatible. six months later, the patient’s sample was sent again as she required transfusion and the antibody identification test confirmed the presence of anti-d in addition to the already identified antibodies with anti-c, anti-e and anti-kell specificities. the anti-d used for the rhd typing demonstrated that the patient’s sample reacted strongly (3+ to 4+). the previous patient’s d typing demonstrated the same findings using different rhd typing reagents. genotyping was performed to explain anti-d’s paradoxical findings in the serologically normal rhd positive patient. analysis of the rhd gene and sequencing revealed that the patient harboured dau-3 rhd allele (v279m, t379m) described in african ethnic origin. anti-d immunisation in patients with scd harbouring partial d alleles is a problem despite giving phenotypically matched blood transfusion as current serological d typing may not detect some partial d variants harbouring some of the dau alleles. molecular testing should be considered for patients with scd on chronic transfusion who develop anti-d even when the rhd typing reacts strongly with the d typing reagents as some partial rhd variant may give normal reaction with rhd typing reagents. the abo blood group discrepancies among patients referred to the red cell reference laboratory at the department of blood banks services *louza al-mashaykhi,1 hawra allawati,2 raya al-muhaidri,2 zainab al fana alarimi2 1oman medical specialty board, muscat, oman; 2department of blood banks services, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: al_fannah05@ yahoo.com objectives: the red cell reference laboratory (rcrl) is considered a reference lab for oman’s blood banks. it provides technical support and transfusion advice for all regional blood banks and resolves difficult immunohaematology cases. this study aimed to provide information on the causes of abo discrepancies among referred patients to the rcrl from january 2014 to december 2015. methods: a retrospective analysis was performed on samples referred to abo discrepancy between january 2014 and december 2015. samples referred to rcrl which showed abo discrepancies were analysed as per the classifications into forward and reverse group discrepancies. then further classification of causes of each group was done. results: one thousand eight hundred sixtythree samples were referred to the rcrl in the study period; 42 patients were found to have abo discrepancies with an incidence of 2.25%. 60.8% of abo discrepancies causes were due to reverse abo group discrepancy and of these, 25.49% was an age-related cause which gives a weak antibody reaction on reverse grouping. forward group discrepancy was observed in 39.2% of patients and a subgroup was the common cause seen in this group. three cases showed both reverse and forward group discrepancy. conclusion: the incidence of abo discrepancy among referred patients to rcrl in the study period was found to be 2.25% with the majority (60.8%) of them due to reverse group discrepancy. in order to find compatible blood for recipients, abo discrepancies must be resolved to prevent abo hemolytic transfusion reaction. association between vitamin d binding protein snp rs2282679 and the level of serum 25-hydroxyvitamin d mariya h. n. al-kindi department of biochemistry, sultan qaboos university, muscat, oman. e-mail: maria_alkindi@icloud.com objectives: vitamin d is a secosteroid hormone produced in the skin upon exposure to sunlight. in addition, it can be obtained from food. vitamin d binding protein (vdbp) is found in plasma and is used to transport 25(oh)d from the liver to the kidneys 26–27 february 2020 conference abstracts | e155 and other organs where it is converted to the biologically active vitamin d form, 25(oh)2d. vdbp is highly polymorphic and the plasma concentrations of 25(oh)d depends on different genotypes. vitamin d deficiency is a high prevalence problem worldwide that leads to different health outcomes such as chronic liver disease, muscle weakness, low creatinine clearance and chronic renal diseases. investigate whether the vdbp single nucleotide polymorphism (snp) rs2282679 is associated with the serum level of 25(oh)d in a healthy omani population. methods: 29 dna samples extracted from blood samples collected from healthy omani volunteers along with the vitamin d serum levels were available. polymerase chain reaction (pcr) followed by sanger sequencing was used to determine each sample's genotype. results: almost 70% of the samples had the homozygous major genotype for the vdbp snp rs2282679, whereas only 30% were heterozygous. for the vitamin d level classifications, 13 samples had a deficient level (less than 30 nmol/l), two samples had an insufficient level (30–50 nmol/l) and 14 samples had a sufficient level of vitamin d (more than 50 nmol/l). the chi-square test was used to look for an association between the vdbp snp and the serum level of 25(oh)d in our samples and the p value was 0.652. conclusion: there were no significant association between the vdbp snp rs2282679 and the level of 25(oh)d in the serum among the volunteers in this study. this study should be repeated with a sufficient number of samples to represent the omani population. expression status of the pro-apoptotic caspase-3 gene after knocking down fat4 gene in epithelial ovarian cancer *mayyadah al-maawali,1 shika malgundkar,1 ikram burney,2 fatima al-kindi,1 moza al-kalbani,1 mansour al-moundhri,2 aikou okamoto,1 yahya tamimi1 departments of 1biochemistry and 2medicine, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: u112203@student.squ.edu.om objectives: ovarian cancer (oc) is considered the 7th most common tumour and the 8th most incident neoplasms worldwide. oc is composed of different histological subtypes 90% of which are of epithelial origin. in oman, the 2013 mortality rate of oc was estimated to 0.4 per 100,000 females, accounting for 4.5% of all cancer cases. in a previous oc related study, we have identified a cross-talk between the e2f5 transcription factor, which is involved in the early set-up of oc and the adhesion molecule fat4 gene. the obtained results were validated in mcas, ovsaho and ov2008 ovarian cancer cell lines using qrt-pcr. since e2f5 regulates fat4, we hypothesised that the latter may have a role in oc and operates through apoptosis using different effectors, including caspase-3. this study aimed to monitor the expression of caspase-3 in mcas and ovsaho cell lines treated with sirna to down-regulate fat4 gene expression. methods: the change in the expression of caspase-3 in fat4 sirna treated mcas and ovsaho cell lines was examined using the qrt-pcr and delta-delta-ct method for quantitation. results: significant overexpression of caspase-3 was found after the fat4 gene was knockdown in both cell lines. while mcas cells express caspase-3 gene 1.3 fold higher than normal cells, ovsaho cells express caspase-3 gene 1.7 fold higher than normal cells. conclusion: when fat4 is down-regulated, caspase-3 may have another role than pro-apoptotic effector in epithelial ovarian cancer. hyperhomocysteinemia is associated with n-homocysteinylated albumin formation in prediabetic omani adults *mostafa i. waly,1 ruqaiya m. al-balushi,1 preeja prabakar,1 atikah m.s. al-shekaili,1 amanat ali1,2 1department of food science & nutrition, sultan qaboos university, muscat, oman; 2school of engineering, university of guelph, ontario, canada. *corresponding author’s e-mail: mostafa@squ.edu.om objectives: this study aimed to assess homocysteine (hcy) status and the formation of n-homocysteinylated albumin protein in the sera of prediabetic omani adults. methods: one hundred five female omani college students at sultan qaboos university were recruited voluntarily and screened for prediabetes (impaired fasting blood glucose or impaired glucose tolerance). only 53 study participants were found to be prediabetic and fasting serum samples were collected from this group to measure hcy level and to quantify n-homocysteinylated albumin protein. results: it was observed that the study participants had a comparable age (21.5 ± 1.5 years) and were overweight based on their body mass index (bmi, 26.84 ± 1.19 kg/m2). the measured serum levels of hcy were higher than the normal range (71.25 ± 6.11 µmol/l), suggesting that the prediabetic participants had hyperhomocysteinemia. proteomic measurements of n-homocysteinylation in serum albumin revealed the formation of n-homocysteinylated albumin in all of the assayed serum samples. correlation coefficient analysis revealed that the serum hcy was positively correlated with age and bmi. conclusion: the results suggest that hyperhomocysteinemia was associated with n-homocysteinylated albumin protein's pathological formation, which might be considered a diagnostic marker for prediabetes before aggravating to type 2 diabetes. is a single body site swab sufficient to detect methicillin-resistant staphylococcus aureus from a surveillance swab culture? *issa s. al-mamari,2 zaaima al-jabri,1 badriya al-adawi,3 meher rizvi1 1department of microbiology & immunology, 2college of medicine, sultan qaboos university, muscat, oman; 3diagnostic laboratory of microbiology & immunology, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: issa_almamari@outlook.com objectives: the economic burden for screening and treating the various infections caused by methicillin-resistant staphylococcus aureus (mrsa) is challenging worldwide. early detection of mrsa can reduce further spread of this pathogen in hospital settings. mrsa is detected by either molecular-based methods or culture-based methods. this study aimed to explore the efficiency of culture-based methods in detecting mrsa from three body sites. methods: retrospective data were obtained from electronic patient’s records at the sultan qaboos university hospital of all mrsa positive in-patients from 2016 to 2018. the positivity rate of the culture versus molecular methods to detect mrsa was compared. results: of the 199 patients who met the inclusion criteria: 82.9% (n = 165) were mrsa positive from nasal swabs alone. 4.5% (n = 9) showed positive mrsa from the groin, whereas 4% (n = 8) of the total positive mrsa were axilla positive. mrsa positivity from two different sites simultaneously (nasal and groin, nasal and axilla and axilla and groin) were 5%, 2.5% and 1%, respectively. out of the total mrsa swabs, only 37% were pcr positive, of which 44.8% were nasal positive, 25% had positive axilla sample and none had positive groin samples of total 83 pcr positive. two patients were pcr positive and culture negative. conclusion: collectively, our data have shown that nasal swabs have the highest positivity rate. moreover, it suggests that multiple site surveillance increases the detection rate of mrsa as opposed to a single site. molecular testing could be spared to cases when treatment is needed. first biomedical science conference in oman sultan qaboos university conference hall e156 | squ medical journal, february 2021, volume 21, issue 1 molecular docking studies for discovery of plant-derived urease inhibitors *tanveer alam,1 lubna najam,2 ajmal khan,1 sobia a. khan,1 ahmed al-harrasi1 1natural & medical sciences research center, university of nizwa, nizwa, oman; 2department of chemistry, ccs university, muzaffar nagar, up, india. *corresponding author’s e-mail: tanveer@unizwa.edu.om objectives: a series of natural compounds were isolated from different medicinal plants and characterised using advanced spectroscopic techniques. in order to identify urease inhibitors, 15 natural compounds were screened including alkaloids, carotenoids, flavonoid, lignans and terpenoids. molecular docking study was performed to understand the binding modes of the active compound into the active site of urease enzyme. this study aimed to evaluate the helicobacter pylori urease inhibitory activity of isolated natural compounds for gastric ulcers therapy. methods: urease activity, through indophenols method, was measured by the production of ammonia, as described by weatherburn. thiourea was used as the standard inhibitor of urease. finally, the results were processed by the softwares softmax pro (molecular devices, ca, usa), ms-excel and ez-fit. docking was conducted on moe docking suite (moev2014.09). three-dimensional structure of urease in complex with inhibitor (acetohydroxamic acid) (pdb code 4ubp, resolution 1.55å) was retrieved from rcsb protein databank. results: on this assay, camptothecin exhibited promising inhibition with ic50 value = 130.4 ± 7.884 µm. moreover, emetine hydrochloride, curcumin, karanjin, hypophyllanthine and callophyllolide also showed reduced activity with 98.7 ± 2.251, 26.5 ± 0.262, 21.8 ± 1.081, 18.9 ± 0.619 and 17.5 ± 0.218 µm respectively. conclusion: many natural compounds were isolated and evaluated as novel urease inhibitors and found that camptothecin showed more inhibition and was the most active urease inhibitor. furthermore, the proposed scaffold of urease inhibitor offers convenient further modifications and extensions that could give rise to the structures with improved inhibitory activity against urease enzyme. epidemiology and genotyping of human papillomavirus among omani women attending sultan qaboos university hospital and the royal hospital *zainab al-lawati,1 faryal a. khamis,2 aisha al-hamdani,3 moza al-kalbani,4 fatma a. ramadhan,5 thuria r. al rawahi,6 muhannad f. al-kobaisi1 departments of 1microbiology & immunology, 3pathology and 4obstetrics & gynecology sultan qaboos university, muscat, oman; department of 2medicine, 5pathology and 6obstetrics & gynecology, royal hospital, muscat, oman. *corresponding author’s e-mail: zallawati@squ.edu.om objectives: persistent infection with high-risk (hr) hpv genotypes has been associated with cervical cancer. it is the third most common cancer affecting women in oman with a crude incidence rate of 4.7 and mortality rate of 2.5. no data on the prevalence of hpv infection or its risk factors have been reported in oman. this study aimed to assess the prevalence and genotype distribution of hpv and the risk factors among omani women. methods: cervical samples (n = 258) obtained from omani women aged 18–68 years, attending two tertiary hospitals in oman between september 2014 and april 2015. hpv genotyping were done using a multiplex real time-polymerase chain reaction (rt-pcr) assay. results: 22 different hpv genotypes were detected in 46 women (17.8%) and included 15 hr and 7 lr genotypes. human immunodeficiency virus (hiv) patients (p = 0.052) and oral contraceptives users (p = 0.016) showed significant association with hpv infection. conclusion: the most frequently observed hpv types were hr hpv 82 and lr hpv 54. these findings indicate that the predominant hpv genotypes in oman are different from those seen in worldwide studies. this finding is baseline data to determine the potential impact of preventive measures including using new vaccines to reduce the burden of cervical cancer. a substitute to xylene in deparaffinisation and clearing prior to coverslipping in histopathology *sirin al-dighaishi1 and nasar y. al-wahaibi2 departments of 1histopathology and 2allied health sciences, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: u106489ss@gmail.com objectives: deparaffinisation and clearing before coverslipping are important steps in all staining methods in histopathology. xylene is the most commonly used agent worldwide. however, xylene is toxic. we evaluated safer alternative dewaxing and clearing agents prior to coverslipping in a histopathology laboratory. methods: thirteen different fresh surgical tissues were cut into two halves. one half processed using xylene and the other half processed using ultraclear™. five groups were designed. for each a, b, c and d group, 100 slides were cut from xylene-processed blocks. for group e, 100 slides were cut from ultraclear™-processed blocks. group a is the standard method. group b evaluates ultraclear™ as a dewaxing agent only. group c evaluates ultraclear™ as a clearing agent before coverslipping only. group d evaluates ultraclear™ as both dewaxing and clearing agents before coverslipping. group e evaluates ultraclear™ as both dewaxing and clearing agents before coverslipping. six parameters were evaluated: nuclear staining, cytoplasmic staining, cell morphology, clarity of staining, uniformity of staining and cost. results: groups b, c, and d showed 79% (p = 0.054), 83% (p = 0.221), and 80% (p = 0.079) adequacy when compared with group a (89%), respectively. however, group e showed only 76% (p = 0.016) adequacy. ultraclear™ is more expensive than xylene. conclusion: ultraclear™ is a promising dewaxing agent. it is also a good clearing agent for use before coverslipping in the histopathology laboratory. the cost-benefit balance between laboratory workers' safety, good quality staining and cost-effective strategy needs to be further studied. the effect of calpain activation on cisplatin-induced apoptosis in triplenegative breast cancer cells *zuweina r. al-hadidi,1 khadija h. al-bulushi,2 zaina m. al-alawi,3 nadia y. al-abri,2 shaikha s. al-rawahi,2 shadia m. al-bahlani4 1al diwan polyclinic, muscat, oman; departments of 2pathology and 4allied health sciences, sultan qaboos university, oman; 3al-buraimi hospital, ministry of health, muscat, oman. *corresponding author’s e-mail: zuweinahadidi@gmail.com objectives: globally, breast cancer is the most prevalent type of cancer among women. triple-negative breast cancer is an aggressive sub-type in which the primary treatment approach is chemotherapy. cisplatin is a commonly used chemotherapeutic agent that induces apoptosis through several pathways; er-dependent pathway. however, it is associated with adverse side effects. in order to reduce its side effects, it is usually administrated with other drugs. in the current study, the effect of cyclopiazonic acid (cpa), which is a mycotoxin, on cisplatin-mediated calpain activation, and apoptosis induction in triple-negative breast cancer cells, was investigated. methods: upon cisplatin treatment, endoplasmic reticulum (er) related protein expression was measured 26–27 february 2020 conference abstracts | e157 using the western blotting method. moreover, apoptosis induction in triple-negative breast cancer mda-mb-231 cell line was detected by hoechst stain 33258. results: this study demonstrated that cpa increases intracellular calcium concentration (ca+2); as indicated by calmodulin induction in a concentration-dependent manner. in addition, cpa alone was shown to induce er-stress (indicated by an increase in glucose-regulatory protein 78 (grp 78) expression compared to the control). grp 78 is a molecular chaperone, located on the er, and used as an er stress indicator. as for calpain expression, cpa was able to activate calpain and this activation was detected by the cleavage of alpha (α)-fodrin, which is one of its downstream effectors. like grp 78, caspase-12 (a cysteine protease located in the er) cleavage indicates er-stress. cisplatin significantly induced apoptosis (p <0.05) and showed similar trends to cpa regarding the er-related proteins, except for calpain activation which was not consistent. there was no further effect of cpa on cddp-induced apoptosis. conclusion: cpa was able to induce er stress due to increased calcium influx, activate calpain and eventually lead to apoptosis. hence, cpa might be used in combination with cddp in the treatment of tnbc. detection of e2f1 and akt1 interaction in triple-negative breast cancer cells *asma al-sibani,1 shadia al-bahlani,2 buthaina al-dhahli2 department of 1pathology and 2allied health sciences, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: sybanya95@gmail.com objectives: triple-negative breast cancer (tnbc) is an aggressive subtype of breast cancer that is unresponsive to hormonal and targeted therapy. it can be treated using platinum-based chemotherapy such as cisplatin. however, most patients are at first responsive, eventually relapse and become resistant to additional treatment. many theories were suggested to identify chemoresistance mechanisms and one of them is inhibition of apoptosis by survival proteins. e2f1 is a transcription factor overexpressed in response to dna damage to induce cell death. it is suggested that overexpression of e2f1 following the genotoxic effect of chemotherapy might activate akt1, a survival protein. the current study aimed to detect the interaction between e2f1 and akt1 in tnbc and examine cisplatin's effect on their expression. methods: mda-mb123 cell line (tnbc cell line) was used. cells were treated with varying cisplatin concentrations. cisplatin's effect on e2f1 and akt1 expression was detected by western blot and immunofluorescence staining (if). if was also used with immunoprecipitation to assess the interaction between the two proteins. ip was used as a confirmatory experiment for the interaction. results: western blot and if showed an increase in e2f1 expression and decreased akt1 expression as cisplatin concentration increases. if and ip results suggested a successful interaction between the two proteins. conclusion: the findings confirmed the role of cisplatin on e2f1 and detected its effect on akt1. it also suggested an interaction between e2f1 and akt1, which might be enhanced by cisplatin and involved in the development of chemoresistance in tnbc cells. prolactin receptor expression in cyotomegalovirus positive ovarian cancer *amira al-kharusi,1 najwa al-balushi,1 abdullah al-musalhi2 1department of physiology, sultan qaboos university, muscat, oman; 2university of technology and applied sciences, muscat, oman. *corresponding author’s e-mail: akharusi@squ.edu.om objectives: ovarian cancer (oc) is considered the second most common gynaecological cancer with increased morbidity and mortality in women worldwide. high serum level of prolactin (prl) is found in ocs patients, although it is not yet considered a clinical biomarker for oc. human cytomegalovirus (hcmv) proteins are frequently detected in oc tissue specimens, but the potential impact of hcmv infection on the prl/prl receptor (prlr) system has so far not been investigated. methods: in this study, hcmvs effects on prlr expression were assessed in infected ovarian cancer cells (skov3) by pcr and western blot techniques. expression of hcmv proteins (-ie, -pp65) and prlr in paraffin-embedded oc tissue sections, obtained from patients with oc who underwent surgery, was assessed by immunohistochemistry. results: we found that hcmv infection enhances the expression of prlr and induces the production of prl in oc cells compared to uninfected control cells. we also found an association between extensive prlr levels and extensive hcmv protein expression levels in tissue specimens obtained from oc patients positive for cmv. conclusion: infectious activity of hcmv can stimulate the activation of local growth factors, including the prl/prlr system. hcmv induces prl and prlr transcripts and proteins in hcmv infected ovarian cancer cells. extensive expression of prlr found in hcmv infected oc may provide another mechanism by which hcmv can promote oc's pathogenesis. future studies devoted to blocking hcmv infection and prlr may offer new treatment possibilities for ovarian cancer patients. silybum marianum hydroalcoholic extract as new herbal drug to reduce intraabdominal adhesions *pouya parsaei,1 sayyed y. asadi,2 sareh ezzati,3 mehrdad karimi,4 mahmoud rafieian-kopaei,2 reyhaneh n. esfahani5 1department of food hygiene, islamic azad university, shahrekord, iran; 2medical plants research center and 4department of surgery, shahrekord university of medical sciences, shahrekord, iran; 3department of obstetrics and gynecology, tehran university of medical sciences, tehran, iran; 5faculty of medicine, kashan university of medical sciences, kashan, iran. *corresponding author’s e-mail: pouyaparsaei@yahoo.com objectives: adhesions usually begin to form after surgery during repair of intra-abdominal injured sites. the main cause of adhesion formation is the lack of balance between the formation and destruction of fibrin. in the present study, we examined the silymarin effect on intra-abdominal adhesion. methods: thirty wistar rats were divided into three groups. groups a and b received 1% and 5% concentrations of the s. marianum extract, and group c (control group) received distilled water. after anaesthesia, the abdominal wall was opened and three shallow, longitudinal and transverse 2 cm incisions were made on abdomen right wall. a 4 cm2 piece was removed from the peritoneal surface on the left side. 3 ml of s. marianum extract or distilled water were administered into the abdominal cavity. after two weeks of adhesion degrees, histopathological factors, phenolic and flavonoids were determined and analysed by spss version 16. results: the adhesion degree in groups a and b were significantly lower than control (p <0.05; p = 0.023). in the histopathological examination, significant differences were observed between control and extract-treated groups in histopathological markers (p <0.05). the total phenolic content of s. marianum was 109.7 mg/g gallic acid equivalent; its total flavonoid and flavonol contents were 9 and 5 mg/g rutin equivalent/g. the antioxidant activity of the s. marianum extract was 35% of β-carotene. conclusion: this new drug that contains s. marianum extract has preventive effects on post-laparotomy intra-abdominal adhesion both in macroscopic and microscopic scores. therefore, through further clinical studies, s. marianum extract and its derived compounds might be used in humans as a new herbal drug. first biomedical science conference in oman sultan qaboos university conference hall e158 | squ medical journal, february 2021, volume 21, issue 1 antifibrotic effect of extracted natural products from date palm fruit (phoenix dactylifera l.) *reem al alawi,1,2 mohamed al hamdani,2 jorg d. hoheisel,2 younis baqi1 1department of chemistry, sultan qaboos university, muscat, oman; 2division of functional genome analysis, deutsches krebsforschungszentrum (dkfz), heidelberg, germany. *corresponding author’s e-mail: s81928@student.squ.edu.om objectives: since ancient time, plants were used as a medicine for many diseases. more than half of the world’s population is still using plants for their medical uses as it is a traditionally trusted source. previous studies reported several biological activities of date palm fruit including antioxidant, anti-inflammatory, antibacterial and anticancer activity due to the phytochemical composition. methods: natural products have been extracted from date fruit using the maceration method in different solvents (water, ethanol, acetone and ethyl acetate). these four extracts have been investigated for their biological activities in pancreatic stellate cells (pscs) stimulated with tumour necrosis factor. ethyl acetate extract was isolated into nine fractions using column chromatography based on their polarity behaviour. results: ethyl acetate extract significantly reduced fibrosis compared to the control and other date fruit extracts. ethanol, acetone and ethyl acetate extracts suppressed the cells' proliferation while water extract had almost no effect on proliferation of the activated pscs. conclusion: these findings showed that date fruit has active compound/s which can transform pscs from active to a quiescent state by suppressing the secretion of α-sma. hence, these active compounds may be useful for treating pancreatic fibrosis which would probably boost the effect of known anticancer drugs. computational investigations of the binding of common cystic fibrosis drugs to the atomic structure of cftr *ebtihal al subhi and majid al salmani natural and medical sciences research centre, university of nizwa, nizwa, oman. *corresponding author’s e-mail: 09808315@uofn.edu.om objectives: cystic fibrosis (cf) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (cftr). we aimed to identify potential binding sites of cftr pharmacological modulators and explain differences in drug potency and mechanisms of action. methods: the binding of vx770, vx809, vx661, quercetin and glpg2222 to human cftr (pdb:6msm) using structural docking was investigated. the structures were prepared using pymol and chemdraw software. the swissdock server was used to predict binding parameters and visualised them using ucsf chimera. the change in gibbs free energy (δg) and the number of h-bonds were employed as drug-binding strength indicators. results: all drugs formed a higher number of h-bonds with clusters predicted at the interface between the two nucleotide-binding domains (nbds) or between the nbds and the membrane-spanning domains (msds). quercetin was the best binder at the nbds interface forming 3.75 h-bonds. vx809 binds best at the nbds/msds interface with 1.8 average h-bonds and δg of -14.8 kcal/mol. notably, its structural analogue vx661 formed more h-bonds at these pockets. glpg2222 binds best at the nbds/msds interface. vx770 was the weakest binder to the nbds and fitted well in clusters at the msds. conclusion: we were able to identify potential binding clusters of the studied molecules. notably, our findings of the binding of quercetin and vx809 fitted well with published experimental data. the better formation of h-bond by vx661 when compared to vx809 might explain the differences in drug potency. these results inform drug design strategies for cf treatment. an overview of ecg analysis by wavelet transforms *aasem t. al maamari,1 e. balakrishanan,1 narasimman sundararajan2 departments of 1mathematics and 2earth sciences, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: s34525@student.squ.edu.om objectives: electrocardiogram (ecg) plays an indispensable role in the primary diagnosis, prognosis and survival analysis of heart diseases. in ecg, most useful clinical information is derived from the onset and offset of p, qts and t waves and their amplitudes. detection of such waves in an ecg is difficult due to the time-varying morphology of the signal and the presence of various noise factors. ecg signals' key characteristic is its non-linear dynamic behaviour and that the non-linear component changes conspicuously between normal and abnormal conditions compared to the linear component. in this direction, a relatively recent tool viz, the wavelet transform gains great importance in analysing ecgs by the suitability of its excellent timefrequency localisation characteristics, unlike the traditional fourier analysis. this review aimed to highlight the significance of wavelet analysis, their offshoots and their ability in ecg signal enhancement studies and different denoising techniques besides highlighting its elegance for the evaluation of various pathological conditions. it may be mentioned here that the choice and criteria of mother wavelet also ensure desired results such studies. methods: this work summarises the salient and significant outcomes of wavelet transform applications and its offshoots to ecg analyses available in the literature. a different approach of denoising ecg signal and algorithms for detecting weak constituent waves in ecg and their onset and offset are discussed. results: among comprehensive studies on the wavelet transform in ecg signals, it has a prominent influence of precise location of p, qrs and t waves. it is superior in denoising ecg than other existing methods. criteria for choice of mother wavelets in such studies are also highlighted. conclusion: ecg signals' key characteristic is its non-linear dynamic behaviour and that the non-linear component changes conspicuously between normal and abnormal conditions than the linear component. we can conclude that the wavelet transform is a valuable tool and highly reliable for analysing ecg signals. applications of fractals for feature extraction in eeg signals: an overview *khadija a. al-hassani,1 haniffa m. nasir,1 n. sundararajan2 departments of 1mathematics and 2earth sciences, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: s13639@student.squ.edu.om objectives: fractal structure, being a relatively a recent tool, is gaining great importance in studying non-linear signals such as electroencephalogram (eeg). several algorithms are in vogue to estimate the fractal dimension of eeg signals. the three prevalent techniques that estimate these signals’ fractal dimension are the box-counting method, katz’s algorithm and higuchi’s algorithm. this study aimed to provide an overview of the analysis of eeg signals which are useful to identify and distinguish different states of physiological function of the brain. methods: this work reviews the main result of studies in the literature regarding the fractal dimension estimation in eeg signals by higuchi’s algorithm and other non-linear methods. furthermore, a brief review of higuchi’s 26–27 february 2020 conference abstracts | e159 fractal dimension application's benefits and drawbacks was provided from the medical context. results: among the vast number of studies and discussions on the fractal dimension estimation of eeg signals, an accurate result based on direct approach with higuchi’s algorithm paves the way for extracting a few known disorders associated with the human brain. conclusion: non-linear methods like fractal dimension are more appropriate for analysing the eeg signals for feature extraction and characterisation than the linear methods. computing the fractal dimension of eeg signals with higuchi’s algorithm are very useful since it gives more accurate results compared to the other methods. in contrast, this method showed some drawbacks in some cases of application. there is always a need for enhancement to overcome these drawbacks. myocardial bridging of left anterior descending coronary artery and its clinical implication *anil kumar,1 rosaysela santos,2 penprapa s. klinkhachorn2 1department of anatomy & neurobiology, national university of science and technology, sohar, oman; 2department of pathology, anatomy, and laboratory medicine, west virginia university, morgantown, usa. *corresponding author’s e-mail: anilkumar@nu.edu.om objectives: myocardial bridge (mb) is defined as the muscle overlying the intramural segment of a major epicardial coronary artery, mainly the mid-portion of the left anterior descending coronary artery. mb has been associated with angina, arrhythmia, depressed left ventricular function, myocardial stunning, early death after cardiac transplantation and sudden death. the objectives understudy validate the prevalence and segments of coronaries with mb, length and diameter of bridging segments and the relationship between the presence of bridges and their clinical relevance. methods: seventy-eight formalin-fixed cadaveric heart specimens irrespective of age, gender, and race were collected and serially numbered from 1 to 78. the left coronary artery (lca) was dissected out carefully avoiding damage to the small branches and the number of terminal branches of the main trunk at a subepicardial level was noted. the location, type, number and direction of mb’s were noted. with digital callipers' help, the length of mb was measured, noted and photographs were taken. results: out of the total 78 dissected hearts 68 showed mb in at least one coronary artery or one of its significant branches. the overall prevalence was 87.17%. the maximum length of mb was 5.1 cm. conclusion: the present study adds up the information regarding mb’s prevalence and relationship to coronary arteries. knowledge of mb’s morphology and morphometric details facilitates cardiologists in diagnosis, planning therapeutic strategies and prognostic predictions. december 2007 vol 8 after meeting.indd hyperbaric oxygen treatment for osteomyelitis, osteoradionecrosis and recurrent ear infections susie debus sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 281-283 sultan qaboos university© submitted 10th august 2007 accepted 10th september 2007 in july 2003, i noticed the small pea-sized lump that i had had behind my left ear for several years, had grown rapidly over the weekend. on 2 september, i underwent surgery to remove an adenoid cystic carcinoma of the left superficial parotid gland, grade ii stage ii. the general surgeon who undertook the procedure was recommended to me by the family general practitioner (gp), not an ear, nose and throat (ent) specialist surgeon. the surgery was completed without the use of a drain, with radiotherapy strongly recommended. after surgery, i had a fluid-filled lump, pain, swelling, slight palsy and, following the removal of the stitches, a salivary leak developed. the surgeon removed some of the fluid from the lump and recommended over the following weeks increasing doses of hysocine butyl bromide, universally recommended to dry saliva over the following weeks. he did not think i should be prescribed antibiotics. my local gp, however, prescribed 2 courses of cephalexin. during this time, i had to increase my pain medication, taramadol hydrochloride , to counteract the increasing pain and swelling. as neither the gp nor the surgeon were investigating my slow recovery and suspected infection, an obstetrician friend from brisbane and a pain management specialist in sydney expressed that i should have recovered within 2 to 3 weeks as the surgeon had advised. four weeks later, following 6 appointments to both surgeon and gp and an outpatient visit to the local hospital (the latter two stating that i should re-consult the surgeon), i finally sought a third opinion from another local gp, also a respected surgeon, who is now my family doctor. he immediately took a swab; the results indicated that enterobacter aerogenes, a bowel bacterium, was infecting the surgical site and inhibiting recovery. a double course of ciprofloxacin and raberprazole, to counteract the hysocine butyl bromide, was prescribed. in response to the antibiotics, the wound closed and p a t i e n t ’ s v i e w p o i n t وعدوى ، أ املَنْشَ يُّ عاعِ إِشْ يٌّ مِ ظْ العَ رٌ النَخَ ، ي النِّقْ و مِ ظْ عالج الْتِهابُ العَ يَّة طِ غْ الضَّ رِطُ فْ مُ باالوكسجني الراجعة االذن وجهة نظر مريض سوزي ديبس p.o. box 540, armidale, new south wales 2350, australia email: susie.debus@hotmail.com editor’s note: to highlight a patient’s experience to health care professionals is to get a patient’s perspective on symptom perception, symptom action, symptom formation, response to illness and response to treatment. the present narrative not only vividly describes a patient’s behaviour during illness, but also shows how the information age can enhance a patient’s choice of treatment. while internet surfing in australia in her quest to find ‘answers’, she serendipitously uncovered an article published in the january 1999 sultan qaboos university medical journal (malignant otitis externa and temporal bone osteomyelitis: complete recovery following the adjunctive use of hyperbaric oxygen and antibiotics, p. 47) on hyperbaric oxygen therapy (hbot). she convinced her attending physicians to ‘treat’ her using hbot. she attributes the recent improved quality of her life to this treatment. s u s i e d e b u s 282 the redness and pain subsided considerably. thankfully, the salivary leak ceased on 18 october, though i still had overnight discharges. by the end of october, about to commence 27 treatments of radiotherapy, i suffered a week of severe dizziness and vertigo; this was relieved with metaclopramide. less than two weeks into radiotherapy my ear discharged an extremely smelly yellow thick mucus. it took until nearly the end of my radiotherapy for my oncologist to prescribe triamcinolone+nystat in+gentamicidin+neomycin drops for the discharge. he did not, at the time, believe the infection was serious. the oncologist and resident hospital doctor prescribed 5 courses of oral nystatin for the developing fungal infection in my mouth area. when i returned home the left side of my face was severely burnt from the radiation treatment and my ear was continuing to discharge. my gp eventually relieved the discomfort by syringing my ear and prescribing amphotericin b, a stronger anti-fungal treatment. in january 2004, my ear leaked the same yellowish mucus as during my radiotherapy. i was prescribed 2 courses of ciprofloxacin by my gp’s partner, yet by the end of the month my condition was worsening. i then obtained a referral to see a sydney ent specialist, the first of six ents! after my consultation in february 2004, i finally felt i was receiving appropriate medical attention for my ear infection which had plagued me since october and which was now diagnosed as chronic otitis media, the severest form of ear infection. tests confirmed the presence of both pseudomonas aeruginosa and candida parapsilosis in my ear. the sydney ent immediately admitted me to royal north shore hospital, north sydney. a grommet was inserted and a central line for an assortment of intravenous (iv) antibiotics which included tazocin, gentamicin and meropenem combined with oral fluconazole, an even stronger anti-fungal than previously prescribed. following the insertion of the grommet, my ear leaked for several days with the same fluid as post-surgery. it was several days after the grommet surgery before the ent registrar advised me to wear ear plugs to keep the ear dry during bathing to reduce infection. i continue to do this using a special swimming silicone ear plug in my left ear only. after 9 days in hospital, my head specialist of infectious diseases and microbiology explained i had soft tissue infection and possibly bone infection. during my 4½ weeks hospitalisation, i discussed my complicated medical history with a group of ent specialists, who viewed my ct, mri and gallium scans and offered to write me a medical plan, but i never saw them again. following my discharge, i was prescribed multiple courses of ciprofloxacin and fluconazole. i returned to sydney several times throughout 2004 for follow up appointments with my head specialist. on 2 august 2004, eleven months after my initial surgery, i finally returned to work, but with greatly reduced hours. on a website i discovered that severe otitis media leading to bone infection is a third world disease which is relatively unheard of in the western world. my condition was further complicated by radiotherapy. internet research led to the discovery of a more potent anti-fungal, caspofungin, successful in treating candida parapsilosis. consequently my head specialist organised hospital admission in november to receive caspofungin medication and further iv antibiotics. about 2 months before my admission, i had suffered from another candida ear infection. concerned, i then phoned the sydney ent who prescribed triam cinolone+nystatin+gentamicidin+neomycin drops. however these drops blocked the grommet; it was subsequently removed leaving a hole in my eardrum. in the first week of hospitalisation, one of the resident doctors said i should be sent home as i “looked so well”! prior to my discharge, 3 weeks later, the same resident doctor accompanied the ent registrar, who sat on my bed (you know it’s not good when doctors do that!) and explained that recent x-rays confirmed the presence of a bone infection. the diagnosis at this time described my condition as osteomyelitis (temporal bone), osteoradionecrosis, mastoiditis and prone to recurrent ear infections. on 1 february, 2005 due to liver function abnormalities appearing in my weekly blood tests, i ceased all prescribed treatments including pain medication and advised my head specialist; however, i sought the opinion of a local ent, who used boracic powder to dry the ear discharges and several other times during 2005/06. although my ear continues to discharge intermittently, rather than seek medical treatment i just deal with the discomfort and symptoms, hoping it will not develop into another infection. my local ent referred me to a professor of otology, who dismissed my diagnosis saying i only had temporomandibular joint (tmj) problems, even though i h y p e r b a r i c o x y g e n tr e at m e n t f o r o s t e o m y e l i t i s , o s t e o r a d i o n e c r o s i s a n d r e c u r r e n t e a r i n f e c t i o n s 283 explained that i had been using a dental retainer for years. when i touched the triangular area in front of my ear it felt and sounded like a moist sponge; now it only feels spongy when the swelling worsens. i believe the pressure from the swelling surrounding the surgical site intensifies my muscle and jaw soreness. sometimes my jaw sounds like a creaky door. in january 2005, i wrote to my head specialist requesting hyperbaric oxygen therapy (hbot), for osteomyelitis and osteoradionecrosis researched via the internet. he referred me to the prince of wales diving and hyperbaric unit, randwick, sadly the sole hospital facility in new south wales, only able to treat a maximum of 20 patients per day. i underwent 36 treatments in may-july 2005 and 19 treatments in october-november 2005 without iv or oral medication. the hbot did not relieve me of tinnitus but greatly improved the visible post-surgical swelling and the developing ‘palsy’ around my mouth. the hbot was conducted in both the multiplace and the monoplace chambers. the treatment was initially a very frightening experience but the compression and decompression fortunately did not affect my ear as much as i thought it would. the monoplace chamber seemed to be the most comfortable method for me. gallium, mri and ct brain scans of july 2005 and july 2006 were compared and showed signs of bone regeneration and no sign of cancer. the conclusion was that significant improvement had occurred following hbot although opacification or fluid was still noted. during 2006, a neurologist noted that the anvil and hammer in my left ear appeared distorted. he also noted that my eyes correct the imbalances caused by vertigo and, as a consequence, i frequently suffer from sore and tired eyes. i notice the dizziness more when the swelling and/or ear aching is more intense. i continue to experience speech difficulties: slurring words, having difficulty with enunciation unless i talk very slowly and loudly (partly due to temporary deafness caused by the swelling). i also continue to experience intermittent tingling and numbness around my mouth, tongue and lips. the allodynia, ‘strange’ swellings, moisture in what feels like the eustachian tube and the hole in my ear drum following the removal of the grommet, has left me with hearing difficulties and tinnitus which varies in intensity and symptoms and in response to physical activity. i often suffer from nausea similar to that of all-day morning sickness. c o n c l u s i o n i believe that hbot had significant impact on my condition and resulted in a much more positive prognosis. i recommend hbot for others suffering similar medical complications. to relieve my symptoms i undertake complementary therapies: chiropractic, naturopathy and more recently acupuncture. a c k n ow l e d ge me n t thanks are due to my three beautiful children, dr b hudson, royal north shore hospital and dr m bennett, prince of wales hospital, and their special staff for their care, and to my friend melanie mathiesonsandars for assistance with this article. l i s t o f w e b s i t e s u s e d 1. candida parapsilosis fungaemia treated unsuccessfully with amphotericin b and fluconazole but eliminated with caspofungin: a case report by k deshpande, adelaide sa, http://www.jficm.anzca.edu.au/aaccm/ journal/aaccm-jmarch03-b.htm 2. medlineplus health information a service of the us national library of medicine and the national institutes of health serious otitis (adults) and mastoiditis ,www. nlm.nih.gov/medlineplus/print/ency/article/001034. htm 3. medibank private – cochrane health information acute middle ear infection in babies and children, www.informedhealthonline.com 4. sultan qaboos university journal for scientific research – medical sciences 1999 © malignant otitis externa and temporal bone osteomyelitis: complete recovery following the adjunctive use of hyperbaric oxygen and antibiotics. http://www.squ.edu.om/mj/ archive/jan%201999/abstracts/malignant.html 5. college of medicine, sultan qaboos university, p o box 35, ai-khod123, muscat, sultanate of oman, mjournal@squ.edu.om web site: www.squ.edu.om/ squmj 6. dr elmer m cranton, mount rainer clinic, inc, yelm washington, http://drcranton.com/hbo.htm 7. a patient’s guide hbot, dr. michael woodbridge, hyperbaric physician, the oxygen centre, takapuna, north island new zealand, http://www.medic8. com/healthguide/articles/hyperbaricoxygen/html 8. it’s your health information about hbot, health canada, http://www.hc-sc.gc.ca/english/iyh/medical/ hyperbaric/html. 9. otology seminar osteoradionecrosis of the temporal bone, department of otolaryngology, ent and otology, national taiwan university hospital 10. h t t p : / / w w w. m c . n t u . e d u . t w / d e p a r t m e n t / e n t / seminar93/s20040908.doc. cross-cultural adaptation and psychometric properties of quality of life scales for arabic-speaking adults a systematic review *mohammed al maqbali,1,2 jackie gracey,1 jane rankin,3 lynn dunwoody,4 eileen hacker,5 ciara hughes1 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e125–137, epub. 28 jun 20 submitted 22 jul 19 revisions req. 10 sep & 20 oct 19; revisions recd. 30 sep & 29 oct 19 accepted 9 dec 19 1institute of nursing and health research, ulster university, shore road, jordanstown campus, newtownabbey, uk; 2ministry of health, al buraimi hospital, oman; 3physiotherapy department, cancer centre, belfast health and social care trust, belfast, uk; 4psychology research institute, ulster university, coleraine, uk; 5school of nursing, indiana university, indianapolis, usa *corresponding author’s e-mails: al_maqbali-ma@ulster.ac.uk and mahmedan@hotmail.com qua l i t y o f l i f e ( q o l ) i s a m u lt i -dimensional construct which relies on both personal characteristics as well as contextual and environmental variables.1 in medical research and clinical practice, the assessment of qol is important because it measures the effect of a disease or medical intervention on affected patients. in addition, qol is an essential endpoint in treatment planning for policy-makers, healthcare providers and the patient themselves.2 in recent years, focus on the patient’s functioning, lifestyles and well-being have increased medical interest in tools for measuring qol.2 accordingly, it is necessary to identify robust scales with satisfactory psychometric properties that can be used for this purpose. however, as most qol assessment scales are review التكيف عرب الثقافات واخلصائص النفسية ملقاييس جودة احلياة للسكان البالغني الناطقني ابلعربية مراجعة منهجية حممد املقبايل، جاكي غري�سى، جني رانكني، لني دنوودي، اإيلني هاكر، �سيارا هيوز abstract: this review aimed to explore the psychometric properties of quality of life (qol) scales to identify appropriate tools for research and clinical practice in arabic-speaking adults. a systematic search of the cumulative index to nursing and allied health literature® (ebsco information services, ipswich, massachusetts, usa), medline® (national library of medicine, bethesda, maryland, usa), embase (elsevier, amsterdam, netherlands) and psycinfo (american psychological association, washington, district of columbia, usa) databases was conducted according to preferred reporting items systematic reviews and metaanalysis guidelines. quality assessment criteria were then utilised to evaluate the psychometric properties of identified qol scales. a total of 27 studies relating to seven qol scales were found. while these studies provided sufficient information regarding the scales’ validity and reliability, not all reported translation and cross-cultural adaptation processes. researchers and clinicians should consider whether the psychometric properties, subscales and characteristics of their chosen qol scale are suitable for use in their population of interest. keywords: quality of life; cross-cultural comparison; translations; psychometrics; validity and reliability; surveys and questionnaires; systematic review. للبحث املنا�سبة الأدوات لتحديد احلياة جودة ملقايي�س ال�سيكومرتية اخل�سائ�س لتقييم اإىل املنهجية املراجعة هذه تهدف امللخ�ص: واملمار�سة ال�رسيرية لدى ال�سكان البالغني الناطقني بالعربية. مت اإجراء بحث منهجي لقواعد البيانات الفهر�س الرتاكمي للتمري�س املوؤلفات ال�سحية املتحالفة )اإبي�سكو خلدمات املعلومات، اب�سويت�س، ما�سا�سو�ست�س، الوليات املتحدة الأمريكية(، ميدلين )املكتبة الوطنية للطب، بيثي�سدا، ماريالند، الوليات املتحدة الأمريكية(، اآمبي�س )اإل�سيفيري، اأم�سرتدام، هولندا( و�سيكو انفو )اجلمعية الأمريكية لعلم النف�س، وا�سنطن، مقاطعة كولومبيا، الوليات املتحدة الأمريكية( وفًقا لبنود التقارير املف�سلة واملراجعات املنهجية واإر�سادات التحليل التلوي. ثم مت ا�ستخدام معايري تقييم اجلودة لتقييم اخل�سائ�س النف�سية ملقايي�س جودة احلياة املحددة. مت العثور على ما جمموعه 27 درا�سة تتعلق ب�سبعة مقايي�س عنها الإبالغ يتم مل اأنه اإل وموثوقيتها، املقايي�س ب�سحة يتعلق فيما كافية معلومات قدمت الدرا�سات هذه اأن حني يف احلياة. جلودة جميًعا لعمليات الرتجمة والتكيف بني الثقافات. يجب على الباحثني والأطباء التفكري فيما اإذا كانت اخل�سائ�س النف�سية والقيا�سات الفرعية وخ�سائ�س مقيا�س جودة احلياة الذي مت اختياره منا�سبة لال�ستخدام يف ال�سكان الذين يهتمون بهم. وال�ستبيانات؛ امل�سوحات واملوثوقية؛ ال�سالحية النف�سية؛ القيا�سات الرتجمات؛ الثقافات؛ بني مقارنة احلياة؛ جودة املفتاحية: الكلمات مراجعة منهجية. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.002 https://creativecommons.org/licenses/by-nd/4.0/ cross-cultural adaptation and psychometric properties of quality of life scales for arabic-speaking adults a systematic review e126 | squ medical journal, may 2020, volume 20, issue 2 initially designed in english, these scales need to be translated and adapted for use in different languages and cultures. cross-cultural adaptation and translation is a systematic process that prepares questionnaires and scales for use in another setting.3 nevertheless, it is crucial that the scale maintain its content validity after translation and cultural adaptation. reliability refers to the reproducibility or cons istency of scores from one assessment to another, usually assessed via measures of internal consistency, interor intra-rater reliability or test-retest reliability.4 internal consistency is generally reported as an alpha coeff icient ranging from 0 (no correlation) to 1 (perfect corr elation), with values of ≥0.70 and ≥0.90 considered acceptable and highly reliable, respectively.5 in contrast, validity is the ability of the scale to measure the attributes of the construct under consideration (i.e. the degree to which the scale measures that which it is intended to measure). validity is divided into three types: content, construct and criterion validity, with the latter encom passing concurrent and predictive validity.6 worldwide, there are approximately 420 million arabic-speakers living in 23 countries.7 generally, there are two main types of arabic, with the first being modern standard arabic primarily used in the written form in official and educational settings, while the second consists of differing regional and colloquial dialects.8 in 1998, coons et al. conducted the first psychometric study to translate and validate an arabic version of a qol scale.9 since then, many different qol scales have been translated, resulting in a need to determine those which demonstrate satisfactory cross-cultural adaptation and validity. as such, this review aimed to explore the psychometric properties and translation and cross-cultural adaptation processes of arabic qol scales in order to identify appropriate scales that can be used for research and clinical practice in arabicspeaking adults. methods this systematic review was carried out according to the preferred reporting items systematic reviews and metaanalysis guidelines.10 a systematic search of various electronic databases was conducted in order to identify studies investigating qol among arabic-speaking participants published between january 1946 and april 2019, including the cumulative index to nursing and allied health literature® (ebsco information services, ipswich, massachusetts, usa), medline® (national library of medicine, bethesda, maryland, usa), embase (elsevier, amsterdam, netherlands) and psycinfo (american psychological association, washington, district of columbia, usa) databases. the search terms included combinations of freetext words and medical subject headings® (national library of medicine) with boolean operators (i.e. or/ and) as follows: “psychometrics”, “reliability”, “validity” or “instrument validation” and “arabs” or “medicine, arabic” and “functional status”, “wellbeing”, “quality of life”, “health status”, “health and life quality”, “quality of health care”, “assessment”, “patient assessment”, “clinical assessment tools”, “health impact assessment”, “clinical assessment tools”, “outcome assessment”, “mea surement tool” or “questionnaires”. in addition, the ref erence lists of identified articles were screened to find other potential publications that could be included in the analysis. all articles identified during the literature search were assessed to determine their eligibility. articles were considered eligible for inclusion if they: (1) were published in english; (2) involved adults over 18 years of age; (3) were primarily psychometric studies with information concerning validity or reliability; (4) util ised qol measures translated into arabic; (5) involved an arabic-speaking population; and (6) had no restr ictions regarding study design. studies with qol scales developed and validated for a specific disease were excluded; however, those used for multiple types of cancer were permitted. overall, a total of 1,087 articles were identified during the database search; however, this was reduced to 43 following screening of the titles and abstracts, with 27 articles meeting the inclusion criteria after full-text screening [figure 1]. the psychometric properties of identified qol scales were then evaluated according to nine quality assessment criteria suggested by terwee et al., including content validity, internal consistency, criterion validity, construct validity, reproducibility, responsiveness, floor and ceiling effects and interpretability [table 1].11 each scale was given either a positive (+), indeterminate (?) or negative (-) rating for each of these measures, or a rating of 0 if no information was available. terwee et al. recommended presenting the assessment results in a table, but not using an overall score, as this would bestow equal importance on each psychometric property which is not necessarily appropriate.11 the cross-cultural adaptation and translation of the scales was evaluated according to the five-step guidelines of guillemin et al., namely: (1) translation, (2) back-translation, (3) committee review, (4) pre-testing and (5) re-examination of score weighting.12 in the first step, at least two qualified translators should translate the scale from the original language to the target language. in the second step, two independent translators should translate the translated version back into the language of the original version to ensure that the translation reflects the content of the original.12 the third step ideally involves a committee review to mohammed al maqbali, jackie gracey, jane rankin, lynn dunwoody, eileen hacker and ciara hughes review | e127 develop the penultimate version for pre-testing and the fourth step, pilots this version among 30–40 subjects from the target population. the final step should be the re-examination of the weighting of the scores in light of cultural context.12 each study was assessed and given a score of either 1 (poor), 2 (moderate) or 3 (good) for each of these steps, with the overall score representing the mean of all scores obtained. results s t u d y c h a r a c t e r i s t i c s a total of 27 studies were included in the analysis, all of which were published between 1998 and 2019.9,13–38 the majority were conducted in the middle eastern and north african region, including jordan (n = 7), saudi arabia (n = 4), egypt (n = 2), morocco (n = 2), kuwait (n = 2), tunisia (n = 2), lebanon (n = 2), the united arab emirates (uae; n = 2), sudan (n = 1) and qatar (n = 1).9,13,14,16–35,37,38 however, two studies were conducted in the netherlands among samples of moroccan arabic-speaking subjects.15,36 the majority of the studies (n = 21) had translated the qol scales into modern standard arabic suitable for use among all arabic-speaking populations.9,13,18–35,38 however, six had translated the scales into arabic dialects only suitable for specific populations, incl uding moroccan arabic (n = 3), tunisian arabic (n = 2) and egyptian arabic (n = 1).14–17,36,37 all of the studies utilised quantitative research methods, with 20 crosssectional and seven longitudinal surveys. none used a mixed-method approach [table 2].9,13–38 s c a l e c h a r a c t e r i s t i c s overall, the 27 articles included a total of seven selfreporting qol scales that were translated and tested psychometrically in arabic, including: (1) the 12or 36item medical outcomes study short-form (sf-12 or sf36); (2) the dartmouth cooperative functional health assessment charts/world organisation of general practice/family physicians (coop/wonca); (3) the world health organisation quality of life: brief version (whoqol-bref); (4) the euroqol group health status index 5-dimensions (eq-5d); (5) the european organisation for research and treatment of cancer (eortc) quality of life questionnaire core versions 30 or 15 palliative (qlq-c30 or qlq-c15-pal); (6) the functional assessment of cancer therapy-general (fact-g); and (7) the quality of life index (qli). p s y c h o m e t r i c p r o p e r t i e s the psychometric properties of the qol scales are detailed in table 3.9,13–38 none of the studies tested all nine psychometric criteria suggested by terwee et al.11 in terms of content validity, 22 studies had a positive score.9,13–15,18–21,21–30,32,34–48 for the remaining five studies, no information was available.16,17,22,31,33 internal consistency was generally high, with 26 studies scoring positively.9,13,15–38 only one study did not report information regarding internal consistency.14 criterion validity was tested in only two studies, with positive ratings for both.18,19 the remaining 25 studies did not provide any information concerning this psy chometric property.9,13–17,20–38 construct validity was assessed in 22 studies, of which 21 received positive ratings.9,13–15,18–32,37,38 only one study was rated as intermediate for this aspect.16 figure 1: diagram showing the search process used to identify articles included in this systematic review. cross-cultural adaptation and psychometric properties of quality of life scales for arabic-speaking adults a systematic review e128 | squ medical journal, may 2020, volume 20, issue 2 table 1: criteria for assessing the pschometric properties of quality of life scales11 property definition rating* quality criteria content validity the extent to which the domain of interest is comprehensively sampled by the items in the questionnaire + a clear description is provided of the measurement aim, the target population, the concepts that are being measured and the item selection and both target population and investigators or experts are involved in item selection ? a clear description of the aforementioned aspects is missing or only the target population is involved or doubtful† design or methods no target population involvement 0 no information found internal consistency the extent to which items in a scale or subscale are intercorrelated (i.e. measuring the same construct) + factor analyses are performed on an adequate sample size (calculated to be at least seven times the number of items and >100) and cronbach’s alpha(s) is calculated per dimension and cronbach’s alpha(s) is between 0.70–0.95 ? no factor analysis or doubtful† design or methods cronbach’s alpha is <0.70 or >0.95, despite adequate design and methods 0 no information found criterion validity the extent to which scores on a particular questionnaire refer to a gold standard + convincing arguments to support gold standard and correlation with cronbach’s alpha of >0.70 ? no convincing arguments to support gold standard or doubtful† design or methods correlation with cronbach’s alpha of 0.70 and continuous adequate design and methods 0 no information found construct validity the extent to which scores on a particular questionnaire refer to other measures in a manner consistent with theoretically supported hypotheses relating to the concepts being measured + specific hypotheses are formed and at least 75% of the results are in accordance with these hypotheses ? doubtful† design or methods (e.g. no hypotheses) less than 75% of the hypotheses are confirmed, despite adequate design and methods 0 no information found reproducibility agreement the extent to which scores on repeated measures are close to each other (i.e. absolute measurement error) + the sdc is less than the mic or the mic is outside the loa or convicing arguments that the level of agreement is acceptable ? doubtful† design or methods or the mic is not defined and no convincing arguments that the level of agreement is acceptable the mic is less than or equal to the sdc or the mic equals or is inside the loa, despite adequate design and methods 0 no information found reliability the extent to which subjects can be distinguished from each other, despite measurement errors (i.e. relative measurement error) + the icc or cohen’s weighted kappa is >0.70 ? doubtful† design or methods (e.g. time interval not mentioned) the icc or weighed kappa is ≤0.70, despite adequate design and methods 0 no information found responsiveness the ability of a questionnaire to detect clinically important changes over time + the mic is less than the sdc or the mic is outside the loa or the rr is 1.96 or the auc is >0.70 ? doubtful† design or methods the sdc is more than or equal to the mic or the mic equals or is inside the loa or the rr is <1.96 or the auc is 0.70, despite adequate design and methods 0 no information found sdc = smallest detectable change; mic = minimal important change; loa = limits of agreement; icc = intraclass correlation; rr = responsiveness ratio; auc = area under the curve; sd = standard deviation. *ratings were either positive (+), intermediate (?), negative (-) or no information was available (0). †either the study lacks a clear description of its design or methods, the sample size is under 50 subjects in each subgroup analysis or there are important methodological weaknesses in its design or execution. table adapted with permission from terwee cb, bot sd, de boer mr, van der windt da, knol dl, dekker j, et al. quality criteria were proposed for measurement properties of health status questionnaires. j clin epidemiol 2007; 60:34–42.11 mohammed al maqbali, jackie gracey, jane rankin, lynn dunwoody, eileen hacker and ciara hughes review | e129 table 1 (cont’d): criteria for assessing the pschometric properties of quality of life scales11 property definition rating* quality criteria floor and ceiling effects the number of responders who achieve the lowest or highest possible scores + <15% of the respondents achieve the highest or lowest possible scores ? doubtful† design or methods <15% of the respondents achieve the highest or lowest possible scores, despite adequate design and methods 0 no information found interpretability the degree to which one can assign qualitative meaning to quantitative scores + mean and sd scores are presented for at least four relevant subgroups of patients and the mic is defined ? doubtful† design or methods or mean and sd scores are presented for less than four subgroups or no mic is defined 0 no information found sdc = smallest detectable change; mic = minimal important change; loa = limits of agreement; icc = intraclass correlation; rr = responsiveness ratio; auc = area under the curve; sd = standard deviation. *ratings were either positive (+), intermediate (?), negative (-) or no information was available (0). †either the study lacks a clear description of its design or methods, the sample size is under 50 subjects in each subgroup analysis or there are important methodological weaknesses in its design or execution. table adapted with permission from terwee cb, bot sd, de boer mr, van der windt da, knol dl, dekker j, et al. quality criteria were proposed for measurement properties of health status questionnaires. j clin epidemiol 2007; 60:34–42.11 table 2: characteristics of studies involving quality of life scales translated and adapted for arabic-speaking adults (n = 27)9,13–38 author and year of publication country study design type of participants sample size qol scale language cronbach’s α coefficient huijer et al.28 (2013) lebanon cross-sectional mixed cancer patients 200 eortc qlq-c30 standard arabic • overall: <0.70 • range: 0.38–0.80 awad et al.26 (2008) uae cross-sectional breast cancer patients 87 eortc qlq-c30 standard arabic • overall: <0.70 • range: 0.51–0.84 alawadhi and ohaeri35 (2010) kuwait cross-sectional breast cancer patients 348 eortc qlq-c30 standard arabic • overall: 0.91 • range: 0.51–0.84 bener et al.27 (2017) qatar cross-sectional breast cancer patients 678 eortc qlq-c30 standard arabic • overall: 0.91 • range: 0.55–0.89 alawneh et al.25 (2010) jordan cross-sectional mixed cancer patients 175 eortc qlq-c15pal standard arabic • overall: <0.70 • range: 0.72–0.90 lazenby et al.29 (2013) jordan cross-sectional mixed cancer patients 205 fact-g standard arabic • range: 0.80–0.83 zahran et al.30 (2017) egyptian cross-sectional bladder cancer patients 90 fact-g standard arabic • range: 0.80–0.94 al barmawi et al.24 (2018) jordan cross-sectional head and/or neck cancer patients 118 fact-g standard arabic • overall: 0.76 • range: 0.67–0.83 soudy et al.23 (2018) saudi arabia cross-sectional lymphoma patients who had undergone stem cell transplantation 108 fact-g standard arabic • overall: 0.89 • range: 0.67–0.88 coons et al.9 (1998) saudi arabia longitudinal general population 415 sf-36 standard arabic • range: 0.60–0.87 sabbah et al.18 (2003) lebanon cross-sectional general population 524 sf-36 standard arabic • range: 0.70–0.90 hoopman et al.36 (2009) netherlands longitudinal general population subgroup of 377 moroccan subjects sf-36 local dialect (tarifit) • range: 0.63–0.93 hoopman et al.15 (2006) netherlands longitudinal mixed cancer patients subgroup of 79 moroccan patients sf-36 local dialect (tarifit) • range: 0.65–0.94 qol = quality of life; eortc qlq = european organisation for research and treatment of cancer quality of life questionnaire; c30 = core version 30; uae = united arab emirates; c15-pal = core version 15 palliative; fact-g = functional assessment of cancer therapy general; sf-36 = 36-item medical outcomes study short-form; icu = intensive care unit ; sf-12 = 12-item medical outcomes study short-form; eq-5d = euroqol group health status index 5-dimensions; whoqol-bref = world health organisation quality of life: brief version; coop/wonca = dartmouth cooperative functional health assessment charts/world organisation of general practice/family physicians; qli = quality of life index. cross-cultural adaptation and psychometric properties of quality of life scales for arabic-speaking adults a systematic review e130 | squ medical journal, may 2020, volume 20, issue 2 information concerning agreement was present in only one study which received a positive score.38 reliability was investigated in nine studies, of which seven scored positively.9,13,17,25,32,36,37 the remaining two studies received intermediate scores.20,21 two studies provided information regarding responsiveness, with one positive and one intermediate rating.14,15 floor and ceiling effects were tested in six studies, with four scoring positively.15,18,22,36 the other two studies received inter mediate ratings.14,21 only one study reported information concerning interpretability, receiving an intermediate score.13 overall, the sf-36 demonstrated the most robust psychometric properties, followed by the whoqolbref. the sf-36 was tested using eight psychometric criteria, with positive ratings for content validity, int ernal consistency, criterion validity, construct validity, agreement, reliability, responsiveness and floor and ceiling effects.9,15,17,18,22,31,36–38 similarly, the whoqolbref received positive scores for content validity, internal consistency, criterion validity and construct validity, although both reliability and floor and ceiling effects were rated as indeterminate.19–21,33 table 2 (cont’d): characteristics of studies involving quality of life scales translated and adapted for arabic-speaking adults (n = 27) author and year of publication country study design type of participants sample size qol scale language cronbach’s α coefficient khoudri et al.37 (2007) morocco cross-sectional patients discharged from the icu 145 sf-36 standard arabic • overall: ≥0.70 • range: 0.84–0.99 guermazi et al.38 (2012) tunisia cross-sectional general population 130 sf-36 local dialect (tunisian) • overall: 0.94 • range: 0.72–0.89 el-kalla et al.17 (2016) egypt longitudinal patients with burn injuries 40 sf-36 local dialect (egyptian) • overall: 0.8 sheikh et al.31 (2015) saudi arabia cross-sectional khat chewers 300 sf-36 standard arabic • overall: 0.94 • range: 0.72–0.90 khader et al.22 (2011) jordan cross-sectional general population 511 sf-36 standard arabic • range: 0.71–0.90 younsi and chakroun16 (2014) tunisia cross-sectional general population 3,582 sf-12 local dialect (tunisian) • overall: 0.73 aburuz et al.13 (2009) jordan cross-sectional general population 186 eq-5d standard arabic • overall: ≥0.75 bekairy et al.32 (2018) saudi arabia longitudinal mixed patients 80 eq-5d standard arabic • overall: 0.72 ohaeri and awadalla21 (2009) kuwait longitudinal general population 3,303 whoqolbref standard arabic • overall: 0.90 • range: 0.69–0.83 ohaeri et al.20 (2007) sudan cross-sectional general population and psychiatric patients 623 whoqol bref standard arabic • overall: 0.88 (general population), 0.93 (psychiatric patients) and 0.92 (caregivers) bani-issa33 (2011) uae cross-sectional diabetic patients 200 whoqol bref standard arabic • overall: 0.85 • range: 0.89–0.91 dalky et al.19 (2017) jordan cross-sectional family/ caregivers of patients 266 whoqol bref standard arabic • overall: 0.92 hoopman et al.14 (2008) morocco cross-sectional mixed cancer patients subgroup of 37 moroccan patients coop/ wonca local dialect (tarifit) • not reported halabi34 (2006) jordan longitudinal general population and hypertensive, diabetic, cancer and dialysis patients. 35 qli standard arabic • overall: 0.90 qol = quality of life; eortc qlq = european organisation for research and treatment of cancer quality of life questionnaire; c30 = core version 30; uae = united arab emirates; c15-pal = core version 15 palliative; fact-g = functional assessment of cancer therapy general; sf-36 = 36-item medical outcomes study short-form; icu = intensive care unit; sf-12 = 12-item medical outcomes study short-form; eq-5d = euroqol group health status index 5-dimensions; whoqol-bref = world health organisation quality of life: brief version; coop/wonca = dartmouth cooperative functional health assessment charts/world organisation of general practice/family physicians; qli = quality of life index. mohammed al maqbali, jackie gracey, jane rankin, lynn dunwoody, eileen hacker and ciara hughes review | e131 translation and cultural adaptation the processes of translation and cultural adaptation of the qol scales are presented in table 4.9,13–38 in total, 14 studies reported information regarding trans lation and cross-cultural adaptation processes.9,13–15,17, 18,23–25,28–30,34,38 however, only two studies adopted all five steps recommended by guillemin et al.9,12,23 a total of nine studies reported four of the steps, without providing any information regarding the re-evaluation of score weightings.13,14,17,18,28–30,34,38 one study presented a three-step technique (including translation, backtranslation and pre-testing), while another reported only the first two steps.15,24 finally, in one study, a single-step technique consisting solely of forwardtranslation was performed.25 the eortc-qlq-c30, sf-36, fact-g and qli scales received overall mean scores of 3 with regards to table 3: psychometric properties of scales in studies involving quality of life scales translated and adapted for arabic-speaking adults (n = 27)9,13–38 qol scale rating* reproducibility huijer et al.28 (2013) eortc qlq-c30 + + 0 + 0 0 0 0 0 awad et al.26 (2008) eortc qlq-c30 + + 0 + 0 0 0 0 0 alawadhi and ohaeri35 (2010) eortc qlq-c30 + + 0 0 0 0 0 0 0 bener et al.27 (2017) eortc qlq-c30 + + 0 + 0 0 0 0 0 alawneh et al.25 (2010) eortc qlq-c15pal + + 0 + 0 + 0 0 0 lazenby et al.29 (2013) fact-g + + 0 + 0 0 0 0 0 zahran et al.30 (2017) fact-g + + 0 + 0 0 0 0 0 al barmawi et al.24 (2018) fact-g + + 0 + 0 0 0 0 0 soudy et al.23 (2018) fact-g + + 0 + 0 0 0 0 0 coons et al.9 (1998) sf-36 + + 0 + 0 + 0 0 0 sabbah et al.18 (2003) sf-36 + + + + 0 0 0 + 0 hoopman et al.36 (2009) sf-36 + + 0 0 0 0 0 + 0 hoopman et al.15 (2006) sf-36 + + 0 + 0 0 + + 0 khoudri et al.37 (2007) sf-36 + + 0 + 0 + 0 0 0 guermazi et al.38 (2012) sf-36 + + 0 + + + 0 0 0 el-kalla et al.17 (2016) sf-36 0 + 0 0 0 + 0 0 0 sheikh et al.31 (2015) sf-36 0 + 0 + 0 0 0 0 0 khader et al.22 (2011) sf-36 0 + 0 + 0 0 0 + 0 c on te nt v al id it y a ut ho r an d ye ar o f pu bl ic at io n in te rn al c on si st en cy c ri te ri on v al id it y a gr ee m en t r el ia bi lit y c on st ru ct v al id it y r es po ns iv en es s fl oo r a nd ce ili ng ef fe ct s in te rp re ta bi lit y table 3 (cont’d): psychometric properties of scales in studies involving quality of life scales translated and adapted for arabic speaking adults (n = 27)9,13–38 qol scale rating* reproducibility aburuz et al.13 (2009) eq-5d + + 0 + 0 + 0 0 ? bekairy et al.32 (2018) eq-5d + + 0 + 0 + 0 0 0 ohaeri and awadalla21 (2009) whoqolbref + + 0 + 0 ? 0 ? 0 ohaeri et al.20 (2007) whoqolbref + + 0 + 0 ? 0 0 0 bani-issa33 (2011) whoqolbref 0 + 0 0 0 0 0 0 0 dalky et al.19 (2017) whoqolbref + + + + 0 0 0 0 0 hoopman et al.14 (2008) coop/ wonca + 0 0 + 0 0 ? ? 0 halabi34 (2006) qli + + 0 0 0 0 0 0 0 qol = quality of life; eortc qlq = european organisation for research and treatment of cancer quality of life questionnaire; c30 = core version 30; c15pal = core version 15 palliative; fact-g = functional assessment of cancer therapy general; sf-36 = 36-item medical outcomes study short-form; sf-12 = 12 item medical outcomes study short-form; eq-5d = euroqol group health status index 5-dimensions; whoqol-bref = world health organisation qual ity of life: brief version; coop/wonca = dartmouth cooperative functional health assessment charts/world organisation of general practice/family physicians; qli = quality of life index. *ratings were scored as either positive (+), intermediate (?), negative (-) or no inform ation available (0). c on te nt v al id it y a ut ho r an d ye ar o f pu bl ic at io n in te rn al c on si st en cy c ri te ri on v al id it y a gr ee m en t r el ia bi lit y c on st ru ct v al id it y r es po ns iv en es s fl oo r a nd ce ili ng ef fe ct s in te rp re ta bi lit y cross-cultural adaptation and psychometric properties of quality of life scales for arabic-speaking adults a systematic review e132 | squ medical journal, may 2020, volume 20, issue 2 translation and cultural adaptation processes. 17,18,23,24,28– 30,34 in addition, the overall mean score of the coop/ wonca and eq-5d scales was 2.5.13,14 however, there was no information regarding translation or cross-cultural adaptation for any of the studies seeking to validate the whoqol-bref scale.19–21,33 i n d i v i d u a l q u a l i t y o f l i f e s c a l e s european organisation for research and treat ment of cancer quality of life questionnaire the eortc has developed several scales to assess the qol of cancer patients.39–42 the eortc-qlq-c30 consists of nine multi-item scales, five functional subscales (assessing physical, role, cognitive, emotional and social functioning), three symptom subscales (assessing fatigue, pain and nausea/vomiting) and a global health status and qol scale.39 in addition, six items assessing other common symptoms of cancer are included (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties). the first 28 items of the scale are scored on a 4-point likert scale, with scores ranging from 1 (not at all) to 4 (very much).39 the remaining two items are assessed on a seven-point numeric scale. the original version of the eortc-qlq-c30 scored a cronbach’s α coefficient of ≥0.70.39 table 4: cross-cultural adaptation and translation processes of scales in studies involving quality of life scales translated and adapted for arabic-speaking adults (n = 27)9,13–38 qol scale score* huijer et al.28 (2013) eortc qlq-c30 3 3 3 3 n/a 3 awad et al.26 (2008) eortc qlq-c30 n/a n/a n/a n/a n/a n/a alawadhi and ohaeri35 (2010) eortc qlq-c30 n/a n/a n/a n/a n/a n/a bener et al.27 (2017) eortc qlq-c30 n/a n/a n/a n/a n/a n/a alawneh et al.25 (2010) eortc qlq-c15pal 2 n/r n/r n/r n/r 2 lazenby et al.29 (2013) fact-g 3 3 3 3 n/a 3 zahran et al.30 (2017) fact-g 3 3 3 3 n/a 3 al barmawi et al.24 (2018) fact-g 3 3 n/r 3 n/r 3 soudy et al.23 (2018) fact-g 3 3 3 3 3 3 coons et al.9 (1998) sf-36 3 3 2 3 3 2.8 sabbah et al.18 (2003) sf-36 3 3 3 3 n/r 3 hoopman et al.36 (2009) sf-36 n/a n/a n/a n/a n/a n/a hoopman et al.15 (2006) sf-36 2 1 n/r n/r n/r 1.5 khoudri et al.37 (2007) sf-36 n/a n/a n/a n/a n/a n/a guermazi et al.38 (2012) sf-36 3 3 1 3 n/r 2.5 el-kalla et al.17 (2016) sf-36 3 3 3 3 n/r 3 sheikh et al.31 (2015) sf-36 n/a n/a n/a n/a n/a n/a khader et al.22 (2011) sf-36 n/a n/a n/a n/a n/a n/a younsi and chakroun16 (2014) sf-12 n/a n/a n/a n/a n/a n/a aburuz et al.13 (2009) eq-5d 3 2 2 3 n/a 2.5 bekairy et al.32 (2018) eq-5d n/a n/a n/a n/a n/a n/a ohaeri and awadalla21 (2009) whoqolbref n/a n/a n/a n/a n/a n/a tr an sl at io n b ac ktr an sl at io n c om m it te e ap pr oa ch pr ete st in g r ea ss es sm en t o f sc or e w ei gh ti ng o ve ra ll m ea n sc or e w ei gh ti ng a ut ho r an d ye ar o f pu bl ic at io n table 4 (cont’d): cross-cultural adaptation and translation pro cesses of scales in studies involving quality of life scales translated and adapted for arabic-speaking adults (n = 27)9,13–38 qol scale score* ohaeri et al.20 (2007) whoqolbref n/a n/a n/a n/a n/a n/a bani-issa33 (2011) whoqolbref n/a n/a n/a n/a n/a n/a dalky et al.19 (2017) whoqolbref n/a n/a n/a n/a n/a n/a hoopman et al.14 (2008) coop/ wonca 2 2 3 3 n/r 2.5 halabi34 (2006) qli 3 3 3 3 n/r 3 qol = quality of life; eortc qlq = european organisation for research and treatment of cancer quality of life questionnaire; c30 = core version 30; na = not applicable; c15-pal = core version 15 palliative; nr = not reported; fact-g = functional assessment of cancer therapy general; sf-36 = 36-item medical outcomes study short-form; sf-12 = 12-item medical outcomes study short-form; eq-5d = euroqol group health status index 5-dimensions; whoqol-bref = world health organisation quality of life: brief version; coop/wonca = dartmouth cooperative functional health assessment charts/ world organisation of general practice/family physicians; qli = quality of life index. *each step of the process was scored as either good (3), moderate (2) or poor (1). tr an sl at io n b ac ktr an sl at io n c om m it te e ap pr oa ch pr ete st in g r ea ss es sm en t o f sc or e w ei gh ti ng o ve ra ll m ea n sc or e w ei gh ti ng a ut ho r an d ye ar o f pu bl ic at io n mohammed al maqbali, jackie gracey, jane rankin, lynn dunwoody, eileen hacker and ciara hughes review | e133 overall, four studies sought to validate and translate the eortc-qlq-c30 for use in arabic-speaking adults.26–28,35 all of the studies translated the scale into modern standard arabic and were cross-sectional in nature. in total, the overall sample of these studies consisted of 1,313 cancer patients.26–28,35 generally, the scale showed satisfactory psychometric properties consistent with its purpose for use among arabicspeaking cancer patients. in terms of internal cons istency, the coefficient alpha of the arabic versions was >0.70, in line with that of the original version.26–28,35 in the eortc-qlq-c15-pal scale, the 30-item qlq core version is reduced to 15 items for the purposes of addressing qol in palliative care.39,43 the eortcqlq-c15-pal includes three multi-item scales, func tional subscales (assessing physical and emotional func tioning), symptom subscales (assessing fatigue and pain) and a global health status and qol scale.43 the first 14 items of the scale are scored on a 4-point likert scale, with scores ranging from 1 (not at all) to 4 (very much). the final item is assessed on a 7-point numeric scale.43 alawneh et al. investigated the validity and reliability of a standard arabic version of the eortcqlq-c15-pal scale among 175 jordanian mixed cancer patients, with a coefficient alpha of >0.70.25 functional assessment of cancer therapy – general the fact-g scale consists of 27 items assessed on a 5-point likert scale and was originally validated for a population of mixed cancer patients.44 the first part of the scale assesses three qol dimensions (physical well-being, social/family wellbeing and functional well being) using seven items and a fourth (emotional wellbeing) with six items. the scale also has specific items that can be added to the general scale for specific types of cancer.45,46 in addition to cancer, the fact-g scale has been used and validated for use among patients with other chronic illnesses as well as the general population.47–49 four studies were conducted to evaluate the psy chometric properties of arabic versions of the fact-g on 521 subjects in total, each involving a different subtype of cancer patient (mixed, lymphoma, bladder and head-and/or-neck cancer).23,24,29,30 in addition, one study assessed the fact-g in conjunction with a spiritual subscale.29 all four studies were translated into modern standard arabic. the internal consistency of the arabic fact-g scales yielded almost the same results as that of the original scale (coefficient alpha: 0.76–0.89).23,24,29,30,44 however, none of the studies assessed reproducibility properties such as test-retest reliability or agreement.23,24,29,30 medical outcomes study short-form the sf-36 scale is a 36-item multi-purpose health survey consisting of eight multi-item subscales (assessing physical functioning, emotional problems, physical problems, mental health, bodily pain, general health, social functioning and vitality) and one single-item subscale (assessing health transition).50 the total score ranges from 0 to 100, with higher scores indicating a better qol. the reliability of the original sf-36 scale was high, with an intraclass correlation coefficient (icc) of >0.8.50 nine studies evaluated the psychometric properties of arabic versions of the sf-36 scale.9,15,17,18,22,31,36–38 the scale was tested on multiple populations, including the general population (n = 4), burn victims (n = 1), cancer patients (n = 1), patients admitted to an intensive care unit (n = 1) and khat chewers (n = 1), with a total sample size of 2,521.9,15,17,18,22,31,36–38 four studies translated the sf-36 scale into three different dialects of arabic, including moroccan tarifit (n = 2), tunisian (n = 1) and egyptian (n = 1).15,17,36,38 the other five studies translated the scale into standard arabic.9,18,22,31,37 with regards to internal consistency, the coefficient alpha of the arabic sf-36 scale ranged from 0.70–0.94.9,15,17,18,22,31,36–38 test-retest reliability was assessed in four studies, with the icc exceeding 0.70.9,15,17,37,38 the sf-12 scale is a shorter 12-item version of the sf-36 scale and assesses the same eight health domains as the original.51 younsi and chakroun tested the sf-12 scale among 3,582 members of the general population.16 the scale was translated into the tunisian arabic dialect, with a coefficient alpha of 0.73.16 euroqol group health status index 5-dimensions the eq-5d is a 5-item scale assessing five dimensions of qol (mobility, self-care, usual activities, pain/dis comfort and anxiety/depression).52 each item has three possible responses, including no problems, some/moderate problems and extreme problems. in addition, health states are measured using a visual analogue scale ranging from 0 to 100.52 two studies evaluated arabic versions of the eq5d.13,32 both were translated into modern standard arabic. aburuz et al. investigated the validity and reliab ility of the eq-5d in a sample of 186 members of the general population in jordan.13 in contrast, bekairy et al. assessed its use among 80 mixed patients in saudi arabia.32 both arabic eq-5d scales were deemed valid and reliable, with coefficient alphas of ≥0.72. in terms of test-retest reliability, aburuz et al. and bekairy et al. reported cohen’s kappa values of 0.48–1.0 and 0.53–1.00, respectively.13,32 world health organisation quality of life: brief version the whoqol-bref scale is a 26-item questionnaire scored on a 5-point likert scale which was originally validated to measure qol among people with diseases in the general population.53 the scale represents an abbreviated version of the much longer 100-item cross-cultural adaptation and psychometric properties of quality of life scales for arabic-speaking adults a systematic review e134 | squ medical journal, may 2020, volume 20, issue 2 whoqol assessment.54 the whoqol-bref has four subscales (assessing physical health, psychological health, social relationships and environmental health) and two overall qol and general health items. in terms of internal consistency, the coefficient alpha of the original whoqol-bref scale was 0.66–0.84.53 four studies sought to validate standard arabic versions of the whoqol-bref in different countries, including kuwait, sudan, uae and jordan.19–21,33 the total sample size for all four studies was 4,392, including both psychiatric and diabetic patients, family members and caregivers of patients and members of the general population. the coefficient alpha of the arabic whoqol-bref scales ranged from 0.69– 0.93, indicating acceptable internal consistency. in one study, the test-retest reliability of the scale was significant (icc = 0.95).21 dartmouth cooperative functional health assess ment charts/world organisation of general practice/family physicians the coop/wonca scale contains six items assessed using a 5-point likert scale and covering core qol functional domains (physical fitness, feelings, daily activities, social activities, changes in health and overall health).55 the coop/wonca scale was culturally adapted and translated into arabic in only one study.14 hoopman et al. assessed the use of the scale on 37 mixed cancer patients when translated into tarifit, a local dialect of arabic spoken in morocco. the scale was found to have adequate content and construct validity, but its discriminant validity could only be partially confirmed.14 quality of life index the qli scale consists of 70 items scored on a 6-point likert scale assessing health and functioning and socio economic, psychological/spiritual and family-related aspects of qol.56 the scale was designed to assess the qol of both healthy and ill individuals. the original scale has been validated in many different diseases.57–59 in terms of internal consistency, the coefficient alpha of the original qli scale was 0.73–0.99.60 only one study culturally adapted, translated and tested the qli in modern standard arabic.34 the study involved 35 subjects, including both healthy individuals as well as hypertensive, diabetic, cancer and dialysis patients. the reliability of the scale was adequate, with an icc of 0.88–0.97.34 discussion this review identified 27 studies assessing seven qol scales translated and tested for validity and reliability in arabic-speaking adults.9,13–38 none of the scales were originally developed in arabic, with the majority initially developed for use in english. all of the qol scales were consistent in that they assessed both physical and psychological aspects as well as other important components of qol. nevertheless, in order to fully understand qol in arabic-speaking populations, there is a need for qol scales to be properly translated and culturally adapted for use in these populations. all of the studies included in this review utilised quantitative research methods, with 20 cross-sectional and seven longitudinal surveys.9,13–38 cross-sectional studies indicate that the data were collected at a specific point in time without further follow-up, while longitudinal data were collected over different periods of time.61 generally, longitudinal studies give more precise information regarding temporal changes or treatment effects that can have an important impact on the qol of patients. in contrast, researchers conducting cross-sectional analyses will have more difficulty creating a cohesive narrative regarding the impact of medical treatment, interventions or other variables on qol.61 none of the studies in this review evaluated the psychometric criteria as suggested by terwee et al.11 as such, further psychometric studies are required to improve the validity and reliability of arabic versions of qol scales. for instance, only seven studies positively assessed test-retest reliability and only one reported test-retest agreement.9,13,17,25,32,37,38 in terms of specific scales, no reliability properties were reported for the eortc qlq-c30, fact-g, whoqol bref, coop/wonca or qli scales. accordingly, the reliability and validity of these qol scales should be evaluated prior to their use in arabic-speaking populations. selection of an appropriate qol scale is dependent on a number of different factors, including the demo graphic and clinical characteristics of the sample, the psychometric properties of the scale and the number of items included in the scale. most importantly, researchers need to consider the various aspects and domains of qol that require evaluation in their population of interest. for example, if the sample consists of cancer patients, the fact-g or eortc qlq-c30 scales would be most appropriate as both can be used in multiple types of cancer.39–42,44–46 in addition, both scales have been validated among arab cancer patients, as well as members of the general population speaking other languages.23,24,26–30,35,49,62,63 however, it should be noted that the eortcqlq-c30 scale does not address either spiritual or existential components of qol.39 on the other hand, if the sample consists of a general arabic-speaking population, the sf-36 might mohammed al maqbali, jackie gracey, jane rankin, lynn dunwoody, eileen hacker and ciara hughes review | e135 be a better choice in order to provide more generic qol-related information.50 while the studies in this review included a variety of populations, the general population was most frequently studied, perhaps because this choice provides a larger sample size, thus improving the psychometric evaluation. with regards to the coop/wonca scale, this scale was validated by only one study involving a small sample size (n = 37) and translated into a local dialect.14 further examination of the psychometric properties of a modern standard arabic version of this scale is therefore required before it can be recommended for use among other arabic-speaking adults. all seven qol scales identified in this review are of varying lengths, consisting of between 5–70 items. overall, six of the scales contain fewer than 36 items and could therefore be administered between 5–10 minutes.39,44,50,52,53,55 the qli is much longer with a total of 70 items, although the administration time is reported as being approximately 10 minutes.56 unlike other qol scales, the qli weighs satisfaction in a particular domain of qol in terms of importance, so that items with high satisfaction and importance scores receive the highest score. nevertheless, the length of this questionnaire could present an obstacle when conducting research in a clinical setting, as the inclusion of more items in a survey tends to discourage high response rates.64,65 processes of cross-cultural adaptation and translation affect the credibility of an adapted scale by ensuring that the content of the translated scale is equivalent to that of the original. adhering to a systematic and standardised approach, such as that suggested by guillemin et al., produces cultural equivalence and maximises acceptability of the linguistic structure of the translated scale.12 unfortunately, only two studies included in this review followed all five recommended steps.9,23 in contrast, these processes were only partially reported or not reported at all by the remaining 25 studies.13–22,24–38 this may be because the scales had originally been translated into arabic in earlier studies. nevertheless, it is recommended that researchers identify and report detailed information regarding each stage of the cross-cultural adaptation process when translating and adapting qol scales for use in arabicspeaking populations. this review was subject to several limitations. the focus of the analysis was primarily on the psycho metric properties of qol scales; as such, further research is necessary to evaluate the quality of the design and methodologies of the reported studies. in addition, a single researcher undertook the screening and assessed the eligibility of the articles included in the analysis. this may have increased the risk of bias or resulted in possible errors during the data collection process. finally, although a systematic search of multiple electronic databases was conducted using various search terms in different combinations, it is possible that some relevant studies were unintentionally overlooked and not included in the analysis. conclusion this review evaluated the psychometric properties and cultural adaptation and translation processes of arabic versions of qol scales. in general, the studies provided insufficient information regarding the exact processes of translation and cultural adaptation. additionally, while most scales provided sufficient information regarding the content and construct validity and internal consistency of the scales, information related to agreement, respons iveness, floor and ceiling effects and interpretability was lacking. specifically, the test-retest reliability, criterion validity and sensitivity of arabic qol scales requires further validation. future research involving the trans lation and cultural adaptation of qol scales should utilise recommended guidelines to ensure the content of the translated scale is equivalent to that of the original. references 1. verdugo ma, schalock rl, keith kd, stancliffe rj. quality of life and its measurement: important principles and guidelines. j intellect disabil res 2005; 49:707–17. https://doi.org/10.1111/ j.1365-2788.2005.00739.x. 2. romero m, vivas-consuelo d, alvis-guzman n. is health related quality of life (hrqol) a valid indicator for health systems evaluation? springerplus 2013; 2:664. https://doi.org/10.1186/2 193-1801-2-664. 3. beaton de, bombardier c, guillemin f, ferraz mb. guidelines for the process of cross-cultural adaptation of self-report meas ures. spine (phila pa 1976) 2000; 25:3186–91. https://doi.org/10.1 097/00007632-200012150-00014. 4. downing sm. reliability: on the reproducibility of assessment data. med educ 2004; 38:1006– 12. https://doi.org/10.1111/j.13 65-2929.2004.01932.x. 5. cook da, beckman tj. current concepts in validity and relia bility for psychometric instruments: theory and application. am j med 2006; 119:166.e7–16. https://doi.org/10.1016/j.amjmed.20 05.10.036. 6. messick s. standards of validity and the validity of standards in performance asessment. educ meas issues pract 1995; 14:5–8. https://doi.org/10.1111/j.1745-3992.1995.tb00881.x. 7. istizada. complete list of arabic speaking countries: 2018. from: http://istizada.com/complete-list-of-arabic-speakingcountries-2014/ accessed: oct 2019. 8. sadat f, kazemi f, farzindar a. automatic identification of arabic dialects in social media. in: somera ’14: proceedings of the first international workshop on social media retrieval and analysis. new york, usa: association for computing machinery, 2014. pp. 35–40. https://doi.org/10.1145/2632188.2632207. 9. coons sj, alabdulmohsin sa, draugalis jr, hays rd. reliability of an arabic version of the rand-36 health survey and its equivalence to the us-english version. med care 1998; 36:428–32. https://doi.org/10.1097/00005650-199803000-00018. https://doi.org/10.1111/j.1365-2788.2005.00739.x https://doi.org/10.1111/j.1365-2788.2005.00739.x https://doi.org/10.1186/2193-1801-2-664 https://doi.org/10.1186/2193-1801-2-664 https://doi.org/10.1097/00007632-200012150-00014 https://doi.org/10.1097/00007632-200012150-00014 https://doi.org/10.1111/j.1365-2929.2004.01932.x https://doi.org/10.1111/j.1365-2929.2004.01932.x https://doi.org/10.1016/j.amjmed.2005.10.036 https://doi.org/10.1016/j.amjmed.2005.10.036 https://doi.org/10.1111/j.1745-3992.1995.tb00881.x https://doi.org/10.1145/2632188.2632207 https://doi.org/10.1097/00005650-199803000-00018 cross-cultural adaptation and psychometric properties of quality of life scales for arabic-speaking adults a systematic review e136 | squ medical journal, may 2020, volume 20, issue 2 10. moher d, liberati a, tetzlaff j, altman dg; prisma group. preferred reporting items for systematic reviews and metaanalyses: the prisma statement. int j surg 2010; 8:336–41. https://doi.org/10.1016/j.ijsu.2010.02.007. 11. terwee cb, bot sd, de boer mr, van der windt da, knol dl, dekker j, et al. quality criteria were proposed for measurement properties of health status questionnaires. j clin epidemiol 2007; 60:34–42. https://doi.org/10.1016/j.jclinepi.2006.03.012. 12. guillemin f, bombardier c, beaton d. cross-cultural adaptation of health-related quality of life measures: literature review and proposed guidelines. j clin epidemiol 1993; 46:1417–32. https://doi.org/10.1016/0895-4356(93)90142-n. 13. aburuz s, bulatova n, twalbeh m, gazawi m. the validity and reliability of the arabic version of the eq-5d: a study from jordan. ann saudi med 2009; 29:304–8. https://doi.org/10.41 03/0256-4947.55313. 14. hoopman r, terwee cb, aaronson nk. translated coop/ wonca charts found appropriate for use among turkish and moroccan ethnic minority cancer patients. j clin epidemiol 2008; 61:1036–48. https://doi.org/10.1016/j.jclinepi.2007.11.018. 15. hoopman r, terwee cb, muller mj, aaronson nk. translation and validation of the sf-36 health survey for use among turkish and moroccan ethnic minority cancer patients in the netherlands. eur j cancer 2006; 42:2982–90. https://doi. org/10.1016/j.ejca.2006.08.011. 16. younsi m, chakroun m. measuring health-related quality of life: psychometric evaluation of the tunisian version of the sf12 health survey. qual life res 2014; 23:2047–54. https://doi. org/10.1007/s11136-014-0641-8. 17. el-kalla ra, khalaf mm, saad ma, othman em. reliability of the arabic egyptian version of short form 36 health survey questionnaire to measure quality of life in burned patient. med j cairo univ 2016; 84:311–16. 18. sabbah i, drouby n, sabbah s, retel-rude n, mercier m. quality of life in rural and urban populations in lebanon using sf-36 health survey. health qual life outcomes 2003; 1:30. https://doi.org/10.1186/1477-7525-1-30. 19. dalky hf, meininger jc, al-ali nm. the reliability and validity of the arabic world health organization quality of lifebref instrument among family caregivers of relatives with psychiatric illnesses in jordan. j nurs res 2017; 25:224–30. https://doi.org/10.1097/jnr.0000000000000146. 20. ohaeri ju, awadalla aw, el-abassi ah, jacob a. confirmatory factor analytical study of the whoqol-bref: experience with sudanese general population and psychiatric samples. bmc med res methodol 2007; 7:37. https://doi.org/10.1186/1471-2288-7-37. 21. ohaeri ju, awadalla aw. the reliability and validity of the short version of the who quality of life instrument in an arab general population. ann saudi med 2009; 29:98–104. https://doi.org/10.4103/0256-4947.51790. 22. khader s, hourani mm, al-akour n. normative data and psy chometric properties of short form 36 health survey (sf-36, version 1.0) in the population of north jordan. east mediterr health j 2011; 17:368–74. 23. soudy h, maghfoor i, elhassan tam, abdullah e, rauf sm, al zahrani a, et al. translation and validation of the functional assessment of cancer therapy-bone marrow transplant (fact bmt) version 4 quality of life instrument into arabic language. health qual life outcomes 2018; 16:47. https://doi.org/10.11 86/s12955-018-0861-7. 24. al barmawi m, al hadid la, alqudah hn, al hadid wa, shamoun sa. measuring the quality of life among head-and/or neck cancer patients with oral mucositis using the functional assessment of cancer therapy-general in jordan. asia pac j oncol nurs 2018; 5:320–6. https://doi.org/10.4103/apjon.apjon_14_18. 25. alawneh a, yasin h, khirfan g, qayas ba, ammar k, rimawi d, et al. psychometric properties of the arabic version of eortc qlqc15-pal among cancer patients in jordan. support care cancer 2016; 24:2455–62. https://doi.org/10.1007/s00520-015-3018-9. 26. awad ma, denic s, el taji h. validation of the european organization for research and treatment of cancer quality of life questionnaires for arabic-speaking populations. ann n y acad sci 2008; 1138:146–54. https://doi.org/10.1196/annals.1414.021. 27. bener a, alsulaiman r, doodson l, el ayoubi hr. an assess ment of reliability and validity of the european organization for research and treatment of cancer quality of life quest ionnaire c30 among breast cancer patients in qatar. j family med prim care 2017; 6:824–31. https://doi.org/10.4103/jfmpc. jfmpc_17_17. 28. huijer ha, sagherian k, tamim h. validation of the arabic version of the eortc quality of life questionnaire among cancer patients in lebanon. qual life res 2013; 22:1473–81. https://doi.org/10.1007/s11136-012-0261-0. 29. lazenby m, khatib j, al-khair f, neamat m. psychometric pro perties of the functional assessment of chronic illness therapy- spiritual well-being (facit-sp) in an arabic-speaking, predom inantly muslim population. psychooncology 2013; 22:220–7. https://doi.org/10.1002/pon.2062. 30. zahran mh, sheir k, zidan em, ali-el-dein b. validation of the arabic version of the functional assessment of cancer therapy bladder questionnaire in egyptian patients with bladder cancer. arab j urol 2017; 15:110–14. https://doi.org/10.1016/j.aju.2017.01.008. 31. sheikh ka, yagoub u, el-setouhy m, alsanosy r, mohamud sa. reliability and validity of the arabic version of the sf-36 health survey questionnaire in population of khat chewers: jazan region kingdom of saudi arabia. appl res qual life 2015; 10:1–13. https://doi.org/10.1007/s11482-013-9295-x. 32. bekairy am, bustami rt, almotairi m, jarab a, katheri am, aldebasi tm, et al. validity and reliability of the arabic version of the the euroqol (eq-5d): a study from saudi arabia. int j health sci (qassim) 2018; 12:16–20. 33. bani-issa w. evaluation of the health-related quality of life of emirati people with diabetes: integration of sociodemographic and disease-related variables. east mediterr health j 2011; 17:825–30. https://doi.org/10.26719/2011.17.11.825. 34. halabi jo. psychometric properties of the arabic version of quality of life index. j adv nurs 2006; 55:604–10. https://doi. org/10.1111/j.1365-2648.2006.03952_1.x. 35. alawadhi sa, ohaeri ju. validity and reliability of the european organization for research and treatment in cancer quality of life questionnaire (eortc qlq): experience from kuwait using a sample of women with breast cancer. ann saudi med 2010; 30:390–6. https://doi.org/10.4103/0256-4947.67083. 36. hoopman r, terwee cb, devillé w, knol dl, aaronson nk. evaluation of the psychometric properties of the sf-36 health survey for use among turkish and moroccan ethnic minority populations in the netherlands. qual life res 2009; 18:753–64. https://doi.org/10.1007/s11136-009-9491-1. 37. khoudri i, ali zeggwagh a, abidi k, madani n, abouqal r. measurement properties of the short form 36 and healthrelated quality of life after intensive care in morocco. acta anaesthesiol scand 2007; 51:189–97. https://doi.org/10.1111/ j.1399-6576.2006.01225.x. 38. guermazi m, allouch c, yahia m, huissa tb, ghorbel s, damak j, et al. translation in arabic, adaptation and validation of the sf-36 health survey for use in tunisia. ann phys rehabil med 2012; 55:388–403. https://doi.org/10.1016/j.rehab.2012.05.003. 39. aaronson nk, ahmedzai s, bergman b, bullinger m, cull a, duez nj, et al. the european organization for research and treatment of cancer qlq-c30: a quality-of-life instrument for use in international clinical trials in oncology. j natl cancer inst 1993; 85:365–76. https://doi.org/10.1093/jnci/85.5.365. 40. sprangers ma, groenvold m, arraras ji, franklin j, te velde a, muller m, et al. the european organization for research and treatment of cancer breast cancer-specific quality-of-life quest ionnaire module: first results from a three-country field study. j clin oncol 1996; 14:2756–68. https://doi.org/10.1200/jco.19 96.14.10.2756. https://doi.org/10.1016/j.ijsu.2010.02.007 https://doi.org/10.1016/j.jclinepi.2006.03.012 https://doi.org/10.1016/0895-4356%2893%2990142-n https://doi.org/10.4103/0256-4947.55313 https://doi.org/10.4103/0256-4947.55313 https://doi.org/10.1016/j.jclinepi.2007.11.018 https://doi.org/10.1016/j.ejca.2006.08.011 https://doi.org/10.1016/j.ejca.2006.08.011 https://doi.org/10.1007/s11136-014-0641-8 https://doi.org/10.1007/s11136-014-0641-8 https://doi.org/10.1186/1477-7525-1-30 https://doi.org/10.1097/jnr.0000000000000146 https://doi.org/10.1186/1471-2288-7-37 https://doi.org/10.4103/0256-4947.51790 https://doi.org/10.1186/s12955-018-0861-7 https://doi.org/10.1186/s12955-018-0861-7 https://doi.org/10.4103/apjon.apjon_14_18 https://doi.org/10.1007/s00520-015-3018-9 https://doi.org/10.1196/annals.1414.021 https://doi.org/10.4103/jfmpc.jfmpc_17_17 https://doi.org/10.4103/jfmpc.jfmpc_17_17 https://doi.org/10.1007/s11136-012-0261-0 https://doi.org/10.1002/pon.2062 https://doi.org/10.1016/j.aju.2017.01.008 https://doi.org/10.1007/s11482-013-9295-x https://doi.org/10.26719/2011.17.11.825 https://doi.org/10.1111/j.1365-2648.2006.03952_1.x https://doi.org/10.1111/j.1365-2648.2006.03952_1.x https://doi.org/10.4103/0256-4947.67083 https://doi.org/10.1007/s11136-009-9491-1 https://doi.org/10.1111/j.1399-6576.2006.01225.x https://doi.org/10.1111/j.1399-6576.2006.01225.x https://doi.org/10.1016/j.rehab.2012.05.003 https://doi.org/10.1093/jnci/85.5.365 https://doi.org/10.1200/jco.1996.14.10.2756 https://doi.org/10.1200/jco.1996.14.10.2756 mohammed al maqbali, jackie gracey, jane rankin, lynn dunwoody, eileen hacker and ciara hughes review | e137 41. bjordal k, ahlner-elmqvist m, tollesson e, jensen ab, razavi d, maher ej, et al, development of a european organization for research and treatment of cancer (eortc) questionnaire module to be used in quality of life assessments in head and neck cancer. acta oncol 1994; 33:879–85. https://doi.org/10.3109/02841869 409098450. 42. bergman b, aaronson nk, ahmedzai s, kaasa s, sullivan m. the eortc qlq-lc13: a modular supplement to the eortc core quality of life questionnaire (qlq-c30) for use in lung cancer clinical trials. eortc study group on quality of life. eur j cancer 1994; 30a:635–42. https://doi.org/10.1016/09598049(94)90535-5. 43. groenvold m, petersen ma, aaronson nk, arraras ji, blazeby jm, bottomley a, et al. the development of the eortc qlq-c15pal: a shortened questionnaire for cancer patients in palliative care. eur j cancer 2006; 42:55–64. https://doi.org/10.1016/j.ejca.2 005.06.022. 44. cella df, tulsky ds, gray g, sarafian b, linn e, bonomi a, et al. the functional assessment of cancer therapy scale: development and validation of the general measure. j clin oncol 1993; 11:570–9. https://doi.org/10.1200/jco.1993.11.3.570. 45. brady mj, cella df, mo f, bonomi ae, tulsky ds, lloyd sr, et al. reliability and validity of the functional assessment of cancer therapy-breast quality-of-life instrument. j clin oncol 1997; 15:974–86. https://doi.org/10.1200/jco.1997.15.3.974. 46. tong mc, lo ps, wong kh, yeung rm, van hasselt ca, eremenco s, et al. development and validation of the functional assessment of cancer therapy nasopharyngeal cancer subscale. head neck 2009; 31:738–47. https://doi.org/10.1002/hed.21023. 47. cella df, mccain nl, peterman ah, mo f, wolen d. devel opment and validation of the functional assessment of human immunodeficiency virus infection (fahi) quality of life instrument. qual life res 1996; 5:450–63. https://doi.org/10.1007/bf00449920. 48. cella df, dineen k, arnason b, reder a, webster ka, karabatsos g, et al. validation of the functional assessment of multiple sclerosis quality of life instrument. neurology 1996; 47:129–39. https://doi.org/10.1212/wnl.47.1.129. 49. brucker ps, yost k, cashy j, webster k, cella d. general population and cancer patient norms for the functional assessment of cancer therapy-general (fact-g). eval health prof 2005; 28:192–211. https://doi.org/10.1177/0163278705275341. 50. mchorney ca, ware je jr, lu jf, sherbourne cd. the mos 36-item short-form health survey (sf-36): iii. tests of data quality, scaling assumptions, and reliability across diverse patient groups. med care 1994; 32:40–66. https://doi.org/10.10 97/00005650-199401000-00004. 51. ware j jr, kosinski m, keller sd. a 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. med care 1996; 34:220–33. https://doi.org/10.109 7/00005650-199603000-00003. 52. rabin r, de charro f. eq-5d: a measure of health status from the euroqol group. ann med 2001; 33:337–43. https://doi. org/10.3109/07853890109002087. 53. world health organization. development of the world health organization whoqol-bref quality of life assessment: the whoqol group. psychol med 1998; 28:551–8. https://doi. org/10.1017/s0033291798006667. 54. world health organization. the world health organization quality of life assessment (whoqol): development and general psychometric properties. soc sci med 1998; 46:1569–85. https://doi.org/10.1016/s0277-9536(98)00009-4. 55. van weel c. functional status in primary care: coop/wonca charts. disabil rehabil 1993; 15:96–101. https://doi.org/10.310 9/09638289309165878. 56. ferrans ce, powers mj. quality of life index: development and psychometric properties. ans adv nurs sci 1985; 8:15–24. https://doi.org/10.1097/00012272-198510000-00005. 57. rannestad t, skjeldestad fe. ferrans and powers’ quality of life index applied in urinary incontinence research: a pilot study. scand j caring sci 2011; 25:410–16. https://doi.org/10.1111/ j.1471-6712.2010.00852.x. 58. may la, warren s. measuring quality of life of persons with spinal cord injury: substantive and structural validation. qual life res 2001; 10:503–15. https://doi.org/10.1023/a:1013027520429. 59. buck d, jacoby a, massey a, ford g. evaluation of measures used to assess quality of life after stroke. stroke 2000; 31:2004–10. https://doi.org/10.1161/01.str.31.8.2004. 60. ferrans and powers quality of life index. reliability and validity. from: https://qli.org.uic.edu/reliability/reliabilityhome.htm accessed: oct 2019. 61. polit df, beck ct. nursing research: generating and assessing evidence for nursing practice, 10th ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2016. pp. 160–81. 62. nolte s, liegl g, petersen ma, aaronson nk, costantini a, fayers pm, et al. general population normative data for the eortc qlq-c30 health-related quality of life questionnaire based on 15,386 persons across 13 european countries, canada and the unites states. eur j cancer 2019; 107:153–63. https://doi.org/10.1016/j.ejca.2018.11.024. 63. pearman t, yanez b, peipert j, wortman k, beaumont j, cella d. ambulatory cancer and us general population reference values and cutoff scores for the functional assessment of cancer therapy. cancer 2014; 120:2902–9. https://doi.org/10.1002/cncr.28758. 64. mark tl, johnson g, fortner b, ryan k. the benefits and challenges of using computer-assisted symptom assessments in oncology clinics: results of a qualitative assessment. technol cancer res treat 2008; 7:401–6. https://doi.org/10.1177/15330 3460800700508. 65. rolstad s, adler j, rydén a. response burden and questionnaire length: is shorter better? a review and meta-analysis. value health 2011; 14:1101–8. https://doi.org/10.1016/j.jval.2011.06.003. https://doi.org/10.3109/02841869409098450 https://doi.org/10.3109/02841869409098450 https://doi.org/10.1016/0959-8049%2894%2990535-5 https://doi.org/10.1016/0959-8049%2894%2990535-5 https://doi.org/10.1016/j.ejca.2005.06.022 https://doi.org/10.1016/j.ejca.2005.06.022 https://doi.org/10.1200/jco.1993.11.3.570 https://doi.org/10.1200/jco.1997.15.3.974 https://doi.org/10.1002/hed.21023 https://doi.org/10.1007/bf00449920 https://doi.org/10.1212/wnl.47.1.129 https://doi.org/10.1177/0163278705275341 https://doi.org/10.1097/00005650-199401000-00004 https://doi.org/10.1097/00005650-199401000-00004 https://doi.org/10.1097/00005650-199603000-00003 https://doi.org/10.1097/00005650-199603000-00003 https://doi.org/10.3109/07853890109002087 https://doi.org/10.3109/07853890109002087 https://doi.org/10.1017/s0033291798006667 https://doi.org/10.1017/s0033291798006667 https://doi.org/10.1016/s0277-9536%2898%2900009-4 https://doi.org/10.3109/09638289309165878 https://doi.org/10.3109/09638289309165878 https://doi.org/10.1097/00012272-198510000-00005 https://doi.org/10.1111/j.1471-6712.2010.00852.x https://doi.org/10.1111/j.1471-6712.2010.00852.x https://doi.org/10.1023/a:1013027520429 https://doi.org/10.1161/01.str.31.8.2004 https://doi.org/10.1016/j.ejca.2018.11.024 https://doi.org/10.1002/cncr.28758 https://doi.org/10.1177/153303460800700508 https://doi.org/10.1177/153303460800700508 https://doi.org/10.1016/j.jval.2011.06.003 departments of 1anesthesiology, teerthanker mahaveer medical college & research centre, and 2pharmacy practice, college of pharmacy, teerthanker mahaveer university, moradabad, india *corresponding author’s e-mail: mukeshkumar2002@gmail.com مقارنة خباخ النرتوجليسرين ببخاخ الليجنوكايني يف ختفيف تغريات الدورة الدموية لدى مرضى العمليات اجلراحية االختيارية الذين خيضعون لتنظري احلنجرة املباشر والتنبيب الرَُّغامي دراسة استقصائية عشوائية روهيت كومار فار�صني، موكي�ض كومار برا�صاد، ميغا غارج abstract: objectives: this study aimed to compare the effects of nitroglycerin (ntg) versus lignocaine spray in blunting the pressor response during direct laryngoscopy and endotracheal intubation. methods: this study was conducted between january and june 2018 in the department of anesthesiology, teerthankar mahaveer medical college, moradabad, india. a total of 90 elective surgical patients of american society of anesthesiologists physical status grades i or ii were divided into three groups, comprising two treatment groups and one control group. patients in the treatment groups received either one puff (1.5 mg/kg) of lignocaine 10% spray or one puff (400 μg) of ntg spray in the oropharynx one minute prior to the induction of anaesthesia. haemodynamic variables and mean rate pressure product at baseline and one, two, three, four and five minutes post-induction were compared. results: there was a significant reduction in mean heart rate at 3–5 minutes in both treatment groups compared to the control group (p <0.050), as well as lower increases in mean arterial pressure at 1–3 minutes (p <0.050). however, at 2–4 minutes, there was a significantly greater decrease in mean systolic blood pressure in the ntg group compared to both the lignocaine and control groups (p <0.050). moreover, a greater decrease in mean rate pressure product response at 1–5 minutes was observed in the ntg group compared to the lignocaine and control groups (p = 0.001). conclusion: the ntg spray was more effective than lignocaine in attenuating blood pressure increases and rate pressure product during elective laryngoscopy and intubation. keywords: endotracheal anesthesia; intubation; laryngoscopy; lignocaine; nitroglycerin; comparative effectiveness research; india. �صغط ارتفاع حدة تخفيف يف الليجنوكايني ببخاخ النرتوجلي�رسين بخاخ تاأثريات مقارنة اإىل الدرا�صة هذه هدفت الهدف: امللخ�ص: الدم اأثناء تنظري احلنجرة املبا�رس والتنبيب الرَُّغامي. الطريقة: اأجريت هذه الدرا�صة بني يناير ويونيو عام 2018 يف ق�صم التخدير، كلية تريثانكار ماهافري الطبية ،مراد اآباد، الهند. مت تق�صيم ما جمموعه من مر�صى العمليات اجلراحية الختيارية والذين يندرج و�صعهم البدين حتت الدرجتني الوىل اأو الثانية ح�صب ت�صنيف اجلمعية الأمريكية لأطباء التخدير اإىل ثالث جمموعات �صاملة جمموعتي عالج وجمموعة حتكم واحدة. تلقى املر�صى يف جمموعتي العالج اإما ن�صقة واحدة )1.5 مليغرام/كيلوغرام( من بخاخ الليجنوكايني %10 اأو ن�صقة واحدة الدورة متغريات مقارنة متت للتخدير. اخل�صوع من واحدة دقيقة قبل الَفَمِوي البلعوم يف النرتوجلي�رسين بخاخ من ميكروغرام( 400( الدموية ومتو�صط ناجت معدل �رسبات القلب و�صغط الدم عند خط الأ�صا�ض ودقيقة وثانية وثالث واأربع وخم�ض دقائق بعد بدء التخدير. النتائج: كان هناك انخفا�ض اكرب بكثري يف متو�صط معدل �رسبات القلب عند 5-3 دقائق يف كل من جمموعتي العالج مقارنة مبجموعة هناك كان ذلك اىل بالأ�صافة .)p >0.050( دقائق 1-3 عند ال�رسياين ال�صغط متو�صط يف اأقل انخفا�ض وكذلك ،)p >0.050( التحكم انخفا�ض كبري يف متو�صط �صغط الدم النقبا�صي يف جمموعة النرتوجلي�رسين عند 4-2 دقائق مقارنة مع كل من جمموعتي الليجنوكايني جمموعة يف الدم و�صغط القلب �رسبات معدل ناجت ا�صتجابة متو�صط يف اأكرب انخفا�ض لوحظ ، ذلك على عالوة .)p >0.050( والتحكم النرتوجلي�رسين عند 5-1 دقائق مقارنة مبجموعتي الليجنوكايني والتحكم )p = 0.001(. اخلال�صة: كان بخاخ النرتوجلي�رسين اأكرث فعالية من الليجنوكايني يف تخفيف زيادة �صغط الدم وناجت معدل �رسبات القلب و�صغط الدم خالل تنظري احلنجرة والتنبيب الختياريني. الكلمات املفتاحية: تخدير داخل الرُّغاَمى؛ تنبيب؛ تنظري احلنجرة؛ ليجنوكايني؛ نرتوجلي�رسين؛ بحوث مقارنة الفعالية؛ الهند. comparison of nitroglycerin versus lignocaine spray to attenuate haemodynamic changes in elective surgical patients undergoing direct laryngoscopy and endotracheal intubation a prospective randomised study rohit k. varshney,1 *mukesh k. prasad,1 megha garg2 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e316–323, epub. 22 dec 19 submitted 1 apr 19 revision req. 6 may 19; revision recd. 30 may 19 accepted 8 jul 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.007 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ rohit k. varshney, mukesh k. prasad and megha garg clinical and basic research | e317 direct laryngoscopy involves stretching the oropharyngeal tissues while the patient is under general anaesthesia in an attempt to straighten the angle between the mouth and the glottic opening; however, this causes pain and triggers a stress response associated with changes in haemodynamic variables.1,2 subsequently, tracheal intubation leads to the activation of the sympathetic system, along with the release of plasma catecholamines, which in turn elevates the patient’s heart rate (hr) and blood pressure (bp) and can induce arrhythmias.3 while these haemodynamic changes may not be significant in normal individuals, they can be catastrophic for cardiovascular-compromised patients and lead to the development of myocardial ischaemia and infarctions, left ventricular failure, cerebrovascular accidents and dysrhythmias.4,5 the reason for this exaggerated haemodynamic response lies in the activation of the autonomic reflex arc.6 changes in hr, heart rhythm and blood pressure depend on various factors including ease of intubation, depth of anaesthesia, time taken for the intubation and the use of various topical/intravenous (iv) anaesthetic agents beforehand. the effects of these factors on haemodynamic variables usually last between 30 seconds to under 10 minutes following intubation.6 various studies have evaluated the effectiveness of a range of techniques and drugs to minimise the deleterious effects of direct laryngoscopy and endo tracheal intubation.2,7,8 haidry and khan recommended using a mccoy blade instead of a macintosh laryng oscope to avoid pressure on the base of the tongue and lifting the epiglottis.7 other researchers have assessed the use of β-blockers, local anaesthetics (e.g. lignocaine), antihypertensive agents (e.g. phentolamine) and vasodilators (e.g. magnesium) to blunt pressor responses during laryngoscopy.2,8 lignocaine blocks sodium channels in the myo cardium, thus reducing the rate of rise of action potential and altering the conduction velocity through out the his-purkinje system and atrial and ventricular musculature.9 in contrast, the action of nitroglycerin (ntg) on the coronary vessels is not yet fully understood; however, it is believed that ntg increases blood flow to the coronary vessels along with oxygen delivery to the myocardium, if the coronary vessels are dilated immediately prior to the induction of anaesthesia.10 accordingly, both of these drugs would counteract the haemodynamic pressor response during direct laryngoscopy and tracheal intubation. an extensive search of the medline® database (national library of medicine, bethesda, maryland, usa) reveals that there is limited research comparing the effects of intraoral ntg versus lignocaine spray in minimising the deleterious haemodynamic effects of direct laryngoscopy and endotracheal intubation. thus, this comparative study aimed to evaluate the effect of these drugs in blunting the pressor response to direct laryngoscopy and endotracheal intubation. the null hypothesis was that the mean haemodynamic variables of the three study groups would be the same. methods this prospective, randomised, double-blind placebocontrolled study was conducted in the department of anesthesiology, teerthankar mahaveer medical college, moradabad, india, from january to june 2018. a total of 90 adult patients scheduled for elective general surgical procedures and classified as being of american society of anesthesiologists (asa) grades i or ii were included in the study. patients with jaundice, bronchial asthma, epilepsy, uncontrolled diabetes mellitus/hyper tension, metabolic/endocrine disease, a history of previous myocardial infarctions, morbid obesity or any chronic renal, liver or cardiorespiratory disease were excluded. in addition, patients for whom intubation was anticipated to be difficult were not included. a pilot study was conducted which found that systolic bp (sbp) increased by 67.8% among patients in a control group compared to 25% among those who received a single dose of ntg spray. taking into account an alpha error of <0.05 and power of 0.8, a sample size calculation determined that a total of 83 patients was required. in order to compensate for dropouts, patients were allocated into three groups of 30 participants each using a randomised selection method [figure 1]. this involved preparing 90 identical advances in knowledge although various studies have evaluated different interventions to minimise the adverse haemodynamic effects of direct laryngoscopy and endotracheal intubation, there is limited research comparing the effects of intraoral nitroglycerin (ntg) and lignocaine sprays in this context. this study compares the efficacy of these aforementioned sprays in blunting the pressor response to direct laryngoscopy and endotracheal intubation. application to patient care the results of this study suggest that ntg spray is more efficacious than lignocaine in blunting the pressor response to direct laryngoscopy and endotracheal intubation in elective surgical patients. comparison of nitroglycerin versus lignocaine spray to attenuate haemodynamic changes in elective surgical patients undergoing direct laryngoscopy and endotracheal intubation a prospective randomised study e318 | squ medical journal, november 2019, volume 19, issue 4 paper slips with one of the three group allocations and blindly drawing papers until all patients had been allocated to a group. once randomly assigned to each group, none of the patients were lost to follow-up or excluded from the final analysis. the first group received one puff (1.5 mg/kg) of lignocaine 10% spray in the oropharynx one minute prior to the induction of anaesthesia after opening the mouth and protruding the tongue, while the second group received one puff (400 µg) of ntg spray sublingually one minute prior to the induction of anaesthesia. the third group functioned as the control group and no drug was administered prior to induction. in order to ensure double-blinding, doses were administered using veiled spray containers by an independent anaesthesiologist who did not participate further in the study. in this way, both the patients and investigators were unaware of specific group allocations and which drug was being administered in order to prevent any potential bias. on the day of the surgery, all patients were prepared for the procedure. a 20-gauge cannula was secured and an intravenous (iv) infusion of ringer’s lactate solution was administered. in addition, premed ication with 0.2 mg of iv glycopyrrolate, 4 mg of iv ondansetron, 2 mg/kg of iv tramadol and 0.02 mg/kg of iv midazolam was administered 30 minutes prior to the induction of anaesthesia. standard monitors were attached to all patients, including a pulse oximeter and non-invasive bp, electrocardiography and endtidal carbon dioxide monitoring equipment. various baseline haemodynamic parameters—including hr, sbp, diastolic bp (dbp) and mean arterial pressure (map)—were measured using a b40 ge monitor (general electric co., auckland, new zealand). the rate pressure product (rpp) was calculated as the product of hr and sbp. after pre-oxygenation for three minutes using 100% oxygen, all patients were induced with 2 mg/kg of iv propofol and relaxed with 1.5 mg/kg of iv succinylcholine. direct laryngoscopy and endotracheal intubation were performed using a macintosh laryng oscope (welch allyn, skaneateles falls, new york, usa) after placing the patient in a ‘sniffing’ position with an appropriately-sized 7.5or 8.0-mm (for females and males, respectively) cuffed endotracheal tube (smiths medical india pvt. ltd., mumbai, maharashtra, india). the position of the tube was confirmed using capnography. anaesthesia was maintained using an oxygen-nitrous oxide mixture combined with intermittent doses of 0.05 mg/kg of iv vecuronium and isoflurane 1%. at the end of the surgery, 75 mg of intramuscular diclofenac was administered before the reversal of the neuromuscular blockade to pre-empt postoperative pain. muscle relaxation reversal was then accomplished using 0.04 mg/kg of iv neostigmine and 0.01 mg/kg of iv glycopyrrolate. subsequently, after confirming adequate reflexes and respiration, the patient was extubated. during the postoperative period, nausea, vomiting, vital signs, postoperative pain and any other adverse effects were monitored by an anaesthesia nurse. mean haemodynamic values (i.e. hr, sbp, dbp, map and rpp) were recorded at baseline and one, two, three, four and five minutes after the induction of the anaesthesia for patients in all three groups. in addition, intubating responses were compared on a scale of 0–3, with zero indicating poor jaw relaxation, closed vocal cord and severe coughing or bucking when intubated, one signifying minimal jaw relaxation, closing vocal cord and mild coughing when intubated, two indicating moderate jaw relaxation, moving vocal cord and slight diaphragmatic movement when intubated and three signifying good jaw relaxation, open vocal cord and no response to intubation.11 a total score of 8–9 was considered excellent, while total scores of 6–7, 3–5 and 0–2 were indicative of good, fair and poor intubation conditions, respectively.11 data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the comparison of baseline data was performed using an analysis of variance test. in addition, the student’s t-test and chisquared or exact fisher’s tests were used to analyse parametric and non-parametric data, as applicable. a p figure 1: flowchart showing the prospective randomised design used in the current study. ntg = nitroglycerin. rohit k. varshney, mukesh k. prasad and megha garg clinical and basic research | e319 value of <0.050 was considered statistically significant. this study was approved by the institutional ethical committee of teerthanker mahaveer university (#tmmc/iec/2017/47). written informed consent was obtained from all participants and all patients were provided with a detailed explanation of the procedure before it was performed. results all 90 patients included in the study were between 18–60 years old and had body mass indexes of 8–24 kg/m2. there were no significant differences in age, weight, gender distribution, asa grades or laryngoscopy duration according to group allocation [table 1]. in terms of table 1: demographic and anaesthesia-related characteristics of elective surgical patients undergoing direct laryngo scopy and endotracheal intubation (n = 90) characteristic n (%) p value total control group (n = 30) lignocaine group (n = 30) ntg group (n = 30) mean age in years ± sd 41.63 ± 11.91 38.80 ± 11.51 43.10 ± 11.51 43.01 ± 12.57 0.072 mean weight in kg ± sd 55.06 ± 7.91 56.07 ± 7.73 56.47 ± 7.73 52.63 ± 7.97 0.121 gender male 36 (40) 14 (46.7) 10 (33.3) 12 (40) 0.633 female 54 (60) 16 (53.3) 20 (66.7) 18 (60) 0.084 asa grade i 59 (65.6) 17 (56.7) 20 (66.7) 21 (70) 0.132 ii 31 (34.4) 13 (43.3) 10 (33.3) 9 (30) 0.231 mean dl duration in seconds ± sd 23.17 ± 2.54 23.83 ± 2.33 22.17 ± 2.47 23.50 ± 2.57 0.060 ntg = nitroglycerin; sd = standard deviation; asa = american society of anesthesiologists; dl = direct laryngoscopy. table 2: mean heart rates according to intervention group among elective surgical patients undergoing direct laryngo scopy and endotracheal intubation (n = 90) pit in minutes mean hr in bpm ± sd p value control group (n = 30) lignocaine group (n = 30) ntg group (n = 30) control versus lignocaine group control versus ntg group lignocaine versus ntg group baseline 93.77 ± 16.29 91.63 ± 13.41 92.33 ± 8.69 0.581 0.195 0.432 1 97.94 ± 20.77 97.50 ± 13.84 95.03 ± 9.49 0.922 0.494 0.424 2 109.47 ± 16.35 102.90 ± 13.90 99.24 ± 8.24 0.100 0.001* 0.223 3 113.17 ± 15.54 103.77 ± 14.94 104.53 ± 14.85 0.020* 0.030* 0.841 4 110.37 ± 15.42 99.80 ± 15.93 99.67 ± 7.84 0.010* 0.001* 0.972 5 106.90 ± 14.59 94.93 ± 12.95 93.33 ± 8.63 0.001* 0.001* 0.573 pit = post-induction time; hr = heart rate; bpm = beats per minute; sd = standard deviation; ntg = nitroglycerin. *statistically significant at p <0.050. table 3: mean arterial pressure values according to intervention group among elective surgical patients undergoing direct laryngoscopy and endotracheal intubation (n = 90) pit in minutes mean map in mmhg ± sd p value control group (n = 30) lignocaine group (n = 30) ntg group (n = 30) control versus lignocaine group control versus ntg group lignocaine versus ntg group baseline 98.01 ± 7.95 101.00 ± 6.50 99.02 ± 6.77 0.111 0.603 0.251 1 113.80 ± 13.97 103.22 ± 11.15 103.33 ± 10.87 0.001* 0.001* 0.972 2 109.48 ± 19.24 99.16 ± 8.89 96.39 ± 8.53 0.010* 0.001* 0.223 3 108.45 ± 15.46 99.43 ± 7.08 95.27 ± 9.85 0.001* 0.001* 0.06 4 106.71 ± 15.08 100.3 ± 9.20 95.01 ± 8.49 0.060 0.001* 0.020* 5 100.76 ± 12.64 99.31 ± 8.89 96.92 ± 8.22 0.61 0.172 0.284 pit = post-induction time; map = mean arterial pressure; sd = standard deviation; ntg = nitroglycerin. *statistically significant at p <0.050. comparison of nitroglycerin versus lignocaine spray to attenuate haemodynamic changes in elective surgical patients undergoing direct laryngoscopy and endotracheal intubation a prospective randomised study e320 | squ medical journal, november 2019, volume 19, issue 4 hr, patients in the lignocaine group showed a greater decrease at 3–5 minutes compared to the control group (p <0.050), while patients in the ntg group demonstrated a lower increase in hr at 2–5 minutes compared to the control group (p <0.050) [table 2]. at one minute, mean sbp values were 151.84 ± 16.58 mmhg and 133.80 ± 15.62 mmhg in the control and lignocaine groups, respectively (p <0.010). similar results were seen for the ntg group in comparison to the control group (132.40 ± 15.22 mmhg versus 151.84 ± 16.58 mmhg; p <0.010). however, at 2–4 minutes, the greatest decrease in mean sbp values was observed in the ntg group, followed by the lignocaine group and then the control group (p <0.050). at 1–3 minutes post-induction, a lower increase in mean dbp values was observed in the lignocaine group compared to the control group. similarly, ntg resulted in better control in mean dbp at 1–4 minutes compared to the control group. patients receiving lignocaine showed better map control at 1–3 minutes compared to the control group (p <0.010). similarly, at 1–4 minutes post-induction, patients in the ntg group showed better map control than patients in the control group (p = 0.001). however, at minute four, a higher decrease in map was observed among participants receiving ntg compared to those receiving lignocaine (p = 0.020) [table 3]. an intergroup comparison at 1–5 minutes revealed the highest decrease in mean rpp response was in the ntg group, followed by the lignocaine group and then the control group (p = 0.001) [table 4]. based on their intubating scores, patients receiving ntg were in significantly better condition in comparison to patients in the control group (p = 0.001), while lignocaine administration did not result in a significant difference in this aspect (p = 0.243) [table 5]. discussion orotracheal intubation involves two separate stages of airway stimulation; firstly, a direct laryngoscopy is performed to identify the vocal cords, followed by the insertion of an endotracheal tube through the vocal cords into the trachea. takahashi et al. suggested that laryngoscopy followed by intubation produced more significant hypertension in comparison to laryngoscopy alone.12 the mechanisms involved in these procedures act as powerful stimuli for the elevation of haemodynamic parameters, which must be attenuated using adequate premedication, the smooth induction of anaesthesia and rapid intubation.13 the present study was performed in order to evaluate the pressor responses of normotensive patients receiving ntg versus lignocaine oral spray in comparison to a control group during direct laryng oscopy and endotracheal intubation. when sprayed either sublingually or in the oropharynx, ntg can be detected within two minutes and up to about 90 minutes. this agent is metabolised in the liver, table 4: mean rate pressure product values according to intervention group among elective surgical patients undergoing direct laryngoscopy and endotracheal intubation (n = 90) pit in minutes mean rpp ± sd p value control group (n = 30) lignocaine group (n = 30) ntg group (n = 30) control versus lignocaine group control versus ntg group lignocaine versus ntg group baseline 12,002.56 ± 164.53 12,021.86 ± 103.26 12,076.76 ± 83.16 0.591 0.060 0.061 1 14,871.21 ± 344.37 13,045.5 ± 216.19 12,581.97 ± 144.44 0.001* 0.001* 0.001* 2 15,745.07 ± 343.02 13,380.09 ± 121.62 12,308.74 ± 105.81 0.001* 0.001* 0.001* 3 16,138.04 ± 281.12 13,458.97 ± 133.41 12,906.32 ± 165.73 0.001* 0.001* 0.001* 4 15,234.37 ± 260.6 12,901.15 ± 159.62 12,222.53 ± 87.73 0.001* 0.001* 0.001* 5 13,925.86 ± 186.9 12,018.14 ± 121.21 11,743.72 ± 93.29 0.001* 0.001* 0.001* pit = post-induction time; rpp = rate pressure product; sd = standard deviation; ntg = nitroglycerin. *statistically significant at p <0.050 table 5: intubating condition according to intervention group among elective surgical patients undergoing direct laryngo scopy and endotracheal intubation (n = 90) condition n p value control group (n = 30) lignocaine group (n = 30) ntg group (n = 30) control versus lignocaine group control versus ntg group lignocaine versus ntg group excellent/ good 20/10 24/6 28/2 0.243 0.001* 0.134 ntg = nitroglycerin. *statistically significant at p <0.050. rohit k. varshney, mukesh k. prasad and megha garg clinical and basic research | e321 with the active metabolites possessing a half-life of approximately 40 minutes.14 lignocaine 10% sprayed in the oropharynx provides local anaesthetic action within one to five minutes of administration, with the effects lasting approximately 10–15 minutes. it is rapidly metabolised in the liver and excreted in urine; around 90% of the drug is excreted as metabolites, while the rest remains unchanged.15 sukumar et al. conducted a study comparing the effect of an iv bolus of propofol at anaesthesia induction and recovery and suggested that propofol aids in smooth anaesthesia induction, maintenance and early recovery.16 moreover, mishra et al. observed that induction with an iv bolus of propofol in neurosurgical patients leads to better haemodynamic values and earlier recovery compared to thiopentone-isoflurane.17 van den berg et al. compared iv boli of esmolol, ntg, magnesium sulphate, lignocaine and normal saline (as a placebo) to attenuate haemodynamic responses in patients undergoing cataract surgery; the researchers concluded that esmolol resulted in better haemodynamic stability compared to the other agents.18 singh et al. also observed that esmolol results in better modification of the haemodynamic response to laryngoscopy and intubation compared to ntg and lignocaine.6 in the present study, ntg was found to result in better haemodynamic outcomes compared to lignocaine. there was an increase in hr in all three groups at various time intervals post-induction in the current study; this was due to the pressor response generated as a result of laryngoscopy and endotracheal intubation.1–3 however, there was a statistically significant decrease at minute two between the ntg and control groups, while an insignificant decrease was noted between the lignocaine and control groups at the same time interval. this can be attributed to the reflex tachycardia produced due to peripheral vasodilation.2 manjusha et al. compared intraoral ntg spray versus iv ligno caine to attenuate the haemodynamic response due to laryngoscopy and endotracheal intubation.19 their findings support those of the current study, with similar results observed among the three groups at one, three and five minutes post-induction.19 in the present study, sbp was significantly reduced in both the lignocaine and ntg groups compared to the control group at 1–4 minutes post-induction. the statistical analysis showed a significant decrease in sbp in the ntg group compared to the lignocaine group at 2–4 minutes. fassoulaki and kaniaris observed that sbp did not increase significantly with intranasal ntg spray administration during the initial minutes post-intubation and significantly decreased at minutes three and five; in contrast, the control group showed a significant increase in sbp at all recorded time intervals.10 both dbp and map were significantly reduced at 1–3 minutes in the present study in both the lignocaine and ntg groups compared to the control group. moreover, there was a sustained decrease in map with ntg compared to lignocaine, with signif icant results noted after four minutes. these findings are comparable with those of kumari et al. wherein ntg lingual spray was found to be effective in attenuating the pressor response due to laryngoscopy and intubation in terms of preventing significant rises in sbp, dbp and map values in comparison to a control group.20 anant and waghray similarly found that intranasal ntg spray significantly decreased dbp compared to a control group, thus proving ntg spray to be a convenient method of drug administration which significantly attenuates the pressor response caused by laryngoscopy and intubation.21 various studies have supported the fact that ntg blunts the pressor response when administered via either intra nasal, topical or iv routes.19,22 the haemodynamic response to intubation includes increases in hr, map and pulmonary capillary wedge pressure as well as a decrease in ejection fraction; these responses are more pronounced in patients with diseased epicardial arteries which constrict as a result of sympathetic stimulation, thus further compromising coronary perfusion.23 however, the vasodilatory prop erties of ntg can reverse this to some extent, making this drug the best option for patients with low cardiac output and moderately elevated resistance.24 additionally, as rpp correlates with myocardial oxygen demand, this variable is related to the onset of angina pectoris, especially among patients with compromised coronary perfusion.25 in the current study, rpp values were significantly lower in the ntg group compared to the lignocaine and control groups. dichnielsen et al. concluded that intranasal ntg spray effectively attenuates the rpp due to laryngoscopy and endotracheal intubation in patients undergoing coronary artery bypass surgery.26 kamra et al. also noted similar results with a topical ntg ointment.27 hamaya and dohi suggested that topical lignocaine spray inhibits tactile stimulation of the air way primarily due to the direct blockade of mechano receptors.28 in another study, bülow et al. found that a laryngotracheal lignocaine spray resulted in satisfactory intubating conditions from 73–100% during anaesthesia induction using an iv bolus of 2.5 mg/kg of propofol and 30 μg/kg of alfentanil without muscle relaxants.29 in the present study, ntg spray resulted in better intubating conditions compared to the control group. this study was subject to certain limitations. firstly, an invasive arterial line was not used for continuous blood pressure measurements; however, while invasive measurements of arterial pressure are considered to be comparison of nitroglycerin versus lignocaine spray to attenuate haemodynamic changes in elective surgical patients undergoing direct laryngoscopy and endotracheal intubation a prospective randomised study e322 | squ medical journal, november 2019, volume 19, issue 4 more accurate, previous research has demonstrated that non-invasive measurements are still clinically useful.30 moreover, invasive arterial pressure measurements are technically difficult and often complicated and expensive; therefore, such methods are usually reserved for critically-ill patients or those in whom a major fluid shift is expected, not for elective general surgical procedures. additionally, arterial cannulae pose a potential risk of infection. accordingly, invasive arterial pressure monitoring was considered unnecessary. nevertheless, the use of non-invasive arterial pressure monitoring inhibited the measurement of certain haemodynamic variables, such as cardiac output and systolic volume. secondly, the study included only normotensive patients without any associated cardiovascular or cerebrovascular diseases. thus, the findings of this study cannot be extrapolated for patients with ischaemic heart disease, hypertension or airway difficulties. more over, the study did not compare other airway devices, with all patients undergoing direct laryngoscopy and endotracheal intubation using a macintosh laryng oscope (welch allyn) to ensure unbiased results. finally, while the study could have been performed with other induction drugs such as etomidate, which maintains better haemodynamic stability compared to propofol, this was not possible due to a limited supply of this agent at teerthankar mahaveer medical college.31 conclusion this study compared the administration of ntg versus lignocaine spray prior to the induction of anaesthesia for blunting the haemodynamic pressor response to direct laryngoscopy and endotracheal intubation among elective surgical patients. overall, ntg was significantly more effective than lignocaine in attenuating map and rpp changes and maintained equal efficacy in controlling other haemodynamic variables. moreover, this agent resulted in significantly better intubating conditions compared to those observed in the control group. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. kanchi m, nair hc, banakal s, murthy k, murugesan c. haemodynamic response to endotracheal intubation in coro nary artery disease: direct versus video laryngoscopy. indian j anaesth 2011; 55:260–5. https://doi.org/10.4103/0019-5049.82673. 2. grover vk, sharma s, mahajan rp, singh h. intranasal nitro glycerine attenuates pressure response to tracheal intubation in beta-blocker treated hypertensive patients. anaesthesia 1987; 42:884–7. https://doi.org/10.1111/j.1365-2044.1987.tb04119.x. 3. yoo ky, lee ju, kim hs, im wm. hemodynamic and cate cholamine responses to laryngoscopy and tracheal intubation in patients with complete spinal cord injuries. anesthesiology 2001; 95:647–51. https://doi.org/10.1097/00000542-20010900 0-00017. 4. barak m, ziser a, greenberg a, lischinsky s, rosenberg b. hemodynamic and catecholamine response to tracheal intub ation: direct laryngoscopy compared with fiberoptic intubation. j clin anesth 2003; 15:132–6. https://doi.org/10.1016/s09528180(02)00514-7. 5. kitamura t, yamada y, chinzei m, du hl, hanaoka k. attenuation of haemodynamic responses to tracheal intubation by the styletscope. br j anaesth 2001; 86:275–7. https://doi. org/10.1093/bja/86.2.275. 6. singh h, vichitvejpaisal p, gaines gy, white pf. comparative effects of lidocaine, esmolol, and nitroglycerin in modifying the hemodynamic response to laryngoscopy and intubation. j clin anesth 1995; 7:5–8. https://doi.org/10.1016/0952-818 0(94)00013-t. 7. haidry ma, khan fa. comparison of hemodynamic response to tracheal intubation with macintosh and mccoy laryngoscopes. j anaesthesiol clin pharmacol 2013; 29:196–9. https://doi.org/10.4103/0970-9185.111710. 8. padmawar s, patil m. a comparative study of 2% lignocaine vs 50% magnesium sulphate for attenuation of stress responses to laryngoscopy and endotracheal intubation. int j contemp med res 2016; 3:2317–21. 9. gurulingappa, aleem ma, awati mn, adarsh s. attenuation of cardiovascular responses to direct laryngoscopy and intub ation-a comparative study between iv bolus fentanyl, ligno caine and placebo(ns). j clin diagn res 2012; 6:1749–52. https://doi.org/10.7860/jcdr/2012/4070.2619. 10. fassoulaki a, kaniaris p. intranasal administration of nitroglycerine attenuates the pressor response to laryngoscopy and intubation of the trachea. br j anaesth 1983; 55:49–52. https://doi.org/10.1093/bja/55.1.49. 11. cooper r, mirakhur rk, clarke rs, boules z. comparison of intubating conditions after administration of org 9426 (rocuronium) and suxamethonium. br j anaesth 1992; 69:269–73. https://doi.org/10.1093/bja/69.3.269. 12. takahashi s, mizutani t, miyabe m, toyooka h. hemodynamic responses to tracheal intubation with laryngoscope versus light wand intubating device (trachlight) in adults with normal airway. anesth analg 2002; 95:480–4. https://doi.org/10.1213/0 0000539-200208000-00046. 13. rastogi b, gupta k, gupta pk, agarwal s, jain m, chauhan h. oral pregabalin premedication for attenuation of haemo dynamic pressor response of airway instrumentation during general anaesthesia: a dose response study. indian j anaesth 2012; 56:49–54. https://doi.org/10.4103/0019-5049.93344. 14. hashimoto s, kobayashi a. clinical pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its metabolites. clin pharmacokinet 2003; 42:205–21. https://doi.org/10.2165/00003 088-200342030-00001. https://doi.org/10.4103/0019-5049.82673 https://doi.org/10.1111/j.1365-2044.1987.tb04119.x https://doi.org/10.1097/00000542-200109000-00017 https://doi.org/10.1097/00000542-200109000-00017 https://doi.org/10.1016/s0952-8180%2802%2900514-7 https://doi.org/10.1016/s0952-8180%2802%2900514-7 https://doi.org/10.1093/bja/86.2.275 https://doi.org/10.1093/bja/86.2.275 https://doi.org/10.1016/0952-8180%2894%2900013-t https://doi.org/10.1016/0952-8180%2894%2900013-t https://doi.org/10.4103/0970-9185.111710 https://doi.org/10.7860/jcdr/2012/4070.2619 https://doi.org/10.1093/bja/55.1.49 https://doi.org/10.1093/bja/69.3.269 https://doi.org/10.1213/00000539-200208000-00046 https://doi.org/10.1213/00000539-200208000-00046 https://doi.org/10.4103/0019-5049.93344 https://doi.org/10.2165/00003088-200342030-00001 https://doi.org/10.2165/00003088-200342030-00001 rohit k. varshney, mukesh k. prasad and megha garg clinical and basic research | e323 15. aspen pharmacare. xylocaine® 10% pump spray. from: www. aspenpharma.com.au/wp-content/uploads/picmi/cmi/cmi_ xylocainepumpspray.pdf accessed: may 2019. 16. sukumar v, radhakrishnan a, keshavan vh. effect site con centration of propofol at induction and recovery of anaesthesia a correlative dose-response study. indian j anaesth 2018; 62:263–8. https://doi.org/10.4103/ija.ija_670_17. 17. mishra l, rajkumar n, singh s, dubey r, yadav g. a comparative study of propofol and isoflurane anaesthesia using butorphanol in neurosurgery. indian j anaesth 2009; 53:324–9. 18. van den berg aa, savva d, honjol nm. attenuation of the hae modynamic responses to noxious stimuli in patients undergoing cataract surgery. a comparison of magnesium sulphate, esmolol, lignocaine, nitroglycerine and placebo given i.v. with induction of anaesthesia. eur j anaesthesiol 1997; 14:134–47. https://doi.org/10.1097/00003643-199703000-00004. 19. manjusha jr, rao gp, ramakrishna p. attenuation of haemo dynamic responses during laryngoscopy and endotracheal intubation with intraoral glyceryl trinitate spray and intra venous lignocaine: a comparative study. indian j appl res 2015; 5:224–9. 20. kumari i, naithani u, dadheech vk, pradeep ds, meena k, verma d. attenuation of pressor response following intubation: efficacy of nitro-glycerine lingual spray. j anaesthesiol clin pharmacol 2016; 32:69–73. https://doi.org/10.4103/0970-918 5.175668. 21. anant s, waghray mr. hypertensive response to laryngoscopy and intubation: prevention by intranasal nitroglycerine. j anaesth clin pharmacol 1991; 7:111–14. 22. firoozbakhsh f, mohammadi fh, safari s, khashayar p. the effect of intravenous nitroglycerine on blood pressure during intubation. middle east j anaesthesiol 2008; 19:859–67. 23. nooraei n, dehkordi me, radpay b, teimoorian h, mohajerani sa. effects of intravenous magnesium sulfate and lidocaine on hemodynamic variables following direct laryngoscopy and intubation in elective surgery patients. tanaffos 2013; 12:57–63. 24. nishina k, mikawa k, maekawa n, obara h. attenuation of cardiovascular responses to tracheal extubation with diltiazem. anesth analg 1995; 80:1217–22. https://doi.org/10.1097/00000 539-199506000-00026. 25. bruning rs, sturek m. benefits of exercise training on coronary blood flow in coronary artery disease patients. prog cardiovasc dis 2015; 57:443–53. https://doi.org/10.1016/j.pc ad.2014.10.006. 26. dich-nielsen j, hole p, lang-jensen t, owen-falkenberg a, skovsted p. the effect of intranasally administered nitroglycerin on the blood pressure response to laryngoscopy and intub ation in patients undergoing coronary artery by-pass surgery. acta anaesthesiol scand 1986; 30:23–7. https://doi.org/10.11 11/j.1399-6576.1986.tb02360.x. 27. kamra s, wig j, sapru rp. topical nitroglycerin. a safeguard against pressor responses to tracheal intubation. anaesthesia 1986; 41:1087–91. https://doi.org/10.1111/j.1365-2044.1986.tb 12954.x. 28. hamaya y, dohi s. differences in cardiovascular response to airway stimulation at different sites and blockade of the responses by lidocaine. anesthesiology 2000; 93:95–103. https://doi.org/10.1097/00000542-200007000-00018. 29. bülow k, nielsen tg, lund j. the effect of topical lignocaine on intubating conditions after propofol-alfentanil induction. acta anaesthesiol scand 1996; 40:752–6. https://doi.org/10.1111/j.13 99-6576.1996.tb04523.x. 30. drynan ea, raisis al. comparison of invasive versus noninvasive blood pressure measurements before and after hemorrhage in anesthetized greyhounds using the surgivet v9203. j vet emerg crit care (san antonio) 2013; 23:523–31. https://doi.org/10.1111/vec.12075. 31. song jc, lu zj, jiao yf, yang b, gao h, zhang j, et al. etomidate anesthesia during ercp caused more stable haemodynamic responses compared with propofol: a randomized clinical trial. int j med sci 2015; 12:559–65. https://doi.org/10.7150/ ijms.11521. https://doi.org/10.4103/ija.ija_670_17 https://doi.org/10.1097/00003643-199703000-00004 https://doi.org/10.4103/0970-9185.175668 https://doi.org/10.4103/0970-9185.175668 https://doi.org/10.1097/00000539-199506000-00026 https://doi.org/10.1097/00000539-199506000-00026 https://doi.org/10.1016/j.pcad.2014.10.006 https://doi.org/10.1016/j.pcad.2014.10.006 https://doi.org/10.1111/j.1399-6576.1986.tb02360.x https://doi.org/10.1111/j.1399-6576.1986.tb02360.x https://doi.org/10.1111/j.1365-2044.1986.tb12954.x https://doi.org/10.1111/j.1365-2044.1986.tb12954.x https://doi.org/10.1097/00000542-200007000-00018 https://doi.org/10.1111/j.1399-6576.1996.tb04523.x https://doi.org/10.1111/j.1399-6576.1996.tb04523.x https://doi.org/10.1111/vec.12075 https://doi.org/10.7150/ijms.11521 https://doi.org/10.7150/ijms.11521 1 submitted 22 jan 23 1 revision req. 27 feb 23; revision recd. 20 mar 23 2 accepted 3 may 23 3 online-first: june 2023 4 doi: https://doi.org/10.18295/squmj.6.2023.041 5 6 the effect of group prenatal care on empowerment of pregnant adolescents 7 a randomized controlled trial 8 fatemeh malchi,1 *parvin abedi,2 mina iravani,2 elham maraghi,3 eesa 9 mohammadi,4 najmieh saadati5 10 1department of midwifery, nursing and midwifery school, 2reproductive health promotion 11 research center, ahvaz jundishapur university of medical sciences, ahvaz, iran; 3department 12 of biostatics and epidemiology, faculty of public health and 5department of obstetrics and 13 gynecology, fertility infertility and perinatology research center, ahvaz jundishapur 14 university of medical sciences, ahvaz, iran; 4nursing department, faculty of medical sciences, 15 tarbiat modares university, tehran, iran. 16 *corresponding author’s e-mail: parvinabedi@ymail.com. 17 18 abstract 19 objectives: this study aimed to evaluate the effect of group prenatal care on empowerment of 20 pregnant adolescents. methods: in this randomized controlled trial, 294 pregnant adolescents 21 (aged 15-19) were randomly assigned into two groups of group prenatal care (gpnc, n=147) 22 and individual prenatal care (ipnc, n=147). gpnc group received 5 sessions of gpnc (90-120 23 min) during 16-20 weeks of pregnancy, while the control group received individual prenatal 24 care. the empowerment of participants in the two groups was measured using the empowerment 25 scale for pregnant women. data were analyzed using the chi-square test, independent t-test, and 26 adjusted regression test. results: the mean total score of pregnant women’s empowerment in the 27 gpnc and ipnc groups after the intervention was 86.46±4.95 and 81.89±4.75, respectively [ β= 28 6.11, 95% ci: 4.89, 7.33, p<0.0001]. the improvement of dimensions of pregnancy 29 empowerment in gpnc versus ipnc was as follows: self‐efficacy: 18.21 ± 2.12 vs. 16.19 ± 30 mailto:parvinabedi@ymail.com 2 1.79 [β= 2.52, 95% ci: 2.19, 2.86, p<0.0001], future image: 19.57±1.57 vs. 18.95±1.54 [β= 31 0.67, 95% ci: (0.44, 0.9], self-esteem: 21.79 ± 1.75 vs. 20.90 ± 1.85 [β= 0.69, 95% ci: 0.41, 32 0.97, p<0.0001], joy of an addition to the family: 13.13±1.69 vs. 12.84±1.40 [β= 0.51, 95% ci: 33 0.28, 0.74, p=0.009], and support and assurance from others: 13.70 ± 1.1 and 13.04 ± 1.07, [β= 34 0.76, 95% ci: 0.13, 1.65, p<0.0001]. conclusion: group prenatal care can improve adolescent 35 pregnant women’s empowerment. results of the present study can serve as a useful foundation 36 for implementing the group prenatal care model in iran. 37 keywords: adolescent pregnancy; empowerment; centering prenatal care; group prenatal care; 38 iran 39 40 introduction 41 adolescent pregnancy is defined as a pregnancy that occurs when the mother is aged between 13 42 and 19.1 it is one of the main concerns in developing and undeveloped countries.2 every year, 43 about 21 million girls aged 15 to 19 years in undeveloped countries become pregnant, and 44 approximately 12 million of them give birth to their babies.3 adolescent pregnant women may 45 have adverse pregnancy outcomes.4 for example, they are at a greater risk of preterm birth, pre-46 eclampsia, low birth weight, and maternal and neonatal mortality.5 in addition, they often have a 47 low level of education and come from poor socioeconomic status, which can lead to adverse 48 maternal and neonatal outcomes.4 in iran, adolescent pregnancy is expected to increase due to 49 the recent changes in iran’s new population policies aimed at promoting population growth and 50 increasing the young population.6 appropriate prenatal care, however, can improve pregnancy 51 outcomes among adolescent pregnant women.7 such a care aims to optimize the well-being of 52 the adolescent mother and her fetus through education and detection of pregnancy-related 53 adverse outcomes.8 adolescent pregnant women’s access to high-quality prenatal care and their 54 increased knowledge during pregnancy both empower them and decrease pregnancy problems. 55 9,10 empowerment of pregnant adolescent women can improve maternal and neonatal health 56 outcomes.11 empowerment during pregnancy includes promoting a feeling of satisfaction, 57 satisfaction, increasing independence, improving interaction with others, and increasing 58 psychological energy to achieve successful pregnancy and childbirth.12 59 60 3 in iran, prenatal care in public health centers is provided individually by a midwife, while in 61 private clinics, it may be provided by a midwife or an obstetrician. prenatal care is provided in 8 62 individual visits of 10 to 15 minutes. based on this schedule, the average total length of prenatal 63 visits is nearly two hours during pregnancy. thus, this limited time of perinatal visits does not 64 allow to meet the educational needs of pregnant women.13 65 66 group prenatal care has been considered as an efficient and effective way to provide prenatal 67 care.14 one of the known models of group prenatal care is centering pregnancy, which is a 68 woman-centered model of group prenatal care that brings women together into groups.15 group 69 prenatal care is unique in that it is a group, not a class. instead of hierarchical transmission of 70 information, group prenatal care is based on facilitation of sharing experience and knowledge by 71 healthcare providers.15 72 73 in this model of care, 8-12 women with similar gestational age meet in prenatal care sessions 74 which last approximately 60-90 minutes. the pregnant women measure their height and weight 75 and share their experiences in the group session. compared with individual prenatal care, group 76 prenatal care places emphasis on education and social support. in this model of care, pregnant 77 women are engaged in their health care and share their learning, skills, and experiences.15 78 79 evidence suggests that group prenatal care improves pregnancy outcomes such as birth weight, 80 low birth weight (lbw), preterm birth, increased breastfeeding initiation, and increased family 81 planning uptake.16-18 82 83 group prenatal care provides more time for pregnant women to improve their knowledge and 84 active participation in self-care. active participation of mothers in self-care through gpnc can 85 increased their ability to improve their decision-making, self-efficacy, and empowerment.15,19 86 87 given the importance of adolescent pregnancy empowerment in maternal and neonatal health 88 outcomes, and considering paucity of research on this issue in iran, we conducted the current 89 study to evaluate the effect of group prenatal care on adolescent pregnancy empowerment. 90 91 4 methods 92 this study was a parallel randomized controlled trial conducted between august 2021 and july 93 2022. the main objective of the study was to evaluate the effect of gpnc on the empowerment 94 of adolescent women. the specific objectives of the study were to assess the effect of group 95 gpnc on the dimensions of pregnancy empowerment, including self-efficacy, joy of an addition 96 to the family, self-esteem, future image, and support and assurance from others. this study is 97 part of a mixed-method study conducted to evaluate the effect of group prenatal care (gpnc) on 98 adolescent pregnancy outcomes in ahvaz, iran. the design of the study was approved by the 99 ethics committee of ahvaz jundishapur university of medical sciences, ahvaz, iran (ref. id: 100 ir.ajums.rec.1400.235), and it was also registered in the iranian registry for clinical trials 101 (ref no: irct20210703051764n1). each participant signed informed written consent before 102 data collection. 103 104 participants in this study included married adolescent pregnant women aged 15–19 who referred 105 to public health centers in ahvaz, southwest of iran to receive prenatal care. women were 106 eligible to participate in this study if they: were aged 15-19 years, had a gestational age of 16–22 107 weeks with singleton pregnancy, were gravida 1 or 2, and had low-risk and intended pregnancy. 108 exclusion criteria included any medical complications that classified women in high-risk 109 pregnancies such as diabetes and high blood pressure. 110 111 sample size 112 based on the objectives of the study, and according to a previous study20 assuming the power of 113 80 %, α= 0.05, the sample size was calculated to be 132 women for each group using the 114 following formula. given the possible 10% attrition rate, 147 women were considered for each 115 of the intervention and control groups. 116 117 sampling 118 the lead researcher (fm) attended the 37 public health centers existing in ahvaz and screened 119 the health records of eligible adolescent pregnant women who met the inclusion criteria. eligible 120 5 adolescents were then called by phone and were briefed on the general objectives of the study. 121 then individuals who were willing to participate in the study were invited to the health center. in 122 a face-to-face meeting, the participants were given detailed explanations about the study 123 objectives, duration, and method, along with confidentiality of information and their right to 124 withdraw from the study at any stage of the study. 125 126 randomization 127 in this study, after recruiting the eligible women, randomization was performed based on block 128 randomization method (using a random sequence computer program) with a block size of four 129 and six and an allocation ratio of 1:1. to conceal random allocation, the type of intervention was 130 written on a paper and placed inside opaque envelopes, and all envelopes were kept by a person 131 who was not involved in sampling or data collection. because of the nature of the intervention, 132 it was not possible to blind the researchers or the participants. however, both the researcher and 133 the participants did not know about the order of participation until the commencement of the 134 study. after informed consent was obtained, the participants were randomized to receive either 135 individual prenatal care (ipnc) (control group) or gpnc (intervention group) (figure 1). 136 137 setting 138 six public primary health centers (phcs) that had the largest number of adolescent pregnant 139 women among the 37 centers in ahvaz were selected for sampling. ahvaz, the capital of 140 khuzestan province, is one of the most populous cities in iran and is located in the southwest of 141 iran. 142 143 intervention 144 the first prenatal care visit was performed individually at 6–10 weeks of pregnancy. in this 145 session, the demographic questionnaire was completed through face-to-face interview. the 146 adolescents in the intervention group were classified into 25 groups. each group consists of 5 to 147 6 adolescents at approximately the same gestational age who participated in 5 sessions of 90-120 148 min during their pregnancy. 149 150 6 at the beginning of each group session, the lead researcher (fm) individually measured fundal 151 height and auscultated the fetal heart in the space of group. in the first session, adolescent 152 women were taught how to measure their blood pressure and weight. at each session, blood 153 pressure and weight were measured under the supervision of a midwife. after these 154 measurements, the discussion for the session began. the group sessions were conducted in a 155 circle. the content of the discussion was based on a prenatal care booklet issued by the iranian 156 ministry of health (table 1). groups were organized by the lead researcher. a topic that was 157 relevant to the gestational age of the group members was introduced, and the women were asked 158 to present their experiences about it. the adolescent pregnant women were encouraged to 159 participate in prenatal care educational sessions and express their ideas, knowledge, and 160 experiences with respect to care; then the necessary training was provided by the midwife in 161 simple language. the participants were also allowed to raise their questions and concerns about 162 pregnancy and childbirth. other aspects of prenatal care, such as blood and urine tests and 163 ultrasounds, were performed individually by a laboratory technician and a radiographer, and the 164 participants were not involved in these measurements. there was a “private time” at the end of 165 each session dedicated for the participants to ask private questions and for evaluation of urine 166 and blood tests or ultrasounds. the ample time spent with a midwife and peers in gpnc allowed 167 the mothers to talk freely with each other and be more comfortable asking their questions. as a 168 result, they gained a vast amount of useful information. the control group received routine 169 individual prenatal care, provided by a midwife who was employed in the health center. 170 171 measures 172 the data collection instruments were a demographic and obstetric questionnaire and the 173 empowerment scale for pregnant women. the demographic and obstetric questionnaire consisted 174 of questions about age, gestational age, gravidity, education, occupation, education and 175 occupation of the husband, and economic status. 176 177 the content validity of the demographic and obstetric questionnaire was confirmed. participants 178 in the intervention and control groups were asked to complete the demographic and obstetric 179 questionnaire at the outset of the study. the empowerment scale for pregnant women was 180 completed in two phases, namely before intervention (6-10 weeks) and after intervention (38-40 181 7 weeks), by both the intervention and the control groups. the empowerment scale for pregnant 182 women was developed by kameda et al. (2008).12 this questionnaire includes 27 questions in 183 five dimensions, namely self‐-efficacy (including 6 items related to the feeling of being able to 184 manage pregnancy and childbirth), future image (including 6 items related to the images and 185 aims regarding pregnancy, childbirth, hope for the future, and becoming a parent), self-esteem 186 (including 7 items related to acceptance of being pregnant and a mother), support and assurance 187 from others (including 4 items concerning acceptance and support) and a joy of an addition to the 188 family (including 4 items about enjoyment for the addition of a new family member). this 189 questionnaire was scored using a four-point likert scale, ranging from 1 (strongly disagree) to 4 190 (strongly agree). the total scores of the questionnaire ranged from 27 to 108. a higher score 191 indicates higher pregnancy empowerment. the validity and reliability of this questionnaire have 192 been evaluated by hajipour et al. in iran in 2012.21 in this study the internal consistency of the 193 questionnaire using cronbach's alpha was 0.72 with a sample size of forty participants. the 194 stability of the questionnaire using the test-retest method on forty participants with a two-week 195 interval was 80 percent. a midwife assisted the lead researcher with data collection. 196 197 statistical analysis 198 all data were analyzed using spss version 22. the shapiro-wilk test was used for checking the 199 normal distribution of data. the independent t test was used to compare the age, bmi, and mean 200 total score of pregnant women's empowerment in the two groups. chi-square test was used for 201 comparing categorical data such as gravidity, education, economic status, occupation, family 202 support, and extended family. logistic regression was used to detect differences between the two 203 groups in terms of pregnancy empowerment after adjusting for confounding variables. p < 0.05 204 was considered statistically significant. 205 206 ethical approval for this study was granted by the ethics committee of ahvaz jundishapur 207 university of medical sciences (ref. id: ir.ajums.rec.1400.235). 208 209 results 210 at the end of the study, five participants dropped out (the reasons are listed in fig. 1), and 289 211 participants completed the study. the socio-demographic characteristics of the participants in the 212 8 two groups of gpnc and ipnc are shown in table 1. the mean age of participants was 17.42 213 and 17.40 in the gpnc and ipnc groups, respectively (p= 0.085). most of the participants had 214 an elementary education and were categorized at a moderate level regarding their economic 215 status. the two groups did not have any significant differences in terms of age, parity, education, 216 economic status, family support, and occupation. (table 2).the mean total score of the pregnant 217 women’s empowerment of the two groups of gpnc and ipnc before intervention was 78.29 218 ±3.81 and 78.07 ±1.20 respectively (p=0.579). in addition, the two groups had no significant 219 differences regarding all dimensions of empowerment before intervention. (table 3). 220 221 the mean total score of pregnant women’s empowerment in the gpnc and ipnc groups after 222 the intervention was 86.46±4.95 and 81.89±4.75, respectively. based on the results of 223 independent ttest, a statistically significant difference between the two groups was observed 224 after intervention (p<0.0001). after the intervention, the total score of empowerment and all its 225 subscales were higher in the intervention group compared to the control group. based on the 226 result of adjusted linear regression analysis, there were significant post-intervention differences 227 between the two groups regarding the total score of empowerment and all its subscales except for 228 the subscale of “support and assurance from others”. the differences between the gpnc and 229 ipnc groups were as follows: 230 231 self-efficacy: 14.65±1.95 vs. 14.72±1.58; [β= 2.52, 95% ci : 2.19, 2.86], future image: 232 19.57±1.57 vs. 18.95±1.54 [β= 0.67, 95% ci: 0.44, 0.9), the joy of an addition a member to the 233 family:13.13±1.69 vs. 12.84±1.40 [β= 0.51, 95% ci: 0.28, 0.74], support and assurance from 234 others: 12.16±1.30 and vs. 12.28±1.21 [β= 0.76 95% ci: -0.13, 1.65, p=0.094 ) (table 3). 235 236 discussion 237 this study aimed to evaluate the effect of gpnc on adolescent pregnancy empowerment. 238 according to the results, the mean score of the “self‐efficacy” dimension improved significantly 239 in the gpnc group compared to the control group after intervention. active participation of 240 adolescent mothers in self-care increased their ability to improve their decision-making power 241 and self-efficacy which could contribute to empowerment. this finding was similar to the results 242 of heberlin et al’s study.22 furthermore, the mckinnon et al. study found that gpnc improved 243 9 maternal self-efficacy.16in contrast to our findings, however, somji et al. did not find statistically 244 significant differences in self-efficacy between the two groups.23 the difference between their 245 study and the current study could be due to the instrument used to measure pregnant women’s 246 self-efficacy. 247 248 our results also showed that the subscale of self-esteem was improved significantly in the gnpc 249 group compared to the control group. low levels of self-esteem can reduce access to healthcare 250 services and acceptance of effective interventions.24 by contrast, a high level of self-esteem is 251 effective in helping the mother cope with the challenges of pregnancy and childbirth.25 as a 252 result, it can affect the pregnant woman's experience and pregnancy outcomes.26 social support 253 increases the mother’s competence and empowerment by improving her self-esteem and 254 reducing stress during the period of transition to motherhood.27 this study revealed that gpnc 255 affected the self-esteem dimension by providing information, peers, and midwife support. this 256 finding was aligned with herman et al. who found that the information, support, and peer 257 relationships available in group care helped pregnant women to develop their skills and ability to 258 deal with stressful factors and increased promoted their self-esteem and empowerment.28 259 260 the result of the present study showed that the mean score of the “future images” dimension 261 was significantly increased in the gpnc group compared to ipnc group. the future image 262 refers to a realistic picture of the long and short-term aims of pregnancy, childbirth, and 263 motherhood.12 acquiring information and social support helped adolescent pregnant women to 264 improve their mood and self-image, reduce their worries related to pregnancy, and facilitated the 265 acceptance of childbirth.29 266 267 our results showed that the mean score of the “joy of an addition to the family” dimension in the 268 gpnc group significantly increased compared to the ipnc group after intervention. adolescent 269 pregnant women have dual feelings about pregnancy. for some pregnant adolescents, having a 270 child gives them a meaningful life, and it can help them in their transition to adulthood. 271 however, some of them consider pregnancy and motherhood as a negative event.30,31 272 273 10 the education and support provided for pregnant women through gpnc prepared them for the 274 transition to motherhood.22 therefore, it seems that gpnc in the present study could instill the 275 feeling of joy of an addition to the family in adolescent pregnant women by preparing them for 276 motherhood. 277 278 pregnant women are very concerned about their health and their baby’s well-being.32these 279 concerns are often due to inadequate information about the physical and emotional changes 280 associated with pregnancy.30 knowledge acquisition during pregnancy enables women to adapt 281 to the physical and emotional changes associated with pregnancy.32 282 283 holding group care sessions and providing ample opportunities for the mothers to talk about 284 their pregnancy concerns have been found to enhance their knowledge and reduced their 285 worries.22,33 furthermore, interaction with peers in gpnc and the exchange of information and 286 pregnancy experiences provide peer support. therefore, gpnc can lead to informational and 287 emotional support.34 of course, preserving the privacy of participants may be a concern during 288 gpnc. in the current study, none of participants had any concern about lack of privacy. 289 although, a number of studies such as sultana et al. have shown that gpnc facilitates 290 informational and emotional support from peers and health care providers,35 others including 291 kennedy et al. did not find any significant differences in social support measures, and their 292 participants wanted to have private time with the health care provider.36 in this study, although 293 adjusted linear regression analysis did not show any significant difference between the two 294 groups in terms of the subscale of support and assurance from others, there was a significant 295 difference between the two groups based on dependent t-test analysis. in the present study, it 296 seems that gpnc can promote the feeling of receiving support and approval from others. 297 298 according to the findings of this study, after intervention, the total empowerment score was 299 significantly improved in the gpnc group compared to the ipnc group. in other words, 300 compared with ipnc, gpnc has a greater effect on adolescent pregnancy empowerment. this 301 result was supported by el sayed et.al who showed a positive effect of gpnc on pregnant 302 empowerment.37additionally, the study by mckinnon et al. found that gpnc improved 303 empowerment in pregnant women.16 trudnak suggested that women in gpnc received more 304 11 education and support and were more empowered to make decisions about their pregnancy and 305 childbirth. 38 on the contrary, somji et al. found no differences between gpnc and ipnc groups 306 in terms of empowerment.23the difference between their study and the current study could be 307 attributed to the instrument used to measure pregnant women’s empowerment. 308 309 strengths and limitations of the study 310 this is the first study to evaluate the effect of group prenatal care on adolescent pregnancy 311 empowerment in iran. despite its strengths, this study has some limitations. first, the 312 participants could not be blinded to the study condition. however, we used randomization to 313 minimize bias, and the women did not know their grouping before the commencement of the 314 study. second, most of the participants in this study were from low-income families in ahvaz 315 city, and this may affect the generalizability of the results. third, the involvement of the 316 researcher in conducting the group discussion may be a source of bias. 317 318 conclusion 319 group prenatal care can improve adolescent pregnant women’s empowerment. results of the 320 present study can serve as a useful foundation for implementing the group prenatal care model in 321 iran. 322 323 author’s contribution 324 fm, pa, mi and elm were involved in the design of the study. fm collected the data. fm, ns, 325 pa, elm, and eem contributed to data analysis and interpretation. pa and fm prepared the 326 manuscript. all authors read and approved the final manuscript. 327 328 acknowledgments 329 this study was a part of phd dissertation of midwifery and is a part of a larger mixed method 330 study on the effect of group prenatal care on pregnancy outcomes, a mixed method study. the 331 authors would like to thank the research deputy of ahvaz jundishapur university of medical 332 sciences. also, we would like to thank all the women who participated in this study. 333 334 12 conflicts of interest 335 the authors declare no conflicts of interest. 336 337 funding 338 this study was supported by ahvaz jundishapur university of medical sciences (grant no: 339 rhprc-0014). 340 341 references 342 1. mann l, bateson d, black ki: teenage pregnancy. aust. j. gen. pract 2020, 49(6):310-316. 343 doi: 10.31128/ajgp-02-20-5224 344 2. shilton s, chandra-mouli v, paul s, denno dm: facilitators and barriers in the utilization of 345 world health organization’s preventing early pregnancy guidelines in formulating laws, 346 policies and strategies: what do stakeholders in ethiopia say? ijamh 2019; 347 33(5):20190028. https://doi.org/10.1515/ijamh-2019-0028. 348 3. world health organization (who). adolescent pregnancy: evidence brief, 2019. 349 https://www.who.int/news-room/fact-sheets/detail/adolescent-pregnancy. 350 4. amjad s, macdonald i, chambers t, osornio‐vargas a, et al. social determinants of health 351 and adverse maternal and birth outcomes in adolescent pregnancies: a systematic review 352 and meta‐analysis. paediatr perinat epidemiol 2019; 33(1):88-99. 353 https://doi.org/10.1111/ppe.12529. 354 5. karataslı v, kanmaz ag, inan ah, budak a, beyan e. maternal and neonatal outcomes of 355 adolescent pregnancy. j gynecol obstet hum reprod 2019; 48(5):347-350. 356 https://doi.org/10.1016/j.jogoh.2019.02.011. 357 6. karamouzian m, sharifi h, haghdoost aa: iran’s shift in family planning policies: concerns 358 and challenges. ijhpm.2014;3(5):231. https://doi: 10.15171/ijhpm.2014.81. 359 7. heaman mi, martens pj, brownell md, chartier mj, derksen sa, et al. the association of 360 inadequate and intensive prenatal care with maternal, fetal, and infant outcomes: a 361 population-based study in manitoba, canada. j obstet gynaecol can 2019; 41(7):947-362 959. https://doi.org/10.1016/j.jogc.2018.09.006. 363 8. yeo s, crandell jl, jones-vessey k. adequacy of prenatal care and gestational weight gain. j 364 womens health 2016;25(2):117-123. https://doi.org/10.1089/jwh.2015.5468. 365 https://doi.org/10.31128/ajgp-02-20-5224 https://doi.org/10.1515/ijamh-2019-0028 https://www.who.int/news-room/fact-sheets/detail/adolescent-pregnancy https://doi.org/10.1111/ppe.12529 https://doi.org/10.1016/j.jogoh.2019.02.011 https://doi.org/10.15171%2fijhpm.2014.81 https://doi.org/10.1016/j.jogc.2018.09.006 https://doi.org/10.1089/jwh.2015.5468 13 9. pereira ma, camanho as, marques rc, figueira jr: the convergence of the world health 366 organization member states regarding the united nations’ sustainable development 367 goal ‘good health and well-being’. omega 2021; 104:102495. 368 https://doi.org/10.1016/j.omega.2021.102495. 369 10. ehrhardt aa, sawires s, mcgovern t, peacock d, weston m: gender, empowerment, and 370 health: what is it? how does it work? jaids (1999) 2009; 51(suppl 3):s96. https:// 371 doi: 10.1097/qai.0b013e3181aafd54. 372 11. world health organization (who). recommendations on adolescent sexual and reproductive 373 health and rights. 2018. 374 12. kameda y, shimada k: development of an empowerment scale for pregnant women. j of the 375 tsuruma health science society kanazawa university 2008; 32(1):39-48. 376 13. kolahi a-a, abbasi-kangevari m, abdollahi m, ehdaeivand f, arshi s: pattern of prenatal 377 care utilization in tehran: a population based longitudinal study. women birth 2018; 378 31(3):e147-e151. https://doi.org/10.1016/j.wombi.2017.09.013. 379 14. obstetricians aco, gynecologists: acog committee opinion no. 731: group prenatal care. 380 obstet gynecol 2018; 131(3):616-618. doi: 10.1097/aog.0000000000002526 . 381 15. rising ss: centering pregnancy: an interdisciplinary model of empowerment. j nurse‐382 midwifery. 1998; 43(1):46-54. https://doi.org/10.1016/s0091-2182(97)00117-1. 383 16. mckinnon b, sall m, vandermorris a, traoré m, lamesse-diedhiou f, mclaughlin k, et al. 384 feasibility and preliminary effectiveness of group antenatal care in senegalese health 385 posts: a pilot implementation trial. health policy plan 2020; 35(5):587-599. 386 https://doi.org/10.1093/heapol/czz178. 387 17. byerley bm, haas dm: a systematic overview of the literature regarding group prenatal care 388 for high-risk pregnant women. bmc pregnancy childbirth 2017; 17:1-9. 389 https://doi.org/10.1186/s12884-017-1522-2. 390 18. ruiz-mirazo e, lopez-yarto m, mcdonald sd. group prenatal care versus individual 391 prenatal care: a systematic review and meta-analyses. j obstet gynaecol can 2012; 392 34(3):223-229. https://doi.org/10.1016/s1701-2163(16)35182-9. 393 19. massey z, rising ss, ickovics j: centeringpregnancy group prenatal care: promoting 394 relationship‐centered care. jognn. 2006; 35(2):286-294. https://doi.org/10.1111/j.1552-395 6909.2006.00040.x. 396 https://doi.org/10.1016/j.omega.2021.102495 https://doi.org/10.1097%2fqai.0b013e3181aafd54 https://doi.org/10.1016/j.wombi.2017.09.013 https://doi.org/10.1097/aog.0000000000002526 https://doi.org/10.1016/s0091-2182(97)00117-1 https://doi.org/10.1093/heapol/czz178 https://doi.org/10.1016/s1701-2163(16)35182-9 https://doi.org/10.1111/j.1552-6909.2006.00040.x https://doi.org/10.1111/j.1552-6909.2006.00040.x 14 20. l poorali sa, m taghi shakeri, a vatanchi, s khatami. obstetric and perinatal outcomes in 397 primigravid adolescent and adult women. ijogi. 2018; 21(4):1-7. 398 21. hajipour l, hosseini tabaghdehi m, taghizoghi z, behzadi z: empowerment of pregnant 399 women. jhnm. 2016; 26(3):16-24. 400 22. heberlein ec, picklesimer ah, billings dl, covington‐kolb s, farber n, frongillo ea. 401 qualitative comparison of women's perspectives on the functions and benefits of group and 402 individual prenatal care. jmwh. 2016; 61(2):224-234. https://doi.org/10.1111/jmwh.12379. 403 23. somji a, ramsey k, dryer s, makokha f, ambasa c, aryeh b, et al. “taking care of your 404 pregnancy”: a mixed-methods study of group antenatal care in kakamega county, 405 kenya. bmc health serv res. 2022; 22(1):1-15. https://doi.org/10.1186/s12913-022-406 08200-1. 407 24. kurniati a, chen c-m, efendi f, berliana sm: factors influencing indonesian women's use 408 of maternal health care services. health care women int 2018; 39(1):3-18. 409 https://doi.org/10.1080/07399332.2017.1393077. 410 25. raudasoja m, sorkkila m, vehviläinen-julkunen k, tolvanen a, aunola k. the role of self-411 esteem on fear of childbirth and birth experiencej reprod infant psychol.2022; 1-9. 412 https://doi.org/10.1080/02646838.2022.2115989. 413 26. jomeen j, martin cr. self-esteem and mental health during early pregnancy. clin eff nurs. 414 2005; 9(1-2):92-95. https://doi.org/10.1016/j.cein.2004.09.001. 415 27. mcleish j, redshaw m. mothers’ accounts of the impact on emotional wellbeing of 416 organised peer support in pregnancy and early parenthood: a qualitative study. bmc 417 pregnancy childbirth .2017;17(1):1-14. https://doi.org/10.1186/s12884-017-1220-0. 418 28. herrman jw, rogers s, ehrenthal db. women's perceptions of centeringpregnancy: a 419 focus group study. am j matern child nurs. 2012; 37(1):19-26. https://doi: 420 10.1097/nmc.0b013e3182385204. 421 29. regnaert gn: group prenatal care: striving for improved infant outcomes around the 422 world. 2015. 423 30. erfina e, widyawati w, mckenna l, reisenhofer s, ismail d: adolescent mothers' 424 experiences of the transition to motherhood: an integrative review. int j nurs sci 2019; 425 6(2):221-228. https://doi.org/10.1016/j.ijnss.2019.03.013. 426 https://doi.org/10.1111/jmwh.12379 https://doi.org/10.1080/07399332.2017.1393077 https://doi.org/10.1080/02646838.2022.2115989 https://doi.org/10.1016/j.cein.2004.09.001 https://doi.org/10.1016/j.ijnss.2019.03.013 15 31. kavas s: “courage in ignorance”: mothers’ retrospective accounts of early childbearing in 427 turkey. comparative population studies 2022; 47. https://doi.org/10.12765/cpos-2022-428 02 . 429 32. kamali s, ahmadian l, khajouei r, bahaadinbeigy k. health information needs of pregnant 430 women: information sources, motives and barriers. health inf. libr. j 2018; 35(1):24-37. 431 https://doi.org/10.1111/hir.12200. 432 433 33. houshmandpour m, mahmoodi z, lotfi r, tehranizadeh m, kabir k. the effect of midwife-434 oriented group counseling, based on orem’s model on self-care and empowerment, in 435 primiparous women: a clinical trial. shiraz e-med j 2019; 20(3). doi: 436 10.5812/semj.70685. 437 34. renbarger km, place jm, schreiner m. the influence of four constructs of social support on 438 pregnancy experiences in group prenatal care. womens health rep.2021; 2(1):154-162. 439 https://doi.org/10.1089/whr.2020.0113. 440 35. sultana m, ali n, akram r, jahir t, mahumud ra, sarker ar, et al. group prenatal care 441 experiences among pregnant women in a bangladeshi community. plos one 2019, 442 14(6):e0218169. https://doi.org/10.1371/journal.pone.0218169. 443 36. kennedy hp, farrell t, paden r, hill s, jolivet rr, cooper ba, et al. a randomized clinical 444 trial of group prenatal care in two military settings. mil. med. 2011; 176(10):1169-1177. 445 https://doi.org/10.7205/milmed-d-10-00394. 446 37. el sayed ha, abd-elhakam em: effect of centering pregnancy model implementation on 447 prenatal health behaviors and pregnancy related empowerment. ajn. 2018; 7(6):314-448 324. https://doi: 10.11648/j.ajns.20180706.25. 449 38. trudnak te: a comparison of latina women in centeringpregnancy and individual prenatal 450 care: university of south florida; 2011. 451 https://doi.org/10.12765/cpos-2022-02 https://doi.org/10.12765/cpos-2022-02 https://doi.org/10.1111/hir.12200 https://dx.doi.org/10.5812/semj.70685 https://doi.org/10.1089/whr.2020.0113 https://doi.org/10.1371/journal.pone.0218169 https://doi.org/10.7205/milmed-d-10-00394 16 452 figure 1: flow diagram of recruitment and retention of participants in the study. 453 454 assessed for eligibility (n = 530) eligible women giving consent randomized (n = 294) allocated to control group (n = 147) follow-up (n = 145) moved away (n = 1) intra uterine fetal death (n = 1) analyzed (n = 145) allocated to intervention group (n = 147) follow-up (n = 144) moved away (n = 1) not attending group care sessions (n = 2) analyzed (n = 144) excluded (n = 236) not meeting inclusion criteria (n = 220) declined to participate (n = 16) e n ro lm e n t a ll o c a ti o n f o ll o w -u p a n a ly si s 17 table 1: topics discussed in group prenatal care sessions. 455 sessions content first 16 to 20 wk danger signs in pregnancy, dental hygiene, discomforts and common complaints of pregnancy, nutrition, and supplement. second 24 to 30 wk mental health, sexuality third 31 to 34 wk childbirth and the benefits of natural childbirth, how to check fetal movement. fourth 35 to 37 wk preparation for childbirth, breastfeeding, neonatal care fifth 38 wk labor symptoms, the right time for the next pregnancy 456 18 table 2: socio-demographic characteristics of the participants in gpnc and ipnc groups 457 variables gpnc n=147 ipnc n=147 p value mean ± sd * or n (%) age (y) 17.42±1.31 17.40±1.28 0.858 gravidity 0.064 1 138(93.9) 135(91.8) 2 9(6.1) 12(8.2) bmi at base line(kg/m2) 22.48±2.51 22.50±2.31 0.857 education 0.769 primary 24(16.6) 21(14.3) high school 100(68) 102(69.4) high school diploma 24(16.3) 23(15.6) economic status 0.656 good 37(25.1) 42(28.6) moderate 72(49) 70(47.6) poor 38(25.9) 35(23.8) occupation 0.498 housewife 145(98.6) 147(100) employee 2(1.4) 0(0) family support 0.526 very good 124(84.4) 121(82.3) good 22(15) 25(17) fair 0(0) 1(7) inappropriate 1(0.7) 0(0) extended family 0.48 yes 118(80.3) 112(76.2) no 29(19.7) 35(23.8) * standard deviation 458 459 19 table 3: the scores of total empowerment and its dimensions in the gpnc and ipnc groups. 460 variables groups pvalue β * ci ** 95% gpnc n=147 ipnc n=147 mean ±sd self‐efficacy before 14.65±1.95 14.72±1.58 0.997 after 18.21±2.12 16.19±1.79 <0.0001 2.52 (2.19, 2.86) future image before 18.12±1.68 18.09±1.66 0.824 after 19.57±1.57 18.95±1.54 <0.0001 0.67 (0.44, 0.9) self‐esteem before 20.94±1.66 20.63±1.75 0.069 after 21.79±1.75 20.90±1.85 <0.0001 0.69 (0.41, 0.97) joy of an addition to the family before 12.36±1.28 12.34±1.22 0.986 after 13.13±1.69 12.84±1.40 0.009 0.51 (0.28, 0.74) support and assurance from others before 12.16±1.30 12.28±1.21 0.394 after 13.70±1.1 13.04±1.07 <0.0001 0.76 (0.13, 1.65) total score of empowerment before 78.29 ± 3.81 78.07 ± 1.20 0.579 after 86.46±4.95 81.89±4.75 <0.0001 6.11 (4.89, 7.33) *estimating the regression coefficient; **confidence interval 461 ’r + r5‘ قاعدة طريقة بسيطة وشاملة لتشخيص التقرن الشعاعي the ‘5r + r’ rule a simple and comprehensive method for diagnosis of actinic keratosis dear editor, actinic keratoses (aks) or ‘solar keratoses’ are cutaneous lesions that arise on areas of the skin that are chronically exposed to ultraviolet (uv) radiation [figure 1]. aks are considered early manifestations of non-melanoma skin cancer as they can progress to squamous cell carcinoma (scc) which can be invasive and life-threatening. the estimated rate of malignant conversion to scc ranges from 0.025–20% per year and increases with the number of lesions.1 ak is a prevalent disease and a major public health problem due to its growing incidence and its potential for malignant transformation.2 despite this, low awareness of the risk of malignant transformation and lack of standardised methods of diagnosis are the main challenges in ak management.3 to address this unmet need, the authors of this letter have developed a simple, yet comprehensive method of diagnosis. the reddish, rough, recurrent, cephalic region, radiation + risk (5r + r) rule is an easy-to-remember method that can be used in both primary and secondary care settings for routine clinical examinations. this formula is important during the phys ical examination as it can help physicians with regard to differentiating lesions that have a similar appearance. this mnemonic includes ‘rs’ that refer to easily identifiable predictive factors of ak [table 1]. the first ‘r’ is for ‘reddish’ and highlights the need to examine visible characteristics of ak lesions. aks typically present as eryth ematous macules, papules or plaques ranging from skin-coloured to reddish-brown.1 the second ‘r’ stands for ‘rough’ and stresses the need to explore the texture of the lesions. ak lesions are often easily recognised by palpation, presenting a rough surface with a sandpaper-like structure. both colour and thickness of lesions are among the main distinctive features of ak that correlate with clinical grading.1 the third ‘r’ is for ‘cephalic region’ which focuses on the location of ak lesions that tend to develop on the cephalic region that is constantly exposed to uv radiation such as the head and neck.1 the fourth ‘r’ is for ‘uv radiation’, which is the main risk factor for ak development due to its dna-damaging potential.1 chronic exposure to uv radiation leads to the accumulation of mutations that can ultimately result in malignant transformation. thus, lifetime sun exposure, sunburns and other related risk factors should be recorded during the initial evaluation of the patient. likewise, caregivers should check periodically all the exposed areas of the skin for signs of sun damage such as telangiectasia, wrinkles, dryness, dyschromia and elastosis.4 the fifth ‘r’ is for ‘recurrent' because with sun exposure, it is common to find recurrent lesions with a complicated management. new lesions tend to appear frequently in the same sun exposed areas even after proper treatment. this item reinforces the need to follow-up patients periodically to detect recurrent lesions.5 sultan qaboos university med j, february 2019, vol. 19, iss. 1, pp. e81–82, epub. 30 may 19 submitted 23 jan 19 revisions req. 3 feb & 24 feb 19; revisions recd. 3 feb & 26 feb 19 accepted 4 mar 19 figure 1: actinic keratosis on scalp of a patient with different clinical appearance. table 1: the reddish, rough, recurrent, cephalic region, radiation + risk rule for diagnosis of actinic keratoses 5r + r action reddish examine visible signs of ak lesions rough assess the texture and thickness of ak lesions by palpation cephalic region evaluate the location of the lesions radiation check for signs of sun-damaged skin recurrent follow-up periodically on ak lesions + risk manage the lesions to reduce the risk for malignant progression 5r + r = reddish, rough, recurrent, cephalic region, radiation + risk; ak = actinic keratosis. https://doi.org/10.18295/squmj.2019.19.01.017 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. letter to the editor https://creativecommons.org/licenses/by-nd/4.0/ the ‘5r + r’ rule a simple and comprehensive method for diagnosis of actinic keratosis e82 | squ medical journal, february 2019, volume 19, issue 1 finally, ‘+ r’ stands for major risk. although ak carries a risk for malignant transformation, this varies between studies.5 the presence of aks indicate solar damage, which increase the risk for skin cancers. therefore, the risk is not necessarily from the progression of aks to scc but from cumulative solar damage to the skin. all lesions should be managed efficiently through treatment, prevention and follow-up. unfortunately, the united states preventive services task force concluded in 2016 that there was insufficient evidence to assess the benefit and harms of visual skin examination by a clinician for screening for skin cancer in asymptomatic adults.4 nevertheless, the chronic and progressive nature of aks implies a careful examination and periodic review in patients with an increased risk of non-melanoma skin cancer.4,6 the ‘5r + r’ rule is intended to familiarise caregivers with ak diagnosis by proposing a comprehensive method which allows for easy recall. the implementation of this method in clinical practice will require clinical studies demonstrating that routine eval uations of patients following the ‘5r + r’ rule increases early ak detection and decreases the incidence of recurrence and malignant progression. javier dominguez-cruz1 and *ricardo ruiz-villaverde2 1department of dermatology, hospital universitario virgen del rocio, seville, spain; 2department of dermatology, hospital universitario san cecilio, granada, spain *corresponding author’s e-mail: ismenios@hotmail.com references 1. siegel ja, korgavkar k, weinstock ma. current perspective on actinic keratosis: a review. br j dermatol 2017; 177:350–8. https://doi.org/10. 1111/bjd.14852. 2. marks r, rennie g, selwood ts. malignant transformation of solar keratoses to squamous cell carcinoma. lancet 1988; 1:795–7. https://doi.org/10. 1016/s0140-6736(88)91658-3. 3. olsen ea, abernethy ml, kulp-shorten c, callen jp, glazer sd, huntley a, et al. a double-blind, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. j am acad dermatol 1991; 24:738–43. https://doi.org/10. 1016/0190-9622(91)70113-g. 4. werner rn, stockfleth e, connolly sm, correia o, erdmann r, foley p, et al. evidenceand consensus-based (s3) guidelines for the treat ment of actinic keratosis international league of dermatological societies in cooperation with the european dermatology forum short version. j eur acad dermatol venereol 2015; 29:2069–79. https://doi.org/10.1111/jdv.13180. 5. fernández-figueras mt, carrato c, sáenz x, puig l, musulen e, ferrándiz c, et al. actinic keratosis with atypical basal cells (ak i) is the most common lesion associated with invasive squamous cell carcinoma of the skin. j eur acad dermatol venereol. 2015; 29:991-7. https://doi.org/10.1111/jdv.12848. 6. rigel ds, stein gold lf. the importance of early diagnosis and treatment of actinic keratosis. j am acad dermatol 2013; 68:s20–7. https://doi.org/10.1016/j.jaad.2012.10.001. https://doi.org/10.1111/bjd.14852 https://doi.org/10.1111/bjd.14852 https://doi.org/10.1016/s0140-6736%2888%2991658-3 https://doi.org/10.1016/s0140-6736%2888%2991658-3 https://doi.org/10.1016/0190-9622%2891%2970113-g https://doi.org/10.1016/0190-9622%2891%2970113-g https://doi.org/10.1111/jdv.13180 https://doi.org/10.1111/jdv.12848 https://doi.org/10.1016/j.jaad.2012.10.001 department of dermatology, aga khan university hospital, karachi, pakistan *corresponding author’s e-mail: sabeikaraza@gmail.com ومحة بشروية التنظيم وثنائية اجلانب تقرير حالة �سبيكة ر�سا كرياواال، جنم ال�ساهر ر�سوي، �سعدية تب�سم abstract: verrucous epidermal nevi (ven) are benign congenital hamartomas consisting of keratinocytes. histological examination mostly exhibits hyperkeratosis, acanthosis, papillomatosis and, rarely, the features of epidermolytic hyperkeratosis (ehk). we report a case of a 6-year-old boy who presented at aga khan university hospital, karachi, pakistan with bilaterally symmetrical linear epidermal nevi following blaschko’s lines and showing epidermolytic hyperkeratosis on histology. the patient was treated with topical keratolytics and emolients which led to considerable improvement. to the best of the authors’ knowledge, this is the first report of ven from pakistan. keywords: verrucous epidermal nevus; mosaicism; epidermolytic hyperkeratoses; hamartoma; case report; pakistan. امللخ�ص: لوحمات الب�رشوية الثوؤلولية هي اأورام عابية خلقية حميدة تتكون من اخلاليا الكرياتينية. يعر�ض علم االأن�سجة يف الغالب فرط التقرن وال�سواك والورم احلليمي ونادرا ما تكون �سمات فرط التقرن احلال للب�رشة. نعر�ض هنا تقرير حالة ل�سبي يبلغ من العمر 6 �سنوات م�ساب بوحمة ب�رشوية خطية متناظرة ثنائية تتبع خطوط بال�سكو ويظهر فيها فرط التقرن احلال للب�رشة بح�سب الن�سجيات. على حد علمنا، يعترب هذا التقرير االأول للوحمات الب�رشوية الثوؤلولية من باك�ستان. الكلمات املفتاحية: وحمة ب�رشوية ثوؤلولية؛ ف�سي�سائية؛ فرط التقرن احلال للب�رشة؛ ورم عابي؛ تقرير حالة؛ باكستان. bilateral systematised epidermolytic epidermal nevus a case report *sabeika r. kerawala, najam-us-saher rizvi, saadia tabassum sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e124–126, epub. 15 mar 21 submitted 16 apr 20 revision req. 3 jun 20; revision recd. 25 jun 20 accepted 7 jul 20 case report a 6-year-old boy presented to the dermatology clinic in karachi, pakistan with a warty eruption involving his axillae, genitalia, hands and legs but sparing the face, scalp, palms and soles. he was born healthy, full-term and via vaginal delivery from a non-consanguineous marriage. there was no history of collodion membrane, erythroderma or blistering at birth. he had four other siblings, none of whom were affected. he had no hearing loss or other developmental delay. after two months, he developed lesions initially involving only one knee and it progressively spread to other parts of the body during a span of six years. on examination, thick, dry, adherent, hyperpigm ented verrucous scaly plaques were present on his neck, axilla, dorsum of hands and ankles, cubital fossa, flexural and extensor surfaces of elbows and knees [figures 1 and 2]. the rash had a bilaterally symmetrical distribution. the lesion was more prominent on the left lower half of the anterior trunk extending along the mid-line of the genitalia. at all sites, the lesions followed blaschko’s lines. the palms, soles, face, hair and nails were normal. there was no history of mental retardation or any skeletal abnormalities. a biopsy of the epidermal nevi are congenital hamartomas of embryonal ectodermal origin. verrucous epidermal nevi (ven) are composed of hamartomatous proliferation of keratinocytes.1 vens are characterised by skin-coloured to tan verrucous papules and plaques arranged in a blaschkoid pattern [table 1]. the term systematised is used for linear lesions present on more than one site according to levers classification of epidermal nevus.2 bilaterally symmetric ven is also called ichthyosis hystrix. the characteristic histopathology of epidermal nevi exhibits varying acanthosis degrees, papillomatosis and hyperkeratosis and, infrequently, epidermolytic hyperkeratosis.3 epidermolytic epidermal nevi are rare and are thought to exhibit a mosaic form of the congenital ichthyosis, bullous ichthyosiform eryth roderma (bie). we present a case of a 6-year-old boy with bilaterally symmetrical ven following the blaschko’s lines but sparing the face and palmoplantar skin. histology showed features of epidermolytic hyper keratosis. this report intends to highlight the rarity of the clinical presentation and characteristic histology of this case. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.018 case report https://creativecommons.org/licenses/by-nd/4.0/ sabeika r. kerawala, najam-us-saher rizvi and saadia tabassum case report | 125 plaque from the area below the knee showed marked hyperkeratosis, focal coronoid lamella and papillomatosis of the epidermis. the upper layers of the epidermis showed a prominent granular layer, perinuclear vacuolisation and abundant keratohyalin granules in the cytoplasm of keratinocytes. the nuclei were basophilic while the deeper part of the epidermis had usual lining and scattered melanocytes at the basal layer. however, the dermis was unremarkable [figure 3]. based on the above constellation of clinical features and histopathologic findings, a diagnosis of ichthyosis hystrix type of epidermal nevus (systematised type of epidermal nevus) was made. the presence of focal coronoid lamella, previously thought to be specific for porokeratosis, has also been reported in linear epidermal nevus.4 the patient was prescribed topical keratolytics in combination with emollients that led to considerable improvement. prior consent was obtained from the patient’s father for publication of this case. discussion epidermal nevi may be sebaceous, apocrine, eccrine, follicular or keratinocytic. all epidermal nevi are the expressions of a somatic mutation in the genes that regulate cell growth and division. approximately 60% of the epidermal nevi are linear ven, also called keratinocytic nevi.5 the term systematised linear epidermal nevus is used for linear nevi present on more than one body part.2 recently, keratinocytic epidermal nevi are subclassified, based on histology, into epidermolytic and non-epidermolytic.6 the term epidermolytic hyper keratosis, or granular degeneration of the epidermis, refers to a distinctive pattern of compact hyperkeratosis, perinuclear vacuolisation of keratinocytes of the upper layers of epidermis and coarse keratohyalin granules.7 this histologic pattern was seen in several congenital and acquired clinical disorders. the congenital conditions include bullous congenital ichthyosiform erythroderma of brocq, ichthyosis bullosa of siemens, epidermolytic palmoplantar keratoderma of vörner and epithelial nevi. ehk is present in about 5–10% of epidermal nevi and tends to be more warty.7 ven may occur as part of an epidermal nevus syndrome that includes central nervous system and skeletal abnormalities; however, a literature review showed that the epidermolytic variant of epidermal nevus does not have any extracutaneous features.8 mishra et al. reported epidermolytic epidermal nevus in a 3-year-old boy who had no history of blistering at birth and had no extracutaneous features.9 similar findings were evident in the current case. paller et al. found mutations in the k10 gene in lesional skin of patients with epidermolytic epidermal table 1: lesions following a blaschkoid pattern macules and patches papules and plaques incontinentia pigmenti lichen striatus hypomelanosis of ito adult blaschkitis linear and whorled nevoid hypermelanosis darier’s disease nevus depigmentosis linear ven linear fixed drug eruption inflammatory linear ven linear psoriasis linear lichen planus ven = verrucous epidermal nevi. figure 1: verrucous hyperpigmented linear plaques in a 6-year-old boy involving (a) bilateral cubital fossae, axillae, (b) lower abdomen and (c & d) flexural and extensor surfaces of knee joints. figure 3: haemtoxylin and eosin stains showing epidermolytic hyperkeratosis in a 6-year-old boy with (a) focal coronoid lamella at x100 magnification and (b) papillomatosis of the epidermis at x40 magnification. figure 2: hyperpigmented papules and plaques on the (a) dorsum of feet and (b) neck following blaschko’s lines. bilateral systematised epidermolytic epidermal nevus a case report 126 | squ medical journal, february 2021, volume 21, issue 1 nevus, while their offspring who had generalised ehk also had this mutation in 50% of all cell types examined.10 tsubota et al. reported k1 gene mutation in a japanese boy with extensive epidermal nevi with ehk.11 these findings led to the idea that a post-zygotic mutation in one of the bie genes, keratin 1 or keratin 10, occurs in a clone of cells in ven.10–12 mutation analysis was not available at the hospital where the patient presented and therefore was not performed. bie is a rare autosomal dominant disorder of keratinisation which is characterised by blisters and erythroderma at birth. as the child grows, these are gradually replaced by hyperkeratotic pigmented plaques mostly on the joints, scalp and neck. despite their histologic alikeness to bie, patients with epidermolytic ven do not have blistering at birth, which was also evident in the current case.12 patients with this type of epidermal nevus may have offspring that have features of classic bie.1 the clinical features of epidermolytic ven resemble non-epidermolytic ven, the verrucous stage of incontinentia pigmenti, ichthyosis bullosa of siemens and ichthyosis hystrix of curth and macklin.9 the lesions of incontinentia pigmenti follow blaschko’s lines and progress through four different clinical stages (i.e. bullous, verrucous, hyperpigmentation and hypopigmentation). it shows eosinophilic spongiosis on histology. ichthyosis bullosa of siemens is a rare hyperkeratotic blistering condition caused by a mutation in the keratin 2e gene. it is a mild variant of bie and especially involves the flexural sites. areas of skin peeling showing the “mauserung phenomenon” is typical.13 ichthyosis hystrix of curth and macklin exhibits extensive spiky hyperkeratosis with palmoplantar keratoderma and the histology shows hyperkeratosis, binucleate keratinocytes and papillomatosis without epidermolysis.14 treatment of systematised epidermal nevus is largely symptomatic. topical therapies with cortico steroids, retinoic acid, 5-fluorouracil, calcipotriol and podophyllin have been reported.7 abdel aal and happle et al. studied the effect of oral retinoids in systematised ven and found improvement with etretinate within a month and complete regression in 80 days.15,16 surgical excision, carbon dioxide laser and cryotherapy treatment have shown recurrences.7 conclusion we reported a rare case of bilateral symmetrical ven with epidermolytic hyperkeratosis on histology. the nevi are always sporadic and not transmitted to the next generation; however, if the mutation occurs in gonadal cells, the offspring of patients with ven can develop bullous icthyosiform erythroderma. therefore, the patient should be counselled at an appropriate age. extensive skin involvement is also associated with an increased risk of germ-line transmission. references 1. moss c, shahidullah h, burns t, breathnach s, cox n, griffiths c. rook's textbook of dermatology. new jersey, usa: blackwell publishing ltd, 2010. p. 58–60. 2. dhanaraj m, ramalingam m. systematised epidermal nevus a case report. j clin diagn res 2015; 9:wd01. https://doi. org/10.7860/jcdr/2015/9190.5510. 3. boyd as. tumors of the epidermis. in: barnhill rl, crowson an, magro cm, piepkorn mw, eds. dermatopathology, 3rd ed. new york, usa: mcgraw hill medical, 2010. pp. 556. 4. tiwary ak, mishra dk. a unique porokeratotic variant of inflammatory linear verrucous epidermal nevus. indian j paediatr dermatol 2017; 18:237. https://doi.org/10.4103/23197250.206088. 5. rogers m, mccrossin i, commens c. epidermal nevi and the epidermal nevus syndrome. a review of 131 cases. j am acad dermatol 1989; 20:476–88. https://doi.org/10.1016/s01909622(89)70061-x. 6. inamadar ac, palit a, ragunatha s. textbook of paediatric dermatology. new delhi, india: jaypee hights medical pub inc, 2014. p. 470. 7. sarifakioglu e, yenidunya s. linear epidermolytic verrucous epidermal nevus of the male genitalia. pediatr dermatol 2007; 24:447–8. https://doi.org/10.1111/j.1525-1470.2007.00481.x. 8. asch s, sugarman jl. epidermal nevus syndromes: new insights into whorls and swirls. pediatr dermatol 2018; 35:21–9. https://doi.org/10.1111/pde.13273. 9. mishra v, saha a, bandyopadhyay d, das a. bilateral system atized epidermolytic verrucous epidermal nevus: a rare entity. indian j dermatol 2015; 60:397–9. https://doi.org/10.4103/001 9-5154.160495. 10. paller as, syder aj, chan ym, yu qc, hutton e, tadini g, et al. genetic and clinical mosaicism in a type of epidermal nevus. n engl j med 1994; 331:1408–15. https://doi.org/10.1056/ nejm199411243312103. 11. tsubota a, akiyama m, sakai k, goto m, nomura y, ando s, et al. keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis. j invest dermatol 2007; 127:1371–4. https://doi.org/10.1038/sj.jid.5700712. 12. moss c, jones do, blight a, bowden pe. birthmark due to cutaneous mosaicism for keratin 10 mutation. lancet 1995; 345:596. https://doi.org/10.1016/s0140-6736(95)90510-3. 13. whittock nv, ashton gh, griffiths wa, eady ra, mcgrath ja. new mutations in keratin 1 that cause bullous congenital ichth yosiform erythroderma and keratin 2e that cause ichthyosis bullosa of siemens. br j dermatol 2001; 145:330–5. https://doi. org/10.1046/j.1365-2133.2001.04327.x. 14. richard g, ringpfeil f. ichthyoses, erythrokeratodermas, and related disorders. in: bolognia jl, jorizzo jl, rapini rp, eds. dermatology. philadelphia, usa: mosby/elsevier, 2008. pp. 912–16. 15. abdel aal ma. treatment of systematized verrucous epidermal naevus by aromatic retinoid (ro. 10–9359). clin exp dermatol 1983; 8:647–50. https://doi.org/10.1111/j.1365-2230.1983.tb01835.x. 16. happle r, kastrup w, macher e. systemic retinoid therapy of systematized verrucous epidermal nevus (with 1 colour plate). dermatologica 1977; 155:200–5. https://doi.org/10.1159/0002 50999. https://doi.org/10.7860/jcdr/2015/9190.5510 https://doi.org/10.7860/jcdr/2015/9190.5510 https://doi.org/10.4103/2319-7250.206088 https://doi.org/10.4103/2319-7250.206088 https://doi.org/10.1016/s0190-9622%2889%2970061-x https://doi.org/10.1016/s0190-9622%2889%2970061-x https://doi.org/10.1111/j.1525-1470.2007.00481.x https://doi.org/10.1111/pde.13273 https://doi.org/10.4103/0019-5154.160495 https://doi.org/10.4103/0019-5154.160495 https://doi.org/10.1056/nejm199411243312103 https://doi.org/10.1056/nejm199411243312103 https://doi.org/10.1038/sj.jid.5700712 https://doi.org/10.1016/s0140-6736%2895%2990510-3 https://doi.org/10.1046/j.1365-2133.2001.04327.x https://doi.org/10.1046/j.1365-2133.2001.04327.x https://doi.org/10.1111/j.1365-2230.1983.tb01835.x https://doi.org/10.1159/000250999 https://doi.org/10.1159/000250999 1department of child health, sultan qaboos university, muscat, oman; 2department of pediatric cardiology, national heart center, muscat, oman *corresponding author’s e-mail: alsineidiksk@hotmail.com إغالق ثقوب احلاجز البطيين عرب اجللد يف 116 مريضًا جتربة إستخدام وسائل إغالق خمتلفة خلفان �سامل ال�سنيدي، �سامل امل�سكري، اإينب توما�س، بوري�س دمييرتوف، عبد اهلل الفرقاين abstract: objectives: this study aimed to review the experience with percutaneous closure of ventricular septal defects (vsds) at the national heart center (nhc) in muscat, oman. methods: this retrospective study was conducted from november 2008 to december 2017. patients’ electronic medical records were reviewed to identify their clinical, imaging and interventional data before and after the procedure and on the last followup. results: a total of 116 patients, the majority of which were female (58%), underwent 118 percutaneous procedures for vsd closure at a median age of 3.54 years (range: 0.25–33 years) and a median weight of 12 kg (range: 3.5–78 kg). the mean diameter of the vsds as determined by transoesophageal echocardiogram was 5.6 ± 1.9 mm (n = 105). the commonest type of vsd was perimembranous (n = 75, 63.5%). devices were successfully placed during 111 (94.1%) procedures in 109 (94.0%) patients, with the commonest device being a amplatzer™ duct occluder i (st. jude medical, little canada, minnesota, usa; n = 39, 35.1%). there was no mortality. early major cardiac complications occurred in six patients (5.5%) with device embolisation being the commonest (n = 4, 3.7%). the median follow-up period was 19 months (range: 1–84 months) in 89 (81.7%) of the patients. one patient (0.9%) required a permanent pacemaker for a complete heart block. conclusion: this study has demonstrated a good rate of vsd closure with low morbidity and no mortality using the percutaneous approach with different devices. long-term follow-up is needed to specifically evaluate the function of adjacent structures and the long-term effects on conduction systems. keywords: ventricular septal defect; percutaneous coronary intervention; amplatzer occluder device; vascular closure device; heart block; oman. مب�سقط، للقلب الوطني املركز يف اجللد عرب البطيني احلاجز ثقوب اإغالق جتربة اإ�ستعرا�س اىل الدرا�سة هذه هدفت الهدف: امللخ�ص: الإلكرتونية الطبية ال�سجالت مراجعة متت .2017 دي�سمرب اإىل 2008 نوفمرب من ة ال�ْسِتَعاِديَّ الدرا�سة هذه اأجريت الطريقة: ُعمان. للمر�سى لتحديد البيانات ال�رسيرية والت�سويرية والتدخلية قبل وبعد العملية واأثناء اآخر متابعة للمري�س. النتائج: خ�سع ما جمموعه 116 مري�سا لـ 118 عملية عرب اجللد لإغالق ثقوب احلاجز البطيني وكان غالبيتهم من الإناث )%58( مبتو�سط عمر 3.54 �سنة )املدى: 33-0.25 �سنة( ومتو�سط وزن 12 كجم )املدى: 78-3.5 كجم(. كان متو�سط قطر ثقب احلاجز البطيني ح�سبما حدده خمطط �سدى القلب عرب املرئ هو 1.9 ± 5.6 مم )عدد: 105( وكان الثقب حول الغ�ساء هو اكرث اأنواع ثقوب احلاجز البطيني �سيوعا )عدد: 75، %63.5(. مت و�سع و�سائل الغالق بنجاح خالل 111 )%94.1( عملية لـ 109 )%94.0( مري�سا وكان اكرث و�سائل الغالق �سيوعا هي �سدادة جمرى حدثت وفيات. هناك يكن مل .)35.1% ،39 عدد: الأمريكية، املتحدة الوليات ميني�سوتا، كندا، ليتل جود، )�سانت اأمبالتزر نوع من فرتة متو�سط بلغ .)3.7% ،4 = )عدد �سيوًعا الأكرث هو ال�سدادة اإن�سمام وكان )5.5%( مر�سى �ستة يف مبكرة ُعظَمى قلبية م�ساعفات املتابعة 19 �سهًرا )املدى: 84-1 �سهًرا( يف 89 )%81.7( مري�سا. احتاج مري�س واحد )%0.9( اإىل ناظمة قلبية دائمة ب�سبب اإِْح�سار َقْلِبي تام. اخلال�صة: اأظهرت هذه الدرا�سة معدل جيدا لإغالق ثقوب احلاجز البطيني بوا�سطة م�سلك عرب اجللد با�ستخدام و�سائل اإغالق خمتلفة طويلة والتاأثريات املجاورة الرتاكيب وظيفة لتقييم الأجل طويلة متابعة اإىل حاجة هناك وفيات، حدوث وعدم منخف�سة َمَرا�سة مع املدى على اأنظمة التو�سيل الكهربائي للقلب ب�سكل خا�س. الكلمات املفتاحية: ثقب احلاجز البطيني؛ تدخل عرب اجللد؛ و�سيلة اغالق اأمبالتزر؛ اإِْح�ساُر الَقْلب؛ ُعمان. percutaneous closure of ventricular septal defects in 116 patients experience with different devices *khalfan s. al senaidi,1 salim al maskary,2 eapen thomas,2 boris dimitrov,2 abdullah al farqani2 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e352–359, epub. 21 dec 20 submitted 15 jan 20 revisions req. 17 mar & 6 may 20; revisions recd. 8 apr & 17 may 20 accepted 20 may 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.012 clinical & basic research advances in knowledge the results of this study revealed that percutaneous closure of ventricular septal defects (vsds) can be performed safely with limited complications. this study may serve as a reference point for future research on this subject. application to patient care this study provides evidence that percutaneous vsd closure is safe and effective with low risk of complete heart block. https://creativecommons.org/licenses/by-nd/4.0/ khalfan s. al senaidi, salim al maskary, eapen thomas, boris dimitrov and abdullah al farqani clinical and basic research | e353 ventricular septal defect (vsd) is the most common type of congenital heart disease with an incidence of 3–3.5 per 1,000 live births; almost 80% of these vsds are perimembranous.1–3 closure is indicated when the vsd is haemodynamically significant to prevent future complications, including ventricular dysfunction, arrhythmias and pulmonary arterial hypertension.4 surgical approaches traditionally have been the mainstay of therapy in closing vsds.2,3,5,6 surgical approaches, however, have been associated with morbidity and mortality, patient discomfort, sternotomy and scarring.5–8 the transcatheter approach gained cardiologists’ special interest over the last decade due to its encouraging results.9–12 this study aimed to review experiences with percutaneous vsd closure at the national heart center (nhc) of oman. methods this retrospective study included all patients who underwent percutaneous vsd device closure at the nhc from november 2008 to december 2017. medical records were reviewed for clinical evaluation data and findings from electrocardiograms, trans thoracic electrocardiograms (ttes) and transoeso phageal echocardiograms (tees) before and after the intervention and on the last follow-up. the catheter isation database was reviewed to identify patients who underwent attempted transcatheter vsd closure. angiograms and cardiac catheterisation reports were analysed to determine haemodynamics and procedural characteristics. all cardiac catheterisations were done under general anaesthesia by a transfemoral approach under tee guidance. follow-ups were done at one, three and six months post-procedure and then yearly. a successful procedure was defined as one in which a stable device was successfully positioned across the defect with no complications to adjacent structures and no significant residual shunt. adverse events and complications were assessed intraoperatively, before discharge and on subsequent follow-up visits. technical details of the procedure were followed according to a previously established protocol.13 statistical package for the social sciences (spss), version 25.0 (ibm, corp., armonk, new york, usa) was used to analyse the data, which were described as mean ± standard deviation. median and range were used to describe continuous variables and categorical data were expressed as frequencies with percentages. an association analysis of procedure results and risk factors was done. dependent outcome variables were analysed to determine whether procedures were successful, the incident of total early complications and the occurrence of device embolisation. independent variables included in the analysis were patients’ age at the procedure, weight and gender. also included in the analysis was the defect diameter as measured on tte and whether patients were diagnosed with ventricular septal aneurysm. univariate analysis was performed using binary logistic regression. multivariable analysis to study risk factors for the occurrence of dependent variables was performed using multiple logistic regression. odds ratios (or) and their 95% confidence intervals were calculated for the independent variables. differences were considered statistically significant at p <0.05. the study was approved by the royal hospital’s institutional review board. results a total of 116 patients, of which 67 (58%) were female, underwent 118 percutaneous procedures (two patients underwent two device placements) for vsd closure at a median age of 3.54 years (range: 0.25–33 years) and had a median weight of 12 kg (range: 3.5–78 kg) [table 1]. nine patients were over 18 years of age with a mean age of 24.5 ± 3.4 years and a mean weight of 66 ± 8 kg. perimembranous vsd was commonest (n = 75; 63.5%). devices were successfully placed in 109 (94.0%) patients during 111 (94.1%) procedures. the mean diameter of the defects from the right ventricular side was 5.7 ± 2.1 mm (n = 109) as determined by tte and 5.6 ± 1.9 mm (n = 105) as determined by tee [table 2]. mild tricuspid valve regurgitation was present prior to closure in 34 (31.2%) patients and was determined to be moderate in three (2.8%) cases. aortic valve regurgitation was mild in three (2.8%) patients. in total, 56 (51.4%) cases had aneurysmal tissues from the right ventricle side. procedures were abandoned in seven patients (five males and two females) at a median age of 1.7 years (range: 0.58–22 years) and a median weight of eight kg (range: 4–60 kg). abandonment was due to various reasons including haemodynamic instability and hypotension in three patients, worsening aortic regurgitation in one patient, improper orientation and compaction of the device across the defects in two patients and incidental finding of an interrupted inferior vena cava in one patient. in this last patient, the procedure was attempted via a jugular venous approach, which was unsuccessful. analysis of risk factors using univariate analysis revealed that only a larger diameter of the vsd, as determined by tte, was a significant predictor of procedure failure; successful procedures involved vsds with a mean diameter of five mm (range: 2.5– percutaneous closure of ventricular septal defects in 116 patients experience with different devices e354 | squ medical journal, november 2020, volume 20, issue 4 14 mm) while unsuccessful procedures had a mean diameter of eight mm (range: 5–14 mm; p <0.01). multivariable analysis also showed that a larger vsd diameter was a significant predictor for procedure failure (or: 1.60, 95% ci: 1.11–2.30; p = 0.01) [table 3]. all closures were performed through a trans femoral approach. arterio-venous looping was done in 104 (93.7%) procedures, whereas in six (5.4%) procedures the closure was done by a retrograde approach from the femoral artery. in one patient (0.9%), the device was deployed directly from a right ventricular approach. the most common devices used were the amplatzer™ duct occluder i (st. jude medical, little canada, minnesota, usa; adoi) in 39 (35.1%) procedures and the amplatzer™ duct occluder ii (st. jude medical; adoii) in 26 (23.4%) [table 2]. the mean duration of stay in hospital was 2.0 ± 1.6 days. no procedure-related deaths were recorded. immediate complete closure was achieved in 52 (46.8%) procedures, which increased to 69 (62.2%) at day one post-procedure and to 79 out of 89 patients (88.8%) at last follow-up. procedure or device-related complications occurred in 10 (9.2%) patients. of these cases, early major cardiac complications within 12 hours of the procedure occurred in six patients (5.5%); device embolisation occurred in four patients (3.7%). severe tricuspid valve regurgitation occurred in one patient (0.9%); the sixth patient in the series developed severe tricuspid valve stenosis (0.9%). five patients required surgical retrieval of devices (4.6%). in one patient, the device was retrieved by a snare table 1: characteristics of the study population (n = 118 procedures)* characteristic n (%) p value total procedures unsuccessful procedures median age in years (range) 3.54 (0.25–33) 1.7 (0.58–22) 0.48 median weight in kg (range) 12 (3.5–78) 8 (4–60) 0.49 gender 0.13 male 49 5 female 67 2 age in years ≤1 20 (16.9) 2 (1.7) 1–13 81 (68.6) 4 (3.4) 13–18 8 (6.8) 0 (0) ≥18 9 (7.6) 1 (0.8) vsd type perimembranous 75 (63.5) 6 (5.1) high muscular 23 (19.5) 0 (0) mid muscular 9 (7.6) 0 (0) residual postsurgery 7 (5.9) 0 (0) inlet 3 (2.7) 1 (0.8) residual postdevice 1 (0.8) 0 (0) vsd = ventricular septal device. *procedures were carried out in 116 patients; there were seven unsuccessful procedures. table 2: procedural data and devices used for percutaneous closure of ventricular septal defects (n = 111 procedures)* variable n (%) mean ± sd procedure vsd diameter (rv) via tte in mm 109 (98.2) 5.7 ± 2.1 vsd diameter (lv) via tee in mm 46 (41.4) 8.6 ± 2.5 vsd diameter (rv) via tee in mm 105 (94.6) 5.6 ± 1.9 vsd diameter via angiogram in mm 103 (92.8) 5.7 ± 2 mpa pressure in mmhg 79 (71.2) 21 ± 8 lvedp in mmhg 93 (83.8) 10 ± 3.5 qp:qs 87 (78.4) 2 ± 1:1 vsd device adoi 39 (35.1) adoii 26 (23.4) amvsd 16 (14.4) apmvsd 14 (12.6) pfm coil 8 (7.2) cdo 7 (6.3) aso 1 (1.0) device size (lv) in mm 8.7 ± 2.5 device size (rv) in mm 6.7 ± 2.2 sd = standard deviation; vsd = ventricular septal defect ; rv = right ventricle; tte = transthoracic echocardiography; lv = left ventricle; tee = transoesophageal echocardiography; mpa = main pulmonary artery; lvedp = left ventricular end diastolic pressure; qp = pulmonary flow; qs = systemic flow; ado = amplatzer™ duct occluder (st. jude medical, little canada, minnesota, usa); amvsd = amplatzer™ muscular ventr icular septal defect occluder(st. jude medical); apmvsd = amplatzer™ perimembranous ventricular septal defect occlude (st. jude medical); cdo = cocoon duct occlude; aso = amplatzer™ atrial septal occlude (st. jude medical). *procedures were carried out in 109 patients. procedures were abandoned in seven patients due to haemodynamic instability and hypotension in three patients, worsening aortic regurgitation in one patient, improper orientation and compaction of the device across the defects in two patients and incidental finding of an interrupted inferior vena cava in one patient (procedure was attempted via a jugular venous approach but was unsucc essful). khalfan s. al senaidi, salim al maskary, eapen thomas, boris dimitrov and abdullah al farqani clinical and basic research | e355 table 3: univariate and multivariate analysis of risk factors for successful percutaneous closure of ventricular septal defect (n = 118) variable univariate p value multivariate p value procedure success yes no or 95% ci 111 7 median age in years (range) 4 (0.25–33) 1.7 (0.58–21.6) 0.48 1.01 0.67–1.52 0.10 age less than one year 0.41 1.72 0.17–17.70 0.65 yes 18 2 no 93 5 median weight in kg (range) 13 (3.5–78) 8 (4–60) 0.49 1.02 0.86–1.22 0.81 weight less than 10 kg 0.26 6.33 0.38–105.1 0.20 yes 40 4 no 71 3 gender 0.13 0.30 0.05–1.80 0.19 male 45 5 female 66 2 vsd aneurysm present 0.28 a0.68 0.10–4.68 0.69 yes 56 2 no 55 5 median vsd size via tte in mm (range) 5 (2.5–14) 8 (5–14) <0.01 1.60 1.11–2.30 0.01 or = odds ratio; ci = confidence interval; vsd = ventricular septal defect; tte = transthoracic electrocardiogram. table 4: details of early complications after percutaneous closure of ventricular septal defect no. age in months gender weight in kg vsd type vsd size in mm device type (size) adverse event outcome 1 20 m 8.9 pmvsd 9 adoi (10/8) embolisation surgical retrieval 2 6 m 12 pmvsd 9 adoi (12/10) embolisation surgical retrieval 3 14 f 7.4 pmvsd 6 apmvsd (8) embolisation catheter retrieval; same device used 4 13 m 11.2 pmvsd 4 pfm coil (8/6) embolisation catheter retrieval 5 5 f 3.5 pmvsd 4 adoii (5/4) severe tr and severe residual shunt surgical removal and repair 6 36 f 11.7 mm 11 amvsd (12) severe ts surgical removal 7 11 m 5.3 pmvsd 5 pfm coil (10/6) haemolysis and severe residual shunt second device placed (adoii) 8 10 f 5.7 pmvsd 7.5 apmvsd (10) haemolysis improved 9 6 f 4.2 hm 9 amvsd (12) transient seconddegree block improved but chb 21 months later 10 12 m 39 hm 7 adoi (12/10) urinary bladderinjury required surgical exploration of urinary bladder vsd = ventricular septal defect; pmvsd = perimembranous ventricular septal defect; ado = amplatzer™ duct occluder (st. jude medical, little canada, minnesota, usa); apmvsd = amplatzer™ membranous ventricular septal defect occlude (st. jude medical); tr = tricuspid regurgitation; mm = mid muscular ventricular septal defect; amvsd = amplatzer™ muscular ventricular septal defect occlude (st. jude medical); ts = tricuspid stenosis; hm = high muscular ventricular septal defect; chb = complete heart block. percutaneous closure of ventricular septal defects in 116 patients experience with different devices e356 | squ medical journal, november 2020, volume 20, issue 4 table 5: univariate and multivariate analysis of risk factors for early complications of percutaneous closures of ventr icular septal defects (n = 111) variable univariate p value multivariate p value early complications yes no or 95% ci 10 101 median age in years (range) 1.38 (0.33–13.67) 4.42 (0.25–33) 0.11 0.91 0.58–1.42 0.67 age less than one year old 0.06 0.39 0.06–2.73 0.35 yes 4 15 no 6 86 median weight in kg (range) 8.15 (3.5–39) 14 (3.5–78) 0.14 1.01 0.85–1.18 0.96 weight less than 10 kg 0.10 1.54 0.17–13.87 0.70 yes 6 34 no 4 67 gender 0.53 0.66 0.14–3.03 0.59 male 5 40 female 5 61 vsd aneurysm present 0.53 2.31 0.45–11.84 0.32 yes 6 50 no 4 51 median vsd size via tte in mm (range) 6 (3.6–12) 5 (2.5–14) 0.17 1.29 0.95–1.75 0.11 or = odds ratio; ci = confidence interval; vsd = ventricular septal defect; tte = transthoracic electrocardiogram. table 6: univariate and multivariate analysis of risk factors for device embolisation (n = 111) variable univariate p value multivariate p value embolisation present yes no or 95% ci 4 107 median age in years (range) 1.71 (1.08–4.17) 4.33 (0.25–33.08) 0.23 0.05 0.01–5.29 0.21 age less than one year old 0.100 1.38 0.18–14.70 0.100 yes 0 19 no 4 88 median weight in kg (range) 10.05 (7.4–12) 13.50(3.5–78) 0.30 0.61 0.11–3.37 0.57 weight less than 10 kg 0.54 0.16 0.00–184.29 0.61 yes 2 38 no 2 69 gender 0.19 0.17 0.03–9.48 0.40 male 3 42 female 1 65 vsd aneurysm present 0.34 11.18 0.19–647.12 0.24 yes 3 53 no 1 54 median vsd size via tte in mm (range) 6 (3.6–12) 5 (2.5–14) 0.23 1.42 0.77–2.66 0.26 khalfan s. al senaidi, salim al maskary, eapen thomas, boris dimitrov and abdullah al farqani clinical and basic research | e357 catheter. an early significant residual shunt occurred in two (1.8%) patients. pre-existing mild tricuspid valve regurgitation did not change post-procedure. however, moderate regurgitation was detected in two (1.8%) patients. early aortic valve regurgitation was mild in two (2%) patients, although the condition was pre-existing; another patient also had an early mild aortic valve regurgitation before the procedure which improved. complete heart block (chb) was detected in only one patient (0.9%), a symptomatic sixmonth-old girl weighing 4.2 kg with an 11-mm long anterior muscular vsd. a 12-mm amplatzer™ (st. jude medical) muscular vsd (amvsd) occluder was used. however, after releasing the device, a transient 2:1 atrioventricular block was noted. the block improved and the patient was discharged two days later. she presented 21 months later with a recurrence of chb with a heart rate of 56 beats/minute for which a permanent pacemaker was placed. her follow-ups prior to the presentation were completely normal [table 4]. follow-up was possible in 89 (81.7%) patients with a median follow-up period of 19 months (range: 1–84 months). all patients improved clinically. the assessment of risk factors for the occurrence of early complications and device embolisation using univariate and multivariate logistic regression analyses showed no statistically significant association with independent predictors [tables 5 and 6]. discussion percutaneous closure of vsds has gained popularity in the last few years. the procedure has many advantages, but it is not without challenges. in this study, different types of vsds were closed, but the perimembranous type was the most common (63.5%). the reported success rate of the procedure in the literature is high; butera et al. and holzer et al. reported successful closure rates of approximately 96% and 93%, respectively.14,15 the current study found a comparable successful closure rate of 94.1%. the percutaneous approach for vsd closure is challenging in small patients and there are no clear guidelines about the best approaches to use or what devices to select. choosing the correct procedure to use in addressing vsds depends on many factors. infants with low body weight are often referred for surgery. diab et al. reported a series of infants less than one year of age; the smallest infant undergoing a purely percutaneous approach was 3.8 kg.16 narin et al. reported successful percutaneous closure in 12 infants less than 12 months of age using this approach in infants as small as three kg, although one patient in their series developed chb six months post-procedure.17 in the current study, the youngest patient was a symptomatic male aged three months old and weighing 3.5 kg. this patient had a large (eight mm) residual mid muscular post-surgical vsd closed using a 10 mm amvsd occluder uneventfully. the researchers have observed a trend of early complications in younger patients; however, the number of complications among these younger patients was not statistically significance (p = 0.06). holzer et al. reported that patients “with a weight below 10 kg had a significantly higher incidence of adverse events than patients with a weight above 10 kg (58.3% versus 25.0%, p = 0.0285)”.15 therefore, interventionists should be extremely careful in smaller infants in selecting the types of devices and sizes to use when dealing with vsds. moreover, current devices should be improved to reduce complications in this group. appropriate device selection is of fundamental importance to achieve safe closure when dealing with vsds.18 the current researchers primarily select devices based on vsd morphology with preferences for ductal devices for vsds in membranous/upper muscular locations and muscular vsd devices for muscular vsds. adoii, with its softer profile, should be used for vsds close to the aortic valve. it has been observed that 51.4% of the defects had aneurysmal tissues from the right ventricle. in the majority of cases, the researchers aim to deploy the device within the aneurysm if it is large enough to avoid encroaching on the aortic valve. furthermore, the researchers use devices with a smaller right ventricular disc such as duct occluders to avoid entrapment of the tricuspid valve. however, the number of fenestrations and the strength of the aneurysm are limiting factors. the current study, though, did not show the presence of an aneurysm to be a predictor for procedure success or for the occurrence of complications. early complications were observed in 10 (9.2%) patients but fortunately, no deaths occurred. six (5.5%) patients required surgical removal of the devices and repair of the defects with no sequelae. in the current study, there was a relatively small number of patients with large defects. the rate of early complications was comparable to other published literature. butera et al. reported 13 early significant complications in 12 patients (11.5%); two of these complications were related to device embolisation.19 in the current study, no variables were observed which predicted early complications in the analysis model, but valvular regurgitation or stenosis were found to be more concerning complications with device closures. tricuspid, mitral and aortic valve impingement have also been described in the literature. holzer et al. reported an early new or increasing tricuspid and percutaneous closure of ventricular septal defects in 116 patients experience with different devices e358 | squ medical journal, november 2020, volume 20, issue 4 aortic valve regurgitation at a rate of 9.2% for each complication; however, almost all of these patients’ complications were found to have improved on last follow-up.15 in the current series, the tricuspid valve was most commonly involved (n = 2, 1.8%). these complications were mainly related to the relatively larger right sided disc. both patients underwent surgical retrieval of the devices and uneventful vsd patch closure. this finding emphasises again the need to carefully evaluate both semilunar and atrioventricular valves prior to device release. however, not all devicerelated valvular complications can be detected prior to release due to the reconfiguration of the device once the tension of the delivery cable has been released.15 chb is a known significant concerning compl ication post-perimembranous-vsd closure. in the current study, the rate was low (0.9%). holzer et al. and arora et al. observed rates of 2%, 1.9%, respectively.15,20 the proposed mechanism for intraprocedural heart block occurring may be direct mechanical injury by the device, while post-procedural occurrences may be due to local inflammation, oedema and fibrosis triggered by ventricular retention discs.17,18 the patient who developed chb in the current study was small with low body weight and a relatively larger device with two discs. the current researchers believe that the use of ductal devices with just one disc (e.g. adoi) is a major reason for the low incidence of chb in this study; however, further studies are needed to confirm this phenomenon. importantly, it is challenging to completely avoid heart block given the anatomic predisposition toward such defects, especially in patients with perimembranous vsd or in cases where the device is relatively large with large retention discs. regular follow-up is needed as heart block can manifest as a late complication following a procedure even when the immediate post-procedural recovery is uneventful. this study was subject to certain limitations. it was retrospective and limited by the potential for missing data. in addition, the group was not homogenous as it included both paediatric and adult patients so findings cannot be generalised to one particular age group. furthermore, this study is a single-centre study so findings may not be generalisable to larger populations. midterm and follow-up data, however, were reported. conclusion this study has demonstrated a good closure rate of vsds with low morbidity and no mortality using the percutaneous approach with different devices. longterm follow-up is needed to specifically evaluate the function of adjacent structures and the long-term effects of devices on the conduction system. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g m e n t the authors would like to thank dr hashim javad and dr hussain al safar for reviewing this manuscript. references 1. hoffman ji, kaplan s. the incidence of congenital heart disease. j am coll cardiol 2002; 39:1890–900. https://doi.org/10.1016/ s0735-1097(02)01886-7. 2. warnes ca, williams rg, bashore tm, child js, connolly hm, dearani ja, et al. acc/aha 2008 guidelines for the manage ment of adults with congenital heart disease: a report of the american college of cardiology/american heart association task force on practice guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). circulation 2008; 118:e714–833. https://doi.org/10.10 16/j.jacc.2008.10.001. 3. baumgartner h, bonhoeffer p, de groot nm, de haan f, deanfield je, galie n, et al. esc guidelines for the management of grown-up congenital heart disease (new version 2010). eur heart j 2010; 31:2915–57. https://doi.org/10.1093/eurheartj/ ehq249. 4. kidd l, driscoll dj, gersony wm, hayes cj, keane jf, o'fallon wm, et al. second natural history study of congenital heart defects. results of treatment of patients with ventricular septal defects. circulation 1993; 87: i38–51. 5. monro jl, alexiou c, salmon ap, keeton br. reoperations and survival after primary repair of congenital heart defects in children. j thorac cardiovasc surg 2003; 126:511–20. https:// doi.org/10.1016/s0022-5223(03)00115-6. 6. bol-raap g, weerheim j, kappetein ap, witsenburg m, bogers aj. follow-up after surgical closure of congenital ventricular septal defect. eur j cardiothorac surg 2003; 24:511–15. https://doi. org/10.1016/s1010-7940(03)00430-5. 7. andersen hø, de leval mr, tsang vt, elliott mj, anderson rh, cook ac. is complete heart block after surgical closure of ventricular septum defects still an issue? ann thorac surg 2006; 82:948–56. https://doi.org/10.1016/j.athoracsur.2006.04.030. 8. nygren a, sunnegårdh j, berggren h. preoperative evaluation and surgery in isolated ventricular septal defects: a 21 year perspective. heart 2000; 83:198–204. https://doi.org/10.1136/ heart.83.2.198. 9. lock je, block pc, mckay rg, baim ds, keane jf. transcatheter closure of ventricular septal defects. circulation 1988; 78:361–8. https://doi.org/10.1161/01.cir.78.2.361. 10. bass jl, kalra gs, arora r, masura j, gavora p, thanopoulos bd, et al. initial human experience with the amplatzer perimem branous ventricular septal occluder device. catheter cardiovasc interv 2003; 58:238–45. https://doi.org/10.1002/ccd.10406. 11. walavalkar v, maiya s, pujar s, ramachandra p, siddaiah s, spronck b, et al. percutaneous device closure of congenital isolated ventricular septal defects: a single-center retrospective database study amongst 412 cases. pediatr cardiol 2020; 41:591–8. https://doi.org/10.1007/s00246-020-02315-0. https://doi.org/10.1016/s0735-1097%2802%2901886-7 https://doi.org/10.1016/s0735-1097%2802%2901886-7 https://doi.org/10.1016/j.jacc.2008.10.001 https://doi.org/10.1016/j.jacc.2008.10.001 https://doi.org/10.1093/eurheartj/ehq249 https://doi.org/10.1093/eurheartj/ehq249 https://doi.org/10.1016/s0022-5223%2803%2900115-6 https://doi.org/10.1016/s0022-5223%2803%2900115-6 https://doi.org/10.1016/s1010-7940%2803%2900430-5 https://doi.org/10.1016/s1010-7940%2803%2900430-5 https://doi.org/10.1016/j.athoracsur.2006.04.030 https://doi.org/10.1136/heart.83.2.198 https://doi.org/10.1136/heart.83.2.198 https://doi.org/10.1161/01.cir.78.2.361 https://doi.org/10.1002/ccd.10406 https://doi.org/10.1007/s00246-020-02315-0 khalfan s. al senaidi, salim al maskary, eapen thomas, boris dimitrov and abdullah al farqani clinical and basic research | e359 12. bentham jr, gujral a, adwani s, archer n, wilson n. does the technique of interventional closure of perimembranous ventricular septal defect reduce the incidence of heart block? cardiol young 2011; 21:271–80. https://doi.org/10.1017/ s1047951110002039. 13. diab ka, cao ql, hijazi zm. device closure of congenital ventricular septal defects. congenit heart dis 2007; 2:92–103. https://doi.org/10.1111/j.1747-0803.2007.00080.x. 14. butera g, chessa m, carminati m. percutaneous closure of ventricular septal defects. cardiol young 2007; 17:243–53. https://doi.org/10.1017/s1047951107000431. 15. holzer r, de giovanni j, walsh kp, tometzki a, goh t, hakim f, et al. transcatheter closure of perimembranous ventricular septal defects using the amplatzer membranous vsd occluder: immediate and midterm results of an international registry. catheter cardiovasc interv 2006; 68:620–8. https://doi. org/10.1002/ccd.20659. 16. diab ka, cao ql, mora bn, hijazi zm. device closure of muscular ventricular septal defects in infants less than one year of age using the amplatzer devices: feasibility and outcome. catheter cardiovasc interv 2007; 70:90–7. https://doi.org/10.1 002/ccd.21142. 17. narin n, pamukcu o, tuncay a, baykan a, sunkak s, tasci o, et al. percutaneous ventricular septal defect closure in patients under 1 year of age. pediatr cardiol 2018; 39:1009–15. https:// doi.org/10.1007/s00246-018-1852-5. 18. santhanam h, yang l, chen z, tai bc, rajgor dd, quek sc. a meta-analysis of transcatheter device closure of perimem branous ventricular septal defect. int j cardiol 2018; 254:75–83. https://doi.org/10.1016/j.ijcard.2017.12.011. 19. butera g, carminati m, chessa m, piazza l, micheletti a, negura dg, et al. transcatheter closure of perimembranous ventricular septal defects: early and long-term results. j am coll cardiol 2007; 50:1189–95. https://doi.org/10.1016/j.jacc.2 007.03.068. 20. arora r, trehan v, kumar a, kalra gs, nigam m. transcatheter closure of congenital ventricular septal defects: experience with various devices. j interv cardiol 2003; 16:83–91. https:// doi.org/10.1046/j.1540-8183.2003.08006.x. https://doi.org/10.1017/s1047951110002039 https://doi.org/10.1017/s1047951110002039 https://doi.org/10.1111/j.1747-0803.2007.00080.x https://doi.org/10.1017/s1047951107000431 https://doi.org/10.1002/ccd.20659 https://doi.org/10.1002/ccd.20659 https://doi.org/10.1002/ccd.21142 https://doi.org/10.1002/ccd.21142 https://doi.org/10.1007/s00246-018-1852-5 https://doi.org/10.1007/s00246-018-1852-5 https://doi.org/10.1016/j.ijcard.2017.12.011 https://doi.org/10.1016/j.jacc.2007.03.068 https://doi.org/10.1016/j.jacc.2007.03.068 https://doi.org/10.1046/j.1540-8183.2003.08006.x https://doi.org/10.1046/j.1540-8183.2003.08006.x department of dental and maxillofacial surgery, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sayednabeel@squ.edu.om مضاعفات قلع الرحى الثالثة دراسة استعادية من مركز رعاية صحية ثالثي يف ُعمان نبيل �صيد، عبد�لعزيز باكثري، حمبوب با�صا، �صامل �ل�صديري abstract: objectives: this retrospective study aimed to investigate complications associated with the extraction of third molars at a tertiary healthcare centre in oman. methods: all consecutive patients who underwent extraction of one or more impacted third molars under general anaesthesia at sultan qaboos university hospital, muscat, oman, between january 2007 and december 2017 were included. age, gender, indication for extraction, teeth removed, procedure and complications were recorded. results: a total of 1,116 third molars (56% mandibular and 44% maxillary) were extracted and the majority (67.7%) were from female patients. the mean age at extraction was 24 ± 5 years and most patients (77.7%) were 20‒29 years old. the intraoperative and postoperative complication rates were 3.7% and 8.3%, respectively. the intraoperative complications included tuberosity fracture (1.2%), root fracture (1.1%), bleeding (0.7%), soft tissue injury (0.5%) and adjacent tooth damage (0.2%). postoperative complications were sensory nerve injuries (7.2%), swelling/pain/trismus (0.6%) and dry socket (0.5%). nerve injury was temporary in 41 patients and permanent in four cases. a statistically significant relationship was observed between those aged 30‒39 years and dry socket (p = 0.010) as well as bone removal and all postoperative complications (p = 0.001). conclusion: most complications resulting from third molar extractions were minor and within the reported ranges in the scientific literature. however, increased age and bone removal were associated with a higher risk of complications. these findings may help to guide treatment planning, informed consent and patient education. keywords: third molar; tooth extraction; complications; lingual nerve; inferior alveolar nerve; oman. امللخ�ص: الهدف: هدفت هذه �لدر��صة �ال�صتعادية �إىل �لتحقيق يف �مل�صاعفات �ملرتبطة بقلع �لرحى �لثالثة يف مركز رعاية �صحية ثالثي يف �لعام �لتخدير حتت �أكرث �أو و�حدة منح�رصة ثالثة رحى لقلع خ�صعو� �لذين �ملتتالني �ملر�صى جميع ت�صمني مت ُعمان. الطريقة: يف و�الأ�صنان �لقلع، ودو�عي و�جلن�س، �لعمر ت�صجيل مت .2017 ودي�صمرب 2007 يناير بني عمان م�صقط، قابو�س، �ل�صلطان جامعة م�صت�صفى �ملقلوعة، و�الإجر�ء و�مل�صاعفات. النتائج: مت قلع ما جمموعه 1,116 من �الأرحاء �لثالثة )%56 من �لفك �ل�صفلي و %44 من �لفك �لعلوي( وكان غالبية )%67.7( �ملر�صى من �الإناث. كان متو�صط �لعمر عند �لقلع هو 24 ± 5 �صنو�ت وكان معظم �ملر�صى )%77.7( ترت�وح �أعمارهم �مل�صاعفات و�صملت �لتو�يل. على 8.3% و 3.7% �جلر�حية �لعملية بعد وما �لعملية �أثناء �مل�صاعفات معدالت كانت �صنة. 29-20 بني �ملجاورة �الأ�صنان وتلف )0.5%( �لرخوة �الأن�صجة و�إ�صابة ،)1.2%( �الأحدوبة وك�رص ،)0.7%( و�لنزيف ،)1.1%( �جلذر ك�رص �لعملية �أثناء )%0.2(. و�صملت م�صاعفات ما بعد �جلر�حة تورم/�أمل/�زضز )%0.6(، و�ِصْنٌخ جاف %0.5( و�إ�صابات �لع�صب �حل�صي )%7.2(. كانت �إ�صابة �لع�صب موؤقتة يف 41 مري�صا ود�ئمة يف �أربع حاالت. وقد لوحظ وجود عالقة معتد بها �إح�صائيا بني �لذين ترت�وح �أعمارهم بني 39-30 �صنة و�ل�صنخ �جلاف )p = 0.01( وكذلك بني �إز�لة �لعظم وجميع م�صاعفات ما بعد �لعملية �جلر�حية )p = 0.001(. اخلال�صة: كانت معظم �مل�صاعفات �لناجمة عن قلع �لرحى �لثالثة ب�صيطة و�صمن �لنطاقات �لو�ردة يف �الأدبيات �لعلمية. ومع ذلك، �رتبط �لتقدم بالعمر و�إز�لة �لعظم بارتفاع خطر حدوث �مل�صاعفات. قد ت�صاعد هذه �لنتائج يف توجيه تخطيط �لعالج و�ملو�فقة �مل�صتنرية وتثقيف �ملري�س. الكلمات املفتاحية: �لرحى �لثالثة؛ قلع �ل�صن؛ م�صاعفات؛ �لع�صب �لل�صاين؛ �لع�صب �ل�صنخي �ل�صفلي؛ ُعمان. complications of third molar extraction a retrospective study from a tertiary healthcare centre in oman *nabeel sayed, abdulaziz bakathir, mehboob pasha, salim al-sudairy sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e230–235, epub. 5 nov 19 submitted 9 jan 19 revision req. 19 feb 19; revision recd. 13 mar 19 accepted 2 apr 19 advances in knowledge this study supports the available worldwide literature on the complications of third molar extractions in oman. to the best of the authors’ knowledge, the present study is the first to highlight the complications of third molar extractions in oman. application to patient care indications for the removal of third molars and the anticipated outcome should be carefully reviewed during treatment planning. this study represents a continued movement towards the use of evidence-based medicine to discuss and explain outcomes, complications and the risk-benefit ratios with patients before any procedure. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.009 clinical & basic research third molars are the most frequently impacted teeth and might fail to erupt into a normal functional position.1 the prevalence of impacted third molars ranges between 16.7–68.6% across various populations.2–9 studies from the gulf region have reported an impacted third molars rate of 32–40.5%.8,9 a recently published study from oman found that 54.3% of young omani adults between https://creativecommons.org/licenses/by-nd/4.0/ nabeel sayed, abdulaziz bakathir, mehboob pasha and salim al-sudairy clinical and basic research | e231 19–26 years old have at least one impacted third molar.10 extraction of third molars is one of the most common procedures performed by oral surgeons. generally, these surgeries do not encounter difficulties but at times can result in complications; a complication rate of 4.6–30.9% following the extraction of third molars is reported in the literature.11–15 complications may occur intraoperatively or develop during the post operative period. intraoperative complications may include bleeding, damage to adjacent teeth, injury to surrounding tissues, displacement of teeth into adjacent spaces, fracture of the root, maxillary tuberosity or the mandible. postoperative complications may include swelling, pain, trismus, prolonged bleeding, dry socket, infection and sensory alterations of the inferior alveolar nerve (ian) or lingual nerve (ln). to the best of the authors’ knowledge, this is the first study in oman to determine the complications associated with third molar extraction. reporting the associated complications in the omani population is vital, given the reported high prevalence of impacted third molars that may require future extraction. there fore, this study aimed to investigate the various compl ications associated with third molar extraction at sultan qaboos university hospital (squh), muscat, oman. methods this retrospective analytical study was conducted at squh between january 2007 and december 2017 and included all consecutive patients who underwent removal of one or more impacted third molars under general anaesthesia (ga). patient’s records were coll ected using the trakcare electronic patient record (epr) system (intersystems corporation, cambridge, massachusetts, usa). all procedures were performed by consultant oral and maxillofacial surgeons and their designated subordinates who were trained to extract third molars. all patients underwent standard surgical protocol. patients with known bleeding diathesis or who were taking medications which prolonged bleeding were prepared and optimised prior to the procedure and necessary local haemostatic measures were used in all such cases. in the current cases, bleeding was not included as an intraoperative complication. the extraction technique involved the removal of third molars with or without mucoperiosteal flap elev ation and lingual flap retraction, bone removal and tooth sectioning using surgical drills, elevators and/or forceps. after tooth extraction, the sockets were irrigated with chlorhexidine, bony irregularities were corrected and surgical wounds were closed using absorbable sutures. following the procedure, detailed postoperative instructions were given to the patients and suitable antibiotics and analgesics were prescribed. routine follow-up was done after three weeks and, in case of complications, extended follow-up was arranged. clinically significant intraoperative bleeding was managed by applying pressure, packing with surgicel® (ethicon inc., somerville, new jersey, usa) and suturing the sockets. the study variables were age, gender, teeth removed, an indication for extraction, surgical procedure and complications. microsoft excel, version 16.0 (microsoft corp., redmond, washington, usa) was used to create a record of all data collected during the course of this study. all data were analysed using statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). the relationship between study variables and complications and between intra operative and postoperative complications were analysed using chi-squared and fisher’s exact tests. ethical approval was obtained from the ethics committee of the college of medicine and health sciences, sultan qaboos university, muscat, oman (mrec #1239). all data, including patient identification, history and other details remained confidential. results a total of 337 patients had at least one third molar extracted under ga at squh during the study period. from those patients, a total of 1,116 third molars were extracted with the majority (67.7%) from female patients. the mean age of the subjects was 24 ± 5 years (range: 15–55 years) and most (77.7%) were 20–29 years old. the average number of teeth extracted per patient was 3.3 ± 0.9 and 56% were mandibular third molars. the most common indication for molar extraction was pericoronitis (34.1%); in 35.3% of records the reason for removal was not mentioned. approx imately half of third molars (50.4%) were surgically extracted and involved buccal and distal bone removal with or without sectioning the tooth. among nonsurgically extracted teeth, most were maxillary third molars [table 1]. in this study, the rate of intraoperative and postoperative complications was 3.7% and 8.3%, respectively. most intraoperative complications were minor with tuberosity fractures (1.2%) being the most common, followed by fractures of the apical third of the root (1.1%) and bleeding (0.7%). postoperative complications were either inflammatory in nature (1.1%)—included swelling, pain, trismus and dry socket—or related to nerve injuries (7.2%) [table 2]. complications of extraction of third molars a retrospective study e232 | squ medical journal, august 2019, volume 19, issue 3 among the 625 extracted mandibular third molars, 45 cases reported nerve injuries, of which the majority (91.1%) were temporary injuries (ln = 71.1%; ian = 20%), and few (8.9%) were permanent injuries (ln = 6.7%; ian = 2.2%). based on the total extracted mandibular third molars, the overall rate of permanent nerve dam age was found to be 0.7% (ln = 0.5%; ian = 0.2%), while the overall temporary nerve damage was 6.5% (ln = 5.1%; ian = 1.4%). among the ln injury cases, all except four resolved within six months after the procedure. among the ian injury cases, all except two resolved within the first three months after the procedure. three cases of ln injury (0.5%) and one case of ian injury (0.2%) had no recovery of sensation during the twoyear follow-up period and were considered permanent injuries [figure 1]. a statistically significant relationship was observed between patients aged 30–39 years and dry socket (p = 0.010) as well as between bone removal and all postoperative complications (p = 0.001). no other variables, intraoperative complications or post operative complications showed statistically significant relationships. figure 1: timeline of postoperative recovery for lingual nerve and inferior alveolar nerve injuries. ln = lingual nerve; ian = inferior alveolar nerve. table 1: preoperative and intraoperative characteristics of patients who underwent extraction of third molars at sultan qaboos university hospital, muscat, oman bet ween january 2007 and december 2017 (n = 337) characteristic n (%) gender male 109 (32.3) female 228 (67.7) age range in years <20 35 (10.4) 20‒29 262 (77.7) 30‒39 35 (10.4) ≥40 5 (1.5) indication for extraction decay/pulpitis 14 (4.2) chronic pain 42 (12.5) pericoronitis 115 (34.1) cheek bite 16 (4.7) adjacent tooth decay 5 (1.5) orthodontic 11 (3.3) pathology 3 (0.9) prophylactic 8 (2.4) temporomandibular joint disorders 4 (1.2) unknown 119 (35.3) location of extracted third molars (n = 1,116) maxilla 491 (44) mandible 625 (56) average per patient 3.3 operative approach* simple elevation 554 (49.6) bone removal 512 (45.9) tooth sectioning 223 (20) *percentages do not add up to 100% as multiple approaches may have been used. table 2: type and frequency of complications following extraction of third molars complication frequency percentage by patient (n = 337) percentage by tooth (n = 1,116) intraoperative complications root fracture 12 3.6 1.1 bleeding 8 2.4 0.7 tuberosity fracture 6 1.2 1.2* soft tissue injury 6 1.1 0.5 damage adjacent tooth 2 0.6 0.2 postoperative complications swelling/pain/ trismus 7 2.1 0.6 dry socket 6 1.8 0.5 ln injury 35 10.4 5.6† ian injury 10 3.0 1.6† ln = lingual nerve; ian = inferior alveolar nerve. *n = 491 (number of maxillary third molars); †n = 625 (number of mandibular third molars). nabeel sayed, abdulaziz bakathir, mehboob pasha and salim al-sudairy clinical and basic research | e233 discussion complications associated with third molar removal are not uncommon in dental and maxillofacial surgical procedures. complications vary from minor inflamm atory reactions such as pain and swelling to nerve damage, mandibular fracture and severe life-threatening infections.16 in the current study, the overall intra operative and postoperative complication rates were 3.7% and 8.3%, respectively. the majority of reported complications were minor and transient in terms of overall patient health. these complication rates were within the ranges reported in the literature. most studies mainly reported postoperative rather than intraoperative complication rates. azenha et al. demonstrated an overall complication rate of 10.4%, while bui et al. and muhonen et al. reported postoperative complication rates of 9.8% and 9.1%, respectively.12,17,18 the current study showed that complications associated with mandibular third molar extraction occurred more frequently than with maxillary third molars. of the 98 complications documented, 79 (80.6%) were associated with mandibular third molars. most studies related to complications of third molar removal have stated similar findings.12–15 in this study, intraoperative complications were encountered in 40 cases. there were 12 cases of unretrieved root fractures; the root fragments were usually fragments of the apical third and were in close proximity to vital structures such as the inferior alveolar canal (iac) or the maxillary sinus and required additional bone removal for retrieval with possible risk of damage to adjacent structures. in the postoperative period, none of these cases reported any secondary complications. clinically significant intraoperative bleeding was encountered in eight cases (0.7%) in the current study, which is comparable to the reported range of 0.2–5.8%.11 bui et al. determined that the frequency of unexpected haemorrhage was 0.6% and an american age-related third molar study reported a frequency of 0.7%.12,13 the variability of reported rates could be due to the varying definitions and parameters of estimating bleeding. the current study found six cases of tuberosity fracture, all of which were managed conservatively. six cases of soft tissue injury that occurred due to tearing of the adjacent oral mucosal tissue were managed by primary closure. iatrogenic damage to an adjacent tooth was encountered in two cases; in one of those cases, the coronal restoration of an adjacent tooth was fractured. teeth with large restorations or carious lesions are at risk of fracture or damage upon elevation (rate: 0.3–0.4%).15 in the second case of iatrogenic damage, the adjacent second molar was luxated from its socket, which was repositioned and stabilised. during follow-up, it was found to have satisfactory stability without the need for further treatment. furthermore, none of the intraoperative complications revealed any statistically significant association with postoperative complications. the most commonly reported postoperative complication of third molar removal in the literature are dry socket, infection, bleeding and sensory disturb ances due to nerve injuries.11–23 in the present study, the overall postoperative complication rate was 8.3%. extraction of third molars is often associated with expected and typically transient postoperative pain, swelling and trismus; however, at times, this pain may present beyond the first postoperative week and may require additional treatment such as placement of a dressing or administration of antibiotics during a follow-up visit.11 seven such cases were found in the current study based on subjective findings mentioned in the epr. in these cases, the symptoms gradually resolved with supportive measures. the literature reports a frequency of dry socket ranging from 0.3–26% for all extractions and is known to occur more frequently following third molar extraction.11–14 some controlled studies have reported a rate of up to 25–30% after the extraction of mandibular third molars.19 several studies have suggested that increased age, being female, the use of oral contraceptives, smoking, surgical trauma and pericoronitis are risk factors for dry socket.14,19–21 the current study had a relatively low rate of dry socket (0.5%), with all cases occurring in relation to mandibular third molars and four occurred in patients aged 30–39 years old. however, contrary to published literature, dry socket occurred in four males who were non-smokers and two females who were not on oral contraceptives. injuries to the ian and ln are well-known and are frequently occurring complications of third molar extraction. this type of injury is often troubling to both patients and surgeons and may result in considerable morbidity and litigation.22 previous studies have shown widely ranging rates of ln and ian injuries (0–23% and 0.4–8.1%, respectively).12,15,22,23 in the present study, the ln and ian injury rates were 5.6% and 1.6%, respectively. in ln injury, patients usually have a loss of sensation on the affected side of the tongue. in a cadaveric study, kiesselbach and chamberlain found the position of ln to be highly inconsistent, making patients vulnerable to damage throughout the procedure (i.e., during incision, mucoperiosteal flap elevation, lingual flap retraction, tooth sectioning, tooth extraction and suturing).24 complications of extraction of third molars a retrospective study e234 | squ medical journal, august 2019, volume 19, issue 3 in the current cases that had ln injury, the corresponding third molars had been surgically extracted and involved mucoperiosteal flap elevation, lingual flap retraction and bone removal. however, lingual flap retraction and ln injury did not show any statistically significant relationship. there was progressive improvement in the follow-up period with spontaneous resolution of symptoms of ln injury, with most cases resolving within the first three post operative months and 88.6% of cases resolved within six months. in one case, there was a delayed resolution of 12 months; in another case, lns were bilaterally affected and then resolved within one month. in three cases, no improvement was observed in tongue numbness after a two-year follow-up period and these cases were classified as having permanent damage. in cases of ian injury, patients usually have a loss of sensation in the lower lip with or without chin involvement on the affected side. in addition, patients may also present with tingling, tickling or burning sensations. proximity of the third molars to the iac is the most predictive factor for ian injury.22 in the current study, all cases of ian injury radiographically showed that the roots of the extracted teeth were in close proximity to the iac. however, there was no statistically significant relationship between ian injury and proximity of the corresponding tooth to the iac. among all patients who reported with ian injury, the majority (90%) recovered within 3–6 months. in one case, there were no signs of improvement in lip numbness after a two-year follow-up period; thus, this numbness was regarded as permanent damage. in this study, the rate of permanent neurosensory damage to the ln and ian was 0.5% and 0.2%, respectively, which is in line with rates in the literature.22,25 patient factors (e.g. age, medical status, medication regimens and social habits), tooth factors (e.g. type of impaction and tooth position), operative factors (e.g. duration, technique and surgeon experience) and anaesthetic factors (e.g. local and general anaesthesia) have been reported as being associated with compl ications of third molar extraction.11,12 however, there was no statistical relationship in the current study between any of these factors and complications, except age and removal of bone. patients aged 30–39 years had higher rates of dry socket in this study, which is in agreement with published studies.21 rood suggested that permanent damage to the ian and ln was significantly related to bone removal with a surgical drill.26 this suggestion was consistent with the findings from the present study where there was a statistically significant relationship between bone removal and nerve injuries. brann et al. and costantinides et al. found that the rates of ln and ian damage were more frequent when mandibular third molars were extracted under ga compared to local anaesthesia.27,28 this finding could be due to surgical difficulty, preoperative pathology, age or anat omic position.27 postoperative infections after third molar extr action have been frequently reported in the literature, with rates ranging from 0.8–4.2%.11 however, no cases of postoperative infection were encountered in the current study. this study has some limitations. cases of third molar removal performed under local anaesthesia were excluded; including these cases could have resulted in a bigger sample size and more comprehensive compl ication data. furthermore, as this study was retro spective, cases with limited or missing data were encoun tered. a more complete data set could have helped analyse complications more precisely if information had been available detailing anatomic and radiographic positions of teeth, position of the ian, indications for removal, social history including smoking, surgical difficulties and surgeon experience. this shortcoming highlights the necessity for more comprehensive record maintenance and further studies that should include more parameters, such as risk factors that can affect treatment outcome; this may help in minimising complications in third molar extraction. conclusion this retrospective study is the first to analyse the various complications associated with third molar extraction in oman. the results suggest that most complications of third molar extraction are minor and within ranges reported in the literature. however, increased age and bone removal were found to increase the risk of postoperative complications. hence, a careful review of the indications and the necessity of an extraction should be considered preoperatively. these findings may help to improve treatment planning and patient education. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. reference 1. miloro m, ghali ge, larsen pe, waite pd. peterson’s principles of oral and maxillofacial surgery, 2nd ed. london: bc decker inc., 2004. pp. 139. nabeel sayed, abdulaziz bakathir, mehboob pasha and salim al-sudairy clinical and basic research | e235 2. brown lh, berkman s, cohen d, kaplan al, rosenberg m. a radiological study of the frequency and distribution of impacted teeth. j dent assoc s afr 1982; 37:627‒30. 3. fanning ea, moorrees cf. a comparison of permanent mandi bular molar formation in australian aborigines and caucasoids. arch oral biol 1969; 14:999‒1006. https://doi.org/10.1016/00 03-9969(69)90069-7. 4. hugosan a, kugelberg cf. the prevalence of third molars in a swedish population. an epidemiological study. community dent health 1988; 5:121‒38. 5. hashemipour ma, tahmasbi-arashlow mt, fahimi-hanzaei ff. incidence of impacted mandibular and maxillary third molars: a radiographic study in southeast iran population. med oral patol oral cir bucal 2013; 18:e140‒5. https://doi.org/10.4317/ medoral.18028. 6. kaya gs, aslan m, ömezil mm, dayı e. some morphological features related to mandibular third molar impaction. j clin exp dent 2010; 2:12‒17. https://doi.org/10.4317/jced.2.e12. 7. hattab fn, rawashdeh ma, fahmy ms. impaction status of third molars in jordanian students. oral surg oral med oral pathol oral radiol endod 1995; 79:24‒9. https://doi.org/10.10 16/s1079-2104(05)80068-x. 8. haidar z, shalhoub sy. the incidence of impacted wisdom teeth in a saudi community. int j oral maxillofac surg 1986; 15:569‒71. https://doi.org/10.1016/s0300-9785(86)80060-6. 9. hassan ah. pattern of third molar impaction in a saudi pop ulation. clin cosmet investig dent 2010; 2:109‒13. https://doi. org/10.2147/cciden.s12394. 10. al-anqudi sm, al-sudairy s, al-hosni a, al-maniri a. prevalence and pattern of third molar impaction: a retro spective study of radiographs in oman. sultan qaboos univ med j 2014; 14:e388‒92. 11. bouloux gf, steed mb, perciaccante vj. complications of third molar surgery. oral maxillofac surg clin north am 2007; 19:117–28. https://doi.org/10.1016/j.coms.2006.11.013. 12. bui ch, seldin eb, dodson tb. types, frequencies, and risk factors for complications after third molar extraction. j oral maxillofac surg 2003; 61:1379‒89. https://doi.org/10.1016/j.jo ms.2003.04.001. 13. chiapasco m, de cicco l, marrone g. side effects and compl ications associated with third molar surgery. oral surg oral med oral pathol 1993; 76:412‒20. https://doi.org/10.1016/0030-42 20(93)90005-o. 14. haug rh, perrott dh, gonzalez ml, talwar rm. the american association of oral and maxillofacial surgeons age-related third molar study. j oral maxillofac surg 2005; 63:1106‒14. https://doi.org/10.1016/j.joms.2005.04.022. 15. sisk al, hammer wb, shelton dw, joy ed jr. complications following removal of impacted third molars: the role of the experience of the surgeon. j oral maxillofac surg 1986; 44:855‒9. https://doi.org/10.1016/0278-2391(86)90221-1. 16. brauer hu. unusual complications associated with third molar surgery: a systematic review. quintessence int 2009; 40:565‒72. 17. azenha mr, kato rb, bueno rb, neto pj, ribeiro mc. accidents and complications associated to third molar surgeries performed by dentistry students. oral maxillofac surg 2014; 18:459–64. https://doi.org/10.1007/s10006-013-0439-9. 18. muhonen a, ventä i, ylipaavalniemi p. factors predisposing to postoperative complications related to wisdom tooth surgery among university students. j am coll health 1997; 46:39‒42. https://doi.org/10.1080/07448489709595585. 19. blum ir. contemporary views on dry socket (alveolar osteitis): a clinical appraisal of standardization, aetiopathogenesis and management: a critical review. int j oral maxillofac surg 2002; 31:309‒17. https://doi.org/10.1054/ijom.2002.0263. 20. garcia ag, grana pm, sampedro fg, diago mp, rey jm. does oral contraceptive use affect the incidence of complications after extraction of a mandibular third molar? br dent j 2003; 194:453‒5. https://doi.org/10.1038/sj.bdj.4810032. 21. alexander re. dental extraction wound management: a case against medicating postextraction sockets. j oral maxillofac surg 2000; 58:538‒51. https://doi.org/10.1016/s0278-2391(00) 90017-x. 22. jerjes w, upile t, shah p, nhembe f, gudka d, kafas p, et al. risk factors associated with injury to the inferior alveolar and lingual nerves following third molar surgery-revisited. oral surg oral med oral pathol oral radiol endod 2010; 109:335‒45. https://doi.org/10.1016/j.tripleo.2009.10.010. 23. middlehurst rj, barker gr, rood jp. postoperative morbidity with mandibular third molar surgery: a comparison of two tech niques. j oral maxillofac surg 1988; 46:474‒6. https://doi.org/10.1 016/0278-2391(88)90415-6. 24. kiesselbach je, chamberlain jg. clinical and anatomic observations on the relationship of the lingual nerve to the mandibular third molar region. j oral maxillofac surg 1984; 42:565‒7. https://doi.org/10.1016/0278-2391(95)90631-2. 25. carmichael fa, mcgowan da. incidence of nerve damage following third molar removal: a west of scotland oral surgery research group study. br j oral maxillofac surg 1992; 30:78‒82. https://doi.org/10.1016/0266-4356(92)90074-s. 26. rood jp. permanent damage to inferior alveolar and lingual nerves during the removal of impacted mandibular third molars. comparison of two methods of bone removal. br dent j 1992; 172:108‒10. https://doi.org/10.1038/sj.bdj.4807777. 27. brann cr, brickley mr, shepherd jp. factors influencing nerve damage during lower third molar surgery. br dent j 1999; 186:514‒16. https://doi.org/10.1038/sj.bdj.4800155. 28. costantinides f, biasotto m, maglione m, di lenarda r. local vs general anaesthesia in the development of neurosensory disturbances after mandibular third molars extraction: a retrospective study of 534 cases. med oral patol oral cir bucal 2016; 21:e724‒30. https://doi.org/10.4317/medoral.21238. https://doi.org/10.1016/0003-9969%2869%2990069-7 https://doi.org/10.1016/0003-9969%2869%2990069-7 https://doi.org/10.4317/medoral.18028 https://doi.org/10.4317/medoral.18028 https://doi.org/10.4317/jced.2.e12 https://doi.org/10.1016/s1079-2104%2805%2980068-x https://doi.org/10.1016/s1079-2104%2805%2980068-x https://doi.org/10.1016/s0300-9785%2886%2980060-6 https://doi.org/10.2147/cciden.s12394 https://doi.org/10.2147/cciden.s12394 https://doi.org/10.1016/j.coms.2006.11.013 https://doi.org/10.1016/j.joms.2003.04.001 https://doi.org/10.1016/j.joms.2003.04.001 https://doi.org/10.1016/0030-4220%2893%2990005-o https://doi.org/10.1016/0030-4220%2893%2990005-o https://doi.org/10.1016/j.joms.2005.04.022 https://doi.org/10.1016/0278-2391%2886%2990221-1 https://doi.org/10.1007/s10006-013-0439-9 https://doi.org/10.1080/07448489709595585 https://doi.org/10.1054/ijom.2002.0263 https://doi.org/10.1038/sj.bdj.4810032 https://doi.org/10.1016/s0278-2391%2800%2990017-x https://doi.org/10.1016/s0278-2391%2800%2990017-x https://doi.org/10.1016/j.tripleo.2009.10.010 https://doi.org/10.1016/0278-2391%2888%2990415-6 https://doi.org/10.1016/0278-2391%2888%2990415-6 https://doi.org/10.1016/0278-2391%2895%2990631-2 https://doi.org/10.1016/0266-4356%2892%2990074-s https://doi.org/10.1038/sj.bdj.4807777 https://doi.org/10.1038/sj.bdj.4800155 https://doi.org/10.4317/medoral.21238 the introduction of highly active anti-retroviral therapy (haart) has markedly decreased the rates of opportunistic infections, the progression to aids, and the overall mortality for hiv-infected patients.1 in some patients, however, the effective immune reconstitution that follows haart can result in an exuberant inflammatory response leading to paradoxical clinical deterioration. the presence of iris does not mean that haart has failed. in fact it shows that the treatment is effective. in this report, we describe five patients at sultan qaboos university hospital, oman, who developed iris shortly after the initiation of haart. in addition, a literature review on the epidemiology, aetiology, risk factors, pathogenesis, diagnosis and management of infection-related iris is also included in this report. case one a 23 year-old male was diagnosed in 2002 with hiv-1 infection when he presented with cryptococcus neoformans meningitis. at diagnosis, his cd4 count was 58cells/mm3 and the hiv-1 viral load 110,000 ribonucleic acid (rna) copies/ml. he received amphotericin b 1mg/kg intravenously (iv) daily for the first 2 weeks, then flucanozole 400 mg po (per os, i.e. orally) daily for 8 weeks followed by maintenance therapy. cotrimoxazole was started for pneumocystis pneumonia (pcp) prophylaxis. haart (zidovudine, lamivudine, indinavir) was started in march 2003, but was later stopped due to poor compliance. in january 2007, he was again restarted on haart (zidovudine, lamivudine, lopinavir/ritonavir). his pre-haart cd4 count was 35cells/mm3 and hiv-1 viral load was 159,000 squ med j, february 2011, vol. 11, iss. 1, pp.95-103, epub. 12th feb 11 submitted 4th nov 09 revision req. 22nd jun 10, revision recd. 28th jul 10 accepted 6th nov 10 department of medicine, sultan qaboos university hospital, muscat, oman. *corresponding author email: balkhair2000@hotmail.com dåüë˚]e<íe^„j÷˜]<‡ëá”j÷]<ïå^¬c<ì⁄á¯j⁄<ö^„æc ì√q]ü⁄ê<l˜^u<ã∏<‡¬<üëüœi   4   :مفتاح الكلمات          abstract: immune reconstitution inflammatory syndromes (iris) in patients with acquired immune deficiency syndrome (aids) are characterised by atypical manifestations of opportunistic pathogens. these occur in patients experiencing improvement in cd4 cell counts following receipt of highly active anti-retroviral therapy (haart). although well established as a syndrome, iris still presents challenges in diagnosis and management. we report five cases of iris with diverse clinical presentations and due to different infectious aetiologies. a review of the published literature on this syndrome is also included. keywords: hiv; aids; haart; immune reconstitution inflammatory syndrome; iris; tb; atypical mycobacterium; cryptococcus; toxoplasmosis; cryptosporidium; case report; oman unmasking immune reconstitution inflammatory syndrome (iris) a report of five cases and review of the literature *abdullah balkhair,1 sudheer ahamed,1 dilip sankhla2 case report unmasking immune reconstitution inflammatory syndrome (iris) a report of five cases and review of the literature 96 | squ medical journal, february 2011, volume 11, issue 1 rna copies/ml. seven weeks later, he presented with fever and progressive pain and swelling of the right elbow and knee joints. clinical examination revealed swollen, warm and tender right elbow and right knee with effusion and severe restriction of movements. a whole body bone scintigraphy, using technetium-99m-methylene diphosphonate (tc99m-mdp), was done as well as a magnetic resonance imaging (mri) scan of the right elbow and knee joints [figures 1 and 2, respectively]. multifocal septic arthritis of the right elbow and knee joints with osteomyelitis was diagnosed. the right elbow and knee joints were aspirated and drained thick greenish pus. a ziehl-neelsen stain of the aspirate from both sites showed sheets of acid fast bacilli. the patient underwent drainage and debridement of the affected bones; tissues were also sent for mycobacterium and fungal culture. standard quadruple antituberculous therapy (att) and clarithromycin were started while awaiting the culture results. haart was continued and nonsteroidal anti-inflammatory drugs (nsaids) were prescribed. a repeat cd4 count at this presentation showed it had risen to 185 cells/mm3 and hiv1 viral load had dropped to 3350 rna copies/ ml. the culture of the aspirate of both joints and the humeral and femoral bone biopsy revealed growth of non mycobacterium avium complex (non-mac), non-tuberculous mycobacterium which could not be further identified in the public health laboratory. the isolate was sensitive only to figure 1: three -phase bone scintigraphy delayed images show increased radiotracer uptake in right elbow and knee. figure 2a: mri right elbow (stir sequence in coronal plane) demonstrates bone marrow oedema in the lateral epicondyle associated with joint effusion and soft tissue swelling. figure 2b: magnetic resonance image of right knee t1w fs ce in the sagittal plane showing intra osseous abscesses in condyles (not in picture) and patella with joint effusion, synovitis and bone marrow oedema. abdullah balkhair, sudheer ahamed and dilip sankhla case report | 97 ciprofloxacin and clarithromycin while resistant to all standard antitubercular (att) drugs including rifampicin, ethambutol and aminoglycosides. the att treatment was stopped while ciprofloxacin and clarithromycin were continued in addition to haart. the patient made a full recovery and has remained asymptomatic to date. case two a 38 year-old woman was diagnosed in december 2006 with hiv-i infection after presenting with pneumocystis jiroveci pneumonia (pcp) [figure 3]. she had a cd4 count of 8 cells/mm3 and the hiv-1 viral load of 314,000 rna copies/ml at diagnosis. three weeks later she was started on haart (zidovudine, lamivudine and efavirenz). about four weeks after commencing haart, she developed fever, headache and vomiting. the clinical examination showed neck stiffness and positive kernig’s sign. the computed tomography (ct) scan of the brain was normal. a lumbar puncture was performed and the subsequent india ink stain and cryptococcus antigen were both positive in the cerebrospinal fluid (csf). cryptococcus neoformans was later isolated from the csf. the patient received liposomal amphotericin 5mg/kg iv daily for 2 weeks followed by fluconazole 400 mg po daily for 8 weeks and later maintained on oral fluconazole 200 mg daily. haart was discontinued temporarily during the initial phase of treatment (the first two weeks), but was later restarted. at this presentation, the cd4 count was 35cells/mm3 and the hiv-1 viral load was 35,000 rna copies/ml. the patient had a full recovery with follow-up csf cultures documenting sterility. case three a 57 year-old man was diagnosed in august 2006 with hiv-1 infection when he presented with biopsy proven toxoplasma gondii brain abscesses. the cd4 count at presentation was 85cells/mm3 and the hiv-1 viral load was >750,000 rna copies/ml. he was treated with a combination of pyrimethamine 75 mg po daily, sulfadiazine 1g po 6 hourly and folinic acid 15 mg po daily for 6 weeks. he was afterwards put on maintenance therapy. the patient’s symptoms improved as a result of this treatment. a follow up mri brain confirmed resolution of the lesions. haart (zidovudine, lamivudine, abacavir) was then started. eight weeks later, he presented with fever, abdominal pain and diarrhoea. the clinical examination revealed jaundice and tenderness at the right upper quadrant of the abdomen. acute cholangitis was suspected. an mri scan of the abdomen was done [figure 4] and revealed dilated intrahepatic biliary ducts with the contrast uptake suggesting inflammation. the patient underwent upper gastrointestinal (gi) endoscopy, which showed an ulcerative necrotic lesion and areas of hyperaemia involving figure 3: frontal radiograph chest showing bilateral reticular opacities mainly in mid and lower lungs. figure 4: magnetic resonance imaging scan of the abdomen t2w fs in the axial plane reveals dilated intra hepatic bile ducts with signs of cholangitis. unmasking immune reconstitution inflammatory syndrome (iris) a report of five cases and review of the literature 98 | squ medical journal, february 2011, volume 11, issue 1 the entire duodenum. a duodenal aspirate and biopsy showed the presence of cryptosporidium. the stool was also positive for cryptosporidium. the test for cytomegalovirus by polymerase chain reaction (cmv-pcr) was negative. the cd4 count at this presentation was 287cells/mm3 and the hiv1 viral load was 4670 rna copies/ml. the patient was started on paromomycin 500 mg po three times daily and azithromycin 500 mg po once daily. the haart was continued and a complete resolution of the symptoms was achieved. a followup upper gi endoscopy and mri six weeks later were both normal. case four a 30 year-old woman was diagnosed in 2003 with hiv-1 infection during pregnancy. the cd4 count was 20 cells/mm3 and the hiv-1 viral load was >750,000 rna copies/ml. she was then lost to follow-up. in 2005, she presented with severe cmv and candida esophagitis (diagnosis made by upper gi endoscopy and oesophageal biopsy). she was treated with flucanozole 400 mg intravenously (iv) daily and ganciclovir 5mg/kg iv twice daily. pentamidine 300 mg via aerosol once monthly was also started for prophylaxis against pcp as the patient had a severe allergy to sulpha. haart (zidovudine, lamivudine, indinavir) was started. three weeks later, the patient presented with generalised tonic-clonic seizures. the clinical examination was normal. an urgent mri brain scan [figure 5a & b ] was consistent with cerebral toxoplasmosis. the serology for toxoplasmosis was positive in both immunoglobin g and m (igg & igm). a working diagnosis of cerebral toxoplasmosis was made and the patient was started on combination of pyrimethamine 75 mg po daily, clindamycin 450 mg po three times daily and folinic acid 15 mg po daily for 6 weeks and later was put on maintenance therapy. the haart was discontinued temporarily. the cd4 count at this presentation had risen to 84 cells/ mm3 and hiv-1 viral load had fallen to 7130 rna copies/ml. the patient remained asymptomatic during this period with no recurrence of convulsions. a follow-up mri brain scan at the end of 6 weeks of treatment confirmed complete resolution. the same haart regimen was then resumed with no unwanted consequences. case five a 23 year-old man was diagnosed in october 2005 with hiv-1 infection when he presented with uncomplicated salmonella bacteraemia. the cd4 count was 10 cells/mm3 and the hiv-1 viral load was >750,000 rna copies/ml. the us centers for disease control and prevention (cdc) stage at diagnosis was b3. he received ciprofloxacin 400 mg iv twice daily for two weeks. haart figure 5a & 5b: mri brain flair and t1w ce sequences showing enhancing lesion with perilesional oedema in right parietal lobe. abdullah balkhair, sudheer ahamed and dilip sankhla case report | 99 discussion we described five patients with advanced hiv1 infection in whom initiation of haart have resulted in unmasking of an underlying occult opportunistic infection. the five cases have all the classical features suggestive of immune reconstitution inflammatory syndrome (iris). all five had advanced hiv disease with a very high viral load and low cd4 count at the initiation of the therapy (haart). the paradoxical worsening and the presentation, with an opportunistic infection 2–8 weeks after the initiation of haart in all five cases, correlated with the drop in viral load and the rise in cd4 count. the variety of pathology in these five cases associated with iris is also remarkable and is consistent with the common rule of iris that ‘anything is possible’. the haart for hiv infection has been one of the most dramatic progressions in the history of medicine. since its introduction, haart has led to significant declines in aids-associated morbidity and mortality.2 these benefits are, in part, a result of partial recovery of the immune system, manifested by increases in cd4+ t-lymphocyte counts and decreases in plasma hiv-1 viral loads.3 soon after the introduction of haart, (abacavir, lamivudine, efavarinz) was commenced. cotrimoxazole was started for primary prophylaxis for pcp. four weeks after the initiation of haart, he developed fever with left-sided, enlarged, painful cervical lymph-nodes. clinical examination showed multiple left-sided tender cervical lymph-nodes, the largest measuring 3 × 4 cm. both liver and spleen were enlarged. the tuberculin skin test (tst) was non-reactive. the cervical lymph-node biopsy showed sheets of acid-fast bacilli. standard quadruple att was commenced and the haart suspended during the initiation phase of att; nsaids were added. the cd4 count at this presentation had risen to 32 cells/ mm3 and the hiv-1 viral load had fallen to 160,000 rna copies/ml. a culture of the lymph-node grew fully sensitive mycobacterium tuberculosis. the att was continued and the same haart regimen (but with the dose of efavarenz increased to 800 mg daily) was reintroduced after completion of the initiation phase of att. there were no undue side effects. full recovery was achieved with resolution of the lymphadenopathy and regression of the hepatosplenomegaly. table 1: table summarising the cd4 counts of the five patients before and after initiation of haart and the clinical manifestation of iris case number cd4 count (cells/ mm3) at initiation of haart viral load (rna copies/ ml) at initiation of haart cd4 count (cells/ mm3)at time of iris viral load (rna copies/ ml) at time of iris clinical disease characterising iris time to iris (week) antiretroviral regimen outcome 1 35 159,000 185 3350 non tuberculous mycobacterial infection (not specified) of bone and joint 7 zidovudine, lamivudine & lopinavir/ ritonavir. cured 2 8 314,000 35 35,000 cryptococcal meningitis 4 zidovudine, lamivudine & efavirenz cured 3 85 >750,000 287 4670 cryptosporidial cholangitis 8 zidovudine, lamivudine & abacavir cured 4 20 >750,000 84 7130 toxoplasmosis 3 zidovudine, lamivudine& indinavir cured 5 10 >750,000 32 160,000 tuberculous lymphadenitis 4 abacavir, lamivudine & efavirenz cured* note: *patient died later from advanced metastatic kaposi sarcoma legend: haart = highly active anti-retroviral therapy; iris = immune reconstitution inflammatory syndrome; rna = ribonucleic acid. unmasking immune reconstitution inflammatory syndrome (iris) a report of five cases and review of the literature 100 | squ medical journal, february 2011, volume 11, issue 1 clinicians noticed that some patients initiating haart experienced unique symptoms during immune system recovery. in these patients, clinical deterioration occurs despite increased cd4+ t lymphocyte counts and decreased plasma hiv-1 viral loads.4 this clinical deterioration is a result of an inflammatory response of the immune system to both intact subclinical pathogens and residual antigens. because clinical deterioration occurs during immune recovery, this phenomenon has been described as immune restoration disease (ird), immune reconstitution syndrome (irs), and paradoxical reactions. given the role of the host inflammatory response in this syndrome, the term immune reconstitution inflammatory syndrome (iris) has been proposed.5 iris can be defined as a pathological inflammatory response and paradoxical clinical deterioration as a result of haart related immune recovery or reconstitution in hiv infected persons. in other words, iris is a syndrome that occurs because a patient develops an exuberant response to appropriate therapy. iris is now a widely recognised phenomenon that can complicate haart.6, 7, 8 how iris develops is not yet well understood and its pathogenesis remains largely speculative. current theories concerning the pathogenesis of the syndrome involve a combination of underlying antigenic burden, the degree of immune restoration following haart, and host genetic susceptibility. these pathogenic mechanisms may interact and likely depend on the underlying burden of infectious or non-infectious agents. as illustrated in all the five cases above, the majority of patients who develop iris do so within the first 4 to 8 weeks after starting haart. however, the interval between the start of haart and the onset of iris is highly variable, ranging from less than 1 week to several months after haart initiation.9 furthermore, most patients who develop iris have had high viral loads and very low cd4+ t-lymphocyte (cd4+) counts. in this report, all five patients had cd4 counts of <100 cells/mm3 at the start of haart. in addition, three patients had an hiv-1 viral load of >750,000 rna copies/ml. the frequency of iris has not been reported conclusively and the overall incidence of the syndrome itself remains largely unknown, being dependent on the population studied and its underlying opportunistic infections burden. in the largest study of iris to-date, 31.6% of hiv infected patients developed iris while on haart.10 in a large retrospective analysis examining all forms of iris, 25% of patients exhibited one or more disease episodes after initiation of haart.4 other cohort analyses examining all manifestations of iris estimate that 17–23% of patients initiating haart will develop the syndrome.11,12 another study demonstrated that up to one third of patients with hiv/tuberculosis co-infection who begin haart in resource-limited countries could be at risk of developing tuberculosis-associated iris (also known as tb-iris).13 collation of the clinical, immunological and immune-genetic data presented over the last 15 years has identified risk factors for iris.4 a higher viral load and low cd4 t cell count at the start of haart along with a rapid drop in viral load with treatment, as shown in all five cases in this report, has been found to be a favourable setting for iris to occur. in the affected patients, cd4 t cell counts are often <50 cells/mm3 at the start of haart and subsequently increase more than 2–4 fold during the 12 months after initiation of haart, and a significant decrease in hiv load of more than 2 log10 copies/ml is often noted.14 iris manifestations are diverse and depend on the infectious or non-infectious agent involved. these manifestations have not been precisely defined. in general, and as illustrated in the case reports above, they are characterised by fever and worsening of the clinical manifestations of the underlying opportunistic infection. these clinical manifestations may be at the site of a previously recognised opportunistic disease (none of our patients) or may “unmask” disease at new sites not previously known to be infected by the pathogen (none of our patients). they may also represent a response to a previously unrecognised additional pathogen (all five patients reported here). a paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating therapy characterises the syndrome. mycobacterium tuberculosis (tb) is among the most frequently reported pathogens associated with iris. the commonest clinical manifestations of tb-iris are fever, lymphadenopathy and worsening respiratory symptoms.13 in most studies, tb-iris occurs within two months of haart initiation. these studies suggest that the onset of abdullah balkhair, sudheer ahamed and dilip sankhla case report | 101 mycobacterium-associated iris is relatively soon after initiation of haart, and clinicians should maintain a high level of vigilance during this period. the last patient in our report (case five) was a classic case of tb-iris. he presented with fever and cervical lymph-nodes enlargement shortly (four weeks) after initiation of haart. hepatosplenomegaly probably signifies widespread tb disease and its subsequent regression on att further supports this hypothesis. in addition to mycobacterium tuberculosis, nontuberculous mycobacteria are also frequently reported as causative pathogens in iris. mycobacterium avium complex (mac) remains the most frequently reported atypical mycobacterium linked with iris. other atypical mycobacteria are rarely associated with iris. the first patient in our series (case one) had a nontuberculous mycobacterium that was not mac (and could not be further identified) which resulted in a severe form of multiple-site osteomyelitis. this disease manifested shortly after introduction of haart (seven weeks later). furthermore, it occurred at the time of marked immune recovery and marked improvement in cd4 count (cd4 count had risen 4 to 5 fold by then). soon after the introduction of haart, it was observed that some patients presented with an initial or recurrent episode of cryptococcal meningitis during the first few weeks of therapy;15 however, iris with cryptococcal meningitis is rare.16,17 the most common iris syndrome associated with cryptococcal infection is lymphadenitis. iris was reported in 30–33% of hiv-infected patients with cryptococcus neoformans after the initiation of haart.18 lower cd4-cell count and higher hiv-rna concentrations at the onset of infection correlated with a higher risk of iris.18 patients with iris also had a greater reduction in hiv-rna concentration within 90 days of haart initiation,19 and had a greater fungal burden at the onset of infection.18 furthermore, initiation of haart within 30–60 days of the treatment of fungal infection has been associated with a higher risk of iris.20 the second patient (case two) in our report presented with an initial, first episode of cryptococcal meningitis while on haart (3 weeks later). she had an extremely low cd4 count at the time of the initiation of haart (cd4 8 cells/mm3) and had a dramatic immune recovery with a 4-fold cd4 count rise and >1 log reduction in the hiv-1 viral load at time of presentation. the number of reports of iris associated with parasitic diseases is small but increasing. only two cases of suspected iris associated with toxoplasma encephalitis have been reported in published literature. in one case, no clinical details were given.12 in the other, an hiv-infected patient with a nadir cd4 cell count of 83 cells/mm3 presented with a focal seizure after 3 weeks of haart.21 the fourth patient in this report (case four) presents, to our knowledge, only the third reported case in the literature of iris associated with toxoplasma encephalitis. this patient presented with generalised seizures three weeks after initiation of haart. he had an exceptionally low cd4 count (cd4 count 2 years earlier was 20cells/mm3) and a very high hiv-1 viral load (>750,000 rna copies/ ml) at the time of initiation of haart. he had a dramatic immune recovery with a 4-fold cd4 count rise and major reduction in the hiv-1 viral load of > 2 log reduction at the time of presentation with cerebral toxoplasmosis. the diagnosis of cerebral toxoplasmosis was made on the basis of positive serology, multiple ring-enhancing intra-cerebral lesions on an mri scan and a positive response to treatment for toxoplasmosis with complete resolution on follow-up brain imaging. of interest is that there are no frequent reports in the published literature of iris associated with cryptosporidium infection. we here report a rare case of cryptosporidium infection associated with iris. our patient (case three) presented eight weeks following initiation of haart with fever, abdominal pain and diarrhoea. this occurred at a time where immune recovery was dramatic (cd4 count rise from 85 to 287 cells/mm3) and hiv-1 viral load reduction was substantial (hiv-1 viral load reduction > 2 log). endoscopy proven extensive duodenal inflammation and ulcerations were found in addition to clinical, biochemical, and an mri assisted diagnosis of cholangitis. furthermore, the duodenal aspirate and multiple duodenal biopsies confirmed the presence of cryptosporidium. the stool sample was also positive for cryptosporidium. no other aetiologies were identified. the resolution of symptoms and normal subsequent endoscopy further supports the diagnosis of iris associated unmasking immune reconstitution inflammatory syndrome (iris) a report of five cases and review of the literature 102 | squ medical journal, february 2011, volume 11, issue 1 cryptosporidium. to our knowledge this is the first reported case in the literature. diagnosis of iris is clinically challenging and involves differentiation between the progression of the initial opportunistic infection (oi) (including the possibility of antimicrobial resistance and treatment failure); development of a new oi; unrelated organ dysfunction, or drug toxicity. iris should be suspected in patients who show clinical or radiologic deterioration following initiation of haart accompanied with improvement in cd4 count and viral load. since there is no diagnostic test for iris, confirmation of the disease relies heavily upon case definitions incorporating clinical and laboratory data. french et al.7 and shelburne et al.22 published two of the most widely used iris case definitions in the literature. in a recent article, published in the clinical infectious diseases journal, haddow et al. proposed a revised case definition of iris incorporating both definitions along with separate definitions for unmasking and paradoxical iris.23 the current management of iris remains controversial and therapy for iris is largely empiric. there are no well-controlled trials concerning the management of iris. all evidence in the literature regarding the management of iris is found in case reports and small case series reporting on management practice. furthermore, no clear guidelines exist regarding the continuation of haart during iris; therefore, the decision to continue haart in spite of iris should be based on the clinical scenario. if the pathogens involved in iris are not amenable to specific treatment, or if life-threatening events occur and steroids are ineffective, one should consider suspending antiretroviral therapy.24 symptomatic therapy for iris can be tried with nsaids and steroids. immune modulation in some instances is warranted, but specific drugs and protocols are lacking. other modalities tried include thalidomide and intravenous immunoglobulin (ivig) in our report, haart was discontinued temporarily in three patients (cases two, four and five). these patients had cryptococcal meningitis, cerebral toxoplasmosis and tb lymphadenitis respectively. haart was discontinued in the patient with cryptococcal meningitis during the induction phase of treatment (first two weeks) and was restarted thereafter with no complications. in the patient with cerebral toxoplasmosis, haart was suspended until complete resolution of the brain abscesses and associated oedema (six weeks). haart was then reintroduced with no problems. in both scenarios, haart was suspended temporarily to minimise the inflammatory process and its potential unwanted consequences in a critical site (brain). in the patient with tb-iris, haart was suspended during the initiation phase of att (first two months) only to enhance patient compliance with tb treatment. both haart and att were later combined resulting in cure. haart was continued without interruption in the remaining two patients (cases one and three). in the patient with atypical mycobacterium associatedosteomyelitis (case one), in addition to continuing haart, nsaids were used. specific therapy with clarithromycin and moxifloxacin resulted in cure. in the patient with cryptosporidium induced duodenitis and cholangitis (case three), haart was continued and specific prolonged treatment with paromomycin and azithromycin was given resulting in clearance of the parasitic infection and subsequent cure. although some iris cases are short-lived, or cause minor clinical problems, others may result in significant morbidity and sometimes death. however, iris does not appear to have favourable or unfavourable implications about patient survival, with the possible exception of iris associated with cryptococcal meningitis.10 to date, with exception of the patient with tbiris (case five), who died from disseminated kaposi sarcoma, the other four patients have remained well and had optimal clinical, immunologic and virological responses on haart. conclusion our cases establish the fact that iris is a significant problem in the post haart era and is associated with several challenges for the treating physicians. as the use of haart increases around the world (including developing countries where a large number of severely immune-deficient patients are being given haart), physicians managing patients with hiv infection will encounter increasing numbers of patients with iris. the inclusion of iris in the differential diagnosis of a patient who abdullah balkhair, sudheer ahamed and dilip sankhla case report | 103 presents with an inflammatory process after initiating haart allows for a focused approach to diagnosis and therapy. further studies are needed to help us to understand how to deal with this clinically significant problem. guidelines for the management of iris and the use of haart during iris also need to be developed. references 1. mocroft a, ledergerber b, katlama c, kirk o, reiss p, d’arminio monforte a, et al. decline in the aids and death rates in the euro-sida study: an observational study. lancet 2003; 362:22–9. 2. palella fj jr, delaney km, moorman ac, loveless mo, fuhrer j, satten ga, et al. declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. hiv outpatient study investigators. n engl j med 1998; 338:853–60. 3. gea-banacloche jc, clifford lane h. immune reconstitution in hiv infection. aids 1999; 13 suppl a: s25–38. 4. french ma, lenzo n, john m, mallal sa, mckinnon ej, james ir, et al. immune restoration disease after the treatment of immune-deficient hiv-infected patients with highly active antiretroviral therapy. hiv med 2000; 1:107–15. 5. shelburne sa 3rd, hamill rj, rodriguez-barradas mc, greenberg sb, atmar rl, musher dw, et al. immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. medicine (baltimore) 2002; 81:213–27. 6. shelburne sa, hamill rj. the immune reconstitution inflammatory syndrome. aids rev 2003; 5:67–79. 7. french ma, price p, stone sf. immune restoration disease after antiretroviral therapy. aids 2004; 18:1615–27. 8. desimone ja, pomerantz rj, babinchak tj. inflammatory reactions in hiv-1–infected persons after initiation of highly active antiretroviral therapy. ann intern med 2000; 133:447–54. 9. cheng vc, yuen ky, chan wm, wong ss, ma es, chan rm, et al. immune-restitution disease involving the innate and adaptive response. clin infect dis 2000; 30:882–92. 10. shelburne sa, visnegarwala f, darcourt j, graviss ea, giordano tp, white ac jr, et al. incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. aids 2005; 19:399–406. 11. ratnam i, chiu c, kandala nb, easterbrook pj. incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse hiv type 1-infected cohort. clin infect dis 2006; 42:418-27. 12. jevtovic dj, salemovic d, ranin j, pesic i, zerjav s, djurkovic-djakovic o. the prevalence and risk of immune restoration disease in hiv-infected patients treated with highly active antiretroviral therapy. hiv med 2005, 6:140–3. 13. lawn sd, bekker lg, miller rf. immune reconstitution disease associated with mycobacterial infections in hiv-infected individuals receiving antiretrovirals. lancet infect dis 2005; 5:361–73. 14. cooney el. clinical indicators of immune restoration following highly active antiretroviral therapy. clin infect dis 2002; 34:224–33. 15. woods ml, macginley r, eisen d, allworth am. hiv combination therapy: partial immune reconstitution unmasking latent cryptococcal infection. aids 1998; 12:1491–4. 16. skiest dj, hester lj, hardy rd. cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. j infect 2005; 51:e289–97. 17. jenny-avital er, abadi m. immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy. clin infect dis 2002; 35:e128–33. 18. shelburne sa 3rd, darcourt j, white c jr, greenberg sb, hamil rj, atmar rl, et al. the role of immune reconstitution inflammatory syndrome in aidsrelated cryptococcus neoformans disease in the era of highly active antiretroviral therapy. clin infect dis 2005; 40:1045–52. 19. shelburne sa, hamill rj. risk of iris in patients with opportunistic infections during haart. contagion 2005; 2:389–94. 20. lortholary o, fontanet a, memain n, martin a, sitbon k, dromer f. incidence and risk factors of immune reconstitution inflammatory syndrome complicating hiv-associated cryptococcosis in france. aids 2005; 19:1043–9. 21. tsambiras pe, larkin ja, houston sh. case report. toxoplasma encephalitis after initiation of haart. aids read 2001; 11:608–10. 22. shelburne sa, montes m, hamill rj. immune reconstitution inflammatory syndrome: more answers, more questions. j antimicrob chemother 2006; 57:167–70. 23. haddow lj, easterbrook pj, mosam m, khanyile ng, parboosing r, moodley p, et al. defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a south african cohort. clin infect dis 2009; 49:1424–32. 24. battegay m, drechsler h. immune reconstitution. curr opin hiv aids 2006; 1:6–61. submitted 20 dec 22 1 revision req. 21 feb 23; revision recd. 1 mar 23 2 accepted 22 mar 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.027 5 6 intraoperative and postoperative outcomes of modified bidirectional intra-7 umbilical versus infra-umbilical incision for direct trocar insertion in 8 gynecological laparoscopy 9 a randomized controlled trial 10 *atef darwish, mohammad tawfik, amal gaflan, dina darwish 11 12 department of obstetrics & gynecology, women’s health university hospital, assiut 13 university, assiut, egypt. 14 *corresponding author’s e-mail: atef_darwish@yahoo.com 15 16 abstract 17 objectives: to describe a modified curved deep bidirectional intra-umbilical vertical incision for 18 primary trocar insertion and prospectively compare its intraoperative and postoperative outcomes 19 with infra-umbilical incision in gynecologic laparoscopy. methods: between august 2019 and 20 march 2021, 110 patients subjected to direct trocar insertion technique for laparoscopic 21 intervention were classified into two groups. group a comprised 55 cases of infra-umbilical 22 incision while a modified curved longitudinal bidirectional deep intra-umbilical incision was 23 used in group b (55 cases). intraoperative and postoperative assessments were performed. 24 results: there was statistically significant increased numbers of parity, gravidity, and previous 25 cesarean sections; and a smaller number of infertility complaints in group b. likewise, group b 26 expressed a statistically significant less peri-trocar co2 leakage (46 patients, 83.6% versus 28 27 patients, 50.9%) and more tightness of the primary portal entry (45 patients, 81.8% versus 30 28 patients, 54.5%) if compared to group a throughout the whole operation. on follow-up after one 29 month, there was a statistically significant (p-value = 0.029) decreased osas and psas in 30 mailto:dr.abdullahalalawi@gmail.com group b (10.4 ± 4.2 and 11.8 ± 4.3) i.e., better cosmoses when compared to group a (13.3 ± 5.7 31 and 16.0 ± 6.8) respectively. conclusion: performing a modified curved deep bidirectional intra-32 umbilical vertical incision for insertion of primary laparoscopic trocar is a simple and fast step 33 that results in elimination of intraoperative gas leakage and trocar slippage without the need of 34 any additional sutures. aesthetically, it results in a better scar with satisfactory cosmoses if 35 compared to infra-umbilical incision. 36 keywords: laparoscopy; trocar; entry. 37 38 advances in knowledge: 39 • primary trocar umbilical insertion for laparoscopy is the commonest approach. 40 • modified technique results in less gas leakage and trocar slippage. 41 • it is more cosmetic if compared to other access techniques. 42 43 application to patient care: 44 • umbilicus cosmoses is important particularly for females. 45 • the proposed method for laparoscopic entry will help preserve umbilicus cosmoses as it 46 is totally intra-umbilical. 47 48 introduction 49 nowadays, laparoscopic surgery is a well-established modern tool for treating many 50 gynecological disorders as it is followed by rapid wound healing, short hospital stay, less 51 postoperative pain, and better aesthetic results.1 different laparoscopic entry techniques include 52 veress needle insertion, open laparoscopy, and direct trocar insertion without a statistically 53 significant difference regarding patient safety.2 nevertheless, direct trocar insertion is gaining 54 popularity.3 postoperative umbilical scar cosmoses and appearance are important issues for 55 women. as the umbilicus is an important aesthetic component of the abdomen, surgeons are 56 concerned about how to maintain cosmetic appearance of the umbilicus. in addition to 57 psychological upsetting, bad scars may result in pain, tenderness, and itching.4-6 58 some studies compared different types of primary portal for gynecologic laparoscopy,7-8 59 however, there is no universal agreement on an ideal periumbilical incision for gynecologic 60 laparoscopy. moreover, there is lack of studies addressing intraoperative outcomes of different 61 periumbilical incisions. this study aims to introduce a modified curved bidirectional deep intra-62 umbilical incision for primary trocar insertion and prospectively compare its intraoperative and 63 postoperative outcomes with infra-umbilical incision in gynecologic laparoscopy. 64 65 methods 66 this prospective study was performed at the endoscopy unit of the woman’s health university 67 hospital between august 2019 and march 2021 on women in the reproductive age subjected to 68 direct trocar insertion of gynecologic laparoscopy for different indications without any history of 69 previous umbilical operation or umbilical hernia. it was approved by the ethics committee of the 70 faculty of medicine (17100792) and was registered at the clinicaltrials.gov (nct03988348). 71 all women signed consent to participate in this single blinded rct to enter one of two groups by 72 random allocation. they were assigned according to the 10 mm primary laparoscopic direct 73 trocar entry points (infra or a modified intra umbilical) and incision types (transverse versus 74 curved longitudinal) respectively using sealed envelopes. the allocated envelopes were opened 75 just before surgery. 76 77 the sample size was estimated using epi info version 7.2.5.0. using 95% confidence interval and 78 power of 80% assuming percent of unexposed with outcome=5, while percent of exposed with 79 outcome =28. the estimated sample size was 96. adding 15% drop out rate, the total sample size 80 estimated to be 110.9 allocated 110 cases were divided into two groups. group a comprised 55 81 cases subjected to infra-umbilical 10 mm transverse incision while group b comprised 55 cases 82 of a modified curved bidirectional longitudinal intra-umbilical incision for primary laparoscopic 83 direct trocar insertion. exclusion criteria included patients scheduled for 5mm primary trocar 84 insertion, open laparoscopy, verres needle insertion, patients with previous abdominal surgery 85 and scar, umbilical hernia, umbilical infection e.g. pilonidal sinus disease,10 previous 86 laparoscopy, or previous umbilical surgery, scarred, previously burned or hyperpigmented 87 umbilicus. prepubertal or postmenopausal patients were also excluded from this study. 88 89 in the operating room, the umbilicus was prepared by removing all debris using copious amounts 90 of povidone iodine gauze and cotton swabs. preoperatively, the surgeon commented on the shape 91 of the umbilicus11 (figure 1) and any umbilical fascial defect signifying any tiny hernia, 92 tightness of the abdominal muscles and skin laxity. to avoid skin disfigurement, clamps to 93 elevate the abdominal wall in all cases was not used, but toothed forceps was used to facilitate 94 delicate skin cut to avoid slipping of the scalpel. in group a, a 10 mm infra-umbilical transverse 95 incision was done to allow trocar to be inserted without undue resistance from the skin so that 96 the trocar passed directly through the fascia and the peritoneum with ease. in group b, a 10 mm 97 right-sided modified curved deep bidirectional longitudinal intra-umbilical incision was made. 98 the technique started by grasping the right edge of the umbilicus with a toothed forceps. then, a 99 curved vertical incision was made as deep as possible. thereafter, the trocar was inserted inside 100 the incision till the level of the edge of the sleeve passed the skin. at this moment, the trocar was 101 directed transversely (horizontally) on the right side of the umbilicus for one to two centimeters 102 in the subcutaneous tissue. 103 104 the final step was tilting the trocar to the vertical plane to pierce the fascia towards the pelvis 105 (figure 2). by this way the trocar had 2 pathways (bidirectional) until it reached the peritoneal 106 cavity (horizontally then vertically). in both groups, inflation of the peritoneal cavity with co2 107 was done up to a pressure of 12-15 mm hg. surgical procedures were performed using 108 conventional laparoscopic instruments under vision with a rigid 0-degree, 10-millimeter 109 endoscope. intraoperatively, the surgeon commented on easiness of movement of the trocar and 110 telescope, any leakage of co2 alongside the primary trocar and any intraoperative slippage of 111 the trocar during forward and backward movement of the telescope. operative time varied 112 according to the intraperitoneal laparoscopic procedure. this study didn’t report entry site or 113 intraperitoneal complications in both groups. in both groups, the skin incision was sutured using 114 4/0 monocryl subcuticular stitch. patients were offered regular post-laparoscopic surgery care as 115 usual at our institution with on-need analgesics till discharge. they were instructed to take care 116 of the sterile dressings and they came back after one week for check-up and wound dressing. 117 another follow-up visit was scheduled after one month to properly assess the scar as previously 118 consented by the patients. 119 120 we performed both observer scar assessment scale (osas) as well as patient scar assessment 121 scale (psas)12 which compare the wound to the nearby skin. in both scales, the lower the score 122 the better the scar. maximal scores of osas and psas are 50 and 60 respectively. moreover, 123 the patient was clearly asked if she or her partner can see the scar by naked eye or not to assess 124 effect of the incision on aesthetic appearance of the umbilicus. primary outcome of this study 125 was to assess intraoperative performance using two different periumbilical incisions as regards 126 easiness of surgery, co2 leakage and trocar slippage. secondary outcomes were observer and 127 couple satisfactions using either incision. 128 129 statistical program for social science (spss) version 24 was used to analyze data. quantitative 130 data were expressed as mean ±sd. qualitative data were expressed as frequency and percentage. 131 mean (average) is the central value of a discrete set of numbers, specifically the sum of values 132 divided by the number of values. standard deviation (sd) is the measure of dispersion of a set of 133 values. a low sd indicates that the values tend to be close to the mean of the set, while a high 134 sd indicate that the values are spread out over a wider range. independent-samples t-test (t) of 135 significance was used when comparing between two means (for normally distributed data). 136 mann–whitney u (mw) test was used when comparing between two means (for abnormal 137 distributed data). chi-square test (x2) was used when comparing between non-parametric data. 138 probability (p-value) < 0.05 was considered significant (s), < 0.001 was considered as highly 139 significant (hs) and > 0.05 was considered non-significant (ns). 140 141 statement of ethics 142 authors state that subjects have given their written informed consent. assiut university medical 143 school ethical review board approved the study protocol (17100792). 144 145 results 146 this study comprised 110 patients subjected to 10 mm direct trocar insertion for gynecologic 147 laparoscopic surgery. they were divided into two groups. group a comprised 55 cases of 148 transverse infra-umbilical incision while group b comprised 55 cases subjected to modified 149 curved deep bidirectional longitudinal intra-umbilical incision. table 1 shows insignificant 150 difference regarding age, duration of marriage, and history of previous operations, abortion, or 151 duration of infertility between both groups. however, increased numbers of parity, gravidity and 152 previous cesarean sections; and a smaller number of infertility complaints were statistically 153 significant in group b. 154 155 indications of laparoscopic surgery were variable in both groups. in group a, indications were 156 1ry infertility in 24 patients (43.6%), 2ry infertility in 19 patients (34.56%), hematocolpus and 157 hematometra in 1 patient (1.8%), left ectopic pregnancy in 1 patient (1.8%), missed iud threads 158 in7 patients (12.7%), rt. adnexal cyst in 2 patients (3.6%) and rt. ovarian torsion in 1 patient 159 (1.8%). in group b. it was 1ry infertility in 8 patients (14.5%), 2ry infertility in 16 patients 160 (29.1%), 2ry amenorrhea in 1 patient (1.8%), bilateral endometrioma in 1 patient (1.8%), chronic 161 pelvic pain in 2 patients (3.6%), ewing sarcoma for transposition of ovaries in 1 patient (1.8%), 162 undisturbed tubal ectopic pregnancy in 10 patients (18.1%), missed iud in 6 patients (10.9%), 163 right disturbed ectopic pregnancy in 1 patient (1.8%), ovarian cyst in 7 patients (12.7%), adnexal 164 hematoma in 1 patient (1.8%) and laparoscopic monitoring of hysteroscopic metroplasty of a 165 uterine septum in 1 patient (1.8%). 166 167 there was insignificant difference between both groups regarding preoperative assessment of the 168 umbilicus including presence of dimple, shape and appearance, index finger test for minute 169 hernia and use of conical trocar end. the most common umbilical shape noted in both groups 170 was vertical (84 cases, 76.3%) followed by transverse umbilicus (21 cases, 19%). however, there 171 was a statistically significant difference between both groups regarding abdominal wall muscle 172 and skin laxity as shown in table 2. 173 174 group b expressed a statistically significant less peri-trocar co2 leakage (46 patients, 83.6% 175 versus 28 patients, 50.9%) and more tightness of the primary portal entry (45 patients, 81.8% 176 versus 30 patients, 54.5%) if compared to group a throughout the whole operation as seen in 177 table 3. on follow-up after one month, there was a statistically significant (p-value = 0.029) 178 decreased osas and psas in group b (10.4 ± 4.2 and 11.8 ± 4.3) when compared to group a 179 (13.3 ± 5.7 and 16.0 ± 6.8) respectively as shown in table 4 and figure 3. moreover, 47 patients 180 (85.4%) and 23 patients (41.8%) reported failure to see the umbilical scar by naked eye by 181 herself or her partner in group b and a respectively and were satisfied by the aesthetic 182 appearance of the umbilicus. 183 184 discussion 185 primary umbilical trocar insertion is a procedural step of critical importance.13 despite the 186 widespread use of advanced gynecologic laparoscopic surgeries, many surgeons give little 187 attention to skin incisions after lengthy and tedious operations and leave young staff to close 188 abdominal wall incisions. most of gynecologic patients are young and very concerned about 189 aesthetic appearance of their belly. the umbilicus is very essential to the aesthetic appearance of 190 the abdomen14 and umbilical incisions directly affect female cosmoses. 191 192 this study included patients in the reproductive age with exclusion of young girls and 193 postmenopausal cases to eliminate age-related factors of wound healing.15 to minimize study 194 bias, direct trocar insertion was only used in this study with exclusion of cases of open 195 laparoscopy and veress needle insertion. surgical trocars may be bladed (safety) or bladeless, 196 disposable, or reusable, or spiral (corrugated) or non-spiral. trocar end may be pyramidal or 197 conical without a significant difference in literature. an animal study demonstrated that using 198 conical and pyramidal trocars resulted in similar force, deformation, time, and distance of 199 exposed blade if they were of the same size.16 200 201 in this study, trocar type was standardized as bladeless reusable non-spiral with conical end to 202 eliminate the effect of these variables on the incision. incision sites for primary trocar insertion 203 may be infra-umbilical, supra-umbilical, or trans-umbilical.16 supraumbilical incision was 204 excluded as it is seldom used by gynecologists. in a review of laparoscopic practice by general 205 surgeons, approximately half of the laparoscopists preferred the infra-umbilical route and 35.7% 206 the supraumbilical area for entry.6 vertical incision is usually preferred for initial intraperitoneal 207 access as it offered superior cosmetic effects than transverse incision.17 the infra-umbilical 208 incision cuts through the skin, the subcutaneous fat, and the fascia. in contrast, the intra-209 umbilical incision is a linear incision from the skin to the fascia, extending only the length of the 210 umbilical ring. an intra-umbilical incision may take less time, is easier to perform, and is 211 theoretically less traumatic as only the skin and fascia need to be divided. 212 213 nowadays, the intra-umbilical incision is being used more frequently, with the increasing cases 214 of single incision laparoscopic surgery (sils), which has recently been proven to be a feasible 215 alternative for conventional laparoscopic surgery with better cosmetic outcome.18 in a 216 retrospective comparison of gynecologic laparoscopy cases, intra-umbilical incision, and peri-217 umbilical incision (longitudinal/transverse oblique/arc incision according to the bellybutton 218 natural skin folds) were compared. they concluded that intra-umbilical incision should be 219 promoted in gynecologic laparoscopy.19 220 221 postpartum sterilization using intra-umbilical skin incision was more efficient regarding aesthetic 222 concerns and operation time in a rct.8 what’s new in the current prospective rct is to assess 223 the impact of modifications of the intra-umbilical incision on intraoperative and postoperative 224 outcomes (darwish laparoscopic entry). making the incision as deep as possible aims to make it 225 invisible and less liable to cause pain on touch using the maximal benefit of the natural umbilical 226 dimple. addressing this important point would fulfil the requirements of the aesthetic appearance 227 of the umbilicus as the scar was not seen in 47 patients (85.4%) using this modified technique if 228 compared to 23 patients (41.8%) if infra-umbilical incision was made. since most of the 229 umbilical shape of human being is vertical oval (in this study it was seen in 84 cases, 76.3%), 230 vertical incision used in this study in group b is more anatomic than transverse incision used in 231 group a. 232 233 another additional advantage of the modified technique was making a curved intra-umbilical 234 incision (figure 2) to be adapted with the natural curve of the umbilical dimple. in this study, 235 umbilical dimple was present in 95 cases (86.3%) in both groups, so selection of a curved 236 incision in group b was more anatomic. importantly, the surgeon did not use any instrument to 237 elevate the anterior abdominal wall unlike others who usually use pointed towel forceps or 238 kocher forceps11 or other traumatic instruments that may leave a scar and hyperpigmentation 239 adding more disfigurement and psychological upset to the patients. not only does aggressive 240 elevation of the skin around the umbilical region injurious and non-aesthetic, but also it doesn’t 241 add any surgical benefit because the skin and fascia at the umbilicus are in direct contact that is 242 why it is the preferred site for primary entry. this proximity can be explained by the absence of 243 subcutaneous fat and muscle at the umbilicus that makes the midline dissection plane bloodless 244 to the peritoneum.5 245 246 all these technical tricks resulted in a better aesthetic appearance of the umbilicus and lower 247 osas and psas scales (better cosmoses) using this modified technique if compared to the 248 transverse infra-umbilical incision group. this study incorporated patient impressions and 249 comments on all issues of umbilical incision including their comment on the visibility of the scar 250 by herself or her partner which is considered one of the best aesthetic evaluation variables. this 251 step is commonly used after liposuction operations which may affect the appearance and shape 252 of the umbilicus.20 253 254 intraoperative benefits of the modified intra-umbilical to the surgical procedures are many. 255 insertion of the trocar horizontally for one to two centimeters then its direction vertically 256 (bidirectional) adds an advantage of maintaining an airtight seal to avoid gas leakage alongside 257 the trocar and avoiding trocar slippage throughout the operation. this is simply explained by the 258 making fascial perforation away from the alignment with skin incision. trocar dislodgment 259 occurs frequently during laparoscopic surgery particularly in some lean women, those with weak 260 anterior abdominal wall muscle or fascia and those with lax redundant skin. the best example is 261 multiparous or malnourished women. 262 263 the results of this study supported these concepts as the modified bidirectional technique was 264 more successful than classic infra-umbilical technique even in women with increased parity or 265 gravidity who were prone to weak anterior abdominal wall and lax skin (table 2). frequent 266 slippage of the trocar and abdominal deflation is a real distressing problem. abdominal wall 267 emphysema can occur besides the risky prolongation of the surgical procedure.21 to overcome 268 this problem, some authors take a stitch at the fascia and encircle the trocar throughout the 269 procedure.22 others use spiral trocars whether disposable or reusable.23 disposable spiral trocars 270 are very expensive if compared with reusable trocar and cannot be afforded by healthcare 271 authorities in many hospitals particularly developing countries with limited resources. reusable 272 spiral trocar may require more force for insertion that may carry a risk of unintentional injury24 273 due to repeated resistance to the corrugations along the whole shaft. moreover, despite lack of 274 sufficient supporting studies, using 10 spiral trocars with force may be a risk factor for 275 subsequent umbilical trocar-site hernia as previously reported25 due to repeated tears of the 276 fascia. on post-operative follow-up of all cases of this study, using ordinary reusable conical 10 277 mm trocar, there was no case of trocar-site hernia in either group. 278 279 despite being a prospective rct, this study has some limitations. small sample size is a definite 280 limitation. including all types of umbilici in either group would carry a bias as some umbilici are 281 already inverted with a definite dimple while others are protruding which may affect scar 282 appearance and pain scoring. moreover, comments on easiness of movement of trocar and 283 telescope, leakage of co2 and intraoperative slippage of trocar were all subjectively assessed. 284 theoretically, more accurate tools of assessment would be more informative. nevertheless, in 285 some situations, intraoperative observations particularly by expert surgeons would be as accurate 286 and clinically informative as some sophisticated time-consuming tests. in modern statistics, 287 subjectivity is respected and is replaced by awareness of multiple perspectives and context 288 dependence.26 a larger sample size and a multicentre study is needed to achieve a definite 289 conclusion in this respect. 290 291 conclusion 292 from this study, it is concluded that performing curved deep bidirectional longitudinal intra-293 umbilical incision for insertion of primary laparoscopic trocar (darwish laparoscopic entry) is a 294 simple and fast step that results in elimination of intraoperative gas leakage and trocar slippage 295 without the need of any additional sutures. aesthetically, it results in a better scar with 296 satisfactory cosmoses if compared to infra-umbilical incision. 297 298 conflicts of interest 299 the authors declare no conflict of interests. 300 301 funding 302 no funding was received for this study. 303 304 authors’ contribution 305 ad is the principal investigator who conceptualized the study, refined the study protocol, 306 performed many operations, and wrote the full paper. mt conceived the idea, wrote the protocol, 307 performed many operations, supervised the candidate and reviewed the thesis and the full paper. 308 ag was the active candidate who made the interviews, collected data and made all statistical 309 analyses with the aid of a statistician. dd reviewed the paper and made some corrections. all 310 authors approved the final version of the manuscript. 311 312 references 313 1. pitkin rm, parker wh. operative laparoscopy: a second look after 18 years. obstet 314 gynecol 2010; 115: 890-891. 315 2. vilos ga, ternamian a, dempster j, laberge py. no. 193-laparoscopic entry: a 316 review of techniques, technologies, and complications. j obstet gynaecol can. 2017 317 jul;39(7):e69-e84. doi: 10.1016/j.jogc.2017.04.013. pmid: 28625296. 318 3. levy l, tsaltas j. recent advances in benign gynecological laparoscopic surgery. fac 319 rev. 2021 jul 26; 10:60. doi: 10.12703/r/10-60. pmid: 34409423; pmcid: 320 pmc8361750. 321 4. nozaki t, ichimatsu k, watanabe a, komiya a, fuse h. longitudinal incision of the 322 umbilicus for laparoendoscopic single site adrenalectomy: a particular intraumbilical 323 technique. surg laparosc endosc percutan tech 2010; 20: e185-e188. 324 5. kadar n. a new technique of primary trocar insertion for laparoscopy. j am assoc 325 gynecol laparosc 1997; 4: 485-489. 326 6. compeau c, mcleod nt, ternamian a. laparoscopic entry: a review of canadian 327 general surgical practice. can j surg 2011; 54: 315-320. doi: 10.1503/cjs.011210. 328 7. ouyang z, sun jp, tian xl, zhai jj. analysis of the entrance and suture method of 329 umbilical incision in gynecological laparoscopy. zhonghua yi xue za zhi. 2018 jun 330 5;98(21):1713-1716. chinese. doi: 10.3760/cma.j.issn.0376-2491.2018.21.018. pmid: 331 29925152. 332 8. chirdchim, w, wanichsetakul, p, patumanond j (2019). aesthetic outcomes of intra-333 umbilical incision vs infra-umbilical incision in postpartum tubal sterilization: a 334 randomized controlled trial. ramathibodi medical journal, 42(1), 1–9. 335 https://doi.org/10.33165/rmj.2019.42.1.109492. 336 9. bouffard-cloutier a, paré a, mcfadden n. periumbilical vs transumbilical laparoscopic 337 incision: a patients' satisfaction-centered randomised trial. int j surg. 2017 jul;43:86-91. 338 doi: 10.1016/j.ijsu.2017.05.040. epub 2017 may 25. pmid: 28552811. 339 10. isik, arda; wysocki, arkadiusz peter; memiş, ufuk; sezgin, efe; yezhikova, assel; 340 islambekov, yersultan. factors associated with the occurrence and healing of umbilical 341 pilonidal sinus: a rare clinical entity. advances in skin & wound care. 35(8):1-4, 342 august 2022. 343 11. cullen ts. anatomy of the umbilical region. in: cullen ts, editor. embryology, 344 anatomy, and disease of the umbilicus together with diseases of the urachus. 345 philadelphia: wb saunders; 1916. p. 34–89. 346 12. draaijers lj, tempelman fr, botman ya, tuinebreijer we, middelkoop e, kreis rw, 347 van zuijlen pp. the patient and observer scar assessment scale: a reliable and feasible 348 tool for scar evaluation. plast reconstr surg. 2004 jun;113(7):1960-5; discussion 1966-7. 349 doi: 10.1097/01.prs.0000122207.28773.56. pmid: 15253184. 350 13. sakamoto a, kikuchi i, shimanuki h, tejima k, saito j, sakai k, kumakiri j, kitade 351 m, takeda s. initial closed trocar entry for laparoscopic surgery: technique, umbilical 352 cosmesis, and patient satisfaction. gynecol minim invasive ther. 2017 oct-353 dec;6(4):167-172. doi: 10.1016/j.gmit.2017.04.001. epub 2017 jul 19. pmid: 30254907; 354 pmcid: pmc6135191. 355 14. craig sb, faller ms, puckett cl. in search of the ideal female umbilicus. plast reconstr 356 surg. 2000 jan;105(1):389-92. doi: 10.1097/00006534-200001000-00062. pmid: 357 10627008. 358 15. horng hc, chang wh, yeh cc, huang bs, chang cp, chen yj, tsui kh, wang ph. 359 estrogen effects on wound healing. int j mol sci. 2017 nov 3;18(11):2325. doi: 360 10.3390/ijms18112325. pmid: 29099810; pmcid: pmc5713294. 361 16. moreno dg, pereira cam, sant anna rk, de azevedo ru, savio lf, duarte rj, srougi 362 m, passerotti cc. laparoscopic insertion of various shaped trocars in a porcine model. 363 jsls. 2019 apr-jun;23(2):e2019.00002. doi: 10.4293/jsls.2019.00002. pmid: 364 31097906; pmcid: pmc6476561. 365 17. şentürk mb, doğan o, polat m, kılıçcı ç, pulatoğlu ç, tayyar at. cosmetic outcomes 366 of infraumbilical, supraumbilical, and transumbilical entry routes in laparoscopic surgery. 367 turk j surg. 2018 aug 28;34(4):290-294. doi: 10.5152/turkjsurg.2018.4025. pmid: 368 30216176; pmcid: pmc6340657. 369 18. chow a, purkayastha s, nehme j, darzi la, paraskeva p. single incision laparoscopic 370 surgery for appendicectomy: a retrospective comparative analysis. surg endosc. 2010; 371 24:2567–2574. 372 19. baryza mj, baryza ga. the vancouver scar scale: an administration tool and its 373 interrater reliability. j burn care rehabil. 1995; 16:535–538. 374 20. giuliano borille, md, patrícia m a neves, md, gustavo p filho, md, roy kim, md, 375 gabriele miotto, md, prevention of umbilical sagging after medium definition 376 liposuction, aesthetic surgery journal, volume 41, issue 4, april 2021, pages 463–377 473, https://doi.org/10.1093/asj/sjaa051. 378 21. tchartchian g, dietzel j, surrey mw, dewilde rl, bojahr b. saving time during 379 laparoscopy using a new, wall anchoring trocar device. jsls. 2010 apr-jun;14(2):196-9. 380 doi: 10.4293/108680810x12785289144034. pmid: 20932368; pmcid: pmc3043567. 381 22. mohammad hosseini b. tehran's tie: a simple trick to fix the trocar to the abdominal 382 wall and close the entry site of first trocar in laparoscopic surgery. asian j endosc surg. 383 2017 may;10(2):216-218. doi: 10.1111/ases.12352. pmid: 28547929. 384 23. krug f, berner t, psathakis d, roblick u, bruch hp. der spiraltrokar--ein neues 385 trokarkonzept [spiral trocar--a new trocar concept]. chirurg. 2001 mar;72(3):289-97. 386 german. doi: 10.1007/s001040051308. pmid: 11317450. 387 24. kelty cj, super pa, stoddard cj. the driving force in trocar insertion: a comparison 388 between disposable and reusable trocars. surg endosc. 2000 nov;14(11):1045-6. doi: 389 10.1007/s004640000224. pmid: 11116416. 390 25. holzinger f, klaiber c. trokarhernien eine seltene, potenziell gefährliche komplikation 391 nach laparoskopischen eingriffen [trocar site hernias. a rare but potentially dangerous 392 complication of laparoscopic surgery]. chirurg. 2002 sep;73(9):899-904. german. doi: 393 10.1007/s00104-002-0525-2. pmid: 12297955. 394 26. gelman a, hennig c. beyond subjective and objective in statistics. journal of the royal 395 statistical society series a, 2017, vol. 180, issue 4, 967-1033. 396 397 398 figure 1: different shapes of umbilicus in studied cases. a) vertical oval umbilicus, b) 399 transverse funnel-shaped umbilicus, c) outie projecting umbilicus, d) button-like transverse 400 bulging umbilicus. 401 402 403 figure 2: steps of modified intra-umbilical direct trocar insertion. a) deep curved longitudinal 404 intra-umbilical incision, b) insertion of a 10 mm trocar till disappearance of sleeve edge, c) 405 transverse insertion of the trocar for 1-2 cm in horizontal plane in the subcutaneous tissue, d) 406 rotation of the trocar 90 degrees to the vertical plane followed by penetration of the fascia). 407 408 table 1: sociodemographic and obstetric data of the studied groups. 409 group a (n = 55) group b (n = 55) stat. test p-value age (years) mean 28.5 29.1 t = 0.46 0.643 ns ±sd 7.1 6.8 duration of marriage (years) mean 7.2 9.0 mw = 1237.5 0.457 ns ±sd 3.7 7.0 gravidity mean 1.4 2.2 mw = 1048.5 0.004 hs ±sd 1.9 1.9 parity mean 0.8 1.7 mw = 947 < 0.001 hs ±sd 1.4 1.6 abortions mean 0.6 0.5 mw = 1494 0.895 ns ±sd 0.9 0.8 no. of cs mean 0.5 0.9 mw = 1211 0.038 s ±sd 0.7 1.2 previous operation no 54 98.2 % 52 94.5% x2 = 1.03 0.308 ns yes 1 1.8% 3 5.5% infertility no 12 21.8 % 29 52.7% x2 = 11.2 0.001 hs yes 43 78.2 % 26 47.3% infertility duration mean 5.2 4.5 mw = 464.5 0.351 ns ±sd 3.2 3.1 410 411 table 2: intraoperative assessments of umbilicus and abdominal wall in both groups. 412 group a (n = 55) group b (n = 55) x2 p-value shape vertical oval 52 94.5% 47 85.5% 2.5 0.112 ns horizontal oval 3 5.5% 8 14.5% appearance inverted 48 87.3% 46 83.6% 0.29 0.589 ns everted (protruded) 7 12.7% 9 16.4% dimple absent 6 10.9% 9 16.4% 0.69 0.405 ns present 49 89.1% 46 83.6% index finger test for hernia negative 55 100% 55 100% ------ abdominal skin laxity no yes 41 14 74.5% 29 26 52.7% 5.6 0.017 s 25.4% 47.2% abdominal muscles weak 16 29.1% 32 58.1% 9.4 0.002 hs strong 39 70.9% 23 41.8% trocar tip conical 55 100% 55 100% ------ umbilical incision transverse 55 100% 0 0% 110 < 0.001 hs longitudinal 0 0% 55 100% 413 414 table 3: comparisons of intra-operative assessments of umbilicus between studied groups. 415 group a (n = 55) group b (n = 55) stat test p-value easy trocar and telescope movement no 6 10.9% 3 5.5% x2 = 1.08 0.297 ns yes 49 89.1% 52 94.5% leakage of co2 no 28 50.9% 46 83.6% x2 = 13.4 < 0.001 hs yes 27 49.1% 9 16.4% tightness tight 30 54.5% 45 81.8% x2 = 9.4 0.002 s loose 25 45.5% 10 18.2% 416 417 418 squ med j, april 2010, vol. 10, iss. 1, pp. 1-5, epub. 17th apr 10 submitted 28th feb 10 accepted 2nd mar 10 in this issue of the journal, a patient describes her experiences in an omani hospital and her encounter with the health care teams, after a road traffic accident.1 every road traffic crash like hers or so many others should raise the question of whether we are doing enough for our community to prevent road traffic crashes, reduce the injuries and death that result from these accidents, and reduce the long term negative impact on the victims and their families. have you ever answered the mobile phone while driving? have you ever neglected to fasten your seatbelt? have you read your email in your phone or sent an sms while driving or waiting at a traffic light? have you ever accelerated to go through a yellow light? have you exceeded 120 km an hour on the highway? if you have answered “yes” to any of these questions, you are a part of the problem! according to the royal oman police (rop) website, there were 119 road traffic accidents in just the first week of this year resulting in 13 deaths and 141 injured, and those statistics are not unusual. 2 in the first 11 months of 2009, there were 369 traffic accidents simply as a result of dangerous overtaking alone, resulting in 156 deaths and 881 injuries.3 in the first 10 months of 2009, a total of 810 people died and 8,325 were injured on the road. the oman tribune newspaper, in quoting these figures from the rop, pointd out that this “means more than 20 people were killed and injured on the roads everyday” in oman. to further highlight the current interest in this problem, there was recently a two-day workshop on road safety research, organised jointly by the research council (trc) and the rop in muscat.4 the trc plans to invite research proposals on road safety and give scholarships to postgraduate students willing to participate in this research effort. at the workshop, trc invited experts from various parts of the world to discuss the optimal research topics that can be suggested to researchers in oman. his majesty sultan qaboos bin said’s words were received with all seriousness by trc. during his royal tour last year, his majesty said: “what is happening on our roads should be of everybody’s concern. misuse of vehicles of different categories by different people causing many deaths is an irritating and worrisome phenomenon.” when a breadwinner loses his life or ability to earn, the burden on the family is beyond the easy understanding of those who are either comfortably well off or have never been affected by the road traffic crash disease. the orphans and the widows are the real victims of this burden. oman ranks 5th in the list of countries with the highest road accident rates in the world according to who statistics as quoted by oman tribune on 24th feb 2010.5 it is disturbing that the number of road traffic casualties in oman is rising, while it is falling in many developed countries such as great britain.6 in britain, total casualties fell by 3% between 2004 and 2005, and they have been declining ever since, while pedestrian deaths are at a 40-year low.6 norway, sweden and australia have all halved or better than halved their road deaths between 1970 and 2000, and seen further editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; *email: mjournal@squ.edu.om فقدان احلياة واإلعاقة الناجتة عن حوادث الطرق علينا أن نعمل مجيعا اآلن ملك اللمكي editorial life loss and disability from traffic accidents it is imperative we all act now lamk al-lamki life loss and disability from traffic accidents it is imperative we all act now 2 | squ medical journal, april 2010, volume 10, issue 1 decline since then.7 in comparison, oman had 681 road deaths in 2006, 798 in 2007, 951 in 2008 and estimated between 1000 and 1100 in 2009 with approximately 50,000 injured in 2009. most of the developed countries with these declining death rates have been using the haddon’s matrix since william haddon developed it in 1970. haddon’s matrix analyses injury by looking at certain factors which when simplified are “host or road user factors, vector or vehicle factors, physical or road factors, and socio-economic environmental factors” in the horizontal axis of the matrix and “pre-event (crash), during event and post-event” in the vertical axis.8 it should be appreciated that currently the rop is taking a lot of steps to reduce traffic fatalities, but we still need much more. the fatality rate in oman has now reached 30 per 100,000 people and 127 per 100,000 vehicles and 111 per 100,000 licensed drivers, compared to 14 and 17 and 21 respectively for the usa.9 we definitely need more initiatives from the rop, from non-governmental organizations (ngos) and from all of us individual drivers who can play a dramatic role in reducing the death rate if we make more individual and concerted efforts. to do this we need more road safety education for the public. we need more road safety education in the media both on tv and radio programmes than currently. we need them in both arabic and english because many of the accidents that occur in oman are caused by people who do not speak arabic. better road safety education in oman is not only needed for adults but also for pre-license age groups, and this should be a priority in conjunction with speed management. we need to work harder at changing driver behaviour and attitudes towards the risks associated with high speed. the world’s first road traffic death involving a motor vehicle is alleged to have occurred on 31st of august 1896.10 the coroner at that time is reported to have said, “this must never happen again.” we need to ensure that oman goes on record as working towards seeing that that coroner’s words come true here. it is very disheartening to drive on the roads of oman and see children, unsecured by seat belts, freely moving about in cars and even jumping up and down. we see mothers driving with their baby sitting on their lap. the baby is a good shield for the mother in case of an accident, but is that what the mother really wants? we need more vigorous education of such parents. we need to work at eliminating such practices mainly through education, but when necessary, appropriate penalties. another major problem we are having in oman is talking on the telephone while driving. this is a cause of numerous accidents. worse than talking on the phone is sending text messages (sms & mms) while driving. a study carried at monash university accident research center in melbourne, australia, has shown that text messaging results in more than double the risk of crashing than talking wo rk in g to p r ev en t cr as he s th at result in serious in jury or death sa fe v eh ic le s a dm ission to the system (eg. licensing of vehicles and people) safe roads and r oadsides understanding crashes and r isks educ atio n a nd in fo rm at io n safe speeds en fo rc em en t o f ro ad r ules le ad in g to al ert and compliant road users human tolerance to physical force figure 1: the safe systems approach the strategy of “safe crash” to ensure tolerance of human body is not exceeded by the force of the crash.22 road user error 90% road conditions 30% vehical defects 10% figure 2: the three pillars of road safety23 lamk al-lamki editorial | 3 on the cell phone.11 they recommend more effective road safety measures to prevent and mitigate the adverse effects of the cell phone. road safety is currently one of the top priority subjects that are discussed in different countries and by various world organisations, and so should it be also in oman. on 10 march 2010, the un general assembly is scheduled to discuss a new resolution on road safety.12 this resolution is sponsored by the government of the russian federation, and it is based on the “moscow declaration” which was declared at the first global ministerial conference on road safety held in russia on 19–20 november 2009.13 at that conference, there were as many as 1,500 participants, including senior ministers of several countries and representatives of un agencies. the participants declared 2011 to 2020 as a “a decade of action for road safety” it became clear at that global conference that the statistics for road traffic crashes are much worse than initially thought. and indeed, it further confirmed the much higher incidence of deaths and injuries from road traffic accidents in developing and poor countries. the key components of the initiative for the decade would include governmental technical assistance; road traffic education; road safety curriculum development; helmets for kids; safe routes to school; research and evaluation and setting up non-profit helmet assembly plants that employ the physically disabled.14 the moscow declaration that resulted from that meeting in november 2009 acknowledged the roles played by the who, the world bank, and the united nations road safety collaboration.15 they also acknowledged that road traffic injuries are major public health problem leading to more than 1.2 million deaths a year and as many as 50 million injuries or disabilities a year, and confirmed road traffic crashes as the leading cause of death among children and young adult between age 5 and 29. the moscow declaration also showed concern that more than 90% of road traffic accidents occur in low-income and middle-income countries. the annual cost of these deaths and injuries run to over us $65 billion. the declaration was convinced that by year 2020, without appropriate action, road traffic deaths will become one of the leading causes of death in low-income and middle-income countries. the conference invited the un general assembly also to declare the decade 2011-2020 as “decade of action for road safety” with a goal to stabilise and then reduce the forecast of global road deaths by 2020. they declared an 11point resolution that covered all the necessary points related to road traffic accidents from encouragement of collaboration, to improving national data collection, and strengthening of the provision of free hospitals and hospital trauma care.15 the declaration also suggested adopting a standard definition of “road death” as, “a person killed immediately or dying within 30 days as a result of road traffic crash”, to facilitate data collection and international cooperation. the moscow declaration stimulated the formation of several ngos as well as inspiring many individuals and organisations to act to reduce road crash deaths and injuries. they asked the international donor community to provide additional funding in support of global, regional, and country road safety particularly in low and middle-income countries. michael bloomberg committed us $125 million to reduce deaths and injuries on world roads.16 in conjunction with this first global ministerial conference on road safety, the asia injury prevention foundation (aipf) also launched a global helmet vaccine initiative in moscow.14 seven multilateral development banks (mdbs) issued a statement in november 2009 outlining a broad package of measures that each would implement in order to reduce the alarming rise in number of fatalities and casualties in developing countries. the participating mdbs included the african development bank, the asia development bank, the european bank for reconstruction and development, the islamic development bank and the world bank. they are committed to taking leading role in addressing this problem. they stressed the need for a systematic and multi-sectorial response to improving road infrastructure, vehicles and positively influencing road-users as well as enhancing post-crash services. in other words, they are determined to address all the elements of road safety [figure 1] with their shared approach. if nothing is done, road traffic accidents will become the third highest cause of death worldwide by the end of this decade. all nations need to be more active in road safety, particularly the low-income and the middle-income nations. all nations need to implement the basic life loss and disability from traffic accidents it is imperative we all act now 4 | squ medical journal, april 2010, volume 10, issue 1 three pillars of road safety, namely infrastructure, safe vehicles, and road user behaviour [figure 2].17 in addition, as the framework for the decade of action declared, there are two additional pillars, namely road safety management and the postcrash care. thus there are five pillars that need to be given much more attention to save lives. in oman, by far the commonest cause of road deaths is excessive speed which caused 57% of all deaths in 2007; overtaking comes next followed by drivers’ neglect and then improper acts by drivers and vehicle condition. thus 4 out of top 5 causes of death in oman are road user error, and they constituted 89% of the causes of road deaths in 2007. this does not include other road user related factors such as tiredness and alcohol, which constitute a total of only 2% of causes of road deaths in oman. we need to do much more in oman. trc and rop have already started doing something for oman and kudos to them. at the recent workshop, they discussed to varying degrees all the five pillars of road safety.4 the main objectives of that workshop were to create public and media awareness regarding the objectives of trc research programmes on road safety. the international experts who attended exchanged knowledge, views, ideas, and research experience on road safety. the workshop discussed the documentation of social and economic cost; legislation and social policy and programmes; social and human behavioural causes of rta; the social impact of traffic incidents and the role of the family; the effectiveness of awareness programmes; legal and compliance issues; analysis of crashes and trauma care. at the workshop, it was preferred to replace the word “accident” with the current terms in vogue: “collision” and “crash”. the workshop dissected the post-crash services in oman and pointed out major discrepancies in the care that exist in the different regions of oman. this naturally has a major impact on the health outcomes of omani victims of road crashes. the pathways of care and the disparities of emergency care in different regions of oman need to be urgently standardised. we all need to take his majesty’s words on road traffic accidents and injuries more seriously. globally, more than half of the total accidents involve drivers aged 15–44 years, and 73% of them are males, according to the world’s worst drivers.18 the who reports that currently the number of deaths is approximately 1.4 million, which means that more than 3,000 people die on the world’s road everyday.19 in addition, 400,000 young people under the age of 25 are killed on road traffic crash every year, namely 1,049 youngsters everyday. most of these traffic deaths occur in low and middle income countries, particularly among pedestrian cyclists, motorcyclists and those using public transportation according to who archives.20 hazen, from the school of public health in alabama, usa, has written that road traffic injuries are leading cause of morbidity, disability and mortality in less developed countries, quoting the figure of >85% of the 1.2 million deaths in 2006 (new figures now show up to 1.4 million deaths per annum) with 10 times that figure in injuries.21 he points out that road traffic injuries will rank third of all major causes of morbidity and mortality globally by 2020. he also indicates that often many of these are preventable, and the technology and the knowledge to achieve success do exist. in this review article, he highlights the problem and the contributing factors as well as the possible actions to be taken, especially the interventions that have proven effective in industrialised nations, many of which have not yet been adopted in less developed countries.21 basically, what we need to do in oman is what the rop and trc have started to do, but we all have to participate and we have to be much more vigorous. we have to address all the five pillars mentioned above and follow the activities of the un road safety collaboration, which are a part of the decade of action for road safety. oman has to join the decade of action for road safety! we have to be advocates for road safety at the highest governmental levels, increase awareness of risk factors and run activities such as the road safety week and annual remembrance day of prayers for victims of road traffic and support the ngo initiatives. we need to adopt the safe system approach [figure 1] and the road safety strategy “towards zero”.22 we also need to provide guidance to the public for good practice such as seatbelts for front and back passengers; mandatory car seats and secure booster seats for children, and other vital actions.23 we have to be more vigorous in the provision of general road safety education through bilingual audio and visual media as discussed above. relevant research, cost-effective intervention and knowledge management must be combined with lamk al-lamki editorial | 5 the will and determination to develop the science and art of better road safety. we should all see the necessity and urgency of participating passionately and zealously in this effort. references 1. freeman h. smashed to pieces a patient’s view of a road traffic accident. squ med j 2010; 10: 135-7. 2. 119 road accidents in a week. from http:// w w w . r o p . g o v . o m / e n g l i s h / n e w s d e t a i l s . asp?catgid=4&newsid=1845 accessed february 2010. 3. overtaking causes 369 accidents in 11 months. from http://www.rop.gov.om/english/newsdetails. asp?catgid=4&newsid=1836 accessed february 2010. 4. oman tribune. editorial: on the right path. from http://www.omantribune.com/index. php?page=e ditorial_details&id=1496&heading accessed february 2010. 5. oman tribune. supplement 24th february 2010. from www.omantribune.com accessed february 2010. 6. department of transportation, oman. transport statistics. from www.dft.gov.uk/pgr/statistics accessed february 2010. 7. gururaj g. from http://www.nimhans.kar.nic.in/ epidemiology/epidem_who.htm accessed february 2010. 8. haddon’s matrix. from http://en.wikipedia.org/wiki/ haddon_matrix accessed february 2010. 9. us bureau of transportation statistics. from www. bts.gov accessed february 2010. 10. who features 2004: road safety: a public health issue. from http://www.who.int/features/2004/ road_safety/en/ accessed february 2010. 11. hosking sg, young kl, regan ma. the effects of text messaging on young drivers. chin j traumatol 2009; 12:259-62. 12. un general assembly discussion on road safety. from http://www.who.int/mediacentre/events/ meetings/2010/road_safety_20100302/en/index. html accessed february 2010. 13. first global ministerial conference on road safety, 19–20 november 2009. from http://www.who.int/ roadsafety/ministerial_conference/en/index.html accessed february 2010. 14. launch of the global helmet vaccine initiative. first global ministerial conference on road safety, moscow, november 2009. from http:// www.asiainjur y.org/main/updates-newsreader/ items/launch_of_the_global_helmet_vaccine_ initiative_18_november_in_moscow.html accessed february 2010. 15. first global ministerial conference on road safety: time for action. moscow declaration 2009. from http://www.who.int/roadsafety/ministerial_ conference/declaration_en.pdf accessed february 2010. 16. michael bloomberg commits $125 million to reduce deaths and injuries on world’s road. from http:// www.who.int/roadsafety/ministerial_conference/ announcement_bloomberg.pdf accessed february 2010. 17. the three pillars of road safety. european road safety charter. from http://www.erscharter.eu/ signatories/page/13557 accessed february 2010. 18. the world’s worst drivers. car accident statistics from around the world http://www.articlesbase. com/cars-articles/the-worlds-worst-drivers-caraccident-statistics-from-around-the-world-609862. html accessed february 2010. 19. violence and injury prevention and disability (vip). from http://www.who.int/violence_injury_ prevention/road_traffic/en/ accessed february 2010. 20. road traffic accident statistics. from http:// roadtrafficaccidents.net/ accessed february 2010. 21. hazen a, ehiri je. road traffic injuries: hidden epidemic in less developed countries. j natl med assoc 2006; 98:73-82. 22. safe systems approach. from http://www.roadsafe. com/news/article.aspx?article=814 accessed february 2010. 23. davey j. carrs-q fleet safety seminar. from http:// www.carrsq.qut.edu.au/documents/work_related_ road_safety_seminar_presentation.pdf. accessed february 2010. 1department of communicable diseases, 2directorate general for disease surveillance & control and 3directorate general of health services, ministry of health, oman *corresponding author’s e-mail: salabri@gmail.com hiv املعرفة واملواقف واملمارسات املرتبطة بوصمة اإلصابة بفريوس األيدز والتمييز لدى العاملني يف جمال الرعاية الصحية بعمان �صمري �صاه، علي اجلالب، عادل الوهيبي، مها الفوري، برا�صنا راجو، حممود ال�صكيتي، هدى ن�صيب املع�صني، كي�صور دوثادي، اإياد عمر، حممد مقيت اهلل، نليجن مرتا، باراج �صاه، حممد اأمني، ع�صام مرق�س، فيدوانن وايديا، زيانة احلب�صي، اإدري�س العبيداين، �صيف �صامل العربي abstract: objectives: stigma and discrimination undermine the quality of life of people with hiv and their access to health services. this study aimed to assess hiv-related knowledge, attitudes and practices among healthcare workers (hcws) in oman. methods: this cross-sectional study took place between july and november 2016. a questionnaire was distributed to 1,400 government hcws to determine hiv-related knowledge, attitudes and practices. results: a total of 1,281 hcws participated (response rate = 92%). routine tasks, such as dressing wounds, drawing blood and touching clothes, were a cause of concern for 24–52% of hcws. only 69% correctly answered questions regarding the transmission of hiv via eating/drinking and mosquito bites. compared to other hcws, doctors had significantly higher knowledge (mean = 0.46, 95% confidence interval [ci]: 0.19 to 0.73; p <0.001), attitude (mean = 0.77, 95% ci: 0.31 to 1.24; p = 0.001) and practice (mean = 2.07, 95% ci: 1.59 to 2.55; p <0.001) scores. expatriates also scored significantly higher in knowledge (mean = 1.08, 95% ci: 0.93 to 1.23; p <0.001), attitude (mean = 1.23, 95% ci: 0.98 to 1.48; p <0.001) and practice (mean = 1.08, 95% ci: 0.82 to 1.34; p <0.001) compared to omani nationals. finally, those with >15 years’ work experience scored significantly higher on knowledge (mean = −0.60, 95% ci: −1.12 to −0.08; p = 0.025) and attitude (mean = −0.99, 95% ci: −1.87 to −0.10; p = 0.029) compared to those with less experience. conclusion: the high rate of hiv-related stigma among hcws in oman should be rectified in order to achieve the 90-90-90 target set by the joint united nations programme on hiv/aids. keywords: hiv; social stigma; social discrimination; knowledge; attitude; professional practice; healthcare providers; oman. امللخ�ص: الهدف: يقو�س التمييز والو�صمة نوعية احلياة للم�صابني بفريو�س الأيدز، وح�صولهم على اخلدمات الطبية. وتهدف هذه الدرا�صة لتقييم املعارف واملواقف واملمار�صات املرتبطة بو�صمة الإ�صابة بفريو�س الأيدز hiv والتمييز لدى العاملني يف جمال الرعاية ال�صحية بعمان. الطريقة: اأجريت هذه الدرا�صة املقطعية العر�صية ما بني يوليو ونوفمرب من عام 2016م. ووزع ا�صتبيان اإىل 1,400 من العاملني باحلكومة يف جمال الرعاية ال�صحية بعمان لتحديد معارفهم ومواقفهم وممار�صاتهم املتعلقة بو�صمة الإ�صابة بفريو�س الأيدز hiv والتمييز. النتائج: �صارك يف ملء ال�صتبيان 1,281 فردا )كانت ن�صبة ال�صتجابة %92(. وكانت الواجبات الروتينية، مثل ت�صميد اجلروح، و�صحب عينات الدم، ومل�س املالب�س م�صدر قلق عند %52-24 من العاملني يف جمال الرعاية ال�صحية. واأجاب %69 فقط منهم على الأ�صئلة اخلا�صة بطرق انتقال الفريو�س عن طريق الأكل اأو ال�رشب وع�س البعو�س. ووجد اأن لالأطباء معارف اأكرث من غريهم من العاملني يف جمال الرعاية ال�صحية )p >0.001؛ 0.73 اإىل 0.19 :فا�صل املوثوقية %95، 0.46 = املتو�صط(. اأما مواقف الأطباء فقد كانت اأف�صل من غريهم من العاملني يف املهن ال�صحية )p = 0.001؛ 1.24 اإىل 0.31 :فا�صل املوثوقية %95، 0.77 = املتو�صط(. وكانت ممار�صات الأطباء اأف�صل مقارنة بغريهم من العاملني يف املهن ال�صحية فقد كانت: )p >0.001؛ 2.55 اإىل 1.59 :فا�صل املوثوقية %95، 2.07 = املتو�صط(. واأحرز الأجانب قيما اأعلى يف املعارف )p >0.001؛ 1.23 اإىل 0.93 :فا�صل املوثوقية %95، 1.08 = املتو�صط( واملواقف )p >0.001؛ 1.48 اإىل 0.98: فا�صل املوثوقية %95، 1.23 = املتو�صط( واملمار�صات )p >0.001؛ 1.34 اإىل 0.82 :فا�صل املوثوقية %95، 1.08 = املتو�صط( من تلك التي اأحرزها املواطنون. واأخريا، وجد اأن العاملني الذين لديهم خربة يف العمل اأكرث من 15 عاما اأحرزوا قيما اأعلى يف املعارف )p = 0.025؛ 0.08اإىل 1.12:فا�صل املوثوقية %95، 0.60= املتو�صط واملواقف )p = 0.029؛ 0.10اإىل 1.87 :فا�صل املوثوقية %95، 0.99= املتو�صط( و، ممن كانت لديهم خربة اأقل. اخلال�صة: ينبغي العمل على اإنقا�س الن�صبة العالية للو�صمة املرتبطة بفريو�س الأيدز عند العاملني يف جمال الرعاية ال�صحية بعمان حتى تبلغ 90-90-90، بح�صب الهدف املن�صود للربنامج امل�صرتك لالأمم املتحدة حول فريو�س الإيدز/ومر�س الإيدز. الكلمات املفتاحية: الو�صمة الجتماعية؛ التمييز الجتماعي؛ املعارف؛ املواقف؛ املمار�صات املهنية؛ مقدمو الرعاية ال�صحية؛ عمان. knowledge, attitudes and practices related to hiv stigma and discrimination among healthcare workers in oman samir shah,1 ali elgalib,1 adil al-wahaibi,2 maha al-fori,1 prasanna raju,1 mahmood al-skaiti,3 huda n. al-mashani,3 kishor duthade,3 iyad omaar,3 muhammad muqeetullah,3 nilanjan mitra,3 parag shah,3 mohammed amin,3 essam morkos,3 vidyanand vaidya,3 zeyana al-habsi,1 idris al-abaidani,1 *seif s. al-abri2 clinical & basic research sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e29–36, epub. 9 mar 20 submitted 13 jun 19 revisions req. 30 jun & 27 aug 19; revisions recd. 7 jul & 20 sep 19 accepted 7 oct 19 https://doi.org/10.18295/squmj.2020.20.01.005 knowledge, attitudes and practices related to hiv stigma and discrimination among healthcare workers in oman e30 | squ medical journal, february 2020, volume 20, issue 1 as per the joint united nations (un) programme on hiv/aids (unaids), hiv stigma is the “process of devaluation” of people living with hiv, compounded by negative assoc iations attached to the two primary methods of hiv transmission (i.e. sexual intercourse and intravenous drug use).1 subsequently, stigma may result in active discrimination, defined as “the unfair and unjust treat ment of an individual based on his or her real or perceived hiv status”.1 overall, negative judgements and actions towards people living with hiv tend to stem from pre-existing beliefs regarding gender, sexuality, race and class within a broader social context.2 elements of stigma and discrimination can seriously undermine quality of life (qol) and can create barriers to accessing and adhering to essential hiv services, both for people living with hiv and high-risk populations.3–5 many deficiencies in hiv prevention, testing and treat ment services are due to the stigma associated with the disease shown by healthcare workers themselves.6 in health settings, stigma and discrimination compromises the provision and quality of care, which is critical for helping patients adhere to medications and maintain overall health and well-being.5 this study aimed to assess hiv-related knowledge, attitudes and practices among governmental healthcare workers in oman. methods this cross-sectional study was conducted from july to november 2016 and targeted healthcare workers employed in the governmental health sector in oman. doctors, nurses, counsellors, pharmacists and other healthcare workers at ministry of health institutions were invited to participate in the study; however, specialists working at specialised hiv treatment centres were excluded. based on an estimated total population of 33,000 governmental healthcare workers, the necessary sample size was calculated to be 1,034 at a 95% conf idence level and confidence interval of three.7 presuming a 75% response rate, 1,400 participants were recruited. participants were asked to complete a previously validated english-language questionnaire to measure hiv-related stigma and discrimination.8–11 specifically, the questionnaire measured attitudes and practices towards people living with hiv in health services, school and the community, as well as stigma related to the ideas of people living with hiv getting married and having children. in addition, in order to assess basic knowledge of hiv, the un’s standardised five-item hiv awareness questionnaire was incorporated into the survey.11,12 the final questionnaire was tested in a pilot study of 50 healthcare workers, with no modifications subsequently deemed necessary. accordingly, 1,400 copies of the questionnaire were distributed at all government health institutes in the country. initial data were collected and entered into a centrally-created data structure for each governorate, after which the data were cleaned, verified and compiled into a national database. data entry and analysis were performed using an excel spreadsheet, version 2013 (microsoft corp., redmond, washington, usa) and r software (r foundation for statistical computing, vienna, austria). categorical responses were presented as freq uencies and percentages. in addition, responses to knowl edge, attitude and practice questions were scored using a scaled-scoring method, with correct or positive responses given a score of one and incorrect and negative or missing responses given a score of zero. questions with four responses (i.e. not worried, a little worried, worried and very worried) were given a score out of four according to the acceptability of the answer. thereafter, the knowledge, attitude and practice scores were summed up for a total score. mean total knowledge, attitude and practice scores were analysed using multivariate linear regression. this allowed for comparison of the effect size (i.e. estimate of contrast) between groups, after controlling for other variables, and was used to examine the relationship between knowledge, practice and attitude scores and other characteristics. the regression was based on the presence or absence of various factors which were converted into ‘dummy’ variables and were scored as one if present and zero if absent. pearson’s correlation coefficient was used to determine correlations between knowledge and attitude scores, attitude and practice scores and knowledge and practice scores. the level of statistical significance was set at p <0.05. this study received ethical approval and was registered with the directorate general for disease surveillance & control, ministry of health. particip ation in the study was purely voluntary and all data were collected anonymously. advances in knowledge the findings of this study reveal hiv-related knowledge, attitudes and practices among governmental healthcare workers in oman. application to patient care the present study forms a basis for future initiatives to reduce discrimination in healthcare settings, in turn enhancing patient care and improving the quality of life of people living with hiv. samir shah, ali elgalib, adil al-wahaibi, maha al-fori, prasanna raju, mahmood al-skaiti, et al. clinical and basic research | e31 results a total of 1,281 healthcare workers participated in the study (response rate = 92%). of these, 52% were omani nationals and 82% were married. the majority were staff nurses (46%), followed by doctors (25%), pharmacists (10%), laboratory technicians (8%) and other workers (8%) [table 1]. regarding knowledge, there was varying awareness of hiv symptoms and transmission patterns. while 74% were aware that the use of a condom mitigated the risk of contracting hiv and 86% knew that hiv patients were of generally healthy appearance, only 69% correctly answered questions regarding the transmission of hiv via eating/drinking and mosquito bites [table 2]. with regards to attitude, 50% of healthcare workers reported that they would not want to buy fresh vege tables from a vendor living with hiv. moreover, 39% believed that people talk badly about individuals thought to be living with hiv and 41% thought that such indiv iduals lose respect or stature in the community. as for marital and reproductive rights, 52% and 45% indicated that people living with hiv should have the right to marry and have children, respectively [table 3]. in terms of hiv-related practices, 27% of health care workers avoided physical contact when providing care/services to a person living with hiv, 24% were worried or very worried about touching their clothing, 47% were worried or very worried about dressing wounds, 52% were worried or very worried about drawing blood and 55% feared contracting hiv if they came into contact with their saliva [table 4]. a multivariate linear regression analysis was carried out to determine associations between socio demographic characteristics and mean knowledge, attitude and practice scores, after controlling for other variables. compared to other healthcare professionals, doctors scored significantly higher in knowledge (mean = 0.46, 95% ci: 0.19 to 0.73; p <0.001), attitude (mean = 0.77, 95% ci: 0.31 to 1.24; p = 0.001) and practice (mean = 2.07, 95% ci: 1.59 to 2.55; p <0.001). in addition, nurses had significantly higher practice scores compared to laboratory technicians and pharmacists (mean = 2.16, 95% ci: 1.71 to 2.61; p <0.001). pharmacists table 1: sociodemographic characteristics of governmental healthcare workers in oman (n = 1,281) characteristic n (%) total male (n = 392) female (n = 889) nationality omani 669 (52) 128 (33) 541 (61) expatriate* 574 (45) 256 (65) 318 (36) unknown 38 (3) 8 (2) 30 (3) marital status married 1,050 (82) 337 (86) 713 (80) single 204 (16) 51 (13) 153 (17) previously married 14 (1) 1 (<1) 13 (1) unknown 13 (1) 3 (1) 10 (1) profession staff nurse 594 (46) 63 (16) 531 (60) doctor 317 (25) 175 (45) 142 (16) pharmacist 131 (10) 54 (14) 77 (9) laboratory technician 98 (8) 44 (11) 54 (6) other† 103 (8) 48 (12) 55 (6) unknown 38 (3) 8 (2) 30 (3) *including indians, filipinos, egyptians, sudanese, pakistanis, tunisians, etc. †including counsellors, physiotherapists, dental technicians, dieticians, x-ray technicians, health educators, refractionists, medical orderlies, etc. table 2: knowledge of hiv symptoms and transmission methods among governmental healthcare workers in oman (n = 1,281) questionnaire item and response n (%) can having sex with only one faithful, uninfected partner reduce the risk of hiv/aids transmission? yes 714 (56) no 229 (18) no answer* 338 (26) can using condoms reduce the risk of hiv/aids transmission? yes 942 (74) no 159 (12) no answer* 180 (14) can a person who looks healthy have hiv/aids? yes 1,097 (86) no 74 (6) no answer* 110 (9) can sharing a drinking glass or eating with an hiv/aids patient transmit the infection? yes 287 (22) no 882 (69) no answer* 112 (9) can a person get hiv/aids from mosquito bites? yes 186 (15) no 885 (69) no answer* 210 (16) *participants preferred not to respond. knowledge, attitudes and practices related to hiv stigma and discrimination among healthcare workers in oman e32 | squ medical journal, february 2020, volume 20, issue 1 table 3: attitudes related to hiv among governmental healthcare workers in oman (n = 1,281) questionnaire item and response n (%) do you think children living with hiv/aids should be able to attend school with children who are hiv-negative? yes 959 (75) no 311 (24) no answer* 11 (1) if a teacher has hiv/aids but is not sick, should he/she be allowed to continue teaching in school? yes 1,024 (80) no 247 (19) no answer* 10 (1) if you knew that an omani vegetable vendor had hiv/aids, would you buy fresh vegetables from him/her?† yes 614 (48) no 644 (50) no answer* 23 (2) do people talk badly about people living or thought to be living with hiv/aids? yes 498 (39) no 301 (23) no answer* 482 (38) do people living or thought to be living with hiv/aids lose respect or stature in the community? yes 521 (41) no 363 (28) no answer* 397 (31) if a member of your family became infected with hiv/aids, would you want it to remain a secret? yes 982 (77) no 285 (22) no answer* 14 (1) if a member of your family became sick with hiv/ aids, would you be willing to care for him or her in your household? yes 1,136 (89) no 133 (10) no answer* 12 (1) would you be ashamed if someone in your family had hiv/ aids? yes 390 (30) no 874 (68) no answer* 17 (1) should people living with hiv/aids feel ashamed of them selves? yes 284 (22) no 978 (76) no answer* 19 (2) should people living with hiv/aids have the right to marry? yes 669 (52) no 597 (47) no answer* 15 (1) hcws = healthcare workers. *participants preferred not to respond. †assuming that no municipality licence rules restrict the vendor from selling vegetables. table 4: practices related to people living with hiv among governmental healthcare workers in oman (n = 1,281) questionnaire item and response n (%) do you avoid physical contact when providing care or services to a person living with hiv/aids? yes 350 (27) no 771 (60) no answer* 160 (12) how worried would you be if you touched the clothing of a person living with hiv/aids? not worried 571 (45) a little worried 301 (23) worried 191 (15) very worried 118 (9) no answer* 100 (8) how worried would you be if you had to dress the wound of a person living with hiv/aids? not worried 171 (13) a little worried 266 (21) worried 263 (21) very worried 329 (26) no answer* 252 (20) how worried would you be if you had to draw blood from a person living with hiv/aids? not worried 180 (14) a little worried 248 (19) worried 257 (20) very worried 406 (32) no answer* 190 (15) do you fear contracting hiv if you come in contact with the saliva of a person living with hiv/aids? yes 707 (55) no 416 (32) no answer* 158 (12) *participants either did not have direct patient care or preferred not to respond. table 3 (cont’d): attitudes related to hiv among govern mental healthcare workers in oman (n = 1,281) questionnaire item and response n (%) should people living with hiv/aids be allowed to have babies? yes 575 (45) no 683 (53) no answer* 23 (2) in the past 12 months, have you observed any hcws unwilling to care for people living with hiv/aids in your healthcare facility? yes 110 (9) no 1,120 (87) no answer* 51 (4) hcws = healthcare workers. *participants preferred not to respond. †assuming that no municipality licence rules restrict the vendor from selling vegetables. samir shah, ali elgalib, adil al-wahaibi, maha al-fori, prasanna raju, mahmood al-skaiti, et al. clinical and basic research | e33 had the lowest scores for knowledge (mean = −0.30, 95% ci: −0.61 to 0.00), attitude (mean = 0.17, 95% ci: −0.35 to 0.68) and practice (mean = −0.11, 95% ci: −0.64 to 0.43). compared to omani nationals, expatriates scored significantly higher in knowledge (mean = 1.08, 95% ci: 0.93 to 1.23; p <0.001), attitude (mean = 1.23, 95% ci: 0.98 to 1.48; p <0.001) and practice (mean = 1.08, 95% ci: 0.82 to 1.34; p <0.001). finally, those with >15 years’ work experience had significantly greater scores for knowledge (mean = −0.60, 95% ci: −1.12 to −0.08; p = 0.025) and attitude (mean = −0.99, 95% ci: −1.87 to −0.10; p = 0.029) compared to those with less experience [table 5]. positive linear correlations were noted between knowledge and attitude (r = 0.26), attitude and practice (r = 0.28) and knowledge and practice (r = 0.20), with all three correlations being statistically significant (p <0.05 each). discussion according to the classifications of the world health organization, the hiv epidemic in oman is at a low level.13,14 this is in part due to the efforts of the national aids programme established in 1987 and various other measures, including community awareness and regular hiv testing and treatment. in addition, hiv services are provided by 14 specialised treatment centres located across the country. as of the end of 2018, a total of 3,025 cases of hiv had been reported, of which 1,532 (50.6%) were still living.15 most cases occurred among men (68%) and individuals aged 25–44 years old (59%); the greatest risk factor was reportedly heterosexual relations (66%).15 in terms of treatment, 84.3% of people living with hiv received antiretroviral therapy, with 87.5% virally suppressed.15 nevertheless, despite the low prevalence of hiv and the availability of treatment, there is still social stigma towards people living with hiv in oman. in a study of 193 people living with hiv in oman, 70% were unwilling to disclose their hiv status to their friends and family, while 61% were uncomfortable at the prospect of doing so.16 the majority (61%) reported relying on their family for financial and emotional support; this is to be expected in a society where cultural traditions consider family to be of paramount importance. despite the availability of social services, many did not accept government assistance, with 75% claiming fears of a breach of privacy as the primary reason for not doing so.16 table 5: associations between dependent variables and hiv-related knowledge, attitude and practice scores among governmental healthcare workers in oman (n = 1,281) variable knowledge attitude practice mean score (95% ci) p value mean score (95% ci) p value mean score (95% ci) p value profession doctor 0.46 (0.19 to 0.73) <0 .001* 0.77 (0.31 to 1.24) 0.001* 2.07 (1.59 to 2.55) <0.001* nurse 0.17 (−0.08 to 0.42) 0.190 0.50 (0.07 to 0.93) 0.024 2.16 (1.71 to 2.61) <0.001* laboratory technician 0.14 (−0.19 to 0.46) 0.398 0.60 (0.05 to 1.16) 0.033* 0.16 (−0.41 to 0.74) 0.582 pharmacist −0.30 (−0.61 to 0.00) 0.049* 0.17 (−0.35 to 0.68) 0.523 −0.11 (−0.64 to 0.43) 0.694 gender female −0.09 (−0.25 to 0.08) 0.296 −0.07 (−0.35 to 0.21) 0.610 −0.04 (−0.33 to 0.25) 0.778 nationality non-omani 1.08 (0.93 to 1.23) <0.001* 1.23 (0.98 to 1.48) <0.001* 1.08 (0.82 to 1.34) <0.001* years of experience <5 −0.32 (−0.84 to 0.21) 0.233 −0.76 (−1.65 to 0.13) 0.095 −0.26 (−1.19 to 0.67) 0.584 5–15 −0.32 (−0.82 to 0.19) 0.224 -0.64 (−1.5 to 0.23) 0.149 −0.41 (−1.31 to 0.49) 0.372 >15 −0.60 (−1.12 to −0.08) 0.025* −0.99 (−1.87 to −0.10) 0.029* −0.50 (−1.43 to 0.42) 0.284 marital status married −0.19 (−0.9 to 0.52) 0.603 −0.63 (−1.84 to 0.58) 0.309 −0.68 (−1.93 to 0.58) 0.292 previously married −0.62 (−1.56 to 0.33) 0.200 −0.74 (−2.34 to 0.87) 0.369 −1.29 (−2.97 to 0.38) 0.129 single −0.32 (−1.05 to 0.40) 0.385 −0.33 (−1.57 to 0.90) 0.598 −0.58 (−1.87 to 0.70) 0.375 ci = confidence interval. knowledge, attitudes and practices related to hiv stigma and discrimination among healthcare workers in oman e34 | squ medical journal, february 2020, volume 20, issue 1 the current study noted a relatively high rate of hiv-related stigma among healthcare workers in the country. a national survey of households in thailand found that 52.1% of respondents would refuse to buy fresh food from a vendor if they knew that the seller had hiv.17 as the same response was given by 50% of healthcare workers in the current study, this prejudicial attitude is likely to be even more prevalent in the omani community. indeed, discriminatory attitudes may be much more common among members of the general public, given that 39% and 41% of the healthcare workers believed that other people would talk negat ively of those living with hiv and that affected indiv iduals would lose respect or stature in the community, respectively. in the current study, there were relatively good levels of knowledge regarding the use of condoms for hiv prevention (74%) and that people living with hiv often appear healthy (86%). however, knowledge was below expectations regarding hiv transmission methods (69%). a much higher percentage (94.5%) of 200 final-year medical students in vietnam were aware of the usage of condoms for hiv prevention.18 moreover, 24–54% of healthcare workers in the present study were either worried or very worried about performing various day-to-day duties for patients living with hiv. this finding is comparable to other research; in thailand, 32–66% of 738 healthcare providers were worried about similar duties, while 23–67% of more than 1,000 healthcare workers from multiple countries were similarly concerned.8,19 stigma often leads to the avoidance of duties. in the present study, 9% of healthcare workers reported having observed others in their institution being unwilling to care for people living with hiv. a study of 922 nurses in jordan found that 84% of nurses refused to provide care to patients who tested positive for hiv/ aids.20 another study from egypt reported that 72.3% of 65 nurses avoided providing care to patients with hiv/aids.21 in a multinational study conducted in 15 countries and involving more than 1,000 healthcare workers, this statistic ranged from 23–30%.8 however, in a study from italy of 107 hospital nurses with good knowledge about hiv, only 2% refused to care for patients based on their hiv status.22 another study of 450 healthcare practitioners in india found that only 4.1% wished they were allowed to refuse to care for people with hiv/aids.23 in the present study, hiv-related knowledge, attitudes and practices were associated with profession; doctors had significantly greater knowledge, attitude and practice scores compared to other healthcare workers, while nurses had better practice scores compared to laboratory technicians and pharmacists. the latter finding might be explained in part by differences in professional duties, with nurses expected to be more ‘hands on’ in terms of patient care compared to other paramedical professions. in addition, the current study observed significantly higher mean knowledge, attitude and practice scores among expatriates. the exact reason for this result is unknown; however, the authors postulate that it may be because of educational and cultural differences. finally, the present study also showed that more years of work experience yielded significantly higher knowledge and attitude scores. it is a basic human right to choose to marry and/or have children, regardless of hiv status.24 however, 47% and 53% of healthcare workers in the present study did not agree with the idea of such individuals having the right to marry and procreate, respectively. similar findings were reported in a study in india, whereby 41% and 37% of 305 doctors, 77% and 73% of 369 nurses and 88% and 86% of 346 ward staff believed that men and women, respectively, with hiv should be forbidden to marry.25 in a multinational study of over 1,000 healthcare workers, 40% were against people living with hiv having the right to procreate.8 the positive three-way correlation between knowl edge, attitude and practice suggests that improving any one of these factors will have a positive impact on the other two. the findings of the current study have various implications, as they clearly demonstrate the need for more hiv-related interactive training for all healthcare workers in oman. such training is also recommended by unaids to help reduce stigma and discrimination for people living with hiv.6 in addition, an hivrelated stigma and discrimination awareness module should be incorporated into the undergraduate and postgraduate curriculum of all health science degrees. finally, further research is needed to better understand the nature of hiv-related stigma and discrimination, both among healthcare workers and in the general community. such measures will help reduce hivrelated stigma and discrimination in the healthcare system in oman, a crucial requirement if the country aimed to achieve the 90-90-90 target set by unaids by 2020.26 the strengths of this study lie in the nationwide participation of healthcare institutions and the large sample size involving a variety of healthcare professionals. in addition, the sample was fairly representative as every government health sector in oman was given the opport unity to participate in the study. however, there were several limitations. the non-response bias was not measured; as participation was voluntary, it is likely that those who agreed to participate already held strong opinions on the topic. moreover, the study assessed only healthcare workers employed in the government samir shah, ali elgalib, adil al-wahaibi, maha al-fori, prasanna raju, mahmood al-skaiti, et al. clinical and basic research | e35 sector, with variable responses across governorates. as such, those working in the private sector may have very different views and attitudes. in addition, the present study could not explain reasons for higher mean scores among expatriates compared to nationals; further study into this finding is necessary. furthermore, like most other questionnaire-based studies, results in the present analysis may have been affected by response bias. conclusion there was a high level of hiv-related stigma among healthcare workers in the governmental health sector in oman. as such, measures to increase knowledge and support positive attitudes and practices should be implemented at all levels of the healthcare system, geared particularly towards omani nationals. such initiatives are necessary if the country is to meet the 90-90-90 target set by unaids. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. joint united nations programme on hiv/aids. fact sheet: stigma and discrimination. from: http://data.unaids.org/publi cations/fact-she et s03/fs_stig ma_discrimination_en.p df accessed: sep 2019. 2. parker r, aggleton p. hiv and aids-related stigma and discrimination: a conceptual framework and implications for action. soc sci med 2003; 57:13–24. https://doi.org/10.1016/ s0277-9536(02)00304-0. 3. banteyerga h, kidanu a, abebe f, alemayehu m, fiseha b, asazenew a, et al. perceived stigmatization and discrimination by health care providers towards persons with hiv/aids. chapel hill, north carolina, usa: intrahealth international inc., 2005. https://doi.org/10.13140/2.1.3556.7687. 4. feyissa gt, abebe l, girma e, woldie m. stigma and discrimination against people living with hiv by healthcare providers, southwest ethiopia. bmc public health 2012; 12:522. https://doi.org/10.1186/1471-2458-12-522. 5. piot p. how to reduce the stigma of aids: keynote address symposium at the xvi international aids conference. from: http://data.unaids.org/pub/speechexd/2006/200608012_sp_ piot_stigma-speech_en.pdf accessed: sep 2019. 6. joint united nations programme on hiv/aids. confronting discrimination: overcoming hiv-related stigma and discrimination in health-care settings and beyond. from: www.unaids.org/sites/default/files/media_asset/confrontingdiscrimination_en.pdf accessed: sep 2019. 7. ministry of health oman. annual health report 2017: chapter four human resources for health. from: www.moh.gov.om/ en/web/statistics/-/20-52 accessed: sep 2019. 8. nyblade l, jain a, benkirane m, li l, lohiniva al, mclean r, et al. a brief, standardized tool for measuring hiv-related stigma among health facility staff: results of field testing in china, dominica, egypt, kenya, puerto rico and st. chris topher & nevis. j int aids soc 2013; 16:18718. https://doi. org/10.7448/ias.16.3.18718. 9. srithanaviboonchai k, stockton m, pudpong n, chariyalertsak s, prakongsai p, chariyalertsak c, et al. building the evidence base for stigma and discrimination-reduction programming in thailand: development of tools to measure healthcare stigma and discrimination. bmc public health 2017; 17:245. https:// doi.org/10.1186/s12889-017-4172-4. 10. health policy project. measuring hiv stigma and discrimi nation among health facility staff: standardized brief question naire. from: www.healthpolicyproject.com/pubs/49_standardi zedbriefquestionnairemeasuringsd.pdf accessed: sep 2019. 11. multiple indicator cluster survey programme. questionnaire for individual women. from: https://microdata.worldbank.org/ index.php/catalog/10/download/84 accessed: sep 2019. 12. joint united nations programme on hiv/aids. global aids response progress reporting 2016: construction of core indicators for monitoring the 2011 united nations political declaration on hiv and aids. from: https://aidsreportingtool. unaids.org/static/docs/garpr_guidelines_2016_en.pdf accessed: sep 2019. 13. world health organization. definition of key terms: consolidated arv guidelines, june 2013. from: www.who.int/ hiv/pub/guidelines/arv2013/intro/keyterms/en/ accessed: sep 2019. 14. joint united nations programme on hiv and aids. unaids data 2019. from: www.unaids.org/sites/default/files/media_ asset/2019-unaids-data_en.pdf accessed: feb 2020. 15. elgalib a, shah s, al-habsi z, al-fouri m, lau r, al-kindi h, et al. the cascade of hiv care in oman, 2015-2018: a population-based study from the middle east. int j infect dis 2020; 90:28–34. https://doi.org/10.1016/j.ijid.2019.09.017. 16. ministry of health, oman. study on the needs of the plhiv and their caregivers in the sultanate of oman [personal communication]. muscat, oman, 2012. 17. srithanaviboonchai k, chariyalertsak s, nontarak j, assanangkornchai s, kessomboon p, putwatana p, et al. stigmatizing attitudes toward people living with hiv among general adult thai population: results from the 5th thai national health examination survey (nhes). plos one 2017; 12:e0187231. https://doi.org/10.1371/journal.pone.0187231. 18. platten m, pham hn, nguyen hv, nguyen nt, le gm. knowledge of hiv and factors associated with attitudes towards hiv among final-year medical students at hanoi medical university in vietnam. bmc public health 2014; 14:265. https://doi.org/10.1186/1471-2458-14-265. 19. international health policy program, thailand ministry of public health. report of a pilot: developing tools and methods to measure hiv-related stigma and discrimination in health care settings in thailand. nonthaburi, thailand: international health policy program, 2014. 20. hassan zm, wahsheh ma. knowledge and attitudes of jordanian nurses towards patients with hiv/aids: findings from a nationwide survey. issues ment health nurs 2011; 32:774–84. https://doi.org/10.3109/01612840.2011.610562. 21. magdi hm, abd el-fatah sr, nawal aa, afefe ah. knowledge, attitudes and practice of nurses working with hiv/aids patients. egypt j health care 2013; 4:1–14. 22. marranzano m, ragusa r, platania m, faro g, coniglio ma. knowledge, attitudes and practices towards patients with hiv/aids in staff nurses in one university hospital in sicily. epidemiol biostat public health 2013; 10:e8731-1–6. https://doi.org/10.2427/8731. https://doi.org/10.1016/s0277-9536%2802%2900304-0 https://doi.org/10.1016/s0277-9536%2802%2900304-0 https://doi.org/10.13140/2.1.3556.7687 https://doi.org/10.1186/1471-2458-12-522 https://doi.org/10.7448/ias.16.3.18718 https://doi.org/10.7448/ias.16.3.18718 https://doi.org/10.1186/s12889-017-4172-4 https://doi.org/10.1186/s12889-017-4172-4 https://doi.org/10.1016/j.ijid.2019.09.017 https://doi.org/10.1371/journal.pone.0187231 https://doi.org/10.1186/1471-2458-14-265 https://doi.org/10.3109/01612840.2011.610562 https://doi.org/10.2427/8731 knowledge, attitudes and practices related to hiv stigma and discrimination among healthcare workers in oman e36 | squ medical journal, february 2020, volume 20, issue 1 23. yadav ss, yadav s, mishra p. knowledge and risk perception regarding hiv among healthcare workers in a medical college hospital. int j med sci public health 2014; 3:73–5. https://doi. org/10.5455/ijmsph.2013.051020131. 24. global network of people living with hiv/aids. advancing the sexual and reproductive health and human rights of people living with hiv: a guidance package. from: www.unfpa. org/sites/default/files/resource-pdf/guidance_package.pdf accessed: sep 2019. 25. ekstrand ml, ramakrishna j, bharat s, heylen e. prevalence and drivers of hiv stigma among health providers in urban india: implications for interventions. j int aids soc 2013; 16:18717. https://doi.org/10.7448/ias.16.3.18717. 26. joint united nations programme on hiv/aids. 90-90-90: an ambitious treatment target to help end the aids epidemic. from: https://www.unaids.org/sites/default/files/media_asset/ 90-90-90_en.pdf accessed: sep 2019. https://doi.org/10.5455/ijmsph.2013.051020131 https://doi.org/10.5455/ijmsph.2013.051020131 https://doi.org/10.7448/ias.16.3.18717 1department of graduate school of comprehensive human sciences, university of tsukuba, tsukuba, japan; 2department of community nursing, musasahino university, tokyo, japan; 3department of physical therapy, morinomiya university of medical sciences, osaka, japan; 4college of nursing and nutrition, syukutoku university, chiba, japan; 5nursing and medical care, keio university, minato city, japan; 6department of public welfare, tobishima muncipality, tobishima, japan *corresponding author’s e-mail: anmet@md.tsukuba.ac.jp eating behaviour-consumption frequency of certain foods in early childhood as a predictor of behaviour problems 6-year follow-up study ammara ajmal,1 kumi watanabe,1 emiko tanaka,2 yuko sawada,3 taeko watanabe,4 etsuko tomisaki,5 sumio ito,6 rika okumura,6 yuriko kawasaki,6 *tokie anme1 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 225–232, epub. 26 may 22 submitted 21 oct 20 revisions req. 10 dec 20 & 31 jan 21; revisions recd. 6 jan & 9 feb 21 accepted 25 feb 21 https://doi.org/10.18295/squmj.5.2021.103 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. eating behaviour is one of the deter-minants of nutrient access and deficiency in early childhood. food consumption frequency represents how often one consumes certain food items.1 it is evident from previous research that dietary habits acquired in childhood persist throughout life, and early childhood is crucial, as this is when particular dietary habits and sedentary behaviour patterns become established.2,3 eating behaviour is a broad term; recent previous research focusing on the preferences of food items in early childhood reported differences in nutrient intake and unfavourable growth patterns in early childhood.4 food consumption frequency during this developmental stage can have long-term effects on health and cause conditions such as coronary heart disease, diabetes and some cancers.5 currently, there is a trend in the literature moving from the effects of specific nutrients to overall eating behaviour on mental health. previous research has covered the beneficial effects of specific nutrients on cognition and behaviour.6 furthermore, good dietary habits have been found to have positive effects on learning and attention and to reduce behavioural problems.7 behaviour problems are becoming prevalent among children and many such children are unidentified and untreated. early behavioural difficulties are associated with a higher risk of persistence later in life; thus, such early behaviour requires parental attention.8 one review found that there was a lack of evidence from shortabstract: objectives: this study aimed to evaluate food consumption frequency in 1–6-year-olds as an eating behaviour-related predictor of behavioural problems over a span of six years. eating behaviour in early childhood serves as a foundation for future health outcomes. diet patterns can have long-term beneficial or adverse effects on social behaviour development. methods: this longitudinal study was performed based on information obtained between july 2011 and august 2017 provided from a project named ‘community empowerment and care for wellbeing and health longevity’ initiated in 1991; the current study involved 124 mother-child dyads from the project. children aged 1–6 years were studied in july 2011, with a follow-up assessment in august 2017. the primary exposure examined was the frequency of food items intake. the primary outcome was behaviour problems as assessed by the strengths and difficulties questionnaire (sdq). results: the adjusted results suggested that a higher intake of leafy green and light-coloured vegetables were significantly associated with decreased odds of conduct problems and prosocial behaviour problems in japanese children. however, no associations were observed among fruits, milk, small fish, eggs, soybeans, seaweed and any sdq subscales. conclusion: this study shows that eating leafy green and light-coloured vegetables may have a protective effect on a child’s conduct and against prosocial behaviour problems. due consideration should be given to children’s eating habits in the early stages of their lives to ensure better mental health. keywords: child; diet; impulsive behaviour; longitudinal studies; mental health; nutrients; sugars; vegetables. advances in knowledge this study found that eating habits in early childhood can serve as a foundation for future behavioural development. adding leafy green and light-coloured vegetables in the diet at an early age can improve prosocial behaviour and prevent behaviour problems from developing later in life. application to patient care paediatricians, nutritionists and psychiatrists should encourage parents to add vegetables in children’s diet at an early age to reap the beneficial effects on the child’s mental health. https://creativecommons.org/licenses/by-nd/4.0/ eating behaviour-consumption frequency of certain foods in early childhood as a predictor of behaviour problems 6-year follow-up study 226 | squ medical journal, may 2022, volume 22, issue 2 term experimental studies for causality between diet— especially sugar intake—and behavioural problems.9 this review emphasised the need for future studies to explore the association between diet and hyperactivity during childhood. one previous study conducted on korean children reported fewer learning, attention and behaviour problems among children with a higher consumption of dairy products and vegetables.7 childhood is a pivotal period for the development of behaviour and cognition. most previous studies have focussed on the associations between behaviour problems and infant breastfeeding duration or academic achievements.10,11 one of the domains about which these studies do not provide detailed information is the association between early eating habits in terms of food consumption frequency and behaviour problems in the early years of life. a healthy diet is related to better cognitive and behavioural function.12,13 additionally, the consumption of a diet containing saccharides such as fruits and vegetables can improve the symptoms of attention deficit/hyperactivity disorder.13 diets with low levels of micro-nutrients and higher polyunsaturated fatty acids were found to be associated with behavioural problems such as hyperactivity and aggression.11,14 in another study, children with behaviour problems have been reported to be from homes with poor family function. low consumption of vegetables and fruits has also been reported among these families. additionally, in this study, daughters of parents with psychological distress had lower consumption of fruits and vegetables than other children.15 another review also reported that fathers’ involvement in rearing children is associated with reduced behaviour problems.16 dietary patterns in terms of food consumption frequency are known to vary among regions and most studies regarding dietary pattern and behavioural problems have been conducted in western countries. similar studies are needed to explore dietary patterns in asian countries. previous studies have been restricted to diets with a shortage of nutrients or food components. the concept of eating behaviour during childhood is an open research topic, especially regarding its effect on behavioural development. furthermore, little evidence has been provided regarding the assoc iation between eating behaviour in early childhood and behaviour problems later in life. therefore, the purpose of the study was to examine the association between eating behaviour, specifically food cons umption frequency in children aged 1–6 years and their behaviour problems over a span of six years. it is hypothesised that eating behaviour in early childhood could predict behaviour problems in children later in their lives. methods this study used the data from the ‘community empowerment and care for well-being and health longevity’ (cec) cohort. the cec is a longitudinal study that began in 1991 aiming to examine the factors associated with the well-being and health longevity of the residents of a suburban area in central japan with approximately 5,000 residents. questionnaires are distributed to all participants approximately every three years. the goal of the series of surveys was to provide information for creating health-promotion programmes to enhance the residents’ quality of life. to avoid selection bias, this study utilised the questionnaire survey by introducing a complete sampling frame. the survey was conducted by the researchers in collaboration with the municipal government and local volunteers were assigned to distribute the questionnaires and collect them two weeks later to ensure that it was convenient for the residents to participate. during the baseline year, 2011, 185 mothers with children aged 1–6 years responded to the survey. the data of six children from the baseline year were excluded due to the reporting of mental health issues. in the 6-year follow-up, 34 of the mothers who had previously participated were no longer available (due to having moved or other similar reasons) and 21 others were dropped due to having missing values in the strengths and difficulties questionnaire (sdq). therefore, the 2017 data (the most recent year for which data was available) reported by 124 mothers, for whom there was no missing information, were included and analysed in the present study to examine the association between frequency of food consumption and children’s behaviour problems. the authors assessed children’s behaviour problems utilising the parent-reported japanese version of the sdq.17 the sdq is a brief behavioural screening tool incorporating 25 items divided equally among five subscales; 1) conduct problems (e.g. the child often loses his/her temper); 2) emotional symptoms (e.g. the child has many worries or often seems worried); 3) hyperactivity/inattention (e.g. the child is restless, overactive and cannot sit still for long); 4) peer relationship problems (e.g. the child is rather solitary or prefers to play alone); and 5) prosocial behaviour (positive behaviours, e.g. the child is considerate of other people’s feelings). each item is scored using a three-point likert scale (0 = not true, 1 = somewhat true and 2 = certainly true). scores for each item are summed to calculate subscale scores ranging from 0 to 10. subscale scores for conduct problems, emotional symptoms, hyperactivity/inattention and ammara ajmal, kumi watanabe, emiko tanaka, yuko sawada, taeko watanabe, etsuko tomisaki, sumio ito, rika okumura, yuriko kawasaki and tokie anme clinical and basic research | 227 peer relationship problems are used to calculate a total difficulties score (the sum of 20 items), ranging from 0 to 40, and a prosocial behaviour score ranging from 0 to 10. the score for prosocial behaviour is not incorporated in the total difficulty score, as prosocial behaviour is conceptually different from psychological problems. a higher total difficulty score indicates a higher risk of development of subsequent subscale behaviour problems. in contrast, higher scores in prosocial behaviour indicate a lower risk of developing prosocial behaviour problems. continuous sdq scores are meaningful in epidemiological data and suitable for longitudinal studies, as they are sensitive to changes in children.18,19 however, the authors categorised them into ‘normal’ and ‘risk’ groups based on the japanese standard sdq scores (a 20% cut-off measured from the negative region of the spectrum). risk groups were defined by scores of 4–10 points for the conduct problems, emotional symptoms and peer relationship problems scales; 6–10 points for the hyperactivity scale; and 13–40 points for total difficulty.20 for the prosocial behaviour scale, scores of 0–5 points indicate those at risk.20 the parent-reported version of the sdq is as efficient as a semi-structured interview technique and evidence has been provided for strong psychometric properties across several countries.18,21 the reliability of the japanese version of sdq has been previously assessed, with reports showing the internal consistency coefficients (cronbach’s alpha) for the five subscales ranging from 0.52–0.69 and 0.77 for the total difficulty measurement.20 eating behaviour was measured using motherreported items about children’s eating frequency per week for different food items at baseline. mothers were asked ‘how often does your child eat the following per week?: leafy green vegetables (e.g. spinach), lightcoloured vegetables (e.g. cabbage), fruits, soybeans and soy products (e.g. tofu), milk and dairy products, eggs, fish and seaweed’. mothers responded using a four-point likert scale (1 = little, 2 = 1–2 times per week, 3 = 3–4 times per week, 4 = nearly every day). the response alternatives were dichotomised into frequent consumption patterns and rare (infrequent) consumption patterns. consuming a food item 3–4 times per week or more constituted frequent consumption and 0–2 times per week constituted rare consumption.22 the quantity of food intake was not recorded; only the frequency of consumption was recorded for the different food items. the authors collected data from mothers regarding demographic characteristics (i.e. age, gender, family structure and siblings), health information (i.e. any acute illness, having a paediatrician and sleep pattern) and parental care (i.e. mother’s stress, father’s support and parent-child interaction). demographic character istics such as age (date of birth), gender (1 = boy and 2 = girl), family structure (dichotomised as living with father and mother as a nuclear family vs living with parents and grandparents as an extended family), siblings (1 = yes and 2 = no), health information (e.g. acute illness; 1 = yes and 2 = no), sleep condition (dichotomised into sufficient sleep if ‘always’ and insufficient sleep if ‘sometimes’ or ‘not much’; reported by respondents as 1 = yes always, 2 = sometimes and 3 = not much), having a paediatrician (1 = yes and 2 = no), parental information such as mother’s stress (dichotomised into always vs sometimes if response was sometimes, rarely or very little), father support (dichotomised into always proactive vs sometimes if response was ‘sometimes’ or ‘reluctant’) and parental interaction (dichotomised into every day if response was ‘always’ and ‘a few times’ a week if response was ‘3–4’ times/week, ‘1–2’ times/week, or ‘rarely’). the authors chose these variables because they represented factors that could confound the relationship between eating habits and social-emotional development. the main exposure was eating leafy green vegetables, light-coloured vegetables, fruits, soybeans and soy products, milk and dairy products, eggs, fish and seaweed. outcomes were conduct problems, emotional symptoms, hyperactivity/inattention and the scores of the peer relationship problems subscale, prosocial behaviour scale and total difficulty. there were three phases in the present analysis. in the first phase, descriptive statistics were defined using frequencies. in the second phase, fischer’s exact test was used for the bivariate analysis to examine related factors with five aspects of the sdq and total difficulty score. in the third phase, a multiple logistic regression model was used for a multivariable analysis and to explore the association between eating habits and socialemotional development. only those factors meeting statistical significance in the fischer’s exact test were included in the regression model. out of the total six outcomes, conduct problems and prosocial behaviour were based on the result of fischer’s exact test. two exposures were used in each logistic regression model: leafy green vegetables and light-coloured vegetables. the authors adjusted the regression models for demographic characteristics, health information and parental care; both sdq subscales were added separately. the analysis was carried out using sas (university edition; sas institute, cary, nc, usa). statistical significance was set to p <0.05. ethics approval for the cec was provided by the ethics committee of the university of tsukuba (13311). all participants provided written consent before participation. eating behaviour-consumption frequency of certain foods in early childhood as a predictor of behaviour problems 6-year follow-up study 228 | squ medical journal, may 2022, volume 22, issue 2 results in total, data of 124 children aged 1–6 years were used in the study; this sample comprised of 67 (54.0%) boys and 57 (46.0%) girls. of the participants, 99 (79.8%) had siblings and 83 (66.9%) lived with their extended families. in addition, 59 (47.6%) mothers in the dyads were stressed and only 30 (24.2%) fathers supported mothers in childcare [table 1]. regarding the other demographic characteristics (i.e. age, family type, siblings, sleep and father’s support), association with behaviour problems was not evident in the present study. regarding the bivariate association of participant’s characteristics and behaviour problems, conduct behaviour risk in children was significantly associated with mother’s stress (p = 0.02), acute illness (p = 0.04) and having a paediatrician (p = 0.03). prosocial behaviour was found to be significantly associated with gender (p = 0.01) and parent-child interaction (p <0.01) [table 2]. regarding the consumption frequency of milk, fruits, soybean and soy products, eggs, small fish and seaweed, no significant association was revealed in the bivariate analysis. the bivariate analysis between the food consumption frequency and behaviour problems revealed a significant association between conduct behaviour and the frequency of consumption of leafy green (p <0.01) and light-coloured vegetables (p <0.01). additionally, the authors also found a significant association between prosocial behaviour and frequency of consumption of leafy green (p <0.01) and light-coloured vegetables (p <0.01) [table 3]. logistic regression was conducted for the two outcomes that showed significant results in the bivariate analysis. table 4 and table 5 show the multivariable regression analysis results of both unadjusted and adjusted models (adjusted for age, gender, family type, siblings, any acute illness, having a paediatrician, sleep pattern, mother’s stress, father’s support and parent-child interaction) for the conduct problems and prosocial behaviour problems subscales. the multivariable regression analysis showed that children with frequent consumption of leafy green vegetables had 0.12-fold lower odds of conduct behaviour problem and 0.23-fold lower odds of prosocial behaviour problems than children consuming leafy green vegetables rarely. additionally, children with frequent consumption of light-coloured vegetables have 0.19-fold lower odds of conduct behaviour problem and 0.19-fold lower odds of prosocial behaviour problems than children consuming these vegetables rarely. there was strong evidence for associations among frequent consumption of leafy green vegetables, light-coloured vegetables and the sdq subscales (conduct problems and prosocial behaviour). children frequently consuming leafy green and light-coloured vegetables showed a decreased risk of conduct and prosocial behaviour problems, both before and after adjustment. there were no associations between other food groups and any sdq subscales. discussion this study examined the association between eating habits in early childhood (1–6 years old) and behaviour problems over the span of six years in a sample of table 1: participant demographics at the baseline year of the study, 2011 (n = 124) items n rate in percent age in years 1–3 63 50.8 4–6 61 49.2 gender boys 67 54.0 girls 57 46.0 family type nuclear family 41 33.1 extended family 83 66.9 siblings no 25 20.2 yes 99 79.8 acute illness yes 13 10.5 no 111 89.5 enough sleep always 108 87.1 sometimes 16 12.9 having a paediatrician yes 83 66.9 no 41 33.1 mother’s stress yes 59 47.6 no 65 52.4 father’s support yes 30 24.2 no 94 75.8 parent-child interaction everyday 91 73.4 few times a week 33 26.6 ammara ajmal, kumi watanabe, emiko tanaka, yuko sawada, taeko watanabe, etsuko tomisaki, sumio ito, rika okumura, yuriko kawasaki and tokie anme clinical and basic research | 229 table 2: associations between demographic characteristics and behaviour problems six years later (n = 124) demographic variables category total conduct problem prosocial behaviour n (%) p value* n (%) p value* normal group risk group normal group risk group gender boys 67 43 (64.2) 24 (35.8) 0.14 30 (44.8) 37 (55.2) 0.01 girls 57 35 (61.4) 22 (38.6) 36 (63.2) 21 (36.8) acute illness yes 13 5 (38.5) 8 (61.5) 0.04 9 (69.2) 4 (30.8) 0.11 no 111 73 (65.8) 38 (34.2) 57 (51.4) 54 (48.6) having a paediatrician yes 83 47 (56.6) 36 (43.4) 0.03 41 (49.4) 42 (50.6) 0.07 no 41 31 (75.6) 10 (24.4) 25 (61.0) 16 (39.0) mother’s stress yes 59 32 (54.2) 27 (45.8) 0.02 32 (54.2) 27 (45.8) 0.13 no 65 46 (70.8) 19 (29.2) 34 (52.3) 31 (47.7) parent–child interaction everyday 91 60 (65.9) 31 (34.1) 0.08 56 (61.5) 35 (38.5) <0.01 few times a week 33 18 (54.5) 15 (45.5) 10 (30.3) 23 (69.7) *results determine using fischer’s exact test. p values of <0.05 were considered significant. table 3: association between food consumption frequency and behaviour problems six years later food items category total conduct problems prosocial behaviour p value* n (%) normal group risk group normal group risk group leafy vegetables frequently 102 72 (70.6) 30 (29.4) 63 (61.7) 42 (41.2) <0.01 rare 22 6 (27.2) 16 (72.7) 6 (27.3) 16 (72.7) light-coloured vegetables frequently 105 72 (68.6) 33 (31.4) 62 (59.1) 43 (40.9) <0.01 rare 19 6 (31.6) 13 (68.4) 4 (21.1) 15 (78.9) *results of fischer’s exact test. p-values of <0.05 were considered significant. table 4: results of multiple logistic regression showing the odds of conduct problems with relation to eating vegetables food items unadjusted or p value adjusted or* p value or 95% ci or 95% ci leafy green vegetables 0.15 0.05–0.43 <0.001 0.12 0.04–0.41 <0.001 light-coloured vegetables 0.21 0.07–0.61 <0.001 0.19 0.06–0.61 0.005 or = odds ratio; ci = confidence interval. *adjusted for demographic characteristics (age, gender, family type and siblings), health information (any acute illness, having a paediatrician, and sleep pattern), and parental care (mother’s stress, father’s support and parent–child interaction). table 5: results of multiple logistic regression showing the odds of prosocial behaviour problems with relation to eating vegetables food items unadjusted or p value adjusted or* p value or 95% ci or 95% ci leafy green vegetables 0.26 0.09–0.72 0.01 0.23 0.07–0.74 0.01 light-coloured vegetables 0.18 0.05–0.59 <0.01 0.19 0.05–0.69 0.01 or = odds ratio; ci = confidence interval. *adjusted for demographic characteristics (age, gender, family type and siblings), health information (any acute illness, having a paediatrician, and sleep pattern) and parental care (mother’s stress, father’s support and parent–child interaction). eating behaviour-consumption frequency of certain foods in early childhood as a predictor of behaviour problems 6-year follow-up study 230 | squ medical journal, may 2022, volume 22, issue 2 children from a suburban area in central japan. the hypothesis that eating behaviour in early childhood would be associated with behaviour problems was partially supported. of the different food groups, only leafy green vegetables and light-coloured vegetables were associated with factors of behavioural development, such as problems with conduct and prosocial behaviour. the results showed that children who frequently consumed leafy green vegetables and light-coloured vegetables in the early years of their lives showed lower odds for conduct and prosocial behaviour problems. to the best of the authors’ knowledge, this relationship has not been shown previously in studies on early childhood from japan. few studies have explored the relationship between behavioural development and food consumption frequency in early childhood. a recent australian study showed that children who had behavioural problems, lower prosocial behaviours and were from poorly functioning household, consumed fewer fruits and vegetables.15 this is consistent with the results of the present study regarding vegetable intake. however, in the present study, no association was found between fruit intake and behaviour problems. this study sought to examine the effects early childhood eating behaviours have on social behaviour development, filling a gap in the literature from previous research, which focussed on adolescents.22 peacock et al. demonstrated that a ‘junk pattern’ and non-milk extrinsic sugar are associated with total difficulty scores and low prosocial behaviour scores.23 however, these associations were attenuated substantially following adjustment. in this study, the authors did not observe any associations between any food items and total difficulty scores. fish intake is associated with omega-3 fatty acids and an early study in japan and a later review showed that having a high number of behaviour problems is associated with low total omega-3 fatty acid intake.24,25,26 however, a study conducted in australia found no association between fatty acids and attention-deficit/hyperactivity disorder symptoms.27 furthermore, a randomised controlled trial showed no improvement in children with aggression and disruptive behaviour with fish oil treatment.28 the authors can relate these findings to the results of the present study, in that the authors did not find any association between a low intake of fish and behaviour problems. this result could have occurred because the age group measured at baseline was 1–6 years and the frequency of fish intake was lower in the present study’s total sample than it would be with older participants. this study reports findings demonstrating a significant association between vegetable intake and behaviour problems in childhood. the mechanism behind this relationship is not yet clear; however, a possible mechanism may be connected to the function of dopamine in maintaining attention and controlling impulsive behaviour.29 vitamins b6 and c act as coenzymes involved in the production of dopamine and vegetables are a source of vitamin b6 and vitamin c.12 the primary strength of this study was the collection of detailed data from a large prospective cohort in central japan. the collection of data on chronic disease status during the baseline year helped exclude children with a mental illness. moreover, it enabled the investigation of ‘new cases’ of behavioural problems. in addition, the wealth of data collected throughout the cohort permitted the authors to adjust for several potential confounders. a potential limitation of this study was that only one suburban community from central japan was included in the study; therefore, a more comprehensive geographical survey should be conducted to generalise the results. the authors utilised parentally completed sdq scores, which could have led to parents underestimating behavioural problems, which would have decreased the likelihood of associations with other food items. another limitation is that several potential factors that previous studies noted to be associated with behaviour problems, such as the family’s socioeconomic status, parents’ educational level and the mother’s well-being were not included in the questionnaire. the authors aimed to clarify which food item consumed at the baseline year is associated with behaviour development; therefore, the authors did not assess eating behaviour as a time-varying covariate. further detailed investigations are required to explore changes in eating behaviour and behaviour development. it is possible that using food frequency questionnaires to determine underlying eating behaviour may not be an appropriate method for this particular outcome. using a quantitative analysis for each food item could have provided further associations. however, a validation study showed that a food frequency questionnaire could identify those with high and low food intake and showed a moderate capability for ranking individuals by food intake.30 neurodevelopmental disorders, such as conduct disorders, are moderately heritable with different genetic factors; however, it was out of scope for the present study. in the future, genetic factors and biological and environmental factors should be considered together to explore the causality. ammara ajmal, kumi watanabe, emiko tanaka, yuko sawada, taeko watanabe, etsuko tomisaki, sumio ito, rika okumura, yuriko kawasaki and tokie anme clinical and basic research | 231 conclusion keeping the aforementioned admonition in mind, the findings of the present study are consistent with those showing associations between diet and mental health, offering evidence indicating that a diet rich in vegetables could prevent behaviour problems in children. given the considerable pressure of increasing behaviour problems in children, determining whether the introduction of vegetables in the diet could prevent behaviour problems is of principal public health importance. more research is warranted to examine this relationship. future studies should also incorporate some interventional studies to determine whether dietary habits could prevent or improve behaviour problems in children. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by grants-in-aid for scientific research (17h02604). a u t h o r s’ c o n t r i b u t i o n aa conceptualised the study, synthesised the analysis plan, managed and analysed the data, interpreted findings and led the writing of the manuscript. kw was responsible for study coordination, data collection, and subsequent revisions. ett, ys, tw, emt, si, ro, and yk contributed to data collection. ta is the principal investigator on the project and assisted in the revisions of the manuscript. all authors approved the final version of the manuscript. references 1. gomez p, schneid n, delaere f. how often should i eat it? product correlates and accuracy of estimation of appropriate food consumption frequency. food qual prefer 2015; 40:1–7. https://doi.org/10.1016/j.foodqual.2014.07.018. 2. movassagh ez, baxter-jones adg, kontulainen s, whiting sj, vatanparast h. tracking dietary patterns over 20 years from childhood through adolescence into young adulthood: the saskatchewan pediatric bone mineral accrual study. nutrients 2017; 9:990. https://doi.org/10.3390/nu9090990. 3. reilly jj. physical activity, sedentary behaviour and energy balance in the preschool child: opportunities for early obesity prevention. proc nutr soc 2008; 67:317–25. https://doi.org/10.1017/s002 9665108008604. 4. kwon km, shim je, kang m, paik h-y. association between picky eating behaviors and nutritional status in early childhood: performance of a picky eating behavior questionnaire. nutrients 2017; 9:463. https://doi.org/10.3390/nu9050463. 5. world health organization. diet, nutrition, and the prevention of chronic diseases report of a joint who/fao expert consultation. geneva, switzerland: world health organization, 2003. who trs 916. 6. spencer jpe. the impact of fruit flavonoids on memory and cognition. br j nutr 2010; 104:s40–7. https://doi.org/10.1017/ s0007114510003934. 7. park s, cho s-c, hong y-c, oh s-y, kim j-w, shin m-s, et al. association between dietary behaviors and attention-deficit/ hyperactivity disorder and learning disabilities in schoolaged children. psychiatry res 2012; 198:468–76. https://doi. org/10.1016/j.psychres.2012.02.012. 8. treyvaud k, doyle lw, lee kj, roberts g, lim j, inder te, et al. social-emotional difficulties in very preterm and term 2 year olds predict specific social-emotional problems at the age of 5 years. j pediatr psychol 2012; 37:779–85. https://doi. org/10.1093/jpepsy/jss042. 9. bellisle f. effects of diet on behaviour and cognition in children. br j nutr 2004; 92:s227–32. https://doi.org/10.1079/ bjn20041171. 10. belfort mb, rifas-shiman sl, kleinman kp, bellinger dc, harris mh, taveras em, et al. infant breastfeeding duration and mid-childhood executive function, behavior, and socialemotional development. j dev behav pediatr 2016; 37:43–52. https://doi.org/10.1097/dbp.0000000000000237. 11. hinshaw sp. externalizing behavior problems and academic underachievement in childhood and adolescence: causal relationships and underlying mechanisms. psychol bull 1992; 111:127–55. https://doi.org/10.1037/0033-2909.111.1.127. 12. kim jy, kang sw. relationships between dietary intake and cognitive function in healthy korean children and adolescents. j lifestyle med 2017; 7:10–17. https://doi.org/10.15280/jlm.2 017.7.1.10. 13. dykman kd, dykman ra. effect of nutritional supplements on attentional-deficit hyperactivity disorder. integr physiol behav sci 1998; 33:49–60. https://doi.org/10.1007/bf02688675. 14. benton d. the influence of dietary status on the cognitive performance of children. mol nutr food res 2010; 54:457–70. https://doi.org/10.1002/mnfr.200900158. 15. renzaho amn, kumanyika s, tucker kl. family functioning, parental psychological distress, child behavioural problems, socioeconomic disadvantage and fruit and vegetable consump tion among 4-12 year-old victorians, australia. health promot int 2011; 26:263–75. https://doi.org/10.1093/heapro/daq054. 16. jorosi-tsiamo wb, mogobe kd, mokotedi mt. male involvement in child care activities: a review of the literature in botswana. afr j reprod health 2013; 17:35–42. 17. goodman r, scott s. comparing the strengths and difficulties questionnaire and the child behavior checklist: is small beautiful? j abnorm child psychol 1999; 27:17–24. https://doi. org/10.1023/a:1022658222914. 18. goodman a, goodman r. strengths and difficulties question naire as a dimensional measure of child mental health. j am acad child adolesc psychiatry 2009; 48:400–3. https://doi. org/10.1097/chi.0b013e3181985068. 19. ford t, collishaw s, meltzer h, goodman r. a prospective study of childhood psychopathology: independent predictors of change over three years. soc psychiatry psychiatr epidemiol 2007; 42:953–61. https://doi.org/10.1007/s00127-007-0272-2. 20. matsuishi t, nagano m, araki y, tanaka y, iwasaki m, yamashita y, et al. scale properties of the japanese version of the strengths and difficulties questionnaire (sdq): a study of infant and school children in community samples. brain dev 2008; 30:410–5. https://doi.org/10.1016/j.braindev.2007.12.003. 21. stone ll, otten r, engels rcme, vermulst aa, janssens jmam. psychometric properties of the parent and teacher versions of the strengths and difficulties questionnaire for 4 to 12-year-olds: a review. clin child fam psychol rev 2010; 13:254–74. https://doi.org/10.1007/s10567-010-0071-2. 22. øverby n, høigaard r. diet and behavioral problems at school in norwegian adolescents. food nutr res 2012; 56:17231. https://doi.org/10.3402/fnr.v56i0.17231. https://doi.org/10.1016/j.foodqual.2014.07.018 https://doi.org/10.3390/nu9090990 https://doi.org/10.1017/s0029665108008604 https://doi.org/10.1017/s0029665108008604 https://doi.org/10.3390/nu9050463 https://doi.org/10.1017/s0007114510003934 https://doi.org/10.1017/s0007114510003934 https://doi.org/10.1016/j.psychres.2012.02.012 https://doi.org/10.1016/j.psychres.2012.02.012 https://doi.org/10.1093/jpepsy/jss042 https://doi.org/10.1093/jpepsy/jss042 https://doi.org/10.1079/bjn20041171 https://doi.org/10.1079/bjn20041171 https://doi.org/10.1097/dbp.0000000000000237 https://doi.org/10.1037/0033-2909.111.1.127 https://doi.org/10.15280/jlm.2017.7.1.10 https://doi.org/10.15280/jlm.2017.7.1.10 https://doi.org/10.1007/bf02688675 https://doi.org/10.1002/mnfr.200900158 https://doi.org/10.1093/heapro/daq054 https://doi.org/10.1023/a:1022658222914 https://doi.org/10.1023/a:1022658222914 https://doi.org/10.1097/chi.0b013e3181985068 https://doi.org/10.1097/chi.0b013e3181985068 https://doi.org/10.1007/s00127-007-0272-2 https://doi.org/10.1016/j.braindev.2007.12.00 https://doi.org/10.1007/s10567-010-0071-2 https://doi.org/10.3402/fnr.v56i0.17231 eating behaviour-consumption frequency of certain foods in early childhood as a predictor of behaviour problems 6-year follow-up study 232 | squ medical journal, may 2022, volume 22, issue 2 23. peacock pj, lewis g, northstone k, wiles nj. childhood diet and behavioural problems: results from the alspac cohort. eur j clin nutr 2011; 65:720–6. https://doi.org/10.1038/ejcn. 2011.27. 24. itomura m, hamazaki k, sawazaki s, kobayashi m, terasawa k, watanabe s, et al. the effect of fish oil on physical aggression in schoolchildren— a randomized, double-blind, placebo-controlled trial. j nutr biochem 2005; 16:163–71. https://doi.org/10.1016/j. jnutbio.2004.10.009. 25. hamazaki t, hamazaki k. fish oils and aggression or hostility. prog lipid res 2008; 47:221–32. https://doi.org/10.1016/j. plipres.2008.02.001. 26. raine a, portnoy j, liu j, mahoomed t, hibbeln jr. reduction in behavior problems with omega-3 supplementation in children aged 8–16 years: a randomized, double-blind, placebo-controlled, stratified, parallel-group trial. j child psychol psychiatry 2015; 56:509–20. https://doi.org/10.1111/jcpp.12314. 27. ng k-h, meyer bj, reece l, sinn n. dietary pufa intakes in children with attention-deficit/hyperactivity disorder symptoms. br j nutr 2009; 102:1635–41. https://doi.org/10.1017/s00071145 09990821. 28. dean aj, bor w, adam k, bowling fg, bellgrove ma. a random ized, controlled, crossover trial of fish oil treatment for impulsive aggression in children and adolescents with disruptive behavior disorders. j child adolesc psychopharmacol 2014; 24:140–8. https://doi.org/10.1089/cap.2013.0093. 29. bisht at, kukreti vt. role of micronutrients on children with attention deficit hyperactivity disorder: a contentious issue. indian j public health res dev 2014; 5:90. https://doi.org/10.59 58/0976-5506.2014.00019.9. 30. lillegaard itl, øverby n, andersen l. evaluation of a short food frequency questionnaire used among norwegian children. food nutr res 2012; 56:6399. https://doi.org/10.3402/fnr. v56i0.6399. https://doi.org/10.1038/ejcn.2011.27 https://doi.org/10.1038/ejcn.2011.27 https://doi.org/10.1016/j.jnutbio.2004.10.009 https://doi.org/10.1016/j.jnutbio.2004.10.009 https://doi.org/10.1016/j.plipres.2008.02.001 https://doi.org/10.1016/j.plipres.2008.02.001 https://doi.org/10.1111/jcpp.12314 https://doi.org/10.1017/s0007114509990821 https://doi.org/10.1017/s0007114509990821 https://doi.org/10.1089/cap.2013.0093 https://doi.org/10.5958/0976-5506.2014.00019.9 https://doi.org/10.5958/0976-5506.2014.00019.9 https://doi.org/10.3402/fnr.v56i0.6399 https://doi.org/10.3402/fnr.v56i0.6399 1department of family medicine, ministry of health, muscat, oman; 2department of family medicine, oman medical specialty board, muscat, oman; 3department of family medicine and public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asmaalhashmi180@gmail.com abstract: objectives: this study aimed to assess parental knowledge, attitudes and practices regarding antibiotic use for children with upper respiratory tract infections (urtis). methods: a multi-centre cross-sectional study was conducted from september 2018 to april 2019 at 15 randomly selected primary health centres in muscat, oman. a total of 384 parents with children under 12 years old were recruited. a validated questionnaire was utilised to determine knowledge, attitudes and practices regarding antibiotic use for children with urtis. results: all 384 parents participated in the study (response rate: 100%). almost half of the participants (n = 173; 45.1%) agreed that antibiotics were the first and best treatment for urtis in children, with 184 parents (47.9%) reporting that influenza symptoms in children improved more rapidly after the administration of antibiotics and 203 (52.9%) believing that antibiotics prevented complications. the majority (n = 219; 57.0%) of parents never gave their children antibiotics without a prescription, and 291 (75.8%) never used leftover antibiotics. most participants (n = 233; 60.7%) stated that it was the doctor’s decision to prescribe antibiotics, 192 (50.0%) had never asked a physician to prescribe antibiotics for their child and 256 (66.7%) had never changed doctors because they did not prescribe antibiotics. conclusion: this study found that parents had confidence in their healthcare providers; however, it also showed the extent of their lack of knowledge regarding the use of antibiotics for children with urtis. there is a need for both publicand healthcare professional-oriented educational initiatives to promote rational antibiotic usage in oman. keywords: practice, attitudes and health knowledge; antibiotics; drug utilization; parents; children; upper respiratory tract infections; oman. parental knowledge, attitudes and practices regarding antibiotic use for upper respiratory tract infections in children *asma s. al hashmi,1 abir s. al shuhumi,2 rahma m. al kindi3 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e289–296, epub. 21 jun 21 submitted 31 may 20 revision req. 16 jul 20; revision recd. 21 jul 20 accepted 13 aug 20 https://doi.org/10.18295/squmj.2021.21.02.019 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge this study found moderate knowledge, attitudes and practices regarding antibiotic use in children with upper respiratory tract infections (urtis) among omani parents. this finding indicates an increased need for health education campaigns on this topic in order to improve parental awareness and knowledge. results showed great confidence among parents in their treating doctors. therefore, this trust should be used wisely in the interest of health education campaigns towards the appropriate use of antibiotics. to the best of the authors’ knowledge, this study is the first to be conducted in oman to explore parental knowledge, attitudes and practices regarding antibiotic use for children with urtis. application to patient care this study provides data which could form the basis for educational campaigns and initiatives focusing on antibiotic usage to address the public’s misconceptions regarding antibiotic use. greater public awareness would result in better health outcomes and lower the risk of antibiotic resistance. in children, upper respir atory tr ac t infections (urtis) are the most common presenting diagnosis in primary healthcare and the most frequent reason for visits to emergency departments and outpatient clinics.1 urtis are also a major cause of absenteeism from school and unnecessary medical care, affecting both the child and their parents as well as imposing a financial burden on the healthcare system.2,3 it is estimated that a preschool-aged child has an average of 6–8 common colds per year, with approximately 10–15% having 12 or more colds each year.2–4 moreover, the majority of urtis in children are viral in origin and therefore require only symptomatic treatment.2–4 as such, antibiotics are not frequently recommended as they should be used only for very specific indications.5 it is well-known that the inappropriate prescription and use of antibiotics is a main contributor to rising rates of antibiotic resistance as well as increased antibioticrelated side-effects, mortality rates and medical resource waste.6–8 this situation is likely to worsen considering that no new major antibiotic groups have been discovered in the last decade.9 nevertheless, it is estimated that 33% of general practitioners in the uk prescribe antibiotics for children with urtis, despite such prescriptions not being clinically indicated.10 https://creativecommons.org/licenses/by-nd/4.0/ parental knowledge, attitudes and practices regarding antibiotic use for upper respiratory tract infections in children e290 | squ medical journal, may 2021, volume 21, issue 2 according to the world health organization, urtis represented the most common reason for antimicrobial use.5 although irrational antibiotic use is a global problem, it is more prevalent in developing countries such as china.11 a systematic review from china revealed that 83.7% of outpatients presenting with urtis received antibiotics.12 previous studies have identified several factors present worldwide linked to antibiotic misuse including antibiotic availability, diagnostic uncertainty as well as the age and socioeconomic status of the child in question.13–15 one important additional factor is parents’ lack of knowledge, appropriate practices and understanding of indications for antibiotic use in children with urtis; studies conducted in different countries have reported variable levels of parental knowledge regarding antibiotic use.16–20 studies from palestine, jordan, saudi arabia and the united arab emirates (uae) have all highlighted parents’ poor knowledge of antibiotic use in relation to urtis.19–22 in contrast to this finding, a study in cyprus linked antibiotic overuse to doctors’ decisions and not to a lack of parental knowledge.17 a similar finding was observed in greece in which physicians’ overprescription was the main cause of antibiotic misuse.18 in oman, only one previous study has been performed to assess general knowledge of, and attitudes and behaviours towards antibiotic use among the public.23 however, to the best of the authors’ knowledge, no study has yet targeted parents to assess their knowledge, attitudes and practices with regards to antibiotic use for children with urtis. this study, therefore, aimed to assess knowledge of, attitudes towards and practices among omani parents regarding antibiotic use for urtis in children. methods this multicentre cross-sectional study was carried out from september 2018 to april 2019 in randomly selected primary healthcare centres in muscat, oman. muscat governorate is the largest in oman in terms of population density. approximately 32% of oman’s population lives within the muscat governorate, which comprises six wilayats (counties) and 29 governmental primary healthcare centres which are distributed according to the size of the target population within each wilayat.24 the current study included a total of 15 healthcare centres randomly selected from each wilayat in the muscat governorate including three centres which were selected from among the most populated wilayat and one centre chosen from among the least populated wilayat. according to the omani ministry of health, children less than 12 years old are considered members of the paediatric age group and receive medical treatment under the department of child health. after 12 years of age, individuals are considered adolescents and receive their medical treatment together with adults.24 however, according to the omani child law, a child is defined as any person who has not completed 18 years of age.25 in the current study, all adults with children under 12 years old who were attending the selected healthcare centres during the study period were invited to participate in the study. the participants were selected for eligibility during registration at the reception. both fathers and mothers were selected for inclusion; however, parents who did not speak arabic or english, those with learning disabilities/dementia and those who did not have the time to complete the questionnaire were excluded from the study. the necessary sample size was calculated using an online sample size calculator (raosoft inc., seattle, washington, usa) based on an estimated response distribution of 50%, a 5% margin of error and a 95% confidence interval. based on the assumption that the response rate would be 100% due to data being collected through face-to-face interviews, the final sample size was calculated to be 384 participants. data were collected using a pre-tested questionnaire and face-to-face interviews were carried out with individual participants in the waiting area. the questionnaire was previously validated for use in a similar study conducted in palestine.19 in the current study, the arabic version of the questionnaire was used with questions tailored to ensure their applicability to the local population. the final questionnaire was composed of four main sections. the first section focused on sociodemographic data including participant age, gender, education level, monthly income, occupational field and the number and age of their children. the second part of the questionnaire assessed parents’ knowledge of causes of urtis and antibiotic use in children with urtis and included: (1) specific antibiotic names and their use for treating specific symptoms of urtis in children (i.e. fever and influenza-like symptoms); (2) whether antibiotics are the first and best option for treating urtis; (3) the source of parents’ antibiotic-related information; (4) parents’ understanding of the course of urtis, indications for antibiotic use and antibiotic-related side-effects; (5) whether the inappropriate use of antibiotics reduces their efficacy and drives bacterial resistance; (6) whether antibiotics prevent urti complications; and (7) if scientists could produce new antibiotics for resistant bacteria. asma s. al hashmi, abir s. al shuhumi and rahma m. al kindi clinical and basic research | e291 the third section of the questionnaire focused on parents’ practices regarding antibiotic use in children with urtis. parents were asked about: (1) the average length of time they waited before seeking medical advice; (2) symptoms that drove them to seek medical help; (3) different treatment options for urtis; (4) their expectations regarding antibiotic prescriptions in terms of specific urti symptoms; (5) if they had ever given their children antibiotics without a prescription; (6) their reasons for giving their children antibiotics in the absence of medical advice; (7) their beliefs as to why a doctor would prescribe antibiotics; (8) whether they had ever questioned physicians as to the necessity of an antibiotic prescription; (9) whether they had ever demanded their physician prescribe or avoid prescribing antibiotics; (10) whether an antibiotics prescription should be based on parental demand; and (11) whether they followed medical instructions and advice with regards to antibiotic administration. finally, the fourth part of the questionnaire was designed to determine parental attitudes regarding antibiotic use for children with urtis. the parents were asked if: (1) they thought that antibiotics are overused or unnecessarily prescribed; (2) whether they would change doctors because of prescribing or not prescribing antibiotics; (3) whether they ever administered leftover antibiotics to their child; (4) if urtis can resolve without antibiotics; and (5) whether they thought that parents and doctors should be educated regarding judicious antibiotic use. all items on the questionnaire were scored on a 5-point likert scale, with potential responses scored from 1–5 either according to agreement (i.e. from strongly agree to strongly disagree) or frequency of occurrence (i.e. from never to always). data were analysed using statistical package for the social sciences (spss), version 22 (ibm corp., armonk, new york, usa). descriptive statistics were used to describe the sample characteristics, with frequencies and percentages reported for categorical variables and means ± standard deviation for continuous variables. in addition, median scores were calculated based on the participants’ responses to the knowledge, attitude and practice questionnaire items. when scoring items, correct or expected answers were given a score of one, while incorrect or unexpected answers were scored as zero. median scores were calculated out of maximum possible scores of seven, five and five for the knowledge, attitude and practice sections, respectively, while the minimum score was zero for all three categories. for quantitative representations, scores >70% of the possible maximum score were considered good, 30–70% was considered moderate and <30% was considered poor. participation was voluntary and informed consent was obtained prior to data collection. all participants were informed about their right to withdraw from the study at any time and their anonymity and confidentiality were assured and emphasised. ethical approval for this study was granted by the regional research and ethics committee of the directorate general of health services, ministry of health, oman (#mh-dgps/24/2018). results all 384 parents selected for inclusion participated in the study (response rate: 100%). the majority were female (n = 293; 76.3%) and the mean age was 32.7 ± 5.8 years old (range: 20–49 years). the vast majority (n = 383; 99.7%) had children under six years of age, with only one parent (0.3%) having a child between 6–12 years old. in terms of parental education, most fathers had been educated to the secondary level (n = 178; 46.4%) or higher (n = 162; 42.2%). this educational level was similar among mothers (n = 178; 46.4% and n = 173; 45.1%, respectively). more than half of the participants (n = 206; 53.6%) had an average monthly income of 500–1,000 omani rials. only 16.4% (n = 63) of the participants worked in the medical field [table 1]. the majority of participants (n = 312; 81.3%) reported that doctors constituted their main source of information regarding antibiotics followed by pharmacists (n = 62; 16.1%). other reported sources of information included radio/television (n = 4; 1%), family and friends (n = 2; 0.5%), newspapers (n = 1; 0.3%) and other sources (n = 3; 0.8%). in terms of their knowledge regarding antibiotic use for children with urtis, most parents (n = 268; 69.8%) were unable to name any specific antibiotics, while the remainder mentioned augmentin® (glaxosmithkline plc, brentford, uk) and amoxicillin together (n = 47; 12.2%), augmentin® (glaxosmithkline plc) alone (n = 16; 4.2%), amoxicillin alone (n = 32; 8.3%) or other antibiotics (n = 21; 5.5%). almost half of the participants (n = 173; 45.1%) agreed that antibiotics are the first and best treatment for urtis in children. although more than half of the parents (n = 208; 54.2%) believed that most urtis are viral in origin, 184 (47.9%) believed that influenza-like symptoms improved more rapidly with antibiotics. most of the participants were aware that antibiotics have side-effects (n = 233; 60.7%) and that the inappropriate use of antibiotics decreases their efficacy and increases bacterial resistance (n = 233; 60.7%). only 90 parents (23.4%) were under the impression that antibiotics have no side-effects. approximately half (n = 203; 52.9%) believed that antibiotics prevent parental knowledge, attitudes and practices regarding antibiotic use for upper respiratory tract infections in children e292 | squ medical journal, may 2021, volume 21, issue 2 complications from urtis. the majority (n = 190; 49.5%) thought that scientists would be able to develop new antibiotics to counteract antibiotic-resistant bacteria [table 2]. reported side-effects of antibiotic use included decreased immunity (n = 222; 57.8%), antibiotic resistance (n = 142; 37%), kidney injuries (n = 112; 29.2%), allergies (n = 111; 28.9%), liver injuries (n = 99; 25.8%), stomachaches (n = 89; 23.2%) and others (n = 21; 5.5%). approximately half of the participants (n = 188; 49%) reported that they would wait for two days before taking a child with urti symptoms to the hospital; fever (n = 269; 70.1%) and ear pain (n = 235; 61.2%) were the most common reasons for seeking medical advice. more than half (n = 219; 57%) stated that they never gave their children antibiotics without a prescription. among those who did, reported reasons for doing so included having siblings who had been previously prescribed antibiotics for similar conditions (n = 102; 26.6%), believing that the child’s condition was not serious enough to be seen by a doctor (n = 44; 11.5%) and other reasons (n = 19; 4.9%). in addition, 163 parents (42.4%) agreed or strongly agreed that antibiotics are often used without clear indications, while 169 (44%) disagreed or strongly disagreed and 52 (13.5%) were uncertain. parental expectations regarding treatment options for children with urtis included analgaesics (n = 257; 66.9%), antibiotics (n = 161; 41.9%), antihistamines (n = 137; 35.7%), nasal sprays (n = 132; 4.4%) and cough syrups (n = 96; 25%). parents were more likely, however, to expect an antibiotic prescription if their child had symptoms of earache (n = 215; 56%) and fever (n = 211; 54.9%) compared table 2: knowledge regarding antibiotic use for pediatric upper respiratory tract infections among omani participants with children under 12 years old (n = 384) item response, n (%) strongly agree agree disagree strongly disagree uncertain antibiotics can be used to treat any feverish child 44 (11.5) 103 (26.8) 134 (34.9) 71 (18.5) 32 (8.3) children with influenza-like symptoms get better faster when antibiotics are used 40 (10.4) 144 (37.5) 93 (24.2) 57 (14.8) 50 (13) most urtis are viral in origin and are self-limiting; thus, there is no need for antibiotic use 76 (19.8) 132 (34.4) 84 (21.9) 34 (8.9) 58 (15.1) antibiotics do not have any side-effects 33 (8.6) 57 (14.8) 112 (29.2) 121 (31.5) 61 (15.9) the inappropriate use of antibiotics reduces their efficacy and increases bacterial resistance 150 (39.1) 83 (21.6) 35 (9.1) 48 (12.5) 68 (17.7) antibiotics can prevent complications from urtis 59 (15.4) 144 (37.5) 53 (13.8) 45 (11.7) 83 (21.6) scientists can produce new antibiotics for resistantbacteria 65 (16.9) 125 (32.6) 37 (9.6) 22 (5.7) 135 (35.2) urtis = upper respiratory tract infections. table 1: sociodemographic characteristics of omani participants with children under 12 years old (n = 384) characteristic n (%) gender male 91 (23.7) female 293 (76.3) mean age ± sd in years 32.7 ± 5.8 paternal education level primary 44 (11.5) secondary 178 (46.4) higher 162 (42.2) maternal education level primary 33 (8.6) secondary 178 (46.4) higher 173 (45.1) monthly family income in omr <500 68 (17.7) 500–1,000 206 (53.6) >1,000 110 (28.6) employed in the medical field yes 63 (16.4) no 321 (83.6) age of children in years <6 383 (99.7) 6–12 1 (0.3) sd = standard deviation; omr = omani rial. asma s. al hashmi, abir s. al shuhumi and rahma m. al kindi clinical and basic research | e293 to symptoms such as vomiting or coughing (n = 149 each; 38.8% each), common cold-like symptoms (n = 122; 31.8%), a sore throat (n = 114; 29.7%) or nasal drainage (n = 104; 27.1%) [figure 1]. only 29 participants (7.6%) reported that they never asked the doctor whether an antibiotic prescription for their child was necessary, while 184 (47.9%) always inquired, 72 (18.8%) questioned it most of the time, 37 (9.6%) often inquired and 62 (16.1%) sometimes questioned the decision. moreover, half of the parents (n = 192; 50%) never asked the physician to prescribe antibiotics for their child, and 64 parents (16.7%) always asked the doctor to avoid prescribing antibiotics to their children. overall, 258 parents (67.2%) reported that they always followed instructions for proper antibiotic use as directed. most of the participants (n = 233; 60.7%) affirmed that the decision to prescribe antibiotics is based solely on the doctor’s opinion and not at the parent’s request. nevertheless, 58 parents (15.1%) admitted to changing physicians because of not prescribing anti biotics, although 256 (66.7%) had never changed doctors for this reason, and 70 (18.2%) were uncertain whether they had ever done so. on the other hand, 88 parents (22.9%) reported having changed their treating physician because of overly frequent antibiotic prescriptions for their children. the majority of parents (n = 291; 75.8%) had never used leftover antibiotics for their children, despite them developing similar symptoms. more than half of the parents (n = 215; 56%) agreed that urtis usually resolve without antibiotic administration. the vast majority of parents (n = 327; 85.2%) believed that both doctors and parents should be informed of how to wisely use antibiotics [figure 2]. overall, the median knowledge score of the parents was 3 (42.8%), indicating a moderate level of parental knowledge regarding antibiotic use for urtis figure 1: frequency of specific symptoms that omani parents expect will result in an antibiotic prescription for upper respiratory tract infections in their children aged under 12 years old (n = 384). figure 2: frequency of parents’ responses to questions related to attitude towards antiobiotics for upper respiratory tract infections in their children aged under 12 years old (n = 384). table 3: knowledge, practice and attitude scores with parents working in medical and non-medical fields variable mean score ± sd p value* are parents working in the medical field? yes (n = 63) no (n = 321) knowledge 3.98 (1.77) 2.91 (1.59) <0.001 practice 2.54 (1.39) 2.40 (1.39) 0.435 attitude 1.51 (1.28) 1.66 (1.17) 0.266 sd = standard deviation. *using mann-whitney u test parental knowledge, attitudes and practices regarding antibiotic use for upper respiratory tract infections in children e294 | squ medical journal, may 2021, volume 21, issue 2 in children. with regards to attitudes and practices, the median scores were 3 (60%) and 2 (40%), respectively, indicating moderate parental attitudes and practices. on further analysis, parents working in the medical field had significantly better knowledge scores (p <0.001) compared to those not working in the medical field. however, there was no significant difference between the two groups in terms of attitudes (p = 0.266) or practices (p = 0.435) [table 3]. discussion to the best of the authors’ knowledge, this study is the first in oman to assess parental knowledge, attitudes and practices regarding antibiotic use for urtis in children. such findings provide important baseline data which may aid the development of national health strategies. overall, the respondents demonstrated a high degree of confidence in their local doctors and healthcare providers. most participants reported doctors and pharmacists to be their main sources of antibiotic information. in addition, the majority were of the opinion that doctors were the primary decisionmakers when it came to prescribing antibiotics, with few parents changing physicians due to a lack of antibiotic prescriptions. this level of trust in healthcare practitioners supports the application of educational initiatives to raise public awareness of judicious antibiotic usage. although the current study found that omani parents demonstrated a moderate level of knowledge regarding antibiotic use for urtis in children, over twothirds of the parents were unable to name any specific types or brands of antibiotics. a lack of knowledge of medications such as antibiotics can greatly influence the likelihood of their misuse and poor compliance.26 consequently, it is imperative that the health sector take action to educate this group. much of this responsibility is likely to fall on the attending physician who is required to provide detailed information to parents regarding the antibiotic prescribed to their child, including its indications, instructions for use and possible side-effects. pharmacists may also play a role in terms of reminding consumers of how medications should be administered. regardless, all healthcare professionals should seek to maintain appropriate channels of communication and education during the consultation and follow-up process. in the present study, many participants agreed that antibiotics were the first and best treatment for urtis in children, even though more than half were aware that most urtis are viral in origin and self-limiting. similarly, other studies have shown that members of the public worldwide believe that antibiotics can be used for all types of common colds and coughs, irrespective of their exact cause.27–29 furthermore, although the vast majority of participants in the current study were aware that antibiotics have side-effects and that their inappropriate use decreases their effectiveness and leads to bacterial resistance, approximately half nevertheless believed that antibiotics prevented complications from urtis and that scientists would be able to develop new antibiotics. the prevalence of these misconceptions indicates omani parents’ lack of knowledge about and aware ness of antibiotic use and its limitations. indeed, reports worldwide have demonstrated a general lack of knowledge and awareness regarding the basic principles of antibiotic use as well as their indications for treatment.28,30 other studies have also reported common misconceptions regarding antibiotic use specifically for urtis, with many individuals believing that their use results in more rapid recovery and prevents more serious illness.28,31,32 these findings signify an urgent need for health awareness campaigns targeting individuals of all ages, genders and education levels, perhaps by incorporating popular social networking sites to disseminate information. emphasis on patient awareness regarding appropriate antibiotic usage could help to dispel unsubstantiated beliefs and expectations concerning the use of antibiotics for minor or viral illnesses.29 in terms of parental practices and attitudes regarding antibiotic use for paediatric urtis, earache and fever were the symptoms for which parents in the present study most commonly expected antibiotics to be prescribed. this finding is similar to those previously reported in palestine, jordan, saudi arabia and uae.19–22 interestingly, nearly half of the parents in the current study stated that they always asked their doctors about the necessity of prescribing antibiotics, and approximately two-thirds claimed that they always followed medical advice. most respondents stated clearly that it was the doctor’s decision to prescribe antibiotics and that antibiotics should not be prescribed at the parents request. moreover, the majority reported that they had never changed their treating physician if they did not prescribe antibiotics for their children. importantly, the majority of parents never administered antibiotics to their children without a prescription or used leftover antibiotics. in contrast, conflicting findings have been reported from other studies. several researchers have reported that parents and other members of the public often believe that leftover antibiotics can be stored and used for similar symptoms without a doctor’s prescription.21,29,32 while the prevalence of these behaviours appears to be less frequent among omani parents, there is asma s. al hashmi, abir s. al shuhumi and rahma m. al kindi clinical and basic research | e295 nevertheless an urgent need for educational initiatives to avoid serious health consequences, such as increasing rates of bacterial resistance and complications due to antibiotic side-effects and the usage of expired drugs. in particular, the emergence of antibiotic-resistant organisms puts the entire community at risk as it increases the prevalence of serious infections that are difficult to treat, as well as associated increases in mortality rates and hospital admissions.33–35 in oman, a local policy implemented by the ministry of health prohibits pharmacies from selling and dispensing antibiotics without an official prescription.36 it is likely that this policy influenced the attitudes of the respondents, thereby resulting in fairly good antibiotic practices. nevertheless, the vast majority of parents in the current study believed that both parents and doctors would benefit from further information regarding the judicious use of antibiotics. in addition, although parents working in the medical field had better knowledge compared to the rest, there was no significant difference in attitudes and practices. thus, introducing additional educational campaigns targeting healthcare professionals, perhaps consisting of multidisciplinary workshops, courses and training sessions, is important to reinforce rational antibiotic prescription practices and attitudes in oman. this study had strengths as well as limitations. while the response rate was 100%, likely due to collecting data through face-to-face interviews which may have helped to build a stronger rapport with the respondents, the study was conducted solely at health centres in muscat; therefore, the findings might not be representative of other regions in oman. in addition, the study targeted parents attending governmental primary healthcare centres, thus limiting the generalisability of the results for those attending other types of facilities (i.e. private, secondary and tertiary care facilities) or those in the general community. finally, the inclusion of questions referring to the parents’ past experiences with antibiotics and the face-to-face interview format may have led to recall or response biases. conclusion overall, this study found that omani parents have a high degree of confidence in their doctors and healthcare providers when it comes to antibiotic prescription for their children. however, they also demonstrated insufficient levels of knowledge regarding the use of antibiotics in children with urtis. there is an urgent need for educational initiatives and health campaigns to raise awareness and promote rational antibiotic use in oman. a c k n o w l e d g e m e n t the authors would like to thank the respondents for their participation in this study. in addition, the authors extend their sincere gratitude to mr. sathiya muthi, statistician at the oman medical specialty board, for his continuous support and guidance. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. nadeem ahmed m, muyot mm, begum s, smith p, little c, windemuller fj. antibiotic prescription pattern for viral respiratory illness in emergency room and ambulatory care settings. clin pediatr (phila) 2010; 49:542–7. https://doi.org/10.1177/000992 2809357786. 2. west jv. acute upper airway infections. br med bull 2002; 61:215–30. https://doi.org/10.1093/bmb/61.1.215. 3. cotton m, innes s, jaspan h, madide a, rabie h. management of upper respiratory tract infections in children. s afr fam pract (2004) 2008; 50:6–12. https://doi.org/10.1080/20786204. 2008.10873685. 4. simasek m, blandino da. treatment of the common cold. am fam physician 2007; 75:515–20. 5. world health organization. who model prescribing information: drugs used in bacterial infections. from: www. apps.who.int/iris/handle/10665/42372 accessed: jul 2020. 6. bell bg, schellevis f, stobberingh e, goossens h, pringle m. a systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. bmc infect dis 2014; 14:13. https://doi.org/10.1186/1471-2334-14-13. 7. aryee a, price n. antimicrobial stewardship can we afford to do without it? br j clin pharmacol 2015; 79:173–81. https://doi. org/10.1111/bcp.12417. 8. silverman m, povitz m, sontrop jm, shariff sz. antibiotic prescribing for nonbacterial acute upper respiratory infections in elderly persons. ann intern med 2017; 167:758–9. https:// doi.org/10.7326/l17-0438. 9. world health organization. antimicrobial resistance: global report on surveillance 2014. from: www.who.int/antimicrobialresistance/publications/surveillancereport/en/ accessed: jul 2020. 10. easton g, saxena s. antibiotic prescribing for upper respiratory tract infections in children: how can we improve? london j prim care (abingdon) 2010; 3:37–41. https://doi.org/10.1080 /17571472.2010.11493294. 11. currie j, lin w, zhang w. patient knowledge and antibiotic abuse: evidence from an audit study in china. j health econ 2011; 30:933–49. https://doi.org/10.1016/j.jhealeco.2011.05.009. 12. li j, song x, yang t, chen y, gong y, yin x, et al. a systematic review of antibiotic prescription associated with upper respir atory tract infections in china. medicine (baltimore) 2016; 95:e3587. https://doi.org/10.1097/md.0000000000003587. 13. fletcher-lartey s, yee m, gaarslev c, khan r. why do general practitioners prescribe antibiotics for upper respiratory tract infections to meet patient expectations: a mixed methods study. bmj open 2016; 6:e012244. https://doi.org/10.1136/ bmjopen-2016-012244. https://doi.org/10.1177/0009922809357786 https://doi.org/10.1177/0009922809357786 https://doi.org/10.1093/bmb/61.1.215 https://doi.org/10.1080/20786204.2008.10873685 https://doi.org/10.1080/20786204.2008.10873685 https://doi.org/10.1186/1471-2334-14-13 https://doi.org/10.1111/bcp.12417 https://doi.org/10.1111/bcp.12417 https://doi.org/10.7326/l17-0438 https://doi.org/10.7326/l17-0438 https://doi.org/10.1080/17571472.2010.11493294 https://doi.org/10.1080/17571472.2010.11493294 https://doi.org/10.1016/j.jhealeco.2011.05.009 https://doi.org/10.1097/md.0000000000003587 https://doi.org/10.1136/bmjopen-2016-012244 https://doi.org/10.1136/bmjopen-2016-012244 parental knowledge, attitudes and practices regarding antibiotic use for upper respiratory tract infections in children e296 | squ medical journal, may 2021, volume 21, issue 2 14. md rezal rs, hassali ma, alrasheedy aa, saleem f, md yusof fa, godman b. physicians’ knowledge, perceptions and behaviour towards antibiotic prescribing: a systematic review of the literature. expert rev anti infect ther 2015; 13:665–80. https://doi.org/10.1586/14787210.2015.1025057. 15. wong ck, liu z, butler cc, wong sy, fung a, chan d, et al. help-seeking and antibiotic prescribing for acute cough in a chinese primary care population: a prospective multicentre observational study. npj prim care respir med 2016; 26:15080. https://doi.org/10.1038/npjpcrm.2015.80. 16. kumar s, little p, britten n. why do general practitioners presc ribe antibiotics for sore throat? grounded theory interview study. bmj 2003; 326:138. https://doi.org/10.1136/bmj.326.7381.138. 17. rousounidis a, papaevangelou v, hadjipanayis a, panagakou s, theodoridou m, syrogiannopoulos g, et al. descriptive study on parents’ knowledge, attitudes and practices on antibiotic use and misuse in children with upper respiratory tract infections in cyprus. int j environ res public health 2011; 8:3246–62. https://doi.org/10.3390/ijerph8083246. 18. panagakou sg, spyridis n, papaevangelou v, theodoridou km, goutziana gp, theodoridou mn, et al. antibiotic use for upper respiratory tract infections in children: a cross-sectional survey of knowledge, attitudes, and practices (kap) of parents in greece. bmc pediatr 2011; 11:60. https://doi.org.10.1186/1471-2431-11-60. 19. zyoud sh, abu taha a, araj kf, abahri ia, sawalha af, sweileh wm, et al. parental knowledge, attitudes and practices regarding antibiotic use for acute upper respiratory tract infec tions in children: a cross-sectional study in palestine. bmc pediatr 2015; 15:176. https://doi.org/10.1186/s12887-015-0494-5. 20. hammour ka, jalil ma, hammour wa. an exploration of parents’ knowledge, attitudes and practices towards the use of antibiotics in childhood upper respiratory tract infections in a tertiary jordanian hospital. saudi pharm j 2018; 26:780–5. https://doi.org/10.1016/j.jsps.2018.04.006. 21. alrafiaah as, alqarny mh, alkubedan hy, alqueflie s, omair a. are the saudi parents aware of antibiotic role in upper respiratory tract infections in children? j infect public health 2017; 10:579–85. https://doi.org/10.1016/j.jiph.2017.01.023. 22. hammour ka, al-saleh s, hammour wa. parental views on antibiotic use in children with upper respiratory tract infections in dubai. eur j integr med 2019; 29:100917. https://doi.org/10.10 16/j.eujim.2019.05.003. 23. jose j, jimmy b, alsabahi ag, al sabei ga. a study assessing public knowledge, belief and behavior of antibiotic use in an omani population. oman med j 2013; 28:324–30. https://doi. org/10.5001/omj.2013.95. 24. oman ministry of health. department of health information and statistics. directorate general of planning and studies. annual health report 2018. from: www.moh.gov.om/en/web/ statistics/annual-reports accessed: jul 2020. 25. oman ministry of social development. child law. issued by the royal decree no. 22/2014. official gazette no. (-1058). from: https://www.mosd.gov.om/images/rules/childs%20law%20en. pdf accessed: jul 2020. 26. kandakai tl, price jh, telljohann sk, holiday-goodman m. knowledge, beliefs, and use of prescribed antibiotic medications among low-socioeconomic african americans. j natl med assoc 1996; 88:289–94. 27. shehadeh m, suaifan g, darwish rm, wazaify m, zaru l, alja’fari s. knowledge, attitudes and behavior regarding antibiotics use and misuse among adults in the community of jordan: a pilot study. saudi pharm j 2012; 20:125–33. https://doi.org/10.1016/j. jsps.2011.11.005. 28. curry m, sung l, arroll b, goodyear-smith f, kerse n, norris p. public views and use of antibiotics for the common cold before and after an education campaign in new zealand. n z med j 2006; 119:u1957. 29. mcnulty ca, boyle p, nichols t, clappison p, davey p. the public’s attitudes to and compliance with antibiotics. j antimicrob chemother 2007; 60 suppl 1:i63–8. https://doi.org/10.1093/jac/ dkm161. 30. kc ar, n sk, j r. students’ knowledge of antibiotics: a crosssectional study of students in tamil nadu. int j pharm pharm sci 2011; 3:232–3. 31. vanden eng j, marcus r, hadler jl, imhoff b, vugia dj, cieslak pr, et al. consumer attitudes and use of antibiotics. emerg infect dis 2003; 9:1128–35. https://doi.org/10.3201/ eid0909.020591. 32. pechère jc, hughes d, kardas p, cornaglia g. non-compliance with antibiotic therapy for acute community infections: a global survey. int j antimicrob agents 2007; 29:245–53. https:// doi.org/10.1016/j.ijantimicag.2006.09.026. 33. carlet j, jarlier v, harbarth s, voss a, goossens h, pittet d, et al. ready for a world without antibiotics? the pensières antibiotic resistance call to action. antimicrob resist infect control 2012; 1:11. https://doi.org/10.1186/2047-2994-1-11. 34. ganguly nk, arora nk, chandy sj, fairoze mn, gill jp, gupta u, et al. rationalizing antibiotic use to limit antibiotic resistance in india. indian j med res 2011; 134:281–94. 35. costelloe c, metcalfe c, lovering a, mant d, hay ad. effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. bmj 2010; 340:c2096. https://doi.org/10.1136/bmj.c2096. 36. oman ministry of health. directorate general of disease surv eillance and control. antimicrobial guidelines 2016. from: www.moh.gov.om/documents/236878/0/national+antimi crobial+guidelines/c82511c5-63e9-4205-8f49-0f60df4d7aa4 accessed: jul 2020. https://doi.org/10.1586/14787210.2015.1025057 https://doi.org/10.1038/npjpcrm.2015.80 https://doi.org/10.1136/bmj.326.7381.138 https://doi.org/10.3390/ijerph8083246 https://doi.org.10.1186/1471-2431-11-60 https://doi.org/10.1186/s12887-015-0494-5 https://doi.org/10.1016/j.jsps.2018.04.006 https://doi.org/10.1016/j.jiph.2017.01.023 https://doi.org/10.1016/j.eujim.2019.05.003 https://doi.org/10.1016/j.eujim.2019.05.003 https://doi.org/10.5001/omj.2013.95 https://doi.org/10.5001/omj.2013.95 https://doi.org/10.1016/j.jsps.2011.11.005 https://doi.org/10.1016/j.jsps.2011.11.005 https://doi.org/10.1093/jac/dkm161 https://doi.org/10.1093/jac/dkm161 https://doi.org/10.3201/eid0909.020591 https://doi.org/10.3201/eid0909.020591 https://doi.org/10.1016/j.ijantimicag.2006.09.026 https://doi.org/10.1016/j.ijantimicag.2006.09.026 https://doi.org/10.1186/2047-2994-1-11 https://doi.org/10.1136/bmj.c2096 1department of surgery, hamad general hospital, doha, qatar; 2department of obstetrics & gynecology, aga khan university hospital, karachi, pakistan *corresponding author’s e-mail: alismc2051@gmail.com psychosocial impact of covid-19 on healthcare workers a cross-sectional survey from pakistan *syed m. ali1 and sidrah nausheen2 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 82–90, epub. 28 feb 22 submitted 10 sep 20 revision req. 28 oct 20; revision recd. 1 dec 20 accepted 30 dec 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.067 clinical & basic research abstract: objectives: this study aimed to assess the anxiety and depression symptoms in healthcare professionals in pakistan as a result of the coronavirus pandemic. methods: this cross-sectional study was conducted from may to june 2020 and included six different hospitals in pakistan. an english-language demographics questionnaire, a validated covid-19 fear scale, depression scale phq-9 and anxiety scale gad-7 were sent to doctors, nurses and paramedical staff via whatsapp. data were analysed using descriptive statistics, chi-square test and student’s t-test. results: a total of 400 participants were included in this study (response rate: 80.0%); 263 (65.8%) were doctors and 137 (34.3%) were nurses and paramedical staff. of the participants, 57.0% were less than 40 years old and 18.3% were aged above 50. most of the participants (n = 262; 65.5 %) experienced moderate levels of fear and 16.5% (n = 66) experienced a high level of fear. moreover, 19.5% feared death and 56.5% reported social media to be responsible for increasing their fears. on the depression phq-9 and anxiety gad-7 scales, 21.8% (n = 87) reported moderate to severe depression and anxiety symptoms. a significant relationship was demonstrated between the depression level and age, education and profession (p <0.001 each). similarly, anxiety and depression scores were strongly related to the availability of personal protective equipment (p <0.001). conclusion: it was found that 21.8% of healthcare professionals are suffering from moderate to severe depression symptoms, 15.5% had moderate to severe anxiety, whereas 65.5% had moderate symptoms of fear. the predictors are age, education level and co-morbidities. these moderate to high levels of fear and anxiety and depression raise concerns about the psychological well-being of healthcare staff and should be addressed through different programmes. keywords: covid-19; healthcare workers; fear; anxiety; depression; patient health questionnaire; pakistan. advances in knowledge this cross-sectional study examined the harmful effects of covid-19 on healthcare workers’ psychological well-being in a resourcelimited country (pakistan). this study’s results offer an insight into the gravity of the effects of the covid-19 pandemic and recommend ways to deal with such problems by offering proper strategies. the better understanding of the relationship between anxiety and depression and associated factors such as non-availability of personal protective equipment (ppe), age and co-morbidities will help in dealing with mental health issues. application to patient care there is a relationship between healthcare workers’ mental health and the possibility of an increased chance of medical errors. a healthcare worker who suffers from anxiety and depression cannot give their full input, remains tired and exhibits an inefficient thought process. this study highlights the importance of formulating strategies, such as decreasing working hours and provision of ppe among others, to minimise the occurrence of mental health issues among doctors, thereby improving the quality of patient care. the 2019 novel coronavirus (covid-19) resulted in the first pandemic in over a century, which has impacted the world.1,2 this contagious disease has led to concerns, distress and apprehension among individuals across the globe. infections account for a significant proportion of the fear, as the transmission of this virus is rapid and invisible, and results in considerable health deterioration and even death. the appearance of new and resistant strains of the virus continues to put the media and society alike “in awe”.3 the current covid-19 pandemic is occurring during a time in which social media has a rapid and wide reach, and has therefore led to stigmatisation in some cases.4 a global pandemic caused by an unknown agent, severe acute respiratory syndrome(sars)cov-2, and relatively inefficient medical authorities, lacking in readiness, have led to the spread of misinformation and created confusion and anxiety among the public. however, the effect on medical professionals, both physically and psychologically, is much higher https://creativecommons.org/licenses/by-nd/4.0/ syed m. ali and sidrah nausheen clinical and basic research | 83 than the general public, as the former group is more exposed to the virus due to their involvement in the management and care of covid-infected patients and lack of proper personal protective equipment (ppe). “health workers have always been, unfortunately, the mine’s canary in epidemic response, particularly in areas that don’t have strong surveillance systems”.5 the increasing number of infected cases, overwhelming workload, inappropriate media coverage, non-avail ability of particular drugs and inadequate support have contributed to their psychological burden. the situation is worse in lowand middle-income countries such as pakistan compared to developed nations. pakistan reported a covid-19 outbreak in february 2020, with more than 255,769 cases and 5,386 deaths as of july 15, 2020.6 healthcare systems were overburdened and collapsed due to violations of lockdown regulations and standard operating procedures. similarly, weak infrastructure, poor governance, scarcity of basic health needs, increased turnover of positive cases and inconsistent behaviour of the public contributed to the worsening situation. lockdowns, unemployment, financial instability, prohibition of religious and social gatherings, fear of getting the infection and family safety also affected the mental health of the general population.7 during an outbreak of sars in 2003, healthcare workers (hcws) had a fear of infections, which resulted in a lack of interest in work and some experienced anxiety, stress and depression, causing long-term psychological issues.8 similarly, hcws who react strongly to the current covid-19 pandemic are likely to be older with a chronic disease and a pre-existing mental health disease. others are affected by social distancing, isolation and, ultimately, depression. common symptoms of anxiety and stress include numbness, disbelief, anxiety or fear, changes in appetite, lethargy, difficulty in concentrating, insomnia, headaches, fear about one’s health and the well-being of loved ones, worsening of chronic health problems, anger or being short-tempered, etc.9,10 although worldwide focus regarding covid-19 has been mainly on infection control, an appropriate vaccine and effective treatment, the psychological aspect has not received much attention and these implications can be devastating in the long term.11 this study aimed to assess the psychosocial impact of covid-19 on hcws by evaluating the signs and symptoms of fear, anxiety and depression among a group of individuals who are educated and dealing directly with covid-19 patients. few previous studies have also shown psychological implications of this viral pandemic on hcws.9,10 methods this cross-sectional study included hcws (doctors, nurses and paramedical staff ) working in six different hospitals in pakistan from may to june, 2020. a convenient sampling technique was used. an english-language questionnaire was created on google forms (google llc, mountain view, ca, usa) and distributed among the sample via whatsapp (meta platforms, inc., menlo park, california, usa). the contact details of the respondents were acquired from the hospital directory and there were therefore no face-to-face interactions. participants who were found to be depressed and anxious were sent to a psychiatrist for further management. the data collection form was divided into the following three sections: (a) demographics and validated scales evaluated the participants’ level of symptoms of fear, depression and anxiety; (b) a generalised anxiety disorder gad-7 scale and depression phq-9 questionnaire;9 (c) the fear of covid-19 scale.10 the depression scale phq-9 used a 4-point likert scale, ranging from 0 (not at all) to 3 (nearly every day). these scores were added together to obtain a total score ranging from 0 (minimal) to 27(maximal). scores for minimal depression ranged from 1–4, mild depression from 5–9, moderate depression from 10–14, moderately severe depression from 15–19 and severe depression from 20–27. the generalised anxiety scale gad-7 also used a 4-point likert scale, ranging from 0 (not at all) to 3 (nearly every day). scores for mild ranged from 5–9, moderate 10–14 and severe more than 15. we used a cut-off of 10 with a sensitivity of 89% and specificity of 82% for gad-7. for the fear of covid-19 scale, a 5-point likert scale ranging from 1 (strongly disagree) to 5 (strongly agree) was used. these scores were added together to obtain a total fear score; total scores ranged from 7 (minimum) to 35 (maximum). the range of scores for low fear is 7–16, moderate fear is 17–26 and high fear is 27–35. the anxiety gad-7 and depression phq-9 tools have been successfully used in a previous similar study conducted in china, where hcws were assessed for symptoms of anxiety and depression.9 these tools can also be used to assess the symptoms of mental health disorders. the fear of covid-19 scale was validated in an irani population.10 all data were analysed using statistical package for the social sciences (spss), version 19 (ibm corp., armonk, new york, usa). mean scores and standard deviation were attained for continuous variables such as total fear scores and depression psychosocial impact of covid-19 on healthcare workers a cross-sectional survey from pakistan 84 | squ medical journal, february 2022, volume 22, issue 1 scores, while frequency and percentages were used for categorical variables such as characteristics of the participant. associations between the variables such as fear level, depression level and characteristics of the participant were examined using the chi-square test. the student’s t-test evaluated continuous variables. statistical significance was set at p <0.05. a short consent form, attached to the survey form, was sent to the participants, informing them that by completing the survey they are agreeing to participate in the study. their names and personal details and the names of the employee’s hospital were not asked to keep their identities anonymous. permission was obtained from each healthcare centre before proceeding with the study. this study’s proposal was approved by the ethical review committee of aga khan university (erc #2020-4733-10959). the data will be kept safe and password-protected and will only be accessible to the investigators and the department head. the data will be disposed of seven years post-study completion as per the institutional policy. results a total of 400 individuals were included in this study (response rate: 80.0%). of these, 263 (65.8%) were doctors and 137 (34.3%) were nurses and paramedical staff. moreover, 57.0% were less than 40 years old, whereas 18.3% were more than 50 years of age. the majority of the participants (59.3%) had attained a post-graduate education and 32.3% were graduates. in addition, it was found that 51.5% of the respondents reported fearing the disease and its consequences; only 19.5% feared death. in terms of co-morbidities, 10.0% of the participants were asthmatic and another 10.0% were hypertensive; 72.8% had no co-morbidities. approximately 36.0% of participants were working in the covid-19 area and 59.3% had always received proper ppe at the workplace [table 1]. the majority of the participants (n = 262; 65.5%) experienced a moderate level of fear while 16.5% (n = 66) reported a high level of fear and 18.0% (n = 72) scored low on the fear scale. the majority (56.5%) reported that social media was responsible for increasing their fear; 17.0% reported not being able to sleep due to being worried about contracting covid-19. the mean fear score was 20.8 ± 5.6 [table 2]. approximately 26.5 % of the participants (n = 106) experienced a mild level of depression and 47% (n = 188) had mild anxiety, whereas 21.8% (n = 87) showed moderate to severe symptoms of depression and 15.5% (n = 62) showed moderate to severe anxiety. the mean depression score was 10.4 ± 9.8 [table 3]. while assessing factors that cause fear, results showed that comorbidities such as diabetes, hyper tension, asthma and not getting proper ppe in the workplace were not significantly related to participants’ fear levels. however, a significant relationship was found between the fear level and age (p = 0.022), profession (p <0.001), education level (p = 0.004), type table 1: characteristics of participants from six different hospitals in pakistan (n = 400) characteristic n (%) age group in years 20–30 88 (22.0) 30–40 140 (35.0) 40–50 99 (24.8) 50–60 73 (18.3) profession doctor 263 (65.8) nurse 62 (15.5) paramedical 41 (10.3) technician 34 (8.5) education level middle 20 (5.0) higher 14 (3.5) graduate 129 (32.3) postgraduate 237 (59.3) type of fear isolation 116 (29.0) disease 206 (51.5) death 78 (19.5) co-morbidity asthma 40 (10.0) diabetes 29 (7.3) hypertension 40 (10.0) none 291 (72.8) are you provided proper ppe in your workplace? yes 237 (59.3) no 83 (20.8) sometimes 80 (20.0) are you working in a covid-19 isolation area? yes 144 (36.0) no 256 (64.0) ppe = personal protective equipment. syed m. ali and sidrah nausheen clinical and basic research | 85 of fear (p <0.001) and working in the covid-19 area (p < 0.001) [table 4]. a significant relationship was demonstrated between the depression level and all variables, most notably age, profession and education (p <0.001 each). similarly, anxiety and depression scores were strongly related to the availability of ppe (p <0.001) [table 5]. discussion lowand middle-income countries such as pakistan can be characterised by large and highly populated urban regions, inadequate health systems and infra structure, compromised resources such as hcws and medicines, an unstable economy and scarce availability of covid-19-testing kits. consequently, there are high rates of covid-19 infection, affecting millions, including hcws and their families. this study demonstrated that 21.8% of hcws suffered from moderate to severe depression and 15.5% anxiety symptoms and required treatment. a meta-analysis of 12 studies from china and another report from singapore also showed that the prevalence of depression, insomnia and anxiety among hcws during covid-19 was 22.8%, 23.2% and 38.9%, respectively.12 these findings, along with those from the current study, confirm the massive impact of the covid-19 pandemic on hcws’ mental and psychosocial health. a significantly high anxiety level has also been found, indicating a prevalent state of tension that could lead to psychological distress symptoms. the susceptibility of frontline hcws to anxiety and stress during a pandemic has been attributed to an overburdened healthcare system and the risk of contracting the infection.13 outbreaks of sarscov-1, h1n1 influenza, ebola and others, have had a significant psychosocial impact on hcws.14 similar results were found in the current study where 51.5% table 2: distribution of responses to the fear of covid-19 scale (n = 400) item n (%) i am most afraid of coronavirus-19. strongly disagree 21 (5.3) disagree 33 (8.3) neutral 116 (29.0) agree 178 (44.5) strongly agree 52 (13.0) it makes me uncomfortable to think about coronavirus-19. strongly disagree 22 (5.5) disagree 36 (9.0) neutral 77 (19.3) agree 211 (52.8) strongly agree 54 (13.5) my hands become clammy when i think about coronavirus-19. strongly disagree 87 (21.8) disagree 146 (36.5) neutral 79 (19.8) agree 81 (20.3) strongly agree 7 (1.8) i am afraid of losing my life because of coronavirus-19. strongly disagree 47 (11.8) disagree 86 (21.5) neutral 97 (24.3) agree 123 (30.8) strongly agree 47 (11.8) when watching news and stories about coronavirus-19 on social media, i become nervous or scale. strongly disagree 40 (10.0) disagree 51 (12.8) neutral 83 (20.8) agree 147 (36.8) strongly agree 79 (19.8) i cannot sleep because i'm worried about getting coronavirus-19. strongly disagree 101 (25.3) disagree 153 (38.3) neutral 78 (19.5) agree 54 (13.5) strongly agree 14 (3.5) my heart races or palpitates when i think about getting coronavirus-19. strongly disagree 98 (24.5) disagree 142 (35.5) neutral 82 (20.5) agree 69 (17.3) strongly agree 9 (2.3) total score on fear scale low 72 (18.0) moderate 262 (65.5) high 66 (16.5) psychosocial impact of covid-19 on healthcare workers a cross-sectional survey from pakistan 86 | squ medical journal, february 2022, volume 22, issue 1 table 3: distribution of anxiety gad-7 and depression phq-9 scale responses among healthcare workers during the covid-19 pandemic (n = 400) anxiety and depression scales n (%) gad-7 anxiety scale feeling nervous, anxious, or on edge not at all 181 (45.3) several days 125 (31.3) more than half the days 34 (8.5) nearly every day 60 (15.0) not being able to stop or control worrying not at all 221 (55.3) several days 103 (25.8) more than half the days 41 (10.3) nearly every day 35 (8.8) worrying too much about different things not at all 170 (42.5) several days 150 (37.5) more than half the days 33 (8.3) nearly every day 47 (11.8) trouble relaxing not at all 213 (53.3) several days 109 (27.3) more than half the days 42 (10.5) nearly every day 36 (9.0) being so restless that it's hard to sit still. not at all 297 (74.3) several days 54 (13.5) more than half the days 23 (5.8) nearly every day 26 (6.5) becoming easily annoyed or irritable. not at all 244 (61.0) several days 74 (18.5) more than half the days 47 (11.8) nearly every day 35 (8.8) feeling afraid as if something awful might happen. not at all 171 (42.8) several days 116 (29.0) more than half the days 43 (10.8) nearly every day 70 (17.5) total anxiety score none <5 150 (37.5) mild (5–9) 188 ( 47.0) moderate (10–14) 52 ( 13 ) severe (>15) 10 (2.5) phq-9 depression scale little interest or pleasure in doing things. not at all 198 (49.5) several days 118 (29.5) more than half the days 33 (8.3) nearly every day 51 (12.8) feeling down, depressed, or hopeless. not at all 248 (62.0) several days 101 (25.3) more than half the days 26 (6.5) nearly every day 25 (6.3) trouble falling or staying asleep, or sleeping too much. not at all 258 (64.5) several days 77 (19.3) more than half the days 38 (9.5) nearly every day 27 (6.8) feeling tired or having little energy. not at all 230 (57.5) several days 105 (26.3) more than half the days 26 (6.5) nearly every day 39 (9.8) poor appetite or overeating. not at all 286 (71.5) several days 80 (20.0) more than half the days 16 (4.0) nearly every day 18 (4.5) feeling bad about yourself or that you are a failure or have let yourself or your family down. not at all 274 (68.5) several days 67 (16.8) more than half the days 25 (6.3) nearly every day 34 (8.5) trouble concentrating on things, such as reading the newspaper or watching television. not at all 252 (63.0) several days 87 (21.8) more than half the days 22 (5.5) nearly every day 39 (9.8) moving or speaking so slowly that other people could have noticed. or the opposite – being so fidgety or restless that you have been moving around a lot more than usual. not at all 311 (77.8) several days 55 (13.8) more than half the days 18 (4.5) nearly every day 16 (4.0) thoughts that you would be better off dead, or of hurting yourself. not at all 325 (81.3) several days 50 (12.5) more than half the days 12 (3.0) nearly every day 13 (3.3) total score on the depression phq-9 scale none 51(12.8) minimal depression (1–4) 156 (39.0) mild depression (5–9) 106 (26.5) moderate depression (10–14) 60 (15.0) moderately severe depression (15–19) 16 (4.0) severe depression (20–27) 11 (2.8) syed m. ali and sidrah nausheen clinical and basic research | 87 of the respondents were afraid of contracting the virus and suffering from its symptoms, whereas 19.5% feared death. these findings are similar to those of a study conducted in china where 53.8% rated the psychological impact of the outbreak as moderate or severe.15 among those having past experiences of being infected, quarantined or even hospitalised, it was found that quarantined individuals feel more depressed, anxious, isolated, frustrated and helpless than the general population.16 the findings of the current study are also comparable to another study from pakistan, where a significant number of pakistanis experienced anxiety, stress and depression due to covid-19; approximately 89% of hcws were scared for their families and 80% were fearful that they might contract covid-19.17 the media’s intense coverage of the current pandemic exacerbates the fear, anxiety, stress and panic of the public and hcws. the majority of hcws included in the current study (56.5%) reported social media and watching the news to be responsible for increasing their fear. in a recent study in karachi, pakistan, balkhi et al. reported that a high proportion of participants ( 82.8%) found that fake news and un-authenticated information related to covid-19, which was surfacing via social media, was a source of panic.18 according to the current study, 21.8% of the participants had moderate to severe depression and 15.5% had moderate to severe anxiety levels. in contrast, another study from pakistan reported that 72.3% of the participants working in the covid-19 table 4: comparison between fear of covid-19 level and studied variables (n = 400) characteristic total level of fear of covid-19, n (%) p value low moderate high age group in years 0.022 20–30 88 13 (14.8) 60 (68.2) 15 (17.0) 30–40 140 23 (16.4) 83 (59.3) 34 (24.3) 40–50 99 17 (17.2) 72 (72.7) 10 (10.1) 50–60 73 19 (26.0) 47 (64.4) 7 (9.6) profession <0.001 doctor 263 57 (21.7) 179 (68.1) 27 (10.3) nurse 62 8 (12.9) 34 (54.8) 20 (32.3) paramedical 41 3 (7.3) 28 (68.3) 10 (24.4) technician 34 4 (11.8) 21 (61.8) 9 (26.5) education 0.004 middle 20 0 (0.0) 12 (60.0) 8 (40.0) higher 14 2 (14.3) 10 (71.4) 2 (14.3) graduate 129 17 (13.2) 85 (65.9) 27 (20.9) postgraduate 237 53 (22.4) 155 (65.4) 29 (12.2) type of fear <0.001 isolation 116 33 (28.4) 62 (53.4) 21 (18.1) disease 206 28 (13.6) 154 (74.8) 24 (11.7) death 78 11 (14.1) 46 (59.0) 21 (26.9) co-morbidity 0.560 asthma 40 6 (15.0) 28 (70.0) 6 (15.0) diabetes 29 3 (10.3) 21 (72.4) 5 (17.2) hypertension 40 11 (27.5) 21 (52.5) 8 (20.0) none 291 52 (17.9) 192 (66.0) 47 (16.2) are you getting proper ppe in your workplace? 0.970 yes 237 44 (18.6) 154 (65.0) 39 (16.5) no 83 13 (15.7) 57 (68.7) 13 (15.7) sometimes 80 15 (18.8) 51 (63.8) 14 (17.5) are you working in the covid-19 isolation area? <0.001 yes 144 40 (27.8) 91 (63.2) 13 (9.0) no 256 32 (12.5) 171 (66.8) 53 (20.7) ppe = personal protective equipment. psychosocial impact of covid-19 on healthcare workers a cross-sectional survey from pakistan 88 | squ medical journal, february 2022, volume 22, issue 1 isolation ward suffered from moderate to extremely severe depression and 85.7% suffered from moderate to extremely severe anxiety.17 this difference could be due to the inclusion of general hcws in the current study versus those specifically working in covid-19 isolation areas. approximately 36.0% of the participants in the present study were working in covid-19 areas. the findings of the current study were similar to an extensive chinese study that reported psychological distress in almost 35% of the respondents.19 on the other hand, a recent survey from malaysia reported 72.1% experienced moderate to severe anxiety levels, whereas in a study from egypt, 18% reported minimal anxiety, 34% reported mild anxiety and 48% reported moderate anxiety symptoms.20,21 the difference in psychological well-being observed among different countries could be due to differences in healthcare infrastructures. the hcws are at the frontline of dealing with unprecedented traumatic issues resulting from an overwhelming load of cases, exceptionally long work hours as a result of limited resources and an uncertain primary facility. all these factors most likely led to severe anxiety and depression among hcws, affecting their decision-making abilities and causing long-term detrimental effects on their overall well-being. furthermore, this study found that anxiety and depression scores are strongly related to the non-availability of ppe (p <0.001). similarly, a strong association of depression and anxiety was found with table 5: correlation of depression of healthcare workers with the studied variable during the covid-19 pandemic (n = 400) characteristic total depression level, n (%) p value none minimal mild moderate moderately severe severe age group in years <0.001 20–30 88 11 (12.5) 32 (36.4) 23 (26.1) 16 (18.2) 0 (0.0) 6 (6.8) 30–40 140 6 (4.3) 56 (40.0) 36 (25.7) 27 (19.3) 10 (7.1) 5 (3.6) 40–50 99 13 (13.1) 36 (36.4) 34 (34.3) 14 (14.1) 2 (2.0) 0 (0.0) 50–60 73 21 (28.8) 32 (43.8) 13 (17.8) 3 (4.1) 4 (5.5) 0 (0.0) profession <0.001 doctor 263 41 (15.6) 112 (42.6) 81 (30.8) 23 (8.7) 6 (2.3) 0 (0.0) nurse 62 4 (6.5) 21 (33.9) 10 (16.1) 20 (32.3) 3 (4.8) 4 (6.5) paramedical 41 0 (0.0) 16 (39.0) 11 (26.8) 9 (22.0) 5 (12.2) 0 (0.0) technician 34 6 (17.6) 7 (20.6) 4 (11.8) 8 (23.5) 2 (5.9) 7 (20.6) education <0.001 middle 20 0 (0.0) 6 (30.0) 3 (15.0) 11 (55.0) 0 (0.0) 0 (0.0) higher 14 4 (28.6) 2 (14.3) 6 (42.9) 2 (14.3) 0 (0.0) 0 (0.0) graduate 129 20 (15.5) 44 (34.1) 37 (28.7) 17 (13.2) 7 (5.4) 4 (3.1) postgraduate 237 27 (11.4) 104 (43.9) 60 (25.3) 30 (12.7) 9 (3.8) 7 (3.0) type of fear <0.001 isolation 116 29 (25.0) 38 (32.8) 16 (13.8) 26 (22.4) 5 (4.3) 2 (1.7) disease 206 14 (6.8) 94 (45.6) 69 (33.5) 19 (9.2) 5 (2.4) 5 (2.4) death 78 8 (10.3) 24 (30.8) 21 (26.9) 15 (19.2) 6 (7.7) 4 (5.1) co-morbidity <0.001 asthma 40 3 (7.5) 21 (52.5) 12 (30.0) 3 (7.5) 1 (2.5) 0 (0.0) diabetes 29 1 (3.4) 10 (34.5) 13 (44.8) 0 (0.0) 2 (6.9) 3 (10.3) hypertension 40 13 (32.5) 10 (25.0) 10 (25.0) 7 (17.5) 0 (0.0) 0 (0.0) none 291 34 (11.7) 115 (39.5) 71 (24.4) 50 (17.2) 13 (4.5) 8 (2.7) are you getting proper ppe in your workplace? <0.001 yes 237 26 (11.0) 93 (39.2) 65 (27.4) 42 (17.7) 4 (1.7) 7 (3.0) no 83 22 (26.5) 35 (42.2) 17 (20.5) 4 (4.8) 5 (6.0) 0 (0.0) sometimes 80 3 (3.8) 28 (35.0) 24 (30.0) 14 (17.5) 7 (8.8) 4 (5.0) are you working in the covid-19 isolation area? 0.002 yes 144 21 (14.6) 69 (47.9) 36 (25.0) 17 (11.8) 1 (0.7) 0 (0.0) no 256 30 (11.7) 87 (34.0) 70 (27.3) 43 (16.8) 15 (5.9) 11 (4.3) ppe = personal protective equipment. syed m. ali and sidrah nausheen clinical and basic research | 89 education, age, profession and co-morbidities (p <0.001), which have not been reported in any previous study from pakistan. one of the limitations to this study is lack of generalisability, as only the urban population was included; the study sample size was small and, as such, might not have provided sufficient data to be representative of the country as a whole. however, the results can help policymakers monitor the mental health status of hcws during this unusual crisis. adequate planning such as work-hour regulations, programmes for provision of psychological support, training of individual and group skills as well as cognitive behaviour therapy can reduce the number of these mental health issues.22 while there may be some overlap between the concepts of anxiety and fear, the individual scales of anxiety and fear used were validated in previous studies. this minimises the probability of overlap. in addition, the anxiety scale is a general scale, whereas the fear scale is related particularly and specifically to the fear of coronavirus. one of the prime implications caused by prolonged stress and anxiety is burnout syndrome, or emotional fatigue, which leads to energy loss, fatigue, dissociation and depersonalisation. clinical signs are social isolation, anxiety, fear, depression, anger, addictions, personality changes, guiltiness and self-immolation, changes in eating habits, substantial gain or weight loss, loss of memory disorganisation, problems with concentration and sleep disorders. such healthcare worker is a risk for patients and needs immediate treatment. burnout for hcps working during the covid-19 pandemic is associated with factors such as feeling pushed beyond training (high workload), making life-or-death prioritising decisions (high job stress), work impacting the ability to perform household activities (high time pressure) and lack of adequate ppe (limited organisational support).23 finally, this study recommends that utmost protection of hcws’ well-being be provided before the ongoing pandemic creates complete chaos in the healthcare system. a mental health assistance hotline can be set-up to provide psychosocial assistance to hcws. moreover, adequate provision of ppe to staff must be offered to hcws to protect them from contracting the infection.7 conclusion this study reports that 21.8% of the hcws suffered from moderate to severe levels of depression, 15.5% had moderate to severe anxiety whereas 65.5% had a moderate level of fear. the predictors for anxiety and depression due to the effects of covid-19 are age, education level and co-morbidities, all of which raises concerns for professionals’ psychological wellbeing. this should be addressed through different strategies and programmes to allow for better control of the effects of the covid-19 pandemic. online medical advice and strategies for risk reduction of viral transmission between patients and medical workers will help reduce the pressure on hcws. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n sma conceived the study design and executed the study. both authors drafted the manuscript. sn collected the data and edited the manuscript. both authors approved the final version of the manuscript. references 1. guan wj, ni zy, hu y, liang wh, ou cq, he jx, et al. clinical characteristics of coronavirus disease 2019 in china. n engl j med 2020; 382:1708–20. https://doi.org/10.1056/ nejmoa2002032. 2. huang c, wang y, li x, ren l, zhao j, hu y, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet 2020; 395:497–506. https://doi. org/10.1016/s0140-6736(20)30183-5. 3. pappas g, kiriaze ij, giannakis p, falagas me. psychosocial consequences of infectious diseases. clin microbiol infect 2009; 15:743–7. https://doi.org/10.1111/j.1469-0691.2009.02947.x. 4. lin cy. social reaction towards the 2019 novel coronavirus (covid-19). soc health behav 2020; 3:1–2. https://doi. org/10.4103/shb.shb_11_20. 5. world economic forum. what's needed now to protect health workers: who covid-19 briefing. https://www.weforum. org/agenda/2020/04/10-april-who-briefing-health-workerscovid-19-ppe-training/ accessed: dec 2020. 6. world health organization. who coronavirus (covid-19) dashboard. https://covid19.who.int/ accessed: dec 2020. 7. khalid a, ali s. covid-19 and its challenges for the healthcare system in pakistan. asian bioeth rev 2020; 12:551–64. https:// doi.org/10.1007/s41649-020-00139-x. 8. bai y, lin cc, lin cy, chen jy, chue cm, chou p. survey of stress reactions among health care workers involved with the sars outbreak. psychiatr serv 2004; 55:1055–7. https://doi. org/10.1176/appi.ps.55.9.1055. 9. lai j, ma s, wang y, cai z, hu j, wei n, et al. factors assoc iated with mental health outcomes among health care workers exposed to coronavirus disease 2019. jama netw open 2020; 3:e203976. https://doi.org/10.1001/jamanetworkopen.2020.3976. 10. ahorsu dk, lin ck, imani v, saffari m, griffiths md, pakpour ah. the fear of covid-19 scale: development and initial validation. int j ment health addict 2020; 27:1–9. https://doi.org/10.1007/ s11469-020-00270-8. 11. dong l, hu, s, gao j. discovering drugs to treat coronavirus disease 2019 (covid-19). drug discov ther 2020; 14:58–60. https://doi.org/10.5582/ddt.2020.01012. https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.1016/s0140-6736(20)30183-5 https://doi.org/10.1016/s0140-6736(20)30183-5 https://doi.org/10.1111/j.1469-0691.2009.02947.x https://doi.org/10.4103/shb.shb_11_20 https://doi.org/10.4103/shb.shb_11_20 https://doi.org/10.1007/s41649-020-00139-x https://doi.org/10.1007/s41649-020-00139-x https://doi.org/10.1176/appi.ps.55.9.1055 https://doi.org/10.1176/appi.ps.55.9.1055 https://doi.org/10.1001/jamanetworkopen.2020.3976. https://doi.org/10.1007/s11469-020-00270-8 https://doi.org/10.1007/s11469-020-00270-8 https://doi.org/10.5582/ddt.2020.01012 psychosocial impact of covid-19 on healthcare workers a cross-sectional survey from pakistan 90 | squ medical journal, february 2022, volume 22, issue 1 12. pappa s, ntella v, giannakas t, giannakoulis vg, papoutsi e, katsaounou p. prevalence of depression, anxiety, and insomnia among healthcare workers during the covid-19 pandemic: a systematic review and meta-analysis. brain behav immun 2020; 88:901–7. https://doi.org/10.1016/j.bbi.2020.05.026. 13. wilson n, baker m, crampton p, mansoor o. the potential impact of the next influenza pandemic on a national primary care medical workforce. hum resour health 2005; 3:7. https:// doi.org/10.1186/1478-4491-3-7. 14. wu p, fang y, guan z, fan b, kong j, yao z, et al. the psychological impact of the sars epidemic on hospital employees in china: exposure, risk perception, and altruistic acceptance of risk. can j psychiatry 2009; 54:302–11. https:// doi.org/10.1177/070674370905400504. 15. wang c, pan r, wan x, tan y, xu l, ho cs, et al. immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china. int j environ res pub health 2020; 17:1729. https://doi.org/10.3390/ijerph17051729. 16. gómez-durán el, martin-fumadó c, forero cg. the psychological impact of quarantine on healthcare workers. occup environ med 2020; 77:666–74. https://doi.org/10.1136/ oemed-2020-106587. 17. sandesh r, shahid w, dev k, mandhan n, shankar p, shaikh a, et al. impact of covid-19 on the mental health of healthcare professionals in pakistan. cureus 2020; 12:e8974. https://doi. org/10.7759/cureus.8974. 18. balkhi f, nasir a, zehra a, riaz r. psychological and behavioral response to the coronavirus (covid-19) pandemic. cureus 2020; 12:e7923. https://doi.org/10.7759/cureus.7923. 19. qiu j, shen b, zhao m, wang z, xie b, xu y. a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations. gen psychiatry 2020; 33:e100213. https:// doi.org/10.1136/gpsych-2020-100213. 20. wong lp, alias h. temporal changes in psychobehavioural responses during the early phase of the covid-19 pandemic in malaysia. j behav med 2021; 44:18–28. https://doi.org/10.1007/ s10865-020-00172-z. 21. magdy dm, metwally a, magdy o. assessment of community psycho-behavioral responses during the outbreak of novel coronavirus (2019-ncov): a cross-sectional study. aims public health 2022; 9:26–40. https://doi.org/10.3934/public health.2022003. 22. ho cs, chee cy, ho rc. mental health strategies to combat the psychological impact of coronavirus disease 2019 (covid-19) beyond paranoia and panic. ann acad med singap 2020; 49:155–60. https://doi.org/10.47102/annals-acadmedsg.202043. 23. morgantini la, naha u, wang h, francavilla s, acar ö, flores jm, et al. factors contributing to healthcare professional burnout during the covid-19 pandemic: a rapid turnaround global survey. plos one 2020; 15:e0238217. https://doi.org/10.1371/ journal.pone.0238217. https://doi.org/10.1016/j.bbi.2020.05.026 https://doi.org/10.1186/1478-4491-3-7 https://doi.org/10.1186/1478-4491-3-7 https://doi.org/10.1177/070674370905400504 https://doi.org/10.1177/070674370905400504 https://doi.org/10.3390/ijerph17051729 https://doi.org/10.1136/oemed-2020-106587 https://doi.org/10.1136/oemed-2020-106587 https://doi.org/10.7759/cureus.8974 https://doi.org/10.7759/cureus.8974 https://doi.org/10.7759/cureus.7923 https://doi.org/10.1136/gpsych-2020-100213 https://doi.org/10.1136/gpsych-2020-100213 https://doi.org/10.1007/s10865-020-00172-z https://doi.org/10.1007/s10865-020-00172-z https://doi.org/10.3934/publichealth.2022003 https://doi.org/10.3934/publichealth.2022003 https://doi.org/10.47102/annals-acadmedsg.202043 https://doi.org/10.1371/journal.pone.0238217 https://doi.org/10.1371/journal.pone.0238217 jawaharlal institute of postgraduate medical education & research, puducherry, india *corresponding author’s e-mail: mail2manju22@gmail.com pulmonary aspergillus and mucor co-infection a report of two cases ravindra chari m., *manju rajaram, madhusmita m., pampa chtoi, sneha l. sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 495–498, epub. 29 aug 21 submitted 19 may 20 revision req. 22 jul 20; revision recd. 13 aug 20 accepted 9 aug 20 the autoimmune serology work up (antinuclear antibody [ana]) was negative and no mycobacterium tuberculosis was detected in the sputum using a cartridge based nucleic acid amplification test (cbnaat). subsequent work-up with a high resolution computed tomography of the thorax (hrct) and computed tomography bronchial angiography showed an intra-cavitary mass surrounded by a crescent of air (air crescent sign) in the thick-walled cavity of the right upper lobe [figure 1a]. there were prominent tortuous vessels noted in the cavity wall supplied by branches from the right subclavian, intercostals, pulmonary and bronchial arteries along with right middle lobe fibrosis and traction bronchiectasis. due to a suspicion of an invasive fungal disease, a computed tomography (ct) scan of the brain and paranasal sinuses was taken. however, the scan did not show any lesions suggestive of fungal dissemination. the patient underwent emergency upper and middle lobectomy with no surgery-related complications. histopathology of the resected specimen was suggestive of a fungal ball (aspergillus and mucor) colonising the lung cavity without definite tissue or angio-invasion. in addition, there were a few foci of infection in the middle lobe which showed colonies of aspergillus and mucor. the patient was administered liposomal amphotericin b (amb) intravenously at 5 mg/kg/day for a period of 21 days and his post-operative follow-up period of three months, six months and one year after surgery were uneventful. co-infections or consecutive infections of mucormycosis and aspergillosis are very rare and usually observed in immunecompromised patients.1 distinguishing between these infections poses a challenge as both have similar risk factors and clinical features. the following cases demonstrate the importance of tissue diagnosis, variations in treatment response and the need for an aggressive multimodal approach in fungal coinfections to treat a patient. case one a 70-year-old non-diabetic male patient from tamilnadu, presented to a tertiary care centre in puducherry, india in 2017, with a history of haemoptysis (approximately 50 ml/day) associated with intermittent fever; the condition had lasted for a month prior to presentation. the patient also had a history of shortness of breath [mmrc (modified medical research council) grade iii] with no orthopnoea. the patient had received antituberculosis treatment 10 years prior to presentation for five months. the patient was not on any immunosuppressive drugs and did not show signs of diabetes; his random blood sugar (rbs) was 96 mg/dl at the time of presentation and <140 mg/dl during the entire hospital stay. there was no history suggestive of any other systemic or immunological co-morbidity. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.126 case report abstract: co-infections or consecutive infections of mucormycosis and aspergillosis are very rare. additionally, distinguishing between these two infections is also difficult as both these conditions have similar clinical features. we report two similar cases from tamilnadu, who presented to a tertiary care centre in puducherry, india in 2017 (first case) and 2019 (second case). the first case was a 70-year-old, non-diabetic male patient who presented with haemoptysis with a prior history of pulmonary tuberculosis. computed tomography bronchial angiography revealed an air-crescent sign and the histopathological examination showed a fungal ball (aspergillus and mucor) in the right upper lobe and foci of fungal infection in the middle lobe. the second case was a 65-year-old diabetic male patient who presented with blackish expectoration and haemoptysis. a high-resolution computed tomography scan showed a reverse-halo sign in the right upper lobe. the results of the bronchoscopy-guided biopsy were consistent with a diagnosis of mixed mucormycosis and aspergillosis with angioinvasion. both patients responded to amphotericin b with surgical excision of the affected lobe in the first case. a high degree of clinical suspicion, early surgical intervention and antifungal therapy are essential in the treatment of this rare co-infection. keywords:aspergillosis; mucormycosis; bronchoscopy; coinfection; amphotericin b; case report; india. https://creativecommons.org/licenses/by-nd/4.0/ pulmonary aspergillus and mucor co-infection a report of two cases 496 | squ medical journal, august 2021, volume 21, issue 3 case two the second case is of a 65-year-old alcoholic male patient, also from tamilnadu, presenting to a tertiary care centre in puducherry, india, in 2019 with cough associated with blackish mucoid expectoration and haemoptysis; the condition had lasted for two months prior to presentation. a chronic smoker, the patient was experiencing breathlessness (mmrc grade iii) and intermittent fever. he was treated at home with broad-spectrum antibiotics for one week. at the time of presentation, the patient had type-1 respiratory failure, an elevated blood cell count of 12,470/mm3 (normal range: 4,000–7,000 mm3) and altered renal parameters (blood urea of 64 mg/dl [normal range: 15–40 mg/dl], serum creatinine of 1.58 mg/dl [normal range: 0.7–1.2 mg/dl] and rbs of 286 mg/ dl [normal range: 70–140 mg/dl]). the autoimmune serology work up ana was negative. hrct showed right upper lobe central ground-glass opacity surrounded by a ring of consolidation (reverse halo sign) along with a cavitating consolidation involving the right upper and middle lobes suggestive of fungal pneumonia [figure 1b]. to rule out the possibility of a disseminated fungal infection, a ct scan of the brain with the paranasal sinuses was taken; this scan appeared normal. fibre optic bronchoscopy (fob)-guided trans bronchial lung biopsy (tblb) showed dense acute inflammatory cells and fungal colonies morphologically consistent with a diagnosis of mixed mucormycosis and aspergillosis with angio-invasion [figure 2]. as the patient had deranged renal parameters, he was treated with intravenous liposomal amb at 5 mg/kg/day. blood sugars were adequately controlled (maintained at rbs <140 mg/dl) with parenteral insulin. the figure 1: computed tomography of (a) a 70-year-old male patient showing a thick-walled cavity in the right upper lobe with an intracavitary mass surrounded by a crescent of air known as the ‘air crescent sign’ (case one) and (b) a 65-year-old male patient showing central ground-glass opacity surrounded by a complete ring of consolidation known as the ‘reverse halo sign’ (case two). figure 3: chest x-ray of a mixed infection of aspergillus and mucor showing significant radiological resolution after three weeks of amphotericin b therapy in a 65-year-old male patient. figure 2: histopathology of lung biopsy showing aspergillus and mucor in a 65-year-old male patient. this is a periodic acid-schiff staining at x40 magnification showing multiple branching septated hyphae (black arrow) consistent with aspergillus along with broad-based, ribbon-like, non-septate hyphae (red arrow) suggestive of mucor. ravindra chari m., manju rajaram, madhusmita m., pampa chtoi and sneha l. case report | 497 patient responded well to the treatment and improved both clinically and radiologically [figure 3]. written informed consent was obtained from both patients for the publication of these case reports and images. discussion the human respiratory tract is continuously exposed to the environment where various pathogenic organisms either alone or in combination can cause disease, particularly in immune-compromised patients. the risk factors for fungal co-infection include diabetes mellitus, immune-suppression, haematological malignancies and cancer chemotherapy.2 diabetes mellitus is the most common predisposing factor for mucormycosis and other fungal pneumonia.2–5 aspergillus spp. and mucorales are the most common ubiquitous saprophytic opportunistic fungal infections which need specific environmental exposures.6 this combination of disease occurring simultaneously or sequentially in the lungs is rare and is less common than rhino cerebral disease.7 mucormycosis or zygomycosis is a rare opportunistic fungal infection caused by the mucorales order of fungi including the genera rhizopus spp., absidia spp., cunninghamella spp., rhizomucor spp., mucor spp., apophysomyces spp.8 belonging to the mucoraceae family, mucormycosis usually manifests as an invasive infection involving para nasal sinuses, lungs or skin. it may also manifest as disseminated disease.8 aspergillus species are ubiquitous and saprophytic fungi that can cause pulmonary infection commonly after inhalation of its conidia or mycelial fragments from the environment.6 pulmonary aspergillosis has been classified into (1) fungus balls within the cavities (2) invasive aspergillosis (3) allergic bronchial aspergillosis and (4) rhinosinusitis.9 aspergillus colonizes the cavitary lesions especially in the healed tubercular cavities of the lungs.10 inside the cavity, the fungus forms a freely moving fungal ball consisting of fungal hyphae (commonly of aspergillus spp., occasionally of mucor spp. or of both in combination), inflammatory cells and fibrin material.11 fungal toxins erode the walls of the cavity and spread by local destruction, causing massive haemoptysis which can be predominant and sometimes the sole symptom of the disease.12 distinguishing between mucormycosis and aspergillosis by clinical or radiographic signs is difficult as both conditions afflict immune suppressed individuals. such patients also present with similar features of pneumonia. the identification of a causative factor plays a crucial role in the outcome as these two entities respond differently to various antifungal agents. chamiloset al. systematically compared mucormycosis and aspergillosis and concluded that no clear differences were noted clinically and very few differences were observed in the ct findings.13 hence, wherever feasible, confirmation by microscopy is necessary for diagnostic certainty. direct histological examination of the tissue biopsy remains the gold standard in the diagnosis of invasive fungal infections.14 based on the clinical findings, radiological imaging, histopathology and by utilizing the revised definitions from the european organization for research and treatment of cancer/ invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group, a diagnosis of proven invasive fungal infection was established in both the reported cases.14 the choice of antifungal agent must be based on the clinical characteristics and local epidemiology of the fungal infections.15 the infectious diseases society of america (idsa) recommends monotherapy with voriconazole or isavuconazole in aspergillosis. ambdeoxycholate and its lipid derivatives cover aspergillus spp., candida and mucormycetes. these drugs are appropriate options for the initial treatment and in salvage therapy of aspergillus infections in resource-limited settings and conditions where voriconazole cannot be administered.15 itraconazole is one of the preferred agents used to treat aspergillosis.16 surgical excision of the cavity and the involved segment or lobe in the aspergilloma can be done with relatively low morbidity and mortality to achieve complete remission and a symptom-free state.17 intravenous amb (a lipid formulation) is the drug of choice for initial therapy in the case of mucormycosis. adjuvant extensive surgical debridement should also be taken into consideration in selected cases.18 the first case in this report presented with a fungal ball in the post-tubercular cavity of the lung evidenced by hrct, initially thought to be caused by aspergillus spp. later on, as histopathological features were suggestive of the fungal ball (aspergillus and mucor) colonizing the lung cavity, liposomal amb was administered intravenously. the second case was a diabetic patient who presented with pneumonia and a suspicion of fungal aetiology. he was initially started on liposomal amb as part of the treatment procedure. later on, fob guided tblb suggested an aspergillus and mucor co-infection. co-infection with aspergillus and mucor in the post tubercular cavity is rare. there pulmonary aspergillus and mucor co-infection a report of two cases 498 | squ medical journal, august 2021, volume 21, issue 3 are cases reported in the literature where posttubercular cavity in the lung with a mucor fungal ball was treated using liposomal amb.19 though aspergillus is the most common fungus causing the formation of a fungal ball, only 5 case reports (delineating 8 patients) of paranasal fungal balls caused by mucor have been published in the literature.20 it should be noted that there are some reports where invasive pulmonary aspergillus and mucor were countered adequately using high doses of liposomal amb alone.21 however, in a report of pulmonary aspergillus and mucor co-infection in a diabetic patient, outcomes were not satisfactory even with extensive antifungal treatment with intravenous amphotericin and voriconazole.1 delay in diagnosis, non-affordability of new and effective antifungal agents, lack of consensus concerning the dosage and duration of antifungals in mixed infections play a major role in the treatment outcome. conclusion mucormycosis and aspergillosis are rare co-infections that could potentially lead to death. a high degree of suspicion, early detection by a multidisciplinary approach, appropriate antifungal therapy and, if necessary, surgical resection are essential in the treatment of this co-infection. antimicrobial therapy must be rationalized, especially in co-infections with underlying immunosuppressive conditions as there is no clear consensus on the treatment of mixed co-infections that respond differently to standard treatment protocols. references 1. mahadevaiah ah, rajagopalan n, patil m, shivaprasad c. co infection of pulmonary mucormycosis and aspergillosis presenting as bilateral vocal cord palsy. bmj case rep 2013; 2013:bcr2013009615. https://doi.org/10.1136/bcr-2013-009615. 2 petrikkos g, skiada a, lortholary o, roilides e, walsh tj, kontoyiannis dp. epidemiology and clinical manifestations of mucormycosis. clin infect dis 2012; 54:s23–34. https://doi. org/10.1093/cid/cir866. 3. trof rj, beishuizen a, debets-ossenkopp yj, girbes ar, groene veld ab. management of invasive pulmonary aspergillosis in nonneutropenic critically ill patients. intensive care med 2007; 33:1694–703. https://doi.org/10.1007/s00134-007-0791-z. 4 li y, fang w, jiang w, hagen f, liu j, zhang let al. crypto coccosis in patients with diabetes mellitus ii in mainland china: 1993–2015. mycoses 2017; 60:706–13. https://doi.org/10.1111/ myc.12645. 5. nunes jo, pillon kr, bizerra pl, paniago am, mendes rp, chang mr. the simultaneous occurrence of histoplasmosis and cryptococcalfungemia: a case report and review of the liter ature. mycopathologia 2016; 181:891–97. https://doi.org/10.10 07/s11046-016-0036-1. 6. dagenais tr, keller np. pathogenesis of aspergillus fumigatus in invasive aspergillosis. clin microbiol rev 2009; 22:447–65. https://doi.org/10.1128/cmr.00055-08. 7. spellberg b, edwards j, ibrahim a. novel perspectives on mucor mycosis: pathophysiology, presentation, and management. clin microbiol rev 2005; 18:556–69. https://doi.org/10.1128/cmr.1 8.3.556-569.2005. 8. hamilos g, samonis g, kontoyiannis dp. pulmonary mucor mycosis. semin respir crit care med 2011; 32:693–702. https:// doi.org/10.1055/s-0031-1295717. 9. kousha m, tadi r, soubani ao. pulmonary aspergillosis: a clinical review. eurrespir rev 2011; 20:156–74. https://doi. org/10.1183/09059180.00001011. 10. kawamura s, maesaki s, tomono k, tashiro t, kohno s. clin ical evaluation of 61 patients with pulmonary aspergilloma. intern med 2000; 39:209–12. https://doi.org/10.2169/internalmedici ne.39.209. 11. lahiri tk, agarwal d, reddy ge, bajoria a. pulmonary mucora ceous fungal ball. indian j chest dis allied sci 2001; 43:107–10. 12. muqeetadnan m, rahman a, amer s, nusrat s, hassan s, hashmi s. pulmonary mucormycosis: an emerging infection. case rep pulmonol 2012; 2012:120809. https://doi.org/10.11 55/2012/120809. 13. chamilos g, marom em, lewis re, lionakis ms, kontoyiannis dp. predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer. clin infect dis 2005; 41:60–6. https://doi.org/10.1086/430710. 14. de pauw b, walsh tj, donnelly jp, stevens da, edwards je, calandra t, et al. revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (eortc/msg) consensus group. clin infect dis 2008; 46:1813–21. https://doi.org/10.1086/588660. 15. patterson tf, thompson gr 3rd, denning dw, fishman ja, hadley s, herbrecht r, et al. practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america. clin infect dis 2016; 63:e1–e60. https://doi.org/10.1093/cid/ciw326. 16. patterson tf, thompson gr 3rd, denning dw, fishman ja, hadley s, herbrecht r, et al. practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america. clin infect dis 2016; 63:e1–60. https://doi.org/10.1093/cid/ciw326. 17. mohapatra b, sivakumar p, bhattacharya s, dutta s. surgical treatment of pulmonary aspergillosis: a single center experience. lung india 2016; 33:9–13. https://doi.org/10.4103/0970-2113.173077. 18. petrikkos g, drogari-apiranthitou m. zygomycosis in immuno compromised non-haematological patients. mediterr j hematol infect dis 2011; 3:e2011012. https://doi.org/10.4084/mjhid.20 11.012. 19. mekki so, hassan aa, falemban a, alkotani n, alsharif sm, haron a, et al. pulmonary mucormycosis: a case report of a rare infection with potential diagnostic problems. case rep pathol 2020; 2020. https://doi.org/10.1155/2020/5845394. 20. cho hs, yang hs, kim ks. mucormycosis (mucor fungus ball) of the maxillary sinus. ear nose throat j 2014; 93:e18–22. https://doi.org/10.1177/014556131409300904. 21. bergantim r, rios e, trigo f, guimaraes je. invasive coinfection with aspergillus and mucor in a patient with acute myeloid leukemia. clin drug investig 2013; 33:s51–5. https://doi. org/10.1007/s40261-012-0022-4. https://doi.org/10.1136/bcr-2013-009615 https://doi.org/10.1093/cid/cir866 https://doi.org/10.1093/cid/cir866 https://doi.org/10.1007/s00134-007-0791-z https://doi.org/10.1111/myc.12645 https://doi.org/10.1111/myc.12645 https://doi.org/10.1007/s11046-016-0036-1 https://doi.org/10.1007/s11046-016-0036-1 https://doi.org/10.1128/cmr.00055-08 https://doi.org/10.1128/cmr.18.3.556-569.2005 https://doi.org/10.1128/cmr.18.3.556-569.2005 https://doi.org/10.1055/s-0031-1295717 https://doi.org/10.1055/s-0031-1295717 https://doi.org/10.1183/09059180.00001011 https://doi.org/10.1183/09059180.00001011 https://doi.org/10.2169/internalmedicine.39.209 https://doi.org/10.2169/internalmedicine.39.209 https://doi.org/10.1155/2012/120809 https://doi.org/10.1155/2012/120809 https://doi.org/10.1086/430710 https://doi.org/10.1086/588660 https://doi.org/10.1093/cid/ciw326 https://doi.org/10.1093/cid/ciw326 https://doi.org/10.4103/0970-2113.173077 https://doi.org/10.4084/mjhid.2011.012 https://doi.org/10.4084/mjhid.2011.012 https://doi.org/10.1155/2020/5845394 https://doi.org/10.1177/014556131409300904 https://doi.org/10.1007/s40261-012-0022-4 https://doi.org/10.1007/s40261-012-0022-4 self-reported adherence to oral endocrine therapy among breast cancer patients in jordan sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 154–156, epub. 28 feb 22 submitted 24 mar 211 revisions req. 16 may & 22 jun 21; revisions recd. 25 may & 29 jun 21 accepted 7 jul 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.096 letter to the editor dear editor, non-adherence to medications is a significant health issue, as it can reduce the efficacy of therapeutic management and increase the likelihood of relapse.1 ensuring that patients with breast cancer (bc) adhere to the prescribed duration of endocrine therapy (et) is, however, difficult due to the long duration of treatment. several studies have evaluated adherence to et.2–4 to the best of the authors’ knowledge, no studies have been conducted in the middle east to evaluate adherence to et. subsequently, the authors conducted a study to evaluate the level of adherence to et among patients with bc. the study also aimed to describe the patients’ perceptions of et and associations between adherence and patient-related factors. this study was conducted between october 2017 and july 2018 at king hussein cancer center, amman, jordan and involved the administration of a questionnaire to patients being treated for bc. patients were recruited at the hospital’s outpatient pharmacy and the chemotherapy infusion clinic. those who had a refill for et (tamoxifen, anastrazole, examastaine or letrazole) and had been on therapy for at least one month were included. the questionnaire was developed by a survey specialist at the institution since, to the best of the authors’ knowledge, there was no validated, well-established questionnaire in arabic. the questionnaire contained items that were reported by pourcelot et al.2 the questionnaire included questions on adherence (the number of missed doses of et during the previous month) and type and duration of et as well as perception about et. the survey specialist and the clinical investigators assessed the items for clarity and relevance to the patients to establish the face and content validity of the questionnaire. the questionnaire was pilot-tested in a small group of patients for one week and modified based on the feedback received. continuous data were presented as means ± standard deviation, while categorical data were presented as numbers and percentages. a p ≤0.05 was considered statistically significant. analysis of variance test was used to determine any associations between adherence and continuous data while chi-squared test was used for categorical data. ethical approval was granted for this study by the institutional review board (17 khcc 93). the questionnaire contained a statement in the first page which was considered a consent form; all included patients provided informed consent. a total of 202 questionnaires were completed. the mean age of patients was 45.8 ± 10.7 years [table 1]. in the sample, there were 113 patients (55.9%) on tamoxifen, 34 (16.8%) on letrazole, 36 (17.8%) on anastrazole and 10 (5.0%) on exemastane. four patients (2.0%) did not know the name of the et they were taking, and five patients (2.5%) did not answer the question. et had been taken for ≤6 months by 59 patients (29.2%), for 6–12 months by 51 patients (25.2%), for 1–3 years by 77 patients (38.1%) and for 3–5 years by 15 patients (7.4%). in terms of patients’ perceptions about et, approximately two-thirds ( 62.9%) reported that they didn’t know to what extent they needed et and approximately half of the patients (47.2%) didn’t know whether et could help in reducing recurrence of bc. however, the majority of the patients were aware of their treatment plan (89.9%) and reported understanding of their disease (90.8%). most of the patients (86.1%) reported that they had received information on the importance of et from their physicians but only half of the patients (52.0%) reported having received medication counselling from a pharmacist. the only factor that was significantly associated with adherence was the duration of treatment (p = 0.048); the shorter the duration of et, the fewer reported missed doses. this study found a relatively high rate of adherence to et. patients were considered adherent if they took at least 80% of their prescribed medication over a certain period.5 the majority of patients in the current study (99.5%) reported adherence rates of 80% or more over one month. studies have reported high as well as low rates of adherence.2,3,5 in the current study, most participants reported that they had received information on the importance of et, but this information was mostly from their physicians rather than pharmacists. in addition, no association was found between the high adherence and the information provided by physicians; however, this may be due to the nature of the study as there was no objective measure of the physician’s role in the patient’s counselling. the https://creativecommons.org/licenses/by-nd/4.0/ nour faqeer, alia al gharabli, maha dalbah, khawalah ammar, randa agha, hala shannies, hala sroji and rawaa al rabie letter to the editor | 155 only factor associated with adherence was the duration of treatment. a similar association was reported by robinson et al., who found that the rate of adherence decreased from year one of treatment to year five by 50%.4 the present authors were unable to draw any conclusion about adherence over the course of et because of the short duration of follow-up in this study. several studies have evaluated the association between adherence and patient-related factors.2,5 in a cross-sectional survey, the risk factors associated with non-adherence were comorbid conditions, polypharmacy and younger age.2 in the current cohort, age and whether the patient was taking other medications were not significantly associated with adherence. however, the present study has some limitations. the use of a selfadministered questionnaire, as there was no objective measure of adherence for more accurate assessment, might have resulted in an overestimation of adherence. in addition, there was a small number of patients that had taken et for more than three years and the response rate was not calculated. furthermore, the included patients were on et for more than one month which might affect the adherence as the behaviours of patients would change over the period of treatment. this study found a relatively high level of adherence to et among patients with bc. however, there was a gap in the counselling provided by pharmacists. further studies should be conducted to assess adherence for a longer duration and to further investigate the factors that may be associated with non-adherence such as socioeconomic status. a u t h o r s’ c o n t r i b u t i o n nf and ka conceptualised and designed the manuscript. ag, md, ra, hs, hs and rr collected and assembled the data. ka analysed the data. nf, ag and ka wrote the manuscript. all authors approved the final version of the manuscript. *nour faqeer,1 alia al gharabli,1 maha dalbah,1 khawalah ammar,2 randa agha,1 hala shannies,1 hala sroji,1 rawaa al rabie1 1department of pharmacy, king hussein cancer center, amman, jordan; 2office of scientific affairs and research, king hussein cancer center, amman, jordan *corresponding author’s e-mail: nfaker@khcc.jo references 1. hershman dl, shao t, kushi lh, buono d, tsai wy, fehrenbacher l, et al. early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. breast cancer res treat 2011; 126:529–37. https://doi. org/10.1007/s10549-010-1132-4. 2. pourcelot c, orillard e, nallet g, dirand c, billion-rey f, barbier g, et al. adjuvant hormonal therapy for early breast cancer: an epidemiologic study of medication adherence. breast cancer res treat 2018; 169:153–62. https://doi.org/10.1007/s10549-018-4676-3. 3. ali ee, cheung kl, lee cp, leow jl, yap ky, chew l. prevalence and determinants of adherence to oral adjuvant endocrine therapy among breast cancer patients in singapore. asia pac j oncol nurs 2017; 4:283–9. https://doi.org/10.4103/2347-5625.212864. table 1: characteristics of patients with breast cancer on endocrine therapy in jordan (n = 202) characteristic n (%) marital status (n = 200) married 163 (81.5) single 19 (9.5) widowed 13 (6.5) divorced 5 (2.5) educational level (n = 199) bachelor's degree 59 (29.6) high school 58 (29.1) diploma 51 (25.6) master’s or doctoral degree 13 (6.5) others 18 (9.0) area of residence (n = 190) amman 127 (66.8) outside amman 55 (28.9) outside jordan 8 (4.2) family income per month in jordanian dinar (n = 190) <500 98 (51.6) 500–1000 72 (37.9) 1000–2000 16 (8.4) >2000 4 (2.1) nationality (n = 199) jordanian 179 (89.9) other 20 (10.1) family history of breast cancer (n = 199) yes 55 (27.6) no 144 (72.4) on other medications (n = 187) yes 55 (29.4) no 132 (70.6) https://doi.org/10.1007/s10549-010-1132-4 https://doi.org/10.1007/s10549-010-1132-4 https://doi.org/10.1007/s10549-018-4676-3 https://doi.org/10.4103/2347-5625.212864 self-reported adherence to oral endocrine therapy among breast cancer patients in jordan 156 | squ medical journal, february 2022, volume 22, issue 1 4. robinson b, dijkstra b, davey v, tomlinson s, frampton c. adherence to adjuvant endocrine therapy in christchurch women with early breast cancer. clin oncol (r coll radiol) 2018; 30:e9–15. https://doi.org/10.1016/j.clon.2017.10.015. 5. ziller v, kalder m, albert us, holzhauer w, ziller m, wagner u, et al. adherence to adjuvant endocrine therapy in postmenopausal women with breast cancer. ann oncol 2009; 20:431–6. https://doi.org/10.1093/annonc/mdn646. https://doi.org/10.1016/j.clon.2017.10.015 https://doi.org/10.1093/annonc/mdn646 1al-akdhar health centre, 2head of research section, 3head of school health section, directorate general of health services of al-dhahira governorate, ministry of health, ibri, oman; 4deanship of research, university of nizwa, nizwa, oman *corresponding author’s e-mail: ashukaily@hotmail.com الوعي بعوامل خطر اإلصابة بسرطان الثدي واألعراض والفحص الذايت للثدي بني املعلمات العمانيات دراسة مقطعية زوينة الإ�شماعيلية، خالد النا�رصي، اأمل اليعقوبية، اأحمد ال�شكيلي abstract: objectives: this study aimed to assess knowledge of breast cancer (bc) risk factors, warning signs and symptoms and breast self-examination (bse) practice among omani female teachers in al-dhahira governorate. methods: a cross-sectional sample of female teachers aged 20–50 years was collected from january to december 2018 from three wilayats (provinces) in al-dhahira—ibri, dhank and yunqal. a questionnaire that included the breast cancer awareness scale and demographic characteristics was administered. data were analysed using descriptive statistics, regression analysis and pearson’s chi-square test. results: a total of 478 female teachers were included in the study (response rate: 72.4%). the majority of participants (60.5%) had good overall knowledge about bc while 19.9% of participants had excellent overall knowledge. only 9% of participants demonstrating excellent knowledge of bc risk factors. more than half of the participants (56.1%) reported excellent knowledge in screening methods. unfortunately, only 57% of the female teachers indicated practising bse. knowledge of bc symptoms was closely divided between excellent and good levels (45.8 and 42.5%, respectively). bse practice was significantly (p <0.05) correlated with overall knowledge of bc and its symptoms and screening methods, but not with knowledge of bc risk factors. conclusion: this study revealed unsatisfactory overall knowledge of bc risk factors, symptoms, screening methods and bse practice among female omani teachers in al-dhahira governorate. these findings constitute a challenge to healthcare providers to continue developing awareness of bc and providing health information to the public. keywords: breast cancer; awareness; knowledge; breast self-examination; risk factors; signs and symptoms; oman. امللخ�ص: الهدف: هدفت هذه الدرا�شة اإىل تقييم معرفة عوامل خطر الإ�شابة ب�رصطان الثدي، وعالمات التحذير والأعرا�ص وممار�شة الفح�ص الذاتي للثدي بني املعلمات العمانيات يف حمافظة الظاهرة. الطريقة: مت جمع عينة م�شتعر�شة من معلمات ترتاوح اأعمارهن بني 20 و 50 �شنة يف الفرتة من يناير اإىل دي�شمرب 2018 من ثالث وليات يف الظاهرة-عربي، �شنك وينقل. مت اإجراء ا�شتبيان يت�شمن مقيا�ص التوعية ب�رصطان الثدي واخل�شائ�ص الدميوغرافية. مت حتليل البيانات با�شتخدام الإح�شائيات الو�شفية، وحتليل النحدار واختبار مربع كاي بري�شون. النتائج: �شملت الدرا�شة 478 معلمة )معدل ال�شتجابة = %72.4(. كان لدى اأغلبية امل�شاركات )%60.5( معرفة �شاملة جيدة عن �رصطان الثدي قي حني كان لدى %19.9 من امل�شاركات معرفة �شاملة ممتازة باملر�ص. كانت معرفة عوامل اخلطر غري مر�شية، حيث اأظهرت النتائج اأن %9 فقط من امل�شاركات لديهن معرفة ممتازة. وتبني اأن اأكرث من ن�شف امل�شاركات )%56.1( لديهن معرفة ممتازة باأ�شاليب الفح�ص. لالأ�شغ، اأ�شارت 57% فقط من املعلمات اإىل ممار�شة الفح�ص الذاتي للثدي. مت تق�شيم معرفة اأعرا�ص �رصطان الثدي بني امل�شتوى املمتاز واجليد )%42.5 و 45.8% على التوايل(. ارتبطت ممار�شة الفح�ص الذاتي للثدي ب�شكل ملحوظ )p >0.05( باملعرفة الكلية لـ�رصطان الثدي واأعرا�شه وطرق الفح�ص، ولكن لي�ص مع معرفة عوامل خطر �رصطان الثدي. اخلال�صة: ك�شفت هذه الدرا�شة عن معرفة عامة غري مر�شية بعوامل اخلطر والأعرا�ص وطرق الفح�ص وممار�شة الفح�ص الذاتي للثدي لدى املدر�شات العمانيات يف حمافظة الظاهرة. ت�شكل هذه النتائج حتديا ملقدمي الرعاية ال�شحية ملوا�شلة تطوير الوعي ب�رصطان الثدي وتوفري املعلومات ال�شحية لعامة النا�ص. الكلمات املفتاحية: �رصطان الثدي. الوعي؛ املعرفه؛ الفح�ص الذاتي للثدي؛ عوامل اخلطر؛ العالمات والأعرا�ص؛ �شلطنة عمان. awareness of breast cancer risk factors, symptoms and breast self-examination among omani female teachers a cross-sectional study zuweina al-ismaili,1 khalid al-nasri,2 amal al-yaqoobi,3 *ahmed al-shukaili4 sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e194–201, epub. 28 jun 20 submitted 9 sep 19 revision req. 14 nov 19; revision recd. 25 dec 19 accepted 29 jan 20 advances in knowledge this is the first study to assess breast cancer (bc) awareness in rural areas in oman. the study revealed insufficient overall bc knowledge among female omani teachers. application to patient care increased public awareness of bc’s signs, symptoms and risk factors and breast self-examination (bse) practice has a substantial impact on the incidence and outcomes of the disease. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.010 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ zuweina al-ismaili, khalid al-nasri, amal al-yaqoobi and ahmed al-shukaili clinical and basic research | e195 early detection of bc leads to better response to therapy and subsequently improves survival rates. the world health organization stresses promoting awareness of bc in the community and encourages early diagnosis of the disease in the primary care setting. breast cancer (bc) is the second most common cancer worldwide and the most frequently diagnosed life-threatening cancer in women. in 2018, more than two million cases of bc were newly diagnosed among women.1,2 case fatality rates from bc are higher in lowand middle-income countries than in most high-income countries.3–6 these observations have been attributed partially to a lack of awareness of bc risk factors and symptoms and a lack of practice of breast self-examination (bse).4–6 increased public awareness of bc is an important factor that has a substantial impact on early detection of the disease. delayed bc diagnosis in developing countries has been associated with poor bc awareness and barriers to access healthcare services. cancer that is diagnosed at an early stage is more likely to be treated successfully.7–9 in oman, bc is the most common cancer in women, with a median age at diagnosis of 48 years, followed by thyroid cancer and colorectal cancer.10,11 in 2018, a total of 454 cases of bc were reported, representing 34.15% of total cancers in omani women.1,2 this figure indicates a significant rise in bc cases in comparison to previous reports.1,11 according to several studies, increasing incidents of bc are associated with a combination of several risk factors including delayed childbirth, reduced incidence of breastfeeding, obesity, increased consumption of alcohol and a fatty diet, sedentary lifestyle, environ mental pollution, long-term use of hormone replace ment therapy (hrt) containing estrogen and progestin and contraceptive use.12–14 other risk factors for bc have been attributed to molecular and genetic deter minates.15 bc screening can be done by bse, clinical breast examination (cbe) and mammography.16 the effect iveness of bse in reducing bc mortality remains controversial. several studies have shown that trained women practising bse does not reduce bc mortality.17,18 other studies show that bse may have a substantial effect in increasing bc awareness and could encourage women to seek cbe, thus leading to earlier detection.19–21 the effectiveness of cbe is considered higher than bse; however, the sensitivity of cbe is dependent on the amount of time taken to do an examination.22 mammography is used as a sensitive screening method, particularly for women older than 40 years, but it is less effective for younger women.23 studies to assess knowledge of bc and bse practice are limited in oman. only two studies related to bc awareness to oman have been published focusing on muscat governorate.24,25 therefore, further studies are needed. this study aimed to ascertain the knowledge of risk factors, warning signs and symptoms of bc, including bse practice among omani female teachers in al-dhahira governorate. methods in this cross-sectional study, stratified random sampling was used to select participants from a total of 22 governmental female schools in al-dhahira governorate, oman. the schools were selected according to the population size of each wilayat (province). most of al-dhahira’s population (75%) are concentrated in ibri, whereas yanqul and dhank represent only 25% of the governorate’s population. questionnaires were distributed to 22 schools according to the proportion of population in each area (14 schools in ibri, four schools in yanqul and four schools in dhank). the sample size was calculated using online sample size calculator.26 the needed sample size was estimated to be 675 female teachers. schools were selected randomly from each stratum. the study cohort was selected because they were easily accessible and deemed to be educated. all the participants were female teachers aged between 20–50 years old. the study was conducted from january to december 2018. non-omani female teachers, women with a personal history of bc and incomplete questionnaires were excluded. all participants were involved in the national health educational and screening programme initiated in 2010 by the ministry of health. school teachers were included in this programme through the school health section of the directorate general of health services in al-dhahira governorate. regrettably, the success of this programme has not been assessed yet. the findings of this study may contribute to understanding the effectiveness of this programme. data were collected using a self-administered questionnaire which contained seven parts: (1) demo graphic data; (2) general bc knowledge; (3) presence of family history of bc and personal history of breast lump; (4–6) overall knowledge of bc (i.e. knowledge of risk factors, screening methods and symptoms of bc); and (7) practice of bse. the questionnaire was adapted from previously validated breast cancer aware ness surveys.7,25,27 awareness of breast cancer risk factors, symptoms and breast self-examination among omani female teachers a cross-sectional study e196 | squ medical journal, may 2020, volume 20, issue 2 risk factors for bc were assessed according to age, family history, having a personal history of bc, early menarche, late menopause, having the first child after the age of 30, not breastfeeding, recent use of combined oral contraceptive (coc) or hrt, exposure to radiation, obesity, following a sedentary lifestyle, eating a diet high in fat, alcohol consumption or smoking and exposure to environmental pollution. the questionnaire was scored according to awareness of bc risk factors, with 0–6 items considered reflective of poor awareness, 7–12 considered indicative of good awareness and 13–16 items considered excellent awareness. women’s knowledge about screening methods (i.e. cbe, bse and mammography) was assessed by asking three separate questions associated with these methods. poor awareness was reflected in a score of 0–1 items, good awareness was reflected in a score of two items and excellent awareness was reflected in a score of three items. additionally, the questionnaire included eight questions about bc symptoms in relation to breast pain, painless or painful breast lumps, a change in the size of the breast, nipple or skin colour, bloody nipple discharge and a loss of weight and appetite. levels of awareness of symptoms were classified as poor (aware of 0–3 items), good (aware of 4–6 items) and excellent (aware of 7–8 items). overall knowledge was calculated by adding the score of the three subscales (i.e. risk factors, symptoms and screening methods) and was interpreted as poor (aware of 0–11 items), good (aware of 12–20 items) and excellent (aware of 21–27 items). statistical package for the social sciences (spss), version 20 (ibm, corp., armonk, new york, usa) was used to analyse the data. participants’ demographic characteristics were summarised using means and standard deviation (sd) for continuous variables, and frequencies and percentages were used for categorical data. inferential analyses (pearson’s chi-square test and correlation and regression analyses) were also used to analyse the data. descriptive statistics, including percentages, means and sd, were calculated. to find the most important predictors of having better bc and bse knowledge, a logistic regression analysis was used. positive knowledge and practice of bse were considered dependent variables, whereas age, educational level, income, family history of bc, previous history of breast lump, knowledge of general facts about bc and geographical location were considered independent variables. the study was approved by the research and ethics committee at the directorate general of health services of al-dhahira governorate, oman. informed consent was obtained from all participants. results a total of 478 female teachers completed the quest ionnaire (response rate: 72.4%). the mean age of the participants was 33.3 ± 5.5 years old. as shown in table 1, the majority of participants (58.8%) were 30–39 years old, and most had a bachelor’s degree (88.1%). most participants (72.3%) were from ibri, while 17.4% were from dhank and 10.3% were from yanqul. more than half of the women (54.4%) had a monthly income of 1,001–1,500 omani rials (omr), followed by an income of 500–1,000 omr per month (39.1%), and only 6.5% of the participants had an income >1,500 omr per month. in total, 10.5% of participants had a positive family history of bc and 3.5% had a history of a breast lump [table 1]. table 1: demographic characteristics of the included female teachers from al-dhahira governorate (n = 478) variable n (%) age (years) 20–29 131 (27.4) 30–39 281 (58.8) >40 66 (13.8) educational level diploma 46 (9.6) bachelor’s degree 421 (88.1) masters 10 (2.1) phd 1 (0.2) wilayat ibri 346 (72.3) dhank 83 (17.4) yanqul 49 (10.3) income (omr) 500–1000 187 (39.1) 1001–1500 260 (54.4) >1500 31 (6.5) family history of bc yes 50 (10.5) no 418 (87.4) unknown 10 (2.1) personal history of breast lump yes 17 (3.5) no 454 (95) unknown 7 (1.5) omr = omani riyal; bc = breast cancer. zuweina al-ismaili, khalid al-nasri, amal al-yaqoobi and ahmed al-shukaili clinical and basic research | e197 most participants believed that bc is the most common cancer in females and that early detection and treatment will lead to a favourable outcome (86.2% and 94%, respectively). the most reported risk factor was exposure to a high dose of radiation (80.5%), followed by a family history (71.5%) and personal history of bc (68.8%). smoking and environmental pollution were reported by 67.4% and 62.3% of the participants, respectively, as risk factors for bc. some participants reported hormonal factors as a risk factor including recent use of hrt (48.5%), late menopause (36.6%) and the use of coc (32.2%). not breastfeeding (5.6%) was the least identified risk factor [table 2]. regarding the knowledge of screening methods, bse was the most familiar method (88.1%), followed by cbe (71.1%) and mammography (68%). the most reported symptoms of bc were a painless breast lump (82.2%), changes in breast size (82%) and changes in the nipple (80.8%). the least reported symptoms were breast pain (70.9%), a painful breast lump (69.9%) and loss of weight and appetite (50.2%) [table 3]. the latter are considered symptoms of metastasis that appear at the end stage of the disease. overall knowledge of bc was calculated by adding the scores for knowledge of risk factors, screening methods and symptoms of bc. the majority of participants (60.5%) had good overall knowledge about bc, while 19.9% had an excellent overall knowledge. the rest of the participants (19.7%) were categorised as having poor overall knowledge. about half of the participants (49.6%) had good knowledge of bc risk factors, whereas 9% had scores reflective of excellent knowledge of risk factors. more than half of the participants (56.1%) reported excellent knowledge of screening methods. knowledge of bc symptoms (i.e., a painless breast lump; bloody nipple discharge; changes in breast skin colour, breast size or the nipple; breast pain; a painful lump; and loss of weight and appetite) was closely divided between excellent and good levels (45.8 and 42.5%, respectively) [table 4]. the main source of information about bc was received from health institutions (64.7%) followed by the media (31.6%); however, only 3.7% of the participants had obtained information from relatives and friends. table 2: knowledge of risk factors for breast cancer among the included female teachers from al-dhahira governorate (n = 478) risk factor n (%) yes no i don’t know exposure to high doses of radiation 385 (80.5) 19 (4) 74 (15.5) family history of bc 342 (71.5) 53 (11.1) 83 (17.4) personal history of bc 329 (68.8) 43 (9) 106 (22.2) smoking 322 (67.4) 43 (9) 113 (23.6) environmental pollution 298 (62.3) 50 (10.5) 130 (27.2) alcohol 281 (58.8) 38 (7.9) 159 (33.3) no physical exercise 271 (56.7) 65 (13.6) 142 (29.7) high fat intake 246 (51.5) 51 (10.7) 181 (37.9) obesity 237 (49.6) 67 (14) 174 (36.4) use of hrt 232 (48.5) 30 (6.3) 216 (45.2) late menopause (ending periods after the age of 55 years) 175 (36.6) 67 (14) 236 (49.4) use of coc 154 (32.2) 67 (14) 257 (53.8) delivery of first child after 30 years of age 118 (24.7) 123 (25.7) 237 (49.6) old age 101 (21.1) 174 (36.4) 203 (42.5) early menarche (before 12 years old) 76 (15.9) 121 (25.3) 281 (58.8%) not breastfeeding 27 (5.6) 411 (86) 40 (8.4) bc = breast cancer; hrt = hormone replacement therapy; coc = comb ined oral contraceptive. table 3: knowledge of screening methods and symptoms of breast cancer among the included female teachers from al-dhahira governorate (n = 478) variable n (%) yes no i don't know knowledge of screening methods bse 421 (88.1) 22 (4.6) 35 (7.3) cbe 340 (71.1) 34 (7.1) 104 (21.8) mammography 329 (68) 43 (9) 106 (22.2) bc symptoms painless breast lump 393 (82.2) 44 (9.2) 41 (8.6) change in the size of the breast 392 (82) 32 (6.7) 54 (11.3) change in the nipple 386 (80.8) 33 (6.9) 59 (12.3) change in skin colour 366 (76.6) 37 (7.7) 75 (15.7) bloody nipple discharge 364 (76.2) 37 (7.7) 77 (16.1) breast pain 339 (70.9) 89 (18.6) 50 (10.5) painful breast lump 334 (69.9) 93 (19.5) 51 (10.7) loss of weight and appetite 240 (50.2) 74 (15.5) 164 (34.3) bse = breast self-examination ; cbe = clinical breast examination ; bc = breast cancer. awareness of breast cancer risk factors, symptoms and breast self-examination among omani female teachers a cross-sectional study e198 | squ medical journal, may 2020, volume 20, issue 2 multiple regression analysis using backward elim ination method for overall knowledge of bc indicated a significant association with knowledge of the fact that early bc detection can lead to successful treatment (p = 0.001) and that bc is the commonest cancer among females (p = 0.001). among the participants, 57.5% indicated practicing bse. the best timing for practicing bse was assessed among participants. in total, 55.2% of them believed that the best time for practicing bse was after menstr uation while 18% replied that any time was a good time, 13.6% responded when a woman feels breast pain and 13.2% said before menstruation. the majority of participants (54.2%) attributed not practicing bse to a lack of time, while 30.5% did not know how to perform bse. only 8.2% considered bse embarrassing and 7.1% of participants had a fear of finding bc if they practiced bse. bse was significantly correlated with overall knowl edge of bc (p <0.05), screening methods (p <0.001) and knowledge of symptoms (p = 0.014), but not with knowledge of risk factors (p = 0.23). the logistic regression model for practicing bse showed the most powerful associations with knowledge of bc screening methods (p = 0.001), age (p = 0.023), having a personal history of a breast lump (p = 0.042), and geographical location (p = 0.031) [table 5]. among demographic characteristics, age and geo graphical location were significantly associated with bse (p = 0.026 and 0.037, respectively) [table 6]. general knowledge of bc as the most common cancer among females and having a personal history of breast lumps were significantly associated with practicing bse (p = 0.016 and 0.015, respectively). knowledge of general facts about bc were significantly associated with overall knowledge of bc (p = 0.001). discussion this study confirms omani women’s unsatisfactory overall knowledge about bc risk factors and screening methods.24,25 similar observations have previously been made in developed and developing countries, with participants showing poor understanding of major bc risk factors.27–32 because the majority of female teachers involved in the current study had only goodto-poor knowledge of bc, the results indicate that an educational programme is needed to increase awareness of bc risk factors. table 6: variables associated with overall knowledge and practice of breast self-examination among the included female teachers from al-dhahira governorate (n = 478) variables overall bc knowledge practice of bse chisquare value p value chisquare value p value demographic characteristic age 3.11 0.540 7.27 0.026* educational level 12.55 0.051 1.68 0.64 province 5.45 0.244 6.61 0.037* income 6.08 0.193 2.09 0.35 experience with bc family history of bc 1.1 0.881 3.29 0.193 personal history of breast lump 9.07 0.059 7.34 0.015* knowledge of general facts about bc bc is the commonest cancer among females 21.6 0.001* 5.79 0.016* early detection of bc can lead to successful treatment 21.57 0.001* 0.015 0.903 bse = breast self-examination; bc = breast cancer. *statistically significant. table 4: overall knowledge of breast cancer among the included female teachers from al-dhahira governorate (n = 478) variable n (%) excellent good poor overall knowledge 95 (19.9) 289 (60.5) 94 (19.7) knowledge of risk factors 43 (9) 237 (49.6) 198 (41.4) knowledge of screening 268 (56.1) 97 (20.5) 113 (23.4) knowledge of symptoms 219 (45.8) 203 (42.5) 56 (11.7) table 5: logistic regression analysis for the practice of breast self-examination among the included female teachers from al-dhahira governorate (n = 478) variable wald test p value knowledge of bc screening methods 14.327 0.001* age 5.39 0.023* personal history of breast lump 6.34 0.042* wilayat 6.97 0.031* bc = breast cancer. *statistically significant. zuweina al-ismaili, khalid al-nasri, amal al-yaqoobi and ahmed al-shukaili clinical and basic research | e199 unsatisfactory knowledge of bc risk factors was observed with risk factors such as non-breastfeeding, being overweight, having their first pregnancy after 30 years of age, having menopause after the age of 50 and doing less physical activity. this finding agrees with those reported by other studies.28,33 moreover, knowledge of bc risk factors among omani female teachers is different from that reported in previous studies conducted in the region. for instance, the current study showed that most participants (80%) identified exposure to radiation as the highest risk factor for bc, whereas a previous study conducted in muscat showed that only 24% of participants identified exposure to radiation as a risk factor.24 this observation also contrasted with a previous study done in saudi arabia, which showed that participants most often identified not breastfeeding as a bc risk factor, whereas it was the least reported risk factor in the current study.28 similarly, contradictory findings were observed with overall knowledge of bc. overall knowledge in al-dhahira governorate was much higher than in the muscat region.24 this difference may be attributed to differences in the study cohort and ongoing campaigns under the national health educational and screening programme in recent years. this programme may also have had a positive effect on knowledge of screening methods, since the majority of the current participants recognised the most common methods of bc screening (i.e., bse, cbe and mammography). participants’ knowledge related to bse was also satisfactory; most participants were aware of the importance of bse. this finding is much higher than knowledge rates for bse seen in some other studies.24,27–34 nevertheless, omani women’s attitudes towards bse need improvement, since only 57% of participants indicated practicing bse. other studies in saudi arabia reported 67.6% of participants had never tried bse.28 in contrast, a study in uganda revealed that 76.5% of participants practiced bse.29 on questioning current participants about reasons for not practicing bse, 54.2% reported not having time, 30.5% of participants stated that they did not know how to do it and a few reported fear of having bc and embarrassment at the process (8.2% and 7.1% respectively). these findings may be attributed to unawareness of practicing bse. although the usefulness of bse as an appropriate method for early bc detection has been debated in recent years, the awareness of the importance of practicing bse should be encouraged via an intensive health education programme.15,18–22 income and level of education had no association with the level of knowledge or the practice of bse. however, practicing bse, knowledge of bc risk factors and symptoms were significantly correlated (p <0.05) with knowledge of screening methods. this finding may be attributable to increased general awareness of bc and bse among participants through healthcare providers. a similar study conducted in iran revealed an association between educational level and knowledge of bc.31 the sources of information about bc in the current study included health institutions, followed by the media (i.e. tv, radio, and the internet). this finding was inconsistent with previous studies conducted in saudi arabia, the united arab emirates, egypt and yemen, which showed that mass media (i.e. tv and radio) were the main sources of information about bc.28,33–36 therefore, this study suggests that creating awareness of bc through media and campaigns needs to be strengthened in order to raise awareness of bc in the community. the main limitations of this study are that the findings cannot be generalised to all females in the country because the female teachers included in this study were only from al-dhahira governorate and mainly from ibri wilayat (72.4%). such a cohort may not be representative of all females in oman and, to a lesser extent, from al-dhahira governorate. in addition, the response rate of this study (72.4%) should be considered a limitation because in survey research a response rate of ≥80% is expected. conclusion the study revealed insufficient overall bc knowledge (especially knowledge of risk factors and bse practice) among female omani teachers. this finding signals a need for prompt interventions to raise awareness about bc and bse among females. healthcare providers need to continue educating the community about bc. the media, including tv and newspapers, also need to be involved in raising bc awareness. in addition, bc awareness should be included as a part of teacher training programmes at schools and colleges. further studies involving a larger sample size and participants from different sectors are recommended. a c k n o w l e d g e m e n t s the authors would like to thank all participating teachers in this study and research assistants for data collection during the study. we are thankful to the directorate general of education in al aldhahira governorate and all school principals for their cooperation during the study. we also thank the oman cancer association al-dhahira branch for their support during the study. we extend our sincere gratitude to ms elena filimonova, dr joseph j. moore awareness of breast cancer risk factors, symptoms and breast self-examination among omani female teachers a cross-sectional study e200 | squ medical journal, may 2020, volume 20, issue 2 jr. and ms anna snellen, for their excellent editing of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. ferlay j, ervik m, lam f, colombet m, mery l, piñeros m, et al. global cancer observatory: cancer today. international agency for research on cancer. from: https://gco.iarc.fr/today accessed: dec 2019. 2. ferlay j, colombet m, soerjomataram i, mathers c, parkin dm, piñeros m, et al. estimating the global cancer incidence and mortality in 2018: globocan sources and methods. int j cancer 2019; 144:1941–53. https://doi.org/10.1002/ijc.31937. 3. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of inc idence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2018; 68:394–424. https://doi.org/10.3322/ caac.21492. 4. porter p. “westernizing” women’s risks? breast cancer in lowerincome countries. n engl j med 2008; 358:213–6. https://doi. org/10.1056/nejmp0708307. 5. shulman ln, willett w, sievers a, knaul fm. breast cancer in developing countries: opportunities for improved survival. j oncol 2010; 2010:595167. https://doi.org/10.1155/2010/595167. 6. jemal a, bray f, forman d, o'brien m, ferlay j, center m, et al. cancer burden in africa and opportunities for prevention. cancer 2012; 118:4372–84. https://doi.org/10.1002/cncr.27410. 7. rakkapao n, promthet s, moore ma, solikhah s, hurst, cp. assessing breast cancer awareness in thai women: validation of the breast cancer awareness scale (b-cas). asian pac j cancer prev 2017; 18:995–1005. https://doi.org/10.22034/apj cp.2017.18.4.995. 8. rojas k1, stuckey a. breast cancer epidemiology and risk factors. clin obstet gynecol 2016; 59:651–72. https://doi.org/10.1097/ grf.0000000000000239. 9. sun ys, zhao z, yang zn, xu f, lu hj, zhu zy, et al. risk factors and preventions of breast cancer. int j biol sci 2017; 13:1387–97. https://doi.org/10.7150/ijbs.21635. 10. mehdi i, monem ea, al bahrani bj, al kharusi s, nada am, al lawati j, et al. age at diagnosis of female breast cancer in oman: issues and implications. s asian j cancer 2014; 3:101–6. https://doi.org/10.4103/2278-330x.130442. 11. ministry of health (moh). annual report 2016: sultanate of oman, muscat. from: https://www.moh.gov.om/documents /272928/1232802/20+years+cancer+incidence+in+oman. pdf/737ea793-f805-e30c-d045-ea753fe522e5 accessed: dec 2019. 12. george sm, bernstein l, smith aw, neuhouser ml, baumgartner kb, baumgartner rn, et al. central adiposity after breast cancer diagnosis is related to mortality in the health, eating, activity, and lifestyle study. breast cancer res treat 2014; 146:647–55. https://doi.org/10.1007/s10549-014-3048-x. 13. chan ds, vieira ar, aune d, bandera ev, greenwood dc, mctiernan a, et al. body mass index and survival in women with breast cancer—systematic literature review and metaanalysis of 82 follow-up studies. ann oncol 2014; 25:1901–14. https://doi.org/10.1093/annonc/mdu042. 14. forouzanfar mh, foreman kj, delossantos am, lozano r, lopez ad, murray cjl, et al. breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. lancet 2011; 378:1461–84. https://doi.org/10.1016/s01406736(11)61351-2. 15. world health organization. guide to cancer early diagnosis. from: https://apps.who.int/iris/bitstream/handle/10665/25450 0/9789241511940-eng.pdf?sequence=1 accessed: dec 2019. 16. gómez-flores-ramos l, castro-sánchez a, peña-curiel o, mohar-betancourt a. molecular biology in young women with breast cancer: from tumor gene expression to dna mutations. rev invest clin 2017; 69:181–92. https://doi.org/10.24875/ric.17 002225. 17. thomas db, gao dl, ray rm, wang ww, allison cj, chen fl, et al. randomized trial of breast self-examination in shanghai: final results. j natl cancer inst 2002; 94:1445–57. https://doi. org/10.1093/jnci/94.19.1445. 18. hackshaw ak, paul ea. breast self-examination and death from breast cancer: a meta-analysis. br j cancer 2003; 88:1047–53. https://doi.org/10.1038/sj.bjc.6600847. 19. thornton h, pillarisetti rr. ‘breast awareness’ and ‘breast selfexamination’ are not the same. what do these terms mean? why are they confused? what can we do? eur j cancer 2008; 44:2118–21. https://doi.org/10.1016/j.ejca.2008.08.015. 20. al-khamis nk. low awareness of breast cancer and consid erable barriers to early presentation among saudi women at a pri mary care setting. j cancer educ 2018; 33:391–7. https://doi.org/10.1 007/s13187-016-1119-x. 21. hurst cp, promthet s, rakkapao n. factors associated with breast cancer awareness in thai women. asian pac j cancer prev 2019; 20:1825–31. https://doi.org/10.7314/apjcp.2016.17.2.851. 22. mcdonald s, saslow d, alciati mh. performance and reporting of clinical breast examination: a review of the literature. ca cancer j clin 2004; 54:345–61. https://doi.org/10.3322/canjcl in.54.6.345. 23. gøtzsche pc, jørgensen kj. screening for breast cancer with mammography. cochrane database syst rev 2013; 6:cd001877. https://doi.org/10.1002/14651858.cd001877.pub5. 24. renganathan l, ramasubramaniam s, al-touby s, seshan v, al-balushi a, al-amri w, et al. what do omani women know about breast cancer symptoms? oman med j 2014; 29:408–13. https://doi.org/10.5001/omj.2014.110. 25. al junaibi rm, khan sa. knowledge and awareness of breast cancer among university female students in muscat, sultanate of oman a pilot study. j appl pharm sci 2011; 1:146–9. 26. creative research systems. sample size calculator. from: https:// www.surveysystem.com/sscalc.htm accessed: dec 2019. 27. rakkapao n, promthet s, moore ma, hurst cp. development of a breast cancer awareness scale for thai women: moving towards a validated measure. asian pac j cancer prev 2016; 17:851–6. https://doi.org/10.7314/apjcp.2016.17.2.851. 28. dandash kf, al-mohaimeed a. knowledge, attitudes, and practices surrounding breast cancer and screening in female teachers of buraidah, saudi arabia. int j health sci (qassim) 2007; 1:61–71. 29. galukande m, wabinga h, mirembe f, karamagi cd, aseae a. breast cancer risk factors among ugandan women at a tertiary hospital: a case-control study. oncology 2016; 90:356–62. https://doi.org/10.1159/000445379. 30. leslie ns, deiriggi p, gross s, durant e, smith c, veshnesky jg. knowledge, attitudes, and practices surrounding breast cancer screening in educated appalachian women. oncol nurs forum 2003; 30:659–67. https://doi.org/10.1188/03.onf.659-667. 31. breslow ra, sorkin jd, frey cm, kessler lg. americans’ knowledge of cancer risk and survival. prev med 1997; 26:170–7. https://doi.org/10.1006/pmed.1996.0136. https://doi.org/10.1002/ijc.31937 https://doi.org/10.3322/caac.21492 https://doi.org/10.3322/caac.21492 https://doi.org/10.1056/nejmp0708307 https://doi.org/10.1056/nejmp0708307 https://doi.org/10.1155/2010/595167 https://doi.org/10.1002/cncr.27410 https://doi.org/10.22034/apjcp.2017.18.4.995 https://doi.org/10.22034/apjcp.2017.18.4.995 https://doi.org/10.1097/grf.0000000000000239 https://doi.org/10.1097/grf.0000000000000239 https://doi.org/10.7150/ijbs.21635 https://doi.org/10.4103/2278-330x.130442 https://doi.org/10.1007/s10549-014-3048-x https://doi.org/10.1093/annonc/mdu042 https://doi.org/10.24875/ric.17002225 https://doi.org/10.24875/ric.17002225 https://doi.org/10.1093/jnci/94.19.1445 https://doi.org/10.1093/jnci/94.19.1445 https://doi.org/10.1038/sj.bjc.6600847 https://doi.org/10.1016/j.ejca.2008.08.015 https://doi.org/10.1007/s13187-016-1119-x https://doi.org/10.1007/s13187-016-1119-x https://doi.org/10.7314/apjcp.2016.17.2.851 https://doi.org/10.3322/canjclin.54.6.345 https://doi.org/10.3322/canjclin.54.6.345 https://doi.org/10.1002/14651858.cd001877.pub5 https://doi.org/10.5001/omj.2014.110 https://doi.org/10.7314/apjcp.2016.17.2.851 https://doi.org/10.1159/000445379 https://doi.org/10.1188/03.onf.659-667 https://doi.org/10.1006/pmed.1996.0136 zuweina al-ismaili, khalid al-nasri, amal al-yaqoobi and ahmed al-shukaili clinical and basic research | e201 32. izanloo a, ghaffarzadehgan k, khoshroo f, haghiri me, izanloo s, samiee m, et al. knowledge and attitude of women regarding breast cancer screening tests in eastern iran. e cancer med sci 2018; 12:806. https://doi.org/10.3332/ecancer.2018.806. 33. radi sm. breast cancer awareness among saudi females in jeddah. asian pac j cancer prev 2013; 14:4307–12. https://doi. org/10.7314/apjcp.2013.14.7.4307. 34. rahman sa, al-marzouki a, otim m, khalil khayat neh, yousuf r, rahman p. awareness about breast cancer and breast self-examination among female students at the university of sharjah: a cross-sectional study. asian pac j cancer prev 2019; 20:1901–8. https://doi.org/10.31557/apjcp.2019.20.6.1901. 35. boulos dn, ghali rr. awareness of breast cancer among female students at ain shams university, egypt. glob j health sci 2013; 6:154–61. https://doi.org/10.5539/gjhs.v6n1p154. 36. ahmed ba. awareness and practice of breast cancer and breast-self examination among university students in yemen. asian pac j cancer prev 2010; 11:101–5. https://doi.org/10.3332/ecancer.2018.806 https://doi.org/10.7314/apjcp.2013.14.7.4307 https://doi.org/10.7314/apjcp.2013.14.7.4307 https://doi.org/10.31557/apjcp.2019.20.6.1901 https://doi.org/10.5539/gjhs.v6n1p154 1department of basic sciences, college of science and health professions, king saud bin abdulaziz university for health sciences, jeddah, saudi arabia; 2department of microbiology & medical parasitology, faculty of medicine, king abdulaziz university, jeddah, saudi arabia; 3department of curricula and methods of teaching (mathematics), college of sciences, king saud bin abdulaziz university for health sciences, jeddah, saudi arabia; 4department of family medicine, primary care centre, ministry of health, jeddah, saudi arabia; 5college of dentistry, university of hail, hail, saudi arabia; 6department of family medicine, king abdulaziz specialist hospital, aljouf, saudi arabia; 7medical education unit, college of medicine and medical sciences, arabian gulf university, manama, bahrain; 8medical education department, faculty of medicine, suez canal university, ismailia, egypt *corresponding author’s e-mail: doctorhani2000@yahoo.com impact of a preparatory year programme on the students of health professions education colleges perception of students and faculty members ahmed aldarmahi,1 mohammed al-rabia,2 fatimah alserhani,3 hanan alzahrani,4 norah alrabia,5 abdulaziz alrubayyi,6 *hani atwa7,8 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 65–73, epub. 28 feb 22 submitted 27 jul 20 revision req. 12 oct 20; revision recd. 23 nov 20 accepted 16 dec 20 https://doi.org/10.18295/squmj.5.2021.094 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: the preparatory year programme (pyp) at king abdulaziz university, jeddah, saudi arabia, is a one-year programme for students preparing for a full multi-year degree curriculum at a university. it offers a bridge between high-school and university-level studies of the students. this study aimed to evaluate the impact of the king abdulaziz university pyp on students of the health professions education colleges from the viewpoints of the students and the faculty. methods: this descriptive study was conducted between may 2019 and january 2020 at king abdulaziz university, in jeddah, saudi arabia and was based on data collected from both students and faculty to assess their perceptions. the data were collected from students through self-administered questionnaires and from faculty members through structured interviews. descriptive statistics were used for analysis. results: a total of 633 students responded to the questionnaire (response rate: 88.3%), of which almost half agreed that the pyp made them self-confident and reinforced their discipline (49.2% and 46.9%, respectively). less than two-thirds agreed that the preparatory year reinforced their sense of responsibility and helped them adapt to the university educational environment (60.6% and 64.3%, respectively). conversely, more than half (58.5%) disagreed that the preparatory year classes helped them select their majors as well as that the preparatory year prepared them for their major classes (57.2%). a total of 24 faculty members who taught pyp students claimed that there should be careful consideration of the contents of the courses offered to the students in the preparatory year programme, especially the content related to the healthcare profession education. they argued that it is better to have a separate track in the pyp that includes subjects directly related to the study of health professions (such as molecular sciences, genetics, medical terminology, english for medical purposes, etc.). conclusion: the impact of the pyp on students attending the health professions colleges was found to be weak as per the perceptions of both students and faculty members. in-depth studies are necessary for further investigation of this impact. keywords: universities; health occupations; undergraduate medical education; curriculum; saudi arabia. advances in knowledge to the best of the authors’ knowledge, this is the only study that explores the viewpoints of both students and faculty members and provides recommendations on the reform of that important preparatory programme for health professions education students. application to patient care understanding how the preparatory year programme is perceived by health professions education students is essential for improving such programmes. preparation of those students to be competent healthcare providers starts from their first year in health professions education institutions, and a strong preparatory programme is expected to lead to better preparation of those graduates, and, eventually, better healthcare provision to the community. several higher education theories and cognitive models have tried to explain the factors involved in students’ transition from high school to university and help this group adapt to a new academic context.1–5 the preparatory year aims to help students transition from the high school system of teaching/learning to that of a university, familiarise students with various academic disciplines at the university and integrate them into the university environment before they choose the right academic discipline to pursue from the various options given to them.6 the programme also prepares students psychologically for their prospective fields of study in subsequent years.7,8 it was reported that foundation courses for first-year bachelor of medicine and bachelor of surgery students helped in reducing student anxiety and boosting confidence.9 furthermore, these courses offer intensive training programs to put students’ https://creativecommons.org/licenses/by-nd/4.0/ impact of a preparatory year programme on the students of health professions education colleges perception of students and faculty members 66 | squ medical journal, february 2022, volume 22, issue 1 professional careers on the right track and enrich their cultural backgrounds.6 among such courses are english language courses, which have a huge impact on student learning and assessment in subsequent college years.10,11 astin’s involvement theory indicated that pre-college academic experiences could help students’ participation in college experiences.2 the role of the preparatory year programme (pyp) can be explained based on this theory. the pyp at king abdulaziz university is a oneyear programme that helps students prepare for a full multi-year degree curriculum. it offers a bridge between students’ high-school and university-level studies. it has been reported that the existence of the pyp indicates the weaknesses of general education in real-world settings.12,13 one established aim of the pyp is to enable new students to explore the academic disciplines of a university and be familiarised with the campus environment.7,14 as a result, they are provided with the necessary support to become meaningful contributors, both personally and professionally, at the university and beyond.6 moreover, the preparatory year seeks to help students develop a good relationship with the community through official visits to private and governmental institutions and build student’s selfconcept to become an effective person in society.7,15 the following is a quote summarising the many goals of the pyp: “the pyp is but a springboard over which ambitious and hardworking students leap energetically, assisted by their experienced faculty, towards their prospective careers, availing themselves of every moment and making full use of all affordable resources.”16 it is an open invitation for both students and faculty to always be active and on the alert to attain the aspired goals.17,18 at king abdulaziz university, the subjects taught in the pyp include english, biology, chemistry, physics, communication skills, math, statistics and computer skills. these subjects help build a foundation for the scientific track, helping students get into health, engineering and science colleges. not too much is known about the overall impact of the pyps in saudi universities and on the preparation of health professions education students. only a few studies have addressed certain aspects of the pyps in some saudi universities. kaliyadan et al. addressed the topic of english language learning in the pyp.10 however, to the best of the authors’ knowledge, the overall impact of the pyp has not been studied till date. therefore, this study aimed to explore the perception of students and faculty members of the impact of the preparatory year at king abdulaziz university on students attending health professions education colleges (medicine, dentistry, pharmacy, nursing and applied medical sciences) in order to make further improvements to the pyp. methods the study used a descriptive cross-sectional design and was conducted at king abdulaziz university in jeddah, saudi arabia, between may 2019 and january 2020. data were collected from both male and female students (n = 633; 261 males and 372 females) during their first year at medicine, dentistry, applied medical sciences and pharmacy colleges and who had completed the pyp the previous year. additionally, faculty members who taught pyp students (n = 24) were also included in the study. the instruments used for data collection were as follows: 1) a questionnaire based on a 5-point likert scale consisting of 30 items used for obtaining student responses developed and validated by al-rabia et al;19 2) structured interviews administered to faculty members to obtain their views on the different aspects of the preparatory year. the structured interviews were based on a list of 10 open-ended questions to explore the view of pyp teachers on the preparatory year [table 1]. responses to each question were qualitatively analysed by the authors by reading them critically, linking them to the aim of the study and categorising them according to the three pre-established themes: 1) content of the pyp; 2) value of the preparatory year in getting students ready to study in health professions colleges; and 3) need for a separate track for health professions colleges. quantitative data were analysed using the stat istical package for the social sciences (spss), version 24.0 (ibm corp., chicago, illinois, usa). descriptive statistics were applied and a p value of <0.05 was considered statistically significant. qualitative data (viewpoints of faculty members) were analysed and thematic descriptions were applied to the collected data. conversations were recorded by the authors; subsequently, the recordings were transcribed and assessed. data relevant to the pre-established themes were taken into consideration in the analysis. this study is part of a research project approved by the research ethics committee of the faculty of medicine, king abdulaziz university. verbal consent was obtained from all participants in this study. results the study was conducted on a sample of 633 students (response rate: 88.3%) from different health professions education colleges at king abdulaziz ahmed aldarmahi, mohammed al-rabia, fatimah alserhani, hanan alzahrani, norah alrabia, abdulaziz alrubayyi and hani atwa clinical and basic research | 67 university and faculty members who taught students in their preparatory year of university. approximately half of the study’s sample agreed that the preparatory year made them self-confident (49.2%) and reinforced their discipline (46.9%). less than two-thirds agreed that the preparatory year reinforced their sense of responsibility and helped them adapt to the university educational environment (60.6% and 64.3%, respectively). conversely, more than half of them (58.5%) disagreed that the preparatory year classes helped them select their majors and more than half (57.2%) disagreed that the preparatory year prepared them for their major classes [table 2]. nearly two-thirds (64.8%) of the students disagreed that the preparatory year provided opportunities to engage in activities that developed their various personal skills (e.g. social, physical, cultural and creative). more than half of them disagreed that the faculty motivated them to develop their creative and innovative abilities (56.4%), the academic counsellor was helpful (58.5%), the interaction with the academic counsellor was adequate and fruitful (57.7%) and teaching was interactive rather than spoon-fed (53.4%). regarding the ease of communication with faculty, 40.6% answered affirmatively, approximately a quarter of them (24.5%) were neutral and one-third (34.9%) disagreed [table 2]. in general, the mean scores of student responses were low, except for ease of communication with faculty, which was a bit higher. greater percentages of the sample agreed that the assessment tasks were appropriate (45.7%), adequate awareness sessions were planned for newcomers (45.7%), student guidebooks were informative (55.8%), teaching timetables were set appropriately (49.7%) and the academic affair services were easily accessible (41.4%). on the other hand, less than one-third of them (28.9%) agreed that student support services were adequate. almost two-thirds of the students (63.5%) agreed with the appropriateness of the available facilities such as the library, computers, data shows and smart board. while approximately half of them (45.6%) agreed with the appropriateness of the resting areas designed for students, more than half of the students (56.4%) disagreed with the suitability of food-purchasing areas for students [table 2]. approximately half of the students agreed that after the preparatory year, they had confidence in their abilities to research information (51.9%), their thinking skills had improved (46.6%), their computer skills had become more sophisticated (46.1%) and they could access and use learning resources (53.5%). notably, the percentages of people agreeing that their research and scientific writing skills had improved and those who disagreed were more or less similar to each other [table 2]. in all cases, however, it could not be assumed that these changes in the different skills were caused by the involvement in the pyp as there could have been some other confounding factors. there were statistically significant differences among male students from different colleges in their responses to different individual factors studied as part of the questionnaire (p <0.05). however, there was no statistically significant difference among male students of different colleges in terms of their perception of the overall effect of the preparatory year (f = 2.05; p = 0.108) [table 3]. statistically significant differences appeared between pharmacy and dentistry colleges with regard to the following factors: ‘university conduct’, ‘administrative and regulatory matters’ and ‘general perception after completing the preparatory year’. all the differences were due to the higher means scores with regard to the college of pharmacy, specifically. this indicated that there was a bigger effect of the preparatory year on male pharmacy students than that on male dentistry students [table 4]. table 1: open-ended questions exploring the views of preparatory year programme teachers on the preparatory year no. questions 1 what do you think about the preparatory year in terms of its content? 2 what do you think about the preparatory year in terms of its usefulness for health professions education students? 3 do you think that the preparatory year, in its current shape, would help in preparing students to join a health professions college? why/why not? 4 in your opinion, what are the subjects in the preparatory year that the health professions students need not study? 5 in your opinion, what are the subjects that are required to be included in the preparatory year program? 6 do you think that students of health professions colleges need a separate pathway for health professions studies in the preparatory year? why/ why not? 7 do you think that the relative weight of the grades students gain in their preparatory year is suitable as one of the admission criteria in health professions colleges? why/why not? 8 in your opinion, what are the most important challenges during the preparatory year? 9 what are your suggestions for reforming the preparatory year? 10 generally, what is your evaluation of the preparatory year? impact of a preparatory year programme on the students of health professions education colleges perception of students and faculty members 68 | squ medical journal, february 2022, volume 22, issue 1 table 2: student responses to the questionnaire evaluating the perceptions of the impact of the preparatory year progr amme at health professions education colleges of king abdulaziz university, jeddah, saudi arabia (n = 633)* no. statement n (%) disagree neutral agree university conduct 1 the preparatory year made me selfconfident 204 (32.2) 117 (18.5) 312 (49.2) 2 the preparatory year reinforced my discipline 217 (34.3) 119 (18.8) 297 (46.9) 3 the preparatory year reinforced my sense of responsibility 157 (24.8) 93 (14.7) 383 (60.5) 4 the preparatory year helped me adapt to the university educational environment 139 (22.0) 87 (13.7) 407 (64.3) 5 preparatory year classes helped me select my major 370 (58.5) 103 (16.3) 160 (25.3) 6 i feel that the preparatory year classes prepared me well for my major’s classes. 362 (57.2) 103 (16.3) 168 (26.5) perception of faculty, teaching and assessment 7 the preparatory year provided activities that developed my various personal skills (e.g., social, physical, cultural, creative) 410 (64.8) 110 (17.4) 113 (17.9) 8 communication with faculty was easy 221 (34.9) 155 (24.5) 257 (40.6) 9 the faculty motivated me to develop my creative and innovative abilities 357 (56.4) 163 (25.8) 113 (17.9) 10 the faculty showed attributes of professionalism (e.g. honesty, integrity, altruism, etc. 285 (45.0) 184 (29.1) 164 (25.9) 11 my academic counsellor was helpful 370 (58.5) 149 (23.5) 114 (18.3) 12 interactions with my academic counsellor were adequate and fruitful 365 (57.7) 161 (25.4) 107 (16.9) 13 teaching was interactive rather than spoon-feeding 338 (53.4) 164 (25.9) 131 (20.7) 14 feedback on student assessment was helpful 235 (37.1) 208 (32.9) 190 (30.0) administrative and regulatory matters 15 student support services (i.e. academic, social, psychological) were adequate 235 (37.1) 215 (34.0) 183 (28.9) 16 assessment tasks (e.g. tests, projects, assignments) were appropriate 217 (34.3) 127 (20.1) 289 (45.7) 17 introductory (awareness) sessions were planned with the newcomer students 200 (31.6) 144 (22.7) 289 (45.7) 18 students’ guidebook was informative and adequate 149 (23.5) 131 (20.7) 353 (55.8) 19 teaching timetables were set out appropriately 197 (31.1) 122 (19.3) 314 (49.6) 20 academic affairs services (e.g. withdrawal, course additions and deletions, postponing, excuses) were easily accessible 185 (29.2) 186 (29.4) 262 (41.4) facilities and services 21 the facilities (e.g. library, computers, data-shows, smart boards) were appropriate 119 (18.8) 112 (17.7) 402 (63.5) 22 places designated for student rest and sitting were appropriate 219 (34.6) 125 (19.8) 289 (45.7) 23 food purchasing areas were suitable for all students 357 (56.4) 100 (15.8) 176 (27.8) general perception after completing the preparatory year 24 i have confidence in my ability to research information 149 (23.5) 156 (24.6) 328 (51.8) 25 my thinking skills (e.g. interpretation, analysis, inference, explanation) have improved 193 (30.5) 145 (22.9) 295 (46.6) 26 my computer skills became more sophisticated 208 (32.9) 133 (21.0) 292 (46.1) 27 my research skills became more sophisticated 241 (38.1) 178 (28.1) 214 (33.8) 28 my scientific writing skills became more sophisticated 254 (40.1) 157 (24.8) 222 (35.1) 29 i can access and use learning resources (e.g. library and internet resources) 172 (27.2) 122 (19.3) 339 (53.6) 30 my skills in applying knowledge have improved 200 (31.6) 178 (28.1) 255 (40.3) *the 5-point scale was collapsed to 3 points for easy interpretation of results and increasing cell sample size. both “agree” and “strongly agree” were considered as “agree” while both “disagree” and “strongly disagree” were considered as “disagree”. ahmed aldarmahi, mohammed al-rabia, fatimah alserhani, hanan alzahrani, norah alrabia, abdulaziz alrubayyi and hani atwa clinical and basic research | 69 there were statistically significant differences between female students from different colleges with regard to their responses to different individual factors of the questionnaire (p <0.05), except for the ‘facilities and services’ factor. furthermore, there was also a statistically significant difference among female students from different colleges in their perception of the overall effect of the preparatory year (f = 3.24; p = 0.012) [table 5]. there were differences between female students of dentistry and medicine with respect to ‘university conduct’, ‘perception of faculty, teaching and assessment’ and the sum of the whole questionnaire. moreover, there were differences between female students of dentistry and nursing in a few factors, namely ‘perception of faculty, teaching and assessment’, ‘general perception after completing the preparatory year’, and the sum of the whole questionnaire. furthermore, there were differences between female students of dentistry and pharmacy in terms of factors such as ‘general perception after completing the preparatory year’ and the sum of the whole questionnaire. the perception of female dentistry students appears across all of the mentioned observations indicating that there was a greater effect of the preparatory year on female dentistry students than those from the colleges of medicine, pharmacy and nursing [table 6]. t h e m e 1: c o n t e n t o f t h e p r e pa r at o r y y e a r p r o g r a m m e the success of planning for the pyp requires careful consideration of the content of the courses offered to students. according to the 24 included faculty members, revision and update of such courses with the knowledge and skills needed by the students are required. one faculty member indicated, “arabic language is one of the subjects taught to the students in the preparatory year. it is good. however, in the arabic language, the students study only some irrelevant topics to their health professions studies.” another member stated, “some topics studied by the students in biology are outdated. i think we need to pay more attention to the specific and up-to-date medical sciences like molecular biology.” table 3: college-wise mean scores on the factors of the preparatory year programme perception questionnaire for male students attending king abdulaziz university, jeddah, saudi arabia (n = 261) factors† sum of squares df mean square f p value* university conduct 621.94 3 207.31 3.92 0.009 perception of faculty, teaching and assessment 706.27 3 235.42 4.54 0.004 administrative and regulatory matters 608.12 3 202.71 5.30 0.001 facilities and services 641.24 3 213.75 7.09 <0.001 general perception after completing the preparatory year 100.70 3 33.57 3.14 0.026 sum of the whole questionnaire 3777.07 3 1259.02 2.05 0.108 anova = analysis of variance; df = degrees of freedom. *statistically significant at p <0.05. †analysis done using anova. table 4: college-wise differences in responses to the preparatory year programme questionnaire for male students attending king abdulaziz university, jeddah, saudi arabia (n = 261) factors (dependent variable)† college (a) mean (a) college (b) mean (b) mean difference (a – b) p value* university conduct dentistry 18.16 pharmacy 22.57 ‒4.41 0.005 perception of faculty, teaching and assessment applied medical sciences 17.66 dentistry 21.97 ‒4.31 0.003 dentistry 21.97 medicine 18.52 3.45 0.041 administrative and regulatory matters dentistry 14.24 pharmacy 18.61 ‒4.37 0.001 facilities and services applied medical sciences 16.25 dentistry 20.33 ‒4.08 <0.001 dentistry 20.33 medicine 17.20 3.13 0.009 general perception after completing the preparatory year dentistry 9.10 pharmacy 10.64 ‒1.54 0.045 *statistically significant at p <0.05. †means determined using tukey's range test. impact of a preparatory year programme on the students of health professions education colleges perception of students and faculty members 70 | squ medical journal, february 2022, volume 22, issue 1 t h e m e 2: va l u e o f t h e p y p i n q u a l i f y i n g s t u d e n t s t o s t u d y i n h e a lt h p r o f e s s i o n s c o l l e g e s the pyp consists of general subjects that are similar to those studied at the high school level. the content of subjects related to health professions studies (i.e. biology, chemistry and physics courses) is small and general in nature. for preparing health professions students, such content should be strengthened and made up-to-date. this was clearly indicated in the responses of some of the faculty members interviewed. one of the members indicated, “most of the courses in the preparatory year program are general courses that don’t help prepare the students to study in the health professions colleges. attention should be paid to such courses to make them relevant to the goal of that program.” a faculty member also mentioned, “we are preparing students to study medical sciences so it is better to give them the background knowledge for such sciences in the preparatory year, and no need to waste their time in studying irrelevant content.” t h e m e 3: n e e d f o r a s e pa r at e t r a c k f o r h e a lt h p r o f e s s i o n s c o l l e g e s in general, faculty members felt the need for a separate track in the preparatory year for health professions colleges. they claimed that the presence of a separate track would provide a better chance to include subjects that were directly related to the study of health professions (such as molecular sciences, genetics, medical terminology and english for medical purposes). a faculty member indicated, “a separate track for health professions students would be a great idea that will better help them be prepared for further studies in that sensitive field of study.” another member also stated, “having a separate track for health professions students will help avoid wasting the time of the students in studying irrelevant content that will not fit well in their preparation for studying in health professions education colleges.” table 5: college-wise mean scores on the factors of the preparatory year programme perception questionnaire for female students attending king abdulaziz university, jeddah, saudi arabia (n = 372) factors† sum of squares df mean square f p value* university conduct 406.43 4 101.61 2.59 0.037 perception of faculty, teaching and assessment 546.09 4 136.52 3.59 0.007 administrative and regulatory matters 416.50 4 104.13 3.37 0.010 facilities and services 101.64 4 25.41 1.16 0.340 general perception after completing the preparatory year 163.89 4 40.97 4.86 0.001 sum of the whole questionnaire 5237.22 4 1309.31 3.24 0.012 anova = analysis of variance; df = degrees of freedom. *statistically significant at p <0.05. †analysis done using anova. table 6: college-wise differences in responses to the preparatory year programme questionnaire for female students attending king abdulaziz university, jeddah, saudi arabia (n = 372) factor (dependent variable)† college (a) mean (a) college (b) mean (b) mean difference (a – b) p value* university conduct dentistry 25.34 medicine 21.98 3.36 0.022 perception of faculty, teaching and assessment dentistry 23.40 medicine 19.71 3.69 0.007 dentistry 23.40 nursing 20.43 2.97 0.053 administrative and regulatory matters applied medical sciences 21.05 nursing 18.16 2.89 0.007 general perception after completing the preparatory year dentistry 10.23 pharmacy 7.82 2.41 <0.001 dentistry 10.23 nursing 8.39 1.84 0.004 sum of the whole questionnaire dentistry 99.23 medicine 89.30 9.93 0.043 dentistry 99.23 pharmacy 87.41 11.82 0.031 dentistry 99.23 nursing 89.41 9.82 0.048 *statistically significant at p <0.05. †means determined using tukey's range test. ahmed aldarmahi, mohammed al-rabia, fatimah alserhani, hanan alzahrani, norah alrabia, abdulaziz alrubayyi and hani atwa clinical and basic research | 71 discussion a primary principle upon which the pyp was originally based is that it is an important transitional stage between high school and university that prepares students for a new academic context by alleviating the anxiety of studying in a university, giving them a solid linguistic base of the foreign language used for instruction and helping them shift from adolescent education to adult learning.10,21,22 however, results from the current study indicate that the impact of the pyp on the students, in general, was weak. these findings are similar to those found by alkathiri in his evaluation of the pyp.20 although teaching, assessment and student support are the most important activities in the pyp and as such, special attention should be given to them, it is clear from the student responses that they perceive teaching, faculty and assessment negatively and are unsatisfied. as stated by alkathiri, it seems to be a big challenge to attract and train qualified faculty for the success of the pyp.20 zeller and zlotkowski argued that universities should strive to appeal to qualified faculty for the preparatory year, else the effectiveness of the programme may be questioned continuously, which will be reflected in the impact on the quality of the outputs of the preparatory year. this, in turn, may affect the review of the importance of such programmes in the future.23,24 students in the preparatory year are in need of guidance and assistance. student support services are one of the most important services these students need to support their transition into university life. to offer good support to these students, policies and practices should be in place and be consistent with academic policies. starting from admissions to the end of the year, preparatory year officials must regard clear instructions, effective communication and support for the achievement of all means of success as their responsibilities.12,25,26 for the success of any academic curriculum, suitable and enough educational facilities should be made available to students.27 in a similar study, alghamdi reported an average level of satisfaction of preparatory year students with the services offered by the university.28 although cafeterias and food purchasing areas are not educational facilities, they are considered to play a very important role in making students’ on-campus life easier. furthermore, the influence of the academic advisor is very important, and as such, their role should be strengthened such that the students can benefit well from it. the academic advisor should be more interactive with the students and help them in different aspects of their lives. this is important as the preparatory year is the first university year for the students and they may feel lost and need much help from their academic advisors. these advisors can orient students to the rules and regulations of the institution and also guide them through the academic processes in the university. the current study showed that more than half the students did not perceive the teaching process as being interactive. in this regard, the preparatory year faculty members need to make their lectures more interactive and give the students an active role in their learning as adults in order to help them change their mindset from dependent pupils to independent learners. this will lead to the development of students’ cognitive skills and help them navigate medical studies at the university that require the use of higher cognitive skills.29 additionally, the preparatory year faculty need to promote creative skills in students by creating a safe learning environment. this could be done by intellectually stimulating the students to discover, develop and use their creative and critical thinking skills.20 the mean scores for the female students were greater than those for males across all factors, except the ‘general perception after completing the preparatory year’ factor, where the mean scores were more favourable for the male students. the differences were statically significant indicating that although female students reported more satisfaction than male students in the preparatory year, the preparatory year was reported to have a greater impact on the latter. in saudi arabian universities, there is a separation between male and female campuses. the faculty within each of these campuses are also different from each other. this is expected to be the primary reason for the differences in mean scores of different factors. the reason behind high scores for females may be that there is a better educational and aesthetic environment on their campus. on the other hand, male students’ mean scores were potentially higher on the ‘general perception after completing the preparatory year’ factor in relation to the other factors as they do not seem to depend mainly on the preparatory. this finding would need further explanatory research. regarding the remaining two factors, namely ‘perception of faculty, teaching and assessment’ and ‘facilities and services’, the differences appeared between male dentistry students and both male medicine and male applied medical sciences students indicating that there was a greater impact of the preparatory year on male dentistry students than that on medicine and applied medical sciences male students in terms of those two factors. impact of a preparatory year programme on the students of health professions education colleges perception of students and faculty members 72 | squ medical journal, february 2022, volume 22, issue 1 dentistry students (both males and females) perceived the effect of the preparatory year more positively than the students in other health colleges. this might be due to the fact that the former group believed that the subjects they studied in that year (especially physics) benefited them greatly in their dentistry subjects. much like any study of this sort, this study has its limitations too. firstly, the study focused only on a single university. although king abdulaziz university is the biggest government university in saudi arabia, findings would have been more valuable and generalisable had more universities been included. secondly, the study regarded students and faculty members as the most important stakeholders when considering participant selection; however, it would have been of great value to also include university officials responsible for the pyp as part of the interviews or via focus groups. conclusion the impact of the preparatory year on students attending health professions education colleges at king abdulaziz university was weak. this seemed to be the opinion of both students and faculty members. additionally, there was no statistically significant difference between males and females. special courses for health professions students should be included in a year often regarded as being important for a student. the authors recommend further in-depth studies in this field to understand the effect of different components of the preparatory year on students and to formulate recommendations for improvement and reformations for decision-makers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors would like to thank all the students and faculty members who participated in this study. a special thanks is given to the deanship of the preparatory year at king abdulaziz university for facilitating this work. a u t h o r s’ c o n t r i b u t i o n aha, ma-r and hat conceptualised the work. fa, ma-r, hal and hat prepared the research plan. all authors participated in data collection and analysis. all authors contributed to drafting the manuscript. hat, ma-r, na and aba edited the final draft. all authors approved the final version of the manuscript. references 1. tinto v. classrooms as communities. exploring the educational character of student persistence. j high educ 1997; 68:599–623. https://doi.org/10.2307/2959965. 2. astin aw. student involvement: a developmental theory for higher education. j college student devel 1999; 40:518–29. 3. pascarella e, terenzini . how college affects students: a third decade of research, vol 2. san francisco: john wiley & sons, 2005. 4. padgett rd, goodman km, johnson mp, saichaie k, umbach pd, pascarella et. the impact of college student socialization, social class, and race on need for cognition. new directions institutional res 2010; 145:99–111. https://doi.org/10.1002/ir.324. 5. price l. modelling factors for predicting student learning outcomes in higher education. in: gijbels d, donche v, richardson jte, vermunt jd, eds. learning patterns in higher education: dimensions and research perspectives. abingdon: routledge, 2014, pp. 56–77. 6. adelman c. the toolbox revisited: paths to degree completion from high school through college. from: http://www2.ed.gov/ rschstat/research/pubs/toolboxrevisit/toolbox.pdf accessed: jul 2020. 7. barefoot bo. current institutional practices in the first college year. in: upcraft ml, gardner jn, barefoot bo, eds. challenging and supporting the first year student: a handbook for improving the first year of college, 1st ed. san francisco: jossey-bass, 2005, pp. 47–63. 8. bettinger e, boatman a, long bt. student supports: develop mental education and other academic programs. future child 2013; 23:93–115. https://doi.org/10.1353/foc.2013.0003. 9. patel j, akhani p. a study of perception of first-year mbbs students toward orientation program and foundation course at entry level. nat j physiol pharm pharmacol 2017; 7:920–3. https//doi.org/10.5455/njppp.2017.7.0412301052017. 10. kaliyadan f, thalamkandathil n, parupalli sr, amin tt, balaha mh, al bu ali wh. english language proficiency and academic performance: a study of a medical preparatory year program in saudi arabia. avicenna j med 2015; 5:140–4. https://doi. org/10.4103/2231-0770.165126. 11. mirgani z, shantakumari n, hassan i. predictors of student performance in foundation year of medical school. sys rev pharm 2020; 11:201–5. 12. hart research associates. it takes more than a major: employer priorities for college learning and student success. from: https://www.aacu.org/research/it-takes-more-than-a-majoremployer-priorities-for-college-learning-and-student-success accessed: nov 2020. 13. baum s, kurose c, mcpherson m. an overview of american higher education. future child 2013; 23:17–39. https://doi. org/10.1353/foc.2013.0008. 14. edmunds ja., bernstein l, unlu f, glennie ej, willse jt, smith a, et al. expanding the start of the college pipeline: ninth-grade findings from an experimental study of the impact of the early college high school model. j res educ effective 2012; 5:136–59. https://doi.org/10.1080/19345747.2012.656182. 15. howell js, kurlaender m, grodsky ee. postsecondary prep aration and remediation: examining the effect of the early assessment program at california state university. j policy anal manag 2010; 29:726–48. https://doi.org/10.1002/pam.20526. 16. preparatory year handbook. imam abdulrahman bin faisal university, dammam, saudi arabia. from: https://www.iau.edu. sa/sites/default/files/resources/prepyearhandbooknewadddes. compressed.pdf accessed: nov 2020. https://doi.org/10.2307/2959965 https://doi.org/10.1002/ir.324 https://doi.org/10.1353/foc.2013.0003 http://https//doi.org/10.5455/njppp.2017.7.0412301052017 https://doi.org/10.4103/2231-0770.165126 https://doi.org/10.4103/2231-0770.165126 https://doi.org/10.1353/foc.2013.0008 https://doi.org/10.1353/foc.2013.0008 https://doi.org/10.1080/19345747.2012.656182 https://doi.org/10.1002/pam.20526 ahmed aldarmahi, mohammed al-rabia, fatimah alserhani, hanan alzahrani, norah alrabia, abdulaziz alrubayyi and hani atwa clinical and basic research | 73 17. barefoot bo, griffin bq, koch ak. enhancing student success and retention throughout undergraduate education: a national survey. from: https://static1.squarespace.com/static/59b0c486d 2 b 8 5 7 f c 8 6 d 0 9 a e e / t / 5 9 b a d 3 3 4 1 2 a b d 9 8 8 a d 8 4 d 6 9 7 / 1 5 0 5 4 1 5 9 9 0 5 3 1 / j n g i n at i o n a l _ s u r v e y _ w eb . p d f accessed: nov 2020. 18. barnett ea, bork rh, mayer ak, pretlow j, washington hd, weiss mj. bridging the gap: an impact study of eight develop mental summer bridge programs in texas. new york: columbia university, national center for postsecondary research, 2012. 19. al-rabia m, shawwa la, gouda e, aldarmahi a, asfour h, atwa h. validation of a questionnaire evaluating the effect of a preparatory year on qualifying students for studying at health professions education faculties. afr j health prof educ 2021; 13:72–6. https://doi.org/10.7196/ajhpe.2021.v13i1.1273. 20. alkathiri n. preparatory year (first year experience). saudi j high educ 2014; 11:65–70. 21. al asmari a. a comparative analysis of preparatory year students’ fl anxiety. int j english linguistics 2015; 5:50–62. https://doi.org/10.5539/ijel.v5n4p50. 22. de clercq1 m, galand b, frenay m. transition from high school to university: a person-centered approach to academic achievement. eur j psychol educ 2017; 32:39–59. https://doi. org/10.1007/s10212-016-0298-5. 23. zeller wj. first-year student living environments. in: upcraft ml, gardner jn, barefoot bo, eds. challenging and supporting the first-year student: a handbook for improving the first year of college. san francisco: jossey-bass, 2005, pp. 410–27. 24. zlotkowski e. service learning and the first-year student. in: upcraft ml, gardner jn, barefoot bo, eds. challenging and supporting the first-year student: a handbook for improving the first year of college. san francisco: jossey-bass, 2005. 25. alexander js, gardner j. beyond retention: a comprehensive approach to the first college year. from: https://www.dropbox. com/s/xltxyxhxu0wsctt/beyond-retention-a-comprehensiveapproach-to-fy.pdf accessed: nov 2020. 26. alaqeeli s. the preparatory year: global perspectives and local practices. saudi j high educ 2014; 11:45–64. 27. kern de, thomas pa, hughes mt. curriculum development for medical education: a six-step approach, 2nd ed. baltimore: johns hopkins university press, 2009. 28. alghamdi os. satisfaction of preparatory year students with university services. world j educ 2015; 5:117–29. https://doi. org/10.5430/wje.v5n5p117. 29. duggan pm, palmer e, devitt p. electronic voting to encourage interactive lectures: a randomized trial. bmc med educ 2007; 7:25. https://doi.org/10.1186/1472-6920-7-25. https://doi.org/10.7196/ajhpe.2021.v13i1.1273 https://doi.org/10.5539/ijel.v5n4p50 https://doi.org/10.1007/s10212-016-0298-5 https://doi.org/10.1007/s10212-016-0298-5 https://doi.org/10.5430/wje.v5n5p117 https://doi.org/10.5430/wje.v5n5p117 https://doi.org/10.1186/1472-6920-7-25 submitted 14 mar 23 1 revisions req. 1 may & 21 may 23; revisions recd. 5 may & 29 may 23 2 accepted 6 jun 23 3 online-first: june 2023 4 doi: https://doi.org/10.18295/squmj.6.2023.042 5 6 supra-sternal notch tuberculous abscess in child 7 mohamed bhairis,1 massine el hammoumi,1 meryem kabiri,2,3 8 *el hassane kabiri,1,3 9 10 1department of thoracic surgery, mohammed v military teaching hospital, rabat, morocco; 11 2department of pediatrics, rabat children hospital, rabat, morocco; 3faculté de médecine et de 12 pharmacie, université mohammed v, rabat, morocco 13 *corresponding author’s e-mail: hassankabiri@yahoo.com 14 15 a 14-year-old student boy was referred to our thoracic surgery department at a university hospital 16 in rabat, morocco (november 2019) for a growing swelling of the suprasternal notch observed five 17 weeks prior to his admission to our department (figure: 1a). the vaccination protocol was complete 18 including bacillus calmette-guérin (bcg). clinical examination showed a well-limited, fluctuating 19 swelling, 10 cm in diameter, located in the suprasternal notch, without movement on swallowing, 20 and without associated cervical or axillary nodes. blood tests were normal, except for an elevated 21 erythrocyte sedimentation rate (45 mm/h). an ultrasound of the neck revealed a collection of thick 22 fluid independent of the thyroid gland. neck and thorax computed tomography (ct) scan shows a 23 fluid collection with densification of anterior and superior cervicothoracic fat. 24 25 anterior and superior cervicothoracic fat measuring approximately 125 × 71 × 52 mm (figure 1 b). 26 fine-needle aspiration and cytology (fnac) were performed with pus aspiration; with negative 27 microbiologic evaluation and cultures, the patient underwent surgical debridement (figure 1 c). 28 histopathologic examination (figure 1d) showed the presence of a giganto-cellular granuloma with 29 caseous necrosis; mycobacterium tuberculosis culture was negative and the diagnosis of tuberculosis 30 was confirmed by rapid pcr assay. 31 32 the patient received anti-tubercular treatment: 2 months of rifampicin (r)-isoniasid (h) 33 pyrazinamide (z) and 4 months of rifampicin isoniasid (2rhz4rh) with a good clinical 34 response. 35 mailto:hassankabiri@yahoo.com 36 written consent of the patient has been obtained for publication. 37 38 comment 39 tuberculosis can involve and disseminate all organs; chest wall tuberculosis is a rare extrapulmonary 40 localization and reaching 20-40% of all tuberculosis cases. 41 42 chest wall tuberculosis is a rare extrapulmonary location and accounts for 1-5% of all 43 musculoskeletal involvement1. isolated supra-sternal soft tissue tuberculous cold abscess is 44 exceptional. differential diagnosis includes thyroid swelling2,3 vascular malformations, thyroglossal 45 duct cysts, dermoid cysts, or reactive and infectious lymphadenitis. 46 in the pubmed database khalil4, vijay2 and asayama3 reported respectively three, one and one case 47 of suprasternal notch2-4. it has been more described in immunocompetent individuals but 48 immunosuppression should be researched in all cases . the clinical expression is dominated by 49 swelling, sometimes there is sternal pain2. 50 51 chest ct is the best examination to demonstrate the presence of costal or sternal lysis, 52 pleuropulmonary and mediastinal lesions. confirmation of tb disease is obtained by bacteriological 53 and/or pathological data. 54 the genexpert study is a rapid and efficient technique for the diagnosis of tuberculosis compared to 55 microscopy. 56 57 therapeutic management combines anti-tubercular medical treatment (6 to 12 months) with fine 58 needle aspiration (fna)2, 4 for diagnosis and small swalling but surgical debridement is mandatory 59 to reduce the risk of recurrence 1,3 in other cases. 60 61 the resolution is generally good with the combination of anti-bacillary treatment within 6 months 62 and complete surgical debridement can be performed to minimize local complications. 63 64 authors’ contribution 65 mb performed the observation. meh and mk composed the manuscript. ehk edited the final draft. 66 all authors approved the final version of the manuscript. 67 68 references 69 1. riahi, i., fradi, r., jaafoura, h. et al. a cervical tuberculous abscess mimicking a fourth branchial 70 cleft cyst in a child: pcr, the key to fast diagnosis. egypt j otolaryngol 2020 ;36:14. 71 https://doi.org/10.1186/s43163-020-0001672 2.vijay v, vaishya r. tuberculous suprasternal notch abscess in a child. bmj case rep 2016; 19: 73 bcr-2015-214269. https://doi: 10.1136/bcr-2015-214269 74 3. asayama i, ishikawa t, yamada t, kitagawa w, shimizu k. a case of tuberculous granuloma 75 at the supra-sternal notch that was difficult to differentiate from a thyroid tumor. med sci monit 76 2004;10: 37-40. pmid: 15278001 77 4. khalil ea, elsiddig ke, elsafi me, el-hag ia, elkhidir im, suleiman g, et al. trans r soc trop 78 med hyg. 2000; 94:58-60. https://doi: 10.1016/s0035-9203(00)90440-1 79 80 81 figure 1: (a): large fluctuant swelling in the suprasternal notch. (b): ct scan of the neck and 82 chest showing a mass on suprasternal space. (c): operative view debridement of the mass. (d): 83 pathological micrograph (he x 40): giganto-cellular granuloma with caseous necrosis 84 https://pubmed.ncbi.nlm.nih.gov/27095807/?from_term=sternal+tuberculosis+in+children&from_sort=pubdate&from_pos=4 https://pubmed.ncbi.nlm.nih.gov/15278001/?from_term=tuberculous+suprasternal+&from_sort=pubdate&from_pos=7 https://pubmed.ncbi.nlm.nih.gov/15278001/?from_term=tuberculous+suprasternal+&from_sort=pubdate&from_pos=7 adenoid ameloblastoma with dentinoid a systematic review *sanpreet s. sachdev, tabita j. chettiankandy, manisha a. sardar, yogita adhane, aakruti m. shah, alphonsa e. grace sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 325–338, epub. 25 aug 22 submitted 7 apr 21 revisions req. 4 jul & 15 aug 21; revisions recd. 30 jul & 25 aug 21 accepted 1 sep 21 department of oral pathology and microbiology, government dental college and hospital, mumbai, india *corresponding author’s e-mail: sunpreetss@yahoo.in the process of odontogenesis involves complex molecular interactions. disruptions in these interactions may result in a distinct spectrum of neoplasms, unique to the jaws, that are collectively termed odontogenic tumours (ots).1 the world health organization (who) has defined ots as lesions derived from epithelial, ectomesenchymal and/or mesenchymal elements that are or have been a part of the tooth-forming apparatus.2,3 owing to their development from various components of the toothforming apparatus, ots may present a considerable histopathological diversity. two or more distinct tumour entities may coexist within the same lesion and are reported as hybrid tumours. ide et al. defined these as lesions showing the combined histopathological characteristics of two or more previously recognised tumours and/or cysts of different categories.4 these tumours have not been included in the 2017 who classification system of odontogenic neoplasms due to the inadequate number of reported cases.5 one such variant of the hybrid odontogenic tumour may exhibit the histological features of both ameloblastoma (am) and adenomatoid odontogenic tumour (aot). this hybrid odontogenic tumour was first reported by slabbert et al. in 1992 as dentinoameloblastoma.6 the diagnostic term adenoid ameloblastoma with dentinoid (aad) was first reported by the armed forces institute of pathology in 1994 by brannon.7 over time, various terminologies have been associated with the lesions, such as atypical plexiform ameloblastoma with dentinoid, ameloblastoma with features of dentinoid, hybrid ameloblastoma and aot originating within an unicystic ameloblastoma and atypical adenoid ameloblastoma.8–13 as a result of the paucity of reported cases of the lesions, the data available regarding their pathogenesis, clinical behaviour, diagnosis and prognosis are limited. the present systematic review aimed to collectively present the demographic details, clinical features, histopathological patterns, molecular markers, treatment performed and the outcomes of the cases of aad found in the literature in english. another objective was to improve the understanding of the lesions with respect to their clinical characteristics, varied histopathological morphology and prognosis. this systematic review has been registered in the international prospective register of systematic reviews – prospero (record id: https://www.crd.york.ac.uk/ prospero/display_record.php?recordid=207062). methods case reports and case series of aad were retrieved by a systematic search of scientific databases, including ovid (walter kluwer, new york, usa), medline (national library of medicine, maryland, usa), pubmed central (national library of medicine), web of science citation index expanded (clarivate analytics, london, uk) and google scholar (google, mountain view, usa) with the keywords ‘adenoid’ or ‘adenomatoid’ and ‘ameloblastoma’ and ‘dentinoid’. an additional search was performed using keywords ‘hybrid’ and ‘odontogenic’ and ‘tumours’ and the retrieved literature was scanned to identify any cases reported with a name differing review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.127 abstract: this article aimed to collectively present the demographic, clinical, radiographic and histopathological features as well as the treatment performed along with its outcome for all the cases of adenoid ameloblastoma with dentinoid (aad) reported in scientific literature till date. ameloblastoma and adenomatoid odontogenic tumours are the most common odontogenic neoplasms. however, aad, a hybrid variant of the two lesions, is found to be extremely rare. the lesion comprises of characteristic histopathological features of ameloblastoma and adenomatoid odontogenic tumour and shares certain clinical characteristics with either of the entities. aad may be considered to be present at the more aggressive end of spectrum of benign odontogenic neoplasms. owing to the frequent tendency of the lesions to be underdiagnosed, careful histopathological screening of submitted biopsies is warranted. with the increase in number of reported cases in the recent years, it is likely to be included as a separate entity in the upcoming world health organization classification. keywords: odontogenic tumors; adenomatoid odontogenic tumor; adenoameloblastoma; immunohistochemistry. https://creativecommons.org/licenses/by-nd/4.0/ adenoid ameloblastoma with dentinoid a systematic review 326 | squ medical journal, august 2022, volume 22, issue 3 from aad. additionally, case reports and case series of aad were also scanned from cross-references. c r i t e r i a f o r s e l e c t i o n a n d e x c l u s i o n the case reports and case series of the lesions co-localised within the same primary lesion site, exhibiting the histopathological characteristics of both am and aot and available in english language were included in this review. however, lesions with uncertain diagnostic criteria, unclear histopathological characteristics and the absence of features of both the entities found co-locally were excluded from the review [figure 1]. in order to be classified as aad, a lesion should present characteristic histopathological features of both am and aot in association with extracellular dentinoid material. therefore, the reported cases were included in this study if their histopathological pictures comprised a combination of at least one of the features of am and aot, respectively, along with dentinoid material [table 1]. with respect to the am component, any of the histopathological variants of solid/conventional am as well as unicystic ameloblastoma (uam), peripheral am and metastatic am were considered to be eligible for inclusion. overall, in terms of the labels used in the present systematic review for the respective histological features, the following definite diagnostic formula denoting the minimum criteria for a lesion to be considered as aad was proposed: in addition to these minimum requisite features, lesions presenting other peculiar features, such as the table 1: coded labels provided to various histopatholo gical features in the present systematic review ameloblastoma component am-f follicles of odontogenic epithelium with peripheral tall columnar ameloblast-like cells with reversal of polarity and central stellate reticulum-like cells in the form of follicles within a mature connective tissue stroma am-p odontogenic epithelium infiltrating into a mature connective tissue stroma in the form of interlacing strands or plexuses uam cystic lesion having lumen lined by tall columnar cells with hyperchromatic nuclei exhibiting nuclear palisading with reversal of polarity and cytoplasmic vacuolisation (gorlinvickers criteria)14 adenomatoid odontogenic tumour component aot-s sheets/islands/cords/whorling of spindle to ovoid shaped odontogenic epithelial cells aot-d duct-like structures lined by epithelial cells with eosinophilic material/cystic space in the lumen aot-r rosette-like structures consisting of two layers of low to tall columnar epithelial cells with eosinophilic material/cystic space centrally in the lumen dentinoid material dm extracellular homogenous eosinophilic material (dentinoid) other features cc presence of clear cells within the tumor islands in aot component of the lesion. gc presence of ghost cells within odontogenic epithelial nests/islands in the aot component or within ameloblastomatous epithelium am = ameloblastoma; uam = unicystic ameloblastoma; aot = adeno matoid odontogenic tumour; dm = dentinoid material; cc = clear cells; gc = ghost cells. figure 1: prisma flow chart indicating selection process of articles for final qualitative synthesis in the present systematic review. am-f / am-p / uam + aot-s / aot-d + dm sanpreet s. sachdev, tabita j. chettiankandy, manisha a. sardar, yogita adhane, aakruti m. shah and alphonsa e. grace review | 327 t ab le 2 : s um m ar is ed p ar am et er s of c as es o f a de no id a m el ob la st om a w it h de nt in oi d a ut ho r an d ye ar o f pu bl ic at io n a ge in ye ar s g en de r d ur at io n a rc h si de sy m pt om r ad io gr ap hi c fe at ur e h is to pa th ol og ic al fe at ur e sp ec ia l s ta in s/ ih c fi na l d ia gn os is t re at m en t (w it h nu m be r of re cu rr en ce s) fo llo w up w ith n ed sl ab be rt e t a l.6 (1 99 2) 24 m al e n /p m n le ft sw el lin g u l r l a m -f , a m -p , a o t -s , d m v an g ie so n + m as so n’ s tr ic hr om e + c on go r ed – a lc ia n bl ue – d en tin oa m elo bl as to m a w e n /p m at su m ot o et al .8 (2 00 1) 19 m al e 1 m o m n r ig ht sw el lin g w d u l r l a m -p , a o t -s , a o t -d , d m m uc ic ar m in e + a lc ia n bl ue + a ty pi ca l p le xi fo rm a m w ith d en tin oi d m ar su pi al is at io n + en uc le at io n; (1 r ec a ft er 2 y r) ; w e 2. 5 yr ev an s et a l.9 (2 00 4) 39 m al e n /p m n c m sw el lin g w d u l r l a m -p , a o t -s , a o t -d , d m , c c n /p a m w ith fe at ur es o f a o t w e; w e + cu re tt ag e en uc le at io n + cu re tt ag e; (3 re cs o ve r a 16 -y r pe ri od ); sr 18 m o z ha ng e t a l.1 0 (2 00 6) 64 fe m al e 16 m o m n c m sw el lin g + pa re st he si a w d u l r l w ith r o cl us te rs a m -f , a o t -s , a o t -r , d m , g c n /p h yb ri d od on to ge ni c tu m or c ha ra ct er is tic o f c c o t, s ol id m ul tic ys tic a m a nd a o t sr 3 y r jiv an e t a l.1 2 (2 00 7) 40 m al e 7 m o m n c m sw el lin g w d u l r l u a m , a o t -s , a o t -d , a o t -r , d m c al re tin in + + in cy st ic li ni ng a o t o ri gi na tin g w ith in a un ic ys tic a m n /p n /p g ha se m im or id an i e t al .15 (2 00 8) 19 fe m al e 2 m o m x r ig ht sw el lin g w d u l r l a m -p , a o t -s , a o t -d , d m n /p a a d ex ci si on n /p id e et a l.1 6 (2 00 9) 44 m al e n /p m x c m n /p w d u l r l a m -p , a o t -s , a o t -d , a o t 4, d m c al re tin in + a a d en ; e xc is io n; (3 r ec s ov er a 11 -y ea r pe ri od ) p ar tia l m ax ill ec to m y 8 yr so no ne e t a l.1 7 (2 01 1) 35 fe m al e 1 ye ar m n r ig ht sw el lin g + nu m bn es s w d u l r l w ith r o fo ci a m -p , a o t -s , a o t -d , a o t -r , d m , g c c on go r ed – v an g ie so n + a a d sr 6 m o sa xe na e t a l.1 8 (2 01 2) 45 m al e 2 w k m x le ft sw el lin g d iff us e r l a m -p , a m 4 a o t -d , a o t -s , d m n /p a a d w e (3 r ec s) s r n /p ya m az ak i e t al .11 (2 01 4) 31 fe m al e n /p m n r ig ht n on e w d u l r l w ith s cl er ot ic ar ea in d is ta l po rt io n a m -f , a m -p , a o t -s , a o t -d , d m , c c c k 17 + c al re tin in + k i67 + c on go r ed + c k 19 + + h yb ri d a m a nd a o t sr 36 m o lo yo la e t a l.1 3 (2 01 5) 55 24 m al e fe m al e 5 m o 6 m o m n m x le ft le ft sw el lin g sw el lin g n /p w d u l r l a m -f , a m -p , a o t -s , a o t -d , d m c k 19 : + + k i67 + + c k 8/ 18 – n on e a a d a de no id a m (h yb ri d/ m ix ed o do nt og en ic tu m ou r) 1 re c; s r w e 10 8 m o 6 m o n /p = n ot p ro vi de d; m n = m an di bl e; m x = m ax ill a; c m = c ro ss in g m id lin e; w d = w el lde fin ed ; p d = p oo rl y de fin ed ; u l = un ilo cu la r; m l = m ul til oc ul ar ; r l = ra di ol uc en cy ; r o = ra di op aq ue ; w e = w id e ex ci si on ; s r = su rg ic al re se ct io n; r ec = re cu rr en ce . adenoid ameloblastoma with dentinoid a systematic review 328 | squ medical journal, august 2022, volume 22, issue 3 t ab le 2 (c on t’d .): s um m ar is ed p ar am et er s of c as es o f a de no id a m el ob la st om a w it h de nt in oi d a ut ho r an d ye ar o f pu bl ic at io n a ge in ye ar s g en de r d ur at io n a rc h si de sy m pt om r ad io gr ap hi c fe at ur e h is to pa th ol og ic al fe at ur e sp ec ia l s ta in s/ ih c fi na l d ia gn os is t re at m en t (w it h nu m be r of re cu rr en ce s) fo llo w up w ith n ed lo yo la e t a l.1 3 (2 01 5) 31 40 16 m al e m al e fe m al e 1 m o n /p 2 m o m n m n m n r ig ht c m r ig ht sw el lin g sw el lin g, nu m bn es s, pa ra st he si a sw el lin g w d r l w d u l r l u l r l a m -f , a m -p , a o t -s , a o t -d , d m n on e c al re tin in + + p5 3 ++ n on e a de no id g ra nu la r ce ll a m w ith d en tin oi d a ty pi ca l a de no id a m a a d h em im an di bu le ct om y h em im an di bu le ct om y w e 18 m o 14 m o 12 m o k um ar e t a l.1 9 (2 01 3) 55 m al e 3 m o m n r ig ht sw el lin g, pa in , pa re st he si a w d u l r l a m -p , a o t -s , a o t -d , a o t -r , d m , g c c k 19 + a a d sr 36 m o sa le hi ne ja d et al .20 (2 01 6) 34 fe m al e 43 m o m x r ig ht sw el lin g pd r l a m -f , a m -p , a o t -d , d m c k 19 + + k i67 + + c k 8/ 18 + a a d 9 re cs ; s r 19 m o k ha le le e t a l.2 1 (2 01 6) 33 fe m al e 48 m o m x r ig ht sw el lin g + pa in n /p a m -f , a m -p , a o t -s , a o t -d , a o t -r , d m c k 19 + + k i67 + + c k 8/ 18 – a a d 5 re cs ; s r + r ad io th er ap y + ne ck d is se ct io n n /p sa th ya na ra ya n et a l.2 2 ( 20 17 ) 51 m al e 72 m o m x c m sw el lin g + pa in pd r l u a m , a o t -s , a o t -d , a o t -r , d m c k 19 + + k i67 + + c k 8/ 18 + a a d 5 re cs ; s r 76 m o r ai e t a l.2 3 (2 01 7) 47 m al e 18 m o m x c m sw el lin g n /p a m -f , a o t -s , a o t -d , d m c k 19 + + k i67 + + c k 8/ 18 + a a d 2 re cs ; s r + r ad io th er ap y + ne ck d is se ct io n 52 m o a do rn ofa ri as et a l.2 4 ( 20 18 ) 15 37 46 fe m al e m al e fe m al e 12 m o 12 m o n /p m n m n m n n /p le ft n /p sw el lin g sw el lin g + pa in n /p u l r l w d m l r l u l r l a m -f , a o t -s , a o t -d , d m a m -f , a o t -s , a o t -d , d m , c c c k 7 – c k 14 – c k 19 + im p3 – k i67 + p5 3 – c k 7 – c k 14 – c k 19 + + im p3 – k i67 + p5 3 – c k 7 – c k 14 – c k 19 + + im p3 – k i67 + p5 3 – a m w ith a de no id fe at ur es sr sr sr n /p n /p n /p n /p = n ot p ro vi de d; m n = m an di bl e; m x = m ax ill a; c m = c ro ss in g m id lin e; w d = w el lde fin ed ; p d = p oo rl y de fin ed ; u l = un ilo cu la r; m l = m ul til oc ul ar ; r l = ra di ol uc en cy ; r o = ra di op aq ue ; w e = w id e ex ci si on ; s r = su rg ic al re se ct io n; r ec = re cu rr en ce . sanpreet s. sachdev, tabita j. chettiankandy, manisha a. sardar, yogita adhane, aakruti m. shah and alphonsa e. grace review | 329 t ab le 2 (c on t’d .): s um m ar is ed p ar am et er s of c as es o f a de no id a m el ob la st om a w it h de nt in oi d a ut ho r an d ye ar o f pu bl ic at io n a ge in ye ar s g en de r d ur at io n a rc h si de sy m pt om r ad io gr ap hi c fe at ur e h is to pa th ol og ic al fe at ur e sp ec ia l s ta in s/ ih c fi na l d ia gn os is t re at m en t (w it h nu m be r of re cu rr en ce s) fo llo w up w ith n ed a do rn ofa ri as et a l.2 4 ( 20 18 ) 34 n /p 15 82 46 fe m al e fe m al e m al e m al e m al e n /p n /p 12 m o 36 m o n /p m n n /p m n m n n /p n /p sw el lin g n /p sw el lin g sw el lin g n /p u l r l u l r l u l r l m l r l u l r l a m -f , a o t -s , a o t -d , d m , c c a m -f , a o t -s , a o t -d , d m , c c a m -f , a o t -d , d m , c c , g c a m -f , a o t -d , d m , c c c k 7 – c k 14 – c k 19 + im p3 – k i67 + p5 3 – c k 7 – c k 14 – c k 19 + + im p3 – k i67 + p5 3 – c k 7 – c k 14 + + c k 19 + + im p3 – k i67 + p5 3 – c k 7 – c k 14 + + c k 19 + + im p3 – k i67 + p5 3 – c k 7 – c k 14 + + c k 19 + im p3 – k i67 + p5 3 – a m w ith a de no id fe at ur es sr sr sr sr sr n /p n /p n /p n /p n /p a rr ud a et a l.2 5 (2 02 0) 51 fe m al e n /p m x le ft n on e w d u l r l a m -p , a o t -s , a o t -d , d m a lc ia n bl ue a a d 1 re c; s r 10 8 m o n /p = n ot p ro vi de d; m n = m an di bl e; m x = m ax ill a; c m = c ro ss in g m id lin e; w d = w el lde fin ed ; p d = p oo rl y de fin ed ; u l = un ilo cu la r; m l = m ul til oc ul ar ; r l = ra di ol uc en cy ; r o = ra di op aq ue ; w e = w id e ex ci si on ; s r = su rg ic al re se ct io n; r ec = re cu rr en ce . adenoid ameloblastoma with dentinoid a systematic review 330 | squ medical journal, august 2022, volume 22, issue 3 presence of clear cells within the tumour islands in the aot component of the lesion and ghost cells within the odontogenic epithelial nests/islands in the aot component or within ameloblastomatous epithelium were also included and discussed in this review. moreover, the desmoplastic changes, which may occur in the stromal component of am, are now regarded as a histopathological variant of am rather than a distinct entity.5 however, these additional features are not considered as definitive criteria for the lesion, but rather represent varying stages of odontogenic cell differentiation in the lesion. d ata e x t r a c t i o n data on the demographic, clinical, radiographic and histopathological features and molecular markers were assessed. the treatment performed and their outcomes in all the reported cases were elicited. in order to minimise the risk of bias in quality assessment, the authors were divided into two groups that independently screened the cases and extracted the data from the included articles. the data was entered into meta-analysis sheets (ms office excel, 2016; microsoft redmond campus, redmond, wa, usa). results and discussion a total of 29 reported cases of aad were extracted from 18 publications available in english. the comprehensive findings following a detailed review of all the cases are collectively summarised [tables 2 and 3]. the first case of aad was reported by slabbert et al. in 1992, and till date, only 29 cases of aad have been reported.6 the low number of reported cases are reflective of the rarity of aad. it is possible that several cases of aad might be overlooked by pathologists as am or aot, depending on the predominance of either entity in the microscopic examination. this possibility is supported by the fact that 4 out of 45 cases of am were re-assessed and re-classified as aad in a retrospective study conducted by loyola et al.13 therefore, the actual number of cases might be much higher than those reported in the literature. with increasing case reports on the tumours and subsequent increase in the awareness amongst pathologists, hybrid lesions, such as aad, are identified accurately, which is in-line with the fact that more than half of the cases of aad (n = 19) were reported during the years 2015–2020. thus, more cases of aad may be expected to be reported in the following years. the mean age of the patients presenting the lesion was 38.97 ± 27.43 (range: 15–82) years. the maximum table 3: summary of various parameters observed following review of case reports and case series of adenoid amelo blastoma with dentinoid (n = 29) parameters n age in years lowest 15 highest 82 mean ± sd 38.97 ± 27.43 gender males 16 females 13 mandible 18 left 3 cm 4 right 6 maxilla 9 left 3 cm 3 right 3 mandible and maxilla (side not provided) 7 symptoms asymptomatic swelling 16 pain 3 paresthesia/numbness 4 radiographic well defined unilocular radiolucency 20 well-defined multilocular radiolucency 2 poorly defined radiolucency 2 radiolucent lesion with radiopaque foci 3 features of am component follicular 9 plexiform 9 mixed 9 unicystic ameloblastoma 2 changes in am component desmoplastic 1 granular cells 1 squamous metaplasia 8 features of aot component duct-like structures 19 sheets/whorls of cells 18 rosette-like structures 6 other histological features clear cells 9 ghost cells 4 recurrences cases reporting recurrences 12 maximum number of recurrences in a single case 9 follow-up details not provided 13 sd = standard deviation; cm = centre; am = ameloblastoma; aot = adeno matoid odontogenic tumour. sanpreet s. sachdev, tabita j. chettiankandy, manisha a. sardar, yogita adhane, aakruti m. shah and alphonsa e. grace review | 331 number of cases occurred in the fourth decade (n = 10), followed by the second and fifth decades (n = 5 each) of life, and the least number of cases were reported in the seventh decade or above [figure 2]. the pattern of age distribution of the lesion was identical to that of am and relatively less similar to aot, which tends to occur in first or second decade.26 unlike aot, which is more common in females, am does not exhibit gender predilection.27 in the case of aad, the reported cases comprised of 16 males and 13 females, yielding a ratio of nearly 1:1. the absence of gender predilection in aad was also similar to that observed in am. the cases of aad occurred twice more frequently in the mandible (n = 18) compared to maxilla (n = 9), with a slight predilection for the right (n = 9) compared to the left side (n = 6). considering the lower frequency of lesions in the maxilla, it may be deduced that a high percentage of lesions occurring on the left side were in the maxilla (3/6 maxillary aad), whereas aad occurring in the mandible exhibited a predilection for the right side (6/9 cases). in seven instances, the lesion involved the entire arch on both sides crossing the midline, indicating the aggressive potential of the lesion. interestingly, the tendency of the lesion to infiltrate both sides was equal in both the jaws, encompassing the entire mandible (n = 4) or maxillary jaw along with maxillary sinus and orbital floor (n = 3). approximately two-third of aots have been reported to occur in the maxillary jaw with a predilection for the left side, while am frequently tends to occur in the posterior region of the mandibular jaw with a slight predilection for the right side.26 thus, the pattern of occurrence of aad in the jaws is similar to aot in the maxilla and am in the mandible. similar to the clinical presentation of both aot and am, most of the patients presented an asymptomatic swelling (n = 16), which was accompanied by pain in only three cases. paraesthesia and numbness were elicited in four cases, with all the lesions inevitably involving the mandibular posterior region. pain, paraesthesia and numbness are also associated with am lesions, albeit uncommonly, and could be attributed to the tumour mass impinging on the peripheral nerves or secondary infection.28 the radiographic evaluation revealed that the lesion presented as a well-defined unilocular radiolucency (n = 20), which was similar to that commonly noted in aot. loyola et al. reported only two cases, which presented a poorly defined radiolucent lesion occurring in the maxillary jaw involving the nasal fossa, nasal and paranasal sinuses, as well as the orbit.13 in cases of large am or aot, similar involvement of nasal and maxillary sinuses with poorly defined lesions has been reported.27 the slow, painless clinical course of the lesion as well as the thin and porous maxillary bone might be the factors that lead to lesions’ extensive, poorly defined radiolucency.29 multilocularity was observed in only 2 out of 8 cases reported by adorno-farias et al.24 it is observed in the radiographic images of am, wherein the tumour exhibits the septae of bone extending into the radiolucent tumour mass.30 in three cases, radiopaque foci were also displayed within the unilocular radiolucency in the mandible. in all these cases, ghost cells and dystrophic calcifications were noted on the histopathologic examination for focal radiopacities.10,11,17 furthermore, the histopathology of the am component of the tumour revealed that nine cases had a predominant plexiform pattern of ameloblastlike cell proliferation, nine cases exhibited a follicular pattern, and another nine cases comprised a mixture of both patterns. the follicular and plexiform histopathological patterns in isolated and mixed forms are similar in cases of am, which was similar to the current findings.31 only two cases had uam associated with aot, suggesting that most aads are associated with solid/multicystic am. desmoplastic changes are infrequently noted in ameloblastoma owing to the loss of expression of notch receptors representing an early stage of cell differentiation.32,33 this phenomenon is observed figure 2: number of reported cases of adenoid ameloblastoma with dentinoid belonging to various age groups. adenoid ameloblastoma with dentinoid a systematic review 332 | squ medical journal, august 2022, volume 22, issue 3 in aad cases, wherein only one case, reported by salehinejad et al., presented features of desmoplastic am.20 in addition to the desmoplastic changes in the stroma, the lesion also comprised of large amounts of granular cells. granular cell ameloblastoma is a rare subtype of ameloblastoma, in which granular cells are located in the centre of the follicles.34 thus, only one case of granular cells occurring centrally within the ameloblastic follicles and desmoplastic changes within the connective tissue stroma in aad has yet been reported.20 squamous metaplasia occurring within the central stellate reticulum-like cells of am follicles is an occasional histological finding termed ‘acanthomatous ameloblastoma’.27 squamous metaplasia was observed in all the eight cases reported by adorno-farias et al. amongst them, seven lesions occurred in the mandibular jaw, whereas the clinical details of one case were unreported.24 the current findings were in accordance with the inference of bansal et al., which stated that the occurrence of squamous metaplasia is common in am cases occurring in the mandible than maxilla.35 the other component associated with am in the case of aad is that of aot. the biological mechanism underlying this mixture is yet to be elucidated. the transformation from one lesion to another seems to be a possible pathogenic mechanism.36 the term ‘adenomatoid’ is derived from ‘adḗn’, which means gland, and ‘-oma’, which means swelling or tumour. the peculiar feature of aot that led to the derivation of the term is the presence of duct-like structures lined by cuboidal or columnar epithelial cells.26 previous studies on the retention of extracellular matrix molecules in the duct-like structures of aot suggested a key role of osteonectin in the formation and maintenance of duct-like architecture.37 duct-like structures were detected in the histopathological images of 19 out of 29 reported aad cases in this study. in addition to these duct-like structures, areas comprising the odontogenic epithelial cells proliferating in the form of sheets, cords, trabeculae and whorls are also observed in aot in 18 cases. another characteristic feature noted in aot is the formation of nests or rosette-like structures by odontogenic epithelial cells.19 herein, rosette-like structures were noted in only a few cases (n = 6); thus, their presence was not considered a definite criterion for the diagnosis of aad. an associated extracellular homogenous dentinoid material of varying amounts is invariably present in addition to the am and aot components in aad. dentinoid is defined as a non-mineralised tissue, which is collagenous in nature and intimately associated with odontogenic epithelium.38 the earliest interpretation of the eosinophilic material in aad as dentinoid was proposed by slabbert et al. in 1992.6 the study found that the material was positively stained for collagen via van gieson and mason’s trichrome staining, negatively for amyloid staining by congo red and negatively for keratin by formic acid alcian blue stain. the interpretation of the collagenous nature of dentinoid in aad was further supported by sonone et al. via positive van gieson staining and negative congo red staining.17 since collagen and bone are also primarily constituted of collagen fibres, the dentinoid material is controversially considered as bone globules or cementum.26,27 the formation of dentinoid material in epithelial tumours is a result of a metaplastic process rather than epithelial–ectomesenchymal interaction. this phenomenon could be attributed to the gene products usually present in normal ectomesenchymal cells and the ameloblast-like cells of mixed odontogenic tumours.39 the outcome was the conversion of epithelial cells by subsequent interaction and coexpression of the mesenchymal phenotype. thus, the neoplastic epithelial cells committed to ameloblastic differentiation could produce extracellular material of variable composition in a few tumours.23 the lesions represent various directions for tumour differentiation, based on the initial inductive stimulus, the degree of odontogenesis prior to the stimulus and the variation in the metaplastic process.40 the clinicopathological significance and prognostic value of the dentinoid material in aad have not yet been determined and warrants further study. the formation of dentinoid material has also been described in some malignant odontogenic neoplasms, such as primary intraosseous odontogenic carcinoma and odontogenic carcinoma.41 the presence of cellular atypia in concomitance with other signs of malignancy in aad may render ameloblastic carcinoma (amca) or odontogenic carcinoma as an appropriate diagnosis. furthermore, the adenoid or duct-like structure might also be present in amca. however, the enamel organ-like structures or buds are not observed in odontogenic carcinoma with dentinoid.42 cellular atypia and abnormal mitosis were described in only one case of aad reported by khalele and al-shiaty.21 presumably, the possibility of aad with features of malignancy to be diagnosed as amca further adds to the challenge of acknowledging the exact frequency of reported cases of aad. the case reports of these malignant neoplasms with dentinoid emphasising the cellular morphologies rather than the glandular sanpreet s. sachdev, tabita j. chettiankandy, manisha a. sardar, yogita adhane, aakruti m. shah and alphonsa e. grace review | 333 component might have been missed, which pose as a limitation to the present review strategy. along with dentinoid, other types of extracellular materials have been identified in various studies. matsumoto et al. reported that some of the cystic or duct-like spaces in aad were positive for alcian blue and mucicarmine staining.8 yamazaki et al. found certain areas of amyloid-based extracellular material indicated by positive congo red staining.11 adornofarias et al. demonstrated pseudoducts with paspositive material.24 loyola et al. stated that although basophilic mucoid material may be observed within the duct-like spaces, secretory component was not detected.13 in the most recent case of aad reported by arruda et al., alcian blue staining revealed a significant amount of basophilic material and scarce pas-positive eosinophilic material in duct-like spaces, indicating its mucoid nature.25 nine cases of aad consisted of clear cells in a varied proportion of the tumour cell population. clear cells may be noted in tumours of the head and neck and could be a resultant product due to artifacts of fixation, lack of cell organelles and intracellular accumulation of various substances, such as glycogen, mucin, lipids, tonofilaments and immature zymogen granules.43 the clear cell changes could be attributed to tumour progression or secondary to clonal expansion.44 furthermore, the population of neoplastic cells comprising the ots is derived from the dental lamina, which appears to be clear in routine he-stained sections due to the abundance of glycogen content.45 ghost cells were detected in four reported cases of aad. the exact nature of ghost cells remains controversial; however, these cells might be the product of abortive enamel matrix or aberrant keratin formation.46,47 the presence of variable dysplastic material along with ghost cells reflects varied productive or inductive potentiality resulting from prosoplasia of the odontogenic epithelium.48 the ghost cells are common in other odontogenic tumours, such as calcifying epithelial odontogenic tumour (ceot), and should be differentiated from aad as they do not comprise the adenoid areas. regarding the origin of cells in a tumour and subsequent diagnosis, various biomolecules are identified by immunohistochemistry (ihc).49 the odontogenic tumours, particularly odontogenic epithelial cells, are associated with various biomarkers owing to complex genetic and epigenetic factors involved in their differentiation.50 the expression of ihc markers assessed in the reported cases of aad has been summarised [table 4]. the most employed markers for ihc differentiation of epithelial cells are known as cytokeratins (cks). cks comprise a group of at least 20 polypeptides constituting specific intermediate filaments of epithelial cells. the various epithelia or carcinoma associated with these cks are characterised by a specific pattern of polypeptides.51 ck14 has been identified as the primary, intermediate filament of odontogenic epithelium, present in the dental lamina, reduced enamel epithelium, duct-like structures of aot, and in almost all the cells of the enamel organ associated with the secretory activity of the odontogenic epithelial cells.52 strong immunopositive staining for ck14 was observed in several central and peripheral cells of tumour islands and the adenoid structures and surrounding cells in 6 out of 8 cases, as reported by adorno-farias et al.24 the negative expression of ck14 suggests the regions of advanced amelogenesis with the loss of cellular secretory activity, indicating the protective stage of amelogenesis.52 strong and diffuse positive immunostaining for ck19 staining was observed in 12 out of 15 cases of aad. ck19 is homogenously expressed in the stellate reticulum-like cells, peripheral preameloblast-like cells, areas of squamous metaplasia, some cells of the adenoid structures and areas with whorled appearance.11,13,24 it has been hypothesised that ck19 characterises ameloblasts and preameloblasts with complete differentiation. the negative immunoexpression of the molecule implied that stimuli could not activate the final differentiation process in these tumoral cells.52 ck7 has been identified in the epithelial cells of hertwig’s epithelial root sheath and weakly in the stellate reticulum cells and dental lamina near the enamel organ.53 the strong expression in odontogenic cysts and tumours, such as glandular odontogenic cyst and ceot, confirmed their origin from hertwig’s epithelial root sheath cells. however, it is not expressed table 4: summary of immunohistochemical markers in reported cases of adenoid ameloblastoma with dentinoid (n = 29) marker expression total positive negative ck14 6 8 14 ck19 12 3 15 ck7 0 8 8 ck8/18 3 2 5 ck17 1 0 1 calretinin 4 0 4 ki-67 (low) 10 (high) 5 15 p53 (high) 1 (low to negative) 8 9 imp3 0 8 8 adenoid ameloblastoma with dentinoid a systematic review 334 | squ medical journal, august 2022, volume 22, issue 3 in tumours, such as ameloblastoma, which develop from the enamel organ.54 all the eight cases of aad in the series reported by adorno-farias et al. were found to be ihc-negative for ck7.24 although ck8/18 is present in the simple epithelium, such as ductal cells, its positive expression has been demonstrated in cases involving dysplastic epithelia, including leukoplakia and oral squamous cell carcinoma.55 the study by wato et al. on the expression of cytokeratins in the variants of am identified it as a component in plexiform ameloblastoma.56 the weakly positive staining of ck8/18 has also been reported previously in the epithelial cells of the ductal component in aot.57 furthermore, ck8/18 was found to be focally positive in 3 out of 5 cases of aad reported by loyola et al.13 similarly, ck17 involved in carcinomas of stratified squamous epithelia constitutes a component of cks in am.56,58 moreover, ck17 expression in aad was detected only in one case by yamazaki et al., wherein it was focally positive in cells containing the am, but not the aot component.11 the expression of calretinin, a 29-kda calciumbinding protein, has been demonstrated in am but not in the other types of odontogenic cysts.59 although the underlying biological mechanism is not yet known, calretinin acts as a mediator of intracellular calcium ion signalling, i.e. a secondary messenger intervening in cellular proliferation and differentiation.60 it is also considered as a specific ihc marker for neoplastic ameloblastic epithelium, which is expressed only in am and in odontogenic keratocyst but not in aot.61,62 in corroboration with these findings, the ihc expression of calretinin was investigated in all aad cases (n = 4); subsequently, focal but intense positive immunoexpression, limited to the cells in the am component of the tumour, was noted. in addition to the biomolecules that aid in identifying the origin or type of cells in question, specific markers indicate the proliferative activity of the cells. the expression of the human ki-67 protein is analysed and evaluated to assess the proliferative activity in a lesion.63 the fraction of ki67-positive tumour cells, commonly known as ki-67 labelling index, determines the fraction of a given cell population in the active growth phase and is often correlated with the aggressiveness of any lesion.64 ki67 expression was variable in aad cases, wherein it was borderline to low in the majority of the reported cases (n = 10).11,20–25 however, the mean value of proliferative index as assessed by ki-67 positive cells (72.4 ± 24.9 positive cells per high-power field) in the five cases of aad reported by loyola et al. was found to be higher than aot and am and was closer to that observed in amca. they inferred that the higher ki-67 indices in aad were reflective of its inherent aggressive biological nature.13 p53 is also a routinely employed proliferative marker for malignancy and acts as a regulatory checkpoint in the cell cycle.65 normal cellular levels of wild-type p53 protein are low, and their half-life is short.66,67 mutant p53 products have a retarded degradation and elevated stability that contributes to their nuclear accumulation.68 thus, mutant p53 proteins are detected by ihc, rendering positive nuclear-staining signals, and have been frequently associated with malignant tumours. p53 expression was low to negative in all the cases (n = 8) reported by adorno-farias et al.24 the study also concluded that the lesion could be differentiated from amca, since the latter has a high p53 expression. however, in the case reported by khalele et al., the lesion exhibited a strong positive expression for p53, indicating a high proliferation potential of aad, and thus a prolonged interval of follow-up is essential in such cases.21 igf-2 mrna binding protein 3 (imp3) is a posttranscriptional regulatory factor involved in embryonic development, and its aberrant expression has been associated with oncogenesis.69 imp3 was not expressed in any of the cases (n = 8) reported by adorno-farias et al., which ruled out the carcinomatous nature of the lesion.24 overall, aad could be deemed less aggressive than amca because of negative staining for p53, imp3 and low expression of ki-67 in most cases. the primary purpose of employing an ihc panel inclusive of proliferative markers is to correctly identify the nature of the lesion and subsequently determine the prognosis of the lesion. once the prognosis of the lesion is determined, the surgeon can confidently decide the treatment plan. despite low proliferative indices on ihc analysis, multiple recurrences of the lesion were reported in more than 50% of cases of aad, including post-surgical follow-up of the patients (n = 10). amongst these, seven cases showed occurrence in the maxilla. the reason for recurrence in most of the maxillary aads has been suggested as the inability to achieve a complete excision with adequate margin in maxilla, owing to porous structures with high vascularity within which the lesion infiltration makes removal of all the neoplastic cells rather challenging.13 another reason for the aggressive nature and recurrence of aad suggested by khalele and al-shiaty was the inherent aggressive biological potential of the lesion, as indicated by strong immunoexpression of p53 protein.21 the tendency to aggressively invade the local structures in am has been attributed to the degradation of extracellular matrix, resulting from an increase in matrix metalloproteinases and receptor activator of sanpreet s. sachdev, tabita j. chettiankandy, manisha a. sardar, yogita adhane, aakruti m. shah and alphonsa e. grace review | 335 nuclear factor-kappa b ligand along with increased mobility of neoplastic cells due to loss of syndecan-1.70 on the other hand, aot is clinically well-contained. the lack of direct contact of neoplastic epithelium with the adjacent bone tissue and induction of reactive bone formation by osteonectin have been suggested as factors responsible for limited destruction in aot.70 thus, additional studies are essential to establish a correlation between the expression of these molecular markers and the prognosis of the lesion in aad. in only seven cases, there was no evidence of disease on post-surgical follow-up. however, the follow-up period was 1–3 years in most of the cases, while aad is known to recur even after nine years of treatment.9 the maximum number of recurrences in a single case of aad was reported by loyola et al., wherein the lesion had recurred nine times.13 thus, it can be estimated that aad has a recurrence rate of ≥75%, although the precise rate could not be determined owing to the lack of post-treatment follow-up in almost 33% (n = 12) of reported cases and the paucity of the available literature of the lesion. moreover, most of the recurrences were due to the underdiagnosis of the lesion as aot and subsequent conservative treatment. the reason for the tendency of aad to be misdiagnosed could be attributed to the predominance of aot-like areas in the histopathological image, which might overshadow the am areas, thereby leading to a benign diagnosis and conservative treatment.13 multiple recurrences of the lesion following wide excision suggested the lesion should be treated aggressively.8,9,13,16 all the cases treated with surgical resection had no evidence of recurrence for a variable follow-up period from six months to nine years. also, the recurrences after the surgical resection of the lesion in the absence of disease until the time of the report except in one case wherein the patient had another recurrence.13 thus, surgical resection could be deemed appropriate treatment for aad cases, while in cases involving maxillary sinus and floor of the orbit or those recurring even after excision, radiotherapy with radical neck dissection may be preferred.13 in the case of aad with uam component, simple wide excision of the lesion was sufficient with no evidence of disease after a one-year follow-up, although evaluation of outcomes with prolonged follow-up period in more such cases is warranted.22 conclusion aad is a rare hybrid odontogenic tumour with less than 30 cases reported to date. the lesion may occur at any age and commonly presents as an asymptomatic swelling in the mandible. histopathologically, the lesion might vary due to follicular, plexiform, or mixed am or uam in conjunction with whorls of epithelial islands, duct-like structures, and infrequently, rosette-like structures of aot along with a dentinoid component. other features, such as granular cells, clear cells, ghost cells and desmoplasia, are seldom noted in aad. furthermore, the lesion is frequently mis diagnosed as am or aot, and the individual entities composing the lesions owing to the abundance of either component in an incisional biopsy overshadows the other component. this leads to underdiagnosis of the lesion as aot in several instances, and subsequent conservative treatment results in recurrence. thus, it is imperative to identify the features of each component in the histopathological specimens of the odontogenic tumour to rule out such hybrid tumours. although molecular studies suggest that the lesion is relatively benign compared to amca, its aggressive clinical involvement cannot be overlooked as it has been reported to involve both sides of the jaws and extend to paranasal sinuses and orbital floor. multiple recurrences following wide excision of the lesion indicated that the lesion should be treated aggressively, placing it at the aggressive end of the spectrum of benign odontogenic lesions. therefore, an accurate diagnosis of the lesion to determine the treatment plan and the subsequent prognosis is imperative. with the increasing number of cases reported in the last decade, aad may be included as a distinct odontogenic neoplasm in the future. consequently, a large number of aad cases could be reported in the forthcoming future owing to an increase in the available literature on hybrid odontogenic tumours. this would provide clarity to the surgeons and pathologists regarding the diagnosis, management and prognosis of the entity. moreover, future research on the genetic aspects of the tumour could elucidate the pathogenesis of aad. a u t h o r s’ c o n t r i b u t i o n ss, tc, ms and ya conceptualised and defined the work. ss and tc conducted the initial literature review and devised the basic search strategy. ms, as and ag modified the search strategy. all the authors contributed to performing the search and collecting data from the eligible articles. ss, tc, ma and ya analysed and interpreted the data. ss, tc and as drafted the manuscript, while critical revision of the adenoid ameloblastoma with dentinoid a systematic review 336 | squ medical journal, august 2022, volume 22, issue 3 manuscript was done by ms and ag. all authors approved the final version of the manuscript. references 1. ruch jv, lesot h, begue-kim c. odontoblast differentiation. int l dev biol 1995; 39:51–68. 2. fauchard p. le chirurgien dentiste, ou traité des dents. tome 1-2. paris: pierre jean mariette, 1746. 3. barnes l, everson wj, reichart p, sidradinsky d. pathology and genetics: head and neck tumors. 5th ed. lyon: iarc press, 2005. 4. ide f, horie n, shimoyama t, sakashita h. so-called hybrid odontogenic tumors: do they really exist? oral med pathol 2001; 6:13–21. https://doi.org/10.3353/omp.6.13. 5. el naggar ak, chan jk, grandis jr, takata t, slootweg pj. who classification of head and neck tumours. 4th ed. lyon: iarc, 2017. 6. slabbert h, altini m, crooks j, uys p. ameloblastoma with dentinoid induction: dentinoameloblastoma. j oral pathol med 1992; 21:46–8. https://doi.org/10.1111/j.1600-0714.1992. tb00969.x. 7. brannon rb. adenoid ameloblastoma with dentinoid. washington (dc). armed forces institute of pathology 1994; 1–94. 8. matsumoto y, mizoue k, seto k. atypical plexiform amelo blastoma with dentinoid: adenoid ameloblastoma with dentinoid. j oral pathol med. 2001; 30:251–4. https://doi.org/10.1034/ j.1600-0714.2001.300410.x. 9. evans bl, carr rf, phillipe lj. adenoid ameloblastoma with dentinoid: a case report. oral surg oral med oral pathol oral radiol endod 2004; 98:583–8. https://doi.org/10.1016/j. tripleo.2004.02.077. 10. zhang w, chen yu, geng n, bao d, yang m. a case report of a hybrid odontogenic tumour: ameloblastoma and adenomatoid odontogenic tumour in calcifying cystic odontogenic tumour. oral oncol extra 2006; 42:287–90. https://doi.org/10.1016/j. ooe.2006.07.003. 11. yamazaki m, maruyama s, abé t, babkair h, fujita h, takagi r, et al. hybrid ameloblastoma and adenomatoid odontogenic tumor: report of a case and review of hybrid variations in the literature. oral surg oral med oral pathol radiol 2014; 118:12–18. https://doi.org/10.1016/j.oooo.2013.08.032. 12. jivan v, altini m, meer s, mahomed f. adenomatoid odontogenic tumor (aot) originating in a unicystic ameloblastoma: a case report. head neck pathol 2007; 1:146–9. https://doi.org/10.10 07/s12105-007-0005-6. 13. loyola am, cardoso sv, de faria pr, servato jp, eisenberg al, dias fl, et al. adenoid ameloblastoma: clinicopathologic description of five cases and systematic review of the current knowledge. oral surg oral med oral pathol oral radiol 2015; 120:368–77. https://doi.org/10.1016/j.oooo.2015.05.011. 14. vickers ra, gorlin rj. ameloblastoma: delineation of early histopathologic features of neoplasia. can 1970; 26:699–710. https://doi.org/10.1002/1097-0142(197009)26:3<699::aidcncr2820260331>3.0.co;2-k. 15. ghasemi-moridani s, yazdi i. adenoid ameloblastoma with dentinoid: a case report. arch iran med. 2008; 11:110–12. https://doi.org/08111/aim.0021. 16. ide f, mishima k, saito i, kusama k. diagnostically challenging epithelial odontogenic tumors: a selective review of 7 jawbone lesions. head neck pathol 2009; 3:18–26. https://doi.org/10.10 07/s12105-009-0107-4. 17. sonone a, hande a, chaudhary m, bonde r, sheorain a, agni n. adenoid ameloblastoma with dentinoid and ghost cells. a composite odontogenic tumour: a rare case report and review of the literature. oral surg 2011; 4:77–81. https://doi. org/10.1111/j.1752-248x.2010.01109.x. 18. saxena k, jose m, chatra lk, sequiera j. adenoid ameloblastoma with dentinoid. j oral maxillofac pathol 2012; 16:272–76. https://doi.org/10.4103/jomfp.jomfp_53_15. 19. kumar k, shetty dc, wadhwan v, dhanapal r, singh hp. dentinoameloblastoma with ghost cells: a rare case report with emphasis on its biological behavior. dent res j 2013; 10:103–7. https://doi.org/10.4103/1735-3327.111809. 20. salehinejad j, gholami m, eshghpour m, mehri t. an infrequent histopathological subtype of ameloblastoma: adenoid granular cell ameloblastoma with dentinoid. dent res j 2016; 13:376–8. https://doi.org/10.4103/1735-3327.187878. 21. khalele bao, al-shiaty ra. adenoid ameloblastoma with dentinoid and cellular atypia: a rare case report. ital j med 2016; 10:238–40. https://doi.org/10.4081/itjm.2016.639. 22. sathyanarayana vk, srigiri h, cheemalavagupalli m, vankadara s, malika g. a rare case of adenomatoid odontogenic tumour with unicystic ameloblastoma. j clin diagnostic res 2017; 11:5–6. https://doi.org/10.7860/jcdr/2017/23623.9412. 23. rai hk, pai sm, dayakar a, supriya h. adenoid ameloblastoma with dentinoid: a rare hybrid variant. j oral maxillofac pathol 2017; 21:319. https://doi.org/10.4103/jomfp.jomfp_53_15. 24. adorno-farias d, muniz vr, soares ap, cury pr, rabelo rg, fernández-ramires r et al. ameloblastoma with adenoid features: a series of eight cases. acta histochem 2018; 120:468–76. https://doi.org/10.1016/j.acthis.2018.05.006. 25. arruda jaa, noronha ms, abreu lg, et al. adenoid ameloblastoma in the posterior maxilla: a case report and review of the literature. oral maxillofac surg 2020; 24:243–9. https://doi.org/10.1007/s10006-020-00830-1. 26. reichart p, philipsen h. odontogenic tumors and allied lesions. london, uk: quintessence publishing co ltd, 2004. pp. 41–116. 27. sivapathasundharam b, rajendran r. odontogenic tumors. in: sivapathasundharam b, ed. shafer's textbook of oral pathology e-book. 8th ed. india: elsevier health sciences, 2020. pp. 100–15. 28. ueno s, nakamura s, mushimoto k, shirasu r. a clinicopathologic study of ameloblastoma. j oral maxillofac surg 1986; 44:361–5. https://doi.org/10.1016/s0278-2391(86)80031-3. 29. iordanidis s, makos ch, dimitrakopoulos j, kariki h. ameloblastoma of the maxilla. case report. aus dent j 1999; 44:51–5. https://doi.org/10.1111/j.1834-7819.1999.tb00536.x. 30. odontogenic epithelial tumors. in: white s, pharaoh m, eds. oral radiology – principles and interpretation, 6th ed. china: mosby elsevier, 2009. pp. 373–85. 31. nagi r, sahu s, rakesh n. molecular and genetic aspects in the etiopathogenesis of ameloblastoma: an update. j oral maxillofac pathol 2016; 20:497. https://doi.org/10.4103/0973029x.190954. 32. philipsen hp, reichart pa, takata t. desmoplastic amelo blastoma (including “hybrid” lesion of ameloblastoma). biological profile based on 100 cases from the literature and own files. oral oncol 2001; 37:455–60. https://doi.org/10.1016/s13688375(00)00111-1. 33. siar ch, nakano k, han pp, nagatsuka h, ng kh, kawakami t. differential expression of notch receptors and their ligands in desmoplastic ameloblastoma. j oral pathol med 2010; 39:552–8. https://doi.org/10.1111/j.1600-0714.2009.00871.x. https://doi.org/10.3353/omp.6.13 https://doi.org/10.1111/j.1600-0714.1992.tb00969.x https://doi.org/10.1111/j.1600-0714.1992.tb00969.x https://doi.org/10.1034/j.1600-0714.2001.300410.x https://doi.org/10.1034/j.1600-0714.2001.300410.x https://doi.org/10.1016/j.tripleo.2004.02.077 https://doi.org/10.1016/j.tripleo.2004.02.077 https://doi.org/10.1016/j.ooe.2006.07.003 https://doi.org/10.1016/j.ooe.2006.07.003 https://doi.org/10.1016/j.oooo.2013.08.032 https://doi.org/10.1007/s12105-007-0005-6 https://doi.org/10.1007/s12105-007-0005-6 https://doi.org/10.1016/j.oooo.2015.05.011 https://doi.org/10.1002/1097-0142(197009)26:3<699::aid-cncr2820260331>3.0.co;2-k https://doi.org/10.1002/1097-0142(197009)26:3<699::aid-cncr2820260331>3.0.co;2-k https://doi.org/08111/aim.0021 https://doi.org/10.1007/s12105-009-0107-4 https://doi.org/10.1007/s12105-009-0107-4 https://doi.org/10.1111/j.1752-248x.2010.01109.x https://doi.org/10.1111/j.1752-248x.2010.01109.x https://doi.org/10.4103/1735-3327.111809 https://doi.org/10.4103/1735-3327.187878 https://doi.org/10.4081/itjm.2016.639 https://doi.org/10.7860/jcdr/2017/23623.9412 https://doi.org/10.4103/jomfp.jomfp_53_15. https://doi.org/10.1016/j.acthis.2018.05.006. https://doi.org/10.1007/s10006-020-00830-1 https://doi.org/10.1016/s0278-2391(86)80031-3 https://doi.org/10.1111/j.1834-7819.1999.tb00536.x https://doi.org/10.4103/0973-029x.190954 https://doi.org/10.4103/0973-029x.190954 https://doi.org/10.1016/s1368-8375(00)00111-1 https://doi.org/10.1016/s1368-8375(00)00111-1 https://doi.org/10.1111/j.1600-0714.2009.00871.x sanpreet s. sachdev, tabita j. chettiankandy, manisha a. sardar, yogita adhane, aakruti m. shah and alphonsa e. grace review | 337 34. gardner dg, heikinheimo k, shear m, philipsen hp, coleman h. ameloblastoma. in: barnes l, eveson jw, reichart p, sidransky d. world health organization classification of tumors, pathology and genetics of head and neck tumors. lyon: iarc press; 2005. pp. 296–300. 35. bansal m, chaturved tp, bansal r, kumar m. acanthomatous ameloblastoma of anterior maxilla. j ind soc pedodont preventive dent 2010; 28:209–11. https://doi.org/10.4103/09704388.73797. 36. yoon jh, kim hj, yook ji, cha ih, ellis gl, kim j. hybrid odontogenic tumour of calcifying odontogenic cyst and amelo blastic fibroma. oral surg oral med oral pathol oral radiol endod 2004; 98:80–4. https://doi.org/10.1016/j.tripleo.2004.01.003. 37. murata m, cheng j, horino k, hara k, shimokawa h, saku t. enamel proteins and extracellular matrix molecules are colocalized in the pseudocystic stromal space of adenomatoid odontogenic tumor. j oral pathol med 2000; 29:483–90. https:// doi.org/10.1034/j.1600-0714.2000.291002.x. 38. gardner dg, farquhar da. a classification of dysplastic forms of dentin. j oral pathol 1979; 8:28–46. https://doi.org/10.1111/ j.1600-0714.1979.tb01620.x. 39. papagerakis p, peuchmaur m, hotton d, ferkdadji l, delmas p, sasaki s, et al. aberrant gene expression in epithelial cells of mixed odontogenic tumors. j dent res 1999; 78:20–30. https:// doi.org/10.1177/00220345990780010201. 40. tanaka h, takigawa t, owo m, matsumoto h, fukumoto w. a case of malignant transformation of calcifying of odontogenic cyst. jpn j oral maxiillofac 1975; 21:664. 41. punnya a, kumar gs, rekha k, vandana r. primary intraosseous odontogenic carcinoma with osteoid/dentinoid formation. j oral pathol med 2004; 33:121–4. https://doi.org/10.1111/ j.1600-0714.2004.00029.x. 42. mariano fv, gondak ro, scarini jf, da silva ec, caravina g, scapulatempo-neto c, almeida op, altemani a, mosqueda taylor a. odontogenic carcinoma with dentinoid in long-term follow-up with 2 recurrences. int j surg pathol 2020; 28:181–7. https://doi.org/10.1177/1066896919871662. 43. maiorano e, altini m, favia g. clear cell tumors of the salivary glands, jaws and oral mucosa. sem diagnostic pathol 1997; 14:203–12. 44. nappi o, mills s, swanson p, wick m. clear cell tumours of unknown nature and origin: a systemic approach to diagnosis. sem diagnostic pathol 1997; 14:164–74. 45. jain a, shetty dc, juneja s, narwal n. molecular characterization of clear cell lesions of head and neck. j clin dent res 2016; 10:ze18. 46. yoshida m, kumamoto h, ooya k, mayanagl h. histopath ological and immunohistochemical analysis of calcifying odont ogenic cysts. j oral pathol 2001; 30:582–8. https://doi. org/10.1034/j.1600-0714.2001.301002.x. 47. hong sp, ellis gl, hartman ks. calcifying odontogenic cyst: a review of ninety-two cases with reevaluation of their nature as cysts or neoplasms, the nature of ghost cells, and subclassification. oral surg oral med oral pathol 1991; 72:56–64. https://doi.org/10.1016/0030-4220(91)90190-n. 48. mankapure pk. ghost cells and its histogenesis: a narrative review. ijss case reports & reviews 2015; 2:35–9. 49. hornick jl. novel uses of immunohistochemistry in the diagnosis and classification of soft tissue tumors. modern pathol 2014; 27:s47–63. https://doi.org/10.1038/modpathol.2013.177. 50. sandoval-basilio j, gonzález-gonzález r, bologna-molina r, isiordia-espinoza m, leija-montoya g, alcaraz-estrada sl, et al. epigenetic mechanisms in odontogenic tumors: a literature review. arch oral biol 2018; 87:211–7. https://doi. org/10.1016/j.archoralbio.2017.12.029. 51. moll r, franke ww, schiller dl, geiger b, krepler r. the catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. cell 1982; 31:11–24. https://doi.org/10.1016/0092-8674(82)90400-7. 52. crivelini mm, de araújo vc, de sousa so, de araújo ns. cytokeratins in epithelia of odontogenic neoplasms. oral dis 2003; 9:1–6. https://doi.org/10.1034/j.1601-0825.2003.00861.x. 53. gratzinger d, salama me, poh cf, rouse rv. ameloblastoma, calcifying epithelial odontogenic tumor, and glandular odontogenic cyst show a distinctive immunophenotype with some myoepithelial antigen expression. j oral pathol med 2008; 37:177–84. https://doi.org/10.1111/j.1600-0714.2007.00613.x. 54. martínez-martínez m, mosqueda-taylor a, carlosbregni r, pires fr, delgado-azañero w, neves-silva, et al. comparative histological and immunohistochemical study of ameloblastomas and amcas. med oral pathol oral cir. bucal 2017; 22:e324–32. https://doi.org/10.4317/medoral.21901. 55. gires o, mack b, rauch j, et al. ck8 correlates with malignancy in leukoplakia and carcinomas of the head and neck. biochem biophys res commun 2006; 343:252–9. https://doi. org/10.1016/j.bbrc.2006.02.139. 56. wato m, chen y, fang yr, he zx, wu ly, bamba y, hida t, hayashi h, ueda m, tanaka a. immunohistochemical expression of various cytokeratins in ameloblastomas. j oral med pathol 2006; 11:67–74. https://doi.org/10.3353/omp.11.67. 57. larsson å, swartz k, heikinheimo k. a case of multiple aotlike jawbone lesions in a young patient–a new odontogenic entity? j oral pathol med 2003; 32:55–62. https://doi.org/10.1034/ j.1600-0714.2003.00046.x. 58. cohen-kerem r, madah w, sabo e, et al. cytokeratin-17 as a potential marker for squamous cell carcinoma of the larynx. ann otol rhinol laryngol 2004; 113:821–7. https://doi. org/10.1177/000348940411301008. 59. mosqueda-taylor a. new findings and controversies in odontogenic tumors. med oral patol oral cir bucal 2008; 13:e555–8. 60. sundaragiri sk, chawda j, gill s, odedra s, parmar g. calretinin expression in unicystic ameloblastoma: an aid in differential diagnosis. j oral biosci 2010; 52:164–9. https://doi. org/10.1016/s1349-0079(10)80046-5. 61. koneru a, hallikeri k, nellithady gs, krishnapillai r, prabhu s. immunohistochemical expression of calretinin in ameloblastoma, adenomatoid odontogenic tumor, and keratocystic odontogenic tumor. appl immunohistochem mol morphol 2014; 22:762–7. https://doi.org/10.1097/pai.0000000000000005. 62. devilliers p, liu h, suggs c, simmons d, daly b, zhang s, et al. calretinin expression in the differential diagnosis of human ameloblastoma and keratocystic odontogenic tumor. am j surg pathol 2008; 32:256–60. https://doi.org/10.1097/ pas.0b013e3181452176. 63. scholzen t, gerdes j. the ki-67 protein: from the known and the unknown. j cell physiol 2000; 182:311–22. https:// doi.org/10.1002/(sici)1097-4652(200003)182:3<311::aidjcp1>3.0.co;2-9. 64. ueda t, aozasa k, tsujimoto m, ohsawa m, uchida a, aoki y, ono k, matsumoto k. prognostic significance of ki-67 reactivity in soft tissue sarcomas. cancer 1989; 63:1607–11. https://doi.org/10.1002/1097-0142(19890415)63:8<1607::aidcncr2820630827>3.0.co;2-1. 65. hupp tr, meek dw, midgley ca, lane dp. regulation of the specific dna binding function of p53. cell 1992; 71:875–86. https://doi.org/10.1016/0092-8674(92)90562-q. 66. montenarh m: biochemical properties of the growth suppressor/oncoprotein p53. oncogene 1992; 7:1673–80. https://doi.org/10.4103/0970-4388.73797 https://doi.org/10.4103/0970-4388.73797 https://doi.org/10.1016/j.tripleo.2004.01.003 https://doi.org/10.1034/j.1600-0714.2000.291002.x https://doi.org/10.1034/j.1600-0714.2000.291002.x https://doi.org/10.1111/j.1600-0714.1979.tb01620.x https://doi.org/10.1111/j.1600-0714.1979.tb01620.x https://doi.org/10.1177/00220345990780010201 https://doi.org/10.1177/00220345990780010201 https://doi.org/10.1111/j.1600-0714.2004.00029.x https://doi.org/10.1111/j.1600-0714.2004.00029.x https://doi.org/10.1177/1066896919871662 https://doi.org/10.1034/j.1600-0714.2001.301002.x https://doi.org/10.1034/j.1600-0714.2001.301002.x https://doi.org/10.1016/0030-4220(91)90190-n https://doi.org/10.1038/modpathol.2013.177 https://doi.org/10.1016/j.archoralbio.2017.12.029 https://doi.org/10.1016/j.archoralbio.2017.12.029 https://doi.org/10.1016/0092-8674(82)90400-7 https://doi.org/10.1034/j.1601-0825.2003.00861.x https://doi.org/10.1111/j.1600-0714.2007.00613.x https://doi.org/10.4317/medoral.21901 https://doi.org/10.1016/j.bbrc.2006.02.139 https://doi.org/10.1016/j.bbrc.2006.02.139 https://doi.org/10.3353/omp.11.67 https://doi.org/10.1034/j.1600-0714.2003.00046.x https://doi.org/10.1034/j.1600-0714.2003.00046.x https://doi.org/10.1177/000348940411301008 https://doi.org/10.1177/000348940411301008 https://doi.org/10.1016/s1349-0079(10)80046-5 https://doi.org/10.1016/s1349-0079(10)80046-5 https://doi.org/10.1097/pai.0000000000000005 https://doi.org/10.1097/pas.0b013e3181452176 https://doi.org/10.1097/pas.0b013e3181452176 https://doi.org/10.1002/(sici)1097-4652(200003)182:3<311::aid-jcp1>3.0.co;2-9 https://doi.org/10.1002/(sici)1097-4652(200003)182:3<311::aid-jcp1>3.0.co;2-9 https://doi.org/10.1002/(sici)1097-4652(200003)182:3<311::aid-jcp1>3.0.co;2-9 https://doi.org/10.1002/1097-0142(19890415)63:8<1607::aid-cncr2820630827>3.0.co;2-1 https://doi.org/10.1002/1097-0142(19890415)63:8<1607::aid-cncr2820630827>3.0.co;2-1 https://doi.org/10.1016/0092-8674(92)90562-q adenoid ameloblastoma with dentinoid a systematic review 338 | squ medical journal, august 2022, volume 22, issue 3 67. oren m, maltzman w, levine aj: post-translational regulation of the 54k cellular tumor antigen in normal and transformed cells. mol cell biol 1981; 1:101–10. https://doi.org/10.1128/ mcb.1.2.101. 68. finlay ca, hinds pw, levine aj: the p53 proto-oncogene can act as a suppressor of transformation. cell 1989; 57:1083–93. https://doi.org/10.1016/0092-8674(89)90045-7. 69. deforzh, e., vargas, t.r., kropp, j., vandamme, m., pinna, g., polesskaya, a. imp-3 protects the mrnas of cyclins d1 and d3 from gw182/ago2-dependent translational repression. int j oncol 2016; 49:2578–88. https://doi.org/10.3892/ijo.2016.3750. 70. modolo f, biz mt, martins mt, machado de sousa so, de araújo ns. expression of extracellular matrix proteins in adenomatoid odontogenic tumor. j oral pathol med 2010; 39:230–5. https://doi.org/10.1111/j.1600-0714.2009.00846.x. https://doi.org/10.1128/mcb.1.2.101 https://doi.org/10.1128/mcb.1.2.101 https://doi.org/10.1016/0092-8674(89)90045-7. https://doi.org/10.3892/ijo.2016.3750 https://doi.org/10.1111/j.1600-0714.2009.00846.x the impact of covid-19 on urology practice in oman sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e404–405, epub. 21 dec 20 submitted 17 may 20 revision req. 13 jul 20; revision recd. 15 jul 20 accepted 13 aug 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.023 letter to the editor أتثري كوفيد-19 على ممارسة جراحة املسالك البولية يف ُعمان dear editor, there have been many changes in the healthcare sector due to the current covid-19 pandemic. in the future, we will have to deal with the post-covid-19 era. the aim of this article is to highlight the impact of covid-19 on urology practice in oman in relation to local and international responses as well as emphasised the importance of telemedicine in the continuity of care for our patients and discuss how we can be better prepared for future pandemics. the covid-19 disease is caused by the virus called sars coronavirus-2 (sars cov-2).1 up to october 25, there were 42,512,186 confirmed cases of covid-19 worldwide including 1,147,301 deaths. in oman, there were 111,837 confirmed cases of covid-19 with 1,147 deaths.2 i n t e r n at i o n a l c h a n g e s the first impact on urology education that occurred was the postponement of the 35th annual congress of the european association of urology (eau), which was to be held in amsterdam from 20 march to 17 july, 2020. this was followed by the announcement of converting the eau20 congress (17–19 july) to a virtual event. all international urological bodies have released guidelines to direct urologists on how to deal with the pandemic and how to prioritise urological procedures. the eau guidelines office rapid reaction group released the updated guidelines only two weeks after the release of the official guidelines at the end of march 2020.3 the main aim was to aid clinicians in making management decisions that reflected on local circumstances by the introduction of a chart that divided priorities into different levels [table 1].4 l o c a l c h a n g e s at the department of surgery in sultan qaboos university hospital, muscat, oman, certain changes were adopted resulting in a reduction of outpatient department (opd) patients and elective operating theater (ot) cases by 70% and 100%, respectively. all booked cases in opd were triaged by consultants at least a week earlier while non-urgent cases were given new dates and stable follow-up patients were given refill prescriptions. the hospital adopted an effective policy that allowed patients to refill their medications by sending a whatsapp (facebook inc., menlo park, california, usa) message with their medical record number and the name of the clinic without having to attend the opd. this policy helped to avoid crowding of the opd areas. the emergency and oncology cases remained largely unaffected with a monthly average of 18 and 10 cases, respectively. however, the number of covid-19 positive cases who underwent operations is not known mainly because screening of patients who were scheduled for surgery and were asymptomatic or at risk of covid-19 had not yet been implemented. other implementations included: (1) training of staff on the use of personal protective equipment; (2) enforcing the ot guidelines to categorise patients into emergency, oncological and non-oncological urgent cases with the allocation of a covid-19 ot room; and (3) starting online teaching for medical students at different levels using zoom (zoom, san jose, usa), where the tutor joins the students in live interactive sessions. the oman urology society (ous) also implemented actions to deal with the covid-19 pandemic. all society members were kept updated table 1: levels of priority as defined by the european association of urology guidelines office rapid reaction group4 priority category low priority intermediate priority high priority emergency definition clinical harm very unlikely if postponed six months clinical harm possible if postponed 3–4 months, but unlikely clinical harm very likely if postponed more than six weeks life threatening situation. likely to have presented via a&e despite the current pandemic a&e = accident and emergency department. https://creativecommons.org/licenses/by-nd/4.0/ mohamed s. al-marhoon letter to the editor | e405 about local and international guidelines related to covid-19 and were informed of webinars to update their knowledge. the 2nd ous international conference, in collaboration with the arab association of urology to be held on 1–3 october 2020, was converted to a virtual conference in view of the increasing covid-19 cases in the region. on an individual basis, members were involved in remote patient consultations through telephone, whatsapp (facebook inc.) or email communications. ous is supporting the activities of the oman medical association in dealing with the covid-19 pandemic. p o s t-c o v i d-19 e r a it is now clear that this pandemic will last several months until effective vaccination or definitive treatment becomes available. in order to overcome this and future pandemics, virtual healthcare solutions need to be introduced, such as telemedicine with applications including tele-consultation, tele-education and tele-research. tele-consultation entails connecting with the patients by audio and video (e-visits) with an interactive medical consultation. this can be conducted using several softwares such as zoom (zoom, san jose, california, usa), gotomeeting (logmein inc., boston, massachusetts, usa), skype (facebook inc.), facetime (facebook inc.), google meet (google, mountain view, california, usa) and microsoft team (microsoft, redmond, washington, usa). the concept of telemedicine in oman has been explored and implemented with limitations in select hospitals and specialties such as teleradiology. however, it is not widely used in oman mainly due to legal issues, high cost, technical complexity as well as a lack of current local regulatory requirements such as the health insurance portability and accountability act in the usa. if properly adopted, telemedicine can help patients during pandemics such as covid-19, when access to the healthcare system has been limited, as well as during routine normal life situations to compensate for hospital-bed shortages and the lack of some medical specialists in remote areas of the country. tele-consultation could be a useful system to physicians who are inspecting medical data of patients located in remote areas that may be performed either in real-time or asynchronously. an effective telemedicine system has unique requirements such as a telemedicine workstation, communication network, human perception of media and telemedicine security.5 physicians should adhere to the applicable laws governing the practice of telemedicine as set by organisations such as the american medical association.6 recently, the omani ministry of health has circulated guidelines to regulate the practice of telemedicine in oman and some government and private hospital have started to implement them. mohamed s. al-marhoon department of surgery, sultan qaboos university, muscat, oman e-mails: msalmarhoon@gmail.com and mmarhoon@squ.edu.om references 1. maginn w. covid-19 what-you-need-to-know. from: www.warrenmaginn.com/environment/caronavirus-what-you-need-to-know accessed: jul 2020. 2. world health organization. who coronavirus disease (covid-19). from https://covid19.who.int accessed: oct 2020. 3. european association of urology guidelines. 2020 edition. arnhem, the netherlands: european association of urology guidelines office; 2020. https://uroweb.org/guidelines. 4. ribal mj, cornford p, briganti a, knoll t, gravas s, babjuk m, et al. european association of urology guidelines office rapid reaction group: an organisation-wide collaborative effort to adapt the european association of urology guidelines recommendations to the coronavirus disease 2019 era. eur urol 2020; 78: 21–8. https://doi.org/10.1016/j.eururo.2020.04.056. 5. altaei mh, abdul-mehdi zt. telemedicine requirements for treatment network in oman. j adv comput netw 2013; 1: 246–9. https:// doi.org/10.7763/jacn.2013.v1.49. 6. chaet d, clearfield r, sabin je, skimming k, council on ethical and judicial affairs american medical association. ethical practice in telehealth and telemedicine. j gen intern med 2017; 32:1136–40. https://doi.org/10.1007/s11606-017-4082-2. https://doi.org/10.1016/j.eururo.2020.04.056 https://doi.org/10.7763/jacn.2013.v1.49 https://doi.org/10.7763/jacn.2013.v1.49 https://doi.org/10.1007/s11606-017-4082-2 departments of 1surgery and 2pathology, jawaharlal institute of postgraduate medical education and research, puducherry, india *corresponding author’s e-mail: drvikramkate@gmail.com the diagnostic dilemma of ruptured liver metastasis in a patient with lung cancer a case report k.s. jayanth,1 shivakumar madan,1 balakrishnan gurushankari,1 sathasivam sureshkumar,1 amaranathan anandhi,1 rajesh n.g.,2 *vikram kate1 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 421–425, epub. 25 aug 22 submitted 24 feb 21 revision req. 19 apr 21; revision recd. 5 may 21 accepted 3 jun 21 abdominal pain, breathlessness (modified medical research council grade 3) and intermittent high-grade fever for 15 days.6 the patient had a history of loss of appetite and significant weight loss over two months. the patient did not have any history of vomiting, jaundice, prior hospitalisation or surgeries. she had no known medical comorbidities. she gave a history of usage of firewood as fuel for cooking purposes in an ill-ventilated house for the past 25 years. she had no history of tobacco or alcohol consumption. on examination, the patient was afebrile, anaemic, anicteric and breathless with a respiratory rate of 26/min. the patient’s blood pressure was 110/70 mmhg and her pulse rate was 110/min. abdominal examination revealed an 8 × 6 cm soft, ill-defined, tender mass in the right hypochondrium. on digital rectal examination, no growth or deposits were palpable. on auscultation of bilateral lung fields, reduced breath sounds were heard in both infra-mammary, infra-axillary and infrascapular areas, with no added respiratory sounds, possibly suggesting pleural effusion. preliminary blood investigations showed haemoglobin of 9.1 g/ dl and leukocytosis of 15,510 cells/mm3 with normal renal parameters and electrolytes. liver function tests showed normal bilirubin and transaminase levels with only a mild elevation of alkaline phosphatase (228 iu/l). chest radiograph, ultrasound (usg) abdomen and contrast-enhances computed tomography (cect) of abdomen and thorax was carried out [table 1]. the cect of her abdomen and thorax carcinoma of the lung is one of the lethal cancers with the commonest sites of dissemination being brain, liver, contralateral lung, adrenals and bone.1,2 although rupture of liver lesions such as liver abscess, hepatic adenomas, haemangiomas and focal nodular hyperplasia have been reported in the literature, rupture of malignant tumours is relatively uncommon.3 spontaneous rupture of hepatocellular carcinoma (hcc) is reported in approximately 10% of cases due to its hypervascularity and decreased coagulation factors as a result of underlying liver cirrhosis.4,5 however, spontaneous rupture of a metastatic liver tumour is rarely documented in the literature when compared to hcc and other liver lesions.4,5 rupture of liver metastasis in a patient with lung cancer is even more rare with isolated cases mentioned in the literature. we report a case of ruptured liver metastasis from an adenocarcinoma of the lung presenting with subcapsular collection and massive pleural effusion mimicking a ruptured liver abscess, associated with portal and hepatic venous thrombosis, challenging the clinical diagnosis. to the best of the authors’ knowledge, no such case has been reported. case report a 42-year female patient, a homemaker from a village of south india, was brought by ambulance to the emergency department of a tertiary care hospital in 2020 with complaints of dull-aching right upper this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.091 case report abstract: spontaneous rupture of a metastatic liver tumour is rarely documented in the literature when compared to hepatocellular carcinoma and other liver lesions, especially from a lung primary. we report a case of ruptured liver metastasis from an adenocarcinoma of the lung mimicking ruptured liver abscess, challenging the clinical diagnosis. a 42-year-female patient presented to a tertiary care institute in 2020 with complaints of abdominal pain, breathlessness and fever. on examination, the patient was tachypnoeic with a right hypochondriac mass. a contrast-enhanced computed tomography of abdomen and thorax revealed an ill-defined heterogeneously enhancing lesion in the liver with a communicating subcapsular collection and hypo-enhancing lesions in the left lobe and heterogeneously enhancing lesion in the left lung. adenocarcinoma of the lung with hepatic metastasis was confirmed with a core needle biopsy. the patient was managed conservatively with intravenous antibiotics, intercostal drainage tube and gefitinib. however, despite best efforts, the patient succumbed to the disease. keywords: metastasis; spontaneous rupture; hepatocellular carcinoma; thyroid transcription factor; liver abscess; case report; india. https://creativecommons.org/licenses/by-nd/4.0/ the diagnostic dilemma of ruptured liver metastasis in a patient with lung cancer a case report 422 | squ medical journal, august 2022, volume 22, issue 3 revealed an ill-defined heterogeneously enhancing lesion in the liver with a communicating subcapsular collection and hypo enhancing lesions in the left lobe and heterogeneously enhancing lesion in the left lung [figures 1a and b]. the portal vein thrombosis was managed with intravenous heparin as it was an acute thrombosis (<60 days) and thought to be of infective pathology [figures 2a and b]. ultrasound-guided aspiration from the subcapsular collection revealed no organism on culture and a fine needle aspiration cytology was carried out from the liver lesion which was nondiagnostic. pleural fluid aspiration was done twice as a therapeutic procedure and yielded brownish fluid suggestive of sterile necrosis. the aspirate was tested for malignant cytology, but was negative both times [table 1]. the effusion was attributed to reactive fluid collection secondary to the large liver lesion, as is well documented in large liver lesions of malignant as well as infective pathologies. with cect revealing a heterogenous ill-defined lesion in the lower lobe of the left lung, a usg-guided core needle biopsy from the lung and liver lesion was carried out which revealed features of adenocarcinoma of the lung with hepatic metastasis [figure 3]. the patient was managed conservatively with intravenous empirical antibiotics in view of persistent febrile spikes and leukocytosis. she was transferred to the intensive care unit for monitoring and management in view of respiratory distress and desaturation. an intercostal drainage tube was placed in view of the deterioration of tachypnoea, as a palliative procedure for the massive pleural effusion which rapidly reaccumulated despite multiple therapeutic aspirations. the biopsy samples of the lung and liver were sent for assessing epidermal growth factor receptor (egfr) status and egfr mutation was found. the patient was started on an oral tyrosine kinase inhibitor, gefitinib. however, the patient’s tachypnoea continued to worsen and despite best efforts, there was no response to the treatment and the patient succumbed to the disease. the cause of death was reported as severe respiratory failure and acidosis due to intractable pleural effusion and septicaemia secondary to disseminated lung adenocarcinoma with a ruptured liver metastatic lesion. appropriate consent has been obtained from the patient and the attenders for publication of this case. figure 1: contrast enhanced computed tomography (cect) of the abdomen and the thorax. a: coronal section of cect abdomen and thorax showing heterogenous hypodense lesion in the right lobe of liver (yellow arrow), possible site of subcapsular rupture (red arrowhead), massive pleural effusion (white arrowhead), inferior vena cava (ivc) compression with hepatic vein thrombosis (blue arrowhead). b: axial section of cect abdomen and thorax showing left lower lobe lung heterogenous ill-defined lesion (yellow arrow) and heterogenous hypodense lesion in right lobe of liver with multiple satellite lesions (red arrow). figure 2: contrast enhanced computed tomography (cect) of the abdomen and the thorax. a: axial section of portal phase cect of the abdomen and pelvis showing hypodense filling defect in the right branch of the portal vein (arrow). normally enhancing left branch of the portal vein is seen. b: coronal reformation of the venous phase of cect abdomen and pelvis revealing a hypodense filling defect in the supra-hepatic segment of the inferior vena cava suggestive of thrombus (arrowhead). k.s. jayanth, shivakumar madan, balakrishnan gurushankari, sathasivam sureshkumar, amaranathan anandhi, rajesh n.g. and vikram kate case report | 423 discussion we report a case of carcinoma of the lung with ruptured liver metastasis which led to a diagnostic dilemma due to a dubious presentation mimicking a liver abscess. although carcinoma of the lung is frequently accompanied by liver metastasis, the incidence of rupture is scarce.7 the mechanism of spontaneous rupture of hepatic metastasis is not clear but there are several factors reported in the literature such as tumour necrosis, vascularity, location (subcapsular) and impaired coagulation.7,8 in the present case, the probable cause of rupture may be the subcapsular location and necrotic hepatic metastasis which may be due to the presence of portal vein thrombosis. the commonly observed symptoms in patients with ruptured liver metastasis are nonspecific abdominal pain, discomfort followed by haemodynamic instabilities, fever in case of infected collection or as a part of the systemic inflammatory response (sirs), acute liver failure and multi-organ dysfunction syndrome.8 in the present case, the patient presented with fever, non-specific abdominal pain, sirs (heart rate >90 beats/min and respiratory rate >20/min) and a soft and tender mass in the right hypochondrium. abdominal usg is the initial investigation carried out followed by cect which is ideal in differentiating hcc, liver metastasis and liver abscess. but it has its limitation in hypervascular metastasis. peripheral location, discontinuity of the hepatic surface with surrounding haemoperitoneum are the characteristic ct findings in a ruptured hcc, which can be extrapolated to liver metastasis as well.4 similarly, in the present case ct revealed multiple liver lesions with subcapsular collection from primary in the lung. the left lower lobe pulmonary lesion visualised on ct was not characteristic of lung carcinoma but was later proven by pathological examination to be the primary. the patient gave a history of firewood usage for cooking purposes. indoor air pollution with medium particulate matter especially due to usage of biomass fuel has been noted to be an independent risk factor for lung adenocarcinoma in non-smokers.9,10 portal vein thrombosis is infrequently associated with hcc and can be due to tumour extension or due to benign thrombosis in cirrhosis or prothrombotic states. it causes liver hypovascularity and may induce necrosis in the tumour. piscaglia et al. reported that portal vein thrombosis in a patient with known hepatic malignancy should be appropriately investigated for benign versus malignant cause for thrombosis.11 patients with benign thrombus can be considered table 1: description of the radiological and histological characteristics of the current case radiological and histological investigations findings chest radiograph bilateral moderate pleural effusion (right more than left). ultrasound abdomen an ill-defined heterogenous predominantly hypoechoic collection in the right lobe of the liver with no internal vascularity and a large subcapsular collection around segments 7 and 8, possibly suggestive of a ruptured pyogenic abscess or hepatocellular carcinoma. portal vein showed an echogenic filling defect in the main branch extending into the proximal right and left branches suggestive of portal venous thrombosis. contrast enhanced computed tomography abdomen and thorax an 8.5 × 7.5 × 6.5 cm ill-defined heterogeneously enhancing lesion with fluid attenuating areas and hypo enhancing areas in segments 7 and 8 of the liver with hyperdense contents within. this lesion was communicating with a subcapsular collection with a thickness of 2.7 cm, overlying the segments 6 and 7, suggesting a subcapsular rupture. multiple, clustered, ill-defined and a few discrete heterogeneously hypo-enhancing lesions were noted surrounding the above lesion and two similar hypo enhancing lesions were noted in the left lobe of the liver, around 2 × 2 cm. no significant washout of contrast was noted on venous or delayed phases. portal and hepatic venous thrombosis was noted, but there was no evidence of direct extension of the lesion into the veins, suggesting a benign thrombosis. right massive pleural effusion with collapse of right middle and lower lobes was noted, but there was no direct extension of tumour into the pleural cavity; left moderate pleural effusion was also noted. a clustered heterogeneously hypoenhancing lesion with lobulated margin measuring 3.6 × 5 × 3 cm was noted in the anterior and lateral basal segments of lower lobe of the left lung, which was possibly infective and was suggested for biopsy correlation. a suspicion of infective or malignant pathology was considered. core-needle biopsy from the lung lesion features of adenocarcinoma of the lung with focal areas of bronchoalveolar pattern of spread and occasional foci of necrosis with tumour cells staining positive for egfr. core-needle biopsy from the liver lesion a malignant, possibly metastatic tumour focally infiltrating the hepatic parenchyma displaying abundant cytoplasm, pleomorphic nuclei and brisk mitotic activity. immunohistochemistry showed positive ck-7 and ttf-1 suggesting the lesion to be metastases from a primary in the lung. ck-20, estrogen receptor and glypican 3 were found to be negative. cytology from the pleural fluid negative for malignancy. egfr = epidermal growth factor receptor; ck = cytokeratin; ttf = thyroid transcription factor. the diagnostic dilemma of ruptured liver metastasis in a patient with lung cancer a case report 424 | squ medical journal, august 2022, volume 22, issue 3 for hepatic transplant whereas malignant thrombosis is a contraindication. hepatic venous thrombosis leading to budd-chiari syndrome is most commonly caused by hypercoagulable states and can lead to acute hepatic necrosis and failure. it is very rarely seen due to neoplasms of the liver and can be a poor prognosis for the patient. in the current case, the metastatic liver lesion had concomitant portal venous and hepatic venous thrombosis which is an extremely rare occurrence and may have contributed to the significant areas of necrosis and possibly the rupture.12,13 diagnosis of non-small cell lung carcinoma is based on histopathology with immunohistochemical markers. treatment of spontaneous rupture of hepatic metastasis depends on the tumour as well as patient factors such as the tumour size, location, severity of bleeding, active bleeding and haemodynamic stability of the patient.3,14 there are various treatment modalities available for ruptured liver metastasis ranging from conservative to surgical resection. a staged approach was advocated in a recent report where the active bleeding is managed by less invasive trans-arterial angioembolisation (tae), hepatic wedge resection, lobectomy or suture ligation of the bleeder followed by hepatic resection.14 conservative management of ruptured liver metastasis focuses on correcting coagulopathy, close-monitoring and stabilisation of the patient followed by imaging to confirm haemostasis. there are conflicting studies regarding the conservative management in the literature. a retrospective study from taiwan reported a higher survival rate at 30 days in patients undergoing immediate hepatectomy or a two-staged procedure (tae followed by hepatectomy) compared to conservative management.15 on the contrary, a retrospective study on patients with ruptured hcc and a case report on ruptured liver metastasis in a pancreatic adenocarcinoma were managed successfully with conservative management.14,16 similarly, in the present case, the patient was managed conservatively but had a poor outcome. although several treatment options are available in the management of ruptured liver metastasis, the prognosis seems to be poorer in these cases. ruptured liver metastasis is detrimental in a patient with lung cancer; therefore, early diagnosis with a risk assessment for rupture, close monitoring for high-risk candidates with a selective intervention based on tumour biology and patient factors are the key components for the management of these cases. conclusion spontaneous rupture of the liver metastasis is rare, even rarer in a case of adenocarcinoma of the lung. close monitoring by risk assessment, especially in subcapsular liver secondaries is warranted for early diagnosis and prompt management in case of rupture. more studies are required to find a suitable treatment in such cases. the physician has to decide between a two-staged approach or conservative management based on the patient’s haemodynamic stability, tumour characteristics and availability of resources. this report emphasises the importance of the knowledge of rare possible complications of this common condition in order to avoid a diagnostic dilemma. figure 3: histopathology of lung and liver lesion. a: haematoxylin and eosin stain (h&e) at ×40 magnification showing a core of lung parenchyma with tumor cells in the lower part of the core arising from the alveolar wall forming a bronchioloalveolar pattern and infiltrating the lung parenchyma. b: h&e stain at ×200 magnification showing lung parenchyma infiltrated by tumor cells arising in glandular pattern exhibiting moderate nuclear atypia and pleomorphism. c: diaminobenzidine with haematoxylin counterstain at ×400 magnification showing liver parenchyma infiltrated by metastatic deposits of adenocarcinoma from lung, highlighted by thyroid transcription factor–1 (immunohistochemistry with dako monoclonal antibody, usa). k.s. jayanth, shivakumar madan, balakrishnan gurushankari, sathasivam sureshkumar, amaranathan anandhi, rajesh n.g. and vikram kate case report | 425 a u t h o r c o n t r i b u t i o n s vk conceptualised the work. sm, bg and ksj conducted the literature review. sm, bg, rng and ksj collected and processed the data. bg, ss, aa rng and ksj contributed to data analysis and interpretation. sm, bg and ksj drafted the manuscript. vk, ss, aa and rng supervised the work and critically reviewed the manuscript. all authors approved the final version of the manuscript. references 1. riihimäki m, hemminki a, fallah m, thomsen h, sundquist k, sundquist j, et al. metastatic sites and survival in lung cancer. lung cancer 2014; 86:78–84. https://doi.org/10.1016/j.lung can.2014.07.020. 2. morgensztern d, ng sh, gao f, govindan r. trends in stage distribution for patients with non-small cell lung cancer: a national cancer database survey. j thorac oncol 2010; 5:29–33. https://doi.org/10.1097/jto.0b013e3181c5920c. 3. gulati a, vyas s, lal a, harsha s, gupta v, nijhawan r, et al. spontaneous rupture of hepatic metastasis from choriocarcinoma: a review of imaging and management. ann hepatol 2009; 8:384–7. 4. choi bg, park sh, byun jy, jung se, choi kh, han j-y. the findings of ruptured hepatocellular carcinoma on helical ct. br j radiol 2001; 74:142–6. https://doi.org/10.1259/ bjr.74.878.740142. 5. chen z-y. etiology and management of hemmorrhage in spontaneous liver rupture: a report of 70 cases. world j gastroenterol 2002; 8:1063–6. https://doi.org/10.3748/wjg. v8.i6.1063. 6. rajala k, lehto jt, sutinen e, kautiainen h, myllärniemi m, saarto t. mmrc dyspnoea scale indicates impaired quality of life and increased pain in patients with idiopathic pulmonary fibrosis. erj open res 2017; 3:00084-2017. https://doi. org/10.1183/23120541.00084-2017. 7. mochimaru t, minematsu n, ohsawa k, tomomatsu k, miura h, betsuyaku t, et al. hemoperitoneum secondary to rupture of a hepatic metastasis from small cell lung cancer during chemotherapy: a case with a literature review. intern med 2017; 56:695–9. https://doi.org/10.2169/internalmedicine.56.6828. 8. goto y, tobino k, yoshimine k, sueyasu t, okahisa m, sakabe m, et al. an autopsy case of ruptured liver metastases from small cell lung cancer: a case report and literature review. respir med case rep 2020; 30:101039. https://doi. org/10.1016/j.rmcr.2020.101039. 9. mu l, liu l, niu r, zhao b, shi j, li y, et al. indoor air pollution and risk of lung cancer among chinese female non-smokers. cancer causes control 2013; 24:439–50. https://doi.org/ 10.1007/s10552-012-0130-8. 10. behera d, balamugesh t. indoor air pollution as a risk factor for lung cancer in women. j assoc physicians india 2005; 53:190–2. 11. piscaglia f, gianstefani a, ravaioli m, golfieri r, cappelli a, giampalma e, et al. criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation. liver transplantation 2010; 16:658–67. https://doi.org/10.1002/lt.22044. 12. goto y, uchino y, sasaki s, shirahama n, nomura y, akiba j, et al. complete spontaneous necrosis of hepatocellular carcinoma accompanied by portal vein tumor thrombosis: a case report. int j surg case rep 2018; 44:220–5. https://doi.org/10.1016/j. ijscr.2018.02.045. 13. sabol tp, molina m, wu gy. thrombotic venous diseases of the liver. j clin transl hepatol 2015; 3:189–94. https://doi.org/ 10.14218/jcth.2015.00014. 14. rahul a, robin f, adarsh h. spontaneous rupture of hepatic metastasis from pancreatic adenocarcinoma. case rep oncol med 2016; 2016:6968534. https://doi.org/10.1155/2016/6968534. 15. hsueh kc, fan hl, chen tw, chan dc, yu jc, tsou ss, et al. management of spontaneously ruptured hepatocellular carc inoma and hemoperitoneum manifested as acute abdomen in the emergency room. world j surg 2012; 36:2670–6. https:// doi.org/10.1007/s00268-012-1734-6. 16. leung kl, lau wy, lai pb, yiu ry, meng wc, leow ck. spontaneous rupture of hepatocellular carcinoma: conservative management and selective intervention. arch surg 1999; 134:1103–7. https://doi.org/10.1001/archsurg.134.10.1103. https://doi.org/10.1016/j.lungcan.2014.07.020 https://doi.org/10.1016/j.lungcan.2014.07.020 https://doi.org/10.1097/jto.0b013e3181c5920c https://doi.org/10.1259/bjr.74.878.740142 https://doi.org/10.1259/bjr.74.878.740142 https://doi.org/10.3748/wjg.v8.i6.1063 https://doi.org/10.3748/wjg.v8.i6.1063 https://doi.org/10.1183/23120541.00084-2017 https://doi.org/10.1183/23120541.00084-2017 https://doi.org/10.2169/internalmedicine.56.6828 https://doi.org/10.1016/j.rmcr.2020.101039 https://doi.org/10.1016/j.rmcr.2020.101039 https://doi.org/ 10.1007/s10552-012-0130-8 https://doi.org/ 10.1007/s10552-012-0130-8 https://doi.org/10.1002/lt.22044 https://doi.org/10.1016/j.ijscr.2018.02.045. https://doi.org/10.1016/j.ijscr.2018.02.045. https://doi.org/ 10.14218/jcth.2015.00014 https://doi.org/ 10.14218/jcth.2015.00014 https://doi.org/10.1155/2016/6968534 https://doi.org/10.1007/s00268-012-1734-6 https://doi.org/10.1007/s00268-012-1734-6 https://doi.org/10.1001/archsurg.134.10.1103 the covid-19 pandemic, defined as a public health emergency of international concern by the world health organisation (who) on 30 january 2020, has forced governments to take several public health mitigation measures including social and physical distancing, mask-wearing and hand hygiene.1 such public health measures might become barriers to physical activity with major consequences on lifestyle during the covid-19 pandemic.2,3 physical activity is defined as any movement of the body, involving skeletal muscles and consuming energy.4 based on the who recommendations, 150 minutes of moderate-intensity physical activity or 75 minutes of high-intensity physical activity is mandated for individuals to achieve health benefits.5 physical activity and participation in sports have been shown to have protective effects against covid-19.6–8 additionally, physical activity is also a leading protective factor for chronic diseases that increase the severity and mortality rate of covid-19.2 as of january 2021, covid-19 has caused approximately 2 million deaths worldwide.9 however, noteworthy is the fact that physical inactivity leads to 3.6 million deaths worldwide annually.10 during the covid-19 pandemic, the level of physical activity has been shown to have decreased.11,12 based on the socio-ecological model, individual, interpersonal and environmental factors and governmental, community and organisational policies appear to have impact on physical activity.13 challenges at the individual and interpersonal levels in engaging in physical activity consist of a variety of domains. outlining the benefits of exercise, including positive effects on the immune system, might motivate more people to exercise regularly.14,15 existing evidence indicates that moderate level of physical activity improves the immune system and reduces the risk of respiratory tract infection.16 challenges at the environmental level consist of maintaining social distancing, sports clubs closure, cancelling and postponing matches.17,18 public exercise facilities are locked down and limited opportunities for exercise are available.2 home-based exercises, engaging in physical activity in a less crowded environment, considering the safe distance, and disinfecting probably contaminated surfaces (including sports equipment) could be a solution to this issue.19 public space innov ations might be considered as a motivation for engaging in physical activity.5,20 challenges at the governmental, community and organisational levels consist of current governmental policies related to quarantine and isolation during the covid-19 pandemic which prohibit individuals from any outdoor activities (united kingdom, italy, spain, etc.).12,19,21,22 current covid-19 related policies might affect the level of physical activity. as an example, following the nation-wide lockdown, italy showed a 48.7% decrease in the regional daily step count while in sweden, which mainly issued gathering limitations and social distancing advice, a 6.9% decrease was reported.12 as another example, physical inactivity increased in spain following covid-19 quarantine.22 other critical considerations at the governmental level include the need for investments and addressing the inconsistencies in policies.5 physical activity action plan during covid-19 pandemic according to a who report titled “global action plan on physical activity (gappa) 2018–2030, more active people for a healthier world”, gappa-systembased approaches are mandated to increase physical activity.5 four main objectives should be targeted in the physical activity action plan including creating active society, active people, active environments and active systems. however, it is recommended that the four main objectives of gappa be modified according to the current covid-19. the recommendations based on the aforementioned four objectives will be discussed below in tandem. creating active society is related to improving knowledge about the benefits of physical activity taking community standards, culture and beliefs into consideration.5 providing information via social media about the benefits of physical activity on the prevention of covid-19 is an applicable strategy.23 1sports medicine research center, neuroscience institute, tehran university of medical sciences, tehran, iran; 2school of nursing and midwifery, tehran university of medical sciences, tehran, iran; 3department of sports and exercise medicine, school of medicine, tehran university of medical sciences, tehran, iran *corresponding author’s e-mail: selk1360@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. action plan to increase physical activity during the covid-19 pandemic amir-hossein memari,1 *maryam selk-ghaffari,1 afifeh khosravi,1,2 ramin kordi1,3 editorial sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 514–516, epub. 25 nov 21 submitted 14 oct 20 revision req. 4 jan 21; revision recd. 11 jan 21 accepted 20 jan 20 https://doi.org/10.18295/squmj.4.2021.053 amir-hossein memari, maryam selk-ghaffari, afifeh khosravi and ramin kordi editorial | 515 during the covid-19 pandemic, the following policybased actions are recommended to increase physical activity with the objective of creating active people in the society through the intervention of physical activity stakeholders: (1) implementing applicable social campaigns to increase knowledge regarding the protective effects of physical activity against viral tract infections (covid-19) and keeping active during the pandemic; (2) implementing communitybased initiatives in virtual public spaces that introduce and educate individuals on home-based exercise programmes suited to a variety of age groups with any level of ability (these programmes would ideally require a low budget, minimal equipment and be adaptable to the local culture); and (3) developing and conducting training courses for coaches and exercise experts to enhance their skills and utilisation of information in creating physical activity opportunities considering the social distancing and protection roles.19,24 creating active environments, spaces and places is the second objective of gappa.5 creating an active environment is related to providing appropriate, accessible and safe spaces for individuals of all ages with any level of ability to engage in physical activity. although data available to make a recommendation in this domain are limited, existing evidence has showed that access to green and public spaces might increase the level of physical activity.20 during the covid-19 pandemic, the following policy actions are recommended to increase physical activity with the objective of creating active environments: improving the infrastructure of walking and cycling networks considering the principles of social distancing by widening the sidewalks and dedicating specific cycling routes on roads through the intervention of governments and municipalities.25 creating active people is the third objective of gappa.5 this objective is related to providing and improving the availability of exercise and physical activity programmes and opportunities to support individuals of any age and ability to engage in physical activity.5 the following recommendations have been proposed for physical activity experts, physicians and stakeholders: (1) developing guidelines for home-based exercises through the intervention of physical activity experts.; (2) developing guidelines for professional athletes including cardiorespiratory considerations, necessary assessments and sanitary protocols before and during matches for safe return to the sport through the intervention of sport federations; (3) reinforcing the development and implementation of high-quality, virtual physical education and schoolbased physical activity programmes for children and adolescents through the intervention of physical activity stakeholders; and (4) applying and improving virtual patient evaluation and management systems in patients recovering from covid-19 to improve physical activity and conduct pulmonary rehabilitation via physicians.19,26–28 creating active systems, governance, and policies is the fourth objective of gappa. creating active systems is related to develop and reinforce leadership, management, the co-operation of physical activity-related sectors, physical activity workforce skills, advocacy, and surveillance data systems to increase physical activity.2,5 resource mobilisation and improving coordination via governments are mandated in the success of the physical activity action plan.5 governmental intervention in improving data and surveillance systems to determine the physical activity level and barriers among patients and healthy individuals during the covid-19 pandemic is required.2 the level of physical inactivity is increasing worldwide as a consequence of the covid-19 pandemic and urgent actions are required to take place through collaborations with and/or interventions by governments, physical activity stakeholders and experts.5 highlighting the impact of physical activity in reducing the severity and mortality of covid-19 might be beneficial.6–8 based on the socio-ecological model to reduce physical inactivity, the development of a set of ‘physical activity during covid-19 guidelines’ via expert intervention, guidelines for safe return to sports for athletes via sports federations, school-based virtual physical activity interventions via stakeholders and exercise-based rehabilitation following covid-19 via physicians are mandated.5 governmental cooperation is required to implement such action plans during covid-19 considering the covid-19 preventive principles.2 international reinforcements (such as those provided by the who) might be beneficial in the success of the programme during the covid-19 pandemic. a u t h o r s’ c o n t r i b u t i o n a-hm and ms-g contributed to developing the concept and design of the work. ak conducted the literature assessment and information extraction. ms-g drafted the manuscript. a-hm and rk revised the original manuscript. all authors conducted the critical review of the final draft and approved final version of the manuscript. action plan to increase physical activity during the covid-19 pandemic 516 | squ medical journal, november 2021, volume 21, issue 4 references 1. sohrabi c, alsafi z, o’neill n, khan m, kerwan a, al-jabir a, et al. world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19). int j surg 2020; 76:71–6. https://doi.org/10.1016/j.ijsu.2020.02.034. 2. sallis jf, adlakha d, oyeyemi a, salvo d. an international physical activity and public health research agenda to inform covid-19 policies and practices. j sport health sci 2020; 9:328–34. https://doi.org/10.1016/j.jshs.2020.05.005. 3. mattioli av, puviani mb, nasi m, farinetti a. covid-19 pandemic: the effects of quarantine on cardiovascular risk. eur j clin nutr 2020; 74:852–5. https://doi.org/10.1038/s41430020-0646-z. 4. caspersen cj, powell ke, christenson gm. physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. public health rep 1985; 100:126–31. 5. world health organization. global action plan on physical activity 2018-2030: more active people for a healthier world. geneva: world health organization; 2018. who/nmh/ pnd/18.5. pp. 1–104. 6. hamer m, kivimäki m, gale cr, batty gd. lifestyle risk factors, inflammatory mechanisms, and covid-19 hospitalization: a community-based cohort study of 387,109 adults in uk. brain behav immun 2020; 87:184–7. https://doi.org/10.1016/j. bbi.2020.05.059. 7. halabchi f, mazaheri r, sabeti k, yunesian m, alizadeh z, ahmadinejad z, et al. regular sports participation as a potential predictor of better clinical outcome in adult patients with covid-19: a large cross-sectional study. j phys act health 2020; 18:8–12. https://doi.org/10.1123/jpah.2020-0392. 8. mohamed a, alawna m. role of increasing the aerobic capacity on improving the function of immune and respiratory systems in patients with coronavirus (covid-19): a review. diabetes metab syndr 2020; 14:489–96. https://doi.org/10.1016/j. dsx.2020.04.038. 9. dong e, du h, gardner l. an interactive web-based dashboard to track covid-19 in real time. lancet infect dis 2020; 20:533–4. https://doi.org/10.1016/s1473-3099(20)30120-1. 10. rosenbaum s, ward pb. the simple physical activity quest ionnaire. lancet psychiatry 2016; 3:e1. https://doi.org/10.1016/ s2215-0366(15)00496-4. 11. martinez ez, silva fm, morigi tz, zucoloto ml, silva tl, joaquim ag, et al. physical activity in periods of social distancing due to covid-19: a cross-sectional survey. cien saude colet 2020; 25:4157–68. https://doi.org/10.1590/1413812320202510.2.27242020. 12. tison gh, avram r, kuhar p, abreau s, marcus gm, pletcher mj, et al. worldwide effect of covid-19 on physical activity: a descriptive study. ann intern med 2020; 173:767–70. https:// doi.org/10.7326/m20-2665. 13. pratt m, perez lg, goenka s, brownson rc, bauman a, sarmiento ol, et al. can population levels of physical activity be increased? global evidence and experience. prog cardiovasc dis 2015; 57:356–67. https://doi.org/10.1016/j. pcad.2014.09.002. 14. mabry r, koohsari mj, bull f, owen n. a systematic review of physical activity and sedentary behaviour research in the oil-prod ucing countries of the arabian peninsula. bmc public health 2016; 16:1003. https://doi.org/10.1186/s12889-016-3642-4. 15. midhet fm, sharaf fk. impact of health education on lifestyles in central saudi arabia. saudi med j 2011; 32:71–6. 16. halabchi f, ahmadinejad z, selk-ghaffari m. covid-19 epidemic: exercise or not to exercise; that is the question. asian j sports med 2020; 11:e102630. https://doi.org/10.5812/asjsm.102630. 17. wong ay-y, ling sk-k, louie lh-t, law gy-k, so rc-h, lee dc-w, et al. impact of the covid-19 pandemic on sports and exercise. asia pac j sports med arthrosc rehabil technol 2020; 22:39–44. https://doi.org/10.1016/j.asmart.2020.07.006. 18. hassanzadeh-rad a, halabchi f. stadiums as possible hot spots for covid-19 spread. asian j sports med 2020; 11:e103178. https://doi.org/10.5812/asjsm.103178. 19. dwyer mj, pasini m, de dominicis s, righi e. physical activity: benefits and challenges during the covid-19 pandemic. scand j med sci sports 2020; 30:1291–4. https://doi.org/10.1111/sms.13710. 20. mitra r, moore sa, gillespie m, faulkner g, vanderloo lm, chulak-bozzer t, et al. healthy movement behaviours in children and youth during the covid-19 pandemic: exploring the role of the neighbourhood environment. health place. 2020; 65:102418. https://doi.org/10.1016/j.healthplace.2020.102418. 21. stephen s, issac a, jacob j, vijay v, radhakrishnan rv, krishnan n. covid-19: weighing the endeavors of nations, with time to event analysis. osong public health res perspect 2020; 11:149–57. https://doi.org/10.24171/j.phrp.2020.11.4.02. 22. lópez-bueno r, calatayud j, andersen ll, balsalobre-fernández c, casaña j, casajús ja, et al. immediate impact of the covid-19 confinement on physical activity levels in spanish adults. sustain ability 2020; 12:5708. https://doi.org/10.3390/su12145708. 23. hayes m. social media and inspiring physical activity during covid-19 and beyond. manag sport leis 2020; 1–8. https:// doi.org/10.1080/23750472.2020.1794939. 24. son js, nimrod g, west st, janke mc, liechty t, naar jj. promoting older adults’ physical activity and social wellbeing during covid-19. leis sci 2020; 43:287–94. https://doi. org/10.1080/01490400.2020.1774015. 25. lai ky, webster c, kumari s, sarkar c. the nature of cities and the covid-19 pandemic. curr opin environ sustain 2020; 46:27–31. https://doi.org/10.1016/j.cosust.2020.08.008. 26. dominski fh, brandt r. do the benefits of exercise in indoor and outdoor environments during the covid-19 pandemic outweigh the risks of infection? sport sci health 2020; 16:583–8. https://doi.org/10.1007/s11332-020-00673-z. 27. löllgen h, bachl n, papadopoulou t, shafik a, holloway g, vonbank k, et al. recommendations for return to sport during the sars-cov-2 pandemic. bmj open sport exerc med 2020; 6:e000858. https://doi.org/10.1136/bmjsem-2020-000858. 28. wang tj, chau b, lui m, lam g-t, lin n, humbert s. physical medicine and rehabilitation and pulmonary rehabilitation for covid-19. am j phys med rehabil 2020; 99:769–74. https:// doi.org/10.1097/phm.0000000000001505. squ med j, may 2011, vol. 11, iss. 2, pp. 207-213, epub. 15th may 11 submitted 3rd nov 10 revision req. 20th dec 10, revision recd. 3rd jan 11 accepted 8th feb 11 1department of family medicine & public health, sultan qaboos university, muscat, oman; 2residents in family medicine, oman medical specialty board, oman; 3nursing department, outpatients clinic, sultan qaboos university hospital, muscat, oman. *corresponding author email: mhalazri@squ.edu.om <óïüπ<<ì⁄çœπ]<ìë^¬ü÷]<<ïåáq<ó◊¬<ümˆi<:÷]<ÿ⁄]á√÷] ·^€ �¬<ª<ìè÷ê˘]<ìèví÷]<ìë^¬ü÷]<ÿ^•<ª<îü”ä÷] óïüπ]<üøfi<<ì„qê<‡¬<ìè¬áfi<ìâ]öå       2 19             :مفتاح الكلمات abstract: objectives: the quality of services delivered to type 2 diabetic patients in primary health care has an important impact on long-term outcomes. the aim of this study is to explore diabetic patients’ views of factors affecting quality of diabetic services delivered in primary care in oman, a developing country with a high burden of diabetes. methods: semi-structured face to face interviews were conducted with 19 type 2 diabetic patients recruited from four selected primary healthcare centres (phcs) in muscat region, the capital city of oman. a framework approach was used to analyse the qualitative data. results: participants identified several factors which could affect the quality of diabetic services provided in phcs: delays in the follow-up process; lack of continuity of care; diabetes educational materials unavailable in waiting areas; shortage of omani nurses able to speak the patients’ language; inadequate explanations from the attending primary care physician (pcp); under involvement of dieticians in patient management; delays in provision of laboratory results; inadequate supplies of diabetic medication between appointments, and long waits to see ophthalmologists. conclusion: several factors were identified by diabetic patients that may influence the quality of diabetic services provided in the phc setting in oman. health care professionals and decision makers in the ministry of health (moh) and other health care sectors in oman should consider patients’ views and concerns in order to improve the quality of diabetic care services in primary health care. keywords: quality; interviews; type 2 diabetes; primary care; oman factors affecting the quality of diabetic care in primary care settings in oman a qualitative study on patients’ perspectives *mohammed al-azri,1 hilal al-azri,2 fatma al-hashmi,2 samira al-rasbi,3 kawther el-shafie,1 abdullah al-maniri1 clinical & basic research factors affecting the quality of diabetic care in primary care settings in oman a qualitative study on patients’ perspective 208 | squ medical journal, may 2011, volume 11, issue 2 advances in knowledge 1. the quality of services provided to patients with type 2 diabetes in the primary care setting could affect the outcomes of care including long term diabetic complications. 2. patients’ views of the quality of diabetic services provided in primary care settings in developing counties, including oman, remained a relatively unexplored research topic. application to patient care 1. patients with type 2 diabetes identified several factors which could affect the quality of diabetic services provided in primary care settings in oman, including : delays in the follow-up process, in provision of laboratory results, and in seeing ophthalmologists; lack of continuity of care; inadequacies in physician explanations and dieticians’ involvement; undersupply of educational materials and diabetic medication, and shortage of omani nurses able to speak the patients’ language. 2. health care professionals and policy makers in oman should consider patients’ views if they want to improve diabetic services and reduce long term diabetes related complications. diabetes has been considered as the greatest challenge in primary care1 and primary care physicians (pcps) play a major role in the care of diabetic patients.2 evidence showed that good diabetic control reduces the risk of cardiovascular and micro-vascular complications;3 hence, the quality of care delivered to type 2 diabetic patients has an impact on the long term outcomes.4 nonetheless, the quality of care provided to diabetic patients in primary care in some developing countries appears to be suboptimal.3 oman, a high income country with a total population of 3.2 million (2.0 million omanis and 1.2 expatriates),5 has experienced substantial socioeconomic development. this development has been accompanied by remarkable changes in lifestyle towards a “westernised pattern”; this is reflected in changes in nutrition, less physical activity and thus an increased burden of diabetes, obesity, hypertension and hyperlipidemia.6 currently, oman is among the top ten countries worldwide in terms of high prevalence of diabetes.7 in a study published in 2006, the prevalence of diabetes (fasting blood glucose ≥ 7 mmol/l) in muscat, the capital city of oman, was 17.7% and in rural areas was 10.5%. furthermore, the estimated death rate from diabetes in the year 2002 in oman was 16.8 per 100,000 population.8 despite the immense advances that have been made in the management and treatment of diabetes in recent years, many patients do not achieve optimal outcomes and continue to experience devastating complications that result in decreased length as well as quality of life. a cross-sectional observational study conducted in 2009 at six general health centres in muscat showed that more than 70% of omanis with type 2 diabetes obtained all their diabetic care service requirements at every visit; however, only 2.4 % of them achieved the indicators of good outcomes of diabetic care.9 patients with type 2 diabetes often feel challenged by their disease and multiple personal, psychosocial factors influence their daily decisions which in turn could affect their diabetic metabolic state, longterm glycaemic control, and risk of developing long-term complications.10 in addition, there are other factors at multiple levels that impede health care systems’ ability to deliver high-quality diabetic services including provider-oriented factors (e.g. lack of knowledge about guidelines, lack of time with patients), and system-oriented factors (e.g. lack of specialty care services, lack of interdisciplinary team approaches, long patient waiting times for services).11 furthermore, some health care providers tend to view their own management strategy as scientifically legitimate and have focused on managing numbers rather than attempting to understand the patient’s concept of their disease and their treatment goals. this could lead to frustration, unsatisfactory outcomes and serious obstacles in achieving the optimum outcomes.12 patient's views on the quality of primary health care are vital for better health care delivery. the aim of this study was, therefore, to explore diabetic patients’ views of factors affecting the quality of diabetic services delivered in primary care in oman, a developing country with high burden of diabetes. methods the study was carried out in four public primary care health centres (pchcs) in the governorate of muscat, the political and the economic hub of oman. pchcs in muscat have specific days (1–2 per week) when they provide free diabetic care mohammed al-azri, hilal al-azri, fatma al-hashmi, samira al-rasbi, kawther el-shafie and abdullah al-maniri clinical and basic research | 209 services for patients with type 2 diabetes through special diabetic clinics. usually, diabetic patients would have a regular follow-up every month or sometimes every two or three months depending on the progression of the disease and on outcomes. patients are seen first by a diabetic nurse who checks their blood pressure, fasting blood sugar, weight, height and body mass index (bmi). patients are then be seen by pcps who might use specific guidelines in the management of diabetes.13 moreover, a dietician visits the health centre twice a week to offer advice on lifestyle modifications for referred patients. in this study, a qualitative research approach was selected to collect data from patients. qualitative enquiry helps in exploring areas where there is likely to be complexity and diversity of experiences and perspectives of patients with diabetes.14 therefore, we developed a topic guide for individual interviews using some of the available literature and our local experience.15,16 the topic guide was piloted in the first two interviews to assess the comprehensibility of the language, the relevance and logical progression of the questions. all the patients were selected based on convenient sampling. potential rich-informant patients were identified by their pcp and then invited by the research team to participate in the study. patients suffering from diabetes for less than two years were excluded from the study. the number of patients was based on the saturation of the data.17 a quiet consultation room in the pchc was selected for the interviews. the interviews were in arabic language and each interview lasted 30 to 45 minutes. the interview was carried out by two researchers with one of them questioning the participant and other was observing as well as helping with logistical issues such as recording and taking notes. all the interviews were recorded and transcribed verbatim. using the interview guide, participants were asked and probed about their experiences and views of different aspects of diabetic care services provided in the diabetic clinic at their pchc including: the effectiveness of appointment system; suitability of the waiting area; waiting time before consulting doctor; the role of nurses and doctors and nutritionists; the efficiency of laboratory test and pharmacy procedures, and the availability of diabetes health education. also, they were asked for their views on the services provided in the clinic including those of the laboratory, pharmacy and the dietician. the study was approved by the research and ethics committee (rec) of the ministry of health (moh). prior to each individual interview, written informed consent was obtained from participants who agreed to participate in the study. the study was conducted between march and june 2010. the framework approach, widely used for qualitative analysis, was employed to analyse data.18 as the framework highlights the associations between participants’ attitudes, perceptions and experiences, it fitted well with the aims of this study. data analysis was conducted by the research team; findings emerging from the analysis were regularly discussed and refined as part of an ongoing interactive process. the final analysis and findings were mutually agreed by the research team. the recruitment of participants continued until data saturation was achieved.17 significant findings from patients' quotes were translated to english and translated back into arabic by a blinded researcher. results nineteen patients, 11 males and eight females, were interviewed in the study. their age ranged from 21 to 67 years with an average of 41 years. ten patients were educated up to secondary level and the remaining had college and postgraduate education. ten patients had had type 2 diabetes for 2–4 years; seven for 5–9 years and three had had suffered from it for more than 10 years. two main themes emerged from the data analysis of the factors affecting quality of care from the patients’ perspective. the first was communication and continuity of care with health care professionals; the second was the timely provision and convenient location of certain services. t h e m e o n e: c o m m u n i c at i o n a n d c o n t i n u i t y o f c a r e w i t h h e a lt h c a r e p r o f e s s i o n a l s in many health centres, there are still expatriate nurses from india and south asia and they cannot communicate well with patients in their native arabic language. thus, some participants stated that they prefer the diabetic nurse to speak arabic so that their problems could be understood. “she factors affecting the quality of diabetic care in primary care settings in oman a qualitative study on patients’ perspective 210 | squ medical journal, may 2011, volume 11, issue 2 (the diabetic nurse) greets me and takes care of me, but i prefer an arabic speaking nurse, so i can understand her well” (patient 7). participants commented that there was lack of detail explanation about the importance of life style modification on their health when consulting their pcps. “the doctors advise me to exercise, but they do not tell me why it is important” (patient 3). other participants felt unhappy because the attending pcp did not explain the results of the previous investigations and the actions that they should consider; thus, they had to remind the pcp to give them the results at every visit. “doctors don’t tell me about my results unless i remind them… and they take no action” (patient 5). although participants appreciated the importance of seeing the dietician for the benefit of their health, some of them felt that pcps did not refer them as expected. “it is necessary to see the dietician at least twice a year … i need to know more about my diet but i did not get any referral…” (patient 1). participants highlighted the importance of continuity of care; they should be able to consult the same pcp when attending the clinic. most of them preferred to be seen by the same pcp at every visit so that their problems could be understood; they also highlighted their unwillingness to repeat the same story when consulting with a different pcp. “i prefer to see the same doctor on every visit, so we can understand each other well …. i do not like to repeat my history on every visit” (patient 6). t h e m e t w o: p r o v i s i o n o f s e r v i c e s at t h e r i g h t t i m e a n d p l a c e participants expressed their discomfort regarding the intervals between visits to the diabetic clinic. they felt that their regular visits should be every month or maximum every two months and should not to be delayed because of difficulty in obtaining an early appointment. “sometimes i need to take appointment within a month, but the nearest appointment is available only after 3 months” (patient 7). other participants expressed their concern regarding the long waiting time to see the pcp in the diabetic clinic in the day of their appointment. “sometimes, i go for my appointment on time, but, i have to wait for two hours until the doctor finishes with the patients who came before me … i feel tired and bored” (patient 9) participants were dissatisfied because of the difficulty in obtaining early appointments with the ophthalmologist in the hospital, which is part of the annual diabetic review. “i have not seen the eye doctor for last 5 years … i am not reminding the doctor because i do not like to go to the hospital …. i will only get an appointment after months” (patient 14). other participants commented that their medications finished before their next appointment. the regulations of the moh prevent the pcp from prescribing drugs for more than one month. this is not enough to cover the patients’ needs until next appointment in the diabetic clinic. “if my medicine finishes before my appointment, i have to see the walk-in doctor, if there is crowding i get bored and i leave …” (patient 16). some participants were unhappy about the delay of their laboratory results report when coming for their follow-up as the majority of investigations are sent to the nearest hospitals and it can take several weeks to get the results. “they (doctors) asked me to come after two weeks for the results, but my results were not ready…” (patient 2). therefore, some participants suggest that a copy of the laboratory results be sent by e-mail and tand that they are informed by a telephone based system (sms) when their results are ready so that they can make appointments with their pcp accordingly. “i suggest if they can send a copy of the results through e-mail …. at least send an sms when the results are ready” (patient 8). some participants commented on the waiting area in the clinic. they prefer the male waiting area to be separate from the female waiting area so they feel more at ease. other participants suggested that the patient waiting area for the diabetic clinic should be separated from the general patients waiting area. this would enable them to get the chance to share their experiences of diabetes with other diabetic patients while waiting to see the pcp. “i will feel more comfort if they separate the males from the females in the waiting area…”(patient 10). “i like it if they separate the diabetic patients from the general clinic patients … so i can share my experience with other diabetic patients” (patient 12). other participants suggested keeping some diabetic educational materials in the waiting area so they can utilise their time for something beneficial such as reading about diabetes while waiting to see mohammed al-azri, hilal al-azri, fatma al-hashmi, samira al-rasbi, kawther el-shafie and abdullah al-maniri clinical and basic research | 211 the pcp. “in the waiting area there are no pamphlets or health education materials about diabetes …. i would like to sit and read something that could benefit me …” (patient 11). discussion to our knowledge this is the first study conducted in oman to explore the factors which influence the quality of diabetic care provided in the phc setting from the perspective of type 2 diabetic patients. several factors were identified which could affect the quality of diabetic care including delays in getting appointments; lack of proper utilisation of the waiting area for the purpose of health education; language barriers with diabetic nurses; inadequate provision of continuity of care; lack of sufficient clarification of disease related issues; delays in obtaining investigation results; long waits for ophthalmology appointments, inadequate supplies of prescribed medications to cover the time between appointments, and lack of referrals to dieticians. participants in some health centres found it difficult to communicate with the diabetic clinic nurses as they were expatriates and could not speak arabic. research from elsewhere found that language barriers can be a risk factor for adverse outcomes and quality of care in diabetes; nurses, on the other hand, perceived language barriers with their patients as an impediment to quality care delivery and as a source of workplace stress.19-21 in the case of oman, large numbers of expatriate nurses contribute to the health care workforce. nonetheless, the overall omanization rate (replacement of expatriate professionals by omanis) in minsitry of health and other health care institutions in oman has grown over the years; the percentage of omani nurses in 2007 was 64% of total nurses compared to only 12% in the year 1990.5 this omanization of the health care workforce, which includes nurses, could help to overcome the language barriers in the future. participants emphasised the importance of continuity of care in diabetic clinics. good continuity of care is associated with better outcomes and improves the quality of care among diabetes patients in primary health care, for example by reducing macrovascular complications and associated nonvascular comorbidity.22 indeed, continuity is highly valued and preferred by most diabetic patients and other patients with chronic diseases compared with acute or minor problems.23,24 it has been found that maintaining continuity of care with the same health care provider improves the quality of life for diabetic patients and enhances the clinical management of the disease by improving the outcomes and decreasing diabetic related complications.25 patients with diabetes should be able to consult the same physician frequently as this would increase their satisfaction, trust and confidence and hence they would be more likely to adhere to the doctor's recommendations, thus improving their outcomes and quality of life.24,25 also, as a result of continuity, the doctor would know the patient well and would be more likely to identify appropriate therapies and, thereby, also improve the outcomes.26 however our patients identified significant lack of continuity which led to difficulties in building good patientdoctor relationships (e.g. familiarity, understanding, explanations). this could impede the provision of a good standard of care.27 participants’ also emphasised that the quality of their diabetic care could be affected by long waiting times either for getting their next appointment at the diabetic clinic at their health centre, or at specialty clinics such as the ophthalmology one in the hospital. long appointment waiting times limit the opportunity for the early detection, evaluation and management of new diabetic problems leading to poor diabetic control, increased risk of complications and poor quality of life.28 the availability of more pcps to manage patients with diabetes in primary care on a regular basis was found to improve the process of diabetic care such as regular measurements of haemoglobin a1c, lipid profiles and retinal eye examinations which ultimately improve the outcomes.29 participants highlighted the importance of utilising the waiting room for diabetes education and they also wanted to have group-based health education about diabetes and lifestyle modifications. using waiting rooms for educational purposes has been shown to be effective for patient education.30 patient education has been found to be an important factor in patient adherence to therapy; educating diabetic patients about lifestyle changes is an important factor for good diabetic control.31 group-based study for diabetic patients has also been shown to be effective in improving patients’ factors affecting the quality of diabetic care in primary care settings in oman a qualitative study on patients’ perspective 212 | squ medical journal, may 2011, volume 11, issue 2 knowledge and confidence about their diabetes.32 although the emerging findings from the analysis were discussed and refined by the research team which increased the credibility of the study, we believe that similar studies should be repeated in other countries as diabetic patients’ views and experiences might be different within the context of their national primary health care system setting. furthermore, the sample of patients was homogenous selected by convenient sampling methodology, thus, they might not represent all diabetic users of phcs in oman. conclusion this study is an attempt to explore diabetic patients’ perceptions regarding the quality of health care services provided in primary care setting in oman. several recommendations emerged from this study relevant for the practice and policy of primary care organisation in order to improve diabetic care services and hence improve the quality of diabetic care. waiting areas could be used to educate patients about their diabetes as the level of literacy in oman is rising. thus, providing patients with educational materials and leaflets highlighting important information about diabetes (complications, need for compliance with lifestyle changes and medication) might help increase patients’ awareness and improve outcomes. another challenge for the quality of diabetes care in the phc is the shortage of local specialised diabetic nurses. the moh and other governmental education bodies in oman should consider developing postgraduate programmes to train omani nurses in the proper management of diabetes care. this would avoid communication problems and misunderstandings that may occur with patients which can increase chances of medical errors which could affect the quality of care. according to the current prescribing policy in oman, pcps can write prescriptions and repeat prescriptions for chronic diseases such as diabetes for only one month. patients sometimes travel from a long distance to their pchc so it could be difficult for them to obtain medication every month and therefore they could run short of medication before their next diabetic appointment. the moh should consider changing the current prescribing strategy by allowing pcps to prescribe drugs for diabetics for at least 3 months. c o n f l i c t o f i n t e r e s t the authors reported no conflict of interest. a c k n o w l e d g m e n t s we would like to thank all the health centres and patients who agreed to participate in this study. references 1. spann sj, nutting pa, galliher jm, peterson ka, pavlik vn, dickinson lm, et al. management of type 2 diabetes in the primary care setting: a practicebased research network study. ann fam med 2006; 4:23−31. 2. khunti k. use of multiple methods to determine factors affecting quality of care of patients with diabetes. fam pract 1999; 16:489−94. 3. alberti h, boudriga n, nabli m. "damm sokkor": factors associated with the quality of care of patients with diabetes: a study in primary care in tunisia. diabetes care 2007; 30:2013−18. 4. zgibor jc, rao h, wesche-thobaben j, gallagher n, mcwilliams j, korytkowski mt. improving the quality of diabetes care in primary care practice. j healthc qual 2004; 26:14−21. 5. ghosh b. health workforce development planning in the sultanate of oman: a case study. hum resour health 2009; 11:7−47. 6. al-lawati ja, mohammed aj, al-hinai hq, jousilahti p. prevalence of the metabolic syndrome among omani adults. diabetes care 2003; 26:1781– 5. 7. international diabetes federation. prevalence estimates of diabetes mellitus (dm), 2010. from: w w w. d i a b e t e s a t l a s . o r g / c o n t e n t / p r e v a l e n c e estimates-diabetes-mellitus-dm-2010 accessed: november 2010. 8. al-moosa s, allin s, jemiai n, al-lawati j, mossialos e. diabetes and urbanization in the omani population: an analysis of national survey data. popul health metr 2006; 24:4−5. 9. al-mandhari a, al-zakwani i, el shafie o, alshafaee m, woodhouse n. quality of diabetes care: a cross-sectional observational study in oman. squ med j 2010; 9:32−6. 10. funnell mm, anderson rm. empowerment and self-management of diabetes. clin diabetes 2004; 22:123−7. 11. suwattee p, lynch jc, pendergrass ml. quality of care for diabetic patients in a large urban public hospital. diabetes care 2003; 26:563−8. 12. freeman j, loewe r. barriers to communication about diabetes mellitus. patients' and physicians' mohammed al-azri, hilal al-azri, fatma al-hashmi, samira al-rasbi, kawther el-shafie and abdullah al-maniri clinical and basic research | 213 different view of the disease. j fam pract 2000; 49:507−512. 13. ministry of health, oman. diabetes mellitus management guideline for primary health care, 2003. from: www.moh.gov.om/reports/ diabetesaftercorrection1.pdf accessed: november 2010. 14. khunti k. use of multiple methods to determine factors affecting quality of care of patients with diabetes. fam pract 1999; 16:489−94. 15. nicolucci a, greenfield s, mattke s. selecting indicators for the quality of diabetes care at the health systems level in oecd countries. int j qual health care 2006; 18:26−30. 16. meulepas ma, braspenning jc, de grauw wj, lucas ae, harms l, akkermans rp, et al. logistic support service improves processes and outcomes of diabetes care in general practice. fam pract 2007; 24:20−5. 17. pope c, ziebland s, mays n. analysing qualitative data. bmj 2000; 320:114−6. 18. ritchie j, spencer l. qualitative data analysis for applied policy research. in: bryman a, burgess r, eds. analysing qualitative data. london: routledge, 1994. pp. 173−94. 19. caraway lt. the impact of language barriers on the health care of latinos in the united states: a review of the literature and guidelines for practice. j midwifery womens health. 2002; 47:80−96. 20. andrew b, misty w, myrna r, anna r, marietta b, stephen lb, et al. impact of language barrier on acute care medical professionals is dependent upon role. j prof nurs 2006; 22:355−8. 21. brown af, gerzoff rb, karter aj, gregg e, safford m, waitzfelder b, et al. health behaviors and quality of care among latinos with diabetes in managed care. am j public health 2003; 93:1694−8. 22. wändell pe. quality of life of patients with diabetes mellitus. an overview of research in primary health care in the nordic countries. scand j prim health care 2005; 23:68−74. 23. overland j, yue dk, mira m. continuity of care in diabetes: to whom does it matter? diabetes res clin pract 2001; 52:55−61. 24. kearley ke, freeman gk, heath a. an exploration of the value of the personal doctor-patient relationship in general practice. br j gen pract 2001; 51:712−8. 25. hanninen j, takala j, keinanen-kiukaanniemi s. good continuity of care may improve quality of life in type 2 diabetes. diabetes res clin pract 2001; 51:21−7. 26. o'connor pj, desai j, rush wa, cherney lm, solberg li, bishop db. is having a regular provider of diabetes care related to intensity of care and glycemic control? j fam pract 1998; 47:290−7. 27. saultz jw, lochner j. interpersonal continuity of care and care outcomes: a critical review. ann fam med 2005; 3:159−66. 28. wang js, lin sy, sheu wh, lee it, tseng ln, song ym. effects of patient volume on quality of outpatient diabetes care. diabetes res clin pract 2009; 84:27−9. 29. holmboe es, wang y, tate jp, meehan tp. the effects of patient volume on the quality of diabetic care for medicare beneficiaries. med care 2006; 44:1073−7. 30. brazier cw. waiting room classes: effective use of waiting time in a diabetes clinic. j am diet assoc 1999; a107. 31. van den arend ijm, stolk rp, krans hmj, grobbee de, schrijvers ajp. management of type 2 diabetes: a challenge for patient and physician. patient educ couns 2000; 40:187−94. 32. adriaan v, frank s. perspectives on education and counseling for diabetes patients. patient educ couns 2004; 53:251−5. squ med j, april 2010, vol. 10, iss. 1, pp. 106-113, epub. 17th apr 10 submitted 14th june 09 revision req. 6th oct 09, revision recd. 1st nov 09 accepted 21st dec 09 complications involving the abdominal wall, particularly port site hernias, were not expected when laparoscopic procedures were first introduced. with the increasing number of laparoscopic procedures in abdominal surgery, more port site hernias were observed. port site herniation is a rare, but potentially dangerous complication, following laparoscopic surgery. visceral herniation into the abdominal trocar entry sites is occasionally mentioned, but seldom reported.1–4 kadar et al. in a large retrospective case review found the incidence of port site hernias after operative laparoscopy to be (0.17%).4 in another study, the incidence was 0.47%, but none of the cases in the study had small bowel obstruction, secondary to herniation through the trocar entry sites.5 in another multicentre, prospective, randomised clinical trial by bhoyrul et al. to study the complications related to laparoscopic port design, with a follow-up period of 6 to 18 months, there were no incisional hernias in any of the patients in the study.6 in another study done by nezhat, evaluating the postoperative complication of laparoscopic procedures done on 5,300 patients, only one case needed laparoscopically assisted bowel resection following a strangulated port site hernia.7 most of the port site herniations are in the extra umbilical port site.4,8 the risk factors for the development of trocar site hernias include: the trocar diameter, the trocar design, preexisting fascial defects, and some operationand patientrelated factors.9 department of surgery, sultan qaboos university hospital, muscat, oman. *to whom correspondence should be addressed. email: dralwahaibi@hotmail.com انِْفتاق األمعاء الدقيقة من منفذ املنظار بعد عملية استئصال الورم العضلي من الرحم تقرير حالة غازي ال�شفيع، خليفة ال�هيبي، اأحمد العزري، هاين القا�شي، عبداهلل احلارثي امللخ�ص: اْنِفتاق االأمعاء الدقيقة من خالل العي�ب اللفافية نتيجة اجلراحة باملنظار من خالل فتحة دخ�له حالة نادرة لكنها ميكن اأن تك�ن ذي م�شاعفات خطرية. من املف�شل جدا غلق اللفافة يف منطقة منفذ املنظار التي تك�ن بح�ايل 10 ملم اأو اأكرث لتفادي م�شاعفات كهذه. ندرج هنا حالة انفتاق لالأمعاء الدقيقة تعر�شت للخنق من منفذ املنظار بعد عملية ا�شتئ�شال ال�رم الع�شلي من الرحم. مت قطع اجلزء املختنق من االأمعاء مع اجراء تفاغر اأويل ملعاجلة تلك امل�شاعفات. ندرج هذه احلالة مع مراجعة االأدبيات ملناق�شة ع�امل االختطار وطرق تفادي مثل هذه امل�شاكل بعد عمليات املنظار. مفتاح الكلمات: انفتاق بطني، انفتاق من منفذ املنظار، اجلراحة باملنظار، م�شاعفات، تقرير حالة ؛ ُعمان. abstract: bowel herniation, through fascial defects secondary to laparoscopic surgery at the site of trocar entry, is a rare, but potentially serious, complication. closure of the fascia at port sites measuring 10mm or more has been highly recommended to avoid such complications. we report a case of a small bowel which herniated and strangulated through the port site immediately after laparoscopic myomectomy. resection of the strangulated bowel with primary anastomosis was required to manage this complication. we present this case report with literature review to discuss the risk factors and the methods to prevent such a complication post laparoscopic surgery. keywords: ventral hernia; laparoscopy; complications; case report; oman port site herniation of the small bowel following laparoscopic-myomectomy a case report ghazi a elshafie, *khalifa al-wahaibi, ahmed al-azri, hani al-qadhi, abdullah al-harthi case report ghazi a elshafie, khalifa al-wahaibi, ahmed al-azri, hani al-qadhi and abdullah al-harthi case report | 107 the following report describes a case of a trocar site hernia that evolved to a strangulated small bowel after laparoscopic myomectomy. we describe the significance of complete closure of the fascial defect at the trocar site in the prevention of this condition and the risk factors involved, as well as the importance of early diagnosis to avoid serious subsequent events. case report a 42 year-old lady, who had had a previous laparoscopic cholecystectomy in chennai, travelled abroad for treatment of her chronic abdominal pain, secondary infertility and second degree vaginal prolapse. she was 158 cm in height and weighed 85 kg. she underwent a hysteroscopy with fothergill’s operation and laparoscopic myomectomy. under general anaesthesia the patient was put in the lithotomy position. the hysteroscopy showed a subseptate uterus so septal resection was done. the anterior vaginal wall and posterior vaginal wall reflected off the cervix. the cervix was amputated 5 cm away from the internal os and homeostasis was secured. a fothergill’s suture was applied to cervix and a neocervix created. complete homeostasis was then secured and there was no undue bleeding. a 12 mm trocar for the laparoscope was placed in the supraumbilicus area. the pneumoperitoneum was then established with carbon dioxide and the intraperitoneal pressure was maintained at 10 mm hg. two more 10 mm trocars were inserted in the right and left iliac fossas. all trocars used were the bladed type. the uterus had two fibroids. one was 2 cm in diameter and deep seated in the anterior uterine wall. it was not indenting the cavity and hence it was not removed. the other fibroid was 2 cm in diameter and situated in the posterior uterine wall. a myomectomy was done, and the specimen was removed through the 12 mm supraumbilical port without extending the skin incision. complete homeostasis was secured. the fascial defect was closed at the umbilical port site, while the fascia in the right and left iliac fossas port sites was not sutured. the overlying skin was sutured. in the initial post operative period, the patient was asymptomatic and tolerated a normal diet. the patient then returned to oman seven days after her surgery ten days later she was admitted to sultan qaboos university hospital with a history of colicky abdominal pain and bilious vomiting, but had normal bowel habits. on physical examination, her abdomen was soft and there was no tenderness. her umbilical wound showed some serous discharge. there was a 4 cm x 4 cm tense mobile non-tender fluctuant mass in the left iliac fossa just below the left-sided port site. aspiration was done for the underlying clinically diagnosed seroma, which revealed 10 ml of sero-sanguinous fluid. an abdominal x-ray was done and was normal so the patient was treated conservatively. on fifteenth post operative day, the patient had an episode of figure 1: computed tomography (ct) scan shows the dilated small bowel which is protruding into the muscular layer of the abdominal wall (arrow). figure 2: computed tomography (ct) scan, coronal view, shows the entrapped small bowel loops in the muscular layer of the abdominal wall (arrow). port site herniation of the small bowel following laparoscopic-myomectomy a case report 108 | squ medical journal, april 2010, volume 10, issue 1 excessive vomiting and severe epigastiric pain, her last bowel movement had been 2 days previously and she had not passed any flatus per rectum for one day. the abdominal x-ray was repeated and showed evidence of small bowel obstruction (dilated small bowel, with multiple air fluid levels). this was followed with an abdominal computed tomography (ct) scan which showed evidence of a left-sided abdominal wall incisional hernia with entrapped bowel loops between the abdominal muscles [figures 1, 2, and 3] the patient then was moved to the operating room. under general anaesthesia and full aseptic condition, a 1 cm infraumbilical incision was made. a 10 mm trocar was introduced using an open technique. pneumoperitoneum was achieved using carbon dioxide. a 10 mm camera was introduced. incarcerated small bowel loops were found herniating through the previous left-sided port site. a 5 mm trocar was introduced in right iliac fossa under direct vision; reduction of the herniated bowel loops was attempted laparoscopically, but this was difficult technically. another attempt was made to release the incarcerated bowel loops through the abdominal wall. a transverse skin incision was made at the previous left-sided port site; subcutaneous and fascial planes were carefully dissected out. a seropurulent collection was found and multiple twisted bowel loops which were stuck to the abdomen wall. multiple attempts to manipulate and reduce the hernia failed. the procedure was converted to an open laparotomy. a midline incision was made extending from just above the umbilicus to the suprapubic area. the hernia contents were reduced by extending the fascial defect. multiple distended jejunal loops were found, with a 20 cm area of ischaemic bowel. resection and stapled primary anastamosis was done. the abdomen was washed with a copious amount of warm saline and an antibiotic based solution. the fascia over the hernia site was closed using a non-absorbable continuous suture. the midline incision was closed with a nonabsorbable suture for the fascia and an absorbable subcuticular suture for the skin. no drain was required and the skin over the hernia site was kept open over loose skin sutures which were closed 5 days later after daily dressing. the patient went home on the 6th post operative day with no complications. we saw her in our outpatient clinic a month after her discharge with no further complications. discussion port-site herniation, which is one of the major complications after laparoscopic procedures, can sometimes develops into serious complications, such as bowel obstruction due to incarceration into the fascial defect at the port site. boughey et al. have reported four cases of richter’s hernia that occurred at a port site after laparoscopic surgery3 the frequency of incisional hernias was significantly higher for 12 mm than for 10 mm trocars. the frequency of incisional hernias at extraumbilical 10 mm and 12 mm trocar insertion sites was 0.23% and 3.1% respectively4 suggesting that the wound created by a larger port carries a greater risk of herniation. incisional hernias were also significantly more common if the fascia was left open, as it the case in our patient. most surgeons now routinely close the fascia of port sites to prevent this complication.4 according to previous reports, port site herniation apparently happens more often with the use of figure 3: computed tomography (ct) scan, sagittal view, shows the dilated small bowel which is protruding into the muscular layer of the abdominal wall (arrow). ghazi a elshafie, khalifa al-wahaibi, ahmed al-azri, hani al-qadhi and abdullah al-harthi case report | 109 bladed type trocars than non-bladed type trocars.10 indeed, kolata demonstrated, in a pig experimental model, that the wounds made by the non-bladed trocar were narrower than those created by bladed trocars11 several reports even concluded that port sites created by non-bladed trocars do not require fascial closure.10 our current case support this theory as a 10 mm bladed trocar was used here and also suggests that the thick preperitoneum is a potential space that allows the development of bowel herniation. a previous report also described port site herniation, despite the closure of the superficial layer of the fascial defect.12 holzinger and klaiber made an attempt to classify trocar hernias by their onset and related features. they classified trocar hernias into the early-onset type, the lateonset type and the special type. according to this classification our case belongs to the early-onset type that occurred immediately after the operation, with a small-bowel obstruction.9 the risk factors for the development of trocar site hernias include: 1) the trocar diameter; 2) the trocar design; 3) preexisting fascial defects;9 4) enlargement of a port site to remove a specimen; 5) high blood glucose levels; 6) obesity; 7) increase intra-abdominal pressure as in chronic obstructive airway disease; or 8) extensive manipulation of the trocar during relatively prolonged surgical duration, which might enlarge the trocar site and thus induce bowel herniation.13 the current case had the following risk factors: obesity, the use of a trocar with a large diameter (10 mm), the use of a bladed trocar and the lack of fascia closure. most surgeons will recommend closure of port sites, especially those measuring 10 mm or more2,6 and associated with any of the risk factors described above; unfortunately, this was not done in our case with a 10 mm port site. the prevention of extra-umbilical incisional hernias and dehiscences appears to be more achievable when the closure is performed under laparoscopic vision. both the aponeurosis and the peritoneal membrane should be treated;14 however, it is sometimes difficult to completely close the defect, including the peritoneum, especially in obese patients. shaher reviewed different wound closure techniques by a literature search.15 in this review, old methods using classical instruments, including the deschamps needle, are also seen to be useful as well as special wound devices designed for port site closure. elashry et al. described a prospective randomised study demonstrating that the carterthomason device was faster and resulted in fewer port-closure-related complications among eight different techniques tested.16 insertion of a surgical plug into the muscular layer of trocar wounds has also been proposed by chiu et al.17 alternatively, tangential insertion of a trocar through the abdominal wall might be effective in reducing the size of fascial defects. moreover, recent publications have demonstrated that radially expanding type trocars could be useful to avoid the necessity of closing the fascial defect.18 from the clinical point of view, we recommend serial radiological examinations of the abdomen as early as possible for any case with suspected bowel obstruction. in our case, intestinal obstruction was missed on an initial normal abdominal x-ray despite the patient been symptomatic, but the repeated x-ray and ct scan showed evidence of small bowel obstruction. moreover, special attention should be paid to patients with risk factors for port site hernia such as: obesity, the use of large bladed trocars and the lack of fasical defect closure during surgery. conclusion port-site herniation is a rare, but very dangerous complication, after laparoscopic procedures. closure of a port site of more than 10mm is highly recommended especially with patients with risk factors such as: obesity, the use of large bladed trocars and the lack of fasical defect closure during surgery. immediate diagnosis and management of port sites hernias will prevent further complications. a c k n o w l e d g e m e n t s the authors would like to thank dr. geetha haripriya of the prashanth fertility research centre in chennai for providing a detailed description of the treatment abroad. references 1. patterson m, walters d, browder w. postoperative bowel obstruction following laparoscopic surgery. am surg 1993; 59:656–7. 2. itoh t, fuji n, taniguchi h, watanabe t, kosuga t, kashimoto k, et al. port site herniation of the small bowel following laparoscopy-assisted distal gastrectomy: a case report. j med case reports 2008; 2:48. port site herniation of the small bowel following laparoscopic-myomectomy a case report 110 | squ medical journal, april 2010, volume 10, issue 1 3. boughey jc, notingham jm, walls ac. richter’s hernia in the laparoscopic era. four case reports and review of the literature. surg laparosc endosc percutan tech 2003; 13:55–8. 4. kadar n, reisch h, liu cy, manko gf, gimpelson r. incisional hernias after major laparoscopic gynecologic procedures. am j obstet gynecol 1993; 168:1493–5. 5. filip v, pleşa c, târcoveanu e, bradea c, moldovanu r. incisional hernias after operative laparoscopy. rev med chir soc med nat iasi 2000; 104:83–6. 6. bhoyrul s, payne j, steffes b, swanstrom l, way lw. a randomized prospective study of radially expanding trocars in laparoscopic surgery. j gastrointest surg 2000; 4:392–7. 7. nezhat c, nezhat f, seidman ds, nezhat c. incisional hernias after operative laparoscopy. j laparoendosc adv surg tech a 1997; 7:111–15. 8. lajer h, widecrantz s, heisterberg l. hernias in trocar ports following abdominal laparoscopy. a review. acta obstet gynecol scand 1997; 76:389– 93. 9. holzinger f, klaiber c. trocar site hernias. a rare but potentially dangerous complication of laparoscopic surgery. chirurg 2002; 73:899–904. 10. liu cd, mcfadden dw. laparoscopic port sites do not require fascial closure when nonbladed trocars are used. am surg 2000; 66:853–4. 11. kolata rj, ransick m, briggs l, baum d. comparison of wounds created by non-bladed trocars and pyramidal tip trocars in the pig. j laparoendosc adv surg tech a 1999; 9:455–61. 12. margossian h, pollard rr, walters md. small bowel obstruction in a peritoneal defect after laparoscopic burch procedure. j assoc gynecol laparosc 1999; 6:343–5. 13. tonouchi h, ohmori y, kobayashi m, kusunoki m. trocar site hernia. arch surg 2004; 139:1248–56. 14. le bouëdec g, kauffmann p, mille p, scherrer c, raiga j, dauplat j. post-laparoscopic incisional hernia. a propos of a case. j chir (paris) 1995; 132:259–63. 15. shaher z. port closure techniques. surg endosc 2007; 21:1264–74. 16. elashry om, nakada sy, wolf js jr, figenshau rs, mcdougall em, clayman rv. comparative clinical study of port-closure techniques following laparoscopic surgery. j am coll surg 1996; 183:335– 44. 17. chiu cc, lee wj, wang w, wei pl, huang mt. prevention of trocar-wound hernia in laparoscopic bariatric operations. obes surg 2006; 16:913–18. 18. johnson wh, fecher am, mcmahon rl, grant jp, pryor ad. versastep trocar hernia rate in unclosed fascial defects in bariatric patients. surg endosc 2006; 20:1584–6. 1department of studies & research, directorate general of planning & studies, ministry of health, al buraimi, oman; 2department of registration & licensing, directorate general of nursing affairs, ministry of health, muscat, oman; 3renal dialysis unit, sohar hospital, sohar, oman; 4department of staff development & training, al nahdha hospital, muscat, oman *corresponding author’s e-mails: aysha-alsaadi@hotmail.com الوعي بأمهية حقوق املرضى واإللتزام هبا عند األطباء واملمرضني يف عمان دراسة حتليلية مقطعية عرضية يف مستويات خمتلفة من الرعاية الصحية عائ�صة نا�رص �ل�صاعدية، �صالح عمار �صليمان، ر�وية علي �ل�صبلية، فاطمة يعقوب �جلابرية abstract: objectives: this study aimed to determine the extent to which physicians and nurses in oman were aware of the importance of and adhere to patients’ rights and whether this differed according to role, nationality, position and institutional healthcare level. methods: this analytical cross-sectional study was carried out between december 2015 and march 2016 at various governmental healthcare institutions in oman. a self-administered questionnaire was distributed to 1,385 practitioners at all healthcare levels. results: a total of 1,213 healthcare practitioners (response rate: 87.58%) completed the survey, of which 685 (56.47%) were nurses and 528 (43.53%) were physicians. overall, awareness of the importance of patients’ rights was high (91.51%), although adherence to these rights in practice was low (63.81%). the right of the patient to be informed was considered least important and was least adhered to (81.2% and 56.39%). nationality, role and institutional level were significantly associated with awareness (p = 0.002, 0.024 and 0.034, respectively). non-omani staff were significantly more likely than omani staff to be aware of (odds ratio [or] = 1.696; p = 0.032) and adhere to (or = 2.769; p <0.001) patient rights. furthermore, tertiary care staff were twice as likely as primary care staff to perceive the importance of patient rights (or = 2.076; p = 0.019). while physicians were more likely than nurses to be aware of the importance of patient rights, this difference was not significant (or = 1.516; p = 0.126). conclusion: these findings may help inform measures to enhance awareness of and adherence to patients’ rights in oman. keywords: medical ethics; patient rights; awareness; adherence; physicians; nurses; oman. امللخ�ص: الهدف: هدفت هذه �لدر��صة لتحديد مدى وعي �الأطباء و�ملمر�صني يف ُعمان باأهمية حقوق �ملر�صى و�الإلتز�م بها، وعما �إذ� كان ذلك �لوعي و�اللتز�م يتفاوت بتفاوت �لوظيفة و�جلن�صية و�لدور �لوظيفي وم�صتوى �لرعاية �ل�صحية للموؤ�ص�صة. الطريقة: �أجريت هذه �لدر��صة �لتحليلية �ملقطعية �لعر�صية يف �لفرتة ما بني دي�صمرب 2015م ومار�س 2016م يف موؤ�ص�صات رعاية �صحية حكومية خمتلفة بعمان. مت توزيع ��صتمار�ت ��صتبيان على 1,385 ممار�ًصا �صحيا على جميع م�صتويات �لرعاية �ل�صحية. النتائج: �صارك يف �ال�صتبيان 1,213 ممار�صا �صحيا )بلغ معدل �ال�صتجابة %87.58(، وك�ن منهم 685 )%56.47( من �ملمر�صني و�ملمر�صات، و 528 )%43.53( من �الأطباء. تبني �أن وعي �الأطباء و�ملمر�صني باأهمية حقوق �ملر�صى كان عاليا على وجه �لعموم )%91.51(، غري �أن مدى �اللتز�م بتلك �حلقوق يف و�قع �لعمل كان منخف�صا )63.81%(. �أحقية �ملري�س يف �حل�صول على �ملعلومات بالن�صبة لهم �أقل �أهمية من غريه، كما �أن �اللتز�م بذلك كان قليال )%81.2 و %56.39، على �لتو�يل(. ووجدت عالقة ذ�ت داللة �ح�صائية بني م�صتوى �إدر�ك �أهمية حقوق �ملر�صى وجن�صية مقدمي �لرعاية �ل�صحية ووظيفتهم وم�صتوى �لرعاية )p = 0.032( وكان م�صتوى �الدر�ك باأهمية حقوق �ملر�صى �أعلى بـ 1.696 مرة .)0.024 و 0.034، على �لتو�يل ،p = 0.002( ل�صحية للموؤ�ص�صة� لدى �الأطباء و�ملمر�صني من غري �لعمانيني عنه لدى �لعمانيني، فيما كان م�صتوى �اللتز�م بحقوق �ملر�صى لديهم �أكرب بــ 2.769 مرة، مقارنة بالكادر �ل�صحي �لعماين )p >0.001(. وباالإ�صافة �إىل ذلك، كان م�صتوى �الإدر�ك باأهمية حقوق �ملر�صى �أعلى مرتني ( 2.076 )لدى �لكادر �ل�صحي بامل�صتوى �لثالث من �لرعاية �ل�صحية عنه لدى �لعاملني مبر�كز �لرعاية �ل�صحية �الأولية )p = 0.019(. وكان �الأطباء �أكرث �إدر�كا من �ملمر�صني باأهمية حقوق �ملر�صى، غري �أن ذلك �الختالف ال يعتد به �ح�صائيا )or = 1.516 ؛ p = 0.126(. اخلال�صة: قد ت�صاعد هذه �لنتائج يف تعزيز �لتد�بري �لر�مية �إىل زيادة �لوعي بحقوق �ملر�صى يف ُعمان و�اللتز�م بها. الكلمات املفتاحية: �أخالقيات �لطب؛ حقوق �ملر�صى؛ �الإدر�ك؛ �الإلتز�م؛ �الأطباء؛ �لتمري�س؛ ُعمان. awareness of the importance of and adherence to patients’ rights among physicians and nurses in oman an analytical cross-sectional study across different levels of healthcare *aisha n. al-saadi,1 salah b. a. slimane,2 rawya a. al-shibli,3 fatema y. al-jabri4 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e201–208, epub. 5 nov 19 submitted 4 dec 18 revision req. 9 jan 19; revision recd. 23 feb 19 accepted 18 mar 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.005 clinical & basic research advances in knowledge this study found that while awareness of the importance of patients’ rights was high among nurses and physicians in oman, adherence to these rights in actual practice was low. non-omani staff were significantly more likely to be aware of and adhere to patient rights in comparison to omani staff. tertiary care staff were twice as likely to be aware of the importance of patient rights compared to staff from primary healthcare institutions. https://creativecommons.org/licenses/by-nd/4.0/ awareness of the importance of and adherence to patients’ rights among physicians and nurses in oman an analytical cross-sectional study across different levels of healthcare e202 | squ medical journal, august 2019, volume 19, issue 3 the right to lead a healthy life is widely considered to be a fundamental human right.1 as such, promoting and assuring patients’ rights is an essential part of modern healthcare. in 1994, the world health organization (who) published a detailed declaration outlining the primary principles of patients’ rights in europe.2 in oman, royal decree #26/75 acknowledges patients as individuals with human rights and assures all citizens of their right to equal access to free of charge healthcare.3 by 2050, the omani ministry of health (moh) aims to have a responsive, equitable and efficient healthcare system that not only offers evidence-based care but also satisfies patients and attends to their needs.4 previous research has revealed that awareness of patient rights by healthcare providers positively influences patient satisfaction.5,6 moreover, a lack of observance of these rights in clinical practice erodes trust between patients and healthcare professionals and can endanger the life and safety of the patient.6,7 while physicians have been reported to have better knowledge of patient rights compared to nurses, both groups demonstrate similar levels of adherence in actual practice.6,8–10 in saudi arabia, healthcare professionals working at primary healthcare institutions were found to have little knowledge regarding the rights of their patients; furthermore, a lack of knowledge of patients’ rights, lack of standards and the legal system were identified as being barriers to the observance of patient rights in practice.11 patients’ rights are best protected when health care workers are aware and conscious of these rights.12–14 as such, data are needed regarding current levels of awareness of the importance of patients’ rights. however, to the best of the authors’ knowledge, no study has yet been conducted in oman on this topic. this study therefore aimed to determine levels of awareness of and adherence to patients’ rights among physicians and nurses in oman and potential associations with role, nationality, position and institutional healthcare level. such findings may help decision-makers to take necessary steps to improve educational measures in this regard and improve the implementation of patients’ rights in practice. methods this analytical cross-sectional survey was carried out between december 2015 and march 2016 at various governmental institutions. physicians and nurses were initially targeted as they constitute a large proportion of the healthcare workforce in oman and usually spend more time performing routine daily tasks with patients compared to other health professionals. of the 17,007 physicians and nurses working at moh institutions, 9,750 (57.33%) are omani nationals and 7,257 (42.67%) are expatriates.15 a proportional stratified sampling technique was used to access approximately 8% of this population, assuming a 95% confidence level and a margin of error of 3%. the final sample size was 1,385 participants, including 663 physicians (47.87%) and 722 nurses (52.13%) from all primary healthcare centres, nine secondary hospitals and three tertiary institutions in oman. an online sample size calculator (raosoft inc., seattle, washington, usa) was initially used to calculate the sample size; subsequently, a proportional size approach was implemented to determine the precise number of healthcare professionals targeted at each institution. data were collected from the participants using a two-part english self-reported questionnaire designed specifically for this study. the first section of the questionnaire collected demographic information, incl uding role, gender, years of experience, institutional level, position and nationality. the second part was designed to evaluate awareness of the importance of patients’ rights and frequency of observing these rights in clinical practice. as the official oman patient rights charter was not yet developed, 40 principles outlined in the who declaration on the promotion of patients’ rights in europe were utilised.2,16 these items were divided into six domains: (1) respect and appreciation; (2) sufficient and timely information; (3) consent; (4) privacy and confidentiality; (5) care and treatment; and (6) partic ipation in healthcare plan. participants rated the imp ortance of each item on a five-point likert scale, with scores of 1–5 being unimportant, slightly important, moderately important, important and very important, respectively. adherence to each item was similarly measured on a five-point likert scale, with scores of 1–5 indicating never, rarely, often, daily and always, respectively. the questionnaire was tested for content validity and relevance by a senior expert at the moh and all necessary modifications were implemented. the internal consistency of the tool was verified, with alpha coefficients of 0.92 and 0.94 for the importance and frequency of adherence subscales, respectively. a pilot application to patient care the findings of this study may help decision-makers formulate strategies to educate both healthcare providers and patients on this topic and ensure that such rights are observed in clinical practice. this would result in a radical improvement in the provision of healthcare in oman and enhance patient safety and satisfaction. aisha n. al-saadi, salah b. a. slimane, rawya a. al-shibli and fatema y. al-jabri clinical and basic research | e203 study of the survey was conducted in august 2015 with 49 healthcare professionals working in primary and secondary institutions in al buraimi governorate. the final version of the questionnaire took into consid eration the comments of the pilot group with regards to intelligibility, clarity and language. the questionnaires were then distributed to participants by the head of the nursing department at each healthcare institution. completed questionnaires were returned anonymously to confidential boxes placed in the office of the head of department. data were analysed using the statistical package for the social sciences (spss), version 20.0 (ibm corp, armonk, new york, usa). prior to analysis, the raw data were processed for incompleteness, duplication and inaccuracy before being cleaned; moreover, some variables were combined (including total importance and adherence scores) for ease of analysis. results were presented using descriptive statistics in the form of freq uencies, percentages, means and standard deviations. a chi-squared test and logistic regression model were used to assess the association between importance and adherence scores and demographic characteristics. the level of statistical significance was set at p <0.05. this study was approved by the research ethical review & approval committee of the moh. all participants filled a written informed consent form that accompanied each questionnaire along with a covering letter explaining the purpose and voluntary nature of the study and assuring the respondents’ anonymity. results a total of 1,213 healthcare practitioners (response rate: 87.58%) took part in the study, of which 685 were nurses (56.47%) and 528 were physicians (43.53%). more than half were of omani nationality (53.5%) and the majority were female (68.51%). a total of 679 healthcare practitioners were clinicians (55.98%), 141 had managerial responsibilities (11.62%) and 393 held both positions (32.4%). participants had varying figure 1: overall frequency of perceived importance of and adherence to patients’ rights among physicians and nurses working at governmental healthcare institutions in oman (n = 1,213). table 1: demographic characteristics of physicians and nurses working at governmental healthcare institutions in oman (n = 1,213) characteristic n (%) gender male 382 (31.49) female 831 (68.51) nationality omani 649 (53.5) non-omani 564 (46.5) role nurse 685 (56.47) physician 528 (43.53) position clinician 679 (55.98) management 141 (11.62) both 393 (32.4) years of experience ≤5 266 (21.93) 6–10 328 (27.04) >10 619 (51.03) institutional level primary 489 (40.31) secondary 386 (31.82) tertiary 338 (27.87) figure 2: perceived importance of each patients’ rights domain among physicians and nurses working at governmental healthcare institutions in oman (n = 1,213). awareness of the importance of and adherence to patients’ rights among physicians and nurses in oman an analytical cross-sectional study across different levels of healthcare e204 | squ medical journal, august 2019, volume 19, issue 3 degrees of experience, ranging from ≤5 years (21.93%) to >10 years (51.03%). overall, 40.31%, 31.82% and 27.87% worked in primary, secondary and tertiary healthcare centres, respectively [table 1]. overall, there was a high level of perception of the importance of patient rights among physicians and nurses (91.51%), although actual adherence was low (63.81%) [figure 1]. the domain of patients’ rights per ceived to be most important was respect and appreciation (97.53%), while the least important domain was the patients’ right to be informed (81.2%) [figure 2]. similarly, the domain of respect and appreciation reflected the highest level of adherence (85.66%), while the domain least adhered to was that of sufficient and timely information (56.39%) [figure 3]. in terms of specific rights, 1,077 nurses and physicians (88.79%) rated a patient’s right to be treated with dignity as being very important. the provision of honest care to dying patients was the right most frequently observed in clinical practice (71.81%). nationality, role and institutional level were signif icantly associated with perception of the importance of patients’ rights (p = 0.002, 0.024 and 0.034, respectively). there was also a significant relationship between adher ence to patients’ rights and nationality (p <0.001) [table 2]. in the logistic regression analysis, nationality remained figure 3: frequency of adherence to each patients’ rights domain among physicians and nurses working at governmental healthcare institutions in oman (n = 1,213). table 2: associations between levels of awareness of the importance of and adherence to patients’ rights status and demo graphic characteristics among physicians and nurses working at governmental healthcare institutions in oman (n = 1,213) characteristic n (%) p value n (%) p value importance adherence yes no yes no gender male 354 (92.67) 28 (7.33) 0.325 248 (64.92) 134 (35.08) 0.585 female 756 (90.97) 75 (9.03) 526 (63.3) 305 (36.7) nationality omani 579 (89.21) 70 (10.79) 0.002 353 (54.39) 296 (45.61) <0.001 non-omani 531 (94.15) 33 (5.85) 421 (74.65) 143 (25.35) role nurse 616 (89.93) 69 (10.07) 0.024 429 (62.63) 256 (37.37) 0.330 physician 494 (93.56) 34 (6.44) 345 (65.34) 183 (34.66) position clinician 626 (92.19) 53 (7.81) 0.626 435 (64.06) 244 (35.94) 0.643management 128 (90.78) 13 (9.22) 94 (66.67) 47 (33.33) both 356 (90.59) 37 (9.41) 245 (62.34) 148 (37.66) years of experience ≤5 242 (90.98) 24 (9.02) 0.936 170 (63.91) 96 (36.09) 0.1306–10 301 (91.77) 27 (8.23) 195 (59.45) 133 (40.55) >10 567 (91.6) 52 (8.4) 409 (66.07) 210 (33.93) institutional level primary 438 (89.57) 51 (10.43) 0.034 321 (65.64) 168 (34.36) 0.279secondary 352 (91.19) 34 (8.81) 234 (60.62) 152 (39.38) tertiary 320 (94.67) 18 (5.33) 219 (64.79) 119 (35.21) aisha n. al-saadi, salah b. a. slimane, rawya a. al-shibli and fatema y. al-jabri clinical and basic research | e205 a significant predictor, with non-omani practitioners significantly more likely to be aware of the importance of patient rights (odds ratio [or] = 1.696; p = 0.032) and more likely to adhere to these rights (or = 2.769; p <0.001) in comparison to omani staff. in addition, staff working at tertiary care centres were twice as likely to be aware of the importance of patient rights compared with those working in primary healthcare institutions (or = 2.076; p = 0.019), although there was no significant difference in terms of adherence (or = 0.848; p = 0.664). while physicians were more likely than nurses to be aware of the importance of patient rights, this difference was not significant (or =1.516; p = 0.126) [table 3]. discussion from a patient’s perspective, the attitude and behaviour of their healthcare provider is the most important criterion to evaluate the quality of healthcare services rendered.10,17 awareness of and adherence to patients’ rights therefore help to promote and sustain an effective relationship between patients and healthcare staff.2 as such, the importance of patients’ rights should be valued highly by all personnel in healthcare institutions. the current study was conducted in order to determine the extent to which physicians and nurses in oman were aware of and adhere to various internationally accepted patient rights and potential associations with role, nationality, position and healthcare institutional level. in the present study, nurses and physicians in oman demonstrated a high level of awareness of the importance of patients’ rights; however, adherence to these rights in actual practice was fairly low. ducinskiene et al. revealed similar results, in which physicians and nurses in lithuania were well-informed regarding patients’ rights but did not always take them into consideration in practice.18 similarly, sheikhtaheri et al. found that nurses’ awareness of the patients’ bill of rights in iran was acceptable, while observance in clinical practice was subpar.9 as noted by farzianpour et al., awareness of patients’ rights does not necessarily guarantee that such rights are observed in practice.5 these findings indicate that other factors apart from staff awareness and knowledge may need to be looked at in order to promote the observation of patients’ rights in clinical practice. moreover, these results indicate that healthcare providers do not implement all patients’ rights in practice; therefore, it is vital to devise strategies to improve adherence levels. there was little variation in the current study in terms of the perceived importance of each of the six domains of patients’ rights, suggesting that nurses and physicians in oman consider all domains to be important. overall, the most important domain was respect and appreciation, particularly the patients’ right to be treated with dignity. other studies conducted in saudi arabia and iraq have reported similar results in which the most important rights were those that emanated from the care and respect domains.19,20 this could be due to the fact that patient rights included in this domain are deemed elemental human rights and constitute a fundamental part of the treatment process. in contrast, the current study found that the least important domain was related to the patient’s right to information; moreover, this domain was also least adhered to in clinical practice. failure to observe this right is commonly reported in the international literature.21–23 in ducinskiene et al.’s study, only half of the participating physicians agreed that informing patients of their diagnosis, medical results and treat ment methods was a necessary right.18 in singapore, a survey of medical professionals found that staff did not routinely inform patients of the benefits of their table 3: logistic regression analysis of associations between awareness of the importance of and adherence to patients’ rights status among physicians and nurses working at governmental healthcare institutions in oman (n = 1,213) variable importance adherence or (95% ci) p value or (95% ci) p value gender (female versus male) 1.262 (0.734–2.171) 0.401 1.090 (0.872–1.626) 0.273 nationality (omani versus non-omani) 1.696 (1.047–2.746) 0.032 2.769 (2.102–3.648) <0.001 role (physician versus nurse) 1.516 (0.889–2.585) 0.126 1.197 (0.885–1.619) 0.244 position (both clinician and mgt versus mgt alone) 1.136 (0.565–2.284) 0.970 1.045 (0.674–1.617) 0.994 position (clinician versus mgt) 1.315 (0.666–2.598) 0.372 1.089 (0.716–1.656) 0.655 years of experience (>10 versus 1–5 years) 1.103 (0.652–1.865) 0.984 1.057 (0.771–1.451) 0.237 years of experience (6–10 versus 1–5 years) 1.205 (0.672–2.160) 0.568 0.829 (0.587–1.171) 0.125 institutional level (secondary versus primary) 1.178 (0.740–1.875) 0.392 0.812 (0.610–1.082) 0.349 institutional level (tertiary versus primary) 2.076 (1.175–3.670) 0.019 0.848 (0.624–1.150) 0.664 or = odds ratio; ci = confidence interval; mgt = management. awareness of the importance of and adherence to patients’ rights among physicians and nurses in oman an analytical cross-sectional study across different levels of healthcare e206 | squ medical journal, august 2019, volume 19, issue 3 proposed treatment or of their available treatment options.24 nekoei moghaddam et al. and sabzevari et al. similarly found that the patient right least adhered to was the right to receive adequate and appropriate information.25,26 reasons for neglecting this right might include a lack of awareness or reluctance to recognise this right by healthcare providers. accordingly, there is a need for increased educational efforts aimed at healthcare professionals, with particular emphasis on the patient’s right to the provision of sufficient and timely information. the current study observed significant positive associations between awareness of the importance of patients’ rights and the nationality, role and institutional level of the healthcare providers. in particular, nationality remained a significant predictor during logistic regression analysis, with non-omani staff 1.7-times more likely to perceive the importance of patients’ rights and 2.8-times more likely to adhere to these rights compared to omani staff. the reason for this finding is unknown; however, it may be that some of the non-omani staff had previously received additional education or training regarding patients’ rights in other countries. awareness of the importance of patients’ rights also differed signif icantly according to institutional level, with patients’ rights twice as likely to be perceived as important by tertiary compared to primary healthcare workers. a previous study conducted in oman reported patient dissatisfaction with patient-provider interactions in primary healthcare, including an unfriendly/unwelcoming tone, lack of privacy during consultation, poor attention/ eye contact, lack of encouragement to ask questions and an inability to participate in medical dialogue.27 in terms of role, while physicians in the present study had significantly higher levels of awareness compared to nurses, there was no significant difference in terms of adherence; moreover, this factor was not significant during the logistic regression analysis. previous research conducted in developing countries has indicated lower levels of awareness of patients’ rights among nurses compared to doctors, with studies conducted in turkey, india and egypt reporting moderate levels of awareness among the former.6,10,28–30 the current study found no significant associations between years of experience and either perception of the importance of or adherence to patients’ rights. in contrast, other researchers have reported significantly higher levels of awareness among those with longer work experience.31,32 in addition, there were no significant differences in the present study in terms of position and gender. this finding is in agreement with previous research from iran which reported no relationship between gender and awareness of patients’ rights.33 unfortunately, when patients feel their rights are being violated, they may seek alternative mechanisms to meet their needs, such as attending emergency departments with primary healthcare problems or relying on self-management or self-medication to treat common medical conditions.34,35 such health-seeking behaviours can have serious implications, not only on the individual’s health, but also on the healthcare system as a whole. therefore, healthcare professionals’ knowledge of and implementation of patients’ rights should be evaluated regularly; moreover, continuous education on this subject should be provided. barriers to a lack of adherence to patients’ rights among physicians and nurses may include a lack of knowledge, poor attitudes and job-related factors such as low salaries, stress/burnout and long working hours.8,14 in addition, healthcare professionals may also be faced with insufficient standards and a lack of necessary hospital equipment and staff.11,36,37 it is therefore important that such barriers be identified and appropriate strat egies put in place in oman in order to ensure that patient rights are adequately observed. this study was subject to certain limitations. due to the lack of previous studies on this topic in oman, the findings could not be compared with those of similar national research. similarly, the authors could not benefit from other researchers’ experiences when designing the questionnaire. moreover, this study was conducted prior to the development and publication of the official patient rights charter by the moh in oman.15 future studies are therefore recommended to evaluate healthcare providers’ awareness of and attitudes towards the rights outlined in this official charter at governmental hospitals, health centres and psychiatric hospitals in oman. in addition, further research is necessary to determine barriers to the implementation of patients’ rights in oman so that appropriate strategies can be developed to overcome them. conclusion nurses and physicians in oman demonstrated a high level of awareness of the importance of patients’ rights; however, actual adherence to these rights in practice was low. non-omani staff were found to have significantly higher levels of awareness of and adherence to patients’ rights compared to omani staff. additionally, tertiary hospital staff were twice as likely to perceive patients’ rights to be important compared to primary healthcare practitioners. strategies are needed to ensure that patient rights are adequately recognised and protected in oman. aisha n. al-saadi, salah b. a. slimane, rawya a. al-shibli and fatema y. al-jabri clinical and basic research | e207 c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. council of europe treaty office. details of treaty no.005: convention for the protection of human rights and fundamental freedoms. from: http://conventions.coe.int/treaty/en/treaties/ html/005.html accessed: feb 2019. 2. world health organization regional office for europe. a declaration on the promotion of patients’ rights in europe: european consultation on the rights of patients, amsterdam 28-30 march 1994. from: www.who.int/genomics/public/eu_ declaration1994.pdf accessed: feb 2019. 3. world health organization regional health systems observatory. health system profile: oman. from: http://apps.who.int/medici nedocs/documents/s17304e/s17304e.pdf accessed: feb 2019. 4. oman ministry of health. content resources: health vision 2050. from: www.moh.gov.om/en/web/directorate-general-ofplanning/resources accessed: feb 2019. 5. farzianpour f, rahimi foroushani a, shahidi sadeghi n, ansari nosrati s. relationship between’ patient’s rights charter’ and patients’ satisfaction in gynecological hospitals. bmc health serv res 2016; 16:476. https://doi.org/10.1186/s12913-016-1679-9. 6. mohammad nejad e, begjani j, abotalebi g, salari a, ehsani sr. nurses awareness of patients rights in a teaching hospital. j med ethics hist med 2011; 4:2. 7. ozdemir mh, ergönen ta, sönmez e, can io, salacin s. the approach taken by the physicians working at educational hospitals in izmir towards patient rights. patient educ couns 2006; 61:87–91. https://doi.org/10.1016/j.pec.2005.02.013. 8. al-muammar sa, gari dmk. doctors’ knowledge of patients’ rights at king fahd hospital of the university. j family comm unity med 2017; 24:106–10. 9. sheikhtaheri a, jabali ms, dehaghi zh. nurses’ knowledge and performance of the patients’ bill of rights. nurs ethics 2016; 23:866–76. https://doi.org/10.1177/0969733015584967. 10. uçar m. ethical aspects of health services in the military context. taf prev med bull 2005; 4:37–45. 11. albishi aa. the saudi patients’, physicians’, and nurses’ perceptions of and lived experience with patients’ rights in saudi arabia: qualitative phenomenological study. phd thesis, 2004, george manson university, fairfax, virginia, usa. 12. ghodsi z, hojjatoleslami s. knowledge of students about patient rights and its relationship with some factors in iran. procedia soc behav sci 2012; 31:345–8. https://doi.org/10.1016/j.sbspro.2 011.12.065. 13. iltanen, s, leino-kilpi h, puukka p, suhonen r. knowledge about patients’ rights among professionals in public health care in finland. scand j caring sci 2012; 26:436–48. https://doi. org/10.1111/j.1471-6712.2011.00945.x. 14. alghanim sa. assessing knowledge of the patient bill of rights in central saudi arabia: a survey of primary health care providers and recipients. ann saudi med 2012; 32:151–5. https://doi.org/10.5144/0256-4947.2012.151. 15. department of health information & statistics. annual health report 2012 chapter four. oman: ministry of health. pp. 5–7. 16. times of oman. patients’ rights and duties document launched in oman. from: https://timesofoman.com/article/95002 accessed: feb 2019. 17. zebiene e, razgauskas e, basys v, baubiniene a, gurevicius r, padaiga z, et al. meeting patient’s expectations in primary care consultations in lithuania. int j qual health care 2004; 16:83–9. https://doi.org/10.1093/intqhc/mzh006. 18. ducinskiene d, vladickiene j, kalediene r, haapala i. awareness and practice of patient’s rights law in lithuania. bmc int health hum rights 2006; 6:10. https://doi.org/10.1186/1472698x-6-10. 19. saleh ha, khereldeen mm. physicians’ perception towards patients’ rights in two governmental hospitals in mecca, ksa. int j pure appl sci technol 2013; 17:37–47. 20. khalaf sk, al-asadi jn, abed ah, shami sa, al-shamry h. knowledge and attitudes towards patient’s rights among health care providers in primary care health centers in basrah. int j med pharm sci 2014; 4:7–14. 21. changole j, bandawe c, makanani b, nkanaunena k, taulo f, malunga e, et al. patients’ satisfaction with reproductive health services at gogo chatinkha maternity unit, queen elizabeth central hospital, blantyre, malawi. malawi med j 2010; 22:5–9. https://doi.org/10.4314/mmj.v22i1.55899. 22. kuzu n, ergin a, zencir m. patients’ awareness of their rights in a developing country. public health 2006; 120:290–6. https://doi.org/10.1016/j.puhe.2005.10.014. 23. vaskooei eshkevari k, karimi m, asnaashari h, kohan n. the assessment of observing patients’ rights in tehran university of medical sciences’ hospitals. j med ethics his med 2009; 2:47–54. 24. tay csk. recent developments in informed consent: the basis of modern medical ethics. int j rheum dis 2005; 8:165–70. https://doi.org/10.1111/j.1479-8077.2005.00143.x. 25. nekoei moghaddam m, amiresmaeili m, ghobaninia r, sharifi t, tabatabaie ss. awareness of patients’ rights charter and respecting it from the perspective of patients and nurses: a study of limited surgical centers in kerman city, 2013. bioeth j 2014; 4:31–56. 26. sabzevari a, kiani ma, saeidi m, jafari sa, kianifar h, ahanchian h, et al. evaluation of patients’ rights observance according to patients’ rights charter in educational hospitals affiliated to mashhad university of medical sciences: medical staffs’ views. electron physician 2016; 8:3102–9. https://doi. org/10.19082/3102. 27. abdulhadi n, al shafaee m, freudenthal s, ostenson cg, wahlström r. patient-provider interaction from the perspec tives of type 2 diabetes patients in muscat, oman: a qualitative study. bmc health serv res 2007; 7:162. https://doi.org/10.1 186/1472-6963-7-162. 28. büken no, büken e. emerging health sector problems affecting patient rights in turkey. nurs ethics 2004; 11:610–24. https:// doi.org/10.1191/0969733004ne742oa. 29. abou zeina ha, el nouman aa, zayed ma, hifnawy t, el shabrawy em, el tahlawy e. patients’ rights: a hospital survey in south egypt. j empir res hum res ethics 2013; 8:46–52. https://doi.org/10.1525/jer.2013.8.3.46. 30. kumari k, kumari v, bishnoi ak. an exploratory study to assess the knowledge, expressed practices and barriers in protection of patients’ rights among nurses at mmims&r hospital, mullana, ambala. iosr j nurs health sci 2013; 2:55–60. https://doi. org/10.9790/1959-0255560. 31. parsapoor a, mohammad k, afzali hm, ala’eddini f, larijani b. unsatisfied patient’s rights: a survey on the views of patients, nurses and physicians. j med ethics hist med 2012; 5:4. 32. abu saq ih, al-hutaylah nm, al-shahrani ma, abualiat zm, al-qahtani am, al-shaybah fh, et al. assessment of primary health care physicians’ awareness about patients’ rights. med j cairo univ 2017; 85:651–5. https://doi.org/10.1186/s12913-016-1679-9 https://doi.org/10.1016/j.pec.2005.02.013 https://doi.org/10.1177/0969733015584967 https://doi.org/10.1016/j.sbspro.2011.12.065 https://doi.org/10.1016/j.sbspro.2011.12.065 https://doi.org/10.1111/j.1471-6712.2011.00945.x https://doi.org/10.1111/j.1471-6712.2011.00945.x https://doi.org/10.5144/0256-4947.2012.151 https://doi.org/10.1093/intqhc/mzh006 https://doi.org/10.1186/1472-698x-6-10 https://doi.org/10.1186/1472-698x-6-10 https://doi.org/10.4314/mmj.v22i1.55899 https://doi.org/10.1016/j.puhe.2005.10.014 https://doi.org/10.1111/j.1479-8077.2005.00143.x https://doi.org/10.19082/3102 https://doi.org/10.19082/3102 https://doi.org/10.1186/1472-6963-7-162 https://doi.org/10.1186/1472-6963-7-162 https://doi.org/10.1191/0969733004ne742oa https://doi.org/10.1191/0969733004ne742oa https://doi.org/10.1525/jer.2013.8.3.46 https://doi.org/10.9790/1959-0255560 https://doi.org/10.9790/1959-0255560 awareness of the importance of and adherence to patients’ rights among physicians and nurses in oman an analytical cross-sectional study across different levels of healthcare e208 | squ medical journal, august 2019, volume 19, issue 3 33. arbabisarjou a, zare s, shahrakipour m, kadkhodaie a. the rate of nurses’ awareness about patient’s bill of rights in teaching hospitals affiliated to the zahedan university of medical sciences in 2016. int j med res health sci 2016; 9s:620–4. 34. rehmani r, norain a. trends in emergency department utilization in a hospital in the eastern region of saudi arabia. saudi med j 2007; 28:236–40. 35. panda a, pradhan s, mohapatro g, kshatri js. predictors of over-the-counter medication: a cross-sectional indian study. perspect clin res 2017; 8:79–84. https://doi.org/10.4103/22293485.203043. 36. kagoya hr, kibuule d, mitonga-kabwebwe h, ekirapa-kiracho e, ssempebwa jc. awareness of, responsiveness to and practice of patients’ rights at uganda’s national referral hospital. afr j prim health care fam med 2013; 5:491. https://doi.org/10.4 102/phcfm.v5i1.491. 37. anbari z, mohammadi m, taheri m. satisfying patients’ rights in iran: providing effective strategies. iran j nurs midwifery res 2015; 20:184–9. https://doi.org/10.4103/2229-3485.203043 https://doi.org/10.4103/2229-3485.203043 https://doi.org/10.4102/phcfm.v5i1.491 https://doi.org/10.4102/phcfm.v5i1.491 departments of 1computer science, 2biochemistry, 3biology, 5genetics and 7physiology, sultan qaboos university, muscat, oman; 4mohammed bin rashid university for medicine and health science, dubai, united arab emirates; 6department of sleep medicine and physiological measurements, canadian health center, muscat, oman *corresponding author’s e-mail: ahamid@squ.edu.om estimate of the homa-ir cut-off value for identifying subjects at risk of insulin resistance using a machine learning approach *abdelhamid abdesselam,1 hamza zidoum,1 fahd zadjali,2 rachid hedjam,1 aliya al-ansari,3 riad bayoumi,4 said al-yahyaee,5 mohammed hassan,6 sulayma albarwani7 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 604–612, epub. 25 nov 21 submitted 10 apr 20 revisions req. 1 jul & 9 nov 20; revisions recd. 25 sep & 23 nov 20 accepted 3 dec 20 https://doi.org/10.18295/squmj.4.2021.030 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study describes an unsupervised machine learning approach used to estimate the homeostatic model assessment-insulin resistance (homa-ir) cut-off for identifying subjects at risk of ir in a given ethnic group based on the clinical data of a representative sample. methods: the approach was applied to analyse the clinical data of individuals with arab ancestors, which was obtained from a family study conducted in nizwa, oman, between january 2000 and december 2004. first, homa-ir-correlated variables were identified to which a clustering algorithm was applied. two clusters having the smallest overlap in their homa-ir values were retrieved. these clusters represented the samples of two populations, which are insulin-sensitive subjects and individuals at risk of ir. the cut-off value was estimated from intersections of the gaussian functions, thereby modelling the homa-ir distributions of these populations. results: a homa-ir cut-off value of 1.62 ± 0.06 was identified. the validity of this cut-off was demonstrated by showing the following: 1) that the clinical characteristics of the identified groups matched the published research findings regarding ir; 2) that a strong relationship exists between the segmentations resulting from the proposed cut-off and those resulting from the two-hour glucose cut-off recommended by the world health organization for detecting prediabetes. finally, the method was also able to identify the cut-off values for similar problems (e.g. fasting sugar cut-off for prediabetes). conclusion: the proposed method defines a homa-ir cut-off value for detecting individuals at risk of ir. such methods can identify high-risk individuals at an early stage, which may prevent or delay the onset of chronic diseases such as type 2 diabetes. keywords: unsupervised machine learning; cluster analysis; insulin resistance; diabetes mellitus, type ii. advances in knowledge a machine learning approach to estimate the homeostatic model assessment-insulin resistance (homa-ir) cut-off value for identifying individuals at risk of ir in a given ethnic group is described. identification of subjects at risk is fast and inexpensive since it consists of comparing an individual’s homa-ir value to the defined cutoff. a homa-ir cut-off value of 1.62 is proposed to identify individuals at risk of ir among the arab population living in nizwa, oman. applications to patient care identified at-risk individuals are recommended to undergo an additional investigation using the euglycaemic clamp test for confirming or rejecting the diagnosis. this is of high importance for public health, as it identifies high-risk individuals at an early stage, which may prevent or at least delay the onset of chronic diseases such as type 2 diabetes and cardiovascular disease. insulin resistance (ir) is a synonym for impaired insulin action, such as inhibition of hepatic glucose production and insulinmediated glucose disposal.1,2 ir increases the incidence of metabolic syndrome (mets), which has emerged as a major pathophysiological factor in the development and progression of many common noncommunicable diseases, including type 2 diabetes mellitus (t2dm), polycystic ovary syndrome, dyslipidaemia, hypertension, cardiovascular disease (cvd), obesity and cancer.2,3 detecting this condition is, therefore, significantly important for public health. several studies have illustrated a high prevalence of diabetes, impaired glucose tolerance, obesity and hypertension among arab populations of the middle east.4 in oman, the first cause of premature death is cvd, and the fourth cause is t2dm.5 therefore, there is a need to prevent and control cvd and t2dm in oman. ir is an early marker of the development of these diseases; primary prevention requires the identification of high-risk individuals at an early stage. the gold standard for investigating and quantifying ir is the hyperinsulinaemic (euglycaemic) clamp.6 given the complicated nature of the ‘clamp’ technique and potential dangers of hypoglycaemia in some patients, several surrogate estimates for ir have been proposed, abdelhamid abdesselam, hamza zidoum, fahd zadjali, rachid hedjam, aliya al-ansari, riad bayoumi, said al-yahyaee, mohammed hassan and sulayma albarwani clinical and basic research | 605 such as the homeostatic model assessment (homair), quicki and matsuda.6–8 homa-ir is the most popular among all of these indices due to the simplicity of the underlying mathematical model (homa-ir = fasting glucose (mm) × fasting insulin (mu/l)/22.5). homa-ir has been validated to be highly correlated with the hyperinsulinaemic (euglycaemic) clamp (r = 0.82; p <0.0001) as well as with the minimal model approximation of the metabolism of glucose (r = −0.66; p <0.001).9,10 several studies have shown that the cutoff value for homa-ir depends on the ethnicity of the subjects.5,11 therefore, this value has to be adapted for each ethnic group to reflect the prevailing normal glycaemic level. several statistical methods for estimating the homa-ir cut-off value have been reported in the literature. most of these methods determine the cutoff values from reference ranges where percentiles or receiver operating characteristic (roc) curves are applied.2 the use of the percentile method of analysis within a general population lacks the classification of subjects; therefore, it lacks sensitivity and specificity. reported roc curve analyses are limited, as they are based on healthy subjects and patients with t2dm or mets, whereas ir is well established in an advanced disease state. machine learning (ml) is a discipline of artificial intelligence that has proven to be very efficient in solving classification and prediction problems. the majority of ml algorithms can be categorised into two groups.12 the first category is supervised ml where a model is trained on a range of inputs (variables or features) that are associated with known outcomes (labels). in medicine, this might represent training a model to relate a person’s characteristics (e.g. height, weight and smoking status) to a certain outcome (e.g. onset of diabetes within five years). once the algorithm is successfully trained, it becomes capable of making predictions when applied to new data. when the prediction is discrete (e.g. benign or malignant), the model is referred to as a classification. however, when it is of a continuous value (e.g. an individual’s life expectancy), the model is referred to as a regression. the most common supervised learning algorithms used in medicine are decision trees, logistic regression, support vector machines and artificial neural networks. the second category is unsupervised learning, which does not involve predefined outcomes (labels) and does not need a training phase. this learning type is used to find hidden structures (or clusters) that occur within datasets. the most common methods used in this category are dimension reduction algorithms such as principal component analysis (pca), association rules generation such as association rule mining and clustering algorithms such as k-means and a selforganising map. recently, several ml-based methods for defining homa-ir cut-off values have been proposed. altuve et al.13 employed a k-means clustering algorithm to perform an unsupervised classification of subjects based on unidimensional observations (homa-ir and the matsuda indexes separately) and multidimensional observations (insulin and glucose samples obtained from the oral glucose tolerance test). their results indicated that when using the homa-ir index alone, the clusters are related to ir; however, when using homa-ir with other variables, the insulin-resistant cluster also contains normal samples. they argued that this could indicate that the normal samples either develop ir or already have the metabolic disorder. one of the drawbacks of this work was that it labelled subjects with homa-ir greater than 2.5 as insulin resistant, which is not necessarily true. stern et al. developed three decision trees (decision rules) based on clinical and laboratory measurements of 2,321 individuals from 17 european sites, san antonio, texas and the pima indian reservation.14 the first model was based on both clinical and laboratory measurements; it achieved an area under curve (auc) of 90%. the second model was developed from clinical variables only and achieved an auc of 85%. the last one was developed from clinical and lipid measurements and achieved an auc of 85%. these results indicated that ir can be defined using simple decision trees. qu et al. proposed an ml approach to defining the homa-ir cut-off for americans of mexican descent.11 they first identified homa-ir-correlated variables using two classification methods (support vector machine and bayesian logistic regression); then, they ran a clustering algorithm (k-means with k = 2) using the identified variables to obtain two reference groups representing insulin-resistant and normal individuals. finally, the sensitivity and specificity of a series of homa-ir cut-off values were tested against the reference groups using matthews’ correlation coefficient (mcc). a cutoff value of 3.80 corresponding to the highest mcc value was chosen. in this study, an unsupervised ml method is proposed, which given a statistically representative sample of an ethnic group, automatically estimates a homa-ir cut-off value for identifying individuals at risk of ir. this approach was applied to an omani population living in nizwa, oman, but it can be used to estimate the appropriate homa-ir cut-off value of any other population based on the clinical and biochemical variables of a statistically representative sample. estimate of the homa-ir cut-off value for identifying subjects at risk of insulin resistance using a machine learning approach 606 | squ medical journal, november 2021, volume 21, issue 4 methods data were obtained from the oman family study, which was conducted during the period 2000–2004.15 the dataset was obtained from a previous study on 1,344 individuals of arab ancestry as part of the oman family study conducted in the nizwa region of oman.15–17 the data included measures of 26 variables representing anthropometric data, 24-hour systolic and diastolic blood pressures (syst and diast, respectively), fasting and two-hour glucose and insulin, fasting lipid profile, hormone profile and liver function test. study parameters were measured using a standard clinical biochemistry lab. plasma insulin, growth hormone, free thyroxine (ft4) and triiodothyronine (ft3) were measured using the automated beckman coulter access 2 immunoassay system (beckman coulter, california, usa). plasma leptin (lept) levels were measured using a coated tube immuno-radiometric kit (diagnostic systems laboratories, texas, usa). for routine biochemical parameters, the automated beckman synchron cx7 (beckman coulter) was used to measure plasma glucose, glycated haemoglobin (hba1c), total cholesterol (chol) and high-density lipoprotein (hdl) cholesterol, triglycerides (tg) and alanine transaminase (alt). very-low-density lipoprotein (vldl) and ldl lipoprotein were calculated as follows: vldl (mmol/l) = tg (mmol/l) / 2.2 and ldl (mmol/l) = chol − (vldl + hdl). the 24-hour ambulatory blood pressure (bp) was also measured (schiller ag, baar, switzerland). the percentage of total body fat was measured using the electro-impedance model. further details on data collection have been described by bayoumi et al. and zadjali et al.16,18 a data cleaning operation was conducted to remove samples with missing data or outlier values. details of this operation are provided in the results section. the final cleaned dataset included the measurements of 26 clinical variables collected from 798 individuals (338 males and 460 females). to determine the homa-ir cut-off, a three-step approach was adopted, which was similar to the one adopted by qu et al.11 for analysing the americans of mexican descent dataset; however, different techniques were used in this study. first, the homair-correlated variables were identified. then, this study’s own clustering algorithm was run to identify two reference groups representing samples of the two populations—individuals at risk of ir and those with normal insulin sensitivity (nir), respectively. based on the assumption that the homa-ir values of the two populations were normally distributed, the parameters of their gaussian functions were estimated, and their intersections were used as an estimate of the sought cut-off value. a detailed description of this process is provided in subsequent sections. there were three major differences with qu et al.’s approach. firstly, qu et al.’s feature selection method was based on two classification techniques (support vectors machine and bayesian logistic regression) trained on a labelled dataset (where patients with homa-ir >2.6 were labelled as insulin resistant and the rest as normal, which was questionable since the objective was to precisely define this threshold).11 however, in the method adopted by the current researchers, the selection did not depend on any initial assumption about the homa-ir cut-off; instead, a statistical technique (pearson correlation) was used to pre-select a subset of homa-ir-correlated variables. secondly, qu et al. used a k-means algorithm to determine the two reference groups, while a new clustering algorithm (minimum overlap k-means clustering algorithm) was developed for determining the two reference groups for the present work. finally, qu et al. tested several cut-off values in the range (minimum homa-ir value, maximum homa-ir value) and selected the value that best fit the reference groups. their best fit was identified using mcc, while the cut-off in this study was defined by the intersection of the gaussian functions that modelled the homa-ir distributions of the two populations—individuals at risk of ir and those with nir. the following subsections contain additional details about the proposed method, indicate the assumptions of the researchers and provide their justifications for making those assumptions. as mentioned above, the first step in the method proposed in this study consisted of determining two reference groups representing the samples of two populations. since ir is a complex metabolic disorder that may impact the levels of several correlated clinical variables, identifying and including those variables in the analysis process might lead to early detection of the disorder.19 for this reason, the researchers’ clustering operation included, in addition to homair, a selected subset of variables that correlated with homa-ir. moreover, it is known that feature selection is used to remove irrelevant, redundant and ‘noisy’ features. this process has several advantages.20 it speeds up the learning process and allows the building of a simpler and more accurate model, which leads to better predictors. the researchers’ feature selection algorithm consisted of ranking the variables according to their correlations with homa-ir and eliminating those with low correlation values. the relevance of a feature f to homa-ir was evaluated using the pearson correlation coefficient defined in the following equation: abdelhamid abdesselam, hamza zidoum, fahd zadjali, rachid hedjam, aliya al-ansari, riad bayoumi, said al-yahyaee, mohammed hassan and sulayma albarwani clinical and basic research | 607 where cov(x,y) is the covariance between features x and y, and σx is the standard deviation of feature x. with the remaining features, all possible combinations (subsets) were generated and the one that produced the best binary clustering using the k-means++ algorithm was selected. the best clustering was defined as the one that minimised the overlap between the homa-ir values of the resulting clusters. this process was called the minimum overlap k-means clustering algorithm. since k-means is known to minimise within-cluster variances, adding the minimum overlap between the homa-ir means constraint resulted in a clustering having a double property—samples from the same cluster had similar clinical characteristics (k-means property), and those in two different clusters had significantly different homa-ir values (minimum overlap property). therefore, it was speculated that the two resulting clusters contained subjects with nir and those at risk of ir, respectively. the two identified clusters were simply samples of the two populations—individuals at risk of ir and those with nir. their respective homa-ir means (mean_ir, mean_nir) and standard deviations (std_ir, std_nir) were used to estimate the means and standard deviations of the populations they represented as well as the 95% confidence intervals [mean_ir1, mean_ir2] and [mean_nir1, mean_ nir2] for the estimated means.21 the x-coordinate (cut-off 1) of the intersection point between the gaussian functions modelled by the means of ir1 and nir1 along with their standard deviations represented the lower value of the sought cut-off point. while the x-coordinate (cut-off 2) of the intersection point between the gaussian functions modelled by the means of ir2 and nir2 along with their standard deviations represented the upper value of the sought cut-off point. the homa-ir cut-off value was set to (cut-off 1 + cut-off 2)/2, and the confidence interval to [cut-off 1, cut-off 2]. the main assumption made in these calculations was the normality of the two populations based on the normality of large samples from these populations. the major processes of the proposed method consisted of the following: first, a list l most correlated variables with homa-ir was selected using the pearson correlation; then, the k-means++ algorithm (k set to 2) was applied to each subset of the list l. the subset producing clusters with the least overlap in terms of homa-ir values were selected and the two resulting clusters represented the samples of the two populations. finally, the intersections of the gaussian functions modelling the two populations’ homa-ir distributions were used to define the sought cut-off point and its confidence interval as explained earlier. this study was approved by the medical research committee at sultan qaboos university. written and signed or thumb-printed and rubber-stamped informed consent was obtained from each participant or a parent and/or legal guardian if participants were under the age of 18 years. results all calculations were performed using python and related libraries, including the ml library sklearn (https://scikit-learn.org) and the statistics library scipy.stats (https://docs.scipy.org/doc/scipy/reference/ stats.html). as mentioned earlier, the initial dataset consisted of 1,344 samples. first, samples having missing data in any of the 26 variables were removed. this resulted in a new dataset of 1,003 samples. then, the outliers (those samples with homa-ir values’ z-scores >3) were identified and removed, which resulted in a final dataset size of 798 samples that had valid values for 26 variables (338 males and 460 females). correlation values between homa-ir and the 26 variables were calculated. variables with correlation values less than 0.1 were removed, which led to a subset of 16 variables: fasting plasma insulin (insu0), fasting plasma glucose (sug0), two-hour postprandial glucose concentration (sug2), lept, waist circumference (wst), body mass index (bmi), vldl, tg, percentage of fat (perf), 24-hour diast and syst, hba1c, chol, alt, human growth hormone (hgh) and ft4. sug0 and insu0 were also removed from the list to avoid having a clustering result dominated by these two variables, as they were redundant with the homa-ir variable that was included in the clustering process (homa-ir = [sug0 × insu0]/22.5). the main benefit of the preselection step was that it significantly reduced the search space in the feature selection stage (from 226 subsets to 214 subsets) as well as reduced the noise effect that the non-correlated (and weakly-correlated) variables with homa-ir would have created on the clustering results. table 1 shows the correlation values between homa-ir and the 26 variables. all possible subsets of the 14 variables (i.e. 16,383 subsets) were generated to which the proposed minimum overlap k-means clustering algorithm was applied. the variable values were codified using reference ranges that were consistent with the recommendations of the world health organization corr(ƒ, homa-ir) = cov(ƒ, homa-ir) σƒσ homa-ir [equation 1] estimate of the homa-ir cut-off value for identifying subjects at risk of insulin resistance using a machine learning approach 608 | squ medical journal, november 2021, volume 21, issue 4 and the omani ministry of health.22,23 figure 1 shows the homa-ir histograms of the two reference groups, which were produced as a result of the clustering. the first group consisted of 621 individuals representing a sample of the non-insulin-resistant population; it had a homa-ir mean of 0.88 ± 0.43. the second group consisted of 177 individuals representing a sample of individuals at risk of ir; it had a homa-ir mean of 2.71 ± 0.88. the optimal subset of variables producing these groups consisted of homa-ir, vldl, syst and alt. normality tests on the homa-ir values of the two groups were conducted using the python function (scipy.stats.normaltest) that implements d’agostino and pearson’s algorithm. this algorithm combines skew and kurtosis to produce an omnibus test of normality.24 the results obtained (p = 6.74e-14 for the normal group and p = 2.06e-12 for the ir group) confirmed the normality of the two samples’ homair values. their respective homa-ir means and standard deviations (0.88 ± 0.43, 2.71 ± 0.88) were used to estimate the 95% confidence intervals of the nir and ir population’s means (0.84–0.91 and 2.58–2.84, respectively).21 the x-coordinate of the intersection of the gaussian functions modelled by (0.84, 0.43), (2.58, 0.88) was equal to 1.56. it represented the lower value of the sought homa-ir cut off, and the x-coordinate of the intersection of the gaussian functions modelled by (0.91, 0.43), (2.84, 0.88) was equal to 1.68. it represented the upper value of the sought homair cut off. the homa-ir cut-off was set to (1.56 + 1.68)/2 = 1.62 and the confidence interval to (1.56– 1.68). figure 2 shows the gaussians’ graphs that modelled the two populations and their intersections. ideally, such work should be evaluated either by testing its performance on a labelled dataset (dataset where the samples are labelled as insulin resistant or normal) or using a longitudinal study where the validity of the predictions made by the method is checked against the evolution of the health status of the subjects. since none of these possibilities were available to the researchers, alternative means were adopted for the evaluation. as an alternative way to quantitatively evaluate the performance of the method, it was used to solve a similar problem where labelled data were available. the chosen problem was related to the definition of the sug0 cut-off for identifying prediabetes, since this study’s dataset could be used and the samples could be labelled based on the standard cut-off value of 5.6 mm. the sug0-correlated variables were first identified, and the minimum overlap k-means clustering algorithm was applied to them. the sug0 means and standard deviations of the resulting reference groups were used to estimate the means and standard deviations of the corresponding populations and to evaluate the cut-off value. the identified sug0 cutoff was 5.89 mm and the 95% confidence interval was (5.83–5.95). this study’s dataset was then segmented using both cut-off points (5.6 mm and 5.89 mm) and the level of agreement between the two classifications was evaluated. two agreement measures were used;25 the first was the percent agreement, which was defined as follows: table 1: correlation coefficients between the variables and homa-ir parameter r p value insu0 in mm 0.975 <0.0001 sug0 in mm 0.442 <0.0001 lept in ng/ml 0.389 <0.0001 waist circumference in cm 0.337 <0.0001 body mass index in kg/m2 0.322 <0.0001 percentage of fat 0.297 <0.0001 diast in mmhg 0.273 <0.0001 hba1c in % 0.270 <0.0001 sug2 in mm 0.250 <0.0001 syst in mmhg 0.228 <0.0001 tg in mm 0.206 <0.0001 vldl in mm 0.205 <0.0001 alt in u/l 0.189 <0.0001 total cholesterol in mm 0.145 <0.0001 plasma cortisol in nmol/l 0.097 0.014 alp in u/l 0.091 0.014 age in years 0.076 0.0001 tsh in mu/l 0.057 0.091 gender 0.012 0.800 hdl in mm -0.060 0.002 plasma albumin in g/dl -0.060 0.023 ige in u/ml -0.066 0.043 total plasma proteins in g/l -0.079 0.087 total bilirubin in μmol/l -0.095 0.001 hgh in ng/ml -0.108 0.066 ft4 in μg/dl -0.147 <0.0001 homa-ir = homeostatic model assessment-insulin resistance; insu0 = fasting plasma insulin; sug0 = fasting blood glucose; lept = plasma leptin; diast = diastolic blood pressure; hba1c = glycated haemoglobin; sug2 = two-hour blood glucose; syst = systolic blood pressure; tg = plasma triglycerides; vldl = very-low-density lipoprotein; alt = alanine amino transferase; alp = alkaline phosphatase; tsh = thyroid-stimulating hormone; hdl = high-density lipoprotein; ig = immunoglobulin; hgh = human growth hormone; ft4 = free thyroxine. abdelhamid abdesselam, hamza zidoum, fahd zadjali, rachid hedjam, aliya al-ansari, riad bayoumi, said al-yahyaee, mohammed hassan and sulayma albarwani clinical and basic research | 609 the second was the kappa agreement, which was defined as follows: where pr(a) is the observed agreement, and pr(e) is the chance agreement. the percent agreement value was 0.89 and the kappa agreement value was 0.72. these results demonstrated the suitability of the proposed method for defining the sug0 cut-off for prediabetes identification. a chi-square test for independence shows how two sets of data are independent of each other. in this study, a chi-square test was used to check the relationship between the segmentation resulting from the identified homa-ir cut-off value (1.62) and the segmentation produced by the standard sug2 cut-off value (7.8 mm) for identifying pre-diabetes. table 2 summarises the distribution of the samples among the four categories (non-ir who are normal, non-ir who are pre-diabetic or diabetic, ir who are normal and ir who are pre-diabetic or diabetic). the python function (scipy.stats.chi2_contin gency) returned a chi-square statistic of 21.10, and a p value of 4.37e-6, which indicated a strong relationship between the two segmentations. table 3 shows the means and standard deviations of the clinical variable values for the two groups resulting from the segmentation by a homa-ir threshold of 1.62. the table shows that the mean values of almost all variables were higher for the ir group (i.e. group at risk of ir) than the nir group (i.e. the normal group). the only variable that showed an opposite relationship was ft4. table 2: distribution of this study’s dataset samples among the four categories defined by the homa-ir cut-off value of 1.62 and sug2 cut-off value of 7.8 mm two-hour glucose non-diabetic prediabetic and diabetic nir (below the cut-off value of 1.62) 523 63 ir (above the cut-off value of 1.62) 162 50 homa-ir = homeostatic model assessment-insulin resistance; sug2 = two-hour postprandial glucose concentration; nir = normal insulin sensitivity; ir = insulin resistance. figure 1: homeostatic model assessment-insulin resistance histograms with insulin resistance (ir) reference group (red) and non-ir reference group (green). figure 2: gaussian graphs modelling the two populations and used for estimating the homeostatic model assessmentinsulin resistance cut-off value. number of agreements pr(a) pr(e) [equation 2] [equation 3]k = number of total scores 1 pr(e) estimate of the homa-ir cut-off value for identifying subjects at risk of insulin resistance using a machine learning approach 610 | squ medical journal, november 2021, volume 21, issue 4 discussion the proposed ml approach was adopted to define the homa-ir cut-off value for identifying individuals at risk of ir among an omani arab population living in nizwa. a cut-off value of 1.62 was obtained as optimum. this value was within the range of literaturereported cut-off values (1.44–3.87) for different ethnic groups [table 4]. the experiment described in this work demonstrated the validity of the proposed approach in identifying cut-off values in cases of problems similar to the one under investigation. the result of the chi-square test (p = 4.36e-6) indicated a strong relationship between the two segmentations: ir/nir and normoglycaemia/hyper glycaemia. table 2 shows that 89.25% of the nir individuals (523 out of 586) were characterised as having normoglycaemia as expected from the nir individuals. it also shows that there were 162 (23.65%) individuals with normoglycaemia who were included in the ir category. as in the case of altuve et al., it was argued by the researchers that these might have been the subjects who were developing ir or already had the metabolic disorder.13 such individuals should undergo a more thorough medical investigation starting with a euglycaemic clamp, which might help in identifying ir individuals at an early stage and, therefore, prevent or at least delay the onset of chronic disease. the mean values in the ir group were larger than those in the nir group for almost all variables [table 3]. the only variable that showed an opposite relationship was ft4. a quick review of the literature indicated that these results aligned with the outputs of several research works. for example, a seventable 3: characteristics of the identified clusters variable* mean ± sd p value ir nir insu0 in mm 9.82 ± 3.16 3.49 ± 1.61 <0.001 sug0 in mm 5.84 ± 0.77 5.32 ± 0.54 <0.001 sug2 in mm 6.89 ± 2.32 6.21 ± 1.52 <0.001 plasma leptin in ng/ml 37.67 ± 25.66 22.56 ± 19.32 <0.001 body mass index in kg/m2 26.96 ± 4.94 24.11 ± 4.59 <0.001 waist circumference in cm 86.34 ± 14.47 78.20 ± 12.53 <0.001 vldl in mm 0.52 ± 0.28 0.41 ± 0.23 <0.001 tg in mm 1.15 ± 0.62 0.91 ± 0.51 <0.001 percentage of fat 26.89 ± 10.41 21.93 ± 9.65 <0.001 diast in mmhg 82.82 ± 8.61 77.58 ± 8.47 <0.001 syst in mmhg 124.65 ± 11.73 118.87 ± 11.89 <0.001 hba1c in % 5.47 ± 0.70 5.15 ± 0.63 <0.001 total cholesterol in mm 4.96 ± 1.05 4.72 ± 1.03 <0.001 alt in u/l 22.25 ± 12.43 17.97 ± 9.85 <0.001 ft4 in μg/dl 10.14 ± 1.64 10.48 ± 1.75 <0.001 homa-ir 2.54 ± 0.89 0.83 ± 0.39 <0.001 sd = standard deviation; ir = insulin resistance; nir = normal insulin sensitivity; insu0 = fasting plasma insulin; sug0 = fasting blood glucose; sug2 = two-hour blood glucose; vldl = very-low-density lipoprotein; tg = plasma triglycerides; diast = diastolic blood pressure; syst = systolic blood pressure; hba1c = glycated haemoglobin; alt = alanine aminotrans ferase; ft4 = free thyroxine; homa-ir = homeostatic model assessment insulin resistance. *only variables with a correlation with homa-ir ≥0.1 are shown. table 4: some homa-ir cut-offs reported in the lit erature2,11,32,33 country subjects cutoff statistical method sweden healthy population 2.00 75th percentile france healthy population 3.80 75th percentile brazil healthy adult subjects 2.77 90th percentile usa healthy adult subjects (hispanic and non-hispanic) 2.73 66th percentile usa cross-sectional sample of adults 3.80 ml (clustering) portugal non-obese nondiabetic adults 2.33 90th percentile iran healthy adult subjects 3.87 roc classified by mets iran cross-sectional sample (healthy and diabetic adult women) 2.63 95th percentile china healthy children and adolescents 3.00 95th percentile japan cross-sectional sample of nondiabetic adults 1.70 roc classified by mets caucasus rural population, non-diabetic 2.29 75th percentile thailand cross-sectional sample 1.55 90th percentile china (hong kong) cross-sectional sample 1.44 75th percentile 2.03 75th percentile 90th percentile homa-ir = homeostatic model assessment-insulin resistance ; ml = machine learning ; roc = receiver operating characteristic; mets = metabolic syndrome. abdelhamid abdesselam, hamza zidoum, fahd zadjali, rachid hedjam, aliya al-ansari, riad bayoumi, said al-yahyaee, mohammed hassan and sulayma albarwani clinical and basic research | 611 year longitudinal study conducted on 1,734 subjects concluded that converters to t2dm had significantly higher bmi, wst, tg concentration and bp than non-converters.26 ir was found to be associated with increased tg and vldl levels and decreased hdl levels.27,28 liver function tests are frequently ordered for patients with mets to monitor the development of non-alcoholic fatty liver disease. a study involving 1,309 non-diabetic individuals concluded that increased m-glutamyltransferase and alt were biomarkers of both systemic and hepatic ir.29 additionally, sub-clinical hypothyroidism is associated with higher insulin levels and ir, which correlates positively with thyroid-stimulating hormone (tsh) levels and negatively with ft3 and ft4.30 lept is a body fat biomarker that can play a major role as a predictor of ir syndrome; a study conducted on 80 individuals showed a positive relationship between lept and ir syndrome.31 the current study described an unsupervised ml approach for assessing the ir condition using the clinical data of a sample representing an ethnic group while taking into consideration the confounding variables. it allowed the researchers to estimate a cutoff homa-ir value that identifies individuals at risk of ir. this threshold can be used as a warning signal, suggesting that subjects with homa-ir greater than the identified threshold should undergo the hyperinsulinaemic (euglycaemic) clamp to confirm or reject the prognosis. it is the responsibility of the clinician to ensure that the health condition of the patient permits conducting the proposed test. to further validate this cut-off value, a longitudinal follow-up study on healthy subjects is warranted to study the prognostic power of the cut-off value in identifying subjects who develop t2dm. moreover, it would be more informative to apply this approach to samples of the major ethnic groups living in different parts of oman. the output of such research work is expected to define ethnicity-dependent homa-ir cut-off values. finally, it should be indicated that the proposed approach depends on three important factors: 1) at the data collection level, samples included in the dataset should be statistically representative of the ethnic group under investigation; 2) during the implementation of the code associated with the proposed approach, there is a need to properly tune two parameters—the one identifying the outliers that are to be removed and the one indicating the correlated variables that are to be kept; 3) the normality (or near normality) of the ir and nir populations. conclusion the homa-ir model is a good indicator of insulin sensitivity in population studies and displays ethnic variability in the cut-off values. in this study, a cut-off value of 1.62 ± 0.06 was identified in an arab omani population living in nizwa. this approach will be helpful in future population studies concerning t2dm and mets. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n aa, fz and aa-a conducted the literature review. aa, hz and rh designed the model. rb, sy, mh and sa collected the data. aa, fz and rb analysed the results. hz, rh and aa-a edited the manuscript. all authors reviewed and approved the final version of the manuscript. references 1. wu c-z, lin j-d, hsia t-l, hsu c-h, hsieh c-h, chang j-b, et al. accurate method to estimate insulin resistance from multiple regression models using data of metabolic syndrome and oral glucose tolerance test. j diabetes investig 2014; 5:290–6. https://doi.org/10.1111/jdi.12155. 2. tang q, li x, song p, xu l. optimal cut-off values for the homeostasis model assessment of insulin resistance (homair) and prediabetes screening: developments in research and prospects for the future. drug discov ther 2015; 9:380–5. https://doi.org/10.5582/ddt.2015.01207. 3. patel tp, rawal k, bagchi ak, akolkar g, bernardes n, da silva dias d, et al. insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes. heart fail rev 2016; 21:11–23. https://doi.org/10.1007/s10741-0159515-6. 4. al-lawati ja, mohammed aj, al-hinai h, jousilahti p. prevalence of the metabolic syndrome among omani adults, diabetes care 2003; 26:1781–5. 5. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 6. greenfield ms, doberne l, kraemer f, tobey t, and reaven g. assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. diabetes 1981; 30:387–92. https://doi.org/10.2337/diab.30.5.387. 7. chen h, sullivan g, and quon mj. assessing the predictive accuracy of quicki as a surrogate index for insulin sensitivity using a calibration model. diabetes 2005; 54:1914–25. https:// doi.org/10.2337/diabetes.54.7.1914. 8. matsuda m and defronzo ra. insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. diabetes care 1999; 22:1462–70. https://doi.org/10.2337/diacare.22.9.1462. estimate of the homa-ir cut-off value for identifying subjects at risk of insulin resistance using a machine learning approach 612 | squ medical journal, november 2021, volume 21, issue 4 9. bonora e, targher g, alberich m, bonadonna r, saggiani f, zenere mb, et al. homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. diabetes care 2000; 23:57–63. https://doi.org/10.2337/diacare.23.1.57. 10. ascaso jf, pardo s, real jt, lorente r, priego a, carmena r. diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. diabetes care 2003; 26:3320–5. 11. qu h-q, li q, rentfro ar, fisher-hoch sp, mccormick jb. the definition of insulin resistance using homa-ir for americans of mexican descent using machine learning. plos one 2011; 6:e21041. https://doi.org/10.1371/journal.pone.0021041. 12. sidey-gibbons jam, sidey-gibbons cj. machine learning in medicine: a practical introduction. bmc med res methodol 2019; 19:64. https://doi.org/10.1186/s12874-019-0681-4. 13. altuve m, severeyn e, wong s. unsupervised subjects classification using insulin and glucose data for insulin resistance assessment. 2015 20th symposium on signal processing, images and computer vision (stsiva), bogota 2015. pp. 1–7. https://doi.org/10.1109/stsiva.2015.7330444. 14. stern se, williams k, ferrannini e, defronzo ra, bogardus c, stern mp. identification of individuals with insulin resistance using routine clinical measurements. diabetes 2005; 54:333–9. https://doi.org/10.2337/diabetes.54.2.333. 15. man t, nolte im, jaju d, al-anqoudi zam, munoz ml, hassan mo, et al. heritability and genetic correlations of obesity indices with ambulatory and office beat-to-beat blood pressure in the oman family study. j hypertens 2020; 38:1474–80. https://doi.org/10.1097/hjh.0000000000002430. 16. bayoumi ra, al-yahyaee sa, albarwani sa, rizvi sg, alhadabi s, al-ubaidi ff, et al. heritability of determinants of the metabolic syndrome among healthy arabs of the oman family study. obesity (silver spring) 2007; 15:551–6. https:// doi.org/10.1038/oby.2007.555. 17. hassan mo, albarwani s, al yahyaee s, al haddabi s, rizwi s, jaffer a, et al. a family study in oman: large, consanguineous, polygamous omani arab pedigrees. community genet 2005; 8:56–60. https://doi.org/10.1159/000083341. 18. zadjali f, al-yahyaee s, hassan mo, albarwani s, bayoumi ra. association of adiponectin promoter variants with traits and clusters of metabolic syndrome in arabs: family-based study. gene 2013; 527:663–9. https://doi.org/10.1016/j.gene.20 13.06.057. 19. samuel vt, shulman gi. integrating mechanisms for insulin resistance: common threads and missing links. cell 2012; 148:852–71. https://doi.org/10.1016/j.cell.2012.02.017. 20. feng t. improving feature selection techniques for machine learning, ph.d. dissertation 2007, georgia state university. 21. navidi w. statistics for engineers and scientists, international edition. chap. 5, mcgraw-hill, 2006. 22. world health organization, idf. definition and diagnosis of diabetes mellitus and intermediate hyperglycemia 2006. from: https://www.who.int/diabetes/publications/definition%20 and%20diagnosis%20of%20diabetes_new.pdf accessed: nov 2020 23. barakat mn, al-shereiqi sz. operational and management guideline for the national non-communicable disease screening program, 2010; ministry of health, sultanate of oman. 24. d’agostino r, pearson es. tests for departure from normality, empirical results for the distributions of b2 and √ b1. biometrika 1973; 60:613–22. https://doi.org/10.2307/2335012. 25. mchugh ml. interrater reliability: the kappa statistic. biochem med (zagreb) 2012; 22:276–82. 26. haffner sm, mykkanen l, festa a, burke jp, stern mp. insulinresistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects. circulation 2000; 101:975–80. https://doi.org/10.1161/01.cir.101.9.975. 27. howard bv. insulin resistance and lipid metabolism. am j cardiol 1999; 84:28j–32j. https://doi.org/10.1016/s0002-9149(99)00355-0. 28. al-mahmood ak, afrin sf, hoque n. dyslipidemia in insulin resistance: cause or effect. bangladesh j med biochem 2014; 7: 27–31. 29. bonnet f, ducluzeau ph, gastaldelli a, laville m, anderwald ch, konrad t, et al. liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women. diabetes 2011; 60:1660–1667. https://doi.org/10.2337/db10-1806. 30. vyakaranam s, vanaparthy s, nori s, palarapu s, bhongir av. study of insulin resistance in subclinical hypothyroidism. int j health sci res 2014; 4:147–53. 31. shebl th, azeem na, younis ha, soliman am, ashmawy am, ali mmn. relationship between serum leptin concentration and insulin resistance syndrome in patients with type 2 diabetes mellitus. j current medical research and practice 2017; 2:125–32. https://doi.org/10.4103/jcmrp.jcmrp_33_16. 32. do hd, lohsoosthorn v, jiamjarasrangsi w, lertmaharit s, williams ma. prevalence of insulin resistance and its relationship with cardiovascular disease risk factors among thai adults over 35 years old. diabetes res clin pract 2010; 89:303–8. https:// doi.org/10.1016/j.diabres.2010.04.013. 33. lee ch, shih azl, woo yc, fong chy, leung oy, janus e, et al. optimal cut-offs of homeostasis model assessment of insulin resistance (homa-ir) to identify dysglycemia and type 2 diabetes mellitus: a 15-year prospective study in chinese. plos one 2016; 11:e0163424. https://doi.org/10.1371/journal. pone.0163424. squ med j, february 2011, vol. 11, iss. 1, pp. 104-108, epub. 12th feb 11 submitted 25th aug 10 revision req. 14th dec 10, revision recd. 18th dec 10 accepted 8th jan 11 vasoactive intestinal polypeptide (vip) secreting tumours are a rare cause of chronic1 or occasionally acute2 secretory diarrhoea and more than 90 percent are found in the pancreas.3 the tumour incidence is estimated to be one in 10 million persons per year.4 they are now referred to as vipomas; 10% of them are neural in origin and found mainly in children. the first description of an association between a pancreatic islet cell tumour and watery diarrhoea was by priest and alexander in 1957.5 one year later, verner and morrison described 2 similar patients.6 the association between watery diarrhoea and elevated vip levels was reported by bloom in 1973,7 and the clinical syndrome later confirmed when five healthy subjects developed profuse diarrhoea within 4 hours of receiving an infusion of porcine vip.8 synonyms include the watery-diarrhoeahypokalaemia-achlorhydria (wdha) syndrome, the verner-morrison syndrome and pancreatic cholera. functioning neuroendocrine tumours (nets) of the pancreas may secrete a variety of different polypeptides causing a variety of different syndromes; those that secrete an excess of vip are termed vipomas, and usually present with chronic refractory diarrhoea and are often malignant at presentation.1 differential diagnoses include enterotoxin production by vibrio cholera and e.coli, departments of 1medicine and 3pathology sultan qaboos university hospital, muscat, oman; departments of 2surgery, 4radiology & molecular imaging and 5medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman. *corresponding author email: omayma0@hotmail.com <‡⁄<ì€~ï<l^耓<ìè◊œje<ì~ç<ï^è£<îöá <é^œfic çë^iáë3“]<ö^œ√e<<t¯√÷]<çe<ƒ⁄<á]2÷]  57  20 12 100    :مفتاح الكلمات abstract: we report the case of a 57-year-old male physician who presented with a life threatening secretory and refractory diarrhoea of around 20 l/day. this was complicated by severe hypotension, hypokalaemia, hypercalcaemia, renal failure requiring dialysis, metabolic acidosis, cardiorespiratory arrest and ventilation for 12 days. his diarrhoea responded immediately to the first dose of a therapeutic trial of subcutaneous octreotide 100 mcg 8 hourly which was started on clinical grounds alone before any investigations were carried out. after one day he was extubated and his blood pressure returned to normal. when a functioning neuroendocrine tumour is suspected clinically, the use of octreotide can, as in this case, be life saving. keywords: vipoma; diarrhoea; pancreatic tumour; neuroendocrine tumour; octreotide; chromogranin a; cardiopulmonary arrest; case report; oman vipoma crisis immediate and life saving reduction of massive stool volumes on starting treatment with octreotide *omayma elshafie,1 christopher grant,2 aisha al-hamdani,3 rajeev jain,4 nicholas woodhouse5 case report omayma elshafie, christopher grant, aisha al-hamdani, rajeevjain and nicholas woodhouse case report | 105 rectal vilous adenomas and bile salt entropathy. case report a previously fit sri lankan doctor presented to his local hospital with a history of well controlled diabetes mellitus for 5 years and hypertension for 15 years; his medications were valsartan, atenolol and mixtard insulin. he had noted loose watery motions for 2–3 years which he attributed to irritable bowel syndrome (ibs). three months before being referred here, his diarrhoea had worsened and he was admitted with diabetic ‘ketoacidosis’ and treated with intravenous insulin (iv) and fluids. two days later, he developed acute renal failure requiring haemodialysis for 3 days. he was treated with ciprofloxacin and discharged after two weeks. three weeks later, he was again readmitted with profuse watery diarrhoea, confusion, vomitting and acute renal failure. investigations revealed creatinine >300 µmol/l (normal range [nr] 59–106), potassium 2.5 mmol/l (nr 3.5–5.0) and calcium of 3.5 mmol/l (nr 2.2–2.5). during catheter insertion for haemodialysis he vomited and aspirated his stomach contents resulting in a cardiorespiratory arrest. he was intubated and ventilated for 12 days during which time he had haemodialysis for three days, together with upper and lower gastrointestinal (gi) endoscopies which revealed a fluid filled stomach and colon with normal appearing mucosa. on his final admission to the referring hospital, he was started on ciprofloxacin, metronidazole, octreotide 50 mcg twice daily as a neuroendocrine tumour was considered as one of the differential diagnoses. after several days, however, the diarrhoea still persisted and metronidazole was added to treat possible antibiotic-associated diarrhoea. extubation failed on at least two occasions; he was then transferred to sultan qaboos university hospital by aeroplane on a ventilator, intravenous fluid and ionatropes. during the flight his blood pressure fell to 30 systolic. on arrival here, he was gravely ill with a blood pressure (bp) of 45/30 on dopamine and iv fluids. the serum creatinine was now 180 µmol/l, potassium 2.8 mmol/l, hco3 10 mmol/l (nr 22– 29), hb 19 gm/dl (n 11.5–15.0). the estimated stool volume before receiving octreotide was as much at 20 liters/day as within 12 hours he had passed 12 liters by rectal tube. an endocrine consultation was asked for 12 hours after his admission and based on his history, the presence of secretory odourless diarrhoea, hypokalaemia and metabolic acidosis, a clinical diagnosis of vipoma was made. the patient was then immediately started on a therapeutic trial of octreotide, 100 mcg 8 hourly, after taking blood samples to test for for vip, chromogranin a and other hormone levels. his response was dramatic and similar to a patient treated with long acting octreotide in 1985 who also had an immediate cessation of diarrhoea.9 one day later, the diarrhoea had improved substantially; he was extubated, the dopamine stopped and his bp returned to normal. by day four, his electrolyte profile was normal without any additional therapy [table 1]. an abdominal ultrasound revealed an 8 cm mass in the left upper quadrant. computed tomography (ct) and magnetic resonance imaging (mri) scans table 1: stool volume: response to octreotide 100 mcg 8 hourly. figure 1: mri scan showing pancreatic tail mass 8.2 x 7.5 cm with necrosis. vipoma crisis immediate and life saving reduction of massive stool volumes on starting treatment with octreotide 106 | squ medical journal, february 2011, volume 11, issue 1 [figure 1] of the abdomen revealed an 8.2 x 7.5 cm well encapsulated and necrotic pancreatic tail mass with no evidence of metastases. after three weeks on octreotide, the patient had gained 7 kg and felt quite normal. on day 21, he underwent a distal pancreatectomy and splenectomy [figure 2]. no liver, peritoneal or lymph node metastases were seen. the patient had an uneventful postoperative course and the diarrhoea has not since recurred. the octreotide was stopped four days after surgery. histological examination revealed a net with partial capsular invasion [figure 3] strongly positive for chromogrannin a [figure 4] and vip. a minority of cells were positive for glucagon and pancreatic polypeptide (pp). the margins of the pancreas were free of tumour and the spleen was normal. two weeks post surgery, the repeated vip test revealed a level of 46 and chromogranin a 37, both normal (table 2). an octreoscan performed 14 weeks after surgery showed no evidence of recurrence. discussion this patient’s symptoms improved immediately with the introduction of octreotide in a dose of 100 mcg thrice daily having previously failed to respond to a much smaller dose. vip is a 28 aminoacid polypeptide which is widely distributed throughout the body and normally functions as a neurotransmitter. in the gut, vip regulates the blood flow, smooth muscle activity, pancreatic and intestinal secretions and inhibits gastric acid production. it also stimulates intestinal water, sodium and chloride secretion, inhibits resorption and increases colonic potassium secretion.10 vipomas are rare nets with only 241 cases reported worldwide until 1998.11 our patient’s presentation was typical with copious watery odourless diarrhoea, hypokalaemia and metabolic acidosis.12 the secretory nature of the diarrhoea was confirmed by its failure to respond to fasting. hypokalaemia results from losses in the stool and the acidosis from a combination of dehydration, hypotension and renal failure which was profound in our patient due to his massive stool volumes estimated to be up to 20 litres/day. this is much more than the usually reported volumes of 6–8 litres daily,12.13 hyperglycaemia occurs in one third of patients and results from increased hepatic glucogenolysis caused by the elevated vip levels.4 however, this was not the mechanism in our figure 2: specimen: pancreatic tail with tumour and spleen. figure 3: partial capsular invasion by the tumour. figure 4: immunohistochemistry stain positive for vasoactive intestinal polypeptide (shown as dark brown). omayma elshafie, christopher grant, aisha al-hamdani, rajeevjain and nicholas woodhouse case report | 107 patient as his insulin requirement did not change following treatment with octreotide, resection of the tumour, and normalisation of the vip levels. the patient’s hypercalcaemia resolved during treatment with octreotide and intravenous fluids excluding associated hyperparathyroidism; it was related either to dehydration induced hyperalbuminaemia or to increased bone resorption caused by excessive vip or other peptides produced by the tumour.13 octreotide controls symptoms and normalises vip levels in nearly 90% of patients often with extensive metastatic disease.4 because our patient was so ill, octreotide was given as an immediate therapeutic trial before tumour localisation studies were carried out. the results were remarkable and gratifying; the diarrhea improving substantially after his first 100 mcg injection [tables 1 and 2]. octreotide was continued until 4 days after surgery at which time he had gained 7 kg. more than 70% of vipoma patients present with metastatic disease.13 fortunately, this was not the case here, but his tumour was large and histologically reported as a tumour of uncertain behaviour. he will therefore be followed up with serial vip measurements and, if indicated, further octreotide scanning. conclusion to conclude, this was a case of unexplained massive watery diarrhoea which responded immediately to octreotide treatment. clinicians facing similar cases should prescribe a therapeutic trial of octreotide without waiting for the results of investigations as it might be life saving. a c k n o w l e d g e m e n t s we thank dr dhia al-layla of sultan qaboos hospital, salalah, oman, for suggesting the possible diagnosis of a neuroendocrine tumor (vipoma) and referring the patient to us. we also thank professor gordon stamp (royal postgraduate medical school, london) for reviewing the slides and the vip immunostaining. references 1. peng sy, li jt, liu yb, fang hq, wu yl, peng ch, et al. diagnosis and treatment of vipoma in china: (case report and 31 cases review) diagnosis and treatment of vipoma. pancreas 2004; 28:93–7. 2. singh, hm, teller t, esrason kt, abbas ma. vipoma: a rare cause of acute diarrhea. surgical rounds 2007; 414:8. 3. ectors n. pancreatic endocrine tumors: diagnosis pitfalls. hepatogastroenterol 1999; 46:679. 4. friesen sr. update on the diagnosis and treatment of rare neuroendocrine tumors. surg clin north am 1987; 67:379. 5. priest wm, alexander mk. islet cell tumour of the pancreas with peptic ulceration, diarrhea and hypokalaemia. lancet 1957; 273:1145–7. 6. verner jv, morrison ab. islet cell tumour and a syndrome of refractory watery diarrhea and hypokalaemia. am j med 1958; 25:374. 7. bloom sr, polak jm, pearse age. vasoactive intestinal peptide and waterydiarrhoea syndrome. lancet 1973; 2:14–16. 8. kane mg, o'dorisio tm, krejs gj. production of secretory diarrhoea by intravenous infusion of vasoactive intestinal polypeptide. n engl j med 1983; 309:1482–5. 9. maton pn, o'dorisio tm, howe ba, mcarthur ke, howard jm, cherner ja, et al. effect of a longacting somatostatin analogue (sms 201–995) in a patient with pancreatic cholera. n engl j med 1985; 312:17–21. 10. sitaraman sv, goldfinger se. the vipoma s y n d r o m e ; f r o m : h t t p : / / w w w. u p t o d a t e . c o m / online/content/topic.do?topickey=gi_dis/35882 &selectedtitle=1%7e150&source=search_result accessed: aug 2010. 11. soga j, yakuwa y. vipoma/diarrhoeagenic syndrome: a statistical evaluation of 241 reported cases. j exp clin cancer res 1998; 17:389–400. 12. amir a, ghaferi, aa, chojnacki ka, long wd, cameron jl, yeo cj. pancreatic vipomas: subject review and one institutional experience. j gastrointest surg 2008; 12:382–93. 13. mekhijian hs, o’dorisio tm. vipoma syndrome. semin oncol 1987; 14:282–91. table 2: serum peptide and electrolyte levels before (day 0) and upon discharge. cg-a: chromogranin a time vip ng/l cg-a µg/l k mmol/l crea µmol/l hco3 mmol/l ca mmol/l admission day 0 900 240 2.5 180 10 3.5 post surgery day 31 46 37 4.1 70 26 2.2 normal range <65 <100 >3.5 <104 >18 <2.6 1department of nursing, school of nursing & midwifery and 2the collaboration center of meta-analysis research, torbat heydariyeh university of medical sciences, torbat heydariyeh, iran; 3nursing and midwifery care research center, mashhad university of medical sciences, mashhad, iran; 4student research committee, torbat heydariyeh university of medical sciences, torbat heydariyeh, iran; 5center of excellence “teleorto” for telediagnostics and treatment of disorders and injuries of the locomotor system, department of medical informatics and telemedicine, medical university of warsaw, warsaw, poland *corresponding author’s e-mail: ranjbarh1@thums.ac.ir مواقف ووعي املمرضات والقابالت السريرايت اإليرانيات جتاه التمريض والرعاية الصحية عن بعد دراسة مقطعية ح�سني رنجرب، حممود بخيش، فائزه مهدي زاده، ووجيچ كلينكوسيك abstract: objectives: this study aimed to examine the attitudes and awareness of iranian clinical nurses and midwives towards telenursing and telehealth also referred to as e-health. methods: the cross-sectional study was conducted from february to august 2019 in iran. nurses and midwives were randomly recruited from hospitals affiliated with mashhad university of medical sciences in mashhad, iran using a stratified cluster random sampling method. data were collected using a reliable and valid persian-language questionnaire consisting of 32 close-ended survey items to examine internet/computer access, daily internet use and awareness of and general attitude towards telehealth and telenursing; statistical analyses were performed. results: a total of 523 nurses and midwives were included in this study (response rate: 94.4%). the mean age and duration of clinical practice were 33.36 ± 7.46 and 8.88 ± 6.73 years, respectively. the majority of participants recognised the definition of telenursing (66.7%) and telehealth (80.1%). a positive attitude towards telenursing and telehealth was reported by 73.0% of the participants. clinical nurses and midwives with a master's degree were more aware of the definition of telehealth compared to those with undergraduate bachelor degrees (p = 0.03). additionally, midwives significantly more frequently presented a positive attitude towards telehealth and telenursing compared to nurses (86.2% versus 71.2%; p = 0.01). conclusion: the positive attitude of the current participants was an important factor in the promotion of telenursing and telehealth. the implementation of educational and infrastructure developmental programs can help speed up executional processes in these fields. keywords: telenursing; telemedicine; nurses; midwives; attitude; awareness; iran. والرعاية التمري�ض جتاه الإيرانيات ال�رسيريات والقابالت املمر�سات ووعي مواقف فح�ض اإىل الدرا�سة هذه هدفت الهدف: امللخ�ص: يف فرباير اإىل اأغ�سط�ض 2019 من املقطعية الدرا�سة اأُجريت الإلكرتونية. الطريقة: ال�سحة با�سم ا ي�سار اإليها اأي�سً والتي بعد عن ال�سحية با�ستخدام اإيران م�سهد، يف الطبية للعلوم م�سهد جلامعة التابعة امل�ست�سفيات من ع�سوائي ب�سكل والقابالت املمر�سات اختيار مت اإيران. م وموثوق باللغة الفارسية يحتوي على 23 من كَّ طريقة اأخذ العينات الع�سوائية العنقودية الطبقية. مت جمع البيانات با�ستخدام ا�ستبيان حُمَ والوعي املعلومات ل�سبكة اليومي وال�ستخدام املعلومات/الكمبيوتر �سبكة اإىل الو�سول فر�ض لبحث املغلقة ال�ستق�سائية الدرا�سة بنود جمموعه ما الدرا�سة هذه �سملت النتائج: الإح�سائية. التحليالت اإجراء ومت بعد عن والتمري�ض ال�سحية الرعاية جتاه العام واملوقف 523 ممر�سة وقابلة )معدل ال�ستجابة: %94.4(. كان متو�سط العمر ومدة املمار�سة ال�رسيرية هو 7.46 ± 33.36 و 6.73 ± 8.88 �سنة على التوايل. اأقرت غالبية امل�ساركات بتعريف التمري�ض عن بعد )%66.7( والرعاية ال�سحية عن بعد )%80.1(. مت الإف�ساح عن موقف اإيجابي جتاه التمري�ض والرعاية ال�سحية عن بعد من قبل %73.0 من امل�ساركات. كانت املمر�سات والقابالت ال�رسيريات احلا�سالت على درجة )p = 0.03( اجلامعية. البكالوريو�ض درجات على احلا�سالت باأولئك مقارنة ُبعد عن ال�سحية الرعاية بتعريف وعيًا اأكرث املاج�ستري بالإ�سافة اإىل ذلك، اأظهرت القابالت ب�سكل ملحوظ ومتكرر موقًفا اإيجابًيا جتاه الرعاية ال�سحية والتمري�ض عن بعد مقارنة باملمر�سات )p = 0.01؛ %71.2 مقابل %86.2(. اخلال�صة: كان املوقف الإيجابي للمشاركني عاماًل مهمًا يف تعزيز التمري�ض والرعاية ال�سحية عن بعد. ميكن اأن ي�ساعد تنفيذ الربامج التعليمية وتطوير البنية التحتية يف ت�رسيع العمليات التنفيذية يف هذه املجالت. الكلمات املفتاحية: متري�ض عن بعد؛ تطبيب عن بعد؛ ممر�سات؛ قابالت؛ موقف؛ وعي؛ اإيران. iranian clinical nurses’ and midwives’ attitudes and awareness towards telenursing and telehealth a cross-sectional study *hossein ranjbar,1,2 mahmoud bakhshi,3 faezeh mahdizadeh,4 wojciech glinkowski5 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e50–57, epub. 15 mar 21 submitted 4 feb 20 revisions req. 21 apr & 14 jun 20; revisions recd. 13 may & 7 jul 20 accepted 29 jul 20 https://doi.org/10.18295/squmj.2021.21.01.007 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge this study’s results suggests that awareness of and attitudes towards telenursing and telehealth among clinical nurses and midwives in iran are relatively high. https://creativecommons.org/licenses/by-nd/4.0/ hossein ranjbar, mahmoud bakhshi, faezeh mahdizadeh and wojciech glinkowski clinical and basic research | e51 most countries face numerous health challenges including a growing elderly population, the need for home-care and a lack of nursing staff for direct patient care services at home.1 in addition to these challenges, rapid technological progress and healthcare spending has led nursing staff to use information and communication technologies (ict) in their work to respond appropriately to patients.2 based on available evidence, ict can improve healthcare outcomes and reduce associated costs.3–5 the growing use of ict, through telenursing and telehealth, is a promising advance in the provision of health services that minimise health concerns.6 telehealth or e-health, is the general use of ict to provide health-related services to patients from a distance.7 telenursing, as a branch of telehealth, is the use of ict for providing nursing care at a distance. it may be delivered simply by sending nursing documents digitally or by providing more complex care to patients at home through the internet and online tools. fujino and kawamoto reported that the non-use or misuse of telenursing technologies can have adverse effects on the professional performance of health staff.8 hence, clinical nurses and midwives need to learn ict and telenursing to achieve professional progress.9 as an innovative approach, telenursing should be introduced into nursing and midwifery curricula to help these professionals develop appropriate strategies for implementing this technology.9,10 it is essential that clinical nurses and midwives develop a positive attitude towards telenursing and telehealth to better use them in clinical practice.7 despite the importance of telehealth, previous studies in ethiopia and ghana showed that health sciences students lacked sufficient knowledge of ict and were unable to use this type of technology in their clinical practice.11,12 another study in iran confirmed that medical staff knowledge of and attitude towards health-related ict was insufficient.13 in another study on the awareness, attitudes and readiness of iranian clinical staff in the field of telemedicine, researchers found that although physicians’ and laboratory and radiological technicians’ knowledge of telemedicine was low, their attitudes towards it were positive.14 several studies following experimental designs have indicated the effectiveness of telenursing in iran and other countries.15–23 however, little is known about iranian nurses and midwives’ attitudes toward telehealth. descriptive studies are typically done when there is little known about a research subject; this kind of study provides a sound foundation for designing empirical investigations to develop higher levels of knowledge than can be achieved through correlational and experimental designs.24 telehealth is becoming more necessary for better performance in nurses’ and midwives’ professional practice. to the best of the authors’ knowledge, it has not been clearly identified whether iranian nurses and midwives have sufficient knowledge and attitudes towards telenursing and telehealth to implement this approach to their patient care. to fill this information gap, this study aimed to examine iranian clinical nurses’ and midwives’ attitudes towards and awareness of telenursing and telehealth. methods this cross-sectional study was conducted from february to august 2019 in hospitals affiliated with mashhad university of medical sciences in mashhad, iran. participants were selected by a stratified and cluster random sampling method. a total of 13 hospitals affiliated with mashhad university of medical sciences were assigned into two categories, based on their size, (large and small).within the large category were ghaem and emam reza hospitals, while within the small category were omid, hasheminejad, om-ol-banin and khatam-al-anbia hospitals. these institutions were randomly chosen as the target hospitals. the inclusion criteria consisted of those who were willing to participate, had a bachelor of science (bs) or master of science (ms) in nursing or midwifery and had completed at least one year of clinical work. all individuals who had not completed the questionnaire were excluded from the study. two members of the research team held a bs in health information technologies and were oriented by the research team and directed to the hospitals to collect the current research will support the design of future quantitative studies in telenursing and telehealth in addition to the identification of related factors. application to patient care a heightened awareness of and a fairly positive attitude towards telenursing and telehealth will accelerate the development and utilisation of this technology in treatment and patient care. telenursing and telehealth increase the range of healthcare services by meeting patients’ health needs from a distance. iranian clinical nurses’ and midwives’ attitudes and awareness towards telenursing and telehealth a cross-sectional study e52 | squ medical journal, february 2021, volume 21, issue 1 data. data were collected using a demographic form and a research survey. the demographic form consisted questions pertaining to personal data such as age, gender, primary degree, academic degree, professional position and duration of clinical practice. a list of all participants who were appropriate for inclusion was developed. these individuals were then visited by the research team members. individuals who were willing to participate in the study completed the study’s survey. a 32-item, close-ended, questionnaire designed by glinkowski et al. was used in this study.25 the tool was designed to investigate internet/computer access, daily internet use and general attitude toward telehealth and telenursing as well as the level of awareness of the same. the rating scale of attitude was based on a fivepoint likert scale, with five indicating strongly agree, four indicating agree, three indicating difficult to say, two indicating disagree and one indicating strongly disagree. participants who answered strongly agree or agree to the attitude questions were identified as participants with a positive attitude towards telenursing and telehealth. higher scores on attitude items also indicated a more definite attitude towards telenursing and telehealth. the questionnaire also contained two multiple-choice questions comprising information on the definition of telenursing and telehealth. a correct response garnered a score of one and an incorrect response was assigned a zero. the original english questionnaire was translated into persian following a forward-backward process once permission have been secured by the questionniare’s original author via correspondence. content validity was assessed by a group of experts including three nursing experts and two specialists in ict. the reliability of this questionnaire was also assessed by the cronbach’s alpha coefficient (α = 0.77). the investigation was first piloted on 30 nurses and midwives to determine the final sample size based on a level of confidence at 1.96. the minimum sample size was determined to be 478 but the sample size was increased to 550 to allow for a 15% attrition rate with the view of improving the validity of the data. the data were analysed using mann-whitney u, chi-square tests and spearman’s rank correlation coefficient with statistical package for the social sciences (spss), version 16.0 ibm, corp., chicago, illinois, usa). the significance level was set at p <0.05. the ethics committee of torbat heidariyeh univ ersity of medical sciences (ir.thums.rec.1396.28) approved the study. all participants were given information about the purpose, aim and methodology of the research. they were also assured that contribution to the research was voluntary and confidentiality of the data and anonymity of the participants would be strictly maintained. the research team obtained verbal consent for participation and the final response to the questionnaire items was agreed upon to be equivalent to a final consent signature. results a total of 554 questionnaires were submitted, of which 31 were incomplete; therefore, the final sample size was 523 (response rate: 94.4%). the mean ± standard deviation (sd) of age and the duration of clinical practice of the included participants was 33.36 ± 7.46 and 8.88 ± 6.73 years, respectively [table 1]. among the 523 participants, 519 (99.2%) had access to a computer and the internet. however, less than half (n = 246; 47.0%) of the participants indicated using the internet for 2–3 hours/day and 164 (31.4%) participants used the internet for less than one hour each day. a total of 108 (20.7%) participants indicated more than three hours of internet use daily and only five (1.0%) participants did not use the internet at all. most participants knew the definition of telenursing (n = 349; 66.7%) and telehealth (n = 419; 80.1%) and the majority (n = 382; 73.0%) had a positive attitude towards telenursing and telehealth. only 159 (30.4%) participants believed that the use of telenursing in undergraduate studies would benefit future healthcare workers. however, answering this item was difficult for 235 (44.9%) participants. approximately table 1: demographic characteristics of iranian clinical nurses and midwives (n = 523) charcteristic n (%) gender male 90 (17.2) female 433 (82.8) academic degree in nursing or midwifery bs 500 (95.6) ms 23 (4.4) specialty nursing 458 (87.6) midwifery 65 (12.4) professional position supervisor 16 (3.1) head nurse 37 (7.1) nurse 405 (77.4) midwife 65 (12.4) bs = bachelor of science; ms = master of science. hossein ranjbar, mahmoud bakhshi, faezeh mahdizadeh and wojciech glinkowski clinical and basic research | e53 one-third (n = 192; 36.7%) of the participants agreed that using telenursing as a complementary method of patient care in their future work had value; 193 (36.9%) participants agreed or strongly agreed that telenursing could improve the nursing staff ’s effectiveness. the answer to this statement was difficult for 190 (36.3%) participants. most of the participants (n = 386; 73.8%) disagreed that telenursing can increase the cost of patient care. approximately one-quarter of participants (n = 140; 26.8%) agreed that telenursing might decrease direct contact between healthcare workers and patients but 107 (20.5%) did not. it was difficult for 161 (30.8%) participants to answer that table 2: selected questionnaire statements and showing participants’ attitudes, on a five-point likert scale, towards telenursing and telehealth (n = 523) statement n (%) strongly disagree disagree difficult to say agree strongly agree telenursing in undergraduate studies would benefit future healthcare workers 37 (7.1) 92 (17.6) 235 (44.9) 131 (25.0) 28 (5.4) telenursing would be as a complementary method of patient care 19 (3.6) 86 (16.4) 191 (36.5) 192 (36.7) 35 (6.7) telenursing might decrease direct contact between healthcare workers and patients 23(4.4) 107(20.5) 161(30.8) 140(26.8) 92(17.6) telenursing might be widely used in environmental nursing 35(6.6) 118(22.6) 112(21.4) 219(41.9) 39(7.5) telenursing can increase the efficacy of clinical staff. 44 (8.4) 96 (18.4) 190 (36.3) 144 (27.5) 49 (9.4) telenursing can increase the cost of patient care. 160 (30.6) 226 (43.2) 107 (20.5) 23 (4.4) 7 (1.3) telenursing can facilitate the direct contact of clinical staff with patients. 19 (3.6) 86 (16.4) 191 (36.5) 192 (36.7) 35 (6.7) telenursing may be widely used in community health nursing. 17 (3.3) 74 (14.1) 149 (28.5) 219 (41.9) 64 (12.2) telenursing may be widely used in diabetes nursing. 5 (1.0) 24 (4.6) 120 (22.9) 210 (40.2) 164 (31.4) telenursing may be widely used in long-term nursing. 4 (0.8) 32 (6.1) 139 (26.6) 216 (41.3) 132 (25.2) table 3: mean participant scores on awareness of the definition of telenursing and telehealth according to gender, academic degree and specialty (n = 523) variable telenursing p and z value* telehealth p and z value* mean ± sd mean ± sd gender male female 0.75 ± 0.43 0.64 ± 0.47 z = −1.95* p = 0.05 0.88 ± 0.33 0.78 ± 0.01 z = −2.29* p = 0.02 academic degree in nursing or midwifery bs ms 0.65 ± 0.47 0.86 ± 0.34 z = −2.10* p = 0.03 0.79 ± 0.40 0.86 ± 0.34 z = −0.84* p = 0.40 speciality nursing midwifery 0.67 ± 0.47 0.64 ± 0.48 z = −0.38* p = 0.69 0.77 ± 0.41 0.96 ± 0.17 z = −3.62* p <0.001 sd = standard deviation; bs = bachelor of science; ms = master of science. *z value calculated using mann-whitney u test. table 4: mean participant scores on attitude towards tele nursing and telehealth by academic degree and specialty (n = 523) variable mean ± sd p and z value* academic degree in nursing or midwifery bs ms 85.20 ± 11.04 90.65 ± 9.64 z = -2.36 p = 0. 01 specialty nursing midwifery 84.97 ± 11.19 88.70 ± 9.26 z = -2.55 p = 0.01 sd = standard deviation; bs = bachelor of science; ms = master of science *z value calculated using mann-whitney u test. iranian clinical nurses’ and midwives’ attitudes and awareness towards telenursing and telehealth a cross-sectional study e54 | squ medical journal, february 2021, volume 21, issue 1 question. some of the participants (n = 219; 41.9%) believed that telenursing might be widely used in environmental nursing [table 2]. most participants indicated that they understood requirements related to internet service (n = 420; 80.3%), landline-based phones (n = 280; 53.5%) or mobile phones (n = 377; 72.1%) to carry out telenursing activities. the overall mean ± sd awareness score for tele nursing and telehealth was 0.80 ± 0.39 and 0.66 ± 0.47, respectively. a significant difference was identified in the level of awareness of the definition of telehealth between genders, with males showing higher mean scores compared to females (0.88 ± 0.33 versus 0.78 ± 0.01; p = 0.02). participants with a ms degree also had a higher mean score in the field of telehealth definition compared to those holding a bs degree (0.86 ± 0.34 versus 0.65 ± 0.47; p = 0.03). clinical midwives were significantly more aware of the meaning of telehealth compared to clinical nurses (0.96 ± 0.17 versus 0.77 ± 0.41; p <0.001) [table 3]. significant differences in the attitudes towards telenursing and telehealth based on academic degrees were identified; those with a ms had a higher mean attitude score compared to those with a bs (90.65 ± 9.64 versus 85.20 ± 11.04; p = 0.01). clinical midwives also had more positive attitudes towards telenursing and telehealth compared to clinical nurses (88.70 ± 9.26 versus 84.97 ± 11.19; p = 0.01) [table 4]. a weak inverse relationship was identified between attitude and age of participants in relation to tele nursing and telehealth (rs = −0.10; p = 0.01). a weak inverse relationship was also identified between attitude and job experience in relation to telenursing and tele health (rs = −0.10; p = 0.02). discussion the current study aimed to investigate iranian clinical nurses’ and midwives’ attitudes towards telenursing and telehealth. the study found that most participants knew the definition of telenursing and telehealth; in previous studies, students of nursing were also familiar with these terms’ meanings.25,26 most participants in the current study believed that telenursing might decrease direct contact between healthcare workers and patients. hence, clinical nurses and midwives need to develop ict skills and telenursing approaches to achieve professional connection.9 most participants thought that telenursing might be a complementary method of patient care in their work. a national survey of e-health in australia found that 52% of participants agreed that e-health can improve nursing practices, while less than half (48%) assumed that e-health competencies could be developed as a way to enhance the healthcare services given to patients.10 in another study, more than 50% of medical practitioners believed that telemedicine would elevate their clinical performance, and 66% of participants thought that telemedicine might boost healthcare quality.27 hicks et al. found that approxiamtely onethird of the surveyed health professionals agreed that technological applications in the healthcare system have a large effect on their work.28 in the current study, 193 (36.9%) participants believed that telenursing could enhance staff efficacy in the health system and 386 (73.8%) participants believed that telenursing could reduce nursing care costs. glinkowski et al. also indicated that telenursing could decrease healthcare expenditures, facilitate contact with patients and enhance medical staff productivity.25 meher et al. concluded that more than half of the studied medical practitioners presumed that telemedicine reduces time wasting as well as the cost of visiting patients in healthcare centres.29 according to the results of the current study, most participants had access to the internet via a computer or tablet. access to a personal computer (pc) and the internet is essential for the successful launch of telemedicine. computer access and literacy are a cornerstone of technological advances and training for health professionals because most information communication and transactions requires internet access.30 few participants in the current study indicated having insufficient pc and internet access to achieve virtual connections with patients. such connectivity is essential and all nursing and midwifery staff should have easy access to a pc and the internet, especially at work, to maximise telehealth and telenursing capacity. the mean age of participants in this study was 33 years, with an average of nine years of previous clinical work. a weak inverse relationship between the age of participants and recognition of the definition of telenursing was found, with younger and less-experienced participants being more aware of telenursing. in general, younger participants were also more familiar with ict-related facilities such as computers and telemedicine than older health professionals; this result is in line with boringi et al.’s finding.31 another study showed that younger doctors were more willing to use telemedicine and e-health care.29 this finding could be due to the fact that telemedicine is a relatively new concept and requires ict tools such as smartphones and online media that are mainly used by younger generations who have increased exposure of technology.31,32 hossein ranjbar, mahmoud bakhshi, faezeh mahdizadeh and wojciech glinkowski clinical and basic research | e55 health professionals are dealing with many challenges and obstacles in their path to executing telemedicine successfully.25 the studied literature highlighted that a lack of short-term courses and training was a significant hindrance to the adoption of e-health technology. in addition, the other main barriers to adopting e-health included lack of time, guidance and incentives on the part of organisations as well as a lack of access to appropriate technology.10,30 on the other hand, inadequate information about technology-based infrastructure such as the internet and telephones have made it challenging to implement telemedicine in both developing and developed countries. therefore, governments and hospitals, are recomm ended to provide internet facilities to eliminate such problems.30,32 another key finding of the current study was that the midwives were more aware of the definition of telehealth than nurses. midwives also had more positive attitudes toward telenursing and telehealth than nurses. telehealth awareness may increase if all healthcare students are obliged to pass one academic unit of ict within their educational programmes. however, these issues require further investigation in the iranian context. the current study also found a significant difference in attitude scores based on academic degrees attained, with ms-holding participants also achieving a higher average telehealth score than those with bs degrees. the observed difference may have resulted from an additional unit, ict, in the academic curricula of both nurses and midwives studying at this level. experts have not thoroughly implemented telenursing in the healthcare field; however, according to the findings of the current study, telenursing skills are seen as desirable as reflected in the positive attitudes of nurses and midwives. the integration of innovative technologies in nursing, which is a complex and rapidly-changing profession even without the addition of technology to care provision, appears to be a fundamental challenge.10 several factors should be considered when implementing telenursing practices including the introduction of telenursing and tele medicine in educational coursework as a new approach to healthcare as well as ongoing professional training to this end.25 in fact, a lack of systematic e-health training has been reported by earlier studies.10,13,25 it appears irrational to expect e-health nursing practice to be viewed as routine unless participants become acquainted before entering the profession with its various fundamental concepts, principles and applications through academic training courses.10 medical universities, therefore, should implement a comprehensive, knowledge-improvement programme focused on telenursing and telemedicine. making this change would support clinical applications and practices of e-health and provide nursing and midwifery students with sufficient facilities to increase their knowledge on health-based ict by strengthening educational infrastructure.13 earlier studies have shown that the majority of students have a positive attitude towards the role of telenursing in their future practice and achievement in clinical nursing; 70% of student surveyed indicated a need to include telenursing in academic courses.25 according to grady and schlachtafairchild, 89% of participants agreed that telenursing should be part of primary nursing education.33 the limitation of the present study was that the research sites were restricted to hospitals affiliated to only mashhad university of medical sciences. therefore, the findings may not be generalisable to other health centres and hospitals. moreover, a small number of clinical nurses and midwives with postgraduate degrees participated, which decreases the reliability of the findings in the evaluation of knowledge of and attitudes towards telenursing. although most of the current participants had a positive attitude towards telenursing and telehealth and knew the definition of these concepts, it is vital for all healthcare workers to have a positive attitude towards and improve their knowledge of integrating ict in healthcare. educational planners, health centre managers and academic instructors can use such research results to expand the use of ict for patient care. finally, more research based on the findings of the current study should be undertaken in other health centres and hospitals and with more participants with postgraduate degrees in order to determine why differences in findings exist. conclusion based on the findings of the current study, most iranian nurses and midwives are aware of the definition of telenursing and telehealth. most participants indicated a belief that telenursing might be a complementary method of patient care in their work. there was a weak inverse relationship in participants’ ages in relation to knowing the meaning of telenursing; midwives were more aware of the meaning of telehealth than nurses. midwives also presented more positive attitudes toward telenursing and telehealth than nurses. participants with a ms also had a higher mean attitude score compared to those with a bs. positive attitudes of the participants are important in promoting telenursing and telehealth. the implementation of educational and infrastructure development programmes can help speed up executional processes in these fields. iranian clinical nurses’ and midwives’ attitudes and awareness towards telenursing and telehealth a cross-sectional study e56 | squ medical journal, february 2021, volume 21, issue 1 a c k n o w l e d g e m e n t s the authors would like to express their sincere gratitude to all participants, clinical nurses and midwives who have cooperated in conducting this research. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. de araújo novaes m, basu a. chapter 14 disruptive tech nologies: present and future. in: gogia s, ed. fundamentals of telemedicine and telehealth. 1st ed. london, uk: academic press, 2019. pp. 305–30. https://doi.org/10.1016/c2017-0-01090-x. 2. tomaselli g, garg l, gupta v, xuereb pa, buttigieg sc, vassallo p. communicating corporate social responsibility in healthcare through digital and traditional tools: a two-country analysis. in: zhang z, ed. novel theories and applications of global information resource management. gainesville, florida, usa: igi global, 2020. pp. 184–208. https://doi.org/10.4018/978-17998-1786-4. 3. majeed mt, khan fn. do information and communication tech nologies (icts) contribute to health outcomes? an empirical analysis. qual quant 2019; 53:183–206. https://doi.org/10.100 7/s11135-018-0741-6. 4. yamashita t, yamashita k, sato m, takase y. effect of walking on depression prevalence for diabetes using information comm unication technology: prospective study. geriatr gerontol int 2019; 19:1147–52. https://doi.org/10.1111/ggi.13787. 5. downes e, horigan a, teixeira p. the transformation of health care for patients: information and communication technology, digiceuticals, and digitally enabled care. j am assoc nurse pract 2019; 31:156–61. https://doi.org/10.1097/jxx.0000000000000109. 6. schmeida m, mcneal r, mossberger k. policy determinants affect telehealth implementation. telemed j e health 2007; 13:100–7. https://doi.org/10.1089/tmj.2006.0017. 7. kumar s, snooks h, eds. telenursing. london, uk: springer, 2011. https://doi.org/10.1007/978-0-85729-529-3. 8. fujino y, kawamoto r. effect of information and communication technology on nursing performance. comput inform nurs 2013; 31:244–50. https://doi.org/10.1097/nxn.0b013e3182842103. 9. souza-junior vd, mendes ia, mazzo a, godoy s. application of telenursing in nursing practice: an integrative literature review. appl nurs res 2016; 29:254–60. https://doi.org/10.101 6/j.apnr.2015.05.005. 10. edirippulige s, smith ac, young j, wootton r. knowledge, perceptions and expectations of participants in e-health: results of a survey in a children’s hospital. j telemed telecare 2006; 12:35–8. https://doi.org/10.1258/135763306779380255. 11. woreta sa, kebede y, zegeye dt. knowledge and utilization of information communication technology (ict) among health science students at the university of gondar, north western ethiopia. bmc med inform decis mak 2013; 13:31. https://doi. org/10.1186/1472-6947-13-31. 12. peprah p, abalo em, agyemang-duah w, gyasi rm, reforce o, nyonyo j, et al. knowledge, attitude, and use of mhealth tech nology among students in ghana: a university-based survey. bmc med inform decis mak 2019; 19:220. https://doi.org/10.1186/ s12911-019-0947-0. 13. sadoughi f, hemmat m, valinejadi a, mohammadi a, majdabadi ha. assessment of health information technology knowledge, attitude, and practice among healthcare activists in tehran hospitals. int j comput sci netw secur 2017; 17:155–8. 14. hoerbst a, hackl wo, de keizer n, prokosch hu, hercigonjaszekeres m,de lusignan s. exploring complexity in health: an interdisciplinary systems approach: proceedings of mie2016. 1st ed. amsterdam, the netherlands: ios press, 2016. 15. sadeghmoghadam l, ahmadi babadi s, delshad noghabi a, nazari s, farhadi a. effect of telenursing on aging perception of iranian older adults. educ gerontol 2019; 45:476–82. https:// doi.org/10.1080/03601277.2019.1657263. 16. javadi p, nejat n, golaghaie f, sharifi m. the effects of nurseled telephone-based support on supportive care needs among women with breast cancer: a randomized clinical trial. nurs midwifery stud 2019; 8:7–13. https://doi.org/10.4103/nms. nms_94_17. 17. mohamed sa, fashafsheh ih. effect of educational intervention and telephone follow-up program on knowledge, practice and quality of life among patients with urinary diversion: a quasiexperimental study. int j nurs 2019; 6:58–71. https://doi.org/10.1 5640/ijn.v6n1a7. 18. rezaei m, jalali r, heydarikhayat n, salari n. effect of telenursing and face-to-face training techniques on quality of life in burn patients: a clinical trial. arch phys med rehabil 2020; 101:667–73. https://doi.org/10.1016/j.apmr.2019.10.197. 19. tajalli s, imani a, hamzehkhani m, shafiei e, fallahi m, khalesi n, et al. effect of telenursing on level of anxiety in parents of hosp italised premature neonates in neonatal intensive care unit. j clin diagn res 2020; 14:lc1-4. https://doi.org/10.7860/jcdr/2 020/42933.13489. 20. shahrokhi a, azimian j, amouzegar a, oveisi s. the effect of telenursing on referral rates of patients with head trauma and their family’s satisfaction after discharge. j trauma nurs 2018; 25:248–53. https://doi.org/10.1097/jtn.0000000000000382. 21. rangraz jeddi f, nabovati e, hamidi r, sharif r. mobile phone usage in patients with type ii diabetes and their intention to use it for self-management: a cross-sectional study in iran. bmc med inform decis mak 2020; 20:24. https://doi.org/10.1186/ s12911-020-1038-y. 22. mussi fc, palmeira cs, santos cast, guimarães ac, lima ml, nascimento tsd. effect of nursing telemonitoring on the knowl edge of obese women: clinical trial. rev bras enferm 2019; 72:212–19. https://doi.org/10.1590/0034-7167-2018-0500. 23. machado tmd, santana rf, vaqueiro rd, dos santos ctb, de souza pa. telephone follow-up of the elderly after cataract surgery. br j vis impair 2020; 38:184–95. https://doi.org/10.11 77/0264619619874825. 24. grove sk, burns n, gray j. the practice of nursing research: appraisal, synthesis, and generation of evidence. 7th ed. phila delphia, pennsylvania, usa: saunders, 2013. https://doi.org/10.7 748/ns2013.04.27.31.30.b1488. 25. glinkowski w, pawłowska k, kozłowska l. telehealth and tele nursing perception and knowledge among university students of nursing in poland. telemed j e health 2013; 19:523–9. https://doi.org/10.1089/tmj.2012.0217. 26. ghorbanzadeh k, fallahi-khoshknab m, seyed bagher maddah s, izadi darghahlo m. telehealth and telenursing knowledge and attitude among students of nursing in ardebil university of medical sciences. iran j nurs 2017; 30:42–52. https://doi. org/10.29252/ijn.30.107.42. 27. demartines n, freiermuth o, mutter d, heberer m, harder f. knowledge and acceptance of telemedicine in surgery: a survey. j telemed telecare 2000; 6:125–31. https://doi.org/10.1258/135 7633001935167. https://doi.org/10.1016/c2017-0-01090-x https://doi.org/10.4018/978-1-7998-1786-4 https://doi.org/10.4018/978-1-7998-1786-4 https://doi.org/10.1007/s11135-018-0741-6 https://doi.org/10.1007/s11135-018-0741-6 https://doi.org/10.1111/ggi.13787 https://doi.org/10.1097/jxx.0000000000000109 https://doi.org/10.1089/tmj.2006.0017 https://doi.org/10.1007/978-0-85729-529-3 https://doi.org/10.1097/nxn.0b013e3182842103 https://doi.org/10.1016/j.apnr.2015.05.005 https://doi.org/10.1016/j.apnr.2015.05.005 https://doi.org/10.1258/135763306779380255 https://doi.org/10.1186/1472-6947-13-31 https://doi.org/10.1186/1472-6947-13-31 https://doi.org/10.1186/s12911-019-0947-0 https://doi.org/10.1186/s12911-019-0947-0 https://doi.org/10.1080/03601277.2019.1657263 https://doi.org/10.1080/03601277.2019.1657263 https://doi.org/10.4103/nms.nms_94_17 https://doi.org/10.4103/nms.nms_94_17 https://doi.org/10.15640/ijn.v6n1a7 https://doi.org/10.15640/ijn.v6n1a7 https://doi.org/10.1016/j.apmr.2019.10.197 https://doi.org/10.7860/jcdr/2020/42933.13489 https://doi.org/10.7860/jcdr/2020/42933.13489 https://doi.org/10.1097/jtn.0000000000000382 https://doi.org/10.1186/s12911-020-1038-y https://doi.org/10.1186/s12911-020-1038-y https://doi.org/10.1590/0034-7167-2018-0500 https://doi.org/10.1177/0264619619874825 https://doi.org/10.1177/0264619619874825 https://doi.org/10.7748/ns2013.04.27.31.30.b1488 https://doi.org/10.7748/ns2013.04.27.31.30.b1488 https://doi.org/10.1089/tmj.2012.0217 https://doi.org/10.29252/ijn.30.107.42 https://doi.org/10.29252/ijn.30.107.42 https://doi.org/10.1258/1357633001935167 https://doi.org/10.1258/1357633001935167 hossein ranjbar, mahmoud bakhshi, faezeh mahdizadeh and wojciech glinkowski clinical and basic research | e57 28. hicks ll, boles ke, hudson st, koenig s, madsen r, kling b, et al. an evaluation of satisfaction with telemedicine among health-care professionals. j telemed telecare 2000; 6:209–15. https://doi.org/10.1258/1357633001935374. 29. meher sk, tyagi rs, chaudhry t. awareness and attitudes to telemedicine among doctors and patients in india. j telemed telecare 2009; 15:139–41. https://doi.org/10.1258/jtt.2009.003011. 30. abodunrin ol, akande tm. knowledge and perception of e-health and telemedicine among health professionals in lautech teaching hospital, osogbo, nigeria. int j health res 2009; 2:51–8. https://doi.org/10.4314/ijhr.v2i1.55388. 31. boringi m, waghray s, lavanya r, babu db, badam rk, harsha n, et al. knowledge and awareness of teledentistry among dental professionals a cross-sectional study. j clin diagn res 2015; 9:zc41–4. https://doi.org/10.7860/jcdr/2015/13303.6320. 32. ibrahim mim, phing cw, palaian s. evaluation of knowledge and perception of malaysian health professionals about tele medicine. j clin diagn res 2010; 4:2052–7. 33. grady jl, schlachta-fairchild l. report of the 2004-2005 inter national telenursing survey. comput inform nurs 2007; 25:266–72. https://doi.org/10.1097/01.ncn.0000289163.16122.c2. https://doi.org/10.1258/1357633001935374 https://doi.org/10.1258/jtt.2009.003011 https://doi.org/10.4314/ijhr.v2i1.55388 https://doi.org/10.7860/jcdr/2015/13303.6320 https://doi.org/10.1097/01.ncn.0000289163.16122.c2 departments of 1child health and 2metabolic & genetic disease, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: mnaggari@squ.edu.om;mnaggari@yahoo.com;mnaggari@hotmail.com transient insulin resistance in propionic acidaemia knowing is half the battle *mohamed a. el-naggari,1 marwa rady,1 khalid althihli2 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 648–651, epub. 25 nov 21 submitted 13 jul 20 revisions req. 17 sep & 1 nov 20; revisions recd. 6 oct & 4 nov 20 accepted 24 nov 20 case report this case report describes a nine-month-old boy known to have ppa. he was diagnosed at birth through screening, as his elder brother had already been diagnosed with the same disease. the diagnosis was confirmed genetically following elevated propionylcarnitine in dried blood spots. he presented to the emergency department of a tertiary care hospital in muscat, oman, in 2018 with a three-day history of poor oral intake and lethargy. no history of fever, vomiting, loose motion or contact with a sick person was reported by the family. he was admitted with breathlessness and altered sensorium. on initial assessment, he was found to be drowsy and had acidotic breathing, weak peripheral pulses and delayed capillary refill without fever. investigations revealed severe metabolic acidosis, mild lactic acidosis, elevated anion gap and hyperammonaemia. initially, plasma glucose was normal with significant ketonuria. other than hypernatremia, electrolytes were in the normal range [table 1]. the patient was admitted to paediatric intensive care unit due to his depressed sensorium, severe meta bolic crisis and respiratory distress that necessitated mechanical ventilation. fluid resuscitation was given in the form of normal saline bolus 20 ml/kg followed by double maintenance of intravenous (iv) dextrose 10% and 0.9% sodium chloride solution. he was given iv carnitine at a dose of 300 mg/kg/day. in addition, iv glucose infusion was started with a glucose infusion propionic acidaemia (ppa) is caused by genetic mutations which affect amino acid and odd-chain fatty acid metabolism due to the deficiency of propionyl-coa carboxylase resulting in the defective conversion of propionyl-coa to methylmalonyl-coa. the disorder is inherited in an autosomal recessive manner and its incidence varies across the world. while the estimated incidence in the usa is approximately 1 in 105,000 to 1 in 130,000 it is as high as 1 in 20,000 in some middle eastern countries.1–4 most patients with classic ppa present, in the first few days of life, with progressive encephalopathy. even patients who are stabilised with protein restriction, carnitine supplementation and decontamination of gut bacterial flora are at risk of recurrent metabolic crisis.5 these are usually characterised by a variable combination of metabolic acidosis, elevated anion gap, hyperammonemia and ketosis.6 even patients with a stable condition are at risk of developing complications that include developmental delay, intellectual disability, seizures, basal ganglia hyperintensities, autistic features, deafness, optic atrophy, cardiomyopathy and long qtc abnormalities.7,8 hypoglycaemia is a commonly described finding during metabolic decompensation of organic acidaemias, but hyperglycaemia has been rarely described in a patient with ppa as is seen in the current case.9,10 there is also a paucity of studies addressing the pathophysiology of disease and clinical correlates for this complication.9 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.039 case report abstract: propionic acidaemia (ppa) is a disorder of amino acid and odd-chain fatty acid metabolism. hypoglycaemia is a more commonly described finding rather than hyperglycaemia during metabolic decompensation of ppa. there is a high mortality rate in patients with organic acidaemias having severe insulinresistant hyperglycaemia. we report a nine-month-old boy with ppa who was admitted to tertiary care hospital in muscat, oman, in 2018 with metabolic decompensation, persistent hyperglycaemia and transient insulin resistance. hyperglycaemia did not respond to high insulin infusion. plasma glucose only improved when glucose infusion rate (gir) reached 7 mg/kg/min. the patient has full recovery and was discharged, with follow up plan. it is important to balance the gir to achieve the targeted insulin level, beyond which the risks of hyperglycaemia start to outweigh the potential anabolic benefits of additional insulin secretion. timely clinical attention should be given to achieve adequate caloric delivery through alternative sources other than high gir to permit better glycaemic control, especially when insulin-resistant hyperglycaemia is present. keywords: propionic acidaemia; insulin resistance; infant; case report; oman. mohamed a. el-naggari, marwa rady and khalid althihli case report | 649 rate (gir) of 8 mg/kg/min, which was then increased to 12 mg/kg/min after four hours of admission. iv lipids was started at a dose of 2 g/kg/day. these measures were aimed at delivering a caloric intake of 120–150 kcal/kg/day to promote anabolism. metabolic acidosis was aggressively managed with iv sodium bicarbonate bolus at a dose of 1 mmol/kg followed by continuous bicarbonate infusion titrated to blood gas at a rate that did not exceed 1.5 mmol/kg/hour. hyperammonaemia was additionally treated with iv ammonia scavenger therapy with iv sodium benzoate at a dose of 250 mg/ kg and sodium phenylbutyrate at a dose of 250 mg/kg, both delivered as loading and maintenance doses. the initial repeat ammonia level was 123 mcg/dl; a loading dose of carglumic acid (100 mg/kg) was administered followed by maintenance doses of 25 mg/kg/dose every six hours. the patient’s plasma glucose was significantly elevated outside the upper limit of detection in the glucometer that was used. insulin therapy was started early for the anticipated hyperglycaemia with an initial dose of 0.1 iu/kg/hr; this dose was later increased in the first six hours to 0.4 iu/kg/hr for persistent uncontrolled hyperglycaemia. gir was kept in the range of 8–10 mg/kg/min (5th–11th hours after admission) as a measure of attempted suppression of catabolism as per the protocol of the treatment of metabolic crisis.11,12 urine dipstick showed significant glucosuria and ketonuria with associated polyuria (urine output of 8.6 ml/kg/hr). with persistent ketones in the urine, feeding was not started and gir remained high. the patient’s plasma glucose remained very high despite escalating insulin infusion dose reaching 1.4 iu/kg/hr in the following six hours. associated severe electrolyte disturbances including hypokalaemia, hypocalcaemia, hypophosphataemia and hypomagnesaemia were recorded. iv correction was given for all these disturbances, with persistent severe hypokalaemia being a prominent side effect of the high dose of insulin infusion. the child remained critically sick on mechanical ventilation. his acidosis improved with continuous iv infusion of bicarbonate leading to discontinuation after normal ph was maintained. it was only after 18 hours subsequent to his admission with this severe condition that his urine dipstick was negative for ketones; nasogastric feeding was started to provide protein at 1 g/kg/day. his plasma glucose recorded high readings (>20 mmol/l) for more than 10 hours notwithstanding the escalation of the dose of insulin infusion. the plasma glucose reading decreased only after gradually and cautiously minimising the gir after 12 hours of admission given the concern about catabolism inducing further metabolic decompensation in this child with ppa. the patient has full recovery and was discharged with a follow-up plan. guardian consent was obtained for publication purposes. discussion ppa, organic aciduria, is considered a major health burden in the arab world due to high rates of consanguinity.13 both hypoglycaemia and hyperglycaemia could be part of the initial presentation of organic aciduria, including ppa. lehnert et al. reported the first observation of the unexplained bouts of hyperglycaemia in a patient with ppa.14 the literature review showed a high mortality rate in patients with organic acidaemias who presented with table 1: initial blood investigation results of a nine-month old boy with propionic acidaemia test patient’s results reference range arterial blood gas ph 7.11 7.35–7.45 pco2 in mmol/l 21 35–48 hco3 in mmol/l 8 23–30 be in mmol/l -24.3 -2 to +2 lactate in mmol/l 2 0.5–1.6 anion gap in mmol/l 40 5–13 serum ammonia in mcg/dl 173 30–50 serum electrolyte sodium in mmol/l 160 135–145 potassium in mmol/l 4 3.5–6.1 chloride in mmol/l 103 98–107 renal function urea in mmol/l 5 2.1–7.1 creatinine in μmol/l 23 15–31 bone profile calcium in mmol/l 2.42 2.17–2.55 phosphate in mmol/l 1.8 1.16–2.1 alkaline phosphatase in units/l 240 0–280 liver function alt in iu/l 40 14–59 ast in iu/l 30 15–35 protein in g/l 65 64–82 albumin in g/l 40 38–54 pco2 = partial pressure of carbon dioxide; hco3 = bicarbonate; be = base excess; alt = alanine aminotransferase; iu = international unit; ast = aspartate aminotransferase. transient insulin resistance in propionic acidaemia knowing is half the battle 650 | squ medical journal, november 2021, volume 21, issue 4 severe insulin-resistant hyperglycaemia. in conjunction with encephalopathy, hyperammonaemia and severe metabolic acidosis, hyperglycaemia may be a marker of more serious metabolic decompensation.15,16 it should be noted that the clinical presentation of ppa can be misdiagnosed as diabetic ketoacidosis.15,16 although hyperglycaemia, including insulin-res istant hyperglycaemia, has been reported in patients with different organic acidaemia (including isovaleric acidaemia, methylmalonic acidaemia and ppa), the underlying mechanism remains largely unknown and it is presumed to be multifactorial. reduced muscle and hepatic uptake of glucose, coupled with iv lipid-related fatty-acid-induced insulin resistance, are postulated to be the underlying mechanisms.10 lipotoxicity and hyperglycaemia will cause hyperactivation of protein phosphatase 2a, which leads to reduced phospho rylation of insulin receptors (ir) and insulin receptor substrate (irs).17 mitochondrial dysfunction causes the same effect through activation of serine/threoninespecific kinases. hyperinsulinaemia hyperactivates ph domain and leucine rich repeat protein phosphatase 1 and growth factor receptor-bound protein 14, which decreases akt serine 473 phosphorylation competition for irs binding to ir.17 the notable improvement in glycaemic control with reduction of gir may clinically support this possibility. as was seen in the current case, plasma glucose started to improve when the rate of glucose infusion of 7 mg/kg/min was reached. plasma glucose gradually decreased to 10 mmol/l when insulin infusion stopped. the first negative urine dipstick for glucosuria was done when the gir dropped to 5–6 mg/kg/min, and at that time, the insulin infusion rate was at 0.4 iu/ kg/hr [figure 1]. although most metabolic emergency protocols recommend high gir to bring in more insulin secretion that may promote anabolism, there is no evidence to suggest that patients receiving exogenous insulin to combat hyperglycaemia recover faster or quickly achieve positive nitrogen balance compared to patients relying on their endogenous insulin secretion to combat hyperglycaemia that may accompany high gir. the long-term risk of diabetes and pancreatic exhaustion caused by repeated exposure to high gir with a recurrent metabolic crisis is a matter of concern. unfortunately, this has not been followed in patients with metabolic disorders. conclusion an important challenge that needs to be addressed is achieving a balanced gir, which is considered to be enough to achieve the targeted insulin level beyond which risks of hyperglycaemia start to outweigh potential anabolic benefits of additional insulin secretion. given the few case reports published so far, insulin-resistant hyperglycaemia in the context of metabolic decompensation associated with organic aciduria, seems to be a poor prognostic factor. timely clinical attention should be provided to achieve adequate caloric delivery through alternative sources instead of through high gir to permit better glycaemic control, especially when insulin-resistant hyperglycaemia is present. a u t h o r s’ c o n t r i b u t i o n man drafted the introduction. man and ka drafted the discussion and references. mr drafted the case presentation. ka revised the case presentation with management. man edited the manuscript. all authors approved the final version of the manuscript. references 1. couce ml, castiñeiras de, bóveda md, baña a, cocho ja, iglesias aj, et al. evaluation and long-term follow-up of infants with inborn errors of metabolism identified in an expanded screening programme. mol genet metab 2011; 104:470–5. https://doi.org/10.1016/j.ymgme.2011.09.021. 2. chace dh, diperna jc, kalas ta, johnson rw, naylor ew. rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns. clin chem 2001; 47:2040–4. https://doi. org/10.1093/clinchem/47.11.2040. figure 1: metabolic profile during glucose and insulin administration of a nine-month-old boy with propionic acidaemia. mohamed a. el-naggari, marwa rady and khalid althihli case report | 651 3. rashed ms. clinical applications of tandem mass spectrometry: ten years of diagnosis and screening for inherited metabolic diseases. j chromatogr b biomed sci appl 2001; 758:27–48. https://doi.org/10.1016/s0378-4347(01)00100-1. 4. al-shamsi a, hertecant jl, al-hamad s, souid ak, al-jasmi f. mutation spectrum and birth prevalence of inborn errors of metabolism among emiratis: a study from tawam hospital metabolic center, united arab emirates. sultan qaboos univ med j 2014; 14:e42–9. https://doi.org/10.12816/0003335. 5. jurecki e, ueda k, frazier d, rohr f, thompson a, hussa c, et al. nutrition management guideline for propionic acidemia: an evidenceand consensus-based approach. mol genet metab 2019; 126:341–54. https://doi.org/10.1016/j. ymgme.2019.02.007. 6. grünert sc, müllerleile s, de silva l, barth m, walter m, walter k, et al. propionic acidemia: neonatal versus selective metabolic screening. j inherit metab dis 2012; 35:41–9. https:// doi.org/10.1007/s10545-011-9419-0. 7. nizon m, ottolenghi c, valayannopoulos v, arnoux jb, barbier v, habarou f, et al. long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. orphanet j rare dis 2013; 8:148. https://doi.org/10.1186/1750-1172-8-148. 8. pena l, burton bk. survey of health status and complications among propionic acidemia patients. am j med genet a 2012;158a:1641–6. https://doi.org/10.1002/ajmg.a.35387. 9. pena l, franks j, chapman ka, gropman a, ah mew n, chakrapani a, et al. natural history of propionic acidemia. mol genet metab 2012; 105:5–9. https://doi.org/10.1016/j. ymgme.2011.09.022. 10. filippi l, gozzini e, cavicchi c, morrone a, fiorini p, donzelli g, et al. insulin-resistant hyperglycaemia complicating neonatal onset of methylmalonic and propionic acidaemias. j inherit metab dis 2009; 32:s179–86. https://doi.org/10.1007/ s10545-009-1141-9. 11. baumgartner mr, hörster f, dionisi-vici c, haliloglu g, karall d, chapman ka, et al. proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. orphanet j rare dis 2014; 9:130. https://doi.org/10.1186/ s13023-014-0130-8. 12. chapman ka, gropman a, macleod e, stagni k, summar ml, ueda k, et al. acute management of propionic acidemia. mol genet metab 2012; 105:16–25. https://doi.org/10.1016/j. ymgme.2011.09.026. 13. zayed h. propionic acidemia in the arab world. gene 2015; 564:119–24. https://doi.org/10.1016/j.gene.2015.04.019. 14. lehnert w, junker a, wehinger h, zöberlein hg, baumgartner r, ropers hh. [propionic acidemia associated with hypertrophic pyloric stenosis and bouts of severe hyperglycemia (author's transl)]. monatsschr kinderheilkd 1980; 128:720–3. https://doi. org/10.1007/978-3-662-38563-0_193. 15. dweikat im, naser en, abu libdeh ai, naser oj, abu gharbieh nn, maraqa nf, et al. propionic acidemia mimicking diabetic ketoacidosis. brain dev 2011; 33:428–31. https://doi. org/10.1016/j.braindev.2010.06.016. 16. joshi r, phatarpekar a. propionic acidemia presenting as diabetic ketoacidosis. indian pediatr 2011; 48:164–5. 17. boucher j, kleinridders a, kahn cr. insulin receptor signaling in normal and insulin-resistant states. cold spring harb perspect biol 2014; 6:a009191. https://doi.org/10.1101/ cshperspect.a009191. 1cardiovascular research center and 2department of surgery, kermanshah university of medical sciences, kermanshah, iran *corresponding author’s e-mail: a.asadmobini@gmail.com كيس دم أذيين أمين به حجارة متدلية من اجليب التاجي فريدون �شابزي، اأغيغ حيدري، عطيفة اأ�شدموبيني، حممد باقر حيدري abstract: cardiac blood cysts are rare benign neoplasms, usually involving the cardiac valves and are remnants of the chiari network. they are usually detected in the first six months of life and rarely occur in children or adults. we report a 76-year-old male patient who was referred to the imam ali hospital affiliated with kermanshah university of medical sciences, kermanshah, iran, in 2018 with dyspnoea. transthoracic echocardiography revealed a small patent foramen ovale (pfo) and a circumferential mobile cystic mass in the right atrium, with the impression of a tumour or thrombus. the patient underwent open-heart surgery with cardiopulmonary bypass to repair to pfo and remove the intra-atrial lesion. during surgical examination of the right atrial cavity, a blood cyst containing small stone-like structures on the coronary sinus valve of the right atrium was found. the post-operative course was uneventful and no recurrence of tumour was detected during six months of follow-up. to the best of our knowledge, this is the first reported case of a right atrial blood cyst with a few nodule-like stones in an adult with pfo in iran and the second case in an adult with pfo worldwide. keywords: cyst; coronary sinus; adult; operative surgical procedure; case report; iran. امللخ�ص: اأكيا�س دم القلب هي اأورام حميدة نادرة وت�شمل عادة ال�شمامات القلبية وهي بقايا من �شبكة �شياري. عادة ما يتم اكت�شافها يف االأ�شهر ال�شتة االأوىل من احلياة ونادرا ما تظهر يف االأطفال اأو البالغني. نعر�س هنا حالة ملري�س يبلغ من العمر 76 عاًما والذي مت اإحالته تخطيط ك�شف التنف�س. �شيق ب�شبب 2018 عام يف اإيران، كرمان�شاه، الطبية، للعلوم كرمان�شاه جلامعة التابع علي االإمام م�شت�شفى اإىل �شدى القلب عرب ال�شدر عن وجود ثقب بي�شاوي كامن �شغري وكتلة كي�شية كفافية متحركة يف االأذين االأمين تعطي انطباع عن وجود ورم اأو جتلط. خ�شع املري�س جلراحة قلب مفتوح مع جمرى جتاوز قلبي رئوي الإ�شالح الثقب البي�شاوي الكامن واإزالة االآفة داخل االأذين. اأثناء الفح�س اجلراحي للتجويف االأذيني االأمين مت العثور على كي�س دم على �شمام اجليب التاجي يف االأذين االأمين يحتوي على هياكل �شغرية ت�شبه احلجارة. كانت امل�شار بعد العملية اجلراحية بال م�شاعفات ومل يتم اكت�شاف اأي تكرار للورم خالل ال�شتة اأ�شهر من املتابعة بعد العملية. على حد علمنا هذه هي اأول حالة يتم االإبالغ فيها عن وجود كي�س دم اأذيني اأمين يحتوي على بع�س احلجارة التي ت�شبه العقيدات يف �شخ�س بالغ لديه ثقب بي�شاوي كامن يف اإيران واحلالة الثانية لدى �شخ�س بالغ م�شاب بثقب بي�شاوي كامن حول العامل. الكلمات املفتاحية: كي�س؛ جيب تاجي؛ بالغ؛ عملية جراحية؛ تقرير حالة؛ اإيران. right atrial blood cyst with stones suspended from the coronary sinus feridoun sabzi,1 aghigh heydari,1 *atefeh asadmobini,1 mohammad b. heidari2 sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e161–163, epub. 8 sep 19 submitted 25 dec 18 revisions req. 17 feb & 1 apr 19; revisions recd. 14 mar & 10 apr 19 accepted 18 apr 19 blood cyst of the right atrium with a connecting stalk to the coronary sinus valve is a lesion that rarely occurs in adults.1 these cysts are remnants of the chiari network (can) which comprises of fine trabeculae of fibrous tissue floating along the direction of blood flow to the tricuspid valve (tv).2 the congenital aberrant regression of the primitive embryological network’s plate leads to the formation of a diverticulum with an internal wall lined with cobblestone-like epithelium and an outer layer covered with fibrous tissue.3,4 these unusual cysts are filled with venous and non-coagulable blood and may partially occlude the orifice of the tv or inferior vena cava (ivc). however, they are benign lesions and in asymptomatic cases should be left untreated, yet pre-operative differential diagnosis from other similar cystic lesions is difficult. the presence of intra-cystic homogeneous echo density with the absence of a calcified rim in the external wall, strongly justifies the presence of a blood cyst. if clear pre-operative delineation from other masses is not possible by imaging modalities and symptoms arise, the cyst should be resected. this report describes a large mobile right atrial blood cyst reported in a patient with dyspnoea and patent foramen ovale (pfo) based on the results of transthoracic echocardiography (tte). case report a 76-year-old male patient was referred to the imam ali hospital affiliated with the kermanshah university of medical sciences, kermanshah, iran, in 2018 with dyspnoea that had persisted for two weeks. he had no history of coronary artery disease, chest pain or hypertension. physical examination was normal with this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.014 case report https://creativecommons.org/licenses/by-nd/4.0/ right atrial blood cyst with stones suspended from the coronary sinus e162 | squ medical journal, may 2019, volume 19, issue 2 no heart murmurs or other abnormal finding such as tachycardia or tachypnoea. routine laboratory tests and thrombophilia screening were normal. electrocardiogram results showed an irregular rhythm due to premature atrial contraction without any evidence of right or left bundle branch block. the patient’s chest x-ray was normal. subsequently, a tte was performed for further delineation of dyspnoea and possible left ventricular dysfunction or valve abnormalities. tte revealed a small pfo and a large mobile cystic mass connected to the atrial side of the coronary sinus valve with a short stalk prolapsing into the tv and the right ventricular cavity during each diastolic phase [figure 1]. in addition, transoesophageal echocardiography (toe) showed no evidence of tricuspid malfunction or right ventricular inflow occlusion caused by this large mass. left ventricular ejection fraction was normal. the cystic lesion was well demarcated from the right atrial cavity with a distinct, circumferential border, a thin homogenous wall and an echo-lucent internal cavity. however, some echo-density points were detected and attributed to intra-cystic calcifications. the coronary angiogram was normal. based on the toe findings, a circumferential thrombus, hydatid cyst or myxoma were included in the differential diagnoses. as a result, the patient underwent open-heart surgery with cardiopulmonary bypass for removal of the intra-atrial lesion and repair of the pfo. after infusion of cardioplegia and incision of the right atrium, a black blood filled cystic mass was found. the cystic mass with its short stalk was connected to the coronary sinus valve [figure 2]. the stalk of mass was excavated from its base by removal of the subendocardial layer [figure 3]. in addition, the pfo was closed using prolene sutures. the patient was weaned from cardiopulmonary bypass and had an uneventful course. histological examination revealed a blood cyst with internal cobblestone-like endothelium [figure 4]. the stone-like nodules were not evaluated by a pathologist. discussion anomalies of the can have been detected in necropsy examinations in 1.3–4% of the total population.5 it is an aberrant embryologic anomaly produced by incomplete regression of the remnants of the primitive sinus venosus valve. the can originates from the eustachian valve of the ivc continuing in the direction of the superior vena cava (svc) valve.6 it has been previously reported that this network is rarely associated with thromboemboli or thrombus formation. can usually has a specific shape with many fenestrations in its wall; however, it can also present in a cystic or cord-like shape or a diverticulum.7,8 hans chiari was the first author who described a case series of patients with a fenestrated ivc valve connected superiorly to the svc valve by a cord-like fibrotic stalk.9 although some studies have reported blood cysts of the right atrium, no study has yet figure 3: photograph of the surgically removed blood cyst from the right atrium of a 76-year-old male patient showing gross pathology of a cyst filled with saline. figure 2: intraoperative photographs of an open-heart surgery of a 76-year-old male patient showing a black blood filled cystic mass. figure 4: haematoxylin and eosin at x10 magnification showing a thin epithelial layer with internal cobblestonelike endothelium of the surgically excised blood cyst. figure 1: transthoracic echocardiogram of the heart of a 76-year-old male patient showing a cystic mass in the right atrium (arrow). feridoun sabzi, aghigh heydari, atefeh asadmobini and mohammad b. heidari case report | e163 sinus valve. blood cysts should be considered in the differential diagnosis of atrial cystic lesions detected during echocardiography. references 1. bae ch, kwon oc, lee s, lee ch, cho jw. cystic mass on right atrium of unusual form of chiari's network: a case report. korean j thorac cardiovasc surg 2012; 45:254–6. https://doi. org/10.5090/kjtcs.2012.45.4.254. 2. kim mj, jung ho. anatomic variants mimicking pathology on echocardiography: differential diagnosis. j cardiovasc ultrasound 2013; 21:103–12. https://doi.org/10.4250/jcu.2013.2 1.3.103. 3. bendadi f, van tijn da, pistorius l, freund mw. chiari's network as a cause of fetal and neonatal pathology. pediatr cardiol 2012; 33:188–91. https://doi.org/10.1007/s00246-0110114-6. 4. erdogan sb, akansel s, sargın m, mete met, arslanhan g, aka sa. a case of a large chiari network mimicking a right atrial thrombus. north clin istanb 2017; 4:270–2. https://doi. org/10.14744/nci.2017.76094. 5. schwimmer-okike n, niebuhr j, schramek gg, frantz s, kielstein h. the presence of a large chiari network in a patient with atrial fibrillation and stroke. case rep cardiol 2016; 2016:4839315. https://doi.org/10.1155/2016/4839315. 6. shivadeep s, anandaraja s, devi jansirani d. chiari network: an embryological remnant a case report and review. int j clin cardiol 2015; 2:3. https://doi.org/10.23937/2378-2951/1410038. 7. pellett aa. the chiari network in an echocardiography student. echocardiography 2004; 21:91–3. https://doi.org/10.1111/j.074 2-2822.2004.03069.x. 8. jansirani dd, deep ss, anandaraja s. anatomical study of chiari network and the remnant of left venous valve in the interior of right atrium. anat res int 2015; 2015:247680. https://doi.org/10.1155/2015/247680. 9. islam ak, sayami la, zaman s. chiari network: a case report and brief overview. j saudi heart assoc 2013; 25:225–9. https://doi.org/10.1016/j.jsha.2012.12.002. 10. centella t, moya jl, muñoz m, reguero em. images in cardiovascular medicine. giant endocardial blood cyst in the right atrium: echocardiographic and magnetic resonance imaging features. circulation 2008; 117:3250–1. https://doi.org/10.1161/ circulationaha.107.734814. 11. otsuka k, terasaki f, iimori a, tonari s, shimomura h, ito t, et al. right atrial blood cyst with total occlusion of the right coro nary artery. heart vessels 2007; 22:208–10. https://doi.org/10.1 007/s00380-006-0972-7. 12. otsuka h, arinaga k, fukuda t, takaseya t, shojima t, takagi k, et al. double right atrial blood cysts. ann thorac surg 2016; 101:e147–9. https://doi.org/10.1016/j.athoracsur.2015.10.021. 13. loukas m, sullivan a, tubbs rs, weinhaus aj, derderian t, hanna m. chiari’s network: review of the literature. surg radiol anat 2010; 32:895–901. https://doi.org/10.1007/s00276010-0639-z. 14. alegría-barrero e, alegría-barrero a, gavira gómez jj, rábago juan-aracil g. chiari's network and paroxysmal atrial fibrillation. rev esp cardiol 2011; 64:727–8. https://doi.org/10.1 016/j.recesp.2010.11.003. 15. michelena hi, mulvagh sl, schaff hv, enriquez-sarano ml, klarich kw. a heart-shaped mass inside a heart: echocardiographic diagnosis, pathology, and surgical repair of a flail tricuspid valve caused by a large blood-filled cyst. j am soc echocardiogr 2007; 20:771.e3–6. https://doi.org/10.1016/j. echo.2006.11.019. reported a blood cyst with a coronary sinus valve origin, as is in the current case.10–12 in the normal embryologic process, the sinus venosus valve completely disappears by the 15th gestational week, while in aberrant congenital processes, some parts of the ivc and svc valves are not regressed by the 100th day of gestational age. this aberrant congenital process leads to the presence of remnants of the valve after the 15th gestational week, when ivc and svc are separated completely from one another. therefore, this network that existed between two structures is stretched and ruptured to form various shapes and contours. there is possibly an important relationship between the presence of autism spectrum disorder, pfo and can. in the 15th week of the embryologic period, almost all interatrial septal defects have been closed; the presence of an ebstein anomaly is usually concomitant with the can.13 the increased rate of right-to-left shunt in the current patient is related to many factors, such as low compliance of the right ventricle caused by chronic obstructive pulmonary disease or aging, stretching of the pfo due to the mass and the increased right atrial pressure caused by the presence of the tumour. the presence of a right atrial aneurysm is another common associated anomaly in can and has been reported in 21% of subjects.13 rare can complications include atrial fibrillation (af), endocarditis and its role as a barrier to implantation of a pacemaker.9,14 the preoperative diagnosis of rare can with blood cyst is usually difficult and can be incorrectly diagnosed as thrombus, myxoma or hydatid cyst.15 in the present case, the subject was found to have af and pfo with no evidence of thrombus or atrial aneurysm. the right atrial lesion with a free floating thrombus, hydatid cyst or myxoma were the differential diagnoses as tte findings revealed a thin wall cystic mass without the presence of calcification in the mass’s core. according to the angiography results, the right coronary artery did not show tumour blush. histologic examination determined that the lesion was a blood cyst with can origin. although a blood cystic lesion has been reported previously in one case, the current case had two unique characteristics: (1) the cyst originated from the coronary sinus valve; and (2) few stone-like structures were found in the cyst sack.1 conclusion a rare case of a large blood cyst of the coronary sinus valve was reported in a patient with a pfo defect and af. to the best of the authors’ knowledge, this is the second reported case of a blood cyst in an adult patient with pfo; although this case has the unique characteristic of a cyst originating from the coronary https://doi.org/10.5090/kjtcs.2012.45.4.254 https://doi.org/10.5090/kjtcs.2012.45.4.254 https://doi.org/10.4250/jcu.2013.21.3.103 https://doi.org/10.4250/jcu.2013.21.3.103 https://doi.org/10.1007/s00246-011-0114-6 https://doi.org/10.1007/s00246-011-0114-6 https://doi.org/10.14744/nci.2017.76094 https://doi.org/10.14744/nci.2017.76094 https://doi.org/10.1155/2016/4839315 https://doi.org/10.23937/2378-2951/1410038 https://doi.org/10.1111/j.0742-2822.2004.03069.x https://doi.org/10.1111/j.0742-2822.2004.03069.x https://doi.org/10.1155/2015/247680 https://doi.org/10.1016/j.jsha.2012.12.002 https://doi.org/10.1161/circulationaha.107.734814 https://doi.org/10.1161/circulationaha.107.734814 https://doi.org/10.1007/s00380-006-0972-7 https://doi.org/10.1007/s00380-006-0972-7 https://doi.org/10.1016/j.athoracsur.2015.10.021 https://doi.org/10.1007/s00276-010-0639-z https://doi.org/10.1007/s00276-010-0639-z https://doi.org/10.1016/j.recesp.2010.11.003 https://doi.org/10.1016/j.recesp.2010.11.003 https://doi.org/10.1016/j.echo.2006.11.019 https://doi.org/10.1016/j.echo.2006.11.019 submitted 14 feb 23 1 revision req. 21 mar 23; revision recd. 5 apr 23 2 accepted 3 may 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.033 5 6 the burden of human parechoviruses on children in oman 7 a retrospective study 8 aws al-farsi,1 zaid alhinai,1 fatma ba alawi,2 khuloud al maamari,2 9 laila s. al yazidi3 10 11 1college of medicine and health sciences, sultan qaboos university, muscat, oman; 12 departments of 2microbiology & immunology and 3child health, sultan qaboos university 13 hospital, muscat, oman. 14 *corresponding author’s e-mail: lailay@squ.edu.om 15 16 abstract 17 objectives: to study the burden, clinical and laboratory features, and outcome of human 18 parechoviruses (hpevs) infection among children managed at sultan qaboos university 19 hospital (squh). methods: this is a retrospective study of children (< 18 years of age) with 20 molecular proven hpevinfection managed at squh between january 2017 and december 21 2019. data was collected from patients’ medical records and analyzed to describe the 22 demographic, clinical and laboratory features, management and outcome. results: hpev was 23 detected in 61 patients, 44 (72%) of whom were males. the median age of these patients was 24 9 months (iqr, 6-15 months). hpev was detected throughout the year without any 25 significant peaks. the majority of our patients (51; 84%) had co-infection with other viruses. 26 forty-eight (79%) children with hpev infection required hospitalization and their median 27 hospital length of stay was 5 days (iqr, 3 8 days). ex-prematurity (10; 16%) was the most 28 common comorbidity seen among this group. fever (41; 67%) and cough (41; 67%) were the 29 most common presenting symptoms among these children.two-third of children with hpev 30 infection in this cohort were managed for lower respiratory tract infection and none for 31 meningitis. gastroenteritis was not common in our study, only 8 children had diarrhoea. all 32 children had a full recovery. conclusion: hpevs does not show a clear seasonality in oman. 33 most of the children were < 2 years of age and had a viral co-infection. outcomes of hpevs 34 were favorable, with no mortalities, but thorough follow-up of neurological outcomes was 35 lacking. 36 keywords: children; parechovirus; infection; outcome; oman. 37 38 advances in knowledge 39 the majority of children infected with hpev were males, younger than 2 years, and 40 had a viral co-infection. 41 hpev does not show a clear seasonality in oman. 42 no reported mortality in this group. 43 44 application to patient care 45 this study focused on assessing the burden of hpev infection among children in 46 oman and describe their clinical and laboratory features. 47 this study’s findings will help pediatricians understand the complete clinical picture 48 and outcomes of this virus in oman. 49 50 introduction 51 human parechoviruses (hpevs) can cause gastrointestinal, severe respiratory tract, and central 52 nervous system infections in children.1,2 they belong to the picornaviridae family consisting 53 of non-enveloped positive-sense single-stranded rna viruses3 and are transmitted mainly by 54 the respiratory droplets and faecal-oral routes.4,5 there are two species of hpevs: parechovirus 55 a and parechovirus b.6 parechovirus a is further divided into 19 genotypes, of which hpev-56 1, hpev-3, and hpev-6 are the most common genotypes associated with human disease.6–8 57 the prevalence and seasonality of the virus differ from one place to another due to the 58 differences in hpev genotypes and age.6 59 60 hpev infection is usually asymptomatic or associated with mild respiratory and 61 gastrointestinal symptoms in children.8 some infants present with fever, irritability, and 62 sometimes rash and they are described as “hot, red, and angry babies”.8 the less common 63 clinical features include seizures, distended abdomen, liver failure, and pseudo-appendicitis.8 64 it can also be associated with sepsis like-disease and meningoencephalitis.7 a study from iran 65 showed that hpevs were a common cause of aseptic meningitis and sepsis like-disease 66 compared to human enteroviruses in children less than 8 years of age between 2009 and 2011.9 67 another iranian study reported that hpev-1 was the main cause of diarrhea among other hpev 68 genotypes.10 zhu et al., reported in their study that hpev infection was more common in 69 children younger than 2 years of age.11 central nervous system involvement with hpevs might 70 result in long-term complications including white matter abnormalities, cerebral palsy, and 71 neurodevelopmental sequelae.6,12 mortality from hpev infection is rare among healthy 72 children.13 73 74 hpev infection is common across the globe and is not specific to a particular region. australia 75 reported 3 epidemics of hpev-3 between 2013 and 2018.7,8 in several european studies, hpev 76 infection was seen in about 3-8% of children presenting to the emergency department with a 77 febrile illness.8,14,15 the seasonality of the virus is not very clear but it depends mainly on the 78 most common genotype present in that particular area.6 a study in iran showed that hpev-1 79 infection rates peaked during spring and autumn, while on the other hand rahimi et al., reported 80 that there was no significant difference in seasonality of hpevs in iran as it was detected 81 throughout the year.9,10 hpev-1 infections appear more in the summer and autumn periods of 82 the year in the united states, denmark and australia compared to germany which showed a 83 decrease in the rates in the summer.6,16–18 in spain, a study showed that the number of hpev 84 cases increased during both summer and spring.19 in hong kong and northern ireland, studies 85 showed that the rates of hpev infection in children were much higher during winter.2,20,21 86 87 there is limited data on the burden and outcome of hpev infection among omani children. 88 little importance has been given to hpev infection in the middle east region. therefore, the 89 results of this study will help pediatricians and healthcare professionals in oman and in the 90 neighboring countries to get a better understanding of the burden of this virus in the region. 91 the aim of this study was to identify all confirmed cases of hpev infection among children 92 presenting to sultan qaboos university hospital (squh), describe their clinical and laboratory 93 features and their outcome. 94 95 methods 96 this retrospective study was conducted at squh, one of the major tertiary care facilities in 97 muscat governorate, sultanate of oman. the study included all symptomatic children under 98 18 years of age managed at squh with a positive hpev pcr from respiratory and 99 cerebrospinal fluid (csf) specimens over a period of 3 years (january 2017 december 2019). 100 exclusion criteria were age greater than or equal to 18 years, asymptomatic infection, or having 101 insufficient data in the medical records. the patients’ demographics, clinical details, 102 investigation results, treatments, and outcomes of the infection were collected from the squh 103 patient electronic medical records (trakcare®). 104 105 lower respiratory tract infection (lrti) was defined as the presence of abnormal lung 106 examination results or infiltrates (new possible or definite) seen in chest x-ray, or oxygen need 107 in conjunction with a diagnosis made by a physician at presentation.22 secondary bacterial 108 pneumonia was defined as the presence of lrti with infiltrates on chest x-ray, and physician’s 109 decision to treat the child with antibiotics for 5 days or more.22 prematurity was defined as a 110 birth that happens before 37 weeks of gestation. the definitions of hypotension, tachycardia 111 and tachypnea was based on the reference ranges of the pediatric advanced life support 112 (pals) booklet. fever was defined as an elevated temperature of 38°c or greater. 113 114 respiratory specimens were collected by nasopharyngeal aspirate (npa), throat or nasal 115 swabs. real-time multiplex polymerase chain reaction (real time-pcr) for respiratory and 116 cerebrospinal viruses were used to detect hpev nucleic acid. ftd respiratory pathogens 21 117 kits were used to test respiratory samples for the following targets: human coronaviruses 118 (oc43, hku1, nl63 and 229e), hpevs, human bocavirus, parainfluenza viruses (1, 2, 3 and 119 4), influenza viruses (a and b), rhinovirus, rsv, human metapneumovirus, adenovirus, 120 enteroviruses, and mycoplasma pneumonia. hpev can cause meningitis as well. csf samples 121 for all children with impression of meningoencephalitis during the study period were tested for 122 herpes simplex viruses 1 &2 (hsv 1/2), varicella zoster virus (vzv), hpevs, enteroviruses 123 and mumps using ftd viral meningitis kits. 124 125 the statistical package for the social sciences software (spss, version 25) was used to 126 analyze data collected from all children who had met the inclusion criteria. to compare two 127 categorical variables, chi-square or fisher's exact test was used. for non-normally distributed 128 continuous variables, mann-whitney u test was used. a p-value of less than 0.05 was 129 considered significant. comparison was done between children with isolated hpev and those 130 with infection with co-viruses to see if those with co-infection have more severe disease and 131 subsequently worse outcome. 132 133 ethical approval was obtained from the medical research ethics committee (mrec) at the 134 college of medicine and health sciences (comhs) in may 2020 (mrec#2109). 135 136 results 137 sixty-one children were managed for symptomatic hpev infection during the study period, 138 among whom 44 (72%) children were males. all patients were of omani nationality and the 139 median age was 9 months (iqr, 6-15 months). 140 141 the results revealed that 48 (79%) patients were hospitalized and their median hospital length 142 of stay was 5 days (iqr, 3-8 days). most of these patients 24 (39%) were admitted to the 143 regular ward while only 7 (12%) were admitted to the pediatric intensive care unit (picu) for 144 respiratory support. the most common comorbidity seen among hpev infected patients was 145 ex-prematurity as shown in table 1. eight of the preterm babies (80%) required oxygen therapy 146 and either admission to high dependency or picu admission. 147 figure 1 shows that hpev infection was detected throughout the year. 148 149 all positive specimens for hpevs were respiratory specimens. the majority of these specimens 150 were nasopharyngeal aspirates (48 specimens; 79%) followed by throat swabs (11 specimens; 151 18%). a lumbar puncture was not performed to any of these cases, as there was no suspicion 152 of meningitis or encephalitis. hpev pcr is part of our csf viral multiplex pcr panel and 153 none of the patients who were investigated for meningitis during the study period had hpev 154 meningitis. 155 156 fever (41 cases, 67%) and cough (41 cases, 67%) were the most common presenting symptoms 157 in our patients with hpevs. seven children had rash. two-third of children with hpevs were 158 managed for lrti. gastroenteritis was not common; only eight children had diarrhea. hpev 159 pcr is not part of gastrointestinal panel in our hospital but we assumed that hpev causes the 160 diarrhea in patients with confirmed hpev from respiratory tract. there were no cases of 161 meningitis or encephalitis. tachypnea (49 cases, 80%), tachycardia (27 cases, 44%) and 162 wheezing (36 cases, 59%) were the most common findings on clinical examination. apnea, 163 stridor and hypoxia were reported in 4 (7%), 6 (10%) and 28 (46%) children respectively. 164 165 co-infection with other viruses was common. fifty-one children (84%) had a co-infection with 166 other viruses including 34 (56%) with only one virus, 10 (16%) with two viruses, five (8%) 167 with three viruses and two (3%) with four viruses. rhinovirus (30 cases; 49%) followed by 168 adenovirus (14 cases; 23%) were the most common viruses causing co-infection with hpevs. 169 170 children with isolated hpev and those co-infected with other viruses were compared. sodium 171 level was lower in children with isolated hpev (median 137, iqr 135-138 vs 139, iqr 136-172 141, p = 0.024). wheezing showed a lower frequency trend among children with isolated 173 hpev, however it did not reach a statistical significance (p = 0.075) as shown in table 2. 174 175 none of our patients developed sepsis, acute kidney injury or liver dysfunction. two children 176 ( 7-month and 12-month old) presented with febrile seizure during the hpev infection. all 177 patients with hpevs in this cohort had full recovery. no long-term follow-up provided for 178 these children, so we could not comment on their neurological outcome. 179 180 discussion 181 the results of this study highlight the burden of hpev infection on our health care system, as 182 the majority needed hospital admission. in our cohort, 44 (72%) of hpev infected patients 183 were males which is a similar finding in studies from iran, china and usa.2,10,13 the median 184 age of children managed for hpev infection in our study was 9 months (iqr, 6-15 months) 185 which is similar to what has been described recently by an australian study that found a median 186 age of 8 months (iqr, 6.0-11.7 months).18 this increase in susceptibility to hpev infection 187 after 6 months of age might be due to the waning of immunity provided by maternal 188 antibodies.18 the most common comorbidities seen among children with hpevs in our cohort 189 was ex-prematurity (10; 16%). premature birth was also identified as a risk factor for hpev 190 and its complications in a study from australia.12 191 192 when compared to rsv infection in our institution, (48; 79%) of hpev infections required 193 hospitalization compared to (57; 94%) of rsv infection (unpublished data) which highlights 194 the virus’s burden on the healthcare facilities. in addition, 7 (12%) of children with hpev in 195 our cohort required admission to the picu for respiratory support, which again shows that 196 hpev can cause severe infection in children. an australian study presented similar findings 197 with their patients having a median length of stay of 4 days (iqr, 2-13 days) and 15 (25%) of 198 the children in their cohort were admitted to the intensive care unit.7 199 200 viral co-infection was very common in our cohort as 51 (84%) of our patients with hpev 201 infection have co-infection with other viruses which is similar to what other studies have 202 shown.2,13,18 rhinovirus was the most common virus causing co-infection in our patients and 203 this agrees with the findings of two previous studies.2,13 204 205 hpev infection was detected throughout the year, with a relative increase in cases in the fall 206 and winter months. the relative increase in hpev cases during fall and winter might be because 207 of the opening of schools and the probability of having different hpev genotypes circulating 208 in oman, which results in different seasonality patterns. in addition, this rise might be due to 209 the decrease in temperatures from late summer to winter. the seasonality of hpev described 210 in our study is similar to what has been described by rahimi et al., in iran which showed that 211 the virus appears throughout the year without any significant differences between the various 212 seasons.9 this could be because of the close proximity of oman to iran and relatively similar 213 weather and might share similar viral genotypes. studies from hong kong and australia 214 showed very clear seasonality compared to what we see in oman.2,7,20 215 216 the majority of our patients with hpevs were managed for lrti. few patients (8; 13%) had 217 gastroenteritis and none were managed for meningitis. this might be because of the hpev 218 genotypes, which is present in oman. hpev-1 causes respiratory and mild gastrointestinal 219 infection in children compared to hpev-3 which usually causes severe central nervous system 220 infection in neonates.2 therefore, it is likely that hpev-1 is the main circulating genotype in 221 our setting since no cases of meningitis were seen among our cohort and most of the children 222 were older than 6 months. 223 224 our study suggests that hpev infection is a benign infection in children as we reported no 225 mortality in any of our patients similar to what has been described recently in the united 226 states.13 we could not comment on the neurological outcomes as long-term follow-up was 227 lacking in our cohort. 228 229 this study has several limitations. the first limitation is the relatively small sample size. this 230 might be because data was collected from only one center (squh) and because not all the 231 children with respiratory symptoms are tested for hpevs, which makes it likely that there is an 232 underestimation of the number of hpev infections reported in our study. as such, results from 233 our study may not necessarily reflect the experience in other tertiary, secondary, and primary 234 healthcare settings. another limitation of this study is that hpev genotypes were not identified 235 and hence not possible to compare the severity of infections among the different genotypes and 236 the seasonal distribution of infection with other communities. furthermore, the retrospective 237 design of the study was another limitation because some patients had incomplete medical data. 238 in addition, presence of co-infection in most of our patients makes it difficult to make sure that 239 the clinical picture is fully explained by hpev infection in these patients. finally, this study 240 might not completely assess the burden of hpev infections in omani primary healthcare 241 facilities but we believe it is a good representation of the burden of this virus among children 242 in a tertiary healthcare setting. 243 244 future work includes conducting a multicenter study in oman to assess the burden of hpev 245 infections among children especially neonates to assess the severity. in addition, studies on 246 hpev genotypes are also recommended in order to have a complete understanding of the 247 burden of hpevs on oman healthcare facilities. 248 249 conclusion 250 hpevs does not show a clear seasonality in oman. most of the children were < 2 years of age 251 and had a viral co-infection. outcomes of hpevs were favorable, with no mortalities, but 252 thorough follow-up of neurological outcomes was lacking. 253 254 conflicts of interest 255 the authors declare no conflict of interests. 256 257 funding 258 no funding was received for this study. 259 260 authors’ contribution 261 ly conceptualized the study and supervised the work. aa collected the data. za analyzed the 262 data. fba and kam interpreted the virology data. aa, fba and kam drafted the manuscript. 263 za, fba, kam and ly revised the manuscript. all authors approved the final version of the 264 manuscript. 265 266 references 267 1. benschop ksm, schinkel j, minnaar rp, pajkrt d, spanjerberg l, kraakman hc, et 268 al. human parechovirus infections in dutch children and the association between 269 serotype and disease severity. clin infect dis. 2006;42(2):204–10. 270 2. chiang gpk, chen z, chan mcw, lee shm, kwok ak, yeung acm, et al. clinical 271 features and seasonality of parechovirus infection in an asian subtropical city, hong 272 kong. plos one. 2017;12(9):1–15. 273 3. joki-korpela p, hyypiä t. parechoviruses, a novel group of human picornaviruses. 274 ann med. 2001;33(7):466–71. 275 4. harvala h, simmonds p. human parechoviruses: biology, epidemiology and clinical 276 significance. j clin virol. 2009;45(1):1–9. 277 5. sharp j, bell j, harrison cj, nix wa, oberste ms, selvarangan r. human 278 parechovirus in respiratory specimens from children in kansas city, missouri. j clin 279 microbiol. 2012;50(12):4111–3. 280 6. olijve l, jennings l, walls t. human parechovirus : an increasingly recognized 281 cause of. clin microbiol rev [internet]. 2018;31(nov 2017, 31 (1) e00047-17):1–17. 282 available from: https://doi.org/10.1128/cmr.00047-17. 283 7. khatami a, mcmullan bj, webber m, stewart p, francis s, timmers kj, et al. sepsis-284 like disease in infants due to human parechovirus type 3 during an outbreak in 285 australia. clin infect dis. 2015;60(2):228–36. 286 8. britton pn, jones ca, macartney k, cheng ac. parechovirus: an important emerging 287 infection in young infants. med j aust. 2018;208(8):365–9. 288 9. rahimi p, naser hm, siadat sd, sohrabi a, mostafavi e, motamedirad m, et al. 289 genotyping of human parechoviruses in iranian young children with aseptic 290 meningitis and sepsis-like illness. j neurovirol. 2013;19(6):595–600. 291 10. ghazi f, ataei z, dabirmanesh b. molecular detection of human parechovirus type 1 292 in stool samples from children with diarrhea. int j infect dis [internet]. 293 2012;16(9):e673–6. available from: http://dx.doi.org/10.1016/j.ijid.2012.05.1020 294 11. zhu yn, ye yh, zhang z, wu yj, chen l, wang j, et al. prevalence and molecular 295 characterization of parechovirus a in children with acute gastroenteritis in shenzhen, 296 2016–2018. arch virol [internet]. 2020;165(6):1377–84. available from: 297 https://doi.org/10.1007/s00705-020-04587-6 298 12. britton pn, dale rc, nissen md, crawford n, elliott e, macartney k, et al. 299 parechovirus encephalitis and neurodevelopmental outcomes. pediatrics. 2016;137(2). 300 13. tomatis souverbielle c, wang h, feister j, campbell j, medoro a, mejias a, et al. 301 year-round, routine testing of multiple body site specimens for human 302 parechovirus in young febrile infants. j pediatr [internet]. 2020; available from: 303 https://doi.org/10.1016/j.jpeds.2020.10.004 304 14. cordey s, l’huillier ag, turin l, gervaix a, posfay barbe k, kaiser l. enterovirus 305 and parechovirus viraemia in young children presenting to the emergency room: 306 unrecognised and frequent. j clin virol [internet]. 2015;68:69–72. available from: 307 http://dx.doi.org/10.1016/j.jcv.2015.05.003 308 15. vollbach s, müller a, drexler jf, simon a, drosten c, eis-hübinger am, et al. 309 prevalence, type and concentration of human enterovirus and parechovirus in 310 cerebrospinal fluid samples of pediatric patients over a 10-year period: a retrospective 311 study. virol j [internet]. 2015;12(1):1–6. available from: 312 http://dx.doi.org/10.1186/s12985-015-0427-9 313 16. van der sanden s, de bruin e, vennema h, swanink c, koopmans m, van der 314 avoort h. prevalence of human parechovirus in the netherlands in 2000 to 2007. j 315 clin microbiol. 2008;46(9):2884–9. 316 17. fischer tk, midgley s, dalgaard c, nielsen ay. human parechovirus infection, 317 denmark. emerg infect dis. 2014;20(1):83–7. 318 18. wang cyt, ware rs, lambert sb, mhango lp, tozer s, day r, et al. parechovirus 319 a infections in healthy australian children during the first 2 years of life: a 320 community-based longitudinal birth cohort study. clin infect dis. 2019;(xx):1–9. 321 19. cabrerizo m, trallero g, pena mj, cilla a, megias g, muñoz-almagro c, et al. 322 comparison of epidemiology and clinical characteristics of infections by human 323 parechovirus vs. those by enterovirus during the first month of life. eur j pediatr. 324 2015;174(11):1511–6. 325 20. chan pks, chan mcw, nelson eas, leung tf. human parechovirus infection in 326 hong kong neonates, infants, and young children: abridged secondary publication. 327 hong kong med j = xianggang yi xue za zhi. 2020;26(3):8–11. 328 21. davis j, fairley d, christie s, coyle p, tubman r, shields md. human parechovirus 329 infection in neonatal intensive care. j pediatr infect dis. 2015;34(2):121–4. 330 22. ogimi c, englund ja, bradford mc, qin x, boeckh m, waghmare a. characteristics 331 and outcomes of coronavirus infection in children: the role of viral factors and an 332 immunocompromised state. j pediatric infect dis soc. 2019;8(1):21–8. 333 334 335 336 table 1: demographic features of hpev patients managed at sultan qaboos university 337 during the study period: 338 table 1: demographic features of hpev patients (n=61) gender male, n (%) 44 (72%) female, n (%) 17 (28%) governorate muscat, n (%) 24 (39%) al batinah, n (%) 20 (33%) ash sharqiyah, n (%) 9 (15%) ad dakhiliya, n (%) 7 (12%) dhofar, n (%) 1 (2%) nationality omani, n (%) 61 (100%) non-omani, n (%) 0 (0%) age (months) median 9 months iqr 6-15 months site of sample npa, n (%) 48 (79%) throat swab, n (%) 11 (18%) nasal swab, n (%) 2 (3%) admission admitted, n (%) 48 (79%) regular ward, n (%) 24 (39%) high dependency unit, n (%) 17 (28%) paediatric intensive care unit, n(%) 7 (12%) length of hospital stay (days), n=48 median 5 days iqr 3-8 days co-morbidities premature birth, n (%) 10 (16%) asthma, n (%) 7 (12%) other atopic disease, n (%) 3 (5%) immunocompromised, n (%) 6 (10%) neurological impairment, n (%) 6 (10%) sickle cell trait, n (%) 4 (7%) congenital heart disease, n (%) 3 (5%) npa: nasopharyngeal aspirate 339 340 table 2: comparison of clinical, laboratory and radiological features between isolated 341 hpev and co-infected hpev managed at sultan qaboos university during the study 342 period: 343 344 table 2: comparison between isolated hpev and hpev with coinfection only parechovirus n = 10 coinfection n = 51 p value missing male gender, n (%) 5 (50%) 39 (77%) 0.12 0 age, months, median (iqr) 10 (6-15) 9 (6-15) 0.82 0 weight, kg, median (iqr) 7.6 (4.9-9.9) 8.0 (6.0-9.2) 0.85 2 length of stay, days, median (iqr) 7 (5-44) 5 (3-8) 0.13 13 wbc, median (iqr) 10.3 (9.2-13.7) 12.2 (7.9-16.1) 0.85 6 anc, median (iqr) 3.7 (2.3-6.2) 4.7 (2.8-8.9) 0.25 6 alc, median (iqr) 5.6 (5.3-6.3) 4.5 (2.9-7.4) 0.66 6 platelet, median (iqr) 430 (279-645) 371 (279-471) 0.21 6 crp, median (iqr) 38.5 (9.8-86) 23 (9-58.5) 0.28 10 alt, median (iqr) 17.5 (10.3-21) 18.5 (15-46.3) 0.37 47 total bilirubin, median (iqr) 4 (3) 3.5 (3-5) 0.81 48 albumin, median (iqr) 37 (26.3-42.5) 39 (36.8-43.3) 0.30 39 sodium, median (iqr) 137 (135-138) 139 (136-141) 0.024 7 creatinine, median (iqr) 19 (17.8-25.8) 20.5 (18-23) 0.62 7 cxr infiltrates, n (%) 4 (50%) 26 (68%) 0.42 15 documented fever, n (%) 8 (80%) 33 (64.7%) 0.47 0 maximum temperature, °c, median (iqr) 38.9 (37.839.4) 38.3 (37.6-39.1) 0.53 1 lowest oxygen saturation, %, median (iqr) 96 (90.3-99) 95 (89-97) 0.37 0 tachypnea, n (%) 10 (100%) 39 (78%) 0.18 1 tachycardia, n (%) 4 (40%) 23 (45.1%) 1.0 0 premature birth, n (%) 2 (40%) 8 (26.7%) 0.61 26 sickle cell, n (%) 0 (0%) 1 (2%) 1.0 0 preceding duration of symptoms, median (iqr) 3.5 (2.3-4.8) 3 (1-4) 0.38 7 nasal congestion, n (%) 7 (70%) 36 (70.6%) 1 0 cough, n (%) 6 (60%) 41 (80.4%) 0.22 0 wheezing, n (%) 3 (30%) 33 (64.7%) 0.075 0 retractions, n (%) 4 (40%) 26 (51.0%) 0.731 0 crackles/crepitations, n (%) 4 (40%) 27 (52.9%) 0.51 0 apnea, n (%) 1 (10%) 3 (5.9%) 0.52 0 cyanosis, n (%) 3 (30%) 4 (7.8%) 0.08 0 stridor, n (%) 1 (10%) 5 (9.8%) 1 0 diarrhea, n (%) 1 (10%) 7 (13.7%) 1 0 rash, n (%) 2 (20%) 5 (10%) 0.32 0 lrti, n (%) 5 (50%) 36 (70.6%) 0.27 0 secondary pneumonia, n (%) 4 (40%) 20 (39.2%) 1 0 highest level of care needed admitted, n (%) 9 (90%) 39 (76.5%) 0.67 0 picu, n (%) 1 (10%) 6 (11.8%) 1 0 highest level of respiratory support needed oxygen, n (%) 6 (60%) 21 (41.2%) 0.32 0 hfnc, n (%) 0 (0%) 4 (7.8%) 1 0 niv, n (%) 1 (10%) 11 (22%) 0.32 0 invasive ventilation, n (%) 0 (0%) 3 (5.9%) 1 0 antibiotics, n (%) 9 (90%) 33 (64.7%) 0.15 0 antiviral, n (%) 3 (30%) 21 (41.2%) 0.73 seizure, n (%) 0 (0%) 2 (3.9%) 1 0 encephalopathy, n (%) 0 (0%) 0 (0%) 0 hypotension/shock, n (%) 0 (0%) 0 (0%) 0 acute kidney injury, n (%) 0 (0%) 0 (0%) 0 acute liver failure, n (%) 0 (0%) 0 (0%) 0 readmission within 28 days, n (%) 1 (10%) 3 (5.9%) 0.52 0 chronic morbidity, n (%) 0 (0%) 0 (0%) 0 death, n (%) 0 (0%) 0 (0%) 0 abbreviations: wbc: white blood cells; iqr: interquartile range; anc: absolute neutrophil count; alc: 345 absolute lymphocyte count; crp:c-reactive protein; alt: alanine transaminase; cxr: chest x-ray; lrti: 346 lower respiratory tract infection. 347 348 349 350 faculty of management and medical information, kerman university of medical sciences, kerman, iran *corresponding author’s e-mail: emohsenbeigi@gmail.com التحدايت والنتائج السلبية لتنفيذ آليات للتعويض بناًء على نظام تصنيف اجملموعة املرتبط ابلتشخيص مراجعة منهجية حم�سن باروين، ليلى �أحمديان، ح�سني �سابري �أناري، �إلهام حم�سن بيكي abstract: in health insurance, a reimbursement mechanism refers to a method of third-party repayment to offset the use of medical services and equipment. this systematic review aimed to identify challenges and adverse outcomes generated by the implementation of reimbursement mechanisms based on the diagnosis-related group (drg) classification system. all articles published between 1983 and 2017 and indexed in various databases were reviewed. of the 1,475 articles identified, 36 were relevant and were included in the analysis. overall, the most frequent challenges were increased costs (especially for severe diseases and specialised services), a lack of adequate supervision and technical infrastructure and the complexity of the method. adverse outcomes included reduced length of patient stay, early patient discharge, decreased admissions, increased re-admissions and reduced services. moreover, drg-based reimbursement mechanisms often resulted in the referral of patients to other institutions, thus transferring costs to other sectors. keywords: health insurance; third-party payments; reimbursement mechanisms; diagnosis-related groups; quality of health care; patient outcome assessment; systematic review. امللخ�ص: يف نظام �لتاأمني �ل�سحي، ت�سري �آلية �ل�سد�د �إىل طريقة �ل�سد�د لطرف ثالث لتعوي�ض ��ستخد�م �خلدمات و�ملعد�ت �لطبية. تهدف هذه �ملر�جعة �ملنهجية �إىل حتديد �لتحديات و�لنتائج �ل�سلبية �لناجتة عن تنفيذ �آليات �ل�سد�د على �أ�سا�ض نظام ت�سنيف �ملجموعة �ملرتبطة بالت�سخي�ض. متت مر�جعة جميع �ملقاالت �ملن�سورة بني عامي 1983 و 2017 و�ملفهر�سة يف قو�عد �لبيانات �ملختلفة. من بني 1,475 مقالة مت حتديدها، كانت 36 مقالة ذ�ت �سلة ومت ت�سمينها يف �لتحليل. ب�سكل عام، كانت �لتحديات �الأكرث �سيوًعا هي �لتكاليف �ملتز�يدة )خا�سة �لنتائج �سملت �لطريقة. وتعقيد �لتقنية �لتحتية و�لبنية �ملنا�سب �الإ�رش�ف ونق�ض �ملتخ�س�سة(، و�خلدمات �ل�سديدة للأمر��ض بالن�سبة �ل�سلبية تقليل مدة �إقامة �ملري�ض، و�خلروج �ملبكر للمري�ض، و�نخفا�ض معدل �الإدخال، وزيادة حاالت �إعادة �الإدخال وتقليل �خلدمات. علوة على ذلك، غالًبا ما �أدت �آليات �ل�سد�د �مل�ستندة �إىل �ملجموعة �ملرتبطة بالت�سخي�ض �إىل �إحالة �ملر�سى �إىل موؤ�س�سات �أخرى، وبالتايل حتويل �لتكاليف �إىل قطاعات �أخرى. الكلمات املفتاحية: �لتاأمني �ل�سحي؛ مدفوعات �لطرف �لثالث؛ �آليات �ل�سد�د؛ �ملجموعات ذ�ت �ل�سلة بالت�سخي�ض؛ جودة �لرعاية �ل�سحية؛ تقييم نتائج �ملري�ض؛ مر�جعة منهجية. challenges and adverse outcomes of implementing reimbursement mechanisms based on the diagnosis-related group classification system a systematic review mohsen barouni, leila ahmadian, hossein saberi anari, *elham mohsenbeigi sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e260–270, epub. 5 oct 20 submitted 21 nov 19 revision req. 20 jan 20; revisions recd. 25 feb 20 accepted 16 apr 20 https://doi.org/10.18295/squmj.2020.20.03.004 review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. the diagnosis-related group (drg) classification system is a method of categorising patients for health insurance purposes in order to control costs and facilitate repayment by third party providers for the use of medical services and equipment.1 using this system, patients are classified according to a range of variables, including primary and secondary diagnoses, age, gender, the presence of comorbidities/complications and treatment(s) prov ided. the intention behind this type of system is to classify patients into a limited number of groups in order to form clinically meaningful yet relatively homogeneous resource consumption patterns.2 a drg-based reimbursement mechanism was first introduced in the usa in 1983 as a component of the medicare programme, before being adopted by other countries around the world soon thereafter.3 although the primary goals of drg-based reim bursement mechanisms vary worldwide, most aim to increase transparency and efficiency, especially in https://creativecommons.org/licenses/by-nd/4.0/ mohsen barouni, leila ahmadian, hossein saberi anari and elham mohsenbeigi review | 261 european countries.4–6 indeed, increasing transparency, providing effective care, controlling costs and impr oving the quality of care are some of the advantages reported for this method of reimbursement in hospital settings.7 however, this type of system is also subject to various challenges and adverse outcomes, for instance by unintentionally encouraging hospitals to preferentially admit more cost-effective patients.8 it has also been claimed that this type of payment system inspires a shift from traditional inpatient to outpatient care as a cost-saving measure.9 researchers have previously evaluated the effects of implementing drg-based repayment systems.10 however, to the best of the authors’ knowledge, none have yet sought to systematically evaluate the challenges and potential negative effects of this type of system. therefore, the objective of this article was to systematically review the challenges and adverse outcomes generated by the implementation of drgbased reimbursement mechanisms. methods this systematic review was conducted in line with the preferred reporting items for systematic reviews and meta-analysis guidelines.11 a literature search was conducted to identify all english-language articles assessing the challenges and adverse outcomes of drg based reimbursement mechanisms published between january 1983 and february 2017 and indexed in the scopus® (elsevier, amsterdam, the netherlands), medline® (national library of medicine, bethesda, maryland, usa) or embase® (elsevier) databases. search terms related to challenges and drgbased reimbursement mechanisms were combined using boolean operators (i.e. “challenge”, “barrier”, “problem”, “difficulty”, “disadvantage” or “weakness” and “drg”, “diagnosis-related groups”, “case-mix” or “case mix”) in order to identify relevant articles in which these terms appeared in the publication title, keywords and/or abstract. following the literature search, identified articles were reviewed and the abstracts assessed by two evaluators to determine if they were fit for inclusion in the analysis. in cases of inter-evaluator disagreement, the full text of the articles was assessed in order to come to a consensus. articles were selected for further full-text review if they explored the challenges and adverse outcomes generated by the implementation of a drg-based reimbursement mechanism. all types of articles except reviews and letter to editors were included in the analysis. articles focusing on other mechanisms of reimbursement, such as fee-for-service or global budget systems, were excluded. in addition, articles focusing on the measurement, calculation, development and structure of the mechanism and those solely examining positive or beneficial outcomes were also excluded. subsequently, the studies were assessed to determine their quality based on criteria proposed by kmet et al.12 depending on the design of the study, two evaluators independently ranked the studies using different sets of criteria for qualitative and quantitative studies. any disagreements were discussed until a consensus was reached. implementation challenges were categorised as either leadership-related, managerial, organisational, technical or personnelrelated according to a previously described template.13 adverse outcomes were classified as per the model developed by fourie et al.9 overall, a total of 1,475 articles were identified during the literature search, of which 343 were duplicates. after reviewing the titles and abstracts, 892 non-relevant articles were also excluded. subsequently, 240 articles underwent further full-text review; of these, 55 articles were excluded due to lack of access to the full text, 75 articles were review articles or letters to the editor and 44 were written in languages other than english. furthermore, 29 articles were removed due to their lack of relevance and one qualitative article was excluded due to its low quality (i.e. a quality score of <50%). the final analysis therefore included 36 articles [figure 1]. a standardised data collection form was developed and completed by two researchers. the data collected included bibliographic information, the study setting, the country in which the study was performed and any challenges and adverse figure 1: flowchart showing the search strategy used to identify articles for inclusion in the systematic review. challenges and adverse outcomes of implementing reimbursement mechanisms based on the diagnosis-related group classification system a systematic review 262 | squ medical journal, august 2020, volume 20, issue 3 table 1: quality analysis* of studies assessing the implementation of reimbursement mechanisms based on the diagnosis-related group classification system14–49 criteria score quantitative studies qualitative studies mixed-method studies† question/objective sufficiently described? 2 2 2 2 2 2 2 2 1 2 2 2 2 2 2 2 2 2 + 2 1 + 2 1 + 2 2 + 2 study design evident and appropriate? 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 + 2 2 + 2 2 + 2 2 + 2 context for the study clear? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 2 1 2 2 2 2 connection to a theoretical framework/wider body of knowledge? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 2 1 2 2 2 2 sampling strategy described, relevant and justified? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a 2 2 2 2 2 data collection methods clearly described and systematic? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 2 1 2 2 2 2 data analysis clearly described and systematic? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 2 2 2 2 2 2 use of verification procedure(s) to establish credibility? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 0 0 1 2 0 2 2 reflexivity accounted for? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 0 0 0 0 0 0 0 method of subject/comparison group selection or source of information/ input variables described and appropriate? 2 2 2 2 2 2 2 2 2 2 2 2 2 2 n/a n/a n/a 2 2 2 2 subject (and comparison group, if applicable) characteristics sufficiently described? 2 2 2 2 2 2 2 2 2 2 2 2 2 2 n/a n/a n/a 2 2 2 2 if interventional and random allocation was possible, was it described? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a if interventional and blinding of investigators was possible, was it reported? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a if interventional and blinding of subjects was possible, was it reported? n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a outcome and (if applicable) exposure measure(s) well-defined and robust for measurement/misclassification bias? means of assessment reported? 2 2 2 2 2 2 2 2 2 2 2 2 2 2 n/a n/a n/a 2 2 2 2 sample size appropriate? n/a n/a 2 1 2 n/a 2 1 n/a n/a n/a 2 2 1 n/a n/a n/a 2 2 n/a n/a analytic methods described/justified and appropriate? 2 1 2 1 2 2 2 2 2 2 2 2 2 2 n/a n/a n/a 2 2 2 2 some estimate of variance is reported for the main results? 2 1 0 0 2 0 0 2 0 2 2 1 2 1 n/a n/a n/a 2 0 2 0 controlled for confounding? n/a n/a n/a n/a 0 n/a n/a n/a n/a 1 0 1 1 1 n/a n/a n/a n/a 0 0 n/a results reported in sufficient detail? 2 2 2 2 2 2 2 2 2 2 2 2 2 2 n/a n/a n/a 2 2 2 2 conclusions supported by the results? 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 + 2 2 + 2 1 + 2 1 + 2 total score out of maximum 18/ 18 16/ 18 18/ 20 16/ 20 20/ 22 16/ 18 18/ 20 19/ 20 15/ 18 19/ 20 18/ 20 20/ 22 21/ 22 19/ 22 16/ 20 14/ 18 14/ 20 37/ 40 33/ 42 34/ 40 33/ 38 n/a = not applicable. *as per criteria adapted from kmet et al.12 each criterion was assessed based on compliance, with scores of zero indicating no, 1 indicating partial compliance and 2 indicating full compliance. †for mixed-method studies, the qualitative and quantitative components were assessed separately, as indicated by plus signs (+) for criteria spanning both categories. m ul ti pl e s tu di es 14 ,1 7, 34 –3 7, 40 ,4 2– 46 h en se n et a l.4 7 ( 20 05 ) z ha n et a l.3 2 ( 20 07 ) r oe de r e t a l.2 6 ( 20 01 ) r og er s e t a l.1 5 ( 19 90 ) m ul ti pl e st ud ie s1 6, 31 pa te l48 (1 98 8) h or n et a l.3 8 ( 19 86 ) sa nd er so n et a l.2 7 ( 19 89 ) m ul ti pl e st ud ie s2 4, 28 ,3 9 m ul ti pl e st ud ie s1 9, 23 h ur le y et a l.2 1 ( 19 90 ) w ol fe a nd d et m er 49 (1 98 8) m en ke e t a l.2 2 ( 19 98 ) b ul l41 (1 98 8) n ot m an e t a l.2 9 ( 19 87 ) w is en sa le a nd w al dr on 33 (1 99 1) so dz i-t et te y et a l.2 5 ( 20 12 ) g ol db er g an d es te s1 8 ( 19 90 ) ly le s2 0 (1 98 6) b ra y et a l.3 0 ( 19 94 ) mohsen barouni, leila ahmadian, hossein saberi anari and elham mohsenbeigi review | 263 outcomes identified regarding the implementation of drg-based reimbursement mechanisms. in cases of disagreement, a third researcher was contacted to provide the deciding vote. data analysis was performed using an excel spreadsheet, version 2013 (microsoft corp., redmond, washington, usa). the results were presented using descriptive statistics. results a total of 36 articles assessing the challenges and adverse outcomes of drg-based reimbursement mechanisms were included in the final analysis.14–49 of these, the majority (n = 28; 77.8%) were published in 1990 or before.15–21,23,24,27–29,31,34,35,37–46,48,49 most studies (n = 31; 86.1%) were set in the usa.15–24,28–46,48,49 data collection strategies included observation (n = 2; 5.6%), in-person (n = 4; 11.1%) or telephone (n = 2; 5.6%) interviews, paper-based (n = 2; 5.6%) or electronic (n = 1; 2.8%) questionnaires, checklists (n = 1; 2.8%) and reviews of patient/hospital records (n = 26; 72.2%), annual reports (n = 8; 22.2%) and transcripts (n = 1; 2.8%).14–49 almost two-thirds (n = 23; 63.9%) of the studies were set in hospitals, with the rest set in medical centres (n = 6; 16.7%), nursing homes (n = 2; 5.6%), trauma centres (n = 2; 5.6%), home health agencies (n = 2; 5.6%) or rehabilitation centres (n = 1; 2.8%).14–49 a total of 29 studies (80.6%) were quantitative in nature.14–17,19,21–24,26–28,31,32,34–40,42–49 in addition, there were three qualitative (8.3%) and four mixed-method (11.1%) studies.18,20,25,29,30,33,41 in terms of quality assessment, qualitative, quantitative and mixedmethod studies received scores of >70%, >80% and >85%, respectively; however, quantitative studies were generally higher in quality compared to qualitative and mixed-method studies [table 1].14–49 table 2 summarises the studies which ident ified challenges in the implementation of drg-based reimbursement mechanisms.25–49 overall, 15 studies (41.7%) reported managerial challenges.25,30,32,34–36,38–40, 42–47 of these, 12 (80%) indicated that drg-based reimbursement mechanisms were not suitable for certain services due to the high cost involved and the likelihood of financial loss, including skin care, trauma, fibrocystic disease, heart surgery, rare diseases, urology disorders, mental disorders, intensive care and the care of elderly and paediatric patients.34–36,38–40,42–47 the remaining three studies (20%) reported delayed reimbursement of hospital fees, increased expenses in educational hospitals (especially at baseline and in rural areas), poor medical recordkeeping and a lack of coding rules and standards.25,30,32 two studies (5.6%) examined organisation environment challenges, including poor compliance with guidelines, the misfiling and potential loss of patients records and physicians being pressured to discharge patients prematurely.25,33 technical challenges were reported by nine studies (25%), particularly data coding and misclassification issues and drg creeping (i.e. upgrading or upcoding patients).25–28,31,32,37,42,47 personnel-related challenges were also reported by eight studies (22%); of these, one of the most important was a lack of familiarity among physicians with the drg classification system and misconceptions regarding the objectives of the mechanism.25,29,30,33,34,41,42,48,49 no leadership challenges were reported by any of the studies. studies assessing adverse outcomes resulting from the implementation of drg-based reimbursement mechanisms are described in table 3.14–24,32–49 overall, 11 studies (30.6%) examined the rate of early discharge, all of which noted an increase following implementation of the mechanism.15,17–20,22,23,33,41,47,48 the motivation for this was due to awareness on the part of both physicians and hospital administrators of patients’ costs and the desire to reduce the length of hospital stay and increase efficiency. five studies (13.9%) evaluated readmission rates; of these, four (80%) observed that the implementation of drg-based reimbursement mechanisms resulted in increased readmission due to the low quality of services provided initially and premature discharge.14,19,22,23 in contrast, the remaining study revealed no change in the rate of re-admission.17 nine studies (25%) measured length of patient stay.14,16,17,19,22–24,37,38 the majority (n = 8; 88.9%) found that the duration of hospital stay was reduced following the implementation of drg-based reim bursement mechanisms; reasons for this included preserving resources, reducing costs and improving efficiency.14,17,19,22–24,37,38 only one indicated that the average length of stay increased.16 two studies (5.6%) examined the number of services provided to patients; in the first, there was no change in the number of services provided to patients after implementation of the reimbursement mechanism, while the second found that access to certain services or technologies was restricted after implementation of the reimbursement mechanism since the system increased performance monitoring.17,23 mortality rate was assessed as an outcome in four studies (11.1%).14,15,20,23 one study showed that the mortality rate increased following implementation of a drg-based reimbursement mechanism.20 in contrast, two studies showed a reduction in mortality rate.14,23 challenges and adverse outcomes of implementing reimbursement mechanisms based on the diagnosis-related group classification system a systematic review 264 | squ medical journal, august 2020, volume 20, issue 3 table 2: challenges in the implementation of reimbursement mechanisms based on the diagnosis-related group classification system25–49 author and year of study setting type of study type of challenges management process organisation environment technical systems personnel sodzi-tettey et al.25 (2012) ghana mixed-method • delays in reimbursement • poor compliance with guidelines • inadequate filing system • classification problems • severe personnel shortage • lack of familiarity with drg among physicians roeder et al.26 (2001) germany quantitative n/a n/a • drg variants differed in degree and detail • questionable grouping of cases • inaccuracies in diagnostic coding • classification problems n/a sanderson et al.27 (1989) uk quantitative n/a n/a • irregularities in diagnostic and operative coding • inaccuracies in diagnostic coding n/a horn et al.28 (1985) usa quantitative n/a n/a • failure to account for illness severity n/a notman et al.29 (1987) usa qualitative n/a n/a n/a • lack of familiarity with drg among physicians • misconceptions regarding drg among physicians bray et al.30 (1994) usa mixed-method • increased costs per discharge in rural hospitals n/a n/a • less effort made by physicians to improve the hospital’s financial performance bredenberg and lagoe31 (1987) usa quantitative n/a n/a • lack of sensitivity to different types of procedures n/a zhan et al.32 (2007) usa quantitative • low-quality medical recordkeeping • lack of rules and standards for coding n/a • drg creeping n/a wisensale and waldron33 (1991) usa qualitative n/a • pressure on doctors to discharge patients prematurely n/a • reduction of nurses and other support staff muñoz et al.34 (1989) usa quantitative • financial loss n/a n/a • refusal to admit patients muñoz et al.35 (1988) usa quantitative • financial loss n/a n/a n/a zwanziger et al.36 (1991) usa quantitative • financial loss n/a n/a n/a vollertsen et al.37 (1988) usa quantitative n/a n/a • classification problems • drg creeping n/a horn et al.38 (1986) usa quantitative • financial loss n/a n/a n/a thomas et al.39 (1988) usa quantitative • financial loss n/a n/a n/a pasternak et al.40 (1986) usa quantitative • financial loss n/a n/a n/a bull41 (1988) usa qualitative n/a n/a n/a • guiding patients to outpatient departments joy and yurt42 (1990) usa quantitative • financial loss n/a • failure to account for illness severity n/a muñoz et al.43 (1988) usa quantitative • financial loss n/a n/a n/a munoz et al.44 (1989) usa quantitative • financial loss n/a n/a n/a munoz et al.45 (1989) usa quantitative • financial loss n/a n/a n/a muñoz et al.46 (1989) usa quantitative • financial loss n/a n/a n/a n/a = not available; drg = diagnosis-related group. mohsen barouni, leila ahmadian, hossein saberi anari and elham mohsenbeigi review | 265 however, none of these studies reported a significant link between this outcome and the reimbursement mechanism. no change in mortality rate was observed in the final study.15 nine studies (25%) evaluated the number of admissions.14,15,18,23,33,34,38,42,49 of these, all but one (n = 8; 88.9%) indicated that the admission rate was reduced following implementation of the drg-based reimbursement mechanisms in order to preserve resources.14,15,23,33,34,38,42,49 hospital efficiency was assessed as an outcome in 14 studies (38.9%), all of which observed an increase in inefficiency.16,32,34–36,38–40,42–49 a total of 13 studies (36%) examined the impact of the reimbursement methods on transferring costs by directing patients to other healthcare institutions or centres.14,15,17–24,35,37,41 only one of these indicated that implementation of the reimbursement mechanism did not lead to the transfer of costs to other institutions.14 the other studies found that patient costs were often transferred to other institutions in order to help reduce costs, especially for patients requiring rehabilitation services and those ≥65 years old. in particular, patients were often transferred to nursing homes or nursing care centres (n = 6; 46.2%), outpatient departments (n = 3; 23.1%), non-therapeutic sections (n = 1; 7.7%) and home-based services (n = 1; 7.7%).15,17–24,35,37,41 discussion prospective reimbursement mechanisms, particularly those based on the drg classification system, are usually implemented by healthcare policymakers in order to improve efficiency, ensure the optimal allocation of resources and control costs.50,51 such mechanisms are also viewed favourably by insurance agencies as they allow for the distribution of financial risk between customers and service providers.52 however, the current review indicated that the implementation of these systems can be subject to various challenges, the most important of which was increased costs, especially for patients with severe diseases and those requiring specialised services.34–36,38–40,42–47 other challenges included the failure to follow necessary guidelines, inadequate supervision, poor knowledge of the system among healthcare personnel (especially physicians and nurses), lack of technical infrastructure and the complexity of the method in question.25–27,29,32 several studies noted that drg-based reimbursement mechanisms failed to appropriately calculate disease severity and the cost of certain services.28,42,47 according to leister and stausberg, neglecting to consider disease risk and appropriate diagnostic classifications based on disease severity can cause hospitals to lose valuable resources when delivering care to high-risk patients and those with severe illnesses.53 in such cases, hospitals utilising these systems may choose not to admit such patients or to discharge them earlier in order to increase efficiency and cut costs. as such, drg classification systems should be set up based on the number, type and severity of disease in each case and allow users to modify the assigned group based on these factors; this would ensure the more equitable calculation of fees and improve accessibility to healthcare and the quality of services rendered.28,34,35 roeder et al. deemed the establishment of standard drg units and different types of drgs to be especially challenging.26 another systematic review similarly highlighted this to be a major hindrance to the implementation of drg-based reimbursement mechanisms in mainland china.54 variations in the lifestyles and types of patients attending hospitals in different geographical regions can often result in differences in treatment patterns, medical costs, demand for services and the overall burden of disease. these represent major barriers to the data collection necessary to establish appropriate classification groups that reflect the actual economic and clinical situation.54 however, only one of the studies included in the current review referred to this problem.36 other studies highlighted various organisational and technical challenges related to drg-based table 2 (cont’d): challenges in the implementation of reimbursement mechanisms based on the diagnosis-related group classification system25–49 author and year of study setting type of study type of challenges management process organisation environment technical systems personnel patel48 (1988) usa quantitative n/a n/a n/a • early discharge of patients • restricted access to certain products, technologies and services • conflict between physicians wolfe and detmer49 (1988) usa quantitative n/a n/a n/a • motivation among surgeons for patient selection n/a = not available; drg = diagnosis-related group. challenges and adverse outcomes of implementing reimbursement mechanisms based on the diagnosis-related group classification system a systematic review 266 | squ medical journal, august 2020, volume 20, issue 3 table 3: adverse outcomes resulting from the implementation of reimbursement mechanisms based on the diagnosis-related group classification system14–24,32–49 author and year of study setting type of study outcome quality of care access to care efficiency of care early discharge readmission rate length of stay service provision mortality rate admission rate efficiency transfer of costs busato and von below14 (2010) switzerland quantitative n/a increased decreased n/a decreased decreased n/a no effect rogers et al.15 (1990) usa quantitative increased n/a n/a n/a no effect no effect n/a increased vulgaropulos et al.16 (1990) usa quantitative n/a n/a increased n/a n/a n/a inefficient n/a evans et al.17 (1990) usa quantitative increased no effect decreased no effect n/a n/a n/a increased goldberg and estes18 (1990) usa mixedmethod increased n/a n/a n/a n/a decreased n/a increased tresch et al.19 (1988) usa quantitative increased increased decreased n/a n/a n/a n/a increased lyles20 (1986) usa mixed-method increased n/a n/a n/a increased n/a n/a increased hurley et al.21 (1990) usa quantitative n/a n/a n/a n/a n/a n/a n/a increased menke et al.22 (1998) usa quantitative increased increased decreased n/a n/a n/a n/a increased gay and kronenfeld23 (1990) usa quantitative increased increased decreased n/a decreased decreased n/a increased morrisey et al.24 (1988) usa quantitative n/a n/a decreased n/a n/a n/a n/a increased zhan et al.32 (2007) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a wisensale and waldron33 (1991) usa qualitative increased n/a n/a n/a n/a decreased n/a n/a muñoz et al.34 (1989) usa quantitative n/a n/a n/a n/a n/a decreased inefficient n/a muñoz et al.35 (1988) usa quantitative n/a n/a n/a n/a n/a decreased inefficient increased zwanziger et al.36 (1991) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a vollertsen et al.37 (1988) usa quantitative n/a n/a decreased n/a n/a n/a n/a increased horn et al.38 (1986) usa quantitative n/a n/a decreased n/a n/a decreased inefficient n/a thomas et al.39 (1988) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a pasternak et al.40 (1986) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a bull41 (1988) usa qualitative increased n/a n/a n/a n/a n/a n/a increased joy and yurt42 (1990) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a muñoz et al.43 (1988) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a munoz et al.44 (1989)usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a munoz et al.45 (1989) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a muñoz et al.46 (1989) usa quantitative n/a n/a n/a n/a n/a n/a inefficient n/a hensen et al.47 (2005) germany quantitative increased n/a n/a n/a n/a n/a inefficient n/a patel48 (1988) usa quantitative increased n/a n/a decreased n/a n/a n/a n/a wolfe and detmer49 (1988) usa quantitative n/a n/a n/a n/a n/a decreased n/a n/a n/a = not available. mohsen barouni, leila ahmadian, hossein saberi anari and elham mohsenbeigi review | 267 reimbursement mechanisms, including inadequate filing systems, poor recordkeeping, the misclassification of diseases, irregularities in the coding of procedures and diagnoses and an overall lack of coding rules and standards.25–27,32 indeed, some studies showed that classification problems led to the possibility of drg creeping, which refers to a tendency to upgrade or upcode patients to allow for the hospital to receive higher reimbursements.32,37 in a study of 239 hospitals under the medicare programme, hsia et al. identified the rate of drg coding errors to be 20.8%, of which 61.7% significantly favoured the hospital.55 in order to avoid this problem, coding standards and rules should be established and enforced in every hospital to ensure the correct codes are utilised. several studies in the current systematic review identified misconceptions among physicians and nurses regarding the drg-based system, compounded by a lack of familiarity with the system.25,29 in some cases, healthcare personnel were uninterested in controlling costs.30 however, wild et al. noted that sharing profits with physicians and encouraging them to help balance the budget would intensify conflict between physicians; moreover, they might feel torn between their commitments to providing the best care to the patient and controlling costs.7 one of the studies included in the current review noted that the drg-based reimbursement mechanism increased costs, particularly in the year of implementation and in rural healthcare settings and educational hospitals.30 this finding may be due to several reasons, including a larger number of patients with severe illness presenting to educational hospitals, the lack of involvement of the physicians in improving the hospital’s financial performance, poor financial management and primary productivity control processes.30 on the other hand, drg-based reimbursement mechanisms were deemed unsuitable in certain circumstances by other studies due to the lack of appropriate moderators, resulting in financial loss for the institution.38–40 although most drg-based reimbursement systems are introduced as cost-controlling measures, this can lead to undesirable outcomes that can affect the quality of the health services provided.4,56,57 this type of system results in a clear incentive for healthcare providers to preferentially admit patients with lower costs or restrict the provision of expensive services, leading to an unfair access to healthcare.58 in particular, vulnerable patient groups such as the elderly, children, immigrants and those suffering from chronic illness, heart failure or multiple illnesses may be disproportionately affected.34,48,49 hospitals should therefore commit to providing an equal level of care to all patients by monitoring the performance of physicians. additionally, providing standard protocols and guidelines for clinical decision-making may also be helpful to ensure a set level of quality of care while still controlling costs. in the current review, drg-based reimbursement systems also led to other alarming outcomes, such as reducing essential services and admissions, encouraging early discharge, reducing length of stay, increasing re-admission and transferring costs to other sectors by directing patients to other healthcare institutions.14–24,32–49 other researchers have similarly shown that the implementation of this type of system often results in a reduction in length of stay in order to cut costs and improve hospital efficiency.54,59–61 in a two-year study conducted in the uk, farrar et al. found that the length of stay among patients with pelvic fractures increased following implementation of a drg-based reimbursement mechanism.62 likewise, the implementation of such mechanisms have resulted in increased rates of early discharge and subsequent emergency visits.54,63–65 however, others noted no significant differences in readmission, mortality and admission rates following implementation of the system.60,66,67 it is as yet unfeasible to conclude that drgbased reimbursement mechanisms are directly linked to substantial changes in quality of care for various reasons. first, none of the studies included in the present review could unequivocally attribute care outcomes to the implementation of the system, particularly since long-term effects can only be determined over years or even decades. therefore, continuous quality monitoring is crucial at all hospitals. second, while certain measurable clinical indicators like mortality and infection rates are important indicators of quality of care, other indirect factors also play a large role, including determinants of nursing care, interaction time between patients and physicians and the level of training received by healthcare professionals. third, observed changes in the quality of care may not be explicitly related to the reimbursement mechanism in question, but to other factors, such as competition between hospitals or increased transparency. this research was subject to several limitations. first, the full text of some articles was not available due to the date of publication; furthermore, several more recent articles available on this topic were published in languages other than english. second, the majority of the included studies were from high-income countries; therefore, developing countries were not adequately represented, a fact which may limit the generalisability of the results. third, the number of search terms and databases may not have been sufficiently challenges and adverse outcomes of implementing reimbursement mechanisms based on the diagnosis-related group classification system a systematic review 268 | squ medical journal, august 2020, volume 20, issue 3 comprehensive to retrieve all relevant articles on this topic. finally, most studies retrieved during the literature search reported both positive and adverse outcomes of drg-based reimbursement mechanisms, with few focusing on administrative challenges. future research is recommended to evaluate administrative challenges generated by the implementation of drgbased reimbursement mechanisms, especially with regards to leadership. conclusion reimbursement mechanisms based on the drg classification system are gradually replacing fee-forservice systems in many countries. however, the implementation of such mechanisms can face certain challenges, such as a lack of familiarity with the system among physicians, poor medical recordkeeping and issues with data coding. recommended solutions include revising drg classifications based on disease complexity, severity and complications and the number and type of illnesses, establishing new drgs for patients with severe diseases, establishing moderators for vulnerable patient groups and incorporating an increased budget for particularly unusual or complex cases. moreover, hospitals should implement extensive training at different levels, ensure effective communication with physicians and develop standard protocols for clinical decision-making. a c k n o w l e d g e m e n t s the preliminary version of this research was submitted as part of a phd thesis in the field of healthcare management at the kerman university of medical sciences, kerman, iran, in 2017. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this research was funded with the aid of a grant from the kerman university of medical sciences (grant #96000524). references 1. witter s, ensor t, jowett m, thompson r. health economics for developing countries: a practical guide. london, uk: macmillan education, 2000. 2. fetter rb. diagnosis related groups: understanding hospital performance. interfaces (providence) 1991; 21:6–26. https:// doi.org/10.1287/inte.21.1.6. 3. wiley m. from the origins of drgs to their implementation in europe. in: busse r, geissler a, quentin w, wiley m, eds. diagnosis-related groups in europe: moving towards transparency, efficiency and quality in hospitals. berkshire, uk: open university press, 2011. pp. 3–7. 4. or z, häkkinen u. drgs and quality: for better or worse? in: busse r, geissler a, quentin w, wiley m, eds. diagnosisrelated groups in europe: moving towards transparency, efficiency and quality in hospitals. berkshire, uk: open university press, 2011. pp. 141–55. 5. quentin w, scheller-kreinsen d, blümel m, geissler a, busse r. hospital payment based on diagnosis-related groups differs in europe and holds lessons for the united states. health aff (millwood) 2013; 32:713–23. https://doi.org/10.1377/hlthaff.20 12.0876. 6. tan ss, serdén l, geissler a, van ineveld m, redekop k, heurgren m, et al. drgs and cost accounting: which is driving which? in: busse r, geissler a, quentin w, wiley m, eds. diagnosis-related groups in europe: moving towards transparency, efficiency and quality in hospitals. berkshire, uk: open university press, 2011. pp. 85–100. 7. wild v, carina f, frouzakis r, clarinval c, fässler m, elger b, et al. assessing the impact of drgs on patient care and prof essional practice in switzerland (idoc): a potential model for monitoring and evaluating healthcare reform. swiss med wkly 2015; 145:w14034. https://doi.org/10.4414/smw.2015.14034. 8. langenbrunner jc, cashin cs, o’dougherty s. designing and implementing health care provider payment systems: how-to manuals. washington dc, usa: world bank, 2009. 9. fourie c, biller-andorno n, wild v. systematically evaluating the impact of diagnosis-related groups (drgs) on health care delivery: a matrix of ethical implications. health policy 2014; 115:157–64. https://doi.org/10.1016/j.healthpol.2013.11.014. 10. koné i, maria zimmermann b, nordström k, simone elger b, wangmo t. a scoping review of empirical evidence on the impacts of the drg introduction in germany and switzerland. int j health plann manage 2019; 34:56–70. https://doi.org/10.1002/ hpm.2669. 11. moher d, liberati a, tetzlaff j, altman dg; prisma group. preferred reporting items for systematic reviews and metaanalyses: the prisma statement. bmj 2009; 339:b2535. https://doi.org/10.1136/bmj.b2535. 12. kmet lm, lee rc, cook ls. standard quality assessment criteria for evaluating primary research papers from a variety of fields. edmonton, canada: alberta heritage foundation for medical research, 2004. 13. beaumaster s. information technology implementation issues: an analysis. ph.d. thesis, 1999, virginia polytechnic institute and state university, blacksburg, virginia, usa. 14. busato a, von below g. the implementation of drg-based hospital reimbursement in switzerland: a population-based perspective. health res policy syst 2010; 8:31. https://doi. org/10.1186/1478-4505-8-31. 15. rogers wh, draper d, kahn kl, keeler eb, rubenstein lv, kosecoff j, et al. quality of care before and after implementation of the drg-based prospective payment system: a summary of effects. jama 1990; 264:1989–94. https://doi.org/10.1001/ jama.1990.03450150089037. 16. vulgaropulos sp, lyle cb, sessions jt. potential economic impact of applying drg-based prospective payment categories to inflammatory bowel disease patients. dig dis sci 1990; 35:577–81. https://doi.org/10.1007/bf01540404. 17. evans rl, halar em, hendricks rd, lawrence kv, kirk c, bishop ds. effects of prospective payment financing on rehabilitation outcome. int j rehabil res 1990; 13:27–35. https://doi.org/10.1097/00004356-199003000-00003. https://doi.org/10.1287/inte.21.1.6 https://doi.org/10.1287/inte.21.1.6 https://doi.org/10.1377/hlthaff.2012.0876 https://doi.org/10.1377/hlthaff.2012.0876 https://doi.org/10.4414/smw.2015.14034 https://doi.org/10.1016/j.healthpol.2013.11.014 https://doi.org/10.1002/hpm.2669 https://doi.org/10.1002/hpm.2669 https://doi.org/10.1136/bmj.b2535 https://doi.org/10.1186/1478-4505-8-31 https://doi.org/10.1186/1478-4505-8-31 https://doi.org/10.1001/jama.1990.03450150089037 https://doi.org/10.1001/jama.1990.03450150089037 https://doi.org/10.1007/bf01540404 https://doi.org/10.1097/00004356-199003000-00003 mohsen barouni, leila ahmadian, hossein saberi anari and elham mohsenbeigi review | 269 18. goldberg sc, estes cl. medicare drgs and post-hospital care for the elderly: does out of the hospital mean out of luck? j appl gerontol 1990; 9:20–35. https://doi.org/10.11 77/073346489000900103. 19. tresch dd, duthie eh jr, newton m, bodin b. coping with diagnosis related groups: the changing role of the nursing home. arch intern med 1988; 148:1393–6. https://doi.org/10.1 001/archinte.1988.00380060157028. 20. lyles ym. impact of medicare diagnosis-related groups (drgs) on nursing homes in the portland, oregon metropolitan area. j am geriatr soc 1986; 34:573–8. https://doi.org/10.1111/j.153 2-5415.1986.tb05762.x. 21. hurley j, linz d, swint e. assessing the effects of the medicare prospective payment system on the demand for va inpatient services: an examination of transfers and discharges of problem patients. health serv res 1990; 25:239–55. 22. menke tj, ashton cm, petersen nj, wolinsky fd. impact of an all-inclusive diagnosis-related group payment system on inpatient utilization. med care 1998; 36:1126–37. https://doi. org/10.1097/00005650-199808000-00003. 23. gay eg, kronenfeld jj. regulation, retrenchment--the drg experience: problems from changing reimbursement practice. soc sci med 1990; 31:1103–18. https://doi.org/10.1016/02779536(90)90232-h. 24. morrisey ma, sloan fa, valvona j. medicare prospective pay ment and posthospital transfers to subacute care. med care 1988; 26:685–98. https://doi.org/10.1097/00005650-19880700 0-00004. 25. sodzi-tettey s, aikins m, awoonor-williams jk, agyepong ia. challenges in provider payment under the ghana national health insurance scheme: a case study of claims management in two districts. ghana med j 2012; 46:189–99. 26. roeder n, rochell b, juhra c, mueller m. empirical comparison of drg variants using cardiovascular surgery data: initial results of a project at 18 german hospitals. aust health rev 2001; 24:57–80. https://doi.org/10.1071/ah010057. 27. sanderson hf, storey a, morris d, mcnay ra, robson mp, loeb j. evaluation of diagnosis-related groups in the national health service. community med 1989; 11:269–78. 28. horn sd, bulkley g, sharkey pd, chambers af, horn ra, schramm cj. interhospital differences in severity of illness. problems for prospective payment based on diagnosis-related groups (drgs). n engl j med 1985; 313:20–4. https://doi. org/10.1056/nejm198507043130105. 29. notman m, howe kr, rittenberg w, bridgham r, holmes mm, rovner dr. social policy and professional self-interest: phy sician responses to drgs. soc sci med 1987; 25:1259–67. https://doi.org/10.1016/0277-9536(87)90124-9. 30. bray n, carter c, dobson a, watt jm, shortell s. an examination of winners and losers under medicare’s prospective payment system. health care manage rev 1994; 19:44–55. https://doi. org/10.1097/00004010-199424000-00007. 31. bredenberg pa, lagoe rj. mastectomies for malignancy: a drg-based hospital utilization analysis. j surg oncol 1987; 35:19–23. https://doi.org/10.1002/jso.2930350105. 32. zhan c, elixhauser a, friedman b, houchens r, chiang yp. modifying drg-pps to include only diagnoses present on admi ssion: financial implications and challenges. med care 2007; 45:288–91. https://doi.org/10.1097/01.mlr.0000256969.34461.cf. 33. wisensale sk, waldron rj. applying the family impact statement to drgs: implications for future policymaking. lifestyles 1991; 12:89–102. https://doi.org/10.1007/bf00987299. 34. muñoz e, luber j, birnbaum e, mulloy k, cohen jr, wise l. hospital costs and resource characteristics for cardiothoracic surgical hospital deaths. ann thorac surg 1989; 47:735–40. https://doi.org/10.1016/0003-4975(89)90129-x. 35. muñoz e, angus g, calabro s, mulloy k, wise l. drgs, costs, and outcome for plastic surgical patients. plast reconstr surg 1988; 82:116–24. https://doi.org/10.1097/00006534-198882010-00021. 36. zwanziger j, davis l, bamezai a, hosek sd. using drgs to pay for inpatient substance abuse services: an assessment of the champus reimbursement system. med care 1991; 29:565–77. https://doi.org/10.1097/00005650-199106000-00015. 37. vollertsen rs, nobrega ft, michet cj jr, hanson tj, naessens jm. economic outcome under medicare prospective payment at a tertiary-care institution: the effects of demographic, clinical, and logistic factors on duration of hospital stay and part a charges for medical back problems (drg 243). mayo clin proc 1988; 63:583–91. https://doi.org/10.1016/s0025-6196(12)64888-5. 38. horn sd, horn ra, sharkey pd, beall rj, hoff js, rosenstein bj. misclassification problems in diagnosis-related groups: cystic fibrosis as an example. n engl j med 1986; 314:484–7. https:// doi.org/10.1056/nejm198602203140805. 39. thomas f, clemmer tp, larsen kg, menlove rl, orme jf jr, christison ea. the economic impact of drg payment policies on air-evacuated trauma patients. j trauma 1988; 28:446–52. https://doi.org/10.1097/00005373-198804000-00005. 40. pasternak lr, dean jm, gioia fr, rogers mc. lack of validity of diagnosis-related group payment systems in an intensive care population. j pediatr 1986; 108:784–9. https://doi.org/10.1016/ s0022-3476(86)81069-1. 41. bull mj. influence of diagnosis-related groups on discharge planning, professional practice, and patient care. j prof nurs 1988; 4:415–21. https://doi.org/10.1016/s8755-7223(88)80092-9. 42. joy sa, yurt rw. an all-payor prospective payment system (pps) based on diagnosis-related-groups (drg): financial imp act on reimbursement for trauma care and approaches to mini mizing loss. j trauma 1990; 30:866–73. https://doi.org/10.10 97/00005373-199007000-00017. 43. muñoz e, rosner f, chalfin d, goldstein j, margolis ib, wise l. financial risk and hospital cost for elderly patients: ageand non-age-stratified medical diagnosis related groups. arch intern med 1988; 148:909–12. https://doi.org/10.1001/archi nte.1988.00380040149021. 44. munoz e, barrios e, johnson h, goldstein j, mulloy k, chalfin d, et al. pediatric patients, race, and drg prospective hospital pay ment. am j dis child 1989; 143:612–16. https://doi.org/10.100 1/archpedi.1989.02150170114035. 45. munoz e, lory m, josephson j, goldstein j, brewster j, wise l. pediatric patients, drg hospital payment, and comorbidities. j pediatr 1989; 115:545–8. https://doi.org/10.1016/s0022-3476 (89)80278-1. 46. muñoz e, wilkins s, mallet e, goldstein j, sterman h, wise l. financial risk and hospital cost for elderly patients in non-age stratified urology drgs. urology 1989; 33:445–8. https://doi. org/10.1016/0090-4295(89)90048-4. 47. hensen p, fürstenberg t, luger ta, steinhoff m, roeder n. case mix measures and diagnosis-related groups: opportunities and threats for inpatient dermatology. j eur acad dermatol venereol 2005; 19:582–8. https://doi.org/10.1111/j.1468-3083.2 005.01258.x. 48. patel k. physicians and drgs: hospital management alter natives. eval health prof 1988; 11:487–505. https://doi.org/10.1 177/016327878801100405. 49. wolfe bl, detmer de. diagnosis related groups (drgs): efficiency and/or quality producing? some evidence from surgical patients. health serv manag res 1988; 1:19–28. https://doi.org/10.1177/095148488800100103. 50. turner-stokes l, sutch s, dredge r, eagar k. international casemix and funding models: lessons for rehabilitation. clin rehabil 2012; 26:195–208. https://doi.org/10.1177/0269215511417468. https://doi.org/10.1177/073346489000900103 https://doi.org/10.1177/073346489000900103 https://doi.org/10.1001/archinte.1988.00380060157028 https://doi.org/10.1001/archinte.1988.00380060157028 https://doi.org/10.1111/j.1532-5415.1986.tb05762.x https://doi.org/10.1111/j.1532-5415.1986.tb05762.x https://doi.org/10.1097/00005650-199808000-00003 https://doi.org/10.1097/00005650-199808000-00003 https://doi.org/10.1016/0277-9536%2890%2990232-h https://doi.org/10.1016/0277-9536%2890%2990232-h https://doi.org/10.1097/00005650-198807000-00004 https://doi.org/10.1097/00005650-198807000-00004 https://doi.org/10.1071/ah010057 https://doi.org/10.1056/nejm198507043130105 https://doi.org/10.1056/nejm198507043130105 https://doi.org/10.1016/0277-9536%2887%2990124-9 https://doi.org/10.1097/00004010-199424000-00007 https://doi.org/10.1097/00004010-199424000-00007 https://doi.org/10.1002/jso.2930350105 https://doi.org/10.1097/01.mlr.0000256969.34461.cf https://doi.org/10.1007/bf00987299 https://doi.org/10.1016/0003-4975%2889%2990129-x https://doi.org/10.1097/00006534-198882010-00021 https://doi.org/10.1097/00005650-199106000-00015 https://doi.org/10.1016/s0025-6196%2812%2964888-5 https://doi.org/10.1056/nejm198602203140805 https://doi.org/10.1056/nejm198602203140805 https://doi.org/10.1097/00005373-198804000-00005 https://doi.org/10.1016/s0022-3476%2886%2981069-1 https://doi.org/10.1016/s0022-3476%2886%2981069-1 https://doi.org/10.1016/s8755-7223%2888%2980092-9 https://doi.org/10.1097/00005373-199007000-00017 https://doi.org/10.1097/00005373-199007000-00017 https://doi.org/10.1001/archinte.1988.00380040149021 https://doi.org/10.1001/archinte.1988.00380040149021 https://doi.org/10.1001/archpedi.1989.02150170114035 https://doi.org/10.1001/archpedi.1989.02150170114035 https://doi.org/10.1016/s0022-3476%2889%2980278-1 https://doi.org/10.1016/s0022-3476%2889%2980278-1 https://doi.org/10.1016/0090-4295%2889%2990048-4 https://doi.org/10.1016/0090-4295%2889%2990048-4 https://doi.org/10.1111/j.1468-3083.2005.01258.x https://doi.org/10.1111/j.1468-3083.2005.01258.x https://doi.org/10.1177/016327878801100405 https://doi.org/10.1177/016327878801100405 https://doi.org/10.1177/095148488800100103 https://doi.org/10.1177/0269215511417468 challenges and adverse outcomes of implementing reimbursement mechanisms based on the diagnosis-related group classification system a systematic review 270 | squ medical journal, august 2020, volume 20, issue 3 51. tan ss, chiarello p, quentin w. knee replacement and diag nosis-related groups (drgs): patient classification and hospital reimbursement in 11 european countries. knee surg sports traumatol arthrosc 2013; 21:2548–56. https://doi.org/10.1007/ s00167-013-2374-6. 52. lüthi hj, widmer pk. drg system design: a financial risk perspective. oper res health care 2017; 13–14:23–32. https:// doi.org/10.1016/j.orhc.2017.03.002. 53. leister je, stausberg j. comparison of cost accounting methods from different drg systems and their effect on health care quality. health policy 2005; 74:46–55. https://doi.org/10.1016/j. healthpol.2004.12.001. 54. gao f. systematic review of the impacts of diagnosis related groups and the challenges of the implementation in mainland china. ph.d. thesis, 2013, university of hong kong, pokfulam, hong kong. 55. hsia dc, krushat wm, fagan ab, tebbutt ja, kusserow rp. accuracy of diagnostic coding for medicare patients under the prospective-payment system. n engl j med 1988; 318:352–5. https://doi.org/10.1056/nejm198802113180604. 56. street a, o’reilly j, ward p, mason a. drg-based hospital payment and efficiency: theory, evidence, and challenges. in: busse r, geissler a, quentin w, wiley m, eds. diagnosisrelated groups in europe: moving towards transparency, efficiency and quality in hospitals. berkshire, uk: open university press, 2011. pp. 119–40. 57. cots f, chiarello p, salvador x, castells x, quentin w. drg-based hospital payment: intended and unintended consequences. in: busse r, geissler a, quentin w, wiley m, eds. diagnosis-related groups in europe: moving towards transparency, efficiency and quality in hospitals. berkshire, uk: open university press, 2011. pp. 101–18. 58. mason a, street a, verzulli r. private sector treatment centres are treating less complex patients than the nhs. j r soc med 2010; 103:322–31. https://doi.org/10.1258/jrsm.2010.100044. 59. schwartz mh, tartter pi. decreased length of stay for patients with colorectal cancer: implications of drg use. j healthc qual 1998; 20:22–5. https://doi.org/10.1111/j.1945-1474.1998. tb00268.x. 60. cheng sh, chen cc, tsai sl. the impacts of drg-based payments on health care provider behaviors under a universal coverage system: a population-based study. health policy 2012; 107:202–8. https://doi.org/10.1016/j.healthpol.2012.03.021. 61. louis dz, yuen ej, braga m, cicchetti a, rabinowitz c, laine c, et al. impact of a drg-based hospital financing system on quality and outcomes of care in italy. health serv res 1999; 34:405–15. 62. farrar s, yi d, sutton m, chalkley m, sussex j, scott a. has payment by results affected the way that english hospitals provide care? difference-in-differences analysis. bmj 2009; 339:b3047. https://doi.org/10.1136/bmj.b3047. 63. castro j, hector e. diagnostic related groups (drgs): resourceful tools for financial crisis times? rev cienc salud 2011; 9:73–82. 64. mccall n, korb j, petersons a, moore s. reforming medicare payment: early effects of the 1997 balanced budget act on postacute care. milbank q 2003; 81:277–303. https://doi. org/10.1111/1468-0009.t01-1-00054. 65. gillen r, tennen h, mckee t. the impact of the inpatient rehabilitation facility prospective payment system on stroke program outcomes. am j phys med rehabil 2007; 86:356–63. https://doi.org/10.1097/phm.0b013e31804a7e2f. 66. kahn kl, keeler eb, sherwood mj, rogers wh, draper d, bentow ss, et al. comparing outcomes of care before and after implementation of the drg-based prospective payment system. jama 1990; 264:1984–8. https://doi.org/10.1001/ jama.1990.03450150084036. 67. lave jr, frank rg, taube c, goldman h, rupp a. the early effects of medicare’s prospective payment system on psychiatry. inquiry 1988; 25:354–63. https://doi.org/10.1007/s00167-013-2374-6 https://doi.org/10.1007/s00167-013-2374-6 https://doi.org/10.1016/j.orhc.2017.03.002 https://doi.org/10.1016/j.orhc.2017.03.002 https://doi.org/10.1016/j.healthpol.2004.12.001 https://doi.org/10.1016/j.healthpol.2004.12.001 https://doi.org/10.1056/nejm198802113180604 https://doi.org/10.1258/jrsm.2010.100044 https://doi.org/10.1111/j.1945-1474.1998.tb00268.x https://doi.org/10.1111/j.1945-1474.1998.tb00268.x https://doi.org/10.1016/j.healthpol.2012.03.021 https://doi.org/10.1136/bmj.b3047 https://doi.org/10.1111/1468-0009.t01-1-00054 https://doi.org/10.1111/1468-0009.t01-1-00054 https://doi.org/10.1097/phm.0b013e31804a7e2f https://doi.org/10.1001/jama.1990.03450150084036 https://doi.org/10.1001/jama.1990.03450150084036 2008-issue1.indd sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 5-9 sultan qaboos university© submitted 22nd may 2007 accepted 3rd december 2007 care of diabetic retinopathy patients in oman *rajiv khandekar,1 ali jaffer mohammed,2 jawad a al-lawati3 diabetes mellitus is a public health problem in both developing and developed countries with one of its complications being diabetic retinopathy (dr). as the life expectancy of people with diabetes has increased owing to improved health care, the prevalence of dr is rising. dr is therefore now included in the list of priority diseases of the who’s vision 2020 strategy to eliminate all preventable cases of blindness by the year 2020. in oman, a comprehensive programme approach to dr was adopted in 1998. oman’s system of screening for and treating dr is considered to be a good model in the region. the programme approach for eye care of people with diabetes in oman has strengths and weaknesses. this editorial describes these, along with future challenges and solutions to handle them, including the use in oman of modern technology to manage the eye complications of diabetes. however, strategies for educating people about their role in primary prevention of dr and the development of rehabilitation services for visually impaired diabetics still need urgent implementation. d i a b e t e s m e l l i t u s a n d d i a b e t i c r e t i n o p a t h y diabetes mellitus (dm) is a clinical syndrome characterized by hyperglycaemia. long standing damage to the system causes serious complications mainly affecting the nervous system, the kidneys and the eyes.1 dm causes visual impairment due to eye complications such as diabetic retinopathy (dr), glaucoma, cataract, neuropathies and frequent eye infections. dr is the most serious of the possible eye complications. the long duration of dm, and poor glycaemic and lipid control are the major risk factors for the occurrence and progression of dr.2 nearly 75% of persons with ≥15 year duration of diabetes show changes in the eye due to dr. the risk of dr is very high among persons with insulin dependent diabetes mellitus (iddm). persons with non-insulin dependent diabetes mellitus (niddm) are, however, often detected late and hence their eyes can have dr changes when the dm is first detected.3 timely detection and management of dr not only causes regression, but also delays irreversible visual impairment. w o r l d s i t u a t i o n f o r d i a b e t i c r e t i n o p a t h y a n d r o l e o f t h e w o r l d h e a l t h o r g a n i s a t i o n the world health organisation urged its member countries and all partners to prioritize the prevention of blindness and in the world health assembly in 1999 endorsed a resolution called vision 2020 the right to sight. this initiative aims to eliminate avoidable blindness by the year 2020. initially cataract, trachoma, onchocerciasis and childhood blindness were defined as the priority eye diseases, 4 but subsequently dr and glaucoma were also added.5 dr is the leading cause of visual impairment in industrialized countries. in many developing countries, rapid socioeconomic development, changes in life style and improved health services have resulted in the rise of non-communicable and chronic diseases. thus dr is a global public health problem and hence experts have 1eye & ear health care, non-communicable diseases control department, directorate general of health affairs, ministry of health, oman; 2directorate general of health affairs, ministry of health, oman; 3department of non-communicable disease control, ministry of health, oman *to whom correspondence should be addressed. email: rajshpp@omantel.net.om e d i t o r i a l عمان في السكر داء بسبب الشبكية باعتالل عيون املصابني رعاية اللواتي جواد محمد، جعفر علي خانديكار، راجيف r a j i v k h a n d e k a r , a l i j a f f e r m o h a m m e d a n d j awa d a a l awat i 6 prepared guidelines for managing dr.6 the eastern mediterranean region (emr) of who also recommended its member countries to adopt an organised approach to controlling visual disabilities due to dr.7 interestingly in 1998, oman had already included dr as one of its priority health issues, while standard operating procedures for eye screening and management were laid down in 2000.8 in view of the epidemic of diabetes in all gulf cooperation council countries, a planning meeting was jointly organized by the international agency for the prevention of blindness – eastern mediterranean region in june 2006. oman participated in preparing recommendations for the programme approach for the region. t h e s i t u a t i o n i n o m a n f o r d i a b e t e s m e l l i t u s a n d d i a b e t i c r e t i n o p a t h y the sultanate of oman has a population of 2.5 million people, of which 1.88 million are indigenous omanis.9 surveys in 1991 and in 2000 revealed that the prevalence of dm was 10% among the ≥20 year old omani population. a further 10% of people in this age group had impaired glucose tolerance.10, 11 the ministry of health therefore established a national diabetes control programme within its public health approach to non-communicable and chronic diseases. it was adequately represented in the 5th five year health plan prepared in 1995.12 in 1999, a national diabetes registry was initiated and regional teams for management of the programme were formed. a health information and management system for diabetes was also established in that year. by the end of 2005, the ministry of health had registered around 48,972 diabetics and nearly 5,000 new cases are added each year.13 as renal dialysis centres and cardiology units are established in regional hospitals, the patients with diabetes are likely to live longer; hence the risk of developing visual impairment due to advanced dr will also increase. thus, a large number of people with diabetes in oman will seek eye care and the trend will increase in coming years.14 a study in 2002 in oman, showed that nearly 15% of registered diabetics had dr.15 in 2003, it was reported that 20% of persons newly diagnosed with niddm suffer from dr.16 the annual regional reports of the eye health care programme from all regions provide information on dr. in 2005, ophthalmologists in oman reported 1,357 new cases of dr.13 this suggests an annual incidence rate of 2.7%. if we assume that a person lives for 7 years after diagnosis of dr, the prevalence of dr could therefore be as high as 20%. indeed, ophthalmologists at rustaq hospital in the south batinah region found that 20% of people with diabetes suffered from dr.17 on the other hand, osama et al have reported the prevalence of dr to be as high as 40% in the buraimi region of oman.18 thus dr among omani diabetics is a major public health issue. in addition, evidence based information suggests that people with diabetes have 20 times more risk of developing visual impairment compared to the general omani population,19 while nine percent of the registered people with diabetes were suffering from glaucoma.20 periodic eye examination is therefore crucial for the early detection and management of the eye complications of diabetes. m a n a g e m e n t o f d i a b e t i c r e t i n o p a t h y i n o m a n c ur r e n t s y ste m the eye health care programme piloted the eye screening of diabetics in two regions of oman in 199899; this was expanded in all regions in 2000. family physicians and diabetologists refer registered diabetics to ophthalmologists at the nearest eye unit for annual eye examination. nearly 65 qualified ophthalmologists note the ocular manifestations of diabetes at institutions with secondary level eye care facilities in oman. ophthalmologists in these units use a panretinal indirect ophthalmoscope and a volk lens. senior ophthalmologists at regional hospitals confirm dr changes. they use bio-microscopes to evaluate the anterior segment of eyes and with the help of +90 d lens and examine the retina for dr changes. if the diagnosis is not conclusive or a more advanced type of eye management is needed, patients are referred to the specialists of the vitriol-retina unit at al-nahdha hospital, muscat. this is the tertiary eye care unit of the ministry of health. the regional and national supervisory teams monitor the progress of this referral system. within the country, the national eye health care program has established linkages with the diabetes control program, primary health care program, department of health education and health promotion, ophthalmic services in sister organisations, eye clinics of the private sector and local non-governmental c a r e o f d i a b e t i c r e t i n o pat h y pat i e n t s i n o m a n 7 organisations. the national and regional eye and diabetes control programme teams jointly supervise the dr control programme. the regional teams visit all health institutions at least once in six months and review activities related to eye care of people with diabetes. they prepare supervisory reports, provide feedback to parent institutions to improve the eye care and propose additional measures to the regional administrators. every year, regional teams evaluate the progress and achievements of the previous year, exchange their experiences and plan the eye care of people with diabetes for the next year. the ‘wilayat health’ is now involved in defaulter retrieval and eye health education of people with diabetes. r e f e r r a l p r o b l e m s f o r d i a b e t i c e y e c a r e a n d s o m e t e c h n i c a l s o l u t i o n s due to the risk of precipitating an acute attack of glaucoma, physicians cannot dilate the pupil for fundus examination at primary health centres; hence it is necessary to refer them to specialised units. retina specialists laid down the protocol for diagnosis, management and reference of cases with dr to the tertiary level in 2001. this referral problem, together with the need for ophthalmologists to perform eye check ups and screening on an annual basis and the large number of people with diabetes, results in a heavy workload for the secondary and tertiary eye care services. this could compromise the care of other priority eye diseases; therefore, alternate strategies should be planned. in addition, the literature suggests that the agreement rate of dr screening by physicians compared to ophthalmologists was only 64%;21 therefore, to improve both the screening and management of dr, technological advances should be adopted in oman. trained ophthalmic technicians could carry out digital documentation so that ophthalmologists would then just examine a limited number of problem cases. equipment for laser treatment, mainly for pan retinal photocoagulation is in fact already available in most of the regional hospitals with ophthalmologists conducting 908 sessions of laser therapy in different regions in 2005.13 the facilities for fluorescein angiography and treating diabetic maculopathy are, however, not available in all regions. hence, in 2005, 81% of dr patients were still treated at the tertiary unit of al nahdha hospital, muscat. 6 however, technologies for transferring the fundus images are beginning to be used to link institutions with experts and units photographing the images of retina. this client friendly approach will surely reduce the cost of screening and number of defaulters. in the vision 2020 – oman document, dr is one of the priority eye diseases. accordingly the 6th and 7th five-year health plans included strategies to address this problem. in the 6th five-year plan of the ministry of health (2001-2005), new regional autonomous hospitals (ibra, sur, sohar, nizwa and salalah) received laser facilities to manage diabetic retinopathy.22 in the 7th five-year plan (2006-2010), adequate resource allotment is proposed to manage the eye care of people with diabetes. each regional hospital would be given digital documentation and modern laser equipment.23 the laser destroys part of retina to increase oxygen supply to the vital central part with the outcomes depending on many factors. it would be interesting to study the impact of laser treatment of dr in oman. the results will help us in promoting this intervention to prospective clients. diabetes centres were also commissioned in 2007 in muscat, sur, ibri and nizwa. comprehensive care of persons with diabetes will therefore soon be easily accessible in many regions. h e a l t h e d u c a t i o n an examination of the retina helps physicians to determine the progress of the dm and the status of micro-vascular changes in other organs. hence the need for periodic eye examinations should be emphasized to patients, their relatives and family physicians. it is also crucial for the public health units of a country to integrate screening and management of diabetic retinopathy into their diabetes control programmes.6 in oman, health education materials for the eye care of diabetics are distributed to people with diabetes and their relatives. at the time of ‘world diabetes day’ and ‘world sight day’, campaigns are organized to increase awareness about visual disabilities among people with diabetes. use of mass media and group discussions within diabetes societies could further increase awareness of these issues in the community. the knowledge, attitudes and practices of persons with diabetes, if studied, will help us to identify strong and weak areas and improve the awareness campaigns in oman. r a j i v k h a n d e k a r , a l i j a f f e r m o h a m m e d a n d j awa d a a l awat i 8 n a t i o n a l r e g i s t e r f o r s i g h t t h r e a t e n i n g d i a b e t i c r e t i n o p a t h y in 2005, in order to strengthen eye care of people with diabetes, the national eye care programme introduced a sight threatening diabetic retinopathy register (stdr). defaulters for eye examination and management are noted among those diabetics registered with the stdr. staff of medical record sections and ophthalmology departments then contact the defaulters to find the cause of defaulting and arrange another appointment on a priority basis. the defaulter retrieval system for stdr in different regions using different categories of health staff needs to be closely studied as the outcomes will guide other countries aiming to adopt it. d i a b e t e s a n d b l i n d n e s s diabetes was not a significant contributor to blindness in the 1996 oman eye study,24 but dr contributed significantly in posterior segment pathologies. this group was responsible for 16% of ‘low vision’ disability in ≥ 40 years old omani population in 2005. 25 this confirms that, in spite of all efforts, many persons with diabetes eventually lose their eyesight. they will need vocational or rehabilitative facilities. unfortunately, limited facilities are at present available in oman. people who have become blind due to diabetes are provided with a monthly sustenance allowance by the ministry of social affairs. c o n c l u s i o n improved health services will increase the life expectancy of people with diabetes, who are likely to suffer from dr. the focus from primary prevention of dr should not be shifted, but eye care units should be periodically strengthened through the adoption of technological advances. the programme approach to eye care for diabetes is now established in oman, but awareness of health issues among persons with diabetes should be further raised so that stringent control of diabetes and compliance to ophthalmologists’ advice are achieved. a c k n ow l e d g m e n t s we thank the ministry of health staff of the eye department and diabetes control programme who undertake different activities related to eye care of people with diabetes. we appreciate the permission given by the ministry of health administrators to permit us to use their health information. r e f e r e n c e s 1. edwards crw, baird jd, frier bm, shepherd j, toft ad. endocrine and metabolic diseases including diabetes mellitus. in: davidson’s principles and practice of medicine 17thedition. new york: churchill livingstone, 1995. p. 724 – 762. 2. stanga pe, boyd sr, hamilton am. ocular manifestations of diabetes mellitus. curr opin ophthalmol 1999; 10:483-489. 3. klein r, klein be, moss se, davis md, demets dl. the wisconsin epidemiologic study of diabetic retinopathy iii. prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. arch ophthalmol 1984; 102:527-532. 4. pararajasegaram r. vision 2020 the right to sight: from strategies to action. am j ophthalmol 1999; 128:359-360. 5. foster a, resnikoff s. the impact of vision 2020 on global blindness. eye 2005; 19:1133-1135. 6. world health organization. prevention of blindness from diabetes mellitus. report of a who consultation in geneva, switzerland 9-11 nov 2005. geneva: who in 2006. p.1-3. 7. report on the conference on ‘vision 2020 planning for eastern mediterranean region’ dec. 2003, cairo, egypt. who/emr/pbl/03.1. from http://whilibdoc. who.emr/2003/who pbl/03.1 pdf. accessed july 2006. 8. ministry of health, diabetic eye in eye health care manual. 2nd edition. muscat: al nahdha printing press, 2000. p. 25-27. 9. ministry of national economy, oman. census 2003. monthly bulletin issued by the administration of the 2003 census, 13th edition. muscat: ministry of national economy, 2004. p. 20. 10. asfour mg, lambourne a, soliman a, al-behlani s, al-asfoor d, bold a, et al. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabet med 1995; 12:1122-1125. 11. al-lawati ja, mohammed aj, al-hinai hq, jousilahti p. prevalence of the metabolic syndrome among omani adults. diabetes care 2003; 26:1781-1785. 12. ministry of health, oman. 5th five year health plan 1995-2000. program for control of non-communicable diseases. muscat: international printing press, 1996. p. 12-15. 13. ministry of health. sultanate of oman annual health report year 2005, muscat: ministry of health. p. 9-55. c a r e o f d i a b e t i c r e t i n o pat h y pat i e n t s i n o m a n 9 14. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954-957. 15. khandekar r, al lawatii j, mohammed aj, al raisi a. diabetic retinopathy in oman: a hospital based study. br j ophthalmol 2003; 87:1061-1064. 16. ministry of health, oman. diabetes mellitus management guidelines for primary health care. 2nd edition. muscat: ministry of health, 2003. p.35-43. 17. evaluation of eye health care program in south batinah region. newsletter of department of surveillance and disease control. muscat: ministry of health 1993, vol. 2:1. 18. el haddad oa, saad mk. prevalence and risk factors for diabetic retinopathy among omani people with diabetes. br j ophthalmol 1998; 82:901-906. 19. khandekar r, mohammed aj. visual disabilities among people with diabetes in oman. saudi med j 2005; 26:836-841. 20. khandekar r, zutshi r. glaucoma among omani diabetic patients: a cross-sectional descriptive study: oman diabetic eye study 2002. eur j ophthalmol 2004; 14:19-25. 21. okoli u, mackay k. an evaluation of diabetic retinopathy screening models. j public health med 2002; 24:190-195. 22. ministry of health, sultanate of oman 6th five-year health plan, non-communicable disease control program. muscat: international printing press, jan 2001. p. 49-60. 23. ministry of health, sultanate of oman. domain -13: non-communicable diseases. in: 7th five-year health plan for health development 2006-2010. muscat: international printing press, 2006. p. 155-158. 24. khandekar r, mohammed aj, negrel ad, riyami aa. the prevalence and causes of blindness in the sultanate of oman: the oman eye study (oes). br j ophthalmol 2002; 86:957-962. 25. khandekar r, mohammed aj, raisi aa. prevalence squ med j, april 2010, vol. 10, iss. 1, pp. 6-11, epub. 17th apr 10 submitted 26th dec 09 revision req. 31st jan 10, revision recd. 9th feb 10 accepted 16th feb 10 in the past several decades, there has been an incredible increase in the privatisation of medical education with rapid expansion in the number of private medical schools. this trend has had widespread implications globally and influenced medical educational policies all over the world. privatisation is the act of reducing the role of government or increasing the role of the private institutions of society in satisfying people’s needs; it means relying more on the private sector and less on government.1 hence the privatisation of medical education can be defined as “medical education being imparted by an organization which is not a part of the government bureaucracy.” private medical schools can be totally autonomous or partially autonomous (controlled at various levels and in various degrees by government). they can be profit-generating institutions (revenues which enrich one individual or a consortium) or non-profit institutions which are more society centered. this article is essentially based on print and electronic data available from the world directory of medical schools published by who,2 the international medical education directory maintained by foundation for advancement of international medical education and research and medical literature.3 global nature of the trend: examples there has been a worldwide boom in private medical education. india tops the list with the largest numbers of medical schools within one country (271). out of these about 137 are privately owned institutions.4,5,6 next comes the united states with 62 private institutions out of a total of 131 medical schools.7 american private universities are heavily supported by government research grants and usually are non-profit institutions.8 in asia, there are 79 medical schools in japan, with 50 governmental and 29 private colleges.9 other countries like malaysia (11 private institutions),10 thailand,3 and the philippines 3 have also ventured heavily into private medical education. in europe, the united kingdom, with a total of 44 medical schools, private medical education is a relatively new entrant with only one private school, the university of buckingham medical school.3,11,12 similarly, germany also has only one private school out of a total of 36.13 medical education in greece14 (seven medical schools ) and the netherlands (eight medical schools) 15 is fully government funded, while spain has only two private institutions out of a total of 28.16 in the oceania region, australia has 19 medical colleges with only two being private medical universities.3,17 new zealand has two schools, both of which are government funded.18 the pacific islands have 6 schools, most of which are private.3,4 recently there has been a spurt of private medical colleges in the caribbean region. department of pharmacology, gulf medical university, ajman, united arab emirates email: shehnazilyas@yahoo.com خصخصة التعليم الطيب ِوْجهات نظر مع منظور عاملي �شيد اليا�س �شيهناز editorial privatisation of medical education viewpoints with a global perspective syed i shehnaz syed i shehnaz editorial | 7 many of these 56 schools are private institutions which have become alternate destinations for aspiring american and canadian students.4,19 in south america, chile has a total of 60 schools, 35 of them private,20 while in africa, nigeria has only 2 private medical colleges out of a total of 34 schools21 whereas sudan has eight.22 in the gulf cooperative council countries (gcc countries), there are a total of 32 medical colleges. yemen has four private medical colleges, the united arab emirates (uae) has three and bahrain has two. saudi arabia, qatar and oman have one private medical college each. kuwait has no private medical college.3,23however, in countries like china,24 france,25 south africa2,3 and canada26 medical training is under the full control of the state. forces bringing about the trend the reasons for the sudden increase in private medical schools are manifold. on the one hand, in many developing countries, due to the population explosion, the demand for places at medical schools is greater than the available supply. in addition, governments are unable to meet the medical needs of society due to both economic constraints and limited infrastructure.27 on the other hand, the booming private sector economy means more aspirants from the expanding middle class are entering the medical field. this increase of wealth amongst a subset of society has led to a differential growth of private medical schools in the richer and healthier states/countries.6 in the developed countries, the emergence of new private schools has been driven by workforce shortages. the demands of the population for increased use of recent technological advances in medicine as well as higher average life spans has increased the requirement for medical services in these countries.28 globalisation has resulted in an increased demand for medical professionals from foreign countries (outsourcing). this lure of increased income has led to more entrants into health professions. this enhanced need for medical schools is fulfilled by private medical schools. indian physicians form the bulk of foreign trained physician in all the major five developed countries (uk, us, canada, australia and new zealand) 29 and this correlates with the fact that india has the greatest number of private medical institutions in the world.4, 6 india has also become the leading country promoting ‘medical tourism’. a similar situation can also be found in countries like malaysia and thailand which advertise cheaper medical care to foreign patients. this lucrative demand for “exported” medical services may be instrumental in the mushrooming of private medical colleges in india and malaysia. changes in government policies in many countries have resulted in the climate being more conducive to privatisation. in india, relaxed regulations resulted in a growth spurt in private medical colleges in the mid-1980s. political leaders and businessmen found new avenues to make large earnings from private medical schools in the form of high tuition fees. many regional governments want to appease their electorate from different caste and ethnic groups. hence they also support the opening of private medical schools by specific minority and ethnic groups.27 total or partial lack of medical education facilities in some countries (eritrea, somalia, namibia, botswana) 4,30 or stringent admission criteria (usa, canada)4,19,31 may have resulted in the residents of these countries going to other countries for their medical education. advantages of privatisation more medical schools, whether private or public, can meet the need of an ever expanding population and have the potential of enhancing access to health care for all sections of society. there is a strong relationship between the number of medical schools and physician density;4 hence, more medical schools in low density areas will certainly increase the physician density. the dependency of the local population on expatriate doctors can also be reduced and the health care needs of the local population can be adequately catered for.30,32 more medical schools (public or private) will also create more job opportunities for everyone. there will be a healthy competition between the private and public medical institutions benefiting the prospective job candidate.30 chances of improvements in the government-run colleges will be greater so as to ‘keep up’ with the private sector. the monopoly in medical education by governmentprivatisation of medical education view points with a global perspective 8 | squ medical journal, april 2010, volume 10, issue 1 run institutions will be substantially reduced, as alternatives become available for students, faculty and the community. a further advantage is that, with privatisation, medical education will not be dependent on policies driven by political scenarios and could eventually become the sole responsibility of various private medical institutions. in some private medical colleges, with sound financial backing, up to date facilities and technology can reach the students faster than in government colleges. there will be no “red tape” involved as far as infrastructure and facilities are concerned. disadvantages of privatisation usually, the primary intention of the trusts/agencies running the profit generating medical colleges is to earn money through a business venture. this is typically the yardstick against which all decisions regarding the institution are made. the common factor in all the private medical colleges around the globe is that they are more expensive than the public medical schools. medical education has become costlier over time and the burden of debt on medical school graduates increases due to the high tuition fees in private medical schools.5,33,34, the quality of students entering programmes in private institutions is more often dependent on their paying capacity rather than their merit. some institutions do insist on minimum standards of admissions, but these standards are definitely below those required by state-owned schools. hence the quality of the doctors coming out of these institutions is likely to be compromised.35 the quality of training provided in private medical colleges is also questionable.35,36 major problems facing the private medical colleges are poor staffing, poor quality of training and high student /teacher ratios. the staff frequently lack proper training in medical education.36 many of the faculty work in these colleges on a part-time basis, or are appointed only for the purpose of accreditation (short term appointments). in some countries, the increased demand for teaching faculty is met by faculty with dual appointments.36,37 deficiencies in physical infrastructure with a shortage of equipment, laboratories, cadavers or prosected specimens and chemicals are also rampant.34 there is also a reduced availability of patients for clinical teaching in private medical schools. this is because the number of in-patients in the private hospitals of richer countries tends to be less due to their reduced length of stay, sicker patients avoid examinations by students, and an admission of increasing number of elderly patients who are in no condition to give a history due to cognitive impairment.38 scarcity of “clinical material” in private medical colleges in the poorer developing countries is due to the lack of patient paying capacity as the private hospitals are much costlier than the government-run hospitals.6,36 it has been observed that government support has always helped to improve the quality of education, in particular by covering the increases in costs as laboratory science has evolved. this means that “when government support declines, so too do intellectual standards.”39 many newly formed private colleges are not accredited by the national accreditation body. accreditation is a quality control measure for maintaining high standards of medical education and of health care for the nation. it also instills public confidence in medical schools and ensures that graduates’ competencies comply with national standards.40 the absence of accreditation for some of these private medical colleges will result in a questionable future for their graduates as their qualifications may not be nationally and internationally recognised. a further disadvantage of privatisation is that there is a lack of social and racial diversity in private institutions. their medical students usually come from privileged backgrounds.34,39,41 also with an increase in tuition fees there will be a further rise in the socioeconomic status of these students.42,43 as a result of the high tuition fees, under-represented minority groups will have restricted access to medical education. racial diversity among health professionals results in better communication and improved health care delivery for ethnic minority patients; formation of a culturally competent health care workforce; maintenance of high quality of medical education and increased medical and public health research.44,45 this lack of racial and socioeconomic diversity in private medical colleges will, in the long run, affect patient care. most of the private institutions are set up in richer and healthier states or regions with a higher syed i shehnaz editorial | 9 ratio of medical school admissions to population.5,6,27 medical students from rural areas are more likely to practice in rural areas than those from urban upbringings.46,47 hence these factors will result in a misdistribution of doctors and resources and favour urban over rural areas. more medical colleges will result in an anticipated oversupply and misdistribution with too many new doctors entering the medical profession. this will result in a future lack of job opportunities for fresh graduates. already in malaysia, there has been a ban on opening any more private medical colleges due to the projected excess of doctors.10 some private medical schools isolate medical education from the health care system, as they are exclusively an educational industry. all the immigrant medical students in these schools are obligated to go to their home country after education. in fact, the whole purpose of many of the newly opened medical schools (in the caribbean islands, for example) is to produce doctors for the usa or canada.4,19,31 guidelines for privatisation of medical education the deficiencies found in private medical colleges can be removed if there is stringent monitoring and enforcing of international standards by government and health agencies. fees should be standardised and more stringent entry criteria should be imposed for candidates so that the quality of the graduates does not suffer. to ensure availability of patients for clinical teaching, medical schools with no training hospitals or inadequate clinical materials should be required to sign memoranda of understanding with teaching hospitals, general practice clinics, and private hospitals. private universities can become community-based medical schools, with the majority of students’ exposure to patients in the community rather than in hospitals.17 multidisciplinary clinical skills laboratories can help the students learn basic clinical skills in simulated environments using models and simulators, simulated patients, and standardised patients.38 mandatory accreditation should be introduced and non-compliant institutions should be placed on probation with their student enrollment suspended or accreditation withdrawn. in fact, with the mobility of the health professional workforce, international accreditation seems to be the way of the future. regulating accreditation boards should ensure that the curricula in all private medical schools are clearly defined and tailored to meet the needs of the society. the curriculum should be scrutinised carefully and the colleges kept up to date with the recent advances in science, medical education and health. continuous curriculum evaluations done by the medical colleges themselves should become a norm. current teaching and learning methods promoting student-centered, competency-based learning and problem-solving abilities should be emphasised. the ‘ideal’ overall teacher-student ratio should be maintained. faculty development programmes should be made mandatory. the number of private medical schools should be limited and a reduction in student intake enforced. quality, rather than quantity, should be the priority. a regulatory cap should be imposed on regions with very large numbers of medical colleges and measures should be taken to ensure more medical colleges are set up in rural areas. the access to medical education for students from ethnic and social minorities should be increased. this can be done by affirmative action, as in us schools, or by a reservation system as in india. conclusion in light of the limitations of the available information, concrete conclusions on the merits and demerits of privatisation cannot be formulated. nevertheless, privatisation is definitely a useful tool for addressing some of the problems faced today in the field of medical education and it also serves to enlarge the health manpower resources. however, as with any other powerful tool, if used indiscriminately, it can cause more harm than good. the way forward is more stringent monitoring of private institutions by governments and other authorities. private institutions should be goal directed and outcome focused. they should assume responsibility for their products, be they medical graduates, research results, or models of health service delivery. they should accept the kudos as well as the brickbats for the outcomes. privatising medical education should not mean that governments lose the ability to direct medical privatisation of medical education view points with a global perspective 10 | squ medical journal, april 2010, volume 10, issue 1 education. the unplanned growth of substandard medical colleges should be curtailed and quality should be emphasised over quantity. as advocated so long ago by flexner, the numbers of sub-standard medical schools should be drastically reduced by closing those not meeting the stipulated standards, while encouraging the growth of those, public or private, which have the potential to contribute to the health of the nation. a c k n o w l e d g m e n t the author is grateful to professor rc bandaranayake for his guidance and encouragement. references 1. savas e.s. privatization and public-private partnerships. new york: chatham house publishers/ seven bridges press, 2000. 2. world health organization. world directory of medical schools. from http://www.who.int/hrh/ wdms/en/index.html. accessed oct 2009. 3. foundation for advancement of international medical education and research. international medical education directory. from https://imed. faimer.org. accessed oct 2009. 4. boulet j, bede c, mckinley d, norcini j. an overview of the world’s medical schools. med teach 2007; 29:20–6. 5. supe a, burdick wp. challenges and issues in medical education in india. acad med 2006; 81:1076–80. 6. sood r. medical education in india. med teach 2008; 30:585–91. 7. association of american medical colleges. medical schools. from http://www.aamc.org/medicalschools. htm. accessed oct 2009. 8. bloche mg. should government intervene to protect nonprofits? health aff (millwood) 1998; 17:7–25. 9. kozu t. medical education in japan. acad med 2006; 81:1069–75. 10. lim vk. medical education in malaysia. med teach 2008; 30:119–23. 11. nellis h, sikora k. independent medical school is long overdue. bmj 2005; 330:537 12. cohen d, fišter k. rejecting political correctness. bmj 2005; 330:62. 13. chenot jf. undergraduate medical education in germany. ger med sci 2009; 7:doc02. 14. georgantopoulou c. medical education in greece. med teach 2009; 31:13–7. 15. cate ot. medical education in the netherlands. med teach 2007; 29:752–7. 16. palés j, gual a. medical education in spain: current status and new challenges. med teach. 2008; 30:365-9. 17. lawson ka, chew m, van der weyden mb. the new australian medical schools: daring to be different. mja 2004; 181:662–6. 18. fitzjohn j, wilkinson t, gill d, mulder r. the demographic characteristics of new zealand medical students: the new zealand wellbeing, intentions, debt and experiences (wide) survey of medical students 2001 study. n z med j 2003; 116:u626. 19. van zanten m, boulet jr. medical education in the caribbean: variability in educational commission for foreign medical graduate certification rates and united states medical licensing examination attempts. acad med 2009; 84:s13–6. 20. cruz-coke r. the evolution of chilean universities from 1981 to 2004. rev med chil 2004; 132:1543–9. 21. ibrahim m. medical education in nigeria. med teach 2007; 29:901–5. 22. fahal ah. medical education in the sudan: its strengths and weaknesses. med teach 2007; 29:910–4 23. abdulrahman kab. the current status of medical education in the gulf cooperation council countries. ann saudi med 2008; 28:83–8. 24. lam tp, wan xh, ip msm. current perspectives on medical education in china. med educ 2006; 40:940–9. 25. doan bd, lévy d, pavot j. demographic forecasts of medical workforce supply in france (2000-2050). [what numerus clausus for what future?] cah sociol demogr med 2004; 44:101–48. 26. gray jd, ruedy j. undergraduate and postgraduate medical education in canada cmaj 1998; 158:1047– 50. 27. mahal as, mohanan m. growth of private medical education in india. med educ 2006; 40:1009–11. 28. brooks pm, lapsley hm, david b butt. medical workforce issues in australia: “tomorrow’s doctors — too few, too far”. med j aust 2003; 179:206–8. 29. mullan f. doctors for the world: indian physician emigration. health affairs (millwood) 2006; 25:380– 93. 30. muula as. every country or state needs two medical schools. croat med j 2006; 47:669–72. 31. mcavinue mb, boulet jr, kelly wc, seeling ss, opalek a. u.s. citizens who graduated from medical schools outside the united states and canada and received certification from the educational commission for foreign medical graduates, 19832002. acad med 2005; 80:473–8. 32. broadhead rl, muula as. creating a medical school for malawi: problems and achievements. bbmj 2002 325:384–7. syed i shehnaz editorial | 11 33. elam cl, scott kl, gilbert la, hartmann ba. a comparison of applicant and matriculant trends, and rising costs of medical education in united states medical schools and at the university of kentucky college of medicine. j ky med assoc 2003; 101:201–7. 34. bhatt vr. medical education: at what cost? student bmj 2006; 14:265–308. 35. mahal as, shah n. implications of the growth of dental education in india. j dent educ 2006; 70:884– 91. 36. kumar s. report highlights shortcomings in private medical schools in india. bmj 2004; 328:70. 37. ananthakrishnan n. acute shortage of teachers in medical colleges; existing problems and possible solutions. nat med j india 2007; 20:25–9. 38. crotty bj. more students and less patients: the squeeze on medical teaching resources. med j aust 2005; 183:444–5. 39. duffin j. occasional essay: what goes around, comes around: a history of medical tuition. cmaj 2001; 164:50–6. 40. azila nm, tan cp. accreditation of medical schools: the question of purpose and outcomes. med j malaysia 2005; 60 suppl d:35–40. 41. mcmanus ic. the social class of medical students. med educ 1982; 16:72–5. 42. kassebaum dg, szenas pl, schuchert mk. on rising medical student debt: in for a penny, in for a pound. acad med 1996; 71:1124–34. 43. kwong jc, dhalla ia, streiner dl baddour re, waddell ae, johnson il. effects of rising tuition fees on medical school class composition and financial outlook. cmaj 2002; 166:1023–8. 44. cohen jj, gabriel ba,terrell c. the case for diversity in the health care workforce. health aff (millwood) 2002; 21:90–102. 45. magnus sa, mick ss. medical schools, affirmative action, and the neglected role of social class. am j public health 2000; 90:1197–201. 46. kassebaum dg, szenas pl. rural sources of medical students, and graduates’ choice of rural practice. acad med 1993; 68:232–6. 47. easterbrook m, godwin m, wilson r, hodgetts g, brown g, pong r, et al. rural background and clinical rural rotations during medical training: effect on practice location. cmaj 1999; 160:1159–63. department of rheumatology, mohamed kassab institute of orthopedics, la manouba, tunisia *corresponding author’s e-mail: bennessibdorra@gmail.com مرض ابجيت العظام عند املرضى الذين تقل أعمارهم عن 40 عاًما تقرير حالتني ومراجعة لألدبيات كوثر معطي �هلل، درة بالنصيب، �آمنة لبان، حنان فرجاين، منى بوعزيز، �ضياء القفال، وفاء الحامدي abstract: paget’s disease of bone (pdb) is a focal disorder of accelerated skeletal remodelling that is uncommon in patients under the age of 40 years; it is more prevalent in older individuals. we report two cases of pdb diagnosed in early adulthood at the mohamed kassab institute of orthopedics, la manouba, tunisia. the first case was a 35-year-old male patient who presented in 2011 with a seven-month history of hip pain. the second case was a 39-year-old female patient who presented 2014 with chronic lower back pain. the pdb diagnosis was confirmed with clinical, biological and radiological investigations. both patients were doing well on follow-up. some previous cases have been reported in the literature, differing from the presented cases in some aspects; data of pdb features at differing ages is still insufficient. early recognition of this clinical entity in young patients is important as early treatment can affect the progression of the disease. keywords: paget’s disease of bone; young adults; diagnosis; case report; tunisia. امللخ�ص: مر�ض باجيت �لعظام هو ��ضطر�ب حموري يف ت�ضارع �إعادة ت�ضكيل �لهيكل �لعظمي وهو �أمر غري �ضائع يف �ملر�ضى �لذين تقل �أعمارهم عن 40 عاًما؛ فهو �أكرث �نت�ضاًر� لدى �لأ�ضخا�ض �لأكرب �ضنا. نبلغ هنا عن حالتني من مر�ض باجيت �لعظام مت ت�ضخي�ضهما يف بد�ية اب جلر�حة �لعظام، �ملنوبة، تون�ض. كانت �حلالة �لأوىل لرجل يبلغ من �لعمر 35 عاًما قدم يف عام 2011 يعاين مرحلة �لبلوغ يف معهد حممد ك�ضَّ من �آلم يف �لورك ملدة �ضبعة �أ�ضهر. �أما �حلالة �لثانية فكانت لمر�أة تبلغ من �لعمر 39 عاًما قدمت يف عام 2014 وكانت تعاين من �آلم مزمنة �أ�ضفل �لظهر. مت تاأكيد ت�ضخي�ض مر�ض باجيت �لعظام من خالل �لفحو�ضات �ل�رسيرية و�لبيولوجية و�لإ�ضعاعية. كان كال �ملري�ضني يف حالة جيدة خالل عملية �ملتابعة. مت �لإبالغ عن بع�ض �حلالت �ل�ضابقة يف �لأدبيات و�لتي تختلف عن �حلالتني �ملعرو�ضتني يف بع�ض �جلو�نب؛ ل تز�ل �لبيانات عن خ�ضائ�ض مر�ض باجيت �لعظام يف خمتلف �لأعمار غري كافية. يعد �لتعرف �ملبكر على هذ� �لكيان �ل�رسيري عند �ملر�ضى �ل�ضباب �أمًر� مهًما لأن �لعالج �ملبكر ميكن �أن يوؤثر على تطور �ملر�ض. الكلمات املفتاحية: مر�ض باجيت �لعظام؛ �ضباب بالغني؛ ت�ضخي�ض؛ تقرير حالة؛ تون�ض. paget’s disease of bone in patients under 40 years two case reports and review of the literature kaouther maatallah, *dorra ben nessib, emna labbène, hanene ferjani, mouna bouaziz, dhia kaffel, wafa hamdi sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e127–131, epub. 15 mar 21 submitted 27 feb 20 revision req. 6 may 20; revision recd. 11 jun 20 accepted 12 jul 20 decreased range of motion of the left hip, associated with muscular weakness. laboratory tests showed an elevated serum level of alkaline phosphatase (alp) at 287 ui/l (upper limit of reference range: 130 ui/l). serum levels of calcium, phosphate, erythrocyte sedimentation rate (esr) and c-reactive protein (crp) were normal. pelvic and left hip radiographs showed sclerosis of the head and neck of the left femur with cortical thickening and a coarse trabecular pattern [figure 1a]. the computed tomography (ct) scan confirmed these findings [figure 1b]. the magnetic resonance imaging (mri) of the pelvis showed coarse trabecular thickening in low signal intensity on t1 and t2 with preservation of normal fatty bone marrow signal in between [figure 1c and d]. the planar scintigraphy images showed increased radiotracer uptake in the head and neck of the left femur [figure 2]. no neurological complications were paget’s disease of bone (pdb) is a focal disorder of accelerated skeletal remodelling that can involve a single bone (monostotic) or multiple bones (polyostotic). the resulting anomalous structure of the bone is responsible for pain, deformity and skeletal fragility.1 pdb is uncommon under the age of 40 years and its prevalence increases with age.2 herein, we report two cases of pdb diagnosed in early adulthood. case one a 35-year-old north-african male patient presented to the department of rheumatology at the mohamed kassab institute of orthopedics, la manouba, tunisia, in 2011 with a seven-month history of hip pain. he had no family history of paget’s disease, cancer or other musculoskeletal disorders. on examination, he had a this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.019 case report https://creativecommons.org/licenses/by-nd/4.0/ paget’s disease of bone in patients under 40 years two case reports and review of the literature e128 | squ medical journal, february 2021, volume 21, issue 1 detected. given the typical radiographic findings and the absence of warning signs such as morning stiffness, deterioration in general condition and an increase in the inflammatory markers, pdb was considered as the most probable diagnosis. a course of intravenous (iv) pamidronate for three days resulted in clinical improvement and a decrease in the level of alp to 81 ui/l. regular six-monthly follow-ups were performed for nine years. although the range of motion of the left hip remained reduced on examination, the patient was satisfied with the treatment results and did not report any complaint. the follow-up radiographs did not show significant changes compared to the baseline data and the blood levels of calcium, phosphorus, alp, creatinine, esr and crp were within normal limits. case two a 39-year-old north-african female patient, with no family history of paget’s disease or other bone disorders, was referred to the department of rheumatology in 2014 for chronic lower back pain. a thorough clinical examination did not reveal any significant findings. the level of alp was 174 ui/l. pelvic and right hip radiographs showed enlargement and sclerosis of the right ischiopubic ramus with cortical thickening, thickening of the ilio-ischial line and a coarse trabecular pattern [figure 3]. the bone scintigraphy revealed increased radionuclide uptake in the same region. in view of the chronicity of pain, overall well-being, normal level of calcium and typical radiographic abnormalities, the patient was diagnosed with pdb. considering the site of pdb, it was decided to treat the patient with pamidronate 60 mg iv infused for three consecutive days (september 2014). after an initial clinical and biological improvement, a flare-up was observed after four years. the alp level increased from 116 ui/l (january 2018) to 168 ui/l (february 2019). therefore, zoledronic acid infusion was administered after which the patient’s clinical condition and biochemical markers began to improve. in the last follow-up visit (december 2019), she had no pain. laboratory tests were within the reference ranges and the alp level decreased from 168 ui/l to 61 ui/l. the last follow-up radiographs were comparable to the initial findings. discussion pdb is a focal disorder initiated by overactive osteoclastic bone resorption followed by a compensatory increase in osteoblastic new bone formation. typically, it is more prevalent in older individuals and prevalence increases with advancing age.3 we report two cases of pdb in patients under the age of 40 years. considering the typical radiographic appearance of paget's disease on the one hand, and figure 1: anteroposterior radiograph of the left hip and coronal t2-weighted and t1-weighted magnetic resonance images of the pelvis of a 35-year-old male patient (case one). a: axial computed tomography scan of the left hip. b: sclerotic changes of the head and neck of the left femur with cortical thickening and coarse trabecular pattern. c: t2and d: t1-weighted images showing coarse trabecular thickening with preservation of normal fatty bone marrow signal in-between. figure 2: the technetium 99m-methyl diphosphonate planar scintigraphy images of a 35-year-old male patient (case one) showing increased radiotracer uptake in the head and neck of the left femur (arrow). figure 3: anteroposterior radiograph of the pelvis (a) and the right hip (b) of a 39-year-old female patient (case two) showing enlargement and sclerosis of the right ischiopubic ramus with cortical thickening, thickening of the ilioischial line (arrow) and coarse trabecular pattern. kaouther maatallah, dorra ben nessib, emna labbène, hanene ferjani, mouna bouaziz, dhia kaffel and wafa hamdi case report | e129 ta bl e 1: c as e re po rt s of y ou ng a du lt s w it h pa ge t’s d is ea se o f b on e5 – 12 a ut ho r an d ye ar o f pu bl ic at io n g en de r in it ia l c om pl ai nt sy m pt om (s ) du ra ti on a ge o f di ag n os is in y ea rs fa m il y hi st or y of p ag et ’s di se as e m on os to ti c/ po ly os to ti c si te o f t he d is ea se in it ia l a l p co n ce nt ra ti on in i u /l t re at m en t a l p co n ce nt ra ti on af te r tr ea tm en t in iu /l r ai e t a l.5 (2 01 4) m al e sw el lin g of th e m an di bl e an d in th e ri gh t su pr ao rb ita l r eg io n 5 ye ar s 26 n o po ly os to tic m an di bl e, fr on ta l b on e 82 5 m an er o r ui z et a l.6 (2 00 4) m al e c oi nc id en ta l d ia gn os is (r ou tin e ch ec kup ) 30 n o m on os to tic r ig ht h em ip el vi s 2, 09 0 r is ed ro na te 21 9 m al e c oi nc id en ta l d ia gn os is 36 n o m on os to tic r ig ht h em ip el vi s 49 1 r is ed ro na te 91 pa nd e et a l.7 (2 00 1) m al e su bo cc ip ita l p ai n 9 m on th s 36 ye s m on os to tic c 2 ve rt eb ra 40 2 c lo dr on at e 16 5 fe m al e fr ac tu re o f t he r ig ht r ad iu s 8 ye ar s 34 ye s po ly os to tic 57 0 c lo dr on at e fo ur bi oc he m ic al re la ps es z ill ik en s et a l.8 (2 00 6) fe m al e h ea da ch es , d iz zi ne ss a nd sq ue ak in g no is es in h er ri gh t e ar 3 m on th s 37 n o m on os to tic sk ul l tw ic e as h ig h as n or m al r is ed ro na te n or m al is at io n b an ni st er e t al .9 (1 98 6) m al e d ef or m ity a nd di sc om fo rt o f t he r ig ht sh in 16 n o m on os to tic r ig ht ti bi a g re is s an d m cl ou gh lin 10 (1 98 4) m al e fr ac tu re o f t he h um er us 31 n o m on os to tic le ft h um er us 11 1 k im e t a l.1 1 (1 99 7) m al e d ef or m iti es o f a rm s an d le gs 30 y ea rs 55 ye s po ly os to tic le ft h um er us , r ig ht fa ci al re gi on , r ig ht c la vi cl e, r ib s an d lo ng b on es o f l ow er lim bs 76 5 w hy te e t a l.1 2 (1 98 5) m al e m us cl e pa in a nd w ea kn es s 11 y ea rs 30 n o po ly os to tic h um er us , i lia , f em or a, is ch ia a nd r ig ht p ub is 43 5 c al ci to ni n c ur re nt c as es m al e h ip p ai n 7 m on th s 35 n o m on os to tic le ft fe m ur 28 7 pa m id ro ni c ac id 81 fe m al e lo w er b ac k pa in 39 n o m on os to tic r ig ht is ch io pu bi c ra m us 17 4 pa m id ro ni c ac id 95 a lp = a lk al in e p ho sp ha ta se ; i u = in te rn at io na l u ni ts . paget’s disease of bone in patients under 40 years two case reports and review of the literature e130 | squ medical journal, february 2021, volume 21, issue 1 the absence of warning signs (deterioration of the general condition, increased inflammatory markers or hypercalcaemia) on the other hand, a biopsy was not performed on our two patients. in fact, mixed pictures of lysis and sclerosis lead to the distinctive radiographic appearance of paget’s disease and biopsy is rarely required to establish the diagnosis.4 in addition, given the positive outcomes demonstrated both clinically and biologically and the long follow-up periods, malignant bone tumours were excluded. there have been some cases of pdb in young adults reported in the literature [table 1].5–12 the preponderance of males noted among these cases agreed with data related to older patients.13 as in the elderly, the most common clinical presentation includes pain, bone deformities and fractures; the majority of patients have monostotic involvement.13 according to a recent systematic review of 332 cases of pdb of all ages, the alp levels were 10 times higher than the normal limit in the majority of patients with a mean value of 1200.8 ui/l.13 therefore, it seems that the initial values of alp are lower in young patients. data provided by medical literature comparing pdb features according to age is still insufficient. to the best of the authors’ knowledge, two retrospective studies which included a large number of patients with pdb have compared a younger group of patients (under 40) to an older group [table 2].2,14 choma et al. found that the younger group had less axial but more monostotic involvement.2 despite the relative rarity of paget’s disease in african-american patients, a significant number of african-americans was reported in the younger group.2 conversely, in a catalonian retrospective study conducted by holgado et al., pdb diagnosed in early adult life was found to be more extensive (predo minance of polyostotic forms and a higher coutris extension index) but less active (renier’s activity index).14 the alp values were found to be significantly higher than in patients diagnosed after age 40. these results, contrasting with previous data reported by choma et al., may be explained by the limited number of young patients (n = 18) and the absence of male preponderance (50%).2,14 in fact, the number of affected bones and the values of alp levels were found to be higher in women.14 the low risk of malignancy in younger patients was noted in both studies and in previous studies as well.2,14–16 this may be attributable to early diagnosis and prompt treatment. by counteracting bone catabolism, the bisphosphonates remain the cornerstone of medical management.17 in a retrospective study conducted by zati and bilotta, 18 out of 119 patients with pdb developed sarcoma.18 considering the absence of sarcoma developing in patients treated with bisphosphonates, it has been suggested that this therapeutic option may potentially have a preventative effect on the degeneration of pbd. in fact, the inhibitory effect of bisphosphonates on osteosarcomatous cells has been previously demonstrated in vitro.19,20 further investigations are required to confirm or refute this finding. table 2: previous studies investigating paget’s disease of bone in young adults2,14 n (%) author and year of publication choma et al.2 (2004) holgado et al.14 (2005) location usa catalonia, spain sample size 521 314 patients under 40 (%) 52 (10) 18 (5.7) features of the younger age group mean age in years ± sd (range) gender ratio family history first presentation (frequency) axial involvement appendicular involvement most commonly affected site (frequency) monostotic involvement associated malignancy 35.4 ± 5.5 (18–40) 1: 1 3 (17) pain (44) pathologic fracture (14) incidental diagnosis (44) pain (11) 27 (53) 37 (71) tibia pelvis (61) lumbar spine (50) skull (45) 37 (71) 5 (27.7) 0 (0) 0 (0) kaouther maatallah, dorra ben nessib, emna labbène, hanene ferjani, mouna bouaziz, dhia kaffel and wafa hamdi case report | e131 in summary, several ‘red flags’ should be noted as early predictors of the pdb diagnosis in order to initiate prompt treatment: family history of pdb, fractures without an apparent cause, an even moderate increase in alp levels and mri images showing preservation of normal fatty bone marrow signal. several unanswered questions remain regarding the natural history of this disease as it appears in younger patients. the role of heredity requires further investigation; it has been known for many years that pdb sometimes occurs in more than one member of a family. genealogical studies support a hereditary disposition for pdb, perhaps mediated by an immune deficiency.11 another hypothesis has been advanced by renier and audran who investigated the progression of pagetic lesions over the years.21 they found that bone lesions could have started before the age of 30 in 64% of patients diagnosed with this disease at the age of 70 or older. the authors concluded that pbd may have started and gone unnoticed in early adult life and was then first noticed at a later age.21 conclusion paget’s disease may be a disease of young adults that remains undiagnosed until later in life. early treatment of these patients can affect the progression of the disease, hence early diagnosis is very important. therefore, an even moderate increase in alp levels associated with early radiological lesions should be taken into consideration. references 1. lyles kw, siris es, singer fr, meunier pj. a clinical approach to diagnosis and management of paget’s disease of bone. j bone miner res 2001; 16:1379–87. https://doi.org/10.1359/jbmr.2 001.16.8.1379. 2. choma tj, kuklo tr, islinger rb, murphey md, temple ht. paget’s disease of bone in patients younger than 40 years. clin orthop relat res 2004;202–4. https://doi.org/10.1097/000 03086-200401000-00033. 3. morales-piga aa, rey-rey js, corres-gonzález j, garcíasagredo jm, lópez-abente g. frequency and characteristics of familial aggregation of paget’s disease of bone. j bone miner res 1995; 10:663–70. https://doi.org/10.1002/jbmr.5650100421. 4. cundy t. paget’s disease of bone. metabolism 2018; 80:5–14. https://doi.org/10.1016/j.metabol.2017.06.010. 5. rai h, pai sm, dayakar a, javagal v. a rare incident of paget’s disease of bone in early adult life. j oral maxillofac pathol 2014; 18:s147–50. https://doi.org/10.4103/0973-029x.141373. 6. manero ruiz fj, urruticoechea arana a, medrano san ildefonso m, pecondón español a. [bone paget’s disease in the young adult]. rev clin esp 2004; 204:532–4. https://doi. org/10.1157/13066177. 7. pande kc, ashford ru, dey a, kayan k, mccloskey ev, kanis ja. atypical familial paget’s disease of bone. joint bone spine 2001; 68:257–61. https://doi.org/10.1016/s1297319x(01)00267-6. 8. zillikens mc, ginai az, pols ha. [a young woman with headaches and skull anomalies: a long road to the diagnosis 'paget’s disease']. ned tijdschr geneeskd 2006; 150:2150–4. 9. bannister p, roberts m, sheridan p. recurrent hypercalcaemia in a young man with mono-ostotic paget’s disease. postgrad med j 1986; 62:481–3. https://doi.org/10.1136/pgmj.62.728.481. 10. greiss m, mcloughlin sj. pathological fracture of the humerus in a young adult with paget’s disease of bone. injury 1984; 16:204–6. https://doi.org/10.1016/0020-1383(84)90163-3. 11. kim gs, kim sh, cho jk, park jy, shin mj, shong yk, et al. paget bone disease involving young adults in 3 generations of a korean family. medicine (baltimore) 1997; 76:157–69. https:// doi.org/10.1097/00005792-199705000-00002. 12. whyte mp, daniels eh, murphy wa. osteolytic paget’s bone disease in a young man. rapid healing with human calcitonin therapy. am j med 1985; 78:326–32. https://doi. org/10.1016/0002-9343(85)90444-9. 13. wang qy, fu sj, ding n, liu sy, chen r, wen zx, et al. clinical features, diagnosis and treatment of paget’s disease of bone in mainland china: a systematic review. rev endocr metab disord 2020; 21:645–5. https://doi.org/10.1007/s11154-02009544-x. 14. holgado s, rotés d, gumà m, monfort j, olivé a, carbonell j, et al. paget’s disease of bone in early adult life. ann rheum dis 2005; 64:306–8. https://doi.org/10.1136/ard.2004.021139. 15. mckenna rj, schwinn cp, soong ky, higinbotham nl. osteogenic sarcoma arising in paget’s disease. cancer 1964; 17:42–66. https ://doi.org/10.1002/1097-0142(196401)17:1<42::aidcncr2820170108>3.0.co;2-u. 16. porretta ca, dahlin dc, janes jm. sarcoma in paget’s disease of bone. j bone joint surg am 1957; 39-a:1314–29. https://doi. org/10.2106/00004623-195739060-00009. 17. reid ir. management of paget’s disease of bone. osteoporos int 2020; 31:827–37. https://doi.org/10.1007/s00198-019-05259-1. 18. zati a, bilotta tw. degeneration of paget’s disease into sarcoma: clinical and therapeutic influencing factors. chir organi mov 2008; 92:33–7. https://doi.org/10.1007/s12306008-0043-6. 19. sonnemann j, eckervogt v, truckenbrod b, boos j, winkelmann w, van valen f. the bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro. anticancer drugs 2001; 12:459–65. https://doi.org/10.10 97/00001813-200106000-00007. 20. mackie ps, fisher jl, zhou h, choong pf. bisphosphonates regulate cell growth and gene expression in the umr 106-01 clonal rat osteosarcoma cell line. br j cancer 2001; 84:951–8. https://doi.org/10.1054/bjoc.2000.1679. 21. renier jc, audran m. progression in length and width of pagetic lesions, and estimation of age at disease onset. rev rhum engl ed 1997; 64:35–43. https://doi.org/10.1359/jbmr.2001.16.8.1379 https://doi.org/10.1359/jbmr.2001.16.8.1379 https://doi.org/10.1097/00003086-200401000-00033 https://doi.org/10.1097/00003086-200401000-00033 https://doi.org/10.1002/jbmr.5650100421 https://doi.org/10.1016/j.metabol.2017.06.010 https://doi.org/10.4103/0973-029x.141373 https://doi.org/10.1157/13066177 https://doi.org/10.1157/13066177 https://doi.org/10.1016/s1297-319x%2801%2900267-6 https://doi.org/10.1016/s1297-319x%2801%2900267-6 https://doi.org/10.1136/pgmj.62.728.481 https://doi.org/10.1016/0020-1383%2884%2990163-3 https://doi.org/10.1097/00005792-199705000-00002 https://doi.org/10.1097/00005792-199705000-00002 https://doi.org/10.1016/0002-9343%2885%2990444-9 https://doi.org/10.1016/0002-9343%2885%2990444-9 https://doi.org/10.1007/s11154-020-09544-x https://doi.org/10.1007/s11154-020-09544-x https://doi.org/10.1136/ard.2004.021139 https://doi.org/10.1002/1097-0142%28196401%2917:1%3c42::aid-cncr2820170108%3e3.0.co%3b2-u https://doi.org/10.1002/1097-0142%28196401%2917:1%3c42::aid-cncr2820170108%3e3.0.co%3b2-u https://doi.org/10.2106/00004623-195739060-00009 https://doi.org/10.2106/00004623-195739060-00009 https://doi.org/10.1007/s00198-019-05259-1 https://doi.org/10.1007/s12306-008-0043-6 https://doi.org/10.1007/s12306-008-0043-6 https://doi.org/10.1097/00001813-200106000-00007 https://doi.org/10.1097/00001813-200106000-00007 https://doi.org/10.1054/bjoc.2000.1679 intellectual profile of children with autism spectrum disorder identification of verbal and nonverbal subscales predicting intelligence quotient watfa al-mamari,1 *ahmed b. idris,1 ahlam gabr,1 saquib jalees,1 muna al-jabri,2 reem abdulrahim,3 abeer al-mujaini,1 m. mazharul islam,4 mohamed al-alawi,5 samir al-adawi5 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 386–393, epub. 29 aug 21 submitted 8 apr 20 revisions req. 29 jun & 13 aug 20; revisions recd. 9 jul & 18 aug 20 accepted 30 sep 20 departments of 1child health, 2nursing and 3clinical & biochemical genetics, sultan qaboos university hospital; departments of 4statistics and 5behavioural medicine, sultan qaboos university, muscat, oman *corresponding author’s e-mail: ahmed30411@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.001 clinical & basic research abstract: objectives: this study aimed to explore the intelligence quotient (iq) profile among children with autism spectrum disorder (asd) and identify the most important subscales that predict the iq. the analysis of an intellectual profile with age and gender differentials and the identification of a battery of subscales of intelligence are important for clinical management of asd among children and for facilitating placement for remedial and educational services. methods: data were collected through an exploratory study of 100 children aged between three and 13 years, who were referred to the department of child health and development in sultan qaboos university hospital, a tertiary hospital, in oman between june 2016 and june 2019. results: among the 100 participants of this study, 79% were male, resulting in a male–female ratio of 4:1. the mean of full-scale iq was found to be 68.6 ± 18.1. furthermore, the mean of nonverbal iq (73.5 ± 17.5) was significantly higher than that of verbal iq (65.5 ± 17.6). finally, more than half (61%) of the children were observed to have had mild to moderate impairment in their iq levels. conclusions: age and gender showed no significant association with iq level. the regression analysis identified nonverbal fluid reasoning, nonverbal visual-spatial processing, nonverbal working memory and verbal knowledge as the significant predictors of total iq. the crucial dimensions of verbal and nonverbal iq identified in this study can be used to evaluate complicated cases. keywords: autism; intelligence; oman. advances in knowledge the intellectual profile of omani autistic children is described on the stanford–binet intelligence scales ( fifth edition; sb-5). a prediction concerning the total intelligence quotient (iq) of omani autistic children is offered concerning the most important verbal and nonverbal subscales. applications to patient care the prediction of the total iq scores of autistic children from specified subscales can facilitate a better understanding of cognitive abilities in difficult cases where performing a full iq test is challenging. the significant dimensions of verbal and nonverbal iq identified in this study can be used to evaluate difficult cases. au t i s m s p e c t r u m d i s o r d e r ( a s d ) i s characterised by deficits in social communication and social interaction along with restricted and repetitive patterns of behaviour, interests or activities.1 enhancing understanding, awareness and recognition of asd is crucial given its globally increasing prevalence. review articles point to median global estimates released in 2012 that suggested asd’s prevalence worldwide to be about 62 per 10,000 persons.2 the recalculated analysis of the center for disease control and prevention (cdc) in the us estimated a prevalence of 240 per 10,000 in 2018.3 the recognition of children with asd is also increasing in developing countries, but the prevalence rate in these countries has generally been noted to be lower than that observed in the industrialised countries.4 this has been attributed to cross-cultural variations in the presentation of asd as well as a lack of registry and services for children with asd.5 a recent study suggests that the prevalence of asd among omani children (0–14) who fulfilled the diagnostic and statistical manual of mental disorders (dsm-5) criteria jumped to 20.4 per 10,000 in 2018, whereas it was 1.4 per 10,000 in 2011.6 intelligence has been perceived as a stable measure among the general population.7 however, the picture is not sufficiently clear after the introduction of the autism phenotype and given that the concept of the stability of intelligence quotient (iq) is still under discussion. for instance, on the one hand, some authors postulated that intellectual abilities in children with autism are stable over time, mirroring the general population studies.8,9 on the other hand, others documented improvement in the iq of autistic children and linked that to improvement in autism symptoms.10,11 the above discrepancy can be https://creativecommons.org/licenses/by-nd/4.0/ watfa al-mamari, ahmed b. idris, ahlam gabr, saquib jalees, muna al-jabri, reem abdulraheem, abeer al-mujaini, m. mazharul islam, mohamed al-alawi and samir al-adawi clinical and basic research | 387 partially explained by the idea that subtests and index scores of iq in autistic children are driven by those measures which represent characteristic strengths and weaknesses in autism phenotypic features.12,13 on the other hand, intellectual abilities showed variability concerning autism symptomatology across different iq assessment tools. this was further demonst rated by the better performance of autistic patients on the raven progressive matrices, a well-established tool assessing complex reasoning, compared to that on the wechsler intelligence scales (wisc).14 further more, autistic patients showed better performance on the leiter international performance scale when compared to that on the stanford–binet intelligence scales (fifth edition; sb-5).15 drawing on these findings, the characterisation of subscales in intellectual function has been indicated to overcome the existing constraints and to add to the body of knowledge. moreover, quantification of intellectual functioning has the potential to define the direction for intervention, both remedial and rehabilitative, in addition to the admin istrative decision and professional communication.16 there are a plethora of studies that examine the most suitable instrument in assessing the intellectual capacity in asd.13 presently, it appears that wisc and the sb-5 have garnered the highest empirical support.17 however, there is a dearth of documentation on how children with asd in societies in transition, such as those in oman, fare on such intellectual measures. while the importance of quantifying intellectual functioning among children with asd has been incr easingly gaining ground,18 to the best of our knowledge, there are no studies, barring a few exceptions, that focus on populations in the arab-islamic countries that have reported the profile of intellectual functioning in children with asd.19 to fill the gap in the literature, this study deciphers the profile of children with asd in oman using the sb-5. to lay the ground for their remedial and educational intervention, it is essential to ascertain the performance of such a paediatric population on indices of intellectual functioning using this scale.20 a related aim of this study is to explore the profile of autistic children on the sb-5 and predict the total iq regarding the most important subscales which carry the highest variability. this can facilitate a better understanding of cognitive abilities in those difficult cases where performing a full iq test is challenging. methods oman’s national healthcare service is free for its citizens. tertiary care in this country is largely compartmentalised and centralised. the first point of contact for most children with special needs and talent is a primary healthcare centre or an educational setting. these children are thereafter referred to relevant services in tertiary hospitals. the present cohort was retrospectively extracted from sultan qaboos university hospital’s (squh) department of child health’s developmental paediatric clinic. participants in the present study consisted of consecutive patients who were either being followed-up or were referred for such services. the inclusion criteria consisted of subjects whose diagnostic and clinical observations indicated the presence of asd as detailed below. clinical and demographic information were collected from patients’ hospital medical records. the exclusion criteria included participants who were blind, deaf or otherwise seriously impaired by sensory or motor disorders that would render them inaccessible for protracted evaluation of intellectual functioning. omani children with asd who were aged between three and 13 years were identified as eligible participants for this study from the hospital registry at the developmental clinic, squh. the study period was between june 2016 and june 2019. during this period, there were 334 cases diagnosed as asd in the developmental paediatric clinic at squh by utilising gold standard methods. a convenient sampling method was employed to select cases that fulfilled the inclusion criteria. a total of 100 children (79 males and 21 females) were identified to participate in this study. the adequacy of the sample (of 100 children) for evaluating the iq profile of children with asd was examined by statistical power analysis. generally, ‘power’ refers to the number of observations required to avoid a type ii error in testing a hypothesis. the power analysis of the sample of 100 children indicated that it would provide a power of 0.91 for estimating the iq of children with asd within five units of the population value with a 95% confidence level. asd was diagnosed based on the dsm-5 criteria which were applied to the clinical history provided by the parents of the study subjects, direct clinical observations of the children and a review of prior evaluations and records of early interventions if any were available. the assessment of asd was conducted by a multidisciplinary team consisting of a psychologist, an occupational therapist, a speech therapist, paediatricians and a social worker, and it was headed by an experienced developmental paediatrician who was well versed in diagnosing asd by applying the dsm-5 criteria.1 the sb-5 was used to measure the participants’ intellectual ability. the sb-5 taps into five weighted factors through verbal and nonverbal subtests. the five intellectual profile of children with autism spectrum disorder identification of verbal and nonverbal subscales predicting intelligence quotient 388 | squ medical journal, august 2021, volume 21, issue 3 factors tested were knowledge, quantitative reasoning, nonverbal visual-spatial processing (nvvsp), nonverbal working memory (nvwm) and nonverbal fluid reasoning (nvfr). this study considered five cognitive profile groups: ‘average and above level of iq’ (iq = 90–129), ‘low average level of iq’ (iq = 80–89), ‘borderline impaired level of iq’ (iq = 70–79), ‘mildly impaired level of iq’ (iq = 55–69) and ‘moderately impaired level of iq’ (iq = 40–54). the superior (iq = 120–129) and higher average (iq = 110–119) categories were combined into one category of average and above because, in the sample, a very small number of children had superior and higher average iq levels, giving the categories very low statistical power for analysis. this study was ethically approved by the medical research and ethics committee at sultan qaboos university. this study adhered to the principles laid out in the world medical association’s declaration of helsinki (1964–2008) concerning ethical human research vis-à-vis participant confidentiality, privacy and management of data. the study considered iq levels (measured in full scale) as the outcome variable and the demographic characteristics (such as age and gender) and subscales of both verbal and nonverbal iq as the explanatory or predictor variables. both descriptive and inferential statistical techniques were used for data analysis. frequency distribution was used to describe the demographics and iq profiles of the selected sample of children with asd. one-way analysis of variance (anova) and correlation analysis were conducted to examine the statistically significant relationship between full-scale iq and background characteristics. a p value of <0.05 was considered statistically significant. multivariate statistical analyses using the general ised linear model approach were carried out to ascertain the significant predictors of the intellectual ability of the children with asd being studied. it is worth mentioning here that our response variable (full-scale iq score) is a count variable with overdispersion (variance = 326.51 > mean = 68.6) and a skewed distribution (skewness = 0.745), which is the usual characteristic of count variables. verbal and nonverbal iq and all the iq subscales are also count variables measured in an interval scale. as such, the count variable violates the basic assumptions of continuity, normality and homoscedas ticity of the ordinary least square regression technique and the standard test statistics, such as the t-test, for testing a hypothesis.21 for modelling count data, poisson regression is a natural choice. however, the most serious limitation of poisson regression is that it assumes that the variance of the distribution of the count response variable is equal to its mean which is usually termed as the equidispersion property. however, the response variable in this study is overdispersed. for the over-dispersed count variable, negative binomial (nb) regression is one of the alternative models to be used.22,23 thus, this study employed an nb regression model with a log link function for estimating the regression coefficients (β). for the convenience of interpreting the estimated coefficients, the incidence rate ratio (irr) was calculated by exponentiating the beta coefficient, i.e. irr = exp(β), for each category of the predictors. the 95% confidence interval (ci) of the irr was also provided. the statistical package for the social sciences (spss), version 25, (ibm corp., armonk, new york, usa) was used for all statistical analyses. to test the internal consistency and reliability of the iq measurement scales, the cronbach index was used.24 a high value of alpha = 0.91 indicates an adequate level of reliability of the measurements. given that the observed total iq scores and the verbal and nonverbal subscales’ scores were obtained through a counting process, the poisson rate test was employed for testing the hypothesis regarding the mean or difference between two means instead of the standard t-test.25 in fact, the poisson rate is nothing but the mean of the distribution. the statistical package minitab has the tool used for running the poisson rate test on the data. results table 1 presents the distribution of the children with asd participating in this study according to their gender, age and iq classification profiles. of the 100 participating children, 79 (79%) were males and 21 (21%) were females. the age of the children at the time of the study ranged between three and 13 with a mean age of 7.1 ± 2.5 years. two-thirds (75%) of the participating children were aged 6–13 years. both male and female children had a similar age distribution. in terms of the performance of full-scale iq measures, the mean iq level among children with asd was 68.6 ± 18.1, ranging between 40 and 129. according to the five cognitive profile groups considered in this study, more than half (61%) of the children were found to have mild to moderate impairment in iq level (iq score <70), while 16% were found to have average and above level of iq (iq = 90–129) and 14% had a borderline impaired or delayed level of iq (iq = 70–79). the distribution of iq, as previously mentioned, was found to be positively skewed with skewness of 0.745. this value of skewness indicates that the full-scale iq measure was moderately skewed. the mean of watfa al-mamari, ahmed b. idris, ahlam gabr, saquib jalees, muna al-jabri, reem abdulraheem, abeer al-mujaini, m. mazharul islam, mohamed al-alawi and samir al-adawi clinical and basic research | 389 nonverbal iq was found to be 73.5 ± 17.5, while that of verbal iq was 65.5 ± 17.6 [table 1]. the level of full-scale iq varied with age, but the differences were not statistically significant. the iq level showed a u-shaped pattern with age. younger children below six years of age tended to have a higher average iq score than their older counterparts. the nonverbal and verbal iq also showed a similar pattern of distribution with age. however, the relation was found to be statistically significant in the case of verbal iq [table 1]. female children with asd were found to have a slightly higher average iq level (69.7 ± 18.5) than their male counterparts (68.3 ± 18.1). this is also true for verbal and nonverbal iq level. however, the male-female differences in iq levels were found to be statistically insignificant [table 1]. to further examine the association between age and gender with iq profile groups, chi-square analysis was performed. the results presented in figure 1 showed no significant association between age and cognitive groups (χ2 = 10.467, p = 0.234) [figure 1]. however, it was found that there were more younger children (age groups 3–5 and 6–8 years) in the mildly impaired as well as in the borderline impaired groups, while there were more older children (age group 9–13 years) in the moderately impaired and low average groups. younger children were more likely to have an average and above level of iq than their older counterparts. the gender of the children also showed no significant association with cognitive groups (χ2 = 4.639, p = 0.326) [figure 2]. however, male children were found to be more likely to be mildly impaired or borderline impaired than the female children, while table 1: mean and standard deviation of full-scale intelligence quotient, nonverbal intelligence quotient and verbal intelligence quotient by age and gender, oman, 2020 full-scale iq nonverbal iq verbal iq mean ± sd (95% ci) f, p value mean ± sd (95% ci) f, p value mean ± sd (95% ci) f, p value age 1.40, 0.251 1.77, 0.175 3.62, 0.031 3–5 73.3 ± 19.9 (65.1–81.5) 79.2 ± 17.3 (72.4–85.9) 72.3 ± 19.3 (64.7–79.9) 6–8 65.9 ± 15.9 (61.4–70.5) 71.5 ± 16.5 (65.0–77.9) 61.2 ± 15.1 (56.3–68.1) 9–13 69.2 ± 19.9 (60.9–77.4) 72.0 ± 19.2 (64.4–79.5) 67.0 ± 18.8 (59.6–74.4) gender 0.11, 0.748 0.01, 0.932 0.47, 0.494 male 68.3 ± 18.1 (61.2–75.4) 73.6 ± 17.6 (66.7–80.5) 64.8 ± 17.6 (57.9–71.7) female 69.7 ± 18.5 (62.4–76.9) 73.2 ± 17.9 (66.1–80.2) 67.8 ± 17.8 (60.8–74.8) total 68.6 ± 18.1 (65.0–72.2) 73.5 ± 17.5 (70.1–77.0) 65.5 ± 17.6 (62.0–68.9) iq = intelligence quotient; sd = standard deviation; ci = confidence interval. figure 1: percentage distribution of children according to intelligence quotient profile groups and age, oman, 2020. intellectual profile of children with autism spectrum disorder identification of verbal and nonverbal subscales predicting intelligence quotient 390 | squ medical journal, august 2021, volume 21, issue 3 female children were often in a low average cognitive group compared to their male counterparts (23.8% versus 5.1%). overall, the mean iq for nonverbal scales was found to be significantly higher than that of verbal iq (z = 6.85, p < 0.001) [table 2]. however, not all components or subscales of nonverbal iq were higher than the corresponding components or subscales of verbal iq. among the five subscales of both verbal and nonverbal iq, the means of ‘verbal knowledge’ (vk) and ‘verbal quantitative reasoning’ were found to be higher than those of nonverbal subscales, but the differences were not statistically significant. on the other hand, nvfr, nvvsp and nvwm were found to be significantly higher than those of verbal subscales. to evaluate the predictive validity of verbal and nonverbal subscales’ scores in explaining the iq performance of children with asd, correlation analysis followed by regression analyses were performed. table 3 presents the zero-order correlation coefficients between full-scale iq scores and the 10 verbal and nonverbal subscale’ scores along with the intercorrelation among the latter. the significance tests of the estimated correlation coefficients were also conducted. the results indicate that all the correlation coefficients were found to be positive and significant at the p <0.001 level. full-scale iq scores have a strong correlation with the 10 subscales’ scores, ranging from r = 0.709 to r = 0.853. the amount of total variation (measured by r2) in iq level explained by the subscales ranged from 50% to 73%. this indicates that figure 2: percentage distribution of children according to intelligence quotient profile groups and gender, oman, 2020. table 2: mean and standard deviation of verbal and nonverbal intelligence quotient subscales and statistical significance test of the difference between means of verbal and nonverbal subscales, oman, 2020 iq subscales mean ± sd z* p value 95% ci for difference of mean verbal nonverbal fluid reasoning 3.87 ± 3.39 5.93 ± 3.66 6.58 < 0.001 (1.45, 2.67) knowledge 5.34 ± 3.46 5.16 ± 3.24 0.56 0.579 (–0.81, 0.45) quantitative reasoning 4.79 ± 3.55 4.66 ± 3.46 0.42 0.672 (–0.73, 0.47) visual-spatial processing 3.91 ± 3.59 7.36 ± 3.62 10.28 < 0.001 (2.79, 4.11) working memory 3.99 ± 2.82 5.29 ± 3.42 4.27 < 0.001 (0.70, 1.89) total iq 65.46 ± 17.60 73.53 ± 17.54 6.85 < 0.001 (5.76, 10.38) ci = confidence interval, iq: intelligence quotient, sd: standard deviation. *z : poisson rate test for count data. table 3: zero-order correlations between total intelligence quotient and intelligence quotient subscales, oman, 2020 iq nvfr nvk nvqr nvvsp nvwm vfr vk vqr vvsp vwm iq 1 0.819* 0.824* 0.853* 0.709* 0.768* 0.823* 0.796* 0.805* 0.835* 0.778* iq = intelligence quotient; nvfr = nonverbal fluid reasoning; nvk = nonverbal knowledge; nvqr = nonverbal quantitative reasoning; nvvsp: non verbal visual-spatial processing; nvwm = nonverbal working memory; vfr = verbal fluid reasoning; vk = verbal knowledge; vqr = verbal quantit ative reasoning ; vvsp = verbal visual-spatial processing ; vwm = verbal working memory. *indicates p value <0.001. watfa al-mamari, ahmed b. idris, ahlam gabr, saquib jalees, muna al-jabri, reem abdulraheem, abeer al-mujaini, m. mazharul islam, mohamed al-alawi and samir al-adawi clinical and basic research | 391 both verbal and nonverbal subscales are important in predicting overall iq level and there is a significant linear relationship between iq level and the subscales’ levels. to identify the verbal and nonverbal subclasses that have significant predictive power in explaining the overall iq level, the regression technique was employed. after checking the assumptions of linearity, multicollinearity and homoscedasticity of the predictor variables, a generalised linear regression model with nb log link was fitted with iq level as the outcome variable and the verbal and nonverbal subscales as well as age and gender of the children with asd as the predictors. the results of the standardised residual analysis indicated that the assumption of linearity and homoscedasticity has been met. although there was a moderate to strong correlation between the predictors, the low (<5) variance inflation factors (vifs) indicate that multicollinearity was not an issue. the resulting model could describe 92% of the variability in total iq by the predictors considered in the model, as the adjusted r2 was observed to be 0.92. the likelihood-ratio chi-square value of 356.5 with 12 degrees of freedom and the p value < 0.001 indicated that the model significantly improved the prediction of total iq. table 4 presents the results of the regression analysis. the results indicate that nvfr, nvvsp and nvwm and vk are the significant predictors of total iq. the level of iq is likely to be increased by 1.3% with a one-unit increase in nvfr (irr = 1.013, 95% ci: 1.002, 1.023, p = 0.020). similarly, a one-unit increase in the nonverbal vsp increased the iq level by 1.5% (irr = 1.015, 95% ci: 1.003, 1.025, p = 0.012). among the five verbal subscales, only vk appeared as a significant predictor of iq level. however, nonverbal quantitative reasoning and verbal quantitative reasoning appeared as marginally significant (0.05 <p <0.10) predictors of iq level. gender and age of the children with asd did not show any significant effect on iq level. discussion this is a cross-sectional study on children with asd to explore their intellectual profile with age and gender differentials and to identify a short battery of the verbal and nonverbal subscales that predict their full-scale iq. among the 100 participants of this study, 79% were male, resulting in a male-female ratio of 4:1, which is in line with the global scenario of the gender distribution of more males with asd than females.2 half of the cases of this study were between the ages of six and eight years. the mean iq of the autistic children in the study sample was observed to be 68.6 ± 18.1. this is comparable to the total iq which was found to be 70.4 in a study for the validity of the sb-5.20 moreover, another study found the mean iq of the samples from a special needs and autism project in table 4: negative binomial regression analysis of the intelligence quotient among children with autism spectrum disorders, oman, 2020 parameter irr 95% ci of irr p value collinearity statistics: vif lower upper intercept 39.145 34.139 44.885 < 0.001 gender (female) 1.013 0.953 1.077 0.682 1.803 age 1.008 0.995 1.021 0.223 1.096 nonverbal fluid reasoning 1.013 1.002 1.023 0.020 2.870 nonverbal knowledge 1.008 0.995 1.022 0.207 3.255 nonverbal quantitative reasoning 1.011 0.999 1.024 0.083 3.706 nonverbal visual-spatial processing 1.015 1.003 1.025 0.012 2.143 nonverbal working memory 1.011 1.001 1.022 0.038 2.304 verbal fluid reasoning 0.996 0.984 1.008 0.517 3.434 verbal knowledge 1.012 1.009 1.028 0.047 3.266 verbal quantitative reasoning 1.010 0.999 1.021 0.088 2.764 verbal visual-spatial processing 1.005 0.994 1.017 0.371 3.502 verbal working memory 1.008 0.995 1.022 0.208 2.592 ci = confidence interval; irr = incidence rate ratio; vif = variance inflation factor. intellectual profile of children with autism spectrum disorder identification of verbal and nonverbal subscales predicting intelligence quotient 392 | squ medical journal, august 2021, volume 21, issue 3 the uk to be 69.4 ± 24.1.26 the mean of nonverbal and verbal iq was found to be 73.5 ± 17.5 and 65.5 ± 17.6, respectively.26 this indicates that the nonverbal subscales outnumbered their verbal counterparts, which the other studies also indicate.27,28 the findings of this study revealed that more than half (61%) of the participating children with asd fall in the category of ‘mild to moderate’ impairment. this finding differs from that found in the uk dataset or the cdc surveillance dataset in which more than a quarter of the participants with asd were found to have had average or above-average iqs.26,29 this could be attributed to the severity of cases at the detection point. in oman’s settings of underdiagnosis, the more severe cases tend to be diagnosed more than the mild ones and the mild cases tend to go undetected in mainstream schools and/or misclassified as intellectual disability or other learning disabilities.6,30 male profiles were not significantly different from female ones, either in our cohort or in a study of canadian children with asd.31 this can be attributed to the proximity of age groups as the mean age of the canadian children was 7.07 ± 2.50 years which was similar among males and females. after controlling the effect of age and gender, the regression analysis identified a shorter number of verbal and nonverbal subscales as significant predictors of full-scale iq. interestingly, among the 10 subscales, nvfr, nvvsp, nvwm and vk were noted, in this study, to be significant predictors of total iq. children with asd scored the highest on the nvvsp subscale, with a mean score of 7.36 ± 3.625, while the lowest scores were on the verbal fluid reasoning (vfr) scale with a mean score of 3.87 ± 3.395. in line with this finding, one study found that vfr scores were low and nvvsp scores were comparable to our cohort with a mean score of 7.27 ± sd 4.28.32 in general, intellectual profiles were found to be constant between high and low iq groups across many studies, essentially reflecting the influence of autism on psychometric assessment.33,34 the predictability of nvfr, nvvsp, nvwm and vk of the total iq went up to 92%, thereby indicating their helpfulness in assessing difficult cases of autism in children. this study found high calculated power and predictability of certain subscales of iq in autistic children. however, the fact that this is a single-centre study is considered a limitation. undoubtedly, the findings of this study can pave the road for future research and further testing of variables predicting iq in autistic children. conclusion to the best of our knowledge, this is the first study that examines intellectual profile and their verbal and nonverbal predictors among children diagnosed with asd in oman. the present study suggests no difference in iq between male and female children. it finds non-verbal iq to be significantly higher than verbal iq across both genders. the most important determinants of total iq achievement among variable subscales are nvfr, nvvsp, nvwm and vk. these variables can indeed assist as reliable dimensions in evaluating iq, thus, defining the direction for intervention and professional communication going forward. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n wm and ai conceptualized the idea and drafted the manuscript. sj, wm, ag, am and ai did the clinical assessment. the data collection was done by mj, ag and am. sj revised the initial manuscript versions. the data management and data analysis was done by ra, ai and mi. ma and sa revised the final manuscript. all authors approved the final version of the manuscript. references 1. american psychiatric association. diagnostic and statistical manual of mental disorders (dsm-5®). fifth ed. washington: american psychiatric association, 2013. 2. elsabbagh m, divan g, koh y, kim ys, kauchali s, marcín c, et al. global prevalence of autism and other pervasive devel opmental disorders. autism res 2012; 160–79. https://doi. org/10.1002/aur.239. 3. xu g, strathearn l, liu b, bao w. corrected prevalence of autism spectrum disorder among us children and adolescents. jama 2018; 319:505. https://doi.org/10.1001/jama.2018.0001. 4. samadi sa, mcconkey r. autism in developing countries: lessons from iran. autism res treat 2011; 2011:1–11. https:// doi.org/10.1155/2011/145359. 5. ouhtit a, al-farsi y, al-sharbati m, waly m, gupta i, al-farsi o, et al. underlying factors behind the low prevalence of autism spectrum disorders in oman: sociocultural perspective. sultan qaboos university med j 2015; 15:e213–17. 6. al-mamri w, idris ab, dakak s, al-shekaili m, al-harthi z, alnaamani am, et al. revisiting the prevalence of autism spectrum disorder among omani children: a multicentre study. sultan qaboos univ med j 2019; 19:e305–9. https://doi. org/10.18295/squmj.2019.19.04.005. https://doi.org/10.1002/aur.239 https://doi.org/10.1002/aur.239 https://doi.org/10.1001/jama.2018.0001 https://doi.org/10.1155/2011/145359 https://doi.org/10.1155/2011/145359 https://doi.org/10.18295/squmj.2019.19.04.005 https://doi.org/10.18295/squmj.2019.19.04.005 watfa al-mamari, ahmed b. idris, ahlam gabr, saquib jalees, muna al-jabri, reem abdulraheem, abeer al-mujaini, m. mazharul islam, mohamed al-alawi and samir al-adawi clinical and basic research | 393 7. canivez gl, watkins mw. long-term stability of the wechsler intelligence scale for childrenthird edition among demographic subgroups: gender, race/ethnicity, and age. j psychoeduc assess 1999; 17:300–13. https://doi.org/10.1177/073428299901700401. 8. charman t, taylor e, drew a, cockerill h, brown ja, baird g. outcome at 7 years of children diagnosed with autism at age 2: predictive validity of assessments conducted at 2 and 3 years of age and pattern of symptom change over time. j child psychol psychiatry allied discip 2005; 46:500–13. https://doi. org/10.1111/j.1469-7610.2004.00377.x. 9. stevens mc, fein da, dunn m, allen d, waterhouse lh, feinstein c, et al. subgroups of children with autism by cluster analysis: a longitudinal examination. j am acad child adolesc psychiatry 2000; 39:346–52. https://doi.org/10.1097/00004583200003000-00017. 10. sigman m, mcgovern cw. improvement in cognitive and language skills from preschool to adolescence in autism. j autism dev disord 2005; 35:15–23. https://doi.org/10.1007/ s10803-004-1027-5. 11. turner lm, stone wl, pozdol sl, coonrod ee. follow-up of children with autism spectrum disorders from age 2 to age 9. autism 2006; 10:243–65. https://doi.org/10.1177/1362361306 063296. 12. mayes sd, calhoun sl. wisc-iv and wiat-ii profiles in children with high-functioning autism. j autism dev disord 2008; 38:428–39. https://doi.org/10.1007/s10803-007-0410-4. 13. nader a, jelenic p, souli i. discrepancy between wisc-iii and wisc-iv cognitive profile in autism spectrum: what does it reveal about autistic cognition? plos one 2015; 12:1–17. https://doi.org/10.1371/journal.pone.0144645. 14. dawson m, soulières i, gernsbacher ma, mottron l. the level and nature of autistic intelligence. psychol sci 2007; 18:657–62. https://doi.org/10.1111/j.1467-9280.2007.01954.x. 15. grondhuis sn, mulick ja. comparison of the leiter international performance scale revised and the stanford-binet intelligence scales, 5th edition, in children with autism spectrum disorders. am j intellect dev disabil 2013; 118:44–54. https://doi.org/10.1 352/1944-7558-118.1.44. 16. billstedt e, gillberg ic, gillberg c. autism in adults: symptom patterns and early childhood predictors: use of the disco in a community sample followed from childhood. j child psychol psychiatry 2007; 11:1102–10. https://doi.org/10.1111/j.14697610.2007.01774.x. 17. baum kt, shear pk, howe sr, bishop sl. a comparison of wisc-iv and sb-5 intelligence scores in adolescents with autism spectrum disorder. autism 2015; 19:736–45. https://doi. org/10.1177/1362361314554920. 18. hedvall a, westerlund j, fernell e, norrelgen f, billstedt e, gillberg c. preschoolers with autism spectrum disorder followed for 2 years: those who gained and those who lost the most in terms of adaptive functioning outcome. j autism dev disord 2015; 11:3624–33. https://doi.org/10.1007/s10803-0152509-3. 19. hussein h, taha gra, almanasef a. characteristics of autism spectrum disorders in a sample of egyptian and saudi patients: transcultural cross sectional study. child adolesc psychiatry ment health 2011; 5:1–12. https://doi.org/10.1186/1753-2000-5-34. 20. roid gh. stanford-binet intelligence scale, 5th editión: tech nical manual, 5th ed. itasca, illinois: riverside publishing, 2003. 21. mccullagh p, nelder j. generalized linear models, 2nd ed. london: chapman and hall, 1989. 22. cameron ac, trivedi pk. regression analysis of count data, 2nd ed. cambridge: cambridge university press, 2013. 23. winkelmann r, zimmermann kf. count data models for demographic data. math popul stud 1994; 4:205–221. https:// doi.org/10.1080/08898489409525374. 24. cronbach lj. coefficient alpha and the internal structure of tests. psychometrika 1951; 16:297–334. 25. sichel hs. on a significance test for two poisson variables. applied statistics 1973; 22:50–8. 26. charman t, pickles a, simonoff e, chandler s, loucas t, baird g. iq in children with autism spectrum disorders: data from the special needs and autism project (snap). psychol med 2011; 41:619–27. https://doi.org/10.1017/s0033291710000991. 27. williams dl, goldstein g, kojkowski n, minshew nj. do individuals with high functioning autism have the iq profile associated with nonverbal learning disability? res autism spectr disord 2008; 2:353–61. https://doi.org/10.1016/j.rasd.20 07.08.005. 28. ankenman k, elgin j, sullivan k, vincent l, bernier r. nonverbal and verbal cognitive discrepancy profiles in autism spectrum disorders: influence of age and gender. am j intellect dev disabil 2014; 119:84–99. https://doi.org/10.1352/19447558-119.1.84. 29. maenner mj, rice ce, arneson cl, cunniff c, schieve la, carpenter la et al. potential impact of dsm-5 criteria on autism spectrum disorder prevalence estimates. jama psychiatry 2014; 71:292. https://doi.org/10.1001/jamapsychiatry.2013.3893. 30. coo h, ouellette-kuntz h, lloyd jev, kasmara l, holden jja, lewis mes. trends in autism prevalence: diagnostic substit ution revisited. j autism dev disord 2008; 38:1036–46. https:// doi.org/10.1007/s10803-007-0478-x. 31. coolican j, bryson se, zwaigenbaum l. brief report: data on the stanford-binet intelligence scales (5th ed.) in children with autism spectrum disorder. j autism dev disord 2008; 38:190–7. https://doi.org/10.1007/s10803-007-0368-2. 32. matthews nl, pollard e, ober-reynolds s, kirwan j, malligo a, smith cj. revisiting cognitive and adaptive functioning in children and adolescents with autism spectrum disorder. j autism dev disord 2014; 45:138–56. https://doi.org/10.1007/ s10803-014-2200-0. 33. harris sl, handleman js, burton jl. the stanford binet profiles of young children with autism. spec serv sch 1991; 6:135–43. 34. mayes sd, calhoun sl. analysis of wisc-iii, stanfordbinet:iv, and academic achievement test scores in children with autism. j autism dev disord 2003; 33:329–41. https://doi. org/10.1023/a:1024462719081. https://doi.org/10.1177/073428299901700401 https://doi.org/10.1111/j.1469-7610.2004.00377.x https://doi.org/10.1111/j.1469-7610.2004.00377.x https://doi.org/10.1097/00004583-200003000-00017 https://doi.org/10.1097/00004583-200003000-00017 https://doi.org/10.1007/s10803-004-1027-5 https://doi.org/10.1007/s10803-004-1027-5 https://doi.org/10.1177/1362361306063296 https://doi.org/10.1177/1362361306063296 https://doi.org/10.1007/s10803-007-0410-4 https://doi.org/10.1371/journal.pone.0144645 https://doi.org/10.1111/j.1467-9280.2007.01954.x https://doi.org/10.1352/1944-7558-118.1.44 https://doi.org/10.1352/1944-7558-118.1.44 https://doi.org/10.1111/j.1469-7610.2007.01774.x https://doi.org/10.1111/j.1469-7610.2007.01774.x https://doi.org/10.1177/1362361314554920 https://doi.org/10.1177/1362361314554920 https://doi.org/10.1007/s10803-015-2509-3 https://doi.org/10.1007/s10803-015-2509-3 https://doi.org/10.1186/1753-2000-5-34 https://doi.org/10.1080/08898489409525374 https://doi.org/10.1080/08898489409525374 https://doi.org/10.1017/s0033291710000991 https://doi.org/10.1016/j.rasd.2007.08.005 https://doi.org/10.1016/j.rasd.2007.08.005 https://doi.org/10.1352/1944-7558-119.1.84 https://doi.org/10.1352/1944-7558-119.1.84 https://doi.org/10.1001/jamapsychiatry.2013.3893 https://doi.org/10.1007/s10803-007-0478-x https://doi.org/10.1007/s10803-007-0478-x https://doi.org/10.1007/s10803-007-0368-2 https://doi.org/10.1007/s10803-014-2200-0 https://doi.org/10.1007/s10803-014-2200-0 https://doi.org/10.1023/a:1024462719081 https://doi.org/10.1023/a:1024462719081 departments of 1behavioural medicine, 2family medicine & public health, 3biochemistry, sultan qaboos university; 4oman medical specialty board, muscat, oman *corresponding author’s e-mail: mirza@squ.edu.om socio-demographic and clinical profiles of adult attention deficit hyperactivity disorder patients in a university hospital in oman *hassan mirza,1 salim al-huseini,4 shamsa al-jamoodi,4 naser al-balushi,1 amira al-hosni,1 moon-fai chan,2 fahad zadjali3 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 206–211, epub. 26 may 22 submitted 13 oct 20 revision req. 9 dec 20 & 8 feb 21; revision recd. 18 jan & 21 feb 21 accepted 23 feb 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.104 clinical & basic research attention deficit hyperactivity disorder (adhd) is a common childhood neurodevelopment disorder, which manifests as inattention, hyperactivity and impulsivity and persists for at least six months in at least two settings (e.g. school, home or social situations).1 these clinical symptoms must have an impact on social, academic or occupational functioning to warrant a clinical diagnosis of adhd. according to the diagnostic and statistical manual of mental disorders, fifth edition (dsm-5),1 the symptoms of inattention are evident in children in their schoolwork, as the child fails to pay close attention to details, makes repetitive careless mistakes, gets easily distracted and has difficulty sustaining attention. whereas the symptoms of hyperactivity and impulsivity include difficulty remaining seated in the classroom, fidgeting, blurting out answers before questions have been completed and difficulty waiting their turn in activities or games. however, the presentation of adhd symptoms among adults differs from that in children as the cluster of symptoms related to hyperactivity reduces over time and manifests as restlessness. moreover, inattention as a symptom in adults with adhd may manifest as difficulty meeting deadlines at college or work or forgetting appointments.2,3 the dsm-5 outlines three subtypes of adhd: (1) primarily hyperactive and impulsive, (2) primarily inattentive and (3) combined. abstract: objectives: although attention deficit hyperactivity disorder (adhd) is typically considered a condition affecting children, there is evidence that children diagnosed with adhd continue to suffer from this condition after the age of 18. this study aimed to describe the socio-demographic and clinical characteristics of adult adhd patients in oman and evaluate their association with the disorder’s different subtypes. methods: this retrospective study included adult patients with adhd from the outpatient clinic at sultan qaboos university hospital, muscat, oman. data from medical records from january 2018 to april 2020 were collected. socio-demographic characteristics, clinical profiles and psychiatric comorbidities were examined. results: this study included 100 adults who fulfilled the standard diagnosis of adhd, with 54.0% (n = 54) and 46.0% (n = 46) from the inattentive and combined subtypes, respectively. it was found that adhd was more prevalent among males (64.0%) than females (36.0%), with the inattentive subtype being more predominant among females. the adhd patients with the inattentive subtype were associated with comorbid substance use disorders (odds ratio [or] = 11.29; p = 0.049), personality disorders (or = 7.96; p = 0.017) and major depressive disorder (or = 15.94; p = 0.002) compared to patients predominantly with the combined subtype. conclusion: this study echoes the findings from the current literature that adult patients with adhd commonly have comorbid psychiatric disorders, leading to significant functional impairment. psychiatric comorbidities must be identified and urgently treated for better clinical and functional outcomes in adult patients with adhd. keywords: neurodevelopmental disorder; attention deficit hyperactivity disorder; adult; comorbidity; psychiatry; oman. advances in knowledge this is the first report from oman and the gulf cooperation council region focusing on attention deficit hyperactivity disorder (adhd) among adults. this study compares the clinical characteristics of patients from the middle east to those from the west. furthermore, this study explores a new area of research and encourages further studies among similar cohorts. application to patient care as sultan qaboos university hospital is a new and adult-only adhd service in oman, this study raises awareness of this condition among patients and clinicians. further expansion of services, as a result of this study, have clearly indicated the complexity of the comorbidities presenting in those with adult adhd. https://creativecommons.org/licenses/by-nd/4.0/ hassan mirza, salim al-huseini, shamsa al-jamoodi, naser al-balushi, amira al-hosni, moon-fai chan and fahad zadjali clinical and basic research | 207 each of these subtypes is distinguished by a set of clinical symptoms in the diagnostic criteria. research has shown that 30–50% of those diagnosed with adhd in childhood continue to experience the core symptoms of the condition after the age of 18.4 in the usa, the prevalence of adult adhd is estimated to be more than 4%.5 moreover, males are generally more likely to be diagnosed with adhd than females, with a male-to-female ratio of approximately 3:1 in clinical samples and females predominantly presenting with the inattentive subtype.6 as with children with adhd, many adults with adhd are diagnosed with comorbid psychiatric disorders such as mood and anxiety disorders, personality disorders and substance use disorders (sud).7 many undiagnosed adhd cases in adults present when they come into contact with mental health services due to other psychiatric disorders and treating the comorbid condition requires treatment independent from that of adhd.8 the adult adhd clinic at the sultan qaboos university hospital (squh) began as a pilot project to cater to the needs of the adults with symptoms of adhd and help those using the service aimed at younger individuals’ transition to the adult adhd services.9 this study sought to address the current gap in the literature as no studies from oman, or its neighbouring countries, have compared the clinical characteristics of patients from the middle east to those from the west or examined the psychiatric comorbidities among adult adhd patients. examining potential associations is essential for diagnostic precision and accuracy and better clinical and functional outcomes. methods this retrospective cohort study included adult patients diagnosed with adhd in an outpatient clinic at sultan qaboos university hospital (squh), muscat, oman. this adult adhd clinic is the only adhd clinical service in the country. all patients between the ages of 18 and 60, who attended the clinic over a period of two years from january 2018 to april 2020, had a full psychiatric evaluation and fulfilled the diagnostic criteria of adult adhd based on the dsm-5 were included.10 this diagnosis requires the presence of a set of clinical symptoms for a specific period and an impact on social, academic or occupational function. the cohort of patients in this study was a mixture of those who were either diagnosed for the first time before the age of 18 but continued to experience symptoms into adulthood, or accessed the service for the first time after turning 18. similarly, some adults with adhd were parents or first-degree relatives of children with adhd who were never diagnosed due to a lack of awareness. patients who had comorbidities of intellectual disability, epilepsy and autism spectrum disorders were excluded from the study. the following variables were obtained from each patient: age, gender, marital status (single, married and divorced), educational level, occupation, history of substance misuse, family history of adhd, history of self-harm/suicidal attempt and forensic history. the psychiatric comorbidities were classified as bipolar affective disorder, schizophrenia, obsessivecompulsive disorder, major depressive disorder, anxiety disorder and personality disorder. the presenting symptoms were explored to determine the subtype of adhd: predominantly inattentive presentation, predominantly hyperactive-impulsive presentation or a combined presentation. descriptive statistics were used to explore the profiles of the patients with adhd, according to their demographic and clinical variables. first, a univariate comparison was carried out between the adhd subtypes (inattentive/hyperactive and impulsive versus combined), evaluated using a chi-squared test, fisher’s exact test and mann–whitey u test to reveal the association and differences between the demographic and clinical variables. following this, the bivariate (unadjusted) and multivariate (adjusted) regression analyses were used. in the regression model, the following significant variables were used in an attempt to identify the risk factors associated with adhd subtypes while adjusted by each other: gender, age of diagnosis, comorbid sud, personality disorders, major depressive disorder, anxiety disorder, sleep-wake disorders and history of self-harm/suicidal attempt. data were analysed using the statistical package for the social sciences (spss), version 23.0 (ibm spss inc., chicago, il, usa). the level of significance was set at p <0.05. ethics approval was granted by the college of medicine and health sciences at sultan qaboos university, muscat, oman (mrec 2260). the study was conducted as per the declaration of helsinki and the american psychological association with regards to ethical human research, including confidentiality, privacy and data management. results a total of 100 adult patients who had adhd were included in this study, of which 54 (54.0%) were classified as the inattentive subtype and 46 (46.0%) the combined subtype. of this sample, adhd was noted to be more prevalent among males (64.0%) than females socio-demographic and clinical profiles of adult attention deficit hyperactivity disorder patients in a university hospital in oman 208 | squ medical journal, may 2022, volume 22, issue 2 (36.0%) and the average age of patients was 22.6 ± 6.4 years. almost 80% (n = 79) of the adult patients with adhd had a school education; 21% had dropped out of school. the average age of adhd diagnosis was 13.8 ± 3.0 years. major depressive disorder was the most commonly associated comorbidity among the adhd patients (28.0%), followed by anxiety disorder (23.0%), personality disorders (18.0%), sleep-wake disorders (15.0%) and sud (10.0%). more than 50% (n = 52) of the study participants had family members with an adhd diagnosis. a small percentage of them had a history of self-harm/suicidal attempt (9.0%) and forensic records (6.0%). over half of the participants (62.0%) had been prescribed methylphenidate stimulant therapy and the remainder (38.0%) had received non-stimulant therapy [table 1]. the multivariate analysis indicated that some demographic and clinical characteristics demonstrated significant association with adult adhd, specifically for the inattentive subtype. the model had a good-fit according to the hosmer–lemeshow test (r2 = 1.934; p = 0.963), nagelkerke’s r2 was 0.676 and the overall predicting power (sensitivity = 0.852, specificity = 0.848) was 0.850. for adult patients with adhd, female participants were 14 times (or = 14.47; p <0.001) more likely to be diagnosed with the inattentive subtype than male patients. patients with the inattentive subtype were significantly associated with comorbid sud (or =11.29; p = 0.049), personality disorders (or = 7.96; p = 0.017) and major depressive disorder (or = 15.94; p = 0.002) compared to patients predominantly with the combined subtype [table 2]. discussion the current study evaluated the clinical subtypes of adult patients with adhd and their association with psychiatric comorbidities in oman, making it the first report from this region to highlight the clinical characteristics of adult patients with adhd. in this study, the majority of patients were male, with a maleto-female ratio of approximately 1.8:1; this is in line with the consensus that males are more likely to be diagnosed with adhd, with higher male-to-female ratios found among clinical than population-based samples.11 this ratio discrepancy tends to decrease with an increase in age.12,13 a study among children with adhd in oman reported a male-to-female ratio of 3.6:1, further supporting the aforementioned trend.14 evidence has shown that there is a gender variation regarding the subtypes of adhd, with females being diagnosed more often with the inattentive subtype, table 1: demographic and clinical characteristics of adult attention deficit hyperactivity disorder in oman (n = 100) characteristic n (%) gender female 36 (36.0) male 64 (64.0) marital status single 92 (92.0) married 8 (8.0) job unemployed 5 (5.0) employed 19 (19.0) student 76 (76.0) educational level school drop-out 21 (21.0) high school diploma 66 (66.0) higher education 13 (13.0) age in years median (range) 20.0 (18–47) mean ± sd 22.6 ± 6.4 age of diagnosis in years median (range) 13.0 (6–21) mean ± sd 13.8 ± 3.0 adhd subtype inattentive 54 (54.0) combined 46 (46.0) comorbidity substance use disorders 10 (10.0) psychosis 1 (1.0) bipolar affective disorder 3 (3.0) personality disorders 18 (18.0) major depressive disorder 28 (28.0) anxiety disorder 23 (23.0) obsessive-compulsive disorder 3 (3.0) sleep-wake disorders 15 (15.0) family history of adhd 52 (52.0) history of self-harm/suicidal attempt 9 (9.0) history of forensic record 6 (6.0) history of hospital admission 6 (6.0) name of prescribed medication methylphenidate 62 (62.0) atomoxetine 19 (19.0) other medication 19 (19.0) sd = standard deviation; adhd = attention deficit hyperactivity disorder. hassan mirza, salim al-huseini, shamsa al-jamoodi, naser al-balushi, amira al-hosni, moon-fai chan and fahad zadjali clinical and basic research | 209 table 2: analysis of attention deficit hyperactivity disorder subtypes and the association/difference of demographic and clinical measurements (n = 100) characteristic n (%) univariate* multivariate§ adhd subtype p value or p value inattentive (n = 54) combined (n = 46) gender female 30 (55.6) 6 (13.0) <0.001 14.47 <0.001 male (ref ) 24 (44.4) 40 (87.0) marital status single 51 (94.4) 41 (89.1) 0.465† married (ref ) 3 (5.6) 5 (10.9) job unemployed 4 (7.4) 1 (2.2) 0.375† employed 9 (16.7) 10 (21.7) 0.619 student (ref ) 41 (75.9) 35 (76.1) educational level below high school diploma 11 (20.4) 10 (21.7) 0.728† high school 35 (64.8) 31 (67.4) 0.762† higher education (ref ) 8 (14.8) 5 (10.9) age in years median (range) 21.5 (18–47) 19.0 (18–47) 0.548‡ age of diagnosis in years median (range) 13.0 (6–21) 14.0 (10–20) 0.006‡ 1.25 0.05 mean ± sd 13.0 ± 2.9 14.8 ± 2.9 presence of comorbidity substance use disorders 2 (3.7) 8 (17.4) 0.041† 11.29 0.049 psychosis 0 (0.0) 1 (2.2) 0.460† bipolar affective disorder 1 (1.9) 2 (4.3) 0.593† personality disorders 14 (25.9) 4 (8.7) 0.025 7.96 0.017 major depressive disorders 25 (46.3) 3 (6.5) <0.001 15.94 0.002 anxiety disorders 18 (33.3) 5 (10.9) 0.008 2.6 0.271 obsessive-compulsive disorders 1 (1.9) 2 (4.3) 0.593† sleep-wake disorders 13 (24.1) 2 (4.3) 0.006 6.28 0.1 family history of adhd 26 (48.1) 26 (56.5) 0.404 history of self-harm/suicidal attempt 1 (1.9) 8 (17.4) 0.011† 0.018 0.146 history of forensic record 2 (3.7) 4 (8.7) 0.410† history of admission in a psychiatric unit 4 (7.4) 2 (4.3) 0.684† name of prescribed medication methylphenidate 37 (68.5) 25 (54.3) 0.146 atomoxetine 7 (13.0) 12 (26.1) 0.095 adhd = attention deficit hyperactivity disorder; or = odds ratio; sd = standard deviation. *using chi-square test. †using fisher’s exact test. ‡using mann–whitney u test. §logistic regression (hosmer–lemeshow test: chi-square = 1.934; p = 0.963, nagelkerke’s r2 = 0.676; sensitivity = 0.852, specificity = 0.848, overall = 0.850). socio-demographic and clinical profiles of adult attention deficit hyperactivity disorder patients in a university hospital in oman 210 | squ medical journal, may 2022, volume 22, issue 2 whereas male patients are usually diagnosed with the hyperactive/impulsive or combined subtype.15 findings from the current study were consistent with the existing literature; of the 36 female patients diagnosed with adult adhd, 83.3% (n = 30) were diagnosed with the inattentive subtype (or = 14.47; p <0.001) and 16.7% (n = 6) the combined subtype. although male patients are commonly diagnosed with the combined or hyperactive/impulsive subtype of adhd during childhood, data derived from a longitudinal study indicated that the natural trajectory of the condition leads to a decline in hyperactivity symptoms over time, with inattention and impulsivity remaining significantly present.16 interestingly, in the current study, none of the patients were diagnosed with the predominantly hyperactive/impulsive subtype of adhd, in agreement with currently emerging evidence that this particular subtype of adhd is very rare among adults, raising doubts as to its validity.17 it is known that adhd impacts the educational and socioeconomic outcomes of those affected.18 in the current clinical sample, 21.0% did not complete their high school diploma, which supports existing literature from oman that dropping out of school is one of the negative ramifications of adhd.14 moreover, the presence of psychiatric comorbidity is the rule rather than the exception in patients with adhd, leading to greater clinical and functional impairment.19 during childhood, adhd is highly comorbid with oppositional defiant and conduct disorder, anxiety and mood disorders and specific learning disorder.20 it is estimated that 80% of adults with adhd have at least one comorbid psychiatric disorder. despite this, adhd remains underdiagnosed and undertreated in the adult population.21 comparably, the current study’s findings strongly suggest that adhd in adults is highly comorbid with other mental health disorders. in this study, 10.0% of the adult patients with adhd had sud; although its association was significant (or=11.29; p = 0.049), its prevalence was lower compared to the current literature, which can be explained by the modest sample size.22 personality disorders were reported in 18.0% of the participants in the current study (or = 7.96; p = 0.017) which is consistent with another study from this field.23 furthermore, depression is highly prevalent among adult adhd patients, with a prevalence of 16–31%, resulting in increased illness severity and functional impairment.24 the current study’s results confirm this as 28.0% of the patients were diagnosed with comorbid major depressive disorder (or = 15.94; p = 0.002). the study’s strength is that it examined all adult patients attending the only adhd clinical service in the country, the first study of its kind in the arabian gulf to explore the clinical profile of adult adhd and its associated psychiatric comorbidities. the limitations include the relatively small sample size and the chance that adults with milder symptoms of adhd who may not have accessed the tertiary hospital service might have been missed. in addition, due to the small sample size, the associated factors identified in the logistic analysis were not used to assess determinants. conclusion the main findings of this study showed that female patients were more likely to be diagnosed with the inattentive subtype of adhd compared to male patients. patients with the inattentive subtype of adhd were significantly found to have other comorbid mental health conditions, such as sud, personality disorders and major depressive disorder, compared to patients with predominantly the combined subtype. therefore, psychiatric comorbidities must be identified and treated vigilantly for better clinical and functional outcomes in adult patients with adhd. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n hm designed the study and drafted the manuscript. sah and saj collected the data, while sah and mfc analysed the data and interpreted the results. nab and fz critically reviewed the manuscript and aah revised it. all authors approved the final version of the manuscript. references 1. american psychiatric association. diagnostic and statistical manual of mental disorders. 5th ed. washington, d.c.: american psychiatric association, 2013. p. xliv, p. 947. https://doi.org/10.1 176/appi.books.9780890425596. 2. wender ph. attention-deficit hyperactivity disorder in adults. psychiatr clin north am 1998; 21:761–74. https://doi.org/10.10 16/s0193-953x(05)70039-3. 3. faraone sv, biederman j, mick e. the age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. psychol med 2006; 36:159–65. https://doi. org/10.1017/s003329170500471x. 4. ginsberg y, quintero j, anand e, casillas m, upadhyaya hp. underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: a review of the literature. prim care companion cns disord 2014; 16:pcc.13r01600. https://doi.org/10.4088/ pcc.13r01600. https://doi.org/10.1176/appi.books.9780890425596 https://doi.org/10.1176/appi.books.9780890425596 https://doi.org/10.1016/s0193-953x(05)70039-3 https://doi.org/10.1016/s0193-953x(05)70039-3 https://doi.org/10.1017/s003329170500471x https://doi.org/10.1017/s003329170500471x https://doi.org/10.4088/pcc.13r01600 https://doi.org/10.4088/pcc.13r01600 hassan mirza, salim al-huseini, shamsa al-jamoodi, naser al-balushi, amira al-hosni, moon-fai chan and fahad zadjali clinical and basic research | 211 5. kessler rc, adler l, barkley r, biederman j, conners ck, demler o, et al. the prevalence and correlates of adult adhd in the united states: results from the national comorbidity survey replication. am j psychiatry 2006; 163:716–23. https:// doi.org/10.1176/ajp.2006.163.4.716. 6. ramtekkar up, reiersen am, todorov aa, todd rd. sex and age differences in attention-deficit/hyperactivity disorder symptoms and diagnoses: implications for dsm-v and icd-11. j am acad child adolesc psychiatry 2010; 49:217–28.e1–3. https:// doi.org/10.1016/j.jaac.2009.11.011. 7. assessing adults with adhd and comorbidities. prim care companion j clin psychiatry 2009; 11:25. https://doi.org/10.40 88/pcc.7129bs4c. 8. torgersen t, gjervan b, rasmussen k. adhd in adults: a study of clinical characteristics, impairment and comorbidity. nord j psychiatry 2006; 60:38–43. https://doi.org/10.1080/0803948050 0520665. 9. mirza h. child and adolescent mental health services in oman. london j prim care (abingdon) 2018; 10:121–22. https://doi.or g/10.1080/17571472.2018.1482661. 10. dsm-5® diagnostic criteria for adult adhd. from www. qandadhd.com accessed: nov 2020. 11. slobodin o, davidovitch m. gender differences in objective and subjective measures of adhd among clinic-referred children. front hum neurosci 2019; 13:441. https://doi.org/10.3389/fnh um.2019.00441. 12. solberg bs, halmøy a, engeland a, igland j, haavik j, klungsøyr k. gender differences in psychiatric comorbidity: a populationbased study of 40 000 adults with attention deficit hyperactivity disorder. acta psychiatr scand 2018; 137:176–86. https://doi. org/10.1111/acps.12845. 13. huang cl, weng sf, ho ch. gender ratios of administrative prevalence and incidence of attention-deficit/hyperactivity disorder (adhd) across the lifespan: a nationwide populationbased study in taiwan. psychiatry res 2016; 244:382–7. https:// doi.org/10.1016/j.psychres.2016.08.023. 14. mirza h, roberts e, al-belushi m, al-salti h, al-hosni a, jeyaseelan l, et al. school dropout and associated factors among omani children with attention-deficit hyperactivity disorder: a cross-sectional study. j dev behav pediatr 2018; 39:109–15. https://doi.org/10.1097/dbp.0000000000000522. 15. biederman j, mick e, faraone sv, braaten e, doyle a, spencer t, et al. influence of gender on attention deficit hyperactivity dis order in children referred to a psychiatric clinic. am j psychiatry 2002; 159:36–42. https://doi.org/10.1176/appi.ajp.159.1.36. 16. wilens te, dodson w. a clinical perspective of attentiondeficit/hyperactivity disorder into adulthood. j clin psychiatry 2004; 65:1301–13. https://doi.org/10.4088/jcp.v65n1003. 17. gibbins c, weiss md, goodman dw, hodgkins ps, landgraf jm, faraone sv. adhd-hyperactive/impulsive subtype in adults. ment illn 2010; 2:e9. https://doi.org/10.4081/mi.2010.e9. 18. keilow m, wu c, obel c. cumulative social disadvantage and risk of attention deficit hyperactivity disorder: results from a nationwide cohort study. ssm popul health 2020; 10:100548. https://doi.org/10.1016/j.ssmph.2020.100548. 19. larson k, russ sa, kahn rs, halfon n. patterns of comorbidity, functioning, and service use for us children with adhd, 2007. pediatrics 2011; 127:462–70. https://doi.org/10.1542/peds.2010-0165. 20. bélanger sa, andrews d, gray c, korczak d. adhd in children and youth: part 1-etiology, diagnosis, and comorbidity. paediatr child health 2018; 23:447–53. https://doi.org/10.1093/pch/pxy109. 21. katzman ma, bilkey ts, chokka pr, fallu a, klassen lj. adult adhd and comorbid disorders: clinical implications of a dimen sional approach. bmc psychiatry 2017; 17:302. https://doi.org/10.1 186/s12888-017-1463-3. 22. van emmerik-van oortmerssen k, van de glind g, van den brink w, smit f, crunelle cl, swets m, et al. prevalence of attentiondeficit hyperactivity disorder in substance use disorder patients: a meta-analysis and meta-regression analysis. drug alcohol depend 2012; 122:11–19. https://doi.org/10.1016/j.drugalcdep.20 11.12.007. 23. matthies s, philipsen a. comorbidity of personality disorders and adult attention deficit hyperactivity disorder (adhd)-review of recent findings. curr psychiatry rep 2016; 18:33. https://doi.org/10.1007/s11920-016-0675-4. 24. knouse le, zvorsky i, safren sa. depression in adults with attention-deficit/hyperactivity disorder (adhd): the mediating role of cognitive-behavioral factors. cognit ther res 2013; 37:1220–32. https://doi.org/10.1007/s10608-013-9569-5. https://doi.org/10.1176/ajp.2006.163.4.716 https://doi.org/10.1176/ajp.2006.163.4.716 https://doi.org/10.1016/j.jaac.2009.11.011 https://doi.org/10.1016/j.jaac.2009.11.011 https://doi.org/10.4088/pcc.7129bs4c https://doi.org/10.4088/pcc.7129bs4c https://doi.org/10.1080/08039480500520665 https://doi.org/10.1080/08039480500520665 https://doi.org/10.1080/17571472.2018.1482661 https://doi.org/10.1080/17571472.2018.1482661 https://doi.org/10.3389/fnhum.2019.00441 https://doi.org/10.3389/fnhum.2019.00441 https://doi.org/10.1111/acps.12845 https://doi.org/10.1111/acps.12845 https://doi.org/10.1016/j.psychres.2016.08.023 https://doi.org/10.1016/j.psychres.2016.08.023 https://doi.org/10.1097/dbp.0000000000000522 https://doi.org/10.1176/appi.ajp.159.1.36 https://doi.org/10.4088/jcp.v65n1003 https://doi.org/10.4081/mi.2010.e9 https://doi.org/10.1016/j.ssmph.2020.100548 https://doi.org/10.1542/peds.2010-0165 https://doi.org/10.1093/pch/pxy109 https://doi.org/10.1186/s12888-017-1463-3 https://doi.org/10.1186/s12888-017-1463-3 https://doi.org/10.1016/j.drugalcdep.2011.12.007 https://doi.org/10.1016/j.drugalcdep.2011.12.007 https://doi.org/10.1007/s11920-016-0675-4 https://doi.org/10.1007/s10608-013-9569-5 تأثري األمراض املصاحبة على البقاء على قيد احلياة بني مرضى سرطان الدم النخاعي املزمن باستخدام معيار تشارلسون لالعتالل املشرتك دراسة استعادية من البصرة، العراق ون، �أ�صعد خلف، �إيالف �صالح ون ح�صُّ ر�فد َعبُّود، ح�صُّ abstract: objectives: in chronic diseases, comorbidities are known to have a strong negative association with overall survival (os). this study aimed to use the charlson comorbidity index (cci) to examine the effect of comorbidities on os among patients with chronic myeloid leukaemia (cml) treated with tyrosine kinase inhibitors. methods: this retrospective study was conducted between january 2006 and october 2016 and included 247 cml patients treated at the basra oncology & haematology centre, basra, iraq. information from hospital records was used to calculate cci scores and patients were divided into groups based on scores of 2–3 (cci1 group) or ≥4 (cci2 group). the os was calculated using kaplan-meier curves. results: there were 177 (71.7%) patients in the cci1 group and 70 (28.3%) in the cci2 group. overall, patients in the cci1 group were significantly younger compared to those in the cci2 group (median age: 35 versus 60 years; p <0.001); however, the gender distribution was similar in both groups (male-to-female ratio of 1:1.06 versus 1:1.18, respectively; p = 0.683). diabetes mellitus was the most common comorbidity (17%), followed by hypertension (12%) and gastrointestinal diseases (6%). there were no significant differences in mortality between the groups (9.6% versus 8.6%; p = 0.801). in total, 69.6% of all deaths were related to cml progression rather than to the presence of comorbidities. conclusion: no significant correlation was found between cci score and os among cml patients in basra. however, larger long-term prospective studies are needed to evaluate associations with median age at diagnosis and disease severity and to develop region-specific prognostic scales. keywords: comorbidity; chronic myeloid leukemia; mortality; survival analysis; chronic diseases; iraq. امللخ�ص: الهدف: من �ملعروف �أنه يف �الأمر��س �ملزمنة يكون لالأمر��س �مل�صاحبة �رتباط �صلبي قوي مع �لبقاء على قيد �حلياة ب�صكل عام. تهدف هذه �لدر��صة �إىل ��صتخد�م معيار ت�صارل�صون لالعتالل �مل�صرتك لفح�س تاأثري �الأمر��س �مل�صاحبة على �لبقاء على قيد �حلياة ب�صكل عام بني مر�صى �رصطان �لدم �لنخاعي �ملزمن �لذين عوجلو� مبثبطات �لتريوزين كيناز. الطريقة: �أجريت هذه �لدر��صة �ال�صتعادية بني يناير 2006 و�أكتوبر 2016 و�صملت 247 من مر�صى �رصطان �لدم �لنخاعي �ملزمن و�لذين عوجلو� يف مركز �لب�رصة لالأور�م و�أمر��س �لدم، تق�صيم ومت �مل�صرتك لالعتالل ت�صارل�صون معيار نقاط جمموع الحت�صاب �مل�صت�صفى �صجالت يف �ملعلومات ��صتخد�م مت �لعر�ق. �لب�رصة، �ملر�صى �إىل جمموعات على �أ�صا�س جمموع �لنقاط: 2-3 )�ملجموعة �الوىل( �أو 4≤ )�ملجموعة �لثانية(. ومت �حت�صاب معدل �لبقاء على قيد �ملجموعة يف )28.3%( 70 و �الأوىل �ملجموعة يف مري�صا )71.7%( 177 هناك كان ماير. النتائج: كابالن منحنيات با�صتخد�م �حلياة �لثانية. وب�صكل عام كان عمر مر�صى �ملجموعة �الأوىل �أ�صغر بكثري مقارنة مبر�صى �ملجموعة �لثانية )متو�صط �لعمر: 35 مقابل 60 �صنة على ،1:1.18 مقابل 1:1.06 من �الإناث �إىل �لذكور )ن�صبة �ملجموعتني كال يف مت�صابها �جلن�صني بني �لتوزيع كان بينما ،)p >0.001 ؛ �لتو�يل؛ p = 0.683(. كان د�ء �ل�صكري �العتالل �مل�صرتك �الأكرث �صيوًعا )%17(، يليه �رتفاع �صغط �لدم )%12( و�الأمر��س �مَلَعِدية �مَلَعِوية )%6(. مل تكن هناك فروقات ذ�ت داللة �إح�صائية يف معدل �لوفيات بني �ملجموعتني )%9.6 مقابل %8.6؛ p = 0.801(. ويف �ملجمل كان ما ن�صبته %69.6 من جميع �لوفيات مرتبطا بتطور �رصطان �لدم �لنخاعي �ملزمن ولي�س ب�صبب وجود �الأمر��س �مل�صاحبة. اخلال�صة: مل يتم �لعثور على عالقة ذ�ت داللة �إح�صائية بني جمموع نقاط معيار ت�صارل�صون لالعتالل �مل�صرتك و�لبقاء على قيد �حلياة بني مر�صى �رصطان �لدم �لنخاعي �ملزمن يف �لب�رصة. ومع ذلك هناك حاجة �إىل در��صات م�صتقبلية �أو�صع وطويلة �الجل لتقييم �رتباطات متو�صط �لعمر عند �لت�صخي�س مع �صدة �ملر�س وتطوير مقايي�س �لتنبوؤ �خلا�صة بكل منطقة. الكلمات املفتاحية: �العتالل �مل�صرتك؛ �رصطان �لدم �لنخاعي �ملزمن؛ وفيات؛ حتليل �لبقاء على قيد �حلياة؛ �الأمر��س �ملزمنة؛ �لعر�ق. impact of comorbidities on survival among patients with chronic myeloid leukaemia using the charlson comorbidity index retrospective study from basra, iraq *rafid a. abood,1,2 hasson m. hasson,2 asaad a. khalaf,3 elaf m. saleh2 sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e236–241, epub. 5 nov 19 submitted 14 dec 18 revision req. 9 jan 19; revision recd. 5 feb 19 accepted 28 feb 19 advances in knowledge the median age of patients with chronic myeloid leukaemia (cml) in basra, iraq, was lower compared to those reported in western countries. the majority of deaths were attributable to disease progression, rather than the presence of comorbidities. 1department of medicine, basra college of medicine, 2basra oncology & haematology centre, basra, iraq; 3department of public health, basra health directorate, basra, iraq *corresponding author’s e-mail: rafidalkhalidy79@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.010 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ rafid a. abood, hasson m. hasson, asaad a. khalaf and elaf m. saleh clinical and basic research | e237 larger prospective studies are needed to confirm the findings of the current study and to evaluate the potential role of comorbidity treatment on survival. such data may help in the development of region-specific prognostic scales. application to patient care there is no decrease in overall survival due to the presence of comorbidities among chronic myeloid leukaemia patients in basra, iraq, and patients may present at a younger age in comparison to those in western countries. worldwide, chronic myeloid leukaemia (cml) accounts for approximately 15% of all types of leukaemia in adults.1 although there is paucity of epidemiological data, the incidence of cml is usually considered similar across the globe.2,3 studies from north america and europe have reported an age-adjusted incidence of 0.6–2 and 0.7–1 per 100,000 individuals, respectively.3,4 however, in iraq, the age-standardised incidence of leukaemia has been reported as 3.9–4.3 per 100,000 individuals.5,6 the varying prevalence and mortality rates of cml may be due to differences in accessibility to treatment options; for example, the availability of tyrosine kinase inhibitors (tkis) has significantly decreased annual cml-related mortality rates to <2–3%.2,7 ironically, however, this decrease in mortality has increased the prevalence of cml worldwide.2,3,8 comorbidities are defined as distinct additional clinical conditions that either pre-exist or occur during the course of a primary disease.9 comorbidities have a strong negative association with overall survival (os) among patients with chronic diseases; for example, in cancer patients, comorbidities can affect the diagnosis, treatment and outcomes.10 comorbidities can also increase the cost of treatment and decrease the patient’s quality of life.11 the presence of comorbidities has been shown to influence os in chronic lymphocytic leukaemia (cll).10,12 similarly, comorbidities have also been reported to have a negative impact on os among cml patients; however, there is no effect on treatment success with tkis.13,14 the impact of comorbidities on disease outcomes can be measured by a well-established and validated 20-item risk-scoring tool, the charlson comorbidity index (cci).15,16 this tool is based on the principle that age and the presence and severity of comorbidities increase the likelihood of mortality among patients who receive treatment for chronic illnesses. scores for each item range from 1–6, with the maximum score given in the presence of a metastatic tumour or acquired immune deficiency syndrome; age is also considered a risk factor, with an additional point for each completed decade beyond 40 years.15 to the best of the authors’ knowledge, the use of prognostic scales such as the cci has not been adequately studied among cml patients in iraq and other middle eastern countries. this study aimed to evaluate the effect of comorbidities and age on os among patients with cml treated with imatinib or other tkis using the cci. methods this retrospective study was conducted between january 2006 and october 2016 at the basra oncology & haematology centre, basra, iraq. a total of 285 cml cases registered at the basra oncology & haematology centre during the study period were reviewed. only cml patients treated with tkis and who underwent regular follow-up were enrolled in the study (n = 247). patients who discontinued treatment for over three months continuously (including pregnant women) and those who did not have regular follow-up visits during the study period were excluded at the time of screening. the clinical and demographic information necess ary to calculate cci scores were extracted from the patients’ hospital records, including age, gender, date of diagnosis, duration of treatment, outcome and cause of death. the medical records also included a detailed patient history and results of a physical examination in addition to the initial cci score, an essential part of early assessment for every patient prior to receiving therapy. the overall cci scores were calculated acc ording to table 1.15 based on their scores, patients were divided into two groups; those with scores of 2–3 were assigned to the cci1 group, while patients with higher scores of ≥4 were allocated to the cci2 group. in cases where patients had a history of past ill nesses that fell within the cci parameters (i.e. aortic aneurysms of ≥6 cm, dementia, chronic pulmonary disease or peptic ulcer disease), the previous diagnosis and management of the illness was reviewed with relevant specialists, if necessary. in order to evaluate the molecular response to tki treatment, patients under went regular breakpoint cluster region-abelson murine leukaemia screening every six months using the genexpert® assay (cepheid inc., sunnyvale, california, usa). in order to avoid bias, the analyst was blinded to the patient details. the statistical analysis was conducted using epi info™ software, version 3.3 (centers for disease control and prevention, atlanta, georgia, usa). the impact of comorbidities on survival among patients with chronic myeloid leukaemia using the charlson comorbidity index retrospective study from basra, iraq e238 | squ medical journal, august 2019, volume 19, issue 3 cause of death was evaluated and recorded individually for each patient while the mortality rate was calculated for the overall study population. for the purposes of the study, os was defined as the time between diagnosis and death, irrespective of the administration of tkis. the os probabilities were calculated using kaplanmeier curves. a p value of <0.05 was considered stat istically significant. this study was reviewed and approved by the medicine ethical committee of basra college of med icine, basra, iraq (#569). all procedures and protocols involved in this study were conducted in accordance with the principles of the revised declaration of helsinki. results a total of 285 cml cases were registered at the basra oncology & haematology centre during the study period; of these, 247 (86.7%) patients treated with tkis and followed-up regularly were included in the analysis. the median age of these patients was 43.5 years (range: 5–102 years old) and the male-to-female ratio was 1:1.09 [table 2]. based on their cci scores, 177 (71.7%) patients were allocated to the cci1 group (i.e. those with lower cci scores) and 70 (28.3%) to the cci2 group (i.e. those with higher cci scores). patients in the cci1 group were considerably younger than those in the cci2 group (median age: 35 versus 60 years; p <0.001). however, the gender distribution was similar in both groups (male-to-female ratio of 1:1.06 versus 1:1.18; p = 0.683) [table 3]. the median duration of follow-up was 50 months (range: 2–198 months). the most common comorb idity was diabetes mellitus (17%), followed by hyper tension (12%) and gastrointestinal disorders (6%). the least common comorbidities were hepatitis, neurological disorders and other cancers (1% each) [figure 1]. almost all (94%) of the patients were initially pres cribed 400 mg of imatinib; however, 88 (38%) of which were later switched to 800 mg of nilotinib. in contrast, table 1: weighted scores for each item of the 20-item charlson comorbidity index15 item weighting 1. age score of 1 for every decade over 40 years of age 2. history of myocardial infarct (not ecg changes alone) score of 1 per item 3. congestive heart failure 4. peripheral vascular disease including aortic aneurysms of ≥6 cm 5. cerebrovascular disease (i.e. accident with mild or no residual impact or a transient ischaemic attack) 6. dementia 7. chronic pulmonary disease 8. connective tissue disease 9. peptic ulcer disease 10. mild liver disease without portal hypertension and including chronic hepatitis 11. diabetes without end-organ damage (excluded in patients on dietary control alone) 12. haemiplegia score of 2 per item 13. moderate or severe renal disease 14. diabetes with end-organ damage (i.e. retinopathy, neuropathy, nephropathy or brittle diabetes) 15. tumour without metastasis (excluded if >5 years since diagnosis) 16. leukaemia (acute or chronic) 17. lymphoma 18. moderate or severe liver disease score of 3 19. metastatic tumour score of 6 per item20. acquired immune deficiency syndrome ecg = electrocardiography. table 2: age and gender distribution of patients with chronic myeloid leukaemia in basra, iraq (n = 247) age in years n (%) cumulative percentage male (n = 118) female (n = 129) total <10 2 (1.7) 2 (1.6) 4 (1.6) 1.6 10–19 8 (6.8) 6 (4.7) 14 (5.7) 7.3 20–29 18 (15.3) 15 (11.6) 33 (13.4) 20.6 30–39 24 (20.3) 29 (22.5) 53 (21.5) 42.1 40–49 20 (16.9) 25 (19.4) 45 (18.2) 60.3 50–59 29 (24.6) 27 (20.9) 56 (22.7) 83 ≥60 17 (14.4) 25 (19.4) 42 (17) 100 table 3: age and gender distribution according to comorb idity groups of patients with chronic myeloid leukaemia in basra, iraq (n = 247) characteristic total group* p value cci1 (n = 177) cci2 (n = 70) median age in years (range) 43.5 (5–102) 35 (5–59) 60 (37–102) <0.001 male-to-female ratio 1:1.09 1:1.06 1:1.18 0.683 cci = charlson comorbidity index. *as assessed using the charlson comorbidity index, with patients receiving scores of 2–3 or ≥4 assigned to the cci1 and cci2 groups, respectively.15 rafid a. abood, hasson m. hasson, asaad a. khalaf and elaf m. saleh clinical and basic research | e239 15 patients who were initially administered nilotinib continued taking it throughout the study period. overall, 55.7% of patients responded to treatment; however, 14.9% had suboptimal results and 29.4% failed to respond at all. a total of 23 patients died during the study period, resulting in a mortality rate of 9.3%. the median age of those who died was 44 years, while the median age of those who survived was 43 years. mortality rates were similar for patients of both genders and across both cci1 and cci2 groups [table 4]. there was no significant difference in mortality according to the cci score (9.6% versus 8.6%; p = 0.801). of the 23 deaths, analysis showed that 69.6% were related to cml progression, rather than comorbidity burden. the remaining 30.4% of deaths were due to ischaemic heart disease (8.7%), other cancers (8.7%; including one case each of transitional cell carcinoma of the bladder and laryngeal cancer), renal failure (4.3%), a cerebrovascular-related accident (4.3%) and a war injury (4.3%). figure 2 shows the kaplan-meier cumulative survival curve for the two groups across the follow-up period. discussion the cci tool assesses the presence and severity of various comorbidities as parameters in the prognostic analysis of chronic diseases and has been utilised successfully among patients with a variety of illnesses, including cml, cll and myelodysplastic syndrome.10,12,13,15 among cml patients, clinical studies have utilised the cci to evaluate the effect of comorb idities on os, event-free survival, remission rates, progression of the disease to accelerated phase or blast crisis, onset of complications, compliance to treatment and all-cause or cancer-specific mortality rates.13,14,17–21 in cml, most previous studies have evaluated the association between cci and survival outcomes in patients being treated with imatinib; however, breccia et al. reported its use among those treated with other tkis (i.e. dasatinib).13,14,17–21 figure 1: frequency of comorbidities among patients with chronic myeloid leukaemia in basra, iraq (n = 247). table 4: mortality rate according to comorbidity groups among patients with chronic myeloid leukaemia in basra, iraq (n = 247) group* n (%) dead alive total male female total male female cci1 (n = 177) 17 (9.6) 9 (5.1) 8 (4.5) 160 (90.4) 77 (43.5) 83 (46.9) cci2 (n = 70) 6 (8.6) 3 (4.3) 3 (4.3) 64 (91.4) 29 (41.4) 35 (50) total 23 (9.3) 12 (4.9) 11 (4.5) 224 (90.7) 106 (42.9) 118 (47.8) cci = charlson comorbidity index. *as assessed using the charlson comorbidity index, with patients receiving scores of 2–3 or ≥4 assigned to the cci1 and cci2 groups, respectively.15 figure 2: kaplan-meier survival curve showing cumulative survival according to comorbidity groups* among patients with chronic myeloid leukaemia in basra, iraq (n = 247). cci = charlson comorbidity index. *as assessed using the charlson comorbidity index, with patients receiving scores of 2–3 or ≥4 assigned to the cci1 and cci2 groups, respectively.15 impact of comorbidities on survival among patients with chronic myeloid leukaemia using the charlson comorbidity index retrospective study from basra, iraq e240 | squ medical journal, august 2019, volume 19, issue 3 as the availability of tkis has markedly decreased mortality rates among cml patients, appropriate information regarding risk factors or poor prognostic markers can help in the individualisation of therapy.7 as such, findings from the present study may be helpful as a basis for the development of a modified risk assessment system for patients with cml in iraq. use of an appropriate prognostic scale can help in the appropriate selection of tkis, proper monitoring during treatment and assessment of survival outcomes and treatment response among affected patients.7 in the present study, the median age of cml patients at the time of diagnosis was 43.5 years; this is younger in comparison to patients reported in western populations.13,14,17 similar findings have been reported in other iraqi epidemiological studies; however, unlike the current study, these previous reports described cml as being more common among males than females.22,23 as the median age of the patient population was younger in the present study, cci scoring was ageadjusted for assessment purposes. as with previous studies from other countries, diabetes was found to be the most common comorbidity reported among cml patients in the current study.13,14,17,20 previous research suggests that higher cci scores are significantly associated with lower os probabilities, with inverse associations noted between cci scores and os among chronic phase cml patients in japan, italy and germany.13,14,19 saussele et al. observed that higher cci scores were significantly associated with lower os probabilities (p <0.001), even after excluding age from the cci calculation.13 the presence of comorbidities at the time of diagnosis has also been associated with poor survival outcomes among cml patients being treated with tkis, with comorbidities having more impact on survival than the disease itself.12 similarly, imataki et al. documented a significant logrank association between comorbidity at diagnosis and survival among cml patients on tki treatment (p = 0.0136).20 breccia et al. also reported that comor bidities had a similar impact on median os and noncml-related deaths.19 in contrast, the present retrospective analysis did not reveal a significant difference in mortality rates among cml patients according to cci scores. instead, the study found that 69.6% of deaths in the patient population were due to cml and not the presence or severity of comorbidities. this was in contrast to the findings of saussele et al. and uemura et al., who reported that mortality among cml patients was more dependent on comorbidities than cml.13,14 this difference in findings may be because of the more aggressive behaviour of cml among the iraqi people. as such, mutational studies are recommended for iraqi patients with primary and secondary failure to investigate the nature of cml in this population. other prognostic scales available for use among cml patients include the sokal index, hasford risk score, karnofsky performance scale index (kpsi) and the european treatment and outcome study (eutos) score.24–26 it is likely that varying results regarding os in cml patients reported by different studies is due to the selection of disparate prognostic markers and scoring systems, thereby highlighting the need for a uniform prognostic scoring system for cml patients. of the cci, eutos and kpsi scales, saussele et al. found that cci was the most powerful predictor for os in german patients with cml.13 similarly, the authors of the current study plan to compare the aforementioned prognostic scores among cml patients being treated with tkis at the basra oncology & haematology centre. additionally, further research evaluating the application of the cci tool among older patients is necessary. the limitations of the current study include its retrospective design, the limited sample size and the lack of availability of data regarding management of the comorbidities identified in the study population. although there was no correlation between cci and os, further analysis using a larger dataset is needed to generate stronger evidence for this finding. additionally, future studies should investigate the correlation between age at disease onset and patient outcome. conclusion the median age of cml patients in basra was lower than epidemiological data reported from other countries. moreover, the cci score was not significantly assoc iated with os; for the majority of patients, disease progression due to cml itself was the cause of death, rather than the presence or severity of comorbidities. further research into the development of more accurate region-specific prognostic scoring systems to evaluate risk-based outcomes among cml patients would facili tate individualised treatment for this population. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. djouadi k, abdennebi n, harieche f, nacer ra, hamladji rm, bouchakour a, et al. epidemiological approach of chronic myeloid leukemia: algerian-tunisian study. blood 2016; 128:5440. rafid a. abood, hasson m. hasson, asaad a. khalaf and elaf m. saleh clinical and basic research | e241 2. world health organization. chronic myelogenous leukemia: union for international cancer control 2014 review of cancer medicines on the who list of essential medicines. from: www.who.int/selection_medicines/committees/expert/20/ applications/cml.pdf accessed: feb 2019. 3. höglund m, sandin f, simonsson b. epidemiology of chronic myeloid leukaemia: an update. ann hematol 2015; 94:s241–7. https://doi.org/10.1007/s00277-015-2314-2. 4. rohrbacher m, hasford j. epidemiology of chronic myeloid leuk aemia (cml). best pract res clin haematol 2009; 22:295–302. https://doi.org/10.1016/j.beha.2009.07.007. 5. hussain ra, habib os. incidence of cancer in basrah: results of a household survey. asian pac j cancer prev 2015; 16:163–7. https://doi.org/10.7314/apjcp.2015.16.1.163. 6. habib os, khalaf aaa, hasan jg, alrudainy la, hasson hm, salih hm, et al. pattern of leukaemia in basrah. ann coll med mosul 2013; 39:154–9. https://doi.org/10.33899/mmed.2 013.81277. 7. huang x, cortes j, kantarjian h. estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. cancer 2012; 118:3123–7. https://doi.org/10.1002/cncr.26679. 8. cortes je, silver rt, khoury hj, kantarjian hm. chronic mye loid leukemia. from: www.cancernetwork.com/chronic-mye loid-leukemia/chronic-myeloid-leukemia accessed: feb 2019. 9. feinstein ar. the pre-therapeutic classification of co-morbidity in chronic disease. j chronic dis 1970; 23:455–68. https://doi. org/10.1016/0021-9681(70)90054-8. 10. goede v, cramer p, busch r, bergmann m, stauch m, hopfinger g, et al. interactions between comorbidity and treat ment of chronic lymphocytic leukemia: results of german chronic lymphocytic leukemia study group trials. haematologica 2014; 99:1095–100. https://doi.org/10.3324/haematol.2013.096792. 11. sarfati d, koczwara b, jackson c. the impact of comorbidity on cancer and its treatment. ca cancer j clin 2016; 66:337–50. https://doi.org/10.3322/caac.21342. 12. wang r, gross cp, halene s, ma x. comorbidities and survival in a large cohort of patients with newly diagnosed myelodysplastic syndromes. leuk res 2009; 33:1594–8. https://doi.org/10.1016/ j.leukres.2009.02.005. 13. saussele s, krauss mp, hehlmann r, lauseker m, proetel u, kalmanti l, et al. impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized cml study iv. blood 2015; 126:42–9. https://doi. org/10.1182/blood-2015-01-617993. 14. uemura m, imataki o, kawachi y, kawakami k, hoshijima y, matsuoka a, et al. charlson comorbidity index predicts poor outcome in cml patients treated with tyrosine kinase inhibitor. int j hematol 2016; 104:621–7. https://doi.org/10.1007/s12185016-2074-3. 15. charlson m, szatrowski tp, peterson j, gold j. validation of a combined comorbidity index. j clin epidemiol 1994; 47:1245–51. https://doi.org/10.1016/0895-4356(94)90129-5. 16. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chronic dis 1987; 40:373–83. https://doi.org/10.1016/0021-9681(87)90171-8. 17. breccia m, molica m, colafigli g, zacheo i, latagliata r, tafuri a, et al. correlation between charlson comorbidity index and outcome in patients with chronic phase chronic myeloid leuk emia treated with second-generation tyrosine kinase inhibitors upfront. leuk lymphoma 2015; 56:2206–7. https://doi.org/10.3 109/10428194.2014.993391. 18. breccia m, latagliata r, stagno f, luciano l, gozzini a, castagnetti f, et al. charlson comorbidity index and adult comorbidity evaluation-27 scores might predict treatment com pliance and development of pleural effusions in elderly patients with chronic myeloid leukemia treated with second-line dasatinib. haematologica 2011; 96:1457–61. https://doi.org/10.3324/haem atol.2011.041251. 19. breccia m, luciano l, latagliata r, castagnetti f, ferrero d, cavazzini f, et al. age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival. leuk res 2014; 38:1173–6. https://doi. org/10.1016/j.leukres.2014.06.020. 20. imataki o, uchida s, oku m, yokokura s, uemura m, kadowaki n. the charlson comorbidity index predicts survival following tyrosine kinase inhibitor treatment in chronic myeloid leukemia patients. blood 2015; 126:5146. 21. iurlo a, ubertis a, artuso s, bucelli c, radice t, zappa m, et al. comorbidities and polypharmacy impact on complete cytogenetic response in chronic myeloid leukaemia elderly patients. eur j intern med 2014; 25:63–6. https://doi.org/10.1 016/j.ejim.2013.11.002. 22. hasan km. evaluation of chronic myeloid leukemia patients and their molecular responses to tyrosine kinase inhibitors in erbil city, iraq. iraqi j hematol 2018; 7:1–7. https://doi. org/10.4103/ijh.ijh_28_17. 23. alameri a, al-khudhair m, batool g, al-mudhafer a, murad n. epidemiology of chronic myeloid leukemia in iraqi patients. in: 14th congress of the european hematology association, berlin, germany, june 4–7, 2009. haematologica 2009; 94:s578. 24. sokal je, cox eb, baccarani m, tura s, gomez ga, robertson je, et al. prognostic discrimination in “good-risk” chronic granu locytic leukemia. blood 1984; 63:789–99. 25. hasford j, pfirrmann m, hehlmann r, allan nc, baccarani m, kluin-nelemans jc, et al. a new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa: writing committee for the collaborative cml prognostic factors project group. j natl cancer inst 1998; 90:850–8. https://doi.org/10.1093/jnci/90.11.850. 26. hasford j, baccarani m, hoffmann v, guilhot j, saussele s, rosti g, et al. predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with cml on imatinib treatment: the eutos score. blood 2011; 118:686–92. https://doi.org/10.1182/blood-2010-12-319038. https://doi.org/10.1007/s00277-015-2314-2 https://doi.org/10.1016/j.beha.2009.07.007 https://doi.org/10.7314/apjcp.2015.16.1.163 https://doi.org/10.33899/mmed.2013.81277 https://doi.org/10.33899/mmed.2013.81277 https://doi.org/10.1002/cncr.26679 https://doi.org/10.1016/0021-9681%2870%2990054-8 https://doi.org/10.1016/0021-9681%2870%2990054-8 https://doi.org/10.3324/haematol.2013.096792 https://doi.org/10.3322/caac.21342 https://doi.org/10.1016/j.leukres.2009.02.005 https://doi.org/10.1016/j.leukres.2009.02.005 https://doi.org/10.1182/blood-2015-01-617993 https://doi.org/10.1182/blood-2015-01-617993 https://doi.org/10.1007/s12185-016-2074-3 https://doi.org/10.1007/s12185-016-2074-3 https://doi.org/10.1016/0895-4356%2894%2990129-5 https://doi.org/10.1016/0021-9681%2887%2990171-8 https://doi.org/10.3109/10428194.2014.993391 https://doi.org/10.3109/10428194.2014.993391 https://doi.org/10.3324/haematol.2011.041251 https://doi.org/10.3324/haematol.2011.041251 https://doi.org/10.1016/j.leukres.2014.06.020 https://doi.org/10.1016/j.leukres.2014.06.020 https://doi.org/10.1016/j.ejim.2013.11.002 https://doi.org/10.1016/j.ejim.2013.11.002 https://doi.org/10.4103/ijh.ijh_28_17 https://doi.org/10.4103/ijh.ijh_28_17 https://doi.org/10.1093/jnci/90.11.850 https://doi.org/10.1182/blood-2010-12-319038 departments of 1obstetrics & gynaecology and 2radiology, sohar hospital, ministry of health, sohar, oman *corresponding author’s e-mail: 1shashikiran@gmail.com abstract: paraovarian cysts constitute about 10% of all adnexal masses in females and occur most commonly in the third and fourth decades of life. these cysts are benign and usually uncommon in adolescence. such cysts pose a diagnostic challenge while distinguishing them from ovarian cysts clinically and during radiological investigations. we report a rare case of a 13-year-old female patient with bilateral paraovarian cysts, including a giant cyst in right mesosalpinx presenting to sohar hospital, oman in 2018. the definitive origin of the huge mass on the right side of abdominal cavity could not be established in the current case despite contrast enhanced computerized tomography. it was only on laparoscopic exploration that this mass was identified as a giant paraovarian cyst. both the giant cyst and a smaller paraovarian cyst on the left side were enucleated with minimally invasive surgery while preserving the fertility of the patient. only one other similar case of bilateral paraovarian cysts in an adolescent, including a giant cyst managed with laparoscopy, has been documented previously. keywords: adolescent; parovarian cyst; laparoscopy; ultrasonography; minimally invasive surgical procedures; case report; oman. non-tender huge abdominal mass in an adolescent bilateral paraovarian cysts *shashi kiran,1 shiekha s. jabri,1 yasser a. razek,2 meka n. devi1 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e308–311, epub. 21 jun 21 submitted19 may 20 revisions req. 22 jul 20 & 6 sep 20; revisions recd. 26 aug 20 & 6 sep 20 accepted 22 sep 20 again. the patient had been experiencing irregular menstruation since attaining menarche one year earlier. an extremely large, non-tender mass arising from the pelvis and reaching just above the umbilicus was discovered during per abdominal examination. ultrasonography of the abdomen revealed a right ovarian cyst with a small area of hyperechogenicity and no probe tenderness. contrast enhanced computerized tomography (cect) showed a large pelvic-abdominal, nonenhancing cystic lesion, measuring 11 × 20 × 23 cm (anteroposterior × transverse × craniocaudal) in size, displacing the surrounding viscera [figure 1]; additionally, a rim of free fluid, likely representing a right adnexal cyst, was noted. a cyst of similar density measuring 3.5 × 3.3 × 4.3 cm in size was observed on the left side. examinations of the uterus and other viscera were unremarkable. the levels of lactate dehydrogenase, alpha-fetoprotein, beta-human chorionic gonadotropin, thyroid function tests and cancer antigen 125, along with routine laboratory workup, were all within normal limits. the patient’s haemoglobin was 11 g/dl. the patient underwent laparoscopic exploration under general anaesthesia. after a veress needle introduced through palmer’s point was deemed unsatisfactory, a 10 mm primary trocar was inserted in the supraumbilical area (hasson’s technique) following which two accessory ports, each measuring 5 mm, were created in the left and right iliac fossae. a giant paraovarian cyst extending to a part of the ovary was visualised in the field on the right side. [figure 2]. paraovarian cysts represent about 10% of all adnexal masses in women and occur, most commonly, in third and fourth decades of life.1 they usually arise from the mesothelium covering the peritoneum.2 they can also emerge from the paramesonephric tissue. but in rare cases they can develop from the mesonephric remnants.2 these cysts are usually benign and giant paraovarian cysts are extremely uncommon during adolescence.3,4 they are often difficult to clinically distinguish from ovarian masses, appearing similar to ovarian cysts even using ultrasonography.5 traditionally, these cysts have been labelled as being ‘large’ when they are more than five cm and ‘giant’ when they are over 15 cm in diameter.6 contrast enhanced computerized tomography (cect) established this mass as a huge adnexal cyst. since the origin of this mass could not be decided, laparoscopy was performed to determine the origins of the cyst and treat it simultaneously. very few cases of bilateral paraovarian cysts of this size have been documented among adolescents.5,7,8 we report a case of bilateral paraovarian cysts in an adolescent, in whom one cyst qualified as a giant cyst that was treated using laparoscopy. case report a 13-year-old female patient presented to the gynaecology clinic at sohar hospital, oman in 2018 with persistent vaginal bleeding for almost one month. the bleeding would pause for five days only to resume this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.022 case report https://creativecommons.org/licenses/by-nd/4.0/ case report | e309 tube. the specimen was removed using a laparoscopic tissue retrieval bag. the right ovary was reconstructed using absorbable knotless barbed antibacterial (polydioxanone) sutures. a paraovarian cyst measuring 3–4 cm in size was visible on the left fallopian tube. this cyst was also peeled off and haemostasis was ensured. pelvic irrigation was performed with normal saline. all ports were removed under direct vision and gas was deflated from the supraumbilical port. about 200 ml of blood was lost during the whole procedure. polyglactin number 0 was used to close the fascia and suture number 3–0 of the same material was used for closure of other ports. the intra-operative and postoperative courses were uneventful and the patient was discharged on the third day following surgery. at the time of writing, the patient was doing well and her menstrual irregularity had resolved after treatment with oral mefenamic acid. histopathology of the specimen obtained from the giant cyst [figure 3] and the smaller cyst from left side established the diagnosis of paraovarian cysts consistent with benign serous cystadenoma. there were no solid components found in either of the specimens. the patient’s parent provided consent for publication of this case report. discussion giant paraovarian cysts are extremely uncommon in adolescents.4 they are usually benign and rarely malignant.8 radiological tools are crucial in identifying and locating cystic growths and their extensions. although magnetic resonance imaging (mri) is the investigative technique of choice in delineating the extent and margins of a cyst, due to non-availability, cect findings were relied on.9 nevertheless, ovarian cysts may still be indistinguishable from paraovarian cysts.10 surgical exploration is the ultimate solution for diagnosis and management. it is well-known that laparotomy facilitates direct visual inspection and the cyst wall was punctured using a trocar and about three litres of clear fluid was aspirated. the giant cyst was visibly found to be emerging from paraovarian structures on the right side adjacent to the ipsilateral ovary. the ampullary and fimbrial ends of the fallopian tube were not visible. a linear incision was made on the cyst wall and the cyst was completely peeled off from its bed paying close attention to the fallopian figure 1: a contrast enhanced computerised tomography scan showing (a) a transverse view (measuring 20 cm) and (b) a craniocaudal view (measuring 23 cm) of the cystic lesion (arrows) in the abdomen of a 13-year-old female patient. figure 2: intraoperative views showing a giant paraovarian cyst extending to a part of the ovary in a 13-year-old female patient. (a) the arrowhead points to the aspirated giant paraovarian cyst and the arrow points to the right fallopian tube. (b) the arrowhead points to the left ovary, the white arrow points to the right fallopian tube with ovary underneath and the black arrow points to the collapsed giant ovarian cyst. figure 3: histopathology of a specimen obtained from the giant paraovarian cyst on the right side of the ovary at 100x magnification consistent with a diagnosis of a benign serous cystadenoma. shashi kiran, shiekha s jabri, yasser a razek and meka n. devi is preferable for large tumours/cysts. nevertheless, it was decided to proceed with a minimally invasive procedure (i.e. laparoscopy), while complete preparation for a laparotomy was ensured in case the largeness of the cyst posed a difficulty during the procedure. during laparoscopic cystectomy, cysts are decompressed following which the shrunken specimen is removed.11 while there is a potential risk of fluid spillage, careful handling renders this risk negligible. conservative ovarian surgery including enucleation of the cyst and preservation of the ovary and fallopian tubes is the standard treatment to preserve fertility in these adolescents.8 laparoscopy through palmer’s point was undertaken for the current patient. as this attempt failed, hasson’s technique was resorted to and successful removal of both cysts was ensured with minimal bleeding and preservation of the ovaries and fallopian tubes. parovarian cysts are known to be usually asymptomatic.8 however, pressure effects from giant cysts may affect neighbouring organs and lead to pain or torsion, perforation and even haemorrhage.12 while giant paraovarian cysts in adolescents are a rare occurrence, bilateral paraovarian cysts in this age group are even rarer. they are reported more often in adults.12–14 the current case presented with bilateral paraovarian cysts, one of them fitting the definition of a giant cyst. an initial presenting symptom was excessive vaginal bleeding which could have been due to an immature hypothalamo-pituitary-ovarian axis since no uterine or endocrinological cause could be identified. although giant cysts are almost always benign, diligent diagnostic work-up, including imaging and tumour markers is desirable to rule out malignancy.8 normal levels of tumour markers and histopathology ruled out malignancy in this case. laparoscopic removal of giant unilateral parovarian cysts in adolescents is well documented.9,15,16 although bilateral parovarian cysts in adolescents have been reported to be treated with laparoscopy, these cysts were relatively small.7 more recently, a report of a giant paratubal cyst in a teenager managed with laparotomy was published.17 however, only one report has documented a case of bilateral parovarian cysts treated with laparoscopic enucleation of a giant parovarian cyst in the adolescent age group with a size comparable to the current patient.4 to the best of the author’s knowledge, this is the second reported case of bilateral paraovarian cysts in an adolescent including a giant cyst that was managed with laparoscopy. conclusion giant paraovarian cysts are an uncommon occurrence during adolescence. we report a rare case of an adolescent with bilateral paraovarian cysts, one of them fitting the description of a giant cyst. the patient was managed with a fertility-sparing, minimally invasive surgery. despite radiological investigations, there was a dilemma in arriving at a preoperative diagnosis. the extent and margins of the giant cyst could only be delineated during laparoscopic exploration. successful overcoming of the challenges of preserving fertility and post-surgical cosmetic appearance prompted the documentation of this case. references 1. macarthur m, mahomed aa. laparoscopy in the diagnosis and management of a complicated paraovarian cyst. surg endosc 2003; 17:1676–7. https://doi.org/10.1007/s00464-003-4211-3. 2. athey pa, cooper nb. sonographic features of paraovarian cysts. am j roentgenol 1985; 144:83–6. https://doi.org/10.2214/ ajr.144.1.83. 3. savelli l, ghi t, de iaco p, ceccaroni m, venturoli s, cacciatore b. paraovarian/paratubal cysts: comparison of transvaginal sonographic and pathological findings to establish diagnostic criteria. ultrasound obstet gynecol 2006; 28:330–4. https://doi.org/10.10 02/uog.2829. 4. zvizdic z, bukvic m, murtezic s, skenderi f, vranic s. giant paratubal serous cystadenoma in an adolescent female: case report and literature review. j pediatr adolesc gynecol 2020; 33:438–40. https://doi.org/10.1016/j.jpag.2020.03.010. 5. alpern mb, sandler ma, madrazo bl. sonographic features of parovarian cysts and their complications. am j roentgenol 1984; 143:157–60. https://doi.org/10.2214/ajr.143.1.157. 6. dolan ms, boulanger sc, salameh jr. laparoscopic management of giant ovarian cyst. jsls 2006; 10:254–6. 7. upadhyaya m, cusick e. bilateral inflamed paratubal cysts. j surg case rep 2012; 2012:12. https://doi.org/10.1093/jscr/20 12.9.12. 8. erikci vs, payza d, hoşgör m. giant parovarıan cyst: a case report. j surg open access 2015; 1. https://doi.org/10.16966/24 70-0991.103. 9. leanza v, coco l, genovese f, pafumi c, ciotta l, leanza g, et al. laparoscopic removal of a giant paratubal cyst complicated by hydronephrosis. g chir 2013; 34:323–5. 10. durairaj a, gandhiraman k. complications and management of paraovarian cyst: a retrospective analysis. j obstet gynaecol india 2019; 69:180–4. https://doi.org/10.1007/s13224-018-1152-2. 11. eltabbakh g. laparoscopic surgery for large ovarian cystsreview trends. gynecol oncol 2016; 2:109. 12. sima mukopdhyay. giant paraovarian cyst. j obstet gynecol india 2006; 56:352–3. 13. rijal p, pokharel h, chhetri s, pradhan t, agrawal a. bilateral huge fimbrial cysts with torsion of right fallopian tube. health renaissance 2012; 10:153–4. https://doi.org/10.3126/hren. v10i2.6588. e310 | squ medical journal, m ay 2021, volume 21, issue 2 non-tender huge abdominal mass in an adolescent bilateral paraovarian cysts https://doi.org/10.1007/s00464-003-4211-3 https://doi.org/10.2214/ajr.144.1.83 https://doi.org/10.2214/ajr.144.1.83 v v https://doi.org/10.1016/j.jpag.2020.03.010. https://doi.org/10.2214/ajr.143.1.157 https://doi.org/10.1093/jscr/2012.9.12 https://doi.org/10.1093/jscr/2012.9.12 https://doi.org/10.16966/2470-0991.103 https://doi.org/10.16966/2470-0991.103 https://doi.org/10.1007/s13224-018-1152-2 https://doi.org/10.3126/hren.v10i2.6588 https://doi.org/10.3126/hren.v10i2.6588 case report | e311 16. torres jp, íñiguez rd. quiste paraovárico gigante en la infancia. reporte de un caso [giant paraovarian cyst in childhood case report]. rev chil pediatr 2015; 86:117–20. https://doi/ org/10.1016/j.rchipe.2015.04.023. 17. shah nh, kale kg, paranjape sh, shah vn. successful laparoscopic management of a giant paraovarian cyst in an adolescent female. j postgrad gynecol obstet 2016; 3. 14. sagili h, krishnan m, dasari p. huge bilateral paramesonephric cysts in a 25-year-old nulliparous woman. j clin diagn res 2013; 7:2589–90. https://doi.org/10.7860/jcdr/2013/6563.3597. 15. damle lf, gomez-lobo v. giant paraovarian cysts in young adolescents: a report of three cases. j reprod med 2012; 57:65–7. shashi kiran, shiekha s jabri, yasser a razek and meka n. devi https://doi/org/10.1016/j.rchipe.2015.04.023 https://doi/org/10.1016/j.rchipe.2015.04.023 https://doi.org/10.7860/jcdr/2013/6563.3597 according to the world health organization (who), the original definition of adverse drug reaction (adr) is “a response to a drug that is noxious and unintended and occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.1 adrs pose a common clinical problem and a significant cause of morbidity and mortality.2 pharmacovigilance is defined as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”.3 n e e d f o r p h a r m a c o v i g i l a n c e when a new medication is released in the market, information about its adverse effects becomes available, which may result in its withdrawal, restrictions in use and labelling changes. some adverse effects are a cause of concern among healthcare professionals and the public. data on drug efficacy and safety are usually based on the experience of thousands of people who participated in controlled clinical trials.4 rare adverse events may not always be identified in clinical trials because of the lack of long-term safety data and unforeseen interactions with coexisting clinical conditions or other drug therapies.2,4 risks and benefits associated with medications can be better understood only after their use by a wider group of people and monitoring for a longer period.2 characterisation of a new drug’s complete safety profile relies on clinicians’ careful observation of its effects in the ‘real world’ practice; pharmacovigilance is the observational science that helps in this process.4 pharmacovigilance helps identify the safety concerns associated with medications and helps regulatory agencies or manufacturers make decisions regarding withdrawal, restrictions in use or labelling changes for medications. p h a r m a c o v i g i l a n c e s y s t e m s a n d s p o n ta n e o u s r e p o r t i n g pharmacovigilance employs various methods to monitor the safety of medications with spontaneous reporting being the most common one. spontaneous reporting is done by people who make a connection between a drug and a suspected drug-induced event. this data about suspected adrs are collected in a central database.5 although spontaneous reporting is critical for drug safety monitoring and should be considered a professional responsibility, under-reporting of adrs is a limitation of current pharmacovigilance systems.2 despite the inherent limitations of spont aneous reporting, it provides crucial evidence for generating a hypothesis regarding the association bet ween a drug and an adverse event.5 carefully planned post-marketing studies and ongoing systematic eval uation using linked databases can help construct efficient pharmacovigilance systems.2 pharmacovigilance serves as an indicator of clin ical care standards that are practised within a country.6 every country has its own pharmacovigilance progr amme due to the differences in several factors— including predominant diseases, prescribing practices, the genetic composition of the population, diet, and people’s traditions. these factors can influence the pattern, presentation and incidence of adrs.7 in response to the thalidomide disaster in 1961, the who initiated the programme for international drug monitoring (pidm) and has an active who collaborating centre for international drug monitoring (uppsala monitoring centre, sweden), which promotes pharmacovigilance at the country level. the who programme is a worldwide collaboration of 140 full and 30 associate-member countries and contributes towards patient safety worldwide.8 safety information received from pharmacovigilance centres helps design drug utilisation practices, essential drugs programmes, standard treatment guidelines and national and institutional formularies.6 regulatory authorities maintain databases of adverse event reports and analyse them systematically for new safety signals; one striking case report, an unusual pattern of adverse events or a collection of adverse event reports exceeding the expected level in usual clinical experience which might initiate a targeted and comprehensive investigation and analysis.4 p h a r m a c o v i g i l a n c e i n p r a c t i c e a healthcare system that includes pharmacovigilance promotes the safety of medications by minimising 1school of pharmacy, university of nizwa, nizwa, oman; 2directorate general of pharmaceutical affairs and drug control, ministry of health, muscat, oman *corresponding author’s e-mail: jimmy.jose@unizwa.edu.om pharmacovigilance basic concepts and an overview of the system in oman *jimmy jose,1 mohammed h. al rubaie,2 hussain al ramimmy,2 shirly s. varughese2 editorial sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e161–163, epub. 21 jun 21 submitted 25 aug 20 revision req. 7 oct 20; revision recd. 4 nov 20 accepted 10 nov 20 https://doi.org/10.18295/squmj.2021.21.02.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ adrs’ occurrence and provides a warning network of various healthcare providers, regulators, manufacturers and consumers to take remedial actions in a timely and orderly manner.9 the key stakeholders involved in pharmacovigilance are patients, healthcare professionals, governments and pharmaceutical companies.2 among these stakeholders, healthcare professionals play the most significant role. pharmacovigilance is a multidisciplinary approach that includes the collaboration of multiple disciplines such as clinicians, pharmacists, nurses and dentists. a clinician’s role in handling adrs is essential not only for patients’ safety but also for drug safety monitoring at the population level.7 pharmacists monitor the ongoing safety of medicines and are the most responsible members of the multidisciplinary team to establish and maintain an effective pharmacovigilance programme in a practice setting. pharmacists provide information related to medication safety after critical evaluation.9 the exclusive role of nurses in pharmacovigilance is identifying adrs, which is difficult for other healthcare providers.10 dentists may help build a better pharmacovi gilance system by adopting pharmacovigilance practices and reporting adrs that are useful for dentistry as a whole.11 pharmacovigilance education and training in healthcare professionals helps construct a better pharmacovigilance system in clinical practice.6 key pharmacovigilance aspects should be integrated into existing programmes as well as courses for medical, pharmacy, dentistry and nursing education.12 although basic knowledge about adrs can be acquired through undergraduate pharmacology textbooks and curricula, additional educational efforts are needed to inculcate the habit of drug safety and pharmacovigilance among medical students.2,7 these students should be trained so that they could be able to report adrs in their area.7 competence in handling adrs in clinical practice is also important for drug safety monitoring at the population and individual patient levels.12 healthcare professionals should possess the skills required to critically evaluate drug information and decide how a drug’s safety profile might be applied to a particular patient.6 educating and training healthcare professionals and linking the clinical experience of drug safety with research and health policies can enhance effective patient care.9 p h a r m a c o v i g i l a n c e s y s t e m i n o m a n to address the need for an effective system for routine drug safety monitoring and to ensure public health protection in oman, the ministry of health (moh) joined the who pidm in 1995.13,14 the background activities were initiated in the international commun ication section under the drug control department and all healthcare professionals working in both govern ment and private sectors in oman were involved in the programme. in 2015, the department of pharmacovi gilance and drug information (dpvdi) was established as the national pharmacovigilance centre (npvc), following a restructuring of departments in the moh, oman. pharmacovigilance activities in dpvdi are based on the directorate general of pharmaceutical affairs and drug control in the moh [figure 1]. dpvdi also collaborates with international stakeholders, such as the who and the uppsala monitoring centre (umc), sweden, for matters related to the safety of medicines. there are 34 regional pharmacovigilance centres and 80 sub-regional pharmacovigilance centres functioning under the npvc in oman. the adr reporting algorithm of the omani npvc is depicted in figure 2.15 the total number of adrs reported at the npvc in the initial years of the adr monitoring programme was limited; however, it increased through constant awareness programmes, workshops and training focused on healthcare professionals at regional and institution levels. the total number of reports submitted to the umc in 2019, 2018 and 2017 were 2,472, 1,703 and 2,196, respectively. the dpvdi was instrumental in developing guidelines such as the guideline on good pharmacovigilance practices in oman, guide for reporting adverse drug reactions and quality problems, guide for direct healthcare professional communications and a supplement to chapter 11 that focused on marketing authorisation holders and pharmaceutical manufacturing companies.15,16 these guidelines will facilitate the activities related to pharmacovigilance within the country. pharmacovigilance is an ongoing process during medication use and is an essential component of clinical practice that promotes safe medication use through prevention, identification, analysis, management and documentation of adverse effects and drugrelated problems. stakeholders involved in pharmaco vigilance include patients, healthcare professionals, drug manufactures and regulatory agencies. a multidisc iplinary approach with healthcare professionals such as pharmacists, clinicians, nurses and dentists is essential for developing an effective pharmacovigilance system. teaching pharmacovigilance aspects to future healthcare professionals as a part of their curriculum will ensure effective use of these aspects during clinical practice. although oman is a part of the global pharmacovigilance for several years and has an active pharmacovigilance system, continuing awareness and pharmacovigilance basic concepts and an overview of the system in the sultanate of oman e162 | squ medical journal, may 2021, volume 21, issue 2 editorial | e163 training programmes for healthcare professionals are required to develop an effective system and make it a part of patient safety. references 1. world health organization. international drug monitoring: the role of national centres. technical report series. geneva, switzerland: world health organization. n0 498. 2. pillans pi. clinical perspectives in drug safety and adverse drug reactions. expert rev clin pharmacol 2008; 1:695–705. https:// doi.org/10.1586/17512433.1.5.695. 3. world health organization. pharmacovigilance. from: https:// www.who.int/medicines/areas/quality_safety/safety_efficacy/ pharmvigi/en/ accessed: nov 2020. 4. trontell a. expecting the unexpected--drug safety, pharmacovigilance, and the prepared mind. n engl j med 2004; 351:1385–7. https://doi.org/10.1056/nejmp048187. 5. krska j, cox ar. adverse drug reactions. in: whittlesea c, hodson k, eds. clinical pharmacy and therapeutics, 6th ed. london: elsevier, 2019. pp. 66–80. 6. world health organization. the importance of pharmaco vigilance. safety monitoring of medicinal products. from: https://apps.who.int/iris/bitstream/handle/10665/42493/ a75646.pdf accessed: nov 2020. 7. shankar p r, subish p, mishra p, dubey a k. teaching pharma covigilance to medical students and doctors. indian j pharmacol 2006; 38:316–19. 8. world health organization. the story of umc and the who programme. uppsala monitoring centre. from: https://www. who-umc.org/global-pharmacovigilance/who-programmef o ri n t e r n a t i o n a l d r u g m o n i t o r i n g / w h o p r o g r a m m e members/ accessed: nov 2020. 9. international pharmaceutical federation. fip statement of policy the role of the pharmacist in pharmacovigilance. from: https://www.fip.org/file/1464#:~:text=against%20this%20 background%2c%20fip%20asserts,pharmacovigilance%20 p r o g r a m m e s % 2 c % 2 0 a n d % 2 0 r e c o m m e n d s % 2 0 t h a t % 3 a & t e x t = p h a r m a c i s t % 2 0 p r a c t i t i o n e r s % 2 0 %e2%80%a2%20should%20understand,the%20safe%20use%20 of%20medicines accessed: nov 2020. 10. mendes marques ji, polónia jm, figueiras ag, costa santos cm, herdeiro mt. nurses' attitudes and spontaneous adverse drug reaction reporting: a case-control study in portugal. j nurs manag 2016; 24:409–16. https://doi.org/10.1111/jonm.12337. 11. carnelio s, khan sa, rodrigues g. pharmacovigilance in clinical dentistry: overlooked or axiomatic? gen dent 2011; 59:24–80. 12. van eekeren r, rolfes l, koster as, magro l, parthasarathi g, al ramimmy h, et al. what future healthcare professionals need to know about pharmacovigilance: introduction of the who pv core curriculum for university teaching with focus on clinical aspects. drug saf 2018; 41:1003–11. https://doi. org/10.1007/s40264-018-0681-z. 13. directorate general of pharmaceutical affairs and drugs control. pharmaceutical newsletter 2016 vol. 24/3. from: https://www. m o h . g o v . o m / d o c u m e n t s / 1 6 5 3 9 / 1 7 4 8 7 0 0 / n e w s l e t ter+vol++24-3.pdf/985a5395-dd0f-4337-b0d0-688784920a6f accessed: nov 2020. 14. directorate general of pharmaceutical affairs and drugs control. units under the department. from: https://www.moh. gov.om/en/web/dgpadc/directorates accessed: nov 2020. 15. directorate general of pharmaceutical affairs and drug control. guide for: reporting adverse drug reactions & quality problems by healthcare professionals. from: https://www.moh. gov.om/documents/16539/1767901/guide+for+reporting+ adverse+drug+reactions+%26+quality+problems.pdf/0aca64f27d3e-4bf6-8578-772e1c144aff accessed: nov 2020. 16. directorate general of pharmaceutical affairs and drugs control. guidelines and policies issued by directorate general of pharmaceutical affairs and drug control. from: https:// www.moh.gov.om/en/web/dgpadc/-9 accessed: nov 2020. figure 1: organisational structure for pharmacovigilance activities in oman. dgpadc = directorate general of pharmaceutical affairs and drug control; dpvdi = department of pharmacovigilance and drug information. figure 2: adverse drug reactions reporting algorithm of the omani national pharmacovigilance centre.15 jimmy jose, mohammed h. al rubaie, hussain al ramimmy and shirly s. varughese https://doi.org/10.1586/17512433.1.5.695 https://doi.org/10.1586/17512433.1.5.695 https://doi.org/10.1056/nejmp048187 https://doi.org/10.1111/jonm.12337 https://doi.org/10.1007/s40264-018-0681-z https://doi.org/10.1007/s40264-018-0681-z genitourinary symptoms associated with chlamydia trachomatis and neisseria gonorrhoeae infections in a tertiary care hospital in oman zakariya al-muharrmi,1 *richard lau,2 ahad al-balushi,1 alyazi al-saadi,1 zeyana al-habsi,3 ali elgalib,3 samir shah,3 maha al-fouri,3 bader al-rawahi,3 seif al-abri4 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 382–386, epub. 25 aug 22 submitted 14 apr 21 revision req. 13 jun 21; revision recd. 12 jul 21 accepted 17 aug 21 1department of microbiology, sultan qaboos university hospital, muscat, oman; 2hiv/aids/sti section and 3department of communicable disease control, 4directorate general for disease surveillance & control *corresponding author’s e-mail: richard9m2bx@hotmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.115 clinical & basic research abstract: objectives: this study aimed to determine the pattern of clinical presentations associated with chlamydia trachomatis and neisseria gonorrhoeae infections. methods: a retrospective cohort study was conducted between 2015 and 2020 and included patients attending sultan qaboos university hospital, muscat, oman, who were tested for these infections using nucleic acid amplification. results: a total of 408 women and 89 men were included. a total of 11 infections were identified in women (n = 11, 2.7%) and 14 in men (n = 14, 15.7%). chlamydia accounted for almost all infections in women (n = 10, 90.9%), commonly presenting with lower abdominal pain or abnormal vaginal bleeding. in men, urethral discharge/dysuria syndrome was the most common presentation and chlamydia was identified in eight men and gonorrhoea in six; a majority of all infections were seen in patients ≤35 years old. conclusion: the relative prevalence of two common sexually transmitted infections (stis) among patients with genitourinary symptoms at a tertiary referral hospital have been described. the pattern of their presentations will inform the design of prospective studies to improve surveillance and guide public health policy in oman. this study highlights the need for a multi-sectoral approach involving all providers to enable comprehensive sti surveillance. keywords: sexually transmitted diseases; chlamydia trachomatis; neisseria gonorrhoeae; oman. advances in knowledge aetiological assessment of genitourinary symptoms is an important epidemiological tool in understanding the clinical presentation and relative prevalence of sexually transmitted infections (stis). -this is the first study conducted in oman to describe how nucleic acid amplification diagnostics are used to diagnose two common and curable stis in a tertiary hospital setting. application to patient care symptoms alone are not sufficiently sensitive or specific in identifying stis. the study supports the wider availability of diagnostic tests and the transition towards an aetiological approach to sti case management in oman. sexually transmitted infections (stis)are an important focus of public health policy in oman. a key aspect for sti control is the early and efficacious management of patients, using either a syndromic approach or clinical management based on laboratory tests (aetiological approach). the latter approach, especially when using highly accurate and sensitive molecular diagnostic tests, has the advantage of identifying the specific sti pathogen(s) so that targeted antimicrobial therapy can be administered, with the potential of improving sti case management and surveillance as well as avoiding unnecessary and wasteful treatments. oman’s public health services have largely relied on the syndromic management approach, with the utilisation of flowcharts (algorithms) for each of the five recognised sti syndromes—male urethral discharge, vaginal discharge, lower abdominal (pelvic) pain in women, scrotal swelling and genital ulceration.1 laboratory tests are not undertaken for most sti patients who receive syndromic management. nevertheless, periodic laboratory-based aetiological assessments are necessary to check for the relevance of the flowcharts and laboratories play a key role in sti surveillance, research programmes and forming public health policies.2–4 in contrast to public health services, sultan qaboos university hospital (squh), muscat, oman, has been providing sti diagnostics for the detection of neisseria gonorrhoeae and chlamydia trachomatis infections since 2014 for patients presenting with genitourinary symptoms, including infertility. these are two of the most common curable stis and are associated with significant sexual and reproductive morbidity including adverse birth outcomes, pelvic inflammatory disease, tubal factor infertility, ectopic pregnancy and epididymo-orchitis.5–7 https://creativecommons.org/licenses/by-nd/4.0/ zakariya al-muharrmi, richard lau, ahad al-balushi, alyazi al-saadi, zeyana al-habsi, ali elgalib, samir shah, maha al-fouri, bader al-rawahi and seif al-abri clinical and basic research | 383 there are regional differences in the prevalence of chlamydia and gonorrhoea, with the middle east and north africa (mena) region having relatively low rates of both infections in either gender compared to other regions, notably the americas and western pacific region.5 while cultural influences and adherence to religious teachings may explain some of these differences in the mena region, stigma, embarrassment, lack of awareness and limited access to molecular diagnostic tests may also account for under-reporting. as the aetiology of sti syndromes in oman has never previously been studied using molecular diagnostic tests, the purpose of this exploratory study was to investigate the relative prevalence of chlamydia and gonorrhoea associated with genitourinary symptoms to inform patient care and identify areas of sti surveillance that may require strengthening. methods this was a retrospective cohort study of patients who attended squh and tested for gonorrhoea and chlamydia. squh is a 600-bed university teaching hospital and tertiary referral centre based in the seeb wilayat (district) in the muscat governorate, the capital of oman. the study population consisted of women who were tested between january and december 2020 and men who were tested between january 2015 and december 2020. the xpert® ct/ng (cepheid inc., sunnyvale, california, usa) nucleic acid amplification test (naat) was used for chlamydia and gonorrhoea detection from endocervical swabs (women) or firstcatch urine specimens (men).8 women who were pregnant and patients who had taken antibiotics in the previous two weeks or had invalid naat results (from improper sample processing, polymerase chain reaction inhibition or sample processing control not being detected in the test sample) were excluded. tests for hiv and syphilis were offered to patients diagnosed with chlamydia and gonorrhoea and to those requesting screening. the test results were recorded and matched with the patients’ sociodemographic information (age, gender, marital status), the type of clinic they attended and their main presenting symptom. descriptive statistics were used to describe the study population. the differences between groups were assessed using the chi-square test. significance was defined at as p value of ≤ 0.05 and a 95% confidence interval (ci) was calculated for a proportion using wilson’s method for small samples.9 based on their clinical presentation, women were grouped into one of five categories: (1) lower abdominal (pelvic) pain; (2) abnormal vaginal bleeding (menorrhagia, irregular, interand post-coital bleeding); (3) abnormal vaginal discharge (malodour, increased volume, altered colour); (4) asymptomatic women attending for infertility assessment; or (5) women attending for contraception, pre-operative assessment and urogynaecological symptoms. men were categorised into two groups—(1) those with urethral discharge/ dysuria syndrome or (2) those with other presentations including asymptomatic, scrotal or abdominal pain, haematuria, investigation of fever and unspecified presentations. the data collection process was affected due to clinical and laboratory resources being diverted to manage the on-going covid-19 pandemic. these resource limitations meant that it was not possible to collect and collate more data for women presenting before 2020. the study was approved by the medical research ethics committee, college of medicine and health sciences, squh (squ-ec/210/19). all data collected for this study were anonymised and identifiable details were removed. results a total of 416 women attended squh with genital or gynaecological symptoms including infertility in 2020. table 1: sociodemographic characteristics of patients attending sultan qaboos university hospital who were tested for chlamydia and gonorrhoea in women in 2020 and in men between 2015 and 2020 (n = 497) characteristic n (%) female (n = 408) male (n = 89) nationality omani 394 (96.6) 84 (94.4) non-omani 14 (3.4) 5 (5.6) age distribution in years mean 36.5 33.8 median 35.95 31.2 range 16.5–66.7 14.3–81.1 marital status married 398 (97.5) 39 (43.8) divorced 5 (1.2) 0 (0) widowed 4 (1.0) 0 (0) single 1 (0.2) 35 (39.3) undisclosed 0 (0) 15 (16.9) genitourinary symptoms associated with chlamydia trachomatis and neisseria gonorrhoeae infections in a tertiary care hospital in oman 384 | squ medical journal, august 2022, volume 22, issue 3 eight women were excluded from the study because they were either pregnant (n = 5) or had invalid test results (n = 3); therefore, a total of 408 women were included in this study [table 1]. the majority of the women (n = 235, 57.6%) attended the gynaecology clinic, some (n = 159, 39.0%) attended the infertility clinic and the remainder (n = 14, 3.4%) attended other clinical services (accident and emergency = 13, general medicine = 1). a total of 10 (2.5%) women were infected with chlamydia, nine (2.2%) of whom were mono-infected and one woman dually infected with chlamydia and gonorrhoea. one (0.25%) woman was mono-infected with gonorrhoea. lower abdominal (pelvic) pain and abnormal vaginal bleeding presentations accounted for most infections [table 2]; however, symptoms alone were not sufficiently specific or sensitive in correlation with infection [figure 1]. women aged 26–35 years had the highest prevalence of chlamydial infection (7/10, 70%) [figure 2]. more infections were identified in women ≤35 years old than in those >35 years old (chi-squared = 7.83; p = 0.0051). data on 99 men who attended squh and were tested for gonorrhoea and chlamydia between 2015 and 2020 were collected. some patients were excluded (n = 10) due to invalid naat test results. the data for the remaining 89 men were included and analysed [table 1]. most patients (n = 44, 49.4%) presented with urethral discharge and/or dysuria syndrome. chlamydia was detected in eight men (9.0%) and gonorrhoea in six (6.7%); there were no dual infections [table 2]. although tests on men were ordered from a wider range of clinics within squh, with most tests being ordered by infectious diseases (n = 22) and general medicine (n = 21) clinics, more infections were disproportionately identified in men attending the accident and emergency (n = 2/3, 67.0%), student health (n = 3/6, 50.0%) and family practice clinics (n = 4/18, 22.0%). compared to women, infections appeared to occur in younger men more often [figure 1]; however, group comparisons were not possible because of the modest sample size of men. discussion this study describes the relative prevalence of two important, curable stis in symptomatic patients figure 1: prevalence of chlamydial infection in percentage with 95% confidence intervals in women presenting with lower abdominal pain, abnormal vaginal bleeding, abnormal vaginal discharge and infertility. lap = abdominal pain; avb = abnormal vaginal bleeding ; avd = abnormal vaginal discharge. table 2: main symptom or presentation and detection of gonorrhoea and chlamydia in women and men (n = 497) main symptom or presentation total n chlamydia and gonorrhoea negative chlamydia positive only gonorrhoea positive only chlamydia and gonorrhoea positive female 408 lower abdominal pain 55 50 4 0 1 abnormal vaginal bleeding 40 38 2 0 0 abnormal vaginal discharge 42 40 1 1 0 infertility assessment 165 163 2 0 0 other 106 106 0 0 0 male 89 urethral discharge and/or dysuria 44 31 8 5 0 other 45 44 0 1 0 zakariya al-muharrmi, richard lau, ahad al-balushi, alyazi al-saadi, zeyana al-habsi, ali elgalib, samir shah, maha al-fouri, bader al-rawahi and seif al-abri clinical and basic research | 385 presenting to a tertiary care hospital in muscat, oman. the most common presentation in symptomatic women was lower abdominal pain, a cardinal feature of pelvic inflammatory disease (pid) and associated with a 17% risk of infertility after one episode.10 although the prevalence of infection was highest for this symptom in women, it was not significantly different from other presentations in this cohort, suggesting that symptoms alone are not sufficiently sensitive or specific to reliably identify an sti [figure 2]. given the significant caseload attributed to chlamydial infection, the study illustrates the importance of widening access to sti diagnostics beyond clinic-based syndromic case management to screen for infections before complications such as pid develop. the costeffectiveness of such a strategy will, however, depend on the local prevalence of these infections, how they present and the behavioural characteristics of the local population. in the current female cohort, an age of ≤35 years was identified as a significant sti risk factor; this was consistent with epidemiological studies that demonstrated a higher risk in younger women.11–13 however, age may also be a confounder linked to other social, cultural or behavioural factors such as duration of relationship, partner behaviour and condom use that will require further analysis in a prospective study. the much higher prevalence of gonorrhoea in men compared to women (6.7% versus 0.5%) could be explained by the self-selection of men with more symptomatic infections, as male gonococcal urethritis tends to produce a more vigorous inflammatory response than corresponding gonococcal urethritis or cervicitis in women, which can often be asymptomatic or associated with non-specific symptoms. in contrast, the smaller size of the male cohort may disproportionately reflect more symptomatic men electing to seek acute care elsewhere (possibly private clinics) for reasons of confidentiality. the observations support the need for a prospective multi-centre study incorporating other providers of sti care and completion of an anonymised patient questionnaire to identify risk behaviours that may explain these differences. the current study has several limitations. the patients included in the study were those that chose to seek healthcare for their symptoms from one provider (squh) in muscat and may not be representative of patients living elsewhere or accessing other providers in the rest of the country/city. as with any retrospective study, there are also inherent biases that may hinder the applicability of the present findings to the wider population. recording of particular symptoms (and not recording others) by the attending clinician could lead to selection bias. misclassification bias may also have occurred when data were abstracted from the clinical records. a further consideration is that many different clinicians (especially for men) were involved in patient care; therefore, the recording of symptoms as risk factors may be less accurate than what could be achieved through a prospective cohort study. conclusion this exploratory study provides insight into the relative prevalence of two common stis and their presentations. the study findings support age-targeted, culturally appropriate prevention and education strategies as well as broadening the availability of sti diagnostic tests to detect asymptomatic stis, especially in women. the study also highlights the need in oman for a multi-sectoral approach involving all providers to enable comprehensive sti surveillance. figure 2: distribution of chlamydia and gonorrhoea cases by age and gender. genitourinary symptoms associated with chlamydia trachomatis and neisseria gonorrhoeae infections in a tertiary care hospital in oman 386 | squ medical journal, august 2022, volume 22, issue 3 a u t h o r s’ c o n t r i b u t i o n s zam, rl and zah designed the study. aab and aas retrieved and collated clinical and laboratory data. all the authors were responsible for drafting and critical appraisal of the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t s the authors declare no conflict of interests. f u n d i n g no funding was received for this study. references 1. alary m, abreu h, anupong c, ballard r, jakobsone i, kahindo m, et al. guidelines for the management of sexually transmitted infections. geneva, switzerland: who publications, 2001. from: http://apps.who.int/iris/bitstream/handle/10665/42782/ 9 2 4 1 5 4 6 2 6 3 _ e n g . p d f ; j s e s s i o n i d = b 6 9 c c 0 e c cf43c5e8fa35c7b9748c82ae?sequence=1 accessed: july 2021 2. rietmeijer ca, mungati m, machica a, mugurungi o, kupara v, rodgers l, et al. the etiology of male urethral discharge in zimbabwe: results from the zimbabwe sti etiology study. sex transm dis 2018; 45:56–60. https://doi.org/10.1097/ olq.0000000000000696. 3. tadesse e, teshome m, amsalu a, shimelis t. genital chlamydia trachomatis infection among women of reproductive age attending the gynaecology clinic of hawassa university referral hospital, southern ethiopia. plos one 2016; 11:e0168580. https://doi.org/10.1371/journal.pone.0168580. 4. newman la, wi t, sharkey l, broutet n, temmerman m, toskin i. a tool for strengthening sti surveillance at the country level. geneva, switzerland: who publications, 2015. from: https://apps.who.int/iris/handle/10665/161074 accessed: jul 2021. 5. newman la, rowley j, vander hoorn s, wijesooriya ns, unemo m, low n, et al. global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. plos one 2015; 10:e0143304. https://doi.org/10.1371/journal. pone.0143304. 6. reekie j, donovan b, guy r, hocking js, kaldor jm, mak d, et al. risk of ectopic pregnancy and tubal infertility following gonorrhoea and chlamydia infections. clin infect dis 2019; 69:1621–3. https://doi.org/10.1093/cid/ciz145. 7. tang w, mao j, li kt, walker js, chou r, fu r, et al. pregnancy and fertility-related adverse outcomes associated with chlamydia trachomatis infection: a global systematic review and metaanalysis. sex transm infect 2020; 96:322–9. https://doi. org/10.1136/sextrans-2019-053999. 8. gaydos ca, van der pol b, jett-goheen m, barnes m, quinn n, clark c, et al. performance of the cepheid ct/ng xpert rapid pcr test for detection of chlamydia trachomatis and neisseria gonorrhoeae. j clin microbiol 2013; 51:1666–72. https://doi. org/10.1128/jcm.03461-12. 9. confidence limits for a proportion. from: https://epitools. ausvet.com.au/ciproportion accessed: jul 2021. 10. price mj, ades ae, soldan k, welton nj, macleod j, simms i, et al. the natural history of chlamydia trachomatis infection in women: a multi-parameter evidence synthesis. health technol assess 2016; 20:1–250. https://doi.org/10.3310/hta20220. 11. holmes kk. the chlamydia epidemic. jama 1981; 245:1718–23. https://doi.org/10.1001/jama.1981.03310420010002. 12. adams ej, charlett a, edmunds wj, hughes g. chlamydia trachomatis in the united kingdom: a systematic review and analysis of prevalence studies. sex transm infect 2004; 80:354–62. https://doi.org/10.1136/sti.2003.005454. 13. rowley j, vander hoorn s, korenromp e, low n, unemo m, abu-raddad lj, et al. chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. bull world health organ 2019; 97:548–62p. https://doi. org/10.2471/blt.18.228486. https://doi.org/10.1097/olq.0000000000000696 https://doi.org/10.1097/olq.0000000000000696 https://doi.org/10.1371/journal.pone.0168580 https://doi.org/10.1371/journal.pone.0143304 https://doi.org/10.1371/journal.pone.0143304 https://doi.org/10.1093/cid/ciz145 https://doi.org/10.1136/sextrans-2019-053999 https://doi.org/10.1136/sextrans-2019-053999 https://doi.org/10.1128/jcm.03461-12 https://doi.org/10.1128/jcm.03461-12 https://doi.org/10.3310/hta20220 https://doi.org/10.1001/jama.1981.03310420010002. https://doi.org/10.1136/sti.2003.005454. https://doi.org/10.2471/blt.18.228486 https://doi.org/10.2471/blt.18.228486 1directorate general of planning and studies, ministry of health, muscat, oman; 2department of family medicine and public health, sultan qaboos university, muscat, oman *corresponding author’s e-mail: mhalazri@squ.edu.om فهم تصور املرأة العمانية عن احلياة بعد تشخيص سرطان الثدي اآ�سيا الريامي، ناديا نورعبد الهادي، حممد العزري abstract: objectives: there is a rising burden of breast cancer (bc) in the eastern mediterranean region (emr), and its sociopsychological impact is a quickly growing health concern in this region. because understanding cancer patients’ perceptions of life is integral to their treatment, they are also a concern for healthcare providers. this qualitative study, therefore, explored changes in omani women’s perceptions of life after a bc diagnosis. methods: semi-structured interviews were conducted individually with 21 omani women undergoing treatment for bc at the oncology ward of muscat’s royal hospital from march to may 2017. the collected data were subjected to qualitative content analysis. results: after their cancer diagnosis, the women appeared to pass through three main stages in their coping processes. first, they passed through a stage of severe psychosocial distress and diminishment in personal identity. next, they evolved strategies for coping based on cultural, religious and family resources. finally, the women experienced acceptance and submission to the reality of the cancer as god’s will with changes in attitudes and perceptions of the meaning of life. conclusion: a bc diagnosis impacts omani women severely, affecting their lives dramatically. they adopt coping strategies based on cultural, religious and spiritual beliefs. healthcare providers need to acknowledge and facilitate women’s spiritual and cultural coping strategies as an integral part of their treatment which holds potential to improve their prognosis. such strategies should be individualised to suit each woman’s experiences, perceptions and needs. keywords: breast neoplasm; culture; perceptions; life; women; oman. امللخ�ص: الهدف: يعترب �رشطان الثدي واحد من اأ�رشع امل�ساكل ال�سحية انت�سارا يف اإقليم �رشق املتو�سط )emr( والذي ي�ساحبه عبء متزايد يف التاأثري االجتماعي والنف�سي للمري�ض. وبالتايل فاإن منط احلياة والقيم الثقافية والنف�سيه ملر�سى ال�رشطان هي من املتغريات للن�ساء احلياة منط على املوثره االمور اكت�ساف هو الدرا�سة هذه من الهدف ان العالج. من يتجزاأ ال جزًء اعتبارها يجب التي املهمة العمانيات امل�سابات ب�رشطان الثدي. الطريقة: اأجريت مقابالت فردية �سبه منتظمة مع 21 امراأة عمانية مت ت�سخي�ض اإ�سابتهن ب�رشطان الثدي. مت اختيار الن�ساء من ق�سم االأورام يف امل�ست�سفى ال�سلطاين بني شهري مارس و مايو 2017. مت حتليل البيانات با�ستخدام حتليل املحتوى النوعي. النتائج: يبدو اأن الن�ساء العمانيات مررن بثالث مراحل رئي�سة يف عمليات التاأقلم بعد ت�سخي�ض اإ�سابتهن ب�رشطان الثدي. اأواًل من اأ�سا�ض على التكيف يف ا�سرتاتيجيات التطوراىل ذلك بعد ال�سخ�سية. الهوية وت�سائل ال�سديد واالجتماعي النف�سي ال�سيق من مرحلة املعتقدات والعوامل الثقافية والدينية والعائلية واأخرًيا اختيار القبول بالواقع لت�سخي�ض ال�رشطان كم�سيئة من اهلل مل�ساحبة التغريات يف احلياه منط يوؤثرعلى مما كبري ب�سكل العمانية املراأة يوؤثرعلى ال�رشطان مر�ض ت�سخي�ض احلياة. اخلال�صة: معنى واإدراك اجتاه املواقف اإىل ال�سحية الرعاية مقدموا يحتاج والدينية. الثقافية والعوامل املعتقدات من اأ�سا�ض على تاأقلم ا�سرتاتيجيات تبني ي�ساحبه والكن اإمكانية على ينطوي والذي العالج من يتجزاأ ال كجزء وت�سهيلها للمراأة النف�سيه احلاله ملواجهة وذالك منا�سبه ا�سرتاتيجيات ا�ستنباط حت�سني توقعات �سرياملر�ض. يجب اأن تكون هذه اال�سرتاتيجيات تتنا�سب مع جتارب كل امراأة على حده لت�سوراتها واحتياجاتها. الكلمات املفتاحية: اورام الثدي؛ ثقافه؛ ت�سور؛ احلياة؛ الن�ساء؛ عمان. understanding the perceptions of omani women regarding life after a breast cancer diagnosis asya al-riyami,1 nadia n. abdulhadi,1 *mohammed al-azri2 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e360–367, epub. 21 dec 20 submitted 15 jan 20 revision req. 12 mar 20; revision recd. 26 mar 20 accepted 27 apr 20 https://doi.org/10.18295/squmj.2020.20.04.013 clinical & basic research advances in knowledge breast cancer (bc) diagnosis and treatments have several negative consequences for omani women’s perceptions of life. omani women diagnosed with bc adopt several coping strategies to improve their perceptions of life. these strategies are constructed out of cultural, religious and spiritual beliefs. the participating omani women tended to seek more fundamental lifestyles to fulfil the essential needs of life per maslow’s hierarchy of needs. application to patient care healthcare providers caring for omani women with bc should develop sensitivity towards the cultural, religious and spiritual factors that help these women cope with the disease. integrating women’s personally evolved coping strategies into professional consultations on and management of their cases may also improve their satisfaction with care and adherence to treatment regimens. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ asya al-riyami, nadia n. abdulhadi and mohammed al-azri clinical and basic research | e361 breast cancer (bc) is the most common cancer affecting women globally, with an estimated 2.1 million cases diagnosed each year. it represents 10% of all cancers diagnosed annually and approximately 15% of all cancer deaths among women.1 in the eastern mediterranean region (emr), bc is a leading cause of death and disability among women.2 women in these countries usually present at later stages of the disease which leads to lower survival rates and negative impacts on their life perceptions compared to their counterparts in the developed world.3 psychological symptoms of distress such as anxiety and depression are commonly found among bcaffected women in the emr even years after diagnosis.4,5 these women are also at risk of developing a spectrum of psychological morbidities such as fatigue, negative thoughts, suicidal thoughts, fear of dying, a sense of loneliness and poor sexual and body images which all affect their perceptions of their own lives.5 these perceptions are further affected by challenges to their psychosocial and cultural belief systems, impacting their prognosis.4,5 women’s self-perceptions and their expectations about their futures as individuals and social beings undergo changes upon realisation that they have bc. the complexity of the situation makes these changes difficult to define. in quantitative and mixed methods studies, the term quality of life (qol) is often used to describe such self-perceptions. because the current study followed a qualitative methodology, the authors framed the study not around a general investigation of qol but instead on women’s perceptions of their lives.6 emotional distress triggered by a bc diagnosis may have a profound psychosocial impact on bc survivors’ life perceptions including their thoughts, emotions, attitudes and expectations; this distress is a predictor of treatment outcomes.7,8 there are psychological interventions, however, that have been found to help improve patients’ perceptions of life and, consequently, their prognosis.9,10 special attention needs to be given to patients whose perceptions of care priorities significantly differ from those of their caregivers.11 the few studies conducted in arab countries on the impact of bc on patients’ life perceptions endorse the importance of patients’ functional abilities, spiritual beliefs, relationships with family and friends and the availability of medical and psychological care.12,13 oman is an arab country in the emr, situated in the southeastern corner of the arabian peninsula. out of an estimated country-wide population of 4.6 million, 2.5 million are omani nationals.14 in this rapidly urbanising nation, about 21% of the total population reside in the national capital region, muscat. bc accounts for 24.50% of all cancers affecting omani women, and 12.79% of all malignancies in the omani population.15 most cases are diagnosed at younger ages (median: 49 years). compared to western women, however, omani women tend to present for diagnosis later, leading to lower mean (63%) five-year survival rates.15,16 omani cancer patients from all parts of the country are referred for oncology treatment at the two major hospitals in muscat: the royal hospital and the sultan qaboos university hospital. previous studies on omani women with bc showed that their main apprehensions centred on losing their femininity, cancer spreading to other parts of the body, the side effects of chemotherapy and genetic risks for their daughters.4,17 the strong bc stigma prevalent in omani society causes some patients to believe they are being pitied by others, leading to social withdrawal.4 despite such barriers, most omani women diagnosed with bc are able to tap into traditional resources such as family support, religion and belief in god’s will and power, which appears to guide them towards submission and acceptance of the reality of their cancer, with associated beneficial results on their lives. this study sought to understand the perceptions of omani women regarding their lives after bc diagnosis. for research that aims to understand people’s lived experiences and their perceptions of those experiences, a qualitative approach is preferred.18–20 methods participants were recruited for this study between march and may 2017. the regional interview guide developed by the reproductive health working group (rhwg), a network of scholars from several arab countries and turkey, was adopted for this study. the rhwg guide uses concepts from medical, public health and social science to study women’s health in its broader cultural context.21 the areas of research interest were the emotional and cognitive experiences and perceptions of women diagnosed with bc and their impact on their lives. the rhwg topic guide was followed for collecting data because it is based on the combined expertise of several healthcare professionals and researchers who have brought their experiences and knowledge of bc-affected women from different arabic countries.21 the questions, which cover the impact of bc on each participant’s perception of her life, include ‘‘how has your life been affected after diagnosis with breast cancer (work, household chores, leisure, etc.)’’ and ‘‘what were the reactions of your husband, family, friends to your disease and understanding the perceptions of omani women regarding life after a breast cancer diagnosis e362 | squ medical journal, november 2020, volume 20, issue 4 why? what were the strategies you used to cope with the diagnosis?’’ the present research team reviewed and modified the interview topics guide according to findings from pilot interviews conducted with five omani women. the purposive sampling strategy aimed for a maximum variation and was used to obtain a wider range of knowledge and lived experiences of women diagnosed at different cancer stages (i.e. local, metastasis) and on different cancer treatments (i.e. surgery, chemotherapy, radiotherapy, combined).22 all participants were from the royal hospital, muscat, oman, which treats the largest number of bc in-patients hailing from all parts of oman. as generalisability is not an expected outcome of qualitative research, choosing patients from a single hospital was considered methodologically acceptable.18 participants were recruited from the oncology ward over several visits. semi-structured face-toface interviews were conducted individually with each woman, and each interview lasted 30–45 minutes. before each ward visit, the head nurse briefed the second co-author on the medical and psychophysiological status of all participants to be visited that day. this procedure helped minimise intrusive queries to the patient. the second co-author accompanied by the assistant head nurse visited the women daily for approximately two weeks. on a single day, only 3–4 women were interviewed to allow enough time for the interviews and to prevent daily repetition of the visit. each interview lasted 45–60 minutes and was audio-recorded with patients’ agreement and transcribed verbatim. qualitative content analysis is a widely used qualitative research technique and was applied inductively to analyse the data.20 the steps involved in inductive content analysis include open coding and creating categories and abstraction.23 the transcripts were read several times by all three researchers to obtain a thorough sense of the entire text. the notes and headings were added to the text during reading, and the headings were transferred from the margins to coding sheets. the codes were then compared based on differences and similarities and sorted into categories and subcategories. the abstraction involved formulating a general description where each category was named using content-characteristic words. the subcategories with similar events and incidents were also grouped together as categories and categories were then grouped as main categories. the proofs of abstraction were continued as far as was reasonably possible.23 a general definition of the main themes and subthemes were organised as appropriate. the first major theme was cancer diagnosis and impact on perception of life and subthemes were impact on personal identity and ability to discuss the illness. the second major theme was coping strategies and the subthemes were reliance on family support and submission to god’s will. the third major theme was new perceptions of qol. the contents of the categories were discussed between all the authors. disagreements were debated until consensus was reached. the data collection was stopped after 21 women when the saturation point in the analysis was achieved which was established as the point at which no new codes were occurring in the data and no new information could be elicited.20,23 this study was approved by the research and ethical review and approval committee of the ministry of health of oman (221/16). the purpose of the study was explained to the women individually. they were guaranteed confidentiality and anonymity of all collected data and assured that participation or non-participation would not affect the care they received. written informed consent was obtained from the women who were recruited into the study. results a total of 21 omani women participated in this study. their ages ranged from 25–63 (median: 42) years. most participants were married (n = 18), urban residents (n = 12) and unemployed (n = 14) [table 1]. the period since bc diagnosis ranged from two months to seven years with a median of 2.4 years. ten participants were undergoing chemotherapy at the time of the interviews. the majority (n = 15) were unaware of the stage of their cancer at the time of the interviews, although most had been advised of their cancer’s staging at the time of their diagnosis [table 2]. the participants revealed experiencing different emotions including strong reactions when they were given their cancer diagnosis and also shared the impact of the disease on their personal priorities, spiritual life and perceptions of family structure and support. from analysis, three themes emerged—the emotional trauma of cancer diagnosis, the evolution of coping strategies and changes in their perceptions of life. these stages are subsequently discussed and are illustrated by representative quotations from the transcribed text.20,23 the bc diagnosis was shocking for the women and created much anxiety. the participants also felt exhausted due to the side effect of chemotherapy, which affected their daily normal activities. a minority of participants, however, revealed that they did not feel much anxiety around a possible bc diagnosis as asya al-riyami, nadia n. abdulhadi and mohammed al-azri clinical and basic research | e363 they had expected it due to a history of cancer in their families: “of course i am shocked till now. i faced huge panic during the previous period and i feel weak now with the chemotherapy, all my life changed. earlier, i had only migraines and my life was better” (woman 18). “i feel tired and cannot even go to the supermarket, but allah will give me back good things if i accept my fate” (woman 12). “i expected to have cancer; my mother died with cancer and my sister has leukaemia, i was a bit cool while waiting for the result” (woman 5). some women felt that the suffering of bc was enormous compared to their previous illnesses: “now i realized that all the previous illnesses i got and went several times to the hospital were trivial, were nothing, now only i am really and seriously ill” (woman 17). “before, when someone said take care of yourself table 1: participants’ socio-demographic characteristics of omani women attending at the oncology ward of the royal hospital, muscat, oman (n = 21) characteristic n (%) age at time of diagnosis in years 25–35 4 (19.0) 36–45 10 (47.6) 46–55 5 (23.8) 56–65 2 (9.50) age range in years 25–63 median age in years 42 marital status single 1 (4.7) married 18 (85.7) divorced 1 (4.7) widow 1 (4.7) educational level no formal education 8 (38.1) primary education 4 (19.0) secondary school education 5 (23.8) college/above 4 (19.0) residential locality urban 12 (57.1) rural 9 (42.8) employment status employed 7 (33.3) unemployed 14 (66.6) table 2: clinical data as perceived by of omani women attending at the oncology ward of the royal hospital, muscat, oman (n = 21) condition n (%) disease stage at the time of diagnosis* local 3 (14.3) metastasis 0 (0) does not know 7 (33.3 stage 1 2 (9.5) stage 2 4 (19.0) stage 3 3 (14.3) stage 4 2 (9.5) cancer stage at the time of interviews local 1 (4.7) metastasis 3 (14.3) does not know 15 (71.4) stage 1 0 (0) stage 2 1 (4.7) stage 3 1 (4.7) stage 4 0 (0) disease duration mean duration 2.4 years range of duration 2 months–7 years perception of initial management (previous) total mastectomy only 3 (14.3) partial mastectomy only 1 (4.7) chemotherapy only 5 (23.8) radiotherapy only 0 (0) surgery with chemotherapy 4 (19.0) surgery with chemotherapy and radiotherapy 8 (38.1) perception of medical management (current) surgery only 0 (0) chemotherapy 10 (47.6) radiotherapy 1 (4.7) chemotherapy and radiotherapy 0 (0) surgery with chemotherapy 1 (4.7) surgery with chemotherapy and radiotherapy 0 (0) supplementary medicines (e.g. hormonal, adjuvant therapy, zometa, etc.) 8 (38.1) does not know 1 (4.7) *as perceived by the participants understanding the perceptions of omani women regarding life after a breast cancer diagnosis e364 | squ medical journal, november 2020, volume 20, issue 4 or your health, i was considering as casual and unintended words, just words, but now i realize how valuable it was” (woman 13). women developed a perception of bodily disfigurement and physical appearance due to the potentially devastating consequences of treatment side-effects including alopaecia and mutilation. these physical changes can cause dissatisfaction with appearance, perceived loss of femininity and body integrity and a decreased feeling of physical attractiveness, thus impacting sexual lives. as a result, the women expressed feelings of nervousness and being out of harmony with their husbands and families: “the worse thing is that i felt i was an incomplete woman, no breast and no hair” (woman 3). “i was nervous and badly upset, i stopped caring about my husband or my sexual life and did not feel in love with him, one breast was removed, the hair has fallen. i am now half a woman” (woman 2). the women struggled with their identity as mothers and described themselves as falling short of being good mothers. some of them expressed anxieties and concerns over their unfulfilled obligations toward their children in case of their early death and feared that their children would become half-orphans: “i am thinking of my children, what would happen to them if i died?” (woman 15). “now i am thinking about my loans, i panic about not settling them if anything happened to me. i was not thinking of that before the illness” (woman 8). women reported being insecure talking about their breast cancer with families or friends either to protect them from the impact of their diagnosis or might be because of the concern of being stigmatised. only a few felt like discussing this after starting treatment but they refrained from giving details: “i absolutely do not want to talk about this (breast cancer diagnosis)” (woman 20). “i can talk with my family (of breast cancer) but not in detail” (woman 10). the women now wished to live in peace with their relatives. family relationships previously taken for granted had now become important. they also felt closer to their in-laws and friends whose emotional support made them feel happy. some women felt that their relationships with their husband, family and friends improved after diagnosis. they perceived that they were receiving more emotional and moral support than prior to diagnosis: “i felt closer to my husband, my family and friends after i got the cancer. we were not really close to each other before the illness” (woman 1). “now i have no problems with my husband’s family unlike before, now they are treating me better and showing a lot of sympathy, that was not the case at all before my illness as there were a lot of conflicts and aggressiveness in our relations” (woman 12). women expressed the belief that all illnesses, including cancer, come from allah (god). they expressed their deep wish to be more religious and closer to god than ever before through prayer and recitation of the holy quran. despite the physical side effects of chemotherapy, they said they strove to submit to god’s will and, through acceptance of their divinely determined destiny, seek his support and approval. this relationship, they said, provided them with the strength to face afflictions. they also felt that their failing allah’s test might otherwise lead to more disasters and divine retributions: “what happened has happened, what is the use of crying and making noise (dhajah)? …yes i was sad at the beginning, but now i feel better because i accepted my fate and left everything to allah, this made me strong, and less anxious, praise be to allah” (woman 6). “i accepted what allah wrote for me; i believe it is for good reasons, thanks to allah” (woman 14). “yes, they removed a part of my body but this illness is from allah. should i be angry or fight with allah?” (woman 21). the women’s perception of what constituted a desirable life was fundamentally altered by their illness. prior to their diagnosis, they said, they sought wealth and social status. now such erstwhile benchmarks of qol were perceived as trivial. currently, they seemed to equate qol with more fundamental necessities such as physical health, family support and satisfaction of basic life requirements: “quality of life (now) means good health, good family relations and peace, all this changed after my illness, i am unhappy…” (woman 5). “i made a huge effort and collected money to have a beautiful villa and that was my main dream, but i see my dream now as very trivial, good health is a major issue now…” (woman 3). “now only after getting cancer i realised that money or wealth are nothing, they are not valuable if you have cancer, i only want now to recover and get my good health back. quality of life means good health” (woman 21). “imagine how life looks like with illness like cancer?” (woman 8). “it is almost the same, because if you accept what is written to you by god, it means you will live your life in a good way, you will be satisfied and you will feel happy” (woman 3). “quality of life and satisfaction with life are the same, yes, the same” (woman 5). women now wished to accept their life and fate asya al-riyami, nadia n. abdulhadi and mohammed al-azri clinical and basic research | e365 with self-esteem irrespective of their standard of living. the general attitude seemed to be moving towards finding satisfaction and meaning in the present life and abandoning desires for social prestige and luxuries: “it is acceptance; it is important to accept all the afflictions to be able to survive” (woman 5). “yes, we have to accept, it is not possible to fight the fate” (woman 11). “now, i do not look for luxury or anything. it is only health, it is the main component of quality and also satisfaction with life, how can you do anything or achieve anything if you are not in good health” (woman 13). discussion to the researchers’ knowledge, this qualitative study is the first conducted in oman to understand the effect of a bc diagnosis on the life perceptions of omani women. the participants indicated that bc diagnosis was a life-changing event, and the women were left emotionally traumatised with compromised identities. the participants described anticipating more trauma and losses, refusing to discuss their illness with others and, for some, becoming socially reclusive. to cope with the emotional and physical trauma of cancer, they sought out strategies based on cultural values and religious beliefs. these strategies included increased religiosity and submission to god’s will, acceptance of the inevitability of the disease and a strong shift in perceptions of life towards satisfying the basic needs such as health and family togetherness.5 this finding is congruent with those of other studies, confirming that women diagnosed with bc usually experience a precipitous change in their lives, and psychological symptoms begin emerging even as they await diagnostic results; however, they adopt various strategies to cope with their distress.4,5,24 the participants revealed that their family relations, earlier taken for granted, had now become warm and vital. here they may have been supported by omani tradition which is collective in nature and puts great value on sharing aspects of life between relatives and neighbours. studies suggest that social and familial support render symptoms more bearable and help enhance the life perceptions of bc-affected women.5,25 participants’ religious convictions were found to be strong and homogeneous. they expressed the conviction that cancer was a test from god and expressed a wish to submit to divine will by becoming more religious. while islam considers physical and mental well-being as measures of good health, it also teaches that everything is determined by the sovereign will of god who is the source of all health and illness.26 the task of the devotee is to fully submit to god’s will. the impact of islamic submission to divine will on women’s lives was studied among a cohort of bc patients in singapore where several women reported spiritual experiences with attendant enhancements of their life.27 while the current participants did not report spiritual experiences as part of their devotional activities, the potential of such experiences for enhancing life perceptions among cancer patients is increasingly gaining researcher attention.28 previous research with cancer patients who engage in buddhist mindfulness meditation (a secular meditation which seeks to observe and accept the reality of the present moment) found spiritual experiences leading to sustained enhancement of patients’ experience of life.29 neuroscientific investigations also endorse the possibility that spiritual practices geared towards submission and acceptance of reality may improve cancer patients’ life perceptions.30 such findings emphasise the need for all caregivers to acknowledge the life-enhancing benefits of submission/acceptance-oriented spiritual practices for bc patients and facilitate these to the highest extent possible. another significant takeaway from the current study is the emphatic manner in which the participants declared that their perceptions of life had changed drastically in the process of dealing with the reality of bc. living with bc caused them to dismiss their former aspirations to wealth and social status as trivial and gravitate towards more basic needs such as physical health, family support and submitting to divine will. this dramatic shift can be explained by maslow’s hierarchy of needs where the basic ones— physical survival, personal safety, sense of belonging and being loved—need to be satisfied before secondary needs such as ego, esteem and self-actualisation can be contemplated.31,32 it could be hypothesised that such a step-down in the hierarchy of needs leaves the mind relatively free for engaging in religious practices based on submission and acceptance and paves the way to spiritual transcendence as manifested in studies elsewhere.31 healthcare providers need to be aware that such downward shifts in the need-hierarchy among bc patients is a natural and possibly beneficial coping mechanism which supports patients through transitions. it is essential to establish trustworthiness of findings in qualitative research. a reasonable degree of credibility was achieved by the way the interviews were conducted including the questions asked. the understanding the perceptions of omani women regarding life after a breast cancer diagnosis e366 | squ medical journal, november 2020, volume 20, issue 4 researchers independently reviewed the transcripts during regular team meetings and explored the patients’ underlying reasoning.19,23 despite this approach, the study has certain limitations. the interview transcripts showed significant conformity in the participant responses which is a characteristic of collective cultures which seek social unity. the findings may not be applicable to women living under more individualistic cultural norms such as in the west.33 indeed, this study was not designed to filter out cultural characteristics. finally, this study’s methodology would have been stronger if triangulation was incorporated through, for example, interviewing patients’ family members and healthcare providers whose influences are critical in the lives of omani women diagnosed with bc. conclusion this qualitative study reveals that omani women felt emotionally devastated by bc diagnoses. using traditional support systems from culture, family and religion, women were able to reorient themselves by anchoring to fundamental values and accepting the reality of their illness as part of a divine plan. the findings underscore the need of healthcare providers to be aware of the experiences, perceptions and coping strategies of omani women with bc. healthcare providers should regard their patients’ lives, actively understand them and incorporate familiarisation strategies as much as possible into overall treatment plans. these findings are likely to be relevant to other arab islamic countries with socio-demographic and cultural characteristics similar to those of oman. healthcare providers who work with women with bc in such countries should be aware of the importance of culturally determined factors such as social cohesion, religion and spirituality in achieving better qol. these needs imply highly individualised care which requires caregivers to be cognisant of cultural values and beliefs, individual understanding of the illness and patients’ knowledge of and expectations around treatment. caregivers need to respect and facilitate patients’ spiritual practices, particularly those geared towards submission and acceptance of diagnoses, as these are known to enhance the lives of women with bc. while paying attention to women’s expectations, feelings and needs, it is essential that a caregiver’s own beliefs and value systems are not imposed on patients. a team approach may be preferable and should be one that includes the treating doctor, trained nurses, psychiatrists, health educators, dieticians and close family members. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors thank the members of rhwg as well as all the participating women and the staff working in the women’s oncology ward of the royal hospital for their cooperation. references 1. world health organization (who). cancer—breast cancer. secondary cancer–breast cancer 2019. from: www.who.int/ cancer/prevention/diagnosis-screening/breast-ancer/en/ accessed: mar 2020. 2. world health organization. guidelines for the early detection and screening of breast cancer. from: apps.who.int/iris/ handle/10665/119811 accessed: mar 2020. 3. elobaid y, aw tc, lim jnw, hamid s, grivna m. breast cancer presentation delays among arab and national women in the uae: a qualitative study. ssm popul health 2016; 2:155–63. https://doi.org/10.1016/j.ssmph.2016.02.007. 4. al-azri m, al-awisi h, al-rasbi s, el-shafie k, al-hinai m, al-habsi h, et al. psychosocial impact of breast cancer diagnosis among omani women. oman med j 2014; 29:437–44. https:// doi.org/10.5001/omj.2014.115. 5. al-azri m, al-awisi h, al-moundhri m. coping with a diagnosis of breast cancer-literature review and implications for developing countries. breast j 2009; 15:615–22. https://doi. org/10.1111/j.1524-4741.2009.00812.x. 6. national wellness institute of australia (nwia). definitions of wellbeing, quality of life and wellness. from: www.scribd.com/ document/131650029/definitions-of-wellbeing-quality-oflife-and-wellness accessed: mar 2020. 7. conley c, bishop b, andersen b. emotions and emotion regulation in breast cancer survivorship. healthcare 2016; 4:56. https://doi.org/10.3390/healthcare4030056. 8. haddou rahou b, el rhazi k, ouasmani f, nejjari c, bekkali r, montazeri a, et al. quality of life in arab women with breast cancer: a review of the literature. health qual life outcomes 2016; 14:64. https://doi.org/10.1186/s12955-016-0468-9. 9. hunter ms, coventry s, hamed h, fentiman i, grunfeld ea. evaluation of a group cognitive behavioural intervention for women suffering from menopausal symptoms following breast cancer treatment. psychooncology 2009; 18:560–3. https://doi. org/10.1002/pon.1414. 10. world health organization. cancer prevention and control in the context of an integrated approach. from: apps.who.int/gb/ ebwha/pdf_files/eb140/b140_31-en.pdf accessed: mar 2020. 11. meropol nj, egleston bl, buzaglo js, benson ab 3rd, cegala dj, diefenbach ma, et al. cancer patient preferences for quality and length of life. cancer 2008; 113:3459–66. 12. alawadi sa, ohaeri ju. health–related quality of life of kuwaiti women with breast cancer: a comparative study using the eortc quality of life questionnaire. bmc cancer 2009; 9:222. https://doi.org/10.1186/1471-2407-9-222. https://doi.org/10.1016/j.ssmph.2016.02.007 https://doi.org/10.5001/omj.2014.115 https://doi.org/10.5001/omj.2014.115 https://doi.org/10.1111/j.1524-4741.2009.00812.x https://doi.org/10.1111/j.1524-4741.2009.00812.x https://doi.org/10.3390/healthcare4030056 https://doi.org/10.1186/s12955-016-0468-9 https://doi.org/10.1002/pon.1414 https://doi.org/10.1002/pon.1414 https://doi.org/10.1186/1471-2407-9-222 asya al-riyami, nadia n. abdulhadi and mohammed al-azri clinical and basic research | e367 13. huijer ha-s, abboud s. health-related quality of life among breast cancer patients in lebanon. eur j oncol nurs 2012; 16:491–7. https://doi.org/10.1016/j.ejon.2011.11.003. 14. national center for statistics and information. population clock. from: www.ncsi.gov.om/pages/ncsi.aspx accessed: mar 2020. 15. al-lawati na, al-bahrani bj, al-raisi ss, al-lawati ja. twenty-year trends of cancer incidence in omanis, 1996–2015. oman med j 2019; 34:361–87. 16. al-lawati ja, al-zakwani i, fadhil i, al-bahrani bj. cancer incidence in oman (1996-2015). oman med j 2019; 34:271–3. https://doi.org/10.5001/omj.2019.55. 17. al-azri mh, al-awisi h, al-rasbi s, al-moundhri m. coping with a diagnosis of breast cancer among omani women. j health psychol 2014; 19:836–46. https://doi.org/10.1177/13 59105313479813. 18. leung l. validity, reliability, and generalizability in qualitative research. j family med prim care 2015; 4:324–7. https://doi. org/10.4103/2249-4863.161306. 19. hammarberg k, kirkman m, de lacey s. qualitative research methods: when to use them and how to judge them. hum reprod 2016; 31:498–501. https://doi.org/10.1093/humrep/dev334. 20. patton mq. qualitative evaluation and research methods. sage publications, 1990. 21. dejong j, zurayk h, myntti c, tekçe b, giacaman r, bashour h, et al. health research in a turbulent region: the reproductive health working group. reprod health matt 2017; s1:4–15. https://doi.org/10.1080/09688080.2017.1379864. 22. palinkas la, horwitz sm, green ca, wisdom jp, duan n, hoagwood k. purposeful sampling for qualitative data collection and analysis in mixed method implementation research. adm policy ment health 2015; 42:533–44. https:// doi.org/10.1007/s10488-013-0528-y. 23. elo s, kyngäs h. the qualitative content analysis process. j adv nurs 2008; 62:107–15. https://doi.org/10.1111/j.1365-2648.200 7.04569.x.5. 24. montazeri a. health-related quality of life in breast cancer patients: a bibliographic review of the literature from 1974 to 2007. j exp clin cancer res 2008; 27:32. https://doi. org/10.1186/1756-9966-27-32. 25. attum b, waheed a, shamoon z. cultural competence in the care of muslim patients and their families. treasure island: statpearls publishing, 2019. 26. sabry wm, vohra a. role of islam in the management of psychiatric disorders. indian j psychiatry 2013; 55:s205–14. https://doi.org/10.4103/0019-5545.105534. 27. devi m, fong k. spiritual experiences of women with breast cancer in singapore: a qualitative study. asia pac j oncol nurs 2019; 6:145. https://doi.org/10.4103/apjon.apjon_77_18. 28. rudaz m, ledermann t, grzywacz j. the influence of daily spiritual experiences and gender on subjective well-being over time in cancer survivors. arch psychol religion 2019; 41:159–71. https://doi.org/10.1177/0084672419839800. 29. masel e, schur s, watzke h. life is uncertain. death is certain. buddhism and palliative care. j pain symptom manage 2012; 44:307–12. https://doi.org/10.1016/j.jpainsymman.2012.02.018. 30. salsman jm, fitchett g, merluzzi tv, sherman ac, park cl. religion, spirituality, and health outcomes in cancer: a case for a meta-analytic investigation. cancer 2015; 121:3754–9. https://doi.org/10.1002/cncr.29349. 31. koltko-rivera m. rediscovering the later version of maslow's hierarchy of needs: self-transcendence and opportunities for theory, research, and unification. rev gen psychol 2006; 10:302–17. https://doi.org/10.1037/1089-2680.10.4.302. 32. mawardika t, afiyanti y, rahmah h. gynecological cancer inpatients need more supportive nursing care than outpatients: a comparative study. bmc nurs 2019; 18. https://doi. org/10.1186/s12912-019-0355-x. 33. al-adawi s, al-zakwani i, obeid y, zaidan z. neurocognitive functioning in women presenting with undifferentiated somatoform disorders in oman. psychiatry clin neurosci 2010; 64:555–64. https://doi.org/10.1111/j.1440-1819.2010.02117.x. https://doi.org/10.1016/j.ejon.2011.11.003 https://doi.org/10.5001/omj.2019.55 https://doi.org/10.1177/1359105313479813 https://doi.org/10.1177/1359105313479813 https://doi.org/10.4103/2249-4863.161306 https://doi.org/10.4103/2249-4863.161306 https://doi.org/10.1093/humrep/dev334 https://doi.org/10.1080/09688080.2017.1379864 https://doi.org/10.1007/s10488-013-0528-y https://doi.org/10.1007/s10488-013-0528-y https://doi.org/10.1111/j.1365-2648.2007.04569.x.5 https://doi.org/10.1111/j.1365-2648.2007.04569.x.5 https://doi.org/10.1186/1756-9966-27-32 https://doi.org/10.1186/1756-9966-27-32 https://doi.org/10.4103/0019-5545.105534 https://doi.org/10.4103/apjon.apjon_77_18 https://doi.org/10.1177/0084672419839800 https://doi.org/10.1016/j.jpainsymman.2012.02.018 https://doi.org/10.1002/cncr.29349 https://doi.org/10.1037/1089-2680.10.4.302 https://doi.org/10.1186/s12912-019-0355-x https://doi.org/10.1186/s12912-019-0355-x https://doi.org/10.1111/j.1440-1819.2010.02117.x departments of 1radiology and 2internal medicine, the royal hospital, muscat, oman; 3department of radiology, oman medical specialty board, muscat, oman. *corresponding author’s e-mail: alumairi1@yahoo.com the findings of pulmonary nocardiosis on chest high resolution computed tomography single centre experience and review of literature *rashid s. al umairi,1 nenad pandak,2 mohammed al busaidi3 clinical & basic research sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 357–361, epub. 25 aug 22 submitted 21 apr 21 revision req. 9 jun 21; revision recd. 29 jul 21 accepted 19 aug 21 https://doi.org/10.18295/squmj.9.2021.131 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: pulmonary nocardiosis is a rare opportunistic infection that is often encountered in immunocompromised patients, in particular those with the hiv infection and in solid organ transplant recipients. as the number of immunocompromised patients increase, the number of patients with pulmonary nocardiosis is also expected to increase. this study aimed to analyse both the chest high resolution computed tomography (hrct) findings of patients with confirmed pulmonary nocardiosis and review the imaging features of pulmonary nocardiosis in the literature. methods: this retrospective study was conducted at the royal hospital, muscat, oman, to identify patients with a diagnosis of pulmonary nocardiosis between january 2006 and january 2019. accordingly, nine patients with pulmonary nocardiosis were identified, but three patients were excluded as no chest hrct images were available. patient clinical presentation was recorded and chest hrct images were retrospectively reviewed. results: a total of six patients were enrolled in this study. all were male and with a mean age of 41 ± 11 years. three patients were immunocompromised, two of whom had undergone a renal transplant. the main hrct findings were cavitary nodules/masses, non-cavitary nodules/masses, septal thickening, centrilobular nodules, ground glass opacities, consolidation, pleural effusion, pleural thickening, enlarged lymph nodes and necrotic lymph nodes. conclusion: pulmonary nocardiosis shows various findings in a chest ct, the most common of which are pulmonary nodules and masses. awareness of these findings can help radiologists with a diagnosis in the appropriate clinical settings. keywords: pulmonary nocardiosis; computed tomography; oman. advances in knowledge the findings of this study demonstrate that pulmonary nocardiosis can have different findings in chest computed tomography (ct) including pulmonary nodules, masses and consolidation. application to patient care this study highlights the most common findings of pulmonary nocardiosis in chest high resolution ct. this can help establish early diagnosis and start treatment without delay. nocardiosis is a rare infection caused by a group of aerobic, weakly staining, grampositive and partially acid-fast bacteria called nocardia, which can be found in water, dust, soil, stagnant matter and decaying vegetation.1 humans contract a nocardia infection mainly through inhalation or direct inoculation through the skin. the most susceptible people to nocardiosis are immunocompromised patients, in particular patients with impaired cell immunity such as individuals with the hiv infection and solid organ transplant recipients. approximately one-third of nocardiosis cases occur in immunocompetent patients.2–4 with the increasing number of immunocompromised patients due to advanced transplant procedure, the use of immunotherapies and the increase in the number of patients infected with human immunodeficiency virus, the number of patients suffering from nocardiosis might increase as well.5 clinically, patients with pulmonary nocardiosis present with non-specific symptoms such as fever, dyspnoea and productive cough, making the clinical diagnosis difficult. if the correct diagnosis can be made early, patients can be started on treatment without delay, thereby preventing the dissemination of the infection to other parts of the body, especially the brain, which is associated with high mortality rates.6,7 therefore, immediate diagnosis and treatment of pulmonary nocardiosis is essential to lower disease morbidity and mortality. in the literature, there have been a few studies on pulmonary high resolution computed tomography (hrct) findings in patients with pulmonary nocardiosis.2,8–15 therefore, this study aimed to review the chest hrct findings in pulmonary nocardiosis and compare the findings with published studies in the literature. methods this retrospective study searched the electronic database of the royal hospital, muscat, oman, to identify https://creativecommons.org/licenses/by-nd/4.0/ the findings of pulmonary nocardiosis on chest high resolution computed tomography single centre experience and review of literature 358 | squ medical journal, august 2022, volume 22, issue 3 thickening/effusion. extra-thoracic findings were also recorded, if present. the chest hrct findings were defined according to the glossary of terms for thoracic imaging proposed by the fleischner society.16 the scientific research committee of the royal hospital, muscat, oman approved this retrospective single institution study and has waived informed consent (src#8/20 19). results all six included patients with pulmonary nocardiosis were males and aged between 29–59 years (mean patients with a confirmed diagnosis of pulmonary nocardiosis who were treated between january 2006 and january 2019. accordingly, nine patients with pulmonary nocardiosis were identified, but three were excluded as they did not have chest ct findings. clinical presentations at the time of presentation and related medical history were documented. the hrct images were reviewed by a cardiothoracic radiologist and evaluated for consolidation, centrilobular nodules, nodules/masses, ground-glass opacities, inter lobular septal thickening, bronchial wall thickening, cavitation, enlarged hilar/mediastinal lymph node(s) (defined as having a diameter of >1 cm) and pleural figure 1: a & b: computed tomography (ct) scan (lung window setting) of the chest of a 42-year-old male post-renal transplant patient showing bilateral multiple pulmonary nodules of variable sizes; some of the nodules show central cavitation (arrow) and a cavitary mass in the posterior segment of the right upper lobe (arrowhead). c: ct scan of the chest of a 59-year-old male patient with pulmonary nocardiosis (lung window setting) showing bilateral multiple pulmonary nodules of various sizes; some of the nodules show a ground glass hallow. d: ct scan of the chest of a 28-yearold male patient (lung window setting) with glomerulonephritis on steroids showing bilateral lower lobe consolidation and bilateral pleural effusions. figure 2: computed tomography (ct) chest scan of a 29-year-old male post-renal transplant patient showing a mass surrounded by ground glass halo in the right lower lobe (arrow) in the (a) mediastinal window and (b) lung window. ct chest scan of a 59-year-old male with pulmonary nocardiosis showing a mass with areas of low attenuation in the right lower lobe (asterisk) associated with a right pleural effusion. pulmonary nodules are also seen in the left lower lobe in the (c) mediastinal window and (d) lung window (arrows). rashid s. al umairi, nenad pandak and mohammed al busaidi clinical and basic research | 359 age: 41 ± 11 years). three patients were immuno compromised, two of whom had undergone a renal transplant and one was on corticosteroids. of the immunocompetent patients, one had bronchiectasis and one had gastrobronchial fistula as a complication of gastric sleeve surgery. all patients had respiratory symptoms, including fever (n = 6, 100%) and cough (n = 5, 83.3%), sputum production (n = 3, 50%), dyspnoea (n = 3, 50%) and chest pain (n = 3, 50%) [table 1]. the most common ct findings were cavitary nodules/masses (n = 4, 66.7%) [figures 1a and b], non-cavitary nodules/masses (n = 3, 50%) [figures 1c and 2], septal thickening (n = 4, 66.7%), centrilobular nodules (n = 3, 50%), ground glass opacities (n = 2, 33.3%) and consolidation (n = 1, 16.7%) [figure 1d]. four patients (66.7%) had enlarged lymph nodes, two of whom had necrotic lymph nodes [figure 3 and table 2]. this study also summarised the studies with more than two cases that reviewed the radiological features of pulmonary nocardiosis since 1995.2,8–11,13–15 [table 3]. discussion nocardiosis is a rare disease that frequently affects immunocompromised patients, especially patients with impaired cellular immunity related to hiv infection and solid organ transplantation. however, approx figure 3: computed tomography chest scan in the mediastinal window of a (a) 59-year-old male with pulmonary nocardiosis showing a right paratracheal lymph node (arrow) and a (b) 42-year-old male with pulmonary nocardiosis showing a necrotic mediastinal lymph node (arrow). table 1: clinical characteristics of patients with pulmonary nocardiosis (n = 6) characteristic n (%) mean age ± sd in years (range) 41 ± 11 (29–59) underlying condition diabetes 1 (16.7) glomerulonephritis 2 (33.3) interstitial lung disease 1 (16.7) renal transplant 2 (33.3) smoking 1 (16.7) gastrobronchial fistula 1 (16.7) bronchiectasis 1 (16.7) presenting symptoms fever 6 (100) cough 5 (83.3) chest pain 3 (50.0) sputum 3 (50.0) haemoptysis 3 (50.0) dyspnea 3 (50.0) diagnosis bronchial lavage 1 (16.7) ct guided biopsy 1 (16.7) sputum microscopy 1 (16.7) open lung biopsy 1 (16.7) pleural effusion analysis 1 (16.7) sd = standard deviation; ct = computed tomography. table 2: chest computed tomography findings of patient with pulmonary nocardiosis (n = 6) finding n (%) consolidation 1 (16.7) masses 1 (16.7) nodules 2 (33.3) cavity 1 (16.7) cavitary mass 3 (50.0) cavitary nodule 1 (16.7) halo sign 2 (33.3) ground glass opacities 2 (33.3) centrilobular nodules 3 (50) septal thickening 4 (66.7) bronchial wall thickening 5 (83.3) pleural effusion 3 (50.0) pleural thickening 1 (16.7) enlarged lymph nodes 4 (66.7) necrotic lymph nodes 2 (33.3) the findings of pulmonary nocardiosis on chest high resolution computed tomography single centre experience and review of literature 360 | squ medical journal, august 2022, volume 22, issue 3 imately one-third of patients with nocardiosis are immunocompetent, which is concordant with this study’s findings where three out of the six enrolled patients were immunocompetent.3,17,18 pulmonary nocardiosis usually occurs through the direct inhalation of the nocardia species.18 patients with pulmonary nocardiosis usually have non-specific symptoms, making the clinical diagnosis difficult. the definitive diagnosis is usually based on histopathologic examination and/or culture, which are time-consuming. however, difficulty in isolation and the slow growth of nocardia delay the diagnosis and initiation of the appropriate treatment, leading to disease dissemination and an increase in the morbidity and mortality related to the disease.2,6,7 various hrct findings of pulmonary nocardiosis have been reported in the literature, including consolidation with or without cavitation, cavitary and non-cavitary pulmonary nodules/masses, ground glass opacities, centrilobular nodules, interlobular septal thickening, a crazy paving pattern, pleural effusion and chest wall extension. the results of these studies show that the most common hrct findings are nodules/ masses with or without cavitation. the largest study by blackmon et al. examined 53 patients with pulmonary nocardiosis; the most common findings by chest ct were airspace disease and nodules.14 oszoyoglu et al. analysed seven cases of pulmonary nocardiosis after lung transplantation and found that the most common chest hrct finding was pulmonary nodules, seen in 71% of the patients.11 sato et al. reported hrct findings of 18 patients with pulmonary nocardiosis and found that 94.4% patients had a nodule or mass, 77.8% had ground-glass opacity and 77.8% had interlobular septal thickening.10 tsujimoto et al. found that ground glass opacity and septal thickening were the most common findings seen in 85.7% of the patients, followed by bronchial wall thickening and crazy paving, as seen in 71.4% of the cases.9 mehrian et al. analysed 25 patients and found that the most common hrct findings were pulmonary nodules (96%) and consolidation (76%).15 more recently, liu et al. described nine patients with pulmonary nocardiosis and found that eight of them had consolidation, of which three had cavitation and six had masses/nodules, of which three had cavitation.2 in the present study, the most common ct findings of pulmonary nocardiosis were lung nodules/ masses, of which four showed cavitation. four patients had septal thickening and three had centrilobular nodules. the current findings are similar to what has been reported in the literature; however, necrotic lymph nodes were noted in two patients as well, a table 3: summary of the chest computed tomography findings of reported cases of pulmonary nocardiosis buckley et al.13 (1995) 24 8 20 8 7 yoon et al.8 (1995) 5 4 3 4 3 blackmon et al.14 (2011) 53 39 41 21 6 7 8 oszoyoglu et al.11 (2007) 7 1 1 5 2 1 1 sato et al.10 (2016) 18 6 17 12 14 0 14 1 2 tsujimoto et al.9 (2012) 7 1 5 1 6 1 6 5 4 5 4 mehrian et al.15 (2015) 25 19 24 13 8 1 12 3 10 4 liu et al.2 (2017) 9 8 6 2 4 4 4 4 4 2 total 148 86 1 121 55 3 8 33 5 26 5 27 16 17 17 14 3 0 a ut ho r a nd y ea r o f p ub lic at io n n um be r o f c as es c on so lid at io n c on so lid at io n w it h ca vi ta ti on n od ul es /m as se s c av it at io n c av it ar y no du le s b ro nc hi ec ta si s b ro nc hi al w al l t hi ck en in g h al o si gn g ro un d gl as s o pa ci ti es pl eu ra l e ffu si on c en tr ilo bu la r n od ul es pl eu ra l t hi ck en in g se pt al th ic ke ni ng ly m ph n od es c ra zy p av in g pa tt er n c he st w al l e xt en si on n ec ro ti c ly m ph n od es rashid s. al umairi, nenad pandak and mohammed al busaidi clinical and basic research | 361 finding that has not been previously reported in the literature. the differential diagnosis for pulmonary nocar diosis includes other causes of lung consolidation, cavit ation and nodules such as other infections, vasculitis and malignancy. pulmonary actinomycosis is a lung infection that can have similar radiological findings as pulmonary nocardiosis. however, patients with actinomycosis are usually immunocompetent, have poor dentition and are at a higher risk of aspirating infected oropharyngeal secretions. pulmonary tuber culosis is another pulmonary infection that can present with cavitation, however it tends to involve the apical segments of the upper lobes and superior segments of the lower lobes and these are usually associated treein-bud nodules. in the clinical setting of pulmonary infection, nocardiosis should be considered as a differential diagnosis of pulmonary nodules and masses. conclusion pulmonary nocardiosis is a rare infection that commonly occurs in patients with impaired cell-mediated immunity, but can also be seen in immunocompetent patients. in the chest hrct, pulmonary nocardiosis shows a wide spectrum of findings, most commonly lung nodules/ masses with or without cavitation. in the appropriate clinical setting, the radiologist should include pulmonary nocardiosis in the differential diagnosis of pulmonary nodules and masses. a u t h o r s’ c o n t r i b u t i o n ru supervised the work and drafted the manuscript. np reviewed and edited the manuscript and mb collected the data and revised the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. mcneil mm, brown jm. the medically important aerobic actinomycetes: epidemiology and microbiology. clin microbiol rev 1994; 7:357–417. https://doi.org/10.1128/cmr.7.3.357. 2. liu b, zhang y, gong j, jiang s, huang y, wang l. ct findings of pulmonary nocardiosis: a report of 9 cases. j thorac dis 2017; 9:4785–90. https://doi.org/10.21037/jtd.2017.09.122. 3. lederman er, crum nf. a case series and focused review of nocardiosis: clinical and microbiologic aspects. medicine (baltimore). 2004; 83:300–13. https://doi.org/10.1097/01.md.0000141100.30871.39. 4. beaman bl, burnside j, edwards b, causey w. nocardial infections in the united states, 1972-1974. j infect dis 1976; 134:286–9. https://doi.org/10.1093/infdis/134.3.286. 5. filice ga. nocardiosis in persons with human immunodeficiency virus infection, transplant recipients, and large, geographically defined populations. j lab clin med 2005; 145:156–62. https:// doi.org/10.1016/j.lab.2005.01.002. 6. wang hk, sheng wh, hung cc, chen yc, lee mh, lin ws, et al. clinical characteristics, microbiology, and outcomes for patients with lung and disseminated nocardiosis in a tertiary hospital. j formos med assoc 2015; 114:742–9 https://doi. org/10.1016/j.jfma.2013.07.017. 7. husain s, mccurry k, dauber j, singh n, kusne s. nocardia infection in lung transplant recipients. j heart lung transplant 2002; 21:354–9. https://doi.org/10.1016/s1053-2498(01)00394-1. 8. yoon hk, im jg, ahn jm, han mc. pulmonary nocardiosis: ct findings. j comput assist tomogr 1995; 19:52–5. https:// doi.org/10.1097/00004728-199501000-00010. 9. tsujimoto n, saraya t, kikuchi k, takata s, kurihara y, hiraoka s, et al. high-resolution ct findings of patients with pulmonary nocardiosis. j thorac dis 2012; 4:577–82. https:// doi.org/10.3978/j.issn.2072-1439.2012.11.07. 10. sato h, okada f, mori t, ono a, nakayama t, ando y, et al. high-resolution computed tomography findings in patients with pulmonary nocardiosis. acad radiol 2016; 23:290–6. https://doi.org/10.1016/j.acra.2015.11.008. 11. oszoyoglu aa, kirsch j, mohammed tl. pulmonary nocardiosis after lung transplantation: ct findings in 7 patients and review of the literature. j thorac imaging 2007; 22:143–8. https://doi. org/10.1097/01.rti.0000213583.21849.5c. 12. kanne jp, yandow dr, mohammed tl, meyer ca. ct findings of pulmonary nocardiosis. ajr am j roentgenol 2011; 197:w266–72. https://doi.org/10.2214/ajr.10.6208. 13. buckley ja, padhani ar, kuhlman je. ct features of pulmonary nocardiosis. j comput assist tomogr 1995; 19:726–32. https:// doi.org/10.1097/00004728-199509000-00007. 14. blackmon kn, ravenel jg, gomez jm, ciolino j, wray dw. pulmonary nocardiosis: computed tomography features at diagnosis. j thorac imaging 2011; 26:224–9. https://doi.org/10.10 97/rti.0b013e3181f45dd5. 15. mehrian p, esfandiari e, karimi ma, memari b. computed tomography features of pulmonary nocardiosis in immuno compromised and immunocompetent patients. pol j radiol 2015; 80:13–17. https://doi.org/10.12659/pjr.892042. 16. hansell dm, bankier aa, macmahon h, mcloud tc, muller nl, remy j. fleischner society: glossary of terms for thoracic imaging. radiology 2008; 246:697–722. https://doi. org/10.1148/radiol.2462070712. 17. beaman bl, beaman l. nocardia species: host-parasite relationships. clin microbiol rev 1994; 7:213–64. https://doi. org/10.1128/cmr.7.2.213. 18. batista mv, pierrotti lc, abdala e, clemente wt, girao es, rosa dr, et al. endemic and opportunistic infections in brazilian solid organ transplant recipients. trop med int health 2011; 16:1134–42. https://doi.org/10.1111/j.1365-3156.2011.02816.x. https://doi.org/10.1128/cmr.7.3.357 https://doi.org/10.21037/jtd.2017.09.122 https://doi.org/10.1097/01.md.0000141100.30871.39 https://doi.org/10.1093/infdis/134.3.286 https://doi.org/10.1016/j.lab.2005.01.002 https://doi.org/10.1016/j.lab.2005.01.002 https://doi.org/10.1016/j.jfma.2013.07.017 https://doi.org/10.1016/j.jfma.2013.07.017 https://doi.org/10.1016/s1053-2498(01)00394-1 https://doi.org/10.1097/00004728-199501000-00010 https://doi.org/10.1097/00004728-199501000-00010 https://doi.org/10.3978/j.issn.2072-1439.2012.11.07 https://doi.org/10.3978/j.issn.2072-1439.2012.11.07 https://doi.org/10.1016/j.acra.2015.11.008 https://doi.org/10.1097/01.rti.0000213583.21849.5c https://doi.org/10.1097/01.rti.0000213583.21849.5c https://doi.org/10.2214/ajr.10.6208 https://doi.org/10.1097/00004728-199509000-00007 https://doi.org/10.1097/00004728-199509000-00007 https://doi.org/10.1097/rti.0b013e3181f45dd5 https://doi.org/10.1097/rti.0b013e3181f45dd5 https://doi.org/10.12659/pjr.892042 https://doi.org/10.1148/radiol.2462070712 https://doi.org/10.1148/radiol.2462070712 https://doi.org/10.1128/cmr.7.2.213 https://doi.org/10.1128/cmr.7.2.213 https://doi.org/10.1111/j.1365-3156.2011.02816.x 1department of pharmacology, saveetha medical college and hospital, chennai, india; 2formerly department of pharmacology, gulf medical university, ajman, united arab emirates e-mail: shehnazilyas@yahoo.com دراسة طولية مدهتا مخس سنوات عن البيئة التعليمية يف منهج طيب متكامل حديثًا �صيد اإليا�ض �صهناز abstract: objectives: the college of medicine at gulf medical university (gmu), ajman, united arab emirates, was subjected to a curricular reform, which shifted the institution from a traditional curriculum to a hybrid, studentcentred, integrated curriculum. there are no previous studies analysing the consequences of such a curricular modification on the educational environment (ee). therefore, this study aimed to analyse the ee of a pioneer cohort of the innovative curriculum over their five-year course of study. methods: this prospective longitudinal study was conducted between september 2009 and september 2013 at the college of medicine. the dundee ready education environment measure questionnaire was completed by a pioneer cohort of students at the start of each academic session for five consecutive years. the mean overall, subscale and individual statement scores were evaluated using the kruskal-wallis and wilcoxon-rank sum tests. results: a total of 178 responses were collected (response rate: 90.4%). the mean overall score throughout the five years of study was 130/200. a significant difference in the scores (p <0.05) was observed as the students proceeded through the course. the overall and subscale scores were significantly higher in the first and final years of study. analysis of the statements recognised the medical knowledge of the teachers’ and students’ awareness of empathy and social interactions as persistent strengths of the college over the entire course of study. a curricular overload, a want for support systems for stressed students, students’ waning interest levels and assessment strategies emerged as areas that warranted further attention. conclusion: the pioneer cohort of the new curriculum rated their ee as positive throughout their five years of study at gmu. an examination of individual statements revealed the programme’s strengths and areas for improvement for the institution. keywords: curriculum; environment; longitudinal study; medical students; perception; undergraduate medical education; united arab emirates. امللخ�ص: الهدف: قامت كلية الطب يف جامعة اخلليج الطبية يف الإمارات العربية املتحدة موؤخًرا بتعديل املناهج الدرا�صية بحيث حولت املناهج الدرا�صية التقليدية اإىل منهج متكامل مركزه الطالب. ل تتوفر درا�صات �صابقة حتلل نتائج تعديالت كهذه على املناهج الدرا�صية واأثرهاعلى البيئة التعليمية. تهدف هذه الدرا�صة اإىل حتليل نتائج البيئه التعليمية لفئة رائدة من الطالب ا�صتخدموهذه املناهج املبتكرة على مدار درا�صتهم ملدة خم�ض �صنوات. الطريقة: اأجريت هذه الدرا�صة الطولية امل�صتقبلية بني �صبتمرب 2009 واأيلول 2013 يف كلية الطب. مت جمع نتائج ا�صتبيان دندي لقيا�ض ا�صتعداد بيئة التعليم من الفئة امل�صتهدفة من الطالب يف بداية كل �صنة اأكادميية ملدة خم�ض �صنوات متتالية. مت تقييم متو�صط الدرجات الإجمالية والفرعية لال�صتبيان با�صتخدام اختبارات جمموع ترتيب كرو�صكال والي�ض ويلكوك�صون. النتائج: مت وجد .130/200 هي للدرا�صة اخلم�ض ال�صنوات خالل املتو�صطة الإجمالية النتيجة كانت .)90.4% ال�صتجابة: )معدل ا�صتبانه 178 جمع اختالف كبري ذا دللة اإح�صائية يف الدرجات )p >0.05( مع تقدم الطالب يف الدورة الدرا�صية. كانت الدرجات الإجمالية والفرعية اأعلى بكثري يف ال�صنوات الأوىل والأخرية من الدرا�صة. عند حتليل النتائج وجد اأن املعرفة الطبية للمعلمني واإدراك الطالب للتعاطف والتفاعل الجتماعي هي نقاط قوة ثابتة للكلية على مدار فرتة الدرا�صة. ومن ناحية اأخرى وجد اأن الزيادة يف عبء املناهج الدرا�صية ، واحلاجة الهتمام. من املزيد ت�صتدعي التي املجالت هي التقييم وا�صرتاتيجيات الهتمام م�صتوى وانخفا�ض املجهدين للطالب دعم اأنظمة اإىل اخلال�صة: �صنف الطالب الذين طبقو املنهج اجلديد للبيئة التعليمية على اأنه كان اإيجابيا طوال �صنوات الدرا�صة اخلم�ض يف جامعة اخلليج الطبية. ك�صف تقييم البيانات الفردية عن نقاط قوة الربنامج وجمالت حت�صينه يف اجلامعة. الكلمات املفتاحية: املناهج الدرا�صية؛ بيئة؛ درا�صة طولية؛ طالب الطب؛ املعرفة؛ التعليم الطبي اجلامعي؛ الإمارات العربية املتحدة. a five year longitudinal study of the educational environment in a newly integrated medical curriculum syed i. shehnaz1,2 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e335–344, epub. 22 dec 19 submitted 13 mar 19 revision req. 8 may 19; revision recd. 28 may 19 accepted 20 jun 19 advances in knowledge the pioneer cohort of students perceived a sustained positive ee in the new organ-system-based integrated curriculum over their entire course of study. a curricular overload, a want for a support system for stressed students, students’ waning interest levels and assessment strategies emerged as persistent areas that warrant further development. application to patient care students are major stakeholders in a medical curriculum and their experiences in the ee can influence their learning outcomes. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.009 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ a five year longitudinal study of the educational environment in a newly integrated medical curriculum e336 | squ medical journal, november 2019, volume 19, issue 4 the educational environment (ee) of anyinstitution influences the scholastic experiences of the students.1,2 favourable educational out comes are strongly shaped by an encouraging ee. as “any new curriculum cannot be sensibly separated from its learning milieu, with the introduction of a new curriculum creating repercussions in the learning milieu, and these repercussions, in turn, affecting the new curriculum and moderating its impact,” the active curriculum of any institution has a primary influence on its ee.1 students’ perceptions of ees have been measured through the dundee ready education environment measure (dreem) questionnaire.2–5 dreem has been used to give institutional feedback, assess new or changed curricula, compare different medical schools’ ees and evaluate multiple teaching sites’ ee differences.6–12 students’ expectations of ees at the start of the first year have also been compared with their actual experiences.13 although studies have compared the perceptions of students at two given points in time, no studies have scrutinised the long-term consequences of curricular reform on ee.13–16 the bachelor of medicine bachelor of surgery (mbbs) programme at the college of medicine (com) at gulf medical university (gmu), ajman, united arab emirates, is a five-year programme followed by a one-year internship. the com reformed its curriculum from a discipline-based model to a student-centred, modular, integrated curriculum. in the english-medium programme, the new curriculum is divided into three phases. phase one consists of one year and introduces the basics of medical science. phase two is two years and includes studying the organ systems in an integrated manner. phase three is two years and consists of clinical clerkship training. during the course of this study, the final year of the clinical clerkship training took place in a tertiary hospital which was not part of the principal teaching hospital. as curriculum is a partial determinant of an institution’s ee, any curricular reform will potentially transform an institution’s ee.1 however, the long-term effects of gmu’s curricular change on ee has not been previously assessed. the ee at gmu, therefore, both prior and subsequent to the curricular change, was analysed.12 this study aimed to analyse the ee of the pioneer/first cohort involved in the revised curriculum over their entire course of study and investigate any gender or ethnic differences as they relate to students’ perceptions. the longitudinal evaluation of the ee assessed the impact of the new curriculum as it matured and determined whether changes were occurring in the correct direction. moreover, the utilisation of a standardised tool, the dreem questionnaire, for the same cohort over their entire curriculum captured more comprehensive and evolving viewpoints, allev iating any personality differences arising due to the diversity in different cohorts. subsequently, the results of this study may provide indispensable input for impr oving the curriculum to maximise student learning. methods this prospective longitudinal study was conducted between september 2009 and september 2013. the dreem questionnaire was used to determine the com’s ee. this questionnaire has 50 statements which are distributed among five subscales—students’ perceptions of learning, students’ perceptions of teachers, students’ academic self-perceptions, students’ perceptions of atmosphere and students' social self-perceptions. the statements are scored on a five-point likert scale ranging from zero for ‘strongly disagree’ to four for ‘strongly agree’ with the maximum attainable score of 200.17 the dreem questionnaire underwent pilot testing and explanations were provided for some statements for better understanding. from the second year onwards, the dreem questionnaire was administered at the commencement of each academic year for five consecutive years. the questionnaires were distributed to a convenience sample of students attending class on the days that surveys were conducted every year. any new entrants to the course (i.e. transfer students from other univ ersities or those from a previous batch) were excluded from the study. the research objectives were explained and participants were instructed to answer the quest ionnaire based on their experiences in the previous academic year. regular contact with the programme’s first cohort emphasising their contribution in resolving issues with the new curriculum and apprising them of publications involving them were strategic in preventing survey fatigue.12 as the ee is deeply influenced by the curriculum, students’ perceptions of their ee can provide indispensable input for designing better curricular strategies to maximise learning. enhanced learning outcomes and improved curricular designs will eventually have bearing on the achievements, satisfaction and success of future doctors. learning and teaching approaches can be developed that foster problem-solving skills in future physicians for the benefit of the communities they will serve. syed i. shehnaz clinical and basic research | e337 statistical analysis was conducted using statistical package for the social sciences (spss), version 24 (ibm corp., armonk, new york, usa). means ± standard deviation in the overall, subscale and individual statement scores between all five years were evaluated with the kruskal-wallis test. if any significant variances were observed, pairwise comparisons were used. the wilcoxon-rank sum and kruskal-wallis tests were utilised to analyse gender and ethnic differences, respectively. a p value of 0.05 was considered stat istically significant. for analysis, statements were considered as either reflective of excellence, areas that could be enhanced or areas of shortcoming if their mean scores were ≥3, 2–3 or ≤2, respectively. the scores for negative statements were reversed so as to facilitate exact conclusions about the statements. high reversed scores indicated that more students disagreed with the statements. informed consent was obtained from all partic ipants and their confidentiality was assured. ethical approval was attained from the institutional ethics review committee of gmu. results a total of 178 responses were obtained during the fiveyear course of study (overall response rate: 90.4%). the response rates for the first to fifth year were 94%, 90%, 92.5%, 97% and 73%, respectively. most respondents were female (62.5%) and of multi-ethnic descent [tables 1 and 2]. the majority of students were of asian descent, from the indian subcontinent (67.5%) followed by africans (20.8%) and arabs (11.7%). the cronbach’s alpha coefficient was 0.93 which suggests excellent internal consistency and reliability of the dreem questionnaire with the current sample. although the alpha coefficient for the subscale “social self-perceptions” was low, the other subscales indicated satisfactory reliability, with perceptions of learning at 0.82, perceptions of teachers at 0.75, academic selfperceptions at 0.75, perceptions of atmosphere at 0.81 and social self-perceptions at 0.63. a significant pattern of difference in the overall scores was observed as the students proceeded through the entire course (p = 0.02). the mean overall scores were significantly higher between the first and second year and the fourth and final year of the study when compared to the scores in the second and third years and third and fourth years of study (p = 0.02 and 0.02 versus 0.09 and 0.06, respectively). no significant differences were detected between the mean overall scores between the second and third years and between the third and fourth years [table 1]. significant differences were identified in the mean subscale scores of students’ “perceptions of teachers”, “academic self-perceptions” and “perceptions of atmosphere” for all responses. the mean subscale scores of “perceptions of learning”, “perceptions of teachers” and “academic self-perception” were statistically sign ificantly higher in the first year of study when compared to the scores in the second year (p = 0.03, 0.006 and 0.007, respectively). similarly, higher mean scores were also observed for “perceptions of atmosphere” in the final year as compared to the scores in the fourth year (p = 0.007) [table 2]. among the five subscales, “academic self-per ception” had the highest mean score for all responses and in all the years except in the final year. “perceptions of atmosphere” was the highest scoring subscale in the final year. in all years, except the third year, and for all responses, the “social self-perceptions” subscale obtained the lowest mean scores. “perceptions of teachers” was recognised as the subscale with the lowest scores in the third year [table 2]. table 1: mean characteristics and mean global dundee ready education environment measure scores of the pioneer cohort after a curricular change by year of study (n = 178) characteristic n (%) first year (n = 44) second year* (n = 40) third year* (n = 37) fourth year (n = 35) fifth year (n = 22) all responses (n = 178) gender male 17 (38.6) 16 (41) 12 (33.3) 12 (34.3) 9 (40.9) 66 (37.5) female 27 (61.4) 23 (59) 24 (66.7) 23 (65.7) 13 (59.1) 110 (62.5) mean age ± sd in years 19.98 ± 2.0 21.22 ± 2.1 22.20 ± 2.5 22.85 ± 2.28 23.18 ± 1.05 21.70 ± 2.37 mean global dreem score ± sd (% of maximum score) 135.41 ± 22.13 (67.7) 123.33 ± 22.58 (61.7) 130.3 ± 21.61 (65.2) 126.11 ± 20.96 (63.1) 135.27 ± 14.49 (67.6) 129.79 ± 21.43 (64.9) p = 0.02 p = 0.09 p = 0.06 p = 0.02 p value 0.02 dreem = dundee ready education environment measure; sd = standard deviation. *one student did not indicate gender. a five year longitudinal study of the educational environment in a newly integrated medical curriculum e338 | squ medical journal, november 2019, volume 19, issue 4 the highest score was from statement 15: “the students have good friends in this school” in the first to fourth years and in the entire sample. however, statement 2: “the teachers are knowledgeable” garnered the highest scores in the final year. students in the first year, final year and throughout all five years perceived that teaching emphasised factual learning too much as statement 25 obtained the lowest score. in the second, third and fourth years, the lowest scores were given to statements 3, 14 and 17: “there is a good support system (help) for students who get stressed”, “the students are rarely bored in this course” and “cheating is a problem in this school”, respectively [tables 3 and 4]. statistically significant differences across all years were observed for eight statements, of which many had significantly higher scores in the first year compared to the second year. the highest mean scores for all but five statements were observed either in the first or final years of study. statements 10, 27, 46 and 47 had their highest scores observed in the third year and the highest scores for statement 49 were reported in the second year [tables 3 and 4]. the statements with mean scores above three, representing areas of excellence in all years, were state ments 2, 15, 31 and 33: “the teachers are knowledge able”, “the students have good friends in this school”, “the students have learned a lot about empathy in their profession” and “the students feel comfortable in class socially”, respectively. the areas of shortcoming, as highlighted by scores ≤2 over the five years, were statements 3, 14, 17, 25 and 27: “there is a good support system (help) for students who get stressed”, “the students are rarely bored in this course”, “cheating is a problem in this school”, “the teaching gives too much importance to factual learning” and “the students are able to memorise all they need”, respectively. the other 41 statements’ scores reflected areas that could be enhanced [tables 3 and 4]. no significant gender differences were observed in the overall scores throughout the five years. although males reported more positive scores for “social selfperceptions” (p = 0.04) in comparison to females across the five years of study, no other significant gender differ ences in subscale scores were observed [table 2]. males also gave significantly higher scores to ten statements than females. however, female students did not perceive that “the teachers are authoritarian” (statement 9) compared to males, therefore this was scored higher than the males (2.29 ± 0.91 versus 1.95 ± 1.01) [table 5]. significant ethnic differences (p <0.05) were det ected in overall scores, with students of african ethnicity (141.44 ± 22.56) generally giving higher scores than asian (131.63 ± 20.11) or arab students (119.43 ± 18.02). similarly, the subscales “perceptions of learning” and “perceptions of teachers” and 13 other statements also revealed statistically significantly differences based on ethnicity [tables 2 and 5]. in general, students in the first and final years showed more positive perceptions as they had two (4%) and one (2%) statement with a mean score of ≤2, and 11 (22%) and 12 (24%) statements with a mean score of ≥3, respectively [figure 1]. table 2: mean dundee ready education environment measure subscale scores of the pioneer cohort after a curricular change by year of study, gender and ethnicity (n = 178) dreem subscale (maximum score) mean dreem score ± sd (% of maximum score) year of study all responses (n = 178) p value gender* p value ethnicity† p value one (n = 44) two (n = 40) three (n = 37) four (n = 35) five (n = 22 male (n = 66) female (n = 110) asian (n = 81) african (n = 25) arab (n = 14) students’ perceptions of learning (48) 33.36 ± 5.21 (69.5) 30 ± 7.1 (62.5) 31.14 ± 6.2 (64.9) 29.94 ± 6.29 (62.4) 32.41 ± 3.3 (67.5) 31.35 ± 6.03 (65.3) 0.60 31.8 ± 7.07 (66.3) 31.07 ± 5.39 (64.7) 0.75 31.43 ± 5.89 (65.5) 35.12 ± 6.23 (73.2) 28.43 ± 4.6 (59.2) 0.007 p = 0.03 students’ perceptions of teachers (44) 29.98 ± 5.08 (68.1) 27.33 ± 5 (62.1) 27.51 ± 5.13 (62.5) 27.89 ± 5.36 (63.4) 29.73 ± 4.87 (67.6) 28.43 ± 5.18 (64.6) 0.02 29.52 ± 5.09 (67.1) 27.82 ± 5.18 (63.2) 0.08 29.16 ± 4.3 (66.3) 31.48 ± 5.03 (71.5) 25 ± 5.95 (56.8) 0.002 p = 0.006 students’ academic selfperceptions (32) 22.41 ± 4.13 (70) 20 ± 4.22 (62.5) 22.14 ± 4.1 (69.2) 21.31 ± 3.79 (66.6) 21.59 ± 3.35 (67.5) 21.49 ± 4.05 (67.2) 0.02 22.06 ± 4.12 (68.9) 21.15 ± 4.02 (66.1) 0.45 21.62 ± 4.1 (67.6) 22.72 ± 4.17 (71) 20.14 ± 2.71 (62.9) 0.23 p = 0.007 p = 0.005 students’ perceptions of atmosphere (48) 31.45 ± 7.17 (65.5) 29.53 ± 6.52 (61.5) 31.24 ± 6.25 (65.1) 29.89 ± 5.66 (62.3) 32.91 ± 4.14 (68.6) 30.85 ± 6.26 (64.3) 0.047 31.77 ± 6.39 (66.2) 30.32 ± 6.2 (63.2) 0.33 31.09 ± 6.19 (64.8) 34.16 ± 6.07 (71.2) 29.07 ± 4.55 (60.6) 0.06 p = 0.03 p = 0.007 students’ social selfperceptions (28) 18.21 ± 4.66 (65) 16.47 ± 4.34 (58.8) 18.27 ± 3.65 (65.3) 17.09 ± 3.67 (61) 18.64 ± 3.65 (66.6) 17.66 ± 4.12 (63.1) 0.10 18.68 ± 3.89 (66.7) 17.06 ± 4.17 (60.9) 0.04 18.33 ± 3.67 (65.5) 17.96 ± 4.96 (64.1) 16.79 ± 4.58 (60) 0.54 p = 0.03 dreem = dundee ready education environment measure; sd = standard deviation. *two students did not indicate gender. †58 students did not indicate their ethnicity. syed i. shehnaz clinical and basic research | e339 discussion the role of curriculum is important to the ee because curriculum changes are essentially changes in the ee.1 gmu’s curricular reform emphasises a student-centred approach that had an encouraging influence on the studied ee as reflected in the significantly higher scores of second year students in the integrated curriculum.12 the results of the current study indicated that this effect was sustainable, with a positive ee maintained over five years as the curriculum progressed. table 3: mean dundee ready education environment measure statement scores of the pioneer cohort after a curricular change by year of study (n = 178) item # dreem subscale statement mean dreem score ± sd p valueyear one (n = 44) year two (n = 40) year three (n = 37) year four (n = 35) year five (n = 22) all responses (n = 178) students’ perceptions of learning 16 the teaching is sufficiently concerned to develop the student’s competence. 2.95 ± 0.65 2.43 ± 1.11 2.68 ± 0.85 2.54 ± 1.01 2.91 ± 0.68 2.69 ± 0.9 0.13 p = 0.02 20 the teaching is well focused. 2.91 ± 0.56 2.38 ± 0.95 2.81 ± 0.70 2.54 ± 0.85 2.82 ± 0.73 2.69 ± 0.79 0.02 p = 0.005 p = 0.03 22 the teaching is sufficiently concerned to develop the students’ confidence. 3.0 ± 0.48 2.63 ± 0.87 2.73 ± 0.77 2.66 ± 0.84 2.82 ± 0.59 2.77 ± 0.74 0.25 p = 0.04 24 the teaching time is put to good use. 2.91 ± 0.71 2.38 ± 1.13 2.62 ± 0.86 2.26 ± 1.09 2.5 ± 0.96 2.55 ± 0.97 0.03 p = 0.02 students’ perceptions of teachers 2 the teachers are knowledgeable. 3.16 ± 0.68 3.1 ± 0.63 3.08 ± 0.49 3.0 ± 0.59 3.5 ± 0.51 3.14 ± 0.61 0.01 p = 0.003 6 the teachers are patient with the hospital patients. 3.0 ± 0.75 2.5 ± 0.78 2.89 ± 0.84 2.71 ± 0.75 3.0 ± 0.69 2.81 ± 0.79 0.007 p = 0.002 p = 0.01 18 the teachers have good communication skills with hospital patients. 2.91 ± 0.88 2.5 ± 0.91 2.76 ± 0.93 2.51 ± 0.98 2.95 ± 0.79 2.71 ± 0.92 0.046 p = 0.02 29 the teachers are good at providing feedback to students. 2.2 ± 0.98 1.83 ± 1.24 2.19 ± 1.02 2.34 ± 1.06 2.73 ± 0.99 2.21 ± 1.09 0.04 students’ academic self-perceptions 5 learning strategies which worked for the students before continue to work for them now. 2.52 ± 0.9 1.93 ± 1.14 2.24 ± 0.98 2.43 ± 0.92 2.5 ± 0.96 2.31 ± 1 0.053 p = 0.007 10 the students are confident about passing this year. 3.02 ± 0.79 2.6 ± 0.93 3.38 ± 0.72 2.89 ± 0.8 2.82 ± 0.91 2.95 ± 0.86 0.002 p = 0.04 p <0.001 p = 0.006 26 the students’ work last year has been a good preparation for this year’s work. 3.07 ± 0.7 2.68 ± 0.83 3.05 ± 0.74 2.89 ± 0.76 2.45 ± 1.01 2.87 ± 0.81 0.01 p = 0.02 p = 0.02 27 the students are able to memorise all they need. 2.09 ± 1.05 1.70 ± 1.09 2.22 ± 1.13 1.89 ± 0.96 2.1 ± 0.96 2.0 ± 1.06 0.19 p = 0.04 students’ perceptions of atmosphere 11 the atmosphere is relaxed during the hospital-ward teaching. 2.77 ± 0.91 2.6 ± 0.87 2.92 ± 0.76 2.57 ± 0.92 3.05 ± 0.65 2.76 ± 0.85 0.10 p = 0.04 12 the timetable of this school is appropriate. 2.48 ± 1.05 1.83 ± 1.15 2.24 ± 1.14 1.86 ± 1.26 2.05 ± 1.29 2.11 ± 1.18 0.07 p = 0.008 17 *cheating is a problem in this school. 1.98 ± 1.30 2.1 ± 1.26 2.05 ± 1.25 1.63 ± 1.14 2.32 ± 1.09 1.99 ± 1.23 0.24 p = 0.02 36 the students are able to concentrate well. 2.66 ± 1.08 2.25 ± 1.06 2.57 ± 0.84 2.51 ± 0.92 2.64 ± 0.66 2.52 ± 0.95 0.19 p = 0.03 43 the atmosphere motivates the students as learners. 2.68 ± 0.91 2.2 ± 1.14 2.62 ± 0.98 2.46 ± 1.01 2.73 ± 0.63 2.52 ± 0.98 0.16 p = 0.04 students’ social self-perceptions 4 *the students are too tired to enjoy this course. 2.14 ± 1.21 1.93 ± 1.16 2.43 ± 1.17 2.09 ± 1.07 2.36 ± 0.9 2.17 ± 1.13 0.29 p = 0.04 14 the students are rarely bored in this course. 2.09 ± 1.31 1.43 ± 1.22 1.95 ± 1.15 1.66 ± 1.03 2.14 ± 0.94 1.83 ± 1.18 0.07 p = 0.02 15 the students have good friends in this school. 3.36 ± 0.81 3.25 ± 0.93 3.49 ± 0.51 3.14 ± 0.73 3.41 ± 0.59 3.33 ± 0.75 0.35 p = 0.04 dreem = dundee ready education environment measure; sd = standard deviation. *indicates negative statements with reversed scores. higher scores for these statements shows that more students disagreed with the statement. a five year longitudinal study of the educational environment in a newly integrated medical curriculum e340 | squ medical journal, november 2019, volume 19, issue 4 the ee is likely to be dynamic during the early years of a curricular change. during this phase, the educational climate needs to be closely monitored to ensure that the new curriculum is being correctly implemented and progressing in the correct direction. additionally, any new medical curriculum should continue to be receptive to evolving trends in the community, healthcare advances and innovative teaching-learning practices; as a result, ongoing curriculum renewal becomes an essential requirement.18 the current findings, in fact, contribute to the evidencebased renewal process of the current curriculum. the mean overall score over all five years (130/200) was higher than that reported by most medical schools in the gulf cooperation council (gcc) countries, with studies from saudi arabia reporting scores of 107/200, 102/200, 100/200, 97/200 and 90/200; a yemeni study reported a score of 100/200 and a study from kuwait reported scores of 109/200 and 106/200.3,7,9,19–22 although schools in saudi arabia and kuwait have similar student-centred curricula, the current ee was observed to be more conducive to learning as reflected by the higher overall score.7,20,22 the well-accepted, student-centred nature of the studied curriculum, table 4: mean dundee ready education environment measure subscale statement scores without statistical significance of the pioneer cohort after a curricular change by year of study (n = 178) item # dreem subscale statement mean dreem score ± sd year one (n = 44) year two (n = 40) year three (n = 37) year four (n = 35) year five (n = 22) all responses (n = 178) students’ perceptions of learning 1 the students are encouraged to participate in class. 3.07 ± 0.7 2.78 ± 0.95 2.97 ± 0.93 2.91 ± 0.85 3.23 ± 0.69 2.97 ± 0.84 7 the teaching is often stimulating. 2.91 ± 0.8 2.58 ± 0.93 2.84 ± 0.9 2.69 ± 0.8 3 ± 0.54 2.79 ± 0.83 13 the teaching is “student-centred”. 2.91 ± 0.71 2.78 ± 1 2.76 ± 0.86 2.74 ± 0.74 2.91 ± 0.68 2.81 ± 0.81 25 *the teaching gives too much importance to factual learning. 1.77 ± 1.16 1.88 ± 1.07 1.78 ± 1.06 1.94 ± 0.97 1.95 ± 0.95 1.85 ± 1.05 38 the students are clear about the learning objectives of the course. 2.68 ± 0.83 2.53 ± 0.93 2.3 ± 1 2.34 ± 1.03 2.68 ± 0.89 2.5 ± 0.94 44 the teaching encourages the students to be active learners. 2.89 ± 0.72 2.78 ± 0.77 2.65 ± 0.92 2.6 ± 1.01 2.77 ± 0.61 2.74 ± 0.82 47 long-term learning is given importance over short-term learning. 2.77 ± 0.94 2.65 ± 0.86 2.86 ± 0.75 2.57 ± 0.88 2.5 ± 0.86 2.69 ± 0.86 48 *the teaching is too “teacher-centred”. 2.59 ± 0.9 2.25 ± 1.13 2.14 ± 1.08 2.14 ± 0.97 2.32 ± 1 2.3 ± 1.03 students’ perceptions of teachers 8 *the teachers ridicule the students. 2.86 ± 1.09 2.65 ± 0.95 2.76 ± 0.8 2.6 ± 1 2.5 ± 1.1 2.70 ± 1 9 *the teachers are authoritarian. 2.34 ± 0.89 2.18 ± 0.96 1.92 ± 1.09 2.17 ± 0.86 2.14 ± 1.04 2.16 ± 0.96 32 the teachers provide constructive criticism. 2.75 ± 0.78 2.43 ± 1.04 2.41 ± 1.07 2.57 ± 0.78 2.73 ± 0.83 2.57 ± 0.91 37 the teachers give clear examples. 2.89 ± 0.54 2.68 ± 0.76 2.73 ± 0.65 2.83 ± 0.62 2.73 ± 0.77 2.78 ± 0.66 39 *the teachers get angry in class. 2.66 ± 1.08 2.38 ± 1.03 2.16 ± 1.09 2.31 ± 0.90 2.59 ± 1.1 2.42 ± 1.05 40 the teachers are well-prepared for their classes. 2.89 ± 0.69 2.88 ± 0.72 2.62 ± 0.72 2.63 ± 0.84 2.32 ± 1 2.71 ± 0.79 50 *the students irritate the teachers. 2.32 ± 1.1 2.23 ± 1.14 2 ± 1.03 2.2 ± 0.99 2.55 ± 1.22 2.24 ± 1.09 students’ academic self-perceptions 21 the students feel they are being well-prepared for their profession. 2.66 ± 0.83 2.38 ± 0.9 2.51 ± 0.9 2.43 ± 0.92 2.77 ± 0.81 2.53 ± 0.88 31 the students have learned a lot about empathy in their profession. 3.05 ± 0.89 3.05 ± 0.64 2.95 ± 0.88 3.0 ± 0.42 3.09 ± 0.68 3.02 ± 0.73 41 students’ problem solving skills are being well developed here. 2.89 ± 0.75 2.8 ± 0.82 2.89 ± 0.52 2.71 ± 0.71 2.86 ± 0.64 2.83 ± 0.7 45 much of what students have to learn seems relevant for a career in medicine. 3.11 ± 0.58 2.88 ± 0.79 2.89 ± 0.81 3.09 ± 0.51 2.91 ± 0.53 2.98 ± 0.67 students’ perceptions of atmosphere 23 the atmosphere is relaxed during lectures. 2.7 ± 0.93 2.7 ± 0.82 2.81 ± 0.88 2.94 ± 0.59 3.05 ± 0.88 2.81 ± 0.78 30 there are opportunities for the students to develop interpersonal skills. 2.68 ± 0.98 2.88 ± 0.69 2.81 ± 0.78 2.91 ± 0.61 2.91 ± 0.81 2.83 ± 0.79 33 the students feel comfortable in class socially. 3.0 ± 0.86 3.13 ± 0.46 3.03 ± 0.5 2.91 ± 0.78 3.23 ± 0.43 3.04 ± 0.65 34 the atmosphere is relaxed during seminars/tutorials 3.02 ± 0.85 2.78 ± 0.86 2.95 ± 0.52 3.0 ± 0.34 3.05 ± 0.65 2.95 ± 0.69 35 *the students find the experience (of studying here) disappointing. 2.3 ± 1.23 1.88 ± 1.14 1.92 ± 1.06 1.86 ± 1.22 2.27 ± 1.03 2.03 ± 1.15 42 the enjoyment outweighs the stress of studying medicine. 2.3 ± 1.23 2.18 ± 1.24 2.41 ± 1.09 2.29 ± 1.02 2.64 ± 1.05 2.33 ± 1.14 49 the students’ feel able to ask the questions they want. 2.89 ± 0.81 3.03 ± 0.53 2.92 ± 0.55 2.94 ± 0.59 3.0 ± 0.76 2.95 ± 0.65 students’ social self-perceptions 3 there is a good support system (help) for students who get stressed. 2.14 ± 1.11 1.75 ± 1.3 1.59 ± 1.21 1.74 ± 0.95 2.09 ± 1.19 1.85 ± 1.17 19 the students’ social life is good. 2.98 ± 1.02 2.78 ± 1.1 3.05 ± 1.03 2.91 ± 0.92 3.14 ± 0.83 2.96 ± 1 28 the students seldom feel lonely. 2.59 ± 1.3 2.58 ± 1.15 2.65 ± 1.01 2.57 ± 0.95 2.73 ± 0.99 2.61 ± 1.1 46 the students’ accommodation is pleasant. 2.91 ± 1.24 2.78 ± 1.23 3.11 ± 0.94 2.97 ± 0.92 2.77 ± 0.92 2.92 ± 1.08 dreem = dundee ready education environment measure; sd = standard deviation. *indicates negative statements with reversed scores. higher scores for these statements shows that more students disagreed with the statement. syed i. shehnaz clinical and basic research | e341 opens channels of communication with students with regular emphasis on the theoretical underpinnings of the change, the well-planned execution of the change, the backing of all stakeholders, feelings of faculty ownership, numerous faculty development programmes and continuous evaluations and feedback from students probably contributed to the positive, persistent curricular change.23,24 according to one interpretation of dreem scores, the ee of gmu over five years was “more positive than negative” (overall score range: 101–150).25 throughout the five years, learning was perceived to be “more positive” (subscale score range: 25–36); teachers were “moving in the right direction” (subscale score range: 23–33); academic self-perception was “more on the positive side” (subscale score range: 17–24); the atmosphere was “more positive” (subscale score range: 25–36); and social self-perceptions were “not too bad” (score range: 15–21). these results emphasise the importance of consistency in maintaining a positive ee in gmu over the entire course of study of the revised programme’s pioneer cohort. the highest subscale scores for “academic self perceptions” and “perceptions of atmosphere” indicated table 5: mean dundee ready education environment measure significant subscale statement scores with gender and ethnic differences of the pioneer cohort after a curricular change across all years of study (n = 178) item # dreem subscale statement mean dreem score ± sd gender p value ethnicity p valuemale female asian african arab students’ perceptions of learning 7 the teaching is often stimulating. 2.94 ± 0.86 2.7 ± 0.81 0.03 2.78 ± 0.89 3.08 ± 0.57 2.5 ± 0.94 0.15 20 the teaching is well-focused. 2.73 ± 0.83 2.66 ± 0.77 0.49 2.79 ± 0.61 2.96 ± 0.79 2.0 ± 0.96 <0.001 24 the teaching time is put to good use. 2.55 ± 1.04 2.55 ± 0.95 0.94 2.6 ± 0.94 3.08 ± 0.64 1.57 ± 1.22 <0.001 25 *the teaching gives too much importance to factual learning. 1.71 ± 1.15 1.95 ± 0.99 0.13 1.77 ± 1.06 2.4 ± 1.04 1.71 ± 0.99 0.045 students’ perceptions of teachers 2 the teachers are knowledgeable. 3.27 ± 0.62 3.06 ± 0.6 0.02 3.19 ± 0.62 3.32 ± 0.48 3.0 ± 0.88 0.48 6 the teachers are patient with the hospital patients. 3.02 ± 0.75 2.7 ± 0.79 0.005 2.81 ± 0.74 3.08 ± 0.57 2.79 ± 1.12 0.36 8 *the teachers ridicule the students. 2.82 ± 0.96 2.62 ± 1 0.25 2.88 ± 0.84 2.76 ± 1.01 2.0 ± 1.3 0.04 9 *the teachers are authoritarian. 1.95 ± 1.01 2.29 ± 0.91 0.03 2.28 ± 0.91 2.44 ± 0.92 1.93 ± 1.14 0.32 29 the teachers are good at providing feedback to students. 2.48 ± 1.03 2.05 ± 1.1 0.01 2.06 ± 1.14 2.76 ± 1.01 1.86 ± 1.03 0.02 32 the teachers provide constructive criticism. 2.67 ± 0.87 2.51 ± 0.95 0.37 2.57 ± 0.84 3.0 ± 0.87 2.21 ± 0.98 0.02 37 the teachers give clear examples. 2.91 ± 0.65 2.69 ± 0.66 0.02 2.83 ± 0.59 3.08 ± 0.64 2.14 ± 0.95 <0.001 40 the teachers are well-prepared for their classes. 2.79 ± 0.81 2.66 ± 0.78 0.25 2.78 ± 0.67 2.96 ± 0.89 2.07 ± 1 0.004 students’ academic self-perceptions 31 the students have learned a lot about empathy in their profession. 3.2 ± 0.56 2.92 ± 0.8 0.03 3.01 ± 0.75 3.32 ± 0.48 2.64 ± 1 0.04 45 much of what students have to learn seems relevant for a career in medicine. 3.06 ± 0.58 2.94 ± 0.72 0.35 3.04 ± 0.62 3.16 ± 0.47 2.71 ± 0.47 0.03 students’ perceptions of atmosphere 11 the atmosphere is relaxed during the hospital-ward teaching. 2.82 ± 0.91 2.73 ± 0.82 0.44 2.81 ± 0.87 3.12 ± 0.67 2.36 ± 1 0.03 30 there are opportunities for the students to develop interpersonal skills. 3.05 ± 0.69 2.7 ± 0.82 0.006 2.75 ± 0.81 3.08 ± 0.57 2.79 ± 0.8 0.23 34 the atmosphere is relaxed during seminars/tutorials. 3 ± 0.78 2.92 ± 0.64 0.18 2.9 ± 0.75 3.24 ± 0.52 2.64 ± 0.75 0.02 36 the students are able to concentrate well. 2.58 ± 0.95 2.47 ± 0.97 0.60 2.59 ± 0.85 2.88 ± 0.88 2.14 ± 1.03 0.04 students’ social self-perceptions 15 the students have good friends in this school. 3.47 ± 0.66 3.25 ± 0.79 0.045 3.43 ± 0.76 3.28 ± 0.46 3.14 ± 1.03 0.14 19 the students’ social life is good. 3.15 ± 0.88 2.83±1.05 0.04 3.07 ± 0.82 2.8 ± 1.12 3.21 ± 1.12 0.25 28 the students seldom feel lonely. 2.89 ± 1.13 2.45 ± 1.05 0.003 2.83 ± 0.99 2.44 ± 1.16 2.36 ± 1.15 0.13 dreem = dundee ready education environment measure; sd = standard deviation. *indicates negative statements with reversed scores. higher scores for these statements shows that more students disagreed with the statement. figure 1: mean individual dundee ready education environment measure item scores by year of study of the pioneer cohort after a curricular change. scores of ≤2 indicate areas of shortcoming, scores of 2–3 indicate areas that could be enhanced and scores of ≥3 indicate areas of strength. a five year longitudinal study of the educational environment in a newly integrated medical curriculum e342 | squ medical journal, november 2019, volume 19, issue 4 the high acceptance of the innovative curriculum with its student-centred approach whereas the lowest subscale scores in “social self-perceptions” in almost all years indicated persistent areas of shortcoming. the adeptness of the teachers, sensitisation of students towards empathy, a camaraderie with friends and social comfort levels in the classes were identified as persistent areas of excellence with scores ≥3 while an emphasis on factual learning, waning interest levels of students, a propensity towards academic dishonesty, the inability of students to memorise and a deficit of support systems for stressed students were areas of shortcoming (scores ≤2). most of these shortcomings have been recognised by other medical schools as well and indicate common issues faced by medical students globally.3–5,8,15,20,22 these results should aid curricular reform committees in re-examining the areas necessitating remedial interventions and allow them to consolidate areas of excellence. frequent faculty development programmes and familiarising teachers with the theoretical under pinnings of the new curriculum may have resulted in positive perceptions of the faculty. continuing these programmes for new faculty members will prevent any future impediment to curricular progress.23 however, the emphasis on factual learning, students’ diminishing interest levels and students’ difficulty in memorising facts indicate a curricular overload and intensive efforts should be advocated to address these issues. many studies have reported high levels of stress among medical students in all types of curricular programmes and the lack of strategies for handling this.26 although endeavours have been made to offer a support system for stressed students in the form of academic preceptors and easier accessibility to clinical psychologists at gmu, these efforts have not been adequate. it is recommended that stress management techniques be introduced in formal training sessions from the first year to encourage stress resilience and self-care among the students.27 the predicament of academic dishonesty can be addressed by reviewing the assessment strategies and establishing an institutional culture of integrity.4,28 the dreem scores indicated that students in the first and final year have significantly more positive perceptions of the ee. the positive perceptions in the first year may be due to initial enchantment with the novel curriculum and not a deterioration in the ee as no significant differences in the scores were observed with the subsequent two cohorts.29 moreover, a consistent deterioration in medical students’ perceptions of their ee as they proceed through a course of study, especially in hybrid delivery and problem-based learning curricula, has been previously reported.30 positive perceptions in the final year may be due to more conducive learning experiences in the tertiary hospital supervising clinical training. other studies have reported no such differences in perceptions about ee between different clinical training sites.10,11 these positive perceptions will also be communicated to the academic leadership with the aim of consolidating favourable learning experiences in the future. although no significant gender differences were observed for the overall scores, the subscale score of “social self-perceptions” and individual statement analysis indicated that males had generally more positive perceptions of the gmu programme than females. other studies have also reported the more critical attitude of females among students from gcc countries.7,9 however, to the best of the author’s knowledge, differences in perception of ee based on ethnicity have not been reported elsewhere. although not exactly comparable to the current study, evolutions around perceptions of ee over time have been previously investigated.14–16 edgren et al. investigated their ees of a swedish school twice in a two-year period and found that their high overall score was maintained after two years of curricular reform.14 a similar study in saudi arabia observed a more positive ee following quality improvements compared to three years earlier.15 another institution in aruba reassessed their ee after six months of curricular change and recounted significant improvements in their scores.16 the limitations of the current study are the self-reported nature of the data and the inability to generalise the results due to the involvement of just one institution. these results, nevertheless, measure the sustained impact of a curricular change on ee for the first time in any medical school in the gcc countries. monitoring ee by evaluating perceptions in the future will give more valuable input on the success of the school’s curricular approaches. qualitative indepth analysis of the highlighted problem areas might also act as a delimiter in this study. conclusion the long-term effects of a newly introduced integrated curriculum on the ee of a medical school have been investigated for the first time anywhere in the gcc countries. the mean overall score for all responses (130/200) showed that the curricular reform had a sustained and encouraging influence on the ee at gmu throughout the pioneer cohort’s course of study. the overall and subscale scores were significantly higher in the first and final years of the study. no significant gender differences were noted in the overall scores. syed i. shehnaz clinical and basic research | e343 the statement analyses recognised the knowledge of the faculty, students’ awareness about empathy and social interactions as persistent strengths of the school over the entire course. a curricular overload, a want of support systems for stressed students, students’ waning interest levels and assessment strategies emerged as areas that warranted remedial attention. a c k n o w l e d g e m e n t s the author wishes to thank all the medical students of gmu for participating in this study. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. genn jm. amee medical education guide no.23 (part 1): curriculum, environment, climate, quality and change in medical education a unifying perspective. med teach 2001; 23: 337–44. https://doi.org/10.1080/01421590120063330. 2. roff s, mcaleer s, ifere os, bhattacharya s. a global diagnostic tool for measuring educational environment: comparing nigeria and nepal. med teach 2001; 23:378–82. https://doi.org/10.10 80/01421590120043080. 3. al-hazimi a, al-hyiani a, roff s. perceptions of the educational environment at the medical school in king abdul aziz university, saudi arabia. med teach 2004; 26:570–3. https://doi.org/10.1080/01421590410001711625. 4. bassaw b, roff s, mcaleer s, roopnarinesingh s, de lisle j, teelucksingh s, et al. students’ perspectives of the educational environment, faculty of medical sciences, trinidad. med teach 2003; 25:522–6. https://doi.org/10.1080/0142159031000 137409. 5. jiffry mt, mcaleer s, fernando s, marasinghe rb. using the dreem questionnaire to gather baseline information on an evolving medical school in sri lanka. med teach 2005; 27:348–52. https://doi.org/10.1080/01421590500151005. 6. till h. identifying the perceived weaknesses of a new curriculum by means of the dundee ready education environment measure (dreem) inventory. med teach 2004; 26:39–45. https://doi.org/10.1080/01421590310001642948. 7. bouhaimed m, thalib l, doi sa. perception of the educational environment by medical students undergoing a curriculum transition in kuwait. med princ pract 2009; 18:204–8. https://doi.org/10.1159/000204351. 8. riquelme a, oporto m, oporto j, méndez ji, viviani p, salech f, et al. measuring students' perceptions of the educational climate of the new curriculum at the pontificia universidad católica de chile: performance of the spanish translation of the dundee ready education environment measure (dreem). educ health (abingdon) 2009; 22:112. 9. al-hazimi a, zaini r, al-hyiani a, hassan n, gunaid a, ponnamperuma g, et al. educational environment in traditional and innovative medical schools: a study in four undergraduate medical schools. educ health (abingdon) 2004; 17:192–203. https://doi.org/10.1080/13576280410001711003. 10. varma r, tiyagi e, gupta jk. determining the quality of educational climate across multiple undergraduate teaching sites using the dreem inventory. bmc med educ 2005; 5:8. https://doi.org/10.1186/1472-6920-5-8. 11. carmody df, jacques a, denz-penhey h, puddey i, newnham jp. perceptions by medical students of their educational environment for obstetrics and gynaecology in metropolitan and rural teaching sites. med teach 2009; 31:e596–602. https://doi.org/10.3109/01421590903193596. 12. shehnaz si, sreedharan j. students' perceptions of educational environment in a medical school experiencing curricular transition in united arab emirates. med teach 2011; 33:e37–42. https://doi.org/10.3109/0142159x.2011.530312. 13. miles s, leinster sj. medical students’ perceptions of their educational environment: expected versus actual perceptions. med educ 2007; 41:265–72. https://doi.org/10.1111/j.1365-29 29.2007.02686.x. 14. edgren g, haffling ac, jakobsson u, mcaleer s, danielsen n. comparing the educational environment (as measured by dreem) at two different stages of curriculum reform. med teach 2010; 32:e233–8. https://doi.org/10.3109/01421591003706282. 15. mojaddidi ma, khoshhal ki, habib f, shalaby s, el-bab me, al-zalabani ah. reassessment of the undergraduate educ ational environment in college of medicine, taibah university, almadinah almunawwarah, saudi arabia. med teach 2013; 35:s39–46. https://doi.org/10.3109/0142159x.2013.765554. 16. shankar pr, bharti r, ramireddy r, balasubramanium r, nuguri v. students' perception of the learning environment at xavier university school of medicine, aruba: a follow-up study. j educ eval health prof 2014; 11:9. https://doi.org/10.3352/ jeehp.2014.11.9. 17. roff s, mcaleer s, harden rm, al-qahtani m, ahmed au, deza h, et al. development and validation of the dundee ready education environment measure (dreem). med teach 1997; 19:295–9. https://doi.org/10.3109/01421599709034208. 18. mcleod p, steinert y. twelve tips for curriculum renewal. med teach 2015; 37:232–8. https://doi.org/10.3109/014215 9x.2014.932898. 19. zawawi ah, elzubeir m. using dreem to compare graduating students' perceptions of learning environments at medical schools adopting contrasting educational strategies. med teach 2012; 34:s25–31. https://doi.org/10.3109/0142159x.2012.656747. 20. hasan t, gupta p. assessing the learning environment at jazan medical school of saudi arabia. med teach 2013; 35:s90–6. https://doi.org/10.3109/0142159x.2013.765546. 21. al-ayed ih, sheik sa. assessment of the educational environment at the college of medicine of king saud university, riyadh. east mediterr health j 2008; 14:953–9. 22. karim j, al-halabi b, marwan y, sadeq h, dawas a, al-abdulrazzaq d. the educational environment of the undergraduate medical curriculum at kuwait university. adv med educ pract 2015; 6:297–303. https://doi.org/10.2147/ amep.s81729. 23. bland cj, starnaman s, wersal l, moorehead-rosenberg l, zonia s, henry r. curricular change in medical schools: how to succeed. acad med 2000; 75:575–94. https://doi.org/10.1097/000 01888-200006000-00006. 24. shehnaz si, sreedharan j, gomathi kg. faculty and students’ perceptions of student experiences in a medical school undergoing curricular transition in the united arab emirates. sultan qaboos univ med j 2012; 12:77–85. 25. mcaleer s, roff s. a practical guide to using the dundee ready education environment measure (dreem). in: genn jm, ed. curriculum, environment, climate, quality and change in medi cal education—a unifying perspective. dundee: amee secret ariat, centre for medical education, university of dundee, 2001. pp. 29–31. https://doi.org/10.1080/01421590120063330 https://doi.org/10.1080/01421590120043080 https://doi.org/10.1080/01421590120043080 https://doi.org/10.1080/01421590410001711625 https://doi.org/10.1080/0142159031000137409 https://doi.org/10.1080/0142159031000137409 https://doi.org/10.1080/01421590500151005 https://doi.org/10.1080/01421590310001642948 https://doi.org/10.1159/000204351 https://doi.org/10.1080/13576280410001711003 https://doi.org/10.1186/1472-6920-5-8 https://doi.org/10.3109/01421590903193596 https://doi.org/10.3109/0142159x.2011.530312 https://doi.org/10.1111/j.1365-2929.2007.02686.x https://doi.org/10.1111/j.1365-2929.2007.02686.x https://doi.org/10.3109/01421591003706282 https://doi.org/10.3109/0142159x.2013.765554 https://doi.org/10.3352/jeehp.2014.11.9 https://doi.org/10.3352/jeehp.2014.11.9 https://doi.org/10.3109/01421599709034208 https://doi.org/10.3109/0142159x.2014.932898 https://doi.org/10.3109/0142159x.2014.932898 https://doi.org/10.3109/0142159x.2012.656747 https://doi.org/10.3109/0142159x.2013.765546 https://doi.org/10.2147/amep.s81729 https://doi.org/10.2147/amep.s81729 https://doi.org/10.1097/00001888-200006000-00006 https://doi.org/10.1097/00001888-200006000-00006 a five year longitudinal study of the educational environment in a newly integrated medical curriculum e344 | squ medical journal, november 2019, volume 19, issue 4 26. elzubeir ma, elzubeir ke, magzoub me. stress and coping strategies among arab medical students: towards a research agenda. educ health (abingdon) 2010; 23:355. 27. thomas se, haney mk, pelic cm, shaw d, wong jg. developing a program to promote stress resilience and self-care in first-year medical students. can med educ j 2011; 2:e32–6. 28. glick sm. cheating at medical school. bmj 2001; 322:250–1. https://doi.org/10.1136/bmj.322.7281.250. 29. shehnaz si, arifulla m. the evolving educational environment in a medical school undergoing curricular change in the united arab emirates. gulf med j 2014; 3:s170–9. from: https://www. gulfmedicaljournal.com/download/supplement1_14/sup114%20(24).pdf accessed: may 2019. 30. schwartz pl, loten eg. effect of year in school on medical students' perceptions evaluated with the cognitive behavior survey, attitudes toward social issues in medicine survey, and learning environment questionnaire. teach learn med 2004; 16:333–44. https://doi.org/10.1207/s15328015tlm1604_6. https://doi.org/10.1136/bmj.322.7281.250 https://doi.org/10.1207/s15328015tlm1604_6 departments of 1surgery, 2medicine and 3anaesthesia, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drjayakrish@hotmail.com اسرتواح الصدر املستمر الناسور اجلنيب السنخي بسبب ثقب يف الفقاعة عادل حمد الكندي، جاياكري�شنان باالكري�شنان، �شيف حممد املبيح�شي، نا�رش عبد اهلل الكمياين persistent pneumothorax alveolar pleural fistula due to a hole in a bulla adil h. al kindi,1 *jayakrishnan b.,2 saif m. al mubaihsi,2 nasser a. al kemyani3 a 22-year-old male patient, previously treated for pulmonary tuberculosis, presented to sultan qaboos university hospital, muscat, oman in 2017 with sudden onset shortness of breath. chest x-ray showed a pneumothorax on the left side [figure 1a]. a 20f chest tube was placed and connected to a closed pleural drainage chamber with low suction. the lung failed to expand fully even after ten days. a computed tomography scan showed a large multiloculated pneumothorax with large bulla in the left apical region. thoracoscopy revealed multiple emphy sematous bullae in the left lung. air was found to be leaking from a clean hole on one side of a large bulla in the left apex [figure 1b]. this alveolar-pleural fistulalike behaviour probably accounted for the continuing air leak and the persistence of the pneumothorax. the left lung apex including the bullae was resected using an endo-gia™ stapler (medtronic plc, minneapolis, minnesota, usa). the staple line was covered with dissected parietal pleura. mechanical pleurodesis was performed on the rest of the pleura. the lung sub sequently inflated fully and remained expanded on follow-up one month later. comment the major cause of persistent pneumothorax is an ongoing air leak, which is indicated by prolonged air bubbling into the chest drainage system. air leaks are classified as: grade 1, during forced expiration (cough) only; grade 2, expiratory only; grade 3, inspiratory only; or grade 4, continuous.1 a common cause of persistent air leak is an alveolar-pleural fistula, a communication between the pulmonary parenchyma, distal to a segmental bronchus and the pleural space. this is different from a bronchopleural fistula which, by definition, is a communication between a main stem, lobar or segmental bronchus and the pleural space. sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e164–165, epub. 8 sep 19 submitted 19 dec 18 revision req. 9 jan 19; revision recd. 14 jan 19 accepted 24 jan 19 figure 1: a: chest x-ray of a 22-year-old male patient showing pneumothorax on the left side and collapsed lung margins (arrows). b: thoracoscopic photograph showing a clean hole (arrow) in a bulla on the upper lobe of the left lung. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.015 interesting medical image https://creativecommons.org/licenses/by-nd/4.0/ adil h. al kindi, b. jayakrishnan, saif m. al mubaihsi and nasser a. al kemyani interesting medical image | e165 common causes include a ruptured bulla, cavitary neoplasm, fibrotic sarcoidosis, radiation fibrosis, inter stitial lung diseases, necrotising pneumonia and postthoracic surgical intervention.2 this is often difficult to identify and is seldom seen as clearly as in the current patient. references 1. dugan kc, laxmanan b, murgu s, hogarth dk. management of persistent air leaks. chest 2017; 152:417−23. https://doi. org/10.1016/j.chest.2017.02.020. 2. chaturvedi a, lee s, klionsky n, chaturvedi a. demystifying the persistent pneumothorax: role of imaging. insights imaging 2016; 7:411−29. https://doi.org/10.1007/s13244-016-0486-5. https://doi.org/10.1016/j.chest.2017.02.020 https://doi.org/10.1016/j.chest.2017.02.020 https://doi.org/10.1007/s13244-016-0486-5 تقييم اجلاهزية للوقاية من اساءة معاملة األطفال يف سلطنة ٌعمان منى ال�صعدونية، اآ�صيا النعماين، ح�صن �صاحلني، مها املنيف، ماجد العي�صى abstract: objectives: this study aimed to evaluate oman’s readiness for implementing large-scale child maltreatment prevention (cmp) programmes. methods: this cross-sectional study was conducted between may and august 2016 in oman. participants, referred to as key informants, were individuals with influence and decision-making powers over cmp. the multidimensional readiness assessment for the prevention of child maltreatment tool, developed by the world health organization with the help of collaborators from middleand low-income countries, was used to assess 10 dimensions of readiness, each with a maximum score of 10. results: a total of 49 participants were included in this study (response rate = 98%). the mean total score for the 10 dimensions was 50.17 out of 100 possible points. the participants showed high mean readiness scores on legislation, mandates and policies (9.08) followed by knowledge of cmp (7.55), institutional resources and links (6.12), willingness to address the problem (5.35), informal social resources (5.15) and current programme implementation and evaluation (5.10). participants had low scores in readiness in association with human and technical resources (2.44), attitudes towards cmp (2.90), scientific data on cmp (3.06) and material resources (3.46). conclusion: the results of this study indicate that oman has a moderate level of readiness to implement largescale evidence-based prevention programmes against child maltreatment; however, several dimensions still need to be strengthened. it is important to develop a national strategy that outlines a framework for organising and prioritising efforts towards cmp. keywords: child maltreatment; program development; attitude; world health organization; oman. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل تقييم جاهزية �صلطنة ُعمان لتنفيذ برامج الوقاية من ا�صاءة معاملة الأطفال على نطاق وا�صع. اإليهم وامل�صار امل�صاركون، كان ُعمان. �صلطنة يف 2016 واأغ�صط�س مايو بني ما الفرتة يف امل�صتعر�صة الدرا�صة هذه اأجريت الطريقة: كخرباء رئي�صيني، اأفراداً ذوي نفوذ وميتلكون �صالحيات اتخاذ القرار يف جمال وقاية الأطفال من ا�صاءة املعاملة. مت ا�صتخدام اأداة تقييم اجلاهزية املتعددة الأبعاد للوقاية من ا�صاءة معاملة الأطفال التي طورتها منظمة ال�صحة العاملية مب�صاعدة متعاونني من البلدان ذات الدخل املتو�صط واملنخف�س وذلك لتقييم 10 اأبعاد للجاهزية واعطاء 10 نقاط لكل بعد منها كحد اق�صى. النتائج: �صملت هذه الدرا�صة ما جمموعه 49 م�صاركا )معدل ال�صتجابة = %98(. كان متو�صط جمموع النقاط لالأبعاد الع�رشه هو 50.17 من اأ�صل 100 نقطة ميكن احل�صول عليها. اأظهر امل�صاركون درجات عالية من اجلاهزية من حيث القوانني والت�رشيعات الق�صائية وال�صيا�صات )9.08( متبوعة مب�صتوى الإملام بالوقاية من ا�صاءة معاملة الطفال )7.55( واملوارد والروابط الدولية )6.12( والرغبة يف معاجلة امل�صكلة )5.35( واملوارد الجتماعية غري الر�صمية )5.15( وتنفيذ الربنامج احلايل وتقييمه )5.1(. حقق امل�صاركون نقاط منخف�صة بالن�صبة جلاهزيتهم املتعلقة باملوارد الب�رشية والتقنية )2.44( ومواقفهم جتاه الوقاية من ا�صاءة معاملة الأطفال )2.9( وتوافر البيانات العلمية عن الوقاية من ا�صاءة معاملة الطفال )3.06( واملوارد املادية )3.46(. اخلال�صة: ت�صري نتائج هذه الدرا�صة اإىل اأن �صلطنة ُعمان لديها م�صتوى متو�صط من اجلاهزية لتنفيذ برامج الوقاية من ا�صاءة معاملة الأطفال على نطاق وا�صع وب�صكل قائم على الأدلة. ومع ذلك ل تزال هناك عدة اأبعاد بحاجة للتعزيز. من املهم و�صع اإ�صرتاتيجية وطنية حتدد اإطاًرا لتنظيم اجلهود وترتيب اأولوياتها نحو الوقاية من ا�صاءة معاملة الطفال. الكلمات املفتاحية: ا�صاءة معاملة الطفل؛ تطوير برنامج ؛ موقف؛ منظمة ال�صحة العاملية؛ ُعمان. child maltreatment prevention readiness assessment in oman *muna al saadoon,1 asia al numani,2 hassan saleheen,3,4 maha almuneef,3,5 majid al-eissa3–5 clinical & basic research sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e37–44, epub. 9 mar 20 submitted 29 apr 19 revision req. 17 jun 19; revision recd. 14 jul 19 accepted 8 aug 19 advances in knowledge this study is the first in oman to explore the readiness of the country to provide child maltreatment prevention (cmp) programmes. obtained readiness scores could be used as a benchmark to compare oman with other countries or to develop prevention programmes. this study has helped identify gaps in the existing system regarding cmp programmes. application to patient care addressing identified gaps in cmp readiness will have a positive impact on child well-being in oman. https://doi.org/10.18295/squmj.2020.20.01.006 1department of child health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2department of women and child health, ministry of health, muscat, oman; 3king abdullah international medical research center, riyadh, saudi arabia; 4national family safety program, ministry of national guard health affairs, riyadh, saudi arabia; 5department of pediatrics, king abdullah specialized children’s hospital, riyadh, saudi arabia *corresponding author’s e-mail: munasa@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. child maltreatment (cm) is a problem affecting children worldwide. it appears in different forms including physical, emotional and sexual abuse/neglect. according to the united nations international children’s education fund, appro ximately 95,000 children die due to homicide each year globally.1 in 2002, it is estimated that 53,000 children (75% males and 25% females) died due to homicide https://creativecommons.org/licenses/by-nd/4.0/ child maltreatment prevention readiness assessment in oman e38 | squ medical journal, february 2020, volume 20, issue 1 worldwide.2 approximately 22,000 of these homicide victims were 15–17 years old.2 the world health organ ization (who) has suggested a high rate of cm in all countries and it is estimated that around one-quarter of all adults were subjected to physical abuse as children.3 studies from arab nations have indicated the existence of cm, however, the actual size of this problem is not known because of the underreporting of child abuse.4 the use of corporal punishment in egypt has been reported as a problem and, in jordan, 27% of surveyed male college students reported being a victim of sexual abuse before the age of 14.5,6 publications from gulf cooperation council (gcc) countries have suggested that cm is common but underreported.4,7 a study conducted in saudi arabia among 2,043 adolescents in 2012 revealed that 75% had been subjected to psy chological abuse, 57% had been physically abused, 50% had been neglected and 14% had been sexually abused.8 in bahrain, al-mahroos reported 150 child abuse and neglect (can) victims, wherein 50 had been physically abused, 87 had been sexually abused and 10 had been both physicallyand sexually-abused.7 published case reports have indicated cm in oman.9 koul et al. reported five children between 1–11 years old with munchausen syndrome by proxy.10 al-saadoon et al. conducted a case series discussing six children who had been subjected to cm, with the aim of increasing the level of awareness of cm among medical professionals and highlighting difficulties encountered in diagnosing cm and providing optimal care for it.11 in 2015, oman’s ministry of social devel opment (mosd) reported 102 cases of cm, 54% of which were male.12 in total, 56.9% were cases of neglect, 23.5% were cases of physical abuse, 18.6% were cases of sexual abuse and 1% had been emotionally abused.12 oman ratified the convention on the rights of the child (crc) in 1996 and its two optional protocols in 2004.13,14 after ratification, several sections of the omani legislation were promulgated to strengthen child protection and better support cm prevention (cmp). this legislation includes but is not limited to the care and rehabilitation of the disabled act, juvenile accountability act, trafficking in persons act and the omani child law issued in may 2014 (royal decree no. 22/2014).15 in 2008, the mosd issued a decree for the establishment of 11 multi-disciplinary child protection working teams, subsequently upgraded to child protection committees, that were tasked with investigating, following-up, managing and rehabilitating victims of cm (ministerial decree no. 78/2008). the mosd also established a welfare and rehabilitation home for such children through the newly developed family protection department.14 the omani child law and omani penal code forbids all forms of physical and psychological violence against children, including deliberate humiliation, physical harm, maltreatment, neglect and exploitation.14,15 since the creation of these laws, many public awareness campaigns have advocated for child protection and child rights and have included family education activities on child development, psychological health and educational needs.13,14 governmental and nongovernmental bodies have also produced television and radio programmes, publications and printed materials discussing articles of the crc. in addition, there are training programmes on child rights for professionals and families.14 in 2016, the child protection hotline was launched in oman to receive reports concerning child protection issues.13 by evaluating the practiced prevention strategies, future strategies and programmes can be consolidated and/or improved. the readiness assessment for the prevention of child maltreatment (rap-cm) tool was developed by the who to evaluate a country’s consid eration of cmp. this tool was administered in mostly middle-income countries in 2011 and in all gcc countries, including oman, in 2016 (data not yet published).16,17 the rap-cm consists of 10 dimensions that, when combined, yield a numerical representation of a country’s consideration of cmp: dimension 1 measures attitudes towards cmp; dimension 2 examines knowledge of cmp; dimension 3 looks at a country’s scientific data on cmp; dimension 4 measures current cmp programme implementation and evaluation; dimension 5 reflects legislation, mandates and policies; dimension 6 considers a country’s willingness to address the cm problem; dimension 7 examines institutional resources and links; dimension 8 measures material resources; dimension 9 reflects human and technical resources and dimension 10 examines informal social resources (non-institutional). each dimension is evaluated by two questions except dimension 4, which is evaluated by one question. most questions have closed responses except the question(s) in dimensions 2, 4 and 7 which require listing programmes, risk factors or conseq uences. the findings of the who report indicated that almost all participating countries had a low-tomoderate level of readiness for cmp.16,17 the mean score of gcc countries on the rap-cm was 46.32, with dimension 5 yielding the highest score (7.97) while the lowest score was for dimension 9 (1.85). this study aimed to evaluate oman’s readiness for implementing large-scale cmp programmes. muna al saadoon, asia al numani, hassan saleheen, maha almuneef and majid al-eissa clinical and basic research | e39 methods this cross-sectional study was conducted between may and august 2016 in oman. participants were individuals with influence and decision-making power over cmp, including policy makers, programme planners, admin istrators, high-level practitioners and civil servants with a strong interest in cm. these participants, also referred to as key informants, were from different types of organisations and selected based on specific categories to ensure representation from all relevant organisations and sectors. a total of 50 key informants were approached but only those that consented to completing the interview were included. the national family safety program (nfsp) in saudi arabia was the lead site for the study. prior to data collection, the principal investigator in oman attended a two-day training workshop at the nfsp in collaboration with the who. the methodology and aims of the study, interview techniques, data collection tool and accuracy of collection, ethical considerations and data transfer were discussed with the principal investigator and other site investigators for standard isation of study outcomes at all sites. the rap-cm tool was developed by the who in collaboration with individuals from brazil, north macedonia, malaysia, saudi arabia and south africa.18,19 the questionnaire was translated into arabic for the purpose of the current study and back-translated for comparison. ethical approval was obtained from the institutional review board of the king abdullah inter national medical research center at the ministry of national guard health affairs, riyadh, saudi arabia (rc 15/067) and the ethics committee of the college of medicine and health sciences at sultan qaboos univ ersity, muscat, oman (squ-ec/013/16, mrec 1233). a convenience sampling technique was used to recruit participants who were representative at the national level. potential participants were initially cont acted via telephone calls in which they were invited to participate in the study and agreed on an appointment day for the interview. all interviews were initiated by sharing an invitation letter describing the goals and confidentiality of the study. informed consent was obtained from each participant before starting the inter views. each interview took approximately 30 minutes to complete. no incentive was offered for participation. no obstacles were encountered during the data collection phase except for interview scheduling difficulties. the scoring of the questionnaires, data entry processes and statistical analyses were conducted at the study’s lead site. data were analysed using statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa). frequency distrib utions were calculated for all aspects of the sample including participants’ socioeconomic characteristics and responses to various interview items. according to the scoring system provided by the who, the responses to most items (except dimension 4) are scored on a scale of 0–2, with zero corresponding to a negative evaluation of a statement, one to a low level of an attribute and two as the highest possible level of an attribute.18 scores were first calculated for each respondent. then, mean scores for all participants in table 1: raw and mean scores for the 10 dimensions of the readiness assessment for the prevention of child maltreatment tool in oman (n = 49) dimension of rap-cm tool raw score* mean score† dimension 1: attitudes towards cmp 1.16 2.90 dimension 2: knowledge of cmp 3.02 7.55 dimension 3: scientific data on cmp 1.22 3.06 dimension 4: current programme implementation and evaluation 2.04 5.10 dimension 5: legislation, mandates and policies 3.63 9.08 dimension 6: willingness to address the problem 2.14 5.35 dimension 7: institutional resources and links 2.44 6.12 dimension 8: material resources 1.38 3.46 dimension 9: human and technical resources 0.98 2.44 dimension 10: informal social resources (non-institutional) 2.06 5.15 total scale 20.07 50.17 rap-cm = readiness assessment for the prevention of child maltreatment; cmp = child maltreatment prevention *scores were out of 4. †scores were on a 10-point scale. figure 1: participants’ mean scores in each of the 10 dimensions of the readiness assessment for the prev ention of child maltreatment tool on a scale of 1–10 in oman (n = 49). child maltreatment prevention readiness assessment in oman e40 | squ medical journal, february 2020, volume 20, issue 1 table 2: participants’ responses to the 10 dimensions of the readiness assessment for the prevention of child maltreatment tool in oman (n = 49) dimension of rap-cm tool category n (%) dimension 1: attitudes towards cmp 1. in oman, compared to other health and social problems, how much of a priority is cmp (i.e. taking measures to prevent cm before it occurs)? high priority moderate priority low priority/don’t know 7 (14.3) 22 (44.9) 20 (40.8) 2. do you think that measures taken so far to prevent cm in oman have been adequate? adequate neither adequate/nor inadequate inadequate 2 (4.1) 17(34.7) 30 (61.2) dimension 2: knowledge of cmp 1. in your opinion, what are the main types of consequences of cm for the victim in oman? please list as many types as you can think of. 5 or more types mentioned 1–4 types mentioned 32 (65.3) 17 (34.7) 2. what do you think are the main types of risk factors for cm in oman? please list as many types as you can think of. 5 or more types mentioned 1–4 types mentioned no types mentioned/don’t know 19 (38.8) 29 (59.2) 1 (2.0) dimension 3: scientific data on cmp 1. is there data on the magnitude and distribution of cm in general in oman? if so, how good is the quality of these data? yes and the quality is good yes, but the quality is low/fair or don’t know about quality no data exists/don’t know 4 (8.2) 27 (55.1) 18 (36.7) 2. is there data on the magnitude and distribution of child sexual abuse available in oman? if so, how good is the quality of these data? yes and quality is good yes, but the quality is low/fair or don’t know about quality no data exists/don’t know 1 (2.0) 23 (46.9) 25 (51.0) dimension 4: current programme implementation and evaluation 1. please list the names of cm programmes you are aware of that are currently being or have in the past been implemented in oman. 5 or more programmes listed 4 programmes listed 2–3 programmes listed 1 programmes listed no programmes listed/don’t know 7 (14.3) 10 (20.4) 18 (36.7) 6 (12.2) 8 (16.3) dimension 5: legislation, mandates and policies 1. are any governmental or non-governmental agencies officially mandated with cmp in oman? yes no 41 (83.7) 8 (16.3) 2. is there an official policy–or are there official policies– specifically addressing cmp in oman? if so, can you tell me about it/them? yes no don’t know 41 (83.7) 6 (12.2) 2 (4.1) dimension 6: willingness to address the problem 1. in oman, are there political leaders who express strong commitment to the issue of cmp and are taking effective measures to address the problem? yes unclear no/don’t know 26 (53.1) 13 (26.5) 10 (20.4) 2. how intensive have communication efforts been concerning cmp in oman? intensive moderate weak/don’t know 6 (12.2) 28 (57.1) 15 (30.6) dimension 7: institutional resources and links 1. can you list the names of any institutions currently involved in cmp? please list as many as you can think of. 5 or more institutions listed 1–4 institutions listed no institutions listed/don’t know 32 (65.3) 15 (30.6) 2 (4.1) 2. can you list the names of any partnerships, alliances, coalitions or networks of institutions in oman that are wholly or in a large part dedicated to cmp? please list as many types as you can think of. 3 or more listed 1–2 listed none listed/don’t know 11 (22.4) 19 (38.8) 19 (38.8) rap-cm = readiness assessment for the prevention of child maltreatment; cmp = child maltreatment prevention; cm = child maltreatment. muna al saadoon, asia al numani, hassan saleheen, maha almuneef and majid al-eissa clinical and basic research | e41 each dimension and mean total scores on a scale of 1–10 were calculated. the scores for each dimension were categorised as follows: a mean score of five or above represents high readiness and a mean score below five represents low readiness.17,18 results a total of 49 participants were included in this study (response rate: 98%). participants were predominantly female (73.5%) and more than half (59.1%) worked in governmental organisations, while some (20.4%) represented non-governmental organisations (ngos). oman’s mean total score for the 10 dimensions was 50.17 out of a possible 100 points. the participants expressed high readiness scores in dimension 5 (9.08), followed by dimensions 2 (7.55), 7 (6.12), 6 (5.35), 10 (5.15) and 4 (5.10). participants perceived the lowest readiness in dimensions 8 (3.46), 3 (3.06), 1 (2.90) and 9 (2.44) [table 1 and figure 1]. in dimension 2 (knowledge of cmp), the majority of participants (65.3%) were able to list more than five consequences of cm. in dimension 4 (current programme implementation and evaluation), most participants (71.4%) listed two or more cmp progr ammes. for dimension 6 (willingness to address the problem), more than half of the participants (53.1%) reported that oman has political leaders who express strong commitment to the issue of cmp and are taking effective measures to address the problem. many partic ipants (65.3%) in dimension 7 (institutional resources and links) listed five or more institutions currently involved in cmp [table 2]. in dimension 1 (attitudes towards cmp), few participants (14.3%) thought that cmp is given a high priority in oman compared to other social and health problems. in dimension 3 (scientific data on cmp), the majority of participants (55.1%) thought that data on the magnitude and distribution of cm exists but it is of low/fair quality or did not know about the quality. some participants (14.3%) in dimension 8 (material resources) believed there was no dedicated budget for cmp in oman’s governmental institutions. in dimension 9 (human and technical resources), the majority of participants (77.6%) reported that the number of professionals specialising in cmp was inadequate for large-scale implementation of cmp programmes and most participants (63.3%) stated that some or few undergraduate or postgraduate educational institutions devoted curricular attention to cmp [table 2]. table 2 (cont’d): participants’ responses to the 10 dimensions of the readiness assessment for the prevention of child maltreatment tool in oman (n = 49) dimension of rap-cm tool category n (%) dimension 8: material resources 1. does the ministry (or department) of social welfare (or nearest equivalent in the country) have a dedicated budget for cmp? yes no don’t know 16 (32.7) 7 (14.3) 26 (53.1) 2. are there dedicated budgets in other parts of the government (e.g. other ministries, departments, etc.) in oman for cmp besides the ministry (or department) of social welfare? yes no don’t know 11 (22.4) 7 (14.3) 30 (61.2) dimension 9: human and technical resources 1. overall in oman, do you think the number of professionals specialising in child maltreatment prevention is adequate for large-scale implementation of cmp programmes? adequate neither adequate nor inadequate inadequate/there are none/don’t know 4 (8.2) 7 (14.3) 38 (77.6) 2. how widely available are undergraduate or postgraduate educational institutions that devote some of the curriculum to cmp? widely available some or few available none available/don’t know 1 (2.0) 31 (63.3) 17 (34.7) dimension 10: informal social resources (non-institutional) 1. what level of citizens’ participation is there typically in efforts to address various health and social problems in oman? high moderate low/don’t know 16 (32.7) 19 (38.8) 14 (28.6) 2. how good at getting things done through their joint efforts are the people living in oman? good moderate poor/don’t know 18 (36.7) 14 (28.6) 17 (34.7) rap-cm = readiness assessment for the prevention of child maltreatment; cmp = child maltreatment prevention; cm = child maltreatment. child maltreatment prevention readiness assessment in oman e42 | squ medical journal, february 2020, volume 20, issue 1 discussion this is the first study to explore oman’s cmp readiness. overall, the results showed that oman has a moderate level of readiness to provide cmp programmes as the overall score was 50.17. oman ranked second in comp arison to other gcc countries in the who gcc report and had the highest scores for dimension 2 (knowledge of cmp) and 5 (legislation, mandates, and policies) [figure 2]. oman’s score was also higher than values reported from other countries that used a similar tool and obtained scores ranging from 31.2–45.8.16,17 the dimensions with the highest scores concerned legislation, mandates and policies followed by know ledge of cmp, which is similar to the finding from gcc countries and other countries that conducted similar studies.16,17 the scores of these two dimensions may have been positively affected by the establishment of the national committee for family affairs to monitor the implementation of the crc and the enactment of oman’s child law in 2014. furthermore, the high mean score for dimension 5 (legislation, mandates, and policies) reflects that agencies are officially mandated to uphold cmp in oman. many of the child law articles ensure obligation of the state and guardians to assure prevention of cm. for example, article 7 in the civil rights chapter gives the child the right to be protected from violence, exploitation and abuse. the social rights legislation comprehensively covered most of the risk factors of cm so that children in oman may live in a cohesive family, enjoying adequate standards of living in the context of freedom and human dignity.15 the participation in training workshops and activities targeting professionals working with children might explain the high level of knowledge found in this study.13 dimensions 7 (institutional resources and links) and 4 (current programme implementation and eval uation) also had high mean scores in the current study. other countries in the who gcc report had variable scores in these domains. for example, the lowest score among gcc countries for dimension 7 was 2.27 and the highest was 7.61; oman had a score of 6.12. dimension 4 scored lower with a range of 1.05–5.22; oman’s score was 5.10. the scores were even lower in a 2011 study.16,17 after oman’s child law was passed, different governmental bodies and ngos started to address the problem of cm by initiating awareness and advocacy activities, which could explain the obtained score. however, one reason for moderate scores in some dimensions may be that the current focus is on child protection requirements rather than prevention. for example, the mosd launched child protection committees with representatives from different govern mental bodies and ngos, which enhanced the links between the institutions.13 however, it appears the committees focus has been on dealing with reported cases of cm and providing protection and rehabili tation for victims, siblings and families. this role may have been created as a result of identification of victims of cm by the ministry of health (moh) since 2007, thereby resulting in a greater effort to initiate protection services for detected cases. a similar programme was also initiated in the ministry of education.12 the training programmes that were conducted by different institutions improved the detection rate of victims with more demand for child protective services. the limited involvement of informal social resources (dimension 10) in cmp activities likely does not reflect a lack of interest in cm. this finding might simply be due to a generalised low involvement of communities and individuals in voluntary work. the mean score of this dimension indicates an average level of citizens’ participation in addressing various health and social problems in oman. similarly, low scores (2.7–4.1) were obtained in this dimension in north macedonia, malaysia, saudi arabia, south africa and brazil in 2011.16 the scores for gcc countries were slightly higher and ranged from 3.75–5.61; oman received a score of 5.15. the dimensions that showed the lowest scores dealt with scientific data on cmp (dimension 3), attitudes toward cmp (dimension 1), material resources (dimension 8) and human and technical resources (dimension 9). this finding was similar to the results obtained by other gcc countries in the who gcc report with the exception of attitudes toward cmp, in which the united arab emirates had a high score compared to oman (5.44 versus 2.90, respectively). research is still at an early stage of development in oman as there are no population-based studies on cm. however, a few small-scale studies have measured figure 2: total child mistreatment prevention readiness scores on the readiness assessment for the prevention of child maltreatment tool among gulf cooperation council countries uae = united arab emirates; sa = saudi arabia. muna al saadoon, asia al numani, hassan saleheen, maha almuneef and majid al-eissa clinical and basic research | e43 the prevalence of cm and some of the associated risk factors.10,11,20 recently, data collection systems have been established in the moh with the launch of the notification of suspected cases of cm in 2007 as well as in the mosd with the activation of child protection committees in 2014.12 however, the results of the current study indicate inadequate communication or not sharing these data with professionals across different governmental sectors and ngos. professionals are not satisfied with the level of commitment and effort directed towards cmp in oman from both governmental and non-governmental sectors. this dissatisfaction may reflect a level of expectation of professionals working in that area, who aimed to provide a high level of service to families and children in order to prevent cm. in addition to data-sharing, material, human and technical resources are important in improving cmp programmes. participants’ responses indicated that the existing resources are inadequate, which might also be related to the expectations of the participants and a sense that more effort is required to provide better services. numerous public awareness campaigns have adv ocated for child protection and children’s rights (e.g. family education activities on the stages of a child’s dev elopment, psychological health and educational needs).13,14 governmental and non-governmental bodies also have produced numerous television and radio programmes as well as provided publications and printed materials covering the crc articles. these bodies have also dev eloped and disseminated training programmes on the rights of the child for professionals and families.14 nevertheless, the results of this study show that there is a demand for more effort in this area. this study was subject to some limitations. the small sample size should be considered when inter preting the results of this study. in addition, bias that might arise from the selection of the participants and collecting the data through face-to-face interviews. the study indicates a need to address the dimensions of the rap-cm with low scores. in response to these low scores, the authors make a number of recomm endations. first, a national strategy is needed that outlines a framework for organising and prioritising efforts towards cmp. such a strategy would also provide a direction for organisations that are involved in cmp and would highlight the role of public and private engagement. second, it is important to initiate a child welfare centre with an adequate budget that will take responsibility for coordinating all services provided to children in order to assure the delivery of all rights and protection from violation of any stipulated rights. third, it is important to implement specifically tailored and evidence-based cmp programmes directed towards different target groups, including children and care givers in the country. for example, compulsory parenting programmes might target parents and couples planning to get married. nationwide and sustainable awareness campaigns are required which focus on changing public attitudes and social norms that encourage violence. the materials used for this purpose should be age-appro priate, user-friendly and in an accessible format. fourth, at a certain stage, an evaluation of existing intervention programmes will be needed in order to provide inform ation about their strengths and limitations. in addition, these evaluations should identify excellent regional and international cmp programmes for the purpose of collaboration and for adaptation into the omani context. fifth, it is important that oman establishes a unified nationwide registry for data collection including the use of valid and reliable instruments for measuring cm and ensuring the dissemination of results to decision-makers, researchers and the public. this step would also facilitate and encourage research in the field of cm and ensure the dissemination of results to these stakeholders. sixth, the implementation of all of the articles in oman’s child law should be enhanced by accelerating the issue of executive regulations. it is essential to increase the knowledge of all concerned, including professionals and the public at large, about oman’s child law with the aim of emphasising the responsibilities of people, the rights of children and the repercussions for violators. seventh, it is essential that stakeholders improve intersectoral collaboration for preventing and combatting cm and increasing the contribution and number of ngos in oman that work for children’s rights. eighth, the government should allocate a fixed and specific budget for preventing and combatting cm within the concerned ministries. finally, it is important that the entities with specialised expertise in the cm field can offer interdisciplinary training programmes. this training might be in the form of in-service training, providing continuous devel opment opportunities, supporting graduate and post graduate education in the identification and manage ment of cm cases and encouraging young scientists to conduct research on cm. conclusion the results of this study indicate that oman has a moderate level of readiness to implement large-scale evidence-based prevention programmes against cm; however, several dimensions still need to be strength ened. the participants in this study, who are also stake holders, made many recommendations that could improve cmp in oman. it is important to develop a national strategy that outlines a framework for organ child maltreatment prevention readiness assessment in oman e44 | squ medical journal, february 2020, volume 20, issue 1 ising and prioritising efforts towards cmp. it is also recommended that a child welfare centre be established to take responsibility for coordinating all services provided to children in order to assure the delivery of all rights and protection from violation of any of their stipulated rights. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by king abdullah international medical research center at the ministry of national guard health affairs in saudi arabia (rc15/067). references 1. united nations children's fund. hidden in plain sight: a statistical analysis of violence against children. from: http:// files.unicef.org/publications/files/hidden_in_plain_sight_ statistical_analysis_en_3_sept_2014.pdf accessed: jul 2019. 2. united nations general assembly. promotion and protection of the rights of children. from: https://undocs.org/a/61/299 accessed: jul 2019. 3. world health organization. child maltreatment. from: www. who.int/mediacentre/factsheets/fs150/en/ accessed: jul 2019. 4. al-mahroos ft, al-amer e. reported child sexual abuse in bahrain: 2000-2009. ann saudi med 2011; 31:376 –82. https:// doi.org/10.4103/0256-4947.83218. 5. youssef rm, attia ms, kamel mi. children experiencing violence. ii: prevalence and determinants of corporal punishment in schools. child abuse negl 1998; 22:975–85. https://doi.org/10.1016/s0145-2134(98)00084-2. 6. jumaian a. prevalence and long-term impact of child sexual abuse among a sample of male college students in jordan. east mediterr health j 2001; 7:435–40. 7. al-mahroos ft. child abuse and neglect in arab peninsula. saudi med j 2007; 28:241–8. 8. al-eissa ma, albuhairan fs, qayad m, saleheen h, runyan d, al-muneef m. determining child maltreatment incidence in saudi arabia using the icast-ch: a pilot study. child abuse negl 2015; 42:174–82. https://doi.org/10.1016/j.chiabu.2014.08.016. 9. al-saadoon m, al-shamousi k. discharge against medical advice among children in oman: a university hospital experience. sultan qaboos univ med j 2013; 13:534–8. 10. koul rl, chacko a, al-lamk z, al-amri am, al-khusaiby s. munchausen syndrome by proxy. saudi med j 2000; 21:482–6. 11. al-saadoon m, al-sharbati m, nour ie, al-said b. child maltreatment: types and effects: series of six cases from a university hospital in oman. sultan qaboos univ med j 2012; 12:97–102. 12. national centre for statistics and information. our children between care and development. from: www.ncsi.gov.om/elibr a r y / p a g e s / l i b r a r y c o n t e n t d e t a i l s . a s p x ? i t e m i d =ogrscq6kgjdxo%2b6%2bio7k%2fa%3d%3d accessed: jul 2019. 13. al zughair m; ministry of social development. [child right and child protection policies in sultanate of oman]. from: https://www.mosd.gov.om/images/worpaper/sheet%2027.pdf accessed: jul 2019. 14. united nations. consideration of reports submitted by states’ parties under article 44 of the convention: combined third and fourth periodic reports of states’ parties due in 2012: oman. from: www.refworld.org/docid/56a1edf94.html accessed: jul 2019. 15. ministry of legal affairs. child law. from: https://www.mosd. gov.om/images/rules/childs%20law%20en.pdf accessed: jul 2019. 16. mikton c, power m, raleva m, makoae m, al-eissa m, cheah i, et al. the assessment of the readiness of five countries to implement child maltreatment prevention programs on a large scale. child abuse negl 2013; 37:1237–51. https://doi. org/10.1016/j.chiabu.2013.07.009. 17. almuneef m, qayad m, noor ik, al-eissa ma, albuhairan fs, inam s, et al. multidimensional model to assess the readiness of saudi arabia to implement evidence based child maltreatment prevention programs at a large scale. child abuse negl 2014; 38:527–32. https://doi.org/10.1016/j.chiabu.2013.08.001. 18. almuneef ma, qayad m, inam s, al eissa m, al buhairan f, noor i. child maltreatment prevention readiness assessment country report: saudi arabia. from: https://www.who.int/ violence_injury_prevention/violence/child/saudi_arabia_rap_ cm.pdf.pdf?ua=1 accessed: jul 2019. 19. world health organization. handbook for the readiness assessment for the prevention of child maltreatment (rap-cm). from: www.who.int/violence_injury_prevention/violence/chi ld/cmp_readiness/en/index.html accessed: jul 2019. 20. koul r, al-futaisi am, al-sadoon m, el-nour i, chacko a, hira m, et al. vehicular entrapment and heat stroke in three children: is it a form of child neglect? oman med j 2010; 25:222–4. https://doi.org/10.5001/omj.2010.61. https://doi.org/10.4103/0256-4947.83218 https://doi.org/10.4103/0256-4947.83218 https://doi.org/10.1016/s0145-2134%2898%2900084-2 https://doi.org/10.1016/j.chiabu.2014.08.016 https://doi.org/10.1016/j.chiabu.2013.07.009 https://doi.org/10.1016/j.chiabu.2013.07.009 https://doi.org/10.1016/j.chiabu.2013.08.001 https://doi.org/10.5001/omj.2010.61 submitted 14 mar 23 1 revision req. 13 apr 23; revision recd. 18 apr 23 2 accepted 3 mar 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.034 5 6 erythematous plaque in the left axillary region 7 a diagnostic challenge where dermoscopy can help 8 maria d. pegalajar-garcía,1 jose mellado,2 *ricardo ruiz-villaverde,1 9 francisco j. navarro-triviño1 10 11 1dermatology department, hospital universitario san cecilio, granada, spain; 12 2pathological anatomy, analizalab-hla inmaculada, granada. spain. 13 *corresponding author’s e-mail: ismenios@hotmail.com 14 15 a 70-year-old male patient was attended in our outpatient dermatological clinic for a 16 plaque on left axillae of unknown time of evolution. physical examination revealed an 17 erythematous plaque with no desquamative component (fig. 1a). dermoscopy showed 18 thick reticular white lines, white clods, and structureless areas (fig. 1b), dotted and linear 19 vessels, and a sessile projection in the lower part of the plaque. histological examination 20 using a 4 mm punch biopsy revealed a hyperkeratotic epidermis without dyskeratosis, with 21 intraepidermal infiltration of dysplastic cells distributed singly and in clusters (fig.1c). 22 immunohistochemistry staining of this tumoral component was positive for gcdfp-15, 23 mammaglobin and ck7, and negative for hmb45 and s-100 protein, which was 24 consistent with the diagnosis of extramammary paget's disease (empd). complementary 25 examinations (body-tc, a complete blood test with hemogram, liver and renal function, 26 ions, protein s100b and psa; colonoscopy and mammary ecography) ruled out the 27 presence of concomitant tumour. the lesion was completely removed through wide local 28 excision and primary closure, with no local recurrence or distant metastasis during the 29 following 12-months. he is currently under long-term follow-up with periodic revisions 30 every 6 months. 31 32 comment 33 empd is an infrequent cutaneous adenocarcinoma with unknown incidence, which 34 predominantly affects postmenopausal caucasian women and asian men aged between 60 35 and 80 years old. it is usually presented as a slow-growing rounded or oval erythematous 36 plaque, asymptomatic or pruritic, located in genital, perianal or, less frequently, axillary 37 regions.1 dermoscopy is a non-invasive technique which raises suspicion of empd. 38 pigmented, whitish and reddish structures represent the main groupof dermoscopy 39 patterns. glomerular and dotted vessels are the most common vascular patterns. lava lake 40 structures (baw) and cloud-like structureless areas (waw) were described by 41 payapvipapong et al.4 none of the patients had axillary lesions, practically all of them 42 were located in the ano-genital region. this could explain the fact that we have not 43 observed baw and waw in our patient. histology allows to distinguish between empd 44 and other diagnoses such as langerhans cell histiocytosis, bowen’s disease, amelanotic 45 melanoma and mycosis fungoides (table 1).1 46 the most relevant prognostic factor is the presence of underlying malignancy, either a 47 contiguous tumour (23% of cases) or a distant one (8%-46% of cases). underlying cancer 48 screening might include a complete physical examination with lymph node and breast 49 examination. complementary tests may include urine cytology and colonoscopy for both 50 genders, psa blood test and digital rectal examination in male patients, and papanicolaou 51 test and mammography in female patients.2 52 primary cases, as the one we present, are usually indolent, with good survival rates. wide 53 local excision is the gold standard treatment, although imiquimod, photodynamic therapy 54 or radiotherapy could be considered in non-surgical cases.1,3 recurrence rates are 55 considerably elevated regardless of the treatment, so a long-term follow-up based on a 56 careful physical examination is highly recommended.1 57 the authors have obtained patient consent for publication purposes. 58 59 authors’ contribution 60 all authors contributed equally in the conceptualization, design, data acquisition, analysis 61 and write up of the manuscript. 62 63 references 64 1.simonds rm, segal rj, sharma a. extramammary paget's disease: a review of the 65 literature. int j dermatol. 2019;58:871-879. doi: 10.1111/ijd.14328 66 2. schmitt ar, long bj, weaver al, mcgree me, bakkum-gamez jn, brewer jd et al. 67 evidence-based screening recommendations for occult cancers in the setting of newly 68 diagnosed extramammary paget disease. mayo clin proc. 2018;93:877-883. 69 10.1016/j.mayocp.2018.02.024 70 3. liao x, liu x, fan x, lai j, zhang d. perianal paget's disease: a clinicopathological 71 and immunohistochemical study of 13 cases. diagn pathol. 2020;15:29. 10.1186/s13000-72 020-00952-w 73 4. payapvipapong k, nakakes a, tanaka m. lava lake structure and cloud-like 74 structureless area: new clues for diagnosing extramammary paget disease. j eur acad 75 dermatol venereol. 2017;31(10):e459-e461. doi: 10.1111/jdv.14279. 76 77 78 figure 1: (a) round erythematous plaque with slightly raised edges without scaling or 79 ulceration, located on the left axilla (black arrow: biopsy area); (b) dermoscopy showed 80 milky red structureless areas, reticular white lines (red arrow) and white clods (black 81 arrow). dotted and linear vessels (asterisk) werethe vascular pattern identified; (c) 82 epidermis with hyperkeratosis without dyskeratosis, with a component of dysplastic cells 83 distributed singly and in clustered, with the following features (black arrow): large cells 84 with pale cytoplasm and irregular nuclei with visible nucleoli, most of them just above the 85 epidermal basal layer, with others ascending to intermediate epidermal strata (h&e 4x). 86 spontaneously occurring epidural haematomas (sedh) are an uncommon entity. the possible causes are neoplastic lesions, craniofacial infections, bleeding disorders, uraemia, sinus thrombosis, heart surgery, arteriovenous malformation and intra-diploic epidermoid cysts. the case reported by ahmad et al. is the only case of spontaneous posterior fossa epidural haematoma which occurred in a child with a cardiopulmonary bypass.1 we report the first case of spontaneous posterior fossa epidural haematoma in a patient of sigmoid sinus thrombosis secondary to mastoiditis. case report a 40 year-old man was referred to the outpatients department of c.s.m. medical university hospital, india, with complaints of mild headache and incoordination. he had a 10-year history of recurrent right ear discharge which had been treated by oral antibiotics, but had no ear discharge at the time of presentation. he had no history of bleeding diathesis or trauma and was not a known case of any medical ailment. on examination, he was conscious, oriented and higher mental functions were normal. all his cranial nerves were intact with no signs of meningitis. he had an impaired tandem gait with no positive cerebellar signs. his haematological parameters, including renal function test, liver squ med j, february 2011, vol. 11, iss. 1, pp. 108-111, epub. 12th feb 11 submitted 13th may 10 revision req. 23rd jun 10, revision recd. 11th aug 10 accepted 24th aug 10 department of neurosurgery, c.s.m. (chattrapati sahuji maharaja, previously king george’s) medical university, lucknow, uttar pradesh, india 226003. email: dr_kaifmohd@yahoo.co.in < �9èq̌<ö^n �}<ª<gfäjë<^ �é�§]< �h^„ �j÷] ìèà◊§]<<ïüà£]<<ìè ^q<—á <îá⁄å<›öêê ì÷^u<üëüœi    40       :مفتاح الكلمات abstract: spontaneously occurring epidural haematomas are an uncommon entity. a spontaneous post fossa epidural haematoma due to sigmoid sinus thrombosis secondary to mastoiditis has not been reported in english medical literature. we report a 40 year-old man who presented to us with headache and incoordination. a magnetic resonance imaging (mri) confirmed epidural sub-acute bleeding in the right side of posterior fossa with mastoiditis and right sigmoid sinus thrombosis. a right suboccipital craniotomy and evacuation of the haematoma was done and the patient was relieved of his complains. keywords: haematoma, epidural; cranial fossa posterior; sinus thrombosis; mastoiditis; case report; india mastoiditis causing sinus thrombosis and posterior fossa epidural haematoma case report mohamed kaif case report mohamed kaif case report | 109 function test and coagulation profile, were normal. the magnetic resonance imaging (mri) scan of his brain with a venogram was already available and showed a well defined extra axial lesion on right side of the posterior cranial fossa posteromedially to the right mastoid with hypointense signal on t1w, t2w and gre images [figure 1] and peripherally hyperintense on t1w and t2w image suggestive of early subacute epidural bleeding. the right mastoid showed t1 hypointense and t2 hyperintense lesion suggestive of mastoiditis. a magnetic resonance (mr) venogram imaging scan demonstrated a right sigmoid sinus thrombosis [figure 2]. as both the mri and the venogram demonstrated a haematoma with thrombosed right sigmoid sinus, no other investigation was done and surgery was planned. a retromastoid suboccipital craniotomy was done and an epidural organised clot of 30 ml volume evacuated. a craniotomy was preferred over craniectomy as peroperatively no evidence of infection was found and the craniotomy prevents a bone defect. the free bone flap was washed with chloramphenicol saline and kept in chloramphenicol saline during the surgery. mild oozing was noted from the transverse sinus region which was managed by packing with absorbable haemostat (surgicel®, ethicon, inc., summerville, nj, usa). the patient was complaint free in the postoperative period and was subsequently transferred to the ear nose and throat department for the management of right mastoiditis and then modified radical mastoidectomy after 4 weeks. the haematoma was confirmed on histopathology and the culture was found to be sterile. discussion spontaneously occurring cranial epidural haematomas have been reported in the literature worldwide. liedbeck et al. in 1848 reported the first case of sedh in a patient with haemophilia.2 schnieder et al., in 1951, were the first to report a case of sedh in a case of craniofacial infection in autopsy of two patients.3 to date there have been 55 reported cases of sedh [table 1]. there are seven possible causes for sedhs mentioned in the world literature. the commonest possible cause for spontaneous epidural haematoma reported in the international literature is neoplastic condition.4-11 the most common type of sedh is hepatocellular carcinoma reported in seven cases. the other neoplastic conditions mentioned are eosinophilic granuloma,5 langerhans’ cell histiocytosis,6 lung carcinoma,7 ovarian carcinoma,8 malignant fibrous histiocytoma,9 and ewing's sarcoma.10 the second commonest possible cause for figure 1: a: axial t1-weighted magnetic resonance image showing hypointense signal with peripheral hyperintensity and right mastoid showing hypointense signal; b: axial t2-weighted image showing hypointense signal with peripheral hyperintensity and right mastoid showing hyperintense signal; c: gradientecho sequence showing hypointense signal. figure 2: magnetic resonance venography demonstrating thrombosis in the right sigmoid sinus. mastoiditis causing sinus thrombosis and posterior fossa epidural haematoma case report 110 | squ medical journal, february 2011, volume 11, issue 1 sedh reported is associated craniofacial infection which was present in 17 of the 55 reported cases.12-19 two mechanisms have been proposed for such bleeding. the first is arteritis, which results in weakening of the meningeal vessel wall and causes subsequent bleeding. the second mechanism proposed is progressive detachment of the dura mater from the inner table of the skull by the accumulation of exudates, pus, or air. the next most common cause reported is bleeding disorders. there are 11 case reports of bleeding disorders causing sedh. the possible causes mentioned are haemophilia,20 thrombocytopenia, hypofibrinogenaemia21 and vitamin k deficiency. epidural haematomas (edh) are reported to be caused by chronic renal disease and uraemia.22 the coagulation abnormalities associated with uraemia or heparin use during haemodialysis may be the factors responsible for the edh in such patients. platelet dysfunction, as has been reported in uraemia, may further explain edh formation in these patients. there are two case reports of sedh in patients of cardiopulmonary bypass.1,23 ahmad et al. reported a case of spontaneous posterior fossa epidural haematoma in a child who had undergone a cardiopulmonary bypass. this was the first reported case of spontaneous posterior fossa extradural hematoma.1 other causes of spontaneous extradural haematoma reported are dural vascular anomalies and intradiploic epidermoid cysts.11 knopman et al. reported a case of sedh secondary to venous sinus thrombosis.24 the mechanism for the development of the haematoma is that the venous haemodynamic pressure increases secondary to poor outflow, causing tension on the proximal venous system. this tension causes blood to dissect between leaflets of the proximal sinus and into the epidural space. mastoiditis is known to cause sigmoid sinus thrombosis.25 our patient developed spontaneous posterior fossa epidural haematoma secondary to sigmoid sinus thrombosis which was due to mastoiditis. this is the first reported case of sedh of the posterior fossa in sigmoid sinus thrombosis due to mastoiditis. conclusion spontaneously occurring edh is an uncommon entity. certain conditions have been reported to be associated with sedh such as craniofacial infections, hepatocellular carcinoma and bleeding disorders. craniofacial infections are the most commonly associated condition. this is the first case report of sigmoid sinus thrombosis secondary to mastoiditis thus causing edh of the posterior cranial fossa. references 1. ahmad fu, pandey p, mahapatra ak. spontaneous posterior fossa extradural hematoma a rare complication following cardiac surgery. pediatr neurosurg 2005; 4:49–51. 2. liedbeck pj. hygiea 10:363, 1848 (cited in reference 58). 3. schneider rc, hegarty wm. extradural hemorrhage as a complication of otological and rhinological infections. ann otol rhinol laryngol 1951; 60:197– 206. 4. endo m, hamano m, watanabe k, wakai s. combined chronic subdural and acute epidural hematoma secondary to metastatic hepatocellular cancer: case report. no shinkei geka 1999; 27:331– 4. table 1: reported cases of spontaneous epidural haematomas with aetiology aetiology example neoplastic condition hepatocelluar carcinoma4 eosinophilic granuloma5 langerhan's cell histiocytosis6 lung carcinoma7 ovarian carcinoma8 malignant fibrous histiocytoma9 ewing's sarcoma10 intradiploic epidermoid11 craniofacial infection fontal sinusitis12 middle ear suppuration13 orbital cellulites14 pansinusitis15 maxillary sinusitis16 cleft palate with frontal sinusitis17 sphenoiditis18 nasal polyps19 coagulation abnormality haemophila20 hypofibrinogenemia21 uraemia22 heart surgery open heart surgery23 cardiopulmonary bypass surgery1 mohamed kaif case report | 111 5. cho dy, liau wr, chiang ip. eosinophilic granuloma with acute epidural hematoma: a case report. pediatr neurosurg 2001; 35:266–9. 6. chen hc, shen wc, chou dy, chiang ip. langerhans cell histiocytosis of the skull complicated with an epidural hematoma. ajnr am j neuroradiol 2002; 23:493–5. 7. hassan mf, dhamija b, palmer jd, hilton d, adams w. spontaneous cranial extradural hematoma: case report and review of literature. neuropathol 2009; 29:480–4. 8. anegawa s, hirohata s, tokutomi t, kuramoto s. spontaneous epidural hematoma secondary to dural metastasis from an ovarian carcinoma – case report. neurol med chir (tokyo) 1989; 29:854–6. 9. leung g, yip p, fan yw. spontaneous epidural haematoma associated with radiation-induced malignant fibrous histiocytoma. j r coll surg edinb 1999; 44:404–6. 10. aslam e, imran m, faridi nm. bilateral parietal extradural metastatic ewing’s sarcoma simulating acute epidural hematoma. j coll physicians surg pak 2006; 16:543–4. 11. wani aa, ramzan au, kirmani ar, bhatt ar, hamdani n, zargar j. intradiploic epidermoid causing spontaneous extradural hematoma: case report. j neurosurg 2008; 62:e971. 12. kelly dl jr, smith jm. epidural hematoma secondary to frontal sinusitis: case report. j neurosurg 1968; 28:67–9. 13. clein lj. extradural haematoma associated with middle ear infection. can med assoc j 1970; 102:1183–4. 14. schneider rc, tytus js. extradural hemorrhage: factors responsible for the high mortality rate. ann surg 1955; 142:938–48. 15. ataya nl. extradural haematoma secondary to chronic sinusitis: a case report. j laryngol otol 1986; 100:951–3. 16. rajput aj, rozdilsky b. extradural hematoma following frontal sinusitis: report of a case and review of the literature. arch otolaryngol 1971; 94:83–6. 17. griffiths sj, jatavallabhula ns, mitchell rd. spontaneous extradural haematoma associated with craniofacial infections: case report and review of the literature. br j neurosurg 2002; 16:188–91. 18. moonis g, granados a, simon sl. epidural hematoma as a complication of sphenoid sinusitis and epidural abscess: a case report and literature review. clin imaging 2002; 26:382–5. 19. marks sm, shaw md. spontaneous intracranial extradural hematoma. j neurosurg 1982; 57:708–9. 20. cooper na, lynch m.: delayed haemorrhagic disease of the newborn with extradural haematoma. br med j 1979; 1:164–5. 21. kuwayama n, takahashi s, sonobe m, sugita k. spontaneous bilateral extradural hematoma: case report. j neurosurg 1985; 62:139–41. 22. shahlaie k, fox a, butani l, boggan je. spontaneous epidural hemorrhage in chronic renal failure: a case report and review. pediatr nephrol 2004; 19:1168– 72. 23. hoffman hj, mustard wt. spontaneous intracranial extradural hematoma occurring during open heart surgery. can j surg 1973; 16:130–1 24. knopman j, tsiouris aj, souweidane mm. j neurosurg pediatr 2008; 2:416–19. 25. zheng fx, chao y. spontaneous intracranial extradural hematoma: case report and literature review. neurol india 2009; 57:324–6. 2department of otorhinolaryngology-head and neck surgery, 1college of medicine, imam mohammad ibn saud islamic university, riyadh, saudi arabia; 3department of ent, college of medicine, majmaah university, al-majmaah, saudi arabia *corresponding author’s e-mail: bindahmash.a@gmail.com أعراض اجلهاز العضلي اهليكلي املرتبطة ابلعمل لدى األطباء املقيمني يف ختصص األنف واألذن واحلنجرة وجراحة الرأس والعنق عبد املجيد بن دهم�س، فرا�س اخلليوي، عبدال�سالم االحمري، عا�سم م�سطفى �سديد، عبدالرحمن م�سعل احلربي، ُعمري احل�سني abstract: objectives: work-related musculoskeletal disorders in saudi arabia are not often reported in the literature. this study aimed to identify musculoskeletal symptoms among otorhinolaryngology residents in saudi arabia. methods: this cross-sectional survey-based study was conducted in may 2018 and included residents registered in the saudi otorhinolaryngology-head and neck surgery board training programme, riyadh, saudi arabia. the nordic musculoskeletal questionnaire was used to assess musculoskeletal symptoms in addition to demographic and occupational factors, including operating position and the average number of operating hours. results: a total of 45 residents (response rate: 68.2%) completed the survey, including 33 males (73.3%) and 12 females (26.7%). most residents (91.1%) reported at least one musculoskeletal symptom. the most commonly reported musculoskeletal over the previous 12 months were shoulder complaints (64.4%) followed by neck complaints (60%). in the short term (i.e. within seven days preceding the survey), neck complaints were more common than shoulder complaints (28.9% versus 20%). lower back complaints were the most common cause of activity limitation (24.4%) followed by shoulder complaints (13.3%), while those with neck complaints reported it as a cause for visiting a physician (8.9%). hip and thigh complaints were significantly more frequent among residents with operation times of eight hours or more compared to those who operating for less than eight hours (42.9% versus 5.9%; p = 0.021). conclusion: a high incidence of shoulder, neck and lower back complaints was found in this study. residency is an ideal time in an otorhinolaryngologist’s career to implement programmes in ergonomic best practices before bad habits are developed. keywords: otorhinolaryngology; musculoskeletal abnormalities; symptoms and signs; workplace; ergonomics; saudi arabia. امللخ�ص: الهدف: ال يتم يف كثري من االأحيان ذكر اال�سطرابات الع�سلية الهيكلية املرتبطة بالعمل يف اململكة العربية ال�سعودية يف االأدبيات. هدفت هذه الدرا�سة اإىل التعرف على اأعرا�س اجلهاز الع�سلي الهيكلي لدى االأطباء املقيمني يف برنامج االأنف واالأذن واحلنجرة يف اململكة العربية ال�سعودية. الطريقة: اأجريت هذه الدرا�سة املعتمدة على اال�ستق�ساء املقطعي يف مايو 2018 و�سملت االأطباء املقيمني امل�سجلني يف ال�سعودية. العربية اململكة الريا�س، والعنق، الراأ�س جراحة جمل�س تدريب واحلنجرة-برنامج واالأذن االأنف الأمرا�س ال�سعودي الربنامج الدميوغرافية العوامل اإىل باالإ�سافة الهيكلية الع�سلية االأعرا�س لتقييم االأوربي ال�سمال لدول الهيكلي الع�سلي اال�ستبيان ا�ستخدام مت واملهنية، مبا يف ذلك الو�سعية اثناء العمل ومتو�سط عدد �ساعات العمل. النتائج: اأكمل 45 مقيًما االأ�ستبيان )معدل اال�ستجابة: 68.2%(، منهم 33 ذكًرا )%73.3( و 12 اأنثى )%26.7(. اأبلغ معظم املقيمني )%91.1( عن عر�س ع�سلي هيكلي واحد على االأقل. وكانت اأكرث احلاالت الع�سلية الهيكلية �سيوًعا خالل االثني ع�رش �سهًرا املا�سية هي �سكاوى الكتف )%64.4( تليها �سكاوى العنق )%60(. يف املدى الق�سري )اأي يف غ�سون االأيام ال�سبعة التي �سبقت الدرا�سة( كانت �سكاوى العنق اأكرث �سيوًعا من �سكاوى الكتف )%28.9 مقابل %20(. كانت �سكاوى اأ�سفل الظهر هي ال�سبب االأكرث �سيوًعا لتقييد الن�ساط )%24.4( تليها �سكاوى الكتف )%13.3(، يف حني اأبلغ من لديهم �سكاوى العنق اأنها ملدة عمل اأوقات لديهم الذين املقيمني بني ملحوظ وب�سكل تكرارا اأكرث والفخذ الورك �سكاوى كانت الطبيب )8.9%(. لزيارة �سبب كانت ثماين �ساعات اأو اأكرث مقارنة مع اأولئك الذين يعملون الأقل من ثماين �ساعات )%42.9 مقابل %5.9؛ p = 0.021(. اخلال�صة: مت اكت�ساف ن�سبة عالية من حدوث �سكاوى الكتف والرقبة واأ�سفل الظهر يف هذه الدرا�سة. االإقامة الطبية هي الوقت املثايل يف مهنة طبيب االأنف واالأذن واحلنجرة لتنفيذ برامج يف اأف�سل املمار�سات املريحة قبل تنامي العادات ال�سيئة. الكلمات املفتاحية: طب االأنف واالأذن واحلنجرة؛ االأ�سطرابات الع�سلية الهيكلية؛ االأعرا�س والعالمات؛ مكان العمل؛ املمار�سات املريحة؛ اململكة العربية ال�سعودية. work-related musculoskeletal symptoms in otorhinolaryngology-head and neck surgery residents *abdulmajeed bin dahmash,1 feras alkholaiwi,2 abdussalam alahmari,3 asem m. shadid,1 abdulrahman m. alharbi,1 omair al hussain2 clinical & basic research sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e202–208, epub. 28 jun 20 submitted 12 jun 19 revision req. 2 sep 19; revision recd. 25 sep 19 accepted 17 oct 19 https://doi.org/10.18295/squmj.2020.20.02.011 advances in knowledge otorhinolaryngology residents are susceptible to work-related musculoskeletal disorders. it is important to develop awareness of good ergonomic practices among physicians to create better workplace ergonomics. along with this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ abdulmajeed bin dahmash, feras alkholaiwi, abdussalam alahmari, asem m. shadid, abdulrahman m. alharbi and omair al hussain clinical and basic research | e203 work-related musculoskeletal disorders (wrmsds) are often reported by healthcare professionals, including nurses and dentists.1,2 such injuries are often the leading cause of premature retirement.3 for surgeons, the prevalence rate of subjective musculoskeletal complaints ranges between 17.5–50.0% for neck and upper and lower back pain.1 orthopaedic surgeons, obstetricians and gynaecologists have also been found to show an incidence of shoulder, neck and back pain.4–6 surgeons and residents in surgical specialties are at high risk for developing wrmsds due to the demands of surgery during which they remain in fixed postures for long hours.7 over longer periods of time, exposure to biomechanical stressors may also intensify musculoskeletal injuries in the workplace.8 during an operation, surgeons often assume postures such as head-bent and back-bent, making them highly susceptible to physical discomfort.9 laparoscopic procedures limit body movement and demand a static upright body posture, contributing to numerous ergonomic risk factors.10 furthermore, repetitive wrist motions during surgery and static neck postures can aggravate musculoskeletal issues.11,12 wrmsds among otorhinolaryngology-head and neck surgery (orl-hns) residents are not often reported in the literature. in a study on work postures of operating room staff, kant et al. compared general surgeons and orl-hns surgeons and reported that orl-hns had better working posture than general surgeons, but both had poor work posture during more than 80% of their operating time.13 surgeons performing endoscopic sinus surgery suffer from the physical constraints of these surgeries, while laryngologists working without arm support are at risk of shoulder and back strains.1,14 as per surveys in the usa, 62% of paediatric otorhinolaryngologists experience pain and discomfort attributed to their work.15,16 few studies have examined musculoskeletal symptoms among surgeons in various specialties. therefore, this study aimed to identify the prevalence of work-related musculoskeletal symptoms among orl-hns residents. in addition, this study will evaluate whether demographic factors such as age and gender, as well as occupational/ergonomic factors including operating position and the average number of operating hours, were significantly associated with musculoskeletal complaints. methods this cross-sectional survey-based study was conducted in may 2018. all 66 residents registered in the saudi otorhinolaryngology-head and neck surgery board training programme, riyadh, saudi arabia from postgraduate year two to five were approached to participate. residents in postgraduate year one were excluded as they had received little otorhinolaryngology training and were rotating in other specialties. the questionnaire was distributed by a senior resident during the weekly academic activities with the saudi orl-hns board training programme. the survey was adapted from the previously valid ated nordic musculoskeletal questionnaire (nmq).17 the first part of this two-part survey included items on gender, age, height, weight, postgraduate year, average hours in the operating room/week, handedness, average hours of sleep per day and amount of exercise per week. the operating position was assessed using a self-reported five-point likert scale ranging from 1 ‘sitting all the time’ to 5 ‘standing all the time’. the second section inquired about musculoskeletal symptoms in nine anatomical regions according to the nmq incl uding the neck, shoulders, elbows, wrists/hands, upper back, lower back, hips/thighs, knees and ankles/feet. a slight modification was made to the questionnaire; participants were asked whether they had long-term (i.e. during the 12 months preceding the survey) and recent (i.e. seven days preceding the survey) complaints in each anatomic region. the questionnaire also assessed whether participants had visited a physician for these problems and whether they had been prevented from carrying out normal activities during the last 12 months due to these complaints. statistical analysis was performed using statistical package for social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa) and rstudio, version 1.3 (rstudio, inc., boston, massachusetts, usa). categorical data such as gender and age were presented as frequencies and percentages while cont inuous data were presented as means and standard dev iation. in addition, the prevalence of complaints per adequately spaced breaks, such a practice can translate into better surgical performance for otorhinolaryngology residents. application to patient care there is a relationship between surgeon fatigue and perceived medical errors. this relationship, in conjunction with the findings of this study, indicate the importance of implementing good ergonomic practices, and of practitioners learning to adopt acceptable postures during surgery and taking breaks between procedures. work-related musculoskeletal symptoms in otorhinolaryngology-head and neck surgery residents e204 | squ medical journal, may 2020, volume 20, issue 2 each anatomic region was reported as a frequency and percentage. bar plots were also used to visualise results. a chi-square test was performed to assess whether age, gender, operating position or the average number of operating hours were significantly associated with musculoskeletal complaints in any of the nine anatomic regions. the level of statistical significance was set at 0.05. institutional review board (irb) approval was obtained from the medical research unit of the college of medicine at imam mohammad ibn saud islamic university, riyadh, saudi arabia (irb code: 0030/03/2018-48). the purpose of the study was explained to the residents before obtaining informed consent. results a total of 45 residents (response rate: 68.2%) completed the survey. most participants were 28–30 years old (64.4%) and the majority of participants were male (73.3%) [table 1]. only four participants (8.9%) did not report any musculoskeletal discomfort. the remaining 41 part icipants (91.1%) reported at least one musculoskeletal complaint. shoulder complaints were most commonly reported within the past year (64.4%) followed by complaints associated with the neck (60%) [figure 1]. table 1: characteristics of residents in the otorhinolaryng ology-head and neck surgery board training programme, riyadh, saudi arabia (n = 45) age characteristic n (%) age age in years 25–27 16 (35.6) 28–30 29 (64.4) gender female 12 (26.7) male 33 (73.3) marital status married 21 (46.7) unmarried 24 (53.3) residency level pgy 2 11 (24.4) pgy 3 11 (24.4) pgy 4 15 (33.3) pgy 5 8 (17.8) exercise in days per week 0 18 (40.0) 1 8 (17.8) 2 10 (22.2) 3 9 (20) average hours of sleep per day 6 12 (26.7) 7 22 (48.9) 8 8 (17.8) ≥9 3 (6.7) operating position sitting all the time 1 (2.2) sitting most of the time 8 (17.8) equally standing and sitting 13 (28.9) standing most of the time 16 (35.6) standing all the time 7 (15.6) dominant hand left 5 (11.1) right 40 (88.9) mean weight in kg ± sd 73.69 ± 15.20 mean height in cm ± sd 170.78 ± 8.13 mean bmi in kg/m2 ± sd 25.10 ± 3.77 mean number of operations per week ± sd 2.31 ± 1.33 mean hours in operating room per week ± sd 8.00 ± 3.6 p gy = programme year ; kg = kilogram ; sd = standard de viation ; cm = centimetre; bmi = body mass index. figure 1: anatomical illustration of each musculoskeletal complaint by anatomical region in the 12 months pre ceding the survey. abdulmajeed bin dahmash, feras alkholaiwi, abdussalam alahmari, asem m. shadid, abdulrahman m. alharbi and omair al hussain clinical and basic research | e205 however, neck complaints were more common than shoulder complaints within the week preceding the survey (28.9% versus 20%). elbow complaints (9%) were the least commonly reported complaint. lower back complaints were the most common cause of activity limitation (24.4%) followed by shoulder complaints (13.3%). lower back complaints were the most common reason for visiting a physician (11.1%) [figure 2]. shoulder complaints were most commonly reported by females during 12 months preceding the survey (75%) while neck complaints were the most commonly reported musculoskeletal complaints among males (63.6%). wrist/hand complaints were more frequently reported by females than males (50% versus 27.3%). the remaining musculoskeletal complaints were almost equally prevalent in males and females except for shoulder complaints, which were more common in females than males (75% versus 60.6%). [figure 3]. no statistically significant association was found between age and gender and the prevalence of figure 2: impact of musculoskeletal complaints of residents (n = 45). figure 3: musculoskeletal complaints of residents stratified by gender. table 2: association of gender and age of residents with musculoskeletal complaints within the 12 months preceding the study (n = 45) region of the body n (%) p value* n (%) p value* gender age in years female (n = 12) male (n = 33) 25–27 (n = 16) 28–30 (n = 29) neck 6 (50.0) 21 (63.6) 0.630 8 (50.0) 19 (65.5) 0.484 shoulder 9 (75.0) 20 (60.6) 0.589 10 (62.5) 19 (65.5) 1.000 upper back 5 (41.7) 14 (42.4) 1.000 5 (31.2) 14 (48.3) 0.429 elbows 1 (8.3) 3 (9.1) 1.000 1 (6.2) 3 (10.3) 1.000 wrists/hands 6 (50.0) 9 (27.3) 0.283 8 (50.0) 7 (24.1) 0.152 lower back 7 (58.3) 19 (57.6) 1.000 9 (56.2) 17 (58.6) 1.000 hips/thighs 4 (33.3) 9 (27.3) 0.980 6 (37.5) 7 (24.1) 0.546 knees 5 (41.7) 9 (27.3) 0.577 6 (37.5) 8 (27.6) 0.725 ankles/feet 4 (33.3) 10 (30.3) 1.000 5 (31.2) 9 (31.0) 1.000 *using chi-square test. work-related musculoskeletal symptoms in otorhinolaryngology-head and neck surgery residents e206 | squ medical journal, may 2020, volume 20, issue 2 musculoskeletal complaints [table 2]. none of the complaints were significantly associated with body position during operating. however, the percentages were consistently higher in residents who spent most or all their time in a standing position [table 3]. hip/thigh complaints were positively and significantly correlated to the residents who operated for eight hours or more compared to residents who operated for less than eight hours (42.9% versus 5.9%; p = 0.021). upper back complaints were also more common among residents who operated for more than eight hours compared to those who operated less than eight hours but was not statistically significant (53.6% versus 23.5%; p = 0.096) [table 3]. discussion the working hours of orl-hns practitioners involve prolonged standing, occasionally repetitive movements and the exertion of substantial forces on tissues. all these factors are associated with wrmsds.13,18 additionally, head and neck surgeries are associated with physical and movement constraints associated with operating table height and the posture and movements of surgeons and their assistants. in the current study, a high percentage of workrelated musculoskeletal symptoms were found in orl-hns residents (91.1%), which is similar to the rates reported by a canadian study amongst orlhns surgeons (97%).1 cavanagh et al. reported a 62% incidence rate among paediatric otorhinolaryngologists and vijendran et al. reported that 47.4% of included otorhinolaryngologists had musculoskeletal issues.12,15 in the present study, shoulder, neck and lower back complaints were most commonly reported which is similar to the survey conducted among 325 ear, nose and throat consultants in the uk, where the incidence of neck and back pain was reported to be 72%.19 in the current study females were more likely to report shoulder, wrist and hand complaints. a similar finding was also reported by mirmohammadi et al., who found a significant difference in wrmsds among female nurses compared to male nurses in iran.20 however, the difference in complaints from male and female residents in the present study was not statistically significant, which could be due to the study’s small sample size. shoulder, neck and lower back complaints were most commonly reported due to surgical practice and could be attributed to sustained postures, awkward positioning during surgery and taking inadequate breaks. ergonomics associated with the height of the operating table, repetitive movements of the wrists as well as inadequate assistance could aggravate these issues. back and neck pain are generally attributed to prolonged sitting in a stooped position as well as prolonged posture in a forward bending position that can fatigue the extensor musculature, aggravating myofascial pain in muscles of the lower back.21,22 previous studies indicate that a surgeon’s physical position when operating is a risk factor for wrmsds; however, the association between musculoskeletal symptoms with standing and sitting positions during surgery was insignificant in this study.12,23–25 in the present study, spending eight hours or more operating was a significant predictor of hip/thigh symptoms. table 3: association of position during operation and operating hours with musculoskeletal complaints of residents within the 12 months preceding the survey (n = 45) region of the body n (%) p value* n (%) p value* operating position operating hours per week sitting or sitting and standing (n = 22) standing (n = 23) <8 hours (n = 17) ≥8 hours (n = 28) neck 11 (50.0) 16 (69.6) 0.301 8 (47.1) 19 (67.9) 0.286 shoulder 13 (59.1) 16 (69.6) 0.673 8 (47.1) 21 (75.0) 0.115 upper back 8 (36.4) 11 (47.8) 0.634 4 (23.5) 15 (53.6) 0.096 elbows 4 (18.2) 0 (0.0) 0.106 2 (11.8) 2 (7.1) 1.000 wrists/hands 7 (31.8) 8 (34.8) 1.000 5 (29.4) 10 (35.7) 0.913 lower back 12 (54.5) 14 (60.9) 0.899 7 (41.2) 19 (67.9) 0.148 hips/thighs 4 (18.2) 9 (39.1) 0.222 1 (5.9) 12 (42.9) 0.021 knees 6 (27.3) 8 (34.8) 0.824 5 (29.4) 9 (32.1) 1.000 ankles/feet 4 (18.2) 10 (43.5) 0.131 4 (23.5) 10 (35.7) 0.600 *using chi-square test. abdulmajeed bin dahmash, feras alkholaiwi, abdussalam alahmari, asem m. shadid, abdulrahman m. alharbi and omair al hussain clinical and basic research | e207 previous studies indicate that increased working hours is a risk factor for wrmsd.26 lower back symptoms were the most common cause of activity limitation and seeking medical attention in this study. furthermore, a study on orthopaedic residents showed that neck symptoms were the dominant cause of stopping surgeries.4 orl-hns and otorhinolaryngology residents are susceptible to wrmsd. it is important to create awareness among physicians of good ergonomic practice, including adopting acceptable postures during surgery and taking breaks between procedures. this practice is especially important considering the established relationship between surgeon fatigue and perceived medical error.27,28 therefore, better ergonomics at the workplace along with adequately spaced breaks for otorhinolaryngology residents can translate into better surgical performance. future research applying a validated ergonomic assessment like the rapid entire body assessment is highly recommended. however, this study was subject to some limitations. the cross-sectional survey-based nature of the study is a limitation and future longitudinal studies on wrmsd are recommended. this study may also be prone to recall bias. nevertheless, this study still provides beneficial information on the incidence of work-related musculoskeletal issues among orlhns residents in saudi arabia. conclusion a high incidence of shoulder, neck and lower back complaints was found among orl-hns residents in saudi arabia. this study underscores the need for ergonomic considerations while planning resident workload as longer work hours were more likely to contribute to musculoskeletal complaints. residency is an ideal time in an otorhinolaryngologist’s career to implement teaching programmes around ergonomics to train for best ergonomic practices before bad habits form. future studies among board-certified otorhinolaryngologists are recommended to identify the effect of musculoskeletal disorders on their longterm careers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bolduc-bégin j, prince f, christopoulos a, ayad t. work-related musculoskeletal symptoms amongst otolaryngologists and head and neck surgeons in canada. eur arch otorhinolaryngol 2018; 275:261–7. https://doi.org/10.1007/s00405-017-4787-1. 2. szeto gp, ho p, ting ac, poon jt, cheng sw, tsang rc. workrelated musculoskeletal symptoms in surgeons. j occup rehabil 2009; 19:175–84. https://doi.org/10.1007/s10926-009-9176-1. 3. milerad e, ekenvall l. symptoms of the neck and upper extrem ities in dentists. scand j work environ health 1990:129–34. https://doi.org/10.5271/sjweh.1807. 4. knudsen ml, ludewig pm, braman jp. musculoskeletal pain in resident orthopaedic surgeons: results of a novel survey. iowa orthop j 2014; 34:190–6. 5. dolan lm, martin dh. backache in gynaecologists. occup med (lond) 2001; 51:433–8. https://doi.org/10.1093/occmed/51.7.433. 6. yoong w, sanchez-crespo j, rob j, parikh m, melendez j, pillai r, et al. sticks and stones may break my bones: work-related ortho paedic injuries sustained during obstetrics and gynaecology training. j obstet gynaecol 2008; 28:478–81. https://doi.org/10.10 80/01443610802091396. 7. rambabu t, suneetha k. prevalence of work related musculo skeletal disorders among physicians, surgeons and dentists: a comparative study. ann med health sci res 2014; 4:578–82. https://doi.org/10.4103/2141-9248.139327. 8. jain nb, higgins ld, losina e, collins j, blazar pe, katz jn. epidemiology of musculoskeletal upper extremity ambulatory surgery in the united states. bmc musculoskelet disord 2014; 15:4. https://doi.org/10.1186/1471-2474-15-4. 9. berguer r, rab gt, abu-ghaida h, alarcon a, chung j. a comp arison of surgeons’ posture during laparoscopic and open surg ical procedures. surg endosc 1997; 11:139–42. https://doi.org/1 0.1007/s004649900316. 10. karp sj, morris jpg. blueprints surgery. 5th ed. philadelphia, pennsylvania, usa: lippincott williams & wilkins, 2008. 11. esposito c, el ghoneimi a, yamataka a, rothenberg s, bailez m, ferro m, et al. work-related upper limb musculoskeletal dis orders in paediatric laparoscopic surgery. a multicenter survey. j pediatr surg 2013; 48:1750–6. https://doi.org/10.1016/j.jped surg.2013.01.054. 12. vijendren a, yung m, sanchez j, duffield k. occupational musculoskeletal pain amongst ent surgeons are we looking at the tip of an iceberg? j laryngol otol 2016; 130:490–6. https://doi.org/10.1017/s0022215116001006. 13. kant ij, de jong lc, van rijssen-moll m, borm pj. a survey of static and dynamic work postures of operating room staff. int arch occup environ health 1992; 63:423–8. https://doi.org/10.1 007/bf00386939. 14. ayad t, péloquin l, prince f. ergonomics in endoscopic sinus surgery: systematic review of the literature. j otolaryngol 2005; 34:333–40. https://doi.org/10.2310/7070.2005.34507. 15. cavanagh j, brake m, kearns d, hong p. work environment discomfort and injury: an ergonomic survey study of the amer ican society of pediatric otolaryngology members. am j oto laryngol 2012; 33:441–6. https://doi.org/10.1016/j.amjoto.2011.10.022. 16. statham mm, sukits al, redfern ms, smith lj, sok jc, rosen ca. ergonomic analysis of microlaryngoscopy. laryngoscope 2010; 120:297–305. https://doi.org/10.1002/lary.20686. 17. kuorinka i, jonsson b, kilbom a, vinterberg h, biering-sørensen f, andersson g, et al. standardised nordic questionnaires for the analysis of musculoskeletal symptoms. appl ergon 1987; 18:233–7. https://doi.org/10.1016/0003-6870(87)90010-x. 18. buckle pw, devereux jj. the nature of work-related neck and upper limb musculoskeletal disorders. appl ergon 2002; 33:207–17. https://doi.org/10.1016/s0003-6870(02)00014-5. https://doi.org/10.1007/s00405-017-4787-1 https://doi.org/10.1007/s10926-009-9176-1 https://doi.org/10.5271/sjweh.1807 https://doi.org/10.1093/occmed/51.7.433 https://doi.org/10.1080/01443610802091396 https://doi.org/10.1080/01443610802091396 https://doi.org/10.4103/2141-9248.139327 https://doi.org/10.1186/1471-2474-15-4 https://doi.org/10.1007/s004649900316 https://doi.org/10.1007/s004649900316 https://doi.org/10.1016/j.jpedsurg.2013.01.054 https://doi.org/10.1016/j.jpedsurg.2013.01.054 https://doi.org/10.1017/s0022215116001006 https://doi.org/10.1007/bf00386939 https://doi.org/10.1007/bf00386939 https://doi.org/10.2310/7070.2005.34507 https://doi.org/10.1016/j.amjoto.2011.10.022 https://doi.org/10.1002/lary.20686 https://doi.org/10.1016/0003-6870%2887%2990010-x https://doi.org/10.1016/s0003-6870%2802%2900014-5 work-related musculoskeletal symptoms in otorhinolaryngology-head and neck surgery residents e208 | squ medical journal, may 2020, volume 20, issue 2 19. babar-craig h, banfield g, knight j. prevalence of back and neck pain amongst ent consultants: national survey. j laryngol otol 2003; 117:979–82. https://doi.org/10.1258/002221503322683885. 20. mirmohammadi s, yazdani j, etemadinejad s, asgarinejad h. a cross-sectional study on work-related musculoskeletal dis orders and associated risk factors among hospital health cares. procedia manuf 2015; 3:4528–34. https://doi.org/10.1016/j.pro mfg.2015.07.468. 21. kumar vk, kumar sp, baliga mr. prevalence of work-related musculoskeletal complaints among dentists in india: a national cross-sectional survey. indian j dent res 2013; 24:428–38. https://doi.org/10.4103/0970-9290.118387. 22. forde ms, punnett l, wegman dh. pathomechanisms of work related musculoskeletal disorders: conceptual issues. ergo nomics 2002; 45:619–30. https://doi.org/10.1080/00140130210 153487. 23. kazancioglu ho, bereket mc, ezirganli s, ozsevik s, sener i. musculoskeletal complaints among oral and maxillofacial sur geons and dentists: a questionnaire study. acta odontol scand 2013; 71:469–74. https://doi.org/10.3109/00016357.2012.696688. 24. capone ac, parikh pm, gatti me, davidson bj, davison sp. occupational injury in plastic surgeons. plast reconstr surg 2010; 125:1555–61. https://doi.org/10.1097/prs.0b013e3181d62a94. 25. esposito c, najmaldin a, schier f, yamataka a, ferro m, riccipetitoni g, et al. work-related upper limb musculoskeletal disorders in pediatric minimally invasive surgery: a multi centric survey comparing laparoscopic and sils ergonomy. pediatr surg int 2014; 30:395–9. https://doi.org/10.1007/s00383-013-3437-y. 26. epstein s, sparer eh, tran bn, ruan qz, dennerlein jt, singhal d, et al. prevalence of work-related musculoskeletal disorders among surgeons and interventionalists: a systematic review and meta analysis. jama surg 2018; 153:e174947. https://doi.org/10.10 01/jamasurg.2017.4947. 27. gawande aa, zinner mj, studdert dm, brennan ta. analysis of errors reported by surgeons at three teaching hospitals. surgery 2003; 133:614–21. https://doi.org/10.1067/msy.2003.169. 28. shanafelt td, bradley ka, wipf je, back al. burnout and self reported patient care in an internal medicine residency program. ann intern med 2002; 136:358–67. https://doi.org/10.7326/00 03-4819-136-5-200203050-00008. https://doi.org/10.1258/002221503322683885 https://doi.org/10.1016/j.promfg.2015.07.468 https://doi.org/10.1016/j.promfg.2015.07.468 https://doi.org/10.4103/0970-9290.118387 https://doi.org/10.1080/00140130210153487 https://doi.org/10.1080/00140130210153487 https://doi.org/10.3109/00016357.2012.696688 https://doi.org/10.1097/prs.0b013e3181d62a94 https://doi.org/10.1007/s00383-013-3437-y https://doi.org/10.1001/jamasurg.2017.4947 https://doi.org/10.1001/jamasurg.2017.4947 https://doi.org/10.1067/msy.2003.169 https://doi.org/10.7326/0003-4819-136-5-200203050-00008 https://doi.org/10.7326/0003-4819-136-5-200203050-00008 role of transient receptor potential vanilloid 4 channel in skin physiology and pathology *ammar boudaka, mallak al-yazeedi, intisar al-lawati sultan qaboos university med j, may 2020, vol. 20, iss. 2, pp. e138–146, epub. 28 jun 20 submitted 28 jul 19 revision req. 17 sep 19; revision recd. 3 nov 19 accepted 3 dec 19 department of physiology, college of medicine & health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: boudaka@squ.edu.om in the human body, the skin is the largest organ and is composed of three primary layers. the epidermis, the outermost superficial layer, is composed of multiple layers of keratinocytes. basal keratinocytes divide to produce suprabasal keratinocytes that pass through several stages of differentiation and ultimately give rise to non-nucelated cells in the super ficial stratum corneum. the cornified keratinocytes in conjunction with the dense intercellular structures comprise the impermeable hydrophobic skin barrier that prevents noxious substances and pathogens from getting into the human body and halts water vapor isation from the body. melanocytes residing adjacent to the basal keratinocytes manufacture melanin and deliver it to neighboring keratinocytes. the epidermal antigen-presenting cells, known as langerhans cells, capture exogenous and endogenous antigens and present them to the regional draining lymph nodes to provoke an immune response. the dermis, the middle layer of skin, is composed of extracellular matrix, collagen, fibroblasts, endothelial cells and mast cells. it maintains the skin through the provision of nutrients and oxygen via its extensive vascular network and is the main contributor to the physical properties of the skin as an excessive deposition of extracellular matrix, collagen and fibroblast could lead to abnormal wound healing. it also conveys the sensory nerve endings from the epidermis to the deeper layer of the skin and hosts the hair follicles. the hypodermis, the innermost layer of skin, is mainly formed of adipose tissue that functions as a heat insulator and acts as an energy storage site.1 as an integrative system, the skin maintains homeostasis, provides an immunological barrier, synth esises melanin pigments and plays a major role in sensation. current evidence indicates that transient receptor potential (trp) channels play a crucial role in mediating and adjusting these different functions.2 furthermore, disturbances in the expression or function review دور قناة ُمْسَتقبلة فانلويد 4 ذات اجلهد املؤقت يف وظائف اجللد وأمراضه عمار بودقة، مالك اليزيدية، انت�صار اللواتية abstract: transient receptor potential vanilloid 4 (trpv4) channel responds to temperature, as well as various mechanical and chemical stimuli. this non-selective cation channel is expressed in several organs, including the blood vessels, kidneys, oesophagus and skin. in the skin, trpv4 channel is present in various cell types such as keratinocytes, melanocytes and sensory neurons, as well as immune and inflammatory cells, and engages in several physiological actions, from skin homeostasis to sensation. in addition, there is substantial evidence implicating dysfunctional trpv4 channel—in the form of either deficient or excessive channel activity—in pathological cutaneous conditions such as skin barrier compromise, pruritus, pain, skin inflammation and carcinogenesis. these varied functions, combined with the fact that trpv4 channel owns pharmacologically-accessible sites, make this channel an attractive therapeutic target for skin disorders. in this review, we summarize the different physiological and pathophysiological effects of trpv4 in the skin. keywords: trpv4; skin; epidermis; keratinocytes; pain; pruritis; melanoma. امللخ�ص: ت�صتجيب قناة ُم�ْصَتقبلة فانلويد 4 ذات اجلهد املوؤقت للحرارة بالأ�صافة اىل حمفزات ميكانيكية وكيميائية خمتلفة. توجدهذه القناة غري النتقائية لاليونات املوجبة يف العديد من اأع�صاء اجل�صم ، مبا يف ذلك الأوعية الدموية والكلى واملريء واجللد. ويف اجللد اخلاليا وكذلك احل�صية الع�صبية واخلاليا ال�صباغية واخلاليا الكرياتينية اخلاليا مثل اخلاليا، من خمتلفة اأنواع يف القناة هذه توجد ذلك اإىل بالإ�صافة الإح�صا�س. اإىل اجللد ا�صِتْتباب من ترتاوح التي الوظيفية العمال من العديد يف تنخرط حيث واللتهابية، املناعية هناك قدر كبري من الأدلة التي ت�صري اإىل وجود اختاللت وظيفية بهذه القناة، اما على هيثة نق�س اأو فرط يف ن�صاط القناة، يف حالت مر�صية جلدية مثل اختالل حاجز اجللد واحلكة والأمل واللتهاب اجللدي والت�رسطن. هذه الوظائف املتنوعة، اإىل جانب حقيقة امتالك هذه القناة ملوا�صع ميكن الو�صول اإليها دوائيا، جتعلها هدًفا جذاًبا لعالج ا�صطرابات اجللد. يف هذا ال�صتعرا�س نلخ�س الآثار الوظيفية والفيزيولوجيا املر�صية املختلفة لهذه القناة يف اجللد. الكلمات املفتاحية: قناة ُم�ْصَتقبلة فانلويد 4 ذات اجلهد املوؤقت؛ جلد؛ َب�رَسة؛ خاليا كرياتينية؛ اأمل؛ حكة؛ ورم ميالنيني. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.02.003 https://creativecommons.org/licenses/by-nd/4.0/ ammar boudaka, mallak al-yazeedi and intisar al-lawati review | e139 of these channels can result in abnormal keratinocyte differentiation, skin pigmentary and inflammatory diseases and possibly carcinogenesis. overall, trp channels are non-selective cation channels that mediate the influx of calcium ions (ca2+), magnesium and monovalent cations into different cells.2 a functional trp channel is formed of a central hydrophilic channel pore surrounded by four subunits consisting of six transmembrane protein segments with cand n-terminals protruding into the cytoplasm.3,4 to date, the trp superfamily is composed of a total of 29 members divided into seven subfamilies based on amino acid arrangement, including the ankyrin, canonical, melastin, mucolipin, polycystin, no-mecha noreceptor potential and vanilloid (trpv) subfamilies.2,5,6 these channels are found in various tissues and organs, with almost every cell expressing at least one subtype, and engage in several physiological cellular processes, including proliferation, apoptosis, cell death, mechanosensation, cell volume regulation, secretion, control of vascular permeability and blood vessel tone, as well as angiogenesis.7–11 moreover, trp channels can be gated by a wide range of physical and chemical stimuli such as mechanical forces, temperature and various ions and small molecules.12,13 seemingly, trp channels are crucial players in multiple facets of health and ailment.14 like other tissues and organs in the body, the skin expresses many different trp subtypes that signif icantly influence its proliferation, growth and integrity via different mechanisms, as well as its functioning in both healthy and diseased states.15,16 the skin has an extracellular calcium gradient, consisting of low levels near the basal keratinocytes and relatively higher concen trations around the superficial epidermal keratinocytes. several types of trp channels mediate calcium influx into sensory neurons, immune cells, keratinocytes and melanocytes in the skin; this potentially explains how these channels affect cellular proliferation, differ entiation, cell migration, cytotoxicity and the secretion of paracrine and autocrine chemicals.17 calcium is of particular importance to epidermal keratinocytes as it promotes their progressive differentiation while being pushed apically by actively dividing basal cells.18 abnormal homeostasis of calcium, as in conditions such as darier’s disease or hailey-hailey disease, leads to poor adhesion between keratinocytes, disrupted epidermal differentiation, keratosis and other skin malfunctions.19,20 another important function of trp channels is their ability to cause membrane depolarisation as a result of thermal, mechanical and chemical stimuli.2 subsequently, trp channel-mediated depolarisation triggers action potential firing in cutaneous sensory neurons, leading to sensations of temperature, itching and pain.21 furthermore, trp channel stimulation can also depolarise non-excitable cells and alter other cellular processes, such as the release of adenosine triphosphate (atp) from keratinocytes.22 the fourth member of the trpv subfamily (trpv4) was initially reported as an osmoor mechano sensor that can be stimulated by moderate warmth (>27°c) and ultraviolet (uv) light, as well as stimulated or inhibited by various chemical stimuli, including gsk1016790a, the synthetic phorbol ester 4α-phorbol 12,13-didecanoate and hc-067047.23–30 like other subtypes, trpv4 is expressed throughout the body including the hippocampal neurons, endothelial cells, oesophageal, gastric and urinary bladder epithelia as well as skin keratinocytes, where it contributes to numerous physiological processes.9,10,26,30–33 figure 1 illustrates the various functions of trpv4 channels in different skin cells. although several trpv4 agonists and antagonists have been studied in animal models, none have yet been tested in human clinical trials [table 1].29,34–49 figure 1: diagram illustrating the functional expression of transient receptor potential vanilloid 4 channel in different skin cells. atp = adenosine triphosphate. role of transient receptor potential vanilloid 4 channel in skin physiology and pathology e140 | squ medical journal, may 2020, volume 20, issue 2 this review will discuss the functional expression of trpv4 channel in various types of cells in the skin, as well as its contribution to different cutaneous physiological and pathological processes. epidermal barrier function in the skin, the epidermal barrier restricts extensive epidermal water loss and prevents dehydration and noxious substances and pathogens from entering the body. this barrier function is upheld by a hydrophobic cornified layer formed of an uninterrupted sheet of keratin-rich cells enclosed in an extracellular unionised lipid layer.50,51 other equally indispensable structures include the intercellular junctions underneath this cornified layer, such as the adherens junctions (ajs) and tight junctions (tjs).52,53 in mice, trpv4 is expressed in epidermal kera tinocytes and its stimulation—either by temperature or selective agonists—accelerates barrier regeneration.54,55 moreover, trpv4 is specifically colocalised with aj components, mainly β-catenin and e-cadherin, at the plasma membrane of these keratinocytes, thus supp orting its role in epidermal barrier homeostasis.33 warm temperatures provoke trpv4-mediated ca2+ influx into keratinocytes, resulting in their subsequent differentiation and cell-cell contact formation.33 this promotes the development of an intact cell-cell junction dependent barrier, including both tjs and ajs, and is disrupted in trpv4-deficient mice.33 thermal and chemical stimulation of trpv4 channel also elevates intracellular calcium in human keratinocytes and contributes to the formation of intercellular junctions, thus reinforcing intercellular barrier integrity in both ex vivo and in vitro experiments, with the knockdown of this channel compromising the formation of augmented transepithelial resistance in cultures of human keratinocytes.56 indeed, trpv4 activation due to warm temperatures and chemical agonists reinforces the tj-associated barrier of human keratinocytes via the upregulation of tj structural proteins occludin and claudin-4, and accelerates barrier function recovery in ex vivo human skin after cornified layer removal.57 however, while there is evidence supporting the function of trpv4 in skin barrier formation, its role in wound healing has not yet been elucidated. sensory functions there is substantial evidence supporting the involve ment of trpv4 channel in the transduction of different sensory modalities. in some cases, these functions are mediated by the neurally-expressed trpv4 channel, while in other cases these are mediated via expression in keratinocytes and other skin-residing cells. t h e r m o c e p t i o n the conscious or unconscious perception of atmospheric temperature is a physiological process that is pivotal for body temperature homeostasis and the avoidance of dangerous or life-threatening thermal extremes. cutaneously, heat is perceived by free nerve endings that connect to small diameter fibres or by epidermal keratinocytes with abundant trpv4 expression.25,58 in table 1: animal studies involving transient receptor potential vanilloid 4 channel agonists and antagonists29,34–49 selectivity in vivo (route/ species) agonist 4αpdd29,34 non-selective + (intraplantar/ mice) pma29 non-selective 5,6-eet38–40 non-selective dmapp41 non-selective + (intraplantar/ mice) baa42 non-selective n-arachidonoyl taurine43 non-selective apigenin44 unknown cbdv and thcv29 non-selective rn-174745 non-selective gsk1016790a29,36 non-selective + (iv, sc/mice) antagonist gd3+46 non-selective trpv la3+46 non-selective trpv rr29,46,47 non-selective capsazepine48 non-selective trpv rn-173448 selective butamben48 non-selective citral48 selective gsk20537,48 selective + (topical/mice) hc-06704735,48 selective + (sc/mice) gsk219387448,49 non-selective + (iv, ip/mice & rats) pdd = phorbol-12,13-didecanoate; pma = phorbol 12-myristate 13-acetate; eet = epoxyeicosatrienoic acids; dmapp = dimethylallyl pyrophosphate; baa = bisandrographolide a; cbdv = cannabidivarin; thcv = tetrahy drocannabidivarin; sc = subcutaneous; iv = intravenous; trpv = tran sient receptor potential vanilloid; gd3+ = gadolinium; la3+ = lanthanum; rr = ruthenium red; ip = intraperitoneal. ammar boudaka, mallak al-yazeedi and intisar al-lawati review | e141 mice, warm temperatures elicit currents in primary keratinocytes, with most heat-elicited responses seemingly mediated by trpv4.54 it is possible that trpv4 participates in the ca2+ homeostasis of keratinocytes in response to slight variations in skin temperature, which might in turn affect ca2+-dependent processes, such as keratinocyte proliferation and differentiation or intercellular junction formation.59,60 on the other hand, another explanation is that trpv4 expression in keratinocytes results in the secretion of mediators such as atp, which in turn stimulates adjacent afferent nerve fibres and, hence, the transduction of warmth.61–63 additionally, trpv4 is involved in sensations of innocuous warmth, although the effect in trpv4-deficient mice was modest and condition-dependent, with the mice exhibiting pref erences for slightly warmer temperatures during a thermal gradient assay.64 m e c h a n o s e n s at i o n mechanosensation involves the transduction of mech anical stimuli into neural signals, with mechanoreceptors in the skin responsible for the sensation of touch. both lowand high-threshold dorsal root ganglion (drg) neurons express trpv4 channel.58 in addition to its expression by free nerve endings, trpv4 is also present in cutaneous mechanosensory terminals, including merkel nerve endings, meissner corpuscles and intra epidermal and penicillate terminals. this distribution indicates that the sensation of pressure by trpv4 channel is transmitted through aand c-fibres, where it plays a role in cutaneous mechanosensation.58 another possibility is that trpv4 channel in keratinocytes respond to mechanical stimuli by releasing atp, which is subsequently recognised by the neighbouring sensory fibres that mediate mechanotransduction.61–63 n o c i c e p t i o n nociception refers to the detection of stimuli causing pain. significantly elevated levels of trpv4 expression in keratinocytes have been observed among patients with breast pain, correlating with the higher expression of nerve growth factor in these keratinocytes and, hence, sensitisation of the nociceptive nerve fibres.65 furthermore, trpv4 has been implicated in osmotically evoked pain behaviours and acute mechanical noci ception, as well as mechanical hyperalgesia in inflamm atory and neuropathic pain.66–76 while trpv4 does not contribute to the normal somatosensory detection of mechanical stimuli, it plays an important role in mechanical hyperalgesia, as it interacts with α2β1 integrin and the src proteintyrosine kinase to form a molecular complex that functions only in the setting of nerve injury or inflamm ation.77 additionally, kinins can sensitise trpv4 to induce mechanical hyperalgesia, a mechanism thought to contribute to the maintenance of mechanical hyper algesia and paclitaxel-induced chronic pain in mice; accordingly, these receptors may present potential targets for the treatment of chemotherapy-induced neuropathy.34 some proalgesic factors, such as protease-activate receptor 2 agonists, also provoke mechanical hyper algesia mediated by trpv4 channel.78 in diabetic mice, trpv4 blockade by the selective antagonist hc067047 prevented the development of mechanical allodynia, an effect seemingly independent of changes in the expression level of trpv4 in the sensory neurons.35,79 moreover, inflammation-induced thermal hyperalgesia is reportedly impaired in trpv4-deficient mice.80 sunburn-associated hyperalgesia additionally, trpv4 is involved in hyperalgesia assoc iated with sunburn. exposure to uvb rays induced a trpv4-mediated calcium influx into cultured mouse keratinocytes, with the subsequent release of endothelin (et)-1, a pruriceptive/nociceptive peptide.81 furthermore, uvb-induced inflammation, as well as thermal and mechanical hyperalgesia, are reduced in trpv4-def icient mice or those treated with trpv4 channel blockers.81 following sunburn, knocking out kera tinocyte-specific trpv4 in mice curtailed the secretion of proinflammatory factor interleukin (il)-6, conseq uently decreasing the numbers of recruited neutrophils and macrophages.81 similarly, trpv4 immunoreactivity is increased in human skin after exposure to uvb rays.81 a recent study found that γ-irradiation of keratinocytes prompted trpv4-mediated atp release, thereby stimulating the p2y11 receptor and resulting in the release of il-6 and il-8 via the p38 mitogen-activated protein kinase (mapk)-nuclear factor-κb signalling pathway.82 there fore, as both trpv4 and et-1 apparently play a role in acute photodermatitis in humans, trpv4 channel may be a potential curative target for uvband γ irradiation-induced dermatitides.82 p r u r i t u s chronic itching is a major clinical symptom in many skin disorders. itch-sensitive neurons are stimulated by a wide range of exogenous itch-causing compounds (i.e. pruritogens). additionally, keratinocytes and skin resident immune cells have the ability to release endogenous pruritogens—including atp, ets, prosta glandins, histamine, nitric oxide and serotonin—which can directly activate or sensitize the primary sensory neurons and cause itching, thus implying that the skin plays a role in the inception of itching sensations.83,84 in both humans and mice, several trp channels are role of transient receptor potential vanilloid 4 channel in skin physiology and pathology e142 | squ medical journal, may 2020, volume 20, issue 2 key mediators of itching sensations as they directly activate the peripheral pruriceptors or mediate the release of pruritogens from keratinocytes and other skin-resident cells.84–86 the involvement of trpv4 in the sensation of itching is supported by a growing amount of data; for instance, in mice, the subcutaneous injection of gsk1016790a, a trpv4 agonist, induced itch-related behaviours.36 moreover, trpv4 contributes to histamine and serotonin-induced acute itching, although its exact role is uncertain.87 an intradermal injection of serotonin in trpv4-deficient mice induced significantly less scratching compared to wild-type controls.88 serotonin induced itching is also suppressed by the pharmacol ogical inhibition of trpv4 or 5-hydroxytryptamine (ht)-2 receptor, suggesting that 5-ht2-mediated itching is interceded by a downstream trpv4dependent pathway.88 on the other hand, scratching behaviours evoked by histamine injection reportedly differ little between trpv4-deficient and wild-type mice.88 in a murine model of chronic itching, trpv4 activation promoted downstream 5-ht signalling, with trpv4-expressing keratinocytes and dermal macro phages involved in non-allergyand allergy-related chronic itching, respectively.89 moreover, scratching behaviours evoked by all histaminergic pruritogens (including histamine, et-1 and compound 48/80) were significantly diminished in keratinocyte-specific, tamoxifen-induced trpv4-deficient mice; moreover, the topical application of a trpv4 blocker, gsk205, on wild-type mice also reduced scratching reactions evoked by these pruritogens.37 these findings indicate that trpv4 channel plays a role in histaminergic itching. histamine induces a trpv4-dependent ca2+ influx into the keratinocyte through the histamine h1, h3 or h4 receptors, resulting in the phosphorylation of mapk and extracellular signal-regulated kinase (erk), and triggering signalling of the itching sensation.37 however, it is not clear if topically-applied inhibitors of trpv4, histamine receptors or mapk/erk signalling pathways also act on cutaneous sensory nerve endings in addition to skin-resident cells. besides the phenotypic differences, whether trpv4 expression in the skin or the drg neurons is the main mediator of itch is still an open question; akiyama et al. proposed that serotoninevoked scratching was mediated by trpv4 functionally expressed in drg neurons, whereas chen et al. theorised that histaminergic itching was mediated by trpv4 expressed in epidermal keratinocytes.37,88 chloroquine (cq) is another well-established pruritogen which can be used to induce acute histamine independent itch model in mice. interestingly, two studies reported different outcomes with regards to cq-elicited itching in trpv4-null mice; in the first, cqelicited itching was significantly elevated in trpv4 deficient mice in comparison with wild-type mice, whereas the other study found that cq-induced scratching was not affected in trpv4-deficient mice.37,88 therefore, the exact role of trpv4 in mediating acute itching warrants further research. regulation of hair follicle cycle a recent study reported trpv4-positive immunore activity in intact human hair follicles during the anagen growth phase, with immunoreactivity detected in the cortex of the bulbar hair shaft as well as the inner and outer root sheath layers of the hair follicle epithelium.90 moreover, in vitro trpv4 activation increased the number of apoptotic cells in areas with matrix keratinocytes and inhibited hair elongation, suggesting a regulatory role in hair follicle cycling.90 role in skin diseases an overview of the contribution of trpv4 to different cutaneous diseases and its potential role in treatment is shown in table 2.33,55,57,81,91–100 n o n-m a l i g n a n t d i s e a s e s acne vulgaris is one of the most common skin diseases in humans and is characterised by the overproduction of sebum, unwanted sebocyte proliferation and inflamm ation.101 in human sebocytes, trpv4 is functionally expressed and its activation exerts both lipostatic and antiproliferative effects.91 as such, trpv4 could be potentially beneficial in acne treatment. additionally, several genetic trpv4 mutations reportedly cause charcot-marie-tooth disease type 2c, a hereditary neurodegenerative disease associated with sensori motor neuropathy.92–94 rosacea is a chronic dermatitis that is accompanied by neurogenic inflammation. compared with healthy skin, different types of rosacea display elevated expr essions of different trpv channels (including trpv4), at either the molecular or protein levels, suggesting that trpv dysregulation may be an important mechanism underlying the initiation and maintenance of this condition.95 additionally, trpv4 expression is elevated in both langerhans and dermal cells in rosacea and can be stimulated under inflammatory conditions and by rosacea-related factors; accordingly, trpv4 could be involved in the underlying inflammation in rosacea.95 a recent study revealed that trpv4 is a key driver for ammar boudaka, mallak al-yazeedi and intisar al-lawati review | e143 mast cell-mediated skin inflammation in rosacea.102 m a l i g n a n t a n d p r e m a l i g n a n t d i s e a s e s although trpv4-related immunoreactivity and mess enger ribonucleic acid transcripts are maintained at high levels in healthy or inflamed skin, they are abrogated in keratinocytic tumours. in both premalignant lesions and non-melanoma skin cancers, trpv4 is markedly downregulated or even absent, seemingly as a result of the release of keratinocyte-derived il-8, suggesting that the selective downregulation of trpv4 appears to be an early diagnostic marker of skin carcinogenesis.96 moreover, in human melanoma a375 cell lines, trpv4 stimulation suppresses cell proliferation and induces cell apoptosis.97 a recent study revealed that trpv4 stimulation, with calcium signalling involvement, mediates human melanoma a375 cell death by regulating the akt pathway-driven antitumour process.98 while the involvement of trpv4 in tumourigenesis has yet to be fully explored, these findings suggest that trpv4 expression might serve as a prognostic or early diagnostic biomarker in human melanomas, while trpv4 activation could even hold potentially curative properties.98 conclusion overall, trpv4-mediated processes are not only limited to sensory functions, such as itching and pain, but also play a crucial role in keratinocyte proliferation and differentiation as well as skin barrier formation, maintenance and regeneration. therefore, modifying trpv4 function could improve skin barrier function, especially in conditions where there is a breach in the cornified layer-dependent barrier. moreover, trpv4 channel may be involved in certain diseases, thus providing possibilities for therapeutic targeting. for example, trpv4 inhibition could help in the treatment of uvb-induced inflammation and acne vulgaris, whereas trpv4 activation or upregulation could be of therapeutic value in the treatment of both melanoma and non-melanoma skin cancers. a c k n o w l e d g e m e n t the authors would like to thank ms. malak boudaka for her contribution to the artwork for figure 1. references 1. mescher al. junqueira’s basic histology: text and atlas, 15th ed. new york, usa: mcgraw hill, 2018. 2. nilius b, owsianik g. the transient receptor potential family of ion channels. genome biol 2011; 12:218. https://doi.org/10.11 86/gb-2011-12-3-218. 3. kassmann m, harteneck c, zhu z, nürnberg b, tepel m, gollasch m. transient receptor potential vanilloid 1 (trpv1), trpv4, and the kidney. acta physiol (oxf ) 2013; 207:546–64. https://doi.org/10.1111/apha.12051. 4. caterina mj. transient receptor potential ion channels as part icipants in thermosensation and thermoregulation. am j physiol regul integr comp physiol 2007; 292:r64–76. https://doi.org/10.11 52/ajpregu.00446.2006. 5. venkatachalam k, montell c. trp channels. annu rev biochem 2007; 76:387–417. https://doi.org/10.1146/annurev.biochem.75.1 03004.142819. 6. wu lj, sweet tb, clapham de. international union of basic and clinical pharmacology: lxxvi current progress in the mammalian trp ion channel family. pharmocol rev 2010; 62:381–404. https://doi.org/10.1124/pr.110.002725. 7. persson pb. trps revisited. acta physiol (oxf ) 2015; 214:6–7. https://doi.org/10.1111/apha.12492. 8. yao x, garland cj. recent developments in vascular endothelial cell transient receptor potential channels. circ res 2005; 97:853–63. https://doi.org/10.1161/01.res.0000187473.85419.3e. table 2: potential role of transient receptor potential vanilloid 4 channel in various skin diseases33,55,57,81,91–100 disease involvement of trpv4 potential therapeutic benefit barrierrelated diseases • activation induces barrier recovery and promotes the tight-junction barrier between keratinocytes.55,57,99 • genetic deletion is associated with leaky cell-cell junctions.33,100 • potentially beneficial for treating skin barrier comprise and inducing barrier recovery. uv-induced skin diseases • involved in hyperalgesia associated with sunburn.81 • a potential curative target for uvbinduced and γ irradiationinduced dermatitides. acne vulgaris • activation inhibits sebocytes proliferation and suppresses lipid synthesis.91 • could have potentially curative properties. rosacea • mediates mast cell activation. • reduces expression dysregulation.95 • inhibition could have potentially curative properties. charcot marie tooth disease (type 2c) • several trpv4 mutations produce neurodegenerative condition including dry skin and hair loss.92–94 malignant melanoma • mediates cell apoptosis with decreased expression.96–98 • could be utilised as an early diagnostic or prognostic marker. • activation could have potentially curative properties. trpv4 = transient receptor potential vanilloid 4; uv = ultraviolet. https://doi.org/10.1186/gb-2011-12-3-218 https://doi.org/10.1186/gb-2011-12-3-218 https://doi.org/10.1111/apha.12051 https://doi.org/10.1152/ajpregu.00446.2006 https://doi.org/10.1152/ajpregu.00446.2006 https://doi.org/10.1146/annurev.biochem.75.103004.142819 https://doi.org/10.1146/annurev.biochem.75.103004.142819 https://doi.org/10.1124/pr.110.002725 https://doi.org/10.1111/apha.12492 https://doi.org/10.1161/01.res.0000187473.85419.3e role of transient receptor potential vanilloid 4 channel in skin physiology and pathology e144 | squ medical journal, may 2020, volume 20, issue 2 9. mihara h, suzuki n, boudaka aa, muhammad js, tominaga m, tabuchi y, et al. transient receptor potential vanilloid 4-dep endent calcium influx and atp release in mouse and rat gastric epithelia. world j gastroenterol 2016; 22:5512–19. https://doi. org/10.3748/wjg.v22.i24.5512. 10. mihara h, boudaka a, sugiyama t, moriyama y, tominaga m. transient receptor potential vanilloid 4 (trpv4)-dependent calcium influx and atp release in mouse oesophageal kerat inocytes. j physiol 2011; 589:3471–82. https://doi.org/10.1113/ jphysiol.2011.207829. 11. mochizuki t, sokabe t, araki i, fujishita k, shibasaki k, uchida k, et al. the trpv4 cation channel mediates stretch-evoked ca2+ influx and atp release in primary urothelial cell cultures. j biol chem 2009; 284:21257–64. https://doi.org/10.1074/jbc.m1 09.020206. 12. caterina mj, julius d. the vanilloid receptor: a molecular gate way to the pain pathway. annu rev neurosci 2001; 24:487–517. https://doi.org/10.1146/annurev.neuro.24.1.487. 13. flockerzi v. an introduction on trp channels. handb exp phar macol 2007; 179:1–19. https://doi.org/10.1007/978-3-540-34891-7_1. 14. nilius b, owsianik g, voets t, peters ja. transient receptor potential cation channels in disease. physiol rev 2007; 87:165–217. https://doi.org/10.1152/physrev.00021.2006. 15. lumpkin ea, caterina mj. mechanisms of sensory transduction in the skin. nature 2007; 445:858–65. https://doi.org/10.1038/ nature05662. 16. caterina mj. trp channel cannabinoid receptors in skin sensation, homeostasis, and inflammation. acs chem neurosci 2014; 5:1107–16. https://doi.org/10.1021/cn5000919. 17. tóth bi, oláh a, szöllősi ag, bíró t. trp channels in the skin. br j pharmacol 2014; 171:2568–81. https://doi.org/10.1111/ bph.12569. 18. yuspa sh, henninngs h, tucker rw, jaken s, kilkenny ae, roop dr. signal transduction for proliferation and differ entiation in keratinocytes. ann n y acad sci 1988; 548:191–96. https://doi.org/10.1111/j.1749-6632.1988.tb18806.x. 19. sakuntabhai a, dhitavat j, burge s, hovnanian a. mosaicism for atp2a2 mutations causes segmental darier’s disease. j invest dermatol 2000; 115:1144–7. https://doi.org/10.1046/j.15 23-1747.2000.00182.x. 20. hu z, bonifas jm, beech j, bench g, shigihara t, ogawa h, et al. mutations in atp2c1, encoding a calcium pump, cause hailey-hailey disease. nat genet 2000; 24:61–5. https://doi. org/10.1038/71701. 21. basbaum ai, bautista dm, scherrer g, julius d. cellular and molecular mechanisms of pain. cell 2009; 139:267–84. https://doi.org/10.1016/j.cell.2009.09.028. 22. zhao p, barr tp, hou q, dib-hajj sd, black ja, albrecht pj, et al. voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. pain 2008; 139:90–105. https://doi.org/10.1016/j.pain.2008.03.016. 23. liedtke w, choe y, martí-renom ma, bell am, denis cs, sali a, et al. vanilloid receptor-related osmotically activated channel (vr-oac), a candidate vertebrate osmoreceptor. cell 2000; 103:525–35. https://doi.org/10.1016/s0092-8674(00)00143-4. 24. strotmann r, harteneck c, nunnenmacher k, schultz g, plant td. otrpc4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. nat cell biol 2000; 2:695–702. https://doi.org/10.1038/35036318. 25. güler ad, lee h, iida t, shimizu i, tominaga m, caterina m. heat-evoked activation of the ion channel, trpv4. j neurosci 2002; 22:6408–14. https://doi.org/10.1523/jneurosci.22-15 06408.2002. 26. watanabe h, vriens j, suh sh, benham cd, droogmans g, nilius b. heat-evoked activation of trpv4 channels in a hek293 cell expression system and in native mouse aorta endothelial cells. j biol chem 2002; 277:47044–51. https://doi. org/10.1074/jbc.m208277200. 27. white jp, cibelli m, urban l, nilius b, mcgeown jg, nagy i. trpv4: molecular conductor of a diverse orchestra. physiol rev 2016; 96:911–73. https://doi.org/10.1152/physrev.00016.2015. 28. willette rn, bao w, nerurkar s, yue tl, doe cp, stankus g, et al. systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: part 2. j pharmacol exp ther 2008; 326:443–52. https://doi.org/10.1124/jpet.107.134551. 29. watanabe h, davis jb, smart d, jerman jc, smith gd, hayes p, et al. activation of trpv4 channels (hvrl-2/mtrp12) by phorbol derivatives. j biol chem 2002; 277:13569–77. https://doi.org/10.1074/jbc.m200062200. 30. everaerts w, zhen x, ghosh d, vriens j, gevaert t, gilbert jp, et al. inhibition of the cation channel trpv4 improves bladder function in mice and rats with cyclophosphamideinduced cystitis. proc natl acad sci u s a 2010; 107:19084–9. https://doi.org/10.1073/pnas.1005333107. 31. shibasaki k, suzuki m, mizuno a, tominaga m. effects of body temperature on neural activity in the hippocampus: regulation of resting membrane potentials by transient rec eptor potential vanilloid 4. j neurosci 2007; 27:1566–75. https://doi.org/10.1523/jneurosci.4284-06.2007. 32. boudaka a, al-suleimani m, al-lawati i, baomar h, al-siyabi s, zadjali f. downregulation of endothelial transient receptor potential vanilloid type 4 channel underlines impaired endo thelial nitric oxide-mediated relaxation in the mesenteric arteries of hypertensive rats. physiol res 2019; 8408:219–31. https://doi.org/10.33549/physiolres.933952. 33. sokabe t, fukumi-tominaga t, yonemura s, mizuno a, tominaga m. the trpv4 channel contributes to intercellular junction form ation in keratinocytes. j biol chem 2010; 285:18749–58. https:// doi.org/10.1074/jbc.m110.103606. 34. costa r, bicca ma, manjavachi mn, segat gc, dias fc, fernandes es, et al. kinin receptors sensitize trpv4 channel and induce mechanical hyperalgesia: relevance to paclitaxelinduced peripheral neuropathy in mice. mol neurobiol 2018; 55:2150–61. https://doi.org/10.1007/s12035-017-0475-9. 35. dias fc, alves vs, matias do, figueiredo cp, miranda alp, passos gf, et al. the selective trpv4 channel antagonist hc 067047 attenuates mechanical allodynia in diabetic mice. eur j pharmacol 2019; 856:172408. https://doi.org/10.1016/j.ejph ar.2019.172408. 36. kittaka h, yamanoi y, tominaga m. transient receptor potential vanilloid 4 (trpv4) channel as a target of crotamiton and its bimodal effects. pflugers arch 2017; 469:1313–23. https://doi.org/10.1007/s00424-017-1998-7. 37. chen y, fang q, wang z, zhang jy, macleod as, hall rp, et al. transient receptor potential vanilloid 4 ion channel functions as a pruriceptor in epidermal keratinocytes to evoke histaminergic itch. j biol chem 2016; 291:10252–62. https://doi.org/10.1074/jbc.m116.716464. 38. vriens j, owsianik g, fisslthaler b, suzuki m, janssens a, voets t, et al. modulation of the ca2 permeable cation channel trpv4 by cytochrome p450 epoxygenases in vascular endothelium. circ res 2005; 97:908–15. https://doi.org/10.1161/01.res.000 0187474.47805.30. 39. vriens j, owsianik g, janssens a, voets t, nilius b. determinants of 4 alpha-phorbol sensitivity in transmembrane domains 3 and 4 of the cation channel trpv4. j biol chem 2007; 282:12796–803. https://doi.org/10.1074/jbc.m610485200. 40. watanabe h, vriens j, prenen j, droogmans g, voets t, nillus b. anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate trpv4 channels. nature 2003; 424:434–8. https://doi.org/10.1038/nature01807. 41. bang s, yoo s, yang tj, cho h, hwang sw. nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via trpv4 activation. br j pharmacol 2012; 166:1433–43. https://doi.org/10.1111/j.1476-5381.2012.01884.x. https://doi.org/10.3748/wjg.v22.i24.5512 https://doi.org/10.3748/wjg.v22.i24.5512 https://doi.org/10.1113/jphysiol.2011.207829 https://doi.org/10.1113/jphysiol.2011.207829 https://doi.org/10.1074/jbc.m109.020206 https://doi.org/10.1074/jbc.m109.020206 https://doi.org/10.1146/annurev.neuro.24.1.487 https://doi.org/10.1007/978-3-540-34891-7_1 https://doi.org/10.1152/physrev.00021.2006 https://doi.org/10.1038/nature05662 https://doi.org/10.1038/nature05662 https://doi.org/10.1021/cn5000919 https://doi.org/10.1111/bph.12569 https://doi.org/10.1111/bph.12569 https://doi.org/10.1111/j.1749-6632.1988.tb18806.x https://doi.org/10.1046/j.1523-1747.2000.00182.x https://doi.org/10.1046/j.1523-1747.2000.00182.x https://doi.org/10.1038/71701 https://doi.org/10.1038/71701 https://doi.org/10.1016/j.cell.2009.09.028 https://doi.org/10.1016/j.pain.2008.03.016 https://doi.org/10.1016/s0092-8674%2800%2900143-4 https://doi.org/10.1038/35036318 https://doi.org/10.1523/jneurosci.22-15-06408.2002 https://doi.org/10.1523/jneurosci.22-15-06408.2002 https://doi.org/10.1074/jbc.m208277200 https://doi.org/10.1074/jbc.m208277200 https://doi.org/10.1152/physrev.00016.2015 https://doi.org/10.1124/jpet.107.134551 https://doi.org/10.1074/jbc.m200062200 https://doi.org/10.1073/pnas.1005333107 https://doi.org/10.1523/jneurosci.4284-06.2007 https://doi.org/10.33549/physiolres.933952 https://doi.org/10.1074/jbc.m110.103606 https://doi.org/10.1074/jbc.m110.103606 https://doi.org/10.1007/s12035-017-0475-9 https://doi.org/10.1016/j.ejphar.2019.172408 https://doi.org/10.1016/j.ejphar.2019.172408 https://doi.org/10.1007/s00424-017-1998-7 https://doi.org/10.1074/jbc.m116.716464 https://doi.org/10.1161/01.res.0000187474.47805.30 https://doi.org/10.1161/01.res.0000187474.47805.30 https://doi.org/10.1074/jbc.m610485200 https://doi.org/10.1038/nature01807 https://doi.org/10.1111/j.1476-5381.2012.01884.x ammar boudaka, mallak al-yazeedi and intisar al-lawati review | e145 42. smith pl, maloney kn, pothen rg, clardy j, clapham de. bisandrographolide from andrographis paniculata activates trpv4 channels. j biol chem 2006; 281:29897–904. https://doi.org/10.1074/jbc.m605394200. 43. saghatelian a, mckinney mk, bandell m, patapoutian a, cravatt bf. a faah-regulated class of n-acyl taurines that activates trp ion channels. biochemistry 2006; 45:9007–15. https://doi.org/10.1021/bi0608008. 44. ma x, he d, ru x, chen y, cai y, bruce ic, et al. apigenin, a plant-derived flavone, activates transient receptor potential vanilloid 4 cation channel. br j pharmacol 2012; 166:349–58. https://doi.org/10.1111/j.1476-5381.2011.01767.x. 45. klausen tk, pagani a, minassi a, ech-chahad a, prenen j, owsianik g, et al. modulation of the transient receptor pot ential vanilloid channel trpv4 by 4alpha-phorbol esters: a structure-activity study. j med chem 2009; 52:2933–9. https://doi.org/10.1021/jm9001007. 46. nilius b, vriens j, prenen j, droogmans g, voets t. trpv4 calcium entry channel: a paradigm for gating diversity. am j physiol cell physiol 2004; 286:c195–205. https://doi.org/10.1152/ajpcell.00 365.2003. 47. lee jh, park c, kim sj, kim hj, oh gs, shen a, et al. different uptake of gentamicin through trpv1 and trpv4 channels determines cochlear hair cell vulnerability. exp mol med 2013; 45:e12. https://doi.org/10.1038/emm.2013.25. 48. vincent f, acevedo a, nguyen mt, dourado m, defalco j, gustafson a, et al. identification and characterization of novel trpv4 modulators. biochem biophys res commun 2009; 389:490–4. https://doi.org/10.1016/j.bbrc.2009.09.007. 49. gradilone sa, masyuk tv, huang bq, banales jm, lehmann gl, radtke bn, et al. activation of trpv4 reduces the hyper proliferative phenotype of cystic cholangiocytes from an ani mal model of arpkd. gastroenterology 2010; 139:304–14.e2. https://doi.org/10.1053/j.gastro.2010.04.010. 50. kalinin ae, kajava av, steinert pm. epithelial barrier function: assembly and structural features of the cornified cell envelope. bioessays 2002; 24:789–800. https://doi.org/10.1002/bies.10144. 51. proksch e, brandner jm, jensen jm. the skin: an indispensable barrier. exp dermatol 2008; 17:1063–72. https://doi.org/10.11 11/j.1600-0625.2008.00786.x. 52. tsukita s, furuse m. claudin-based barrier in simple and stratified cellular sheets. curr opin cell biol 2002; 14:531–6. https://doi.org/10.1016/s0955-0674(02)00362-9. 53. niessen cm. tight junctions/adherens junctions: basic str ucture and function. j invest dermatol 2007; 127:2525–32. https://doi.org/10.1038/sj.jid.5700865. 54. chung mk, lee h, mizuno a, suzuki m, caterina mj. trpv3 and trpv4 mediate warmth-evoked currents in primary mouse keratinocytes. j biol chem 2004; 279:21569–75. https://doi.org/10.1074/jbc.m401872200. 55. denda m, sokabe t, fukumi-tominaga t, tominaga m. effects of skin surface temperature on epidermal permeability barrier homeostasis. j invest dermatol 2007; 127:654–9. https://doi. org/10.1038/sj.jid.5700590. 56. kida n, sokabe t, kashio m, haruna k, mizuno y, suga y, et al. importance of transient receptor potential vanilloid 4 (trpv4) in epidermal barrier function in human skin keratinocytes. pflugers arch 2012; 463:715–25. https://doi.org/10.1007/s004 24-012-1081-3. 57. akazawa y, yuki t, yoshida h, sugiyama y, inoue s. activation of trpv4 strengthens the tight-junction barrier in human epidermal keratinocytes. skin pharmacol physiol 2013; 26:15–21. https://doi.org/10.1159/000343173. 58. suzuki m, watanabe y, oyama y, mizuno a, kusano e, hirao a, et al. localization of mechanosensitive channel trpv4 in mouse skin. neurosci lett 2003; 353:189–92. https://doi.org/10.1016/j. neulet.2003.09.041. 59. hennings h, michael d, cheng c, steinert p, holbrook k, yuspa sh. calcium regulation of growth and differentiation of mouse epidermal cells in culture. cell 1980; 19:245–54. https://doi.org/10.1016/0092-8674(80)90406-7. 60. watt fm, mattey dl, garrod dr. calcium-induced reorg anization of desmosomal components in cultured human kera tinocytes. j cell biol 1984; 99:2211–15. https://doi.org/10.1083/ jcb.99.6.2211. 61. peier am, reeve aj, andersson da, moqrich a, earley tj, hergarden ac, et al. a heat-sensitive trp channel expressed in keratinocytes. science 2002; 296:2046–9. https://doi.org/10.1 126/science.1073140. 62. chung mk, lee h, caterina mj. warm temperatures activate trpv4 in mouse 308 keratinocytes. j biol chem 2003; 278:32037–46. https://doi.org/10.1074/jbc.m303251200. 63. souslova v, cesare p, ding y, akopian an, stanfa l, suzuki r, et al. warm-coding deficits and aberrant inflammatory pain in mice lacking p2x3 receptors. nature 2000; 407:1015–17. https://doi.org/10.1038/35039526. 64. lee h, iida t, mizuno a, suzuki m, caterina mj. altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. j neurosci 2005; 25:1304–10. https://doi. org/10.1523/jneurosci.4745.04.2005. 65. gopinath p, wan e, holdcroft a, facer p, davis jb, smith gd, et al. increased capsaicin receptor trpv1 in skin nerve fibres and related vanilloid receptors trpv3 and trpv4 in kera tinocytes in human breast pain. bmc womens health 2005; 5:2. https://doi.org/10.1186/1472-6874-5-2. 66. alessandri-haber n, joseph e, dina oa, liedtke w, levine jd. trpv4 mediates pain-related behavior induced by mild hyper tonic stimuli in the presence of inflammatory mediator. pain 2005; 118:70–9. https://doi.org/10.1016/j.pain.2005.07.016. 67. alessandri-haber n, yeh jj, boyd ae, parada ca, chen x, reichling db, et al. hypotonicity induces trpv4-mediated no ciception in rat. neuron 2003; 39:497–511. https://doi.org/10.1 016/s0896-6273(03)00462-8. 68. liedtke w, friedman jm. abnormal osmotic regulation in trpv4-/mice. proc natl acad sci u s a 2003; 100:13698–703. https://doi.org/10.1073/pnas.1735416100. 69. suzuki m, mizuno a, kodaira k, imai m. impaired pressure sensation in mice lacking trpv4. j biol chem 2003; 278:22664–8. https://doi.org/10.1074/jbc.m302561200. 70. segond von banchet g, boettger mk, könig c, iwakura y, bräuer r, schaible hg. neuronal il-17 receptor upregulates trpv4 but not trpv1 receptors in drg neurons and mediates mechanical but not thermal hyperalgesia. mol cell neurosci 2013; 52:152–60. https://doi.org/10.1016/j.mcn.2012.11.006. 71. sierra h, cordova m, chen cj, rajadhyaksha m. confocal imaging-guided laser ablation of basal cell carcinomas: an ex vivo study. j invest dermatol 2015; 135:612–15. https://doi.org/10.1 038/jid.2014.371. 72. chen y, williams sh, mcnulty al, hong jh, lee sh, rothfusz ne, et al. temporomandibular joint pain: a critical role for trpv4 in the trigeminal ganglion. pain 2013; 154:1295–304. https://doi.org/10.1016/j.pain.2013.04.004. 73. alessandri-haber n, dina oa, joseph ek, reichling d, levine jd. a transient receptor potential vanilloid 4-dependent mechan ism of hyperalgesia is engaged by concerted action of inflamm atory mediators. j neurosci 2006; 26:3864–74. https://doi.org/10.1 523/jneurosci.5385-05.2006. https://doi.org/10.1074/jbc.m605394200 https://doi.org/10.1021/bi0608008 https://doi.org/10.1111/j.1476-5381.2011.01767.x https://doi.org/10.1021/jm9001007 https://doi.org/10.1152/ajpcell.00365.2003 https://doi.org/10.1152/ajpcell.00365.2003 https://doi.org/10.1038/emm.2013.25 https://doi.org/10.1016/j.bbrc.2009.09.007 https://doi.org/10.1053/j.gastro.2010.04.010 https://doi.org/10.1002/bies.10144 https://doi.org/10.1111/j.1600-0625.2008.00786.x https://doi.org/10.1111/j.1600-0625.2008.00786.x https://doi.org/10.1016/s0955-0674%2802%2900362-9 https://doi.org/10.1038/sj.jid.5700865 https://doi.org/10.1074/jbc.m401872200 https://doi.org/10.1038/sj.jid.5700590 https://doi.org/10.1038/sj.jid.5700590 https://doi.org/10.1007/s00424-012-1081-3 https://doi.org/10.1007/s00424-012-1081-3 https://doi.org/10.1159/000343173 https://doi.org/10.1016/j.neulet.2003.09.041 https://doi.org/10.1016/j.neulet.2003.09.041 https://doi.org/10.1016/0092-8674%2880%2990406-7 https://doi.org/10.1083/jcb.99.6.2211 https://doi.org/10.1083/jcb.99.6.2211 https://doi.org/10.1126/science.1073140 https://doi.org/10.1126/science.1073140 https://doi.org/10.1074/jbc.m303251200 https://doi.org/10.1038/35039526 https://doi.org/10.1523/jneurosci.4745.04.2005 https://doi.org/10.1523/jneurosci.4745.04.2005 https://doi.org/10.1186/1472-6874-5-2 https://doi.org/10.1016/j.pain.2005.07.016 https://doi.org/10.1016/s0896-6273%2803%2900462-8 https://doi.org/10.1016/s0896-6273%2803%2900462-8 https://doi.org/10.1073/pnas.1735416100 https://doi.org/10.1074/jbc.m302561200 https://doi.org/10.1016/j.mcn.2012.11.006 https://doi.org/10.1038/jid.2014.371 https://doi.org/10.1038/jid.2014.371 https://doi.org/10.1016/j.pain.2013.04.004 https://doi.org/10.1523/jneurosci.5385-05.2006 https://doi.org/10.1523/jneurosci.5385-05.2006 role of transient receptor potential vanilloid 4 channel in skin physiology and pathology e146 | squ medical journal, may 2020, volume 20, issue 2 74. alessandri-haber n, dina oa, yeh jj, parada ca, reichling db, levine jd. transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. j neuro sci 2004; 24:4444–52. https://doi.org/10.1523/jneurosci.024 2-04.2004. 75. chen y, yang c, wang zj. proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor pot ential ankyrin 1 in paclitaxel-induced neuropathic pain. neuro science 2011; 193:440–51. https://doi.org/10.1016/j.neuroscien ce.2011.06.085. 76. ding xl, wang yh, ning lp, zhang y, ge hy, jiang h, et al. involvement of trpv4-no-cgmp-pkg pathways in the devel opment of thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats. behav brain res 2010; 208:194–201. https://doi.org/10.1016/j.bbr.2009.11.034. 77. alessandri-haber n, dina oa, joseph ek, reichling db, levine jd. interaction of transient receptor potential vanilloid 4, integrin, and src tyrosine kinase in mechanical hyperalgesia. j neurosci 2008; 28:1046–57. https://doi.org/10.1523/jneuro sci.4497-07.2008. 78. grant ad, cottrell gs, amadesi s, trevisani m, nicoletti p, materazzi s, et al. protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. j physiol 2007; 578:715–33. https://doi.org/10.1113/jphysiol.2006.121111. 79. facer p, casula ma, smith gd, benham cd, chessell ip, bountra c, et al. differential expression of the capsaicin rec eptor trpv1 and related novel receptors trpv3, trpv4 and trpm8 in normal human tissues and changes in traumatic and diabetic neuropathy. bmc neurol 2007; 7:11. https://doi. org/10.1186/1471-2377-7-11. 80. todaka h, taniguchi j, satoh ji, mizuno a, suzuki m. warm temperature-sensitive transient receptor potential vanilloid 4 (trpv4) plays an essential role in thermal hyperalgesia. j biol chem 2004; 279:35133–8. https://doi.org/10.1074/jbc.m4 06260200. 81. moore c, cevikbas f, pasolli ha, chen y, kong w, kempkes c, et al. uvb radiation generates sunburn pain and affects skin by activating epidermal trpv4 ion channels and triggering endothelin-1 signaling. proc natl acad sci u s a 2013; 110:e3225–34. https://doi.org/10.1073/pnas.1312933110. 82. ohsaki a, tanuma si, tsukimoto m. trpv4 channel-regulated atp release contributes to γ-irradiation-induced production of il-6 and il-8 in epidermal keratinocytes. biol pharm bull 2018; 41:1620–6. https://doi.org/10.1248/bpb.b18-00361. 83. bautista dm, wilson sr, hoon ma. why we scratch an itch: the molecules, cells and circuits of itch. nat neurosci 2014; 17:175–82. https://doi.org/10.1038/nn.3619. 84. xie z, hu h. trp channels as drug targets to relieve itch. pharmaceuticals 2018; 11:e100. https://doi.org/10.3390/ph110 40100. 85. akiyama t, carstens e. neural processing of itch. neuro science 2013; 250:697–714. https://doi.org/10.1016/j.neurosci ence.2013.07.035. 86. luo j, feng j, liu s, walters et, hu h. molecular and cellular mechanisms that initiate pain and itch. cell mol life sci 2015; 72:3201–23. https://doi.org/10.1007/s00018-015-1904-4. 87. caterina mj, pang z. trp channels in skin biology and pathophysiology. pharmaceuticals (basel) 2016; 9:e77. https://doi.org/10.3390/ph9040077. 88. akiyama t, ivanov m, nagamine m, davoodi a, carstens mi, ikoma a, et al. involvement of trpv4 in serotonin-evoked scrat ching. j invest dermatol 2016; 136:154–60. https://doi.org/10.10 38/jid.2015.388. 89. luo j, feng j, yu g, yang p, mack mr, du j, et al. transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonaller gic chronic itch. j allergy clin immunol 2018; 141:608–19.e7. https://doi.org/10.1016/j.jaci.2017.05.051. 90. szabó il, herczeg-lisztes e, szegedi a, nemes b, paus r, bíró t, et al. trpv4 is expressed in human hair follicles and inhibits hair growth in vitro. j invest dermatol 2019; 139:1385–8. https://doi.org/10.1016/j.jid.2018.11.020. 91. oláh a, tóth bi, borbíró i, sugawara k, szöllõsi ag, czifra g, et al. cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. j clin invest 2014; 124:3713–24. https://doi.org/10.1172/jci64628. 92. auer-grumbach m, olschewski a, papić l, kremer h, mcentagart me, uhrig s, et al. alterations in the ankyrin domain of trpv4 cause congenital distal sma, scapuloperoneal sma and hmsn2c. nat genet 2010; 42:160–4. https://doi.org/10.1038/ ng.508. 93. deng hx, klein cj, yan j, shi y, wu y, fecto f, et al. scapuloperoneal spinal muscular atrophy and cmt2c are allelic disorders caused by alterations in trpv4. nat genet 2010; 42:165–9. https://doi.org/10.1038/ng.509. 94. landouré g, zdebik aa, martinez tl, burnett bg, stanescu hc, inada h, et al. mutations in trpv4 cause charcot-marietooth disease type 2c. nat genet 2010; 42:170–4. https://doi. org/10.1038/ng.512. 95. sulk m, seeliger s, aubert j, schwab vd, cevikbas f, rivier m, et al. distribution and expression of non-neuronal transient receptor potential (trpv) ion channels in rosacea. j invest dermatol 2012; 132:1253–62. https://doi.org/10.1038/jid.2011.424. 96. fusi c, materazzi s, minocci d, maio v, oranges t, massi d, et al. transient receptor potential vanilloid 4 (trpv4) is down regulated in keratinocytes in human non-melanoma skin cancer. j invest dermatol 2014; 134:2408–17. https://doi.org/10.1038/ jid.2014.145. 97. olivan-viguera a, garcia-otin al, lozano-gerona j, abarca-lachen e, garcia-malinis aj, hamilton kl, et al. pharmacological activation of trpv4 produces immediate cell damage and induction of apoptosis in human melanoma cells and hacat keratinocytes. plos one 2018; 13:e0190307. https://doi.org/10.1371/journal.pone.0190307. 98. zheng j, liu f, du s, li m, wu t, tan x, et al. mechanism for regulation of melanoma cell death via activation of thermo-trpv4 and trpv2. j oncol 2019; 2019:7362875. https://doi.org/10.11 55/2019/7362875. 99. kida n, sokabe t, kashio m, haruna k, mizuno y, suga y, et al. importance of transient receptor potential vanilloid 4 (trpv4) in epidermal barrier function in human skin keratinocytes. pflugers arch 2012; 463:715–25. https://doi.org/10.1007/s0042 4-012-1081-3. 100. sokabe t, tominaga m. the trpv4 cation channel: a molecule linking skin temperature and barrier function. commun integr biol 2010; 3:619–21. https://doi.org/10.4161/cib.3.6.13461. 101. oláh a, bíró t. targeting cutaneous cannabinoid signaling in inflammation a “high” -way to heal? ebiomedicine 2017; 16:3–5. https://doi.org/10.1016/j.ebiom.2017.01.003. 102. di_nardo a, mascarenhas n, wang z. trpv4 is a key driver for mast cell activation in ll37mediated skin inflammation. j dermatol sci 2017; 86:e69. https://doi.org/10.1016/j.jderm sci.2017.02.201. https://doi.org/10.1523/jneurosci.0242-04.2004 https://doi.org/10.1523/jneurosci.0242-04.2004 https://doi.org/10.1016/j.neuroscience.2011.06.085 https://doi.org/10.1016/j.neuroscience.2011.06.085 https://doi.org/10.1016/j.bbr.2009.11.034 https://doi.org/10.1523/jneurosci.4497-07.2008 https://doi.org/10.1523/jneurosci.4497-07.2008 https://doi.org/10.1113/jphysiol.2006.121111 https://doi.org/10.1186/1471-2377-7-11 https://doi.org/10.1186/1471-2377-7-11 https://doi.org/10.1074/jbc.m406260200 https://doi.org/10.1074/jbc.m406260200 https://doi.org/10.1073/pnas.1312933110 https://doi.org/10.1248/bpb.b18-00361 https://doi.org/10.1038/nn.3619 https://doi.org/10.3390/ph11040100 https://doi.org/10.3390/ph11040100 https://doi.org/10.1016/j.neuroscience.2013.07.035 https://doi.org/10.1016/j.neuroscience.2013.07.035 https://doi.org/10.1007/s00018-015-1904-4 https://doi.org/10.3390/ph9040077 https://doi.org/10.1038/jid.2015.388 https://doi.org/10.1038/jid.2015.388 https://doi.org/10.1016/j.jaci.2017.05.051 https://doi.org/10.1016/j.jid.2018.11.020 https://doi.org/10.1172/jci64628 https://doi.org/10.1038/ng.508 https://doi.org/10.1038/ng.508 https://doi.org/10.1038/ng.509 https://doi.org/10.1038/ng.512 https://doi.org/10.1038/ng.512 https://doi.org/10.1038/jid.2011.424 https://doi.org/10.1038/jid.2014.145 https://doi.org/10.1038/jid.2014.145 https://doi.org/10.1371/journal.pone.0190307 https://doi.org/10.1155/2019/7362875 https://doi.org/10.1155/2019/7362875 https://doi.org/10.1007/s00424-012-1081-3 https://doi.org/10.1007/s00424-012-1081-3 https://doi.org/10.4161/cib.3.6.13461 https://doi.org/10.1016/j.ebiom.2017.01.003 https://doi.org/10.1016/j.jdermsci.2017.02.201 https://doi.org/10.1016/j.jdermsci.2017.02.201 departments of 1internal medicine and 6family medicine & public health, 3college of medicine and health sciences, sultan qaboos university, muscat, oman; 2department of internal medicine, al-nahdha hospital, muscat, oman; 4department of medicine, sultan qaboos university hospital, muscat, oman; 5department of research, oman medical specialty board, muscat, oman *corresponding author’s e-mail: alfutaisia@gmail.com assessing barriers to insulin therapy among omani diabetic patients attending three main diabetes clinics in muscat, oman *abdulla al futaisi,1 magdi alosali,2 ali al-kazrooni,3 salim al-qassabi,2 sumaia al-gharabi,4 sathiya panchatcharam,5 abdulaziz m. al-mahrezi6 clinical & basic research sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 525–531, epub. 7 nov 22 submitted 3 feb 21 revision req. 22 mar 21; revision recd. 16 may 21 accepted 8 jun 21 https://doi.org/10.18295/squmj.6.2021.086 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to identify the main barriers that prevent patients with diabetes mellitus from accepting insulin therapy. methods: this cross-sectional study was conducted from may to december 2019. convenience sampling was used to recruit participants from three diabetes clinics in muscat, oman. eligible participants were interviewed in person based on a pre-prepared questionnaire. the questionnaire, which was administered in arabic, includes demographic data and 19 specific items on barriers to insulin therapy. results: a total of 201 participants (response rate: 93%) were enrolled in the study. the most common barriers were as follows: concern of frequent blood glucose checking (36.3%), long-term injections (33.8%), side-effects of insulin (29.9%) and weight gain (29.4%). needle phobia was considered a barrier by only 9% of the participants. overall, 125 (62.2%) participants were willing to initiate insulin therapy despite the presence of these barriers and only 20 (10%) of them were influenced by these barriers to such a degree that they rejected the insulin therapy. conclusion: the majority of participants had no identifiable reasons to stop them from accepting insulin therapy. effective strategies should be developed to address each of the main barriers to improve acceptance and adherence to insulin therapy. keywords: diabetes mellitus; insulin; treatment refusal; needles; phobic disorders; hypoglycemia; weight gain; oman. advances in knowledge this study found that the main barriers to the initiation of insulin therapy, from the perspective of patients, were concerns about the need for frequent blood glucose checking, long-term therapy, side-effects of insulin and weight gain. needle phobia was found not to be among the main barriers to the initiation of insulin therapy. the identifiable barriers did not influence the decision of the participants on whether to accept insulin therapy or not. application to patient care it is important to address the main barriers to the initiation of insulin therapy with the patient to ensure their acceptance and adherence. health education to diabetic patients must include clear messages on the common myths and misperceptions of insulin therapy. community awareness campaigns are needed to improve awareness about the safety and value of insulin therapy for patients with diabetes mellitus. diabetes mellitus (dm) is considered a chronic disease that threatens the world. in 2019, the international diabetes federation reported that 463 million people worldwide had diabetes and its related deaths were estimated at 4.2 million. unfortunately, 72% of people with diabetes are in the age range of 20–64 years, which creates a high economic burden on majority of the countries.1 type 1 diabetes (t1dm) is usually caused by an absolute insulin deficiency that results from the destruction of beta cells of the pancreas islets.2 type 2 diabetes (t2dm) is the most common type of diabetes and it results from a progressive insulin secretory defect, in addition to insulin resistance.2 numerous pharmacological options are widely available for the management of diabetes. these include commonly used options such as metformin, sulphonylureas, meglitinides, thiazolidinediones and dpp-4 inhibitors. other classes of drugs that have been recently added include glp-1 receptor agonists and sglt2 inhibitors.2 however, since diabetes is a progressive disease and oral hypoglycaemic agents (oha) eventually lose their effectiveness, a big proportion of diabetic patients will eventually need to switch to insulin therapy, either alone or along with oha. insulin therapy is still considered the most effective pharmacological option for the treatment of diabetes.2 moreover, studies have shown that early https://creativecommons.org/licenses/by-nd/4.0/ assessing barriers to insulin therapy among omani diabetic patients attending three main diabetes clinics in muscat, oman 526 | squ medical journal, novemebr 2022, volume 22, issue 4 initiation of insulin therapy resulted in lower rate of complications and a slower decline in the function of beta cells of the pancreas.3–5 poor glycaemic control is multifactorial: it could be due to healthcare workers-related factors, patient-related factors such as poor adherence, or factors related to the disease itself.6,7 poor control leads to multiple microvascular and macrovascular complications such as end-stage kidney disease and cardiovascular disease, which would eventually cause early death.7,8 late initiation and refusal of insulin therapy have been identified to be among the main causes of poor glycaemic control and the development of irreversible complications.9 patient beliefs and misconceptions have been implicated in being important barriers to insulin therapy.7 such barriers would either lead to poor adherence or refusal of insulin therapy. needle phobia has been identified as a main barrier and has been reported to contribute significantly to the refusal of insulin therapy.10 usually, patients prefer oral medications over needles due to its ease and convenience. injection-based therapy is mostly feared due to the nescience on how to inject and the misconceptions including that injections must always be administered by doctors or experienced caregivers and that they are associated with complications.11 numerous studies have been undertaken to identify the most important barriers to the initiation of insulin therapy.10–15 these barriers include criticisms such as ‘insulin must be administered life-long’, ‘insulin could cause organ damage’ and ‘insulin is a treatment option only for severe disease’.12 additionally, fear of stigma, lack of emotional support from the people around them and lack of support from their own physicians.13 moreover, studies have revealed these barriers to be influenced by culture and healthcare system-related factors, which are unique and different for each country in the world.8,13,14,16 besides, focused health education on insulin therapy and appropriate self-care management have been recommended as being crucial to address these barriers.17 hence, it is important to study the barriers to insulin therapy and find appropriate strategies to address each barrier to optimise the management of diabetic patients. the lack of any previous published studies addressing this important area necessitates, with even greater importance, that this study be conducted. thus, this study aimed to identify the main barriers to the initiation of insulin therapy among patients with dm in oman and estimate the influence of these barriers on the decision of patients to accept or reject insulin therapy. methods this cross-sectional study was conducted at the diabetes clinics at sultan qaboos university hospital, bowsher polyclinic and a’seeb polyclinic, muscat, oman, from may to december 2019. all diabetic patients who were ≥18 years old and who attended these clinics during the study period were invited to participate in the study, except those who were known to have severe mental disorders. a minimum sample size of 195 patients was calculated based on anecdotal evidence of an estimated barrier prevalence rate of 15% with a 5% margin of error and 95% confidence interval. the patients, who agreed to participate, were interviewed in person by a main investigator to fill out a pre-prepared questionnaire and were given an overview about insulin therapy (indications, types, methods of initiation and administration). convenience sampling method was used to recruit eligible participants from the three diabetes clinics. the questionnaire comprised the following items: demographic data (age, gender, occupation, monthly income and education), diabetes-related information (type of diabetes, type of treatment and number of injections per day, if on insulin therapy) and 19 specific items on barriers to insulin therapy. these items were adopted and modified from previous similar studies.18–20 the constructed questionnaire was subsequently validated by three subject experts for content, appropriateness and relevance. a four-point likert scale was used to classify the importance of each barrier as ‘not at all important’, ‘sometimes important’, ‘frequently important’ or ‘very important’. a three-point scale was used to determine the impact of each barrier on the patients’ acceptance or rejection to insulin therapy as ‘accept insulin therapy’, ‘borderline’ or ‘reject insulin therapy’. the questionnaire was translated from english to arabic following the standard procedure of forward-and-backward translation. the questionnaire was administered in arabic. a pilot study involving 20 participants was carried out to test the reliability of the questionnaire, and it achieved a cronbach's alpha of 82.1%. the data were entered and analysed in both epidata version 4.6 and using the statistical package for the social sciences (spss) version 24.0 (ibm corp., armonk, new york, usa). percentages and frequencies were among the descriptive statistics that were used, while continuous data were presented with mean and standard deviation. for the prevalence, 95% confidence intervals were reported. informed consent was requested from all the participants prior to their enrolment in the study. the abdulla al futaisi, magdi alosali, ali al-kazrooni, salim al-qassabi, sumaia al-gharabi, sathiya panchatcharam and abdulaziz m. al-mahrezi clinical and basic research | 527 ethical approval for this study was granted from the medical research ethics committee (mrec) of the college of medicine and health sciences of sultan qaboos university (mrec#1655). results in total, 218 of the 233 patients who were initially invited (response rate: 93%) agreed to participate in the study. none were excluded based on the exclusion criteria of the study. a total of 17 questionnaires were excluded due to significant missing information; thus, 201 remaining questionnaires were eventually analysed. the average age of the participants was 40.54 ± 15.17 years. there were 122 (60.7%) male participants and 91 (45.3%) were employed while 110 (54.7%) were retired or unemployed. a total of 88 (43.8%) had a diploma, bachelor and higher level qualification, while 113 (56.2) had a secondary, intermediate or primary school qualifications or were illiterate. only 14 (7.0%) participants had a low income (<300 omani rials) and the remaining had moderate to high income (300– ≥1,000 omani rials) [table 1]. the majority of patients (n = 84, 41.8%) had t1dm, 63 (31.3%) had t2dm and 54 (26.9%) were unaware of the type of diabetes they had. data analysis revealed the following as the most common barriers: frequent blood glucose checking for 73 (36.3%) participants, long-term insulin injections for 68 (33.8%), side-effects of insulin for 60 (29.9%), weight gain for 59 (29.4%), inconvenience of the insulin injections for 58 (28.9%), busy life schedule for 55 (27.6%), dependence on insulin for 55 (27.4%), hypoglycemia for 48 (24%), pain and discomfort of injections for 46 (22.9%) and lifestyle interference for 45 (22.5%) participants. needle phobia was considered a barrier only by a minority of the participants (n = 18, 9%; 95% confidence interval: 5–14) [figure 1 and table 2]. other barriers such as those related to difficulty to learn, difficulty to inject due to physical disabilities, lack of support from family, fear of stigma or feeling of personal failure had no major impact and were not considered barriers. all of these constituted less than 20% [table 2]. overall, 125 (62.2%) patients were willing to initiate insulin therapy despite the presence of barriers to insulin therapy and only 20 (10%) of them were influenced by these barriers to such a degree that they had to reject insulin therapy. the remaining 56 (27.8%) patients were still hesitant about insulin initiation and table 1: socio-demographic and clinical characteristics of the study population (n = 201) variables n (%) mean age in years ± sd 40.54 ± 15.17 gender male 122 (60.7) female 79 (39.3) occupational status unemployed 73 (36.3) employed 83 (41.3) self-employed 8 (4.0) retired 37 (18.4) monthly income in omr low (<300) 14 (7.0) moderate (300–1000) 108 (53.7) high (>1000) 79 (39.3) education illiterate 14 (7.0) primary 13 (6.5) intermediate 28 (13.9) secondary school 58 (28.9) diploma 32 (15.9) bachelor’s and above 56 (27.9) diabetes type type 1 84 (41.8) type 2 63 (31.3) don’t know 54 (26.9) type of treatment no medication 4 (2.0) tablets 46 (22.9) insulin injections 95 (47.3) tablets and insulin 50 (24.9) insulin pump 6 (3.0) number of injections per day 1 15 (9.9) 2 25 (16.6) 3 42 (27.8) 4 64 (42.4) >4 5 (3.3) sd = standard deviation; omr = omani rial. assessing barriers to insulin therapy among omani diabetic patients attending three main diabetes clinics in muscat, oman 528 | squ medical journal, novemebr 2022, volume 22, issue 4 requested more time to decide [table 3]. discussion this study identified the following as the main barriers to the initiation of insulin therapy: concern of frequent blood glucose checking, long-term injections, sideeffects of insulin and weight gain. needle phobia was not found to be a major concern for the participants of this study. furthermore, these barriers did not seem to influence the decision of the subjects as to whether or not they accept the insulin therapy. the concern of frequent blood glucose checking was among the main barriers in this study. in this study, the two main factors that may have contributed table 2: the responses of the participants regarding the importance of each barrier to initiation of insulin therapy items n (%) not at all important sometimes important frequently important very important needle phobia 146 (72.6) 37 (18.4) 10 (5.0) 8 (4.0) feeling of personal failure* 141 (70.5) 39 (19.5) 9 (4.5) 11 (5.5) pain, discomfort of injections 83 (41.3) 72 (35.8) 29 (14.4) 17 (8.5) lifestyle interference* 100 (50.0) 55 (27.5) 27 (13.5) 18 (9.0) concern of hypoglycaemia* 81 (40.5) 71 (35.5) 30 (15.0) 18 (9.0) concern of insulin side-effects 90 (44.8) 51 (25.4) 32 (15.9) 28 (13.9) concern of insulin as a cause of long-term diabetes complications 95 (47.3) 38 (18.9) 29 (14.4) 39 (19.4) remarkably busy life schedule* 92 (46.2) 52 (26.1) 25 (12.6) 30 (15.1) concern of weight gain 110 (54.7) 32 (15.9) 25 (12.4) 34 (16.9) concern of dependence on insulin 108 (53.7) 38 (18.9) 28 (13.9) 27 (13.4) concern of frequent blood glucose checking 96 (47.8) 32 (15.9) 38 (18.9) 35 (17.4) inconvenience 110 (54.7) 33 (16.4) 24 (11.9) 34 (16.9) concern of stigma* 151 (75.5) 28 (14.0) 11 (5.5) 10 (5.0) difficult to learn 164 (81.6) 22 (10.9) 4 (2.0) 11 (5.5) difficultly to inject due to physical disabilities 152 (75.6) 22 (10.9) 16 (8.0) 11 (5.5) cannot inject myself 171 (85.1) 11 (5.5) 4 (2.0) 15 (7.5) no other person who can inject me 155 (77.1) 20 (10.0) 14 (7.0) 12 (6.0) lack of support from family for insulin treatment 164 (81.6) 15 (7.5) 15 (7.5) 7 (3.5) lack of general family support 172 (85.6) 15 (7.5) 10 (5.0) 4 (2.0) *the sum of the responses of this item is <201 due to missing responses. figure 1: the most common barriers to the initiation of insulin therapy amongst the participants of the study. abdulla al futaisi, magdi alosali, ali al-kazrooni, salim al-qassabi, sumaia al-gharabi, sathiya panchatcharam and abdulaziz m. al-mahrezi clinical and basic research | 529 to this finding were the low level of education among the participants and the fact that the majority of them were on insulin therapy, which usually requires frequent blood glucose monitoring. wallace and matthews attributed this barrier either to the fear of hypoglycaemia owing to patient beliefs that insulin has an immediate action or to the patient’s worry about hyperglycaemia and their intention to seek rapid improvement.7 other major barriers identified in this study included concern of long-term injections and its sideeffects. similar findings were demonstrated in a study that was conducted in the usa. insulin therapy was feared, as the subjects in the study mistakenly believed that insulin medication could lead to amputations (15%), renal failure (32%), strokes (19%), heart attacks, blindness (20%) and early death (19%).10 another study demonstrated the concern of hypoglycaemia as a barrier to insulin initiation, especially among those who had increased their doses of insulin.11 most patients with t2dm are overweight at the onset of diagnosis with an average body mass index of 27.5 kg/m2 as shown in the united kingdom prospective diabetes study.22 the presence of two medical problems, namely diabetes and obesity, at an early stage, discourages the patients and physicians to adopt any treatment that might induce weight gain. indeed, studies have revealed fear of weight gain as a big concern in such patients, especially if they have been treated with insulin.7,11 usually, people prefer oral drugs over needles due to the pain and discomfort of injections.9,14,15 in the current study, 46 (22.9 %) patients found insulin treatment inconvenient due to this reason. most people think that insulin restricts their life schedule and themselves from their work or sports.7,21 furthermore, it might be associated with carrying the needles wherever the patients go unlike oral medications, which are easier to carry especially for frequent travellers.9,15 these findings are consistent table 3: the responses of the participants regarding the impact of each barrier as to accept or reject insulin therapy items n (%) accept insulin therapy borderline reject insulin therapy needle phobia 146 (72.6) 47 (23.4) 8 (4.0) feeling of personal failure* 141 (70.5) 48 (24) 11 (5.5) pain and discomfort of injections 83 (41.3) 101 (50.2) 17 (8.5) lifestyle interference* 100 (50.0) 82 (41) 18 (9.0) concern of hypoglycemia* 81 (40.5) 101 (50.5) 18 (9.0) concern of insulin side-effects 90 (44.8) 83 (41.3) 28 (13.9) concern of insulin as a cause of long-term diabetes complications 95 (47.3) 67 (33.3) 39 (19.4) remarkably busy life schedule* 92 (46.2) 77 (38.7) 30 (15.1) concern of weight gain 110 (54.7) 57 (28.3) 34 (16.9) concern of dependence on insulin 108 (53.7) 66 (32.8) 27 (13.4) concern of frequent blood glucose checking 96 (47.8) 70 (34.8) 35 (17.4) inconvenience 110 (54.7) 57 (28.3) 34 (16.9) concern of stigma* 151 (75.5) 39 (19.5) 10 (5.0) difficult to learn 164 (81.6) 26 (12.9) 11 (5.5) difficult to inject due to physical disabilities 152 (75.6) 38 (18.9) 11 (5.5) cannot inject myself 171 (85.1) 15 (7.5) 15 (7.5) no other person that can inject me 155 (77.1) 34 (17) 12 (6.0) lack of support from family for insulin treatment 164 (81.6) 30 (15) 7 (3.5) lack of general family support 172 (85.6) 25 (12.5) 4 (2.0) overall 125 (62.2) 56 (27.8) 20 (10) *the sum of the responses of this item is <201 due to missing responses. assessing barriers to insulin therapy among omani diabetic patients attending three main diabetes clinics in muscat, oman 530 | squ medical journal, novemebr 2022, volume 22, issue 4 with the results of the current study, which showed that insulin initiation was rejected due to lifestyle interference (22.5%), inconvenience of the insulin needles treatment (28.9%) and busy life schedule (27.6%). insulin therapy might be initiated for a short period to combat severe hyperglycaemia such as in newly diagnosed t2dm patients. however, some of these patients might be reluctant to start insulin due to their fear of dependence to insulin and the concern of being dependent on it life-long.9,10,17 this fact was also demonstrated in 55 (27.3 %) patients. difficulty to learn is an infrequent barrier to insulin initiation that was documented in 15 (7.5%) patients of this study. this can be seen more commonly among inhabitants of rural areas where people are expected to not have enough education and access to medical services. thus, their knowledge about the disease and available therapies might be lacking.21 moreover, few patients have concern of stigma, which is mostly related to the use of insulin, administration of insulin injection in public or the shame of telling people of their chronic disease, and believe that it might affect their relationships or connections with others.12 the prevalence of the needle phobia in the current study was only 9%, as opposed to the findings of a qualitative study, which was conducted in five different countries (germany, sweden, the netherlands, united kingdom and usa). the researchers reported a high prevalence (43.7%) of needle phobia among their subjects.17 this phobia seemed to be unaffected by the variation in who gives the injection or where it is given.17 a systematic review conducted by mclenon et al. reported a higher prevalence of needle phobia in females, young adults and in specific countries.23 thus, this low prevalence in the present study could be attributed to the predominant age and gender of the participants, in addition to country-specific factors. most participants in this study were willing to initiate insulin therapy despite confirming the presence of barriers. this might be explained by the possibility that these barriers are not strong enough to influence their final decision on insulin therapy. moreover, concerns about the complications of poorly controlled diabetes and side-effects of other treatments could also lead to insulin acceptance.12 the findings of this study are important since it gives physicians an insight about the barriers to insulin initiation from the perspective of the patients. this is the first critical step to develop strategies that appropriately address these myths and misconceptions to aim for the better care of diabetic patients in oman.16,24,25 this study has several important limitations. the questionnaire-based design of the study is dependent on self-reported responses, which are usually influenced by social desirability. since most responses obtained from the interviews, particularly those related to the barriers among participants who were already on insulin therapy, are dependent on their ability for recall, recall information bias can be considered a limitation. the responses to questionnaires are usually influenced by the level of education and there was a big proportion of subjects who had low level of education. moreover, this tool is limited by its ability to capture attitudes and not real behaviours. the relationship between barriers and the decision to accept or reject insulin is also hypothetical and the responses might not reflect the final decision. the study population, which is limited to the attendants of outpatient clinics, is not representative of the general population, which affects the generalisability of the findings. conclusion this study addressed the barriers that might influence the decision to accept or reject insulin therapy amongst diabetic patients in oman. the main barriers were the concern of frequent blood glucose checking, longterm therapy and side-effects. most study participants reported no impact of these barriers on their final decision to accept or reject insulin therapy. contrary to the findings of other similar studies, needle phobia was found not to be a major barrier to insulin initiation in this study. a u t h o r s’ c o n t r i b u t i o n aaf, ma, saq, sag, sp and aam conceptualised and designed the study. aaf, ma, aak, saq and sag collected the data. aaf, sp and aam analysed and interpreted the data. aaf, ma, saq and aam drafted the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. international diabetes federation. idf diabetes atlas 9th edition 2019. https://www.diabetesatlas.org accessed: may 2021. 2. classification and diagnosis of diabetes: standards of medical care in diabetes-2018. diabetes care 2018; 41:s13–27. https:// doi.org/10.2337/dc18-s002. https://doi.org/10.2337/dc18-s002 https://doi.org/10.2337/dc18-s002 abdulla al futaisi, magdi alosali, ali al-kazrooni, salim al-qassabi, sumaia al-gharabi, sathiya panchatcharam and abdulaziz m. al-mahrezi clinical and basic research | 531 3. li y, xu w, liao z, yao b, chen x, huang z, et al. induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of β-cell function. diabetes care 2004; 27:2597–602. https://doi.org/10.2337/dia care.27.11.2597. 4. weng j, li y, xu w, shi l, zhang q, zhu d, et al. effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multi centre randomised parallel-group trial. lancet 2008; 371:1753–60. https://doi.org/10.1016/s0140-6736(08)60762-x. 5. harrison lb, adams-huet b, raskin p, lingvay i. β-cell function preservation after 3.5 years of intensive diabetes therapy. diabetes care 2012; 35:1406–12. https://doi.org/10.2337/dc11-2170. 6. bin rsheed a, chenoweth i. barriers that practitioners face when initiating insulin therapy in general practice settings and how they can be overcome. world j diabetes 2017; 8:28–39. https://doi.org/10.4239/wjd.v8.i1.28. 7. wallace tm, matthews dr. poor glycaemic control in type 2 diabetes: a conspiracy of disease, suboptimal therapy and attitude. qjm 2000; 93:369–74. https://doi.org/10.1093/qjmed/93.6.369. 8. alramadan mj, afroz a, hussain sm, batais ma, almigbal th, al-humrani ha, et al. patient-related determinants of glycae mic control in people with type 2 diabetes in the gulf cooperation council countries: a systematic review. j diabetes res 2018; 9389265. https://doi.org/10.1155/2018/9389265. 9. polonsky wh, fisher l, guzman s, villa-caballero l, edelman sv. psychological insulin resistance in patients with type 2 diabetes: the scope of the problem. diabetes care 2005; 28: 2543–5. https://doi.org/10.2337/diacare.28.10.2543. 10. karter aj, subramanian u, saha c, crosson jc, parker mm, swain be, et al. barriers to insulin initiation. diabetes care 2010; 33:733–5. https://doi.org/10.2337/dc09-1184. 11. petznick am. identifying and addressing barriers to insulin acceptance and adherence in patients with type 2 diabetes mellitus. j am osteopath assoc 2013; 113:s6–16. 12. abu hassan h, tohid h, amin mr, long bidin mb, muthupalaniappen l, omar k. factors influencing insulin acceptance among type 2 diabetes mellitus patients in a primary care clinic: a qualitative exploration. bmc fam prac 2013; 14:164. https://doi.org/10.1186/1471-2296-14-164. 13. tan am, muthusamy l, ng cc, phoon ky, ow jh, tan nc. initiation of insulin for type 2 diabetes mellitus patients: what are the issues? a qualitative study. singapore med j 2011; 52:801–9. 14. chen k, tseng h, huang y, chuang y. the barriers to initiating insulin therapy among people with type 2 diabetes in taiwan a qualitative study. j diabetes metab 2012; 3:3–6. https://doi. org/10.4172/2155-6156.1000194. 15. wibisono ah, lestari a, sorensen l, hill p. fear of injections among people with type 2 diabetes: overview of the problem. j diabetes nurs 2017; 21:91–5. 16. peyrot m, rubin rr, lauritzen t, skovlund se, snoek fj, matthews dr, et al. international dawn advisory panel. resistance to insulin therapy among patients and providers: results of the cross-national diabetes attitudes, wishes, and needs (dawn) study. diabetes care 2005; 28:2673–9. https:// doi.org/10.2337/diacare.28.11.2673. 17. brod m, alolga sl, meneghini l. barriers to initiating insulin in type 2 diabetes patients: development of a new patient education tool to address myths, misconceptions and clinical pealities. patient 2014; 7:437–50. https://doi.org/10.1007/s40271-014-0068-x. 18. hussein a, mostafa a, areej a, mona am, shimaa a, najd ag, et al. the perceived barriers to insulin therapy among type 2 diabetic patients. afr health sci 2019; 19:1638–46. https://doi. org/10.4314/ahs.v19i1.39. 19. shafie pour mr, sadeghiyeh t, hadavi m, besharati m, bidaki r. the barriers against initiating insulin therapy among patients with diabetes living in yazd, iran. diabetes metab syndr obes 2019; 12:1349–54. https://doi.org/10.2147/dmso.s200867. 20. russell-jones d, pouwer f, khunti k. identification of barriers to insulin therapy and approaches to overcoming them. diabetes obes metab 2018; 20:488–96. https://doi.org/10.1111/dom.13132. 21. tan wl, asahar sf, harun nl. insulin therapy refusal among type ii diabetes mellitus patients in kubang pasu district, kedah, malaysia. singapore med j 2015; 56:224–7. https://doi.org/10.11 622/smedj.2014170. 22. king p, peacock i, donnelly r. the uk prospective diabetes study (ukpds): clinical and therapeutic implications for type 2 diab etes. br j clin pharmacol 1999; 48:643–8. https://doi.org/10.10 46/j.1365-2125.1999.00092.x. 23. mclenon j, rogers mam. the fear of needles: a systematic review and meta-analysis. j adv nurs 2019; 75:30–42. https:// doi.org/10.1111/jan.13818. 24. balogh eg, perez-nieves m, cao d, hadjiyianni ii, ashraf n, desai u, et al. key strategies for overcoming psychological insulin resistance in adults with type 2 diabetes: the uk subgroup in the emotion study. diabetes ther 2020; 11:1735–44. https:// doi.org/10.1007/s13300-020-00856-4. 25. peyrot m, rubin rr, kruger df, travis lb. correlates of insulin injection omission. diabetes care 2010; 33:240–5. https://doi. org/10.2337/dc09-1348. https://doi.org/10.2337/diacare.27.11.2597 https://doi.org/10.2337/diacare.27.11.2597 https://doi.org/10.1016/s0140-6736(08)60762-x https://doi.org/10.2337/dc11-2170 https://doi.org/10.4239/wjd.v8.i1.28 https://doi.org/10.1093/qjmed/93.6.369 https://doi.org/10.1155/2018/9389265 https://doi.org/10.2337/diacare.28.10.2543 https://doi.org/10.2337/dc09-1184 https://doi.org/10.1186/1471-2296-14-164 https://doi.org/10.4172/2155-6156.1000194 https://doi.org/10.4172/2155-6156.1000194 https://doi.org/10.2337/diacare.28.11.2673 https://doi.org/10.2337/diacare.28.11.2673 https://doi.org/10.1007/s40271-014-0068-x https://doi.org/10.4314/ahs.v19i1.39 https://doi.org/10.4314/ahs.v19i1.39 https://doi.org/10.2147/dmso.s200867 https://doi.org/10.1111/dom.13132 https://doi.org/10.11622/smedj.2014170 https://doi.org/10.11622/smedj.2014170 https://doi.org/10.1046/j.1365-2125.1999.00092.x https://doi.org/10.1046/j.1365-2125.1999.00092.x https://doi.org/10.1111/jan.13818 https://doi.org/10.1111/jan.13818 https://doi.org/10.1007/s13300-020-00856-4 https://doi.org/10.1007/s13300-020-00856-4 https://doi.org/10.2337/dc09-1348 https://doi.org/10.2337/dc09-1348 abstract: workplace environment can have a considerable impact on the physical, psychological and maternal health of pregnant healthcare workers. this article aimed to summarise the impact of work-related ergonomic stressors on pregnancy outcomes for healthcare workers, along with potential interventions to resolve these stressors. a narrative review analysis using the pearl growing strategy was conducted between february 2019 and june 2020 to identify english-language articles published between 2000 and 2020. a total of 89 studies were identified from the scopus (elsevier, amsterdam, netherlands), medline® (national library of medicine, bethesda, maryland, usa) databases and google scholar (google llc, menlo park, california, usa). the results indicated that poor work-related ergonomics had detrimental effects on pregnancy outcomes, resulting in spontaneous abortions, preterm delivery, low birth weight babies and infertility. policymakers and employers should conduct ergonomic assessments and implement appropriate practices to ensure the safety of pregnant healthcare workers. keywords: healthcare workers; physical ergonomics; pregnancy outcomes; occupational health; occupational exposure. ergonomic stressors among pregnant healthcare workers impact on pregnancy outcomes and recommended safety practices *frincy francis,1 sheeba e. johnsunderraj,1 divya k. y.,2 divya raghavan,1 atiya al-furgani,1 lily p. bera,3 aniamma abraham4 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e172–181, epub. 21 jun 21 submitted 9 mar 20 revisions req. 18 may & 19 jul 20; revisions recd. 1 jul & 15 aug 20 accepted 13 sep 20 departments of 1maternal & child health and 2community & mental health, college of nursing, sultan qaboos university, muscat, oman; 3department of maternal & child health, college of nursing, all india institute of medical sciences, bhopal, india; 4directorate of nursing, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: frincyshalom@gmail.com the world health organisation estimatesthat there are approximately 34.4 million healthcare workers worldwide including doctors, nurses, pharmacists and other types of community healthcare providers, of which an increasing proportion are female.1,2 despite recent improvements in workplace technology and practices, occupational hazards remain an important cause of morbidity and mortality world wide.3 in particular, healthcare professionals have a high prevalence of musculoskeletal disorders, ranging from 50–90% among nurses to 86.7% among rectovaginal surgeons, 67% among orthopaedic surgeons and 91% among sonographers.4 ergonomics refers to the study of factors likely to affect interactions between an individual and their working environment.5,6 approximately 59 million healthcare workers around the globe are exposed to ergonomic hazards daily.2,7 according to the international ergonomics association, ergonomics is defined as a “scientific discipline that applies theory, principles, data, and methods to optimise human well-being. it evaluates tasks, jobs, environments, and systems to make it compatible with the needs, abilities, and limitations of people”.8 the application of ergonomic principles in a workplace had been found to prevent musculoskeletal disorders and increase both productivity and job satisfaction among employees.9,10 certain ergonomic hazards are either created or exacerbated by pregnancy.11,12 adverse pregnancy outcomes have been linked to poor working conditions including prolonged standing, lifting heavy objects, long working hours and psychological stress.12 moreover, poor ergonomic practices often exaggerate existing discomfort, resulting in increased rates of work absenteeism, sick leave and a lack of motivation among pregnant healthcare workers.13 appropriate accommodations are therefore necessary to enhance the comfort of pregnant employees and help them to handle work-related stress as well as the innate physical challenges associated with pregnancy.12,14 this article aimed to review the available literature concerning the impact of work-related ergonomic stressors on pregnancy outcomes for healthcare workers, along with feasible solutions to prevent and mitigate such risks. methods this narrative review was conducted from february 2019 to june 2020. the primary objective was to highlight the impact of work-related ergonomic stressors on pregnancy outcomes among healthcare workers, as well as to recommend ergonomic interventions to prevent these stressors. the scopus review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.004 https://creativecommons.org/licenses/by-nd/4.0/ review | e173 (elsevier, amsterdam, netherlands), medline® (national library of medicine, bethesda, maryland, usa) databases and google scholar (google llc, mountain view, california, usa) were searched electronically to identify relevant articles for inclusion. to ensure a holistic approach, the following search terms were used: “healthcare workers”, “physical ergonomics”, “pregnancy outcomes”, “occupational safety”, “hospital ergonomics” and “recommendations”. the inclusion criteria comprised all englishlanguage articles published between 2000 and 2020 reporting the impact of work-related ergonomic stressors on pregnancy outcomes in healthcare workers and pregnancy-specific ergonomic interventions for hospital units. articles related to pregnant women working in other professions were excluded, as were those published prior to 2000 or written in other languages. all types of articles were deemed eligible for inclusion including experimental studies such as randomised controlled trials and quasi-controlled trials, as well as cohort studies, observational studies and surveys. case reports, action research studies and qualitative studies detailing conceptual information were also included to emphasise the importance of optimal ergonomic practices for pregnant women. as the sources of the retrieved articles were highly variable, the literature search was conducted using the pearl growing strategy.15 this approach was deemed most suitable as the review focused on a specific population (i.e. pregnant healthcare workers). an article extraction checklist listing the inclusion and exclusion criteria was utilised during retrieval in order to confirm the relevancy and appropriateness of each article. a total of eight primary articles were retrieved following the initial screening of titles and abstracts. subsequently, 46 secondary articles were identified from the reference lists of the primary articles. a further 35 articles were identified via bibliographic mining of the secondary articles. overall, a total of 89 articles met the inclusion criteria and were included in the narrative analysis [figure 1]. although the findings of the literature search were initially compiled according to preconceived themes, these were revised based on data extracted from the articles. four main themes were therefore applied as follows: (1) ergonomic-related physiological changes in pregnancy; (2) ergonomic stressors and pregnancy outcomes; (3) the psychological impact of ergonomic stressors; and (4) recommended safety practices for pregnant healthcare workers including ergonomic assessment methods. results and discussion the following section narratively discusses findings from articles related to work-related ergonomic stressors and their impact on pregnant healthcare workers including stressors and activities related to the working environment. in addition, strategies to overcome or mitigate the impact of these stressors are also recommended based on the findings of the literature review. ergonomic-related physiological changes in pregnancy a pregnant employee requires additional attention and care due to certain physiological and pathological changes that arise during pregnancy. in particular, gait, balance, spinal curvature and pain alter considerably as the pregnancy progresses.16 moreover, various anatomical, physical, psychological and biochemical changes occur in order to ensure haemostasis, meet the increasing demands of the developing fetus and prepare for labour.17,18 such changes also affect the quality of life of the expectant mother.19–22 backache and waddling gait occur due to increased levels of relaxin and oestrogen hormones, joint laxity, hypermobility and spinal curvature; in turn, this figure 1: diagram showing the selection process used to identify articles included in the narrative analysis. frincy francis, sheeba e. johnsunderraj, divya k. y, divya raghavan, atiya al-furgani, lily p. bera and aniamma abraham increases the rate of falls among pregnant women.23–26 in the second trimester, several symptoms cease while other physiological adaptations continue.23,24,27 abnormal conditions can cause anaemia, fluid retention and physiological oedema, thereby compressing the nerves and resulting in numbness and pain in the extremities.18,19,25 many pregnant women also experience increased levels of tiredness, varicose veins, back pain, muscular cramps, braxton hicks contractions and poor sleep quality.26–28 pregnancy ailments are often exacerbated by the presence of ergonomic stressors at work.14 e r g o n o m i c s t r e s s o r s a n d p r e g n a n c y o u t c o m e s a pregnant employee is more vulnerable to certain occupational hazards, such as radiation exposure (at >100 millirems), infectious bioagents, heavy lifting and prolonged working hours (>12 hours per shift), due to their impact on fetal development.29,30 expectant mothers should therefore be protected from harmful working conditions, especially after the first trimester.31 this includes ergonomic stressors related to various negative pregnancy outcomes such as spontaneous abortions, prematurity, low birth weight babies and stillbirths. biological and chemical agents a study of 7,500 pregnant nurses working in chemo therapy administration showed a significant increase in the rate of spontaneous miscarriage after handling cytotoxic drugs.32 in addition, exposure to biological agents such as cytomegalovirus, hepatitis b, human parvovirus b19 and rubella can cause birth defects, low birth weight babies, miscarriages and developmental disorders.33 in particular, seroprevalence rates of cytomegalovirus have been found to be very high among nurses working with immunocompromised and paediatric patients, as well as other healthcare workers in close contact with infected patients or those who provide personal hygiene care like bathing and toileting.34 ionising radiation sources of ionising radiation such as x-rays and gamma rays can cause infertility, miscarriage, birth defects, low birth weight babies and developmental disorders.30 in a study from israel evaluating 934 pregnant physiotherapists, the researchers reported a significant association between shortwave exposure and low birth weight babies.35 a prospective cohort study of 1,025 female laboratory technicians found that exposure to radio immunoassay work and radio labelling at approximately 16 gestational weeks increased the rate of preterm delivery.36 in addition, the risk of major fetal malformations was elevated among workers exposed to organic solvents.36 overexertion and heavy lifting several studies have shown that factors such as physical overexertion, irregular working hours and heavy lifting are associated with an increased risk of spontaneous abortion among pregnant women.29,31,37 as such, employees should be careful when lifting and manoeuvring objects away from the body as the pregnancy progresses.16 lifting heavy weights (>10 kg) during pregnancy shifts the centre of gravity forward, affecting balance and potentially increasing the risk of falling.38,39 moreover, lifting heavy loads also increases the risk of preterm birth.38 an elevated risk of stillbirth and spontaneous abortion related to physical effort, lifting heavy objects and working for long hours without rest has been observed among nursing assistants, aides and other female employees.40–42 high levels of physical activity during pregnancy increase the demand for oxygen, reducing fetal nutrition supply and putting stress on the endocrine system. exhaustion, lifting heavy objects, long work hours without rest and high noise levels (>85 decibels) during pregnancy has been linked to low birth weight babies.31,43−46 prolonging working hours and standing prolonged or irregular working hours have been found to increase the risk of small-for-gestational-age babies, with this risk aggravated by other working conditions including night shifts, prolonged standing, increased noise exposure and high psychological needs with low support.47–49 the prevalence of preterm labour among orthopaedic surgeons during their first pregnancies was 11.1%, gradually increasing to 12.5% in second pregnancies and 20% in third pregnancies.50 urologists have also shown an increased risk of premature labour compared to the general population, likely due to prolonged working hours and continuous standing (>3 hours per day).51 there is also a significant relationship between number of hours worked per week and premature rupture of the membranes.52 overall, 8.8% of women working 40 hours per week report premature labour, which indicates that occupational fatigue caused by prolonged working hours can lead to preterm delivery.52,53 occupational fatigue during pregnancy is also believed to lower capacity to endure pain during vaginal delivery, as well as energy levels, potentially affecting the decision to perform a caesarean section.54 falls a retrospective cohort study from the usa found the incidence of falls among employed pregnant women to be 26.6%, of which 13.1% occurred at the workplace and the majority during the second and third trimesters.55 overall, pregnant healthcare workers reported the ergonomic stressors among pregnant healthcare workers impact on pregnancy outcomes and recommended safety practices e174 | squ medical journal, may 2021, volume 21, issue 2 review | e175 fourth highest prevalence of workplace falls, with rates of 7.9% among dentists, physician assistants, pharmacists and doctors, 5.2% among nurses and 1.3% among dental hygienists, technicians and health aides. certain fall-related risk factors—such as slippery floors, rushing/hurrying and carrying equipment/ objects—were found to contribute to 66.3% of workplace falls.55 various obstetric complications such as placental separation, uterine rupture and fetal death can occur due to fall-related trauma; other possible injuries include fractures, strains, sprains and head injuries.56 musculoskeletal injuries musculoskeletal disorders are commonly reported by nurses and this risk is exacerbated in pregnancy, particularly during late gestation.57,58 the occupational tasks of healthcare workers can contribute to these injuries, such as the need to manually handle patients, pull and push beds and trolleys and move or hold awkward body positions while performing patient care procedures.59 the prevalence of musculoskeletal disorders over a 12-month period was 39% among 200 nurses working at a hospital in ajman, saudi arabia.60 over half of the participants also reported routinely engaging in awkward body positions, working without positional changes and repetitive tasks.60 in addition, working in a confined space has been positively correlated with back pain severity at 34 gestational weeks.12 wrist pain has been reported by 90% of sonographers due to the routine use of transducers for scanning, with grip technique and pressure being contributing factors.61,62 muscle strain is aggravated more by pinch grip compared to power grip, as the former technique applies five times more force than the latter.63 an association has also been established between grip strength and muscle function, with lower grip strength increasing the risk of injury and disability.64 a longitudinal study assessing the hand grip strength of pregnant women reported a significant reduction in grip strength from the first to the third trimester, a finding attributed to the metabolic, musculoskeletal and hormonal changes which occur in pregnancy.65 psychological impact of ergonomic stressors all domains of ergonomics are interconnected; for instance, a poorly designed workstation can create stress, thereby altering behaviour which in turn can induce changes in cognitive function and overall performance.66 although workplace ergonomics primarily focus on physical factors, employers should also consider workers’ mental workload, creativity and productivity. the relationship between environmental risks at work and fetal outcomes remains inconclusive. in general, standard working conditions present little hazard to infant health; however, pregnancy may significantly impact maternal psychosocial wellbeing in the workplace.46 supporting employees through skill development and coping mechanisms is therefore an important component of workplace ergonomics. making suitable adjustments to physical, cognitive and organisational ergonomic domains can help employees to remain efficient during pregnancy. in particular, stress during pregnancy has negative outcomes; as such, psychological assessments and counselling should be performed.67 moreover, previous research indicates an association between poor job control, lack of workplace support and increased levels of workplace stress and the development of depressive symptoms during pregnancy.68 excessive or insufficient workloads, unclear tasks or instructions, poor support and rotating shifts adversely impacts both work quality and pregnancy outcomes.69 r e c o m m e n d e d s a f e t y p r a c t i c e s ergonomic assessment methods employers can utilise various ergonomic assessment methods to ensure an optimised working environment for their employees. they should begin by identifying risks for work-related disorders that stem from poor ergonomic practices, for instance by utilising the computer-based sonex system which predicts the development of work-related musculoskeletal disorders and offers preventive measures to improve a worksite’s ergonomics.70 subsequently, various available programs are available to provide ergonomic consultations and financial support to obtain ergonomic devices, an effective step in reducing musculoskeletal disorders.71 one particularly useful approach is heuristic evaluation, a general ergonomics inspection method based on accepted theoretical principles and past design experience which allows employers to either create their own structured evaluation checklist or use existing checklists.72 with regards to physical ergonomics, posturebased analysis can be employed to help identify areas of concern, with higher scores indicative of poor posture due to deviation from a neutral standing position. specifically, the rapid upper limb assessment (rula) provides a swift evaluation of the potential for upper limb disorders, while the rapid entire body assessment (reba) considers the intensity of work performed by the whole body to evaluate the risk of musculoskeletal disorders.73 both rula and reba assess specific postures during repetitive tasks.73 another potential method is the revised national frincy francis, sheeba e. johnsunderraj, divya k. y, divya raghavan, atiya al-furgani, lily p. bera and aniamma abraham institute for occupational safety and health lifting equation (rnle), an example of a biomechanicsbased assessment which determines maximum weight limitations to prevent overexertion injuries related to manual tasks involving pulling, moving, lifting and transferring.74,75 based on the rnle, a lifting index of >1.0 indicates a high risk of injury.74 conducting regular ergonomics evaluations is necessary to ensure a suitable and safe work envi ronment. ideally, a task force should be formed to conduct routine ergonomic assessments for the purposes of early risk detection.76 while there is currently no published evaluation method specific to pregnant women, the development of such a method would greatly improve the quality of life of pregnant employees. in particular, longer working hours and shift work have major implications for the shortand long-term health of both mothers and their infants.47−53 these findings may help inform decision-making on occupational directives or workplace design for the prevention of adverse pregnancy outcomes. healthcare administrators should plan and conduct awareness programmes regarding the potential impact of ergonomic stressors and poor work posture on employees.77 in addition, the ergonomic safety and comfort of pregnant healthcare workers should be prioritised, especially as working conditions are linked to increased rates of sick leave and absenteeism in this population group.78 fall risk assessments among pregnant workers although fall risk assessments are routinely performed for hospitalised patients, most health institutions do not conduct such assessments for workers. nevertheless, it is highly recommended that fall risk assessments be provided for pregnant healthcare workers due to the high risk of falling for this population group.55 a few examples of fall risk assessment tools for pregnant women include the obstetric fall risk assessment system, the maternity fall risk assessment scale and the fall risk assessment for perinatal patients instrument.79–81 such tools can be modified and used to assess fall risk among pregnant healthcare workers. potential preventative strategies several preventative strategies can be used to address ergonomic stressors in pregnant women, such as maintaining ideal posture, taking frequent breaks and avoiding heavy lifting, loud noises and electromagnetic fields.46,82 potential accommodations to address common ergonomic stressors related to adverse pregnancy risks are shown in table 1.31–39,43– 46,48,52–56,61,64,65,71,78–100 viable solutions to avoid heavy lifting by pregnant healthcare workers include apparatuses to lift and transfer patients, biomechanical training, larger rooms and additional team members for support during patient transfers.83 in particular, hydraulic or power-operated mechanical lifts should be provided to help lift patients from a bed to a stretcher or a chair, with appropriate training for caregivers to minimise risk of injury.84 implementation of a minimal lifting or no lifting policy in healthcare institutions is not only cost-effective, but also results in greater satisfaction and fewer injuries among nursing staff.85,86 according to the american medical association, pregnant workers at ≤24 gestational weeks may safely lift up to 23 kg repetitively; subsequently, the weight limit should be reduced to 11 kg.87 with regards to intermittent lifting, it is safe to lift up to 23 kg, even after 30 gestational weeks.87 as the pregnancy progresses, the abdominal muscles stretch to accommodate the growing fetus, especially in the third trimester. therefore, in order to maintain appropriate body mechanics, workstations should be designed so that the pregnant worker can maintain a reach distance of 38–50 cm. considering this need for additional space is essential when planning clinical workstations in hospitals.88,89 a previous study found that use of a concave desk board while using a computer for 20 minutes helped pregnant women increase muscle activity in their upper right trapezius and decrease muscle activity in the lower back, thus minimising back discomfort in late pregnancy.90 sitstand ergonomic units and standing desks are also potential solutions for alternating work posture while performing repetitive tasks.91,92 prolonged standing among pregnant healthcare professionals should be limited to <3 hours.82 anti-slip flooring can help to prevent falls among pregnant workers; similarly, warning signs should be placed near wet or slippery floors by housekeeping staff. ensuring safety in restrooms is also essential to minimise fall risk. in terms of work attire, pregnant workers should be encouraged to select comfortable work shoes for prolonged standing, with a good base and no laces to reduce the risk of slipping or tripping.93 finally, the first line of defence in preventing infection, especially when exposed to biological agents such as cytomegalovirus, is adherence to universal precautions like hand hygiene and use of personal protective equipment. it is also essential to minimise the risk of work-to-home contamination by requiring workers to change clothes at their workplace and providing laundry services.94 implications for practice in oman globally, the number of female healthcare professionals has increased, especially in medicine.1,2 a similar trend has been reported in oman, with women accounting ergonomic stressors among pregnant healthcare workers impact on pregnancy outcomes and recommended safety practices e176 | squ medical journal, may 2021, volume 21, issue 2 review | e177 for 64% of medical students at the sultan qaboos university in 2015, 61.5% of resident doctors employed by the ministry of health and 42% of all doctors.101 various ergonomic deficiencies were also identified in a survey of typical offices in oman including issues related to workstation design, furniture and working hours; in addition, the survey participants reported major health problems including eyestrain (58%), shoulder pain (45%), back pain (43%), arm pain (35%) and neck pain (30%).102 table 1: impact of ergonomic stressors during pregnancy and recommended practices31–39,43–46,48,52–56,61,64,65,71,78–100 ergonomic stressor risk in pregnancy recommended practice for safety work shifts (evening/ night shifts) • preterm delivery • sga babies • gestational htn • avoid night shifts • permit convenient shift changes prolonged working hours (≥40 hours/week) • iugr • preterm delivery • dehydration • threatened miscarriage • instrumental delivery due to maternal exhaustion • reassign shifts • reduce working hours to 6 hours per day prolonged standing (≥3 hours) • decreased fetal growth rate • provide sit-stand ergonomic units or ergonomic chairs with footrests • limit continuous standing to <3 hours prolonged bending • increased back pain • provide a chair with minimal rocking facilities to alter the centre of gravity overexertion (physically demanding work) • preterm delivery • lbw babies • decreased fetal growth rate • reduce physical demands in the workplace • ensure minimal physical strain lifting, moving and transferring • musculoskeletal injuries • maternal exhaustion • lbw babies • provide additional staff support • install hydraulic or power-operated mechanical lifts • implement a no lifting policy body posture issues (repetitive jobs and awkward positions) • lower back pain • pelvic girdle pain • wrist pain • muscle spasms • sprains • altered grip strength • consider a reach distance of 38–50 cm in workstation layouts, particularly in the third trimester • alternate posture/position every 2 hours • install concave desk boards for computers occupational fatigue • prom • preterm delivery • caesarean section delivery due to maternal exhaustion • take a 10-minute break every hour • provide comfortable rest rooms • avoid night shifts work-related falls • placental separation • uterine rupture • fetal death • fractures • injuries • conduct mandatory fall risk assessments • install anti-slip flooring • place caution boards near wet floors • wear comfortable shoes high noise exposure (>85 decibels) • lbw babies • avoid loud or noisy environments exposure to biological and chemical agents • infertility • birth defects • decreased fetal growth rate • impaired fetal brain development • preterm delivery • lbw babies • miscarriage • developmental disorders • implement mandatory universal precautions (i.e. handwashing, wearing ppe, etc.) • minimise the possibility of work-to-home contamination exposure to ionising radiation • miscarriage • lbw babies • preterm delivery • birth defects • wear appropriate ppe stress • decreased psychological wellbeing • depression • gestational htn • conduct routine psychological assessments and counselling sessions • ensure a supportive work environment sga = small for gestational age; htn = hypertension; iugr = intrauterine growth restriction; lbw = low birth weight; prom = premature rupture of the membranes; ppe = personal protective equipment. frincy francis, sheeba e. johnsunderraj, divya k. y, divya raghavan, atiya al-furgani, lily p. bera and aniamma abraham accordingly, a health and safety management system should be implemented to help identify, prevent, treat and mitigate ergonomic-related hazards posing a threat to pregnant healthcare workers in oman. ideally, this system should proactively assess and correct identified hazards before workers are injured or become ill.103 this can be achieved through a comprehensive programme to promote the safe lifting, handling and transfer of patients. such a programme would require focused management leadership, participation from employees, early hazard appraisal, anticipation and control, education and training and routine evaluation and improvement activities.105 ergonomic measures without sufficient management support have shown to have limited success in reducing work related health problems in healthcare workers.106 currently, there is a dearth of research concerning ergonomic stressors and its impact on pregnant workers in the gcc region, particularly for those in healthcare occupations. statistical data are necessary to determine the impact of ergonomic stressors on work-related injuries, absenteeism and job turnover in order to assess and mitigate these issues. as such, a well-planned evidence-based ergonomic analysis of pregnant healthcare employees in oman is recommended to determine how ergonomic principles impact the occupational safety and productivity of this population group. conclusion this review sought to assess the impact of various ergonomic stressors on pregnancy outcomes among healthcare workers. reducing work-related risks for pregnant workers can increase employee productivity and safety in healthcare units, whereas poor workrelated ergonomics can have serious maternal and fetal consequences including spontaneous abortions, preterm delivery, low birth weight babies and infertility. in order for policymakers to address these concerns, a national research-based ergonomic analysis must be performed to assess the effects of ergonomic stressors on the health and safety of pregnant workers in oman, specifically those employed in healthcare settings. references 1. world health organization. world health report: health workers chapter one: a global profile. from: https://www.who.int/ whr/2006/06_chap1_en.pdf accessed: aug 2020. 2. joseph b, joseph m. the health of the healthcare workers. indian j occup environ med 2016; 20:71–2. https://doi.org/10.4103/0 019-5278.197518. 3. rushton l. the global burden of occupational disease. curr environ health rep 2017; 4:340–8. https://doi.org/10.1007/ s40572-017-0151-2. 4. dong h, zhang q, liu g, shao t, xu y. prevalence and associated factors of musculoskeletal disorders among chinese healthcare professionals working in tertiary hospitals: a crosssectional study. bmc musculoskelet disord 2019; 20:175. https://doi.org/10.1186/s12891-019-2557-5. 5. salvendy g, ed. handbook of human factors and ergonomics, 4th ed. hoboken, new jersey, usa: wiley, 2012. https://doi. org/10.1002/9781118131350. 6. pheasant s, haslegrave cm. bodyspace: anthropometry, ergo nomics and the design of work, 3rd ed. boca raton, florida, usa: crc press, 2005. 7. hamid a, ahmad as, dar s, sohail s, akram f, qureshi mi. ergonomics hazards and musculoskeletal disorders among workers of health care facilities. curr world environ 2018; 13:251–8. https://doi.org/10.12944/cwe.13.2.10. 8. karwowski w. ergonomics and human factors: the paradigms for science, engineering, design, technology and management of human-compatible systems. ergonomics 2005; 48:436–63. https://doi.org/10.1080/00140130400029167. 9. buckle p. ergonomics and musculoskeletal disorders: overview. occup med (london) 2005; 55:164–7. https://doi.org/10.1093/ occmed/kqi081. 10. zakerian sa, monazzam mr, dehghan sf, mohraz mh, safari h, asghari m. relationship between knowledge of ergonomics and workplace condition with musculoskeletal disorders among nurses. world appl sci j 2013; 24:227–33. https://doi. org/10.5829/idosi.wasj.2013.24.02.651. 11. adinma ji, adinma ed, umeononihu os, oguaka v, adinmaobiajulu nd, oyedum so. prevalence, perception and risk factors for musculoskeletal discomfort among pregnant women in southeast nigeria. j musculoskelet disord treat 2018; 4:63. https://doi.org/10.23937/2572-3243.1510063. 12. tapp lm. the pregnant worker and ergonomics. in asse professional development conference and exposition 2001 jan 1. american society of safety engineers. downloaded from http://onepetro.org/assppdce/proceedings-pdf/asse01/ a l l a s se 0 1 / a s se 0 1 6 2 5 / 1 8 9 5 9 3 3 / a s s e 0 1 6 2 5 . p d f / 1 accessed: aug 2020 13. rogers b, buckheit k, ostendorf j. ergonomics and nursing in hospital environments. workplace health saf 2013; 61:429–39. https://doi.org/10.1177/216507991306101003. 14. cheng pl, pantel m, smith jt, dumas ga, leger ab, plamondon a, et al. back pain of working pregnant women: identification of associated occupational factors. appl ergon 2009; 40:419–23. https://doi.org/10.1016/j.apergo.2008.11.002. 15. hadfield r. pearl growing as a strategy in systematic literature searches. from: https://www.mediwrite.com.au/medical-writi ng/pearl-growing/ accessed: aug 2020. 16. yoo h, shin d, song c. changes in the spinal curvature, degree of pain, balance ability, and gait ability according to pregnancy period in pregnant and non-pregnant women. j phys ther sci 2015; 27:279–84. https://doi.org/10.1589/jpts.27.279. 17. soma-pillay p, nelson-piercy c, tolppanen h, mebazaa a. physiological changes in pregnancy. cardiovasc j afr 2016; 27:89–94. https://doi.org/10.5830/cvja-2016-021. 18. muallem mm, rubeiz ng. physiological and biological skin changes in pregnancy. clin dermatol 2006; 24:80–3. https:// doi.org/10.1016/j.clindermatol.2005.10.002. 19. yikar sk, nazik e. the effect of complaints during pregnancy on quality of life. int j caring sci 2018; 11:623–6. 20. huizink ac, de medina pg, mulder ej, visser gh, buitelaar jk. coping in normal pregnancy. ann behav med 2002; 24:132–40. https://doi.org/10.1207/s15324796abm2402_10. ergonomic stressors among pregnant healthcare workers impact on pregnancy outcomes and recommended safety practices e178 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.4103/0019-5278.197518 https://doi.org/10.4103/0019-5278.197518 https://doi.org/10.1007/s40572-017-0151-2 https://doi.org/10.1007/s40572-017-0151-2 https://doi.org/10.1186/s12891-019-2557-5 https://doi.org/10.1002/9781118131350 https://doi.org/10.1002/9781118131350 https://doi.org/10.12944/cwe.13.2.10 https://doi.org/10.1080/00140130400029167 https://doi.org/10.1093/occmed/kqi081 https://doi.org/10.1093/occmed/kqi081 https://doi.org/10.5829/idosi.wasj.2013.24.02.651 https://doi.org/10.5829/idosi.wasj.2013.24.02.651 https://doi.org/10.23937/2572-3243.1510063 https://doi.org/10.1177/216507991306101003 https://doi.org/10.1016/j.apergo.2008.11.002 https://doi.org/10.1589/jpts.27.279 https://doi.org/10.5830/cvja-2016-021 https://doi.org/10.1016/j.clindermatol.2005.10.002 https://doi.org/10.1016/j.clindermatol.2005.10.002 https://doi.org/10.1207/s15324796abm2402_10 review | e179 21. alzboon g, vural g. factors influencing the quality of life of healthy pregnant women in north jordan. medicina (kaunas) 2019; 55:278. https://doi.org/10.3390/medicina55060278. 22. buen m, amaral e, souza rt, passini r jr, lajos gj, tedesco rp, et al. maternal work and spontaneous preterm birth: a multicenter observational study in brazil. sci rep 2020; 10:9684. https://doi.org/10.1038/s41598-020-66231-2. 23. błaszczyk jw, opala-berdzik a, plewa m. adaptive changes in spatiotemporal gait characteristics in women during pregnancy. gait posture 2016; 43:160–4. https://doi.org/10.1016/j.gaitpo st.2015.09.016. 24. okanishi n, kito n, akiyama m, yamamoto m. spinal curv ature and characteristics of postural change in pregnant women. acta obstet gynecol scand 2012; 91:856–61. https://doi.org/10.1 111/j.1600-0412.2012.01400.x. 25. dehghan f, haerian bs, muniandy s, yusof a, dragoo jl, salleh n. the effect of relaxin on the musculoskeletal system. scand j med sci sports 2014; 24:e220–9. https://doi.org/10.1111/ sms.12149. 26. inklebarger j, galanis n, michael j, gyer g. pregnancy-related hormonal influences on the musculoskeletal system, lumbopelvic structures and peripheral joints: some practical consider ations for manual therapists. int j med sci clin inventions 2017; 4:2816–22. https://doi.org/10.18535/ijmsci/v4i4.01. 27. motosko cc, bieber ak, pomeranz mk, stein ja, martires kj. physiologic changes of pregnancy: a review of the literature. int j womens dermatol 2017; 3:219–24. https://doi.org/10.1016/j. ijwd.2017.09.003. 28. taşkıran n. pregnancy and sleep quality. j turk soc obstet gynecol 2011; 8:181–7. https://doi.org/10.5505/tjod.2011.14880. 29. lawson cc, whelan ea, hibert en, grajewski b, spiegelman d, rich-edwards jw. occupational factors and risk of preterm birth in nurses. am j obst gynecol 2009; 200:51.e1–8. https:// doi.org/10.1016/j.ajog.2008.08.006. 30. shaw p, duncan a, vouyouka a, ozsvath k. radiation exposure and pregnancy. j vasc surg 2011; 53:28s–34s. https://doi. org/10.1016/j.jvs.2010.05.140. 31. banerjee b. physical hazards in employment and pregnancy outcome. indian j community med 2009; 34:89–93. https:// doi.org/10.4103/0970-0218.51224. 32. lawson cc, rocheleau cm, whelan ea, hibert en, grajewski b, spiegelman d, et al. occupational exposures among nurses and risk of spontaneous abortion. am j obst gynecol 2012; 206:e1–8. https://doi.org/10.1016/j.ajog.2011.12.030. 33. gilani s, giridharan s. is it safe for pregnant health-care professionals to handle cytotoxic drugs? a review of the literature and recommendations. ecancermedicalscience 2014; 8:418. https://doi.org/10.3332/ecancer.2014.418. 34. sobaszek a, fantoni-quinton s, frimat p, leroyer a, laynat a, edme jl. prevalence of cytomegalovirus infection among health care workers in pediatric and immunosuppressed adult units. j occup environ med 2000; 42:1109–14. https://doi. org/10.1097/00043764-200011000-00015. 35. lerman y, jacubovich r, green ms. pregnancy outcome following exposure to shortwaves among female physiotherapists in israel. am j ind med 2001; 39:499–504. https://doi.org/10.1002/ ajim.1043. 36. zhu jl, knudsen le, andersen am, hjollund nh, olsen j. laboratory work and pregnancy outcomes: a study within the national birth cohort in denmark. occup environ med 2006; 63:53–8. https://doi.org/10.1136/oem.2005.021204. 37. caruso cc. reducing risks to women linked to shift work, long work hours, and related workplace sleep and fatigue issues. j womens health (larchmt) 2015; 24:789–94. https://doi. org/10.1089/jwh.2015.5481. 38. escribá-agüir v, perez-hoyos s, saurel-cubizolles mj. physical load and psychological demand at work during pregnancy and preterm birth. int arch occup environ health 2001; 74:583–8. https://doi.org/10.1007/s004200100259. 39. hathout hm, el-dalatony mm, anwar mm, al-batanony ma, shehata na. work related risk factors and pregnancy outcome between working women. egypt j occup med 2015; 39:119–33. https://doi.org/10.21608/ejom.2015.815. 40. juhl m, strandberg-larsen k, larsen ps, andersen pk, svendsen sw, bonde jp, et al. occupational lifting during pregnancy and risk of fetal death in a large national cohort study. scand j work environ health 2013; 39:335–42. https://doi.org/10.5271/ sjweh.3335. 41. bonde jp, jørgensen kt, bonzini m, palmer kt. risk of mis carriage and occupational activity: a systematic review and meta-analysis regarding shift work, working hours, lifting, standing and physical workload. scand j work environ health 2013; 39:325–34. https://doi.org/10.5271/sjweh.3337. 42. lee w, jung sw, lim ym, lee kj, lee jh. spontaneous and repeat spontaneous abortion risk in relation to occupational characteristics among working korean women: a crosssectional analysis of nationally representative data from korea. bmc public health 2019; 19:1339. https://doi.org/10.1186/ s12889-019-7728-7. 43. burdorf a, brand t, jaddoe vw, hofman a, mackenbach jp, steegers ea. the effects of work-related maternal risk factors on time to pregnancy, preterm birth and birth weight: the generation r study. occup environ med 2011; 68:197–204. https://doi.org/10.1136/oem.2009.046516. 44. hunicke r, roberts e, roberts l. how do we know if a worksite is safe for a pregnant worker? in: teratology primer, 3rd ed. reston, virginia, usa: society for birth defects research & prevention, 2007. 45. hohmann c, grabenhenrich l, de kluizenaar y, tischer c, heinrich j, chen cm, et al. health effects of chronic noise exposure in pregnancy and childhood: a systematic review initiated by enrieco. int j hyg environ health 2013; 216:217–29. https://doi.org/10.1016/j.ijheh.2012.06.001. 46. salihu hm, myers j, august em. pregnancy in the workplace. occup med (lond) 2012; 62:88–97. https://doi.org/10.1093/ occmed/kqr198. 47. mozurkewich el, luke b, avni m, wolf fm. working conditions and adverse pregnancy outcome: a meta-analysis. obstet gynecol 2000; 95:623–35. https://doi.org/10.1016/s00 29-7844(99)00598-0. 48. snijder ca, brand t, jaddoe v, hofman a, mackenbach jp, steegers ea, et al. physically demanding work, fetal growth and the risk of adverse birth outcomes: the generation r study. occup environ med 2012; 69:543–50. https://doi.org/10.1136/ oemed-2011-100615. 49. croteau a, marcoux s, brisson c. work activity in pregnancy, preventive measures, and the risk of delivering a small-forgestational-age infant. am j public health 2006; 96:846–55. https://doi.org/10.2105/ajph.2004.058552. 50. hamilton ar, tyson md, braga ja, lerner lb. childbearing and pregnancy characteristics of female orthopaedic surgeons. j bone joint surg am 2012; 94:e77. https://doi.org/10.2106/ jbjs.k.00707. 51. lerner lb, stolzmann kl, gulla vd. birth trends and pregnancy complications among women urologists. j am coll surg 2009; 208:293–7. https://doi.org/10.1016/j.jamcollsurg.2008.10.012. 52. palmer kt, bonzini m, harris ec, linaker c, bonde jp. work activities and risk of prematurity, low birth weight and preeclampsia: an updated review with meta-analysis. occup environ med 2013; 70:213–22. https://doi.org/10.1136/oemed-2012-101032. frincy francis, sheeba e. johnsunderraj, divya k. y, divya raghavan, atiya al-furgani, lily p. bera and aniamma abraham https://doi.org/10.3390/medicina55060278 https://doi.org/10.1038/s41598-020-66231-2 https://doi.org/10.1016/j.gaitpost.2015.09.016 https://doi.org/10.1016/j.gaitpost.2015.09.016 https://doi.org/10.1111/j.1600-0412.2012.01400.x https://doi.org/10.1111/j.1600-0412.2012.01400.x https://doi.org/10.1111/sms.12149 https://doi.org/10.1111/sms.12149 https://doi.org/10.18535/ijmsci/v4i4.01 https://doi.org/10.1016/j.ijwd.2017.09.003 https://doi.org/10.1016/j.ijwd.2017.09.003 https://doi.org/10.5505/tjod.2011.14880 https://doi.org/10.1016/j.ajog.2008.08.006 https://doi.org/10.1016/j.ajog.2008.08.006 https://doi.org/10.1016/j.jvs.2010.05.140 https://doi.org/10.1016/j.jvs.2010.05.140 https://doi.org/10.4103/0970-0218.51224 https://doi.org/10.4103/0970-0218.51224 https://doi.org/10.1016/j.ajog.2011.12.030 https://doi.org/10.3332/ecancer.2014.418 https://doi.org/10.1097/00043764-200011000-00015 https://doi.org/10.1097/00043764-200011000-00015 https://doi.org/10.1002/ajim.1043 https://doi.org/10.1002/ajim.1043 https://doi.org/10.1136/oem.2005.021204 https://doi.org/10.1089/jwh.2015.5481 https://doi.org/10.1089/jwh.2015.5481 https://doi.org/10.1007/s004200100259 https://doi.org/10.21608/ejom.2015.815 https://doi.org/10.5271/sjweh.3335 https://doi.org/10.5271/sjweh.3335 https://doi.org/10.5271/sjweh.3337 https://doi.org/10.1186/s12889-019-7728-7 https://doi.org/10.1186/s12889-019-7728-7 https://doi.org/10.1136/oem.2009.046516 https://doi.org/10.1016/j.ijheh.2012.06.001 https://doi.org/10.1093/occmed/kqr198 https://doi.org/10.1093/occmed/kqr198 https://doi.org/10.1016/s0029-7844%2899%2900598-0 https://doi.org/10.1016/s0029-7844%2899%2900598-0 https://doi.org/10.1136/oemed-2011-100615 https://doi.org/10.1136/oemed-2011-100615 https://doi.org/10.2105/ajph.2004.058552 https://doi.org/10.2106/jbjs.k.00707 https://doi.org/10.2106/jbjs.k.00707 https://doi.org/10.1016/j.jamcollsurg.2008.10.012 https://doi.org/10.1136/oemed-2012-101032 53. newman rb, goldenberg r,l moawad ah, iams jd, meis pj, das a, et al. occupational fatigue and preterm premature rupture of membranes: national institute of child health and human development maternal-fetal medicine, units network. am j obstet gynecol 2001; 184:438–46. https://doi. org/10.1067/mob.2001.110312. 54. hung s, morrison dr, whittington la, fein sb. prepartum work, job characteristics, and risk of cesarean delivery. birth 2002; 29:10–17. https://doi.org/10.1046/j.1523-536x.2002.00150.x. 55. dunning k, lemasters g, levin l, bhattacharya a, alterman t, lordo k. falls in workers during pregnancy: risk factors, job hazards, and high risk occupations. am j ind med 2003; 44:664–72. https://doi.org/10.1002/ajim.10318. 56. curet mj, schermer cr, demarest gb, bieneik ej 3rd, curet lb. predictors of outcome in trauma during pregnancy: identif ication of patients who can be monitored for less than 6 hours. j trauma 2000; 49:18–25. https://doi.org/10.1097/00005373200007000-00003. 57. taghinejad h, azadi a, suhrabi z, sayedinia m. musculoskeletal disorders and their related risk factors among iranian nurses. biotechnol health sci 2016; 3:e34473. https://doi.org/10.17795/ bhs-34473. 58. alex mr. occupational hazards for pregnant nurses. am j nurs 2011; 111:28–37. https://doi.org/10.1097/01.naj.000039 3056.01687.40. 59. waters t, collins j, galinsky t, caruso c. niosh research efforts to prevent musculoskeletal disorders in the healthcare industry. orthop nurs 2006; 25:380–9. https://doi.org/10.10 97/00006416-200611000-00007. 60. gopal k, thomas m, sreedharan j. work-related musculoskeletal disorders (wmsd) in hospital nurses: prevalence and coping strategies. in: 4th annual scientific meeting of gulf medical university oral proceedings 2012. gulf med j 2012; 1:s159–63. 61. evans k, roll s, baker j. work-related musculoskeletal dis orders (wrmsd) among registered diagnostic medical sono graphers and vascular technologists: a representative sample. j diagn med sonogr 2009; 25:287–99. https://doi.org/10.1177/87 56479309351748. 62. harrison g, harris a. work-related musculoskeletal disorders in ultrasound: can you reduce risk? ultrasound 2015; 23:224–30. https://doi.org/10.1177/1742271x15593575. 63. hill jj 3rd, slade md, russi mb. anthropometric measurements, job strain, and prevalence of musculoskeletal symptoms in female medical sonographers. work 2009; 33:181–9. https:// doi.org/10.3233/wor-2009-0865. 64. roberts hc, denison hj, martin hj, patel hp, syddall h, cooper c, et al. a review of the measurement of grip strength in clinical and epidemiological studies: towards a standardized approach. age ageing 2011; 40:423–9. https://doi.org/10.1093/ ageing/afr051. 65. żelaźniewicz a, pawłowski b. maternal hand grip strength in pregnancy, newborn sex and birth weight. early hum dev 2018; 119:51–5. https://doi.org/10.1016/j.earlhumdev.2018.03.004. 66. tanja-dijkstra k, pieterse me. the psychological effects of the physical healthcare environment on healthcare personnel. cochrane database syst rev 2011; 1:cd006210. https://doi. org/10.1002/14651858.cd006210.pub3. 67. glover v. maternal depression, anxiety and stress during preg nancy and child outcome: what needs to be done. best pract res clin obstet gynaecol 2014; 28:25–35. https://doi.org/10.10 16/j.bpobgyn.2013.08.017. 68. yeh ss, lee cn, wu yh, tu nc, guo yl, chen pc, et al. occupational hazard exposures and depressive symptoms of pregnant workers. j occup environ med 2018; 60:e134–8. https://doi.org/10.1097/jom.0000000000001255. 69. yang hj, kao fy, chou yj, huang n, chang ky, chien ly. do nurses have worse pregnancy outcomes than non-nurses? birth 2014; 41:262–7. https://doi.org/10.1111/birt.12118. 70. pavlovic-veselinovic s, hedge a, veselinovic m. an ergonomic expert system for risk assessment of work-related musculoskeletal disorders. int j ind ergon 2016; 53:130–9. https://doi. org/10.1016/j.ergon.2015.11.008. 71. fujishiro k, weaver jl, heaney ca, hamrick ca, marras ws. the effect of ergonomic interventions in healthcare facilities on musculoskeletal disorders. am j ind med 2005; 48:338–47. https://doi.org/10.1002/ajim.20225. 72. butlewski m. heuristic methods aiding ergonomic design. in: stephanidis c, antona m (eds). universal access in humancomputer interaction: design methods, tools, and interaction techniques for e-inclusion. berlin, heidelberg: springer, 2013. pp. 13–20. https://doi.org/10.1007/978-3-642-39188-0_2. 73. ansari na, sheikh mj. evaluation of work posture by rula and reba: a case study. iosr j mech civ eng 2014; 11:18–23. https://doi.org/10.9790/1684-11431823. 74. waters t, occhipinti e, colombini d, alvarez-casado e, fox r. variable lifting index (vli): a new method for evaluating variable lifting tasks. hum factors 2016; 58:695–711. https:// doi.org/10.1177/0018720815612256. 75. waters tr, macdonald la, hudock sd, goddard de. prov isional recommended weight limits for manual lifting during pregnancy. hum factors 2014; 56:203–14. https://doi.org/10.11 77/0018720813502223. 76. abedini r, choobineh ar, hasanzadeh j. patient manual handling risk assessment among hospital nurses. work 2015; 50:669–75. https://doi.org/10.3233/wor-141826. 77. janowitz il, gillen m, ryan g, rempel d, trupin l, swig l, et al. measuring the physical demands of work in hospital settings: design and implementation of an ergonomics assessment. appl ergon 2006; 37:641–58. https://doi.org/10.1016/j.apergo.2005.08.004. 78. villar r, serra l, serra c, benavides fg. working conditions and absence from work during pregnancy in a cohort of healthcare workers. occup environ med 2019; 76:236–42. https://doi.org/10.1136/oemed-2018-105369. 79. heafner l, suda d, casalenuovo n, leach ls, erickson v, gawlinski a. development of a tool to assess risk for falls in women in hospital obstetric units. nurs womens health 2013; 17:98–107. https://doi.org/10.1111/1751-486x.12018. 80. xu m, tan w, li q, cheng s. design, application and eval uation of maternal fall risk assessment scale. biomed res 2017; 28:1315–20. 81. hutcheson j, waggoner b. development of falls risk tool specific to obstetric patients. in: abstracts presented at the national neonatal, advanced practice, and national mother baby nurses conference las vegas, nv, september 13-16, 2017. neonatal netw 2017; 36:e33. https://doi.org/10.1891/0730-0832.36.6.e18. 82. karol s, robertson mm. implications of sit-stand and active workstations to counteract the adverse effects of sedentary work: a comprehensive review. work 2015; 52:255–67. https:// doi.org/10.3233/wor-152168. 83. vieira er, kumar s, coury hj, narayan y. low back problems and possible improvements in nursing jobs. j adv nurs 2006; 55:79–89. https://doi.org/10.1111/j.1365-2648.2006.03877.x. 84. li j, wolf l, evanoff b. use of mechanical patient lifts decreased musculoskeletal symptoms and injuries among health care workers. inj prev 2004; 10:212–16. https://doi.org/10.1136/ ip.2003.004978. 85. carlson ea. safe patient handling and movement: a guide for nurses and other health care providers. orthop nurs 2008; 27:153. https://doi.org/10.1097/01.nor.0000315634.76417.c4. ergonomic stressors among pregnant healthcare workers impact on pregnancy outcomes and recommended safety practices e180 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1067/mob.2001.110312 https://doi.org/10.1067/mob.2001.110312 https://doi.org/10.1046/j.1523-536x.2002.00150.x https://doi.org/10.1002/ajim.10318 https://doi.org/10.1097/00005373-200007000-00003 https://doi.org/10.1097/00005373-200007000-00003 https://doi.org/10.17795/bhs-34473 https://doi.org/10.17795/bhs-34473 https://doi.org/10.1097/01.naj.0000393056.01687.40 https://doi.org/10.1097/01.naj.0000393056.01687.40 https://doi.org/10.1097/00006416-200611000-00007 https://doi.org/10.1097/00006416-200611000-00007 https://doi.org/10.1177/8756479309351748 https://doi.org/10.1177/8756479309351748 https://doi.org/10.1177/1742271x15593575 https://doi.org/10.3233/wor-2009-0865 https://doi.org/10.3233/wor-2009-0865 https://doi.org/10.1093/ageing/afr051 https://doi.org/10.1093/ageing/afr051 https://doi.org/10.1016/j.earlhumdev.2018.03.004 https://doi.org/10.1002/14651858.cd006210.pub3 https://doi.org/10.1002/14651858.cd006210.pub3 https://doi.org/10.1016/j.bpobgyn.2013.08.017 https://doi.org/10.1016/j.bpobgyn.2013.08.017 https://doi.org/10.1097/jom.0000000000001255 https://doi.org/10.1111/birt.12118 https://doi.org/10.1016/j.ergon.2015.11.008 https://doi.org/10.1016/j.ergon.2015.11.008 https://doi.org/10.1002/ajim.20225 https://doi.org/10.1007/978-3-642-39188-0_2 https://doi.org/10.9790/1684-11431823 https://doi.org/10.1177/0018720815612256 https://doi.org/10.1177/0018720815612256 https://doi.org/10.1177/0018720813502223 https://doi.org/10.1177/0018720813502223 https://doi.org/10.3233/wor-141826 https://doi.org/10.1016/j.apergo.2005.08.004 https://doi.org/10.1136/oemed-2018-105369 https://doi.org/10.1111/1751-486x.12018 https://doi.org/10.1891/0730-0832.36.6.e18 https://doi.org/10.3233/wor-152168 https://doi.org/10.3233/wor-152168 https://doi.org/10.1111/j.1365-2648.2006.03877.x https://doi.org/10.1136/ip.2003.004978 https://doi.org/10.1136/ip.2003.004978 https://doi.org/10.1097/01.nor.0000315634.76417.c4 review | e181 86. engkvist il. evaluation of an intervention comprising a no lifting policy in australian hospitals. appl ergon 2006; 37:141–8. https://doi.org/10.1016/j.apergo.2005.05.008. 87. macdonald la, waters tr, napolitano pg, goddard de, ryan ma, nielsen p, et al. clinical guidelines for occupational lifting in pregnancy: evidence summary and provisional recomm endations. am j obstet gynecol 2013; 209:80–8. https://doi. org/10.1016/j.ajog.2013.02.047. 88. nelson a, matz m, chen f, siddharthan k, lloyd j, fragala g. development and evaluation of a multifaceted ergonomics program to prevent injuries associated with patient handling tasks. int j nurs stud 2006; 43:717–33. https://doi.org/10.1016/j. ijnurstu.2005.09.004. 89. szeto gp, wong tk, law rk, lee ew, lau t, so bc, et al. the impact of a multifaceted ergonomic intervention program on promoting occupational health in community nurses. appl ergon 2013; 44:414–22. https://doi.org/10.1016/j.apergo.2012.10.004. 90. dumas ga, upjohn tr, delisle a, charpentier k, leger a, plamondon a, et al. posture and muscle activity of pregnant women during computer work and effect of an ergonomic desk board attachment. int j ind ergon 2009; 39:313–25. https://doi. org/10.1016/j.ergon.2008.03.003. 91. danquah ih, kloster s, holtermann a, aadahl m, bauman a, ersbøll ak, et al. take a stand! a multi-component intervention aimed at reducing sitting time among office workers: a cluster randomized trial. int j epidemiol 2016; 46:128–40. https://doi. org/10.1093/ije/dyw009. 92. finch le, tomiyama aj, ward a. taking a stand: the effects of standing desks on task performance and engagement. int j environ res public health 2017; 14:939. https://doi.org/10.33 90/ijerph14080939. 93. szeto gp, law ky, lee e, lau t, chan sy, law sw. multifaceted ergonomic intervention programme for community nurses: pilot study. j adv nurs 2010; 66:1022–34. https://doi.org/10.11 11/j.1365-2648.2009.05255.x. 94. cannon mj, davis kf. washing our hands of the congenital cytomegalovirus disease epidemic. bmc public health 2005; 5:70. https://doi.org/10.1186/1471-2458-5-70. 95. pompeii la, savitz da, evenson kr, rogers b, mcmahon m. physical exertion at work and the risk of preterm delivery and smallfor-gestational-age birth. obstet gynecol 2005; 106:1279–88. https://doi.org/10.1097/01.aog.0000189080.76998.f8. 96. van beukering md, van melick mj, mol bw, frings-dresen mh, hulshof ct. physically demanding work and preterm delivery: a systematic review and meta-analysis. int arch occup environ health 2014; 87:809–34. https://doi.org/10.1007/s00420-0130924-3. 97. anand n, gandhi a, varma v, kaur s. ergonomically designed workstation for pregnant workers in apparel industry. iosr j humanit soc sci 2014; 19:14–23. https://doi.org/10.9790/083719561423. 98. cai c, vandermeer b, khurana r, nerenberg k, featherstone r, sebastianski m, et al. the impact of occupational shift work and working hours during pregnancy on health outcomes: a systematic review and meta-analysis. am j obstet gynecol 2019; 221:563–76. https://doi.org/10.1016/j.ajog.2019.06.051. 99. suzumori n, ebara t, matsuki t, yamada y, kato s, omori t, et al. effects of long working hours and shift work during pregnancy on obstetric and perinatal outcomes: a large prospective cohort study japan environment and children’s study. birth 2020; 47:67–79. https://doi.org/10.1111/birt.12463. 100. specht io, hammer pe, flachs em, begtrup lm, larsen ad, hougaard ks, et al. night work during pregnancy and preterm birth: a large register-based cohort study. plos one 2019; 14:e0215748. https://doi.org/10.1371/journal.pone.0215748. 101. mohamed na, abdulhadi nn, al-maniri an, al-lawati nr, al-qasmi am. the trend of feminization of doctors’ workforce in oman: is it a phenomenon that could rouse the health system? hum resour health 2018; 16:19. https://doi.org/10.1186/s12 960-018-0283-y. 101. shikdar aa, al-kindi ma. office ergonomics: deficiencies in computer workstation design. int j occup saf ergon 2007; 13:215–23. https://doi.org/10.1080/10803548.2007.11076722. 103. springer t. ergonomics for healthcare environments. from: https ://skgtexas .com/wp-content/uploads/2020/04/healt hcare_ergonomics.pdf accessed: aug 2020. 104. van der beek aj, dennerlein jt, huysmans ma, mathiassen se, burdorf a, van mechelen w, et al. a research framework for the development and implementation of interventions preventing work-related musculoskeletal disorders. scand j work environ health 2017; 43:526–39. https://doi.org/10.5271/sjweh.3671. 105. coskun beyan a, dilek b, demiral y. the effects of multifaceted ergonomic interventions on musculoskeletal complaints in intensive care units. int j environ res public health 2020; 17:3719. https://doi.org/10.3390/ijerph17103719. frincy francis, sheeba e. johnsunderraj, divya k. y, divya raghavan, atiya al-furgani, lily p. bera and aniamma abraham https://doi.org/10.1016/j.apergo.2005.05.008 https://doi.org/10.1016/j.ajog.2013.02.047 https://doi.org/10.1016/j.ajog.2013.02.047 https://doi.org/10.1016/j.ijnurstu.2005.09.004 https://doi.org/10.1016/j.ijnurstu.2005.09.004 https://doi.org/10.1016/j.apergo.2012.10.004 https://doi.org/10.1016/j.ergon.2008.03.003 https://doi.org/10.1016/j.ergon.2008.03.003 https://doi.org/10.1093/ije/dyw009 https://doi.org/10.1093/ije/dyw009 https://doi.org/10.3390/ijerph14080939 https://doi.org/10.3390/ijerph14080939 https://doi.org/10.1111/j.1365-2648.2009.05255.x https://doi.org/10.1111/j.1365-2648.2009.05255.x https://doi.org/10.1186/1471-2458-5-70 https://doi.org/10.1097/01.aog.0000189080.76998.f8 https://doi.org/10.1007/s00420-013-0924-3 https://doi.org/10.1007/s00420-013-0924-3 https://doi.org/10.9790/0837-19561423 https://doi.org/10.9790/0837-19561423 https://doi.org/10.1016/j.ajog.2019.06.051 https://doi.org/10.1111/birt.12463 https://doi.org/10.1371/journal.pone.0215748 https://doi.org/10.1186/s12960-018-0283-y https://doi.org/10.1186/s12960-018-0283-y https://doi.org/10.1080/10803548.2007.11076722 https://doi.org/10.5271/sjweh.3671 https://doi.org/10.3390/ijerph17103719 1 submitted 22 jan 23 1 revision req. 20 mar 23; revision recd. 2 apr 23 2 accepted 16 may 23 3 online-first: july 2023 4 doi: https://doi.org/10.18295/squmj.7.2023.043 5 6 robotic appendicectomy 7 a review of feasibility 8 hossein arang1 and *michael el boghdady2,3 9 10 1king’s college nhs foundation trust, london, uk; 2department of general surgery, guys’ 11 and st thomas’ hospital nhs foundation trust, london, uk; 3university of edinburgh, 12 scotland, uk. 13 *corresponding author’s e-mail: michael.elboghdady@nhs.net 14 15 abstract 16 acute appendicitis is one of the most common abdominal emergencies. there has been an 17 increasing trend in the use of robotic surgery in abdominal surgery. however, it remains 18 underutilised in emergency surgeries. we aimed to systematically review robotic 19 appendicectomies (ra) feasibility. a 20-year systematic review was performed in 20 compliance with prisma guidelines. mersqi score was applied for quality assessment. 21 the research protocol was registered with prospero. the search resulted in 1242 citations, 22 of which 9 articles were included. quality scores mean:10.72(sd=2.56). the endpoints 23 across the studies were: rate of conversion to open surgery, length of hospital stay, blood loss 24 and operative time. ra is safe and feasible technique in elective and emergency settings with 25 minimal blood loss. the operating time and the hospital stay were within acceptable limits. 26 the major drawback of robotic surgery is its high cost and limited availability. future studies 27 are recommended to evaluate ra with a focus on its application during emergency and on its 28 cost-effectiveness. 29 keywords: robot surgery; robotic-assisted surgery; robot enhanced surgery; robotic 30 surgical procedure; appendectomy; appendicectomy; robotic appendicectomy; 31 gastrointestinal surgical procedure. 32 33 2 introduction 34 acute appendicitis is known to be the most common abdominal surgical emergency in the 35 world, with around 50,000 acute appendicectomies performed annually in the uk.1 36 laparoscopic appendicectomy (la) is considered the gold-standard management and is 37 recommended over open appendectomy in all patient groups.2,3 however, the covid-19 38 pandemic brought a new challenge for surgeons undertaking laparoscopic procedures, with its 39 safety being debated out of fear of contaminated aerosol transmission to healthcare 40 workers.4,5 41 42 over the last decade, there has been an increasing trend in the routine use of robotic surgery 43 in several surgical specialties and nearly all surgical subspecialties have adopted it.6,7 the use 44 of the robotic system is known to improve precision, visualisation, spatial flexibility, and 45 stability, compared with traditional laparoscopic techniques.8,9 in particular, robotic surgery 46 has shown to reduce the risk of potential viral transmission to the surgeons and theatre staff 47 as it allows them to be remote from the patient and each other.4,10,11 although routinely used 48 in elective cases, robotic surgery remains generally unexplored and potentially underutilised 49 in emergency surgeries.9,12,13 50 51 this study aimed to systematically review robotic appendicectomy (ra) procedures in 52 elective and emergency settings and study its indications and feasibility. 53 54 methods 55 this study was registered with prospero register for systematic reviews. the systematic 56 review was performed in compliance with the prisma guidelines.14 57 58 search strategy 59 a 20-year literature search using the search terms’’ robotic appendectomy’’ and ‘’robotic 60 appendicectomy’’ was carried out on pubmed, sciencedirect and cochrane databases for 61 articles published from 2002 to april 2022 [figure 1]. mesh terms were used and did not 62 reveal any new relevant citations. 63 64 inclusion and exclusion criteria 65 all citations directly related to robotic appendicectomy were included in this study. 66 conference abstracts, letters to editors and non-english publications were excluded. 67 3 68 procedure 69 the procedure comprised of two authors for citations inspection, which were systematically 70 reviewed against the inclusion and exclusion criteria. the final list of citations was completed 71 in consensus between the two authors. the search items were studied from the nature of the 72 article, the date of publication, the aims and findings of the studies in relation to the robotic 73 appendicectomy procedures and the type of robotic system used. in case the type of robotic 74 system was not clearly mentioned in the manuscripts, corresponding authors were contacted 75 for confirmation of the included type of robotic surgery. in only one study, the type of the 76 used robotic system was not clearly mentioned, and authors were not reachable. 77 78 quality assessment and synthesis 79 the retrieved citations were read for further assessment for eligibility. our method for 80 identifying and evaluating data complied with the prisma checklist and has been reported 81 in line with assessing the methodological quality of systematic reviews (amstar 2).15 82 there was a good compliance with amstar 2 tool. reporting ‘’yes’’ in 11 criteria and 83 ‘’partial yes’’ in two. the ‘’no’’ were related to meta-analysis, which was not applicable in 84 this study. 85 86 the medical education research study quality instrument (mersqi) was used for quality 87 assessments of studies.16 this score contains 10 items that reflect 6 domains of study quality 88 including study design, sampling, type of data, validity, level of data analysis, and outcomes. 89 the score represented the mean of two independent assessors’ quality estimations of each 90 citation. mersqi’s maximum score was 18 with a potential range from 5 to 18. the 91 maximum score for each domain was 3. the mean quality score was calculated to be 10.72 92 (sd= 2.56) = moderate quality score of citation ~ 11. high quality score was ≥13 and low-93 quality score was 5-9. 94 95 risk of bias within and across studies 96 the risk of bias was assessed in a blind manner; and we calculated the mean score between 97 two raters if the scores did not match. we also controlled for accumulated risk of bias by 98 grading the body of evidence of the findings according to mersqi score. 99 100 4 results 101 citation selection and characteristics 102 this 20-year systematic search resulted in 1346 citations. after scanning the titles and 103 abstracts, relevant citations were extracted (fig. 1). the inclusion and exclusion criteria were 104 applied, duplicated and irrelevant citations were excluded. a final list of 9 citations was 105 suitable to the research rationale. the full texts of the articles were read by two authors for 106 further evaluation. the tabular analysis of the citations for ra procedures is presented in 107 table 1, which comprises details about studies such as the published journals, aims and 108 findings of the studies, robotic system, quality scores and evidence grades of the studies.17 to 109 25 110 111 risk of bias within and across studies 112 we applied mersqi scores in our systematic review as it has been demonstrated to be a 113 reliable and valid instrument for measuring methodological quality in research.16 in addition, 114 to decrease the risk of bias within studies in our systematic review, we excluded 115 recommendations, letters to editors, abstracts and commentaries. the full texts of the 116 retrieved citations were read for further assessment for eligibility. there was risk of bias 117 within studies, which consisted of the small number of papers that studied ra procedures; 118 however, there was a good number of ra procedures included in the included cohort studies. 119 120 results of quality and evidence-grade assessments 121 for the included citations, the mean quality score was calculated to be 10.72 (sd= 2.56) and 122 the scores ranged from 6.5 to 13.5, with 4 high quality, 2 moderate and 3 low quality studies. 123 124 results of individual studies 125 a total of 174 procedures were included in this review, 161 elective, 12 emergency and one 126 interval ra. four citations reached high quality through mersqi scores. only one study did 127 not specify the exact number of the included ra procedures. 128 129 akl et al.’s retrospective analysis of 107 patients underwent elective ra in conjunction with 130 other robotic gynaecological procedures between 2004 and 2007 was performed. the main 131 objective was to evaluate the feasibility and safety of ra. the patients had a postoperative 132 follow-up period of at least six weeks. the researchers encountered no perioperative 133 complications related to concomitant during gynaecological procedures with no conversion 134 5 required in any of the procedures. additionally, the researchers found that ra could be 135 performed effectively without significantly affecting the operative time. 136 137 bütter et al.’s study aimed to measure the outcome of the first paediatric da vinci surgery 138 programme in canada among 41 children. all the procedures were completed without the 139 need for conversion to open or laparoscopic surgery. the researchers found that the use of the 140 robotic system offered them a significant advantage compared to laparoscopic surgery. these 141 included: markedly enhanced magnification and 3d visualisation, increased instrument 142 dexterity and improved precision and ease of suturing. 143 144 hüttenbrink et al.’s study aimed to investigate the safety and benefit for 53 patients 145 undergoing incidental ra during robotic-assisted laparoscopic radical prostatectomy 146 (ralrp) between 2012 and 2014. the findings supported the consideration of the 147 coincidental ra as no intraoperative or postoperative complications were encountered. in 148 addition, the median hospital stay was 5 days, which was similar when compared to other 149 ralrp procedures during the same period. 150 151 quilici et al.’s citation included a cohort study of 34,984 patients in which the value, cost and 152 fiscal impact of robotic procedures for abdominal surgeries were compared to open and 153 laparoscopic counterparts. the cost of ra was significantly higher compared to the 154 laparoscopic technique with an average total cost per case of $13,210 versus $7709 for la, 155 respectively. in addition, the mean duration of robotic surgery was longer when compared to 156 laparoscopic technique in abdominal surgery. however, this study contained few ra 157 procedures, which made it difficult to obtain a valid comparison between the different 158 surgical approaches. furthermore, the use of robotic technology for abdominal surgical 159 procedures provided no significant difference in clinical outcomes versus the other surgical 160 techniques. 161 162 synthesis of the studies 163 there was difference in the endpoints across the studies. these included: rate of conversion 164 to open surgery, length of postoperative hospital stays, intraoperative blood loss and 165 operative time. the length of hospital stay mean was 5.2 and estimated blood loss 22.5 ml. 166 167 6 conversion rate and intra-operative complications 168 akl et al. evaluated the safety and feasibility of elective ra during gynecologic robotic 169 surgery.17 in this study of 107 patients, none required conversion to laparoscopic or open 170 surgery. another study by hüttenbrink et al. reported on 53 patients who underwent elective 171 ra during robotic-assisted laparoscopic prostatectomy (ralrp).22 the researchers reported 172 no intraoperative or postoperative complications related to incidental ra and encouraged its 173 consideration for patients scheduled for robotic-assisted prostate surgery. 174 175 length of stay 176 kelkar et al. aimed to analyse the safety and effectiveness of the versius surgical system in 177 its first-in-human use of 30 patients undergoing gynaecological or general surgical 178 procedures.24 four patients with acute appendicitis underwent emergency ra with an average 179 length of hospital stay of 4 days (2-7 days). 180 181 yao et al. evaluated the feasibility and safety of the surgical robot, micro hand s. between a 182 total of 81 cases of robotic surgery, 3 patients had emergency ra for acute appendicitis with 183 an average postoperative hospital stay of 6.3 days. 23 184 185 hüttenbrink et al. reported an average postoperative hospital stay of 5 days for elective ra 186 during ralrp vs 6 days for all other ralrp performed in the same period of time.22 187 188 estimated blood loss 189 kelkar et al.reported that the estimated blood loss was negligible (<5ml) in all four patients 190 who had an emergency ra for acute appendicitis.24 yao et al. reported an intraoperative 191 blood loss of 40.0 ml amongst the 3 patients who had emergency ra. 23 192 193 operative time 194 kelkar et al. reported a median operative time of 105 min (80-135 min) amongst the four 195 emergency ra with yao et al. reporting a similar operative time of 130.0 min between the 196 emergency ra cases.23, 24 197 198 akl et al. reported an average time of 3.4 min (range 2-6) for ra after measuring the 199 operative time of 10 consecutive robotic cases.17 the authors concluded that ra can be 200 performed effectively without any significant difference in the operative time. 201 7 202 on the other hand, quillici et al. concluded that the mean duration of robotic surgery was 203 significantly longer when compared to laparoscopic surgery; however, there were too few ra 204 to obtain a valid comparison between the different surgical approaches. 25 205 206 discussion 207 to our knowledge, this is the first review to study robotic appendicectomy procedures. our 208 study showed that ra can be considered as a feasible and safe technique, mainly in elective 209 settings. indications of ra were acute and chronic appendicitis, mucocele resection, as well 210 as being performed in conjunction with other robotic gynaecological and urological 211 procedures. 212 213 laparoscopic appendicectomy remains the gold standard for the management of appendicitis, 214 due to its benefits such as the lower incidence of wound infections, less postoperative pain 215 and shorter hospital stay in comparison to open appendicectomy.26 whilst the available 216 literature on the use of robotic surgery in appendicectomy is somewhat limited, surgeons 217 have reported more dexterity, greater precision, better visualisation and improved range of 218 motion with its utilisation in abdominal surgery.8, 9, 27 these major features have led to its 219 widespread adoption in difficult operative access and technically challenging procedures.28 220 221 particularly in light of the covid-19 pandemic, surgeons considered robotic surgery as a safe 222 alternative to clear the backlog of operations whilst reducing the risk of potential viral 223 transmission. the offered advantages of robotic surgery include operating with lower 224 pneumoperitoneum pressures, reducing the length of hospital stay and minimising contact 225 between the patient and healthcare workers during surgery after trocars placement.11, 29, 30 226 227 despite the advantages, drawbacks of robotic surgery still include limited availability and 228 additional specialised surgical robotic training. in addition, the increased cost of robotic 229 surgery remains one of its main limitations when compared to laparoscopic or open surgery. 230 the robotic surgery requires specialised training and its cost of acquiring, operating and 231 maintaining a surgical robotic system is significantly more expensive when compared to 232 other surgical techniques.25, 31, 32 233 234 8 our study included three robotic systems: the da vinci robot, the versius and the micro hand 235 s. the da vinci robot launched in 1999 and has remained the predominant robotic surgical 236 system for over 20 years. however, with a cost of £1.7 million per robot, £1,000 per patient 237 for disposables and £140,000 maintenance fees per year, newer cost-effective systems have 238 emerged to improve on the da vinci.33, 34 the novel micro hand s has demonstrated 239 significantly lower hospitalisation and operative costs in comparison to the da vinci robotic 240 system, (p< 0.05). the surgical instruments of the micro hand s have unlimited use whereas 241 the instruments of the da vinci surgical robot have a 10-use limit. furthermore, the surgical 242 instruments of the micro hand s robot cost about 1,000 yuan per set which is roughly 243 equivalent to £119 vs 2,000 yuan per set for the da vinci, which is roughly equivalent to 244 £239.35, 36 the versius surgical system is the first uk built surgical robot and is said to be the 245 next major rival to the da vinci. although reports are limited about specific costs of the novel 246 system, the versius robot offers the advantages of being smaller, more versatile and more 247 portable, improving its cost-effectiveness.34 248 249 the main limitation of this review was the limited number of citations that studied ra and 250 the absence of randomised trials during this 20-year period. however, there was a good 251 number of procedures in the cohort studies included in this review. future research is needed 252 to further evaluate the strengths and weaknesses of each robotic surgical system in 253 appendicectomy, with a particular focus on its application during emergency settings and on 254 its cost-effectiveness. 255 256 conclusion 257 the present review included studies revealing robotic appendicectomy as a safe and feasible 258 technique. ra could be performed effectively without the need for conversion and minimal 259 blood loss. the operating time and the hospital stay were within acceptable limits. however, 260 the major drawback of robotic surgery is its high cost. future studies are recommended to 261 further evaluate the different robotic surgical systems in appendicectomies, with a focus on 262 its application during emergency procedures and on its cost-effectiveness. 263 264 references 265 1. baird, d., simillis, c., kontovounisios, c., rasheed, s., & tekkis, p. p. (2017). acute 266 appendicitis. bmj (clinical research ed.), 357, j1703. 267 https://doi.org/10.1136/bmj.j1703 268 https://doi.org/10.1136/bmj.j1703 9 2. sauerland, s., jaschinski, t., & neugebauer, e. a. (2010). laparoscopic versus open 269 surgery for suspected appendicitis. the cochrane database of systematic reviews, 270 (10), cd001546. https://doi.org/10.1002/14651858.cd001546.pub3 271 3. page, a. j., pollock, j. d., perez, s., davis, s. s., lin, e., & sweeney, j. f. (2010). 272 laparoscopic versus open appendectomy: an analysis of outcomes in 17,199 patients 273 using acs/nsqip. journal of gastrointestinal surgery : official journal of the society 274 for surgery of the alimentary tract, 14(12), 1955–1962. 275 https://doi.org/10.1007/s11605-010-1300-1 276 4. el boghdady m, ewalds-kvist bm. laparoscopic surgery and the debate on its 277 safety during covid-19 pandemic: a systematic review of recommendations. 278 surgeon. 2021 apr;19(2):e29-e39. doi: 10.1016/j.surge.2020.07.005. epub 2020 aug 279 11. pmid: 32855070; pmcid: pmc7418789. 280 5. bjs commission team, bjs commission on surgery and perioperative care post-281 covid-19, british journal of surgery, volume 108, issue 10, october 2021, pages 282 1162–1180, https://doi.org/10.1093/bjs/znab307 283 6. sheetz, k. h., claflin, j., & dimick, j. b. (2020). trends in the adoption of robotic 284 surgery for common surgical procedures. jama network open, 3(1), e1918911. 285 https://doi.org/10.1001/jamanetworkopen.2019.18911 . 286 7. de'angelis, n., khan, j., marchegiani, f., bianchi, g., aisoni, f., alberti, d., 287 ansaloni, l., biffl, w., chiara, o., ceccarelli, g., coccolini, f., cicuttin, e., 288 d'hondt, m., di saverio, s., diana, m., de simone, b., espin-basany, e., fichtner-289 feigl, s., kashuk, j., kouwenhoven, e., … catena, f. (2022). robotic surgery in 290 emergency setting: 2021 wses position paper. world journal of emergency surgery : 291 wjes, 17(1), 4. https://doi.org/10.1186/s13017-022-00410-6 292 8. ran, l., jin, j., xu, y., bu, y., & song, f. (2014). comparison of robotic surgery 293 with laparoscopy and laparotomy for treatment of endometrial cancer: a meta-294 analysis. plos one, 9(9), e108361. https://doi.org/10.1371/journal.pone.0108361 295 9. roh, h. f., nam, s. h., & kim, j. m. (2018). robot-assisted laparoscopic surgery 296 versus conventional laparoscopic surgery in randomized controlled trials: a 297 systematic review and meta-analysis. plos one, 13(1), e0191628. 298 https://doi.org/10.1371/journal.pone.0191628 299 10. kimmig, r., verheijen, r., rudnicki, m., & for sergs council (2020). robot 300 assisted surgery during the covid-19 pandemic, especially for gynecological cancer: 301 https://doi.org/10.1002/14651858.cd001546.pub3 https://doi.org/10.1007/s11605-010-1300-1 https://doi.org/10.1093/bjs/znab307 https://doi.org/10.1001/jamanetworkopen.2019.18911 https://doi.org/10.1186/s13017-022-00410-6 https://doi.org/10.1371/journal.pone.0108361 https://doi.org/10.1371/journal.pone.0191628 10 a statement of the society of european robotic gynaecological surgery (sergs). 302 journal of gynecologic oncology, 31(3), e59. https://doi.org/10.3802/jgo.2020.31.e59 303 11. moawad, g. n., rahman, s., martino, m. a., & klebanoff, j. s. (2020). robotic 304 surgery during the covid pandemic: why now and why for the future. journal of 305 robotic surgery, 14(6), 917–920. https://doi.org/10.1007/s11701-020-01120-4 306 12. sudan, r., & desai, s. s. (2012). emergency and weekend robotic surgery are 307 feasible. journal of robotic surgery, 6(3), 263–266. https://doi.org/10.1007/s11701-308 011-0289-0 309 13. osagiede, o., spaulding, a. c., cochuyt, j. j., naessens, j. m., merchea, a., 310 crandall, m., & colibaseanu, d. t. (2019). factors associated with minimally 311 invasive surgery for colorectal cancer in emergency settings. the journal of 312 surgical research, 243, 75–82. https://doi.org/10.1016/j.jss.2019.04.089 313 14. moher, d., liberati, a., tetzlaff, j., altman, d. g., & prisma group (2009). 314 preferred reporting items for systematic reviews and meta-analyses: the prisma 315 statement. bmj (clinical research ed.), 339, b2535. 316 https://doi.org/10.1136/bmj.b2535 317 15. shea, b. j., reeves, b. c., wells, g., thuku, m., hamel, c., moran, j., ... & henry, 318 d. a. (2017). amstar 2: a critical appraisal tool for systematic reviews that include 319 randomised or non-randomised studies of healthcare interventions, or both. bmj, 358. 320 16. reed, d. a., cook, d. a., beckman, t. j., levine, r. b., kern, d. e., & wright, s. 321 m. (2007). association between funding and quality of published medical education 322 research. jama, 298(9), 1002–1009. https://doi.org/10.1001/jama.298.9.1002 323 17. akl, m. n., magrina, j. f., kho, r. m., & magtibay, p. m. (2008). robotic 324 appendectomy in gynaecological surgery: technique and pathological findings. the 325 international journal of medical robotics + computer assisted surgery : mrcas, 4(3), 326 210–213. https://doi.org/10.1002/rcs.198 327 18. yi, b., wang, g., li, j., jiang, j., son, z., su, h., & zhu, s. (2016). the first clinical 328 use of domestically produced chinese minimally invasive surgical robot system 329 "micro hand s". surgical endoscopy, 30(6), 2649–2655. 330 https://doi.org/10.1007/s00464-015-4506-1 331 19. yi, b., wang, g., li, j., jiang, j., son, z., su, h., zhu, s., & wang, s. (2017). 332 domestically produced chinese minimally invasive surgical robot system "micro 333 hand s" is applied to clinical surgery preliminarily in china. surgical endoscopy, 334 31(1), 487–493. https://doi.org/10.1007/s00464-016-4945-3 335 https://doi.org/10.3802/jgo.2020.31.e59 https://doi.org/10.1007/s11701-020-01120-4 https://doi.org/10.1007/s11701-011-0289-0 https://doi.org/10.1007/s11701-011-0289-0 https://doi.org/10.1016/j.jss.2019.04.089 https://doi.org/10.1136/bmj.b2535 https://doi.org/10.1001/jama.298.9.1002 https://doi.org/10.1002/rcs.198 https://doi.org/10.1007/s00464-015-4506-1 https://doi.org/10.1007/s00464-016-4945-3 11 20. bütter, a., merritt, n., & dave, s. (2017). establishing a pediatric robotic surgery 336 program in canada. journal of robotic surgery, 11(2), 207–210. 337 https://doi.org/10.1007/s11701-016-0646-0 338 21. orcutt, s. t., anaya, d. a., & malafa, m. (2017). minimally invasive appendectomy 339 for resection of appendiceal mucocele: case series and review of the literature. 340 international journal of surgery case reports, 37, 13–16. 341 https://doi.org/10.1016/j.ijscr.2017.05.027 342 22. hüttenbrink, c., hatiboglu, g., simpfendörfer, t., radtke, j. p., becker, r., teber, 343 d., hadaschik, b., pahernik, s., & hohenfellner, m. (2018). incidental appendectomy 344 during robotic laparoscopic prostatectomy-safe and worth to perform?. langenbeck's 345 archives of surgery, 403(2), 265–269. https://doi.org/10.1007/s00423-017-1630-5 346 23. yao, y., liu, y., li, z., yi, b., wang, g., & zhu, s. (2020). chinese surgical robot 347 micro hand s: a consecutive case series in general surgery. international journal of 348 surgery (london, england), 75, 55–59. https://doi.org/10.1016/j.ijsu.2020.01.013 349 24. kelkar, d., borse, m. a., godbole, g. p., kurlekar, u., & slack, m. (2021). interim 350 safety analysis of the first-in-human clinical trial of the versius surgical system, a 351 new robot-assisted device for use in minimal access surgery. surgical endoscopy, 352 35(9), 5193–5202. https://doi.org/10.1007/s00464-020-08014-4 353 25. quilici, p. j., wolberg, h., & mcconnell, n. (2022). operating costs, fiscal impact, 354 value analysis and guidance for the routine use of robotic technology in abdominal 355 surgical procedures. surgical endoscopy, 36(2), 1433–1443. 356 https://doi.org/10.1007/s00464-021-08428-8 357 26. jaschinski, t., mosch, c. g., eikermann, m., neugebauer, e. a., & sauerland, s. 358 (2018). laparoscopic versus open surgery for suspected appendicitis. the cochrane 359 database of systematic reviews, 11(11), cd001546. 360 https://doi.org/10.1002/14651858.cd001546.pub4 361 27. lanfranco, a. r., castellanos, a. e., desai, j. p., & meyers, w. c. (2004). robotic 362 surgery: a current perspective. annals of surgery, 239(1), 14–21. 363 https://doi.org/10.1097/01.sla.0000103020.19595.7d 364 28. köckerling f. (2014). robotic vs. standard laparoscopic technique what is 365 better?. frontiers in surgery, 1, 15. https://doi.org/10.3389/fsurg.2014.00015 366 29. huddy, j. r., crockett, m., nizar, a. s., smith, r., malki, m., barber, n., & tilney, 367 h. s. (2022). experiences of a "covid protected" robotic surgical centre for 368 https://doi.org/10.1007/s11701-016-0646-0 https://doi.org/10.1016/j.ijscr.2017.05.027 https://doi.org/10.1007/s00423-017-1630-5 https://doi.org/10.1016/j.ijsu.2020.01.013 https://doi.org/10.1007/s00464-020-08014-4 https://doi.org/10.1007/s00464-021-08428-8 https://doi.org/10.1002/14651858.cd001546.pub4 https://doi.org/10.1097/01.sla.0000103020.19595.7d https://doi.org/10.3389/fsurg.2014.00015 12 colorectal and urological cancer in the covid-19 pandemic. journal of robotic 369 surgery, 16(1), 59–64. https://doi.org/10.1007/s11701-021-01199-3 370 30. sparwasser, p., brandt, m. p., haack, m., dotzauer, r., boehm, k., gheith, m. k., 371 mager, r., jäger, w., ziebart, a., höfner, t., tsaur, i., haferkamp, a., & borgmann, 372 h. (2021). robotic surgery can be safely performed for patients and healthcare 373 workers during covid-19 pandemic. the international journal of medical robotics + 374 computer assisted surgery : mrcas, 17(4), e2291. https://doi.org/10.1002/rcs.2291 375 31. amodeo, a., linares quevedo, a., joseph, j. v., belgrano, e., & patel, h. r. (2009). 376 robotic laparoscopic surgery: cost and training. minerva urologica e nefrologica = 377 the italian journal of urology and nephrology, 61(2), 121–128. 378 32. gkegkes, i. d., mamais, i. a., & iavazzo, c. (2017). robotics in general surgery: a 379 systematic cost assessment. journal of minimal access surgery, 13(4), 243–255. 380 https://doi.org/10.4103/0972-9941.195565 381 33. bennett, k. (2012). robotic surgery: da vinci® and beyond. the bulletin of the 382 royal college of surgeons of england, 94(1), 8-9. 383 10.1308/147363512x13189526438431 384 34. khandalavala, k., shimon, t., flores, l., armijo, p. r., & oleynikov, d. (2020). 385 emerging surgical robotic technology: a progression toward microbots. ann laparosc 386 endosc surg, 5, 3-3. doi10.21037/ales.2019.10.02 387 35. zeng, y., wang, g., li, z., lin, h., zhu, s., & yi, b. (2021). the micro hand s vs. 388 da vinci surgical robot-assisted surgery on total mesorectal excision: short-term 389 outcomes using propensity score matching analysis. frontiers in surgery, 8, 390 656270. https://doi.org/10.3389/fsurg.2021.656270 391 36. luo, d., liu, y., zhu, h., li, x., gao, w., li, x., zhu, s., & yu, x. (2020). the 392 microhand s robotic-assisted versus da vinci robotic-assisted radical resection for 393 patients with sigmoid colon cancer: a single-center retrospective study. surgical 394 endoscopy, 34(8), 3368–3374. https://doi.org/10.1007/s00464-019-07107-z 395 396 https://doi.org/10.1007/s11701-021-01199-3 https://doi.org/10.1002/rcs.2291 https://doi.org/10.4103/0972-9941.195565 https://doi.org/10.3389/fsurg.2021.656270 https://doi.org/10.1007/s00464-019-07107-z 13 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 figure 1: flow diagram of the systematic search 438 439 440 441 442 443 444 445 446 records identified through database searching pubmed (n =73) science direct (n=1268) cochrane library (n=5) s cr e e n in g in cl u d e d e li g ib il it y id e n ti fi ca ti o n records screened (n =1239) records excluded** (n = 1228) case reports, recommendations, conference abstracts, letters, editorials, reviews, commentaries, out of scope citations and non-english full-text articles assessed for eligibility (n = 11) full-text articles excluded (n = 2) studies included in qualitative synthesis (n = 9) 14 table 1: tabular analysis of included citations 447 author (year) journal type of study objective patients (n) indications robotic system findings/outcomes mersqi scores* (quality) akl et al. (2008) the internation al journal of medical robotics and computer assisted surgery cohort study to assess the feasibility, safety and pathological findings of incidental ra in patients undergoing robotic gynecological surgery. altogether elective ra 107 patients. chronic pelvic pain and gynecological malignancies. da vinci robotic system incidental ra was performed safely and effectively in conjunction with other robotic gynecological procedures with no perioperative complications related to appendicectomy. 13 (high) yi et al. (2015) surgical endoscopy case series to assess the safety and feasibility of the chinese minimally invasive surgical robot system “micro hand s” in its first clinical use altogether 3 patients (emergenc y ra=2) acute appendicitis micro hand s robotic surgery the robot system “micro hand s” was safe and effective with no intraoperative complications or technical problems being encountered with its use. at three-month follow up, patients had no adverse reactions. 8 (low) yi et al. (2016) surgical endoscopy case report to develop and validate one low-cost and easy-use minimally invasive surgical robot system “micro hand s” that surgeons can use to resolve the complicated surgeries challenge. altogether 10 patients (emergenc y ra=3) acute appendicitis micro hand s robotic surgery no intraoperative complications or technical problems were encountered with the use of the domestic produced “micro hand s” all patients recovered and were discharged from hospital without complications. 8 (low) bütter et al. (2016) journal of robotic surgery cohort study to present the results of the first pediatric robotic surgery program in canada. altogether 41 children interval ra=1 interval appendicectom y. da vinci robotic system all robotic procedures were completed without conversion, with no technical failures due to the robotic system. 13 (high) orcutt et al. (2017) internation al journal of surgery case series to present cases with appendiceal mucoceles that altogether 2 patients mucocele of appendix unclear the robotic approach allowed meticulous dissection and 6.5 (low) 15 case reports were successfully treated with minimally invasive approaches. elective ra=1 intact removal of appendiceal mucocele with no intra or postoperative complications. hüttenbri nk et al. (2017) langenbec k’s archives of surgery cohort study to investigate the safety and patients benefit of incidental appendicectomy during ralrp. altogether 53 patients elective ra=53 histopathol ogy: inconspicu ous=33, postinflam matory changes=1 1, chronic appendiciti s=4, appendiciti s=3 and neoplasia= 2 ralrp with incidental appendicectom y. da vinci robotic system incidental appendicectomy during ralrp is a feasible and safe procedure and could be considered for patients scheduled for robot-assisted prostate surgery. 13.5 (high) yao et al. (2020) internation al journal of surgery cohort study to evaluate the feasibility and safety of the micro hand s surgical robot in general surgery. altogether 81 patients (emergenc y ra=3) acute appendicitis micro hand s robotic surgery ra was successfully performed in all 3 patients. the operation time(min) 130.0, blood loss (ml) 40.0 and hospital stay (day) 6.3 11 (moderate) kelkar et al. (2020) surgical endoscopy cohort study to provide an initial safety analysis of the first 30 surgical procedures performed using the versisus surgical system. altogether 30 patients (emergenc y ra=4) acute appendicitis versius surgical system ra was successfully carried out in all 4 patients. the operation time ranged between 80135 minutes and estimated intraoperative blood loss was negligible. 10 (moderate) quilici et al. (2021) surgical endoscopy cohort study to define the value, cost, and fiscal impact of robotic-assisted procedures in abdominal surgery and altogether 34,984 patients (few unspecified number ra) abdominal surgery including aa. da vinci surgical system ra were performed at a higher cost vs laparoscopic appendicectomy, with an average total cost per case $13,210 vs $7709. 13.5 (high) 16 provide clinical guidance for its routine use. robotic technology for gastrointestinal pro cedures is significantly more expensive than other surgical techniques. 448 ra = robotic appendicectomy; aa = acute appendicitis; ralrp = robot-assisted radical 449 prostatectomy. 450 *mersqi 451 • low quality 5-9 452 • moderate quality 10-12 453 • high quality ≥13 454 1wellington regional genetics laboratory, wellington hospital, wellington, new zealand; 2diagnostic genetics, labplus, auckland city hospital, auckland, new zealand; 3department of pathology, sidra medicine, doha, qatar *corresponding author’s e-mail: dlove@sidra.org تقدير ِإْمراِضيَّة املتغريات اجلينية ملورث سرطان الثدي )1( باستخدام الدالئل االرشادية اليت أصدرهتا الكلية األمريكية لعلم اجلينوم الطيب ومجعية علم األمراض اجلزيئي اأجنيال براون، من�صور زمانبور، دونالد لوف، وديربا برو�رس abstract: objectives: molecular diagnostic laboratories screen for mutations in disease-causing genes in order to confirm a clinical diagnosis. the classification of dna variants as ‘pathogenic’ or ‘likely pathogenic’ mutations creates a workflow bottleneck, which becomes increasingly challenging as greater number of genes are screened. the classification challenge is also acute if there are conflicting reports regarding pathogenicity and differing classification criteria between laboratories. this study aimed to compare two procedures for the classification of variants in the breast cancer (brca)1 gene. methods: this bioinformatic study was conducted at labplus, auckland, new zealand, from february to june 2017. dna was extracted from peripheral blood samples of 30 patients and gene library construction was carried out using a commercially available targeted panel for the brca1 and brca2 genes. the genes were subsequently sequenced and the sequence data analysed. the guidelines published by the american college of medical genetics and genomics and the association for molecular pathology (acmg/ amp) provides a comprehensive framework for the interpretation of variants in genes that are associated with mendelian disorders. the use of these guidelines were compared to the variant classifications that were achieved by reference to those reported in the brca exchange database. results: the results showed concordance between the two classification protocols for a panel of 30 brca1 gene variants, although the transparency in following the acmg/amp guidelines provides a diagnostic laboratory with a generalisable approach that allows laboratorydirected revisions to be undertaken in light of new information. conclusion: the acmg/amp-based guidelines were applied to a cohort of patients with brca1 gene variants. the use of these guidelines provides a system which creates consistency in variant interpretation and supports subsequent clinical management. keywords: brca1 gene; bioinformatics; dna sequencing; nonsense codon; splice donor site; new zealand. الت�صخي�ض تاأكيد بغر�ض للمر�ض املحدثة املورثات يف طفرات وجود عن بالتحري اجلزيئي الت�صخي�ض معامل تقوم الهدف: امللخ�ص: الكلينيكي. ويف�صي ت�صنيف متغريات احلم�ض الريبي النووي املنزوع الأوك�صجني )دنا( اإىل كونها متغريات )ممر�صة( اأو )يحتمل اأن تكون ممر�صة( لختناق �صري العمل. وهو حتٍد يزداد �صعوبة مع زيادة عدد املورثات التي ينبغي فح�صها. وكذلك يغدو ع�رس الت�صنيف اأكرث حدًة اإذا كانت هنالك تقارير مت�صاربة من خمتلف املعامل حول حتديد الإمرا�صية ومعايري الت�صنيف نف�صها. وتهدف هذه الدرا�صة ملقارنة طريقتني لت�صنيف املتغريات اجلينية ملورث براكا 1. الطريقة: اأجريت هذه الدرا�صة املعلوماتية احليوية يف خمتربات )لب بل�ض( يف اوكالند بنيوزيلندا بني فرباير ويونيو من عام 7102م. ومت يف هذه الدرا�صة ا�صتخال�ض دنا من عينات دم طرفية لثالثني مري�صا، وان�صاأت مكتبة مورثات با�صتخدام لوحة م�صتهدفة ملورثات ال�رسطان براكا 1 وبراكا 2 متوفرة جتاريا. ومت عمل ت�صل�صل تتابعي لها وحتليل املعلومات امل�صتقاة. تقدم الدلئل الر�صادية التي اأ�صدرتها الكلية الأمريكية لعلم اجلينوم الطبي وجمعية علم الأمرا�ض اجلزيئي اإطارا �صامال لتف�صري املتغريات اجلينية املرتبطة بالأمرا�ض امَلْنِدِليَّة. متت مقارنة نتائج ا�صتخدام النوعني من الدلئل الر�صادية لت�صنيف املتغريات اجلينية املتح�صل عليها يف قاعدة بيانات )براكا( التبادلية. النتائج: اأثبتت النتائج وجود اتفاق بني الت�صنيفني يف لوحة مكونة من ثالثني متغريا جينيا لرباكا 1. غري اأن �صفافية اللتزام بالدلئل الر�صادية التي اأ�صدرتها الكلية الأمريكي لعلم اجلينوم الطبي وجمعية علم الأمرا�ض اجلزيئي توفر ملعمل الت�صخي�ض نهجا معمما تتيح اإمكانية املراجعة والتعديل يف النتائج حني ظهور معلومات جديدة. اخلال�صة: ا�صتخدمت الدلئل الر�صادية التي اأ�صدرتها الكلية الأمريكية لعلم اجلينوم الطبي وجمعية علم الأمرا�ض اجلزيئي يف ت�صخي�ض املتغريات اجلينية لرباك 1 عند فئة من املر�صى. يوفر ا�صتخدام تلك الدلئل الر�صادية ات�صاقا يف تف�صري املتغريات اجلينية، ويوؤازر التدابري العالجية الإكلينيكية الالحقة. الكلمات املفتاحية: مورث براك 1؛ املعلوماتية احليوية؛ ت�صلل دانا التتابعي؛ راِمَزٌة ُهَراِئيَّة؛ موقع مانح الو�صلة؛ نيوزيلندا. determination of pathogenicity of breast cancer 1 gene variants using the american college of medical genetics and genomics and the association for molecular pathology guidelines angela brown,1 mansour zamanpoor,1 *donald r. love,2,3 debra o. prosser2,3 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e324–334, epub. 22 dec 19 submitted 7 apr 19 revision req. 30 may 19; revision recd. 23 jun 19 accepted 16 jul 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.008 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ angela brown, mansour zamanpoor, donald r. love and debra o. prosser clinical and basic research | e325 bre ast c ancer is the most common malignancy among women, both in developed and developing countries, accounting for one in ten of all new cancers diagnosed worldwide.1 approx imately 5% of breast and ovarian cancers occurs as a result of variants in the breast cancer (brca)1 gene (mim# 113705; nm_007294.3; locus reference genomic [lrg]_292), which is localised to the long arm of chromosome 17 at band q21 and comprises 23 exons. variants within the brca1 gene are associated with an 80–90% lifetime risk of breast cancer.2 patients with pathogenic variants in the brca1 gene frequently have a positive family history of breast and ovarian cancer and are often diagnosed at a young age. they may also have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general.3 another gene implicated in breast cancer, brca2 (mim# 600185; nm_000059.3; lrg_293), is localised to the long arm of chromosome 13 at band q13.1 and comprises 27 exons.4 patients who carry a mutation in the brca2 gene have an average risk of 45% for breast cancer and 11% for ovarian cancer by the age of 70 years.5 there is an elevated risk for prostate cancer in brca2 gene carriers and an increased risk of pancreatic, head and neck, stomach and other cancers in patients with a mutation in either of these genes.5 germline pathogenic variants in both the brca1 and brca2 genes are expressed in an autosomal dominant manner.6 most brca1 or brca2 gene variants are point mutations or small insertions or deletions.7 in 2–12% of high-risk families, there may be a large genomic rearrangement.5 therefore, it is important to identify patients with disease-causing variants within the brca1 or brca2 genes as this may enable early treatment options such as surgery, including bilateral prophylactic mastectomy or bilateral prophylactic oophorectomy. the correct classification of variants is paramount in order to avoid invasive outcomes for patients who are not at a high risk of developing cancer. accurate classification also determines whether predictive testing for other ‘at risk’ family members would be of value. standardisation, in terms of variant classification, is a complex topic characterised by several challenges such as the failure to develop standards, a lack of consensus and incompatible implementation of agreed standards.8 these issues should be addressed in order to provide a consistent framework for reporting variants. identifying a causative variant allows patients and families to be aware of the risks and therefore pursue appropriate management. if the significance of a variant is unknown, then the clinician should decide how to deal with this finding for their patient and the patient’s relatives. the heightened uncertainty resulting from a variant of unknown significance can be distressing for patients.9 in order to manage and enable consistent and reproducible reporting of these variants, the establishment of universal guidelines is necessary. to address the need for internationally stand ardised guidelines for variant nomenclature, a working group was set-up to initiate this process.10,11 currently the responsibility for the maintenance and refinement of these guidelines is carried out by the human genome variation society (hgvs), and an online tool, termed mutalyzer, has been developed for laboratories to check the description of sequence variants.12 many online tools have become available to assist in variant interpretation such as clinvar (www.ncbi. nlm.nih.gov/clinvar/), which aggregates information about genomic variation and its relationship with human health. in addition, the 1000 genomes project (www.1000genomes.org) and the exome aggregation consortium (exac; http://exac.broadinstitute.org/), the latter being superseded by gnomad (https:// gnomad.broadinstitute.org/), are useful in obtaining the frequencies of variants in large populations. disease specific databases are also available in order to aid standardisation. in the case of variants detected in the brca1/2 genes, useful online resources include the breast cancer information core (bic; https://research.nhgri. nih.gov/bic/) and the enigma consortium (http:// enigma.ini.usc.edu/). an enigma member works collaboratively towards the classification of variants and contributes data from families with unclassified sequence variants and/or conducts statistical analysis or laboratory-based assays. critically, a more global and gene-targeted effort in gathering and collating data, termed the brca challenge, was launched by the global alliance for genomics and health. as a result of the brca challenge, the brca exchange (https:// advances in knowledge this study reports the use of internationally-accepted criteria for the classification of dna variants in the context of the breast cancer 1 gene. application to patient care this study emphasises that universally adopted criteria for classifying dna variants assists in the consistent confirmation of clinical diagnoses and the genetic counselling of family members regarding their risks. determination of pathogenicity of breast cancer 1 gene variants using the american college of medical genetics and genomics and the association for molecular pathology guidelines e326 | squ medical journal, november 2019, volume 19, issue 4 brcaexchange.org/) was launched. this initiative comb ines brca1/2 genes variant data from many resources such as clinvar, lovd (www.lovd.nl/), bic, exac (and gnomad), 1000 genomes, esp (http://evs. gs.washington.edu/evs), exlovd and enigma into the world’s largest source of non-proprietary brca variant-level data, which has enabled the expert review of thousands of variants. adding to this gene-specific effort, the american college of medical genetics and genomics and the association for molecular pathology (acmg/amp) published standards and guidelines for the interpretation of sequence variants in 2015.13 these guidelines describe a framework for classifying mendelian variants using a list of 28 criteria for determining the impact of a variant. with these guidelines, variants are classified as ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’ or ‘benign’. in the authors’ laboratory, next-generation sequ encing (ngs) analysis using targeted brca1 and brca2 gene panels was validated for diagnostic testing in 2014. the acmg/amp guidelines were published and incorporated into testing at the facility as soon as they were published in 2015. this study aimed to classify brca1 gene variants according to acmg/ amp guidelines and compare the classifications to those reported in the brca exchange. methods this bioinformatic study was conducted at labplus, auckland, new zealand, from february to june 2017. dna was extracted from peripheral blood samples of 30 patients referred to the northern hub of the genetic health services new zealand for brca1/2 gene mutation screening. the diagnostic referrals were forwarded for testing based on the cancer institute new south wales guidelines for genetic testing for heritable mutations in the brca1 and brca2 genes. library construction was carried out using the commercially available targeted panel for the brca1 and brca2 genes from multiplicom (agilent tech nologies, inc, the netherlands). sequencing was perf ormed using a gs-junior (roche holding ag, basel, switzerland) platform. data analysis was undertaken using jsi seqnext software (jsi medical systems gmbh, ettenheim, germany). in accordance with the amp and college of american pathologists ngs validation guidelines, a minimum of 30 reads was considered sufficient for minimum depth of coverage.14 if fewer than 30 reads were obtained, sanger-based sequencing was performed to ensure a reliable result. analysis included evaluating the coding regions and exon-intron boundaries (±20 base pairs) of the entire brca1 gene. alamut® interactive biosoftware (www.interactivebiosoftware.com/doc/alamut-visual/2.6/splicing.html) figure 1: workflow for classification of variants used in the current study (n = 30). pvs = very strong evidence of pathogenicity; pm = moderate evidence of pathogenicity; pp = supporting evidence of pathogenicity; lsdb = locusspecific database; brca = breast cancer; iarc =international agency for research on cancer; ps = strong evidence of pathogenicity. angela brown, mansour zamanpoor, donald r. love and debra o. prosser clinical and basic research | e327 was used to aid in the interpretation of the variants. as recommended by the acmg/amp guidelines, the nomenclature used to describe the variants is based on human genome variation society guidelines. the reference sequence for this gene was derived from the lrg database. an outline of the approach taken to classify the 30 brca1 gene variants according to the acmg/amp guidelines is shown in figure 1. the classification categories were assigned by applying a series of criteria. the criteria were divided into seven attributes based on the acmg/amp guide lines. in terms of evidence of pathogenicity these criteria were: very strong (pvs1), strong (ps1-4), moderate (pm1-6) and supporting (pp1-5). in terms of benign impact, the criteria were: stand-alone evidence (ba1), strong evidence (bs1-bs4) and supporting evidence (bp1-bp7) [table 1]. the outcome of each call for a particular variant was incorporated to give a final score, which was used to determine the final classification from the five-tiered system [table 2]. table 1: criteria used in the investigators’ laboratory for variant classifications based on american college of medical genetics and genomics and the association for molecular pathology guidelines criteria description pvs1 frameshift/nonsense/start codon/splice junction ± 2 base pairs/exonic deletion. ps1 for missense: the same amino acid change at the same codon is known to be pathogenic (different nucleotide position). the same amino acid change to be counted as strong evidence must also, by acmg definition, be a class 5. if the “other variant” is a class 4, then this evid ence become “moderate” rather than “strong” and can only be used to count as supporting evidence for the variant of interest to be a class 4 (likely pathogenic). ps2 de novo (paternity confirmed) in a patient with the disease, no family history and phenotype reasonably specific for the disorder. ps3 functional study supports damaging effect. ps4 prevalence in affected pts > prevalence in controls–or is statistically significant. where a significant number of cases have been reported carrying the variant and showed similar phenotype, it can be used as a “moderate” evidence without or. pm1 in mutational hot spot/critical domain (without benign variations). pm2 absent from population databases or extremely low maf. slightly higher is acceptable for recessive conditions. pm3 for recessive disorders: in trans with known mutation. pm4 in-frame insertion/deletion in non-repeat region or stop-loss variant that results in protein length changes. pm5 for missense: a known mutation occurs at same codon (different amino acid residue). the “known” mutation occurred at the same codon must be either a class 4 or 5 by acmg definition. pm6 not present in parents (i.e. assumed de novo) and phenotype reasonably specific for the disorder (without confirmation of paternity and maternity). pp1 co-segregation with disease (increased weighting may be applied if stronger evidence available). pp2 for missense: in this gene missense variants are usually pathogenic. pp3 bioinformatic analysis predicts pathogenic (protein and/or splice). pp4 phenotype is highly specific for this single genetic aetiology. pp5 a reputable source lists variant as pathogenic but doesn’t state how the classification was determined (reput able sources are clinvar at three or four stars). ba1 maf ≥5% in any of the population databases. bs1 allele frequency above expected for disorder. bs2 found in a healthy individual when full penetrance is expected at that age (in correct zygosity for disorder). bs3 functional study supports benign effect. bs4 doesn’t co-segregate with disease (beware: penetrance). bp1 for missense: in this gene missense variants are usually benign. bp2 observed in trans with a pathogenic variant (for domin ant inheritance) or in cis with a pathogenic variant (any inheritance pattern). bp3 in-frame insertion/deletion in a repetitive region without a known function. bp4 bioinformatic analysis predicts benign (protein and splice). bp5 variant found in a case with an alternative molecular basis for disease. bp6 a reputable source lists variant as benign (reputable sources are clinvar at three or four stars): the reput able source must be experts in this disease e.g. a lsdb or a lab that has longstanding experience. “no evidence” means no evidence of their classification details and does not mean no reference at all. where the classif ication is present but no details on their individual criteria, it is considered “no evidence”. the reference or paper it cites can still be investigated. however, if the detailed criteria is provided, then each evidence must be weighted and this option is no longer viable. bp7 for synonymous/intronic: splice predictions are benign. at present, if a synonymous/intronic variant is given benign prediction by splice programmes it can be class ified as class 2 without the need to investigate conservation. pvs = very strong evidence of pathogenicity; ps = strong evidence of patho genicity; acmg = american college of medical genetics and geno mics; or = odds ratio; pm = moderate evidence of pathogenicity; pp = supp orting evidence of pathogenicity; ba = stand-alone evidence of benign impact; bs = strong evidence of benign impact; bp = supporting evidence of benign impact; lsdb = locus-specific database. table 2: criteria used to allocate variants into the five american college of medical genetics and genomics and the association for molecular pathology classes class requirement 1. benign ba1 maf ≥5% or 2 bs 2. likely benign 1 bs + 1 bp or 2 bs. only bp7 needed for synonymous 3. uncertain conflicting information or doesn’t meet criteria of another class 4. likely pathogenic 1 pvs + 1 pm; 1 ps + 1 pm; 1 ps + 2 pp 3 pm; 2 pm + 2 pp; 1 pm + 4 pp 5. pathogenic 1 pvs + 1 ps; 1 pvs + 2 pm; 1 pvs + 1 pm + 1 pp; 1 pvs + 2 pp 2 ps; 1 ps + 3 pm; 1 ps + 2 pm + 2 pp; 1 ps + 1 pm + 4 pp ba = stand-alone evidence of benign impact; bs = strong evidence of benign impact; bp = supporting evidence of benign impact; pvs = very strong evid ence of pathogenicity; pm = moderate evidence of pathogenicity; ps = strong evidence of pathogenicity; pp = supporting evidence of pathogenicity. determination of pathogenicity of breast cancer 1 gene variants using the american college of medical genetics and genomics and the association for molecular pathology guidelines e328 | squ medical journal, november 2019, volume 19, issue 4 all diagnostic referrals gave informed consent. the national multi-region ethics committee of new zealand has ruled that cases of patient management do not require formal ethics committee approval. results a total of 30 variants were classified in this study, of which 27 were classified as pathogenic (class 5), two variants were classified as likely pathogenic (class 4) and one variant was classified as unknown significance table 3: summary of the patients classified in this study (n = 30) no. nucleotide change based on hgvs nomenclature amino acid change based on hgvs nomenclature brca1 gene (lrg_292) exon number lsdb classification (brca exchange) classification based on the acmg/amp guidelines 1 c.66dup p.(glu23argfs*18) 2 pathogenic class 5 2 c.117_118del p.(cys39*) 3 pathogenic class 5 3 c.212+1g>t p.? not reviewed class 5 4 c.212+2t>c p.? not reviewed class 5 5 c.220c>t p.(gln74*) 5 pathogenic class 5 6 c.427g>t p.(glu143*) 6 pathogenic class 5 7 c.1018del p.(val340*) 10 pathogenic class 5 8 c.1298_1299dup p.(ser434profs*8) 10 not reviewed class 4 9 c.1374del p.(asp458glufs*17) 10 not reviewed class 5 10 c.1953dup p.(lys652glufs*21) 10 pathogenic class 5 11 c.1961dup p.(tyr655valfs*18) 10 pathogenic class 5 12 c.2071del p.(arg691aspfs*10) 10 pathogenic class 5 13 c.2074del p.(his692metfs*9) 10 pathogenic class 5 14 c.2188_2201del p.(glu730thrfs*5) 10 pathogenic class 5 15 c.2280_2281del p.(glu761lysfs*6) 10 not reviewed class 4 16 c.2447a>g p.(his816arg) 10 not reviewed class 3 17 c.2475del p.(asp825glufs*21) 10 pathogenic class 5 18 c.2681_2682del p.(lys894thrfs*8) 10 pathogenic class 5 19 c.3143del p.(gly1048valfs*14) 10 pathogenic class 5 20 c.3254_3255dup p.(leu1086aspfs*2) 10 pathogenic class 5 21 c.3400g>t p.(glu1134*) 10 pathogenic class 5 22 c.3607c>t p.(arg1203*) 10 pathogenic class 5 23 c.3706_3707del p.(asn1236tyrfs*7) 10 pathogenic class 5 24 c.3718c>t p.(gln1240*) 10 pathogenic class 5 25 c.3756_3759del p.(ser1253argfs*10) 10 pathogenic class 5 26 c.3759dup p.(lys1254*) 10 pathogenic class 5 27 c.4065_4068del p.(asn1355lysfs*10) 10 pathogenic class 5 28 c.4113del p.(cys1372valfs*21) 11 pathogenic class 5 29 c.4327c>t p.(arg1443*) 12 pathogenic class 5 30 c.5152+1g>t p.? pathogenic class 5 hgvs = human genome variation society; brca = breast cancer; lrg = locus reference genomic; lsdb = locus-specific database; acmg/amp = american college of medical genetics and genomics and the association for molecular pathology. angela brown, mansour zamanpoor, donald r. love and debra o. prosser clinical and basic research | e329 table 4: criteria used to classify breast cancer 1 gene variants no. nucleotide change type summary of criteria evidence used for classification 1 c.66dupa frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars. brca exchange pathogenic) 2 c.117_118deltg nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars. brca exchange pathogenic) 3 c.212+1g>t canonical splice site pvs1, pm2, pp3 pvs1 as splice junction ± 2 base pairs pm2 as absent from population databases (1000 genomes, exac and esp) pp3 as in silico evidence predicts splicing to be affected (agreement from all four algorithms used in the investigators’ laboratory)† 4 c.212+2t>c canonical splice site pvs1, pm2, pp3 pvs1 as splice junction ± 2 base pairs pm2 as absent from population databases (1000 genomes, exac and esp) pp3 as in silico evidence predicts splicing to be affected (agreement from 3/4 algorithms used in the investigators’ laboratory: mes, nnsplice and hsf)† 5 c.220c>t nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar) 6 c.427g>t nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as maf = 0.00010/12 (exac); absent from esp pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 7 c.1018delg nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 8 c.1298_1299dupcc frameshift pvs1, pm2 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) 9 c.1374delc frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange not yet reviewed) 10 c.1953dupg frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 11 c.1961dupa frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as maf = 0.000008/1 (exac); absent from 1000 genomes and exac pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 12 c.2071dela frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 13 c.2074delc frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 14 c.2188_2201del14 frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 15 c.2280_2281deltg frameshift pvs1, pm2 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) 16 c.2447a>g missense pm2 pm2 as maf = 0.000008/1 (exac); 0.0116/0.0/0.0077 (esp); maf = 0.00008/1 (go-esp) 17 c.2475delc frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 18 c.2681_2682delaa frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) pvs = very strong evidence of pathogenicity; pm = moderate evidence of pathogenicity; pp = supporting evidence of pathogenicity; nmd = nonsensemediated decay; brca = breast cancer *nmd prediction based on the premature termination codon not occurring in the 3’ most exon or the 3’-most 50bp of the penultimate exon; †using splice site prediction programme (www.interactive-biosoftware.com/doc/alamut-visual/2.6/splicing.html), mes (http://genes.mit.edu/burgelab/maxent/xmaxentscan_scoreseq.html), nnsplice (www.fruitfly.org/seq_tools/splice.html) and hsf (www.umd.be/hsf3/). determination of pathogenicity of breast cancer 1 gene variants using the american college of medical genetics and genomics and the association for molecular pathology guidelines e330 | squ medical journal, november 2019, volume 19, issue 4 (class 3) [table 3]. the details of evidence used to classify each variant are shown in table 4. other than the missense mutation (c.2447a>g), the remaining variants were assigned pvs1. the rationale for this classification was that all of these variants were either nonsense (variants 2, 5–7, 21, 22, 24, 26 and 29), frameshift (variants 1, 8–15, 17– 20, 23, 25, 27 and 28) or canonical ±1 or 2 splice site (variants 3, 4 and 30) variants. the acmg/amp guidelines assign these variants as pvs1 as they can often be assumed to disrupt gene function by leading to complete absence of the gene product by lack of transcription or nonsense-mediated decay (nmd) of the altered transcript.13 variants predicted not to table 4 (cont.): criteria used to classify breast cancer 1 gene variants no. nucleotide change type summary of criteria evidence used for classification 19 c.3143delg frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 20 c.3254_3255dupga frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 21 c.3400g>t nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 22 c.3607c>t nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as maf = 0.00008/1 (go-esp), 0.0/0.0227/0.0077. absent from 1000 genomes and exac pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 23 c.3706_3707delaa frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 24 c.3718c>t nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 25 c.3756_3759delgtct frameshift pvs1, ps4, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* ps4 as this variant has been reported in multiple patients with breast and ovarian cancer pm2 as maf = 0.00002/3 (exac), maf = 0.0210/263 (go-esp), 2.1934/1.9231/2.1013 (esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 26 c.3759dupt nonsense pvs1, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 27 c.4065_4068deltcaa frameshift pvs1, ps4, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* ps4 as this variant is reported in multiple patients with breast and ovarian cancer pm2 as maf = 0.00002/2 (exac). absent from population databases (1000 genomes and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 28 c.4113delg frameshift pvs1, pm2, pp5 pvs1 as frameshift (predicted to undergo nmd)* pm2 as absent from population databases (1000 genomes, exac and esp) pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 29 c.4327c>t nonsense pvs1, ps4, pm2, pp5 pvs1 as nonsense (predicted to undergo nmd)* ps4 as this variant is reported to be a common cause of breast and ovarian cancer in the french canandian population but also observed in individuals from other ethnicities. pm2 as maf = 0.00002/3 (exac), absent from esp pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) 30 c.5152+1g>t canonical splice site pvs1, pm2, pp3, pp5 pvs1 as splice junction ± 2 base pairs pm2 as absent from population databases (1000 genomes, exac and esp) pp3 as in silico evidence predicts splicing to be affected (agreement from all four algorithms used in the investigators’ laboratory)† pp5 as listed as pathogenic by a reputable source (clinvar-pathogenic at three stars; brca exchange pathogenic) pvs = very strong evidence of pathogenicity; pm = moderate evidence of pathogenicity; pp = supporting evidence of pathogenicity; nmd = nonsensemediated decay; brca = breast cancer *nmd prediction based on the premature termination codon not occurring in the 3’ most exon or the 3’-most 50bp of the penultimate exon; †using splice site prediction programme (www.interactive-biosoftware.com/doc/alamut-visual/2.6/splicing.html), mes (http://genes.mit.edu/burgelab/maxent/xmaxentscan_scoreseq.html), nnsplice (www.fruitfly.org/seq_tools/splice.html) and hsf (www.umd.be/hsf3/). angela brown, mansour zamanpoor, donald r. love and debra o. prosser clinical and basic research | e331 trigger nmd have been defined as those that lead to a stop codon 50 nucleotides before or within the last exon.15 it is also suggested that variants in close proximity to the translation initiation codon can also escape nmd due to downstream reinitiation.16 in this study, the most 5’ variant was c.66dupa, which is in exon 2, 66 nucleotides downstream from the first nucleotide; it is therefore not considered very close to the translation initiation codon. the most 3’ exon with a variant in this gene was in exon 17. given that exon 18–23 contain 436 nucleotides, it was concluded that none of the current detected variants would prevent nmd from occurring. therefore, pvs1 was assigned to each frameshift and nonsense variant. for the three splice site variants (variants 3, 4 and 30), alamut visual software (interactive biosoftware, rouen, france) predicted that skipping of exons 4 and 17 was very likely. both exons 4 and 17 are 78 base pairs or 26 amino acids long. skipping of these exons would lead to an in-frame deletion of this protein, which would normally lead to assigning criterion pm4. however, exons 4 and 17 encode part of the really interesting new gene and brca1 c-terminus domains, which are essential for the proteins role as a tumour suppressor.17 therefore, the investigators decided that they had sufficient evidence to assign criterion pvs1 to these three variants. variant frequencies were assessed in population databases including 1000 genomes, exac and esp. variants were assigned the pm2 criterion if the variant was absent or had an extremely low frequency in population databases. the databases examined for each variant are described in table 4. in the investigators’ laboratory, clinvar was considered a reputable disease database and the pp5 criterion was assigned to any variant with a pathogenic interpretation in clinvar that had expert panel review status. variants designated pp3 were those in which in silico data had been obtained [table 4]. the ps4 criterion can be assigned to variants with an increased prevalence in affected individuals compared to the controls. in this study, ps4-assigned variants were those that had been reported to be seen in multiple patients with breast and ovarian cancer. the investigators’ variant classification approach led to one variant being classified as class 3; two as class 4 and 27 as class 5. in the case of the class 3 variant (variant 16), it satisfied criterion pm2 as it was present at an extremely low frequency in population databases. this variant had conflicting evidence for pathogenicity in clinvar as did in silico prediction software. in addition, there was an absence of publications describing this variant. the two class 4 variants (variants 8 and 15) were classified as likely pathogenic as there was a lack of supporting clinvar evidence and no literature was found describing these variants. table 3 provides a summary of the classification together with those present in the brca exchange. the classification of variants in the brca exchange were concordant with the acmg/ampbased classifications. discussion the purpose of this study was to classify 30 variants detected in the brca1 gene according to the acmg/ amp guidelines. the variants described in the current study were detected prior to the implementation of these guidelines, and as a result they had not been curated consistently. for the initial classification, a variety of online resources had been used such as: the bic database; their clinvar status and their inter national agency for research on cancer class. included in the study were seventeen frameshift, nine nonsense, three intronic variants and a single missense variant. the classification of the variants was weighted heavily on the type of variant, the frequency of the variant and the clinvar classification. brca1 exhibits an autosomal dominant pattern of inheritance.18 therefore, a heterozygous variant has potential to cause disease. the majority of clinically significant deleterious mutations within the brca1 and brca2 genes have been reported to be protein-truncating mutations, while a small number are missense mutations.5 the majority of variants in this study were either frameshift or nonsense mutations. the investigators’ interpretation of the acmg/amp guidelines enabled the majority (97%) of the variants to be assigned pvs1. the criteria were sufficient to enable all but one of the variants to be classified as either ‘likely pathogenic’ or ‘pathogenic’, thus providing an informative result for clinicians who could focus on the clinical management table 5: summary of the implications and consequences of variant classifications class further revision reported as predictive testing familial segregation analysis 1 no not reported no no 2 biannually not reported no no 3 annual uncertain clinical significance no yes 4 annual likely pathogenic yes (counselling required) no 5 no pathogenic yes (counselling required) no determination of pathogenicity of breast cancer 1 gene variants using the american college of medical genetics and genomics and the association for molecular pathology guidelines e332 | squ medical journal, november 2019, volume 19, issue 4 of patients with these variants in the future. use of the current methodology based on acmg/amp variant classification guidelines gave final calls with a high level of concordance to well-curated locus-specific databases. all 24 variants in this study that were listed as patho genic by the brca exchange were also classified as class 5 pathogenic variants. recent evaluations of the acmg/amp guidelines have been published.19,20 one study examined the class ification findings across nine laboratories in the usa.19 although these findings showed that the use of the acmg/amp guidelines did not initially improve interlaboratory concordance, they did provide a common framework to facilitate resolution of the differences when discussed subsequently.19 in addition, maxwell et al. classified 1,640 variants and summarised that their findings supported the clinical utility of acmg/ amp variant-classification guidelines.20 outside of the usa, other countries are adopting these guidelines. in november 2016, a consensus statement was issued by the association for clinical genomic science (acgs). it recommended use of the acmg/amp guidelines for germline variant classification and interpretation in uk diagnostic genetic laboratories performing testing of rare disease and familial cancers.21 this development highlights that there is an international effort in place to standardise variant interpretation. these guidelines were recognised to provide a starting point for further refinements and extensions in the future.22 the sequence variant interpretation (svi) working group has begun this process, taking on the task of improving the current acmg/amp recommendations in order to develop quantitative approaches to variant interpretation. as a result of this, the acgs published best practice guidelines for variant classification in 2018.21 according to the acmg/amp guidelines, the pvs1 criterion provides a very strong level of confidence in assigning pathogenicity; however, there are certain caveats to this criterion. the factors to take into consideration when assigning pvs1 include: ensuring that loss of function is a known disease mechanism; using caution when interpreting loss of function variants at the extreme 3’ end of a gene; attention to splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact; the presence of multiple transcripts and assuming that a null variant will lead to disease if found in an exon where no other pathogenic variants have been described. due to concerns that inappropriate use of this criterion may have a signif icant impact on a patient’s well-being, the svi working group has produced recommendations for interpreting the loss of function pvs1 acmg/amp variant criterion.23 these recommendations provide a detailed description of the types of variants that can be assigned this classification, as well as a decision tree to aid in variant interpretation. the pp5 criterion was frequently used in the current study. this criterion requires that a reputable source lists the variant as pathogenic but doesn’t state how the classification was determined. this criterion is appropriate when information is obtained from a clinical laboratory that has long-standing expertise in the disease area. within the current laboratory, it was thought appropriate to apply pp5 when there was a clinvar review with three stars supporting patho genicity. the svi working group suggested that pp5 (along with its benign equivalent, bp6) be removed from the criteria. this is due to the fact that clinvar has become so successful that submissions with ‘assertion criteria provided’ account for the majority of cases uploaded and that sufficient primary evidence is now available.22 the pp3 criterion was used in this study alongside pvs1 for intronic variants. although not stated in the acmg/amp guidelines, the svi working group has suggested avoiding using pp3 together with pvs1 as the evidence is based on the same set of data and has the potential to lead to errors in classification.23 if that suggestion had been followed in the current study, two of the three canonical splice site variants (variants 3 and 4) would be reclassified as class 4 (from class 5) but the remaining variant (variant 30) would remain a class 5. table 5 summarises the implications to the laboratory and to the clinic regarding the consequences of variant classification. having the acmg/amp guidelines in place allows the laboratory to assign an appropriate frequency of revisions. as discussed above, refinement of the acmg/ amp guidelines has already began and will continue to evolve over time. within the investigators’ laboratory, the development of a work-up document for internal use following the acmg/amp guidelines has enabled a more systematic approach to variant interpretation and proved a useful resource in achieving rigour regarding variant classification. the refinement of these guidelines will continue to improve the interpretation of variants, ultimately leading to an improvement in patient care. for the classification of variants in this study the following criteria were not used: ps2 (de novo-paternity confirmed); pm6 (assumed de novo, but without confirmation); pp1 (co-segregation with disease); bs4 (lack of segregation in affected members) and pp4 (patient’s phenotype or family history is highly specific for a disease with a single genetic aetiology). information angela brown, mansour zamanpoor, donald r. love and debra o. prosser clinical and basic research | e333 was not available regarding family history, the inheritance of the variants or the patients’ clinical status. although the majority of the variants described here were classified as pathogenic without this additional information, this is not always going to be the case and the availability of as much information as possible is essential to provide accurate variant classification. the advantage of an approach that adheres to international guidelines is the acknowledgement that variant classification requires objectivity but recognising that best practice is aspirational. while the bcra exchange classifications were used as a benchmark, recent work of cusin et al. provides a salutary lesson.24 these authors highlight the importance of including information regarding the molecular and cellular impacts of variants, which need to be retrieved in a comput ationally accessible format.24 this is especially so for class 3 variants that currently suffer from a paucity of functional data, as well as limited clinical impact data due to the logistic challenges of performing familial segregation analysis. diagnostic laboratories should play a larger role in addressing the latter, while research laboratories should address the former. conclusion the use of acmg/amp guidelines for the class ification of dna variants allows a diagnostic labor atory to benchmark their classifications against other laboratories so as to achieve consistency in outcomes. this benchmarking also enables clinicians to have confidence in the veracity of diagnostic reports and provides a transparent process that is subject to objective evidence. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. ferlay j, hery c, autier p, sankaranarayanan r. global burden of breast cancer. in: li, c., ed., breast cancer epidemiology, springer, new york. 2010; 1–19. 2. gayther sa, warren w, mazoyer s, russell pa, harrington pa, chiano m, et al. germline mutations of the brca1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. nat genet 1995; 11:428–33. https://doi.org/10.1038/ng1295-428. 3. bergthorsson jt, ejlertsen b, olsen jh, borg a, nielsen kv, barkardottir rb, et al. brca1 and brca2 mutation status and cancer family history of danish women affected with multifocal or bilateral breast cancer at a young age. j med genet 2001; 38:361–8. https://doi.org/10.1136/jmg.38.6.361. 4. wooster r, neuhausen sl, mangion j, quirk y, ford d, collins n, et al. localization of a breast cancer susceptibility gene, brca2, to chromosome 13q12-13. science 1994; 265:2088–90. https://doi.org/10.1126/science.8091231. 5. balmaña j, diez o, rubio i, castiglione m; esmo guidelines working group. brca in breast cancer: esmo clinical practice guidelines. ann oncol 2010; 21 suppl 5:v20–2. https://doi. org/10.1093/annonc/mdq161. 6. petrucelli n, daly mb, pal t. brca1and brca2-associated hereditary breast and ovarian cancer. in: adam mp, ardinger hh, pagon ra, wallace se, bean ljh, stephens k, eds. gene reviews®. seattle, usa: university of washington, seattle, 1993–2019. https://www.ncbi.nlm.nih.gov/books/nbk1247/. 7. mcveigh tp, cody n, carroll c, duff m, farrell m, bradley l, et al. recurrent large genomic rearrangements in brca1 and brca2 in an irish case series. cancer genet 2017; 214–15:1–8. https://doi.org/10.1016/j.cancergen.2017.02.001. 8. cargill cf. why standardization efforts fail. j electronic publishing 2011; 14. http://doi.org/10.3998/3336451.0014.103. 9. hoffman-andrews l. the known unknown: the challenges of genetic variants of uncertain significance in clinical practice. j law biosci 2018; 4:648–57. https://doi.org/10.1093/jlb/lsx038. 10. antonarakis se. recommendations for a nomenclature system for human gene mutations. nomenclature working group. hum mutat 1998; 11:1–3. https://doi.org/10.1002/(sici)10981004(1998)11:1<1::aid-humu1>3.0.co;2-o. 11. den dunnen jt, antonarakis se. mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. hum mutat 2000; 15:7–12. https://doi.org/10.1002/ (sici)1098-1004(200001)15:1<7::aid-humu4>3.0.co;2-n. 12. wildeman m, van ophuizen e, den dunnen jt, taschner pe. improving sequence variant descriptions in mutation databases and literature using the mutalyzer sequence variation nomen clature checker. hum mutat 2008; 29:6–13. https://doi.org/10.10 02/humu.20654. 13. richards s, aziz n, bale s, bick d, das s, gastier-foster j, et al. standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the american college of medical genetics and genomics and the assoc iation for molecular pathology. genet med 2015; 17:405–24. https://doi.org/10.1038/gim.2015.30. 14. roy s, coldren c, karunamurthy a, kip ns, klee ew, lincoln se, et al. standards and guidelines for validating next-generation sequencing bioinformatics pipelines: a joint recommendation of the association for molecular pathology and the college of american pathologists. j mol diagn 2018; 20:4–27. https://doi.org/10.1016/j.jmoldx.2017.11.003. 15. palacios im. nonsense-mediated mrna decay: from mechanistic insights to impacts on human health. brief funct genomics 2013; 12:25–36. https://doi.org/10.1093/bfgp/els051. 16. perrin-vidoz l, sinilnikova om, stoppa-lyonnet d, lenoir gm, mazoyer s. the nonsense-mediated mrna decay pathway triggers degradation of most brca1 mrnas bearing pre mature termination codons. hum mol genet 2002; 11:2805–14. https://doi.org/10.1093/hmg/11.23.2805. 17. findlay gm, daza rm, martin b, zhang md, leith ap, gasperini m, et al. accurate classification of brca1 variants with saturation genome editing. nature 2018; 562:217–22. https://doi.org/10.1038/s41586-018-0461-z. 18. hodgson s. mechanisms of inherited cancer susceptibility. j zhejiang univ sci b 2008; 9:1–4. https://doi.org/10.1631/jzus. b073001. 19. amendola lm, jarvik gp, leo mc, mclaughlin hm, akkari y, amaral md, et al. performance of acmg-amp variantinterpretation guidelines among nine laboratories in the clinical sequencing exploratory research consortium. am j hum genet 2016; 99:247. https://doi.org/10.1016/j.ajhg.2016.06.001. https://doi.org/10.1038/ng1295-428 https://doi.org/10.1136/jmg.38.6.361 https://doi.org/10.1126/science.8091231 https://doi.org/10.1093/annonc/mdq161 https://doi.org/10.1093/annonc/mdq161 https://www.ncbi.nlm.nih.gov/books/nbk1247/ https://doi.org/10.1016/j.cancergen.2017.02.001 http://doi.org/10.3998/3336451.0014.103 https://doi.org/10.1093/jlb/lsx038 https://doi.org/10.1002/%28sici%291098-1004%281998%2911:1%3c1::aid-humu1%3e3.0.co%3b2-o https://doi.org/10.1002/%28sici%291098-1004%281998%2911:1%3c1::aid-humu1%3e3.0.co%3b2-o https://doi.org/10.1002/%28sici%291098-1004%28200001%2915:1%3c7::aid-humu4%3e3.0.co%3b2-n https://doi.org/10.1002/%28sici%291098-1004%28200001%2915:1%3c7::aid-humu4%3e3.0.co%3b2-n https://doi.org/10.1002/humu.20654 https://doi.org/10.1002/humu.20654 https://doi.org/10.1038/gim.2015.30 https://doi.org/10.1016/j.jmoldx.2017.11.003 https://doi.org/10.1093/bfgp/els051 https://doi.org/10.1093/hmg/11.23.2805 https://doi.org/10.1038/s41586-018-0461-z https://doi.org/10.1631/jzus.b073001 https://doi.org/10.1631/jzus.b073001 https://doi.org/10.1016/j.ajhg.2016.06.001 determination of pathogenicity of breast cancer 1 gene variants using the american college of medical genetics and genomics and the association for molecular pathology guidelines e334 | squ medical journal, november 2019, volume 19, issue 4 20. maxwell kn, hart sn, vijai j, schrader ka, slavin tp, thomas t, et al. evaluation of acmg-guideline-based variant classification of cancer susceptibility and non-cancer-associated genes in families affected by breast cancer. am j hum genet 2016; 98:801–17. https://doi.org/10.1016/j.ajhg.2016.02.024. 21. ellard s, baple el, owens m, eccles dm, turnbull c, abbs s, et al. acgs best practice guidelines for variant classification 2018. association for clinical genomic science. https://www. acgs.uk.com/quality/best-practice-guidelines/. 22. biesecker lg, harrison sm. the acmg/amp reputable source criteria for the interpretation of sequence variants. genet med 2018; 20:1687–8. https://doi.org/10.1038/gim.2018.42. 23. abou tayoun an, pesaran t, distefano mt, oza a, rehm hl, biesecker lg, et al. recommendations for interpreting the loss of function pvs1 acmg/amp variant criterion. hum mutat 2018; 39:1517–24. https://doi.org/10.1002/humu.23626. 24. cusin i, teixeira d, zahn-zabal m, rech de laval v, gleizes a, viasolo v, et al. a new bioinformatics tool to help assess the significance of brca1 variants. hum genomics 2018; 12:36. https://doi.org/10.1186/s40246-018-0168-0. https://doi.org/10.1016/j.ajhg.2016.02.024 https://doi.org/10.1038/gim.2018.42 https://doi.org/10.1002/humu.23626 https://doi.org/10.1186/s40246-018-0168-0 department of radiology and molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: dranjalinm@gmail.com evaluation of diagnostic value of spect/ct imaging in post-radioiodine therapy in thyroid cancer asma al hatmi, *anjali jain, alok k. mittal, samir hussain sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 74–81, epub. 28 feb 22 submitted 30 jun 20 revision req. 1 nov 20; revision recd. 30 nov 20 accepted 26 dec 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.054 clinical & basic research abstract: objectives: this study aimed to investigate the value of single photon emission computed tomography/ computed tomography (spect/ct) imaging in well-differentiated thyroid cancer (dtc) after radioiodine (i-131) ablation/therapy for clinical staging and risk stratification. it also aimed to determine whether spect/ct would change the management plan or predict the clinical outcomes of dtc patients. methods: a total of 78 dtc patients underwent first post radioiodine therapy “whole body iodine-131 scintigraphy (wbs) along with spect/ct” at the department of radiology and molecular imaging, sultan qaboos university hospital, muscat, oman, between january 2014 and august 2017. differences between wbs and spect/ct, change in clinical staging, risk stratification and management were recorded. the clinical outcome at 6–12 months was recorded. a generalised mcnemar test was used to assess disagreement between wbs and spect/ct. results: according to the american thyroid association (ata) risk stratification, the sample showed low (35.8%), intermediate (53.8%) and high-risk groups (10.2%) on wbs, which changed to 44.8%, 38.4% and 16.6%, respectively, on spect/ct imaging. overall change in risk stratification was noted in 16.7% and tnm stage in 11.5% of patients after spect/ct imaging. spect/ct changed the therapeutic plan and clinical outcome in 19.2% of patients. conclusion: spect/ct allows better detection and characterisation of metastatic lymph nodes and distant metastasis in dtc patients compared to wbs imaging alone. it alters tnm staging, ata risk classification and management in a significant number of patients. it is recommended that spect/ ct should be done routinely along with wbs in well-differentiated thyroid carcinoma. keywords: thyroid cancer; iodine; ablation techniques; spect/ct; oman. advances in knowledge spect/ct has influenced american thyroid association risk stratification, tnm staging, management plan and clinical outcome in thyroid cancer patients. application to patient care this study recommends that spect/ct should be an integral part of whole body i-131 scintigraphy imaging protocol in differentiated thyroid cancer patients. thyroid cancer has a good prognosis andis considered a treatable disease. the 5-year survival rates are 99.8% for localised disease, 97.0% for regional metastases and 57.3% for distant metastases in well-differentiated thyroid cancer (dtc).1–3 it affects females more than males. the incidence of dtc is increasing globally over time due to the early detection of small lesions, which constitutes 87% of new cases.4,5 it is the second most common cancer among the omani population as reported by the ministry of health in 2016.6 treatment protocols of thyroid cancer patients vary depending on the initial american thyroid association (ata) risk classification.2 ata has divided thyroid cancer patients into three risk groups—low, intermediate and high risk.5 radioactive iodine (rai) treatment is an important aspect in the management of intermediateand high-risk group patients.2 after total thyroidectomy, patients receive the first dose of radioactive iodine and routinely undergo post-therapy planar whole body scintigraphy (wbs) which detects residual thyroid tissue, lymph nodes and distant metastasis.3,4 the addition of single photon emission computed tomography/computed tomography (spect/ct) to planar wbs increases the diagnostic accuracy by improving the anatomic localisation of iodine uptake in the scan which changes the clinical stage and ata risk classification.1,7 this further leads to alteration in the management plan such as the need for additional imaging, biopsy, surgery and external beam radiation or other systemic therapies.1,3 in addition to excellent three-dimensional local isation of abnormal iodine uptake, spect/ct helps in attenuation correction as well as detecting non-iodine avid distant metastases, which has a tremendous impact on the clinical outcome and rate of survival in dtc patients.3,8,9 many institutions recommend i-131 spect/ct as part of the imaging protocol in selected high-risk patients with inconclusive findings on planar https://creativecommons.org/licenses/by-nd/4.0/ asma al hatmi, anjali jain, alok k. mittal and samir hussain clinical and basic research | 75 imaging.1–3 this study examined the importance of spect/ct with i-131 wbs in omani patients, as there was no such similar study done locally. methods this retrospective study was conducted at sultan qaboos university hospital, muscat, oman. a computerised search of medical records of the patient database was made from the hospital information system and radiology information system (intellispace pacs enterprise, philips healthcare informatics inc., usa). a total of 183 patients who underwent postrai (ablation/therapy) whole body scintigraphy were recorded from january 2014 to august 2017. the inclusion criteria were: 1) patients with histopathologically proven well-differentiated thyroid carcinoma who underwent first rai therapy after total thyroidectomy; 2) patients on whom both, wbs planar and spect/ct were performed on the same day; and 3) availability of 6–12 months follow-up with diagnostic i-131 wbs. five patients were excluded because they did not have well-differentiated thyroid cancers on histopathology and another 94 patients were excluded as spect/ct was not performed. six patients were excluded because of the unavailability of 6–12 months follow up or diagnostic i-131 scan after the first therapy dose. finally, a total of 78 patients were included in the current study [figure 1]. after thyroidectomy, all patients received a high dose of radio-iodine for ablation/therapy. a diagnostic radioiodine scan was not performed as a protocol. oral radioiodine dose was administered based on the surgical and pathological status of the tumour. patients were classified into ata low, intermediate or highrisk groups. a 1.1–3.7 gbq of rai was administered to lowto intermediate-risk groups and >3.7 gbq was administered to high-risk group patients and patients with metastases as per departmental protocol. all patients were prepared with adequate thyroid hormone stimulation before the rai therapy. the majority of patients (83.4%) were kept off thyroxin for one month, while 16.6% of patients received recombinant thyroid-stimulating hormone (tsh) injection for thyroid hormone stimulation. a low iodine diet was recommended one week before rai therapy. whole-body i-131 imaging was performed 3–7 days after the radioiodine dose on symbia t-series dual-head spect gamma camera with multidetector ct scanner (siemens healthcare a/s, denmark). both wbs planar and spect/ct were acquired. initially, anterior and posterior wb planar images were acquired at a speed of 12 cm/minute with high energy parallel hole collimator matrix of 256 × 1,024 and photopeak at 364 kev with a 15% window. additional planar anterior images of the neck and lateral images of the abdomen were also acquired. at the same time, spect/ct images of the neck and chest were acquired from the skull base to the diaphragm. spect was acquired in step-and-shoot mode with 32 views and 180 degree rotation per detector. acquisition time was between 30–60 seconds per step. images were acquired with high energy parallel hole collimator with matrix of 128 × 128 and photopeak of 364 kev with a 15% window. ct images were acquired at 130 kev, reference mas 30 with 5 mm slice thickness. axial, sagittal and coronal reconstruction of images was done on the siemens workstation (siemens healthcare a/s). both wbs and spect/ct images were interpreted by a senior nuclear medicine physician, blinded to other laboratory and radiological image results. first, the planar images were interpreted. any foci of uptake higher than the surrounding background (other than the physiological sites of uptake) were considered abnormal. foci of abnormal iodine uptake in the medial portion of the lower neck, approximately in the thyroid bed, were categorised as positive for residual thyroid tissue. an abnormal focus of uptake in the lateral part of the neck was considered as lymph node metastases. foci of uptake that are very close to the medial part of the neck were equivocal for lymph node metastases.3 when more than one focus of uptake were seen in the medial part of the neck, the one with prominent uptake was considered as a residual tissue and the rest of the foci were interpreted as equivocal for lymph node metastases [figure 2]. foci of abnormal iodine uptake in mediastinum were categorised as mediastinal lymph node metastases, while abnormal foci adjacent to mediastinum were considered equivocal for lymph node metastases. abnormal uptake in lung fields was considered as positive or equivocal for lung metastases. all areas of abnormal uptake beyond the neck and chest were also considered as positive or equivocal for metastatic foci and possible locations (bone, brain, liver, etc.) were also recorded.3 the findings were recorded as positive, negative and equivocal for thyroid bed, lymph node metastasis and distant metastasis. spect/ct images were also reviewed as a second step. similarly, spect/ ct images were interpreted as positive and negative for thyroid bed, lymph node metastases and distant metastases. non-iodine avid lesions seen on ct were also recorded. changes observed in the interpretation of wbs planar and spect/ct were noted. changes in ata risk stratification and tnm staging were recorded.5,10 all patients were grouped into ata low-, evaluation of diagnostic value of spect/ct imaging in post-radioiodine therapy in thyroid cancer 76 | squ medical journal, february 2022, volume 22, issue 1 intermediateor high-risk groups and also categorised into four stages according to the 8th edition of the american joint committee on cancer (ajcc)/tnm staging of thyroid cancer. changes in management plans like biopsies, additional cross-sectional imaging and further therapies were recorded. clinical outcome like complete remission or additional treatment were noted on the 6–12 months follow-up. a database in the spss programme, version 23 (ibm corp., armonk, new york, usa) was created for statistical analysis. by using the generalised mcnemar test, disagreement between wbs planar and spect/ ct was assessed in three groups, including thyroid bed, lymph node metastases and distant metastasis. a p-value of <0.05 was considered statistically significant. this study was approved by sultan qaboos university hospital’s medical research ethical committee and did not require informed consent (mrec# 1567). results among the 78 patients included in our study, 64 (82%) were females and 14 (18%) were males. the age of the patients ranged from 7–76 years with a mean age of 41.6 ± 16. papillary carcinoma was the most common histopathology presenting in 96% of patients compared to follicular and papillary carcinoma with poorly differentiated components in 3% and 1% of patients, respectively. these included nine patients of mixed papillary with follicular carcinoma, two patients with an oncocytic variant, one with a diffuse sclerosing type and one with hurthle cell carcinoma. a background of multinodular goitre (mng) was reported in 14% of patients, 6% had graves’ disease, 10% had hashimoto thyroiditis and 19% lymphocytic thyroiditis. tsh levels for all patients during iodine administration were >30 miu/l. thyroglobulin (tg) levels ranged between 1–67,795 µg/l and tg antibodies were positive in 20.5% of patients. patients received high doses of radioactive iodine with activities ranging from 980–7,900 mbq. there was total agreement between wbs planar and spect/ct image findings in residual thyroid tissue uptake. out of 78 patients, 77 showed positive iodine uptake in thyroid bed on both, wbs planar and spect/ct images, suggesting residual thyroid tissue. only one patient did not show any iodine uptake in the thyroid bed on both planar and spect/ct images. there was a significant difference noted between the wbs planar and spect/ct images pertaining to lymph node metastases. on wbs planar imaging, 22 out of 78 patients were positive for lymph node metastases and 17 patients were equivocal for lymph node metastases. out of the 22 patients (positive for lymph node metastases on wbs planar imaging), only 12 were positive on spect/ct images. in the remaining 10 patients (with false-positive lymph nodal uptake on wbs planar images), uptake was seen in thyroid bed on spect/ct images. these 10 patients showed complete remission at 6–12 months follow-up with no requirement for a second rai dose. all equivocal lymph node metastases on wbs planar images were negative for lymph node metastases figure 2: thyroid bed versus lymph nodal metastases in a 76-year-old male patient. (a) anterior and (b) posterior i-131 whole body planar images reveal multiple foci of iodine uptake in medial and right lateral neck region consistent with thyroid bed residual and neck lymphadenopathy. (c) coronal spect/ct images of the neck showing iodine avid foci are localised in post-operative thyroid bed with no neck lymph nodal metastasis. figure 1: flowchart showing the selection process used for patient enrolment. asma al hatmi, anjali jain, alok k. mittal and samir hussain clinical and basic research | 77 on spect/ct imaging. the remaining 39 patients were negative for lymph node metastases on both wbs planar and spect/ct. there was a statistically significant difference between wbs planar and spect/ct imaging for lymph node metastases (p <0.01) [figure 2]. wbs planar imaging has shown distant metastases in five patients while two patients were equivocal for distant metastases. the most common site of metastases was the lung followed by bone and liver. spect/ct confirmed distant metastases in five patients, while two equivocal findings on wbs planar imaging turned out to be negative on spect/ct. there was a statistically significant difference between wbs and spect/ct imaging in distant metastases (p <0.01) [figure 3]. in addition, the ct portion of the spect/ ct also detected lung nodules in seven patients. these nodules did not show any iodine uptake on the post-therapy scan. two of these patients showed complete resolution of nodules in the 6–12 months follow-up diagnostic i-131 wbs with normal tg levels (<1 µg/l), denoting these nodules were likely to be inflammatory. however, five patients in the 6–12 months follow-up showed persistent lung nodules with raised tg levels and were suspicious for metastases. histopathologically, two patients showed papillary carcinoma with an oncocytic variant, one with poorly differentiated components, one follicular carcinoma and one papillary carcinoma. these patients were further evaluated by f-18 fluoro-deoxyglucose positron emission tomography/ computed tomography (fdg pet/ct) scan, which revealed abnormal increased fdg uptake and was considered as distant metastases of dtc. all of these patients were referred to an oncology centre and were treated with other systemic therapies (three patients) and radiotherapy (two patients) [figure 4]. the difference between wbs planar imaging and spect/ct imaging categorising in the thyroid bed, neck lymph node and distant metastasis is well demonstrated in figure 5. eight out of 10 patients with negative lymph node metastases on spect/ct imaging were restratified figure 4: non-iodine avid distant metastases in a 73-year-old male patient. (a) anterior and (b) posterior i-131 whole body planar images do not reveal any abnormal distant metastases. (c) spect/ct axial image showing non-avid multiple small pulmonary nodules. (d) 18-f fdg pet-ct axial fused image showing avid pulmonary nodules consistent with distant metastases. figure 3: iodine avid distant metastases in a 67-year-old female patient. (a) anterior and (b) posterior i-131 whole body planar images reveal multiple areas of abnormal iodine avid distant metastases. (c) spect/ct coronal image showing iodine avid multiple lung, liver and skeleton distant metastases. evaluation of diagnostic value of spect/ct imaging in post-radioiodine therapy in thyroid cancer 78 | squ medical journal, february 2022, volume 22, issue 1 from the intermediate to the low-risk group. risk stratification in two patients did not change due to the presence of extra thyroidal tumour extension. five out of seven patients with non-iodine avid metastases were restratified to high-risk group. ata thyroid cancer risk stratification in these patients was reported as low(35.8%), intermediate (53.8%) and high-risk groups (10.2%) on planar imaging, which changed to 44.8%, 38.4% and 16.6%, respectively, after spect/ct imaging. the overall change in risk stratification was noted in 13 (16.7%) out of 78 patients [table 1]. the percentage of change in tnm staging was smaller than the change in risk stratification. out of 10 patients with negative lymph nodes on spect/ ct, tnm staging did not change in eight patients. these patients were <55 years old and continued to be categorised as stage i according to tnm staging for thyroid cancer. spect/ct down-staged the disease in two patients, as they were >55 years of age. the status of seven patients with non-iodine avid lesions changed from m0 to m1, thus upstaging the disease. the overall change in clinical staging was seen in nine (11.5%) patients. all patients showing change in tnm staging and risk classification were from intermediateto high-risk groups. twelve patients with positive lymph nodes metastases on spect/ct imaging did not show remission at 6–12 months follow-up. these findings were correlated with neck usg and ct scans. out of these 12 patients, one underwent re-surgery for complete lymph nodal dissection after confirmation of disease on fine needle aspiration cytology (fnac). the rest of the patients underwent second rai therapy. ten false-positive lymph node metastases on wbs planar imaging (negative on spect/ct) showed complete remission on 6–12 months followup and did not require further rai therapy, leading to change in clinical outcome. all five patients with non-iodine avid metastases on spect/ct (proven with f-18 fdg pet/ct) were upstaged from m0 to m1, which resulted in a change in the management plan. a total of 15 (19.2%) patients showed changes in clinical outcome and management plan. ten patients with negative lymph nodes went into remission on follow-up, while five patients with non-iodine avid metastases required further treatment in terms of systemic therapy and radiotherapy. discussion spect/ct has become very popular in recent years. with the availability of hybrid cameras, it is being used frequently in nuclear medicine departments. both functional and structural imaging can be performed at the same time, giving maximum benefit in terms of diagnosis and further management. spect/ct is also being used with wbs planar imaging in dtc resulting in substantial advantage for diagnosis and localisation of the disease.11–19 in the current study, all patients with dtc, who underwent both wbs planar and spect/ct imaging after the first rai therapy were included. all the patients with only thyroid bed residual uptake showed no contradiction between wbs planar and spect/ ct findings. in some previous studies, spect/ct was acquired only in cases of diagnostic uncertainty and was not performed for clear thyroid bed residual uptake.7,15 in the current study, all patients with residual thyroid bed tissue also underwent spect/ct and had complete remission after the first round of rai therapy. another study has shown similar results in thyroid bed uptake.3 figure 5: bar graph showing a comparison of results between (a) wbs planer imaging and (b) spect/ct imaging. there is no discrepancy in thyroid bed residual tissue, while there is a significant change in interpretation of neck lymph node and distant metastasis. table 1: change in risk stratification after spect/ct thyroid cancer risk stratification (%) whole body planar imaging spect/ct low 35.8 44.8 intermediate 53.8 38.4 high 10.2 16.6 spect/ct = single photon emission computed tomography/computed tomography. asma al hatmi, anjali jain, alok k. mittal and samir hussain clinical and basic research | 79 different studies in the literature have shown the advantage of spect/ct over wbs planar imaging in lymph node metastases, distant metastasis and in the management of dtc patients.20–25 in the current study, there was a disagreement in nodal metastases between wbs planar and spect/ct imaging (p <0.01). these patients with false-positive nodes on wbs planar were downgraded on spect/ct images with complete remission of the disease at six months follow-up. on wbs planar imaging, these areas of iodine uptake were seen in the lateral or superior part of the neck and were interpreted as lymph node metastases, while they could be anatomically localised as residual thyroid tissue on three-dimensional tomographic acquisition of spect/ct images. similarly, foci of uptake equivocal for lymph node metastases on wbs planar could also be delineated as residual thyroid tissue in the thyroid bed on spect/ct. in total, 34% of lymph nodal disease status was changed with spect/ct, which is similar to previously reported results in the literature.7,16 these studies changed and reclassified the lymph nodal status in 34–36.4% of patients with spect/ct imaging. however; these studies also interpreted lymph nodal disease from n0 status to n1 and from nx status to n1. in the current study, lymph nodal status changed only from n1/nx to n0. this could be explained either by differences in interpretation of findings on wbs planar with high suspicion of lymph nodal metastases. it may also be due to differences in surgical techniques and higher number of neck dissection during surgery in the current study, reducing the possibility of residual lymph nodal disease. findings with distant metastases have also shown significant disagreement between wbs planar and spect/ct imaging (p <0.01). two patients in the current study with equivocal finding of distant metastases were found negative on spect/ct. as shown by other studies, spect/ct reduced the number of indeterminate foci of metastases and also differentiated between benign physiological uptake from pathological uptake.3,18 in the current study, one of the foci in the mediastinum was localised to be oesophageal uptake. in another patient, diffuse linear uptake of iodine was seen in the lung, which was characterised as infective on ct images and showed resolution after a course of antibiotic. this is possible as the ct portion of spect/ct not only localises foci of uptake but also characterises the disease. maruoka et al. have shown alteration of equivocal findings to benign findings in 38% of patients.3 the current study also showed a similar finding, although the number was much smaller. the detection of non-iodine avid lesions is very important in management since these patients cannot be treated with radioactive iodine and would need other treatment options. diagnosis of these lesions on the post-therapy scan would save time and cost of additional imaging and would lead to proper management of the patient. non-iodine lesions are also of prognostic significance and have a worse prognosis. in previous studies, authors have seen noniodine avid lesions in 21% of patients, while in the current study it was 9%.2 according to the literature, dedifferentiated thyroid cancer can show noniodine avid metastasis in 30% of cases and it is highly associated with certain aggressive histopathology like solid, insular and trabecular variants of poorly differentiated cancer, hürthle cell carcinoma, papillary thyroid cancer with cribriform, columnar or tall cell variants.1 the current study showed a significant difference in wbs planar and spect /ct imaging in ata risk stratification, tnm staging and management and thus the outcome of dtc. the current findings are similar to other studies where risk classification was changed in 6.4%, 25% and 35.6% of patients, respectively, after spect/ct and change in tnm stage was seen in 6.1%, 25.9% and 21% of patients.2,3,16,20,26 similarly, change in therapeutic plan was observed in 2.0%, 24% and 19.4% of patients after spect/ct.3,7,19 this variability in results may be explained due to differences in the qualitative assessment of image findings, patient population, age, histopathologies and variation in study protocols. some studies have performed diagnostic i-131 scan before rai therapy, while others did not.27,28 other studies have performed spect/ct only in equivocal cases, while some studies did not include low-risk patients, as these patients were not treated with rai.14,29 there were differences in study samples and type of analyses (lesion-based vs patientbased).2,19 overall, additional spect/ct imaging improves diagnostic accuracy, anatomic localisation and helps in further characterisation of lesions, especially equivocal areas of iodine uptake and non-avid iodine lesions. this alters the tnm staging and initial risk stratification of the patients. the management plan also changes accordingly and it avoids additional imaging in most cases. this study has limitations. it was a single-centre retrospective study with a small sample size and short term follow-up. secondly, metastases were diagnosed on thyroglobulin levels and imaging results, while histopathology was not always available. another limitation in this study was interpretation of wbs planar images with multiple foci of uptake in neck, where one prominent uptake was considered residual thyroid tissue and the rest of them as lymph node evaluation of diagnostic value of spect/ct imaging in post-radioiodine therapy in thyroid cancer 80 | squ medical journal, february 2022, volume 22, issue 1 metastases due to limitation of planar images to localise the area of uptake. it has been seen on spect/ ct images that residual thyroid tissue can be seen as multiple foci of uptake. conclusion spect/ct is a powerful diagnostic tool that allows better detection and further characterisation of lymph node and distant metastasis of well-differentiated thyroid carcinoma compared to wbs planar imaging alone. it also alters risk stratification, clinical staging and management plan of patients. it is recommended that spect/ct should be routinely performed in the evaluation of well-differentiated thyroid carcinoma patients after radioiodine therapy. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n aj and sh conceptualised the work. aj supervised the work. aah prepared the proposal and collected the data. aah and aj analysed and interpreted the data. aah drafted the manuscript. aj and akm reviewed and edited the drafted manuscript. akm collected, labelled and formatted the images. all authors approved the final version of the work. references 1. anca ma. radioiodine scintigraphy with spect/ct: an impor tant diagnostic tool for thyroid cancer staging and risk strati fication. j nucl med technol 2014; 42:170–80. https://doi. org/10.2967/jnumed.111.104133. 2. grewal rk, tuttle rm, fox j, borkar s, chou jf, gonen m, et al. the effect of posttherapy 131i spect/ct on risk classification and management of patients with differentiated thyroid cancer. j nucl med. 2010; 51:1361–7. https://doi.org/10.2967/ jnumed.110.075960. 3. maruoka y, abe k, baba s, isoda t, sawamoto h, tanabe y, et al. incremental diagnostic value of spect/ct with 131-i scintigraphy after radioiodine therapy in patients with welldifferentiated thyroid carcinoma. radiology 2012; 265:902–9. https://doi.org/10.1148/radiol.12112108. 4. avram am, fig lm, frey ka, gross md, wong kk. preablation i131 scans with spect/ct in postoperative thyroid cancer patients: what is the impact on staging? j clin endocrinol metab 2013; 98:1163–71. https://doi.org/10.1210/jc.2012-3630. 5. haugen br, alexander ek, bible kc, doherty gm, mandel sj, nikiforov ye, et al. 2015 american thyroid association manage ment guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. thyroid 2016; 26:1–133. https:// doi.org/10.1089/thy.2015.0020. 6. ministry of health. cancer incidence in oman 2016. from: https://www.moh.gov.om/documents/272928/1232802/can cer+incidence+in+oman+2016/3ff52524-8983-6088-147bfd09f7f262b4 accessed: nov 2020. 7. kohlfuerst s, igerc i, lobnig m, gallowitsch hj, gomez-segovia i, matschnig s, et al. post therapeutic (131)i spect/ct offers high diagnostic accuracy when the findings on conventional planar imaging are inconclusive and allow a tailored patient treatment regimen. eur j nucl med mol imaging 2009; 36:886–93. https://doi.org/10.1007/s00259-008-1044-2. 8. durante c, haddy n, baudin e, leboulleux s, hartl d, travagli jp, et al. longterm outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. j clin endocrinol metab 2006; 91:2892–9. https://doi.org/10.1210/jc.2005-2838. 9. bybel b, brunken rc, difilippo fp, neumann dr, wu g, cerqueira md. spect/ct imaging: clinical utility of an emerging tech nology. radiographics 2008; 28:1097–113. https://doi.org/10.1 148/rg.284075203. 10. tuttle rm, haugen b, perrier nd. updated american joint committee on cancer/tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer (eighth edition): what changed and why? thyroid 2017; 27:751–6. https://doi.org/10.1089/thy.2017.0102. 11. yamamoto y, nishiyama y, monden t, matsumura y, satoh k, ohkawa m. clinical usefulness of fusion of 131i spect and ct images in patients with differentiated thyroid carcinoma. j nucl med 2003; 44:1905–10. 12. ruf j, lehmkuhl l, bertram h, sandrock d, amthauer h, humplik b et al. impact of spect and integrated low-dose ct after radioiodine therapy on the management of patients with thyroid carcinoma. nucl med commun 2004; 25:1177–82. https://doi.org/10.1097/00006231-200412000-00004. 13. tharp k, israel o, hausmann j, bettman l, martin wh, daitzchman m et al. impact of 131i-spect/ct images obtained with an integrated system in the follow-up of patients with thyroid carcinoma. eur j nucl med mol imaging 2004; 31:1435–42. https://doi.org/10.1007/s00259-004-1565-2. 14. chen l, luo q, shen y, yu y, yuan z, lu h, et al. incremental value of 131i spect/ct in the management of patients with differential thyroid carcinoma. j nucl med 2008; 49:1952–7. https://doi.org/10.2967/jnumed.108.052399. 15. wong kk, zarzhevsky n, cahill jm, frey ka, avram am. incremental value of diagnostic 131i spect/ct fusion imaging in the evaluation of differentiated thyroid carcinoma. ajr am j roentgenol 2008; 191:1785–94. https://doi.org/10.2214/ajr.0 8.1218. 16. schmidt d, szikszai a, linke r, bautz w, kuwert t. impact of 131i spect/spiral ct on nodal staging of differentiated thyroid carcinoma at the first radioablation. j nucl med 2009; 50:18–23. https://doi.org/10.2967/jnumed.108.052746. 17. wang h, fu hl, li jn, zou rj, gu zh, wu jc. the role of single-photon emission computed tomography/computed tomography for precise localization of metastases in patients with differentiated thyroid cancer. clin imaging 2009; 33:49–54. https://doi.org/10.1016/j.clinimag.2008.06.024. 18. aide n, heutte n, rame jp, rousseau e, loiseau c, henryamar m, et al. clinical relevance of single-photon emission computed tomography/computed tomography of the neck and thorax in postablation 131i scintigraphy for thyroid cancer. j clin endocrinol metab 2009; 94:2075–84. https://doi. org/10.1210/jc.2008-2313. 19. spanu a, solinas me, chessa f, sanna d, nuvoli s, madeddu g. 131i spect/ct in the follow-up of differentiated thyroid carcinoma: incremental value versus planar imaging. j nucl med 2009; 50:184–90. https://doi.org/10.2967/jnumed.108.056572. https://doi.org/10.2967/jnumed.111.104133 https://doi.org/10.2967/jnumed.111.104133 https://doi.org/10.2967/jnumed.110.075960 https://doi.org/10.2967/jnumed.110.075960 https://doi.org/10.1148/radiol.12112108 https://doi.org/10.1210/jc.2012-3630 https://doi.org/10.1089/thy.2015.0020 https://doi.org/10.1089/thy.2015.0020 https://doi.org/10.1007/s00259-008-1044-2 https://doi.org/10.1210/jc.2005-2838 https://doi.org/10.1148/rg.284075203 https://doi.org/10.1148/rg.284075203 https://doi.org/10.1089/thy.2017.0102 https://doi.org/10.1097/00006231-200412000-00004 https://doi.org/10.1007/s00259-004-1565-2 https://doi.org/10.2967/jnumed.108.052399 https://doi.org/10.2214/ajr.08.1218 https://doi.org/10.2214/ajr.08.1218 https://doi.org/10.2967/jnumed.108.052746 https://doi.org/10.1016/j.clinimag.2008.06.024 https://doi.org/10.1210/jc.2008-2313 https://doi.org/10.1210/jc.2008-2313 https://doi.org/10.2967/jnumed.108.056572 asma al hatmi, anjali jain, alok k. mittal and samir hussain clinical and basic research | 81 20. wong kk, sisson jc, koral kf, frey ka, avram am. staging of differentiated thyroid carcinoma using diagnostic 131i spect/ct. ajr am j roentgenol 2010; 195:730–6. https://doi. org/10.2214/ajr.09.3458. 21. barwick t, murray i, megadmi h, drake wm, plowman pn, akker sa, et al. single photon emission computed tomography (spect)/ computed tomography using iodine-123 in patients with differentiated thyroid cancer: additional value over whole body planar imaging and spect. eur j endocrinol 2010; 162:1131–9. https://doi.org/10.1530/eje-09-1023. 22. xue yl, qiu zl, song hj, luo qy. value of 131 i spect/ct for the evaluation of differentiated thyroid cancer: a systematic review of the literature. eur j nucl med mol imaging 2013; 40:768–78. https://doi.org/10.1007/ s00259-012-2310-x. 23. avram am, esfandiari nh, wong kk. preablation 131-i scans with spect/ct contribute to thyroid cancer risk stratification and 131-i therapy planning. j clin endocrinol metab 2015; 100:1895–902. https://doi.org/10.1210/ jc.2014-4043. 24. shen ct, wei wj, qiu zl, song hj, luo qy. value of post therapeutic (131)i scintigraphy in stimulated serum thyrog lobulin-negative patients with metastatic differentiated thyroid carcinoma. endocrine 2016; 51:283–90. https://doi.org/10.10 07/s12020-015-0660-4. 25. wong kk, zarzhevsky n, cahill jm, frey ka, avram am. hybrid spect/ct and pet-ct imaging of differentiated thyroid carcinoma. br j radiol 2009; 82:860–76. https://doi. org/10.1259/bjr/25645894. 26. szujo s, sira l, bajnok l, bodis b, gyory f, nemes o, et al. the impact of post-radioiodine therapy spect/ct on early risk stratification in differentiated thyroid cancer; a bi-institutional study. oncotarget 2017; 8:79825–34. https://doi.org/10.18632/ oncotarget.19781. 27. ciarallo a, rivera j. radioactive iodine therapy in differentiated thyroid cancer: 2020 update. ajr am j roentgenol 2020; 215:285–291. https://doi.org/10.2214/ajr.19.22626. 28. ahmed n, niyaz k, borakati a, marafi f, birk r, usmani s. hybrid spect/ct imaging in the management of differentiated thyroid carcinoma. asian pac j cancer prev 2018; 19:303–8. https://doi.org/10.22034/apjcp.2018.19.2.303. 29. lamartina l, leboulleux s, terroir m, hartl d, schlumberger m. an update on the management of low-risk differentiated thyroid cancer. endocr relat cancer 2019; 26:r597–610. https://doi. org/10.1530/erc-19-0294. https://doi.org/10.2214/ajr.09.3458 https://doi.org/10.2214/ajr.09.3458 https://doi.org/10.1530/eje-09-1023 https://doi.org/10.1007/ s00259-012-2310-x https://doi.org/10.1210/ jc.2014-4043 https://doi.org/10.1007/s12020-015-0660-4 https://doi.org/10.1007/s12020-015-0660-4 https://doi.org/10.1259/bjr/25645894 https://doi.org/10.1259/bjr/25645894 https://doi.org/10.18632/oncotarget.19781 https://doi.org/10.18632/oncotarget.19781 https://doi.org/10.2214/ajr.19.22626 https://doi.org/10.22034/apjcp.2018.19.2.303 https://doi.org/10.1530/erc-19-0294 https://doi.org/10.1530/erc-19-0294 college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia; department of pediatrics, king fahad hospital of the university, al-khobar, saudi arabia e-mail: saalkhater@iau.edu.sa perception of saudi undergraduate students towards professionalism in medicine suzan a. alkhater sultan qaboos university med j, august 2021, vol. 21, iss. 2, pp. 378–385, epub. 29 aug 21 submitted 26 jun 20 revision req. 09 aug 20; revision recd. 30 aug 20 accepted 23 sep 2020 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.019 clinical & basic research abstract: objectives: professionalism has garnered immense attention in medical education due to increased societal accountability and focus on excellence in healthcare. however, less attention has been given to identifying attitudes about professionalism in medical students who are the future advocates of the healthcare system. this study aimed to assess perceptions of saudi undergraduate medical students towards professionalism. methods: a crosssectional survey was carried out among second and sixth year students of the college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia, in september 2018. a self-administered professionalism questionnaire was anonymously completed. students were asked to provide their level of agreement with 18 survey items using a 5-point likert scale. results: overall, 288 students participated in the study (males: 49.3% and females: 50.7%), with a response rate of 90%. the median professionalism score was high (71.0; range: 64–76) regardless of age, gender or level of education. similar high scores were noted in the following subscales: excellence, 20.0 (range: 18–21); respect for others, 17.0 (14–18); altruism, 12.0 (10–13); duty, 8.0 (7–9); accountability, 7.0 (6–8) and honour and integrity, 8.0 (7–10). no gender differences were observed in the majority of subscales. however, males demonstrated higher scores in the duty subscale (males: 9.0 versus females: 8.0; p = 0.026). conclusion: medical students demonstrated high professionalism scores. future studies are needed to assess the impact of the course curriculum on their level of professionalism over time. keywords: attitudes; curriculum; medical students; professionalism; survey; saudi arabia. advances in knowledge the current literature shows an increased focus on medical professionalism in various contexts due to the positive impact of professional performance on the healthcare provided. the findings of this study reveal how undergraduate medical students at a saudi university perceive professionalism. application to patient care the study can help raise awareness of the significance of professionalism among students, faculty and the administration of medical universities. increased focus on teaching strategies on medical professionalism to medical graduates could contribute to their future success. implementing the learned attributes of professionalism during medical students’ undergraduate years could contribute to their future success and positively influence the quality of healthcare services provided. in recent years, the topic of professionalism has been in the spotlight as a mechanism for improving healthcare standards. the increased focus on professionalism in medicine can be attributed to increased demands for optimal performance by physicians, societal accountability and continuous professional development of medical students and trainees.1 one important area of development is the continuing emphasis on empathy toward the patient, which several studies have shown may suffer, if efforts are not undertaken during training to maintain proper attitudes and values.2 the medical school years provide the foundation during which lifelong professional standards are initiated and potentially established. the years that one spends as an undergraduate medical student represent a critical period that shapes future doctors. depending on a school’s vision for teaching professionalism, students are taught the art of professionalism either via principles integrated into their curriculum or by establishing a model of behaviour for these future doctors. in fact, studies have shown that medical students primarily learn professional values by following their role models through a ‘hidden curriculum’.3 this phenomenon is now well described in the literature as professional identity formation.4 although the best means of implementing the learned attributes of professionalism during undergraduate training remain uncertain, it is clear that integrating professionalism into the curriculum can positively influence the quality of healthcare provided.5,6 due to the positive impact of professional performance by healthcare providers, the current https://creativecommons.org/licenses/by-nd/4.0/ suzan a. alkhater clinical and basic research | 379 literature shows an increased focus on medical professionalism in various contexts. as a result, many studies tend to present various teaching strategies that medical educators can implement in undergraduate medical school curricula to impart professionalism to students.6–8 having recognised the value of teaching the art and science of professionalism to undergraduates and trainees, scholars have urged institutions to assess the attitudes of students and graduates towards professionalism and to measure the efficacy of the strategies implemented in the curriculum.9 however, these observations are difficult to generalise, primarily because the techniques used to teach professionalism vary widely.6,10 what complicates matters even further is the absence of a universally agreed-upon definition of the term ‘professionalism’ and the qualities or values that it constitutes.10–12 to address the variations in teaching methods and changes in curriculum development, diverse assessment tools are essential for evaluating the professionalism of recent medical graduates who have participated in new educational strategies.9 the undergraduate medical curriculum in saudi arabia has recently undergone a major shift from a traditional teacher-centred model to a self-directed learning model in which the student is the focus of attention, with the teacher merely acting as a facilitator of the learning process.13 this paradigm shift in learning strategy can result in different trends, attitudes and perceptions about professionalism that must be addressed according to the needs of the environment, including cultural demands, if any. a report on how medical professionals from arabic countries view the concept of professionalism in an arabian context acknowledged the existence of cultural differences that emphasise the need to add domains that address faith, values and history to the existing six domains of the american board of internal medicine (abim) framework of professionalism, which include ‘altruism’, ‘accountability’, ‘excellence’, ‘honour and integrity’, ‘duty’ and ‘respect’.14,15 western literature assessing students’ attitudes towards professionalism is rich; however, there are few studies in the arab world.14,16 measuring the attitudes of medical students towards professionalism becomes particularly important as institutes and national accreditation boards place increased emphasis on professionalism in medical practice.17 this study aimed to assess the perceptions of saudi undergraduate medical students towards professionalism in a single university and to compare levels of professionalism according to age, gender and level of education. methods this cross-sectional study was conducted at the college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia, in september 2018. the study invited all medical students enrolled in their second and sixth year (final year) of the bachelor of medicine and surgery (mbbs) programme to participate (n = 320). to ensure that the call for participation in the study reached the maximum number of students, the invitation was made in the students’ respective classrooms on the first day of classes and during the opening of new courses. instruction to students was provided by the researcher. information about the purpose of the table 1: items of the self-administered professionalism instrument developed by chisholm et al. administered to secondand sixth-year students enrolled in the college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia18 1 i do not expect anything in return when i help someone. 2 i attend class/clerkship/work daily. 3 if i realize that i will be late, i contact the appropriate individual at the earliest possible time to inform them. 4 if i do not follow through with my responsibilities, i readily accept the consequences. 5 i want to exceed the expectations of others. 6 it is important to produce quality work. 7 i complete my assignments independently and without supervision. 8 i follow through with my responsibilities. 9 i am committed to helping others. 10 i would take a job where i felt i was needed and could make a difference even if it paid less than other positions. 11 it is wrong to cheat to achieve higher rewards (i.e. grade or money). 12 i would report a medication error even if no one else was aware of the mistake. 13 i am able to accept constructive criticism. 14 i treat all patients with the same respect, regardless of perceived social standing or ability to pay. 15 i address others using appropriate titles and names. 16 i am diplomatic when expressing ideas and opinion. 17 i accept decisions of those in authority. 18 i am respectful to individuals who have different backgrounds than mine. tenets: excellence (items 2, 5, 7, 8, 17), respect for others (items 14, 15, 16, 18), altruism (item 1, 9, 10), duty (items 6, 13), accountability (items 3, 4), honour and integrity (items 11, 12). perception of saudi undergraduate students towards professionalism in medicine 380 | squ medical journal, august 2021, volume 21, issue 3 study, a description of the questionnaire and disclosure of the privacy policy were provided. the researcher explained to students that their participation was entirely voluntary and that participants could opt out of the study at any time. after instructions were given and informed written consent to participate in the study was obtained, the students were asked to complete the survey anonymously and confidentially. even if the students were working in the same class, they were expected to respond without discussing the items on the questionnaires with other students; thus, they were not aware of the other participants’ answers. this single-blind communication was practiced throughout the survey to ensure the individuality of the responses. the identity of the participants was not revealed to the investigators conducting the survey or during the analysis. questionnaires were collected on the same day they were distributed. the questionnaire used was a self-administered tool developed by chisholm et al. to assess professionalism that was later validated and found reliable when used to assess pharmacy and medical students.18–22 the professionalism instrument consists of a questionnaire that includes 18 statements (items) that measure the abim’s six tenets of professionalism. participants responded to each item using a 5-point likert scale with a corresponding scoring system consisting of the following responses: ‘strongly disagree’ (1), ‘disagree’ (2), ‘neutral’ (3), ‘agree’ (4) and ‘strongly agree’ (5). therefore, the higher the rating on the scale, the higher the level of professionalism [table 1]. the questionnaire was written in english and was manually distributed. demographic information on gender, age and year of study was also requested. prior to utilisation, the scale items were reviewed for clarity, comprehensiveness and content validity by the investigators and senior faculty members. the instrument was also pretested in a pilot study to check the students’ responses and assess the clarity and suitability of the items. this pilot study was performed on five females and five males who were randomly selected from secondand sixth-year classes. the students answered the items with ease; therefore no adjustments were required and their responses were added to the dataset. figure 1: the responses of 139 second-year students from the college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia, to items on the professionalism instrument. figure 2: the responses of 149 sixth-year students from the college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia, to items on the professionalism instrument. suzan a. alkhater clinical and basic research | 381 sample size was addressed by the authors of a systematic review of tools for assessing professionalism in pharmacy practice (which included the tool developed by chisholm et al).23 the researchers determined that a sample size of 150 was sufficient but more than 300 was desirable. the four studies considered eligible for review in the analysis ranged in size from 231 to 1,202. thus, for the current study, the sample size of 288 was deemed to be more than sufficient. a composite score for the entire professionalism scale and scores for the various subscales (tenets) were computed; the higher the score, the greater the level of professionalism associated with the student. demographic data are presented as numbers and frequencies. student responses to the professionalism instrument were normally distributed according to the kolmogorov-smirnov test and the shapiro-wilk’s test. hence the scores are reported as median and interquartile range in the tables. cronbach’s alpha coefficient was used to estimate the internal consistency of the assessment. since the total scores on the professionalism scale and subscales were not normally distributed, they are reported as medians and ranges (minimum, maximum) and the comparisons by age groups, gender and educational level were analysed by the mann-whitney u test. the level of significance was set at p <0.05. the data were analysed using statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa). the graphs were made using the r package likert, version 1.3.5 (r foundation for statistical computing, vienna, austria). written informed consent was obtained from the participants. the study received ethical approval from the institutional review board. table 2: comparison of the professionalism scale and sub scale scores across age groups according to the american board of internal medicine’s tenets of professionalism (n = 288) scale/subscale (min, max) overall median (iqr) <20 years median (iqr) 20–30 years median (iqr) p value* professionalism (18, 90) 71.0 (64–76) 73.0 (64–79) 70.0 (65–75) 0.094 subscale scores excellence (5, 25) 20.0 (18–21) 20.0 (17–22) 19.0 (18–21) 0.077 respect for others (4, 20) 17.0 (14–18) 17.0 (15–19) 16.0 (14–18) 0.311 altruism (3, 15) 12.0 (10–13) 12.0 (11–13) 11.5 (10–13) 0.013 duty (2, 10) 8.0 (7–9) 8.5 (7–9) 8.0 (7–9) 0.424 accountability (2, 10) 7.0 (6–8) 6.0 (5–7) 7.0 (6–8) 0.035 honour and integrity (2, 10) 8.0 (7–10) 9.0 (6–10) 8.0 (7–9) 0.644 min, max = minimum, maximum score; iqr = interquartile range. *p values based on the mann-whitney u test. table 3: comparison of the professionalism scale and sub scale scores by gender according to the american board of internal medicine’s tenets of professionalism (n = 288) scale/subscale (min, max) overall median (iqr) median for males (iqr) median for females (iqr) p value* professionalism (18, 90) 71.0 (64–76) 70.5 (64–76) 71.0 (66–77) 0.330 subscale scores excellence (5, 25) 20.0 (18–21) 19.0 (17–21) 20.0 (18–22) 0.091 respect for others (4, 20) 17.0 (14–18) 16.0 (14–18) 17.0 (15–18) 0.183 altruism (3, 15) 12.0 (10–13) 12.0 (10–13) 12.0 (10–13) 0.585 duty (2, 10) 8.0 (7–9) 9.0 (7–9) 8.0 (7–9) 0.026 accountability (2, 10) 7.0 (6–8) 6.0 (5–8) 7.0 (6–8) 0.374 honour and integrity (2, 10) 8.0 (7–10) 8.0 (6–9) 8.0 (7–10) 0.097 min, max = minimum, maximum score; iqr = interquartile range. *p values based on the mann-whitney u test. table 4: comparison of the professionalism scale and subscale scores across educational level according to the american board of internal medicine’s tenets of professionalism (n = 288) scale/subscale (min, max) overall median (iqr) second year median (iqr) sixth year median (iqr) p value* professionalism (18, 90) 71.0 (64–76) 72.0 (65–77) 70.0 (64–75) 0.105 subscale scores excellence (5, 25) 20.0 (18,–21) 20.0 (18–22) 19.0 (17–21) 0.016 respect for others (4, 20) 17.0 (14–18) 17.0 (15–19) 17.0 (14–18) 0.529 altruism (3, 15) 12.0 (10–13) 12.0 (10–13) 11.0 (10–13) 0.033 duty (2, 10) 8.0 (7–9) 8.0 (7–9) 8.0 (7–9) 0.592 accountability (2, 10) 7.0 (6–8) 7.0 (5–7) 7.0 (6–8) 0.203 honour and integrity (2, 10) 8.0 (7–10) 9.0 (6–10) 8.0 (7–9) 0.501 min, max = minimum, maximum score. *p values based on the mann-whitney u test; iqr = interquartile range. perception of saudi undergraduate students towards professionalism in medicine 382 | squ medical journal, august 2021, volume 21, issue 3 results of the 320 questionnaires distributed, 288 students responded (response rate: 90%). the participants included 139 second-year students (males: 66 [47.5%] and females: 73 [52.5%]) and 149 sixth-year students (males: 76 [51%] and females: 73 [49%]). the age of the participants ranged from 19 to 30 years. for the analysis, the age group of the participants was divided into two categories, <20 and 20–30 years old. a total of 90 (64.7%) second-year students were aged <20 years of age and 149 (100%) sixth-year students were 20–30 years old. the reliability analysis of the professionalism scale and subscales showed that cronbach’s alpha values for the professionalism scale were 0.904 for second-year students and 0.873 for sixth-year students, indicating high reliability of the instrument within each class. the ‘excellence’, ‘respect for others’ and ‘altruism’ subscales had acceptable cronbach’s alpha values. however, ‘duty’, ‘honour and integrity’, and ‘accountability’ subscales had poor cronbach’s alpha values (<0.6); therefore, the findings of these subscales need to be interpreted with caution. the majority of the second-year and sixthyear students either agreed or strongly agreed with the statements on the professionalism instrument, indicating the likelihood of a high level of profession alism in both groups [figures 1 and 2]. the overall median score on the professionalism scale was 71.0 (range: 64–76); this score was higher in students who were >20 years old than it was in older participants, but the difference did not reach statistical significance (73.0 versus 70.0; p = 0.094). the difference in scores for the ‘excellence’, ‘respect for others’, ‘duty and honour’ and ‘integrity’ subscales according to the age group of the participants, was not statistically significant. however, in the ‘altruism’ subscale, the score was significantly higher among younger students than older students (12.0 versus 11.5; p = 0.013). in the ‘accountability’ subscale, the score was higher among older students than younger students (7.0 versus 6.0; p = 0.035) [table 2]. the median score on the professionalism scale according to gender was 71.0 for females and 70.5 for males (p = 0.330). the scores for ‘excellence’, ‘respect for others’, ‘altruism’, ‘accountability’ and ‘honour and integrity’, though visibly different across multiple subscales, did not differ significantly according to gender. however, in the ‘duty’ subscale, the score was significantly higher among males than females (9.0 versus 8.0; p = 0.026) [table 3]. the median score on the professionalism scale according to the students’ level of education was 72.0 for second-year and 70.0 for sixth-year students (p = 0.105). the scores for the ‘respect for others’, ‘duty’, ‘accountability’ and ‘honour and integrity’ subscales did not yield a statically significant difference according to the students’ level of education. however, the scores were significantly higher among second-year students than sixth-year students in the ‘excellence’ (20.0 vs. 19.0; p = 0.016) and ‘altruism’ (12.0 versus 11.0; p = 0.033) subscales [table 4]. discussion the initiation and development of optimal profess ional behaviours among medical students are becoming increasingly necessary. therefore, the saudimed frame work recognises professionalism as one of the six comp etencies required by saudi medical graduates.24 these tenets include a scientific approach to practice, patient care, community-orientedpractice, communication and collaboration, professionalism and research and scholarship. essential methods for promoting profess ionalism include creating an educational environment that promotes the development of positive attitudes towards professionalism among undergraduate medical students.24 professionalism among medical graduates can be ensured only if sincere efforts are made to effectively measure it using reliable instruments. therefore, perfecting tools to measure professionalism has been a focus in recent years.25 in this study, students from two specific time points in the mbbs programme were studied: the secondand sixth-years. students in their second year of medical school were selected because this year represents the students’ first encounter with the medical curriculum. the first year of the programme is a preparatory year and represents the influence of general education on the student before joining the medical school programme. the other group comprised sixth-year (final year) students of the medical college who have experienced the entirety of the mbbs curriculum. this latter group represents the influence of the medical school programme on the students’ perception of professionalism. these two levels of study were selected to compare the two ends of the medical education curriculum and measure attitudes across undergraduate medical education. among the students surveyed, the median profess ionalism score was high. this finding is consistent with previous studies, which showed that medical students had above-average professionalism scores or high knowledge of professionalism.20,26 however, the findings in our study differ from those of other studies, which reported that medical students had unfavourable levels of professionalism and inadequate theoretical knowledge about professionalism.27,28 furthermore, it was found that, overall, the professionalism score was suzan a. alkhater clinical and basic research | 383 slightly higher among younger students than older students. the difference, however, was not statistically significant. previous studies have noted a decline in professionalism scores as students advance through their clinical clerkship.27 compared with sixth-year students, the second-year students in the current study had significantly higher scores on the ‘altruism’ and ‘excellence’ subscales. altruism, which is the essence of professionalism, emphasises the best interest of patients and not self-interest.15 the reason for this observation was not clear, but a similar observation was made by bhutto et al., who found that preclinical students had higher scores than clinical students on the ‘altruism’ subscale.20 additionally, in the current study, second-year students had significantly higher scores compared with sixth-year students on the ‘excellence’ subscale, which entails a conscientious effort to exceed ordinary expectations and make a commitment to life-long learning. it is likely that as sixth-year students approach graduation, they tend to be overwhelmed with the stress of clinical clerkships and specific marking schemes of medical schools that do not emphasise excellence. however, this idea contrasts with the finding of a previous study showing that clinical students had a higher level of excellence than preclinical students.20 in the current study, no gender differences in the level of professionalism were found, a finding consistent with the results of previous studies.20,27,28 this suggests that the approaches used in delivering training on professionalism among the students appear to be gender-neutral. in addition, there were no differences in most of the subscale scores according to gender. however, compared to females, male students had significantly higher scores in the ‘duty’ subscale, which deals with the free acceptance of a commitment to service. the difference may be due to different gender roles in the setting due to cultural or religious reasons. future studies need to explore the potential reasons for gender differences in this subscale. although there were no differences in scores according to age groups, there were differences in subscale scores for ‘altruism’ and ‘accountability’. compared to students who were 20–30 years old, younger students had a significantly higher score on the ‘altruism’ subscale. the reason for this observation is not clear. furthermore, it was found that students <20 years of age had significantly lower scores on the ‘accountability’ subscale, which requires that physicians are accountable to their patients, society and their profession.15 perhaps this is due to older students being more likely to be mature and have more experience in being held accountable for their actions. this study intended to measure the perceptions of professionalism in saudi medical students; such studies can help raise awareness among students, faculty and the administration of saudi universities of the significance of professionalism to ensure standardised healthcare practices and contribute to the success of medical graduates. this study is among the few that have investigated professionalism among medical students in saudi arabia following the implementation of the saudimed framework to the new curriculum.29,30 secondly, this study used a questionnaire with high internal consistency and whose tenets have been validated in the arabian context.14 finally, this instrument and/or the tenets of professionalism used by this instrument have been adapted to assess professionalism among medical students in other parts of the arab region, asia and elsewhere.19–21,26,27 this study had some limitations. the instrument had a very low internal consistency for the ‘account ability’ subscale; overall, the items of this subscale were rated lowest by the survey participants. the reasons for these differences among subscales are not clear; however, social and cultural differences in how reprimand and punishment are perceived may contribute to lower accountability scores in this setting. several studies on academic integrity among saudi students have shown that some students tended to recommend more lenient sanctions.30,31 thus, there is a need to strengthen the level of accountability during their training. also, since professionalism is context-specific and culturally sensitive, there is a need to adapt the ‘accountability’ subscale to fit the arabic context. future studies should consider refinements of the instrument to obtain better internal consistency for the ‘accountability’ subscale. conclusion this study found that medical students in the surveyed institution had high scores of professionalism. the findings of the present study could be used to improve the training of undergraduate medical students on professionalism. future studies should assess the impact of the curriculum on the students’ profession alism scores after adjusting for the effect of socio demographic characteristics of the participants. more over, there is a need to explore the contextual issues affecting the subscales of professionalism according to the gender and level of education of the students and a longitudinal study is needed to assess the impact of the course curriculum on their levels of professionalism over time. perception of saudi undergraduate students towards professionalism in medicine 384 | squ medical journal, august 2021, volume 21, issue 3 a c k n o w l e d g e m e n t s special thanks are extended to dr. mona al-sheikh, associate professor of physiology and head of medical education department and examination center at imam abdulrahman bin faisal university, college of medicine, for her leadership and support of this project. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. cruess r, cruess s. updating the hippocratic oath to include medicine's social contract. med educ 2014; 48:95–100. https:// doi.org.10.1111/medu.12277. 2. batt-rawden sa, chisolm ms, anton b, flickinger te. teaching empathy to medical students: an updated, systematic review. acad med 2013; 88:1171–7. https://doi.org.10.1097/ acm.0b013e318299f3e3. 3. lehmann l, sulmasy l, desai s, acp ethics, professionalism and human rights committee. hidden curricula, ethics, and prof essionalism: optimizing clinical learning environments in becoming and being a physician: a position paper of the american college of physicians. ann intern med 2018; 168:506–8. https://doi. org/10.7326/m17-2058. 4. sethi a, schofield s, mcaleer s, ajjawi r. the influence of postgraduate qualifications on educational identity formation of healthcare professionals. adv health sci educ theory pract 2018; 23:567–85. https://doi.org/10.1007/s10459-018-9814-5. 5. brennan md. the role of professionalism in clinical practice, medical education, biomedical research and health care admin istration. j transl int med 2016; 4:64–5. https://doi.org/10.15 15/jtim-2016-0017. 6. birden h, glass n, wilson i, harrison m, usherwood t, nass d. teaching professionalism in medical education: a best evid ence medical education (beme) systematic review. beme guide no. 25. med teach 2013; 35:e1252–66. https://doi.org/10 .3109/0142159x.2013.789132. 7. guraya sy, guraya ss, almaramhy h. the legacy of teaching medical professionalism for promoting professional practice: a systematic review. biomed pharm j 2016; 9:809–17. https://doi. org/10.13005/bpj/1007. 8. al-eraky mm. twelve tips for teaching medical professionalism at all levels of medical education. med teach 2015; 37:1018–25. https://doi.org/10.3109/0142159x.2015.1020288. 9. guraya sy, guraya ss, mahabbat na, fallatah ky, al-ahmadi ba, alalawi hh. the desired concept maps and goal setting for assessing professionalism in medicine. j clin diagn res 2016; 10:je01–5. https://doi.org/10.7860/jcdr/2016/19917.7832. 10. deangelis cd. medical professionalism. jama 2015; 313:1837–8. https://doi.org/10.1001/jama.2015.3597. 11. altirkawi k. teaching professionalism in medicine: what, why and how? sudan j paediatr 2014; 14:31–8. 12. birden h, glass n, wilson i, harrison m, usherwood t, nass d. defining professionalism in medical education: a systematic review. med teach 2014; 36:47–61. https://doi.org/10.3109/01 42159x.2014.850154. 13. telmesani a, zaini rg, ghazi ho. medical education in saudi arabia: a review of recent developments and future challenges. east mediterr health j 2011; 17:703–7. 14. abdel-razig s, ibrahim h, alameri h, hamdy h, haleeqa ka, qayed ki, et al. creating a framework for medical profession alism: an initial consensus statement from an arab nation. j grad med educ 2016; 8:165–72. https://doi.org/10.4300/ jgme-d-15-00310.1. 15. american board of internal medicine. medical professionalism in the new millennium: the physicians charter. from: https:// abimfoundation.org/what-we-do/physician-charter accessed: aug 2020. 16. abdulrahman m, alsalehi s, husain zsm, nair sc, carrick fr. professionalism among multicultural medical students in the united arab emirates. med edu online 2017; 22:1372669. https://doi.org/10.1080/10872981.2017.1372669. 17. tekian as, al ahwal ms. aligning the saudimed framework with the national commission for academic accreditation and assessment domains. saudi med j 2015; 36:1496–7. https://doi. org/10.15537/smj.2015.12.12916. 18. chisholm ma, cobb h, duke l, mcduffie c, kennedy wk. development of an instrument to measure professionalism. am j pharm educ 2006; 70:85. https://doi.org/10.5688/aj700485. 19. nakamura m, altshuler d, chadwell m, binienda j. clinical skills development in student-run free clinic volunteers: a multi-trait, multi-measure study. bmc med educ 2014; 14:250. https://doi.org/10.1186/s12909-014-0250-9. 20. bhutto sn, asif m, jawaid m. professionalism among medical students at two public sector universities – a comparative study. j postgrad med inst 2015; 29:3–8. 21. akhund s, shaikh za, ali sa. attitudes of pakistani and pakistani heritage medical students regarding professionalism at a medical college in karachi, pakistan. bmc res notes 2014; 7:150. https://doi.org/10.1186/1756-0500-7-150. 22. chisholm-burns ma, spivey ca, jaeger mc, williams j, george c. development of an instrument to measure pharmacy student attitudes toward social media professionalism. am j pharm educ 2017; 81:65. https://doi.org/10.5688/ajpe81465. 23. dubbai h, adelstein b-a, taylor s, shulruf b. definition of professionalism and tools for assessing professionalism in pharmacy practice: a systematic review. j educ eval health prof 2019; 16:22. https://doi.org/10.3352/jeehp.2019.16.22. 24. shadid am, bin abdulrahman ak, bin dahmash a, aldayel ay, alharbi mm, alghamdi a, et al. saudimeds and canmeds frameworks: similarities and differences. adv med educ pract 2019; 10:273–8. https://doi.org/10.2147/amep.s191705. 25. li h, ding n, zhang y, liu y, wen d. assessing medical profess ionalism: a systematic review of instruments and their measure ment properties. plos one 2017; 12:e0177321. https://doi.org/1 0.1371/journal.pone.0177321. 26. husain ne, elsheikh nma, elsheikh mn, mahmoud a, sukkar my, ibnouf mam, et al. final year medical students and profession alism: lessons from six sudanese medical schools? j public health emerg 2018; 2:27. https://doi.org/10.21037/jphe.2018.08.01. 27. sobani zu, mohyuddin mm, syed as, farooq f, qaiser kn, gani f, et al. professionalism in medical students at a private medical college in karachi, pakistan. j pak med assoc 2013; 63:935–9. https://doi.org.10.1111/medu.12277 https://doi.org.10.1111/medu.12277 https://doi.org.10.1097/acm.0b013e318299f3e3 https://doi.org.10.1097/acm.0b013e318299f3e3 https://doi.org/10.7326/m17-2058 https://doi.org/10.7326/m17-2058 https://doi.org/10.1007/s10459-018-9814-5 https://doi.org/10.1515/jtim-2016-0017 https://doi.org/10.1515/jtim-2016-0017 https://doi.org/10.3109/0142159x.2013.789132 https://doi.org/10.3109/0142159x.2013.789132 https://doi.org/10.13005/bpj/1007 https://doi.org/10.13005/bpj/1007 https://doi.org/10.3109/0142159x.2015.1020288 https://doi.org/10.7860/jcdr/2016/19917.7832 https://doi.org/10.1001/jama.2015.3597 https://doi.org/10.3109/0142159x.2014.850154 https://doi.org/10.3109/0142159x.2014.850154 https://doi.org/10.4300/jgme-d-15-00310.1 https://doi.org/10.4300/jgme-d-15-00310.1 https://doi.org/10.1080/10872981.2017.1372669 https://doi.org/10.15537/smj.2015.12.12916 https://doi.org/10.15537/smj.2015.12.12916 https://doi.org/10.5688/aj700485 https://doi.org/10.1186/s12909-014-0250-9 https://doi.org/10.1186/1756-0500-7-150 https://doi.org/10.5688/ajpe81465 https://doi.org/10.3352/jeehp.2019.16.22 https://doi.org/10.2147/amep.s191705 https://doi.org/10.1371/journal.pone.017732 https://doi.org/10.1371/journal.pone.017732 https://doi.org/10.21037/jphe.2018.08.01 suzan a. alkhater clinical and basic research | 385 28. seif-farshad m, bazmi s, amiri f, fattahi f, kiani m. know ledge of medical professionalism in medical students and phy sicians at shahid beheshti university of medical sciences and affiliated hospitals-iran. medicine 2016; 95:e5380. https://doi. org/10.1097/md.0000000000005380. 29. sattar k, abdulghani hm, meo sa, soliman mm, tauseef a, irshad m, et al. shaping medical professionalism in preclinical medical students: students perspective. biomed res 2017; 28:1001–5. 30. al-qahtani m, roff s. using the dundee polyprofessionalism inventory i: academic integrity to map student professionalism in 3 arab gulf countries. mededpublish 2017; 6:32. https://doi. org/10.15694/mep.2017.000201. 31. sattar k, roff s, meo sa. your professionalism is not my professionalism: congruence and variance in the views of medical students and faculty about professionalism. bmc med educ 2016; 16:285–7. https://doi.org/10.1186/s129090160807-x. https://doi.org/10.1097/md.0000000000005380 https://doi.org/10.1097/md.0000000000005380 https://doi.org/10.15694/mep.2017.000201 https://doi.org/10.15694/mep.2017.000201 https://doi.org/10.1186/s12909-0160807-x https://doi.org/10.1186/s12909-0160807-x 1departamento de biociencias, facultad de veterinaria, universidad de la república, montevideo, uruguay; 2instituto nacional de las mujeres, ministerio de desarrollo social, montevideo, uruguay; 3instituto de investigación médica m. y m. ferreyra (inimec-conicet-universidad nacional de córdoba) and facultad de psicología, universidad nacional de córdoba, córdoba, argentina *corresponding author’s e-mail: paulruiz@fvet.edu.uy change in psychoactive substance consumption in relation to psychological distress during the covid-19 pandemic in uruguay *paul ruiz,1 florencia semblat,2 ricardo m. pautassi3 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 198–205, epub. 26 may 22 submitted 9 dec 20 revisions req. 27 jan & 5 apr 21; revisions recd. 15 mar & 13 apr 21 accepted 16 may 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.106 clinical & basic research abstract: objectives: this study aimed to analyse how the health crisis associated with the covid-19 pandemic affected psychoactive substance consumption in uruguay. methods: an online survey was answered by 1,916 uruguayan citizens between march and april 2020 regarding psychoactive substance use before and after the instauration of a recommended quarantine, increases in frequency and volume of use (during the quarantine) of the psychoactive substance they reported as having consumed the most in the year prior to the quarantine and psychological distress experienced during the last month. results: the main substances consumed during the quarantine were alcohol, tobacco, marijuana and psychopharmaceuticals. approximately 28% of respondents increased the volume (and 17.7%, the frequency) of use of the substance they had consumed the most the year before the instauration of the quarantine. moreover, 5.7% initiated the consumption of a new psychoactive substance during the quarantine, mostly marijuana and psychopharmaceuticals. psychological distress was significantly higher among women, participants under 30 and among those that increased the volume of their most or second preferred psychoactive substance. the group reporting an increase in the volume of use exhibited greater psychological distress. conclusion: these results indicate an association between the instauration of the recommended quarantine in uruguay and greater psychoactive substance use during the period as well as an association between increased psychoactive substance use during this period and levels of psychological stress. these results are relevant in terms of public health and policies. keywords: covid-19; substance use; psychological distress; alcohol abuse; marijuana use; quarantine; uruguay. advances in knowledge certain precautionary measures taken for covid-19 such as quarantine can affect substance use. the psychoactive substances that showed a greater increase in consumption during the early phase of the covid-related quarantine in uruguay were alcohol, tobacco, marijuana and psychopharmaceuticals. an association was found between an increase in substance use and the levels of psychological distress. it is likely that the reported increase in the use of these substances indicates self-medicating behaviour, aimed at overcoming symptoms of anxiety and stress experienced during the pandemic. application to patient care psychological discomfort was greater in women and those under 30 years of age. women were more likely to have increased their tobacco and psychopharmaceuticals use. men were more likely to increase their marijuana and cocaine use. uruguay has endured several epidemics (the scarlet fever in 1836, yellow fever in 1857 and cholera in 1868) and pandemics (the flu in 1918); yet, research on how those events affected mental health is not available.1,2 the first positive cases of covid-19, the disease induced by a novel coronavirus referred to as severe acute respiratory syndrome coronavirus 2 (sars-cov-2), were detected in late 2019 in wuhan, china, although it emerged in uruguay in march 2020. by mid-march, four cases had been detected in uruguay and the disease had spread to several latin-american countries, prompting the uruguayan government to enforce a country-wide health emergency. the government established health and safety measures such as home quarantine and recommended non-mandatory closure of educational centres and public events and restriction of social gatherings. viral outbreaks, such as the one linked to sars in china in the early 2000s, exert significant consequences on mental health. wu et al. found that health workers who submitted to mandatory quarantine during the sars outbreak exhibited significantly more symptoms of alcohol use disorders three years later than those who had not experienced quarantine.3 bai et al. described stress-related symptoms in health workers from taiwan, who underwent quarantine during the outbreak.4 similarly, hawryluck et al. studied a sample of canadians exposed to quarantine measures and reported symptoms of posttraumatic stress disorder https://creativecommons.org/licenses/by-nd/4.0/ paul ruiz, florencia semblat and ricardo m. pautassi clinical and basic research | 199 (ptsd) and depression in 28.9% and 31.2% of the sample, respectively.5 interestingly, there was a positive association between the length of the quarantine and the prevalence of ptsd symptoms. the assessment of the effects of covid-19 on mental health is still ongoing, although preliminary data indicate an increase in stress, anxiety, insomnia, depression and fear across the globe.6,7 a study conducted in russia reported an increase in somatisation, phobias and sleep disorder symptoms since the beginning of the covid-19 pandemic.8 moreover, a survey conducted in italy on 2,291 participants showed an increase in anxiety disorders (32.1%) and ptsd (7.6%) compared to the period before the covid-19 outbreak.9 similarly, a survey on 7,236 chinese people revealed a high prevalence of symptoms of generalised anxiety (35.1%), depression (20.1%) and sleep disorders (18.2%), which mainly affected those ≤35 years old.10 information focused on the use of substances during the pandemic is still scarce; however, research conducted in india shows that 25% of the sampled participants exhibited symptoms of severe depression, anxiety (28.0%) or stress (11.6%) and these scores were associated with problematic alcohol drinking.11 australia reported an increase in the frequency of alcohol consumption during the covid-19 pandemic, which was in-turn associated with high levels of psychological distress.12 in some cases, the abrupt disruption of access to the substances was associated with severe complications. for instance, india reported a significant increase in hospital emergencies for treating alcohol abstinence, which was associated with a peak in suicide reports.13,14 in the usa, friedman et al. documented an increment of overdose-related cardiac arrests during the covid-19 pandemic, as registered by emergency medical services.15 reinstadler et al. showed that during the initial lockdown in response to the onset of the pandemic in austria, caffeine and cannabis use increased, amphetamine and methamphetamine use decreased and methylenedioxymethamphetamine use showed no significant changes.16 moreover, the global drug survey reported that cannabis and alcohol were the most consumed psychoactive substances during the covid-19 pandemic.17 in south america, a recent study has shown that the quarantine imposed in argentina to mitigate the spread of covid-19 was associated with temporal displacement of alcohol consumption (i.e. consumption during the weekend shifted to weekdays) as well as an increase in marijuana use among those who already consumed it before the pandemic.18 overall, these results are consistent with mckay’s hypothesis, which postulates an increase in psychoactive substance use during the covid-19 pandemic due to overstimulation of interoceptive awareness and arousal as well as an increase in anxiety.19 these changes promote the consumption and potential abuse of psychoactive substances in general; however a specific increase in alcohol and marijuana use has been reported due to their rewarding and antianxiety effects. notably, the market for addictive substances has been impacted during the pandemic as well.20,21 in uruguay, where the current research took place, press releases have suggested a significant (~30%) increase in the sale of wines; however, there is a dearth of scientific data on these issues. nonetheless, it is known that marijuana and alcohol rank among the most consumed psychoactive substances in uruguay. specifically, a recent nation-wide study revealed that among uruguayans aged 15–65 years, alcohol (52%) and tobacco (33%) were the substances with the highest level of habitual consumption (i.e. in the last 30 days), although lifetime prevalence of psychopharmaceuticals (27.2%), marijuana (23.3%) and cocaine (6.8%) use was also elevated.22 the general aim of the present study was to assess the potential impact of the covid-19 pandemic on the use of psychoactive substances in uruguay. specifically, the study investigated changes in frequency and quantity of such use over the period before and during the recommended quarantine and assessed factors (e.g. psychological stress) associated with heightened psychoactive substance use during and prior to the recommended quarantine. the differences in the occurrence of psychological stress as a function of age and gender were also analysed. these are factors that, in prior research, proved relevant in modulating psychological stress or to be involved in psychoactive substance self-administration.18,23 methods this cross-sectional study included uruguayan citizens aged at least 18 years. an online survey was conducted from 26 march (13 days after the recommended quarantine commenced) to 5 april 2020. the instruments used were compiled in an online questionnaire created using google forms. the link to the survey was distributed through email listings and academic and social networks such as facebook (facebook inc., menlo park, california, usa), instagram (instragram inc. menlo park, california, usa), twitter (twitter inc., san francisco, california, usa) and whatsapp (whatsapp inc., menlo park, california, usa), among others. thus, the sample was collected using convenience sampling. the invitation change in psychoactive substance consumption in relation to psychological distress during the covid-19 pandemic in uruguay 200 | squ medical journal, may 2022, volume 22, issue 2 emphasised the anonymity and academic nature of the study and contained a link. clicking the link redirected prospective participants to an active consent form, which led to the survey upon completion. there was no compensation for participating in the study. the inclusion criteria were being 18 years old or older, residing in uruguay and having consumed a psychoactive substance during the year before the recommended quarantine. several questions were asked about biological gender, age, place of residence (uruguay is divided into 19 departments), type of isolation during the recommended quarantine (total: leaving the household only for essentials; partial: leaving the household less frequently than usual), number of days spent in quarantine at the time of assessment, usual number of hours spent isolated/quarantined at home each day, employment status and, among those who reported working, weekly working hours. based on the study by pilatti et al., participants were asked about their use of psychoactive drugs during the 12-month period prior to the beginning of the recommended quarantine.18 participants chose among nine pre-set options—alcohol, marijuana, tobacco, cocaine, hallucinogens, ectasis, stimulants, ‘pasta’ (an inter mediate substance that is obtained during the manufac turing of cocaine hydrochloride and is somewhat popular in uruguay) or psychopharmaceutical substances without medical prescription such as benzodiazepines and an ‘other’ option. participants could answer ‘yes’ to several of those options. they were then asked which of those substances they had used the most during the last year. with respect to that psychoactive substance (i.e. their individually preferred or ‘firstchoice’ drug), they were asked about the frequency of use in the 12 months before the recommended quarantine (providing 10 options, ranging from daily to just once in the year) and during the recommended quarantine. following this, respondents were asked about their perception (yes/no) of heightened quantity of consumption (i.e. during the quarantine with respect to the year prior to the quarantine) of the psychoactive substance they had reported to use the most during the last year. in more detail, the specific question was ‘with regard to the drug that you used the most during the last year, did you notice that the volume of consumption increased during the recommended quarantine compared to the previous year (i.e. if it was alcohol, did you drink more glasses or litres; if it was tobacco, did you smoke more cigarettes; if it was marijuana, did you use more joints, etc.)?’. the answers to the question on individually preferred or first-choice psychoactive substance (during the last year) given by the different participants were obviously dissimilar. questions assessing the initiation of use of psychoactive substances during the quarantine (indicating that it had never been tried before) were also included. psychological distress was assessed via the kessler scale. this scale has 10 items in a five point likert-scale-type format. scores ranged from 10 to 50 (where higher values indicate higher levels of psychological distress) and provided information on unspecific psychological distress (anxiety or depression symptoms) suffered during the last month.24 a score under 20 indicates a normal level of psychological distress and those scoring 20–24, 25–29 and 30 or more exhibit mild, moderate or severe levels of psychological distress, respectively.25 in this study, the reliability (calculated via cronbach’s alpha) of the scores of the scale was adequate (α = 0.88) and similar to that reported in another study, in which the scale was applied to a different uruguayan sample.23 all the data were analysed using statistica 8.0 (statsoft inc., tulsa, usa). descriptive analyses of variables measuring psychoactive substance use (i.e. type of drug), time spent in quarantine and psychological distress were conducted separately based on gender (male, female), area of residence (the capital montevideo, rest of the country) and age (under or over 30 years). an analysis of variance (anova) using age and gender as between-groups factors was conducted on kessler scores. a one-way anova analysed whether the levels of psychological distress differed as a function of frequency of drug use (daily drug use, weekly drug use, some days of the week or no drug use) during the quarantine. separate anovas analysed whether those who reported to begin the use of new drugs or increased the volume of their main or second drug of choice during the quarantine manifested significantly higher levels of psychological distress than those who did not report those behaviours. a type i error was set at 0.05. one of the purposes of the study was to find factors associated with heightened psychoactive substance use during and prior to the recommended quarantine. as indicated, each participant identified the substance they had used the most during the year before the quarantine (i.e. the ‘preferred’ psychoactive substance) and then answered if they had increased the volume of use of that substance during the recommended quarantine. a binary logistic regression model on this dichotomous outcome (yes/no, as asked concerning increased volume of use of the ‘preferred’ psychoactive substance during the quarantine) was conducted. biological gender, age in years, type of quarantine (partial or total), region of residence (montevideo or other departments), psychoactive substance of choice paul ruiz, florencia semblat and ricardo m. pautassi clinical and basic research | 201 (i.e. most used substance) during the year before the quarantine and absolute kessler scores were variables used altogether to differentiate participants who had increased the volume of use from those who had not. a separate binary regression forecasted membership in the group that had showed a self-reported increase in the frequency of use of the preferred psychoactive substance using the predictor variables described above. for both logistic regressions and due to the low number of subjects exhibiting certain categories of response, the first-choice psychoactive substances were re-categorised as follows: tobacco (0, i.e. reference category against which odds ratios [ors] for the other substance were computed), alcohol (1), marijuana (2) and others (3). this study was designed and conducted in adherence to the indications of the declaration of helsinki. privacy and data confidentiality were maintained throughout the process. a specific ethical agreement is not needed in uruguay for the type of survey employed. results the survey was completed by 1,916 participants. a total of 53 cases were dismissed due to response inconsistencies; thus, the final sample was 1,863. uruguay’s population (~3.5 million) has slightly more women (51.6%) than men, and close to 40% of the population lives in montevideo. the country’s median age is 32.8 years.26 the sample consisted of approximately 66% women (mean age = 31.3 ± 0.3 years; 72.7% resided in montevideo) [table 1]. nearly 40% of the sample was in partial isolation (i.e. leaving the household less frequently than usual) at the time of the survey, whereas the remaining 61.4% was in total isolation (i.e. leaving the household only for buying essential goods or emergency essentials). at the time of the survey, participants had spent a mean of 13 ± 3.9 days in isolation. slightly less than half of the sample (44%) exhibited normal distress scores, whereas 19.3%, 17.9% and 18.7% exhibited mild, moderate and high levels of distress, respectively [tables 2 and 3]. approximately, one third of the participants (30.3%) reported daily use of the psychoactive substance of choice during the quarantine, whereas 23.9% reported using psychoactive substances several days a week and 9.1% once a week. a portion (28%) of the sample reported having increased the volume of the psycho active substance of choice during isolation and 17.7% reported an increase in the frequency of use. a minority (5.7%) reported having initiated the use of new psycho active substances, mainly marijuana or psychopharma ceuticals, during the quarantine [table 3]. prevalence of psychoactive substance use during the year before the quarantine was 89.7% (alcohol), 55.8% (marijuana), 40.9% (tobacco), 20.8% (psycho pharmaceuticals), 17.4% (hallucinogens), 14.1% (ecstasy), 10.8% (cocaine), 4.7% (stimulants), 1.3% (ketamine) and 0.4% (pasta). when asked about the most consumed psychoactive substance (i.e. the psychoactive substance of choice) during the past year, the majority indicated alcohol (54.7%), followed by tobacco and marijuana (19.2% and 16.7%, respectively), psychopharmaceuticals (6.9%) and cocaine (0.9%) [table 4]. the anova on kessler total scores indicated significantly higher levels of psychological distress in those aged ≤30 (f1,1859 = 52.1; p <0.001) and in women (f1,1861 = 104.1; p <0.001). the interaction between age and gender was not significant. the levels of psychological distress were affected by the frequency of psychoactive substance use during the quarantine (f5,1397 = 5.2; p <0.001). least significant difference post-hoc tests indicated that participants reporting daily psychoactive substance use during the quarantine exhibited significantly higher levels of psychological distress (22.89 ± 0.33) than those who reported using psychoactive substances on a weekly basis (21.02 ± 0.51) or only during some days of the week (21.4 ± 0.34; p <0.05). similarly, those who used new psychoactive substances (f1,1850 = 38.5; p <0.001) or increased the volume of their preferred psychoactive substance (i.e. that substance used the most during the year table 1: gender-wise distribution of socio-demographic data of uruguayan citizens including information regarding age, geographical area and type of isolation during the covid-19 pandemic (n = 1,863) characteristic n (%) male (n = 636) female (n = 1,227) age* in years mean 32.7 ± 0.4 31.3 ± 0.3 <30 290 (45.6) 697 (56.8) >30 345 (54.3) 529 (43.1) geographic area montevideo 472 (74.2) 892 (72.7) rest of the country 164 (25.8) 335 (27.3) type of isolation total† 349 (54.9) 795 (64.8) partial‡ 287 (45.1) 432 (35.2) *two participants did not provide their age in the survey. †total: leaving the household only for essentials. ‡partial: leaving the household less frequently than usual. change in psychoactive substance consumption in relation to psychological distress during the covid-19 pandemic in uruguay 202 | squ medical journal, may 2022, volume 22, issue 2 table 4: frequency distribution of participants that selected a given psychoactive substance as their individually preferred or ‘first-choice’ drug during the year prior to the current survey among uruguayan citizens (n = 1,863) characteristic total n (%) alcohol tobacco marijuana psychopharmaceuticals cocaine *other drugs gender male 636 345 (54.2) 102 (16.0) 146 (23.0) 23 (3.6) 10 (1.6) 10 (1.6) female 1,227 674 (54.9) 255 (20.8) 165 (13.4) 106 (8.6) 7 (0.6) 20 (1.6) geographic area montevideo 1,364 753 (55.2) 254 (18.6) 230 (16.9) 93 (6.8) 11 (0.8) 23 (1.7) rest of the country 499 266 (53.3) 103 (20.6) 81 (16.2) 36 (7.2) 6 (1.2) 7 (1.4) age group† in years <30 987 547 (55.4) 158 (16.0) 207 (21.0) 53 (5.4) 6 (0.6) 16 (1.6) >30 874 470 (53.8) 199 (22.8) 104 (11.9) 76 (8.7) 11 (1.3) 14 (1.6) type of isolation total‡ 1,144 630 (55.1) 217 (19.0) 187 (16.3) 85 (7.4) 7 (0.6) 18 (1.6) partial§ 719 389 (54.1) 140 (19.5) 124 (17.2) 44 (6.1) 10 (1.4) 12 (1.7) *drugs such as lysergic acid diethylamide, ecstasy, ketamine and others. †two participants did not provide their age in the survey. ‡total: leaving the household only for essentials. §partial: leaving the household less frequently than usual. table 2: socio-demographic data of uruguayan citizens including information regarding participants’ employment hours and isolation during covid-19 (n = 1,863) characteristic mean ± sd number of days in isolation number of hours a day in isolation number of working hours per week gender male 12.9 ± 0.2 19 ± 0.2 25.9 ± 0.8 female 13 ± 0.1 19 ± 0.2 21 ± 0.5 geographic area montevideo 12.9 ± 0.1 19.1 ± 0.2 24.3 ± 0.5 rest of the country 13.2 ± 0.2 18.7 ± 0.2 18.3 ± 0.8 age group in years <30 12.9 ± 0.1 19.2 ± 0.2 17.9 ± 0.6 >30 13.1 ± 0.1 18.7 ± 0.2 28.1 ± 0.6 type of isolation total* 13.2 ± 0.1 20.4 ± 0.2 20.7 ± 0.6 partial† 12.7 ± 0.1 16.8 ± 0.2 25.8 ± 0.7 sd = standard deviation. *total: leaving the household only for essentials. †partial: leaving the household less frequently than usual. table 3: self-reported initiation of a new drug use during the recommended quarantine and psychological distress scores (based on the kessler psychological distress scale) as a function of gender, geographic area, age group and type of isolation during covid-19 among uruguayan citizens (n = 1,863) characteristic total initiation of a new drug psychological distress n (%) mean ± sd gender male 636 33 (5.2) 19.4 ± 0.2 female 1,227 73 (6.0) 23 ± 0.2 geographic area montevideo 1,364 84 (6.2) 21.9 ± 0.2 rest of the country 499 22 (4.4) 21.5 ± 0.3 age group* in years <30 987 62 (6.3) 22.9 ± 0.2 >30 874 44 (5.0) 20.5 ± 0.2 type of isolation total† 1,144 55 (4.8) 21.8 ± 0.2 partial‡ 719 51 (7.1) 21.7 ± 0.2 sd = standard deviation. *two participants did not provide their age in the survey; †total: leaving the household only for essentials; ‡partial: leaving the household less frequently than usual. paul ruiz, florencia semblat and ricardo m. pautassi clinical and basic research | 203 before the quarantine; f1,1872 = 44.2; p <0.001) or the volume but not the frequency of their second most preferred psychoactive substance (f1,1247 = 9.5; p <0.01), manifested significantly higher levels of psychological distress than those who did not report those behaviours. the logistic regression model was statistically significant (χ2 = 162.05; p <0.001). the model (nagelkerke’s r2) explained 12% of the variance and the hosmer–lemeshow test was not significant (χ2 = 4.25; p >0.80), corroborating the good fit. overall, the correct classification of cases was 72.4%, although the sensitivity of the model was low. specifically, sensitivity and specificity were 16.1% and 94.7%, respectively. in other words, the model’s ability to correctly forecast membership in the group that reported increased volume of the preferred psychoactive substance (i.e. that which was used the most during the year before the quarantine) was rather low. only two factors achieved statistical significance: psychological distress and the preferred psychoactive substance. higher distress scores were associated with a significantly higher probability of membership in the group that increased the volume of use of the substance of first choice (or = 1.05; 95% confidence interval [ci]: 1.03–1.06; p <0.001). moreover, those who reported using alcohol (or = 3.28, 95% ci: 2.15–5.00; p <0.001) or the ‘other’ category item (which included cocaine and psychopharmaceuticals [or = 2.97, 95% ci: 1.92–4.60; p <0.001]) as their drug of first choice were significantly more likely to be included in the group of increased volume of use than those using the reference category item (tobacco). the model was statistically significant (χ2 = 63.56; p <0.001), but the amount of variance explained was very low (nagelkerke’s r2= 0.06) and the hosmer– lemeshow test was also significant (χ2 = 37.06; p <0.001). altogether, it can be said that the model did not exhibit a good fit. this result was further corroborated by the positive and negative prediction values, which revealed the lack of proper classification (i.e. sensitivity and specificity were 0.0% and 100.0%, respectively). discussion this study presents relevant information on how the measures instituted to prevent the dissemination of the covid-19 pandemic affected psychoactive substance use in uruguay. the objective was to analyse differences in the occurrence of psychological stress in terms of factors such as age and gender that, in prior research, proved to be relevant in modulating psychological stress or involved in psychoactive substance selfadministration. traditionally, men exhibit greater psychoactive substance use than women, although the latter progress more rapidly to problematic alcohol consumption than the former and psychological distress tends to be greater in women than in men.18,24,26 involvement in psychoactive substance use during the recommended home quarantine was also analysed and found to be associated with levels of psychological stress, among other variables. previously, it was reported that psychological distress was associated with negative, alcohol-related consequences in uruguayans aged 18–60 years.23 a sizable portion of the sample (18.7%) exhibited a high level of distress during the recommended quarantine. this report is troublesome, as prolonged exposure to psychological distress increases the likelihood of suffering from anxiety and depression. this finding implies that the health system in uruguay, and likely across the region, will probably have to face the challenge of a second wave of covid-19-related disabilities, involving alterations in mental health. moreover, it was found that psychological distress was associated with an increase in the volume of use of the individual’s psychoactive substance of choice and that those who reported daily use of this psychoactive substance or began to use a new psychoactive substance during the quarantine, exhibited higher levels of psychological distress than those who did not. these findings are consistent with previous reports from brazil and uruguay, indicating an association between psychological distress and psychoactive substance consumption.27,28 a previous study from the same authors as the current study, conducted years before the covid-19 outbreak, also linked the level of psychological distress to alcohol-related consequences in uruguayan youth.23 in the current study, the authors also found that levels of psychological stress were significantly higher in women than in men. close to a quarter of the sample reported an increase in the quantity of their preferred psychoactive substance use during the recommended quarantine. almost 20% of the sample showed an increase in the frequency of use of their preferred drug of choice and a sizable 30% exhibited daily psychoactive substance use. as was found in other countries, alcohol was the substance most used during the quarantine.29,30 alcohol and marijuana use are strongly driven by the need to reduce ongoing or anticipated negative effects related to psychological distress.31,32 thus, it is likely that the reported increase in the use of these substances indicates self-medicating behaviour, aimed at overcoming symptoms of anxiety and stress. consistent with this hypothesis, it was found that change in psychoactive substance consumption in relation to psychological distress during the covid-19 pandemic in uruguay 204 | squ medical journal, may 2022, volume 22, issue 2 kessler scores in those reporting daily psychoactive substance use during the quarantine were significantly higher than those observed in participants that consumed psychoactive substances either weekly or during some days of the week or that did not use psychoactive substances during the period. the results of the binary regression analyses were also consistent with the hypothesis that the increase in substance use during the recommended quarantine was driven by the need to reduce negative effects. specifically, membership in the target group (i.e. participants who reported an increase in the volume of use of the preferred psychoactive substance) was associated with greater psychological distress scores. notably, the likelihood of exhibiting such increase in volume was approximately three times higher in participants whose drug of first choice (during the year before the quarantine) was alcohol or drugs such as cocaine, psychopharmaceuticals or analgesics than in participants whose preferred drug was tobacco. the separate binary regression analysing factors associated with an increase in the frequency of use of the preferred psychoactive substance did not provide meaningful information. it should be noted, however, that the psychological distress scale used in the current study lacks validation in uruguay, which detracts from the validity of these findings. another limitation is that only two types of self-isolation (partial and total) were inquired about. future studies should further dissect the type of experiences that define isolation in the context of covid-19-related or other quarantines. conclusion this study presented the novel finding that during the first stage of the covid-19 pandemic, psychological distress levels were relatively high in the uruguayan population, particularly among women and those under 30 years of age. moreover, 28.3% of the participants increased the volume of use of the psychoactive substance they had reported using the most in the year before the quarantine and 17.7% increased the frequency of such use. those who reported such an increase in volume also reported higher levels of psychological distress than those who did not. these results indicate an association between the instauration of the recommended quarantine in uruguay and greater psychoactive substance use during the period. the findings from this study are relevant in context of its implications in the creation of more robust public health policies that can cater to the well-being of this psychologically vulnerable population. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n pr and fs conceptualised the study. all authors were involved in project administration. pr and rmp contributed to the visualisation, while fs and rmp performed the investigation. all authors collected the data and rmp analysed the data. all authors were involved in drafting the manuscript. all authors approved the final version of the manuscript. references 1. burgues s. la pandemia de gripe en uruguay (1918–1919). americanía. rev eur estud latinoam 2017; 6:167–206. 2. pollero r. similitudes y diferencias entre las epidemias del pasado y la pandemia actual de covid-19 en uruguay. claves. rev historia 2020; 6:317–26. https://doi.org/10.25032/crh.v6i10.17. 3. wu p, liu x, fang y, fan b, fuller c, guan z, et al. alcohol abuse/dependence symptoms among hospital employees exposed to a sars outbreak. alcohol alcohol 2008; 43:706–12. https://doi.org/10.1093/alcalc/agn073. 4. bai y, lin c, lin c, chen j, chue c, chou p. survey of stress reactions among health care workers involved with the sars outbreak. psychiatr serv 2004; 55:1055–7. https://doi. org/10.1176/appi.ps.55.9.1055. 5. hawryluck l, gold w, robinson s, pogorski s, galea s, styra r. sars control and psychological effects of quarantine, toronto, canada. emerg infect dis 2004; 10:1206–12. https://doi.org/10.3 201/eid1007.030703. 6. jiang x, deng l, zhu y, ji h, tao l, liu l, et al. psychological crisis intervention during the outbreak period of new coronavirus pneumonia from experience in shanghai. psychiatr res 2020; 286:112903. https://doi.org/10.1016/j.psychres.2020.112903. 7. torales j, o’higgins m, castaldelli-maia j, ventriglio a. the outbreak of covid-19 coronavirus and its impact on global mental health. int j soc psychiatry 2020; 66:317–20. https://doi. org/10.1177/0020764020915212. 8. enikolopov sn, boyko om, medvedeva ti, vorontsova ou, kazmina oy. dynamics of psychological reactions at the start of the pandemic of covid-19. psychol-educ stud 2020; 12:108–26. https://doi.org/10.17759/psyedu.2020120207. 9. casagrande m, favieri f, tambelli r, forte g. the enemy who sealed the world: effects quarantine due to the covid-19 on sleep quality, anxiety, and psychological distress in the italian population. sleep med 2020; 75:12–20. https://doi.org/10.1016/j.sleep.2020. 05.011. 10. huang y, zhao n. generalized anxiety disorder, depressive symptoms, and sleep quality during the covid-19 outbreak in china: a web-based cross-sectional survey. psychiatry res 2020; 288:1–6. https://doi.org/10.1016/j.psychres.2020.112954. 11. verma s, mishra a. depression, anxiety, and stress and sociodemographic correlates among the general indian public during covid-19. int j soc psychiatry 2020; 66:756–62. https://doi. org/10.1177/0020764020934508. https://doi.org/10.25032/crh.v6i10.17 https://doi.org/10.1093/alcalc/agn073 https://doi.org/10.1176/appi.ps.55.9.1055 https://doi.org/10.1176/appi.ps.55.9.1055 https://doi.org/10.3201/eid1007.030703 https://doi.org/10.3201/eid1007.030703 https://doi.org/10.1016/j.psychres.2020.112903 https://doi.org/10.1177/0020764020915212 https://doi.org/10.1177/0020764020915212 https://doi.org/10.17759/psyedu.2020120207 https://doi.org/10.1016/j.sleep.2020.05.011 https://doi.org/10.1016/j.sleep.2020.05.011 https://doi.org/10.1016/j.psychres.2020.112954 https://doi.org/10.1177/0020764020934508 https://doi.org/10.1177/0020764020934508 paul ruiz, florencia semblat and ricardo m. pautassi clinical and basic research | 205 12. biddle n, edwards b, gray m, sollis k. alcohol consumption during the covid-19 period: may 2020. centre for social research & methods, australian national university. from: https://csrm. cass.anu.edu.au/research/publications/alcohol-consumptionduring-covid-19-period-may-2020 accessed: apr 2021. 13. narasimha v, shukla l, mukherjee d, menon j, huddar s, panda u, et al. complicated alcohol withdrawal—an unintended conseq uence of covid-19 lockdown. alcohol alcohol 2020; 55:350–3. https://doi.org/10.1093/alcalc/agaa042. 14. ahmed s, khaium m, tazmeem f. covid-19 lockdown in india triggers a rapid rise in suicides due to the alcohol withdrawal symptoms: evidence from media reports. int j soc psychiatry 2020; 66:827–9. https://doi.org/10.1177/0020764020938809. 15. friedman j, beletsky l, schriger d. overdose-related cardiac arrests observed by emergency medical services during the us covid-19 epidemic. jama psychiatry 2021; 78:562–4. https://doi.org/10.1001/jamapsychiatry.2020.4218. 16. reinstadler v, ausweger v, grabher a, kreidl m, huber s, grander j, et al. monitoring drug consumption in innsbruck during coronavirus disease 2019 (covid-19) lockdown by wastewater analysis. sci total environ 2021; 757:1–11. https:// doi.org/10.1016/j.scitotenv.2020.144006. 17. grebely j, cerdá m, rhodes t. covid-19 and the health of people who use drugs: what is and what could be? int j drug policy 2020; 83:1–10. https://doi.org/10.1016/j.drugpo.20 20.102958. 18. pilatti a, read j, pautassi r. elsa 2016 cohort: alcohol, tobacco, and marijuana use and their association with age of drug use onset, risk perception, and social norms in argentinean college freshmen. front psychol 2017; 8:1452. https://doi.org/10.3389/ fpsyg.2017.01452. 19. mckay d. covid-19 stress and substance use: current issues and future preparations. j anxiety disord 2020; 74:102274. https://doi.org/10.1016/j.janxdis.2020.102274. 20. di trana a, carlier j, berretta p, zaami s, ricci g. consequences of covid-19 lockdown on the misuse and marketing of addictive substances and new psychoactive substances. front psychiatry 2020; 11:1–4. https://doi.org/10.3389/fpsyt.2020.584462. 21. european monitoring centre for drugs and drug addiction (emcdda). impact of covid-19 on drug markets, drug use, drug-related harms and responses in south european neighbourhood policy countries. from: https://www.emcdda. e uropa .e u/public ations/ad-ho cpublic ation/impact-ofcovid-19-on-drug-markets-drug-use-drug-related-harmsand-responses-in-south-european-neighbourhood-policycountries_en accessed: apr 2021. 22. junta nacional de drogas. vi encuesta nacional de hogares sobre el consumo de drogas. informe de investigación. from: https ://w w w.gub.uy/junta-nacional-droga s/sites/juntanacional-drogas/files/2018-01/oud_4ta_encuesta_drogas_ uruguay_hogares_2006.pdf accessed: apr 2021. 23. ruiz p, pilatti a, pautassi r. consequences of alcohol use, and its association with psychological distress, sensitivity to emotional contagion, and age of onset of alcohol use, in uruguayan youth with or without a college degree. alcohol 2020; 82:91–101. https://doi.org/10.1016/j.alcohol.2019.09.001. 24. kessler r, andrews g, colpe l, hiripi e, mroczek d, normand s, et al. short screening scales to monitor population prevalences and trends in non-specific psychological distress. psychol med 2002; 32:959–76. https://doi.org/10.1017/s0033291702006074. 25. andrews g, slade t. interpreting scores on the kessler psychological distress scale (k10). aust n z j public health 2001; 25:494–7. https://doi.org/10.1111/j.1467-842x.2001.tb00310.x. 26. randall c, roberts j, del boca f, carroll k, connors g, mattson m. telescoping of landmark events associated with drinking: a gender comparison. j stud alcohol 1999; 60:252–60. https:// doi.org/10.15288/jsa.1999.60.252. 27. merchán-hamann e, leal e, basso m, garcía e, reid p, kulakova o, et al. comorbilidad entre abuso/dependencia de drogas y el distrés psicológico en siete países de latinoamérica y uno del caribe. texto & contexto—enfermagem 2012; 21:87–95. https://doi.org/10.1590/s0104-07072012000500012. 28. domenech d, mann r, strike c, brands b, khenti a. estudio de la prevalencia de la comorbilidad entre el distrés psicológico y el abuso de drogas en usuarios del portal amarillo, montevideo— uruguay. texto & contexto—enfermagem 2012; 21:174–84. https://doi.org/10.1590/s0104-07072012000500022. 29. stanton r, to q, khalesi s, williams s, alley s, thwaite t, et al. depression, anxiety, and stress during covid-19: associations with changes in physical activity, sleep, tobacco, and alcohol use in australian adults. int j environ res public health 2020; 17:4065. https://doi.org/10.3390/ijerph17114065. 30. wardell j, kempe t, rapinda k, single a, bilevicius e, frohlich j, et al. drinking to cope during the covid-19 pandemic: the role of external and internal stress-related factors in coping motive pathways to alcohol use, solitary drinking, and alcohol problems. alcohol clin exp res 2020; 44:2073–83. https://doi. org/10.1111/acer.14425. 31. bravo a, sotelo m, pilatti a, mezquita l, read j. depressive symptoms, ruminative thinking, marijuana use motives, and marijuana outcomes: a multiple mediation model among college students in five countries. drug alcohol depend 2019; 204:107558. https://doi.org/10.1016/j.drugalcdep.2019.107558. 32. leeies m, pagura j, sareen j, bolton j. the use of alcohol and drugs to self-medicate symptoms of posttraumatic stress disorder. depress anxiety 2010; 27:731–6. https://doi.org/10.1002/da.20677. https://doi.org/10.1093/alcalc/agaa042 https://doi.org/10.1177/0020764020938809 https://doi.org/10.1001/jamapsychiatry.2020.4218 https://doi.org/10.1016/j.scitotenv.2020.144006 https://doi.org/10.1016/j.scitotenv.2020.144006 https://doi.org/10.1016/j.drugpo.2020.102958 https://doi.org/10.1016/j.drugpo.2020.102958 https://doi.org/10.3389/fpsyg.2017.01452 https://doi.org/10.3389/fpsyg.2017.01452 https://doi.org/10.1016/j.janxdis.2020.102274 https://doi.org/10.3389/fpsyt.2020.584462 https://doi.org/10.1016/j.alcohol.2019.09.001 https://doi.org/10.1017/s0033291702006074 https://doi.org/10.1111/j.1467-842x.2001.tb00310.x https://doi.org/10.15288/jsa.1999.60.252 https://doi.org/10.15288/jsa.1999.60.252 https://doi.org/10.1590/s0104-07072012000500012 https://doi.org/10.1590/s0104-07072012000500022 https://doi.org/10.3390/ijerph17114065 https://doi.org/10.1111/acer.14425 https://doi.org/10.1111/acer.14425 https://doi.org/10.1016/j.drugalcdep.2019.107558 https://doi.org/10.1002/da.20677 submitted 5 sep 21 1 revisions req. 24 oct 21 & 4 jan 22; revisions recd. 23 nov 21 & 18 jan 22 2 accepted 2 mar 22 3 online-first: march 2022 4 doi: https://doi.org/10.18295/squmj.3.2022.026 5 6 severe injuries in 9 children: is it due to child neglect? 7 case series from a regional hospital in oman 8 shamsa s. al balushi 9 10 department of pediatrics, ministry of health, muscat, oman 11 e-mail: shamsalkone@yahoo.com 12 13 abstract 14 child abuse and neglect (can) is a global phenomenon and has many forms. child neglect is the 15 most common form observed. can are serious incidents with medicolegal implications for the 16 caregivers. the recognition of can is still in its early stages in the middle eastern cultures such as 17 in oman where parental authority over children is traditionally sacrosanct. this case series presents 18 nine serious incidents from a regional hospital in oman that appears to fulfil the definition of child 19 neglect. all cases presented were diagnosed by suspected child abuse and neglect (scan) team. 20 this paper provides evidence that child neglect exists in oman and had resulted in death of some 21 children and led to significant physical, psychological and social sequelae in others. it also 22 addresses risk factors and management recommendations. the article also highlights scan team 23 experience along with the limitations of the current child protection services (cps) in oman. 24 keywords: child abuse; child neglect; child protection services; case series; oman 25 26 introduction 27 child abuse and neglect (can), also known as child maltreatment, is a global problem. 1 as per 28 world health organization (who), it includes all forms of physical and/or psychological ill-29 treatment, neglect or negligent treatment, sexual abuse and commercial or other exploitation, 30 resulting in actual or potential harm to the child‘s health, survival, development or dignity in the 31 context of a relationship of responsibility, trust or power. 2 child neglect, the most common form of 32 can, can occur in physical and emotional forms. 3 the prevalence of child neglect is estimated at 33 163/1000 for physical neglect and 184/1000 for emotional neglect. 1 in 2008, one-third of can 34 investigations in canada involved neglect. 4 35 mailto:e-mail:%20shamsalkone@yahoo.com mailto:e-mail:%20shamsalkone@yahoo.com 36 though well-studied and socially accepted in the euro-american populations, the concept is still 37 relatively new in the arabian gulf region. there is scarcity of studies reporting can in the arab 38 peninsula, which is sometimes attributed to a ‗culture of silence.‘ 5 medically reported cases thus 39 may represent the tip of the iceberg. 6 in oman, the available limited data suggest that all known 40 forms of can are prevalent. 7 41 42 the sultanate of oman ratified the convention on the rights of the child (crc) in 1996 8 and the 43 country‘s ministry of health has sought to implement international norms for management of can 44 as laid out in its clinical guidelines on child abuse and neglect. 9 however, the traditional omani 45 arab society (like its middle eastern peers) has a culture that consider parents—especially the 46 father—as the final authority for the wellbeing of their offspring. understandably, there is some 47 resistance from the community regarding medico-legal interference in child welfare. 5 thus, legal 48 action for can cases often tend to be avoided as demonstrated by the cases discussed below. 49 this paper aims to add to the emerging evidence that child neglect exists in oman and is associated 50 with significant trauma in children and even occasional deaths. the nine cases reported here have 51 been evaluated by the team that monitors suspected child abuse and neglect (scan) at rustaq 52 hospital (a regional hospital in oman) in 2020–21 and are proposed as examples of child neglect. 53 the fact that all the nine cases have emerge from a small region over just 9 months indicates the 54 necessity to study and act on this much-ignored problem. 55 56 this paper briefly recounts the nine cases of child neglect and how the hospital scan team 57 experienced and managed each. it brings out the risk factors, management recommendations, as 58 well as the practical limitations of the current child protection services (cps) in oman. ethical 59 permission was obtained from research and ethics review approval committee at the regional 60 health directorate, rustaq. verbal consent for the publication of each case was obtained from the 61 guardians. 62 63 the scan team: constitution and management 64 the scan team at the rustaq hospital (a regional secondary hospital) was constituted in 2020, led 65 by a pediatrician specialized in child abuse and neglect (the author of this paper). the medical 66 evaluation of the identified cases by scan team was conducted according to the international 67 standards. 10-12 as there is no qualified social worker in the hospital, the team has appointed a nurse 68 with a bachelor‘s degree in community health. there are physicians assigned from different wards 69 in the hospital including the er to notify the scan team of suspected cases. a radiologist and an 70 ophthalmologist are also part of the team when such evaluation is required. 71 72 in the cases described below, the history was obtained in a non-leading manner by interviewing the 73 caregivers, and where possible, the child. the scan team also interviewed other family members 74 where required to triangulate the data. the family‘s perceptions and concerns were acknowledged 75 and the team avoided the common pitfall of blaming the caregivers, rather engaged them in the 76 management plan. all children were medically examined for signs of other types of abuse or 77 neglect and to rule out other medical diagnoses. where can was suspected, there was continuous 78 liaison with the police, general prosecution, and the child protection delegate (social worker 79 assigned by ministry of social development (mosd). 80 81 case reports 82 case one 83 a 2-year-old toddler presented with chemical burn involving 20% body surface including eyes, 84 face, chest, and limbs. he required intubation and admission in the paediatric intensive care unit 85 (picu). his mother had an untreated mental disorder. born ‗unwanted,‘ the child was in the care of 86 an aunt since birth. on the day of injury, this aunt had a job interview, and she left the child in the 87 care of the mother at the latter‘s house. in the toilet used by the child, the father had left an opened 88 bottle of highly corrosive acid (sewage opener) for two days, and the child consumed it. the mother 89 later admitted of being aware of the bottle while the child was in toilet. the father of the child 90 admitted that the care of three other siblings of the child were also being neglected due to maternal 91 mental illness and his work commitments. the information provided in the case were mainly taken 92 from his primary caregiver (his aunt) which are consistent with the physical examination of the 93 child and with information given later by both parents. 94 95 the child remained hospitalised for two months and underwent multiple operations. he developed 96 significant disfigurement of his face in addition to vision and breathing problems. he also showed 97 symptoms of post-traumatic stress disorder (ptsd). meanwhile his caregiver (aunt) also admitted 98 being stressed with her own social and financial pressures. they were both referred for 99 psychological support in a specialised centre. the team was able to procure psychological and 100 financial assistance to them. the mother was encouraged to attend her missed psychiatric sessions. 101 however, efforts to bring the child‘s three siblings for medical examination were unsuccessful and 102 the current child protection system in oman failed to take further intervention. 103 104 case two 105 a baby boy, diagnosed with trisomy 21 at birth, was lost to follow up and then seen at age of 6 106 months when he was brought to the emergency room (er) by his grandmother with fever and 107 breathing difficulty for one week. he was diagnosed with heart failure (hf). before starting 108 treatment, the grandmother took away the child against medical advice claiming that his primary 109 caregiver (parents) were refusing admission and that they would take him to another hospital. 110 scan team tried to call the parents to ask about the child but received no response. child 111 protection delegate was involved but failed to bring the child back to hospital. the child was 112 brought again at age of 8 months with hf but again taken away against medical advice. scan 113 team was not involved this time. the child was brought back at age of 9 months for a routine 114 appointment and was found to have severe pulmonary hypertension and huge tamponade which 115 required pericardiocentesis. no home visit or legal escalation for child neglect was conducted. 116 117 case three 118 a 10-year-old boy was brought to er in critical condition which required immediate ventilation 119 and picu admission. the child sustained severe traumatic brain injury, grade iv liver injury, grade 120 v kidney injury, multiple fractures and lung contusion. he stayed for two months in picu and 121 underwent multiple operations. he had seizures and was on multiple anticonvulsants. on discharge, 122 the child was in a vegetative state. 123 124 scan team interviewed the mother, step-father, older brothers and uncles. the child was living 125 with his maternal grandparents as his father had died and his mother had married an old man and 126 was living in a very small accommodation. he was visiting his mother frequently. on the day of 127 injury, child was visiting his mother at her home when a cooking gas cylinder burst severely 128 injuring him and three others. the cylinder was kept in the narrow kitchen, just beside the 129 bedrooms and living room even though there was space for it outside the kitchen. the mother and 130 her husband had underestimated the safety risk. the child‘s uncles and older brothers raised their 131 concerns on the safety of the children at their mother‘s home. multidisciplinary team meeting was 132 conducted to plan social assistance for childcare after discharge. scan team has been following up 133 the child and his family situation. though the child protection delegate was involved, no home visit 134 was conducted by him and no legal action was taken. 135 136 case four 137 a 2-year-old girl was found drowsy, excessively sweating and very warm to touch after being 138 entrapped in a car for two hours. her mother had been driving with five children. when they arrived 139 home, she locked the car assuming everybody was out and then got busy with cooking. even 140 though the mother was notified that the child was not around, she assumed that she was playing. 141 on presentation to the hospital, the child had abnormal movements and features of heat stroke with 142 deranged liver and renal functions. she was managed in picu and recovered within 48 hours with 143 no neurological or behavioural sequelae. the liver and renal functions were normalised. the scan 144 team extensively counselled the parents and discussed the case with the child protection delegate 145 who interviewed the family by phone. 146 147 case five 148 a 13-month-old girl developed severe upper airway obstructive symptoms which required 149 ventilation and picu admission after ingesting hot water. her father had boiled water to prepare 150 formula, poured it into an open container which he left on the floor. though her parents were in the 151 same room they were not actively supervising her, and were alerted by her screams. with burns 152 involving anterior neck and upper anterior chest area, the child was ventilated for two days due to 153 severe airway obstruction. on follow up, she had no breathing or feeding issues. the scan team 154 gave extensive counselling to the parents. 155 156 case six 157 an 18-month-old boy sustained skull-fracture, intracranial and lung contusion and liver hematoma 158 that required picu admission after a fall from staircase at home. the balustrade had holes that 159 enabled the child to climb onto the guard-rail and ride down. he did this repeatedly. one week prior 160 to the injury a fall was prevented as his clothes became stuck. despite that incident, no effective 161 preventive measures were taken by the caregivers. in this case the child‘s injuries healed with no 162 sequelae. scan team counselled both parents. the child protection delegate was involved, but did 163 not engage in communication with the family. 164 165 case seven 166 a 4-year-old boy presented with burns involving 20% of the body surface area. he was intubated in 167 er due to peri-oral burn and lips swelling. at the day of injury, his uncle had taken him and other 168 four children, all below 12 years of age, to watch him burn dry grass in a small, closed room to get 169 rid of insects that infested the goats he had been keeping there. as the children huddled at the 170 entrance to watch, the uncle doused the grass with petrol and set light to it. fire went out-of-control, 171 severely burning this child and causing milder burns in other two children. after hospitalisation, the 172 uncle was counselled by scan team and the child protection delegate was informed. no further 173 actions were taken. 174 175 case eight 176 a15-month-old toddler was brought to the er with no breathing and no pulse after drowning in a 177 home swimming pool for an unknown period. the event happened when the mother was busy in the 178 kitchen. the pool was unfenced with easy access to small children. child survived after 20 minutes 179 of resuscitation however remained ventilator-dependent with severe neurological sequelae and died 180 after 3 months. the event was witnessed by four older siblings aged below 12 years. they 181 developed symptoms of ptsd, and scan arranged a management plan. however, the children did 182 not show up as the parents did not consider the intervention necessary. 183 184 case nine 185 a 4-year-old girl diagnosed with sickle cell disease (scd) was brought to the er in a state of 186 cardio-respiratory arrest with deep jaundice and severe pallor. the investigation results were: hb: 187 0.5 g/dl (n:11.5-15.5), platelets: 10x9/l (n:150-450), reticulocytes: 5% (n:0.2-2), urea 13mmol/l 188 (n:3.5-5.5), c-reactive protein: 243 (n<5), bilirubin: 117.5 umol/l (n<20). the child died despite 189 resuscitation attempts. scan team interviewed the parents who explained that the child had pain in 190 limbs, lethargy, and loss of appetite for two days, which was managed at home with pain 191 medications. on the morning of the day of presentation, the lethargy increased and child was 192 moaning. mother went to sleep and left the child and her siblings in the living room, and the father 193 left for work. when he returned, he found the child unconsciousness and brought her to the er. 194 parents have another child with scd and they acknowledged that they had been counselled about 195 the disease, but that this child‘s disease was mild. medical records indicated that her scd was not 196 being followed up, nor was she on any treatment, which the parents confirmed during the interview. 197 one year earlier the same child had been brought to the er with deep laceration near the eye after 198 falling from the staircase. the mother developed prolonged grief disorder and was referred for 199 treatment. the delegate called the caregiver by phone. no further action was taken in this case. 200 201 discussion 202 child neglect is the most common form of can. 3 at its core, neglect is a situation where the 203 child‘s normal development and safety is impeded by the failure of the caregiver to meet the child‘s 204 basic needs. 13,14 there are various types of child neglect as shown in table 1. 205 206 this paper features nine serious cases attributable to child neglect that were presented at the er of 207 rustaq hospital, a secondary regional hospital in oman, during a period of nine months. all cases 208 required picu admission except for one child (case 9) who died in er. eight out of the nine cases 209 were below the age of 5 years. at least in six cases there were preventable factors and warning 210 signs. if these signs had been heeded and timely action taken, the injuries might have been avoided. 211 a likely case of chronic neglect of several children in a family is illustrated by case-1. leaving an 212 ―unwanted‖ child even for a short time with his mentally ill mother seems prima facie an instance 213 of neglect by the caregivers, the aunt, and the father. it also represents significant neglect of home 214 safety by leaving open a dangerous chemical in a child‘s toilet. the fact that the father did not 215 present the remaining children for counselling despite invitation from the scan team is yet another 216 indication of ongoing chronic child neglect. 217 218 case-2 and case-9 represent severe professional challenge for any dedicated pediatrician. here the 219 caregivers not only neglected their child‘s serious symptoms, but after presentation refused medical 220 care. such phenomenon has been studied in oman and remedial procedural changes have been 221 made in hospitals. 17-19 the difficulty lies in the implementation, as the omani-arab tradition gives 222 primacy to parental authority over external intervention. however, over the years the state has been 223 increasingly able to intervene in clear cases of child neglect. 20 224 225 case 3 is an example of suboptimal home environment in the home of a non-custodial parent. the 226 child was exposed to physical neglect and ended up in a vegetative state due to explosion of gas 227 cylinder placed in a narrow kitchen. on the other hand, factors beyond parent‘s control such as 228 economic deprivation might explain the lower safety levels. therefore, various factors need be 229 considered before attributing cases to child neglect. 230 231 the economic deprivation argument may be less relevant in cases 4-8. these cases illustrate the 232 lack of caregiver attention to toddlers and perhaps a lack of awareness on child safety among 233 caregivers. in case 8, absence of physical safety provisions in a home swimming pool and absence 234 of supervision took the life of a toddler. in case 4, a mother fails to check for her infant left in the 235 car even after being reminded. similar cases with heat stroke and lack of supervision have been 236 reported in omani literature. 17,21 237 238 challenges faced and management recommendation 239 deciding whether a caregiver‘s behaviour was neglectful is often difficult. each case is unique with 240 many causative factors. therefore, attention and sensitivity while working with the family and the 241 child protection team is important. the team should aim to identify harm and to explore the factors 242 that led to neglect and with the intention to prevent similar occurrences, rather than presuming any 243 intentionality from the side of the parents because most seek the child‘s welfare. 22 244 245 several factors usually interact and result in neglect. 23 parental factors such as mental health issues 246 as in case 1 and child-related factors such as younger age. 23-26 lack of community centres and other 247 supportive resources are also associated with higher prevalence of neglect. 23 in case1, for example, 248 if there were alternative supportive resources such as a nearby nursery, the injury could have been 249 prevented. economic deprivation, as in case 3, might explain some unsafe home environments. 250 additionally, the traditional status of the father as having the ultimate say on the child makes 251 medical non-compliance more likely, as in cases 2 and 9. 252 253 it is apparent from the discussed cases that there is suboptimal management of can cases. in any 254 of these cases no legal action was taken, or home visits made. randomized controlled trials have 255 demonstrated that home visits are effective in reducing can in a society. 27 in addition, requests for 256 bringing siblings of the injured child for medical examination were not complied with. in fact, cases 257 4, 5, 6 and 8 give sufficient grounds for investigating the home environment of the caregivers. 258 there is also insufficient monitoring of home environments where children visit their non-custodial 259 parents and relatives. possible causes for such deficiency may include the underestimation of the 260 importance of the situation among professionals working with children. 28 traditional reticence in 261 the arab omani population against revealing family matters to outsiders may also play a role. 262 these can be modified over time through public education. health professionals need to be trained 263 to change false attitudes and to be more alert to abusive practices and behaviours of parents and 264 other caregivers 28 and to intervene (in a culturally appropriate manner) not only in one‘s own 265 family but also in one‘s neighbourhood. 266 267 conclusion 268 child neglect does exist in oman as it does elsewhere but is less visible here due to cultural factors 269 and inadequate social monitoring systems. the nine cases discussed in this paper, emerging from a 270 small region from oman during a short period, add to the evidence for occurrence of serious 271 incidents that sometimes result in death, as well as the medical and psychological sequalae in the 272 survivors and their families. this report highlights the need to upgrade and implement effective 273 community-based services and provide proper social support to victims and their families. there is 274 an absolute need for culturally adapted community awareness campaigns to help prevent child 275 neglect and minimise its significant adverse shortand long-term impacts. 276 277 references 278 1. stoltenborgh, m., bakermns-kranenburg, m. j., alink, l. r. a., & van ijzendoorn, m. h.. the 279 prevalence of can across the globe: review of a series of meta-analyses. child abuse rev 2015; 280 24(1), 37–50.doi: 10.1002/car.2353. 281 2. world health organization. child maltreatment, 2020. from: https://www.who.int/news-282 room/fact-sheets/detail/child-maltreatment accessed november, 2021. 283 3. br keeshin, h dubowitz. childhood neglect: the role of the paediatrician. paediatr child health 284 2013;18(8):e39-e43. 285 4. public health agency of canada. canadian incidence study of reported child abuse and 286 neglect – 2008: major findings.ottawa, canada .pp. 31. 287 5. al-saadoon, m., al-adawi, m. & al-adawi, s. socio-cultural constraints in protecting child 288 rights in a society in transition: a review and synthesis from oman. child ind res 2021; 14: 289 239–267. https://doi.org/10.1007/s12187-020-09759-z 290 6. al-mahroos f. child abuse and neglect in the arab peninsula. saudi med j 2007; 28:241–8. 291 7. al balushi s, morantz g & dougherty g. the emergence of child protection capacities in 292 oman.sultan qaboos univ med j 2021; doi: https://doi.org/10.18295/squmj.5.2021.073. 293 8. unicef oman. charting progress towards child protection in sultanate of oman – findings of a 294 national consultative workshop. muscat, oman: unicef. p.6. 295 9. oman ministry of health (moh). clinical guidelines on child abuse and neglect from: 296 https://www.moh.gov.om/documents/272928/3240138/clinical+guidelines+on+child+abuse+and297 +neglect.pdf/2a70b656-fe6c-a04a-9bdd-a6520db4b163. accessed september, 2021. 298 10. cindy w. christian, committee on child abuse and neglect: the evaluation of suspected 299 child physical abuse. pediatrics 2015;135;e1337. doi: 10.1542/peds.2015-0356. 300 11. christian cw, levin av, aap council on child abuse and neglect, aap section on 301 ophthalmology, american association of certified orthoptists, american association for pediatric 302 ophthalmology and strabismus, american academy of ophthalmology: the eye examination in 303 the evaluation of child abuse. pediatrics. 2018;142(2):e2018141. doi: https:// doi. org/ 10. 1542/ 304 peds. 2018-1411. 305 12. fisher-owens sa, lukefahr jl, tate ar, aap american academy of pediatrics, section on oral 306 health committee on child abuse and neglect, american academy of pediatric dentistry, council on 307 clinical affairs, council on scientific affairs, ad hoc work group on child abuse and neglect: oral and 308 dental aspects of child abuse and neglect. pediatrics. 2017;140(2):e20171487. doi: 309 10.1542/peds.2017-1487. 310 https://www.who.int/news-room/fact-sheets/detail/child-maltreatment https://www.who.int/news-room/fact-sheets/detail/child-maltreatment https://doi.org/10.1007/s12187-020-09759-z https://doi.org/10.18295/squmj.5.2021.073 https://www.moh.gov.om/documents/272928/3240138/clinical+guidelines+on+child+abuse+and+neglect.pdf/2a70b656-fe6c-a04a-9bdd-a6520db4b163 https://www.moh.gov.om/documents/272928/3240138/clinical+guidelines+on+child+abuse+and+neglect.pdf/2a70b656-fe6c-a04a-9bdd-a6520db4b163 13. b. marc, i. hanafy. children: neglect. in: encyclopedia of forensic and legal medicine, 311 second edition, jason payne-james, roger w. byard. elsevier, 2016, pp. 482-490. 312 14. dubowitz h, bennett s. physical abuse and neglect of children. the lancet 2007; vol 369, 313 pp1891-9. doi:10.1016/s0140-6736(07)60856-3 314 15. allnock d: child neglect: the research landscape. in: r gardner (ed): tackling child neglect: 315 research, policy and evidence based practice, 101-129. jessica kingsley publishers, 2016 316 16. blumenthal a: child neglect i: scope, consequences, and risk and protective factors. montreal 317 qc: centre for research on children and families. available at: 318 http://cwrp.ca/sites/default/files/publications/en/141e.pdf 319 17. al-saadoon m, al-sharbati m, el nour i, al-said b. child maltreatment types and effects: 320 series of six cases from a university hospital in oman. sultan qaboos univ med j 2012;vol. 12, 321 iss. 1, pp. 97-102 322 18. al-sadoon m and al-shamousi k. discharge against medical advice among children in oman 323 a university hospital experience. sultan qaboos univ med j 2013; vol. 13, iss. 4, pp. 534-538. 324 19. al saadoon m, al mahrouqi h, al jaafari n, al maawali h. reasons of discharge against 325 medical advice among children in oman:squh experience. conference poster presented at:14th 326 ispcan european regional conference on child abuse and neglect; 2015 sep; bucharest, 327 romania. 328 20. al saadoon m. impact of child law on hospital protection services:sultan qaboos university 329 hospital (squh) experience. poster presented at: ispcan asia pacific regional conference on 330 child abuse and neglect; 2015 oct; malaysia. 331 21. koul r, al-futaisi a, al-sadoon m, el-nour i, chacko a, hira m, et al. vehicular entrapment 332 and heat stroke in three children: is it a form of child neglect?. oman med j 2010. 333 doi:10.5001/omj.2010.61. 334 22. trocmé n, knoke d, fallon b, maclaurin b. differentiating between substantiated, suspected, 335 and unsubstantiated maltreatment in canada. child maltreat 2009;14:4-16. 336 23. avedibegović e and brkić m. child neglect-causes and consequences. psychiatr danub 2020; 337 vol. 32, suppl. 3, pp 337-342. 338 24. lamont a, price-robertson r: risk and protective factors for child abuse and neglect. cfca 339 resource sheet, 2017. available at: https://aifs.gov.au/cfca/publications/risk-and-protective-factors-340 child-abuse-and-neglect 341 25. appleyard k, berlin lj, rosanbalm kd, dodge ka. preventing early child maltreatment: 342 implications from a longitudinal study of maternal abuse history, substance use problems, and 343 offspring victimization. prev sci 2011;vol. 12, pp.139-49. 344 http://dx.doi.org/10.1016/s0140-6736(07)60856-3 http://cwrp.ca/sites/default/files/publications/en/141e.pdf 26. mulder tm, kuiper kc, van der put ce, assink m: risk factor for child neglect: a meta-345 analytic review. child abuse negl 2018; 77:198-210. 346 27. macmillan hl, wathen cn, barlow j, fergusson dm, leventhal jm, taussig hn. 347 interventions to prevent child maltreatment and associated impairment. the lancet 2009;373:250-348 66.doi: 10.1016/s0140-6736(08)61708-0 349 28. al saadoon m, al hadifi f, al-said b.recognition of child abuse: are we using same 350 definition. poster presented at: ispcan asia pacific regional conference on child abuse and 351 neglect; 2015 oct; malaysia. 352 353 https://doi.org/10.1016/s0140-6736(08)61708-0 table 1: types of neglect 354 type of neglect defention physical inadequate food, clothing, shelter, hygiene medical failure to provide prescribed medical care or treatment or failure to seek appropriate medical care in a timely manner dental failure to provide adequate dental care or treatment supervisional failure to provide age-appropriate supervision emotional failure to provide adequate nurturance or affection, failing to provide necessary psychological support, or allowing children to use drugs and/or alcohol educational failure to enroll a child in school or failure to provide adequate home schooling, failure to comply with recommended special education, allowing chronic truancy other includes exposing children to domestic violence, or engaging or encouraging children to participate in illegal activities such as shoplifting or drug dealing adapted from reference 15&16. 355 how the covid-19 pandemic affects the definition of a condition? a commentary on the diagnostic process of autism spectrum disorder *mona rafiei and amirhossein memari sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e164–165, epub. 21 jun 21 submitted 20 aug 20 revision req. 26 oct 20; revision recd. 30 nov 20 accepted 9 dec 20 neuroscience institute, tehran university of medical sciences, tehran, iran *corresponding author’s e-mail: m_rafiei@alumnus.tums.ac.ir autism spectrum disorders (asds) are known to adversely affect communication and social skills. according to the diagnostic and statistical manual of mental disorders (dsm)-5, social communication and interaction are of paramount importance in assessing asd. generally, social and environmental factors play a considerable role in psychological disorders and influence the process of development and socialisation.1 in the past decades, multiple studies have shown an increase in the rate of asd diagnosis.2 it is assumed to be the cause of the rise in asd diagnosis which ultimately led to the updating of the dsm-iv to the currently used dsm-5.3 however, it has been suggested that the application of diagnostic criteria is subject to clinical judgement by experts and can be inconsistent. the clinician must also obtain the patient’s history either from caregiver or child.3 in general, the involved individuals’ perception and experiences can affect the diagnostic process. in march 2020, the world health organization (who) characterised the covid-19 epidemic as a pandemic.4 during the covid-19 pandemic, experts suggested social distancing as an effective way of controlling the spread of this viral respiratory infection. some months later the who stated that covid-19 would be a disease that we would have to live with for some time and that some form of social distancing should return to the lives of the people. different countries took different measures in terms of their lockdown policies and therefore each society experienced a specific situation based on their government’s decision.4 many studies have researched the effects of quarantine and social distancing on mental status/ health.5,6 a study has shown that covid-19 has had psychological effects and led to increased difficulties among those with asd.7 individuals have to modify their behaviour, routines and adapt their attitude to changing environment. in fact, social media and social networking has enhanced interpersonal communication as people have acquired different communication skills, which has led to the creation of more groups, an increase in experiences and events that are social in nature.8 a possible explanation for this is that social norms can drive human behaviour.9 in the context of the covid-19 pandemic, social distancing can cause a change in daily routine and may cause changes in autistic behaviours, and therefore it may also alter the definition and diagnostic criteria of asd. as autistic behaviours are defined on a spectrum, there may be different interpretations among experts and between many diagnostic tools and manuals. being a spectrum, the matter of relativity should be considered in asds diagnosis; for example, when society is more interactive, group activities and team working are encouraged and individuals who appear to be introverted and have less sociable traits may be diagnosed with asd. on the other hand, when social isolation becomes an inevitable aspect of life, the line separating a non-asd life and an asd life shift and become blurred. since the beginning of 2020, individuals have been experiencing the fear of being infected with covid-19, mental issues, lack of information, lack of in-person contact, etc; this can have problematic and enduring effects on different social groups.10 while many genetic factors are considered in asd occurrence, the role of environmental factors in behavioural phenotypes is also evident.11 to some extent, a situational change can affect a definition of a condition which is assumed to have both genetic and environmental aspects. as far as children who may be more interested in ‘screen’ activities rather than physical activities, sedentary behaviours will increase in a situation where all team-sports and gatherings are forbidden.12 this can result in social avoidance traits long after the pandemic ends such as handwashing for those with obsessive-compulsive disorder and repetitive behaviour in non-asd people. pre-pandemic, children with asd benefited from social inclusion but it seems that nowadays people are getting used to autistic-like normality and those children cannot have social interaction as before.13 as a consequence of pandemic-induced isolation, the diagnostic criteria used for detecting autistic traits comment this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.002 https://creativecommons.org/licenses/by-nd/4.0/ comment | e165 will probably need modification. as several criteria are needed for the diagnosis of asd, clinicians may rely on criteria other than those related to social communication for the diagnosis of asd. previously, some experts had called asd the ‘new normal’ and hypothesised that the condition we know as the autism spectrum is in fact an evolutionary change of mind.14 taking the current pandemic into consideration, it is notable that asd seems to be reconsidered as the new normal. roy et al. stated that pandemic-related anxiety can lead to behavioural changes in society.15 in light of this, amaral and de vries stated that it is not the process of diagnosis but the confounding factors caused by the pandemic that can be misleading and will affect the prevalence of asd.16 although epidemiological phenomena are transient, they can impact different groups of people seriously in different aspects of life, after the phenomenon is ended. the impact can be more visible in individuals with previous history of mental health disorders.17 future research should focus on whether social distancing changes normal social behaviours and interest in peers as this could lead to a change in diagnostic criteria of asd. references 1. goldson e. advances in autism—2016. adv pediatr 2016; 63:333–55. https://doi.org/10.1016/j.yapd.2016.04.014. 2. kodak t, bergmann s. autism spectrum disorder: characteristics, associated behaviors, and early intervention. pediatr clin north am 2020; 67:525–35. https://doi.org/10.1016/j.pcl.2020.02.007. 3. bartolotta t, rizzolo d. recognizing autism spectrum disorder. jaapa 2019; 32:22–6. https://doi.org/10.1097/01.jaa.0000569 776.76198.e1. 4. who director-general's opening remarks at the media briefing on covid-19 11 march 2020. from: https://www. who.int/dg/speeches/detail/who-director-general-s-openingremarks-at-the-media-briefing-on-covid-19---11-march-2020 accessed: nov 2020 5. pfefferbaum b, north cs. mental health and the covid-19 pandemic. n engl j med 2020; 383:510–12. https://doi.org/10.10 56/nejmp2008017. 6. singh s, roy d, sinha k, parveen s, sharma g, joshi g. impact of covid-19 and lockdown on mental health of children and adolescents: a narrative review with recommendations. psychiatry res 2020; 293:113429. https://doi.org/10.1016/j.psy chres.2020.113429. 7. colizzi m, sironi e, antonini f, ciceri ml, bovo c, zoccante l. psychosocial and behavioral impact of covid-19 in autism spectrum disorder: an online parent survey. brain sci 2020; 10:341. https://doi.org/10.3390/brainsci10060341. 8. reid chassiakos yl, radesky j, christakis d, moreno ma, cross c. children and adolescents and digital media. pedia trics 2016; 138:e20162593. https://doi.org/10.1542/peds.2016-2593. 9. fehr e, schurtenberger i. normative foundations of human cooperation. nat hum behav 2018; 2:458–68. https://doi. org/10.1038/s41562-018-0385-5. 10. wang g, zhang y, zhao j, zhang j, jiang f. mitigate the effects of home confinement on children during the covid-19 outbreak. lancet 2020; 395:945–7. https://doi.org/10.1016/s0140-6736(2 0)30547-x. 11. posar a, visconti p. autism in 2016: the need for answers. j pediatr (rio j) 2017; 93:111–19. https://doi.org/10.1016/j.jped.20 16.09.002. 12. bidzan-bluma i, lipowska m. physical activity and cognitive functioning of children: a systematic review. int j environ res public health 2018; 15:800. https://doi.org/10.3390/ijerph1 5040800. 13. harper cb, symon jb, frea wd. recess is time-in: using peers to improve social skills of children with autism. j autism dev disord 2008; 38:815–26. https://doi.org/10.1007/s10803-0070449-2. 14. draves w. is autism the new normal? from: https://lern.org/ article/is-autism-the-new-normal/ accessed: nov 2020. 15. roy d, tripathy s, kar sk, sharma n, verma sk, kaushal v. study of knowledge, attitude, anxiety & perceived mental health care need in indian population during covid-19 pandemic. asian j psychiatr 2020; 51:102083. https://doi.org/10.1016/j. ajp.2020.102083. 16. amaral dg, de vries pj. covid-19 and autism research: perspectives from around the globe. autism res 2020; 13:844–69. https://doi.org/10.1002/aur.2329. 17. yao h, chen j-h, xu y-f. patients with mental health disorders in the covid-19 epidemic. lancet psychiatry 2020; 7:e21. https://doi.org/10.1016/s2215-0366(20)30090-0. mona rafiei and amirhossein memari https://doi.org/10.1016/j.yapd.2016.04.014 https://doi.org/10.1016/j.pcl.2020.02.007 https://doi.org/10.1097/01.jaa.0000569776.76198.e1 https://doi.org/10.1097/01.jaa.0000569776.76198.e1 https://doi.org/10.1056/nejmp2008017 https://doi.org/10.1056/nejmp2008017 https://doi.org/10.1016/j.psychres.2020.113429 https://doi.org/10.1016/j.psychres.2020.113429 https://doi.org/10.3390/brainsci10060341 https://doi.org/10.1542/peds.2016-2593 https://doi.org/10.1038/s41562-018-0385-5 https://doi.org/10.1038/s41562-018-0385-5 https://doi.org/10.1016/s0140-6736%2820%2930547-x https://doi.org/10.1016/s0140-6736%2820%2930547-x https://doi.org/10.1016/j.jped.2016.09.002 https://doi.org/10.1016/j.jped.2016.09.002 https://doi.org/10.3390/ijerph15040800 https://doi.org/10.3390/ijerph15040800 https://doi.org/10.1007/s10803-007-0449-2 https://doi.org/10.1007/s10803-007-0449-2 https://doi.org/10.1016/j.ajp.2020.102083 https://doi.org/10.1016/j.ajp.2020.102083 https://doi.org/10.1002/aur.2329 https://doi.org/10.1016/s2215-0366%2820%2930090-0 1department of dermatology, rustaq extended health institute, rustaq, oman; 2department of medicine, rustaq hospital, rustaq, oman *corresponding author’s e-mail: raqiya.al-rajaibi@mail.mcgill.ca carbamazepine-induced stevens-johnson syndrome/toxic epidermal necrolysis overlap treated successfully with oral cyclosporin case report and literature review *raqiya al rajaibi,1 thuraiya al rumhi,1 al mur al abri2 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 491–494, epub. 29 aug 21 submitted 22 apr 20 revisions req. 1 jul & 13 sep 20; revisions recd. 12 aug & 26 sep 20 accepted 21 oct 20 facility where she was prescribed intravenous (iv) hydrocortisone and iv antibiotics and her intake of carbamazepine was discontinued. unfortunately, her condition deteriorated and she subsequently developed dysphagia. she decided to leave, against medical advice, to seek a second medical opinion. consequently, she was re-admitted to ar rustaq hospital after three days of her symptoms. the initial examination of the patient revealed her to be very ill, dehydrated, febrile and tachycardiac. her skin examination revealed multiple maculopapular rashes covering over 50% of body surface area (bsa; using the rule of nines), with some dusky areas. there was skin peeling over the ear pinna, cheeks and abdomen (around 15% of her bsa) with some flaccid bullae over the anterior part of the neck and acral areas [figure 1]. the blistered area was positive for nikolsky’s sign. red conjunctival mucosa with multiple erosions in the mouth and genital mucosa were also noted. initial laboratory results revealed elevated c-re active protein levels (139 mmol/l), elevated erythro cyte sedimentation rate (49 mm/h), a normal white blood cell count of 4.7 x 103/ul with normal differential counts (neutrophils 2.89 x 103/µl and eosinophil 0.05 x 103/µl), normal random blood sugar levels and normal renal (including electrolytes, creatinine and urea) and liver function tests. a multidisciplinary team was involved in patient management, including those drawn from the fields of ophthalmology, dentistry, ear, nose and throat (ent), internal medicine and dermatology. the patient had stevens johnson syndrome (sjs) and toxic epidermal necrolysis (ten) are skin conditions that have been observed following reactions to certain drugs.1–4 several therapies can be used to treat sjs/ten; however, there is currently no standard treatment option.5 previous studies have shown that cyclosporine (csa) can be used to treat sjs/ten off-label.2 csa has shown promising therapeutic effectiveness in curing similar diseases, although its therapeutic role has not yet been fully understood.2,3,6–10 here, we present a case from oman of sjs/ten being successfully treated using oral csa and providing supportive management. the current report will also provide a brief review of the literature concerning the use of csa in the treatment of sjs/ten. case report a 38-year-old female nurse was admitted to ar rustaq hospital, rustaq, oman, in 2019 with a three-day history of fever and sore throat, as well as skin eruptions and oral mucosal and conjunctival ulcerations. she did not suffer from any chronic disease apart from recurrent arthralgia and was not on any regular medication except various pain killers for her arthralgia as required. additionally, she did not have any drug allergies. her symptoms began on day 10 of her using carbamazepine. the patient had been taking carbamazepine for the first time as a pain killer following several failed pain medications. the patient had been admitted for one day to a private healthcare this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.002 case report abstract: stevens johnson syndrome (sjs) and toxic epidermal necrolysis (ten) are acute life-threatening mucocutaneous drug reactions. several therapies have been used in the treatment of sjs/ten but none of them have yet been established as the gold standard treatment. studies have shown that cyclosporine (csa) can be used off-label in ten/sjs, which has shown promising therapeutic effectiveness in such diseases. here we report a 38-year-old woman who presented to ar rustaq hospital, rustaq, oman in 2019 with sjs/ten overlap and was treated successfully with csa along with supportive management. this case report also includes a literature review on the use of csa in the treatment of sjs/ten. keywords: stevens johnson syndrome; toxic epidermal necrolysis; drug-induced abnormality; cyclosporine; drug eruption; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ carbamazepine-induced stevens-johnson syndrome/toxic epidermal necrolysis overlap treated successfully with oral cyclosporin case report and literature review 492 | squ medical journal, august 2021, volume 21, issue 3 initially been admitted to the intensive care unit for monitoring purposes and was then shifted to the medical ward. she was managed with iv hydration, frequent petroleum jelly application on the skin lesions and heparin prophylaxis. furthermore, she was started on an oral dose of csa of 5 mg/kg/day. at ar rustaq hospital, csa is considered to be costeffective and readily available compared to other alternative therapies such as iv immunoglobulin (ivig), etanercept and plasmapheresis. the patient gradually improved and showed skin re-epithelisation on day three of csa administration. additionally, no new skin lesions were noted. she was then discharged on day six when her dose was reduced to 3 mg/kg/day. in a follow-up appointment in the dermatology clinic after nine days, the patient showed remarkable improvement. subsequently, the csa was discontinued. in total, she had received a gradually decreasing dose of csa for 15 days [figure 2]. the patient has given informed consent for the publication of her case in a medical journal. discussion sjs and ten are severe mucocutaneous drug reactions. the difference between these two conditions is based on the percentage of bsa involvement and type of skin lesions. sjs involves detachment 10% of bsa, plus widespread erythematous, purpuric macules or flat atypical target lesions. an overlap of the two conditions, sjs/ten, involves detachment 10–30% of bsa, plus widespread erythematous, purpuric macules or atypical target-like annular patches. ten, alone, is detachment of 30% of bsa, plus widespread erythematous, purpuric macules or atypical target lesions. ten without spots leads to large epidermal sheets, of around 10% bsa, without purpuric macules or target lesions.1,3 the overall combined incidence of sjs, sjs/ten overlap and ten is estimated to be 2–7 per million cases per year, with a mortality rate of approximately 25–35%.1,2 sjs/ten can manifest through varying symptoms such as fever, mucositis, anorexia, and skin tenderness. these symptoms are then followed by cutaneous lesions, such as targetoid lesions, vesicles and bullae in addition to rapidly progressing sloughing of the skin within a few days.1,6 the case detailed here fits the category of sjs/ ten overlap, given that the patient had peeling and blistering of around 10–15% of bsa and widespread maculopapular skin lesions. the pathogenesis of sjs/ten has not yet been sufficiently understood.3 most of the cases are preceded by exposure to certain medications.1,3 many medications have been identified as the likely cause of sjs/ten, such as nsaids, anticonvulsants, antibiotics and allopurinol.1,2 other non-drug causes of sjs/ figure 2: image of a 38-year-old female patient at recovery (achieved mainly through the use of oral cyclosporine), two months after the first presentation. figure 1: maculopapular rash of the skin of a 38-year-old female patient with some dusky areas and skin peeling (as seen during admission). raqiya al rajaibi, thuraiya al rumhi and al mur al abri case report | 493 ten include mycoplasma pneumonia infection, hiv, dengue virus, the mumps-rubella vaccination and the use of contrast agents for imaging purposes.1 certain genetic factors have also been found to be associated with an increased risk of sjs/ten.3 the patient, in this case, was of indian origin and developed sjs/ten after taking carbamazepine. being of indian or asian origin increases the risk of anticonvulsant-induced sjs/ten, as individuals of these nationalities have a high prevalence of the hla-b*1502 phenotype.4 unfortunately, the hla phenotyping for this patient could not be sent for due to technical and financial reasons. management of sjs/ten should be initiated by first discontinuing the suspected agent, along with providing comprehensive supportive care.5 a multidisciplinary team should be created involving critical care experts, including those belonging to dermatology, infectious disease, ophthalmology and ent fields along with a wound care nurse and a dietician.2,5 supportive care is best delivered in the burn or intensive care unit, which would mainly focus on the assessment of airway, renal function, fluid and electrolyte balance, nutrition, skin and ocular surfaces, pain control and prevention of infection.5 in addition to supportive care, several potential therapies have been proposed, including ivig, glucocorticoids, plasmapheresis, csa and tnf-a inhibitors (such as etanercept).5,6 however, none of these therapies have yet been established as the gold standard treatment for sjs/ten.5 csa is a wellestablished medication that has been used to cure several dermatological diseases.2 a review of the current literature indicates that csa may slow down the progression of sjs/ten.2,7–8 csa has been found to be effective in reducing the mortality rate of sjs/ ten, the duration of recovery and contributing to early discharge from the hospital.7 the proposed mechanism of action of csa in sjs/ten is through inhibiting the function, reducing the production of cytokines by cytotoxic t cells and natural killer cells.6 additionally, it reduces granulysin levels, which has recently been noted to have an important role in the pathogenesis of sjs/ten related to cell apoptosis.1,3 an observational recordbased study compared the use of csa and supportive treatment with using supportive treatment alone.7 it was found that the standardised mortality ratio was 0.32 in the csa group, which is nearly 3.3 times lower than that in the supportive treatment group. moreover, the time of re-epithelisation of the skin, duration of recovery and stabilisation were significantly lower in the csa group, at p = 0.007, p = 0.01 and p < 0.001, respectively.7 a meta-analysis by gonzalez et al. assessed 71 patients with epidermal necrolysis. of these, 49 patients were treated with csa and five of the treated patients died (10.2%). it should be noted that in this group, 11.8 (24.1%) deaths were expected, according to the score for ten. of the 22 patients who were treated with non-csa therapies, seven died (31.8%), when 6.4 deaths (29.1%) were expected.8 in 2018, a meta-analysis of nine observational studies, with a total of 256 sjs/ten patients, revealed a significant reduction in risk of mortality following csa therapy (standardised mortality ratio of 0.320; 95% ci: 0.119–0.522; p = 0.002).2 in addition, a retrospective study from 2014 revealed that the use of csa over ivig may offer a higher chance of recovery in the sjs/ten treatment (standardised mortality ratio of 0.43 over 1.43, respectively).9 in 2010, allanore et al. conducted the first open phase ii trial to determine the safety and possible benefit of csa treatment for sjs and ten.10 it concluded that csa lowered both the death rate and the progression of detachment to a greater degree than expected.10 the results of these studies support the effectiveness of csa (at a dose of 3–5 mg/kg/day, starting treatment at the earliest) in reducing the chance of mortality and rapid cessation of the sjs/ ten disease progression.2–3,6–10 conclusion this case report demonstrates a successful experience of the administration of csa, along with supportive care, in the management of sjs/ten overlap. this finding was supported following a thorough review of the currently available literature. however, future randomised controlled trials would be the most effective in confirming the efficacy of csa. a u t h o r s’ c o n t r i b u t i o n all authors were involved in the treatment of the patient. ra collected all the patient’s data and took her consent. ra and ta conducted the literature review, drafting and revising of the manuscript. all authors read and approved the final version of the manuscript references 1. schwartz ra, mcdonough ph, lee bw. toxic epidermal necro lysis: part i: introduction, history, classification, clinical features, systemic manifestations, etiology and immunopathogenesis. j am acad dermatol 2013; 69:173.e1–13. https://doi.org/10.10 16/j.jaad.2013.05.003. 2. ng qx, deyn mlzqd, venkatanarayanan n, ho cyx, yeo ws. a meta-analysis of cyclosporin treatment for stevens-johnson syndrome/toxic epidermal necrolysis. j inflamm res 2018; 11:135–42. https://doi.org/10.2147/jir.s160964. https://doi.org/10.1016/j.jaad.2013.05.003 https://doi.org/10.1016/j.jaad.2013.05.003 https://doi.org/10.2147/jir.s160964 carbamazepine-induced stevens-johnson syndrome/toxic epidermal necrolysis overlap treated successfully with oral cyclosporin case report and literature review 494 | squ medical journal, august 2021, volume 21, issue 3 3. thong b. stevens-johnson syndrome / toxic epidermal necrolysis: an asia-pacific perspective. asia pac allergy 2013; 3:215–23. https://doi.org/10.5415/apallergy.2013.3.4.215. 4. stern rs, divito sj. stevens-johnson syndrome and toxic epidermal necrolysis: associations, outcomes and pathobiology thirty years of progress but still much to be done. j invest dermatol 2017; 137:1004–8. https://doi.org/10.1016/j.jid.2017.01.003. 5. schneider ja, cohen pr. stevens-johnson syndrome and toxic epidermal necrolysis: a concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. adv ther 2017; 34:1235–44. https://doi.org/10.1007/ s12325-017-0530-y. 6. schwartz ra, mcdonough ph, lee bw. toxic epidermal necro lysis: part ii: prognosis, sequel, diagnosis, differential diagnosis, prevention and treatment. j am acad dermatol 2013; 69:187e1–16. https://doi.org/10.1016/j.jaad.2013.05.002. 7. mohanty s, das a, ghosh a, sil a, gharami rc, bandyopadhyay d, et al. effectiveness, safety and tolerability of cyclosporine versus supportive treatment in stevens–johnson syndrome/toxic epi dermal necrolysis: a record-based study. indian j dermatol vnereol leprol 2017; 83:312–16. https://doi.org/10.4103/ijdvl.ijdvl_201_16. 8. gonzalez-harrada c, rodriguez-martin s, cochaferio l, lerma v, gonzalez o, lorente ja, et al. cyclosporin use in epidermal necrolysis in associated with an important mortality reduction: evidence from three different approaches. j invest dermatol 2017; 137:2092–100. https://doi.org/10.1016/j.jid.2017.05.022. 9. kirchhof mg, miliszewski ma, sikora s, papp a, dutz jp. retro spective review of stevens-johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporin. j am acad dermatol 2014; 71:941–7. https:// doi.org/10.1016/j.jaad.2014.07.016. 10. valeyrie-allanore l, wolkenstein p, brochard l, ottonen n, maître b, revus j, et al. open trial of cyclosporin treatment for steven-johnson syndrome and toxic epidermal necrolysis. br j dermatol 2010; 163:847–53. https://doi.org/10.1111/j.13652133.2010.09863.x. https://doi.org/10.5415/apallergy.2013.3.4.215 https://doi.org/10.1016/j.jid.2017.01.003 https://doi.org/10.1007/s12325-017-0530-y https://doi.org/10.1007/s12325-017-0530-y https://doi.org/10.1016/j.jaad.2013.05.002 https://doi.org/10.4103/ijdvl.ijdvl_201_16 https://doi.org/10.1016/j.jid.2017.05.022 https://doi.org/10.1016/j.jaad.2014.07.016 https://doi.org/10.1016/j.jaad.2014.07.016 https://doi.org/10.1111/j.1365-2133.2010.09863.x https://doi.org/10.1111/j.1365-2133.2010.09863.x department of fundamentals and administration, college of nursing, sultan qaboos university, muscat, oman *corresponding author’s e-mail: mickaelj@squ.edu.om effectiveness of an interactive educational video on knowledge, skill and satisfaction of nursing students jansirani natarajan, *mickael a. joseph, zainab s. al shibli, safa s. al hajji, diana k. al hanawi, arwa n. al kharusi, intisar m. al maqbali sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 546–553, epub. 7 nov 22 submitted 9 jun 21 revisions req. 5 aug & 4 nov 21; revisions recd. 6 oct & 11 nov 21 accepted 24 nov 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2.2022.013 clinical & basic research abstract: objectives: this study aimed to compare the interactive educational video-based strategy with traditional general demonstration in regard to teaching a basic nursing skill. nursing education requires innovative teaching strategies for teaching fundamental nursing skills to ensure proficient nurses for the future. however, nursing educators face challenges in teaching and retaining the skill competency and knowledge of the nursing students, given shortages of nursing faculty and scarcity of opportunities for clinical practice. methods: this crosssectional comparative study followed 55 nursing students enrolled in the fundamentals of nursing laboratory course, college of nursing, sultan qaboos university, muscat, oman, during the spring 2020 semester. the control group was taught using traditional general demonstration-based teaching of the oral medication procedure, while the experimental group learned the same skill through an interactive educational video. the knowledge, skill competency and satisfaction levels of both groups were assessed post-intervention using standardised questionnaires. results: there was no statistical difference between the two groups in knowledge level and skill competency scores. regarding satisfaction, 92% of the students were satisfied with video learning and 87% with the traditional approach. conclusion: the interactive video learning strategy for learning fundamental nursing skills is as effective as the traditional face-to-face general demonstration-based approach. keywords: nursing; instructional film and video; knowledge; personal satisfaction; education; teaching; oman. advances in knowledge using an interactive video as a strategy for learning a nursing skill is as effective as the traditional face-to-face general demonstrationbased approach, although further studies are required to confirm this finding. interactive videos to learn fundamental nursing skills support learning and promote student achievement and satisfaction. applications to patient care with the spread of covid-19 still being a threat, using technological strategies such as videos are of utmost importance so nursing students can learn the necessary skills anytime and anywhere. watching interactive videos before coming to class allows students to better prepare for the class, thus reducing time for lectures and providing more time for practice and feedback. using interactive videos could enhance nursing clinical skills, which are critical for patient care. ensuring high levels of competency in learning medication administration skills may reduce medical errors and healthcare costs and enhance patient safety. nursing students are equipped with basic nursing skills in the fundamentals of nursing laboratory course. these skills are often reviewed during their course of study and their time as nurses in the clinical setting. the quality of patient care and patient safety can be compromised when basic skills are not learned properly and this compromise can even cause permanent disability or endanger patients’ lives in severe cases.1 general laboratory-based demonstrations of skills are the most common strategies used to teach basic nursing skills to nursing students. the approach involves explaining the procedure, showing students how to perform it step by step and supporting students in practicing the skill to acquire knowledge and competency.2–4 however, as new teaching methods are evolving, the approaches to training nursing students also must be upgraded. technology has made everything easier and faster and is attractive to the millennial generation of nursing students.5 one such technology that is gaining greater attention in the educational field is the use of interactive educational videos. using interactive educational videos is an innovative teaching approach to teaching fundamental nursing skills to undergraduate nursing students who live their daily lives equipped with highly advanced mobile technology.6 such videos, when used to complement face-to-face education, have been found to improve students’ competencies as well as their https://creativecommons.org/licenses/by-nd/4.0/ jansirani natarajan, mickael a. joseph, zainab s. al shibli, safa s. al hajji, diana k. al hanawi, arwa n. al kharusi and intisar m. al maqbali clinical and basic research | 547 learning.7 nursing educators are encouraged to use various forms of technology to enhance the learning experiences of nursing students, as emphasised in the vision statement of the american national league for nursing.8 educational videos convey information to the learner through aural and visual sensory channels simultaneously, which may result in better learning outcomes.9 in addition, videos are more consistent (in terms of the steps used in teaching nursing skills) than demonstrations of skills by different nursing faculty.10 branigan remarked that an increasing number of educators are embracing video as an instructional tool because of the rise in the number of multimediaenabled computers at colleges and the lower cost of video-editing equipment and software.10 a growing trend of active usage of social media for networking and communication has also been observed among today’s youth.11 a systematic review revealed that highly informative educational videos with authoritative speakers that posed questions had a positive impact on the learning interest of students and their selfreported knowledge gains.12 furthermore, students have expressed that educational videos improve their memory of new information and provide better intelligibility.11 videos also provide greater opportunities for students with diverse learning styles to learn at their own pace, for instance, when taught in the context of a flipped classroom—an instructional strategy wherein students listen to the lectures at home and engage in active learning during class time.13 interactive educational videos can increase the learning-related self-confidence and self-motivation of nursing students.14,15 student satisfaction and skill competencies were found to have been improved in a study conducted among korean nursing students that compared the use of educational video with traditional methods.16 additionally, nursing students’ knowledge has been shown to improve when educational videos were used for theory and clinical learning.17 overall, educational videos are considered an adequate teaching approach for students to learn fundamental skills independently and at their own pace. nevertheless, despite the numerous advantages of educational videos, nursing faculty and students have been reluctant to adopt this approach because of a misconception that the traditional method of general demonstration results in better student outcomes.18 however, the traditional method of teaching nursing skills in a fundamentals of nursing course consumes faculty time and other resources. clinical instructors may need to repeat their explanation many times as students have different levels of understanding. clinical instructors are also generally restricted to using only a single technique to explain the concept and skill, as they do not have adequate time to deliver the information using multiple methods, which may not ensure the understanding of all students. the use of interactive educational videos can solve most of the problems faced by nursing students and clinical instructors of a fundamentals of nursing course, thus saving resources and time. a review of the literature has revealed a dearth of studies on the use of interactive educational videos for learning fundamental nursing skills in the middle east. therefore, this study aimed to compare the knowledge, skill and competency of learning the procedure of administrating oral medication among the fundamentals of nursing students using either an interactive educational video or the traditional general demonstration approach. moreover, this study sought to describe the satisfaction levels of students with both strategies. the topic was chosen because errors in administering medication are common among nursing students in the clinical setting worldwide.19 methods this quantitative study was conducted at the college of nursing, sultan qaboos university, muscat, oman, and involved second-year nursing students enrolled in the fundamentals of nursing laboratory course in the spring 2020 semester. this study used a quantitative comparative design. the college offers the baccalaureate of nursing (bsn) and master of nursing programmes to students from various parts of oman. as the college has a multinational faculty, the interactive educational video technology could be beneficial to the new faculty in ensuring uniformity in teaching a skill. two laboratory groups already existed for this course based on students’ enrolment in the course. the authors randomly assigned one of the two (n = 30) as the control group, which then learned medication administration skills using a traditional demonstration method. students from the other group (n = 25) were assigned to the experimental group and learned the same procedure by watching an interactive educational video prepared by the faculty. this recruitment meets the requirements of sample size for a study with a 95% confidence interval for a sample size of 50 participants. using g power analysis, a sample size of 54 students was needed with the medium effect size of d = 0.5 and power of 0.70. the students in the control group came to the laboratory on two days (sunday and monday) of one week for eight hours each day. they were exposed to face-to-face laboratory demonstrations of oral medication administration performed effectiveness of an interactive educational video on knowledge, skill and satisfaction of nursing students 548 | squ medical journal, november 2022, volume 22, issue 4 by the fundamentals of nursing instructor. the demonstration started with a presentation of an overview of medication administration using a microsoft powerpoint 2016 (microsoft corporation, redmond, washington, usa), followed by a face-toface general demonstration in the laboratory by an expert course faculty. the demonstration was followed by the faculty answering the students’ questions and clarifying uncertainties. then, the students performed the procedure in front of their clinical instructors and were evaluated using the procedure checklists. the experimental group came to the laboratory on two different days from the control group (wednesday and thursday) of one week for six hours each day. the students watched an interactive video about the medication administration skill on their own time at home and came to class prepared to perform the procedure. after they had reached the laboratory, an overview of the procedure was presented to the students with the same powerpoint (microsoft corporation) presentation as the control group and their questions were answered for clarification. then, the students performed the procedure in front of their group clinical instructors and were evaluated using the procedure checklists. after the procedure demonstrations, both groups of students answered a survey on satisfaction using standardised questionnaires. an interactive educational video is defined as a teaching approach that uses a digital video containing interactions via gestures, voice and touch.20 in this study, the interactive educational video was developed based on the nine events of instruction for designing an instructional material as outlined by gagné.21 gagné’s events are: (1) to gain attention; (2) to describe the goal; (3) to stimulate prior knowledge; (4) to present the material to be learned; (5) to provide guidance for learning; (6) to elicit performance; (7) to provide feedback; (8) to assess performance; and (9) to enhance retention and transfer. when video materials match these steps, higher levels of achievement in student learning outcomes and learner engagement can be accomplished.22 the interactive educational video was developed by the experienced course coordinator and uploaded to moodle, version 3.11.2 (moodle, perth, australia; the learning management system accessed by students), two days before their laboratory session. to ensure consistency, the same faculty performed the face-to-face demonstration and were present in the video. the video was created with the help of the technical support team at the college of nursing. the video was recorded in the skill laboratory at the college of nursing, where the faculty performed the administration of oral medications on a trained standardised patient using all the equipment available in the laboratory and following a checklist developed for this course. the video was recorded in one session, which lasted around two hours. in addition, a concise voice narration was recorded to help clarify the demonstration in the video. the technical team used adobe premiere pro (adobe stock, san jose, california, usa) to edit the video and sync it with the voiceover. the video was divided into three parts, each six minutes long. the parts consisted of an overview of medication administration as a recorded powerpoint (microsoft corporation) presentation, a demonstration of the oral medication administration on a standardised patient and a discussion of the aftercare and other policies to be considered while administering oral medications in the clinical setting. the final version of the oral medication video was shared with two professors from the fundamentals of nursing course and two clinical instructors to verify the accuracy and the quality of the video, before it was released to the students participating in this study. a knowledge questionnaire regarding the oral medication administration procedure was developed by the course coordinator based on the national council licensure examination-pattern multiplechoice questions (mcqs) and peer-reviewed by two experts. five questions were scored, with a score of 5 indicating an excellent level of knowledge, 3–4 a good level of knowledge and 1–2 a poor level of knowledge. the test–retest reliability scores were 0.8, indicating high reliability. a performance checklist for an oral medication administration was developed for the objective structured clinical examination (osce) by the course team based on the textbook for the fundamentals of nursing course and approved by the department board.23 the mean inter-rater score was 0.9, indicating high reliability. satisfaction with the interactive educational videos was measured with the evaluation of satisfaction for the video-based interactive education method in professional skills training questionnaire developed by arslan et al.24 it comprises 17 items designed to assess every stage of the learning processing, starting with watching the videos. for each item, the participant could choose 1 (disagree), 2 (neutral) or 3 (agree) as their level of satisfaction, with 17 being the minimum and 51 being the maximum possible score. in the study, the total score was converted to a percentage, with a result of 60% or above indicating a high satisfaction level. cronbach’s alpha was 0.9, indicating very good internal consistency and showing the tool’s high reliability.24 jansirani natarajan, mickael a. joseph, zainab s. al shibli, safa s. al hajji, diana k. al hanawi, arwa n. al kharusi and intisar m. al maqbali clinical and basic research | 549 the student evaluation of educational quality (seeq) questionnaire was used to assess the students’ satisfaction levels after general demonstration of the skill. it is a five-point likert scale developed by coffey and gibbs (5 is strongly agree and 1 is strongly disagree) and consists of 12 items enquiring about the classroom demonstration.25 the resulting scores were converted to percentages and a score above 60% was considered satisfactory. the seeq questionnaire has a high level of reliability, with cronbach’s alpha ranging from 0.88 to 0.97.26 the control group had general demonstration and hands-on practice of the procedure on the first day. re-demonstration of the procedure in osce was evaluated by two nursing faculty with the help of the checklist after the students had answered the knowledge quiz. finally, the participants were asked to complete the seeq survey to evaluate their satisfaction levels. the experimental group watched the interactive educational video recording of the oral medication procedure, then came to the laboratory to practice. they completed a knowledge quiz after a brief review of the procedure in the video. the students performed the procedure in the laboratory, which was evaluated by two teams of faculty. the questionnaire regarding satisfaction with the video-based interactive education was completed by the students at the end of the laboratory session, during the scheduled laboratory hours and with the permission of the course coordinators. they could complete it in six hours as they had saved some time otherwise spent on demonstration by watching the interactive educational video. the collected data were checked for completeness, and scores were calculated and entered by two investigators to ensure the accuracy of the entered data. data analysis was performed with the statistical packages for social sciences (spss), version 24 (ibm, armonk, new york, usa). independent sample t and chi-squared tests were used to compare the scores of skill competency and knowledge of both groups of students. levels of satisfaction for both groups were calculated and presented as frequency, percentage and mean scores, but they were not compared as the two questionnaires were different. ethical approval was obtained from the research and ethics committee at the college of nursing (con/gp/2020/04) and permission was received from the fundamentals of nursing laboratory course coordinators. the procedure was explained to the students in detail and written informed consent was provided by the participants in both groups. data confidentiality was maintained. names and identification numbers of the students were coded and the collected data were stored in a locked cabinet. permission to use the questionnaires was obtained from their respective authors. the interactive educational video on oral medication administration was shared with both groups after the completion of the study period so that both could benefit equally from the interactive educational video. results a total of 55 nursing students were included in this study. the study participants were enrolled from the college of nursing’s bsn programme and had registered in the fundamentals of nursing laboratory course for the spring 2020 semester. a total of 34 (61.81%) students were females and 21 (38.19%) were males and aged between 19 and 21 years. the first objective was to compare the knowledge of both groups (control and experimental) regarding appropriate oral medication administration procedures. knowledge was assessed using five mcqs developed by the course experts. scores were assigned as 1 or 2 (poor), 3 or 4 (good) and 5 (excellent). the majority of students (36, 65.45%) had a good level of knowledge regarding oral medication administration and there was no significant difference between the control and experimental groups (χ2 [2,55] = 2.626; p = 0.269) [table 1]. table 1: comparison of medication administration knowledge scores between the control and experimental groups (n = 55) knowledge scores* n (%) χ2 p value experimental group (n = 25) control group (n = 30) total (n = 55) excellent 2 (8.0) 0 (0.0) 2 (3.64) 2.626 0.269 good 15 (60.0) 21 (70.0) 36 (65.45) poor 8 (32.0) 9 (30.0) 17 (30.91) *a score of 5 was considered excellent, 3 and 4 were considered good and 1 and 2 were considered poor. effectiveness of an interactive educational video on knowledge, skill and satisfaction of nursing students 550 | squ medical journal, november 2022, volume 22, issue 4 the second objective was to compare the skill competency scores of both groups. skill competency of the participants in performing oral medication procedure was evaluated by two evaluators using a standardised checklist; the average was the final score of the participants. scores <40% were classified as poor performance, 40–80% as good performance and >80% as excellent performance. the majority of students (n = 35, 63.64%) displayed good performance scores and none were in the poor performance category. there was no significant difference in the skill performance of both groups (χ2 [1,55] = 0.262; p = 0.609) [table 2]. the third objective was to describe the satisfaction level of the students who learned the procedure by the traditional demonstration method (control group). these students were asked to rate their satisfaction with the general demonstration using a five-point likert scale anchored by 1 (strongly disagree) and 5 table 2: competency scores of oral medication administration skill for the control and experimental groups (n = 55) skill performance* n (%) χ2 p value experimental group (n = 25) control group (n = 30) total (n = 55) excellent performance 10 (40) 10 (33.33) 20 (36.36) 0.262 0.609 good performance 15 (60) 20 (66.67) 35 (63.64) *a score between 40–80% was considered a good performance and above 80% was considered an excellent performance. table 3: control group satisfaction scores with the general demonstration (n = 30) general demonstration satisfaction items* mean ± sd class size is appropriate. 3.33 ± 0.994 the class activities were engaging. 3.77 ± 1.073 the class environment was inviting. 3.63 ± 1.066 the class was fun. 3.90 ± 1.213 i was bored in the class. 3.50 ± 1.106 i enjoyed going to class. 3.73 ± 1.143 i felt comfortable to voice my opinion during class. 3.73 ± 1.081 i learned from my peer experiences. 3.63 ± 1.129 i felt my presence was valued in the class. 3.67 ± 0.994 i felt comfortable approaching the instructor. 3.90 ± 1.062 the instructor encourages class discussions. 4.13 ± 1.137 i recommend this teaching method to be continued for future. 3.97 ± 0.765 sd = standard deviation. *scores based on a 5-point likert scale. table 4: experimental group satisfaction scores with the interactive educational video (n = 25) video satisfaction scores of the experimental group* mean ± sd the video recordings are very important in understanding the procedure steps. 2.56 ± 0.651 the use of video was important for continuing interest in the course. 2.20 ± 0.577 watching the videos prior to the laboratory session was beneficial in my preparation for the laboratory session. 2.40 ± 0.764 the ‘important points’ stated for skills in the videos are very valuable. 2.32 ± 0.690 i would like there to be videos for all of the skills. 2.28 ± 0.792 the videos decreased my stress during the laboratory. 2.04 ± 0.676 the sounds/images of the videos were very clear. 2.08 ± 0.812 the explanation of the skills steps in the videos helped me to pronounce the terms correctly. 2.36 ± 0.700 the procedure steps in the videos were very clear. 2.64 ± 0.638 i can control the video easily (to watch the steps again, to advance and to rewind). 2.48 ± 0.823 the use of different learning materials (video) increased my learning. 2.48 ± 0.586 i prefer educational video to traditional laboratory explanation. 2.20 ± 0.707 i feel more responsibility in learning through video than through the traditional way. 2.24 ± 0.663 the video showing provided for me to access knowledge more rapidly. 2.40 ± 0.645 the video showing advanced my learning. 2.56 ± 0.651 i was entertained while learning with the video showing. 2.44 ± 0.712 narrating explanation for the skills steps during the video helped me to understand the procedure. 2.44 ± 0.651 sd = standard deviation. *scores based on a 3-point likert scale. jansirani natarajan, mickael a. joseph, zainab s. al shibli, safa s. al hajji, diana k. al hanawi, arwa n. al kharusi and intisar m. al maqbali clinical and basic research | 551 (strongly agree). the students in the control group were satisfied with the demonstration, with mean scores >3.5 for all items and 26 (86.70%) students in the control group considered traditional demonstration as highly satisfactory [table 3 and figure 1]. the fourth objective was to describe the satisfaction level of the students who learned the procedure by the interactive educational video (experimental group). these participants rated the videos using a three-point likert scale. a mean score of 2.5 and above on the items indicated a high level of satisfaction. the video recordings were reported to be very important in understanding the procedure steps (mean = 2.56). the procedure steps in the videos were very clear (mean = 2.64), with students agreeing that ‘i can control the video easily (to watch the steps again, to advance, to rewind’ (mean = 2.48), ‘the use of different learning materials (video) increased my learning’ (mean = 2.48) and ‘the video showing advanced my learning’ (mean = 2.56) [table 4]. furthermore, 23 (92%) students were highly satisfied with the interactive educational video learning strategy [figure 1]. discussion the advanced technologies accessible to the new generation of nursing students have created opportunities for nursing educators to use interactive educational video recording as a teaching approach to help students learn and practice nursing skills. the current study aimed to assess the effectiveness of using an interactive educational video over traditional demonstration on students’ knowledge gain, clinical skills competency and levels of satisfaction. the results revealed no statistical differences between the knowledge, skill competency scores and satisfaction levels of the study groups, indicating that both teaching approaches have similar student outcomes. this is similar to the findings of the studies on video learning for basic nursing skills among turkish nursing students as well as on teaching the subcutaneous injection administration procedure using face-to-face demonstration versus computer-assisted learning among turkish nursing students.24,27 vicdan used instagram (meta platforms, menlo park, california, usa) to teach intramuscular injection administration to students enrolled in the fundamentals of nursing course.4 the results showed no statistical difference of knowledge and competency scores between groups. in all these studies, the results indicate that the outcomes of interactive video learning for teaching nursing skills were as good as the traditional face-toface demonstration method. this is a positive sign, suggesting interactive videos may appropriately be integrated into fundamental nursing skills courses. indeed, another study revealed that educational video learning was better than traditional general demonstration for learning a urinary catheterisation procedure, with a significant improvement in knowledge and competency scores.14 nursing students in the experimental group were satisfied with all aspects of the experience and indicated higher satisfaction levels with several items, including clarity of the procedure’s steps, feasibility to watch at their own pace or many times and the enhancement of their interest to learn through advanced technology. these findings are similar to those of studies carried out among nursing students learning web-based medication application skills.16,28,29 another study conducted among students on antenatal examination revealed significantly higher levels of knowledge and competency scores in groups of students subjected to online videos, suggesting that this approach may be appropriately implemented in other courses.30 nevertheless, the control group students who witnessed the traditional general demonstration also exhibited high satisfaction levels. since they were second-year nursing students and it was their first experience of learning skills, they may have appreciated face-to-face student–faculty interactions and valued the opportunity to ask questions in the classroom. while students preferred the social presence of the faculty during the demonstration of skills, they were satisfied with the encouragement they received in their discussion at the end of the sessions. this may encourage faculty to introduce a flipped classroom approach among fundamentals of nursing course students when learning basic skills. this approach may improve their critical thinking, clinical judgement, learning motivation, communication and teamwork skills.13 moreover, in this study, the experimental group had a six-hour laboratory session each day figure 1: students’ satisfaction with the skill general demonstration and the interactive educational video approach. effectiveness of an interactive educational video on knowledge, skill and satisfaction of nursing students 552 | squ medical journal, november 2022, volume 22, issue 4 for two days, while the control group had eighthour laboratory sessions. as the nursing students in the experimental group watched the interactive educational videos at home, a total of four hours was gained and reduced from the face-to-face laboratory session. thus, interactive educational videos could be used to save time in the classroom, which can then be utilised to build on the previously acquired knowledge. this study is not without its limitations. first, the results cannot be generalised, as the study was conducted at a single institution in oman and on a single nursing fundamental skill. furthermore, research should be done among different courses in the bsn programme with larger sample sizes and including more than one institution. a more rigorous research design, such as a randomised controlled trial, is recommended to control the effect of confounding variables on the findings of future studies. conclusion this study shows that an interactive educational video approach can be easily adopted for undergraduate nursing students learning basic nursing skills, as it is as effective as traditional methods in achieving student learning outcomes. in future studies, a combination of technology (using interactive educational videos to demonstrate nursing skills) and face-to-face, handson demonstration should be investigated and used to determine if it yields a better outcome. however, this study shows that when face-to-face meetings are not possible (e.g. during lockdowns due to the covid-19 pandemic), a switch to online interactive educational videos could be made without fear of falling short of necessary programme outcomes. a u t h o r s’ c o n t r i b u t i o n jn designed the study and supervised the project. zss, ssh, dkh, ank and imm conducted the experiment and collected the data. jn and maj analysed and interpreted the results. maj designed and prepared the tables and figures. jn and maj drafted the manuscript. all the authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bloomfield j, roberts j, while a. the effect of computerassisted learning versus conventional teaching methods on the acquisition and retention of handwashing theory and skills in pre-qualification nursing students: a randomised controlled trial. int j nurs stud 2010; 47:287–94. https://doi.org/10.1016/j. ijnurstu.2009.08.003. 2. forehand jw, miller b, carter h. integrating mobile devices into the nursing classroom. teach learn nurs 2017; 12:50–2. https://doi.org/10.1016/j.teln.2016.09.008. 3. o’connor s, andrews t. smartphones and mobile applications (apps) in clinical nursing education: a student perspective. nurse educ today 2018; 69:172–8. https://doi.org/10.1016/j. nedt.2018.07.013. 4. vicdan ak. assessment of the effect of mobile-assisted education regarding intramuscular injection by using the instagram app. nurs pract today 2020; 7:61–71. https://doi.org/10.18502/npt. v7i1.2302. 5. montenery sm, walker m, sorensen e, thompson r, kirklin d, white r, et al. millennial generation student nurses’ perceptions of the impact of multiple technologies on learning. nurs educ perspect 2013; 34:405–9. https://doi.org/10.5480/10-451. 6. risling t. educating the nurses of 2025: technology trends of the next decade. nurse educ pract 2017; 22:89–92. https://doi. org/10.1016/j.nepr.2016.12.007. 7. terry vr, terry pc, moloney c, bowtell l. face-to-face instruction combined with online resources improves retention of clinical skills among undergraduate nursing students. nurse educ today 2018; 61:15–19. https://doi.org/10.1016/j.nedt.2017.1 0.014. 8. nln. a vision for the changing faculty role: preparing students for the technological world of health care. nurs educ prespect 2015; 36:134. 9. mayer r. ten research-based principles for designing multi media instruction. from: https://www.learntechlib.org/primar y/p/180549/ accessed: nov 2021. 10. branigan c. video goes to school. part i: whether watching or recording, students find video engaging. 2005. from: h t t p : / / w e b . a r c h i v e . o r g / w e b / 2 0 0 9 1 2 0 7 2 1 0 9 3 5 / h t t p : / / w w w . e s c h o o l n e w s . c o m / n e w s / t o p n e w s / i n d e x . c f m ? i = 3 6 2 9 4 & c f i d = 3 0 1 9 8 9 0 4 & c f to k e n = 3 6 7 5 5 4 3 4 accessed: nov 2021. 11. kosterelioglu i. student views on learning environments enriched by video clips. univers j educ res 2016; 4:359–69. https://doi.org/10.13189/ujer.2016.040207. 12. wijnker w, bakker a, van gog t, drijvers p. educational videos from a film theory perspective: relating teacher aims to video characteristics. br j educ technol 2019; 50:3175–97. https:// doi.org/10.1111/bjet.12725. 13. goedhart ns, blignaut-van westrhenen n, moser c, zweekhorst mbm. the flipped classroom: supporting a diverse group of students in their learning. learning environ res 2019; 22:297–310. https://doi.org/10.1007/s10984-019-09281-2. 14. chuang y-h, lai f-c, chang c-c, wan h-t. effects of a skill demonstration video delivered by smartphone on facilitating nursing students’ skill competencies and self-confidence: a randomized controlled trial study. nurse educ today 2018; 66:63–8. https://doi.org/10.1016/j.nedt.2018.03.027. 15. zayim n, ozel d. factors affecting nursing students’ readiness and perceptions toward the use of mobile technologies for learning. comput inform nurs 2015; 33:456–64. https://doi. org/10.1097/cin.0000000000000172. 16. lee n-j, chae s-m, kim h, lee j-h, min hj, park d-e. mobilebased video learning outcomes in clinical nursing skill education: a randomized controlled trial. comput inform nurs 2016; 34:8–16. https://doi.org/10.1097/cin.0000000000000183. https://doi.org/10.1016/j.ijnurstu.2009.08.003 https://doi.org/10.1016/j.ijnurstu.2009.08.003 https://doi.org/10.1016/j.teln.2016.09.008 https://doi.org/10.1016/j.nedt.2018.07.013 https://doi.org/10.1016/j.nedt.2018.07.013 https://doi.org/10.18502/npt.v7i1.2302 https://doi.org/10.18502/npt.v7i1.2302 https://doi.org/10.5480/10-451 https://doi.org/10.1016/j.nepr.2016.12.007 https://doi.org/10.1016/j.nepr.2016.12.007 https://doi.org/10.1016/j.nedt.2017.10.014 https://doi.org/10.1016/j.nedt.2017.10.014 https://doi.org/10.13189/ujer.2016.040207 https://doi.org/10.1111/bjet.12725 https://doi.org/10.1111/bjet.12725 https://doi.org/10.1007/s10984-019-09281-2 https://doi.org/10.1016/j.nedt.2018.03.027 https://doi.org/10.1097/cin.0000000000000172 https://doi.org/10.1097/cin.0000000000000172 https://doi.org/10.1097/cin.0000000000000183. jansirani natarajan, mickael a. joseph, zainab s. al shibli, safa s. al hajji, diana k. al hanawi, arwa n. al kharusi and intisar m. al maqbali clinical and basic research | 553 17. alkhalaileh m, hasan a, al-rawajfah o. evaluate the effectiveness of clinical simulation and instructional video training on the nursing students’ knowledge about cardio-pulmonary resuscitation: comparative study. am j educ res 2017; 5:172–8. 18. devi b, khandelwal b, das m. comparison of the effectiveness of video-assisted teaching program and traditional demonstration on nursing students learning skills of performing obstetrical palpation. iran j nurs midwifery res 2019; 24:118. https://doi. org/10.4103/ijnmr.ijnmr_35_18. 19. asensi-vicente j, ismael jr, vizcaya-moreno mf. medication errors involving nursing students: a systematic review. nurse educ 2018; 43: e1–5. https://doi.org/10.1097/nne.0000000000 000481. 20. joel mh, ashipala do, kamenye e. interactive video technology as a mode of teaching: a qualitative analysis of nursing students’ experiences at a higher education institution in namibia. int j high educ 2021; 10:83–91. https://doi.org//10.5430/ijhe.v10n2p83. 21. gagné rm. conditions of learning and theory of instruction. holt, rinehart and winston: usa. 1985. 22. thorpe r. digital technology in classrooms: video in teaching and learning. nhk broadcasting studies 2008; 6:2145. 23. kozier bj, erb g, berman at, snyder s, frandsen g, buck m, et al. fundamentals of canadian nursing: concepts, process, and practice, 4th ed. pearson canada: canada. 2018. 24. arslan gg, ozden d, goktuna g, ayik c. a study on the satisfaction of students for the time spent watching video-based learning during their basic nursing skills’ training. int j caring sci 2018; 11:427–36. 25. coffey m, gibbs g. the evaluation of the student evaluation of educational quality questionnaire (seeq) in uk higher education. assess eval high educ 2001; 26:89–93. https://doi. org/10.1080/02602930020022318. 26. centra ja. reflective faculty evaluation: enhancing teaching and determining faculty effectiveness. the jossey-bass higher and adult education series, 1st ed. new york, usa: wiley, 1993. 27. vicdan ak. teaching subcutaneous injection using face-to-face and computer-assisted training. int j caring sci 2018; 11:344–52. 28. bahar a. effects of web based instructional video supported education on basic skills training. new j med 2015; 32:141–7. 29. pinar g, abay h, akalin a. the effect of scenario-based simulation training technology on knowledge and skills of maternity nursing students in turkey. int j dev res 2016; 6:8096–101. 30. scaria t, valsaraj p, pias m. the effectiveness of video teaching over lecture cum demonstration in improving knowledge and skill, of nursing students on antenatal examination. int j nurs educ 2013; 5:228–30. https://doi.org/10.4103/ijnmr.ijnmr_35_18. https://doi.org/10.4103/ijnmr.ijnmr_35_18. https://doi.org/10.1097/nne.0000000000000481 https://doi.org/10.1097/nne.0000000000000481 https://doi.org//10.5430/ijhe.v10n2p83 https://doi.org/10.1080/02602930020022318 https://doi.org/10.1080/02602930020022318 1department of radiology, ibri regional hospital, ibri, oman; 2department of radiology and molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asmaalhatmi1989@gmail.com imaging manifestation of synovitis, acne, pustulosis, hyperostosis and osteitis syndrome *asma alhatmi1 and sameer b. raniga2 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 306–308, epub. 26 may 22 submitted 7 apr 21 revision req. 27 may 21; revision recd. 25 jun 21 accepted 21 apr 21 a 43-year-old male patient with a history of left radical nephrectomy for renal cell carcinoma (rcc) on surveillance was presented to the rheumatology clinic of a tertiary care hospital in muscat, oman, in 2019 with severe pain at the manubrium and right sternoclavicular joint associated with acne-like lesions in both the palms and soles that was present for the past two years. on examination, swelling, redness and tenderness were present over the manubrium and right sternoclavicular joint. there were acne-like lesions in the back, soles and palms. laboratory investigations showed elevated inflammatory markers, including erythrocyte sedimentation rate and the total count of white blood cells and neutrophils. a computed tomography (ct) of the chest, bone scintigraphy with single-photon emission computed tomography/ ct and whole-body f-18 fluorodeoxyglucosepositron emission tomography/ct (fdg-pet/ ct) showed multiple bone lesions. a diagnosis of synovitis, acne, pustulosis, hyperostosis and osteitis (sapho) syndrome was made. non-steroidal antiinflammatory drugs (nsaids), prednisolone and methotrexate were administered, which resulted in a dramatic improvement in the patient's condition. this report demonstrates how multiple imaging modalities can help in diagnosing sapho syndrome along with the provided history and medical background. early and accurate diagnosis is essential for the correct management and achieving a good outcome. the reporting of the current case does not contravene with the regulations of the local institutional review board. comment sapho is a rare syndrome that was first reported by chamot et al. in 1987.1 other cases have been reported in the west and japan.1,2 the underlying pathophysiology is still unclear, although many hypotheses attributed this condition to a group of genetic, immunologic and infectious factors.2,3 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.8.2021.098 interesting medical image figure 1: (a) anterior views of the whole body bone scan provided with reconstructed scintigraphy with single-photon emission computed tomography/computerised tomography images in (b) sagittal and (c) coronal views showing intense uptake at the proximal end of the right clavicle (red arrows) and manubrium sterni (blue arrows). faint radiotracer uptake were noted at the left sternoclavicular joint and left first rib. https://creativecommons.org/licenses/by-nd/4.0/ asma alhatmi and sameer b. raniga interesting medical image | 307 sapho syndrome is a benign condition affecting mainly young and middle-aged adults and can be managed conservatively.3 early diagnosis and proper management will improve the clinical outcomes and prognosis.1 clinical history, along with dermatological and radiological manifestations, is essential to diagnose sapho syndrome. any one of these criteria are considered adequate to make the diagnosis: 1) multifocal osteitis with or without skin lesions; 2) sterile acute, subacute or chronic arthritis associated with pustular psoriasis, palmoplantar pustulosis, acne or hidradenitis suppurativa; and 3) sterile osteitis combined with one of the skin manifestations.1,3 however, the diagnosis of sapho syndrome sometimes could be challenging, especially if skin manifestations are absent.1 in the current case, the patient presented with severe pain at the manubrium and right sternoclavicular joint associated with acnelike lesions in both palms and soles, which meet the criteria of diagnosis. different modality imaging like x-ray, ct, bone scintigraphy and magnetic resonance image (mri) may help to diagnose sapho syndrome; however, the whole body bone scintigraphy using 99mtcmethylene-diphosphonate is considered the most sensitive modality in detecting early bony involvement when these changes are absent or subtle in other modalities.2,4 anterior chest wall bones involving both sternoclavicular junction and manubrium sterni are considered the most common location for early bony changes of sapho syndrome, followed by the spine and, to a lesser extent, sacroiliac joints.1,5 in the current case, these locations were involved apart from the normal appearance of both sacroiliac joints [figures 1 and 2]. the radiological appearance of sapho syndrome depends on the stage of progression, which may start with osteolysis in the early stage, followed by osteitis, hyperostosis and osteosclerosis.4 a bone scan usually gives a characteristic pattern of uptake called bull's head appearance centred at the sternoclavicular joints and manubrium sterni [figure 1a]. although plain radiograph is non-specific, sometimes it may show changes if clinically suspected such as osteitis and hyperostosis of sternoclavicular joint, sclerotic bony changes of vertebral bodies and sacroiliitis.3,4 the ct modality gives more details about osteoarticular erosive changes, particularly of the anterior chest wall.4 an mri is advised in cases of the suspected active inflammatory process of spondylodiscitis. sapho spine lesions may appear as body corner erosions or erosive changes of the disc with narrowing of disc space.2,4 the current patient had a bone scan and ct scan, which showed similar comparable changes to the above-mentioned findings of sapho syndrome [figures 1a and 2]. an fdg-pet/ct scan was performed to exclude the possibility of sclerotic metastasis in the background of rcc and was reported as negative (image not provided). nsaids with or without antibiotics are considered the first-line therapy for sapho syndrome.5 many studies have proven the role and usefulness of bisphosphonates, steroids and biologic agents as treatment options, particularly for skin and articular manifestations.2,5 in the current case, nsaids, prednisolone and methotrexate were administered resulting in an improvement of the patient’s condition with a good outcome on follow-up. a u t h o r s c o n t r i b u t i o n aa collected the clinical data, medical images, made the literature review, wrote the manuscript draft and revised the manuscript. sr chose the appropriate images and reviewed the manuscript drafts before submissions with error correction. both authors approved the final version of the manuscript. figure 2: computed tomography scans of the sternum (a) and spine (b) showing bony erosion and hyperostosis changes on the right sternoclavicular joint (red arrow) and sclerotic osteitis changes on either side of the sterno-manubrial joint (yellow arrows). multiple scattered osteosclerotic lesions in the thoracic and lumbar spine (b and c) with relatively normal disc spaces (white arrows). a whole-body f-18 fluorodeoxyglucose-positron emission tomography/computerised tomography showed no definite focal radiotracer uptake on these lesions and both sacroiliac joints are grossly normal (images not provided). imaging manifestation of synovitis, acne, pustulosis, hyperostosis and osteitis syndrome 308 | squ medical journal, may 2022, volume 22, issue 2 references 1. zimmermann p, curtis n. synovitis, acne, pustulosis, hyperostosis, and osteitis (sapho) syndrome a challenging diagnosis not to be missed. j infect 2016; 72 suppl:s106–14. https://doi. org/10.1016/j.jinf.2016.04.030. 2. singh ak, ranjan rs. sapho syndrome: a radiological case report. indian j radiol imaging 2020; 30:84–8. https://doi. org/10.4103/ijri.ijri_203_18. 3. liu s, tang m, cao y, li c. synovitis, acne, pustulosis, hyper ostosis, and osteitis syndrome: review and update. ther adv musculoskelet dis 2020; 12:1759720x20912865. https://doi. org/10.1177/1759720x20912865. 4. colina m, govoni m, orzincolo c, trotta f. clinical and radio logic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single-center study of a cohort of 71 subjects. arthritis rheum 2009; 61:813–21. https://doi.org/10.1002/art.24540. 5. matzaroglou ch, velissaris d, karageorgos a, marangos m, panagiotopoulos e, karanikolas m. sapho syndrome diagnosis and treatment: report of five cases and review of the literature. open orthop j 2009; 3:100–6. https://doi.org/ 10.2174/18743 25000903010100. https://doi.org/10.1016/j.jinf.2016.04.030 https://doi.org/10.1016/j.jinf.2016.04.030 https://doi.org/10.4103/ijri.ijri_203_18 https://doi.org/10.4103/ijri.ijri_203_18 https://doi.org/10.1177/1759720x20912865 https://doi.org/10.1177/1759720x20912865 https://doi.org/10.1002/art.24540 https://doi.org/ 10.2174/1874325000903010100 https://doi.org/ 10.2174/1874325000903010100 division of endocrinology, david geffen school of medicine, university of california los angeles, los angeles, california, usa e-mail: runyu@mednet.ucla.edu إفراز هرمون القشرة الكظرية من ورم الكارسينويد الرئوي والذي مت تشخيصة بأستخدام التصوير املقطعي بواسطة لنظري املشع جاليوم68 ران يو adrenocorticotropic hormone-secreting, subcentimetre lung carcinoid identified by 68gallium-dotatate positron emission tomography scan run yu a 64-year-old male patient presented to the endocrine clinic at david geffen school of medicine, university of california, los angeles, usa, in 2018 with fatigue and weight gain for 1.5 years and bilateral thigh muscle pain and weakness for a few months. he also had hypertension and type-2 diabetes but no known osteoporosis. physical examination noted cushingoid features—such as truncal obesity and proximal amyotrophy; therefore, cushing’s syndrome was suspected. he did not take cortico steroids. levels of 24-hour urinary free cortisol, mid night salivary cortisol, morning cortisol levels after 1 mg dexamethasone and random morning adreno corticotropic hormone (acth) were elevated over multiple measurements [table 1]. subsequently, the patient was diagnosed with acth-dependent cushing’s syndrome. pituitary magnetic resonance imaging (mri) scans showed normal pituitary gland without evidence of sultan qaboos university med j, may 2019, vol. 19, iss. 2, pp. e166–167, epub. 8 sep 19 submitted 21 oct 18 revision req. 23 dec 18; revision recd. 3 jan 19 accepted 17 jan 19 figure 1: 68ga-dotatate positron emission tomography/computed tomography (pet/ct) with contrast scans of a 64-year-old male patient with ectopic cushing’s syndrome showing the (a) coronal and (b) axial views of fused dotatate pet/ct and (c) coronal and (d) axial views of chest ct with an abnormal signal in the left upper lung nodule (arrows). this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.02.016 interesting medical image https://creativecommons.org/licenses/by-nd/4.0/ run yu interesting medical image | e167 pituitary or suprasellar masses. inferior petrosal sinus sampling demonstrated no lateralisation or central-to peripheral acth gradient before or after corticotropin releasing hormone administration, suggesting a peripheral source of acth secretion. computed tomography (ct) scans of the neck, chest, abdomen and pelvis for a recent trauma did not identify clear tumours in the lungs, pancreas or other organs. 68gallium(ga)-dota tate positron emission tomography (pet)/ct scan with contrast showed a 9 × 6 mm, left upper lobe pulmonary nodule with a maximum standardised uptake value of 3 as the only abnormal finding [figure 1]. the patient underwent left upper lung lobe wedge resection. at 8:00 a.m. on post-operative day 1, acth level was 2 pg/ml and cortisol 4 µg/dl; on post-operative day 2, at the same time, acth level was 7 pg/ml and cortisol 2 µg/dl, indicating complete remission of acthdependent cushing’s syndrome. surgical histology revealed a low-grade neuroendocrine tumour which is a typical lung carcinoid without lymph node metastasis. immunocytochemistry showed a positive expression of acth. the patient was treated with hydrocortisone with a plan of gradual dose tapering. he was followedup for eight months post-operatively. all cushingoid features, including hypertension and diabetes, disapp eared after the tumour resection. comment the current patient had elevated levels of 24-hour urine free cortisol and midnight saliva cortisol and unsuppressed levels of morning cortisol after taking dexamethasone. these findings are a clear indication of cushing’s syndrome, which is defined as autonomous cortisol over-production.1 as his random morning acth levels were also elevated, his cushing’s syndrome was acth-dependent.1 although the vast majority of acth-dependent cushing’s syndromes are caused by acth-secreting pituitary tumours, some are caused by acth-secreting tumours from other organs (e.g. ectopic cushing’s syndrome), such as the lungs and pancreas.2 the normal pituitary gland of this patient revealed by an mri scan suggested ectopic cushing’s syndrome, which was confirmed by inferior petrosal sinus sampling.1,2 locating an ectopic acthsecreting tumour can be challenging as it is often small and difficult to find by conventional imaging such as ct, mri including diffusion weighted imaging, octreotide scan or fluorodeoxyglucose pet.3,4 68ga-dotatate pet utilises a positron-emitting radioisotope-linked somatostatin analogue and has much higher spatial resolution and sensitivity than an octreotide scan in identifying neuroendocrine tumours, which comprise most ectopic acth-secreting tumours.2,5,6 as shown in the current case, 68ga-dotatate pet is usually combined with contrast-enhanced ct and is the most sensitive imaging method in locating a covert ectopic acth-secreting tumour.3 references 1. nieman lk. diagnosis of cushing's syndrome in the modern era. endocrinol metab clin north am 2018; 47:259−73. https://doi.org/10.1016/j.ecl.2018.02.001. 2. alexandraki ki, grossman ab. the ectopic acth syndrome. rev endocr metab disord 2010; 11:117−26. https://doi.org/10.1 007/s11154-010-9139-z. 3. isidori am, sbardella e, zatelli mc, boschetti m, vitale g, colao a, et al. conventional and nuclear medicine imaging in ectopic cushing's syndrome: a systematic review. j clin endocrinol metab 2015; 100:3231−44. https://doi.org/10.1210/ jc.2015-1589. 4. razek aa. diffusion magnetic resonance imaging of chest tumors. cancer imaging 2012; 12:452−63. https://doi.org/10.11 02/1470-7330.2012.0041. 5. kunikowska j, lewington v, krolicki l. optimizing somato statin receptor imaging in patients with neuroendocrine tumors: the impact of 99mtc-hynictoc spect/spect/ct versus 68ga-dotatate pet/ct upon clinical management. clin nucl med 2017; 42:905−11. https://doi.org/10.1097/rlu.00000000 00001877. 6. yu r, wachsman a. imaging of neuroendocrine tumors: indi cations, interpretations, limits, and pitfalls. endocrinol metab clin north am 2017; 46:795−814. https://doi.org/10.1016/j. ecl.2017.04.008. table 1: laboratory investigations of a 64-year-old male patient with ectopic cushing’s syndrome investigation measurement one measurement two measurement three measurement four normal range 24-hour urinary free cortisol levels in µg/day 95.5 198.1 202.9 221.7 ≤60 midnight salivary cortisol levels in µg/dl 0.430 0.736 0.929 <0.112 morning cortisol levels after 1 mg dexamethasone in µg/dl 14 19 <1.8 random morning acth levels in pg/ml 70 98 99 6–59 acth = adrenocorticotropic hormone. https://doi.org/10.1016/j.ecl.2018.02.001 https://doi.org/10.1007/s11154-010-9139-z https://doi.org/10.1007/s11154-010-9139-z https://doi.org/10.1210/jc.2015-1589 https://doi.org/10.1210/jc.2015-1589 https://doi.org/10.1102/1470-7330.2012.0041 https://doi.org/10.1102/1470-7330.2012.0041 https://doi.org/10.1097/rlu.0000000000001877 https://doi.org/10.1097/rlu.0000000000001877 https://doi.org/10.1016/j.ecl.2017.04.008 https://doi.org/10.1016/j.ecl.2017.04.008 departments of 1anaesthesia & icu, 2radiology and 3paediatric surgery, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drnigelkuriakose@gmail.com حتدايت اجملرى التنفسي والتخدير يف طفلة لديها شعبة هوائية مرتاكبة مع قوس األهبر املزدوج نايجل كورياكو�س، حممد الإ�شماعيلي، �شمري رانيجا، روهيت داتي، علي العبادي، زينب البلو�شية abstract: bronchus suis or tracheal bronchus is an accessory bronchus arising from the trachea above the carina. double aortic arch is a congenital vascular anomaly with persistence of both left and right aortic arches beyond fetal life which can form a vascular ring compressing the major airways and may be symptomatic. we report the case of a 16-month-old girl who had recurrent episodes of respiratory distress requiring multiple hospitalisations and was diagnosed at the sultan qaboos university hospital, muscat, oman in 2019 with a double aortic arch compressing upon a tracheal bronchus causing symptomatic emphysema of the right upper lobe. this report presents anaesthetic and airway challenges during the patient’s lobectomy. a single lumen cuffed endotracheal tube was successfully used as a bronchial blocker to occlude the origin of the aberrant bronchus. the position of the tube was confirmed intraoperatively using fibreoptic bronchoscopy. following her discharge, she continued to have recurrent episodes of respiratory distress and three months after her last appointment she succumbed to her illness. to the best of the authors’ knowledge, this is the first such reported case in oman. keywords: bronchus; trachea; aortic arch; endotracheal intubation; bronchoscopy; anesthesia; lobar pneumonia; oman. امللخ�ص: ال�شعبة الهوائية اخلنزيرية اأو الق�شبة الرغامية هي ق�شبة هوائية اإ�شافية نا�شئة من الق�شبة الهوائية فوق م�شتوى اجلوؤجوؤ. قو�س الأبهر املزدوج هو �شذوذ خلقي يف الأوعية الدموية ناجت عن ا�شتمرار قو�شي الأبهر الأي�رس والأمين اإىل ما بعد مرحلة اجلنني وميكن اأن ت�شكل حلقة وعائية ت�شغط على املجاري الهوائية الرئي�شية وقد توؤدي اإىل ظهور اأعرا�س مر�شية. يف هذا املقال، نعر�س حالة طفلة تبلغ من العمر 16 �شهراً كانت تعاين من نوبات متكررة من �شيق التنف�س تطلبت دخوًل متكررا اإىل امل�شت�شفى ومت ت�شخي�شها يف م�شت�شفى جامعة ال�شلطان قابو�س مب�شقط يف عمان عام 2019 بقو�س الأبهر املزدوج الذي ي�شغط على الق�شبة الرغامية م�شببا انتفاخ يف الف�س العلوي للرئة اليمنى. يعر�س هذا التقرير حتديات التخدير واملجرى التنف�شي اأثناء ا�شتئ�شال الف�س الرئوي للمري�شة. مت ا�شتخدام الأنبوب داخل الرغامى ذو التجويف املفرد بنجاح كحاجز لل�شعب الهوائية لإغالق من�شاأ ال�شعبة الهوائية ال�شاذة. مت تاأكيد مو�شع اأنبوب الرغامى اأثناء اجلراحة با�شتخدام تنظري الق�شبات الليفي. بعد خروجها من امل�شت�شفى، ا�شتمرت اإ�شابتها بنوبات متكررة من �شيق التنف�س وبعد ثالثة اأ�شهر من اآخر موعد للمراجعة ا�شت�شلمت ملر�شها. على حد علم املوؤلفني، تعترب هذه احلالة الأوىل من نوعها التي مت الإبالغ عنها يف عمان. الكلمات املفتاحية: �شعبة هوائية؛ الرغامى؛ قو�س الأبهر؛ تنبيب الرغامى؛ تنظري الق�شبات؛ التخدير؛ التهاب رئوي ف�شي؛ ُعامن. airway and anaesthetic challenges in a child with bronchus suis and superimposed double aortic arch a case report *nigel kuriakose,1 mohamed al-ismaili,1 sameer raniga,2 rohit date,1 ali al-abady,1 zainab al-balushi3 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e132–136, epub. 15 mar 21 submitted 9 apr 20 revision req. 11 jun 20; revision recd. 7 jul 20 accepted 29 jul 20 requires a high index of clinical suspicion and is confirmed using imaging techniques. a persistent double aortic arch presenting with compression of a bronchus suis has not been reported in the literature. case report a 16-month-old girl was diagnosed with bronchus suis and double aortic arch. she was born full-term and at one week of life started developing respiratory distress with recurrent respiratory tract infections requiring repeated hospitalisations and occasional bronchus suis, also known as pig bronchus or tracheal bronchus, is an aberrant bronchus arising from the tracheal wall above the carina and is usually asymptomatic.1 although a normal variant in pigs, the incidence of bronchus suis in humans is 0.1–3% of which the most common is an aberrant bronchus to the right upper lobe.1 double aortic arch is a congenital vascular anomaly where the left and right aortic arches persist beyond fetal life. it can form a complete or incomplete vascular ring that can compress major airways and the oesophagus. the diagnosis of these two conditions this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.020 case report https://creativecommons.org/licenses/by-nd/4.0/ nigel kuriakose, mohamed al-ismaili, sameer raniga, rohit date, ali al-abady and zainab al-balushi case report | e133 ventilatory support. chest x-rays showed right upper lobe consolidation/collapse which was treated as lobar pneumonia. a computed tomography (ct) scan performed during the sixth hospital admission at 16 months revealed an accessory bronchus arising from the posterolateral aspect of the trachea supplying the entire right side approximately 9 mm proximal to the carina suggestive of a bronchus suis. there was a focal luminal stenosis of the bronchus suis approximately 1 cm from its origin along with marked hyperinflation of the affected right upper lobe [figure 1]. ct angiography revealed a persistent rightsided aortic arch, a midline descending aorta and an incomplete left aortic arch [figure 2]. the accessory tracheal bronchus was markedly compressed between the abnormally placed right-sided descending aorta and the right pulmonary artery [figure 3]. the left lung appeared small. the left pulmonary artery was absent with the left lung receiving arterial supply mainly from the bronchial arteries and multiple pleural branches. an urgent lobectomy to relieve pressure effects of the emphysematous lobe on the normal lung tissue was performed. preoperative echocardiography showed only mild pulmonary hypertension with pulmonary artery pressures of 30 mmhg. the child was on oxygen preoperatively via nasal cannula at 1 l/ min. her haemoglobin was 9.5 g/dl with neutrophilic leucocytosis. her capillary blood gas showed a ph = 7.404, partial pressure of carbon dioxide = 51 mmhg, partial pressure of oxygen = 34 mmhg, serum bicarbonate concentration = 29.6 mmol/l, base excess = 7.6 meq/l and lactate level = 2.7 mmol/l. on auscultation there was bilateral wheeze. on the day of surgery, the patient was still symptomatic. intravenous access was secured. following adequate preoxygenation, she was induced with intravenous fentanyl 2–3 µg/kg, propofol 2–3 mg/kg and cisatracurium 0.02–0.03 mg/ kg. the trachea was intubated using c-mac® (karl storz se & co. kg, tuttlingen, germany) and 4.5 mm internal diameter single lumen tube (covidien shiley™ cuffed basic endotracheal tubes, medtronic, minneapolis, minnesota, usa). inflation pressure was limited and kept below 20 cm of water to avoid further hyperexpansion of the emphysematous lobe. figure 1: pre-operative computed tomography scan of the chest of a 16-month-old girl showing the presence of an accessory bronchus (blue arrow) on the right side arising directly from the supracarinal trachea at a distance of 8-9 mm from the carina, suggestive of a tracheal bronchus. entire right upper lobe is supplied by this accessory bronchus and there is marked focal thinning of the tracheal bronchus approximately 1 cm from its origin (red arrow). there is associated hyperinflation of the upper lobe of the right lung with paucity of the bronchovascular markings. figure 3: sagittal reformatted computed tomography scan of the chest of a 16-month-old girl showing compression of the accessory tracheal bronchus (red arrow) between the anomalous right-sided aortic arch and pulmonary artery leading to luminal stenosis and bronchomalacia. figure 2: coronal reformatted computed tomography scan of the lungs of a 16-month-old girl showing rightsided aortic arch (red arrow) with a midline descending aorta. airway and anaesthetic challenges in a child with bronchus suis and superimposed double aortic arch a case report e134 | squ medical journal, february 2021, volume 21, issue 1 figure 4: schematic diagram showing position of the endotracheal tube cuff at the origin of aberrant bronchus for right upper lobe isolation. general anaesthesia was maintained with oxygen, air and sevoflurane. fibreoptic bronchoscopy was done which confirmed the presence of aberrant right upper lobe bronchus arising from the posterolateral wall of the trachea 8–9 mm proximal to the carina. it was fully compressed approximately 1 cm beyond its origin, which correlated with the preoperative ct findings. the left main bronchus was patent and normal in size. the right main bronchus was normal and gave rise to the right middle lobe and lower lobe bronchi. the endotracheal tube tip was positioned just above the carina with the aim of having the inflated cuff occlude the origin of the aberrant bronchus thus aiding in the thoracotomy and lobectomy [figure 4]. in addition to standard intraoperative monitors, nasopharyngeal temperature and invasive left radial arterial pressure were monitored. normothermia was maintained using warming blanket and fluid warmer. right posterolateral thoracotomy through the fifth intercostal space was done in left lateral position. after dissection and separation of lobar arteries, veins and bronchus, the endotracheal tube was withdrawn under bronchoscopic guidance and the aberrant bronchus was transilluminated to help surgeons confirm its position. the right upper lobe was manually emptied of air and the endotracheal tube was then repositioned. on reinstitution of intermittent positive-pressure ventilation, the right upper lobe remained deflated confirming the proper placement of the endotracheal tube cuff at the origin of the aberrant bronchus. ventilation parameters were maintained at a tidal volume = 70 ml, frequency = 26 breaths/min, oxygen fraction = 55% and positive end-expiratory pressure (peep) = 0–5 cm of water. a brief episode of desaturation during lung retraction was successfully managed using the fraction of inspired oxygen = 100% and peep = 5 cm of water. the patient remained stable for the remainder of the procedure. intraoperative analgesia was achieved using intravenous fentanyl. neuromuscular blockade was maintained using intermittent boluses of cisatracurium. at the end of the surgery, the patient was kept intubated and was transferred to the pediatric intensive care unit with stable haemodynamics for postsurgical observation and adequate pain management. post-operative analgesia was maintained with intravenous morphine infusion. the patient was extubated the next day and discharged from the hospital on post-operative day 17. post-operative echocardiography after two months showed a worsened pulmonary artery pressure of 57 mmhg for which she was started on sildenafil. she had regular follow-up appointments for seven months. she continued to have recurrent episodes of respiratory distress for which she was on home oxygen and diuretics. the congenital absence of left pulmonary artery (causing decreased lung perfusion and v/q mismatch) along with the right upper lobectomy may explain the persistent symptoms of her respiratory distress. three months after her last appointment the child succumbed to her illness. as no autopsy was performed, the exact cause of death could not be ascertained. consent was obtained over the telephone from the child’s father regarding the publication of this case report. discussion tracheal bronchus was first described in 1785.2 the right upper lobe bronchus normally originates approximately 1–3 cm distal to the carina. in the current patient, it arose from the right lateral wall of the trachea at a distance of <1 cm proximal to the carina.3,4 an aberrant bronchus is normally the result of additional tracheal outgrowth during early embryogenesis.5 bronchus suis is usually right sided with greater predilection amongst males.6 it is commonly seen among syndromic children especially down’s syndrome and other bronchopulmonary anomalies.1,7 vascular rings and the presence of a double aortic arch account for <1% of congenital heart diseases.8 hommel gave the first anatomical description of a double aortic arch in 1737 while gross performed the first surgical correction in 1945.9 classically, a double aortic arch is divided into three different types: right dominant aortic arch (75%), left dominant aortic arch (18%) and the balanced type (7%).10 clinical symptoms with a double aortic arch usually appear in the first six nigel kuriakose, mohamed al-ismaili, sameer raniga, rohit date, ali al-abady and zainab al-balushi case report | e135 months of life.11 the double aortic arch usually causes respiratory symptoms in 91% and gastrointestinal symptoms in 40% of cases.10,11 the finding of a double aortic arch is usually an isolated cardiovascular malformation. in a study of 113 patients, coexisting cardiac anomalies occurred only in eight (7%); while in another study of 81 patients with double aortic arch such anomalies appeared in 14 patients (17%).8 in the current patient, other than the asymptomatic patent foramen ovale, no cardiac abnormalities were noted. the current case is unique as no previous literature on the coexistence of tracheal bronchus with double aortic arch could be found. challenges with airway management due to the presence of tracheal bronchus and double aortic arch have been reported separately for thoracic and nonthoracic surgeries, as well as for ventilation in the intensive care unit.12 due to its multifarious presentation, an undiagnosed tracheal bronchus during thoracic surgery may interfere with lung isolation and/ or ventilation strategies depending on the surgical site and the type of one-lung ventilation device used.13 the preoperative condition of these patients is often challenging for anaesthesiologists. in the current case, the bronchial compression was revealed by respiratory distress and recurrent respiratory tract infections. such children with recurrent respiratory tract infections coming for a corrective procedure maybe misdiagnosed.14 this may aggravate the symptoms of chronic airway obstruction through edema and inflammation. meticulous preoperative evaluation is essential to comprehensively evaluate the presence of any compression, deviation or malformation of airways and the great vessels. the assessment for such patients should include a fibreoptic bronchoscopy for associated tracheal lesions such as tracheobronchomalacia and tracheal stenosis.15 intraoperative one lung ventilation may be needed to prevent contamination of the dependent lung or to facilitate dissection during thoracotomy. double-lumen tubes (dlt) may help the purpose. the smallest size of available conventional dlt is 26 fr which is suitable for children above eight years of age. in the current patient, there was no question of lung soiling and hence complete lung isolation was not warranted with the approval of the surgeons. other available options for paediatric one-lung ventilation includes single-lumen endobronchial tubes, micro-cuff tubes, marraro bilumen tubes and bronchial blockers. single lumen endobronchial tubes are longer than standard endotracheal tubes but with smaller external diameters and smaller cuffs. an important feature of these endobronchial tubes is a narrow bronchial cuff and a relatively short distance from the proximal edge of that cuff to the distal tip of the tube. hence, there is less chance of the bronchial cuff obstructing the upper lobe bronchus and the margin of safety is much larger compared to standard endotracheal tubes. a double lumen tube is used for neonates and small children up to two or three years of age and consists of two uncuffed tubes that are moulded together so as to function like conventional dlts.16 the smallest univent tube has an internal diameter of 3.5 mm and is used for children less than six years of age. the smallest arndt paediatric endobronchial blocker is 5 fr which may be suitable for children more than two years of age as it requires at least a 4.5 mm internal diameter endotracheal tube. a fogarty catheter can also be used for lung isolation in infants. a single-lumen endotracheal tube is viewed as the simplest method of obtaining lung isolation. the technique for placement is straightforward and can be accomplished with standard intubation equipment. the current patient only needed occlusion of the aberrant bronchus which could be achieved with the inflated cuff of a normal single lumen endotracheal tube. in the current patient, although the right upper lobe was emphysematous, it could have been contributing to the ventilation and oxygenation while the hyperinflated right upper lobe compressed other areas of the lung. meanwhile, the occlusion and surgical manipulation of the right upper lobe could be the reason for the transient episode of desaturation intraoperatively. postoperatively, airway obstruction may persist in approximately 30% of cases despite surgical correction which may warrant artificial ventilation or continuous positive airway pressure ventilation.8 conclusion this case report highlights that clinicians should consider rare anatomical variants such as a coexisting bronchus suis and a double aortic arch in children who present with repeated pneumonia, stridor or emphysematous lobes when other common aetiologies are excluded. the use of a single lumen cuffed endotracheal tube for lobe isolation and intraoperative fibreoptic bronchoscopy for positional confirmation would be a pragmatic choice in the airway management of these patients. airway and anaesthetic challenges in a child with bronchus suis and superimposed double aortic arch a case report e136 | squ medical journal, february 2021, volume 21, issue 1 references 1. ikeno s, mitsuhata h, saito k, hirabayashi y, akazawa s, kasuda h, et al. airway management for patients with a tracheal bronchus. br j anaesth 1996; 76:573–5. https://doi.org/10.1093/bja/76.4.573. 2. lai km, hsieh mh, lam f, chen cy, chen tl, chang cc. anesthesia for patients with tracheal bronchus. asian j anesthesiol 2017; 55:87–8. https://doi.org/10.1016/j.aja.2017.09.002. 3. wong dt, kumar a. case report: endotracheal tube malposition in a patient with a tracheal bronchus. can j anaesth 2006; 53:810–13. https://doi.org/10.1007/bf03022798. 4. barat m, konrad hr. tracheal bronchus. am j otolaryngol 1987; 8:118–22. https://doi.org/10.1016/s0196-0709(87)80034-0. 5. dosi ra, jain a, joshi p, motiwale s, songara a. a rare case of a tracheal bronchus. jacp 2018; 6:76–9. https://doi.org/10.4103/ jacp.jacp_28_17. 6. singh k, agrawal a, sahu d, chaudhary m. extremely rare congenital tracheobronchial anomaly of bronchus suis: a hidden cause of pulmonary infection. lung india 2017; 34:577-9 7. bertrand p, navarro h, caussade s, holmgren n, sánchez i. airway anomalies in children with down syndrome: endoscopic findings. pediatr pulmonol 2003; 36:137–41. https://doi.org/10.10 02/ppul.10332. 8. houba a, bensghir m, ahtil r, slioui b, balkhi h, lalaoui sj. double aortic arch presenting with respiratory distress: a case report and review of the literature. saudi j anaesth 2017; 11:483–5. https://doi.org/10.4103/sja.sja_249_17. 9. hardin re, brevetti gr, sanusi m, bhaskaran d, burack jh, genovesi mh, et al. treatment of symptomatic vascular rings in the elderly. tex heart inst j 2005; 32:411–415. 10. backer cl, mavroudis c, rigsby ck, holinger ld. trends in vascular ring surgery. j thorac cardiovasc surg 2005; 129:1339–47. https://doi.org/10.1016/j.jtcvs.2004.10.044. 11. alsenaidi k, gurofsky r, karamlou t, williams wg, mccrindle bw. management and outcomes of double aortic arch in 81 patients. pediatrics 2006; 118:e1336–41. https://doi. org/10.1542/peds.2006-1097. 12. agarwal s, banks ma, dalela s, bates wb, castresana mr. incidental finding of tracheal bronchus complicating the anesthetic management of a left video-assisted thoracoscopic procedure. j anaesthesiol clin pharmacol 2016; 32:106–8. https://doi.org/10.4103/0970-9185.168167. 13. moon yj, kim sh, park sw, lee ym. the implications of a tracheal bronchus on one-lung ventilation and fibreoptic bronchoscopy in a patient undergoing thoracic surgery: a case report. can j anaesth 2015; 62:399–402. https://doi. org/10.1007/s12630-014-0293-8. 14. zhang q, fu z, dai j, geng g, fu w, tian d. recurrent wheezing and cough caused by double aortic arch,not asthma. case rep cardiol 2017. article id 8079851, 4 pages, 2017. https://doi.org/10.1155/2017/8079851. 15. lee dk, kim ym, kim hz, lim sh. right upper lobe tracheal bronchus: anesthetic challenge in one-lung ventilated patients -a report of three cases. korean j anesthesiol 2013; 64:448–50. https://doi.org/10.4097/kjae.2013.64.5.448. 16. marraro g. selective endobronchial intubation in paediatrics: the marraro paediatric bilumen tube. pediatr anesth 1994; 4:255–8. https://doi.org/10.1111/j.1460-9592.1994.tb00174.x. https://doi.org/10.1093/bja/76.4.573 https://doi.org/10.1016/j.aja.2017.09.002 https://doi.org/10.1007/bf03022798 https://doi.org/10.1016/s0196-0709%2887%2980034-0 https://doi.org/10.4103/jacp.jacp_28_17 https://doi.org/10.4103/jacp.jacp_28_17 https://doi.org/10.1002/ppul.10332 https://doi.org/10.1002/ppul.10332 https://doi.org/10.4103/sja.sja_249_17 https://doi.org/10.1016/j.jtcvs.2004.10.044 https://doi.org/10.1542/peds.2006-1097 https://doi.org/10.1542/peds.2006-1097 https://doi.org/10.4103/0970-9185.168167 https://doi.org/10.1007/s12630-014-0293-8 https://doi.org/10.1007/s12630-014-0293-8 https://doi.org/10.1155/2017/8079851 https://doi.org/10.4097/kjae.2013.64.5.448 https://doi.org/10.1111/j.1460-9592.1994.tb00174.x department of surgery, jawaharlal institute of postgraduate medical education and research, puducherry, india *corresponding author’s e-mail: k26uday74@yahoo.co.in abdominoscrotal haematocele in an adult and its successful treatment *uday s. kumbhar, oseen shaikh, sandeep bhattarai sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 144–148, epub. 28 feb 22 submitted 13 oct 20 revision req. 9 dec 20; revision recd. 11 jan 21 accepted 10 feb 21 fluctuant; there was a cross fluctuation between the abdominal and scrotal swelling. the transillumination test was negative in the scrotal swelling. ultrasonography of the abdomen and scrotum showed a large hypoechoic collection with internal echoes >20 cm in size in the left-lower abdomen with extension into the left inguinoscrotal region with normal bilateral testis. contrast-enhanced computed tomography of the abdomen showed a large hypodense retroperitoneal cystic lesion measuring 24 × 16 cm in the entire left side of the abdomen with the craniocaudal extent from the left lobe of the liver up to the pelvic brim. anteriorly it was extending up to the anterior abdominal wall displacing entire intraperitoneal structures to the right side. another hypodense cystic lesion was present in the left hemiscrotum measuring 18 × 9 cm with few septations and communication with the abdominal cyst which was diagnostic of ash [figure 2]. the bilateral testis appeared normal; however, the size of the left testis was a little smaller than the right. subsequently, a diagnostic laparoscopy was done. pneumoperitoneum was created by open technique with a 10 mm trocar in the right lumbar region. two working ports were used; one 5 mm trocar was placed in the right lumbar region 7 cm above and lateral to the umbilicus and another 10 mm trocar was placed 6 cm below the umbilicus in the midline. there was a large retroperitoneal cystic lesion occupying most of the left half of the abdomen. it had displaced the sigmoid and descending colon medially. craniocaudally it extended from the left lobe of the liver up to the pelvic brim. abdominoscrotal hydrocele (ash) isdefined as hydrocele extending into the abdominal cavity forming two intercommunicating compartments.1 ash, also called hydrocele en-bisac, is a rare variant of a hydrocele that can occur commonly in the paediatric age group but is rarely seen in the adult population. patients are usually asymptomatic or present with variable sized abdominoscrotal swelling. ash can become complicated due to bleeding inside the sac, which can occur due to trauma, malignancy or be spontaneous leading to the formation of haematocele.2 the exact aetiology of ash is not known, but various theories have been proposed. these theories explain disease occurrence either as an extension of the scrotal sac into the abdomen or abdominal sac into scrotum or both. it is diagnosed clinically, and imaging is used to support the diagnosis.3 treatment can be conservative or surgical. in adults, treatment is done by surgical means, either via an open or laparoscopic approach. case report a 57-year-old male patient presented to a tertiary care hospital in puducherry, india, in 2019 with left-sided scrotal swelling for the previous 15 years and abdominal pain for the past two months. there were no other symptoms such as altered bowel or bladder habits. the patient was a non-alcoholic, non-smoker with no comorbidities. on examination, there was a large leftside scrotal hydrocele and large left-lower abdominal swelling [figure 1]. abdominal swelling was soft, nontender and had a smooth surface. scrotal swelling was this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.068 case report abstract: abdominoscrotal hydrocele (ash) is a variant of hydrocele that rarely occurs in adults. ash has two sacs, one in the scrotum and one in the abdomen connected through the inguinal canal. abdominoscrotal haematocele is a rare complication of ash. we report a 57-year-old male patient who presented to a tertiary care hospital in puducherry, india, in 2019 with complaints of swelling in the scrotum for 15 years and abdominal pain for two months. both the swellings were soft and cross fluctuation was present. imaging confirmed the diagnosis of ash. during a diagnostic laparoscopy, the abdominal sac was decompressed and found to have thick brownish fluid suggestive of haematocele. it was demonstrated that both sacs were connected. due to difficulty in the dissection of the sac, the procedure was converted to an open procedure. both the sacs were excised and lytle’s repair was done for the dilated internal ring. the patient recovered and no recurrence of any swelling in the abdomen or scrotum was found at the end of a one-year follow-up. keywords: testicular hydrocele; scrotal hydrocele; testicular haematocele; scrotal haematocele; laparoscopic surgical procedure; laparoscopic surgery; case report; india. https://creativecommons.org/licenses/by-nd/4.0/ uday s. kumbhar, oseen shaikh and sandeep bhattarai case report | 145 inferiorly the cyst extended into the inguinal canal through the deep inguinal ring. due to the large size of the cyst and inadequate access for the dissection, a decision was made to decompress the cyst. initially, the cyst was punctured using a veress needle which was inserted transcutaneously. it was not possible to do an effective aspiration as the fluid was thick and brown to greenish in colour. the veress needle was replaced with a 5 mm trocar and 1,500 ml of fluid was aspirated. another 10 mm trocar was placed through the bottom of the scrotum into the hydrocele sac [figure 3] and 650 ml of the fluid was drained which had the same characteristics as the abdominal fluid. there were two openings at the cranial pole of the sac, one of which was communicating with the abdominal cyst [figure 3]. the retroperitoneal cyst was dissected from the lateral abdominal wall. once the dissection proceeded medially, it was impossible to separate the cyst from the sigmoid colon and its mesentery. due to the risk of inadvertent injury, the decision was made for open surgery conversion. the retroperitoneal cyst was approached transabdominally using a left inguinal incision. the cyst was opened and brownish muddy fluid was evacuated. the cyst wall was completely excised; it was extending into the scrotum through the inguinal canal. a separate vertical incision was made over the scrotum. the hydrocele sac was opened and the contents were found to be similar to those in the abdomen, suggestive of haematocele. in addition, the testis had haematomas. a decision was taken for a left orchidectomy. both the abdominal and scrotal sacs were dissected and the communication between the two sacs was well demonstrated [figure 3]. complete excision of both the sacs along with the intercommunicating tract was done. the internal ring was mildly dilated; however, there was no weakening of the abdominal wall. hence, lytle’s repair was done for the dilated internal ring. subsequently, the port sites, inguinal and scrotal incisions were closed. the patient was discharged after eight days without any complication. the patient was under regular follow-up. operative site wounds healed completely, and the scrotum regained its normal size [figure 4]. no recurrence of any swelling in the abdomen or scrotum at the end of a one-year followfigure 1: photograph of a 57-year-old male patient showing abdominal and scrotal swelling. figure 2: contrast-enhanced computed tomography images showing large hypointense-walled collection of 24 × 16 cm in the left side of the retroperitoneum extending into the ipsilateral inguinoscrotal region measuring 18 × 9 cm. figure 3: intraoperative images showing (a) scrotal trocar (arrow) and (b) trans-scrotal endoscopic view of the scrotal sac with the opening of communication (arrow) with abdominal sac as well as (c) communication between abdominal sac and scrotal sac by passage of laparoscopic suction cannula (arrows). abdominoscrotal haematocele in an adult and its successful treatment 146 | squ medical journal, february 2022, volume 22, issue 1 up was found. written informed consent was obtained from the patient to use his images for publication purposes. discussion hydrocele is an accumulation of fluid between the layers of tunica vaginalis. it can occur in infants or adults. an infantile hydrocele is due to persistent patent processus vaginalis. adult or vaginal hydrocele occurs when fluid collection occurs between tunica vaginalis, where processus vaginal is obliterated. a variant of hydrocele, called “hydrocele of the cord” occurs due to partial closure of processus vaginalis. ash is a rare variant of hydrocele characterised by scrotal hydrocele extending into the abdomen as cystic abdominal swelling through the inguinal canal. ash is defined as a hydrocele extending into the abdominal cavity forming two intercommunicating compartments.1 dupuytren first described this in 1834 and it was called dupuytren hydrocele or hydrocele en-bisac.4 in 1919, bickle proposed a new term for hydrocele en-bisac called abdominoscrotal hydrocele.5 ash is a rare entity and has been reported both in infants and old age. it is seen more commonly in the paediatric age group than adults. overall, in adults, there are less than 250 cases reported in the literature. india has the highest incidence of ash in the world.3 literature review suggests that ash is more common on the right side than the left. ash is usually a congenital anomaly; it starts from birth as an inguinoscrotal swelling that extends to the abdomen. it may be missed in childhood and may present in adult life. sac of ash extends through the inguinal canal and this part of the sac acts as an isthmus between the two sacs giving a dumbbell shape appearance.2 interestingly, the current patient presented with predominant left-sided scrotal swelling and nonspecific abdominal pain. the abdominal sac can be retroperitoneal or preperitoneal. the sac is usually covered with the transversalis fascia. the abdominal sac may be of variable size and shape and can be as large as a football.1 although the scrotal sac is of varying size, it is usually small. these sacs can be unilocular or multilocular. there is intercommunication between the two sacs without any communication with the peritoneal cavity. there are various theories proposed for the development of ash. dupuytren hypothesised that ash occurs due to an extension of the scrotal sac into the abdomen through the inguinal canal whenever the scrotal sac is under high pressure.1 jacobson hypothesised that ash occurs as a result of an extension of infantile hydrocele.6 others added another concept to this hypothesis: the coexistence of inguinal defect and infantile hydrocele.7 roller hypothesised that encysted hydrocele of cord and ordinary hydrocele might form ash; however, they did not explain the intercommunication between the sacs.8 some other theories have been proposed but these have been less accepted. ash can occur due to an extension of the preformed peritoneal sac into the scrotum through the inguinal canal and/or due to the flow of fluid downwards through persistent processus vaginalis, which acts as a one-way valve.1,9 ash occurring in the paediatric age group is known to have spontaneous regression, but such resolution has not been noted in adults. the patient presents with painless inguinoscrotal swelling and abdominal swelling which may be variable in size. scrotal swelling may be reducible or partially emptied in the supine position. cross-fluctuation may be present due to the intercommunication of the two sacs, which is diagnostic for ash. the presence of ‘springing back ball sign’ and hourglass transillumination are diagnostic of ash.10 in the current patient, there was the presence of cross-fluctuation, but it was not transilluminating. this may be because of the muddy brownish fluid contents due to haemorrhage in the cyst. other associated anomalies are contralateral hydrocele, hernia, ectopic testis, cryptorchidism and various urinary tract anomalies. in the current patient, there was no associated congenital anomaly. long-standing ash may have complications such as testicular dysmorphism, hydronephrosis, lymphedema, pyocele, torsion, haematocele and rarely malignancy, which can be either testicular or paratesticular.11–14 the presence of haematocele or bleeding inside the sac can occur and should raise the suspicion of the existence of malignancy. it can occur as an acute figure 4: photograph of the patient taken one month after the surgery during follow-up showing healed port sites, inguinal and scrotal scars. uday s. kumbhar, oseen shaikh and sandeep bhattarai case report | 147 or chronic event and may be discovered accidentally. haematocele can occur due to spontaneous rupture or trivial trauma or malignancy.13,14 the current patient had haematocele as a complication that probably developed over last two months as the patient presented with pain. in terms of diagnosis, ultrasound can provide information about the size and contents of the sac. computed tomography (ct) and magnetic resonance imaging (mri) are additional investigations that can confirm the diagnosis and differentiate it from other diseases that mimic ash. the presence of malignancy, associated congenital abnormality or presence of testicular dysmorphism, can be seen in ct and mri. in the current case, there was a presence of testicular atrophy without any other congenital abnormality. the presence of a haematocele may not be diagnosed preoperatively, even with an imaging technique; often a haematocele will be diagnosed intraoperatively. in the current case, imaging was not suggestive of a haematocele and showed testicular atrophy. ash can be treated with a conservative or surgical approach. a conservative approach with the expectant spontaneous resolution has been seen in asymptomatic and uncomplicated paediatric ash; still, such an approach is not useful in adults as spontaneous resolution does not occur in adults. surgical procedures include excision of the sac, aspiration or incision and drainage.1 excision of the sac is the ideal treatment option, which can be done laparoscopically or by open approach. a laparoscopic approach was first tried in 2004 and boulhadiba et al. performed the first successful laparoscopic ash excision in 2007.15 excision of the abdominal sac along with partial excision of the scrotal sac with eversion is the most standard technique used. sac can be excised en-bloc with cord and testis whenever there is suspicion of testicular atrophy or testicular malignancy. partial excision of the scrotal sac with drainage of the abdominal sac can also be done. in the current patient, both sacs could be excised entirely with the removal of the left testis as there were testicular haematomas and atrophy. laparoscopy helps in confirming the diagnosis and is used in definitive management. the presence of large ash and for a long period of time may make the laparoscopic treatment difficult due to adhesion or proximity to a vital structure, as was seen in the current case. clinicians should be cautious with patients dealing with large ash as open conversion may be required. this case is an example of complicated ash where preoperative imaging studies did not show any evidence of complications within ash. even in complicated ash, the authors recommend laparoscopic treatment of ash if the sacs can be excised safely. in addition, there may be a concomitant hernia in patients with ash or it may develop in the future if the internal ring is dilated. simultaneous repair of the dilated internal ring or hernia repair, if present, can prevent the future occurrence of a hernia. conclusion ash is a rare entity; although described mainly in the paediatric age group, it can also occur in adults as was seen in the current case. clinical findings assisted by radiological imaging are the diagnostic modalities. ash is usually asymptomatic and the development of symptoms is a sign of complicated ash. abdomino scrotal haematocele is a rare complication of ash and to the best of the authors’ knowledge, this is the first report to document such a case. surgical excision is the definitive treatment in such cases and can be performed by an open or laparoscopic approach. the presence of a concomitant hernia or weak abdominal wall should be repaired at the same time. if there is a presence of only a dilated internal ring, it can be repaired at index surgery. a u t h o r s’ c o n t r i b u t i o n os and usk drafted the manuscript. sb collected the relevant data. usk conducted a critical revision of the manuscript. all authors approved the final version of the manuscript. references 1. gadelkareem ra. abdominoscrotal hydrocele: a systematic review and proposed clinical grading. afr j urol 2018;24:83–92. https://doi.org/10.1016/j.afju.2018.01.006. 2. ross jh, kay r. abdominoscrotal hydrocele in the infant. clinpediatr (phila) 1992;31:317–19. https://doi.org/10.1177/000992 289203100514. 3. mishra j, behera tk, rout b, jena k, ray mohapatra ck. hydrocele-en-bisac in a young adult: a rare encounter. anz j surg 2013;83:581–2. https://doi.org/10.1111/ans.12220. 4. dupuytren g. de l’hydrocèle et de sesprincipalesvariétés.in: bailliêre g, ed. leçonsorales de cliniquechirurgicale. paris, france. 1834. pp 444–45. 5. bickle lw. abdominal or bilocular hydrocele. br med j 1919: 2;13. 6. cuervo jl, ibarra h, molina m. abdominoscrotal hydrocele: its particular characteristics. j pediatrsurg 2009;44:1766–70. https://doi.org/10.1016/j.jpedsurg.2008.12.002. 7. singh d, aga p, goel a. giant unilateral hydrocele ''en-bisac'' with right hydronephrosis in an adult: a rare entity. indian j urol2011;27:142–3. https://doi.org/10.4103/0970-1591.78413. https://doi.org/10.1016/j.afju.2018.01.006 https://doi.org/10.1177/000992289203100514 https://doi.org/10.1177/000992289203100514 https://doi.org/10.1111/ans.12220 https://doi.org/10.1016/j.jpedsurg.2008.12.002 https://doi.org/10.4103/0970-1591.78413 abdominoscrotal haematocele in an adult and its successful treatment 148 | squ medical journal, february 2022, volume 22, issue 1 8. roller c. abdominoscrotal hydrocele. jama 1934: 103;671–2. https://doi.org/10.1001/jama.1934.72750350001010 9. celayir ac, akyüz u, ciftlik h, gürbüz a, danişmend n. a critical observation about the pathogenesis of abdominoscrotal hydroceles. j pediatrsurg 2001;36:1082–4. https://doi.org/10.10 53/jpsu.2001.24760. 10. cozzi da, mele e, ceccanti s, pepino d, d’ambrosio g, cozzi f.infantile abdominoscrotal hydrocele: a not so benign condition. j urol2008;180:2611–15. https://doi.org/10.1016/j.ju ro.2008.08.054. 11. avolio l, chiari g, caputo ma, bragheri r. abdominoscrotal hydrocele in childhood: is it really a rare entity? urology 2000;56:1047–9. https://doi.org/10.1016/s0090-4295(00)00801-3. 12. belman ab.abdominoscrotal hydrocele in infancy: a review and presentation of the scrotal approach for correction. j urol 2001; 165:225–7. https://doi.org/10.1097/00005392-2001 01000-00065. 13. estevão-costaj, morgado h, soares-oliveira m, campos m, carvalhojl. hemorrhagicabdominoscrotal hydrocele. a challenging entity. j pediatrsurg 2005;40:731–3. https://doi.org/10.1016/j. jpedsurg.2005.01.012. 14. bisceglia m, dor db, carosi i, vairo m, pasquinelli g. paratesticular mesothelioma. report of a case with comprehensive review of literature. advanatpathol 2010;17:53–70. https://doi.org/10.109 7/pap.0b013e3181c66fbc. 15. bouhadiba n, godbole p, marven s. laparoscopic excision of abdominoscrotal hydrocele. j laparoendoscadvsurg tech a 2007;17:701–3. https://doi.org/10.1089/lap.2006.0249. https://doi.org/10.1001/jama.1934.72750350001010 https://doi.org/10.1053/jpsu.2001.24760 https://doi.org/10.1053/jpsu.2001.24760 https://doi.org/10.1016/j.juro.2008.08.054 https://doi.org/10.1016/j.juro.2008.08.054 http://v https://doi.org/10.1097/00005392-200101000-00065 https://doi.org/10.1097/00005392-200101000-00065 https://doi.org/10.1016/j.jpedsurg.2005.01.012 https://doi.org/10.1016/j.jpedsurg.2005.01.012 https://doi.org/10.1097/pap.0b013e3181c66fbc https://doi.org/10.1097/pap.0b013e3181c66fbc https://doi.org/10.1089/lap.2006.0249 research in mental health during the covid-19 pandemic quality versus quantity sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e406–407, epub. 21 dec 20 submitted 8 jun 20 revision req. 29 jul 20; revision recd. 13 aug 20 accepted 26 aug 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.024 letter to the editor البحث يف الصحة العقلية أثناء جائحة كوفيد-19 اجلودة ِإزاء الكمية dear editor, over the last several months, covid-19 has significantly influenced everyday living globally. the pandemic has resulted in limitations to the lifestyles of most individuals. it has also significantly influenced medical research. according to the publications on pubmed® (national library of medicine, bethesda, maryland, usa), the number of articles found using the search-term “covid-19” was 18,170 by 2 june 2020. out of these, 18,161 (99.95%) articles were published in 2020. by 7 august 2020, a total of 38,522 articles were found (2.12 times increase in 66 days). when searching for articles related to mental health associated with covid-19, 655 (3.66%) articles were found by 2 june and 1,662 (9.15%) articles by 7 august 2020. all the articles related to mental healthcare in the context of covid-19 were published during 2020. up to 7 august 2020, the total number of articles related to mental health in pubmed was 371,520. over the past year, 37,365 articles were published with 4.45% being related to covid-19 and mental health. reports suggest that researchers are confined to covid-19 research and all other dimensions of healthcare have been put aside.1,2 knowledge related to covid-19 has been ubiquitously disseminating during the current pandemic raising everybody’s concern, with researchers being no exception.3 recently, publications on the role of hydroxycholoquine in covid-19 management have been retracted from reputed journals due to uncertainty of data and evidence, which influenced decision-making worldwide.4 there are several reasons behind the shifting of focus towards covid-19 research during the current pandemic which resulted in a healthcare crisis. during this period, multiple domains of healthcare were adversely affected directly or indirectly.5 lockdown protocols during this pandemic have reduced accessibility to healthcare services with mental illness being no exception.6–8 this is a major contributor to the increased focus on covid-19 research which became a priority for every affected nation as well as its healthcare professionals. governments and international bodies are encouraging research of covid-19 for its effective control.9 this heightened attention by researchers worldwide resulted in a significant increase covid-19-based research. as there is a constant flow of new information related to covid-19 (e.g. pathogenesis or management) and the fact that researchers of the 21st century never witnessed a pandemic of such extent, researchers were encouraged to gather evidence through intensive research to understand covid-19 better. fast-tracked approval by ethics committees, fast-tracked publication by publishing houses and calls for covid-19-related papers for special issues of various national and international journals attracted researchers to a relatively easy and rapid publication process. it has been reported that the increased focus on covid-19 by researchers has resulted in proliferation of covid-19-related research, not all of which is impactful.7 when many studies attempt to measure similar phenomenon in a similar population at the same time period, not all of them may add to the existing information/ evidence. it is important to explore the research gaps and evaluate the unexplored domains that may give a meaningful conclusion. furthermore, the focus on covid-19 must not suppress the funding of ongoing research into other medical conditions of public health significance such as malnutrition and tuberculosis, which kills more people every year than covid-19.5,10 to date, most of the available research has explored the epidemiology of mental health issues during covid-19 and the association of covid-19 with brain changes and the mental health of children, caregivers and healthcare professionals.11,12 it has been noticed that there is a global shortage of mental healthcare professionals and an even greater shortage of researchers. as publishing houses receive a large number of submissions and many fast-track their review process, they run the risk of not receiving high-quality feedback resulting in publication of poorhttps://creativecommons.org/licenses/by-nd/4.0/ sujita k. kar, vikas menon, s. m. yasir arafat and russell kabir letter to the editor | e407 quality research. a large number of publications/submissions on covid-19 were retracted or withdrawn due to poor quality and ethical concerns.9 study methodology and design as well as the tools used to measure different mental health constructs also determine the quality of research. unfortunately, most of the mental health research during the covid-19 pandemic does not meet the desired quality.13,14 futhermore, dynamics of the pandemic are rapidly changing as are public health priorities. considering the rapidly evolving scenario of health priorities, recommendations may need constant updating.15,16 the generalisability of research findings also requires cautious interpretation. the significant increase in covid-19-related research has caused a strain on precious researcher time and resources. researchers should refrain from poor-quality research, study duplications and irrational trials.17 any type of public tragedy or catastrophe is connected to major social, economic and political disturbances. therefore, knowing the mental health determinants during such a crisis is crucial for resilience-building and mitigating anxiety and psychological distress. sujita k. kar,1 vikas menon,2 s. m. yasir arafat,3 *russell kabir4 1department of psychiatry, king george's medical university, lucknow india; 2department of psychiatry, jawaharlal institute of postgraduate medical education and research, puducherry, india; 3department of psychiatry, enam medical college and hospital, dhaka, bangladesh; 4school of allied health, faculty of health, education, medicine, and social care, anglia ruskin university, chelmsford, united kingdom. corresponding author’s e-mail: russell.kabir@anglia.ac.uk references 1. brainard j. scientists are drowning in covid-19 papers. can new tools keep them afloat? from: https://www.sciencemag.org/ news/2020/05/scientists-are-drowning-covid-19-papers-can-new-tools-keep-them-afloat accessed: aug 2020. 2. nature index. coronavirus research publishing: the rise and rise of covid-19 clinical trials. from: https://www.natureindex.com/newsblog/the-top-coronavirus-research-articles-by-metrics accessed: aug 2020. 3. lee sa. how much “thinking” about covid-19 is clinically dysfunctional? brain behav immun 2020; 87:97–98. https://doi.org/10.1016/j. bbi.2020.04.067. 4. mehra mr, ruschitzka f, patel an. retraction—hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. the lancet 2020; 395:1820. https://doi.org/10.1016/s0140-6736(20)31324-6. 5. andrade c. covid-19: humanitarian and health care crisis in a third world country. j clin psychiatry 2020; 81:20com13383. https:// doi.org/10.4088/jcp.20com13383. 6. kumar a, rajasekharan nayar k, koya sf. covid-19: challenges and its consequences for rural health care in india. public health pract 2020; 1:100009. https://doi.org/10.1016/j.puhip.2020.100009. 7. eijt m, de kort y, bongers i, bierbooms j, westerink j, ijsselsteijn w. mental health care goes online: practitioners’ experiences of providing mental health care during the covid-19 pandemic. cyberpsychol behav soc netw 2020. https://doi.org/10.1089/cyber.2020.0370. 8. siedner mj, kraemer jd, meyer mj, harling g, mngomezulu t, gabela p, et al. access to primary healthcare during lockdown measures for covid-19 in rural south africa: an interrupted series analysis. bmj open 2020; 10:e043763. https://doi.org/10.1101/2020.05.15.20103226. 9. world health organization (2020) global research on coronavirus disease (covid-19). from: https://www.who.int/emergencies/diseases/ novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov accessed: aug 2020. 10. bhargava a, shewade hd. the potential impact of the covid-19 response related lockdown on tb incidence and mortality in india. indian j tuberc 2020 in press. https://doi.org/10.1016/j.ijtb.2020.07.004. 11. xiong j, lipsitz o, nasri f, lui lmw, gill h, phan l, et al. impact of covid-19 pandemic on mental health in the general population: a systematic review. j affect disord 2020; 277:55–64. https://doi.org/10.1016/j.jad.2020.08.001. 12. vindegaard n, benros me. covid-19 pandemic and mental health consequences: systematic review of the current evidence. brain behav immun 2020; 89:531–42. https://doi.org/10.1016/j.bbi.2020.05.048. 13. nieto i, navas jf, vázquez c. the quality of research on mental health related to the covid-19 pandemic: a note of caution after a systematic review. brain behav immun health 2020; 7:100123. https://doi.org/10.1016/j.bbih.2020.100123. 14. dobler cc. poor quality research and clinical practice during covid-19. breathe (sheff.) 2020; 16:200112. https://doi. org/10.1183/20734735.0112-2020. 15. de sousa a, mohandas e, javed a. psychological interventions during covid-19: challenges for low and middle income countries. asian j psychiatr 2020; 51:102128. https://doi.org/10.1016/j.ajp.2020.102128. 16. ransing r, adiukwu f, pereira-sanchez v, ramalho r, orsolini l, teixiera als, et al. mental health interventions during the covid-19 pandemic: a conceptual framework by early career psychiatrists. asian j psychiatr 2020; 51:102085. https://doi.org/10.1016/j. ajp.2020.102085. 17. glasziou pp, sanders s, hoffmann t. waste in covid-19 research. bmj 2020; 369:m1847. https://doi.org/10.1136/bmj.m1847. https://doi.org/10.1016/j.bbi.2020.04.067 https://doi.org/10.1016/j.bbi.2020.04.067 https://doi.org/10.1016/s0140-6736%2820%2931324-6 https://doi.org/10.4088/jcp.20com13383 https://doi.org/10.4088/jcp.20com13383 https://doi.org/10.1016/j.puhip.2020.100009 https://doi.org/10.1089/cyber.2020.0370 https://doi.org/10.1101/2020.05.15.20103226 https://doi.org/10.1016/j.ijtb.2020.07.004 https://doi.org/10.1016/j.jad.2020.08.001 https://doi.org/10.1016/j.bbi.2020.05.048 https://doi.org/10.1016/j.bbih.2020.100123 https://doi.org/10.1183/20734735.0112-2020 https://doi.org/10.1183/20734735.0112-2020 https://doi.org/10.1016/j.ajp.2020.102128 https://doi.org/10.1016/j.ajp.2020.102085 https://doi.org/10.1016/j.ajp.2020.102085 https://doi.org/10.1136/bmj.m1847 1institute of research & medical consultations, imam abdul rahman bin faisal university, dammam, saudi arabia; 2division of biological chemistry, medical university innsbruck, innsbruck, austria; 3department of psychiatry & behavioural sciences, niazi medical & dental college, sargodha, pakistan *corresponding author’s e-mail: rkfarooq@iau.edu.sa مراجعة بيبليومرتية ألحباث الصحة النفسية يف الكليات الطبية يف باكستان ر�ي خالد فاروق، زوهيب �صيد، علي ذو �لقرنني abstract: objectives: mental health is a less frequently explored area of medical research as both developing and developed countries lack competent human resources and funding for this purpose. reviewing mental health research can help medical professionals appreciate the progress of understanding and identify problems in this area. this systematic review examined the status of mental health research carried out in medical education institutions and tertiary healthcare hospitals across pakistan over the past 70 years. methods: pubmed® (national library of medicine, bethesda, maryland, usa), was searched for articles published between 1947 and 2017 related to mental health with an emphasis on the exclusive affiliation of the first author with a medical college in pakistan. results: a total of 118 articles were included in this study. the number of published research-based studies has increased steadily over the past years. however, there are indicators of a lack of quality research, such as no declaration of conflict of interest or the identification of a funding source and a general lack of publications in a journal with a high impact factor. conclusion: the findings of this study have shown a steady improvement in the quantity and quality of mental health research conducted in pakistani medical colleges/universities. however, a lack of funding, training and faculty induction policies may be hindering the establishment of a research culture and contributing to the slow progression of mental health research in pakistan. keywords: medical education; mental health; research; psychiatry in literature; pakistan. امللخ�ص: الهدف: �ل�صحة �لنف�صية هي جمال �أقل �صرب� يف �الأبحاث �لطبية حيث تفتقر كل من �لبلد�ن �لنامية و�ملتقدمة �إىل �ملو�رد �لب�رصية وحتديد فهم يف �لتقدم تقدير يف �لطبيني �ملهنيني ت�صاعد �ن ميكنها �لنف�صية �ل�صحة �أبحاث مر�جعة �لغر�س. لهذ� و�لتمويل �ملخت�صة �لطبي �لتعليم موؤ�ص�صات يف �أجريت �لتي �لنف�صية �ل�صحة �أبحاث حالة بفح�س �ملنهجية �ملر�جعة هذه قامت �ملجال. هذ� يف �مل�صاكل pubmed® وم�صت�صفيات �لرعاية �ل�صحية �لثالثية يف جميع �أنحاء باك�صتان على مدى �ل�صنو�ت �ل�صبعني �ملا�صية. الطريقة: مت �لبحث يف )�ملكتبة �لوطنية للطب، بيثي�صد�، ماريالند، �لواليات �ملتحدة �الأمريكية( عن مقاالت ن�رصت يف �لفرتة بني عامي 1947 و 2017 و�لتي تتعلق بال�صحة �لنف�صية مع �لرتكيز على كون �ملوؤلف �الأول ينتمي ح�رصيا �ىل كلية طب يف باك�صتان. النتائج: �أدرج ما جمموعه 118 مقاال يف هذه �لدر��صة. �زد�د عدد �لدر��صات �ملن�صورة و�مل�صتندة �إىل �الأبحاث ب�صكل مطرد خالل �ل�صنو�ت �ملا�صية. غري �أن هناك موؤ�رص�ت على وجود نق�س يف �الأبحاث ذ�ت �جلودة، مثل عدم �لت�رصيح عن ت�صارب �مل�صالح �أو حتديد م�صدر �لتمويل ونق�س عام يف عدد �ملقاالت �ملن�صورة مبجالت ذ�ت معامل تاأثري مرتفع. اخلال�صة: �أظهرت نتائج هذه �لدر��صة حت�صنا مطرد� يف كمية ونوعية �أبحاث �ل�صحة �لنف�صية �لتي �أجريت يف �لكليات/�جلامعات �لطبية �لباك�صتانية. غري �أن �الفتقار �إىل �لتمويل و�لتدريب و�ل�صيا�صات �لتي حتث �أع�صاء هيئة �لتدري�س قد يعوق �إقامة ثقافة بحثية وي�صاهم يف �لتقدم �لبطيء الأبحاث �ل�صحة �لنف�صية يف باك�صتان. الكلمات املفتاحية: �لتعليم �لطبي؛ �ل�صحة �لنف�صية؛ �بحاث؛ �لطب �لنف�صي يف �الأدبيات �لعلمية؛ باك�صتان. bibliometric review of mental health research in medical colleges of pakistan *rai k. farooq,1 zohaib syed,2 ali zulqernain3 clinical & basic research sultan qaboos university med j, august 2019, vol. 19, iss. 3, pp. e242–247, epub. 5 nov 19 submitted 26 feb 19 revision req. 1 apr 19; revision recd. 14 apr 19 accepted 8 may 19 advances in knowledge the findings of this analysis highlight an increase in the quantity of mental health research from pakistan but has also found gaps in policy and practice that need to be addressed to improve the quality and depth of the research. the results of the study show that more clinicians need to be educated about declaring conflict of interest, patient informed consent and disclosure of funding. application to patient care this study highlights the most important area currently under examination in pakistan, depression and other mood disorders, which are also the most prevalent psychiatric disorders in the country. policy changes are needed to enable the training of more physicians and scientists, which will improve pakistan’s research output and contribute to improving patient care. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.03.011 https://creativecommons.org/licenses/by-nd/4.0/ rai k. farooq, zohaib syed and ali zulqernain clinical and basic research | e243 a successful healthcare system is characterised by vision and strategy, flexibility and autonomy in decision-making, path dependency, as well as synergy and harmony with cultural preferences.1,2 evidence-based medical research contributes significantly to the well-being of a society; thus, medical research is considered mandatory for a well-functioning healthcare system.3,4 however, the establishment of a research culture is inhibited in many countries by its low prioritisation and budget constraints. for example, pakistan spends less than 3% of its gross national budget on healthcare.5 in addition to restricted resource allocation, an environment that promotes healthcare research is also lacking. there is a dearth of research output from developing countries and the quality of research has been reported as low, leading to an underrepresentation in leading inter national medical journals.6 the impact of medical research journals originating from developing countries is also low. only approxi mately 2% of journals published in developing countries are cited in the science citation index (clarivate analytics, philadelphia, usa).7 in addition, technol ogical advances have further widened the healthcare research gap between developed and developing countries.8 monitoring such trends in medical publ ication of scientific literature can help evaluate pro gress and the development of policies.9 mental health research is one of the most neglected and undervalued areas in health policy, funding and research in developing countries, where communicable diseases are prioritised.10 in developing countries, the scarcity of mental health resources, including the capacity for conducting research, adversely contributes to this crisis.11 middleand low-income countries represent 90% of the world’s population; however, these countries account for only 6% of the literature published in the world’s six leading mental health journals.12 in 2009, pakistan was 122nd in the world health organization’s ranking of healthcare systems and in the provision of healthcare services.13 this ranking is worrying for a country which ranks sixth in terms of population. the scarcity of allocated resources for mental healthcare is reflected in pakistan’s low research output. despite a considerable number of medical education institutions in the country, research training and research output do not meet the aims of healthcare policy and planning by the pakistan medical research council.14 therefore, this review aimed to assess the qual itative and quantitative aspects of mental health research originating from medical education institutions in pakistan. methods pubmed® (national library of medicine, bethesda, maryland, usa) was used to search for mental health articles published from 1947 to 2017 originating from medical colleges/universities in pakistan. multiple searches were performed where the search terms “pakistan” and “mental health” were paired with “medical college”, “medical university” or “health sciences”. mental health research terms such as “depression”, “depressive disorder”, “bipolar affective disorder”, “psychosis” and “schizophrenia” were also included in order to refine the search. only articles related to mental health where the first author was affiliated exclusively with a medical college/university (public or private) in pakistan were included. publ ications where the first author had dual or multiple affiliations were excluded as any one of the other affiliations could have been with institutions outside of pakistan. in addition to quantifying the number of articles published per year, the known parameters of research quality (e.g. the type and design of the study, impact factor of the journal, declaration of source of funding and conflict of interest) were analysed. results in total, 458 mental health articles were identified and 246 duplicates were removed from the analysis. of the 212 remaining publications, 94 were excluded as the first author was not exclusively affiliated with a medical college/university in pakistan. finally, a total of 118 articles were included in this study [figure 1]. figure 1: diagram of the methodology showing the number of publications identified, screened and included in the current study. bibliometric review of mental health research in medical colleges of pakistan e244 | squ medical journal, august 2019, volume 19, issue 3 the number of mental health articles from pakistan has risen steadily since 1993 and more than half (55.9%) of the included articles were published after 2013 [figure 2a]. the majority of articles (83.9%) were research studies of which more than half (56.6%) were studies examining the prevalence of different symptoms in different segments of the population, including medical students, hospital staff and patients admitted to hospitals with medical or surgical co morbidities not directly related to mental health including chronic illness. review articles were the second most common type of publication (12.7%) [figure 2b]. among the crucial parameters that were severely lacking in the included articles were the disclosure of financial aid and conflicts of interest. funding sources were not listed in 86.4% of studies while conflict of interest was withheld in 59.3% of studies; 9.3% of studies declared their source of funding and 36.4% stated the absence of a conflict of interest [figure 3]. another aspect that determines quality of research is the impact factor of the publishing journal, which is an indirect measure of a journal’s readership.15 the two journals that published most of the included studies were the journal of pakistan medical association (impact factor: 0.718; 27.9%) and the journal of college figure 2: a: number of publications from 1947 to 2017 about mental health from first authors affiliated with a med ical institution in pakistan. b: distribution of the types of articles published between 1947 and 2017 (n = 118). figure 4: a: five journals with the highest number of publications included in the current study (n = 59). b: frequency of publications per impact factor of the publishing journals (n = 118). jpma = journal of pakistan medical association; jcpsp = journal of college of physicians & surgeons of pakistan; jamca = journal of ayub medical college abbottabad; pjms = pakistan journal of medical sciences; ajp = asian journal of psychiatry. figure 3: distribution of the frequency of declaration of (a) any conflict of interest and (b) source of funding of articles published between 1947 and 2017 about mental health where the first author was affiliated with a medical institution in pakistan (n = 118). rai k. farooq, zohaib syed and ali zulqernain clinical and basic research | e245 of physicians and surgeons pakistan (impact factor: 0.372; 8.5%) [figure 4a]. in total, 69.5% of studies were published in journals with an impact factor, but a total of 44.1% were published in journals with impact factors less than one [figure 4b]. most studies (85.6%) were related to depression. there was only one research article published on bipolar affective disorder in 1991, yet seven review articles were published on this subject by a single author in the span of four years (2014–2017). in addition, seven articles were found using the keyword “schizophrenia” [figure 5]. none of these seven articles on schizophrenia declared funding sources and only one declared an absence of a conflict of competing interests. discussion an evaluation of the overall status of mental health research can serve as a valuable indicator of whether a country’s policy aims and goals have been met. this study highlights pakistan’s achievements and shortcomings in establishing a research culture in its medical education institutions during the previous 70 years. in addition, this study focused on affiliated medical colleges/universities and their potentially valuable contributions to the country’s medical research. the current results are in accordance with previously published reviews on this subject.16 the results of this study indicate a steady improvement in the parameters of a quality research culture. however, based on these results and given pakistan’s population of almost 200 million and a minimum of 400 psychiatrists in teaching hospitals, medical colleges or private practices, an average of four publications per year is a relatively low research output. various factors may account for the low quantity and quality of research output in medical colleges/ universities in pakistan; budget allocation for health and medical research is the most important issue in this regard. of the studies that declared a source of funding, none were funded by the public sector, which may reflect the low access of pakistani medical professionals to research funds. this may show a lack of interest by mental health practitioners, researchers and public sector funding agencies in creating an environment that supports securing grants. for this reason, medical education institutions have not been able to benefit from available research funding opportunities. no study included in the current study declared benefitting from the national research program for universities provided by the higher education commission of pakistan. this loss of financial support opportunities could be due to insufficient expertise to convince grant reviewers and/or a lack of commitment by the researchers. certain faculty induction policies by the country’s regulatory authority, the pakistan medical and dental council (pmdc) may be contributing to the lack of quality and quantity of publications. the pmdc has imposed a ban on recruiting lecturers and professors without a bachelor of medicine/bachelor of surgery to teach in medical colleges and teaching hospitals across pakistan.17 this policy deprives researchers without basic medical degrees the opportunity to work in medical colleges. developing countries, including pakistan, are plagued by corruption and unfair policies which are counterproductive to the healthcare sector.18 the lack of commitment to establishing a supportive research environment can also be seen in the absence of well-equipped molecular biology and biotechnology departments in most medical colleges and universities across pakistan.19 in addition, public sector colleges and universities lack funding mechanisms for research. the website of the oldest and most prestigious seat of medical learning in pakistan, king edward medical university, for example, has no mention of any funding mechanism to support research projects in the university at undergraduate or postgraduate level.19 the most popular post-graduate clinical training programmes are those offered by the college of phy sicians and surgeons pakistan (cpsp); this institution offers post-graduate degrees in clinical specialties and subspecialties.20 the cpsp requires its clinical fellows to acquire research skills and submit a research dissertation in order to be able to take the fellowship’s exit examination.21 although this college offers fellow ships in basic medical sciences, it still has no system for providing research funding. clinicians who are primarily focused on clinical excellence cannot dedicate themselves to research training and conducting projects, partly due to the absence of funding. without funding, figure 5: frequency of publications about different areas of mental health included in the current study (n = 118). bibliometric review of mental health research in medical colleges of pakistan e246 | squ medical journal, august 2019, volume 19, issue 3 there is a risk of compromising the quality of a research dissertation.22 in addition, there is a dearth of research capacity due to a lack of infrastructure, absence of physician-scientists, a shortage of training in research and a lack of competent supervision.23 reforming this system will require deeper understanding and commitment to necessary changes.24 the significance of physician-scientists has been acknowledged in both general and mental health research.25 building and retaining a cohort of involved individuals in this area of expertise can be achieved by broadening the focus of healthcare and initiating research programmes.26 research-oriented policies, better research funding facilities and an encouraging and enabling environment for researchers in public and private sector medical colleges/universities can help gather insight into the dynamics of policies and delivery of healthcare training to residents of one of the most populous countries of the world. however, this study did have some limitations. a major limitation is that only the pubmed® (national library of medicine) database was searched as this might have excluded possible publications that met the inclusion criteria; this search was purposefully structured to include pakistani journals not indexed in other databases. focusing exclusively on mental health research in medical colleges/universities may have resulted in some studies being omitted if they had not been carried out by specialists not affiliated with a medical college/university. future studies with broader inclusion criteria may provide more detailed results of the research achievements and impart a clearer idea of how to improve the research output in pakistan. conclusion the current findings are encouraging as the quantitative as well as qualitative measures of mental health research in pakistan have shown steady improvement over the last decade. however, certain policy changes are needed to cultivate a better research culture in pakistan. the foremost change needed is to develop a system for funding research in medical education institutions. a c k n o w l e d g e m e n t the authors would like to thank dr asma humayun for her suggestions and feedback on the manuscript draft. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. mills a. health care systems in lowand middle-income countries. n engl j med 2014; 370:552–7. https://doi.org/10.1 056/nejmra1110897. 2. green a, rana m, ross d, thunhurst c. health planning in pakistan: a case study. int j health plann manag 1997; 12:187–205. https://doi.org/10.1002/(sici)1099-1751(199707/09)12:3< 187::aid-hpm479>3.0.co;2-0. 3. institute of medicine. the value, importance, and oversight of health research. in: nass sj, levit la, gostin ol, eds. beyond the hipaa privacy rule: enhancing privacy, improving health through research. washington, dc, usa: national academies press, 2009. 4. steinwachs dm, hughes rg. health services research: scope and significance. in: hughes rg, ed. patient safety and quality: an evidence-based handbook for nurses. maryland, usa: agency for healthcare research and quality, 2008. pp. 1–15. 5. the global economy. pakistan: health spending as percent of gdp. from: www.theglobaleconomy.com/pakistan/health_sp ending_as_percent_of_gdp/ accessed: apr 2019. 6. sumathipala a, siribaddana s, patel v. under-representation of developing countries in the research literature: ethical issues arising from a survey of five leading medical journals. bmc med ethics 2004; 5:e5. https://doi.org/10.1186/1472-6939-5-5. 7. smith r. publishing research from developing countries. stat med 2002; 21:2869–77. https://doi.org/10.1002/sim.1291. 8. salager-meyer f. scientific publishing in developing countries: challenges for the future. j english acad purp 2008; 7:121–32. https://doi.org/10.1016/j.jeap.2008.03.009. 9. gaillard j. use of publication lists to study scientific prod uction and strategies of scientists in developing countries. scientometrics 1992; 23:57–73. https://doi.org/10.1007/bf020 20914. 10. pittet d, allegranzi b, storr j, bagheri nejad s, dziekan g, leotsakos a, et al. infection control as a major world health organization priority for developing countries. j hosp infect 2008; 68:285–92. https://doi.org/10.1016/j.jhin.2007.12.013. 11. saraceno b, saxena s. mental health resources in the world: results from project atlas of the who. world psychiatry 2002;1:40–4. 12. patel v, sumathipala a. international representation in psy chiatric literature: survey of six leading journals. br j psychiatry 2001; 178:406–9. https://doi.org/10.1192/bjp.178.5.406. 13. the patient factor. world health organization’s ranking of the world’s health systems. from: www.thepatientfactor.com/cana dian-health-care-information/world-health-organizationsranking-of-the-worlds-health-systems/ accessed: apr 2019. 14. ghaffar a, zaidi s, qureshi h, hafeez a. medical education and research in pakistan. lancet 2013; 381:2234–6. https://doi. org/10.1016/s0140-6736(13)60146-4. 15. garfield e. the meaning of the impact factor. int j clin heal psychol 2003; 3:363–9. 16. naqvi ha, khan mm. mapping exercise of mental health research and researchers in pakistan. j pak med assoc 2007; 57:294–8. 17. pakistan medical & dental council. regulations for the appoint ment/promotions of faculty professional staff/examiners/prin cipals/administrative staff in undergraduate & postgraduate medical & dental institutions of pakistan 2017. from: http://pmdc.org.pk/linkclick .aspx?fileticket=tengamqg fbc%3d&tabid=404&mid=1064 accessed: apr 2019. https://doi.org/10.1056/nejmra1110897 https://doi.org/10.1056/nejmra1110897 https://doi.org/10.1002/%28sici%291099-1751%28199707/09%2912:3%3c187::aid-hpm479%3e3.0.co%3b2-0 https://doi.org/10.1002/%28sici%291099-1751%28199707/09%2912:3%3c187::aid-hpm479%3e3.0.co%3b2-0 https://doi.org/10.1186/1472-6939-5-5 https://doi.org/10.1002/sim.1291 https://doi.org/10.1016/j.jeap.2008.03.009 https://doi.org/10.1007/bf02020914 https://doi.org/10.1007/bf02020914 https://doi.org/10.1016/j.jhin.2007.12.013 https://doi.org/10.1192/bjp.178.5.406 https://doi.org/10.1016/s0140-6736%2813%2960146-4 https://doi.org/10.1016/s0140-6736%2813%2960146-4 rai k. farooq, zohaib syed and ali zulqernain clinical and basic research | e247 18. junaidi i. corruption allegations rock pmdc again. from: www.dawn.com/news/1325852 accessed: apr 2019. 19. king edward medical university. home page. from: http:// kemu.edu.pk/ accessed: apr 2019. 20. college of physicians & surgeons pakistan. home. from: www. cpsp.edu.pk/ accessed: apr 2019. 21. college of physicians & surgeons pakistan. training programs. from: www.cpsp.edu.pk/fcps.php accessed: apr 2019. 22. iqbal mp. what ails medical research in pakistan? role of institutions. pak j med sci 2015; 31:1287–9. https://doi.org/10.1 2669/pjms.316.9337. 23. qureshi ma, qureshi ms, khanani mr. health and research in pakistan. lancet 2013; 382:1245. https://doi.org/10.1016/ s0140-6736(13)62091-7. 24. nishtar s, bhutta za, jafar th, ghaffar a, akhtar t, bengali k, et al. health reform in pakistan: a call to action. lancet 2013; 381:2291–7. https://doi.org/10.1016/s0140-6736(13)60813-2. 25. burke jd jr, pincus ha, pardes h. the clinician-researcher in psychiatry. am j psychiatry 1986; 143:968–75. https://doi. org/10.1176/ajp.143.8.968. 26. kupfer dj, hyman se, schatzberg af, pincus h, reynolds cf 3rd. recruiting and retaining future generations of physician scientists in mental health. arch gen psychiatry 2002; 59:657–60. https://doi.org/10.1001/archpsyc.59.7.657. https://doi.org/10.12669/pjms.316.9337 https://doi.org/10.12669/pjms.316.9337 https://doi.org/10.1016/s0140-6736%2813%2962091-7 https://doi.org/10.1016/s0140-6736%2813%2962091-7 https://doi.org/10.1016/s0140-6736%2813%2960813-2 https://doi.org/10.1176/ajp.143.8.968 https://doi.org/10.1176/ajp.143.8.968 https://doi.org/10.1001/archpsyc.59.7.657 december 2008 no white pages.indd impact of geographical proximity on health care seeking behaviour in northern oman *ahmed al-mandhari,1 samir al-adawi,2 ibrahim al-zakwani,3 mohammed al-shafaee,1 liyam eloul4 1departments of family medicine & public health and 2behavioural sciences, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; 2department of pharmacy, sultan qaboos university hospital, muscat, sultanate of oman; 4stanford university, usa *to whom correspondence should be addressed. email: manar96@yahoo.com sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 310-318 sultan qaboos university© submitted 29th april 2008 accepted 21st july 2008 c l i n i c a l a n d b a s i c r e s e a r c h في الصحية للرعاية كسبب لسلوك اللجوء اجلغرافي القرب تأثير شمال عمان ليام الول محمد الشافعي، الزكواني، ابراهيم سمير العدوي، املنظري، أحمد القليل من القت ــة الصحي للرعاية ــي واللجوء اجلغراف بني القرب العالقة ــان ف ــة الصحية السياس على تأثيرها من على الرغم ــص: الهــدف: امللخ يلجأون الذين بني املرضى الصحية استخدام الرعاية وسلوك اجلغرافي القرب بني العالقة هذه الورقة إلى تقييم تهدف الطبية. األدبيات في االهتمام 428 ل ــخصية املقابلة الش طريق عن 2006-2007 وذلك ــنتي س خالل املعلومات جمع مت عمان. الطريقة: ــمال ش مناطق في الطبية ــارة لالستش القرب اجلغرافي بني العالقة حتليل مت عمان. شمال مبناطق اتلفة األولية الصحية الرعاية ملراكز املراجعني بني املرضى من عشوائيا اختيارهم مت مريضا القرب تفضيل أن ــات البيان أظهرت ــر. النتائج: املتغي متعددة حتوف االمداديات ــتخدام باس وذلك األخرى واملؤثرات ــة الصحي للرعاية ــوء للج ــبب كس جلسات التثقيف وحضور الشعبي للطب السابق ــتخدام واالس الزوجية باحلالة وثيقا ارتباطا مرتبط الصحية للرعاية اللجوء ــباب أس كأحد اجلغرافي الصحية للرعاية للجوء قويا سببا اجلغرافي القرب يظل حيث الدراسات السابقة تدعم البحث اخلالصة: نتائج في املاضي. التطعيم الصحي وإجراء الورقة. محتوى السلوك في ذلك على واالجتماعية النفسية العوامل تأثير مناقشة مت عمان. في عمان. سريرية ، دراسة عربي/إسالمي ، ، الصحية الرعاية استخدام ، الكلمات: القرب اجلغرافي مفتاح abstract objectives: despite its impact on health policy, the relationship between geographical proximity and health care seeking has received scant attention in the medical literature. this paper aims to evaluate the relationship between geographic proximity and health care usage behaviour among patients seeking medical consultation in the northern region of oman. methods: during 20062007, data was collected via face-to-face interviews among 428 randomized patients seeking medical consultation in various primary health care centres in the northern region of oman. the association between geographical proximity as a reason to seek health care and other predictors was also analysed using multivariable logistic regression. results: the data suggest that preference for geographical proximity as a reason for seeking health care is strongly associated with marital status, previous exposure to traditional medicine and health education, as well as history of immunisation. conclusion: this finding supports the view from elsewhere that geographical proximity remains a strong catalyst for care seeking in oman. the psychosocial factors affecting care seeking are discussed. keywords: geographic proximity; health care utilization; arab/islamic; clinical-based study; oman. advances in knowledge • the study shows that geographical proximity remains a strong catalyst for health care seeking in oman. • socio-cultural teaching appears to play a major part in what may appear to be a paradoxical and idiosyncratic relationship between geographical proximity and health care seeking behaviour. • the study stimulates the need to conduct further studies that look more closely at the issues of health care seeking behaviour, particularly in remote areas and with regard to the use of traditional medicine centres. i m pa c t o f fa c t o r s o n g e o g r a p h i c a l p r o x i m i t y a s a r e a s o n o f h e a lt h c a r e s e e k i n g b e h av i o u r i n n o r t h e r n o m a n 311 since the world health organization launched ‘health for all by year 2000’, 1 many health planners in developing countries have expanded and diversified health care services in order to achieve viable health equity. however, one source of attrition around this endeavour is the lack of understanding surrounding care seeking behaviour among health care consumers. an understanding of care seeking behaviour can act as a basis on which to lay the groundwork for developing strategies to improve awareness and to identify barriers to timely interventions and treatments. attention to care seeking behaviour would likely impact health care utilisation and, albeit indirectly, reduce the high maternal and infant mortality rates, as well as heightening the health indicators of a country. various studies have converged on the view that the use of health care services is related to factors such as service accessibility and quality of service, beliefs underpinning avoidance of distress and individual differences.2, 3, 4, 5 although most of these studies have been derived from a variety of populations, to our knowledge, few studies examine the factors leading to health care seeking behaviour in arab populations,6, 7 and their generalisation is often limited to specific clinical populations.8, 9 this paper attempts to examine the factors associated with the utilisation of health care among general health care consumers in oman, an arab/islamic country situated in the south-eastern corner of the arabian peninsula. once observers labelled oman the “tibet of arabia” or characterized it as a “beleaguered hermit kingdom”10 due to its isolation and mediaevallike society; however, oman has experienced rapid modernisation in the past few decades. the british medical journal has stated that, “money from oil has brought omanis progress through development in less than 20 years, development that took a thousand years in europe”.11 two of the major benefits of the recent modernisation in oman are the major improvement in the standard of living, and the establishment of a modern health care delivery system. hospital bed space grew from 12 beds in a single hospital in 1970 to 4,549 beds and more than 150 health centres in 2006. 11 with the improvements in health care, the country has experienced a significant decline in maternal and child mortality. studies from other countries around the world are beginning to show that the use of health care services is related to geographical proximity to health care centres.12, 13, 14, 15, 16 emerging views suggest that many clinical conditions and their outcomes often depend, among other things, on the geographical proximity of care facilities.17, 18 for example, in some emerging economies in many parts of the world, health care accessibility is limited to urban areas,19 20 and therefore health inequity has been heightened simply due to an asymmetry in the availability of health care services reflecting an urban-rural disparity.21, 22 in some studies, it has been reported that morbidity and mortality in a clinical population are invariably related to the geographical proximity of the health care centres.23 although the ability to access health care is influenced by myriad factors, the relationship between care seeking and distance travelled has not been widely reported in developing countries.24, 25 this is problematic when one bears in mind that in many developing countries there exists a drastic disparity in the availability of health care services between different geographical regions of the country. with the spread of universal free health care in oman, the question remains: ‘how does geographic proximity contribute to care seeking and, by implication, health equity in the country?’ the recent rise in affluence in oman has blurred the once-clear gap between rural and urban environments, as social services and infrastructure developments have spread equally to all regions of the country. 12 the united nations children’s fund 26 has estimated that for the past several years 96 percent of the population of oman has had access to health care services. the population density of oman has been estimated at 8.3/km². the bulk of the population is located in the towns and villages adjacent to the capital, muscat, and towns along the northern batinah coast. the rest of the population is distributed throughout the southern and interior regions of the country. in a recent health application to patient care • some populations are sparsely distributed in many parts of a country, therefore health planners have been obliged to build health care services that can be accessed by all. this is particularly applicable to preventive services such as vaccination. a h m e d a l m a n d h a r i , s a m i r a l a d aw i , i b r a h i m a l z a k wa n i , m o h a m m e d a l -s h a fa e e a n d l i ya m e l o u l 312 system ranking, the who ranked oman as the most “efficient” health care system in the world in terms of outcome.27 therefore, given the quality of the health care services, and the geographical characteristics of the country, oman, is an interesting ground to explore the influence of geographical proximity to health care centres on health care seeking behaviour. it is hypothesised that health care seeking behaviour is invariably characteristic short distance as a reason to seek healthcare p-value no (n=46) yes (n=382) age, mean ± sd, years 29±12 33±12 0.034 gender, n (%) 0.399 female 31 (67%) 233 (61%) male 15 (33%) 149 (39%) marital status, n (%) 0.001* single, divorced, widowed 26 (57%) 121 (32%) married 20 (43%) 261 (68%) literacy, n (%) 0.539 illiterate (cannot read or write) 6 (13%) 70 (18%) literate (can read or write) 40 (87%) 312 (82%) attended a health education program 0.035* no 37 (80%) 248 (65%) yes 9 (20%) 134 (35%) history of chronic illness, n (%) 0.518 no 33 (72%) 256 (67%) yes 13 (28%) 126 (33%) takes regular medication, n (%) 0.533 no 30 (65%) 231 (60%) yes 16 (35%) 151 (40%) number of visits attended per month 0.253 mean±sd 1.67±2.53 1.27±2.30 median (absolute range) 1 (0 to 15) 1 (0 to 30) reason to seek healthcare, n (%) 0.065 treatment of acute condition 25 (54%) 142 (37%) follow-up visit 12 (26%) 118 (31%) vaccination or other 9 (20%) 122 (32%) source of healthcare, n (%) 0.080 government 34 (74%) 272 (71%) private 7 (15%) 29 (8%) traditional 5 (11%) 81 (21%) sd = standard deviation. percentages are column percents. p-values were generated using student’s and wilcoxon mann-whitney tests, pearson’s χ2 test, and fisher’s exact test whenever appropriate. table 1: demographic, clinical and health resource characteristics of the study cohort stratified by geographical proximity to a health centre as a reason to seek healthcare (n = 428). i m pa c t o f fa c t o r s o n g e o g r a p h i c a l p r o x i m i t y a s a r e a s o n o f h e a lt h c a r e s e e k i n g b e h av i o u r i n n o r t h e r n o m a n 313 influenced by the geographical proximity of care centres to target populations. m e t h o d s st udy a r e a a n d p o p ul ati o n according to the world bank, oman is categorised as an upper-middle-income economy.28 the majority of oman’s population is located either in the north or in the far south of the sultanate; these two regions are separated by a stretch of desert known as the empty quarter. for logistical reasons, the present study was limited to the northern regions of oman, which include a number of larger coastal towns, including the capital, muscat, as well as a number of towns in the more mountainous interior. this population segment was found to reflect the ethno-cultural variety present in omani society.29 data c o l l e c ti o n oman offers universal free health care to its approximately 2.5 million citizens. the present study was conducted in 2006-2007 in a number of public hospitals located in the region of interest. data was collected using face-to-face interviews. for consistency, and to accommodate illiterate patients, questionnaires were read out loud to the subjects rather than being self-administered. the interviews were conducted by trained researchers, predominantly second and third year medical students from the college of medicine and health sciences, sultan qaboos university. during our preparation for this study, the interviewers were trained to read out the items of the questionnaire and to code the responses with precision and reliability; we observed substantial inter-coding agreement for the scale items (r = 0.86, p < 0.001). the study population consisted of omani patients visiting the sampled health centres. inclusion criteria required participants to be at least 18 years old and cognitively intact. the participant sample was randomised in the following way: one out of every five patients entering the reception area of each health centre for a routine outpatient visit was invited to volunteer for an interview. the participants were explicitly informed that any information they provided in the course of the interview would remain completely anonymous and that their participation would not in any way affect their treatment. no invited patient declined to be interviewed. the interview process was carried out in the health centres over a two week period. at each health centre a minimum of 50 patients per research assistant were interviewed during the span of this study. data from the ministry of health have shown that, on average, the present targeted health care centres cater to the needs of approximately 90% of the population of this particular region of oman.30 in total, 428 subjects participated in this study. a s se s sme n t me a sur e s the questionnaire was developed to fit the situation on the ground, using a number of items that have been used in previous studies, modified for the present context.31, 32 as detailed in table 1, the information elicited from the participants included demographic data such as age, sex, marital status, and level of education. in addition, other information germane to the framework of care seeking, such as history of chronic illnesses, usual source of health care, frequency of health care facility usage, and attendance at health education sessions was also sought. the concept of geographical proximity, although variously defined elsewhere, in the present context is defined as a measure of nearness to the health care setting. this item was elicited by asking the participants whether they perceived the nearest health centre as close to them or as far away. the answers were quantified in terms of (1) ‘yes’ or (0) ‘no’. the final questionnaire was pre-tested and piloted on convenience samples among students and staff at the college of medicine and health sciences. stati sti c a l a n a ly si s descriptive statistics were used to illustrate the data. for categorical variables, frequencies and percentages were reported. differences between groups were analysed using pearson’s χ2 tests or fisher’s exact tests (for cells of less than 5). for continuous variables, means and standard deviations (±sd) or medians and absolute ranges were presented as appropriate. mean differences between groups were analysed using the student’s t-test and the wilcoxon mann-whitney test whenever appropriate. the association between participants’ geographical proximity to a health centre as a reason to seek health care and various other predictors were analysed using multivariable logistic regression. the predictors in the model included age, gender, marital status, literacy, history of chronic illness, use of regular chronic medications, type of health care resource facility attended, a h m e d a l m a n d h a r i , s a m i r a l a d aw i , i b r a h i m a l z a k wa n i , m o h a m m e d a l -s h a fa e e a n d l i ya m e l o u l 314 reason for attending the health care resource facility, number of visits to a health care facility, and attending a health education program. all of the variables in the logistic model were entered simultaneously. the multivariate logistic model was extensively examined by evaluating the model’s assumptions and overall model fit. the overall model fit was assessed using the hosmer & lemeshow goodness-of-fit statistic.33 this approach analyses the actual responses versus the predicted responses; theoretically, the observed and expected counts should be close or equal. based on the χ2 distribution, a hosmer & lemeshow statistic with a p-value greater than 0.05 is considered a good fit. another measure of good fit is the area under the receiver operating curve (roc). 34 the roc is a graph of sensitivity versus one-minus-specificity, as the threshold cut-off is varied, and also calculates the area under the curve. sensitivity is the fraction of true positives, while specificity is the fraction of the true negatives. the roc provides a measure of the model’s discriminatory power. a model with perfect prediction has an roc of 1.0, while an area of 0.5 provides no better discrimination than chance. an a priori two-tailed level of significance was set at the 0.05 level. statistical analyses were performed using stata (data analysis and statistical software) version 9.2. r e s u l t s the study enrolled a total of 428 participants. the demographic, clinical and health care resource characteristics of the cohort are shown in table 1. the overall mean age of the cohort was 33 ± 12 years with an age range from 18 to 74 years. sixty two percent (n = 264) of the participants were females. the majority of the participants were married (n = 281, 66%), literate (n = 352, 82%), did not have a history of chronic illness (n = 289, 68%) and were not taking regular medications (n = 261, 61%). most of them listed the government as their main source of health care (n = 306, 72%). however, 20% (n = 86) of the participants listed their main source of health care delivery as being from a traditional system. the reasons to seek health care included visits for treatment of acute ailments (n = 167, 39%), follow-up visits (n = 130, 30%), and visits for vaccination (n = 131, 31%). only just over a third of the participants had attended health education programmes (n = 143, 33%). the final model was significant [wald χ2 (12) = 32.21; log likelihood = -129.9298; p = 0.001] and all the variables accounted for 11 percent of the variance in the model (pseudo r2 = 0.11). furthermore, the goodness-of-fit statistics indicated an overall good model fit (hosmer & lemeshow χ2 (8) = 13.78, p = 0.087; area under the roc curve = 0.75). married participants were 2.56 times more likely to endorse close proximity to a health care centre as a reason to seek health care than the unmarried participants (95% ci 1.24 to 5.29, p = 0.011). the participants using traditional health care compared with those using government health care sources were 2.95 times more likely to use close proximity to a health care centre as a reason to seek health care (95% ci 1.03 to 8.44, p = 0.043). furthermore, those attending the health care centre for vaccination compared to those attending the centre for the treatment of acute conditions were 3.53 times more likely to use close proximity to a health care centre as a reason to seek health care (95% ci 1.47 to 8.48, p < 0.001). additionally, the participants that had attended health education programs were 2.28 times more likely to endorse close proximity to a health care centre as a reason to seek health care resources than those who had not attended health education programs (95% ci 1.03 to 5.04, p = 0.042). d i s c u s s i o n some interesting findings have emerged from the present data. first of all, close inspection of the descriptive analysis suggests that geographical proximity was preferred among omanis of a slightly greater age (33±12 versus 29±12, years), who were married, or who had sought health education. furthermore, geographical proximity was perceived to play a significant role among omanis who had sought health care for medically acute complications, those attending follow-up visits or those who were seeking vaccination. in logistic regression, four factors appeared to have the greatest impact on the trajectory between geographical proximity and care seeking. first of all, being married was a significant predictor for endorsing geographical proximity as essential for health care seeking. a possible explanation for this is that being married would entail parenthood and, for most people in oman, embracing a more connected lifestyle within the extended family. in traditional omani society, individuals who have reached puberty are expected to marry, at least in rural communities. newly married couple often reside in the paternal family’s residence, which requires them to fulfil the typical role of a memi m pa c t o f fa c t o r s o n g e o g r a p h i c a l p r o x i m i t y a s a r e a s o n o f h e a lt h c a r e s e e k i n g b e h av i o u r i n n o r t h e r n o m a n 315 ber of the extended family. marriage itself is considered a sacred and unbreachable institution that entails procreation. current population patterns in oman fit with a second phase ‘demographic transition’ which entails a declining death rate complemented by a high birth rate, with the bulk of the population falling in the infant to adolescent age group.35 while infant mortality was 242 per 1,000 live births in 1970, it has since fallen to 13 per 1,000 live births in 2004.36 the fertility rate, which indexes the average number of children per couple, was 7.2 in the 1970’s, to 6.6 in 1990s and more recently has become 3.4.37 having a greater number of children in the household is likely to increase the frequency with which an individual would need to attend a health care centre, thus making it vital to have health care at one’s reach. it is likely that being married will correlate highly with parenthood, and that child care is one cause for an individual to prefer geographical proximity to health care centres. health education is the second variable that played a major role in determining preference for close proximity to health care services. the data suggest that subjects who have attended health education programs were more likely to suggest close proximity to a health care centre as a reason to seek health care resources than those who did not attend health education programmes. there are two potential explanations for this finding. one is the possibility that those who seek health education are the type of people who are generally overly concerned about their health. the literature abounds with reports describing how some individuals insist that they are ‘diseased’ despite repeated assurance to the contrary. such patients tend to seek care in primary as well as tertiary medical settings, and account for a large number of consultations, ‘doctor shopping’, unnecessary tests, multiple surgeries, and a variety of other procedures which result in what is known in some hospitals as the ‘fat file syndrome’.38 it is possible that those who are overly concerned about their health have a tendency to attend health education courses, and therefore are more likely also to prefer geographical proximity to health care. individuals with such a disposition would therefore prefer a short distance to their health care centre because it represents quick accessibility to health care and, subjectively, provides reassurance in the event of ill health. another possibility is that those who have attended health education courses may have been exposed to one’s propensity for disease and ill-health. awareness about potential risk factors for illness may instil a preference for geographical proximity to health care centres. while immunisation campaigns have been met with some resistance in certain parts of the world, with universal free health care oman has succeeded spectacularly in overcoming rampant infectious diseases.39, 40 disease eradication and immunisation programs are quickly reaching all corners of the country. therefore, it was not seemingly surprising that vaccination plays an important role in care seeking in the present data. it can be speculated that the improvement in quality of life in oman, among other things, assisted by a universal immunisation programme, has heightened omanis’ faith in modern health care to the extent that proximity to a health care centre is considered an essential pathway for disease eradication and prevention. the final variable that made a significant contribution to the significance of geographical proximity was the tendency to seek traditional medicine. it has been reported that the traditional health care system meets 60-80 percent of health care needs in many parts of the world.41 traditional medicine, sometime referred to as ethno-medicine, is a vague term used loosely to distinguish ancient culture-bound health care practices that existed before the application of modern scientific medicine. despite the poor efficacy of ethno-medicine from a scientific perspective,42 there is evidence that its popularity knows no bounds in many parts of the world.43 the reason for such an esteemed status involves the fact that its explanatory models are deeply grounded in the local folklore concepts of health and illness. contrary to modern health care, traditional medicine does not relegate human beings to mechanistic organisms.44 there is also the suggestion that some of the healing rituals common in traditional medicine may serve as psychotherapeutic support.45 within this relevant discourse, reports have emerged to suggest that there are a substantial number of health care seekers who transverse both traditional and modern health care systems, often in tandem.46 given this complex situation, it is not therefore surprising that those subjects who have utilised traditional medicine may also prefer to have close proximity to modern health care centres. it would be theoretically interesting in the future to index psychosocial correlates of care seeking behaviour among those people who have a tendency to seek help from both traditional and modern health a h m e d a l m a n d h a r i , s a m i r a l a d aw i , i b r a h i m a l z a k wa n i , m o h a m m e d a l -s h a fa e e a n d l i ya m e l o u l 316 care settings. there are issues that warrant caution in interpreting the results of this study. first of all, the generalisation of this study may be limited by the fact that the data was collected only in one specific region of oman, and was restricted to those seeking health care services. there is evidence to suggest that people in a clinical setting tend to respond differently to questioning than those approached in a community setting.47 notwithstanding this view, the study focused on factors affecting health care seeking behaviour and therefore it was practical to explore a clinical population. an important omission in the present study is that the actual distance between the patient’s domicile and the health care centre was not examined. previous studies have suggested an inverse relationship between travel distance and health care utilisation,48 and the fact that sampling was conducted in health care centres may have skewed our results. secondly, data was collected using an interview method rather than a self-administered format. this may have confounded patient responses because of lack of anonymity. since the literacy rate in oman is 74.4 percent, it was decided to read the items to all subjects, rather than allowing them to selfadminister the survey. it is possible that this approach may have resulted in a reluctance to reveal sensitive information. there is an indication that the lay public in oman regard their doctor with high esteem, and as someone one could confide in.49 however, there is no indication that the items on the questionnaire were overly sensitive. thirdly, the items on the questionnaire had not been subjected to protracted validation methods, and therefore the efficacy of the questions may be uncertain, both psychometrically and conceptually. this is especially the case given that this study was conducted in a cultural setting where research is not usual, and among patients who are not often studied. further research of a similar nature but with more rigorous methodology is therefore recommended. c o n c l u s i o n with the much-heralded ‘health for all by year 2000’,1 a genuine effort to heighten health care delivery that transcends geographic location has been attempted in many parts of the world. because some populations are sparsely distributed, health planners have been obliged to build health care services that can be accessed by all. however, that is a dearth of studies that have examined the relationship between the geographical proximity of health care centres to the target population and health care utilisation. from the present study conducted in oman, the data suggest that there are four factors that play a part in the relationship between geographical proximity and health care seeking: demographic variables such as marital status, history of health education and vaccination, as well as previous exposure to traditional medicine. socio-cultural teaching appears to play a major part in what may appear to be a paradoxical and idiosyncratic relationship between geographical proximity and health care seeking. the study stimulates the need to conduct further studies that look more closely at the issues of health care seeking behaviour, particularly in remote areas and with regard to the use of traditional medicine centres. r e f e r e n c e s 1. who/unicef. alma-ata 1978, primary health care. geneva: who, 1978. 2. ben-shlomo y, naqvi h, baker i. ethnic differences in health care seeking behavior and management for acute chest pain: secondary analysis of the minap dataset 2002-2003. heart 2007; 94:354-359. 3. haynes r. geographical access to health care. in: gulliford mc, morgan m, eds. access to health care. london: routledge, 2003. p. 13–35. 4. weiner sj, vangeest jb, abrams ri, moswin a, warnecke r. avoiding free care at all costs: a survey of uninsured patients choosing not to seek emergency services at an urban county hospital. j urban health 2006; 83:244-252. 5. onwujekwe o. inequities in healthcare seeking in the treatment of communicable endemic diseases in southeast nigeria. soc sci med 2005; 61:455-463. 6. al-krenawi a, graham jr, dean yz, eltaiba n. crossnational study of attitudes towards seeking professional help: jordan, united arab emirates (uae) and arabs in israel. int j soc psychiatry 2004; 50:102-114. 7. eapen v, ghubash r. help-seeking for mental health problems of children: preferences and attitudes in the united arab emirates. psychol rep 2004; 94:663-667. 8. rizk de, hassan my, shaheen h, cherian jv, micallef r, dunn e. the prevalence and determinants of health care-seeking behavior for fecal incontinence in multiparous united arab emirates females. dis colon rectum 2001; 44:1850-1856. 9. rizk dee, shaheen h, thomas l, dunn e, hassan my. the prevalence and determinants of health care-seeking behavior for urinary incontinence in united arab emirates women. int urogynecol j pelvic floor dysfunct 1999; 10:160-165. i m pa c t o f fa c t o r s o n g e o g r a p h i c a l p r o x i m i t y a s a r e a s o n o f h e a lt h c a r e s e e k i n g b e h av i o u r i n n o r t h e r n o m a n 317 10. peterson je. oman’s diverse society: southern oman. middle east j 2004; 58:254. 11. ministry of health annual health report 2007. department of information and statistics, directorate general of planning. muscat: ministry of health, 2007. 12. israelski d, gore-felton c, power r, wood mj, koopman c. sociodemographic characteristics associated with medical appointment adherence among hiv-seropositive patients seeking treatment in a county outpatient facility. prev med 2001: 33:470-475. 13. meechan g, collins j, petrie kj. the relationship of symptoms and psychological factors to delay in seeking medical care for breast symptoms. prev med 2003; 36: 374-378. 14. sudha g, nirupa c, rajasakthivel m, sivasusbramanian s, sundaram v, bhatt s, et al. factors influencing the care seeking behaviour of chest symptomatics: a community-based study involving rural and urban population in tamil nadu, south india. trop med int health 2003; 8:336-341. 15. ross sm, turner c. physical proximity as a possible facilitator in post-detoxification treatment-seeking among chemically dependent veterans. addict behav 1994; 19:343-348. 16. adams j, white m. socio-economic deprivation is associated with increased proximity to general practices in england: an ecological analysis. j public health 2005; 27:80–81. 17. billi je, pai cw, spahlinger da. the effect of distance to primary care physician on health care utilization and disease burden. health care manage rev 2007; 32:2229. 18. arcury ta: the effects of geography and spatial behavior on health care utilization among the residents of a rural region. health serv res 2005; 40:135-155. 19. kloos h, assefa y, adugna a, mulatu ms, mariam dh. utilization of antiretroviral treatment in ethiopia between february and december 2006: spatial, temporal, and demographic patterns. int j health geogr 2007; 645. 20. onah he, ikeako lc, iloabachie gc. factors associated with the use of maternity services in enugu, southeastern nigeria. soc sci med 2006; 63:1870-1878. 21. gregory pm. impact of geographic proximity to cardiac revascularization services on service utilization. medical care 2000; 38:45 22. engelman kk. impact of geographic barriers on the utilization of mammograms by older rural women. j am geriatr soc 2002; 50:62-68. 23. tonelli m, manns b, culleton b, klarenbach s, hemmelgarn b, wiebe n, et al.: alberta kidney disease network. association between proximity to the attending nephrologist and mortality among patients receiving hemodialysis. cmaj 2007; 177:1039-1044. 24. uzochukwu bs, onwujekwe oe: socio-economic differences and health seeking behavior for the diagnosis and treatment of malaria: a case study of four local government areas operating the bamako initiative programme in south-east nigeria. int j equity health 2004; 3:6. 25. amoran o, lawoyin t, lasebikan v: prevalence of depression among adults in oyo state, nigeria: a comparative study of rural and urban communities. aust j rural health 2007; 15:211-215. 26. unicef: the state of the world’s children 1997. oxford: oxford university press, 1997. 27. jamison dt, sandbu me. global health. who ranking of health system performance. science 2001; 293:15951596. 28. the world bank. world development report 2007: development and the next generation. washington, dc: the world bank, 2006. 29. ministry of health: national health survey 2000. musact: ministry of health, 2000. 30. national health survey 2000: study of lifestyle risk factors. directorate of research and studies and directorate of general health planning (vol.1). muscat: ministry of health, 2000. 31. jenkinson c, coulter a, bruster s. the picker patient experience questionnaire: development and validation using data from in-patient surveys in five countries. int j qual health care 2002; 14:353-358. 32. cheng jw, kalis mm, feifer s. patient-reported adherence to guidelines of the sixth joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. pharmacotherapy 2001; 21:828-841. 33. hosmer dw jr, lemeshow s. applied logistic regression. 2nd ed. john wiley & sons: new york, 2001. 34. hardin j, hilbe j. generalized linear models and extensions; college station, tx: stata press, 2001. 35. mohammed nsa. population and development of the arab gulf states: the case of bahrain, oman and kuwait. basingstoke: ashgate pub ltd, 2004. 36. sulaiman aj, al-riyami a, farid s, ebrahim gj. oman family health survey 1995. j trop pediatr 2001; 47:s133. 37. unicef. oman. from http://www.unicef.org/infobycountry/oman_statistics.html. accessed april 2008. 38. al lawati j, al lawati n, al siddiqui m, antony sx, al naamani a, martin rg, et al. psychological morbidity in primary health care in oman: a preliminary study. squ j sci res: med sci 2000; 2:105-110. 39. al-dhahry sh, koul rl, al-busaidy sm, al-awaidy st, a h m e d a l m a n d h a r i , s a m i r a l a d aw i , i b r a h i m a l z a k wa n i , m o h a m m e d a l -s h a fa e e a n d l i ya m e l o u l 318 al-khusaiby sm, suleman aj. poliomyelitis in oman. i. the last outbreak? acta trop 2001; 80:125-130. 40. khandekar r, mohammed aj, al raisi a, kurup p, shah s, dirir mh, et al. prevalence and distribution of active trachoma in children of less than five years of age in trachoma endemic regions of oman in 2005. ophthalmic epidemiol 2006; 13:167-172. 41. al-adawi s. a glimpse into traditional outlook towards health: a literature review. j med humanit 1993; 14:6779. 42. nicholson t. complementary and alternative medicines (including traditional maori treatments) used by presenters to an emergency department in new zealand: a survey of prevalence and toxicity. n z med j 2006; 119: u1954. 43. han gs, ballis h. ethnomedicine and dominant medicine in multicultural australia: a critical realist reflection on the case of korean-australian immigrants in sydney. j ethnobiol ethnomed 2007; doi: 10.1186/17464269-3-1. 44. chan cl, ho rt, fu w, chow ay. turning curses into blessings: an eastern approach to psychosocial oncology. j psychosoc oncol 2006; 24:15-32. 45. ricotti v, delanty n. use of complementary and alternative medicine in epilepsy. curr neurol neurosci rep 2006; 6:347-353. 46. de-graft aikins a. healer shopping in africa: new evidence from rural-urban qualitative study of ghanaian diabetes experiences. bmj 2005; 331:737. 47. bursi f, weston sa, redfield mm, jacobsen sj, pakhomov s, nkomo vt, et al. systolic and diastolic heart failure in the community. jama 2006; 296:2209-2216. 48. lavela sl, smith b, weaver fm, miskevics sa. geographical proximity and health care utilization in veterans with sci&d in the usa. soc sci med 2004; 59:2387-2399. 49. al-jabri aa, dorvlo ass, al-rahbi s, al-abri j, aladawi s. knowledge of tuberculosis among medical professionals and university students in oman. east mediterr health j 2006; 12:509-521. submitted 24 dec 22 1 revision req. 26 jan 23; revision recd. 26 feb 23 2 accepted 28 mar 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.035 5 6 trichodysplasia spinulosa 7 *ayida al khalili,1 elsa maciagowski,2 khue nguyen,2 kevin a. 8 watters3 9 10 1dermatology unit, department of family medicine and public health, sultan qaboos 11 university hospital, sultan qaboos university, muscat, oman; departments of 12 2dermatology and 3pathology, mcgill university health center, montreal, canada 13 *corresponding author’s e-mail: a.alkhalili@hotmail.com 14 15 abstract: 16 trichodysplasia spinulosa (ts) is a unique, rare clinical and histological dermatologic 17 entity described mainly in setting of immunosuppression. it is caused by a novel human 18 polymoavirus, trichodysplasia spinulosa-associated polyomavirus (tspyv). we report a 19 biopsy-proven case of ts in a renal transplant patient presented to dermatology 20 outpatient clinic in montreal, canada in 2015. reduction of immunosuppression and/or 21 anti-viral therapy is the main therapeutic strategies used to treat such cases. our patient 22 was managed with valgancyclovir with no obvious response. subsequently, a trial of 23 topical imiquimod was commenced. awareness of ts can prompt early diagnosis and 24 management to prevent possible complications. 25 keywords: trichodysplasia spinulosa, immunosuppression, organ-trasplant, human 26 polyomavirus. 27 28 mailto:a.alkhalili@hotmail.com introduction 29 trichodysplasia spinulosa (ts) is a rare cutaneous manifestation due to viral infection 30 affecting mainly immunosuppressed hosts. the majority of the patients are solid organ 31 recipients or patients diagnosed with hematological malignancies.1 32 33 given its rarity, in most cases there is a potential delay in diagnosis. moreover, the 34 pathogenesis of ts is not completely understood. few therapeutic options are suggested 35 by published case reports and no standard therapies are approved yet.2 36 37 we present a case of ts in a renal transplant recipient and review the main characteristic 38 features of this entity. 39 40 case report 41 a male in his 60s presented to the dermatology outpatient clinic in montreal, canada in 42 2015 for evaluation of facial papules. these were of two-month duration and 43 progressively increasing in number, affecting the whole face but more concentrated on 44 the nose. there was mild facial pruritus. the patient was a kidney transplant recipient 45 since july 2014 for hypertensive nephropathy. he was on therapy with mycophenolic 46 acid (myfortic) and tacrolimus (advagraf). medical history was positive for, 47 osteoarthritis, gout and iga gammopathy (monoclonal gammopathy of undetermined 48 significance). his other medications include amlodipine, phosphate, magnesium, 49 pantoprazole and asa. 50 51 skin examination revealed follicular flesh-coloured to pinkish monomorphic papules 52 mainly on central face involving the forehead and nose with central white protruding 53 spines. scalp, mucosal membranes, palms and soles were not affected (figure 1). 54 55 considering his immunosuppressive status, our differential diagnosis includes mainly 56 infectious etiologies such as molluscum contagiosum, filiform verrucae and 57 trichodysplasia spinulosa of immunosuppression. we have also considered idiopathic 58 follicular hyperkeratotic spicules or other adnexal pathologies such as sebaceous 59 hyperplasias, trichoepitheliomas, fibrofolliculomas, trichodiscomas and facial fibrous 60 papules (angiofibromas) as possibilities. 61 62 histopathological exam of one of the papules showed dilated follicular infundibulae with 63 keratin plugs and viral-like changes with large irregular eosinophilic/basophilic 64 trichohyalin like granules within the inner root sheath cells consistent with 65 trichodysplasia spinulosa (figure 2). additional test such as electron microscopy or 66 polymerase chain reaction was not performed. 67 68 based on typical clinical findings in the setting of renal transplantation and suggestive 69 histologic features, the patient was diagnosed with trichodysplasia spinulosa. he was 70 managed initially with oral valganciclovir without adequate response. subsequently, a 71 trial of topical imiquimod was commenced. unfortunately, he was lost to follow up in 72 dermatology clinic. 73 74 verbal informed consent was obtained from the patient for publication. 75 76 discussion 77 trichodysplasia spinulosa is a rare clinicopathologic skin entity primarily described in 78 immunosuppressed individuals. it is caused by trichodysplasia spinulosa79 associated polyomavirus (tspyv).2 80 81 the first case of ts was reported in 1995 by izakovic et al., describing a new entity with 82 spiny follicular hyperkeratosis thought to be related to cyclosporine treatment.3 83 84 four years later, possible polyomavirus association with ts was described by haycox et 85 al. electron microscopy findings of lesional skin were consistent with polyomavirus-86 induced changes and the condition was termed trichodysplasia spinulosa.4this was 87 confirmed only in 2010 when a novel double-stranded dna virus was isolated from the 88 hyperkeratotic lesions using a rolling-circle amplification detection method.5 the 89 presence of 1 million viral load in lesional skin compared to non-lesional skin further 90 reinforced the causal relationship.6 91 92 tspyv is a member of polyomaviridae family. bkpyv and jcpyv are the first members 93 discovered in 1970s to infect human.7 these are linked to transplant-related kidney 94 disease and progressive multifocal leukoencephalopathy, respectively.8 95 96 there are four novel members from the same family linked to cutaneous conditions 97 mainly in association with immunosuppression including tspyv. merkel cell 98 polyomavirus (mcpyv) is linked to a rare neuroendocrine tumour of the skin, merkel 99 cell carcinoma (mcc) with overall viral prevalence of 80% of the cases. human 100 polyomavirus 6 (hpyv6) and 7 (hpyv7) are associated with unique pruritic dyskeratotic 101 dermatoses in immunosuppressed individuals.7 102 103 exposure to tspyv occurs at a very young age and usually follows an asymptomatic 104 latent course. seroprevalence of tspyv in immunocompetent adults is 105 high, reaching up to 80%. moreover, seroprevalence increases even more in 106 immunocompromised individuals and more in patients with ts.1, 6 interestingly, only a 107 minority of immunosuppressed hosts will develop ts clinically. 1 van der meijden et al. 108 proposed that the cause of ts is primary polyomavirus infection in immunocompromised 109 hosts rather than reactivation of a latent viral infection which can explain the rarity of this 110 condition.9 further studies are required to uncover other variables that cause the disease 111 in specific patient populations. the only evidenced dermatologic clinical phenotype of 112 tspyv is ts.1 113 114 clinically, ts appears as flesh-coloured to erythematous follicular-based papules 115 concentrated on the central face with white spicules protruding from the papules. it can 116 progress to alopecia especially of the eyebrows and thickening of the skin leading to 117 leonine faces.10 ts can also affect the trunk, extremities and neck.6 118 119 the distinctive histopathological features of ts involve acanthosis of the epidermis, 120 aberrant large, distended follicles with dilated infundibulum and presence of large 121 eosinophilic, trichohyaline granules within excessive proliferating inner root sheath cells 122 of the hair bulb.10, 8 123 124 the classic clinical setting and characteristic histologic findings are usually sufficient to 125 make the diagnosis. further testing with pcr detection of the virus from the lesions and 126 electron microscopy studies can also be used to confirm the diagnosis.10 127 128 in a recent review article, curma et al. reported data of all published cases of ts in 129 pubmed until april 2020. a total of sixty cases were reviewed. almost all patients were 130 immunosuppressed. the main associated conditions were hematolymphoid malignancies 131 (including multiple myeloma, acute and chronic lymphocytic leukemia, acute myelocytic 132 leukemia, non-hodgkin’s lymphoma, b-cell lymphoma and myelodysplastic syndrome) 133 or solid organ transplant recipients (including kidney, kidney/pancreatic, heart, lung, 134 liver, intestinal and multivisceral transplant). other associations include systemic lupus 135 erythematosus on immunosuppressive therapy, gorlin’s syndrome on vismodegib 136 treatment, hiv and bcell lymphoma and myocarditis.1 137 138 interestingly, ts was reported in the setting of remission of lymphoma with a new 139 diagnosis of colon cancer and in the setting of lymphoma relapse. 11, 12 this adds to our 140 limited understanding of the pathogenesis of the disease. 141 142 jose et al. reviewed ts cases associated with solid organ transplant and emphasized that 143 it appears during the first year after transplant with the highest level of 144 immunosuppression.2 our patient had developed ts within the first year following his 145 renal transplant. he was diagnosed promptly with characteristic morphology, location of 146 the eruption and histology features. 147 148 managing ts is challenging. however, reduction of immunosuppression is the mainstay 149 of treatment. this might not be always feasible given the risk of organ rejection or flare 150 of the underlying disease. next line of management is antiviral treatment including 151 topical cidofovir 1%-3% or oral valganciclovir.2 particularly, 3% topical cidofovir might 152 be the most efficient.1 topical tazarotene and manual extraction were reported useful in 153 single case reports.13, 14oral leflunomide was reported to dramatically improve the 154 condition in two organ transplant patients.15 spontaneous regression has also been 155 described but took longer.2 156 157 conclusion 158 ts is an emerging folliculocentric viral infection that occurs predominantly in immune159 altered individuals. since the rate of organ transplantation and relative 160 immunosuppression are increasing globally, ts may become more prevalent. we present 161 this case to increase awareness of this unique dermatosis to health care providers for early 162 diagnosis and prompt treatment to prevent facial disfigurement. our knowledge is still 163 inadequate to explain many aspects of ts. 164 165 authors’ contribution 166 aak performed the literature review and primary manuscript construction. em reviewed 167 the case details and edited the manuscript. kn did a general review and edited the entire 168 manuscript. kaw reviewed the histopathology slides, literature review on the pathology 169 section and did a general review and grammatical editing of the manuscript. all authors 170 approved the final version of the manuscript. 171 172 references 173 1. curman p, näsman a, brauner h. trichodysplasia spinulosa: a comprehensive review 174 of the disease and its treatment. j eur acad dermatol venereol. 175 jeadv. 2021;35(5):1067-76. doi:10.1111/jdv.17081. 176 2. jose a, dad t, strand a, tse jy, plotnikova n, boucher hw et al. trichodysplasia 177 spinulosa: case reports and review of literature. transpl infect dis 2020;22(5):e13342. 178 doi:10.1111/tid.13342. 179 3. izakovic j, büchner sa, düggelin m, guggenheim r, itin ph. [hair-like 180 hyperkeratoses in patients with kidney transplants. a new cyclosporin side-effect]. 181 hautarzt 1995;46(12):841-6. doi:10.1007/s001050050350. 182 4. haycox cl, kim s, fleckman p, smith lt, piepkorn m, sundberg jp et al. 183 trichodysplasia spinulosa--a newly described folliculocentric viral infection in an 184 immunocompromised host. j investig dermatol symp proc 1999;4(3):268-71. 185 doi:10.1038/sj.jidsp.5640227. 186 5. van der meijden e, janssens rw, lauber c, bouwes bavinck jn, gorbalenya ae, 187 feltkamp mc. discovery of a new human polyomavirus associated with trichodysplasia 188 spinulosa in an immunocompromized patient. plos one 2010;6(7):e1001024. 189 doi:10.1371/journal.ppat.1001024. 190 6. wu jh, nguyen hp, rady pl, tyring sk. molecular insight into the viral biology and 191 clinical features of trichodysplasia spinulosa. br j dermatol 192 2016;174(3):490-8. doi:10.1111/bjd.14239. 193 7. jeles k, katona m, csoma e. seroprevalence of four polyomaviruses linked to 194 dermatological diseases: new findings and a comprehensive analysis. viruses 195 2022;14(10). doi:10.3390/v14102282. 196 8. kazem s, van der meijden e, feltkamp mc. the trichodysplasia spinulosa-associated 197 polyomavirus: virological background and clinical implications. apmis 198 2013;121(8):770-82. doi:10.1111/apm.12092. 199 9. van der meijden e, horváth b, nijland m, de vries k, rácz ek, diercks gf et al. 200 primary polyomavirus infection, not reactivation, as the cause of trichodysplasia 201 spinulosa in immunocompromised patients. j infect dis 202 2017;215(7):1080-4. doi:10.1093/infdis/jiw403. 203 10. narayanan d, rady pl, tyring sk. recent developments in trichodysplasia 204 spinulosa disease. transpl infect dis 2020;22(6):e13434. doi:10.1111/tid.13434. 205 11. thomas rs, lear w, bohlke a. trichodysplasia spinulosa in the setting of colon 206 cancer. cutis. 2018;102(4):262-4. 207 12. osswald ss, kulick kb, tomaszewski mm, sperling lc. viral-associated 208 trichodysplasia in a patient with lymphoma: a case report and review. j cutan pathol 209 2007;34(9):721-5. doi:10.1111/j.1600-0560.2006.00693.x. 210 13. campbell rm, ney a, gohh r, robinson-bostom l. spiny hyperkeratotic 211 projections on the face and extremities of a kidney transplant recipient. arch dermatol 212 2006;142(12):1643-8. doi:10.1001/archderm.142.12.1643-d. 213 14. barton m, lockhart s, sidbury r, wang r, brandling-bennett h. trichodysplasia 214 spinulosa in a 7-year-old boy managed using physical extraction of keratin spicules. 215 pediatr dermatol 2017;34(2):e74-e6. doi:10.1111/pde.13045. 216 15. pierrotti lc, urbano prp, nali l, romano cm, bicalho cds, arnone m et al. 217 viremia and viruria of trichodysplasia spinulosa-associated polyomavirus before the 218 development of clinical disease in a kidney transplant recipient. transpl infect dis 219 2019;21(4):e13133. doi:10.1111/tid.13133. 220 221 222 figure 1a: skin-coloured monomorphic papules on central face, forehead and nose with 223 protruding central whitish spines. 224 225 226 figure 1b: a close-up image of the papules with white central spines. 227 228 229 230 231 232 233 figure 2a: dilated follicular infundibulae with keratin plugs (white arrow) and viral 234 epithelial changes (black arrow) consistent with trichodysplasia spinulosa. h&e staining 235 x10 236 237 238 figure 2b: higher magnification of the irregular outer root sheath with tspyv viral 239 epithelial perinuclear eosinophilic/basophilic changes (black arrow). h&e staining x20 240 submitted 27 dec 21 1 revisions req. 27 feb & 22 may 22; revisions recd. 19 apr & 27 may 22 2 accepted 16 jun 22 3 online-first: august 2022 4 doi: https://doi.org/10.18295/squmj.8.2022.051 5 6 para-cardiac inflammatory mass compressing the heart 7 a possible association with covid-19 8 ahmad mirdamadi,1 amir m.m. sadeghi,2 mohsen m.m. sadeghi,3 majid 9 rabani,4 *shakiba hassanzadeh5 10 11 1department of cardiology, medical school, islamic azad university, najafabad branch, 12 isfahan, iran; 2department of cardiovascular surgery, isfahan university of medical sciences, 13 isfahan, iran; 3department of cardiac surgery, chamran heart center, isfahan university of 14 medical sciences, isfahan, iran; 4cardiac ward, khanevadeh hospital, isfahan, iran; 5division 15 of pathology, nickan research institute, isfahan, iran 16 *corresponding author’s e-mail: shak.hassanzadeh@gmail.com 17 18 abstract 19 infection with the sars-cov-2 virus causes coronavirus disease 2019 (covid-19). covid-19 20 usually affects the lungs but may also involve other organs such as the heart. we report a case of 21 a para-cardiac mass in a previously healthy 45-year-old man who developed persistent dyspnea 22 following sars-cov-2 infection. the patient underwent cardiac surgery since the mass was 23 attached to the pericardium and was causing constrictive pericarditis. the pathology report 24 indicated an inflammatory pattern for the mass. based on our knowledge there has been no 25 previous report of developing a para-cardiac inflammatory mass after sars-cov-2 infection. in 26 conclusion, we would like to increase awareness regarding the possibility of developing a para-27 cardiac inflammatory mass following covid-19. 28 keywords: sars-cov-2; pericarditis; constrictive pericarditis; covid-19; cardiac tumor; 29 mediastinal tumor 30 mailto:shak.hassanzadeh@gmail.com 31 introduction 32 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is caused by the sars-cov-2 33 virus. the most common clinical manifestations of sars-cov-2 infection are respiratory 34 symptoms; however, this infection may also involve other organs such as the heart and kidneys.1 35 some of the most common cardiac complications following coronavirus disease 2019 (covid-36 19) include myocarditis, pericardial effusion and tamponade, myocardial infarction (mi), 37 arrhythmias, acute heart failure (hf) with cardiogenic shock, and pericarditis. most of these 38 patients have shortness of breath and chest pain.1 on the other hand, primary cardiac tumors are 39 very rare and have an incidence of 0.001%–0.03% on autopsy findings and about 90% of them 40 are benign.2 in addition, 6 to 10% of primary cardiac tumors are primary pericardial masses 41 which are also usually benign. the clinical signs and symptoms of pericardial masses include 42 dyspnea, edema, pleural effusion, orthopnea, pericardial effusion, or murmur.3 we report a case 43 of a previously healthy 45-year-old male who developed persistent dyspnea and edema following 44 his recovery from sars-cov-2 infection. cardiac evaluation revealed a para-cardiac mass 45 (attached to the pericardium) and constrictive pericarditis for which he underwent cardiac 46 surgery. the mass was removed and pathological evaluation reported an inflammatory mass. 47 this study follows the principles of the declaration of helsinki. ethics approval from an 48 international review board was not applicable. informed consent was obtained from the patient 49 for the publication of the information and images. 50 51 case report 52 a 45-year-old male came to our clinic complaining of persistent exertional dyspnea and edema 53 in 2021. the patient had a history of hospital admission been due to covid-19 two months 54 earlier and his symptoms had developed following his sars-cov-2 infection. based on the 55 medical records of his previous admission, the patient was a healthy and active individual with 56 no limiting conditions and there was no report of any thoracic lesions. upon evaluation, a large 57 hypoechoic mass with a size of 9×3.1cm was observed on echocardiography, (figure 1). the 58 report was suggestive of a possible extra pericardial inflammatory mass or a large hematoma 59 with central liquefaction over the right atrium (ra) and right ventricle (rv) that had 60 compressive effects. in addition, there was bilateral pleural effusion (pe) which was turbid with 61 possible exudative effusion. there was also a mild to moderate rv dysfunction as well as a 62 moderate left ventricular (lv) systolic dysfunction with normal lv size. lv ejection fraction 63 (lvef) by simpson’s mode was 45%. based on the echocardiography result, although there was 64 no thickening or calcification of the pericardium, physiological constrictive pericarditis was 65 assumed to have occurred due to a mass. therefore, the patient was referred to a cardiac surgeon 66 with the impression of a localized exudative para-cardiac mass or hematomata to remove the 67 mass, evaluate the pericardium, and drain the pleural effusion. a multi-slice high-resolution 68 computed tomography (hrct) scan of the chest revealed bilateral mild pleural effusion. in 69 addition, there was patchy and ground-glass opacity in the right lower lobe (rll) which was 70 suggestive of a sequel of his previously sars-cov-2 infection. linear atelectasis was detected 71 in both the right and left upper lobes as well as the left lower lobe (lll). the report also noted 72 minimal atelectasis with pericardial effusion (figure 2). evaluation with cardiac magnetic 73 resonance (cmr) confirmed the findings detected on echocardiography and ct scan. ct scan 74 and mri images are shown in figure 2. consequently, based on the results of echocardiography, 75 ct scan, and cmr, a diagnosis of para-cardiac mass with compressive effects on the heart and 76 physiological constrictive pericarditis was established and the patient was scheduled for surgery. 77 treatment with anti-inflammatory drugs (such as corticosteroids or interleukin-receptor 78 antagonist) to reduce the para-cardiac mass was not initiated before cardiac surgery. on 79 admission, his condition was good with unremarkable signs and normal physical examination. 80 the patient had no significant medical or family histories and did not use any medication. 81 laboratory results and electrocardiography (ecg) were also normal. a summary of the patient’s 82 laboratory workup is shown in table 1. a day after admission, the patient underwent open-heart 83 surgery with general anesthesia for two hours. upon surgery, a median sternotomy was 84 performed and a large mass with the size of 10x4x3cm with severe adhesion to the ra and rv 85 was detected (figure 3). cardiopulmonary bypass (cpb) with an arterial cannula in the 86 ascending aorta was established and the venous return was achieved through the femoral vein. 87 with beating heart bypass surgery, the mass was completely excised by sharp and blunt 88 dissections. subsequently, the patient was weaned from cpb without any difficulty. chest 89 closure was performed with the placement of two drains (mediastinal and right pleural). there 90 were no signs of any complications during surgery. the patient was discharged from the hospital 91 four days later with stable vital signs and no evidence of post-surgical complications. the 92 macroscopic pathological evaluation of the mass revealed a 10×6×3.5cm mass with elastic 93 brown tissue and a soft cystic change at the center of the tissue. on microscopic evaluation, some 94 lesions had necrosis, neutrophilic infiltration, and foamy macrophages. in addition, some of the 95 fibrotic areas contained lymphocytic infiltration and lympho-plasma cells. however, there was 96 no evidence of malignancy or granuloma. the patient did not have any medical complaints on 97 his cardiology and cardiosurgery follow-up visits. 98 99 informed consent was obtained from the patient for publication of this case report and any 100 accompanying images. 101 102 discussion 103 there have been reports of cardiovascular complications and death or deterioration of pre-104 existing cardiac disorders following influenza infection.1 sars-cov-2 infection may also lead 105 to cardiovascular complications. post-covid-19 cardiac complications include myocarditis 106 (42.1%), pericardial effusion (15.8%), acute mi (15.8%), cardiac arrhythmias (10.5%), rv 107 mural thrombus with pulmonary embolism (5.3%), acute hf with cardiogenic shock (5.3%), 108 cardiac tamponade, takotsubo cardiomyopathy, pericarditis, and myopericarditis.1 in addition, 109 the majority of symptoms of post-covid-19 cardiac complications include shortness of breath 110 (52.6%), chest pain (36.8%), fever (26.3%), cough (26.3%), fatigue (10.5%), abnormal troponin 111 levels (68.4%), abnormal b-type natriuretic peptide (bnp) levels (42.1%), and st-segment 112 elevation (52.6%).1 different factors are involved in myocardial injury and the development of 113 cardiovascular complications of covid-19 and include an increased hypercoagulable status, 114 systemic inflammatory response to a viral infection which may lead to increased metabolic 115 activity, angiotensin-converting enzyme 2 (ace2) expression on cardiac cells (which act as a 116 receptor for the sars-cov2 virus leading to the invasion of the cardiac cells by the virus), and 117 direct viral injury of cardiac cells.1 118 119 on the other hand, around 90% of primary cardiac tumors are benign including myxoma (50%), 120 fibroelastoma (26%), fibroma (6%), lipoma (4%), inflammatory myofibroblastic tumors (imts) 121 (< than 5%), and other benign tumors.2 primary pericardial masses are also usually benign and 122 constitute about 6% to 10% of primary cardiac tumors. these benign primary pericardial masses 123 include lipomas, pericardial cysts, and paragangliomas, and hemangiomas. in addition, 124 pericardial tumors are associated with some disorders such as erdheim-chester disease and 125 igg4-related disease. the clinical signs and symptoms of pericardial masses include dyspnea, 126 edema, pleural effusion, orthopnea, pericardial effusion, or murmur.3 inflammatory 127 pseudotumors of the pericardium are among the primary pericardial tumors that are benign. 128 although the exact cause of inflammatory pseudotumors is unknown, these masses have been 129 reported to occur following surgery, trauma, igg4-related sclerosing disease, or infection (with 130 bacteria such as mycoplasma and nocardia). in addition, some have argued that inflammatory 131 pseudotumors develop through a low-grade neoplastic process.4 cardiac and pericardial tumors 132 are rare and to our knowledge, there have been no reports of sars-cov-2 infection inducing the 133 development of a cardiac or para-cardiac mass (that may present as a cardiac mass such as in our 134 case). we report a previously healthy 45-year-old male that developed persistent dyspnea and 135 edema following sars-cov-2 infection. he underwent cardiac surgery due to the presence of a 136 compressive mass with physiological constrictive pericarditis. the pericardium was intact and 137 the mass was removed. the pathology report indicated an inflammatory nature for the mass. 138 confirmation of an association between the development of a para-cardiac inflammatory mass 139 and sars-cov-2 infection requires further investigation. 140 141 conclusion 142 we report the first reported case of a para-cardiac mass development following sars-cov-2 143 infection in a previously healthy 45-year-old man. 144 145 author contributions 146 am, ams, and mmmr, mr clinically managed the patient. the primary draft was conducted by 147 sh. am, ams, mmmr, and mr conducted the first edit. all authors have read and approved 148 the final manuscript. 149 150 references 151 1. bhandari b, neupane s, khanal r, lnu k, wert y, komanduri s. covid-19 pericarditis 152 mimicking an acute myocardial infarction: a case report and review of literature. j community 153 hosp intern med perspect 2021; 11(3):315-21. https://doi.org/10.1080/20009666.2021.1896429. 154 https://doi.org/10.1080/20009666.2021.1896429 2. deng md, han jy, lin k, tang h. cardiac inflammatory myofibroblastic tumor in 155 interventricular septum: a rare case report. medicine (baltimore) 2018; 97(48):e13219. 156 https://doi.org/10.1097/md.0000000000013219. 157 3. maleszewski jj, anavekar ns. neoplastic pericardial disease. cardiol clin 2017; 35(4):589-158 600. https://doi.org/10.1016/j.ccl.2017.07.011. 159 4. restrepo cs, vargas d, ocazionez d, martínez-jiménez s, betancourt cuellar sl, gutierrez 160 fr. primary pericardial tumors. radiographics 2013; 33(6):1613-30. 161 https://doi.org/10.1148/rg.336135512. 162 163 table 1. a summary of the patient’s laboratory workup before surgery. 164 laboratory test result normal range wbc 109/l 8.77 adult: 5-10 rbc 106/ul 4.27 (low) male: 4.7-6.1 hb g/dl 11.5 (low) male: 13.2-16.2 hct % 34.8 (low) male: 39-52 neutrophil % 63.5 (high) 40-60 lymphocyte % 28.8 20-40 platelets 103/ml 469 (high) 150-450 ptt seconds 64 30-45 pt seconds 18.1 (high) 12-16.5 inr (ratio) 1.36 ratio: 1.34 blood group o positive esr (1hr) mm/hr 67 (high) <10 crp mg/l 32.5 (high) up to 6 magnesium mg/dl 2.2 1.8-2.6 hbs ag (index) negative <1: negative hcv ab (index) non-reactive non-reactive: <0.9 hiv (ifa) (index) non-reactive negative: <0.25 abbreviations: white blood cells (wbc), red blood cells (rbc), hemoglobin (hb), 165 hematocrit (hct), ptt (partial thromboplastin time), pt (prothrombin time), inr 166 (international normalized ratio), esr (erythrocyte sedimentation rate), crp (c-reactive protein), 167 https://doi.org/10.1097/md.0000000000013219 https://doi.org/10.1016/j.ccl.2017.07.011 https://doi.org/10.1148/rg.336135512 hbs ag (hepatitis b virus surface antigen), hcv ab (hepatitis c virus antibody), hiv (human 168 immunodeficiency virus), and indirect fluorescent antibody (ifa). 169 170 171 figure 1. echocardiography: a large hypoechoic mass (size: 9x3.1cm in size) suggestive of an 172 extra pericardial inflammatory mass or a large hematoma with central liquefaction over the right 173 atrium (ra) and right ventricle (rv) causing compressive effects. 174 175 176 figure 2. a. multi-slice high-resolution computed tomography (hrct) scan of the chest 177 revealing bilateral mild pleural effusion; patchy and ground-glass opacity in the right lower lobe 178 (rll) [suggestive of a sequel of the patient’s previously covid-19 infection]; linear 179 atelectasis in both the right and left upper lobes as well as the left lower lobe (lll); minimal 180 atelectasis with pericardial effusion; arrow showing the mass. b and c. mri of the chest; 181 arrows showing the mass (rv: right ventricle; lv: left ventricle; pe; pleural effusion). 182 183 184 figure 3. a. image of the large mass (size of 10x4x3cm) that was excised upon surgery. b, c, 185 and d. microscopic evaluation of the mass (some lesions had necrosis, neutrophilic infiltration, 186 and foamy macrophages; some of the fibrotic areas contained lymphocytic infiltration and 187 lympho-plasma cells. no evidence of malignancy or granuloma). 188 2008-issue1.indd sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 11-19 sultan qaboos university© submitted 20th january 2008 accepted 4th february 2008 department of family medicine and public health, sultan qaboos university hospital, muscat, sultanate of oman email: zakiyaq@squ.edu.om qualitative research and its uses in health care zakiya q al-busaidi r e v i e w abstract although relatively uncommon in health care research, qualitative research is now receiving recognition and is increasingly used in health care research with social and cultural dimensions. unlike quantitative research, which is deductive and tends to analyze phenomena in terms of trends and frequencies, qualitative research seeks to determine the meaning of a phenomenon through description. it aims to develop concepts that aid in the understanding of natural phenomena with emphasis on the meaning, experiences and views of the participants. differences among qualitative researchers exist on matters of ontology, epistemology, data collection methods and methods of evaluation. the aim of this article is not to act as a practical guide on how to conduct qualitative research, but is an attempt to give an introduction to qualitative research methods and their use in health-related research. keywords: health care; qualitative research; phenomenology; ethnography; interviews, semi-structured; focus groups. الصحية الرعاية في واستعماالته البحث النوعي البوسعيدي زكية ــتغلني املش ــاط أوس بني اهتماما ورواجا بدأت تلقى أنها اال ، الصحية الرعاية بحوث في النوعي البحث طرق ــتعمال اس من قلة الرغم على امللخص: حتليل على تعتمد والتي ، املتعارف عليها الكمية البحوث عن البحوث من النوع هذا ويختلف والثقافية. ــاد األجتماعية األبع ذات الصحية ــاث باألبح في ــاعد تس تكوين مفاهيم وهدف األخيرة البحث. قيد الظواهر ووصف ــير تفس على النوعية البحث طرق تعتمد بينما االحصائية، بالطرق الظواهر بعلم يتعلق فيما النوعية البحوث ــن اختالفات ايضا ضم هناك . ــاركني املش نظر ووجهات وخبرات معنى على التأكيد مع الطبيعية ــر الظواه ــم فه ، القيام بالبحث النوعي كيفية حول عملي دليل تقدمي املراجعة هذه من الهدف ليس النتائج. البيانات وحتليل جمع وطريقة املعرفة ــة ونظري ــود الوج . الصحية البحوث مجال في واستخداماتها النوعية البحث طرق الى ولكنها محاولة لوضع مدخال . االهتمام ، مجموعات منظم نصف املقابالت ، ، االثنية ، اجلغرافيا علم الظواهر ، النوعي البحث الصحية ، الرعاية : الكلمات مفتاح qualitative research is defined as an umbrella term covering an array of inter-pretative techniques which seek to describe, decode, translate and otherwise come to terms with the meaning, not the frequency, of certain more or less naturally occurring phenomena in the social world.1,2 as a method of inquiry, it was first used by sociologists and anthropologists in the early twentieth century, although it existed much earlier than that in its non-structural form. researchers studied cultures and groups in their own and foreign settings and told stories of their experience long before then. in the 1920s and 1930s, social anthropologists and sociologists implemented a more focused approach compared to the old unsystematic and journalistic style used in those days. since the 1960s, qualitative research has experienced a steady growth starting with the development of grounded theory and new publications in ethnography.3, 4 the number of books, articles and papers related to qualitative research has increased tremendously during the past 20 years and more researchers, including health-related professionals, have moved to a more qualitative paradigm adapting and modifying these approaches to the study needs of their own areas. 4 since qualitative research does not aim to enumerate, it is sometimes viewed as the exact opposite to quantitative methods and the two methods are frequently presented as antagonists. quantitative research is based on structure and uses experiments and surveys as methods. in addition, it is deductive in nature and uses statistical sampling methods. in contrast, qualitative research is described as an action research using observation and interview methods. it is inductive in nature and depends on the purposeful z a k i ya q a l b u s a i d i 12 selection of participants. whereas quantitative researchers use reliability as a way of verification, qualitative researchers use validity. recently, there has been a growing recognition that the quantitative-qualitative debate and distinction is unnecessary and that it would be more fruitful for the relation between the two methods to be complementary and overlapping rather than exclusive.6 in fact, neither qualitative nor quantitative research is superior to the other; there are weaknesses and strengths in each method. qualitative and quantitative research methods can indeed be seen as complementary and both are necessary to provide an understanding of a phenomenon. several researchers have argued that the research questions and the phenomenon under investigation should determine the methodology to used.7, 8, 9 the crucial question, therefore, is not “what is the best research method?” but “what is the best research method for answering this question most effectively and efficiently?” 10 so, while qualitative and quantitative research may well investigate similar topics, each will address a different type of question. holman sums up this position: “true understanding in medicine cannot be achieved without adding qualitative methods to the research arsenal”.11 traditional quantitative methods, such as randomised controlled trials, are the appropriate means of testing, for example, the effect of an intervention or a treatment, while a qualitative exploration of beliefs and understandings is needed to find out why the results of research are often not implemented in clinical practice. the aim of qualitative research is to develop concepts that can help us understand social phenomena in natural settings, giving emphasis on the meanings, experiences and views of the participants.10 qualitative research methods are the most suitable for this approach because of their emphasis on people’s lived experience. they are considered to be well suited for locating the meanings that people place on the events, processes, and structures of their lives and their perceptions, presuppositions and assumptions. 5 in his advice to graduate students, patton lists a number of conditions that are suitable for a qualitative study. these include: questions about people’s experiences; inquiry into the meanings people make of their experiences; studying a person in the context of her or his social/interpersonal environment and research where it is difficult to develop a standardised instrument due to the lack of knowledge on the phenomenon.12 a r g u m e n t s f o r a n d a g a i n s t q u a l i t a t i v e m e t h o d s there are major differences of opinions among qualitative researchers on matters of ontology and epistemology as well as the methods to be used and criteria of evaluation. there are also disagreements about the nature, purpose, status and practice of its methods. a large number of authors take a predominantly method-based approach; authors such as miles and huberman5 and patton 12 put emphasis on data collection techniques. another approach is to classify qualitative research according to research traditions, i.e. whether phenomenological, grounded theory or ethnography, amongst others. authors such as creswel9 and denzin and lincolin3 prefer this approach, which has the advantage of being based on systematisation of knowledge providing a sense of order and orientation. on the other hand, it has the disadvantage of oversimplification, ignoring the issues of the research question and conceptual frameworks used and the way these issues can shape the research process and the findings.13 in addition, some researchers have decided to classify qualitative research according to the research question or the method of analysis. although the majority of qualitative researchers stress that qualitative research is inductive in nature, in contrast to quantitative research which is deductive, there are qualitative researchers who argue that both can be used for different purposes and at different times, and that qualitative research can be done in a deductive way where prior assumptions are tested on new cases.14 retroduction, which is defined as the movement backward and forward between theory and data or the combination of deduction and induction, is said to be a characteristic of qualitative research.11 the degree of deduction or induction and which one follows the other depends on the research question.12. guba and lincoln15 used the term “emergent design” to describe a qualitative study design that emerges as the study progresses in response to the researcher’s early observations. there are also qualitative studies in health care that base their research questions on the results of prior literature of quantitative studies on the subject.16, 17 while the research questions in these studies were relatively precise, the method used was flexible. miles and huberman5 state that no study con13 q ua l i tat i v e r e s e a r c h a n d i t s u s e s i n h e a lt h c a r e forms exactly to a standard methodology and that the researcher bends the methodology to the peculiarities of the study. according to creswell,9 traditions of inquiry used “need not be pure, and one might mix procedures from several”. mixing approaches and procedures is encouraged by some authors and regarded as a creative approach to qualitative research.12 studies using qualitative research in health care have been criticised for the misguided separation of method from theory and of technique from the conceptual underpinnings.18 however, qualitative health researchers respond by stating that the choice of method and how it is used can perfectly well be matched to what is being studied rather than to the methodological leanings of the researcher.10 it has been suggested that incorporating qualitative research method experts into health research teams enriches research and ensures that the right methodology is used for answering the right questions. finally, using qualitative methods in health-related research has resulted in more insight into health professionals’ perceptions of lay participation in care and identification of barriers to changing healthcare practice. q ua l i tati v e r e se a r c h a ppr oa c h e s grounded theory, phenomenology and ethnography are three approaches used in qualitative research. grounded theory approach is a commonly used qualitative method in the social sciences to inductively generate or discover a theory out of the data.9 phenomenology and ethnography are more commonly used qualitative approaches in health care and will be highlighted below. ph e n ome n o l o g y one of the major strengths of qualitative research is its emphasis upon understanding the phenomenon of interest holistically and in its context. the term phenomenology is popular and widely embraced, but its meaning has become confusing and faint. different researchers refer to phenomenology differently. it can refer to an inquiry paradigm, an interpretive theory, a philosophy, an analytical perspective, a major qualitative research tradition or a research method framework.12 in spite of the differences, all of these approaches share the focus of phenomenology, which is exploring how human beings make sense of experience and the meaning they give to these experiences. phenomenology is being used in the social and human sciences including sociology, education, psychology, nursing and health sciences.9 phenomenologists are interested in how people put together the phenomena they experience in such a way as to make sense of the world and develop a worldview. they assume commonality in human experience and focus on meaning-making as the essence of human experience. the essence is the core meaning mutually understood through a phenomenon commonly experienced.12 the phenomenon under study may be emotions, relationships, a programme, an organisation or a culture.12 bracketing is one of the central ideas in phenomenology. it means that the researcher has to set aside all of his prejudgments and his previous experience about the phenomena and approach the field with an open mind, imagination and intuition. although important, bracketing is often said to be a difficult task.9 patton12 describes the difference between conducting a phenomenological study and using a phenomenological perspective to a study. he argues that, “one can employ a general phenomenological perspective to elucidate the importance of using methods that capture people’s experience of the world without conducting a phenomenological study that focuses on the essence of shared experience”. e th n o gr a ph y in ethnography, the researcher studies the structure and function of a group of people. an example of a structure or configuration is the kinship, while the function refers to patterns of relationships affecting and regulating behaviour.9 the aim of ethnographic studies is to give a holistic picture of the social group studied, attempting to describe aspects of the cultural and social system of that particular group. these aspects could be the group history, religion, economy, politics or environment. data collection methods vary in ethnographic studies with observation and interviews being the most popular methods. although some authors expressed concern that anthropological methods may be misused or applied superficially by the medical profession,19 others, however, expressed the need for acknowledging and incorporating ethnographic methods in health care research.20 savage19 explains that today the term ethnography can be applied to any small-scale social research carried out in everyday settings and uses several methods evolving in design z a k i ya q a l b u s a i d i 14 and focusing on an individual’s meanings and explanations. in health care, ethnography has been used in topics related to health beliefs and practices, allowing these issues to be viewed in the context in which they occur and therefore helping broaden the understanding of behaviours related to health and illness.20 in addition, there has been an increase in the amount of cross-cultural research and a change in the form of this research. recently, more short-term ethnographic and cross-cultural studies have been undertaken, for example, studies sponsored by international development agencies or student exchange projects.12 q u a l i t a t i v e r e s e a r c h i n s t r u m e n t s qualitative research instruments used for data collection include interviews, observations, and analysis of documents. interviews are the most common techniques used to gather research information. there are three types of interviews: structured, semi-structured and unstructured, described in some books as structured, informed and guided, respectively.13 the semi-structured interview is more commonly used in health care-related qualitative research. such an interview is characteristically based on a flexible topic guide that provides a loose structure of openended questions to explore experiences and attitudes. it has the advantage of great flexibility, enabling the researcher to enter new areas and produce richer data. in addition, it helps the researcher to develop a rapport with the informants. semi-structured interviews elicit people’s own views and descriptions and have the benefit of uncovering issues or concerns that have not been anticipated by the researcher.6 they are commonly used when the aim is to gain information on the perspectives, understandings and meanings constructed by people regarding the events and experiences of their lives. however, this type of interviewing is claimed to reduce the researcher’s control over the interview situation and take a longer time to conduct and analyse, in addition to the difficulties of the analysis process.21 in health care, interviews are the appropriate tool to be used if the research is concerned with interpersonal aspects of care or if the available evidence is limited.6 another qualitative research instrument that can be used in health care research is the focus group. focus group interviews have the advantage of being more time efficient as more people can be interviewed for the same amount of time. they also provide a richer source of data. on the other hand, focus group interviews tend to document the ‘public’ rather than the ‘private’ views of the individuals. in addition some people do not interview well in-group situations.13 t h e u s e o f t h e i n t e r v i e w g u i d e some qualitative researchers are reluctant to plan a design of their study in advance of the data collection. they argue that the phenomenon studied must first be discovered and they describe their design as emergent. however, increasingly more qualitative researchers appear ready to define a research question and develop an interview guide prior to starting the data collection.11 patton defines an interview guide as a series of topics or broad interview questions which the researcher is free to explore and probe with the interviewee.12 the advantage of an interview guide is that it helps the interviewer pursue the same basic lines of inquiry with each person interviewed and manage the interviews in a more systematic and comprehensive way. the findings of earlier work are increasingly being used as a facilitator for further research. however, concepts drawn from earlier work are supposed to be held lightly and to be subject to reformulation or rejection by the researcher especially as the study goes on and the research progresses.11 the extent to which such a flexibility of design is important will vary depending on the topic and the aim of the study. s a m p l i n g sampling strategies in qualitative research are largely determined by the purpose of the study. statistical representativeness is not considered as a prime requirement in qualitative research and is not normally sought. furthermore, qualitative data collection is more time consuming and expensive, which makes the use of a probability sample impractical.6 the aim of sampling in qualitative research is to identify specific groups of people who hold characteristics or live in circumstances relevant to the phenomena being studied. in this way, identified informants are expected to enable enriched exploration of attitudes and aspects of behaviour relevant to the research.10 two types of samples used in qualitative research, maximum variation and homogenous samples, are explained below. according to patton, 12 maximum variation sam15 q ua l i tat i v e r e s e a r c h a n d i t s u s e s i n h e a lt h c a r e pling is where the researcher attempts to study a phenomenon by seeking out settings or persons that represent the greatest differences in that phenomenon. a maximum variation sample documents diverse variations and identifies important common patterns by representing diverse cases to develop fully multiple perspectives about the cases.9 this means that the participants are sampled based on particular predetermined criteria in order to cover a range of constituencies, such as different age, cultural background or class.6 similarly, the researcher can select the setting of the data collection on the basis that it is sufficiently similar to other settings in which generalisation is sought. this way the researcher is demonstrating the possibility that the setting studied is representative of the population studied.2 in homogeneous sampling, the researcher chooses a small homogenous sample with the purpose of describing some particular subgroups in depth.12 the sample size in qualitative research is not determined by fixed rules, but by factors such as the depth and duration of the interview and what is feasible for a single interviewer.22 although it is theoretically possible to carry out qualitative research on large samples, qualitative researchers find themselves obliged by time and resource limits to trade breadth for depth.11 the sample size for interview studies is usually much smaller than those of a quantitative research, usually not exceeding 50 participants, although this can vary with the research question asked.6 patton12 states, “there are no rules for sample size in qualitative inquiry”. in other words, sample size depends on the aim of the study and what is possible, given the time and resources available. a n a l y s i n g q u a l i t a t i v e r e s e a r c h although there are plenty of guidelines for analysing qualitative research, applying these guidelines requires judgment and creativity because each qualitative study is unique.12 a researcher might also be confused by the different terms used by qualitative researchers when describing analysis. analysis might be described as interpretation, making sense of data, or transforming data. analysis is sometimes presented to indicate different procedures based on language, theory or what is described as interpretive/descriptive analysis.11 however, overlap can take place between these different methods and a researcher might decide to use a method of analysis that is based on language, such as symbolic interactionist, while using grounded theory to develop a theory at the same time. most of the analytical approaches to qualitative research in health care are ‘generic’ and are not labelled within one of the specific traditions of qualitative research. a common approach in most of these studies is general and inductive in nature, but does not comply with the very systematic and rigorous inductive approach of grounded theory. in addition, it has been described that many researchers use a simple two-level analysis scheme followed by a more specific level. this means that the researcher can initiate the analysis based on the conceptual framework used in order to produce more inductive data, and the coding moves from the descriptive to the more interpretative and inferential codes.5 c o m p u t e r u s e i n q u a l i t a t i v e d a t a a n a l y s i s qualitative research studies typically produce very large amount of data that needs to be managed efficiently. computer packages can improve the efficiency of data management.11 computer programs provide a way of storing and retrieving material. they are therefore useful in locating cases, statements, phrases or even words, thereby replacing the tedious and timeconsuming process of “cutting and pasting” and “colour coding”. the use of computer packages, however, is claimed to distance the analyst from the data, 11 and may take the place of a close and careful analysis. using a computer programme can lead to quantitative analysis instead of qualitative, for example, counting occurrences, giving more weight to more frequent events, and ignoring isolated incidences.23 in addition, computer programmes are said to fix and label categories during the analysis process and the researcher may be reluctant to change these categories.9 furthermore, the researcher is required to learn the computer programme, which may add to the time and effort he or she will need to spend on the research project. the researcher also has to be aware of the limitations of computer programmes. while computer packages can help with the intensive process of analysis and the management of large data sets, they are not a substitute for “immersion” in the data, and thorough knowledge that can enable the researcher to make comparisons, identify patterns and develop interpretations.6 there z a k i ya q a l b u s a i d i 16 are different packages available: ethnograph, atlas and nud.ist are the mostly used. qsr nvivo is a new product developed by the makers of nud.ist and is user-friendlier, more suitable for individual research projects and more visually attractive than previous packages. t h e r o l e o f t h e r e s e a r c h e r i n q u a l i t a t i v e r e s e a r c h patton12 states that, “the human element in qualitative research is both its strength and weakness”. it is considered a point of strength because it allows human insight and experience to develop new understandings of the world, and a point of weakness because it depends heavily on the researcher’s skills, creativity, training and intellect. qualitative methods depend on both critical and creative thinking and the balance between the two in conducting the study and interpreting its results. the role of the researcher is approached differently according to the type of research tradition used. a phenomenologist researcher is required to bracket his/her own assumptions when collecting data. on the other hand, in an ethnographic study, the effect of the researcher on the interview and the interaction is seen as inevitable and important in shaping the results of the study. although practising clinicians routinely interview patients during their clinical work, interviewing is a well-established technique in sociology and related disciplines. one of the differences between clinical and research-aimed interviews lies in their different purposes. the usual aim of the clinical interview is to fit the patient’s problem into the appropriate medical category for diagnosis and management. on the other hand, the aim of a qualitative research interview is to discover the interviewee’s own meaning and avoid prior assumptions and preset categories.22 having said that, there are general skills in clinical interviewing that can be useful, such as listening and observation. a good level of self-awareness is necessary in the researcher in order to reduce possible biases. researchers in qualitative research need to consider how they are perceived by interviewees and the effect of features related to the researcher, such as class, race, and sex on the interview. this question is more important if the interviewee knows that the interviewer is a doctor. it has been described that a patient, or someone who is likely to be become one, may give what he or she thinks is a desirable response, thinking that the doctor will be pleased. r i g o u r i n q u a l i t a t i v e r e s e a r c h health field research is generally quantitative and based on biomedical traditions and experimental methods. in this field, qualitative research is criticized for being subject to researcher bias and for lacking reproducibility and generalisability.10 researchers presenting their qualitative work in health-related research are partly responsible for this view. many qualitative researchers neglect the importance of giving an adequate description of their theoretical concepts and methods used in their research. a systematic research method is also essential when conducting qualitative research. rigour in qualitative research includes procedures taken at different stages of the research process including during data collection and analysis. several procedures have been described to increase rigour in qualitative research. for example, triangulation is commonly used as a way of validating of data. tr i a n g ul ati o n in triangulation, the researcher uses multiple methods, sources, researchers or theories to provide evidence that strengthens his or her study. triangulation provides different ways of looking at the same phenomenon and adds credibility and confidence in the conclusions drawn from the study. there are two main types of triangulation, triangulation of sources and analyst triangulation. patton12 defines triangulation of sources as “checking out the consistency of different data sources within the same method”. when using this type of triangulation, the researcher compares the perspectives of people from different points of view. for example, studies in programme evaluation might compare the views of staff, clients or funding bodies.12 studies in health care have used this method of verification to study the accounts of doctors, patients, and managers in order to identify similarities and differences in views. an example is the study of patients’ versus doctors’ agendas in general practice.23 both similarities and differences from different sources, when given reasonable explanation, could contribute significantly to the credibility of the findings. triangulation with multiple analysts can also be used as a method of verification. it is defined as “having two or more persons independently analyse the same qualitative data and compare their findings”.12 17 q ua l i tat i v e r e s e a r c h a n d i t s u s e s i n h e a lt h c a r e q u a l i t a t i v e r e s e a r c h i n h e a l t h c a r e m a n a g e m e n t recently, there has been a greater acceptance of the qualitative approach, even as a stand-alone method, in health care research. institutions that control funding for medical research have developed ethical guidelines for assessing qualitative studies which indicates formal acceptance of this form of research within an area previously dominated by quantitative methods.13 more qualitative research articles are published in health-related journals, in addition to a new qualitative research journal (qualitative health research). quality of health care is one of the areas where qualitative methods can be used. the concept of quality in health care is multidimensional and multifaceted and some of the questions asked related to the quality of care or services may not be acquiescent to quantitative methods.6 qualitative research offers a variety of methods to be used for identifying what is really important to both patients and carers. it can also be used to identify and detect obstacles to change and the reasons why improvement does not occur.6 it is therefore an essential component of health services research because it enables us to reach areas not amenable to quantitative research, for example, lay and professional health beliefs. in addition, qualitative description can be a prerequisite of quantitative research, particularly in areas that have received little previous investigation. qualitative research is widely used to study issues related to doctor-patient interaction especially in general practice. studies concerning patients’ versus doctors’ agendas in general practice and general practitioners perceptions of effective health care are examples.23, 24 recently there have been more studies concentrating on patients’ own perceptions and views regarding their health and health care services, for example a study on women’s views on the impact of operative delivery in the second stage of labour.25 another example is the study on middle-aged person’s experience of living with severe heart failure.26 another area where qualitative research is being used in health care is to identify obstacles and barriers to practice change by exploring the reasons behind certain behaviours. a good example of this is the study of patients’ decisions about whether or not to take anti-hypertensive drugs.27 there are similar studies on issues such as the use of antibiotics in general practice and patient compliance. in addition to issues related to the patients’ perception, some qualitative studies concentrated on factors fostering the doctor’s motivation and the effect of doctors’ social life and culture, in addition to issues related to the doctor’s own health. examples are the study by dumelow et al.28 on the relation between a career and family life for english hospital consultants. another example is a study aimed at exploring general practitioners’ perceptions of the effects of their profession and training on their attitudes to illness in themselves and colleagues.29 qualitative work can help in identifying cultural and social factors that affect health care positively or negatively. such information can be helpful in improving service delivery.6 studies on patients from ethnic minorities have identified administrative and language barriers that affected health care and shed light on some of the beliefs and behaviours of these patients that might have affected help seeking and compliance. good examples are the studies by bush et al.30 exploring the influences on smoking in bangladeshi and pakistani adults in the uk, and the multi-centre crosscultural postnatal depression study.31 there has been an increasing interest and use of qualitative research methods in primary health care and general practice articles. britten32 states that “the nature of general practice is such that a variety of research methods are needed to explore all its intricacies” he adds that qualitative methods can enrich research in general practice by opening up areas not amenable to quantitative methods, topics such as patient satisfaction, doctor-patient interaction, in addition to identifying and explaining attitudes, beliefs and behaviour. in addition, qualitative research has been used in the assessment of new technology methods used in health care. for example, the studies on the implementation of the national health system information technology programme in the uk.11, 33 c o n c l u s i o n qualitative research methods are receiving an increasing recognition in health care related research. the use of qualitative research in health care enables researchers to answer questions that may not be easily answered by quantitative methods. moreover, it seeks to understand the phenomenon under study in the context of the culture or the setting in which it has been studied, therefore, aiding in the development of new research instruments, such as questionnaires z a k i ya q a l b u s a i d i 18 that are more culturally acceptable. however, because health care related research has, for decades, been based on quantitative methods, the introduction of a new method requires researchers in health care who attempt to use it, to have a thorough understanding of its theoretical basis, methodology and evaluation techniques. a c k n ow l e d g me n ts i would like to thank sultan qaboos university, oman, for granting me a scholarship to do my phd at the university of nottingham, uk. i am also grateful to my phd supervisor, dr margaret oates, for her guidance and support. r e f e r e n c e s 1. al-busaidi z. rethinking somatisation: the attitudes and beliefs about mental health in omani women and their general practitioners. phd thesis, school of community health sciences, university of nottingham, uk, 2005. 2. van manen m. researching lived experience: human science for an action sensitivity pedagogy. london: althouse press, 1990. 3. denzin n, lincoln y. the sage handbook of qualitative research. thousands oaks, ca: sage publications, 2005. 4. holloway i. basic concepts for qualitative research. oxford: blackwell science, 1997. 5. miles m, huberman m. qualitative data analysis: an expanded sourcebook. beverly hills, ca: sage publications 1994. 6. pope c, van royen p, baker r. qualitative methods in research on health care quality. qual saf health care 2002; 11:148-152. 7. silverman d. doing qualitative research: a practical handbook. london: sage publications, 2005. 8. mays n, pope c. reaching parts other methods cannot reach: an introduction to qualitative methods in health and health services research. bmj 1995; 311:42-45. 9. creswell jw. qualitative inquiry and research design: choosing among five traditions. london: sage publications, 2007. 10. mays n, pope c. qualitative research: rigour and qualitative research. bmj 1995; 311:109-122. 11. murphy e, dingwall r, greatbatch d, parker s, watson p. qualitative research methods in health technology assessment: a review of the literature. health technol assess 1998; 2:3-9. 12. patton mq. qualitative evaluation methods.ca: sage publications, 2002. 13. grbich c. qualitative research in health. london: sage publications, 1999. 14. glaser b, strauss a. the discovery of grounded theory: strategies of qualitative research. chicago, il: aldine publishing, 1967. 15. guba e, lincoln y. competing paradigms in qualitative research. in: denzin n, lincoln y, ed. handbook of qualitative research. thousands oakes, ca: sage publications. 1994. p. 105-117. 16. gantley m, davies d, murcott a. sudden infant death syndrome: links with infant care practices. bmj 1993; 306:16-20. 16. bloor m. bishop berkeley and the adenotonsillectomy engima: an exploration of the social construction of medical disposals. sociology 1976; 10:43-61. 18. lambert h, mckevitt c. anthropology in health research: from qualitative methods to multidisplinarity. bmj 2002; 325:210-213. 19. meyer j. qualitative research in health care: using qualitative methods in health related active research. bmj 2000; 320:178–181. 20. savage m. revisiting classic qualitative studies. forum: qualitative social research [on-line journal], 6(1), art. 31. from: www.qualitative-research.net/fqs-texte/105/05-1-31-e.htm. accessed january 2005. 21. smith ja, harre r, van langenhove l. rethinking methods in psychology. london: sage publications, 2001. 22. britten n. qualitative research: qualitative interviews in medical research. bmj 1995; 311:251-25. 23. barry ca, bradley cp, britten n, stevenson f, barber n. patients unvoiced agendas in general practice consultations: qualitative study. bmj 2000; 320:1246-1250. 24. tomlin z, humphrey c, rogers s. general practitioners’ perceptions of effective health care. bmj 1999; 318:1532-1535. 25. murphy d, pope c, frost j, eliebling r. women’s views on the impact of operative delivery in the second stage of labour: qualitative interview study. br med j 2003; 327:1132-1135. 26. nordgren l, asp m, fagerberg i. living with moderatesevere chronic heart failure as a middle-aged person. qualitative health research 2007; 17:4-13. 27. benson j, britten n. patients’ decisions about whether or not to take antihypertensive drugs: qualitative study. br med j 2002; 325: 873-876. 28. dumelow c, littlejohns, p, griffiths s. (2000) relation between a career and family life for english hospital consultants: qualitative semistructured interview 19 q ua l i tat i v e r e s e a r c h a n d i t s u s e s i n h e a lt h c a r e study. br med j 2000; 320:1437-1440. 29. thompson wt, cupples me, skan di, bradley t. challenge of culture, conscience, and contract to general practitioners’ care of their own health: qualitative study. br med j 2001; 323:728-731. 30. bush j, white m, kai j, rankin j, bhopal r . understanding influences on smoking in bangladeshi and pakistani adults: community based, qualitative study. br med j 2003; 326:962-968. 31. oates m r, cox jl, neema p, asten p, glangeaud-freudenthal n, figueiredo b, et al. postnatal depression across countries and cultures: a qualitative study. br j psychiatry 2004;184: 10-16. 32. britten n. qualitative research and general practice. br j gen pract 1993; 43:270-271. 33. hendy j, fulop n, reeves b, hutchings a, collin s. implementing the nhs information technology programme: qualitative study of progress in acute trusts. br med j 2007; 334:1360. 1oman medical specialty board, muscat, oman; departments of 2surgery and 3radiology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: edwinmay2013@gmail.com don’t miss the target a case of neurofibromatosis type 1 ola hamdani,1 buthaina al-yahyai,1 *edwin stephen,2 ibrahim abdelhady,2 hanan al-mawaali,2 rashid al-sukaiti,3 khalifa al-wahaibi2 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 589–590, epub. 7 nov 22 submitted 11 oct 21 revision req. 8 dec 21; revision recd. 6 jan 22 accepted 19 jan 22 a 27-year-old male patient, with no diagnosed comorbidities, presented to a vascular surgery clinic in muscat, oman, in 2021 referred as a case of lymphangioma, after an ultrasound was done elsewhere. he presented with a history of a progressively enlarging left lateral arm swelling, that he noticed two years earlier when receiving an intramuscular injection for analgesia, following an injury to the leg while playing football. examination revealed hyper-pigmented spots, cafeau-lait macules, distributed over his body [figure 1]. the swelling was overlying the lateral aspect of the left arm, measuring approximately 12 × 7 cm. it was non-tender and firm with limited mobility. there were similar smaller swellings over his chest, back and other limbs. magnetic resonance imaging (mri) was performed after a clinical diagnosis of neurofibromatosis type 1 (nf-1). this revealed a classical appearance of neurofibroma known as the target sign [figure 2]. patient’s consent was obtained prior to taking and using his photos and images for publication purposes. comment neurofibromatosis is an autosomal dominant neurocutaneous disorder; there are two types: nf-1 and nf-2. nf-1 comprises approximately 96% of all cases and affects 1 in 3,000 individuals worldwide and presents with cutaneous and non-cutaneous manifestations.1 commonly, it presents with café au lait spots, neurofibromas, axillary or groin freckling and optic manifestations. other complications of the disease include seizures, problems with digestion, psychological burdens and developmental delay including delay in learning to walk and talk. nf-2 usually presents with schwannomas and meningiomas.2,3 there are three varieties of neurofibroma’s: localised, diffuse and plexiform. classically, radiologists have recognised two types of neurofibroma: the discrete mass/nodular form and the diffuse or plexiform variety.2 on mri, plexiform neurofibromas present with the pathognomonic ‘target sign’ depicted as lesions with central hypointensity and surrounding hyperintense rim on t2-weighted images, representing fibro collagenous and myxoid components, respectively. a ‘reverse target sign’, on t1-weighted images after intravenous (iv) gadolinium-based contrast administration, is seen as central enhancement with peripheral hypointensity.4 venous malformations mimic the classical ‘target sign’ seen in plexiform neurofibromas, whereby the central hypointense focus represents a phlebolith in a dilated venous channel. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2.2022.014 interesting medical image figure 1: photograph of the chest of a 27-year-old male patient showing café-au-lait macules and multiple swellings in the arms. https://creativecommons.org/licenses/by-nd/4.0/ don’t miss the target a case of neurofibromatosis type 1 590 | squ medical journal, november 2022, volume 22, issue 4 phleboliths are also noted as a focal hyperintensity on gradient-recalled echo sequences. other mridifferentiating features of venous malformations include a hyperintense, lobulated and septated lesion on t2weighted images and iv contrast enhancement of its cavernous section without arteriovenous shunting on dynamic mri.4 nf-1, with its various manifestations, is a clinical diagnosis and its management requires the involvement of a multidisciplinary team. patients are referred to surgeons to excise the neurofibroma when the patient is symptomatic with pain, there has been a recent increase in size, the tumour results in a neurological deficit or has a high risk of rupture and bleeding. plexiform neurofibromas have significant morbidity due to the way it infiltrates surrounding structures, it’s unpredictable growth and its potential to bleed.5 a u t h o r s’ c o n t r i b u t i o n es conceptualised the manuscript. oh, by, ia and rs performed the literature review. oh, bh, ia, hm, rs and kw drafted the manuscript. es revised the manuscript. all authors approved the final version of the manuscript. references 1. le c, bedocs pm. neurofibromatosis [internet]. treasure island, florida, usa: statpearls publishing, 2022. from: www. ncbi.nlm.nih.gov/books/nbk459329/ accessed: jan 2022. 2. ferner re, gutmann dh. chapter 53 neurofibromatosis type 1 (nf1): diagnosis and management. in: said g, krarup c, eds. handbook of clinical neurology. volume 115. amsterdam, netherlands: elsevier, 2013. pp 939–55. https:// doi.org/10.1016/b978-0-444-52902-2.00053-9. 3. grover dsb, kundra dr, grover dh, gupta dv, gupta dr. imaging diagnosis of plexiform neurofibromaunravelling the confounding features: a report of two cases. radiol case rep 2021; 16:2824–33. https://doi.org/10.1016/j.radcr.2021.06.025. 4. o’keefe p, reid j, morrison s, vidimos a, difiore j. unexpected diagnosis of superficial neurofibroma in a lesion with imaging features of a vascular malformation. pediatr radiol 2005; 35:1250–3. https://doi.org/10.1007/s00247-005-1565-9. 5. stephen e, kariyattil r, mittal a, al-azri f, al-wahaibi k. spontaneous near fatal hemorrhage neurofibromatosis type 1 of the scalp. oman med j 2020; 37:e387. https://doi.org/10.5001/ omj.2022.02. figure 2: magnetic resonance imaging of the left arm of a 27-year-old male patient showing (a) the localised lesion laterally (arrowhead) with plexiform lesion medially (arrow) and (b) an axial view showing the target sign (arrow). the target sign refers to a central area with low signal intensity, surrounded by a high signal intensity and is sometimes referred to as a bull’s eye sign. https://doi.org/10.1016/b978-0-444-52902-2.00053-9. https://doi.org/10.1016/b978-0-444-52902-2.00053-9. https://doi.org/10.1016/j.radcr.2021.06.025. https://doi.org/10.1007/s00247-005-1565-9 https://doi.org/10.5001/omj.2022.02 https://doi.org/10.5001/omj.2022.02 december 2008 no white pages.indd abstract varicella zoster infections are considered to be mild and ubiquitous infections predominantly affecting the paediatric population. however, in adults and in specific groups of patients, such as those who are immunosuppressed, varicella infections can be fulminant and life threatening. we here present a case report of a young female patient with a normal immune system who had a fulminant varicella infection with multiorgan involvement. key words: chickenpox; herpes virus 3, human; rhabdomyolysis; disseminated intravascular coagulation; pneumonia; case report; oman fulminant varicella zoster infection with multiorgan involvement a case report *sudheer p s ahamed,1 abdullah balkhair,2 rajan krishnan2 sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 339-343 sultan qaboos university© submitted 10th february 2008 accepted 29th june 2008 varicella virus infection in humans can result in two distinct clinical syndromes: chicken-pox and herpes zoster. chickenpox, which develops after initial exposure to the virus, is a common trivial illness of childhood characterised by typical exanthem and a self-limited course. however, in adults, varicella can behave differently with much more severity and involvement of different organ systems. 1, 2 this is more common in immunosuppressed patients and those on chemotherapy.3 in the following case report, we present a case of fulminant varicella infection with multiorgan involvement in an immunocompetent young adult. c a s e r e p o r t our patient was a 22 year old, unmarried, female university student; a non-smoker with no history of any significant medical illness. the patient first presented to her local health centre in ibri, oman with a history of sudden onset of severe back ache radiating to both lower limbs. she also had had a mild fever of 2 days duration. the patient was prescribed analgesic medications and discharged home from the primary centre. she presented the next day to the local hospital in ibri with the characteristic rash of chickenpox involving her face and trunk. she continued to be febrile during this presentation and also continued to have severe back ache. the patient had been exposed two weeks previously to chickenpox in her family. she was seen 1department of medicine, armidale rural referral hospital, armidale, new south, wales, australia; 2department of medicine, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: sudheerahamed@hotmail.com أعضاء لعدة املصيب اخلاطف يّ املعدي احلُماقِ ي اقِ النُّطَ يْروس الفَ مرض حالة تقرير كريشنان راجان باخلير، اهللا عبد احامد، سودير الكبار، في لكن ــال. األطف تصيب ما غالبا والتي ــار االنتش ــعة واس املعدية اخلفيفة من األمراض احلماقي النطاقي الفيروس ــدوى ع ــر ــص: يعتب امللخ في نقص من تعاني ال ــابة ش حلالة امرأة تقرير هنا ندرج للحياة. ومهددا خاطفا بالفيروس العدوى يكون املناعة، بنقص املصابني املرضى ــد ــة عن خاص احلماقي. النطاقي بالفيروس جسدها في عديدة أعضاء أصيبت والتي املناعة عمان. الرئة، التهاب يَة، األَوعِ لَ داخِ ُنْتَثِرُ امل ثُّرُ التَّخَ ات، الرُّبَيْدَ الَلُ انْحِ إنسان، ،٣ احلَأل فَيروسُ اق، الكلمات: احلُمَ مفتاح c a s e r e p o r t s u d h e e r p s a h a m e d , a b d u l l a h b a l k h a i r a n d r a j a n k r i s h n a n 340 by the internist on call who made a clinical diagnosis of chickenpox. routine investigations were done and showed elevated liver enzymes with a severely altered profile. her chest radiograph was normal. the patient was admitted to the ibri hospital and started on oral famcyclovir and intravenous ceftriaxone. the patient continued to be febrile throughout her stay in this secondary care institution. the repeat liver function tests showed a further rise and in her liver enzymes and worsening coagulation with high prothrombin time (pt) and activated partial thromboplastin time (aptt). her fibrin degradation product (fdp) value was reported as very high at 640; however, there was no bleeding from any sites of the body. she received fresh frozen plasma (ffp) and the antibiotics and antiviral drug were continued. the patient was transferred the next day to our institution, sultan qaboos university hospital, for further care. on arrival, she was febrile, drowsy and severely tachycardic and tachypneoic with a pulse rate of 140 and respiratory rate of 30. pulse oxymetry revealed her saturation to be 70% in room air. the polymorphic rash with vesicles and swabs was still present, but limited to the face and trunk. the chest examination revealed fine crepitations bilaterally. there were no focal neurological deficits and abdominal examination did not reveal any organomegaly. the liver span was found to be 7 cm clinically. the patient was immediately admitted to the intensive care unit and was started on noninvasive ventilation. blood investigations and an urgent chest x-ray were done revealing bilateral nonhomogenous haziness extending up to the mid zone. the liver functions revealed very high enzymes with aspartate aminotransferase in the range of 5555u/l and alanine aminotransferase 2225 u/l with normal bilirubin. the coagulation profile showed gross derangement with high pt time, aptt and thrombin time values. a complete blood count revealed severe polymorphonuclear leucocytosis with thrombocytopenia. her blood was sent for varicella serology and polymerase chain reaction (pcr) and also for serology for other viral haemorrhagic fevers such as dengue and crimean-congo. the provisional working diagnosis at this stage was fulminant varicella infection with pneumonia, hepatitis and disseminated intravascular coagulation with consumptive coagulopathy along with super added sepsis. the patient was started on acyclovir at a dose of 10 mg/kg 8 hourly and the antibiotics were upgraded to meropenem and amikacin. cryoprecipitate, ffp and platelet concentrate were administered on suggestion of the haematologist. the patient tolerated the noninvasive ventilation for the next 24 hours, but on the second day of admission she desaturated and had to be intubated and mechanically ventilated. she also started to have fresh bleeding from the foley catheter and the nasogastric tube. this was associated with a drop in her haemoglobin. her coagulation profile continued to be deranged in spite of repeated cryoprecipitate and ffp transfusions. her liver functions also continued to worsen. an ultrasound of her abdomen did not reveal any evidence of obstruction to the biliary tract or reduction in liver size. vancomycin was added to cover the possibility of staphylococcal sepsis. her varicella serology was negative for immunoglobulins (igg and igm) indicating the susceptibility for infection and the varicella zoster virus polymerase chain reaction (vzv pcr) in her blood was reported as positive indicating ongoing viraemia. other serological tests, including human immunodeficiency virus (hiv), dengue and crimean-congo fevers were negative. a peripheral smear examination showed evidence of disseminated intravascular coagulation (dic) and suggested sepsis, with no underlying haematological abnormalities. on the third day of admission, the patient continued to complete blood count coagulation profile liver function tests renal function tests haemoglobin(hb)11.2gram/ prothrombin time (pt) 18.8 seconds alanine amino transferase (alt) 1278 u/l sodium (na ) 132mmol/l neutrophil 80% international normalised ratio (inr) 1.65 aspartate aminotransferase (ast) 2550 u/l potassium (k+ ) 4.3mmol/l lymphocyte 16.4% activated partial thromboplastin time (aptt) 40 seconds alkaline phosphatase (alp) 316 u/l urea 1.92 mmol/l (5.4mg/dl) platelets 235 cells/mm3 bilirubin 44.6 micromol/litre (27mg/dl) creatinine 38.89 micromol/litre (0.44mg/dl) table 1: laboratory investigations at ibri hospital f u l m i n a n t va r i c e l l a z o s t e r i n f e c t i o n w i t h m u lt i o r g a n i n v o lv e m e n t 341 be sick and her ventilatory requirements rose significantly. a repeat chest x-ray showed extension of the haziness bilaterally, especially on the left side. an urgent pulmonology opinion was sought and the patient underwent an emergency bronchoscopy during which thick gelatin like mucous plugs were removed from both sides. the lungs cleared significantly after this procedure and the ventilatory requirements in terms of oxygen requirement and positive end-expiratory pressure (peep) started decreasing over the next few days. however, her coagulation continued to be abnormal for the next 3 days although the liver function tests showed a progressive decline in the enzymes, but with a rising bilirubin level. this bilirubin was predominantly unconjugated and was thought to be a result of the ongoing haemolysis. a pcr performed on a bronchoalveolar lavage specimen revealed the deoxyribonucleic acid of the varicella zoster virus. on advice of the haematologist, the patient continued to receive packed red blood cells concentrate, platelet concentrates, ffp and cryoprecipitates based on her coagulation profile. the patient started showing signs of improvement in terms of coagulation profile by the 7th day of admission and over the next few days her ffp and cryoprecipitate requirements came down. bleeding from the catheter and nasogastric tube stopped by the 10th day and the ventilatory parameters showed a steady improvement. the liver function test also gradually improved with normalization of her enzymes and bilirubin. she was extubated on the 14th day of admission, but had a resurgence of fever the next day and a repeat sputum culture grew pseudomonas aeruginosa. she was continued on antibiotics and vigorous chest physiotherapy. she became afebrile two days later and was shifted to the ward on 17th day of admission. the patient continued to improve steadily and was discharged on the 21st day of admission. her varicella serology was repeated in the second week and came out to be positive indicating an acute infection. a repeat vzr pcr was negative. the final diagnosis at discharge was severe varicella zoster infection with varicella hepatitis, pneumonia and coagulopathy. d i s c u s s i o n varicella zoster is a dna virus belonging to the family of herpes viridae and causes the two distinct clinical syndromes of varicella chickenpox and herpes zoster. the attack rate for varicella is approximately 90% in susceptible individuals. in the majority of the cases, especially in children, varicella is a very mild infection characterised by skin lesions, low grade fever and malaise. the skin lesions include maculopapules, vesicles and swabs in various stages of development and appear on the trunk and face initially, before spreading date day-1 day-2 day-3 day-5 day-10 day-12 day-15 day-17 compelete blood count haemoglobin total count neutrophil lymphocyte platelets 10.9 30.9 76.6 18.7 75 6.7 23.2 79 16.8 76 8.3 27.7 88.4 8.7 90 8.4 16.1 77.1 11.3 32 8.2 9.9 61.2 18.8 72 10.2 10.2 72 11.4 203 11.2 12.2 74.9 10.6 494 9.9g/dl 10.7cells/mm3 74.9% 13.4% 495 cells/mm3 liver function test alt ast alp albumin bilirubin protein 2524 5555 357 280 530.1 520 2327 4360 416 270 649 490 860 2958 185 310 906.3 540 245 540 160 280 2907 500 87 89 161 300 1333 600 67 49 155 320 1060 630 49u/l 49 u/l 170 u/l 350 g?l 974 чmol/litre 710 g/l coagulation profile pt inr aptt thrombin time 18.2 1.77 76 54.6 14.6 1.42 58 59.4 13 1.25 48 34.6 11 1.05 39 24 11.1 1.06 38 13.8 11.4 1.09 36 13.8 11 seconds 1.05 32.7 seconds 13.9 seconds varicella serology -ve igm+ alt = alanine aminotransferase; ast = aspartate aminotransferase; alp = alkaline phosphatase; pt = prothombin time; inr = international normalized ratio; aptt = activated partial thromboplastin time table 2: results of laboratory investigations on the patient s u d h e e r p s a h a m e d , a b d u l l a h b a l k h a i r a n d r a j a n k r i s h n a n 342 to other parts of the body. the patient is infectious 48 hours before the onset of the rash and throughout the vesicle development until all the vesicles are crusted. the severity of rash varies from person to person. immunocompromised patients tend to have a more severe rash and are more prone to visceral involvement.3 our patient was a 22 year old healthy female student and the reason for the fulminating nature of her varicella remains unclear. the diagnosis of varicella was confirmed serologically as well as with vzv pcr. she initially had severe back ache, which is not a characteristic presentation of varicella. the cause for this symptom could be a myeloradiculopathy which has been reported as a neurological complication of varicella infection. 3 the rapidity of clinical deterioration and involvement of multiple organ systems of the body was the most striking feature in this patient. the patient had a clear chest x-ray initially, only developing features of pneumonia on the 4th day of admission, followed by rapid respiratory deterioration needing urgent intubation. special emphasis has to be placed on the role of bronchoscopy in these patients, which will help in clearing the thick gelatin like mucous plugs, especially in cases of nonresolving pneumonias. the severe coagulopathy leading to disseminated intravascular coagulation needed constant support with cryoprecipitate and ffp along with platelet concentrates. the use of appropriate antibiotics to prevent bacterial infections, especially by streptococcus and staphylococcus, also helped in controlling the features of sepsis in this patient. our case emphasizes the fact that varicella infection in immunocompetent adults can be severely complicated and potentially fatal. various studies have shown the rate of visceral involvement in varicella infection in the immunocompromised to be around 3050% and, in the absence of treatment, 15% of cases can be fatal.1, 4 however, there are no authoritative studies to show the magnitude of visceral involvement or fatality with varicella infection in immunocompetent individuals. in a recent study conducted in saudi arabia, the complication rate in varicella infection was found to be 1.5% and the overall fatality rate was found to be 0.05%.5 another study in germany, done to assess the epidemiological pattern of varicella complications, revealed the majority as neurological with encephalitis leading the list.6 this was followed by infectious complications; in particular infection by streptococcus pyogenes was associated with a worse outcome. other known complications of varicella include myocarditis, hepatitis, rhabdomyolysis with renal failure, acute glomerulonephritis and arthritis.7, 8 the possibility of these complications and the unpredictability of the severity of varicella infection in adults indicates the need for early treatment with antivirals and immunisation in seronegative adults.9 c o n c l u s i o n our case demonstrates the fact that varicella infections can be life threatening even in immunocompetent adult patients. the pattern of involvement of multiple systems is also of interest and made the management of this patient quite challenging. the importance of supportive care and significance of early bronchosfigure 1: gelatinous plugs from the lung being removed bronchoscopically figure 2: chest x-ray on the day of admission f u l m i n a n t va r i c e l l a z o s t e r i n f e c t i o n w i t h m u lt i o r g a n i n v o lv e m e n t 343 copy for the removal of gelatinous mucous plugs in the management of varicella pneumonia needs to be stressed in addition to antiviral therapy. our case also rightly raises the question of the importance of vaccination against varicella virus infections at least in patients with high risk of developing a severe disease.10 r e f e r e n c e s 1. whitley rj. varicella zoster virus infections. in: harrisons principles of internal medicine. 16th ed. new york: mcgraw hill, 2006. p. 1042-1045. 2. hollensten u, thalahamer f, burggmann h. dic and rhabdomyolysis in fulminant varicella infection case report and review of literature. infection 1998; 306308. 3. arvin. a. ageing, immunity and varicella zoster viruses. n eng j med june 2005; 352:2266-2267. 4. brunnel pa. varicella zoster infections. in: cecil text book of medicine. philadeplhia: wb saunders & co, 1985. p. 88 5. almuneef m, memish za, balkeyhh, altoaiby b, helmy m. chickenpox complications in saudi arabia: is it time for routine varicella vaccinations? int j inf diseases 2006; 10:156-161. 6. ziebold c, vonkries r, lang r, weigl j, schmitt hj. severe complications of varicella in previously healthy children in germany a 1 year survey. paediatrics 2001;108:e79 7. al langawi m, al-marri mr, al soub h. rhabdomyolysis associated with varicella infection. int j clinical practice 2001; 55:484-485. 8. cameron jc, allan g, johnston agf. severe complications of chickenpox in hospitalized children in uk and ireland. arch dis childhood; 2007; 92:1051-1052. 9. gershon aa, katz sl. perspective on varicella vaccine. j infect dis 2008; 1:197. 10. varicella vaccine information. centre for disease control. from www.cdc.gov. accessed december 2007. 1department of community & mental health, college of nursing, sultan qaboos university, muscat, oman; 2department of psychiatry, kasturba medical college, and 4department of data science, prasanna school of public health, manipal academy of higher education, udupi, india; 3department of nephrology, kasturba hospital, udupi, india *corresponding author’s e-mail: blessy.v@squ.edu.om دراسة متابعة حول أتثري العالج السلوكي املعريف على االلتزام ابلغسيل الكلوي جتربة عشوائية منتظمة بلي�شي بر�بها فال�شار�ج، �رشيباثي بهات، ر�فيندر� بر�بهو، �آ�شا كاماث abstract: objectives: patients with chronic kidney disease (ckd) undergoing haemodialysis often experience a myriad of psychosocial problems, resulting in poor adherence to their therapeutic regimen. this study aimed to examine the effect of cognitive behaviour therapy (cbt) on dialysis, fluid, drug and diet adherence among a previously reported sample of ckd patients undergoing haemodialysis. methods: a randomised controlled trial was conducted between january 2013 to febrary 2014 on a random selection of 67 ckd patients attending a tertiary multispecialty hospital in india. the experimental group (n = 33) was exposed to cbt, whereas the control group (n = 34) received non-directive counselling. a haemodialysis adherence scale was developed and used to assess adherence to the treatment regimen. the effect size was calculated using cohen’s d statistics. results: at six months, mean reductions from baseline were observed in the experimental group in terms of interdialytic weight gain (−1.23 kg; effect size: 0.57), systolic blood pressure (−22.18 mmhg; effect size: 0.71) and diastolic blood pressure (−10.06 mmhg; effect size: 0.72), whereas mean increases were noted in haemoglobin (+0.75 g/dl; effect size: 0.31) and adherence to dialysis (+0.94; effect size: 0.51), fluids (+16.34; effect size: 2.30), diet (+61.19; effect size: 4.75) and drugs (+10.73; effect size: 1.3). differences from baseline were significantly higher in the experimental group compared to the control group (p = 0.001 each). conclusion: these results show that cbt is more effective than non-directive counselling for improving therapeutic adherence and physiological, clinical parameters among ckd patients undergoing haemodialysis. keywords: chronic kidney disease; hemodialysis; patient adherence; cognitive behavior therapy; hemoglobin; weight gain; blood pressure; randomized controlled trial. امللخ�ص: الهدف: غالًبا ما يعاين �ملر�شى �مل�شابون مبر�ض �لكلى �ملزمن �لذين يخ�شعون للغ�شيل �لكلوي من عدد ال يح�شى من �مل�شكالت �لنف�شية و�الجتماعية مما يوؤدي �إىل �شعف �اللتز�م بنظامهم �لعالجي. هدفت هذه �لدر��شة �إىل فح�ض تاأثري �لعالج �ل�شلوكي �ملعريف على �اللتز�م بالغ�شيل �لكلوي و�لتقيد بال�شو�ئل و�الأدوية و�لنظام �لغذ�ئي يف عينة مت �الإبالغ عنها �شابًقا من مر�شى �لكلى �ملزمن �لذين يخ�شعون للغ�شيل �لكلوي. ا من مر�شى �لكلى �ملزمن و�لذين مت �ختيارهم ع�شو�ئيا الطريقة: �أجريت جتربة ع�شو�ئية منتظمة من يناير 2013 �إىل فرب�ير 2014 على 67 مري�شً ممن يح�رشون �إىل م�شت�شفى ثالثي متعدد �لتخ�ش�شات يف �لهند. تعر�شت �ملجموعة �لتجريبية )n = 33( للعالج �ملعريف �ل�شلوكي، بينما تلقت �ملجموعة �ملرجعية )n = 34( م�شورة غري توجيهية. مت تطوير مقيا�ض �اللتز�م بالغ�شيل �لكلوي و��شتخد�مه لتقييم �اللتز�م بنظام �لعالج. مت ح�شاب حجم �لتاأثري با�شتخد�م �إح�شائيات كوهني د. النتائج: لوحظت باملجموعة �لتجريبية خالل �شتة �أ�شهر �نخفا�شات يف متو�شط زيادة �لوزن بني جل�شات �لغ�شيل )0.57 :حجم �لتاأثري؛ كجم 1.23-( و�شغط �لدم �النقبا�شي )0.71 :حجم �لتاأثري؛ ملم زئبق 22.18-( و�شغط �لدم �النب�شاطي )0.72 :حجم �لتاأثري؛ ملم زئبق 10.06-( مقارنة بخط �الأ�شا�ض، يف حني لوحظت زياد�ت يف متو�شط �لهيموجلوبني )0.31 :حجم �لتاأثري؛ جم/دي�شيلرت 0.75+( و�اللتز�م بالغ�شيل �لكلوي )0.51 :حجم �لتاأثري؛ 0.94+( و�لتقيد بال�شو�ئل )2.30 :حجم �لتاأثري؛ 16.34+( و�لنظام �لغذ�ئي )4.75 :حجم �لتاأثري؛ 61.19+( و�الأدوية )1.3 :حجم �لتاأثري؛ 10.73+(. كانت �لفروق عن خط �الأ�شا�ض �أعلى بكثري يف �ملجموعة �لتجريبية مقارنة باملجموعة �ملرجعية )لكل منهما p = 0.001(. اخلال�صة: تظهر هذه �لنتائج �أن �لعالج �ملعريف �ل�شلوكي �أكرث فعالية من �مل�شورة غري �لتوجيهية لتح�شني �اللتز�م �لعالجي و�ملعايري �لف�شيولوجية و�ل�رشيرية بني �ملر�شى �مل�شابني مبر�ض �لكلى �ملزمن �لذين يخ�شعون للغ�شيل �لكلوي. الكلمات املفتاحية: مر�ض �لكلى �ملزمن؛ غ�شيل كلوي؛ �لتز�م �ملري�ض؛ عالج �شلوكي معريف؛ هيموجلوبني؛ زيادة �لوزن؛ �شغط �لدم؛ جتربة ع�شو�ئية منتظمة. follow-up study on the effect of cognitive behaviour therapy on haemodialysis adherence a randomised controlled trial *blessy p. valsaraj,1 shripathy m. bhat,2 ravindra prabhu,3 asha kamath4 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e58–65, epub. 15 mar 21 submitted 4 feb 20 revisions req. 25 mar & 10 jun 20; ; revisions recd. 13 may & 26 jun 20 accepted 1 jul 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.008 clinical & basic research advances in knowledge to the best of the authors’ knowledge, this is the first study in india to evaluate the effect of cognitive behaviour therapy (cbt) on patients with chronic kidney disease (ckd) undergoing haemodialysis using both objective physiological indicators along with subjective measures of therapeutic adherence. application to patient care the results of this follow-up study support the inclusion of cbt in the routine management of ckd to improve treatment adherence. such measures may increase the cost-effectiveness of care and decrease the burden of disease in this patient population. https://creativecommons.org/licenses/by-nd/4.0/ blessy p. valsaraj, shripathy m. bhat, ravindra prabhu and asha kamath clinical and basic research | e59 chronic kidney disease (ckd) is one of the 20 most common disorders globally, with a prevalence rate of 11–13%.1 according to the global burden of disease study, there was a 32% increase in renal failure-related deaths between 2005 and 2015.2 in kidney disease, the management of fluctuations in blood pressure, blood sugar and other parameters is challenging and there is a high risk of death due to heart disease and other causes.3 ongoing haemodialysis is a critical and life-sustaining form of treatment for patients diagnosed with ckd, especially as kidney transplantation is not always feasible for legal, financial or medical reasons.4 as such, there has been a considerable rise in the usage of maintenance dialysis in recent years.5 however, patients often find it difficult to adhere to a regular regimen involving the strict administration and control of fluid, diet, medications and many hours of dialysis.6 mcdade-montez et al. reported that up to 18% of patients quit haemodialysis within four years due to depression.7 other researchers have similarly found depressive symptoms to represent a significant early warning sign of poor outcomes and mortality among ckd patients.8,9 in india, adherence to dialysis is often low due to the lack of standard dialysis services in government hospitals and inadequate medical insurance to support treatment costs at private facilities.5 end-stage renal disease represents a considerable drain on healthcare funding due to the enormous costs and prolonged nature of treatment, particularly among developing countries.10 non-adherence to dialysis is associated with higher rates of morbidity and mortality.11 moreover, the aftermath of non-adherence in the context of chronic illnesses such as ckd often results in the wasting of valuable healthcare resources and poor health outcomes and quality of life.12 in turn, adherence to haemodialysis treatment and stable laboratory and physiological indicators are related to positive healthcare outcomes.13 interventions involving cognitive or behavioural components have been shown to improve patient compliance.8,14 cognitive behaviour therapy (cbt) is a form of psychotherapy that aims to elicit, examine and replace negative thoughts to encourage emotional regulation and positive behavioural changes.15 this type of therapy is considered to be especially useful for patients with chronic diseases who face difficulties in following strict therapeutic regimens or to help alleviate common psychological conditions such as anxiety and depression.16–20 for example, dysfunctional thoughts such as ‘nothing can improve my condition’ can result in harmful emotions and practices such as missing dialysis sessions or skipping prescribed medicines, further reinforcing problematic beliefs.17 a previous randomised controlled trial was conducted to determine the effect of cbt on anxiety and depression among 67 patients undergoing haemodialysis.20 there was a significant reduction in mean anxiety (f = 76.739; p = 0.001) and depression (f = 57.326; p = 0.001) scores in the experimental group compared to the control group. however, the initial study focused solely on improvements in anxiety and depression rather than patient adherence to treatment.20 therefore, the current follow-up study’s objective was to examine the efficacy of cbt intervention on therapeutic adherence among patients with ckd, including dialysis, fluid, diet, and drug adherence. methods as previously reported, a randomised controlled trial was conducted between january 2013 to febrary 2014 at the haemodialysis unit of a tertiary multispecialty hospital in india.20 the trial was conducted in accordance with the consolidated standards of reporting clinical trials guidelines.21 the target population consisted of ckd patients aged 20 to 65 years undergoing maintenance dialysis for at least one year and who had scored >7 in any of the subscales of the hospital anxiety depression scale.20 patients who could not read and write either english or the regional language of kannada were excluded from the trial, as were patients who required ambulation assistance, those waiting for a kidney transplant and individuals who were being treated for a psychiatric illness. in order to detect a difference of 25% and at a power of 80% and a 95% confidence level, the necessary sample size was calculated to be 33, accounting for a 20% attrition rate and based on an expected prevalence of general treatment adherence of 50%. a total of 150 patients were screened for eligibility, of which 60 were excluded, 10 dropped out and 13 discontinued treatment, resulting in a final sample of 67 participants.20 computer-generated block randomisation was applied to assign patients to either group.22 a total of 33 and 34 participants were thus allocated to the experimental and control groups, respectively. both groups were given routine care during dialysis; however, the experimental group received cbt, whereas the control group received nondirective counselling. the study was single-blinded by concealing the participants to the type of intervention follow-up study on the effect of cognitive behaviour therapy on haemodialysis adherence a randomised controlled trial e60 | squ medical journal, february 2021, volume 21, issue 1 received. in addition, group allocation was kept confidential from dialysis staff and nephrologists as these individuals recorded information regarding certain adherence indicators, such as interdialytic weight gain (idwg), blood pressure and haemoglobin. full details of the study design have been previously published elsewhere [figure 1].20 according to group allocation, a specialist in psychiatric mental health nursing with prior cbt training administered either cbt or non-directive counselling to the patients.20 the therapist spent an equal amount of time with patients in both groups, with all participants receiving information concerning the importance of adherence. the cbt was admin istered over the course of 10 individual sessions conducted on a weekly basis, with each session lasting approximately 50 minutes to one hour. cognitive, behavioural and didactic techniques were taught in order to alter maladaptive thoughts and non-adherent behaviours.20 a specific cbt module (including the objectives, techniques and roles of both the therapist and patient), diary (with daily homework for patients) and manual (reference material for the therapist on how to carry out the therapy) were developed. these documents were validated by nine experts in related fields, including clinical psychologists, psychiatric nurses, psychiatrists, nephrologists and dieticians. data were collected via patient records, laboratory testing and personal interviews with the patients and caregivers at three distinct points in time: (1) at base line before the intervention; (2) at three months post intervention; and (3) at six months post-intervention. a haemodialysis adherence scale was developed specif ically for the purposes of this study. appropriate and relevant items were generated following an extensive literature review and discussion with experienced neph rologists, dialysis technicians, dieticians and dialysis patients and their caregivers. the final version of the scale included five sub scales: the adherence indicators, dialysis adherence, fluid adherence, diet adherence and drug adherence subscales. items in the adherence indicators section consisted of data sourced directly from the patients’ laboratory results and medical records, while inform ation in the dialysis, fluid, diet and drug adherence subscales were collected during personal interviews with the participants, corroborated by interviews with the patient’s caregiver (i.e. the parent, spouse or child regularly accompanying the patient to the hospital for the dialysis). figure 1: flowchart showing the randomised controlled trial design utilised in the current study. reproduced with permission from valsaraj bp, bhat sm, latha ks. cognitive behaviour therapy for anxiety and depression among people undergoing haemodialysis: a randomised control trial.20 blessy p. valsaraj, shripathy m. bhat, ravindra prabhu and asha kamath clinical and basic research | e61 the adherence indicators subscale assessed phys iological markers of adherence based on laboratory results and data from the patients’ clinical records. weight and blood pressure measurements were documented by the dialysis unit staff directly using calibrated electronic weighing machine and sphygmomanometers while haemoglobin was tested in the hospital laboratory. an average of two consecutive weight measurements were taken to indicate actual idwg, as the gap between two dialysis sessions in a given week varied between two and three days. the dialysis adherence subscale consisted of five items assessing the frequency of skipping, shortening or delaying dialysis sessions, clarifying doubts with the healthcare team and the need for extra dialysis sessions (i.e. as an emergency measure in case of breathing difficulties due to fluid overload). the fluid adherence subscale consisted of 15 items concerning fluid intake and fluid control behaviours. the diet adherence subscale consisted of 55 items assessing the consumption of various food categories (i.e. cereals, pulses, vegetables, fish, meat, fruits, nuts, snacks, sweets, pickles and oils) and cooking methods.23 the drug adherence subscale consisted of 11 items concerning the frequency of buying and taking prescribed medic ations or supplements (i.e. phosphorous binders or multivitamin and calcium supplements). compliance table 1: baseline physiological indicators and adherence scores according to group allocation* among patients with chronic kidney disease undergoing haemodialysis at a tertiary multispecialty hospital in india (n = 67) indicator mean ± sd f value experimental group (n = 33) control group (n = 34) idwg in kg 4.47 ± 0.92 4.39 ± 0.78 1.35 systolic bp in mmhg 167.33 ± 19.68 163.59 ± 18.53 0.04 diastolic bp in mmhg 98.24 ± 9.52 95.35 ± 8.29 0.15 hb in g/dl 7.55 ± 1.18 7.62 ± 1.09 0.32 dialysis adherence score 13.30 ± 1.02 13.38 ± 0.95 0.07 fluid adherence score 34.27 ± 2.88 33.85 ± 2.46 0.30 diet adherence score 138.45 ± 5.85 136.18 ± 4.69 0.14 drug adherence score 22.39 ± 4.09 22.71 ± 3.47 2.59 sd = standard deviation; idwg = interdialytic weight gain; bp = blood pressure; hb = haemoglobin. *the experimental group received cognitive behaviour therapy while the control group received non-directive counselling. table 2: differences in physiological indicators and adherence scores over time according to group allocation* among patients with chronic kidney disease undergoing haemodialysis at a tertiary multispecialty hospital in india (n = 67) variable mean ± sd df f ratio p value effect size experimental group (n = 33) control group (n = 34) idwg in kg baseline 4.47 ± 0.92 4.39 ± 0.78 2, 130 60.41 0.001 0.57at 3 months 3.18 ± 0.77 4.30 ± 0.57 at 6 months 3.24 ± 0.63 4.69 ± 0.47 systolic bp in mmhg baseline 167.33 ± 19.68 163.59 ± 18.53 2, 130 76.66 0.001 0.71at 3 months 144.85 ± 13.49 162.65 ± 17.81 at 6 months 145.15 ± 12.78 165.59 ± 17.09 diastolic bp in mmhg baseline 98.24 ± 9.52 95.35 ± 8.29 2, 130 29.01 0.001 0.72at 3 months 87.27 ± 6.26 94.12 ± 7.83 at 6 months 88.18 ± 6.35 95.88 ± 7.83 hb in g/dl baseline 7.55 ± 1.18 7.62 ± 1.09 2, 130 44.69 0.001 0.31at 3 months 8.08 ± 1.19 7.52 ± 1.12 at 6 months 8.30 ± 1.23 7.52 ± 0.95 sd = standard deviation; df = degrees of freedom; idwg = interdialytic weight gain; bp = blood pressure; hb = haemoglobin. *the experimental group received cognitive behaviour therapy while the control group received non-directive counselling. follow-up study on the effect of cognitive behaviour therapy on haemodialysis adherence a randomised controlled trial e62 | squ medical journal, february 2021, volume 21, issue 1 with erythropoietin and antihypertensive medications was excluded from the latter subscale after a pilot study, since these agents were found not to be prescribed to all patients. the scoring for each subscale was based on the responses to each of the items. in the dialysis and drug adherence subscales, most of the items were scored based on the frequency of the behaviour on a 3-point scale as either 1 for ‘always’, 2 for ‘sometimes’ or 3 for ‘never’. in the fluid and diet subscales, scoring was based on the frequency of consumption of the drink or food item as either 1 for ‘daily’, 2 for ‘once per week’, 3 for ‘once every 15 days’, 4 for ‘once per month’ or 5 for ‘never’. reverse scoring was applied for positive behaviours; as such, a high score indicated high adherence. the scale was validated by nine experts from related disciplines and was pretested for feasibility on five patients. in addition, inter-rater and test-retest reliability was found to be acceptable (r = 0.9 and 0.89, respectively). data were analysed using the statistical package for the social sciences (spss), version 22 (ibm corp., armonk, new york, usa). a repeated measure analysis of variance model was applied without adjusting for baseline variables to compare outcomes both within and between the two groups. differences were calculated between mean variables or scores at baseline compared to those at six months for both groups. the effect size was calculated using cohen’s d statistics. a p value of <0.050 was considered stat istically significant. ethical approval for this study was obtained from the institutional ethics committee of kasturba hospital, karnataka, india (ecr/146/inst/ka/2013). administrative permission to conduct the study was taken from the medical superintendent and the unit head of the dialysis unit. all participants provided informed consent after receiving information regarding the nature, duration and possible risks and benefits of the study including the right to withdraw at any point. results this follow-up study included 67 previously reported patients with ckd undergoing maintenance dialysis.18 as described elsewhere, the majority of patients in the experimental and control groups were 43–65 years old (67% and 66%, respectively), male (70% and 71%, respectively), married (79% and 79%, respectively) and had started dialysis treatment one to three years prior to data collection (58% and 56%, respectively).20 the physiological indicators and adherence scores of the groups at baseline are shown in table 1. at six months, there was a significant reduction in idwg in the experimental group compared to the control group (−1.23 kg versus −0.3 kg; effect size: 0.57; p = 0.001). in addition, there was a significant difference in both systolic (−22.18 mmhg versus +2 mmhg; effect size: 0.71; p = 0.001) and diastolic (−10.06 mmhg versus +0.53 mmhg; effect size: 0.72; p = 0.001) blood pressure at six months. there was also a significant increase in haemoglobin in the experimental group compared to the control group (+0.75 g/dl versus −0.1 g/dl; effect size: 0.31; p = 0.001) at six months [table 2]. furthermore, there was a significant increase in dialysis adherence scores at six months in the experimental group compared to the control group (+0.94 versus −0.06; effect size: 0.51; p = 0.001). there was also a significant increase in fluid adherence scores (+16.34 versus +1.21; effect size: 2.30; p = 0.001). at six months, the experimental group's diet adherence scores improved significantly compared to the control group (+61.19 versus +2.17; effect size: 4.75; p = 0.001). finally, the increase in drug adherence scores at six months was significantly higher in the experimental group than the control group (+10.73 versus +2.38; effect size: 1.3; p = 0.001) [figure 2]. figure 2: chart showing mean adherence scores over time among patients with chronic kidney disease undergoing haemodialysis at a tertiary multispecialty hospital in india (n = 67). the experimental group (n = 33) received cognitive behaviour therapy while the control group (n = 34) received non-directive counselling. blessy p. valsaraj, shripathy m. bhat, ravindra prabhu and asha kamath clinical and basic research | e63 discussion the current study provides evidence that cbt resulted in a considerable increase in overall patient adherence to treatment compared to a control group receiving non-directive counselling, with significant improve ments noted in terms of idwg, systolic blood pressure, diastolic blood pressure, haemoglobin, dialysis adherence, fluid adherence, diet adherence and drug adherence. in particular, these improvements were sustained at both three and six months following the intervention. thus, the present study's findings support those of earlier research indicating that cognitive and behavioural techniques have a significant impact on compliance to recommended diet, fluids, drugs and dialysis.14,24 in another randomised controlled trial, sharp et al. found that cbt resulted in a reduction in mean idwg among 56 patients receiving haemodialysis, with a significant difference between initial and follow-up weight values over a long-term assessment (p <0.001), a finding indicative of improved adherence over time.17 cukor et al. similarly affirmed that 65 haemodialysis patients receiving cbt experienced more significant improvements in idwg compared to a wait-list control group (p = 0.002).25 in contrast, nozaki et al. observed a reduction in daily weight gain compared to baseline measurements among both haemodialysis patients receiving nurse-delivered cbt patient educ ation and those receiving structured patient education; however, the cbt group demonstrated longer maint enance of weight gain improvements (12 weeks versus eight weeks).26 in the current study, it was anecdotally observed that participants were able to make dietary choices with a greater degree of confidence after attending the cbt sessions; this form of therapy helped them to feel responsible for their adherence behaviours, whereas before they felt hopeless and less attentive to their treatment as a whole. with regards to fluid adherence, sagawa et al. reported that cbt resulted in a high rate (65%) of optimal liquid consumption during the intervention phase among 10 japanese patients on chronic haemodialysis, with patients achieving their fluid intake goal approximately 75% of the time without the need for personalised reinforcement of the behaviour.27 in turn, anson et al. described a patient with a history of fluid overload and non-adherence who was able to reduce his daily fluid intake from 2.7–4.4 l to <1.8 l after undergoing cbt.28 the researchers also noted a decline in both relapse frequency and the total amount of liquid consumed throughout therapy.28 hare et al. reported a significant longitudinal difference in oedematous status among 15 patients on peritoneal dialysis with a history of non-adherence to fluid restrictions who underwent an intervention involving educational, cognitive and behavioural components, a finding which was considered indicative of improvements in adherence to fluid self-management behaviours.29 on par with the present study's findings, moattari et al. identified a significant difference in systolic blood pressure, diastolic blood pressure, idwg and haemoglobin and haematocrit levels in the experimental group following an empowerment programme with comparable cognitive and behavioural components.30 in contrast, barnett et al. found that pre-dialysis mean blood pressure did not improve significantly following a patient education programme among 26 non-compliant patients with end-stage renal disease.31 yurtkuran et al. found that a 12-week yogabased exercise programme improved erythrocyte and haematocrit counts by 11% and 13%, respectively, among 37 haemodialysis patients.32 cbt intervention in the present study also had an activity component in the fifth session in which the participants were encouraged to rate the present level of activity from 1 to 10 and they were reinforced to gradually increase the level of overall activity including any form of exercise of their choice. the present study obtained a large effect size on fluid, diet and drug adherence, a medium effect size on idwg, blood pressure and dialysis adherence and a small effect size on haemoglobin. likely, the marked reduction in fluid consumption and improvements in diet and drug adherence contributed to the changes in other adherence indicators such as idwg, blood pressure and haemoglobin. however, participants with low levels of haemoglobin at baseline may have had ongoing blood loss due to poor adherence to erythropoietin based on the high cost of this type of treatment. unfortunately, it was not possible to include other laboratory parameters which might be better indicators for drug and dietary adherence, such as serum phosphate and serum albumin, due to lack of consent for these tests from the participants. as the tests were paid for by the patients themselves, only essential laboratory investigations could be ordered by the treatment team. moreover, the treatment team was careful to avoid adding to the patients' financial burden, particularly as many individuals had lost their jobs as a result of their disease. in addition, many participants claimed that they wanted to avoid any ‘unnecessary’ blood loss, which they believed would ensue from such testing. the current study was subject to certain limitations. it is possible that participants in the experimental and control groups may have communicated details of the chosen intervention with each other. moreover, the follow-up study on the effect of cognitive behaviour therapy on haemodialysis adherence a randomised controlled trial e64 | squ medical journal, february 2021, volume 21, issue 1 results may have been affected by measurement bias. however, it was observed that most exchanges of information between participants in different groups focused primarily on day-to-day symptoms and diseaserelated issues rather than adherence. furthermore, most patients arrived at the haemodialysis unit at their exact appointment times which were staggered over different shifts so that they had less opportunity to interact with each other. finally, data were collected using three different methods—reviews of the patient records, laboratory testing and personal interviews with the patients and caregivers—in order to avoid potential contamination of the data and measurement bias. conclusion when used as an adjunct therapy for patients under going maintenance haemodialysis, cbt improves dialysis, fluid, diet and drug adherence and is beneficial for reg ulating physiological indicators of therapeutic adherence such as idwg, blood pressure and haemoglobin. in light of these findings, cbt is recommended among ckd patients to improve therapeutic adherence in this population. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. hill nr, fatoba st, oke jl, hirst ja, o’callaghan ca, lasserson ds, et al. global prevalence of chronic kidney disease: a systematic review and meta-analysis. plos one 2016; 11:e0158765. https://doi.org/10.1371/journal.pone.0158765. 2. wang h, naghavi m, allen c, barber rm, bhutta za, carter a, et al. global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the global burden of disease study 2015. lancet 2016; 388:1459–544. https://doi. org/10.1016/s0140-6736(16)31012-1. 3. centers for disease control and prevention. national chronic kidney disease fact sheet, 2017. from: www.cdc.gov/diabetes/ pubs/pdf/kidney_factsheet.pdf accessed: jun 2020. 4. shin sj, lee jh. hemodialysis as a life-sustaining treatment at the end of life. kidney res clin pract 2018; 37:112–18. https:// doi.org/10.23876/j.krcp.2018.37.2.112. 5. valsaraj bp, bhat sm, prabhu r, dinesh n. a qualitative research on the experience of haemodialysis in south karnataka: lived experience of persons undergoing haemodialysis. j krishna inst med sci univ 2014; 3:90–100. https://doi.org/10.9790/195903123135. 6. peterson ra, kimmel pl, sacks cr, mesquita ml, simmens sj, reiss d. depression, perception of illness and mortality in patients with end-stage renal disease. int j psychiatry med 1991; 21:343–54. https://doi.org/10.2190/d7va-fweu-jn5y-td3e. 7. mcdade-montez ea, christensen aj, cvengros ja, lawton wj. the role of depression symptoms in dialysis withdrawal. health psychol 2006; 25:198–204. https://doi.org/10.1037/02786133.25.2.198. 8. thomas b, wulf b, bikbov b, perico n, cortinovis m, de vaccaro kc, et al. maintenance dialysis throughout the world in years 1990 and 2010. j am soc nephrol 2015; 26:2621–33. https://doi.org/10.1681/asn.2014101017. 9. nesse rm. is depression an adaptation? arch gen psychiatry 2000; 57:14–20. https://doi.org/10.1001/archpsyc.57.1.14. 10. lysaght mj. maintenance dialysis population dynamics: current trends and long-term implications. j am soc nephrol 2002; 13:s37–40. 11. morgan l. a decade review: methods to improve adherence to the treatment regimen among hemodialysis patients. nephrol nur j 2000; 27:299–304. https://doi.org/10.1111/j.17 55-6686.2001.tb00127.x. 12. denhaerynck k, manhaeve d, dobbels f, garzoni d, nolte c, de geest s. prevalence and consequences of non-adherence to hemodialysis regimens. am j crit care 2007; 16:222–35. https://doi.org/10.1097/jnr.0000000000000309. 13. world health organization. adherence to long-term therapies: policy for action meeting report, 4-5 june 2001. from: https:// apps.who.int/iris/handle/10665/66984 accessed: jun 2020. 14. kaveh k, kimmel pl. compliance in hemodialysis patients: multidimensional measures in search of a gold standard. am j kidney dis 2001; 37:244–66. https://doi.org/10.1053/ajkd.20 01.21286. 15. beck, at. advances in cognitive theory and therapy. annu rev clin psychol 2014; 10:1–24. https://doi.org/10.1146/annurevclinpsy-032813-153734. 16. matteson ml, russell c. interventions to improve hemodialysis adherence: a systematic review of randomised-controlled trials. hemodial int 2010; 14:370–82. https://doi.org/10.1111/j.15424758.2010.00462.x. 17. sharp j, wild mr, gumley ai, deighan cj. a cognitive behavioral group approach to enhance adherence to hemodialysis fluid restrictions: a randomised controlled trial. am j kidney dis 2005; 45:1046–57. https://doi.org/10.1053/j.ajkd.2005.02.032. 18. duarte ps, miyazaki mc, blay sl, sesso r. cognitive-behavioral group therapy is an effective treatment for major depression in hemodialysis patients. kidney int 2009; 76:414–21. https://doi. org/10.1038/ki.2009.156. 19. cukor d. use of cbt to treat depression among patients on hemodialysis. psychiatr serv 2007; 58:711–12. https://doi. org/10.1176/appi.ps.58.5.711. 20. valsaraj bp, bhat sm, latha ks. cognitive behaviour therapy for anxiety and depression among people undergoing haemo dialysis: a randomised control trial. j clin diagn res 2016; 10:vc06–10. https://doi.org/10.7860/jcdr/2016/18959.8383. 21. schulz kf, altman dg, moher d. consort 2010 statement: updated guidelines for reporting parallel group randomised trials. j pharmacol pharmacother 2010; 1:100–7. https://doi. org/10.4103/0976-500x.72352. 22. friedman lm, furberg cd, demets dl. fundamentals of clinical trials, 3rd ed. new york, usa: springer, 1998. 23. valsaraj bp, valsaraj p, bhat sm, prabhu r, george a. devel opment of dietary guidelines for persons undergoing hemo dialysis. iosr j nurs health sci 2014; 3:31–5. https://doi. org/10.9790/1959-03123135. https://doi.org/10.1371/journal.pone.0158765 https://doi.org/10.1016/s0140-6736%2816%2931012-1 https://doi.org/10.1016/s0140-6736%2816%2931012-1 https://doi.org/10.23876/j.krcp.2018.37.2.112 https://doi.org/10.23876/j.krcp.2018.37.2.112 https://doi.org/10.9790/1959-03123135 https://doi.org/10.9790/1959-03123135 https://doi.org/10.2190/d7va-fweu-jn5y-td3e https://doi.org/10.1037/0278-6133.25.2.198 https://doi.org/10.1037/0278-6133.25.2.198 https://doi.org/10.1681/asn.2014101017 https://doi.org/10.1001/archpsyc.57.1.14 https://doi.org/10.1111/j.1755-6686.2001.tb00127.x https://doi.org/10.1111/j.1755-6686.2001.tb00127.x https://doi.org/10.1097/jnr.0000000000000309 https://doi.org/10.1053/ajkd.2001.21286 https://doi.org/10.1053/ajkd.2001.21286 https://doi.org/10.1146/annurev-clinpsy-032813-153734 https://doi.org/10.1146/annurev-clinpsy-032813-153734 https://doi.org/10.1111/j.1542-4758.2010.00462.x https://doi.org/10.1111/j.1542-4758.2010.00462.x https://doi.org/10.1053/j.ajkd.2005.02.032 https://doi.org/10.1038/ki.2009.156 https://doi.org/10.1038/ki.2009.156 https://doi.org/10.1176/appi.ps.58.5.711 https://doi.org/10.1176/appi.ps.58.5.711 https://doi.org/10.7860/jcdr/2016/18959.8383 https://doi.org/10.4103/0976-500x.72352 https://doi.org/10.4103/0976-500x.72352 https://doi.org/10.9790/1959-03123135 https://doi.org/10.9790/1959-03123135 blessy p. valsaraj, shripathy m. bhat, ravindra prabhu and asha kamath clinical and basic research | e65 24. welch jl, thomas-hawkins c. psycho-educational strategies to promote fluid adherence in adult hemodialysis patients: a review of intervention studies. int j nurs stud 2005; 42:597–608. https://doi.org/10.1016/j.ijnurstu.2004.09.015. 25. cukor d, ver halen n, asher dr, coplan jd, weedon j, wyka ke, et al. psychosocial intervention improves depression, quality of life, and fluid adherence in hemodialysis. j am soc nephrol 2014; 25:196–206. https://doi.org/10.1681/asn.2012111134. 26. nozaki c, oka m, chaboyer w. the effects of a cognitive behav ioural therapy programme for self-care on haemodialysis patients. int j nurs pract 2005; 11:228–36. https://doi.org/10.1111/ j.1440-172x.2005.00525.x. 27. sagawa m, oka m, chaboyer w. the utility of cognitive, therapy on chronic haemodialysis patients’ fluid intake: a preliminary examination. int j nurs stud 2003; 40:367–73. https://doi.org/10.1016/s0020-7489(02)00100-1. 28. anson hm, byrd mr, koch ei. cognitive behavioral treatment to improve adherence to haemodialysis fluid restrictions: a case report. case rep med 2009; 2009:835262. https://doi. org/10.1155/2009/835262. 29. hare j, clark-carter d, forshaw m. a randomised controlled trial to evaluate the effectiveness of a cognitive behavioural group approach to improve patient adherence to peritoneal dialysis fluid restrictions: a pilot study. nephrol dial transplant 2014; 29:555–64. https://doi.org/10.1093/ndt/gft477. 30. moattari m, ebrahimi m, sharifi m, rouzbeh j. the effect of empowerment on the self-efficacy, quality of life, and clinical and laboratory indicators of patients treated with hemodialysis: a randomised controlled trial. health qual life outcomes 2012; 10:115. https://doi.org/10.1186/1477-7525-10-115. 31. barnett t, yoong tl, pinikahana j, si-yen t. fluid compliance among patients having haemodialysis: can an educational programme make a difference? j adv nurs 2008; 61:300–6. https://doi.org/10.1111/j.1365-2648.2007.04528.x. 32. yurtkuran m, alp a, yurtkuran m, dilek k. a modified yogabased exercise program in hemodialysis patients: a randomised controlled study. complement ther med 2007; 15:164–71. https://doi.org/10.1016/j.ctim.2006.06.008. https://doi.org/10.1016/j.ijnurstu.2004.09.015 https://doi.org/10.1681/asn.2012111134 https://doi.org/10.1111/j.1440-172x.2005.00525.x https://doi.org/10.1111/j.1440-172x.2005.00525.x https://doi.org/10.1016/s0020-7489%2802%2900100-1 https://doi.org/10.1155/2009/835262 https://doi.org/10.1155/2009/835262 https://doi.org/10.1093/ndt/gft477 https://doi.org/10.1186/1477-7525-10-115 https://doi.org/10.1111/j.1365-2648.2007.04528.x https://doi.org/10.1016/j.ctim.2006.06.008 1department of obstetrics & gynaecology, faculty of medicine, al-balqa applied university, amman, jordan; 2gynecology & obstetrics section, the specialty hospital, amman, jordan; 5department of obstetrics & gynecology, 3faculty of medicine, the hashemite university, amman, jordan; 4department of obstetrics & gynaecology, faculty of medicine, yarmouk university, irbid, jordan *corresponding author’s e-mail: ismaiel.mahfouz@bau.edu.jo إعادة العمليات اجلراحية غري املخطط هلا بعد جراحات أمراض النساء تقرير من االردن ا�سماعيل اأبو حمفوظ، ابتهال اأبو �سهاب، هبة اأبو �سليم، �سامل اأبو حمفوظ، قا�سم �سهاب، فداء الع�سلي abstract: objectives: unplanned return to the operating theatre refers to an unplanned reoperation following a primary surgical procedure and can result in serious complications. the rate of unplanned reoperations is often used as a measure of in-hospital quality monitoring and improvement. this study aimed to review the prevalence rate and features of unplanned gynaecological reoperations at a major general hospital in jordan. methods: this retrospective study took place between january 2011 and january 2018 at the specialty hospital in amman, jordan. the medical records of all women who underwent unplanned reoperations following a primary gynaecological procedure during this period were reviewed. results: a total of 4,895 primary gynaecological procedures were performed during the study period, of which 4,175 (85.3%) were elective and 720 (14.7%) were emergency operations. there were 15 unplanned reoperations (0.3%); of these, 14 (93.3%) followed elective procedures and one (6.7%) followed an emergency surgery. most reoperations were performed following hysterectomies (53.3%). bleeding was the predominant reason for reoperation (93.3%), with the source of the bleeding successfully identified in 71.3% of cases. in terms of outcome, none of the cases required a subsequent reoperation and there were no mortalities. conclusion: the rate of unplanned reoperation at a hospital in jordan was 0.3%. unplanned reoperations occurred primarily as a result of bleeding following hysterectomies. development of care pathways may reduce surgical complications and rates of unplanned reoperation. keywords: reoperation; gynecology; surgical specialties; intraoperative complications; hysterectomy; clinical audit; jordan. امللخ�ص: الهدف: الرجوع غري املخطط له اإىل غرفة العمليات يعرف باإعادة العملية اجلراحية غري املخطط لها بعد العملية اجلراحية الأولية اجلودة ملراقبة كمقيا�س لها املخطط غري العمليات اإعادة معدل ا�ستخدام يتم ما غالًبا خطرية. م�ساعفات اىل يوؤدي اأن املمكن ومن وحت�سينها داخل امل�ست�سفى. هدفت هذه الدرا�سة اإىل مراجعة معدل انت�سار وخ�سائ�س اإعادة العمليات اجلراحة الن�سائية غري املخطط لها يف م�ست�سفى عام رئي�سي يف الأردن. الطريقة: اأجريت هذه الدرا�سة ال�ستعادية بني يناير 2011 ويناير 2018 يف امل�ست�سفى التخ�س�سي يف عمان، الأردن. متت مراجعة ال�سجالت الطبية جلميع الن�ساء اللواتي خ�سعن لإعادة العمليات اجلراحية الغري خمطط لها بعد خ�سوعهن اإىل اإجراءات جراحية ن�سائية اأولية خالل هذه الفرتة. النتائج: مت اإجراء ما جمموعه 4,895 اإجراًء جراحي ن�سائي اأويل خالل فرتة الدرا�سة، منها 4,175 )%85.3( كانت اختيارية و 720 )%14.7( عمليات طارئة. كانت هناك 15 عملية اإعادة جراحة غري خمطط لها )%0.3(؛ منها، 14 )%93.3( كانت بعد عمليات جراحية اختيارية، وواحدة )%6.7( بعد عملية جراحية طارئة. مت اإجراء معظم اإعادة العمليات بعد ا�ستئ�سال الرحم )%53.3( وكان النزيف هو ال�سبب الرئي�سي لإعادة اجلراحة )%93.3(، وقد مت حتديد م�سدر النزيف بنجاح يف %71.3 من احلالت. من حيث النتيجة، مل تتطلب اأي من احلالت اإعادة التدخل اجلراحي يف وقت لحق ومل تكن هناك حالت وفاة. اخلال�صة: بلغ معدل اإعادة العمليات غري املخطط لها يف م�ست�سفى بالأردن %0.3 وكان ال�سبب الرئي�سي هو النزيف بعد ا�ستئ�سال الرحم. قد يوؤدي تطوير م�سارات الرعاية اإىل تقليل امل�ساعفات اجلراحية ومعدلت اإعادة العمليات اجلراحية الغري خمطط لها. التدقيق الرحم؛ ا�ستئ�سال العملية؛ اأثناء امل�ساعفات اجلراحية؛ التخ�س�سات الن�ساء؛ طب اجلراحية؛ العمليات اإعادة املفتاحية: الكلمات ال�رسيري؛ الأردن. unplanned reoperation following gynaecological surgeries a report from jordan *ismaiel abu mahfouz,1 ibtehal abu shabab,2 heba abu saleem,2 salem abu mahfouz,3 qasem shehab,4 fida asali5 clinical & basic research sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e368–373, epub. 21 dec 20 submitted 7 jan 20 revision req. 25 mar 20; revision recd. 9 apr 20 accepted 4 may 20 https://doi.org/10.18295/squmj.2020.20.04.014 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge few reports have been published focusing on unplanned reoperations following gynaecological procedures compared to other surgical specialities. this study found that the rate of unplanned reoperations at a major general hospital in jordan was 0.3%. moreover, unplanned reoperations occurred primarily as a result of bleeding following hysterectomies. application to patient care the findings of this study may encourage healthcare practitioners in jordan to implement care pathways to reduce unplanned reoperation rates and encourage early recognition of gynaecological procedures likely to require an unplanned return to the operating theatre, thereby reducing associated morbidity and mortality rates. https://creativecommons.org/licenses/by-nd/4.0/ ismaiel abu mahfouz, ibtehal abu shabab, heba abu saleem, salem abu mahfouz, qasem shehab and fida asali clinical and basic research | e369 according to the american college of obstetricians and gynecologists, an unplanned reoperation is defined as a “return to the theatre due to complications or untoward outcomes related to the initial surgery”.1 between 1979 and 2006, 26.5% of all inpatient surgical procedures performed for adult women in the usa were obstetrical or gynaecological in nature.2 while unplanned reoperations are rarely reported following gynaecological surgical operations, these procedures nevertheless carry the risk of morbidity and mortality.3 in addition, surgical complications and adverse events can occur despite the provision of appropriate perioperative care.4–6 the rate of reoperation can be a useful marker for quality monitoring and improvement purposes.7 however, there is a paucity of research regarding reoperation rates in gynaecological procedures compared to other surgical specialties. to the best of the authors’ knowledge, the most recent report regarding unplanned reoperations in gynaecology was published in 2011.8 as such, this study aimed to retrospectively review the rate of unplanned gynaecological reoperations at a major general hospital in jordan, determine reasons and triggering factors for reoperation and identify specific procedures more likely to require an unplanned reoperation. methods this retrospective study took place between january 2011 and january 2018 at the gynecology & obstetrics section of the specialty hospital in amman, jordan. this department provides general gynaecological services in addition to reproductive endocrinology, urogynaecology and gynaecology-oncology services. the medical records of all women who had undergone unplanned reoperations during the study period were identified from the hospital database. women were only included in the study if they had received a primary gynaecological surgery as well as an unplanned reoperation within the same admission period. information was collected from the medical records including age, body mass index (bmi), the presence of comorbidities such as diabetes mellitus, hypertension or previous abdominal operations, type of primary surgical operation (i.e. the operation for which the woman was admitted) and whether it was an elective or emergency procedure, the cause of any unplanned reoperations and factors triggering the reoperation such as bleeding, changes in vital signs or a drop in haemoglobin (hb) level. in addition, data were recorded to determine length of time between identification of the complication and return to the operating theatre (ot), blood transfusion requirements, admission to the intensive care unit (icu) and overall patient outcomes. data analysis was performed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the results were presented using descriptive statistics. means and standard deviations were reported for normally distributed and continuous variables. ethical approval for this study was granted by the institutional review board of the specialty hospital. results over the seven-year study period, a total of 4,895 primary gynaecological operations were performed including 4,175 (85.3%) elective operations and 720 (14.7%) emergency procedures. all procedures were performed for non-malignant pathologies. moreover, 12.8% of the primary surgeries were minimal access procedures, comprising hysteroscopic (79.4%) and laparoscopic (20.6%) procedures [table 1]. overall, there were 15 unplanned reoperations (0.3%) of which 14 (93.3%) followed elective operations and one (6.7%) followed an emergency operation. the mean age and bmi of the women requiring reoperation was 39.3 ± 12.7 years and 24.6 ± 3.8 kg/m2, respecively. moreover, 53.3% of the women had various comorbidities [table 2]. all of the primary surgeries were performed by a consultant gynaecologist or by trainees under the direct supervision of a consultant. in addition, all reoperations were performed by consultants assisted by trainees. according to the operative notes for the women who underwent unplanned reoperations, the attending gynaecologists documented moderate degrees of adhesion between the uterus, ovaries and other pelvic organs in four of the abdominal hysterectomies. there were no other special remarks in the operation notes for the remaining cases. six women (40%) had an unplanned reoperation following an abdominal hysterectomy, resulting in a surgery-specific reoperation rate of 0.9%. in addition, two unplanned reoperations (13.3%) followed a vaginal hysterectomy, with or without a concomitant anterior and/or posterior vaginal wall repair; as such, the surgery-specific reoperation rate was 0.7%. the combined rate of unplanned reoperations after hysterectomies was 0.8%. furthermore, two unplanned reoperations (13.3%) followed a cervical dilatation and curettage (d&c) procedure, resulting in a surgery-specific reoperation rate of 0.6%. in addition, three cases (20%) followed an anterior and posterior vaginal wall repair, with the reoperation rate after such procedures being 0.3%. one case (6.7%) followed an unplanned reoperation following gynaecological surgeries a report from jordan e370 | squ medical journal, november 2020, volume 20, issue 4 open myomectomy, resulting in a surgery-specific reoperation rate of 0.1%. the final case (6.7%) followed marsupialisation of a bartholin’s gland abscess [table 3]. none of the minimal access procedures were complicated by unplanned reoperations. regarding the reason for reoperation, 14 women (93.3%) were reoperated due to surgical bleeding, while one woman (6.7%) was reoperated because of a right-sided ureteral injury. for those who underwent reoperation due to bleeding, the site of the bleeding was successfully identified in 10 cases (71.4%) [table 4]. no bleeding site was identified in the remaining four cases (28.6%). for the remaining case, investigation of postoperative right-sided hydronephrosis by cystourethroscopy and retrograde pyelography revealed a right-sided ureteral injury. vaginal bleeding was the triggering factor for reoperation in 53.3% of cases; other triggers included decreases in hb concentration, changes in blood pressure and heart rate suggestive of hypovolaemia and abdominal and loin pain followed by a renal ultrasound showing hydronephrosis [table 5]. the mean drop in hb was 3.3 ± 1.2 g/dl (range: 2–5 g/dl). the mean time interval between the primary operation and reoperation was 12.3 ± 8.3 hours. the reoperations occurred in <6 hours in four cases (26.7%), 6–12 hours in five cases (33%), and 12–24 hours in seven cases (46.7%). moreover, 11 women (73.3%) required transfusions of blood or blood components, with a mean of 2.7 ± 2 units transfused. in addition, three women (20%) required overnight admission to the icu. none of the women required further reoperations and all were discharged in good health. no mortalities were reported following any of the reoperations. table 1: primary gynaecological surgeries performed over a seven-year period at the specialty hospital, amman, jordan (n = 4,895) primary surgery n (%) anterior and posterior vaginal wall repair 1,191 (24.3) laparotomy* 987 (20.2) open myomectomy 793 (16.2) abdominal hysterectomy 650 (13.3) laparoscopy† 129 (2.6) hysteroscopy† 498 (10.2) d&c 350 (7.2) vaginal hysterectomy 297 (6.1) d&c = dilatation and curettage. *such as an ovarian cystectomy or oophorectomy. †minimal access procedures. table 2: comorbidities among women who underwent unplanned reoperations over a seven-year period at the specialty hospital, amman, jordan (n = 15) comorbidity n (%) dm 1 (6.7) htn 1 (6.7) dm and htn 1 (6.7) previous abdominal surgery 4 (26.7) dm and previous abdominal surgery 1 (6.7) dm = diabetes mellitus; htn = hypertension. table 3: rate of reoperation according to primary gynaec ological surgery over a seven-year period at the specialty hospital, amman, jordan (n = 15) surgery n (%) rate of reoperation* in % abdominal hysterectomy 6 (40) 0.9 vaginal hysterectomy 2 (13.3) 0.7 anterior and posterior vaginal wall repair 3 (20) 0.3 d&c 2 (13.3) 0.6 open myomectomy 1 (6.7) 0.1 marsupialisation of bga† 1 (6.7) d&c = dilatation and curettage; bga = bartholin’s gland abscess. *according to type of surgery; †the total number of patients who had mar supialisation was not determined. table 4: bleeding sites among women who underwent unpl anned reoperations due to surgical bleeding over a seven year period at the specialty hospital, amman, jordan (n = 14) site n (%) vaginal vault 2 (14.3) infundibulopelvic vascular pedicle 2 (14.3) vaginal wall* 3 (21.4) cervix 1 (7.1) subrectus space 1 (7.1) vulvar skin† 1 (7.1) *following anterior and posterior vaginal wall repair. †following marsupi alisation of a bartholin’s gland abscess. table 5: triggering factor for reoperation among women who underwent unplanned reoperations over a seven-year period at the specialty hospital, amman, jordan (n = 15) factor n (%) vaginal bleeding 8 (53.3) drop in hb 3 (21.4) abdominal pain, drop in hb and change in vital signs 3 (21.4) loin pain and hydronephrosis* 1 (7.1) hb = haemoglobin. *as visualised using ultrasonography. ismaiel abu mahfouz, ibtehal abu shabab, heba abu saleem, salem abu mahfouz, qasem shehab and fida asali clinical and basic research | e371 discussion reporting and analysing adverse events may improve standards of care for surgical patients.9 in the current study, the rate of unplanned reoperations was 0.3% among gynaecological surgeries conducted over a seven-year period. similar rates have been reported in other studies (0.03%).8,10 a study by dierks et al. indicated that 11% of unplanned reoperations were gynaecological in nature; moreover, the researchers noted that unplanned reoperations were underreported for various reasons including lack of agreement over what constituted an adverse surgical outcome, confusion regarding the goal or objective of reporting and lack of clarity over who should report it. in addition, medical staff may choose not to report poor surgical outcomes for various reasons which may include fear of stigma or litigation.11 in the present study, the vast majority (93.3%) of unplanned reoperations occurred following elective procedures. this is consistent with findings reported by mahfouz et al. in a previous retrospective review of primary gynaecological procedures.8 in contrast, guevara et al. found that patients who underwent general emergency surgeries were more likely to have an unplanned reoperation compared to patients who had elective procedures.12 this difference is likely related to variations between gynaecological and general surgical populations. more than half of the unplanned reoperations in the current study (53.3%) occurred following a hysterectomy, with the rate of unplanned reoperations for this type of surgery being 0.8%. hysterectomies remain a very common gynaecological operation worldwide and are usually performed for benign reasons.13,14 lambaudie et al. reported a comparable overall reoperation rate after a hysterectomy (0.8%) with rates of perioperative bladder, ureteral and intestinal injuries being 0.9%, 0.06% and 0.6%, respectively; moreover, excessive bleeding (i.e. blood loss of >500 ml) was reported in 2.8% of women.14 vaginal wall repair for pelvic organ prolapse accounted for 24.3% of all primary gynaecological surgical procedures performed in the present study. the unplanned reoperation rate for this surgery was 0.3%, with the cause of reoperation being bleeding in all three cases. serious complications after pelvic floor repair are rare; fritel et al. reported that only 2.8% of women who underwent surgery for pelvic floor dysfunction sustained a serious complication either during surgery or in the early postoperative period.15 in the present study, 13.3% of unplanned reoperations occurred following a d&c procedure, with a surgery-specific unplanned reoperation rate of 0.6%. in the first case, intraoprative findings identified cervical bleeding caused by trauma during instrumentation, while no bleeding site was identified in the second case. the high rate of unplanned reoperation after a relatively minor procedure such as a d&c may be due to hospital practices of allowing junior doctors to perform these procedure with minimal direct supervision. in addition, the failure to identify a bleeding site in the second case may have been because the bleeding originated from the uterus and was not related to direct injury from the instruments. postoperative haemorrhage is a recognised complication after a d&c with a prevalence rate of 0.05–4.9%.16 however, severe bleeding may indicate other causes such as a pseudo-aneurysm.17 the only emergency procedure in the present study which was complicated by an unplanned return to the ot was a case involving marsupialisation of bartholin’s gland abscess, in which bleeding was the cause for the reoperation. marzano and haefner reported that a bartholin’s cyst or abscess accounted for 2% of all gynaecological consultations.18 however, while marsupialisation procedures may be complicated by haemorrhage, there are no published reports regarding the rate of unplanned reoperation for haemorrhage following marsupialisation.19 in contrast, none of the minimal access procedures in the current study were followed by unplanned reoperations. this may be because the majority of such procedures were diagnostic in nature and performed by consultants. alternatively, as these surgeries are often performed on an outpatient basis, some women requiring reoperation may have presented to other institutions. naveiro fuentes et al. reported that 1.93% of 2,888 gynaecological endoscopic surgeries resulted in major complications, with seven cases of bowel perforation identified postoperatively.20 reactionary bleeding refers to bleeding which occurs within the first 24 hours of surgery.21 this was the most common cause of unplanned reoperations in the current study, accounting for 93.3% of all cases. a previous retrospective review of unplanned reoperations in primary gynaecological procedures showed a similarly high percentage (100%).8 fortunately, all cases of bleeding in the present cohort were successfully controlled following the first reoperation. in contrast, ashton et al. found that 0.45% of patients may require more than one reoperation to control reactionary bleeding.22 unplanned reoperations may be necessary as a result of damage to organs near the operating field such as injuries to the bowel or urinary tract, with clinical presentation varying according to the organ involved.13 in the current study, the incidence of unplanned reoperation following gynaecological surgeries a report from jordan e372 | squ medical journal, november 2020, volume 20, issue 4 ureteral injuries following an abdominal hysterectomy was 0.2%. another study reported a comparatively low incidence of 0.35%.23 in the present study, one woman (7.1%) had a right-sided ureteral injury following an abdominal hysterectomy and underwent a right salpingo-oophorectomy performed for abnormal uterine bleeding, revealing a 10 × 10 cm ovarian mass. the patient subsequently underwent a successful ureteral resection with end-to-end anastomosis. tijani et al. reported that gynaecological operations account for up to 70% of iatrogenic ureteral injuries.24 vaginal bleeding from the vaginal vault, walls or cervix was the triggering factor for reoperation in over 50% of cases in the current study. in these cases, the bleeding was overt and was immediately brought to the attention of the medical staff. however, cases of intra-abdominal and subrectus bleeding were less obvious and it was the changes in vital signs and drop in hb levels which eventually raised the suspicion of internal bleeding. therefore, no single factor should be considered in the evaluation of possible reactionary bleeding; clinical presentation, changes in vital signs and drop in hb concentration should all be considered.8 chamsy et al. proposed that routine postoperative testing of hb levels had little clinical benefit when planning postoperative care following a laparoscopic hysterectomy; instead, the researchers suggested that this be reserved for women with clinical signs suggestive of acute blood loss.25 all of the women in the present study returned to the ot for an unplanned reoperation within the first 24 hours of the primary procedure, with almost 60% returning in 12 hours or less. this rapid turnaround time reflects prompt recognition and intervention of potential surgical complications; furthermore, there were no fatalities following any of the unplanned reoperations. overall, mortality rates from gynaecological surgeries are extremely low; a retrospective study of 4,614 gynaecological procedures over a 10-year period recorded 14 deaths, resulting in a mortality rate of 0.3%.2 prompt recognition and timely resuscitation can reduce the mortality associated with serious surgical complications.26 in the present study, all of the primary surgical procedures were performed by a consultant or by a trainee under the direct supervision by a consultant, while all reoperations were performed by a consultant assisted by trainees. the presence of resident doctors alongside consultants in the ot during primary surgical procedures did not seem to affect the subsequent rate of unplanned reoperation. a recent meta-analysis similarly showed that the involvement of resident doctors in obstetrics and gynaecology surgery was not associated with increased risks of injury to adjacent organs, unplanned returns to the ot or wound infection rates.27 setting standards of care in gynaecology has been shown to improve patient outcomes, with responsibility for this task usually falling to international professional organisations such as the royal college of obstetricians and gynaecologists.28–30 furthermore, cases of unplanned reoperation should be reviewed by a departmental committee and discussed in morbidity and mortality meetings in order to provide doctors and surgeons with the opportunity to learn from these adverse events. ideally, the findings of the current study will encourage hospital policy-makers to implement special care pathways for surgical procedures such as hysterectomies which were associated with a higher incidence of unplanned reoperations. such care pathways may include preoperative evaluation and the perioperative involvement of additional senior gynaecologists if the surgery proves difficult. in addition, additional postoperative care may help to increase early recognition and prompt intervention of surgical complications, thereby reducing morbidity and mortality. certain limitations of this study need to be acknowledged including the retrospective nature of the study design, relatively low numbers of unplanned reoperation cases and the fact that the data were sourced from a single hospital. these factors limit the generalisability of the results. moreover, most endoscopic procedures are performed on an outpatient basis following discharge from hospital; as such, some women may have had complications necessitating a return to the ot and were admitted to another hospital. however, analysis of the complications following minimal access procedures was outside the scope of the present study. conclusion the rate of unplanned reoperation in the current study was 0.3%, with bleeding being the most common cause of reoperation. certain surgical procedures such as hysterectomies were associated with a higher incidence of unplanned reoperations. however, no mortalities were reported following unplanned reoperation, likely as a result of the early recognition of complications and rapid re-intervention. the development of special care pathways for procedures which carry a higher risk of unplanned reoperation may reduce surgical complications and the rate of unplanned reoperations. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. ismaiel abu mahfouz, ibtehal abu shabab, heba abu saleem, salem abu mahfouz, qasem shehab and fida asali clinical and basic research | e373 f u n d i n g no funding was received for this study. references 1. american college of obstetrics and gynaecologists. quality improvement in women’s health care, 2nd ed. washington dc, usa: american college of obstetrics and gynaecologists, 2000. 2. oliphant ss, jones ka, wang l, bunker ch, lowder jl. trends over time with commonly performed obstetric and gynecologic inpatient procedures. obstet gynecol 2010; 116:926–31. https://doi.org/10.1097/aog.0b013e3181f38599. 3. gómez garcía mt, fuentes rozalén am, del cerro el, selva rm, diana cs, rodríguez cc, et al. analysis of mortality associated with gynecological surgery between 2000 and 2010 at the general hospital of albacete, spain. j gynecol surg 2011; 32:43–50. https://doi.org/10.1089/gyn.2015.0028. 4. sokol dk, wilson j. what is a surgical complication? world j surg 2008; 32:942–4. https://doi.org/10.1007/s00268-0089471-6. 5. aspden p, wolcott j, bootman j, cronenwett l, eds. preventing medication errors: quality chasm series. washington dc, usa: national academies press, 2007. 6. croissant k, shafi mi. preoperative and postoperative care in gynaecology. obstet gynaecol reprod med 2009; 19:68–74. https://doi.org/10.1016/j.ogrm.2008.11.007. 7. birkmeyer jd, hamby ls, birkmeyer cm, decker mv, karon nm, dow rw. is unplanned return to the operating room a useful quality indicator in general surgery? arch surg 2001; 136:405–11. https://doi.org/10.1001/archsurg.136.4.405. 8. mahfouz i, asali f, wiltshire r, sayer tr, phillips ch. unplanned return to the operating theatre in gynaecology: five years’ experience. eur j obstet gynecol reprod biol 2011; 157:222–5. https://doi.org/10.1016/j.ejogrb.2011.03.019. 9. chung kc, kotsis sv. complications in surgery: root cause analysis and preventive measures. plast reconstr surg 2012; 129:1421–7. https://doi.org/10.1097/prs.0b013e31824ecda0. 10. connolly tp. unplanned return to operating room in a comm unity hospital-based obstetrics and gynecology residency. j am osteopath assoc 2003; 103:123–5. 11. dierks mm, huang zs, siracuse jj, tolchin s, moorman dw. diagnostic, surgical judgment, and systems issues leading to reoperation: mining administrative databases. am j surg 2010; 199:324–9. https://doi.org/10.1016/j.amjsurg.2009.09.020. 12. guevara oa, rubio-romero ja, ruiz-parra ai. unplanned reoperations: is emergency surgery a risk factor? a cohort study. j surg res 2013; 182:11–16. https://doi.org/10.1016/j. jss.2012.07.060. 13. clayton rd. hysterectomy. best pract res clin obstet gynaecol 2006; 20:73–87. https://doi.org/10.1016/j.bpobgyn.2005.09.007. 14. lambaudie e, boukerrou m, cosson m, querleu d, crépin g. [hysterectomy for benign lesions: perioperative and early post operative complications]. ann chir 2000; 125:340–5. https:// doi.org/10.1016/s0003-3944(00)00205-4. 15. fritel x, campagne-loiseau s, cosson m, ferry p, saussine c, lucot jp, et al. complications after pelvic floor repair surgery (with and without mesh): short-term incidence after 1873 inclusions in the french vigi-mesh registry. bjog 2020; 127:88–97. https://doi.org/10.1111/1471-0528.15956. 16. kwon jh, kim gs. obstetric iatrogenic arterial injuries of the uterus: diagnosis with us and treatment with transcatheter arterial embolization. radiographics 2002; 22:35–46. https:// doi.org/10.1148/radiographics.22.1.g02ja0735. 17. kim ya, han yh, jun kc, jeon mk, lee es. uterine artery pseudoaneurysm manifesting delayed postabortal bleeding. fertil steril 2008; 90:849.e11–4. https://doi.org/10.1016/j. fertnstert.2007.07.1372. 18. marzano da, haefner hk. the bartholin gland cyst: past, present, and future. j low genit tract dis 2004; 8:195–204. https://doi.org/10.1097/00128360-200407000-00006. 19. lee wa, wittler m. bartholin gland cyst. in: statpearls. treasure island, florida, usa: statpearls publishing, 2019. 20. naveiro fuentes m, rodríguez-oliver a, naveiro rilo jc, gonzález paredes a, aguilar romero mt, fernández parra j. complications of laparoscopic gynecologic surgery. jsls 2014; 18:e2014.00058. https://doi.org/10.4293/jsls.2014.00058. 21. erian m, mclaren g, khalil a. reactionary hemorrhage in gynecological surgery. jsls 2008; 12:81–4. 22. ashton p, beischer n, cullen j, ratten g. return to theatre: experience at the mercy maternity hospital, melbourne 19711982. aust n z j obstet gynaecol 1985; 25:159–69. https://doi. org/10.1111/j.1479-828x.1985.tb00635.x. 23. liapis a, bakas p, giannopoulos v, creatsas g. ureteral injuries during gynecological surgery. int urogynecol j 2001; 12:391–3. https://doi.org/10.1007/pl00004045. 24. tijani kh, onwuzurigbo ki, ojewola rw, afolabi bb, akanmu no. iatrogenic ureteric injuries in a nigerian teaching hospital: experience in the last decade. east afr med j 2011; 88:304–9. 25. chamsy dj, louie my, lum da, phelps al, mansuria sm. clinical utility of postoperative hemoglobin level testing following total laparoscopic hysterectomy. am j obstet gynecol 2014; 211:224.e1–7. https://doi.org/10.1016/j.ajog.2014.04.003. 26. almoudaris am, burns em, mamidanna r, bottle a, aylin p, vincent c, et al. value of failure to rescue as a marker of the standard of care following reoperation for complications after colorectal resection. br j surg 2011; 98:1775–83. https://doi. org/10.1002/bjs.7648. 27. bougie o, zuckerman sl, switzer n, how j, sey m. influence of resident involvement in obstetrics and gynaecology surgery on surgical outcomes: systematic review and metaanalysis. j obstet gynaecol can 2018; 40:1170–7. https://doi. org/10.1016/j.jogc.2017.10.035. 28. o’dowd m. standards for gynecologic surgery. j obstet gynaecol india 2013; 63:7–13. https://doi.org/10.1007/s13224013-0405-3. 29. haynes ab, weiser tg, berry wr, lipsitz sr, breizat ah, dellinger ep, et al. a surgical safety checklist to reduce morbidity and mortality in a global population.n engl j med 2009; 360:491–9. https://doi.org/10.1056/nejmsa0810119. 30. royal college of obstetricians and gynaecologists. rcog strategy. from: www.rcog.org.uk/en/about-us/what-we-do/ rcog-strategy/ accessed: apr 2020. https://doi.org/10.1097/aog.0b013e3181f38599 https://doi.org/10.1089/gyn.2015.0028 https://doi.org/10.1007/s00268-008-9471-6 https://doi.org/10.1007/s00268-008-9471-6 https://doi.org/10.1016/j.ogrm.2008.11.007 https://doi.org/10.1001/archsurg.136.4.405 https://doi.org/10.1016/j.ejogrb.2011.03.019 https://doi.org/10.1097/prs.0b013e31824ecda0 https://doi.org/10.1016/j.amjsurg.2009.09.020 https://doi.org/10.1016/j.jss.2012.07.060 https://doi.org/10.1016/j.jss.2012.07.060 https://doi.org/10.1016/j.bpobgyn.2005.09.007 https://doi.org/10.1016/s0003-3944%2800%2900205-4 https://doi.org/10.1016/s0003-3944%2800%2900205-4 https://doi.org/10.1111/1471-0528.15956 https://doi.org/10.1148/radiographics.22.1.g02ja0735 https://doi.org/10.1148/radiographics.22.1.g02ja0735 https://doi.org/10.1016/j.fertnstert.2007.07.1372 https://doi.org/10.1016/j.fertnstert.2007.07.1372 https://doi.org/10.1097/00128360-200407000-00006 https://doi.org/10.4293/jsls.2014.00058 https://doi.org/10.1111/j.1479-828x.1985.tb00635.x https://doi.org/10.1111/j.1479-828x.1985.tb00635.x https://doi.org/10.1007/pl00004045 https://doi.org/10.1016/j.ajog.2014.04.003 https://doi.org/10.1002/bjs.7648 https://doi.org/10.1002/bjs.7648 https://doi.org/10.1016/j.jogc.2017.10.035 https://doi.org/10.1016/j.jogc.2017.10.035 https://doi.org/10.1007/s13224-013-0405-3 https://doi.org/10.1007/s13224-013-0405-3 https://doi.org/10.1056/nejmsa0810119 telemedicine is the delivery of real-time healthcare services via digital communication technologies remotely rather than face-to-face encounters between a patient and a provider.1 compared to initial forms of telephone consultation, telemedicine recently underwent a major transformation, namely the utilisation of video conferencing through the latest technologies. telehealth covers a broader spectrum than telemedicine with more diverse uses such as disease screening, disaster management and healthcare delivery. in addition, telehealth serves educational and administrative purposes (e.g. remote teaching, teleconferencing and teleproctoring).2 the purpose of telemedicine is to ensure the provision of cost-effective, timely and equitable services to all with safe communication between patients and doctors during pandemics.3 the use of telemedicine as a modality to deliver healthcare services remotely has been practiced for decades; however, data remains scarce with regard to the extent of its use in various countries around the world. a study in the usa examined telemedicine use among medicaid enrolees and found only 0.1% were telemedicine users out of 45,233,602 enrolees from 22 states.4 another study, found that although routine telemedicine has been implemented in all regions of norway and in 68% of hospitals, its actual utilisation remains low compared to in-person visits.5 the poor use of telemedicine in clinical practice indicates that challenges still prevent its widespread use. since the 2019 start of the novel coronavirus disease (covid-19) pandemic, the utilisation of telemedicine in various healthcare services has rapidly increased.6 in fact, the pandemic stimulated many health institutions and academic hospitals to implement telemedicine in healthcare promptly and appropriately. a study on the current use of telehealth in american academic orthopaedic departments found that 83% of the 106 institutions presently offering telehealth visits only recently implemented such services in direct response to the covid-19 pandemic.7 the overall disruption of healthcare services caused by this highly contagious disease resulted in a noticeable reduction of outpatient service activities – locally and internationally.8–10 avoiding exposure to covid-19 is the best prevention method thus far; therefore, many outpatient clinic appointments have been cancelled and elective operations rescheduled to minimise the risk of transmission – limiting the outbreak and enabling healthcare providers to deal with the acute influx of covid-19 cases. continuous medical support is a crucial feature of modern medicine to ensure high quality of life and fewer complications from chronic diseases. it also minimises unwanted hospital admissions. as outpatient services form the backbone of a good healthcare system, a sudden interruption of such services and the cancellation of clinic appointments may result in shortand long-term consequences. missed clinic appointments may result in stress and anxiety disorders adversely affecting the quality of life and may even extend to the worsening of an illness and development of complications.11 this may require urgent interventions that could further overwhelm an already exhausted healthcare system. natural disasters are known for their distressing effects on healthcare infrastructure.12 the longer the service disruption, the longer the duration required for efficient reimplementation. for example, it took almost two years to improve primary care access for medicaid beneficiaries aged 18 to 64 years old, after the 2005 chlorine spill in south carolina, usa as declaration of the disaster initially was denied.13 access to secondary and tertiary care may take even longer to recover. previous studies from developed countries reported exacerbated illnesses, complications or even 1department of child health, sultan qaboos university, muscat, oman; 2faculty of biology, medicine and health, university of manchester, manchester, united kingdom *corresponding author’s e-mail: amnaf@squ.edu.om التطبيب عن بعد يف عصر كوفيد-19 وما بعده أفق جديد ح�سني ال�سّفار، وطفة املعمرية، اآمنة الفطي�سية telemedicine in the era of covid-19 and beyond a new horizon hussain alsaffar,1,2 watfa almamari,1 *amna al futaisi1 editorial sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e277–279, epub. 21 dec 20 submitted 17 jun 20 revision req. 17 aug 20; revision recd. 30 aug 20 accepted 1 sep 20 https://doi.org/10.18295/squmj.2020.20.04.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ telemedicine in the era of covid-19 and beyond a new horizon e278 | squ medical journal, november 2020, volume 20, issue 4 death as a result of the interruption of medical services during natural disasters; hence, the active pursuit of a strategy to manage non-communicable diseases during exceptional situations.14 the importance of telemedicine became more evident during the covid-19 pandemic, as healthcare professionals across the globe tried different creative ways to communicate efficiently with their patients using virtual clinics (i.e. phone calls, emails and video-based conferencing).15,16 the profound impact of the covid-19 pandemic on healthcare services has accelerated the utilisation of telemedicine to fulfil various needs of acute and chronic patients. one of its first functions was prescription refills, where healthcare institutes from different countries considered different ways to ensure safe prescription refills that would not increase the risk of covid-19 transmission.17 as, in general, lockdowns lengthened and the pandemic continued to threaten healthcare delivery and continuity, virtual clinics became a necessity.18 in the era of covid-19, with all its unique challenges, adopting telemedicine is a strong alternative to “face-to-face” consultations but not a replacement. telemedicine is beneficial in protecting healthcare staff as well as monitoring and managing patients.19 the department of child health at sultan qaboos university hospital, muscat, oman, initiated virtual clinic services in order to maintain the care given to children in outpatient clinics when the country went into lockdown on march 16th 2020. the service began approximately one month later when logistics, coding and security for privacy concerns had been addressed so that the project could start safely and effectively. virtual clinics varied from telephone consultations to video-based clinics. different platforms were available for video-based consultations. however, according to the availability, technical support, ease of use and healthcare staff ’s technical skills, zoom (zoom video communications, inc., san jose, california, usa) and google meet (google, llc, mountain view, california, usa). were selected. these platforms have been endorsed by other healthcare systems internationally.20–22 there was initially a fear that virtual clinic appointments might not be accepted culturally by our patients. however, surprisingly, patients were not intimidated by the change to virtual clinic appointments and even requested the continued use of this system even after the pandemic is over, as they feel comfortable using videoconferencing especially when they have the ability to book their own appointments. in the duration of one month, neurology, endocrine and developmental paediatric speciality had appointments with 280 patients through virtual clinics. the consult ations were mostly for follow-up patients (n = 180) and there were 100 new patients. some technical issues included audio connections (sometimes the personal settings of devices would prohibit new applications from accessing the microphone) and poor internet connectivity. patients cancelling their appointments at the last minute and rescheduling their appointments multiple times during a week also posed a problem. this observation is however limited by the small number of patients. we recommend that virtual clinics be implem ented during the covid-19 pandemic in all of oman’s healthcare facilities, as well as throughout the middle east where appropriate, to maintain the service provision when patients are in lockdown/isolation. in addition to reducing exposure and controlling the outbreak, it reduces the burden on the healthcare system by lowering the demand for personal protective equipment. this method of communication would be even more beneficial if it were integrated with the existing electronic medical record system. given the major advantages gained from virtual consultations, we anticipate that the use of telemedicine will continue to increase and become an integral part of clinical practice in many countries. in the coming decade, telemedicine is projected to mature thanks to the high volume of interconnected consumer healthcare devices and improved connectivity from high-speed 5g data.23 as technology continues to advance at lower costs, telemedicine will enrich education and research and improve access to care, emergency responses and the delivery of general and specialty care in diverse clinical settings. references 1. hilty dm, ferrer dc, parish mb, johnston b, callahan ej, yellowlees pm. the effectiveness of telemental health: a 2013 review. telemed j e health 2013; 19:444–54. https://doi. org/10.1089/tmj.2013.0075. 2. burke bl jr, hall rw; section on telehealth care. telemedicine: pediatric applications. pediatrics 2015; 136:e293–308. https://doi.org/10.1542/peds.2015-1517. 3. mahajan v, singh t, azad c. using telemedicine during the covid-19 pandemic. indian pediatr 2020; 57:652–7. https:// doi.org/10.1007/s13312-020-1895-6. 4. douglas md, xu j, heggs a, wrenn g, mack dh, rust g. assessing telemedicine utilization by using medicaid claims data. psychiatr serv 2017; 68:173–8. https://doi.org/10.1176/ appi.ps.201500518. 5. zanaboni p, knarvik u, wootton r. adoption of routine telemedicine in norway: the current picture. glob health action 2014; 7:22801. https://doi.org/10.3402/gha.v7.22801. 6. mann dm, chen j, chunara r, testa pa, nov o. covid-19 transforms health care through telemedicine: evidence from the field. j am med inform assoc 2020; 27:1132–5. https://doi. org/10.1093/jamia/ocaa072. https://doi.org/10.1089/tmj.2013.0075 https://doi.org/10.1089/tmj.2013.0075 https://doi.org/10.1542/peds.2015-1517 https://doi.org/10.1007/s13312-020-1895-6 https://doi.org/10.1007/s13312-020-1895-6 https://doi.org/10.1176/appi.ps.201500518 https://doi.org/10.1176/appi.ps.201500518 https://doi.org/10.3402/gha.v7.22801 https://doi.org/10.1093/jamia/ocaa072 https://doi.org/10.1093/jamia/ocaa072 hussain alsaffar, watfa almamari and amna al futaisi editorial | e279 7. parisien rl, shin m, constant m, saltzman bm, li x, levine wn, et al. telehealth utilization in response to the novel coronavirus (covid-19) pandemic in orthopaedic surgery. j am acad orthop surg 2020; 28:e487–92. https://doi. org/10.5435/jaaos-d-20-00339. 8. ateev mehrotra, michael chernew, david linetsky, hilary hatch, and david cutler. the impact of the covid-19 pandemic on outpatient visits: a rebound emerges. the commonwealth fund, may 2020. from: https://www. commonwealthfund.org/publications/2020/apr/impact-covid19-outpatient-visits accessed: aug 2020. 9. provenzano da, sitzman bt, florentino sa, buterbaugh ga. clinical and economic strategies in outpatient medical care during the covid-19 pandemic. reg anesth pain med 2020; 45:579–85. https://doi.org/10.1136/rapm-2020-101640. 10. khera a, baum sj, gluckman tj, gulati m, martin ss, michos ed, et al. continuity of care and outpatient management for patients with and at high risk for cardiovascular disease during the covid-19 pandemic: a scientific statement from the american society for preventive cardiology. am j prev cardiol 2020; 1:100009. https://doi.org/10.1016/j.ajpc.2020.100009. 11. torres o, rothberg mb, garb j, ogunneye o, onyema j, higgins t. risk factor model to predict a missed clinic appointment in an urban, academic, and underserved setting. popul health manag 2015; 18:131–6. https://doi.org/10.1089/ pop.2014.0047. 12. randolph r, chacko s, morsch g. disaster medicine: public health threats associated with disasters. fp essent 2019; 487:11–16. 13. runkle jd, zhang h, karmaus w, martin ab, svendsen er. prediction of unmet primary care needs for the medically vulnerable post-disaster: an interrupted time-series analysis of health system responses. int j environ res public health 2012; 9:3384–97. https://doi.org/10.3390/ijerph9103384. 14. ryan b, franklin rc, burkle fm jr, aitken p, smith e, watt k, et al. identifying and describing the impact of cyclone, storm and flood related disasters on treatment management, care and exacerbations of noncommunicable diseases and the implications for public health. plos curr 2015; 7. https://doi.org/10.1371/currents. dis.62e9286d152de04799644dcca47d9288. 15. relias media. family planning centers find creative ways to provide services during pandemic: home-based testing, telemedicine are options. contraceptive tech update 2020; 41:1 16. tuckson rv, edmunds m, hodgkins ml. telehealth. n engl j med 2017; 377:1585–92. https://doi.org/10.1056/ nejmsr1503323. 17. elbeddini a, yeats a. pharmacist intervention amid the coronavirus disease 2019 (covid-19) pandemic: from direct patient care to telemedicine. j pharm policy pract 2020; 13:23. https://doi.org/10.1186/s40545-020-00229-z. 18. american academy of family physicians (aafp), using telehealth to care for patients during the covid-19 pandemic. from: https://www.aafp.org/family-physician/ patient-care/current-hot-topics/recent-outbreaks/covid-19/ covid-19-telehealth.html accessed: aug 2020. 19. doshi a, platt y, dressen jr, mathews bk, siy jc. keep calm and log on: telemedicine for covid-19 pandemic response. j hosp med 2020; 15:302–4. https://doi.org/10.12788/jhm.3419. 20. lee akf, cho rhw, lau ehl, cheng hk, wong ewy, ku pkm, et al. mitigation of head and neck cancer service disruption during covid-19 in hong kong through telehealth and multi-institutional collaboration. head neck 2020; 42:1454–9. https://doi.org/10.1002/hed.26226. 21. garg sk, rodbard d, hirsch ib, forlenza gp. managing new-onset type 1 diabetes during the covid-19 pandemic: challenges and opportunities. diabetes technol ther 2020; 22:431–9. https://doi.org/10.1089/dia.2020.0161. 22. wootton ar, mccuistian c, packard dag, gruber va, saberi p. overcoming technological challenges: lessons learned from a telehealth counseling study. telemed j e health 2019; 26:1278–83. https://doi.org/10.1089/tmj.2019.0191. 23. contreras cm, metzger ga, beane jd, dedhia ph, ejaz a, pawlik tm. telemedicine: patient-provider clinical engagement during the covid-19 pandemic and beyond. j gastrointest surg 2020; 24:1692–7. https://doi.org/10.1007/s11605-02004623-5. https://doi.org/10.5435/jaaos-d-20-00339 https://doi.org/10.5435/jaaos-d-20-00339 https://doi.org/10.1136/rapm-2020-101640 https://doi.org/10.1016/j.ajpc.2020.100009 https://doi.org/10.1089/pop.2014.0047 https://doi.org/10.1089/pop.2014.0047 https://doi.org/10.3390/ijerph9103384 https://doi.org/10.1371/currents.dis.62e9286d152de04799644dcca47d9288 https://doi.org/10.1371/currents.dis.62e9286d152de04799644dcca47d9288 https://doi.org/10.1056/nejmsr1503323 https://doi.org/10.1056/nejmsr1503323 https://doi.org/10.1186/s40545-020-00229-z https://doi.org/10.12788/jhm.3419 https://doi.org/10.1002/hed.26226 https://doi.org/10.1089/dia.2020.0161 https://doi.org/10.1089/tmj.2019.0191 https://doi.org/10.1007/s11605-020-04623-5 https://doi.org/10.1007/s11605-020-04623-5 is there an association between variceal bleed and helicobacter pylori infection in cirrhotic patients with portal hypertension? a prospective cohort study sathyanarayan varuna,1 sathasivam sureshkumar,1 balakrishnan gurushankari,1 elangovan archana,1 subair mohsina,1 *vikram kate,1 vairappan balasubramanian,2 thulasingam mahalakshmy3 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 539–545, epub. 7 nov 22 submitted 21 apr 21 revision req. 25 jul 21; revision recd. 15 aug 21 accepted 15 sep 21 departments of 1surgery, 2biochemistry & preventive and 3social medicine, jawaharlal institute of postgraduate medical education and research, pondicherry, india *corresponding author’s e-mail: drvikramkate@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.136 clinical & basic research abstract: objectives: this study aimed to determine the association between helicobacter pylori infection and variceal bleeding as well as rebleeding in cases of cirrhosis with portal hypertension. methods: this prospective cohort study included patients with bleeding oesophageal varices and was conducted at the department of surgery, jawaharlal institute of postgraduate medical education and research, pondicherry, india, from august 2016 to july 2018. results: a total of 190 patients were assessed for eligibility, of which 159 patients were included in this study. among the 159 patients, 124 (78.0%) had alcohol-related liver disease and eight had hepatitis b virus-related liver disease. seven patients with varices had bled neither at presentation nor during the follow-up period. a total of 78 (49.1%) patients were h. pylori infected. the primary outcome, which was correlation between prevalence of h. pylori and the incidence of bleeding/rebleeding from varices as well as encephalopathy found that patients with oesophageal varices (adjusted risk [ar] = 0.714) and h. pylori infection (ar = 0.682) had a lower risk of variceal rebleeding. among h. pylori-negative patients, pepsinogen i was higher in patients with rebleeding (30.7 versus 14.4 ng/ml; p <0.001). the secondary outcome, which was correlation of the site of bleeding with h. pylori infection and the association of the ratio of pepsinogen i/ii with bleeding showed that among h. pylori-positive patients, the ratio of pepsinogen i/ii was higher in patients with rebleeding (2.9 versus 1.3 ng/ml; p = 0.023). conclusion: h. pylori infection was associated with a lower risk of rebleeding in cases of cirrhosis with portal hypertension. irrespective of the status of the h. pylori infection, rebleeding was associated with increased levels of gastric acid output, as demonstrated by the level of pepsinogen. keywords: pepsinogen; hepatic encephalopathy; gastric acid; helicobacter pylori; india. advances in knowledge this study found that rebleeding episodes in patients with oesophageal varices were significantly less in cases with helicobacter pylori infection. a comparison between the oesophageal and gastric varices found that the risk of rebleeding was higher in the latter. child–pugh class b and c patients were documented as having a higher risk of rebleeding. pepsinogen levels are also directly correlated with the risk of rebleeding ; higher levels were associated with an increased risk of rebleeding. application to patient care the findings of the present study suggest that the routine eradication of h. pylori infection might not be necessary for patients with bleeding oesophageal varices, as the presence of h. pylori infection is found to be associated with a lower risk of rebleeding. higher pepsinogen levels are associated with increased acid output, which in turn is associated with an increased risk of rebleeding ; thus it can be postulated that acid reduction measures may be necessary to reduce the risk of rebleeding. helicobacter pylori infec tion is a universal bacterial infection that remains a common cause of morbidity and mortality.1–3 it is now known that h. pylori infection is associated not only with chronic gastritis and peptic ulcer disease but also with mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma.2 bleeding from varices is one of the most common causes of upper gastrointestinal (ugi) bleeding and is at times fatal in patients with liver cirrhosis.4 oesophageal varices cause the oesophagogastric junction patulous to increase acid reflux into the oesophagus, thus increasing the risk of bleeding.5 the prevalence of h. pylori infection is significantly less in patients with gastro-oesophageal reflux disease (gerd) compared to those without gerd, indicating a possible low acid output with h. pylori. in sakamoto et al.’s prospective analysis, they proposed a possible negative correlation between variceal bleeding and rebleeding and h. pylori infection due to a possible reduction in the gastric acid output.4 however, the proposed negative association has not been clearly established. https://creativecommons.org/licenses/by-nd/4.0/ is there an association between variceal bleed and helicobacter pylori infection in cirrhotic patients with portal hypertension? a prospective cohort study 540 | squ medical journal, november 2022, volume 22, issue 4 serum pepsinogen is an indirect marker of gastric acid output. it helps in quantifying the gastric acid output and establishing the gastric mucosal atrophy caused by h. pylori. in h. pylori-negative patients, pepsinogen (pg) i correlates with the maximal acid output, whereas in h. pylori-positive cases, a ratio of pg i and ii correlates better with the maximal gastric acid output.5 on analysis of the results, the authors reported a direct correlation of pg i and pg i/ii ratio with acid secretion irrespective of h. pylori status, whereas there was no direct correlation between pg ii and acid secretion.5 h. pylori, being an ammoniaproducing organism, may increase the incidence of hepatic encephalopathy in patients with cirrhosis.5,6 a few reports have recommended eradication therapy, suggesting that h. pylori increases the incidence of hepatic encephalopathy.5,6 considering the possible negative association of h. pylori infection with the incidence of rebleeding, h. pylori eradication to prevent the risk of hepatic encephalopathy needs to be considered with utmost caution. the current study was carried out to determine the role of h. pylori infection in reducing variceal bleeding and rebleeding in patients with cirrhosis and portal hypertension. methods this prospective cohort study was conducted at the department of surgery, jawaharlal institute of postgraduate medical education and research (jipmer), pondicherry, india, from august 2016 to july 2018. all patients with a diagnosis of bleeding oesophageal varices during the study’s period were included. patients with non-variceal causes of ugi bleeding; patients on drugs that reduce acid output, such as proton pump inhibitors (ppi), in the six weeks preceding the study; and patients who had received h. pylori eradication in the preceding three months were excluded from the study. cirrhosis and portal hypertension were diagnosed using ultrasonography and upper gastrointestinal endoscopy (ugie), respectively. liver cirrhosis was diagnosed by the presence of altered liver echoes on ultrasonography.7 the presence of oesophageal or gastric varices was taken as an indicator of portal hypertension. during endoscopy, biopsies for h. pylori diagnosis were performed at four different sites of the stomach—two at the antrum and two at the corpus.8 one biopsy each from the corpus and antrum was used for rapid urease testing for h. pylori, which was conducted with a solution prepared and standardised at the authors’ institute. the second set of biopsies from the corpus and antrum was sent for histopathological examination of h. pylori using giemsa stain. if fresh or altered blood was found in the stomach, biopsies were performed during subsequent follow-up endoscopy, as the presence of blood in the stomach is known to affect the results of h. pylori testing.9,10 patients were considered positive for h. pylori infection if either the urease or histopathology was positive or both were positive. patients were considered negative for h. pylori only if both the tests were negative. endoscopic variceal band ligation or sclerotherapy was done as per the standard protocol. approximately 5 ml of blood was collected from the patients in a fasting state by venepuncture and the serum was separated by centrifugation. the samples were labelled and stored at -20°c. the samples were analysed for serum pg i and ii levels using separate enzyme-linked immunosorbent assay kits for each of the subtypes (ray biotech inc., peachtree corners, georgia, usa).11 bleeding/rebleeding was defined as either haematemesis or melena or both.4 hepatic encephalopathy was diagnosed based on the presence of clinical symptoms, including loss of orientation to time and place, agitation, the presence of asterixis, stupor or coma, the improvement of these features with standard treatment for hepatic encephalopathy and the absence of any other cause of neurological impairment in the patient’s history and also during follow-up.12 portal hypertensive gastropathy (phg) was defined as changes in the mucosa of the stomach in patients with portal hypertension.13 the changes included friability of the gastric mucosa and the presence of ecstatic vessels that had a mosaic pattern in endoscopy. patients were followed-up for bleeding/ rebleeding, incidence and development of hepatic encephalopathy at three-month intervals up to nine months, till the end of the study or till the patient’s death, whichever occurred first. the primary outcome measures were the prevalence of h. pylori infection in patients with oesophageal/gastric/gastro-oesophageal varices due to liver cirrhosis with portal hypertension and the correlation of h. pylori infection with the incidence of bleeding/rebleeding from varices and with encephalopathy. the secondary outcome measures included the correlation of the site of bleeding with h. pylori infection and the determination of the association of pg i and pg ii and pg i/ii ratio with variceal bleeding and h. pylori infection. data regarding various demographic and clinicopathologic variables were recorded at the time of enrolment, which included age, gender, ultrasonography of the abdomen, findings at ugie, grade of varices, site of varices and child–pugh sathyanarayan varuna, sathasivam sureshkumar, balakrishnan gurushankari, elangovan archana, subair mohsina, vikram kate, vairappan balasubramanian and thulasingam mahalakshmy clinical and basic research | 541 score at presentation. considering the prevalence of h. pylori infection in variceal bleeding patients to be 34.9–52%, with an alpha error of 5%, and the power of the study to be 80%, the sample size was calculated to be 150.4,13,14 considering a 10% dropout rate, a sample size of 165 was determined for the study. the sample size was calculated using openepi® software (www.openepi.com) for windows 8 (microsoft corp., redmond, washington, usa). statistical analysis was done using the statistical package for the social sciences (spss), version 19.0 (ibm corp., chicago, illinois, usa). numerical data such as serum pepsinogen levels and pepsinogen ratios were expressed in the form of medians (interquartile range); categorical data such as gender, aetiology of cirrhosis, location of bleeding varices, portal gastropathy and the child–pugh class were expressed in the form of proportions. numerical data were analysed using the mann–whitney u test or the kruskal–wallis test, and categorical data were analysed using a chi-squared test or fisher’s exact test. a p value of less than 0.05 was considered statistically significant. this study was approved by the institute ethics committee of jipmer prior to the commencement of the study (jip/iec/2016/27/885). participants were included in the study after obtaining written, informed consent, and they were allowed the freedom table 1: factors predicting variceal rebleeding on univariate analysis (n = 152) characteristic total n (%) rr (95% ci) p value* rebleed present no rebleed total 152 58 (38.2) 94 (61.8) male 121 51 (42.1) 70 (57.9) 1.86 (0.9–3.7) 0.045 female 31 7 (22.6) 24 (77.4) ref alcohol-induced cirrhosis 118 50 (42.4) 68 (57.6) 1.80 (0.9–3.4) 0.073 non-alcohol induced cirrhosis 34 8 (23.5) 26 (76.5) ref oesophageal varices 127 44 (34.6) 83 (65.4) ref gastric varices 25 14 (56.0) 11 (44.0) 1.61 (1.1–2.5) 0.045 grade 1/2 oesophageal varices 93 31 (33.3) 62 (66.7) ref grade 3/4 oesophageal varices 59 27 (45.8) 32 (54.2) 1.38 (0.9–2.1) 0.124 no phg 70 28 (40.0) 42 (60.0) 1.13 (0.6–1.9) 0.892 mild phg 48 18 (37.5) 30 (62.5) 1.06 (0.6–1.9) severe phg 34 12 (35.3) 22 (64.7) ref h. pylori positive 73 20 (27.4) 53 (72.6) ref h. pylori negative 79 38 (48.1) 41 (51.9) 1.75 (1.1–2.7) 0.009 child-pugh’s class a 43 3 (7.0) 40 (93.0) ref child-pugh’s class b 82 42 (51.2) 40 (48.8) 7.31 (2.4–22.3) <0.001 child-pugh’s class c 27 13 (48.1) 14 (51.9) 6.87 (2.2–22.0) rr = relative risk; ci = confidence interval; ref = reference; phg = portal hypertensive gastropathy; h. = helicobacter. *using chi-squared test. table 2: multivariate logistic regression showing factors predicting variceal rebleeding. variable ar (95% ci) p value* male gender 1.079 (0.296–3.941) 0.908 alcoholic cirrhosis 1.276 (0.381–4.272) 0.692 oesophageal varices 0.714 (0.555–0.920) 0.009 grade 3/4 varices 1.366 (1.015–1.840) 0.040 positive h. pylori 0.682 (0.469–0.993) 0.046 child-pugh’s class b 6.435 (2.131–19.432) 0.001 child-pugh’s class c 4.814 (1.520–15.254) 0.008 *dependent variable was the presence or absence of rebleeding. ar = adjusted risk; ci = confidence interval; h. = helicobacter. is there an association between variceal bleed and helicobacter pylori infection in cirrhotic patients with portal hypertension? a prospective cohort study 542 | squ medical journal, november 2022, volume 22, issue 4 to withdraw at any point of time during the study. all the provisions of the declaration of helsinki were followed in the study. the study was registered at www.ctri.gov.in (clinical trials registry-india ref no: ctri/2018/04/013357). results a total of 190 patients were assessed for eligibility during the study period; some patients were excluded and a final sample size of 159 patients were included in the study. the total number of males and females was 127 and 32, respectively. overall, 124 patients (78.0%) had alcohol-related liver disease, eight patients had hepatitis b virus-related liver disease and only one patient had hepatitis c virus-related liver disease. the aetiology of cirrhosis in 26 patients (16.4%) was not known (idiopathic). in total, 30 patients were lost to follow-up, and 11 patients died during the course of the study. the median follow-up period was nine months. seven patients with varices had bled neither at presentation nor during the follow-up period. therefore, the analysis was carried out with 152 patients. on univariate analysis, male gender (relative risk [rr] = 1.86; p = 0.045), gastric varices (rr = 1.61; p = 0.045), h. pylori-negative status (rr = 1.75; p = 0.009) and child–pugh class b and c (p = 0.001) were found to be significantly associated with rebleeding episodes [table 1]. the prevalence of h. pylori infection among cirrhotic patients with portal hypertension was found to be 49.1%. patients with h. pylori infection were found to have less rebleeding episodes than those without it (adjusted risk [ar] = 0.682, 95% confidence interval [ci] = 0.469–0.993; p = 0.046). patients belonging to child–pugh class b (ar = 6.435, 95% ci = 2.131–19.432; p = 0.001) and child–pugh class c (ar = 4.814, 95% ci = 1.520–15.254; p = 0.008) had higher rebleeding episodes compared to patients in child–pugh class a [table 2]. a total of seven out of 11 patients who had encephalopathy were h. pylori infected (rr = 1.83); however, this difference was not statistically significant (p = 0.363). the site of variceal bleeding in patients was independent of h. pylori status (p = 0.237) [table 3]. among patients negative for h. pylori infection, rebleeding was significantly associated with higher levels of pg i (30.7 versus 14.4 ng/ml; p <0.001). among patients positive for h. pylori infection, rebleeding was associated with a higher ratio of pg i/ ii (2.9 versus 1.3 ng/ml; p = 0.023) [figure 1]. table 3: correlation of various factors with helicobacter pylori infection characteristic total n (%) p value* h. pylori present h. pylori absent total 159 78 (49.1) 81 (50.9) male 127 62 (48.8) 65(51.2) 0.905 female 32 16 (50.0) 16 (50.0) alcoholinduced cirrhosis 124 59 (47.6) 65(52.4) 0.62 non-alcohol induced cirrhosis 35 19 (54.3) 16 (45.7) oesophageal varices 133 68 (51.1) 65 (48.9) 0.237 gastric varices 26 10 (38.5) 16 (61.5) grade 1/2 oesophageal varices 100 52 (52.0) 48 (48.0) 0.334 grade 3/4 oesophageal varices 59 26 (44.1) 33 (55.9) no phg 75 40 (53.3) 35 (46.7) 0.223 mild phg 49 19 (38.8) 30 (61.2) severe phg 35 19 (54.3) 16 (45.7) child-pugh’s class a 48 31 (64.6) 17 (35.4) 0.026 child-pugh’s class b 83 37 (44.6) 46 (55.4) child-pugh’s class c 28 10 (35.7) 18 (64.3) h. = helicobacter; phg = portal hypertensive gastropathy. *using chi-squared test. figure 1: comparison of pepsinogen i and pepsinogen i/ii ratio between patients with rebleeding and those without it. hp = helicobacter pylori. *using kruskal-wallis test. sathyanarayan varuna, sathasivam sureshkumar, balakrishnan gurushankari, elangovan archana, subair mohsina, vikram kate, vairappan balasubramanian and thulasingam mahalakshmy clinical and basic research | 543 discussion the presence of h. pylori was considered a topic of interest for the present study because some researchers have postulated that mucosal inflammation resulting from h. pylori infection might weaken the mucosa and may trigger bleeding from varices. in contrast, others have suggested that by causing atrophic gastritis and reducing acid output from the stomach, it might reduce variceal bleeding episodes.4,5 in the present study, the prevalence of h. pylori infection among cirrhotic patients with portal hypertension was 49.1%. many studies have been published on the prevalence of h. pylori infection and its association with cirrhosis and portal hypertension, albeit with conflicting results.15–18 while some studies have found that h. pylori infection is more prevalent among cirrhotic patients compared to the general population, others have found no such difference. previous studies have shown the prevalence of h. pylori infection in a similar population to be 67–83.3%.15,16 the present study found that the prevalence of h. pylori infection was lower among cirrhotic patients compared to the general population. previous studies have shown that viral cirrhotic patients have a higher prevalence of h. pylori infection than those with other aetiologies of cirrhosis.19,20 however, in the present study, the majority of the patients had alcohol-induced cirrhosis (78.0%) with associated phg (52.8%), which probably accounted for the lower prevalence of h. pylori, as studies have shown that phg does not favour h. pylori colonisation.13 in the present study, as expected, patients belonging to child–pugh class b and c had higher rebleeding episodes compared to child–pugh class a; this can act as a confounding factor when correlating with h. pylori. however, multivariate analysis revealed h. pylori infection to be a protective factor. in the present study, h. pylori infected patients were found to have lesser rebleeding episodes than those patients without it (ar = 0.682, 95% ci = 0.469–0.993; p = 0.046). this supports the theory that h. pylori infection, when present, leads to gastritis and reduces acid output, which is a protective action against variceal bleeding. sakamoto et al., in their cross-sectional study, found that patients with h. pylori infection had a significantly lower risk of bleeding from varices compared to patients without h. pylori infection (odds ratio = 0.475; p = 0.019).4 gastric acid is believed to be responsible for variceal rupture and bleeding. in the current study, among h. pylori-positive individuals, in whom pg i/ii ratio correlates closely with gastric acid output, it was found that the median of the pg i/ii ratio was significantly higher among patients with rebleeding than among those without it (2.9 versus 1.3 ng/ml; p = 0.023). among h. pylori negative individuals, in whom pg i correlates closely with gastric acid output, it was found that the median of pg i was significantly higher among patients with rebleeding compared to those without it (30.7 versus 14.4 ng/ml; p <0.001). this shows that, both in the presence and absence of h. pylori infection, patients with rebleeding episodes had higher pepsinogen levels, probably reflecting more gastric acid output, compared to those who had no rebleeding. the site of variceal bleeding was almost similar among patients positive or negative for h. pylori infection. though gastric acid reflux into the lower oesophagus is a physiological phenomenon, in cases of cirrhotic patients, it is postulated that this refluxed gastric acid causes breaks in the epithelium covering the oesophageal varices, which in turn causes variceal rupture and triggers a bout of haematemesis. h. pylori, by causing chronic atrophic gastritis and reducing gastric acid output, in turn, reduces gastric acid reflux into the lower oesophagus and hence is protective against variceal rupture. this is supported by some previous studies, which have shown that long-term ppi therapy in patients with liver cirrhosis can reduce variceal bleeding rates probably due to the same mechanism.21 the present study found no difference in the risk of development of hepatic encephalopathy between those with h. pylori infection and those without it. the prevalence of hepatic encephalopathy in the present study was relatively low. the total number of patients who had hepatic encephalopathy in the present study was 11 (6.9%); seven patients who were h. pylori positive were found to have hepatic encephalopathy compared to four patients who were h. pylori negative. however, this difference was not statistically significant. calvet et al. conducted a prospective study and found that h. pylori was not independently associated with the development of hepatic encephalopathy.12 the results of the present study are consistent with the aforementioned study probably because patients with only overt hepatic encephalopathy were included in both the studies. a systematic review of 20 studies by hu et al. was conducted in china to determine the association between the risk of hepatic encephalopathy and that of h. pylori infection.22 the review found that the prevalence of h. pylori infection was higher in patients with hepatic encephalopathy than those without it.22 in the present study, the effect of h. pylori could have been masked by the lower prevalence of hepatic encephalopathy. is there an association between variceal bleed and helicobacter pylori infection in cirrhotic patients with portal hypertension? a prospective cohort study 544 | squ medical journal, november 2022, volume 22, issue 4 the strengths of the present study are that it is one of a very small number of studies on the association between h. pylori infection and variceal bleeding and the only prospective study evaluating the association between h. pylori infection and variceal rebleeding. the limitations are that the study included only patients with overt hepatic encephalopathy, excluding those with minimal hepatic encephalopathy and subclinical hepatic encephalopathy, which could have resulted in the underdiagnosis of hepatic encephalopathy in the studied patients. the present study showed that h. pylori has an inverse relationship with episodes of rebleeding from oesophagogastric varices in cirrhotic patients with portal hypertension; hence, eradication of h. pylori may not be recommended routinely. conclusion this prospective analytical study found that the rebleeding episodes were significantly less among those who had h. pylori infection compared to those without it. compared to gastric varices, oesophageal varices were found to have a significantly lower risk of rebleeding. location of the bleeding varices was not found to be significantly different between h. pylori positive and negative patients. patients belonging to the child–pugh class b and c and those with grade 3/4 varices had higher rebleeding episodes. irrespective of the h. pylori infection status, patients with rebleeding had higher levels of pepsinogen, indicating high gastric acid output. furthermore, there was no difference in the level of serum pepsinogen between h. pylori positive and negative patients. the present study did not find an association between h. pylori infection and encephalopathy. h. pylori-infected patients were found to have significantly less rebleeding episodes, with no significant increase in the incidence of encephalopathy. hence, routine h. pylori eradication may not be recommended for all cirrhotic patients with portal hypertension, as the present study showed that h. pylori was protective against variceal bleeding episodes. consequently, eradication of h. pylori might precipitate variceal bleeding episodes and may only be considered for symptomatic h. pylori infections. a u t h o r s’ c o n t r i b u t i o n ss and vk conceptualised and designed the study. sv was responsible for the data collection. sv and vb were responsible for the investigation. bg, ea, sm and vk contributed to the validation of the study. sm designed the methodology. sv, bg, ea, vk and tm were involved in data analysis and interpretation. ss, vk, vb and tm supervised the work. sv drafted the initial manuscript. ss, bg, ea, sm, vk, vb and tm were involved in drafting and revising the manuscript. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t the authors would like to acknowledge the assistance of dr prem kumar, junior resident, department of preventive and social medicine, jawaharlal institute of postgraduate medical education and research, pondicherry, india, for the statistical analysis. c o n f l i c t s o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g the study was funded by the intramural research grant offered by the jawaharlal institute of postgraduate medical education and research, pondicherry, india. references 1. linz b, balloux f, moodley y, manica a, liu h, roumagnac p, et al. an african origin for the intimate association between humans and helicobacter pylori. nature 2007; 445:915–18. https://doi.org/10.1038/nature05562. 2. mitchell hm. the epidemiology of helicobacter pylori. curr top microbiol immunol 1999; 241:11–30. https://doi. org/10.1007/978-3-642-60013-5_2. 3. roubaud baudron c, franceschi f, salles n, gasbarrini a. extragastric diseases and helicobacter pylori. helicobacter 2013; 18:44–51. https://doi.org/10.1111/hel.12077. 4. sakamoto y, oho k, toyonaga a, kumamoto m, haruta t, inoue h, et al. effect of helicobacter pylori infection on esophagogastric variceal bleeding in patients with liver cirrhosis and portal hypertension. j gastroenterol hepatol 2013; 28:1444–9. https://doi.org/10.1111/jgh.12221. 5. iijima k, sekine h, koike t, imatani a, ohara s, shimosegawa t. serum pepsinogen concentrations as a measure of gastric acid secretion in helicobacter pylori-negative and -positive japanese subjects. j gastroenterol 2005; 40:938–44. https://doi. org/10.1007/s00535-005-1677-x. 6. demirtürk l, yazgan y, zci o, ozel m, toğrol e, gültepe m, et al. the effect of helicobacter pylori eradication on gastric juice and blood ammonia concentrations and on visual evoked potentials in cirrhotics. helicobacter 2001; 6:325–30. https:// doi.org/10.1046/j.1083-4389.2001.00039.x. 7. kudo m, zheng rq, kim sr, okabe y, osaki y, iijima h, et al. diagnostic accuracy of imaging for liver cirrhosis compared to histologically proven liver cirrhosis. a multicenter collabo rative study. intervirology 2008; 51:17–26. https://doi.org/10.1 159/000122595. 8. das r, sureshkumar s, sreenath gs, kate v. sequential versus concomitant therapy for eradication of helicobacter pylori in patients with perforated duodenal ulcer: a randomized trial. saudi j gastroenterol 2016; 22:309–15. https://doi.org/10.41 03/1319-3767.187605. 9. laine la, nathwani ra, naritoku w. the effect of gi bleeding on helicobacter pylori diagnostic testing: a prospective study at the time of bleeding and 1 month later. gastrointest endosc 2005; 62:853–9. https://doi.org/10.1016/j.gie.2005.09.019. https://doi.org/10.1038/nature05562 https://doi.org/10.1007/978-3-642-60013-5_2 https://doi.org/10.1007/978-3-642-60013-5_2 https://doi.org/10.1111/hel.12077 https://doi.org/10.1111/jgh.12221 https://doi.org/10.1007/s00535-005-1677-x. https://doi.org/10.1007/s00535-005-1677-x. https://doi.org/10.1046/j.1083-4389.2001.00039.x https://doi.org/10.1046/j.1083-4389.2001.00039.x https://doi.org/10.1159/000122595 https://doi.org/10.1159/000122595 https://doi.org/10.41 03/1319-3767.187605 https://doi.org/10.41 03/1319-3767.187605 sathyanarayan varuna, sathasivam sureshkumar, balakrishnan gurushankari, elangovan archana, subair mohsina, vikram kate, vairappan balasubramanian and thulasingam mahalakshmy clinical and basic research | 545 10. mittal s, trakroo s, kate v, jagdish s. evaluation of the effect of presence of blood in the stomach on endoscopic diagnostic tests for helicobacter pylori infection. indian j med microbiol 2011; 29:379–82. https://doi.org/10.4103/0255-0857.90170. 11. samloff im. cellular localization of group i pepsinogens in human gastric mucosa by immunofluorescence. gastroenterology 1971; 61:185–8. https://doi.org/10.1016/ s0016-5085(19)33596-6. 12. calvet x, nogueras c, roqué m, sanfeliu i. helicobacter pylori is not a risk factor for hepatic encephalopathy. dig liver dis 2001; 33:414–19. https://doi.org/10.1016/s15908658(01)80013-x. 13. batmanabane v, kate v, ananthakrishnan n. prevalence of helicobacter pylori in patients with portal hypertensive gastropathy--a study from south india. med sci monit 2004; 10:133–6. 14. villalan r, maroju nk, kate v, ananthakrishnan n. is helicobacter pylori eradication indicated in cirrhotic patients with peptic ulcer disease? trop gastroenterol 2006; 27:166–8. 15. kate v, ananthakrishnan n, ratnakar c, badrinath s. anti h. pylori igg seroprevalence rates in asymptomatic children and adults from south india. indian j med microbiol 2001; 19:20–5. https://doi.org/10.1016/s0255-0857(21)03367-3. 16. prasad s, mathan m, chandy g, rajan dp, venkateswaran s, ramakrishna bs, et al. prevalence of helicobacter pylori in southern indian controls and patients with gastroduodenal disease. j gastroenterol hepatol 1994; 9:501–6. https://doi. org/10.1111/j.1440-1746.1994.tb01281.x. 17. costable nj, greenwald da. upper gastrointestinal bleeding. clin geriatr med 2021; 37:155–72. https://doi.org/10.1016/j. cger.2020.09.001. 18. elsebaey ma, tawfik ma, elshweikh sa, negm ms, elnaggar mh, alghazaly gm, et al. impact of helicobacter pylori infection on gastric variceal bleeding among patients with liver cirrhosis. gastroenterol res pract 2019; 2019:6529420. https:// doi.org/10.1155/2019/6529420. 19. feng h, zhou x, zhang g. association between cirrhosis and helicobacter pylori infection: a meta-analysis. eur j gastroenterol hepatol 2014; 26:1309–19. https://doi. org/10.1097/meg.0000000000000220. 20. pogorzelska j, łapińska m, kalinowska a, łapiński tw, flisiak r. helicobacter pylori infection among patients with liver cirrhosis. eur j gastroenterol hepatol 2017; 29:1161–5. https:// doi.org/10.1097/meg.0000000000000928. 21. lin l, cui b, deng y, jiang x, liu w, sun c. the efficacy of proton pump inhibitor in cirrhotics with variceal bleeding: a systemic review and meta-analysis. digestion 2021; 102:117– 27. https://doi.org/10.1159/000505059. 22. hu bl, wang hy, yang gy. association of helicobacter pylori infection with hepatic encephalopathy risk: a systematic review. clin res hepatol gastroenterol 2013; 37:619–25. https://doi.org/10.1016/j.clinre.2013.05.004. department of biochemistry, sultan qaboos university, muscat, oman author e-mails: naiwardi@squ.edu.om and nadiaalwardy@gmail.com مبادرات تطوير أعضاء هيئة التدريس يف كلية الطب والعلوم الصحية، جامعة السلطان قابوس، مسقط، ُعمان نادية الوردية abstract: faculty development is necessary to improve and update teaching and learning methodologies. as such, a variety of learning activities have been designed to improve teaching competencies of individual teachers. the college of medicine & health sciences at sultan qaboos university, muscat, oman, recognised the need for teacher training in order to bring faculty up-to-date in teaching and assessment methodologies. a programme of regular and one-time interventions consisting of short courses, workshops and a series of lectures was offered. feedback from the participants and facilitators led to programme expansion and enhancement. this special contribution discusses the impact of the programme on faculty and the college. keywords: teacher training; medical education; oman. جمموعة ت�صميم مت النحو، هذا وعلى وحتديثها. والتعلم التدري�س مناهج لتح�صني �رضورًيا التدري�س هيئة اأع�صاء تطوير يعد امللخ�ص: قابو�س، ال�صلطان بجامعة ال�صحية والعلوم الطب كلية اأدركت وقد للمعلمني. التدري�س كفاءات لتح�صني التعليمية الأن�صطة من متنوعة توفري مت فقد والتقييم. التدري�س منهجيات يف التدري�س هيئة اأع�صاء تطوير اأجل من املعلمني تدريب اإىل احلاجة ُعمان، �صلطنة م�صقط، من الواردة الآراء ودلت املحا�رضات. من و�صل�صلة عمل وور�س ق�صرية دورات من ويتكون واحدة ملرة اأو منتظمة بطريقة يقدم برنامج التدري�س هيئة اأع�صاء على الربنامج هذا تاأثري اخلا�صة امل�صاهمة هذه وتناق�س وحت�صينه. الربنامج تو�صيع اإىل واملي�رّضين امل�صاركني والكلية. الكلمات املفتاحية: تدريب املعلمني؛ التعليم الطبي؛ ُعمان. faculty development initiatives at the college of medicine & health sciences, sultan qaboos university, muscat, oman nadia al wardy special contribution sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e271–278, epub. 5 oct 20 submitted 19 aug 19 revision req. 23 oct 19; revision recd. 23 jan 20 accepted 19 feb 20 https://doi.org/10.18295/squmj.2020.20.03.005 it has been long assumed that knowing how to teach is part of content expertise. even when it was recognised as a separate skill, it was assumed that teaching expertise can be learned through apprenticeship.1 it is now understood that to develop the art of teaching, teachers require training.2 many medical schools have realised the importance of teacher training to improve faculty performance in their academic instructional roles and most schools now offer faculty development programmes to enhance faculty members’ teaching and assessment skills. a broad range of topics and learning activities and a variety of approaches which are based on educational theories have emerged to improve teachers’ teaching competencies.1–5 the need for these programmes has emerged as a result of new trends in teaching and assessment, curriculum changes, evolving professional requirements and accreditation and quality assurance bodies.6 mclean et al. summarised the major trends and driving forces in medical education which have potentially influenced faculty development over the years.7 theories of student learning, reforms to make learning environments more student-centred, selfdirected learning trends, an emphasis on outcomebased education and developing competencies around patient safety and professionalism, a growing interest in evidence-based medicine and changing patterns of healthcare have all led to the evolution of faculty development.7 faculty development programmes are delivered to clinicians, basic scientists, dentists, nurses and allied health professionals, and the interventions in which these practitioners learn are designed to include individual and mixed participation and focus on teaching in classrooms and clinical settings. topics such as teaching and learning approaches, acquisition of specific teaching skills, assessment, curriculum development, leadership and scholarship are covered. the type of programmes offered as part of these trainings include fellowships and scholarships, short this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ faculty development initiatives at the college of medicine & health sciences, sultan qaboos university, muscat, oman e272 | squ medical journal, august 2020, volume 20, issue 3 courses, seminar series, peer observations, self-study and web-based trainings and objective structured teaching encounters (ostes). these experiences are delivered through instructional methods including small group discussions, didactic lectures, role-play, films and videotaped reviews of performance and experiential learning.8 certain features of these faculty development programmes have proven important to enhance faculty teaching effectiveness, including delivering information about principles of teaching and learning using diverse educational methods, as well as providing feedback and supporting these programmes through experiential learning approaches.9 prolonged exposure to trainings and longitudinal programmes have been found to be more effective than onetime interventions as well as trainings centring on content relevant to the educational responsibilities of participants.8,10–12 more recently, there has been a surge in advocacy for faculty development that takes place informally in the workplace environment through communities of practice (cops). such training leads to faculty developing specific skills and expertise. this outcome is attributable to the authentic environment and participants’ abilities to learn through experience, observation, reflection and feedback.10,13 systematic evaluation of faculty development programmes is important to make sure that intended outcomes have been achieved and to assess whether any aspects of the programme need to be revised before future trainings take place. the kirkpatrick model is used to evaluate programmes according to participants’ reactions and knowledge acquired, their consequential behaviours and the results of the learning.14 many faculty development programmes use self-administered questionnaires to evaluate satisfaction with the educational activities and individual sessions (i.e. reaction).8 such data, although useful for making changes to a programme and following-up with participants about their planned changes, does not provide the organisers information about the knowledge or skills that participants have gained. changes in behaviour can be assessed through commitment-to-change statements from participants, follow-up participant surveys or interviews and observations from participants, students, residents, programme coordinators and external evaluators, to learn if any change has occurred.15–18 the ultimate evaluation would be achieved through hard-tomeasure outcomes such as organisational change or changes in student behaviour or patient outcomes that are multiplicative and reciprocal. these types of outcomes are rarely reported.8,19 there are several challenges and barriers related to faculty development such as a lack of institutional support in terms of the value assigned to teaching, teachers’ misconceptions about their own abilities and benefits of the training and the difficulty of measuring long-term outcomes of faculty development programmes.7 the college of medicine & health sciences (comhs) at sultan qaboos university (squ), muscat, oman, recognised the need for teacher training and bringing faculty up-to-date in teaching and assessment methodologies. the overarching objective of making such improvements was to enhance the educational mission of the comhs. in 2002, the first medical education conference at squ was held. the conference was preceded by a three-day “train the trainer” course in health professions education that was conducted by internationally renowned faculty in medical education and was attended by many senior faculty. the course was received so well by the college’s faculty that the dean at the time decided to institute this as a regular bi-annual activity. as such, the dean appointed a small group of faculty to organise the course on a regular basis. these individuals, who became the core drivers of faculty professional development initiatives, had different departmental affiliations and either formal qualifications or a strong interest in medical education. eventually, this core group proposed the formation of a medical education unit which was established in 2006 and faculty development activities continued. this special contribution describes the need for such a programme in the comhs. this paper presents information on the programme’s inception and implementation as well as ways to evaluate its outcomes. the discussion evolved from a teaching/ learning framework and learning theories, both of which have contributed to a fundamental under standing of evidence-based practice. finally, future directions for faculty development in the comhs at squ are proposed. it is hoped this information will provide faculty development lessons to institutes with a similar set-up and experiences as the comhs. identifying the need for faculty development in the college of medicine and health sciences n e w c u r r i c u l u m a n d a s s e s s m e n t the implementation of an outcome-based curriculum in 2008 followed by an aligned new assessment system created two types of need in the comhs. first, faculty recognised a need for the development of specific nadia al wardy special contribution | e273 instructional skills related to teaching and assessment for all those holding teaching responsibilities. second, the faculty saw a need for leadership skills for curr iculum planners and change agents. the comhs and squ hospital (squh) have a total teaching staff number of approximately 336. in addition, there are 204 affiliated faculty from ministry of health (moh) hospitals and health centres, the armed forces hospital (afh) and the royal oman police hospital. the faculty needed to be trained regularly to update their knowledge base in tandem with recent advances in educational methodologies. additionally, they needed to improve their teaching skills and align them with new curricular requirements. in 2003, a survey of assessment practices in the comhs demonstrated the need for specialised workshops to enhance the skills of faculty in written, practical and clinical competence as well as professional behaviour assessment and standard setting in exam inations. in 2007, another questionnaire was sent to all staff in the comhs for their input about an area in medical education in which they needed training. in addition, participants who attended different educational workshops held in the college were asked, at the end of each workshop, to prioritise follow-up topics of medical education they wanted to learn more about from a provided list. after analysis of this feedback, these topics were identified as assessment, course and curriculum design, teaching and learning, e-learning and research in medical education. in 2006, comhs became a member of the international databases for enhanced assessments and learning (ideal) consortium, an international group dedicated to sharing medical student assessment information. one purpose of this group is to promote research for developing international standards to assess medical competence. to assist in developing these standards, specially designed workshops were needed to increase awareness of current assessment practice. training needs of the medical educ at i o n u n i t c o r e g r o u p a small group of faculty members took part in constructing the proposal for what would become the comhs medical education unit. these individuals were expected to be a core group of trainers who would contribute to the unit’s mission of faculty development. it was imperative that these trainers would be formally qualified in medical education. although it would have been ideal for these individuals to pursue qualifications in medical education (e.g. a certificate, diploma or master’s degree), an in-house programme was developed instead. decision-makers determined that such a programme would provide adequate training, reach a wider audience and support faculty members’ development without requiring them to take time off or be away from professional duties for long periods. developments in medical informatics a n d u s e o f s i m u l at o r s i n m e d i c a l e d u c at i o n the establishment of the clinical skills laboratory in 2010 resulted in the realisation of a need for faculty involved in teaching clinical skills to be trained in new teaching and assessment methodologies involving simulators and mannequins, computer-based simul ations, virtual reality and simulated patients. programme design to facilitate these changes to teaching approaches and assessment, it was important to adopt an outcomebased approach as change of behaviour was the intended outcome.20,21 the programme needed to increase faculty awareness of current trends in medical education, introduce new medical concepts and improve practitioners’ current practice. the objectives of the educational activities that would support this change (e.g. courses, workshops, lectures, etc.) were formulated in terms of knowledge, skills and attitudes that participants could acquire and implement as a result of attending these courses. resources available in terms of funding, facilities and facilitators were identified in addition to the number of participants who could be accommodated. participation from a variety of specialties was sought because learning in interprofessional teams enables practitioners to work better together.22 the teaching and learning strategies adopted applied the andragogical principles of social learning and motivation where participants were provided with opportunities to reflect on their practice, design relevant educational activities and receive feedback from their peers.23 the target audience were multidisciplinary and interprofessional, so it was important to start with a team who could contribute a variety of skills, subject matter and medical education expertise to ensure the success of the programme.23 thus, a small group of faculty with different departmental affiliations who had either a formal qualification or a strong interest in medical education were given the responsibility of organising the programme. faculty development initiatives at the college of medicine & health sciences, sultan qaboos university, muscat, oman e274 | squ medical journal, august 2020, volume 20, issue 3 implementation the literature shows that faculty development progr ammes range from longitudinal fellowships to short courses and seminar series, peer observations, selfstudy, online training and ostes.8 programmes can be delivered with the support of small-group disc ussions, didactic lectures, role-plays, films and analyses of videotaped performances as well as through experiential learning approaches.8 the delivery format should be dictated by the desired outcomes and the research available on the link between the approach used and student learning models.7 in the comhs, the format of the faculty development activities ranged from short courses/workshops, half-day activities and a series of lectures. these approaches were chosen because the faculty development aimed to enhance faculty members’ general skills in teaching, learning and assessment. some of these activities were offered on an annual basis while others occurred only once or twice depending on specific needs. r e g u l a r c o u r s e s the certificate courses in health professions education the certificate courses in health professions education (chpe) is a three-day “train the trainer” workshop in health professions education which was originally initiated by the gulf cooperation council deans’ forum and implemented for the first time in jeddah, saudi arabia. when the first medical education conf erence was held at squ in 2002, it had been preceded by the chpe, which was attended by many senior faculty. the chpe course was well received, and it was adopted as a regular activity of the college. since 2002, 17 chpe courses have been held and approximately 700 faculty have been certified. the original chpe covered several competency areas including how to plan and implement an educational activity and evaluate whether learning had taken place. the objectives were that by the end of the course participants would be aware of principles of adult learning and teaching and also of trends in healthcare practice and education. in addition, the course aimed for participants to develop skills in planning an educational activity systematically, communicating with large and small groups, facilitating student learning in cognitive, psychomotor and affective domains and selecting and using appropriate instructional media. the final objective was that participants would become aware of the principles and purposes of student assessment in the three domains of learning. day one of the chpe course included the principles of learning, teaching and curriculum design; day two covered skills in facilitating student learning; and day three focussed on student assessment and teacher evaluation. this content included core principles and concepts that were applicable to a diverse range of participants and was conducted in the format of interactive lectures and small group activities that included micro-teaching, peer teaching, reflection and feedback. reading material was given to the participants prior to the start of the course to provide background knowledge and enhance learning during the educational activities. although participation in the course was not mandatory for squh or comhs faculty, as is the case in the majority of faculty development programmes, it was strongly recommended by the dean of the college.8 attendance to this course, however, was required for affiliation with the college for teachers who were coming from other health institutes in oman. most participants were squh clinical faculty followed by the comhs’s academic faculty and finally by moh hospitals and institutes as well as the afh. the fact that the bulk of the trainees for that first training came from squh and comhs is likely because the course was held at the comhs and was easily accessible to the squh and comhs faculty. participation was limited to 40–45 participants due to resource considerations and number of facilitators available. the original chpe course was conducted by three invited international faculty in medical education, two of whom had designed the course. these were professors of anatomy, surgery and family medicine as well as professors of medical education. a core group of local faculty were selected based on their qualifications, expertise, service on relevant educational committees and strong interest in medical education to support the international faculty. this core group consisted of faculty (i.e. associate professor, assistant professor, senior consultant, consultant, senior registrar) who had departmental affiliations in biochemistry, anatomy, child health, medicine, surgery and radiology. some held formal teaching qualifications, including masters or postgraduate diplomas in medical education. eventually, this group of ‘local experts’ expanded to include interested members from other departments, and the group became trained to the level at which they could replace the international faculty who had originally conducted the chpe course. student assessment workshop following feedback from participants of the chpe about an area of medical education that needed nadia al wardy special contribution | e275 further development, a three-day workshop devoted exclusively to the topic of student assessment was designed and conducted for the first time in 2004. the workshop became an annual activity attended by approximately 350 faculty who had previously attended the chpe. the competencies covered were principles of student assessment including the characteristics of a good test, skills in designing newer methods of student assessment and skills in using test scores for making educational decisions, particularly in relation to setting standards. the first day of the workshop covered principles of student assessment, characteristics of a good test and testing higher cognitive skills. the second day focused on testing psychomotor, communication and professional skills. finally, the third day covered setting and maintaining examination standards and making decisions based on test scores. as with chpe, the topics were delivered in the format of interactive lectures and small group activities. one-time interventions table 1 shows short courses (1–5-day duration) that were conducted as one-time activities to reinforce the topics introduced in chpe and student assessment workshop (saw) and provide in-depth training to faculty. table 2 shows focused, half-day activities, that addressed a particular issue.24 some courses were offered once, while others were available to interested parties more than once. the short courses were conducted by internationally renowned facilitators in medical education while the half-day activities were conducted by local experts. participant numbers ranged were 20–100 college, hospital and affiliated faculty. lecture series in 2011, a lecture series in medical education was initiated. the series consisted of one-hour presentations that offered information on new topics or acted as refreshers on certain aspects in need of consolidation [table 3]. attendance to this activity, however, was not satisfactory, perhaps because the topics covered were not perceived as being as important as those offered during courses or workshops. programme evaluation and outcomes evaluations of faculty development activities in the comhs (i.e. chpe, saw and short courses) were collected via self-reported data. the participants’ responses showed a high level of satisfaction (unpublished data). the majority of participants rated the courses as very good, agreed that attending these courses/workshops would help them in their responsibilities as teachers and indicated their table 1: short courses conducted at the college of medicine & health sciences at sultan qaboos university, muscat, oman, from 2006–2015 course duration in days year conducted ideal train the trainer 3 2006 curriculum development and assessment 2 2009 continuous assessment of clinical skills and professional behaviour 1 2010 designing integrated questions 1 2010 team-based learning 5 2011 advances in the assessment of clinical competence 3 2012 clinical teaching and feedback 2 2012 facilitating small group and simulation-based learning 2 2015 ideal = international databases for enhanced assessments and learning. table 2: half-day activities conducted at the college of medicine & health sciences at sultan qaboos university, muscat, oman, from 2007–2018 activity year conducted item analysis workshops 2007 and 2008 instructional design for online courses 2010 how to design a poster using ppt 2010 using aspects of medical informatics to assist with research 2010 and 2011 moodle workshops 2010, 2011 it workshops 2009, 2010, 2011 and 2012 use of ideal databanks 2007, 2008, 2009, 2010 and 2011 editing and manipulating images for medical purposes 2012 data analysis using spss 2012 and 2013 academic advising 2014 online medical education resources 2014 constructing and grading a minicex 2015 and 2016 team-based learning 2017 and 2018 ppt = powerpoint; it = information technology; ideal = international databases for enhanced assessments and learning ; spss = statistical package for the social sciences; cex = clinical evaluation exercise . faculty development initiatives at the college of medicine & health sciences, sultan qaboos university, muscat, oman e276 | squ medical journal, august 2020, volume 20, issue 3 willingness to apply what they learned in their workplace. a substantial number of participants who were followed-up after attending chpe and saw reported that they reviewed and changed their teaching objectives, wrote new teaching objectives, introduced changes to their teaching methodologies, reviewed and constructed new questions and took steps to evaluate their teaching. this outcome is consistent with what has been reported in the literature.10 for example, leslie et al. reported that participants of faculty development programmes showed high satisfaction with the content and teaching methodologies and that they acquired knowledge of educational principles and teaching strategies; they also reported changes in their teaching behaviours.10 open comments collected on content, organis ation, duration, teaching formats and future needs resulted in introducing slight changes to the regular course over time to suit the needs of the curriculum and the course participants . new topics such as teambased learning were introduced while others were removed and converted to specific learning topics that were offered separately from the regular courses. several college outcomes can be attributed, at least in part, to the faulty development programme. in 2013, the comhs of squ was fully accredited by the association for medical education in the eastern mediterranean region in cooperation with the world federation for medical education for a period of 10 years.25 in 2014, it was selected as the best medical college in the arab world by the sheikh hamdan bin rashid al maktoum award for medical sciences.26,27 these achievements cannot be attributed to the faculty development programme alone. curricular changes, a new assessment system and faculty development in the postgraduate programme were occurring at the same time. the faculty development programme, nevertheless, made a substantial contribution. other reported outcomes of faculty development programmes were new responsibilities associated with teaching, assessment and leadership positions and increased scholarship and faculty promotion.10 most faculty in the comhs’s educational and leadership positions have participated in the faculty development programme. however, it is difficult to link these achievements exclusively to the faculty development programme. many of the skills required for these positions, however, are developed through such programmes.10 future directions faculty development at the comhs has concentrated on bringing faculty up-to-date on current trends in medical education and improving their general skills as they relate to the need of the new curriculum and assessment. these skills need to be consolidated and built upon to include focused workshops on topics such as blueprinting, continuous assessment of clinical skills, question banking and teaching and assessment of professionalism as these are the current issues under discussion in the comhs. to ensure transfer of skills and knowledge into the workplace, a move from workshops to the workplace and taking advantage of experiential learning is being advocated.19,28 therefore, accessible and effective faculty development that expands the teaching expertise of clinicians and moves beyond the apprenticeship model is needed.29,30 such professional development could include strategies that foster cops and harness the added value of social and professional networks.8,10,31,32 in the long term, an ongoing longitudinal progr amme leading to teaching certification is needed. these longitudinal programmes have shown to have multiple benefits. apart from improved teaching performance, participants in such programmes have been found to be more self-aware, acquired new leadership roles and increased their academic productivity. such programmes also foster the creation of social networks and develop a sense of community.8 there is also a need for an ongoing programme which would lead to a degree in medical education for individuals who are interested in such a career. completing such a programme would link to the expectation that these individuals would play a major part in future curriculum and assessment design, implementation and evaluation and as facilitators in faculty development activities. implementing a degree in medical education would require institutional table 3: lecture series topics in medical education offered at the college of medicine & health sciences at sultan qaboos university, muscat, oman, from 2011–2016 topic designing study guides how good is good enough? team-based learning open access publishing tips on how to create the best ppt presentations oste edgar dales learning pyramid item analysis of mcqs ppt = powerpoint; oste = objective structured teaching examination; mcq = multiple choice question. nadia al wardy special contribution | e277 support. without such support in the form of release time and academic promotion, a change in the organ isational culture that fosters and values learning would not be possible.8 conclusion implementation of a faculty development programme needs to respond to specific institutional needs. in this article, a programme which responded to the needs of the comhs has been described. a programme of regular and one-time interventions following the principles of teaching and learning was adopted at squ’s comhs and was perceived as beneficial based on the feedback from participants and facilitators. the programme had a substantial impact on the college based on improvements witnessed after its implementation. a c k n o w l e d g e m e n t the author wishes to thank professor bazdawi al riyami for his vision and leadership in starting the fd program and professors mansour al moundhri and omar al rawas for its continuation and progress. the author also wishes to thank the core group for faculty development initiatives in the college, the recent facilitators in chpe and student assessment workshop, and the technical and academic staff of the medical education department. special appreciation goes to professor hossam hamdy for the inception of chpe through the gcc dean’s forum and for professor raja bandaranayake for the design of the first chpe and saw. references 1. wilkerson l, irby dm. strategies for improving teaching practices: a comprehensive approach to faculty development. acad med 1998; 73:387–96. https://doi.org/10.1097/00001888199804000-00011. 2. benor de. faculty development, teacher training and teacher accreditation in medical education: twenty years from now. med teach 2000; 22:503–12. https://doi.org/10.1080/01421590 050110795. 3. skeff km, berman j, stratos g. a review of clinical teaching improvement methods and a theoretical framework for their evaluation. in: edwards jc, marier rl, eds. clinical teaching for medical residents: roles, techniques, and programs. new york, usa: springer, 1988. pp. 92–120. 4. steinert y. faculty development in the new millennium: key challenges and future directions. med teach 2000; 22:44–50. https://doi.org/10.1080/01421590078814. 5. steinert y. faculty development: from workshops to comm unities of practice. med teach 2010; 32:425–8. https://doi. org/10.3109/01421591003677897. 6. jonas hs, etzel si, brazansky b. education programs in us medical schools. jama 1992; 268:1083–90. https://doi.org/10.1 001/jama.1992.03490090025009. 7. mclean m, cilliers f, van wyk jm. faculty development: yesterday, today and tomorrow. med teach 2008; 30:555–84. https://doi.org/10.1080/01421590802109834. 8. steinert y, mann k, anderson b, barnett bm, centeno a, naismith l, et al. a systematic review of faculty development initiatives designed to enhance teaching effectiveness: a 10year update: beme guide no. 40. med teach 2016; 38:769–86. https://doi.org/10.1080/0142159x.2016.1181851. 9. steinert y, mann k, centeno a, dolmans d, spencer j, gelula m, et al. a systematic review of faculty development initiatives designed to improve teaching effectiveness in medical education: beme guide no. 8. med teach 2006; 28:497–526. https://doi.org/10.1080/01421590600902976. 10. leslie k, baker l, egan-lee e, esdaile m, reeves s. advancing faculty development in medical education: a systematic review. acad med 2013; 88:1038–45. https://doi.org/10.1097/ acm.0b013e318294fd29. 11. stes a, min-leliveld m, gijbels d, van petegem p. the impact of instructional development in higher education: the state-ofthe-art of the research. educ res rev 2010; 5:25–49. https://doi. org/10.1016/j.edurev.2009.07.001. 12. burgess a, matar e, neuen b, fox gj. a longitudinal faculty development program: supporting a culture of teaching. bmc med educ 2019; 19:400. https://doi.org/10.1186/s12909-0191832-3. 13. steinert y. faculty development in the health professions: a focus on research and practice. dordrecht, the netherlands: springer, 2014. 14. kirkpatrick d. evaluating training programs: the four levels. san francisco, usa: berrett-koehler, 1998. 15. lockyer jm, fidler h, ward r, basson rj, elliott s, toews j. commitment to change statements: a way of understanding how participants use information and skills taught in an educational session. j contin educ health prof 2001; 21:82–9. https://doi.org/10.1002/chp.1340210204. 16. wakefield jg. commitment to change: exploring its role in changing physician behaviour through continuing education. j contin educ health prof 2004; 24:197–204. https://doi. org/10.1002/chp.1340240403. 17. armson h, elmslie t, roder s, wakefield j. is the cognitive complexity of commitment-to-change statements associated with change in clinical practice? an application of bloom’s taxonomy. j contin educ health prof 2015; 35:166–75. https:// doi.org/10.1002/chp.21303. 18. kogan jr, conforti ln, yamazaki k, iobst w, holmboe es. commitment to change and challenges to implementing changes after workplace-based assessment rater training. acad med 2017; 92:394–402. https://doi.org/10.1097/acm.0000000000001319. 19. fernandez n, audétat mc. faculty development program evaluation: a need to embrace complexity. adv med educ pract 2019; 10:191–9. https://doi.org/10.2147/amep.s188164. 20. davis n, davis d, bloch r. continuing medical education: amee education guide no 35. med teach 2008; 30:652–66. https://doi.org/10.1080/01421590802108323. 21. lockyer j, bursey f, richardson d, frank jr, snell l, campbell c, et al. competency-based medical education and continuing professional development: a conceptualization for change. med teach 2017; 39:617–22. https://doi.org/10.1080/014215 9x.2017.1315064. 22. hammick m, olckers l, campion-smith c. learning in interprofessional teams: amee guide no 38. med teach 2009; 31:1–12. https://doi.org/10.1080/01421590802585561. 23. ramani s, mcmahon gt, armstrong eg. continuing prof essional development to foster behaviour change: from prin ciples to practice in health professions education. med teach 2019; 41:1045–52. https://doi.org/10.1080/0142159x.2019.1615608. https://doi.org/10.1097/00001888-199804000-00011 https://doi.org/10.1097/00001888-199804000-00011 https://doi.org/10.1080/01421590050110795 https://doi.org/10.1080/01421590050110795 https://doi.org/10.1080/01421590078814 https://doi.org/10.3109/01421591003677897 https://doi.org/10.3109/01421591003677897 https://doi.org/10.1001/jama.1992.03490090025009 https://doi.org/10.1001/jama.1992.03490090025009 https://doi.org/10.1080/01421590802109834 https://doi.org/10.1080/0142159x.2016.1181851 https://doi.org/10.1080/01421590600902976 https://doi.org/10.1097/acm.0b013e318294fd29 https://doi.org/10.1097/acm.0b013e318294fd29 https://doi.org/10.1016/j.edurev.2009.07.001 https://doi.org/10.1016/j.edurev.2009.07.001 https://doi.org/10.1186/s12909-019-1832-3 https://doi.org/10.1186/s12909-019-1832-3 https://doi.org/10.1002/chp.1340210204 https://doi.org/10.1002/chp.1340240403 https://doi.org/10.1002/chp.1340240403 https://doi.org/10.1002/chp.21303 https://doi.org/10.1002/chp.21303 https://doi.org/10.1097/acm.0000000000001319 https://doi.org/10.2147/amep.s188164 https://doi.org/10.1080/01421590802108323 https://doi.org/10.1080/0142159x.2017.1315064 https://doi.org/10.1080/0142159x.2017.1315064 https://doi.org/10.1080/01421590802585561 https://doi.org/10.1080/0142159x.2019.1615608 faculty development initiatives at the college of medicine & health sciences, sultan qaboos university, muscat, oman e278 | squ medical journal, august 2020, volume 20, issue 3 24. sultan qaboos university. about medical education and informatics department. from: www.squ.edu.om/medicine/ departments/list-all-departments/medical-education-andinformatics accessed: jan 2020. 25. sultan qaboos university. from: https://www.squ.edu.om/ qao/accredition-road-map/college-of-medicine-and-healthscience-comhs. accessed: july 2019. 26. sheikh hamdan bin rashid al maktoum award for medical sciences. from: http://www.hmaward.org.ae/ accessed: jan 2020. 27. sultan qaboos university. from: https://www.squ.edu.om/ squmedia/details-page/articleid/2120/squ-college-ofmedicine-wins-hamdan-medical-award. accessed: july 2019. 28. campbell n, wozniak h, philip rl, damarell ra. peersupported faculty development and workplace teaching: an integrative review. med educ 2019; 53:978–88. https://doi. org/10.1111/medu.13896. 29. rassie k. the apprenticeship model of clinical medical education: time for structural change. n z med j 2017; 130:66– 72. 30. wilkinson tj. rethinking apprenticeship. n z med j 2017; 130:7–8. 31. o'sullivan ps, irby dm. reframing research on faculty dev elopment. acad med 2011; 86:421–8. https://doi.org/10.1097/ acm.0b013e31820dc058. 32. de carvalho-filho ma, tio ra, steinert y. twelve tips for implementing a community of practice for faculty development. med teach 2020; 42:143–9. https://doi.org/10.1080/014215 9x.2018.1552782. https://doi.org/10.1111/medu.13896. https://doi.org/10.1111/medu.13896. https://doi.org/10.1097/acm.0b013e31820dc058 https://doi.org/10.1097/acm.0b013e31820dc058 https://doi.org/10.1080/0142159x.2018.1552782 https://doi.org/10.1080/0142159x.2018.1552782 submitted 12 apr 23 1 revision req. 21 may 23; revision recd. 31 may 23 2 accepted 12 jul 23 3 online-first: july 2023 4 doi: https://doi.org/10.18295/squmj.7.2023.046 5 6 efficacy of ropivacaine for sub-arachnoid block in patients with recent 7 history of scorpion sting 8 a case series 9 *saurabh trivedi, hemendra bhardwaj, tapan k. sahoo, 10 seema gupta 11 12 department of anaesthesia & critical care, chirayu medical college & hospital, bhopal, 13 india. 14 *corresponding author’s e-mail: drst23@gmail.com 15 16 abstract 17 failure of sub-arachnoid block (sab), due to resistance to bupivacaine after a recent scorpion 18 sting can lead to multiple block attempts and subsequent conversion to general anaesthesia. 19 we report this case series of 10 patients with successful sab with newly launched 0.75% 20 hyperbaric ropivacaine, in patients with recent scorpion sting. thus, intrathecal hyperbaric 21 ropivacaine may be considered as the local anaesthetic agent of choice in patients with 22 scorpion sting to prevent failure of sab. 23 keywords: bupivacaine; ropivacaine; scorpion sting; spinal anaesthesia 24 25 introduction 26 spinal anesthesia or sub-arachnoid block (sab) is a commonly practised technique of 27 anaesthesia for most below-umbilical procedures.1 clinical data has shown a correlation 28 between previous history of scorpion sting and resistance to sab with bupivacaine, an 29 amino-amide local anaesthetic.2,3 30 31 ropivacaine (2,6-dimethylphenyl, 1-propylpiperidine,2-carboxamide) is a piperidine-32 carboxamidebased amide, prepared as pure s-enantiomer.4 multiple studies have shown that 33 ropivacaine is a safe and effective local anesthetic (la) for regional anaesthesia techniques. 34 hyperbaric preparation of ropivacaine (0.75%) for sab have recently been launched in india, 35 and its efficacy and safety for intra-thecal administration has been documented.5 36 37 we report successful sub-arachnoid blockage with ropivacaine in patients with confirmed 38 history of recent scorpion sting. 39 40 case series 41 this case series includes 10 patients of either gender, aged 18-70 years, with a history of 42 scorpion sting within 5 years, undergoing below umbilical surgeries under sab, between 43 august 2022 and november 2022 at a tertiary care hospital of central india [table 1]. 44 patients with confirmed history of scorpion sting in pre-anaesthetic check-up , were further 45 evaluated for the number of stings, duration since last sting and severity of the sting [grade 46 1local pain & paraesthesia at the sting site, grade 2local pain and paraesthesia existing at 47 the sting site as well as proximal to the sting site, grade 3grade 2 factors with added cranial 48 nerve (increased oral secretions, blurry vision, rapid tongue movement, nystagmus), or 49 skeletal neuromuscular dysfunction (flailing of the extremities and tetanus-like arching of the 50 back) with or without autonomic dysfunction, grade 4includes both cranial nerve and 51 skeletal muscle dysfunction, hyperthermia, rhabdomyolysis, pulmonary oedema, multiple 52 organ failures].6 53 54 a written-informed consent was obtained from all the patients for publication purposes. after 55 standard fasting of 8 hours, patients were shifted to operation theatre and standard monitors 56 applied and baseline vitals were noted. a single operator performed all the sab, using 25 57 gauze, 90 mm becton dickinson (bd), quinke needle, at l3-4 interspace in the sitting 58 position, with a standard dose of 3.2 ml, 0.75% hyperbaric ropivacaine. the patients were 59 positioned supine immediately after drug administration and assessment for autonomic, 60 sensory, and motor blockage was done by a blinded observer (trained anesthesiologist) 61 immediately after supine positioning. 62 63 haemodynamic parameters were noted every minute for 5 minutes from the time of supine 64 positioning, and every 5 minutes afterwards for 20 minutes. 65 66 sensory blockage was assessed using pin-prick method, using a two-point scoring system (067 normal sensation, 1loss of pain sensation but pressure sensation intact, 2 – loss of pain & 68 pressure sensation). a score of 1 and 2 at t10 level, were considered as onset and completion 69 of sensory block, respectively. 70 71 bromage scale7 was used for motor blockage assessment. bromage grade ii and iv were 72 considered as onset and completion of motor block, respectively. the block was considered 73 adequate when a complete sensory and motor blockage was achieved at t-10 level, and 74 planned surgery was started. in case of inadequate blockage (a sensory score of 0 or 1 with 75 bromage grade < iv) at 20 minutes after sab, it was considered a block failure. on the 76 completion of surgery, patients were shifted to post-anaesthesia care units for monitoring. 77 the time for onset and completion of sensory and motor blockage, and block failure were 78 assessed for association with number, duration, and severity of sting. 79 80 results 81 the mean time to onset of sensory and motor block was 78.8 and 94.2 seconds respectively, 82 and the mean time to completion of sensory and motor blockage was 117 and 146.7 seconds 83 respectively. all 10 patients achieved complete sensory and motor blockage within 20 84 minutes and none of the sab failed. 85 86 out of 10 patients, 5 patients had a history of single sting, 3 patients had 2-5 stings and 2 87 patients >5 stings. the mean time to onset and completion of sensory and motor blockage 88 was more in patients with history of multiple (>2) stings (figure 1-a). patients with sting 89 within one year had relatively faster onset of sensory and motor block as compared to 90 patients with sting between 1 to 5 years (figure 1-b). patients with clinical grade 2 and 3 91 sting had relatively delayed onset and completion of blockage (figure 1-c). no episode of 92 post-spinal hypotension (fall in mean arterial pressure (map) > 20% from baseline) was 93 observed in our patients, except patient 4 (figure 2). 94 95 discussion 96 scorpion sting is a common occurrence in indian sub-continent. usually harmless, with 97 manifestations like severe pain, and burning sensation at the site of sting. systemic 98 manifestations like myocardial infarction, acute pulmonary oedema, cardiogenic shock and 99 death are very rare.8 thus, a large rural population coming for elective surgical procedures, 100 may give history of grades 1 or 2 sting.6 101 102 the scorpion venom is a weak acid (ph 6.5) and highly complex mixture of salts, 103 nucleotides, biogenic amines, enzymes, mucoproteins, and neurotoxins, acting on ion 104 channels specifically voltage gated sodium channels (vgsc). out of various scorpion toxins, 105 alpha and beta toxins are known to bind to mammalian vgsc. the alpha toxin binds 106 extracellularly to s3-s4 loop in domain iv and extracellular part of segment s5-s6 of domain 107 i.9 the beta toxin binds to extracellular part of segment 4 of domain ii.9 the binding site of 108 local anesthetics (la) is segment 6 of domain iv of alpha subunit of vgsc.10 panditrao et 109 al.2,3 had described the resistance to intrathecal bupivacaine in patients with a history of 110 scorpion sting, and postulated that scorpion toxin itself or the antibodies against the toxin are 111 responsible for the development of resistance to intrathecal bupivacaine. 112 113 amrita et al.11 demonstrated adequate sensory and motor block after sab with 0.75% 114 hyperbaric ropivacaine in 2 patients with a history of scorpion sting with documented 115 resistance to bupivacaine on subcutaneous la testing. similarly, the present case series 116 demonstrated successful sub-arachnoid block with 0.75% hyperbaric ropivacaine in 10 117 patients with a history of scorpion sting. out of 10 patients, 5 patients had a history of single 118 sting, 3 patients had 2-5 stings and 2 patients >5 stings. the mean time to onset and 119 completion of sensory and motor blockage was more in patients with history of multiple (>2) 120 stings as compared to single sting. this may be due to the antibodies against scorpion venom 121 that had accumulated with multiple stings as postulated by panditrao et al.2,3 122 patients with sting history between 1-5 years had comparatively delayed onset and 123 completion of sensory and motor blockage as compared to patients with a sting within 1 year. 124 patients with clinical grade 2 and 3 sting had relatively delayed onset and completion of 125 sensory and motor blockage. 126 127 molecular modelling of local anesthetic binding with vgsc has demonstrated the differences 128 in the relative alignment of aromatic part of ropivacaine as compared to other la on vgsc. 129 the aromatic part of ropivacaine aligns towards the outer side of vgsc whereas the aromatic 130 part of bupivacaine aligns towards the inner side of the channel.12,13 this differential 131 alignment of aromatic ring may contribute to the difference in resistance of the two la 132 caused by scorpion sting. further, action of ropivacaine on gamma aminobutyric acid a 133 (gaba-a) and n-methyl-d-aspartate (nmda) receptors,14,15 facilitates its la action, 134 thereby decreasing the chances of its resistance in patients with a scorpion sting. thus, 135 differences in the three-dimensional structures of ropivacaine and bupivacaine may confer 136 differences in the activity of their enantiomers in the complex biological environment of the 137 receptors,4 and may be responsible for the success of intra-thecal ropivacaine in patients with 138 scorpion sting. 139 140 conclusion 141 intrathecal hyperbaric ropivacaine may be considered as the local anaesthetic agent of choice 142 in patients with scorpion sting to prevent failure of sub-arachnoid block. further scientific 143 studies are needed to further validate these findings. 144 145 authors’ contribution 146 concept and design of study was made by st. st, hb, tks and sg were involved in 147 defining intellectual content, literature search, data acquisition, data analysis, statistical 148 analysis, manuscript preparation, manuscript editing, and manuscript review of the article. 149 all authors approved the final version of the manuscript. 150 151 references 152 1. wulf hf. the centennial of spinal anesthesia. anesthesiology. 1998;89:500–6. 153 2. panditrao mm, panditrao mm, sunilkumar v, panditrao am. effect of previous scorpion 154 bite(s) on the action of intrathecal bupivacaine: a case control study. indian j anaesth. 2013 155 may;57(3):236-40. 156 3. panditrao mm, panditrao mm, khan mi, yadav n. does scorpion bite lead to development 157 of resistance to the effect of local anaesthetics? indian j anaesth. 2012 nov;56(6):575-8. 158 4. mcclure jh. ropivacaine. br j anaesth. 1996;76:300–7. 159 5. fettes pd, hocking g, peterson mk, luck jf, wildsmith ja. comparison of plain and 160 hyperbaric solutions of ropivacaine for spinal anaesthesia. br j anaesth 2005;94:107-11. 161 6. isbister g. k., bawaskar h. s. scorpion envenomation. the new england journal of 162 medicine 2014, 371(5), 457–463. 163 7. craig d, carli f. bromage motor blockade score a score that has lasted more than a lifetime. 164 can j anaesth. 2018 jul;65(7):837-838. 165 8. agrawal a, kumar a, consul s, yadav a. scorpion bite, a sting to the heart, indian j crit 166 care med. 2015 apr;19(4):233-6. 167 9. catterall wa, cestèle s, yarov-yarovoy v, yu fh, konoki k, scheuer t. voltage-gated 168 ion channels and gating modifier toxins. toxicon. 2007 feb;49(2):124–41. 169 10. ragsdale ds, mcphee jc, scheuer t, catterall wa. molecular determinants of state-170 dependent block of na+ channels by local anesthetics. science. 1994 sep 16;265(5179):1724–171 8. 172 11. rath a, reena r. scorpion bite and failed spinal anesthesia: is ropivacaine the answer? 173 minerva anestesiol. 2023 apr;89(4):368-369. doi: 10.23736/s0375-9393.22.16958-0. 174 12. lipkind gm, fozzard ha. molecular modeling of local anesthetic drug binding by 175 voltage-gated sodium channels. mol pharmacol. 2005 dec;68(6):1611–22. 176 13. li w, ding l, liu hm, you q. synthesis, biological evaluation, and molecular docking 177 of ropivacaine analogs as local anesthetic agents. med chem res. 2018 mar 1;27(3):954–65. 178 14. yang y, si jq, fan c, ma kt, cheng hj, li l. effects of ropivacaine on gaba-179 activated currents in isolated dorsal root ganglion neurons in rats, chin. j appl physiol 2013 180 may;29(3):263-6. 181 15. zhang l, tanabe k, yanagidate f, kawasaki y, chen g, dohi s, et al. different effects 182 of local anesthetics on extracellular signal-regulated kinase phosphorylation in rat dorsal horn 183 neurons. eur j pharmacol. 2014 jul 5;734:132-6. 184 185 table 1: demographic profile & block parameters 186 age (years) gender asaps surgery number of times of scorpion sting number of stings in past 5 years duration since last sting (months) severity of sting with clinical grade sensory blockage onset / completion (seconds) motor blockage onset / completion (seconds) 38 female 1 fistulect omy 1 1 48 mild / 1 80 / 135 85 / 140 62 male 2 right inguinal hernia repair 1 1 42 mild /1 65 / 90 82 / 120 38 male 1 left femur external fixation 3 2 4 mild /1 56 / 82 72 / 110 70 female 2 right proxima l femur nailing 1 1 12 mild /1 39 / 50 55 / 67 58 male 2 right inguinal hernia repair 6 3 18 moderate /2 94 / 140 70 / 166 26 male 1 left inguinal hernia repair 1 1 16 mild /1 46 / 68 48 / 70 56 male 2 rt inguinal hernia repair 1 1 44 mild /1 72 / 90 80 / 120 50 male 1 end to end urethrop lasty 6 3 48 severe / 3 135 / 175 155 / 190 56 male 2 right inguinal hernia repair 2 2 22 moderate /2 115 / 140 125 / 190 55 male 2 right inguinal hernia repair 4 2 48 moderate /2 90 / 200 130 / 294 asa-ps – american society of anesthesiologists physical status. 187 188 189 figure 1: a) association between number of scorpion stings and mean block time, b) 190 association between duration since last scorpion sting and mean block time, c) association 191 between clinical severity grade of scorpion sting and mean block time. 192 193 6 0 .4 8 7 1 1 4 .5 7 0 1 0 9 1 1 2 .5 8 6 .6 1 4 0 .6 1 5 7 .5 1 0 3 .4 1 9 8 1 7 8 1 s t i n g 2 t o 5 s t i n g s > 5 s t i n g s m e a n t im e ( s e c o n d s ) number of scorpion sting ( a ) a s s o c i a t i o n b e t w e e n n u m b e r o f s t i n g s & m e a n b l o c k t i m e 5 6 7 2 .5 8 8 .4 8 2 9 9 .5 1 3 8 7 2 8 4 .5 1 0 6 .4 1 1 0 1 2 3 .2 5 1 7 2 .8 < 1 2 m o n t h s 1 2 t o 2 4 m o n t h s 2 4 t o 4 8 m o n t h s m e a n t im e ( s e c o n d s ) duration since last sting ( b ) a s s o c i a t i o n b e t w e e n t i m e s i n c e l a s t s t i n g & m e a n b l o c k t i m e 5 9 .6 7 1 0 2 .5 1 1 2 .5 8 5 .8 3 1 7 0 1 5 7 .5 7 0 .3 3 1 2 7 .5 1 3 2 .5 1 0 4 .5 0 2 4 2 1 7 8 1 2 3 m e a n t im e ( s e c o n d s ) clinical severity grades of scorpion sting ( c ) a s s o c i a t i o n b e t w e e n s e v e r i t y g r a d i n g o f s c o r p i o n s t i n g & m e a n b l o c k t i m e sensory blockage onset time (seconds) sensory blockage completion time (seconds) motor blockage onet time (seconds) motor blockage completion time (seconds) 194 figure 2: variation of mean arterial pressure with time in each patient. 195 1 submitted 28 dec 21 1 revision req. 13 feb 22; revision recd. 13 mar 22 2 accepted 27 apr 22 3 online-first: may 2022 4 doi: https://doi.org/10.18295/squmj.5.2022.038 5 6 exclusive breastfeeding 7 barrier analysis among omani mothers 8 samia al-ghannami,1 salima al-mamari,1 danielle chekaraou,2 caroline 9 abla,3 ibtisam al-ghmmari,1 amna al-ajmi,1 saleh al-shammkhi,1 10 ruqaiya m. al-balushi,4 fatma al-mamari,1 *ruth m. mabry5 11 12 1department of nutrition, ministry of health, muscat, oman; 2rdc international public 13 health solutions, phoenix, arizona, usa; 3independent public health consultant, arlington, 14 texas, usa; 4department of food science and nutrition, college of agricultural and marine 15 sciences, sultan qaboos university, muscat, oman; 5independent public health consultant, 16 muscat, oman. 17 *corresponding author: rmmabry@gmail.com 18 19 abstract 20 objectives: less than a quarter of omani infants < 6 months are exclusively breastfed. 21 therefore, this study aimed to examine individual barriers and supports to exclusive 22 breastfeeding and identify potential policy and programmatic interventions in oman. 23 methods: a cross-sectional barrier analysis was carried out among a purposive sample of 24 omani women 45 “doers” (who exclusively breastfed their infants) and 52 “non-doers” 25 (who do not) – who were selected and interviewed by trained enumerators in health clinics in 26 various parts of the country. a barrier analysis tool, adapted for the omani context, covered 27 12 common determinants of behavior adoption using open-ended questions regarding 28 participants’ perceptions about exclusive breastfeeding including positive and negative 29 consequences, self-efficacy and social norms. qualitative analysis involved coding and 30 tabulating as well as thematic analysis. results: mothers report that motivation for exclusive 31 breastfeeding include the perception that it leads to healthier children, is easy, readily 32 available and therefore convenient and that mothers report an elevated level of family support 33 mailto:rmmabry@gmail.com 2 for breastfeeding. barriers included perceived milk insufficiency and mother’s employment. 34 conclusion: to achieve the 2025 exclusive breastfeeding target of 50%, public health action 35 should focus on emphasizing the benefits and convenience of exclusive breastfeeding and 36 building women’s confidence in their ability to produce sufficient milk. these efforts will 37 require increasing the knowledge and skills of community and health care workers and 38 establishing monitoring mechanisms. expanding paid maternity leave and supportive 39 workplace policies are necessary to encourage working women to exclusively breastfeed. 40 keywords: breastfeeding, breastfeeding barriers, breastfeeding support, exclusive 41 breastfeeding, nutrition policy, oman, health promotion. 42 43 advances in knowledge 44  incentives to exclusively breastfeed for omani women include the perception that it leads 45 to healthier children, that it is easy to do, readily available and therefore convenient. 46  barriers to exclusively breastfeeding include perceived mother’s milk insufficiency, 47 mother’s employment, and limited familial support. 48  creating an enabling environment for exclusively breastfeeding in oman involves scaling 49 up existing programs that vigilantly seek to remove the identified barriers and shaping 50 messages that emphasize the benefits of breastfeeding to both infant and mother, the 51 convenience, and the ability of women to produce sufficient mother’s milk for their 52 infants. 53 54 application to patient care 55  key messages for promoting exclusive breastfeed include that it is easy to do, readily 56 available and convenient, affirm women’s ability to produce sufficient milk for their 57 infants and should target both mothers of young infants as well as their families. 58  existing programmes such as the community support group and the who baby 59 friendly hospital initiatives should continue to engage in individual and group 60 counseling, immediate breastfeeding support following delivery, and lactation 61 management; renewed efforts to increase knowledge and skills of health professionals 62 and community volunteers would ensure their sustainability. 63 64 introduction 65 3 exclusive breastfeeding, where infants are given only mother’s milk during the first 6 months 66 of life and no other food or water, is a key intervention that has a major impact on child 67 mortality and morbidity.1 mother’s milk contains all the needed nutrients for an infant’s first 68 6 months of life, provides immunity to disease through maternal antibodies, increases 69 intelligence and likely reduces overweight and diabetes.1 for women, breastfeeding protects 70 against breast cancer, improves birth spacing and may protect against ovarian cancer and type 71 2 diabetes.1-2 an estimated 823,000 child deaths and 20 000 deaths due to breast cancer could 72 be averted annually if all infants were breastfed, including initiation within one-hour of birth, 73 exclusively breastfeed for the full 6-month period and continued breastfeeding.1 74 75 less than a quarter of omani infants < 6 months are exclusively breastfed,3 markedly less 76 than the world health organization (who)/united nations children fund (unicef) global 77 target for 2025 of at least 50%.4 the low prevalence of exclusive breastfeeding during the 78 first four months of life (31.9%) in oman has not changed in the past 20 years; however, the 79 prevalence of continued breastfeeding beyond 12 months increased from 66.8% in 2000 to 80 80.0% in 2017. however, the decline in early initiation (within one hour of birth) 87.1% and 81 82.0% and the current low rate of exclusive breastfeeding for the first six months (23.2%) 82 is concerning3 not only in oman but also in the region as a whole.5-6 83 84 a wide range of factors, including social and cultural attitudes, marketing of infant formula, 85 health systems and workplace, community settings and individual attitudes affect whether or 86 not women initiate breastfeeding early, and maintain exclusive and continued breastfeeding 87 for up to 2 years.2 barrier analysis, based on the health belief model7 and the theory of 88 reasoned action8 has identified 12 determinants of behavior: perceived self-efficacy, 89 perceived social norms, perceived positive consequences, perceived negative consequences, 90 perceived action efficacy, access, perceived susceptibility/risk, perceived severity, cues for 91 action, policy, culture and perceived divine will.9 high self-efficacy is a strong predictor of 92 breastfeeding.10 social norms and positive or negative consequences, like support and advice 93 from family and the health system, influence mothers’ confidence in breastfeeding.2 while, 94 marketing of infant formula, working status including short maternity leaves, and inadequate 95 support to mothers of young infants influence mothers’ perceptions of sufficiency of maternal 96 milk for breastfeeding and their ability to breastfeed and are some of the numerous reasons 97 for low levels of exclusive breastfeeding around the world.2 although similar evidence is 98 emerging from several countries of the arabian gulf,11-14 greater understanding is needed to 99 4 better guide policy-makers in addressing the low prevalence of exclusive breastfeeding.3 100 thus, this study aimed to examine individual barriers and supports to exclusive breastfeeding 101 and identify potential policy and programmatic interventions in oman. 102 103 methods 104 research design 105 descriptive qualitative study design was used to identify the factors that prevent and facilitate 106 a target group from adopting a preferred behavior,15 in this case exclusively breastfeed 107 infants aged 0 – 6 months. using the barrier analysis (ba) methodology, this study explores 108 twelve determinants of behavior which influence a desired behavior: perceived self-efficacy, 109 perceived social norms, perceived positive consequences, perceived negative consequences, 110 perceived action efficacy, access, perceived susceptibility/risk, perceived severity, cues for 111 action, policy, culture and perceived divine will.9 since defining the behavior to be assessed 112 is an essential step in a ba study, the behavior defined was mothers of children 0 to 6 113 months feed them only mother’s milk. 114 115 setting and relevant context 116 despite a socio-cultural environment supportive of breastfeeding, exclusive breastfeeding 117 remains low in oman.16 employment, marketing of breastmilk substitutes, inadequate health 118 care support and insufficient mother’s milk are some of the key barriers identified by women 119 in the arabian gulf.11-14 although policies and strategies are in place to encourage 120 exclusively breastfeeding, further work is needed if oman is to achievement the 121 unicef/who global target of 50% exclusive breastfeeding. face-to-face interviews, based 122 on a barrier analysis assessment tool, were conducted in ministry of health primary health 123 care clinics in five governorates from 10 – 14 march 2019. a 5-day training covered change 124 theory, effective interviewing techniques, a thorough review of the data collection tool, a pre-125 test, and data entry was completed prior to the field work to ensure high quality results. 126 127 sampling strategy 128 to assess exclusive breastfeeding, purposive sampling methods were used to recruit omani 129 mothers with infants aged 4 to 9 months to participate; 4-months was identified as the lower 130 age limit to capture as many ‘doers’ as possible; the 9-months upper limit was identified to 131 minimize recall bias. in order to identify a sufficient number of doers, the ba methodology 132 allows for researchers to ‘relax a behavior’; thus, the tool defined “doers” as mothers who 133 5 exclusively breastfed their infants for the first 4 months of life rather than the recommended 6 134 months of exclusive breastfeeding.4 recruitment was monitored using an excel sheet until the 135 recommended number of respondents was reached. 136 137 research team 138 the enumerators, identified by the health management team in each region, were health care 139 workers with qualitative research experience. prior to conducting the survey, 22 enumerators 140 including 19 women and three men from five governorates (muscat, al dakhilyah, dhofar, 141 north ash sharqiya, south al batinah) and the moh nutrition team (six people) were trained 142 in muscat for five days on the ba methodology and interviewing skills. the training took 143 place from 3 to 7 march 2019. all enumerators were required to exhibit key qualifications 144 with a 90% or greater on the quality improvement verification checklist average scores 145 during training prior to the field work. 146 147 tool 148 the ba questionnaire contained two sections: items to screen/classify respondents as doers 149 or non-doers and items to assess barriers and supports based on their classification. the 150 barrier analysis included six open-ended questions, one question for perceived positive and 151 negative consequences and two questions each for perceived self-efficacy and perceived 152 social norms (table 1). questions on perceived access, cues for action, susceptibility/risk, 153 severity, efficacy, perception of divine will, culture and policy had discrete responses; 154 respondents were encouraged to provide details for the last two areas (culture and policy). 155 questions varied slightly between doers and non-doers. a question addressing universal 156 motivators, looking at what mothers want more than anything in life, was included since this 157 information is useful when designing promotional campaigns. 158 159 the questionnaire was developed and contextualized to the omani context in english 160 following the standard ba questionnaire design guidelines and translated into arabic. it was 161 then validated by the ministry of health (moh) nutrition team and enumerators during 162 training by pilot testing with 27 doers and non-doers to ensure clarity for each question in the 163 local arabic dialect. the research protocol was approved by the unicef ethical review 164 board. 165 166 data collection 167 6 22 trained enumerators approached each potential participant at a health clinic, found a semi-168 private place to conduct a face-to-face interview, introduced the study and obtained informed 169 consent. eligible women who consented to be part of the study were then screened to 170 determine their status as doer or non-doer before proceeding with the survey interview. 171 during the interview, enumerators were encouraged to probe participants to prompt them for 172 further details, if needed (table 1). 173 174 data analysis 175 completed questionnaires were scanned and sent via email to the moh nutrition team in 176 muscat. qualitative analysis involved coding, tabulating, and thematic analysis of the data by 177 the central nutrition team. once responses were coded and tabulated, they were entered into a 178 barrier analysis tabulation sheet 9 to calculate estimated relative risk and odds ratios to 179 identify significant differences between doers and non-doers. for barrier analysis, an 180 estimated relative risk (rr) is the preferred approach to presenting findings as it provides 181 more accurate estimates of association.9 significance was determined by p-value of less than 182 0.05, with a confidence interval of 95%. 183 184 results 185 the team interviewed 97 women (45 doers and 52 non-doers) in the five governorates. as 186 shown in table 2, the thematic determinants that emerged during the interviews varied 187 significant between doers and non-doers across six areas studied: perceived self-efficacy, 188 perceived social norms, perceived positive and negative consequences, perceived action 189 efficacy, universal motivator. 190 191 perceived self-efficacy (what makes it easy or difficult) 192 the reasons about the importance of exclusive breastfeeding were statistically similar 193 between doer and non-doer mothers. mother’s availability to breastfeed, not having 194 difficulties breastfeeding and the benefits to a child’s health including the immune system 195 and growth and development were the most common reasons. to examine belief in ability to 196 do a particular behavior respondents were asked, “what makes it (or what would make it) 197 easier or more difficult” for you to exclusively breastfeed your baby for the first 6 months of 198 life. doers were 5.4 times (p=0.018) more likely than non-doers to say, “it is easy because i 199 think it is important” and 2.8 times (p=0.011) more likely to say, “it is easy because it is 200 available and ready for the child and it requires no preparation” than non-doers. non-doers 201 7 were significantly 4.2 times (p=0.014) more likely to say, “it is difficult (to exclusively 202 breastfeed) because i work outside the home” than doers. in addition, non-doers were 3.5 203 times (p=0.010) more likely than doers to say, “it is difficult when there is not enough milk, 204 especially in the beginning”. 205 206 perceived consequences (positive and negative) 207 the most common perceived positive consequence of exclusive breastfeeding among all 208 respondents was related to the child’s health and well-being. other common responses among 209 both groups included delays in pregnancy and mother’s health. doers were 10.8 times 210 (p=0.043) more likely to say, “i can save money and time because it is free, easy, and takes 211 no time to prepare” than non-doers and 3.1 times (p=0.023) more likely to say, “it helps the 212 mother lose the weight gained with the pregnancy” than non-doers. nearly 20% of non-213 doers mentioned “the baby does not get enough milk and is not satisfied and then loses 214 weight”; a concern not expressed by doers. 215 216 social norms/access 217 the social norms determinant refers to an individual’s perception of the approval or 218 disapproval of exclusively breastfeeding by people considered to be important in an 219 individual’s life. respondents were asked who approves or disapproves of them exclusively 220 breastfeeding their child for the first six months of life doers were 2.7 times (p=0.034) more 221 likely to say, “my husband approves of me only giving breastmilk to my baby for the first 6 222 months” and 2 times (p=0.065) more likely to say, “my mother approves of me only giving 223 breastmilk to my baby for the first 6 months” than non-doers. on the other hand, the access 224 determinant has many different facets, it includes the degree of availability of the needed 225 products or services required to adopt a behavior. respondents were asked how difficult is it 226 (or would it be) to get the support needed to exclusively breastfeed? non-doers were 2.6 227 times (p=0.034) more likely to say, “it is somewhat difficult to get the support i need to give 228 only breast milk to my baby for the first 6 months” than doers. 229 230 perceived action efficacy 231 to examine the belief that a behavior will avoid a certain problem, respondents were asked 232 about the likelihood of an infant becoming malnourished if exclusively breastfeed. non-233 doers were 2.6 times (p=0.027) more likely to say, “it is somewhat likely that my child will 234 become malnourished if i give him only breastmilk to 6 months of age” than doers 235 8 demonstrating that non-doers express doubt of the benefit of exclusive breastfeeding to 236 protect children from malnourishment. 237 238 universal motivators 239 respondents were asked what they wanted more than anything in life to identify key factors 240 motivate most people, irrespective of other variables. family health and children’s education 241 were common universal motivators among both doers and non-doers. non-doers were 2.9 242 times (p=0.027) more likely to say, “i want happiness and peace more than anything from 243 life” than doers. 244 245 discussion 246 this study identified barriers and supports for exclusive breastfeeding in oman. incentives to 247 exclusively breastfeed include the perception that exclusive breastfeeding leads to healthier 248 children, is easy, readily available and therefore convenient. support from husbands and 249 mothers is also noted as necessary for successful breastfeeding. barriers to exclusive 250 breastfeeding included perceived milk insufficiency, mother’s employment, and limited 251 family support. despite high knowledge about the benefits of breastfeeding to both the 252 mother and child, the barriers identify reasons for the low exclusive breastfeeding rates in 253 oman. similar barriers have been described globally17-18 and in neighboring countries.11-14 254 255 individual experiences play a major role in determining whether or not a mother exclusively 256 breastfeeds her infant. the perception of insufficient milk supply mentioned by participants 257 in this study as well as research in this region. is an important reason why women stopped 258 exclusively breastfeeding during their infant’s first six months and/or introduce formula or 259 weaning food.12-14, 18-19 for example, more than half of study participants in saudi arabia and 260 one-in-three study participants in qatar discontinued breastfeeding due to their perception of 261 lack of sufficiency mother’s milk.14, 19 breastfeeding difficulties and perceptions that infant 262 crying is perceived hunger in the early weeks undermine mothers’ confidence making her 263 assume that she has insufficient milk and thus, introduce infant formula.2 encouraging new 264 mothers to exclusively breastfeed requires building confidence in their ability to produce 265 sufficient milk for their infants. 266 267 the participants from this barrier analysis study highlighted the importance of family support 268 in promoting infant feeding practices: doers were almost four times as likely to believe that it 269 9 was not difficult to get support compared to the non-doers although traditional culture is 270 supportive of breastfeeding, older women family members have a great influence on mothers’ 271 breastfeeding practices, especially new mothers unfamiliar with breastfeeding.12-13 272 researchers from the region have shown that some grandmothers and fathers are supportive 273 of exclusive breastfeeding, while others may advise introducing water, formula, or other 274 food.11-13 although infant formula were not frequently mentioned in our study, their 275 marketing is ubiquitous in the region and are undermining efforts to improve breastfeeding 276 including women’s own ability to breastfeed.2, 13-14, 19-21 although stronger regulations were 277 enacted in may 202122 and includes stronger regulations aligned to the code for marketing 278 infant formula23-24 further research would be useful to examine their influence on exclusive 279 breastfeeding in oman, especially on new mothers and their circle of family support. 280 281 oman has introduced several interventions to promote breastfeeding including the 282 community support group program,25 lactation counselors for the who multicentre growth 283 reference study26 and the who baby friendly hospital initiative.20 strengthening these 284 programs through the inclusion of individual and group counseling, immediate breastfeeding 285 support following delivery, and lactation management, will require renewed efforts to 286 increase knowledge and skills of health professionals and community volunteers, 287 strengthening monitoring and ensuring their sustainability.2, 5 these programs should address 288 the key barriers identified in this barrier analysis by emphasizing the benefits and 289 convenience of exclusive breastfeeding to both the infant and mother and building women’s 290 confidence in producing sufficient milk for their infants and how exclusive breastfeeding can 291 contribute to a happy and peaceful life. 292 293 mother’s employment is major barrier to exclusive breastfeeding in oman. globally, it a 294 critical factor that influences women’s decisions to initiate breastfeeding, exclusively 295 breastfeed, and continue breastfeeding into the second year.2 about one quarter of the omani 296 workforce are women and it is expected in increase.27-28 although oman has maternity leave 297 protection,28 it does not meet the international labor organization’s 14-week minimal 298 standard.29 mothers are unable to adhere to exclusive breastfeeding due to the short leave, the 299 lack of child care and the challenges of expressing milk2 and is widely reported in the region 300 two-thirds of the participants in a study in the united arab emirates did not exclusively 301 breastfeed their infants for six months due to short maternity leave.13 al nuaimi, et al20 302 highlights employment as a key factor for low breastfeeding rates in the arabian gulf. 303 10 reducing barriers for working mothers by expanding maternity leave, providing lactation 304 rooms and nursing breaks can improve breastfeeding rates and improve workforce 305 performance.2, 11, 13, 20 306 307 the results of this research is being used to strengthen the breastfeeding promotion 308 programme within the ministry of health including determining the key messages for a 309 nation-wide exclusive breast feeding campaign, sharing findings with staff working in the 310 maternal and child health and health education programmes so that they can strengthen ebf 311 promotion within their own programmes and using the findings as part of the training of 312 lactation consultants currently working in secondary hospitals. the findings are also being 313 used to advocate for strengthening family-friendly policies to be more supportive of exclusive 314 breastfeeding, a key barrier identified in this study. 315 316 this study used a verified methodology9 and included respondents from the governorates 317 where a majority of the omani population reside. more non-doers were recruited from the 318 southern-most governorate due to the extremely low level of breastfeeding in one governorate 319 while additional doers were recruited from the other four governorates. it provides a broad 320 overview of the most common determinants of breastfeeding in the country. however, a more 321 focused study on the southern province would be useful to identify more focused 322 interventions. although the enumerators were rigorously trained and conducted the field 323 work, coding was carried out by the nutrition core team which may have led to some 324 margin of error of interpretation. although the sample size is small and participants were 325 from various regions of the country, the results may not be generable to the whole population. 326 327 conclusion 328 women in oman experience similar barriers to breastfeeding as women around the world. 329 scaling up existing interventions, policies and programs requires not only continuing to 330 emphasize the benefits and convenience of exclusive breastfeeding but also building 331 women’s confidence in their ability to produce sufficient milk. these expansions will require 332 increasing the knowledge and skills of community and health care workers. national 333 campaigns could highlight how exclusive breastfeeding contributes to a happy and peaceful 334 life and encourage support from family members. expanding paid maternity leave and other 335 policies that encourage working women to exclusively breastfeed is also needed. 336 337 11 conflict of interest 338 the authors declare no conflicts of interest. 339 340 funding 341 unicef 342 343 acknowledgements 344 thanks to the women who participated in this study. this manuscript is based on unicef 345 funded research conducted by the authors. the views expressed in this paper are those of the 346 authors and do not necessarily reflect those of the ministry of health of oman. 347 348 authors’ contribution 349 sa-g, sa-m, dc and ca conceptualized the study. sa-g, dc and ca worked on the 350 methodology utilized in the study. dc and ca authored the research tools. ia-g, aa-a, sa-351 s, rma-b and fa-m collected the data. all authors were involved in data analysis. sa-m, 352 dc, ca and rmm interpreted the results. sa-m and rmm drafted the manuscript. all 353 authors approved the final version of the manuscript. 354 355 references 356 1. victora, c. g.; bahl, r.; barros, a. j. d.; frança, g. v. a.; horton, s.; krasevec, j., 357 et al., breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. the 358 lancet 2016, 387 (10017), 475-490. doi: https://doi.org/10.1016/s0140-6736(15)01024-7 359 2. rollins, n. c.; bhandari, n.; hajeebhoy, n.; horton, s.; lutter, c. k.; martines, j. c., 360 et al., why invest, and what it will take to improve breastfeeding practices? the lancet 2016, 361 387 (10017), 491-504. doi: 362 3. ministry of health oman, oman national nutrition survey 2017. ministry of health, 363 o., ed. ministry of health: muscat, oman, 2017. 364 4. world health organization; unicef, global nutrition targets 2025, breastfeeding 365 policy brief (who/nmh/nhd/14.7). world health organization: geneva, 2014. 366 5. al-jawaldeh, a.; abul-fadl, a., assessment of the baby friendly hospital initiative 367 implementation in the eastern mediterranean region. children 2018, 5 (3), 41. doi: 368 https://doi.org/10.1016/s0140-6736(15)01024-7 12 6. al-jawaldeh, a.; abul-fadl, a.; tawfik, a., in-depth analysis of mortality in 369 relation to malnutrition in children under-five of age in the eastern mediterranean region. 370 j nutr weight loss 2018, 2 (112), 2. doi: 371 7. parsa, p.; masoumi, z.; parsa, n.; parsa, b., parents' health beliefs influence 372 breastfeeding patterns among iranian women. oman med j 2015, 30 (3), 187-92. doi: 373 10.5001/omj.2015.40 374 8. humphreys, a. s.; thompson, n. j.; miner, k. r., assessment of breastfeeding 375 intention using the transtheoretical model and the theory of reasoned action. health 376 education research 1998, 13 (3), 331-341. doi: 377 9. kittle, b., a practical guide to conducting a barrier analysis. 2nd ed.; 2017. 378 10. brockway, m.; benzies, k.; hayden, k. a., interventions to improve breastfeeding 379 self-efficacy and resultant breastfeeding rates: a systematic review and meta-analysis. 380 journal of human lactation 2017, 33 (3), 486-499. doi: 381 11. nasser, a.; omer, f.; al-lenqawi, f.; al-awwa, r.; khan, t.; el-heneidy, a., et al., 382 predictors of continued breastfeeding at one year among women attending primary healthcare 383 centers in qatar: a cross-sectional study. nutrients 2018, 10 (8), 983. doi: 384 12. radwan, h.; sapsford, r., maternal perceptions and views about breastfeeding 385 practices among emirati mothers. food and nutrition bulletin 2016, 37 (1), 73-84. doi: 386 13. al ketbi, m. i.; al noman, s.; al ali, a.; darwish, e.; al fahim, m.; rajah, j., 387 knowledge, attitudes, and practices of breastfeeding among women visiting primary 388 healthcare clinics on the island of abu dhabi, united arab emirates. international 389 breastfeeding journal 2018, 13 (1), 26. doi: 390 14. elmougy, a.; matter, m.; shalaby, n.; el-regal, m.; abu ali, w.; aldossary, s., et 391 al., knowledge, attitude and practice of breastfeeding among working and non-working 392 mothers in saudi arabia egyptian journal of occupational medicine 2018, 42 (1), 133-150. 393 doi: 394 15. davis jr., t. p. barrier analysis facilitator guide: a tool for improving behavior 395 change communication in child survival and community development programs; food for 396 the hungry: washington, dc, 2004. 397 16. ministry of health, o., oman national nutrition survey. ministry of health, o., ed. 398 ministry of health: muscat, 2018. 399 17. pérez-escamilla, r.; curry, l.; minhas, d.; taylor, l.; bradley, e., scaling up of 400 breastfeeding promotion programs in lowand middle-income countries: the 401 13 “breastfeeding gear” model. advances in nutrition 2012, 3 (6), 790-800. doi: 402 10.3945/an.112.002873 403 18. brown, c. r.; dodds, l.; legge, a.; bryanton, j.; semenic, s., factors influencing 404 the reasons why mothers stop breastfeeding. canadian journal of public health 2014, 105 405 (3), e179-e185. doi: 406 19. hendaus, m. a.; alhammadi, a. h.; khan, s.; osman, s.; hamad, a., breastfeeding 407 rates and barriers: a report from the state of qatar. international journal of women's health 408 2018, 10, 467. doi: 409 20. al-nuaimi, n.; katende, g.; arulappan, j., breastfeeding trends and determinants: 410 implications and recommendations for gulf cooperation council countries. sultan qaboos 411 univ med j 2017, 17 (2), e155-e161. doi: 10.18295/squmj.2016.17.02.004 412 21. al-ghannami, s. s.; al-shammakhi, s. m.; al-jawaldeh, a.; al-mamari, f. a.; al-413 gammaria, i. k.; al-aamry, j. a., et al., rapid assessment of marketing of unhealthy foods 414 to children in mass media, schools and retail stores in oman. east mediterr health j 2019, 415 25. doi: 416 22. ministry of commerce, i. a. i. p. o., marketing regulation of designated products for 417 infants and young children (os 1649/2021). standards, d. g. o. s. a., ed. ministry of 418 commerce, industry and investment promotion: muscat, oman, 2021. 419 23. ministry of health oman, the omani code for marketing of breast milk substitutes. 420 ministry of health, oman: muscat, oman, 1998. 421 24. world health organization, marketing of breast-milk substitutes: national 422 implementation of the international code: status report 2016. world health organization: 423 geneva, switzerland, 2016. 424 25. ministry of health oman, community-based initiative strategy. ministry of health: 425 muscat, oman, 2017. 426 26. prakash, n. s.; mabry, r. m.; mohamed, a. j.; alasfoor, d., implementation of the 427 who multicentre growth reference study in oman. food and nutrition bulletin 2004, 25 428 (1_suppl_1), s78-s83. doi: 429 27. al-hasani, m. women's employement in oman. the university of queensland, the 430 university of queensland, 2015. 431 28. zerovec, m.; bontenbal, m., labor nationalization policies in oman: implications for 432 omani and migrant women workers. asian and pacific migration journal 2011, 20 (3-4), 433 365-387. doi: 434 14 29. ahmed, s.; fielding, d., changes in maternity leave coverage: implications for 435 fertility, labour force participation and child mortality. social science & medicine 2019, 241, 436 112573. doi: 437 438 15 table 1: barrier analysis assessment tool 439 doers non-doers perceived self-efficacy 1a. what makes it easy for you to give only breast milk to your baby from birth to 6 months? [probe] 1b. what would make it easier for you to give only breast milk to your baby from birth to 6 months? [probe] 2a. what makes it difficult for you to give only breast milk to your baby from birth to 6 months? [probe] 2b. what would make it difficult for you to give only breast milk to your baby from birth to 6 months? [probe] perceived positive and negative consequences 3a. what are the advantages of only giving breast milk to your baby from birth to 6 months? [probe] 3b. what would be the advantages of only giving breast milk to your baby from birth to 6 months? [probe] 4a. what are the disadvantages of only giving breast milk to your baby from birth to 6 months? [probe] 4b. what would be the disadvantages of only giving breast milk to your baby from birth to 6 months? [probe] perceived social norms 5a. who are all of the people that approve of you only giving breast milk to your baby from birth to 6 months? [probe] 5b. who are all of the people that would approve of you only giving breast milk to your baby from birth to 6 months? [probe] 6a. who are all of the people that disapprove of you only giving breast milk to your baby from birth to 6 months? [probe] 6b. who are all of the people that would disapprove of you only giving breast milk to your baby from birth to 6 months? [probe] perceived access 7a. how difficult is it for you to get the support you need to give only breastmilk to your baby from birth to six months old? would 7b. how difficult would it be to get the support your need to give only breast milk to your baby from birth to 6 months? would you 16 you say that it is very difficult, somewhat difficult, or not difficult at all? a. very difficult b. somewhat difficult c. not difficult at all say that it would be very difficult, somewhat difficult, or not difficult at all? a. very difficult b. somewhat difficult c. not difficult at all perceived cues for action / reminders 8a. how difficult is it to remember to give only breast milk to your baby from birth to 6 months? would you say that it is very difficult, somewhat difficult, or not difficult at all? a. very difficult b. somewhat difficult c. not difficult at all 8b. how difficult would it be to remember to give only breast milk to your baby from birth to 6 months? would you say that it would be very difficult, somewhat difficult, or not difficult at all? a. very difficult b. somewhat difficult c. not difficult at all perceived susceptibility / risk 9. how likely is it that your baby will become malnourished in the next year? would you say that is it very likely, somewhat likely, or not likely at all? a. very difficult b. somewhat difficult c. not difficult at all perceived severity 17 10. how serious would it be if your baby became malnourished? would you say that it would be a very serious, somewhat serious, or not serious at all? a. very difficult b. somewhat difficult c. not difficult at all action efficacy 11. how likely is it that your baby will become malnourished if you give only breast milk to your baby for the first 6 months? would you say that it is very likely, somewhat likely or not likely at all? a. very difficult b. somewhat difficult c. not difficult at all perception of divine will 12. does islam approve of mothers giving only breastmilk to their babies for the first six months? a. very difficult b. somewhat difficult c. not difficult at all culture 13. are there any cultural rules or taboos against only giving breast milk to your baby from birth to 6 months? a. yes b. maybe / i don’t know c. no 18 if yes, briefly explain: policy 14. are there any teachings, recommendations, policies, laws or regulations that make it more likely that you give only breast milk to your baby from birth to 6 months? a. yes b. maybe / i don’t know c. no if yes, briefly explain: universal motivators 15. now i’m going to ask you a question not at all related to what we have been discussing. what do you want more than anything from life? [probe] 440 19 table 2: determinants of exclusive breastfeeding among omani women (n=97) 441 emerging thematic determinants % doers (#) n=45 % nondoers (#) n=52 difference between doers and non-doers (% points) odds ratio (confidence interval) estimate relative risk p-value 1. self-efficacy: what makes it easier? breastmilk is available, ready and requires no preparation 38 (17) 15 (8) 22 3.34 (1.27, 8.76) 2.84 0.011 i think it is important (not specified) 16 (7) 2 (1) 14 9.39 (1.11, 79.61) 5.42 0.018 if i deliver the baby easily and have good health 0 12 (6) 12 0.00 0.00 0.021 i do not have any problems with breastfeeding or positioning the baby for feeding. 13 (6) 21 (11) 8 0.57 (0.19, 1.70) 0.60 0.230 it helps with the baby's growth and development 13 (6) 12 (6) 2 1.18 (0.35, 3.95) 1.16 0.514 i know that it improves my baby's immune system, keeps him from getting illnesses. 16 (7) 15 (8) 1 1.01 (0.34, 3.05) 1.01 0.600 20 i am available and free to breastfeed my child any time. 27 (12) 27 (14) 0 0.99 (0.40, 2.43) 0.99 0.581 2. self efficacy: what makes it difficult? it is not difficult 40 (18) 4 (2) 36 16.67 (3.59, 77.28) 8.27 <0.001 there is not enough milk, especially in the beginning. 11 (5) 33 (17) 22 0.26 (0.09, 0.77) 0.28 0.010 i work outside of the home. 7 (3) 25 (13) 18 0.21 (0.06, 0.81) 0.24 0.014 i have to be away from home and there is no place to breastfeed. 24 (11) 8 (4) 17 3.88 (1.14, 13.23) 3.13 0.023 sometimes the baby does not want to nurse or take my breastmilk from a bottle. 16 (7) 27 (14) 11 0.50 (0.18, 1.38) 0.53 0.134 i have problems with my breasts or nipples (painful, swollen, cracked or inverted nipples) 22 (10) 27 (14) 5 0.78 (0.31, 1.97) 0.79 0.384 i have too many things to do so i get busy and tired. 16 (7) 12 (6) 4 1.41 (0.44, 4.56) 1.36 0.388 3. perceived positive consequences: what are the advantages? 21 helps the mother lose the weight gained with the pregnancy. 24 (11) 8 (4) 17 3.88 (1.14, 13.23) 3.13 0.023 safe for the child to drink and doesn't cause side effects or allergies. 20 (9) 8 (4) 12 3.00 (0.86, 10.52) 2.55 0.070 it helps with brain development of the child and makes him intelligent. 13 (6) 21 (11) 8 0.57 (0.19, 1.70) 0.60 0.230 improves the health of the mother and protects from illnesses. 20 (9) 13 (7) 7 1.61 (0.55, 4.74) 1.52 0.277 decreases the chance that the mother will get cancer. 9 (4) 13 (7) 5 0.63 (0.17, 2.30) 0.65 0.352 delays pregnancy; good for birth spacing. 20 (9) 17 (9) 3 1.19 (0.43, 3.33) 1.17 0.467 it improves weight and the immunity of the baby and keeps him healthy. 96 (43) 94 (49) 1 1.32 (0.21, 8.25) 1.28 0.569 increases the bonding between mother and child. 16 (7) 15 (8) 0 1.01 (0.34, 3.05) 1.01 0.600 4. perceived negative consequences: what are the disadvantages? the baby does not get enough milk and is not satisfied and then loses weight. 0 17 (9) 17 0.00 0.00 0.003 there are no disadvantages / i don't know. 64 (29) 58 (3) 7 1.33 (0.58, 3.02) 1.29 0.319 22 the child becomes too attached to me and then i cannot leave him to go do other things i need to do. 13 (6) 10 (5) 4 1.45 (0.41, 5.10) 1.39 0.398 5. perceived social norms: who approves? husband 87 (39) 69 (36) 17 2.89 1.02, 8.19) 2.66 0.034 mother 78 (35) 62 (32) 16 2.19 (0.89, 5.37) 2.04 0.065 sister 42 (19) 56 (29) 14 0.58 (0.26, 1.30) 0.61 0.130 mother-in-law 31 (14) 23 (12) 8 1.51 (0.61, 3.71) 1.44 0.254 sisters-in-law 16 (7) 21 (11) 6 0.69 (0.24, 1.95) 0.71 0.330 doctors, nurses and health workers 13 (6) 17 (9) 4 0.74 (0.24, 2.25) 0.76 0.400 6. perceived social norms: who disapproves? my mother 7 (3) 13 (7) 7 0.46 (0.11, 1.89) 0.49 0.225 my sisters 16 (7) 10 (5) 6 1.73 (0.51, 5.89) 1.62 0.281 23 no one 44 (20) 38 (20) 6 1.28 (0.57, 2.88) 1.25 0.348 my sisters-in-law 13 (6) 17 (9) 4 0.74 (0.24, 2.25) 0.76 0.400 my friends 11 (5) 15 (8) 4 0.69 (0.21, 2.27) 0.71 0.378 7. perceived access: how difficult is it to get the support you need to ebf? very difficult 0 8 (4) 8 0.00 0.00 0.078 somewhat difficult 13 (6) 31 (16) 17 0.35 (0.12, 0.98) 0.38 0.034 not difficult at all 87 (39) 62 (32) 25 4.06 (1.46, 11.32) 3.65 0.005 8. perceived cues for action: how difficult is it to remember to give your baby only breastmilk? very difficult 2 (1) 2 (1) 0 1.16 (0.07, 19.08) 1.14 0.715 somewhat difficult 9 (4) 17 (9) 8 0.47 (0.13, 1.63) 0.49 0.181 not difficult at all 89 (40) 81 (42) 8 1.90 (0.60, 6.06) 1.81 0.207 9. perceived susceptibility/risk: how likely is it that your baby will become malnourished in the coming year? very likely 7 (3) 0 7 10.64 0.096 24 somewhat likely 24 (11) 40 (21) 16 0.48 (0.20, 1.15) 0.51 0.073 not likely at all 69 (31) 58 (30) 11 1.62 (0.70, 3.75) 1.55 0.177 10. perceived severity: how serious would it be if your child became malnourished? very serious 40 (18) 48 (25) 8 0.72 (0.32, 1.61) 0.74 0.277 somewhat serious 49 (22) 42 (22) 7 1.30 (0.58, 2.91) 1.27 0.328 not serious at all 11 (5) 10 (5) 1 1.18 (0.32, 4.35) 1.16 0.534 11. action efficacy: how likely is it that your child will become malnourished if you feed him only breastmilk to 6 months? a. very likely 2 (1) 8 (4) 5 0.27 (0.03, 2.53) 0.30 0.229 b. somewhat likely 16 (7) 35 (18) 19 0.35 (0.13, 0.93) 0.38 0.027 c. not likely at all 82 (37) 58 (30) 25 3.39 (1.32, 8.70) 3.06 0.008 12. perception of divine will: does islam approve of giving only breastmilk? a. yes 89 (40) 83 (43) 6 1.67 (0.52, 5.42) 1.60 0.284 25 b. maybe 2 (1) 8 (4) 5 0.27 (0.03, 2.53) 0.30 0.229 c no 9 (4) 10 (5) 1 0.92 (0.23, 3.64) 0.92 0.592 13. culture: are there any taboos or myths that prevent women from practicing the behaviour? a. yes 18 (8) 13 (7) 4 1.39 (0.46, 4.19) 1.34 0.379 b. maybe 0 0 0 1.000 c. no 82 (37) 87 (45) 4 0.72 (0.24, 2.17) 0.75 0.379 14. policy: are there any laws or regulations that make it more likely women will exclusively breastfeed? a. yes 67 (30) 58 (30) 9 1.47 (0.64, 3.36) 1.41 0.243 b. maybe 7 (3) 6 (3) 1 1.17 (0.22, 6.09) 1.15 0.590 c. no 27 (12) 37 (19) 10 0.63 (0.26, 1.51) 0.66 0.206 15. universal motivators happiness and peace 11 (5) 29 (15) 18 0.31 (0.10, 0.93) 0.34 0.027 26 to be a good mother and raise good children. 27 (12) 10 (5) 17 3.42 (1.10, 10.63) 2.85 0.026 to please god 16 (7) 12 (6) 4 1.41 (0.44, 4.56) 1.36 0.388 money and financial stability / a good job or source of income 24 (11) 21 (11) 3 1.21 (0.47, 3.12) 1.18 0.442 health for myself and my family 64 (29) 65 (34) 1 0.96 (0.42, 2.21) 0.96 0.546 a good education and future for my children 24 (11) 25 (13) 1 0.97 (0.38, 2.45) 0.97 0.570 a house 13 (6) 13 (7) 0 0.99 (0.31, 3.19) 0.99 0.612 442 مستوى احلديد يف املصل لألطفال املصابني بأمراض القلب اخللقية يف الغوس، نيجرييا اديجوموكي اإتيول، بركات انيما�صاهون، اولي�صاميدوا جنوكامنا abstract: objectives: cyanotic congenital heart disease (cchd) predisposes patients to iron deficiency due to compensatory secondary erythrocytosis. this study aimed to determine the serum iron status and prevalence of iron deficiency among children with cyanotic congenital heart disease attending the paediatric cardiology outpatient clinic of lagos state university teaching hospital, lagos, nigeria. methods: this cross-sectional casecontrol study took place between may and october 2015 at the lagos state university teaching hospital. a total of 75 children with cyanotic congenital heart disease and 75 apparently healthy age-, genderand socioeconomicallymatched controls were analysed to determine serum iron status and the prevalence of iron deficiency as defined by the world health organization criteria. results: the mean age of the children was 47.5 ± 2.9 months (range: 6–144 months old). iron deficiency was significantly more frequent among cchd patients compared to control subjects (9.3% versus 0%; p = 0.006). while latent iron deficiency was more prevalent among children in the control group compared to those with cchd, this difference was not statistically significant (13.3% versus 9.3%; p = 0.303). no cases of iron deficiency anaemia were observed in the studied sample. conclusion: neither the children in the control group nor those with cchd had iron deficiency anaemia. however, iron deficiency was significantly more prevalent among children with cchd in lagos. periodic serum iron status screening is therefore recommended for this population. keywords: congenital heart defects; cyanosis; iron deficiency anemia; children; case-control studies; nigeria. امللخ�ص: الهدف: يوؤهب مر�ض القلب اخللقي املزمن املر�صى لنق�ض احلديد ب�صبب كرثة كريات الدم احلمراء التعوي�صية. هدفت هذه الدرا�صة اإىل حتديد حالة احلديد يف امل�صل وانت�صار نق�ض احلديد بني الأطفال امل�صابني باأمرا�ض القلب اخللقية امل�صحوبه بالزرقة الذين يح�رسون اإىل العيادة اخلارجية لأمرا�ض القلب لدى الأطفال يف م�صت�صفى جامعة ولية لجو�ض التعليمي، لجو�ض، نيجرييا. الطريقة: اأجريت هذه من يعانون طفاًل 75 جمموعه ما حتليل مت التعليمي. لجو�ض ولية جامعة م�صت�صفى يف 2015 واأكتوبر مايو بني امل�صتعر�صة الدرا�صة اأمرا�ض القلب اخللقية امل�صحوبه بالزرقة و 75 طفال كمجموعه �صابطة مطابقة يف العمر واجلن�ض واأي�صا احلالة الجتماعية والقت�صادية لتحديد حالة احلديد يف الدم وانت�صار نق�ض احلديد بينهم على النحو املحدد يف معايري منظمة ال�صحة العاملية. النتائج: كان متو�صط عمر الأطفال 2.9 ± 47.5 �صهر )املدى: 144-6 �صهًرا(. كان نق�ض احلديد اأكرث تواجدا ب�صكل ملحوظ بني مر�صى اأمرا�ض القلب اخللقية امل�صحوبه بالزرقة مقارنة مع الأ�صخا�ض يف املجموعه ال�صابطة )%9.3 مقابل p = 0.006 ،0%(. بينما كان نق�ض احلديد الكامن اأكرث انت�صاًرا بني الأطفال يف املجموعة ال�صابطة مقارنة باأولئك الذين يعانون من اأمرا�ض القلب اخللقية امل�صحوبه بالزرقة، ومل يكن ذو دللة اإح�صائية )%13.3 مقابل %9.3؛ p = 0.303(. مل تكن هناك حالت فقر الدم ب�صبب نق�ض احلديد يف كل عينة الدرا�صة. اخلال�صة: مل يتم ت�صجيل اأي حالت فقر الدم الناجم عن نق�ض احلديد لدى الأطفال يف املجموعة ال�صابطة ول الأطفال امل�صابني باأمرا�ض القلب اخللقية امل�صحوبه بالزرقة. ومع ذلك، كان نق�ض احلديد اأكرث انت�صارا ب�صكل ملحوظ بني الأطفال الذين يعانون من اأمرا�ض القلب اخللقية امل�صحوبه بالزرقة يف لجو�ض. لذلك ين�صح فح�ض حالة احلديد يف امل�صل الدوري لهذه الفئة من ال�صكان. الكلمات املفتاحية: عيوب القلب اخللقية؛ زرقة؛ فقر الدم بعوز احلديد؛ الأطفال؛ درا�صات احلالت واملجموعة ال�صابطة؛ نيجرييا. serum iron status of children with cyanotic congenital heart disease in lagos, nigeria adejumoke y. itiola,1 *barakat a. animasahun,2 olisamedua f. njokanma3 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e345–351, epub. 22 dec 19 submitted 24 feb 19 revisions req. 10 apr & 30 may 19; revisions recd. 24 apr & 19 jun 19 accepted 11 jul 19 advances in knowledge this study found iron deficiency to be significantly more prevalent among children with cyanotic congenital heart disease (cchd) compared to a matched control group. no cases of iron deficiency were noted among children in the control group according to the criteria of the world health organization; however, latent iron deficiency was more common in the control group. application to patient care based on these findings, periodic serum iron status assessment and treatment is recommended for children with cchd in this setting. as children of both groups were found to have latent iron deficiency, routine counselling would also be beneficial for the caregivers of children to stress the importance of iron-rich foods and meal fortification. 1department of paediatrics, faith city hospital, lagos, nigeria; 2department of paediatrics & child health, college of medicine, lagos state university, lagos, nigeria; 3department of paediatrics, lagos state university teaching hospital, lagos, nigeria *corresponding author’s e-mail: deoladebo@yahoo.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.010 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ serum iron status of children with cyanotic congenital heart disease in lagos, nigeria e346 | squ medical journal, november 2019, volume 19, issue 4 cyanotic congenital he art dise ase (cchd) is characterised by hypoxia resulting in physiologically-increased erythropoiesis which, if unabated, leads to iron deficiency.1 this predisposes children to growth retardation, impaired immune function, delayed behavioural, mental and psy chomotor development and decreased work capacity.2–5 the extreme manifestation of iron deficiency is an anaemic state.6 however, the clinical detection of anaemia based on pallor is hampered by the occurrence of hypoxia-induced polycythaemia in cchd.7 labor atory tests and periodic screening are therefore manda tory for diagnosis.8 overall, cchd accounts for an estimated third of congenital heart disease cases.9 treatment is usually surgical, with the cost of repair ranging from $10,000– $50,000 usd, depending on setting.10 unfortunately, this is often beyond the economic means of the average nigerian family; as such, surgical correction of the defect is usually delayed due to financial constraints.10,11 accordingly, cchd-related comorbidities such as iron deficiency should be treated promptly to improve clinical outcomes in affected children. however, there is a paucity of local studies on the iron status of nigerian children with cchd, particularly in settings where iron deficiency and iron deficiency anaemia are reportedly common.11–13 a recent study reported that the prevalence of iron deficiency among children with cchd in ibadan, nigeria, was high (35%).11 conventional tests for iron deficiency such as mean corpuscular volume, serum ferritin levels and transferrin saturation (tsat) have limited value due to varying sensitivities and specificities, especially as results may be affected by acute or chronic inflammatory conditions, genetic polymorphisms and sickle cell disease states.12,14,15 other researchers have also reported that expected microcytic, hypochromic and erythrocyte findings are often absent in cyanotic patients with iron deficiency.16 this study aimed to assess serum iron status and the prevalence of iron deficiency among children with cchd in lagos, nigeria, in comparison to a matched control group. the research questions for the study were: (1) what is the prevalence of iron deficiency in children with cyanotic congenital heart disease; and (2) what is the prevalence of iron deficiency anaemia in children with cyanotic congenital heart disease. the null hypotheses were: (1) there is no statistically significant difference between the prevalence of iron deficiency in children with cyanotic congenital heart disease and those of the appropriate ageand gender-matched controls; and (2) there is no statistically significant difference between the prevalence of iron deficiency anaemia in children with cyanotic congenital heart disease and those of the appropriate ageand gender-matched controls. these findings are expected to increase awareness regarding the need for routine monitoring and prompt treatment, thereby reducing morbidity in this patient group. methods this cross-sectional case-control study was carried out between may and october 2015 at the department of paediatrics at lagos state university teaching hospital which is an urban tertiary healthcare centre in ikeja, lagos, nigeria. a total of 150 children were recruited consecutively over the six-month period, including 75 consecutive children with cchd and 75 control subjects matched for age, gender and socioeconomic status. classification and matching for the latter variable was performed according to previous research.17 the estimated sample size was determined according to the following equation for comparative studies:18 where zα is the normal standard deviation corresp onding to a 95% confidence interval (1.96), zβ is the power set at 80% (0.84), p is the average of previously reported prevalence rates of iron deficiency in children with cchd (16.9%) and controls (27.5%) and d is the minimum difference to be detected by the study (20%).19 this calculation resulted in a minimum of 67 subjects; however, as the non-response rate was set at 10%, the final number of subjects was calculated to be 74. this was then rounded up to 75 subjects for ease of calculation, each of whom were subsequently matched for age, gender and socioeconomic class with a control subject. in terms of inclusion criteria, the case group included patients diagnosed with echocardiographyconfirmed cchd attending the outpatient paediatric cardiology clinic who had not undergone corrective surgery and who were between six months and 12 years old. only subjects who had had no symptoms or signs attributable to an acute illness within the preceding four weeks were included in the study. children who had undergone a partial exchange transfusion, blood transfusion or repeated phlebotomy in the past three months were excluded, as well as those who had received iron supplementation prior to recruitment or had been diagnosed with sickle cell anaemia or other chronic illnesses. the control group comprised of apparently healthy children recruited from general n = (zα + zβ) 2 × 2p (1–p) [equation 1] d2 adejumoke y. itiola, barakat a. animasahun and olisamedua f. njokanma clinical and basic research | e347 outpatient clinics and other specialty clinics within the same age range. children were deemed healthy if they had had no symptoms or signs attributable to illness within the preceding four weeks. children in both the case and control groups underwent venepuncture performed according to the guidelines of the world health organization (who).20 an lh 750 hematology analyser (beckman coulter inc., brea, california, usa) was used to perform an automated complete blood count using whole blood samples with ethylenediaminetetraacetic acid added. serum ferritin levels were measured using a human ferritin enzyme immunoassay test kit with a calibration range of 0–800 ng/ml (ferritin accubind elisa kit, monobind inc., lake forest, california, usa). serum iron levels and total iron-binding capacity (tibc) were measured using a reagent set (teco diagnostics, anaheim, california, usa). unsaturated iron-binding capacity was determined by adding ferrous iron ions to the serum so that they would bind to transferrin at unsaturated binding sites.21 as per the who criteria, a diagnosis of iron deficiency was defined according to cut-off serum ferritin levels of <12 ng/l or <15 ng/l for children aged <5 years old and ≥5 years old, respectively.8 in turn, iron deficiency anaemia was diagnosed for subjects with serum ferritin levels of <12 ng/l or <15 ng/l for children aged <5 years old and ≥5 years old, respectively, in the presence of haemoglobin concentrations at least two standard deviations below that of the normal population at the same age.22 all data collected were stored on a personal computer. statistical analysis was performed using an excel spreadsheet, version 2010 (microsoft inc., red mond, washington, usa) and the statistical package for the social sciences (spss), version 20.0 (ibm corp., armonk, new york, usa). means, medians, standard deviations and ranges were calculated for continuous variables, while categorical variables were represented as frequencies and percentages. continuous variables were compared using a student’s t-test, while categ orical variables were compared with fisher’s exact test. a kolmogorov-smirnov nonparametric test was used to determine the normality of continuous data; subsequently, a student’s t-test was used to compare normally-distributed data, while a mann-whitney u test was used for skewed or non-normally distributed data. the degree of agreement between different methods used to evaluate the same parameter was estimated using kappa statistics. a p value of 0.050 was deemed statistically significant. ethical approval for this study was obtained from the ethics committee of lagos state university teaching hospital (lrec/10/06/398). written informed consent was obtained from the parents/caregivers of participants. moreover, all children found to be iron-deficient during the course of the study received prompt and appropriate treatment. results this study included 150 children, of which 75 were cchd patients and 75 were apparently healthy controls [equation 1]. the mean age of the children was 47.5 ± 2.9 months (range: 6–144 months old). in terms of age distribution, 26 children with cchd (34.7%) were <24 months old, 30 (40%) were between 24–59 months old and 19 (25.3%) were ≥60 months old. as the controls were age-matched, there were equal numbers of children in each age group in the control group. in the cchd group, tetralogy of fallot (tof) was the most common heart lesion (52%), followed by double-outlet right ventricle (dorv; 12%). the least common diagnoses were ebstein anomalies and complex heart disease (1.3% each) [table 1]. although all of the study population had normal haemoglobin concentrations, mean haemoglobin concentrations were significantly higher among children with cchd compared to those in the control group (13.8 ± 3.9 g/dl versus 10.3 ± 0.8 g/dl; p <0.001). mean serum iron, serum ferritin, tibc and tsat values were compared between children with cchd and apparently healthy controls according to age group. among children aged 6–23 months, mean serum iron levels were significantly lower in the cchd group compared to the control group (162.8 ± 10.8 µg/dl table 1: frequency of heart lesions among children with cyanotic congenital heart disease in lagos, nigeria (n = 75) lesion n (%) tetralogy of fallot 39 (52) double-outlet right ventricle 9 (12) tga 6 (8) critical pulmonary stenosis 4 (5.3) eisenmenger complex 4 (5.3) pulmonary atresia with vsd 4 (5.3) truncus arteriosus 3 (4) tricuspid atresia 2 (2.7) tapvc 2 (2.7) ebstein anomaly 1 (1.3) complex heart disease 1 (1.3) tga = transposition of the great arteries; vsd = ventricular septal defect; tapvc = total anomalous pulmonary venous connection. serum iron status of children with cyanotic congenital heart disease in lagos, nigeria e348 | squ medical journal, november 2019, volume 19, issue 4 versus 171.6 ± 5.6 µg/dl; p <0.001); a similar finding was documented for tsat (48.7 ± 24.9% versus 52.6 ± 15.0%; p = 0.040). however, there were no significant intergroup differences regarding mean tibc and serum ferritin levels [table 2]. for the 24–59-month-old age group, serum iron levels were also significantly lower in the cchd group compared to controls (167.7 ± 39.7 µg/dl versus 169.7 ± 7.3 µg/dl; p <0.001), although none of the other biochemical parameters were significantly different between the cchd and control groups [table 3]. similar findings were noted for 60–144-month-old children, with serum iron levels significantly reduced in the cchd group (163.1 ± 5.6 µg/dl versus 169.6 ± 10.3 µg/dl; p = 0.001), while none of the other biochemical parameters differed significantly [table 4]. the prevalence rates of frank and latent iron deficiency are shown in figure 1. overall, seven (9.3%) children with cchd had an iron deficiency whereas figure 1: prevalence of iron deficiency among children with cyanotic congenital heart disease and age-matched controls in lagos, nigeria (n = 150). cchd = cyanotic congenital heart disease. table 2: iron status parameters among 6–23-month-old children with cyanotic congenital heart disease and age-matched controls in lagos, nigeria (n = 52) parameter mean ± sd; median (range) z score p value* cchd group (n = 26) control group (n = 26) serum iron in µg/dl 162.8 ± 10.8; 166.4 (130.3–175.9) 171.6 ± 5.6; 173.9 (154.8–176.4) 3.555 <0.001† serum ferritin in ng/dl 80.4 ± 56.3; 62.0 (2.0–200.0) 52.5 ± 27.2; 43.0 (18.0–110.0) 1.678 0.093 tibc in µg/dl 379.8 ± 111.5; 414.2 (111.7–579.3) 351.7 ± 98.4; 344.8 (182.8–577.8) 1.206 0.228 tsat in % 48.7 ± 24.9; 39.4 (30.2–149.9) 52.6 ± 15.0; 50.8 (29.9–91.2) 2.050 0.040† sd = standard deviation; cchd = cyanotic congenital heart disease; tibc = total iron-binding capacity; tsat = transferrin saturation. *using a mann-whitney u test. †statistically significant at p <0.050. table 3: iron status parameters among 24–59-month-old children with cyanotic congenital heart disease and age-matched controls in lagos, nigeria (n = 60) parameter mean ± sd; median (range) z score p value* cchd group (n = 30) control group (n = 30) serum iron in µg/dl 167.7 ± 39.7; 161.4 (141.4–357.6) 169.7 ± 7.3; 170.7 (148.0–179.4) 3.818 <0.001† serum ferritin in ng/dl 61.9 ± 52.1; 39.0 (2.0–205.0) 87.7 ± 63.2; 4.0 (12.0–220.0) 1.504 0.133 tibc in µg/dl 392.1 ± 98.1; 396.1 (209.9–500.5) 352.5 ± 81.5; 338.8 (224.3–582.1) 1.637 0.102 tsat in % 45.3 ± 14.0; 40.9 (26.1–80.0) 60.4 ± 10.9; 50.7 (30.3– 76.1) 1.904 0.057 sd = standard deviation; cchd = cyanotic congenital heart disease; tibc = total iron-binding capacity; tsat = transferrin saturation. *using a mann-whitney u test. †statistically significant at p <0.050. table 4: iron status parameters among 60–144-month-old children with cyanotic congenital heart disease and age-matched controls in lagos, nigeria (n = 38) parameter mean ± sd; median (range) z score p value* cchd group (n = 19) control group (n = 19) serum iron in µg/dl 163.1 ± 5.6; 162.1 (152.0–178.9) 169.6 ± 10.3; 173.3 (138.5–179.1) 3.338 0.001† serum ferritin in ng/dl 82.5 ± 61.5; 8.0 (7.0–201.0) 62.2 ± 58.3; 40.0 (13.0–215.0) 1.306 0.174 tibc in µg/dl 394.5 ± 112.7; 407.7 (218.1–632.8) 370.7 ± 96.6; 381.4 (133.9–524.9) 0.554 0.580 tsat in % 44.9 ± 14.6; 39.6 (26.9–82.0) 50.4 ± 20.9; 46.2 (30.9–129.2) 0.932 0.351 sd = standard deviation; cchd = cyanotic congenital heart disease; tibc = total iron-binding capacity; tsat = transferrin saturation. *using a mann-whitney u test. †statistically significant at p <0.050. adejumoke y. itiola, barakat a. animasahun and olisamedua f. njokanma clinical and basic research | e349 iron deficiency was not documented among the control group (9.3% versus 0%; p = 0.006). in contrast, latent iron deficiency was found to be more common in controls compared to subjects with cchd; however, this difference was not significant (13.3% versus 9.3%; p = 0.303). no cases of iron deficiency anaemia were documented in the study population in either group. in terms of specific heart diseases, three (7.7%) out of 39 children with tof, two (33.3%) out of six with tga and one (11.1%) out of nine with dorv were irondeficient. the remaining iron-deficient child was the only patient with an ebstein anomaly. with regards to age, iron deficiency occurred in five (8.9%) out of 56 and two (10.5%) out of 19 children who were <5 and ≥ 5 years old, respectively. in the cchd group, mean serum ferritin levels were significantly lower in iron-deficient subjects compared to those who were iron-sufficient (7.7 ± 4.6 ng/dl versus 84.0 ± 11.7 ng/dl; p <0.001), while the mean tibc was significantly higher in iron-deficient subjects (479.5 ± 98.7 µg/dl versus 377.2 ± 104.7 µg/dl; p = 0.017). however, there was no significant difference in mean serum iron levels and tsat between iron-deficient and iron-sufficient children with cchd [table 5]. discussion the overall prevalence of iron deficiency among children with cchd in the current study was 9.3%. other researchers have reported comparable prevalence rates of 12.5% and 16.9% in italy and kenya, respectively.19,23 similarities in these rates may be related to the age groups of the targeted populations, as both of the aforementioned studies recruited children up to 12 years of age.19,23 however, much higher rates have been reported in turkey (52.5–63.6%).24,25 this may again be due to population variation, as iron deficiency is reportedly higher in children under five years.13 nevertheless, when the analysis in the present study was limited to under-five-year-olds, the prevalence rate was 8.9%, which is still much lower than that reported in turkey.24,25 aside from methodological differences, other explanations for differing prevalence rates may be due to local geographical and nutritional factors beyond the scope of the present study. it is unlikely that the difference is due to the specific cchd type, as both the current study and previous studies reported similar frequencies of various heart lesions.22–25 in the present study, the spectrum of cchd followed expected patterns, with tof accounting for more than half of all patients. other heart diseases identified were consistent with those reported in previous research from nigeria.26 although the prevalence of iron deficiency among children with cchd was low in the present study, it was still significantly higher than that noted among the age-, genderand socioeconomicallymatched controls, in whom no documented case of iron deficiency was observed. this finding supports the theory that chronic hypoxia results in increased haemopoiesis and iron depletion in children with cchd.7 nevertheless, it is worth noting that even though none of the control group met the who criteria for diagnosing frank iron deficiency, latent iron deficiency was more frequently diagnosed in this group compared to the cchd group (13.3% versus 9.3%). frank and latent iron deficiency refer to the progressive depletion of iron stores on a continuum. the deterioration of iron status from iron sufficiency to latent deficiency has been demonstrated in a longitudinal study of patients with cchd.24 it is therefore pertinent to address the importance of iron fortification in the general population and iron supple mentation in iron-deficient children with cchd. such measures will help to reduce the morbidities to which children with iron deficiency are predisposed, including growth retardation, impaired immune function, impaired behavioural, mental and psycho motor development and decreased work capacity.2–5 in the present study, children with cchd had significantly higher mean haemoglobin concentrations in comparison to healthy controls. this finding is in line with previous research.11 an uncorrected table 5: iron status parameters according to iron sufficiency among children with cyanotic congenital heart disease in lagos, nigeria (n = 75) parameter mean ± sd t value p value iron-deficient children (n = 7) iron-sufficient children (n =68) serum iron in µg/dl 163.8 ± 6.2 165.1 ± 9.9 0.123 0.573 serum ferritin in ng/dl 7.7 ± 4.6 84.0 ± 11.7 3.664 <0.001* tibc in µg/dl 479.5 ± 98.7 377.2 ± 104.7 2.460 0.017* tsat in % 43.0 ± 17.7 46.5 ± 14.1 0.598 0.522 sd = standard deviation; tibc = total iron-binding capacity; tsat = transferrin saturation. *statistically significant at p <0.050. serum iron status of children with cyanotic congenital heart disease in lagos, nigeria e350 | squ medical journal, november 2019, volume 19, issue 4 congenital cyanotic heart lesion keeps the body in a state of constant hypoxia.27 hypoxia, in turn, triggers the physiological release of erythropoietin which stimulates the bone marrow to produce more erythro cytes, leading to an increase in oxygen-carrying capacity.28 moreover, mean serum iron levels in the current study were significantly lower in the cchd group compared to the controls, regardless of age. previously documented studies have reported similar findings.5,24 in cchd, low serum iron levels can be explained by the presence of hypoxaemia in which adaptive mechanisms increase the delivery of oxygen to the tissue, resulting in a rightward shift in the oxygenhaemoglobin dissociation curve. persistent hypoxia and the corresponding increase in red cell mass place a continuous demand on iron stores, predisposing children with cchd to iron deficiency.27 mean tibc values were also higher in the present study among iron-deficient compared to iron-sufficient children with cchd; soliman et al. reported similar findings.2 as a parameter, tibc indicates the maximum amount of iron needed to saturate transferrin, the primary protein involved in iron transport.6 thus it is not surprising that mean tibc is higher in the presence of iron deficiency. the findings of the current study answered the previously posed research questions. there was a significant difference in the number of cchd cases with iron deficiency compared to the controls, allowing for the rejection of the null hypothesis proposed for the first research question. moreover, a pattern suggestive of progressive iron depletion was observed, with patients manifesting both latent and frank iron deficiency. however, none of the subjects had iron deficiency anaemia; hence, the null hypothesis can be accepted for the second research question. this study was subject to certain limitations. c-reactive protein, a marker of inflammation was not measured; this could have been a confounding cause of elevated serum ferritin. however, efforts were made to exclude subjects with symptoms and or signs of infections within four weeks preceding the study. in addition, it would have been ideal to perform bone marrow aspiration, which is the gold standard test for iron deficiency, however the invasive nature of this procedure was not feasible, acceptable or costeffective in the present study. the current study was able to demonstrate the occurrence of iron deficiency in subjects with cchd and document the presence of latent iron deficiency in children with cchd and apparently healthy controls. this emphasises the need for periodic iron status checks of these children and nutritional counselling for parents of children attending the lagos state university teaching hospital. conclusion in lagos, nigeria, the prevalence of iron deficiency among children with cchd was 9.3%. routine serum iron status assessment should therefore be carried out periodically in this setting, with those children found deficient referred for treatment. latent iron deficiency was also fairly common among both cchd subjects and apparently healthy controls. accordingly, parents and caregivers should be routinely counselled on the importance of iron-rich foods and the benefits of meal fortification, regardless of disease status. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. tempe dk, virmani s. coagulation abnormalities in patients with cyanotic congenital heart disease. j cardiothorac vasc anesth 2002;16:752–65. https://doi.org/10.1053/jcan.2002.128436. 2. soliman at, al dabbagh mm, habboub ah, adel a, humaidy na, abushahin a. linear growth in children with iron deficiency anemia before and after treatment. j trop pediatr 2009; 55:324–7. https://doi.org/10.1093/tropej/fmp011. 3. beard j, deregnier ra, shaw md, rao r, georgieff m. diagnosis of iron deficiency in infants. lab med 2007; 38:103–8. https://doi.org/10.1309/7kj11rx758uklxxm. 4. lozoff b, jimenez e, wolf aw. long-term developmental outcome of infants with iron deficiency. n engl j med 1991; 325:687–94. https://doi.org/10.1056/nejm199109053251004. 5. tay el, peset a, papaphylactou m, inuzuka r, alonsogonzalez r, giannakoulas g, et al. replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/or the eisenmenger syndrome. int j cardiol 2011; 151:307–12. https://doi.org/10.1016/j.ijcard.2010.05.066. 6. thompson rb, proctor sj, eds. a short textbook of haematology, 6th ed. london, uk: urban & schwarzenberg, 1984. pp. 153–87. 7. rosove mh, perloff jk, hocking wg, child js, canobbio mm, skorton dj. chronic hypoxaemia and decompensated erythrocytosis in cyanotic congenital heart disease. lancet 1986; 2:313–15. https://doi.org/10.1016/s0140-6736(86)90005-x. 8. world health organization. iron deficiency anemia: assessment, prevention and control a guide for programme managers. from: www.who.int/nutrition/publications/micron utrients/anaemia_iron_deficienc y/who_nhd_01.3/en/ accessed: jun 2019. 9. olney rs, ailes ec, sontag mk. detection of critical congenital heart defects: review of contributions from prenatal and newborn screening. semin perinatol 2015; 39:230–7. https://doi.org/10.1053/j.semperi.2015.03.007. https://doi.org/10.1053/jcan.2002.128436 https://doi.org/10.1093/tropej/fmp011 https://doi.org/10.1309/7kj11rx758uklxxm https://doi.org/10.1056/nejm199109053251004 https://doi.org/10.1016/j.ijcard.2010.05.066 https://doi.org/10.1016/s0140-6736%2886%2990005-x https://doi.org/10.1053/j.semperi.2015.03.007 adejumoke y. itiola, barakat a. animasahun and olisamedua f. njokanma clinical and basic research | e351 10. falase b, sanusi m, majekodunmi a, ajose i, idowu a, oke d. the cost of open heart surgery in nigeria. pan afr med j 2013; 14:61. https://doi.org/10.11604/pamj.2013.14.61.2162. 11. ogunkunle oo. erythrocyte indices of iron status in children with cyanotic congenital heart disease at the university college hospital, ibadan. niger j paediatr 2013; 40:75–8. https://doi. org/10.4314/njp.v40i1.14. 12. fajolu ib, grange oa, renner jk, odunukwe nw, njokanma of, ahmed oa, et al. prevalence of iron deficiency in children 6-24 months in lagos. nig q j hosp med 2007; 17:97–100. https://doi.org/10.4314/nqjhm.v17i3.12553. 13. akodu os, disu ea, njokanma of, kehinde oa. iron deficiency anemia among apparently healthy pre-school children in lagos, nigeria. afr health sci 2016; 16:61–8. https://doi.org/10.4314/ahs.v16i1.8. 14. mangosongo b, kalokola fm, munubhi ek, mpembeni r. iron deficiency in sickle cell anaemia patients in dar es salaam, tanzania. tanzan med j 2004; 19:6–8. https://doi.org/10.4314/ tmj.v19i1.39190. 15. beard jl. iron biology in immune function, muscle metabol ism and neuronal functioning. j nutr 2001; 131:568s–79s. https://doi.org/10.1093/jn/131.2.568s. 16. kaemmerer h, fratz s, braun sl, koelling k, eicken a, brodherr-heberlein s, et al. erythrocyte indexes, iron meta bolism, and hyperhomocysteinemia in adults with cyanotic congenital cardiac disease. am j cardiol 2004; 94:825–8. https://doi.org/10.1016/j.amjcard.2004.06.014. 17. oyedeji ga. socio-economic and cultural background of hospitalised children in ilesha. niger j paediatr 1985; 12:111–17. 18. kirkwood br, sterne jac. calculation of required sample size. in: essential medical statistics, 2nd ed. oxford, uk: wileyblackwell, 2001. pp. 413–28. 19. lang’o mo, githanga jn, yuko-jowi ca. prevalence of iron deficiency in children with cyanotic heart disease seen at kenyatta national hospital and mater hospital nairobi. east afr med j 2009; 86:s47–51. https://doi.org/10.4314/eamj. v86i12.62901. 20. world health organization. who guidelines on drawing blood: best practices in phlebotomy. from: www.who.int/ infection-prevention/publications/drawing_blood_best/en/ accessed: jun 2019. 21. obeagu ei, eze vu, alaeboh ea, ochei kc. determination of haematocrit level and iron profile study among persons living with hiv in umuahia, abia state, nigeria. j bioinnovation 2016; 5:464–71. 22. pesce ma. reference ranges for laboratory tests and procedures. in: kliegman rm, behrman re, jenson hb, stanton bf, eds. nelson textbook of pediatrics, 18th ed. philadelphia, pennsylvania, usa: saunders, 2007. pp. 2943–54. 23. drossos c, thanapoulos b, papadimitrou t, milingos m, papadimitrou a, kostantelloy e, et al. [incidence of anemia in congenital heart diseases]. pediatr med chir 1981; 3:309–12. 24. onur cb, sipahi t, tavil b, karademir s, yoney a. diagnosing iron deficiency in cyanotic heart disease. indian j pediatr 2003; 70:29–31. https://doi.org/10.1007/bf02722740. 25. olcay l, ozer s, gürgey a, saraçlar m, ozme s, bilgiç a, et al. parameters of iron deficiency in children with cyanotic congenital heart disease. pediatr cardiol 1996; 17:150–4. https://doi.org/10.1007/bf02505204. 26. animasahun ba, madise-wobo ad, falase ba, omokhodion si. the burden of fallot’s tetralogy among nigerian children. cardiovasc diagn ther 2016; 6:453–8. https://doi.org/10.21037/ cdt.2016.05.04. 27. perloff jk, rosove mh, child js, wright gb. adults with cyanotic congenital heart disease: hematologic management. ann intern med 1988; 109:406–13. https://doi.org/10.7326/000 3-4819-109-5-406. 28. jelkmann w. regulation of erythropoietin production. j physiol 2011; 589:1251–8. https://doi.org/10.1113/jphysiol.2010.195057. https://doi.org/10.11604/pamj.2013.14.61.2162 https://doi.org/10.4314/njp.v40i1.14 https://doi.org/10.4314/njp.v40i1.14 https://doi.org/10.4314/nqjhm.v17i3.12553 https://doi.org/10.4314/ahs.v16i1.8 https://doi.org/10.4314/tmj.v19i1.39190 https://doi.org/10.4314/tmj.v19i1.39190 https://doi.org/10.1093/jn/131.2.568s https://doi.org/10.1016/j.amjcard.2004.06.014 https://doi.org/10.4314/eamj.v86i12.62901 https://doi.org/10.4314/eamj.v86i12.62901 https://doi.org/10.1007/bf02722740 https://doi.org/10.1007/bf02505204 https://doi.org/10.21037/cdt.2016.05.04 https://doi.org/10.21037/cdt.2016.05.04 https://doi.org/10.7326/0003-4819-109-5-406 https://doi.org/10.7326/0003-4819-109-5-406 https://doi.org/10.1113/jphysiol.2010.195057 3neuroscience research center, institute of neuropharmacology, 1kerman university of medical sciences, kerman, iran; 2nursing research center, school of nursing and midwifery, kerman university of medical sciences, kerman, iran *corresponding author's e-mails: ahmadianle@yahoo.com and l.ahmadian@kmu.ac.ir the experience of healthcare professionals providing mental health services to mothers with postpartum depression a qualitative study nazanin jannati,1 jamileh farokhzadian,2 *leila ahmadian3 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 554–562, epub. 25 nov 21 submitted 28 apr 20 revisions req. 11 jun, 19 aug & 15 oct 20; revisions recd. 2 jul, 1 sep & 21 oct 20 accepted 27 oct 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.031 clinical & basic research abstract: objectives: this study aimed to describe the experience of healthcare professionals in providing mental health services to women with postpartum depression (ppd). methods: in this qualitative study, data were collected through semi-structured interviews with five physicians, five midwives and five psychologists from 14 urban healthcare centres in kerman, iran, from april 2019 to september 2019. purposeful sampling was used to select the participants. data were qualitatively analysed using a content analysis approach. results: data analysis revealed the main theme of the study: ‘the long way ahead for comprehensive, integrated and responsive mental health services’. this theme included four categories: ‘postpartum depression challenges’, ‘social and personal factors’, ‘structural challenges’ and ‘need for change in mental health services’. the participants described that depression diagnosis is difficult due to insufficient knowledge among healthcare providers and the hidden signs of ppd. they also described how different factors such as economic and cultural factors, personality traits, a community's lack of knowledge, negative attitude towards depression and limited family support might cause depression. moreover, providing mental health services involves certain challenges, such as limited human resources, insufficient financial resources and incomplete or inefficient policy-making. conclusion: although measures have been taken to provide mental health services, there are many challenges regarding providing mental health services to mothers. therefore, serious measures should be taken to improve mental health services and re-define the existing measures. informing the community, empowering the healthcare providers and attempting to change the community's attitudes and beliefs can affect the mental healthcare of women with depression. keywords: postpartum depression; mental health services; community mental health services; mental disorders; depressive disorder; iran. advances in knowledge family-related factors can play an essential role in ensuring access to mental health services. patients and families with financial issues and a lack of awareness about mental health services cannot properly benefit from these services. therefore, policy-makers are advised to consider facilitators and barriers while creating mental health service programmes. there is a need to take steps to overcome the barriers to accessing mental health services. future mental health programmes should increase the health system's capacity in terms of both trained healthcare workers and facilities. applications to patient care changing the community's beliefs and attitudes towards postpartum depression (ppd) could help in delivering effective care to mothers with depression. identifying the challenges of and barriers to providing mental healthcare services to mothers with ppd can lead to the designing and implementation of better treatment and management services by policy-makers. postpartum depression (ppd) is a common depressive disorder that negatively affects mothers, children and families.1 the prevalence of this disorder following child birth among women is 19.8% in developing countries and is 25.3% in iran.2 the long-term health consequences of ppd are persistent depressive disorder (dysthymia), marital problems and conflicts, lower quality of the mother-child relationship and impacts on a child's cognitive and emotional development.3 more than 50% of women are exposed to one or more risk factors of ppd, but only 10–15% of them are considered clinically depressed.4 there is evidence that even when ppd is diagnosed in mothers, appropriate treatment may not be provided.5 considering the destructive and adverse effects of ppd on the infant and family life, its timely diagnosis and treatment during the first weeks after childbirth are essential.6 however, the challenge of providing effective mental health services to depressed mothers persists. some studies have examined healthcare providers’ experiences with providing mental health services to mothers with ppd. for example, in a qualitative study in brazil, santos junior et al. explored healthcare providers’ nazanin jannati, jamileh farokhzadian and leila ahmadian clinical and basic research | 555 experiences of offering services to mothers with ppd. their results showed that healthcare providers had limited time to provide services and had limited access to the diagnostic techniques for identifying women at risk of developing ppd.7 rush explored nurses’ experiences of helping depressed mothers in australia.8 the results of the study showed that nurses need considerable training to detect depression symptoms and decide on the appropriate treatment methods. bell et al. also identified barriers and facilitators of ppd services in canada.9 in their study, barriers and facilitators were divided into five categories: accessibility and proximity, appropriateness and fit, stigma, encouragement to seek help and personal characteristics. moreover, a study by higgins et al. showed that maternity care units are fragmented and do not have a mental health specialist.10 in a study by jomeen et al., the results showed uncertainty in both managing women with psychological health problems and appropriate care access; it was found that consistent referral pathways are required to ensure the successful measurement of women's psychological well-being.11 a study by bina et al. showed that preparation, behaviours, awareness and perceived expertise are significant factors that contribute to the perceived readiness to perform ppd screening initiatives.5 in another study, skoog et al. showed that a credible psychological interview is required when asking about their moods in some groups of mothers.12 the aforementioned studies were conducted in developed countries to explore healthcare providers' experiences of providing mental health services to depressed individuals. to the best of the authors' knowledge, no study has explored the experience of healthcare professionals with mental health services in developing countries such as iran. therefore, to address this gap in the existing literature, the present study aimed to describe primary healthcare professionals' experience of providing mental health services to women with ppd. methods this qualitative study was conducted using a content analysis approach. to apply this approach, a systematic and rule-guided classification method was used. the content analysis approach guides researchers to the most appropriate classes or themes and helps to describe text materials while considering words, phrases, latent contents and contexts.13 this study was conducted from april to september 2019 at 14 urban healthcare centres in kerman, iran. kerman is classified as one of the metropolises of iran due to its urban size and population. according to the 2016 census, the city’s population was 3,164,718.14 there are 14 healthcare centres in different parts of the city, which differ in terms of socio-economic conditions. therefore, the study sample was recruited from all of these centres for maximum diversity. in these healthcare centres, mental health services were introduced as a part of primary care in 1989. in some healthcare centres, a licensed psychologist is present to provide specialist mental healthcare. in centres with no psychologists available, mental health services are offered by a professionally qualified midwife. this study used a purposeful sampling method and sampling continued until data saturation. data collection was stopped when no new information or themes emerged or were observed from the data and further data collection became redundant. purposeful sampling requires choosing the rich and diverse experience of healthcare providers.15 in each centre, a few eligible participants were selected by the first researcher. healthcare providers who worked in healthcare centres were invited. this invitation letter included the aim of the study and the inclusion criteria. inclusion criteria was defined as follows: (1) working on a family health team; (2) having more than five years of experience in providing care to mothers and pregnant women; and (3) having an education table 1: : socio-demographic characteristics of 15 health care providers from 14 urban healthcare centres in kerman, iran participant code age gender job work experience in years p1 32 female psychologist 8 p2 35 male physician 10 p3 38 female physician 12 p4 32 male psychologist 8 p5 29 female midwife 5 p6 29 male psychologist 8 p7 42 female midwife 24 p8 39 female psychologist 12 p9 36 female midwife 12 p10 40 male physician 14 p11 28 male psychologist 12 p12 46 female physician 18 p13 42 male midwife 10 p14 36 male midwife 8 p15 32 male physician 6 the experience of healthcare professionals providing mental health services to mothers with postpartum depression a qualitative study 556 | squ medical journal, november 2021, volume 21, issue 4 level equivalent to or higher than a bachelor’s degree in midwifery, psychology or medicine. for maximum variation, purposeful sampling was applied to gather rich and varied insights and experiences. healthcare providers of different genders and ages from different positions and with varying years of work experience and degrees were recruited. the sample consisted of 15 healthcare providers (five physicians, five midwives and five psychologists). participants had been working in healthcare centres for many years, usually in the diagnosis, prevention and treatment department. data were collected using face-to-face, semistructured and in-depth interviews. the first researcher, with experience in qualitative research, conducted all the interviews in persian which were then translated into english. the first researcher went to the healthcare centres to describe the study’s aims, encourage healthcare providers to participate in the research and schedule an interview. interviews with participants were held in their healthcare centres ensuring that the everyday routines of participants were not disturbed. topic-guided questions were formulated based on specific study goals in a research panel with faculty members of medical informatics and nursing departments with a background in community health nursing and experience in in-depth interviews for qualitative studies. a variety of trigger questions were originally planned and posed to create a comfortable environment and prompt answers from participants using the qualitative techniques. at first, participants were asked to describe their experience of providing mental health services to mothers with ppd. then, more questions were asked according to the interview question’s guide. the questions were as follows: ‘what are your experiences of making a depression diagnosis and offering screening services to mothers with ppd?’; ‘would you please describe your experiences regarding the treatment of mothers with ppd?’; ‘what strategies do you use to identify mothers with ppd? how do healthcare providers assist these mothers?’; ‘what barriers and challenges have you experienced during the provision of mental health services to mothers with ppd?’; ‘what facilitators did you experience in table 2: categories and subcategories obtained through content analysis related to 15 healthcare providers’ experience of delivering services to mothers with postpartum depression in kerman, iran main theme categories subcategories open code the long way ahead for comprehensive, integrated and responsive mental health services postpartum depression challenges • the difficulty of diagnosing ppd • ppd consequences • unavailability of a test for depression • different depressive symptom patterns • the effect of maternal depression on the baby social, family and personal factors • limited family support • economic and cultural factors • personality traits • lack of awareness and negative attitude of the community towards depression • infidelity in marriage • financial problems and poverty • personality differences between mothers • social stigma structural challenges • barriers faced by mental health professionals • economic barriers to mental health services • the unfavourable physical environment of health centres • incomplete or inefficient policy-making • lack of human resources • lack of sufficient skills of mental health professionals • no separate room • crowded healthcare centres • lack of follow-up due to a large number of patients • not evaluating the ability and skill of mental health professionals need for change in mental health services • promising steps in diagnosis and treatment • informing the community and ensuring social contribution • supporting mothers • empowering healthcare providers • changing the attitudes and beliefs of the community • insurance support and coverage of mental health services • informing people about ppd • educating spouses about depression among women • training mental health professionals on ppd • cultural diversity and mental health • fighting ppd and its stigma • increasing access to mental health services ppd = postpartum depression. nazanin jannati, jamileh farokhzadian and leila ahmadian clinical and basic research | 557 the provision of mental health services to mothers with ppd?’. further questions were asked based on the information obtained from the participants. the mean duration of the interviews was 60 minutes. all interviews took place in a quiet room at the participants' workplace in the healthcare centres. all the interviews were audio-recorded and then transcribed verbatim using microsoft word (microsoft corp., redmond, washington, usa). data were analysed using the conventional qualitative content analysis method proposed by graneheim and lundman.16 iterations in the method consisted of several actions: initially, the first researcher transcribed all the interviews. the researchers then read the transcripts multiple times for a general interpretation of the content and initial coding was done individually. the text was broken into units of context which were then condensed. each unit of meaning consisted of terms and sentences containing similarly related aspects. then, the researcher abstracted and labelled the condensed meaning units through open codes. after that, categories and subcategories were created based on the similarity or difference of the codes. finally, the researcher extracted the data concepts. triangulation analysis was used to discuss the content of the categories. in case of disagreements, discussions were held and clarifications were offered to reach a consensus. lincoln and guba’s criteria were used to determine the trustworthiness of the data, which included credibility, confirmability, dependability and transferability.17 first, audio recording and transcription were used to ensure the correct representation of the participants’ views and improve the credibility of the findings.18 in-depth descriptions of existing healthcare practices were presented to allow readers to judge the relevance of the results to their settings, thereby enhancing transferability.19 an audit trail, including audio recordings, transcripts, interview guides, data analysis products and field notes, was used to ensure dependability and conformability.20 two researchers (jf, nj) read the transcriptions several times for an overall understanding of the content and to determine meaning units, perform an initial coding and interpret the data independently.16,21 the two researchers manually merged codes, classified them based on their similarities and established subcategories and categories independently. following this, they developed the coding scheme (code name, code definition, categories, subcategories, text examples and coding rules).16,21 in this process, the researchers met regularly to discuss agreements and discrepancies within assigned codes, categories and subcategories. moreover, an external expert in qualitative health research provided additional instruction, which led to further modifications. letters had been sent to the healthcare managers for ethical considerations and asking them for permission to interview the healthcare workers. moreover, informed consent was obtained from each participant before initiating the study. this study has been approved by the ethics committee of kerman university of medical sciences (ir.kmu. rec.1396.1548). results the data analysis revealed the main theme of the study: the long way ahead for comprehensive, integrated and responsive mental health services. it was found that there are many challenges to providing comprehensive mental health services. as a result of these challenges, several things need to be addressed. the participants reported that it is also challenging to diagnose and treat ppd, resulting in ppd consequences. the results are explained in the following sections using direct quotations of the participants. the researchers identified one main theme, four categories and 15 subcategories of mental health services that healthcare providers are perceived to provide [tables 1 and 2]. it was found that there are some challenges in diagnosing and treating ppd, including ‘the difficulty of diagnosing ppd’ and ‘ppd consequences’. the participants believed that it was difficult to diagnose a mother with ppd due to many reasons: considering ppd as a reasonable condition, insufficient knowledge of healthcare providers about ppd signs and hidden signs of ppd. according to participant 2, ‘‘some people do not consider depression to be a disease and think it is normal for a woman to have insomnia, changes in weight and appetite and have fatigue and not enjoy life after childbirth. moreover, healthcare providers do not have sufficient knowledge of ppd. therefore, it would be difficult for them to diagnose ppd’’. it was observed that the lack of timely diagnosis and treatment of a woman with ppd had many negative consequences, such as low quality of life, weak maternal relationships, reduced infant growth and development, marital problems and even suicidal thoughts. according to participant 9, ‘‘women have problems in marital relationships. one of the mothers did not enjoy the relationship with her husband. she was depressed and had no sexual desire. her husband was also dissatisfied. she even could not communicate with her family members’’. the participants believed that many factors in society and family play an essential role in the experience of healthcare professionals providing mental health services to mothers with postpartum depression a qualitative study 558 | squ medical journal, november 2021, volume 21, issue 4 ppd. since ppd treatment and diagnosis are both demanding processes, attention to social and family factors to prevent depression should be prioritised as these factors are associated with an increased risk of ppd. taking steps to strengthen the everyday living conditions before, during and after pregnancy provides incentives for enhancing the mental health of mothers and reducing the risk of mental health disorders associated with society, family and personal factors. this category includes four subcategories: limited family support, economic and cultural factors, personality traits, lack of awareness and negative attitude of the community towards depression. it appeared that family and social support plays a vital role in causing depression. family support can affect ppd. certain factors such as a husband's addiction, betrayal, inattentiveness and lack of support were among the factors that were reported by the participants. participant 7 mentioned that ‘‘a woman was depressed because of her inattentive husband. her husband was going out with his friends and betrayed his wife’’. according to participants' opinions, economic and cultural factors can lead to depression by creating nervous tensions. economic factors such as poverty, unemployment and inappropriate nutrition and cultural factors such as the stigma of ppd are among the causes of ppd. ‘‘a woman suffered from ppd due to her husband's unemployment and lack of income. because of financial problems and poverty, she could not prepare food and carry out necessary tests during pregnancy. moreover, stigma about depressed mothers is a barrier to improving their mental health’’, said participant 11. there was an association between the personality traits of mothers and depression. for example, mood states and personality traits, ability to adapt, ability to communicate and individual interest in recreation can affect a mother’s susceptibility to depression. according to participant 14, ‘‘some mothers are unhappy. however, some mothers have a happy mood. mother’s personality plays a causal role in the start of the ppd’’. the awareness and attitude of the community towards mental health disorders were found to be of particular importance. while diagnosing and treating depression in the community, healthcare providers face problems such as people’s lack of awareness about depression, depression stigma, limited referral options for depression, considering depression a reasonable condition and side effects of antidepressants. participant 12 mentioned, ‘‘in our society, people consider depression unpleasant and the depressed patient is labelled a manic person. in some cases, depression is regarded as a temporary disease. these problems are due to the community's lack of awareness about ppd. a depressed mother did not use prescribed drugs since she was worried about the side effect of these drugs on her baby's health’’. it is difficult to provide effective mental health services while many structural challenges exist. the healthcare system needs healthcare providers who are experts in mental health to diagnose and treat women with ppd. moreover, providing financial support for depressed mothers, free mental health services and a suitable environment is essential for moving towards comprehensive, integrated and responsive mental healthcare services. the participants believed that a lack of mental health professionals and insufficient knowledge of healthcare providers about ppd were among the many mental health service delivery challenges. according to participant 2, “there are 30 to 40 patients every day, but we have just [one] mental health expert. moreover, we cannot follow-up with all the patients because of the few numbers of mental health experts. some psychologists do not have enough knowledge, so proper mental health services are not provided”, said participant 15. it was observed that there were financial barriers to providing mental health services to the community. for example, insurance did not cover the cost of mental health services and mental health services are expensive. therefore, paying for these services was not possible for some patients. according to participant 13, “all people do not have access to free and decent mental health services due to the high cost. unfortunately, insurance agencies do not cover mental health services”. it was found that many patients with mental health disorders wanted to keep their problems a secret. hence, there should be a physical location and a separate room for providing these patients with mental health services. “a calm, comfortable and private environment is essential for examining and treating women with ppd. unfortunately, the necessary standards for having a confidential environment have not been met in some medical centres”, said participant 8. it was found that there were healthcare policy challenges to providing mental health services. these challenges include a lack of organisation, lack of integrated policies and instructions, lack of access to free mental health services and lack of assessment of healthcare providers’ skills. according to participant 13, ‘‘since the distribution of human resources has not been done correctly among healthcare centres, mental health experts provide mental health services nazanin jannati, jamileh farokhzadian and leila ahmadian clinical and basic research | 559 once a week in each healthcare centre. therefore, the proper division of mental health experts requires the implementation of efficient policies’’. the data showed that the efforts were not adequate for providing comprehensive, integrated and responsive mental health services, and therefore, mental health services need to change. some subcategories under this category were identified as follows: ‘promising steps in diagnosis and treatment’; ‘informing the community and ensuring social contribution’; ‘supporting mothers’; ‘empowering the healthcare providers’; and ‘changing the attitude and belief of the community’. different services are provided by healthcare centres to diagnose ppd; however, these services are not free or available to everyone. these services included using different scales such as the edinburgh postnatal depression scale (epds) to diagnose depression, referring patients to a mental health professional for further examination, following-up with patients, arranging psychotherapy sessions and drug therapy. however, there is a need to provide more effective services. participant 6 explained, ‘‘we use epds to diagnose women who suffer from ppd. then, we hold psychotherapy sessions for women. if the problem is not solved, i will refer the woman to a psychologist in the hospital for further examination’’. it was found that it is essential to inform the community about depression. people have to consider ppd as a mental disorder as this awareness would be necessary for diagnosing and treating ppd. for example, educating husbands about ppd would lead to increased family awareness. therefore, ppd can be diagnosed and treated in a timely manner. participant 6 mentioned, ‘‘we teach husbands how to interact with their depressed spouses. we ask them to gain control over things and also to help their women stay in treatment’’. it was found that one of the most challenging aspects that healthcare providers face is that depressed patients do not receive enough support. measures such as mothers’ breastfeeding, availability of followup health plans, increased access to healthcare centres, financial support of women and insurance coverage for mental health services can help women receive timely mental health services. according to participant 9, ‘‘one of the reasons for the absence of patients and the lack of motivation in depressed patients is the lack of financial support and insurance coverage for services. if insurance supports mothers to address their financial problems, mothers are motivated to apply for mental health services’’. it was found that one of the significant factors that can increase healthcare quality was the empowerment of healthcare providers. there is a need for new training for healthcare providers to update their knowledge about the latest methods of diagnosing and treating ppd. according to participant 1, ‘‘mental health training can help healthcare providers to empower their skills, but more education is needed. healthcare providers are also interested in such training to enhance their skills’’. it was found that the community’s belief and attitude towards depression have a significant impact on a patient’s disease acceptance and compliance with treatment. therefore, public attitude towards depression, the stigma of depression and community culture need to be changed. ‘‘the negative beliefs of families affect mothers with ppd. people need to be educated to accept ppd and then ask for help. so, the public attitude needs to be changed’’, said participant 2. discussion a commonly occurring depressive disorder, ppd negatively affects a multitude of individuals including mothers, children and families.1 the present study aimed to describe the experience of primary healthcare professionals experience of providing mental health services to women with ppd across 14 urban healthcare centres in kerman, iran. the results from the current study suggested that cases of ppd may not commonly be identified and diagnosed in healthcare centres. the participants in this study stated that insufficient knowledge of healthcare professionals affects the identification of symptoms of ppd and the lack of apparent symptoms makes the diagnosis of ppd difficult. this finding was consistent with that of goldsmith, who found that nurses had difficulties screening for ppd.22 according to the results of the current study, ppd has detrimental effects on mothers and the quality of marital relationships. in agreement with these results, one study has confirmed that ppd is associated with maternal struggle and numerous negative consequences for offspring.23 this study’s findings showed that limited family support, economic, cultural and religious events occurring in society and susceptible personality traits and characteristics can lead to ppd and this was consistent with other studies.24–26 based on healthcare professionals’ experiences, limited family support was found to be one of the causes of ppd. as in the present study, a study by matthey et al. showed that the partner’s lack of support was reported as being one of the leading causes of depression.27 the lack of awareness of the public regarding ppd was found to be another cause of depression in the current study. as in the case of the present study’s findings, the experience of healthcare professionals providing mental health services to mothers with postpartum depression a qualitative study 560 | squ medical journal, november 2021, volume 21, issue 4 kingston et al. also showed that most women did not seek help for depression due to their insufficient knowledge.28 removing barriers relating to social, family and personal factors is one solution for the improvement of mothers’ mental health. in addition, other challenges and barriers to mental health services need to be identified and addressed. participants of the current study described that mothers had a negative attitude towards antidepressants along with concerns about their side effects. therefore, mothers did not take antidepressants and had low treatment compliance. in agreement with the present study’s results, hirst and moutier’s review also indicate mothers’ hesitation to take antidepressants due to their concerns about the complications of these drugs for themselves and their newborns.29 according to the present study’s findings, it appears that mothers must accept depression as a curable illness to improve depression treatment. this result was in agreement with that reported by feeley et al., revealing that mothers who consider depression as a disease are more willing to use mental health services than those who consider it a common illness and a part of motherhood.30 one of the strategies suggested in the present study was changing the community’s attitude and belief towards ppd. in bell's study, more than 37% of women diagnosed with depression refused treatment and did not accept their illness.9 according to the experience of healthcare professionals in this study, solving this problem requires cultural promotion and training surrounding mental health issues to better combat this condition. moreover, in other studies, it has been shown that the provision of follow-ups and accessibility of healthcare centres are significant for increasing a patient’s motivation to seek treatment for the disease.9,31 the current study’s findings demonstrated that there are structural challenges to providing mental health services. in line with the results of the present study, other studies have indicated that the lack of insurance coverage, budget issues and the lack of financial resources make patients unable to seek help, leading to many mental health problems.32 as in the present study, healthcare professionals’ limitations in time and lack of sufficient environmental resources were mentioned as two main leading factors that lead to undiagnosed depression in junior et al.’s study.7 the findings from the current study showed that the physical environment of the health centres should be designed to make patients with mental disorders feel comfortable. another study also reported that the accessibility of health facilities and the availability of high-quality care, healthcare providers and equipment in the health centre are factors that affect mental health services.33 based on the current results, incomplete or inefficient policy-making was found to be among the critical factors leading to a shortage of human resources in mental health services and a lack of follow-up care for patients suffering from ppd. in line with the present study’s results, another study introduced the weakness of governmental structures as a leading cause of the inaccessibility of mental health facilities and services.7 these weaknesses included a lack of evidence-based guidelines for the care of women with postpartum mood disorders, failure of prioritising mental healthcare and the lack of coordination among different organisations as barriers to mental health service delivery. on the other hand, the healthcare providers’ lack of training and the inaccurate evaluation of the patient's condition were reported as other essential factors. in line with the present study's finding, a study from brazil mentioned that the lack of appropriate professional training for ppd was a problem mentioned by healthcare professionals.7 additionally, the limited knowledge of healthcare professionals about prenatal mental health problems has contributed to a lack of diagnosis and treatment of perinatal mental health problems as identified in other studies.34,35 therefore, the provision of mental health training for healthcare professionals should be prioritised. the participants believed that it is essential to use reliable tools to diagnose depression. other studies have also highlighted the importance of using valid screening tools in routine care.37 studies have also suggested that psychosocial interventions are required to prevent or alleviate the adverse consequences of antenatal depression.38 the results of this study showed that the evaluation of mothers’ mental health in the postpartum period was performed routinely using epds in healthcare centres. besides epds, there are different scales for measuring depression in primary care, such as the beck depression inventory self-reporting questionnaire and the patient health questionnaire.39 however, the use of these scales is not common in health centres in iran. chew-graham et al. revealed that the examination of depressive symptoms is not a part of the routine and mandatory care.40 each patient is not referred to a physician for the examination and diagnosis of depression which was in contrast to the findings from the present study. this difference could be because of clinicians’ obligation to screen mothers after delivery following the implementation of the health reform plan in iran. in this regard, healthcare professionals are obliged to provide mental health services. nazanin jannati, jamileh farokhzadian and leila ahmadian clinical and basic research | 561 if a mother’s epds score indicates acute ppd, she is then referred to a psychologist for further examination. consistent with the present study’s findings, other studies have revealed that a person suffering from depression requires further examinations.29 this is primarily because some mothers may not have answered certain questions accurately as a result of misunderstanding them and the epds is used only as part of an initial screening.41 therefore, in such cases, the patient needs to go on to receive appropriate examination under a psychologist’s expert supervision. finally, with regard to the diagnosis, treatment and prevention of depression, the participants in this study suggested that informing the community about ppd through mass media can help. they also suggested that it would be helpful to inform the patient’s family about the presence of psychologists in health centres. one study examined the effects of the quality of relationships with family and friends on a person’s well-being in adulthood.42 it was noted that adults with good relationships with their families were more likely to have positive friendships and higher self-esteem; they were also more likely to display fewer symptoms of depression than those with negative relationships. this study specifically explored the experience of healthcare professionals in their provision of mental health services to women; the relationship between ppd and women’s social status in their life was not explored. future studies can provide critical insight in this regard. this study has two significant limitations. first, contact with the participants was limited after their preliminary interview. the participants were sent their transcripts and uniquely defined categories and they were encouraged to comment, correct perspectives and enhance accuracy. only seven replies were received with minor contributions and corrections. second, the study was conducted in one region. due to regional variations in culture and traditions, similar studies are needed in other areas of the country, private sectors and even other countries in order to provide more generalisable results. despite its limitations, this study offers valuable insights into the experience of healthcare professionals of providing mental health services to women with ppd in iran. to the best of the authors’ knowledge, these areas have not been explored elsewhere in the literature. conclusion despite the availability of mental health services, there are many problems with the provision of mental health services to depressed mothers. efforts have already been made at the community level to provide mental health services. solving these problems requires the accurate identification of these problems, appropriate decision-making and further research. the results from this study can guide educators and experts in the provision of more effective mental health services to mothers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n nj, la and jf formed the concept and designed the study, acquired and interpreted the data and drafted the paper. jf arranged the logistics of the study. nj and jf had the main responsibility for analysis of the data. all three authors read and approved the final version of the manuscript. references 1. sudhanthar s, sheikh z, thakur k. postpartum depression screening: are we doing a competent job? bmj open qual 2019; 8:e000616. https://doi.org/10.1136/bmjoq-2018-000616. 2. veisani y, delpisheh a, sayehmiri k, rezaeian s. trends of postpartum depression in iran: a systematic review and metaanalysis. depress res treat 2013; 2013:291029. https://doi. org/10.1155/2013/291029. 3. paquin c, côté sm, tremblay re, séguin jr, boivin m, herba cm. maternal depressive symptoms and children’s cognitive devel opment: does early childcare and child’s sex matter? plos one 2020; 15:e0227179. https://doi.org/10.1371/journal.pone.0227179. 4. e. bj. psychometric testing of immigrants and natives in an acute psychiatry facility. ment illn 2017; 9:48–51. https://doi. org/10.1108/mi.2017.6987. 5. bina r, glasser s, honovich m, levinson d, ferber y. nurses perceived preparedness to screen, intervene, and refer women with suspected postpartum depression. midwifery 2019; 76:132–41. https://doi.org/10.1016/j.midw.2019.05.009. 6. yonkers ka, ramin sm, rush aj, navarrete ca, carmody t, march d, et al. onset and persistence of postpartum depression in an inner-city maternal health clinic system. am j psychiatry 2001; 158:1856–63. https://doi.org/10.1176/appi.ajp.158.11.1856. 7. santos junior hpo, rosa gualda dm, de fatima araujo silveira m, hall wa. postpartum depression: the (in) experience of brazilian primary healthcare professionals. j adv nurs 2013; 69:1248–58. https://doi.org/10.1111/j.1365-2648.2012.06112.x. 8. rush p. the experience of maternal and child health nurses responding to women with postpartum depression. matern child health j 2012; 16:322–7. https://doi.org/10.1007/s10995010-0688-2. 9. bell l, feeley n, hayton b, zelkowitz p, tait m, desindes s. barriers and facilitators to the use of mental health services by women with elevated symptoms of depression and their partners. issues ment heal nurs 2016; 37:651–9. https://doi.or g/10.1080/01612840.2016.1180724. 10. higgins a, tuohy t, murphy r, begley c. mothers with mental health problems: contrasting experiences of support within maternity services in the republic of ireland. midwifery 2016; 36:28–34. https://doi.org/10.1016/j.midw.2016.02.023. the experience of healthcare professionals providing mental health services to mothers with postpartum depression a qualitative study 562 | squ medical journal, november 2021, volume 21, issue 4 11. jomeen j, glover l, jones c, garg d, marshall c. assessing women’s perinatal psychological health: exploring the exper iences of health visitors. j reprod infant psychol 2013; 31:479–89. https://doi.org/10.1080/02646838.2013.835038. 12. skoog m, berggren v, hallström ik. ‘happy that someone cared’—non-native-speaking immigrant mothers’ experiences of participating in screening for postpartum depression in the swedish child health services. j child heal care 2018; 23:118–30. https://doi.org/10.1177/1367493518778387. 13. sandelowski m. what’s in a name? qualitative description revisited. res nurs health. 2010; 33:77–84. https://doi. org/10.1002/nur.20362. 14. statistical center of iran. population of cities in iran. 2016. from: https://www.amar.org.ir/english accessed: oct 2020. 15. patton mq. qualitative evaluation and research methods. 3rd ed. newbury park, ca, usa; 2002. 16. graneheim uh, lundman b. qualitative content analysis in nursing research: concepts, procedures and measures to achieve trustworthiness. nurse educ today 2004; 24:105–12. https://doi.org/10.1016/j.nedt.2003.10.001. 17. lincoln ys, guba eg. but is it rigorous? trustworthiness and authenticity in naturalistic evaluation. new dir progr eval 1986; 1986:73–84. https://doi.org/10.1002/ev.1427. 18. tong a, sainsbury p, craig j. consolidated criteria for reporting qualitative research (coreq): a 32-item checklist for interviews and focus groups. int j qual heal care 2007; 19:349–57. https://doi.org/10.1093/intqhc/mzm042. 19. manfred stommel cw. clinical research: concepts and principles for advanced practice nurses. usa: lippincott williams & wilkins. 2004. 20. haber dwgl-wj. nursing and midwifery research: methods and appraisal for evidence based practice. australia: elsevier. 2012. 21. long t, johnson m. rigour, reliability and validity in qualitative research. clin eff nurs 2000; 4:30–7. https://doi.org/10.1054/ cein.2000.0106. 22. goldsmith me. postpartum depression screening by family nurse practitioners. j am acad nurse pract 2007; 19:321–7. https://doi.org/10.1111/j.1745-7599.2007.00232.x. 23. o’hara mw, mccabe je. postpartum depression: current status and future directions. annu rev clin psychol. 2013;9:379–407. https://doi.org/10.1146/annurev-clinpsy-050212-185612. 24. kim ge, choi h-y, kim e-j. impact of economic problems on depression in single mothers: a comparative study with married women. plos one 2018; 13:e0203004–e0203004. https://doi.org/10.1371/journal.pone.0203004. 25. tucker jn, grzywacz jg, leng i, clinch cr, arcury ta. return to work, economic hardship, and women’s postpartum health. women health 2010; 50:618–38. https://doi.org/10.1080/0363 0242.2010.522468. 26. eastwood jg, phung h, barnett b. postnatal depression and socio-demographic risk: factors associated with edinburgh depression scale scores in a metropolitan area of new south wales, australia. aust n z j psychiatry 2011; 45:1040–6. https://doi.org/10.3109/00048674.2011.619160. 27. matthey s, barnett b, ungerer j, waters b. paternal and maternal depressed mood during the transition to parenthood. j affect disord 2000; 60:75–85. https://doi.org/10.1016/s01650327(99)00159-7. 28. kingston de, mcdonald s, austin m-p, hegadoren k, lasiuk g, tough s. the public’s views of mental health in pregnant and postpartum women: a population-based study. bmc pregnancy childbirth 2014; 14:84. https://doi.org/10.1186/1471-2393-14-84. 29. hirst kp, moutier cy. postpartum major depression. am fam physician 2010; 82:926–33. 30. feeley n, bell l, hayton b, zelkowitz p, carrier m-e. care for postpartum depression: what do women and their partners prefer? perspect psychiatr care 2016; 52:120–30. https://doi. org/10.1111/ppc.12107. 31. horowitz ja, murphy ca, gregory ke, wojcik j. best prac tices: community-based postpartum depression screening: results fromthe care study. psychiatr serv 2009; 60:1432–4. https://doi.org/10.1176/appi.ps.60.11.1432. 32. taghva a, farsi z, javanmard y, atashi a, hajebi a, khademi m. stigma barriers of mental health in iran: a qualitative study by stakeholders of mental health. iran j psychiatry 2017; 12:163–71. 33. devkota g, basnet p, thapa b, subedi m. factors affecting utilization of mental health services from primary health care (phc) facilities of western hilly district of nepal. plos one 2021; 16:e0250694. https://doi.org/10.1371/journal.pone.0250694. 34. megnin-viggars o, symington i, howard lm, pilling s. exper ience of care for mental health problems in the antenatal or postnatal period for women in the uk: a systematic review and meta-synthesis of qualitative research. arch womens ment health 2015; 18:745–59. https://doi.org/10.1007/s00737-015-0548-6. 35. dennis c-l, chung-lee l. postpartum depression help-seeking barriers and maternal treatment preferences: a qualitative systematic review. birth 2006; 33:323–31. https://doi.org/10.1111/j.1523536x.2006.00130.x. 36. teng l, robertson blackmore e, stewart de. healthcare worker’s perceptions of barriers to care by immigrant women with postpartum depression: an exploratory qualitative study. arch womens ment health 2007; 10:93–101. https://doi.org/10.1007/s00737-007-0176-x. 37. georgiopoulos am, bryan tl, wollan p, yawn bp. routine screening for postpartum depression. j fam pract 2001; 50:117–22. 38. rwakarema m, premji ss, nyanza ec, riziki p, palacios-derflingher l. antenatal depression is associated with pregnancy-related anxiety, partner relations, and wealth in women in northern tanzania: a cross-sectional study. bmc womens health 2015; 15:68. https://doi.org/10.1186/s12905-015-0225-y. 39. kerr lk, kerr jr ld. screening tools for depression in primary care: the effects of culture, gender, and somatic symptoms on the detection of depression. west j med 2001; 175:349–52. https://doi.org/10.1136/ewjm.175.5.349. 40. chew-graham ca, sharp d, chamberlain e, folkes l, turner km. disclosure of symptoms of postnatal depression, the perspectives of health professionals and women: a qualitative study. bmc fam pract 2009; 10:7. https://doi.org/10.1186/1471-2296-10-7. 41. delrosario ga, chang ac, lee ed. postpartum depression: symptoms, diagnosis, and treatment approaches. jaapa 2013; 26:50–4. https://doi.org/10.1097/01720610-201302000-00009. 42. fuller-iglesias hr, webster n, antonucci tc. adult family relationships in the context of friendship. res hum dev 2013; https://doi.org/10:10.1080/15427609.2013.786562. 1department of internal medicine, patliputra medical college and hospital, dhanbad, india; 2department of cardiology, sree chitra tirunal institute for medical sciences & technology, trivandrum, india; 3department of cardiovascular radiology, all india institute of medical sciences, new delhi, india *corresponding author’s e-mail: avinashmani1@gmail.com causal relationship of the transverse left ventricular band and bicuspid aortic valve manoj k. dubey,1 *avinash mani,2 vineeta ojha3 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 403–407, epub. 29 aug 21 submitted 5 jul 20 revision req. 3 sep 20; revision recd. 17 sep 20 accepted 4 oct 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.020 clinical & basic research the bicuspid aortic valve (bav) is the most common congenital lesion found in the adult population, with an overall incidence of 0.4–2.2%.1 aortic stenosis and aortic regurgitation develop over time, with aortic stenosis being more common among those whose age has advanced. the development of aortic stenosis imposes undue haemodynamic stress on the left ventricle.2 bavs are also associated with aortopathy which may be due to genetic or haemodynamic factors. these have far-reaching consequences as they can lead to aortic aneurysm and aortic dissection.3 detection of bav is done mainly with the help of transthoracic echocardiography (tte). the diagnosis relies on the visualisation of two aortic cusps with or without a raphe and two commissures in the short-axis view. tte has a sensitivity of 87.7% and specificity of 88.3% in the diagnosis of bav.4 however, the identification of bavs can be difficult in the presence of severe calcification and fibrosis or a very prominent raphe, which may be masquerading as a third coaptation line. detection of bicuspid aetiology is necessary as these valves tend to undergo stenosis at an earlier age as compared to the tricuspid valves and can more commonly develop infective endocarditis.6,7 regular follow-up is required for the detection of any complications. the transverse left ventricular (lv) band has been considered to be a benign anatomical variant, with similar incidence in patients with structural heart disease and a normal heart.8 several studies have shown the presence of the conduction tissue and myocardial cells in lv bands, which are in continuity with left bundle branch of the conduction system.8,9 the transverse lv band has been associated with the presence of early repolarisation changes on an electrocardiogram.10 however, they are not a specific substrate for arrhythmias such as ventricular tachycardia.11 thick robust transverse lv bands are believed to be associated with increased wall stress of the left ventricle. increased wall stress can be noted abstract: objectives: bicuspid aortic valve (bav) is the most common congenital lesion found in adults. it can be seen in combination with a transverse left ventricular (lv) band. this study aimed to find an essential relationship between the presence of transverse ventricular band and bav. methods: a total of 13 patients from a tertiary care centre in india with transverse lv band were investigated during a six-month period from january 2019 to july 2019. lv band thickness and gradients at the site of the lv band were evaluated as part of its effect on lv haemodynamics. the morphology of the aortic valve and lv outflow tract gradients was assessed. results: the mean age of the participants was 41 years. a majority had a bav (n = 11). average thickness of the lv band was 6.2 mm and the average mean aortic gradient was 4 mmhg. sequestration of blood was noted at the level of the transverse band in all the patients with two separate jets at the left ventricular outflow tract. the anterolateral jet was deflected from the transverse band and showed higher velocity compared to the other jet, causing turbulence at the bav. no correlation was found between the thickness of the transverse band and aortic valve gradient. conclusion: presence of a robust transverse lv band can serve as a surrogate marker for bav. keywords: bicuspid aortic valve; aortic stenosis; ventricular outflow obstruction; hemodynamics. advances in knowledge transverse left ventricular (lv) band has been considered a vestigial part of the ventricle. however, the role played by this band in presence of other disorders is insufficiently known. lv band is likely to play an important role in the haemodynamics of the bicuspid aortic valve (bav). bidirectional flow at the level of the lv band may help reduce the ventricular strain imposed by the increased afterload in the presence of the bav. application to patient care in patients with aortic stenosis, determination of aortic valve morphology plays a crucial role in determining future management. in heavily calcified valves where valve morphology is unclear, detection of a thick robust left ventricular (lv) band may serve as an indicator to the presence of a bicuspid aortic valve (bav). https://creativecommons.org/licenses/by-nd/4.0/ causal relationship of the transverse left ventricular band and bicuspid aortic valve 404 | squ medical journal, august 2021, volume 21, issue 3 in conditions with raised afterload and lv outflow obstruction (lvoto) or in the case of bav.12 thus, the presence of bavs could be associated with thick robust lv bands. this study aimed to evaluate the relationship between bavs and the presence of transverse lv bands. another aim of this study was to determine whether the presence of a robust lv band can give an indirect evidence of bicuspid morphology of stenosed aortic valve. methods this is a prospective observational single-centre study, conducted at a tertiary care hospital in india, over a period of six months from january 2019 to july 2019. all patients who underwent two-dimensional tte for the diagnosis of a cardiac disease were screened for the presence of transverse lv band. the patients, above 18 years of age who were detected to have transverse lv band via tte were included in this study, whereas patients with lv dysfunction, poor echo window and ambiguous aortic valve morphology were excluded. baseline demographics and clinical character istics, including risk factors, of all the study participants were collected. prior history of cardiac disease was evaluated. coronary artery disease was defined in terms of a patient having a history of myocardial infarction or angina on regular anti-anginal and anti-platelet drugs. all the patients in the current study underwent tte on the vivid t8 machine (ge healthcare systems, chicago, usa), using a linear echocardiography probe of 3.5 mhz frequency. those lv bands that were visible in at least two views were considered to be definite. the internal lv dimensions and ejection fraction were recorded. the presence of wall motion abnormality and valvular disease was also noted alongside the characteristics of the lv bands in terms of position, extent, point of insertion and average dimension. thereafter, the effect of the lv bands on lv haemodynamics was evaluated and the dimensions of the lv band were correlated with the severity of the outflow gradient. baseline data were collected using a structured questionnaire and have been presented as summary statistics. categorical variables have been presented as proportions, whereas continuous variables have been presented as means and standard deviations. the correlation analysis was conducted using spearman’s correlation coefficient to evaluate the relationship between the dimensions of the lv bands and aortic valve gradients. all statistical analyses were performed using statistical package for the social sciences (spss) version 25.0 (ibm corp., armonk, new york, usa). informed and written consent was obtained from the patients. this study was approved for exemption from institutional permission by the institutional review board. results a total of 13 patients were included in this study. the mean age of the study population was 41.1 years with males comprising 53.8% (n = 7) of the participants table 1: baseline demographic characteristics of patients with a bicuspid aortic valve (n =13) baseline characteristics mean ± sd age in years 41.1 ± 12.9 body surface area in metres 1.62 ±0.34 left ventricular internal dimension (in mm) lvedd 43.6 ± 6.3 lvesd 26.8 ± 5.4 left ventricular ejection fraction 69.6 ± 4.5 peak aortic gradient in mmhg 24.5 ± 16.3 mean aortic gradient in mmhg 14.1 ± 11.3 aortic valve area in cm2 1.62 ± 0.67 indexed aortic valve area in cm2/m2 1.05 ± 0.47 transverse lv band thickness in mm 6.2 ± 1.8 baseline characteristics n (%) males 7 (53.8) females 6 (46.2) diabetes mellitus 3 (23.1) hypertension 7 (53.8) dyslipidaemia 4 (30.7) family history of cardiac disease 0 (0) coronary artery disease 2 (15.4) ar grade 2+ 2 (15.4) sd=standard deviation; lvedd = left ventricular end-diastolic dimension; lvesd = left ventricular end-systolic dimension; lv = left ventricle; ar = aortic regurgitation. figure 1: parasternal short axis view showing a bicuspid aortic valve (a) in the open state during ventricular systole (b) with a raphe in a patient obtained via transthoracic echocardiography. manoj k. dubey, avinash mani and vineeta ojha clinical and basic research | 405 [table 1]. majority (85%) of the patients had a bav [figure 1] and transverse lv band was noted in all the patients [figure 2]. the average thickness of the lv band imaged was 6.2 mm. the most robust lv band had a dimension of 8 mm (n = 5), whereas the slenderest band had a dimension of 3 mm (n = 1). the average aortic valve area for patients with lv band was 1.62 ± 0.67 cm2, whereas the average indexed aortic valve area was 1.05 ± 0.47 cm2/m2. the average peak gradient across the aortic valve was noted to be 24.5 mmhg and the average peak velocity was 2.3 m/s. mean aortic gradient in the study population was 14.1 ± 11.3 mmhg. sequestration of blood was noted at the level of the transverse band in all the patients [figure 3]. most cases (80%) demonstrated two separate jets at the left ventricular outflow tract (lvot). the septal side of the lvot demonstrated a straight jet from the lv apex, while the anterolateral jet was deflected from the transverse lv band towards the lvot. pulse wave doppler analysis revealed that the anterolateral jet had a higher velocity than the septal jet and caused turbulence at the bicuspid valve [figure 4]. the correlation analysis showed that there was no significant correlation between the aortic valve gradient and thickness of the lv band (r = 0.423; p = 0.15). furthermore, the aortic valve area did not show any significant correlation with lv band thickness (r = −0.48; p = 0.09). discussion the current study aimed to evaluate the relationship between transverse lv band and bav. a majority of the patients participating in this study were young individuals without major comorbidities. all the patients had normal ventricular function on echocardiography with a majority of them having a bav. distinct transverse lv bands were noted in all of these patients. a previous study had associated the presence of lv band with structural and functional changes involving lv systolic and diastolic dysfunction.13 however, none of the patients in the current study had any evidence of systolic or diastolic dysfunction. the same study had also found that transverse lv bands are associated with mitral regurgitation.13 based on the orientation of the lv band, different types of lv bands have been described in the relevant literature. the most common location of the lv band is between the posteromedial papillary muscle and ventricular septum.14 it has been proposed that the transverse lv band which straddles the septum and the lateral wall of the ventricle prevents ventricular dilatation in the event of ventricular remodelling.15 the presence of lv band between the posteromedial papillary muscle and septum can prevent ventricular dilatation after an infero-posterior wall myocardial infarction. similarly, the lv band located between the free wall and the septum can inhibit ventricular figure 2: parasternal and apical long axis views showing a robust left ventricular band (arrows) extending from the interventricular septum to the posterior wall of the left ventricle obtained via transthoracic echocardiography. figure 3: pulse wave doppler at the level of transverse band showing bidirectional flow due to deflection of blood by the band in a patient with a bicuspid aortic valve. figure 4: pulse wave doppler analysis of (a) septal jet and (b) anterolateral jet in the left ventricular outflow tract showing higher velocity of anterolateral jet in a patient with a bicuspid aortic valve. causal relationship of the transverse left ventricular band and bicuspid aortic valve 406 | squ medical journal, august 2021, volume 21, issue 3 dilatation after an anterior wall myocardial infarction. a reduction in the ventricular dilatation during remodelling can also reduce tethering of mitral leaflets, which can effectively reduce functional mitral regurgitation.15 thus, the presence of a transverse lv band may be associated with the preservation of the ventricular architecture. this can account for the nondilated ventricles observed during the present study despite the presence of increased haemodynamic stress of bav and aortic stenosis. the presence of bav with or without the valvular dysfunction can impose a significant haemodynamic burden on the left ventricle. studies using cardiac magnetic resonance imaging (mri) have demonstrated markedly abnormal helical flow in ascending aorta in bav patients. this abnormal flow was also seen in bav patients without any degree of stenosis.16 an abnormal leaflet motion during cardiac cycle (wrinkling of valve tissue and excessive doming of valve leaflets) was noted in the current study, which resulted in an increased turbulence across the valve even when the valve was not stenotic. the cause of such abnormal motion is probably the unequal leaflet length. a turbulent helical flow across the aortic orifice can produce shear stress and lead to medial degeneration via the activation of matrix metalloproteinase pathways.17 barker et al. used computational flow dynamics in mri to investigate wall shear stress (wss) in patients with bav.18 all patients with bav had abnormal flow in the ascending aorta and transverse arch, while the flow was completely normal in patients with tricuspid aortic valve. bav patients are likely to have jet flow impingement along the greater curvature of the ascending aorta, leading to wss.19 lv parameters have also been studied in the presence of bav. in a cohort of 58 children with bav, cardiac mri showed that elevated aortic peak velocity and wss had a negative correlation with lv global longitudinal strain.20 cardiac mri analysis in a cohort of bav subjects showed that patients with valvular dysfunction had significantly elevated lv mass and peak wss in the ascending aorta.21 a positive correlation was noted between extracellular volume fraction and aortic wss, indicating significant ventricular remodelling in the face of elevated shear stress. all this evidence points to the presence of elevated haemodynamic stress on the left ventricle in the presence of bav, which predisposes it to ventricular remodelling. the left ventricle needs a compensatory mechanism to counteract this haemodynamic burden. this can manifest in the form of the hypertrophied lv band. the hypertrophied lv band contains myocardial tissue and conductive tissue having properties of contraction and relaxation. thus, they can prevent the overstretching of the left ventricle.22 the transverse lv band helps to sequester blood proximally during diastole and diverts it towards the lvot in an effort to reduce the haemodynamic stress during systole.21 the hypertrophy of the lv band is likely related to the added haemodynamic stress posed by the bav where it attempts to prevent lv dilatation and remodelling. the authors hypothesise that this may be the probable reason for hypertrophied lv bands in bav patients with low aortic gradients. the thickness of the transverse band was usually similar to the moderator band of the right ventricle as observed in this study. furthermore, no definite correlation was found between the thickness of the lv band and the aortic valve gradient or the aortic valve area in the current study. however, the presence of a robust lv band in all patients with bav could not be demonstrated in this series. there is paucity of data on the presence of transverse lv band in patients with bav and aortic stenosis. further studies are required to delineate the lv haemodynamics in patients with bav and lv band. mri studies can help in determining the changes in ventricular remodelling observed in patients with bav and transverse lv band. echocardiography has been a robust modality for the detection of transverse lv bands.15 thus, in conditions where the aortic valve morphology is not clear due to heavy calcification, the presence of a robust lv band may offer an indication of the presence of bav in the absence of other confounding factors such as ventricular dilatation and mitral regurgitation. this study had some limitations. first, the sample size was small due to financial constraints. second, complete dimensions of the lv band could not be measured by echocardiography and only thickness was taken as a marker of the robustness of the structure. finally, cardiac mri could not be performed to evaluate lv remodelling in patients with bav and lv band due to financial constraints and lack of availability of mri facilities at our centre. larger studies are warranted in patients with bav and lv band to understand the interplay of haemodynamics. conclusion the presence of a robust transverse lv band may serve as a surrogate marker for bav. larger studies using cardiac mri are required to prove a definite association between robust lv band and dysfunctional bav. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. manoj k. dubey, avinash mani and vineeta ojha clinical and basic research | 407 f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n mkd and am were involved with the conceptualisation and design of the study as well as data collection and analysis. mkd, am and vo equally contributed to the preparation of the manuscript. vo was responsible for image preparation and graphics. all the authors reviewed and approved the final version of the manuscript. references 1. hoffman jie, kaplan s. the incidence of congenital heart disease. j am coll cardiol 2002; 39:1890–900. https://doi.org/10.1016/ s0735-1097(02)01886-7. 2. carter-storch r, moller je, christensen nl, rasmussen lm, pecini r, søndergård e, et al. end-systolic wall stress in aortic stenosis: comparing symptomatic and asymptomatic patients. open heart 2019; 6:e001021. https://doi.org/10.1136/openhrt-20 19-001021. 3. abdulkareem n, smelt j, jahangiri m. bicuspid aortic valve aortopathy: genetics, pathophysiology and medical therapy. interact cardiovasc thorac surg 2013; 17:554–9. https://doi. org/10.1093/icvts/ivt196. 4. hillebrand m, koschyk d, ter hark p, schüler h, rybczynski m, berger j, et al. diagnostic accuracy study of routine echocard iography for bicuspid aortic valve: a retrospective study and meta-analysis. cardiovasc diagn ther 2017; 7:367–79. https:// doi.org/10.21037/cdt.2017.05.03. 5. galan a, zoghbi wa, quiñones ma. determination of severity of valvular aortic stenosis by doppler echocardiography and relation of findings to clinical outcome and agreement with hemodynamic measurements determined at cardiac catheter ization. am j cardiol 1991; 67:1007–12. https://doi.org/10.10 16/0002-9149(91)90175-k. 6. eroglu ag, babaoglu k, saltık l, oztunç f, demir t, ahunbay g, et al. echocardiographic follow-up of congenital aortic valvular stenosis. pediatr cardiol 2006; 27:713–19. https://doi.org/10.10 07/s00246-006-1321-4. 7. de mozzi p, longo ug, galanti g, maffulli n. bicuspid aortic valve: a literature review and its impact on sport activity. br med bull 2008; 85:63–85. https://doi.org/10.1093/bmb/ldn002. 8. malouf j, gharzuddine w, kutayli f. a reappraisal of the prev alence and clinical importance of left ventricular false tendons in children and adults. br heart j 1986; 55:587–91. https://doi. org/10.1136/hrt.55.6.587. 9. thakur rk, klein gj, sivaram ca, zardini m, schleinkofer de, nakagawa h, et al. anatomic substrate for idiopathic left ventr icular tachycardia. circulation 1996; 93:497–501. https://doi. org/10.1161/01.cir.93.3.497. 10. liu y, mi n, zhou y, an p, bai y, guo y, et al. transverse false tendons in the left ventricular cavity are associated with early repolarization. plos one 2015; 10. https://doi.org/10.1371%2f journal.pone.0125173. 11. lin fun-chung, wen ming-shien, wang chun-chieh, yeh san-jou, wu delon. left ventricular fibromuscular band is not a specific substrate for idiopathic left ventricular tachycardia. circulation 1996; 93:525–8. https://doi.org/10.1161/01.cir.93.3.525. 12. saikrishnan n, mirabella l, yoganathan ap. bicuspid aortic valves are associated with increased wall and turbulence shear stress levels compared to trileaflet aortic valves. biomech model mechanobiol 2015; 14:577–88. https://doi.org/10.1007/s10237014-0623-3. 13. hall me, halinski ja, skelton t, alexander mn, winniford m, fox e. left ventricular false tendons are associated with left ventr icular dilation and impaired left ventricular systolic and diastolic function. j am coll cardiol 2016; 67:1325. https://doi.org/10.1 016%2fj.amjms.2017.05.015. 14. luetmer ph, edwards wd, seward jb, tajik aj. incidence and distribution of left ventricular false tendons: an autopsy study of 483 normal human hearts. j am coll cardiol 1986; 8:179–83. https://doi.org/10.1016/s0735-1097(86)80110-3. 15. silbiger jj. left ventricular false tendons: anatomic, echocard iographic, and pathophysiologic insights. j am soc echocardiogr 2013; 26:582–8. https://doi.org/10.1016/j.echo.2013.03.005. 16. bissell mm, hess at, biasiolli l, glaze sj, loudon m, pitcher a, et al. aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type. circ cardiovasc imaging 2013; 6: 499–507. https://doi.org/10.1161/ circimaging.113.000528. 17. ruddy jm, jones ja, stroud re, mukherjee r, spinale fg, ikonomidis js. differential effect of wall tension on matrix metal loproteinase promoter activation in the thoracic aorta. j surg res 2010; 160:333–9. https://doi.org/10.1016/j.jss.2008.12.033. 18. barker aj, markl m, bürk j, lorenz r, bock j, bauer s, et al. bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta. circ cardiovasc imaging 2012; 5:457–66. https://doi.org/10.1161/circimaging.112.973370. 19. yassine nm, shahram jt, body sc. pathogenic mechanisms of bicuspid aortic valve aortopathy. front physiol 2017; 8:687. https://doi.org/10.3389/fphys.2017.00687. 20. stefek ha, berhane h, robinson jd, reilly b, ruh a, markl m, et al. comprehensive mr analysis of cardiac function, aortic hemo dynamics and left ventricular strain in pediatric cohort with isolated bicuspid aortic valve. pediatr cardiol 2019; 40:1450–9. https://doi.org/10.1007/s00246-019-02157-5. 21. geiger j, rahsepar aa, suwa k, powell a, ghasemiesfe a, barker aj, et al. 4d flow mri, cardiac function, and t1-mapping: association of valve-mediated changes in aortic hemodynamics with left ventricular remodeling. j magn reson imaging 2018; 48:121–31. https://doi.org/10.1002/jmri.25916. 22. philip s, cherian km, wu m, lue h. left ventricular false tendons: echocardiographic, morphologic, and histopathologic studies and review of the literature. pediatr neonatol 2011; 52:279–86. https://doi.org/10.1016/j.pedneo.2011.06.007. https://doi.org/10.1016/s0735-1097(02)01886-7 https://doi.org/10.1016/s0735-1097(02)01886-7 https://doi.org/10.1136/openhrt-2019-001021 https://doi.org/10.1136/openhrt-2019-001021 https://doi.org/10.1093/icvts/ivt196 https://doi.org/10.1093/icvts/ivt196 https://doi.org/10.21037/cdt.2017.05.03 https://doi.org/10.21037/cdt.2017.05.03 https://doi.org/10.1016/0002-9149(91)90175-k https://doi.org/10.1016/0002-9149(91)90175-k https://doi.org/10.1007/s00246-006-1321-4 https://doi.org/10.1007/s00246-006-1321-4 https://doi.org/10.1093/bmb/ldn002 https://doi.org/10.1136/hrt.55.6.587 https://doi.org/10.1136/hrt.55.6.587 https://doi.org/10.1161/01.cir.93.3.497 https://doi.org/10.1161/01.cir.93.3.497 https://doi.org/10.1371%2fjournal.pone.0125173 https://doi.org/10.1371%2fjournal.pone.0125173 https://doi.org/10.1161/01.cir.93.3.525 https://doi.org/10.1007/s10237-014-0623-3 https://doi.org/10.1007/s10237-014-0623-3 https://doi.org/10.1016%2fj.amjms.2017.05.015 https://doi.org/10.1016%2fj.amjms.2017.05.015 https://doi.org/10.1016/s0735-1097(86)80110-3 https://doi.org/10.1016/j.echo.2013.03.005 https://doi.org/10.1161/circimaging.113.000528 https://doi.org/10.1161/circimaging.113.000528 https://doi.org/10.1016/j.jss.2008.12.033 https://doi.org/10.1161/circimaging.112.973370 https://doi.org/10.3389/fphys.2017.00687 https://doi.org/10.1007/s00246-019-02157-5 https://doi.org/10.1002/jmri.25916 https://doi.org/10.1016/j.pedneo.2011.06.007 teaching paediatrics in iraq amid the covid-19 pandemic sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e408–409, epub. 21 dec 20 submitted 11 jul 20 accepted 16 sep 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.025 letter to the editor تدريس طب األطفال يف العراق يف ِخَضم جائحة كوفيد-19 dear editor, on 11 march 2020, world health organization announced novel coronavirus disease (covid-19) a pandemic after its spread from wuhan, china to many parts of the world infecting hundreds of thousands of people. due to its quick emergence, spatial extent and grave aftermaths, the covid-19 pandemic can be considered a once-ina-century global disaster. it has imposed negative impacts on various environmental, social, economic and health aspects.1,2 the influence of covid-19 on medical education is multifaceted including disrupting routines in medical faculties and hospitals, cancelling clerkships that are essential for relationship building and skill acquisition and students’ loss of the opportunity for personal development through conference presentations which is essential in differentiating applicants during the process of residency application. lost opportunities could have a critical impact on students’ career trajectory.3 students are also more likely to be affected in terms of changes in grading, cessation of clinical rotations, alterations in medical licensing examinations and consequences on mental health status.4 in iraq, medical education has been disrupted due to the antecedent decades of conflict, corruption, violence, poor administration and under-investment in academic teaching.5 substantial efforts were geared to reform medical curriculum, promote students skills and plan opportunities for development.6 however, the emergence of covid-19 in iraq in february 2020 has curtailed these efforts. the government of iraq ordered a lockdown as the numbers of positive covid-19 cases continued to rise. universities and medical colleges have closed. students have stayed at home and medical teaching has been suspended.7 in a step to continue learning and save the academic year, in march 2020 the ministry of higher education and scientific research in iraq decided to replace in-person classes with online equivalents.8 in the process of online teaching pediatrics (otp) in iraq, teaching staff have employed google classroom (google, llc, mountain view, california, usa) to deliver audio-visual lectures and educational medical videos and images as well as set online discussions with students on various topics in paediatrics. similarly, students have presented seminars and taken part in formative and summative assessments. challenges facing otp in iraq are manifold. disrupted infrastructures, in particular disturbed electricity distribution, slow internet services, impaired technical skills, time limits and the absence of institutional strategies are the major key barriers influencing the implementation of otp. as students are not accustomed to the process of digital preparation to undertake assessments which usually requires clinical exposure, disappointing effects on examination performance and competency are expected. despite recruitment of teaching staff in workshops and seminars on the process of online teaching, teaching staff were not fully competent in developing and delivering online content. poor technical skills in a substantial number of students resulted in negative attitudes towards e-learning environments. these challenges were more devastating for final year students waiting for their final assessments. they lost clinical clerkships and electives that are important determinants of allocation. despite all challenges encountered in otp, it has been possible to sustain, at least to some extent, students’ knowledge and collaborative essence as well as commitment and dedication to paediatrics. in the light of the continuing covid-19 pandemic, further ingenuities for teaching students are expected to emerge. the covid-19 pandemic has dramatically changed the landscape of medical education in iraq. the crisis has actually taught many lessons. first, online teaching, irrespective of its limitations (i.e. no training, little preparation and insufficient bandwidth), is fruitful and advantageous in terms of comfort, accessibility, offering more time for studying or external commitments due to lack of commute, welcoming environment to students with illness or physical disability and encouraging student-centred learning. second, everything is unpredictable and we must be ready to confront challenges during the current as well as future crises. though this abrupt crisis did not give us https://creativecommons.org/licenses/by-nd/4.0/ mahmood d. al-mendalawi letter to editor | e409 much time to plan, it is important to understand that meticulous planning is key. third, students should possess certain skills such as critical thinking, problem-solving and importantly adaptability to overcome crises. academic institutions need to set resilience in their systems to prioritise the presence of these skills in their students. fourth, integrating information technology in medical education is a worthy investment. it is expected to become more used in the near future as online teaching will eventually become the core element of education. faculty members of the department of paediatrics at al-kindy college of medicine, university of baghdad, are planning to comprehensively evaluate otp at the end of academic year 2020. for successful online teaching, it is recommended to provide support to infrastructures (network, electricity and devices), platforms (stability, interaction and the ability to improve) and preparedness of educators (educational workshops) and students (proper technique and learning support). it is also recommended that institutions concentrate on increasing the efficiently of the use of technology by looking into a technology with less procurement and maintenance costs but with the ability to enhance effective educational processes. training the faculty and educators on employing new online modalities and developing lesson plans with decreased cognitive load and increased interactivities is crucial. as online teaching is not a substitute for face-to-face (i.e. traditional) teaching, blended teaching utilising both types is becoming the new norm during the academic year 2020/2021 in iraq and it might continue even after the subsidence of the covid-19 pandemic. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq. e-mail: mdalmendalawi@yahoo.com references 1. sarkodie sa, owusu pa. global assessment of environment, health and economic impact of the novel coronavirus (covid-19). environ dev sustain 2020:1–11. https://doi.org/10.1007/s10668-020-00801-2. 2. smith bj, lim mh. how the covid-19 pandemic is focusing attention on loneliness and social isolation. public health res pract 2020; 30:3022008. https://doi.org/10.17061/phrp3022008. 3. ferrel mn, ryan jj. the impact of covid-19 on medical education. cureus 2020; 12:e7492. https://doi.org/10.7759/cureus.7492. 4. akers a, blough c, iyer ms. covid-19 implications on clinical clerkships and the residency application process for medical students. cureus 2020; 12:e7800. https://doi.org/10.7759/cureus.7800. 5. al-shamsi m. medical education in iraq: issues and challenges. int j med educ 2017; 8:88–90. https://doi.org/10.5116/ijme.58b1.c927. 6. al-mendalawi md. medical curricular reform in iraq. clin teach 2018; 15:262–4. https://doi.org/10.1111/tct.12700. 7. government of iraq. covid-19: iraqi government announces new measures. from: https://gds.gov.iq/covid-19-iraqi-governmentannounces-new-measures/ accessed: nov 2020. 8. central library. notice from the ministry of higher education and scientific research. from: https://www.uomosul.edu.iq/news/en/ libcentral/55114 accessed: nov 2020. https://doi.org/10.1007/s10668-020-00801-2 https://doi.org/10.17061/phrp3022008 https://doi.org/10.7759/cureus.7492 https://doi.org/10.7759/cureus.7800 https://doi.org/10.5116/ijme.58b1.c927 https://doi.org/10.1111/tct.12700 1department of medical diagnostic imaging, college of health sciences, university of sharjah, sharjah, united arab emirates; 2college of medicine and 3medical education center, university of sharjah, sharjah, united arab emirates; 4school of medicine, university of limerick, ireland; 5oral and craniofacial health department, college of dental medicine, university of sharjah, sharjah, united arab emirates *corresponding author’s e-mail: welshami@sharjah.ac.ae bridging the gap in online learning anxiety among different generations in health professions education *wiam elshami,1 coumaravelou saravanan,2 mohamed h. taha,2,3 mohamed e. abdalla,4 mohamed abuzaid,1 sausan al kawas5 clinical & basic research sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 539–548, epub. 25 nov 21 submitted 24 jul 20 revision req. 28 sep 20; revision recd. 14 oct 20 accepted 28 oct 20 https://doi.org/10.18295/squmj.4.2021.040 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to examine the effects of an individual’s generation group on anxiety related to online learning among students and online learning and teaching activities among faculty. methods: this crosssectional study was conducted at the university of sharjah, sharjah, united arab emirates, in april 2020 using the online course anxiety scale. the questionnaires were sent to 370 undergraduate students and 81 faculty members via email and the responses were stratified by generation. descriptive statistics and an independent sample t-test was used to compare the mean scores of online learning anxiety with gender and previous experience among faculty and students. results: a total of 358 students and 70 faculty members completed the questionnaire (response rate: 96.8% and 86.4%, respectively). only 5.7% of the faculty (compared to 54.7% of the students) enjoyed browsing internet resources during online learning. among the faculty, 75.7% experienced anxiety during online teaching compared to 37.7% of students. of the faculty, 92.3% of baby boomers felt anxious compared to 70.5% and 76.9% of x and y generations, respectively. conclusion: while students of generations z and y enjoyed browsing the internet during online learning, the generation z students were anxious during online discussions and concerned about the misinterpretation of their written communication. anxiety among faculty members was related to confusion regarding the use of the internet and computers and misinterpretations of text-based messages. keywords: anxiety; online learning; generations; work engagement; medical education; united arab emirates. advances in knowledge it was found that students and faculty members from various generations differ in terms of their interaction, learning and teaching skills. the overall findings of this study indicated that faculty members were more anxious about online learning compared to students. students enjoyed online learning, but generation z students were more anxious about online discussions and worried about written communication. applications to patient care this study highlighted the anxiety related to online learning and related concerns of students and faculty. anxiety of this sort would affect the quality of the learning experience and the overall satisfaction of students and faculty. faculty and institutions could utilise the results from such studies to collaborate and create a supportive working environment in order to reduce stress, encourage faculty members to master innovative online teaching methods and enrich existing healthcare with betterformed healthcare professionals. online learning, e-learning and blended (or hybrid) learning are terms that are all related to the use of technologies in learning and teaching. types of online learning can range from a supplementary tool to a fully online degree programme that offers enriched instructional features.1 online learning is beneficial for students and instructors as it provides multiple advantages such as flexibility, convenience and reduced educational costs.2,3 moreover, it maximises the use of learning resources and supports active learning.4 use of technology in education improves engagement in online learning and it is important to stimulate students’ interest to achieve the learning outcomes.5 engaging in online learning has also been shown to lead to cognitive development and high levels of success.6 despite these advantages, students and faculty face challenges while using technology in online learning. challenges associated with the use of technology in online learning can lead to anxiety and negatively influence student performance.5 the ability to use technology is influenced by age and different generational groups have various capabilities.7 the current students of the medical and health sciences belong to generations that socially interact using technology to ensure connectedness.8 to optimise the efficacy of learning and facilitate online learning, it is important to understand each generation’s way of learning and teaching.8,9 moreover, educators need to update their teaching methods, curriculum design bridging the gap in online learning anxiety among different generations in health professions education 540 | squ medical journal, november 2021, volume 21, issue 4 and assessments to achieve the best from teachers and students.8 a generation comprises a group of people born in the same period. although there is no exact formula to calculate the span of each generation, ranges of 15 to 18 years with differences of three to four years between different sources were noted in the literature.8,9 in gen eral, there are four main generations in the field of educ ation: baby boomers (born between 1946 and 1964);10 generation x (born between 1965 and 1980); gener ation y or millennials (born between 1981 and 1996); and generation z or centennials (born after 1997).8,11 baby boomers were taught using traditional educational methods because technological development was still in its early stages.12 baby boomers tend to be competitive, self-disciplined and idealistic; this has significantly impacted how they learn and consequently influenced their teaching methods.9,13 generation x individuals are more experienced with technology than baby boomers. they tend to be resourceful, problem-solvers and realitydriven individuals who value freedom and work-life balance.9,14 generation y individuals (millennials) are viewed as confident, team-oriented and open-minded students compared with previous generations. despite their optimistic personalities, they have relatively short attention spans and demonstrate the need for instant feedback.15 generation z individuals are referred to as multimodal learners because they have independent learning skills, which allow them to succeed with digital resources.16,17 the average age of current students is at the border between the millennials and generation z, while the average age faculty members falls in the baby boomer and generation x groups.18,19 different generations have different beliefs, priorities and motivations, resulting in a variation in their interaction, learning and teaching skills.20 therefore, the differences in teaching and learning styles between these two groups (faculty and students) must be considered in the medical education arena. students of the y and z generations have different experiences and traditional teaching approaches have proven to be ineffective and unexciting to them.21,22 instructors in the generation x and baby boomer age groups are less immersed in technology.23 current students have a profound understanding of technology and social connectedness. they communicate, learn and interact very differently compared to their instructors.9 instructors are being challenged to update their instruction methods to suit new generations of students in order to maintain high-quality education delivery.9,24 additionally, the advancement in medical knowledge that has taken place during the last 50 years has exceeded the knowledge attained in the previous 500 years.9,23 a change in teaching methods is important to accommodate the vast amount of information and deliver it in a student-centred way rather than in a way that reflects a passive learning style.23 thus, the use of technology in online learning is the key to promoting generation y and generation z students’ engagement in learning.17 nevertheless, internet self-efficacy and abilities to use the internet successfully as a learning tool and knowledge-sharing medium vary among students.25 internet self-efficacy has a constructive impact on students’ motivation to perform new online learning tasks.26 negative emotions and beliefs are significant barriers to the success of online students.27 consequently, online teaching and learning most likely leads to anxiety among both faculty and students.28 therefore, attention must be given to anxiety and burnout, as self-efficacy and confidence to tackle online anxiety would enhance overall online satisfaction for students and faculty.9,29 online anxiety is defined as apprehension to gain knowledge due to the use of the internet.25 the main concerns with online anxiety are the human aspects of internet use, connectivity and exchange of knowledge and not the physical use of devices.25 therefore, it is important to assess anxiety during online learning to initiate active support and improve future learning experiences. the current study aimed to examine the effects of the generation group that individuals belonged to on anxiety concerning online learning among students and online learning and teaching activities among faculty. methods a cross-sectional study was conducted at the medical and health sciences colleges (medicine, pharmacy, dental and health sciences), university of sharjah, sharjah, united arab emirates. an online questionnaire was e-mailed to 370 undergraduate students and 81 faculty members involved in online learning for theoretical courses in spring 2020 to invite them participate in the study. the sample size was calculated using the formula of a finite population. the calculation indicated that the study needed a minimum of 358 students and 81 faculty members and convenience sampling was used. the online questionnaire included a study information sheet. all data were coded to ensure anonymity. the study used a validated questionnaire (cronbach’s α = 0.93) along with the online course anxiety scale.5 the questionnaire consisted of two wiam elshami,coumaravelou saravanan,mohamed h. taha, mohamed e. abdalla, mohamed abuzaid and sausan al kawas clinical and basic research | 541 parts: (1) sociodemographic information and (2) an anxiety scale to measure anxiety towards online courses. the anxiety scale consisted of 18 items related to nervousness, anxiety, relaxation, apprehension, excitement, enjoyment, fear, confusion, confidence and empowerment. scoring was done on a five-point likert scale ranging from 1 = strongly disagree to 5 = strongly agree. the questionnaire was pilot-tested online and some items were modified slightly. statistical analysis was done using statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa). descriptive statistics were used to identify the mean, standard deviation and percentage of responses to online learning anxiety after seven positive items on the anxiety scale were re-coded. participants were categorised according to their generations: baby boomers (>55 years old), generation x (39–55 years old), generation y (21–38 years old) and generation z (≤20 years old). an independent sample t-test was used to compare the mean scores of online learning anxiety with gender and previous experience among faculty and students. the significance level was fixed at p <0.05. the study was granted ethical approval from the research ethical committee of the university (rec-20-04-26-01). participants were informed that participation in the study was voluntary and that they could withdraw from the study at any time without any consequences. consent was obtained online from all participants and they were provided with contact information in case they wanted to clarify any doubts or ask questions. results a total of 358 students (response rate: 96.8%) and 70 faculty members (response rate: 86.4%) completed the online questionnaire. a total of 93.6% (n = 335) of the students were female and 6.4% (n = 23) were male. the average age of students was 21.08 years. of the students, 231 (64.5%) belonged to generation y. a majority of the students (n = 257, 71.8%) had no previous experience with online learning. an average of four online courses were attended by students during the covid-19 pandemic compared with one course before the pandemic. of the faculty members, 52.9% (n = 37) were male and 47.1% (n = 33) were female. the average age of the faculty members was 46.17 years. most of the faculty (n = 44, 62.9%) belonged to generation x, while only 18.6% (n = 13) belonged to the baby boomer generation. a majority of the faculty (n = 58, 82.9%) had no previous experience with online teaching [table 1]. in their responses to the online course anxiety scale, a large proportion of the faculty reported confusion when working with the internet during online teaching (80.0%), whereas only 25.4% of the students were confused. similarly, 75.7% of faculty members reported anxiousness compared with 37.7% of students. nevertheless, 54.7% of the students enjoyed browsing online teaching and learning resources compared to 5.7% of faculty members. likewise, 52.5% of students reported feeling relaxed when working with computers during online learning compared with 14.3% of faculty [table 2]. with regard to the evaluation based on generations of the students and faculty, the present study revealed that 40.9% of the generation z students felt anxious during online learning compared with 35.9% of generation y students [table 3]. while 76.9% of generation y faculty felt anxious during online table 1: characteristics of participating students and faculty members from the university of sharjah, sharjah, united arab emirates characteristic n (%) student (n = 358) gender male 23 (6.4) female 335 (93.6) generation z 127 (35.5) y 231 (64.5) previous experience with online learning yes 101 (28.2) no 257 (71.8) year of study 1 52 (14.5) 2 55 (15.4) 3 75 (21.0) 4 127 (35.6) 5 49 (13.7) faculty (n = 70) gender male 37 (52.9) female 33 (47.1) generation y 13 (18.6) x 44 (62.9) bb 13 (18.6) previous experience with online teaching yes 12 (17.1) no 58 (82.9) z = generation z (≤20 years old); y = generation y (21–38 years old); x = generation x (39–55 years old); bb = baby boomer (>55 years old). bridging the gap in online learning anxiety among different generations in health professions education 542 | squ medical journal, november 2021, volume 21, issue 4 learning, 70.5% of generation x and 92.3% of baby boomers felt anxious [table 4]. a total of 48% of the generation z students became nervous during online discussions compared with 38.1% of generation y students [table 3]. while 15.4% of generation y faculty became nervous when required to participate in online discussions, 15.9% of generation x faculty and 7.7% of the baby boomers became nervous [table 4]. a total of 59% of the generation z students were concerned about the misinterpretation of text-based messages in the online environment compared with 39.8% of the generation y students [table 3]. while 61.5% of generation y faculty were concerned about the aforementioned misinterpretation, 61.4% of generation x faculty and 92.3% of the baby boomers shared a similar concern [table 4]. a total of 67.7% of the generation z students felt confident about navigating internet resources for teaching and learning compared to 53.2% of the generation y students [table 3]. while 15.4% of the generation y faculty felt confident about navigating internet resources for teaching and learning, 13.6% of the generation x faculty and none of the baby table 2: responses of students and faculty members from the university of sharjah to items on the online course anxiety scale2 item percentage m ± sd disagree neutral agree i am insecure about my computer skills. student 42.7% 26.3% 31.0% 2.8 ± 1.3 faculty 68.6 24.3 7.1 2.1 ± 0.9 i am anxious when i work on computers during online learning. student 41.1 21.2 37.7 2.9 ± 1.4 faculty 2.9 21.4 75.7 4.1 ± 0.8 i am quite relaxed when i work with computers during online learning. student 22.9 24.6 52.5 3.4 ± 1.2 faculty 47.1 38.6 14.3 2.5 ± 1.0 i am apprehensive about working on computers. student 19.8 40.5 39.7 3.2 ± 1.0 faculty 81.4 11.4 7.1 1.9 ± 1.0 i avoid working on computers. student 52.8 18.4 28.8 2.6 ± 1.2 faculty 27.1 31.4 41.4 3.2 ± 1.2 i am less intimidated by computers than most other people i know. student 24.0 38.8 37.2 3.2 ± 1.1 faculty 12.9 10.0 77.1 4.0 ± 1.2 i feel confident about navigating internet resources for teaching and learning. student 13.1 28.5 58.4 3.6 ± 1.0 faculty 64.3 24.3 11.4 2.2 ± 1.2 i get anxious when i am required to use internet resources. student 46.1 30.4 23.5 2.7 ± 1.2 faculty 60.0 24.3 15.7 2.2 ± 1.2 i get nervous about getting lost in cyberspace. student 37.7 27.4 34.9 2.9 ± 1.3 faculty 4.3 31.4 64.3 3.8 ± 1.0 i get excited about using the internet for online learning. student 15.6 48.6 35.8 3.3 ± 1.0 faculty 2.9 24.3 72.9 4.0 ± 0.9 i enjoy browsing internet resources for teaching and learning. student 8.7 36.6 54.7 3.6 ± 1.0 faculty 70.0 24.3 5.7 2.1 ± 0.9 i get confused when working with the internet for online learning. student 46.6 27.9 25.4 2.7 ± 1.1 faculty 5.7 14.3 80.0 4.1 ± 0.9 i feel confident about navigating internet resources for teaching and learning. student 27.7 29.1 43.3 3.2 ± 1.2 faculty 71.4 15.7 12.9 2.1 ± 1.1 i get anxious when i think about logging into my online course. student 44.1 25.4 30.4 2.8 ± 1.2 faculty 70.0 18.6 11.4 2.1 ± 1.1 i get nervous when i am required to participate in online discussions. student 30.2 28.2 41.6 3.2 ± 1.3 faculty 51.4 34.3 14.3 2.4 ± 1.1 i am apprehensive about enrolling in other online courses. student 18.4 53.4 28.2 3.1 ± 0.9 faculty 57.1 18.6 24.3 2.6 ± 1.2 i am scared that someone will misinterpret my textbased messages in the online environment. student 23.2 30.2 46.6 3.3 ± 1.1 faculty 2.9 30.0 67.1 3.9 ± 0.8 wiam elshami,coumaravelou saravanan,mohamed h. taha, mohamed e. abdalla, mohamed abuzaid and sausan al kawas clinical and basic research | 543 boomers felt confident about navigating the internet [table 4]. regarding enjoyment derived from browsing internet resources for teaching and learning, 59.1% of the generation z students enjoyed browsing the internet compared with 52.4% of the generation y students [table 3]. in comparison, 15.4% of the generation y faculty, 4.5% of the generation x faculty and none of the baby boomers enjoyed browsing the internet [table 4]. the overall score on the anxiety scale across both groups ranged from 18–90 based on 18 items ranging from 1 (strongly disagree) to 5 (strongly agree). the students’ scores on the anxiety scale ranged from 18–87 (56.8 ± 8.3) and 36–83 (54.9 ± 7.8) for the z and y generations, respectively. faculty scores on the anxiety scale ranged from 45–69 (54.0 ± 7.4), 34–90 (53.2 ± 8.8) and 41–86 (63.3 ± 7.3) for the y, x and baby boomer generations, respectively [table 5]. table 3: generation-based differences in the responses of students from the university of sharjah to items on the online course anxiety scale2 item generation percentage mean ± sd disagree neutral agree i am insecure about my computer skills. z 40.9 25.2 33.9 2.8 ± 1.3 y 43.7 26.8 29.4 2.7 ± 1.3 i am anxious when i work on computers during online learning. z 40.2 18.9 40.9 3.0 ± 1.4 y 41.6 22.5 35.9 2.9 ± 1.3 i am quite relaxed when i work with computers during online learning. z 22.8 26.0 51.2 3.4 ± 1.2 y 22.9 23.8 53.2 3.4 ± 1.2 i am apprehensive about working on computers. z 22.0 44.9 33.1 3.2 ± 1.0 y 18.6 38.1 43.3 3.2 ± 1.0 i avoid working on computers. z 46.5 21.3 32.3 2.8 ± 1.2 y 56.3 16.9 26.8 2.5 ± 1.2 i am less intimidated by computers than most other people i know. z 22.8 44.1 33.1 3.1 ± 1.0 y 24.7 35.9 39.4 3.2 ± 1.1 i feel confident about navigating internet resources for teaching and learning. z 6.3 26.0 67.7 3.8 ± 0.9 y 16.9 29.9 53.2 3.5 ± 1.1 i get anxious when i am required to use internet resources. z 47.2 29.1 23.6 2.7 ± 1.1 y 45.5 31.2 23.4 2.7 ± 1.2 i get nervous about getting lost in cyberspace. z 41.7 27.6 30.7 2.9 ± 1.3 y 35.5 27.3 37.2 3.0 ± 1.3 i get excited about using the internet for online learning. z 11.8 50.4 37.8 3.3 ± 0.9 y 17.7 47.6 34.6 3.3 ± 1.0 i enjoy browsing internet resources for teaching and learning. z 7.9 33.1 59.1 3.7 ± 1.0 y 9.1 38.5 52.4 3.6 ± 0.9 i get confused when working with the internet for online learning. z 42.5 31.5 26.0 2.8 ± 1.1 y 48.9 26.0 25.1 2.6 ± 1.2 i am confident about working in the online environment. z 26.8 32.3 40.9 3.2 ± 1.2 y 28.1 27.3 44.6 3.2 ± 1.2 i get anxious when i think about logging into my online course. z 38.6 25.2 36.2 3.1 ± 1.3 y 47.2 25.5 27.3 2.7 ± 1.2 i get nervous when i am required to participate in online discussions. z 22.8 29.1 48.0 3.4 ± 1.2 y 34.2 27.7 38.1 3.0 ± 1.3 i am apprehensive about enrolling in other online courses. z 17.3 52.0 30.7 3.2 ± 0.9 y 19.0 54.1 26.8 3.1 ± 0.9 i am scared that someone will misinterpret my text-based messages in the online environment. z 11.8 29.1 59.1 3.6 ± 0.9 y 29.4 30.7 39.8 3.1 ± 1.2 i feel empowered in my online course. z 37.0 40.9 22.0 2.8 ± 1.0 y 19.9 45.9 34.2 3.2 ± 1.0 sd = standard deviation; z = generation z (≤20 years old); y = generation y (21–38 years old). bridging the gap in online learning anxiety among different generations in health professions education 544 | squ medical journal, november 2021, volume 21, issue 4 the mann–whitney u test showed there was no significant difference between male (n = 23) and female (n = 335) students in terms of anxiety (u = 3,460; p = 0.413), but the t-test showed that there was a significant difference between male (n = 37) and female (n = 33) faculty in terms of online anxiety (t [2,588]; p = 0.012). there was a significant difference between students with prior (n = 101) and no prior (n = 257) online experience in terms of online anxiety (u = 10,193; p =0.002) but no significant differences among faculty (t [−1.180]; p = 0.256). there was also a significant difference between faculty (n = 70) and students (n = 358) in terms of anxiety (u = 10,044; p = 0.009) [table 6]. discussion the results showed that 80.0% of the faculty and 25.4% of students were confused when working with the internet during online teaching/learning. only 5.7% of faculty, compared with 54.7% of students, enjoyed browsing internet resources for teaching and learning. it is worth mentioning that in the current study, most of the faculty belonged to generation x, while students represented both the generation y and z. these findings were supported by previous studies that revealed that the use of technology is dominated by the y and z generations.14 technology does not replace good teachers but enhances the teaching table 4: generation-based differences in the responses of 70 faculty members from the university of sharjah to items on the online course anxiety scale2 item gen percentage mean ± sddisagree neutral agree i am insecure about my computer skills. y 61.5 23.1 15.4 2.1 ± 1.2 x 75.0 18.2 6.8 2.0 ± 0.9 bb 53.8 46.2 0.0 2.4 ± 0.7 i am anxious when i work on computers during online learning. y 0.0 23.1 76.9 3.2 ± 0.8 x 4.5 25.0 70.5 4.0 ± 0.9 bb 0.0 7.7 92.3 4.3 ± 0.6 i am quite relaxed when i work with computers during online learning. y 30.8% 53.8% 15.4% 2.5 ± 1.1 y 30.8 53.8 15.4 2.5 ± 1.1 x 52.3 31.8 15.9 2.5 ± 1.1 i am apprehensive about working on computers. bb 46.2 46.2 7.7 2.5 ± 0.9 y 76.9 23.1 0.0 1.8 ± 0.8 x 84.1 4.5 11.4 2.0 ± 1.1 i avoid working on computers. bb 76.9 23.1 0.0 1.9 ± 0.8 y 30.8 23.1 46.2 3.2 ± 1.3 x 25.0 29.5 45.5 3.3 ± 1.2 i am less intimidated by computers than most other people i know. bb 30.8 46.2 23.1 3.0 ± 1.2 y 0.0 23.1 76.9 4.2 ± 0.8 x 13.6 2.3 84.1 4.1 ± 1.2 i feel confident about navigating internet resources for teaching and learning. bb 23.1 23.1 53.8 3.7 ± 1.3 y 61.5 23.1 15.4 2.1 ± 1.2 x 61.4 25.0 13.6 2.3 ± 1.3 i get anxious when i am required to use internet resources. bb 76.9 23.1 0.0 2.0 ± 0.7 y 46.2 23.1 30.8 2.5 ± 1.6 x 61.4 22.7 15.9 2.2 ± 1.2 i get nervous about getting lost in cyberspace. bb 69.2 30.8 0.0 2.1 ± 0.8 y 0.0 23.1 76.9 4.1 ± 0.8 x 4.5 34.1 61.4 3.9 ± 1.0 i get excited about using the internet for online learning. bb 7.7 30.8 61.5 3.5 ± 0.9 y 0.0 23.1 76.9 4.2 ± 0.8 x 4.5 22.7 72.7 4.0 ± 1.0 i enjoy browsing the internet resources for teaching and learning. bb 0.0 30.8 69.2 3.8 ± 0.7 y 46.2 38.5 15.4 2.4 ± 1.1 x 77.3 18.2 4.5 2.0 ± 0.9 i get confused when working with the internet for online learning. bb 69.2 30.8 0.0 2.1 ± 0.8 y 0.0 23.1 76.9 4.1 ± 0.8 x 9.1 11.4 79.5 4.0 ± 1.0 i am confident about working in the online environment. bb 0.0 15.4 84.6 4.2 ± 0.7 y 61.5 23.1 15.4 2.1 ± 1.2 x 75.0 9.1 15.9 2.1 ± 1.1 i get anxious when i think about logging into my online course. bb 69.2 30.8 0.0 2.1 ± 0.8 y 61.5 23.1 15.4 2.1 ± 1.2 x 72.7 13.6 13.6 2.1 ± 1.2 i get nervous when i am required to participate in online discussions. bb 69.2 30.8 0.0 2.1 ± 0.8 y 61.5 23.1 15.4 2.1 ± 1.2 x 50.0 34.1 15.9 2.5 ± 1.1 i am apprehensive about enrolling in other online courses. bb 46.2 46.2 7.7 2.4 ± 1.0 y 46.2 23.1 30.8 2.5 ± 1.3 x 56.8 15.9 27.3 2.7 ± 1.3 i am scared that someone will misinterpret my text-based messages in the online environment. bb 69.2 23.1 7.7 2.2 ± 0.9 y 0.0 38.5 61.5 3.9 ± 0.9 x 4.5 34.1 61.4 3.7 ± 0.8 i feel empowered in my online course. bb 0.0 7.7 92.3 4.3 ± 0.6 y 0.0 38.5 61.5 3.9 ± 0.9 x 4.5 34.1 61.4 3.7 ± 0.8 bb 0.0 7.7 92.3 4.3 ± 0.6 gen = generation; sd = standard deviation; y = generation y (21–38 years old); x = generation x (39–55 years old); bb = baby boomer (>55 years old). wiam elshami,coumaravelou saravanan,mohamed h. taha, mohamed e. abdalla, mohamed abuzaid and sausan al kawas clinical and basic research | 545 process and the incorporation of techno-pedagogical skills is the key factor in promoting students’ engagement with online learning.5,30,31 therefore, it is important to explore the strategies of updating the technological skills of faculty members to facilitate the learning process.32 in the current study, 75.7% of the faculty and 37.7% of students experienced anxiety during online teaching. it was found that 92.3%, 70.5% and 76.9% of the faculty members from the baby boomer, x and y generations, respectively, felt anxious. this finding was in agreement with the literature documenting that baby boomers are less competent with technology than generation y and x.33 modern learners are more anxious in any new learning situation;34 this explains the findings of the current study, as most of the students did not have previous experience with online learning.33 student advising and academic counselling are required to reduce students’ anxiety because it acts as a barrier to an efficient learning experience.25 in 2017, alanazy found that the use of computer applications can cause anxiety among untrained faculty.34 it has also been reported that internet anxiety decreases the use of online learning, which lessens the chances of gaining knowledge and reduces the benefit of the learning experiences.25,35 therefore, it is important to provide educational support to minimise online course anxiety for both students and faculty. the results from the present study revealed that 59.1% of the generation z students enjoyed browsing online resources compared with 52.4% of the generation y students. furthermore, 15.4% of the generation y faculty enjoyed browsing internet resources for teaching and learning compared with 4.5% of the generation x faculty and none of the baby boomers. a growing body of literature has reported that generation x is more competent with technology than baby boomers, while y and z are the technology generations.8,23 nevertheless, generation z is the best in using digital resources and does not seem to be overwhelmed with the information overload on the internet.23 traditional teaching approaches have proven to be ineffective and unexciting to generation y and z students.36 therefore, to maintain the delivery of highquality healthcare in the country for future generations, educators need to customise instructional methods to fulfil the needs of newer generations of learners.37,38 teaching generation y and z students provides opportunities to try new approaches and interact with learners in interesting and dynamic ways.30 online medical education became an inevitable reality as the covid-19 pandemic began to restructure medical and health professionals’ education and lead to the development of online forms of active learning methods. medical educators were challenged to draft strategies to engage students in online learning and translate knowledge into practice.38,30 therefore, it is important to improve the current teaching methods used in the medical field to train a high-quality health care provider.30 the present study revealed that generation z (48.0%) and generation y (38.1%) students became nervous during online discussions. this finding supported previous research that reported generation z students’ lack of critical thinking skills,17 which are important for discussion forums.39 adding assignments that help in the development and improvement of critical thinking and problem-solving skills is crucial for these generations.40,41 the findings revealed that almost half of the students and two-thirds of the faculty were scared of misinterpretations of text-based messages in the online environment. faculty student communication helps create an online community for sharing ideas and engaging in learning.24 it is obvious that students table 6: differences in anxiety levels based on gender and prior online experience of students and faculty members from the university of sharjah obtained using the online course anxiety scale2 variable student faculty mean rank sor p value mean ± sd p value gender 0.413 0.012 male 162.43 3,736.00 50.94 ± 6.75 female 180.67 60,525.00 55.90 ± 8.98 prior online learning/teaching experience 0.002 0.256 yes 207.08 20,915.00 50.6 ± 8.8 no 168.66 43,346.00 53.8 ± 8.0 total anxiety score 221.44 79,277.00 0.009 178.99 ± 12,529.00 0.009 sor = sum of ranks; sd = standard deviation. table 5: overall score of students and faculty members from the university of sharjah on the online course anxiety scale2 generation mean ± sd maximum minimum student z 56.8 ± 8.3 87 18 y 54.9 ± 7.8 83 36 faculty y 54.0 ± 7.4 69 45 x 53.2 ± 8.8 90 34 bb 63.3 ± 7.3 86 41 sd = standard deviations; max = maximum; min = minimum; z = gen eration z (≤20 years old); y = generation y (21–38 years old); x = gen eration x (39–55 years old); bb = baby boomer (>55 years old). bridging the gap in online learning anxiety among different generations in health professions education 546 | squ medical journal, november 2021, volume 21, issue 4 who have better online self-efficacy feel relatively comfortable expressing themselves in writing.43 it has been reported that misinterpreted text communication is common in online learning.44 the differences in understanding can be related to cultural differences and previous experiences. combining audio and visual components could help express emotions and add personal elements to the feedback and discussion.45,46 it has been reported in the literature that medical students are suffering from academic stress and anxiety.47 similarly, students from colleges of health sciences had high stress levels and lower psychological well-being due to their educational responsibilities and online learning.48,49 therefore, it is necessary to provide a supportive learning environment for medical and health science students in order to produce well-prepared healthcare workers. moreover, the opportunity to share exper iences with colleagues, stakeholders, leaders, accred itation bodies and clinical training sites is essential for cultivating an effective learning process.30 in the present study, students who had prior online experiences experienced less anxiety. this finding was consistent with a previous study that showed that students who had prior online experience exhibited less anxiety compared with others.39 previous studies have revealed that students who lack technical skills and do not receive clear instructions and feedback from the instructor are apprehensive about communicating their ideas in writing and are prone to anxiety.50 a limitation of this study was that it was conducted during the covid-19 pandemic when there was a sudden and rapid shift to complete online learning. the findings of the study cannot be generalised to all students as the study only included students of medical and health sciences. further research that includes students from different colleges is needed. moreover, it is necessary to conduct studies that explore the challenges of online learning and teaching in order to improve the quality of online learning. additionally, intervention studies to reduce anxiety in online learning might help the medical education community. online learning has become the new normal following the start of the covid-19 pandemic with medical educators being required to work hard to provide an adequate learning experience to their students.46 being an innovative and technology-literate educator is the key to engaging new generations of online learners. techno-pedagogical skills are crucial for communicating effectively with students and supporting their learning. providing training workshops for both students and faculty, in which one shares their experiences with all concerned parties, will add more value to the online learning process. anxious people are often not open to sharing their feelings with medical experts or friends but they can do so through anonymous means. predictions of anxiety can be made using machine learning algorithms.51,52 future studies are recommended since they can help support the well-being of students and faculty. moreover, academic advising and psychological support are vital to achieving the best learning experience during these changing times. conclusion in the current study, generation z students were more confident about navigating internet resources for online learning. generation x and baby boomer faculty members were not as confident about the same when compared with generation y faculty. additionally, students from both generations y and z enjoyed browsing internet resources for teaching and learning more as opposed to faculty in all generations. students and faculty were both anxious during online learning, but baby boomer faculty members were most anxious. students with previous online learning experiences were significantly less anxious and no significant difference was found among faculty. there was no significant difference between the anxiety level of male and female students, while female faculty members were more anxious about online teaching than male faculty members. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n all authors contributed to the conception of the study. ma collected the data and worked on coding. we analysed the data. we and mht drafted the initial manuscript. all authors revised and edited the manuscript. all authors approved the final version of the manuscript. references 1. hung ml, chou c, chen ch, own zy. learner readiness for online learning: scale evelopment and student perceptions. comput educ 2010; 55:1080–90. https://doi.org/10.1016/j. compedu.2010.05.004. 2. rekkedal t, qvist-eriksen s. support services in e-learningan evaluation study of students' needs and satisfaction. eur j open distance elearn 2004; 7. wiam elshami,coumaravelou saravanan,mohamed h. taha, mohamed e. abdalla, mohamed abuzaid and sausan al kawas clinical and basic research | 547 3. halsne am. online versus traditionally delivered instruction: a descriptive study of learner characteristics in a community college setting. loyola university chicago; 2002. 4. phillips jm. strategies for active learning in online continuing education. j contin educ nurs 2005; 36:77–83. https://doi. org/10.3928/0022-0124-20050301-08. 5. bolliger du, halupa c. student perceptions of satisfaction and anxiety in an online doctoral program. distance educ 2012; 33:81–98. https://doi.org/10.1080/01587919.2012.667961. 6. hoskins sl, van hooff jc. motivation and ability: which students use online learning and what influence does it have on their achievement? brit j educ technol 2005; 36:177–92. https://doi.org/10.1111/j.1467-8535.2005.00451.x. 7. ersoz s, demir askeroğlu e. generations x, y, z and their perception of e-government services: case of turkey. online j commun media technol 2020; 10:e202002. https://doi. org/10.29333/ojcmt/6428. 8. dimock m. defining generations: where millennials end and generation z begins. from: https://www.pewresearch.org/ fact-tank/2019/01/17/where-millennials-end-and-generationz-begins/ accessed: oct 2020. 9. prater mr. teaching millennials and generation z: new opportunities in undergraduate medical education. in: gotian r, kang y, safdieh j. handbook of research on the efficacy of training programs and systems in medical education. hershey: igi global, 2020. pp. 72–91. 10. m joanna mellor ds, helen rehr ds, editors. baby boomers: can my eighties be like my fifties? springer publishing company; 2005. 11. colby sl, ortman jm. the baby boom cohort in the united states: 2012 to 2060. from: https://da7648.approby.com/m/ fda06b00de5d112c.pdf accessed: oct 2020. 12. zemke r, raines c, filipczak b. generations at work. new york, ny, usa: american management association, 2000. 13. akar f. examining the meaningful work level of generation x and generation y teachers. elem educ online 2020; 19:1225–41. https://doi.org/10.17051/ilkonline.2020.728029. 14. persada sf, miraja ba, nadlifatin r. understanding the gener ation z behavior on d-learning: a unified theory of acceptance and use of technology (utaut) approach. int j emerg technol learn 2019; 14:20–33. https://doi.org/10.3991/ijet.v14i05.9993. 15. tanner l. who are the millennials? defence research and development canada ottawa (ontario) centre for operational research and analysis. from: https://apps.dtic. mil/sti/citations/ada550986 accessed: oct 2020. 16. pousson jm, myers ka. ignatian pedagogy as a frame for universal design in college: meeting learning needs of generation z. educ sci 2018; 8:193. https://doi.org/10.3390/ educsci8040193. 17. shatto b, erwin k. moving on from millennials: preparing for generation z. j contin educ nurs 2016; 47:253–4. https://doi. org/10.3928/00220124-20160518-05. 18. gauer j, jackson jb. relationships of demographic variables to usmle physician licensing exam scores: a statistical analysis on five years of medical student data. adv med educ pract 2018; 9:39–44. https://doi.org/10.2147/amep.s152684. 19. skarupski ka, welch c, dandar v, mylona e, chatterjee a, singh m. late-career expectations: a survey of full-time faculty members who are 55 or older at 14 u.s. medical schools. acad med 2020; 95:226–33. https://doi.org/10.1097/ acm.0000000000002847. 20. bickel j, brown aj. generation x: implications for faculty recruitment and development in academic health centers. acad med 2005; 80:205–10. https://doi.org/10.1097/00001888200503000-00003. 20. dicheva d, dichev c, agre g, angelova g. gamification in education: a systematic mapping study. j educ technol society 2015; 18:75–88. 22. poole sm, kemp e, patterson l, williams k. get your head in the game: using gamification in business education to connect with generation y. j excellence in business educ 2014; 3. 23. roberts dh, newman lr, schwartzstein rm. twelve tips for facilitating millennials’ learning. med teach 2012; 34, 274–78. https://doi.org/10.3109/0142159x.2011.613498. 24. ersoz s, demir askeroğlu e. generations x, y, z and their perception of e-government services: case of turkey. online j commun media technol 2020; 10:e202002. https://doi. org/10.29333/ojcmt/6428. 25. warner do, nolan m, garcia-marcinkiewicz a, schultz c, warner ma, schroeder dr, et al. adaptive instruction and learner interactivity in online learning: a randomized trial. adv health sci educ theory pract 2020; 25:95–109. https://doi. org/10.1007/s10459-019-09907-3. 26. alqurashi e. predicting student satisfaction and perceived learning within online learning environments. distance education 2019; 40:133–48. https://doi.org/10.1080/01587919 .2018.1553562. 27. zembylas m. adult learners’ emotions in online learning. distance educ 2008; 29: 71–87. https://doi.org/10.1080/0158 7910802004852. 28. khalil r, mansour ae, fadda wa, almisnid k, aldamegh m, alnafeesah a, et al. the sudden transition to synchronized online learning during the covid-19 pandemic in saudi arabia: a qualitative study exploring medical students’ perspectives. bmc med educ 2020; 20:285. https://doi.org/10.1186/s12909020-02208-z. 29. shen d, cho mh, tsai cl, marra r. unpacking online learning experiences: online learning self-efficacy and learning satisfaction. internet high educ 2013; 19:10–17. https://doi. org/10.1016/j.iheduc.2013.04.001. 30. roberts c. how medical education can help in a covid-19 crisis. clin teach 2020; 17:241. https://doi.org/10.1111/tct.13183. 31. lee j, lee y, gong s, bae j, choi m. a meta-analysis of the effects of non-traditional teaching methods on the critical thinking abilities of nursing students. bmc med educ 2016; 16:240. https://doi.org/10.1186/s12909-016-0761-7. 32. bawa p. retention in online courses: exploring issues and solutions—a literature review. sage open 2016; 6:1–11. https://doi.org/10.1177/2158244015621777. 33. twenge jm. generational changes and their impact in the classroom: teaching generation me. med educ 2009; 43:398–405. https://doi.org/10.1111/j.1365-2923.2009.03310.x. 34. alanazy sm. factors affecting faculty attitude for adopting online learning at aljouf university, saudi arabia. j educ learn 2017; 7:154–62. https://doi.org/10.5539/jel.v7n1p154. 35. brosnan m, joiner r, gavin j, crook c, maras p, guiller j, et al. the impact of pathological levels of internet-related anxiety on internet usage. j educ comput res 2012; 46:341–56. https:// doi.org/10.2190/ec.46.4.b. 36. alabbasi d. exploring graduate students’ perspectives towards using gamification techniques in online learning. turk online j distance educ 2017; 18:180–96. https://doi.org/10.17718/ tojde.328951. 37. desy jr, reed da, wolanskyj ap. milestones and millennials: a perfect pairing—competency-based medical education and the learning preferences of generation y. mayo clin proc 2017; 92:243–50. https://doi.org/10.1016/j.mayocp.2016.10.026. 38. waljee jf, chopra v, saint s. mentoring millennials. jama 2018; 319:1547–8. https://doi.org/10.1001/jama.2020.3085. bridging the gap in online learning anxiety among different generations in health professions education 548 | squ medical journal, november 2021, volume 21, issue 4 39. abdous m. influence of satisfaction and preparedness on online students’ feelings of anxiety. internet high educ 2019; 41:34-44. https://doi.org/10.1016/j.iheduc.2019.01.001. 40. oh eg, huang whd, hedayati mehdiabadi a, ju b. facil itating critical thinking in asynchronous online discussion: comp arison between peerand instructor-redirection. j comput high educ 2018; 30:489–509. https://doi.org/10.1007/s12528-018-9180-6. 41. abuzaid mm, elshami w. integrating of scenario-based simul ation into radiology education to improve critical thinking skills. rep med imaging 2016; 9:17–22. https://doi.org/10.2147/ rmi.s110343. 42. frye b. understanding student engagement among online clinical students during academic residency experience. j educ online 2020; 17:n1. 43. hung ml, chou c, chen ch, own zy. learner readiness for online learning: scale development and student perceptions. comput educ 2010; 55:1080–90. https://doi.org/10.1016/j.comp edu.2010.05.004. 44. denoyelles a, zydney jm, chen b. strategies for creating a community of inquiry through online asynchronous discussions. j online learn teach 2014; 10:153–65. 45. covelli bj. online discussion boards: the practice of building community for adult learners. j contin high educ 2017; 65:139–45. https://doi.org/10.1080/07377363.2017.1274616. 46. elshami w, taha mh, abuzaid m, saravanan c, al kawas s, abdalla me. satisfaction with online learning in the new normal: perspective of students and faculty at medical and health sciences colleges. med educ online 2021; 26:1920090. https:// doi.org/10.1080/10872981.2021.1920090. 47. eva eo, islam mz, mosaddek as, rahman mf, rozario rj, iftekhar am, et al. prevalence of stress among medical students: a comparative study between public and private medical schools in bangladesh. bmc res notes 2015; 8:1–7. https://doi.org/10.1 186/s13104-015-1295-5. 48. he fx, turnbull b, kirshbaum mn, phillips b, klainin-yobas p. assessing stress, protective factors and psychological wellbeing among undergraduate nursing students. nurse educ today 2018; 68:4–12. https://doi.org/10.1016/j.nedt.2018.05.013. 49. reeve k, shumaker c, yearwood e, crowell n, riley j. perceived stress and social support in undergraduate nursing students' educational experiences. nurse educ today 2013; 33:419–24. https://doi.org/10.1016/j.nedt.2012.11.009. 50. müller t. persistence of women in online degree-completion programs. int rev res open distributed learn 2008; 9:1–18. https://doi.org/10.19173/irrodl.v9i2.455. 51. priya a, garg s, tigga np. predicting anxiety, depression and stress in modern life using machine learning algorithms. procedia comput sci 2020; 167:1258–67. https://doi.org/10.1016/j.procs.2 020.03.442. 52. kumar p, garg s, garg a. assessment of anxiety, depression and stress using machine learning models. procedia comput sci 2020; 171:1989–98. https://doi.org/10.1016/j.procs.2020.04.213. 1bapuji dental college and hospital, davanagere, karnataka, india; 2dayanand sagar college of dental sciences, bangalore, karnataka, india *corresponding author’s e-mail: pujacyavagal@gmail.com abstract: objectives: the aim of the current study was to compare urinary cotinine levels, nicotine dependence and physical effects related to smoking in smokers before and after laser auricular acupuncture, psychological counselling and a combination of laser treatment with counselling. methods: this study was carried out from february to july 2019 in india. a total of 60 smokers were randomly allocated to three interventional groups. urinary cotinine levels, nicotine dependence and physical effects due to smoking were evaluated using nicalert strips (nymox pharmaceutical corp., quebec, canada) the fagerström questionnaire and a visual analogue scale, respectively, at baseline and one month post-intervention. pearson’s chi-square, kruskal wallis analysis of variance and wilcoxon sign rank tests were used for statistical analyses. results: there was a significant reduction in urinary cotinine levels and nicotine dependence and significant improvement in behaviour and physical effects related to smoking in all groups post-intervention (p <0.05). reduction in nicotine dependence was significantly higher in the laser group (4.4 ± 1.66) compared to other groups (p <0.01). reduction in urinary cotinine levels was highest in the laser with counselling group (0.85 ± 0.3) compared to the other groups. there was a significant reduction in irritability, headache, craving for smoking, tiredness and anxiety as well as a substantial increase in calmness, unpleasant taste of smoking, the ability to concentrate and appetite in the laser auricular acupuncture group compared to the other groups (p <0.01) conclusion: laser auricular acupuncture alone and in combination with psychological counselling can reduce nicotine dependence among smokers. keywords: auricular acupuncture; laser; nicotine; tobacco dependence; india. efficacy of laser auricular acupuncture for smoking cessation a randomised controlled trial *puja c. yavagal1 and nagesh l.2 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e275–281, epub. 21 jun 21 submitted 28 may 20 revision req. 10 aug 20; revision recd. 25 aug 20 accepted 9 sep 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.017 clinical & basic research advances in knowledge auricular laser acupuncture alone and in combination with psychological counselling reduces nicotine dependence among smokers. application to patient care low-level laser therapy can be used to stimulate auricular acupoints to reduce nicotine dependence related to smoking. it can also be used as an adjunct therapy along with psychological counselling. laser acupuncture is a non-invasive, aseptic and painless therapy which can reduce the withdrawal symptoms associated with smoking cessation. addiction to smoking is a complex condition which can disturb a person’s life, leading to health problems, deterioration of vital organs, systemic complications and often premature death.1 the world health organization (who) classifies tobacco dependence in the category of ‘diseases, symptoms or conditions’. to address this disease, smoking cessation strategies play a pivotal role in saving current smokers from smoking-related mortality and morbidity. the success of such strategies, however, is limited. in a review article based on 633 studies of the most available interventions for smoking cessation, viswesvaran and schmidt concluded that the average observed success rate across all methods was just 19% with a 6.4% success rate for placebo controls.2 conventional techniques for smoking cessation have demonstrated a relatively low success rate, quick relapse and unpleasant withdrawal symptoms. of individuals using conventional approaches to quitting smoking, 20% reported that such treatments had failed in helping them quit smoking.3 many smokers, therefore, search for help in complementary and alternative medicine (cam). in a study by sood et al., 27% of subjects indicated using cam as an aid for tobacco cessation, and 67% reported interest in the future use of cam for smoking cessation.3 studies have shown therapeutic effects of acupuncture, considered a cam, for tobacco dependence, but further proof of this intervention’s efficacy is needed.4 stimulating auricular acupoints affects the limbic system of the brain, and specifically the reward centre. this modulation of the reward system is mediated through auricular branches of the trigeminal, the vagus nerve and the superior cervical plexus leading to greater restfulness and sleep management at the supraoptic chiasma. when smokers experience withdrawal systems during smoking cessation, stimulating auricular acupoints leads to modulation of reward pathways and the https://creativecommons.org/licenses/by-nd/4.0/ efficacy of laser auricular acupuncture for smoking cessation a randomised controlled trial e276 | squ medical journal, may 2021, volume 21, issue 2 release of dopamine and serotonin, thereby minimising withdrawal effects.5 low-level lasers (defined by wavelengths between 405–904 nm), which are a part of the electromagnetic spectrum, are used in acupuncture treatments and are non-invasive compared to needle acupuncture. painless non-invasive laser beams directed at specific acupoints for a few minutes per point for 3–5 sessions has been shown to achieve smoking cessation.6 this form of non-invasive, aseptic and painless therapy has advantages over traditional forms of acupuncture, especially in patients with phobias of needles. the effectiveness of laser acupuncture for smoking cessation, however, needs to be explored further.6 studies conducted on laser acupuncture for smoking cessation have shown inconsistent results due to heterogeneity of subjects’ and control groups’ ages, wavelength and power of lasers used, duration of treatment and acupoints treated. no studies have been carried out with the indian population and, most importantly, the majority of the studies have considered only subjective outcomes.6 this study, therefore, aimed to compare urinary cotinine levels, nicotine dependence and physical effects related to smoking after one month of laser acupuncture treatment with three groups of smokers. one group received only laser acupuncture, one received only counselling and one received a combination of laser acupuncture and counselling. methods the study, a randomised controlled exploratory clinical trial with concurrent parallel design and an active arm trial, had an estimated sample size of 47. the sample size (n) was estimated using the following formula: where zα/2 = 1.96, zβ = 0.84, p1 = 25% and p2 = 5.6% as expected sample proportions.7 considering a 20% dropout rate, 56 smokers (approximated to 60) were recruited to the study. inclusion criteria were young adults 18–35 years old who had smoked 100 cigarettes in their lifetime and currently smoked cigarettes daily or on some days (nondaily).8 current smokers who consented to participate and who had never been on any form of tobacco cessation therapy were included in the study. subjects with a known history of cardiac problems; diabetes mellitus (dm); epilepsy; lacking skin sensation near acupuncture points; suffering from undiagnosed fever, severe skin lesions or infection at and around acupuncture points; on psychiatric medications or unable to attend scheduled appointments were excluded. using computer software, a sequence of random numbers was generated to guide subjects’ random allocation (i.e. concealed randomisation) to the interventional groups. this allocation was done by a person uninvolved in the study who was given the random numbers within sealed opaque envelopes. once a patient had been determined to fulfill eligibility criteria and consented to enter the trial, an envelope was opened and the patient was offered the allocated treatment. all interventions were done by an investigator who was not blinded to the treatment procedure. group one were treated with only laser auricular acupuncture at days one, three, seven and 14. group two underwent psychological counselling for smoking cessation, with one session per week for a total of four sessions. group three were treated with a combination of laser acupuncture and psychological counselling for smoking cessation. urinary cotinine levels are widely used biomarkers among tobacco users. these levels have high sensitivity compared to blood cotinine levels, and the test is non-invasive.9 nicalert urinary cotinine strips (nymox pharmaceutical corporation, quebec, canada) were used for semi-quantitative estimation of cotinine in urine. this validated test determines if an individual has been exposed to tobacco products such as cigarettes within the past 48 hours.10 a labelled, sterile, disposable container was given to each participant to collect approximately 25 ml of midstream clear urine with aseptic precautions. the sample was tested within four hours of collection by a trained person not involved in the study who was blinded to participants’ treatment allocations. nicotine dependence was assessed with the help of the widely used standard fagerström questionnaire.11 level of addiction was interpreted as low (scores 0–4), medium (score 4–6) or high (>6). trained personnel not involved in the study administered the fagerström questionnaire. diode laser equipment (laboratory silberbauer, medical electronics, vienna, austria) with a power output of 36 mw, a wavelength of 660 nm, a beam area of 0.3 cm2, energy delivered at 7.2 joules per cm2 per point per session and a point probe contact method was used in continuous wave mode. the dose was calculated based on litscher’s guidelines.12 the investigator was trained to give laser therapy by a certified laser therapist before the start of the study and used protective eye wear. the national acupuncture detoxification association (nada) protocol suggests stimulating five auricular acupoints. acupuncture n = 2 × (zα/2 + zβ) × [p1(1 p1) + p2(1 p2)] / 2 × (p1p2) [equation 1] puja c. yavagal and nagesh l. clinical and basic research | e277 points stimulated on each ear included :“shen men,” “sympathetic” (“autonomic”), “kidney,” “liver,” and “lung”.13 the laser beam was directed at ten acupoints in contact mode. the total treatment duration was 10 minutes (one minute/point) per session. a total of four treatment sessions on days one, three, seven and 14 were given to every subject. the counselling intervention was done by following a combination of the 5a framework for interventions and the transtheoretical model.14,15 the subjects were counselled for 30 minutes per week, undergoing four sessions in one month. the stage of change in every subject was assessed at every counselling stage. the stages of change were precontemplation (stage one: not thinking of quitting); contemplation (stage two: ambivalent, but thinking of quitting); preparation (stage three: planning to quit); action (stage four: quit); maintenance (stage five: maintaining cessation) and relapse (stage six: returned from the action or the maintenance stage to an earlier stage).15 at every stage of change seen, the appropriate component of the 5as was used to bring about and reinforce the tobacco cessation behaviour. subjects’ physical effects experienced before, after and during the course of treatment were assessed for irritability, tiredness, calmness, anxiety, cravings, unpleasant taste when smoking, headaches, ability to concentration and appetite on a 10-point visual analogue scale (vas).16 statistical package for the social sciences (spss), version 22 (ibm corp., armonk, new york, usa) was used for data analyses. the significance level was fixed at p <0.05. data distribution was not normal, so nonparametric tests were applied. pearson’s chi-squared, kruskal wallis analysis of variance and wilcoxon sign rank tests were used. ethical clearance was obtained from the institutional review board of the college where the study was conducted (bdc/377/2017-18 dated 5-72017). the trial was registered under the clinical trial registry of india (ctri/2017/08/009317). voluntary written informed consent was obtained from each participant before beginning any intervention and after explaining the intended treatment, the possible outcomes, complications and the need for follow-up. results a total of 60 smokers met the eligibility criteria. study participants’ mean age was 32.93 ± 3.09 years. there were no significant differences in the distribution of participants across groups based on age, socioeconomic status, duration of smoking, nicotine dependence, behavioural stage or urinary cotinine levels (p >0.05). there was a highly significant reduction in urinary cotinine levels, nicotine dependence and the number of cigarettes/bidis smoked per day and a significant improvement in behaviour and physical effects related to smoking in all interventional groups one month post-intervention (p <0.05 each). a post-intervention reduction in nicotine dependence was significantly higher (p <0.01) in the laser group (4.4 ± 1.66) compared to groups two (2.15 ±1.47) and three (2.55 ± 1.23) [table 1]. the highest reduction in urinary cotinine levels and the number of cigarettes/bidis smoked per day were observed in the laser with counselling group (0.85 ± 0.3) when compared to the other groups (h = 6.08; p = 0.4) [tables 2 & 3]. improvements in behavioural changes were similar across different groups. there was a significant reduction (p <0.01) in physical effects associated with smoking, such as irritability, headache, craving smoking, tiredness and anxiety in the laser group compared to the other two interventional groups, and a significant increase (p <0.01) in the physical effects associated with smoking such as calmness, unpleasantness in the taste of smoking, ability to concentrate and appetite in the laser group compared to the other groups [table 4]. table 1: comparison of fagerström scores between the groups of the current study interventional groups pre-intervention fagerström scores post-intervention fagerström scores difference between preand postintervention fagerström scores mean ± sd median (iqr) mean ± sd median (iqr) mean ± sd* median (iqr) p value group one 6.95 ± 1.63 6.95 (3–9) 2.55 ± 1.39 3 (0–5) 4.4 ± 1.66ab 4 (1–8) <0.01 group two 5.3 ± 2.22 5 (2–10) 3.15 ± 1.08 3 (1–5) 2.15 ± 1.47a 2 (0–5) group three 5.65 ± 1.22 6 (3–8) 3.1 ± 1.4 3(1–7) 2.55 ± 1.23b 3 (0–5) kruskal wallis anova value (p value) 18.55 (<0.01) sd = standard deviation; iqr = interquartile range; anova = analysis of variance; group one = laser group; group two = counselling group; group three = laser + counselling group. *same letters indicate significant differences between groups with post hoc, mann-whitney u test, aa groups one and two (p <0.01), bb groups one and three (p <0.01). efficacy of laser auricular acupuncture for smoking cessation a randomised controlled trial e278 | squ medical journal, may 2021, volume 21, issue 2 discussion results of the present study revealed that auricular laser acupuncture was effective in reducing nicotine dependence as indicated by a reduction in fagerström test scores, urinary cotinine levels, number of cigarettes/bidis smoked per day and an improvement in physical effects related to smoking and behavioural stage of quitting smoking at one month postintervention. auricular laser acupuncture along with psychological counselling also had the considerable effect of reducing nicotine dependence as compared to only psychological counselling. the use of laser auricular acupuncture for smoking cessation had been explored earlier in other studies, but no other study to the best of researchers’ knowledge had compared it with psychological counselling by assessing urinary cotinine levels, nicotine dependence using the fagerström test or employing a vas to measure the physical effects experienced by smokers. because of these considerations, a direct comparison of the present study with other studies where laser auricular acupuncture was used could not be made for a number of reasons. laser parameters used in the study were based on standard guidelines stated by litscher et al. and reported based on world association for laser therapy guidelines.12 different studies on laser acupuncture, however, have used different wavelengths from those used in the current study.7,17,18 additionally, in the current study, interventions were spaced at the first, third, seventh and 14th days so as to compensate for the withdrawal symptoms caused by nicotine deprivation corresponding to a low level of serotonin and dopamine. spacing of treatments have differed across studies. despite these differences in methodology, the results of the current study are similar to some studies of laser acupuncture. tan et al. found that laser stimulation on auricular points produced an overall success rate of over 80% in quitting cigarette smoking; similarly, lim found it resulted in 87.5% of smokers quitting.19,20 kerr et al. showed effective results of laser table 3: comparison of cigarettes/bidis consumed daily between the groups of the current study interventional groups pre-intervention cigarettes/bidis smoked per day post-intervention cigarettes/bidis smoked per day difference between pre and post-intervention intra-group comparison wilcoxson-sign rank value (p value) mean ± sd median (iqr) mean ± sd median (iqr) mean ± sd median (iqr) group one 18.25 ± 8.35 12.2 (13–24) 9.85 ± 5.86 10 (1–24) 8.4 ± 4.0 6.5 (2–16) z = −3.94 (<0.01)* group two 15.4 ± 7.95 14.0 (4–36) 8.4 ± 5.08 8 (1–22) 7 ± 4.49 7.0 (0–14) z = −3.83 (<0.01)* group three 17.4 ± 6.77 17.5 (5–24) 9.95 ± 4.14 10.0 (3–24) 8.05 ± 4.67 8.5 (2–14) z = −3.84 (<0.01)* intergroup comparison kruskal-wallis anova (p value) 1.21 (0.51) 1.43 (0.48) 1.51 (0.47) sd = standard deviation ; iqr = interquartile range ; group one = laser group; group two = counselling group; group three = laser + counselling ; anova= analysis of variance. *statistically significant. table 2: comparison of urinary cotinine levels between the groups of the current study intervention groups pre-intervention urinary cotinine levels post-intervention urinary cotinine levels difference between preand post-intervention l4 l5 l6 l1 l2 l4 l5 l6 mean ± sd median (iqr) group one 0 7 13 0 0 5 13 2 0.80 ± 0.6 1 (0–2) group two 0 12 8 1 0 4 13 2 0.70 ± 0.3 0 (0–4) group three 0 14 16 0 1 2 13 4 0.85 ± 0.3 1 (0–4) number of subjects 0 28 37 1 1 11 39 8 kruskal-wallis anova value (p value) 6.08 (0.4) percentage of subjects 0 38 62 1.7 1.7 18.3 65 13.3 chi-squared (p value) 6.91 (0.032) 6.27 (0.9) sd = standard deviation; iqr = interquartile range; 0 = no detectable level of tobacco use; l1 (10–30 ng/ml) and l2 (30–100 ng/ml) = no use of tobacco products; l3 (100–200ng/ml) = cut-off level and positive for tobacco use; l4 (200–500 ng/ml), l5 (500–1000ng/ml) and l6 (>1000ng/ml) = use of tobacco product; group one = laser group; group two = counselling group; group three = laser + counselling group; anova = analysis of variance. puja c. yavagal and nagesh l. clinical and basic research | e279 acupuncture for smoking cessation compared to a sham acupuncture group.7 mostyn et al. also arrived at similar results, but the trial was uncontrolled.17 a cochrane meta-analysis, in contrast, demonstrated no superior effects of laser acupuncture over control groups which received placebo treatments, or groups that received sham and conventional acupuncture (i.e. with needles).6 according to another study, body acupuncture in combination with auricular acupuncture was not more effective than auricular acupuncture alone.2 the first two days are crucial during the smoking cessation period during which an increase in serotonin level in the brain tissue mediated by acupuncture can help reduce withdrawal symptoms.21 there was significant improvement (p <0.05) in physical effects related to smoking in the current study. the reason for this improvement could be the stimulation of the sympathetic auricular point and liver points, which are associated with relaxation of internal organs and resolving aggression, respectively, thereby leading to positive effects such as increased levels of endorphins secretion.22 subjects who underwent laser therapy (i.e. groups one and three) experienced an increased unpleasant taste for smoking post-intervention. similar findings have been observed in other studies, with participants reporting that, because cigarettes came to taste like burnt ash and were associated with malodoar, they had a decreased urge to smoke. table 4: comparison of physical effects due to smoking based on visual analogue scale scores between interventional groups post intervention physical effect related to smoking groups pretest median vas score post-test median vas score difference between pre and post-intervention vas scores kruskal wallis anova test (p value) post hoc mann whitney u test mean ± sd median (iqr) group z value (p value) irritability 1 6.5 5 1.65 ± 0.74 2 (0–3) 22.76 (<0.01) 1 & 2 62.0 (<0.01)* 2 6 6 0.35 ± 0.2 0 (-1–2) 2 & 3 170 (0.37) 3 7 7 0.5 ± 0.4 0.5 (0–1) 1 & 3 50 (<0.01)* tiredness 1 7 5 2.0 ± 1.25 2 (0–6) 22.76 (<0.01) 1 & 2 62 (<0.01)* 2 6.5 5.5 1.05 ± 0.05 1 (-1–4) 2 & 3 170 (0.3) 3 7 7 0.40 ± 0.28 0 (-1–2) 1 & 3 50 (<0.01)* calmness 1 7 5 1.85 ± 1.08 2 (0–4) 19.20 (<0.01) 1 & 2 3.6 (<0.01)* 2 6.5 6 0.6 ± 0.49 0.5 (-1–3) 2 & 3 -1.97 (0.04)* 3 7 7 0.40 ± 0.08 0 (0–2) 1 & 3 -2.27 (0.023)* anxiety 1 7 5 1.75 ± 0.91 2 (1–5) 22.86 (<0.01) 1 & 2 27.5 (<0.01)* 2 6 5 0.8 ± 0.32 1 (0–3) 2 & 3 110 (0.01)* 3 7 7 0.15 ± 0.04 0 (0–3) 1 & 3 132 (0.04) cravings 1 7.5 3 4.4 ± 1.66 4 (1–8) 18.55 (<0.01) 1 & 2 62 (<0.01)* 2 5 3 2.15 ± 1.42 2 (0–5) 2 & 3 160 (0.2) 3 6 3 2.55 ± 1.23 3 (0–5) 1 & 3 73 (<0.01)* unpleasant taste while smoking 1 7 3.5 2.6 ± 1.42 3 (0–4) 16.86 (<0.01) 1 & 2 79 (0.001)* 2 6 5.5 0.60 ± 1.69 0 (-3–4) 2 & 3 181.5 (0.6) 3 7 6 0.70 ± 1.17 1 (-2–2) 1 & 3 64.5 (<0.01)* headache 1 7 5 1.6 ± 1.5 1 (-2–4) 11.52 (0.003) 1 & 2 118.3 (0.002)* 2 6.5 6 0.35 ± 0.06 1 (-2–4) 2 & 3 179 (0.5) 3 7 7 0.25 ± 0.06 0 (-1–2) 1 & 3 78.5 (0.001)* ability to concentrate 1 7 5.5 1.55 ± 0.6 1.5 (-2–5) 10.55 (0.005) 1 & 2 121.5 (0.02)* 2 6.5 6 0.55 ± 0.1 1 (-2–2) 2 & 3 162 (0.2) 3 7 7 0.4 ± 0.06 0 (0–2) 1 & 3 90 (0.002)* appetite 1 7 5 2.1 ± 1.41 2 (0–6) 22.51 (<0.01) 1 & 2 73.5 (<0.01)* 2 6.5 6 0.6 ± 0.3 1 (-2–2) 2 & 3 146 (0.11) 3 7 7 0.3 ± 0.2 0 (-1–2) 1 & 3 47 (<0.01) vas = visual analogue scale; sd = standard deviation group 1 = laser group; group 2 = counselling group; group 3 = laser + counselling group. *statistically significant. efficacy of laser auricular acupuncture for smoking cessation a randomised controlled trial e280 | squ medical journal, may 2021, volume 21, issue 2 in the present study, very few subjects reported headaches. these headaches were ill-defined and coupled with irritability. headaches are recognised symptoms of smoking withdrawal due to an inability in smokers to build-up their own endorphin levels. similar experiences have been noted in other studies.7,19 the current study had a few limitations. the sample size was small, and observations were made one month post-intervention, limiting the generalisability of the study results and long-term effects of the intervention. urinary cotinine values, which determine tobacco exposure within the past 48 hours, were expressed as a range and were therefore not very sensitive to changes in nicotine levels. participants met the same mentor for the duration of the intervention possibly leading to exaggerated reports of good results. in short, social desirability bias could have influenced the results. it is recommended that researchers undertake longterm studies with large sample sizes in which sensitive objective measures of nicotine dependence are used such as gas chromatography. assessment of changes in the serotonin and dopamine levels in the body after laser auricular acupuncture could lead to insights on its mechanism of action. it is recommended to further test the efficacy of laser acupuncture along with alternative aids to reduce nicotine dependence. conclusion auricular laser acupuncture alone and in combination with psychological counselling reduced nicotine dependence among smokers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this trial was funded by rajiv gandhi university of health sciences, bangalore, karnataka -560041, india, under order number rgu/adv.res/br/001/2017-18 dated 21 december 2017. a c k n o w l e d g e m e n t we acknowledge the help rendered by dr. chandrashekar m. yavagal, professor and head, department of pediatric dentistry, maratha mandal’s nathajirao g. halgekar institute of dental sciences & research centre, belgaum, india towards calculation of laser dosage for stimulating acupoints. references 1. baler rd, volkow nd. addiction as a systems failure: focus on adolescence and smoking. j am acad child adolesc psychiatry 2011; 50:329–39. https://doi.org/10.1016/j.jaac.2010.12.008. 2. viswesvaran c, schmidt fl. a meta-analytic comparison of the effectiveness of smoking cessation methods. j appl psych 1992; 77:554–61. https://doi.org/10.1037/0021-9010.77.4.554. 3. sood a, ebbert jo, sood r, stevens sr. complementary treatments for tobacco cessation: a survey. nicotine tob res 2006; 8:767–71. https://doi.org/10.1080/14622200601004109. 4. world health organization. acupuncture: review and analysis of reports on controlled clinical trials. from: www.who.int/iris/ handle/10665/42414 accessed: aug 2020. 5. oleson t. neurophysiological basis of auricular acupuncture. in: stux g, hammerschlag r, eds. clinical acupuncture: scientific basis. berlin–heidelberg: springer-verlag, 2001. pp. 97–112. 6. white ar, rampes h, liu jp, stead lf, campbell j. acupunc ture and related interventions for smoking cessation. cochrane database syst rev 2014; 1:cd000009. https://doi.org/10.1002/1 4651858. 7. kerr cm, lowe pb, spielholz ni. low level laser for the stimulation of acupoints for smoking cessation: a double blind, placebo controlled randomized trial and semi structured interviews. j chinese med 2008; 86:46–51. 8. centers for disease control and prevention. health behaviors of adults: united states, 2005-2007. from: www.cdc.gov/nchs/ data/series/sr_10/sr10_245.pdf accessed: aug 2020. 9. raja m, garg a, yadav p, jha k, handa s. diagnostic methods for detection of cotinine level in tobacco users: a review. j clin diagnostic res 2016; 10:ze04–6. https://doi.org/10.7860/ jcdr/2016/17360.7423. 10. lee a, gin t, chui pt, tan pe, chiu ch, tam tp. the accuracy of urinary cotinine immunoassay test strip as an add-on test to self-reported smoking before major elective surgery. nicotine tob res 2013; 15:1690–5. https://doi.org/10.1093/ntr/ntt039. 11. heatherton tf, kozlowski lt, frecker rc, fagerström ko. the fagerström test for nicotine dependence: a revision of the fager ström tolerance questionnaire. br j addict 1991; 86:1119–27. https://doi.org/10.1111/j.1360-0443.1991.tb01879.x. 12. litscher g, opitz g. technical parameters for laser acupuncture to elicit peripheral and central effects: state-of-the-art and short guidelines based on results from the medical university of graz, the german academy of acupuncture, and the scientific literature. evid based complement alternat med 2012; 697096. https://doi.org/10.1155/2013/984763. 13. stuyt eb, voyles ca. the national acupuncture detoxification association protocol, auricular acupuncture to support patients with substance abuse and behavioral health disorders: current perspectives. subst abuse rehabil 2016; 7:169–80. https://doi. org/10.2147/sar.s99161. 14. tobacco tc. a clinical practice guideline for treating tobacco use and dependence: 2008 update: a us public health service report. am j prev med 2008; 35:158–76. https://doi.org/10.10 16/j.amepre.2008.04.009. 15. prochaska jo, redding c, evers k. the transtheoretical model and stages of change. in: glanz k, lewis fm, rimer bk, eds. health behavior and health education: theory, research and practice, 3rd ed. san francisco: jossey-bass publications, 2001. pp. 60–84. https://doi.org/10.1016/j.jaac.2010.12.008 https://doi.org/10.1037/0021-9010.77.4.554 https://doi.org/10.1080/14622200601004109 https://doi.org/10.1002/14651858 https://doi.org/10.1002/14651858 https://doi.org/10.7860/jcdr/2016/17360.7423 https://doi.org/10.7860/jcdr/2016/17360.7423 %20https://doi.org/10.1093/ntr/ntt039 https://doi.org/10.1111/j.1360-0443.1991.tb01879.x https://doi.org/10.1155/2013/984763 https://doi.org/10.2147/sar.s99161 https://doi.org/10.2147/sar.s99161 https://doi.org/10.1016/j.amepre.2008.04.009 https://doi.org/10.1016/j.amepre.2008.04.009 puja c. yavagal and nagesh l. clinical and basic research | e281 16. aun c, lam ym, collect b. evaluation of the use of visual analogue scale in chinese patients. pain 1986; 25:215–21. https://doi. org/10.1016/0304-3959(86)90095-3. 17. mostyn dcr, eng rd, kristina hachey cg, mandel a. laser acupuncture therapy for the treatment of tobacco addiction. from: www.theralase.com/wp-content/uploads/2014/05/smoking cessation-clinical-study.pdf accessed: aug 2020. 18. collet jp, ducruet t, robinson ar. systematic follow-up of a cohort of smokers who received a standard smoking cessation intervention with soft laser therapy. j complement integr med 2008; 5:1–9. https://doi.org/10.1164/ajrccm.156.6.9612096. 19. tan ch, sin ym, huang xg. the use of laser on acupuncture points for smoking cessation. am j acupunct 1987; 15:137–41. 20. lim rc. painless laser acupuncture for smoking cessation. med acupunct 2018; 30:159–62. https://doi.org/10.1089/acu.2018.1295. 21. cabioglu mt, ergene n, tan ü. smoking cessation after acupunc ture treatment. int j neurosci 2007; 117:571–8. https://doi. org/10.1080/00207450500535289. 22. kurebayashi lfs, gnatta jr, borges tp, belisse g, coca s, minami a, et al. the applicability of auriculotherapy with needles or seeds to reduce stress in nursing professionals. rev esc enferm usp 2012; 46:86–92. https://doi.org/10.1590/ s0080-62342012000100012. https://doi.org/10.1016/0304-3959%2886%2990095-3 https://doi.org/10.1016/0304-3959%2886%2990095-3 https://doi.org/10.1164/ajrccm.156.6.9612096 https://doi.org/10.1089/acu.2018.1295 https://doi.org/10.1080/00207450500535289 https://doi.org/10.1080/00207450500535289 https://doi.org/10.1590/s0080-62342012000100012 https://doi.org/10.1590/s0080-62342012000100012 department of family medicine & public health, 1sultan qaboos university hospital and 3sultan qaboos university, muscat, oman; 2directorate general of primary health care, ministry of health, north batinah region, oman *corresponding author’s e-mail: albelushi11@hotmail.com سلس البول لدى النساء العمانيات مدي انتشاره وعوامل اخلطر والتأثري على جودة احلياة مي�صاء حامد الكيومية، زليخة عي�صى البلو�صية، �صاجناي جاجو، عبد العزيز حممود املحرزي abstract: objectives: urinary incontinence (ui) in women is a common health problem which can have a negative impact on quality of life (qol). this study aimed to determine the prevalence, risk factors and impact of ui on the qol of omani women attending primary healthcare centres in muscat, oman. methods: this crosssectional study was conducted at three primary healthcare centres in muscat from april to august 2018. women who were 20–50 years of age, not pregnant, not in the six-month postnatal period, not seriously ill and not diagnosed with pelvic organ prolapse were included. a self-administered questionnaire using the international consultation incontinence questionnaire-short form was used to evaluate the frequency, severity and impact of ui on qol. results: a total of 1,070 women were included in this study (response rate = 92.5%). the mean age was 31.39 ± 7.64 years. ui was reported by 369 (34.5%) women, of whom 182 (49.3%) had stress ui, 97 (26.3%) had urgency ui, 88 (23.8%) had mixed ui and two (0.5%) had other ui. age, body mass index (bmi), having been married or employed, hypertension, cough, constipation and vaginal or assisted vaginal delivery during the previous birth were significant risk factors for ui. only 41 (11.1%) out of the 369 women with ui had ever sought medical advice despite the fact that more than two thirds of the women with ui reported negative effects on their qol. conclusion: ui is a common medical problem in oman. several risk factors, including age and bmi, were identified. despite its negative consequences for qol, women were found to be reluctant to seek medical attention for the condition. keywords: urinary incontinence; prevalence; risk factors; quality of life; oman. امللخ�ص: الهدف: يعد �صل�س البول لدى الن�صاء م�صكلة �صحية �صائعة ميكن اأن يكون لها تاأثري �صلبي على جودة احلياة تهدف هذه الدرا�صة اإىل حتديد مدى انت�صار �صل�س البول واأ�صبابه ومدى تاأثريه على جودة احلياة لدى الن�صاء العمانيات املرتددات على مراكز الرعاية ال�صحية الأولية يف حمافظة م�صقط يف �صلطنة عمان. الطريقة: اأجريت هذه الدرا�صة امل�صتعر�صة يف ثالثة مراكز للرعاية ال�صحية الأولية يف م�صقط بعد ما اأ�صهر �صتة فرتة يف اأو حوامل، ول�صن عاًما، 50 و 20 بني اأعمارهن ترتاوح اللواتي الن�صاء و�صملت 2018 اأغ�صط�س اإىل اأبريل من الولدة، اأو م�صابات باأمرا�س خطرة اأو يعانني من مر�س هبوط احلو�س. الدرا�صة ا�صتخدمت الن�صخة العربية املعباأة ذاتيا للنموذج الدويل ل�صل�س البول جلمع البيانات. النتائج: �صاركت يف الدرا�صة 1,070 امراأة )مبعدل ا�صتجابة = %92.5( ومبتو�صط عمر 7.6 ± 31.39 �صنة حيث اأظهرت الدرا�صة اأن 369 اإمراة يعانني من �صل�س البول بن�صبة )%34.5(، منهن 182 اإمراأة بن�صبة )%49.3( يعانني من �صل�س البول الإجهادي )stress ui(، و 97 لديهن �صل�صل البول الإحلاحي )urge ui( اأي بن�صبة )%26.3(، بينما 88 اإمراأة بن�صبة )%23.8(. يعانني من النوع املختلط mixed iu و2 اإمراأة بن�صبة )%0.5( لديهن �صل�س البول لأ�صباب اأخرى. وت�صري الدرا�صة باأن العمر وموؤ�رش كتلة اجل�صم )bmi( وارتفاع �صغط الدم وال�صعال والإم�صاك والولدة املهبلية وكون املراأة متزوجة اأو موظفة اأو ا�صتخدام اأدوات م�صاعدة خالل اخر ولدة من العوامل اخلطرة لالإ�صابة مبر�س �صل�س البول. كما اأ�صارت الدرا�صة اأن 41 اإمراأة فقط بن�صبة )%11.1( من اأ�صل 369 اإمراأة ممن يعانني من �صل�س البول قد طلنب امل�صورة الطبية على الرغم من اأن اأكرث من ثلثي الن�صاء ذكرن وجود اآثار �صلبية على حياتهن. اخلال�صة: �صل�س البول م�صكلة طبية �صائعة يف �صلطنة عمان لها العديد من امل�صببات اأهمها العمر وموؤ�رش كتلة اجل�صم، وعلى الرغم من عواقبها ال�صلبية على جودة احلياة اإل اأن اأغلب الن�صاء يرتددن يف طلب امل�صورة الطبية. الكلمات املفتاحية: �صل�س البول؛ ح انت�صار؛ عوامل اخلطر؛ جودة احلياة؛ �صلطنة عمان. urinary incontinence among omani women prevalence, risk factors and impact on quality of life maisa h. al kiyumi,1 *zaleikha i. al belushi,2 sanjay jaju,3 abdulaziz m. al mahrezi1 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e45–53, epub. 9 mar 20 submitted 2 jul 19 revision req. 28 aug 19; revision recd. 2 sep 19 accepted 20 sep 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.007 clinical & basic research advances in knowledge as this study is the first of its type conducted in oman, it will increase women’s awareness of urinary incontinence (ui). this study will enhance knowledge of the detrimental effects of ui on quality of life (qol). this study will elaborate on the health-seeking behaviour for ui to detect any misconceptions and myths about the condition. application to patient care in light of the finding that so few women with ui seek medical help for the condition, a screening programme for ui in women with risk factors should be implemented at the primary care level. those with ui should be offered proper treatment that corresponds to the severity of their condition. in this way, the detrimental effects of ui on qol might be attenuated by early detection and treatment. misconceptions about ui found by this study should be addressed at the primary care level, which will lead to better qol. https://creativecommons.org/licenses/by-nd/4.0/ urinary incontinence among omani women prevalence, risk factors and impact on quality of life e46 | squ medical journal, february 2020, volume 20, issue 1 urinary incontinence (ui) is defined as any involuntary loss of urine.1 it is a common problem but is underreported, underdiagnosed and undertreated.2 more than 250 million women are affected worldwide and this number is expected to increase to more than 300 million over the coming years.3 the prevalence of ui varies by country, ranging from 4.8–58.4% with a median prevalence of 27.6%.4 studies conducted in the other gulf cooperative council countries (i.e. qatar, saudi arabia and kuwait) revealed ui prevalence rates of 20.7%, 41.4% and 54.5%, respectively.5–7 this wide variation in the estimate of prevalence could be attributed to differences in the research methodologies used. the burden of ui has increased over time and is expected to increase more in the developing regions of africa, south america and asia than in other regions of the world.3 studies have identified increasing age, body mass index (bmi) and the number of deliveries as significant risk factors for developing ui.8 despite the positive association between age and ui, studies have shown that ui is also common in middle-aged and younger groups.9,10 ui has been reported to have negative effects on qol.11 a study conducted in turkey revealed that 87.2% of women with ui stated that it had a negative impact on their qol.11 surprisingly, only a small percentage of women with this condition seek medical help or advice.6 this finding might be related to common misunderstandings towards ui such as the belief that “there is no treatment available” and that it is “a common problem that everyone woman faces”.12 to the best of the authors’ knowledge, no previously published studies have examined the prevalence of and risk factors associated with ui in oman. hence, this study aimed to determine the prevalence of ui and identify its subtypes. in addition to identifying associated risk factors, this study assessed the impact of ui on qol in women in oman. methods this cross-sectional study was conducted at three primary healthcare centres (phcs; al mabeela, al mawaleh and al khodh health centres) located in al seeb wilayat, muscat, oman, between april and august 2018. all healthy non-pregnant females between 20–50 years of age who were able to read and write and were attending the health centres for any reason were invited to participate in the study. subjects were excluded if they were in the postnatal period (i.e. delivered in the past six months), required a wheelchair for basic mobility, were attending the phc for emergency services or had been diagnosed with pelvic organ prolapse. this study constitutes the first phase of a two phase research project. individuals of this age group was specifically targeted for two reasons. first, consenting women in this age group were expected to be more willing to enrol in phase two of the study, which involved measuring the effects of home-based pelvic floor muscle exercise training on decreasing symptoms of ui, improving qol and strengthening pelvic floor muscles. second, women in this age group were expected to have enough education to independently complete the selfadministered questionnaire. a consecutive sampling methodology was used for recruiting subjects. the sample size was calculated with an absolute precision of 3% and a 95% confidence interval (ci). based on an anticipated prevalence of 40%, the ideal sample size was estimated at 1,024 participants.6 at each phc, a trained staff nurse identified all consecutive female patients who fulfilled the inclusion criteria, explained the purpose of the study and invited them to participate. the subjects were enrolled by allocating each participant a unique number in chronological order at each study site. weights and heights were measured by the staff nurse. in addition, the nurse kept a record of those who chose not to participate and the reasons for not participating. the participants were asked to complete a selfadministered questionnaire. the first part of the quest ionnaire collected data related to age, educational back ground, marital status, occupation, monthly income, smoking status, history of constipation or cough and history of conditions such as diabetes mellitus, hyper tension, asthma or recurrent urinary tract infections. obstetric data included maternal age at first birth, number of pregnancies, number of spontaneous or assisted vaginal and caesarean section (cs) deliveries, weight of the largest baby delivered, history of episiotomy during last delivery and the duration of last delivery. the second part of the questionnaire consisted of a validated arabic-version of the international consultation incontinence questionnaire-short form (iciq-sf), which is a brief and psychometrically robust instrument for evaluating the frequency, severity and impact of ui on qol.13 the iciq-sf asks participants to report frequency of ui, amount of leakage, overall impact of ui on qol and the situation surrounding the leakage. the iciq-sf is scored from 0–21 with higher scores indicating increased severity. the survey was first validated in the uk and has been translated into 35 languages. it is widely used and the arabicmaisa h. al kiyumi, zaleikha i. al belushi, sanjay jaju and abdulaziz m. al mahrezi clinical and basic research | e47 version has been validated in egypt, syria and saudi arabia.13–15 women are classified as having stress ui (sui) if they answer ‘yes’ to either or both of the following statements: (1) urine leaks occur during coughing or sneezing and/or (2) urine leaks occur when physically active/exercising. a woman is diagnosed with urgency ui (uui) if urine leakage occurs before she can get to a toilet. women are diagnosed with mixed ui (mui) if they have features of both sui and uui. a classification of other ui is used for those who answer ‘yes’ to the following statements: urine leaks occur (1) during sleep, (2) when finished urinating and dressed, (3) for no obvious reason or (4) all the time. women with sui were interviewed by the principal and co-principal investigators and were invited to participate in phase two of the study, which was concurrently nested within phase one. women who were diagnosed with uui, mui or other ui were offered proper medical advice and consultation in their allocated phc. the third part of the questionnaire included four statements about medical advice-seeking behaviour and were answered as either ‘yes’ or ‘no’. if answered with ‘yes’, then further questions about the type of treatment offered were answered. if the answer was ‘no’, the participant was asked to select a reason for not seeking medical advice. the four choices given were ‘leakage of urine affects all women and there is no need to worry about it’, ‘i feel embarrassed to disclose this issue to a doctor’, ‘i hope to have spontaneous recovery from leakage’ and ‘leakage of urine is incurable’. the prevalence estimates of types of ui were reported as numbers and percentages. the baseline characteristics and risk factors were compared between subjects having ui and those not having ui. the obstetric characteristics of the two groups were analysed in the subsample of women who had given birth; it would not have been appropriate to include those who had not given birth. the analysis was done using an unpaired student’s t-test or chi-squared test as appropriate. binary logistic regression analysis was done for the total sample and subsample of women who had ever given birth to determine the likelihood of having ui using the significant variables on chisquare testing as predictor variables. seeking medical advice and qol among those having ui was described in numbers, central tendencies and cumulative proportions as appropriate. a p value of <0.05 was considered significant. ethical approval was granted by the directorate general of planning and studies of the ministry of health, muscat, oman (moh/csr/17/6555). written informed consent was obtained from each participant. results a total of 1,070 women were included in this study (response rate = 92.5%); 87 women chose not to participate, stating lack of time as the main reason. sociodemographic characteristics of non-participants were similar to the women who were recruited. the mean age of the participants was 31.39 ± 7.64 years. most participants (60.2%) were overweight or obese. the proportion of various risk factors for ui considered in this study ranged from 1.0–10.5% [table 1]. the majority of women had had normal vaginal deliveries during their last childbirth (73.2%) and their last pregnancy had been within five years of participating in the study (62.8%). in total, 300 women (43.7%) had an episiotomy during their last delivery [table 2]. a total of 369 respondents (34.5%) suffered from ui of which most suffered from sui (49.3%) followed by uui (26.3%), mui (23.8%) and other ui (0.5%). based on the overall scores of the iciq-sf, 332 out of 369 participants (90%) had mild to moderate ui. in the subgroup of women who had given birth, the prevalence of ui increased to 41.5% and a marginal increase in the prevalence of sui and mui were also noted. most women with ui reported a mild to moderate effect of ui on their qol (62%) [table 3]. a significant association (p ≤0.001) was found between ui and age, marital status, bmi, employment status, monthly income of the family, hypertension, cough, constipation and mode of delivery during last birth (i.e. normal vaginal delivery and vacuum or forceps-assisted vaginal delivery). no significant association was found between ui and age at first birth and the remaining characteristics [table 4]. a logistic regression analysis was performed to study the effects of significant variables on the likelihood that participants would develop ui; the model was found to be statistically significant (χ2 [15 degrees of freedom] = 120.284; p <0.001). being married (odds ratio [or] = 2.26, 95% ci: 1.58–3.23; p <0.001) or divorced (or = 2.48, 95% ci: 1.28–4.82; p = 0.007) were significantly associated with an increase in the likelihood of exhibiting ui compared to those who were single. participants who were employed (or = 1.46, 95% ci: 1.09–1.94; p = 0.009), had hypertension (or = 1.73, 95% ci: 1.00–2.98; p = 0.049), a cough for more than one month (or = 2.73, 95% ci: 1.77–4.20; p <0.001), constipation lasting for more than one month (or = 2.18, 95% ci: 1.40–3.40; p = 0.001), delivering a baby via normal vaginal delivery (or = 2.18, 95% ci: 1.24–3.83; p = 0.006) or vacuum or forceps-assisted vaginal delivery (or = 5.04, 95% urinary incontinence among omani women prevalence, risk factors and impact on quality of life e48 | squ medical journal, february 2020, volume 20, issue 1 table 1: baseline characteristics and risk factors of urinary incontinence among omani women (n = 1,070) characteristic n (%) age in years 20–30 31–40 41–50 mean ± sd 546 (51.0) 367 (34.3) 157 (14.7) 31.39 ± 7.64 body mass index category underweight normal overweight obese mean ± sd 78 (7.3) 348 (32.5) 284 (26.5) 360 (33.6) 27.51 ± 6.81 marital status single married widowed divorced 302 (28.2) 705 (65.9) 9 (0.8) 54 (5.0) educational level none up to preparatory* secondary and higher 7 (0.7) 115 (10.7) 948 (88.6) employment status not employed employed 616 (57.6) 454 (42.4) monthly income of family in omr <500 500–1000 >1000 340 (31.8) 505 (47.2) 225 (21.0) risk factors for urinary incontinence diabetes mellitus yes no 46 (4.3) 1024 (95.7) hypertension yes no 70 (6.5) 1000 (93.5) asthma yes no 39 (3.6) 1031 (96.4) recurrent urogenital infection yes no 106 (9.9) 964 (90.1) smoking yes no 11 (1.0) 1059 (99.0) cough lasting for more than one month yes no 112 (10.5) 958 (89.5) constipation lasting for more than one month yes no 104 (9.7) 966 (90.3) sd = standard deviation; omr = omani rials. *includes grades 1–9. table 2: distribution of obstetricand urinary incontinence related characteristics among omani women who have given birth (n = 686) characteristic n (%) number of pregnancies ≤3 4–6 7–9 ≥10 413 (60.2) 218 (31.8) 43 (6.3) 12 (1.7) age at first birth in years 14–17 18–21 22–25 26–29 30–33 ≥34 mean ± sd 31 (4.5) 158 (23.0) 300 (43.7) 110 (16.0) 63 (9.2) 24 (3.5) 24 ± 4.5 number of normal vaginal deliveries 0 1–3 4–6 7–9 102 (14.9) 410 (59.8) 149 (21.7) 25 (3.6) number of caesarean sections 0 1–3 4–6 475 (69.2) 190 (27.7) 21 (3.1) years since last pregnancy <5 5–10 11–15 >15 431 (62.8) 173 (25.2) 55 (8.0) 27 (3.9) number of abortions 0 1 2 3 ≥4 514 (74.9) 105 (15.3) 45 (6.6) 11 (1.6) 11 (1.6) mode of delivery during last birth normal vaginal assisted vaginal (with vacuum or forceps) caesarean section 502 (73.2) 22 (3.2) 162 (23.6) episiotomy during last delivery yes no 300 (43.7) 386 (56.3) labour persisted for >24 hours yes no 177 (25.8) 509 (74.2) weight of largest baby in kg ≥4 <4 83 (12.1) 603 (87.9) sd = standard deviation. maisa h. al kiyumi, zaleikha i. al belushi, sanjay jaju and abdulaziz m. al mahrezi clinical and basic research | e49 table 3: prevalence of urinary incontinence and charact eristics of urinary leakage according to the international consultation incontinence questionnaire-short form among omani women (n = 1,070) characteristic n (%) ui yes no 369 (34.5) 701 (65.5) type of ui (n = 369) uui sui mui other ui 97 (26.3) 182 (49.3) 88 (23.8) 2 (0.5) women who have given birth (n = 686) ui present yes no 285 (41.5) 401 (58.5) type of ui (n = 285) uui sui mui other ui 65 (22.8) 149 (52.3) 70 (25.6) 1 (0.4) iciq-sf item frequency of ui (n = 1,070) never about once a week or less often two to three times a week about once a day several times a day all the time 701 (65.5) 258 (24.1) 48 (4.5) 21 (2.0) 35 (3.3) 7 (0.7) amount of leakage (n = 1,070) none a small amount a moderate amount a large amount 701 (65.5) 318 (29.7) 45 (4.2) 6 (0.6) qol interference from ui (n = 369) none mild moderate severe very severe 98 (26.6) 166 (45.0) 63 (17.0) 23 (6.2) 19 (5.1) iciq categories (n = 369) mild moderate severe very severe 210 (56.9) 122 (33.1) 34 (9.2) 3 (0.8) ui = urinary incontinence; uui = urgency urinary incontinence; sui = stress urinary incontinence; mui = mixed urinary incontinence; iciqsf = international consultation incontinence questionnaire-short form; qol = quality of life. table 4: comparison of baseline and obstetric characteristics and risk factors among omani women with or without urinary incontinence (n = 1,070) characteristic n (%) p value*ui present (n = 369) ui absent (n = 701) age in years 20–30 31–40 41–50 161 (43.6) 134 (36.3) 74 (20.1) 385 (54.9) 233 (33.2) 83 (11.8) <0.001 marital status single married widowed divorced 63 (17.1) 278 (75.3) 3 (0.8) 25 (6.8) 239 (34.1) 427 (60.9) 6 (0.9) 29 (4.1) <0.001 body mass index category† underweight normal overweight obese 17 (4.7) 101 (27.7) 92 (25.2) 155 (42.5) 55 (8.0) 239 (34.7) 190 (27.6) 205 (29.8) <0.001 educational level none up to preparatory‡ secondary and higher 2 (0.5) 36 (9.8) 331 (89.7) 5 (0.7) 79 (11.3) 617 (88.0) ≥0.05 employment status unemployed employed 183 (49.6) 186 (50.4) 433 (61.8) 268 (38.2) <0.001 monthly income of family in omr <500 500–1000 >1000 118 (32.0) 152 (41.2) 99 (26.8) 222 (31.7) 353 (50.4) 126 (18.0) 0.001 diabetes mellitus yes no 18 (4.9) 351 (95.1) 28 (4.0) 673 (96.0) ≥0.05 hypertension yes no 37 (10.1) 332 (90.0) 33 (4.7) 670 (95.4) 0.001 asthma yes no 17 (4.6) 352 (95.4) 22 (3.1) 679 (96.9) ≥0.05 recurrent urogenital infection yes no 63 (17.1) 306 (82.9) 43 (6.1) 658 (93.9) ≥0.05 smoking yes no 6 (1.6) 363 (98.4) 5 (0.7) 696 (99.3) ≥0.05 cough lasting more than one month yes no 68 (18.4) 301 (81.6) 44 (6.3) 657 (93.7) <0.001 constipation lasting more than one month yes no 58 (15.7) 311 (84.3) 46 (6.6) 655 (93.4) <0.001 ui = urinary incontinence; omr = omani rials. †there was some missing data; n = 365 for those with ui and n = 689 for those without ui. ‡includes grades 1–9. §percentages are out of women who had given birth who had urinary incontinence (n = 285) and those who did not (n = 401). urinary incontinence among omani women prevalence, risk factors and impact on quality of life e50 | squ medical journal, february 2020, volume 20, issue 1 ci: 1.68–15.06; p = 0.004) were significantly more likely to experience ui [table 5]. only 41 (11.1%) out of 369 women with ui had ever sought medical advice about their condition. for those who sought medical advice the following treatments were offered: pelvic floor exercises (39.0%), medication (51.2%) and surgery (9.8%). of the 315 women who gave reasons for not seeking medical advice for ui, the most commonly given reason was “i hope to have spontaneous recovery from leakage” (42.9%), followed by “leakage of urine affects all women and there is no need to worry about it” (28.9%), “leakage of urine is incurable” (19.7%) and “i feel embarrassed to disclose this issue to a doctor” (8.6%) [table 6]. table 4 (cont’d): comparison of baseline and obstetric charact eristics and risk factors among omani women with or without urinary incontinence (n = 1,070) characteristic n (%) p value*ui present (n = 369) ui absent (n = 701) years since last pregnancy§ <5 5–10 11–15 >15 166 (58.2) 82 (28.8) 22 (7.7) 15 (5.3) 265 (66.1) 91 (22.7) 33 (8.2) 12 (3.0) ≥0.05 age at first birth in years† 14–17 18–21 22–25 26–29 30–33 ≥34 11 (3.8) 75 (26.1) 115 (40.4) 44 (15.3) 27 (9.4) 13 (4.5) 20 (5.0) 84 (20.8) 183 (45.6) 66 (16.4) 36 (8.9) 12 (3.0) ≥0.05 number of pregnancies† ≤3 4–6 7–9 ≥10 171 (60.0) 87 (30.5) 21 (7.4) 6 (2.1) 242 (60.3) 131 (32.7) 22 (5.5) 6 (1.5) ≥0.05 number of abortions† 0 1 2 3 ≥4 206 (72.3) 47 (16.5) 23 (8.1) 5 (1.8) 4 (1.4) 308 (76.8) 58 (14.5) 22 (5.5) 6 (1.5) 7 (1.7) ≥0.05 number of vaginal deliveries† 0 1–3 4–6 7–9 40 (14.0) 166 (58.2) 68 (23.9) 11 (3.9) 62 (15.5) 244 (60.8) 81 (20.2) 14 (3.5) ≥0.05 number of caesarean sections† 0 1–3 4–6 200 (70.2) 80 (28.1) 5 (1.8) 275 (68.6) 110 (27.4) 16 (4.0) ≥0.05 mode of delivery during last birth† normal vaginal assisted vaginal caesarean section 210 (73.7) 15 (5.3) 60 (21) 292 (72.8) 7 (1.8) 102 (25.5) 0.001 episiotomy during last delivery† yes no 136 (47.7) 149 (52.3) 164 (40.9) 237 (59.1) ≥0.05 labour persisted for >24 hours† yes no 79 (27.7) 206 (72.3) 98 (24.4) 303 (75.6) ≥0.05 weight of largest baby in kg† <4 ≥4 250 (87.7) 35 (12.3) 353 (88.0) 48 (12.0) ≥0.05 ui = urinary incontinence; omr = omani rials. †there was some missing data; n = 365 for those with ui and n = 689 for those without ui. ‡includes grades 1–9. §percentages are out of women who had given birth who had urinary incontinence (n = 285) and those who did not (n = 401). table 5: logistic regression analysis to determine the likeli hood that women with risk factors have urinary incontinence risk factor or (95% ci) p value marital status (married) 2.26 (1.58–3.23) <0.001 marital status (divorced) 2.48 (1.28–4.82) 0.007 employed 1.46 (1.09–1.94) 0.009 hypertension 1.73 (1.00–2.98) 0.049 cough lasting more than one month 2.73 (1.77–4.20) <0.001 constipation lasting more than one month 2.18 (1.40–3.40) 0.001 normal vaginal delivery 2.18 (1.24–3.83) 0.006 vacuumor forceps-assisted vaginal delivery 5.04 (1.68–15.06) 0.004 or = odds ratio; ci = confidence interval. table 6: medical advice-seeking behaviour among omani women with urinary incontinence (n = 362)* question and response n (%) did you seek medical advice for your problem? yes no 41 (11.3) 321 (88.7) treatment offered among those who sought medical advice for their ui (n = 41) pelvic floor exercises (i.e. kegel exercises) medication(s) surgery 16 (39.0) 21 (51.2) 4 (9.8) reasons for not seeking medical advice for ui (n = 315)† leakage of urine affects all women and there is no need to worry about it i feel embarrassed to disclose this issue to a doctor i hope to have spontaneous recovery from leakage leakage of urine is incurable 91 (28.9) 27 (8.6) 135 (42.9) 62 (19.7) ui = urinary incontinence. *some women did not respond (n = 7). †some women did not complete this section (n = 6). maisa h. al kiyumi, zaleikha i. al belushi, sanjay jaju and abdulaziz m. al mahrezi clinical and basic research | e51 discussion this study revealed that ui is a common condition among omani women. increasing age, obesity, cough or constipation and vaginal or assisted vaginal delivery during the last birth were found to be significant predictors of ui. the prevalence of ui among omani women in this study was 34.5%, which is lower than the reported percentage in several other studies.6,7,16 a study of ui conducted in germany and denmark found that the prevalence of ui was 48.3% and 46.4%, respectively.16 similarly, higher prevalence rates than the current study were reported in saudi arabia and kuwait (41.4% and 54.5%, respectively).6,7 on the other hand, prevalence rates in qatar and turkey were lower than in the current study (20.7% and 23.9%, respectively).5,11 the variation in the prevalence rates of ui across different studies could be explained by differences in the ui definitions used, sampling methods and age groups included.17 moreover, the tendency to report a higher prevalence of ui was noted in studies using in-person interviews compared with self-administered questionnaires.18 sui was the most common type of ui in this study, which is consistent with multiple studies conducted worldwide.4–6,8,10,19,20 fewer studies identified mui as the most common type of ui.7,11,21 within the age groups in the current study, older women were more likely to have ui than not have ui compared to the other age groups; subgroup age analyses revealed that almost half of the women aged between 41–50 had ui. furthermore, 161 (43.6%) women between 20–30 years had ui. the higher prevalence of ui in women in the younger age group could be explained by the lower marriage and childbirth ages in oman; a study revealed that about three-quarters of women were already married by the age of 20 in oman.22 additionally, lack of awareness about the importance of pelvic floor muscle exercises during the antenatal and postnatal periods could have also contributed to this high prevalence.5 similar to the findings of previous studies, this study demonstrated a positive association between bmi and ui.7–9,16,21 the underlying reasons for this strong relationship are still unknown. one theory suggests that increased weight leads to increased intra-abdominal pressure, urethral mobility and detrusor instability, which eventually results in ui.23 while women who are/were married were at a higher risk of developing ui compared to single women, such an association is to be expected, especially because such women tend to be older and age was found to be a significant risk factor for ui in the current study. this study revealed a significant association between employment status and ui. being more aware of ui symptoms and their possible impact on work performance, and especially the worry of unintentional urination, might be reasons for this finding.24 hypertension was identified as a significant risk factor for ui in the current study. a similar finding has been reported in other larger studies.11,25 the underlying mechanism for this finding is not well understood and additional studies are required. the current study did not show a significant association between asthma and ui. however, it revealed that cough and constipation are significant risk factors for ui. these findings are consistent with those from previous studies and might be explained by the increased intra-abdominal pressure due to longstanding cough and constipation.6,9 both cough and constipation might lead to excessive loading on the arcus tendineus fasciae of the pelvis.26 this study showed that normal or assisted vaginal delivery during a woman’s last birth was strongly associated with ui. damage to the innervation of the pelvic floor muscles during vaginal delivery has been proposed as a cause of ui.27 nevertheless, the current study showed that neither the number of vaginal deliveries nor css during previous deliveries were a significant predictor of ui. evidence indicates that the process of pregnancy rather than childbirth itself, is strongly associated with ui.28 contrary to what has been reported in the literature, no significant association between parity and ui was found in this study.6–9,12,19,29 low parity, which is defined by the world health organization as less than five pregnancies, was reported by more than two-thirds of participants in this study.30 low parity, therefore, might be the main reason for this finding. some studies have found that women who are 28 years or older at their first delivery are 1.82 times more likely to develop sui than other women.31 however, the current study did not reveal such a correlation which might be due to the younger age (mean = 24 ± 4.5 years) at first birth in the majority of the participants in this study. this study showed that qol was negatively affected in the majority of women with ui. this finding is consistent with other studies conducted worldwide.4,5,8,11,20 this effect is well understood and to be expected in muslim countries where being dry is considered a prerequisite for the five daily prayers. the negative impact of ui on qol may extend to social-emotional relationships, exercise and sport, employment, travel and sleep.24 feelings of stigmatisation, humiliation and fear of becoming urinary incontinence among omani women prevalence, risk factors and impact on quality of life e52 | squ medical journal, february 2020, volume 20, issue 1 incontinent in public situations may lead to social and recreational withdrawal. similarly, the feeling of embarrassment during sexual activities in women with ui and its consequences for low self-esteem and anxiety might seriously affect relationships.8,20,24,32,33 evidence has suggested that women with ui perceive the condition as a barrier to exercise and are forced to give up enjoyable activities such as swimming and long walks.34,35 this study highlights the importance of early detection of ui to prevent its negative consequences on qol. healthcare providers should be more vigilant and proactive in cases of ui. phc physicians should screen female patients routinely for symptoms suggestive of ui, particularly targeting those at higher risk for this condition. furthermore, myths about ui among omani women should be properly addressed through media and health awareness campaigns. this study had some limitations. it was based on a self-reported questionnaire and no objective measures such as clinical assessment or urodynamic studies were performed. however, the iciq-sf has been found to be a reliable and well-validated tool which correlates well with objective measures. as some information collected in this study was based on the ability to remember past events, there is a possibility of recall bias. additionally, this study followed a cross-sectional design which does not imply a causal relationship. moreover, setting an age limit for the study’s participants might have resulted in an underestimation of the true prevalence of ui in oman. finally, this study did not include a voiding diary (bladder diary) to assess the severity of ui; doing so would have increased the reliability of the information presented by the study’s participants. conclusion based on this study’s findings, ui is a common condition among omani women and sui is the most common type. age, bmi, having been married or employed, cough, constipation and vaginal or assisted vaginal delivery during the previous birth were identified as significant risk factors for ui in omani women. despite its negative consequences on qol, only a small proportion of participants had sought medical advice for the condition because of misconceptions about ui. future longitudinal studies utilising objective assessment tools are needed to confirm the current findings. a c k n o w l e d g e m e n t the authors would like to thank the women who participated in this study and the nurses from almawaleh, al-khoudh and al-maabelah health centres| for their great efforts and help in data collection. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the deanship of research fund at sultan qaboos university, muscat, oman (rf/med/fmco/18/01). references 1. abrams p, andersson ke, apostolidis a, birder l, bliss d, brubaker l, et al. 6th international consultation on incontinence. recommendations of the international scientific committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse and faecal incontinence. neurourol urodyn 2018; 37:2271–2. https://doi.org/10.1002/nau.23551. 2. muller n. what americans understand about how they are affected by bladder control problems: highlights of recent nationwide consumer research. urol nurs 2005; 25:109–15. 3. irwin de, kopp zs, agatep b, milsom i, abrams p. worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. bju int 2011; 108:1132–8. https://doi.org/10.1111/ j.1464-410x.2010.09993.x. 4. minassian va, drutz hp, al-badr a. urinary incontinence as a worldwide problem. int j gynaecol obstet 2003; 82:327–38. https://doi.org/10.1016/s0020-7292(03)00220-0. 5. ghafouri a, alnaimi ar, alhothi hm, alroubi i, alrayashi m, molhim na, et al. urinary incontinence in qatar: a study of the prevalence, risk factors and impact on quality of life. arab j urol 2014; 12:269–74. https://doi.org/10.1016/j.aju.2014.08.002. 6. al-badr a, brasha h, al-raddadi r, noorwali f, ross s. prevalence of urinary incontinence among saudi women. int j gynaecol obstet 2012; 117:160–3. https://doi.org/10.1016/j. ijgo.2011.12.014. 7. al-sayegh na, al-batool l, al-qallaf a, al-fadhli h, al-sharrah s. urinary incontinence in kuwait: prevalence and risk factors of men and women. int j health sci 2014; 2:47–57. https://doi. org/10.15640/ijhs.v2n4a4. 8. lasserre a, pelat c, guéroult v, hanslik t, chartier-kastler e, blanchon t, et al. urinary incontinence in french women: prevalence, risk factors, and impact on quality of life. eur urol 2009; 56:177–83. https://doi.org/10.1016/j.eururo.2009.04.006. 9. chiarelli p, brown w, mcelduff p. leaking urine: prevalence and associated factors in australian women. neurourol urodyn 1999; 18:567–77. https://doi.org/10.1002/(sici)1520-6777(1999) 18:6<567::aid-nau7>3.0.co;2-f. 10. hannestad ys, rortveit g, sandvik h, hunskaar s; norwegian epincont study. epidemiology of incontinence in the county of nord-trøndelag. a community-based epidemiological survey of female urinary incontinence: the norwegian epincont study. epidemiology of incontinence in the county of nordtrøndelag. j clin epidemiol 2000; 53:1150–7. https://doi.org/10.1 016/s0895-4356(00)00232-8. https://doi.org/10.1002/nau.23551 https://doi.org/10.1111/j.1464-410x.2010.09993.x https://doi.org/10.1111/j.1464-410x.2010.09993.x https://doi.org/10.1016/s0020-7292%2803%2900220-0 https://doi.org/10.1016/j.aju.2014.08.002 https://doi.org/10.1016/j.ijgo.2011.12.014 https://doi.org/10.1016/j.ijgo.2011.12.014 https://doi.org/10.15640/ijhs.v2n4a4 https://doi.org/10.15640/ijhs.v2n4a4 https://doi.org/10.1016/j.eururo.2009.04.006 https://doi.org/10.1002/%28sici%291520-6777%281999%2918:6%3c567::aid-nau7%3e3.0.co%3b2-f https://doi.org/10.1002/%28sici%291520-6777%281999%2918:6%3c567::aid-nau7%3e3.0.co%3b2-f https://doi.org/10.1016/s0895-4356%2800%2900232-8 https://doi.org/10.1016/s0895-4356%2800%2900232-8 maisa h. al kiyumi, zaleikha i. al belushi, sanjay jaju and abdulaziz m. al mahrezi clinical and basic research | e53 11. kocak i, okyay p, dundar m, erol h, beser e. female urinary incontinence in the west of turkey: prevalence, risk factors and impact on quality of life. eur urol 2005; 48:634–41. https://doi. org/10.1016/j.eururo.2005.04.017. 12. seshan v, muliira jk. self-reported urinary incontinence and factors associated with symptom severity in community dwelling adult women: implications for women's health promotion. bmc womens health 2013; 13:16. https://doi. org/10.1186/1472-6874-13-16. 13. avery k, donovan j, peters tj, shaw c, gotoh m, abrams p. iciq: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence. neurourol urodyn 2004; 23:322–30. https://doi.org/10.1002/nau.20041. 14. hashim h, avery k, mourad ms, chamssuddin a, ghoniem g, abrams p. the arabic iciq-ui sf: an alternative language version of the english iciq-ui sf. neurourol urodyn 2006; 25:277–82. https://doi.org/10.1002/nau.20212. 15. al-shaikh g, al-badr a, al maarik a, cotterill n, al-mandeel h. reliability of arabic iciq-ui short form in saudi arabia. urol ann 2013; 5:34–8. https://doi.org/10.4103/0974-7796.106964. 16. schreiber pedersen l, lose g, høybye mt, elsner s, waldmann a, rudnicki m. prevalence of urinary incontinence among women and analysis of potential risk factors in germany and denmark. acta obstet gynecol scand 2017; 96:939–48. https://doi. org/10.1111/aogs.13149. 17. bedretdinova d, fritel x, panjo h, ringa v. prevalence of female urinary incontinence in the general population according to different definitions and study designs. eur urol 2016; 69:256–64. https://doi.org/10.1016/j.eururo.2015.07.043. 18. thom d. variation in estimates of urinary incontinence prevalence in the community: effects of differences in definition, population characteristics, and study type. j am geriatr soc 1998; 46:473–80. https://doi.org/10.1111/j.1532-5415.1998.tb02469.x. 19. kılıç m. incidence and risk factors of urinary incontinence in women visiting family health centers. springerplus 2016; 5:1331. https://doi.org/10.1186/s40064-016-2965-z. 20. barghouti ff, yasein na, jaber rm, hatamleh ln, takruri ah. prevalence and risk factors of urinary incontinence among jordanian women: impact on their life. health care women int 2013; 34:1015–23. https://doi.org/10.1080/07399332.2011. 646372. 21. melville jl, katon w, delaney k, newton k. urinary incontinence in us women: a population-based study. arch intern med 2005; 165:537–42. https://doi.org/10.1001/archinte.165.5.537. 22. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32–42. 23. subak ll, richter he, hunskaar s. obesity and urinary incontinence: epidemiology and clinical research update. j urol 2009; 182:s2–7. https://doi.org/10.1016/j.juro.2009.08.071. 24. sinclair aj, ramsy in. the psychosocial impact of urinary incontinence in women. obstet gynaecol 2011; 13:143–8. https://doi.org/10.1576/toag.13.3.143.27665. 25. hsieh ch, lee ms, lee mc, kuo tc, hsu cs, chang st. risk factors for urinary incontinence in taiwanese women aged 20–59 years. taiwan j obstet gynecol 2008; 47:197–202. https://doi. org/10.1016/s1028-4559(08)60080-7. 26. aoki y, brown hw, brubaker l, cornu jn, daly jo, cartwright r. urinary incontinence in women. nat rev dis primers 2017; 3:17042. https://doi.org/10.1038/nrdp.2017.42. 27. snooks sj, setchell m, swash m, henry mm. injury to innervation of pelvic floor sphincter musculature in childbirth. lancet 1984; 2:546–50. https://doi.org/10.1016/s0140-6736(84) 90766-9. 28. foldspang a, mommsen s, djurhuus j. prevalent urinary incontinence as a correlate of pregnancy, vaginal childbirth, and obstetric techniques. am j public health 1999; 89:209–12. https://doi.org/10.2105/ajph.89.2.209. 29. zhou hh, shu b, liu tz, wang xh, yang zh, guo yl. association between parity and the risk for urinary incontinence in women: a meta-analysis of case-control and cohort studies. medicine (baltimore) 2018; 97:e11443. https://doi.org/10.1097/ md.0000000000011443. 30. aliyu mh, jolly pe, ehiri je, salihu hm. high parity and adverse birth outcomes: exploring the maze. birth 2005; 32:45–59. https://doi.org/10.1111/j.0730-7659.2005.00344.x. 31. masue t, wada k, nagata c, deguchi t, hayashi m, takeda n, et al. lifestyle and health factors associated with stress urinary incontinence in japanese women. maturitas 2010; 66:305–9. https://doi.org/10.1016/j.maturitas.2010.04.002. 32. nilsson m, lalos a, lalos o. the impact of female urinary incontinence and urgency on quality of life and partner rela tionship. neurourol urodyn 2009; 28:976–81. https://doi.org/10. 1002/nau.20709. 33. illiano e, mahfouz w, giannitsas k, kocjancic e, vittorio b, athanasopoulos a, et al. coital incontinence in women with urinary incontinence: an international study. j sex med 2018; 15:1456–62. https://doi.org/10.1016/j.jsxm.2018.08.009. 34. brown wj, miller yd. too wet to exercise? leaking urine as a barrier to physical activity in women. j sci med sport 2001; 4:373–8. https://doi.org/10.1016/s1440-2440(01)80046-3. 35. nygaard i, thom dh, calhoun ea. urinary incontinence in women. in: litwin ms, saigal cs, eds. urologic diseases in america. washington dc, usa: us government printing office, 2004. pp. 71–106. https://doi.org/10.1016/j.eururo.2005.04.017 https://doi.org/10.1016/j.eururo.2005.04.017 https://doi.org/10.1186/1472-6874-13-16 https://doi.org/10.1186/1472-6874-13-16 https://doi.org/10.1002/nau.20041 https://doi.org/10.1002/nau.20212 https://doi.org/10.4103/0974-7796.106964 https://doi.org/10.1111/aogs.13149 https://doi.org/10.1111/aogs.13149 https://doi.org/10.1016/j.eururo.2015.07.043 https://doi.org/10.1111/j.1532-5415.1998.tb02469.x https://doi.org/10.1186/s40064-016-2965-z https://doi.org/10.1080/07399332.2011.646372 https://doi.org/10.1080/07399332.2011.646372 https://doi.org/10.1001/archinte.165.5.537 https://doi.org/10.1016/j.juro.2009.08.071 https://doi.org/10.1576/toag.13.3.143.27665 https://doi.org/10.1016/s1028-4559%2808%2960080-7 https://doi.org/10.1016/s1028-4559%2808%2960080-7 https://doi.org/10.1038/nrdp.2017.42 https://doi.org/10.1016/s0140-6736%2884%2990766-9 https://doi.org/10.1016/s0140-6736%2884%2990766-9 https://doi.org/10.2105/ajph.89.2.209 https://doi.org/10.1097/md.0000000000011443 https://doi.org/10.1097/md.0000000000011443 https://doi.org/10.1111/j.0730-7659.2005.00344.x https://doi.org/10.1016/j.maturitas.2010.04.002 https://doi.org/10.1002/nau.20709 https://doi.org/10.1002/nau.20709 https://doi.org/10.1016/j.jsxm.2018.08.009 https://doi.org/10.1016/s1440-2440%2801%2980046-3 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 95-96, epub 16th mar 2009 submitted 19th oct 09 revision req. 7th dec 08, revision recd. 26th jan 09 accepted 7th feb 09 posture-related displacement of subclavian catheter in obese patients *mohammad salman mirza, mohammad shafiq subclavian line placement is a common procedure and complications, including cath-eter tip displacement, are rare. in the supine posture, the breasts in obese female patients placed in the standard recommended position for the subclavian line placement may allow a successful uneventful procedure. however once the patient assumes a sitting or an erect position, due to the lax skin and the weight of the breast, the site of insertion and anchorage on the skin moves down considerably. this leads to a loss in length of the intravascular part of the central venous (cv) catheter. the images show the catheter displacement in an obese patient of bmi 46. in figure 1, the cv catheter tip is seen well in the superior vena cava. figure 2 shows the cv catheter with the patient in sitting position. note the “reverse z” curve in the cv line; this indicates that the spot of insertion on the skin has moved down considerably. clinically, the tip was confirmed not to be in the vein. this patient had pneumoperitoneum, from a small gastric perforation. the chest x-ray in the supine position does not show the gas under the diaphragm which is seen in the erect xray. in figure 3, the displaced position of the spot of insertion may be noted. the clavicle and sternum have المرضى عند وَة التَّرْقُ تَ تَحْ ما ارٌ ثْطِ لقِ الوضعية اإلزاحة المصابين بالبدانة شفيق محمد مرزا، سلمان محمد i n t e r e s t i n g m e d i c a l i m a g e figure 1: chest x-ray in supine position after central venous catheter placement figure 2: in the erect x-ray, the tip of the central venous catheter is seen to have moved to a site just below the clavicle department of surgery, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: drsalmanmirza@hotmail.com m o h a m m a d s a l m a n m i r z a a n d m o h a m m a d s h a f i q 96 been marked. a tape measure shows the extent of displacement medially and caudally. the arrow indicates the position where the point of insertion should have been. in figure 4, the cv catheter has been placed in the left subclavian vein, in the same patient. the tip is seen beyond the superior vena cava. figure 5, shows the x-ray in erect position for the same cv catheter. it may be noted that the tip of the line has moved out by a few centimeters. the “z” curve is again noticed showing the point of insertion well below the clavicle. this time the line remained effective as the initial length inserted had been long. to minimise the loss in length the following precautions are recommended: 1. in obese female patients, the subclavian cv catheter can be inserted while taking into account the displaced position of the breast which tends to slip laterally and upwards in the supine position. an assistant may retract the breast downwards and medially while selecting the position of insertion on the skin. 2. a chest x-ray should be done to confirm the cv catheter position in the sitting or erect position in such patients. 3. jugular line placement may be an alternative in these types of patients. r e f e r e n c e s 1. nizet jl, piérard-franchimont c, piérard ge. influence of body posture and gravitational forces on shear wave propagation in the skin. dermatology 2001; 202:17780. 2. ryu hg, bahk jh, kim jt, lee jh. bedside prediction of the central venous catheter insertion depth. br j anaesth 2007; 98:225-7. epub 2007 jan 8. 3. lucey b, varghese jc, haslam p, lee mj. routine chest radiographs after central line insertion: mandatory postprocedural evaluation or unnecessary waste of resources? cardiovasc intervent radiol 1999; 22:381-4. 4. guidelines on the insertion of central venous catheters using the landmark technique from http://www.leedsth.nhs.uk/sites/emibank/clinicians/guidelines/documents/centralvenouslines.pdf accessed september 2008. 5. hermanns-le t, jonlet f, scheen a, pierard ge. age and body mass index-related changes in cutaneous shear wave velocity. exp gerontol 2001; 36:363-72. figure 3: picture of central venous catheter taken in sitting position figure 4: subclavian central venous catheter passed on the left side in the same patient figure 5: chest x-ray of patient in erect position women’s reproductive health and rights through the lens of the covid-19 pandemic mona larki,1 farangis sharifi,2 *robab l. roudsari2,3 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e166–171, epub. 21 jun 21 submitted 26 aug 20 revision req. 28 sep 20; revision recd. 3 nov 20 accepted 11 nov 20 1student research committee, school of nursing & midwifery, mashhad university of medical sciences, mashhad, iran; 2nursing and midwifery care research center, mashhad university of medical sciences, mashhad, iran; 3department of midwifery, school of nursing and midwifery, mashhad university of medical sciences, mashhad, iran *corresponding author’s e-mail: latifnejadr@mums.ac.ir, rlatifnejad@yahoo.com the united nations population fund (unfpa) and the regional office for asia and the pacific have demonstrated that sexual and reproductive health and rights (srhr) are critical challenges for public health that demand significant global speculation and investment.1,2 in 2018, the guttmacher-lancet commission on srhr predicted that nearly all 4.3 billion reproductive-age persons worldwide will have insufficient reproductive healthcare over their reproductive years.3 estimating the potential impact of covid-19 prevalence on sexual and reproductive health (srh) in lowand middle-income countries suggests that there are challenges.4 covid-19 was reported by the world health organization (who) as a pandemic in 2020.5 it is the largest global public health crisis in a century, with overwhelming health and socioeconomic consequences.2,6 it seems that the pandemic is exacerbating prior inequalities and uncovering vulnerabilities in social, political and financial systems which are conseq uently enhancing the effects of the pandemic.7 additionally, the clinical context of sexual and reproductive health (srh), health sector effects and delays or interruptions in the routine availability of srh facilities, such as prenatal and postnatal checks, safe abortion, contraception, hiv/aids and other sexually transmitted diseases, should not be ignored. other factors merit attention, such as the potential increase in gender-based violence and sexual harassment as well as the impact of covid-19 stigma and sexism and its impact on srh clients and staffs.8 the interagency working group on reproductive health has recommended that considering the effect of covid-19 on health systems, comprehensive srh programs should be retained as long as the infrastructure is not overstretched by covid-19 case management.9 considering that realising the right to reproductive health for all, without discrimination, is a critical issue, the programme of action committed to ensure equal access to srh by 2015.10 the international conference on population and development+25 summit was convened in november 2019 to mobilise the political will and financial allocations desperately required to do so, but this promise is far from being fulfilled.10 the 2030 agenda for sustainable development clearly highlighted the comprehensive access to srh care services in communities.11 in addition, the who has stressed that during the covid-19 pandemic “all countries must strike a fine balance between protecting health, minimizing economic and social disruption, and respecting human rights”.12 ultimately, women’s choices and rights to srh services must be respected, regardless of the covid-19 outbreak.12 women and girls’ special health needs include safe childbirth, family planning and reproductive healthcare.7 however, their access to quality srh services as well as insurance coverage for health costs is likely to be limited in disastrous circumstances. this can be seen in countries with catastrophic health spending such as some asian and african countries as well as in marginalised communities and those subject to multiple inequalities based on ethnicity, age, race, socioeconomic status, disability, sexual orientation and geographical area.7,13,14 obstructive sociocultural norms and gender stereotypes can restrain women’s capacity to receive health services too.12 in previous pandemics, an increased level of detrimental health consequences such as reduced access to healthcare services in relation to family planning, abortion, prenatal care, hiv, gender-based violence and mental health were reported.15,16 this poor level of accessibility resulted in increased rates and sequela due to unintended pregnancies, unsafe abortions, pregnancy complications, sexually transmitted infections (stis), intimate partner violence, depression, suicide, posttraumatic stress disorder and maternal and infant mortality.15 for instance, the ebola epidemic was anticipated to cause 120,000 preventable maternal deaths due to poor accessibility to healthcare services and fears among pregnant women of being infected in healthcare facilities.15 based on the results of an ecological analysis in guinea, the number of monthly visits for family planning decreased from an average of 531 during the pre-ebola period to 242 visits at the ebola outbreak peak (i.e. a 51% decrease); it did however recover during the post-ebola period.17 the comment this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.003 https://creativecommons.org/licenses/by-nd/4.0/ comment | e167 study found that from an average of 2,053 visits per month pre-ebola, antenatal care visits decreased by 41% during ebola and then improved to just 63% of the pre-ebola level (recovery gap of 37%; p <0.001).17 furthermore, in another study, ebola infection in pregnancy was associated with high maternal mortality and nearly 100% incidence of fetal death.18 unfpa has reported that during the covid-19 pandemic unknown and unfolding social distance interventions and school closures has left teens and young people worldwide without access to critical knowledge, resources and protections related to srh.19 a world vision report about school closures due to covid-19 in sub-saharan africa stipulated that during crises, school closures “can result in girls spending more time with men and boys than they would were they to be in school, leading to greater likelihood of engagement in risky sexual behaviour and increased risk of sexual violence and exploitation”.20 furthermore, lockdowns and quarantine as well as social distancing impedes the distribution of in-person comprehensive sexuality education (cse).19 to overcome these obstacles, it is important to provide young people with new and engaging ways to connect to each other such as remote channels and tools (e.g. video and mobile telephone, emails, applications, social networks, interactive voice), which could provide virtual sex education by engaging participants from broad geographical areas who are excluded from conventional services.18,19 commonly, women’s and girls’ challenges in relation to srh during the pandemic include violence against women and girls (vawg), lack of access to high-quality maternity services in pregnancy, loss of family planning, increased unplanned pregnancies and impaired maternal mental health, which is discussed.8,21 violence against women and girls gender-based violence due to the covid-19 lockdown has increased due to the increasing difficulties to provide safe shelters and support to women who are in need of help.22 the challenge of vawg will most likely worsen in the ongoing covid-19 pandemic. this is because communities are confronted with insecurity as well as health and economic difficulties which themselves add pressure and strain on the general population and is heightened by the limited and confined living environment.23 there is an approximately one-third reduction in progress towards eliminating gender-based violence by 2030 due to the covid-19 pandemic.23 in the future, the impact of covid-19 movement restrictions and self-quarantine are the most important issues which could increase women’s confrontation and conflict with violent partners.24 intensifying household pressures and financial strains could likewise have a role. evidence shows that since the start of the covid-19 pandemic, reports related to vawg, especially domestic violence, have increased in different countries. however, gender-based violence is currently only recorded by few countries. for example, france reported a 30% rise in the incidence of domestic violence since 17 march 2020; argentina reported a 25% increase since the beginning of their lockdown on 20 march 2020; cyprus and singapore experienced an increase in the amount of calls received for gender-based violence of 30% and 33%, respectively; and several other nations, such as canada, germany, usa and the uk, have reported a rise in the gender-based violence rates in their countries.25 the unfpa has forecasted that an estimated 31 million more cases of intimate partner violence will occur as a result and during an average lockdown of six months with a 14–16 million increase in cases every three months.26 female genital mutilation (fgm) is classified as violence against women. approximately 200 million women worldwide have currently experienced fgm, which is considered a human rights violation.27 fgm is an expression of entrenched gender inequality.27 the unfpa stated that it is practiced in communities around the world, but is not endorsed or condoned by any religion; while it is often perceived to be an islamic custom because it is practiced by some muslim groups, it is also practiced by non-islamic groups such as christians, ethiopian jews and followers of traditional african religions.27 girls are reportedly at increased risk of undergoing fgm as a prerequisite to marriage in countries such as ethiopia, kenya, nigeria and sudan and suggests a harmful coping mechanism related to economic fallout and school closures.28 it is anticipated that due to the disruptions caused by covid-19, there will be a one-third reduction in the advancement towards ending fgm by 2030.26 avenir health (glastonbury, connecticut, usa), johns hopkins university (baltimore, maryland, usa) and victoria university (footscray, australia) estimate that substantial levels of 6-month lockdown-related disruptions may cause significant delays in ending fgm, possibly leading to around two million more fgm cases over the next decade than would have occurred otherwise.29 the unfpa and united nations educational, scientific and cultural organization recommended that, where movement is restricted and areas are difficult to reach, priority should be given to ensure access to prevention, security and care resources for girls and women at risk.30 mona larki, farangis sharifi and robab l. roudsari maternity services in pregnancy pregnancy is a physiological state that predisposes women to viral respiratory contaminations. due to the physiological changes within the immune and respiratory systems, pregnant women are at greater risk and more susceptible to the morbidity and mortality caused by covid-19 including much more severe respiratory infections.31 respiratory illness due to covid-19 in pregnant women must be considered with utmost priority and should be treated immediately because of increased risk of its adverse consequences.32 the unfpa proposed a sustainable antenatal care service delivery model in line with the context of various countries that identifies how services should be organised to provide a core antenatal care package. it particularly focuses on whom (cadre), where (system level) and how (platform) in relation to the set of interventions that should be provided at each antenatal care contact.33 redistributing maternity care staff away from general medical areas during the pandemic will probably lead to an increase in poor maternal and neonatal outcomes.32 it is expected that pregnant women and their families will probably encounter increased anxiety and stress within the community concerning the spread of covid-19. table 1: actions in response to the sexual and reproductive health emergency during the covid-19 pandemic21,41–43 challenge action violence against women and girls implementation of the online course "essential services package for women and girls' survivors of violence".41† coordination for the creation of a mobile application to assist survivors of sexual abuse.41† for youth at risk of violence in or near their homes, locating safe homes, shelters or social service referrals.42 training public officials and healthcare professionals on the national protocols for response to sexual assault.42 strengthening the capacity of the telephone hotline for receiving complaints about gender-based violence and providing survivors with support and referrals.42 maternity service in pregnancy providing srh care at home for pregnant women to prevent the risk of infection.41† developing a telephone-based model for information and advice for pregnant women, postpartum women and caregivers of newborns.41† working together with other humanitarian agencies and officials to fulfil the needs of priority medical centres and temporary shelters for returnees, with a focus on the needs of pregnant women and young people.41† the use of telemedicine for counselling and screening for known risk factors for covid-19.42 distribution of ppe/srh supplies both through the health for peace project and the interagency strategy for reduction of maternal mortality in indigenous populations.41† family planning and unintended pregnancy providing mobile family planning services for priority areas.41† providing telemedicine services and the delivery of contraceptives.41† informing teens on when and how to receive contraceptive counselling and services during the covid-19 response including changes, if any, to service delivery times, location, etc.42 providing multi-month supplies with clear information about the method and how to access referral care for adverse reactions.42 creating alternate service modalities (such as pharmacy, shops or community-based service) for contraception that are more available to teenagers.42 setting up hotlines to offer information and guidance on self-use of contraceptives, side effects, choice of method and other srhr questions for teens.41† maternal mental health using formal mental well-being screening of new mothers.21 providing occupational therapy for infants and their mothers due to nutritional concerns.43 srh = sexual and reproductive health; ppe = personal protective equipment; srhr = sexual and reproductive health and rights. *this report focused solely on latin american and the caribbean region; †in coordination with a ministry of health/government entity/national authority. women’s reproductive health and rights through the lens of the covid-19 pandemic e168 | squ medical journal, may 2021, volume 21, issue 2 comment | e169 as a result, maternity services should be prioritised as fundamental core health services throughout the covid-19 pandemic.32,33 family planning and unintended pregnancies provision of contraceptive methods as well as different srh services and supplies, which are essential to womens’ and girls’ health, empowerment and dignity, will be influenced by the covid-19 pandemic, as supply chains are affected globally. in consideration of the influence of covid-19 on the restrictions to access to family planning facilities, it is predicted that there will be an increase in teen pregnancies, which in turn may cause those teenagers to drop out of school and have adverse consequences in their future.32 teenage pregnancy is related to a lack of knowledge and facilities for srh, child marriage, risks to health and well-being and elevated poverty and insecurity.34 social norms on sex and limited resources are barriers to gaining crucial knowledge about srh, thus raising the risk of unintended pregnancies, stis and transmission of hiv. for women, the effects of an unmet demand for contraceptives may be devastating, leading to high maternal mortality and illegal abortions.35 issues of stigma and social norms can result in health providers and the individuals’ families to marginalise unmarried pregnant teenage girls when they attempt to pursue srh services.36 evidence shows that the effect of reduced reproductive health services and products between march and august 2020 in 37 countries has led to an extra 1.3 million unintended pregnancies.37 this may result in an additional 1.2 million unsafe abortions and 5,000 pregnancy-related complications.37 maternal mental health the risk of perinatal mental health morbidity can be inflated by factors such as acute stress, emergency and crisis circumstances as well as natural disasters. it is also possible that pregnant women became vulnerable during the covid-19 pandemic to mental health issues.38 to reduce the risk of covid-19 infection, maternal services have been impacted, which has resulted in the incidents where women are unable to get the advantage from the routine use of caesarean section. they were refused the right to breastfeed, could not be accompanied by a birthing companion during labour and experienced routine isolation of birthing persons from their infants.39 undoubtedly, economic implications of the extended pandemic and financial uncertainties associated with it could further increase the psychological strain and exacerbate the emotional well-being of pregnant women and new mothers. some may adopt unhealthy strategies, such as alcohol consumption and substance abuse, to cope with the effects of the pandemic, thereby contributing to current mental health concerns.38 there is recent anecdotal evidence that indicates maternity-related workers limit maternal options and rights (such as using regular labour induction, separation of mother and infant) to protect the mother and/or infant; however, such procedures are not acceptable on the basis of existing evidence and are likely to be correlated with physical and psychological damage for both mother and infant.39 actions to achieve sexual and reproductive rights during the covid-19 pandemic in periods of crisis, particularly health crises, the role of srhr advocacy is paramount; it helps to hold governments responsible for their national and inter national srhr commitments and their responsibility for delivering critical services as well as emphasise the essential nature of srhr programmes. in response to health crises, such as the covid-19 pandemic, advocating for new methods of providing srh programmes is important. advocacy for the implementation and/or acceptance of telemedicine, online meetings and the use of social media resources and the availability of cse have been crucial aspects of an effective srhr response to the pandemic.40 the current covid-19 outbreak has had some additional impacts on individuals’ srh because of quarantine measures as well as social distancing that have been put in place for all, troubles in provision of standard healthcare services due to the acute burden that covid-19 has placed on health systems and as a consequence of the conceivable collapse of the health care systems and prioritisation of specific services and techniques other than srh.26 therefore, international agencies and researchers published various actions to ensure srh throughout the covid-19 pandemic [table 1].21,41–43 conclusion in critical situations such as disease outbreaks, the health sectors focus their resources on managing critical issues and preventing adverse events in healthcare. as a result, access to srh services becomes more difficult and this mostly affects women mona larki, farangis sharifi and robab l. roudsari and girls who have unique needs. policymakers and healthcare providers must be aware of the significant link between the global prevalence of covid-19 and the challenges posed by the pandemic to srh to take appropriate action. lack of adequate attention to the health needs of girls and women in crises may lead to devastating consequences such as increased maternal and infant mortality, increased number of unsafe abortions and failure to prevent pregnancy. therefore, providing srh services to girls and women, despite the changing economic status, social environment and logistic barriers that enable inadequate access to srh services, should be a priority for health interventions and should occur at different levels of healthcare systems in developed and developing countries. references 1. unfpa asia-pacific regional office coronavirus (2019-ncov) guidance document. from: https://china.unfpa.org/en/public ations/200206001 accessed: nov 2020 2. united nations population fund. coronavirus disease (covid-19) pandemic unfpa global response plan. from: www.unfpa. org/resources/coronavirus-disease-covid-19-pandemic-unfpaglobal-response-plan accessed: nov 2020. 3. starrs am, ezeh ac, barker g, basu a, bertrand jt, blum r, et al. accelerate progress-sexual and reproductive health and rights for all: report of the guttmacher–lancet commission. lancet 2018; 391:2642–92. https://doi.org/10.1016/s0140-6736 (18)30293-9. 4. riley t, sully e, ahmed z, biddlecom a. estimates of the potential impact of the covid-19 pandemic on sexual and reproductive health in low-and middle-income countries. int perspect sex reprod health 2020; 46:73–6. https://doi.org/10.13 63/46e9020. 5. ashokka b, loh mh, tan ch, su ll, young be, lye dc, et al. care of the pregnant woman with covid-19 in labor and delivery: anesthesia, emergency cesarean delivery, differential diagnosis in the acutely ill parturient, care of the newborn, and protection of the healthcare personnel. am j obstet gynecol 2020; 223:66–74.e3. https://doi.org/10.1016/j.ajog.2020.04.005. 6. poon lc, yang h, kapur a, melamed n, dao b, divakar h, et al. global interim guidance on coronavirus disease 2019 (covid-19) during pregnancy and puerperium from figo and allied partners: information for healthcare professionals. int j gynecol obstet 2020; 149:273–86. https://doi.org/10.1002/ ijgo.13156. 7. united nations. policy brief: the impact of covid-19 on women. from: https://asiapacific.unwomen.org//media/headq uarters/attachments/sections/librar y/publications/2020/ p o l i c y b r i e f t h e i m p a c to f c o v i d 1 9 o n w o m e n e n . pdf?la=en&vs=1406 accessed: nov 2020. 8. tang k, gaoshan j, ahonsi b, ali m, bonet m, broutet n, et al. sexual and reproductive health (srh): a key issue in the emergency response to the coronavirus disease (covid19) outbreak. reprod health 2020; 17:59. https://doi.org/10.1186/ s12978-020-0900-9. 9. mambo sb, sikakulya fk, ssebuufu r, mulumba y, wasswa h, thompson k, et al. sexual and reproductive health and rights challenges among ugandan youth during covid-19 pandemic lockdown: an online cross-sectional study. res sq 2020. https://doi.org/10.21203/rs.3.rs-48529/v1. 10. ravindran tks, govender v. sexual and reproductive health services in universal health coverage: a review of recent evidence from lowand middle-income countries. sex reprod health matters 2020; 28:1779632. https://doi.org/10.1080/2641 0397.2020.1779632. 11. lee bx, kjaerulf f, turner s, cohen l, donnelly pd, muggah r, et al. transforming our world: implementing the 2030 agenda through sustainable development goal indicators. j public health policy 2016; 37:13–31. https://doi.org/10.1057/s41271-016-0002-7. 12. world health organization. coronavirus disease (covid-19) and sexual and reproductive health. from: www.who.int/ reproductivehealth/publications/emergencies/covid-19srh/en/ accessed: nov 2020. 13. canadian association of midwives. reproductive justice during the covid-19 pandemic: a call to action from midwives. from: https://canadianmidwives.org/wpcontent/uploads/2020/05 / r e p r o d u c t i v e j u s t i c e c a l l a c t i o n c o v i d 1 9 _ v f _ eng_20200512.pdf accessed: nov 2020. 14 hera right to health & development. universal health cov erage for sexual and reproductive health in the asia-pacific region. from: https://asiapacific.unfpa.org/en/publications/universalhealth-coverage-sexual-and-reproductive-health-asia-pacific accessed: nov 2020. 15. seven issues affecting women and girls during covid-19 pandemic. from: https://www.fsg.org/sites/default/files/7%20 issues%20affecting%20women%20during%20covid-19_0.pdf accessed: nov 2020. 16. hall ks, samari g, garbers s, casey se, diallo dd, orcutt m, et al. centring sexual and reproductive health and justice in the global covid-19 response. lancet 2020; 395:1175–7. https:// doi.org/10.1016/s0140-6736(20)30801-1. 17. camara bs, delamou a, diro e, béavogui ah, el ayadi am, sidibé s, et al. effect of the 2014/2015 ebola outbreak on reproductive health services in a rural district of guinea: an ecological study. trans r soc trop med hyg 2017; 1:22–9. https://doi.org/10.1093/trstmh/trx009. 18. black bo, caluwaerts s, achar j. ebola viral disease and pregnancy. obstet med 2015; 8:108–13. https://doi.org/10.10 93/trstmh/trx009. 19. united nations population fund. fearning beyond the classroom: adapting comprehensive sexuality education programming during the covid-19 pandemic. from: www.unfpa.org/sites/ default/files/resource-pdf/learning_beyond_the_classroom. pdf accessed: nov 2020. 20. world vision. covid-19 aftershocks: access denied: teenage pregnancy threatens to block a million girls across sub-saharan africa from returning to school. from: https://reliefweb.int/ report/world/covid-19-aftershocks-access-denied-teenagepregnancy-threatens-block-million-girls accessed: nov 2020. 21. barlow k, sepulveda a. the promotion of positive mental health for new mothers during covid-19. world occup ther bull 2020; 76:86–9. https://doi.org/10.1080/14473828.2020.1822577. 22. european parliamentary forum for sexual & reproductive rights, international planned parenthood federation. sexual and reproductive health and rights during the covid-19 pandemic. from: https://www.ippfen.org/sites/ippfen/files/20 20-04/sexual%20and%20reproductive%20health%20during%20 the%20covid-19%20pandemic.pdf accessed: nov 2020. 23. united nations population fund. impact of the covid-19 pandemic on family planning and ending gender-based viol ence, female genital mutilation and child marriage. from https ://w w w.unfpa .org/sites/default/files/resourcepdf/ covid-19_impact_brief_for_unfpa_24_april_2020_1.pdf accessed: nov 2020. 24. sharifi f, larki m, roudsari rl. covid-19 outbreak as threat of violence against women. j midwifery reprod health 2020; 3:2376–9. https://doi.org/10.22038/jmrh.2020.16036. women’s reproductive health and rights through the lens of the covid-19 pandemic e170 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1016/s0140-6736%2818%2930293-9 https://doi.org/10.1016/s0140-6736%2818%2930293-9 https://doi.org/10.1363/46e9020 https://doi.org/10.1363/46e9020 https://doi.org/10.1016/j.ajog.2020.04.005 https://doi.org/10.1002/ijgo.13156 https://doi.org/10.1002/ijgo.13156 https://doi.org/10.1186/s12978-020-0900-9 https://doi.org/10.1186/s12978-020-0900-9 https://doi.org/10.21203/rs.3.rs-48529/v1 https://doi.org/10.1080/26410397.2020.1779632 https://doi.org/10.1080/26410397.2020.1779632 https://doi.org/10.1057/s41271-016-0002-7 https://doi.org/10.1016/s0140-6736%2820%2930801-1 https://doi.org/10.1016/s0140-6736%2820%2930801-1 https://doi.org/10.1093/trstmh/trx009 https://doi.org/10.1093/trstmh/trx009 https://doi.org/10.1093/trstmh/trx009 https://doi.org/10.1080/14473828.2020.1822577 https://doi.org/10.22038/jmrh.2020.16036 comment | e171 25. kumar n. covid 19 era: a beginning of upsurge in unwanted pregnancies, unmet need for contraception and other women related issues. eur j contracept reprod health care 2020; 4: 323–5. https://doi.org/10.1080/13625187.2020.1777398. 26. united nations population fund. impact of the covid-19 pandemic on family planning and ending gender-based viol ence, female genital mutilation and child marriage. from: www. unfpa.org/sites/default/files/resource-pdf/covid-19_impact_ brief_for_unfpa_24_april_2020_1.pdf accessed: nov 2020. 27. united nations population fund. female genital mutilation (fgm) frequently asked questions. from: https://www.unfpa. org/resources/female-genital-mutilation-fgm-frequentlyasked-questions accessed: nov 2020. 28. united nations population fund. resilience in action: lessons learned from the joint programme during the covid-19 crisis. from: https://www.unfpa.org/sites/default/files/resource-pdf/ resilience_in_action-_lessons_learned_from_ the_joint_programme_during_the_covid-19_ crisis.pdf accessed: nov 2020. 29. bellizzi s, nivoli a, lorettu l, ronzoni ar. human rights during covid-19 pandemic: the issue of female genital mutilations. public health 2020; 185:53–4. https://doi.org/10.1016/j.puhe.20 20.05.037. 30. united nations population fund, united nations international children's emergency fund. covid-19 disrupting sdg 5.3: eliminating female genital mutilation. from: https://www. unicef.org/media/68786/file/external-tehnical-note-oncovid-19-and-fgm.pdf accessed: nov 2020. 31. latifnejad roudsari r. the possibility of covid-19 vertical transmission: could it be excluded? j midwifery reprod health 2020; 3:2264–6. https://doi.org/10.22038/jmrh.2020.16043. 32. united nations population fund. covid-19 technical brief for maternity services. from www.unfpa.org/resources/covid19-technical-brief-maternity-services accessed: nov 2020. 33. larki m, sharifi f, roudsari rl. models of maternity care for pregnant women during covid-19 pandemic. east mediterr health j 2020; 26:994–8. https://doi.org/10.26719/emhj.20.097. 34. united nations educational, scientific and cultural organ ization. covid-19 aftershocks: access denied: teenage preg nancy threatens to block a million girls across sub-saharan africa from returning to school. from: https://reliefweb.int/ report/world/covid-19-aftershocks-access-denied-teenagepregnancy-threatens-block-million-girls accessed: nov 2020. 35. lokot m, avakyan y. intersectionality as a lens to the covid-19 pandemic: implications for sexual and reproductive health in development and humanitarian contexts. sex reprod health matters 2020; 1:1764748. https://doi.org/10.1080/26410 397.2020.1764748. 36. lokot m, avakyan y. intersectionality as a lens to the covid-19 pandemic: implications for sexual and reproductive health in development and humanitarian contexts. sex reprod health matters 2020; 28:1764748. https://doi.org/10.1080/26410397.2 020.1764748. 37. church k, gassner j, elliott m. reproductive health under covid-19 challenges of responding in a global crisis. sex reprod health matters 2020; 28:1–3. https://doi.org/10.1080/2 6410397.2020.1773163. 38. thapa sb, mainali a, schwank se, acharya g. maternal mental health in the time of the covid-19 pandemic. acta obstet gynecol scand 2020; 99:817–18. https://doi.org/10.1111/ aogs.13894. 39. topalidou a, thomson g, downe s. covid-19 and maternal and infant health: are we getting the balance right? a rapid scoping review. pract midwife 2020; 23. 40. international planned parenthood federation. ensuring sexual and reproductive safety in times of covid-19: ippf member associations’ advocacy good practices & lessons learned. from: www.ippf.org/resource/advocacy-good-practices-lessonslearned-ensuring-sexual-reproductive-safety-during-covid accessed: nov 2020. 41. united nations population fund. latin america and the caribbean region covid-19 situation report no. 7 (rep orting period: 1 31 august 2020). from: https://reliefweb.int/ report/argentina/latin-america-and-caribbean-region-covid19-situation-report-no-7-reporting-period accessed: nov 2020. 42. united nations population fund. responding to the sexual and reproductive health needs of adolescents during the covid-19 crisis. from: https://www.unfpa.org/sites/default/ files/resource-pdf/not_on_pause.pdf accessed: nov 2020. 43. barlow k, sepulveda a. the promotion of positive mental health for new mothers during covid-19. world federation of occupational therapists bulletin 2020. https://doi.org/10.1080 /14473828.2020.1822577. mona larki, farangis sharifi and robab l. roudsari https://doi.org/10.1080/13625187.2020.1777398 https://doi.org/10.1016/j.puhe.2020.05.037 https://doi.org/10.1016/j.puhe.2020.05.037 https://doi.org/10.22038/jmrh.2020.16043 https://doi.org/10.1080/26410397.2020.1764748 https://doi.org/10.1080/26410397.2020.1764748 https://doi.org/10.1080/26410397.2020.1764748 https://doi.org/10.1080/26410397.2020.1764748 https://doi.org/10.1080/26410397.2020.1773163 https://doi.org/10.1080/26410397.2020.1773163 https://doi.org/10.1111/aogs.13894 https://doi.org/10.1111/aogs.13894 https://doi.org/10.1080/14473828.2020.1822577 https://doi.org/10.1080/14473828.2020.1822577 december 2008 no white pages.indd sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 344-346 sultan qaboos university© submitted 8th april 2008 accepted 9th july 2008 laboratory department, al-nahdha hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: sure5155@omantel.net.om compound heterozygosity for hb s and hb s-oman case report *suresh venugopal, alphonsa shaju, suchata dhuri, thuraiya al-harthy, khalid b jabal abstract the haematological and clinical findings of a three year old omani girl, phenotypically compound heterozygote for hb s and hb s oman, are presented, further substantiated by family studies. the necessity of reviewing cases with sickle cell haemoglobin in oman is stressed. keywords: haemoglobin s oman; haemoglobin s disease; abnormal haemoglobin; haemoglobinopathies; sickle cell anaemia; sickle cell trait; case report; oman. لِيّ املِنْجَ للهيموغلوبني بٌ وت املُرَكَّ الزَّيْجُ ايُرُ تَغَ � العماني لِيّ املِنْجَ والهيموغلوبني حالة تقرير جبل بيت سليم خالد احلارثي، ، ثريا شاجو، سوجاتا ذوري فينوجوبال، ألفونسا سوؤيش للهيموغلوبني وت الزَّيْجُ ايُرُ لتَغَ املركب رِيّ اهِ الظَّ طِ النَّمَ سنوات ثالث عمرها عمانية لطفلة السريرية والفحوص الدم فحوص نتائج امللخص: أظهرت حاالت وضرورة مراجعة ــة أهمي على هنا نؤكد العائلي. التاريخ ــة بدراس بعد فيما النتائج هذه ودعمت ، ــي العمان لِيّ ِنْجَ امل ــني والهيموغلوب ــيّ لِ ِنْجَ امل عمان. املنجلي في الدم بفقر اإلصابة رَيَّةِ الكُ لَّةُ خَ ، املنجلي الدم فقر ، الدم أمراض ، الطبيعي غير ، الهيموغلوبني املنجلي العماني ، الهيموغلوبني لِيّ ِنْجَ امل الكلمات: الهيموغلوبني مفتاح عمان. لِيَّة ، ِنْجَ امل the classical sickle cell trait has one βs mutation (β6 glu‡ val). hb s-oman has two mutations in cis. in the same β chain, one the classical βs mutation (β6 glu ‡ val), and the second (β121 glu ‡ lys), identical to that found in a variant namely hb o arab. hb soman increases the sickling tendencies, but the clinical symptomatology is influenced by co-existing alpha thalassaemia. no homozygous hb s-oman has been reported in the literature. c a s e r e p o r t a three year old omani girl from the al-kindi tribe from barka, a town on the coast about 80 km northwest of muscat, presented to the ear, nose and throat department of al-nahdha hospital in september 2007 with complaints of recurrent sore throat, 5-6 times a year. the clinical diagnosis was recurrent acute follicular tonsillitis. the past history revealed that she was diagnosed to have sickle cell anaemia with a history of haemolytic crises and frequent admissions to a tertiary care hospital and had had a recent blood transfusion. a tonsillectomy was planned and a complete blood cell count (cbc) and sickling test were requested as preoperative investigations. the cbc showed, among other parameters: hb 9.34g/dl; red blood cell count 3.45 x 1012/l; haematocrit 22.4%; mean cell volume 65fl; mean cell haemoglobin 27.1pg; c a s e r e p o r t 345 c o m p o u n d h e t e r o z y g o s i t y f o r h b s a n d h b s o m a n mean cell haemoglobin concentration 41.7g/dl and red cell distribution width 18.9%. the sickling test was positive. from the blood film examination, the most important feature was the presence of many napoleon hat x-shaped red blood cells and classical sickle cells [figure 1]. the white blood cell count was 5.53 x 109/l (normal 6 -18) and platelet count was 552 x 109/l (normal 150 450). given the presence of numerous napoleon hat x-shaped red blood cells in the blood film with moderate anaemia and a positive sickling test, the presence of hb s-oman was suspected and the patient was referred to the genetic blood screening unit of our hospital. the results of this screening were as follows: g6pd activity was normal; the high performance liquid chromatography (hplc) profile showed: hb a 49%; hb a2 2.3%; hb f 30.8%; hb s 12.3% and a presumptively hb s-oman 5.6% in the hbc window. the presence of hb a was believed to be due to the recent blood transfusion. the family studies revealed the hplc profile of the father (also from the al-kindi tribe) to be: hb a 70%; hb a2 3%; hb f1%; hb s26% and he was diagnosed as having sickle cell trait. he was clinically asymptomatic. the hplc profile of the mother showed: hb a 83%; hb a2 3%; hb f 1%, and an abnormal component in the hbc window, very likely hb s-oman 13%, so she was diagnosed to have having the hb soman trait. the two brothers of the index case had normal hplc profiles. d i s c u s s i o n this case report stresses the importance of examining the blood film, which revealed the presence of napoleon hat x-shaped red blood cells [figure1] characteristic of red blood cells containing hbs-oman.1, 2, 3 the presence, in addition, of classical sickle cells in the smear, as seen in figure 1, prompted family studies, and confirmed the inheritance of hb s and hb soman in this patient. thus she was diagnosed as compound heterozygote for hb s and hb s-oman during a follow up at al-nahdha hospital, after the blood transfusion, the hplc profile of the patient revealed the presence of hb s-oman at 12% and hb s at 25% matching with the level observed in her parents for respective abnormal haemoglobins. the first report of hb s-oman in the literature was by langdown jv et al. in 1989.4 the first description of compound heterozgosity for hb s/hb s-oman in a one year old female from oman was reported in 2002.1 the pathophysiology of the sickle syndrome in this compound heterozygote patient must be the result of interaction between hbs and hbs-oman, the sickle mutation (β6val) favouring sickling and the o-arab mutation (β121lys) favouring haemolysis and changes in red blood cell shape.5 it is important to note that such patients who are compound heterozygotes for hb s and hb s-oman behave clinically like sickle cell anaemia. our case, who had frequent admissions to hospital with haemolytic crises and who received numerous blood transfusions, fully supports this fact. our study highlights the importance of reviewing the sickle cell cases in oman carefully, including those categorised as hbc trait or sickle cell disease (as hbsoman behaves as hbc on hplc). the mother of this patient, who is heterozygous for hb s-oman (13%), is clinically asymptomatic. published reports state that the clinical manifestations in heterozygous hb s-oman are only observed in individuals having more than 20% of hb s-oman, whereas individuals with a lower percent of hb s-oman (14% and below), and concomitant homozygosity for single gene deletional alpha thalassaemia, are clinically asymptomatic, and have only slight to moderate red blood cell changes.3 thus both exploration of alpha thalassaemia and family studies will be useful in predicting the clinical outcome. figure 1: smear showing napoleon hat x-shaped red blood cells, characteristic of red blood cells containing hbs oman 346 s u r e s h ve n u g o pa l , a l p h o n s a s h a j u, s u c h ata d h u r i , th u r a i ya a l h a r t h y a n d k h a l i d b j a b a l c o n c l u s i o n a patient who has compound heterozygosity for hb s and hb s-oman behaves clinically like a case of sickle cell anaemia. an awareness of existence of hb s-oman, an eye for napoleon hat x-shaped cells on blood film, a review with hplc in all cases of known sickle cell anaemias, along with family studies, is recommended to unearth cases of hb s-oman. r e f e r e n c e s 1. jahdhamy r, makki h, farrell g, azzawi s. a case of compound heterozygosity for hb s-oman. br j haematology 2002; 116:504. 2. venugopal s, asila ns, nafisa mz, laitha mn, mathew s. hemoglobin s-oman trait – a sickling variant. oman med j 1999; 1:23-24. 3. ronald ln, daar s, jose r, sandra ms, gravell d, bouhassira e, et al. hb s – oman heterozygote – a new dominant sickle syndrome. blood 1998; 92:4375-4382. 4. langdown jv, williamson d, knight cb, rubenstein d, carrell rw. br j haematology 1989; 71: 443-444. 5. ronald ln, rajagopal k, slaheddine f, jacques e, nathalie g, jose r, et al. the erythrocyte effects of haemoglobin oarab. br j haematology 1999; 107:516-521. paediatric covid-19 infection in iraq is it not prevalent or underestimated? sultan qaboos university med j, august 2020, vol. 20, iss. 3, pp. e374–375, epub. 5 oct 20 submitted 23 jun 20 accepted 12 aug 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.03.021 letter to the editor مرض كوفيد-19 عند أطفال العراق هل هو غري سائد أم مل يتم تقييم مدى انتشاره dear editor, since the emergence of coronavirus disease 2019 (covid-19), caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), in late december 2019 in wuhan, china, the disease has infected hundreds of thousands of people worldwide. its outbreak has led the world health organization (who) to announce a pandemic in march 2020.1 the disease affects primarily t-lymphocytes, particularly cluster of differentiation (cd) 4+ and cd8+ t-cells, resulting in reducing the numbers and interferon-γ production by cd4+ t-cells. these immunological surrogate markers could be beneficial because of their association with the severity of covid-19 infection.2 data on paediatric covid-19 cases are rare. recently published data suggests that children constitute 1–5% of diagnosed covid-19 cases. in 90% of cases, the disease was diagnosed as asymptomatic, mild or moderate and deaths have been extremely rare. up to 6.7% of cases might be severe but are generally seen in patients younger than 1 year of age and in those who have underlying diseases.3 the numbers of paediatric covid-19 cases is a matter of concern in iraq and worldwide. due to financial constraints, testing for covid-19 was introduced on the limited basis in iraq utilising mainly rapid tests and to a lesser extent polymerase chain reaction tests of nasopharyngeal swabs. although such limited testing capacity can’t precisely determine the actual case definition rate, 115,332 covid-19 cases and 4,535 deaths were registered until july 29, 2020 in iraq.4 the rise in covid-19 cases is expected to continue based on different factors, notably active contact-tracing, increased testing capacity across the country and poor adherence to the guidelines of infection prevention measures as well as the loosening of movement-restrictions, particularly in impoverished and overcrowded areas. in iraqi kurdistan, four cases of paediatric covid-19 were reported.5 however, across other parts of the country, 4,043 positive paediatric cases out of 946,761 tested samples were detected by july 28, 2020 with a positivity rate of 0.4%.6 the actual rate of paediatric covid-19 cases is underestimated in iraq. the plausible explanations are manifold, namely (1) the milder clinical course of the disease in children compared to adults mimicking simple flu and, thus, these cases might escape the attention of treating paediatricians; (2) limited awareness of paediatricians about the disease itself; (3) popular misbeliefs/misinformation among the public on the seriousness of the disease; and (4) constrained laboratory testing capacity. with the current state of the disrupted healthcare system in iraq due to decades of conflict and underinvestment in healthcare services, the risks of potential paediatric covid-19 infection in an already accelerating humanitarian crisis are multifaceted.7 infected children represent an infection reservoir that might act as spreader of infection in the community. available data suggests that vaccine preventable diseases in iraq are still occurring in high incidence and causing outbreaks precipitated by the fluctuation in vaccine coverage (60–80%).8 the extended period of curfew affecting the implementation of national vaccination campaigns on one hand and the extended ban of international flights influencing the import of vaccines to iraq on the other hand are expected to substantially put children at increased risk of missing routine vaccination schedules and devastate the suffering in the currently 62 camps of refugees and internally displaced people across the country. in these unprecedented times, the united nations children's fund and the who could jointly play a pivotal role in improving the care for children in iraq, saving their lives, defends their rights, help fulfil their potential and prevent the spread of the disease through application of the following measures: (1) promoting good nutrition and hygiene practices; (2) providing access to water, food, education and healthcare; (3) developing proper, friendly https://creativecommons.org/licenses/by-nd/4.0/ mahmood d. al-mendalawi letter to the editor | e375 information on covid-19 to children and families; (4) recommending following national guidelines on covid-19 preventive measures such as physical distancing, hand washing and proper coughing and sneezing hygiene; (5) providing equipment and supplies for covid-19 testing; and (6) importantly calling on the iraqi government to invest more in healthcare services and intensify vaccination campaigns to cover children with missed vaccinations, once the covid-19 pandemic is contained. early detection, registration, isolation, proper management of cases, increasing alertness of paediatricians and public and following infection prevention practices as well as vaccine development (solicited to be launched soon) represent the mainstay in the control of the paediatric cases of covid-19 in iraq. mahmood d. al-mendalawi department of paediatrics, al-kindy college of medicine, university of baghdad, baghdad, iraq e-mail: mdalmendalawi@yahoo.com references 1. world health organization. virtual press conference on covid-19. – 11 march 2020. from: https://www.who.int/docs/default-source/ coronaviruse/transcripts/who-audio-emergencies-coronavirus-press-conference-full-and-final-11mar2020.pdf?sfvrsn=cb432bb3_2 accessed: aug 2020 2. chen g, wu d, guo w, cao y, huang d, wang h, et al. clinical and immunological features of severe and moderate coronavirus disease 2019. j clin invest 2020; 130:2620–9. https://doi.org/10.1172/jci137244. 3. tezer h, bedir demirdağ t. novel coronavirus disease (covid-19) in children. turk j med sci 2020; 50:592–603. https://doi.org/10.3906/ sag-2004-174. 4. worldometer. coronavirus. world/countries/iraq. from: www.worldometers.info/coronavirus/country/iraq/ accessed: aug 2020. 5. merza ma, haleem al mezori aa, mohammed hm, abdulah dm. covid-19 outbreak in iraqi kurdistan: the first report characterizing epidemiological, clinical, laboratory, and radiological findings of the disease. diabetes metab syndr 2020; 14:547–54. https://doi. org/10.1016/j.dsx.2020.04.047. 6. world health organization. coronavirus disease covid-19 dynamic infographic dashboard for iraq. from: https://app.powerbi. com/vie w?r=e yjrijoinjljmdhiymitz tlhms00mdlhltg3mjitmdnmm2fhnze5nmm4iiwidc i6imy2mtbjmgi3lw jkmjq tngizos04mtbiltnkyzi4mgfmyju5mcisimmiojh9 accessed: aug 2020. 7. devi s. reconstructing iraq. lancet 2018; 392:541–2. https://doi.org/10.1016/s0140-6736(18)31731-8. 8. lafta r, hussain a. trend of vaccine preventable diseases in iraq in time of conflict. pan afr med j 2018; 31:130. https://doi.org/10.11604/ pamj.2018.31.130.16394. https://doi.org/10.1172/jci137244 https://doi.org/10.3906/sag-2004-174 https://doi.org/10.3906/sag-2004-174 https://doi.org/10.1016/j.dsx.2020.04.047 https://doi.org/10.1016/j.dsx.2020.04.047 https://doi.org/10.1016/s0140-6736%2818%2931731-8 https://doi.org/10.11604/pamj.2018.31.130.16394 https://doi.org/10.11604/pamj.2018.31.130.16394 submitted 5 jan 23 1 revision req. 20 feb 23; revision recd. 14 mar 23 2 accepted 19 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.036 5 6 an unusual presentation of choriocarcinoma in a postmenopausal woman 7 a case report 8 *aref zribi,1 reem al mazroui,2 raza sayani,2 ikram a burney1 9 10 1women health program and 2department of radiology, sultan qaboos comprehensive cancer 11 care and research centre, muscat, oman. 12 *corresponding author’s e-mail: arefdoc@gmail.com 13 14 abstract 15 choriocarcinoma (cc) is a malignant neoplasm of the trophoblastic tissue, with a potential to 16 metastasize to distant organs. a limited case of gestational cc develops after a long latent 17 period. we describe the case of a 52-year-old postmenopausal woman who developed metastatic 18 choriocarcinoma presumably of gestational origin, 8 years after the last pregnancy, and 2 years 19 after the last menstrual period. the patient was diagnosed with cc metastatic to the brain, 20 spleen, lung and the kidney. the β-human chorionic gonadotrophin level was found to be raised 21 (1,292,867 miu/ml). the international federation of gynecologic oncology (figo) risk score 22 was calculated to be 14 (very high risk). the patient was initially treated with whole-brain 23 radiotherapy (wbrt) and splenic artery embolization because of a hemoperitoneum. afterwards 24 the patient received systemic treatment using the standard ema/co regimen till complete 25 serological remission. 26 keywords: choriocarcinoma; postmenopausal; latent period; brain; oman. 27 28 29 30 introduction 31 choriocarcinoma (cc) is a malignant neoplasm of the trophoblastic tissue, with a potential to 32 metastasize to distant organs.1 there are two sorts, gestational and non-gestational cc. majority 33 of cases of gestational cc are intra-uterine, and only 0.8-4 % develop in ectopic locations.2.3 the 34 non-gestational cc arise in the gonads, usually in the reproductive age. a limited cases of 35 gestational cc develop after a long dormant period.4.5 gestational cc has been reported to 36 develop between 5 weeks and up to 38 years after gestation, and even after menopause.4 37 approximately 30 % of cases of gestational cc are metastatic at the time of diagnosis.4 the 38 tumor metastasizes most commonly to the lungs (60-75%), vagina (40-50%), brain (15-20%), 39 liver (15-20%), spleen (10%), intestines (5-10%), and the heart (4%).6-9 here, we illustrate the 40 case of metastatic cc in a 52-year-old postmenopausal lady, growing 8 years after the last 41 pregnancy, and 2 years after the last menstrual period. 42 43 case report 44 a 52-year-old female, menopausal for two years, was brought to the emergency room with a 45 history of headache and an episode of seizure. there was no history of loss of consciousness. 46 past medical history revealed an episode of vaginal bleeding 8 years back, for which the patient 47 underwent dilatation and curettage, and was diagnosed to have a molar pregnancy. she had no 48 other past medical history of significance. on physical examination, the patient was conscious, 49 oriented to time, place and person, vitally stable, and had normal power and tone in both upper 50 and lower limbs. there was no facial asymmetry, and all cranial nerves were intact. 51 gynecological exam revealed a normal vulva; cervix was irregular and the uterus was bulky. 52 there was no vaginal bleeding. 53 magnetic resonance imaging (mri) showed a large space occupying lesion involving the right 54 frontal lobe, measuring 36 x 33 mm, with surrounding vasogenic edema and midline shift to the 55 left, and subfalcine herniation in the frontal area. several lesions involving the right parietal and 56 the occipital lobes, largest measuring 20 x 20 mm, were also identified (figure 1). the ct scan 57 of the body cavity showed heterogeneous appearance of the endometrial cavity, and multiple 58 hypodense lesions in the spleen, largest measuring up to 24 mm, and a small lesion in the right 59 kidney. a soft tissue nodule in the right middle lobe of the lung and in the left lung apex were 60 also seen. mri of the pelvis showed normal endometrial thickness and signal intensity, no 61 adnexal masses, and no enlarged pelvic lymph nodes or ascites (figure 2). 62 other than the splenic lesion, no other lesion was large enough to biopsy. the β-human chorionic 63 gonadotrophin (β-hcg) level was found to be raised (1,292,867 miu/ml; normal <5 miu/ml). 64 in absence of tissue diagnosis, no mass in the adnexal region, and a very high level of β-hcg, a 65 diagnosis of gestational cc was made. the international federation of gynecologic oncology 66 (figo) risk score was calculated to be 14 (very high risk). 67 after admission to the hospital, the patient developed fever, and was found to have 68 staphylococcus aureus bacteremia, the bacteria being sensitive to cefazolin. in addition, the 69 patient was treated with levetiracetam and dexamethasone. the case was discussed in tumor 70 board. because of the midline shift and impending herniation, the patient was initially treated 71 with whole-brain radiotherapy (wbrt) to a dose of 25gy in 10 fractions. after radiotherapy, 72 systemic treatment was commenced using induction chemotherapy, consisting of etoposide and 73 cisplatin. four days after receiving the 1st dose, the patient developed tachycardia (hr 140/min, 74 regular, low volume). electrocardiogram revealed sinus rhythm. the hemoglobin was found to 75 be very low at 3 g/dl. an urgent ct scan of the abdomen showed hemoperitoneum and a 76 significant progression in the size of the metastases to the spleen, which had breached the 77 capsule (figure 3). splenic artery embolization was carried out leading to a complete occlusion 78 of the artery and a rapid arrest of further bleeding (figure 4). systemic chemotherapy was 79 continued, as the standard ema/co regimen, till complete serological remission. at the time of 80 serological remission, ct scan of the body cavity revealed near complete resolution of the 81 splenic and lung lesions. end-of-treatment ct scan and mri of the brain confirmed the 82 radiologic remission. oral and written consent were taken from the patient for publication 83 purposes. 84 85 discussion 86 we report the successful treatment of a post-menopausal women, diagnosed to have stage iv, 87 high risk cc, most likely of gestational origin, 8 years after the evacuation of a hydatidiform 88 mole, and managed with wbrt and splenic artery embolization, before being treated with 89 systemic chemotherapy. 90 the vast majority of cases occur in women less than 35 years of age, usually within one year 91 following the diagnosis of hydatidiform mole (60% of cases), or abortion (30%) and after a 92 normal or ectopic pregnancy (10%).10.11 a higher incidence is reported from africa, asia and 93 south america, with an estimated incidence of 1 in 500-3000 pregnancies in south-east asia. 94 the occurrence in postmenopausal period is uncommon.12 furthermore, only a countable cases 95 have been described after a long latent time from the last pregnancy. 96 the risk of hydatidiform mole raise significantly with increasing mother age.13 cc can develop 97 anytime between 5 weeks to several decades after antecedent pregnancy or even after 98 menopause.14.15 desai published a case of cc in a 73-year-old patient, developing 38 years after 99 pregnancy and 23 years after her last menstrual menses.5 o’neill reported the case of cc in a 57-100 year old lady, 22 years after the last known pregnancy.1 similarly, okamoto reported the case of 101 cc in a 53-year old lady, 23 years after an elective abortion.16 sonobe reported the case of a 50-102 year old lady with cc 23 years after the last pregnancy.17 ito reviewed the literature of late 103 presentation of cc. the authors noted that the latent period was more than 2 years in 7.5% of 104 patient with cc.18 a long latent period from last pregnancy can be explained by an 105 asymptomatic pregnancy. alternatively, the trophoblastic tissue retained in the uterus following 106 the antecedent pregnancy could lie dormant for several years before transformation to 107 malignancy. 108 a limitation of this case report is the lack of tissue evidence of recurrence. a biopsy from the 109 metastatic cc is usually not carried out due to a risk of hemorrhage, however, the very high β-110 hcg level, serially increasing in presence of metastases is known to occur frequently in cc. in 111 the setting of an antecedent molar pregnancy, albeit, 8 years earlier, the patient was diagnosed to 112 have recurrence of cc. 113 114 conclusion 115 cc is one of the most curable gynecological cancer, and should be included in the differential 116 diagnosis of cancer occurring in postmenopausal woman. a few cases of a long latent period 117 after the last pregnancy have been reported, however, the mechanism of late onset of cc is not 118 known. retained trophoblastic tissue or an asymptomatic pregnancy between the last known 119 pregnancy and the diagnosis of cc may explain, however, the actual cause remains speculative. 120 non-gestational cc should be considered an alternative diagnosis in such cases. 121 122 conflicts of interest 123 the authors declare no conflict of interests. 124 125 funding 126 no funding was received for this study. 127 128 authors’ contribution 129 az and iab managed the case. ram provided the images. rs managed the splenic artery 130 embolization. az, ram and rs drafted the manuscript. iab reviewed the manuscript. all 131 authors approved the final version of the manuscript. 132 133 references 134 1. o'neill cj, houghton f, clarke j, mccluggage wg. uterine gestational 135 choriocarcinoma developing after a long latent period in a postmenopausal woman: the 136 value of dna polymorphism studies. int j surg pathol. 2008 apr;16(2):226-9. doi: 137 10.1177/1066896907307038. 138 2. rettenmaier ma, khan hj, epstein hd, nguyen d, abaid ln, goldstein bh. gestational 139 choriocarcinoma in the fallopian tube. j obstet gynecol 2013;33: 140 912.doi: 10.3109/01443615.2013.834879 141 3. chen, m.-j., yang, j.-h., lin, m.-c., ho, h.-n. and yang, y.-s. an unusual gestational 142 choriocarcinoma occurring primarily on the surface of a subserous leiomyoma. bjog: 143 https://doi.org/10.3109/01443615.2013.834879 an international journal of obstetrics & gynaecology, 2004;111: 188-190 144 doi.org/10.1046/j.1471-0528.2003. 00048.x 145 4. hassadia a, kew fm, tidy ja, wells m, hancock bw. ectopic gestational trophoblastic 146 disease: a case series review. j reprod med. 2012 ;57(7-8):297-300. pmid: 22838244. 147 5. desai nr, gupta s, said r, desai p, dai q. choriocarcinoma in a 73-year-old woman: a 148 case report and review of the literature. j med case rep. 2010; 4:379. doi: 10.1186/1752-149 1947-4-379. 150 6. weiss s, amit a, schwartz mr, kaplan al. primary choriocarcinoma of the vulva. int j 151 gynecol cancer. 2001;11(3):251-4. doi: 10.1046/j.1525-1438.2001.01005. x. 152 7. wang l, wan y, sun y, zhang x, cheng x, wu m et al. pure non-gestational uterine 153 choriocarcinoma in postmenopausal women: a case report with literature review. cancer 154 biol ther. 2019;20(9):1176-1182. doi: 10.1080/15384047.2019.1617564. 155 8. tsukamoto n, iwasaka t, kashimura y, uchino h, kashimura m, matsuyama t. 156 gestational trophoblastic disease in women aged 50 or more. gynecol oncol. 157 1985;20(1):53-61. doi: 10.1016/0090-8258(85)90124-6. 158 9. mangla m, singla d, kaur h, sharma s. unusual clinical presentations of 159 choriocarcinoma: a systematic review of case reports. taiwan j obstet gynecol. 2017 160 ;56(1):1-8. doi: 10.1016/j.tjog.2015.05.011. 161 10. paradinas fj. pathology and classification of trophoblastic tumours gynaecologic 162 oncology (edited by: coppleson m) churchill livingstone, london 1992;2:1013-1026. 163 11. acosta-sison h. ab initio choriocarcinoma; two unusual cases. obstet gynecol. 164 1959;13(3):350-2. pmid: 13633153. 165 12. fox h and buckley ch. the female genital tract and ovaries in. oxford text book of 166 pathology (edited by: mcgee jod, isaacson pg, wright na) oxford university press, 167 new york 1992; 2a:1565-1639 168 13. samal sk, rathod s, ghose s. postmenopausal choriocarcinoma: a rare case report. j 169 midlife health. 2014;5(3):159-61. doi: 10.4103/0976-7800.141229. 170 https://doi.org/10.1046/j.1471-0528.2003.00048.x 14. hassadia a, kew fm, tidy ja, wells m, hancock bw. ectopic gestational trophoblastic 171 disease: a case series review. j reprod med. 2012;57(7-8):297-300. pmid: 22838244. 172 15. soper jt, mutch dg, schink jc; american college of obstetricians and gynecologists. 173 diagnosis and treatment of gestational trophoblastic disease: acog practice bulletin 174 no. 53. gynecol oncol. 2004;93(3):575-85. doi: 10.1016/j.ygyno.2004.05.013. 175 16. okamoto t, nomura s, nakanishi t, yamada s, tomoda y. a case of uterine 176 choriocarcinoma with spontaneous rupture twenty-three years following the antecedent 177 pregnancy. j obstet gynaecol res. 1997;23(2):189-95. doi: 10.1111/j.1447-178 0756.1997.tb00830.x. 179 17. sonobe h, taguchi k, ogawa k, yoshioka t. latent vaginal choriocarcinoma in a 180 postmenopausal woman. acta pathol jpn. 1976;26(5):611-8. doi: 10.1111/j.1440-1827. 181 1976.tb00518. x. 182 18. ito h, tanaka t, watanabe h, yakushiji k, sato h, ito k. the nature of gestational 183 choriocarcinoma latent over two years. nihon sanka fujinka gakkai zasshi. 1985; 184 37(5):730-4. 185 186 187 figure1: a) coronal t2-weighted magnetic resonance imaging (mri) reveals hemorrhagic 188 lesion within the subcortical region of right parietal lobe measuring 2.7 x 2.2 cm with adjacent 189 vasogenic edema; b) axial contrast-enhanced t1-weighted mri reveals multiple, enhanced, 190 nodular lesions; c) susceptibility weighted imaging demonstrates multiple hypointense, 191 hemorrhagic lesions in the cortical and subcortical areas. 192 193 194 figure2: a) sagittal t2-weighted mr reveals normal uterus with normal endometrial stripe 195 thickness and signal. sagittal contrast-enhanced fat-suppressed t1-weighted mr image; b) 196 demonstrates normal enhancement with no tumor seen. 197 198 199 figure3: contrast enhanced ct performed after 25 days from initial ct because patient showed 200 sudden drop of hemoglobin. coronal reformat ct (a-b) reveals newly developed moderate 201 hemoperitoneum with rapid increase in size of splenic hemorrhagic masses (black arrow) that are 202 likely the cause of the retroperitoneal bleed. in addition, the right renal mass has also progressed 203 in size (white arrow) 204 205 206 207 208 209 210 211 212 213 214 figure 4: splenic artery embolization (distal technique). a) celiac angiogram shows large round 215 mass medial to the spleen corresponding to the known metastatic deposit (black arrow). no 216 active extravasation; b) distal splenic artery branches are selected. abnormal blush with active 217 extravasation was seen from a branch of splenic artery (white arrow); c) a 2.7f progreat 218 microcatheter was then inserted co-axially through the 5f catheter and advanced. this was super 219 selectively cannulated and embolization was then performed with pva particles and coils. no 220 further extravasation seen (image c). 221 departments of 1maternal & child health and 2fundamentals & administration, college of nursing, sultan qaboos university, muscat, oman *corresponding author e-mails: girija@squ.edu.om and girija16964@gmail.com reverse mentoring and intergenerational learning in nursing bridging generational diversity *girija madhavanprabhakaran,1 frincy francis,1 leodoro j. labrague2 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 472–478, epub. 7 nov 22 submitted 25 oct 21 revision req. 4 jan 22; revision recd. 15 feb 22 accepted 22 mar 22 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2022.027 special contribution abstract: this article aimed to discuss the scope of reverse mentoring and intergenerational learning in nursing. accordingly, it discusses the characteristics, significance, benefits, conceptual framework, implementation strategy and application of reverse mentoring in nursing. reverse mentoring occurs when a technically competent younger employee mentors a senior experienced employee and reciprocally exchanges the work culture and soft skills. diverse intergenerational learning spurs innovation through the sharing of knowledge, skills, competencies, norms and values. thus, reverse mentoring helps to enhance the quality of education, practice-outcomes and employee development. it should be adopted for a multigenerational workforce to promote diversity, keep employees technically competent and updated in ever-changing nursing profession. presently, the covid-19 pandemic has given rise to an urgent need for technical competency and knowledge sharing among the diverse multigenerational nursing workforce. therefore, a reverse-mentoring strategy is proposed as a sustainable cost-effective intergenerational knowledge-sharing tool for the current era of economic crisis. keywords: mentoring; covid-19; cultural diversity; learning; nursing; preceptorship; intergenerational relations; mentorship. the key challenge faced during the covid-19 pandemic was knowledge sharing among a multigenerational diverse workforce. as generations differ in their work ethic, knowledge, skills, attitudes, values and communication styles, it is a challenge for organisations to achieve their visions through collaborative teamwork; this also poses barriers to intergenerational learning.1 reverse mentoring (rm) is a cross-generational approach that assigns talented and willing young employees as mentors to older senior employees, supported by the organisational vision to bridge the technology divide between the two generations and develop future leaders.2 overcoming challenges of intergenerational learning through rm approach would be a suitable strategy for the nursing profession both in practice and academia. it is well-documented that an intergenerational learning programme provides opportunities for the transfer of knowledge, skills, competencies, wisdom, norms and values between generations and provides lifelong learning and sharing between generations.3 the rm strategy is an opportunity for intergenerational knowledge sharing and, thus, developing and enhancing intergenerational team spirit.4 in today’s digital age, rm is an important tool for developing talent and promoting unity between different generations. by bringing generations together through rm, younger employees develop professional relationships with leaders and exchange skills, knowledge and attitudes to become empowered emerging leaders for the future. in the context of the covid-19 pandemic, due to the enforcement of lockdowns and physical distancing along with the emergence of a global economic crisis, all organisations can adopt the cost-effective rm approach to build a technically competent workforce. therefore, this paper aimed to discuss the scope of the rm approach for intergenerational learning in nursing practices and academia. accordingly, it provides an overview of the characteristics, significance, benefits, conceptual framework, implementation strategy and application of rm in nursing. s i g n i f i c a n c e o f r m demographic shifts in the workforce are inevitable. the 2019 deloitte millennial survey reports that globally, in the near future, millennials will make up 75% of the workforce, most baby boomers will retire and the number of generation x employees will decline.5 in the current era of diverse staff, rm is proposed to be a tool for developing an engaged and committed multigenerational workforce and it bridges the generational gap. kwoh, in her work ‘reverse mentoring cracks workplace’, highlights the importance of millennials in an organisation, as they often bring new, innovative ideas and skills to the table and they are techsavvy, racially diverse, socially well-connected and collaborative by nature.6 on the other hand, baby https://creativecommons.org/licenses/by-nd/4.0/ girija madhavanprabhakaran, frincy francis and leodoro j. labrague special contribution | 473 boomers typically provide experience, best practices and a long history of good work ethic. interactions between people from different generations bring out the best in people, as they help them realise the value of diverse perspectives and push them to think innovatively and creatively.7 a new way of working such as remote working, teleworking and flexible working enabled by high technology has gained significance in light of the covid-19 pandemic.8,9 during times of global lockdown and physical distancing measures, the rm approach within organisations would be a suitable strategy to facilitate intergenerational learning among a diverse group of staff. the global nursing workforce comprises three different generations with differences in professional backgrounds, ideologies, beliefs, work practices and attitudes. the three generations based on the birth year include the baby boomers (1946 to 1964), generation x (1965 to 1980) and the millennials or generation y (1981 to 2000). the presence of all these generations in the current workforce has created significant diversity. statistics demonstrate that out of over 3.1 million nurses, 50.2% are baby boomers, 30.4% are generation xers and 19.4% are millennials.10 a strength and weakness analysis of these three categories indicates major differences, where 73% of workers agreed that baby boomers are hardworking but lack technical skills, generation xers are good relationship builders and revenue generators and millennials are enthusiastic learners with technical and social media skills as assets. understanding the different categories of nurses and analysing their strengths and weaknesses can help devise and implement a well-planned rm programme for organisations, which can enhance the quality of healthcare services offered and improve patient safety.11 intergenerational communication and interaction with priority to health and well-being create opport unities for positive intergenerational interactions and, thus, reduce the gap between diverse generations.3 as online teaching–learning activities have become ubiquitous during the covid-19 pandemic, the rm approach and intergenerational learning are significant means to empower diverse faculty. research findings revealed that rm is an efficient tool for sharing knowledge through creative involvement, leadership development and the development of intergenerational relationships based on mutual acceptance.12 the increasing worldwide diversity in nurses and nursing faculties demands this intergenerational mentoring approach both in practice and nursing education. in the context of the global economic crisis caused by the covid-19 pandemic, organisations can adopt the rm approach to build a technically competent workforce, as it is cost effective. it is highly essential to think of new strategies of mentoring, ones that would promote knowledge and skill transfer and overcome the challenges of the current pandemic by enhancing the technical competency of a diversified workforce, both in nursing practice and academia. although previous studies report that organisations promote generational diversity, as it guarantees team spirit and performance, doing so can create challenges in knowledge transfer.13 despite the advantages of rm, its application is limited, indicating the need for more efforts to promote the rm approach for intergenerational learning among diverse generations in modern organisations.8 e s s e n t i a l c h a r a c t e r i s t i c s o f r e v e r s e m e n t o r i n g mentoring is a best-practice leadership development programme, through which employers hope to inculcate commitment in employees by treating them as unique resources for competitive advantage.14 satterly et al. developed an intergenerational mentoring model, for which they recommended the rm model, as the latter considers the age and experience of the faculty.15 this intergenerational mentoring model acknowledges the skills each generation brings to the academic environment and is based on the slogan ‘everyone leads; everyone learns’. rm ensures continuous organisational learning by meeting specific needs collectively and efficiently through creating role models and offering carrier-related and psychological support, along with target-oriented education ensuring career development for leaders and the success of both individuals and organisations.2,16 interpersonal comfort, trust and mutual respect between employees and employers are emphasised. the main features of the rm process are its innovative non-hierarchical approach, the novice level of the mentors and a bidirectional relationship. compartmentalised mentoring on new skills such as the latest applications, informatics, podcasts, e-learning and electronic databases are focused. it also ensures continuous organisational learning with respect to cultural differences by meeting specific identified needs collectively and efficiently.2,11,15 the success of rm depends on the degree of mentor/ mentee relationship, their level of engagement and the type and amount of organisational support; in this regard, the engagement of higher officers and a conducive organisational culture are the main organisational support needed for the successful accomplishment of rm.11 clarke et al. recommended certain essential attributes and behaviours for both mentees and mentors to ensure successful rm [table 1].17 reverse mentoring and intergenerational learning in nursing bridging generational diversity 474 | squ medical journal, november 2022, volume 22, issue 4 theoretical base and conceptual framework of reverse mentoring as mentioned earlier, satterly et al. developed an intergenerational mentoring model and recommended rm model that considered the age and experience of the faculty.15 rm is outlined using various theories, and the use of theoretical frameworks in rm continues to expand as more and more intergenerational learning strategies are made into practice. rm is more rooted in social and learning theories.11,18 this paper focuses on adult learning (andragogy) and social theoretical bases to relate the concepts in rm. in the intergenerational mentoring model, learning is based on the adult learning theory by knowles, as it identifies all key elements, including a learner’s need to know, self-concept, experience, readiness to learn, orientation to learning and motivation.19 when exploring the theoretical support for rm, zauschnerstudnicka related the adult learning theory to rm from an educational perspective.18 rm meets the adult developmental needs of both the mentee and mentor. adult learners obtain new knowledge first through understanding and then application at work, where they examine their work, synthesise new answers to solve problems and evaluate various strategies and solutions to benefit the organisation and themselves. social theories consider mentors as role models. rm has been used traditionally as a social exchange tool to leverage the expertise of generations. many studies have used the social exchange theory and leader–member exchange (lmx) theory as a theoretical framework.20 mentoring has been related to the social exchange theory due to its focus on dyadic relationships, reciprocity and the relationship that develops as an important element for individuals’ growth in their careers. the social exchange theory has been extended into the leadership domain with the lmx theory. lmx is goal-directed intergenerational learning focusing on the innovative technological advancement of seniors by pairing them with expert juniors, which also paves the way to facilitate emotional intimacy and socialising with the younger generation [figure 1]. o v e r v i e w a n d o u t c o m e s o f r e v e r s e m e n t o r i n g the mentor and mentee attributes explain, in a glimpse, what characteristics or contributions the mentor and table 1: expected behaviours of effective mentors and mentees in reverse mentoring expected behaviours mentor mentee respects and acknowledges the expertise of the mentee shows respect for the skills of the mentor acknowledges the limitations of the mentee who has extensive responsibilities articulates their needs clearly to the mentor encourages joint-learning objectives and ensures skill outcomes may require practice and review to improve specific skills provides a comfortable learning environment adopts affective-based learning, allowing changes in attitude identifies the resources required to achieve set goals formulates objective-based activities to achieve goals provides opportunities for the mentee to assess their own needs and progress conducts periodic self-reflection actively listens to the needs of the mentee to improve crossgenerational communication acknowledges areas for improvement and verbalises them to their mentor figure 1: the conceptual framework of reverse mentoring. girija madhavanprabhakaran, frincy francis and leodoro j. labrague special contribution | 475 mentee have and the outcomes they achieve with the rm process [figure 2]. additionally, the figure reflects the functions involved in the process, along with the characteristics of the relationship between the mentee and mentor. the figure also portrays the benefits for the organisation, including a sustainable, healthy work culture with job satisfaction contributing to low attrition and good outcomes. i m p l e m e n tat i o n s t r at e g y f o r r e v e r s e m e n t o r i n g introducing rm in an organisation can be considered either as a standalone mentoring programme or as part of existing mentoring initiatives. perceived organisational support (pos) and lmx are the two social exchange mechanisms explained by chaudhuri and ghosh.20 in this regard, pos ensures collaboration bet ween employees and the organisation and fosters employee morale by making them feel valued for their contributions. concerning lmx, intergenerational exchange is where seniors are paired with juniors to achieve a predetermined goal related to current technological advancements. such pairings facilitate emotional intimacy and socialising with the younger generation. there is no one-size-fits-all rm programme, as each organisation has a unique workplace culture and generational gap.21 nonetheless, each institution should embrace the concept of rm and foster it wherever possible. s t e p s t o i m p l e m e n t a n e f f e c t i v e r e v e r s e m e n t o r i n g p r o g r a m m e i n a n o r g a n i s at i o n the aim of rm should focus on specific organisational visions and goals. appropriate pairing, clear goals and set guidelines are crucial factors for rm. organisations should plan and initiate rm programmes meticulously and sequentially [figure 3]. at first, a thorough initial assessment of the setting, nature of the employees and the organisational vision and mission are the fundamentals for identifying and setting objectives based on the needs and skills in initiating the rm programme. the initial assessment is the benchmark when it comes to applying rm in organisations. the next important step is appropriately matching mentors and mentees based on identified needs and skills. effective mentoring is based on the partners’ chemistry. right pairing is important, and it is mostly centred on commitment and a passion to figure 2: overview and outcomes of reverse mentoring figure 3: process of implementing reverse mentoring. rm = reverse mentoring. reverse mentoring and intergenerational learning in nursing bridging generational diversity 476 | squ medical journal, november 2022, volume 22, issue 4 share. then, the plan of the intergenerational model of rm is implemented with administrative support. the key step to consider for effective implementation is the development of rm agreement. this step calls for the definition of the specific reasons for mentoring and the development of mentoring goals and plans. specific policies and protocols act as frameworks to be followed. at this stage, both the mentee and mentor must agree on the rules and regulations. for this purpose, a written agreement must be agreed upon by both parties. after this agreement, the next step is to consider the negotiation of agreements. rm requires rules but also embraces a workplace flexibility culture to facilitate new learning. execution and practice by the mentee for a contract period is the next step. the mentor must ensure that the mentee practices the new concepts and tools. afterwards, ongoing feedback is established to evaluate their progress continuously based on the agreed objectives. this is followed by the analysis of the impact and feasibility of the rm programme. based on the analysis, the programme either continues with the same plan or is modified and restructured to suit organisational needs and implement new plans.18,21 reverse mentoring and intergenerational learning in nursing medicine, nursing and all medical professions are dynamically advancing. this diverse set of professionals needs constant and continual education on swift technological innovations. advances in technology have a tremendous impact, both in practice and academia, which means that seniors need to develop new technological competency cost-effectively and conveniently. most hospital units have diverse nursing popul ations, ranging from traditionalists, baby boomers and generation x to generation y/millennials, all of which come with their own sets of skills and values. hence, nurse managers need to support and promote intergenerational learning in nursing units. an example of this is that a 28-bed oncology clinical unit implemented the latest, completely computerised method of charting patient details. overall, the unit had 21 registered nurses who were equally distributed between baby boomers, generation x and millennials. as millennials demonstrate strong computer skills, they were recruited to support the rest of the team members while the new charting system got implemented. eventually, the millennials, known as the ‘super users’, fell into the mentoring role, thus offering full support in slowly transitioning the nurses belonging to the baby boomers and generation x categories. as stated by the millennials, the new mentoring role made them feel valued and they developed cohesiveness with the team while the senior nurses learned the charting system with their help. hence, rm is instrumental in creating a synergistic work environment for all.22 a similar but unique kind of rm programme among healthcare workers was implemented in the st. thomas’ and grey’s nhs foundation trust in 2018; it was known as reverse mentoring for equality, diversity and inclusion (remedi). in this case, a senior white staff member was the mentee and the junior staff from the black and minority ethnic group was the mentor. the programme was initiated to enhance openness, understand cultural differences and minimise discrimination. the mentee often held an administrative position, and remedi allowed exploring the subject’s equality, diversity and inclusion practices at individual, departmental, organisational and symbolic levels.23 on another note, aemmi and moonaghi conducted a review to investigate the benefits of intergenerational programmes for children and older adults and their application in the healthcare system, and they concluded that intergenerational learning provided the best resources for the social and emotional growth of children and older adults.3 moreover, they recommended that this approach be used for nursing care, education and follow-up in healthcare systems. furthermore, the impact of intergenerational learning among young people and older adults during covid-19 was explored in china by lyu et al.24 the main focus of intergenerational sharing was on pandemic prevention, health and fitness, traditional culture and information literacy. the study reported that both generations shared and gained more knowledge on health, life skills and values. in particular, the older generation become more perceptive in their learning and behaviours, and the younger generation cultivated the concept of lifelong learning and closer relationships.24 ultimately, rm is a simpler, low-cost way to bridge the learning gap than investing in training and development. this cross-generational training can be achieved by maintaining the traditional mentor– mentee pairing. each organisation can embrace the rm concept as complementary to traditional mentoring to enhance workplace relationships. pairing and collaboration on projects and research can interconnect the employees in organisational, global, academic and social perspectives. the ever-changing academic environment demands that diverse nursing faculty undergo mentoring to girija madhavanprabhakaran, frincy francis and leodoro j. labrague special contribution | 477 learn about the new technology used in education. the familiarity of the current generation with informatics and their skills in handling innovative technology are important factors for their social interconnection and collaboration, while senior faculty can pass on their work ethic and best practices to junior mentors. in this regard, rm can help address generation gaps that are academic in nature. thus, in light of the knowledge and experience of millennials in technology and innovative approaches to teaching, the use of rm would help the senior nursing faculty effectively meet the learning needs of the current generation of students who are accustomed to online platforms. considering the intergenerational nature of the workforce, three steps must be carried out for rm: (1) assessing the needs and skillsets of faculty, (2) grouping and matching faculty based on their needs and skills and (3) implementing intergenerational faculty mentoring. the diversity of academic departments in size and structure does not allow a specific model to be adopted on a unilateral basis; rather, it calls for varying models of rm in each department to cater to specific needs. ultimately, the goal of intergenerational mentoring is to enhance learning and knowledge sharing among multigenerational participants. on another note, the faculty and students in the higher education sector has increasingly become intergenerational. in the 21st century, presence of novice millennials, generation xers and baby boomers in the faculty demands intergenerational collaboration through rm models, which do not have a hierarchical framework. as everyone is with the potential to learn and lead, this innovative knowledge sharing within education and practice areas contributes to enhancing each individual’s essential skills and boosting selfesteem, thus contributing to organisational goals and missions. through rm and intergenerational collab oration, educational interconnections are fostered and faculty development is enhanced, improving the teaching-learning dynamics and services. hence, rm can be very useful in nursing education. for example, quality and safety education in nursing (qsen) recommends informatics and teamwork as core competencies of student learning outcomes.25 older faculty members would find it difficult to keep up with new technologies such as e-learning modules, apps, online forums and electronic databases; on the other hand, millennials always have their finger on the pulse of advancing technology. rm can bridge this gap between generations, as it reduces generational tension through creative discussion and fosters understanding by building trust, positive attitudes and mutual respect. by doing so, rm equips diverse faculties with the ability to serve young students with advanced skills in online education. currently, all higher education organisations must remain technologically adept, challenging and competitive and consider how to effectively manage their demographically diverse faculty who serve technically competent students. though boomers and millennials are two fundamentally opposed workforce segments, rm programmes allow them to excel in online teaching–learning environments. the proper pairing, experience and personality of a mentor are common challenges experienced in mentoring in medical academia.26 therefore, appropriate planning, pairing, mentoring workshops, organisational guidelines and a culture of support are essential for smooth rm. limitations although rm is promising for the upward growth of an organisation, its potential limitations could affect the initiation and acceptance of this approach. cross-cultural differences could complicate smooth relationships. communication is a key challenge among diverse employees, and encouraging an amicable and accepting mentality among multicultural diverse generations would help them set aside their egos and enhance professional growth. furthermore, a lack of confidence felt by young mentors in interacting with seniors and power imbalances in pairing could hinder information exchange. however, through mutual respect, effective communication skills, professionalism and reciprocity, along with effective organisational culture building and support, rm can be implemented well. overall, rm is highly necessary to enhance intergenerational learning in the nursing field. conclusion rm is the best practice for intergenerational learning. this bidirectional innovative approach can transform and empower a multi-generational diverse workforce. it reduces the digital divide among diverse faculty and practitioners with positive outcomes at the individual, departmental and organisational levels. though sequential steps are recommended for rm implementation, each organisation must tailor it to suit its specific needs while planning and implementing an rm programme. with dynamic technological innovations, advancing healthcare and the era of online and technology-based nursing education, the role of junior faculty as a mentor to senior faculty augments intraand interdisciplinary collaboration reverse mentoring and intergenerational learning in nursing bridging generational diversity 478 | squ medical journal, november 2022, volume 22, issue 4 in all aspects of service, education and research and ensures better healthcare outcomes. mutual respect, reciprocity and effective communication reduce the potential limitations of rm. a u t h o r s’ c o n t r i b u t i o n all authors contributed to this work from the conception of the idea till the review of the final edition of the manuscript. gm conceptualised the topic and prepared an initial draft of the manuscript. ff and ljl made a substantial contribution to the design and preparation of the manuscript. all authors were involved in drafting and revising the manuscript for intelligent content. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t we sincerely acknowledge cambridge proofreading llc for its editorial and proofreading services. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. twenge jm, campbell sm, hoffman bj, lance ce. generational differences in work values: leisure and extrinsic values increasing, social and intrinsic values decreasing. j manag 2010; 36:1117–42. https://doi.org/10.1177/0149206309352246. 2. murphy wm. reverse mentoring at work: fostering crossgenerational learning and developing millennial leaders. hum resour manage 2012; 51:549–73. https://doi.org/10.1002/hrm.2 1489. 3. aemmi sz, moonaghi hk. intergenerational learning program: a bridge between generations. int j pediatr 2017; 5:6713–21. https://doi.org/10.22038/ijp.2017.28072.2430. 4. gadomska-lila k. effectiveness of reverse mentoring in creating intergenerational relationships. j organ chang manag 2020; 33:1313–28. https://doi.org/10.1108/jocm-10-2019-0326. 5. parsons l. reverse mentoring scheme provides senior leaders with fresh perspectives. from: https://www2.deloitte.com/uk/ en/pages/impact-report-2019/stories/reverse-mentoring.html accessed: feb 2022. 6. kwoh l. reverse mentoring cracks workplace. from: https:// www.wsj.com/articles/sb1000142405297020376480457706005 1461094004 accessed: feb 2022. 7. fry r. millennials overtake baby boomers as america’s largest generation. from: https://www.pewresearch.org/fact-tank/2020 /04/28/millennials-overtake-baby-boomers-as-americaslargest-generation/ accessed: feb 2022. 8. gerards r, de grip a, weustink a. do new ways of working increase informal learning at work? pers rev 2020; 50:1200–15. https://doi.org/10.1108/pr-10-2019-0549. 9. singh s, thomas n, numbudiri r. knowledge sharing in times of a pandemic: an intergenerational learning approach. knowl process manag 2021; 28:153–64. https://doi.org/10.1002/kpm.1669. 10. smith sd, galbraith q. motivating millennials: improving practices in recruiting, retaining, and motivating younger library staff. j acad librariansh 2012; 38:135–44. https://doi. org/10.1016/j.acalib.2012.02.008. 11. bradley university. nursing leadership & generational differences. from: https://onlinedegrees.bradley.edu/blog/nurse-leadership -through-multi-generational-differences/ accessed: feb 2022. 12. dominguez n, hager m. mentoring frameworks: synthesis and critique. int j mentor coach educ 2013; 2:171–88. https://doi. org/10.1108/ijmce-03-2013-0014. 13. becker kl, richards mb, stollings j. better together? examining benefits and tensions of generational diversity and team performance. j intergener relatsh 2020; ahead-of-print:1–21. https://doi.org/10.1080/15350770.2020.1837708. 14. onyia va, asikhia ou, egbuta ou, makinde go. rethinking mentorship and organisational commitment in nigerian academia. int j economics commerce manag 2019; 7:823–50. 15. satterly ba, cullen j, dyson da. the intergenerational mentoring model: an alternative to traditional and reverse models of mentoring. mentor tutoring: partnersh learn 2018; 26:441–54. https://doi.org/10.1080/13611267.2018.1530172. 16. deangelis kl. reverse mentoring at the hartford: crossgenerational transfer of knowledge about social media. chestnut hill, usa: sloan center on aging & work, boston college, 2013. 17. clarke aj, burgess a, diggele c, mellis c. the role of reverse mentoring in medical education: current insights. adv med educ pract 2019; 10:693. https://doi.org/10.2147/amep.s179303. 18. zauschner-studnicka s. a model for reverse-mentoring in education. int j soc behav educ econ business indust eng 2017; 11:546–53. https://doi.org/10.5281/zenodo.1129019. 19. knowles ms. andragogy: adult learning theory in perspective. community coll rev 1978; 5:9–20. https://doi.org/10.1177/009 155217800500302. 20. chaudhuri s, ghosh r. reverse mentoring: a social exchange tool for keeping the boomers engaged and millennials committed. hum resour dev rev 2012; 11:55–76. https://doi.org/10.1177/15 34484311417562. 21. crosby j. debra arbit of bridgeworks on helping companies resolve clashes among generations. from: http://www.startrib une.com/a-conversation-with-debra-arbit-of-bridgeworkshelping-companies-resolve-clashes-among-generations/38787 0212/?refresh=true accessed: feb 2022. 22. reinbeck dm, fitzsimons v. four generations of nurses bridge digital divide. nurs crit care 2015; 10:18–20. https://doi. org/10.1097/01.ccn.0000466774.93177.25. 23. raza a, onyesoh k. reverse mentoring for senior nhs leaders: a new type of relationship. future healthc j 2020; 7:94–6. https://doi.org/10.7861/fhj.2019-0028. 24. lyu k, xu y, cheng h, li j. the implementation and effectiveness of intergenerational learning during the covid-19 pandemic: evidence from china. int rev educ 2020; 66:833–55. https:// doi.org/10.1007/s11159-020-09877-4. 25. brady ds. using quality and safety education for nurses (qsen) as a pedagogical structure for course redesign and content. int j nurs educ scholarsh 2011; 8:1. https://doi.org/10.2202/1548923x.2147. 26. straus s, chatur f, taylor m. issues in the mentor–mentee rela tionship in academic medicine: a qualitative study. acad med 2009; 84:135–9. https://doi.org/10.1097/acm.0b013e31819301ab. https://doi.org/10.1177/0149206309352246 https://doi.org/10.1002/hrm.21489 https://doi.org/10.1002/hrm.21489 https://doi.org/10.22038/ijp.2017.28072.2430 https://doi.org/10.1108/jocm-10-2019-0326 https://doi.org/10.1108/pr-10-2019-0549 https://doi.org/10.1002/kpm.1669 https://doi.org/10.1016/j.acalib.2012.02.008 https://doi.org/10.1016/j.acalib.2012.02.008 https://doi.org/10.1108/ijmce-03-2013-0014 https://doi.org/10.1108/ijmce-03-2013-0014 https://doi.org/10.1080/15350770.2020.1837708 https://doi.org/10.1080/13611267.2018.1530172. https://doi.org/10.2147/amep.s179303 https://doi.org/10.5281/zenodo.1129019 https://doi.org/10.1177/009155217800500302 https://doi.org/10.1177/009155217800500302 https://doi.org/10.1177/1534484311417562 https://doi.org/10.1177/1534484311417562 https://doi.org/10.1097/01.ccn.0000466774.93177.25 https://doi.org/10.1097/01.ccn.0000466774.93177.25 https://doi.org/10.7861/fhj.2019-0028 https://doi.org/10.1007/s11159-020-09877-4 https://doi.org/10.1007/s11159-020-09877-4 https://doi.org/10.2202/1548-923x.2147 https://doi.org/10.2202/1548-923x.2147 https://doi.org/10.1097/acm.0b013e31819301ab departments of 1clinical physiology and 2medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com delays in presentation by patients with st elevation myocardial infarction a single centre experience from oman suhaib almashari,1 yasir al-malki,1 adil al-riyami,2 *sunil k. nadar2 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 283–287, epub. 26 may 22 submitted 12 nov 20 revision req. 13 jan 21; revision recd. 22 jan 21 accepted 25 feb 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.069 brief communication abstract: objectives: to assess the causes of delay for presentation with st elevation myocardial infarction (stemi). methods: patients who presented with stemi to the emergency department at the sultan qaboos university hospital, muscat, oman between january 2017 and december 2019 and were admitted for primary angioplasty were included in this study. results: a total of 101 patients were included with a mean age of 54.8 + 10.8 years and the majority were male patients (n = 80; 79.2%). the median (interquartile range) pain-to-door time was 60 min (30–120 min). there were 66 (65.4%) patients who arrived within 90 minutes. all except one arrived by privately arranged transport. feeling that the pain was not important (61.0%) or not cardiac (22.8%) were the main reasons for delay. being diabetic was the only patient factor that predicted delay. conclusion: a high proportion of patients presenting to our institution with a stemi arrived within recommended times. however more public education is required to improve awareness about the importance of early evaluation of chest pain. keywords: st elevation myocardial infarction; prehospital emergency care; oman. patients with an st segment elevation myocardial infarction (stemi) constitute a medical emergency.1 it is imperative that such patients are treated as quickly as possible. the european society of cardiology guidelines on the management of stemi recommend that patients are treated with a ‘door-to-balloon’ (dtb) time (time taken from presentation to the emergency department [ed] until the occluded artery is open) of less than 90 minutes.1 all hospitals that provide round the clock access to primary percutaneous coronary interventions (ppci) have mechanisms that would facilitate short dtb times. however, the time taken from the onset of pain to first medical contact, either paramedic in the ambulance or the ed staff or the time from the onset of pain until arriving at a thrombolysis or angioplasty capable hospital for those self-presenting (i.e. ‘painto-door’ [ptd] time) are equally important. several studies have shown that the longer the patient delays presentation, the worse the possible outcomes.2 this has led public health authorities in many countries to study ptd times and evaluate possible factors that could delay patients’ presentation and implement strategies that would improve patient awareness of the need for early presentation.3,4 such data, however, is lacking from the middle-east. previous studies from the region have reported on the delays. but did not evaluate the reasons for delay.5,6 this study aimed to assess the ptd times in patients presenting with a stemi at our institution and to understand the factors that might have caused any delay. methods this was a retrospective study involving patients who presented with a stemi at the sultan qaboos university hospital, muscat, oman, between january 2017 and december 2019. all patients who presented with a stemi and were taken up for primary angioplasty during this period were considered for inclusion in this study. eligible patients were identified and their electronic health records (ehr) were retrieved to acquire the required information. this information included the ptd time, the clinical features, education level and employment status of the patients and mode of transport to the hospital. where information was not available, patients were contacted by telephone for additional information after ascertaining that they were well. we excluded patients where complete data was not available or where we were unable to communicate with them— either due to language differences or unavailability of the contact details. we also excluded patients who had first presented to another hospital and were then transferred to our institute for ppci as their ehr were incomplete. we also excluded patients who developed a stemi whilst admitted in hospital for another medical complaint. the european society of cardiology guidelines recommend a dtb time of 60 minutes for those presenting to a hospital with ppci facilities and 90 minutes for those presenting to hospitals without ppci facilities (including transfer times).1 studies https://creativecommons.org/licenses/by-nd/4.0/ delays in presentation by patients with st elevation myocardial infarction a single centre experience from oman 284 | squ medical journal, may 2022, volume 22, issue 2 have shown that those who present with a pain-toballoon time (time from symptom onset to opening the occluded artery) of less than 180 minutes have the best prognosis.2,7 a cut off time of 90 minutes was therefore used in the analysis to determine those who arrived early or late. statistical analysis was performed using statistical package for the social sciences (spss) version 21 (ibm corp., chicago, illinois, usa). data was presented as number (%), mean + standard deviation or median (interquartile range [iqr]). data analysis was done using chi-squared test or student t-test as appropriate. binary logistic regression was performed to study the factors that affected any delay to presentation. the outcome measure was whether the patient had presented late or not (beyond 90 minutes of chest pain) and the input variables included age, gender, educational and occupational status and premorbid conditions. ethical approval was obtained from the research committee of the sultan qaboos university (#2288). results a total of 268 patients were eligible for the study. however, complete information was available for 101 patients with a mean age of 54.8 + 10.8 years and 80 (79.2%) patients being male. approximately half of the patients were diabetic (55.4%) and hypertensive (51.5%) while dyslipidaemia (73.3%) and smoking (67.3%) were the most common risk factors. the majority of the patients had either anterior (50.5%) or inferior (39.6%) mi [table 1]. a total of 22 (21.8%) patients had attended up to primary school or less, 59 (58.4%) had completed secondary school while 20 (19.8%) had attended university. around half (n = 49; 48.5%) were either unemployed or retired, whilst the remaining (n = 52; 51.5%) were inactive employment. the ptd time ranged from 20 minutes to 25 hours with a median (iqr) of 60 minutes (30–120 minutes). more than half (n = 66) of the patients reached the hospital within the recommended time of 90 minutes since the onset of pain. most of the patients were brought in by a relative or friend (n = 90; 89.1%), while 9 patients drove themselves to the hospital. only one patient had called an ambulance whilst another came by taxi. when analysing the factors that affected the ptd time, the only factor that had a significant difference in the two groups was the presence of diabetes (p = 0.007) [table 2]. the patients who presented late were slightly older but no statistical significance was observed. diabetic patients were more likely to have a delay in reaching the hospital. the gender, previous medical history or other demographic features such as education or employment history were not statistically significant. of those who presented late (n = 35), the main reasons for delay were thinking that this pain was not important (n = 21; 60%) or thinking that it was related to gas or stomach pain (n = 8; 22.8%). five patients (14.2%) did not have anyone to bring them and had to wait for transport while another one patient delayed coming as he was just visiting muscat and was by himself. discussion “time is muscle” is the often quoted dictum guiding the management of patients with stemi.8 there has been a considerable amount of investment of resources and manpower to improve dtb times in patients once they seek medical attention either by the paramedics in the ambulance or by the ed staff. and indeed, many centres have demonstrated falling dtb times over the years.9 yet, a major determinant of outcomes in patients with stemi that remains unchanged is prehospital delays, with patients seeking medical help table 1: clinical features of the patients who presented with a stemi at the sultan qaboos university hospital, muscat, oman, between january 2017 and december 2019 (n = 101) clinical feature n (%) gender male 80 (79.2) female 21 (20.8) site of mi anterior 51 (50.5) inferior 40 (39.6) posterior 4 (4.0) lateral 6 (5.9) diabetes 56 (55.4) hypertensive 52 (51.5) dyslipidaemia 74 (73.3) smoking 68 (67.3) previous mi 9 (8.9) previous pci 17 (16.8) previous cabg 0 (0) positive family history 74 (73.3) mi = myocardial infarction ; pci = percutaneous coronary intervention; cabg = coronary artery bypass grafting. suhaib almashari, yasir al-malki, adil al-riyami and sunil k. nadar brief communication | 285 late after the onset of chest pain. various studies have demonstrated that approximately 40–65% of patients with stemi present more than two hours after the onset of symptoms.10,11 in the current study, the median ptd time was found to be 60 minutes and the majority of patients reached the hospital within 90 minutes. this is very encouraging and reassuring and appears better than published data from the region.5,6 the gulf-heart study, which analysed all acute coronary syndrome from the arabian gulf region, reported a median ptd time of 178 minutes with almost 80% of patients arriving within 12 hours of symptom onset.6 a subsequent study by the same group involving the six gulf countries studying only stemi found a similar median ptd time of 175 minutes but with a higher proportion (90%) of patients arriving within 12 hours of symptom onset.5 another study from jordan in 2015 on 160 patients reported a median ptd time of eight hours where none of the patients presented to hospital within one hour from symptom onset.12 similarly taghaddosi et al. found that 65.5% of patients from iran presented after two hours of symptom onset.13 the shorter ptd times in the current study could reflect better awareness as compared to these former studies. studies have demonstrated that there are multiple factors affecting ptd times.5,10,11,13,14 patients’ perception of chest pain is one of the main reasons for late presentation.12,14 some patients feel that the pain is not severe enough to be a heart attack or that it could be heartburn or indigestion.15,16 this is especially true with diabetic, elderly and female patients. these groups of patients, especially those with diabetes, have been shown to have atypical symptoms and perceive chest pain differently than non-diabetic patients.17,18 in addition, many studies have shown that diabetes, along with female gender and elderly age, are predictors of late diagnosis of mi.17,19 in the current study, it was found that misperception of the pain was the main reason for delay in presentation. furthermore, it was evident that being diabetic was the only predictor of late presentation. therefore, public education should focus on encouraging people to take any form of chest pain seriously and seek medical attention as soon as possible, especially if they have any cardiac risk factors. patients with diabetes should also be made aware that they could perceive chest pain differently. mode of transport has also been implicated in delays in many studies reporting the underuse of ambulance service.5,10 data from the usa obtained from the rapid early action for coronary treatment (react) trial conducted in 20 cities across the country demonstrated that only approximately 23% had called the emergency services, whilst more than 60% came by privately arranged transport and astonishingly 16% had driven themselves.20 in the current study as well, only one patient arrived by ambulance and the rest were brought in by privately arranged transport (relatives, friends, colleagues table 2: characteristics of patients based on whether there was a delay (n = 101) no delay in presentation (n = 66) delay in presentation (n = 35) p value* age (mean ± sd) 53.9 ± 10.3 56.5 ± 10.9 0.25 gender male 52 (78.8) 28 (80.0) 0.88 female 14 (21.2) 7 (20.0) diabetic 23 (34.9) 22 (62.9) 0.007 hypertensive 29 (43.9) 20 (57.1) 0.20 dyslipidemic 19 (28.8) 8 (22.9) 0.52 smoker 22 (33.3) 10 (28.6) 0.66 site of mi anterior 34 (51.5) 17 (48.6) 0.63 inferior 25 (37.9) 15 (42.9) posterior 2 (3.0) 2 (5.7) lateral 5 (7.6) 1 (2.9) previous mi 4 (6.1) 5 (14.3) 0.16 previous pci 11 (16.7) 6 (17.1) 0.95 family history 19 (28.8) 8 (22.9) 0.52 education illiterate or upto primary school 11 (16.7) 11 (31.4) 0.23high school 41 (62.1) 18 (51.4) university graduate 14 (21.2) 6 (17.1) employment unemployed 29 (43.9) 20 (57.1) 0.21 employed 37 (56.1) 15 (42.9) transport by themselves 4 (6.1) 5 (14.3) 0.43 relative/ friend 60 (90.9) 30 (85.8) ambulance 1 (1.5) 0 (0) taxi 1 (1.5) 0 (0) sd = standard deviation; mi = myocardial infarction; pci = percutaneous coro nary intervention. *analysis by student t-test or chi-square test as appropriate. delays in presentation by patients with st elevation myocardial infarction a single centre experience from oman 286 | squ medical journal, may 2022, volume 22, issue 2 or taxi) or even by themselves. in the arabian gulf region, the use of emergency medical service (ems) ambulances is generally low. in the gulf race 3ps study, approximately 25% of patients all over the gulf region and 19% of patients in oman with stemi used the ambulance service.5 this is also similar to findings from a previous study from oman where almost all patients with out-of-hospital cardiac arrest were brought to the hospital by someone known to them.21 this in itself is not harmful, as long as transportation can be arranged quickly. indeed in the current study, proximity to the hospital and the fact that the study was conducted in muscat, where transport could be arranged quickly, could partly explain the low ptd times. retrospective analysis from the react trial showed that patients who were brought in by private transportation arrived quicker than those arriving by ems.22 however, those arriving by ems had earlier treatment as many of them had electrocardiograms done by the ems personnel. in the gulf race 3ps study, as well, those arriving by ems had a longer ptd time, as the ems would take them directly to the pci capable centre rather than the nearest hospital.5 waiting for transport or waiting for someone to be free to bring them to a hospital could potentially add to the delay as was the case with a few of the patients in the current study. the general public should be encouraged to call for ems if private transport is not available. public health education campaigns via electronic media and mass media campaigns have been shown to be useful in improving awareness of a variety of conditions such as diabetes and smoking cessation.23 however, their role in other conditions such as salt reduction have not been as successful.24 there have been studies examining the role of public education campaigns to increase awareness regarding early presentation of chest pain. a study from sweden in the early 1990s demonstrated that mass media campaigns—advertising on the radio, public transport and television—helped to increase the percentage of patients with stemi that were eligible to receive thrombolysis.25,26 the react trial was a randomised control trial in the usa where one city of a predetermined pair, was subjected to 18-months of targeted educational campaigns through various modalities to increase appropriate patient actions for acute myocardial infarction symptoms, while the paired city did not have such an intervention.22 they found that despite this intensive 18 month targeted education, there was no difference in the time from symptom onset to arrival in hospital. however, it significantly increased appropriate ems call outs. nevertheless, it is important to remind patients, especially those who are at high risk for cardiovascular disease, about the importance of not neglecting any type of chest pains and seeking help early. the current study had a few limitations. most of the patients who were eligible for the study had incomplete data and a large number of patients had to be excluded, which could have affected the validity of the study. much of the data was collected retrospectively; however, it was incomplete in many cases and patients had to be contacted by telephone to get additional information. this retrospective collection of data would have brought in some recall bias. similarly, the researchers were unable to contact some eligible patients with incomplete data due to incorrect contact details. finally, this was a single centre study with a small sample size. a nationwide study would be a better representation of different regions in the country. conclusion the majority of patients with a stemi sought medical help within 90 minutes of pain. patient misperception of chest pain was a main reason for delay. larger studies involving other centres and other areas of oman would help gain a better understanding of the true causes of delay in presentation of patients with chest pain. health education programmes for the public are recommended to ensure better recognition of cardiac-related chest pain and also highlight the importance of avoiding delays with chest pain and seeking immediate medical help. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n sa and yam collected the data. skn analysed the data. aar and skn drafted and edited the manuscript. all authors approved the final version of the manuscript. references 1. ibanez b, james s, agewall s, antunes mj, bucciarelli-ducci c, bueno h, et al. 2017 esc guidelines for the management of acute myocardial infarction in patients presenting with stsegment elevation: the task force for the management of acute myocardial infarction in patients presenting with st-segment elevation of the european society of cardiology (esc). eur heart j 2018; 39:119–77. https://doi.org/10.1093/eurheartj/ehx393. https://doi.org/10.1093/eurheartj/ehx393 suhaib almashari, yasir al-malki, adil al-riyami and sunil k. nadar brief communication | 287 2. shiomi h, nakagawa y, morimoto t, furukawa y, nakano a, shirai s, et al. association of onset to balloon and door to balloon time with long term clinical outcome in patients with st elev ation acute myocardial infarction having primary percutaneous coronary intervention: observational study. bmj 2012; 344:e3257. https://doi.org/10.1136/bmj.e3257. 3. alsamara m, degheim g, gholkar g, hiner e, zughaib m. is symptom to balloon time a better predictor of outcomes in acute st-segment elevation myocardial infarction than door to balloon time? am j cardiovasc dis 2018; 8:43–7. 4. pereira h, pinto fj, cale r, pereira e, mello s, vitorino s, et al. the stent for life initiative: factors predicting system delay in patients with st-segment elevation myocardial infarction. rev port cardiol (engl ed) 2018; 37:681–90. https://doi.org/10.10 16/j.repc.2018.01.011. 5. alhabib kf, sulaiman k, al sj, almahmeed w, alsheikh-ali aa, amin h, et al. patient and system-related delays of emergency medical services use in acute st-elevation myocardial infarction: results from the third gulf registry of acute coronary events (gulf race-3ps). plos one 2016; 11:e0147385. https://doi. org/10.1371/journal.pone.0147385. 6. alhabib kf, sulaiman k, al-motarreb a, almahmeed w, asaad n, amin h, et al. baseline characteristics, management practices, and long-term outcomes of middle eastern patients in the second gulf registry of acute coronary events (gulf race-2). ann saudi med 2012; 32:9–18. https://doi.org/10.5144/02564947.2012.9. 7. rollando d, puggioni e, robotti s, de la, ferrari bm, vardanega a, et al. symptom onset-to-balloon time and mortality in the first seven years after stemi treated with primary percutaneous coronary intervention. heart 2012; 98:1738–42. https://doi. org/10.1136/heartjnl-2012-302536. 8. gibson cm, de lemos ja, antman em. time is muscle in primary pci: the strength of the evidence grows. eur heart j 2004; 25:1001–2. https://doi.org/10.1016/j.ehj.2004.04.029. 9. yudi mb, hamilton g, farouque o, andrianopoulos n, duffy sj, lefkovits j, et al. trends and impact of door-to-balloon time on clinical outcomes in patients aged <75, 75 to 84, and ≥85 years with st-elevation myocardial infarction. am j cardiol 2017; 120:1245–53. https://doi.org/10.1016/j.amjcard.2017.07.005. 10. beig jr, tramboo na, kumar k, yaqoob i, hafeez i, rather fa, et al. components and determinants of therapeutic delay in patients with acute st-elevation myocardial infarction: a tertiary care hospital-based study. j saudi heart assoc 2017; 29:7–14. https://doi.org/10.1016/j.jsha.2016.06.001. 11. saczynski js, yarzebski j, lessard d, spencer fa, gurwitz jh, gore jm, et al. trends in prehospital delay in patients with acute myocardial infarction (from the worcester heart attack study). am j cardiol 2008; 102:1589–94. https://doi.org/10.1016/j.amj card.2008.07.056. 12. darawad mw, alfasfos n, saleh z, saleh am, hamdan-mansour a. predictors of delay in seeking treatment by jordanian patients with acute coronary syndrome. int emerg nurs 2016; 26:20–5. https://doi.org/10.1016/j.ienj.2015.09.003. 13. taghaddosi m, dianati m, fath gharib bj, bahonaran j. delay and its related factors in seeking treatment in patients with acute myocardial infarction. arya atheroscler 2010; 6:35–41. 14. novak k, aljinovic j, kostic s, capkun v, novak rk, batinic t, et al. pain to hospital times after myocardial infarction in patients from dalmatian mainland and islands, southern croatia. croat med j 2010; 51:423–31. https://doi.org/10.3325/cmj.2010.51.423. 15. berman n, jones mm, de coster da. 'just like a normal pain', what do people with diabetes mellitus experience when having a myocardial infarction: a qualitative study recruited from uk hospitals. bmj open 2017; 7:e015736. https://doi.org/10.1136/ bmjopen-2016-015736. 16. goel pk, srivastava sk, ashfaq f, gupta pr, saxena pc, agarwal r, et al. a study of clinical presentation and delays in management of acute myocardial infarction in community. indian heart j 2012; 64:295–301. https://doi.org/10.1016/s0019-4832(12)60090-x. 17. poorhosseini h, saadat m, salarifar m, mortazavi sh, geraiely b. pre-hospital delay and its contributing factors in patients with st-elevation myocardial infarction; a cross sectional study. arch acad emerg med 2019; 7:e29. 18. sharma a, sekaran nk, coles a, pagidipati nj, hoffmann u, mark db, et al. impact of diabetes mellitus on the evaluation of stable chest pain patients: insights from the promise (prospective multicenter imaging study for evaluation of chest pain) trial. j am heart assoc 2017; 6:e007019. https://doi.org/10.1161/ jaha.117.007019. 19. jager b, farhan s, rohla m, christ g, podczeck-schweighofer a, schreiber w, et al. clinical predictors of patient related delay in the vienna st-elevation myocardial infarction network and impact on long-term mortality. eur heart j acute cardiovasc care 2017; 6:254–61. https://doi.org/10.1177/2048872616633882. 20. brown al, mann nc, daya m, goldberg r, meischke h, taylor j, et al. demographic, belief, and situational factors influencing the decision to utilize emergency medical services among chest pain patients. rapid early action for coronary treatment (react) study. circulation 2000; 102:173–8. https://doi.org/10.1161/01. cir.102.2.17. 21. nadar sk, mujtaba m, al-hadi h, sadiq m, al-riyami a, ali m, et al. epidemiology, outcomes and coronary angiography findings of patients following out-of-hospital cardiac arrest: a singlecentre experience from oman. sultan qaboos univ med j 2018; 18:e155–60. https://doi.org/10.18295/squmj.2018.18.02.006. 22. luepker rv, raczynski jm, osganian s, goldberg rj, finnegan jr, jr., hedges jr, et al. effect of a community intervention on patient delay and emergency medical service use in acute coronary heart disease: the rapid early action for coronary treatment (react) trial. jama 2000; 284:60–7. https://doi.org/10.1001/ jama.284.1.60. 23. wakefield ma, loken b, hornik rc. use of mass media campaigns to change health behaviour. lancet 2010; 376:1261–71. https:// doi.org/10.1016/s0140-6736(10)60809-4. 24. trieu k, mcmahon e, santos ja, bauman a, jolly ka, bolam b, et al. review of behaviour change interventions to reduce population salt intake. int j behav nutr phys act 2017; 14:17. https://doi.org/10.1186/s12966-017-0467-1. 25. blohm m, herlitz j, hartford m, karlson bw, risenfors m, luepker rv, et al. consequences of a media campaign focusing on delay in acute myocardial infarction. am j cardiol 1992; 69:411–13. https://doi.org/10.1111/j.1365-2796.1991.tb00439.x. 26. herlitz j, blohm m, hartford m, karlson bw, luepker r, holmberg s, et al. follow-up of a 1-year media campaign on delay times and ambulance use in suspected acute myocardial infarction. eur heart j 1992; 13:171–7. https://doi.org/10.1093/ oxfordjournals.eurheartj.a060142. https://doi.org/10.1136/bmj.e3257 https://doi.org/10.1016/j.repc.2018.01.011 https://doi.org/10.1016/j.repc.2018.01.011 https://doi.org/10.1371/journal.pone.0147385 https://doi.org/10.1371/journal.pone.0147385 https://doi.org/10.5144/0256-4947.2012.9 https://doi.org/10.5144/0256-4947.2012.9 https://doi.org/10.1136/heartjnl-2012-302536 https://doi.org/10.1136/heartjnl-2012-302536 https://doi.org/10.1016/j.ehj.2004.04.029 https://doi.org/10.1016/j.amjcard.2017.07.005 https://doi.org/10.1016/j.jsha.2016.06.001 https://doi.org/10.1016/j.amjcard.2008.07.056 https://doi.org/10.1016/j.amjcard.2008.07.056 https://doi.org/10.1016/j.ienj.2015.09.003 https://doi.org/10.3325/cmj.2010.51.423 https://doi.org/10.1136/bmjopen-2016-015736 https://doi.org/10.1136/bmjopen-2016-015736 https://doi.org/10.1016/s0019-4832(12)60090-x https://doi.org/10.1161/jaha.117.007019 https://doi.org/10.1161/jaha.117.007019 https://doi.org/10.1177/2048872616633882 https://doi.org/10.1161/01.cir.102.2.17 https://doi.org/10.1161/01.cir.102.2.17 https://doi.org/10.18295/squmj.2018.18.02.006 https://doi.org/10.1001/jama.284.1.60 https://doi.org/10.1001/jama.284.1.60 https://doi.org/10.1016/s0140-6736(10)60809-4 https://doi.org/10.1016/s0140-6736(10)60809-4 https://doi.org/10.1186/s12966-017-0467-1 https://doi.org/10.1111/j.1365-2796.1991.tb00439.x https://doi.org/10.1093/oxfordjournals.eurheartj.a060142 https://doi.org/10.1093/oxfordjournals.eurheartj.a060142 submitted 1 mar 22 1 revisions req. 18 apr, 9 jun & 30 jun 22; revisions recd. 20 may, 23 jun & 1 2 aug 22 3 accepted 10 aug 22 4 online-first: august 2022 5 doi: https://doi.org/ 10.18295/squmj.8.2022.052 6 7 severe neonatal presentation of progressive familial intrahepatic cholestasis type 4 in an 8 omani infant 9 samira al housni,1 khalid al-thihli,2 dafalla rahmatalla,3 10 yasser wali,3 *yusriya al rawahi3 11 12 1 pediatric department, oman medical specialty board, muscat, oman; 2 department of genetics, sultan 13 qaboos university hospital, sultan qaboos university, muscat, oman; 3 child health department, 14 sultan qaboos university hospital, sultan qaboos university, muscat, oman. 15 *corresponding author’s e-mail: yusria@squ.edu.om 16 17 abstract 18 progressive familial intrahepatic cholestasis type 4 (pfic4) is a relatively newly described 19 autosomal recessive disorder caused by biallelic mutations in the gene encoding tight junction 20 protein 2 (tjp2) which is located in chromosome 9q21. pfic4 is characterized by cholestasis 21 with or without other extrahepatic manifestations. bleeding tendency due to vitamin k deficiency 22 is a well-known complication of cholestasis. we present a neonate who presented with 23 cholestasis and multiple intracranial bleeds. he was found to have severe coagulopathy and his 24 genetic work up revealed a homozygous variant mutation in tjp2 gene causing pfic4. he had 25 persistent cholestasis that necessitated an internal biliary diversion with some clinical 26 improvement. 27 keywords: jaundice; intracranial haemorrhage; progressive familial intrahepatic cholestasis 28 type 4 29 30 introduction 31 hereditary cholestasis is a group of rare autosomal recessive liver disorders, which are caused by 32 defects in genes related to the secretion and transport of bile salts and lipids. it is characterized 33 by intrahepatic cholestasis, pruritus, jaundice and malabsorption.1 progressive familial 34 intrahepatic cholestasis (pfic) is one of the phenotypic manifestations of hereditary cholestasis 35 with onset in early infancy that can progress to end-stage liver disease. it accounts for 10-15% of 36 the causes of cholestasis in pediatric patients and is the cause of 10-15% of liver transplants in 37 this population.1,2 pfic types 1 and 2 usually present in infancy as infantile cholestasis 38 characterized by low to normal gamma-glutamyl transferase (ggt). however, pfic type 3 39 presents in older children and it is associated with high ggt.3 with advancement and increasing 40 availability of genetic testing technologies rare types of pfic are becoming recognized over the 41 past decade. 4 pfic type 4 is a newly described clinical entity caused by biallelic mutations in 42 tjp2. the clinical spectrum of this condition has not been fully elucidated. we report a neonate 43 who presented with jaundice and severe coagulopathy at the age of 3 weeks and was found to 44 have a homozygous nm_004817.3:c.2417g>a, p.trp806ter,pathogenic variant in the tjp2 45 gene. 46 47 case report 48 a one-month-old boy presented to the emergency department at a tertiary care hospital with 49 one-week history of progressive jaundice, poor feeding, dark discoloration of the urine and 2 50 days history of irritability. there was no history of acholic stools, vomiting, fever or any 51 drug/herbal medicine intake. the patient was born to apparently healthy parents related as first 52 cousins. he was delivered at 36 weeks of gestation via normal vaginal delivery with birth weight 53 of 1.9 kg (< 3rd percentile), length of 47cm and head circumference of 31cm (<3rd percentile). 54 mother had gestational diabetes mellitus (gdm). the patient has 2 healthy older siblings (figure 55 1). there was no family history of unexplained death, liver disease, bleeding disorders, or 56 malignancy. 57 58 physical examination revealed an irritable, pale infant with generalized icterus. his growth 59 parameters were below the third percentile (weight 2.5 kg, z-score -2.9, and length 48 cm, z-60 score -2.8). he had no dysmorphic features. his anterior fontanelle was full and pulsatile. his 61 pupils were equal and reactive to light. he had no focal neurological deficit. his abdominal 62 examination revealed a firm palpable liver 2 cm below the right costal margin. there was no 63 clinical splenomegaly or ascites. he had no cutaneous findings suggestive of bleeding tendency. 64 65 investigations revealed severe anemia with hemoglobin 3.8 g/dl (10-14), high reticulocytes 5% 66 (0.2-2) and low hematocrit of 0.12 l/l (0.33-0.39). lactate dehydrogenase (ldh) was elevated 67 at 782 u/l (120-300). coagulation profile showed markedly prolonged pt and aptt with high 68 inr of > 17.4 (0.9-1.12). liver chemistry demonstrated conjugated hyperbilirubinemia with 69 raised transaminases and normal gamma-glutamyl transferase (ggt). total bilirubin was 237 70 umol/l (0-17) and 84% of it was conjugated, alanine aminotransferase (alt) 79 u/l (normal 71 <40), aspartate aminotransferase (ast) 261u/l (normal <41), and ggt 36 u/l (normal <200) 72 (table 1). metabolic workup including, newborn metabolic screen, urine reducing substances, 73 ammonia and ck level were all normal. investigations for infective and endocrine causes were 74 all negative. brain magnetic resonant image (mri) showed intracranial bleed with multiple 75 parenchymal, intraventricular and extra-axial hemorrhages. the liver appeared of normal size 76 and echotexture on ultrasound examination of the abdomen, and remained so on follow up 77 examination during the neonatal period. 78 79 the patient was intubated and mechanically ventilated and kept on brain protective measures. he 80 received packed red blood cells and fresh frozen plasma. he was also commenced on 81 intravenous vitamin k. cefotaxime and ampicillin were initiated to cover the possibility of 82 infections. he developed a generalized tonic-clonic seizure and was started on phenobarbital. he 83 did not require any surgical intervention. his coagulation profile improved the following day and 84 he was extubated after 2 days. the intracranial bleeding was clinically attributed to a late onset 85 vitamin k deficiency with superimposed cholestatic liver disease. as the patient had normal 86 ggt and the initial work up for neonatal cholestasis were negative, pfic and bile acid synthetic 87 defects were the main differential diagnosis. he underwent ultrasound guided liver biopsy, and 88 the histopathology revealed marked cholestasis with bile plugs along with feathery degeneration 89 and rosetting (fig 2a &b). whole exome sequencing revealed a homozygous 90 nm_004817.3:c.2417g>a, p.trp806ter pathogenic variant in in the tjp2 gene, consistent with 91 a diagnosis of pfic 4. he was also found to have a heterozygous likely pathogenic c.1642g>t 92 (p.glu548ter) variant in itgb3 gene (nm_000212.3). parental heterozygosity for the variant in 93 tjp2 was confirmed. the variant in itgb3 was proven to be paternally inherited. biallelic 94 pathogenic variants in this gene are related to autosomal recessive glanzmann thrombasthenia 95 type 2. 96 97 the patient was commenced on ursodeoxycholic acid and fat-soluble vitamin supplements. after 98 discharge, he continued taking ursodeoxycholic acid, fat-soluble vitamin supplements and 99 phenobarbital. he was kept on breastfeeds and medium-chain triglyceride-based formula. he 100 remains seizure free and the repeated electroencephalogram (eeg) was normal. at age of 9 101 months he underwent internal biliary diversion. when he was last assessed at the age of 11 102 months, he was able to cruise around objects, but still unable then to stand alone. he was able to 103 drink from a cup. he had monosyllables, and he recognized his siblings by their names. he had 104 no seizures. he remained clinically jaundiced with no pruritus. his weight was 5.4 kg (z-score -105 5), length was 64 cm (z-score -3 sd). his liver chemistry has improved gradually (table 1). 106 the family consented for publication of this case report. 107 108 discussion 109 pfic4 is among the most recently described forms of pfic, and it is caused by mutations in the 110 tight junction protein-2 (tjp2) gene.5 so far, a few cases of pfic4 have been reported 111 worldwide.4,6 to the best of our knowledge, this is the first report of an arab patient with severe 112 neonatal presentation of pfic4. 113 114 truncating variants, as seen in the patient we describe, are known to be causative of tjp2-115 related pfic4.7 a total of 15 nonsense variants have been described in tjp2 so far.4,8 patients 116 with pfic4 present with severe progressive cholestasis during infancy or early childhood. they 117 are also at a higher risk of acquiring hepatocellular carcinoma.8 serum ggt activity is typically 118 normal or low. in addition to cholestasis, extrahepatic features have been identified in pfic4 119 patients, including respiratory and neurological disorders.6 the mechanism of cholestasis in 120 pfic 4 is due inappropriate function of the tight junction’s protein at the hepatocytes. that 121 results in leakage of cytotoxic bile salts into the paracellular space, causing damage to the 122 surrounding liver cells.9 the purpose of the biliary diversion surgery is to bypass the 123 enterohepatic circulation, thereby lowering the amount of bile salts that are reabsorbed by the 124 terminal ilium. these surgeries sometimes have led to improvement in some pfic patients.9 the 125 patient we report so far has no extra-hepatic manifestations, and although the afp and 126 ultrasonographic appearance of the liver are not suggestive of malignancy at present, the concern 127 about future development of hepatocellular carcinoma (hcc) in this child cannot be excluded. 128 despite the small number of patients with disorder reported so far, age-dependent penetrance of 129 some mutations and notable clinical variabilities in some families have already been 130 recognized.10 131 132 the patient we report had a severe neonatal presentation with coagulopathy and multiple 133 intracranial bleeds. this maybe explained on the basis of cholestatic liver disease and vitamin k 134 deficiency, particularly owing to the drastic improvement in coagulopathy with the supportive 135 therapy and vitamin k administration. however, the possible contribution of the heterozygous 136 likely pathogenic variant identified in the itgb3 gene to the severity of coagulopathy arguably 137 has some legitimate ground. both dominant and recessive phenotypes associated with 138 coagulopathy have been described in relation to this gene.11-13 although the variant identified 139 was inherited from an asymptomatic parent the possibility of this variant being dominant with 140 variable penetrance cannot be excluded. 141 142 given the poorly defined risk of hepatocellular carcinoma and lack of reliable clinical predictors 143 of this complication among patients with pfic4, the patient is under close follow up and 144 monitoring with low threshold for consideration of liver transplantation when clinically merited. 145 146 conclusion 147 in summary, our patient is the first reported patient with pfic 4 in the arab population. this 148 case reports highlights few important points. first, for any neonate with normal ggt cholestasis, 149 pfic is a potential differential diagnosis and pfic4 is among the most recently described forms 150 of pfic. secondly, late onset vitamin k deficiency bleeding can be secondary to fat-soluble 151 vitamin malabsorption due to neonatal cholestasis. thirdly, tjp2 gene mutation have been 152 reported to be associated with hepatocellular carcinoma, hence it is important to closely monitor 153 pfic4 patients from this perspective. 154 155 author contribution 156 this manuscript has been contributed to, seen and approved by all the authors. all the authors 157 fulfill the authorship credit requirements. samira al housni, khalid al-thihli, dafalla 158 rahmatalla, yasser wali and yusriya al rawahi wrote the first draft of this manuscript. khalid 159 al-thihli, yasser wali and yusriya al rawahi were involve in revising the manuscript. 160 161 references 162 1. gaur k, sakhuja p. progressive familial intrahepatic cholestasis: a comprehensive review 163 of a challenging liver disease. indian j pathol microbiol. 2017;60(1):2-7. doi: 164 10.4103/0377-4929.200040. pmid: 28195083. 165 2. torfenejad p, geramizadeh b, haghighat m, dahghani sm, zahmatkeshan m, honar n, 166 et al. progressive familial intrahepatic cholestasis and its subtypes: the first report 167 from iran. iran j pediatr. 2016; 26(6):e6497. doi: 10.5812/ijp.6497 168 3. srivastava a. progressive familial intrahepatic cholestasis. j clin exp hepatol 2014; 169 4:25–36.doi: 10.1016/j.jceh.2013.10.005 170 4. sambrotta m, strautnieks s, papouli e, rushton p, clark be, parry da, et al. mutations 171 in tjp2 cause progressive cholestatic liver disease. nat genet. 2014;46: 326-328. 172 doi: 10.1016/j.jceh.2013.10.005 173 5. vitale g, gitto s, vukotic r, raimondi f, andreone p. familial intrahepatic cholestasis: 174 new and wide perspectives. dig liver dis. 2019;51(7):922-933. 175 doi: 10.1016/j.dld.2019.04.013 176 6. sticova e, jirsa m, pawłowska j. new insights in genetic cholestasis: from molecular 177 mechanisms to clinical implications. can j gastroenterol hepatol. 2018; 26: 2313675. 178 doi: 10.1155/2018/2313675 179 7. https://www.ncbi.nlm.nih.gov/clinvar/?term=tjp2[gene]. last accessed may 14, 2022. 180 8. zhou s, hertel pm, finegold mj, wang l, kerkar n, wang j et al. hepatocellular 181 carcinoma associated with tight-junction protein 2 deficiency. hepatology .2015 182 ;62(6):1914-1916. doi: 10.1002/hep.27872 183 9. amirneni s, haep n, gad ma, soto-gutierrez a, squires je, florentino rm. molecular 184 overview of progressive familial intrahepatic cholestasis. world j gastroenterol. 185 2020;26(47):7470-7484. doi:10.3748/wjg.v26.i47.7470 186 http://dx.doi.org/10.5812/ijp.6497 https://doi.org/10.1016/j.jceh.2013.10.005 https://doi.org/10.1016/j.dld.2019.04.013 https://doi.org/10.1155/2018/2313675 https://doi.org/10.1002/hep.27872 10. wei cs, becher n, friis jb, ott p, vogel i, grønbæk h. new tight junction protein 2 187 variant causing progressive familial intrahepatic cholestasis type 4 in adults: a case report. 188 world j gastroenterol. 2020;26(5):550-561. doi: 10.3748/wjg.v26.i5.550 189 11. nurden at, fiore m, nurden p, pillois x. glanzmann thrombasthenia: a review of 190 itga2b and itgb3 defects with emphasis on variants, phenotypic variability, and mouse 191 models. blood. 2011; 118 (23): 5996–6005. doi: https://doi.org/10.1182/blood-2011-07-192 365635 193 12. nurden at, pillois x, fiore m, alessi mc, bonduel m, dreyfus m, et al. expanding the 194 mutation spectrum affecting αiibβ3 integrin in glanzmann thrombasthenia: screening of 195 the itga2b and itgb3 genes in a large international cohort. hum mutat. 2015 196 may;36(5):548-61. doi: 10.1002/humu.22776 197 13. bury, l., zetterberg, e., leinøe, e. b., falcinelli, e., marturano, a., manni, g, et al. a 198 novel variant glanzmann thrombasthenia due to co-inheritance of a lossand a gain-of-199 function mutation of itgb3: evidence of a dominant effect of gain-of-function mutations. 200 haematologica. 2018 jun;103(6):e259-e263. doi: 10.3324/haematol.2017.180927 201 table 1: the patient blood tests over 11 months period. 202 biochemical parameter reference value at admission age 2 months age 3 months age 4 months age 8 months age 11 months total bilirubin 0-17 umol/l 269 23 132 110 302 58 direct bilirubin 0-4 237 203 122 99 81 56 alt 0-41 u/l 79 488 111 63 207 102 ast 0-40 u/l 261 768 130 86 309 164 ggt < 203 u/l 36 47 35 36 27 31 inr 0.9-1.1 17.4 1.1 1.06 1.06 1.17 1.2 afp 0-7 kiu/l 1934 nd nd nd 116 20 albumin 38-54 g/l 28 32 39 42 39 33 hemoglobin 10-14 g/dl 3.8 9.1 10.6 11.7 11.3 10.9 alt, alanine transaminase; afp; alpha-fetoprotein, ast, aspartate transaminase; ggt, gamma 203 glutamyl transferase; inr, international normalized ratio, nd; not done. 204 205 206 https://dx.doi.org/10.3748%2fwjg.v26.i5.550 https://doi.org/10.1182/blood-2011-07-365635 https://doi.org/10.1182/blood-2011-07-365635 https://dx.doi.org/10.3324%2fhaematol.2017.180927 207 figure 1: family pedigree of the patient. 208 209 210 211 figure 2a: h&e stain of the liver biopsy demonstrating cholestasis with bile plugs (green 212 arrow) along with feathery degeneration (red arrow) and rosetting. 213 214 215 216 figure 2b: h&e stain of the liver biopsy demonstrating feathery degeneration (red arrow). 217 1department of pediatric intensive care, royal hospital, muscat, oman; 2department of research, oman medical specialty board, muscat, oman *corresponding author’s e-mail: dr.samishaikh@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: a modified blalock-taussig (mbt) shunt procedure is a common palliative surgery used to treat infants and children with cyanotic congenital heart disease (cchd). this study aimed to report the outcomes of infants and children undergoing mbt shunt procedures in oman. in addition, risk factors associated with early mortality, inter-stage mortality and reintervention were assessed. methods: this retrospective cohort study was conducted from january 2016 to december 2018 at the national heart centre, muscat, oman. all paediatric patients with cchd undergoing mbt shunt procedures as a primary palliative procedure during this period were included. data were retrieved from electronic hospital records. kaplan-meier survival curves were used to describe overall survival. results: a total of 50 infants and children were included in this study. the in-hospital mortality and interstage mortality rates were 10% and 6.7%, respectively. preoperative mechanical ventilation (odds ratio [or] = 3.00, 95% confidence interval [ci]: 1.98–4.76; p = 0.007) and cardiopulmonary bypass (or = 4.09, 95% ci: 2.44–6.85; p = 0.002) were significant risk factors for early mortality. in-hospital and interval surgical reintervention rates were 12% and 13.3%, respectively. following the primary shunt procedure, the median time to second-stage surgery was 15.5 months (range: 5.0–34.0 months). conclusion: the findings of this study support those reported in international research regarding the risks associated with mbt shunt surgeries. in particular, preoperative mechanical ventilation and cardiopulmonary bypass were significant risk factors for early mortality. keywords: pediatrics; congenital heart diseases; cardiovascular surgical procedures; modified blalock-taussig procedure; patient outcome assessment; hospital mortality; risk factors; oman. outcomes of infants undergoing modified blalock-taussig shunt procedures in oman a retrospective study *samiuddin shaikh,1 khaloud s. al-mukhaini,1 abdul hakeem al-rawahi,2 omer al-dafie1 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 457–464, epub. 29 aug 21 submitted 9 may 20 revision req. 9 jul 20; revision recd. 6 aug 20 accepted 26 aug 20 https://doi.org/10.18295/squmj.8.2021.125 clinical & basic research advances in knowledge outcomes following modified blalock-taussig (mbt) shunt procedures vary worldwide. to the best of the authors’ knowledge, this is the first study to report outcomes following mbt shunt procedures performed in oman. this study identifies various risk factors for mortality following this procedure in the local population. these findings provide a baseline for future comparative analysis at both the regional and international level. application to patient care knowledge of likely outcomes following mbt shunt procedures in a local setting will be useful to help the parents of infants and children with cyanotic congenital heart disease make informed treatment choices. moreover, the findings of this study may result in modifications to clinical practice, thereby improving outcomes. in particular, certain high-risk patient categories warrant extra vigilance, such as those requiring preoperative mechanical ventilation or intraoperative cardiopulmonary bypass. in oman, the incidence of congenital heartdisease is approximately 7.1 per 1,000 live births; of these, 21.7% are diagnosed with cyanotic congenital heart disease (cchd).1 many infants with cchd and inadequate pulmonary blood flow require palliative interventions early in life in order to alleviate severe cyanosis.2 these include maintaining the patency of the ductus arteriosus, either by using a cardiac catheter to percutaneously insert a stent or by surgically creating a systemic-to-pulmonary artery shunt.3 a modified blalock-taussig shunt (mbt) is the most common type of systemic-to-pulmonary artery shunt wherein the ipsilateral innominate or subclavian artery is connected to the pulmonary artery using a prosthetic graft made of polytetrafluoroethylene.3 however, despite considerable improvements in congenital heart surgery in recent years, mbt shunt procedures are still associated with significant morbidity and mortality.4–6 for instance, in-hospital mortality rates following mbt shunt procedures range from 7.3–9.8%.4,5 moreover, even after discharge, between 5–13.9% of patients do not survive long enough to undergo the next stage of surgery in the form of a glenn shunt or total correction procedure.5,6 various risk factors have been identified as resulting in worse outcomes for patients receiving mbt shunts, including the age and weight of the child at the time of surgery, the size of the shunt, pulmonary atresia with intact ventricular septum https://creativecommons.org/licenses/by-nd/4.0/ outcomes of infants undergoing modified blalock-taussig shunt procedures in oman a retrospective study 458 | squ medical journal, august 2021, volume 21, issue 3 (paivs) and preoperative shock or acidosis.5,7–9 the immediate postoperative period following insertion of the mbt shunt is when the patient is most vulnerable. according to petrucci et al., 33% of deaths in neonates undergoing mbt shunt procedures occurred within 24 hours of surgery, with 75% occurring within the first month.10 moreover, the procedure can result in complications such as pulmonary overcirculation (30%) and shunt failure including shunt thrombosis or stenosis (8–23%).11,12 risk factors for shunt failure include the use of small shunts or a central shunt, as well as postoperative extracorporeal membrane oxygenation (ecmo) support.11,12 to the best of the authors’ knowledge, no established data have yet been reported regarding the outcomes of mbt shunt procedures among paediatric cases in oman, particularly in terms of morbidity and mortality. as such, this study aimed to determine outcomes of infants with cchd following mbt shunt procedures in oman and evaluate risk factors associated with early mortality, inter-stage mortality and reintervention. methods this retrospective cohort study was conducted from january 2016 to december 2018 at the national heart centre in muscat, oman. this centre receives referrals from all over the country for infants and children with congenital heart diseases who require assessment, surgical intervention or cardiac catheterisation. all neonates and infants who underwent mbt shunt procedures as a primary palliative procedure during the study period were identified using the surgical database. patients were excluded if they had undergone mbt shunt surgeries as part of a norwood procedure—i.e. an aortic arch reconstruction plus atrial septectomy and mbt shunt or a right ventricleto-pulmonary artery conduit, usually performed in cases of hypoplastic left heart syndrome—or to alleviate hypoxia after pulmonary artery banding. information regarding the patients’ demographic characteristics, underlying anatomical details, surgical notes, postoperative clinical notes, outpatient followup visits and outcome data were collected from the surgical database and electronic hospital record system. patients were classified as duct-dependent if they required an infusion of prostaglandins to ensure ductus arteriosus patency and/or if the patent ductus arteriosus was the main source of pulmonary blood flow. all patients were followed-up either until they underwent the next stage of surgery—consisting of either a total correction or stage 2 palliation (i.e. a glenn procedure)—or for a minimum of one year after the index procedure (i.e. december 2019). data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the outcome variables of interest included early mortality, inter-stage mortality and survival to next stage of surgery. early mortality was defined as mortality occurring within 30 days of the index operation, while inter-stage mortality (i.e. interval mortality) was defined as mortality occurring between 30 days after the index operation and the next surgical stage. survival to the second stage of surgery was defined as survival from the initial surgery to the next planned surgical intervention. categorical variables were presented as frequencies and percentages, while continuous variables were presented as medians and interquartile ranges (iqrs). kaplan-meier survival curves were used to describe overall survival. univariate associations were assessed using a chi-squared test, along with odds ratios (ors) and 95% confidence intervals (cis) wherever applicable. a p value of <0.050 was considered statistically significant. ethical approval for this study was obtained through the institutional ethical approval board of the royal hospital as well as the centre of studies and research of the ministry of health in oman (src#120/2018 code #9368). the need for patient consent was waived in view of the retrospective nature of the study. results a total of 50 paediatric patients with cchd underwent mbt shunt procedures as a first palliative surgery during the study period. the primary indication for the procedure was to provide a stable source of pulmonary blood flow sufficient to maintain systemic oxygen saturation (spo2) at 75–85%. the median age at surgery was 22.5 days (iqr: 7.2–90.0 days) and the median weight was 3.2 kg (iqr: 2.7–4.2 kg). over half of the patients (n = 26; 52%) were neonates (i.e. ≤28 days old). the underlying diagnosis was either single ventricle (n = 25; 50%) or biventricular (n = 25; 50%) defects. a total of 20 patients (40%) received preoperative mechanical ventilation. nine patients (18%) had previously undergone failed attempts at cardiac catheterisation (e.g. ductal stents) prior to the mbt shunt procedure [table 1]. among those with single ventricle defects, the majority had paivs (n = 7; 28%), followed by tricuspid atresia and pulmonary atresia (n = 4; 16%), tricuspid atresia and restrictive ventricular septal defect (vsd; samiuddin shaikh, khaloud s. al-mukhaini, abdul hakeem al-rawahi and omer al-dafie clinical and basic research | 459 n = 4; 16%), unbalanced atrioventricular septal defect (avsd) and hypoplastic right ventricle (n = 2; 8%), pulmonary atresia and double-inlet left ventricle (n = 2; 8%), pulmonary atresia with avsd and total anomalous pulmonary venous connection (n = 2; 8%) and other defects (n = 4; 16%). for those with biventricular defects, the most common underlying diagnosis was pulmonary atresia and vsd (n = 10; 40%), followed by tetralogy of fallot (n = 7; 28%), dextro-transposition of the great arteries with vsd and pulmonary stenosis (n = 3; 12%), avsd and tetralogy of fallot (n = 2; 8%) and other defects (n = 3; 12%). a sternotomy was the most common approach for the surgery (n = 45; 90%). a total of 16 patients (32%) required cardiopulmonary bypass during the shunt procedure due to haemodynamic instability or for other concomitant procedures. the innominate or subclavian artery was used as the proximal arterial connection in 35 cases (70%). the median shunt size was 4 mm (range: 3–5 mm), with a mean shunt-toweight ratio of 1.25 in neonates. the median duration of mechanical ventilation, length of stay in intensive care and total length of postoperative hospital stay was two days (range: 0–19 days), six days (range: 1–31 days) and 13 days (range: 1–76 days), respectively [table 2]. upon arrival to intensive care, all patients received an infusion of unfractionated heparin and were subsequently transitioned to low-dose aspirin once they could be fed enterally. after the primary shunt procedure, three patients (6%) required ecmo support and six (12%) had to undergo shunt revision during the same hospitalisation period. a total of five patients died within 30 days of the index operation; subsequently, three of the remaining 45 patients died after discharge but before the second table 1: baseline characteristics of infants and children with cyanotic congenital heart disease undergoing modified blalock-taussig shunt procedures in oman (n = 50) characteristic n (%) age in days at time of surgery ≤28 26 (52) >28 24 (48) median (iqr) 22.5 (7.2–90.0) gender male 27 (54) female 23 (46) weight in kg at time of surgery <2.5 7 (14) ≥2.5 43 (86) median (iqr) 3.2 (2.7–4.2) underlying diagnosis single ventricle defect 25 (50) biventricular defect 25 (50) circulation status duct-dependent 30 (60) non-duct-dependent 20 (40) preoperative mechanical ventilation yes 20 (40) no 30 (60) preoperative acidosis* yes 9 (18) no 41 (82) unsuccessful preoperative cardiac catheter interventions yes 9 (18) no 41 (82) iqr = interquartile range. *defined by an arterial blood ph value of <7.3. table 2: surgical details and outcomes of infants and children with cyanotic congenital heart disease undergoing modified blalock-taussig shunt procedures in oman (n = 50) variable n (%) surgical approach sternotomy 45 (90) thoracotomy 5 (10) cardiopulmonary bypass yes 16 (32) no 34 (68) arterial connection innominate/subclavian 35 (70) other 15 (30) other surgical/non-surgical details median shunt size in mm (range) 4 (3–5) mean postoperative spo2 in % ± sd 82.6 ± 6.3 median duration of postoperative mv in days (range) 2 (0–19) median duration of icu stay in days (range) 6 (1–31) median duration of hospital stay in days (range) 13 (1–76) median age at second-stage surgery in months (range) 15.5 (5–34) spo2 = oxygen saturation; sd = standard deviation; mv = mechanical ventilation; icu = intensive care unit. outcomes of infants undergoing modified blalock-taussig shunt procedures in oman a retrospective study 460 | squ medical journal, august 2021, volume 21, issue 3 stage surgery, resulting in early mortality and interstage mortality rates of 10% and 6.7%, respectively. of the five early mortalities, four (80%) had single ventricle defects and one (20%) had biventricular defects. the biventricular patient died due to myocardial dysfunction and low cardiac output syndrome on the sixth postoperative day. among the four early mortalities in the single ventricle group, two (50%) died due to myocardial dysfunction, one (25%) due to septic shock and one (25%) due to preoperative hypoxic-ischaemic encephalopathy and cardiac arrest during an attempt at ductal stenting. all three patients who died during the inter-stage period had single ventricle defects; of these one (33.3%) died due to a chest infection and sepsis, while cause of death could not be determined in the other two patients (66.7%) as they died at home. during the inter-stage period, in addition to the three patients (6.7%) who died, one patient (2.2%) was labelled as not suitable for further surgeries and three patients (6.7%) were lost to follow-up. the median interval before the second stage of surgery was 15.5 months (range: 5.0–34.0 months). overall, 11 patients (24.4%) who survived >30 days from the index operation required reintervention in the form of either surgical shunt revision (n = 6; 54.5%) or catheter interventions (n = 5; 45.5%). most of these interventions were performed for patients with biventricular defects (n = 9; 81.8%) and those with an underlying diagnosis of pulmonary atresia and vsd (n = 8; 72.7%). differences in baseline variables and outcomes between the single ventricle and biventricular groups are shown in table 3. the majority of in-hospital deaths occurred within the first 10 days of surgery [figure 1]. according to the univariate analysis, preoperative mechanical ventilation (or = 3.00, 95% ci: 1.98–4.76; p = 0.007) and intraoperative cardiopulmonary bypass (or = 4.09, 95% ci: 2.44–6.85; p = 0.002) were the only statistically significant risk factors for in-hospital mortality. while other factors such as prematurity and underlying genetic conditions showed an increased association with in-hospital mortality, these differences were not statistically significant [table 4]. table 3: outcomes according to diagnosis among infants and children with cyanotic congenital heart disease undergoing modified blalock-taussig shunt procedures in oman (n = 50) variable type of diagnosis, n (%) p value single ventricle (n = 25) biventricular (n = 25) median age in days at time of surgery (iqr) 13 (4–50) 74 (15–107) 0.020 median weight in kg at time of surgery (iqr) 3.1 (2.6–3.6) 3.4 (2.9–5.2) 0.271 early mortality* 4 (16) 1 (4) 0.048 inter-stage mortality† 3 (12) 0 (0) median age at second-stage surgery in months (iqr) 12 (6.8–14) 22 (16–24) 0.019 reintervention during initial hospitalisation‡ 2 (8) 4 (16) 0.049 reintervention during the interval period§ 2 (8) 9 (36) iqr = interquartile range. *defined as mortality occurring within 30 days of the index operation. †defined as mortality occurring between 30 days after the index operation and the next surgical stage. ‡surgical shunt revision. §surgical shunt revision or catheter intervention. figure 1: kaplan-meier curves showing (a) overall survival and (b) hazard of death after index surgery among infants and children with cyanotic congenital heart disease undergoing modified blalock-taussig shunt procedures in oman (n = 50). samiuddin shaikh, khaloud s. al-mukhaini, abdul hakeem al-rawahi and omer al-dafie clinical and basic research | 461 discussion in this study, the rate of in-hospital mortality among paediatric cchd cases following primary mbt shunt procedures was 10%, while the rate of inter-stage mortality was 6.7%. these results are in line with those reported in the literature.7,11 indeed, several studies have indicated a paradoxical rise in mortality following mbt shunt procedures in recent years; for instance, dorobantu et al. observed that overall 30-day mortality increased from 5.1% between 2000–2006 to 9.8% between 2007–2012, while bove et al. reported a rise in mortality from 7% between 1995–2002 to 11% between 2002–2013.5,6 brown et al. noted that systemic-to-pulmonary artery shunt procedures were the only type of cardiac surgery to demonstrate increased mortality in a large national paediatric population.13 a number of factors could explain this disturbing phenomenon. first, it appears that fewer patients with biventricular defects (especially those with tetralogy of fallot) are offered mbt shunts as a treatment option.5,11 second, palliative shunt surgery may be employed in more complex cases such as those involving underlying univentricular heart defects. third, it is possible that cardiac catheterisation is used with greater frequency among patients with suitable anatomies, thus resulting in surgical shunt procedures being reserved for those with more complex or challenging anatomies.5,11 patients with single ventricle defects have a high risk of adverse outcomes following mbt shunt surgeries, including death.5–7,11,14 in the current study, all but one of the patients who died within 30 days of the index procedure had single ventricle defects; moreover, the early mortality rate for this group was 16%. similar findings have been reported in larger cohorts.6,7 in a study of 730 patients with mbt shunts, mckenzie et al. reported an in-hospital mortality rate of 15% in single ventricle cases versus 3% in biventricular cases.15 in another study of 1,273 neonatal patients who received mbt shunts, petrucci et al. found rates of discharge mortality to be 5.1%, 7.2% and 15.6% for patients with biventricular defects, single ventricle defects (excluding those with hypoplastic left heart syndrome) and paivs, respectively.10 similar trends regarding lesion-specific variations in mortality have been described elsewhere. alsoufi et al. observed higher mortality following mbt shunt procedures among patients with atrial isomerism and paivs in a single ventricle cohort.7 in the present study, patients with single ventricle defects had an increased risk of in-hospital mortality, although this association was not statistically significant. it is likely that the higher incidence of concomitant anomalies and underlying genetic syndromes, the complex nature of the cardiac anatomical structures and the coexistence of coronary pathologies serve to make patients with single ventricle defects more vulnerable to adverse outcomes. moreover, the volume overload imposed on a single ventricle heart by systemic-topulmonary artery shunts—including mbt shunts— may predispose these patients to adverse outcomes even in the long term.16 table 4: risk factors associated with early mortality among infants and children with cyanotic congenital heart disease undergoing modified blalock-taussig shunt procedures in oman (n = 50) variable number of deaths per category or (95% ci) p value age (≤28 versus >28 days) 0.58 (0.09–3.83) 0.661 weight (≤2.5 versus >2.5 kg) 1.000 prematurity 3/11 6.94 (0.99–47.61) 0.064 genetic condition 2/5 9.34 (1.10–76.92) 0.072 comorbidity 2/13 2.06 (0.30–13.88) 0.595 single ventricle defect 4/25 4.56 (0.47–43.47) 0.349 duct dependency 4/30 2.92 (0.30–2.85) 0.636 preoperative mechanical ventilation 5/20 3.00 (1.98–4.76) 0.007 unsuccessful preoperative shunt-related procedures 2/9 3.60 (0.50–25.64) 0.216 non-innominate/ subclavian arterial connection 3/15 4.13 (0.61–27.78) 0.152 cardiopulmonary bypass 5/16 4.09 (2.44–6.85) 0.002 associated procedure (e.g. pa plasty) 3/12 5.98 (0.87–41.66) 0.080 postoperative spo2 of >85% 2/16 1.47 (0.10–4.52) 0.518 shunt revision during initial hospitalisation 2/6 6.84 (0.66–52.63) 0.103 shunt size-toweight ratio of >1.2 2/21 1.09 (0.17–7.19) >0.999 or = odds ratio; ci = confidence interval; pa = pulmonary artery; spo 2 = oxygen saturation. outcomes of infants undergoing modified blalock-taussig shunt procedures in oman a retrospective study 462 | squ medical journal, august 2021, volume 21, issue 3 in the current study, preoperative mechanical ventilation and intraoperative cardiopulmonary bypass were the only statistically significant risk factors for early mortality. preoperative mechanical ventilation is a known predictor of adverse outcomes following paediatric cardiac surgery.17 in an analysis of 25,476 paediatric congenital heart surgeries, jacobs et al. found that discharge mortality was significantly higher in patients who were mechanically ventilated preop eratively compared to overall mortality for neonates (15.1% versus 9.88%), infants (11.5% versus 2.91%) and children (14.4% versus 0.92%; p <0.001).18 similar observations have been described post-mbt shunt surgery.10,14 on the whole, the need for preoperative mechanical ventilation reflects the precarious condition of these infants, which may explain the greater occurrence of adverse outcomes following surgery in such cases. it is also plausible that mechanical vent ilation itself contributes to poor outcomes by altering the systemic-to-pulmonary blood flow ratio and increasing the need for sedation and neuromuscular blockade and the risk of pulmonary complications. therefore, it is advisable to avoid elective intubation in this high-risk population, if possible.19,20 moreover, performing a cardiopulmonary bypass during an mbt shunt procedure has frequently been associated with mortality, particularly among single ventricle patients.7,15 in this context, a cardiopulmonary bypass is generally performed due to preoperative haemodynamic instability or the need for concomitant cardiac surgery. there are several possible explanations for the association between cardiopulmonary bypass and adverse outcomes following mbt shunt procedures including activation of the inflammatory and coagulation cascades, alterations in pulmonary compliance and myocardial dysfunction and the decrease in diastolic pressure.7,15 in addition, previous studies have reported other predictors of mortality following mbt shunt procedures among paediatric cchd cases such as low birth weight, underlying genetic syndromes, duct dependency and higher mbt shunt size-to-weight ratios.7 while these factors were not statistically significant predictors of mortality in the present study, it is possible that the small sample size precluded further analysis. in the immediate postoperative period following mbt shunt procedures, two predominant reasons for increased early morbidity and mortality include the occurrence of shunt blockade (due to kinking or thrombosis) and pulmonary overcirculation (also known as over-shunting).21 in the current study, 12% of patients required surgical shunt revision due to shunt blockade during the same hospital admission period, of which one-third later died. in contrast, pulmonary overcirculation (i.e. maintaining spo2 at >85%) was not a significant risk factor for early mortality. this probably reflects an underestimation of the prevalence of this factor, given that the majority of in-hospital deaths were due to myocardial dysfunction and low cardiac output. over-shunting is one of the major causes of ventricular dysfunction and low cardiac output syndrome after mbt shunt procedures.21 palliative mbt shunt procedures lead to unstable circulation, with patients at high risk of death even after being discharged from hospital. previous research indicates that the rate of inter-stage mortality after mbt shunt surgeries varies from 3–11%.9 in the present study, the inter-stage mortality rate was 6.7%; this finding is in line with other published research, despite being calculated over a longer period of time.11 during the interval period, patients with mbt shunts are at an increased risk of acute adverse events caused by alterations to the systemic-to-pulmonary blood flow or due to acute shunt thrombosis, especially during periods of concomitant illness (e.g. diarrhoea or sepsis). longer interval periods can also render the shunt inadequate due to neointimal proliferation or somatic growth, mandating reintervention.22 cardiac catheterisation using a ductal or right ventricle outflow tract (rvot) stent has been proposed as an alternative to an mbt shunt.23 comparative research has indicated that this alternative strategy is not inferior to mbt shunts in terms of clinical outcomes and is superior in terms of other variables like hospital mortality.23–25 however, a sizeable number of cases in which attempts at ductal/rvot stenting fail have been found to eventually require mbt shunts.23 while this subgroup of patients were observed to have a higher risk of death in the current study, the small study population precluded further analysis. as such, further research to compare outcomes between ductal stenting and mbt shunt procedures in a local setting might be helpful to guide patient selection. the overall rate of surgical reintervention in the current study was 24%. while this is similar to the rate reported by bentham et al., it remains unarguably high.24 moreover, half of these interventions took place prior to hospital discharge. o’connor et al. reported that 9.7% of 207 patients required reintervention before discharge, whereas do et al. observed the rate of in-hospital shunt failure requiring reintervention to be 7.3% among 9,172 at-risk infants.26,27 prevention of early shunt failure and reintervention is very important as these events entail considerable mortality and morbidity.26,27 reasons for the high rate of reintervention in the current cohort are not entirely clear and require further evaluation; however, it is worth mentioning samiuddin shaikh, khaloud s. al-mukhaini, abdul hakeem al-rawahi and omer al-dafie clinical and basic research | 463 that most reinterventions were performed for biventricular patients with underlying diagnoses of pulmonary atresia and vsd, especially during the interval period. this is understandable considering the complex nature of this lesion, with many surgeons preferring to employ a staged approach with regards to the initial placement of the mbt shunt to allow for the growth of the pulmonary arteries.28,29 as pulmonary atresia and vsd was the most common underlying diagnosis in the biventricular group, this could also possibly explain the longer interval period before the second-stage surgery among these patients. worldwide, outcomes following mbt shunt proc edures are still poor compared to other types of conge nital heart surgery.5,6,13 however, there nevertheless remains room to improve outcomes of this surgery among infants in oman. suggestions to decrease early mortality include improved patient selection with regards to the decision for surgical intervention compared to interventional cardiac catheterisation, the selection of appropriate shunt sizes, optimum anticoag ulation to prevent shunt thrombosis and standardised postoperative management.30 similarly, shorter interval periods, pre-emptive patient management during periods of concomitant illness and greater awareness of risk factors among community healthcare profess ionals and parents may serve as strategies to improve survival after discharge. this study was subject to certain limitations. as the study was conducted at a single centre, utilised a retrospective design, involved non-standardised procedures and included a comparably small number of patients, it may have been affected by bias. thus, the results need to be interpreted in the background of institutional practices and the specific study population. notwithstanding these limitations, the findings of this study contribute to knowledge regarding the outcomes of palliative mbt shunt procedures in infants with cchd in oman. moreover, these results may serve as a platform for targeted strategies to improve outcomes in this setting. conclusion in the current study, mbt shunt procedures were found to carry an extremely high risk of mortality and reintervention in the treatment of cchd in a paediatric population. these findings reflect those reported in the existing global literature. in particular, preoperative mechanical ventilation and cardiopulmonary bypass represented significant risk factors for early mortality. further studies are needed to compare outcomes between mbt shunt procedures and cardiac catheter interventions in order to guide patient selection in this setting. a c k n o w l e d g m e n t authors would like to thank dr. hamood al kindi bsc,msc,md,frcsc, consultant pediatric cardiac surgery , national heart center , royal hospital and sultan qaboos university hospital , muscat , sultanate of oman; for valuable suggestions in manuscript writing. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n ss and ksm conceived and designed the study and drafted the manuscript. ss, ksm and od collected the data. ahr performed the statistical analysis and interpreted the results. all authors approved the final version of the manuscript. references 1. subramanyan r, joy j, venugopalan p, sapru a, al khusaiby sm. incidence and spectrum of congenital heart disease in oman. ann trop paediatr 2000; 20:337–41. https://doi.org/10.1080/02 724936.2000.11748155. 2. yee l. cardiac emergencies in the first year of life. emerg med clin north am 2007; 25:981–1008. https://doi.org/10.1016/j. emc.2007.08.001. 3. kiran u, aggarwal s, choudhary a, uma b, kapoor pm. the blalock and taussig shunt revisited. ann card anaesth 2017; 20:323–30. https://doi.org/10.4103/aca.aca_80_17. 4. santro t, d’udekem y, zannino d, hobbes b, konstantinov ie, brizard c, et al. determinants of acute events leading to mortality after shunt procedure in univentricular palliation. j thorac cardiovasc surg 2019; 158:1144–53.e6. https://doi. org/10.1016/j.jtcvs.2019.03.126. 5. dorobantu dm, pandey r, sharabiani mt, mahani as, angelini gd, martin rp, et al. indications and results of systemic to pulmonary shunts: results from a national database. eur j cardiothorac surg 2016; 49:1553–63. https://doi.org/10.1093/ ejcts/ezv435. 6. bove t, vandekerckhove k, panzer j, de groote k, de wolf d, françois k. disease-specific outcome analysis of palliation with the modified blalock-taussig shunt. world j pediatr congenit heart surg 2015; 6:67–74. https://doi. org/10.1177/2150135114558690. 7. alsoufi b, gillespie s, mori m, clabby m, kanter k, kogon b. factors affecting death and progression towards next stage following modified blalock-taussig shunt in neonates. eur j cardiothorac surg 2016; 50:169–77. https://doi.org/10.1093/ ejcts/ezw017. https://doi.org/10.1080/02724936.2000.11748155 https://doi.org/10.1080/02724936.2000.11748155 https://doi.org/10.1016/j.emc.2007.08.001 https://doi.org/10.1016/j.emc.2007.08.001 https://doi.org/10.4103/aca.aca_80_17 https://doi.org/10.1016/j.jtcvs.2019.03.126 https://doi.org/10.1016/j.jtcvs.2019.03.126 https://doi.org/10.1093/ejcts/ezv435 https://doi.org/10.1093/ejcts/ezv435 https://doi.org/10.1177/2150135114558690 https://doi.org/10.1177/2150135114558690 https://doi.org/10.1093/ejcts/ezw017 https://doi.org/10.1093/ejcts/ezw017 outcomes of infants undergoing modified blalock-taussig shunt procedures in oman a retrospective study 464 | squ medical journal, august 2021, volume 21, issue 3 8. dirks v, prêtre r, knirsch w, buechel er, seifert b, schweiger m, et al. modified blalock taussig shunt: a not-so-simple palliative procedure. eur j cardiothorac surg 2013; 44:1096–102. https:// doi.org/10.1093/ejcts/ezt172. 9. hobbes b, d’udekem y, zannino d, konstantinov ie, brizard c, brink j. determinants of adverse outcomes after systemic-topulmonary shunts in biventricular circulation. ann thorac surg 2017; 104:1365–70. https://doi.org/10.1016/j.athoracsur.2 017.06.043. 10. petrucci o, o’brien sm, jacobs ml, jacobs jp, manning pb, eghtesady p. risk factors for mortality and morbidity after the neonatal blalock-taussig shunt procedure. ann thorac surg 2011; 92:642–52. https://doi.org/10.1016/j.athoracsur.2011.02.030. 11. sasikumar n, hermuzi a, fan cp, lee kj, chaturvedi r, hickey e, et al. outcomes of blalock-taussig shunts in current era: a single center experience. congenit heart dis 2017; 12:808–14. https://doi.org/10.1111/chd.12516. 12. vitanova k, leopold c, von ohain jp, wolf c, beran e, lange r, et al. reasons for failure of systemic-to-pulmonary artery shunts in neonates. thorac cardiovasc surg 2019; 67:2–7. https://doi.org/10.1055/s-0037-1621706. 13. brown kl, crowe s, franklin r, mclean a, cunningham d, barron d, et al. trends in 30-day mortality rate and case mix for paediatric cardiac surgery in the uk between 2000 and 2010. open heart 2015; 2:e000157. https://doi.org/10.1136/ openhrt-2014-000157. 14. mohammadi s, benhameid o, campbell a, potts j, joza j, al-habib h, et al. could we still improve early and interim outcome after prosthetic systemic-pulmonary shunt? a risk factors analysis. eur j cardiothorac surg 2008; 34:545–9. https://doi.org/10.1016/j.ejcts.2008.06.001. 15. mckenzie ed, khan ms, samayoa ax, vener ds, ishak ym, santos ab, et al. the blalock-taussig shunt revisited: a contemp orary experience. j am coll surg 2013; 216:699–706. https:// doi.org/10.1016/j.jamcollsurg.2012.12.027. 16. gewillig m. the fontan circulation. heart 2005; 91:839–46. https://doi.org/10.1136/hrt.2004.051789. 17. ciociola ec, kumar kr, zimmerman ko, thompson ej, harward m, sullivan ln, et al. association between preop erative respiratory support and outcomes in paediatric cardiac surgery. cardiol young 2020; 30:66–73. https://doi.org/10.1017/ s1047951119002786. 18. jacobs jp, o’brien sm, pasquali sk, kim s, gaynor jw, tchervenkov ci, et al. the importance of patient-specific pre operative factors: an analysis of the society of thoracic surgeons congenital heart surgery database. ann thorac surg 2014; 98:1653–9. https://doi.org/10.1016/j.athoracsur.2014.07.029. 19. guzzetta na, foster gs, mruthinti n, kilgore pd, miller be, kanter kr. in-hospital shunt occlusion in infants undergoing a modified blalock-taussig shunt. ann thorac surg 2013; 96:176–82. https://doi.org/10.1016/j.athoracsur.2013.03.026. 20. meckler gd, lowe c. to intubate or not to intubate? transporting infants on prostaglandin e1. pediatrics 2009; 123:e25–30. https://doi.org/10.1542/peds.2008-0641. 21. soo kw, brink j, d’udekem y, butt w, namachivayam sp. major adverse events following over-shunting are associated with worse outcomes than major adverse events after a blocked systemic-to-pulmonary artery shunt procedure. pediatr crit care med 2018; 19:854–60. https://doi.org/10.1097/pcc.00000 00000001659. 22. marino bs, tabbutt s, maclaren g, hazinski mf, adatia i, atkins d, et al. cardiopulmonary resuscitation in infants and children with cardiac disease: a scientific statement from the american heart association. circulation 2018; 137:e691–782. https://doi.org/10.1161/cir.0000000000000524. 23. benson l, van arsdell g. comparisons between ductal stenting and blalock-taussig shunts for infants with ductal-dependent pulmonary circulation. circulation 2018; 137:602–4. https:// doi.org/10.1161/circulationaha.117.031998. 24. bentham jr, zava nk, harrison wj, shauq a, kalantre a, derrick g, et al. duct stenting versus modified blalock-taussig shunt in neonates with duct-dependent pulmonary blood flow: associations with clinical outcomes in a multicenter national study. circulation 2018; 137:581–8. https://doi.org/10.1161/ circulationaha.117.028972. 25. glatz ac, petit cj, goldstein bh, kelleman ms, mccracken ce, mcdonnell a, et al. comparison between patent ductus arteriosus stent and modified blalock-taussig shunt as palliation for infants with ductal-dependent pulmonary blood flow: insights from the congenital catheterization research collaborative. circulation 2018; 137:589–601. https://doi.org/10.1161/circu lationaha.117.029987. 26. o’connor mj, ravishankar c, ballweg ja, gillespie mj, gaynor jw, tabbutt s, et al. early systemic-to-pulmonary artery shunt intervention in neonates with congenital heart disease. j thorac cardiovasc surg 2011; 142:106–12. https://doi.org/10.1016/j. jtcvs.2010.10.033. 27. do n, hill kd, wallace as, vricella l, cameron d, quintessenza j, et al. shunt failure-risk factors and outcomes: an analysis of the society of thoracic surgeons congenital heart surgery database. ann thorac surg 2018; 105:857–64. https://doi.org/10.1016/j. athoracsur.2017.06.028. 28. lertsakulpiriya k, vijarnsorn c, chanthong p, chungsomprasong p, kanjanauthai s, durongpisitkul k, et al. current era outcomes of pulmonary atresia with ventricular septal defect: a single center cohort in thailand. sci rep 2020; 10:5165. https://doi. org/10.1038/s41598-020-61879-2. 29. van puyvelde j, meyns b, rega f. pulmonary atresia and a ventricular septal defect: about size and strategy. eur j cardiothorac surg 2016; 49:1419–20. https://doi.org/10.1093/ ejcts/ezv443. 30. ismail sr, almazmi mm, khokhar r, almadani w, hadadi a, hijazi o, et al. effects of protocol-based management on the post-operative outcome after systemic to pulmonary shunt. egypt heart j 2018; 70:271–8. https://doi.org/10.1016/j.ehj.20 18.09.007. https://doi.org/10.1093/ejcts/ezt172 https://doi.org/10.1093/ejcts/ezt172 https://doi.org/10.1016/j.athoracsur.2017.06.043 https://doi.org/10.1016/j.athoracsur.2017.06.043 https://doi.org/10.1016/j.athoracsur.2011.02.030 https://doi.org/10.1111/chd.12516 https://doi.org/10.1055/s-0037-1621706 https://doi.org/10.1136/openhrt-2014-000157 https://doi.org/10.1136/openhrt-2014-000157 https://doi.org/10.1016/j.ejcts.2008.06.001 https://doi.org/10.1016/j.jamcollsurg.2012.12.027 https://doi.org/10.1016/j.jamcollsurg.2012.12.027 https://doi.org/10.1136/hrt.2004.051789 https://doi.org/10.1017/s1047951119002786 https://doi.org/10.1017/s1047951119002786 https://doi.org/10.1016/j.athoracsur.2014.07.029 https://doi.org/10.1016/j.athoracsur.2013.03.026 https://doi.org/10.1542/peds.2008-0641 https://doi.org/10.1097/pcc.0000000000001659 https://doi.org/10.1097/pcc.0000000000001659 https://doi.org/10.1161/cir.0000000000000524 https://doi.org/10.1161/circulationaha.117.031998 https://doi.org/10.1161/circulationaha.117.031998 https://doi.org/10.1161/circulationaha.117.028972 https://doi.org/10.1161/circulationaha.117.028972 https://doi.org/10.1161/circulationaha.117.029987 https://doi.org/10.1161/circulationaha.117.029987 https://doi.org/10.1016/j.jtcvs.2010.10.033 https://doi.org/10.1016/j.jtcvs.2010.10.033 https://doi.org/10.1016/j.athoracsur.2017.06.028 https://doi.org/10.1016/j.athoracsur.2017.06.028 https://doi.org/10.1038/s41598-020-61879-2 https://doi.org/10.1038/s41598-020-61879-2 https://doi.org/10.1093/ejcts/ezv443 https://doi.org/10.1093/ejcts/ezv443 https://doi.org/10.1016/j.ehj.2018.09.007 https://doi.org/10.1016/j.ehj.2018.09.007 the molecular pathways of lung damage by e-cigarettes in male wistar rats *rivan v. suryadinata1 and bambang wirjatmadi2 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 436–441, epub. 29 aug 21 submitted 15 apr 20 revisions req. 9 jun, 29 jul & 24 aug 20; revisions recd. 23 jun, 6 aug & 2 sep 20 accepted 8 sep 20 1department of public health, universitas surabaya, surabaya, indonesia; 2department of public health, universitas airlangga, surabaya, indonesia *corresponding author’s e-mail: rivan.virlando.suryadinata@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.003 clinical & basic research abstract: objectives: this study aimed to analyse the stages of lung tissue damage caused by exposure to electronic cigarette (e-cigarette) smoke. the negative health effects of e-cigarettes remain debatable. several studies have shown the adverse effects, but others opine that e-cigarettes are safer to use than their tobacco counterparts. there is, however, a possibility that the long-term health effects, such as respiratory and even kidney function impairment, are presently not obvious. the amounts of increased free radicals and pro-inflammatory cytokines from e-cigarettes result in various physiological disorders, which trigger cell damage and even cell death in the body. methods: an experimental study was conducted between march and september 2019 in airlangga university using a control and an experimental group of male wistar rats to assess the levels of malondialdehyde, interleukin (il)-8, il-10, matrix metalloprotein-8 and type-2 collagen. the results were obtained using immunohistochemical staining methods on alveolar macrophages through hematoxylin-eosin staining. results: the results showed that exposure to e-cigarette smoke caused an increase in free radicals, triggered an inflammatory process and degraded the type-2 collagen present in the lung tissue. conclusion: exposure to e-cigarette smoke can cause cell damage in lung tissues. keywords: e-cigarettes; lungs; immunohistochemistry; hematoxylin; eosin. advances in knowledge this study explains the mechanism of lung tissue damage due to exposure to electronic cigarette (e-cigarette) smoke from the airway to the cells of lung tissues. the damage caused by e-cigarettes reaches the type-2 collagen, which indirectly affects the cartilages of the respiratory tract. application to patient care this research aims to analyse the impact of the damage caused by e-cigarettes to enable its use as a reference in educating the public to avoid or reduce using them. th e u s e o f e l e c t r o n i c c i g a r e t t e s (e-cigarettes) increases every year. they are usually advertised as products that have low nicotine levels and are often seen as a viable alternative to smoking cessation. consequently, most people believe e-cigarettes are safer than their tobacco counterparts.1 in addition, aggressive marketing from e-cigarette producers accelerates and increases its use among users.2 while various studies have shown the short-term adverse effects, such as an increase in free radicals and/or respiratory/airway inflammation, the long-term risks of exposure and use remain unknown because it is still a recent innovation.3,4 however, various physiological disorders arising from cell damage caused by e-cigarette smoke pose a safety concern.5 the e-cigarette is an electronic device that utilises battery power.6 its use is different from tobacco cigarettes, which require the burning of natural tobacco leaves. it involves a heating process conducted on metals containing a liquid, either nicotine, propylene glycol or vegetable glycerol, which is used as a solvent or flavour.6 the metal and the liquid are heated to give off steam that is inhaled by the user. the various types of metals and materials used in the manufacturing process of these e-cigarettes increasingly raise concerns regarding its level of safety for users.7 the resulting steam produced also causes inflammation in the airways, reduces immunological defence and triggers lung tissue damage.8 e-cigarettes contain high concentrations of free radicals that are approximately 1016 molecules/ puff. these free radicals, in turn, consist of reactive oxygen species (ros) and reactive nitrogen species (rns). upon inhalation, free radicals are neutralised by enzymatic antioxidants such as superoxide dismutase, glutathione peroxidase and catalase. however, when these free radicals are inhaled or taken in excess, complete neutralisation will be impossible. this would consequently trigger cellular damage and inflammatory response through the release of pro-inflammatory cytokines by macrophage cells.9 one of these cytokines is interleukin-8, which plays a role in cellular rupture and damage. other cytokines include the neutrophil chemotactic factor, which releases neutrophils into lung tissue. increased interleukin (il)-8 secretion will stimulate the release of a metalloprotein-8 matrix into the lung tissues.10 https://creativecommons.org/licenses/by-nd/4.0/ rivan v. suryadinata and bambang wirjatmadi clinical and basic research | 437 metalloprotein matrix is an endopeptidase synthesised by neutrophils and expressed in various inflammatory cells when these neutrophils are activated by different inflammatory mediators of cell damage.11 therefore, metalloprotein matrix is not expressed in healthy cells or tissues, so it is often a parameter for the diagnosis of tissue damage.12 excessive metalloprotein-8 matrix will affect the collagen structure and function in respiratory cartilages by increasing the degradation of type-2 collagen.13 such damage occurring in the lung tissue for an extended amount of time would increase the risk of pulmonary fibrosis. this would render the tissue damage irreversible and result in various diseases, including pulmonary hypertension, cardiovascular problems and lung cancer.14 this study aims to determine the stages of lung tissue damage through increased free radicals and inflammatory responses; these indirectly result in increased numbers of alveolar macrophages that cause damage to lung tissues. this research was done by comparing a group of experimental animals (male wistar rats) that were exposed to e-cigarette smoke to a control group. methods in this study conducted between march and september 2019 in airlangga university, male wistar rats were used because there was’t menstrual cycle in the subjects, which signifies no changes in hormone levels. during care and maintenance of experimental animals, the 3r principle of replacement, refinement and reduction was applied. the animals were kept in accordance with standard natural conditions of two cycles (12 hours of light and 12 hours of dark) and provided with healthy food and water. e-cigarettes were used in this study, each containing 6 mg of nicotine. the liquid was heated using a coil made of nickel. the experimental method involved streaming smoke into a smoking chamber sized 70 × 50 × 30 cm. the rats were included in the chamber only when an appropriate smoke exposure had been given in accordance with the experimental duration. malondialdehyde, il-8, il10, metalloprotein-8 matrix and type-2 collagen require an immunohistochemistry (ihc) staining method for assessment. ihc assesses the expression of each sample quantitatively. the values are the average numbers of positive cells observed for each preparation. the data for each sample is the average value of the immunoreactive score observed in 10 different fields of view (lp) using a magnification of 400× on a light microscope. the histological examination started with the removal of pulmonary organs of the rats to make preparations for the hematoxylin-eosin staining method. the assessment involves calculating the mean number of alveolar macrophages in 10 visual fields per preparation. observations were carried out under objective magnifications of 40× using an immersion microscope. figure 1: the methodology flowchart of an experimental study conducted on male wistar rats assessing the levels of malondialdehyde (mda), interleukin (il)-8, il-10, matrix metalloprotein-8 (mmp-8) and type-2 collagen following electronic-cigarette smoke exposure. the molecular pathways of lung damage by e-cigarettes in male wistar rats 438 | squ medical journal, august 2021, volume 21, issue 3 in this study, the experiment was divided into two groups. the first was the control group, which was given only food without any exposure to e-cigarette smoke. the second group was given food and exposed to e-cigarette smoke for two minutes daily during the 4-week period of the experiment [figure 1]. the results of this study were obtained via a ratio data focused on the average number of positive cells from malondialdehyde, il-8, il-10, matrix metalloprotein (mmp)-8 and type-2 collagen in the lung tissue as well as the mean number of alveolar macrophages in each group. data analysis was performed via t-test analysis using statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the next stage of the data analysis was performed using the partial least square (pls) test to observe the effects between the variables. this study received ethical approval from the health research ethics committee, faculty of public health, universitas airlangga. results the results of this study were obtained by comparing the average number of positive cells in 10 varying lps between the control and experiment groups for malondialdehyde, il-8, il-10, mmp-8 and type-2 collagen. the mean value and standard deviation of each variable in both groups are definite. the t-test revealed a significant difference in the number of positive cells between the control and experiment groups [figures 2a, 2b and 3]. in the experiment group, the number of positive cells from malondialdehyde (24.30 ± 0.82), il-8 (15.49 ± 0.56), il-10 (6.88 ± 0.35) and the mmp-8 matrix (12.01 ± 0.35) were significantly higher than those in the control group from malondialdehyde (6.80 ± 0.28), il-8 (5.86 ± 0.27), il-10 (3.91 ± 0.20) and the mmp8 matrix (7.14 ± 0.23). additionally, the number of positive cells of type-2 collagen in the control group (14.19 ± 0.47) was significantly higher than those in the experiment group (5.26 ± 0.27) [figure 3]. figure 2: immersion microscopic scans at 100x magnification showing a higher number of cells positive for malondialdehyde as seen in (a) the experiment group compared to (b) the control group of male wistar rats based on positive antigen-antibody reactions expressed through the brownish-black cytoplasm. figure 3: the mean value and standard deviation as seen in the experimental group compared to the control group of male wistar rats in a study assessing the levels of malondialdehyde, interleukin (il)-8, il-10, matrix metalloprotein-8 and type-2 collagen following electronic-cigarette smoke exposure. figure 4: immersion microscopic scans at 100x magnification showing a higher number of alveolar macrophage cells as seen in (a) the experimental group as compared to (b) the control group of male wistar rats in a study assessing the levels of malondialdehyde, interleukin (il)-8, il-10, matrix metalloprotein-8 and type-2 collagen following electronic-cigarette smoke exposure. rivan v. suryadinata and bambang wirjatmadi clinical and basic research | 439 the results of this study were obtained by comparing the mean number of alveolar macrophages per preparation in 10 lp between the control and experiment groups [figures 4a and 4b]. the standard deviation and average value of alveolar macrophages were observed for each group. t-test results exhibited a difference in the number of alveolar macrophages between both groups (p <0.001), where the experiment group (53.26 ± 0.93) had a greater number of positive cells compared to the control group (21.86 ± 1.12) [figure 3]. the results of the correlation test uncovered a strong association between malondialdehyde, il-8, il-10, matrix mmp-8, type-2 collagen and alveolar macrophages present in lung tissue (r >0.80) [table 1]. discussion this research shows an increase in various parameters that can impact health negatively. it has been observed that the content found and inhaled from e-cigarettes will cause lung tissue damage. free radicals passing through the airways trigger oxidative stress and set off lipid peroxidation, increasing the levels of malondialdehyde, as shown in the immunohistochemical micrographs [figures 2 and 4]. e-cigarette smoke that enters and passes through the airway will increase the number of free radicals.15 when these free radicals become excessive or abundant, oxidative stress also increases, which causes further lipid peroxidation and cell damage.16 the product of a lipid peroxidation reaction is malondialdehyde, which is one of the final metabolic by-products of peroxidase and hence, a commonly used marker of increased free radicals in the body.17 the increase in malondialdehyde levels in the experiment group in this study was due to free radicals from e-cigarettes entering the respiratory tract. cell damage causes cell necrosis, which in turn results in cellular debris, often called damageassociated molecular patterns (damps) in the micro-environment.18 debris of cells stimulate the body’s immune system by increasing the number of alveolar macrophages in the lung tissues. the first stage of immune defence in the body is carried out by m-1 alveolar macrophages through the process of phagocytosis.19 the debris of cells that have been phagocytosed by these macrophages will stimulate the secretion of various cytokines that help initiate an inflammatory reaction, one of which is il-8.20 whenever these reactions occur excessively, one of the m-2 macrophage cells will play a role in regulating the inflammatory process. macrophage cells express il-10, which acts as an anti-inflammatory agent.21 the results of this study showed an increase in levels of interleukin-8 and a decrease in levels of interleukin-10 in the treatment group. this change in interleukin levels would cause an excessive inflammatory reaction in the lung tissue. the increased inflammatory response in lung tissue in the experiment group stimulates alveolar macrophage and the secretion of metalloprotein-8 matrix, which is formed from the degranulation of polymorphonuclear neutrophils (pmns) during the inflammatory reaction.22 non-pmn cells that experience these reactions, such as epithelial cells of the human bronchi, also produce a metalloprotein-8 matrix. this demonstrates the influence of the inflammatory process on the increase in metalloprotein-8 matrix in lung tissues.22 an excessive increase stimulates the degradation of type-2 collagen tissue found in the cells. this type of collagen is the main active protein in cartilage tissues. in the airways, it is abundant in the trachea, until it reaches the small bronchial tubes. increased synthesis and secretion of type-2 collagen causes structural and functional disorders of cartilage. inflammation due to foreign particles damages the bronchial wall and is one of the risk factors of pulmonary fibrosis.23 the increase in alveolar macrophage, metalloprotein-8 matrix and type-2 collagen that occurred in the experimental group of the current study can increase the risk of fibrosis in the lung tissue. the body’s ability to regulate inflammation is mainly through the secretion of anti-inflammatory cytokines, namely il-10. these cytokines are produced by t helper 2 cells, which inhibit the activation of t helper 1 cells that play a role in increasing the number of macrophages in the lung tissue.24 in addition, il10 is also needed to inhibit pathogen clearance and improve immunopathological conditions.25,26 this was evidenced in the current study by the increase table 1: the results of the correlation-test for each group of male wistar rats in a study assessing the levels of malondialdehyde, interleukin (il)-8, il-10, matrix metalloprotein-8 and type-2 collagen following electronic-cigarette smoke exposure protein mda* il-8† il-10‡ mmp8§ collagen type-2 il-8† 0.995 il-10‡ 0.980 0.983 mmp-8§ 0.989 0.991 0.977 collagen type-2 −0.993 −0.992 −0.977 −0.991 alveolar macrophage 0.995 0.995 0.994 0.994 −0.996 *mda = malondialdehyde; †il-8 = interleukin-8; ‡il-10 = interleukin-10; §mmp-8 = matrix metalloprotein-8. the molecular pathways of lung damage by e-cigarettes in male wistar rats 440 | squ medical journal, august 2021, volume 21, issue 3 of various parameters of the inflammatory response in the group exposed to e-cigarette smoke, which was contrasted with the control group results. each parameter shows a relationship in the inflammatory response process caused by exposure to e-cigarette smoke, which forms a molecular pathway for lung tissue damage. conclusion exposure to e-cigarette smoke increases free radicals in the airways through increased malondialdehyde. this causes modifications in pro-inflammatory cytokines found in the lung tissue, such as il-6 and il8, resulting in changes in the metalloprotein-8 matrix and commencing type-2 collagen degradation. hence, this study showed a molecular pathway through its short-term negative impact caused by e-cigarette smoke that modifies the inflammatory process in the lung tissue and triggers the onset of lung tissue damage. a c k n o w l e d g e m e n t the authors are grateful to all team members who contributed to this research. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n both authors contributed equally to data collection, analysis and drafting the manuscript. both authors reviewed the results and approved the final version of the manuscript. references 1. kalkhoran s, glantz sa. e-cigarettes and smoking cessation in real-world and clinical settings: a systematic review and meta-analysis. lancet respir med 2016; 4:116–28. https://doi. org/10.1016/s2213-2600(15)00521-4. 2 brandon th, goniewicz ml, hanna nh, hatsukami dk, herbst rs, hobin ja, et al. electronic nicotine delivery systems: a policy statement from the american association for cancer research and the american society of clinical oncology. j clin oncol 2015; 33:952–63. https://doi.org/10.1200/jco.20 14.59.4465. 3. suryadinata rv, wirjatmadi b, adriani m, sumarmi s. the effects of exposure duration to electronic cigarette smoke on differences in superoxide dismutase and malondialdehyde in blood of wistar rats. int j curr pharm res 2019; 11:13–6. https://doi.org/10.22159/ijcpr.2019v11i3.34084. 4. chun lf, moazed f, calfee cs, matthay ma, gotts je. pulmonary toxicity of e-cigarettes. am j physiol cell mol physiol 2017; 313:l193–206. https://doi.org/10.1152/ajplung.00 071.2017. 5. reinikovaite v, rodriguez ie, karoor v, rau a, trinh bb, deleyiannis fw, et al. the effects of electronic cigarette vapour on the lung: direct comparison to tobacco smoke. eur respir j 2018; 51:1701661. https://doi.org/10.118/13993003.01661-2017. 6. glynos c, bibli si, katsaounou p, pavlidou a, magkou c, karavana v, et al. comparison of the effects of e-cigarette vapor with cigarette smoke on lung function and inflammation in mice. am j physiol cell mol physiol 2018; 315:l662–72. https:// doi.org/10.1152/ajplung.00389.2017. 7. wollscheid ka, kremzner me. electronic cigarettes: safety concerns and regulatory issues. am j heal pharm 2009; 66:1740–2. https://doi.org/10.2146/ajhp090127. 8. sussan te, gajghate s, thimmulappa rk, ma j, kim jh, sudini k, et al. exposure to electronic cigarettes impairs pulmonary antibacterial and anti-viral defenses in a mouse model. plos one 2015; 10:e0116861. https://doi.org/10.1371/journal.pone.0116861. 9. goel r, durand e, trushin n, prokopczyk b, foulds j, elias rj, et al. highly reactive free radicals in electronic cigarette aerosols. chem res toxicol 2015; 28:1675–7. https://doi.org/10.1021/ acs.chemrestox.5b00220. 10. thirkettle s, decock j, arnold h, pennington cj, jaworski dm, edwards dr. matrix metalloproteinase 8 (collagenase 2) induces the expression of interleukins 6 and 8 in breast cancer cells. j biol chem 2013; 288:16282–94. https://doi.org/10.1074/jbc.m1 13.464230. 11. sirniö p, tuomisto a, tervahartiala t, sorsa t, klintrup k, karhu t, et al. high-serum mmp-8 levels are associated with decreased survival and systemic inflammation in colorectal cancer. br j cancer 2018; 119:213–9. https://doi.org/10.1038/ s41416-018-0136-4. 12. ostridge k, williams n, kim v, bennett m, harden s, welch l, et al. relationship between pulmonary matrix metalloprot einases and quantitative ct markers of small airways disease and emphysema in copd. thorax 2016; 71:126–32. https://doi. org/10.1136/thoraxjnl-2015-207428. 13. craig vj, zhang l, hagood js, owen ca. matrix metallo proteinases as therapeutic targets for idiopathic pulmonary fibrosis. am j respir cell mol biol 2015; 53:585–600. https:// doi.org/10.1165/rcmb.2015-0020tr. 14. fujimoto h, kobayashi t, azuma a. idiopathic pulmonary fibrosis: treatment and prognosis. clin med insights circ respir pulm med 2016; 9:179-85. https://doi.org/10.4137/ ccrpm.s23321. 15. indraswari pii, lorensia a, suryadinata rv. analysis effect of nutrition intake on lung function of active smoker and non smoker. j kesehat masy 2018; 14:247–53. https://doi.org/10.15 294/kemas.v14i2.14947. 16. phaniendra a, jestadi db, periyasamy l. free radicals: properties, sources, targets, and their implication in various diseases. indian j clin biochem 2015; 30:11–26. https://doi.org/10.1007/ s12291-014-0446-0. 17. suryadinata rv, wirjatmadi b. the role of selenium micro nutrients as antioxidants in exposure to e-cigarette smoke. asian j pharm clin res 2019; 12:265–8. https://doi.org/10.22159/ ajpcr.2019.v12i18.34454. 18. suryadinata rv, lorensia a, sefania k. efectiveness of lime peel extract (citrus aurantifolia swingle) against c-reactive protein levels in alloxan-induced wistar rats. glob med heal commun 2021; 9(1):23–28. https://doi.org/10.29313/gmhc. v9i1.6227. https://doi.org/10.1016/s2213-2600(15)00521-4 https://doi.org/10.1016/s2213-2600(15)00521-4 https://doi.org/10.1200/jco.2014.59.4465 https://doi.org/10.1200/jco.2014.59.4465 https://doi.org/10.22159/ijcpr.2019v11i3.34084 https://doi.org/10.1152/ajplung.00071.2017 https://doi.org/10.1152/ajplung.00071.2017 https://doi.org/10.118/13993003.01661-2017 https://doi.org/10.1152/ajplung.00389.2017 https://doi.org/10.1152/ajplung.00389.2017 https://doi.org/10.2146/ajhp090127 https://doi.org/10.1371/journal.pone.0116861 https://doi.org/10.1021/acs.chemrestox.5b00220 https://doi.org/10.1021/acs.chemrestox.5b00220 https://doi.org/10.1074/jbc.m113.464230 https://doi.org/10.1074/jbc.m113.464230 https://doi.org/10.1038/s41416-018-0136-4 https://doi.org/10.1038/s41416-018-0136-4 https://doi.org/10.1136/thoraxjnl-2015-207428 https://doi.org/10.1136/thoraxjnl-2015-207428 https://doi.org/10.1165/rcmb.2015-0020tr https://doi.org/10.1165/rcmb.2015-0020tr https://doi.org/10.4137/ccrpm.s23321 https://doi.org/10.4137/ccrpm.s23321 https://doi.org/10.15294/kemas.v14i2.14947 https://doi.org/10.15294/kemas.v14i2.14947 https://doi.org/10.1007/s12291-014-0446-0 https://doi.org/10.1007/s12291-014-0446-0 https://doi.org/10.22159/ajpcr.2019.v12i18.34454 https://doi.org/10.22159/ajpcr.2019.v12i18.34454 https://doi.org/10.29313/gmhc.v9i1.6227 https://doi.org/10.29313/gmhc.v9i1.6227 rivan v. suryadinata and bambang wirjatmadi clinical and basic research | 441 19. land wg. the role of damage-associated molecular patterns (damps) in human diseases: part ii: damps as diagnostics, prognostics and therapeutics in clinical medicine. sultan qaboos univ med j 2015; 15:e157–70. http://www.ncbi.nlm. nih.gov/pubmed/26052447. 20. ito y, correll k, zemans rl, leslie cc, murphy rc, mason rj. influenza induces il-8 and gm-csf secretion by human alveolar epithelial cells through hgf/c-met and tgf-α/egfr signaling. am j physiol cell mol physiol 2015; 308:l1178–88. https://doi.org/10.1152/ajplung.00290.2014. 21. han x, boisvert w. interleukin-10 protects against atherosclerosis by modulating multiple atherogenic macrophage function. thromb haemost 2015; 113:505–12. https://doi.org/10.1160/ th14-06-0509. 22. prikk k, maisi p, pirilä e, reintam ma, salo t, sorsa t, et al. airway obstruction correlates with collagenase-2 (mmp-8) expr ession and activation in bronchial asthma. lab investig 2002; 82:1535–45. https://doi.org/10.1097/01.lab.0000035023.53893.b6. 23. wilson ms, wynn ta. pulmonary fibrosis: pathogenesis, etiology and regulation. mucosal immunol 2009; 2(2): 103–121. https:// doi.org/10.1038/mi.2008.85. 24. steen eh, wang x, balaji s, butte mj, bollyky pl, keswani sg. the role of the anti-inflammatory cytokine interleukin-10 in tissue fibrosis. adv wound care (new rochelle). 2020; 9:184-98. https://doi.org/10.1089/wound.2019.1032. 25. kevin n, daniel g, eleanor m. il-10: the master regulator of immunity to infection. j immunol 2008; 180:5771–7. https:// doi.org/10.4049/jimmunol.180.9.5771. 26. al-hariri mt, eldin tg, hashim t, chathoth s, alswied a. propolis modulates inflammatory mediators and improves histopathology in male rats with l-arginine-induced acute pancr eatitis. sultan qaboos univ med j 2019; 19:103–7. https://doi. org/10.18295/squmj.2019.19.02.004. http://www.ncbi.nlm.nih.gov/pubmed/26052447 http://www.ncbi.nlm.nih.gov/pubmed/26052447 https://doi.org/10.1152/ajplung.00290.2014 https://doi.org/10.1160/th14-06-0509 https://doi.org/10.1160/th14-06-0509 https://doi.org/10.1097/01.lab.0000035023.53893.b6 https://doi.org/10.1038/mi.2008.8 https://doi.org/10.1038/mi.2008.8 https://doi.org/10.1089/wound.2019.1032 https://doi.org/10.4049/jimmunol.180.9.5771 https://doi.org/10.4049/jimmunol.180.9.5771 https://doi.org/10.18295/squmj.2019.19.02.004 https://doi.org/10.18295/squmj.2019.19.02.004 department of pathology, mohammed bin rashid university of medicine and health sciences, college of medicine, dubai, united arab emirates author’s e-mails: lakhtakiar@yahoo.com and ritu.lakhtakia@mbru.ac.ae virtual microscopy in undergraduate pathology education an early transformative experience in clinical reasoning ritu lakhtakia sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 428–435, epub. 29 aug 21 submitted 22 may 20 revision req. 13 jul 20; revision recd. 12 aug 20 accepted 10 sep 20 https://doi.org/10.18295/squmj.4.2021.009 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: whole-slide imaging and virtual microscopy (vm) have revolutionised teaching, diagnosis and research in histopathology. this study aimed to establish the feasibility of achieving early integration of clinical reasoning with undergraduate pathology teaching on a vm platform and to determine its student-centricity through student feedback. methods: this study was conducted at the mohammed bin rashid university of medicine and health sciences, dubai, united arab emirates, between august and december 2017. a total of 38 vm-centred clinical cases were introduced to 49 students in an integrated undergraduate medical curriculum. the cases were aligned to curricular objectives, reinforced the pathologic basis of disease with critical thinking and were delivered across 15 interactive small-group sessions. a simulated cross-disciplinary integration and judicious choice of pertinent diagnostic investigations were linked to principles of management. feedback was obtained through a mixed-methods approach. results: user-friendliness, gradual learning curve of vm and annotation-capacity were scored as 4–5 (on a likert scale of 1–5) by 91.84%, 87.76% and 83.67% of the participants, respectively. most students agreed that the content matched the stage of learning (81.63%), theme of the week (91.84%) and development of a strong clinical foundation (77.55%). integration (85.71%) and clinico-pathological correlation (83.67%) were the strengths of this educational effort. high student attendance (~100%) and improved assessment scores on critical thinking (80%) were observed. software lacunae included frequent logouts and lack of note-taking tools. easy access was a significant student-centric advantage. conclusion: a vm-centred approach with a clinico-pathological correlation has been successfully introduced to inculcate integrated learning. using the pathologic basis of disease as a fulcrum and critical reasoning as an anchor, a digitally-enabled generation of medical students have embraced this educational tool for tutor-guided, student-centred learning. keywords: digital technology; pathology; microscopy; medical education; united arab emirates. advances in knowledge digital pathology is an enabler of integrated undergraduate medical education, blending clinical presentations with morphologic evidence of diseases to reinforce its pathophysiologic basis. judicious use of virtual microscopy (vm) in health profession-related education is invaluable in preparing future health professionals. electronic tools are vital to student-centred learning in contemporary medical education. application to patient care vm is increasingly being adopted in diagnostic practices, revolutionising modern histopathology laboratories. it is appropriate that future doctors are sensitised to its manifold applications, while student-centred learning in today’s digital generation is enhanced. the teaching of diseased conditions in undergraduate medical education has been dominated for more than two centuries by a macroscopic display of specimens mounted in pathology museums and microscopic cellular changes on glass slides.1 over the last quarter-century, museums have reinvented learning through audiovisual compositions and tours.2 the 21st century witnessed a transformation of the microscopic demonstration of diseases through the marriage of digital image capture (whole-slide imaging [wsi]) with software capabilities (virtual microscopy [vm]). this has resulted in a revolutionary transition in learning, liberating students from laboratory benchtop microscopes for conventional light microscopy (clm).3,4 pathology instructors have utilised this opportunity to design innovative teaching modules, while student-millennials have discovered ease and interest in tapping into this platform ‘on the go’, through computers and hand-held computing devices.5 the vertical integration of undergraduate learning with postgraduate training and subsequent entry into physician practice or academic career paths demands a nuanced, stage-specific exposure to modern technology. digital microscopy has provided an opportunity for a second opinion on challenging diagnoses through remote consultation; several centres have shifted completely to virtual https://creativecommons.org/licenses/by-nd/4.0/ ritu lakhtakia clinical and basic research | 429 histopathology.6 quality control programmes have increasingly transited to virtual slides to maintain speciality accreditation norms in histopathology. sound underpinnings of microscopic evidence of diseases prepare physicians, irrespective of their chosen speciality, to make more informed decisions through multidisciplinary team meetings. thus, it makes sense to embrace technology-enhanced microscopy and blend it with clinical emphasis to prepare future doctors. this study was carried out in the newly established college of medicine (com) at mohammed bin rashid university of medicine and health sciences (mbru), dubai healthcare city, united arab emirates, which has an accredited, integrated medical curriculum with a student-centred, tutorenabled, educational philosophy. digital learning and electronic assessment underpin the curricular experience. the six-year mbbs programme has nine programme learning outcomes (plos) to graduate a safe and competent doctor who practices evidence-based medicine with ethical attributes and a knowledge of modern healthcare systems. good communication, advocacy and teamwork are essential hallmarks of this future physician with a strong capacity for self-directed learning. in the first pre-clinical year, students are introduced to structure and function, essentials of medical practice, bioethics, epidemiology and biostatistics. the second and thirdyear curricula integrate clinical manifestations and principles of management with disease morphology and its pathophysiologic basis. this study was undertaken within a four-credit general pathology course in the first semester of year two. the course introduces disease mechanisms and manifestation and specifically aligns with the plos in terms of knowledge and competency with clinicopathological correlation, communication, advocacy, peer education and self-directed learning. there is a spiral continuum with preceding basic sciences and succeeding clinical, stepwise learning. the emphasis is on clinical case-based teaching and early clinical-skills orientation in tandem, through simulations and hospital experience. thus, this study was based on the constructivist theory of learning and aimed to enhance the spiral nature of the medical curriculum. this study on digital pathology and vm as an educational intervention aimed to: a) establish the feasibility of achieving early integration of clinical reasoning with pathology teaching on a virtual microscopy platform and b) determine the studentcentricity of this teaching modality through student feedback. the objectives, design, delivery, student experience and assessment on this e-learning platform were analysed in this study. the likely impact of this innovative educational intervention is early integration of clinical reasoning with the fundamentals of disease and digital empowerment of 21st-century medical practitioners. the intent is to establish a continuum of undergraduate–postgraduate medical education. methods an educational innovation of e-learning through vm was established at the com, mbru, dubai healthcare city, united arab emirates. this is a new medical school that had its first cohort intake in 2016. the sixyear mbbs programme has three pre-clinical years followed by three clinical years. the first cohort intake had 54 students. a total of 49 students who progressed to year two participated in this study between august and december 2017. students were introduced to vm through integrated clinical case-based tutorials in the general pathology course which runs in the first semester of year two. a web-based platform, philips pathxl tutor software (cirdan pathxl tutor, lisburn, ireland), was utilised for this educational delivery, accessed through an institutional subscription. it provided a whole scanned microscopic slide inventory comprising histology and histopathology slides that illustrated a range of common disease processes across organ systems. dynamic vm viewing was accessed from the cloud of the software provider. the software tools enabled clinical case content to be built by tutors, by combining text and static pictures (clinical, radiology, electrophysiologic, macroscopic disease, multimedia, tables, etc.) and linking them with dynamic vm. tutor training and student orientation formed part of the initiation process. initial hurdles in software manipulation and annotation were reported to the website support team, who responded with software update solutions. this enabled a smooth and eventfree educational delivery. vm-centred clinical case teaching was introduced in two-hour practical sessions within the general pathology course. the cases illustrated the week’s teaching theme and objectives such as cell injury, inflammation, oedema and thrombosis through fatty change, acute appendicitis, pulmonary oedema and thrombo-embolism, respectively. one case example of the 25 clinical scenarios taught during the semester is illustrated in figure 1. additional images and multimedia (e.g. radiology, electrocardiography, haema tology, microbiology reports, etc.) were included virtual microscopy in undergraduate pathology education an early transformative experience in clinical reasoning 430 | squ medical journal, august 2021, volume 21, issue 3 as appropriate. the clinical cases were designed inhouse to inculcate an early clinico-pathophysiologicmorphologic integration with the resultant ability to optimise the choice of investigation and rationalise diagnosis and management. whole-slide images were uploaded to the case either alone or with normal histology slides to contrast normal with abnormal (e.g. normal myocardium with ischaemic necrosis in infarction) or features of two disease processes (e.g. lobar pneumonia versus bronchopneumonia). slides were annotated to allow students to identify and discuss disease changes with the tutor and peers. clinical complexity was appropriate to the stage of learning and integrated with the students’ parallel learning of clinical skills and other diagnostic disciplines such as radiology, haematology, biochemistry, microbiology, etc. a total of 15 interactive teaching sessions lasting two hours each, in a small group format, were conducted in a well-equipped computer laboratory [figure 2]. students had access to prepared cases on the website ‘on the go’ through their laptops, ahead of the formal scheduled discussion. the tutor projected the webpage live while students conducted the discussion. tutor and student-annotated areas on vm were addressed. case content was probed through interactive questions directed towards clinicopathological correlations, critical reasoning and logical thinking, and focused on identifying gaps in knowledge and comprehension. follow-up enquiries from students, individually or through forums, closed the loop. student feedback was obtained at mid-semester through anonymous tutor-designed surveys and at end-semester through formal university-enabled electronic feedback on the courses. the surveys elicited the students’ experience with vm (four questions) and content (five questions) through a mixed-methods approach. quantitative responses on satisfaction with the vm experience on a four-item questionnaire were measured on a 5-point likert scale where 1 = lowest and 5 = highest. a five-item questionnaire on case content was scored from 1–3 as ‘agree’, ‘partly agree’ and ‘disagree’, respectively [figures 3 and 4]. qualitative responses sought anonymous, open-ended comments addressing lacunae and positive learning experiences for the improvement of the module and reinforcement of strengths, respectively. tutor feedback entailed inputs regarding course appropriate case creation; learning curve on inform ation technology (it) tools including expertise and time management, navigation and ease of teaching on the web-based programme, mutual satisfaction between teacher and student in handling the oneon-one computer sessions and software support and troubleshooting by the website maintenance team. an objective-structured practical examination (ospe) was conducted through the philips tutor figure 2: an interactive virtual microscopy session in progress in the computer laboratory at the mohammed bin rashid university of medicine and health sciences, dubai, united arab emirates. students dynamically manipulate the virtual microscope and discuss the questions and annotations with the tutor. figure 1: composite illustration of a vm-centred prototype case (1 of 25 clinical scenarios) showing acute appendicitis. a clinical vignette integrates the anatomical basis of location of pain and the gross appearance of the operated appendix. microscopic comparison of a normal (blue arrow) and diseased (red arrow) appendix at low magnification (upper right) and transmural neutrophilic infiltration at a higher magnification is possible. ritu lakhtakia clinical and basic research | 431 software’s online testing and examination generation module (olt) portal. it was weighted at 15% of the course’s semester assessment. students were provided formative guidance in the e-assessment of skills and in the question format. the skill domain was tested through ospe stations that mirrored the teaching. analysis of clinical vignettes centred on vm explored students’ identification of disease morphology, for example, granulomas with clinicopathologic correlation and pathophysiologic interpretation of disease patterns. the format included vm slide-based annotations, multiple choice questions (mcqs) and short answers. a sample question is illustrated in figure 5. the emphasis was not on mastery over histologic diagnosis, but on stage-appropriate knowledge of pathologic change that explains a clinical or radiologic manifestation or functional alteration due to disease. an irb exempt review was approved for this educational research: reference mbru-irb-2019-014. informed consent was obtained from the students. results for user friendliness, 45 out of 49 students (91.84%) scored ease of software-use between 4–5. specific suggestions for improvement were related to frustration with the ‘time-out’ mode, which required repeated log-in. the inability to write ‘notes’ on the figure 3: quantitative responses of students’ experience with virtual microscopy on a likert scale of 1–5 where 1 is lowest and 5 is highest (n = 49). figure 4: student feedback on case content during a virtual microscopy course scaled quantitatively as ‘agree’, ‘partly agree’ and ‘disagree’ (n = 49). figure 5: example of the virtual microscopy software output showing a question that integrates clinical reasoning with disease morphology. virtual microscopy in undergraduate pathology education an early transformative experience in clinical reasoning 432 | squ medical journal, august 2021, volume 21, issue 3 same webpage while class discussions were ongoing was a further challenge. the capacity to manipulate vm images showed a gradual learning curve; 43 students (87.76%) scored this attribute as a 4 or 5. a part of the learning adaptation was the gradual recognition of cellular patterns from normal to abnormal. annotation usage by students earned a score of 4–5 by 41 students (83.67%). the interactive capacity of this tool, especially in out-of-class feedback, was especially useful, demonstrating self-directed learning [figure 3]. this course was the students’ first introduction to disease concepts and clinico-pathological correlation. a total of 40 out of 49 students (81.63%) agreed that the content matched the stage of learning. furthermore, 45 (91.84%) students agreed that there was a correlation of practical cases to the didactic theme of the week. a total of 38 students (77.55%) agreed that the course establishes a clinical foundation. in qualitative feedback, students expressed their initial struggle with clinical reasoning and a self-perceived gradual growth in capacity as they reached the end of the course, which was specifically attributed to case content. they identified frequent cross-integration with clinical skill learning in a simulated setting within the same semester. in addition, 42 students (85.71%) agreed that the course cross-integrates pathology cases with other diagnostic modalities. the feedback acknowledged developing specific links with haematology, biochemistry and microbiology and critical learning of laboratory investigations in specific diseases. students made particular mention of achieving vertical integration of disease identification in pathology with previous sensitisation to imaging in anatomy. clinico-pathological correlation appeared to be a strength of this teaching format, with 41 students (83.67%) agreeing that there was development of logical analysis of a clinical presentation. student engagement was demonstrated by a near-100% attendance across 15 face-to-face sessions [figure 4]. content design, developed in-house, was intellect ually stimulating, resulting in a robust synthesis with the course’s learning objectives. at each step, clinical reasoning, as the ultimate goal of pathology teaching, remained the guiding principle. creation of case scenarios, familiarisation with software and it trouble shooting was demanding. the most rewarding aspect was the interactive delivery and steady improvement in the students’ analytical abilities over the period of study. the software assessment format, which allowed for the complex assembly of text, vm, annotations and static images, was effective in creating items that tested disease recognition and critical thinking. the mean ospe score of 82.14% (range 60–100%) was similar to the average of the final semester theory examination. in the ospe, students performed best on questions that integrated the analysis of symptoms, signs and radiology (80%), with a lower average on functional correlations with organ disease (75%), reflective of the early stage of learning. assessment, in turn, provided an opportunity for formative feedback—individually and collectively—to address lacunae in fundamental disease concepts. discussion digital technology is ubiquitous and is an essential fact of human existence today whether in a social or professional arena. in the early 20th century, clm display, at first through analogue and later through digital video cameras, led to the evolution of telemedicine as a means of distance education. it was utilised by diagnostic disciplines such as radiology and anatomic pathology to enable second-opinion consultations by experts or for diagnostic coverage to remote areas.7 however, in educational terms, telepathology restricted display and manipulation to the instructor-operator. this prevented the exploratory learning that determines knowledge–skill integration. pioneering efforts were made to explore replacing clm with vm in the early 21st century.8,9 over the subsequent years, it became clear that the next logical step would be its application to medical teaching and diagnostic practice with the advancement of resolution in wsi.3,4 today, it has become an enabling force in pathology education in many medical schools across the world, while efforts for standardising its usage in diagnostic practice are ongoing.10,11 multicentric validation studies in recent times have provided an impetus to its acceptance, both in routine diagnostic reporting and for off-site frozen-section reporting.12,13 virtual microscopy will play a vital role in the sharing of whole-slide images for research access across the scientific community as this facility expands, bridging opportunities across developing and developed nations.14 in pathology education, wsi and vm have over come several shortcomings of the traditional microscope: (1) the need for producing multiple glass slides from limited tissues for individual viewing by a large number of students; (2) the limitation of the number of slides in cytology preparation; (3) replenishment of slides for faded stains or broken/lost slides; (4) individual supervision during the learning process; and (5) laboratory-bound access to learning. there are, in addition, two potent arguments for vm in undergraduate medical education: the ease with which a generation born to the digital age accepts and enjoys it and the robust shift from tutor-directed to ritu lakhtakia clinical and basic research | 433 student-centred learning, as it is a ‘take-anywhere’, ‘use-anytime’ tool. the ergonomic ease of vm over clm can hardly be overemphasised. in the setting of a new medical school, the use of vm ab initio provided all these advantages. the students in this study cohort had limited parallel experience on microscope hardware usage in two practicals each for the microbiology and haematology courses delivered in the same semester. however, students showed rapid engagement with the webbased platform, which provided ease of access and content exploration. microscopic slide resolution was excellent and matched glass slide clarity during teaching and learning. while the students have excellent digital skills growing up as a digitally enabled generation, vm was virgin territory. once mastered, the ease of image manipulation provided a gaming effect to stimulate student learning. an interesting off-shoot was the high rate of student attendance, validating enthusiasm for this simulated learning platform and its perceived benefits. marchevsky et al. reported the switchover to case-based teaching of pulmonary pathophysiology on digitised images aided by text and audio recordings in the university of california-los angeles, guided by a pathologist-pulmonologist tutor team.8 observation over a four-year period reported stimulated student interest upping attendance from 30–40% to 100% and progressive student satisfaction.8 in the current study cohort, student attendance had been unprecedented, validating student interest. steinberg et al.’s study illustrating cytopathology applications in clinical practice to second year students, using 10 electronic, interactive modules and evaluation by mcqs showed demonstrable student satisfaction.9 wsi and vm adaptive tutorials were used in a randomised crossover trial as tools to introduce cytopathology to senior medical students at the university of new south wales, who were previously naïve to the subject matter.15 physician assistants exposed to video-assisted microscopy showed significantly higher practical examination scores compared to five previous cohorts that used conventional microscopy.16 this is attributed largely to two processes. first, the discussions that go beyond textbook facts to real-life simulated cases and problem-solving capability that allows students to take ownership of the process; and second, the design of the assessment itself that stimulates critical thinking, which is a consequence of the students’ approach to these sessions.6 at a new medical school, introduction of vm from the beginning, when creating an integrated curriculum and choosing a digital format of delivery, was a wellconsidered decision. the continuum of learning normal histology in tandem with histopathology on a dynamic image mode was perceived by students as an enriching experience. students’ interpretive capacity improved from their first exposure continually through the semester and dramatically in the following semesters, as they followed pathology learning in the organ systems (data not shown). students had the freedom to explore and annotate images within the construct of clinical cases; the simulation provided an enriched, clinically relevant interpretation of disease while encouraging collaborative peer learning, as also reported by others.17 the focus on clinical reasoning, on the one hand, takes away the tedium of looking at static images of morphologic changes and learning by rote to ‘spot’ diseased cells and tissues. on the other hand, it avoids the ocular adaptation challenges to the physical microscope and its restricted availability, as it is confined to the educational site. there is a strategic approach that graduate students take, from initially engaging in simple disease-based integrative learning to dealing with the complexities of presentation-based differential diagnosis in their third year with increasing clinical maturity. the foundation laid in year two transits to pathology teaching within six integrated organ-systems courses over the next three semesters (years two and three) of the curriculum. in this way, within and across the organ systems, spiral learning is achieved. a vmcentred approach enhances this learning journey and will lead students to the clerkship years, armed with a robust understanding of diseases. vm has already entered the arena of graduate medical education in histopathology, haematology and dermatology, wherein large libraries of digitised slides, available via open access or through subscription, enable the mastery of a range of disease diagnoses beyond the confines of clinical training sites.18,19 in a nation-wide survey in the usa across 52 histopathology residency programmes, 82% used web-based digital slide collections.18 in-training and certification examinations now use a vm platform. in addition, anatomic pathology and cytopathology quality assurance programmes have already adopted it to ensure safe diagnostic expertise.20,21 thus, the continuum of undergraduate–postgraduate learning of vm is now an established need. continuing efforts and validation have brought vm into the realm of diagnostic histopathology with some centres having taken the leap to exclusive digital practice.22,23 medical practice, whatever the chosen specialty, rests on sound knowledge, skills and attitudes. visual demonstrations of disease recognition, whether clinical virtual microscopy in undergraduate pathology education an early transformative experience in clinical reasoning 434 | squ medical journal, august 2021, volume 21, issue 3 or in diseased organs, assume multiple forms and the vm mode has brought another nuance to learning styles. almost all hospital-based specialty practice entails multidisciplinary team (mdt) meetings to secure rational and comprehensive management decisions. today, vm in one form or another, occupies centre-stage in an mdt’s ultimate aim of making informed decisions on patient management.6 irrespective of the chosen specialty, it will become a vital cog in the learning wheel of a competent medical professional when practicing safe medical care; hence, its use early in the educational process seems entirely appropriate. this study was subject to two main limitations. first, the instructional strategy was implemented in the first cohort of students at a new medical school; hence, it lacks a comparison with a control group that underwent simultaneous conventional microscopy teaching. second, the analyses can be improved by surveying the same cohort once they enter clinical clerkship, to reflect on the value of early clinical reasoning integrated with student-centred teaching of vm pathology. conclusion digital pathology and vm span the continuum of learning about disease mechanisms and appearances from undergraduate or postgraduate levels to continued medical education. the art of its usage relies on the careful construction of teaching content, to make it the backbone for clinical reasoning and critical thinking. this study demonstrates its successful implementation in integrated clinical teaching in a new medical school and establishes its utility through student satisfaction and assessment. its usage finds vindication in the current covid-19 pandemic when remote digital delivery has proven to be the saviour of education. vm is, today, an integral part of quality assurance, research and multidisciplinary meetings for patient management. its introduction into diagnostic practice and specialised cross-consultations is a work in progress, subject to validation and regulation. the growing digital platform, integrated with advances in high-resolution images, holds the future of education, research and patient care. c o n f l i c t o f i n t e r e s t the author declares no conflicts of interest. f u n d i n g no funding was received for this study. references 1. marreez ym, willems ln, wells mr. the role of medical museums in contemporary medical education. anat sci educ 2010; 3:249–53. https://doi.org/10.1002/ase.168. 2. nesi g, santi r, taddei gl. art and the teaching of pathological anatomy at the university of florence since the nineteenth century. virchows arch 2009; 455:15–19. https://doi.org/10.10 07/s00428-009-0794-y. 3. dee fr. virtual microscopy in pathology education. hum pathol 2009; 40:1112–21. https://doi.org/10.1016/j.humpath.2009.04.010. 4. foster k. medical education in the digital age: digital whole slide imaging as a learning tool. j pathol inform 2010; 1:14. https://doi.org/10.4103/2153-3539.68331. 5. saco a, bombi ja, garcia a, ramírez j, ordi j. current status of whole-slide imaging in education. pathobiology 2016; 83:79–88. https://doi.org/10.1159/000442391. 6. orah m, rotimi o. telepathology in low resource african settings. front public health 2019; 7:264. https://doi.org/10.3389/fpu bh.2019.00264. 7. weinstein rs, graham ar, richter lc, barker gp, krupinski ea, lopez am, et al. overview of telepathology, virtual microscopy, and whole slide imaging: prospects for the future. hum pathol 2009; 40:1057–69. https://doi.org/10.1016/j.humpath.2009.04.006. 8. marchevsky am, relan a, baillie s. self-instructional “virtual pathology” laboratories using web-based technology enhance medical school teaching of pathology. hum pathol 2003; 34:423–9. https://doi.org/10.1016/s0046-8177(03)00089-3. 9. steinberg dm, chan ty, freedman ja, grimm la, ling l, lehmann hp, et al. teaching cytopathology to second-year medical students. an interactive, case-based approach. acta cytol 2002; 46:481–9. https://doi.org/10.1159/000326865. 10. campbell ws, hinrichs sh, lele sm, baker jj, lazenby aj, talmon ga, et al. whole slide imaging diagnostic concor dance with light microscopy for breast needle biopsies. hum pathol 2014; 45:1713–21. https://doi.org/10.1016/j.humpath.20 14.04.007. 11. eccher a, neil d, ciangherotti a, cima l, boschiero l, martignoni g, et al. digital reporting of whole-slide images is safe and suitable for assessing organ quality in preimplantation renal biopsies. hum pathol 2016; 47:115–20. https://doi. org/10.1016/j.humpath.2015.09.012. 12. baidoshvili a, stathonikos n, freling g, bart j, 't hart n, van der laak j, et al. validation of a whole-slide image-based teleconsultation network. histopathology 2018; 73:777–83. https://doi.org/10.1111/his.13673. 13. pradhan d, monaco se, parwani av, ahmed i, duboy j, pantanowitz l. evaluation of panoramic digital images using panoptiq for frozen section diagnosis. j pathol inform 2016; 7:26. https://doi.org/10.4103/2153-3539.181770. 14. lee lmj, goldman hm, hortsch m. the virtual microscopy database-sharing digital microscope images for research and education. anat sci educ 2018; 11:510–15. https://doi.org/10.10 02/ase.1774. 15. van es sl, kumar rk, pryor wm, salisbury el, velan gm. cytopathology whole slide images and adaptive tutorials for senior medical students: a randomized crossover trial. diagn pathol 2016; 11:1. https://doi.org/10.1186/s13000-016-0452-z. 16. mcdaniel mj, russell gb, crandall sj. innovative strategies for clinical microscopy instruction: virtual versus light micros copy. j physician assist educ 2018; 29:109–14. https://doi. org/10.1097/jpa.0000000000000198. 17. braun mw, kearns kd. improved learning efficiency and increased student collaboration through use of virtual micros copy in the teaching of human pathology. anat sci educ 2008; 1:240–6. https://doi.org/10.1002/ase.53. https://doi.org/10.1002/ase.168 https://doi.org/10.1007/s00428-009-0794-y https://doi.org/10.1007/s00428-009-0794-y https://doi.org/10.1016/j.humpath.2009.04.010 https://doi.org/10.4103/2153-3539.68331 https://doi.org/10.1159/000442391 https://doi.org/10.3389/fpubh.2019.00264 https://doi.org/10.3389/fpubh.2019.00264 https://doi.org/10.1016/j.humpath.2009.04.006 https://doi.org/10.1016/s0046-8177(03)00089-3 https://doi.org/10.1159/000326865 https://doi.org/10.1016/j.humpath.2014.04.007 https://doi.org/10.1016/j.humpath.2014.04.007 https://doi.org/10.1016/j.humpath.2015.09.012 https://doi.org/10.1016/j.humpath.2015.09.012 https://doi.org/10.1111/his.13673 https://doi.org/10.4103/2153-3539.181770 https://doi.org/10.1002/ase.1774 https://doi.org/10.1002/ase.1774 https://doi.org/10.1186/s13000-016-0452-z https://doi.org/10.1097/jpa.0000000000000198 https://doi.org/10.1097/jpa.0000000000000198 https://doi.org/10.1002/ase.53 ritu lakhtakia clinical and basic research | 435 18. vallangeon bd, hawley js, sloane r, bean sm. an assessment of pathology resident access to and use of technology: a nationwide survey. arch pathol lab med 2017; 141:431–6. https://doi.org/10.5858/arpa.2016-0228-oa. 19. kent mn, olsen tg, feeser ta, tesno kc, moad jc, conroy mp, et al. diagnostic accuracy of virtual pathology vs traditional microscopy in a large dermatopathology study. jama dermatol 2017; 153:1285–91. https://doi.org/10.1001/jamadermatol.2017.3284. 20. ross j, greaves j, earls p, shulruf b, van es sl. digital vs traditional: are diagnostic accuracy rates similar for glass slides vs whole slide images in a non-gynaecological external quality assurance setting? cytopathology 2018; 29:326–34. https://doi. org/10.1111/cyt.12552. 21. van es sl, greaves j, gay s, ross j, holzhauser d, badrick t. constant quest for quality: digital cytopathology. j pathol inform 2018; 9:13. https://doi.org/10.4103/jpi.jpi_6_18. 22. goacher e, randell r, williams b, treanor d. the diagnostic concordance of whole slide imaging and light microscopy: a systematic review. arch pathol lab med 2017; 141:151–61. https://doi.org/10.5858/arpa.2016-0025-ra. 23. stathonikos n, veta m, huisman a, van diest pj. going fully digital: perspective of a dutch academic pathology lab. j pathol inform 2013; 4:15. https://doi.org/10.4103/2153-3539.114206. https://doi.org/10.5858/arpa.2016-0228-oa https://doi.org/10.1001/jamadermatol.2017.3284 https://doi.org/10.1111/cyt.12552 https://doi.org/10.1111/cyt.12552 https://doi.org/10.4103/jpi.jpi_6_18 https://doi.org/10.5858/arpa.2016-0025-ra https://doi.org/10.4103/2153-3539.114206 domestic violence against infertile women a systematic review and meta-analysis farangis sharifi,1 jamshid jamali,2 mona larki,3 *robab l. roudsari3,4 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 14–27, epub. 28 feb 22 submitted 7 oct 20 revision req. 31 jan 21; revision recd. 4 mar 21 accepted 7 apr 21 1student research committee, 4department of midwifery, school of nursing and midwifery, mashhad university of medical sciences, mashhad, iran; 2social determinants of health research center, mashhad university of medical sciences, mashhad, iran; 3nursing and midwifery care research center, mashhad university of medical sciences, mashhad, iran *corresponding author’s e-mail: rlatifnejad@yahoo.com violence against women, especially partnerand sexual violence, is one of the most pressing public health concerns affecting women today.1 in addition to violating basic human rights, violence of this sort affects the physical, sexual, reproductive, emotional, mental and social health of both the individual and their family. unfortunately, more than a third (30%) of women in the world have reported that they have experienced some form of physical and/ or sexual violence in their lifetime by their partner/ non-partner. globally accrued data reported by the world health organization (who) has shown that spousal physical or sexual violence varies from 15% in japan to 70% in ethiopia and peru.2 additionally, 38% of murders of women has been reported to be committed by their intimate partners.1 spousal violence often has negative effects on an individual’s chronic conditions, physical diseases and healthrisk behaviours.3 domestic violence (dv) has also been shown to have a significant effect on women's reproductive health.4 often, such women are of poor health and receive less medical care than others. many other problems caused by violence against women include the subsequent harm to the health and wellbeing of their children, the effect of dv on economic development and ultimately, the failure to achieve the millennium development goals (mdgs).1,2 risk factors for dv include low levels of education, having a mother with a history of violence, young age, socio-economic status, low income, unemployment, childhood abuse, alcohol abuse, gender inequality, male dominance over a woman in a relationship and a general attitude of accepting violence.2,5 infertility is a public health issue affecting a large part of the world's population. research from developing countries has shown that one in four women is infertile with many studies indicating the psychological and social effects of infertility.6–14 dv against infertile women includes physical, psycho logical and sexual abuse.15 it has been demonstrated that 1.8–61.8% of infertile women experience different types of violence.16–18 infertility often becomes a signif icant source of stress leading to sudden changes in women's relationships with family members and society.19 in some communities, women are considered to be the cause of infertility and factors such as level of education, employment status, independence, and social status appear to determine risk of violence against such women.4 dv has been also reported to be associated with forced marriage, treatment with invitro fertilisation (ivf), drug abuse, women's emotional status, addiction, smoking or drug abuse of the spouse and mental and physical diseases of the husband.20 although a systematic review by steller et al. showed evidence for a relationship between infertility and intimate partner violence (ipv), they acknowledged that the availability of data was limited, leaving them with only 21 studies for the review.21 moreover, the study carried out by steller et al. was only a systematic review with a narrative report of ipv and no metaanalysis was conducted on the prevalence of violence against infertile women. it also seems that after more review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.075 abstract: domestic violence (dv) against infertile women is an important health concern affecting their well-being. this systematic review and meta-analysis investigated the prevalence of dv against infertile women. the study was done based on the preferred reporting items for systematic reviews and meta-analysis (prisma) guideline. various international electronic databases were utilised in order to retrieve the necessary data. articles were included if they were cross-sectional studies published in english and in persian journals and investigated the prevalence of dv against infertile women up to may 2020. out of 630 studies, 26 cross-sectional studies were systematically reviewed, from which 15 studies were included in the meta-analysis. the experiences of dv varied widely among the infertile women (14.987–88.918%). the results of meta-analysis showed that the prevalence of dv stood at 47.163% (95% confidence interval: 34.660–59.850). psychological and emotional violence were among the most common types of violence. considering the high rate of dv, it is recommended that policymakers address the issue by providing supportive care to such vulnerable populations, including educational and counselling services. keywords: female infertility; violence; domestic violence; intimate partner violence. https://creativecommons.org/licenses/by-nd/4.0/ farangis sharifi, jamshid jamali, mona larki and robab l. roudsari review | 15 than five years of conducting the last review on the topic, there is a need for an updated investigation of the research in this area including more recent studies on the violence against infertile women. in their study titled “factors related to violence against infertile women”, hajizade-valokolaee et al. used a qualitative method and an ecological approach in which a number of qualitative themes were extracted.22 given the importance of women‘s rights, the fact that infertile women are a group at risk of ipv and in need of support and considering that no comprehensive review has been done recently in this field, the present systematic review and meta-analysis was conducted to investigate the prevalence of dv against infertile women. methods this systematic review and meta-analysis was perf ormed in accordance with the preferred reporting items for systematic reviews and meta-analyses (prisma) guideline. s e a r c h s t r at e g y the process of data collection entailed a thorough search of various english-language databases including pubmed, scopus, web of science, ovid and google scholar as well as persian databases including iran medex and scientific information database (sid) for relevant articles. the following keywords were used for a search of the titles, abstracts or keywords of the articles: apostrophe ‘sterility’, ‘subfertility’, ‘infertility’, ‘violence’, ‘domestic violence’, ‘intimate partner violence’ and ‘spousal abuse’. the ‘and’ and ‘or’ operators were used between each keyword, with no time limit. additionally, the references of the retrieved articles were also searched for any remaining articles that was possibly relevant to the current study. all of the aforementioned searches were independently performed by two reviewers and in case of disagreement in certain cases, a third party was consulted. the data collection period lasted from the beginning of march to the end of august 2020. i n c l u s i o n c r i t e r i a articles in both englishand persian-languages were included in the present review if they assessed prev alence of dv in infertile women until may 5th, 2020. after independent assessment by the authors, eligible studies were included in the study while expert opinions, newspaper articles, book chapters, dissertations, conf erence presentations, reviews, editorials, brief commun ications and case reports were excluded [figure 1]. s t u d y s e l e c t i o n as part of the article selection process, one of the researchers reviewed the titles and abstracts of the articles for relevance. in the initial search of the online databases, 630 studies were extracted including 311 articles from pubmed, 129 from scopus, 76 from web of science, 100 from google scholar, five from ovid, one from sid and four from magiran databases. four additional articles were obtained from searching through the references of relevant articles. a total of 145 articles were excluded due to duplication and 485 articles remained. after screening the titles figure 1: flowchart showing the study selection process used for identifying articles included in the current systematic review and meta-analysis. domestic violence against infertile women a systematic review and meta-analysis 16 | squ medical journal, february 2022, volume 22, issue 1 and abstracts, 410 articles were removed based on the inclusion and exclusion criteria and a total of 75 articles were retained. after assessment of the full text of the articles for eligibility, 49 articles were excluded in accordance with the study criteria yielding a final total of 26 studies for qualitative synthesis (systematic review). of the 26 articles, 15 were presumed to be eligible for quantitative analysis and were included in the meta-analysis. among these 15 articles, 15 reported the overall prevalence of dv and 14, 12 and 11 articles reported only physical violence, psychological violence or sexual violence, respectively [figure 1]. d ata e x t r a c t i o n a total of 26 descriptive studies were used for systematic review. all the included studies were about dv and infertility in women. titles and abstracts were evaluated to select eligible studies and some articles were excluded given the study criteria. following this, the full text of the selected articles was checked for relevance based on the inclusion criteria. data including the article title, authors, year of publication, journal name, research location, sample size, sampling method, inclusion criteria, exclusion criteria, type of questionnaire used to assess the prevalence of violence and its types among participants, method of scoring the questionnaire, reliability of the questionnaire and the study findings were extracted into two checklists by the first and second authors. q u a l i t y a s s e s s m e n t a checklist was designed to assess quality of the studies [table 1]. this checklist was the same as the critical appraisal skills programme tool for descriptive/crosssectional studies and was specifically used to address the question of the present study, and has been used in a previous systematic reviews.23,24 the questionnaire consisted of 18 items and the score of each item was either 0 or 1; if the study met the desired criteria, a score of 1 was given and if the required criteria were not met, a score of 0 was given. the total score of the checklist ranged from 0–18. consequently, based on their scores, all included studies were classified into three levels: (1) "high quality studies", including the studies scoring 75% and above (13 points or higher) of the total score; (2) "medium quality studies", including the studies scoring between 50–75% (9–12 points) of the total score; and (3) "low quality studies", including the studies scoring below 50% of the total score (8 points or less).24 the results of quality assessment of the articles showed that 22 studies (81.5%) were classified as being high quality, four studies (14.8%) as medium quality and one low quality study (3.7%). d ata s y n t h e s i s a n d a n a ly s i s after careful reading and examination, 15 studies were included in the meta-analysis of the overall prevalence of total score of domestic violence against infertile women. it should be noted that one more article, in which the total score of violence had not been reported and just the frequency of different types of violence was reported, was included in the metaanalysis of different types of domestic violence. all the included studies had reported the score of dv in infertile women. a test for heterogeneity was applied using the chi-square test and i2 statistics (i2 = 98.68%, p <0.0001). according to this test, the overall estimates were calculated using the random-effects metaanalysis model. data analysis was carried out using the medcalc® statistical software package, version 19.4.1 (medcalc software, ostend, belgium). table 1: list of criteria based on the critical appraisal skills programme tool for descriptive/cross-sectional studies to assess the quality of articles on domestic violence against infertile women23 value study participants a was the sample representative of a defined population? b a description is included of at least two sociodemographic variables (e.g. age, sex, economical status, educational status, etc.) c inclusion and/or exclusion criteria are provided d participation rates (defined as the % age of eligible patients who gave their informed consent) are included and these rates exceed 70% e information is given about the ratio between nonresponders versus responders violence assessment f a standard questionnaire is used g are measurement tools available or described? h is the method of reliability and its measures justified? study design i is the setting for data collection justified? j is the sample size sufficient? k is the method of sampling justified? l a primary objective of the study is to examine the dv in infertile women m it is clear how the data were collected (e.g. interview, questionnaire) results n are the results significant and meaningful (p value)? o is there a summary of the bottom-line result of the trial in one sentence (key findings)? p is there an in-depth description of the analytic process? q is sufficient data presented to support the findings? r are the findings explicit? dv = domestic violence. farangis sharifi, jamshid jamali, mona larki and robab l. roudsari review | 17 table 2: characteristics of 26 studies assessing domestic violence against infertile women15,16,18,20,25–46 author (year) country study design sampling tool n relevant findings quality using casp aduloju et al.38 (2015) nigeria crosssectional convenient semistructured questionnaire on violence 131 •total dv = 31.2% •psychological dv: >50% •dv associated with unemployment, polygamous marriage, husband’s social habits, primary infertility and prolonged duration of infertility. •no significant differences in the age of the women, duration of marriage and duration of infertility. high akpinar et al.33 (2019) turkey crosssectional convenient aas 142 •total dv = 47.9% •psychological dv = 76.5% •physical dv = 17.6% •sexual dv = 4.4% •physical and sexual abuse = 1.5% •risk factors included low educational and economic level and living in a compound family. moderate akyuz et al.36 (2013) turkey comparative descriptive convenient sdvw 228 •emotional, economic and sexual violence scores were higher in the infertile group. •the verbal violence score was lower. high alijani et al.28 (2018) iran crosssectional consecutive cts2 379 •total dv = 88.9% •physical violence = 25.9 % •sexual violence = 28.2% •no relationships between violence and women’s educational status, men’s jobs, place of residence, alcohol consumption and drug addiction. •risk factors included men being smokers and women being of younger age. high ameh et al.15 (2007) nigeria crosssectional consecutive demographic and dv questionnaire 233 •total dv = 41.6% •physical abuse = 17.5% •psychological torture = 51.5% •verbal abuse = 39.2% •educational level, parity, type of marriage and duration of infertility were not statistically significant. moderate ardabily et al.16 (2011) iran crosssectional convenient cts2 400 •total dv = 61.8 •psychological dv = 33.8% •physical dv = 14% •sexual dv = 8% high bondade et al.35 (2018) turkey crosssectional convenient ham-a, ham-d, who violence against women instrument 100 •total dv = 50% •psychological violence = 34% •physical violence = 11% •sexual violence = 5% •the prevalence of anxiety disorder and depressive disorder was high among the ipv group. high dhont et al.44 (2011) rwanda survey structured questionnaire 312 •dv more frequently in the survey by infertile than fertile couples. •infertility was important determinant for the psycho-social consequences suffered. moderate etesami pour et al.31 (2011) iran comparative descriptive simple random family violence and sexual satisfaction, disorders questionnaire 100 •the rate of mental, physical and economical violence in infertile women was significantly higher than fertile ones. •significant interaction effect between education of women and the rate of couple abuse was not observed in fertile and infertile groups. high farzadi et al.30 (2014) iran crosssectional convenient modified questionnaire of violence against women 200 •experienced at least one type of physical violence = 45% •sexual violence ≈ 54% •psychological violence = 82% high iliyasu et al.39 (2016) nigeria crosssectional systematic random dhs, cts2 373 •total dv = 35.9% •psychological violence = 94.0% •sexual = 82.8% •verbal = 35.1% •physical forms = 18.7% •multiple forms of violence = 25.4% •lack of formal education, employment in the informal sector and having an unemployed spouse or one with low level of education were all independently associated with ipv. high lotfy et al.40 (2019) egypt crosssectional convenient iwevds 304 •the most common forms of dv were psychological violence and verbal abuse. •predictors included wife’s age, residency, previous intra cytoplasmic sperm injection, divorce threats from and fear of husband. high mansour et al.41 (2018) egypt crosssectional convenient researchermade questionnaire, general health questionnaire 246 •psychological violence was found to be the most common type of violence followed by sexual and physical violence. •the severity of dv had a significant correlation with the social class of the woman, chronic disease of the husband, duration of marriage and trial of icsi treatment. high n = total number of infertile women; casp = critical appraisal skills program; dv = domestic violence; aas = abuse assessment scale; sdvw = questionnaire and scale for marital violence against women; cts2 = revised conflict tactics scale; ham-a = hamilton anxiety rating scale; ham-d = hamilton depression rating scale; ipv = intimate partner violence; dhs =demographic and health survey instrument; iwevds = interview questionnaire of infertile women’s exposure to violence determination scale; pss = perceived stress scale; icsi = intracytoplasmic sperm injection; sfps = stigma of fertility problems scale; nfhs-3 = national family health survey 3; fsfi = domestic violence inventory and female sexual function index; ivf = in vitro fertilisation; mqs = marital quality scale; pasnp = partner abuse scale, non-physical; npaps = non-physical abuse of partner scale. domestic violence against infertile women a systematic review and meta-analysis 18 | squ medical journal, february 2022, volume 22, issue 1 table 2 (cont’d.): characteristics of 26 studies assessing domestic violence against infertile women15,16,18,20,25–46 author (year) country study design sampling tool n relevant findings quality using casp ozturk et al.25 (2021) usa survey convenient aas, pss, social support questions, sfps 786 •total dv = 21.8% •emotional abuse = 30.3% •physical abuse = 21.8% •experiencing high levels of stigma. •one in five infertile women were exposed to emotional or physical violence. high ozturk et al.45 (2017) turkey crosssectional convenient iwevds 301 •total dv = 32.5% •emotional dv = 21.8% •physical dv = 31.9% •sexual dv = 21.8% •verbal dv = 38.7% high pasi et al.42 (2011) india survey nfhs-3 2,023 •experienced physical and/or sexual violence in the last 12 months = 77.8% low poorn owrooz et al.27 (2019) iran crosssectional convenient fsfi 147 •total dv = 56.6% •physical violence = 34% •sexual violence = 27.2% •psychological violence = 52.4% •physical, sexual and psychological violence were higher in infertile women than fertile women. high sahin et al.34 (2018) turkey crosssectional questionnaires administered through the face-to-face interview method, beck anxiety inventory 774 •total dv = 15.0% •emotional dv = 56.1% •physical violence = 11% •sexual dv = 21.9% •verbal dv = 11% •associated factors included being a woman aged 25 years and above, education level of high school and above, unemployment, addiction to smoking and alcohol, obesity, marriage more than once, being 19 years of age and below at the time of the first marriage, being married for four or less years, primary infertility, being infertile for two years and below and a family history of infertility. •anxiety levels were significantly higher among infertile women with a history of dv. high sami and ali 45,46 (2012) pakistan crosssectional convenient aas 400 •dv = 64% •physical violence = 23.1% •verbal violence = 60.8% high sheikhan et al.20 (2014) iran crosssectional convenient dv questionnaire 400 •experienced dv = 34.7% •physical violence = 5.3% •emotional violence = 74.3% •sexual violence = 47.3% •dv was significantly associated with unwanted marriage, number of ivf treatments, drug abuse, emotional status of the women, smoking, addiction or drug abuse by the spouse, mental and physical diseases of the husband. high sis çelik et al.32 (2018) turkey crosssectional simple random iwevds 423 •total dv = 72%. •physical violence = 30% •sexual violence = 6% •emotional violence = 62% •economic violence = 19%. •associations existed between violence against women and husband's low education level, living in a rural area, husband’s classification as a ‘worker’ based on employment type, low level of income and primary infertility. •no significant associations between domestic violence and women’s age, educational level and employment status of women, husband’s age, type of family, duration of infertility and marriage. high satheesan and satyarana yana43 (2018) india crosssectional simple random mqs 30 •total dv = 47%. •women who experienced violence were more likely to report poor quality of marital relationship, higher levels of distress and lower resilience than women who did not. •experience of at least one form of intimate partner violence emerged as a significant predictor of psychological distress. moderate solanki et al.37 (2018) nigeria survey nigeria demographic and health survey 8,646 •lower dv among childless women. high tabrizi et al.29 (2016) iran crosssectional random sampling general health questionnaire 384 •the violence rate was significant among families with infertile women, women with husbands educated at the primary level or below and among women with lower economic status. •lengthened duration of marriage and increased awareness of the infertile women was associated with higher rates of the violence. •a strong relationship existed between all components of violence and the total general health score. high taebi et al.26 (2016) iran crosssectional convenient pasnp, npaps 131 •a significant difference existed between the mean scores of perceived non-physical partner abuse and factor of infertility. high n = total number of infertile women; casp = critical appraisal skills program; dv = domestic violence; aas = abuse assessment scale; sdvw = questionnaire and scale for marital violence against women; cts2 = revised conflict tactics scale; ham-a = hamilton anxiety rating scale; ham-d = hamilton depression rating scale; ipv = intimate partner violence; dhs = demographic and health survey instrument; iwevds = interview questionnaire of infertile women’s exposure to violence determination scale; pss = perceived stress scale; icsi = intracytoplasmic sperm injection; sfps = stigma of fertility problems scale; nfhs-3 = national family health survey 3; fsfi = domestic violence inventory and female sexual function index; ivf = in vitro fertilisation; mqs = marital quality scale; pasnp = partner abuse scale, non-physical; npaps = non-physical abuse of partner scale. farangis sharifi, jamshid jamali, mona larki and robab l. roudsari review | 19 results o v e r v i e w o f t h e s e l e c t e d s t u d i e s out of the 630 articles reviewed, a total of 26 articles, of which 24 were english and two in persian, were included in the study.15,16,18,20,25–46 one of the reviewers who was fluent in both persian and english, indepen dently translated the persian articles into the english language. this was then double-checked by another reviewer. one study had been conducted in usa, a high-income country while the rest were from various middleand low-income countries.25 table 2 presents table 2 (cont’d.): characteristics of 26 studies assessing domestic violence against infertile women15,16,18,20,25–46 author (year) country study design sampling tool n relevant findings quality using casp yildizhan et al.18 (2009) turkey crosssectional convenient structured questionnaire modified from aas 122 •total dv = 33.6% •physical abuse = 31.7% •forced sexual intercourse = 7.3% •dv in case of a female infertility factor = 78% •verbal abuse = 63.4% •economic deprivation = 29.2% high n = total number of infertile women; casp = critical appraisal skills program; dv = domestic violence; aas = abuse assessment scale; sdvw = questionnaire and scale for marital violence against women; cts2 = revised conflict tactics scale; ham-a = hamilton anxiety rating scale; ham-d = hamilton depression rating scale; ipv = intimate partner violence; dhs = demographic and health survey instrument; iwevds = interview questionnaire of infertile women’s exposure to violence determination scale; pss = perceived stress scale; icsi = intracytoplasmic sperm injection; sfps = stigma of fertility problems scale; nfhs-3 = national family health survey 3; fsfi = domestic violence inventory and female sexual function index; ivf = in vitro fertilisation; mqs = marital quality scale; pasnp = partner abuse scale, non-physical; npaps = non-physical abuse of partner scale. table 3: forest plot showing the prevalence of total domestic violence against infertile women according–the fixed and random effects models (n = 15) author (year of publication) total sample size proportion of dv in % 95% ci weight in % fixed random poornowrooz et al.27 (2019) 147 56.463 48.046–64.613 3.36 6.65 sis çelik et al.32 (2018) 423 72.340 67.813–76.552 9.62 6.77 satheesan and satyaranayana43 (2018) 30 46.667 28.342–65.674 0.70 6.04 bondade et al.35 (2018) 100 50.000 39.832–60.168 2.29 6.57 alijani et al.28 (2018) 379 88.918 85.317–91.896 8.62 6.76 sahin et al.34 (2018) 774 14.987 12.545–17.699 17.58 6.79 iliyasu et al.39 (2018) 373 35.925 31.051–41.025 8.48 6.76 akpinar et al.33 (2017) 142 47.887 39.440–56.424 3.24 6.64 ozturk et al.45 (2017) 301 32.558 27.293–38.170 6.85 6.74 aduloju et al.38 (2015) 170 31.176 24.304–38.719 3.88 6.67 sheikhan et al.20 (2014) 400 34.750 30.087–39.641 9.10 6.76 sami et al.46 (2012) 400 57.000 51.987–61.909 9.10 6.76 ardabily et al.16 (2011) 400 61.750 56.790–66.535 9.10 6.76 yildizhan et al.18 (2009) 122 33.607 25.310–42.720 2.79 6.61 ameh et al.15 (2007) 233 41.631 35.230–48.248 5.31 6.71 total (fixed effects) 4,394 45.610 44.132–47.094 100.00 100.00 total (random effects) 4,394 47.163 34.660–59.850 100.00 100.00 domestic violence against infertile women a systematic review and meta-analysis 20 | squ medical journal, february 2022, volume 22, issue 1 a summary of all 26 studies that met the inclusion criteria. these studies were descriptive, had identified violence against infertile women as a primary or secondary objective and most of them were crosssectional and survey-based. p r e va l e n c e o f d o m e s t i c v i o l e n c e a g a i n s t i n f e r t i l e w o m e n in the present study, the percentage of violence against infertile women varied from 15% to nearly 89%. a majority of the studies were from iran (eight articles) and turkey (seven articles).16,18,20,26–36,45 in addition, nigeria accounted for four articles while egypt and india each accounted for two articles.15,37–43 usa, rwanda and pakistan each accounted for one article.25,44,46 in the current study, the highest rate of dv (88.9%) was reported in iran.28 however, the overall frequency of dv varied greatly in this country from 34.7–88.9%.15,16,18,20,25–46 table 3 presents the total estimated prevalence of violence against infertile women. prevalence rates obtained from 15 studies ranged between 14.987% (95% ci: 12.545–17.699%) and 88.918% (95% ci: 85.317–91.896%). overall, the pooled prevalence was equal to 47.163% using random–effects model (95% ci: 34.660–59.850%). p r e va l e n c e o f t y p e s o f d o m e s t i c v i o l e n c e i n i n f e r t i l e w o m e n according to the items on the globally used revised conflict tactics scales, types of dv against women includes physical, psychological and sexual violence.16 the overall prevalence of violence against infertile women was obtained from 15 studies considered for the current evaluation with a sum total of 4,394 participants.15,16,18,20,27,28,32–35,38,39,43,45,46 a sub-total of 12 studies with 3,872 participants reported psychological table 4: forest plot showing the prevalence of domestic psychological violence against infertile women (n = 12) author (year of publication) total sample size proportion of domestic psychological violence in % 95% ci weight in % fixed random poornowrooz et al.27 (2019) 147 52.381 43.991–60.673 3.81 8.28 sis çelik et al.32 (2018) 423 61.939 57.123–66.586 10.92 8.37 bondade et al.35 (2018) 100 34.000 24.822–44.153 2.60 8.21 alijani et al.28 (2018) 379 85.752 81.822–89.112 9.78 8.37 sahin et al.34 (2018) 774 12.532 10.282–15.073 19.95 8.40 iliyasu et al.39 (2018) 373 33.780 28.992–38.828 9.63 8.37 akpinar et al.33 (2017) 142 8.451 4.443–14.296 3.68 8.27 ozturk et al.45 (2017) 301 6.977 4.370–10.467 7.78 8.35 farzadi et al.30 (2014) 200 82.000 75.962–87.063 5.18 8.32 sheikhan et al.20 (2014) 400 25.750 21.533–30.330 10.32 8.37 ardabily et al.16 (2011) 400 33.750 29.126–38.616 10.32 8.37 ameh et al.15 (2007) 233 21.459 16.367–27.293 6.02 8.33 total (fixed effects) 3,872 34.943 33.442–36.466 100.00 100.00 total (random effects) 3,872 36.964 21.385–54.084 100.00 100.00 farangis sharifi, jamshid jamali, mona larki and robab l. roudsari review | 21 and emotional violence and this type of violence was the most common compared to the rest.15,16,20,27,28,30,32–35,39,45 a total of 14 studies with 4,394 participants reported the presence of or increase in physical violence.15,16,18,20,27, 28,30,32–35,39,45,46 also, 11 studies with 3,460 participants reported sexual violence.16,18,20,27,28,30,32–35,39 it should be noted that just in one article, only the frequency of different types of violence was separately reported, whereas the total score of violence was not reported.30 the results of the meta-analysis done for the current study showed that the rates of psychological, physical and sexual violence were 36.964 (95% ci: 21.385–54.084), 14.183 (95% ci: 8.271–21.367) and 14.289 % (95% ci: 7.206–23.281), respectively [tables 4–6]. although, verbal violence is often cited as part of psychological violence, its frequency had been mentioned separately in six studies ranging from 11% to 63.4%.15,18,34,39,45,46 nevertheless, in one study, verbal violence was lower in infertile women.36 according to the results from some studies, several types of violence had been expressed simultaneously.25,39,42 additionally, there was also an increase in economic violence (for example, economic deprivation) according to some reports [table 2].18,31,32,36 c o m pa r i s o n o f d o m e s t i c v i o l e n c e i n f e r t i l e a n d i n f e r t i l e w o m e n five studies reported the comparison of dv in fertile and infertile women.27,31,36,37,44 out of these, four studies showed that infertility was a significant factor in increasingspousal violence against women and the table 5: forest plot showing the prevalence of domestic physical violence against infertile women (n = 14) author (year of publication) total sample size proportion of domestic physical violence in % 95% ci weight in % fixed random poornowrooz et al.27 (2019) 147 34.014 26.410–42.276 3.36 7.01 sis çelik et al.32 (2018) 423 30.024 25.690–34.639 9.62 7.25 bondade et al.35 (2018) 100 11.000 5.621–18.830 2.29 6.85 alijani et al.28 (2018) 379 25.858 21.521–30.576 8.62 7.24 sahin et al.34 (2018) 774 2.455 1.484–3.807 17.58 7.31 iliyasu et al.39 (2018) 373 6.702 4.384–9.735 8.48 7.23 akpinar et al.33 (2017) 142 8.451 4.443–14.296 3.24 7.00 ozturk et al.45 (2017) 301 10.299 7.106–14.299 6.85 7.20 farzadi et al.30 (2014) 200 45.000 37.975–52.175 4.56 7.11 sheikhan et al.20 (2014) 400 1.750 0.706–3.572 9.10 7.24 sami et al.46 (2012) 400 15.500 12.095–19.425 9.10 7.24 ardabily et al.16 (2011) 400 14.000 10.752–17.792 9.10 7.24 yildizhan et al.18 (2009) 122 10.656 5.797–17.532 2.79 6.94 ameh et al.15 (2007) 233 7.296 4.307–11.425 5.31 7.14 total (fixed effects) 4,394 12.111 11.162–13.111 100.00 100.00 total (random effects) 4,394 14.183 8.271–21.367 100.00 100.00 domestic violence against infertile women a systematic review and meta-analysis 22 | squ medical journal, february 2022, volume 22, issue 1 remaining one study showed no increase in this regard.27,31,36,44 however, one of these studies showed that the rate of spousal violence was lower among childless women.37 d e t e r m i n a n t s o f d o m e s t i c v i o l e n c e i n i n f e r t i l e w o m e n infertility factors whether infertility is caused by a male or female factor is important in determining the type of psychosocial consequences.44 a study by yildizhan et al. showed that the rate of violence against women with the infertility factor was 78% while among the others, the infertility factor had not been found to be associated with violence.15,18,32 primary infertility was also associated with dv.32,34,38 while some studies showed that prolongation of infertility, increase in the duration of marriage and marriage under 19 years of age could be potential predictors of and were associated with increased violence, another study showed that a marriage duration of less than four years could be responsible for the increase in violence.29,34,38,41 an infertility period of less than two years and a family history of infertility and obesity in women were also associated with violence.34 a study on individuals with a higher frequency of treatment using the in vitro fertilisation approach showed that the prevalence of violence against infertile women was lower.20 in other studies however, intracytoplasmic sperm injection (icsi) was a predictive factor and was associated with increased violence.40,41 in yet another study, no association had been found between childbirth and violence against infertile women [table 2].37 demographic factors although some studies showed no association between women's age and dv, other studies were showed that young and old age was, in fact, associated with violence.28,32,34,38,40 in some studies, no relationship was found between the age of the wife and domestic violence.32,38 nevertheless, another study showed the rate of violence to be higher in younger age women.28 additionally, in table 6: forest plot showing the prevalence of domestic sexual violence against infertile women (n = 11) author (year of publication) total sample size proportion of domestic sexual violence in % 95% ci weight in % fixed random poornowrooz et al.27 (2019) 147 27.211 20.205–35.159 4.26 8.96 sis çelik et al.32 (2018) 423 5.910 3.861–8.601 12.22 9.22 bondade et al.35 (2018) 100 5.000 1.643–11.283 2.91 8.79 alijani et al.28 (2018) 379 28.232 23.754–33.054 10.95 9.21 sahin et al.34 (2018) 774 4.910 3.497–6.677 22.33 9.29 iliyasu et al.39 (2018) 373 29.759 25.162–34.680 10.77 9.20 akpinar et al.33 (2017) 142 2.113 0.438–6.050 4.12 8.95 farzadi et al.30 (2014) 200 54.000 46.828–61.052 5.79 9.07 sheikhan et al.20 (2014) 400 16.500 12.997–20.508 11.55 9.21 ardabily et al.16 (2011) 400 8.000 5.536–11.106 11.55 9.21 yildizhan et al.18 (2009) 122 2.459 0.510–7.018 3.54 8.88 total (fixed effects) 3,460 13.514 12.393–14.697 100.00 100.00 total (random effects) 3,460 14.289 7.206–23.281 100.00 100.00 farangis sharifi, jamshid jamali, mona larki and robab l. roudsari review | 23 some studies, no significant relationship was found between violence and women’s level of education, husbands’ age, place of residence and level of spousal violence; whereas in a few studies, low level of education and living in a village were determinants of violence against women.15,28,31–34,39,40 with regard to employment, unemployment of the women was associated with an increase in violence against them.34,38,39 on the other hand, although one study showed the unemployment of men was not related to violence, some others showed that unemployment and having low-level jobs were significantly associated with violence against women.28,32,38,39 similarly, there was a significant increase in violence against infertile women belonging to families with low economic status and low social class.29,32,41 according to the results from a few studies, no association was found between family type or type of marriage and violence.15 however, there were a few other studies that showed a significant relationship between family type, involuntary marriage, polygamy and remarriage.20,33,34,38 while a study by alijani et al. showed that alcohol consumption and drug addiction were not associated with dv, a few other studies did show that couples' addiction had been reported to increase dv.20,28,34,38 additionally, a study conducted in nigeria showed that there was no association between religion and ethnicity and intimate partner violence.38 psychological factors of couples dv was significantly associated with women's emotional status and their husband's mental and physical diseases.20,41 notably, the prevalence of anxiety disorders and depression was higher among those exposed to dv and there was a significant relationship between components of violence and their general health score.29,34,35 discussion this study was done to investigate prevalence of dv against infertile women. existing evidence showed that infertile women are vulnerable to and often experience all of types of dv. similar to the findings from the study by staller et al., the most frequent type of violence against infertile women by the husband was psychological and emotional violence.21 it seems this issue might be due to a country’s progressive transition from a traditional to a modern society. as per a study done previously, sexual violence had also been reported as an important factor associated with women’s infertility.47 the results of the present study showed a significant difference in results between fertile and infertile women. in most of the reviewed articles, infertility was an important factor determining the increase in spousal violence against women, a trend that is inline with the findings from the current review.29,31,36,44 paradoxically, however, the results from a study done by solanke et al. indicated that the rate of violence was lower among childless women, also the rate of violence against women was higher among those with two or three children compared to childless women.37 this difference in results could be due to the sociocultural differences that exist between the various communities studied as part of the current review as well as the differences in the measurement tools being used. infertility factor (female or male factor), type of infertility (primary or secondary), duration of infertility and prolonged duration of infertility, duration of marriage and number of attempts for assisted repro ductive techniques were among the essential deter minants of domestic violence and its psychosocial consequences.29,32,34,38,40,41,44 in a study by hajizadehvalokolaee et al., duration of infertility and younger age at marriage were among the key factors playing a role in the violence against infertile women.22 since duration of infertility has been shown to be related to marital life satisfaction, a drop in such satisfaction could potentially lead to increased violence in marital life.20 marriage at an early age may often lead the male spouse to exercise power over their younger female spouse.22,28,34 in many cultures, there is a social stigma attached to infertility that women try to avoid.48,49 openly, identifying the spouse, who is infertile often increases the violence between partners.36 for instance, with respect to variables as age, couples’ educational level and occupation of the husband, although in some studies no relationship was found but in others, older age, having young age, low level of education, being employed and type of employment occupation of the husband, and rurality were all determinanats of violence against infertile.15,28,31–34,38,39,40 the findings regarding the relationship between demographic factors and spousal violence against infertile women were contradictory. for example, there were factors such as age, education level of a couple and occupation of the wife, although in some studies no relationship had been found, other studies showed that older age, having young husbands who smoked, low level of education, being employed, type of employment and rurality were all determining factors in committing violence against infertile women.15,28,30,32,34,38,39,40 domestic violence against infertile women a systematic review and meta-analysis 24 | squ medical journal, february 2022, volume 22, issue 1 the results from the current systematic review were consistent with the study by hajizade-valokolaee et al.22 the empowerment of women is positively correlated with education and educated women and men seem to have a better view of family, gender and infertility, factors that all are effective in reducing violence against women.20,31–34,39 additionally, the increase in violence was significant among families with infertility issues that are of low economic status and social class, echoing trends similar to those from the study by hajizade-valokolaee et al.22,29,32,41 a study by sheikhan et al. showed that tendencies for domestic violence was higher in men with high-income status than those who were unemployed.20 a few studies also indicated a significant relationship between addiction, family type, unwanted marriage, polygamy and remarriage and domestic violence.20,33,34,38 it seems that in all of the aforementioned cases, cultural characteristics emerged as the most determinant factors in modulating the effect of the other remaining risk factors. in a systematic review by coker, spousal violence was strongly associated with hazards relating to risky sexual behaviour such as unwanted pregnancies and abortions, sexually transmitted infections and polygamy.50 previous studies on the general female population have also shown that risk factors for spousal violence against women include lower level of education, young age, socio-economic status, low income, unemployment, alcohol abuse, gender inequality and an acceptance of violence.2 all of these risk factors also seem to be the cause for the increased violence against infertile women in lowand middle-income societies. according to the results of the present systematic review, dv was shown to have a significant relationship with the emotional and mental state of couples.29,34,35 extant literature has also provided similarly strong evidence stating that dv is associated with psychological stress.20,21,32,51 violence against infertile women and the resulting stress could also have an impact on infertility treatments.22,52 furthermore, since infertile women are prone to violence by their husbands, this problem increases the challenges of infertility.32 thus, preventing dv will be important in reducing not only the burden of infertility but also the long-term costs for the individuals, economy and public health in general, as shown in both the present study and the study by stellar et al. in this regard, it would be essential for women who are referred to reproductive clinics to be supported and examined for spousal violence. consistent with the results from multinational studies on violence against women reported by the who, findings from the present study revealed the various adverse effects of violence on personal (physical and psychological harm) and social dimensions (including disease burden, costs, and adverse effects on children) of infertility.53 given that the experience of infertility is an instinctively stressful situation, its aggravation due to physical and psychological injuries caused by the accompanying dv is not unexpected.54 infertility healthcare providers should consider the possibility of dv against women and its potential psychological consequences, as a large proportion of women believed that the acts of violence against women has been committed by their husbands and the need for well-designed and well-executed services will continue to be vital for the victims.40 education of victims and early intervention would not only help such vulnerable women but also prevent violence against the future children. it is also recommended that infertility management be done with the help of a full-fledged consulting team including psychologists, reproductive health professionals and gynaecologists, taking into account the problem of violence and its risk factors. education of the couples, participation of programme planners in this field, awareness and education of the community and taking into account the local socio-cultural practices should be at the forefront of awareness programmes. an important factor to be taken into consideration is the issue of blaming women, especially in cases where they are the cause for infertility.26,55 it would then be important for men to participate in the counselling process and various other support programs.56 a strength of the current study was the large number of articles that were accrued. however, although the studies included in the systematic review and meta-analysis were from different countries, most of them belonged to the asian and african continents as the studies available from other countries were limited. this issue limits generalisation of results to countries outside of the aforementioned regions. the second major limitation was the use of varied methods and tools across all the included studies. therefore, it is recommended that future reviews use more consistent and better comparative study methods and tools, comprehensive multi-centre studies and preferably more cohort studies. conclusion given that infertility and the associated dv is a significant public health issue, it would be necessary to pay attention to infertile women to ensure the quality of their of reproductive health. the current systematic review and meta-analysis investigated the prevalence of dv against infertile women. the prevalence rates farangis sharifi, jamshid jamali, mona larki and robab l. roudsari review | 25 obtained from 15 studies ranged between 14.987% and 88.918%. since multiple factors have been shown to influence the incidence of violence against women, identifying the factors associated with violence against infertile women can be effective in planning interventions to reduce violence and treat infertility. in this regard, there were also a number of demographic, infertility and psychological factors associated with dv. due to the number of potential threats posed by dv, including its effect on future pregnancies and children, proper ipv screening is required. policies and programs creating awareness around the issue, reducing the tendencies to blame women for infertility, promoting monogamy, expanding access to education and employment and empowering women could help reduce spousal violence. future studies should focus on producing more generalizable results by including data from more countries and studies employing more homogenous methods and tools. f u n d i n g this study received funding equivalent to five million iranian rials from the mashhad university of medical sciences, mashhad, iran. a u t h o r s’ c o n t r i b u t i o n fs and rlr contributed to the study conception and design. fs and rlr performed the literature search, study selection, data collection and risk of bias assessment. jj conducted the meta-analysis and ran the software. fs drafted the manuscript under the supervision of rlr. all authors read and approved the final version of the manuscript. references 1. world health organization. violence against women. from: https://www.who.int/news-room/fact-sheets/detail/violenceagainst-women accessed: jan 2021 2. world health organization. preventing intimate partner and sexual violence against women: taking action and generating evidence. geneva: world health organization. from: https:// w w w.who.int/violence_injur y_pre vention/publications/ violence/9789241564007_eng.pdf accessed: jan 2021 3. pengpid s, peltzer k. lifetime spousal violence victimization and perpetration, physical illness, and health risk behaviours among women in india. int j environ res public health 2018; 15:2737. https://doi.org/10.3390/ijerph15122737. 4. akyüz a, şahiner g, bakir b. marital violence: is it a factor affecting the reproductive health status of women? j fam violence 2008; 23:437–45. 5. vos t, astbury j, piers l, magnus a, heenan m, stanley l, et al. measuring the impact of intimate partner violence on the health of women in victoria, australia. bull world health organ. 2006; 84:739–44. 6. rutstein so, shah ih. infecundity, infertility, and childlessness in developing countries. demographic and health surveys (dhs) comparative reports no. 9. from:https://www.who.int/ reproductivehealth/publications/infertility/dhs_9/en/2004 accessed: jan 2021. 7. luk bh-k, loke ay. the impact of infertility on the psycholo gical well-being, marital relationships, sexual relationships, and quality of life of couples: a systematic review. j sex marital ther 2015; 41:610–25. https://doi.org/10.1080/0092623x.2014.958789. 8. piva i, lo monte g, graziano a, marci r. a literature review on the relationship between infertility and sexual dysfunction: does fun end with baby making? eur j contracept reprod health care 2014; 19:231–7. https://doi.org/10.3109/13625187.2014. 919379. 9. greil al, slauson-blevins k, mcquillan j. the experience of infertility: a review of recent literature. sociol health illn 2010; 32:140–62. https://doi.org/10.1111/j.1467-9566.2009.01213.x. 10. gao j, zhang x, su p, liu j, shi k, hao z, et al. relationship between sexual dysfunction and psychological burden in men with infertility: a large observational study in china. j sex med 2013; 10:1935–42. https://doi.org/10.1111/jsm.12207. 11. palha ap, lourenço mf. psychological and cross-cultural aspects of infertility and human sexuality. sexual dysfunction: beyond the brain-body connection. 2011;31:164-83. https:// doi.org/10.1159/000328922. 12. podolska m, bidzan m. infertility as a psychological problem. ginekol pol 2011; 82: 44–9. 13. takaki j, hibino y. family-related opinions and stressful situations associated with psychological distress in women undergoing infertility treatment. int j environ res public health 2014; 11:9068–81. https://doi.org/10.3390/ijerph110909068. 14. fardiazar z, amanati l, azami s. irrational parenthood cognitions and health-related quality of life among infertile women. int j gen med 2012; 5:591. https://doi.org/10.2147/ ijgm.s32225. 15. ameh n, kene t, onuh s, okohue j, umeora o, anozie o. burden of domestic violence amongst infertile women attending infertility clinics in nigeria. niger j med 2007; 16:375–7. https://doi. org/10.4314/njm.v16i4.37342. 16. ardabily he, moghadam zb, salsali m, ramezanzadeh f, nedjat s. prevalence and risk factors for domestic violence against infertile women in an iranian setting. int j gynaecol obstet 2011; 112:15–7. https://doi.org/10.1016/j.ijgo.2010.07.030. 17. leung tw, ng ehy, leung wc, ho pc. intimate partner violence among infertile women. int j gynaecol obstet 2003; 83:323-4. http://pascal-francis.inist.fr/vibad/index.php?action= getrecorddetail&idt=15297107. 18. yildizhan r, adali e, kolusari a, kurdoglu m, yildizhan b, sahin g. domestic violence against infertile women in a turkish setting. int j gynaecol obstet 2009;104:110–12. https://doi.org/10.10 16/j.ijgo.2008.10.007. 19. babu bv, kar sk. domestic violence in eastern india: factors associated with victimization and perpetration. public health 2010; 124:136–48. https://doi.org/10.1016/j.puhe.2010.01.014. 20. sheikhan z, ozgoli g, azar m, alavimajd h. domestic violence in iranian infertile women. med j islam repub iran 2014; 28:152. 21. stellar c, garcia-moreno c, temmerman m, van der poel s. a systematic review and narrative report of the relationship between infertility, subfertility, and intimate partner violence. int j gynaecol obstet 2016; 133:3–8. https://doi.org/10.1016/j. ijgo.2015.08.012. https://doi.org/10.3390/ijerph15122737 https://doi.org/10.1080/0092623x.2014.958789 https://doi.org/10.3109/13625187.2014.919379 https://doi.org/10.3109/13625187.2014.919379 https://doi.org/10.1111/j.1467-9566.2009.01213.x https://doi.org/10.1111/jsm.12207 https://doi.org/10.1159/000328922 https://doi.org/10.1159/000328922 https://doi.org/10.3390/ijerph110909068 https://doi.org/10.4314/njm.v16i4.37342 https://doi.org/10.4314/njm.v16i4.37342 https://doi.org/10.1016/j.ijgo.2010.07.030 http://pascal-francis.inist.fr/vibad/index.php?action=getrecorddetail&idt=15297107 http://pascal-francis.inist.fr/vibad/index.php?action=getrecorddetail&idt=15297107 http://v http://v https://doi.org/10.1016/j.puhe.2010.01.014 https://doi.org/10.1016/j.ijgo.2015.08.012 https://doi.org/10.1016/j.ijgo.2015.08.012 domestic violence against infertile women a systematic review and meta-analysis 26 | squ medical journal, february 2022, volume 22, issue 1 22. hajizade-valokolaee m, khani s, fooladi e, peivandi s. rel ated factors of violence against women with infertility: a syst ematic review study based on an ecological approach. electron physician 2017; 9:5834–43. https://doi.org/10.1016/j.ijgo.2015.0 8.012. 23. casp. cross-sectional stydy appraisal tool 2014. from: https:// cebma.org/wp-content/uploads/critical-appraisal-questionsfor-a-cross-sectional-study-july-2014-1.pdf accessed: jan 2021. 24. bahri n, latifnejad roudsari r, tohidinik hr, sadeghi r. attitudes towards menopause among iranian women: a systematic review and meta-analysis. iran red crescent med j. iran red crescent med j 2016; 18:e31012. https://doi. org/10.5812/ircmj.31012. 25. ozturk r, bloom tl, li y, bullock lfc. stress, stigma, violence experiences and social support of us infertile women. j reprod infant psychol 2021; 39:1–13. https://doi.org/10.1080/0264683 8.2020.1754373. 26. taebi m, gandomani sj, nilforoushan p, gholamidehaghi a. association between infertility factors and non-physical partner abuse in infertile couples. iran j nurs midwifery res 2016; 21:368–71. https://doi.org/10.4103/1735-9066.185577. 27. poornowrooz n, jamali s, haghbeen m, javadpour s, sharifi n, mosallanezhad z. the comparison of violence and sexual function between fertile and infertile women: a study from iran. j clin diagn res 2019; 13:9–11. https://doi.org/10.7860/ jcdr/2019/37993.12516. 28. alijani f, keramat a, gardeshi zh, khosravi a, afzali m, habibi f. domestic violence and its related risk factors among women attending infertility clinic in north of iran. am j exp clin res 2018; 5:267–72. 29. tabrizi fm, sheikhi n, feizbakhsh n, behroozi lak t. exposure of infertile women to violence and related factors in women referring to urmia infertility center in 2015. nurs midwifery j. 2016; 13:853–62. 30. farzadi l, ghasemzadeh a, bahrami asl z, mahinib m, shirdel h. intimate partner violence against infertile women. j clin res gov 2014; 4:147–51. https://doi.org/10.13183/jcrg.v3i2.168. 31. etesami pour r, banihashemian k. comparison of sex disorders and couple abuse among fertile and infertile women. j birjand univ med sci 2011; 18:10–17. 32. sis çelik a, kirca n. prevalence and risk factors for domestic violence against infertile women in a turkish setting. eur j obstet gynecol reprod biol 2018; 231:111–6. https://doi.org/10.1 016/j.ejogrb.2018.10.032. 33. akpinar f, yilmaz s, karahanoglu e, ozelci r, coskun b, dilbaz b, et al. intimate partner violence in turkey among women with female infertility. sex marital ther 2019; 34:3–9. https://doi.org /10.1080/14681994.2017.1327711. 34. sahin s, ilcioglu k, unsal a. domestic violence and anxiety levels in infertile women. cukurova med j 2018; 43:777–84. https://doi.org/10.17826/cumj.331064. 35. bondade s, iyengar rs, shivakumar bk, karthik kn. intimate partner violence and psychiatric comorbidity in infertile women a cross-sectional hospital based studyindian j psychol med. 2018; 40:540–6. https://doi.org/10.4103/ijpsym.ijpsym_158_18. 36. akyuz a, seven m, şahiner g, bilal b. studying the effect of infertility on marital violence in turkish women. int j fertil steril 2013; 6:286. 37. solanke bl, bisiriyu al, oyedokun a. is the likelihood of spousal violence lower or higher among childless women? evidence from nigeria demographic and health surveys. bmc womens health 2018; 18. https://doi.org/10.1186/s12905-018-0514-3. 38. aduloju po, olagbuji nb, olofinbiyi ab, awoleke jo. prev alence and predictors of intimate partner violence among women attending infertility clinic in south-western nigeria. eur j obstet gynecol reprod biol 2015; 188:66–9. https://doi.org/10.10 16/j.ejogrb.2015.02.027. 39. iliyasu z, galadanci hs, abubakar s, auwal ms, odoh c, salihu hm, et al. phenotypes of intimate partner violence among women experiencing infertility in kano, northwest nigeria. int j gynae col obstet 2016; 13332–6. https://doi.org/10.1016/j.ijgo.2015.08.010. 40. lotfy m, hamdy ma, mansour afi, gharib wf, ghoneim hm, abbas am, et al. prevalence and risk factors for domestic violence among infertile egyptian women: a cross-sectional study. eur j contracept reprod health care 2019; 24:362–7. https://doi.org /10.1080/13625187.2019.1642467. 41. mansour f, mohdy ha. intimate partner violence among women with female infertility. am j nurs 2018; 6:309–16. https://doi. org/10.1016/s0020-7292(03)00298-4. 42. pasi al, hanchate ms, pasha ma. infertility and domestic violence: cause, consequence and management in indian scenario. biomed res 2011; 22:255–8. 43. satheesan cs, satyaranayana v. quality of marital relationship, partner violence, psychological distress, and resilience in women with primary infertility. int j community med public health 2018; 5:734–9. https://doi.org/10.18203/2394-6040.ijcmph20180259. 44. dhont n, van de wijgert j, coene g, gasarabwe a, temmerman m. ‘mama and papa nothing’: living with infertility among an urban population in kigali, rwanda. hum reprod 2011; 26:623–9. https://doi.org/10.1093/humrep/deq373. 45. ozturk r, taner a, guneri se, yilmaz b. another face of violence against women: infertility. pak j med sci 2017; 33:909–14. https://doi.org/10.12669/pjms.334.12862. 46. sami n, ali ts. domestic violence against infertile women in karachi, pakistan. asian rev soc sci 2012; 1:15–20. 47. deyhoul n, mohamaddoost t, hosseini m. infertility-related risk factors: a systematic review. ijwhr 2017; 5:24–9. https:// doi.org/10.15296/ijwhr.2017.05. 48. roudsari rl, jafari h, taghipour a. the relationship of socio cultural beliefs and infertile couples' attitude towards reprod uctive donation: a descriptive-correlational study. int j reprod biomed 2019; 17:315–324. https://doi.org/10.18502/ijrm.v17i5.4599. 49. hadizadeh-talasaz f, roudsari rl, simbar m. decision for dis closure: the experiences of iranian infertile couples undergoing assisted reproductive donation procedures. hum fertil 2015; 18: 265–75. https://doi.org/10.3109/14647273.2015.1076579. 50. coker al. does physical intimate partner violence affect sexual health? a systematic review. trauma violence abuse 2007; 8:149–77. https://doi.org/10.1177/1524838007301162. 51. yim is, kofman yb. the psychobiology of stress and intimate partner violence. psychoneuroendocrinology 2019; 105:9–24. https://doi.org/10.1016/j.psyneuen.2018.08.017. 52. maleki-saghooni n, amirian m, sadeghi r, roudsari rl. effect iveness of infertility counseling on pregnancy rate in infertile patients undergoing assisted reproductive technologies: a system atic review and meta-analysis. int j reprod biomed 2017; 15:391–402. https://doi.org/10.29252/ijrm.15.7.391. 53. abramsky t, watts ch, garcia-moreno c, devries k, kiss l, ellsberg m, et al. what factors are associated with recent intimate partner violence? findings from the who multi-country study on women's health and domestic violence. bmc public health 2011; 11:109. https://doi.org/10.1186/1471-2458-11-109. 54. zagami se, roudsari rl, janghorban r, bazaz smm, amirian m, allan ht. a qualitative study of the experiences of iranian infertile couples after unsuccessful assisted reproductive technologies. ijwhr 2019; 7:331–8. https://doi:10.15296/ijwhr.2019.55. 55. geethanjali r, prabhakar k. ngos role in domestic violence among the infertility women in prakasam district. int j soc sci tomorrow 2012. 56. karimi fz, taghipour a, latifnejad roudsari r, kimiaee sa, mazloum sr, amirian m. psycho-social effects of male infertility in iranian women: a qualitative study. iran j obstet gynecol infertil 2016; 19:20–32. https://doi.org/10.1016/j.ijgo.2015.08.012 https://doi.org/10.1016/j.ijgo.2015.08.012 https://doi.org/10.5812/ircmj.31012 https://doi.org/10.5812/ircmj.31012 https://doi.org/10.1080/02646838.2020.1754373 https://doi.org/10.1080/02646838.2020.1754373 https://doi.org/10.4103/1735-9066.185577 https://doi.org/10.7860/jcdr/2019/37993.12516 https://doi.org/10.7860/jcdr/2019/37993.12516 https://doi.org/10.13183/jcrg.v3i2.168 https://doi.org/10.1016/j.ejogrb.2018.10.032 https://doi.org/10.1016/j.ejogrb.2018.10.032 https://doi.org/10.1080/14681994.2017.1327711 https://doi.org/10.1080/14681994.2017.1327711 https://doi.org/10.17826/cumj.331064 https://doi.org/ 10.4103/ijpsym.ijpsym_158_18 https://doi.org/10.1186/s12905-018-0514-3 https://doi.org/10.1016/j.ejogrb.2015.02.027 https://doi.org/10.1016/j.ejogrb.2015.02.027 https://doi.org/10.1016/j.ijgo.2015.08.010 https://doi.org/10.1080/13625187.2019.1642467 https://doi.org/10.1080/13625187.2019.1642467 https://doi.org/10.1016/s0020-7292(03)00298-4 https://doi.org/10.1016/s0020-7292(03)00298-4 https://doi.org/10.18203/2394-6040.ijcmph20180259 https://doi.org/10.1093/humrep/deq373 https://doi.org/10.12669/pjms.334.12862 https://doi.org/10.15296/ijwhr.2017.05 https://doi.org/10.15296/ijwhr.2017.05 https://doi.org/10.18502/ijrm.v17i5.4599 https://doi.org/10.3109/14647273.2015.1076579 https://doi.org/10.1177/1524838007301162 https://doi.org/10.1016/j.psyneuen.2018.08.017 https://doi.org/10.29252/ijrm.15.7.391 https://doi.org/10.1186/1471-2458-11-109 https://doi:10.15296/ijwhr.2019.55 farangis sharifi, jamshid jamali, mona larki and robab l. roudsari review | 27 57. bright cf, bagley b, pulliam i, newton as. domestic violence and pregnancy: a cbpr coalition approach to identifying needs and informing policy. prog community health partnersh 2018; 12:35-44. https://doi.org/10.1353/cpr.2018.0019. 58. roudsari rl, bidgoly mr, mousavifar n, gharavi mm. the effect of collaborative counseling on perceived infertilityrelated stress in infertile women undergoing ivf. iran j obstet gynecol infertil. 2011;14:22–31. 59. bidgoli mr, roudsari rl. the effect of the collaborative infertility counseling model on coping strategies in infertile women undergoing in vitro fertilization: a randomized contr= olled trial. ijwhr 2018; 6:47–54. https://doi.org/10.15296/ ijwhr.2018.09. https://doi.org/10.1353/cpr.2018.0019 https://doi.org/10.15296/ijwhr.2018.09 https://doi.org/10.15296/ijwhr.2018.09 1department of pulmonology, sultan qaboos comprehensive cancer care & research centre, muscat, oman; 2department of medicine, oman medical specialty board, muscat, oman; 3department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drjayakrish@hotmail.com pneumothorax or skin fold? mind the gap *jayakrishnan b,1 ali al-jamali,2 saif al-mubaihsi,3 jamal al-aghbari3 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 591–592, epub. 7 nov 22 submitted 16 nov 21 revision req. 9 jan 22; revision recd. 17 jan 22 accepted 2 feb 22 a 73-year-old male patient with unresectable, advanced dedifferentiated retroperitoneal liposarcoma being treated with palliative chemotherapy was admitted to a tertiary care hospital in muscat, oman, in 2020 with early satiety, poor oral intake, dehydration and ascites. a routine chest radiograph showed features of bilateral pneumothorax [figure 1a]. however, at the time of the presumed radiological diagnosis, the patient was neither breathless nor desaturating and was haemodynamically stable. a computed tomography scan was done suspecting an extra thoracic shadow, such as a skin fold, which showed well expanded lungs without any evidence of pneumothorax [figure 1b]. the patient and the relatives were reassured and no intervention was done. consent was obtained from the patient to publish the details of his illness as well as his radiology images. comment the curved shadow of skin folds can mimic the visceral pleural margin and can often be misinterpreted as a pneumothorax leading to unnecessary interventions.1 the area lateral to this sharp margin can often be perceived darker than the lung medial to it.2 optical illusions such as mach band effect are often helpful in demarcating the boundaries of anatomic structures with different optical densities on radiographs.3 however, they sometimes can also be mistaken for disease as was seen in the current case where a negative mach band effect near a skin fold suggested pneumothorax. pseudo-pneumothorax is usually seen when the film cassette is kept behind the patient with loose skin in a sitting or supine position. the features differentiating this artefact includes, a broader opaque density that fades medially, not following the expected border of the separated visceral pleura, terminating abruptly, extending beyond the pleural space over the chest wall and maybe more than one skin fold with two or more parallel lines.4 the absence of lung markings beyond this sharp curvilinear line as a differentiating feature may, at times, be limited as in the current case. repeating the chest radiograph or a thoracic ultrasound are useful tools, but may not always resolve the dubious radiographic findings. the radiograph may still show the artefact and the ultrasound is accurate only when used by skilled operators.4 computed tomography of the chest is the most sensitive and specific test for diagnosis of pneumothorax. in addition to the skin folds, the pleural line can also be mimicked by clothing or bed sheet folds, oxygen reservoir masks, elevated hemidiaphragm, rib or scapular borders, lung blebs or colonic interposition. these artefacts, when misinterpreted as pneumothorax, can lead to unnecessary and often catastrophic interventions this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2.2022.015 interesting medical image figure 1: a: chest radiograph of a 73-year-old male patient showing features suggestive of pneumothorax bilaterally with curvilinear lines (arrows) mimicking collapsed lung borders. b: computed tomography of the chest showing fully expanded lungs without any evidence of pneumothorax. https://creativecommons.org/licenses/by-nd/4.0/ pneumothorax or skin fold? mind the gap 592 | squ medical journal, november 2022, volume 22, issue 4 and pneumothorax should be ruled out before any therapeutic procedure, especially when the clinical suspicion is low. a u t h o r s’ c o n t r i b u t i o n all authors were involved in patient care. jb wrote the initial manuscript draft and finalised the submission. aj, sm and ja contributed to the literature review. all authors reviewed and approved the final version of the manuscript. references 1. niazi ak, minko p, nahrstedt cj, morris ar, saha pj, elliott k, et al. a case of pseudo-pneumothorax with complications. cureus 2018; 10:e3263. https://doi.org/10.7759/cureus.3263. 2. kishimoto k, watari t, tokuda y. pseudo-pneumothorax: skin fold is an excellent imitator. bmj case rep 2018; 2018:bcr2018226360. https://doi.org/10.1136/bcr-2018-226360. 3. buckle ce, udawatta v, straus cm. now you see it, now you don't: visual illusions in radiology. radiographics 2013; 33:2087–102. https://doi.org/10.1148/rg.337125204. 4. kattea mo, lababede o. differentiating pneumothorax from the common radiographic skinfold artifact. ann am thorac soc 2015; 12:928–31. https://doi.org/10.1513/annalsats.2014 12-576as. https://doi.org/10.7759/cureus.3263 https://doi.org/10.1136/bcr-2018-226360 https://doi.org/10.1148/rg.337125204 https://doi.org/10.1513/annalsats.201412-576as https://doi.org/10.1513/annalsats.201412-576as december 2008 no white pages.indd abstract objective: identification of relevant allergens that are prevalent in each environment which may have diagnostic and therapeutic implications in allergic diseases. this study aimed to identify the pattern of sensitisation to inhalant allergens in omani patients with asthma, allergic rhinitis and rhinoconjunctivitis. methods: the study was carried out during three consecutive years (2004-2006) at the allergy skin test laboratory of sultan qaboos university hospital, oman. records of patients who had undergone an allergy skin prick test with a referring diagnosis of asthma, allergic rhinitis or rhinoconjunctivitis were reviewed. two panels were used during the 3 years period. the frequencies of positive skin tests were analysed. results: 689 patients were tested, 384 for the first panel and 305 for the second panel. in the first panel, the commonest positive allergens were: house dust mites (37.8%), hay dust (35.4%), feathers (33.3%), sheep wool (26.6%), mixed threshing dust (25.8%), cat fur (24.2%), cockroach (22.7%), straw dust (22.7%), horse hair (7.4%), maize (6.%), grasses (.5%), cotton flock (0.7%), trees (0.4%), cow hair (7.8%), alternaria alternata (3.6%), aspergillus niger (3.4%), and aspergillus fumigatus (.3%). in the second panel, the commonest positive allergens were also house dust mites: dermatophagoides pteronyssinus (50.8%), dermatophagoides farinae (47.9%); mesquite (prosopis glandulosa) (35.7%), russian thistle (salsola kali) (34.4%), cockroach (32.%), bermuda grass (cynodon dactylon) (9.7%), grass mix-five standard (8.0%), wheat cultivate (4.%), cats (3.8%), penicillium notatum (4.3%), alternaria tenius (3.9%), aspergillus niger (3.3%), feather mix (3.0%), dog (2.6%), horse hair and dander (2.6%), and aspergillus fumigatus (.6%). conclusion: the pattern of sensitisation to environmental allergens in oman seems to be similar to other reports from the arabian peninsula. methods to identify and characterise environment specific allergens the pattern of sensitisation to inhalant allergens in omani patients with asthma, allergic rhinitis and rhinoconjunctivitis *salem h al-tamemi,1 azza n al-shidhani,1 rashid k al-abri,2 balaji jothi,3 omar a al-rawas,4 bazdawi m al-riyami4 departments of 1child health, 2surgery, 3clinical physiology, sultan qaboos university hospital, muscat, sultanate of oman; 4department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman. *to whom correspondence should be addressed. email: tamemi@squ.edu.om املصابني العمانيني عند املستنشقة أرِجات تَ سْ للمُ التحسيس منط والعينني األنف وحساسية الربو، مبرض الريامي بازدوي الرواس، عمر باالجي جوثي، ، العبري راشد الشيذاني، التميمي، عزا سالم احلساسية. أمراض وعالج تشخيص عملية مهما في يكون أن ميكن كل بيئة في املنتشرة املهمة النشوقة تَأرِجات ُسْ امل على امللخص: الهدف: التعرف والعينني. األنف ــية وحساس الربو مبرض املصابني العمانيني عند ــوقة النش ــتَأرِجات سْ للمُ ــيس التحس نوعية على التعرف تهدف إلى ــة هذه الدراس اجللد فحص حساسية مختبر في (2006-2004) متتالية ــنوات س ثالث خالل ــية أجروا فحص احلساس الذين املرضى ــجالت مراجعة س مت الطريقة: احلساسية من مستخلصات استخدام مت كما والعينني. األنف وحساسية الربو يعانون من أنهم والذي تبني قابوس السلطان جامعة مستشفى في عدد النتائج: كان ــتخدم. مس بيئي ــتأرج مس لكل اجللدي ــية احلساس لفحص املوجبة البيانات ــاب مت حس مختلفتني. فترتني في مختلفني مصنعني في ــنة، 30 س هو تكرر عمر أكثر وكان 5-81 عاما، بني العمر تراوح . الثانية الفترة و305 في في الفترة األولى 384 منهم مت فحص ، 689 املرضى (26.6%) اخلرفان وصوف الطيور(33.3%) ريش ثم ،(35.4%) القش غبار يليها ، (37.8%) غبار البيت ــوس س كانت أرِجات ــتَ ُسْ أكثر امل األولى الفترة ــاب ، واألعش (16.1%) الذرة %17.4 و اخليول ــعر %22.7 وغبار القصب%22.7 و ش الصراصير %24.2 و القطط ــعر وش (25.8%) الوط والغبار ناء خْ الدَّ يَّةُ اشِ الرَّشَّ و (3.4%) وداء السَّ يَّةُ اشِ الرَّشَّ و (3.6%) ُتَناوِبَة امل والنَّوباءُ (7.8%) البقر وشعر (10.4%) (10.7 %) واألشجار والقطن (11.5%) ــجر ،ش (47.9%) الدقيق ة مَ تَضِ قْ مُ ،(50.8%) ــة ُنْتَسَّ امل ةُ مَ تَضِ ُقْ امل أيضا: البيت غبار ــوس ــتَأرِجات س ُسْ امل أكثر كانت الفترة الثانية في أما .(1.3%) نبات احلنطة ، (18%) خليط أعشاب ، (19.7%) برمودا عشب ، (32.1%) الصراصير كالي) (34.4%) (سالسوال روسي ثيستل ، (35.7%) الغاف الطيور ريش خليط ، (3.3%) ــوداء السَّ يَّةُ اشِ الرَّشَّ ، (3.9%) ــريطية الش ، النوباء (4.3%) يَّنَة ُعَ امل ــيَّةُ نَسِ ِكْ امل ، (13.8%) ــعرالقطط ، ش (14.1%) تَأرِجات ُسْ عن امل الناجتة ــية احلساس اخلالصة: طبيعة .(1.6%) الدخناء ــية والرشاش (2.6%) وقشرته اخليول ــعر ش (2.6%) الكالب ــعر ، ش (3%) وتصنيفها البيئة في اخلاصة النشوقة تَأرِجات ُسْ على امل التعرف .طرق العربية في اجلزيرة نشرت لدراسات مشابهة تبدوا عمان النشوقة البيئية في والعينني. األنف وعالج مرضى الربو وحساسية تشخيص على يساعد رمبا عمان. فحص اجللد، سلطنة تَأرِجات, ُسْ امل العينني ، ، األنف حساسية ، ، الكلمات: الربو مفتاح sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 319-324 sultan qaboos university© submitted 26rd february 2008 accepted 8th may 2008 c l i n i c a l a n d b a s i c r e s e a r c h s a l e m h a l -ta m e m i , a z z a n a l -s h i d h a n i , r a s h i d k a l a b r i , b a l a j i j o t h i , o m a r a a l r awa s a n d b a z d aw i m a l r i ya m i 320 environmental allergens are important immunopathogens that contribute to the pathophysiology of allergic diseases represented mainly by bronchial asthma, allergic rhinitis and rhinoconjuctivitis. it is very important to identify the most relevant allergens in each environment as they differ from one to another. this has diagnostic and therapeutic implications. these patients may benefit from environmental allergen control measures and, where medical therapy is not sufficient to control their symptoms, immunotherapy might be beneficial; hence, the identification of allergens is vital. atopy is the tendency of an individual to develop specific ige against common allergens in the environment. ige mediates the early phase response of an allergic reaction by involving mast cells as an effecter cell that release chemical mediators which are responsible for the clinical features of an allergic reaction.1, 2 asthma is a worldwide problem that affects around 10-15% of all populations. in omani children, as assessed by isaac study, the prevalence rates of reported diagnoses of asthma and allergic rhinitis were higher in older children, 20.7% and 10.5%, compared with 10.5% and 7.4% respectively, in younger children.3 asthma is a chronic inflammatory airway disease characterised by the presence of inflammatory cells and cytokines in the airway mucosa that lead to inflammation responsible for the symptoms of asthma. the etiology of asthma is multifactorial, the role of allergy in asthma is well established; for example, there is a strong link between house dust mites (hdm) sensitisation and the development of asthma.4, 5 allergic rhinitis is a common medical condition characterised by nasal, throat, and ocular itching; rhinorrhea; sneezing; nasal congestion and, less frequently, coughing. patients could be sensitised to perennial or seasonal allergens that are present in the environment. patients with allergic rhinitis may benefit from specific immunotherapy in case medical treatment is insufficient to control their symptoms.6, 7, 8 there is now evidence supporting a link between asthma and allergic rhinitis which may have therapeutic implications.9 most of the experience of environmental allergies comes from the western hemisphere. there are several studies conducted in neighbouring countries which have shown a different pattern of allergies from the west.10-15 little is known about the pattern of environmental allergies in oman.16 the aim of this study was to identify the patadvances in knowledge • environmental allergens are well identified and characterised in western countries, but only a few reports have been published on environmental allergies from the arabian peninsula, mainly from kuwait and saudi arabia. • each environment may have unique allergens that may contribute to the pathogenesis of allergic diseases. • this paper highlights the pattern of sensitisation in omani patients with asthma, allergic rhinitis and rhinoconjunctivitis, • the common and uncommon allergens are identified for skin testing in omani patients. this opens up the potential for other allergens to be included in the panel of skin testing. application to patient care • patients should be tested with a panel of allergen extracts that would identify the highest number of sensitising agents that may contribute to their allergic disease; hence measures could be instituted to avoid exposure to the responsible allergens. • immunotherapy for allergic diseases is dependent on identifying the sensitising agents. • this can make postoperative management more specific and result oriented. like a pollen survey may help in the management of patients with allergic asthma, allergic rhinitis and rhinoconjunctivitis. key words: asthma; allergic; rhinitis; conjunctivitis; allergens; skin tests; oman. th e pat t e r n o f s e n s i t i s at i o n t o i n h a l a n t a l l e r g e n s i n o m a n i pat i e n t s w i t h a s t h m a , a l l e r g i c r h i n i t i s & r h i n o c o n j u n c t i v i t i s 321 tern of sensitisation to inhalant allergens in omani patients with asthma, allergic rhinitis and rhinoconjunctivitis. m e t h o d s medical records of allergy skin tests of patients with a referring diagnosis of asthma, or allergic rhinitis or rhinoconjunctivitis for three consecutive years 20042006 were reviewed. the patients had been referred to the allergy skin test laboratory from the pulmonary, ent, child health, and other clinics at sultan qaboos university hospital (squh) and ministry of health hospitals in oman. squh is the referral centre for allergy skin testing for the whole country. the allergy laboratory is supervised by pulmonologists and recently by an allergist. patients consents verbally for the skin prick tests. there were two panels of extracts used during the three year period, bought from two different companies, and represented by two different graphs in the results. the panel of allergens used consisted of common inhalant allergens believed to be of significance. in the first period, the extracts used were bought from bencard company. in the second period, the extracts used were bought from allergy laboratories, inc., usa. skin prick tests were performed by qualified technicians according to standard method.17 disposable greenlan needles, lancet 23g, were used to prick the skin. histamine positive control and diluent negative control were used. a skin test was considered positive when a wheal was 3 mm greater than the negative control. eight patients (7 from the first period and 1 from figure 1: number of patients with positive tests and cumulative percentage of positive tests during the first period number = 689 percentage % age category < 12 years ≥ 12 years sex male female nationality omani non-omani referring clinic chest ent child health ophthalmology other diagnosis asthma allergic rhinitis rhinoconjuctivitis 28 661 314 375 635 54 264 327 9 1 88 271 420 13 4.1 95.9 45.6 54.4 92.2 7.8 38.3 47.5 1.3 0.1 12.8 39.3 61.0 1.9 table 1: patient data s a l e m h a l -ta m e m i , a z z a n a l -s h i d h a n i , r a s h i d k a l a b r i , b a l a j i j o t h i , o m a r a a l r awa s a n d b a z d aw i m a l r i ya m i 322 the second period) were not included in the analysis as they had negative histamine control; none tested positive for negative control. using the statistical package for the social sciences (spss), data were entered into two different sheets. for the analysis of baseline characteristics, the data were combined and frequencies were calculated. the two panels of allergens were analysed separately, as they are different and the frequencies were calculated. r e s u l t s there were a total of 689 patients with asthma, allergic rhinitis and rhinoconjuctivitis tested during the study period. a total of 384 were tested for the first panel and 305 for the second panel. the youngest patient was 5 years old and the oldest 81 years old; the median age was 30 years. the majority of patients were referred from the chest and ent clinics. of the patients tested, 39.2% had a diagnosis of asthma, 61.3% allergic rhinitis and 1.9% rhinoconjuctivitis. baseline data are summarised in table 1. during the first period [figure 1], the commonest positive allergen was house dust mites with 37.8% of patients being sensitis ed, hay dust (35.4%), straw dust (22.7%), mixed threshing dust (25.8%), grasses (11.5%) (in 11 cases the extract was not available), trees (10.4%), maize (16.1%), cotton flock (10.7%), animal allergens, sheep wool (26.6%), horse hair (17.4%), cat fur (24.2%), cow hair (7.8%), feathers (33.3%), cockroaches (22.7%) (in 19 cases the extract was not available); mould allergens: alternaria alternata (3.6%), aspergillus niger (3.4%), and aspergillus fumigatus (1.3%). during the second period [figure 2], the commonest positive allergens were also house dust mites: dermatophagoides pteronyssinus (50.8%), dermatophagoides farinae (47.9%); pollen allergens: mesquite (prosopis glandulosa) (35.7%), russian thistle (salsola kali) (34.4%), bermuda grass (cynodon dactylon) (19.7%), grass mix-five standard (18.0%) and wheat cultivate (14.1%) [in 2 cases the extracts were not available]; animal allergens: cat (13.8%), dog (2.6%), horse hair and dander (2.6%), feather mix 3.0%; moulds: aspergillus niger (3.3%), aspergillus fumigatus (1.6%), penicillium notatum (4.3%) [in 11 cases the extract was not available] and alternaria tenius (3.9%) and cockroach (32.1%). figure 2: number of patients with positive tests and cumulative percentage of positive tests during the second period th e pat t e r n o f s e n s i t i s at i o n t o i n h a l a n t a l l e r g e n s i n o m a n i pat i e n t s w i t h a s t h m a , a l l e r g i c r h i n i t i s & r h i n o c o n j u n c t i v i t i s 323 d i s c u s s i o n in this study, we are able to demonstrate that house dust mites are the commonest sensitisation in omani patients; half of all patients were sensitised to them which is in agreement with other studies conducted on asthmatic patients elsewhere.18 about one third of patients were sensitised to mesquite tree and russian thistle, both common plants in oman. grasses contributed to 10% of cases. however, there are other plants in oman that are potentially allergenic like date palm (phoenix dactylifera), a widely planted tree in oman, for which it may be necessary to test. the families of chenopodiaceous and compositae plants both exist in oman and may contribute to sensitising agents. hay dust, straw dust and mixed threshing contributed to about one third in the first period, but these were not individual allergens. one third of patients were sensitised to cockroaches implicating a significant contribution. in oman, animals are not often allowed into houses, but sometimes there are domestic cats and dogs that stay around houses and people might get exposed to their allergens. horses are mainly raised in stables and exposure might be limited to people that work with them. the difference in rate of sensitisation between the two panels could be because of lack of standardised allergen extracts from different manufacturers. some people raise cattle, goat and sheep in small farms attached to the backyard of their houses. pigeons are found in oman; it is not a common practice to keep them inside houses, however exposure to their feathers is still possible as they nest on buildings. there were more patients sensitised to animals and birds in the first period than in the second period. this might be due to variation in allergen extracts because of lack of standardised allergens made by different manufacturers. goats are raised in omani farms and sometimes close to houses therefore it might be an important allergen that should be tested in conjunction with sheep. in general, not all patients necessarily need to be tested unless there is a history of exposure or ownership of a certain animal or bird. oman is a warm country with a dry weather, except in the coastal area where it may be humid in the summer. houses are usually exposed to sun all year around and well ventilated, and usually there are no basements. moulds grow in humid places and are well known to cause allergies; their environmental control might be more amenable than other allergens and immunotherapy is readily available, hence all patients should be tested. in both study periods, they did not contribute significantly in patients tested; however, it might be useful to use mixtures of moulds rather than individual ones to minimise skin pricks and, if immunotherapy is contemplated, individual moulds could then be tested. c o n c l u s i o n the pattern of sensitisation to environmental allergens in oman seems to be more or less similar to other reports published from arabian peninsula. methods to identify and characterise unique allergens through a pollen survey may still be necessary. this will help in the management of patients with asthma and rhinoconjuctivitis who are sensitised to environmental allergens and may benefit from environmental control measures and immunotherapy. a c k n ow l e d g me n ts this study was approved by the institutional review board (scientific & ethics committee) of college of medicine at sultan qaboos university r e f e r e n c e s 1. arshad sh, karmaus w, matthews s, mealy b, dean t, frischer t, et al. space study group (study of prevention of allergy in children of europe). association of allergy-related symptoms with sensitisation to common allergens in an adult european population. j investig allergol clin immunol 2001; 11:94-102. 2. arshad sh, tariq sm, matthews s, hakim e. sensitization to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. pediatrics 2001; 108:e33. 3. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. a relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirol 2003; 8:69-76. 4. johnson jr, wiley re, fattouh r, swirski fk, gajewska bu, coyle aj, et al. continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. am j respir crit care med 2004; 169:378385. epub nov 2003. 5. arshad sh, hamilton rg, adkinson nf jr. repeated aerosol exposure to small doses of allergen. a model for chronic allergic asthma. am j respir crit care med 1998; 157:1900-1906. 6. hellings pw, fokkens wj. allergic rhinitis and its impact on otorhinolaryngology. allergy 2006; 61:656-664. 7. frew aj, powell rj, corrigan cj, durham sr. efficacy s a l e m h a l -ta m e m i , a z z a n a l -s h i d h a n i , r a s h i d k a l a b r i , b a l a j i j o t h i , o m a r a a l r awa s a n d b a z d aw i m a l r i ya m i 324 and safety of specific immunotherapy with sq allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. allergy clinic immunol, 2006; 117:319325. 8. varney va, tabbah k, mavroleon g, frew aj. usefulness of specific immunotherapy in patients with severe perennial allergic rhinitis induced by house dust mite: a double-blind, randomized, placebo-controlled trial. clin exp allergy 2003; 33:1076-1082. 9. sale r, silvestri m, battistini e, defilippi ac, sabatini f, pecora s, et al. nasal inflammation and bronchial reactivity to methacholine in atopic children with respiratory symptoms. allergy 2003; 58:1171-1175. 10. al-dowaisan a, fakim n, khan mr, arifhodzic n, panicker r, hanoon a, et al. salsola pollen as a predominant cause of respiratory allergies in kuwait. ann allergy asthma immunol 2004; 92:262-267. 11. behbehani n, arifhodzic n, al-mousawi m, marafie s, ashkanani l, moussa m, et al. the seasonal variation in allergic rhinitis and its correlation with outdoor allergens in kuwait. int arch allergy immunol 2004; 133:164-167. epub feb 2004. 12. al mousawi m, behbehani n, arifhodzic n, lovel h, woodcock a, custovic a. environmental allergens in kuwait. allergy 2001; 56:1237-1238. 13. ezeamuzie ci, thomson ms, al-ali s, dowaisan a, khan m, hijazi z. asthma in the desert: spectrum of the sensitising aeroallergens. allergy 2000; 55:157-162. 14. kwaasi aa, parhar rs, harfi h, tipirneni p, al-sedairy st. major allergens of date palm (phoenix dactylifera l.) pollen. identification of ige-binding components by elisa and immunoblot analysis. allergy 1993; 48:511518. 15. al-nahdi m, al-quorain aa. sex distribution and common allergens of bronchial asthma in a saudi arabian (eastern province) population. allergol immunopathol (madr) 1987; 15:389-391. 16. al-amri m, al-rawas oa, al-riyami bms, richens er. atopy in omani patients with asthma. squj sci res med sci 2002; 4:15-23. 17. skin tests used in type i allergy testing position paper. eaaci. sub-committee on skin tests of the european academy of allergology and clinical immunology. allergy 1989; 44:1– 59. 18. dibek, me, reha, cm. skin prick test results of child patients diagnosed with bronchial asthma. allergol immunopathol (madr) 2007; 35:21-24. 2008-issue1.indd screening of patients with snoring and obstructive sleep apnoea using heart rate variability indices omar al rawas,1 bazdawi al-riyami,1 christopher goddard,2 *mohammed o hassan3 يّ النَّومِ دادِيُّ االنْسِ سِ النَفَ طاعُ وانْقِ بالشخير املصابني املرضى حتري القلب نبضات ب تغير ناسِ مَ باستخدام عثمان حسن محمد قودارد كرستوفر الريامي، بزدوي عمر الرواس، هو العرض النهار أثناء النعاس بفرط الشخير مصحوبا االنتشار. واسعة االضطرابات هما من يّ النَّومِ دادِيُّ االنْسِ سِ النَفَ طاعُ وانْقِ اخلالصة: الشخير حديثا استخدمت . يّ ــدادِيُّ النَّومِ االنْسِ سِ النَفَ طاعُ انْقِ بشدة القلب نبضات ــرعة س تغير يرتبط . يّ النَّومِ ــدادِيُّ سِ االنْسِ طاعُ النَفَ النْقِ ــارا انتش األكثر عليه معول بشكل املمكن من . يّ النَّومِ دادِيُّ االنْسِ سِ النَفَ طاعُ بانْقِ املرضى املصابني عن للتحري 24 ساعة ملدة القلب نبضات ة رْعَ سُّ طيطُ تَخْ تقنية : الطريقة التحويلي. فورير برنامج باستعمال بالتحليل الطيفي القلب نبضات سرعة في تغيرا تسبب إرادي التي الال العصبي مكونات اجلهاز دراسة مت الشخير يعانون من 10 أشخاص و يّ النَّومِ دادِيُّ االنْسِ سِ طاعُ النَفَ مصابون بانْقِ 13 منهم ، والعمر الوزن في متقاربون 23 شخصا الدراسة شملت العاشرة الساعة من ابتداءا في املنزل 24 ساعة ملدة القلب تخطيط تسجيل مت . قابوس السلطان جامعة مبستشفى النوم مختبر في تشخيصهم السريع. التحويلي ــتعمال برنامج فورير باس باملنزل القلب تخطيط ومن النوم مختبر من ــتخرجة املس القلب لنبضات الطيفي بالتحليل وقمنا . ليال الشخير مرضى من بكثير يّ أقصر النَّومِ دادِيُّ سِ االنْسِ النَفَ طاعُ انْقِ مرضى عند القلب لنبضات الزمنية أن الفترات القلب في تخطيط النتائج: تبني االنسدادي النفس بانقطاع املصابني عند إحصائيا معتد ــكل بش أعلى القلب ــرعة نبضات الطيف لس ض لكثافة فِ ُنْخَ امل التَّرَدُّدُ . (p<0.01) لوحده جهاز استطاع . اموعتني في متساوية الذبذبة العالية حلزم الطيف كثافة نتائج طاقة كانت . (p< 0.0001) بالشخير املصابني في النومي عنه طاقة ــتخدام اس من ــتفادة االس اخلالصة: ميكن ــدادي. االنس النفس وانقطاع ــخير بالش مصابا 13 مريضا على الليل التعرف خالل القلب تخطيط الشخير من يعانون الذين ملعرفة األشخاص ، النوم أثناء القلب نبضات لقياس التحويلي فورير برنامج باستعمال املنخفضة الترددية للحزمة الطيف . االنسدادي النومي النفس بانقطاع املصحوب القلب. نبضات سرعة تغير ، النومي االنسدادي النفس الكلمات: انقطاع مفتاح sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 21-25 sultan qaboos university© submitted 23rd january 2008 accepted 2nd february 2008 departments of 1medicine, 2medical physics unit, 3physiology, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: mhassan@squ.edu.om abstract objective: snoring and obstructive sleep apnea (osa) are common disorders. snoring associated with excessive daytime sleepiness is the most prevalent symptoms of osa. heart rate variability (hrv) is altered in patients with osa and the degree of alteration may be linked to the severity of osa. alterations in hrv in 24 hour tachograms have recently been used in screening osa patients. autonomic components causing hrv can be reliably studied using spectral analysis techniques involving fast fourier transformation (fft). methods: twenty-three subjects, 3 with severe osa and 0 controls matched for age and body mass index, were selected from patients who had undergone polysomnography (psg) for snoring at sultan qaboos university hospital, oman. a 24hour electrocardiogram (ecg) holter recording was done at home, starting at 0am. spectral analysis of ecg from sleep holter and psg recordings was analysed using fast fourier transformation (fft). results: the ecg rr intervals of snorers with osa were significantly shorter than in snorers without osa (p<0.0). the low frequency (lf) spectral densities of hrv from polysomnography and holter were significantly higher in osa patients than in snorers, (p< 0.000). the power spectral density of the high frequency bands was similar in the two groups. the overnight ecg holter accurately identified all 3 snorers with severe osa. conclusion: the spectral power of the lf band obtained using fft of sleep hrv from holter tachograms may be a useful and cost effective test in identifying snorers with severe osa. key words: obstructive sleep apnea; heart rate variability. c l i n i c a l a n d b a s i c r e s e a r c h o m a r a l r awa s , b a z d aw i a l r i ya m i , c h r i s t o p h e r g o d d a r d , m o h a m m e d o h a s s a n 22 snoring and obstructive sleep apnea (osa) are common disorders that affect bothmen and women. snoring and excessive daytime sleepiness are the most prevalent symptoms of sleep apnea, which in turn is associated with cardiovascular and cerebrovascular complications. 1, 2, 3 the recognition of osa and snoring as a health problem has grown worldwide and the number of subjects who seek medical help for problems with snoring and with concern about osa and daytime sleepiness is increasing. in the general population, the greatest challenge for primary care providers lies in determining which patients with these symptoms warrant further evaluation, as most patients with osa snore, but most snorers do not have osa.4 in developed countries, the cost of investigating these symptoms has increased considerably during the last decade as the only reliable method for the diagnosis of osa until now has been overnight polysomnography (psg),5 which is a cumbersome, time consuming and expensive procedure requiring specially trained polysomnographers, despite evolving newer software which allows rapid analysis. this, together with long waiting lists of patients, has lead to the search for faster and less expensive diagnosis. heart rate variability, or short-term changes in the rr intervals, of a continuously recorded electrocardiogram (tachogram), is the consequence of various influences of the autonomic nervous system on heart rate.7, 8 heart rate variability (hrv) is altered in patients with osa and this alteration is evident even in the absence of hypertension, heart failure, or other diseases.9, 10 the degree of alteration in hrv variability may be linked to the severity of osa.11 alterations in hrv in 24 hour tachograms have recently been used in screening patients with osa.12 autonomic components causing hrv can be reliably studied using spectral analysis techniques. after akselrod13 introduced power spectral analysis (psa) of short-term heart rate fluctuations as a non-invasive quantitative probe of beat-to-beat cardiovascular autonomic control, the study of hrv has become a rapidly expanding field in clinical research14, 15 the analysis gives selective information on sympathetic and parasympathetic functions and the reproducibility of hrv findings in osa have been confirmed by several studies.16, 17 power spectral density (psd) provides the basic information of how power, or variance, is distributed as a function of frequency. fast fourier transformation (fft) is the most widely used nonparametric method for the calculation of psd.16, 17 the advantages of fft are the simplicity of the algorithm used, the high processing speed, and no data pre-processing is required. in addition, fft software is readily available in most cardiovascular analyses packages and end-users are not required to have advanced computer knowledge. three main spectral components can be distinguished in a spectrum calculated from short (2-5 minutes) and long segment (24 hours) of electrocardiographic recordings: very low frequency (vlf, 0.00080.04 hz), low frequency (lf, 0.04-0.14 hz) and high frequency (hf, 0.15-0.45 hz). the distribution of the power and the central frequency of lf and hf are not fixed, but may vary in relation to changes in autonomic modulations of heart rate. in normal humans, shortterm rr interval variability occurs predominantly at lf which may be due to baroreceptor, sympathetic and parasympathetic modulations and hf which is synchronous with the respiratory frequency.16 the physiological explanation of the vlf component is much less defined, and the existence of a specific physiological advances in knowledge • learn how to utilize heart rate variability for advanced diagnostics • perform signal processing on heart rate intervals by using spectral analysis software which is available free in the web • develop awareness that sleep apnea can affect heart rate variability. • sleep apnea can also present with snoring. applications to patient care. • short listing of patients for full sleep studies • holter ecg can be performed at home • polysomnography is essential for the definitive diagnosis of sleep apnea s c r e e n i n g o f pat i e n t s w i t h s n o r i n g a n d o b s t r u c t i v e s l e e p a p n o e a u s i n g h e a r t r at e va r i a b i l i t y i n d i c e s 23 process attributable to these heart period changes has been questioned. however, using fft and sub-band decomposition of overnight hrv in patients with osa, we and other workers have shown that the vlf band is augmented in snorers with osa as compared to snorers without osa.18, 19 the aim of this study was to evaluate the use of fft for the spectral analysis of hrv as a method for screening patients presenting with snoring as the only symptom, in an attempt to identify those who might have osa and short list them for polysomnography. the accuracy of the identification algorithm depends mainly on the accuracy of the electrocardiogram qrs waveform detection (r peak detector), that is used to obtain the r-r intervals (rri) in milliseconds from the raw electrocardiogram (ecg) data. data are the normal-to-normal (nn) intervals obtained directly from the qrs detector without any smoothing and filtering steps; therefore, it could contain false intervals, missed and/or ectopic beats. the qrs detection is accomplished by open source ecg analysis software, an arrhythmia detection software, available on the physionet website.16 the basis of this simple approach to exclude false rri by binding rri within lower and upper limits, is typically 400-2000 msec so that all rr intervals beyond these limits are excluded. m e t h o d s overnight psg was performed using a digital polygraph (heritage model 15 astro-med inc, ma, usa). the psg recording included an electroencephalogram (eeg), ocular and leg electromyography, heart rate tachogram, oxygen saturation, snoring and body position. sleep stages and apnea/hypopnea index (ahi) identification were verified manually by a qualified polysomnographer who used 30-second epochs according to standard criteria. scoring of all computerised studies was done manually in a manner identical to that used for paper studies.20 subjects with osa episodes with an ahi > 30/ hour were considered as having severe osa while those with an ahi of < 5/ hour were considered as normal. the study subjects were snorers with no other symptoms. they were selected from the pool of all polysomnography studies performed in our laboratory between the year 19982003 (total 187 studies). the selection of subject was based on the following: a. osa group a. severe osa (ahi>30/hour) b. no osa treatment c. no evidence of hypertension, heart failures, diabetes or hypothyroidism b. control group (snorers without osa) a. no osa (ahi <5/hour) b. no evidence of hypertension, heart failure, diabetes or hypothyroidism a total of twenty-three subjects were included for this study (13 with severe osa and 10 age and body mass index matched controls). subject characteristics are shown in table 1. all study subjects had a 24 hour ecg recording at home using an ecg analyser with an analogue to digital converter (pathfinder 4, rr tools, reynolds). ecg data from the time the patient recorded going to bed until the time of awakening were selected for the analysis. thirty segments of 5 minutes each of lead ii of the ecg from psg and from holter recordings were selected by an ecg technologist who was blind to the study. ectopic beats, movement artifacts and rr intervals +100 msec were manually removed. another set of data was analysed without visual editing. ecg data was then analysed using the matlab software (mathworks, usa) with a sampling frequency of 200 msec and a validated qrs detector identification algorithm with an automated rejection of ectopic beats and missing data artifacts.21, 22 student’s one-tailed t-test was used to compare the psd of the different frequencies while the 95% confidence interval was used to compare the lf bands of psg and holter records in the two groups. osa n:13 (8m, 5f) snorers n:10 (7m, 3f) age (years) 37.3 (4.2) 38.1 (3.9) bmi (kg/m2) 34.6 (5.2) 33.1 (6.0) ahi/ hour 35.3 (4.5) 4.0 (1.2) r-r (msec) 792 (45) 811 (56) values expressed as mean (sd); ahi: apnea hypopnea index table 1: characteristics of the study subjects o m a r a l r awa s , b a z d aw i a l r i ya m i , c h r i s t o p h e r g o d d a r d , m o h a m m e d o h a s s a n 24 r e s u l t s figure 1 shows the power spectral densities in absolute values obtained from rr values of tachograms recorded during sleep using psg and holter recordings in snorers with and without osa. the rr intervals of snorers with osa are significantly shorter than in snorers without osa (p<0.01). there was no difference in the vlf, lf or hf spectral densities in the manually edited and unedited ecgs. the lf frequency spectral densities of hrv from psg and holter recordings were significantly higher in osa patients than in snorers, (p< 0.0001). the psd of the hf bands were similar in the two groups. the overnight ecg holter accurately identified all 13 snorers with severe osa. the vlf components, however, had very high spectral densities in both methods, and showed a very wide scatter and overlap with the lf bands in most patients. nonetheless, the vlf from psg and holter recordings accurately identified the same 13 snorers with osa. d i s c u s s i o n the main findings of this study are that the lf frequency spectral densities of hrv from psg and holter recordings were significantly higher in osa patients than in snorers. second, patients with severe osa, who are likely to have or develop complications can be detected early for full psg. third, complications of osa such as heart failure, hypertension and obesity have been shown to contribute to the psd of the lf band in osa9, 23 and therefore these complications can only increase the sensitivity of the test. using this method, shorter periods of holter recordings can be used in patients hospitalized for continuous positive airway pressure (cpap) titration or other reasons and several patients can be studied per night. the main strengths of this method are that it is simple, cost effective, non-invasive and can be performed at home; in addition, manual editing is not required as the software is capable of removing movement artifacts, ectopic beats and extremes of tachycardia and bradycardia, which are characteristic of osa episodes and are known to interfere with the spectral analysis. although the ecgs were recorded using two different methods and under different conditions in the laboratory (psg) and at home (holter), they clearly demonstrate that the method and the environment of recording do not influence the outcome as both contain ecgs recorded during all sleep stages. the results also show that the lf using fft and the vlf using sub-band decomposition as shown in our previous study18 were accurate in identifying snorers with osa. fft, as compared to other algorithms, is commercially available in most hrv software and does not require advanced computer knowledge as does sub-band decomposition. although the vlf band was found to be augmented in osa in this and another study, 18, 19 we found it had a very wide scatter as compared to the lf band. apart from ranking patients for psg, this method may be useful in centres where there are no psg facilities and in patients with clearly reported and observed symptoms, or when some patients refuse this cumbersome procedure. in spite of this valuable scientific observation, this method will not replace the full psg of the diagnosis of osa. the study of hrv using holter ecg after cpap treatment in osa patients warrants further investigation. the main limitation of this test is that it has been limited only to small number of severe cases of osa and controls and this was due to the stringent criteria we used for the selection of subjects. the power spectral densities in this study were not converted to normalised units so as to show the importance of the vlf component; this may be important in less severe cases of osa, but it requires lengthy data processing. further studies, using simple techniques on less severe cases, will be required. c o n c l u s i o n the lf band obtained using fft for spectral analysis of hrv obtained from overnight holter tachograms may *p= 0.0001 for difference between the lf band of osa and snorer subjects. figure 1: very low ( vlf), low (lf) and high (hf) frequency bands from polysomnography and holter ecgs in snorers with and without obstructive sleep apnea (osa) s c r e e n i n g o f pat i e n t s w i t h s n o r i n g a n d o b s t r u c t i v e s l e e p a p n o e a u s i n g h e a r t r at e va r i a b i l i t y i n d i c e s 25 be a useful and cost effective test in identifying snorers with severe osa. r e f e r e n c e s 1. guilleminault c, tilkian a, dement wc. the sleep apnea syndromes. ann rev med 1976; 27:465-485. 2. leung str, bradley d. sleep apnea and cardiovascular disease. am j respir crit care med 2001; 164:21472165. 3. dyken me, somers vk, yamada t, ren zy, zimmerman mb. investigating the relationship between stroke and obstructive sleep apnea. stroke 1996; 27:401–407. 4. young t, peppard pe, gottlieb dj. epidemiology of obstructive sleep apnea. am j respir crit care med 2002; 165:1217-1239. 5. taha bh, dempsey ja, weber sm, badr ms, skatrud jb, young tb, et al. automated detection and classification of sleep-disordered breathing from conventional polysomnography data. sleep 1997; 20:991-1001. 6. kirby sd, eng p, danter w, george cf, francovic t, ruby rr, et al. neural network prediction of obstructive sleep apnea from clinical criteria. chest 1999; 116:409-415. 7. pagani m, montano n, porta a, malliani a, abboud fm, birkett c, et al. the relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. circulation 1997; 95:1441-1448. 8. van ravenswaaij-arts cm, kollee la, hopman jc, stoelinga gb, van geijn hp. heart rate variability. ann intern med 1993; 118:436-447. 9. narkiewicz k, montano n, cogliati c, van de borne pjh, dyken me, somers vk. altered cardiovascular variability in obstructive sleep apnea. circulation 1998; 98:10711077. 10. keyl c, lemberger p, pfeifer m, hochmuth k, geisler p. heart rate variability in patients with daytime sleepiness suspected having sleep apnea syndrome: a receiver-operating characteristic analysis. clin sci 1997; 92:335-343. 11. somers vk, dyken me, clary mp, abboud fm. sympathetic neural mechanisms in obstructive sleep apnea. j clin invest 1995; 96:1897-1904. 12. stein pk, duntley sp, domitrovich pp, nishith p, carney rm. a simple method to identify sleep apnea using holter recordings. j cardiovasc electrophysiol 2003; 14:467473. 13. akselrod s, gordon d, hubel fa, shannon dc, barger as, cohen rj. power spectrum analysis of heart rate variability; a quantitative probe of beat-to-beat cardiovascular control. science 1981; 213:220-222. 14. parati g, saul p, di rienxo m, manicia g. spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation. a critical appraisal. hypertension 1995; 25:1276-1286. 15. kamath mv, fallen el. power spectral analysis of heart rate variability: a noninvasive signature of cardiac autonomic function. crit rev biomed 1993; 21:245-311. 16. task force of the european society of cardiology and the north american society of pacing and electrophysiology. heart rate variability: standards of measurement, physiological interpretation and clinical use. circulation 1996; 93:1043-1065. 17. macor f, fagard r, vanhoof r, staessen j, thijs l, amery a. power spectral analysis of short-term rr interval and blood pressure variability: comparison of different methods and assessment of reproducibility. high blood pressure 1994; 3:15-21. 18. hossen a, al-ghunaimi b, hassan mo. a new simple algorithm for heart rate variability analysis in patients with obstructive sleep apnea and normal controls. int j bioelectromagetism 2003; 5:238-239. 19. shiomi t, guilleminault c, sasanabe r, hirota i, maekawa m, kobayashi t. augmented very low frequency component of heart rate variability during obstructive sleep apnea. sleep1996; 19:370-377. 20. hori t, sugita y, koga e, shirakawa s, inoue k, uchida s, et al. sleep computing committee of the japanese society of sleep research society. a manual of standardized terminology techniques and scoring system for sleep stages of human subjects, the rechtschaffen and kales 1968 standard. psychiatry clin neurosci 2001; 55:305310. 21. pan j, tompkins wj. quantitative investigation of qrs detection rules using the mitbh/i arrhythmia database. ieee trans. biomed eng 1986; 33:1157-1187. 22. cuiwei l, chongxun z, changfeng t. detection of ecg characteristic points using wavelet transformation. ieee trans biomed eng 1995; 42:21-28. department of dermatology, hospital universitario virgen de la victoria, málaga, spain *corresponding author’s e-mail: gustavo.garriga.martina@gmail.com ixekizumab for patients with plaque psoriasis affected by multiple sclerosis case report enrique herrera-acosta, *gustavo g. garriga-martina, jorge a. suárez-pérez, eliseo a. martínez-garcía, enrique herrera-ceballos sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 488–490, epub. 29 aug 21 submitted 8 jul 20 revision req. 19 aug 20; revision recd. 26 aug 20 accepted 1 sep 20 ixekizumab (80 mg), following the dosage instructions provided in the drug’s datasheet. after four weeks, the patient presented with a pasi of 3 [figure 2]. during the subsequent follow-ups, the patient achieved complete skin clearance (pasi 100 response) and this is maintained at the time of writing this report, i.e. three years after the initiation of the ixekizumab (80 mg) treatment. moreover, no adverse events occurred during this follow-up period and laboratory investigations were normal. as for ms, the disease remains stable with no new symptoms or signs of progression after starting the ixekizumab treatment. the patient signed a written consent to permit the publishing of his clinical data and photographs. discussion pathogenic mechanisms of ms have not yet been sufficiently understood. an autoimmune aetiology must be considered, but genetic and environmental factors may play a role. regarding these immune factors, the roles played by t helper type 1 (th1), th17, cd8+ t cells and macrophages stand out as they attack the proteins that form the myelin sheaths of the central nervous system. this provides the needed scope for a connection being established between psoriasis and ms as they share, at least partially, similar immunopathogenic mechanisms such as the overexpression of the th17 pathway. the evidence concerning this is strong as multiple studies have pointed to the involvement of th17 lymphocytes and their cytokines in the immunopathogenesis of ms.2–4 multiple sclerosis (ms) is an autoimmune demyelinating disorder of the central nervous system. ms shares significant immunopathogenic mechanisms with psoriasis such as the overexpression of th17 lymphocytes and associated cytokines.1,2 we report the case of a patient presenting with ms and severe psoriasis who was successfully treated with ixekizumab (anti-il-17a and il-17a/f monoclonal antibody). to the best of the authors’ knowledge, this is the first case of its kind to be reported in the medical literature. case report we report a 50-year-old male patient with a 40-year history of chronic plaque psoriasis who presented to hospital virgen de la victoria, málaga, spain, in 2019. he was diagnosed with this in 1979 along with primarily progressive ms which made the patient dependent on others for his basic daily activities. his usual medications included muscle relaxants such as baclofen (25 mg every 12 h) and tizanidine hydrochloride (2 mg every 12 h). his psoriasis had been initially treated with methotrexate and acitretin and then switched to ustekinumab (45 mg) due to the inefficacy of the former. however, a psoriasis area severity index (pasi) of 14 persisted after increasing the dose of ustekinumab to 90 mg every eight weeks [figure 1]. due to the ms, for which the use of anti-tumor necrosis factor (tnf) alpha biological agents is not indicated, the treatment was changed to include this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.021 case report abstract: multiple sclerosis (ms) is an autoimmune demyelinating disorder of the central nervous system that shares similar immunopathogenic mechanisms with chronic plaque psoriasis, such as the overexpression of the th17 pathway. we report a 50-year-old male patient with ms and severe chronic plaque psoriasis who presented to hospital virgen de la victoria, málaga, spain, in 2019. he was successfully treated with ixekizumab (anti-interleukin [il]-17a and il-17a/f monoclonal antibody). the treatment achieved complete skin clearance (i.e. a psoriasis area severity index 100 response) with no adverse event and no evidence of progression of the neurological disease either. keywords: psoriasis; ixekizumab; multiple sclerosis; case report; spain. https://creativecommons.org/licenses/by-nd/4.0/ enrique herrera-acosta, gustavo g. garriga-martina, jorge a. suárez-pérez, eliseo a. martínez-garcía and enrique herrera-ceballos case report | 489 conclusion this report presented a patient with ms and severe chronic plaque psoriasis who was successfully treated with ixekizumab. this treatment has proven to be highly effective, bringing about complete skin clearance (pasi 100 response) and safe as there was no evidence of progression of the neurological disease or any adverse event after this treatment. a u t h o r s’ c o n t r i b u t i o n all authors took part in the clinical management of the patient and drafting of the manuscript. all authors approved the final version of this manuscript. references 1. katsara m, apostolopoulos v. editorial: multiple sclerosis: patho genesis and therapeutics. med chem 2018; 14:104–5. https:// doi.org/10.2174/157340641402180206092504. 2. li yf, zhang sx, ma xw, xue yl, gao c, li xy. levels of peri pheral th17 cells and serum th17-related cytokines in patients with multiple sclerosis: a meta-analysis. mult scler relat disord 2017; 18:20–25. https://doi.org/10.1016/j.msard.2017.09.003. 3. moser t, akgün k, proschmann u, sellner j, ziemssen t. the role of th17 cells in multiple sclerosis: therapeutic implic ations. autoimmun rev 2020; 19:102647. https://doi.org/10.10 16/j.autrev.2020.102647. recently, li et al. published a meta-analysis, wherein they found an increase in the proportion of peripheral blood th17 cells and il-17 and il-23 levels in patients with ms when compared with healthy subjects.2 this fact, together with the increased risk of incident psoriasis in patients with ms (amounting to a 54% higher risk than in the healthy population), or the existence of drugs approved for both diseases, such as fumarate, suggests that there is a degree of overlap in the immunopathogenic mechanisms of both these diseases.5,6 however, there are also major differences, as the family of anti-tnf alpha drugs, used in cases of severe psoriasis, is not indicated for patients with demyelinating diseases, including ms, where an exacerbation or recurrence of neurological symptoms has been observed in rare cases.7,8 in contrast, biological anti-interleukin drugs, such as ustekinumab (anti-il-12/23) or secukinumab, have been successful in patients with psoriasis and ms; these drugs have shown no negative effect on the natural history of the neurological disease.9–11 figure 1: baseline photographs of the chest and legs of a 50-year-old male patient with multiple sclerosis and plaque psoriasis at the time of starting treatment with ixekizumab. figure 2: photographs of the chest and legs of a 50-yearold male patient with multiple sclerosis and plaque psoriasis four weeks after the start of treatment with ixekizumab. https://doi.org/10.2174/157340641402180206092504 https://doi.org/10.2174/157340641402180206092504 https://doi.org/10.1016/j.msard.2017.09.003 https://doi.org/10.10 16/j.autrev.2020.102647 https://doi.org/10.10 16/j.autrev.2020.102647 ixekizumab for patients with plaque psoriasis affected by multiple sclerosis case report 490 | squ medical journal, august 2021, volume 21, issue 3 4. bedoya sk, lam b, lau k, larkin j. th17 cells in immunity and autoimmunity. clin dev immunol 2013; 2013:986789. https:// doi.org/10.1155/2013/986789. 5. guido n, cices a, ibler e, huynh t, majewski s, sable k, et al. multiple sclerosis association with psoriasis: a large u.s. popul ation, single centre, retrospective cross-sectional study. j eur acad dermatol venereol 2017; 31:e397–8. https://doi.org/10.11 11/jdv.14205. 6. marrie ra, patten sb, tremlett h, wolfson c, leung s, fisk jd. increased incidence and prevalence of psoriasis in multiple sclerosis. mult scler relat disord 2017; 13:81–6. https://doi. org/10.1016/j.msard.2017.02.012. 7. fernández-espartero mc, pérez-zafrilla b, naranjo a, esteban c, ortiz am, gómez-reino jj, et al. demyelinating disease in patients treated with tnf antagonists in rheumatology: data from biobadaser, a pharmacovigilance database, and a systematic review. semin arthritis rheum 2011; 41:524–33. https://doi. org/10.1016/j.semarthrit.2010.06.004. 8. andreadou e, kemanetzoglou e, brokalaki c, evangelopoulos me, kilidireas c, rombos a, et al. demyelinating disease following anti-tnf treatment: a causal or coincidental association? report of four cases and review the literature. case rep neurol med 2013; 2013:671935. https://doi.org/10.1155/2013/671935. 9. venturini m, zanca a, venturuzzo a, filippini m, frassi m, tincani a, et al. secukinumab for patients with plaque psoriasis affected by multiple sclerosis: a mini-review with a represent0 ative case report. j eur acad dermatol venereol 2020; 34:e110–12. https://doi.org/10.1111/jdv.16035. 10. assefa gt, kaneko s, oguro h, morita e. treatment of psoriasis and psoriatic arthritis with secukinumab after unsatisfactory response to ustekinumab in multiple sclerosis patient. j dermatol 2019; 46:e112–13. https://doi.org/10.1111/1346-8138.14619. 11. chang s, chambers cj, liu ft, armstrong aw. successful treatment of psoriasis with ustekinumab in patients with multiple sclerosis. dermatol online j 2015; 21:13030/qt3bs971cr. https:// doi.org/10.5070/d3217028112. https://doi.org/10.1155/2013/986789 https://doi.org/10.1155/2013/986789 https://doi.org/10.1111/jdv.14205 https://doi.org/10.1111/jdv.14205 https://doi.org/10.1016/j.msard.2017.02.012 https://doi.org/10.1016/j.msard.2017.02.012 https://doi.org/10.1016/j.semarthrit.2010.06.004 https://doi.org/10.1016/j.semarthrit.2010.06.004 https://doi.org/10.1155/2013/671935 https://doi.org/10.1111/jdv.16035 https://doi.org/10.1111/1346-8138.14619 https://doi.org/10.5070/d3217028112 https://doi.org/10.5070/d3217028112 exploring frequency of event reporting as perceived by intensive care unit nurses in the sultanate of oman a quality improvement project qasim al ma’mari,1 *omar al omari,2 loai abu sharour3 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 28–36, epub. 28 feb 22 submitted 5 jul 20 revisions req. 21 sep & 3 nov 20; revisions recd. 10 oct & 11 nov 20 accepted 3 dec 20 1department of nursing, sultan qaboos university hospital; 2department of fundamentals & administration, 3college of nursing, sultan qaboos university, muscat, oman *corresponding author’s e-mail: o.alomari@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.055 clinical & basic research abstract: objectives: little is known about the factors affecting the perceived frequency of event reporting among healthcare workers, especially registered nurses in oman. this study aimed to assess whether fatigue, workload, burnout and work environment as independent variables have a relationship with frequency of event reporting as the dependent variable and to what extent the independent variables predict the frequency of event reporting between nurses working in different intensive care units (icu) in selected hospitals in oman. methods: this cross-sectional study used standardised questionnaires of hospital survey on patient safety culture, a fatigue assessment scale, the maslach burnout inventory-human services survey, the nasa task load index and the practice environment scale of the nursing work index. registered nurses working in icu participated in this study from two referral hospitals in oman between june and september 2018. results: a total of 270 nurses were included in this study (response rate: 90%). there was a statistically significant positive relationship between personal accomplishment and the frequency of event reporting (r = 0.132, p <0.05). regression analysis showed that nurses’ feedback and communication about errors predicted the frequency of event reporting among icu nurses in oman (r2 = 0.214, adjusted r2 = 0.046; f = 12.82, p <0.01). conclusion: personal accomplishment and feedback and communication about error of icu nurses had a positive impact on perceived frequency of event reporting whereas no relationship was found between fatigue, workload, work environment and frequency of event. strategies need to be in place in health organisations to encourage nurses to report errors. keywords: burnout; intensive care units; nurses; fatigue; incident reporting; workplace; oman. advances in knowledge the study found a positive relationship between personal accomplishment and frequency of event reporting among intensive care units’ nurses. feedback and communication about error had a positive impact on the frequency of event reporting by nurses. applications for patient care these findings provide policy-makers and managers in intensive care units with a better understanding of the factors that affect the frequency of event reporting by nurses and maintain patient safety. the results of this study may be considered as the foundation and a valuable resource of knowledge for forthcoming studies and might be used for developing strategies to tackle these factors and identify other factors. patient safety is the field of interest of healthcare organisations around the world when advancing the standard of care delivered.1 worldwide safety is a crucial health issue because of the impact on patients’ outcome and the healthcare system.2 approximately 43 million patient safety incidences occur every year worldwide and medication errors cost an estimated 42 billion usd annually.3 several facts have been identified and published by the who regarding patient safety statistics, including that one in 10 patients may be injured or harmed during the hospitalisation period due to lack of safe practice and 14 of 100 patients get infected in the hospital owing to lack of safe practice.3 several indictors for patient safety have been identified, including rates for pressure ulcers, in-hospital falls with hip fractures, postoperative sepsis, medication errors and central line-associated bloodstream infection.4 in intensive care units (icu), cases of patients are critical and complicated where a simple mistake can lead to negative patient outcomes, such as death.5 around 30% of patients admitted to icu are affected by at least one healthcare-associated infection in countries with high income.2 the institute of medicine (iom) report estimated errors in healthcare institutions as the eighth major cause of death in the united states of america due to preventable causes; thus, there is a need to find out the factors that lead to these errors and modify them.6 https://creativecommons.org/licenses/by-nd/4.0/ qasim al ma’mari, omar al omari and loai abu sharour clinical and basic research | 29 event reporting usage can be a sign of an affirmative safety culture within healthcare institutions.7 reporting patient safety events are a beneficial method for improving patient safety.8 a positive safety culture may be linked to a lower rate of adverse events.9 on the other hand, underreporting of adverse events impedes organisational learning and advancement in patient care.10 the main reason behind underreporting errors by nurses is fear of being blamed in the health organisation.11,12 several strategies working toward patient safety, such as creating an environment of nonblaming culture to encourage nurses to report any errors or near-happening errors, have been performed with the aim to decrease mistakes in healthcare.11 a major barrier for not reporting incidents was punishment cited by a study conducted among icu nurses who were working in provincial hospitals in kwazulu-natal.13 internationally, some studies have been done on healthcare workers, including nurses, to identify the factors that affect patient safety, such as nurse work environment and nurses’ fatigue. for example, a crosssectional, quantitative study assessed the effect of nurses’ work environment on patient safety outcomes in 30 hospitals in ireland, with 1,397 participants. results showed that a positive nurse work environment was associated with increased patient safety measures and increased reporting rates of adverse events.14 in addition, a recent systematic review in the united states showed an association between a good work environment and quality of nurses’ care and improved patient safety outcomes such as reporting of errors.15 another study assessed the effect of hospital working hours on nurses and patient safety (n = 393 nurses). the results showed that long shift hours and overtime are strongly linked to difficulties in being awake through a shift, which leads to the increased risk of making an error; however, the study did not assess the effect of fatigue on reporting errors.16 another study has reached the same conclusion of increasing frequency of errors as a result of fatigue.17 frequency of event reporting in any healthcare institution is important for positive patient safety culture. limited studies were conducted regarding identifying the factors that affect patient safety culture and frequency of event reporting among nurses in gulf countries. in oman, only two studies had been conducted up to the time of conducting this study. the first study was conducted by al-mandhari et al. to assess the perception of patient safety culture among healthcare workers from different units and the results were consistent with international findings of the presence of blaming culture in healthcare institutions.12 the second descriptive study was conducted in oman in 2015 to explore the perception of patient safety and identify elements that affect patient safety culture between nurses recruited from four hospitals.11 results identified some factors that might contribute to frequency of event reporting such as organisational learning and continuous improvement, teamwork within units, hospital support for patient safety and feedback and communication about the error.11 the different work environments of each hospital may have influenced the perception about patient safety because workplace culture can influence the predictors for frequency of event reporting. although limited studies have been conducted in oman regarding this important aspect of patient safety, it is considered a critical indicator for the quality of healthcare according to the ministry of health in oman.18 in oman, a national patient safety team was founded in 2007 to conduct workshops addressing patient safety issues at multiple centres, to be arranged by departments of quality assurance and patient safety.18 recently, the directorate general of quality assurance center was established; it works on continuous improvement and monitoring in performance at all levels and in various units of the ministry and to raise the quality of healthcare services and patient safety in all institutions.19 also, this centre formed policies and procedures that will help in maintaining high level of quality of healthcare services provided by health institutions such as policy and procedure of incident reporting and learning system which was created in 2017.20 in addition, a majority of hospitals in oman adopted an electronic system for reporting incidents and seeking international accreditation.19 in icu, nurses have to be alert in providing safe care without errors as any simple error can lead to the death of a patient. in addition, it is important for nurses to report any errors that happened as a study showed reporting errors lead to improved patient safety.21 from the aforementioned, there is a need to do research on this important aspect among icu nurses to find out the factors affecting frequency of event reporting. so far, no study has been conducted among nurses working in icu in oman to find out if there is a relationship between frequency of event reporting and the hypothesised factors (fatigue, workload, burnout and work environment). with regard to paucity of information, this study first aimed to identify whether factors in icu nurses, namely fatigue, burnout, workload and work environment, were related to the frequency of event reporting. the second aim was to explore to what extent the selected aforementioned variables predicted the frequency of event reporting in oman. identifying these factors that affect frequency exploring frequency of event reporting as perceived by intensive care unit nurses in sultanate of oman a quality improvement project 30 | squ medical journal, february 2022, volume 22, issue 1 of event reporting among nurses who are working in icu will help the higher administration stakeholders and decision-makers establish management protocols to modify these factors to enhance patient safety and increase reporting of any events and, consequently, increase the quality of care and minimise the incidence of adverse events. furthermore, the subsequent costs associated with adverse event incidence will be reduced. methods a cross-sectional descriptive design was utilised to assess if there is a relationship between independent variables (fatigue, workload, burnout and work envi ronment) and the dependent variable (frequency of event reporting) and to identify the predictors of the frequency of event reporting among icu nurses in oman. this study was carried out in two main referral hospitals in oman – royal hospital and sultan qaboos university hospital. these hospitals specialise in critical care treatment. nurses who were working in different icus: neonatal, paediatric and adult icus, a coronary care unit and post cardiac surgery unit, were asked to take part in the study, totalling approximately 500 potential participants. slovin’s formula was utilised to estimate the sample size.22 the estimated sample size was 222 participants; yet, the study’s questionnaire was distributed to 300 participants and 270 responses were received. the authors discussed and provided the leaders of icus with an overview of the study purposes, methods and significance. the authors communicated with potential nurses who had worked in icus for at least 6 months and consented to participate. a package including an information sheet, consent form and the survey was given to participants who met the eligibility criteria (omani and non-omani nurses, who had worked in icus for at least 6 months and agreed to participate). consenting participants were asked to complete the survey, which would later be coded to enable the authors to complete the data collection process. the time-frame for data collection was between june and september 2018. ethical approval was secured from the research ethical committees of the royal hospital ethical committee (src#46/2018) and college of medicine and science at sultan qaboos university (squec/030/18). also, permissions to use the tools were gained by the authors. participation was optional and no identifying data was obtained. documentary assent was secured from all the participants prior to filling the survey. in the current study, five original instruments in the english language were used, including the hospital survey on patient safety culture (hsopsc), maslach burnout inventory-human services survey (mbihss), fatigue assessment scale (fas), nasa task load index (nasa tlx) and practice environment scale of the nursing work index (pes-nwi)[table 1].23–27 statistical package for the social sciences (spss) version 23 (ibm corp., chicago, illinois, usa) was used to manage and analyse the data. before conducting the analysis, the data was cleaned and verified. to describe the sample characteristics, descriptive analysis was used that included the mean, standard deviation, frequency and percentage. in addition, inferential statistics was used, including correlation and regression analyses. pearson’s product-moment correlation coefficient was used to assess the relationship between selected variables (fatigue, burnout, work environment and workload) and frequency of event reporting. standard multiple regression analysis was used to find the relative contribution of the predictors (nurses’ workload, fatigue, work environment and burnout) on frequency of event reporting. to obtain the parsimonious regression model, a three phased method was used. first, the statistical assumptions in relation to normality, linearity, hetero scedasticity and independence of residuals were examined. next, independent variables with a signif icant relationship to frequency of event reporting were entered into the first linear regression model. lastly, variables that had significant correlation in the first linear regression analysis were included in the parsimonious regression model. this type of regression analysis was done to locate the size of the interactions of independent variables in relationship to the correlation matrix, beta weights and their significance level (p value). results a total of 270 nurses participated (response rate: 90%) from sultan qaboos university hospital (squh) and royal hospital. of these, 38 were male and 232 were female. the majority of participants had bachelor's degrees (bsn) while 4.1% had a postgraduate degree (any degree after bsn). the mean working hours per week for critical care nurses was 36.8 ± 3.19 hours [table 2]. the results indicated a small positive relationship between personal accomplishment (pa) and the frequency of events reported among icu nurses in oman (r = 0.132; p = 0.030), which was statistically significant. in addition, there was no significant relationship between fatigue and the frequency of events reported (r = −0.069; p = 0.256). the hsopsc qasim al ma’mari, omar al omari and loai abu sharour clinical and basic research | 31 composites that had a positive relationship with frequency of event reporting were organisational learning-continuous improvement (r = 0.122; p = 0.046), feedback and communication about error (r = 0.214; p <0.001), communication openness (r = 0.128; p = 0.036) and non-blaming response to errors (r = 0.155; p = 0.011) [table 3]. the results of the initial linear regression showed that only the feedback and communication about errors had significant variance for the frequency of events reported; thus, it was inserted in the parsimonious regression model. the results of this parsimonious regression analysis indicated that the feedback and communication about errors predicted table 1: details of the scales used in current study scale description items cronbach's alpha coefficient of previous study cronbach's alpha coefficient for current study hsopsc23 used to evaluate staff perception about patient safety culture in the healthcare setting. the survey tool includes two questions asking participants to provide an overall patient safety score for their unit and to state the number of adverse events they have reported over the past 12 months. the outcome dimensions include ‘overall perceptions of safety’ and ‘frequency of event reporting’. most of the dimensions are scored on a 5-point likert-type scale to reflect the level of agreement, ranging from 1 (‘i strongly disagree’) to 5 (‘i strongly agree’), with 3 scoring a neutral (‘i neither agree nor disagree’). other items are scored on a 5-point frequency scale, ranging from 1 (‘never’) to 5 (‘always’). the survey includes both positively and negatively worded items, so the negative items were reverse coded. 42 items grouped into 12 composites 0.91 0.85 mbi-hss24 used to measure burnout among participants the seven-point frequency scale for all mbi scales is as follows: 0-never,1-a few times a year or less, 2-once a month or less, 3-a few times a month, 4-once a week, 5-a few times a week, 6-every day. the scoring: •ee: high, 27 or over; moderate, 17–26; low, 0–16. •dp: high, 13 or over; moderate, 7–12; low, 0–6. •pa: high, 39 or over; moderate, 32–38; low, 0–31. the combination of high ee, high dp and low pa indicates high burnout. 22 items and it has three dimensions: ee which consists of 9 items; dp which consists of 5 items; and pa which consists of 8 items ee (0.80); pa (0.77); and dp (0.73) pa (0.74); ee (0.86); and dp (0.66). fas25 used to measure fatigue. five questions on the scale reflect physical fatigue and five reflect mental fatigue. the 5-point scoring ranges from 1 (‘never’) to 5 (‘always’). the total score ranges from 10 to 50. a total fas score <22 indicates no fatigue; a score ≥22 indicates fatigue. ten items 0.90 0.76 nasa tlx26 used to measure subjective workload. it provides an overall workload score based on a weighted average of ratings on six subscales: mental demands, physical demands, temporal demands, performance, effort and frustration. each dimension is scored over a 100-point scale, which is subdivided into 20 steps of 5 points each. overall workload is represented by a combination of the six dimensions six items 0.72 0.71 pes-nwi27 used to measure work environment. -the scoring is based on a 4-point likert scale: 1 (‘strongly agree’), 2 (‘agree’), 3 (‘disagree’) and 4 (‘strongly disagree’). the composite is calculated as the mean of the five subscale scores. 31 items 0.935 0.96 demographic data age, gender, education level, income, nationality, hospital type, experience in years and weekly working hours. eight items hsopcs = hospital survey on patient safety culture; mbi-hss = maslach burnout inventory-human services survey; ee = emotional exhaustion, definition: the feeling of being emotionally exhausted at work; dp = depersonalisation, definition: an unfeeling and impersonal response toward patients; pa = personal accomplishment, definition: feelings of competence and successful achievement in one’s work; fas = fatigue assessment scale; nasa tlx = nasa task load index; pes-nwi = practice environment scale of the nursing work index. exploring frequency of event reporting as perceived by intensive care unit nurses in sultanate of oman a quality improvement project 32 | squ medical journal, february 2022, volume 22, issue 1 the frequency of event reporting between icu nurses in oman and it accounted for 21.4% of the variance, with r2 = 0.214, f = 12.82 ( p <0.01) [table 4]. discussion this study was the first to investigate the relationship between the selected variables—including fatigue, workload, burnout and work environment—and the frequency of event reporting among icu nurses in oman. in addition, it was the first study to identify the extent to which the selected variables predicted the frequency of event reporting. results from this study revealed a positive correlation between personal accomplishment (subscale of burnout) and frequency of event reporting. this is in line with a previous study that showed scoring a low grade for patient safety culture was linked to a high level of burnout.28 therefore, nursing managers have to focus on sending their staff for education programmes that specialise in accomplishment motivation, decision-making and stress reduction that will strengthen personal and professional capability and accomplishments. moreover, managers have to address those nurses with good achievement in their monthly unit meeting and reward them. they also have to encourage a sense of accomplishment such as realistic and achievable table 2: characteristics of study participants (n = 270) variable n (%) mean (sd) gender male 38 (14.1) female 232 (85.9) nationality omani 50 (18.5) non-omani 220 (81.5) working hospital sultan qaboos university hospital 130 (48.1) royal hospital 140 (51.9) level of education diploma 90 (33.3) bsc 169 (62.6) postgraduate studies* 11 (4.1) working hours per week 36.84 (3.19) age 33.06 (5.82) work experience 7.01 (5.05) frequency of events reported 10.99 (3.07) nasa tlx 67.90 (17.7) fatigue assessment scale 18.20 (5.4) maslach burnout inventory subscales ee 16.9 (11.3) dp 6.1 (5.46) pa 32.0 (9.32) ee = emotional exhaustion; dp = depersonalisation; pa = personal accomplishment. *any degree after bsn. table 3: pearson’s r correlation coefficient between selected variables (fatigue, burnout, work environment, workload), hsopcs composites and frequency of event reporting (n = 270) variable frequency of event reporting (pearson’s r) p value fatigue assessment scale (fas) −0.069 0.256 nasa workload index −0.062 0.312 work environment 0.070 0.252 burnout subscales ee subscale −0.097 0.113 dp subscale −0.057 0.349 pa subscale 0.132 0.030* teamwork within units 0.046 0.456 supervisor/manager expectations and actions promoting patient safety 0.101 0.097 organisational learningcontinuous improvement 0.122 0.046* management support for patient safety 0.047 0.441 feedback & communication about error 0.214 ≤0.001† communication openness 0.128 0.036* teamwork across units 0.089 0.144 staffing 0.018 0.774 handoffs & transitions 0.007 0.905 non-punitive response to errors 0.155 0.011* patient safety grade 0.116 0.057 overall perceptions of patient safety culture 0.047 0.438 number of events reported 0.011 0.862 hsopcs = hospital survey on patient safety culture; ee = emotional exhaustion; dp = depersonalisation; pa = personal accomplishment. *correlation is significant at p ≤0.05 (2-tailed). †correlation is significant at p ≤0.01 (2-tailed). qasim al ma’mari, omar al omari and loai abu sharour clinical and basic research | 33 targets, constructive feedback, praise and rewards. the current study found that depersonalisation (subscale of burnout) was not correlated with frequency of event reporting. this result was not in line with a study conducted in a united states hospital that assessed the relation between burnout among nurses and patient safety measures involving safety perceptions and reporting behaviour. it showed that burnout among nurses was linked to minimal chances of notifying an incident that could have happened but had been averted and also with less perception of patient safety culture.29 the discrepancy between the current study and the previous study was linked to the ratio of nurses-to-patients in icus. in the current study, the ratio was 1:1 and, in addition, participants reported that they had enough staff to take care of patients. the results of the current study were not in line with the study that showed a high level of burnout was associated with increased adverse patient related events and reduction in quality of care.30 this discrepancy between the current study and the previous study was related to staff-to-patient ratio and type of patients that nurses were caring for. findings from the current study showed that emotional exhaustion was not correlated to frequency of event reporting. the result was in line with a study that showed no correlation between burnout and event-reporting behaviour.29 this result might be due to adequate staffing and ratio of patient-to-staff. as reported, an increase in patient-to-nurse ratio was linked to increased chances of nurses’ burnout.31 results of the current study were inconsistent with the previous study in which there was an association between nurses’ burnout and achieving a bad grade for patient safety culture.14 this inconsistency is related to the ratio of nurse-to-patient reaching 1:3 in some shifts. therefore, managers in icus have to maintain adequate staffing in order to maintain patient safety. the current study results showed that there was no association between nurses’ work environment and frequency of event reporting. this finding was not consistent with a previous study that showed correlation between positive workplace and increased reporting of adverse events by nurses.14 this might be due to adequate staffing, which was reported to have an effect on decreasing the frequency of event reporting;32 in the current study, around 80% of participants reported that they had enough staff to provide high quality of patient care. another reason was the short working hours in each week as the mean of the working hours each week was less than 40 hours in the current study. the nurses’ work environment has been connected to patient safety outcomes through prior research study.33 therefore, administration backing is important and demanding the utilisation of a tool for notifying events in order to foster patient safety instead of punishing nurses for reporting incidences.34 the current study showed that nurses’ workload was not correlated to frequency of event reporting. this finding might be a result of adequate staffing and a majority of nurses (95.9%) reported that they had good teamwork in icus. this finding was not consistent with other studies that linked workload with raised incidences of patient falls, central venous catheter infections as well as an increase in medication errors.35,36 the discrepancy between the current study and others might be due to the nurse-to-patient ratio of the current study, which followed the international standard of one staff to one patient in icus.37 therefore, administrators need to maintain a positive work environment through maintaining adequate staff for each shift by following the international ratio of one staff to one patient to enhance cooperation between each unit in a hospital. the current study indicated that nurses’ fatigue was not correlated with frequency of event reporting. this is because of the short mean working hours per week (37 hours), which is within the recommended working hours for nurses per week to not exceed 40 hours.38 the current study result was not consistent with the study that linked nurses’ fatigue with increased rate of infection that impedes patient safety.39 therefore, administrators need to maintain a positive work environment through putting strategies for assessing nurses’ fatigue in place, not allowing staff to exceed working above 40 hours each week and introducing courses to help staff deal with their fatigue. table 4: regression model of independent variables that predict frequency of event reporting* (n = 270) 95% confidence interval predictor† β se b t lower upper feedback and communication about errors 0.214 0.104 0.371 3.58 0.167 0.575 *dependent variable is frequency of event reporting. †total r2 = 0.214. exploring frequency of event reporting as perceived by intensive care unit nurses in sultanate of oman a quality improvement project 34 | squ medical journal, february 2022, volume 22, issue 1 findings of the current study showed a positive significant statistical correlation between institutional learning continuous improvement, feedback and comm unication about errors, communication openness, non blaming responses in relation to errors and frequency of event reporting among icu nurses (p <0.05). they were in line with a study that assessed the relationship between composites of patient safety culture and the perceived frequency of event reporting among registered nurses.40 this similarity was linked to the extent that all staff in both studies perceived that improvement in previously mentioned items will lead to improvement in patient safety. nursing managers may look at communication techniques in promoting event reporting in patient safety approaches, with a focus on feedback about error and open communication. moreover, the current study showed that discussion and telling others about incidences or errors was a predictor of frequency of event reporting between icu nurses in oman. a study done in oman in 2015 assessed perceived patient safety culture and identified elements affecting this perception among nurses and reported similar results to the current study; although that study also recruited nurses from different wards.11 results of the present study were not in complete agreement with the results of a research done in 2014 that showed that almost all elements of patient safety were predictors for perceived frequency of event reporting;41 in the present study, only feedback and communications about error was a predictor. furthermore, this study showed the importance for all health institutions to create an environment free from retribution after reporting incidences to boost reporting of incidences, which will improve patient safety; this was in line with other studies that showed the same findings.11,42 in addition, the current study showed that increasing communication openness led to increased frequency of event reporting. it indicated that unambiguous, simple and well-constructed language with the right communication skills is vital to enhance safety of patient.43 the results of this research have some implications for top management, decision-makers, leaders and nurses to create policies and work instructions that are needed to make changes, where the current culture of blame should be replaced by a blamefree one that allows nurses to learn from errors and shared experiences. it is recommended that hospital management run symposiums and workshops on strategies, policies and expertise needed to reduce job linked burnout among staff and to study their effect. the current study’s results might be considered as the foundation and a source of data for future research in this field. further research to study other factors that might affect patient safety culture either negatively or positively, such as accreditation and collaboration, is recommended. the current study has some limitations such as using cross-sectional descriptive design. this limits the ability of explaining the cause and effect of association among study variables and the use of non-probability convenience sampling, which might make the study suffer from risk of selection bias. conclusion this study highlights the need to focus on feedback and communication about errors, communication openness and personal accomplishment of staff as it had a direct positive effect on the frequency of event reporting among icu nurses. also, it highlights the emergent need to find solutions to overcome the blame culture that presents in response to reporting errors. the current study’s results indicate that there is a need to work on developing new strategies and guidelines to enhance patient safety and find other factors that might have an effect on the frequency of event reporting by leaders, decision-makers and policy-makers. to enhance patient safety practices, countries around the world and specifically in the arab region, should investigate the patient safety culture in their healthcare organisations. indeed, a method of reporting incidences needs to be enhanced and made more flexible. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n qa collected the data. la analysed the data. qa, oa and la drafted the manuscript and approved the final version of the manuscript. references 1. farzi s, moladoost a, bahrami m, farzi s, etminani r. patient safety culture in intensive care units from the perspective of nurses: a cross-sectional study. iran j nurs midwifery res 2017; 22:372–6. https://doi.org/10.4103/ijnmr.ijnmr_150_16. 2. world health organization. patient safety assessment manual (2nd ed.). from: http://www.who.int/iris/handle/10665/249569 accessed: nov 2020. 3. world health organization. 10 facts on patient safety. from: http://w w w.who.int/features/factfiles/patient_safety/en/ accessed: nov 2020. https://doi.org/10.4103/ijnmr.ijnmr_150_16 qasim al ma’mari, omar al omari and loai abu sharour clinical and basic research | 35 4. agency for healthcare research and quality. patient safety indicators from: http://www.qualityindicators.ahrq.gov/down loads/modules/psi/v50/psi_brochure.pdf accessed: nov 2020. 5. eltaybani s, mohamed n, abdelwareth m. nature of nursing errors and their contributing factors in intensive care units. nurs crit care 2019; 24:47–54. https://doi.org/10.1111/nicc.12350. 6. wolfe a. institute of medicine report: crossing the quality chasm: a new health care system for the 21st century. policy polit nurs pract 2001; 2:233–5. https://doi.org/10.1177/152715 440100200312. 7. macrae c. the problem with incident reporting. bmj qual saf 2016; 25:71–5. https://doi.org/10.1136/bmjqs-2015-004732. 8. pronovost pj, morlock ll, sexton jb, miller mr, holzmueller cg, thompson da, et al. improving the value of patient safety reporting systems. in: henriksen k, battles jb, keyes ma, grady ml, eds. advances in patient safety: new directions and alternative approaches (vol. 1: assessment). rockville: agency for healthcare research and quality, 2008. 9. najjar s, nafouri n, vanhaecht k, euwema m. the relationship between patient safety culture and adverse events: a study in palestinian hospitals. saf health 2015; 1:16. https://doi.org/10. 1186/s40886-015-0008-z. 10. wafer ma. the relationship among organizational structures, patient safety practices, and patient safety event reporting among nurses in hospitals in the united states. the state university of new jersey. phd dissertation. 2015. 11. ammouri aa, tailakh ak, muliira jk, geethakrishnan r, al kindi sn. patient safety culture among nurses. int nurs rev 2015; 62:102–10. https://doi.org/10.1111/inr.12159. 12. al-mandhari a, al-zakwani i, al-kindi m, tawilah j, dorvlo ass, al-adawi s. patient safety culture assessment in oman. oman med j 2014; 29:264–70. https://doi.org/10.5001/omj.2014.70. 13. mjadu tm, jarvis ma. patients’ safety in adult icus: registered nurses’ attitudes to critical incident reporting. int j africa nurs sci 2018; 9:81–6. 14. kirwan m, matthews a, scott pa. the impact of the work environment of nurses on patient safety outcomes: a multi-level modelling approach. int j nurs stud 2013; 50:253–63. https:// doi.org/10.1016/j.ijnurstu.2012.08.020. 15. wei h, sewell ka, woody g, rose ma. the state of the science of nurse work environments in the united states: a systematic review. int j nurs sci 2018; 5:287–300. https://doi.org/10.1016/j. ijnss.2018.04.010. 16. rogers ae, hwang w-t, scott ld, aiken lh, dinges df. the working hours of hospital staff nurses and patient safety. health aff (millwood) 2004; 23:202–12. https://doi.org/10.1377/hlth aff.23.4.202. 17. barker lm, nussbaum ma. fatigue, performance and the work environment: a survey of registered nurses. j adv nurs 2011; 67:1370–82. https://doi.org/10.1111/j.1365-2648.2010.05597.x. 18. who. patient safety. oman. from: http://www.emro.who. int/patient-safety/countries/country-activities-oman.html accessed: nov 2020. 19. ministry of health. directorate general of quality assurance center. from: https://www.moh.gov.om/en/web/directoratequality-assurance-center/introduction accessed: nov 2020. 20. ministry of health. directorate general of quality assurance center. policy and procedure of incident reporting and learning system. from: https://www.moh.gov.om/en/web/directoratequality-assurance-center/policy-and-procedure accessed: nov 2020. 21. scott ld, arslanian-engoren c, engoren mc. association of sleep and fatigue with decision regret among critical care nurses. am j crit care 2014; 23:13–23. https://doi.org/10.4037/ ajcc2014191. 22. ellen s. slovin's formula sampling techniques. from: https:// sciencing.com/slovins-formula-sampling-techniques-5475547. html accessed: nov 2020. 23. sorra js, dyer n. multilevel psychometric properties of the ahrq hospital survey on patient safety culture. bmc health serv res 2010; 10:199. https://doi.org/10.1186/1472-6963-10-199. 24. maslach c, jackson se, leiter mp, schaufeli wb, schwab rl. maslach burnout inventory sampler set manual, general survey, human services survey, educators survey, & scoring guides. mind garden. 1986. 25. michielsen hj, de vries j, van heck gl. psychometric qualities of a brief self-rated fatigue measure: the fatigue assessment scale. journal of psychosomatic research 2003; 54:345–52. https://doi.org/10.1016/s0022-3999(02)00392-6. 26. hoonakker p, carayon p, gurses a, et al. measuring workload of icu nurses with a questionnaire survey: the nasa task load index. iie trans healthc syst eng 2011; 1:131–43. https:// doi.org/10.1080/19488300.2011.609524. 27. lake et. development of the practice environment scale of the nursing work index. res nurs health 2002; 25:176–88. https:// doi.org/10.1002/nur.10032. 28. vifladt a, simonsen bo, lydersen s, farup pg. the association between patient safety culture and burnout and sense of coherence: a cross-sectional study in restructured and not restructured intensive care units. intensive crit care nurs 2016; 36:26–34. https://doi.org/10.1016/j.iccn.2016.03.004. 29. halbesleben jr, wakefield bj, wakefield ds, cooper lb. nurse burnout and patient safety outcomes: nurse safety perception versus reporting behavior. west j nurs res 2008; 30:560–77. https://doi.org/10.1177/0193945907311322. 30. van bogaert p, kowalski c, weeks sm, van heusden d, clarke sp. the relationship between nurse practice environment, nurse work characteristics, burnout and job outcome and quality of nursing care: a cross-sectional survey. int j nurs stud 2013; 50:1667–77. https://doi.org/10.1016/j.ijnurstu.2013.05.010. 31. aiken lh. workforce staffing and outcomes. 7th annual conference of the international medical workforce collab orative. oxford, england, 2003. 32. mark ba, harless dw, mccue m, xu y. a longitudinal examin ation of hospital registered nurse staffing and quality of care. health serv res 2004; 39:279–300. https://doi.org/10.1111/ j.1475-6773.2004.00228.x. 33. friese cr, lake et, aiken lh, silber jh, sochalski j. hospital nurse practice environments and outcomes for surgical oncology patients. health serv res 2008; 43:1145–63. https://doi.org/10.1 111/j.1475-6773.2007.00825.x. 34. arabi ym, owais sma, al-attas k, alamry a, alzahrani k, baig b, et al. learning from defects using a comprehensive man agement system for incident reports in critical care. anaesth intensive care 2016; 44:210–20. https://doi.org/10.1177/03100 57x1604400207. 35. carlesi kc, padilha kg, toffoletto mc, henriquez-roldán c, juan mac. patient safety incidents and nursing workload. rev lat am enfermagem 2017; 25:e2841. https://doi.org/10.1590/15 18-8345.1280.2841. 36. magalhães ammd, dall'agnol cm, marck pb. nursing work load and patient safety: a mixed method study with an ecological restorative approach. rev lat am enfermagem 2013; 21:146–154. https://doi.org/10.1590/s0104-11692013000700019. 37. salesman f, jap j. analysis of professional health provider need in east nusa tenggara until 2018. health syst policy res 2018; 5:68. 38. geiger-brown j, trinkoff am. is it time to pull the plug on 12hour shifts? part 1. the evidence. j nurs adm 2010; 40:100–2. https://doi.org/10.1097/nna.0b013e3181d0414e. https://doi.org/10.1111/nicc.12350 https://doi.org/10.1177/152715440100200312 https://doi.org/10.1177/152715440100200312 https://doi.org/10.1136/bmjqs-2015-004732 https://doi.org/10.1186/s40886-015-0008-z https://doi.org/10.1186/s40886-015-0008-z https://doi.org/10.1111/inr.12159 https://doi.org/10.5001/omj.2014.70 https://doi.org/10.1016/j.ijnurstu.2012.08.020 https://doi.org/10.1016/j.ijnurstu.2012.08.020 https://doi.org/10.1016/j.ijnss.2018.04.010 https://doi.org/10.1016/j.ijnss.2018.04.010 https://doi.org/10.1377/hlthaff.23.4.202 https://doi.org/10.1377/hlthaff.23.4.202 https://doi.org/10.1111/j.1365-2648.2010.05597.x https://doi.org/10.4037/ajcc2014191 https://doi.org/10.4037/ajcc2014191 https://doi.org/10.1186/1472-6963-10-199 https://doi.org/10.1016/s0022-3999(02)00392-6 https://doi.org/10.1080/19488300.2011.609524 https://doi.org/10.1080/19488300.2011.609524 https://doi.org/10.1002/nur.10032 https://doi.org/10.1002/nur.10032 https://doi.org/10.1016/j.iccn.2016.03.004 https://doi.org/10.1177/0193945907311322 https://doi.org/10.1016/j.ijnurstu.2013.05.010 https://doi.org/10.1111/j.1475-6773.2004.00228.x https://doi.org/10.1111/j.1475-6773.2004.00228.x https://doi.org/10.1111/j.1475-6773.2007.00825.x https://doi.org/10.1111/j.1475-6773.2007.00825.x https://doi.org/10.1177/0310057x1604400207 https://doi.org/10.1177/0310057x1604400207 https://doi.org/10.1590/1518-8345.1280.2841 https://doi.org/10.1590/1518-8345.1280.2841 https://doi.org/10.1590/s0104-11692013000700019 https://doi.org/10.1097/nna.0b013e3181d0414e exploring frequency of event reporting as perceived by intensive care unit nurses in sultanate of oman a quality improvement project 36 | squ medical journal, february 2022, volume 22, issue 1 39. montgomery vl. effect of fatigue, workload, and environment on patient safety in the pediatric intensive care unit. pediatr crit care med 2007; 8:s11–6. https://doi.org/10.1097/01. pcc.0000257735.49562.8f. 40. brown jk. relationship between patient safety culture and safety outcome measures among nurses. nursing theses and capstone projects 2015; 247. 41. el-jardali f, sheikh f, garcia na, jamal d, abdo a. patient safety culture in a large teaching hospital in riyadh: baseline assessment, comparative analysis and opportunities for improvement. bmc health serv res 2014; 14:122. https://doi. org/10.1186/1472-6963-14-122. 42. al ma'mari q, abu sharour l, al omari o. predictors of perceptions of patient safety culture and frequency of event reporting by critical care nurses in oman: a model-building approach. crit care shock 2019; 22:230–42. 43. sammer ce, lykens k, singh kp, mains da, lackan na. what is patient safety culture? a review of the literature. j nurs scholarsh 2010; 42:156–65. https://doi.org/10.1111/j.15475069.2009.01330.x. https://doi.org/10.1097/01.pcc.0000257735.49562.8f https://doi.org/10.1097/01.pcc.0000257735.49562.8f https://doi.org/10.1186/1472-6963-14-122 https://doi.org/10.1186/1472-6963-14-122 https://doi.org/10.1111/j.1547-5069.2009.01330.x https://doi.org/10.1111/j.1547-5069.2009.01330.x coronavirus disease 2019 (covid-19), causedby the severe acute respiratory syndrome (sars)-cov-2 virus, was declared by the world health organization as a pandemic on march 11, 2020 to highlight the gravity of a unique healthcare experience that had not been previously experienced since 1918 with the spanish flu pandemic. the increased demand on the healthcare facilities in providing medical care during pandemics creates unique challenges of providing care while ensuring the safety of vulnerable patients and healthcare workers (hcws). hcws are the most important resource in controlling the spread and propagation of the pandemic but they can also be the source for healthcare outbreaks and ongoing community transmission. throughout the history of coronavirus outbreaks and epidemics, the personnel working in healthcare institutions have rarely been spared. in 2003, the sars epidemic quickly spread worldwide with a great proportion of those with the disease being associated with hospital-based outbreaks.1,2 the infected hcws accounted for 37%–63% of suspected sars cases in highly affected countries forcing hospital closure and mandatory quarantine.3,4 in 2012, the second coronavirus epidemic emerged as the middle east respiratory syndrome coronavirus (mers-cov) which, by the end of november 2019, resulted in a total of 2,494 laboratory-confirmed cases globally and associated deaths (case fatality rate: 34.4%).5 the overall proportion of mers-cov infected hcws was 25%, which varied significantly by outbreak from 13–89% (p < 0.001). interestingly, 70% of asymptomatic infections were reported among hcws with no fatalities.6 in oman, a total of 24 cases of mers-cov were reported from 2013 to the end of 2019 including two mild cases in hcws from two separate nosocomial outbreaks and the associated deaths (case fatality rate: 29.2%).7 in the early phase of the covid-19 pandemic, data from wuhan, china, up to 24 february 2020, showed that of 77,262 patients there were 3,387 infected hcws (4.4%); 23 of these individuals had died by april of the same year.8 in a study from wuhan, the source of hcw infection was found to be contact with infected colleagues (n = 12, 10.9%) while 14 (12.7%) were attri buted to community acquisition.9 in areas where comm unity transmission was established, a healthcare cluster was more likely due to lapse in early hcw case detection. this is particularly significant in covid-19 because patients may have mild atypical symptoms and there could be pre-symptomatic transmission.10 a study of two dutch hospitals found that out of 9,705 hcws of which 1,353 were tested for covid-19, a total of 86 (6%) were infected with sars-cov 2 out of which only 3 (3%) had been exposed to an admitted confirmed covid-19 inpatient and that a substantial proportion of hcws were infected with sars cov-2 two weeks prior.11 the first case was admitted to the facility which indicated that their exposure was most likely in the community.11 in a morbidity and mortality weekly report from the centers for disease control and prevention (cdc), 121 hcws were exposed to a patient with unrecognised covid-19 of which 43 became symptomatic; only three were positive for sars cov-2 and all three had had unprotected patient contact.12 in the usa, as of 6 june 2020, it had been reported that nearly 600 frontline hcws died due to covid-19.13 a study from the uk and usa estimated that frontline hcws had a 3.4 fold higher risk than people living in the general community for reporting a positive test, adjusting for the likelihood of receiving a test.14 other studies however, reported lower illness sev erity in hcws and identified personal protective equip ment (ppe) use as a main factor associated with decreased infection risk.15 a retrospective study including 72 hcws 1directorate general for disease surveillance and control, ministry of health, muscat, oman *corresponding author’s e-mail: salabri@gmail.com كوفيد-19 عند العاملني يف جمال الرعاية الصحية وتقدمي الرعاية الصحية اآلمنة أثناء الوابء اأمل �سيف املعنية و�سيف �سامل العربي covid-19 in healthcare workers and serving safe healthcare during the pandemic amal s. al-maani and *seif s. al-abri editorial sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e1–3, epub. 15 mar 21 submitted 25 aug 20 revision req. 7 oct 20; revision recd. 4 nov 20 accepted 10 nov 20 https://doi.org/10.18295/squmj.2021.21.01.001 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ covid-19 in healthcare workers and serving safe healthcare during the pandemic e2 | squ medical journal, february 2021, volume 21, issue 1 rom a large hospital in wuhan found that suboptimal hand hygiene, longer duty hours and working in a high-risk department were associated with contracting covid-19.16 the european cdc analysed data in may 2020 from 15 countries including the uk and found that 23.2% (n = 43,774) of covid-19 cases were among hcws; only 9% of hcws required hospitalisation compared to 17% of non-hcws. furthermore, 1% of hcws presented with severe illness (intensive care unit [icu] admission or respiratory support required) compared to 5% in non-hcws.17 after gender and age-adjusted analysis, hospitalised hcws were still less likely to require icu admission and had a lower case fatality than non-hcws.17 in oman, the number of infected medical doctors and nurses until the end of july 2020 (total confirmed cases nationally: 79,159) were 192 (0.2%) and 508 (0.6%), respectively. four hcws needed icu care and there was one fatality of a 70-year-old physician (personal communication, directorate general for disease surveillance and control, ministry of health, oman). hcws generally have more access and prioritisation for testing and healthcare which facilitates diagnosis and hospitalisation at earlier stages and/or with milder signs and symptoms suggesting that these observed differences could be related to the ‘healthy worker effect’.18 a study looking at different occupations in six asian countries and the risk of covid-19 found that infection in hcws accounted for 3% compared to 12% in non-hcws of local reported cases and in all included countries; the first cases in hcws appeared much later than the first non-hcw cases.19 the study suggested that this likely reflects improved triage, screening and isolation of covid-19 patients, availability of ppe and overall better knowledge and practice of hygiene and infection control within healthcare facilities.19 transmission of a respiratory infection to hcws may also be event-dependent. aerosol generating proc edures (agps), such as intubations and medication nebulisers, have been associated with healthcarerelated outbreaks, even among protected hcws. a cluster of sars in nine hcws from toronto, canada, developed after they cared for a patient around the time of intubation, despite use of full ppe.3 in the usa, although many healthcare workers had unprotected exposures, no documented transmission of sars-cov was found; this is probably due to relative absence of highly infectious patients or highrisk patient procedures.4 a recent analysis by the respiratory protection effectiveness trial suggests the risk of hcws becoming infected with an endemic coronavirus increases approximately two-fold with exposures to agps.20 a number of insights and lessons were gained from the experience with previous coronavirus epidemics (sars and mers) and the current covid-19 pan demic that will help mitigate the risk of hcw infection and help to serve safe healthcare during the next phase of this unique situation. rapid identification and isolation of potentially infectious cases is the key measure in minimising exposures and interrupting the chain of transmission. the implementation of triage systems for infectious diseases in an emergency and outpatient setting is one of the administrative strategies that can ensure rapid identification and isolation; this strategy was implemented early in oman’s healthcare facilities during the current pandemic. communication between public health officials and hospital infection control staff can help enable efficient implementation of control procedures especially where most of the transmission is community driven. the current levels of ppe (i.e. gown/apron, surgical mask, face-shield/ goggles and gloves), engineering and administrative control may not be sufficient if many high-risk patients or procedures qualify for airborne set-up. unprotected exposure among hcws may still occur despite the implementation of facility-wide masking in the absence of administrative and engineering control. therefore, new initiatives for infection control should include measures to improve hcws’ understanding of infection control science and risk assessment principles so that more cost-effective approaches can be implemented, specifically focusing on patients and events that have the highest risk for transmission. references 1. lee n, hui d, wu a, chan p, cameron p, joynt gm, et al. a major outbreak of severe acute respiratory syndrome in hong kong. n engl j med 2003; 348:1986–94. https://doi. org/10.1056/nejmoa030685. 2. ruan yj, wei cl, ee al, vega vb, thoreau h, su st, et al. comparative full-length genome sequence analysis of 14 sars coronavirus isolates and common mutations associated with putative origins of infection. lancet 2003; 361:1779–85. https:// doi.org/10.1016/s0140-6736(03)13414-9. 3. centers for disease control and prevention. cluster of severe acute respiratory syndrome cases among protected health-care workers—toronto, canada, april 2003. mmwr morb mortal wkly rep 2003;52:433–6. 4. peck aj, newbern ec, feikin dr, issakbaeva et, park bj, fehr j, et al. lack of sars transmission and u.s. sars case-patient. emerg infect dis 2004; 10:217–24. https://doi.org/10.3201/ eid1002.030746. 5. world health organization. mers situation update report november 2019. from: http://www.emro.who.int/pandemice p i d e m i c d i s e a s e s / m e r s c o v / m e r s s i t u a t i o n u p d a t e november-2019.html accessed: nov 2020. 6. bernard-stoecklin s, nikolay b, assiri a, bin saeed aa, ben embarek pk, el bushra h, et al. comparative analysis of eleven healthcare-associated outbreaks of middle east respiratory syndrome coronavirus (mers-cov) from 2015 to 2017. sci rep 2019; 9:7385. https://doi.org/10.1038/s41598-019-43586-9. https://doi.org/10.1056/nejmoa030685 https://doi.org/10.1056/nejmoa030685 https://doi.org/10.1016/s0140-6736%2803%2913414-9 https://doi.org/10.1016/s0140-6736%2803%2913414-9 https://doi.org/10.3201/eid1002.030746 https://doi.org/10.3201/eid1002.030746 https://doi.org/10.1038/s41598-019-43586-9 amal s. al-maani and seif s. al-abri editorial | e3 7. world health organization. middle east respiratory syndrome coronavirus (mers-cov) – oman, disease outbreak news 4 march 2019. from: https://www.who.int/csr/don/04-march2019-mers-oman/en/ accessed: nov 2020. 8. zhan m, qin y, xue x, zhu s. death from covid-19 of 23 health care workers in china. n engl j med 2020; 382:2267–8. https://doi.org/10.1056/nejmc2005696. 9. lai x, wang m, qin c, tan l, ran l, chen d, et al. coronavirus disease 2019 (covid-2019) infection among health care workers and implications for prevention measures in a tertiary hospital in wuhan, china. jama netw open 2020; 3:e209666. https://doi.org/10.1001/jamanetworkopen.2020.9666. 10. wei we, li z, chiew cj, yong se, toh mp, lee vj. presymptomatic transmission of sars-cov-2 – singapore, january 23–march 16, 2020. mmwr morb mortal wkly rep 2020; 69:411–15. https://doi.org/10.15585/mmwr.mm6914e1. 11. kluytmans-von den bergh mfq, buiting agm, pas sd, bentvelsen rg, van den bijlaardt w, van oudheusden ajg, et al. sars-cov-2 infection in 86 healthcare workers in two dutch hospitals in march 2020. medrxiv 2020. https://doi.org/ 10.1101/2020.03.23.20041913. 12. heinzerling a, stuckey mj, scheuer t, xu k, perkins km, resseger h, et al. transmission of covid-19 to health care personnel during exposures to a hospitalized patient solano county, california, february 2020. mmwr morb mortal wkly rep 2020; 69:472–6. https://doi.org/10.15585/mmwr. mm6915e5. 13. jewett c, bailey m, renwick d. exclusive: nearly 600 — and counting — us health workers have died of covid-19. from: https://khn.org/news/exclusive-investigation-nearly600-and-counting-us-health-workers-have-died-of-covid-19/ accessed: nov 2020. 14. nguyen lh, drew da, joshi ad, guo cg, ma w, mehta rs, et al. risk of covid-19 among frontline healthcare workers and the general community: a prospective cohort study. medrxiv [preprint] 2020: 2020.04.29.20084111. https://doi.org /10.1101/2020.04.29.20084111. 15. chou r, dana t, buckley di, selph s, fu r, totten am. epidemiology of and risk factors for coronavirus infection in health care workers: a living rapid review. ann intern med 2020; 173:120–36. https://doi.org/10.7326/m20-1632. 16. ran l, chen x, wang y, wu w, zhang l, tan x. risk factors of healthcare workers with coronavirus disease 2019: a retrospective cohort study in a designated hospital of wuhan in china. clin infect dis 2020; 71:2218–21. https://doi. org/10.1093/cid/ciaa287. 17. european centre for disease prevention and control. epidemiology of covid-19. from: https://www.ecdc.europa. eu/en/covid-19/latest-evidence/epidemiology accessed: aug 2020 18. monson rr. observations on the healthy worker effect. j occup med 1986; 28:425–33. https://doi.org/10.1097/00043764-19860 6000-00009. 19. lan fy, wei cf, hsu yt, christiani dc, kales sn. workrelated covid-19 transmission in six asian countries/areas: a follow-up study. plos one 2020; 15:e0233588. https://doi. org/10.1371/journal.pone.0233588. 20. cummings dat, radonovich lj, gorse gj, gaydos ca, bessesen mt, brown ac, et al. risk factors for healthcare personnel infection with endemic coronaviruses (hku1, oc43, nl63, 229e): results from the respiratory protection effectiveness clinical trial (respect). clin infect dis 2020; ciaa900. https://doi.org/10.1093/cid/ciaa900. https://doi.org/10.1056/nejmc2005696 https://doi.org/10.1001/jamanetworkopen.2020.9666 https://doi.org/10.15585/mmwr.mm6914e1 https://doi.org/10.1101/2020.03.23.20041913 https://doi.org/10.1101/2020.03.23.20041913 https://doi.org/10.15585/mmwr.mm6915e5 https://doi.org/10.15585/mmwr.mm6915e5 https://doi.org/10.1101/2020.04.29.20084111 https://doi.org/10.1101/2020.04.29.20084111 https://doi.org/10.7326/m20-1632 https://doi.org/10.1093/cid/ciaa287 https://doi.org/10.1093/cid/ciaa287 https://doi.org/10.1097/00043764-198606000-00009 https://doi.org/10.1097/00043764-198606000-00009 https://doi.org/10.1371/journal.pone.0233588 https://doi.org/10.1371/journal.pone.0233588 https://doi.org/10.1093/cid/ciaa900 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 97-98, epub 16th mar 2009 submitted 1st feb 09 the color atlas of family medicine i agreed to review this book since the idea of an atlas in family medicine was novel to me. i was hoping to get a ‘clear picture’ and i was not disappointed. this is the first comprehensive atlas of family medicine. the compilation of this atlas has required a concerted effort by five editors over many years. sixty contributors with outstanding qualifications, experience, and knowledge were engaged. the atlas presents more than 1,500 superb clinical images, with its primary purpose being to provide useful clinical information for practising physicians, medical students, interns, residents, and other health care professionals. the style and organisation of the atlas have some unique characteristics. readers are urged to spend few minutes reviewing the table of contents at the beginning of the atlas and the topic index. the editors have provided a challenging brief for the 60 contributors. the atlas is divided in to 18 parts that reflects the wide variety of conditions seen by the family physician. family physicians probably see a wider variety of rashes, eye conditions, foot disorders than any other specialty. the book focuses on medical conditions organised by anatomical and physiological system. both adult and childhood conditions are covered. there are special sections on the essence of family medicine, physical/sexual abuse, women’s health and substance abuse. the first chapter begins with an introduction to learning objectives with images and digital photography. then each chapter begins with a patient’s story that ties the photographs to real life stories and introduces the content of the chapter. this is followed by epidemiology, aetiology and pathology, diagnosis, differential diagnosis and management. additional sections on patient’s education and follow-up advice are provided. i am delighted that editors included suggestions of online resources for patients and care providers followed by the key references for further information. this format is maintained throughout. some parts are very lengthy. dermatology, gets 467 pages of its own, excellently illustrated and very well complemented with colour photographs and tables. clearly it is now a major specialty rather than just a subspecialty, which would have merited only two pages. this atlas has 1,095 pages and is not meant to be read from cover to cover. i therefore urge you to check the index whenever you are looking up a topic. approaching a4 size, hard backed, and 4cm thick, it is not a white coat pocket book for even the most stalwart house officer, but it should succeed in being just what it sets out to be, a source of rapid reference, allowing students and junior doctors to get clued up on medical األسرة لطب امللون األطلس جيمس تايسنجر تشوملي، هيدي هي مايوه، سميث، مايندي يوساتني، ريتشارد : احملررون editors: richard p usatine, mindy a smith, ej mayeux jr, heidi chumley, james tysinger publishers: mcgraw-hill medical, 2009. $100 isbn: 978-0-07-147464-1 orders: www.mcgraw-hillmedical.com b o o k r e v i e w b o o k r e v i e w : th e c o l o r at l a s o f fa m i ly m e d i c i n e 98 topics with which they were previously unfamiliar, or where their knowledge has become rusty. this atlas is written for family physicians, but can be invaluable to medical students, residents, and health care providers in primary care. it certainly has much to offer to internists, pediatricians, and dermatologists. it is especially interesting for anyone who loves to look at clinical photographs for learning, teaching, and practising medicine. i hope this atlas will be a welcome aid to all of us and worthy of frequent use. despite the novelty of a family medicine atlas, this book was enjoyable to read. as each chapter is only a few pages long, it is suitable for reading when only short snippets of time are available. if you are new to the idea of a family medicine atlas, or if you would enjoy reading more on the subject from a variety of authors, this would be the book for you. can so many subjects be covered adequately in a single book? you, the reader, must be the ultimate judge. r e v i e w e r rahma al kindi department of family medicine and public health, college of medicine and health sciences, sultan qaboos university, muscat, sultanate of oman email: rkindi@squ.edu.om abstract: infants usually say their first word at the age of 12 months; subsequently, within the next 6–12 months, they develop a vocabulary of approximately 50 words, along with the ability to make two-word combinations. however, late talkers (lts) demonstrate delayed speech in the absence of hearing impairments, cognitive developmental issues or relevant birth history. the prevalence of late language emergence (lle) in toddlers is reported to be 10–15%. studies of lts are both theoretically and clinically significant. early diagnosis and clinical intervention may result in relatively stable speech capabilities by the early school years. the present article aimed to review both theoretical and empirical studies regarding lle within the process of first language acquisition, as well as methods for the early diagnosis of delayed speech in children and the authors’ own clinical and theoretical recommendations. keywords: infants; speech; language development; speech-language pathology; language development disorders; rehabilitation of speech and language disorders. late language emergence a literature review *peyman nouraey,1 mohammad a. ayatollahi,2 marzieh moghadas3 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e182–190, epub. 21 jun 21 submitted 28 apr 20 revision req. 29 jun 2020; revision recd. 9 aug 2020 accepted 16 sep 2020 1research department, gulf college, muscat, oman; 2department of english language, faculty of foreign languages, islamic azad university, sepidan, iran; 3department of behavioral medicine, college of medicine and health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: peyman@gulfcollege.edu.om the prevalence of language problems in children has increased rapidly in recent years.1 in general, such problems usually appear at the age of 2–3 years; however, it is not always easy to distinguish whether a child has a language development disorder or is simply slightly delayed in comparison to their peers.2 at this age, children often demonstrate wide variations in communicative development.3 as such, while many socalled late talkers (lts) speak fewer words at the age of 24 months compared to most other children of the same age, approximately half will catch-up to their typically developing peers by their third birthday.2–4 however, while delays in language development may indicate specific language difficulties, they may alternatively be early indicators of a more general problem such as global developmental delay (gdd), intellectual disability or autism spectrum disorder (asd).5–7 early screening is therefore paramount to determine the need for further evaluation and treatment so as to prevent the development of more significant problems. this review article aimed to summarise current knowledge regarding the evaluation, diagnosis and correlates of late language emergence (lle) in children aged 24–30 months. in addition, the article presents methods for the early diagnosis of delayed speech and the authors’ recommendations for future research and clinical practice. approaches to the study of language until the 1950s, the theory of behaviourism, developed by burrhus frederic skinner, dominated psychological approaches to learning with the focus being on observed behaviours and the external factors believed to determine these behaviours.8 behaviourism offers a view of how agents respond to different types of stimuli, with individual behaviours acquired through conditioning resulting from the reinforcement and repetition of a stimulus-response sequence. noam chomsky was one of the first linguists to dispute this theory, demonstrating that attempts to explain linguistic competence in terms of learning through conditioning were inadequate.9 he pointed out that it is necessary to understand the object of linguistics as the linguistic competence of the agent in question (i.e. psychic reality) and not solely observed behaviour.9 two important elements support this argument. first, the data that linguists need cannot be reduced to spontaneous linguistic products, but primarily consist of the linguistic intuition of speakers, to which the latter have access through introspection and which can be questioned by linguists. the second, developed by chomsky in his criticism of skinner’s theory of verbal behaviour, is that the linguistic competence of speakers goes far beyond what could be obtained through a simple preparation process of stimulus-response sequences, with language learning presupposing an already complex linguistic understanding in newborns.8–9 normal language emergence typically, language development follows a fixed course, although variation does occur in terms of the timing of specific stages.10 the speed with which review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.005 https://creativecommons.org/licenses/by-nd/4.0/ review | e183 individual children acquire first languages depends both on their innate neurocognitive abilities, probably determined genetically, and on their environment and previous encounters with human speech.11 language development is an active process in which the child experiences the language spoken by other humans in their surroundings and is strongly affected by the incentive to communicate with others. from birth, newborns show interest in human voices and are able to produce perceptually distinct units of sound. known as phonemes, these sounds represent the child’s first vocal productions and can be distinguished from the very first weeks of life depending on the child’s state of being (i.e. hunger, pain, appeal, well-being, etc.).12 the mother is often able to attribute meanings to these sounds, thus allowing for the development of the first system of communication. during the second month, these vocalisations diversify into babble and lallation.13 although these sounds appear to initially represent a sensorimotor game (i.e. a source of pleasure for the child), they gradually transform into an interactive game, especially after 5−6 months.14 toddlers use many vocalisations and referential symbolic gestures (i.e. gestures that have meaning) to develop common ground with the individuals with whom they attempt to communicate.8 these communicative gestures—refined through reciprocal social interaction and regulatory behaviours—presage the emergence of language abilities.15 the production of well-articulated syllables begins at 6−8 months.12 from 8–10 months, the child’s vocal productions change according to the language of their surrounding environment. this evolution is associated with the development of non-verbal communication, first by looking, then by smiling (i.e. mimicry).12 finally, around 8–9 months, the child seeks to attract the attention of others, focuses their gaze on what is shown to them and points their finger in the direction of an object.12 at 8–12 months, the child can point to items, shake their head to express “no”, wave goodbye, make sounds that resemble words and imitate an adult’s voice.12 most children speak their first words at 10–12 months.12 these words are usually systematically associated with certain objects and/or situations (i.e. a request or designation). at around 18 months of age, the child begins to progress in their individualisation. the very first sentences—defined as an association of two words, mainly to designate an action—appear between the ages of 20–24 months.12 towards the end of the second year, the child has amassed a vocabulary of 250–300 words. from 26–36 months, the child begins to utter three-word sentences. in the meantime, sentences increase in length and grammar becomes more accurate and complex, including the ability to use prepositions, add ‘ing’ endings to verb stems, affix the plural marker ‘s’ to nouns, use auxiliary verbs, use articles ‘a’ and ‘the’ and negate verbs.12 from 3–5 years, children understand most of what others say to them and their sentences and stories gradually become more complex as their conversational skills improve. the child is able to understand how to start a conversation to get the attention of others and how to take turns listening and speaking during the conversation. by the age of three years, a child’s vocabulary is around 1,000 words, increasing to >5,000 words by five years.12 late language emergence nevertheless, some infants aged 18–24 months may show delayed speech or a limited vocabulary in the absence of any significant hearing issues, cognitive development issues or relevant birth history.2–4 these infants are commonly referred to as late talkers (lts). in most cases, late talking is diagnosed at the age of 24 months based on a productive vocabulary of <50 words and an inability or unwillingness to combine two words together.15–18 in some instances, all stages of language development are delayed, with first words not appearing by two years of age and first sentences not occurring until after the child’s third birthday.18 various studies have reported the prevalence of early language delays to be 10–15%.19–23 other researchers have more specifically reported the prevalence of late talking to be 13% among toddlers.24–26 however, the question as to whether late talking represents a significant problem remains controversial. some studies have shown that approximately 17–26% of lts may demonstrate language impairments up until the age of 6 years.27,28 this delay in language development might result in specific language impairment (sli), also known as developmental language disorder.29 research in lle has both theoretical and clinical significance. from a theoretical perspective, such research may help improve our understanding and knowledge of the developmental pathways leading to language disorders.30 in addition, these studies shed light upon the evolution of linguistic competence over various stages of life, as well as the reliability of linguistic assessment in toddlers and the conceptual distinction between measurements of knowledge peyman nouraey, mohammad a. ayatollahi and marzieh moghadas and information processing.30,31 it is also important to understand the various processes involved in the speech development of lts, as well as any existing gaps and potential solutions. for instance, while it is widely accepted that comprehension occurs prior to language production in toddlers, significant gaps between comprehension and production have been reported in lts.3 from a clinical viewpoint, lle research is also critical to aid clinicians in distinguishing between late bloomers (i.e. children who would eventually catch up to their peers) and those at high risk of learning or language disorders.30 a search of the literature indicates that early identification of late talking and delayed speech may have prognostic value.32 a recent study reported that 31% of lts were diagnosed with asd as well as gdd, thus highlighting the importance of early diagnosis, clinical consultation and special education.7 indeed, some studies have shown that the speech capability of 5-year-old lts can remain relatively stable throughout their school years as a result of early diagnosis and clinical interventions.33,34 however, in some cases, early diagnosis of late talking and speech delays in infants can be hampered by sociocultural beliefs.7 for instance, in certain cultures, there is a common assumption that boys start to talk later than girls, or that late talking might be due to genetic factors.7 therefore, issues regarding late talking are sometimes underestimated by parents, potentially resulting in more serious consequences. although lts can improve by the age of 6–7 years, research shows that such children demonstrate significantly weaker language skills compared to their peers as they get older.32 for instance, a study found that while lts aged 13 years received average scores for a range of standardised language and reading tasks, they nevertheless scored significantly lower for grammar, vocabulary, reading comprehension and verbal memory compared to their peers.35 as such, it has been suggested that lts aged 18–35 months should undergo screening.32 late language emergence versus language disorders language disorders should not be confused with lle as the latter is not necessarily pathological, but a part of progressive learning of linguistic code.15–17 the diagnostic and statistical manual of mental disorders (dsm-v) classifies language disorders as a diagnostic category.36 according to the dsm-v, language disorders refer to conditions wherein children have difficulty acquiring and using language that is not attributable to motor, sensory, cognitive, genetic or other factors.36–38 the family of language disorders covers many different linguistic realities including anarthria/dysarthria, dysglossia, verbal auditory agnosia, asemia and asymbolia. such disorders are usually caused by neuropathy, muscle paralysis, weakened contractility or uncoordi nated movements related to speech.36 a diagnosis of delayed speech before the age of four years is not easy, as children undergo several language development variations up until this time. however, there is a high risk that lts will eventually develop language disorders or remain late bloomers by elementary school age.39,40 language disorders can have severe implications on the life of the child and their family and may necessitate involvement of the care system. collaborative efforts are needed to ensure the early detection and timely correction of speech disorders in children by various stakeholders including doctors, speech therapists, psychologists, teachers and the parents of the child in question. the main approaches to the correction of delayed speech in children includes speech therapy, psychological and pedagogical correctional measures, psychotherapeutic assistance for the child and their family, as well as medical treatment. measuring late language emergence various structured assessment tools have been devel oped to evaluate the expressive phonology abilities of toddlers under the age of 36 months including the toddler phonology test and profiles of early expressive phonological skills tool.39 in general, parents have much more experience with their children than professionals and are better able to assess their child’s impressions and interests. as such, parental word checklists and related questions have proven to be valuable metrics for assessing early language development.41 according to parental reports, the development of expressive vocabulary in bilingual children is comparable to monolingual children when both languages are combined.42 in addition, the age at which such children begin to combine words is identical to that of monolingual children, provided that the bilingual child is considered capable of combining words if they do so in at least one language.42 for the purposes of screening, there are two methods for combining vocabulary data, namely a generalised conceptual dictionary approach which combines words with similar meanings (e.g. english cat and spanish gato) or a generalised vocabulary approach which includes all words from each language, regardless of possible intersections of meaning. for toddlers, the latter late language emergence a literature review e184 | squ medical journal, may 2021, volume 21, issue 2 review | e185 approach is recommended because it is easier to calculate and allows for the size of the vocabulary to be scaled to calculate growth rates for young bilingual children.42 eye-tracking refers to a process in which the subject’s gaze is monitored through a video camera. this technology is widely used in toddler and infant research as it can provide useful data regarding momentby-moment cognitive and lexical processing.43,44 in particular, researchers have used eye-tracking tools to study the relationship between the speed of anticipatory looking in lts and other variables such as age, language input and socioeconomic status (ses).45,46 despite potential errors reported with eyetracking tools, they are a significant contributor to clinical research.47–49 the wait-and-see approach a common approach in dealing with lts is referred to as the wait-and-see approach. in this approach, lts are not referred immediately after they fail in language screening for further evaluation and diagnosis.50 this delay might be due to several reasons. for instance, caregivers’ poor understanding of language development may lead to delayed referral of lts for early clinical intervention.51 in some cases, parents opt for the wait-and-see approach, which might originate from fear of harms, including extra time, increased effort, and anxiety associated with further testing of the child.50 in other words, parents prefer to wait for and see (as the name suggests) their children to catch up to typical peers as they grow older. another delaying factor in reporting early diagnosis of late talking is diagnostic labeling, i.e. being labeled as children who require special education.50 diagnostic labeling may also lead into parents’ stress and anxiety.52 correlates of late language emergence research shows that lts encounter significant barriers with regards to lexical-phonological aspects of word processing, learning and representation.8,53 this means that words in the lexicons of lts are not as wellspecified compared to those of their peers and they require additional speech signals to recognise and analyse words during speech processing.54,55 children with sli in general, and lts in particular, have shown significantly reduced phonological working memory.8 in order to show a similar level of performance, lts and children with sli require at least twice as much practice and training compared to their peers.56 another difficulty faced by lts is their inability to hold non-words in their memory and use them in repetition tasks.57 another deficit is their inability to utilise lexical and/or sub-lexical information in order to facilitate the repetition of non-words similar to words they already know.58,59 according to eye-tracking data, lts are signif icantly less accurate and slower while looking at pictures of familiar words compared to their peers.60 several studies have revealed differences in the gaze patterns of lts (both infants and children) compared to their peers when performing tasks related to word learning and language processing.61–63 in addition, some variations have been reported in the number of fixations made by children with different reading comprehension abilities while trying to comprehend a sentence.64 other studies have reported that adolescents demonstrate a greater number of fixations to the target picture and that children with sli demonstrate slower spoken word recognition compared to agematched controls.65,66 this highlights the significant contribution of eye-tracking technologies when researching childhood speech delays. a number of external factors may also place children at risk for late talking by the age of 2 years. variables that appear to be predictive of delayed speech include parental anxiety regarding possible childhood speech, language or hearing problems, a family history of language impairment or dyslexia (especially in immediate family members such as parents and siblings), delays in pretend-play activities involving object substitution, sociodemographic factors, a family history of learning problems and variations in parenting, child care and early behavioural functioning.67–69 there are often similarities between the language characteristics of lts and those of their parents.70 while some researchers report no difference between what parents say to typically developing children and what they say to lts, others have reported the opposite.4,71 one study found that the parents of children with delayed vocabulary used longer statements when talking to their children, which may reduce the effectiveness of language learning stimulation.72 in addition, the parents of lts indicated that their child’s willingness to communicate was lower compared to normally developing children, which in turn may have a negative impact on the child’s language development. language stimulation is generally considered to be important for language development in children, including the use of short utterances and tactile and repetitive words which engage the interests of the child.72 peyman nouraey, mohammad a. ayatollahi and marzieh moghadas developmental games and social skills also affect the development of normal language.73 in commun ication, the child’s gestures and play abilities are related to symbolic representation and therefore provide information regarding cognitive function.74 games and languages are interrelated and developed in parallel. however, among lts, there is very little spontaneous imitation of behaviour and a lack of object-related or symbolic play, resulting in limited gestural or soundbased communication.74 in turn, research regarding the relationship between communication and social skills among children with normal language development ability shows that the number of words a child uses is related to the range of communication intentions they can express, with these intentions affecting the child’s vocabulary and interaction skills.74 thus, there appears to be a connection between language delay and limited social ability.75 one possible explanation for these findings is that delays in language expression are caused by factors that induce children to communicate with others and promote communication development. therefore, children who lack social motivation do not learn language skills even when the opportunity to do so arises. as such, limited social skills may cause language difficulties.76,77 certain socioeconomic indictors such as maternal education and familial ses have been linked to delayed language acquisition in children, likely due to their role as proxy measures of environmental support for language learning.78 in particular, maternal education predicts the vocabulary development of children as women with lower levels of education usually talk to their children in fewer ways and use limited vocabularies. similarly, other activities that may promote or weaken learning, such as reading or watching television, can also affect language development.79 with regards to ses, growing up in an economically disadvantaged family puts children at high risk for delays in the development of social, cognitive and language skills; such children demonstrating a smaller vocabulary compared to their middle-class peers.80 although ses does not directly affect the quality of language stimulation, it does affect parental availability and therefore the quality of parent-child interaction.81 nevertheless, although children from families with low ses appear to have a slightly higher risk of language impairment, there is concern that the excessive detection of lle among children from families of lower ses may be due to selection bias with regards to the availability of parenting report tools, given that 10th percentile subsamples include two to three times as many children from families of lower ses.82 moreover, research has shown that children from ethnic minorities also have lower mean scores, raising similar questions about the validity of parenting reporting tools in culturally diverse populations.83–85 finally, with the use of standard criteria consisting of expressive vocabulary and word combination, lle was found to be more frequent in two-year-old boys compared to girls, which raises the question of whether different criteria might be needed based on gender.86–88 emotional variables on the part of the parents can also affect the child’s language development by affecting the quality and quantity of communication stimuli. for example, research indicates an association between parental stress and vocabulary delay, with increased parental stress potentially related to delayed vocabulary in 18–39-month-old children.24 similarly, high levels of parental pressure have been linked to reductions in the availability and quality of language stimulation activities, which may be because stressed parents are more sensitive to parental pressure.24 in terms of genetic influences, language delay appears to be more frequent in monozygotic compared to dizygotic twins; however, analysis of the influence of genetics and environmental factors on constant language delay indicates that the latter are more important.89,90 theoretical and clinical recommendations monolingual children whose first language is not english should be referred to a specialist if they demonstrate delays in developing expressive vocabulary and combining words in their native language. since the development of expressive vocabulary is comparable in both monolingual and bilingual children, bilingual children with a limited expressive vocabulary and those who do not combine words into phrases should be monitored and/or referred to a specialist for further screening.42 a genealogical study is recommended to clarify the child’s family history in terms of a hereditary predis position to peculiarities in language development. however, as the establishment of speech is linked to the development of sensory, psyche and motor functions, it is not necessary to prescribe neuropsychiatric develop ment activities to all children, especially at an early age. in order to obtain optimal, objective and comparable results, this estimate must be verified with regards to the correct age, since psychomotor functions in premature infants develop at different times.91 late language emergence a literature review e186 | squ medical journal, may 2021, volume 21, issue 2 review | e187 as even moderate and gradual hearing loss can cause delays in speech development, lts should be screened for hearing impairments.92 deafness should be considered for children in whom there is a total absence of language (i.e. mutism). if partial or complete hearing loss is suspected in a child with an isolated speech delay, an audiological examination is necessary, ideally including an electroencephalogram assessment of auditory evoked potential. the sooner hearing defects are discovered, the sooner it will be possible to begin appropriate corrective work or to equip a hearing aid. an in-depth neuropsychiatric examination is indicated in cases in which delays in the development of speech are associated with general delays in mental development. early diagnosis is particularly critical for children aged <1 year in whom there is extinction of babble, or even later in the face of language regression or major phonetic disorders. in order to inform and validate models for predicting persistent language impairments in children with lle, it is necessary that both practitioners and researchers take part in large-scale research programmes in which screening is combined with longitudinal tracking and additional information about the child and their family. these collaborative efforts should also include work to adapt, implement and validate interventions for children from non-native language families and lower ses backgrounds. despite its difficulties and lack of rapid progress, speech therapy should be undertaken as soon as possible from the age of ≥3 years after an in-depth assessment and continued over the long-term at regular intervals (i.e. at least two sessions per week).92 conclusion although it is difficult to diagnose delayed speech before the age of four years due to natural variations in language development, early clinical interventions can significantly improve the linguistic abilities of lts as they grow older. one potential method of dealing with late talking is the wait-and-see approach wherein no clinical intervention is applied in the hope that the child will eventually catch-up to their typically developing peers. the benefits of this approach include reduced stress and anxiety on the part of the caregiver, particularly in terms of fear of unnecessary diagnostic labelling. however, some researchers argue that this approach is outdated, citing the need for early diagnosis and clinical intervention in order to screen for more serious issues such as gdd or asd, as well as minimise any further adverse effects. references 1. lindsay g, strand s. children with language impairment: prevalence, associated difficulties, and ethnic disproportionality in an english population. front educ 2016; 1:1–14. https://doi. org/10.3389/feduc.2016.00002. 2. roos em, weismer se. language outcomes of late talking toddlers at preschool and beyond. perspect lang learn educ 2008; 15:119–26. https://doi.org/10.1044/lle15.3.119. 3. fenson l, dale ps, reznick js, bates e, thal dj, pethick sj. variability in early communicative development. monogr soc res child dev 1994; 59:1–173. https://doi.org/10.2307/1166093. 4. rescorla l, dahlsgaard k, roberts j. late-talking toddlers: mlu and ipsyn outcomes at 3;0 and 4;0. j child lang 2000; 27:643–64. https://doi.org/10.1017/s0305000900004232. 5. marrus n, hall l. intellectual disability and language disorder. child adolesc psychiatr clin n am 2017; 26:539–54. https:// doi.org/10.1016/j.chc.2017.03.001. 6. mody m, belliveau jw. speech and language impairments in autism: insights from behavior and neuroimaging. n am j med sci (boston) 2013; 5:157–61. https://doi.org/10.7156/v5i3p157. 7. zengin-akkuş p, çelen-yoldaş t, kurtipek g, özmert en. speech delay in toddlers: are they only 'late talkers'? turk j pediatr 2018; 60:165–72. https://doi.org/10.24953/turkjped.20 18.02.008. 8. becker m, ud deen k. language acquisition and development: a generative introduction. cambridge, massachusetts, usa: mit press, 2020. 9. barman b. the linguistic philosophy of noam chomsky. philos prog 2012; 2–3:104–21. https://doi.org/10.3329/pp.v51i1-2.17681. 10. morse af, cangelosi a. why are there developmental stages in language learning? a developmental robotics model of language development. cogn sci 2017; 41:32–51. 11. kidd e, donnelly s, christiansen mh. individual differences in language acquisition and processing. trends cogn sci 2018; 22:154–69. https://doi.org/10.1016/j.tics.2017.11.006. 12. guasti mt. language acquisition: the growth of grammar. cambridge: mit press, 2017. 13. yafie e, giavarini i, maulidia ln. stimulating strategy children experiencing late language emergence (lle) during pandemic covid-19. adv soc sci educ humanit res 2020; 487:193–7. https://doi.org/10.2991/assehr.k.201112.034. 14. piaget, j. mastery play. in: bruner js, jolly a, sylva k, eds. play: its role in development and evolution. london: penguin books ltd, 1976. pp. 268–78. 15. ellis em, thal dj. early language delay and risk for language impairment. perspect lang learn educ 2008; 15:93–100. https://doi.org/10.1044/lle15.3.93. 16. weismer se, evans jl. the role of processing limitations in early identification of specific language impairment. top lang disord 2002; 22:15–29. https://doi.org/10.1097/00011363-2002 05000-00004. 17. thal dj. late-talking toddlers: are they at risk? 1st ed. san diego, california: san diego state university press, 2000. 18. thal dj, marchman va, tomblin jb. late-talking toddlers: characterization and prediction of continued delay. in: rescorla la, dale ps (eds). late talkers: language development, interventions, and outcomes, 1st ed. baltimore, maryland: brookes publishing co., 2013. pp. 169–201. 19. chilosi am, pfanner l, pecini c, salvadorini r, casalini c, brizzolara d, et al. which linguistic measures distinguish tran sient from persistent language problems in late talkers from 2 to 4 years? a study on italian speaking children. res dev disabil 2019; 89:59–68. https://doi.org/10.1016/j.ridd.2019.03.005. peyman nouraey, mohammad a. ayatollahi and marzieh moghadas https://doi.org/10.3389/feduc.2016.00002 https://doi.org/10.3389/feduc.2016.00002 https://doi.org/10.1044/lle15.3.119 https://doi.org/10.2307/1166093 https://doi.org/10.1017/s0305000900004232 https://doi.org/10.1016/j.chc.2017.03.001 https://doi.org/10.1016/j.chc.2017.03.001 https://doi.org/10.7156/v5i3p157 https://doi.org/10.24953/turkjped.2018.02.008 https://doi.org/10.24953/turkjped.2018.02.008 https://doi.org/10.3329/pp.v51i1-2.17681 https://doi.org/10.1016/j.tics.2017.11.006 https://doi.org/10.2991/assehr.k.201112.034 https://doi.org/10.1044/lle15.3.93 https://doi.org/10.1097/00011363-200205000-00004 https://doi.org/10.1097/00011363-200205000-00004 https://doi.org/10.1016/j.ridd.2019.03.005 20. collisson ba, graham sa, preston jl, rose ms, mcdonald s, tough s. risk and protective factors for late talking: an epidem iologic investigation. j pediatr 2016; 172:168–74.e1. https://doi. org/10.1016/j.jpeds.2016.02.020. 21. horwitz sm, irwin jr, briggs-gowan mj, bosson heenan jm, mendoza j, carter as. language delay in a community cohort of young children. j am acad child adolesc psychiatry 2003; 42:932–40. https://doi.org/10.1097/01.chi.0000046889.27264.5e. 22. korpilahti p, kaljonen a, jansson-verkasalo e. identification of biological and environmental risk factors for language delay: the let’s talk steps study. infant behav dev 2016; 42:27–35. https://doi.org/10.1016/j.infbeh.2015.08.008. 23. zubrick sr, taylor cl, rice ml, slegers dw. late language emergence at 24 months: an epidemiological study of prev alence, predictors, and covariates. j speech lang hear res 2007; 50:1562–92. https://doi.org/10.1044/1092-4388(2007/106). 24. kruythoff-broekman a, wiefferink c, rieffe c, uilenburg n. parent-implemented early language intervention programme for late talkers: parental communicative behaviour change and child language outcomes at 3 and 4 years of age. int j lang commun disord 2019; 54:451–64. https://doi.org/10.1111/14 60-6984.12451. 25. prathanee b, purdy sc, thinkhamrop b, chaimay b, ruangdaraganon n, mo-suwan l, et al. early language delay and predictive factors in children aged 2 years. j med assoc thai 2011; 92:930–8. 26. taylor c, zubrick s, rice ml. population and public health perspectives on late language emergence at 24 months as a risk indicator for language impairment at 7 years. in: rescorla la, dale ps (eds). late talkers: language development, inter ventions, and outcomes, 1st ed. baltimore, maryland: brookes publishing co., 2013. pp. 23–40. 27. paul r. clinical implications of the natural history of slow expressive language development. am j speech lang pathol 1996; 5:5–21. https://doi.org/10.1044/1058-0360.0502.05. 28. rescorla l. language and reading outcomes to age 9 in latetalking toddlers. j speech lang hear res 2002; 45:360–71. https://doi.org/10.1044/1092-4388(2002/028). 29. leonard lb. children with specific language impairment, 2nd ed. cambridge: mit press, 2014. 30. fisher el. a systematic review and meta-analysis of predictors of expressive-language outcomes among late talkers. j speech lang hear res 2017; 60:2935–48. https://doi.org/10.1044/2017_ jslhr-l-16-0310. 31. roy p, chiat s. teasing apart disadvantage from disorder: the case of poor language. in: marshall cr (ed). current issues in developmental disorders. london: psychology press ltd., 2013. pp. 125–50. 32. rescorla l. late talkers: do good predictors of outcome exist? dev disabil res rev 2011; 17:141–50. https://doi.org/10.1002/ ddrr.1108. 33. aram dm, hall ne. longitudinal follow-up of children with preschool communication disorders: treatment implications. school psych rev 1989; 18:487–501. https://doi.org/10.1080/02 796015.1989.12085444. 34. long t. early intervention. in: batshaw ml, roizen nj, lotrecchiano gr (eds). children with disabilities, 7th ed. baltimore: brookes publishing co., 2012. pp. 547–57. 35. rescorla l. age 13 language and reading outcomes in latetalking toddlers. j speech lang hear res 2005; 48:459–72. https://doi.org/10.1044/1092-4388(2005/031). 36. american psychiatric association. diagnostic and statistical manual of mental disorders (dsm-5). washington dc: american psychiatric publishing inc., 2013. 37. hawa vv, spanoudis g. toddlers with delayed expressive language: an overview of the characteristics, risk factors and language outcomes. res dev disabil 2014; 35:400–7. https:// doi.org/10.1016/j.ridd.2013.10.027. 38. capone singleton n. late talkers: why the wait-and-see approach is outdated. pediatr clin north am 2018; 65:13–29. https://doi.org/10.1016/j.pcl.2017.08.018. 39. mcintosh b, dodd bj. two-year-olds’ phonological acquisition: normative data. int j speech lang pathol 2008; 10:460–9. https://doi.org/10.1080/17549500802149683. 40. hodges r, baker e, munro n, mcgregor kk. responses made by late talkers and typically developing toddlers during speech assessments. int j speech lang pathol 2017; 19:587–600. https://doi.org/10.1080/17549507.2016.1221452. 41. dale ps. the validity of a parent report measure of vocabulary and syntax at 24 months. j speech hear res 1991; 34:565–71. https://doi.org/10.1044/jshr.3403.565. 42. core c, hoff e, rumiche r, señor m. total and conceptual vocabulary in spanish-english bilinguals from 22 to 30 months: implications for assessment. j speech lang hear res 2013; 56:1637–49. https://doi.org/10.1044/1092-4388(2013/11-0044). 43. bergelson e, swingley d. at 6–9 months, human infants know the meanings of many common nouns. proc natl acad sci u s a 2012; 109:3253–8. https://doi.org/10.1073/pnas.1113380109. 44. mani n, huettig f. prediction during language processing is a piece of cake--but only for skilled producers. j exp psychol hum percept perform 2012; 38:843–7. https://doi.org/10.1037/ a0029284. 45. ellis em, borovsky a, elman jl, evans jl. novel word learning: an eye-tracking study. are 18-month-old late talkers really different from their typical peers? j commun disord 2015; 58:143–57. https://doi.org/10.1016/j.jcomdis.2015.06.011. 46. hurtado n, marchman va, fernald a. does input influence uptake? links between maternal talk, processing speed and vocabulary size in spanish-learning children. dev sci 2008; 11:f31–9. https://doi.org/10.1111/j.1467-7687.2008.00768.x. 47. aslin rn. infant eyes: a window on cognitive development. infancy 2012; 17:126–40. https://doi.org/10.1111/j.1532-7078.20 11.00097.x. 48. creel sc. looking forward: comment on morgante, zolfaghari, and johnson. infancy 2012; 17:141–58. https://doi.org/10.1111/ j.1532-7078.2011.00106.x. 49. morgante jd, zolfaghari r, johnson sp. a critical test of temporal and spatial accuracy of the tobii t60xl eye tracker. infancy 2012; 17:9–32. https://doi.org/10.1111/j.1532-7078.2011.00089.x. 50. singleton nc. late talkers: why the wait-and-see approach is outdated. pediatr clin north am 2018; 65:13–29. https://doi. org/10.1016/j.pcl.2017.08.018. 51. nayeb l, wallby t, westerlund m, salameh ek, sarkadi a. child healthcare nurses believe that bilingual children show slower language development, simplify screening procedures and delay referrals. acta paediatr 2015; 104:198–205. https:// doi.org/10.1111/apa.12834. 52. pierson f. bringing early intervention to her community. asha lead 2014; 19:58–9. https://doi.org/10.1044/leader. ftr3.19022014.58. 53. klee t, pearce k, carson dk. improving the positive predictive value of screening for developmental language disorder. j speech lang hear res 2000; 43:821–33. https://doi. org/10.1044/jslhr.4304.821. 54. mainela-arnold e, evans jl, coady ja. lexical representations in children with sli: evidence from a frequency-manipulated gating task. j speech lang hear res 2008; 51:381–93. https:// doi.org/10.1044/1092-4388(2008/028). late language emergence a literature review e188 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1016/j.jpeds.2016.02.020 https://doi.org/10.1016/j.jpeds.2016.02.020 https://doi.org/10.1097/01.chi.0000046889.27264.5e https://doi.org/10.1016/j.infbeh.2015.08.008 https://doi.org/10.1044/1092-4388%282007/106%29 https://doi.org/10.1111/1460-6984.12451 https://doi.org/10.1111/1460-6984.12451 https://doi.org/10.1044/1058-0360.0502.05 https://doi.org/10.1044/1092-4388%282002/028%29 https://doi.org/10.1044/2017_jslhr-l-16-0310 https://doi.org/10.1044/2017_jslhr-l-16-0310 https://doi.org/10.1002/ddrr.1108 https://doi.org/10.1002/ddrr.1108 https://doi.org/10.1080/02796015.1989.12085444 https://doi.org/10.1080/02796015.1989.12085444 https://doi.org/10.1044/1092-4388%282005/031%29 https://doi.org/10.1016/j.ridd.2013.10.027 https://doi.org/10.1016/j.ridd.2013.10.027 https://doi.org/10.1016/j.pcl.2017.08.018 https://doi.org/10.1080/17549500802149683 https://doi.org/10.1080/17549507.2016.1221452 https://doi.org/10.1044/jshr.3403.565 https://doi.org/10.1044/1092-4388%282013/11-0044%29 https://doi.org/10.1073/pnas.1113380109 https://doi.org/10.1037/a0029284 https://doi.org/10.1037/a0029284 https://doi.org/10.1016/j.jcomdis.2015.06.011 https://doi.org/10.1111/j.1467-7687.2008.00768.x https://doi.org/10.1111/j.1532-7078.2011.00097.x https://doi.org/10.1111/j.1532-7078.2011.00097.x https://doi.org/10.1111/j.1532-7078.2011.00106.x https://doi.org/10.1111/j.1532-7078.2011.00106.x https://doi.org/10.1111/j.1532-7078.2011.00089.x https://doi.org/10.1016/j.pcl.2017.08.018 https://doi.org/10.1016/j.pcl.2017.08.018 https://doi.org/10.1111/apa.12834 https://doi.org/10.1111/apa.12834 https://doi.org/10.1044/leader.ftr3.19022014.58 https://doi.org/10.1044/leader.ftr3.19022014.58 https://doi.org/10.1044/jslhr.4304.821 https://doi.org/10.1044/jslhr.4304.821 https://doi.org/10.1044/1092-4388%282008/028%29 https://doi.org/10.1044/1092-4388%282008/028%29 review | e189 55. alt m, plante e. factors that influence lexical and semantic fast mapping of young children with specific language impairment. j speech lang hear res 2006; 49:941–54. https://doi. org/10.1044/1092-4388(2006/068). 56. ellis weismer s, hesketh lj. the impact of emphatic stress on novel word learning by children with specific language impairment. j speech lang hear res 1998; 41:1444–58. https:// doi.org/10.1044/jslhr.4106.1444. 57. coady ja, evans jl. uses and interpretations of non-word repetition tasks in children with and without specific language impairments (sli). int j lang commun disord 2008; 43:1–40. https://doi.org/10.1080/13682820601116485. 58. coady j, evans jl, kluender kr. role of phonotactic frequency in nonword repetition by children with specific language impairments. int j lang commun disord 2010; 45:494–509. https://doi.org/10.3109/13682820903222783. 59. wing c, kohnert k, pham g, cordero kn, ebert kd, kan pf, et al. culturally consistent treatment for late talkers. commun disord q 2007; 29:20–7. https://doi.org/10.1177/1525740108314862. 60. fernald a, marchman va. individual differences in lexical processing at 18 months predict vocabulary growth in typically developing and late-talking toddlers. child dev 2012; 83:203–22. https://doi.org/10.1111/j.1467-8624.2011.01692.x. 61. borovsky a, elman jl, fernald a. knowing a lot for one’s age: vocabulary skill and not age is associated with anticipatory incremental sentence interpretation in children and adults. j exp child psychol 2012; 112:417–36. https://doi.org/10.1016/j. jecp.2012.01.005. 62. borovsky a, burns e, elman jl, evans jl. lexical activation during sentence comprehension in adolescents with history of specific language impairment. j commun disord 2013; 46:413–27. https://doi.org/10.1016/j.jcomdis.2013.09.001. 63. yu c, smith lb. what you learn is what you see: using eye movements to study infant cross-situational word learning. dev sci 2011; 14:165–80. https://doi.org/10.1111/j.1467-7687.2010.00958.x. 64. nation k, marshall cm, altmann gt. investigating individual differences in children’s real-time sentence comprehension using language-mediated eye movements. j exp child psychol 2003; 86:314–29. https://doi.org/10.1016/j.jecp.2003.09.001. 65. mcmurray b, samelson vm, lee sh, tomblin jb. individual differences in online spoken word recognition: implications for sli. cogn psychol 2010; 60:1–39. https://doi.org/10.1016/j. cogpsych.2009.06.003. 66. andreu l, sanz-torrent m, guàrdia-olmos j. auditory word recognition of nouns and verbs in children with specific language impairment (sli). j commun disord 2012; 45:20–34. https://doi.org/10.1016/j.jcomdis.2011.09.003. 67. hammer cs, morgan p, farkas g, hillemeier m, bitetti d, maczuga s. late talkers: a population-based study of risk factors and school readiness consequences. j speech lang hear res 2017; 60:607–26. https://doi.org/10.1044/2016_jslhr-l-15-0417. 68. olswang lb, rodríguez b, timler g. recommending intervention for toddlers with specific language learning difficulties: we may not have all the answers, but we know a lot. am j speech lang pathol 1998; 7:23–32. https://doi.org/10.1044/1058-0360.0701.23. 69. lyytinen p, eklund k, lyytinen h. language development and literacy skills in late-talking toddlers with and without familial risk for dyslexia. ann dyslexia 2005; 55:166–92. https://doi. org/10.1007/s11881-005-0010-y. 70. girolametto l, bonifacio s, visini c, weitzman e, zocconi e, pearce ps. mother-child interactions in canada and italy: ling uistic responsiveness to late-talking toddlers. int j lang commun disord 2002; 37:153–71. https://doi.org/10.1080/13682820110 116794. 71. paul r. profiles of toddlers with slow expressive language devel opment. top lang disord 1991; 11:1–13. https://doi.org/10.10 97/00011363-199111040-00003. 72. desmarais c, sylvestre a, meyer f, bairati i, rouleau n. syst ematic review of the literature on characteristics of late-talking toddlers. int j lang commun disord 2008; 43:361–89. https:// doi.org/10.1080/13682820701546854. 73. camaioni l, laicardi c. early social games and the acquisition of language. br j dev psychol 1985; 3:31–9. https://doi.org/10.11 11/j.2044-835x.1985.tb00952.x. 74. rubin kh. social and social-cognitive developmental charact eristics of young isolate, normal, and sociable children. in: rubin kh, ross hs (eds). peer relationships and social skills in childhood, 1st ed. new york: springer, 1982. pp. 353–74. 75. ginnsborg j. language and social disadvantage: the effects of socio-economic status on children’s language acquisition and use. in: clegg j, ginsborg j (eds). language and social disadvantage: theory into practice. 2006. pp. 9–27. 76. rice ml, hadley pa, alexander al. social biases toward children with speech and language impairments: a correlative causal model of language limitations. appl psycholinguist 1993; 14:445–71. https://doi.org/10.1017/s0142716400010699. 77. maulana ms. risk of language delay in toddlers with prolonged screen time: evidence based case report. j early child islam educ study 2020; 1:34–48. https://doi.org/10.33853/jecies.v1i1.53. 78. hoff-ginsberg e. the relation of birth order and socioeconomic status to children’s language experience and language develop ment. appl psycholinguist 1998; 19:603–29. https://doi.org/10.10 17/s0142716400010389. 79. rosenqvist j, lahti-nuuttila p, holdnack j, kemp sl, laasonen m. relationship of tv watching, computer use, and reading to children's neurocognitive functions. j appl dev psychol 2016; 46:11–21. https://doi.org/10.1016/j.appdev.2016.04.006. 80. hoff e, tian c. socioeconomic status and cultural influences on language. j commun disord 2005; 38:271–8. https://doi. org/10.1016/j.jcomdis.2005.02.003. 81. pungello ep, iruka iu, dotterer am, mills-koonce r, reznick js. the effects of socioeconomic status, race, and parenting on language development in early childhood. dev psychol 2009; 45:544–57. https://doi.org/10.1037/a0013917. 82. dollaghan ca, campbell tf, paradise jl, feldman hm, janosky je, pitcairn dn, et al. maternal education and measures of early speech and language. j speech lang hear res 1999; 42:1432–43. https://doi.org/10.1044/jslhr.4206.1432. 83. pan ba, rowe ml, singer jd, snow ce. maternal correlates of growth in toddler vocabulary production in low-income families. child dev 2005; 76:763–82. https://doi.org/10.1111/ j.1467-8624.2005.00876.x. 84. rescorla l, achenbach tm. use of the language development survey (lds) in a national probability sample of children 18 to 35 months old. j speech lang hear res 2002; 45:733–43. https://doi.org/10.1044/1092-4388(2002/059). 85. dale ps, price ts, bishop dv, plomin r. outcomes of early language delay: i. predicting persistent and transient language difficulties at 3 and 4 years. j speech lang hear res 2003; 46:544–60. https://doi.org/10.1044/1092-4388(2003/044). 86. rice ml, taylor cl, zubrick sr. language outcomes of 7-yearold children with or without a history of late language emergence at 24 months. j speech lang hear res 2008; 51:394–407. https://doi.org/10.1044/1092-4388(2008/029). 87. rescorla l, alley a. validation of the language development survey (lds): a parent report tool for identifying language delay in toddlers. j speech lang hear res 2001; 44:434–45. https://doi.org/10.1044/1092-4388(2001/035). peyman nouraey, mohammad a. ayatollahi and marzieh moghadas https://doi.org/10.1044/1092-4388%282006/068%29 https://doi.org/10.1044/1092-4388%282006/068%29 https://doi.org/10.1044/jslhr.4106.1444 https://doi.org/10.1044/jslhr.4106.1444 https://doi.org/10.1080/13682820601116485 https://doi.org/10.3109/13682820903222783 https://doi.org/10.1177/1525740108314862 https://doi.org/10.1111/j.1467-8624.2011.01692.x https://doi.org/10.1016/j.jecp.2012.01.005 https://doi.org/10.1016/j.jecp.2012.01.005 https://doi.org/10.1016/j.jcomdis.2013.09.001 https://doi.org/10.1111/j.1467-7687.2010.00958.x https://doi.org/10.1016/j.jecp.2003.09.001 https://doi.org/10.1016/j.cogpsych.2009.06.003 https://doi.org/10.1016/j.cogpsych.2009.06.003 https://doi.org/10.1016/j.jcomdis.2011.09.003 https://doi.org/10.1044/2016_jslhr-l-15-0417 https://doi.org/10.1044/1058-0360.0701.23 https://doi.org/10.1007/s11881-005-0010-y https://doi.org/10.1007/s11881-005-0010-y https://doi.org/10.1080/13682820110116794 https://doi.org/10.1080/13682820110116794 https://doi.org/10.1097/00011363-199111040-00003 https://doi.org/10.1097/00011363-199111040-00003 https://doi.org/10.1080/13682820701546854 https://doi.org/10.1080/13682820701546854 https://doi.org/10.1111/j.2044-835x.1985.tb00952.x https://doi.org/10.1111/j.2044-835x.1985.tb00952.x https://doi.org/10.1017/s0142716400010699 https://doi.org/10.33853/jecies.v1i1.53 https://doi.org/10.1017/s0142716400010389 https://doi.org/10.1017/s0142716400010389 https://doi.org/10.1016/j.appdev.2016.04.006 https://doi.org/10.1016/j.jcomdis.2005.02.003 https://doi.org/10.1016/j.jcomdis.2005.02.003 https://doi.org/10.1037/a0013917 https://doi.org/10.1044/jslhr.4206.1432 https://doi.org/10.1111/j.1467-8624.2005.00876.x https://doi.org/10.1111/j.1467-8624.2005.00876.x https://doi.org/10.1044/1092-4388%282002/059%29 https://doi.org/10.1044/1092-4388%282003/044%29 https://doi.org/10.1044/1092-4388%282008/029%29 https://doi.org/10.1044/1092-4388%282001/035%29 88. paul r, kellogg l. temperament in late talkers. j child psychol psychiatry 1997; 38:803–11. https://doi.org/10.1111/j.1469-761 0.1997.tb01598.x. 89. rutter m, thorpe k, greenwood r, northstone k, golding j. twins as a natural experiment to study the causes of mild lang uage delay: i: design; twin-singleton differences in language, and obstetric risks. j child psychol psychiatry 2003; 44:326–41. https://doi.org/10.1111/1469-7610.00125. 90. plomin r, dale ps. genetics and early language development: a uk study of twins. in: bishop dv, leonard lb (eds). speech and language impairments in children: causes, characteristics, intervention and outcome. london: psychology press ltd., 2000. pp. 35–51. 91. ungerer ja, sigman m. developmental lags in preterm infants from one to three years of age. child dev 1983; 54:1217–28. https://doi.org/10.2307/1129677. 92. mclaughlin mr. speech and language delay in children. am fam physician 2011; 83:1183–8. late language emergence a literature review e190 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1111/j.1469-7610.1997.tb01598.x https://doi.org/10.1111/j.1469-7610.1997.tb01598.x https://doi.org/10.1111/1469-7610.00125 https://doi.org/10.2307/1129677 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 16-23, epub 16th mar 2009 submitted 13th jan 2009 revision req. 7th feb 2009, revision recd. 8th feb 2009, accepted 9th feb 2009 huntington disease (chorea) in the middle east *euan m scrimgeour األوسط الشرق نْتِنْغتُون في هَ ( صُ (رَقَ داء سكرميجر يوان في وكذلك ، ومصر ولبنان وسوريا وعمان السعودية العربية اململكة مثل األوسط ــرق بالش عربية دول عدة في نْتِنْغتُون هَ داء ــخيص امللخص: مت تش واألردن واإلمارات العربية املتحدة اليمن في ــجل يس لم اآلن حلد إذ ، املرض ــخيص في تش نقص هناك يكون رمبا . املنطقة غير عربية بنفس أخرى دول . الغابرة األزمنة في املنطقة دول دخل إلى قد يكون أن ميكن ولهذا ــفر ، والس ا لتجارة طريق تقاطع معروف يقع في هو كما ــط األوس ــرق والش . والعراق اكتشافه مت هنتنغتني قد املشفر للبروتني 100,000 . ولو أن املورث 4 لكل 3 إلى بني يتراوح األوسط الشرق في العرب عند نْتِنْغتُون هَ داء انتشار معدل نْتِنْغتُون هَ داء أصبح . فعال ــكل بش أو لعالجه نْتِنْغتُون داء هَ لتأخير حدوث عالج يوجد ال الراهن الوقت في . معروفة البروتني غير ــك ذل ــة وظيف ــن ، لك واململكة عمان في فروع لها العاملية التي نْتِنْغتُون وذلك بدعم وتعاون جمعية هَ ــبيا ، نس ــاره انتش ندرة من الرغم على الوراثية البحوث اهتمام محط . السعودية العربية . العربي ، الشرق األوسط ، العرق رقص ، نْتِنْغتُون : هَ الكلمات مفتاح marshall centre for infectious diseases training and research, school of biomedical, biomolecular & chemical sciences, university of western australia, australia *email: euan_scrimgeour@yahoo.co.uk abstract huntington disease (hd) has been reported in arab families in several middle east countries including saudi arabia, oman, syria, lebanon, and egypt and in non-arab populations in other countries in the region. it is probably under-reported, and until now, has not been recorded in yemen, the united arab emirates, jordan or in iraq. the middle east has always been on the crossroads of trade and travel, and hd was probably introduced to some of these countries in previous times. the prevalence rate in middle eastern arabs is estimated to vary from 3 to 4 per 00,000. although the hd gene which codes for the protein huntingtin has been identified, the function of this protein is not known. at present, no treatment has been found to delay the onset of hd or to treat it effectively. although relatively rare, hd has increasingly become a focus of international gene research, with the support and collaboration of the international huntington association (iha). the iha has been represented in saudi arabia and oman. key words: huntington; chorea; middle east; arab race. s p e c i a l c o n t r i b u t i o n genetic aspects of heredity and disease have made enormous advances in recent decades especially in regard to our understanding of the molecular basis of gene expression. this has had a significant impact in every branch of medicine, and induced most of us to keep abreast of the fundamentals of basic genetics and its terminology. in brief, a gene is a portion of deoxyribonucleic acid (dna) encoded on a chromosome, which contains a particular set of instructions usually coding for a single protein. each somatic cell contains 23 paired chromosomes, one of each pair derived from each parent. each chromosome (a single very long dna helix) encodes thousands of genes. much of the variation in our body traits such as height, intelligence and blood pressure among ‘normal’ people can be accounted for by our remarkable genetic variability (polymorphism). these genetic differences also influence our ability to meet environmental challenges including those that produce disease. ultimately, all human disease can be considered to result from interaction between our genetic make up and the environment. an example is the development of type 2 diabetes mellitus in susceptible subjects exposed to a high carbohydrate diet. in genetic disorders, the genetic component is so overwhelming that disease manifests without the necessity for environmental challenge. disorders caused by the transmission of a single mutant gene follow h u n t i n g t o n d i s e a s e ( c h o r e a ) i n t h e m i d d l e e a s t 17 three different patterns of inheritance. in autosomal dominant disorders, the individual inherits a single dose of the mutant gene (mutant allele) from one parent (i.e. he or she is heterozygous for the gene) and the disease will be expressed. examples include familial hypercholesterolaemia and marfan’s syndrome. in recessive disorders, the mutant gene is inherited from each parent (i.e. both alleles are mutant) and the patient is homozygous for the gene. again, the disease will be expressed. in populations in which consanguineous marriages occur frequently, i.e. arranged marriages between cousins, certain recessive conditions are more common. familiar examples include sickle cell anaemia and β-thalassemia. in x-linked disorders, the mutant gene is located on the x chromosome. since a female has two x chromosomes, she may be either heterozygous or homozygous for a mutant gene; therefore, the trait may manifest as either dominant or recessive expression. as a male has only one x chromosome, if he inherits the mutant gene, the full syndrome will always be manifested e.g. haemophilia a and duchenne's muscular dystrophy. an example of a relatively rare, but now prominent autosomal dominant condition, is huntington disease (hd) or huntington’s chorea as it was formerly termed. hd is named after an american general practitioner, george huntington, who in 1872 described inherited chorea in families living on long island, new york.1 his single publication earned him enduring recognition, and led ultimately to a worldwide association of medical workers, scientists and affected families (the international huntington’s association), and a massive and intensive research programme which continues today. the number of publications annually is increasing rapidly [figure 1]. c h a r a c t e r i s t i c s a n d p r e v a l e n c e o f h u n t i n g t o n d i s e a s e research on the molecular biology of hd has increased our understanding of aspects of cellular function and gene expression, and incidentally this has shed light on unrelated diseases such as alzheimer’s. the discovery of the general location of the hd gene on chromosome 4 in 1993 using dna marking methods was an important first step toward the human genome project.2 hd is an unique neurodegenerative disease which has three characteristic features: the onset of chorea or choreoathetosis, usually in middle-age, dominant inheritance and progressive dementia. the average doctor in the middle east may never encounter or recognise a case, yet affected families have been documented in arabs in oman,3 saudi arabia,4-6 syria,4 lebanon,4 and egypt,4 and hd has also been recorded in a sudanese family living in jeddah, saudi arabia 7 and in non-arab communities in turkey,8 israel,9 and iran.10 it is probable that foci of hd occur in yemen, the united arab emirates, jordan and iraq, although they do not appear to have been yet identified or reported. although hd may present in early childhood or figure 1: publications on huntington disease listed in the entrez pubmed website of the national library of medicine, washington dc, usa. (www.ncbi.nlm.nih.gov/pubmed) 4500 4000 3500 3000 2500 2000 1500 1000 500 0 to ta l a rt ic le (c u m u la ti ve ) 1950 1960 1980 1990 2000 20101970 e ua n m s c r i m g e o u r 18 in the elderly, commonly it presents in middle life, by which time the patient has probably married, and has adolescent children who have viewed the distressing evolution of the clinical disease. involuntary movements of face (grimacing), and chorea or choreoathetosis (stereotyped, repetitive twitching and jerking movements) of limbs and digits appear, affecting speech and gait. subsequently over a decade or more, intellectual impairment develops with memory loss and behavioural and psychiatric disturbances. the progression is remorseless leading to incapacitation and decease usually within 15 to 20 years. prior to decease, the patient is typically mute, bedfast, and affected by terminal intercurrent infections such as pneumonia. the presentation is so characteristic, that it is relatively easy to suspect the diagnosis when one has already seen a case or observed a videotape of a patient (there is a videotape of an omani patient, ‘maryam’ in the medical library of sultan qaboos university hospital in muscat, oman, and there are also several good videoclips of hd patients listed in the google.com website). every child born to an affected mother or father has a 50% chance of inheriting the anomalous gene, and all gene-positive subjects will ultimately develop the disease unless they die before it presents. genetic studies suggest that spontaneous mutation is rare in hd, among the lowest for any similarly inherited condition.11 transmission from a gene-positive individual is therefore the usual explanation for the occurrence of a case including an apparently sporadic case in a family with no history of hd. the prevalence rate in persons of western european descent is between 3 and 7 cases per 100,000, with the netherlands and the united kingdom historically, being high-prevalence regions. studies have shown that emigration in the 18th and 19th centuries of individuals from western europe introduced the disease to north america, south africa and australia and elsewhere.12 the prevalence rate in individuals of asian or african descent on the other hand, is much lower, in the order of 1 per 1,000,000. the prevalence rates for hd for the middle east are likely to vary from 3 to 4 per 100,000 for the whole region, but there may well be foci of higher prevalence rates adjacent to ports or in isolated communities. for oman, with an arab population of some 3,000,000 persons, it is likely that there are about 100 hd cases in arabs countrywide, of which only about a dozen cases (including anecdotal reports) are known. when a focus of the disease is found in noncaucasian populations, eg black africans in tanzania 13 and zimbabwe,14 or melanesians in papua new guinea,15 there may be evidence that it was introduced by caucasian visitors in earlier times. the relatively high prevalence foci of hd in melanesian families in the remote islands of new britain, and malaita in the new hebrides can probably be explained by the numerous visits by whaling ships from new england, usa, to hunt sperm whales in the coastal waters off these islands in the 18th and 19th centuries. ship’s logs record shore visits by many american sailors to both islands.16 many of the crewmen bore surnames from well-known hd families from new england, a high-prevalence area of the disease.12 in venezuela, it is believed the disease was introduced to the lake maracaibo region between 1860 and 1870 by a spanish sailor.17 in this isolated population, an exceedingly high prevalence rate of up to 700 per 100,000 developed, and as a consequences of intermarriage, some 30% of patients were subsequently identified as being homozygous for the gene. the middle east has always been on the crossroads of trade and travel, and it is not surprising that foci of hd occur in local populations throughout the region. over the years, immigration has brought many individuals from afar to reside in the region, among whom there are likely to have been individuals carrying the trait for hd. in jeddah, the individual who introduced hd to a saudi family, was an afghan migrant.5 although hd has not been reported in afghanistan, the disease certainly occurs there: the individual who introduced hd to australian aboriginal families in the tropical kimberley region of western australia in the late 1880s, was also an afghani, a cameleer who married seven indigenous women.18 in the case of the oman studies, no foreign antecedent could be identified in recent preceding generations. however, with its rich history of past settlement, trade and colonisation (the portuguese ruled muscat and coastal oman during the 17th and first half of the 18th centuries), there must have been many opportunities for introduction of hd.3 oman’s long association with zanzibar and coastal east africa, which it administered until the early 1970s, and the migration of thousands of arab families to oman when independence was achieved in tanzania and kenya, would have been another opportunity for introduction of the disease: hd h u n t i n g t o n d i s e a s e ( c h o r e a ) i n t h e m i d d l e e a s t 19 occurs in tanzania.13 d e v e l o p m e n t o f t h e d i s e a s e the gene which produces the cytoplasmic protein we call ‘huntingtin’ (which is present in every normal cell), i.e. the huntingtin gene (htt), was identified in 1993 on the short arm of chromosome 4 (4p.16.3) by the huntington’s disease collaborative research group.19 this study was conducted in the high prevalence region of venezuela referred to previously. the gene contains a sequence of three dna bases, cytosine-adenine-guanine (cag) repeated multiple times (i.e. cagcag etc). cag is the genetic code for the amino acid glutamine. the range of glutamine repeats in normal huntingtin (htt) is less than 27. like all proteins, this is translated and then affects biological functions, but although in mouse models, it is essential for development and survival, in man its precise function is still unknown. in hd, the abnormal or mutant gene (mhtt) produces a sequence of 36 or more glutamines (polyglutamines) in huntingtin protein, which results in protein aggregation and neuronal degeneration in parts of the brain.20, 21 astrogliosis and loss of neurones especially in the striatum, frontal and temporal cortices are the main sequelae the subthalamic nuclei in the striatum sends control signals to the globus pallidus which initiates and modulates motion, and their impairment, results in the characteristic involuntary movements. the more cag repeats that are present, the earlier hd develops. thus with relatively few repeats, i.e. 3639, the disease may only appear in late old age, but with very large repeats, it can present before 20 yearsof-age (7% of cases) when it is called juvenile hd or the westphal variant. our 6 year old patient in the oman study had 92 cag repeats, and had the typical associated features of rigidity and dystonia.3 the development of the transgenic mouse model for hd (the r6 line) in 1996 (when a cag repeat expansion was inserted into a mouse genome) has been a significant step in investigating the disease,22 and, last year, a new transgenic rhesus monkey model of hd was developed by emory university, atlanta, georgia with a view to improving treatment modalities.23 it is an arresting sight to observe animals with the characteristic involuntary movements of the classical disease. d i a g n o s i s a n d f o l l o w u p the diagnosis of hd is usually confirmed by a neurologist or a psychiatrist. until the availability of dna diagnosis, the differential diagnosis of hd included various conditions including hepatolenticular degeneration, tardive dyskinesia following the use of phenothiazine drugs, parkinson’s disease when overdosed with levodopa and hereditary acanthocytosis. however, with the definitive dna test, the diagnosis can easily be established, with supportive neuroradiology, if available. in the latter, magnetic resonance (mri) imaging or computerised tomography (ct scan) of the brain demonstrates caudate nuclei atrophy with the bicaudate diameter exceeding the normal range of 12.5-15mm. at this point, predictive genetic testing by a blood test of family members at risk of the disease is available to individuals at 18 or more years of age, following full counselling. at no time are individuals encouraged to be tested, it must always be entirely at their own volition. currently, prenatal diagnosis of hd in maternal plasma is being evaluated. 24 it is essential in a hereditary disease of this serious nature, that patients, affected families and individuals at-risk (as well as the medical staff looking after cases), are fully informed about the condition. at all times confidentiality and anonymity for patients and families must be assured. preliminary explanation may be provided by the diagnosing doctors, but this is best followed up by provision of detailed information booklets with representative diagrams of family pedigrees, which the family can study at their leisure. such booklets are provided by the international huntington association (iha) or its regional branches (or related organisations) in english and other major languages. the iha was formed in 1979 in oxford, england, and is now a worldwide organisation mostly of lay people and family members who promote social support for families and patients, collaborate in research projects, act as fund-raisers, and disseminate knowledge of the condition. formerly, the iha did not provide information booklets in arabic, and accordingly, in saudi arabia and in oman, a 3-page arabic information booklet was prepared for local use. this booklet which had representative diagrams of family pedigrees was discussed at length and in detail with family members. it explained the hereditary nature and cause of the disease in simple, non-technical terms, and emphasized that at present there was no curative or e ua n m s c r i m g e o u r 20 preventative medication [figure 2]. this is important as families are likely to consider any resource to find a solution. usually several sessions of explanation and discussion were required before the families felt they were adequately informed about hd. in saudi arabia and in oman, affected families were relieved that a definitive diagnosis and explanation had been reached. in the case of one of the saudi families, the family had long been under the impression that the illness was caused by sorcery and malevolent jinns. although impoverished, they had been attending traditional healers and had tried various expensive, futile remedies. following counselling sessions, they realised that traditional treatment was futile. there are times when the families concerned may reject the diagnosis and seek a second opinion. in jeddah, one family sought a second opinion in uk, and after further neuroradiology and dna studies, still rejected the diagnosis. in the oman study,3 the parents of an affected child refused to accept the diagnosis. one of the parents was mildly symptomatic, but both refused dna tests, and left to seek advice elsewhere. they were lost to follow-up. figure 2: example of first page of basic information notes about huntington disease in arabic used in jeddah, saudi arabia and in oman h u n t i n g t o n d i s e a s e ( c h o r e a ) i n t h e m i d d l e e a s t 21 t r e a t m e n t o p t i o n s unfortunately, despite world-wide trials and research for many decades, no treatment has been found to delay or prevent the onset or to effectively modify the symptoms of this formidable disease.25 medications in use for movement disorders include those which may reduce chorea including haloperidol and fluphenazine, and tetrabenazine (a dopamine depleter).26 for rigidity (eg. in the westphal variant), l-dopa (a dopamine precursor) and pramipexole have been used. when required, antidepressants eg, amitriptyline and mirtazapine, and antipsychotics eg risperidone, haloperidol and buspirone are available. however, the beneficial effects of these neuroleptics have to be balanced with side-effects: there is a saying among hd patients that there are two occasions when they thank the physician, first when a new medication is started, and then when it is stopped. various substances are under investigation for possible neuroprotection, including coenzyme q10 (boosts energy in cells and acts as an antioxidant), minocycline (which inhibits apoptosis) and unsaturated fatty acids. unfortunately, a recent report showed no benefit using an omega-3 fatty acid during 6 months of placebo-controlled evaluation.27 another neurotrophic factor under investigation is brain-derived neurotrophic factor (bdnf) which promotes neurogenesis and is elevated by selective serotonic reuptake inhibitor antidepressants such as citalopram. 28 preclinical studies of fibroblast growth factor 2, which promotes neurogenesis and extends survival time in transgenic mice, and caspase 6 inhibitor, which appears to delay or prevent the onset of clinical hd in transgenic mice, are underway.29 apart from numerous pharmaceutical trials in progress, other approaches to the management of patients include nutritional supplements, and intellectual and enhanced voluntary physical activity (exercise delays some symptoms in the transgenic mouse model). it is a feature of pharmacological and indeed all trials in hd, that many subjects and controls are required for extended longitudinal studies. most trials follow the format of preclinical trials, then phase i, phase ii, and phase iii studies which may take a year or more to evaluate. it is a notable feature of hd families that they are always eager to participate in research projects and drug trials and like to be well-informed about results. m a n a g e m e n t o f t h e d i s e a s e the life-long management of the many thousands of patients and families affected by hd remains a major problem worldwide. since there is no effective remedy, following diagnosis further medical care is often delegated to general physicians, and general practitioners with the support of social workers. when available, support from physiotherapists or occupational therapists is often valuable. in developing countries, inevitably, impoverished families in rural or outlying areas, have no follow-up or medical care (no access to medications or clinics), and families have to look after patients until the end. considerable financial hardship is common when the breadwinner of the family is affected. in jeddah, the sudanese patient was a taxi-driver, and the necessity to abandon work posed serious financial difficulties for his youthful wife and numerous children.7 in most countries especially in developing countries, it is rare to find a doctor or medical worker who can keep in touch with families over many years and visit them from time to time. for those at risk, the implications of a positive gene test are formidable: a young man or woman has observed the effects of the disease in his or her parent unfolding over a decade or more, and knows that there is no effective treatment or prevention. some individuals have committed suicide, become socially irresponsible, or lapsed into substance abuse. the response in many western countries has been the development of ‘gene-positive’ social groups. in perth, western australia there is a large group of young gene-positive individuals who frequently meet socially and discuss their problems together. they are a remarkably cheerful and positive group. facing the disease together clearly boosts morale, and they can keep up to date with progress in research and treatment. when it comes to marriage, a gene positive individual can elect to avoid having children. in regard to personal accident or life insurance or obtaining mortgage or other loans, gene positive individuals or those at risk of hd, are at a major disadvantage. insurance or lending institutions have routinely rejected applications from such individuals.30 the iha has endeavoured to find ways in which these individuals can receive some insurance coverage. the iha has been represented until recently in saudi arabia and oman, but at present the position of local representative is vacant in both countries. this is a most rewarding role, as hd families everywhere e ua n m s c r i m g e o u r 22 are deeply appreciative of medical workers who devote time and interest to their problems. home visits are always warmly received. doctors and health workers who become involved with hd families frequently become long lasting confidants and friends with them. it has been said by some workers, that involvement with hd is addictive. the author has kept in touch by correspondence with one hd family in papua new guinea (last visited in 1988) for over 20 years. the iha and the world federation of neurology research group combine every two years in the world congress on huntington’s disease to bring associations and researchers together to share ideas and research. the first meeting took place in toronto in 2003, and the next meeting will be in vancouver, canada, 12-15 september, 2009. this meeting will no doubt record the outstanding achievements of the past few years, stimulate much discussion and anticipate further developments which may finally offer curative solutions to this formidable condition. c o n c l u s i o n although hd may be a relatively rare neurodegenerative disease, it has become a leading focus for international genetic research. this has led to many significant advances in our understanding of gene function, but despite intensive research over the past two decades, the function of the huntingtin protein, which is produced by the normal huntington gene and which is present in every cell in our body, is still not understood, and no effective treatment has been found for the disease. to those of us who have devoted many years to the study of hd, and have met dozens of patients and many, many families affected by this most devastating disease, there could be no greater hope than that one day, the clinical disease will be arrested, the signs and symptoms reversed or treated effectively, and the onset of the disease in gene positive individuals, wholly prevented. it will no longer be necessary to be the unwelcome bearer of the dreaded news that a gene positive person has inherited a fatal and incurable condition. r e f e r e n c e s 1. huntington g. on chorea. med surg rep 1872; 26:31721. 2. gusella jf, wexler ns, conneally pm, naylor sl, anderson ma, tanzi re et al. “a polymorphic dna marker genetically linked to huntington’s disease”. nature 1983; 306:234-8. 3. scrimgeour em, koul rl, chand pr, tharakan jkj. juvenile onset of huntington’s disease in an omani chld with asymptomatic, at risk parents. j med genet 1997; 34:701. 4. kremer k, goldberg p, andrew se, theilmann j, telenius h, zeisler j et al. a worldwide study of huntington’s disease mutation. n engl j med 1994; 330:1401-6. 5. scrimgeour em, tahoon sa, zawawi th. huntington’s disease in two unrelated arab kindreds, and in an afghan family resident in saudi arabia. j med genet 1994; 31:819-20. 6. bohlega s, mclean d, omer s, al-kawi mz, roos ra, losekoot m et al. huntington’s disease: report on four saudi families. saudi med j 1996; 17:456-9. 7. scrimgeour em, samman y, brock djh. huntngton’s disease in a sudanese family from khartoum. hum genet 1995;96:624-625. 8. atac fb, elibol b, schaefer f. the genetic analysis of turkish patients with huntington’s disease. acta neurol scand 1999; 100:195-8. 9. gazit e, lubomirov l, munakov o, topper a, frydman m, fried k et al. distribution of cag repeats in normal and huntington’s disease patients in israel. clin genet 1998; 54:250-1. 10. banoei mm, houshmand m, panahi ms, shariati p, rostami m, manshadi md et al. huntington’s disease and mitochondrial dna deletions: event or regular mechanism for mutant huntingtin protein and cag repeats. cell mol neurobiol 2007; 27:867-75. 11. hayden mr. huntington’s chorea. berlin & heidleberg: springer verlag, 1981. p. 108. 12. hayden mr. huntington‘s chorea. berlin & heidleberg: springer verlag, 1981. pp. 15-30. 13. scrimgeour em. huntington’s disease in tanzania; j med genet 1981; 18:200-3, 14. scrimgeour em, pfumojena jw. huntington disease in black zimbabwean families living near the mozambique border. am j med genet 1992; 44:762-6. 15. scrimgeour em. huntington’s disease in two new britain families. j med genet 1980; 17:197-202. 16. scrimgeour em. possible introduction of huntington’s chorea into pacific islands by new england whalemen. am j med genet 1983; 15:607-13. 17. avila-giron r. medical and social aspects of huntington’s chorea in the state of zulia, venezuela. advances in neurology 1973; 1:261-6. 18. panegyres pk, mcgrath f. huntington disease in indigenous australians. int med 2008; 38:130-2. 19. macdonald m. a novel gene containing a trinucleotide repeat that is expanded and unstable on huntington’s disease chromosomes. the huntington’s disase colh u n t i n g t o n d i s e a s e ( c h o r e a ) i n t h e m i d d l e e a s t 23 laborative research group. cell 1993; 72:971-83. 20. li sh, li xj. huntingtin and its role in neuronal degeneration. neuroscientist 2004; 10:467-75. 21. benn cl, sun t, sadri-vakili g, mcfarland kn, dirocco dp, yohrling gj, et al. huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to dna in a polyglutamine-dependent manner. j neurosci 2008; 15:10720-33. 22. sathasivam k, hobbs c, mangiarini l, mahal a, turmaine m, doherty p, et al. transgenic models of huntington’s disease. philos trans r soc lond b biol sci 1997; 54:963-9. 23. yang sh, cheng ph, banta h, piotrowska-nitsche k, yang jj, cheng ec, et al. towards a transgenic model of huntington’s disease in a non-human primate. nature 2008; 453:863-4. 24. bustamente-aragones a, trujillo-tiebas mj, gallegomerlo j, rodriguez de alba m, gonzalez-gonzalez c, cantalapiedra d, et al. prenatal diagnosis of huntington disease in maternal plasma: direct and indirect study. eur j neurol 2008; 15:1338-44. 25. bonelli rm, wenning gk. pharmacological management of huntington’s disease: an evidence-based review. curr pharm des 2006; 12:2701-20. 26. fasano a, cadeddu f, guidubaldi a, piano c, soleti f, zinzi p et al. the long-term effect of tetrabenazine in the management of huntington disease. clin neuropharmacol 2008; 31:313-8. 27. dorsey er, shoulson i, leavitt b, ross c, bieck ca, de blieck ea, et al. randomised controlled trial of etheyl-ecosapentaenoic acid in huntington disease: the trend-hd study. arch neurol 2008; 65:1582-9. 28. rose e, saudou f, caboche j. pathophysiology of huntington’s disease: from huntingtin functions to potential treatments. curr opin neurol 2008;21:497-503. 29. jin k, lafevre-bernt m, sun y, chen s, gafni j, crippen d et al. proc natl acad sci usa 2005;102:18189-94. 30. oster e, dorsey er, bausch j, shinaman a, kayson e, oakes d, et al. fear of health insurance loss among individuals at risk for huntington disease. am j med genet 2008; 146a:2070 1departments of microbiology & immunology, national university of science and technology, sohar, oman; 2department of epidemiology and public health, all india institute of medical sciences, mangalgiri, india; 3department of pathology, sohar hospital, sohar, oman; 4department of medical microbiology and immunology, faculty of medicine, mansoura university, egypt *corresponding author’s e-mail: mohanbs@nu.edu.om الستينوتروفوموانس مالتوفيليا أحد مسببات األمراض االنتهازية الناشئة يف مستشفيات الرعاية الثالثية يف حمافظة مشال الباطنة، عمان موهان بيليكاالهايل �صاناثيممابا، فينود بي نامبيار، راجيف اأرافينداك�صان، ن�صوى حممد الق�صبي abstract: objectives: stenotrophomonas maltophilia, a gram-negative non-fermentative bacillus, has emerged as an important nosocomial pathogen in recent years. it is intrinsically resistant to many antibiotics and has the ability to acquire antibiotic resistance by multiple mechanisms. treating stenotrophomonas infections, therefore, is a serious challenge for physicians. this study aimed to investigate the antibiotic susceptibility patterns and risk factors contributing to s. maltophilia infections. methods: a retrospective cross-sectional study was conducted at sohar hospital in sohar, oman. the demographic, clinical and microbiological data of individuals from whom s. maltophilia was isolated between september 2016 and august 2019 were reviewed. descriptive statistics were presented as frequencies and percentages. results: a total of 41 s. maltophilia isolates from clinical specimens of 41 patients were studied. infection occurred predominantly in males (73%) and the majority of patients (88%) were either ≤5 years old or >60 years old. all inpatients had at least one comorbidity while 50% had more than one. all inpatients were exposed to various medical interventions such as intensive care (44%), mechanical ventilation (41%), haemodialysis (25%), foley’s catheterisation (13%) and central venous lines (6%). most patients (81%) were in hospital longer than two weeks. the susceptibility rates of s. maltophilia to minocycline (97%), trimethoprimsulfamethoxazole (93%) and levofloxacin (92%) were high; the rate was lowest for ceftazidime (50%). conclusion: s. maltophilia was found to be an important nosocomial opportunistic pathogen. prolonged hospital stay and exposure to various medical interventions were key factors contributing to the development of infection. minocycline and ceftazidime were found to be the most and least susceptible drugs, respectively. keywords: nosocomial infection; opportunistic infections; fluoroquinolones; hemodialysis; ventilation; oman. امللخ�ص: الهدف: الستينوتروفوموناس مالتوفيليا ، هي ع�صيات غري خممرة �صالبة اجلرام، ظهرت كمر�ض ميكروبي مهم يف امل�صت�صفيات يف ال�صنوات االأخرية. وهذه البكرتيا لديها مقاومة للعديد من امل�صادات احليوية ولديها القدرة على اكت�صاب مقاومة للمضادات احليوية باآليات متعددة. لذلك ، فاإن علج عدوى الستينوتروفوموناس مالتوفيليا ميثل حتدًيا خطرًيا للأطباء. هدفت هذه الدرا�صة اإىل التحقق من اأمناط احل�صا�صية مالتوفيليا. الطريقة: اأجريت درا�صة م�صتعر�صة ا�صرتجاعية يف للم�صادات احليوية وعوامل اخلطر التي ت�صهم يف عدوى الستينوتروفوموناس م�صت�صفى �صحار، عمان. متت مراجعة البيانات الدميوغرافية وال�رسيرية وامليكروبيولوجية للأفراد الذين مت عزل الستينوتروفوموناس مالتوفيليا فيهم خلل الفرتة بني �صبتمرب 2016 واأغ�صط�ض 2019. مت عمل االإح�صاء الو�صفي على �صكل تكرارات ون�صب مئوية. النتائج: متت درا�صة ما جمموعه 41 عزلة من الستينوتروفوموناس مالتوفيليا من العينات ال�رسيرية لـ 14 مري�صا. حدثت العدوى يف الغالب عند الذكور )%73( وكانت غالبية املر�صى )%88( مابني عمر خم�ض �صنوات و 60 �صنة. كان لدى جميع املر�صى املرقدين مر�ض مزمن واحد على االأقل بينما كان لدى %50 اأكرث من واحد. تعر�ض جميع املر�صى املرقدين لتدخلت طبية خمتلفة مثل العناية املركزة )%44(، والتهوية امليكانيكية )%41(، والغ�صيل الكلوي )%25(، وق�صطرة فويل )%13( واخلطوط الوريدية املركزية )%6(. بقي معظم املر�صى )%81( يف امل�صت�صفى ملدة تزيد عن اأ�صبوعني. كانت معدالت ح�صا�صية الستينوتروفوموناس مالتوفيليا للمينو�صيكلني )%97(، و الرتمييثوبرمي-�صلفاميثوك�صازول )%93( والليفوفلوك�صا�صني )92%( وهي ن�صب مرتفعة. كانت احل�صا�صية لعقارل�صيفتازيدمي يف املعدل االأدنى )%50(. اخلال�صة: ال�صتينوروفومونا�ض مالتوفيليا هي اأحد م�صببات االأمرا�ض االنتهازية يف امل�صت�صفيات. كانت االإقامة املطولة يف امل�صت�صفى والتعر�ض للتدخلت الطبية املختلفة من العوامل الرئي�صية التي �صاهمت يف حدوث العدوى. وجد اأن املينو�صكلني اأكرث االأدوية تاأثريعلى هذه البكترييااوال�صيفتازيدمي هو االأقل على التوايل. الكلمات املفتاحية: عدوى امل�صت�صفيات؛ العدوى االنتهازية؛ الفلوروكينولونات؛ غ�صيل الكلى؛ التنف�ض؛ عمان. stenotrophomonas maltophilia an emerging opportunistic nosocomial pathogen in a tertiary care hospital in al batinah north governorate, oman *mohan b. sannathimmappa,1 vinod nambiar,1 rajeev aravindakshan,2 nashwa m. al-kasaby3,4 clinical & basic research sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e66–71, epub. 15 mar 21 submitted 26 feb 20 revisions req. 16 apr & 21 may 20; revisions recd. 27 apr & 21 may 20 accepted 25 jun 20 https://doi.org/10.18295/squmj.2021.21.01.009 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge stenotrophomonas maltophilia infection predominantly occurred in males and in the younger and older age groups. s. maltophilia have shown good susceptibility to all tested antibiotics. s. maltophilia was most sensitive to minocycline and least susceptible to ceftazidime. https://creativecommons.org/licenses/by-nd/4.0/ mohan b. sannathimmappa, vinod b. nambiar, rajeev aravindakshan and nashwa m. al-kasaby clinical and basic research | e67 application to patient care incidence, risk factors and pattern and rate of antimicrobial resistance among s. maltophilia strains vary widely between regions. regularly determining the prevalence of s. maltophilia and antibiotic resistance patterns and updating physicians' knowledge regarding this opportunistic organism will result in better management of s. maltophilia infection. patients would benefit in terms of controlling antimicrobial resistance, reducing treatment failure and lessening mortality rates and financial burden. stenotrophomonas maltophilia, formerly known as xanthomonas maltophilia, is an aerobic, non-fermentative gram-negative bacillus (nfgnb), widely distributed in almost all humid environments including hospital settings.1–3 it survives on almost any humid surface and has been isolated from hospital equipment and supplies including mechanical ventilators, heart-lung machines, indwelling devices (i.e. endotracheal tubes, central venous and urinary catheters), haemodialysis units, endoscopes, nebulisers, disinfectants, hand wash solutions and intravenous fluids.4–7 although generally considered an asymptomatic coloniser or organism of low virulence, s. maltophilia has evolved in the past two decades to become an important opportunistic nosocomial pathogen, especially in critically ill patients.8–13 bypassing natural body defences is pivotal for the development of stenotrophomonas infections.1–7 the infections are particularly common among very young and very old immunocompromised individuals and in patients with chronic respiratory illness, cystic fibrosis, neutropaenia and other immunodeficiency disorders.4,7–10 the risk factors for s. maltophilia infection include prolonged mechanical ventilation, use of indwelling devices, previous exposure to broad-spectrum antibiotics and parenteral nutrition therapy.4,6–8 s. maltophilia is the third most common nfgnb associated with nosocomial infections next to p. aeruginosa and acinetobacter baumannii.11 it is associated with a wide range of infections with pneumonia and bloodstream infections being the two most common manifestations.14 meningitis, brain abscess, urinary tract infection, skin and soft tissue infection, endocarditis and ocular and ear infections are less frequently seen infections caused by s. maltophilia.1,4,5,7 s. maltophilia-associated infections pose serious treatment challenges because they are intrinsically resistant to many antibiotics including aminoglycosides and carbapenems and the bacillus has the ability to acquire resistance to antimicrobial agents by multiple mechanisms.4,14,15 numerous studies have reported trimethoprim-sulfamethoxazole (tmp-smx) as the antibiotic of choice for treating s. maltophilia infections.14–16 fluoroquinolones, minocycline and ceftazidime were also found to be effective drugs.4,16–18 however, recent studies have reported alarming increases in the resistance of stenotrophomonas to these agents.1,12 furthermore, its ability to form biofilm and quorum sensing has posed treatment challenges especially in critically ill patients in intensive care units (icus).1,9,15 there is a paucity in the literature of studies on s. maltophilia in al batinah north governorate, oman. hence, the present study aimed to investigate the antimicrobial susceptibility of s. maltophilia isolated at sohar hospital’s microbiology laboratory, sohar, and reveal related clinical backgrounds such as the spectrum of infection, comorbidity and underlying risk factors contributing to infection. methods this retrospective cross-sectional study was cond ucted at a 400-bed referral ministry hospital in al batinah north governorate, oman. the clinical and microbiological data of 41 s. maltophilia isolates that grew from clinical samples from september 2016 to august 2019 were retrieved from microbiology laboratory records and the al-shifa electronic medical records system. the collected information included patients’ demographic characteristics, length of hospital stay, comorbidities at the time of admission, exposure to medical equipment and instruments, site of infection and the type of clinical specimen processed in the laboratory. all the strains of s. maltophilia isolated from sterile sites such as blood and cerebral spinal fluid and the strains isolated from sites such as skin, mucus membranes, wounds and endotracheal tubes in the presence of clinical signs and symptoms were considered infections and included in the study. s. maltophilia isolated from non-sterile sites such as skin, mucus membranes, wounds and endotracheal tubes in the absence of clinical signs and symptoms were considered colonisation and excluded from the study. repeat isolates from all clinical samples were excluded. s. maltophilia isolates were recovered from different clinical samples including blood, urine and respiratory secretions. the isolates were identified by standard microbiological methods and the automated vitek® 2 system (biomérieux sa, lyon, france). stenotrophomonas maltophilia an emerging opportunistic nosocomial pathogen in a tertiary care hospital in al batinah north governorate, oman e68 | squ medical journal, february 2021, volume 21, issue 1 antimicrobial susceptibility testing was performed using kirby-bauer's disc diffusion method on muellerhinton agar with the following antibiotic panel by using oxoid™ antibiotic susceptibility disks (thermo fisher scientific, waltham, massachusetts, usa): levofloxacin (5 μg), tmp-smx (1.25/23.75 μg) and minocycline (30 µg). for ceftazidime, a minimum inhibitory concentration was determined by the epsilometer test (etest), as recommended by the clinical laboratory standards institute.19 quality control was performed using escherichia coli (atcc 25922) and p. aeruginosa (atcc 27853). the data obtained were entered and analysed using statistical package for social sciences (spss), version 22 (ibm, corp., armonk, new york, usa). descriptive statistics for all variables were derived using epi info 7 for windows (centers for disease control and prevention, atlanta, georgia, usa) and stated mainly as frequency and percentages. antibiotic susceptibility was interpreted as sensitive or resistant. this study was approved by the research and ethical committee of the ministry of health in oman (mh/dhsg/nbg/1923195718/2019). table 1: demographic and clinical characteristics of patients infected with stenotrophomonas maltophilia at a tertiary care hospital in al batinah north governorate, oman (n = 41) characteristic n (%) age in years <1 7 (17) 1–5 7 (17) 6–30 0 (0) 31–60 5 (12) >60 22 (54) gender male 30 (73) female 11 (27) duration of hospital stay (n = 32) <2 days 2 (6) 3–7 days 4 (13) 2–4 weeks 11 (34) >4 weeks 15 (47) source/site of organism isolation* respiratory secretions 15 (37) blood 13 (32) urine 5 (12) wound/pus swab 3 (7) eye swab 2 (5) ear swab 1 (2) synovial fluid 1 (2) cerebrospinal fluid 1 (2) *six s. maltophilia strains were isolated from the clinical samples received from other hospitals, and three strains were isolated from the patients treated in the outpatient department table 2: comorbidity and underlying risk factors of in patients with stenotrophomonas maltophilia infection at a tertiary care hospital in al batinah north governorate, oman (n = 32) comorbidity/risk factor n (%) presence of one comorbidity 32 (100) presence of more than one comorbidity 16 (50) type of cormobidity cardiovascular diseases (hypertension, ihd, chd, etc.) 16 (50) chronic renal diseases (end stage renal disease) 9 (28) pulmonary diseases 8 (25) diabetes 8 (25) congenital/inherited diseases* 7 (22) cns disorders 5 (16) liver cirrhosis and oesophageal varices 1 (3) underlying risk factor icu admission 14 (44) mechanical ventilation 13 (41) haemodialysis 8 (25) foley’s catheterisation 4 (13) central venous line 2 (6) length of hospital stay >two weeks 26 (81) ihd = ischaemic heart disease; chd = congenital heart disease; cns = central nervous system; icu = intensive care unit. *one patient each had cystic fibrosis, guillain-barré syndrome, hirschprung’s disease, cerebral palsy, dandy walker’s disease, krebs’ disease and con genital heart disease. table 3: antibiotic susceptibility pattern of stenotroph omonas maltophilia antibiotic antibiotic susceptibility in % sensitive resistance tmp-smx 93 7 *ceftazidime 50 50 levofloxacin 92 8 minocycline 97 3 tmp-smx = trimethoprim-sulfamethoxazole. *antibiotic sensitivity tested by epsilometer test. mohan b. sannathimmappa, vinod b. nambiar, rajeev aravindakshan and nashwa m. al-kasaby clinical and basic research | e69 results a total of 41 s. maltophilia isolates from various clinical samples received at sohar hospital’s microbiology laboratory were reviewed. s. maltophilia was predominantly isolated from males (73%) compared to females (27%). the majority of the patients (88%) were ≤five years old (34%) or >60 years old (54%). most patients (78%) were inpatients and had a hospital stay of at least two weeks (81%) [table 1]. all inpatients had one comorbidity while 50% had more than one comorbid conditions such as cardiovascular disease (50%), chronic renal disease (28%), pulmonary disease (25%), diabetes (25%), congenital/inherited diseases (22%) or central nervous system disorders (16%). all inpatients had undergone medical interventions including being admitted to the intensive care unit (44%), mechanical ventilation (41%), haemodialysis (25%), foley’s catheterisation (13%) or the insertion of central venous lines (6%). with respect to the source, s. maltophilia was isolated most frequently from blood (32%) followed by endotracheal secretions (24%), sputum (12%), urine (12%), swabs of wounds (7%), eyes (5%) and ears (2%) and synovial (2%) and cerebrospinal (2%) fluid [table 2]. in the present study, the in vitro susceptibility rate of s. maltophilia was highest for minocycline (97%) followed by tmp-smx (93%) and levofloxacin (92%). however, only 50% of s. maltophilia samples showed resistance to ceftazidime [table 3]. discussion s. maltophilia, previously considered a coloniser, has emerged as an important nosocomial pathogen within the past few decades, especially in severely immunodeficient individuals. it can cause serious infections and treating these associated infections can pose a serious challenge because of limited therapeutic options and the rapid development of antimicrobial resistance. the present study investigated antibiotic susceptibility patterns as well as underlying risk factors in patients who acquired s. maltophilia infections. the present study observed a predominance of s. maltophilia isolation from males. most patients had either an immature or weakened immune system and were ≤5 or >60 years of age (88%); these findings were consistent with previous studies.7,8 additionally, all patients had one (100%) while some (50%) had more than one comorbidity such as pulmonary or chronic kidney disease, diabetes or congenital/inherited disorders. in a similar study, kim et al. demonstrated the association of s. maltophilia infection with a variety of comorbid conditions.20 an important feature of s. maltophilia is its ability to asymptomatically colonise biotic or abiotic surfaces due to the formation of biofilm rather than infection, which is often associated with an individual’s decreased immune status.18,20 invasive procedures (e.g. mechanical ventilation, central venous line, foley’s catheterisation and haemodialysis), receiving medical attention in intensive care facilities, prolonged length of hospital stay (more than two weeks), exposure to broad-spectrum antibiotics and immunocompromised status were found to be key underlying risk factors for s. maltophilia infections.18,20 risk factors in the present study group were similar to previous reports.1,12,21 s. maltophilia has developed extensive resistance to most commonly used antibiotics including beta lactams, cephalosporins and macrolides and is intrins ically resistant to carbapenems and aminoglycosides.22 susceptibility data are available for a limited number of antimicrobial agents such as tmp-smx, fluoroquin olones such as levofloxacin and moxifloxacin, ceftazi dime, minocycline and doxycycline.14–15 in the present study, most isolates (93%) were found to be susceptible to tmp-smx. this finding is in line with but slightly lower than reports from ismail et al. where all strains tested with an etest showed susceptibility to tmp-smx.14 however, resistance rates, are increasing and 7% of strains showed resistance to tmp-smx in the present study. this low-level resistance (2–10%) is in accordance with many previous studies.9,14,23 a few outliers, however, have demonstrated high levels of resistance ranging from 10–25%.7,24–26 tmp-smx, therefore, can still be recommended as the first-line drug for empirical therapy of s. maltophilia infections. fluoroquinolones have become reasonable alter natives to treat stenotrophomonas infections. reports have shown that monotherapy with fluoroquinolones achieves equal efficacy to tmp-smx.26,27 the findings of the present study were consistent with many other studies that demonstrated potent in vitro susceptibility of fluoroquinolones against s. maltophilia.26,27 in the present study, 92% of the strains demonstrated susceptibility to levofloxacin. this finding was slightly lower than was found in a study by wu et al. in which all strains isolated from ocular infections were susceptible to levofloxacin and moxifloxacin.26 however, several studies have revealed a resistance rate ranging from 10–50% to fluoroquinolones.14,24,28,29 hence, it is imperative to select antibiotics to treat s. maltophilia infection based on local antimicrobial sensitivity patterns. the clinical value of levofloxacin is greater as it has the advantage of biofilm disruption and achieving much higher concentrations than the minimum inhibitory concentration, especially in respiratory secretions.5,14,24 these advantages make stenotrophomonas maltophilia an emerging opportunistic nosocomial pathogen in a tertiary care hospital in al batinah north governorate, oman e70 | squ medical journal, february 2021, volume 21, issue 1 levofloxacin a better choice among quinolones, esp ecially to treat respiratory infections. in the present study, most of the s. maltophilia isolates (97%) showed in vitro susceptibility to minocycline. this finding is in concordance with the results of looney et al.11 however, the clinical use of minocycline is still limited due to its ototoxicity, although it is highly effective against stenotrophomonas.11 among beta-lactams, anti-pseudomonal beta lactams such as ceftazidime were previously cons idered to be the most effective drugs against s. malto philia.30 however, recent studies have demonstrated a high rate of resistance (>40%) to these antibiotics.24,31,32 the present study results were congruent with the results of those studies, where half of the stenotro phomonas strains showed resistance to these drugs, suggesting increased global resistant trends to ceph alosporins.24,31,32 owing to the rapid emergence of drug-resistant strains of stenotrophomonas for monotherapy (with tmp-smx, fluoroquinolones and other drugs), combination therapy with two or three antibiotics, especially in critical patients with serious infections, have been proposed by several researchers as a way to attain synergism and overcome drug resistance.14,15 gregory et al. demonstrated better in vitro bactericidal effects when using a combination of tmp-smz and moxifloxacin on s. maltophilia when compared to monotherapy.15 although there are not enough data on the in vivo efficacy of combination therapy, several studies have suggested the use of a combination of drugs for treating severe invasive infections, especially in immune-deficient individuals.12,14,15 the present study was subject to certain limitations. first, the sample size was small. second, the study did not assess the prior antibiotic exposure and treatment outcomes of infected patients. third, this study was retrospective; therefore, the culture results were not clinically correlated to determine whether they represented infection or colonisation accurately. finally, this was a single-centre study in oman; hence, the findings may not be generalisable. conclusion s. maltophilia is an important emerging nosocomial opportunistic pathogen. prolonged length of hospital stay and exposure to various invasive medical inter ventions were key factors contributing to infection. tmp-smz, levofloxacin and minocycline showed good in vitro susceptibility against s. maltophilia and are promising therapeutic options. a c k n o w l e d g e m e n t s the authors express their sincere appreciation to all the microbiology laboratory and information and technology staff of sohar hospital for their kindhearted support. the authors would also like to thank dr. ali al-maqbali, research head rerac, north batinah, for his valuable feedback and continuous support. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. adegoke aa, stenström ta, okoh ai. stenotrophomonas maltophilia as an emerging ubiquitous pathogen: looking beyond contemporary antibiotic therapy. front microbiol 2017; 8:2276. https://doi.org/10.3389/fmicb.2017.02276. 2. satish m, mumtaz ma, bittner mj, valenta c. stenotro phomonas maltophilia endocarditis of an implantable cardio verter defibrillator lead. cureus 2019; 11:e4165. https://doi.org/10.7 759/cureus.4165. 3. geller m, nunes cp, oliveira l, nigri r. s. maltophilia pneumonia: a case report. respir med case rep 2018; 24:44–5. https://doi.org/10.1016/j.rmcr.2018.04.004. 4. xun m, zhang y, li bl, wu m, zong y, yin ym. clinical charac teristics and risk factors of infections caused by stenotro phomonas maltophilia in a hospital in northwest china. j infect dev ctries 2014: 8:1000–5. https://doi.org/10.3855/jidc.4236. 5. wu h, wang jt, shiau yr, wang hy, lauderdale tl, chang sc, et al. a multicenter surveillance of antimicrobial resistance on stenotrophomonas maltophilia in taiwan. j microbiol immunol infect 2012; 45:120–6. https://doi.org/10.1016/j.jmii.2011.09.028. 6. brooke js. new strategies against stenotrophomonas maltophilia: a serious worldwide intrinsically drug-resistant opportunistic pathogen. expert rev anti infect ther 2014; 12:1–4. https:// doi.org/10.1586/14787210.2014.864553. 7. gajdács m, urbán e. prevalence and antibiotic resistance of stenotrophomonas maltophilia in respiratory tract samples: a 10-year epidemiological snapshot. health serv res manag epidemiol 2019; 6:2333392819870774. https://doi.org/10.1177/2 333392819870774. 8. singhal l, kaur p, gautam v. stenotrophomonas maltophilia: from trivial to grievous. indian j med microbiol 2017; 35:469–79. https://doi.org/10.4103/ijmm.ijmm_16_430. 9. brooke js. stenotrophomonas maltophilia: an emerging global opportunistic pathogen. clin microbiol rev 2012; 25:2–41. https://doi.org/10.1128/cmr.00019-11. 10. murugesan s, rudrapathy p, samuel s. emergence of unusual gramnegative bacteria among cancer patients in a tertiary care cancer centre at north kerala. online j health allied sci 2018; 17:7. 11. chawla k, vishwanath s, munim fc. nonfermenting gramnegative bacilli other than pseudomonas aeruginosa and acinetobacter spp. causing respiratory tract infections in a tertiary care center. j global infect dis 2013; 5:144–8. 12. juhász e, krizsán g, lengyel g, grósz g, pongrácz j, kristóf k. infection and colonization by stenotrophomonas maltophilia: antimicrobial susceptibility and clinical background of strains isolated at a tertiary care centre in hungary. ann clin microbiol antimicrob 2014; 13:333. https://doi.org/10.1186/s12941-014-0058-9. https://doi.org/10.3389/fmicb.2017.02276 https://doi.org/10.7759/cureus.4165 https://doi.org/10.7759/cureus.4165 https://doi.org/10.1016/j.rmcr.2018.04.004 https://doi.org/10.3855/jidc.4236 https://doi.org/10.1016/j.jmii.2011.09.028 https://doi.org/10.1586/14787210.2014.864553 https://doi.org/10.1586/14787210.2014.864553 https://doi.org/10.1177/2333392819870774 https://doi.org/10.1177/2333392819870774 https://doi.org/10.4103/ijmm.ijmm_16_430 https://doi.org/10.1128/cmr.00019-11 https://doi.org/10.1186/s12941-014-0058-9 mohan b. sannathimmappa, vinod b. nambiar, rajeev aravindakshan and nashwa m. al-kasaby clinical and basic research | e71 13. baidya a, kodan p, fazal f, tsering s, menon pr, jorwal p, et al. stenotrophomonas maltophilia: more than just a colonizer! indian j crit care med 2019; 23:434–6. https://doi.org/10.5005/ jp-journals-10071-23241. 14. ismail n, zam z, hassan sa, rahman za. a combination of trimethoprim-sulfamethoxazole and ceftazidime showed good in vitro activity against stenotrophomonas maltophilia. malays j med sci 2017; 24:21–7. https://doi.org/10.21315/ mjms2017.24.2.3. 15. gregory er, osborne sb, gardner bm, broughton ra. trimethoprim/sulfamethoxazole and moxifloxacin therapy for a pediatric stenotrophomonas maltophilia ventriculoperitoneal shunt infection. j pediatr pharmacol ther 2019; 24:61–5. https://doi.org/10.5863/1551-6776-24.1.61. 16. chang yt, lin cy, chen yh, hsueh pr. update on infections caused by stenotrophomonas maltophilia with particular atten tion to resistance mechanisms and therapeutic options. front microbiol 2015; 6:893. https://doi.org/10.3389/fmicb.2015.00893. 17. falagas me, valkimadi pe, huang yt, matthaiou dk, hsueh pr. therapeutic options for stenotrophomonas maltophilia infections beyond co-trimoxazole: a systematic review. j antimicrob chemo ther 2008; 62:889–94. https://doi.org/10.1093/jac/dkn301. 18. millán-díaz b, gonzález-tabarés l, cobelo-casas c, lópezvázquez m, calviño-varela j. stenotrophomonas maltophilia: a rare cause of peritonitis in capd patients. nefrologia 2017; 37:646–7. https://doi.org/10.1016/j.nefro.2017.03.018. 19. clinical and laboratory standards institute. performance stand ards for antimicrobial susceptibility testing. clsi supplement m100. 27th ed. wayne, pennsylvania, usa: clinical and lab oratory standards institute; 2017. 20. kim ej, kim yc, ahn jy, jeong sj, ku ns, choi jy, et al. risk factors for mortality in patients with stenotrophomonas maltophilia bacteremia and clinical impact of quinolone– resistant strains. bmc infect dis 2019; 19:754. https://doi.org/ 10.1186/s12879-019-4394-4. 21. hotta g, matsumura y, kato k, nakano s, yunoki t, yamamoto m, et al. risk factors and outcomes of stenotrophomonas malto philia bacteraemia: a comparison with bacteraemia caused by pseudomonas aeruginosa and acinetobacter species. plos one 2014; 9:e112208. https://doi.org/10.1371/journal.pone.0112208. 22. brooke js. new strategies against stenotrophomonas maltophilia: a serious worldwide intrinsically drug-resistant opportunistic pathogen, expert rev anti infect ther 2014; 12:1–4. https:// doi.org/10.1586/14787210.2014.864553. 23. toleman ma, bennet pm, bennet bm, jones rn, walsh tr. global emergence of trimethoprim/sulfamethoxozole resistance in stenotrophomonas maltophilia mediated by acquisition of sul genes. emerg infect dis 2007; 13:559–65. https://doi.org/10.32 01/eid1304.061378. 24. farrell dj, sader hs, jones rn. antimicrobial susceptibilities of a worldwide collection of stenotrophomonas maltophilia isolates tested against tigecycline and agents commonly used for s. maltophilia infections. antimicrob agents chemother 2010; 54:2735–7. https://doi.org/10.1128/aac.01774-09. 25. gupta p, kale p, khillan v. resurgence of global opportunistic multidrug-resistant stenotrophomonas maltophilia. indian j crit care med 2018; 22:503–8. https://doi.org/10.4103/ijccm. ijccm_106_18. 26. wu al, yeh lk, ma dh, chen py, lin hc, sun cc, et al. clinical characteristics of stenotrophomonas maltophilia keratitis. cornea 2016; 35:795–800. https://doi.org/10.1097/ico.0000000 000000855. 27. wang yl, scipione mr, dubrovskaya y, papadopoulos j. mono therapy with fluoroquinolone or trimethoprim-sulfamethoxazole for treatment of stenotrophomonas maltophilia infections. anti microb agents chemother 2014; 58:176–182. https://doi.org/10.1 128/aac.01324-13. 28. cho sy, kang ci, kim j, ha ye, chung dr, lee ny, et al. can levofloxacin be a useful alternative to trimethoprimsulfamethoxazole for treating stenotrophomonas maltophilia bacteremia? antimicrob agents chemother 2014; 58:581–3. https://doi.org/10.1128/aac.01682-13. 29. samonis g, karageorgopoulos de, maraki, s, levis p, dimopoulou d, spernovasilis na, et al. stenotrophomonas maltophilia infec tions in a general hospital: patient characteristics, antimicrobial susceptibility, and treatment outcome. plos one 2012; 7:e37375. https://doi.org/10.1371/journal.pone.0037375. 30. zhanel gg, adam hj, baxter mr, fuller j, nichol ka, denisuik aj, et al. antimicrobial susceptibility of 22746 pathogens from canadian hospitals: results of the canward 2007-11 study. j antimicrob chemother 2013; 68:i7–22. https://doi.org/10.10 93/jac/dkt022. 31. chang yt, lin cy, chen yh, hsueh pr. update on infections caused by stenotrophomonas maltophilia with particular atten tion to resistance mechanisms and therapeutic options. front microbiol 2015; 6:893. https://doi.org/10.3389/fmicb.2015.00893. 32. chung hs, hong sg, lee y, kim m, yong d, jeong sh, et al. antimicrobial susceptibility of stenotrophomonas maltophilia isolates from a korean tertiary care hospital. yonsei med j 2012; 53:439–44. https://doi.org/10.3349/ymj.2012.53.2.439. https://doi.org/10.5005/jp-journals-10071-23241 https://doi.org/10.5005/jp-journals-10071-23241 https://doi.org/10.21315/mjms2017.24.2.3 https://doi.org/10.21315/mjms2017.24.2.3 https://doi.org/10.5863/1551-6776-24.1.61 https://doi.org/10.3389/fmicb.2015.00893 https://doi.org/10.1093/jac/dkn301 https://doi.org/10.1016/j.nefro.2017.03.018 https://doi.org/%2010.1186/s12879-019-4394-4 https://doi.org/%2010.1186/s12879-019-4394-4 https://doi.org/10.1371/journal.pone.0112208 https://doi.org/10.1586/14787210.2014.864553 https://doi.org/10.1586/14787210.2014.864553 https://doi.org/10.3201/eid1304.061378 https://doi.org/10.3201/eid1304.061378 https://doi.org/10.1128/aac.01774-09 https://doi.org/10.4103/ijccm.ijccm_106_18 https://doi.org/10.4103/ijccm.ijccm_106_18 https://doi.org/10.1097/ico.0000000000000855 https://doi.org/10.1097/ico.0000000000000855 https://doi.org/10.1128/aac.01324-13 https://doi.org/10.1128/aac.01324-13 https://doi.org/10.1128/aac.01682-13 https://doi.org/10.1371/journal.pone.0037375 https://doi.org/10.1093/jac/dkt022 https://doi.org/10.1093/jac/dkt022 https://doi.org/10.3389/fmicb.2015.00893 https://doi.org/10.3349/ymj.2012.53.2.439 a female child with skin lesions and seizures case report of incontinentia pigmenti sana al-zuhaibi,¹ anuradha ganesh,1 ahmed al-waili,³ faisal al-azri,4 hashim javad,² *amna al-futaisi ² case report squ med j, august 2009, vol. 9, iss. 2, pp. 157-161, epub 30th june 2009 submitted 10th feb 2008 revision req. 30th nov 08, revisions recd. 21st jan 09 & 22nd feb 09 accepted 1st april 09 طفلة مع آفات جلدية وحالة صرع باغ تقرير عن حالة َسلَُس الصِّ سناء الزهيبي، أنورادها غانيش، أحمد الوائلي ، فيصل العزري، هاشم جواد، آمنة الفطيسي اِهرِ الَعَصِبّي تشمل اجللد باغ مرض وراثي نادر مرتبط باجلنس وذو وراثة سائدة. املرض يصيب أجهزة متعددة متعلقة باألَدميِ الظَّ امللخص: َسلَُس الصِّ والعني والشعر واألظافر واألسنان واجلهاز العصبي املركزي. عادة ما يكون املرض قاتال عند الذكور ، بينما يكون ذا أشكال متغيرة سريريا عند اإلناث. ننشر هنا تقريرا عن حالة طفلة عمرها ستة أشهر أدخلت إلى مستشفى جامعة السلطان قابوس )سلطنة عمان( بحالة صرع حديثي الوالدة مصحوبة بآفات جلدية ناقصة الصباغ أو مفرطته و لديها مظاهر عينية وعصبية متعددة غير طبيعية نوقشت في هذا التقرير. مفتاح الكلمات: سلس الصباغ، صرع، عينية، نقص امليالنني اليتو، مرض عصبي، تقرير حالة،عمان abstract: incontinentia pigmenti )ip(, )omim # 308300(, is a rare x-linked dominant condition. it is a multisystemic disease with neuroectodermal findings involving the skin, eyes, hair, nails, teeth, and central nervous system. it is usually lethal in males; the disease has variable expression in an affected female. we report the case of a 6 month old girl who presented at sultan qaboos university hospital, oman, with neonatal seizures and hypopigemented/hyperpigmented skin lesions. she had multiple ophthalmic abnormalities and neurological manifestations which are discussed in this report. keywords: incontinentia pigmenti (ip); seizures; ophthalmic; hypomelanosis of ito; neurologic diseases; case report; oman. departments of 1ophthalmology, ²child health, ³family and community health, and 4radiology & molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: amnaf@squ.edu.om incontinentia pigmenti (ip) type 2, also known as bloch-sulzberger syndrome, is an inherited multisystem neurocutaneous disorder with a low incidence (1% of all neurocutaneous disorders).1 it is an x-linked dominant condition dominant inheritance. the disease is lethal in males, except in rare cases of somatic mosaicism, or mutations in ikbkg, and when the condition occurs in patients with klinefelter syndrome.2,3 typical skin lesions are seen in 100% of (ip) patients.2 other manifestations include dental (90%), skeletal (40%), central nervous system (cns) (40-50%) and ocular (35%) conditions.4,5 patients with ip frequently have systemic involvement, similar to the involvement in patients with hypomelanosis of ito, including cns manifestations. in patients with ip, cutaneous lesions undergo three stages, which may overlap.6 in this report, we discuss the dermatologic, neurological and ophthalmologic findings of a 6 month old female who presented with early onset neonatal seizures and displayed hypopigmented/ hyperpigmented skin lesions. in addition, this child had characteristic ophthalmologic findings. case report this 6 month old girl was born by spontaneous vaginal delivery to healthy non-consanguineous parents with two normal sons. she was referred to sultan qaboos university hospital (squh), oman, from a peripheral hospital for evaluation of abnormal skin lesions and seizures. she was reported to have had hyper/ hypopigmented skin lesions all over her body except the face since she was 6 days old. the skin lesions were noted to be of linear pattern over the upper and lower limbs and of a whorled pattern over the anterior and posterior chest wall. the mother denied the presence of any skin lesion at birth. her examination showed evidence of hypotonia and a female child with skin lesions and seizures case report of incontinentia pigmenti 158 | squ medical journal, august 2009, volume 9, issue 2 mild developmental delay with microcephaly where her head circumference was significantly below the third percentile for age. her weight was below the third percentile, but her height was normal for age. her tone was mildly decreased with normal reflexes and positive babinski reflex. she had a normal visual following, but was not able to respond to sound clinically. other systemic examinations were normal. the child developed clonic seizures at the age of 3.5 months and was commenced on oral phenobarbitone with good seizure control. the computed tomography (ct) scan of the brain (performed at a peripheral hospital) showed atrophy of the frontal horns with corpus callosum agenesis. a chromosomal study showed a normal female karyotype. at squh, a magnetic resonance imaging (mri) of the brain showed hypoplasia of the corpus callosum and hypomyelination with perivetricular white matter hyperintense signal abnormalities [figures 1a and 1b]. electrophysiological testing showed positive visual evoked potential (vep) responses using a flash stimulation, but negative responses for brain stem auditory evoked potentials (baep). an ophthalmologic evaluation was performed at the age of 5 months. the child was able to follow and fixate with both eyes. there was no obvious nystagmus, ocular deviation or ptosis. further examination under anaesthesia revealed bilateral inferior superficial epithelial corneal erosions; there were no stromal infiltrates or any increase in corneal thickness. the corneal size was normal for age in both eyes. she had a bilateral mild form of persistent pupillary membrane. she had a normal red reflex and normal reacting pupils with no evidence of any relative afferent defect. the intraocular pressure was 24mmhg in both eyes. no major refractive error was noted. a dilated fundus examination showed a large optic disc cup (disc cup ratio of 0.8 in both eyes). there were diffuse non-specific retinal pigment epithelial changes. the peripheral retinal examination revealed areas of fibrovascular proliferation with no evidence of retinal traction or detachment [figures 2a and 2b]. the child was started on latanoprost 0.05% eye drops q.h.s. in both eyes with regular follow-ups at the eye clinic. histological studies of the skin lesions and genetic studies were scheduled; unfortunately, the child died from status epilepticus at a peripheral hospital before these studies could be undertaken. discussion ip is characterized by abnormalities of the tissues and organs embryologically derived from ectoderm and neuroectoderm.4 the diagnosis of ip is made on figure 1a: magnetic resonance imaging scan: sag t1w se, midline. there is hypoplasia of the corpus callosum. optic chiasm, pituitary gland and midbrain are grossly normal. figure 1b: magnetic resonance imaging scan: axial t2w se at level of basal ganglia. there is bilateral hyperintense signal abnormality in the periventricular white matter associated with brain atrophy. no imaging findings of acute ischemia or cortical necrosis sana al-zuhaibi, anuradha ganesh, ahmed al-waili, faisal al-azri, hashim javad and amna al-futaisi case report | 159 clinical grounds aided by histological confirmation. the skin lesions may follow the blaschko lines and the initial appearance of skin lesions can be seen immediately after birth or early during the neonatal period. timely recognition of ip by pediatricians and dermatologists is therefore crucial. ip overlaps with hypomelanosis of ito, which is a syndrome with hypopigmented whorls of the skin along the blaschko lines, especially when it presents at the stage of skin hypopigmentaion. chromosomal mosaicism is believed to be the reason that hypomelanosis of ito is so varied in phenotype. certain genes, namely, those on 9q33-qter, 15q11-q13, and xp11, have been implicated in hypomelanosis of ito; however, no consensus exists about the identity of the hypomelanosis of ito gene.5, 6 in around 40-50% of ip cases, there may be neurological problems such as seizures, spasticity, or mental retardation.1 seizure can be the first manifestation of the disease.2 abnormal tooth eruption, malformed tooth crowns, and patchy alopecia are commonly seen. retinal dysplasia can sometimes lead to visual problems. the diagnosis of ip is also aided by family history and a history of miscarriages of the male gender as the disease is prenatally lethal in males. the disease is caused by a genomic rearrangement of the gene for nemo, or nuclear factor kappa b essential modulator (ikbkg-ikk gamma). the defect in the x chromosome is proximal to the gene for factor viii at xq28. 7, 8 although this child was the first affected in her family with two normal male siblings and no previous miscarriages in the family, she had hypopigmented/hyperpigmented lesions suggestive of the disease. initially, the diagnosis was not entertained, despite the skin manifestations, until her presentation with partial seizures. the possibility of hypomelanosis of ito diagnosis was also kept in mind though further evidence of neurological involvement and the eye manifestations were suggestive of ip. the skin lesions in ip manifest in stages that evolve sequentially.7 the onset and duration of each stage vary among individuals; not all individuals experience all four stages.1 typically four dermatological stages are seen: 1) the bullous stage; early blistering with eosinophilia; 2) the verrucous stage: eruption of hyperkeratotic lesions; 3) the hyperpigmentation stage: hyperpigmentation along the lines of blaschko and, finally, 4) the atretic stage: dermal scarring. in the vast majority of cases, the onset of skin changes is before 6 weeks of age.1 our patient had the third stage which was not preceded by the first or second stages. the differential diagnosis of patients presenting with stage 3 and 4 skin lesions includes: hypomelanosis of ito; ip achromians; focal dermal hypoplasia syndrome (goltz syndrome) and x-linked dominant chondrodysplasia punctata. in ip, variable clinical expressions of cns involvement are seen. they include epilepsy, mental retardation, hemiparesis, spasticity, microcephaly, and cerebellar ataxia.5 the pathogenesis of the cns lesion in ip remains unclear.9,10,11 recent brainimaging techniques, such as mri and magnetic resonance angiogram (mra), have provided a better understanding of the nature of the cns pathology. these imaging studies have demonstrated scattered cortical neuronal and white-matter necrosis, figure 2a: retcam fundus photo of the right eye showing large disc cupping and epiretinal pseudoglial tissue superior to the fovea (arrow) figure 2b: retcam fundus photo of the right eye showing large disc cupping and epiretinal pseudoglial tissue superior to the fovea (arrow) a female child with skin lesions and seizures case report of incontinentia pigmenti 160 | squ medical journal, august 2009, volume 9, issue 2 hypoplasia of the corpus callosum, periventricular white-matter cystic lesions, neuronal heterotopia, and cerebral atrophy.12, 13 our patient had evidence of hypoplasia of the corpus callosum and decreased myelination of the white matter and, clinically, both seizures and developmental delay. the presence of cns involvement, such as seizures, in the neonatal period is a poor prognostic sign.4, 6, 7 ocular abnormalities occur in 35% or more of patients and 19% are at risk of severe visual loss in one or both eyes.14,15 a wide range of ophthalmologic findings are seen in patients with ip.7 the commonest reported are strabismus in 18.2% and a retrolental mass or retinal pseudoglioma in 15.4%. there are previous reported cases in literature of multiple corneal abnormalities including megalocornea, corneal oedema, band keratopathy, bullus keratopathy, variable corneal epithelial and stromal changes and iridocorneal attachments.10 the corneal findings in this child were superficial punctuate epithelial erosion and features suggestive of an inflammatory noninfectious process. the posterior segment findings may include multiple retinovascular abnormalities (such as retinal vascular tortuosity, macular capillary dropout, peripheral arteriovenous shunts, retinal neovascularisation, and vitreous haemorrhage). subsequently, preretinal fibrosis, pseudoglioma and traction retinal detachment can result.14 this child had findings suggestive of what looked like pseudogliomas in both eyes [figures 2a and 2b] and peripheral fibrovascular lesions ou with no evidence of retinal traction. holstrom proposed a scheme for following patients with ip and eye manifestations. they recommended that eyes should be examined soon after birth, and then at least monthly for three to four months, at three-month intervals for one year, and twice yearly up to three years. they also recommended that the frequency of examinations should be increased in children with retinal disease. if, at three years of age, no abnormalities, refractive errors or strabismus are found, they state that the follow-up can cease.16 during the ophthalmic follow-up, visual functions should be assessed by both clinical and electrophysiological measures including vep and electroretinography (erg).16,17 any significant refractive errors should be corrected and amblyopia therapy as well as strabismus treatment should be provided.18,19 cryotherapy or laser photocoagulation should be applied for active peripheral retinal abnormalities and tractional retinal detachment should be treated surgically. conclusion in summary, ip or bloch-sulzberger syndrome is a rare x-linked dominant syndrome. it has multisystemic involvement that includes the skin, central nervous system and eyes. in neurocutaneous syndromes, multidisciplinary care with periodic consultations with a paediatric ophthalmologist, neurologist and other specialists depending on the associated anomalies are essential. the differentiation between hypomelanosis of ito and ip can be difficult as the two disorders overlap considerably. clinicians need to be aware of the variable manifestations of this disease for a timely and multidisciplinary management of such patients. acknowledgments thanks are due to the parents of this child who consented to publication of this report and the photos in a medical journal. references 1. landy sj, donnai d. incontinentia pigmenti (blochsulzberger syndrome). j med genet 1993; 30:53-9. 2. traupe h. functional x-chromosomal mosaicism of the skin: rudolf happle and the lines of alfred blaschko. am j med genet 1999; 85324-9. 3. scheuerle ae. male cases of incontinentia pigmenti: case report and review. am j med genet 1998; 77:201-18. 4. türkmen m, eliaçik k, temoçin k, savk e, tosun a, dikicioğlu e. a rare cause of neonatal seizure: incontinentia pigmenti. turk j pediatr 2007; 49:32730. 5. fritz b, kuster w, orstavik kh, naumova a, spranger j, rehder h. pigmentary mosaicism in hypomelanosis of ito. further evidence for functional disomy of xp. hum genet 1998; 103:441-9. 6. glover mt, brett em, atherton dj. hypomelanosis of ito: spectrum of the disease. j pediatr 1989; 115:7580. 7. berlin al, paller as, chan ls. incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. j am acad dermatol 2002; sana al-zuhaibi, anuradha ganesh, ahmed al-waili, faisal al-azri, hashim javad and amna al-futaisi case report | 161 47:169-87. 8. fusco f, bardaro t, fimiani g. molecular analysis of the genetic defect in a large cohort of ip patients and identification of novel nemo mutations interfering with nf-kappab activation. hum mol genet 2004; 13:1763-73. 9. nenci a, huth m, funteh a, schmidt-supprian w, bloch d, metzger p, et al. skin lesion development in a mouse model of incontinentia pigmenti is triggered by nemo deficiency in epidermal keratinocytes and requires tnf signaling. hum mol gene 2006; 15:531-42. 10. nehal ks, pebenito r, orlow sj. analysis of 54 cases of hypopigmentation and hyperpigmentation along the lines of blaschko. arch dermatol 1996; 132:116770. 11. cohen ba. incontinentia pigmenti. neurol clin 1987; 5:361-77. 12. pascual-castroviejo i, roche mc, martinez fernández v, perez-romero m, escudero rm, garcia-peñas jj, et al. incontinentia pigmenti: mr demonstration of brain changes. ajnr am j neuroradiol 1994; 15:1521-7. 13. lee ag, goldberg mf, gillard jh, barker pb, bryan rn. intracranial assessment of incontinentia pigmenti using magnetic resonance imaging, angiography, and spectroscopic imaging. arch pediatr adolesc med 1995; 149:573-80. 14. carney rg. incontinentia pigmenti: a world statistical analysis. arch dermatol 1976; 112:535-42. 15. kasmann-kellner b, jurin-bunte b, ruprecht kw. incontinentia pigmenti (bloch-sulzbergersyndrome): case report and differential diagnosis to related dermato-ocular syndromes. ophthalmologica 1999; 213:63-9. 16. holmstrom, g, thoren k .ocular manifestations of incontinentia pigmenti. acta ophthalmol scand 2000; 78:348-53. 17. o’brien je, feingold m. incontinentia pigmenti a longitudinal study. am j child 1985; 139:711-2. 18. mayer ej, shuttleworth gn, greenhalgh kl. novel corneal features in two males with incontinentia pigmenti. br j ophthalmol 2003; 87:554-6. 19. taylor d, hoyt cs, eds. pediatric ophthalmology and strabismus, 3rd ed. philadelphia: wb saunders, 2004. 1medical department vi/psychosomatic medicine and psychotherapy, university hospital tübingen, tübingen, germany; 2medical informatics, medical education unit, sultan qaboos university, muscat, oman *corresponding author’s e-mail: itmeded@gmail.com can medical students evaluate medical websites? a mixed-methods study from oman teresa loda,1 *ken masters,2 stephan zipfel,1 anne herrmann-werner1 clinical & basic research sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 362–369, epub. 25 aug 22 submitted 1 feb 21 revision req. 18 mar 21; revision recd. 16 apr 21 accepted 24 may 21 https://doi.org/10.18295/squmj.8.2021.114 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to discover the extent to which medical students can evaluate medical websites, evaluation criteria used, factors affecting their abilities and whether a teaching intervention could rectify problems. medical students and practitioners are required to evaluate medical information available on the internet. most current medical students are familiar with the internet, but their ability to evaluate material may require improvement. methods: a class of undergraduate medical students evaluated an unreliable medical website, received a teaching intervention on website evaluation criteria and re-evaluated the same site. this mixed-methods study was conducted at sultan qaboos university, muscat, oman, from september to december 2018. results: a total of 149 (response rate: 82.3%) students participated. students spent, on average, 4.69 hours per day on the internet. no significant correlations were found between demographic indicators and internet time. on a 10-point likert scale, students’ scores ranged from 5–6, with no significant differences between the preand post-intervention evaluations, except for increased polarisation away from the mean. qualitative comments indicated an awareness of relevant criteria but an overall inability to critically apply them. conclusion: the results indicate that one cannot make a blanket statement about medical students’ ability to evaluate medical websites despite their familiarity with technology. moreover, website evaluation should be viewed primarily from the information perspective and that critical thinking ability may play a major role. due to these overriding factors, short interventions are unlikely to have an impact, and other educational strategies should be developed. these are necessary to ensure that medical students can function independently as life-long learners and medical professionals. keywords: internet; medical students; oman. advances in knowledge students of medical and basic medical sciences at sultan qaboos university appear to lack the skills required for appropriately evaluating the trustworthiness and value of medical-related information. a single intervention that identifies and teaches criteria found mixed results. although some students appeared to be initially aware of valid judging criteria, these criteria were frequently incorrectly applied. post-intervention evaluation indicated a similar result of incorrect and inconsistent application of the criteria. part of the reason for the mixed results may be a lack of critical reasoning skills that should have been developed during schooling. applications to patient care healthcare professionals need to keep themselves abreast of new information so that they may deliver high-quality healthcare. currently, in the absence of traditional gatekeepers of knowledge, healthcare professionals must rely on their own ability to appropriately critically evaluate new information. the inability of the medical and basic medical sciences’ students to perform this evaluation points to the need for some form of systematic training to develop these evaluation skills. in the 21 st century, the internet is an essential source of medical information for medical practitioners, students and patients.1–5 the problem with the internet, however, is that it contains too much information and distinguishing good (e.g. accurate, evidence-based and appropriate) information from bad (e.g. inaccurate, unsubstantiated or inappropriate) is time-consuming and difficult.6 before the internet, medical practitioners and students considered librarians to be the gatekeepers of information and, thus, relied on; for information on the internet, in many cases, such human gatekeepers have been removed. physicians rely on medical search engines (e.g. pubmed [us national library of medicine, bethesda, maryland, usa]) or broader search systems (e.g. ebscohost [ebsco information services, ipswich, massachusetts, usa]) to perform gatekeeping, while most medical practitioners mainly use general search engines such as google (google llc, mountain view, california, usa).7,8 physicians are required to critically appraise and evaluate the information they have found.8 experienced physicians can rely on their medical expertise and experience to determine information https://creativecommons.org/licenses/by-nd/4.0/ teresa loda, ken masters, stephan zipfel and anne herrmann-werner clinical and basic research | 363 accuracy; however, information changes over time and medical students and newly-qualified physicians do not always have the required knowledge and expertise to evaluate medical information accuracy and quality.9,10 medical educators are, therefore, concerned about medical students’ ability to critically analyse and review literature.8,11,12 studies of these skills frequently focus on theoretical aspects instead of on the students’ applying these skills.10,12 the development of these skills requires the ability to critically evaluate and appraise medical literature.13 the need to teach these skills has been recognised since 2009 by the uk’s general medical council.14 students’ familiarity with computers and the internet may not translate into an ability to appropriately deal with information from the internet. just like knowing how to read and write does not necessarily mean one knows how to read and write for academic and medical research purposes, knowing how to use the internet does not necessarily mean one knows how to use it for academic, research or medical work; other skills may be needed. even if students are familiar with the technology, one should not assume they can reliably evaluate websites and can, therefore, quickly filter out unreliable websites for themselves. no set of internationally recognised website eval uation criteria exists,8 although there is the honcode system (https://www.hon.ch/honcode/) as well as several guides. a widely cited and popular system for website evaluation is kapoun’s five criteria: accuracy, authority, objectivity, currency and coverage.15 kapoun’s criteria cover most issues or concerns on the accuracy and credibility of any website (or any document) and form a simple and short list which is ideal for introducing students to the skills required for evaluating the information on the internet. considering that the literature has identified the need to understand and develop medical students’ ability to critically analyse textual information and that so much of their information is unfiltered from the internet, this study attempts to answer three research questions: (1) prior to any teaching, to what extent can undergraduate medical students evaluate the quality of a medical-related website, and on what criteria do they base their evaluation?; (2) is their evaluation related to prior computer usage or other experience?; (3) after receiving basic instruction on website evaluation, how would the new knowledge affect their ability to evaluate the same website? methods this mixed-method study was conducted at sultan qaboos university, muscat, oman, from september to december 2018, with 181 medical and basic medical sciences students from the medical informatics i course. students were taught in three sections, on three consecutive days, by the same teacher, at the same venue, using the same notes and methods. as part of their medical and basic medical sciences’ undergraduate degrees, students complete a semester-long medical informatics i course. highlighting and teaching the basics of website evaluation is part of the course. most of the students have been admitted straight from school and may have attended a foundation year at the university, which includes computer literacy. some students are in their first semester and others are in their third. a us-based, health-related website was used in the study. the website’s complete name and url was disclosed to the sultan qaboos university college of medicine and health sciences medical research ethics committee for ethical approval and is available upon request. it is a public website and contains health-related information with superficial indicators of authenticity. the name of the website is ‘global [medical procedure] institute’ and it offers access to textbooks with medical titles. the topics on the website are medical related and it claims to contain open and uncensored information on these medical topics. the ‘about us’ link on the website describes the institute’s history. closer inspection of the website reveals several problems; it has no physical address and no identity or qualifications of the website’s authors or owners. moreover, it is a publishing house. on the ‘about us’ page, only after clicking on a single ‘disclaimer’ link does one find that the information on the website is for ‘educational and informational purposes only’ and is not to be taken as medical advice, that all data on the website should be verified, that it is not endorsed by “the american academy of pediatrics, the fda, cdc or any other federal, state or “official” organization” and that the website does not carry an honcode or any similar certification. finally, the disclaimer’s last line says that the website’s authors are not medical practitioners. all this information is ‘buried’ away from the front page. no medical knowledge is required to determine the reliability of the information on the website. an electronic questionnaire was created for the students to complete anonymously through their learning management system. in addition to students’ demographic data, the questionnaire was based partially on a study that examined students’ ability to create mobile apps, in which students had been asked about their previous information technology (it) and health sciences’ education and training (examples were included in the questionnaire), experience as a can medical students evaluate medical websites? a mixed-methods study from oman 364 | squ medical journal, august 2022, volume 22, issue 3 programmer, electronic device usage and daily hours spent on the internet.16 it was believed that asking about this broad spectrum of experiences would help identify any experiential subtleties that may impact students’ ability to evaluate the website. regarding students’ perception of the website, three questions were asked on the site’s trustworthi ness, whether they would recommend the website to a patient and the website’s overall quality, using a likert scale (0–10). finally, an open-ended question was asked on the students’ reasons and the criteria followed to answer the questions regarding the website’s quality. the overall process followed the standard, established format of a pre-test, single intervention (with practice) and post-test design commonly performed in clinical and non-clinical medical education and training interventions.17–19 the process was as follows: (1) students were directed to the website and allowed to explore it for 10–15 minutes; (2) students completed the anonymous questionnaire (using temporary identifications), incl uding a consent form; (3) for the intervention, the teacher didactically taught the students kapoun’s evaluation criteria and focused on his criteria and related questions (this took approximately 45 minutes and the students were provided notes so that they could refer to them during the subsequent evaluations);15 (4) students worked in pairs or groups of three and evaluated different websites to practice their new skills (they chose a website from a list that excluded the website listed in step 1); and (5) after gaining feedback on and participating in discussions about their practice websites, the students re-evaluated the original website and completed the second questionnaire, which asked for the identification code and the same questions on website evaluation as before. data were included in the analysis only if the student completed both the pre-and post-intervention questionnaires and identified themselves with their temporary usernames consistently. data collected preand post-intervention were compared to track changes in students’ perceptions. the raw quantitative data were captured in microsoft excel, version 2016 (microsoft inc., redmond, washington, usa) by one researcher, and statistical tests were performed. a second researcher independently performed the same statistical tests using the statistical package for the social sciences (spss), version 25.0 (ibm corp., chicago, illinois, usa). the results were inspected and verified by all researchers. as per the kolmogorov–smirnov test, quantitative data were normally distributed. the means, standard deviations and frequencies were also calculated. analysis of variances were conducted to identify significant age differences. to evaluate preand postintervention data, t-tests for dependent samples were used. for correlations, pearson’s correlations were obtained. associations between variables (based on information from the literature) and differences regarding the evaluations were tested. a difference was considered statistically significant at p <0.05. qualitative data were themed by one researcher using qda miner lite, version 2.0.6 (provalis research, montreal, canada) by employing kapoun’s five criteria: accuracy, authority, objectivity, currency and coverage. the comments were subjectively classified as ‘negative’ or ‘positive’, based on the attitude expressed. themes and raw data were inspected and verified by the other researchers. as many students also referred directly to whether or not they would recommend the page to patients, this theme was added. finally, students made more general comments on design and security; therefore, an ‘other’ theme was added as well. ethics approval for the study was obtained from the sultan qaboos university college of medicine and table 1: number of hours spent on the internet per day by the included students (n = 149) hours n (%) percentage <1 1 (0.67) 0.67 1–2 17 (11.4) 11.41 3–4 65 (43.6) 43.62 5–6 37 (24.8) 24.83 7–8 20 (13.4) 13.42 9–10 6 (4) 4.03 11–12 3 (2) 2.01 table 2: students’ preand post-intervention likert scale mean scores when evaluating a medical website (n = 149) question mean ± sd p value preintervention postintervention how trust worthy would you judge the website to be? 5.60 ± 2.50 5.45 ± 2.98 0.471 how likely are you to recommend this website to a patient? 5.28 ± 2.60 4.95 ± 2.82 0.105 how would you judge the quality of the website? 5.30 ± 2.50 5.36 ± 2.79 0.757 teresa loda, ken masters, stephan zipfel and anne herrmann-werner clinical and basic research | 365 health sciences medical research ethics committee (mrec#1792). results of the 181 registered students, a total of 149 (response rate: 82.3%) were included in the study. of these 149 students, 70 (47.0%) were female, 69 (46.3%) were male and 10 (6.7%) did not indicate their gender. the sample’s gender proportions were not statistically different from that of the class population (p = 0.100). the students’ ages ranged from 17 to 21 years (mean age: 18.86 ± 0.80 years). information was obtained on the students’ prior training. there were 12 (8.1%) students who had health-related training, 23 (15.4%) had it-related training and 29 (19.5%) had programming experience. on average, the students spent 4.69 hours on the internet per day [table 1]. no correlation was found between the number of hours spent on the internet and age (r = 0.079; p = 0.340) or gender (p = 0.513). on average, the students spent 22.3% of their internet time on health-related searches. no significant differences were present in the number of hours spent on the internet based on age (r = 0.021; p = 0.713) or gender (male = 19.0 ± 0.77, female = 18.7 ± 0.83; p = 0.069). students’ preand post-intervention likert scale scores and the reasons for their scores were obtained. two important results stand out: (1) on the 10-point likert scale, students rated the websites as being slightly above average. second, no significant change was observed in the ratings made preand postintervention [table 2]. these mean values, however, hide important information on the results’ distribution. the students did not merely give the same answers preand postintervention and a score polarisation tendency was present, with shifts in score increases and decreases [figure 1]. data showed that this polarisation is seen yet again in the score changes. this indicates that, while many students adjusted their ratings correctly after the intervention, many changed their ratings in the opposite direction. this polarisation is obscured by the nominal shift in the mean scores [table 3]. associations were sought between the other variables and the scores allocated for these questions. no demographic or activity variables (age, gender, amount of it training, health training, hours spent on the internet or the usage of the internet for healthrelated searches) were found to be associated with any scores (all p >0.05). as the qualitative data were themed according to kapoun’s criteria, the data were laid out in that format [tables 4 and 5]. in the pre-intervention evaluation, it was found that 54 negative and 46 positive comments could be classified under ‘other’, many of which were unspecific comments about the website’s being of good or bad quality, unattractive, not secure or boring and other personal opinions. additionally, 15 students commented that they did not have the knowledge or expertise to properly comment on the website. in total, students made 134 (53.2%) negative comments and 118 (46.8%) positive comments. of these, 80 (59.7%) of the negative comments and 72 (61.0%) of the positive comments aligned with kapoun’s criteria or were aimed at the site’s value to patients. in the post-intervention evaluation, it was found that 40 negative and 47 positive comments of the students could fall under the ‘other’ category. in total, students made 245 (54.2%) negative comments and figure 1: pre-and post-intervention distribution of scores on students evaluating a medical website. table 3: students’ changes in scores when evaluating a medical website (n = 149) question n (%) lower equal higher how trustworthy would you judge the website to be? 59 (39.6) 43 (28.9) 47 (31.5) how likely are you to recommend this website to a patient? 62 (41.6) 48 (25.5) 39 (32.9) how would you judge the quality of the website? 60 (40.3) 37 (24.8) 52 (34.9) can medical students evaluate medical websites? a mixed-methods study from oman 366 | squ medical journal, august 2022, volume 22, issue 3 207 (45.8%) positive comments. of these, 205 (83.7%) of the negative comments and 160 (77.3%) of the positive comments aligned with kapoun’s criteria or were aimed at the website’s value to patients. discussion this study examined medical students’ ability to evaluate websites, particularly as they would be expected to do so in the absence of traditional gatekeepers such as librarians. the average amount of time these students spent on the internet was typical of students internationally.20 students evaluated a medical-related website, received a teaching intervention and then re-evaluated that same website. no examples of a comparative exercise had been found in the literature; previous studies tested students on reputable or well-controlled websites or students selfselected a broad range of websites and commented on table 4: theme, rating (negative or positive), number of comments and examples before the teaching intervention on students evaluating a medical website theme rating n examples accuracy negative 12 [n]ot all information in the website are correct. some information needs more statistics.[#60] positive 2 [t]he article and studies help to have more accuracy.[#15] authority negative 22 they have not mentioned their level of education or the field they are working in.[#95] positive 27 the website has a lot of references where you know that the information are true and right and know from where they got the information.[#5] objectivity negative 11 [t]he website uses false information to promotes the sales of his book .... the reason for that website is not to help further the medical research domain but for commercial reasons. [#59] positive 0 currency negative 6 the articles are old. so, its information may had changed and not updated.[#65] positive 0 coverage negative 3 it is true that this website have a large information about vaccination but that does not mean that it have everything we need to know.[#55] positive 11 [i]t gives access to pdf 's that help a person with their inquiry and provides alternatives for your problem. [#101] appropriate for patients negative 26 some patient will misunderstand the information because they do not have enough knowledge. [#149] positive 32 [t]his website is useful and make the patient life more easily because it has the necessary information and data for make the right decision.[#30] table 5: theme, rating (negative or positive), number of comments and examples after the teaching intervention on students evaluating a medical website theme rating n examples accuracy negative 23 first point is the accuracy the website promotes false information.[#59] positive 29 [v]ery good website with a high accuracy. [#14] authority negative 63 [i]t does not provide secure information, from trust sources [#109] positive 59 [a]ll the information have a reference and copy right which varify information.[#89] objectivity negative 54 [i]t is looks like an advertisement[#50] positive 12 this website is a good website because it is accurate and objective. [#85] currency negative 27 [n]o updated studies, most of them are old. [#32] positive 17 [i]t was updated recently.[#17] coverage negative 21 [t]he coverage looks incomplete, there are no sources given.[#1] positive 24 [t]here are sources for additional information. [#25] appropriate for patients negative 17 i will not prefer to recommend it for my patients, as it contain some difficult articles. [#132] positive 19 it covered most of the information so it can [be] rated as a good website. i recommend this website for the patients.[#85] teresa loda, ken masters, stephan zipfel and anne herrmann-werner clinical and basic research | 367 them.8,21 for the current study, a highly questionable website was chosen to determine whether or not the students could identify the problems within it. the choice of a single website (rather than multiple) allowed for a more comprehensive view of the website across the full sample of students. while the broad results indicate a positive view of the website, a more detailed evaluation of the data reveals other subtleties and indicates that universal statements on current medical students’ ability to evaluate websites should be treated carefully. with regards to the first research question (prior to any teaching, to what extent can undergraduate medical students evaluate the quality of a medicalrelated website, and on what criteria do they base their evaluation?), students made more negative than positive comments but their overall rating was positive. despite this positive tendency, results show a disparity across the student population, a mixed ability and that one cannot make a blanket statement about their evaluation ability [figure 1a]. the high percentage of alignment between the students’ comments and kapoun’s criteria is encouraging. the high number of positive comments, however, is discouraging. it indicates that even though students are aware of the criteria, their ability to match the case to the criteria is not optimal. these results extend the researchers’ arguments that these skills are necessary for medical students.10–13 furthermore, the current research demonstrates the extent to which these skills are lacking among these students. with regards to the second research question (is their evaluation related to prior computer usage or other experience?), studies have demonstrated an association between familiarity with one technology leading to ease of use with another technology.16,22–24 in this study, no association was found between familiarity with technology and the ability to evaluate websites or improve that ability. this is in agreement with the argument that teaching students the mechanics of using academic and medical search engines is only part of the solution; “the problem remains on how to educate students to critically evaluate information obtained using popular search engines”.8 as no correlation was found between students’ health-related training and evaluation scores, it is apparent that they have no bearing on students’ ability to evaluate websites. with regards to the third research question (after receiving basic instruction on website evaluation, how would this new knowledge affect their ability to evaluate the same website?), when examining the mean scores only, it appears the teaching intervention had no impact on students’ website evaluation ability. the polarisation, however, indicates that the criteria are not necessarily being applied correctly. thus, the answer to this question is that students demonstrated a greater awareness of the criteria taught and, while many applied the criteria correctly, a similar number applied them incorrectly. this situation appears to echo a common complaint from clinical teachers that many students can recite rote-learnt lists of conditions but, when faced with a patient, are unable to match the patient to the list of conditions and arrive at a diagnosis. this indicates that broader critical thinking skills need to be focused on; these skills are derived within a broader educational and sociological context. the lack of association between the level of technological prowess and website evaluation may not be entirely surprising. the reason for this lack of association is that the skillsets required for each may be different and it would be a mistake to consider a website as only a technological entity rather than a source of information requiring critical thought and evaluation. whether one uses kapoun’s criteria or any other system, critical evaluation of information and the required skills for this activity appear to have little to do with technological familiarity. instead, critical insights, reasoning and evaluation skills are needed. an examination of students’ critical thinking skills may, indeed, point to the reasons behind students’ poor evaluation ability. a 2003 united nations (un) report on development in the arab world reported a severe lack of critical thinking skills among school-leaving omanis.25 since then, oman’s higher education institutions have attempted to measure and address this. unfortunately, follow-up studies indicate that omani university students’ critical thinking, interpretation and evaluation scores are significantly below international standards.26–28 critical thinking and critical appraisal skills are essential for medical students; they cannot be assumed and need to be developed.10,11,13 in the current study, the causes of poor critical thinking skills are likely to be from a poor schooling system. the un report argues, “[t]he curricula taught in arab countries seem to encourage submission, obedience, subordination and compliance, rather than free critical thinking. in many cases, the contents of these curricula do not stimulate students to criticise political or social axioms. instead, they smother their independent tendencies and creativity”.25 furthermore, the report goes on to say, “generally speaking, the assigned curricula, starting from preliminary school or even can medical students evaluate medical websites? a mixed-methods study from oman 368 | squ medical journal, august 2022, volume 22, issue 3 before, embody a concept that views education as an industrial production process, where curricula and their content serve as moulds into which fresh minds are supposed to be poured…. students can do little but memorise, recite and perfect rote learning”.25 thus, when considering medical students’ ability to evaluate a website, the results of the current study point to the influence of factors much bigger than just level of knowledge and certainly there is a need for correction on a more profound level than can be accomplished by a single intervention. further research assessing critical thinking skills and its relationship to this evaluative ability would be required for a more definitive understanding of these factors. the current study was limited because it was conducted in a single year on one group of students. moreover, no research has been conducted on the long-term impact of teaching, which could be studied in follow-up research. conclusion this study found that the included undergraduate medical students’ ability to evaluate the quality of health-related websites is mixed. prior exposure to and use of technology has no bearing on this ability. a single intervention has a limited and mixed impact, possibly as a result of poor prior critical thinking skills. given that medical students and health professionals increasingly rely upon websites and other information sources that do not undergo quality control, it is recommended that training and practice of the required skills be reinforced. a u t h o r s’ c o n t r i b u t i o n s tl, km, sz and ah-w conceptualised and designed the study. tl, km and ah-w created the instrument used. instrument and intervention delivery was conducted by km. tl and km analysed the quantitative data. km produced the themes of the qualitative data, while tl, km, sz and ah-w verified the qualitative data. tl, km and ah-w interpreted the data. all authors drafted and revised the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. masters k. access to and use of the internet by south african general practitioners. int j med inform 2008; 77:778–86. https://doi.org/10.1016/j.ijmedinf.2008.05.008. 2. masters k. for what purpose and reasons do doctors use the internet: a systematic review. int j med inform 2008; 77:4–16. https://doi.org/10.1016/j.ijmedinf.2006.10.002. 3. sommerhalder k, abraham a, zufferey mc, barth j, abel t. internet information and medical consultations: experiences from patients’ and physicians’ perspectives. patient educ couns 2009; 77:266–71. https://doi.org/10.1016/j.pec.2009.03.028. 4. moick m, terlutter r. physicians’ motives for professional internet use and differences in attitudes toward the internet-informed patient, physician-patient communication, and prescribing behavior. med 2 0 2012; 1:e2. https://doi.org/10.2196/med20.1996. 5. macleod a, fournier c. residents’ use of mobile technologies: three challenges for graduate medical education. bmj simul technol enhanc learn 2017; 3:99–105. https://doi.org/10.1136/ bmjstel-2016-000185. 6. battineni g, baldoni s, chintalapudi n, sagaro gg, pallotta g, nittari g, et al. factors affecting the quality and reliability of online health information. digit health 2020; 6:2055207620948996. https://doi.org/10.1177/2055207620948996. 7. kritz m, gschwandtner m, stefanov v, hanbury a, samwald m. utilization and perceived problems of online medical resources and search tools among different groups of european physicians. j med internet res 2013; 15:e122. https://doi.org/10.2196/ jmir.2436. 8. ghezzi p, chumber s, brabazon t. educating medical students to evaluate the quality of health information on the web. in: floridi l, illari p, eds. the philosophy of information quality. cham, switzerland: springer international publishing, 2014. pp. 183–99. https://doi.org/10.1007/978-3-319-07121-3_10. 9. burd a, chiu t, mcnaught c. screening internet websites for educational potential in undergraduate medical education. med inform internet med 2004; 29:185–97. https://doi.org/10.1080/ 14639230400005982. 10. watson hr, burr s. research skills in medical education. mededpublish 2018; 7:151. https://doi.org/10.15694/mep.20 18.0000151.1. 11. stark p, ellershaw j, newble d, perry m, robinson l, smith j, et al. student-selected components in the undergraduate medical curriculum: a multi-institutional consensus on assessable key tasks. med teach 2005; 27:720–5. https://doi.org/10.1080/014 21590500271530. 12. murdoch-eaton d, drewery s, elton s, emmerson c, marshall m, smith ja, et al. what do medical students understand by research and research skills? identifying research opportunities within undergraduate projects. med teach 2010; 32:e152–60. https://doi.org/10.3109/01421591003657493. 13. laidlaw a, aiton j, struthers j, guild s. developing research skills in medical students: amee guide no. 69. med teach 2012; 34:e754–71. https://doi.org/10.3109/0142159x.2012.704438. 14. gmc. tomorrow’s doctors: outcomes and standards for undergraduate medical education. london, uk: the general medical council, 2009. 15. kapoun j. teaching undergrads web evaluation: a guide for library instruction. coll res libr news 1998; 59:522–3. https:// doi.org/10.5860/crln.59.7.522. 16. masters k. health professionals as mobile content creators: teaching medical students to develop mhealth applications. med teach 2014; 36:883–9. https://doi.org/10.3109/014215 9x.2014.916783. https://doi.org/10.1016/j.ijmedinf.2008.05.008 https://doi.org/10.1016/j.ijmedinf.2006.10.002 https://doi.org/10.1016/j.pec.2009.03.028 https://doi.org/10.2196/med20.1996 https://doi.org/10.1136/bmjstel-2016-000185 https://doi.org/10.1136/bmjstel-2016-000185 https://doi.org/10.1177/2055207620948996 https://doi.org/10.2196/jmir.2436 https://doi.org/10.2196/jmir.2436 https://doi.org/10.1007/978-3-319-07121-3_10 https://doi.org/10.1080/14639230400005982 https://doi.org/10.1080/14639230400005982 https://doi.org/10.15694/mep.2018.0000151.1 https://doi.org/10.15694/mep.2018.0000151.1 https://doi.org/10.1080/01421590500271530 https://doi.org/10.1080/01421590500271530 https://doi.org/10.3109/01421591003657493 https://doi.org/10.3109/0142159x.2012.704438 https://doi.org/10.5860/crln.59.7.522 https://doi.org/10.5860/crln.59.7.522 https://doi.org/10.3109/0142159x.2014.916783 https://doi.org/10.3109/0142159x.2014.916783 teresa loda, ken masters, stephan zipfel and anne herrmann-werner clinical and basic research | 369 17. ashokka b, dong c, law ls, liaw sy, chen fg, samarasekera dd. a beme systematic review of teaching interventions to equip medical students and residents in early recognition and prompt escalation of acute clinical deteriorations: beme guide no. 62. med teach 2020; 42:724–37. https://doi.org/10.1080/014215 9x.2020.1763286. 18. deliz jr, fears ff, jones ke, tobat j, char d, ross wr. cultural competency interventions during medical school: a scoping review and narrative synthesis. j gen intern med 2020; 35:568–77. https://doi.org/10.1007/s11606-019-05417-5. 19. omer u, danopoulos e, veysey m, crampton p, finn g. a rapid review of prescribing education interventions. med sci educ 2020; 31:273–89. https://doi.org/10.1007/s40670-020-01131-8. 20. galanek jd, gierdowski dc, brooks dc. ecar study of undergraduate students and information technology. louisville, co, usa: ecar, 2018. 21. tannery nh, foust je, gregg al, hartman lm, kuller ab, worona p. use of web-based library resources by medical students in community and ambulatory settings. j med libr assoc 2002; 90:305–9. 22. wiedenbeck s, labelle d, kain v. factors affecting course outcomes in introductory programming. in: dunican e, green t, eds. proceedings of the 16th workshop of the psychology of programming interest group. carlow, ireland: ppig, 2004. pp. 97–110. 23. ivins j, ong mp. psychometric assessment of computing undergraduates. in: romero p, good j, chaparro ea, bryant s, eds. 17th workshop of the psychology of programming interest group. sussex, uk: ppig, 2005. pp. 305–19. 24. bosch n, d’mello s, mills c. what emotions do novices experience during their first computer programming learning session? in: lane h, yacef k, mostow j, pavlik p, eds. lecture notes in computer science. berlin/heidelberg, germany: springer-verlag, 2013. pp. 11–20. 25. undp. arab human development report 2003: building a knowledge society. new york: united nations development programme arab fund for economic and social development, 2003. 26. al barwani t, al yahmadi h, clayton d, al kalbani m, neisler o, al sulaimani h, et al. measuring against expectations: devel opment of a multidimensional profile of university readiness of omani higher education intake 2011–2013 (case of squ). in: quality management & enhancement in higher education 20– 21 february 2012. muscat, oman: sultan qaboos university, 2012. 27. kumar r, james r. evaluation of critical thinking in higher education in oman. int j high educ 2015; 4:33–43. https://doi. org/10.5430/ijhe.v4n3p33. 28. neisler o, clayton d, al-barwani t, al kharusi h, al-sulaimani h. 21st century teacher education: teaching, learning and assessment of critical thinking skills at sultan qaboos university. in: redefining teacher education for the post-2015 era: global challenges and best practices. new york, usa: nova, 2016. pp. 77–95. https://doi.org/10.1080/0142159x.2020.1763286 https://doi.org/10.1080/0142159x.2020.1763286 https://doi.org/10.1007/s11606-019-05417-5 https://doi.org/10.1007/s40670-020-01131-8 https://doi.org/10.5430/ijhe.v4n3p33 https://doi.org/10.5430/ijhe.v4n3p33 prevalence of asthma symptoms in omani schoolchildren 21 abstr ac t. objectives : to determine the prevalence of asthma in omani schoolchildren using the international study of asthma and allergies in children (isaac) protocols. method: the isaac-written questionnaire was completed by a total of 7,067 omani schoolchildren (3,893 children aged 6–7 years of which 56% were boys and 3,174 aged 13–14 years of which 51% were boys) from the 10 health regions in the country. results : the estimated mean national 12-month prevalence of any wheeze, night waking with wheeze, speech limiting wheeze and exercise wheeze were respectively 7.8% , 3.5% , 3.2% and 6.9% for the 6–7 year age group and 8.9% , 2.9% , 4.0% and 19.2% for the 13–14 year age group. both age groups reported high prevalence of night cough (19.6% and 20.9% in the younger and the older children respectively). the prevalence of self-reported asthma diagnosis was higher in the older age group (20.7% vs. 10.5% , p<0.001). in the younger age group, the diagnosis of asthma was more common in boys (12.5% vs. 8.0% , p>0.001), but there was no signifi cant difference between the two sexes in the older age group (22.0% of boys vs. 20.5% of girls). there was nearly three-fold dif ference in the prevalence of self-reported diagnosis of asthma between the regions with the highest and the lowest prevalence of asthma for both young and older children (from 5.3% and 9.5% in musandam to 14.2% and 30.6% in south sharqiya, respectively). conclusion: the results of this fi rst epidemiological survey of asthma in oman indicate that asthma is common in omani children and adolescents. night cough is the most frequent symptom. there is also signifi cant regional variation in pre valence of asthma symptoms and diagnosis within the country and this requires further investigation. key words : asthma, prevalence, isaac, wheezing, night cough, oman, children a sthm a is one of the most common chronic conditions in children and adults worldwide and one with a very high socio-economic cost.1 numerous studies from the developed countries have reported increases in the prevalence of asthma and other allergic conditions (allergic rhinitis and eczema) over the last three decades, with marked variations between and within countries.2–11 the greatest increases in the prevalence of asthma have been reported in children and young adults with up to 20–30% of the children affected in some countries.2–11 studies from developing countries indicate that asthma is common in this part of the world also, with considerable variation in its prevalence between countries.12–18 in 1991, the international study of asthma and allergies in children (isaac ) was formed to maximise the value of epidemiological research into asthma and other atopic disorders by establishing and promoting standardised methodology and facilitating international collaboration by involving as many countries as possible provided they met the requirements of the study protocol.19 has attracted large-scale participation squ journal for scientific research: medical sciences 2001, 1, 21–27 ©2001 sultan qaboos university prevalence of asthma symptoms in omani schoolchildren *bazdawi m.s. al-riyami1, omar a.s. al-rawas1, asya a. al-riyami2, lyla g. jasim2, ali j. mohammed2 1department of medicine, college of medicine, sultan qaboos university, p.o.box: 35, al-khod 123, muscat, sultanate of oman. 2ministry of health, directorate of research, directorate of school health and directorate general of health affairs, p.o.box: 393, muscat, sultanate of oman. *to whom correspondence should be addressed. e-mail: bazdawi@squ.edu.om a l r i y a m i e t a l22 from all parts of the world.10 oman was one of the collaborating centres in phase i of the isa ac project and our participation has yielded the only available data on the prevalence of asthma in this country.10–11 the summary of the results of our centre has been published as part of the isa ac steering committee publications on the worldwide variations in asthma symptoms.10–11 the aim of this paper is to report a detailed analysis of the prevalence of self-reported asthma symptoms and diagnosis in oman and to compare the prevalence of asthma and its symptoms in different regions of the country. m e t h o d p r o t o c o l a n d s u b j e c t s a stratifi ed multistage sampling method was used. the ten health regions of the sultanate of oman [figure 1] were considered as strata. the fi rst stage of sampling consisted of schools randomly selected as primary sample units. in the second stage, one class was chosen from each school as the secondary sample unit. the total national target sample was distributed among the ten regions of the country using the proportion allocation method. the sample frame of the survey was a list of public schools provided by the ministry of education indicating the district and town, number of schools with grades i and ii primary (6–7 years age group) and i and ii preparatory (13–14 years age group). the number of children in these grades was also indicated. to achieve a fi nal total sample size of 6,000 children (3,000 in each age group), a total of 7,625 copies of the questionnaire were distributed (4,079 to the 6–7 age group and 3,546 to the 13–14 age group). the sample size for the 6–7 year age group was kept higher by 15% to allow for the expected lower response rate, since questionnaire had to be fi lled by the parents. a total of 220 schools participated (118 primary and 102 preparatory). of these, 117 (53%) were boys’ schools (66 primary and 51 preparatory). the isa ac -written standardised questionnaire19 was used to identify asthma, allergic rhinitis, atopic eczema and related symptoms. the questionnaire was translated to arabic in the following manner: one of the two bilingual translators translated the questionnaire into arabic and the other translated it back into english and the differences between the back translation and the original english version were resolved. the arabic version of isa ac u . a . e . g u l f o f o m a n a r a b i a n s e a s a u d i a r a b i a dhofar al-wusta al-dakhiliya north sharqia south sharqia muscat so ut h ba tin ah north batinah al-dhahirah musandam y e m e n figure 1. map of the sultanate of oman showing the ten health regions of the country the regions shown above were used as the strata for recruitment of schoolchildren, in proportion to their population density. because of their relatively sparse population, data from musandum and wusta were analysed together. table 1. sex and regional distribution of the two age groups of omani schoolchildren 6 –7 years age group 13–14 years age group boys girls total boys girls total n (%) n (%) n n (%) n (%) n muscat 301 (58) 217 (42) 518 270 (53) 237 (47) 507 batinah (north) 441 (63) 258 (37) 699 256 (43) 343 (57) 599 batinah (south) 213 (45) 256 (55) 469 204 (54) 172 (46) 376 dakhiliya 256 (47) 294 (53) 550 303 (62) 182 (38) 485* sharqiya (south) 220 (68) 101 (32) 321* 90 (49) 93 (51) 183 sharqiya (north) 266 (77) 79 (23) 345* 67 (33) 134 (67) 201* dhahirah 174 (45) 210 (55) 284 177 (50) 176 (50) 353 dhofar 271 (55) 222 (45) 493 217 (58) 159 (42) 376 musandum & wusta 58 (51) 56 (49) 114 40 (43) 54 (57) 94 total national sample 2200 (56) 1693 (44) 3893 1624 (51) 1550 (49) 3174 *significant difference in sex distribution within the group a s t h m a i n o m a n i c h i l d r e n 23 questionnaire was distributed to the schoolchildren and was completed by the parents of the 6–7 year age group and by the children themselves in the 13–14 age group. ethical approval of the study protocol was obtained from both the ministry of health and the ministry of education. d ata p r e s e n tat i o n a n d a n a ly s i s data were collected and entered using the isa ac international data centre protocol,10 and were analysed using spss -9 software package for windows. groups were compared using the chi-square (χ2) test. a p-value of <0.05 was considered statistically signifi cant. r e s u l t s t h e s u b j e c t s the isa ac questionnaire was completed by a total of 7,067 pupils (92.7% response rate) from the ten omani health regions and consisted of two age groups: 3,893 pupils aged 6–7 years (95.4% response rate) and 3,174 pupils aged 13–14 years (89.5% response rate). table 1 shows the sex and regional distribution of the two age groups. although musandum and wusta are separate geographical and health regions [figure 1], their data were analysed together because of their smaller sample sizes. the sex distribution in the total national sample was nearly equal for both age groups (boys constituted 56% of 6–7 year-olds and 51% of the13–14 year-olds). similarly, the sex distribution in the regional samples was nearly even for most regions except for north and south sharqiya and dakhiliya regions; north and south sharqiya regions contained signifi cantly higher number of boys in the 6–7 year age group (77% and 68%, respectively). for the 13–14 years age group, boys predominated (62%) the sample from dakhiliya region while there were more girls (67%) in the sample from north sharqiya. the number of participants belonging to the two age groups varied between regions, ranging from 114 and 94 children in musandum and wusta to 699 and 599 children in north batinah for the young and older age groups respectively. e s t i m at e d n at i o n a l p r e va l e n c e o f s e l f r e p o rt e d a s t h m a s y m p t o m s a n d d i a g n o s i s table 2 shows the prevalence of asthma symptoms and self-reported asthma diagnosis (‘ever had asthma’) in the two study groups. the estimated national cumulative prevalence of any wheeze (‘wheeze ever’), and the 12-month period prevalence of any wheeze, and exercise wheeze were signifi cantly higher in the 13–14 year age group (15.6, 8.9, and 19.2% respectively), compared to the 6–7 year age group (13.8, 7.8 and 6.9% respectively). there was no signifi cant difference between the two groups in the 12-month period prevalence of four or more wheeze attacks, wheeze disturbing sleep, or severe wheeze (‘wheeze limiting speech’). night cough not related to upper respiratory tract infection was equally frequent in both age groups (19.6% and 20.9% in young and older children, respectively). the prevalence of self-reported asthma diagnosis was common in both age groups with the older children having nearly twice the prevalence in younger children (20.7%vs. 10.5%, p<0.001). although, only 8.9% of children aged 13–14 reported any wheeze during the past 12 months, 19.2% of them reported to have had exercise induced wheeze during the same period. table 2. the overall national prevalence (%) of self-reported asthma symptoms and diagnosis in the studied age groups 6 – 7 yrs old (n = 3893) 13 –14 yrs old (n = 3174) pvalue ever wheezed 13.8 15.6 0.04 12-month prevalence of: – any wheeze 7.8 8.9 0.005 – four or more wheeze 2.5 2.6 0.57 – wheeze disturbs sleep 3.5 2.9 0.18 – wheeze limiting speech 3.2 4 0.09 – exercise wheeze 6.9 19.2 <0.001 – night cough 19.6 20.9 0.2 ever had asthma 10.5 20.7 <0.001 table 3. gender difference in the prevalence (%) of self-reported asthma symptoms and diagnosis in two study age groups 6–7 years age group (n = 3893) 13–14 years age group (n = 3174) boys n= 2200 girls n= 1693 p -value boys n= 1622 girls n= 1552 p -value ever wheezed 15.8 11.3 <0.001 16.3 14.9 0.28 12-month prevalence of: – any wheeze 8.5 5.3 <0.001 9.2 8.6 0.59 – 4 or more wheeze 3 2 0.06 3 2.3 0.18 – wheeze disturbs sleep 4 2.8 0.06 3.2 2.6 0.29 – wheeze limiting speech 3.4 3 0.54 4.2 3.7 0.51 – exercise wheeze 7.7 6 0.04 21.5 16.7 <0.001 – night cough 20.3 18.7 0.21 21.3 20.4 0.56 ever had asthma 12.4 8 <0.001 21.4 20 0.35 a l r i y a m i e t a l24 g e n d e r d i f f e r e n c e table 3 shows the prevalence of self-reported asthma symptoms and diagnosis according to gender in the two age groups. in the 6–7 year age group, the cumulative prevalence of wheeze, the 12-month prevalence of ‘any wheeze’, ‘exercise wheeze’, and ‘ever had asthma’ were signifi cantly higher in males. in contrast, there was no signifi cant difference between the two sexes in asthma diagnosis or any of its symptoms in the 13–14 year age group except exercise induced wheeze which was more common in males (21.5% vs. 16.7%, p < 0.001). there was no signifi cant difference between the two sexes in the prevalence of night cough or symptoms of severe asthma (4 or more attacks per week, wheeze that disturbs sleep and speech limiting wheeze) in both age groups. r e g i o n a l va r i at i o n the prevalence of self-reported asthma symptoms and diagnosis in the 10 omani health regions is shown in table 3 (children aged 6–7 years) and table 4 (children aged 13–14 years). there was a signifi cant variation in the prevalence of asthma diagnosis and its symptoms in both age groups, with nearly 3-fold difference in the prevalence of self-reported asthma diagnosis between the highest and lowest prevalence regions. the prevalence of self-reported diagnosis of asthma in south sharqiya was 14.2% and 30.6% for young and older children respectively, compared to 5.3% and 9.6% respectively in musandum and wusta. south and north sharqiya regions (eastern region of oman) had consistently higher prevalence of all asthma symptoms, contrasting with musandum which had the lowest prevalence of all asthma symptoms. d i s c u s s i o n although data from many different countries provide compelling evidence that asthma and other allergic diseases are increasing, these were primarily from the developed countries which might not be representative of the remainder of the world.2–11 the prevalence fi gures may be infl uenced by the difference in disease defi nition and classifi cation, diagnostic methods, and the level of awareness of the disease as well as by the prevalence and distribution of its risk factors.2,6,15 in addition, the causes of the rising trends in asthma and other atopic diseases remain to be identifi ed.10–11 this is the fi rst epidemiological survey on self-reported asthma symptoms and diagnosis in the sultanate of oman. using the isa ac protocol, we found the symptoms suggestive of asthma to be quite common in oman. we also table 4. regional variation in the prevalence (%) of asthma symptoms in omani schoolchildren aged 6 –7 years using the isaac questionnaire 12 – month prevalence of ever wheezed any wheeze wheeze disturbs sleep wheeze limiting speech exercise wheeze night cough ever had asthma muscat 10.4 5.2 2.7 1.7 5.6 17.8 9.5 batinah (north) 16.2 7.7 5.9 2.6 6.2 17.0 10.2 batinah (south) 14.7 6.8 4.3 3.8 6.8 19.6 8.3 dakhiliya 13.8 7.5 2.5 4.7 7.5 20.7 12.2 sharqiya (south) 16.8 8.1 4.7 3.7 10.6 23.4 13.4 sharqiya (north) 15.9 9.3 6.4 3.7 7.5 27.5 14.2 dhahirah 13.8 6.3 3.4 4.9 6.8 20.6 6.8 dhofar 12.8 7.3 2.8 2.3 7.1 16.2 11.8 musandum & wusta 5.3 4.4 0.9 2.6 3.5 15.8 5.3 total national sample 13.8 7.8 3.5 3.2 6.9 19.6 10.5 a s t h m a i n o m a n i c h i l d r e n 25 found signifi cant variation in the prevalence of asthma diagnosis and symptoms between the different regions. n at i o n a l p r e va l e n c e o f s e l f r e p o rt e d a s t h m a s y m p t o m s a n d d i a g n o s i s 6 –7 year age group the estimated national prevalence of parent-reported asthma diagnosis in this age group was 10.5%. this puts oman in the intermediate prevalence compared to the rest of the world for this age group.10 in keeping with the fi ndings in most isa ac centres, boys had signifi cantly higher prevalence than girls for cumulative wheeze, 12-month history of ‘any wheeze’ and ‘exercise wheeze’, and parentreported history of asthma (‘ever had asthma’).10 however there was no signifi cant difference between the two sexes in night cough or any of the symptoms suggestive of severe asthma (the 12-month prevalence of: four or more attacks of wheeze, sleep disturbing wheeze and speech limiting wheeze). only three eastern mediterranean countries (iran, malta and oman) were included this isa ac phase-i optional age group with a mean prevalence of ‘ever had wheeze’ of 6.56%. among these, oman had the highest prevalence of ‘ever had asthma’ and all asthma symptoms except the 12-month prevalence of any wheeze which was slightly higher in malta (7.1% vs. 8.8%).10 13–14 year age group like most participating countries, the prevalence of selfreported asthma symptoms and diagnosis was higher in this age group compared to the younger group.10 this suggests that symptoms starting at young ages persist into adolescence (cumulative effect) or that more new cases develop with time compared to those which resolve spontaneously (net effect). the prevalence of ‘ever had asthma’ in this age group in oman (20.7%) was the highest among the seven eastern mediterranean participating countries: iran (2.7%), kuwait (17.5%), lebanon (11.6%), malta (11.1%), morocco (11.7%) and pakistan (7.3%).10 only six of the 56 participating countries reported prevalence rates higher than 20% (range: 20–28%) in this age group (peru, united kingdom, australia, new zealand, singapore and oman).10 with the exception of oman, in all of these countries and many other countries the reporting of 12-month prevalence of wheeze was higher than ‘ever had asthma’. in contrast, oman was one of the several countries where the reporting of ‘ever had asthma’ was more frequent than ‘ever wheeze’. the cause of this difference is not clear, but it may be due to over-reporting of asthma diagnosis in oman. an table 5. regional variation in the prevalence (%) of asthma symptoms in omani schoolchildren aged 13 –14 years using the isaac questionnaire 12 –month prevalence of: ever wheezed any wheeze wheeze disturbs sleep wheeze limiting speech exercise wheeze night cough ever had asthma muscat 11.6 6.7 1.6 3.0 12.6 21.3 19.1 batinah (north) 19.9 12.7 4.0 5.7 25.7 23.2 25.2 batinah (south) 18.1 10.6 4.3 5.9 18.9 19.4 23.4 dakhiliya 11.5 5.8 3.3 1.6 16.9 19.2 20.2 sharqiya (south) 26.8 14.2 13.3 4.9 31.1 23.0 30.6 sharqiya (north) 16.4 8.5 4.5 2.5 19.4 20.4 26.9 dhahirah 14.2 7.9 1.7 4.2 17.8 19.0 15.0 dhofar 13.8 7.7 2.9 4.0 17.6 21.8 13.8 musandum & wusta 9.6 5.3 2.1 3.2 12.8 18.1 9.6 total national sample 15.6 8.9 2.9 4.0 19.2 20.9 20.7 a l r i y a m i e t a l26 alternative and more plausible explanation is that the diagnosis of asthma may be based on symptoms other than wheeze.20 this is supported by the high prevalence of night cough (20.9%) and exercise-induced wheeze (19.2%). a third possibility is that many of the children with previous history of asthma (‘ever had asthma’) in this age group did not have ‘any wheeze’ during the previous 12 months. in the 13–14 age group, exercise-induced wheeze in the last 12 months was reported more frequently than ‘any wheeze’ within the same period. this pattern was reported in most of (50 of 56) the participating countries.10 on theoretical grounds one would expect the opposite pattern (i.e. the reporting of ‘any wheeze’ to be more frequent than any of its components such as exercise induced wheeze). the reason for this is not clear and has not been previously explained.10 one possibility is that children at this age group, who self-completed the isa ac questionnaire, perceived exercise induced wheeze as a separate entity from the ordinary wheeze of asthma. r e g i o n a l va r i at i o n in the isa ac phase-i, several countries participated with more than one centre (18 countries for 6–7 year age group and 30 countries for 13–14 year age group) and these yielded signifi cant variations in the self-reported asthma symptoms and diagnosis within countries.10 oman participated with only one centre for both age groups. however we sought to determine the difference in asthma and other allergies among the 10 health regions of the country by distributing the total sample among these regions in pro portion to their population. a clear and consistent pattern of regional variation in the prevalence of asthma and symptoms emerged. the eastern region (north and south sharqiya) had the highest asthma diagnosis and symptoms in the country for both age groups and both sexes. in contrast, musandum and wusta (northernmost middle regions respectively) had the lowest prevalence rates for both age groups and both sexes. overall, the north-western regions had less asthma diagnosis and symptoms than the southeastern regions with the interior region (dakhiliya) having intermediate rates. the cause of this variation is not known, but might be due to the difference in the distribution of the risk factors of atopy and asthma in different regions.13,21 there is no information on the prevalence and the regional distribution of the risk factors for asthma and atopy in oman. investigations of these factors in the different regions of the country will not only help elucidating the causes of the regional variation in the prevalence of asthma, but also help in the development of national health and environmental strategies to control asthma and other atopic conditions. c o n c l u s i o n the prevalence of self-reported asthma symptoms and diagnosis is relatively high in oman with signifi cant regional variation within the country. the cause of this high prevalence and its regional variation is not clear, as there are no data on the risk factors for the development of asthma and other allergic diseases. participation in isa ac phase ii may defi ne some of risk factors for asthma in oman which may be different in different regions of the country. a c k n ow l e d g e m e n t we thank muscat pharmacy for their fi nancial assistance towards this study, school health physicians of the ministry of health for distributing and retrieving questionnaires from schools, and mr. khorrum tahlilkar and mr. m. alshukeiry of department of physiology, college of medicine, sultan qaboos university, for data entry. r e f e r e n c e s 1. barnes pj, jonsson b, klim jb. the cost of asthma. eur respir j 1996, 9, 636–42. 2. peter dp. asthma in children: epidemiology – changing prevalence, patterns, and treatment. bmj 1994, 308, 1584–5. 3. peat jk, van den berg rh, green wf, mellis cm, leeder sr, woolcock aj. changing prevalence of asthma in australian children. bmj 1994, 308, 1591–6. 4. aberg n, hesselmar b, aberg b, eriksson b. increase of asthma, allergig rhinitis and eczema in swedish schoolchildren between 1979 and 1991. clin exp allergy 1995, 25, 815–9. 5. busquets rm, anto jm, sunyer j, sancho n, vall o. prevalence of asthma-related symptoms and bronchial responsiveness to exercise in children aged 13–14 yrs in barcelona, spain. eur respir j 1996, 2094–8. 6. nystad w, magnus p, gulsvik a, skarpaas ij, carlsen kh. changing prevalence of asthma in schoolchildren: evidence for diagnostic changes in asthma in two surveys 13 years apart. eur respir j 1997, 10, 1046–51. 7. norman e, nystrom l, jonsson e, stjernberg n. prevalence and incidence of asthma and rhinoconjuctivitis in swedish teenagers. allergy 1998, 53, 28–35. 8. kaur b, anderson hr, austin j et al. prevalence of asthma symptoms, diagnosis and treatment in 12–14 yearold children across great britain (international study of asthma and allergies in childhood, isaac, uk). bmj 1998, 316, 118–24. 9. pearce n, weiland s, keil u, langridge p, anderson hr, strachan d, et al. self-reported prevalence of asthma a s t h m a i n o m a n i c h i l d r e n 27 symptoms in children in australia, england, germany and new zealand: an international comparison using the isaac protocol. eur respir j 1993, 6, 1455–61. 10. asher mi, anderson hr, stewart aw, crane j. worldwide variations in the prevalence of asthma symptoms: the international study of asthma and allergies in childhood (isaac). eur respir j. 1998 12, 315–35. 11. the international study of asthma and allergies in childhood: (isaac) steering committee. worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: isaac. lancet 1998, 25, 1220–1. 12. ramadan fm, mruoeh sm, khoury mn, hajjar ta, khogali m. prevalence of asthma and asthma symptoms in children in urban lebanon. saudi med j 1999, 20, 453–7. 13. al-frayh ar, facharzt m, al-nahdi m, bener ar, al jawadi tq. epidemiology of asthma and allergic rhinitis in two costal regions of saudi arabia. int j allergy immunol 1989, 21, 389–93. 14. al-frayh ar, bener ar, al-jawadi tq. prevalence of asthma among saudi schoolchildren. saudi med j 1992, 13, 521–4. 15. lai ck, douglass c, ho ss, chan j, lau j, wong g et al. asthma epidemiology in the far east. clin exp allergy 1996, 26, 5–12. 16. leung r, bishop j, robertson cf. prevalence of asthma and wheeze in hong kong schoolchildren: an international comparative study. eur respir j 1994, 7, 2046–9. 17. goh dy, chew ft, quek sc, lee bw. prevalence and severity of asthma, rhinitis and eczema in singapore schoolchildren. arch dis child 1996, 74, 131–4. 18. kim yy, cho sh, kim wk, park jk, song sh, jee yk et al. prevalence of childhood asthma based on questionnaire and methacholine bronchial provocation test in korea. clin exp allergy 1997, 27, 761–8. 19. asher mi, keil u, anderson hr, et al. international study of asthma and allergies in children (isaac): rationale and methods. eur respir j. 1995;8:483-91. 20. wright an, holberg cj, morgan wj, taussic lm, halonen m et al. recurrent cough in childhood and its relation to asthma. am j respir crit care med 1996, 153, 1259–65. 21. ulrik cs, backer v, hesse b, dirksen a. risk factors for the development of asthma in children and adolescents: fi ndings from a longitudinal population study. respir med 1996, 90, 623–30. a p p e n d i x core questionnaire for wheezing and asthma (isaac phase i) 1. have you (has your child) ever had wheezing or whistling in the chest at any time in the past? if you have answered ‘no’ please skip to question 6 yes/no 2. have you (has your child) had wheezing or whistling in the chest in the last 12 months? if you have answered ‘no’ please skip to question 6 yes/no 3. how many attacks of wheezing have you (has your child) had in the last 12 months? none / 1–3 / 4–12 / >12 4. in the last 12 months, how often on the average, has your (your child) sleep been disturbed due to wheezing? never woken with wheezing / less than one night per week / one or more nights per week. 5. in the last 12 months, has wheezing ever been severe enough to limit your (your child’s) speech to only one or two words at a time between breaths? yes / no 6. have you (has your child) ever had asthma? yes/no 7. in the last 12 months, has your (your child’s) chest sounded wheezy during or after exercise? yes/no 8. in the last 12 months, have you (your child) had a dry cough at night apart from a cough associated with a cold or flu? yes/no departments of 1family medicine and 2histopathology, ministry of health, muscat, oman; 3department of family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asmaa_9988@hotmail.com prevalence of cytological abnormalities in papanicolaou smears and risk factors for cervical cancer among women in muscat, oman eman al sekri,1 asma al musalhi,1 khadija al abri,1 hunaina al kindi,2 *asma a. al salmani3 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 598–603, epub. 25 nov 21 submitted 17 aug 20 revision req. 17 sep 20; revision recd. 23 sep 20 accepted 8 oct 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.041 clinical & basic research abstract: objectives: this study aimed to estimate the prevalence of cytological abnormalities in papanicolaou (pap) smears and related risk factors among omani women. methods: a cross-sectional study was conducted from march to september 2019 at the gynaecology and family medicine clinics of khoula hospital and sultan qaboos university hospital in muscat. all asymptomatic omani women aged between 21 and 65 years were included. data regarding the participants’ sociodemographic characteristics and known risk factors were collected using a selfreported sheet. pap smears were performed and the results were reported by a cytotechnologist and histopathologist. results: a total of 442 women participated in the study (response rate: 100%). the mean age was 39.0 ± 9.7 years old. the prevalence of cervical cytological abnormalities was 3.7%. there was a significant association between human papillomavirus (hpv) infection and cervical cell abnormalities ( p = 0.017); however, there was no link with hormonal contraception use, pregnancy before the age of 17 years or parity (p >0.050 each). conclusion: the prevalence of cervical cell abnormalities in oman was similar to that observed in arab countries and relatively low in comparison to findings from western countries. a screening program should be implemented at the primary care level. the findings of this study also highlighted the need for a future vaccination program against hpv infections. keywords: cervical cancer; screening; pap smear; human papillomavirus; oman. advances in knowledge the prevalence of cervical cell abnormalities in oman was similar to that observed in arab countries and relatively low in comparison to findings from western countries. there is a significant association between cervical cell abnormalities and human papillomavirus (hpv) infection. applications to patient care the findings related to the prevalence of cervical cell abnormalities suggested that women should visit their gynaecology/family medicine clinic for cervical cancer screening using a pap smear. women with a history of hpv infection need to be screened for the early detection of cervical cell abnormalities. after cardiovascular events, cancer is the leading cause of mortality worldwide due to increasing population growth and life expectancy.1,2 in 2018, cervical cancer was one of seven cancers that together represented half of the annual global incidence and mortality burden of all cancers; moreover, this type of cancer ranked fourth in both incidence and mortality among female cancers, with 570,000 cases and 311,000 deaths.1 worldwide, the distribution of cervical cancer cases varies according to region, with the highest rate reported in sub-saharan africa and southeast asia; in contrast, incidence rates are 7–10 times lower in western asia.3 in oman, cervical cancer is the third most frequent cancer among women, with an average of 77 new diagnoses and 41 deaths reported every year.4 various risk factors have been established in relation to cervical cancer, including smoking, age at first intercourse, number of sexual partners and duration of oral contraceptive use.5–7 in particular, human papillomavirus (hpv) infection plays a major causative role.8 cervical cancer is slow-progressing, and it can take up to 10 years or more for the precancerous cells to become malignant; however, affected cases can be detected sufficiently early, thus improving outcomes.9 the most common screening method for cervical cancer is papanicolaou (pap) smear cytology, which is the cornerstone for cervical cancer screening guidelines.10 however, while these risk factors have been studied extensively in western populations, inconsistent results have been reported from countries in the arabian gulf region, including different patterns and prevalence rates of cervical cytological abnormalities and other cervical cancer risk factors.11–13 significant declines in cervical cancer cases have been reported following the introduction of cervical cancer screening and hpv vaccine programmes; in eman al sekri, asma al musalhi, khadija al abri, hunaina al kindi and asma a. al salmani clinical and basic research | 599 the uk, the incidence rate decreased by 24%, while cervical cancer fell from the top 10 to 14th place in terms of cancer-related deaths in the usa.14–16 unfortunately, up to 85% of global deaths due to cervical cancer occur in developing countries, which can be attributed to the lack of structured screening and hpv vaccine programmes as well as inadequate awareness and knowledge regarding cervical cancer and the importance of routine screening among members of the public.17,18 hence, this study aimed to estimate the prevalence of cervical cytological abnormalities and explore cervical cancer risk factors in an asymptomatic omani population. methods this cross-sectional study was conducted between march and september 2019 at the khoula hospital and sultan qaboos university hospital in muscat, oman. all asymptomatic omani women aged between 21 and 65 years old who attended the gynaecology or family medicine clinics of these hospitals during the study period were included. however, women who were symptomatic (i.e. presenting with vaginal discharge, lower abdominal pain, postcoital bleeding or intermenstrual bleeding) and those diagnosed with cervical or uterine cancer were excluded. based on a prevalence rate of 2.6% at a 95% significance level and taking into consideration a two-sided alpha value of 5% and a 2% margin of error, the necessary sample size was calculated to be 442 participants. trained staff in each hospital distributed the data collection sheet after obtaining consent from participants. all participants filled out an information sheet for the assessment of their sociodemographic characteristics and risk factors, including their age, marital status, number of sexual partners, number of children, history and duration of hormonal contraceptive use, whether they had been pregnant before the age of 17 years, history of hpv vaccination or infection, smoking history and family history of cervical cancer. for illiterate participants, the investigators transcribed verbal responses to each of the questions on the information sheet. subsequently, the women underwent a routine pap smear performed by a physician. cellular material was collected using one of two methods. the first method involved placing the long edge of an ayre spatula on the cervix near the squamocolumnar junction and rotating it 360°; the cellular material was then gently smeared on a clean glass slide and immediately fixed with 95% ethyl alcohol (conventional method). the other method involved brushing the cervix with a cervical cytology brush before placing the tool in a bd surepath™ liquid-based pap test (becton, dickinson & co., franklin lakes, nj, usa). the cytology of the cervical samples was analysed by a cytotechnologist according to the 2014 bethesda classifications, with all abnormal results being reviewed by a histopathologist.19 the results of the pap smear were then recorded in the patient’s medical records and subsequently accessed by the investigators via the electronic hospital information systems. data were analysed using the statistical package for the social science (spss), version 20 (ibm corp., armonk, ny, usa). continuous variables were presented as means with standard deviation, while categorical variables were reported as frequencies and percentages. the prevalence of cytological abnormalities in pap smears was presented as a percentage. associations between cervical cell abnormalities and risk factors of cervical cancer were assessed using a chi-squared test. for cells with low frequencies, fisher’s exact tests were used. the level of statistical significance was set at p <0.050. this study was approved by the research and ethical review and approval committee of the ministry of health as well as the medical research ethics committee of the college of medicine & health sciences, sultan qaboos university. all participants signed a written consent form after being informed that involvement in this study would not affect their treatment. the confidentiality of the information collected was maintained at all times; moreover, the participants were aware of their right to withdraw from the study at any point. results a total of 442 women participated in this study (response rate: 100%), with an equal number of participants from khoula hospital and sultan qaboos university hospital. the mean age of the women was 39.0 ± 9.7 years, with 43.9% (n = 194) aged between 36 and 50 years, 42.3% (n = 187) aged between 21 and 35 years and 13.8% (n = 61) aged between 51 and 65 years. the vast majority (95.7%; n = 423) of the participants were married. in terms of parity, 50.5% (n = 223) had three or more children, 26.5% (n = 117) had less than three children and 23.1% (n = 102) were nulliparous. only 25 women (5.7%) reported having been pregnant before the age of 17 years. overall, 86.4% had never used hormonal contraceptives; among those who had, 35% (n = 21) reported the duration of their use to be under a year. none of the women was a smoker or had previously received the hpv vaccine. a positive family prevalence of cytological abnormalities in papanicolaou smears and risk factors for cervical cancer among women in muscat, oman 600 | squ medical journal, november 2021, volume 21, issue 4 history of cervical cancer was reported by two women (0.5%) and six women were positive for previous hpv infections (1.4%) [table 1]. based on the pap smear results, the overall prevalence rate of cervical cytological abnormalities during the study period was 3.7%. the most frequent table 1: sociodemographic characteristics and cervical cancer risk factors among omani women who underwent papanicolaou smear testing (n = 442) characteristic/risk factor n (%) age in years 21–35 187 (42.3) 36–50 194 (43.9) 51–65 61 (13.8) marital status married 423 (95.7) divorced 12 (2.7) widowed 7 (1.6) pregnancy before 17 years of age yes 25 (5.7) no 417 (94.3) hormonal contraception use yes 60 (13.6) no 382 (86.4) duration of hormonal contraception in months* <12 21 (35) 13–24 18 (30) 25–60 20 (33.3) >61 1 (1.7) number of children 0 102 (23.1) 1–3 117 (26.5) >3 223 (50.5) smoking status yes 0 (0) no 442 (100) history of hpv infection yes 6 (1.4) no 436 (98.6) vaccinated against hpv yes 0 (0) no 442 (100) family history of cervical cancer yes 2 (0.5) no 440 (99.6) hpv = human papillomavirus. *percentages for this variable have been calculated out of the total number of women who reported having ever used hormonal contraception. table 2: frequency of cervical epithelial cell abnormalities among omani women who underwent papanicolaou smear testing (n = 442) type of abnormality n (%) ascus 8 (1.8) lsil 6 (1.4) scc 2 (0.5) none 426 (96.4) ascus = atypical squamous cells of undetermined significance; lsil = low grade squamous intraepithelial lesion; scc = squamous cell carcinoma. table 3: relationship between cervical cancer risk factors and cervical epithelial cell abnormalities among omani women who underwent papanicolaou smear testing (n = 442) risk factor cervical epithelial cell abnormalities n (%) p value yes (n = 16) no (n = 426) age group in years* 21–35 9 (4.8) 178 (95.2) 0.44936–50 6(3.1) 188(96.9) 51–65 1(1.6) 60(98.4) history of hpv infection yes 2 (12.5) 4 (0.9) 0.017 no 14 (87.5) 422 (99.1) pregnancy before 17 years of age yes 0 (0) 25 (5.9) 1.000 no 16 (100) 401 (94.1) hormonal contraception use yes 1 (6.3) 60 (14.1) 0.700 no 15 (93.8) 366 (85.9) parity status primiparous/ multiparous 2 (12.5) 100 (23.5) 0.380 nulliparous 14 (87.5) 326 (76.5) family history of cervical cancer yes 0 (0) 2 (0.5) 1.000 no 16 (100) 424 (99.5) hpv = human papillomavirus. *the percentages were calculated out of the total of each age group. eman al sekri, asma al musalhi, khadija al abri, hunaina al kindi and asma a. al salmani clinical and basic research | 601 epithelial cell abnormalities were atypical squamous cells of undetermined significance (ascus; 1.8%), followed by low-grade squamous intraepithelial lesions (lsils; 1.4%) and squamous cell carcinoma (scc; 0.5%) [table 2]. the frequency of abnormal cervical cytology was significantly higher in women with previous hpv infections (p = 0.017). however, no significant association was observed between abnormal pap smear results and other risk factors for cervical cancer, including age, hormonal contraceptive use, pregnancy before the age of 17 years, a family history of cervical cancer or parity [table 3]. discussion this study aimed to detect the prevalence and characteristics of cervical epithelial cell abnormalities among omani women who underwent pap smear testing. according to the 2014 bethesda system, the overall prevalence of cervical cytological abnormalities was 3.7%.19 this rate was similar to those reported in neighbouring gulf countries, including kuwait (4.4%), saudi arabia (4.3%) and the united arab emirates (uae; 3.6%).11,12,20 comparable rates have also been reported in jordan (3.8%), turkey (2.8%) and iran (4.0%).21–23 these consistently low rates align with research that indicates that the lowest incidence of cervical cancer globally is observed in western asia.24 this is likely due to the highly conservative culture in this region, with most countries being predominantly islamic, thereby limiting the prevalence of sexual behaviours that add to the potential risk. in the current study, no cases of high-grade squamous intraepithelial lesions were noted. previous research has confirmed that ascus is the most common type of epithelial cell abnormality observed in kuwait (2.37%), the uae (2.5%) and saudi arabia (2.9%).11,12,20 however, the prevalence of ascus was much lower among omani women in the present study (1.8%). on the other hand, the rates of both lsils (1.4%) and scc (0.5%) were higher compared to studies from kuwait (0.9% and 0.09%, respectively) and southwestern saudi arabia (1.3% and 0.3%, respectively).12,25 persistent hpv infection increases the risk of progression from precancerous cervical lesions to invasive cancer.26 in the present study, a history of hpv infection was significantly associated with the risk of intraepithelial abnormalities (p = 0.017). in developed countries, the implementation of hpv vaccine programmes and cervical cytology screening has reduced cervical cancer-related mortality by 50–75% over the past 50 years.26 the world health organization recommends that women undergo cervical cancer screening at least once before the age of 45 years.27 indeed, research has shown that most epithelial cell abnormalities are diagnosed in women aged 45 years or older.28 in the present study, the mean age of the women undergoing pap smears was 39 years, thus indicating that this population was a suitable target for cervical cancer screening. however, apart from a history of hpv infection, no association was observed between intraepithelial abnormalities and the prevalence of other established risk factors for cervical cancer; this finding suggested that omani women may display different characteristics compared with other populations. for example, none of the participants was a smoker; in the gulf cooperation council region, smoking is linked to many types of cancer, including cervical cancer.29 moreover, oral contraceptive use is associated with an increased risk of developing cervical intraepithelial abnormalities.30 in contrast, no significant relationship with this variable was observed in the current study. in addition, there were no significant differences for other variables that have been traditionally linked to cervical cancer, such as a family history of the disease, pregnancy before the age of 17 years or parity. this research has some limitations, particularly with regard to its nature. the participants were recruited from two tertiary hospitals in muscat, thereby limiting the generalisability of the results on a national level. however, as these hospitals are visited by women from all over the country and the characteristics of the cohort reflected those of the general population, these concerns are negligible. in addition, collection of the cervical cell samples for cytology was done using two disparate methods (i.e. conventional and liquid-based techniques); nevertheless, there was no significant difference in sampling efficacy or analysis between the two methods. future research is recommended to investigate the suitability and cost-effectiveness of different screening methods for preventable causes of cervical cancer, such as the identification and genotyping of hpv infections. such screening may highlight the need for a national hpv vaccination programme to reduce the incidence and mortality burden of cervical cancer in oman. conclusion this study aimed to assess the prevalence of cytological abnormalities in pap smears and the risk factors for cervical cancer among a cohort of omani women. although the overall prevalence of cervical epithelial cell abnormalities was low, there was a significant prevalence of cytological abnormalities in papanicolaou smears and risk factors for cervical cancer among women in muscat, oman 602 | squ medical journal, november 2021, volume 21, issue 4 association with a history of hpv infection but not with other commonly established cervical cancer risk factors. thus, there is a need for additional research to evaluate the cost-effectiveness of preventive strategies and encourage the early detection of precancerous cervical cells. in particular, national hpv screening and vaccination programmes, which have been successfully implemented in many other countries, may represent a suitable avenue for reducing the burden of cervical cancer in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors would like to thank the deputy of research at squh and kh for their contribution and collaboration in our study and women for their participation a u t h o r s’ c o n t r i b u t i o n es, am, ka and aas conceptualised and designed the study. es, am, ka and hk collected the data. es, am, ka hk and aas analysed and interpreted the results. es, am, ka and hk drafted the manuscript. all authors reviewed the results and approved the final version of the manuscript. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2018; 68:394–424. https://doi. org/10.3322/caac.21492. 2. fidler mm, bray f, soerjomataram i. the global cancer burden and human development: a review. scand j public health 2018; 46:27–36. https://doi.org/10.1177/1403494817715400. 3. ferlay j, soerjomataram i, dikshit r, eser s, mathers c, rebelo m, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer 2015; 136:e359–86. https://doi.org/10.1002/ijc.29210. 4. ico/iarc information centre on hpv and cancer. oman: human papillomavirus and related cancers, fact sheet 2021. barcelona: hpv information centre. from: https://hpvcentre. net/statistics/reports/omn_fs.pdf accessed: sept 2020. 5. jhingran a, russel ah, seiden mv, duska lr, goodman a, lee sl, et al. cancers of the cervix, vulva, and vagina. in: niederhuber je, armitage jo, doroshow jh, kastan mb, tepper je. abeloff ’s clinical oncology, 6th ed. netherlands: elsevier, 2019. pp.1468–507. https://doi.org/10.1016/b978-14557-2865-7.00087-4. 6. ngelangel c, muñoz n, bosch fx, limson gm, festin mr, deacon j, et al. causes of cervical cancer in the philippines: a case-control study. j natl cancer inst 1998; 90:43–9. https:// doi.org/10.1093/jnci/90.1.43. 7. green j, berrington de gonzalez a, sweetland s, beral v, chilvers c, crossley b, et al. risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20–44 years: the uk national case-control study of cervical cancer. br j cancer 2003; 89:2078–86. https://doi.org/10.1038/ sj.bjc.6601296. 8. bosch fx, lorincz a, muñoz n, meijer cj, shah kv. the causal relation between human papillomavirus and cervical cancer. j clin pathol 2002; 55:244–65. https://doi.org/10.1136/ jcp.55.4.244. 9. koss lg, stewart f, foote fw, jordan mj, bader gm, day e. some histological aspects of behavior of epidermoid carcinoma in situ and related lesions of the uterine cervix. a long-term prospective study. cancer 1963; 16:1160–211. https://doi.org/1 0.1002/1097-0142(196309)16:9<1160::aid-cncr28201609 10>3.0.co;2-4. 10. ugboma haa, aburoma hls. pap smear: an important screening technique for preventing and detecting cervical cancer. continental j med res 2010; 4:13–17. http://doi. org/10.5281/zenodo.3528011. 11. ghazal-aswad s, gargash h, badrinath p, al-sharhan ma, sidky i, osman n, et al. cervical smear abnormalities in the united arab emirates: a pilot study in the arabian gulf. acta cytol 2006; 50:41–7. http://doi.org/10.1159/000325893. 12. kapila k, sharma pn, george ss, al-shaheen a, al-juwaiser a, al-awadhi r. trends in epithelial cell abnormalities observed on cervical smears over a 21-year period in a tertiary care hosp ital in kuwait. sultan qaboos univ med j 2015; 15:e112–15. 13. balaha mh, al moghannum ms, al ghowinem n, al omran s. cytological pattern of cervical papanicolaou smear in eastern region of saudi arabia. j cytol 2011; 28:173–7. http://doi. org/10.4103/0970-9371.86343. 14. cancer research uk. cervical cancer statistics. london: cancer research uk, 2020. from: https://www.cancerresearchuk.org/ health-professional/cancer-statistics/statistics-by-cancer-type/ cer vical-cancer/incidence%23heading-ten#heading-z ero accessed: sept 2020. 15. peto j, gilham c, fletcher o, matthews fe. the cervical cancer epidemic that screening has prevented in the uk. lancet 2004; 364:249–56. http://doi.org/10.1016/s0140-6736(04)16674-9. 16. siegel r, naishadham d, jemal a. cancer statistics, 2012. ca cancer j clin 2012; 62:10–29. http://doi.org/10.3322/caac.20138. 17. united nations population fund. comprehensive cervical cancer prevention and control: programme guidance for coun tries. from: https://www.unfpa.org/resources/comprehensivece r v i c a l c a n ce rp r e v e nt i o n a n d co nt r o l p r o g r a m m e guidance-countries accessed: sept 2020. 18. nasar a, waad a, atheer a, nasra a. awareness of cervical cancer and pap smear testing among omani women. asian pac j cancer prev 2016; 17:4825–30. http://doi.org/10.22034/ apjcp.2016.17.11.4825. 19. solomon d, davey d, kurman r, et al. the 2001 bethesda system: terminology for reporting results of cervical cytology. jama 2002; 287:2114–19. http://doi.org/10.1001/jama.287.16.2114. 20. al-kadri hm, kamal m, bamuhair ss, omair aa, bamefleh hs. prevalence and characteristics of abnormal papanicolaou smear in central saudi arabia. saudi med j 2015; 36:117–22. http://doi.org/10.15537/smj.2015.1.9141. 21. maraqa b, lataifeh i, otay l, badran o, nouri yq, issam i, et al. prevalence of abnormal pap smears: a descriptive study from a cancer center in a low-prevalence community. asian pac j cancer prev 2017; 18:3117–21. http://doi.org/10.22034/ apjcp.2017.18.11.3117. 22. atilgan r, celik a, boztosun a, ilter e, yalta t, ozercan r. evaluation of cervical cytological abnormalities in turkish population. indian j pathol microbiol 2012; 55:52–5. http://doi. org/10.4103/0377-4929.94856. eman al sekri, asma al musalhi, khadija al abri, hunaina al kindi and asma a. al salmani clinical and basic research | 603 23. maleki a, ahmadnia e, avazeh a, mazloomzadeh s, molaei b, jalilvand a. prevalence of abnormal papanicolaou test results and related factors among women living in zanjan, iran. asian pac j cancer prev 2015; 16:6935–9. http://doi.org/10.7314/ apjcp.2015.16.16.6935. 24. arbyn m, weiderpass e, bruni l, de sanjosé s, saraiya m, ferlay j, et al. estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. lancet glob health 2020; 8:e191–203. http://doi.org/10.1016/s2214-109x(19)30482-6. 25. elhakeem ha, al-ghamdi as, al-maghrabi ja. cytopathological pattern of cervical pap smear according to the bethesda system in southwestern saudi arabia. saudi med j 2005; 26:588–92. 26. zur hausen h. papillomaviruses and cancer: from basic studies to clinical application. nat rev cancer 2002; 2:342–50. http:// doi.org/10.1038/nrc798. 27. world health organization. the global health observatory: cervical cancer screening. geneva: world health organization. from: https://www.who.int/health-topics/cervical-cancer#tab= tab_1 accessed: sept 2020. 28. banik u, bhattacharjee p, ahamad su, rahman z. pattern of epithelial cell abnormality in pap smear: a clinicopathological and demographic correlation. cytojournal 2011; 8:8. http://doi. org/10.4103/1742-6413.80527. 29. al-zalabani ah. cancer incidence attributable to tobacco smoking in gcc countries in 2018. tob induc dis 2020; 18:18. http://doi.org/10.18332/tid/118722. 30. brabin l, barr f. oral contraceptives and cervical cancer. lancet 2002; 360:409–10. http://doi.org/10.1016/s0140-6736(02)09577-6. 1department of emergency medicine, sohar hospital, sohar, oman; departments of 2accident & emergency and 3radiology, sultan qaboos university hospital, muscat, oman; 4department of emergency medicine, armed forces hospital, muscat, oman; 5department of emergency medicine, royal hospital, muscat, oman; department of emergency medicine, royal oman police hospital, muscat, oman *corresponding author’s e-mail: a_alatbi@hotmail.com the accuracy of point-of-care ultrasound performed by emergency physicians in detecting hydronephrosis in patients with renal colic abdulaziz al-balushi,1 amal al-shibli,2 abdullah al-reesi,2 qazi zia ullah,2 waleed al-shukaili,2 saleh baawain,3 hamoud al-dhuhli,3 mohammed al-shamsi,4 ahmed al-hubaishi,5 *al yaqdhan h. al-atbi6 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 351–356, epub. 25 aug 22 submitted 18 may 21 revision req. 23 jun 21; revision recd. 17 jul 21 accepted 12 aug 21 https://doi.org/10.18295/squmj.9.2021.130 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to determine the accuracy of renal point-of-care ultrasound (pocus) performed by emergency physicians in detecting hydronephrosis in patients with renal colic. methods: this prospective cross-sectional diagnostic study was conducted at the emergency department (ed) of sultan qaboos university hospital from february 2017 to february 2018. all adult patients with suspected renal colic and who could give informed consent were included. the emergency physicians performed pocus on both kidneys and graded hydronephrosis as none, mild, moderate or severe. the pocus grade was compared to the non-contrast computed tomography (ncct) grade. results: a total of 303 participants were enrolled in the analysis. the majority of the study population comprised adult males (247 [81.5%]), and the mean age was 39 years. among the samples, 71.3% of the patients exhibited a degree of hydronephrosis based on ct findings. ultrasounds performed by emergency physicians had a sensitivity of 75.8% (95% ci: 69.5‒81.4), specificity of 55.2% (95% ci: 44.1‒65.8), a positive likelihood ratio of 1.69 (95% ci: 1.32‒2.16) and a negative likelihood ratio of 0.43 (95% ci: 0.32‒0.59) for hydronephrosis using ct as the criterion standard. conclusion: when evaluating patients with suspected renal colic, a bedside renal pocus performed by emergency physicians has a moderate sensitivity to detect hydronephrosis and grade its severity. therefore, it should be utilised in the ed to screen patients for hydronephrosis; however, more training is required to improve the test’s accuracy. keywords: hematuria; hydronephrosis; nephrolithiasis; point-of-care testing; renal colic; ultrasonography; oman. advances in knowledge renal point-of-care ultrasound (pocus) performed by emergency physicians demonstrates moderate sensitivity in detecting hydronephrosis in patients who present to the emergency department with renal colic. there is no correlation between the severity of hydronephrosis and ureteric jet. application to patient care renal pocus is a quick, non-invasive, easily available and safe bedside diagnostic tool for renal stones. renal pocus allows emergency physicians to improve their diagnostic accuracy and disposition and provide better overall patient care. rapid screening for hydronephrosis in the emergency department using renal pocus might exclude obstruction, help focus assessment on other potential diagnoses and allow physicians to select patients for further analyses. urinary tract stones are common among the general population. around 12% of the population will have urinary tract stones during their lifetime.1 in the usa, a survey revealed an increase in the prevalence of renal stones among the population between 1980 and 2014.2 additionally, acute renal colic is one of the common manifestations encountered in the emergency department (ed). in this regard, reports have shown that around 1–2 million ed visits per year in the usa are due to renal colic.2–4 it is described as a sudden onset of severe flank pain that radiates to the groin. this pain is usually caused by a ureteric stone.5 hydronephrosis is defined as the dilatation of the renal pelvis and calyces. it is an indirect sign of distal obstruction in the urinary tract system.6 based on severity, hydronephrosis is categorised into four grades: none, mild, moderate and severe.7 mild hydronephrosis is defined as the dilation of the renal pelvis only. moderate hydronephrosis is defined as the dilatation of the pelvi-calyceal system without renal cortical thinning. severe hydronephrosis is defined as the dilatation of the pelvi-calyceal system associated with cortical thinning.7–9 non-contrast computed tomography (ncct) is considered the gold standard for the diagnosis of urolithiasis and hydronephrosis in ed patients.10–12 however, it is costly and time consuming and exposes patients to significant doses of radiation.13 in contrast, point-of-care ultrasound (pocus) is a non-invasive, https://creativecommons.org/licenses/by-nd/4.0/ the accuracy of point-of-care ultrasound performed by emergency physicians in detecting hydronephrosis in patients with renal colic 352 | squ medical journal, august 2022, volume 22, issue 3 easily available, quick and safe bedside procedure that does not pose any radiation risk.14 furthermore, it allows emergency physicians (ep) to improve their diagnostic accuracy and disposition and provide better overall patient care.14 rapid ed screening for hydronephrosis and absence of ureteric jet might exclude obstruction and help focus assessment on other potential diagnoses and might allow the selection of patients for further analyses. the literature supporting the use of ultrasound by eps to detect hydronephrosis has been growing. studies have demonstrated promising results regarding the sensitivity and specificity of renal pocus performed by eps in detecting hydronephrosis. the sensitivity ranges from 72% to 80% and the specificity ranges from 73% to 83%.15–17 when the urine reaches the terminal portion of the ureter, it gets ejected forcefully into the urinary bladder through the vesicoureteric junction (vuj). the visualisation of the urine efflux using colour doppler ultrasound from the distal end of each ureter into the urinary bladder is called the ureteric jet.18 studies have demonstrated that there is a direct relationship between ureteric jet and the presence of obstructing ureteric stones.19–21 one such study showed that the ureteric jet in an obstructed ureter has less frequency, shorter duration and lower peak velocity when compared with the contralateral normal side.20 nevertheless, the study determined that the presence of a ureteric jet did not rule out significant ureteric obstruction.21 primarily, this study aimed to investigate the accuracy of renal pocus performed by eps in detecting hydronephrosis in patients with renal colic. additionally, the authors hypothesised that the presence of high-grade hydronephrosis indicates an obstructive ureteric stone, which will result in the absence of a ureteric jet. therefore, the study’s secondary aim was to assess the correlation between ureteric jet and the severity of hydronephrosis. methods a prospective cross-sectional diagnostic study was conducted at the ed of sultan qaboos university hospital (squh) from february 2018 to february 2019. squh is a tertiary academic hospital with an annual ed visit of more than 60,000 patients. the study included all adult patients who were suspected to have renal colic, were aged more than 18 years old, were not known to have a renal disease (chronic kidney disease, polycystic kidney disease, etc.), were not enrolled previously in the study, had renal ncct done within 24 hours after bedside ultrasound and gave written consent to be included in the study. the study excluded pregnant patients, female patients aged less than 40 years old and patients who were not able/refused to give consent. the reason female patients aged less than 40 years old were excluded is that the ed protocol for them mandates doing departmental ultrasound as the first step rather than renal ncct. the sample size was calculated based on previous studies that reported the incidence of renal colic. using a confidence interval of 95%, the sample size was estimated to be 300 participants. all scans were done by pocus-certified eps. an extra one-hour renal pocus session was conducted for all providers prior to the start of the study to achieve agreement regarding the labelling and degree of hydronephrosis. the level of those physicians varied between emergency residents, specialists and consultants. after obtaining consent, the eps performed renal pocus on both kidneys using a low-frequency (2-5 mhz) curvilinear probe. the severity of hydronephrosis was then classified as none, mild, moderate or severe [figure 1]. then, the renal pocus grade was compared to the ncct grade, which was interpreted by a senior radiologist blinded to the renal pocus results. the ncct was performed less than 24 hours from the pocus. the flow chart of the study was distributed to the triage nurses, emergency doctors and radiology technicians [figure 2]. the ultrasound images and videos were saved and reviewed by an independent investigator who is an emergency medicine consultant and pocus instructor. this review aimed to ensure that the operators were obtaining the optimum images of the kidneys. after the review, feedback was delivered to individual operators about their performance. the data collection sheet included information on patient demographics, the level of the eps (the operators), the site of the flank pain, the presence or absence of red blood cells (rbcs) in the urine dipstick, the degree of hydronephrosis based on pocus findings and the degree of hydronephrosis based on the ncct findings. the operators identified their findings regarding the degree of hydronephrosis, marked them on the data collection sheet and then dropped the sheet in a sealed box. an independent investigator collected the data sheets later and entered them into epidata (the epidata association, odense, denmark). ncct data about the presence and degree of hydronephrosis, as well as the presence, size and abdulaziz al-balushi, amal al-shibli, abdullah al-reesi, qazi zia ullah, waleed al-shukaili, saleh baawain, hamoud al-dhuhli, mohammed al-shamsi, ahmed al-hubaishi and al yaqdhan h. al-atbi clinical and basic research | 353 location of ureteral stones, were abstracted from the dictated radiology report by an investigator blinded to the renal pocus results. the data were analysed using the statistical package for the social sciences (spss), version 22 (ibm corporation, armonk, new york, usa). ethical approval was obtained from the medical research ethics committee, college of medicine and health sciences, at sultan qaboos university. results a total of 303 participants were enrolled in the analysis. the majority of the study population comprised adult males (247 [81.5%]) and the mean age was 39 years. emergency medicine specialists performed around 67% of the renal pocus, while residents and consultants did the rest. hydronephrosis was present in 216 (71.3%) ncct scans and ureteral stones were present in 207 (68.3%) ncct reports. however, hydronephrosis without ureteral stones was noted in nine (3.0%) ncct scans [table 1]. figure 1: grading hydronephrosis severity using point-of-care ultrasound as (a) mild, (b) moderate and (c) severe. figure 2: flowchart of study procedure. pocus = point-of-care ultrasound; ct= computed tomography; ed = emergency department. table 1: characteristics of the study participants (n = 303) characteristic n (%) mean age in years 39 number of male participants 247 (81.5) haematuria in urine dipstick 234 (78.8) hydronephrosis present on renal pocus 205 (67.5) hydronephrosis present on ncct 215 (71) hydronephrosis pocus grade none 87 (28.7) mild 78 (25.7) moderate 138 (45.5) severe 0 (0.0) ureteral stone present on ncct 207 (68.3) hydronephrosis without ureteral stone on ncct 9 (3.0) ureteric jet present 135 (44.6) absent 168 (55.5) pocus = point-of-care ultrasound; ncct = non-contrast computed tomography. table 2: sensitivity, specificity and likelihood ratio for the presence of hydronephrosis; comparing bedside renal point-of-care ultrasound to non-contrast computed tomography overall population sensitivity: 75.8% (95% ci: 69.5–81.4) positive likelihood ratio: 1.69 (95% ci: 1.32–2.16) specificity: 55.2% (95% ci: 44.1–65.8) negative likelihood ratio: 0.43 (95% ci: 0.32–0.59) mild hydronephrosis sensitivity: 58.33% (95% ci: 44.88%–70.93%) positive likelihood ratio: 1.49 (95% ci: 1.052.10) specificity: 60.76% (95% ci: 49.12%–71.56%) negative likelihood ratio: 0.68 (95% ci: 0.48–0.97) moderate hydronephrosis sensitivity: 64.93% (95% ci: 53.21%–75.46%) positive likelihood ratio: 4.54 (95% ci: 2.34–8.81) specificity: 85.71% (95% ci: 73.78%–93.62%) negative likelihood ratio: 0.41 (95% ci: 0.30–0.65) the accuracy of point-of-care ultrasound performed by emergency physicians in detecting hydronephrosis in patients with renal colic 354 | squ medical journal, august 2022, volume 22, issue 3 furthermore, 21% of the participants were found to have negative rbcs on urine dipstick despite the presence of renal stones in ncct. the mean time between the renal pocus and ncct scan was four hours. figure 3 displays the characteristics of any hydronephrosis on pocus compared with any hydronephrosis on ncct, using the standards for reporting of diagnostic accuracy (stard) format.22 on the other hand, hydronephrosis detected on renal pocus exhibited 75.8% sensitivity and 55.2% specificity, with a positive likelihood ratio of 1.69 (95% ci: 1.32‒2.16) and a negative likelihood ratio of 0.43 (95% ci: 0.32‒0.59), using hydronephrosis on ncct as the criterion standard. patients with mild hydronephrosis had a sensitivity of 58.33% (95% ci 44.88–70.93%), whereas patients with moderate hydronephrosis had a sensitivity of 64.93% (95% ci 53.21–75.46%) [table 2]. although five cases were labelled as severe hydronephrosis on pocus, none were found on ncct. based on the ncct findings, 87 participants (28.7%) had no hydronephrosis, while 78 (25.7%) and 138 (45.5%) patients had mild and moderate hydronephrosis, respectively [table 2]. the ureteric jet was absent in 74.2% of patients who had hydronephrosis and ureteric stones on ncct. the absence of ureteric jet was observed in 51.1% of patients with mild hydronephrosis and 64.6% of patients with moderate hydronephrosis. discussion the findings of this study demonstrated that around two-thirds of patients who presented to the ed with the signs and symptoms of renal colic had hydronephrosis on ncct. this was slightly higher than a prospective study of 670 patients which reported that the rate of hydronephrosis among patients with acute renal colic was 47.5%.16 in the current study, the sensitivity of renal pocus performed by eps was 75.8% (95% ci: 69.5‒81.4), which aligned with the findings of previous studies.15,23 in this regard, herbst et al. studied 670 patients with renal colic and found that the sensitivity to detect hydronephrosis was 72.6% when performed by eps.16 notably, in that study, the sensitivity of renal pocus improved as the degree of hydronephrosis increased. furthermore, the current study demonstrated that renal pocus has a specificity of 55.2% (95% ci: 44.1‒65.8) in detecting hydronephrosis when performed by eps. this result varied from previous studies that reported the specificity of renal pocus to be ranging from 60% to 83%.7,15,16 this variation can be attributed to the experience level of the ultrasound operator and the ultrasonic findings that mimic hydronephrosis. for instance, 32 (10%) participants in the current study were found to have cases such as extra-renal pelvis and cysts that mimic hydronephrosis and were thus interpreted as hydronephrosis. to the best of the authors’ knowledge, there are no previously published studies that examine the relationship between the degree of hydronephrosis and the ureteric jet. in this regard, the study found that no direct relationship is present between the grade of hydronephrosis and ureteric jet. among patients who were identified to have moderate hydronephrosis in the ncct scan (100 patients), ureteric jet was present in 58% and absent in 42%. the absence of microscopic haematuria does not eliminate renal colic as a potential diagnosis. in this sense, haematuria was not present in 21% of participants who had renal stones on ct scans. this finding aligns with those of previously published studies.24,25 this study has a few limitations. first, although the mean time between performing the pocus and the renal ncct was four hours, there were several cases figure 3: a diagram of test characteristics of any hydronephrosis on ultrasonography compared with any hydronephrosis on ct. pocus = point-of-care ultrasound; ncct = non-contrast computed tomography. abdulaziz al-balushi, amal al-shibli, abdullah al-reesi, qazi zia ullah, waleed al-shukaili, saleh baawain, hamoud al-dhuhli, mohammed al-shamsi, ahmed al-hubaishi and al yaqdhan h. al-atbi clinical and basic research | 355 where the ncct scan was done around 10–12 hours after having renal pocus done. hence, maintaining a constant time frame between performing the renal pocus and the ncct will eliminate the possibility of change in the degree of hydronephrosis from mild hydronephrosis to no hydronephrosis and vice versa. second, all the operators underwent a one-hour ultrasound training session only, including a lecture and hands-on practice. increasing the duration of the training session might improve the sensitivity and specificity. third, the study was conducted at squh, which is one of the major academic tertiary hospitals in the country and pocus was introduced earlier to the ed than in other hospitals. therefore, it is difficult to generalise the study outcomes to all other hospitals. conclusion when evaluating patients with suspected renal colic, a bedside renal pocus performed by eps has a moderate sensitivity to detect hydronephrosis and grade its severity. therefore, the utilisation of pocus in the ed to screen patients for hydronephrosis is recommended. furthermore, there is no correlation between the severity of hydronephrosis and ureteric jet. more training and interventional studies are required to improve the accuracy of the test at squh, as it might serve as a helpful screening tool in the ed. a u t h o r s’ c o n t r i b u t i o n s ab, as, ar, hd, ms and ah conceptualised and designed the study. as and ms provided a training session to the investigators of the study. qz and ws collected the data. ws performed the statistical analysis. ab, ar, sb and ah analysed and interpreted the data. ab and as drafted the manuscript. ar, ms and aa critically revised the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. teichman jmh. clinical practice. acute renal colic from ureteral calculus. n engl j med 2004; 350:684–93. https://doi.org/10.10 56/nejmcp030813. 2. feit l, john d, delgado torres n, sinert r. flank pain and hematuria is not always a kidney stone. am j emerg med 2021; 40:225.e1–2. https://doi.org/10.1016/j.ajem.2020.07.046. 3. schoenfeld em, shieh m-s, pekow ps, scales cd, munger jm, lindenauer pk. association of patient and visit characteristics with rate and timing of urologic procedures for patients discharged from the emergency department with renal colic. jama netw open 2019; 2: e1916454. https://doi.org/10.1001/ jamanetworkopen.2019.16454. 4. daniels b, gross cp, molinaro a, singh d, luty s, jessey r, et al. stone plus: evaluation of emergency department patients with suspected renal colic, using a clinical prediction tool combined with point-of-care limited ultrasonography. ann emerg med 2016; 67:439–48. https://doi.org/10.1016/j. annemergmed.2015.10.020. 5. clinicalkey. nephrolithiasis. from: https://www.clinicalkey. co m / # ! / co n t e n t / b o o k / 3 s 2 . 0 b 9 7 8 1 4 5 5 7 5 3 5 9 8 0 0 0 0 8 0 accessed: jul 2021. 6. thotakura r, anjum f. hydronephrosis and hydroureter. in: statpearls [internet]. treasure island, usa: statpearls publishing, 2020. from: http://www.ncbi.nlm.nih.gov/books/ nbk563217/ accessed: jul 2021. 7. pathan sa, mitra b, mirza s, momin u, ahmed z, andraous lg, et al. emergency physician interpretation of point-of-care ultrasound for identifying and grading of hydronephrosis in renal colic compared with consensus interpretation by emergency radiologists. acad emerg med 2018; 25:1129–37. https://doi. org/10.1111/acem.13432. 8. onen a. grading of hydronephrosis: an ongoing challenge. front pediatr 2020; 8:458. https://doi.org/10.3389/fped.2020.0 0458. 9. nguyen ht, benson cb, bromley b, campbell jb, chow j, coleman b, et al. multidisciplinary consensus on the classif ication of prenatal and postnatal urinary tract dilation (utd classification system). j pediatr urol 2014; 10:982–98. https:// doi.org/10.1016/j.jpurol.2014.10.001. 10. fulgham pf, assimos dg, pearle ms, preminger gm. clinical effectiveness protocols for imaging in the management of ureteral calculous disease: aua technology assessment. j urol 2013; 189:1203–13. https://doi.org/10.1016/j.juro.2012.10.031. 11. brisbane w, bailey mr, sorensen md. an overview of kidney stone imaging techniques. nat rev urol 2016; 13:654–62. https://doi.org/10.1038/nrurol.2016.154. 12. coursey ca, casalino dd, remer em, arellano rs, bishoff jt, dighe m, et al. acr appropriateness criteria® acute onset flank pain--suspicion of stone disease. ultrasound q 2012; 28:227–33. https://doi.org/10.1097/ruq.0b013e3182625974. 13. nicolau c, claudon m, derchi le, adam ej, nielsen mb, mostbeck g, et al. imaging patients with renal colic—consider ultrasound first. insights imaging 2015; 6:441–7. https://doi. org/10.1007/s13244-015-0396-y. 14. kim sg, jo ij, kim t, hwang sy, park jh, shin tg, et al. usefulness of protocolized point-of-care ultrasonography for patients with acute renal colic who visited emergency department: a randomized controlled study. medicina (kaunas) 2019; 55:717–28. https://doi.org/10.3390/medicina55110717. 15. watkins s, bowra j, sharma p, holdgate a, giles a, campbell l. validation of emergency physician ultrasound in diagnosing hydronephrosis in ureteric colic. emerg med australas 2007; 19:188–95. https://doi.org/10.1111/j.1742-6723.2007.00925.x. 16. herbst mk, rosenberg g, daniels b, gross cp, singh d, molinaro am, et al. effect of provider experience on clinicianperformed ultrasonography for hydronephrosis in patients with suspected renal colic. ann emerg med 2014; 64:269–76. https://doi.org/10.1016/j.annemergmed.2014.01.012. 17. moak jh, lyons ms, lindsell cj. bedside renal ultrasound in the evaluation of suspected ureterolithiasis. am j emerg med 2012; 30:218–21. https://doi.org/10.1016/j.ajem.2010.11.024. https://doi.org/10.1056/nejmcp030813 https://doi.org/10.1056/nejmcp030813 https://doi.org/10.1016/j.ajem.2020.07.046 https://doi.org/10.1001/jamanetworkopen.2019.16454 https://doi.org/10.1001/jamanetworkopen.2019.16454 https://doi.org/10.1016/j.annemergmed.2015.10.020 https://doi.org/10.1016/j.annemergmed.2015.10.020 https://doi.org/10.1111/acem.13432 https://doi.org/10.1111/acem.13432 https://doi.org/10.3389/fped.2020.00458 https://doi.org/10.3389/fped.2020.00458 https://doi.org/10.1016/j.jpurol.2014.10.001 https://doi.org/10.1016/j.jpurol.2014.10.001 https://doi.org/10.1016/j.juro.2012.10.031 https://doi.org/10.1038/nrurol.2016.154 https://doi.org/10.1097/ruq.0b013e3182625974 https://doi.org/10.1007/s13244-015-0396-y https://doi.org/10.1007/s13244-015-0396-y https://doi.org/10.3390/medicina55110717 https://doi.org/10.1111/j.1742-6723.2007.00925.x https://doi.org/10.1016/j.annemergmed.2014.01.012 https://doi.org/10.1016/j.ajem.2010.11.024 the accuracy of point-of-care ultrasound performed by emergency physicians in detecting hydronephrosis in patients with renal colic 356 | squ medical journal, august 2022, volume 22, issue 3 18. leung vy, chu wc, yeung c, metreweli c. doppler waveforms of the ureteric jet: an overview and implications for the presence of a functional sphincter at the vesicoureteric junction. pediatr radiol 2007; 37:417–25. https://doi.org/10.1007/s00247-007-0433-1. 19. de bessa j, dénes ft, chammas mc, cerri l, monteiro eds, buchpiguel ca, et al. diagnostic accuracy of color doppler sonographic study of the ureteric jets in evaluation of hydro nephrosis. j pediatr urol 2008; 4:113–7. https://doi.org/10.10 16/j.jpurol.2007.10.013. 20. jandaghi ab, falahatkar s, alizadeh a, kanafi ar, pourghorban r, shekarchi b, et al. assessment of ureterovesical jet dynamics in obstructed ureter by urinary stone with color doppler and duplex doppler examinations. urolithiasis 2013; 41:159–63. https://doi.org/10.1007/s00240-012-0542-7. 21. kuzmić ac, brkljacić b, rados m, galesić k. doppler visual ization of ureteric jets in unilateral hydronephrosis in children and adolescents. eur j radiol 2001; 39:209–14. https://doi. org/10.1016/s0720-048x(01)00329-1. 22. bossuyt pm, reitsma jb, bruns de, gatsonis ca, glasziou pp, irwig lm, et al. towards complete and accurate reporting of studies of diagnostic accuracy: the stard initiative. clin radiol 2003; 58:575–80. https://doi.org/10.1016/s0009-9260(03)00258-7. 23. riddell j, case a, wopat r, beckham s, lucas m, mcclung cd, et al. sensitivity of emergency bedside ultrasound to detect hydro nephrosis in patients with computed tomography-proven stones. west j emerg med 2014; 15:96–100. https://doi.org/10.5811/ westjem.2013.9.15874. 24. leslie sw, sajjad h, murphy pb. renal calculi. in: statpearls [internet]. treasure island, usa: statpearls publishing. from: http://www.ncbi.nlm.nih.gov/books/nbk442014/ accessed: jul 2021. 25. mefford jm, tungate rm, amini l, suh d, anderson cl, rudkin se, et al. a comparison of urolithiasis in the presence and absence of microscopic hematuria in the emergency department. west j emerg med 2017; 18:775–9. https://doi. org/10.5811/westjem.2017.4.33018. https://doi.org/10.1007/s00247-007-0433-1 https://doi.org/10.1016/j.jpurol.2007.10.013 https://doi.org/10.1016/j.jpurol.2007.10.013 https://doi.org/10.1007/s00240-012-0542-7 https://doi.org/10.1016/s0720-048x(01)00329-1 https://doi.org/10.1016/s0720-048x(01)00329-1 https://doi.org/10.1016/s0009-9260(03)00258-7 https://doi.org/10.5811/westjem.2013.9.15874. https://doi.org/10.5811/westjem.2013.9.15874. ttps://doi.org/10.5811/westjem.2017.4.33018 ttps://doi.org/10.5811/westjem.2017.4.33018 1national oncology centre and departments of 4pediatric hematology & oncology and 5histopathology, the royal hospital, muscat, oman; departments of 2pediatrics and 3epidemiology, oman medical speciality board, muscat, oman *corresponding author’s e-mail: abeer_albattashi@hotmail.com neuroblastoma among omani children clinical characteristics and survival outcome from a dedicated centre *abeer al-battashi,1 ameera al-rahbi,2 abdulhakeem al-rawahi,3 mohammed mamdouh,4 ibrahim al-ghaithi,4 fatma a. ramadhan5 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 578–584, epub. 25 nov 21 submitted 2 may 20 revisions req. 26 jul & 27 sep 20; revisions recd. 25 aug & 18 oct 20 accepted 25 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.032 clinical & basic research abstract: objectives: a limited number of publications from the middle east have focused on neuroblastoma, a common childhood malignancy. this study describes the clinical characteristics and survival outcome of omani children with neuroblastoma treated at the national oncology centre, oman, between 2010 and 2017. methods: from january 2010 to december 2017, data on omani children aged less than 13 years with neuroblastoma were retrospectively collected. survival data were statistically correlated with known prognostic factors, including age, stage of disease, mycn profile and presence of metastasis. results: a total of 56 omani children were included. in this study. the male to female ratio was 1:1. the mean age at presentation was one year and 10 months. the two most common presenting complaints were body masses (48.2%) and constitutional symptoms (33.9%). approximately, 54.5% were high risk, 35.7% were intermediate risk and 9.8% were low risk. high-risk neuroblastoma was mainly found in children older than one year (76.6%), with low risk mainly observed in children less than one year of age (80%). the overall survival of all groups combined was 74% (p <0.05); the event-free survival (efs) was 67% (p <0.05). the overall survival rates over five years for the high-risk, intermediate-risk and low risk groups were 60%, 88% and 100%, respectively, and the efs was 51%, 79% and 100%, respectively. conclusion: omani children with neuroblastoma mainly presented with masses or constitutional symptoms and had an advanced disease at presentation which was associated with inferior survival. the survival outcomes were reasonably similar to published international data. keywords: neuroblastoma; survival; event-free survival; oman. advances in knowledge the survival of omani patients with neuroblastoma is similar to that of other patients in developed countries despite the considerable challenges. this study highlights the characteristics and management of childhood neuroblastoma in oman; this information can help to consolidate evidence-based interventions and formulate individualised guidelines for developing countries. a higher percentage of opsoclonus myoclonus ataxia syndrome as a presentation of neuroblastoma was observed compared to what has been reported in other publications. omani patients with neuroblastoma are mainly from the muscat and al-batinah regions which corresponds to the population distribution. application to patient care understanding the clinical presentation of neuroblastoma among omani children can help in ensuring early detection and improved outcomes. elaborating the treatment journey that omani children with neuroblastoma undertake using current, standard international management guidelines can be useful. predicting the outcome based on the stage of the disease upon presentation can be useful. neuroblastoma is an extracranial embryonal tumour that mainly affects children, especially those less than five years of age.1 it has a challenging treatment protocol and diverse clinical presentations. neuroblastoma can originate from primitive cells of the sympathetic nervous system in any location in the body.1 typically, it occurs in the adrenal medulla or the paraspinal ganglia. neuroblastoma rarely occurs in adult patients and an increasingly scarce incidence has been noticed in the elderly population.2 when neuroblastoma is suspected, an instant biopsy for histopathological and molecular genetic assessment needs to be performed. other supportive diagnostic tests include urine catecholamines, serum ferritin, lactate dehydrogenase and neuron-specific enolase.3 once the tissue diagnosis is established, patients go through staging with bone marrow assessment and nuclear and cross-sectional imaging to identify distant metastases. neuroblastoma tends to metastasise to different sites, commonly the bone and bone marrow.³ on rare occasions, it can spread to other sites, including the brain.4 abeer al-battashi, ameera al-rahbi, abdulhakeem al-rawahi, mohammed mamdouh, ibrahim al-ghaithi and fatma a. ramadhan clinical and basic research | 579 the treatment of neuroblastoma relies on a constellation of specific factors: age, stage, pathology and molecular biology.5 in accordance with the international neuroblastoma staging system (inss), cases are classified into one of six stages: 1, 2a, 2b, 3, 4 or 4s.5 in 2009, a newer classification system, the international neuroblastoma risk group (inrg), was established to risk stratify patients into different subgroups based on clinical and prognostic implications.6 it grouped patients into very low risk (benign histology), low risk, intermediate risk and high-risk categories based on combinations of certain prognostic markers, including the age of the patient (more or less than 18 months), histopathological differentiation and certain biological markers, including mycn amplification, 11q deletion and the presence of ploidy.7 depending on the risk stratification of the disease, patients undergo either surgery and observation if categorised as low-risk or a lengthy and intense journey of therapy for high-risk individuals. the treatment of high-risk patients includes almost all of the modalities used in the treatment of cancer to date, including conventional chemotherapy, surgery, radiotherapy, autologous bone marrow transplant, immunotherapy and maturation therapy (13-cis retinoic acid).3 in the uk, neuroblastoma accounted for 6% of the total new cancer cases in children between 2001 and 2015 with a five-year overall survival rate of 71% from 2011 to 2015.8 in the usa, the five-year overall survival of the high-risk group was approximately 50% compared to more than 95% for the lowand intermediate-risk groups.9 epidemiological records regarding neuroblastoma in the developing world, specifically the middle east, are scarce. in 2015, a study from egypt showed that 76.7% of patients had stage 4 disease and the majority were older than one year of age (75.8%).10 in 2015, a saudi study of 32 years’ worth of data revealed that high-risk children were also the majority (47.6%) and had the worst survival rates.11 meanwhile, in a 32-year retrospective study from iran, most of the children (54%) were in the advanced stage with a 10-year overall survival rate of approximately 58%.12 overall, these findings highlighted that the main challenge in neuroblastoma cases in the developing world is the failure of early detection. oman is a country on the south-eastern coast of the arabian peninsula with a population of approximately 4.5 million.13 in oman, children aged less than 13 years with solid tumours receive treatment at the national oncology centre, the only oncology centre in the capital of muscat for the treatment of paediatric solid tumours. children with different malignancies share the diagnostic and treatment resources with their adult counterparts. this study retrospectively analysed the initial clinical presentation of omani children with neuroblastoma and the survival outcomes in relation to other prognostic factors which were previously established by recognised international studies.1,3,5–7 the main challenges faced in the management of neuroblastoma in oman have also been discussed and some recommendations to improve the outcomes of patients with an aggressive form of the disease have been provided. table 1: characteristics of omani children with neuro blastoma presenting to and treated at the national oncology centre, oman between 2010 and 2017 (n = 56) characteristic n (%) gender male 28 (50.0) female 28 (50.0) age in weeks mean 174.7 median 102.1 range 2–573.6 histopathology favourable 11 (19.6) unfavourable 26 (46.4) inconclusive 19 (34.0) stage 1 4 (7.1) 2 2 (3.5) 3 14 (25) 4 31 (55.4) 4s 5 (9.0) mycn positive 5 (9.0) negative 10 (17.8) not done 41 (73.2) clinical presentation body masses 27 (48.2) constitutional 19 (33.9) gastrointestinal 15 (26.8) neurological 15 (26.8) respiratory 5 (8.9) neuroblastoma among omani children clinical characteristics and survival outcome from a dedicated centre 580 | squ medical journal, november 2021, volume 21, issue 4 methods data were collected from the royal hospital alshifa patient electronic record system and inputted into a microsoft excel (microsoft corp., redmond, washington, usa) data collection sheet. records of all paediatric patients who were diagnosed with neuroblastoma between 2010 and 2017 were obtained from the medical records department. the data were collected exclusively by the study investigators. the diagnosis of neuroblastoma was established with a histological confirmation of the diagnosis following the world health organization’s (who) classification and staging based on the union for international cancer control (uicc). the mycn amplification was considered positive if neoplastic cells exhibited more than 10 copies using fluorescent in situ hybridisation. staging and risk stratification was done based on the inss and inrg.5,6 in the absence of the mycn testing, risk stratification followed the rest of the parameters in the previously mentioned classification system. all mycn profiling and autologous bone marrow transplants were done in centres outside the country due to their local unavailability. patients older than 13 years of age during diagnosis, patients who abandoned treatment, benign histology cases (very low risk) and patients of non-omani nationality were excluded from the study cohort. for statistical analysis, the statistical package for the social sciences (spss), version 22 (ibm corp., armonk, new york, usa) was used. categorised variables were described as percentages and continuous variables were presented as a mean with standard deviation or a median. proportions were presented as percentages with a 95% confidence interval. the survival rate was illustrated using kaplan mayer survival curves. events for the event-free survival (efs) were relapses, and those for overall survival (os) were deaths. this research was granted ethical approval by the research and ethical review and approval committee of the ministry of health, oman (src#28/2018). results a total of 56 patients were included in this retrospective analysis. the male to female ratio was 1:1. the regional distribution of the patients within oman showed that most patients (35.7%) were from al-batinah, followed by muscat (23.2%), while only 1.8% were from alwusta [figure 1]. this corresponded to the fact that 50% of the population of oman lives in muscat and the al-batinah coastal plain northwest of the capital.7 the mean age at presentation was three years and three months, with ages ranging from two weeks to a maximum of 11 years. children were categorised into three age groups: less than one year of age, as they had shown a better outcome compared to older children in previous studies; one to three years of age; and more than three years old.14 patients were also distributed homogenously for significant statistical comparisons. children were almost equally distributed among the different age groups: 33.9% were less than one year of age, 33.9% were between one and three years of age and the remaining 32.1% were more than three years of age. patients were distributed into different inss groups to determine the appropriate treatment. overall, figure 1: regional distribution of omani children less than 13 years of age with neuroblastoma presenting to and treated at the national oncology centre, oman between 2010 and 2017 (n = 56). figure 2: haematoxylin and eosin stains of the different known histopathological entities of neuroblastoma obtained from omani patients treated at the national oncology centre in oman. a: undifferentiated neuroblastoma at ×10 magnification showing densely packed smallto medium-sized cells that are indiscernible from a small amount of cytoplasm with vague cytoplasmic borders. b: poorly differentiated neuroblastoma at ×4 magnification showing that ≤ 5% of the tumour cells are differentiating neuroblasts. c: ganglioneuroblastoma or differentiating neuroblastoma at ×20 magnification showing that at least 5% of tumour cells are differentiating neuroblasts. d: residual neuroblastoma at ×20 magnification showing mixed histological combinations. abeer al-battashi, ameera al-rahbi, abdulhakeem al-rawahi, mohammed mamdouh, ibrahim al-ghaithi and fatma a. ramadhan clinical and basic research | 581 55.4% were from the stage 4 group, 25.0% were from the stage 3 group, 3.5% were from the stage 2 group and 7.1% were from the stage 1 group, while the 4s group accounted for 9.0% of the total number of patients [table 1]. regarding risk, 54.5% were categorised into the high-risk group, 35.7% into the intermediate-risk group and 9.8% into the low-risk group. among the high-risk group, 23.4% were less than one year of age, 43.3% were between one and three years of age and the remaining 33.3% were more than three years of age at diagnosis. for the intermediate-risk group, 55% were less than one year of age, 40% were between one and three years of age and the remaining 5% were more than three years of age. a total of 80% of the patients in the low risk group were less than one year of age. most of the patients in the high-risk category were males (63.3%), while most of the patients in the intermediateand low-risk groups were females (60% and 80%, respectively). the mean duration of symptoms from the first symptom to the first healthcare visit was approximately 5.25 weeks. although patients had one major presenting complaint upon their initial clinical encounter, they also had other associated symptoms. the two most common presenting complaints were identification of body masses (48.2%) and constitutional symptoms (33.9%). masses were specifically described as lumps that were commonly in the abdomen or neck swelling. constitutional figure 3: kaplan-meier cumulative survival curve showing (a) event-free survival and (b) overall survival for omani patients diagnosed with neuroblastoma, presenting to and treated at the national oncology centre in oman between 2010 and 2017. figure 4: kaplan-meier cumulative survival curves showing age-wise distribution of (a) event-free survival and (b) overall survival for omani patients diagnosed with neuroblastoma presenting to and treated at the national oncology centre in oman between 2010 and 2017. figure 5: kaplan-meier cumulative survival curves according to risk group stratification of (a) event-free survival and (b) overall survival for omani patients diagnosed with neuroblastoma presenting to and treated at the national oncology centre in oman between 2010 and 2017. neuroblastoma among omani children clinical characteristics and survival outcome from a dedicated centre 582 | squ medical journal, november 2021, volume 21, issue 4 symptoms included fever, lethargy, excessive crying and poor oral intake which was associated with weight loss. almost one-third of patients had racoon eye on presentation (28.6%). additionally, 26.8% had gastrointestinal complaints (e.g. diarrhoea, vomiting and/or constipation) with an equal percentage presenting with central nervous system complaints (e.g. opsoclonus myoclonus, seizures and/or lower limb weakness). the least common symptomatology was respiratory (e.g. shortness of breath) which constituted 8.9% of all presenting complaints. subtypes of neuroblastoma included neuro blastoma with opsoclonus myoclonus ataxia syndrome (omas; 14.3%) and 4s neuroblastoma (10.7%). patients with omas were predominantly females with a male to female ratio of 1:4. the most common locations were adrenal (55%), followed by paraspinal primaries (22%). stage 2 and 3 patients constituted 44.4% of the participants each. approximately, 11.2% of the participants had stage 1 disease and none had stage 4. all of the patients are currently in remission and free of neurological symptoms. favourable histology in the form of poorly differentiating or differentiating histological features was seen in 19.6% of the total number of patients [figures 2a and b]. unfavourable histology included undifferentiated neuroblastoma [figure 2c] and constituted 46.4% of the total sample included in this study. approximately, 34% of the neuroblastoma samples had inconclusive histological characterisation mainly due to a small or inadequate tissue sample size that was insufficient for proper assessment. it was observed that residual tumour pathology could reveal a combination of different histological features [figure 2d], mainly due to exposure to neoadjuvant therapy. the most common neuroblastoma site was the suprarenal glands (49%), followed by the paraspinal region (21.4%). meanwhile, 13.5% of patients had a tumour in the suprarenal gland with paraspinal extension. other sites included the mediastinum (7.1%), the pelvis and retroperitoneum (3.6%) and the head and neck (5.4%). in terms of metastasis, the bone was the most common site of involvement, detected in 41% of patients using a meta-iodobenzylguanidine (mibg) scan, a bone scan or both. the second most common site was the bone marrow (35.7%), followed by the liver (14.3%), lungs (10.7%) and brain (5.4%). treatment decisions were based on the constellation of factors making up the risk group of each patient. patients in the low-risk group were treated with observation after surgical resection. the intermediate-risk group was treated with surgical resection and four to eight cycles of chemotherapy for local control and to prevent spread. the main chemotherapy agents used included carboplatin, etop oside, vincristine, cyclophosphamide and doxorubicin. the children in the high-risk group underwent an extensive treatment regimen involving six cycles of induction chemotherapy in accordance with the high risk international treatment recommendations.3 once the remission status was established through imaging and marrow assessments, local control was resorted to in the form of surgery. only two patients in the highrisk group did not undergo surgical excision because of the tumour location (one was paraspinal and the other was maxillary). since 2012, all patients who were eligible for autologous bone marrow transplantation (abmt) using a busulfan and melphalan conditioning regimen have undergone the procedure. after abmt, patients were assessed for residual disease after which they received 13-cis retinoic acid (maturation therapy) with the incorporation of radiation therapy for local control at a dose of 21 gy. specifically, 63.3% of high-risk patients (a total of 20 patients) underwent a transplant. all patients who went through the transplant received radiotherapy. none of the patients received immunotherapy as it was not available. the five-year os and efs rates for all children during the eight-year study period were 74% and 67%, respectively [figure 3]. patients who were 12 months of age and under had excellent os and efs rates compared to the rest of the patients (p = 0.029) [figure 4]. children between one and three years of age and children older than three years of age had similar os rates of 61% and 65%, respectively [figure 4b]. however, the efs rate of children older than three years of age was 52%, while children between one and three years of age had an efs rate of 60% [figure 4a]. the high-risk group had the worst outcome among all groups with a five-year os rate of 60% and an efs rate of 51% (p = 0.029) [figure 5]. the low risk group had an excellent efs rate and an os rate of 100% for both, while for the intermediate-risk group, the os rate was 88% and the efs rate was 79% [figure 5]. discussion although neuroblastoma is a massive challenge for paediatric oncologists worldwide, this condition is especially challenging for paediatric oncologists of the developing world for several reasons. first, the affected children typically present late with progressive symptoms and an advanced stage of the disease. in the present study, the average time of presentation was 5.25 weeks which is considered significant for abeer al-battashi, ameera al-rahbi, abdulhakeem al-rawahi, mohammed mamdouh, ibrahim al-ghaithi and fatma a. ramadhan clinical and basic research | 583 such a rapidly growing malignancy. second, ensuring timely pathological diagnosis and staging (specifically, imaging procedures) can be difficult. third, gathering the proper treatment assets, especially for highrisk patients, can be a huge challenge due to a lack of resources. for example, access to high-dose chemotherapy and immunotherapy might not be possible for some children in the developing world. it has been reported that 73% of patients with neuroblastoma in sub-saharan african countries had presented with metastatic disease due to a lack of proper medical resources and staging systems.15 in oman, access to autologous stem cell transplants was ensured through private or government funds in 2012. however, the delay caused by assigning patients to treatment centres abroad and by having them travel to those centres can impact the outcomes of this already compromised patient population. the initial symptoms of neuroblastoma, like many other childhood malignancies, can be nonspecific and difficult to detect, especially in younger children and infants. in the present study, almost half of the children presented with body masses (48.2%) and almost one-third also had general constitutional symptoms (33.9%). the combination of these two symptoms is vague and hence can be missed by the primary healthcare system, especially in rural areas lacking resources for measures such as laboratory investigations and imaging. respiratory compromise due to lung or mediastinal involvement was the least common symptom in the study population (8.9%). this was supported by the fact that the lungs were found to be an uncommon site of metastasis in these patients (10.7%). according to the literature, omas is reported in approximately 2–3% of patients with neuroblastoma and is believed to be driven by a paraneoplastic autoimmune process that affects the central nervous system.16,17 in the present study, 14.3% of the patients presented with omas which was higher than the figures presented in other reports in the literature.16,17 a further study in this subset of patients is recommended to determine why omas was more common in the present sample. in relation to the inrg system, most of the patients in the present study were high-risk (55.4%); this paralleled the results of previous studies where most children presented with high-risk diseases.18–20 patients less than one year of age had excellent survival rates which can be explained by the fact that 80% of them were in the low-risk group. the inrg system was used for the patients despite the limitations of tumour genetic analysis. staging neuroblastoma requires swift access to cross-sectional and nuclear imaging and tissue examination with a proper histopathological and biological interpretation. with a significant proportion of the people of oman living in rural areas, proper risk stratification can become compromised. in the present study, 34% of the patients’ pathology reports did not classify them into the three known pathological categories: differentiated, poorly differentiated and undifferentiated. additionally, although mycn is an established prognostic factor for neuroblastoma outcomes, only 26.8% of the patients were tested. among the tested samples, 9% were found to be mycn amplified.7,21 since 2018, all omani patients who are newly diagnosed with neuroblastoma are required to get their tumours molecularly evaluated for mycn amplification in laboratories abroad. all patients in the present study who had mycn amplification had a metastatic disease upon presentation. other important biological markers include deletions of 1p or 11q and an unbalanced gain of 17q which were also not available in the current paediatric oncology treatment centre.1 the lack of proper molecular genetic assessment in these patients might have led many patients to be undertreated. this study has several limitations. first, its retrospective nature made it prone to missing information and possible inaccuracies. another drawback was the small sample size. despite being the only paediatric oncology treatment centre for solid tumours in the country, the sample might have still not represented all of the omani paediatric neuroblastoma cases due to a significant number of patients travelling abroad for treatment without seeking any local medical attention considering the significant proportion of children who live in remote areas of oman, access to oncolo gical services can be a significant challenge. in terms of treatment, the local unavailability of autologous stem cell transplant, immunotherapy and local tumour molec ular profiling can have detrimental effects on the outcomes of omani children with neuroblastoma, esp ecially among high-risk patients. previously, evaluation of the mycn profile was not done for most patients unless they were diagnosed outside the country in an institution that ran this test. the main reasons were the lack of resources and a probable misunderstanding of the significance of this test. another major challenge was the lack of adequate diagnostic material for proper pathological classification and the absence of any molecular genetics. this might have subjected the group of high-risk patients to under-treatment and a higher risk for relapse. neuroblastoma among omani children clinical characteristics and survival outcome from a dedicated centre 584 | squ medical journal, november 2021, volume 21, issue 4 conclusion the survival outcomes of omani children with neuroblastoma who were treated at the national oncology center between 2010 and 2017 were comparable to those described in the literature in developed and developing countries. despite the difficulties in diagnosis and management, the results obtained from this study were promising and comparable to published results on international cohorts and they revealed excellent outcomes for intermediateand high-risk neuroblastoma. however, it was observed that the prognosis for a highrisk disease remains rather poor. neuroblastoma appeared as non-specific clinical manifestations in the currently studied cohort. a high level of suspicion for neuroblastoma is necessary, especially in children under five years of age with an abdominal mass and/or bone pain and irritability or fever with an unknown cause. this can only be ensured through proper education of health care providers about this aggressive childhood malignancy. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n aa-b, ama-r and mm were responsible for data collection. aa-b analysed the data. far obtained the pathology data and images. ama-r and aba-r performed the statistical analysis. aa-b, ama-r and far drafted the manuscript. aa-b and ia-g reviewed the manuscript before submission. aba-r and ia-g edited the manuscript. all authors approved the final version of the manuscript. references 1. brodeur gm. neuroblastoma: biological insights into a clinical enigma. nat rev cancer 2003; 3:203–16. https://doi. org/10.1038/nrc1014. 2. suzuki m, kushner bh, kramer k, basu em, roberts s, hammond w, et al. treatment and outcome of adult-onset neuroblastoma. int j cancer 2018; 143:1249–58. https://doi. org/10.1002/ijc.31399. 3. swift cc, eklund mj, kraveka jm, alazraki al. updates in diagnosis, management, and treatment of neuroblastoma. radio graphics 2018; 38:566–80. https://doi.org/10.1148/rg.2018170132. 4. codreanu i, dasanu ca, zhuang h. neuroblastoma with a solitary intraventricular brain metastasis visualized on i-123 mibg scan. j neuroimaging 2014; 24:202–4. https://doi.org/10.11 11/j.1552-6569.2012.00754.x. 5. brodeur gm, pritchard j, berthold f, carlsen nl, castel v, castelberry rp, et al. revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. j clin oncol 1993; 11:1466–77. https://doi.org/10.1200/jco.19 93.11.8.1466. 6. monclair t, brodeur gm, ambros pf, brisse hj, cecchetto g, kaneko khm, et al. the international neuroblastoma risk group (inrg) staging system: an inrg task force report. j clin oncol 2009; 27:298–303. https://doi.org/10.1200/jco.20 08.16.6876. 7. ahmed aa, zhang l, reddivalla n, hetherington m. neuro blastoma in children: update on clinicopathologic and genetic prognostic factors. pediatr hematol oncol 2017; 34:165–85. https://doi.org/10.1080/08880018.2017.1330375. 8. national cancer registration and analysis service. childhood cancer statistics, england, annual report 2018. public health england; 2018. pp. 4–31. 9. the american cancer society. neuroblastoma survival rates by risk. from: https://www.cancer.org/cancer/neuroblastoma/detection-di agnosis-staging/survival-rates.html accessed: apr 2020. 10. al-tonbary y, badr m, mansour a, el safy u, saedd s, hassan t, et al. clinic-epidemiology of neuroblastoma in north east egypt: a 5-year multicenter study. oncol lett 2015 aug; 10:1054–62. https://doi.org/10.3892/ol.2015.3335. 11. al naqib z, ahmed a, al harbi m, al manjomi f, ullah khan z, alanazi a, et al. neuroblastoma in saudi children: a single centre experience (2006–2014). j cancer ther 2015; 6:896–905. https://doi.org/10.4236/jct.2015.610098. 12. mehdiabadi gb, arab e, rafsanjani ka, ansari s, moinzadeh am. neuroblastoma in iran: an experience of 32 years at a referral childrens hospital. asian pac j cancer prev 2013; 14:2739–42. https://doi.org/10.7314/apjcp.2013.14.5.2739. 13. national centre for statistics and information. population. from: https://data.gov.om/search?query=population accessed: mar 2020. 14. xie l, onysko j, morrison h. childhood cancer incidence in canada: demographic and geographic variation of temporal trends (1992–2010). health promot chronic dis prev can 2018 mar; 38:79–115. https://doi.org/10.24095/hpcdp.38.3.01. 15. hadley gp, van heerden j. high-risk neuroblastoma in a subsaharan african country: telling it like it is. tro doct 2017; 47:370–4. https://doi.org/10.1177/0049475517704363. 16. morales la madrid a, rubin cm, kohrman m, pytel p, cohn sl. opsoclonus-myoclonus and anti-hu positive limbic encephalitis in a patient with neuroblastoma. pediatr blood cancer 2012; 58:472–4. https://doi.org/10.1002/pbc.23131. 17. stefanowicz j, izycka-swieszewska e, drozyńska e, pienzk j, połczyńska k, czauderna p, et al. neuroblastoma and opso clonus-myoclonus-ataxia syndrome – clinical and pathological characteristics. folia neuropathol 2008; 46:176–85. 18. lucena jn, alves mts, abib scv, souza go, neves rpc, caran emm. clinical and epidemiological characteristics and survival outcomes of children with neuroblastoma: 21 years of experience at the institute de oncologia pediátrica, in são paulo, brazil. rev paul pediatr 2018; 36:254–260. https://doi. org/10.1590/1984-0462/;2018;36;3;00007. 19. tan c, sabai sm, tin as, quah tc, aung l. neuroblastoma: experience from national university health system, singapore (1987–2008). singapore med j 2012; 53:19–25. 20. parise iz, haddad br, cavalli lr. neuroblastoma in southern brazil: an 11-year study. j pediatr hematol oncol 2006; 28:82–7. https://doi/org/10.1097/01.mph.0000199601.35010.52. 21. campbell k, shyr d, bagatell r, fischer m, nakagawara a, nieto ac, et al. comprehensive evaluation of context depend ence of the prognostic impact of mycn amplification in neuro blastoma: a report from the international neuroblastoma risk group (inrg) project. pediatr blood cancer 2019; 66:e27819. https://doi.org/10.1002/pbc.27819. submitted 31 jan 22 1 revision req. 6 mar 22; revision recd. 24 apr 22 2 accepted 17 may 22 3 online-first: may 2022 4 doi: https://doi.org/10.18295/squmj.5.2022.039 5 6 post-natal anti-retroviral prophylaxis for neonates born to 7 mothers living with resistant human immunodeficiency virus 8 (hiv) infection 9 *laila s. al yazidi,1,2 philip n. britton,1,3,4 nicole gilroy,5 tony lai,1 10 alison kesson1,3,4 11 12 1infectious diseases and microbiology, the children’s hospital at westmead, 13 sydney, australia; 2sultan qaboos university, college of medicine, muscat, oman; 14 3discipline of child and adolescent health, the university of sydney, sydney, 15 australia; 4marie bashir institute for infectious diseases and biosecurity, the 16 university of sydney, sydney, australia; 5centre for infectious diseases and 17 microbiology, westmead hospital nsw, sydney, australia. 18 corresponding author’s email: lailay@squ.edu.om 19 20 abstract 21 mother-to-child transmission (mtct) accounts for the majority of new human 22 immunodeficiency virus (hiv) infections among children worldwide. post-natal 23 prophylaxis along with other preventive measures have been very successful reducing 24 transmission to babies born to mothers living with hiv infection to < 2%. single-drug 25 prophylaxis with zidovudine (zdv) is the mainstay regimen for infants in low-risk 26 transmission settings. the optimal regimen for newborns of women with anti-27 retroviral (arv)-resistant hiv is unknown. we present a baby born to a young 28 mother living with highly resistant perinatally-acquired hiv and we discuss the 29 challenges with giving postnatal arv prophylaxis to her baby given the lack of 30 dosing and safety data for many antiretroviral agents for neonates. the baby received 31 a combination of lamivudine and raltegravir for total of 6 weeks and he was not breast 32 mailto:lailay@squ.edu.om fed. he had negative hiv proviral dna pcr at 6 weeks and 3 months and a negative 33 hiv serology at 18 months of age. 34 keywords: hiv, postnatal prophylaxis, neonate, antiretroviral, resistant. 35 36 introduction 37 mother-to-child transmission (mtct) accounts for the majority of new hiv 38 infections among children.1 successful interventions to prevent mtct include using 39 a combination of antiretroviral therapy for women before and during pregnancy to 40 ensure adequate viral suppression. in addition, optimal infant postnatal antiviral 41 prophylaxis and avoidance of breast feeding play a major role in mtct prevention.2 42 these interventions have significantly reduced the rates of mtct of hiv to < 2% in 43 non-breast feeding infants and to < 5% in breast-feeding infants.1,3 as a consequence, 44 the number of hiv infection in infants have dramatically declined by 40% between 45 2003 and 20144 and it has been estimated that hiv infection was prevented in 46 approximately 22,000 cases in the united states since 1994.3 47 48 hiv drug resistance has been a major challenge for controlling hiv and reducing its 49 associated morbidity and mortality. the who hiv drug resistance report 2021 50 showed that > 10 % of adults and around 50% of infants, newly diagnosed with hiv, 51 have a virus resistant to the non-nucleoside reverse-transcriptase inhibitors (nnrtis). 52 in addition, they found that levels of resistance to nnrtis ranged between 50-97% in 53 adults failing nnrti-based first line art.5 in this case report, we discuss the 54 challenges with giving postnatal arv prophylaxis to neonates born to mothers with 55 resistant virus given the lack of dosing and safety data for neonates for many 56 antiretroviral agents. 57 58 case report 59 a term baby was born at 38 weeks of gestation to a perinatally-hiv infected 24-year-60 old mother with a highly resistant hiv strain. the mother had developed resistance 61 due to adherence issues during her treatment over many years. her virus showed 62 intermediate to high-level resistance to all commonly used nucleoside reverse 63 transcriptase inhibiters (nrti) except lamivudine which had low-level resistance, 64 high level resistance to nevirapine, and intermediate resistance to other non65 nucleoside reverse transcriptase inhibitors (nnrti). the only protease inhibitor (pi) 66 that tested susceptible was darunavir. all integrase inhibitors tested were susceptible. 67 a summary of her antiretroviral resistance profile is included in table 1. when she 68 was planning to get pregnant, she was treated with emtricitabine/tenofovir (truvada), 69 etravirine dolutegravir and darunavir / ritonavir with an undetectable viral load and 70 cd4 count between 200-300/ul through the pregnancy. the baby was born by 71 elective caesarean section at term with apgar score of 9 and 9 at 1 and 5 minutes 72 respectively. we found it challenging to provide advice on postnatal arv 73 prophylaxis given the mother’s hiv antiviral resistance and the limited dosing and 74 safety data on many arv agents for neonates. the baby received lamivudine 2 75 mg/kg/dose twice daily and raltegravir (1.5 mg/kg/dose once daily until 1 week of 76 age, 3 mg/kg/dose twice daily from 1-4 weeks of age and then 6 mg/kg/dose twice 77 daily from 4-6 weeks of age) for a combined total of 6 weeks and he was not breast 78 fed. he had a normal full blood count at 6 weeks of age. unfortunately, there was no 79 baseline hiv pcr done at the first week of life prior to commencing the antiviral 80 prophylaxis. he had a negative hiv proviral dna pcr at 6 weeks, 3, 6 and 12 81 months of age and negative hiv serology at 18 months of age. guardian consent was 82 obtained for publication purposes. 83 84 discussion 85 the strongest individual predictor of risk of mtct is the maternal plasma viral load 86 and the viral suppression was found to be the most effective way to minimize the risk 87 of perinatal transmission.2,6 all pregnant and breast feeding women living with hiv 88 infection should be given arv to optimally suppress viral replication.6,7 prevention 89 of mtct has been a real challenge in cases with arv resistance. resistant virus can 90 be transmitted to the infant during pregnancy and labour and through breast feeding.8 91 arv-resistance appears to be more common in women who acquired hiv infection 92 perinatally. despite that, a recent study from rio de janeiro, showed a high 93 prevalence rate of arv resistant hiv in 17.2% in treatment-naïve patients.6,8 so, this 94 strongly supports the need for resistance testing in pregnant women prior to initiating 95 arv to optimise strategies to avoid mtct of resistant hiv strains to the baby.8 96 97 updated us guidelines recommend that all newborns perinatally exposed to hiv 98 should receive postpartum prophylaxis with selection of the appropriate regimen 99 guided by the level of transmission risk.1,6 for ‘low risk’ groups mothers who 100 received art during pregnancy with undetectable viral load at time of delivery 4 101 weeks of zidovudine (zdv) prophylaxis can be used.1,6 however, the additional 102 benefit of infant prophylaxis may be negligible in such cases.1 there is no uniform 103 definition for a ‘high-risk’ group, but includes arv naïve pregnant woman and 104 women who received insufficient arv therapy during pregnancy resulting in a 105 detectable viral load at the time of delivery.1 a systematic review showed that 106 multidrug regimens have significantly reduced risk of hiv transmission in ‘high-risk’ 107 hiv-exposed infants however, 3 drug regimens were not superior to 2 drugs.1,6 if the 108 neonate has high risk of transmission, the updated us guidelines recommend using 109 presumptive hiv therapeutic regimen with either zdv, lamivudine (3tc) and 110 treatment doses of nevirapine (nvp) or zdv, 3tc and ral from birth for total of 6 111 weeks.6 112 113 the optimal post-natal prophylaxis for newborns of women living with arv-resistant 114 hiv is unknown.6 arv drug-resistant virus may have decreased capacity of 115 replication and transmission but perinatal transmission of multidrug-resistant virus has 116 been reported.2,6,8 two studies showed that arv-resistance does not increase the risk 117 of hiv mtct compared with sensitive hiv strains.2,8 guidelines recommend that in 118 such cases consultation with a paediatric hiv specialist before delivery should be 119 done early.6 there is no evidence that customized prophylaxis, based on maternal 120 drug resistance patterns, are more effective than standard neonatal prophylaxis.6 we 121 advocated for tailoring the postnatal prophylaxis to maternal resistance pattern 122 especially if the baby is at ‘high risk’. we customized a regimen for our patient 123 depending on his maternal viral resistance profile. we gave him raltegravir and 124 lamivudine and he tolerated them very well and they were effective. his hiv pcr at 125 6 weeks, 3 and 6 months and 18-months serology were negative. 126 127 zdv resistance does not affect the indications for use as a prophylaxis.5,9 the 128 rationale for using zdv is that the wild-type virus appeared to be mainly transmitted 129 to infants born to mothers who have mixed virus populations including low-level 130 zdv resistance.9 zdv crosses the placenta readily and it is the best for central 131 nervous system cover compared with other drugs and zdv is beneficial at eliminating 132 a potential reservoir of hiv in the neonate.6,10 133 134 there is limited data on pharmacodynamics/pharmacokinetic, safety, dosing regimen, 135 and toxicity of arv in neonates.11 there is no significant difference in adverse 136 reactions between term neonates receiving combination therapy or zdv alone.12 137 transient hematologic toxicity is the most common side effect.12 paediatric 138 formulations for some protease inhibitors like lopinavir/ritonavir (lpv/r) are 139 available however their use in neonates in the first week of life is not preferred due to 140 safety concerns. lpv/r induced-cardiotoxicity in neonates has been reported 141 previously.6,12 based on post-marketing reports of cardiotoxicity of protease 142 inhibitors, the us food and drug administration (fda) recommends that lpv/r oral 143 solution not be used in term neonates < 14 days of age.6 maraviroc (mvc) was recently 144 approved for use in infants ≥2 kg which may provide an additional option for treatment and 145 prophylaxis of newborns born to mothers with multidrug-resistant hiv-1infection. however, 146 the lack of data and risk of drug interactions of mvc may limit its role for routine use in 147 neonates.6 148 149 we decided to be guided by the maternal viral resistance profile for prophylaxis. we 150 used lamivudine and raltegravir for our patient. there is some data on raltegravir 151 dosing and safety in neonates derived from the impaact p1110 study. in this trial 152 there were no adverse effects detected in the 26 term neonates included.13 our patient 153 did not develop any skin rash or gi symptoms after receiving raltigravir. we note that 154 in december 2017 the fda approved expanded dosing in neonates for raltegravir.14 155 156 conclusion 157 in conclusion, we believe that the postnatal prophylaxis regimen for newborns born to 158 mothers with known or suspected drug resistance should be determined with 159 knowledge of the level of transmission risk and maternal hiv resistance profile 160 notwithstanding the limited therapeutic options in this vulnerable group. such infants 161 at risk of vertical hiv acquisition should also have close monitoring, optimal follow-162 up and prompt initiation of arv therapy where infection has occurred. studies 163 assessing the rates of hiv resistance among neonates are highly required. in addition, 164 more studies are urgently required to assess the efficacy and the safety of more anti-165 retroviral options that can be used for post-natal prophylaxis in babies born to mother 166 with hiv resistant virus. 167 168 author’s contribution 169 pb, ng and ak conceptualized the idea. ak provided the patient’s data. lsay 170 drafted the manuscript and tl drafted the medication dosing. pb, ng, tl and ak 171 revised the manuscript. all authors approved the final version of the manuscript. 172 173 references 174 1. beste s, essajee s, siberry g, hannaford a, dara j, sugandhi n, et al. 175 optimal antiretroviral prophylaxis in infants at high risk of acquiring hiv. pediatr 176 infect dis j. 2018;37(2):169-75. doi: 10.1097/inf.0000000000001700 177 2. teixeria m, nafea s, yeganeh n, santos e, gouvea m, joao e, et al. high 178 rates of baseline antiretroviral resistance among hiv-infected pregnant women in an 179 hiv referral centre in rio de janeiro, brazil. international journal of std & hiv. 180 2014;26(13):922-8. doi: 10.1177/0956462414562477 181 3. little km, taylor aw, borkowf cb, mendoza mcb, lampe ma, weidle pj, 182 et al. perinatal antiretroviral exposure and prevented mother-to-child hiv infections 183 in the era of antiretroviral prophylaxis in the united states, 1994–2010. pediatr 184 infect dis j 2017;36:66–71. doi: 10.1097/inf.0000000000001355 185 4. unicef children, adolescents and aids. 2014 statistics update. unicef, 186 new york. 187 5. hiv drug resistance report 2021. geneva: world health organization; 2021. 188 licence: cc by-nc-sa 3.0 igo 189 6. panel's recommendations for antiretroviral management of newborns with 190 perinatal hiv exposure or hiv infection. available at clinical info hiv.gov. 191 accessed april 2022. 192 7. who.guidelines on when to start antiretroviral therapy and on pre-exposure 193 prophylaxis for hiv. 2015.who. geneva. 194 8. yeganeh n, kerin t, ank b, watts h, camarca m, joao ec, et al. hiv 195 antiretroviral resistance and transmission in mother-infant pairs enrolled in a large 196 perinatal study. clin infect dis. 2018. 17;66(11):1770-7. doi: 10.1093/cid/cix1104 197 9. colgrove r, pitt j, chung p, welles s, japour a. selective vertical transmission of 198 hiv-1 antiretroviral resistance mutations. aids. 1998;12(17):2281-8. doi: 199 10.1097/00002030-199817000-00009 200 10. thomas s. anti-hiv drug distribution to the central nervous system. current 201 pharmaceutical design. 2004;10(12):1313-24. doi: 10.2174/1381612043384835 202 https://dx.doi.org/10.1097%2finf.0000000000001355 11. nuttall jjc. antiretroviral therapy during the neonatal period. south afr j hiv 203 med. 2015;16(1):361. 204 12. smith c, forster je, levin mj, davies j, pappas j, kinzie k, et al. serious 205 adverse events are uncommon with combination neonatal antiretroviral 206 prophylaxis: a retrospective case review. plos. 2015;10:e10127062. doi: 207 10.1371/journal.pone.0127062 208 13. clarke df, acosta ep, chain a, cababasay m, wang j, teppler h, et al. 209 impaact p1110: raltegravir pharmacokinetics and safety in hiv-1 exposed 210 neonates: dose-finding study. poster presented at: conference on retroviruses and 211 opportunistic infections. 2017 feb 13-16; washington. 2020. 1;84(1):70-7.doi: 212 10.1097/qai.0000000000002294. 213 14. fda approves expanded dosing in neonates for raltegravir. frontier science 214 foundation. https://www.frontierscience.org/news/2017/12/11/fda-approves-215 expanded-dosing-in-neonates-for-raltegravir.html last accessed july 2018. 216 https://www.frontierscience.org/news/2017/12/11/fda-approves-expanded-dosing-in-neonates-for-raltegravir.html https://www.frontierscience.org/news/2017/12/11/fda-approves-expanded-dosing-in-neonates-for-raltegravir.html table 1: mother’s antiretroviral resistance profile 217 drug class drug primary mutations secondary mutations profile nucleoside rt inhibitors zidovudine (zdv) d67g (2005) k219kn k219n (2012) l210lw m41l t215c d67g (2004) k219n (2005) l210w (2012) v118i (2012) high-level resistance lamivudine (3tc) m184v (2008) m41l (2012) l210w (2012) m41l l210lw v118i (2012) potential low-level resistance stavudine (d4t) d67g (2005) k219kn k219n (2012) l21w l74v (2004) m4il t210w (2012) t215c d67g (2004) k219n (2005) l210w (2008) m41l (2008) t215y (2004) v118i (2012) high-level resistance emtricitabine (ftc) m184v (2008) m41l (2012) l210w (2012) l210lw m4il v118i (2012) potential low-level resistance didanosine (ddi) k219v (2008) k219kn (2012) l74lv l74v (2012) l210lw l210w (2012) m4il t215c d67g (2005) l210w (2004) k219kn m41l (2004) m184v (2008) t215y (2004) v118i (2012) high-level resistance abacavir (abc) k219n (2008) k219kn (2012) l210lw l210w (2012) l74lv l74v (2012) m4il t215c d67g (2005) k219kn l210w (2004) m41l (2004) m184v (2008) t215y (2004) v118i (2012) high-level resistance tenofovir (tdf) k219kn (2012) l210lw l210w (2012) m4il t215c (2013) d67g (2005) k219kn l210w (2004) m41l (2004) t215c v118i (2012) high-level resistance nonnucleoside rt inhibitors nevirapine (nvp) h2211hy v108iv y181c v108i (2012) v108iv (2013) h221hy (2013) high-level resistance efavirenz (efv) h221hy v108iv y181c v108i (2012) v108iv (2013) h221hy (2013) intermediate resistance rilpivirine (rpv) h221hy y181c v108i (2012) h221hy (2013) intermediate resistance etravirine (etr) h221hy y181c v108i (2012) h221hy (2013) intermediate resistance protease inhibitors indinavir (idv) i47v (2008) i47iv (2013) i54v i54lv (2012) l10f l90m m46i n88d (2005) n88dg (2013) v32i (2012) v32iv (2013) d30dn (2012) d30n (2013) a71v (2008) a71av (2013) l10f (2013) l33i (2013) m36i (2005) n88g (2008) n88dg (2012) q58e (2013) high-level resistance saquinavir (sqv) i54v 154lv (2012) l90m m46i (2013) n88d (2005) n88dg (2013) d30dn (2012) d30n (2013) v32iv (2013) i47iv (2013) a71v (2008) a71av (2013) l10f (2013) l33i (2013) m36i (2005) m46i n88g (2008) n88dg (2012) l10f (2012) q58e (2013) high-level resistance tipranavir (tpv) d30n (2013) d30dn (2012) i47v (2013) i47iv (2013) i54v i54lv (2012) l90m (2013) m46i (2013) n88dg (2013) q58e v32i (2013) v32iv (2013) l90m (2012) a71v (2013) a71av (2013) l10f (2013) l33i (2013) m36i (2005) m46i n88g (2008) n88dg (2012) q58e (2013) intermediate resistance atanazavir (atv) i47v (2008) i47iv (2013) i54v i54lv (2012) l90m m46i n88d (2005) n88dg (2013) v32i (2008) v32iv (2013) d30dn (2012) d30n (2013) a71v (2013) a71av (2013) l10f (2013) l33i (2013) m36i (2005) n88d n88dg (2012) q58e high-level resistance darunavir (drv) d30n (2013) d30dn (2012) i47iv (2013) i54v (2013) i54lv (2012) l90m (2013) m46i (2013) n88dg (2013) v32i (2013) v32iv (2013) a71v (2013) a71av (2013) l10f l33i (2013) m36i (2005) n88g (2008) n88dg (2012) q58e (2013) susceptible lopinavir (lpv) i47v (2008) i47iv (2013) i54v i54lv (2012) l90m m46i v32i (2008) v32iv (2013) d30dn (2012) d30n (2013) n88dg (2013) a71v (2008) a71av (2013) l10f l33i (2013) m36i (2005) n88g (2008) n88dg (2012) q58e (2013) intermediate resistance nelfinavir (nfv) d30n d30dn (2012) i47v (2008) i47iv (2013) i54v i54lv (2012) l10f l90m m46i n88d n88dg (2013) v32i (2008) v32iv (2013) a71v (2008) a71av (2013) l10f (2013) l33i (2013) m36i (2005) n88g (2008) n88dg (2012) q58e high-level resistance fosamprenavir (fpv) i54v i54lv (2012) i47v (2008) i47iv (2013) l10f l90m m46i v32i (2008) v32iv (2013) d30dn (2012) d30n (2013) n88dg (2013) a71v (2008) a71av (2013) l10f (2013) l33i (2013) m36i (2005) n88g (2008) n88dg (2012) q58e (2013) intermediate resistance integrase inhibitor dolutegravir (dtg) susceptible elvitegravir (evg) susceptible raltegravir (ral) susceptible 218 table 2: antiretroviral drug dosing for neonates 219 drug doses note 1 zidovudine (zdv)  ≥ 35 weeks’ gestation at birth: 0 4 weeks of age: 4mg/kg/dose po twice daily age > 4 weeks: 12 mg/kg/ dose po twice daily (increase dose in cases of confirmed hiv infection only)  30 < 35 weeks’ gestation at birth age 0 – 2 weeks: 2mg/kg/dose po twice daily age 2 – 6 weeks: 3mg/kg/dose po twice daily age > 68 weeks: 12 mg/kg/dose po twice daily (increase dose in cases of confirmed hiv infection only)  < 30 weeks’ gestation at birth age 0 – 4 weeks: 2mg/kg/dose po twice daily age 4 – 8 weeks: 3mg/kg/dose po twice daily age > 8 – 10 weeks: 12 mg/kg per dose po twice daily (increase dose in cases of confirmed hiv infection only) if the neonates does not tolerate oral agents, the iv dose should be 75% of the oral dose while maintaining the same dosing interval. 2 abacavir (abc)  ≥ 37 weeks’ gestation at birth age 0 – 1 month: 2 mg/kg/dose po twice daily age 1 < 3 months: 4 mg/kg/ dose po twice daily abc has not been approved yet by the fda for use in neonates <1 month of age. -the current dosing recommendations have been modeled using pk simulation 3 lamivudine (3tc)  ≥32 weeks’ gestation at birth age 0 – 4 weeks: 2 mg/kg/dose po twice daily age > 4 weeks: 4 mg/kg/dose po twice daily 4 nevirapine (nvp)  ≥37 weeks’ gestation at birth age 0 – 4 weeks: 6 mg/kg/dose po twice daily age > 4 weeks: 200 mg/m2 bsa/ dose po twice daily (increase dose in cases of confirmed hiv infection only)  ≥34 to <37 weeks’ gestation at birth age 0 – 1 week: 4 mg/kg/dose po twice daily age 1 – 4 weeks: 6 mg/kg/dose po twice daily age > 4 weeks: 200 mg/m2 bsa/ dose po twice daily (increase dose in cases of confirmed hiv infection only)  ≥32 to <34 weeks’ gestation at birth age 0 – 2 weeks: 2 mg/kg/dose po twice daily age 2 – 4 weeks: 4 mg/kg/dose po twice daily age 4 – 6 weeks: 6 mg/kg/dose po twice daily. age > 4 weeks: 200 mg/m2 bsa/dose po twice daily (increase dose in cases of confirmed hiv infection only) 5 raltegravir (ral)  ≥37 weeks’ gestation at birth and weighing ≥2 kg age 0 – 1 week: 1.5 mg/kg/dose po daily age 1 – 4 weeks: 3 mg/kg/dose po twice daily age 4 – 6 weeks: 6 mg/kg/dose po twice daily no dosing information is available for preterm infants or infants weighing <2 kg at birth. 6 maraviroc (mvc)  infants ≥2 kg : age 0 – 6 weeks: 8 mg/kg/ dose po twice daily -approved recently for infants ≥2 kg -presence of limited data about mvc use in infants and the risk of drug interactions will limit its routine use in neonates 220 submitted 18 mar 23 1 revision req. 7 may 23; revision recd. 25 may 23 2 accepted 2 jul 23 3 online-first: july 2023 4 doi: https://doi.org/10.18295/squmj.7.2023.045 5 6 adherence to medications in patients with ischemic heart disease in oman 7 ahmed al-maskari,1 qasim al-maamari,1 mariya al-abdali,2 hajer al-8 shaaibi,2 sunil k. nadar3 9 10 1directorate of nursing and 3department of medicine, sultan qaboos university hospital, 11 muscat, oman; 2college of medicine and health sciences, sultan qaboos university, muscat, 12 oman. 13 *corresponding author’s e-mail: sunilnadar@gmail.com 14 15 abstract 16 objectives: the aim of this study was to evaluate the level of adherence to medications in 17 patients with ihd in oman and assess the factors influencing it. methods: this was a cross 18 sectional questionnaire-based study among patients with ihd. results: a total of 105 patients 19 (mean age 49.9+11.1 years; 78.1% male) were recruited. most of the patients take the 20 medications by themselves (84 or 80%). 77 patients (73.3%) said that over the preceding two 21 weeks, they missed at least three doses. the reasons for missing included forgetting (100%), too 22 many tablets (57%), not effective (48%) and too many times a day (23%). there were no factors 23 that could be identified that made patients prone to not taking medications. conclusion: 24 medication adherence was low among patients with ihd in oman with high pill burden the most 25 common reason for non-adherence. physicians must keep this in mind when patients are 26 reviewed. 27 keywords: cardiovascular disease, adherence, myocardial infarction. 28 29 mailto:sunilnadar@gmail.com introduction 30 cardiovascular disease are a major cause of morbidity and mortality worldwide. it is estimated 31 that 17.9 million deaths (representing 32% of all deaths) in 2019 were attributed to cvd.1 a 32 major part of the management of cvd lie in adherence to medications and lifestyle changes with 33 the intention of lowering future cardiovascular events and for symptom control.2 medications are 34 prescribed either as primary prevention for those at high risk for future cardiovascular events or 35 secondary prevention of future events for those who have already sustained a cardiovascular 36 event. 37 38 current evidence based practice has led to patients with cvd and those at high risk, being 39 initiated on an increasing number of medications. this can affect adherence and as with other 40 chronic illnesses, non-adherence to medication and lifestyle modifications, remains a major 41 issue.3 studies have demonstrated that adherence is often an issue when given as a long-term 42 preventative strategy rather than for symptom control. this is especially true for hypertensive 43 patients who are often asymptomatic but experience various side effects to medications.4 44 the reported rates of adherence with cardiovascular medications range from 30-70%, with 45 patients often not taking all or part of their prescribed medications.5 poor adherence is a major 46 public health issue such that, the world health organisation (who) in their report on adherence 47 to long term therapies, state that interventions to improve medication adherence might have a far 48 greater impact on the health of the population than any improvement in a specific medical 49 treatment itself.6 50 51 there are many factors that are responsible for poor adherence and understanding these factors in 52 a particular population is key to improving medication adherence and ultimately improving 53 patient care and outcomes. the who has identified five broad categories of factors that affect 54 adherence: 1) socio-economic factors 2) patient-related, 3) therapy-related, 4) co-morbid 55 conditions, and 5) healthcare system-related.6 the first four factors are mainly related to the 56 individual patient and it is important to understand these factors which are very individualised 57 and often related to patient preferences and social and cultural behaviours. these include costs, 58 beliefs regarding medications and treatment, number of pills, side effects of pills, understanding 59 the need for medications, the benefits of it, forgetfulness and overall wellbeing.7-9 60 61 improving medication adherence helps improve cost savings and helps to put into practice 62 lessons learned from clinical trials and ultimately helps to reduce the burden of chronic 63 illnesses.10 early detection of non-adherence can prevent expensive investigations, hospital 64 admissions and unnecessary additional medications and interventions. it is important to ensure 65 high levels of adherence to medications to improve cardiovascular outcomes in the population as 66 a whole.2 67 68 in oman, ihd is a leading cause of mortality and morbidity accounting for around 35% of all 69 deaths in 2020.11 there is dearth of information regarding adherence to medication in the 70 middle-east. the aim of this study was to assess the levels of medication adherence in patients 71 with ihd and the patient related factors affecting it in oman. 72 73 methods 74 this was a cross-sectional study questionnaire based on patients who attended the outpatient 75 clinic at a tertiary hospital in muscat, oman. this was performed between january to december 76 2021. patients aged 18 or over, who were diagnosed to have ihd with a previous mi or 77 undergone pci for stable angina more than a year earlier were included in the study. patients had 78 to be independent and fully alert and oriented to be included in the study, they could take 79 medications either by themselves or be given by a carer. patients who were not able to give 80 consent to the study, or those who had a recent cardiac event or who had a hospitalisation for a 81 cardiovascular event within the preceding 12 months were not included in the study. we chose a 82 sample size of 100 as this is a pilot study. 83 84 the questionnaire was self-developed. it was based in two parts. the first part was about the 85 general demographics of the patients, the number of medications and the total pill burden. the 86 second part of the questionnaire was about their practice of taking medications. it included a 87 question regarding whether they missed more than three doses in the previous two weeks. if they 88 did, they were considered as non-adherent. this was because 3 days out of 14 would work out to 89 an adherence rate of 80% which is the rate accepted by many studies for adequate adherence. 90 this was initially trialled on a few volunteers to adjust the wording, to ensure that there were no 91 difficult or confusing words. the questionnaire was developed in arabic by native arabic 92 speaking staff. 93 94 ethical approval was obtained from the research committee of the sultan qaboos university 95 (mrec #1550). all patients gave informed consent before answering the questionnaire. 96 statistical analysis was performed using spss version 21. data was presented as number (%) or 97 mean + standard deviation (sd) or median (interquartile rangeiqr). data analysis was done by 98 chi-square test or student t-test as appropriate. a p value of <0.05 was considered to be 99 statistically significant. 100 101 results 102 a total of 105 patients (mean age 49.9+11.1 years; 82 or 78.1% male) filled in the 103 questionnaires. the patients were taking a median of 9 (interquartile range (iqr) of 6-10) tablets 104 per day. they were taken a median 3 (iqr 2-3) times a day. most of the patients had a previous 105 mi (100 or 95.2%) with the remaining 5 having chronic stable angina. 87 (82.9%) of patients had 106 a previous pci, while 12 (11.4%) had previous cabg. hypertension was the commonest risk 107 factor (97 or 92.4%) followed by diabetes (87 or 82.9%). 14 patients (13.3%) had a previous 108 stroke. table 1 summarises their demographic features. 109 110 most of our patients take the medications by themselves (84 or 80%), while for the remaining 21 111 (20%) a family member or carer administers the medications. twenty-two patients (%%) use a 112 reminder to help them remember to take medications. this includes a phone app for 12 patients, 113 and a family member for 10. 114 115 77 patients (73.3%) said that over the preceding two weeks, they would have missed at least 116 three doses. the main reason given by our patients for not taking medications regularly are that 117 they simply forgot (77 or 100%), while 44(57%) patients felt that there were too many [table 2]. 118 thirty-seven (48%) felt that they were not effective and 18 didn’t take all the medications as 119 prescribed as it was too many times a day (23%). a further 41 (39%) said that they stop taking 120 the tablets when they feel well. a majority of patients (80 or 76.2%) felt that taking tablets was a 121 burden and 63 (60%) said that they sometimes do not take tablets while travelling. 122 123 table 3 summarises the differences between those who missed more than 3 doses of tablets over 124 the previous 2 weeks with those who said they never missed a single dose. there was no 125 difference between the two groups. there was no difference in age, gender, educational status, or 126 the number of pills or the number of times a day. the cardiovascular risk factors were similar, 127 apart from those who had a previous stroke had a higher number of those who missed tablets (p-128 0.01). although there did not appear to be any difference between the two groups, by binary 129 logistic regression, the only factor that predicted non-adherence was the number of pills taken 130 daily (odds ratio 1.26, 955 confidence interval 1.001-1059, p=0.04) 131 132 discussion 133 the rates of non-adherence were high in our group, with more than three-quarters of those 134 surveyed saying that they had missed multiple doses over the previous two weeks. the findings 135 are similar to those from other studies. adherence to medications in cvd in are low worldwide. 136 in a meta-analysis of around 20 observational studies involving more than 300,000 patients with 137 cvd, it was estimated that the prevalence of poor adherence was as high as 43%.12 for 138 individual risk factors that rate can be even higher. it has been demonstrated that at the end of 139 end of 6 months one-third of patients discontinue their antihypertensive medications, and only 140 around half of all patients persist with their initial therapy at one year.4 141 142 the rates of adherence for primary prevention of cvd are generally lower than those for 143 secondary prevention. patients who have suffered a myocardial infarction or a stroke are more 144 likely to take their medication regularly than those who have not suffered an event.12 however, 145 even for those on secondary prevention, adherence is sub-optimal as demonstrated on a study on 146 4591 post mi patients, where around 18% of patients did not collect their prescriptions even once 147 in the four months following the mi.13 in in a separate cohort of 22,379 post-acs patients, 60% 148 discontinued their statin medication within 2 years of hospitalization.14 149 150 there are many factors that affect adherence to medications.5 these include physician/healthcare 151 related factors, patient factors and socio-economic factors. healthcare factors include busy 152 outpatient consultations, pill burden, access to pharmacies and ease of refills and costs. patient 153 factors include socio-economic factors such as affordability, access to health care, social 154 circumstances, forgetfulness, and understanding of the disease process.15 155 156 beliefs regarding medications, the disease process and its management are an important part and 157 determinant of medication adherence. it has been shown that these beliefs play an important part 158 in medication adherence even among people of middle-eastern origin who live in australia.16 159 beliefs regarding medications include the importance and usefulness of taking medications, and 160 the concern regarding the illness. horne et al, into one of four subgroups according to their 161 attitudes towards medication; sceptical (low necessity, high concerns), ambivalent (high 162 necessity, high concerns), indifferent (low necessity, low concerns), and accepting (high 163 necessity, low concerns).17 the sceptical and ambivalent patients have been shown to have low 164 adherence rates as compared to the other two groups.16;18 education is therefore an important part 165 of ensuring adherence and empowering the patient to take care of their own health by explaining 166 the need for adherence and the benefits. in our cohort of patients, we did not specifically study 167 the beliefs of the patients, though we had asked them whether or not they felt the medications 168 were effective. 169 170 other cultural factors such as the use of traditional medicine, which is high in oman, could also 171 play a role in non-adherence. 19 in this study al-riyami et al found that a high proportion of 172 people prefer to take herbal medications and undergo traditional practices to taking medications 173 for chronic illnesses. scicchitano et al have described the role of “functional foods” or 174 “nutraceuticals” in cardiovascular disease.20 functional foods are described as any food or food 175 ingredient that may provide a health benefit beyond the traditional nutrients it contains,21 while 176 nutraceuticals have been defined as food (or part of a food) that provides medical or health 177 benefits, including the prevention and/or treatment of a disease.22 this concept might explain the 178 benefits of herbal diets and the willingness of the population to try these remedies rather than 179 modern medications and thereby affecting adherence. 180 181 the findings of our study are also in keeping with data from the middle east, where adherence 182 rates ranging from 1.4-88% have been demonstrated in a variety of conditions.23 a previous 183 study from oman on patients with hypertension also revealed that less than 50% of the patients 184 were adherent to medications.24 al-qasem et al performed a systemic review of studies from the 185 middle east and found that the reasons reported by patients for non-adherence in the middle east 186 are similar to those reported in the international literature.23 however, some of the reasons 187 mentioned were unique to the middle-east such as patient dissatisfaction and/or lack of trust in 188 health care providers and lack of social support. poor physician support and explanations and 189 lack of understanding of the need for taking medications has also been described previously from 190 the region.25 191 192 in our study, we could not identify any factor that could predict non-adherence apart from the 193 number of pills. the age, gender, educational status, or marital status did not affect adherence. 194 the use of aids or whether the patient self-medicated or whether it was given by a carer did not 195 affect adherence. it is possible that the small sample size was not able to differentiate between 196 those who were adherent and those who were not. the mean age of our patients was 49 years 197 with only a small proportion of patients above 60 years. this could explain why age did not 198 appear to be a contributing factor. previous studies on adherence to medications for other 199 conditions in the region demonstrated that gender, educational status affected adherence, with 200 female patients and those with lower educational achievement had poorer adherence. in our 201 study we did not demonstrate any difference, possibly again due to the small sample size and 202 general over all poor adherence among all groups. 23;26;27 203 204 the only factor that predicted low adherence was the pill burden. most patients with ihd are on 205 a large number of pills for secondary prevention. after coronary intervention, or on adequate 206 medical therapy, many patients have adequate control of symptoms which then becomes a 207 determinant of poor adherence.8;13;14;28 the average number of pills per patient in our study was 208 around 9 which is a large number. a large proportion of patients felt that they were taking too 209 many tablets and felt burdened by it. it is therefore important for physicians to review patients’ 210 medications at each visit to ensure that patients are not on any medications that they do not need 211 to be on, such as stopping dual antiplatelet therapy after one year (if indicated). the use of 212 combination pills reduces the pill burden and has been demonstrated to improve adherence in 213 patients with cvd with improved clinical outcomes.29 perhaps local health authorities should 214 consider using more combination pills in routine practice. 215 216 assessment of medication adherence is not easy there are many questionnaires that are validated 217 for a variety of conditions.15 however, all of them have their own advantages and disadvantages 218 and has been described elsewhere. we did not use any of these questionnaires, but instead chose 219 to directly ask the patients whether or not they missed any doses in the previous two weeks. 220 although direct questioning has its limitations, we felt this would help us explore reasons behind 221 non-adherence.30 222 223 there were a few limitations to our study. medication adherence is very variable over time, with 224 patients having periods of strict adherence followed by periods of mild to severe nonadherence.31 225 our study only investigated a snapshot of the two weeks preceding the questionnaire. this is 226 therefore not representative of their overall long-term adherence. this study was performed in 227 the outpatient setting of a tertiary hospital in muscat, oman which is a large city. the results are 228 not generalisable to the whole of oman and the rural areas. access to health care, beliefs 229 traditions and customs are different in the different parts of oman, along with different social 230 and economic conditions, all of which play a role in medication adherence and have not been 231 fully assessed in this study. another limitation was the lack of follow up. it would have been 232 useful to have additionally studied the effects of intervention and co-operation between primary 233 and secondary care on the levels of medication adherence as this has been previously 234 demonstrated to be useful in an italian population.32 235 236 our study was limited to omani population and the adherence rates among the expat population 237 might be different due to the different socio-economic conditions. our study sample size was 238 small. this study was conducted just when social restrictions related to the covid pandemic 239 were being lifted. access to healthcare and patients was still not as free as prior to the pandemic. 240 however, this is the first study of its type on adherence to medications among patients with ihd 241 from oman. larger studies are required to fully assess the barriers to optimal medication 242 adherence among patients with ihd from different parts of oman. 243 244 conclusion 245 the rates of medication non-adherence in patients with ihd is high in oman. number of pills 246 was the major determinant of non-adherence. lowering pill burden and frequent review of 247 medications, use of combination pills must be considered in these patients. additionally, more 248 needs to be done to assess the needs of each individual patient in order to improve their 249 understanding of the disease and to improve overall adherence. 250 251 conflicts of interest 252 the authors declare no conflict of interests. 253 254 funding 255 no funding was received for this study. 256 257 authors’ contribution 258 aa, qa, ma, ha were involved in collection of data and contributing to writing the 259 manuscript. skn-data analysis and manuscript writing. all authors approved the final version of 260 the manuscript. 261 262 references 263 1. burden of cardiovascular diseases. available at https://www.who.int/news-room/fact-264 sheets/detail/cardiovascular-diseases-(cvds) accessed on april 2023 265 2. roth ga, mensah ga, fuster v. the global burden of cardiovascular diseases and risks: a 266 compass for global action. j am coll cardiol 2020 dec 22;76(25):2980-1. 267 3. miller nh. compliance with treatment regimens in chronic asymptomatic diseases. am j med 268 1997 feb 17;102(2a):43-9. 269 4. hill mn, miller nh, degeest s, materson bj, black hr, izzo jl, jr., et al. adherence and 270 persistence with taking medication to control high blood pressure. j am soc hypertens 271 2011 jan;5(1):56-63. 272 5. baroletti s, dell'orfano h. medication adherence in cardiovascular disease. circulation 2010 273 mar 30;121(12):1455-8. 274 6. adherence to long term therapies: evidence for action; geneva: world health 275 organization, 2003. available at 276 https://apps.who.int/iris/bitstream/handle/10665/42682/9241545992.pdf?sequence=1&is277 allowed=y accessed on april 2023 278 7. gast a, mathes t. medication adherence influencing factors-an (updated) overview of 279 systematic reviews. syst rev 2019 may 10;8(1):112. 280 8. kvarnstrom k, westerholm a, airaksinen m, liira h. factors contributing to medication 281 adherence in patients with a chronic condition: a scoping review of qualitative 282 research. pharmaceutics 2021 jul 20;13(7). 283 9. magrin me, d'addario m, greco a, miglioretti m, sarini m, scrignaro m, et al. social 284 support and adherence to treatment in hypertensive patients: a meta-analysis. ann behav 285 med 2015 jun;49(3):307-18. 286 10. axon dr, vaffis s, chinthammit c, lott be, taylor am, pickering m, et al. assessing the 287 association between medication adherence, as defined in quality measures, and disease-288 state control, health care utilization, and costs in a retrospective database analysis of 289 medicare supplemental beneficiaries using statin medications. j manag care spec pharm 290 2020 dec;26(12):1529-37. 291 11. cardiovascular disease in oman. available at https://www.worldlifeexpectancy.com/oman-292 coronary-heart-disease accessed on april 2023 293 12. naderi sh, bestwick jp, wald ds. adherence to drugs that prevent cardiovascular disease: 294 meta-analysis on 376,162 patients. am j med 2012 sep;125(9):882-7. 295 13. jackevicius ca, li p, tu jv. prevalence, predictors, and outcomes of primary nonadherence 296 after acute myocardial infarction. circulation 2008 feb 26;117(8):1028-36. 297 14. jackevicius ca, mamdani m, tu jv. adherence with statin therapy in elderly patients with 298 and without acute coronary syndromes. jama 2002 jul 24;288(4):462-7. 299 15. lam wy, fresco p. medication adherence measures: an overview. biomed res int 300 2015;2015:217047. 301 16. shahin w, kennedy ga, cockshaw w, stupans i. the role of medication beliefs on 302 medication adherence in middle eastern refugees and migrants diagnosed with 303 hypertension in australia. patient prefer adherence 2020;14:2163-73. 304 17. horne r, parham r, driscoll r, robinson a. patients' attitudes to medicines and adherence 305 to maintenance treatment in inflammatory bowel disease. inflamm bowel dis 2009 306 jun;15(6):837-44. 307 18. unni e, shiyanbola oo. clustering medication adherence behavior based on beliefs in 308 medicines and illness perceptions in patients taking asthma maintenance medications. 309 curr med res opin 2016;32(1):113-21. 310 19. al-riyami h, al-maskari a, nadar sk, almaskari m. knowledge, attitudes and practices 311 regarding traditional and complimentary medicine in oman. sultan qaboos univ med 312 j 2023 feb;23(1):90-8. 313 20. scicchitano p, cameli m, maiello m, modesti pa, muiesan ml, novo s, et al. 314 nutraceuticals and dyslipidemia: beyond the common therapeutics. j functional foods 6, 315 11-32. 2014. 316 21. ross s. functional foods: the food and drug administration perspective. am j clin nutr 317 2000 jun;71(6 suppl):1735s-8s. 318 22. kalra ek. nutraceutical--definition and introduction. aaps pharmsci 2003;5(3):e25. 319 23. al-qasem a, smith f, clifford s. adherence to medication among chronic patients in 320 middle eastern countries: review of studies. east mediterr health j 2011 apr;17(4):356-321 63. 322 24. al-noumani h, wu jr, barksdale d, alkhasawneh e, knafl g, sherwood g. relationship 323 between medication adherence and health beliefs among patients with hypertension in 324 oman: pilot study. sultan qaboos univ med j 2017 aug;17(3):e329-e333. 325 25. bassam m, behbehani n, farouk h, alsayed m, montestruc f, al-jahdali h, et al. 326 adherence to medication among adult asthma patients in the middle east and north 327 africa: results from the esmaa study. respir med 2021 jan;176:106244. 328 26. al-jahdali h, wali s, salem g, al-hameed f, almotair a, zeitouni m, et al. asthma control 329 and predictive factors among adults in saudi arabia: results from the epidemiological 330 study on the management of asthma in asthmatic middle east adult population study. 331 ann thorac med 2019 apr;14(2):148-54. 332 27. almazrou sh, alfaifi si, alfaifi sh, hakami le, al-aqeel sa. barriers to and facilitators 333 of adherence to clinical practice guidelines in the middle east and north africa 334 region: a systematic review. healthcare (basel) 2020 dec 15;8(4). 335 28. saag kg, bhatia s, mugavero mj, singh ja. taking an interdisciplinary approach to 336 understanding and improving medication adherence. j gen intern med 2018 337 feb;33(2):136-8. 338 29. castellano jm, pocock sj, bhatt dl, quesada aj, owen r, fernandez-ortiz a, et al. 339 polypill strategy in secondary cardiovascular prevention. n engl j med 2022 sep 340 15;387(11):967-77. 341 30. anghel la, farcas am, oprean rn. an overview of the common methods used to measure 342 treatment adherence. med pharm rep 2019 apr;92(2):117-22. 343 31. mathews r, wang w, kaltenbach la, thomas l, shah ru, ali m, et al. hospital variation 344 in adherence rates to secondary prevention medications and the implications on 345 quality. circulation 2018 may 15;137(20):2128-38. 346 32. locuratolo n, scicchitano p, antoncecchi e, basso p, bonfantino vm, brescia f, et al. 347 [follow-up of patients after an acute coronary event: the apulia ponte-sca program]. 348 g ital cardiol (rome) 2022 jan;23(1):63-74. 349 350 table 1: demographics of the participants. 351 number (n=105) percentage age 49.9 ± 11.1 years sex male female 82 23 78.1% 21.9% marital status never married married separated 7 81 17 6.7% 77.1% 16.2% educational status less than primary school secondary school graduate or more 35 49 21 33.7% 46.7% 20% diabetes 87 82.9% hypertension 97 92.4% smoker 46 43.8% previous stroke 46 43.8% previous mi 100 95.2% previous cabg 12 11.4% previous pci 87 82.9% mi = myocardial infarction; cabg = coronary artery bypass grafting; pci = percutaneous 352 coronary intervention. 353 354 table 2: reasons for non-compliance. 355 number (n=77) percentage just forget to take 57 74.02% too many tablets 44 57.1% too many side effects 18 23.3% not effective 37 48.1% many times a day 15 19.4% 356 table 3: differences between those who missed tablets and those who did not. 357 those who did not miss (n=28) those who missed more than 3 doses in last two weeks (n=77) p-value age (years) 49.01 ± 10.1 50.2 ± 11.5 0.61* gender male female 23 (82.1%) 5(17.9%) 59(76.6%) 18(23.4%) 0.60 marital status married single/divorced/widowed 21(75%) 7(25%) 60(77.9%) 17(22.1%) 0.54 educational status primary school or less completed secondary school postgraduate studies 9(32.1%) 12(42.8%) 7(25%) 26(33.7%) 37(48.1%) 14(18.1%) 0.7 number of pills 8(5-10) 9(6-10) 0.24* number of times per day 3(2.5-3) 3(3-3) 0.9* diabetes 21(75%) 66(85.7%) 0.19 hypertension 26(92.8%) 71(92.2%) 0.91 smoker 11(39.2%) 35(45.4%) 0.67 previous cva 0 14(18.1%) 0.01 previous cabg 1(3.5%) 11(14.2%) 0.12 previous pci 21 66(85.7%) 0.19 who gives the pills self carer 22(78.5%) 6(21.5%) 62(80.5%) 15(19.5%) 0.52 use reminder 7(25%) 15(19.5%) 0.53 cva = cerebrovascular accident; pci = percutaneous coronary intervention; cabg = 358 coronary artery bypass grafting. 359 analysis by chi-square test apart from *students t-test and **mann whitney u test. 360 departments of 1internal medicine and 3physiology, sultan qaboos university, muscat, oman; 2department of clinical physiology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: deepali@squ.edu.om pulmonary function test outcomes in adult omani patients preliminary findings from a single-centre study anan al jabri,1 ruqaiya al hinai,1 ruth balaji,2 sharifa al harrasi,2 *deepali s. jaju,2 hajar al rajaibi3 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 400–404, epub. 25 aug 22 submitted 13 oct 20 revisions req. 7 dec 20, 27 jan & 21 mar 21; revisions recd. 30 dec 20, 21 feb & 11 apr 21 accepted 5 may 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.088 brief communication abstract: objectives: this study aimed to document the distribution of pft outcomes among adult omani patients. there is limited information regarding the distribution of pulmonary diseases (pd) in oman. pulmonary function test (pft) outcome patterns could indicate an indirect distribution of pd. methods: this retrospective cross-sectional study was conducted from january to december 2015 at a tertiary hospital in oman. a total of 1,118 adults referred for pfts during this period were included. results: there were 605 (54.1%) female and 513 (45.9%) male patients. the mean age of the patients was 47.11 ± 18.1 years. most patients underwent spirometry with reversibility (36.8%) or full lung function testing with reversibility (29.7%). among the 1,064 patients with conclusive pft outcomes, 39.9% had normal findings, 26.1% had obstructive defects, 19.6% demonstrated restrictive defects and 10.6% had mixed obstructive/restrictive defects. conclusion: this study generated important preliminary data regarding pft outcomes (defects) in omani patients. keywords: pulmonary function tests; spirometry; pulmonary diseases; asthma; chronic obstructive pulmonary disease; oman. according to the world health organization, chronic obstructive pulmonary disease (copd) will become the third leading cause of death by 2030.1 it is therefore essential that all countries work towards practicing evidence-based policymaking and resource planning in order to tackle the increasing burden of non-communicable diseases such as bronchial asthma and copd. although the prevalence of chronic pulmonary diseases in the eastern mediterranean region (emr) is rising, the overall research output in this field is still low.2–4 a recent systematic review was able to substantiate this finding by noting a similar under-representation of data from the emr and the southeast asian and african regions as well.5 pulmonary diseases (pds) can be monitored and distinguished using pulmonary function tests (pfts).6,7 generally, pds can be classified into obstructive or restrictive diseases. obstructive diseases—asthma, chronic bronchitis and emphysema—are characterised by airflow limitations due to narrowing of the anat omic airway or loss of elastic recoil, thereby leading to partial or complete obstruction and increased resistance to air movement.8 restrictive diseases, including sarcoi dosis, pneumoconiosis, acute respiratory distress syndrome and interstitial fibrosis of unknown aetiology, are all denoted by reduced total lung capacity. this is primarily due to factors such as pleural diseases, obesity, interstitial lung disease (ild) or chest wall disorders that restrict the expansion of the lung parenchyma. in certain cases, obstructive and restrictive lung diseases can overlap as well.6 in oman, there is limited information with respect to the burden of common respiratory diseases in the country. in particular, copd remains underdiagnosed, undertreated and limited data are available regarding rates of restrictive diseases or asthma in adults.9,10 pft outcomes are typically corroborated by referring patients to clinicians to help confirm the presence of pds. this study aimed to document the distribution of pft outcomes as obstructive, restrictive and mixed obstructive/restrictive defects in adult omani patients referred for pfts to a tertiary hospital in muscat, oman. methods this retrospective study of pfts was conducted at a tertiary care hospital in muscat from january to december 2015. all adult omani patients referred by clinicians for pfts to assess lung function were included in the study. patients underwent either spirometry using the platinum elite™ body plethysmograph (mgc diagnostics corp., saint paul, minnesota, usa) and the powercube® system (ganshorn medizin electronic, niederlauer, germany) or full lung function (flf) testing using the powercube® system (ganshorn medizin electronic). in the pulmonary laboratory of the https://creativecommons.org/licenses/by-nd/4.0/ anan al jabri, ruqaiya al hinai, ruth balaji, sharifa al harrasi, deepali s. jaju and hajar al rajaibi brief communication | 401 current study centre, spirometry includes estimation of forced vital capacity and forced expiratory volume in the first second, while flf includes spirometry and estimations of lung volumes and diffusion functions. reference equations standardised to an asian population were used to estimate predicted values.6 all patients were instructed to avoid bronchodilators the morning prior to the test to avoid altering any baseline spirometry indices. all of the pft results were interpreted by a specialist according to the criteria of the american thoracic society and european respiratory society.6 information regarding the patients’ sociodemographic characteristics, referring physician, hospital, reasons for referral and pft outcomes was collected. the pft outcomes were categorised into the following groups: normal findings, obstructive defects, restrictive defects, mixed obstructive/restrictive defects and isolated diffusion impairment. the patients with inconclusive findings were excluded from the analysis of pft outcomes. data were analysed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). the results were presented using descriptive statistics including frequencies and percentages and associations between gender and type of test, referring hospital, specialty and pft outcomes were assessed using a chi-squared test. gender differences in age and body mass index (bmi) were calculated using student’s t-test. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences, sultan qaboos university, muscat, oman (mrec 1326). results a total of 1,118 adult patients underwent pfts during the study period. among these patients, 513 (45.9%) were male and 605 (54.1%) were female. compared to female patients, male patients were significantly younger (p = 0.007) and had lower bmi values (p <0.001). most patients underwent spirometry with reversibility (36.8%), followed by full lung function testing with reversibility (29.7%). the majority were referred from a national-level tertiary hospital (76.4%). over half of the sample (52.4%) was referred from the pulmonary medicine department while the remaining patients were referred from other specialties [table 1]. a total of 890 patients (79.6%) were referred for pfts due to respiratory symptoms or conditions including asthma (41.2%), shortness of breath (17.6%), cough (15.5%), ild (8.9%), copd (8.2%), bronchiectasis (7.8%), wheezing (4.1%), obstructive sleep apnoea (2.5%), sarcoidosis (1.9%), systemic lupus erythematosus (1.3%), cystic fibrosis (0.4%) and lung carcinoma (0.3%). the remaining 228 patients (20.4%) were referred for other conditions, including presurgical assessment (11.8%), pre/posttable 1: characteristics of adult omani patients referred for pulmonary function tests to a tertiary hospital in muscat, oman (n = 1,118) characteristic n (%) p value total male (n = 513) female (n = 605) mean age in years ± sd 47.11 ± 18.1 46.57 ± 18.8 47.57 ± 17.5 0.007 mean bmi in kg/m2 ± sd 26.95 ± 7.2 30.64 ± 8.80 <0.001 type of pft performed 0.061 baseline spirometry 107 (9.6) 39 (36.4) 68 (63.6) spirometry with reversibility 411 (36.8) 179 (43.6) 232 (56.4) baseline full lung function testing 268 (24.0) 131 (48.9) 137 (51.1) full lung function testing with reversibility 332 (29.7) 164 (49.4) 168 (50.6) referring hospital 0.001 national tertiary hospital 854 (76.4) 356 (41.7) 498 (58.3) other hospitals or health centres 264 (23.6) 157 (59.5) 107 (40.5) referring specialty 0.002 pulmonary medicine 586 (52.4) 243 (41.5) 343 (58.5) other* 532 (47.6) 270 (50.8) 262 (49.2) sd = standard deviation; bmi = body mass index; pft = pulmonary function test. *including cardiology, internal medicine, haematology, oncology, rheumatology, immunology, surgery and family medicine specialties. pulmonary function test outcomes in adult omani patients preliminary findings from a single-centre study 402 | squ medical journal, august 2022, volume 22, issue 3 bone marrow transplant assessment (5.5%), genetic or immunological diseases (3%), pre/post-chemotherapy assessment (2.1%) and pre-hyperbaric oxygen therapy assessment (0.2%). a total of 271 patients (24.2%) suffered from two or more conditions for a pft referral. overall, the pft findings for 54 patients (4.8%) were inconclusive. of the remaining 1,064 patients (95.2%) with conclusive results, 425 (39.9%) had normal pft findings. however, 311 patients out of 425 suffered from respiratory symptoms or conditions. a total of 278 patients (26.1%) had obstructive defects, 209 (19.6%) had restrictive defects, 113 (10.6%) had mixed obstructive/restrictive defects and 39 (3.7%) had isolated diffusion impairment. a total of 48.9% (n = 136/278) of obstructive defects were evident from spirometry with reversibility. about 60.8% (n = 127/209) of the restrictive defects were identified through flf testing; restrictive signs were evident through spirometry in 82 cases (39.2%) [table 2]. the frequency of isolated diffusion impairment was significantly higher in females compared to males (χ2 = 23.21; p <0.001) [table 3]. discussion the current study aimed to consolidate relevant information regarding the obstructive and restrictive defects as outcomes of pfts among omani adults. the distribution of pft defect patterns could indirectly indicate the distribution of pd patterns. it must be reiterated that although the majority of pfts were done for respiratory symptoms or conditions, one fifth of the pfts were provided for preoperative assessment, obesity, pre-drug and pre-bone marrow studies in which the presence of any defect may not have indicated a respiratory disease. researchers have proposed that spirometry can be incorporated into the assessment of airflow obstruction; however, estimates of spirometryassessed copd burden from epidemiological studies are often inconsistent due to variations in methodology and use of different spirometry cut-off values for interpretation.11 in the current study, spirometry was considered in order to document obstructive defects using standard guidelines.6 alzaabi et al. conducted a review of prevalence studies from the emr and middle eastern and north african regions, excluding oman;12 the researchers noted that the prevalence of copd in these regions was likely underestimated due to an overreliance on clinical diagnosis rather than spirometry findings or international diagnostic guidelines. in the current study centre, patients were usually referred for pfts by a clinician based on suspicion of an obstructive disease. spirometry indices allow for the objective assessment of obstructive impairment compared to reliance on a purely physician-diagnosed conclusion. in the gulf region, lung function testing table 2: outcomes of various types of pulmonary function tests among adult omani patients referred to a tertiary hospital in muscat, oman (n = 1,064)* outcome type of pft performed, n (%) baseline spirometry spirometry with reversibility baseline full lung function testing full lung function testing with reversibility total normal findings 66 (15.5) 136 (32.0) 140 (32.9) 83 (19.5) 425 (39.9) obstructive pd 2 (0.7) 136 (48.9) 15 (5.4) 125 (45.0) 278 (26.1) restrictive pd 31 (14.8) 51 (24.4) 67 (32.1) 60 (28.7) 209 (19.6) combined obstructive/ restrictive pd 3 (2.7) 61 (54.0) 7 (6.2) 42 (37.2) 113 (10.6) diffusion impairment n/a n/a 25 (64.1) 14 (35.9) 39 (3.7) pft = pulmonary function test; pd = pulmonary disease; n/a = not applicable. *excluding patients with inconclusive findings. table 3: gender differences according to pulmonary func tion test outcomes among adult omani patients referred to a tertiary hospital in muscat, oman (n = 1,064)* outcome of pft n (%) χ2 p value total male female normal findings 425 (39.9) 184 (43.3) 241 (56.7) 23.21 <0.001 obstructive pd 278 (26.1) 142 (51.1) 136 (48.9) restrictive pd 209 (19.6) 102 (48.8) 107 (51.2) combined obstructive/ restrictive pd 113 (10.6) 59 (52.2) 54 (47.8) diffusion impairment 39 (3.7) 7 (17.9) 32 (82.1) pft = pulmonary function test ; pd = pulmonary disease. *excluding patients with inconclusive findings. anan al jabri, ruqaiya al hinai, ruth balaji, sharifa al harrasi, deepali s. jaju and hajar al rajaibi brief communication | 403 is generally underutilised with one study reporting that up to 66% of patients had never undergone a pft.3 moreover, peak expiratory flow is rarely used as an indicator of breathing difficulty.13 classifying pds into restrictive, obstructive or other categories is only possible with full lung function testing. the current study utilised data based on both spirometry and flf testing, including the assessment of lung volume and diffusion capacity. the present study showed that obstructive defects were most prevalent, followed by restrictive defects in this limited sample. in 2012, the world health survey reported that the prevalence of physician-diagnosed asthma in the emr region was considerably lower at 2.93%; however, data for this region were limited to a few countries, including pakistan (3.12%), united arab emirates (5.30%), morocco (2.76%) and tunisia (2.74%).14 a recent meta-analysis found that the pooled crude prevalence of spirometry-defined copd in the emr was 13.20%.5 in their study, masjedi et al. reported the pooled prevalence of asthma and copd in the emr to be 9.38% and 5.39%, respectively.4 in the present study, 39.9% of patients with conclusive pft results demonstrated normal findings despite having been referred for respiratory symptoms or conditions. a possible reason behind this could be the fact that respiratory symptoms of such patients were being controlled with various pharmaceutical treatments or that the pfts were performed to assess presenting symptoms. further research to explore reasons for this finding is recommended since this was beyond the scope of the current study. in addition, a significant association was noted between pulmonary defect patterns and gender. in particular, the frequency of obstructive and mixed obstructive/restrictive pulmonary defects were significantly higher in males compared to females, whereas the opposite was true for isolated diffusion impairment. the reasons for these associations are unclear. isolated diffusion impairment could be an indicator of restrictive pulmonary disease, suggesting an early lung disease or an infiltrative process. however, the restrictive defects and low diffusion shown in this study are similar to those from other studies in the region.15,16 a major limitation of the current study was that pulmonary defect patterns could not be meaningfully considered as pd patterns. moreover, isolated diffusion impairment can be documented in non-pulmonary diseases such as cardiac failure; however, this issue was not considered in the current research. furthermore, the present findings cannot be generalized to the country as the entire study sample belonged to a single center. conclusion given the recent increase in the prevalence copd in the emr, the present study was conducted to expand the availability of prevalence data in the aforementioned region. among adult omanis referred to a tertiary hospital for pfts, obstructive defects were found to be present in one-fourth of the sample. restrictive defects were observed in one-fifth of the sample while mixed obstructive restrictive defects were found in one-tenth of the sample. finally, 4% of the sample had isolated diffusion impairment among the referred patients. these preliminary findings of distribution of defects could indicate an indirect distribution of pds in this particular set-up. these statistics also provide baseline evidence and estimates for sample size calculations for future researchers. a u t h o r s’ c o n t r i b u t i o n dsj conceptualised and designed the study and drafted the manuscript. aaj and rah collected and compiled the data. rb and sah provided technical assistance for spirometry procedure. dsj and aaj analysed the data and interpreted the results. har critically reviewed the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. chronic obstructive pulmonary disease. from: http://www.emro.who.int/health-topics/chronic -obstructive-pulmonary-disease-copd/index.html accessed: apr 2020. 2. sweileh wm, al-jabi sw, zyoud sh, sawalha af. bronchial asthma and chronic obstructive pulmonary disease: research activity in arab countries. multidiscip respir med 2014; 9:38. https://doi.org/10.1186/2049-6958-9-38. 3. khadadah m, mahboub b, al-busaidi nh, sliman n, soriano jb, bahous j. asthma insights and reality in the gulf and the near east. int j tuberc lung dis 2009; 13:1015–22. 4. masjedi m, ainy e, zayeri f, paydar r. assessing the prevalence and incidence of asthma and chronic obstructive pulmonary disease in the eastern mediterranean region. turk thorac j 2018; 19:56–60. https://doi.org/10.5152/turkthoracj.2018.17051. 5. adeloye d, chua s, lee c, basquill c, papana a, theodoratou e, et al. global and regional estimates of copd prevalence: systematic review and meta-analysis. j glob health 2015; 5:5–7. https://doi.org/10.7189/jogh.05-020415. 6. pellegrino r, viegi g, brusasco v, crapo ro, burgos f, casaburi r, et al. interpretative strategies for lung function tests. eur respir j 2005; 26:948–68. https://doi.org/10.1183/09031936.05.00035 205. https://doi.org/10.1186/2049-6958-9-38. https://doi.org/10.5152/turkthoracj.2018.17051. https://doi.org/10.7189/jogh.05-020415. https://doi.org/10.1183/09031936.05.00035205. https://doi.org/10.1183/09031936.05.00035205. pulmonary function test outcomes in adult omani patients preliminary findings from a single-centre study 404 | squ medical journal, august 2022, volume 22, issue 3 7. ranu h, wilde m, madden b. pulmonary function tests. ulster med j 2011; 80:84–90. 8. husain an. lung. in: kumar v, abbas ak, aster jc (eds). robbins basic pathology, 9th ed. philadelphia, usa: saunders, 2012. pp. 462–3. 9. al busaidi n, habibulla z, bhatnagar m, al lawati n, almahrouqi y. the burden of asthma in oman. sultan qaboos university medical journal 2015; 15:184–90. 10. al-rawas o. respiratory disorders in oman. in: oman thoracic conference 2013: the oman respiratory society and sultan qaboos university; 29–31 october 2013; muscat, oman. sultan qaboos univ med j 2014; 14:417. 11. scholes s, moody a, mindell js. estimating population prevalence of potential airflow obstruction using different spirometric criteria: a pooled cross-sectional analysis of persons aged 40-95 years in england and wales. bmj 2014; 4:e005685. https://doi.org/10.1136/bmjopen-2014-005685. 12. alzaabi a, toor s, saleem mi. review of copd in middle east and gulf countries. med res arch 2019; 7:1–13. 13. al-busaidi n, soriano jb. asthma control in oman: national results within the asthma insights and reality in the gulf and the near east (airgne) study. sultan qaboos univ med j 2011; 11:45–51. 14. to t, stanojevic s, moores g, gershon as, bateman ed, cruz aa, et al. global asthma prevalence in adults: findings from the cross-sectional world health survey. bmc public health 2011; 12:204. https://doi.org/10.1186/1471-2458-12-204. 15. waness a, el-sameed y, mahboub b, noshi m, jahdali h, vats m, et al. respiratory disorders in the middle east: a review. respirology 2011; 16:755–66. https://doi.org/10.1111/j.14401843.2011.01988.x. 16. jayakrishnan b, al-busaidi n, al-lawati a, george j, al-rawas oa, al-mahrouqi y, et al. clinical features of sarcoidosis in oman: a report from the middle east region. sarcoidosis vasc diffuse lung dis. 2016; 33:201–8. https://doi.org/10.1136/bmjopen-2014-005685. https://doi.org/10.1186/1471-2458-12-204. https://doi.org/10.1111/j.1440-1843.2011.01988.x. https://doi.org/10.1111/j.1440-1843.2011.01988.x. march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 99-100, epub 16th mar 2009 submitted 25th jan 09 murtagh’s patient education have you ever wished for quick access to information to promptly acquaint your-self on your sickness before venturing to a doctor office? another question, if you are a doctor, have you ever run out of words when describing diagnosis and treatment to your patients or sometimes wished to consolidate your health education to your patient in writing? if you have said yes to any of these questions, you share the vision of john murtagh’s volume, patient education, first published in 1992 and now into its fifth edition. the problem with this type of compilation is deciding what to include and what not to include since there are a myriad of medical conditions. the author tells us he started to polish his skills in 1979 when he was involved in producing patient education pamphlets for the royal australian college of general practitioners. the current volume reflects such an evolution and includes descriptions of 223 conditions all duly updated to reflect any twist or turn in the field. the book is divided into two parts. the first part is a collection of explanations of common medical problems with colourful titles from how to make your marriage work to bedwetting. the seven sections of part one carry all the essential information on different conditions. the ailments are arranged with developmental milestones in mind, from cradle to grave. the second part covers general health problems with ailments from hangovers to vertigo. forget wikipedia, as the information in there is often written by unknown experts, while there is a lot of gibberish in google search. this volume contains explanations for patients and carers of common medical problems and neurological and psychiatric conditions likely to be seen in the primary care setting. each condition is nicely presented in a single page and, depending on the nature of the condition, images, figures and tables are also featured with an emphasis on simplicity and non-technicality. recommended literature is also included for those interested. john murtagh has aimed to provide general practitioners or, for that matter, anyone who dispenses health care, with a handy book on common medical conditions, so that patients can be educated about their illnesses. should the doctor in oman get hold of this volume? the answer is emphatically yes though some coverage on psychosocial conditions such as circumcision, issues related to adolescent and more mundane ones such as bereavement needs to be adapted to our local context. despite some minor misgivings from a cross-cultural perspective, the relevancy of this volume goes beyond an a4 page description of each condition. first, in medical education as well as in clinical communication and medical ethics, the trends are to b o o k r e v i e w طريقة مرتاغ حسب املريض تعليم مرتاغ املؤلف: جون author: john murtagh publisher: mcgraw-hill australia, 5th edition, 2008; $60 isbn-978 0070158993 (pbk.) orders: http://www.mhprofessional.com b o o k r e v i e w : m u r ta g h ’ s pat i e n t e d u c at i o n 100 follow a patient-centered approach requiring doctors to work with patients as partners. the doctor and the client should agree on diagnosis, treatment and prevention, the aim being to bestow some responsibility on the patient which can be a catalyst for self-improvement. the traditional, paternalistic doctor-patient relationship where the doctor determines, from his or her perspective, what is best for the patient is increasingly out of favour in this age of quality assurance and patient consent. medical practitioners in the region should wake up to the reality that the new colloquialism for doctor is hakim. this term describes a doctor as a teacher who imparts knowledge, a view widely held during the golden age of islamic medicine, but one that has ceased to be in force in more recent times. secondly, in parallel with the concept of hakim, in modern medicine it has been increasingly recognised that there is a direct relationship between patients’ understanding of their own illness and the resultant coping mechanisms. the assumption is that each patient carries his own ‘doctor’ inside him and it is up to the health care practitioners to awaken such a capacity. by enabling the patient to become a ‘doctor’, each sufferer can achieve a great degree of control over his or her illness. such self-advocacy skills have the net benefit of heightening patients’ satisfaction with medical services and their compliance and adherence to treatment protocols which, of course, often results in better health outcomes. this volume aims to educate patients about their illnesses. in the end, isn’t it the person who experiences the disease who knows best? this is especially true in a world where patients are now seen as consumers with choices. the intended audience of this volume is patients via their family doctors. the volume is a must-have volume for medical students, all medical practitioners and, for that matter, any inquisitive mind. each ailment is described without the jargon often common in medical texts. the book provides the protocol that doctors can use in their clinical settings. in addition to describing illnesses, preventive health advice, some self-help tips for compliance and alternative interventions and the broad field of health promotion are all clearly covered in a4 pages that can be easily photocopied. samir al-adawi department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: adawi@squ.edu.om 1department of medicine, sultan qaboos university hospital, muscat, oman; 2department of microbiology, armed forces hospital, muscat, oman; 3nursing directorate, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: kowhassan@gmail.com abstract: objectives: brucellosis is a highly contagious zoonotic disease which can have serious health implications for affected humans and livestock. this study aimed to evaluate the clinical presentation, geographical distribution and risk factors of brucellosis cases admitted over a four-year period to two hospitals in muscat, oman. methods: this observational study was conducted from january 2015 to december 2018 at the sultan qaboos university hospital and armed forces hospital in muscat. all patients with probable or definitive diagnoses of brucellosis according to the diagnostic criteria of the world health organization were included. relevant data were gathered from the patients’ medical records, including results from standard agglutination tests, brucella enzymelinked immunosorbent assays, bacterial blood or tissue/aspirate cultures and brucella polymerase chain reaction tests. results: a total of 64 patients were diagnosed with brucellosis over the study period. the median age was 31.5 years and 73.4% were male. the majority (95.2%) presented with fever, followed by weight loss (51%), transaminitis (48.4%), peripheral arthritis/arthralgia (15.9%) and back pain (spondylodiscitis/sacroiliitis; 23.4%). overall, 75.5% reported having consumed raw dairy products, while only 25.9% gave a positive history of animal contact. conclusion: patients with brucellosis presented with a wide range of clinical features, the most predominant of which was fever. the majority of patients were residents of or had recently visited salalah and had consumed raw dairy products. these findings highlight the need for healthcare practitioners to maintain a high index of suspicion for this diagnosis. moreover, further regulatory measures are necessary to oversee the sale of raw/unpasteurised dairy products. keywords: brucellosis; bacterial infections; zoonotic bacterial infections; risk factors; epidemiology; oman. clinical presentations of brucellosis over a four-year period at sultan qaboos university hospital and armed forces hospital, muscat, oman *kowthar s. hassan,1 helmut schuster,2 abdullah al-rawahi,3 abdullah balkhair1 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e282–288, epub. 21 jun 21 submitted 29 apr 20 revision req. 1 jul 20; revision recd. 21 jul 20 accepted 11 aug 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.018 clinical & basic research advances in knowledge the findings of the study indicated that patients with brucellosis presented with a wide range of clinical features, the most common of which was fever. in addition, the results indicated that the primary source of infection was food-borne in nature. to the best of the authors’ knowledge, this is the first study to report information regarding cases of human brucellosis in adult patients from various regions of oman. application to patient care based on these findings, clinicians should maintain a high index of suspicion of brucellosis among patients with such presentations in order to avoid unnecessary delays in diagnosis and treatment. moreover, relevant information should be elicited during history-taking with regard to exposure to raw dairy products. brucellosis is an endemic bacterial disease which affects wild and domestic animals all over the globe, principally cattle, goats, sheep, swine and camels.1 annually, more than 500,000 cases of zoonotic infection in humans are reported worldwide, particularly in certain regions such as the mediterranean, middle east, africa and latin america.1,2 the disease is known under various names in different parts of the world, including undulant fever, malta fever and mediterranean fever.3 in the dhofar region of oman, it is known as maradh alhayawan, meaning “disease of animals”. brucellosis is caused by brucella, a genus of small non-motile gram-negative coccobacilli first isolated in 1886 by scottish army surgeon, sir david bruce.4 of the seven known brucella species, four are pathogenic to humans, namely brucella melitensis, b. abortus, b. suis and b. canis. human acquisition of the disease occurs via the consumption of raw milk or dairy products from unpasteurised milk and undercooked meat, as well as contact with fluids from infected animals.5 airborne transmission has also been reported, especially in laboratory personnel.6 while human-tohuman transmission is unusual, rare cases have been reported as a result of blood transfusion, bone marrow transplantation or sexual contact.7–10 in animals, brucellosis causes mastitis, spontaneous abortions, stillbirths and premature infertility.1,2 in humans, brucellosis causes a systemic infection with a highly variable incubation period https://creativecommons.org/licenses/by-nd/4.0/ kowthar s. hassan, helmut schuster, abdullah al-rawahi and abdullah balkhair clinical and basic research | e283 ranging from five days to a few months.11 patients can be clinically asymptomatic, with the infection detected solely upon screening by positive serological findings or can present with a wide spectrum of clinical features that are acute (<8 weeks), subacute (8–52 weeks) or chronic (>52 weeks) in duration. focal disease occurs in approximately 30% of patients and can affect any organ.12,13 in particular, non-specific symptoms—such as fever, night sweats, malaise, weight loss, arthralgia and lymphadenopathy—or features mimicking other diseases can lead to delays in diagnosis and treatment, thus necessitating a high index of suspicion.14 the current study aimed to determine the clinical presentation, geographical distribution and epidemiological risk factors of brucellosis cases admitted over a four-year period to two hospitals in muscat, oman. such information may prove useful to help policymakers address the disease in a concerted manner including the implementation of public awareness campaigns. in addition, regulatory instruments may also be important to detect and contain cases amongst farm animals in order to reduce the reservoir of infection. moreover, an understanding regarding the wide spectrum of clinical presentations of this disease may encourage healthcare practitioners to include brucellosis in the differential diagnosis of patients with similar symptoms. methods this observational study was conducted between january 2015 and december 2018 at the sultan qaboos university hospital (squh) and armed forces hospital (afh) in muscat. initially, data collection was conducted on a retrospective basis for all cases diagnosed in 2015 and 2016. subsequently, over the remaining two years, the study was conducted prospectively. the inclusion criteria comprised all patients with probable or definitive diagnoses of brucellosis according to the diagnostic criteria of the world health organization.15 patients of all nationalities and both genders over 12 years of age were included in the study. cases that had been diagnosed before january 2015 but were on treatment during the period of study were excluded. patients underwent serological testing with standard agglutination tests (sats) using stained suspensions for b. abortus and b. melitensis (remel inc., san diego, california, usa), with sat titres of ≥1 in 160 considered positive. cases of suspected relapse or chronic brucellosis were tested using a brucella immunoglobulin (ig) g and igm enzyme-linked immunosorbent assay (elisa). blood culture samples from suspected brucellosis cases were incubated aerobically for a total of 21 days using either the bact/ alert® 3d microbial detection system (biomérieux sa, marcy-l’étoile, lyon, france) at afh or the bd bactec™ blood culture system (becton, dickinson and co., franklin lakes, new jersey, usa) at squh. sterile site samples were incubated for at least 14 days after plating them on culture plates that included 5% horse blood agar and incubated in aerobic atmospheric conditions. grey-coloured colonies of 1–2 mm in diameter demonstrating positive reactions to oxidase, catalase and urease and grown on blood and/or chocolate blood agar plates were considered characteristic of brucella species, especially when the patient had also received positive sat results. an additional growth characteristic was a faint growth after one day of incubation that gradually became more pronounced after two days. under microscopy, the appearance of gram-negative cocci or coccobacilli in gramstained blood cultures and gram staining of colonies grown from sterile site sample cultures were deemed additional evidence. in general, speciation of the bacteria was not determined as this had no impact on patient management. data were analysed using microsoft excel version 16.48 (microsoft, redmond, usa). descriptive analysis of data is presented as numbers and percentages. this study was approved by the individual institutional research and ethics committees of squh (merc#1890) and afh (fmc-mec 001/2019). results a total of 64 patients were diagnosed with brucellosis over the study period, of which 36 (56.3%) presented to squh and 28 (43.8%) to afh. the male-to-female ratio was 47:17 and the median age was 31.5 years (range: 14–71 years). overall, six patients (9.4%) were diagnosed in 2015, 27 (42.2%) in 2016, 20 (31.3%) in 2017 and 11 (17.2%) in 2018. the diagnosis was made from positive blood cultures alone in three patients (4.7%), positive serology alone in 23 patients (35.9%) or from both positive blood cultures and serology in 34 patients (53.1%). blood cultures were positive in 41 patients (73.2%), serology was positive in 59 patients (93.7%). blood cultures and serology were not done on 8 and 1 patients respectively. three patients (4.7%) grew the bacteria from synovial fluid of the affected knees [table 1]. of these, two patients who had unilateral septic arthritis also had positive blood cultures and serology. the third patient presented with bilateral septic arthritis of prosthetic knee joints. blood cultures were also positive in all three patients but serology was clinical presentations of brucellosis over a four-year period at sultan qaboos university hospital and armed forces hospital, muscat, oman e284 | squ medical journal, may 2021, volume 21, issue 2 negative in one. in terms of risk factors, 40 patients (75.5%) had a history of consumption of raw dairy, one of which was in the form of kami, 15 patients (25.9%) a history of animal contact and data were missing for 17 patients (11 for dairy consumption and 6 for animal contact) [table 2]. with regards to location, 24 patients (37.5%) were from al batinah, particularly the town of almusannah. a total of 17 (26.6%), eight (12.5%), eight (12.5%), five (7.8%) and two (3.1%) patients were from the muscat, a’sharqiyah, ad dakhiliyah, dhofar and al wusta regions, respectively. however, 14 patients (21.9%) originally from outside the dhofar region had acquired the infection during recent trips to salalah where they had consumed raw dairy products from either street vendors (92.9%) or their local hosts (7.1%). in addition, two patients (3.1%) had acquired the infection in europe and one (1.6%) in saudi arabia [table 3]. the most common presentation was fever in 59 patients (95.2%), lasting for three weeks or longer in 41 cases (66%) and with associated night sweats, generalised fatigue and weight loss without any focal symptoms in 34 cases (57.6%). transaminitis was observed in 30 patients (48.4%), while weight loss— either in terms of a measured amount lost or as a visual observation—was reported by 25 patients (51%). back pain was reported in 15 cases (23.4%). three patients had radiological evidence of sacroiliitis, 8 of sponylodiscitis and 4 had normal spinal mri. radiculopathy occurred in two patients (3%) [table 4]. peripheral arthritis/arthralgia was reported in 10 cases (15.9%), including four cases of hip arthritis, three of knee arthritis, one of both knee and elbow arthritis and four cases of knee arthralgia. one of the knee arthritis cases demonstrated involvement of the bilateral prosthetic knee joints. genitourinary involvement in form of prostatitis or epidedymoorchitis occurred solely in six patients of the 47 male patients (12.8%). respiratory manifestations were table 2: risk factors identified among cases of brucellosis presenting over a four-year period to the sultan qaboos university hospital and armed forces hospital, muscat, oman (n = 64) factor n (%) yes no consumption of raw dairy products (n = 53)* 40 (75.5) 13 (24.5) animal contact (n = 58)† 15 (25.9) 43 (74) *data of 11 patients were missing. †data of six patients were missing. table 3: geographical distribution of cases of brucellosis presenting over a four-year period to the sultan qaboos university hospital and armed forces hospital, muscat, oman (n = 64) region n (%) no recent trip to salalah (n = 50) recent trip to salalah* (n = 14) total al batinah 20 (40) 4 (28.6) 24 (37.5) muscat 11† (22) 6 (42.9) 17 (26.6) a’sharqiyah 7 (14) 1 (7.1) 8 (12.5) ad dakhiliyah 5‡ (10) 3 (21.4) 8 (12.5) dhofar 5 (10) 0 (0) 5 (7.8) al wusta 2 (4) 0 (0) 2 (3.1) *including 13 cases that had consumed raw dairy products from street vendors and one case who had consumed raw dairy product(s) from their local host. †including two cases who reported a recent history of consump tion of raw dairy products in europe, one from a tour around europe including turkey and the other in bosnia. ‡including one patient who reported a recent history of consumption of raw dairy products in saudi arabia. table 4: clinical presentations of cases of brucellosis pres enting over a four-year period to the sultan qaboos univ ersity hospital and armed forces hospital, muscat, oman (n = 64) presentation n (%) fever 59 (95.2)* transaminitis 30 (48.4)* weight loss 25 (51)† back problems 15 (23.4)‡ peripheral arthritis 10 (15.9)§ jaundice 8 (12.5) hepatosplenomegaly 7 (10.9) genitourinary problems 6¶ (12.8)// pancytopenia 5 (7.8) respiratory problems 5 (7.8) *not assessed in two cases. †not assessed in 15 cases. ‡including four cases of lower back pain without radiological evidence, two of sacroiliitis, two of cervical spondylodiscitis, one of thoracic spondylodiscitis and six of lumbar spondylodiscitis. §not assessed in one case. ¶all six patients were male. //not assessed in 17 cases, all of whom were females. table 1: type of diagnostic test performed among cases of brucellosis presenting over a four-year period to the sultan qaboos university hospital and armed forces hospital, muscat, oman (n = 64) diagnostic test n (%) nd positive negative blood cultures (n= 56)* 41 (73.2%) 15 (26.8%) 8 serology (n= 63)* 59 (93.7%) 5 (8%) 1 nd = not done. *brucella grew in synovial fluid of three patients. all three had positive blood cultures but serology was positive in two only. kowthar s. hassan, helmut schuster, abdullah al-rawahi and abdullah balkhair clinical and basic research | e285 present in five patients (7.8%) in the form of dry cough; chest radiographs showed lung nodules in one patient, but were normal for the remaining four patients. jaundice was present in eight patients (12.5%) and hepatosplenomegaly in seven (10.9%). five patients (7.8%) had pancytopenia. among those without leukopenia, white cell counts for lymphocytes, neutrophils and monocytes were within normal range and remained so throughout treatment. for eight patients (17%), the erythrocyte sedimentation rate (esr) at presentation was normal; however, this was not assessed in 17 patients. for the remaining 39 patients (83%), the median esr was 45 mm/hour (range: 20–109 mm/hour). levels of c-reactive protein (crp) at presentation were not assessed in 10 cases and were normal in two patients (3.7%). for the remaining 52 patients (96.3%), the median crp level was 58 mg/dl (range: 10–175 mg/ dl). none of the patients presented with cardiac or neuropsychiatric manifestations. relapses occurred in seven patients (10.9%), including one patient with no known risk factors and two who once again consumed raw dairy products. no relevant history was documented for the remaining four patients. all relapses were confirmed via positive serology results, with four also having positive blood cultures. although an attempt was made to measure the rate of serological positivity with treatment, sequential serology was performed in only 17 cases (26.6%). in these patients, the drop in positive serology occurred slowly, taking approximately two months to halve from 1/1,280 to 1/640 and up to a year to halve again from 1/320 to 1/160. discussion the aim of the current study was to investigate the clinical presentation of cases of brucellosis admitted over a four-year period to two hospitals in oman, along with their geographical distribution and any risk factors involved in the acquisition of the disease. according to official data from the ministry of health, brucellosis is a common zoonotic disease in oman.16 an extensive serological survey of four species of domestic animals conducted from 1985–1986 showed high levels of brucella seropositivity, predominantly in the dhofar region.17 overall, 95–99% and 81% of previous cases of brucellosis reported between 1998– 2002 and 2013–2017, respectively, originated from the dhofar region.16,18 similarly, the results of the present study show that the dhofar region played an important role in the geographical distribution of brucellosis cases between 2015–2018, not only for local residents but also for visitors. in particular, salalah, the largest city in dhofar, is an immensely popular tourist destination, particularly during the annual khareef (monsoon) season from june to september due to its cool climate and lush landscape. in the current study, the greatest number of brucellosis cases per year were seen in 2016, a finding which could reflect the high number of visitors to salalah in this year compared to those immediately preceding or following (652,986 visitors in 2016 versus 514,777 and 644,931 visitors in 2015 and 2017, respectively).19 however, this difference in numbers is too low to come to a strong conclusion. the leading cause of human brucellosis cases worldwide is believed to be the transmission of b. melitensis in contaminated sheep and goat milk.5 however, patients acquiring brucellosis in salalah are more likely to have acquired the infection from unpasteurised camel milk. traditionally, camel milk is consumed without being boiled due to the resulting unpleasant change in its taste. in addition to the easy accessibility of unpasteurised camel milk from street vendors, local customs of hospitality encourage the offering of unpasteurised camel milk to guests. one of the patients in the present study was an expatriate teacher who acquired the infection in this manner. the majority of patients in the current study were male (73.4%). a high rate of brucellosis in men (80%) was also reported by awaidy and al hashami.18 while this finding does not necessarily reflect acquisition through occupation as it does in other studies, it may reflect a higher rate of consumption of raw dairy products.20 overall, 75.5% of patients in the current study reported a history of consuming raw dairy products. el-amin et al. reported a similar rate (63%) among infected children from dhofar.21 in particular, one patient in the present study had consumed kami, a popular dairy snack produced in the muscat and al batinah regions of oman. kami is a soft, sour, fermented dairy product which gradually becomes harder when stored at room temperature or refrigerated. various studies have shown that while the milk fermentation process destroys b. melitensis, the b. abortus species is able to survive.22,23 as such, the possible acquisition of brucellosis through kami consumption could be due to the survival of the b. abortus species. animal exposure is another known method of acquiring zoonotic brucellosis.6 levels of exposure can vary from actual caring for the animals to having them in the house or yard without being directly involved in their care. in the current study, only 25.9% of patients reported a history of animal contact. much higher rates of animal exposure (83%) were reported in an earlier study by awaidy and al hashami, possibly due clinical presentations of brucellosis over a four-year period at sultan qaboos university hospital and armed forces hospital, muscat, oman e286 | squ medical journal, may 2021, volume 21, issue 2 to differences in the populations studied.18 however, in cases in which patients denied both raw dairy product consumption and animal contact, one could question the safety of store-bought dairy products and the legitimacy of their pasteurisation claims. brucella can survive in refrigerated temperatures of 4°c for up to six weeks in cream and 100 days in fresh soft cheeses.22 another possibility is that patient history was not adequately obtained in certain cases, or that some patients were unwilling to disclose their history of raw dairy consumption due to the traditional belief that it could not possibly be a cause of illness. alternatively, some patients may have simply forgotten instances of incidental or distant exposure to animals or infrequent consumption of raw dairy products. importantly, some cases in the current study demonstrated strong positive serology but negative blood cultures. this could be due to the insufficient volume of blood samples sent to the laboratory. indeed, in some cases, blood culture sets sent on the same day for the same patient showed contradictory results. therefore, in order to increase the chances of diagnosing brucellosis, it seems reasonable to send both serology and more than one set of blood cultures. another interesting finding of the present study was the growth of brucella from the synovial fluid of a patient with bilateral prosthetic joints in whom serology was negative and blood cultures were positive. it is not uncommon to find negative serology during chronic or relapsing infection phases, as sat results tend to be falsely negative due to the switching from agglutinating to non-agglutinating antibodies.24 a wide range of clinical features are observed among brucellosis patients, both in the current study and in reports from other countries.25–29 this clearly shows that signs and symptoms of brucellosis may vary extensively, ranging from non-specific manifestations to mimickers of other diseases. as such, it is paramount that this disease be considered during differential diagnosis. fever was the most commonly reported symptom in the present study (95.2%) and often lasted longer than three weeks, reflecting the undulant nature of the disease. in contrast, a meta-analysis found that fever was only present in 78% of cases.25 this indicates that fever may be absent in some cases presenting with non-specific symptoms. weight loss occurred in up to 51% of patients in the present study. much lower rates of weight loss were reported in previous research (26.6–42%); this could be due to the inclusion of cases in which the reporting of weight loss relied on visual observation rather than objective measurement.25,26 peripheral arthritis (excluding arthralgia) occurred in 12.5 % of patients, with similar rates reported in neighbouring countries (12–14.3%).26,27 however, there was a greater frequency of spondylitis/spondylodiscitis (12.5% versus 3.1%).26 one of these patients was a young woman who had fallen during pregnancy, sustaining lumbar fractures which led to paraplegia. although she had experienced lower back pain for months beforehand, she attributed this symptom to her pregnancy, thus delaying her diagnosis. various haematological abnormalities in the form of anaemia, leukopenia, leukocytosis and thrombocytopaenia, including immune thrombocytopaenic purpura, have been reported in brucellosis cases, of which the majority are mild and resolve with treatment.14 leukocytosis—a symptom not reported in any of the patients in the current study—was found to occur infrequently in other studies (9–10.8%).26,27 genitourinary system involvement occurred solely in 12.8% of male patients in the present study, in accordance with findings from previous studies (3.7–17.5%).13,26,28 one patient investigated for metastasising prostate cancer due to urinary symptoms, weight loss, lower back pain and high levels of prostate-specific antigen was tested for brucellosis due to a history of prolonged fever and consumption of raw dairy products. his serology was positive and all symptoms resolved upon treatment. pulmonary involvement in the current study occurred at a slightly higher rate than that reported in the literature (7.8% versus ~6%), whereas the opposite was true for hepatosplenomegaly (10.9% versus 23%).25,29 relapses are documented in 5–30% of brucellosis cases, depending on treatment regimen and compliance to therapy; these typically occur within six months of discontinuation of therapy.30 in the present study, relapses occurred in 10.9% of patients, two of whom once more consumed raw dairy products. one patient relapsed despite ceasing to consume raw dairy products and complying with therapy. in general, brucella sat titre levels are slow to drop after treatment; as such, this factor should not be considered indicative of treatment failure.31 an important issue in the prevention of brucellosis is that no human vaccines have yet been approved. while the rb51 animal vaccine was previously disseminated to animals in the dhofar region, it was discontinued after 2010 due to complaints from camel herders that it caused miscarriages. studies have confirmed that the live vaccine may cause abortions and premature births in pregnant dairy cows.32,33 thus, the burden of prevention lies on raising public awareness and curtailing unsafe practices with regard to raw dairy consumption. the current study highlights a number of important points regarding the risk factors, kowthar s. hassan, helmut schuster, abdullah al-rawahi and abdullah balkhair clinical and basic research | e287 epidemiology and presentation of human brucellosis in oman. it is necessary that clinicians maintain a high index of suspicion of brucellosis due to its wide range of clinical presentations, many of which may be nonspecific in nature or mimic other diseases. in addition, the study addresses the importance of obtaining a thorough history of risk factors and sending appropriate samples for diagnostic confirmation. finally, while the findings show that the dhofar region remains the primary geographical location of infections, other areas may also be at risk, particularly in the al batinah region. this study was subject to certain limitations. in general, it is recommended that all samples and cultures containing brucella isolates be processed in a class ii biosafety cabinet (bsc) within a containment level 3 laboratory room or facility, while serology samples should be processed in a class ii bsc.34 however, as containment level 3 facilities for human microbiology diagnostic processes were not available in oman during the study period, samples from suspected brucellosis cases were processed in a class ii bsc within a containment level 2 laboratory. moreover, identification of the precise causative brucella species was limited to only a few patients in whom isolates showed unusual growth characteristics or from whom direct aspirate samples were tested by pcr. as such, the majority of isolates were identified solely to the genus level. conclusion the majority of cases of zoonotic brucellosis infections observed in the present study were acquired as a result of the consumption of raw dairy products in salalah. due to the lack of a vaccine against brucella, the best strategy to prevent infection appears to rely on public education initiatives regarding the dangers of raw dairy product consumption and exposure to animals. informational campaigns should therefore be conducted over public media channels, particularly just before the start of the annual khareef season when large numbers of tourists traditionally visit the dhofar region. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. maurin m. [brucellosis at the dawn of the 21st century]. med mal infect 2005; 35:6–16. https://doi.org/10.1016/j.medmal.20 04.08.003. 2. world health organization. brucellosis in humans and animals. from: www.who.int/csr/resources/publications/brucellosis.pdf accessed: jul 2020. 3. di pierdomenico a, borgia sm, richardson d, baqi m. brucellosis in a returned traveler. cmaj 2011; 183:e690–2. https://doi. org/10.1503/cmaj.091752. 4. bruce d. note on the discovery of a micro-organism in malta fever. practit 1887; 29:161. 5. cooper cw. risk factors in transmission of brucellosis from animals to humans in saudi arabia. trans r soc trop med hyg 1992; 86:206–9. https://doi.org/10.1016/0035-9203(92)90575-w. 6. memish za, mah mw. brucellosis in laboratory workers at a saudi arabian hospital. am j infect control 2001; 29:48–52. https://doi.org/10.1067/mic.2001.111374. 7. ruben b, band jd, wong p, colville j. person-to-person transmission of brucella melitensis. lancet 1991; 337:14–15. https://doi.org/10.1016/0140-6736(91)93332-4. 8. naparstek e, block cs, slavin s. transmission of brucellosis by bone marrow transplantation. lancet 1982; 1:574–5. https:// doi.org/10.1016/s0140-6736(82)92090-6. 9. doganay m, aygen b, eşel d. brucellosis due to blood transfusion. j hosp infect 2001; 49:151–2. https://doi.org/10.1053/jhin.2001.1004. 10. meltzer a, sidi y, smolen g, banai m, bardenstein s, schwartz e. sexually transmitted brucellosis in humans. clin infect dis 2010; 51:e12–15. https://doi.org/10.1086/653608. 11. negrón me, tiller r and kharod g. travel related infectious diseases chapter 4. from: www.cdc.gov/travel/yellobook/2020/ travel-related-infectious-diseases/brucellosis accessed: jul 2020. 12. aygen b, doğanay m, sümerkan b, yildiz o, kayabaş ü. clinical manifestations, complications and treatment of brucellosis: a retrospective evaluation of 480 patients. med mal infect 2002; 32:485–93. https://doi.org/10.1016/s0399-077x(02)00403-1. 13. hasanjani roushan mr, mohrez m, smailnejad gangi sm, soleimani amiri mj, hajiahmadi m. epidemiological features and clinical manifestations in 469 adult patients with brucellosis in babol, northern iran. epidemiol infect 2004; 132:1109–14. https://doi.org/10.1017/s0950268804002833. 14. young ej. brucella species. in: mandell gl, bennett je, dolin r (eds). principles and practice of infectious diseases, 6th ed. philadelphia, pennsylvania: churchill livingstone, 2004. pp. 2669–72. 15. who recommended strategies for the prevention and control of communicable diseases. department of communicable dosease control, prevention and eradication. who/cdc/cpe/smt/2 001.13. page 51. from: https://apps.who.int/iris/handle/10665/6 7088 accessed: jul 2020. 16. oman ministry of health. 2003. brucellosis community health dis. annual records. from: www.moh.gov.om/en_us/web/ statistics/annual-reports accessed: jul 2020. 17. ismaily si, harby ha, nicoletti p. prevalence of brucella antibodies in four animal species in the sultanate of oman. trop anim health prod 1988; 20:269–70. https://doi.org/10.1007/ bf02239996. 18. awaidy sa, al hashami h. zoontic diseases in oman: successes, challenges and future directions. vector borne zoonotic dis 2020; 20:1–9. https://doi.org/10.1089/vbz.2019.2458. 19. national center for statistics and information. from: www. ncsi.gov.om/pages ncsi.aspx accessed: jul 2020. https://doi.org/10.1016/j.medmal.2004.08.003 https://doi.org/10.1016/j.medmal.2004.08.003 https://doi.org/10.1503/cmaj.091752 https://doi.org/10.1503/cmaj.091752 https://doi.org/10.1016/0035-9203%2892%2990575-w https://doi.org/10.1067/mic.2001.111374 https://doi.org/10.1016/0140-6736%2891%2993332-4 https://doi.org/10.1016/s0140-6736%2882%2992090-6 https://doi.org/10.1016/s0140-6736%2882%2992090-6 https://doi.org/10.1053/jhin.2001.1004 https://doi.org/10.1086/653608 https://doi.org/10.1016/s0399-077x%2802%2900403-1 https://doi.org/10.1017/s0950268804002833 https://doi.org/10.1007/bf02239996 https://doi.org/10.1007/bf02239996 https://doi.org/10.1089/vbz.2019.2458 clinical presentations of brucellosis over a four-year period at sultan qaboos university hospital and armed forces hospital, muscat, oman e288 | squ medical journal, may 2021, volume 21, issue 2 20. hall wh. brucellosis. in: evans as (ed). bacterial infections of humans: epidemiology and control, 2nd ed. new york, usa: springer, 1982. pp. 119–35. https://doi.org/10.1007/978-14757-1140-0. 21. el-amin eo, george l, kutty nk, sharma pp, choithramani rs, jhaveri vp, et al. brucellosis in children of dhofar region, oman. saudi med j 2001; 22:610–15. 22. mandell, douglas, and bennett’s principles and practice of infectious diseases. ninth edition. elsevier. 23. zúñiga estrada a, mota de la garaza l, sánchez mendoza m, santos lópez em, filardo kerstupp s, lópez merino e. survival of brucella abortus in milk fermented with a yoghurt starter culture. rev latinoam microbiol 2005; 47:88–91. 24. hench ps, bauer w, dawson mh, hall f, holbrook wp, key ja, et al. the problem of rheumatism and arthritis: sixth rheumatism review. ann intern med 1940; 13:1655–1739. https://doi.org/1 0.7326/0003-4819-13-9-1655. 25. dean as, crump l, greter h, hattendorf j, schelling e, zinsstag j. clinical manifestations of human brucellosis: a systematic review and meta-analysis. plos negl trop dis 2012; 6:e1929. https://doi.org/10.1371/journal.pntd.0001929. 26. buzgan t, karahocagil mk, irmak h, baran ai, karsen h, evirgen o, et al. clinical manifestations and complications in 1028 cases of brucellosis: a retrospective evaluation and review of the liter ature. int j infect dis 2010; 14:e469–78. https://doi.org/10.10 16/j.ijid.2009.06.031. 27. najari hr, sigaroudi mo, rastgoo m. clinical manifestations and laboratory findings of brucellosis at boo-ali-siena hospital of ghazvin province in iran. jundishapur j health sci 2018; 10:e14948. https://doi.org/10.5812/jjhs.14948. 28. afşar h, baydar j, sirmatel f. epididymo-orchitis due to brucellosis. br j urol 1993; 72:104–5. https://doi.org/10.1111/ j.1464-410x.1993.tb06468.x. 29. pappas g, bosilkovski m, akritidis n, mastora m, krteva l, tsianos e. brucellosis and the respiratory system. clin infect dis 2003; 37:e95–9. https://doi.org/10.1086/378125. 30. solera j. update on brucellosis: therapeutic challenges. int j antimicrob agents 2010; 36:s18–20. https://doi.org/10.1016/j. ijantimicag.2010.06.015. 31. almuneef m, memish za. persistence of brucella antibodies after successful treatment of acute brucellosis in an area of endemicity. j clin microbiol 2002; 40:2313. https://doi. org/10.1128/jcm.40.6.2313.2002. 32. fluegel dougherty am, cornish te, o’toole d, boergerfields am, henderson ol, mills kw. abortion and premature birth in cattle following vaccination with brucella abortus strain rb51. j vet diagn invest 2013; 25:630–5. https://doi. org/10.1177/1040638713499570. 33. yazdi hs, kafi m, haghkhah m, tamadon a, behroozikhan am, ghane m. abortions in pregnant dairy cows after vaccination with brucella abortus strain rb51. vet rec 2009; 165:570–1. https://doi.org/10.1136/vr.165.19.570. 34. brucellosis. assessing laboratory risk level and pep. cdc. http://www.cdc.gov/brucellosis/laboratories/risk-level.html. page last reviewed: april 6, 2018. https://doi.org/10.1007/978-1-4757-1140-0 https://doi.org/10.1007/978-1-4757-1140-0 https://doi.org/10.7326/0003-4819-13-9-1655 https://doi.org/10.7326/0003-4819-13-9-1655 https://doi.org/10.1371/journal.pntd.0001929 https://doi.org/10.1016/j.ijid.2009.06.031 https://doi.org/10.1016/j.ijid.2009.06.031 https://doi.org/10.5812/jjhs.14948 https://doi.org/10.1111/j.1464-410x.1993.tb06468.x https://doi.org/10.1111/j.1464-410x.1993.tb06468.x https://doi.org/10.1086/378125 https://doi.org/10.1016/j.ijantimicag.2010.06.015 https://doi.org/10.1016/j.ijantimicag.2010.06.015 https://doi.org/10.1128/jcm.40.6.2313.2002 https://doi.org/10.1128/jcm.40.6.2313.2002 https://doi.org/10.1177/1040638713499570 https://doi.org/10.1177/1040638713499570 https://doi.org/10.1136/vr.165.19.570 august 2007 vol 7 copy.indd evidence based health care a scientific approach to health care *kamlesh bhargava,1 deepa bhargava2 sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 105-107 sultan qaboos university© submitted 21st april 2007 since the second world war, health care has witnessed tremendous advances in basic, applied and pharmacological research. this has resulted in an information overload for health care professionals. initially, evidence from research was not widely available due to lack of resources, but in the past two decades, with the advent of the internet, things have changed rapidly. the internet has become a powerful tool in health care decisions. health care decisions can range from opinion based, with little attention to evidence from research to evidence based, where decisions are derived from scientific research. the term evidence-based medicine (ebm) first appeared in the american college of physicians journal club in 1991.1 the exponential interest in this field can be judged by the pubmed citations: from one in 1992 to 25,184 in april 2007 [figure 1]. ebm requires the integration of the best research evidence, clinical expertise and the patient’s unique values and circumstances [figure 2]. clinical expertise comes from good history taking, physical examination and years of experience and the patient’s values include social and cultural factors besides the individual’s ideas concerns and expectations. in order to make the best decisions in our day to day patient care, we need valid information about prevention, diagnosis, prognosis and treatment. the traditional sources for this information are inadequate because they are out of date (textbooks), frequently wrong (experts), ineffective (didactic continuing medical education), or too overwhelming in their volume and too variable in their validity for practical clinical use (medical journals).2 the two principles of ebm are hierarchy of evidence and insufficiency of evidence alone.3 h i e r a r c h y o f e v i d e n c e evidence available in any clinical decision-making can be arranged in order of strength based on its likelihood of freedom from error. for example, for treatment decisions meta-analyses of well conducted large randomized trails may be the strongest evidence, followed by large multi-centric randomized trails, meta-analysis of well conducted small randomized trails, single centred randomized trails, observational studies, clinical experience or basic science research i n s u f f i c i e n c y o f e v i d e n c e a l o n e evidence alone is not enough it has to be integrated with clinical expertise, patient’s expectations and values. various terms like evidence-based nursing, evidence-based dentistry, evidence-based psychiatry, and evidence-based health care have been used under the generic term of ‘evidence-based medicine’.3 evidence used to make health policy and management decisions for populations has been termed evidence-based health care (ebhc). th e gr ow i n g n e e d f o r e v i d e n c e – b a se d s p e c i a l c o n t r i b u t i o n البحوث نتائج على املبنية الصحية الرعاية الصحية للرعاية علمي مدخل فارجافا ديبا فارجافا، كامليش 1family medicine and public health department, college of medicine and health sciences, sultan qaboos university hospital, p. o. box 35, al-khod 123, muscat, sultanate of oman; 2department of surgery (ent division), sultan qaboos university hospital, p. o. box 38, al-khod 123, muscat, sultanate of oman *to whom correspondence should be addressed. email: drkamlesh@gmail.com k a m l e s h b h a r g ava a n d d e e pa b h a r g ava 106 h e a lth c a r e the need and demand for ebhc is growing rapidly because of the following factors: information overload, rising patient expectations, the introduction of new technologies and ageing populations. in the past, health care managers tended to focus on cost and quality, thus “doing things right” and leaving “doing the right things” to other forces and chance.this situation is rapidly changing and everyone involved in decision making must use evidence to enable them to make decisions about “doing the right things”. these skills are necessary for provision of health care in the 21st century 4 [figure 3]. in situations where there is poor quality evidence, the decision maker will have to depend on his experience, available resources and patients expectations and values. s c o pe o f e v i d e n c e b a se d h e a lt h c a r e : 4 1. producing evidence (research) a. research workers are responsible for producing evidence. for this there are two frameworks, one provided by decision makers information source website cochrane library http://www.update-software.com/ publications/cochrane/ trip database http://www.tripdatabase.com/index.html pubmed http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=pubmed sign guidelines http://www.sign.ac.uk/ sum search http://sumsearch.uthscsa.edu uptodate http://www.utdol.com emedicine http://www.emedicine.com best bets http://www.bestbets.org national guideline clearinghouse http://www.guidelines.gov clinical evidence http://www.clinicalevidence.com/ceweb/ index.jsp table 1: the top 10 most useful sites for obtaining evidence figure 2: to make clinical decisions all the three components evidence, experience and expectations are required figure 1: the exponential increase in the number of articles with evidence-based medicine in the title or abstract in pubmed ( jan 1990 to april 2007) e v i d e n c e b a s e d h e a lt h c a r e 107 commissioned by governments or research councils. the other is provided by the researchers who seek funding to support their research projects. b. making evidence available. it is vital to make the research evidence available especially at the point of care, or the value of the new evidence can never be realized [table2]. c. the evidence obtained can be used in two ways: firstly to improve clinical practice and secondly to improve health service management. 2. evidence-based clinical practice this is an approach to decision making where a clinician uses the best evidence available, in consultation with the patient (evidence-based patient choice), to decide upon which option best suits the patient. evidence-based patient choice is achieved by informing about the risks and benefits of a particular intervention, procedure or surgery and making the patient a partner in the decision making process. one of the strategies used to implement this is the physician-patient partnership program (pppp), which is based on the concept of patientcentred care and the idea of the physician and the patient being partners in problem solving.5 3. evidence-based policy making, purchasing, and management for health services decision makers and managers who are responsible for health care have to make policy decisions in order to allocate funds, purchase or manage resources. with increasing demand and limited resources these decisions will have to be based on evidence. r e f e r e n c e s 1. guyatt gh. evidence-based medicine. acp journal club 1991;114:a-16. 2. straus se, richardson ws, glasziou p, haynes rb. evidence-based medicine. how to practice and teach ebm. 3rd edition. london: churchill livingstone, 2005. p. 2-3. 3. prasad k. introduction to evidence based medicine. in: fundamentals of evidence-based medicine. new delhi: pa meeta publishers, 2005. p.3. 4. gray jam. evidence-based healthcare. in: evidencebased healthcare first edition. new york: churchill livingstone, 1997. p. 3-6. 5. leopold n, cooper j, clancy c. sustained partnership in primary care. j fam pract 1996;42:129-37. figure 3: skills required of a practicing evidence based practitioner 1 submitted 10 jan 23 1 revision req. 23 mar 23; revision recd. 30 mar 23 2 accepted 3 may 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.037 5 6 congenital blood cyst of a child 7 a case report and review of literature 8 *rachid kaddoura,1 issam el rassi,2 zainab al awadi,2 9 mohamed kasem2 10 11 1college of medicine, mohammed bin rashid university of medicine and health 12 sciences, dubai, united arab emirates; 2al jalila children's speciality hospital, united 13 arab emirates. 14 *corresponding author’s e-mail: rachid.kaddoura@students.mbru.ac.ae 15 16 abstract 17 blood-filled cysts of the heart valves are frequently reported at postpartum autopsies of 18 infants. they are seen as round nodules mostly in the paediatric age group in infants less 19 than two months of age and disappear spontaneously within six months of life. we 20 present a unique case of an 11-month-old girl with a blood-filled cyst on the posterior 21 leaflet of the pulmonary valve that was successfully treated. this case report highlights 22 the characteristics and course of a paediatric patient with blood-filled cysts. further 23 studies are yet needed to better understand the diagnostic approaches to blood-filled cysts 24 as well as treatment modalities to fill the gap in clinical settings. 25 keywords: blood filled cysts; pulmonary valve; pulmonary artery; paediatrics; cardiac 26 tumor; cardiology. 27 28 2 introduction 29 blood-filled cysts (bfcs) are rare benign tumors mainly reported as cardiac tumors.1 30 since primary cardiac valve tumors are very uncommon, autopsy studies have provided 31 much of the current detailed information available in the literature.2, 3 numerous 32 parameters, such as tumor classification, location size, growth rate, and susceptibility to 33 embolize, affect the overall clinical presentation. both myxomas and papillary 34 fibroelastomas are the pathological conditions most likely to be related to embolism, with 35 the latter making up most primary valve tumor types.3, 4 moreover, lipomas, myxomas, 36 and rhabdomyomas are all reported as primary cardiac tumors as well. 37 38 bfcs of the heart valves were first reported in 1844 by elsasser.5 bfcs are often found 39 on the atrioventricular valves of newborn infants’ necropsies. they are usually seen as 40 small, rounded, multiple nodules on the atrial surfaces of the atrioventricular valves, but 41 are also seen less often on the ventricular surfaces of the semilunar valves.1-3 in this 42 report we present a rare case of a paediatric patient with a bfc on the pulmonary valve 43 leaflet. 44 45 case report 46 an 11-month-old girl presented to her general paediatrician for a non-cardiac cause at the 47 beginning of the year 2022. she was noted to have a loud systolic heart murmur in the 48 pulmonary area. the child was otherwise well, had no previous history of infections, and 49 has normal clinical examination findings otherwise. 50 51 the echocardiogram demonstrated severe right ventricular outflow obstruction due to a 52 possible cyst on the posterior leaflet of the pulmonary valve. the valve itself looked 53 normal, and there was post-stenotic dilatation of the main pulmonary artery. the gradient 54 across the pulmonary valve was 65 mmhg peak. 55 56 the patient underwent a right heart catheterization. the angiogram showed a cyst fixed 57 on the surface of one of the pulmonary valve leaflets (figure 1). the cyst was mobile 58 with the leaflet, but not causing any regurgitation. no ballooning was done, and the 59 3 patient had a chest ct scan which showed a filling defect in the main pulmonary artery. 60 the ct scan showed normal distal pulmonary arteries and branches, as well as normal 61 lung parenchyma, mediastinum, and no lymphadenopathy. a comprehensive infectious 62 and immunological assessment showed no underlying disease. 63 64 following the discussion with our multidisciplinary team (mdt), we decided to 65 surgically remove the cyst (figure 2). the surgical procedure was uneventful. resection 66 of the whole cyst that was attached to the posterior leaflet of the pulmonary valve was 67 performed, and the gradient decreased to less than 15 mmhg, with moderate pulmonary 68 valve regurgitation. 69 70 the histopathology of the cyst (figure 3) showed a 1*0.5*0.3cm multiloculated cyst, 71 filled with blood, and composed of a thin fibrous wall with focal myxoid changes. the 72 child made full recovery. at age of three, only a 12-mmhg peak gradient at the 73 pulmonary valve was observed, with moderate regurgitation, and no new cysts were 74 noted on any of the heart valves. 75 76 informed and written consent for the patient’s procedure and publication purposes for this 77 case report was obtained from the parents. 78 79 discussion 80 this report presents a unique case of a paediatric patient with a bfc on the posterior 81 leaflet of the pulmonary valve that was successfully managed and treated. unlike the 82 paediatric age group, singular valvular bfcs are rarely reported in older children and 83 adults, this is attributed to the fact that the cysts spontaneously regress in most patients as 84 they age.6 liese et al., cumming and ferguson and sakakibara et al., pa§aoglu et al., and 85 minato et al. reported 12 bfcs of the pulmonary valve that were treated successfully by 86 surgical resection.5-12 87 88 bfcs presents with symptoms of severe valvular stenosis due to the outflow obstruction, 89 as well as regurgitation presenting with signs of cyanosis, although they have mostly 90 4 been reported to be asymptomatic and only discovered incidentally usually on ct scans 91 done for non-cardiac reasons, especially in the infant age group.6,12 the patient presented 92 in this case report, initially went to the general paediatrician (gp) with no cardiac 93 symptoms, and the leading cause of the bfcs discovery was due to a loud systolic 94 murmur detected by the gp. following that, she was referred to the cardiology 95 department and an echocardiogram was done which identified the bfc. echocardiogram 96 is considered to be the gold standard for the diagnosis of bfcs, and in rare cases where a 97 thrombus or bacterial vegetations are suspected, contrast echocardiogram might help 98 differentiate it from cardiac cysts.13 99 100 to date, it is still unknown where the source of bfcs in cardiac valves arise from. 101 several animal studies revealed that 20% of all animal hearts contained bfcs, 102 highlighting its high prevalence.14 regarding the development of bfcs, adult cases have 103 been attributed to blunt trauma to the chest and complications during valvular surgeries, 104 however, their cause in the paediatric age group is still unknown.13 tsutsui et al. 105 suggested that bfcs may originate during the development of valves in early 106 embryogenesis or during early period of life from blood entrapped in valvular crevices or 107 tiny invaginations during development, therefore, a neonate with normal echocardiogram 108 findings can still develop bfcs in early infancy or childhood, while this process is very 109 unlikely to occur at later stages during adulthood.15 another hypothesis suggests that 110 bfcs are primarily due to hematoma formation as a result of blocked small vessels.12 111 furthermore, based on the findings of the histological and ultrastructural analysis, bfcs 112 could be due to the expansion of thin-walled valvular arteries in response to mechanical 113 stress caused by the pressure gradient when atrioventricular valves are closed, developing 114 a cyst.14 however, the presence of bfcs in low-pressure structures like the pulmonary 115 valve cannot be explained by the mentioned theory. therefore, the mentioned hypotheses 116 are quite hard to confirm and the definite formation of a bfc is not yet well established 117 in the current literature. 118 119 in terms of management, paşaoğlu et al. suggested surgically removing the bfcs in the 120 heart at the time of diagnosis independent of the patient’s symptoms.10 this was the 121 5 course of action for the patient presented in this case report. on the other hand, dencker 122 et al. encouraged a more conservative approach in asymptomatic patients and stated that 123 surgical approaches should be kept for symptomatic patients or if the cyst leads to cardiac 124 dysfunction.13 surgical interventions are usually done in order to rule out malignancy and 125 risk of strokes. pharmacological therapies including anticoagulants and beta-blocker use 126 are still controversial with very little evidence available in the current literature.13 this 127 emphasizes the need for more research exploring the outcomes of different management 128 approaches. 129 130 conclusion 131 in summary, we have reported a rare case of bfc above the pulmonary valve in addition 132 to a literature review. although several theories have been postulated regarding the origin 133 of bfcs, it remains unknown. bfcs are rare and are seen as small round nodules on 134 imaging modalities. however, a better understanding of the diagnostic approaches to 135 bfcs as well as treatment modalities is required to ensure an overall better prognosis in 136 both the adult and paediatric age groups. 137 138 conflicts of interest 139 the authors declare no conflict of interests. 140 141 author contributions 142 rk, ier and mk conceptualized and designed the work. rk, ier and mk collected 143 analysed and interpreted the data. rk and mk drafted the manuscript. zaa and mk 144 revised the manuscript. all authors approved the final version of the manuscript. 145 rachid kaddoura: drafting the manuscript. 146 147 references 148 1. yada m, nishina t, sato s, ueda y, yamanaka k. cardiac blood cyst with 149 concomitant papillary fibroelastoma. j cardiol cases. 2021;23(2):73-5. doi: 150 10.1016/j.jccase.2020.09.013 151 6 2. wang y, wang x, xiao y. surgical treatment of primary cardiac valve tumor: 152 early and late results in eight patients. journal of cardiothoracic surgery. 153 2016;11(1):31. 154 3. edwards fh, hale d, cohen a, thompson l, pezzella at, virmani r. 155 primary cardiac valve tumors. ann thorac surg. 1991;52(5):1127-31. doi: 156 10.1016/0003-4975(91)91293-5 157 4. gopaldas rr, atluri pv, blaustein as, bakaeen fg, huh j, chu d. papillary 158 fibroelastoma of the aortic valve: operative approaches upon incidental 159 discovery. tex heart inst j. 2009;36(2):160-3. 160 5. elsässer c. bericht über die ereignisse in der gebäranstalt des catherinen-161 hospital in jahre 1844. med correspondenzblatt. 1844;14:297. 162 6. gallucci v, stritoni p, fasoli g, thiene g. giant blood cyst of tricuspid valve. 163 successful excision in an infant. br heart j. 1976;38(9):990-2. doi: 164 10.1136/hrt.38.9.990 165 7. liese gj, brainard sc, goto u. giant blood cyst of the pulmonary valve. 166 report of a case. n engl j med. 1963;269:465-7. doi: 167 10.1056/nejm196308292690908 168 8. cumming gr, ferguson cc. an elusive tumor of the pulmonary valve 169 associated with a coronary arteriovenous fistula. j thorac cardiovasc surg. 170 1965;50(5):715-20. doi: 10.1002/(sici)1522-726x 171 9. sakakibara s, katsuhara k, iida y, nishida h. pulmonary subvalvular tumor. 172 dis chest. 1967;51(6):637-42. doi: 10.1378/chest.51.6.637 173 10. paşaoğlu i, doğan r, demircin m, bozer ay. blood cyst of the pulmonary 174 valve causing pulmonic valve stenosis. am j cardiol. 1993;72(5):493-4. doi: 175 10.1016/0002-9149(93)91156-c 176 11. minato h, manabe t, masaki h, kawahara y. blood cyst of the pulmonary 177 valve in an adult: report of a case and review of the literature. hum pathol. 178 1997;28(2):252-5. doi: 10.1016/s0046-8177(97)90116-7 179 12. park mh, jung sy, youn hj, jin jy, lee jh, jung ho. blood cyst of 180 subvalvular apparatus of the mitral valve in an adult. j cardiovasc ultrasound. 181 2012;20(3):146-9. doi: 10.4250/jcu.2012.20.3.146 182 7 13. dencker m, jexmark t, hansen f, tydén p, roijer a, lührs c. bileaflet 183 blood cysts on the mitral valve in an adult. journal of the american society 184 of echocardiography. 2009;22(9):1085.e5-.e8. 185 14. marcato ps, benazzi c, bettini g, masi m, della salda l, sarli g, et al. 186 blood and serous cysts in the atrioventricular valves of the bovine heart. vet 187 pathol. 1996;33(1):14-21. doi: 10.1177/030098589603300102 188 15. tsutsui jm, pommerantzeff p, pinto im, rochitte ce, mathias w, jr. 189 characterization of blood-filled cyst by contrast echocardiography and 190 computed tomography. j am soc echocardiogr. 2008;21(6):777.e1-3. doi: 191 10.1016/j.echo.2007.08.044 192 193 194 figure 1: right heart catheter showing circumscribed rounded cysts 195 196 8 197 figure 2: surgical removal of the cyst 198 199 200 figure 3: gross appearance of the cysts 201 departments of 1biomedical imaging and 3anaesthesiology, university malaya, kuala lumpur, malaysia; 2department of radiology; university teknologi mara, selangor, malaysia *corresponding author’s e-mails: marlina352@uitm.edu.my and tanty3011@yahoo.com pulmonary complications of covid-19 a case report wai y. chan,1 *marlina t. ramli hamid,2 yi t. lim,1 ching c. ng,3 nadia f.m. gowdh,1 kartini rahmat1 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 138–143, epub. 28 feb 22 submitted 30 nov 20 revision req. 28 dec 20; revision recd. 16 jan 21 accepted 10 feb 21 of high-grade fever and occasional dry cough. he had recently attended a mass gathering, however there was no known history of close contact with a confirmed or probable covid-19 positive case. clinical examination revealed an elevated body temperature of 38.5°c and bibasal lung crepitations on auscultation. laboratory blood tests revealed a normal neutrophil count of 6.5 × 109/l (normal range: 2.0–7.0 × 109/l), borderline lymphocyte count of 1.14 × 109/l (normal range: 1.0– 3.0 × 109/l), raised c-reactive protein of 137.6 mg/l (normal range: <5.0 mg/l) with high serum ferritin of 2,268 µg/l (normal range: 22.0–322.0 µg/l). the remaining blood investigations were normal. screening tests for respiratory pathogens such as influenza a, influenza b, respiratory syncytial virus, legionella, mycoplasma pneumonia and chlamydia pneumonia were negative. sars-cov-2 was detected in the patient’s oropharyngeal and nasopharyngeal swab specimen through real-time reverse-transcription– polymerase chainreaction assay. the cxr at presentation showed classic peripheral consolidations in both lower zones. on day three of hospitalisation (nine days after the onset of fever), the patient developed worsening dyspnoea despite escalation of oxygen support to a venturi mask. he was then transferred to the intensive care unit (icu) and was put on high flow nasal cannula (hfnc) noninvasive ventilatory support. no clinical improvement was seen despite optimum hfnc setting (fraction of inspired oxygen = 0.6, flow = 60 l/min). the patient was started on empirical intravenous ceftriaxone, azithromycin, hydroxychloroquine, lopinavir/ritonavir covid-19 emerged from wuhan, hubei province, china in december 2019 and rapidly spread worldwide. most affected patients have mild symptoms with good prognosis. however, who-china joint mission on coronavirus disease 2019 reported severe and critical diseases in 13.8% and 6.1% of patients, respectively.1 pneumonia is a common complication of covid-19 infection, whilst acute respiratory distress syndrome (ards) is the most severe sequela. presence of pleural effusion, lung cavitation and lymphadenopathy are associated with severe disease and often carry poorer prognosis.2 many studies have reported common covid-19 chest manifestation on chest x-ray (cxr) and computed tomography (ct), however, studies that described chest complications on imaging are limited. herein, we report a case of severe covid-19 pneumonia, which progressed to multiple pulmonary complications including acute pulmonary embolism, pneumothorax, pneumomediastinum, extensive sub cutaneous emphysema and ruptured lung cysts causing bronchopleural fistula. this case report aims to raise awareness of potential complications, spectrum of respiratory manifestations and sequelae of covid-19 infection. case report a 69-year-old male patient with underlying diabetes mellitus and hypertension presented to the emergency department at a tertiary referral centre in kuala lumpur, malaysia in march 2020 with a 6-day history this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.070 case report abstract: rapid evolution of pulmonary complications associated with severe covid-19 pneumonia often pose a management challenge to clinicians especially in the critical care setting. serial chest imaging enable clinicians to better monitor disease progression and identify potential complications early which may decrease the mortality and morbidity associated with covid-19. we report a 69-year-old male patient with severe covid-19 pneumonia who presented to a tertiary referral centre in kuala lumpur, malaysia, in 2020 with multiple pulmonary complications including lung cavitation, bronchopleural fistula, pneumothorax, pneumomediastinum, subcutaneous emphysema and acute pulmonary embolism. unfortunately, the patient died one month after admission. covid-19 patients may develop pulmonary complications due to a combination of direct viral lung damage, hypoxaemia and high stress ventilation. awareness of covid-19 complications can prompt early diagnosis and timely management to reduce morbidity and mortality. keywords: covid-19; lung; fistula; pneumothorax; pneumomediastinum; case report; malaysia. https://creativecommons.org/licenses/by-nd/4.0/ wai y. chan, marlina t.r. hamid, yi t. lim, ching c. ng, nadia f.m. gowdh and kartini rahmat case report | 139 positive respiratory and blood culture results. cxr done on day 24 of illness demonstrated a new welldefined cystic lesion at the right lower zone [figure 2a]. there was no pneumothorax in the right chest. the left pneumothorax and subcutaneous emphysema had improved. a follow-up ctpa showed residual right pulmonary artery emboli and a large cyst in the consolidated right middle lobe communicating with a and subcutaneous enoxaparin prophylaxis dose based on the best evidence at that point of time during the early phase of covid-19 in malaysia. he remained tachypnoeic with a respiratory rate of >30/min and oxygen saturation of 88–92% with partial pressure oxygen of 51 mmhg on arterial blood gas analysis. the patient eventually required intubation and mechanical ventilation after six hours. highresolution ct (hrct) scan of his chest was done on the next day (day 10 of the illness) which revealed groundglass opacities (ggo) with consolidations and crazypaving patterns in both lung fields, predominantly in a subpleural distribution with approximately 50% total lung involvement. there was also gravity-dependent lung atelectasis in posterior lung bases bilaterally. no cystic lung lesions were noted in this initial ct. in view of worsening respiratory distress, the patient required mechanical ventilation with positive end-expiratory pressure averaging 10–14 cm h2o. on day 18 of illness and approximately one week after commencement of mechanical ventilation, the patient developed worsening oxygenation and extensive subcutaneous emphysema at the neck, chest and abdominal regions. immediate cxr and abdominal x-ray (axr) showed left pneumothorax, pneumo mediastinum as well as extensive subcutaneous emphy sema [figures 1a and b]. positive d-dimer was also detected at the same time. an urgent ct pulmonary angiography (ctpa), which was performed on the same day, showed feft pneumothorax, pneumome diastinum, extensive subcutaneous emphysema and extraperitoneal emphysema extending from the pneumomediastinum were observed. no parenchymal or subpleural cysts were present. there were also worsening dependent consolidations in both lung fields [figures 1c and d]. a filling defect consistent with emboli in the right main pulmonary artery extending to the segmental arteries of the right middle and lower lobes as well as in the segmental branches of the left lower lobe pulmonary artery was also observed [figures 1e and f]. subsequently, a chest tube was inserted for the left pneumothorax and subcutaneous enoxaparin was upgraded to treatment dose in view of the pulmonary embolism diagnosis. the patient was continued on mechanical ventilation due to difficult weaning. possible develop ment of superimposed bacterial infection could have contributed to the worsening respiratory status of the patient. antibiotic treatment was escalated to intravenous (iv) meropenem and vancomycin on day 21 of illness; iv hydrocortisone 50 mg every six hours was initiated for septic shock. this was followed by the addition of iv trimethoprim/sulfamethoxazole as stenotrophomonas maltophilia was found based on figure 1: a: chest x-ray on day 18 of illness showing left pneumothorax, in the form of deep sulcus sign in the left hemithorax (black arrowhead), pneumomediastinum (red arrows). there was also subcutaneous emphysema in both the chest and neck region (white arrows). b: abdominal x-ray demonstrating subcutaneous emphysema involving lower abdominal subcutaneous tissue (red arrowheads). there were also curvilinear lucencies at the upper abdomen suggestive of pneumomediastinum extending to extra-peritoneal space (white arrowheads). c and d: computed tomography pulmonary angiography (ctpa) in coronal and sagittal lung view showing left pneumothorax (red arrowheads), pneumomediastinum (red arrows), subcutaneous emphysema (yellow arrows) and extraperitoneal emphysema (black arrowheads). bilateral multifocal peripheral subpleural ground-glass opacities (blue arrows) and dependent consolidations were seen. e and f: axial and coronal view ctpa in mediastinal window showing filling defects (red arrows) in the right main pulmonary artery extending into the segmental branches of right middle and lower lobes as well as involving the segmental branch of the left lower lobe. pulmonary complications of covid-19 a case report 140 | squ medical journal, february 2022, volume 22, issue 1 segmental bronchus [figures 2b and c]. there were also multiple subpleural cysts, some communicating with each other in the right middle and lower lobes [figure 2d]. at the time, it was postulated that these cysts were likely secondary to underlying severe covid-19 lung changes. however, complication secondary to pulmonary infarct cannot be excluded. the next day, the patient developed right tension pneumothorax secondary to rupture of the lung cysts and an emergency right chest tube insertion was done [figures 3a and b]. unfortunately, despite insertion of double chest tubes over the right lung, the pneumothorax persisted. subsequently, blood pleurodesis was carried out but no clinical improvement was noted. throughout the patient’s icu stay, he required multiple cycles of prone positioning as rescue therapy to improve oxygenation. he also developed multiorgan failure requiring vasopressors and continuous renal replacement therapy. on day 24 of hospitalisation figure 2: a: chest x-ray on day 24 of illness showing a new well-defined cyst (arrows) at right lower zone and resolving left pneumothorax, pneumomediastinum and subcutaneous emphysema. b: axial view follow-up computed tomography pulmonary angiography (ctpa) in mediastinal window demonstrating residual thrombus in the right pulmonary artery (arrow). c: coronal view ctpa in lung window showing a large cyst in a consolidated right middle lobe with communication with adjacent segmental bronchi (arrow). d: axial view ctpa showing communication between the cysts (arrow). there were other several smaller non-communicating subpleural cysts in right middle and lower lobes (not shown). a b c d figure 3: a: chest x-ray on day 25 of illness demonstrating right tension pneumothorax. b: post chest tube insertion showed improving right pneumothorax with several right lower zone cysts (arrows) as seen on previous computed tomography (ct) scans. c and d: coronal and axial view high-resolution ct chest in lung window depicting smaller right middle lobe cysts (black arrows) and loculated right hydropneumothorax (red arrow). there was direct communication between the one of the cysts with the pleural space/pneumothorax suggesting a ruptured cyst causing bronchopleural fistula (white arrow). wai y. chan, marlina t.r. hamid, yi t. lim, ching c. ng, nadia f.m. gowdh and kartini rahmat case report | 141 (day 30 of illness), a fourth ct was performed in view of his worsening clinical condition and difficult ventilation. the ct depicted extensive bilateral consolidation, loculated right hydropneumothorax with a fluid filled cyst and communication between the pulmonary cyst with pleural space and segmental bronchi causing a bronchopleural fistula [figures 3c and d]. despite maximal organ support and medical treatment, the patient’s clinical condition deteriorated and he died on day 31 of illness [table 1]. informed consent for publication purposes was obtained from the patient’s family member. discussion chest imaging is indicated in covid-19 patients for establishing a baseline for the patient’s pulmonary condition, identification of cardiopulmonary comor bidities and for monitoring disease progression. in the event of clinical deterioration, imaging assessment helps to diagnose disease progression and acute cardio pulmonary complications such as pulmonary embolism, superimposed bacterial infection, heart failure or less commonly, complications such as pneumothorax and pneumomediastinum.3,4 typical chest findings in covid-19 patients show bilateral lung involvement with patchy or asymmetric diffuse air space opacities, predominantly in a peripheral, posterior distribution and mainly in the lower lobes.5 in later stages of the disease, ct may show increased ggo, dispersed consolidation, reticular opacities, crazy-paving, bronchiectasis, pleural thickening, septal thickening and involvement of subpleural region.2,5 as the disease progresses, atypical ct features such as pleural effusion, cystic changes, pericardial effusion, nodules and lympha denopathy may be present.2,5 in addition, complications such as pulmonary embolism, pneumothorax, pneumo mediastinum and cavitation or cysts in covid-19 positive patients have emerged which further elucidates the complexity in managing such patients.4 covid-19 pneumonia is described as a unique disease despite fulfilling most of the berlin definition of ards.6 the pathophysiology of this disease is attributed by a hyperimmune reaction of the host which results in massive vascular endothelial injury and alveolar epithelial cell damage.7 in the current case, the patient had no history of smoking or underlying lung pathology. the initial viral infection may impose structural damage to alveoli, particularly at the subpleural regions where ‘stress and strain’ insult is the greatest.2,7,8 this could possibly result in pneumatoceles or cysts in the subpleural areas of consolidation, as was seen in the current case. t ab le 1 : t im el in e of m aj or im ag in g fin di ng s ac co rd in g to d ay o f i lln es s an d da y of h os pi ta lis at io n of a 6 9ye ar -o ld c o v id -1 9po si ti ve m al e pa ti en t d ay o f i lln es s 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 d ay o f h os pi ta lis at io n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 ↓ ↓ ↓ ↓ ↓ ↓ m aj or im ag in g fin di ng s c x r b ila te ra l pe ri ph er al su bp le ur al co ns ol id at io ns a t lo w er z on es h r c t m ul tif oc al pe ri ph er al g g o ; co ns ol id at io ns w ith 50 % o f t ot al lu ng in vo lv em en t c x r n ew le ft p ne um ot ho ra x; pn eu m om ed ia st in um ; e xt en si ve su bc ut an eo us e m ph ys em a a x r su bc ut an eo us e m ph ys em a c t pa a cu te p e; le ft p ne um ot ho ra x; pn eu m om ed ia st in um d is se ct in g in to ex tr ape ri to ne al s pa ce ; e xt en si ve su bc ut an eo us e m ph ys em a c x r n ew r ig ht lo w er z on e cy st s c t pa n ew r ig ht m id dl e an d lo w er lo be c ys ts w ith br on ch ia l c om m un ic at io n; re si du al p e; w or se ni ng lu ng co ns ol id at io ns a nd d ep en de nt at el ec ta si s c x r r ig ht te ns io n pn eu m ot ho ra x se co nd ar y to ru pt ur ed c ys ts ; re so lv es le ft pn eu m ot ho ra x h r c t r ig ht hy dr op ne um ot ho ra x; ru pt ur ed c ys t a nd br on ch op le ur al fi st ul a; ex te ns iv e m ul tif oc al co ns ol id at io ns r t -p c r s w ab fo r s a r sc ov -2 + + + + + + c t v al ue 25 .4 4 22 .1 1 25 .6 8 29 .6 7 31 .3 3 35 .5 3 c x r = ch es t x -r ay ; h rc t = h ig hre so lu tio n co m pu te d to m og ra ph y; g g o = g ro un dgl as s o pa ci tie s; a x r = ab do m in al x -r ay ; c t pa = co m pu te d to m og ra ph y pu lm on ar y an gi og ra ph y; p e = pu lm on ar y em bo lis m ; r tpc r = re al -t im e re ve rs e t ra ns cr ip tio npo ly m er as e c ha in re ac tio n; c t = c yc le th re sh ol d. pulmonary complications of covid-19 a case report 142 | squ medical journal, february 2022, volume 22, issue 1 the development of lung cavitation is uncommon in covid-19 positive patients and could occur secondary to direct lung damage caused by the virus, stress imposed by the mechanical ventilation or may also result from secondary bacterial or fungal infection. possibility of secondary infection must be ruled out in the wake of development of lung cavitation in covid-19 and appropriately managed to improve the patient outcome. the high stresses generated during mechanical ventilation can cause barotrauma leading to bronchial or alveolar rupture, which is evidenced by air leak detected as pneumothorax, pneumomediastinum and subcutaneous emphysema on imaging.4,5,9 furthermore, the current patient developed acute pulmonary embolism during the course of the illness, which further exacerbated the ventilation/perfusion imbalances. klok et al. reported that pulmonary embolism is the most common thrombotic compli cation encountered in patients with covid-19; 1631% of pulmonary embolism are complicated by pulmonary infarction and cavitation complicates 4-7% of pulmonary infarctions.10–13 infarcts with cavities are commonly single, right-sided and after 2 weeks is associated with a large area of consolidation.14 severe covid-19 pneumonia is susceptible to both venous and arterial thromboembolism due to deranged coagulation, excessive inflammation, hypoxia and prolonged immobilisation. in addition, an increased d-dimer concentration at the time of admission is significantly associated with mortality.10,15 hence, judicious use of anticoagulant therapy is prudent in patients with covid-19 pneumonia in the absence of bleeding risk. conclusion the current case highlights the imaging findings of multiple pulmonary complications in a patient with severe covid-19 pneumonia. widespread lung damage, hypoxaemia and high-stress ventilation may lead to severe manifestations as was seen in this case. prompt recognition of these complications, cautious ventilation strategy and timely intervention targeted at the complications should be the direction of care for such patients to reduce morbidity and mortality. a c k n o w l e d g e m e n t s this article was funded by university malaya covid-19 related special research grant (csrg0022020st). we would also like to express our deepest gratitude to all the healthcare workers who have dedicated their time and efforts to battle covid-19 and protect the health of our citizens. a u t h o r s’ c o n t r i b u t i o n lyt and ncc drafted the manuscript. mtrh and cwy conducted the literature review. nfmg prepared the images. cwy, mtrh, nfmg and kr edited the manuscript. all authors approved the final version of the manuscript submitted for publication and take responsibility for the statements in the article. references 1. world health organisation. report of the who-china joint mission on coronavirus disease 2019 (covid-19). geneva, switzerland: world of health organisation. pp. 12. 2. shi h, han x, jiang n, cao y, alwalid o, gu j, et al. radiological findings from 81 patients with covid-19 pneumonia in wuhan, china: a descriptive study. lancet infect dis 2020; 4:425–34. https://doi.org/10.1016/s1473-3099(20)30086-4. 3. rubin gd, ryerson cj, haramati lb, sverzellati n, kanne jp, raoof s, et al. the role of chest imaging in patient management during the covid-19 pandemic: a multinational consensus statement from the fleischner society. chest 2020; 158:106–16. https://doi.org/10.1016/j.chest.2020.04.003. 4. sun r, liu h, wang x. mediastinal emphysema, giant bulla, and pneumothorax developed during the course of covid-19 pneu monia. korean j radiol 2020; 21:541–4. https://doi.org/10.3348/ kjr.2020.0180. 5. salehi s, abedi a, balakrishnan s, gholamrezanezhad a. corona virus disease 2019 (covid-19): a systematic review of imaging findings in 919 patients. ajr am j roentgenol 2020; 215:87–93. https://doi.org/10.2214/ajr.20.23034. 6. ards definition task force, ranieri vm, rubenfeld gd, thompson bt, ferguson nd, caldwell e, et al. acute respiratory distress syndrome: the berlin definition. jama 2012; 307:2526–33. https://doi.org/10.1001/jama.2012.5669. 7. gattinoni l, chiumello d, rossi s. covid-19 pneumonia: ards or not? crit care 2020; 24:154. https://doi.org/10.1186/ s13054-020-02880-z. 8. cressoni m, cadringher p, chiurazzi c, amini m, gallazzi e, marino a, et al. lung inhomogeneity in patients with acute respiratory distress syndrome. am j respir crit care med 2014; 189:149–58. https://doi.org/10.1164/rccm.201308-1567oc. 9. boussarsar m, thierry g, jaber s, roudot-thoraval f, lemaire f, brochard l. relationship between ventilatory settings and baro trauma in the acute respiratory distress syndrome. intensive care med 2002; 28:406–13. https://doi.org/10.1007/s00134001-1178-1. 10. klok fa, kruip mjha, van der meer njm, arbous ms, gommers dampj, kant km, et al. incidence of thrombotic complications in critically ill icu patients with covid-19. thromb res 2020; 191:145–7. https://doi.org/10.1016/j.thromres.2020.04.013. 11. miniati m, bottai m, ciccotosto c, roberto l, monti s. predictors of pulmonary infarction. medicine (baltimore) 2015; 94:e1488. https://doi.org/10.1097/md.0000000000001488. 12. islam m, filopei j, frank m, ramesh n, verzosa s, ehrlich m, et al. pulmonary infarction secondary to pulmonary embolism: an evolving paradigm. respirology 2018; 23:866–72. https:// doi.org/10.1111/resp.13299. https://doi.org/10.1016/s1473-3099(20)30086-4 https://doi.org/10.1016/j.chest.2020.04.003 https://doi.org/10.3348/kjr.2020.0180 https://doi.org/10.3348/kjr.2020.0180 https://doi.org/10.2214/ajr.20.23034 https://doi.org/10.1001/jama.2012.5669 https://doi.org/10.1186/s13054-020-02880-z https://doi.org/10.1186/s13054-020-02880-z https://doi.org/10.1164/rccm.201308-1567oc https://doi.org/10.1007/s00134-001-1178-1 https://doi.org/10.1007/s00134-001-1178-1 https://doi.org/10.1016/j.thromres.2020.04.013 https://doi.org/10.1097/md.0000000000001488 https://doi.org/10.1111/resp.13299 https://doi.org/10.1111/resp.13299 wai y. chan, marlina t.r. hamid, yi t. lim, ching c. ng, nadia f.m. gowdh and kartini rahmat case report | 143 13. rajagopala s, devaraj u, d'souza g. infected cavitating pulmonary infarction. respir care 2011; 56:707–9. https://doi. org/10.4187/respcare.00828. 14. wilson ag, joseph ae, butland rj. the radiology of aseptic cavitation in pulmonary infarction. clin radiol 1986; 37:327–33. https://doi.org/10.1016/s0009-9260(86)80263-x. 15. tang n, li d, wang x, sun z. abnormal coagulation parameters are associated with poor prognosis in patients with novel corona virus pneumonia. j thromb haemost 2020; 18:844–7. https:// doi.org/10.1111/jth.14768. https://doi.org/10.4187/respcare.00828 https://doi.org/10.4187/respcare.00828 https://doi.org/10.1016/s0009-9260(86)80263-x https://doi.org/10.1111/jth.14768 https://doi.org/10.1111/jth.14768 departments of 1surgery and 2social & preventive medicine, faculty of medicine, university of malaya, kuala lumpur, malaysia; 3department of surgery, assunta hospital, petaling jaya, malaysia; 4department of surgery, hospital sultanah bahiyah, alor setar, malaysia; 5department of paediatric surgery, hospital kuala lumpur, kuala lumpur, malaysia *corresponding author’s e-mail: ken4376@hotmail.com انتقال الرعاية يف جراحة األطفال املمارسات ووجهات النظر احلالية جلراحي األطفال يف ماليزيا �صونغ كني تان، اأناند �صامنوجام، حممود دناعي، تندفانام موثوراجنام رامانوجام، موهان اأرونا�صالم نالو�صامي، زكريا زاهاري، ثامبيدوراي راجيندرا راو abstract: objectives: transition of care (toc) from paediatric to adult care is still at an early stage in malaysia. this study aimed to explore current practices and perspectives regarding toc among paediatric surgeons in malaysia. methods: this study was carried out between june and december 2017. all 48 paediatric surgeons currently working in malaysia were invited to participate in a questionnaire-based survey to assess demographic characteristics and practices and perspectives regarding toc. results: a total of 38 paediatric surgeons participated in the survey (response rate: 79.2%). overall, 97.4% did not have an organised toc model in their institution, with most (65.8%) caring for paediatric patients with complex surgical conditions until adulthood. although the majority (86.8%) felt that care should be transitioned to adult surgeons with appropriate credentials, most surgeons (84.2%) nevertheless preferred to be involved in the management of adolescent patients after transition. however, there was no consensus regarding the most suitable age to begin the transition. years of experience as a paediatric surgeon and place of practice did not affect overall toc practice scores (p >0.050 each). the presence of adult comorbidities was considered the most common reason to initiate toc (81.6%), while the lack of toc guidelines was perceived to be the greatest barrier (84.2%). conclusion: this study provides a better understanding of toc from the point of view of paediatric surgeons in malaysia. however, further studies involving other stakeholders (i.e. patients and adult surgeons) are needed to help formulate a suitable and successful toc model in this setting. keywords: transition to adult care; pediatrics; adolescents; surgery; attitudes; professional practice; malaysia. امللخ�ص: الهدف: ل تزال عملية انتقال الرعاية من رعاية الأطفال اإىل رعاية البالغني يف مرحلة مبكرة يف ماليزيا. تهدف هذه الدرا�صة اإىل اإ�صتطالع املمار�صات احلالية ووجهات النظر فيما يتعلق بانتقال الرعاية بني جراحي الأطفال يف ماليزيا. الطريقة: اأجريت هذه الدرا�صة يف الفرتة بني يونيو ودي�صمرب 2017. مت دعوة جميع جراحي الأطفال الـ 48 الذين يعملون حالًيا يف ماليزيا للم�صاركة يف م�صح قائم على جمموعه ما �صارك الرعاية. النتائج: انتقال مبجال يتعلق فيما النظر ووجهات واملمار�صات الدميوغرافية اخل�صائ�ض لتقييم ال�صتبيان 38 جراح اأطفال يف امل�صح )معدل ال�صتجابة: %79.2( ب�صكل عام، مل يكن لدى %97.4 من امل�صاركني منوذج منظم لنتقال الرعاية يف موؤ�ص�صاتهم، حيث اهتم معظمهم )%65.8( باملر�صى الأطفال الذين يعانون من حالت جراحية معقدة حتى مرحلة البلوغ. على الرغم من اأن الغالبية )%86.8( �صعرت اأنه يجب نقل الرعاية اإىل جراحى البالغني املعتمدين، اإل اأن معظم اجلراحني )%84.2( يف�صلون امل�صاركة يف رعاية املر�صى املراهقني بعد النتقال. ومع ذلك، مل يكن هناك توافق يف الآراء ب�صاأن ال�صن الأن�صب لبدء النتقال. مل توؤثر �صنوات اخلربة يف جراحة الأطفال ومكان املمار�صة على نتيجة املمار�صات لنتقال الرعاية )p <0.050 لكل واحد(. مت اعتبار وجود اأمرا�ض م�صاحبة للبالغني ال�صبب الأكرث �صيوًعا لبدء انتقال الرعاية )%81.6( يف حني كان ينظر اإىل عدم وجود دلئل اإر�صادية لنتقال الرعاية على اأنها العائق الأكرب )%84.2(. اخلال�صة: توفر هذه الدرا�صة فهما اأف�صل لنتقال الرعاية من وجهة نظر جراحي الأطفال يف ماليزيا. ومع ذلك، هناك حاجة اإىل مزيد من الدرا�صات التي ت�صمل اأ�صحاب امل�صلحة الآخرين )اأي املر�صى وجراحى البالغني( للم�صاعدة يف �صياغة منوذج منا�صب وناجح لنتقال املر�صى يف هذا الإطار. الكلمات املفتاحية: النتقال اإىل رعاية البالغني؛ طب الأطفال؛ املراهقني؛ اجلراحة؛ الجتاهات؛ املمار�صة املهنية؛ ماليزيا. transition of care in paediatric surgery current practices and perspectives of paediatric surgeons in malaysia *shung k. tan,1 anand sanmugam,1 mahmoud danaee,2 tindivanam m. ramanujam,3 mohan a. nallusamy,4 zakaria zahari,5 thambidorai r. rao1 clinical & basic research sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e352–358, epub. 22 dec 19 submitted 17 mar 19 revision req. 13 may 19; revision recd. 8 jun 19 accepted 30 jun 19 advances in knowledge to the best of the authors’ knowledge, this is the first study to evaluate paediatric surgeons’ perspectives regarding transition of care (toc) in malaysia. the results of this survey suggest that there is a lack of proper guidelines in malaysian institutions when transitioning adolescents with complex surgical conditions to adult care. application to patient care the preliminary results of this study may help to initiate dialogue among stakeholders in malaysia and encourage efforts to improve toc guidelines for this group of patients. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.011 https://creativecommons.org/licenses/by-nd/4.0/ shung k. tan, anand sanmugam, mahmoud danaee, tindivanam m. ramanujam, mohan a. nallusamy, zakaria zahari and thambidorai r. rao clinical and basic research | e353 adolescents with complex medical or surgical conditions usually have ongoing medical issues which require regular followup, monitoring and treatment; however, up to 20–25% may drop out or become lost to follow-up soon after being discharged from paediatric care due to a lack of appropriate organisation and planning when transitioning to adult care.1,2 this can lead to increased morbidity, mortality and poor long-term prognosis and quality of life.3 transition of care (toc) refers to the process whereby adolescents and young adults with chronic physical and medical conditions are transferred from child-centred to adult-oriented healthcare systems.4 the objective is to provide continuous and uninterrupted healthcare appropriate to the developmental age of the patient in order to maximise lifelong functioning.5 transition programmes help to improve follow-up and result in better control of acute and chronic complications.6 the benefits of toc models have been substantiated in various medical subspecialties, including paediatric cardiology, spina bifida, organ transplantation and adolescent urology units.7–10 although toc is practiced in many developed countries such as the usa, canada, uk and australia, its usage in south-east asian nations is still in its infancy.11–13 while healthcare providers in this region agree on the need for toc programmes, actual toc guidelines are still either not established or under-dev eloped. this results in paediatricians caring for adolescent patients well into adulthood and the eventual transfer to adult care occurring in an abrupt, disorganised and ad hoc manner.14,15 over the past three decades, surgical care for infants with congenital surgical conditions in malaysia has improved significantly, resulting in increased survival among infants with conditions such as oeso phageal and bowel atresia, anorectal anomalies and hirschsprung’s disease.16–18 however, without a proper plan for their transition to adult care, adolescents and young adults with complex surgical conditions, who present to surgeons specialising in adult care, can often be referred back to paediatric surgeons. as such, the practices and opinions of paediatric surgeons regarding toc are an essential first step in ensuring a smooth transition to adult care. therefore, this study aimed to explore current practices and perspectives regarding toc among paediatric surgeons in malaysia. methods this study took place between june and december 2017. a universal sampling method was used to target all 48 paediatric surgeons in malaysia currently practicing in public, university and private hospitals. a self-administered english language questionnaire was designed based on published research regarding toc.14 the questionnaire was distributed either via e-mail (39.6%) or in person (60.4%) to all paediatric surgeons. non-responders to the initial survey request were reminded after one month to improve the response rate. during the survey design stage, a literature review was conducted on the topic of toc, followed by a discussion with a focus group composed of four paediatric surgeons and a statistician. survey questions were grouped into three categories. the first section of the survey assessed the participants’ demographic characteristics, while current practices and perspectives regarding toc for adolescents with complex surgical conditions were evaluated in the second and third sections, respectively. an initial draft of the questionnaire was distributed to the focus group for feedback with revisions made according to their recommendations. subsequently, a second draft was distributed to medical practitioners from various specialties to evaluate face and content validity. the questionnaire was then finalised after the validation process. some questions were multiple-choice, for example, some paediatric surgeons indicated that they have adolescent patients whom they managed with adult surgeons or only by themselves. overall practice scores were calculated to reflect actual toc practices in malaysia. the scores were based on responses to four questions from the survey indicating the existence of toc practices and supporting facilities. each question was given a score of either one or zero to indicate answers of “yes” or “no”, respectively. total scores ranged from 0–4, with higher scores representing better practices. mean practice scores were subsequently correlated to the participants’ place of practice and number of years of experience as a paediatric surgeon. in addition, the paediatric surgeons were asked to evaluate five out of 11 factors which they perceived to be the most significant barriers to establishing an organised toc procedure in their institution. participants ranked the five barriers from most to least significant, with one being most significant and five being least significant. only five barriers were ranked instead of all 11 barriers listed so as to avoid questionnaire fatigue. subsequently, the rank of each barrier was determined by calculating frequencies and mean scores, with barriers with a higher frequency and a lower mean value being more significant. the five most frequently cited barriers were then listed and ranked according to their mean scores. transition of care in paediatric surgery current practices and perspectives of paediatric surgeons in malaysia e354 | squ medical journal, november 2019, volume 19, issue 4 the statistical analysis was performed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). demographic data and toc practices and perspectives were reported using descriptive statistics. overall practice scores were compared according to place of practice (i.e. public, university-affiliated or private hospitals) using the kruskal-wallis oneway analysis of variance non-parametric test since the total numbers of surgeons in each category were unequal. the correlation coefficient between years of experience and overall practice scores was calculated using spearman’s test. a p value of <0.05 was deemed statistically significant. ethical permission for this study was granted by the medical research & ethics committee of the ministry of health in malaysia (#nmrr-17-903-35519). informed consent was received from all participants prior to their inclusion in the study. results a total of 38 paediatric surgeons participated in the study (response rate: 79.2%). most worked in the public healthcare system, either in ministry of healthaffiliated (76.3%) or university-affiliated (15.8%) hosp itals; few surgeons worked in private hospitals (7.9%). younger surgeons with 0–5 years of experience were the largest group of respondents (55.3%), followed by both senior surgeons with >20 years of experience and those with 6–10 years of experience (15.8% each) [figure 1]. most surgeons (76.3%) had prior knowledge of the concept of toc, usually obtained during postgraduate training, journal research or conference attendance. with regards to toc practices, the majority of the participants (97.4%) did not have an organised toc model in their institution. in addition, none of the hospitals had a dedicated ward for adolescents with complex surgical conditions, with such patients usually either admitted to paediatric (57.9%) or adult (42.1%) wards. moreover, most paediatric surgeons (67.6%) took care of patients with complex surgical conditions until adulthood. the remaining 32.4% of surgeons discharged patients if they had no active symptoms or did not require active management at that time. the majority of surgeons either managed adolescent patients solely (65.8%) or in conjunction with adult surgeons (26.3%). the remaining 13.2% stated that adult surgeons were the sole healthcare providers for these patients. in terms of their perspectives on toc policies, most respondents (63.2%) thought that written transfer summaries should be endorsed by the consultant or specialist in charge of the patient. the majority (86.8%) believed there was a need for the receiving team to hold appropriate credentials and privileges to manage this group of patients. however, many surgeons (84.2%) still felt that it was their obligation to provide consultation and care even after adolescent patients had been transitioned to adult care. most surgeons (42.1%) considered that an organised toc model should be implemented at their institution within the next 3–5 years, while the remaining 39.5% and 18.4% felt that this should be introduced in ≥5 or 1–2 years, respectively. however, opinions were evenly divided regarding the age group most suitable at which to begin toc [figure 2]. the paediatric surgeons were also surveyed regarding initiating factors for toc. the presence of adult comorbidities (81.6%) was cited as the most common reason for transferring adolescent patients to adult care, followed by a stable disease process (71.1%), pregnancy (60.5%), institutional policies (44.7%) and the patient’s perceived independence to make their own healthcare decisions (44.7%). marriage (26.3%) and college entry (18.4%) were deemed the least important transition triggers [figure 3]. figure 1: years of experience among paediatric surgeons in malaysia (n = 38). figure 2: distribution of opinions regarding the appropriate age to initiate transition of care among paediatric surgeons in malaysia (n = 38). toc = transition of care. shung k. tan, anand sanmugam, mahmoud danaee, tindivanam m. ramanujam, mohan a. nallusamy, zakaria zahari and thambidorai r. rao clinical and basic research | e355 a lack of guidelines was the most frequently cited toc barrier (84.2%) and was also deemed most signif icant by the paediatric surgeons (mean score: 2.37 ± 1.43). institutional policies and lack of awareness among healthcare providers were also ranked highly (mean scores: 2.38 ± 1.63 and 2.86 ± 1.04, respectively). more than half of the respondents (57.9%) indicated that emotional attachment on the part of the patient/ parents was a barrier to transition, while 50% cited the lack of adult healthcare providers familiar with paediatric surgical problems [table 1]. although paediatric surgeons working in university-affiliated hospitals had higher mean overall practice scores compared to those working in private and public hospitals [figure 4], these findings were not significant (kruskal-wallis value = 0.502; p = 0.778). although there was a weak positive correlation between number of years of experience as a paediatric surgeon and mean overall practice score, this was also not significant (r = 0.157; p = 0.357). discussion the results of the current study are important as they reflect actual toc practices and perspectives among the majority of paediatric surgeons currently working in malaysia. such information may help to shed more light on the state of toc and inform future healthcare developments in this region. importantly, the overall positive responses to this survey show an interest in toc and a willingness to improve the care of adolescents with complex surgical conditions among this group of healthcare practitioners. nevertheless, as can be observed in the current study, toc is still not widely practiced among paediatric surgeons in malaysia. the majority of respondents did not have an organised model of transition or a specialised clinic or ward for adolescent patients. indeed, most stated that they cared for adolescent patients up to adulthood, while the remainder discharged patients to adult surgeons without an organised transition procedure. this may be due to the relatively late development of paediatric surgical services in malaysia, which only saw its expansion in 1990.16 moreover, the demographic distribution of the respondents indicated that the majority of the paediatric surgeons were relatively inexperienced, with less than 10 years of experience in this specialty. previous research has stressed the importance of a separate ward for adolescents.19 on top of any underlying medical conditions, adolescents also undergo various developmental, social, psychological and sexual changes. as such, the care of adolescents in a hospital setting can be challenging.20,21 adolescent units are usually managed by trained nursing, medical and ancillary staff who understand the specific needs of this group of patients and have facilities designed to promote privacy, peer-to-peer contact, independence, mobility and educational continuity.22 moreover, adolescent wards allow paediatric and adult practitioners to meet, discuss and manage adolescent patients together in a collaborative fashion. however, table 1: perceived barriers to transition of care among paediatric surgeons in malaysia (n = 38) barrier n (%) mean score* ± sd lack of guidelines 32 (84.2) 2.37 ± 1.43 institutional policies 21 (55.3) 2.38 ±1.63 lack of awareness among healthcare providers 22 (57.9) 2.86 ± 1.04 lack of adult healthcare providers 19 (50) 3.00 ± 1.29 emotional attachment to paediatric care providers 22 (57.9) 3.27 ± 1.62 *respondents were asked to rank five barriers out of 11 which they per ceived to be the most significant, with one being most significant and five being least significant. barriers with higher frequencies and lower mean scores are of greater significance. figure 3: distribution of triggers that initiate transition of care among paediatric surgeons in malaysia (n = 38). figure 4: mean overall transition of care practice scores according to place of practice among paediatric surgeons in malaysia (n = 38). toc = transition of care; moh = ministry of health. transition of care in paediatric surgery current practices and perspectives of paediatric surgeons in malaysia e356 | squ medical journal, november 2019, volume 19, issue 4 even in more developed countries, many young adults are often still admitted to paediatric care, most likely due to disease complexity, failure of transition planning and the lack of appropriate services within the adult healthcare sector.23 these observations show that the implementation of toc procedures can be challenging worldwide and require careful planning and consideration. in the present study, the majority of paediatric surgeons felt that they should continue to provide assistance if requested, even after adolescent patients had been transferred to adult care. however, views regarding the appropriate age to initiate toc were divided. according to paone et al., the toc process can be divided into four stages.24 in stage 1 (i.e. early adolescence, at approximately 10–12 years of age), the patient and their family should be introduced to the concept of transition and the various processes involved. in stage 2 (i.e. middle adolescence, at approximately 13–15 years of age), the patient should be encouraged to take ‘ownership’ of their healthcare and the management of their condition. in stage 3 (i.e. late adolescence, at approximately 16–18 years of age), the patient should be introduced to the adult healthcare team and taught independent healthcare consumer skills. finally, in stage 4 (i.e. young adulthood, at approximately 18–24 years of age), the patient should be discharged from paediatric care and transferred to adult care.24 however, further research is necessary to determine whether adoption of this toc model requires any modification for implementation in local settings in malaysia. effective communication is a key component to a successful transition process. in the current study, most respondents agreed that transfer summaries should be endorsed by a more experienced practitioner such as a consultant or a specialist in order to ensure that relevant information is conveyed to the receiving team. in addition, patients’ medical summaries should also be easily accessible by the patient, transition care provider and adult surgeons. malaysian paediatric surgeons indicated adult comorbidities to be the most common factor for initiating toc procedures, followed by a stable disease process, pregnancy, institutional policies and the patient’s independence and ability to make their own healthcare decisions. while all of the aforementioned factors are relevant issues that require discussion with the adolescent and their parent during the transition period, the main goal should be to prepare adolescents to independently navigate an adult healthcare setting. hence, the readiness of the adolescent should be considered the most important trigger for toc.8 barriers to adequate toc may differ according to practice setting. a healthcare setting with established transition practices may face barriers such as a lack of adult providers, patient health issues and emotional attachment on the part of the patient to their primary care provider.25 in the current study, set in a region where toc is still developing, the main barriers perceived by paediatric surgeons were related to the lack of proper toc guidelines, institutional policies and the lack of awareness among healthcare providers. currently, in light of the growing number of adolescent surgical patients in malaysia, there is a need to streamline and maintain standards of practice as such patients reach adulthood. lack of awareness regarding toc evidently leads to an absence of guidelines and institutional policies, thereby adversely affecting the development of transition care. subsequently, paediatric surgeons often have insufficient knowledge regarding this aspect of care and, even if they are aware of the concept, may be only superficially involved in these processes in actual practice.4 furthermore, both paediatric surgeons and paediatricians may be unsure which adult providers are qualified to manage young adults. in turn, patients and their parents may also be unaware of the need for early toc planning and how to access appropriate adult healthcare services.26 a paucity of adult healthcare providers was also highlighted as another major barrier to toc in the current study. unfortunately, the general surgeonto-population ratio in malaysia is still far from that of developed nations.27 adult surgeons in this region may therefore be overburdened by patients and not able to take on the extra workload involved in caring for adolescents. moreover, adult providers may have insufficient knowledge and training to manage complex health issues in young adults, making it difficult for the patient and their parents to develop a trusting relationship with the adult practitioner.28 nevertheless, the increasing number of paediatric surgeons over the past decade, brought about primarily by the establishment of paediatric surgery fellowship and postgraduate programmes as well as the increase in adult surgery subspecialties, has encouraged the development of toc facilities. it is therefore likely that the number of adult healthcare providers able to care for adolescent patients will improve with continued collaboration between paediatric and adult surgeons. in paediatric care, the parents, guardians and/ or close family members of the patient usually play a key role in decision-making, consent and treatment. furthermore, paediatric practice more commonly emphasises the importance of a childor youth-friendly shung k. tan, anand sanmugam, mahmoud danaee, tindivanam m. ramanujam, mohan a. nallusamy, zakaria zahari and thambidorai r. rao clinical and basic research | e357 environment. in contrast, adolescents attending adult clinics are often expected to be solely responsible with regards to consent, their own treatment and personal well-being, with limited time and resources available for counselling.29 the change from a more protective and nurturing environment to near complete independence can inhibit and intimidate adolescent patients; as such, appropriate resources and counselling services should be offered so that adolescent patients and their parents can more readily adapt to the adult healthcare environment.30 future research to support the development of toc in paediatric surgery in malaysia should investigate various approaches, including the development of registries for paediatric surgical congenital anomalies, guidelines for a successful toc model and, once established, the continuous monitoring of transition programmes. this study was subject to several limitations. first, the anonymity of the participants was difficult to ensure in light of the small study population which was further subdivided into groups based on place of practice. potential respondents might therefore have opted out of the study due to fear of being identified. however, identification numbers were allocated to each respondent and the collection of the questionnaires was performed by a third party to improve the confidence of the respondents. second, the results of this survey may not represent the full spectrum of opinions among all paediatric surgeons in malaysia; in particular, there were fewer responses from surgeons based in private hospitals. third, only paediatric surgeons were included in the study and the opinions of other stakeholders, who are equally important in the development and initiation of toc procedures (i.e. adolescents, their parents and adult surgeons), were not surveyed. finally, this preliminary study explored a general overview of toc practices and perspectives in paediatric surgery, but did not include specific paediatric surgical conditions. conclusion the current study surveyed paediatric surgeons in malaysia and found an absence of clear guidelines or policies in place to address toc issues for adolescents with complex surgical conditions. the results of this study provide a better understanding of transitional care in this region from the point of view of paediatric surgeons. however, further research involving other stakeholders such as patients and adult surgeons is needed to help formulate a suitable and successful transitional care model in this local setting. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. giuliani s, decker e, leva e, riccipetitoni g, bagolan p. long term follow-up and transition of care in anorectal malformations: an international survey. j pediatr surg 2016; 51:1450–7. https://doi.org/10.1016/j.jpedsurg.2016.03.011. 2. daneman d, nakhla m. moving on: transition of teens with type 1 diabetes to adult care. diabetes spectr 2011; 24:14–18. https://doi.org/10.2337/diaspect.24.1.14. 3. jordan a, mcdonagh je. transition: getting it right for young people. clin med (lond) 2006; 6:497–500. https://doi. org/10.7861/clinmedicine.6-5-497. 4. blum rw, garell d, hodgman ch, jorissen tw, okinow na, orr dp, et al. transition from child-centered to adult healthcare systems for adolescents with chronic conditions. j adolesc heal 1993; 14:570–6. https://doi.org/10.1016/1054-139x(93)90143-d. 5. gortmaker sl, sappenfield w. chronic childhood disorders: prevalence and impact. pediatr clin north am 1984; 31:3–18. https://doi.org/10.1016/s0031-3955(16)34532-1. 6. robertson lp, mcdonagh je, southwood tr, shaw kl; british society of paediatric and adolescent rheumatology. growing up and moving on. a multicentre uk audit of the transfer of adolescents with juvenile idiopathic arthritis from paediatric to adult centred care. ann rheum dis 2006; 65:74–80. https://doi. org/10.1136/ard.2004.032292. 7. heery e, sheehan am, while ae, coyne i. experiences and outcomes of transition from pediatric to adult health care services for young people with congenital heart disease: a systematic review. congenit heart dis 2015; 10:413–27. https://doi.org/10.1111/chd.12251. 8. kaufman ba, terbrock a, winters n, ito j, klosterman a, park ts. disbanding a multidisciplinary clinic: effects on the health care of myelomeningocele patients. pediatr neurosurg 1994; 21:36–44. https://doi.org/10.1159/000120812. 9. shemesh e. non-adherence to medications following pediatric liver transplantation. pediatr transplant 2004; 8:600–5. https://doi.org/10.1111/j.1399-3046.2004.00238.x. 10. woodhouse c. adolescent urology and long-term outcomes. chichester, uk: wiley-blackwell, 2015. pp. 1–10. https://doi. org/10.1002/9781118844854.ch1. 11. cabatan mc. transition related dilemmas of persons with developmental disabilities. asian j occup ther 2013; 3:15–26. https://doi.org/10.11596/asiajot.3.15. 12. goh dy. paediatric services: the future direction. ann acad med singapore 2014; 43:343–5. 13. jin yt, chen cm, chien wc. factors influencing transitional care from adolescents to young adults with cancer in taiwan: a population-based study. bmc pediatr 2016; 16:122. https://doi. org/10.1186/s12887-016-0657-z. 14. wong lh, chan fw, wong fy, wong el, huen kf, yeoh ek, et al. transition care for adolescents and families with chronic illnesses. j adolesc health 2010; 47:540–6. https://doi.org/10.10 16/j.jadohealth.2010.04.002. 15. ishizaki y, maru m, higashino h, katsumoto s, egawa k, yanagimoto y, et al. the transition of adult patients with childhood-onset chronic diseases from pediatric to adult healthcare systems: a survey of the perceptions of japanese pediatricians and child health nurses. biopsychosoc med 2012; 6:8. https://doi.org/10.1186/1751-0759-6-8. https://doi.org/10.1016/j.jpedsurg.2016.03.011 https://doi.org/10.2337/diaspect.24.1.14 https://doi.org/10.7861/clinmedicine.6-5-497 https://doi.org/10.7861/clinmedicine.6-5-497 https://doi.org/10.1016/1054-139x%2893%2990143-d https://doi.org/10.1016/s0031-3955%2816%2934532-1 https://doi.org/10.1136/ard.2004.032292 https://doi.org/10.1136/ard.2004.032292 https://doi.org/10.1111/chd.12251 https://doi.org/10.1159/000120812 https://doi.org/10.1111/j.1399-3046.2004.00238.x https://doi.org/10.1002/9781118844854.ch1 https://doi.org/10.1002/9781118844854.ch1 https://doi.org/10.11596/asiajot.3.15 https://doi.org/10.1186/s12887-016-0657-z https://doi.org/10.1186/s12887-016-0657-z https://doi.org/10.10%0a16/j.jadohealth.2010.04.002 https://doi.org/10.10%0a16/j.jadohealth.2010.04.002 https://doi.org/10.1186/1751-0759-6-8 transition of care in paediatric surgery current practices and perspectives of paediatric surgeons in malaysia e358 | squ medical journal, november 2019, volume 19, issue 4 16. nor mbm. 39th a m ismail oration 2012. a long journey of hope the development of paediatric surgery in malaysia. from: www.acadmed.org.my/newsmaster.cfm?&menuid=68&par entid=46&action=view&retrieveid=52 accessed: jun 2019. 17. narasimman s, nallusamy m, hassan s. review of oesophageal atresia and tracheoesophageal fistula in hospital sultanah bahiyah, alor star. malaysia from january 2000 to december 2009. med j malaysia 2013; 68:48–51. 18. goon hk. repair of anorectal anomalies in the neonatal period. pediatr surg int 1990; 5:246–9. https://doi.org/10.1007/ bf00169662. 19. platt h. the welfare of children in hospital. br med j 1959; 1:166–9. https://doi.org/10.1136/bmj.1.5115.166. 20. mackenzie h. teenagers in hospital. nurs times 1988; 84:58–61. 21. godfrey k. the young ones: teenagers in hospital. nurs times 1998; 94:26–8. 22. fisher m. adolescent inpatient units. arch dis child 1994; 70:461–3. https://doi.org/10.1136/adc.70.6.461. 23. lam py, fitzgerald bb, sawyer sm. young adults in children’s hospitals: why are they there? med j aust 2005; 182:381–4. https://doi.org/10.5694/j.1326-5377.2005.tb06755.x. 24. paone m, whitehouse s. on trac: transitioning responsibly to adult care developing a transition initiative for youth and young adults with chronic health conditions and/or special needs in bc. from: www.bcchildrens.ca/transitionto-adult-care/documents/on%20tracbackground2011.pdf accessed: jun 2019. 25. durkin et, zurakowski d, rangel sj, lillehei cw, fishman ln. passing the baton: the pediatric surgical perspective on transi tion. j pediatr surg 2015; 50:1196–200. https://doi.org/10.10 16/j.jpedsurg.2014.10.050. 26. lebensburger jd, bemrich-stolz cj, howard th. barriers in transition from pediatrics to adult medicine in sickle cell anemia. j blood med 2012; 3:105–12. https://doi.org/10.2147/ jbm.s32588. 27. national healthcare statistics initiative, ministry of health malaysia. national healthcare establishments & workforce statistics hospitals 2010: chapter 5 surgical services in malaysian hospitals. from: www.crc.gov.my/nhsi/nhews2010/ accessed: jun 2019. 28. reiss jg, gibson rw, walker lr. health care transition: youth, family, and provider perspectives. pediatrics 2005; 115:112–20. https://doi.org/10.1542/peds.2004-1321. 29. taube-schiff m, yufe s, dettmer e, d’agostino nm, sockalingam s. bridging the gap: patient experiences following transfer of care from a pediatric obesity management program to an adult bariatric surgery program. bariatr surg pract patient care 2016; 11:67–72. https://doi.org/10.1089/bari.2015.0048. 30. gray wn, schaefer mr, resmini-rawlinson a, wagoner st. barriers to transition from pediatric to adult care: a systematic review. j pediatr psychol 2018; 43:488–502. https://doi. org/10.1093/jpepsy/jsx142. https://doi.org/10.1007/bf00169662 https://doi.org/10.1007/bf00169662 https://doi.org/10.1136/bmj.1.5115.166 https://doi.org/10.1136/adc.70.6.461 https://doi.org/10.5694/j.1326-5377.2005.tb06755.x https://doi.org/10.1016/j.jpedsurg.2014.10.050 https://doi.org/10.1016/j.jpedsurg.2014.10.050 https://doi.org/10.2147/jbm.s32588 https://doi.org/10.2147/jbm.s32588 https://doi.org/10.1542/peds.2004-1321 https://doi.org/10.1089/bari.2015.0048 https://doi.org/10.1093/jpepsy/jsx142 https://doi.org/10.1093/jpepsy/jsx142 december 2008 no white pages.indd orthopaedic manifestations of date thorn injury case series s s suresh sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 347-352 sultan qaboos university© submitted 30th april 2008 accepted 18th august 2008 c a s e r e p o r t النخيل بأشواك العظام إصابات مظاهر حاالت مجموعة اس سوريش اس عندالفالحني حتدث االصابات معظم فيها. النخيل زراعة حيث تكثر ــط األوس في أقطار الشرق االنتشار ــعة واس النخيل ــواك االصابات بأش امللخص: جتلب أال وميكن بها العلم دون حتدث ميكن أن األطفال عند هناك اختالطات، لكن االصابات يكون مبكرا ال االصابات وتعالج عندما تكتشف واألطفال. األكثر عرضة لالصابات. تكون ــا فانه ــم اجلس باقي من عرضة األكثر اجلزء أن اليد هي ومبا اختالطات متأخرة. حدوث ــبب في يتس مما اليها ــل األه ــاه انتب املزروعة املناطق في عارية تكون هي االخرى عندما تصاب ميكن أن القدم أن كما والنقي. العظم التهاب أن تعمل آفات تشبه ميكن املنطمرة االشواك من اليد اصابات في ــم لديه الذين الثالثة املرضى عانى ــرة. اختالطات متأخ حصول بعد النخيل ــواك بأش حاالت مصابة ــا خمس هن ــدرج ن ــل. بالنخي في العظام آفات انحالل اآلخرين املريضني كان لدى العظم والنقي. التهاب الى أدت العظم في ــوكة ش من ــكو يش أحدهم وكان ــمحاق، الس التهاب العظام. في اختالطات متاما دون شفيت كل احلاالت العظم. داخل شوكة احداهما لدى وكان املشطية، حالة. تقرير احلبيبي، الغريب اجلسم ورم السمحاق، التهاب والنقي، العظم التهاب العظم، كيس ، املشطية العظام اليد، الكلمات: مفتاح departmentof orthopaedics, ibri regional hospital, muscat, sultanate of oman email: dr.s.s.suresh@gmail.com organic foreign body granuloma, including date thorn, should be considered in the differentials of a lytic lesion with or without sclerotic lesions of the bone.1, 2 the foreign body reaction which results from thorn injury can mimic various bone, joint and soft tissue disorders.1, 2, 3, 4, 5, 6, 7, 8, 9 date palm thorn injuries are common in the sultanate of oman with its extensive farming of date palms. the thorns, lying beneath the trees in places where children play, produce injuries to exposed parts, mostly in the hands, knees and foot. there are various reports of date palm thorn injuries in the literature, with eight cases of metacarpal lesions reported so far.6 there are reports of thorn induced osteomyelitis of the metatarsals and cuboid,10 from areas where people walk barefoot. m e t h o d s data regarding all patients who presented to ibri regional hospital with the following icd (international classification of diseases) codes were reviewed for the last 4 years: abstract date palm thorn injuries are common in middle eastern countries where there are many date palm plantations. most of the injuries happen to workers in the plantation or to children. injuries, if detected, can be treated without subsequent complications, but in children the diagnosis can very easily be missed resulting in late complications. the hand, being the most exposed part of the body, is the most affected. embedded thorns can produce lesions mimicking those of osteomyelitis. the foot is exposed to injuries in people who walk barefoot in the plantations. the author presents five cases of date thorn injury which presented with late complications. all three patients with hand injuries had periostitis, and one of them had an intraosseous thorn producing osteomyelitis. two patients presented with osteolytic lesions of the metatarsals with intraosseous thorn in one patient. all cases recovered completely leaving behind no sequlae of the bony infection. key words: hand; metatarsal; bone cyst; osteomyelitis; periostitis; foreign body granuloma; case report; oman. s s s u r e s h 348 1. w45: foreign body or object entering through the skin 2. l92.3: foreign body granuloma of skin and subcutaneous tissue 3. m60.2: foreign body granuloma of soft tissue not elsewhere classified. 4. m65: synovitis and tenosynovitis there were 253 cases during this four year period with injuries related to foreign body intrusion in the body, of which 137 (54%) were related to injuries by date thorns. eighty-two cases involved the upper extremity, mostly the hand and fingers. fifty-five cases were in the lower extremity, mostly involving the toes and foot. eighteen cases of foreign body granuloma involving the hand and 9 cases of granulomas of the foot were excised in the operating room. the rest of the cases were managed as outpatients. x-rays were done in all cases of granulomas to rule out skeletal lesions due to date thorns. most of the cases also underwent an ultrasound scan to localize the foreign body. there were two cases of skeletal lesions in the foot, one in a 12 year old boy. he presented with pain and swelling of the left foot of one year duration. his xrays showed a lytic lesion of the shaft of the second metatarsal with cortical thickening. the swelling was non-tender and there were no signs of inflammation. the patient underwent curettage of the lesion under general anaesthesia and was found during surgery to have an intraosseous thorn. a lady presented with a swollen right foot, recurfigure 1: ultrasound scan. fb 11 mm lying 5 mm deep to skin, granuloma measuring 24 x 7.6 mm around the thorn figure 2: x-ray of foot showing osteomyelitis of 2nd metatarsal figure 3: ct scan of the right foot showing lytic lesion (arrow) o r t h o pa e d i c m a n i f e s tat i o n s o f d at e th o r n i n j u r y 349 ring for the past two years. she did not recollect any antecedent injury. her x-rays of the foot were doubtful of a lytic lesion of the metatarsal and hence a computed tomography (ct) scan of the foot was done. this showed an osteolytic lesion over the base of the fourth metatarsal. the lesion was curetted and the offending thorn piece was removed from the intermetatarsal space. she eventually recovered fully. three young people children presented with lesions in the small bones of the hands; all boys aged 6, 11 and 16 years respectively. the boy aged 6 years was initially treated for an injury, and was immobilised in a slab for a short while. later on, he presented with pain and swelling of the hand. radiographs after few weeks showed periosteal reaction of the third metacarpal with a lytic lesion over the base of the metacarpal on the left side. the lesion healed after curettage of the lesion and removal of the offending thorn. another boy presented with a swollen right hand after an injury with date thorn. the boy recollected the injury from a date thorn in the garden a month prior to his presentation. there was periosteal reaction over the entire shaft of the fourth metacarpal. the lesion healed after removal of the offending thorn and removal of the granulation tissue. another boy had no definite history of trauma, but presented with painful swelling over the right middle finger. there was periosteal reaction over the dorsum of the proximal phalanx of the middle finger. the lesion was successfully treated by curettage. no age in years /sex clinical details radiology lesion management histopathology 1 6/m fall in garden; pain and swelling of left hand periosteal reaction 3rd metacarpal, lytic lesion base of metacarpal. 2.5 x 1.5 cm mobile non tender swelling dorsum of hand curettage of the cavity, excision of granuloma dense infiltrate of inflammatory cells, mainly neutrophils and macrophages, no foreign body giant cells 2 11/m injury with date thorn in garden periosteal reaction over the shaft of 4th metacarpal soft tissue swelling dorsum of right hand excision of granuloma, two date thorn pieces removed at surgery inflammatory cell infiltration with foreign body giant cells 3 16/m no definite history of trauma periosteal reaction dorsum of proximal phalanx midfinger swollen dorsum of right middle finger offending date thorn with granuloma removed inflammatory cell reaction, with pieces of foreign bodies 4 12/m no definite history of trauma; swelling in dorsum of left foot of 1 year duration osteolytic lesion over the shaft of 2nd metatarsal, with sclerotic margins bony swelling over the dorsum of left foot, over the 2nd metatarsal lesion curetted through a window, granuloma curetted, thorn removed inflammatory cell reaction 5 23/f swelling in right foot of 2 years duration osteolytic lesion base of 4th metatarsal. confirmed with ct scan tender swelling dorsum of right foot over base of 4th and 5th metatarsal thorn removed from interdigital space of 4th and 5th toes. base of 4th metatarsal curetted fibrocollagenous and fibroadipose tissue with inflammatory granulation tissue, with pieces of thorn table 1: characteristics of the date thorn injuries in the five cases s s s u r e s h 350 d i s c u s s i o n date thorn is a modified leaf that ends in a spine of the palm tree, phoenix anarensis, which is widely cultivated in the middle-east countries.2 penetrating injuries of the extremities by date thorn are common in middle eastern countries.2 children are exposed to thorn injuries because of their contact with date palms in gardens or plantations. there may not be any visible signs of injury. if detected, attempts at removal may leave part of the sharp tip of the thorn inside the body. the initial symptoms are usually mild and disappear in a few days, but some patients present late with granuloma or bony pathology.9 a diagnosis of a date thorn foreign body is considered when there is a history of trauma and a periosteal reaction or lytic lesion is seen in the radiographs. a date thorn embedded near a bone can produce a pathological reaction resulting in periostitis or osteomyelitis. a retained thorn can present as synovitis, arthritis, rheumatism, granuloma or osteomyelitis.3, 9, 11, 12, 13, 14, 15 gerle named the pathology “thorn-induced pseudotumor of bone.” maylahn called them thorn-induced “tumors of bone.”3, 7, 13 in most of the cases, the thorn is removed by the patients causing little morbidity. if retained in the tissue it can cause an inflammatory reaction leading to development of foreign body granulomas. a thorn stab produces an acute local inflammatory reaction in the tissues16 even if no part of the thorn remains in the body. antibiotics are indicated only if the culture turns positive for a particular organism. durr et al 6 reported a case of intraosseous thorn in the diaphysis of the fifth metatarsal in a fiftysix year old lady. organic plant material when present in or near a bone can produce lesions in bone that are lytic or sclerotic or a combination of both. 6, 17there is usually a delay in seeking medical help or there is a delay in diagnosis with the mean time of presentation in various reports of around four months.6, 9, 16 granuloma is due to incomplete removal of the date thorn by the patient retaining the sharp tip inside the soft tissue, of which the patient is unaware. most of the thorn related injuries occur in the hand, it being the most exposed body part. so far only eight metacarpal lesions and three phalangeal lesions have been reported.1, 4, 6, 7, 18 the thorn, once entered, produces a granuloma by foreign body reaction, resulting in periosteal reaction or osteolysis. once inside the joint, the thorn can cause synovitis due to a chemical reaction.14 most children do not identify the initial injury, making the diagnosis difficult. the periosteal reaction may mimic osteomyelitis, trauma or ewing’s sarcoma. 7, 13 if the thorn remains in the subperiosteal region this can cause a subperiosteal reaction and periosteal elevation 8 subsequent to this the cortical bone is devitalized resulting in a sequestrum8 a periosteal reaction should also be differentiated from the periosteal reaction of stress fractures, as the lesions of thorn-induced skeletal changes are seen mostly in the paediatric age group. because palm thorns are not radio-opaque, xrays are negative for the foreign body until and unless bony lesions develop. thorns can be seen in the tissues as echogenic structures surrounded by inflammatory hypoechoid tissue during an ultrasound scan. high performance ultrasonography is useful for preoperative assessment of the granuloma and for localizing the foreign body.18 as plain radiographs and even an ultrasound may not show the foreign body, a magnetic resonance imaging (mri) scan may have to be done.12 there are reports8 where even an mri has failed to show the foreign body. date thorn granuloma is usually not suppurative, unless contaminated with organic material from the farm. 9, 11, 17 bacterial growth in date thorn injury is rare 3,12,19 many organisms have been identified in the tissues, though bacterial growth is infrequently reported from date thorn lesions. 19 authors suggest that pantlea agglomearns should be considered in aseptic arthritis of the joints after date thorn injuries. this organism is considered less aggressive and can cause protracted local inflammation 16 date thorn palm may contain some toxic substance, probably an alkaloid substance, which causes osteolytic reactions in the bone 3, 9, 12, 17, 20 kelly, in 1966, 20 was the earliest to prove that the theory, as reported by various authors, of alkaloids in the thorn was wrong as removal of the thorn cures the inflammation. the small bit of retained thorn may not contain enough alkaloids to initiate an inflammatory response. contrary to this, in synovitis the symptoms usually persist after removal of thorn even after partial synovectomy, and total synovectomy is needed for complete resolution.5 the speculation of alkaloids causing the granuloma is not scientifically proven yet. no microorganisms are usually grown from the tissue, and the infection that occurs is secondary.4 yousefzadeh, in 1978, reported a case of sclerotic and lytic lesions in the fifth metacarpal due to thorn-induced granuloma in an eight year old boy. the interval between the entry of foreign o r t h o pa e d i c m a n i f e s tat i o n s o f d at e th o r n i n j u r y 351 body and the appearance of bony changes in the radiographs, in the study by yousefzadeh, ranged from three weeks to two years.15, 20 maylahn,7 as early as 1952, suggested that thorn induced granuloma should be considered in the differentials of bone neoplasms. as early as 1936, maylahn came across a date thorn injury of the fibula resulting in a granuloma and radiological features of ewing’s sarcoma.7 the lesion in the fourth metacarpal of a child was diagnosed by barry1 as due to tuberculous infection. a similar case was treated by dhillon et al17 with antituberculous drugs until a wooden splinter was extruded. tuberculosis was considered in the differential diagnosis by various authors.1, 3, 17, 20 c o n c l u s i o n date thorn granuloma should be kept in mind while treating extremity bone and joint infections in children in the middle east countries. the diagnosis is easy when there is history of injury with a date thorn. the granuloma should be excised and the bone must be debrided after removal of the thorn. appropriate antibiotics must be started after intraoperative culture. date thorn granuloma should be suspected if there are osteolytic or sclerotic lesions in the extremities of children from areas where date palms are grown extensively. r e f e r e n c e s 1. barry m, maffulli n, good c. the missed thorn. acta orthop belg 1992; 58:468-470. 2. suresh ss. date thorn infections of the hand in children. j hand surg (eur) 2008; 33:227-329. 3. balasubramaniam p, prathap k. pseudotumous due to oil palm thorn injury. aust n z j surg 1977; 47:223225. 4. brady rc, sommerkamp g. thorn induced alteraria flexor tenosynovitis of the hand. pediat inf dis j 2001; 20:1097-1098. 5. diog sg, cole wg. plant thorn synovitis: resolution following total synovectomy. j bone joint surg 1990; 72b:514-515. 6. durr hr, stabler a, muller pe, refior hj. thorn-induced pseodotumor of the metatarsal: a case report. j bone joint surg 2001; 83a:580. 7. maylahn dj. thorn-induced “tumors” of bone. j bone joint surg 1952; 34a:386-388. 8. peters v, rubin l, gloster es, aprin h. foreign-body osteitis of the metacarpal bone. clin orthop rel res 1992; 278:69-72. 9. ramanathan ebs, luiz cp. date palm thorn synovitis. j bone joint surg 1990; 72b: 512-513. 10. vidyadhara s, rao sk. thorn prick osteomyelitis of the foot in barefoot walkers: a report of four cases. j orthop surg 2006; 14:222-224. 11. aflatoon k, aboulafia aj, mccarthy e, frassica fj. soft figure 4: date thorn infection of 3rd metacarpal. single arrow: lytic lesion base of metacarpal; double arrow: periosteal reaction figure 5: periosteal reaction of the middle phalanx of right middle finger s s s u r e s h 352 tissue mass in a 5-year old boy. clin orthop rel res 2003; 411:348-354. 12. grainger aj, campbell rsd. post-traumatic bone cyst: a case of the floating fragment. skel radiol 1998; 27: 400-402. 13. gerle rd. thorn-induced pseudo-tumours of bone. br j radiol 1971; 44:642-645. 14. lozano-moreno fj. late complications after a palm thorn injury to the hand. eur j orthoptraumatol 2005; 15:329-332. 15. yousefzadeh dk, jackson jr jh. organic foreign body reaction. report of two cases of thorn-induced granuloma and review of the literature. skel radiol 1978; 3:167-176. 16. peleg r, greenberg d. palm tree thorn injuries a case series of ambulatory patients. j musculoskletal pain 2005; 13:49-52 17. dhillon ms, prasanna hm, goni v, nagi on, wooden splinter-induced pseudo tumor of the metatarsal. foot ankle surg 2000; 6:45-48. 18. chijiwa t, domoto h, miyazaki n. the foreign body granuloma of a plant thorn preoperatively detected by ultrasonography. internet j plastic surg 2006; from http://www.ispub.com/ostia/index. php?xmlfilepath=journals/ijps/archives.xml accessed feb 2008. 19. kratz a, greenberg d, barki y, cohen e, lisshitz m. pantoea agglomerans as a cause of septic arthritis after palm tree thorn injury; case report and literature review. arch dis childhood 2003; 88:542-544. 20. kelly jj. blackthorn inflammation. j bone joint surg 1966; 48b:474-477. submitted 19 may 20 revision req. 22 jul 20; revision recd. 13 aug 20 accepted 9 aug 20 online-first: june 2021 doi: https://doi.org/10.18295/squmj.6.2021.096 pulmonary aspergillus and mucor co-infection a report of two cases ravindra chari m, *manju rajaram, madhusmita m, pampa chtoi, sneha l jawaharlal institute of postgraduate medical education & research, puducherry, india *corresponding author’s e-mail: mail2manju22@gmail.com abstract co-infections or consecutive infections of mucormycosis and aspergillosis are very rare. additionally, distinguishing between these two infections is also difficult as both these conditions have similar clinical features. we report two similar cases from tamilnadu, who presented to a tertiary care centre in puducherry, india in 2017 (first case) and 2019 (second case).the first case was a 70-year-old, non-diabetic male patient who presented with haemoptysis with a prior history of pulmonary tuberculosis. computed tomography bronchial angiography revealed an air-crescent sign and the histopathological examination showed a fungal ball (aspergillus and mucor) in the upper lobe and foci of fungal infection in the middle lobe. the second case was a 65-year-old diabetic male patient who presented with blackish expectoration and haemoptysis. a high-resolution computed tomography scan showed a reverse-halo sign in the right upper lobe. the results of the bronchoscopy-guided biopsy were consistent with a diagnosis of mixed mucormycosis and aspergillosis with angioinvasion. both patients responded to amphotericin b with surgical excision of the affected lobe in the first case.a high degree of clinical suspicion, early surgical intervention and antifungal therapy are essential in the treatment of this rare co-infection. mailto:mail2manju22@gmail.com keywords:aspergillosis; mucormycosis; bronchoscopy; coinfection; amphotericin b; case report; india. introduction co-infections or consecutive infections of mucormycosis and aspergillosis are very rare and usually observed in immune-compromised patients. 1 distinguishing between these infections poses a challenge as both have similar risk factors and clinical features. the following cases demonstrate the importance of tissue diagnosis, variations in treatment response and the need for an aggressive multimodal approach in fungal co-infections to treat a patient. case one a 70-year-old non-diabetic male patient from tamilnadu, presented to a tertiary care centre in puducherry, india in 2017, with a history of haemoptysis (approximately 50 ml/day) associated with intermittent fever; the condition had lasted for a month prior to presentation. the patient also had a history of shortness of breath [mmrc (modified medical research council) grade iii] with no orthopnoea. the patient had received anti-tuberculosis treatment 10 years prior to presentation for five months. the patient was also not on any immunosuppressive drugs and did not show signs of diabetes; his random blood sugar (rbs) was 96 mg/dl at the time of presentation and <140 mg/dl during the entire hospital stay. there was also no history suggestive of any other systemic or immunological co-morbidity. the autoimmune serology work up [antinuclear antibody (ana)] was negative and no mycobacterium tuberculosis was detected in the sputum using a cartridge based nucleic acid amplification test. subsequent work-up with a high resolution computed tomography of the thorax (hrct) and computed tomography bronchial angiography showed an intra-cavitary mass surrounded by a crescent of air (air crescent sign) in the thick-walled cavity of the right upper lobe [figure 1a]. there were prominent tortuous vessels noted in the cavity wall supplied by branches from the right subclavian, intercostals and pulmonary and bronchial arteries along with right middle lobe fibrosis and traction bronchiectasis. due to a suspicion of an invasive fungal disease, a computed tomography (ct) scan of thebrain and paranasal sinuses was taken. however, the scan did not show any lesions suggestive of fungal dissemination. the patient underwent emergency upper and middle lobectomy with no surgery-related complications. histopathology of the resected specimen was suggestive of a fungal ball (aspergillus and mucor) colonizing the lung cavity without definite tissue or angio-invasion. in addition, there were a few foci of infection in the middle lobe which showed colonies of aspergillus and mucor. the patient was administered liposomal amphotericin b (amb)intravenously at 5 mg/kg/day for a period of 21 days and his post-operative follow-up period ofthree months, six months and one year after surgery were uneventful. case two second case is a 65-year-old alcoholic male patient, also from tamilnadu, presented to a tertiary care centre in puducherry, india in2019,with cough associated with blackish mucoid expectoration and haemoptysis; the condition had lasted for two months prior to presentation. a chronic smoker, the patient was experiencing breathlessness (mmrc grade iii) and intermittent fever. he was treated at home with broad-spectrum antibiotics for one week. at the time of presentation, the patient had type-1 respiratory failure, an elevated blood cell count of 12,470/mm3 (normal range: 4,000–7,000 mm3) and altered renal parameters [blood urea of 64 mg/dl (normal range: 15–40 mg/dl), serum creatinine of 1.58 mg/dl (normal range: 0.7–1.2 mg/dl) and rbs of 286 mg/dl (normal range: 70–140 mg/dl]. the autoimmune serology work up (ana) was negative. hrct showed right upper lobe central ground-glass opacity surrounded by a ring of consolidation (reverse halo sign) along with a cavitating consolidation involving the right upper and middle lobes suggestive of fungal pneumonia [figure 1b]. to rule out the possibility of a disseminated fungal infection, a ct scan of the brain with the paranasal sinuses was taken; this scan appeared normal. fibre optic bronchoscopy (fob)-guided trans bronchial lung biopsy (tblb) showed dense acute inflammatory cells and fungal colonies morphologically consistent with a diagnosis of mixed mucormycosis and aspergillosis with angio-invasion [figure 2]. as the patient had deranged renal parameters, he was intravenously treated with liposomal amb at 5 mg/kg/day.blood sugars were adequately controlled (maintained at rbs <140 mg/dl) with parenteral insulin. the patient responded well to the treatment procedure, improving both clinically and radiologically [figure 3]. written informed consent was obtained from both patients for the publication of these case reports and images. discussion the human respiratory tract is continuously exposed to the environment where various pathogenic organisms either alone or in combination can cause disease, particularly in immunecompromised patients. the risk factors for fungal co-infection include diabetes mellitus, immune-suppression, haematological malignancies and cancer chemotherapy. 2 diabetes mellitus is the most common predisposing factor for mucormycosisand other fungal pneumonia. 2–5 aspergillus spp. and mucorales are the most common ubiquitous saprophytic opportunistic fungal infections which need specific environmental exposures. 6 this combination of disease occurring simultaneously or sequentially in the lungs is rare and is less common than rhino cerebral disease. 7 mucormycosis or zygomycosis is a rare opportunistic fungal infection caused by the mucorales order of fungi including the genera rhizopus spp., absidia spp., cunninghamella spp., rhizomucor spp., mucor spp., apophysomyces spp. 8 belonging to the mucoraceae family, mucormycosis usually manifests as an invasive infection involving para nasal sinuses, lungs or skin. it may also manifest as disseminated. 8 aspergillus species are ubiquitous and saprophytic fungi that cause pulmonary infection commonly after inhalation of its conidia or mycelial fragments from the environment. 6 pulmonary aspergillosis has been classified into (1) fungus balls within the cavities (2) invasive aspergillosis (3) allergic bronchial aspergillosis and (4) rhinosinusitis. 9 aspergillus colonizes the cavitary lesions especially in the healed tubercular cavities of the lungs. 10 inside the cavity, the fungus forms a freely moving fungal ball consisting of fungal hyphae (commonly of aspergillus spp., occasionally of mucor spp. or of both in combination), inflammatory cells and fibrin material. 11 fungal toxins erode the walls of the cavity and spread by local destruction, causing massive haemoptysis which can be predominant and sometimes the sole symptom of the disease. 12 distinguishing between mucormycosis and aspergillosis by clinical or radiographic signs is difficult as both conditions afflict immune suppressed individuals. such patients also present with similar features of pneumonia. the identification of a causative factor plays a crucial role in the outcome as these two entities respond differently to various antifungal agents. chamiloset al. systematically compared mucormycosis and aspergillosis and concluded that no clear differences were noted clinically and very few differences were observed in the ct findings. 13 hence, wherever feasible, confirmation by microscopy is necessary for diagnostic certainty. direct histological examination of the tissue biopsy remains the gold standard in the diagnosis of invasive fungal infections. 14 based on the clinical findings, radiological imaging, histopathology and by utilizing the revised definitions from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group, a diagnosis of proven invasive fungal infection was established in both of the reported cases. 14 the choice of antifungal agent must be based on the clinical characteristics and local epidemiology of the fungal infections. 15 the infectious diseases society of america (idsa) recommends monotherapy with voriconazole or isavuconazole in aspergillosis. ambdeoxycholate and its lipid derivatives cover aspergillus spp., candida, and mucormycetes. these drugs are appropriate options for the initial treatment and in salvage therapy of aspergillus infections in resource-limited settings and conditions where voriconazole cannot be administered. 15 itraconazole is one of the preferred agents used to treat aspergillosis. 16 surgical excision of the cavity and the involved segment or lobe in the aspergilloma can be done with relatively low morbidity and mortality to achieve complete remission and a symptom-free state. 17 intravenous amb (a lipid formulation) is the drug of choice for initial therapy in the case of mucormycosis. adjuvant extensive surgical debridement should also be taken into consideration in selected cases. 18 the first case in this report presented with a fungal ball in the post-tubercular cavity of the lung evidenced by hrct, initially thought to be caused by aspergillus spp. later on, as histopathological features were suggestive of the fungal ball (aspergillus and mucor) colonizing the lung cavity, liposomal amb was administered intravenously. the second case was a diabetic patient who presented with pneumonia and a suspicion of fungal aetiology. he was initially started on liposomal amb as part of the treatment procedure. later on, fob guided tblb suggested an aspergillus and mucor co-infection. co-infection with aspergillus and mucor in the post tubercular cavity is rare. there are cases reported in the literature where post-tubercular cavity in the lung with a mucor fungal ball was treated using liposomal amb. 19 though aspergillus is the most common fungus causing the formation of a fungal ball, only 5 case reports (delineating 8 patients) of paranasal fungal balls caused by mucor has been published in the literature. 20 it should be noted that there are some reports where invasive pulmonary aspergillus and mucor was countered adequately using high doses of liposomal amb alone. 21 however, in a report of pulmonary aspergillus and mucor coinfection in a diabetic patient, outcomes were not satisfactory even with extensive antifungal treatment with intravenous amphotericin and voriconazole. 1 delay in diagnosis, non-affordability of new and effective antifungal agents, lack of consensus concerning the dosage and duration of antifungals in mixed infections play a major role in the treatment outcome. conclusion mucormycosis and aspergillosis are rare co-infections that could potentially lead to death. a high degree of suspicion, early detection by a multidisciplinary approach, appropriate antifungal therapy and, if necessary, surgical resection are essential in the treatment of this co-infection. antimicrobial therapy must be rationalized, especially in co-infections with underlying immunosuppressive conditions as there is no clear consensus on the treatment of mixed coinfections that respond differently to standard treatment protocols. references 1. mahadevaiah ah, rajagopalan n, patil m, shivaprasad c. coinfection of pulmonary mucormycosis and aspergillosis presenting as bilateral vocal cord palsy. bmj case rep 2013; 2013:bcr2013009615. https://doi.org/10.1136/bcr-2013-009615. 2. petrikkos g, skiada a, lortholary o, roilides e, walsh tj, kontoyiannis dp. epidemiology and clinical manifestations of mucormycosis.clin infect dis 2012; 54:s23–34. https://doi.org/10.1093/cid/cir866. 3. trof rj, beishuizen a, debets-ossenkopp yj, girbes ar, groeneveldab.management of invasive pulmonary aspergillosis in nonneutropenic critically ill patients. intensive care med 2007; 33:1694–703.doi: 10.1007/s00134-007-0791-z. 4. li y, fang w, jiang w, hagen f, liu j, zhang let al. cryptococcosis in patients with diabetes mellitus ii in mainland china: 1993–2015. mycoses 2017; 60:706–13. doi: 10.1111/myc.12645. 5. nunes jo, pillon kr, bizerra pl, paniago am, mendes rp, chang mrthe simultaneous occurrence of histoplasmosis and cryptococcalfungemia: a case report and review of the literature. mycopathologia 2016; 181:891–97.doi: 10.1007/s11046-016-0036-1. 6. dagenais tr, keller np. pathogenesis of aspergillusfumigatus in invasive aspergillosis.clinmicrobiol rev. 2009 ;22(3):447-65. doi: 10.1128/cmr.00055-08. 7. spellberg b, edwards j, ibrahim a. novel perspectives on mucormycosis: pathophysiology, presentation, and management. clinmicrobiol rev 2005; 18:556–69.doi: 10.1128/cmr.18.3.556-569.2005. 8. hamilos g, samonis g, kontoyiannis dp. pulmonary mucormycosis.seminrespircrit care med. 2011; 32(6):693-702. doi: 10.1055/s-0031-1295717. 9. kousha m, tadi r, soubani ao. pulmonary aspergillosis: a clinical review. eurrespir rev. 2011; 20(121):156-74. doi: 10.1183/09059180.00001011. 10. kawamura s, maesaki s, tomono k, tashiro t, kohno s. . clinical evaluation of 61 patients with pulmonary aspergilloma. intern med 2000; 39:209–12.doi: 10.2169/internalmedicine.39.209. https://doi.org/10.1093/cid/cir866 11. lahiri tk, agarwal d, reddy ge, bajoria a. pulmonary mucoraceous fungal ball. indian j chest dis allied sci 2001; 43:107–10. 12. muqeetadnan m, rahman a, amer s, nusrat s, hassan s, hashmi s. pulmonary mucormycosis: an emerging infection. case rep pulmonol 2012; 2012:120809. https://doi.org/10.1155/2012/120809. 13. chamilos g, marom em, lewis re, lionakis ms, kontoyiannis dp. predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer.clin infect dis 2005; 41:60–6. https://doi.org/10.1086/430710. 14. de pauw b, walsh tj, donnelly jp, stevens da, edwards je, calandra t, et al. revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (eortc/msg) consensus group. clin infect dis 2008; 46:1813–21. https://doi.org/10.1086/588660. 15. patterson tf, thompson gr 3rd, denning dw, fishman ja, hadley s, herbrecht r, et al. practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america. clin infect dis 2016; 63:e1–e60. https://doi.org/10.1093/cid/ciw326. 16. patterson tf, thompson gr 3rd, denning dw, fishman ja, hadley s, herbrecht r, kontoyiannis dp, marr ka, morrison va, nguyen mh, segal bh, steinbach wj, stevens da, walsh tj, wingard jr, young ja, bennett je. practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america. clin infect dis. 2016 aug 15;63(4):e1-e60. doi: 10.1093/cid/ciw326. epub 2016 jun 29. pmid: 27365388; pmcid: pmc4967602 17. mohapatra b, sivakumar p, bhattacharya s, dutta s. surgical treatment of pulmonary aspergillosis: a single center experience. lung india 2016; 33:9–13. https://doi.org/10.4103/0970-2113.173077. 18. petrikkos g, drogari-apiranthitou m. zygomycosis in immunocompromised nonhaematological patients. mediterr j hematol infect dis 2011; 3:e2011012. https://doi.org/10.4084/mjhid.2011.012. https://doi.org/10.1093/cid/ciw326 19. mekki so, hassan aa, falemban a, alkotani n, alsharif sm, haron a, et al. pulmonary mucormycosis: a case report of a rare infection with potential diagnostic problems. case rep pathol 2020; 2020. https://doi.org/10.1155/2020/5845394. 20. cho hs, yang hs, kim ks. mucormycosis (mucor fungus ball) of the maxillary sinus. ear nose throat j 2014; 93:e18–22. https://doi.org/10.1177/014556131409300904. 21. bergantim r, rios e, trigo f, guimaraes je. invasive coinfection with aspergillus and mucor in a patient with acute myeloid leukemia.clin drug investig 2013; 33:s51–5. https://doi.org/10.1007/s40261-012-0022-4. figure 1: computed tomography of a: a 70-year-old male patient showing a thick-walled cavity in the right upper lobe with an intracavitary mass surrounded by a crescent of air known as the ‘air crescent sign’ (case one) and b: a 65-year-old male patient showing central ground-glass opacity surrounded by a complete ring of consolidation known as the ‘reverse halo sign’ (case two). figure 2: histopathology of lung biopsy showing aspergillus and mucor in a 65-year-old male patient. this is a periodic acid-schiff staining at x40 magnification showing multiple branching septated hyphae (black arrow) consistent with aspergillus along with broad-based, ribbon-like, non-septate hyphae (red arrow) suggestive of mucor. figure 3: chest x-ray of a mixed infection of aspergillus and mucor showing significant radiological resolution after three weeks of amphotericin b therapy in a 65-year-old male patient. departments of 1surgery, 2radiology and 3medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: arunoday@squ.edu.om atherosclerotic carotid artery disease where to from the emergency room? university hospital experience ibrahim al kindi,1 sara al adawi,1 edwin stephen,1 saleh ba awain,2 *arunodaya r. gujjar,3 ibrahim abdelhedy,1 hanan al mawaali,1 khalifa al-wahaibi1 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 561–565, epub. 7 nov 22 submitted 30 aug 21 revision req. 3 nov 21; revision recd. 6 dec 21 accepted 6 jan 22 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2022.028 brief communication abstract: objectives: stroke is the second leading cause of death worldwide, resulting in 5.5 million deaths in 2016. vascular interventions, including carotid endarterectomy (cea) and carotid artery stenting, play a major role in stroke prevention, especially when performed early after onset of symptoms. this study aimed to define the role of vascular surgeons in ischaemic stroke management and hence improve referral patterns by creating an algorithm for the referral process. this could reduce time to intervention and optimise patient benefit from intervention. methods: this retrospective study reviewed symptomatic and asymptomatic patients with atherosclerotic disease of the carotid artery who were referred to the vascular surgery unit of sultan qaboos university hospital, muscat, oman, from april 2018 to march 2020 to examine factors influencing recognition of suitable candidates for intervention. following analysis of the data, algorithms/protocols were created to simplify the referral process of symptomatic and asymptomatic carotid artery disease for surgical intervention. results: a total of 38 patients with ischaemic stroke were recognised as having carotid artery stenosis and were referred to the vascular surgery service during the study period. only six met the criteria for cea, four of which underwent the procedure. conclusion: choice of patients for cea involves multiple steps, with potential for missed opportunities. by involving a multidisciplinary team approach, the recommended protocol aims to lead to early and appropriate referral to a vascular surgeon or an interventional radiologist, resulting in increased and optimised intervention in stroke prevention. keywords: stroke; transient ischemic attack; carotid stenosis; carotid endarterectomy; vascular surgery; carotid stent; oman. stroke is recognised as the second leadingcause of death worldwide, resulting in 5.5 million deaths in 2016. it is also the second most common cause of enduring disability, with the global burden of stroke estimated to continue to rise.1 a stroke registry at sultan qaboos university hospital (squh), muscat, oman, enrolling approximately 600 patients with stroke, recognised poor outcomes in almost 60% of cases and attributed this mainly to large artery or cardioembolic strokes.2 previous experiences at the institute, as obtained through a stroke registry, have demonstrated several difficulties in the process of recognition of appropriate patients who would benefit from revascularisation interventions; this pattern is similar to many centres offering carotid endarterectomy (cea). these difficulties include recognising the degree of extracranial arterial stenosis; attributing the lesion as the cause of the current vascular event; excluding downstream (intracranial) arterial disease, which may complicate the intervention; pin-pointing other associated modes of stroke in the same patient (e.g. excluding cardio-embolism or small vessel disease as the primary cause of the index stroke); matching severity of residual neurologic deficits with the need for surgery; compliance to future treatment measures; and, lastly, patient acceptance of the intervention. this complex process of patient selection may lead to missed opportunities in offering appropriate surgical intervention to deserving patients with severe cerebrovascular stenosis. this study aimed to define the role of vascular surgeons in ischaemic stroke management and, hence, improve referral patterns by creating an algorithm for the referral process, which can reduce time to intervention and optimise patient benefit from intervention. methods this retrospective single-centre study included all cases of carotid artery disease referred to the vascular surgery unit at squh between april 2018 and march 2020; cases were analysed for possible carotid intervention. the electronic medical records of such patients were reviewed by the authors to extract demographics, presenting symptoms, underlying cause of stroke (large artery disease, cardio-embolism, small artery disease or others), risk factors, treatment received and outcomes. brain and cerebrovascular imaging studies performed on the patients were reviewed by radiology, neurology and vascular surgery https://creativecommons.org/licenses/by-nd/4.0/ atherosclerotic carotid artery disease where to from the emergency room? university hospital experience 562 | squ medical journal, november 2022, volume 22, issue 4 consultants. the degree of stenosis was calculated using the north american symmrtptomatic carotid endarterectomy trial (nascet) criteria using syngo.via software (siemens healthineers, erlangen, germany). the patients were classified into those who received only best medical therapy (bmt) or cea or were referred for carotid artery stenting (cas). this study was approved by the institutional review board. results a total of 38 patients were recognised as having carotid artery stenosis and were referred to the vascular surgery service during the study period. of these, 31 (81.6%) patients presented with stroke, three (7.9%) with transient ischemic attack (tia) and four (10.5%) were asymptomatic. of the symptomatic patients, 29 (85.3%) were admitted through the emergency department (ed); three (10.3%) of admitted patients were in-patients and two (6.9%) were referred from a peripheral hospital after initial medical treatment for ischaemic stroke. the time from symptom onset to admission through the ed ranged from 30 minutes to three days, with the average being 24 hours. a total of 11 patients presented within the 4.5-hour thrombolysis window, of whom five met the criteria for and received thrombolysis. another 11 patients came after the thrombolysis window but before 24 hours, while five came within 24–72 hours and two came after 72 hours [table 1]. the most common imaging modality that was used to identify carotid stenosis was computed tomography angiography; this was used in 29 patients, with most patients undergoing the scan within five days of admission. of these patients, three (10.3%) had duplex ultrasound done elsewhere before referral to the centre and five (17.2%) had undergone magnetic resonance imaging. one asymptomatic patient had a coronary angiogram with carotid run when a significant carotid stenosis was recognised. a total of 10 (26.3%) patients were identified as having significant unilateral stenosis of the extracranial portion of the internal carotid artery (ica), defined as 70–99% stenosis, while one (2.6%) patient had significant bilateral ica stenosis. seven (18.4%) patients had complete unilateral (100%) occlusion of the extracranial ica, while one (2.6%) had complete bilateral ica occlusion. two (5.3%) other patients had significant unilateral stenosis with contralateral occlusion. the remaining 17 (44.7%) patients had nonsignificant carotid disease [table 2]. among the 10 patients with significant unilateral stenosis, six (60%) were deemed suitable for cea. the remaining four (40%) were not considered candidates for cea due to the presence of haemorrhagic table 1: characteristics of symptomatic and asymptomatic patients with atherosclerotic disease of the carotid artery at sultan qaboos university hospital, muscat, oman (n = 38) characteristic n (%) age in years 40–49 3 (7.9) 50–59 13 (34.2) 60–69 13 (34.2) ≥70 9 (23.7) gender male 22 (57.9) female 16 (42.1) comorbidity none 1 (2.6) single 5 (13.2) multiple 32 (84.2) presentation asymptomatic 4 (10.5) transient ischemic attack 3 (7.9) stroke 31 (81.6) imaging ct angiography 29 (76.3) carotid duplex 3 (7.9) mri 5 (13.2) digital subtraction angiography 1 (2.6) ct = computed tomography; mri = magnetic resonance imaging. table 2: distribution of degree of extracranial carotid artery stenosis according to the north american symptomatic carotid endarterectomy trial criteria (n = 38) degree of occlusion in extracranial portion n (%) significant unilateral stenosis (70–99%) 10 (26.3) complete unilateral occlusion (100%) 7 (18.4) significant bilateral stenosis (70–99%) 1 (2.6) significant unilateral stenosis with contralateral occlusion 2 (5.3) complete bilateral occlusion 1 (2.6) non-significant stenosis 17 (44.7) ibrahim al kindi, sara al adawi, edwin stephen, saleh ba awain, arunodaya r. gujjar, ibrahim abdelhedy, hanan al mawaali and khalifa al-wahaibi brief communication | 563 transformation of the stroke, severe neurologic deficits with no improvement or concomitant intracranial carotid disease. all six eligible patients were offered cea; of these, four (66.7%) patients underwent cea, while two (33.3%) refused. median referral time to vascular surgery service from presentation to ed admission for stroke/tia was five days. out of those referred due to symptomatic ica occlusion, three (8%) were eligible for and underwent cea at 23, 127 and 220 days since onset of symptoms. delay in intervention in these cases was due to patient hesitancy to undergo cea; two (5%) patients agreed to undergo surgery only after experiencing a second stroke. additionally, 10 (26%) patients were found to have total carotid artery occlusion, for which no surgical intervention was indicated; hence, they did not benefit from referral. of those not suitable for cea, one patient was referred for angioplasty of a previous carotid stent and one was advised carotid stenting. the remaining 32 patients were continued on medical therapy, which included aspirin, clopidogrel and statin, in addition to risk factor management. to address and simplify the management of symptomatic and asymptomatic carotid artery disease, algorithms 1 and 2 were proposed [figures 1 and 2, respectively]. discussion stroke is the third leading cause of death in oman, after ischaemic heart disease and road injuries.3 with the incidence of non-communicable diseases, such as diabetes, hypertension, dyslipidaemia and smoking, projected to increase in incidence globally, incidence of stroke is likely to increase as well.4–6 as with other non-communicable diseases, prevention is key to minimising the economic and health burden of stroke. significant advances in the medical management of patients with stroke have enabled reduction of disability and prevention of future vascular events and mortality. however, one aspect of stroke prevention involves the mandatory role of a vascular surgeon and/or an interventional radiologist. atherosclerotic stenosis of extracranial carotid and, rarely, vertebral artery, which is severe enough to limit cerebral blood flow and cause symptoms, has been recognised by several studies to benefit from cea or cas.7–9 this benefit of cea is recognised to be superior to any medical intervention in this context. therefore, the current situation has mandated the need for studying the vascular anatomy figure 1: referral pathway for symptomatic carotid atherosclerotic disease. tia = transient ischaemic attack; mra = magnetic resonance angiography; cta = computed tomography angiography; ich = intracranial haemorrhage; cea = carotid endarterectomy; mrs = modified rankin scale for neurological disability; mca = middle cerebral artery; alc = altered level of consciousness. *time from onset of symptoms to hospital presentation; †more than 50%. figure 2: referral pathway for asymptomatic carotid atherosclerotic disease. cta = computed tomography angiography; mra = magnetic resonance angiography; bmt = best medical therapy; cabg = coronary artery bypass surgery; ica = internal carotid artery; cea = carotid endarterectomy; cas = carotid artery stenting. atherosclerotic carotid artery disease where to from the emergency room? university hospital experience 564 | squ medical journal, november 2022, volume 22, issue 4 of almost every patient with tia or stroke. however, the intervention is associated with risks of procedural stroke as well as mortality. an acceptable balance of benefit and risk is well recognised to be provided by positioning the intervention within about two weeks of onset of an index stroke or tia.10 however, the need for recognising suitable surgical candidates for revascularisation surgery emphasises an urgency in completing the evaluation process of such patients. while many therapies exist for the primary and secondary prevention of stroke, revascularisation is the only interventional modality currently available and can be performed in the form of cea or cas.11 although atherosclerosis may affect intraand/or extracranial arteries, only selected stenotic arterial lesions are amenable to cea.10 medical management is accepted as the best option for intracranial arterial stenosis.12 the nascet, european carotid surgery trial and symptomatic veterans affairs co-operative study trial collectively showed that for patients with severe carotid artery stenosis, cea, when compared to bmt alone, reduces the absolute risk (ar) and relative risk of any stroke at five years by 15.6% and 48%, respectively.13,14 furthermore, in a landmark trial by rothwell et al., it was found that the ar for periprocedural stroke after cea decreased from 30.2% to 17.6% after the initial two-week period from onset of symptoms.14 based on these findings, early recognition and management of ica stenosis in stroke/tia is pertinent to improving outcome and is reflected in the current guidelines by the european society of vascular surgery (esvs) and society of vascular surgery, which recommend intervention within the first 14 days of onset of symptoms and up to 48 hours in cases of tia or stroke-in-evolution.10,15 some select patients, however, with a more marked neurological deficit (mrs 3 or 4), may benefit from a deferred cea after four weeks of onset of symptoms.16 several factors appear to influence decision and timing regarding cea; of those factors, imaging necessary to study the vascular anatomy and degree of stenosis of patients with ischaemic stroke or tia is either not obtained or delayed. most patients are evaluated initially with a computed tomography (ct) scan during their admission, with a ct or a magnetic resonance angiogram scheduled only a few days later. however, this practice is changing with the introduction of access to early mechanical thrombectomy, where a vascular imaging at emergent admission is now considered the standard of care for the recognition of a thrombus in a proximal (accessible) segment of major arteries; this would also enable early recognition of carotid stenosis.17 another issue is that of patient (and family) acceptance. a surgical intervention in the context of a potentially serious or life-threatening condition, such as stroke, is a major hurdle in most patients’ acceptance. moreover, varied factors are recognised to influence acceptability of such interventions. in the current study, most of the above factors were recognised in several patients and influenced treatment decisions as well as timing to imaging or intervention. this study aimed to define the role of vascular surgeons in ischaemic stroke management, sought to decrease patients’ time to intervention, improve referral patterns to the vascular service, allow more time for patient counselling and the planning of procedures and reduce time spent reviewing cases that would not benefit from intervention. earlier studies have recognised that a multidisciplinary approach to carotid artery disease can increase the number of patients undergoing urgent cea while also improving overall outcome in terms of perioperative stroke and death.18 furthermore, the proposed algorithm, which is based on oman’s ministry of health and esvs guidelines for stroke, adds a clear pathway for vascular surgery referrals. in the present study, 11% of referrals were due to asymptomatic atherosclerotic carotid artery disease, most referred from the cardiothoracic surgery unit for patients prior to undergoing coronary artery bypass grafting, or were found incidentally on imaging; hence, a second algorithm was created to facilitate decision making in such asymptomatic patients. both algorithms aimed to simplify referring suitable candidates to the vascular surgery unit while leaving more technical aspects of suitability to the neurology and vascular surgery services. conclusion stroke is a leading and increasing cause of overall morbidity and mortality in oman. the presence of an adequate framework for vascular surgery referrals for patients with atherosclerotic carotid disease can lead to increased patient benefit from revascularisation interventions, such as cea and cas. a multidisciplinary approach to carotid disease will lead to decreased time for patients to undergo these procedures and, hence, increase their overall benefit from the intervention, when indicated. in addition to highlighting the importance of a multidisciplinary team approach to managing stroke in a timely manner, there is also a need for good patient education regarding symptoms of stroke and the importance of early presentation to a hospital and available treatment options. ibrahim al kindi, sara al adawi, edwin stephen, saleh ba awain, arunodaya r. gujjar, ibrahim abdelhedy, hanan al mawaali and khalifa al-wahaibi brief communication | 565 a u t h o r s’ c o n t r i b u t i o n iak was involved in data gathering, literature review and manuscript writing. saa was involved in data gathering and manuscript writing. es contributed to data gathering, literature and manuscript review and final approval. sba was involved in data gathering and image review. arg contributed to data, literature and manuscript review and final approval. ia was involved in data gathering and literature review. ham was involved in data gathering and patient follow-up. kaw was involved in literature review, manuscript writing and final approval. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. katan m, luft a. global burden of stroke. semin neurol 2018; 38:208–11. https://doi.org/10.1055/s-0038-1649503. 2. gujjar ar, nandhagopal r, jacob pc, al-azri f, ganguly ss, rana shoaib h, et al. ischemic stroke outcomes in oman: experience of a university-hospital based stroke registry. j neurol sci 2015; 357:e380. https://doi.org/10.1016/j.jns.2015.08.1353. 3. gbd 2016 healthcare access and quality collaborators. mea suring performance on the healthcare access and quality index for 195 countries and territories and selected subnational locations: a systematic analysis from the global burden of disease study 2016. lancet 2018; 391:2236–71. https://doi.org/10.1016/s014 0-6736(18)30994-2. 4. al-mawali a. non-communicable diseases: shining a light on cardiovascular disease, oman’s biggest killer. oman med j 2015; 30:227–8. https://doi.org/10.5001/omj.2015.47. 5. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 6. al-lawati ja, panduranga p, al-shaikh ha, morsi m, mohsin n, khandekar rb, et al. epidemiology of diabetes mellitus in oman: results from two decades of research. sultan qaboos univ med j 2015; 15:e226–33. 7. randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the mrc european carotid surgery trial (ecst). lancet 1998; 351:1379–87. https://doi. org/10.1016/s0140-6736(97)09292-1. 8. mayberg mr, wilson se, yatsu f, weiss dg, messina l, hershey la, et al. carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. jama 1991; 266:3289–94. https://doi.org/10.1001/jama.1991.03470230047029. 9. ferguson gg, eliasziw m, barr hw, clagett gp, barnes rw, wallace mc, et al. the north american symptomatic carotid endarterectomy trial: surgical results in 1415 patients. stroke 1999; 30:1751–8. https://doi.org/10.1161/01.str.30.9.1751. 10. naylor ar, ricco jb, de borst gj, debus s, de haro j, halliday a, et al. editor’s choice – management of atherosclerotic carotid and vertebral artery disease: 2017 clinical practice guidelines of the european society for vascular surgery (esvs). eur j vasc endovasc surg 2018; 55:3–81. https://doi.org/10.1016/j. ejvs.2017.06.021. 11. sherzai az, elkind ms. advances in stroke prevention. ann n y acad sci 2015; 1338:1–15. https://doi.org/10.1111/nyas.12723. 12. sps3 investigators, benavente or, hart rg, mcclure la, szychowski jm, coffey cs, et al. effects of clopidogrel added to aspirin in patients with recent lacunar stroke. n engl j med 2012; 367:817–25. https://doi.org/10.1056/nejmoa1204133. 13. rothwell pm, eliasziw m, gutnikov sa, fox aj, taylor dw, mayberg mr, et al. analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. lancet 2003; 361:107–16. https://doi.org/10.1016/ s0140-6736(03)12228-3. 14. rothwell pm, eliasziw m, gutnikov sa, warlow cp, barnett hj. endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. lancet 2004; 363:915–24. https://doi.org/10.1016/s0140-6736(04)15785-1. 15. powers wj, rabinstein aa, ackerson t, adeoye om, bambakidis nc, becker k, et al. guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the american heart association/ american stroke association. stroke 2019; 50:e344–418. https:// doi.org/10.1161/str.0000000000000211. 16. pini r, faggioli g, vacirca a, dieng m, goretti m, gallitto e, et al. the benefit of deferred carotid revascularization in patients with moderate-severe disabling cerebral ischemic stroke. j vasc surg 2021; 73:117–24. https://doi.org/10.1016/j.jvs.2020.03.043. 17. kaesmacher j, maamari b, meinel tr, piechowiak ei, mosimann pj, mordasini p, et al. effect of preand in-hospital delay on reperfusion in acute ischemic stroke mechanical thrombectomy. stroke 2020; 51:2934–42. https://doi.org/10.1161/strokea ha.120.030208. 18. bazan ha, caton g, talebinejad s, hoffman r, smith ta, vidal g, et al. a stroke/vascular neurology service increases the volume of urgent carotid endarterectomies performed in a tertiary referral center. ann vasc surg 2014; 28:1172–7. https:// doi.org/10.1016/j.avsg.2013.10.002. https://doi.org/10.1055/s-0038-1649503 https://doi.org/10.1016/j.jns.2015.08.1353 https://doi.org/10.1016/s0140-6736(18)30994-2 https://doi.org/10.1016/s0140-6736(18)30994-2 https://doi.org/10.5001/omj.2015.47 https://doi.org/10.1016/s0140-6736(97)09292https://doi.org/10.1016/s0140-6736(97)09292https://doi.org/10.1001/jama.1991.03470230047029. https://doi.org/10.1161/01.str.30.9.1751 https://doi.org/10.1016/j.ejvs.2017.06.021. https://doi.org/10.1016/j.ejvs.2017.06.021. https://doi.org/10.1111/nyas.12723 https://doi.org/10.1056/nejmoa1204133. https://doi.org/10.1016/s0140-6736(03)12228-3 https://doi.org/10.1016/s0140-6736(03)12228-3 https://doi.org/10.1016/s0140-6736(04)15785-1 https://doi.org/10.1161/str.0000000000000211 https://doi.org/10.1161/str.0000000000000211 https://doi.org/10.1016/j.jvs.2020.03.043. https://doi.org/10.1161/strokeaha.120.030208 https://doi.org/10.1161/strokeaha.120.030208 https://doi.org/10.1016/j.avsg.2013.10.002 https://doi.org/10.1016/j.avsg.2013.10.002 marjolin’s ulcer radiographic and magnetic resonance appearances in two cases *sukhpal sawhney,1 rajeev jain,3 anupam kakaria,1 pradeep chopra2 case report squ med j, august 2009, vol. 9, iss. 2, pp. 162-166, epub 30th june 2009 submitted 21st oct 08 revision req. 17th may 09, revision recd. 18th may 09 accepted 18th may 09 departments of 1radiology & molecular imaging & 2surgery, sultan qaboos university hospital, muscat, sultanate of oman; 3department of radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat , sultanate of oman *to whom correspondence should be addressed. email: sukh@squ.edu.om marjolin’s ulcers are rare malignancies that arise at sites of chronic non-healing wounds and scar wounds. the precise mechanism by which chronic ulcers develop malignancy is unknown. the commonest type of carcinoma arising in the marjolin’s ulcer is a squamous cell carcinoma, followed by basal cell carcinoma. we report two cases of marjolin’s ulcer along with radiographic and mri findings case one a 70 year old man developed a chronic nonhealing ulcer on his right leg following a childhood trauma and presented at sultan qaboos university hospital (squh), oman. the ulcer had become worse during the previous two years. it had started increasing in size, was oozing blood and had become painful. on examination, he had a large fungating ulcerative mass over the antero-lateral aspect of his right lower leg and right inguinal lymph nodes were palpable. the remainder of his physical examination was unremarkable. a punch biopsy of the ulcer revealed well differentiated squamous cell carcinoma. radiographs [figure 1] and a magnetic resonance imaging scan (mri) [figure 2a, 2b & 2c] confirmed the findings of a large polypoidal softtissue mass invading the underlying tibial cortex and marrow. the patient was advised amputation and block dissection which he refused and left the hospital against medical advice. case two an 85 year old man developed an infective ulcer over a chronic wound on his left lower leg which he had sustained 10 years previously. despite local and systemic treatment the ulcer was becoming larger and painful. on presentation at squh, the examination showed a large, polypoidal, fungating ulcerative mass, measuring 7cm x 7cm located on the anterior surface of the tibia. a biopsy of the ulcer was positive for squamous cell carcinoma. the قرحة مارجولني املظاهر الشعاعية وصفات الرنني املغناطيسي يف حالتني سخبال سوهني ، راجيف جني، أنوبام كاكاريا براديب جوبرا امللخص: قرحة مارجولني قرحة خبيثة حتصل في تقرحات الوريد املزمنة والندب واحلروق واجلروح املزمنة . يعطي التصوير الشعاعي معلومات مهمة حول تآكل العظم والتفاعل السمحاقي ، بينما يبني التصوير بالرنني املغناطيسي تفاصيل األنسجة الرخوة بشكل دقيق ، مثل انتشار الورم وعمقه للتصوير وصف مع مارجولني لقرحة حالتني هنا اجملاورة. ندرج الدموية واألوعية األعصاب اصابة أو نقيه، أو العظم قشرة في اصابة وأي وحافاته باألشعة والرنني املغناطيسي. مفتاح الكلمات: قرحة مارجولني، قرحة جروح الساق املزمنة، تصوير الرنني املغناطيسي، تقرير حالة ،عمان. abstract: marjolin’s ulcers are malignancies that arise in chronic venous ulcers, scars, burns, long standing wounds or sinuses. radiography provides important information regarding bone destruction and periosteal reaction, and magnetic resonance )mr( imaging provides excellent soft tissue detail, like tumour extent, depth, margins, any underlying bone cortical or marrow involvement, or involvement of adjacent neuro-vascular structures. we report two cases of marjolin’s ulcer and describe their radiographic and mr appearances. keywords: marjolin’s ulcer; chronic wound; leg ulcers; magnetic resonance imaging; case report; oman sukhpal sawhney, rajeev jain, anupam kakaria and pradeep chopra case report | 163 rest of his physical examination was unremarkable. no metastatic lesions were found on the computed tomography (ct) scan. a tc 99m-mdp bone scan revealed abnormal increased tracer uptake at the local site in the tibia with no other abnormal uptake in the rest of the skeleton. the radiograph [figure 3], a bone scan [figure 4] and mri examinations [figure 5a, 5b & 5c] were performed which revealed a large infiltrative figure 1: (patient 1) a radiograph of right lower leg reveals a lobulated soft tissue mass over the anterolateral surface of the leg. the underlying tibia shows lamellated, thick periosteal reaction and an underlying ill defined lucent lesion in the medullary shaft. figure 2a: (patient 1) transverse t2-weighted magnetic resonance imaging (mri) scan shows a lobulated, pretibial skin and subcutaneous infiltrative soft tissue mass (arrows) extending posteriorly, invading the muscles of the lateral compartment and involving the underlying tibial cortex and medulla (arrowhead). figure 2b: contrast enhanced transverse ti-fat saturated image shows a circumferential mass with patchy intense enhancement and necrotic areas. the bone marrow of the tibia shows a focal moderately enhancing area beneath the mass. figure 2c: contrast enhanced transverse ti-fat saturated image demonstrates the longitudinal extent of the mass and infiltration into the bone. marjolin’s ulcer radiographic and magnetic resonance appearances in two cases 164 | squ medical journal, august 2009, volume 9, issue 2 superficial mass extending through the underlying tibial cortex into the medullary cavity. the patient was advised amputation which he subsequently refused. discussion malignancies that arise in chronic venous ulcers, chronic injuries, scars, burns, chronic osteomyelitis or sinuses are referred to as marjolin’s ulcers. marjolin’s ulcer is an extremely rare condition which is reported to develop in approximately 0.05%1 to 0.05%,2 of long-standing pressure ulcers in patients with spinal cord injuries. a french surgeon, jean-nicolas marjolin, at the university of paris described the occurrence of ulcerating lesions within scar tissue in 1828;3 however, he did not identify the warty ulcers he described as malignant. two years later it was dupuytren4 who noted that these lesions were malignant. the commonest type of carcinoma arising from marjolin’s ulcer is squamous cell carcinoma, followed by basal cell carcinoma. the exact mechanism by which chronic ulcers (wounds) develop malignancy is not known. a variety of causes including chronic irritation and infection (with resulting degeneration and regeneration); decreased vascularity and a weakened epithelium, and elevated expression of proto-oncogenes,5 have been suggested for the susceptibility of chronic wounds to malignant transformation. inflammation, ulceration, and repeated trauma, especially in flexion creases, over many years may provide enough chronic irritation to promote malignant change.6 the pathogenesis of marjolin’s ulcer remains unclear and controversial. early theories suggested that cellular mutations as a result of toxins release by damaged, ischaemic and nutritionally deficient tissues are responsible for neoplastic change. 7 although the latent period between the original injury and the development of marjolin’s ulcer has been documented as being as being as long as 30 years,8 thio et al.9 have reported a case of marjolin’s degeneration that developed in an ulcer only 18 months after the initial injury. bone destruction is the most important radiological finding for the surgeon. it was found in 20 out of 21 patients described by smith et al.5 figure 4: (patient 2) bone scan showed a region of intense uptake in the mid-leg figure 3: (patient 2) a radiograph of the left lower leg revealed a large lobulated soft tissue mass with a central ulcerated area (arrow) encroaching on the on the anterior tibial shaft and causing a punched out osteolytic defect with sclerotic margins (arrowheads). sukhpal sawhney, rajeev jain, anupam kakaria and pradeep chopra case report | 165 in only one patient in their study, bone destruction could not be seen due to sub-optimal quality of the radiograph. both our patients demonstrated bone destruction on radiographs along with periosteal reaction. the mri scan had the advantage of demonstrating excellent soft tissue detail, the extent of the ulcer, its margins, the extension of tumour into cortex and bone marrow, the periosteal reaction and the involvement of surrounding structures. mri scanning is superior to ct as it demonstrates the extent of medullary bone, soft tissue and neuro-vascular involvement. most frequently, both t1 and t2 weighted images are needed to characterise the lesions. t2 weighted images are best suited for soft tissue characterisation and t1 weighted images for distinction between marrow and tumour. short-tau inversion-recovery (stir) sequences are useful for detection of subtle marrow or soft tissue lesions. to date, gadolinium has not significantly improved the histological accuracy of mri except for differentiating solid from cystic lesions and identifying areas of necrosis.10,11 bone scans help to identify areas of increased radioisotope uptake. conclusion to conclude, marjolin’s ulcer is a rare, but important entity, which may be preventable by the early treatment of non-healing ulcers. these ulcers should be followed up with frequent biopsies and imaging evaluation to detect or exclude infiltration of adjacent tissues by an undetected deeper focus of malignancy. the ideal imaging techniques for evaluation of soft-tissues and infiltration of underlying bone and critical neurovascular structures is mri. contrast enhanced transverse t1-fat saturated figure 5b: (patient 2) transverse t2-weighted image demonstrates the infiltration the cortex (arrowheads) and the medullary cavity (*) by the mass. predominantly low signal intensity of the mass reflects the fibrotic nature of squamous cell carcinoma figure 5c: (patient 2) transverse t1-fat saturated contrast-enhanced image at the same level as figure 5b shows intensely enhancing mass with focal necrotic areas, infiltrating into the tibial cortex and medullary cavity. fig5a: (patient 2) sagittal pd-weighted image shows a large lobulated mass with infiltration into and destruction of the cortex with extension into the medullary cavity (arrowheads) marjolin’s ulcer radiographic and magnetic resonance appearances in two cases 166 | squ medical journal, august 2009, volume 9, issue 2 image shows a circumferential mass with patchy intense enhancement and necrotic areas. the bone marrow of the tibia shows a focal moderately enhancing area beneath the mass. contrast enhanced transverse t1-fat saturated image demonstrates the longitudinal extent of the mass and infiltration into the bone. references 1. mustoe t, upton j, marcellino v, tun c, rossier ab, hachend hj. carcinoma in chronic pressure sores: a fulminant disease process. plast reconstr surg 1986; 77:116-21. 2. eltorai im, montroy re, kobayashi m, jakowatz j, guttierez p. marjolin’s ulcer in patients with spinal cord injury. j spinal cord med 2002; 25:191-6. 3. steffann c. marjolin’s ulcer. am j dermatopathol 1984; 6:187-93. 4. applebaum j, burrows wm, greenway hj. acute marjolin’s ulcer. j assoc milit dermatol 1985; 11:57-61. 5. smith j, mello lf, nogueira neto nc, walter m, pinto lw, campos va, et al. malignancy in chronic ulcers and scars of the leg (marjolin’s ulcer): a study of 21 patients. skeletal radiol 2001; 30:331-7. 6. mohamed si, abdullah bjj, singh da, heng ks. ct appearances of marjolin’s ulcer in the left gluteal region of a young man. biomed imaging interv j 2006; 2:e26. 7. treves n, park gt. the development of cancer in burns scars. surg gynecol obstet 1930; 51:749-82. 8. hahn sb, kim dj, jeon ch. clinical study of marjolin’s ulcer. yonsei med j 1990; 31:234-41. 9. thio d, clarkson jhw, misra a, srivastava s. malignant change after 18 months in a lower limb ulcer: acute marjolin’s revisited. brit assoc plast surg 2003; 56: 825-8. 10. phatak sv, kowlwadkar pk. images: squamous cell carcinoma of hand and wrist developing in burn scar. ind j radiol imag 2005; 15:467-8. 11. berquist th. mri of musculoskeletal system. 4th ed. philadelphia: lippincott williams & wilkins, 2001. pp. 827. department of optometry, college of health sciences, university of buraimi, al buraimi, oman *corresponding author’s e-mail: gopi_vankudre@yahoo.co.in barriers and perception towards spectacle wear among a student population of university of buraimi, oman *gopi s. vankudre and babu noushad sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 416–422, epub. 29 aug 21 submitted 15 apr 20 revisions req. 4 may & 9 jul 20; revisions recd. 4 may & 14 aug 20 accepted 17 sep 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.004 clinical & basic research abstract: objectives: the study aimed to evaluate the barriers and perceptions towards spectacle wear among the student population of the university of buraimi, oman. methods: a descriptive, questionnaire-based and cross-sectional study was conducted between december 2017 and may 2018. ophthalmic examination and a standard spectacle prescription protocol were used to identify those with inappropriate spectacle coverage. a selfdesigned and expert validated english-language questionnaire was utilised. a chi-square test was used to assess the association between the participants’ types of perceptions and sociodemographic and refractive error-related profiles. results: in total, 275 students participated in the study (response rate: 17.19%) and 170 (61.8%) were having inappropriate spectacle correction. only 26% of them used spectacles since the majority (73.5%) had never had their eyes examined before this study. most perceived spectacle wear positively (53.5%), followed by some having negative (36.5%) or neutral (10.0%) perceptions. those from a health science background including nursing and optometry had a higher positive perception towards spectacle wear than others (p = 0.012). the difference in the perception scores between myopic and hypermetropic refractive error groups was statistically insignificant (p = 0.882). conclusion: the majority of the participants had had inappropriate vision corrections with spectacles and not undergone any prior ocular examinations. few wore spectacles; however, these were inappropriate given their current refractive status. the reasons for spectacle non-wear were that either new spectacles had been ordered or spectacles were lost or broken. it is recommended that the school eye health initiative be extended to the university level. a holistic eye-health promotional approach toward integrating students, teachers and parents into this initiative can improve spectacle wear within the studied population. keywords: eyeglasses; refractive errors; ametropia; spectacles; patient compliance; oman. advances in knowledge the study’s findings reveal that there is a positive perception of spectacle wear among a university student population in oman. this positive perception is more common among students from health science majors compared to others. despite having a positive perception, compliance towards spectacle wear is poor. non-compliance towards the uptake of ophthalmic services was found to be the main barrier to spectacle wear. application to patient care the study’s results stress the importance of extending the current school eye health initiative implemented in oman to the university level. eye health promotional programmes that integrate students, teachers and parents, can improve spectacle wear and reduce the burden of avoidable blindness within the country. across the world, refractive error is estimated to affect around 2.3 billion persons; 90% of the affected population in which this error remains uncorrected resides in developing countries.1 a recent systematic review on refractive errors in a middle eastern population over 15 years of age observed that the prevalence of myopia, hypermetropia and astigmatism is 30%, 21% and 24%, respectively.2 moreover, a study conducted among the medical student population in saudi arabia observed a predominance of myopic refractive error (53.7%), followed by hyperopia (3.7%) and astigmatism (1.2%). the study also raised concern about the increase in the incidence of refractive errors, especially myopia.3 the increasing prevalence of uncorrected refractive errors in the middle east is becoming a primary public health issue. the studies that have been conducted among the low-income countries have observed that disadvantaged groups, such as those of a specific ethnicity and/or those belonging to lower socioeconomic or educational backgrounds and/or those having to bear the expenditure of spectacles from their own pocket, are at a higher risk of having non-correction of refractive errors.4 despite https://creativecommons.org/licenses/by-nd/4.0/ gopi s. vankudre and babu noushad clinical and basic research | 417 the aforementioned studies and their wide-ranging findings, barriers to refractive corrections have not been sufficiently studied, especially among the young adult population residing in a fast-developing and economically rich country such as oman. spectacle compliance is referred to as the act of regularly wearing the spectacle correction prescribed to the individual. a previous study among the schoolgoing population in oman observed spectacles compliance in 62% of participants in grade 7.5 in another study among omani school children, older students demonstrated better compliance (79.1%) compared to lower-grade students.6 interestingly, compliance was higher among female students compared to male students. it was also higher among the myopic group (72.5%) compared to other groups with refractive errors.6 compliance with spectacle wear is affected by an individual’s or society’s beliefs about spectacle wear by children or young adults. for instance, in developing countries such as africa, spectacle wear is believed to harm ocular health, reflecting poor spectacle wear compliance among this population.1 non-correction of refractive errors adversely impacts affected individuals both physically and mentally. uncorrected refractive error can adversely affect the quality of life, educational status and career opportunities as well as social interaction.1,2,4,6 over time, this imposes an economic burden on the affected individual as well as on the public health system.2 students wearing spectacles have improved vision and hence a better quality of life in this regard, compared to the non-wearing group.7 spectacle-related barriers such as social stigma, associated spectacle related myths such as continuus spectacle uses, adverserly affecting the vision or ‘sunken eyes’, cost and cosmesis have been observed in previous studies to be prohibiting the user from wearing spectacles.8 discomfort, damaged or lost spectacles and low amount of myopia were other identified barriers stated in previous studies.5,9 despite the availability of a simple corrective modality such as spectacles, it is less commonly utilised due to the existing misconceptions and negative perception towards spectacle wear.10,11 due to oman’s status as a high income country (compared to other low-income countries), the economic factor is not a significant barrier to spectacle coverage. spectacle wear is shown to be directly associated with the level of understanding of refractive errors and the perceptions of the affected individuals towards spectacles.1 regional studies on spectacle coverage have been conducted among various age groups, but not among young adults per se. the lifestyle, visual needs and priorities of university students are different from those of school students; the barriers applicable to school children cannot be generalised to university students. uncorrected refractive errors within the population indicate an inadequacy of the eye healthcare system as a simple means for spectacle correction is now available. the incidence of refractive errors is increasing at an alarming rate. international myopia institute estimated 50% of myopia prevalence by the year 2050 from the current 30%.12 correcting even a small amount of refractive error can significantly improve the quality of life and visual function.13 the world health organization (who) recommends regular evaluation of the magnitude of spectacle coverage within the population.14 it is also recommended to identify the barriers of spectacle coverage such as age, gender and socio-economic status to account for any demographic variable that may act as a barrier. the findings of the current study would support, in particular, the enhancement of the refractive error correction facilities that are being provided within the region at present and the overall eye health system in general.6 a majority of the previous studies on spectacle wear have been conducted among school children or teachers. the higher-education student population is more mature and are better decision-makers than the school student population. therefore, the perceptions of these two groups towards spectacle wear cannot be directly compared. furthermore, these need to be explored separately.1 studies have found that spectacle wear is enhanced due to the wearer’s positive perception.8,15 a study among a university student population in saudi arabia observed that the students were unaware of the importance of spectacle wear and their responsibilities towards spectacle correction.15 the study findings highlight the importance of educating the community about refractive error and its correction. ultimately, this could aid the reduction of the burden related to refractive error.15 the findings of the current study can also help the university administration design and implement an figure 1: distribution of reasons for spectacle nonwear among the study’s participants who have refractive errors (n = 170). barriers and perception towards spectacle wear among a student population of university of buraimi, oman 418 | squ medical journal, august 2021, volume 21, issue 3 evidence-based eye care protocol for students. hence, this study aimed to evaluate the barriers experienced by an oman-based university student population and their perceptions concerning spectacle wear. this evaluation aimed to obtain baseline evidence to forecast the future coverage of spectacles and health promotion activities that could facilitate spectacle wear compliance within the country. methods a descriptive, questionnaire-based and cross-sectional study was conducted between december 2017 and may 2018 at the university of buraimi, oman. the entire university student population (1,600 students) that had registered for the spring 2017–18 semester from different majors, genders or socioeconomic regions were invited to partipate in the current study. invitations were sent through their university email ids as well as through messages in/through student groups. the open source epidemiologic statistics for public health version 3.01 (updated 6 april 2013; centre for disease control and prevention, usa) was used to calculate the sample size. it considered a confidence level of 95% and hypothesised a 10% spectacle compliance rate as observed in a previous study among the student population of a university.13 the minimum required sample size was estimated as 128. all volunteering participants who had refractive error without any other ocular abnormality were included in this study. equal preference was given to all the volunteering and eligible participants from different sociodemographic profiles. the eligibility of the study participants was confirmed through a thorough ophthalmic examination including a slitlamp examination. a standard spectacle prescription protocol as per the guidelines of the who was performed among eligible participants.6 those with inappropriate spectacle coverage were further provided with a self-administered questionnaire to evaluate barriers related to spectacle wear and included in the analysis. the questionnaire was developed through a comprehensive literature review.6,9,11 it consisted of three components. the first component collected information regarding the reason for spectacle nonwear at the time of the study. the second and third components collected the responses for perception towards spectacle wear related to utility and psychological factors, respectively; the element of utility consisted of five questions and the psychological component consisted of seven questions. responses to questions were collected using a 5-point likert scale. table 1: association of characteristics and refractive error profiles and participants’ perceptions towards spectacle wear (n = 152) characteristic n (%) p value type of perception total negative positive gender male 12 (32.4) 25 (67.6) 37 (24.3) 0.234 female 50 (43.5) 65 (56.5) 115 (75.7) study major optometry 17 (44.7) 21 (55.3) 38 (25.0) 0.012 nursing 5 (16.7) 25 (83.3) 30 (19.7) business 23 (54.8) 19 (45.2) 42 (27.6) engineering 17 (40.5) 25 (59.5) 42 (27.6) location of residency urban 46 (43.4) 60 (56.6) 106 (69.7) 0.209 rural 16 (34.8) 30 (65.2) 46 (30.3) father’s literacy status university level 15 (40.5) 22 (59.5) 37 (24.3) 0.684high school level 26 (44.8) 32 (55.2) 58 (38.2) elementary level 2 (36.8) 36 (63.2) 57 (37.5) mother’s literacy status university level 5 (29.4) 12 (70.6) 17 (11.2) 0.530high school level 21 (39.6) 32 (60.4) 53 (34.9) elementary level 36 (43.9) 46 (56.1) 82 (53.9) parent working in the medical sciences field yes 37 (45.7) 44 (54.3) 81 (53.3) 0.190 no 25 (35.2) 46 (64.8) 71 (46.7) eye-health expenditure responsibility government/ insurance 59 (43.4) 77 (56.6) 136 (89.5) 0.065 (fisher’s exact test) self 3 (18.8) 13 (81.3) 16 (10.5) refractive error status myopia 57 (41.0) 82 (59.0) 139 (91.4) 0.858hypermetropia 5 (38.5) 8(61.5) 13 (8.6) total 62 (40.8) 90 (59.2) 152 (100) gopi s. vankudre and babu noushad clinical and basic research | 419 the content of the questionnaire was validated with the help of a group of experts.16,17 the validators responded to their agreement related to the appropriateness of the included questions through a dichotomous response (0 = unfavourable; +1 = favourable) for each item. validator responses were collected individually. the questionnaires were recirculated among the same experts following modifications. a minimum 80% of the subject expert’s agreement for each component ensured its validity. the internal reliability of the questionnaire was assessed using cronbach’s alpha (0.76). the first 10 questionnaire responses for all the 12 questionnaire items were considered for internal reliability. the test-retest validity of the questionnaire was assessed using pearson correlation coefficient (r = 0.83). of the participants, 10 individuals who had filled the questionnaire during their first visit were selected randomly and were again contacted after 15 days. they were further asked to resubmit their responses using the same questionnaire. however, these participants were blinded to their previous answers and were also kept unaware of the need for their repeated questionnaire responses after 15 days. as the questionnaire had negative statements related to spectacle wear, and the participants needed to respond on a scale of strongly disagree (–2.00) to strongly agree (+2.00), barrier scores of >0 were considered to indicate negative and <0 positive perception towards spectacle wear. the sum of these ordinal responses was noted as a barrier score. the minimum and maximum scores ranged from –24 to +24, respectively. responses with scores ranging from 1 to 24 and from –1 to –24 were categorised as negative and non-negative perceptions towards spectacle wear, respectively. shapiro–wilk normality distribution tests were performed to identify the normality of the barrier score rated by the participants on a likert scale. the statistical package for the social sciences (spss), version 21 (ibm corp., armonk, new york, usa) was used for data analysis. the components of the questionnaire that included responses related to reasons for spectacle non-wear and components related to psychological aspects were analysed using descriptive statistics. a chi-square test was used to assess the association between the type of perception and the sociodemographic and refractive error profiles of the participants. mann–whitney u test was used to compare the perception scores between myopic and hypermetropic groups. fisher’s exact test was used to identify the association between the barrier score and one variable (eye-health expenditure responsibility). the study obtained ethical permission from the research and ethics committee of the college of health sciences, university of buraimi, oman. this study adhered to the declaration of helsinki. the study details were explained to all the participants who were also informed of their right to withdraw from the study without any consequence or explanation. the study did not involve any participants from vulnerable groups such as those belonging to a lower socioeconomic status and no monetary or nonmonetary benefits were given to the participants. all the study-related information was provided to the participants as a written document and consent was obtained from each involved participant. results a total of 275 students agreed to partake in the study (response rate =17.19%). of these, 170 (61.8%) were identified as having had inappropriate spectacle correction. however, out of the 170 eligible participants, analysis was performed only for 152 participants, as one had mixed astigmatism and 17 had neutral perception; they were excluded from the analysis as the number was low. out of 170 participants who had inappropriate spectacle coverage, including the case of mixed astigmatism, 125 (73.5%) had not had their eyes examined previously. only 28 students (16.5%) were wearing spectacles but the correction was inappropriate considering their existing refractive status [figure 1]. over half of the participants (53.5%) had a positive perception towards spectacle wear, followed by negative (36.5%) and neutral (10.0%) perceptions. the shapiro–wilk normality distribution test indicated non-normal distribution (p <0.001) of the barrier scores among the study population. out of the 152 participants, 62 participants (40.8%) had a negative perception, whereas 90 participants (59.2%) had a positive perception towards spectacle wear. male students (67.6%), the rural population (65.2%), health science students including nursing and optometry (83.3%) and those who financed their eye health expenditure themselves (81.3%) had a positive perception towards spectacle wear. pearson’s chi-square test observed a significant relationship between the type of perception and the study major of participants (p = 0.012) [table 1]. the mann–whitney u test results showed no statistically significant difference in the perception scores of myopic and hypermetropic groups (u = 881, p = 0.882) barriers and perception towards spectacle wear among a student population of university of buraimi, oman 420 | squ medical journal, august 2021, volume 21, issue 3 discussions this study aimed to identify the barriers and perceptions of the university student population towards spectacle wear. nearly two-third (61.8%) of the total participants had inappropriate spectacle corrections. most of the participants with inappropriate spectacle coverage had not undergone ocular examinations (73.5%) earlier, except for their routine school eye health screening programme. further, 16.5% of these participants were wearing spectacles; however, these were inappropriate given their current refractive status. the other reasons for spectacle non-wear included the following: spectacles ordered (1.8%) or spectacles lost (0.6 %) or broken (1.2%). these findings are similar to the observations of gogate et al., whose study included a school student population in india.11 another study among school children in oman observed an increased prevalence of myopia and astigmatism, which was unnoticed by the parents or school authorities due to its low magnitude.5 the lower uptake of spectacle wear among mild myopic cases could be because of the asymptomatic nature of the condition.5 moreover, megbelayin found that only 9.8% of the studied student population who had refractive error wore spectacles; 18.2% did not wear them because of the cost factor and 56.4 % were ignorant of their refractive status.13 a study conducted among undergraduate students of ghana observed that 66% of the population was not aware of the use of spectacles in relieving the ocular symptoms.1 in addition, appoximately half of the studied population (54.2%) believed that wearing spectacles would create an impression of being visually handicapped.1 in contrast, halim et al. found the refractive error prevalence among the school students as 15.9%; 12.1% were not using any kind of correction.18 this highlights the higher prevalence of uncorrected refractive error within the current study. the lesser spectacle compliance rate observed in this study is a matter of concern, especially given that a prior study among omani school children who had refractive errors observed a higher spectacle compliance rate of more than 60%.5,6 interestingly, no participant of the current study was observed or reported to have undergone any refractive surgery and only 1.8% reported to be wearing contact lenses. moreover, most of the participants (53.5%) had a positive perception towards spectacle wear, and only 36.5% had a negative perception. another study, having a similar refractive error prevalence, but a higher spectacle wear rate (80%) among the undergraduate student population in the middle east, found that 42.2% of the participants believed that spectacle wear might cause further visual impairment or increase spectacle dependency.15 teasing by peers in this regard was one of the common reasons for not wearing spectacles among the population below 30 years of age.6 felix and ebenezer study observed that 53.4% of the studied population believed that spectacle usage may lead to the eyes being pushed in and 66.9% felt that spectacle usage was inconvenient.1 a study within an african student population stated that the misbeliefs of the students or their parents related to spectacle wear were associated with spectacle nonwear among the student population.19 in contrast to the negative perceptions observed in these studies, in a study conducted among the adult african population, 2.8% of the participants with refractive error preferred using spectacles because they caused an impression of intelligence among peers.20 the current fashion trends were also observed to be responsible for spectacle wear.20 in felix and ebenezer’s study, 57.2% of the studied population believed that spectacles made the individual look professional.1 as expected, the student participants in the current study who were majoring in health sciences had a positive perception of spectacle wear (p = 0.012). hence, considering the higher positive perception towards spectacle wear, stressing the importance of spectacle correction and ensuring spectacle compliance would not pose a difficulty as there is already acceptance in the population of such an initiative. the change in the compliance pattern and observed lower positive perception towards spectacle wear among female students in the current study, compared to the younger school-going population in a previous study within oman, reflects a negative shift in the perception towards spectacle wear.6 this study uncovered the gender-wise and age-wise change in the behavioural pattern concerning spectacle wear. interestingly, this study observed that the mother’s literacy level was associated with appropriate spectacle wear. halim et al.’s study found that the level of education positively influenced spectacle wear within the community.18 however, their study was unable to ascertain the parent’s education as a determinant for uncorrected refractive error. moreover, their study also stated that the lower economic status of the parent was associated with a lower uptake of refractive correction among the population, which could be sublimated in the current study due to the higher socioeconomic status of the study population. the findings of this study emphasise the need for robust eye health surveillance focusing on young adults of oman. however, the proportional inclusion of students in future studies from different study gopi s. vankudre and babu noushad clinical and basic research | 421 majors and different universities within the region can support these study findings. other reasons for noncompliance towards the uptake of ophthalmic services among the study participants (73.5%) needs to be explored separately through a qualitative study approach. such studies could also be helpful for the eye healthcare industry involved in refractive modalities such as ophthalmic lenses, refractive surgeries or contact lenses. the parameter of appropriate spectacle wear used in this study could be used as an indicator and is suggested to be applied in monitoring the eye health programme at a regional and national level. in addition, it is important to further explore the underlying barriers of spectacle wear. etim et al. observed that inconvenience towards spectacle wear was one of the factors reducing the quality of life among a population with refractive error compared to other modalities such as contact lenses or refractive surgeries.20 as the eye healthcare system is evolving towards a holistic approach rather than alleviating the patient’s symptoms, a similar approach needs to be implemented while providing a spectacle prescription addressing the patient’s concerns.6,21 in line with the national goal of vision 2050 set by oman, and due to change in the ocular disease scenario from earlier infectious to non-infectious over the last few decades, revisions in the health system are needed.6,10,11,22 moreover, as a member of the who’s global eye health action plan 2014–19, there was a need to generate the evidence for the prevalence and the reasons of visual impairment and apply the costeffective strategies to achieve the goal of reduction in avoidable blindness by 25% by the end of 2019.6,20 as observed in the current study’s results, though a higher percentage of the population was found to have a positive perception towards spectacle wear, there is a scope for exploring and rectifying the factors contributing to having a negative perception. a prior study within oman observed inadequate knowledge about the common ocular condition causing visual impairment among the omani adult population, and a holistic approach is recommended to improve the national eye healthcare system output.6 improving the knowledge level can positively change the perception of the community towards spectacle wear. furthermore, eye health promotion activities focusing on spectacle compliance should also integrate the parent and teacher’s role in increasing spectacle compliance.10,11 based on the findings of this study, it is recommended to extend the current school eyescreening programmes to the university level. conclusion a majority of the participants had inappropriate spectacle corrections and had not undergone any prior ocular examination. very few participants wore spectacles; however, these were inappropriate, given their current refractive status. reasons for not wearing spectacles were that new spectacles had been ordered or spectacles were lost or broken. over half of the participants had a positive perception towards spectacle wear. this was higher among students with health-related majors. the study stresses the need to extend the current school eye health initiative within oman, to the university level. a holistic eye health promotional approach integrating students, teachers and parents can help in improving spectacle wear within this population. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n vgs conceptualised and designed the study. vgs developed the research proposal and performed the statistical analysis. nb verified the proposal and provided timely inputs throughout the research process. both the authors discussed the results and contributed to the drafting of the manuscript. both authors approved the final version of the manuscript. references 1. felix am, ebenezer e. attitudes and beliefs of undergraduate students to spectacle wear. optom 2017; 2:1–4. https://doi. org/10.4172/2476-2075.1000123. 2. khoshhal f, hashemi h, hooshmand e, saatchi m, yekta a, aghamirsalim m, et al. the prevalence of refractive errors in the middle east: a systematic review and meta-analysis. int ophth almol 2020; 40:1571–86. https://doi.org/10.1007/s10792-020-01316-5. 3. al–rashidi sh, albahouth aa, althwini wa, alsohibani aa, alnughaymishi aa, alsaeed aa, et al. prevalence refractive errors among medical students of qassim university, saudi arabia: cross-sectional descriptive study. open access maced j med sci 2018; 6:940–3. https://doi.org/10.3889/oamjms.2018.197. 4. johnson gj, minassian dc, weale ra, west sk, gower ew, kuper h, et al. the epidemiology of eye disease, 3rd ed. london; imperial college press, 2012. 5. al harby s, al-asbali t, khandekar r. visual acuity and refractive status of omani students with refractive error in grades 1, 4 and 7: a retrospective cohort study. oman j ophthalmol 2016; 9:27–31. https://doi.org/10.4103/0974-620x.176097. 6. khandekar r, mohammed aj, al raisi a. compliance of spectacle wear and its determinants among schoolchildren of dhakhiliya region of oman: a descriptive study. j sci res med sci 2002; 4:39–43. https://doi.org/10.4172/2476-2075.1000123 https://doi.org/10.4172/2476-2075.1000123 https://doi.org/10.1007/s10792-020-01316-5 https://doi.org/10.3889/oamjms.2018.197 https://doi.org/10.4103/0974-620x.176097 barriers and perception towards spectacle wear among a student population of university of buraimi, oman 422 | squ medical journal, august 2021, volume 21, issue 3 7. khandekar rb, gogri up, al harby s. the impact of spectacle wear compliance on the visual function related quality of life of omani students: a historical cohort study. oman j ophthalmol 2013; 6:199–202. https://doi.org/10.4103/0974-620x.122278. 8. kobia-acquah e, essien e, ablordeppey r, donkor r, ankamah lomotey s, nartey a. attitudes and beliefs of undergraduate students to spectacle wear in ghana. aovs 2018; 8: 00264. https://doi.org/10.15406/aovs.2018.08.00264. 9. marmamula s, narsaiah s, shekhar k, khanna rc. presbyopia, spectacles use and spectacle correction coverage for near vision among cloth weaving communities in prakasam district in south india. ophthalmic physiol opt 2013; 33:597–603. https://doi.org/10.1111/opo.12079. 10. al–rashidi sh, albahouth aa, althwini wa, alsohibani aa, alnughaymishi aa, alsaeed aa, et al. prevalence refractive errors among medical students of qassim university, saudi arabia: cross-sectional descriptive study. open access maced j med sci 2018; 6:940–3. https://doi.org/10.3889/oamjms.2018.197. 11. gogate p, mukhopadhyaya d, mahadik a, naduvilath tj, sane s, shinde a, et al. spectacle compliance amongst rural secondary school children in pune district, india. indian j ophthalmol 2013; 61:8–12. https://doi.org/10.4103/0301-4738.99996. 12. sankaridurg p, tahhan n, kandel h, naduvilath t, zou h, frick kd, et al. imi impact of myopia. invest ophthalmol vis sci 2021; 62:2. https://doi.org/10.1167/iovs.62.5.2. 13. megbelayin eo. barriers to uptake of prescribed refractive spectacles amongst nigerian students. int res j basic clin stud 2013; 1:71–7. 14. world health organization. universal eye health: a global action plan 2014–2019. from: www.who.int/blindness/ap2014 _19_english.pdf?ua=1 accessed: aug 2020. 15. fk a, ag m, sm g, h k, hha m, mr p. attitude of female undergraduates towards spectacle correction of refractive errors. coj nurs healthcare 2018; 4:422–6. https://doi.org/10.31031/ cojnh.2018.04.000588. 16. jacobsen k. introduction to health research methods: a practical guide, 1st ed. burlington, massachusetts; jones & bartlett learning, 2014. 17. bolarinwa oa. principles and methods of validity and reliability testing of questionnaires used in social and health science researches. niger postgrad med j 2015; 22:195–201. https:// doi.org/10.4103/1117-1936.173959. 18. halim a, suganda r, sirait sn, memed fk, syumarti, rini m, et al. prevalence and associated factors of uncorrected refractive errors among school children in suburban areas in bandung, indonesia. cogent med 2020; 7:1737354. https://doi.org/10.108 0/2331205x.2020.1737354. 19. alrasheed sh, naidoo ks, clarke-farr pc. attitudes and perceptions of sudanese high-school students and their parents towards spectacle wear. afr vis eye health 2018; 77. https://doi. org/10.4102/aveh.v77i1.392. 20. etim ba, oraegbunam nh, ibanga aa, okonkwo sn. perception of refractive errors and impact of corrective treatments on adult patients seen at a tertiary health institution in south-south nigeria. j adv med medical res 2018; 27:1–11. https://doi.org/10.9734/jammr/2018/45194. 21. al-mujaini as. knowledge, attitudes, and practices related to common eye diseases among the omani population: how far have we come? oman med j 2020; 35:e96. https://doi. org/10.5001/omj.2020.14. 22. sultanate of oman, ministry of health. health vision 2050. from: www.moh.gov.om/documents/16506/119833/health+vi sion+2050/7b6f40f3-8f93-4397-9fde-34e04026b829 accessed: apr 2020. https://doi.org/10.4103/0974-620x.122278 https://doi.org/10.15406/aovs.2018.08.00264 https://doi.org/10.1111/opo.12079 https://doi.org/10.3889/oamjms.2018.197 https://doi.org/10.4103/0301-4738.99996 https://doi.org/10.1167/iovs.62.5.2 https://doi.org/10.31031/cojnh.2018.04.000588 https://doi.org/10.31031/cojnh.2018.04.000588 https://doi.org/10.4103/1117-1936.173959 https://doi.org/10.4103/1117-1936.173959 https://doi.org/10.1080/2331205x.2020.1737354 https://doi.org/10.1080/2331205x.2020.1737354 https://doi.org/10.4102/aveh.v77i1.392 https://doi.org/10.4102/aveh.v77i1.392 https://doi.org/10.9734/jammr/2018/45194 https://doi.org/10.5001/omj.2020.14 https://doi.org/10.5001/omj.2020.14 1department of medicine, sultan qaboos university hospital, muscat, oman; departments of 2child health, 3physiology and 4biochemistry, sultan qaboos university, muscat, oman corresponding author’s e-mail: ikramburney@hotmail.com abstract: covid-19 has gripped the world with lightning speed. since the onset of the pandemic, activity throughout the world came to a grinding halt. however, business had to continue and people have to learn to live with the virus while the pandemic continues to rage. medical education is no exception and may even deserve special mention, as it prepares frontline workers against the endemics of tomorrow. we discuss here the journey of medical education at the college of medicine and health sciences at sultan qaboos university, muscat, oman, as the pandemic struck the world and oman. this work suggests a roadmap for changes, discusses challenges and proposes measures to mitigate the effects of covid-19 on medical schools. keywords: covid-19; medical education; curriculum; computer simulation; artificial intelligence; oman. covid-19 and the clinical phase of the medical doctorate curriculum in oman challenges and the way forward *ikram a. burney,1 reem abdwani,2 khamis al-hashmi,3 nadia al-wardy,4 muna al-saadoon2 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e191–194, epub. 21 jun 21 submitted 6 jul 20 revision req. 16 sep 20; revision recd. 7 oct 20 accepted 27 oct 20 https://doi.org/10.18295/squmj.2021.21.02.006 sounding board this work is licensed under a creative commons attribution-noderivatives 4.0 international license. the quote above conveys the swiftness with which covid-19 gripped the world starting in early 2020. from the east of china to the west of canada and every country in between, the covid-19 wave has been relentless, the speed of spread has been spectacular and the devastation has been unparalleled in modern human history. the pandemic perils have been unprecedented and the cost has been paid in terms of human life, unemployment, social deprivation, losses in small and large businesses and a slump in world economies. at one point in the pandemic’s progression, every activity seemed to grind to a halt. however, economic and political pressures have forced businesses to return to normal.1 people are learning to live with the virus while the pandemic continues to rage. like other daily activities, the all-important activity of education, undergraduate and postgraduate alike, was suspended due to the pandemic. however, adversity is known to bring opportunity, and many schools, colleges and universities worldwide have undertaken online teaching and learning. the pandemic introduced many new words and phrases to language, such as ‘social distancing’ and ‘smart lockdown’ and one phrase, ‘emergency remote teaching’ (ert), has become part of the teaching vernacular. to continue instruction during the pandemic, sultan qaboos university (squ) introduced ert to differentiate between online and remote teaching.2 online courses and programmes require multiple stages of preparation and extensive measures to ensure effective implementation. however, ert, as the name implies, is teaching remotely under emergency conditions, and those remote conditions could be online or via another mode. the medical doctorate (md) curriculum at the college of medicine and health sciences (comhs) at squ is outcomeand system-based and is integrated vertically and horizontally.3 it is based on clinical presentations rather than on academic disciplines and consists of three phases. students are exposed to clinical medicine early in phases i and ii, while the hospital-based clinical phase (phase iii) consists of clerkships and spans three years. there are four clerkship stages: a 10-week pre-clerkship period, a one calendar-year junior clerkship, a one calendaryear senior clerkship and a 12-week pre-internship. when studies were suspended in march 2020 due to the pandemic, almost 350 students were in clinical rotations in the junior and senior clerkships and preinternships. the squ comhs clinical faculty consists of approximately 500 senior doctors, both at university and affiliated hospitals. when studies resumed, ert was quickly implemented after discussions with stakeholders including students, faculty and administration. students in clinical rotations were engaged through the moodle learning management system and the zoom communication platform. the departments of medical education and informatics played a pivotal role in establishing channels and training the faculty on using moodle and zoom. below are salient features of the ert experience. “it came, it saw, it swept the world!” https://creativecommons.org/licenses/by-nd/4.0/ delivery of clinical phase of the c u r r i c u l u m t h r o u g h e r t several challenges arose in delivering the clinical phase through ert including quickly reviewing the curriculum to see what could be taught online and how converting student-led seminars to faculty-led tutoring sessions, equipping faculty to effectively use learning and communication platforms, deploying in-rotation assessments and dealing with uncertainty. initially, it was not clear how long ert or online mode of teaching would need to continue. in the absence of the opportunity to provide clinical skills teaching, the emphasis of ert was to help students develop clinical reasoning and the ability to apply management skills. the teaching material was specifically designed and prepared to provide students with opportunities to enhance proficiency in pathophysiology, approach presenting and constructing differential diagnoses based on available information, prioritise investigations and formulate a management plan. teaching materials specifically created for students in the clinical phase were provided through moodle. pre-planned sessions were conducted using zoom or bigbluebutton to facilitate interaction on the day of virtual contact with students. before the online sessions, mini-workshops were organised to prepare faculty to use online teaching and learning tools. technical help was available during teaching sessions from the departments of medical education and informatics. clinical rotations in phase iii of the md curriculum are divided into three broad categories, depending on the nature of teaching and learning and the type of patient contact medicine: (1) surgery, child health, obstetrics and gynaecology and family medicine rotations require direct contact with patients; (2) rotations including radiology, molecular imaging and laboratory medicine require on-site as well as seminar-room/side-room learning; and (3) the so-called supportive learning topic rotations (e.g. evidence-based and forensic medicine) require predominantly teaching small groups in seminar rooms. during pandemic restrictions, ert was designed to provide the seminar-room content and discussions in the first two categories of rotations and the entire learning opportunity in the third category. as a result of this exercise, it was possible to reduce the length of rotations so that when the students returned to face-to-face instruction, they would be able to complete the remaining rotations without compromising clinical exposure or delaying academic progression from the junior-to-senior clerkship or the senior clerkship to the pre-internship. the clinical rotation in radiology and molecular imaging illustrates this approach. in this rotation, a group of 20 senior clerkship students rotate for two weeks every six weeks and, given the constraints of space, are divided into smaller groups to be exposed to learning opportunities in three hospitals. in reaction to covid-19, the rotation coordinator provided students e-access to review scans and support online learning. as a result of stakeholder feedback and the ability to engage and interact with several students simultaneously, most of the rotation has now been converted to an online format. the in-rotation assessment is mainly workplace-based and will be done when the students return. the vast majority of in-rotation assessments provide immediate, on-site feedback. providing such specific, descriptive feedback has been shown to have an effect size that matches the usual classroom teaching; therefore, it would be necessary for students not to miss this opportunity to enhance their learning face-to-face.4 the adversity introduced by covid-19 also provided opportunities for curriculum managers to rethink and redesign learning opportunities to accommodate the demands of the pandemic and reshape future education. the faculty’s hidden potential to adapt to rapidly changing circumstances was unearthed, as was the massive potential of using online technologies during the clinical phase of the curriculum. faculty who had long considered making pedagogical changes in their teaching found themselves forced to make those changes in days or weeks and, with a sense of pleasure, found achievement within those changes. the ert helped extend learning opportunities beyond the university’s walls while maintaining the important boundaries of the undergraduate learning experience, including attendance, punctuality and self-directed learning. it is anticipated that after the covid-19 pandemic is controlled, online teaching and learning will remain. most faculty members believe that it should not cease, even when covid-19 restrictions are lifted. w h e r e d o w e g o f r o m h e r e? the current pandemic has provided opportunities to adopt new methods of teaching and learning in medicine. despite integrating e-work practices in other disciplines, academic medicine is only just beginning to utilise advancements in information and educational technologies.5 it seems that conventional lectures will not be as pervasive after the pandemic is over, and methods of information delivery, including remote teaching, may need further enhancement. as for teaching kinesthetic skills, several methods are in use or have been proposed.6 for example, telemedicine could be employed to demonstrate communication and counselling skills, physical covid-19 and the clinical phase of the medical doctorate curriculum in oman challenges and the way forward e192 | squ medical journal, may 2021, volume 21, issue 2 sounding board | e193 examination methods and bedside and surgical procedures; in these situations, students are expected to learn through osmosis and imbibition.7 for the ‘touch and feel skills’, students can review videotapes of practitioners obtaining patient histories and carrying out physical examinations and then demonstrate the skills with a family member, friend or colleague who could be provided with a checklist to guide the student. training through simulations and virtual wards have been proposed for defined learning objectives.8 although using ert to develop medical knowledge, comprehension and clinical reasoning skills is comp arable to traditional forms of learning, outcomes related to behaviour, such as empathy, are less than optimal.9 without financial resources, technological support, standardisation of delivery, and training programmes, professional behaviours cannot be developed. technology-supported approaches cannot replace all aspects of experiential learning or stimulate the satisfaction students get when working on-site in teams, communicating with patients and caregivers and observing and following role models. students can look and listen, but the feel of a medical environment is essential. the students in the clinical phase of clerkship must meet patients and interact with clinical teams face-to-face. furthermore, to prevent significant delays in the academic calendar, it is paramount that clerkship students return to face-to-face medical settings where they will ultimately be required to work to provide human touch and a healing hand. challenges due to students’ return to the workplace students’ return to the workplace is not without significant challenges. the first and foremost issue will be the safety of students, patients and healthcare workers. this concern is due to the added risk that students can pose by increasing the number of individuals working in a clinical care team. students could acquire infections during clinical rotations or import infections from the community, jeopardising staff and inpatients’ safety. second, students are experiencing only limited clinical exposure due to the pandemic. elective surgical procedures and routine care typically provided by major teaching hospitals have been postponed to accommodate patients with covid-19 who require urgent medical attention. patients may be reluctant to come to hospitals or be examined by medical students. furthermore, the physical space in hospitals and health centres may be limited as some space is reserved for treating patients with covid-19. also limited is the number of teaching faculty, as some clinicians are busy caring for patients with covid-19 and others may be asked to stay home after exposure. finally, fear of the unknown, the state of uncertainty and the stigma of being educated within an environment saturated with new “do’s and don’ts” will likely continue to hound students throughout their educations. t h e way f o r wa r d: t h e l i k e ly n e w n o r m a l some of these challenges can be addressed by improving communication, raising awareness, establishing standard operating procedures, implementing safety policies, monitoring incidents and auditing procedures.10,11 these changes aim to effectively manage the safe return of medical and laboratory students as covid-19 continues.12 in the longer run, a transition from ert to well-planned online learning management will be needed. restructuring the three categories of rotations in phase iii may help identify competencies to be achieved through students’ on-site physical presence. other competencies may be achieved through online teaching and learning. this transition will require faculty development, redesigning the curriculum, restructuring and enhancing technical capabilities, introducing new learning material pertinent to the evolving pandemic and redesigning in-rotation assessments. regulatory approval from the accrediting bodies may be required to support changes in teaching and assessment. furthermore, there will be a need to enhance medical students and teachers’ skills to utilise information communication technology (ict) facilities. training students on the use of telemedicine and artificial intelligence for patient care may need to be explored further.13 evidence-based policies for reducing transmission risk have recently been suggested for people who return to work during the ongoing pandemic.1 these measures can be observed at individual, programme and university levels. at an individual level, raising awareness about common symptoms, self-diagnosis, not working if symptomatic, observing personal hygiene, maintaining physical distance from others, practicing good respiratory etiquette and using masks and personal protective equipment have been suggested. at the programme level, teaching will need to be restructured to ensure only a few students are attached to a clinical teaching unit and are staggered through shifts. hybrid teaching would need to be used to limit the presence of students in clinical areas. at the institutional level, workplace cleaning, symptoms monitoring, travel limitations and contact tracing and testing are suggested measures. the rapidly expanding evidence-based literature can be used to better understand ways to curb the speed of the pandemic’s spread.10,12 ikram a. burney, reem abdwani, khamis al-hashmi, nadia al-wardy and muna al-saadoon the will and desire to train and equip the doctors of tomorrow while the pandemic rages today provides an unprecedented opportunity for medical education innovations. it is time that medical schools and curriculum designers move away from informationgiving through ert to providing blended, contemp orary, effective, evidence-based medical education. conclusions herein a medical education journey through the covid-19 lockdown was described. the experience suggests that medical education could be delivered more effectively using online learning platforms and incorporating modern ict. covid-19 catalysed changes in the delivery of medical curricula worldwide. medical education has learnt rapidly from other disciplines using e-work and e-learning before the pandemic started. however, there are opportunities for further innovation by advancing and fine-tuning online learning. as schools transition from traditional teaching and sustain challenges, blended teaching may become the new norm after the pandemic. references 1. barnes m, sax pe. challenges of “return to work” in an ongoing pandemic. n eng j med 2020; 383:779–86. https://doi.org/10.10 56/nejmsr2019953. 2. hodges c, moore s, lockee b, trust t, bond m. the difference between emergency remote teaching and online learning. from: er.educause.edu/articles/2020/3/the-difference-between-emergencyremote-teaching-and-online-learning accessed: oct 2020. 3. sultan qaboos university college of medicine. dean’s message. from: www.squ.edu.om/medicine/about-college/units-secti ons/curriculum-office accessed: oct 2020. 4. hattie j. influences on student learning. from: www.research gate.net/publication/237248564_influences_on_student_ learning accessed: oct 2020. 5. he s, lai d, mott s, little a, grock a, haas mrc, et al. remote e-work and distance learning for academic medicine: best practices and opportunities for future. j grad med edu 2020; 12:256–62. https://doi.org/10.4300/jgme-d-20-00242.1. 6. kee a, archuleta s, dan yy. internal medicine residency training in the covid-19 era—reflections from singapore. j grad med edu 2020; 12:406–8. https://doi.org/10.4300/jg me-d-20-00315.1. 7. prober cg, khan s. medical education reimagined: a call to action. acad med 2013; 88:1407–10. https://doi.org/10.1097/ acm.0b013e3182a368bd. 8. pottle j. virtual reality and the transformation of medical education. fut healthcare j 2019; 6:181–5. https://doi.org/10.7 861/fhj.2019-0036. 9. kononowicz aa, woodham la, edelbring s, stathakarou n, davies d, saxena n, et al. virtual patient simulations in health professions education: systematic review and meta-analysis by the digital health education collaboration. j med internet res 2019; 21:e14676. https://doi.org/10.2196/14676. 10. haushofer j, metcalf cje. which intervention work best in a pandemic. science 2020; 368:1063–5. https://doi.org/10.1126/ science.abb6144. 11. world health organization. coronavirus disease (covid-19) training: online training. from: www.who.int/emergencies/ diseases/novel-coronavirus-2019/training/online-training accessed: oct 2020. 12. habersaat kb, betsch c, danchin m, sunstein cr, böhm r, falk a, et al. ten considerations for effectively managing the covid-19 transition. nat hum behav 2020; 4:677–87. https://doi.org/10.1038/s41562-020-0906-x. 13. hall ak, nousiainen mt, campisi p, damon dagnone j, frank jr, kroeker ki, et al. training disrupted: practical tips for supporting competency-based medical education during the covid-19 pandemic. medical teacher 2020; 42:756–61. https://doi.org/10.1080/0142159x.2020.1766669. covid-19 and the clinical phase of the medical doctorate curriculum in oman challenges and the way forward e194 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1056/nejmsr2019953 https://doi.org/10.1056/nejmsr2019953 https://doi.org/10.4300/jgme-d-20-00242.1 https://doi.org/10.4300/jgme-d-20-00315.1 https://doi.org/10.4300/jgme-d-20-00315.1 https://doi.org/10.1097/acm.0b013e3182a368bd https://doi.org/10.1097/acm.0b013e3182a368bd https://doi.org/10.7861/fhj.2019-0036 https://doi.org/10.7861/fhj.2019-0036 https://doi.org/10.2196/14676 https://doi.org/10.1126/science.abb6144 https://doi.org/10.1126/science.abb6144 https://doi.org/10.1038/s41562-020-0906-x https://doi.org/10.1080/0142159x.2020.1766669 1department of optometry, college of applied medical sciences, qassim university, saudi arabia; 2faculty of optometry and visual sciences, department of binocular vision, al-neelain university, khartoum, sudan *corresponding author’s e-mail: s.rasheed@qu.edu.sa parents’ awareness of and perspectives on childhood refractive error and spectacle wear in saudi arabia *saif h. alrasheed1,2 and waleed m. alghamdi1 clinical & basic research sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 532–538, epub. 7 nov 22 submitted 24 may 21 revision req. 9 aug 21; revision recd. 2 sep 21 accepted 22 sep 21 https://doi.org/10.18295/squmj.10.2021.141 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to assess parents’ awareness of and perspectives on childhood refractive errors in saudi arabia. methods: this cross-sectional study was conducted between october and november 2020 in public schools across different regions of saudi arabia. data were collected using an online questionnaire that assessed parents’ knowledge and perceptions of childhood refractive errors and spectacle wear. results: a total of 358 parents from different regions of saudi arabia completed the questionnaire and were obtained in this study (response rate: 85%). approximately one third (38.3%) of the parents reported that they had never heard of refractive errors and onethird (33.8%) mentioned that uncorrected refractive errors did not lead to visual impairment. the majority (74.0%) cited using eyeglasses as an effective way to manage childhood refractive errors. two-thirds (63.7%) stated that they did not receive any information about paediatric eye care. better knowledge was associated with a higher educational level, female gender and older age (p <0.001, p = 0.008 and p = 0.024, respectively). regarding parents’ perspective on spectacle wear, 13.7% felt that using eyeglasses affected their children’s chances of learning. however, 82.7% supposed that eyeglasses did not affect their children’s employment opportunities. almost a quarter of the sample (22.1%) thought that using eyeglasses would decrease the eye’s power, resulting in childhood visual impairment. conclusion: the level of awareness and perceptions regarding childhood refractive errors and spectacle wear was low among parents. therefore, a policy is needed to improve the awareness and perception of the key stakeholders in this issue, including parents and teachers. keywords: visual impairment; spectacles; parents; attitudes; refractive error; myopia; psychological effect; vision care; eyeglasses. advances in knowledge the level of awareness and perceptions regarding childhood refractive errors and spectacle wear was low among parents. application to patient care a policy is needed to improve the community’s knowledge of childhood eye care, including the importance of early diagnosis and treatment of childhood eye disorders and relevant information should be delivered through public media, radio, television, social media and newspapers. parents’ awareness of childhood refractive errors and related complaints may lead them to pursue early eye care for their children, which could result in prompt diagnosis and treatment of eye disorders and help decrease the causes of avoidable childhood blindness. eye care professionals should help advance parental knowledge of childhood eye care. global estimates indicate that there are approximately 19 million visually impaired children worldwide. of these children, 1.4 million are blind and 17.5 million have reduced vision; most of these cases are found in poor countries.1–3 visual disability due to uncorrected refractive errors (res) affects nearly 250 million individuals globally and studies have revealed that uncorrected res are the leading cause of visual impairment.4–7 the world health organization (who) has also reported that uncorrected res are the leading cause of childhood visual impairment worldwide and it estimated that approximately 80% of reduced vision could be prevented by early diagnosis and management.1,5,8 there are several types of res (ametropia), the most common being hyperopia, myopia and astigmatism. ametropia is more prevalent among asians and europeans and less common among african children.3–7 studies have shown that res, particularly myopia, affect more than one-third of the population globally.4,9,10 while the exact cause of res is still unknown, the common risk factors include inheritance, nutrition, indoor activities, near-vision tasks and the environment. uncorrected res have a significant effect on children and could limit their chances in relation to education, quality of life and efficiency.3,11 earlier studies have reported that visual impairment is low in childhood compared to adulthood and it has a significant negative impact on the lifespan of children, https://creativecommons.org/licenses/by-nd/4.0/ saif h. alrasheed and waleed m. alghamdi clinical and basic research | 533 with an estimated 60% of children dying within one year of becoming blind.11,12 al wadaani et al. reported that the prevalence of childhood res in al hassa, saudi arabia was 13.7%.13 however, another study by aldebasi in the qassim region of saudi arabia revealed the prevalence of childhood res to be 16.3%.14 therefore, increased parental awareness regarding the effect of paediatric uncorrected res is particularly important and could help in prompt diagnosis and management of childhood eye conditions, contributing to a decrease in childhood visual impairment.15 no studies have been conducted to date to assess parents’ awareness of and perspectives on childhood res and spectacle wear in saudi arabia. thus, the current study focused specifically on the knowledge and feelings of parents towards childhood re and spectacle wear because their awareness and beliefs are critical for the success of interventions aimed at reducing childhood visual impairment resulting from uncorrected res. methods this was a cross-sectional study and included randomly selected parents aged between 21 and 55 years who had children enrolled in public schools in different regions of saudi arabia (central, western, eastern, northern and southern regions). the study was conducted between october and november 2020 and included two schools from each region—one for boys and the other for girls. data were collected through an online self-administered questionnaire based on a validated questionnaire by alrasheed et al. and included questions to assess parents’ knowledge and perceptions regarding childhood re and spectacle wear.7,8 the questionnaire was distributed by the selected schools through the parents’ social media groups and was administered in arabic. the inclusion criteria for the study were parents who had children and agreed to participate in the study by signing the consent form. the study sample was calculated using the following formula: where z = 1.96 at a confidence level of 95%, p = outcome of the response, assumed to be 50% for the parents’ awareness of and perspectives on childhood re and spectacle wear for the maximum sample size and e = maximum acceptable sampling error = 5% or 0.05, in decimal notation. accordingly, the resulting value was 384. considering a 10% non-participation rate for the calculated sample size, the final sample size for this study was estimated as 422 parents. data were collected using a validated questionnaire in arabic, which was modified based on the literature review and previously published studies.7,8 the quest ionnaire was checked and evaluated by eye care profess ionals (optometrists and ophthalmologists) and tested with a pilot study of 40 parents. the questionnaire was structured as follows: the first section included the socio-demographic characteristics of the participants. the second section contained questions to assess parents’ awareness of childhood re. the third section covered parents’ beliefs regarding re and spectacle wear. this section included nine positive and negative statements to assess parents’ attitudes and perceptions towards childhood re and spectacle wear. the fourth section included questions related to the prevention and management of childhood visual impairment due to uncorrected re. finally, data were entered into a microsoft excel 2016 spreadsheet, following which statistical analysis was performed by using the statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa). before conducting the analysis, the data were tested for entry mistakes and any lost values. descriptive analyses were used, including the frequencies, proportions, means and standard deviations of the data and p values of <0.05 were considered statistically significant. ethical approval for the study was obtained from the biomedical ethics committee at qassim university (#20-7-03). the study was conducted based on the guidelines of the declaration of helsinki. participation was voluntary and the participants were free to withdraw from the study at any time without citing any reason. results a total of 422 parents from five different regions of saudi arabia were invited to participate in the study. of the 365 questionnaires that were returned, seven incomplete questionnaires were excluded; thus, 358 completed questionnaires were included in this study (response rate: 85%). the study comprised 200 (55.9%) females and 158 (44.1%) males and the mean age of the respondents was 36.9 ± 11.9 years. a total of 32.7% of parents fell within the 21–30 age group and 31.6% within the 31–40 age group, while only 13.9% of participants were more than 50 years of age. regarding the educational levels of the parents, 70.4% had a university degree or higher, 22.1% had secondary certification and only 7.5% had primary education as their highest qualification [table 1]. n = [equation 1] (z^2 × (p) × (1-p)) e^2 parents’ awareness of and perspectives on childhood refractive error and spectacle wear in saudi arabia 534 | squ medical journal, november 2022, volume 22, issue 4 a section of the questionnaire addressed parents’ awareness of childhood res. approximately half (49.2%) the parents said that they knew about res, while 38.3% reported that they had never heard of res. the parents were asked whether they thought that res caused vision loss in children if left untreated. among the respondents, 55.6% mentioned that uncorrected res led to visual impairment, while 33.8% of parents responded in the negative. concerning the effectiveness of using spectacles in the management of res, the vast majority of the parents (74.0%) cited using eyeglasses as a good way to manage childhood res, while 21% of the respondents reported that wearing spectacles was not good for managing childhood res. concerning information related to childhood eye care, 63.7% of the parents stated that they did not receive any information, while 33.2% of parents reported having received some information about childhood eye care. the participants were asked whether they had taken their children for an eye examination. approximately 54.2% of respondents cited that they had taken their children for an eye examination, while 41.6% reported in the negative. regarding whether their children were using any method of correcting res, the majority (70.9%) of parents stated that their children did not use any type of correction, while 27.9% mentioned that their children used glasses and only 1.1% reported that their children used contact lenses [table 2]. finally, a score was calculated for all the questions assessing the level of parental awareness towards childhood res. the minimum score was set as 1 for the ‘no’ response, 2 for ‘i do not know the response’ and 3 for the ‘yes’ response. the average total score was then compared in terms of different demographic variables (gender, age and educational level) using one-way table 1: demographic characteristics of the parents who participated in this study (n = 358) characteristics n (%) gender male 158 (44.1) female 200 (55.9) age in years mean 36.9 ± 11.9 21–30 117 (32.7) 31–40 113 (31.6) 41–50 78 (21.8) >50 50 (13.9) education level primary school 27 (7.5) secondary school 79 (22.1) university degree or higher 252 (70.4) table 2: parents’ knowledge of refractive errors (n = 358) question response n (%) have you ever heard of refractive errors? no 137 (38.3) i do not know 45 (12.6) yes 176 (49.2) do you think that refractive errors cause vision loss for children if they are untreated? no 121 (33.8) i do not know 38 (10.6) yes 199 (55.6) do you think that wearing spectacles is effective in the treatment of refractive errors in children? no 75 (21.0) i do not know 18 (5.0) yes 265 (74.0) have you obtained any information related to child eye health? no 228 (63.7) i do not know 11 (3.1) yes 119 (33.2) have you ever taken your child for an eye examination? no 149 (41.6) i do not know 15 (4.2) yes 194 (54.2) what does your child use for the treatment of refractive errors? glasses 100 (27.9) contact lens 4 (1.1) none 254 (70.9) table 3: comparison of the mean knowledge score of the parents in terms of their age and education level using one-way analysis of variance characteristics mean ± sd p value gender male 2.0886 ± 0.49119 0.008 female 2.2240 ± 0.45834 age <20 2.2833 ± 0.51493 0.024 21–30 2.0850 ± 0.51948 31–40 2.1709 ± 0.49425 41–50 2.3000 ± 0.43019 >50 2.0894 ± 0.33312 education level primary school 1.8545 ± 0.55062 <0.001 secondary school 2.1846 ± 0.45672 university degree or higher 2.1992 ± 0.45994 sd = standard deviation. saif h. alrasheed and waleed m. alghamdi clinical and basic research | 535 analysis of variance. the results revealed that female parents had a higher mean score (2.22 ± 0.46), which was statistically significant (p = 0.008). the 41–50 age group had a higher mean score for knowledge (2.30 ± 0.43), which was statistically significant (p = 0.024). parents with high educational levels had a higher score for awareness (2.1 ± 0.45; p <0.0001) [table 3]. the parents gave a mix of positive and negative answers to the questions concerning their perspectives on childhood res and the use of eyeglasses. to aid in the assessment of parental attitudes and perceptions, a three-point likert scale was used in this section, with choices ranging from ‘disagree’ to ‘agree’ [table 4]. most parents (79.3%) felt that using eyeglasses did not affect their children’s chances of learning, while 13.7% of parents felt that using eyeglasses could affect their children’s chances of learning. however, the difference in the attitudes of the parents was not statistically significant (p = 0.539). the vast majority (82.7%) of parents thought that wearing spectacles did not reduce their children’s employment opportunities, while 14.7% of participants thought that using eyeglasses could decrease their children’s opportunities to find work. the difference in the attitudes of the parents was statistically significant (p = 0.048) in this case. most parents (86.6%) supposed that using eyeglasses would not affect their children’s marriage prospects in the future. interestingly, only 11.5% of parents believed that using eyeglasses could reduce their children’s marriage prospects in the future. in response to the question regarding the use of eyeglasses for the management of re, 22.1% of parents noted that wearing eyeglasses would reduce their children’s vision. nevertheless, 70.1% of parents believed that wearing eyeglasses would not deteriorate their children’s vision, which showed statistical significance (p = 0.005). regarding the question on the psychological effect of wearing spectacles, 45.0% of parents thought that wearing eyeglasses had a psychological effect on their children, while 49.7% responded in the negative. the difference in the perceptions of the parents was not statistically significant (p = 0.224). over one third (39.7%) of the parents believed that wearing eyeglasses could decrease their children’s participation in activities such as sports, while half of the parents thought that wearing eyeglasses did not affect their children’s participation in activities. over half (65.6%) the parents agreed that wearing eyeglasses prevented their children from developing visual impairment; in contrast, 24.0% disagreed with this statement. when asked about the effect of wearing glasses for a long time, 65.9% of participants stated that wearing eyeglasses for a long time did not harm their children’s vision, while 24.3% of parents remarked that using spectacles for a long time would harm their child’s table 4: parents’ attitudes and perceptions towards refractive error and spectacle wear (n = 358) statement total male female p value disagree in % agree in % disagree in % agree in % disagree in % agree in % i think wearing spectacles affects my child’s opportunities for learning. 79.3 13.7 32.7 6.2 46.6 7.5 0.539 i think wearing spectacles could affect my child’s chances of employment. 82.7 14.8 34.4 7.8 48.3 7 0.048 i think using spectacles may affect my child’s future marriage prospects. 86.6 11.5 36.6 5.6 50 5.9 0.229 i believe spectacles could reduce my child’s vision. 70.1 22.1 26 11.7 44.3 10.4 0.005 i believe using spectacles has a psychological effect on children. 49.7 45.0 20.4 20.7 29.3 24.3 0.224 in my opinion, using spectacles could reduce children’s participation in activities such as sports. 52.8 39.7 21.2 19.3 31.6 20.4 0.061 i think the best way to prevent vision loss in my children is having them wear spectacles. 24.0 65.6 12.8 25.4 11.2 42.2 0.058 in my opinion, wearing spectacles for a long time will harm the eyes and may result in early blindness. 65.9 24.3 28.2 12.3 37.7 12.1 0.008 in my opinion, spectacles may be used to relieve distress such as frontal headache, photophobia and tearing. 59.5 27.9 25.4 12.6 34.1 15.4 0.563 parents’ awareness of and perspectives on childhood refractive error and spectacle wear in saudi arabia 536 | squ medical journal, november 2022, volume 22, issue 4 eyes and result in early childhood blindness. the difference in the parents’ perceptions was statistically significant (p = 0.008) in this case. most parents (59.5%) disagreed with the statement that wearing eyeglasses could relieve distress experienced by their children, including frontal headache, while 27.9% of respondents agreed that wearing eyeglasses would reduce eye discomfort. the parents were asked about whom they would approach to seek treatment for their children if they complained of symptoms of decreasing vision. a total of 48.3% of parents stated eye doctors (ophthalmologists) in a public hospital, 21.5% stated ophthalmologists in a private clinic, 21.2% stated optometrists in a public hospital and 8.9% stated optometrists in a private clinic [figure 1]. the parents were asked about when their children’s vision was last examined. almost half (40%) the respondents reported that they had not had their children’s vision tested before and 35.8% stated that their children’s vision was examined one year prior. the parents were asked to give reasons for not taking their children to eye care professionals in the past 12 months. half (52.5%) the parents reported that their child had vision difficulties, 21.1% reported that the vision examination was too expensive and 14% reported that hospitals for the vision examination were located far away [figure 2]. discussion childhood visual impairment due to uncorrected res can be avoided through preventive methods and with periodic vision examinations and preliminary treatment. in developed countries, teenagers are required to undergo an eye test at birth, followed by another at six months.16,17 after six months of age, an average child has reached numerous developmental milestones in their visual functions and can therefore undergo full vision function examinations. a complete eye examination, including visual functions and binocular vision, is essential at preschool age and frequently during school age.16 parents’ awareness of childhood re and related complaints may encourage them to pursue vision care for their children in a timely manner, which could lead to prompt diagnosis and treatment of eye disorders and help reduce the causes of avoidable childhood blindness. therefore, the current study aimed to assess parents’ awareness of and perspectives on childhood re and the use of eyeglasses in saudi arabia. in the current study, 38.3% of parents stated that they did not know the term ‘childhood re.’ this figure is lower compared to the findings of sukati et al., who stated that 53.1% of parents did not know the term ‘childhood re’.18 eye health education programmes are needed to increase parents’ awareness and to figure 1: treatment options sought by parents if their child exhibited symptoms of refractive error (n = 358). figure 2: reasons why parents did not visit an eye care professional for their children (n = 358). saif h. alrasheed and waleed m. alghamdi clinical and basic research | 537 correct their misunderstandings regarding childhood res. furthermore, 33.8% of parents thought that uncorrected res could not cause childhood visual impairment. this result is similar to the findings of a study in india, where 66.7% of respondents accepted the use of spectacles. however, a considerable number of participants (30.5%) supposed that the use of spectacles was not an effective method for managing childhood re.19 therefore, educational interventions to increase parental knowledge of the treatment and prevention of childhood visual impairment due to uncorrected res are important. in this study, almost 63.7% of parents indicated that they had not obtained any information related to childhood eye care. this result is higher than that reported among sudanese parents, where almost 25% of parents stated that they had not obtained information regarding childhood eye care.8 the current study revealed that females had significantly better knowledge than males (p = 0.008). the 41–50 age group had a significantly higher mean knowledge score than the other age groups (p = 0.024). furthermore, knowledge of childhood re was associated with the parents’ educational level (p <0.001). several authors have reported an association between specific demographic characteristics (i.e. age, gender and level of education) of the parents and knowledge of childhood eye care.16,20,21 aldebasi reported that individuals with advanced educational levels showed more knowledge of re than those with elementary educational levels.22 in this study, a considerable proportion of parents supposed that wearing eyeglasses may affect their children’s chances pertaining to learning and employment. this result is similar to those of alrasheed et al., who reported that parents worried that their children may develop vision impairment and have a dim future if they used eyeglasses.7 almost a quarter (22.1%) of the parents in the present study thought that using glasses would reduce the eyes’ vision, which is consistent with the results of studies conducted in sudan and nigeria, where 36.4% and 23.8% of parents, respectively, stated that spectacles would harm children’s vision.7,23 in a survey conducted in southern california, most of the participants experienced distress, sadness and anxiety when they realised that their children needed eyeglasses to improve vision at an early age.24 many parents expressed doubts in the present study, remarking that if their children were advised to use eyeglasses, they would feel as if their children had lost their vision and that it would affect their participation in activities in addition to having an adverse psychological effect. therefore, childhood eye care education should be delivered through public media, radio, television, social media and newspapers to increase the community’s knowledge of and perspectives on childhood eye diseases and to help them understand the importance of early diagnosis and treatment of re. the present study has some limitations. it was cross-sectional and was conducted online; therefore, the collected information was sometimes incomplete. to reduce bias, incomplete questionnaires were excluded from the study. additionally, the participant response rate was slightly low, which may affect the generalisability of the results. the aforementioned limitations notwithstanding, the current study provides insights that could help health policymakers and eye care professionals develop a childhood eye care education plan to improve parents’ awareness of childhood eye care. conclusion the level of awareness regarding childhood res among parents in saudi arabia is low and they have poor perceptions of eyeglasses as a method of re management. the findings of this study show that there is a need to increase the community’s knowledge of re and disprove related myths and misunderstandings by highlighting the importance of prompt detection and treatment of childhood re. therefore, structured educational programmes through mass media are necessary to increase knowledge regarding the effect of childhood re and visual impairment and corresponding treatment modalities. this study recommends the need to devise a policy to improve the knowledge, attitudes and practices of key stakeholders such as parents and teachers. in turn, such an improvement could play a crucial role in addressing the poor knowledge and perceptions regarding the treatment of childhood re and spectacle use in saudi arabia. a u t h o r s’ c o n t r i b u t i o n sa and wa designed the study. sa analysed and interpreted the results. wa drafted the manuscript. both authors discussed the results, commented on the manuscript and approved the final version of the manuscript. a c k n o w l e d g e m e n t s the researchers would like to thank the deanship of scientific research, qassim university, for supporting this project. c o n f l i c t s o f i n t e r e s t the authors declare no conflicts of interest. parents’ awareness of and perspectives on childhood refractive error and spectacle wear in saudi arabia 538 | squ medical journal, november 2022, volume 22, issue 4 f u n d i n g no funding was received for this study. references 1. pascolini d, mariotti sp. global estimates of visual impairment: 2010. br j ophthalmol 2012; 96:614–8. https://doi.org/10.1136/ bjophthalmol-2011-300539. 2. solebo al, rahi j. epidemiology, aetiology, and management of visual impairment in children. arch dis child 2014; 99:375–9. https://doi.org/10.1136/ arch dis child-2012-303002. 3. alrasheed sh, naidoo ks, clarke-farr pc. prevalence of visual impairment and refractive error in school-aged children in the south darfur state of sudan. afr vision eye health 2016; 75:1–9. https://doi.org/10.4102/aveh.v75i1.355. 4. naidoo ks, wallace db, holden ba, minto h, faal hb, dube p. the challenge of uncorrected refractive error: driving the agenda of the durban declaration on refractive error and service develop ment. clin exp optom 2010; 93:131–6. https://doi.org/10.1111/ j.1444-0938.2010.00455.x. 5. bourne rr, flaxman sr, braithwaite t, cicinelli mv, das a, jonas jb, et al. magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis. lancet glob health 2017; 5:888–97. https://doi.org/10.1016/s2214109x(17)30293-0. 6. flaxman sr, bourne rr, resnikoff s, ackland p, braithwaite t, cicinelli mv, et al. global causes of blindness and distance vision impairment 1990–2020: a systematic review and metaanalysis. lancet glob health 2017; 5:1221–34. https://doi. org/10.1016/s2214-109x (17)30393-5. 7. alrasheed sh, naidoo ks, clarke-farr pc. attitudes and perceptions of sudanese high-school students and their parents towards spectacle wear. afr vision eye health 2018; 77:1–7. https://doi.org/10.4102/aveh.v77i1.392. 8. alrasheed sh, naidoo ks, clarke-farr pc. childhood eye care services in the south darfur state of sudan: learner and parent perspectives. afr vision eye health 2016; 75:1–9. https://doi. org/10.4102/aveh.v75i1.315. 9. abdi ahmed z, alrasheed sh, alghamdi w. prevalence of refractive error and visual impairment among school-age children of hargeisa, somaliland, somalia. east mediterr health j 2020; 26:1362–70. https://doi.org/10.26719/emhj.20.077. 10. yu l, li z-k, gao j-r, liu j-r, xu c-t. epidemiology, genetics, and treatments for myopia. int j ophthalmol 2011; 4:658–69. https://doi.org/10.3980/j. issn.2222-3959.2011.06.17. 11. world health organization. global initiative for the elimination of avoidable blindness: action plan 2006–2011. geneva, switzerland: who. from: https://apps.who.int/iris/handle/1066 5/43754 accessed: sept 2021. 12. alrasheed sh, naidoo ks, clarke-farr pc, binnawi kh. building consensus for the development of child eye care services in south darfur state in sudan using the delphi technique. afr j prm health care med 2018; 10:1–9. https://doi.org/10.4102/ phcfm.v10i1.1767. 13. al wadaani fa, amin tt, ali a, khan ar. prevalence and pattern of refractive errors among primary school children in al hassa, saudi arabia. glob j health sci 2012; 5:125–34. https://doi.org/10.5539/gjhs.v5n1p125. 14. aldebasi yh. prevalence of amblyopia in primary school children in qassim province, kingdom of saudi arabia. middle east afr j ophthalmol 2015; 22:86–91. https://doi.org/10.4103/09749233.148355. 15. al-rasheed sh, elmadina aem. the effect of binocular vision problems on childhood academic performance and teachers’ perspectives. pak j ophthalmol 2020; 36:162–7. https://doi. org/ 10.36351/pjo.v36i2.896. 16. baashar as, yaseen aa, halawani ma, alharbi wi, alhazmi ga, alam ss, et al. parents’ knowledge and practices about child eye health care in saudi arabia. int j med dev ctries 2020; 4:454–60. https://doi.org/10.24911/ijmdc.51-1577288335. 17. alrasheed sh, naidoo ks, clarke-farr pc, binnawi kh. building consensus for the development of child eye care services in south darfur state in sudan using the delphi technique. afr j prm health care med 2018; 10:1–9. https://doi.org/10.4102/ phcfm.v10i1.1767. 18. sukati vn, moodley vr, mashige kp. knowledge and practices of parents about child eye health care in the public sector in swaziland. afr j prm health care fam med 2018; 10:1–13. https://doi.org/10.4102/phcfm.v10i1.1808. 19. chawla k, rovers j. survey of patient opinions on eyeglasses and eye care in rural and slum populations in chennai. int j epidemiol 2009; 8:1–5. 20. amiebenomo om, achugwo dc, abah i. parental knowledge and attitude to children’s eye care services. niger j paediatr 2016; 43:215–20. https://doi.org/10.4314/njp.v43i3.11. 21. ormsby gm, arnold al, busija l, mörchen m, bonn ts, keeffe je. the impact of knowledge and attitudes on access to eye-care services in cambodia. asia pac j ophthalmol (phila) 2012; 1:331–5. https://doi.org/10.1097/apo.0b013e31826d9e06. 22. aldebasi y. young public’s awareness to refractive error deficiency. int j health sci (qassim) 2011; 5:9–15. 23. ayanniyi aa, olatunji fo, mahmoud ao, ayanniyi ro. knowledge, and attitude of guardians towards eye health of primary school pupils in ilorin, nigeria. niger postgrad med j 2010; 17:1–5. 24. kodjebacheva gd, maliski s, coleman al. use of eyeglasses among children in elementary school: perceptions, behaviors, and interventions discussed by parents, school nurses, and teachers during focus groups. am j health promot 2015; 29:324–31. https://doi.org/10.4278/ajhp.120315-qual-140. https://doi.org/10.1136/bjophthalmol-2011-300539 https://doi.org/10.1136/bjophthalmol-2011-300539 https://doi.org/10.1136/ arch dis child-2012-303002 https://doi.org/10.4102/aveh.v75i1.355 https://doi.org/10.1111/j.1444-0938.2010.00455.x https://doi.org/10.1111/j.1444-0938.2010.00455.x https://doi.org/10.1016/s2214-109x(17)30293-0 https://doi.org/10.1016/s2214-109x(17)30293-0 https://doi.org/10.1016/s2214-109x (17)30393-5 https://doi.org/10.1016/s2214-109x (17)30393-5 https://doi.org/10.4102/aveh.v77i1.392 https://doi.org/10.4102/aveh.v75i1.315 https://doi.org/10.4102/aveh.v75i1.315 https://doi.org/10.26719/emhj.20.077 https://doi.org/10.3980/j. issn.2222-3959.2011.06.17 https://doi.org/10.4102/phcfm.v10i1.1767 https://doi.org/10.4102/phcfm.v10i1.1767 https://doi.org/10.5539/gjhs.v5n1p125 https://doi.org/10.4103/0974-9233.148355 https://doi.org/10.4103/0974-9233.148355 https://doi.org/ 10.36351/pjo.v36i2.896 https://doi.org/ 10.36351/pjo.v36i2.896 https://doi.org/10.24911/ijmdc.51-1577288335 https://doi.org/10.4102/phcfm.v10i1.1767 https://doi.org/10.4102/phcfm.v10i1.1767 https://doi.org/10.4102/phcfm.v10i1.1808 https://doi.org/10.4314/njp.v43i3.11 https://doi.org/10.1097/apo.0b013e31826d9e06 https://doi.org/10.4278/ajhp.120315-qual-140. march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 101-102, epub 16th mar 2009 submitted 1st feb 09 the current medical diagnosis and treatment 2009 as every year population sizes increase, new diseases are discovered and scientists make new drugs, there is a need for an updated and concise clinical text book for medical practitioners. the current medical diagnosis and treatment (cmdt) authors did a very good job of this by writing a text book which can be updated annually, with a quick reference link to an online preview. it was first published in 1987 to 1999 by appleton & lange and from 2000 till 2009 copyrighted by mcgraw-hill incorporated and has long history of presenting updated medical knowledge in every edition. this 48th edition has outstanding features which make the book easier to use. this text book in internal medicine is trusted, authoritative, and essential to daily practice. it delivers the latest insights into signs, symptoms, epidemiology, etiology, and treatment for over 1,000 diseases and disorders. look at any topic in these pages and find on the spot an evidence-based answer that reflects the most recent developments in diagnosis and treatment. this concise, authoritative reference covers the latest medical advances, prevention strategies, cost-effective treatments, and more. in the chapters you will find comprehensive coverage of inpatient and outpatient care, focusing on the diagnostic tools relevant to day to day practice. there is also a full review of all primary care topics with an annual review of advances in hiv treatment and the essentials of diagnosis for most diseases/disorders. these are complemented by quick-access drug treatment tables, with indexed trade names and updated drug prices and icd codes featured on the inside covers. you will find also diagnostic and treatment algorithms which present important information in an at-a-glance style. up-to-date references provide peerreviewed, evidence-based information. updated topics in this edition include topics in epidemiology, aetiology, and diagnosis and treatment recommendations; sections on asthma (includes 2007 naepp guidelines) and palpitations; more algorithms are provided throughout and there is increased coverage of canadian and international guidelines. the chapter on haemostasis and antithrombotic therapy has been improved. the end of life chapter, now called palliative care & pain management, has been completely revamped. colour inserts have been expanded to 16 pages with the latest developments in hiv infection, including new drugs, recommended treatment regimens, and antiretroviral drug resistance. alternative medicine and complementary therapies are represented with sections on mind-body medicine; clinical hypnosis; biofeedback; mindfulness meditation; stress reduction and cognitive therapy and guided imagery. cmdt online is updated quarterly (www.accessmedicine.com) and provides full electronic access to 2009 لسنة احلالي الطبي والعالج التشخيص باباداكيز ، ماكسني ماكفي احملررون: استيفان editors: stephen j mcphee and maxine papadakis publisher: mcgraw-hill lange. 48th edition, 2009 isbn: 9780071591249 orders: mcgraw-hillmedical.com (hard cover edition $72) on line edition: www.accessmedicine.com (online web access costs $79) b o o k r e v i e w b o o k r e v i e w : th e c u r r e n t m e d i c a l d i a g n o s i s a n d tr e at m e n t 2 0 0 9 102 cmdt 2009 plus expanded basic science information and four online-only chapters: anti-infective chemotherapeutic & antibiotic agents; diagnostic testing & medical decision making; basic genetics, and information technology in patient care. subscribers also receive access to the diagnosaurus with 1000+ differential diagnoses and the current practice guidelines in primary care, 2008. recent references are also provided, with unique identifiers (pubmed, pmid numbers) for rapid downloading of article abstracts and, in some instances, full-text reference articles. as with any book there are a few points that need to be taken into consideration for future improvement. the cardiology chapter needs ecg and echocardiography pictures. some topics such as cardiac resynchronisation theraphy and antiarrythmic drugs are treated as one. new drugs used in acute heart failure, e.g. levosimendan gp2b/3a, are not mentioned; there is nothing on drug-drug interaction, metabolism and the follow-up of patients. there are less flow charts in comparison to kumar & clark’s or davidson’s volumes on clinical medicine. overall this is a very handy annually updated text book which can be used as a reference at a budget price in comparison to other books. it also has useful online access. it would be very interesting and informative for pre-med students and a ready reference for busy primary care practitioners and physicians. r e v i e w e r amir m. al-amri department of internal medicine (cardiology) the royal hospital, muscat, sultanate of oman email: amiralamri@gmail.com submitted 14 jul 21 1 revisions req. 10 oct 21; revisions recd. 12 dec 21 2 accepted 12 jan 22 3 online-first: february 2022 4 doi: https://doi.org/10.18295/squmj.2.2022.016 5 6 the association of human leukocyte antigens complex with type 1 diabetes 7 in omanis 8 mohammed al-balushi,1 samiya al-badi,2 saif al-yaarubi,3 hamad al-9 riyami,4 azza al-shidhani,3 shaima al-hinai,3 ali alshirawi,5 sidgi hasson,1 10 elias said,1 ali al-jabri,1 *aliya al ansari2 11 departments of 1microbiology & immunology, 3child health, 4genetics, 5medicine, college of 12 medicine, 2department of biology, college of science, sultan qaboos university, muscat, 13 oman. 14 *corresponding author’s e-mail: alansari@squ.edu.om 15 16 abstract 17 background: identifying the human leukocyte antigens (hla) high risk alleles, genotypes and 18 haplotypes in different populations is beneficial for understanding their roles in type 1 diabetes 19 (t1d) pathogenesis and intervention practices. objective: the aim of this study was to identify 20 t1d associated hla gene alleles in the omani population. methods: our case-control study 21 included 73 diabetic seropositive children (mean age 9.08±3.27 years) and 110 healthy controls. 22 hla–a, -b, -c, -drb1, and -dqb1 genes were genotyped using sequence specific primer 23 polymerase chain reaction (ssp-pcr). results: two hla class i alleles (b*08, b*58) and three 24 class ii alleles (dqb1*02, drb1*03 and drb1*04) were associated with t1d susceptibility, 25 while one class i (b*51) and three class ii (dqb1*05, dqb1*06, and drb1*16) alleles were 26 associated with t1d protection. hladrb1*03 and dqb1*02 alleles showed the strongest risk 27 association among all alleles. six drb1 residues (e9, s11, s13, y30, v70 and k71) were significantly 28 associated with t1d susceptibility. heterozygous genotypes, hla-drb1*03/*04 and 29 dqb1*02/*03 were significantly associated with t1d susceptibility (p=4.29e-07, or=63.2 and 30 p=0.02, or=3.6, respectively). furthermore, we detected a significant combined action of 31 drb1*03-dqb1*02 haplotype in t1d risk (p=1.76e-05, or=15), and drb1*16-dqb1*05 32 haplotype in protection (p=3.12e-2, or=0.48). conclusion: known hla class ii gene alleles are 33 associated with t1d in omani children. 34 keywords: type 1 diabetes; human leukocytes antigens; zygosity; alleles; residues; haplotypes, 35 case-control study; oman 36 37 advances in knowledge 38  hla class ii alleles (dqb1*02, drb1*03 and drb1*04) are the major genetic risk 39 factors for t1d in omanis. 40  combined action in drb1*16-dqb1*05 haplotype is associated with t1d protection. 41  combined action in drb1*03-dqb1*02 haplotype is associated with t1d risk. 42 application to patient care 43  the associated gene alleles can be used for disease prediction and intervention. 44 45 introduction 46 type 1 diabetes (t1d) is a common incurable chronic autoimmune disease of childhood, with an 47 estimated incidence increase o f 9.5% globally.1 it is a complex disease that develops from 48 collective contribution from genetic, epigenetic, and environmental factors.2 49 50 both the cellular and humoral adaptive immune mechanisms are implicated in t1d. the destruction 51 of β-cells driven by self-reactive cd8+ and cd4+ t cells leads to total insulin deficiency.3 52 autoantibodies to pancreatic islet β-cell autoantigens are detected prior to disease development 53 and are used as biomarkers for β-cells dysfunction and t1d progression.4 54 55 determining the associated environmental triggers, autoimmune-mechanisms and predisposing 56 genetic background hold potentials for interventions through prediction, prevention or slowing 57 down the rate of disease progression. 58 59 t1d estimated heritability is high (0.53 to 0.92) and familial and population based genetic studies 60 identified more than 60 genes, responsible for about 80% of the disease heritability.5 most of the 61 t1d genetic predisposition (60%) is attributed to the human leukocytes antigen (hla) class i and 62 class ii genes, in the major histocompatibility complex (mhc) region, which encode for proteins 63 that present antigenic peptides for cd8+ and cd4+ t cells, respectively.6 64 65 markedly, 45% of the genetic predisposition is attributed to hla class ii genes7, thus, it is 66 considered as a major genetic risk determinant for t1d. the strongest t1d risk is associated with 67 the drb1, dqa1, dqb1 gene alleles and there is a cumulative supporting evidence for the role of 68 drb1 and dqb1 genes in combination as a haplotype.8 in european, more than 95% of t1d 69 cases have dr3 (hla-drb1*0301-dqb1*0201) or dr4 (hla-drb1*04-dqb1*0302). 7 the 70 same hla susceptibility and protection gene alleles and haplotypes were reported in arabs.9 71 72 with the current knowledge about autoantigens, genetic risk alleles and biomarkers, disease 73 interventions are more informed and can be considered at three stages: prior to the development 74 of autoimmunity (primary prevention), after autoimmunity is recognized (secondary prevention) 75 or after diagnosis, if significant numbers of β-cells are left (tertiary prevention). 4 76 77 in a study conducted over two years on omani children with t1d (9 months -14 years), reported 78 incidence rates of 2.45 and 2.62 per 100, 1000 p-y in 1993 and 1994, respectively.10 the reported 79 gender-specific incidence rates among boys and girls were 3.23 and 1.99 per 100,000 p-y in 1993 80 and 2.91 and 1.95 per 100,000 p-y in 1994, respectively. during the two years, they found higher 81 age-specific incidence rates in the 10–14year old group children compared to the younger age 82 group. furthermore, a retrospective (june 2006 to may 2013) analysis of 144 t1d omani children 83 reported that the disease is highly prevalent in the family history of these patients (22%).11 84 85 in oman, the incidence of t1d is comparatively less than other arabs, and also, ketoacidosis 86 reported to be less in the omani cases11. although the omani population is genetically related to 87 mediterranean and west-asian populations12,13, the high frequency of hla-dr2 and -dq1 alleles 88 (drb1*15 and drb1*16, and dqb1*05 and dqb1*06, respectively) were suggested as genetic 89 protection factor against t1d in the omani population.14 however, it remains to be elucidated 90 whether this is true or attributed to low frequency of risk alleles. 91 to identify the potential hla gene alleles associated with t1d risk and/or protection in omanis, 92 we genotyped t1d patients, attending the pediatric clinic at sultan qaboos university hospital 93 (squh) in muscat for hla class i (a, b and c) and class ii (drb1 and dqb1) alleles and 94 compared them to healthy omani controls. 95 96 materials and methods 97 statement on ethics 98 the study was approved by the ethics research committee in the college of medicine and health 99 science. a written informed consent was obtained from all participants guardians enrolled in the 100 study to use their blood sample for research purpose. 101 102 cases and controls 103 one hundred omani diabetic patients attending the pediatric clinic at squh were included based 104 on their medical records (mean age 9.31±3.27 years, 47% male and 53% female). all patients did 105 not have another autoimmune disease or syndrome and the diagnosis of t1d was confirmed by 106 the presence of diabetes autoantibodies to islet cell (ica) and glutamic acid decarboxylase 107 (gada). family history of t1d and t2d in cases was recorded. 108 109 peripheral venous blood samples (5 ml) were collected in edta – anticoagulated vacutainer tubes 110 and stored at -20 ˚c. hla data for 110 healthy potential bone marrow stem cell donors (mean age 111 10.77±3.36 years, 51% male and 49% female) from the national hla database was used as the 112 healthy population control. 113 114 dna was extracted from whole blood samples using qiaamp® dna medi kit according to the 115 manufacturer's instructions (qiagen, hilden, germany). dna concentration and purity was 116 measured using nano drop spectrophotometer (nd 2000; thermo scientific, germany). the 117 extracted dna (20-35 ng/μl) was hla genotyped for hla-a, -b, -c, -drb1, and -dqb1 loci 118 using a commercial sequence specific primer polymerase chain reaction (ssp-pcr) following the 119 manufacturer’s protocol (olerup ssp). the generated genotypes data are at low resolution. 120 121 agarose gel (1.3 %) electrophoresis was used to detect the amplified pcr product. the gel was 122 visualized using the gel documentation system ingenius 3 (syngene) with genesys software. 123 the appearance of the internal control bands in all lanes indicated successful amplification of the 124 studied dna. negative control wells were checked for contamination. hla genotypes for each 125 locus were identified using the olerup ssp score software (version 5.00.72.5t). 126 127 statistical analysis 128 hardy-weinberg equilibrium tests were conducted for each locus using the basic statistics tool 129 (one locus summary) available at hla-net (https://hla-net.eu/tools/basic-statistics). alleles at 130 each locus were considered in hardy-weinberg equilibrium if the observed and expected 131 (estimated) frequencies did not differ significantly (p > 0.05). 132 133 tests for allele associations, zygosity, as well as tests for, independence, difference in association, 134 combined action, interaction, and linkage disequilibrium were conducted using pyhla.15 135 136 the comparison of allele frequencies was performed using fisher's exact test. the p value for each 137 test was corrected for multiple comparisons by fdr. adjusted p values less than 0.05 was 138 considered statistically significant. the strength of the association between hla antigens and t1d 139 was determined by odds ratio (or). an or ≥ 1.5 was associated with susceptibility or ≤ 0.5 with 140 resistance. 141 142 in addition, tests for pockets with significant residues association were conducted using skdm 143 human leukocyte antigen tool.16 144 145 results 146 out of the initially screened 100 t1d patients, 73 (73%, mean age 9.08±3.27 years, 41.1% male 147 and 58.9% female) were included in the study because they were seropositive for gada and/or 148 ica autoantibodies. twenty-six patients (26%) were seronegative (mean age 9.77±3.25 years, 149 61.5% male and 38.5% female), out of which three patients (two males and one female) were 150 heterozygous for mutations in different genes (klf11, wfs1 and hnf1a). about 23% of the 151 seropositive cases have family history of t1d and 59% of t2d. about 19% of the seronegative 152 cases have family history of t1d and 54% of t2d. one patient was excluded as no antibodies test 153 results were reported. 154 155 all tested loci were in hardy-weinberg equilibrium in cases but not in controls (supplementary 156 data). however, as our single center project is considered as a preliminary study, we did conduct 157 the association tests to detect any potential associations. 158 159 hla class i and ii loci are associated with risk and protection of t1d 160 association test results indicated that the risk and protection of t1d in seropositive cases are 161 associated with alleles belonging to the hla class i (hla-b) and class ii, (hla-drb1 and hla-162 dqb1) genes [table 1]. 163 164 the strongest significant susceptibility alleles are the hla-drb1*03 (p=9.19e-11, or= 5) and 165 dqb1*02 (p=9.76e-08, or=3.5). we also observed that the seropositive cases for gada 166 (98.6%), icas (23.3%) or both autoantibodies (21.9%) have more drb1*03 or drb1*04 alleles 167 (95.8%), than the seronegative cases (65.2%) and healthy controls (39%). however, the presence 168 of risk alleles did not correlate with higher gada autoantibody levels and the presence of 169 protection alleles did not correlate with lower levels. 170 171 seronegative cases also, showed significant risk association with hla-drb1*03 and -dqb1*02 172 alleles but to a lesser extent (p=1.74e-3, or= 5.6 and p=1.20e-2, or= 4.4). 173 174 the most significant resistance alleles are hla-dqb1*06 (p=6.40e-05, or=0.05) and hla-175 dqb1*05 (p=9.59e-05, or=0.4). 176 177 zygosity at hla class ii loci is associated with risk and protection of tid 178 the zygosity tests were performed to investigate homozygous, heterozygous, and zygosity 179 associations based on the genotype frequency differences in cases and controls. the results 180 indicated that hla-drb1*03 and dqb1*02 zygosity is associated with disease susceptibility 181 (p=2.3e-05, or=8.2 and p=6.6e-07, or=9.4, respectively), i.e., significantly higher frequency 182 of risk allele homozygous genotypes than risk allele absent genotypes in cases compared to in 183 controls [table 2]. 184 185 notably, heterozygous genotypes, drb1*03/04 and dqb1*02/03 are associated with significant 186 t1d risk (p=4.294e-07, or= 63.2; p=0.02, or =3.6, respectively). 187 188 however, heterozygosity, i.e., higher frequency of risk alleles (b*08, b*58, drb1*03 dqb1*02 189 and drb1*04) heterozygous genotypes than risk allele absent genotypes in cases compared to in 190 controls, is associated with disease protection (p=0.03, or=0.46; p=1.0e-12, or=0.08; p=3.5e-191 06, or=0.17; and p=0.01, or=0.33, respectively). 192 193 t1d protection is associated with zygosity of protective alleles, drb1*16 (p=1.3e-3, or=0.10) 194 and dqb1*05 (p=4.5e-05, or= 0.11) and susceptibility is associated with dqb1*06 195 heterozygosity (p=4.14e-04, or=10.77). 196 197 pocket residues of hla class ii drb1 chain are associated with increased risk of t1d 198 as the hla genotypes dictate the affinity to the presented peptides, the t1d associated hla 199 alleles are implicated in the selective presentation of self-peptides. therefore, we investigated the 200 potentially associated residues in the hla chains using the pocket test. the results showed that 201 six residues (glu-9, e9; ser-11, s11; ser-13, s13; tyr-30, y30; val-70, v70; and lys-71, k71) in 202 pockets 4, 6, 7 and 9 of hla class ii drb1 chain are significantly associated with t1d 203 susceptibility [table 3] [figure 1]. 204 205 the zygosity analysis for five associated residues showed that only the heterozygotes are 206 associated with t1d susceptibility (e9 p=1.547e-7, 6.04; s11 p=3.13e-12, 10.43, s13 p=3.13e-12, 207 10.43, v70 p=7.357e-13, 11.68, and k71 p=3.13e-12, 10.43). in contrast, residue y30 homozygotes 208 (p=1.199e-7, 33.65), heterozygotes (p=0.02305, 6.7) and zygosity (p=8.753e-6, 5.02) are all 209 associated with t1d susceptibility. 210 211 interactions between t1d associated alleles 212 since t1d association with hla alleles reported at the haplotypic context as well as the genotypic 213 context, we also analyzed the associated allele interactions. two haplotypes found to be associated 214 with risk (hla-b*08-drb1*03, p8=1.57e-08, or=12.71 and hla-drb1*03-dq*02, 215 p8=1.66e-12, or=14.99) [table 4] [figure 2]. however, the interaction analysis indicated that 216 drb1*03 association with t1d is independent of b*08 (p5=8.23e-04, p6=1.95e-09), while b*08 217 association is dependent (p3=0.64, p4=1) and that both alleles have a combined effect in disease 218 (p8=1.57e -08) [table 4]. also, our data indicated that a combined -dependent effect of the hla-219 drb1*03-dq*02 haplotype results in t1d susceptibility, while a combined -dependent effect of 220 the drb1*16-dqb1*05 haplotype results in protection [table 4] [figure 2]. 221 222 discussion 223 the risk and protection to t1d in omani are associated with alleles belonging to the hla-b, hla-224 drb1 and hla-dqb1 genes [table 1], which were reported in other populations.8 this was 225 expected as the omani population is genetically related to arab, mediterranean and west-asian 226 populations.12,13,17 227 228 the hla class i alleles associated with t1d susceptibility are b*08 (p=1.82e-02, or= 2.51), 229 b*58, p=2.86e-02, or=2.47) and with protection is b*51 (p=1.82e-02, or=0.41). these 230 associated were reported in previous studies.18 b*08 association with autoimmune diseases was 231 attributed to its presence in linkage disequilibrium (ld) with drb1*03,18 which we observed in 232 both cases and controls [table 4]. furthermore, results indicated that b*08 association is 233 dependent on drb1*03. also, b*58 is part of a significantly associated haplotype in north indians 234 and han chinese and results from both populations suggested that the association is not attributed 235 to the allele itself.19,20 236 237 as predicted by a past study, t1d protection in omanis was found to be associated with hla-238 dr2 (drb1*16) and dq1 (dqb1*05 and dqb1*06) alleles.14 the highest significant resistance 239 alleles are hla-dqb1*06 (p=6.40e-05, or=0.05) and hla-dqb1*05 (p=9.59e-05, or=0.4). 240 however, despite the high frequency of the drb1*16 allele in the omanis compared to other 241 populations21, its significant association with protection is relatively weaker (p= 0.02, or=0.5). 242 this is likely due to the presence of different alleles (drb1*16:01:01, 16:02:01 and 16*64, 243 personal communication) in the omani population and not all are not protective. 244 245 notably, about 96% of the seropositive cases have either drb1*03 or drb1*04 allele but the 246 presence of these alleles did not associate with higher gada autoantibody levels. also, no 247 association was detected between gada autoantibody levels and risk or protection genotypes. 248 249 the zygosity test showed that the hla-drb1*03 and dqb1*02 zygosity are associated with risk, 250 while heterozygosity is associated with protection (p=1.0e-12, or=0.08 and p=3.5e-06, 251 or=0.17, respectively), indicating that the risk associated with both alleles is recessive, as 252 suggested by others.7 also, we detected that heterozygous genotypes, drb1*03/04 (p=4.294e-07, 253 or= 63.2) and dqb1*02/03 (p=0.02, or =3.6), are associated with significant t1d risk. 254 255 in contrast, the protection associated with heterozygosity of the same risk associated alleles may 256 be attributed to the presence of protection alleles in the genotypes. twenty-seven of the hla-257 drb1*03 heterozygous cases (44) have one of the hla-dr2 protection associated alleles (five 258 cases with drb1*15 and 22 with drb1*16) and thirty of the hla-dqb1*02 heterozygous cases 259 (39) have one of the hla-dq1 protection associated alleles (29 cases with dqb1*05 and one 260 with dqb1*06). 261 262 also, the zygosity test showed that the protection associated with dqb1*05 and drb1*16 are 263 significant in homozygosity, suggesting that the protection associated with both alleles is 264 recessive. 265 266 the side chains of self-peptide residues interaction with the binding groove pockets, stabilize the 267 peptide–hla-class ii complex and therefore they are known as the anchor residues. the binding 268 grooves of hla class ii chains are characterized by the properties of the p1, p4, p6 and p9 pockets 269 that specificity the anchor residues.22t1d associated residues 9, 11, 13 and 30 are located in the 270 -sheet floor and their side chains are in the peptide-binding groove, while residues 70 and 71 are 271 in the -helix but their side chains are close to residue 13 [figure 1]. drb1 s13 is in pocket 4, k71 272 in pockets 4 and 7, v70 in pocket 4, s11 in pocket 6, e9 in pockets 6 and 9 and y30 in pocket 6. as 273 s13, v70 and k71 were associated with the strongest disease risk based on the p values and or 274 values, they might be the major contributors from pocket 4. 275 276 s13 and k71 association with t1d susceptibility was reported by others23,24 and they were 277 implicated in joint susceptibility to both t1d and autoimmune thyroid disease.25 s11, s13 and k71 278 residues were also associated with risk to rheumatoid arthritis.26 this suggests common disease 279 mechanisms that operate irrespective of the presented self-peptides. 280 281 transgenic mice expressing tid human class ii susceptibility alleles, showed that mhc class ii 282 molecules present specific autoantigenic peptides, such as gad65 peptides27, which can 283 potentially activate autoreactive cd4+ t cells that is known to assist in targeting  cells by 284 cytotoxic cd8+ and autoantibody producing b cells. 285 286 interaction tests suggested that the association of hla-drb1*03 and -dqb1*02 haplotype with 287 t1d risk is resulting from a combined -dependent effect [table 4]. notably, 78% of cases with 288 this haplotype were gada positive, as reported by others.28 this suggested that both susceptibility 289 hla alleles and anti gad are risk factors for t1dm. however, we did not detect an association 290 between risk alleles and higher gada levels. this may indicate that gada autoantibody level, 291 which is implicated in the destructive process in the islets, is not genetically driven. 292 293 also, the analysis indicated that the association with t1d is resulting from a combined -dependent 294 effect of the drb1*16-dqb1*05 haplotype [table 4]. this haplotype thought to have a protective 295 role, but its rare occurrence in caucasians and east -asians, could not prove its effect in t1d 296 resistance. furthermore, we also believe that drb1*16-dqb1*05 haplotype in omanis could 297 potentially protect autoantibody seropositive first-degree relatives from t1d, like the hla-298 drb1*15:01-dqb1*06:02 haplotype in other populations.6 299 300 although other t1d associated haplotypes were reported in the omani population, such as 301 drb1*04-dqb1*03 (7.7%), drb1*07-dqb1*02 (6.4%) and drb1*15-dqb1*06 (1%) 12, we 302 did not detect significant ld in the investigated group of cases and controls, which is likely due 303 to small sample size. 304 notably, the frequency of seronegative cases (26%) is higher than what was reported from other 305 ethnic groups (20%).29 however, a relatively weaker association of t1d with hla-drb1 and -306 dqb1 alleles in seronegative cases, may reflect the fact that some of the cases may be positive for 307 other autoantibodies associated with t1d that where not tested for in this study or they may show 308 positive on repeat testing, as reported by hameed et al. .30 309 310 a major limitation of the study was the sample size, because it was based on a single center. 311 therefore, we recommend conducting a larger size multi-center study to at least double the cases 312 sample sizes and increase the controls to cases ratio (at least 3:1) to reach acceptable power (≥80%) 313 for verifying our preliminary study results. in addition, sequencing of the associated risk and 314 protection allele should be considered. 315 316 conclusion 317 the majority of the seropositive t1d cases (71%) have family history of t1d and/or t2d. despite 318 the study small sample size, we identified dqb1*02, drb1*03 and drb1*04 as potential risk 319 alleles in gada and/or ica seropositive t1d in omani children. in addition, we detected an 320 association of the drb1*16-dqb1*05 haplotype with t1d protection in a combined -dependent 321 manner. 322 323 acknowledgement 324 we would like to thank all patients and their parents. we also aknowledge the support from dr irfan 325 ullah from the pediatric department at squh, and ms faiza al-yahyai and ms faiza al-ghanami and 326 ms iman al-hadhili from the genetic lab. special thanks to dr felix fan and dr abdelhamid 327 abdesselam for their assistance in utilizing pyhla. 328 329 conflict of interest 330 the authors declare that they have no conflict of interest. 331 332 funding 333 this work was supported by trc fund, oman (rclmedlmicrl14l01). 334 335 authors’ contributions 336 ma-b, aa-j, sh and es developed the proposal. ma-b, sa-b, aa-s, sa-h and aa collected 337 the data. ma-b and ha-r ordered the required materials. ma-b and sa-b conducted the 338 laboratory work. sa-y reviewed the clinical and family histories. sa-b and aa-a analysed the 339 data. aa-a drafted the manuscript. ma-b and sa-y revised the manuscript. all authors 340 approved the final version of the manuscript. 341 342 references 343 1. mobasseri m, shirmohammadi m, amiri t, vahed n, fard hh. prevalence and incidence 344 of type 1 diabetes in the world : a systematic review and meta-analysis. 2020; 10:98-115. 345 doi: https://doi.org/10.34172/hpp.2020.18. 346 2. stankov k, benc d, draskovic d. genetic and epigenetic factors in etiology of diabetes 347 mellitus type 1. pediatrics. 2013; 132:1112-1122. doi: https://doi.org/10.1542/peds.2013-348 1652. 349 3. wållberg m, cooke a. immune mechanisms in type 1 diabetes. trends immunol. 2013; 350 34:583-591. doi: https://doi.org/10.1016/j.it.2013.08.005. 351 4. jacobsen lm, newby bn, perry dj, posgai al, haller mj, brusko tm. immune 352 mechanisms and pathways targeted in type 1 diabetes. curr diab rep. 2018; 18. doi: 353 https://doi.org/10.1007/s11892-018-1066-5. 354 5. lam h v., nguyen dt, nguyen cd. sibling method increases risk assessment estimates 355 for type 1 diabetes. plos one. 2017; 12:1-9. doi: 356 https://doi.org/10.1371/journal.pone.0176341. 357 6. pugliese a. autoreactive t cells in type 1 diabetes. j clin invest. 2017; 127:2881-2891. 358 doi: https://doi.org/10.1172/jci94549. 359 7. dib sa, gomes mb. etiopathogenesis of type 1 diabetes mellitus: prognostic factors for 360 the evolution of residual β cell function. diabetol metab syndr. 2009; 1:1-8. doi: 361 https://doi.org/10.1186/1758-5996-1-25. 362 8. noble ja. immunogenetics of type 1 diabetes: a comprehensive review. j autoimmun. 363 2015; 64:101-112. doi: https://doi.org/10.1016/j.jaut.2015.07.014. 364 9. zayed h. genetic epidemiology of type 1 diabetes in the 22 arab countries. curr diab 365 rep. 2016; 16. doi: https://doi.org/10.1007/s11892-016-0736-4. 366 10. soliman at, al-salmi is, asfour mg. epidemiology of childhood insulin-dependent 367 diabetes mellitus in the sultanate of oman. diabet med. 1996; 13:582-586. doi: 368 https://doi.org/10.1002/(sici)1096-9136(199606)13:6<582::aid-dia114>3.0.co;2-e. 369 11. al-yaarubi s, ullah i, sharef sw, et al. demographic and clinical characteristics of type 1 370 diabetes mellitus in omani children single center experience. oman med j. 2014; 371 29:119-122. doi: https://doi.org/10.5001/omj.2014.29 [doi]. 372 12. albalushi kr. hla class ii (drb1 and dqb1) polymorphism in omanis. j transplant 373 technol res. 2014; 4. doi: https://doi.org/10.4172/2161-0991.1000134. 374 13. al salmi i, metry a, al ismaili f, et al. epidemiology of human leukocyte antigens 375 among omani population. saudi j kidney dis transplant. 2017; 28:1021. doi: 376 https://doi.org/10.4103/1319-2442.215135. 377 14. white ag, leheny w, kuchipudi p, et al. histocompatibility antigens in omanis: 378 comparison with other gulf populations and implications for disease association. ann 379 saudi med. 1999; 19:193-196. doi: https://doi.org/10.5144/0256-4947.1999.193. 380 15. fan y, song yq. pyhla: tests for the association between hla alleles and diseases. 381 bmc bioinformatics. 2017; 18:1-5. doi: https://doi.org/10.1186/s12859-017-1496-0. 382 16. kanterakis s, magira e, rosenman kd, rossman m, talsania k, monos ds. skdm 383 human leukocyte antigen (hla) tool: a comprehensive hla and disease associations 384 analysis software. hum imkanterakis, s, magira, e, rosenman, k d, rossman, m, 385 talsania, k, monos, d s (2008) skdm hum leukoc antigen tool a compr hla dis 386 assoc anal software hum immunol 69(8), 522–525 https//doi.o. 2008; 69:522-525. doi: 387 https://doi.org/10.1016/j.humimm.2008.05.011. 388 17. jahromi m, al-ozairi e. human leukocyte antigen (hla) and islet autoantibodies are 389 tools to characterize type 1 diabetes in arab countries: emphasis on kuwait. dis 390 markers. 2019; 2019. doi: https://doi.org/10.1155/2019/9786078. 391 18. sia c, weinem m. the role of hla class i gene variation in autoimmune diabetes. 392 rev diabet stud. 2005; 2:97-97. doi: https://doi.org/10.1900/rds.2005.2.97. 393 19. zhang j, zhao l, wang b, et al. hla-a*33-dr3 and a*33-dr9 haplotypes enhance the 394 risk of type 1 diabetes in han chinese. j diabetes investig. 2016; 7:514-521. doi: 395 https://doi.org/10.1111/jdi.12462. 396 20. kumar n, mehra nk, kanga u, et al. diverse human leukocyte antigen association of 397 type 1 diabetes in north india. j diabetes. 2019:1-10. doi: https://doi.org/10.1111/1753-398 0407.12898. 399 21. gomes kfb, santos as, semzezem c, et al. the influence of population stratification on 400 genetic markers associated with type 1 diabetes. sci rep. 2017; 7:1-10. doi: 401 https://doi.org/10.1038/srep43513. 402 22. jones ey, fugger l, strominger jl, siebold c. mhc class ii proteins and disease: a 403 structural perspective. nat rev immunol. 2006; 6:271-282. doi: 404 https://doi.org/10.1038/nri1805. 405 23. hu x, deutsch aj, lenz tl, et al. additive and interaction effects at three amino acid 406 positions in hla-dq and hla-dr molecules drive type 1 diabetes risk. nat genet. 407 2015; 47:898-905. doi: https://doi.org/10.1038/ng.3353. 408 24. redondo mj, steck ak, pugliese a. genetics of type 1 diabetes. pediatr diabetes. 2018; 409 19:346-353. doi: https://doi.org/10.1111/pedi.12597. 410 25. menconi f, monti mc, greenberg da, et al. molecular amino acid signatures in the mhc 411 class ii peptide-binding pocket predispose to autoimmune thyroiditis in humans and in 412 mice. proc natl acad sci. 2008; 105:14034-14039. doi: https://doi.org/10.1007/978-1-413 62703-197-4-9. 414 26. raychaudhuri s, sandor c, stahl ea, et al. five amino acids in three hla proteins 415 explain most of the association between mhc and seropositive rheumatoid arthritis. nat 416 genet. 2012; 44:291-296. doi: https://doi.org/10.1038/ng.1076. 417 27. james ea, mallone r, kent sc, dilorenzo tp. t-cell epitopes and neo-epitopes in type 1 418 diabetes: a comprehensive update and reappraisal. diabetes. 2020; 69:1311-1335. doi: 419 https://doi.org/10.2337/dbi19-0022. 420 28. krischer jp, liu x, lernmark å, et al. the influence of type 1 diabetes genetic 421 susceptibility regions, age, sex, and family history on the progression from multiple 422 autoantibodies to type 1 diabetes: a teddy study report. diabetes. 2017; 66:3122-3129. 423 doi: https://doi.org/10.2337/db17-0261. 424 29. wang j, miao d, babu s, et al. prevalence of autoantibody-negative diabetes is not rare at 425 all ages and increases with older age and obesity. j clin endocrinol metab. 2007; 92:88-426 92. doi: https://doi.org/10.1210/jc.2006-1494. 427 30. hameed s, ellard s, woodhead hj, et al. persistently autoantibody negative (pan) type 1 428 diabetes mellitus in children. pediatr diabetes. 2011; 12:142-149. doi: 429 https://doi.org/10.1111/j.1399-5448.2010.00681.x. 430 431 432 figure 1. ribbon model of an hla-dr molecule peptide-binding groove, showing the position 433 and the side-chain of significantly associated residues. the model was based on 3pdo entry from 434 protein data bank and the figure was prepared using swiss-pdbviewer (http://spdbv.vital-it.ch/). 435 436 437 438 hla-b hla-drb1 hla-dqb1 s u sc e p ti b il i ty b*08 drb1*03 dqb1*02 1.82e-02 1.57e-08 9.19e-11 1.66e-12 9.76e-08 http://spdbv.vital-it.ch/ 2.51 4.97 3.47 r e si st a n c e drb1*16 dqb1*05 1.65e-02 3.12e-02 9.59e-05 0.53 0.40 figure 2. a representation of detected combined actions between t1d susceptibility and 439 resistance alleles of hla genes. 440 top corrected p values and bottom odds ratios. the lines connecting gene alleles represent 441 combined actions with p values on top. 442 443 table 1. distribution of significantly associated hla alleles in t1d cases and controls 444 allele cases % ctrl % p value or l95 u95 adjusted p susceptibility drb1*03 49.32 16.36 2.30e-11 4.97 3.07 8.06 9.19e-11 dqb1*02 59.59 29.82 2.44e-08 3.47 2.24 5.39 9.76e-08 drb1*04 19.86 8.18 1.40e-03 2.78 1.48 5.23 2.70e-03 b*08 19.18 8.64 4.00e-03 2.51 1.34 4.69 1.82e-02 b*58 14.38 6.36 1.72e-02 2.47 1.21 5.04 2.86e-02 resistance dqb1*06 0.68 11.47 3.20e-05 0.05 0.01 0.40 6.40e-05 dqb1*05 26.03 46.79 7.19e-05 0.40 0.25 0.63 9.59e-05 drb1*16 20.55 32.73 1.24e-02 0.53 0.33 0.87 1.65e-02 b*51 8.90 19.09 7.30e-03 0.41 0.21 0.80 1.82e-02 drb1*15 3. 42 8.64 5.38e-02 0.38 0.14 1.03 5.38e-02 association test was performed using pyhla program 445 446 table 2. zygosity test results for the associated hla alleles 447 allele hom_p hom_or het_p het_or zyg_p zyg_or drb1*03 0.43 0.63 1.05e-12 0.07 2.27e-05 8.22 dqb1*02 0.32 1.60 3.51e-06 0.17 6.59e-07 9.41 drb1*04 1.00 1.21 0.01 0.35 0.18 3.50 b*08 0.37 2.56 0.04 0.46 0.06 5. 61 b*58 0.63 0.6 0.01 0.33 0.62 1.81 dqb1*06 1.00 1.86 4.14e-04 10.77 0.25 0.17 dqb1*05 0.00 0.19 0.14 1.66 4.51e-05 0.11 drb1*16 0.00 0.10 1.00 1.01 0.00 0.10 b*51 0.45 0.47 0.22 1.67 0.07 0.27 abbreviations: hom, homozygous test (homozygous compared to absent); het, heterozygous test (heterozygous 448 compared to absent); zyg, zygosity test (homozygous compared to heterozygous); or, odds ratio. zygosity test was 449 performed using pyhla program. 450 451 table 3. significant residue associations in the hla-drb1 pockets 452 position amino acid association p value corrected p odds ratio pocket 4 [13,71,78,70,74,26] 13 s + 2.19e-13 1.69e-11 11.46 71 k + 2.19e-13 1.69e-11 11.46 70 v + 3.41e-13 2.63e-11 11.31 pocket 6 [9,11,30] 9 e + 1.98e-7 1.37e-5 5.43 11 s + 1.04e-12 7.20e-11 10.43 30 y + 6.92e-05 4.77e-03 12.29 pocket 7 [28,61,71,47,67] 71 k + 2.19e-13 1.51e-11 11.46 pocket 9 [9,60,57,37,38] 9 e + 1.98e-7 1.37e-5 5.43 residue association test was performed using skdm program 453 454 table 4. significant interaction tests including independent association, difference, action, and linkage disequilibrium (ld) 455 alleles a independent of b b independent of a difference combined action ld in cases ld in controls allele a allele b p3 or3 p4 or4 p5 or5 p6 or6 p7 or7 p8 or8 p9 or9 p10 or10 susceptibility b*08 drb1*03 0.64 1.29 1 0.81 8.23e04 15.67 1.95e09 9.86 0.00 0.08 1.57e08 12.71 0.02 6.4 0.01 4.03 dqb1*02 drb1*03 0.59 2.22 0.25 1.91 3.43e06 7.83 0.10 6.76 0.24 0.28 1.66e12 14.99 1.76e05 25.61 1.32e08 22.13 resistance dqb1*05 drb1*16 0.61 0.52 0.02 0.33 0.50 1.45 1 0.92 0.56 0.36 0.03 0.48 1.76e10 47.24 8.83e11 29.94 if both p3 and p4 are significant, then a is associated with t1d independently of b. 456 if p5 and p6 are significant, then b is associated with t1d independently of a. 457 if both p3 and p5 are significant, then a and b show interaction in t1d. 458 if p7 is significant, then difference between a and b is associated with t1d. 459 if p8 is significant, then a and b have combined action. 460 if p9 is significant, then a and b are in ld in cases. 461 if p10 is significant, then a and b are in ld in controls. 462 interaction tests was performed using pyhla program 463 are scintigraphy and ultrasonography necessary before fine-needle aspiration cytology for thyroid nodules? 29 abstract. objective : to evaluate the effi cacy of scintigraphy, ultrasound and fi ne-needle aspiration in thyroid nodules and to establish the best diagnostic pathway in detecting thyroid cancer. method: two hundred and sixteen patients with thyroid nodules were examined using high-resolution ultrasonography, 99mtc thyroid scintigraphy and ultrasound-guided fi ne-needle aspiration. of these, 113 patients subsequently underwent thyroidectomy. the remaining 103 were followed up for two years without any evidence of malignancy. results : cytopathology classifi ed 71% of the aspirate as benign, 3% as positive for malignancy, 21% as suspected neoplasia and 5% as unsatisfactory. fineneedle aspiration cytology had a sensitivity of 87.5% and specifi city of 80% . on ultrasound 33% of malignant nodules were hypo-echoic and on scintigraphy 16% of solitary cold nodules were malignant. neither test could reliably diagnose thyroid cancer. conclusion: ultrasound-guided fi ne-needle aspiration cytology should be the fi rst test performed in euthyroid patients with a thyroid nodule. scintigraphy and ultrasound imaging should be reserved for follow-up studies and patients who have suppressed levels of thyroid stimulating hormone. key words : thyroid nodule, ultrasonography, thyroid scintigraphy, fi ne-needle aspiration cytology. t he in v estig ation and management of nodular thyroid disease remains a clinical problem. it is more common in women, in older patients, following exposure to ionising radiation and in areas of iodine defi ciency.1–5 clinically detectable thyroid nodules occur in approximately 4–10% of the population, but only 5–30% of those nodules are malignant.6,7 the apparent prevalence of thyroid nodules depends on the technique of detection, which ranges from 30–50% in different ultrasound series, to approximately 50% at autopsy.8–10 the most widely used screening procedure in the evaluation of thyroid nodules was scintigraphy, and the radionuclides used were technetium pertechnetate (99mtc) and iodine-123 (123i).2,10,11 the value of thyroid scintigraphy is in the identifi cation of cold nodules, because they are more likely to be malignant than functioning nodules. the incidence of malignancy in cold nodules is said to vary from 5 to 15% .1,12,13 high-resolution ultrasonography (us) categorises nodules as solid, cystic or mixed, with over 90% accuracy. squ journal for scientific research: medical sciences (2001), 1, 29 –33 ©sultan qaboos university are scintigraphy and ultrasonography necessary before fi ne-needle aspi ration cytology for thyroid nodules? *dilip k. sankhla1 , samir s. hussein2, haddia bererhi3, omeima el shaf ie4, nicholas j. woodhouse4, v.nirmala5 1departments of radiology, 2nuclear medicine, 3medical physics, 4medicine and 5pathology, sultan qaboos university hospital, p.o. box: 38, al-khod 123, muscat, sultanate of oman. *to whom correspondence should be addressed. e-mail: dilipks@omantel.net.om s a n k h l a e t a l30 despite such accuracy, current ultrasonography is unable to reliably separate benign thyroid nodules from malignant ones.2,12,14 fine-needle aspiration (f na) is a well-established diagnostic procedure often used as one of the initial screening tests for patients with thyroid nodules. several studies have shown that following the introduction of fna , the number of thyroid surgical procedures has decreased by 50% while the percentage yield of cancer in operated patients has doubled.2,12–19 this paper presents an analysis of the results we obtained in sultan qaboos university hospital using 99mtcpertechnetate scintigraphy, us and ultrasound-guided f na done at one sitting in patients with thyroid nodular disease. the analysis has been used to decide the best diagnostic approach to the management of thyroid nodules. m e t h o d a total of 216 patients seen in the thyroid clinic with nodular thyroid swelling were referred for investigation. all had high-resolution sonography, 99mtc-pertechnetate scintigraphy and fi ne-needle aspiration under ultrasound guidance on the same day. the ages of the patients ranged from 17 to 88 years (mean 38 years) and 187 (87%) were women. t h e i n v e s t i g at i o n s th y roid scintigr a ph y was done after intra-venous injection of 80 mbq of 99mtc pertechnetate. standard images were obtained after 20 minutes, anterior, both anterior oblique views, and one view with a marker over the abnormal area. high-r esolution sonogr a ph y was performed with a 7.5 mhz linear probe with the patient supine and the neck hyper-extended. fine needle aspir ation (f na) was performed using ultrasound guidance to introduce a 23–25 gauge needle and a 10 ml disposable syringe. aspiration was performed with short back and forth movements while suction was applied. suction was released before the needle was removed from the lesion. the aspirate was expelled on to the glass slides and fi xed with 95% alcohol immediately. the rest of the specimen was rinsed in saline balanced solution. the specimens were sent to the cytopathology laboratory for cytological evaluation. r e s u lt s scintigr a ph y showed that 124/216 (57%) patients had solitary cold nodules, 64/216 (30%) had multiple cold lesions, and 28/216 (13%) had no nodule. sonogr a ph y showed 118/216 (55%) patients to have solitary lesions, 81/216 (38%) with multiple lesions and 17/216 (7%) without nodules [table1]. fine-needle aspir ation results of the 216 patients were grouped as benign (cyst, nodule, lymphocytic thyroiditis, sub-acute thyroiditis), malignant (papillary, medullary, anaplastic, lymphoma), suspicious neoplasia (follicular lesion, follicular neoplasm, hurthle cell neoplasm) and inconclusive (foam cell, cyst fl uid, few follicular cells, too much blood). fine needle aspirates were reported as showing benign cells in 154/216 (71%) patients, malignant in 6/216 (3%), ‘suspicious’ cells in 46/216 (21%) and were inconclusive in 10/216 (5%) [table 2]. surgery was performed in 113 patients, because the cytology result was malignant, suspicious or inconclusive or the patient had a large thyroid mass. the remaining 103 patients were followed up clinically and with us to see any change in nodule size. no patient of this group showed any sign of malignancy during a two year follow up. in the operated group, 16/113 (14%) had a malignant lesion (12 papillary, 2 follicular, 1 medullary, 1 lymphoma) table 1. comparison between results of high resolution ultrasonography (us) and scintigraphy s c i n t i g r a p h y us (%) solitary multiple no nodule solitary 118 (55) 93 13 12 multiple 81 (38) 27 47 7 no nodule 17 (7) 4 4 9 total 216 (100%) 124 (57%) 64 (30%) 28 (13%) table 2. results of fine-needle aspiration cytology (fnac) of thyroid nodules histology in operated patients cytological diagnosis fnac (%) benign malignant (%) benign 154 (71) 53 2 (1.3) malignant 6 (3) 1 5 (83.3) suspicious 46 (21) 37 9 (20) inconclusive 10 (5) 6 0 (0) total 216 97 16 (14) s c i n t i g r a p h y a n d u l t r a s o n o g r a p h y 31 and 97/113 (86%) were benign. of the 64 patients who had a solitary nodule on us, 13/64 (20%) had malignant lesions on histology [figure 1]. out of the 71 solitary lesions detected on scintigraphy, 11/71 (16%) were malignant on histology [figure 2]. eleven percent of the hyper-echoic and 33% hypo-echoic nodules were malignant. six patients who did not show a defi nite nodule on us examination had abnormal scintigraphy. on histology, 3 patients showed features of hashimoto’s thyroiditis and 3 had multi nodular goitre [table 3]. for analysis the inconclusive cytology group (10 cases) were excluded in statistical calculations. the cytological diagnosis of 206 patients was true positive in 14/206 (6.8%), false negative in 2/206 cases (1%), true negative 152/206 (73.7%) and false positive in 38/206 cases (18%) with a sensitivity of 87.5% and specifi city of 80%. d i s c u s s i o n historically, thyroid scintigraphy using 99mtc or 123i has been the foundation for assessment of the thyroid nodule.10,11 nodules detected by thyroid scintigraphy are classifi ed as cold (hypo functioning), hot (hyper functioning) or indeterminate. generally, 85% of thyroid nodules are cold, 10% are indeterminate and 5% are hot. 85% of cold nodules, 90% of indeterminate nodules and 95% of hot nodules are benign.1 the incidence of malignancy in cold nodules varies from 5% to 15%.1,12,13 therefore, although most thyroid nodules are cold, most cold lesions are benign. we observed similar fi ndings: 16% of solitary cold lesions and 11% multiple cold lesions were malignant. while we detected 118 solitary lesions on us, only 93 solitary cold lesions were demonstrated on scintigraphy. the remainder were multiple lesions (13 cases) with no nodule being shown in 12 cases. it has also been observed by solbiati et al20 that us is more sensitive than scintigraphy in detecting nodules. 99mtc-pertechnetate thyroid scintigraphy cannot truly differentiate benign or malignant nodules and cannot be used as the basis for recommending treatment of the nodule, including thyroid surgery. certainly, not all patients with thyroid nodules require thyroid scintigraphy, but it is helpful in cases having suspicious or inconclusive cytology on fna , and in cases with clinical evidence of thyrotoxicosis or having suppressed thyroid stimulating hormone (tsh ). misken and rosen21 described the use of us to examine the thyroid in 1973. originally, us was primarily used to distinguish between cystic and solid thyroid lesions. however, the development of high-resolution, real time, hand-held sonographic probes has allowed the collection of information that enhances clinical examination. us can confi rm the presence of a lesion and defi ne its characteristics better than manual palpation.8 sonography has demonstrated that non-palpable thyroid nodules are 4 times more common than those which are detected clinically.8 unfortunately, us characteristics such as size, echogenicity, and the presence of a halo sign cannot truly differentiate between benign and malignant. hyper-echoic solid nodules are usually benign (96%), but sclerosing papillary neoplasms can also have this appearance. mixed lesions represent solid lesions that have undergone variable degrees of cystic degeneration and are benign in 85% of cases. the rare cystic lesions with smooth wall and echo-free, are almost always benign. hypo-echoic nodules are more likely to be malignant than benign, 63% of hypo-echoic lesions representing malignancy in one series.20 in the present series, 33% of hypo-echoic nodules and 11% of hyper-echoic nodules were malignant. us is useful to guide the needle for f nac of a thyroid nodule although it does not differentiate benign and malignant nodules. it improves the quality of diagnosis in preoperative assessment of thyroid nodules table 3. correlation between ultrasonography (us) texture and histology h i s t o l o g y nodule echotexture no. cases benign malignant hyperechoic 27 24 3 (11) hypoechoic 6 4 2 (33) cystic 8 7 1 (13) mixed 66 56 10 (15) no nodule 6 6 0 (0) total 113 97 16 (14) n o o f p a ti e n ts figure 1. correlation between number of nodules on ultrasonography and histology 51 39 3 13 0 10 20 30 40 50 60 single multiple benign malignant s a n k h l a e t a l32 to select patients for surgery. it may have a more important role in the follow up of a nodule to assess its size and echo pattern once a decision is made not to operate. it can also be most useful in the long-term follow-up of patients with thyroid cancer by detecting small nodules that could represent recurrence of cancer.3, 22, 23 the present study shows that f nac has a high sensitivity of 87.5% and specifi city of 80%. on reviewing other large series of thyroid fnac, the sensitivity of thyroid f na ranges from 65% to 99% and its specifi city from 72% to 100%.15,17,24–29 several f na b series and reviews have been performed to establish the effi cacy of this procedure. in caruso’s24 report on ten series with 9,119 patients, results of needle biopsy were benign in 74%, suspicious and inadequate in 22%, and malignant in 4%. gharib25 evaluated seven series with a total of 18,183 f na where 69% were benign, 27% were suspicious and inconclusive and only 4% were malignant. the suspicious or inconclusive groups were approximately equally divided. of the suspicious group of nodules, 10–30% were ultimately malignant. overall, 70% of patients had a defi nitive diagnosis of either benign or malignant disease by fna . in the present series, 20% of nodules in the suspicious group were malignant on histology . in 216 patients (operated and non-operated), the false negative rate was 1% and the false positive rate 18%, considering both the malignant and suspicious categories as positive. however, it is diffi cult to know the true frequency of false negative results because only a small percentage of patients (approximately 10%) with benign cytological fi ndings undergo surgery.12 the reported false negative rate ranges from 1% to 11%.24,25 because f na is considered a screening procedure, particular attention should be given to minimizing false-negative diagnosis, even at the expense of accepting false-positive diagnosis.30 the f na remains the fi rst test in majority of cases for the evaluation of thyroid nodule. we believe that ultrasound-guided fi ne-aspiration cytology is the most effective method available. ultrasoundguidance allows continuous visualization of the needle during insertion and sampling which results in pin-point accuracy with a high level of safety. it also permits multiple sampling of the same lesion which reduces the risk of obtaining an inadequate sample.22,23 the following thyroid malig nancies can be diagnosed by fna : papillary, follicular variant of papillary, medullary, anaplastic, thyroid lymphoma, and metastases to the thyroid. follicular carcinoma, hurthle cell carcinoma and some cases with cellular atypia cannot be diagnosed by fnac. ultrasound-guided f nac has reduced the cost for evaluation and treatment of thyroid nodules and has improved yield of cancer found at surgery. due to the wide spread acceptance and low morbidity of fna , it has virtually replaced large needle (16–18 gauge) or cutting needle (14 gauge) biopsy procedure for sampling the thyroid. its use should reduce the number of imaging procedures needed. c o n c l u s i o n thyroid nodules are common and only a small percentage is malignant. the initial evaluation of thyroid nodules should effectively select patients for surgery who are likely to have malignancy. it appears from this study that ultrasound-guided f nac should be the fi rst test performed in an euthyroid patient with a thyroid nodule as it is safe, inexpensive, and has a high sensitivity. us is indicated in thyroid nodules with non-suspicious cytological fi ndings for follow up and is also useful in follow-up cases of thyroid malignancies. thyroid scintigraphy should be reserved for patients with indeterminate or inconclusive fi ndings on cytology, those with thyrotoxicosis and patients with suppressed tsh . a c k n ow l e d g e m e n t s the authors thank professor william d. jeans, former head of the department of radiology, sultan qaboos university hospital, for his advice during manuscript preparation and the technical staff of ultrasound and nuclear medicine sections of the department of radiology for help in practical aspects of the study. r e f e r e n c e s 1. rojeski mt, gharib h. nodular thyroid disease. evaluation and management. n engl j med 1985, 313, 428–36. 2. mazzaferi el. management of a solitary thyroid nodule. n engl j med 1993, 328, 553–9. 3. gharib h. fine needle aspiration biopsy of thyroid nodules: advantages limitation and effect. mayo clin proc 1994, 69, 44–9. 4. stoffer rp, welch jw, hellwig c, chesky ve, n o o f p a ti e n ts figure 2. correlation of cold nodules with histology 60 25 3 11 0 10 20 30 40 50 60 70 single multiple benign malignant s c i n t i g r a p h y a n d u l t r a s o n o g r a p h y 33 mccusker en. nodular goitre: incidence, morphology, before and after iodine prophylaxis, and clinical diagnosis. arch intern med 1960, 106, 10–14. 5. hanson ga, komorowski ra, cerietty jm, wilson sd. thyroid gland morphology in young adults: normal subjects verses those with prior low dose neck irradiation in childhood. surgery 1983, 94, 984–8. 6. ashcraft mw, van herie aj. management of thyroid nodules. history and physical examination, blood test, and ultrasonography. head neck surg 1981, 3, 216–30. 7. boring cc, squires ts, tong t. cancer statistics. cancer j clin 1993, 43, 7–26. 8. tan g h, gharib h, reading cc. solitary thyroid nodule comparison between palpation and ultrasonography. arch intern med 1995, 155, 2418–23. 9. ezzat s, sarti da, cain dr, braunstein gd. thyroid incidentalomas. prevalence by palpation and ultrasonography. arch intern med 1994, 154, 1838–40. 10. daniels gh. thyroid nodules and nodular thyroids: a clinical overview. com therapy 1996, 22, 239–50. 11. giuffrida d, gharib h. controversies in the management of cold, hot, and occult thyroid nodules. am j med 1995, 99, 642–50. 12. gharib h. management of thyroid nodules: another look. thyroid today 1997, 20, 1–11. 13. ashcraft mw, van herie aj. management of thyroid nodule. scanning techniques, thyroid suppressive therapy, and fi ne needle aspiration. head neck surg 1981, 3, 297–322. 14. ross ds. evaluation of the thyroid nodule. j nucl med 1991, 32, 2181–92. 15. miller jm, hamburger ji, kini s. the impact of needle biopsy on the pre-operative diagnosis of thyroid nodules. henry ford hosp med j 1980, 28, 145–8. 16. hamberger b, gharib h, melton l fiii, goellner jr, zinsmeister ar . fine needle aspiration biopsy of thyroid nodules. impact on thyroid practice and cost of care. am j med 1982, 73, 381–4. 17. silvermann jf, west rl, larkin ew, park hk, finley jl, swanson ms, et al. the role of fnab in the rapid diagnosis and management of thyroid neoplasm. cancer 1986, 57, 1164–70. 18. miller jm, hamburger ji, kini sr . needle biopsy of the thyroid: an update. surg rounds 1984, 72–81. 19. soloman d. fine needle aspiration of the thyroid: an update. thyroid today 1993, 16, 1–9. 20. solbiati l, volterrani l, rizzatto g, et al. the thyroid gland with low uptake lesions: evaluation by ultrasound. radiology 1985, 155, 187–91. 21. miskin m, rosen i, walfi sh pg. b-mode ultrasonography in assessment of thyroid gland lesions. ann intern med 1973, 80, 505-10. 22. rosen ib, azadian a, walfi sh pg, salem s, lansdown e, bedard yc. ultrasound-guided fi ne-needle aspiration biopsy in the management of thyroid disease. am j surg 1993, 166, 346–9. 23. hatada t, okada k, ishii h, ichii s, utsunomiya j. evaluation of ultrasound-guided fi ne-needle aspiration biopsy for thyroid nodules. am j surg 1998, 175, 133–6. 24. caruso d, mazzaferi el . fine-needle aspiration biopsy in the management of thyroid nodules. endocrinologist 1991, 1, 1194–202. 25. gharib h, goellner jr . fine-needle aspiration biopsy of the thyroid: an appraisal. ann intern med 1993, 118, 282–9. 26. altavilla g, pascale m, nenci i. fine-needle aspiration cytology of thyroid gland diseases. acta cytol 1990, 34, 251–6. 27. caraway np, sneige n, samaan n. diagnostics pitfalls thyroid fi ne-needle aspiration: a review of 394 cases. diagn cytopathol 1993, 9, 345–50. 28. ridway ce. clinical review 30: clinician’s evaluation of a solitary thyroid nodule. j clin endocrinol metab 1992, 74, 231–5. 29. sidawy mk, del vecchio dm, knoll sm. fine-needle aspiration of thyroid nodules-correlation between cytology and histology and evaluation of discrepant cases. cancer (cancer cytopathology) 1997, 81, 253–9. 30. the papanicolaou society of cytopathology task force on standards of practice. guidelines of the papanicolaou society of cytopathology for the examination of fi ne needle aspiration specimens from thyroid nodules. mod pathol 1996, 9, 710–5. college of medicine, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia *corresponding author’s e-mail: aghasa@yahoo.com knowledge and attitude towards corneal donation saudi medical students’ perspective khalid m. aloudah, abdulaziz a. ataweel, *sajida agha, syed waqas h. shah sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 106–112, epub. 28 feb 22 submitted 11 jul 20 revisions req. 22 oct & 22 dec 20; revisions recd. 19 nov 20 & 14 jan 21 accepted 26 jan 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.056 clinical & basic research abstract: objectives: to attain more local corneal donations, awareness of corneal donations must be raised among doctors and medical students. this study aimed to evaluate the knowledge and attitude of medical students regarding corneal donations. methods: this cross-sectional study was conducted among male fifthand final-year medical students at the college of medicine, king saud bin abdulaziz university for health sciences, saudi arabia, between august and october 2019. non-probability convenience sampling was used and an english-language selfadministered questionnaire was administered to evaluate different aspects of the participants’ knowledge regarding and attitudes towards corneal donation. data were analysed using descriptive statistics, analysis of variance, and independent samples t-test. results: a total of 141 students participated in this study (response rate: 53%). a mean score of 3.24 ± 1.86 was achieved by the participants on the knowledge test. approximately 47% of the sample correctly recognised that people who die of aids cannot donate an eye. the most common reason for eye donations was to provide vision to a blind person (47%), while a lack of understanding of benefits to others (55%) and religious beliefs (44%) were seen barriers. the internet was identified by 56% as the most common source of information. there was no significant difference in the knowledge of fifth-year and final-year medical students (3.31 ± 1.84 versus 3.17 ± 1.89; p = 0.65). conclusion: this study showed a low level of knowledge of corneal donations among the participants. raising awareness among medical students is important to increase donation rates. however, media and the internet are not enough to achieve this. basic knowledge of corneal donations to students by organising awareness-raising activities and motivating them for voluntary participation is important to fill this knowledge gap. keywords: knowledge; attitude; cornea; medical students; saudi arabia. advances in knowledge this study showed that the knowledge of corneal donations was low among medical students in saudi arabia. religious beliefs and family pressure were found to be significant hindering factors in corneal donations. application to patient care with an increase in knowledge and a positive attitude, the quality of patient care will improve. individuals with corneal defects will be able to regain their vision through increased awareness of eye donation. physicians will be able to help provide information on eye donation and transplantation to patients and society. strategies should be developed and implemented to raise awareness of corneal donations. furthermore, emphasis should be placed on knowing why some people are willing to donate while others are not. linking the level of awareness and willingness for eye donation among students may help in designing a curriculum and developing strategies for health promotion. corneal diseases are one of the primary causes of visual impairment and blindness, which are commonly reported in developing countries.1,2 corneal transplantation is the most effective method for treating and restoring the sight of blind patients suffering from corneal disease; this can be achieved through the contribution of eye donors. thus, the public should be made aware of the importance of eye donation. however, knowledge of this concept varies from person to person and depends on the culture. in this regard, awareness among doctors of eye donation is significant in attaining more corneal donations at the local level. there is not much literature related to eye donation in the asian-pacific region. the available literature consists of studies focusing on the awareness among students from nursing, academic and medical colleges.3–6 studies conducted among student populations found a lack of awareness on eye donation.7,8 the eye is the most essential organ for humans to experience life. loss of this organ or parts of it impedes a person’s vision, which is an incredible loss to the individual.9 a study suggested that raising awareness of basic eye healthcare and eye donation can help in limiting cases of visual impairment caused by the lack of knowledge, advanced methods, and training.10 since doctors deal with the health aspect of most members of society, the knowledge of the level of https://creativecommons.org/licenses/by-nd/4.0/ khalid m. aloudah, abdulaziz a. ataweel, sajida agha and syed waqas h. shah clinical and basic research | 107 understanding of medical students can provide a good predictive value to what future physicians would know and therefore, what improvements can be made to the system to increase their understanding. the literature suggested that there is a dire need for eye donations worldwide and emphasises physicians’ role in increasing corneal donation rates by improving donor knowledge and addressing their concerns.11 a systemic review conducted in saudi arabia reported that the prevalence of visual impairment and blindness was 2.6%, which is 20 times higher than that in america.12 all concerned governmental and non-governmental organisations must take serious measures to address the issue of shortage of eye donations in any country.13 the current study aimed to assess the level of knowledge of medical students regarding eye donations and to determine the role of future physicians in boosting corneal donation awareness, especially that of students planning to specialise in ophthalmology. using their awareness, these physicians can request the family of the deceased to donate the cornea of the departed, which will help in reducing the wastage of healthy corneas.14 moreover, their contributions will increase local investments for artificial corneas and other cornea-related issues. additionally, to disseminate information effectively and motivate the community and the family of the deceased for corneal donations, medical students should be wellinformed.12 methods this cross-sectional study was conducted among fifth and final-year medical students in phase iii (clinical phase) over a three-month period between august and october 2019 at the college of medicine, king saud bin abdulaziz university for health sciences, saudi arabia. the college has a segregated system, with two separate campuses for male and female students. the latter group was difficult to approach; therefore, only male students were included. the target population was the fifthand final-year male medical students. a non-probability convenience sampling technique was used. the male medical students in the clinical years (phase iii) who agreed to participate in the study were included. non-medical students and pre-clinical students (phase ii) with no exposure to real patients and those who refused to participate were excluded. students were chosen for this study because they were young, were undergoing training in medicine, and were expected to be better informed about the importance of cornea donation. the sample size was calculated using raosoft (raosoft inc., seattle, washington, usa) based on a confidence level of 95% and a 5% margin of error. the total sample size calculated was 266. a validated english-language self-administered questionnaire was used for the study.15 the authors approached students in their respective classes and provided them with printed copies of the questionnaire. pre-testing was done to assess the reliability of the questionnaire for the sample. the 22-item questionnaire enquired about students’ knowledge of eye donation (13 questions) and their ideas and attitudes towards pledging their eyes posthumously (nine questions). the items were related to information sources, knowledge of eye donation, the age limit for donation, reasons for pledging and not pledging eyes, conditions that make for an unfit eye donor, the perfect time to remove eyes after death, the part of the eyeball used for transplantation, donation, medical students’ perspective on revealing the identity of eye donors and ethics concerning the selling of the donated eye or parts of it. all the questions were closeended, with most of the questions having ‘yes’, ‘no,’ and ‘don’t know’ options. the scores for knowledge and attitude domains were obtained by averaging all the responses to obtain an overall result for the knowledge and attitude items. cronbach’s alpha was calculated to assess the reliability of the questionnaire with respect to the study population; cronbach’s alpha was 0.78 for all the items. after data cleaning and assigning codes, statistical package for the social sciences (spss), version 20.0 (ibm corp., chicago, illinois, usa) was used for data analysis. descriptive statistics were presented as frequencies and percentages for categorical variables, and mean ± standard deviation was used for the numerical variables. the analysis of variance (anova) was conducted to highlight the relationship between the correct knowledge score and parental education level. the total score for the correct answers (out of 12) was compared between the fifthand finalyear medical students using the independent samples t-test. the association between the demographics, knowledge scores, and willingness to pledge cornea was determined using regression analysis. a p <0.05 was considered statistically significant. all participants signed the informed consent for the pre-test and for participating in the study. the participants were assured about the confidentiality of data and their rights to withdraw from the study at any point. utmost caution was exercised to ensure their anonymity and confidentiality. the study was approved by the institutional review board of king abdullah international medical research center (code sp18r/44/11). knowledge and attitude towards corneal donation saudi medical students’ perspective 108 | squ medical journal, february 2022, volume 22, issue 1 results a total of 141 students participated in this study (response rate: 53%). the mean age of the participants was 23.4 ± 2.0 years. the participants attained a mean score of 3.24 ± 1.86 out of 12 on the background knowledge test; this shows a poor level of knowledge [table 1]. a large part of the sample (n = 99; 70%) knew about the important role of vitamin a in the prevention of childhood blindness. surprisingly, despite attending the medical college for four years, only 18 (13%) participants knew that there is an eye bank facility in the country and that the perfect time for cornea donation is within 2-6 hours after death [table 2]. a total of 66 (47%) participants knew that people who die from aids cannot donate their eyes and 58 (41%) participants correctly identified that having hepatitis makes a person unfit to make an eye donation. only 2% of the participants believed there were no restrictions to eye donation. providing vision to a blind person as a result of eye donation was the most cited reason for eye donation (n = 66, 47%), followed by cornea donation being a ‘noble initiative’ for many participants (n = 59, 42%). the most common barrier table 1: participant’s parent’s qualifications, age and knowl edge score regarding corneal donations (n = 141) parameter n (%) mean age in years ± sd 23.4 ± 2.0 mean knowledge score ± sd 3.24 ± 1.86 father’s qualification illiterate 1 (1) elementary 7 (5) intermediate 3 (2) high school 16 (11) college 46 (33) postgraduate (masters/phd) 67 (48) did not respond 1 (1) mother’s qualification illiterate 1 (1) elementary 16 (11) intermediate 9 (6) high school 25 (18) college 56 (40) postgraduate (masters/phd) 32 (23) did not respond 2 (1) sd = standard deviation; phd = doctor of philosophy. table 2: frequencies of correct answers and “don’t know” responses to knowledge questions regarding eye donation among medical students in saudi arabia (n = 141)* item # question and response n (%) 1 when should the first eye screening be done? between six months and three years of age 14 (10) don’t know 53 (38) 2 does vitamin a have an important role in the prevention of childhood blindness? yes 99 (70) don’t know 30 (21) 3 whom do you approach for eye donation? eye specialist (ophthalmologist) 52 (37) don’t know 41 (29) 4 what is the age limit for eye donation? less than a year of age 9 (6) don’t know 109 (77) 5 which part of the eyeball is removed from the donor (transplanted structure)? cornea 47 (33) don’t know 69 (49) 6 who should remove the eye from the donor? eye specialist (ophthalmologist) 86 (61) don’t know 40 (28) 7 eyes need to be removed within how much time after death? 2–6 hours 18 (13) don’t know 96 (68) 8 is there any eye bank in saudi arabia? yes 18 (13) don’t know 107 (76) 9 how long can the donor’s eye be preserved before transplanting it to the recipient? 7–12 hours 7 (5) don’t know 104 (74) 10 does the donor or the donor’s family have the right to sell the eye after the donor’s death? yes 20 (14) don’t know 51 (36) 11 will the identity of the donor be revealed to the recipients? yes 26 (18) don’t know 69 (49) 12 do you think that there are synthetic substitutes for a patient in need of an eye donation? yes 39 (28) don’t know 75 (53) 13 are you willing to donate your eyes? yes, willing to donate 36 (26) not willing to donate 105 (74) *does not include incorrect answers to the knowledge items, therefore percentages do not add up to 100%. khalid m. aloudah, abdulaziz a. ataweel, sajida agha and syed waqas h. shah clinical and basic research | 109 to donating eyes was found to be the lack of awareness of the benefits to eye recipients (n = 78, 55%) followed by religious beliefs (n = 62, 44%), family pressure (n = 45, 32%). regarding the source of information, 19 (13%) participants stated that they lacked any knowledge of eye donation. the internet was identified as the most common source of information about eye donation (n = 79, 56%). only 28 participants (20%) reported that lectures had contributed to their current knowledge of eye donation [table 3]. in the study population, 37 (26%) participants expressed their desire to pledge their eyes. an anova test revealed no association between the knowledge score and the education level of the father (p = 0.69) or the mother (p = 0.84) [table 4]. when comparing the knowledge score of fifth-year to final-year students, no significant difference was found (3.27 ± 1.86 versus 3.17 ± 1.89; p = 0.76) [table 5]. the relationship between participants’ demo graphics,knowledge scores, and willingness to pledge their cornea was studied. after adjusting the factors of knowledge score, age, year of study, parental education, and willingness to donate eyes, results indicated an association between knowledge and willingness to donate (odds ratio [or] = 1.31, 95% confidence interval [ci]: 1.02–1.68; p = 0.038). similarly, the sixthtable 3: perceived medical conditions that make the donor unfit for eye donation, reasons for donating and not donating eyes and source of eye donation knowledge among medical students in saudi arabia (n = 141) perceived medical condition n (%) aids 66 (47) don’t know 65 (46) hepatitis 58 (41) blindness caused by optic nerve or retinal disease 44 (31) active syphilis 35 (25) acute viral encephalitis 34 (24) active meningitis 33 (23) rabies 27 (19) acute septicaemia 27 (19) acute leukaemia 26 (18) no restrictions 3 (2) apparent reason for corneal donation providing vision to a blind person 66 (47) cause as noble as others 59 (42) financial benefits 45 (32) eyes donated by a relative or friend 11 (8) other 5 (4) perceived reason for not donating eyes lack of understanding of benefits to others 78 (55) religious 62 (44) familial pressure 45 (32) myths 34 (24) other 10 (7) source of awareness internet 79 (56) doctors 39 (28) lectures 28 (20) television 18 (13) health awareness campaigns 18 (13) friends 17 (12) family 10 (7) other 10 (7) no sources (don’t know) 19 (13) table 4: association between knowledge of eye donation and parental education in medical students in saudi arabia variables n mean knowledge score ± sd* p value father’s qualification less than high school 11 2.6 ± 1.9 0.69 high school 16 3.3 ± 1.8 college 45 3.4 ± 2.3 postgraduate (masters/ phd) 67 3.2 ± 1.8 mother’s qualification less than high school 26 3.5 ± 1.9 0.84 high school 25 3 ± 2.1 college 56 3.3 ± 2.6 postgraduate (masters/ phd) 32 3.1 ± 1.5 sd = standard deviation; phd = doctor of philosophy. *maximum score = 12. table 5: difference between the knowledge levels of two year-groups of medical students based on number of correct answers to 12 knowledge questions year of study n mean ± sd independent samples t-test t value p value fifth year 71 3.27 ± 1.87 0.30 0.76 final (sixth) year 70 3.17 ± 1.89 knowledge and attitude towards corneal donation saudi medical students’ perspective 110 | squ medical journal, february 2022, volume 22, issue 1 year students’ willingness to pledge eyes was almost four times more than that of the fifth-year students (or = 3.86, 95% ci: 1.49–10.04; p = 0.006). however, no association was found between the father’s and mother’s education levels and willingness to donate [table 6]. discussion this study aimed to evaluate medical students’ level of knowledge regarding and attitude towards corneal donations in saudi arabia. although a corneal donation is considered a noble cause, similar to all types of organ donations, the literature suggests there is a shortage of donated corneas, especially in developing countries.16 in particular, this is due to the lack of knowledge among health professionals, the community and medical students.17 it is the responsibility of all concerned parties to develop strategies for increasing awareness of eye donation in society and clarifying misconceptions to increase the number of eye donors.18 the current study’s participants performed well on only a limited number of questions. for instance, 66 (47%) participants knew that people who die from aids cannot donate their eyes; only 18 (13%) knew that the perfect time for donation is within 2–6 hours after death, while a similar study revealed a higher level of knowledge among students (68.7%).19 moreover, the mean knowledge score of the participants was just 3.24 out of 12, which shows a profound lack of knowledge of eye donation. the internet was the main source of knowledge of eye donation for most of the current study’s participants (56%) while television was the primary source for 41% of the medical students in a tertiary care hospital in bangalore, india.20 expectedly, only 26% of the participants were willing to donate their eyes compared to 40.7% in another international study.3 although lack of knowledge would surely have contributed to a decreased desire to donate, another reason could be cultural differences between saudi arabia and other countries.21 in the current study, participants stated that one of the reasons why eye donations must be encouraged is that this can provide vision to a blind person. furthermore, eye donation was regarded as a ‘noble cause’ by some participants.22 nevertheless, another study revealed that the majority of the study population (93%) believed that pledging corneas will be their way of contributing to society even in death. moreover, the other commonly cited reason was the donors would live in the recipients’ vessels even after death.23 regarding the barriers to eye donation, more than half of the current participants believed that the lack of understanding of its benefits to others was the main reason in saudi arabian society. the literature suggests many hindering factors of eye donation. religious beliefs, cultural factors and familial influence were found to be the major issues for eye donation in developed countries.24 although most of the current participants’ parents had at least a college degree, which signified that most of the participants came from educated backgrounds, the reasons for not donating eyes included religious beliefs and familial pressure to not donate. in a study conducted in a medical college with a similar setting, the most commonly cited reason for not pledging cornea was objections from family.23 the current study did not find any association between the knowledge of eye donation, parental education, and willingness to pledge eye; therefore, a further study to compare the level of parental education and attitude towards eye donation on the largest possible sample is recommended. the current study reported a significant assoc iation of knowledge level and the year of study with a willingness to donate eyes. these results are similar to a study that reported the presence of better knowledge and greater willingness to pledge eyes among medical table 6: relationship between characteristics, correct knowledge scores and willingness to donate cornea among medical students in saudi arabia characteristic or (95% ci) p value knowledge score 1.31 (1.02–1.68) 0.0438 mean age 0.90 (0.69–1.17) 0.418 year of study final (sixth) year 3.86 (1.49–10.04) 0.006 fifth year* 1.00 mother’s qualification less than high school 5.84 (0.51–67.33) 0.157 high school 0.59 (0.09–3.83) 0.578 college 1.67 (0.56–5.01) 0.363 postgraduate (masters/ phd)* 1.00 father’s qualification less than high school 0.33 (0.05–2.19) 0.248 high school 0.85 (0.18–3.89) 0.833 college 0.78 (0.23–2.71) 0.698 postgraduate (masters/ phd)* 1.00 or = odds ratio; ci = confidence interval; phd = doctor of philosophy. *reference group. khalid m. aloudah, abdulaziz a. ataweel, sajida agha and syed waqas h. shah clinical and basic research | 111 students.24 however, another study found a lack of knowledge and willingness among third-year medical students.25 overall, the current participants demonstrated a decreased level of knowledge in many areas compared to other international studies, as the participants performed poorly in the knowledge test.19,25 data from the current study showed that relying only on media to increase the knowledge of medical students regarding eye donation is not sufficient. therefore, including different curative and preventative features of corneal blindness through basic eye health care in the curriculum is greatly needed.25 this will help future physicians understand how they can spread awareness of eye donation among patients, family members and friends. the study was subject to certain limitations. first, this study had a poor response rate and the sample comprised only of male participants. since the study findings are based only on male perspectives, to obtain more accurate and generalisable results, female subjects should be included in future studies. second, as this was a single institution-based study with medical students who have similar demographic characteristics, the sample does not encompass the varied demographic and cultural diversity in saudi arabia’s medical student population. finally, this study was cross-sectional in nature and could therefore not determine the cause and effect of the responses. nevertheless, this study provides information that may be useful for academic institutions and health professionals in developing awareness-raising and community-oriented programmes to improve students’ understanding of the important concept of corneal donation. conclusion the study showed that a large percentage of the participants lacked knowledge of eye donation. while it is important to raise awareness of the benefits of donating eyes, the perceived reasons for not donating eyes must be considered and addressed. to raise awareness of eye donation in society as well as to correct any misconceptions, topics related to eye donation must be included in medical curricula, as it may result in an increase in awareness of eye donations from future physicians and the society they interact with. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n kma conceived the idea and swhs designed and implemented the research. aaa collected the data and handled the technical details. kma, aaa, sa and swhs drafted the manuscript. sa supervised the work, performed the computations and reviewed the manuscript. all authors approved the final version of the manuscript. references 1. thylefors b, négrel ad, pararajasegaram r, dadzie ky. global data on blindness. bull world health organ 1995; 73:115–21. 2. whitcher jp, srinivasan m, upadhyay mp. corneal blindness: a global perspective. bull world health organ 2001; 79:214–21. 3. wang x, jin l, wang j, garrett eh, shuman j, yang k, et al. attitudes and knowledge concerning corneal donation in a population-based sample of urban chinese adults. cornea 2016; 35:1362–7. https://doi.org/10.1097/ico.0000000000000943. 4. singh mm, rahi m, pagare d, ingle gk. medical students’ perception on eye donation in delhi. indian j ophthalmol 2007; 55:49–53. https://doi.org/10.4103/0301-4738.29495. 5. gupta a, jain s, jain t, gupta k. awareness and perception regarding eye donation in students of a nursing college in bangalore. indian j community med 2009; 34:122–5. https:// doi.org/10.4103/0970-0218.51235. 6. nekar ms, lokare l, gokhale sa, godbole m, mulkipatil sy, venketesh m. awareness of eye donation among college students of hubli city, karnataka. int j biomed res 2012; 3:201–4. https://doi.org/10.7439/ijbr.v3i4.415. 7. okoye oi, maduka-okafor fc, eze bi. what does the medical student know about eye donation/corneal transplant? the university of nigeria scenario. west indian med j 2010; 59:41–4. 8. huern sy, yee kcs, rajah js, ponniah mp, sapini mib. knowledge, awareness and attitudes on organ donation among undergraduate medical students in malaysia: an analytical cross-sectional study. british j med med res 2016; 16:1–14. https://doi.org/10.9734/bjmmr/2016/26208. 9. pandey nu, gupta ak, jain ak, koushal v, bindra n, minz c. can eye donation rates be increased in hospitals: a pilot study in a tertiary care hospital in north india? public health 2016; 136:141–3. https://doi.org/10.1016/j.puhe.2015.10.026. 10. burton m, habtamu e, ho d, gower ew. interventions for trachoma trichiasis. cochrane database syst rev 2015; 13:cd004008. https://doi.org/10.1002/14651858.cd004008.pub3. 11. bourne rra, flaxman sr, braithwaite t, cicinelli mv, das a, jonas jb, et al. magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis. lancet glob health 2017; 5:e888–97. https://doi.org/10.1016/s2214-109x(17) 30293-0. 12. al-ghamdi as. adults visual impairment and blindness – an overview of prevalence and causes in saudi arabia. saudi j ophthalmol 2019; 33:374–81. https://doi.org/10.1016/j.sjopt.20 19.10.001. 13. golchet g, carr j, harris mg. why don’t we have enough cornea donors? a literature review and survey. optometry 2000; 71:318–28. https://doi.org/10.1097/ico.0000000000000943 https://doi.org/10.4103/0301-4738.29495 https://doi.org/10.4103/0970-0218.51235 https://doi.org/10.4103/0970-0218.51235 https://doi.org/10.7439/ijbr.v3i4.415 https://doi.org/10.9734/bjmmr/2016/26208 https://doi.org/10.1016/j.puhe.2015.10.026 https://doi.org/10.1002/14651858.cd004008.pub3 https://doi.org/10.1016/s2214-109x(17)30293-0 https://doi.org/10.1016/s2214-109x(17)30293-0 http://v http://v knowledge and attitude towards corneal donation saudi medical students’ perspective 112 | squ medical journal, february 2022, volume 22, issue 1 14. saini js. realistic targets and strategies in eye banking. j ophthalmol 1997; 45:141–2. 15. basnet a, basnet p, lamichhane rs, shrestha p. awareness, knowledge and willingness regarding eye donation among dental students of kist medical college and teaching hospital, lalitpur, nepal. j chitwan med col 2019; 9:47–53. https://doi. org/10.3126/jcmc.v9i2.24533. 16. shrivastava s, shrivastava p, jegadeesh r. awareness about eye donation among students in a medical college in kancheepuram district, tamil nadu. taf prev bull 2014; 13:295–300. https:// doi.org/10.5455/pmb.1-1371712815. 17. anwar asmt, lee jm. a survey on awareness and attitudes toward organ donation among medical professionals, medical students, patients, and relatives in bangladesh. transplant proc 2020; 52:687–94. https://doi.org/10.1016/j.transproceed.2019. 12.045. 18. paraz cm, truong ht, sai dk, cajucom-uy hy, chan cl, kassim sm. knowledge and attitudes toward corneal donation among singaporean youth: a cross-sectional study. eye vis (lond) 2016; 3:17. https://doi.org/10.1186/s40662-016-0049-3. 19. chowdhury rk, dora j, nayak mr, sharma pk, rout jp. aware ness of eye donation among medical students. j evid based med health 2017; 4:5360–3. https://doi.org/10.18410/jebmh/2017/1072. 20. vidushi k, manjunatha s. awareness of eye donation among medical students of tertiary care hospital, bangalore. asian pac j health sci 2015; 2:94–8. https://doi.org/10.21276/apjhs.20 15.2.2.15. 21. dibaba fk, goro kk, wolide ad, fufa fg, garedow aw, tufa be, et al. knowledge, attitude and willingness to donate organ among medical students of jimma university, jimma ethiopia: crosssectional study. bmc public health 2020; 20:799. https://doi. org/10.1186/s12889-020-08931-y. 22. duggal m, brar gs, prasad vs, gupta a. public attitude toward eye donation in northwestern india. transplant proc 2003; 35:19–20. https://doi.org/10.1016/s0041-1345(02)03826-5. 23. singh m, bhardwaj a, ahluwalia sk, saini s, qadri s. eye donation: perception and promoting factors among medical students. indian j community health 2012; 3:175–8. 24. lal b, usgaonkar u, narvekar h, venugopal d. awareness and knowledge on eye donation among allied health sciences, medical, and nursing students in goa. j curr ophthalmol 2018; 30:255–62. https://doi.org/10.1016/j.joco.2018.02.002. 25. foreman j, keel s, van wijngaarden p, bourne ra, wormald r, crowston j, et al. prevalence and causes of visual loss among the indigenous peoples of the world: a systematic review. jama ophthalmol 2018; 136:567–80. https://doi.org/10.1001/ jamaophthalmol.2018.0597. https://doi.org/10.3126/jcmc.v9i2.24533 https://doi.org/10.3126/jcmc.v9i2.24533 https://doi.org/10.5455/pmb.1-1371712815 https://doi.org/10.5455/pmb.1-1371712815 https://doi.org/10.1016/j.transproceed.2019.12.045 https://doi.org/10.1016/j.transproceed.2019.12.045 https://doi.org/10.1186/s40662-016-0049-3 https://doi.org/10.18410/jebmh/2017/1072 https://doi.org/10.21276/apjhs.2015.2.2.15 https://doi.org/10.21276/apjhs.2015.2.2.15 https://doi.org/10.1186/s12889-020-08931-y https://doi.org/10.1186/s12889-020-08931-y https://doi.org/10.1016/s0041-1345(02)03826-5 http://v https://doi.org/10.1001/jamaophthalmol.2018.0597 https://doi.org/10.1001/jamaophthalmol.2018.0597 december 2008 no white pages.indd sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 325-332 sultan qaboos university© submitted 23th february 2008 accepted 29th june 2008 1directorate of health services, ministry of health, musandam governorate, oman; 2eye & ear health care, non-communicable disease control section, department of non-communicable disease control, ministry of health, oman *to whom correspondence should be addressed. email: rajshpp@omantel.net.om satisfaction among expectant mothers with antenatal care services in the musandam region of oman *mohammed ghobashi,1 rajiv khandekar2 abstract objectives: as client feedback is useful to improve health service delivery, assessments should be undertaken periodically. this study aimed to determine the level of satisfaction among expectant mothers visiting health institutions for antenatal care services in the ministry of health, musandam region of oman in 2005. methods: this was a cross sectional survey in a hospital setup. women registered in the antenatal clinics of different health institutions of musandam region were interviewed. arabic speaking investigators in six health institutions of musandum region collected personal profiles, details of different antenatal services offered and responses regarding the satisfaction with these services. the number and percentage of responses were calculated to grade the level of satisfaction. results: eighty-three registered women who visited antenatal clinics in six health institutions were interviewed. the overall satisfaction for antenatal care was of excellent grade in 49 (59% 95% confidence interval 48.5 69.6) participants. sixtyseven (8%) women were happy with services at antenatal clinics mainly because of the attitude of the doctors and nursing staff. the leading causes of dissatisfaction were the laboratory services and overcrowding during morning hours. conclusion: the women attending antenatal care services in musandam were highly satisfied with the services offered; however, there was scope for further improvement. the ministry of health in consultation with the caregivers should focus on improving antenatal services. key words: antenatal care; patient satisfaction; oman مسندم في منطقة في الوالدة قبل ما من خدمات احلوامل رضى عمان سلطنة خانديكار راجيف ، غباشة محمد تهدف ــة الدراس هذه لذلك. دوري تقييم عمل كان من الضروري لذا الصحية، اخلدمات ــني تقدمي حتس في مفيد املراجع رأي أن أخذ امللخص: الهدف: مبا ــة دراس الطريقة: هذه .2005 ــنة س خالل ــندم مس منطقة في لوزارة الصحة الصحية للمراكز املراجعات عند احلوامل الرضى ــتوى مس الى معرفة ــتة س في يتقنون اللغة العربية باحثون جمع ــندم. مس منطقة في اتلفة املراجعات للمراكزالصحية احلوامل األمهات مقابلة طريق عن مقطعية والنسب ألجابات األرقام ــاب حس مت اخلدمات. عن تلك رضاهن ــتوى ومس لهن املقدمة باملراجعات واخلدمات املتعلقة املعلومات ــندم مبس صحية مراكز ــاركة 49 مش ــنوى الرضى ممتازا في مس كان ــندم. مبس صحية مراكز ــتة في س ــجلة مس امرأة وثمانني ثالث من املعلومات جمع النتائج: مت احلوامل. خالل فترة الصحية املراكز اخلدمات الصحية في لتقدمي ــرورا س أظهرن (81%) امرأة ــتون وس ــبع س .(69.6 48.5 %95 هي الثقة (%59 فترة اخلالصة: أظهرت الصباح. ــاعات س خالل واالزدحام اتبرات خدمات هو الرضى لعدم ــي الرئيس ــبب الس كان واملمرضات. األطباء ملواقف احلمل، خاصة ــني لتحس مجال هناك لكن ــندم، منطقة مس في تلك املراكز قبل من املقدمة رضاهن باخلدمات باحلوامل اخلاصة الصحية للمراكز املراجعات ــاء النس احلوامل. للنساء اخلدمات حتسني على املراكزوالتركيز تلك في املعنيني الصحة استشارة وزارة على اخلدمات. تلك عمان. املرضى، رضى احلوامل، الكلمات: رعاية مفتاح c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • reviewing the client’s perspective should be an integral part of health programme management. • client satisfaction related to antenatal care services in the musandam region of oman was very good. • feedback of clients should be complemented by direct observations of process and resource evaluation. 326 m o h a m m e d g h o b a s h i a n d r a j i v k h a n d e k a r client satisfaction is the litmus test that enables health programmes to assess the impact of their services; hence, it is an integral part of the ‘quality assurance process’ of health delivery.1 the satisfaction of female clients of antenatal care services has been studied in the past in other countries.2-5 dowswell et al.6 performed a meta-analysis in 2001 to review the work of different researchers on this subject and suggested that more information is still needed. apart from a thesis of a phd student,7 no such feedback has been obtained in the past in oman. our study focuses on a remote area of oman, which has a predominantly muslim health clientele. analysing satisfaction levels with the free services offered in a remote region of a middle eastern country is a useful way to improve the services and can provide a model for others to follow. musandam is the northern most region of oman. as this region is surrounded by part of the united arab emirates, access to the rest of the regions of oman is difficult. the oman ministry of health (moh) provides health services to the 28,378 residents of the region. there are three hospitals and three primary health centres.7 qualified medical doctors and nursing staff provide antenatal care services to expectant mothers in these institutions. staff members were trained in different countries like india, egypt, pakistan and iraq and many of them do not speak arabic. obstetricians provide high quality antenatal, natal and postnatal care at the regional hospital and one local hospital. the 6,136 women aged 15 to 49 years of age in musandam could use these services. the health services charge us $ 2.5 as a case fee. the terrain is so difficult and diverse that the services are offered either by boats or helicopter in some areas of the region. complicated cases are transported to the tertiary care unit situated nearly 500 kilometres away in muscat. ambulances for such critical cases have to travel over mountainous roads, thus imposing unavoidable but definite risks on the patients. the national coverage of antenatal services in oman is more than 99%. around 97.5% of the expectant mothers give birth in the institutions while the rest deliver at homes under the supervision of a trained nurse.8, 9 in 2005, the staff of the moh maternal and child health care program evaluated the satisfaction of expectant mothers who visited the health institutes of musandam region. the authors here present the outcome of this study and propose ways to improve the services. following this study, the mother and child health program of oman was encouraged to undertake similar surveys in other regions. m e t h o d s this was a cross-sectional study approved by the ethical committee of the moh of the musandam region. as no biological product was taken solely for the purpose of research and the study was conducted within the health institutions as part of operational research to improve health care systems, we obtained verbal instead of written consent from the participants. the expectant mothers visiting health institutions of the region between 3 and 9 january 2005 were enrolled in the study. to represent nearly 423 annual deliveries taking place in the region, we selected a sample for our study. we assumed that an excellent grade of satisfaction for the antenatal care services would be 80% of clients. to achieve 90% power and 95% confidence in• communicating with clients in their native language could be the key to satisfying their antenatal service needs. • presence of community support group members or arabic speaking health staff improves cooperation of participants in a study. applications to patient care • health staff should communicate effectively with expectant mothers during their antenatal visits, as this is key to improving their satisfaction. • if possible, waiting time for laboratory tests results should be reduced and clients informed about the normal procedure and time needed for such tests. • the process of health education for expectant mothers in musandam should be reviewed and made more client-friendly. 327 s at i s fa c t i o n a m o n g e x p e c ta n t m o t h e r s w i t h a n t e n ata l c a r e s e r v i c e s i n t h e m u s a n d a m r e g i o n o f o m a n table 1: characteristics of the study population, musandam region, oman no. % age group <20 4 4.8 20 to 24 28 33.7 25 to 29 26 31.3 30 to 34 17 20.5 35 and more 8 9.6 wilayat khasab 50 60.2 deba 23 27.7 bukha 8 9.6 madaha 2 2.4 nationality omani 66 79.5 non-omani 17 20.5 literacy level illiterate 13 15.7 can read & write 4 4.8 school education 51 61.4 higher education 15 18.1 babies in past aborted 25 30.1 no babies 18 21.7 1 to 3 babies 47 56.6 4 or more babies 18 21.7 married life (n = 76) <1 year 10 12.0 1 to 4.9 years 19 22.9 5 to 9.9 years 15 18.1 10 and more years 33 39.8 occupation home maker 68 81.9 teacher 7 8.4 staff nurse 1 1.2 x-ray technician 1 1.2 in air force 1 1.2 head teacher 1 1.2 s. nutrition 1 1.2 missing 3 3.6 pregnancy stage 1st trimester 12 14.5 2nd trimester 21 25.3 3rd trimester 50 60.2 total 83 328 m o h a m m e d g h o b a s h i a n d r a j i v k h a n d e k a r terval of the study with a 10% acceptable error of margin, we needed to interview 78 clients. to compensate for possible refusals, we included five more women. in fact, in the field part of our study, all enrolled agreed to participate thus the final sample was 83 women. the participants were selected in series in a health institution on a randomly selected day and were those coming for an antenatal visit. first, we randomly selected the health institution. then we selected one day from five working days of the week to visit each institution. on that day, we enrolled the women in sequence (meaning pregnant women visiting the clinic one after another as they presented on the day that was randomly fixed for conducting the study in that institution.), as per the number required for that health institution. the numbers interviewed per health institution were based on the proportion of females in the 20 to 40 years age group in that catchment area. arabic speaking omani nursing staff and medical orderlies were our study staff. the community support group (csg) members who were omani nationals were also involved as they were known to most of the participants and hence we could reduce the risk of the impact of involving health staff in the study. these csg members assured the participants that negative responses would not affect the service being offered to them. they were trained in the study methodology. a pilot study to test the methods and the questionnaire was carried out in khasab hospital, musandam, prior to the field work. this helped us in fine-tuning the questions to suit local arabic words as well as standardising the method of conducting the interview. during the study period, the staff visited the female waiting area of the antenatal clinics. they explained the purpose of the study to waiting expectant mothers and obtained their verbal consent to participate. their replies were noted. the response of the person accompanying the patient was not noted, but also considered as additional feedback for administrators. the interview was conducted in a separate room. the available resources, personal care given by the attending staff and the time spent at six places namely reception, the nursing station, doctor’s consultation room, laboratory, counselling and pharmacy were covered in the interview. a close-ended questionnaire was prepared to collect responses. each question had five grades of response. we calculated cumulative points by summing up the responses addressing the same group of questions. to minimize the social desirability bias, we explained the purpose of the survey, involved the csg members in the arabic translation, explained the questions and options for responses, especially if the health staff was non-arabic speaking, and strictly followed the cultural and social norms. the identity of the participants was de-linked from the responses. the person analysing the data was unaware of the study area and the names of the participants. the data was computed using epi data. 10 the frequency and percentage proportions of the important outcomes were calculated using the statistical package for social studies (spss), version 9. we used the parametric method of univariate analysis. each strong positive response was given +2 points. a positive response was given +1 point. an equivocal response was awarded ‘0’ score. a negative answer was considered as poor and was given ‘-1’ score. severe dissatisfaction was graded as ‘very poor’ and given a ‘-2’ score. the overall satisfaction of the expectant mother was graded into ‘excellent’, ‘good’, ‘poor’ and ‘very poor’ categories by using the 25% percentile of the sum of response for different categories of antenatal services. topic level of satisfaction satisfaction with excellent good poor very poor clinic 62 21 0 0 attending doctor 67 16 0 0 attending nurse/midwife 72 11 0 0 waiting time 11 62 8 2 laboratory services 12 11 0 0 pharmacy support 0 81 2 0 total 49 34 0 0 note: the option ‘cannot say’ was not ticked by any participant for any of the questions table 2: satisfaction with different components of antenatal care in the musandam region of oman 329 s at i s fa c t i o n a m o n g e x p e c ta n t m o t h e r s w i t h a n t e n ata l c a r e s e r v i c e s i n t h e m u s a n d a m r e g i o n o f o m a n r e s u l t s eighty-three participants were sequentially enrolled and interviewed in our study. their profile suggests that they were educated and distributed in different wilayats (districts) of musandam region [table 1]. the distribution of 15 to 45 years old participants in relation to the population in different wilayats of musundam region was calculated. the proportion of the target population in khasab, daba, bukha, madah wilayats was 64.6%, 18.3%, 9.4% and 7.7% respectively. the population of madah wilayyat was underrepresented in our study. of the 17 non-omani participants, seven were muslim while five each were of hindu and christian religion. all 66 omani females were muslims. the levels of satisfaction for different components of the antenatal care service delivery were calculated [table 2]. forty-nine respondents (59%) reported an ‘excellent’ grade of overall satisfaction. the rest of the participants reported ‘very good’ levels of satisfaction. waiting times during the visit and the support in the pharmacy fell short of clients’ expectations. the waiting time was counted and compared with the response of the client. the leading causes of satisfaction are given in table 3. the positive behaviour of the health staff and the warm reception mothers received in the antenatal care unit were the most satisfying parts of the services. weakness in the laboratory services, long waiting periods in the clinics, especially during the morning hours, and non-availability of arabic speaking doctors were the areas for improvement [table 4]. we considered waiting time after the registration of a new/old case. a ‘very poor’ grade of satisfaction was considered to be a weak area of antenatal services. the dissatisfaction expressed mainly related to the process of imparting health education (commitment, availability of time and language barrier) and not to the availability of health education material. d i s c u s s i o n the importance of client satisfaction and feedback has been highlighted in the literature,10, 11 but scientists have used different methods of assessing patient satisfaction. noting observations, evaluating available resources, reviewing the attendance with time and even monitoring the time spent at different places of antenatal care are different methods used. in our study, we recorded client’s perception about overall care and also different components of the antenatal care services. each method has advantages and disadvantages. direct observations are more specific and reliable but they do not incorporate clients’ perspectives. feedback from clients is collected only through suggestion boxes in many institutions, but they may mainly contain complaints and rarely positive experiences. even these complaints are written often without proper understanding of the limitations of the providers; hence, the outcomes of such studies should be linked to the review of available resources before interpreting them. our study showed that clients, in general, have a positive opinion of the antenatal care services offered in the musandam region. this matched with the observations of yan t et al.12 and hildingsson et al. 13 in the former study, the participants were pregnant women with foetal anomalies in a province of canada, while the later study covered three european countries. interaction of caregivers with the clients has always been the key to high satisfaction with the service. 14, 15 in our study, an ‘excellent’ grade of satisfaction for subcomponents of health staff behaviour confirms this observation. doctors were considered ideal for imparting technical knowledge, providing emotional topic number % 95% confidence interval reception by health staff is good 47 56.6 45.9-67.3 clear instructions 7 8.4 2.4-14.4 medical orderly available with doctor in anc 5 6.0 0.9-11.1 put number on cards 7 8.4 2.4-14.4 good, clean clinic 8 9.6 3.3-15.9 good clinic arrangement 4 4.8 0.2-9.4 good laboratory services 2 2.4 0.0-5.7 satisfied with service 6 7.2 1.6-12.8 timely work 1 1.2 0.0-3.5 table 3: causes of satisfaction with antenatal care in the musandam region 330 m o h a m m e d g h o b a s h i a n d r a j i v k h a n d e k a r support and assisting in decision making, although female nurses and midwifes were more acceptable as they can reassure pregnant women and alleviate their anxiety. 15 health education and communication in the local language are stressed to improve client satisfaction. 14, 16 in our study, the presence of arabic speaking csg members helped us in overcoming the language barrier between service providers and clients. the dissatisfaction with the laboratory services and facilities and the long waiting period for antenatal care, especially in the morning hours, were noted in our study. we did not note the time taken waiting for a laboratory test and the waiting time for the test results; hence we are not sure if the dissatisfaction of clients about the length of waiting time was genuine or whether it was due to improper counselling about time needed for laboratory procedures. further studies should therefore explore this issue and propose corrective measures if required. these issues were also the reasons for low satisfaction in a study covering four countries including saudi arabia (a neighbouring country of the present study area). 17 few participants in our study were practising a religion other than the muslim one. in addition, we had not planned to study the influence of religion on the main outcomes. hence, we could not associate the client’s religion to the level of satisfaction for antenatal care in our study. tsianakas et al. has reported that health providers’ lack of cultural appreciation was one of the reasons for dissatisfaction among women of islamic background in australia. 18 thus, if antenatal care is delivered with specific consideration to the religion commonly practiced in this area, it will be more acceptable. fifty participants were in their third trimester of pregnancy. in antenatal services, women visit more frequently during this period compared to the earlier trimesters. their response could be a cumulative one of their experience of services not only for the current visit but also of the earlier visits. in such circumstances, high satisfaction is suggestive of availability of satisfactory antenatal services for at least one year in the study area. due to the possibility of misclassification bias, we did not study differential satisfaction in relation to the trimester of pregnancy. sixty-six females (79.5%) had school education in our study. the literate participants are likely to be more aware of newer developments in the field of antenatal care and their expectations are also likely to be higher compared to the illiterate females. in view of the high literacy rate among the participants, the high satisfaction rate for the antenatal care services in our study is worth noting. waiting time has been reported to influence the satisfaction of clients. 5, 17 in our study also, this factor was linked to dissatisfaction with the services; however, it did not match with the time noted independently by field staff. although we did not have any benchmark for the time required at different stages of the antenatal care, grievances about delays, especially in laboratory tests should be taken into consideration in the future. communication by providers to with the women during antenatal visits plays an important role.12, 15 three out of eight doctors were able to speak arabic with patients in our study area. the clients’ stress on the need for arabic speaking doctors and it being one topic number % 95% confidence interval laboratory services 30 36.1 25.8 46.4 crowding clinic in the morning 16 19.3 10.8 27.8 non-availability of arabic speaking doctor 12 14.5 6.9 22.1 health education services not good 6 7.2 1.6 12.8 no explanation of antenatal clinic 6 7.2 1.6 12.8 not listening to complaints of pregnant women 1 1.2 0 3.5 unavailability of gynaecologist 5 6.0 0.9 11.1 long waiting time 5 6.0 0.9 11.1 no sonar test 5 6.0 0.9 11.1 table 4: causes of dissatisfaction among pregnant women, musandam region 331 s at i s fa c t i o n a m o n g e x p e c ta n t m o t h e r s w i t h a n t e n ata l c a r e s e r v i c e s i n t h e m u s a n d a m r e g i o n o f o m a n of the main reasons for dissatisfaction, suggest that language could be a possible barrier in communication between doctors and expectant mothers in our study area. our staff belonged to the ministry of health, the only health service provider in this remote region of oman. the possibility of social desirability bias cannot be ruled out entirely in such circumstances, but the community’s willingness to voice dissatisfaction about deficiencies in governmental services is often observed in hospitals. they give written complaints to the administrators or raise the issue in the majlis al shura (national parliament) through the local representatives. in such a situation, fear of compromised antenatal care is unlikely to be the cause of the high proportion of ‘excellent’ scores in our study. a postal response approach for collecting information has less risk of social desirability bias and was used by brown et al.19 however, such an approach was not feasible in our study as the terrain in the musandam region is very difficult and the community is well accustomed to verbal surveys at their health institutions mainly for estimating the magnitude of key diseases. as our sample was selected by sequential methods all clients that attended the antenatal services during 2005 did not have an opportunity to participate in the study. hence the outcome of the present survey should be generalised with caution for all the expectant mothers of the region. c o n c l u s i o n s the women attending antenatal care services in musandam were highly satisfied with the services offered, but there is scope for further improvement. the ministry of health in consultation with the caregivers should focus on improving antenatal services. a c k n ow l e d g me n ts this subject was the thesis of dr. m ghobashi for his master’s degree in hospital administration. we thank the health administrators of the region of musandam and the maternal and child health care program of oman for its support of the study. we appreciate the contribution of community support group members and of the dedicated nursing staff of the musandam health institutions. we thank the participating women for their overwhelming responses. mr saleh al harby assisted in data entry and statistical analysis. r e f e r e n c e s 1. ivanov ll, flynn bc. utilization and satisfaction with prenatal care services. west j nurs res 1999; 21:372386. 2. seclen-palacin ja, benavides b, jacoby e, velasquez a, watanabe e. is there a link between continuous quality improvement programs and health service users’ satisfaction with prenatal care? an experience in peruvian hospitals. rev panam salud public. 2004; 16:149-157. 3. luyben ag, fleming ve. women’s needs from antenatal care in three european countries. midwifery 2005; 21:212-223. 4. uzochukwu bs, onwujekwe oe, akpala co. community satisfaction with the quality of maternal and child health services in southeast nigeria. east afr med j 2004; 81:293-299. 5. bronfman-pertzovsky mn, lopez-moreno s, magisrodriguez c, moreno-altamirano a, rutstein s. prenatal care at the first level of care: characteristics of providers that affect users’ satisfaction. salud publica mex 2003; 45:445-454. 6. dowswell t, renfrew mj, gregson b, hewison j. a review of the literature on women’s views on their maternity care in the community in the uk. midwifery 2001; 17:194-202. 7. al-mandhari a. quality of phc services in al-dhahira region. phd thesis. liverpool university, uk, 2002. 8. director general of health planning, ministry of health, oman. health status indicators. in: annual health report year 2004. muscat: al zahra printers, 2005. p. 1-4 and 2-2. 9. ministry of health, oman, unicef & unfpa. care during delivery. in: national health survey 2000 reproductive health study. vol. 2. muscat: ministry of health, 2000. p. 96. 10. lauritsen jm, ed. epidata data entry, data management and basic statistical analysis system. odense, denmark: epidata association, 2000-2006. 11. wong st, korenbrot cc, stewart al. consumer assessment of the quality of interpersonal processes of prenatal care among ethnically diverse low-income women: development of a new measure. women’s health issues 2004; 14:118-129. 12. yan t, wen sw, walker mc, beduz ma, kim pc. fetal alert network: women’s satisfaction with the current state of prenatal care for pregnancies complicated by fetal anomalies: a survey of five academic perinatal units in ontario. j obstet gynaecol can 2007; 29:308-314. 13. hildingsson i, rådestad i. swedish women’s satisfaction with medical and emotional aspects of antenatal care. j adv nurs 2005; 52:239-249. 14. tandon sd, parillo km, keefer m. hispanic women’s perceptions of patient-centeredness during prenatal care: a mixed-method study. birth 2005; 32:312-317. 15. douglas s, cervin c, bower kn. what women expect of family physicians as maternity care providers. can fam physician 2007 may; 53:874-879. 16. büchi s, cignacco e, lüthi d, spirig r. needs and expectations of tamil women attending an antenatal care department at a swiss university hospital. pflege 2006; 19:295-302. 17. nigenda g, langer a, kuchaisit c, romero m, rojas g, al-osimy m, villar j, et al. women’s opinions on antenatal care in developing countries: results of a study in cuba, thailand, saudi arabia and argentina. bmc public health. 2003; 20:3-17. 18. tsianakas v, liamputtong p. what women from an islamic background in australia say about care in pregnancy and prenatal testing. midwifery 2002; 18:25-34. 19. brown sj, bruinsma f. future directions for victoria’s public maternity services: is this “what women want”? aust health rev 2006; 30:56-64. 332 m o h a m m e d g h o b a s h i a n d r a j i v k h a n d e k a r 2 1department of studies and research, directorate general of planning and studies, ministry of health, muscat, oman; 2buraimi polyclinic, directorate general of health services, ministry of health, muscat, oman; 3department of biostatistics, arab open university, khaitan, kuwait *corresponding author’s e-mail: challenger.777@hotmail.com women’s knowledge of cervical cancer a cross-sectional study in al buraimi governorate, oman *aisha n. al-saadi,1 aisha h. al-muqbali,2 eihab dawi3 sultan qaboos university med j, august 2021, vol. 20, iss. 3, pp. 450–456, epub. 29 aug 21 submitted 8 jul 20 revision req. 6 sep 20; revision recd. 20 oct 20 accepted 19 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.022 clinical & basic research abstract: objectives: this study aimed to assess knowledge of cervical cancer and its prevention among omani women aged 20–65 years. methods: this cross-sectional study took place across eight primary healthcare institutions in al buraimi governorate, oman, between november 2018 and february 2019. it was carried out on the basis of a predesigned, validated and self-administered questionnaire containing 55 questions. results: data from 791 completed questionnaires were included in the final analysis, which represents a response rate of 79.1%. the results indicated that 86.7% of surveyed women had previously heard of cervical cancer and 13.0% expected this disease to affect them in the future. the results also showed that women were less aware of the association between the human papillomavirus (hpv) and cervical cancer (24.7%). the participants considered the hpv infection and initiation of sexual intercourse below 17 years of age as the lowest risks associated with cervical cancer. moreover, 63.8% of the participants were unaware of the availability of a vaccination ‘against hpv-related cervical cancer’ and many respondents were unaware of a pap test. those women aged over 30 years, married and with a high level of education were more likely to be aware of cervical cancer. conclusion: generally, there was inadequate knowledge and awareness of cervical cancer among women aged 20–65 years. young women aged 20–30 years showed relatively lesser knowledge of cervical cancer as compared to their older counterparts. thus, concerted efforts are needed to promote such awareness among women in oman. keywords: cervical cancer; risk factor; human papillomavirus; vaccine; pap test. advances in knowledge this study provides a broad overview of the level of knowledge of cervical cancer among women aged 20 years and above in al buraimi governorate, oman. application to patient care the results of this study help determine the existing knowledge gaps. this is of great importance for the planning of a cervical cancer prevention programme or awareness-raising campaigns on this subject in oman. it is imperative to increase awareness concerning cervical cancer, which is the world’s fourth most common cancer among women.1 in the less developed regions world, cervical cancer ranks as the second most common cancer among women. in 2018 alone, globally, about 570,000 were diagnosed with cervical cancer and about 311,000 deaths were attributed to it.1 it is also noteworthy that about 85% of the women dying from cervical cancer belong to low and middle-income countries.2 the incidence of cancer in oman is rapidly on the rise.3,4 the country’s figures concerning current incidence of and mortality due to cervical cancer suggest that, 77 women are annually diagnosed with the disease and 41 die from it.5 in oman, cervical cancer ranks third among the most common cancers affecting women aged 15–44 years; its crude incidence rate is 4.7 and mortality rate is 2.5.5 almost all the cases of cervical cancer are related to infection with the human papillomavirus (hpv) that is sexually transmitted.6 a recent study carried out in oman found that the prevalence of hpv in the country was 17.8%.7 cervical cancer is fatal once it reaches the invasive stages but preventable if detected early and adequately treated. vaccination and cytological screening with pap smear are important measures for preventing cervical cancer. the incidence of cervical cancer and the death rate have decreased in developed countries over the last four decades mainly due to improved awareness, better screening and better preventive approaches.8–11 the incidence of cervical cancer in the extended middle east and north africa, including oman, is low. however, age-standardised cervical cancer mortality is disproportionately high relative to that in the western countries, which points to possible barriers to screening and treatment.12 a lack of adequate knowledge about the disease was found to be one of the key barriers at the individual level.13 in oman, only one study has been conducted, to date, to estimate the level of awareness of cervical cancer among women.14 however, the study was restricted to women living in a city, and data were collected from a single hospital. the reported results https://creativecommons.org/licenses/by-nd/4.0/ aisha n. al-saadi, aisha h. al-muqbali and eihab dawi clinical and basic research | 451 indicated a low level of knowledge of cervical cancer among women. studies carried out in other gulf cooperation council (gcc) countries have reached similar findings.15,16 to start with, current data on the level of knowledge of cervical cancer among women in oman need to be collected. this will help in determining knowledge gaps and creating effective programmes for raising public awareness about this disease. the data can also help in organising focused prevention campaigns. therefore, this study aimed to assess the knowledge concerning various aspects of cervical cancer among omani women, aged 20 years and above, visiting outpatient primary care services in the al buraimi governorate. the recommended screening ages for cervical cancer is 25–65. assessing the level of knowledge at a younger age is imperative because of the relatively lower ages of marriage and childbirth in oman.17 methods this analytical cross-sectional survey was carried out between november 2018 and february 2019. a proportional stratified sampling technique was used to access approximately 5% of women aged 20–65 years, living in the catchment area of the eight primary healthcare institutions in al buraimi governorate. the required sample size for the study was calculated using raosoft® (raosoft, inc., seattle, washington, usa). the final sample size was 1,000, assuming a 95% confidence level and a 3% margin of error. a proportional size approach was implemented to calculate the sample size from each healthcare institution. the women attending primary healthcare centres for any reason during the said period of data collection were approached to participate in this study if they met the following inclusion criteria: omani women who were aged 20 years and above, those who did not have cervical cancer and those who could understand the consent form and answer the questionnaire in writing. thus, those women who had been diagnosed with cervical cancer and had undergone a hysterectomy were excluded from the study. pregnant and lactating women were not excluded from the study, as the aim was to assess the knowledge of all women—single or married. an arabic questionnaire was designed specifically for this study. many validated tools covering a wider spectrum of knowledge assessment relating to cervical cancer were reviewed.18–20 the questionnaire was initially developed in the english language based on the reviewed literature and then translated into arabic. a pilot study was conducted among 70 women in june 2018. the questionnaire contained 55 general questions to assess women’s knowledge of cervical cancer covering the following three aspects: 1) general knowledge; 2) factors associated with the occurrence of the disease; 3) preventive measures. all sections included multiple choice questions on qualitative data, except for those related to the section on risk factors assessment that used a six-point likert scale (0 indicating no relationship and 5 indicating a very strong relationship between risk factors and occurrence of cervical cancer).20 the cronbach alpha coefficient was 0.940 for the whole questionnaire and ranged between 0.57 and 0.93 for each of the sections. the test-retest reliability was examined in a subsample (r = 0.769, p <0.001).21 a total of 791 responses were received, which represented a response rate of 79.1%. the convenience sampling method was used to recruit the participants. the data were coded and entered into a computer using statistical package for social sciences (spss), version 25.0 (ibm corp., chicago, illinois, usa). descriptive statistics were used to describe the participants’ characteristics, scores on general knowledge, knowledge of risk factors of cervical cancer and knowledge of primary and secondary prevention. a bivariate analysis using the chi-squared and fischer’s exact tests was also employed to assess the correlation of demographic factors concerning the participants with their knowledge of cervical cancer prevention. p value was used to present the results at 95% confidence intervals. p <0.05 indicated significance. this study was approved by the research and ethical review and approval committee of the ministry of health. the questionnaire was accompanied by a consent form and a cover letter with the latter explaining the study’s purpose and letting the respondents know about their participation being voluntary and their anonymity being maintained. results the sociodemographic data of the 791 respondents participating in the study (79.1%) have been presented in table 1 along with their replies to questions on general knowledge of cervical cancer in table 2. concerning the association of cervical cancer with an infection, two-thirds of the women (n = 320; 40.5%) reported that they did not know of any association, while 276 (34.8%) stated that cervical cancer was not associated with an(y) infection. when the respondents were asked whether there was ‘a method of significantly reducing the risk of cervical women’s knowledge of cervical cancer a cross-sectional study in al buraimi governorate, oman 452 | squ medical journal, august 2021, volume 21, issue 3 cancer’, 447 participants (56.5%) responded positively, while 293 (37.1%) did not know whether there was an effective method. the women’s knowledge regarding the association of 17 factors with the occurrence of cervical cancer was assessed in the second section of the questionnaire. two major aetiological factors table 1: sociodemographic characteristics of female participants from eight primary healthcare institutions in al buraimi governorate, oman (n = 791) characteristics n (%) age (in years) 20–30 310 (39.2) 31–40 380 (48.0) 41–50 93 (11.8) above 50 8 (1) educational level no education 5 (0.6) primary 37 (4.7) secondary 327 (41.3) tertiary 422 (53.4) marital status single 100 (12.7) married 663 (83.8) other (divorced or widow) 28 (3.5) work status working 306 (38.7) not working 485 (61.3) table 2: general knowledge about the subject of cervical cancer among 791 female participants from eight primary healthcare institutions in al buraimi governorate, oman general knowledge about cervical cancer n (%) yes no do not know have you ever heard of cervical cancer? 686 (86.7) 88 (11.1) 17 (2.1) cervical cancer leading ultimately to death? 576 (72.8) 60 (7.6) 155 (19.6) could cervical cancer be associated with another infection? 195 (24.7) 276 (34.8) 320 (40.5) is there any effective way of significantly reducing the risks of this disease? 447 (56.5) 51 (6.4) 293 (37.1) has any one of your relatives suffered from this disease? 106 (13.4) 609 (77.0) 76 (9.6) do you believe you could be affected by this disease in future? 103 (13.0) 219 (27.7) 469 (59.3) table 3: knowledge of the relationship between various risk factors and the likelihood of cervical cancer occurrence among 791 female participants from eight primary healthcare insti tutions in al buraimi governorate, oman risk factors n (%) no relationship moderate very strong relationship young age 500 (63.2) 193 (24.4) 98 (12.4) genetic factors (e.g. cervical cancer in a close family member) 288 (36.4) 197 (24.9) 306 (38.7) human papillomavirus infection 354 (44.8) 203 (25.6) 234 (29.6) human immunodef iciency virus infection 308 (38.9) 182 (23.0) 301 (38.1) younger than 17 years at first fullterm pregnancy 407 (51.5) 185 (23.3) 199 (25.2) multiple sexual partners 257 (32.5) 149 (18.8) 385 (48.7) history of sexually transmitted diseases 269 (34.0) 178 (22.5) 344 (43.5) alcohol abuse 286 (36.2) 201 (25.4) 304 (38.4) smoking or exposure to smoke 309 (39.1) 176 (22.2) 306 (38.7) miscarriages and abortions 266 (33.6) 238 (30.1) 287 (36.3) high parity 334 (42.3) 210 (26.5) 247 (31.2) using birth control pills for a long time (five or more years) 429 (54.2) 187 (23.6) 175 (22.2) use of condoms 369 (46.6) 231 (29.2) 191 (24.2) early menarche 254 (32.1) 259 (32.7) 278 (35.2) breastfeeding 431 (54.5) 187 (23.6) 173 (21.9) use of drugs or psychoactive substances 316 (40.0) 235 (29.7) 240 (30.3) using public swimming pools 317 (40.1) 224 (28.3) 250 (31.6) aisha n. al-saadi, aisha h. al-muqbali and eihab dawi clinical and basic research | 453 were given a higher percentage by the respondents as having ‘no relationship’ with the incidence of cervical cancer. these factors are as follows: hpv infection (44.8%) and being younger than 17 at first full-term pregnancy (51.5%) [table 3]. more than three-fifths of the women who participated in the survey (n = 505, 63.8%) responded negatively, i.e. ‘no’, when asked, ‘have you ever heard of a vaccine that reduces cervical cancer risk?’ [table 4] a majority of the respondents (n = 595, 75.2%) did not know that the risk of cervical cancer development can be reduced by hpv vaccine. only 5.3% answered correctly about the best age for this vaccination. a majority of the respondents (n = 584, 73.8%) agreed to be vaccinated if the vaccine was available and agreed to the vaccine being included in the national immunisation programme for girls in oman (n = 559, 70.7%, p <0.000) [table 4]. over half of the participants (58.0%) were aware that cervical cancer can affect women even with a lack of symptoms in the genital areas. to a question in the survey asking how old women must be ‘to undergo cytological examination (pap smear test)’, three-fifths of the women (n = 481, 60.8%) replied that women would undergo the pap test when they were between 20 and 65 years of age; however, 35.8% (n = 283) reported that this test should be done between 1 and 3 years after marriage. the participants’ knowledge of distressing symptoms and cytological examination have been presented in table 5. the knowledge scores were combined, and according to their mean values, they were categorised as poor knowledge or good knowledge. the bivariate table 4: knowledge of primary prevention of cervical cancer development among 791 female participants from eight primary healthcare institutions in al buraimi governorate, oman lifestyle n (%) yes no do not know antioxidant-rich diet 547 (69.2) 70 (8.8) 174 (22.0) regular physical exercise 645 (81.5) 47 (5.9) 99 (12.6) avoiding highly processed food 531 (67.2) 77 (9.7) 183 (23.1) restraining from casual sex 665 (84.0) 55 (7.0) 71 (9.0) hpv vaccine have you ever heard of a vaccine that reduces cervical cancer risk? 167 (21.1) 505 (63.8) 119 (15.0) does hpv vaccine reduce the development of cervical cancer in a woman? 66 (8.3) 130 (16.4) 595 (75.2) have you ever been vaccinated (hpv vaccine)? 48 (6.1) 635 (80.3) 108 (13.6) would you accept being vaccinated if the vaccine was available? 584 (73.8) 145 (18.3) 62 (7.8) would you agree to include this vaccine in the national immunisation programme for girls in oman? 559 (70.7) 66 (8.3) 166 (21.0) what is the best age to get vaccinated? age (in years) n (%) ≤ 8 187 (23.6) 9–13 61 (7.7) 14–26 42 (5.3) 19–25 22 (2.8) >26 479 (60.6) table 5: the awareness of symptoms and cytological exam ination related to cervical cancer among 791 female partic ipants from eight primary healthcare institutions in al buraimi governorate, oman distressing symptoms n (%) yes no no genital-area symptoms 459 (58.0) 332 (42.0) excessive vaginal bleeding between periods 672 (85.0) 119 (15.0) bloodstained mucus 662 (58.0) 129 (42.0) postcoital bleeding 564 (71.3) 227 (28.7) cytological examination responses (in years) n (%) at what age will females undergo cytological examination in oman (pap smear test)? 17–25 203 (25.7) 20–65 481 (60.8) ≥ 60 107 (13.5) after what period of time should women undergo pap smear test (after marriage and initiation of sexual activity)? (in years) <1 253 (32.0) 1–3 283 (35.8) 4–6 98 (12.4) >6 157 (19.8) how regularly should women be obliged to take the test? every year 450 (56.9) once every three years 212 (26.8) once every five years 66 (8.3) once every 10 years 46 (5.8) once only 17 (2.1) women’s knowledge of cervical cancer a cross-sectional study in al buraimi governorate, oman 454 | squ medical journal, august 2021, volume 21, issue 3 analysis using the chi-squared and fischer’s exact tests revealed that sociodemographic factors were significantly associated with the knowledge of cervical cancer prevention [table 6]. the participants’ age is significantly associated with the knowledge of cervical cancer prevention (χ2 = 10.78, df = 3, p <0.05). the omani women between 20 and 30 years of age were more likely to have poor knowledge. furthermore, a significant statistical association was found between their marital status and knowledge of cervical cancer prevention (χ2 = 6.41, df = 2, p <0.05) and single women were more likely to have poor knowledge. discussion there is limited information in oman regarding the level of knowledge and awareness of cervical cancer. a majority of women participating in this study poorly linked the relationship between hpv infection and occurrence of cervical cancer, which is considered to be the most important aetiological factor for the latter.22 similar results were obtained from studies conducted in other countries.23,24 therefore, it is important to educate women about the role of hpv in the aetiology of cervical cancer and the prevention of this cancer. a well-planned public health campaign to raise awareness will go a long way. it must be noted, however, that the impact that such a campaign would have would largely depend on how well it reaches out to and involves the target group.25 regarding the hpv vaccine, only 21.1% of the participants knew about the vaccine and 5.3% correctly answered the best age for the vaccination. it was expected that a large number of the participants would not know about the hpv vaccine as it is not available in the national immunisation programme. the majority agreed to take the vaccine themselves once it became available and to the inclusion of the vaccine in the national immunisation programme for girls in oman. the acceptability levels for the hpv vaccine were similarly high in other gcc countries.13,14,26 the findings of this study should encourage health policymakers to duly promote the hpv vaccine. one study has shown that implementing a school-based vaccine programme is an effective way of ensuring primary prevention. it ensures high completion and on-time dosing of vaccination.27 the respondents of the current study appeared not to have enough knowledge of cytological screening. the percentages of the study participants who responded correctly to the questions about the recommended pap test time and frequency of routine testing were very low. this may explain why most instances of cervical cancer in the region are discovered rather late in the cancer’s stage.1 the table 6: sociodemographic factors associated with the knowledge of cervical cancer among 791 female participants from eight primary healthcare institutions in al buraimi governorate, oman socioeconomics factors knowledge of cervical cancer bivariate test results n (%) total poor good chi-squared df p value women’s age (in years) 20–30 212 (68) 98 (32) 310 10.78 3 0.013* 31–40 216 (57) 164 (43) 380 41–50 54 (58) 39 (42) 93 >50 6 (75) 2 (25) 8 educational level no education 4 (80) 1(20) 5 10.78 3 0.013* primary 30 (81) 7 (19) 37 secondary 210 (64) 117 (36) 327 tertiary† 244(58) 178 (42) 422 marital status single 73 (73) 27 (27) 100 6.41 2 0.041* married 397 (60) 266 (40) 663 other 18 (64) 10 (36) 28 work status‡ working 160 (57) 119 (43) 279 7.49 1 0.006§ not working 298 (67) 144 (33) 442 *significant at 5% level of significance; †tertiary (institute, college, university); ‡70 missing cases; §significant at 1% level of significance. aisha n. al-saadi, aisha h. al-muqbali and eihab dawi clinical and basic research | 455 uptake of the test will not increase until awareness concerning it is strengthened and the related obstacles are eliminated.28 unlike other studies carried out in other arab, latin and asian communities,29–31 this study showed that women aged between 20 and 30 years had poor knowledge of cervical cancer when compared with older women. this finding is in line with a previous study conducted in oman which shows high uptake of pap smear among women aged ≥30 years.32 for religious reasons, many omani women begin sexual activity after marriage. this study found that there is better knowledge of cervical cancer among women aged over 30 years. an increase in visits to gynaecology clinics and gynaecological check-ups in the case of older, married women is believed to be having a positive impact on their knowledge of such diseases. hence, marital status appears to be an influential factor regarding knowledge about cervical cancer. a supporting observation for this finding of the present study comes from the positive correlation found between knowledge of cervical cancer and marital status by a previous study conducted in oman.32 a major limitation of this study is that the findings are based on data from a single region in oman. however, the results of the present study do provide valuable information and could be of use when planning cervical cancer prevention programmes or awareness-raising campaigns on cervical cancer in oman. conclusion the general level of the participants’ knowledge of cervical cancer in this study is inadequate, especially among those of a younger age. the participants, all of whom were omani women, appear to lack knowledge about the role of hpv infection in the aetiology of cervical cancer and their awareness of the preventive measures is also low. accordingly, an increase in cervical cancer awareness among women in oman is necessary. such efforts should especially include young women. the awareness campaign(s) in this regard could be implemented with the help of appropriate mobile technologies and/or as on-ground campaigns. it is of paramount importance to strengthen the cervical cancer prevention and control initiatives at oman’s primary healthcare facilities to increase the understanding of this disease and, consequently, the women’s willingness concerning the uptake cervical cancer screening services. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n ans conceptualised the idea and research design. the data collection/field work and data management was done by ans and ahm. data analysis and interpretation of results was done by ans and ed. report writing, critical reviewing with intellectual input and writing the manuscript were done by ans. all authors approved the final version of the manuscript. references 1. arbyn m, weiderpass e, bruni l, sanjoséet sd, saraiya m, ferlay j, et al. estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. lancet glob health 2019; 8:191–203. https://doi.org/10.1016/s2214-109x(19)30482-6. 2. world health organization. human papillomavirus (hpv) and cervical cancer. from: www.who.int/en/news-room/fact-sheets/ detail/human-papillomavirus-(hpv)-and-cer vical-cancer. accessed: mar 2020. 3. dey s, soliman as. cancer in the global health era: opportunities for the middle east and asia. asia pac j pub health 2010; 22: 75–82. https://doi.org/10.1177/1010539510372846. 4. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 5. hpv information centre. statistics. from: www.hpvcentre.net/ datastatistics.php accessed: apr 2020. 6. tewari ks, monk bj. invasive cervical cancer, 8th ed. philadelphia: elsevier, 2012. pp. 24–8. 7. al-lawati z, khamis fa, al-hamdani a, al-kalbani m, ramadhan fa, al-rawahi tr, et al. prevalence of human papilloma virus in oman: genotypes 82 and 68 are dominating. int j infect dis 2020; 93:22–27. https://doi.org/10.1016/j. ijid.2019.12.038. 8. adegoke o, kulasingam s, virnig b. cervical cancer trends in the united states: a 35-year population-based analysis. j womens health 2012; 21:1031–7. https://doi.org/10.1089/ jwh.2011.3385. 9. bray f, loos ah, mccarron p, weiderpass e, arbyn m, møller h, et al. trends in cervical squamous cell carcinoma incidence in 13 european countries: changing risk and the effects of screening. cancer epidemiol biomarkers prev 2005; 14:677–86. https://doi.org/10.1158/1055-9965.epi-04-0569. 10. torre la, bray f, siegel rl, ferlay j, lortet-tieulent j, jemal a. global cancer statistics, 2012. ca cancer j clin 2015; 65:87–108. https://doi.org/10.3322/caac.21262. 11. torre la, islami f, siegel rl, ward em, jemal a. global cancer in women: burden and trends. cancer epidemiol biomarkers prev 2017; 26:444–57. https://doi.org/10.1158/1055-9965.epi-16-0858. 12. arbyn m, weiderpass e, bruni l, de sanjosé s, saraiya m, ferlay j, et al. estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. lancet glob health 2020; 8:e191–e203. https://doi.org/10.1016/s2214-109x(19)30482-6. https://doi.org/10.1016/s2214-109x(19)30482-6 https://doi.org/10.1177/1010539510372846 https://doi.org/10.1016/j.ijid.2019.12.038 https://doi.org/10.1016/j.ijid.2019.12.038 https://doi.org/10.1089/jwh.2011.3385 https://doi.org/10.1089/jwh.2011.3385 https://doi.org/10.1158/1055-9965.epi-04-0569 https://doi.org/10.3322/caac.21262 https://doi.org/10.1158/1055-9965.epi-16-0858 https://doi.org/10.1016/s2214-109x(19)30482-6 women’s knowledge of cervical cancer a cross-sectional study in al buraimi governorate, oman 456 | squ medical journal, august 2021, volume 21, issue 3 13. yang h, li sp, chen q, morgan c. barriers to cervical cancer screening among rural women in eastern china: a qualitative study. bmj open 2019; 9:e026413. https://doi.org/10.1136/bmj open-2018-026413. 14. alwahaibi n, alsalami w, alzaabi a, alramadhani n. awareness of cervical cancer and pap smear testing among omani women. asian pac j cancer prev 2016; 17:4825–30. https://doi.org/10.22 034/apjcp.2016.17.11.4825. 15. jassim g, obeid a, al nasheet ha. knowledge, attitudes, and practices regarding cervical cancer and screening among women visiting primary health care centres in bahrain. bmc public health 2018; 18:128. https://doi.org/10.1186/s12889018-5023-7. 16. al-meer fm, aseel mt, al-khalaf j, al-kuwari mg, ismail mf. knowledge, attitude and practices regarding cervical cancer and screening among women visiting primary health care in qatar. east mediterr health j 2011; 17:855–61. https://doi. org/10.26719/2011.17.11.856. 17. islam mm, dorvlo as, al-qasmi am. the pattern of female nuptiality in oman. sultan qaboos univ med j 2013; 13:32–42. https://doi.org/10.12816/0003193. 18. asgarlou z, tehrani s, asghari e, arzanlou m, naghavibehzad m, piri r, et al. cervical cancer prevention knowledge and attitudes among female university students and hospital staff in iran. asian pac j cancer prev 2016; 17:4921–7. https:// doi.org/10.22034/apjcp.2016.17.11.4921. 19. bansal ab, pakhare ap, kapoor n, mehrotra r, kokane am. knowledge, attitude, and practices related to cervical cancer among adult women: a hospital-based cross-sectional study. j nat sci biol med 2015; 6:324–8. https://doi.org/10.4103/09769668.159993. 20. jaglarz k, tomaszewski ka, kamzol w, puskulluoglu m, krzemieniecki k. creating and field-testing the questionnaire for the assessment of knowledge about cervical cancer and its prevention among schoolgirls and female students. j gynecol oncol 2014; 25:81–9. https://doi.org/10.3802/jgo.2014.25.2.81. 21. saadi aa. development and validation of questionnaire to assess knowledge about cervical cancer among women aged 20 to 65 years in oman. asian pac j cancer prev 2021; 22:69–74. https://doi.org/10.31557/apjcp.2021.22.1.69. 22. donders gg, gabrovska m, bellen g. knowledge of cervix cancer, human papilloma virus (hpv) and hpv vaccination at the moment of introduction of the vaccine in women in belgium. arch gynecol obstet 2007; 277:291–8. https://doi. org/10.1007/s00404-007-0487-1. 23. onan a, ozkan s, korucuoglu u, aksakal n, taskiran c, aygun r et al. knowledge on and attitude toward human papillomavirus infection and its vaccine in a turkish subpopulation. turkiye klinikleri j med sci 2009; 29:594–8. 24. schiffman mh, bauer hm, hoover rn, glass ag, cadell dm, rush bb, et al. epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. j natl cancer inst 1993; 85:958–64. https://doi. org/10.1093/jnci/85.12.958. 25. low el, simon ae, lyons j, romney-alexander d, waller j. what do british women know about cervical cancer symptoms and risk factors? eur j cancer 2012; 48:3001–3008. https://doi. org/10.1016/j.ejca.2012.05.004. 26. mwaka ad, orach cg, were em, lyratzopoulos g, wabinga h, roland m. awareness of cervical cancer risk factors and symptoms: cross-sectional community survey in post-conflict northern uganda. health expect 2015; 19:854–67. https://doi. org/10.1111/hex.12382. 27. lim wt, sears k, smith lm, liu g, lévesque le. evidence of effective delivery of the human papillomavirus (hpv) vaccine through a publicly funded, school-based program: the ontario grade 8 hpv vaccine cohort study. bmc public health 2014; 14:1029. https://doi.org/10.1186/1471-2458-14-1029. 28. elbarazi i, raheel h, cummings k, loney t. a content analysis of arabic and english newspapers before, during, and after the human papillomavirus vaccination campaign in the united arab emirates. front public health 2016; 4:176. https://doi. org/10.3389/fpubh.2016.00176. 29. gowda c, dempsey af. medicaid reimbursement and the uptake of adolescent vaccines. vaccine 2012; 30:1682–9. https://doi.org/10.1016/j.vaccine.2011.12.097. 30. acharya pandey r, karmacharya e. cervical cancer screening behavior and associated factors among women of ugrachandi nala, kavre, nepal. eur j med res 2017; 22:32. https://doi. org/10.1186/s40001-017-0274-9. 31. al sairafi m, mohamed fa. knowledge, attitudes, and practice related to cervical cancer screening among kuwaiti women. med princ pract 2009; 18:35–42. https://doi.org/10.1159/000163044. 32. alwahaibi n, alsalami w, alramadhani n, alzaabi a. factors influencing knowledge and practice regarding cervical cancer and pap smear testing among omani women. asian pac j cancer prev 2018; 19:3367–74. https://doi.org/10.31557/apjcp.2018.1 9.12.3367. https://doi.org/10.1136/bmjopen-2018-026413 https://doi.org/10.1136/bmjopen-2018-026413 https://doi.org/10.22034/apjcp.2016.17.11.4825 https://doi.org/10.22034/apjcp.2016.17.11.4825 https://doi.org/10.1186/s12889-018-5023-7 https://doi.org/10.1186/s12889-018-5023-7 https://doi.org/10.26719/2011.17.11.856 https://doi.org/10.26719/2011.17.11.856 https://doi.org/10.12816/0003193 https://doi.org/10.22034/apjcp.2016.17.11.4921 https://doi.org/10.22034/apjcp.2016.17.11.4921 https://doi.org/10.4103/0976-9668.159993 https://doi.org/10.4103/0976-9668.159993 https://doi.org/10.3802/jgo.2014.25.2.81 https://doi.org/10.31557/apjcp.2021.22.1.69 https://doi.org/10.1007/s00404-007-0487-1 https://doi.org/10.1007/s00404-007-0487-1 https://doi.org/10.1093/jnci/85.12.958 https://doi.org/10.1093/jnci/85.12.958 https://doi.org/10.1016/j.ejca.2012.05.004 https://doi.org/10.1016/j.ejca.2012.05.004 https://doi.org/10.1111/hex.12382 https://doi.org/10.1111/hex.12382 https://doi.org/10.1186/1471-2458-14-1029 https://doi.org/10.3389/fpubh.2016.00176 https://doi.org/10.3389/fpubh.2016.00176 https://doi.org/10.1016/j.vaccine.2011.12.097 https://doi.org/10.1186/s40001-017-0274-9 https://doi.org/10.1186/s40001-017-0274-9 https://doi.org/10.1159/000163044 https://doi.org/10.31557/apjcp.2018.19.12.3367 https://doi.org/10.31557/apjcp.2018.19.12.3367 ibri polyclinic, ibri, oman *corresponding author’s e-mail: ph.weaam.al-yaqoobi@hotmail.com أمناط وصف دواء كو اموكسيكالف لألطفال يف جممع عربي الصحي، ُعمان وئام �سعيد اليعقوبية ونادية �سيف املقبالية abstract: objectives: this study aimed to describe patterns of prescribing co-amoxiclav to children aged ≤5 years at a polyclinic in oman and to assess level of adherence to the antibiotic prescription guidelines outlined by the omani ministry of health (moh). methods: this cross-sectional retrospective study was conducted between june and december 2017 at ibri polyclinic (ipc) in ibri, oman. a random sample of 399 children aged ≤5 years who were prescribed a suspension of co-amoxiclav over the four winter months of 2016 were included in the study. the children’s electronic medical records were reviewed to determine whether the prescription complied with moh guidelines. results: the majority of the children were 2–3 years old (52.4%). overall, 73.9% of prescriptions were written by general practitioners, while 26.1% were written by specialists. co-amoxiclav therapy was the first line of management in 90.5% of cases, regardless of category of prescriber. culture tests were ordered in only 43 cases (10.8%), of which five (11.6%) were found to be sensitive to the prescribed co-amoxiclav. conclusion: unnecessary antibiotics were prescribed to many paediatric patients attending ipc. strict enforcement of the moh antibiotic guidelines is needed to reduce irrational or discretionary prescription of this type of antibiotic. healthcare providers should receive additional training in evidence-based methods of prescribing antibiotics. keywords: antibiotics; children; co-amoxiclav; inappropriate prescribing; antibiotic resistance; oman. امللخ�ص: الهدف: هدفت هذه الدرا�سة اإىل و�سف اأمناط �رصف دواء كو اموك�سيكلف للأطفال الذين يقل اأعمارهم عن 5 �سنوات يف جممع العمانية. ال�سحة وزارة حددتها التي احليوية امل�سادات لو�سف االر�سادية بالقواعد االلتزام م�ستوى وتقييم عمان يف ال�سحي عربي الطريقة: اأجريت هذه الدرا�سة اال�ستعادية امل�ستعر�سة بني يونيو وديسمرب من عام 2017 يف جممع عربي ال�سحي، عمان. �سملت الدرا�سة على عينة ع�سوائية من 399 طفًل اأعمارهم 5≥ �سنوات ممن �رصف لهم م�ستعلق الكو اموك�سيكلف خلل اأ�سهر ال�ستاء االأربعة من عام 2016. متت مراجعة ال�سجلت الطبية االإلكرتونية لهوؤالء االأطفال لتحديد ما اإذا كانت الو�سفة الطبية تتوافق مع القواعد االر�سادية لوزارة ال�سحة. بوا�سطة الطبية الو�سفات من 73.9% �رصف مت عام، ب�سكل .)52.4%( �سنوات 2-3 بني ترتاوح اأعمارهم كانت االأطفال غالبية النتائج: النظر بغ�ض احلاالت، من 90.5% يف االأول االإختيار هو اموك�سيكلف كو علج كان اخت�سا�سيني. اأطباء بوا�سطة 26.1% عموم، اأطباء عن فئة الوا�سف. مت طلب اختبارات امل�ستنبت املخربية يف 43 حالة فقط )%10.8(، منها خم�ض حاالت )%11.6( ُوجد اأنها ح�سا�سة للكو اموك�سيكلف. اخلال�صة: مت و�سف امل�سادات احليوية الغري �رصورية للعديد من املر�سى االأطفال املراجعون ملجمع عربي ال�سحي. هناك حاجة اإىل تطبيق �سارم للقواعد االر�سادية لوزارة ال�سحة ب�ساأن امل�سادات احليوية لتقليل من الو�سفات الغري �رصورية لهذا النوع من امل�سادات احليوية. يجب اأن يتلقى مقدمو الرعاية ال�سحية تدريًبا اإ�سافًيا على االأ�ساليب القائمة على االأدلة ل�رصف امل�سادات احليوية. الكلمات املفتاحية: امل�سادات احليوية؛ اأطفال؛ كو اموك�سيكلف؛ و�سف غري منا�سب؛ مقاومة امل�ساد احليوي؛ عمان. patterns of prescribing co-amoxiclav to children in ibri polyclinic, oman *weaam s. al-yaqoubi and nadia s. al-maqbali sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e72–76, epub. 15 mar 21 submitted 15 dec 19 revision req. 13 feb 20; revision recd. 17 apr 20 accepted 16 jun 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.010 clinical & basic research advances in knowledge the results of the study indicate a high rate of unjustified or irrational paediatric antibiotic prescribing by healthcare practitioners at the facility. these findings provide important data which may inform future research in the fields of pharmacy, paediatrics and rural medical care in oman. to the best of the authors’ knowledge, this study is the first to evaluate prescribing patterns of a specific antibiotic (co-amoxiclav) to children at a semi-rural primary healthcare facility in oman. application to patient care the findings of this study may be useful for policymakers and healthcare professionals to more strictly enforce established national guidelines for antibiotic prescribing, in addition to raising awareness among parents regarding the danger of antibiotic misuse among children. since their advent in the 1940s, researchers have warned that the overuse of antibiotics can lead to the proliferation of resistant bacterial strains.1,2 unfortunately, despite the implementation of clear prescription regulations and guidelines, antibiotics are often prescribed as first-line treatment for infections, particularly by primary healthcare physicians.3 in particular, general practitioners often https://creativecommons.org/licenses/by-nd/4.0/ weaam s. al-yaqoubi and nadia s. al-maqbali clinical and basic research | e73 lack the necessary resources or time to conduct pathological investigations and therefore prescribe paediatric antibiotics as a form of prophylaxis, particularly in cases of upper respiratory tract infection, even though most infections of this type are viral in origin.4 in oman, the ministry of health (moh) requires all physicians to order laboratory investigations and prescribe antibiotics only if warranted and in optimal doses based on the child’s age, weight, hepatic and renal function and the severity of the infection; in addition, the prescriber should provide clear and detailed usage and follow-up instructions to all patients.5 however, national trends of antibiotic prescription and consumption are still not well-studied. in 2003, the world health organisation reported the frequent misuse of antibiotics in primary healthcare centres (phcs) in oman.6 a later study reported that doctors employed in private healthcare facilities often overprescribed broad-spectrum antibiotics, with similar trends reported in qatar.7,8 balkhair et al. raised concerns over the increasing prevalence of multidrugresistant organisms observed at a tertiary care hospital in oman, underlining the need to investigate antibiotic consumption patterns in the country.9 amoxicillin is one of the most popular types of paediatric antibiotics prescribed worldwide and is often administered alongside clavulanic acid, with this combination referred to as co-amoxiclav.10 in 2014, a study of 499 omani children under 12 years of age in muscat, the capital city of oman, found that most co-amoxiclav prescriptions were issued to children aged 0–6 years.11 in 2017, co-amoxiclav was the first and second most prescribed antibiotic to paediatric inpatients and outpatients, respectively.12 in ibri, a semi-rural town in al dhahirah governorate, antibiotics comprised 24.7% of all drugs prescribed at the local polyclinic in 2016, the second highest rate among all phcs in the governorate.13 to the best of the authors’ knowledge, no study has yet been conducted to evaluate co-amoxiclav prescribing patterns among children in phcs located in rural or semi-rural regions of oman. accordingly, the present study sought to describe patterns of prescribing a co-amoxiclav suspension to children aged ≤5 years at a polyclinic in ibri and to assess whether such prescriptions adhered to the moh antibiotic prescription guidelines. methods this retrospective cross-sectional study was conducted at the ibri polyclinic (ipc) between june and december 2017. the target population included children aged ≤5 years of any nationality who had attended the general practice, paediatric, dermatology and dental clinics at ipc during the winter months of 2016 (january, february, november and december) and had been prescribed a suspension of co-amoxiclav consisting of 125 mg of amoxicillin and 31 mg of clavulanic acid (augmentin®, glaxosmithkline plc, brentford, uk). in mid-2016, there was a total of 393,625 children aged 0–4 years of both genders and all nationalities in oman.14 as the targeted population size was greater than 10,000, the following formula was used to calculate the necessary sample size:15 based on the above formula, the minimum sample size was calculated to be 384. however, this was increased to 400 to compensate for any incomplete records. children were randomly selected for inclusion in the study by using web-based random number generator software to select specific records from the clinic’s electronic medical records system. one incomplete record was found and excluded, leading to the inclusion of 399 children in the final analysis. data were retrieved from the children’s electronic medical records. specific information was collected from the system including the child’s age, weight and body temperature; dose, frequency and duration of the prescription; documented indications for the prescription; whether a culture was taken and, if so, its result; follow-up visit advice; and whether the prescriber was a specialist (i.e. a paediatric, dermatology or dental specialist) or a general practitioner. subsequently, this information was used to determine whether the prescription adhered to the moh antibiotic guidelines.5 data analysis was performed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). descriptive statistics were calculated, including percentages, means and standard deviations. a paired samples t-test was used to determine differences between the prescribed dose and the ideal dose. in addition, an inferential analysis using pearson’s chi-squared test was conducted to assess correlations. a p value of <0.050 was considered statistically significant. ethical approval for this study was obtained from the research and studies committee of the directorate general of health services, moh, al-dhahirah governorate. the privacy and confidentiality of the collected data was maintained at all times. n = d2 z2 × p × (1-p) [equation 1] patterns of prescribing co-amoxiclav to children in ibri polyclinic, oman e74 | squ medical journal, february 2021, volume 21, issue 1 results of the 399 children included in the study, 375 (94%) were omani and 24 (6%) were expatriates of various nationalities. the majority were male (n = 263; 65.9%). children aged 2–3 years formed more than half (n = 209; 52.4%) of the participants [table 1]. approximately three-quarters (n = 295; 73.9%) of the prescriptions were written by general practitioners, while the remaining 104 prescriptions (26.1%) were written by specialists. the vast majority (n = 351; 88%) of the prescriptions were for upper respiratory tract infections. most children (n = 279; 69.9%) did not receive any follow-up advice. culture tests were ordered in only 43 cases (10.8%). specialists were more than twice as likely to order culture tests compared to general practitioners (18.3% versus 8.1%; p = 0.005) [table 2]. among the 43 cultures taken, only five (11.6%) were found to be sensitive to co-amoxiclav [table 3]. nevertheless, co-amoxiclav was prescribed as the first line of management in 361 cases (90.5%). there was no significant difference between general practitioners and specialists in the use of co-amoxiclav as first-line therapy (90.2% versus 91.3%; p >0.050) [table 4]. a paired samples t-test revealed no significant difference between mean prescribed dose and mean recommended dose according to body weight (5.90 ± 1.69 versus 6.01 ± 1.70 ml; p = 0.386). in addition, specialists were significantly more likely to schedule follow-up visits for their patients compared to general practitioners (35.6% versus 27.8%; r = 0.213; p <0.010). discussion antibiotic therapy carries greater risks for neonates and young children compared to adults.6 in particular, there is the possibility of kidney damage due to drug toxicity as the children’s immature elimination systems may not be able to excrete the antibiotic remnants effectively, sometimes leading to organ failure. moreover, recent research indicates that the administration of antibiotics at an early age may damage the paediatric microbiome, resulting in longterm psychophysiological consequences.17,18 finally, the increasing prevalence of resistant bacteria renders traditional antibiotics less effective.3 according to a study from the usa, paediatric antibiotic use declined sharply between 2000–2010 and then plateaued.19 however, paediatric antibiotic prescribing trends in countries with emerging economies such as oman are not clear. worldwide, it appears that general physicians prescribe more antibiotics compared to specialists, particularly those employed in emergency out-of-hours clinics.20,21 the results of the current study support this trend, with 73.9% of co-amoxiclav prescriptions for children table 1: age distribution of children prescribed co-amoxi clav at a polyclinic in ibri, oman (n = 399) age in years n (%) <1 2 (0.5) 1 41 (10.3) 2 115 (28.8) 3 94 (23.6) 4 70 (17.5) 5 77 (19.3) table 2: frequency of laboratory cultures taken according to category of prescriber among children prescribed coamoxiclav at a polyclinic in ibri, oman (n = 399) prescriber category laboratory cultures, n (%) p value not taken taken general practitioner (n = 295) 271 (91.9) 24 (8.1) 0.005 specialist (n = 104) 85 (81.7) 19 (18.3) table 3: types of pathogens identified and antibiotic sens itivity in cultures taken from children prescribed co-amox iclav at a polyclinic in ibri, oman (n = 43) variable culture, n (%) type of pathogen bacterial 14 (32.6) normal flora 12 (27.9) unspecified 12 (27.9) viral 5 (11.6) sensitivity to co-amoxiclav sensitive 5 (11.6) not sensitive 38 (88.4) table 4: line of co-amoxiclav management according to category of prescriber among children prescribed co-amox iclav at a polyclinic in ibri, oman (n = 399) prescriber category line of management, n (%) p value first second general practitioner (n = 295) 266 (90.2) 29 (9.8) >0.050 specialist (n = 104) 95 (91.3) 9 (8.7) weaam s. al-yaqoubi and nadia s. al-maqbali clinical and basic research | e75 having been written by general practitioners, although the national moh antimicrobial guidelines limit the choice of antibiotics available for prescription by general practitioners.5 ncube et al. reported similar trends in a study of general medical practitioners in south africa.22 research suggests that several behavioural factors may be associated with the tendency to overprescribe antibiotics among physicians.23 these factors include the desire to meet patient expectations or succumbing to patient pressure; time constraints, particularly for general physicians working in busy outpatient clinics; the concept of ‘decision fatigue’ in which an individual’s capacity to make decisions becomes limited after repeated decision-making activities; diagnostic uncertainty; and externalising responsibility in the belief that other doctors would also prescribe antibiotics.23 in western countries, doctors also experience additional pressure to prescribe antibiotics as a result of the risk of medical malpractice lawsuits.24 as yet, no data from oman are available to shed light on the behavioural factors which might influence physicians to prescribe antibiotics. studies on this topic would help achieve a better understanding of and potentially mitigate such pressures on doctors in oman. the empirical prescription of antibiotics is some times warranted based on clinical evidence; however, in most cases, antibiotic therapy should be initiated only based on the results of bacterial cultures.25 in oman, the moh guidelines specify the need for culture testing to ensure that patients receive rational and targeted therapy.5 in the present study, culture tests were conducted in only 10.8% of cases, of which only 32.6% had bacterial infections and only 11.6% were sensitive to the antibiotic prescribed. however, it should be acknowledged that the reliability of culture tests cannot be taken for granted. a retrospective study by el-naggari et al. found the incidence of falsepositive results due to sample contamination to be as high as 46.2% among 344 positive blood cultures obtained at a tertiary hospital in oman.26 in the current study, the majority of paediatric co-amoxiclav prescriptions were issued as the first line of management for upper respiratory tract infections. this practice appears contrary to the national moh antibiotic guidelines.5 according to the national institute of health and care excellence (nice) in the uk, most instances of acute sore throat— whether bacterial or viral in aetiology—tend to be self-limiting and usually resolve within seven days without antibiotics.27 in addition, up to 90% of cases of acute bronchitis are viral and usually resolve without treatment.28 therefore, it is essential that parents in oman be educated regarding the differences between bacterial and viral infections so that they do not seek unnecessary therapy for children with self-limiting conditions. these individuals should also be informed of the long-term health risks associated with the misuse of paediatric antibiotics. the mean dose of co-amoxiclav suspension prescribed by ipc healthcare practitioners in the present study did not differ significantly from the ideal dose outlined in the moh guidelines. doses were calculated according to weight for patients with mild to moderate diseases, with the dosage doubled for severe conditions such as acute otitis media.5 specifically, the dosage of co-amoxiclav is calculated at 0.25 ml/kg administered every 8 hours and is doubled for severe infections. this calculation is based on recommendations from the british national formulary.29 the findings of the present study should be considered in light of certain limitations. first, the target population was confined to children attending a single rural healthcare centre in oman. as such, larger samples taken from multiple healthcare centres in oman could have enhanced the generalisability of the study. second, the data collection period was restricted to the four winter months of 2016 instead of the full year. in future, a more detailed study that addresses the above limitations is recommended. conclusion there was considerable over-prescription of coamoxiclav to children at a semi-rural clinic in oman, indicating that the prescribers did not adhere to the existing moh guidelines on paediatric antibiotic use. as such, these guidelines need to be implemented more strictly, with a greater degree of accountability. continuing medical education activities on evidencebased methods of prescribing antibiotics are needed for healthcare practitioners. in addition, parents should be educated regarding the long-term health risks posed by the misuse of antibiotics in children. finally, the moh should consider publishing educational leaflets on the dangers of antibiotic misuse for distribution at all hospitals, clinics and pharmacies nationwide. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. patterns of prescribing co-amoxiclav to children in ibri polyclinic, oman e76 | squ medical journal, february 2021, volume 21, issue 1 references 1. aminov ri. a brief history of the antibiotic era: lessons learned and challenges for the future. front microbiol 2010; 1:134. https://doi.org/10.3389/fmicb.2010.00134. 2. dietert r. the human superorganism: how the microbiome is revolutionizing the pursuit of a healthy life, 1st ed. london, uk: penguin books, 2016. 3. llor c, bjerrum l. antimicrobial resistance: risk associated with antibiotic overuse and initiatives to reduce the problem. ther adv drug saf 2014; 5:229–41. https://doi.org/10.1177/204 2098614554919. 4. fair rj, tor y. antibiotics and bacterial resistance in the 21st century. perspect medicin chem 2014; 6:25–64. https://doi. org/10.4137/pmc.s14459. 5. directorate general of rational use of medicine, ministry of health. oman national formulary for ministry of health institutions: third edition 2016. from: www.moh.gov.om/ documents/16569/0/onf+2016+-for+e+health+portal. pdf/3f224743-563e-4640-85c1-fe46abe3db93 accessed: apr 2020. 6. world health organization. annual report 2002: essential drugs and medicines policy supporting countries to close the access gap. from: https://apps.who.int/iris/handle/10665/67912 accessed: apr 2020. 7. kutty n. treating children without antibiotics in primary healthcare. oman med j 2011; 26:303–5. https://doi.org/10.5001/omj.2011.77. 8. shaikhan f, rawaf s, majeed a, hassounah s. knowledge, attitude, perception and practice regarding antimicrobial use in upper respiratory tract infections in qatar: a systematic review. jrsm open 2018; 9:2054270418774971. https://doi. org/10.1177/2054270418774971. 9. balkhair a, al-farsi ym, al-muharrmi z, al-rashdi r, al-jabri m, neilson f, et al. epidemiology of multi-drug resistant organisms in a teaching hospital in oman: a one-year hospitalbased study. scientificworldjournal 2014: 2014;157102. https:// doi.org/10.1155/2014/157102. 10. li g, jackson c, bielicki j, ellis s, hsia y, sharland m. global sales of oral antibiotics formulated for children. bull world health organ 2020; 98:458–66. https://doi.org/10.2471/blt.19.235309. 11. al-balushi k, al-ghafri f, al-sawafi f, al-zakwani i. antibiotic prescribing trends in an omani paediatric population. sultan qaboos univ med j 2014; 14:e495–9. 12. oman ministry of health. oman antimicrobial resistance surveillance system: annual report 2017. from: www.moh. gov.om/documents/236878/0/omass+2017/ca052ace-691a1919-7b96-41f79539660a accessed: apr 2020. 13. ministry of health. statistics register (al dhahira) for the year 2016. oman: moh. 14. oman ministry of health. annual health report 2016. from: www.moh.gov.om/documents/274609/1624207/%d9%85%d9 %82%d8%af%d9%85%d8%a9/d7a973be-edf6-48c5-ac7a16cc5f65aeb8 accessed: apr 2020. 15. lewis j. sample size estimation and use of substitute audiences. from: https://www.researchgate.net/publication/228579923_ sample_size_estimation_and_use_of_substitute_audiences accessed: apr 2020. 16. edlin rs, copp hl. antibiotic resistance in pediatric urology. ther adv urol 2014; 6:54–61. https://doi.org/10.1177/17562 87213511508. 17. oldenburg ce, sié a, coulibaly b, ouermi l, dah c, tapsoba c, et al. effect of commonly used pediatric antibiotics on gut microbial diversity in preschool children in burkina faso: a randomized clinical trial. open forum infect dis 2018; 5:ofy289. https://doi.org/10.1093/ofid/ofy289. 18. deans e. microbiome and mental health in the modern environ ment. j physiol anthropol 2016; 36:1. https://doi.org/10.1186/ s40101-016-0101-y. 19. vaz le, kleinman kp, raebel ma, nordin jd, lakoma md, dutta-linn mm, et al. recent trends in outpatient antibiotic use in children. pediatrics 2014; 133:375–85. https://doi. org/10.1542/peds.2013-2903. 20. pulcini c, lions c, ventelou b, verger p. indicators show differences in antibiotic use between general practitioners and paediatricians. eur j clin microbiol infect dis 2013; 32:929–35. https://doi.org/10.1007/s10096-013-1828-6. 21. huibers l, moth g, christensen mb, vedsted p. antibiotic prescribing patterns in out-of-hours primary care: a populationbased descriptive study. scand j prim health care 2014; 32:200–7. https://doi.org/10.3109/02813432.2014.972067. 22. ncube nb, solanki gc, kredo t, lalloo r. antibiotic pres cription patterns of south african general medical practitioners for treatment of acute bronchitis. s afr med j 2017; 107:119–22. https://doi.org/10.7196/samj.2017.v107i2.11276. 23. talkington k, hyun d, zetts r, thomas j. what drives inappropriate antibiotic use in outpatient care? behavioral science strategies can help improve antibiotic prescribing habits. from: www.pewtrusts.org/en/research-and-analysis/ issue-briefs/2017/06/what-drives-inappropriate-antibioticuse-in-outpatient-care accessed: apr 2020. 24. fletcher-lartey s, yee m, gaarslev c, khan r. why do general practitioners prescribe antibiotics for upper respiratory tract infections to meet patient expectations: a mixed methods study. bmj open 2016; 6:e012244. https://doi.org/10.1136/ bmjopen-2016-012244. 25. harris am, bramley am, jain s, arnold sr, ampofo k, self wh, et al. influence of antibiotics on the detection of bacteria by culture-based and culture-independent diagnostic tests in patients hospitalized with community-acquired pneumonia. open forum infect dis 2017; 4:oxf014. https://doi.org/10.1093/ ofid/ofx014. 26. el-naggari ma, al-mulaabed sw, al-muharrmi z, mani r, abdelrahim r, abdwani r. blood culture contaminants in a paediatric population: retrospective study from a tertiary hospital in oman. sultan qaboos univ med j 2017; 17:e202–8. https://doi.org/10.18295/squmj.2016.17.02.011. 27. national institute for health and care excellence. sore throat (acute): antimicrobial prescribing nice guideline [ng84]. from: www.nice.org.uk/guidance/ng84 accessed: apr 2020. 28. albert rh. diagnosis and treatment of acute bronchitis. am fam physician 2010; 82:1345–50. 29. british joint formulary committee. british national formulary (bnf) 76. london, uk: british medical association and royal pharmaceutical https://doi.org/10.3389/fmicb.2010.00134 https://doi.org/10.1177/2042098614554919 https://doi.org/10.1177/2042098614554919 https://doi.org/10.4137/pmc.s14459 https://doi.org/10.4137/pmc.s14459 https://doi.org/10.5001/omj.2011.77 https://doi.org/10.1177/2054270418774971 https://doi.org/10.1177/2054270418774971 https://doi.org/10.1155/2014/157102 https://doi.org/10.1155/2014/157102 https://doi.org/10.2471/blt.19.235309 https://doi.org/10.1177/1756287213511508 https://doi.org/10.1177/1756287213511508 https://doi.org/10.1093/ofid/ofy289 https://doi.org/10.1186/s40101-016-0101-y https://doi.org/10.1186/s40101-016-0101-y https://doi.org/10.1542/peds.2013-2903 https://doi.org/10.1542/peds.2013-2903 https://doi.org/10.1007/s10096-013-1828-6 https://doi.org/10.3109/02813432.2014.972067 https://doi.org/10.7196/samj.2017.v107i2.11276 https://doi.org/10.1136/bmjopen-2016-012244 https://doi.org/10.1136/bmjopen-2016-012244 https://doi.org/10.1093/ofid/ofx014 https://doi.org/10.1093/ofid/ofx014 https://doi.org/10.18295/squmj.2016.17.02.011 august 2007 vol 7 copy.indd trachoma in kenya reflections of ramadan *abdul-majid wangai,1 maryam wangai2 sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 171-173 sultan qaboos university© submitted 12th february 2007 we almost became lunch for crocodiles! we travelled 2 days for medi-cal outreach just before eid el-fitr. after a less than 2 hour flight, we slept in the nearby town, and then next day hired a vehicle for a treacherous 3 hour journey, accompanied by armed guards with ak 47s to ward off any bandits. after that we walked for 2 hours through ankle-deep mud and then had to cross a river now flooded with torrential rain in this otherwise dry desert terrain. we crossed in a canoe-for-hire, which was actually a leaking dug out tree trunk. the river was infested with hungry crocodiles. our head guide/guard, abdalla, kept reminding us what would happen if we capsized: our son would only be a ‘snack’ while even both of us adults would probably only make a modest lunch for one crocodile! once on the other side of the river, we walked a further 40 minutes in the rain, slipping as a usually dusty footpath turned to mud. with no umbrellas, the heat of the desert fortunately quenched the rainwater that soaked our clothes and left us feeling cool. we got to our destination just in time to attend the lunch time prayers in a modest mosque. after prayers, we spent the next 2 hours providing a health clinic for these remote villagers. there were lots of illnesses to care for: the usual malaria, wounds, diabetes and unusually high numbers of urinary retention due to prostatitis and benign prostatic hyperplasia (bph) amongst very young men (in their 40s). on the women’s side of the mosque, there were the usual maternity issues: family planning, vaginal discharges, breast lumps, and paediatric issues: respiratory infections, fever, and gastroenteritis. it was so gratifying to be of service in this remote area where the nearest doctor is way back in the little town we flew into at the beginning of our overland journey. one unusual striking feature of this clinic: no ophthalmologic cases. not a single case of trachoma! it struck us as unusual, as this was an area known for its dryness, lack of basic amenities and poverty, all of them well-known basic ingredients for trachoma.1 in all remote medical camps, we always see lots of blindness from trachoma. we also see many trachoma sequalae: trichiasis, conjunctivitis, blepharitis, entropion and d o c t o r ’ s v i e w p o i n t كينيا في التراخوما رمضان انعكاسات واجني مرمي واجني، ايد عبد editor’s note: the hegemony in the biomedical field is currently held by evidence-based medicine, which excludes subjective and intuitive inputs. counteracting this trend, as medicine is inescapably social and for the matter cultural, there has been increasing interest in an approach that is more patient-centered and takes into account the diversity of human culture. the present discourse presents all the drama and paradox of doctors in rural kenya serendipitously observing how socio-cultural teaching plays a role in mitigating trachoma in a region where it is often considered as endemic. 1medicare wellness medical centres, nairobi and new life homes, kenya. p. o. box 62610, city square 00200, nairobi, kenya; 2ministry of health, republic of kenya, p. o. box 62610, city square 00200, nairobi, kenya *to whom correspondence should be addressed. email: drmajidwangai@yahoo.co.uk a b d u l m a j i d wa n g a i a n d m a r ya m wa n g a i 172 ectropion, which lead to blindness. trachoma is the second major leading cause of blindness after cataract in our african setting,2 so why was there no trachoma here? we reflected on this as we traveled back. it was the same setting, same terrain, same weather patterns, similar african peoples, same everything, except no trachoma. then it struck us; these people were muslim! with all the dirt and filth of the environment; with all the poverty and lack of water; these people must wash their faces, hands 5 times a day before prayers. the community is 100% muslim. so they all wash and consider hygiene as a prerequisite to godliness. then once a day they wash their bodies as part of the ritual preparations for salat prayers! we felt like shouting, “eureka!” such a simple thing, yet we had missed it. to our knowledge we haven’t seen this written up anywhere. the simple fact of being a serious muslim, dedicated to prayer, one of the 5 pillars of islam, is a way of warding off trachoma and its consequential blindness. in the other places where we had run medical camps, the people were either christian or animist. people simply do not have enough water to bathe! they have only enough to drink and cook with. in fact, one is lucky to bathe once a month. in one place, the kids could go for months or years without bathing! we reminisced on our ophthalmology rotation in surgery, 20 years ago in medical school. trachoma is a leading cause of blindness in the world, caused by the organism, chlamydia trachomatis.1 transmission is through direct contact with infectious ocular or nasopharyngeal discharges on fingers or contaminated objects such as towels, clothes and material soiled by secretions from infected people.3 repeated infections establish clinical disease, which is characterized by a follicular reaction in the superior tarsal conjuctiva. as the follicles resolve, they leave subconjuctival scars. this causes opacification of cornea. in other cases, you have inflammation of eyelid margins with a foreign body sensation. the lid margin becomes distorted and scarred. chronic corneal abrasion ensues, visual impairment and blindness follows. the treatment in early disease is simple azithromycin, erythromycin, doxycycline, tetracycline or other macrolides. prevention is simple daily face washing! why cannot local communities exchange blindness for simple face and hand washing? realizing all this, the world health organization designed the safe strategy (surgery for trachomatous trichiasis; antibiotics, facial cleanliness and environmental improvement) in 1996, with the goal of eliminating blinding trachoma by the year 2020.3 the effectiveness of this strategy requires to be evaluated and is bound to be different depending on the chlamydial strain prevalent in various epidemic and endemic regions.4 in 1995, who first published data on global blindness and reported that 15% of cases were due to trachoma. this translates into an estimated 146 million individuals in need of care for active trachoma. of these, 10 million are in need of surgery for trichiasis (eye lashes touching the globe) and 8 million already blind.5 since the bulk of trachoma burden is endemic in poorer rural communities in developing countries (still widespread in the middle east, nothern and sub-saharan africa, india, south east asia and china, but only pockets in latin america, australia and the pacific islands),1 an urgent prevention strategy is imperative. in the light of the safe initiative, the f (face and hand hygiene) is a simple, effective and a cost effective public health endeavour. using religious norms (such as face and hand washing as part of religious prayers) to effect this trachoma prevention activity is a worthwhile venture. this interface of religion and medicine is a lesson we had not previously conceptualized in trachoma control. but there is a question we mused over. why in northern kenya do we have so little trachoma, yet to the north east of us in somalia there is trachoma? there is even more trachoma in afghanistan.1 both countries are over 90% muslim as much as our northern kenya territory (which is 98% muslim). why this discrepancy in trachoma prevalence on similar religious terrains? one easy answer would be security. in somalia and afghanistan, the ravages of war and conflict have left its toll on the people. the insecurity means a lack of basic amenities of life (water, food, shelter) as well as less ability to maintain regular ‘s’alat’s’ (with the usual ablutions) due to the war problems. besides, basic hygiene (waste disposal, clean drinking water) is a big challenge in both countries. insecurity always disrupts community life and displaces people from their regular habits, places and countries. there may be other reasons for this observation. some people identify changing weather patterns, different people groups, geographic terrains, socio-ecotr a c h o m a i n k e n ya 173 nomic status, religious sects (sunni, shia) and available resources as some of the reasons. in our considered view, these do not apply to our situation. the people in somalia (with high trachoma prevalence) have similar characteristics to the northern kenya communities we visited: same sect (sunni), same terrain, same language, same culture and same people group. the only difference is one of security. in other medical entities, insecurity is a risk for increased prevalence. could this be the factor we are seeing here? we welcome your views. now that was quite a trip. we learnt a simple lesson that medical school did not impart to us. and we had to risk being lunch for crocodiles to learn it! r e f e r e n c e s 1. chin j, ascher ms, eds. control of communicable diseases manual. american public health association. 17th edition. baltimore: united book press inc, 2000. p. 504-506. 2. thylefors b, negrel ad, pararajasegaram r, dadzie ky global data on blindness. bull world health organ. 1995; 73:115-121. 3. who 1996 ‘report of planning the global elimination of trachoma’ geneva, switzerland: world health organization; 1996. http://www.who.int/pbd/publications/trachoma/en/get_1996.pdf accessed 31st october 2006. 4. atik b, thanh ttk, luong vq et al. impact of annual targeted treatment on infectious trachoma and susceptibility to reinfection. jama 2006; 296:1488-1497. 5. report of planning for the global elimination trachoma (get). geneva, switzerland: who, 1996. health-related quality of life of children and adolescents with sickle cell disease in the middle east and north africa region a systematic review *suthan pandarakutty,1 kamala murali,2 judie arulappan,3 sulaiman d. al sabei4 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e280–289, epub. 21 dec 20 submitted 2 dec 19 revision req. 26 feb 20; revision recd. 2 apr 20 accepted 15 may 20 1department of nursing, college of health sciences, university of buraimi, al buraimi, oman; 2department of paediatric nursing, rani meyyammai college of nursing, annamalai university, chidambaram, tamil nadu, india; departments of 3maternal & child health and 4fundamentals & administration, college of nursing, sultan qaboos university, muscat, oman *corresponding author’s e-mail: suthan0912@gmail.com sickle cell disease (scd) is a hereditary disorder that often results in complications including acute and chronic pain, severe anaemia, infection and stroke.1 the disease primarily affects the development of red blood cells, resulting in the formation of haemoglobin s (hb s), an abnormal type of haemoglobin which causes red blood cells to become sickle-shaped and inflexible. these abnormal cells clump together in the arteries, blocking blood flow to various organs and causing various complications.1,2 the most common and severe form of scd is sickle cell anaemia (sca) which results when both parents inherit the hb s variant; in contrast, sickle cell trait (sct), which occurs when hb s volume is <50%, is less severe.2,3 overall, scd is linked with high morbidity and mortality particularly among young children under the age of five and adolescents.4–9 in addition, it can have adverse social and economic consequences.10 as such, both the world health organization (who) and the review جودة احلياة املرتبطة بصحة األطفال واملراهقني املصابني بداء اخلالاي املنجلية يف منطقة الشرق األوسط ومشال افريقيا مراجعة منهجية �سوثان بانداركوتي، كاماال مورايل، جودي ارالبان، �سليمان داوؤود ال�سابعي abstract: sickle cell disease (scd) can significantly impair the health-related quality of life (hrqol) of children and adolescents. this review aimed to assess current evidence regarding the hrqol of children and adolescents with scd in the middle east and north africa region. a systematic search of various databases was conducted to identify relevant articles, including medline® (national library of medicine, bethesda, maryland, usa), scopus® (elsevier, amsterdam, the netherlands), cumulative index to nursing and allied health literature®, masader (oman virtual science library, muscat, oman) and ebscohost (ebsco information services, ipswich, massachusetts, usa). a total of 533 articles were identified; however, only 10 were eligible for inclusion in the final analysis. results from these studies showed that children and adolescents with scd had compromised hrqol compared to their healthy peers, particularly in terms of physical, psychosocial, familial, financial and academic functioning. therefore, interventions are necessary to improve overall hrqol outcomes for this population. keywords: sickle cell disease; health-related quality of life; infants; children; adolescents; middle east; north africa. امللخ�ص: ميكن لداء اخلاليا املنجلية اأن ي�سعف ب�سكل كبري جودة احلياة املرتبطة ب�سحة االأطفال واملراهقني. هدفت هذه املراجعة اإىل تقييم االأدلة احلالية املتعلقة باالأطفال واملراهقني امل�سابني بداء اخلاليا املنجلية يف منطقة ال�رشق االأو�سط و�سمال اإفريقيا. مت اإجراء بحث منهجي لقواعد البيانات املختلفة لتحديد املقاالت ذات ال�سلة، مبا يف ذلك ميدالين )املكتبة الوطنية للطب، بيثي�سدا، مرييالند، الواليات املتحدة االأمريكية(، �سكوب�ض )اأيل�سيفري، اأم�سرتدام، هولندا(، الفهر�ض الرتاكمي للتمري�ض واالأدب ال�سحي املتحالف، م�سادر )مكتبة عمان االفرتا�سية للعلوم، م�سقط، عمان(، وايبي�سكو )ايبي�سكو خلدمات املعلومات، اإب�سويت�ض، ما�سات�سو�ست�ض، الواليات املتحدة االأمريكية(. مت حتديد ما جمموعه 533 مقالة؛ ومع ذلك، كان فقط 10 منها موؤهلني لالإدراج يف التحليل النهائي. اأظهرت نتائج هذه الدرا�سات اأن االأطفال واملراهقني امل�سابني البدين االأداء حيث من �سيما ال االأ�سحاء، باأقرانهم مقارنة بال�سحة املرتبطة احلياة جودة يف لنق�ض تعر�سوا قد املنجلية اخلاليا بداء والنف�سي واالجتماعي والعائلي واملايل واالأكادميي. لذلك، فاإنه من ال�رشوري القيام بالتدخالت املنا�سبة لتح�سني النتائج االإجمالية جلودة احلياة املرتبطة بال�سحة لهذه الفئة من ال�سكان. الكلمات املفتاحية: داء اخلاليا املنجلية؛ جودة احلياة املرتبطة بال�سحة؛ الر�سع؛ اأطفال؛ مراهقني؛ ال�رشق االأو�سط؛ �سمال افريقيا. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.04.002 https://creativecommons.org/licenses/by-nd/4.0/ suthan pandarakutty, kamala murali, judie arulappan and sulaiman d. al-sabei review | e281 united nations general assembly have confirmed that scd represents a global public health problem.11 worldwide, approximately 25 million people suffer from scd; according to the who, more than 300,000 infants are born with a major haemoglobin disease every year, of which scd accounts for 200,000 cases.4,12 varying rates of scd have been reported in different regions due to differences in hb s gene prevalence (2– 30%). in the usa, approximately 100,000 are affected by scd, with one in every 365 african-american and 16,300 hispanic-american births, while the sct is reported in one in 13 black or african-american babies.2 a recent survey reported that approximately 12,000–15,000 people were affected in the uk, equivalent to one in 4,600 people.13 in the netherlands, 800 newborns are born with scd every year.14 in contrast, the global burden of scd is more pronounced in the middle east and north africa (mena) region. in africa, approximately 10–15 million people live with scd, with congo and nigeria most affected.4,7,15–17 the high prevalence of scd in this region is likely due to the increased frequency of consanguineous marriages particularly between first-degree relatives.11 high rates of consanguineous marriages have been reported in saudi arabia (42– 67%), sudan (44–63%), qatar (54%), the united arab emirates (40–54%), jordan (29–64%), yemen (40– 45%) and egypt (21–33%).1,18,19 in the middle east, the highest prevalence of scd and sct is in eastern saudi arabia (2.6% and 21%, respectively).20 in 2015, the incidence of paediatric sca was 2,238 in egypt and 25,375 in iraq.21 studies from oman indicate that approximately 3,000 people live with scd, with an estimated 118 new cases every year and sct present in one in 370 live births.22–25 young children and adolescents are more vulnerable to lifelong scd complications such as vasoocclusive crises (vocs), acute splenic sequestration crises, acute chest syndrome (acs), central nervous system infarctions, haemolytic and aplastic crises and avascular hip necrosis.5,26,27 in children, the most common complication of scd is painful vocs.28,29 these occur when the irregularly-shaped red blood cells become stuck in the small vessels, causing multiple organ infarctions including kidney, spleen, bone and brain infarctions.30 risk factors for voc include exposure to cold, hypoxia, acidosis, inflamm ation, fatigue, physical activity and emotional stress.31 a study of omani children revealed that 22% of 240 children with scd developed acs, with 71% of cases preceded by painful vocs.32 in another study of omani children with scd, vocs constituted the main reason for admission in 83% of 316 hospital admissions over a 12-month period.33 current management of scd focuses primarily on the maintenance of health and treatment of acute and chronic complications. several important modal ities such as hydroxyurea (hu) therapy and blood trans fusions, have been found to boost patient outcomes.34,35 in particular, hu therapy reduces the frequency of vocs and acs thereby reducing the need for blood transfusions and associated hospitalisation.36 while stem cell transplantation is the intervention most likely to be curative in nature, this option is often associated with several complications.37 despite recent advances in scd treatment, the health-related quality of life (hrqol) of children and adolescents with scd remains poor compared to their healthy peers particularly with regards to physical, mental, social and academic domains.38,39 although many systematic reviews are available regarding hrqol in children and adolescents with scd, none focus specifically on the mena region. as outlined earlier, the prevalence of scd is much higher in this region; hence, understanding the impact of scd on the hrqol of children and adolescents in this region would be invaluable in order to inform future interventions such as premarital genetic counselling and potential lifestyle modification strategies, and to identify and prioritise patient-care decisions. therefore, this systematic review aimed to summarise and analyse the existing empirical literature with regards to the hrqol of children and adolescents living with scd in the mena region, discuss the implications of these findings on research and clinical practice and suggest strategies for improving hrqol in this region. methods this systematic review was carried out in accordance with the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines.40 a systematic search of various electronic databases was performed to identify articles assessing the hrqol of children and adolescents with scd in the mena region published between january 2010 and march 2020 including the medline® (national library of medicine, bethesda, maryland, usa), scopus® (elsevier, amsterdam, the netherlands), cumulative index to nursing and allied health literature®, masader (oman virtual science library, muscat, oman) and ebscohost (ebsco information services, ipswich, massachusetts, usa) databases. the search terms included the following in various combinations: “health-related quality of life”, “quality of life”, “sickle cell disease”, “sickle cell anaemia”, “middle east”, “north africa”, “infant,” “children” and health-related quality of life of children and adolescents with sickle cell disease in the middle east and north africa region a systematic review e282 | squ medical journal, november 2020, volume 20, issue 4 “adolescents”. all full-text peer-reviewed articles were included in the final analysis if they met the following criteria: (1) the articles constituted research studies assessing the hrqol of children and adolescents with scd aged <21 years; (2) the population of interest was relevant to the mena region; (3) the articles were published in english between january 2010 and march 2020; and (4) the population of interest included all scd genotypes. articles published before 2010 and in languages other than english were excluded, as were systematic reviews, meta-analyses, editorials, case studies, pilot studies and unpublished research, as well as studies focusing on the perspectives of adults, caregivers, parents or healthcare providers. following the initial literature search, the authors screened the titles and abstracts of each relevant article to eliminate duplicate results. in addition, the reference lists of articles retrieved during the database search were reviewed to identify additional articles for inclusion in the analysis. subsequently, two authors independently evaluated the full text of each article to determine its eligibility according to the inclusion criteria, with any disagreements settled by consensus. in the third step, the authors independently collected and consolidated relevant data from the articles as per garrard’s matrix method including the name and profession of the authors, year of publication of the article, purpose, design and setting of the study, period of recruitment, age group, characteristics and size of the sample, type of hrqol instrument, type of rater (i.e. self or proxy) and relevant outcomes from the study. a total of 533 articles were initially identified during the literature search. after removing duplicates, 176 unique articles were available for further screening. of these, 146 articles were removed because they did not meet the criteria. after screening the full text of the remaining 30 articles, 10 articles met the inclusion criteria and were included in the final analysis [figure 1]. two reviewers independently assessed the methodological quality of each study using an adapted version of the newcastle-ottawa quality assessment scale, except for mixed-method studies which were assessed using the mixed methods appraisal tool.41,42 cross-sectional studies were scored out of 8 points, based on sample collection (four items), comparability (one item) and outcome calculation (two items). case-control studies were scored out of 9, based on sample size (four items), comparability (one item) and outcome calculation (three items). cohort studies were scored out of 6, based on sample selection (two items), comparability (one item) and outcome measurement (two items). each item within the sample selection and outcome criteria received a maximum of one point, while items in the comparability criteria received a maximum of two points. in cases where there was a divergence in scoring, the reviewers discussed the item in question until a consensus was reached; if necessary, a third reviewer was consulted. studies with final scores of <50% were considered to be of poor methodological quality. results s t u d y c h a r a c t e r i s t i c s a total of 10 articles were included in the systematic review [table 1].21,43–51 of these, nine were observational studies, including five cross-sectional, two case-control and two cohort studies.21,44–51 the figure 1: diagram showing the search process used to identify articles for inclusion in the systematic review. suthan pandarakutty, kamala murali, judie arulappan and sulaiman d. al-sabei review | e283 table 1: characteristics of studies assessing the health-related quality of life of children and adolescents with sickle cell disease in the middle east and north africa region (n = 10)21,43–51 author and year of publication purpose study design setting type of participants sample size instrument rater relevant findings quality of study* boulassel et al.46 (2019) to investigate factors that affect hrqol in children with sca crosssectional oman children with sca aged 2–16 years and their caretakers 123 pedsql™ v4 scd module self and proxy • children with sca had reduced hrqol scores. • the lowest scores fell on the pain impact subscale, with an average of 41 ± 21% (range: 2.5–100%), suggesting that hrqol is adversely affected by pain. • in contrast, the highest score fell on the worry ii subscale, with an average of 70 ± 28% (range: 12.5–100%). 75% (6/8) kambasu et al.43 (2019) to evaluate the hrqol of adolesc ents with scd mixedmethod uganda children with scd aged 8–17 years and their caretakers 140 pedsql™ generic core scale and fgds with adolescents and caretakers self and proxy • hrqol scores were low in the physical functioning, emotional functioning and academic functioning domains. 75% salih51 (2019) to examine the impact of sca on the qol of school aged children in three dimensions (psychological, social and academic) crosssectional sudan children with sca aged 7–15 years 107 structured questionnaire self • scd posed multiple social and psychological problems that need to be addressed. • common problems included enuresis, depressive symptoms, school absenteeism and deterioration in school performance. 62.5% (5/8) cevher et al.47 (2018) to evaluate qol, clinical effective ness and satisfac tion in children and young adults with scd receiving hu therapy cohort turkey children aged 7–17 years and young adults aged 18–22 years with scd who received hu therapy for ≥1 year 50 (34 children and 16 young adults) chq-pf50 self and proxy • both qol and adherence to hu therapy were low, likely due to the lack of effectiveness of hu therapy, along with comorbidity, concomitant drug use and side-effects. 66.7% (4/6) essawy et al.21 (2018) to evaluate the qol of children with sca crosssectional iraq children with sca aged 6–12 years and their mothers 100 structured questionnaire and interviews self and proxy • sca significantly affected the qol of the children. • two-thirds of the children had poor qol, less than a quarter had neutral qol and few had good qol. • severe pain was reported by 78% of the affected children. 75% (6/8) senol et al.48 (2016) to evaluate qol, clinical effective ness and satisfac tion in patients with btm and sca receiving dfx chelation therapy cohort turkey children aged 5–18 years and adults with btm or sca who received dfx therapy for ≥6 months 72 (37 children and 35 adults) chq-pf50 proxy • patients with sca had significantly lower hrqol scores for general health, physical activity, role/social limitations, parental impacttime and family activities and higher scores for health transition compared to btm patients (p <0.05). 83.3% (5/6) alharbi et al.44 (2016) to assess the hrqol of children with sca crosssectional saudi arabia children with scd aged 6–12 years and their mothers 40 pedsql™ generic core scale self and proxy • scd significantly affected most hrqol domains, including physical, social, emotional and academic wellbeing domains. 87.5% (7/8) sehlo and kamfar45 (2016) to evaluate the association of social support, disease severity and depression on hrqol in children with scd casecontrol saudi arabia children with scd aged 10–15 years and matched healthy controls aged 9–15 years 120 (60 cases and 60 controls) pedsql™ generic core scale self and proxy • disease severity and depression were associated with poor qol in children with scd. 100% (9/9) hrqol = health-related quality of life; sca = sickle cell anaemia; pedsql™ = pediatric quality of life inventory™; v4 = version 4.0; scd = sickle cell disease; fgds = focus group discussions; qol = quality of life; hu = hydroxyurea; chq-pf50 = child health questionnaire parent form 50; btm = β-thalassemia major; dfx = deferasirox; whoqol-bref = world health organisation quality of life brief version; sf-36 v2 = 36-item medical outcomes study short-form version 2. *methodological quality was assessed using an adapted version of the newcastle-ottawa quality assessment scale, except for mixed-method studies, which were assessed using the mixed methods appraisal tool.41,42 cross-sectional, cohort and case-control studies were scored out of 8, 6 and 9, respectively, with scores of <50% considered to indicate poor methodological quality. health-related quality of life of children and adolescents with sickle cell disease in the middle east and north africa region a systematic review e284 | squ medical journal, november 2020, volume 20, issue 4 final study used a mixed-method design involving both quantitative and qualitative measures.43 most of the authors were nurses, medicine or health sciences faculty members, psychiatrists, haematologists, pharmacists or geneticists. four studies were conducted in saudi arabia, two in turkey and one each in iraq, sudan, uganda and oman.21,43–51 most of the studies focused primarily on children and adolescents aged 2–18 years.21,43–46,48,50,51 however, two studies focused both on paediatric and young adult populations aged 18–22 years.47,49 in most cases, self-reported measures were applied to children over the age of 8 years who were literate and capable of comprehension, with caregiver proxy reports utilised for those between 2–8 years.21,43–47,49–51 the sample size for children and adolescents with scd or sca ranged from 37–180.21,43–51 m e a s u r e s o f h e a lt h-r e l at e d q u a l i t y o f l i f e various tools were used to assess the hrqol of children and adolescents with scd. two studies used selfdesigned structured questionnaires completed during interviews.21,51 three studies utilised the generic core scale of the pediatric quality of life inventory™ (pedsql™); in addition, another study applied the pedsql™ scd module scale, version 4.0.43–46 two studies used the child health questionnaire parent form 50.47,48 finally, the who quality of life brief version scale and 36-item medical outcomes study short-form was applied in one study each.49,50 apart from the self-designed questionnaires, all of these instruments have been previously validated for use in different populations and various languages.43–50 d o m a i n s o f h e a lt h-r e l at e d q u a l i t y o f l i f e four distinct hrqol domains were identified in the studies including physical wellbeing, psychological wellbeing, family/financial wellbeing and academic functioning.21,43–51 in certain cases, specific findings from the studies encompassed more than one of these domains because of the interconnected nature of hrqol. p h y s i c a l w e l l-b e i n g boulassel et al. reported that children with sca in oman demonstrated low hrqol scores; in particular, the lowest scores were found on the pain impact scale thereby indicating that hrqol in this cohort was table 1 (cont’d): characteristics of studies assessing the health-related quality of life of children and adolescents with sickle cell disease in the middle east and north africa region (n = 10)21,43–51 author and year of publication purpose study design setting type of participants sample size instrument rater relevant findings quality of study* al jaouni et al.49 (2013) to assess the hrqol of patients with scd and to measure the impact of treatment adher ence on complic ations, disease sev erity, crises and out comes crosssectional saudi arabia patients with scd aged 2–48 years 115 (including 23 children aged 1–12 years, 33 adolescents aged 13–18 years and 25 adults aged 18–48 years) whoqolbref self and proxy • extremely ill patients had significantly lower hrqol scores (p = 0.002). • pain was the main cause of hospitalisation (51.3%). • patients with painful episodes (31.3%) and on regular narcotics had significantly lower hrqol scores (p <0.001). • hrqol scores decreased significantly as pain levels increased. • patients with delayed treatment or those who did not adhere to treatment reported significantly lower hrql scores (p = 0.001). 75% (6/8) amr et al.50 (2011) to evaluate hrqol deficiencies among adolescents with scd casecontrol saudi arabia adolescents with scd aged 14–18 years and ageand gender-matched healthy controls 382 (180 cases and 202 controls) sf-36 v2 self • adolescents with scd reported poorer hrqol scores compared to healthy adolescents, particularly in several hrqol domains, including physical functioning, body pain and general health 88.9% (8/9) hrqol = health-related quality of life; sca = sickle cell anaemia; pedsql™ = pediatric quality of life inventory™; v4 = version 4.0; scd = sickle cell disease; fgds = focus group discussions; qol = quality of life; hu = hydroxyurea; chq-pf50 = child health questionnaire parent form 50; btm = β-thalassemia major; dfx = deferasirox; who qol-bref = world health organisation quality of life brief version; sf-36 v2 = 36-item medical outcomes study short-form version 2. *methodological quality was assessed using an adapted version of the newcastle-ottawa quality assessment scale, except for mixed-method studies, which were assessed using the mixed methods appraisal tool.41,42 cross-sectional, cohort and case-control studies were scored out of 8, 6 and 9, respectively, with scores of <50% considered to indicate poor methodological quality. suthan pandarakutty, kamala murali, judie arulappan and sulaiman d. al-sabei review | e285 adversely affected by pain.46 in uganda, kambasu et al. observed low scores in terms of physical, emotional and academic functioning among adolescents with scd.43 according to cevher et al., both quality of life and adherence to hu therapy was low among paediatric and young adult patients in turkey; this was attributed to the lack of effectiveness of hu therapy, in addition to comorbidity, concomitant drug use and side-effects.47 in iraq, essawy et al. concluded that sca significantly affects the quality of life of children, with more than two-thirds of the cohort noted to have poor quality of life; moreover, the majority (78%) reported being in severe pain.21 among a cohort of scd patients in saudi arabia, al jaouni et al. observed that those who were extremely ill demonstrated significantly lower hrqol scores, with hrqol scores decreasing significantly as pain levels increased.49 in addition, patients with delayed or low adherence to treatment reported lower hrql scores.49 finally, in another study set in saudi arabia, amr et al. showed that adolescents with scd had poorer hrqol scores compared to healthy adolescents, particularly in terms of physical functioning, body pain and general health.50 p s y c h o l o g i c a l w e l l-b e i n g in sudan, salih confirmed that scd caused multiple social and psychological problems among schoolaged children, with enuresis, depressive symptoms, school absenteeism and deterioration in academic performance being most common.51 additionally, sehlo and kamfar reported associations between poor quality of life and disease severity and depression among children with scd in saudi arabia.45 fa m i ly a n d f i n a n c i a l w e l l-b e i n g in turkey, senol et al. reported significantly lower scores among a cohort of children and adolescents with sca for various hrqol-related subscales including general health, physical activity-related limitations, physical functioning, parental impact-time and family activities compared to patients with β-thalassaemia major.48 in addition, the former group demonstrated significantly higher scores in terms of health transition compared to the latter.48 a c a d e m i c f u n c t i o n i n g alharbi et al. found that scd significantly affected most hrqol domains in a group of children in saudi arabia including physical, social, emotional and academic well-being domains.44 discussion children with scd undergo frequent hospitalisation due to painful crises which can affect a myriad of other facets of life including academic achievement, school attendance, social activities and sleep quality.29,52 moreover, scd can affect familial relationships and the ability to engage in routine family activities; for caregivers, looking after a child with scd can represent an emotional and financial burden.53 individuals with scd also encounter stigma for a variety of reasons such as race, disability status, socioeconomic status, chronic pain and delayed growth and puberty.54 this systematic review examined the existing empirical literature regarding the hrqol of children and adolescents with scd in the mena region. overall, this population demonstrated poor hrqol in all domains compared to their healthy peers including physical, psychological, familial, academic, social and financial functioning.21,43–51 palermo et al. reported similar findings in a case-control study comparing 120 healthy children to 58 children with scd.55 using the child health questionnaire, the researchers found that the physical, psychological and social wellbeing of children with scd was reduced in comparison to the healthy control group.55 after applying the pedsql™ instrument, dale et al. found that 63%, 28% and 55% of 124 children and adolescents with scd were at risk of physical disability, poor social functioning and reduced academic performance, respectively.39 such findings highlight the need for urgent strategies to improve the hrqol of children and adolescents with scd. pain is a significant predictor for poor hrqol among children and adolescents with scd and a primary indicator of impaired physical and psychological functioning.56 thornburg et al. found that children with scd undergoing hu therapy demonstrated better physical and cognitive function compared to those who could not take the drug due to the extent of the disorder.57 panepinto et al. revealed that poor physical hrqol scores were correlated with clinical comorbidities, older age and lower family income.58 pain has also been positively associated with increased maternal and caregiver stress and impaired family functioning, thereby leading to poor hrqol outcomes.56 these findings are supported by those of other studies.46,59 as such, careful pain assessment at home and prompt management is recommended in order to promote resilience among children with scd and increase their quality of life. menezes et al. observed statistically significant gender differences in most hrqol domains.52 health-related quality of life of children and adolescents with sickle cell disease in the middle east and north africa region a systematic review e286 | squ medical journal, november 2020, volume 20, issue 4 however, contradictory findings have been reported regarding the effect of gender on pain sensation among children and adolescents with scd. according to andong et al., adolescent girls with scd demonstrated significantly lower levels of physical activity and physical pain; in contrast, kambasu et al. found that pain rates were higher in female children with scd compared to their male counterparts.43,60 therefore, further studies are needed to better understand gender differences in pain perception among children and adolescents with scd so as to tailor pain management strategies accordingly. various studies have reported poor cognitive and psychosocial performance in children and adolescents with scd.58,61,62 in a study conducted in india, patel and pathan reported that children with scd demonstrated low hrqol scores in in physical, psychosocial and cognitive areas.61 these results are supported by other studies which revealed that children with scd had lower self-esteem than healthy children.58,62 with regards to family, wonkam et al. found that mothers of children with scd had a higher risk of depression compared to mothers with healthy children.59 families with children affected by scd often face financial challenges. in many developing countries, national health insurance or social welfare programmes are lacking, thus placing the financial burden of care for children with chronic diseases on the individual family. in nigeria, lagunju et al. observed that families of children with scd often experienced severe hardship due to the child’s medical expenses, adversely affecting the family’s basic needs such as housing and food; moreover, loss of employment resulting from time spent caring for a child with scd also contributed significantly to this burden.34 therefore, countries in the mena region should take steps to help improve existing financial support systems for families affected by paediatric scd, perhaps through the provision of social welfare subsidies or programmes. various studies have shown that children with scd exhibit poor academic functioning compared to healthy children, with pain once again found to be a significant predictor of such outcomes.44,52,56 indeed, children and adolescents with scd are often absent from school, thereby missing out on important educational experiences and daily social activities due to frequent hospitalisation secondary to pain crises, depression, social stigma and poor social support systems.44,52 thus, it is necessary for educators to take necessary steps to improve the academic functioning of children with scd, for instance by establishing school or peer-led support groups and special extracurricular classes for affected children, or by allowing special leeway with regards to high rates of absenteeism for medical reasons. lack of awareness of the disease has been linked with poor hrqol outcomes among children and adolescents with scd, especially as awareness is usually poor among both affected patients and caregivers. shahine et al. found that an increase in awareness on the part of the caregiver was significantly associated with a decrease in the frequency of hospitalisation among children with scd.38 another study carried out by al-azri et al. indicated that the quality of life of children with scd in oman remained low primarily because of a lack of awareness of the disease.63 therefore, health promotion and educational programmes are recommended to increase awareness of scd and promote mandatory premarital screening to reduce the incidence of the disease in the mena region. social support can have a major impact on the resilience of children with scd such as that offered by family members, teachers, peers and friends. several studies have concluded that greater parental support and involvement is significantly linked to decreased depressive symptoms and better quality of life in children with scd.45,64 play therapy is a potential option to help children with scd to express their emotions, improve communication with caregivers and peers and encourage socialisation. similarly, pandarakutty et al. reported that a nurse-led filial therapy and educational intervention resulted in a significant improvement in hrqol scores among a group of children with scd in oman, particularly in terms of reducing emotions, improving knowledge, enhancing parental support and reinforcing family relationships.65 i m p l i c at i o n s f o r f u t u r e r e s e a r c h the findings of this systematic review underline an urgent need for practical measures to improve the hrqol of children and adolescents with scd in the mena region. such initiatives should focus on increasing knowledge and awareness of scd, developing support groups to enhance the psychological wellbeing of children and adolescents with scd and their caregivers, mitigating the economic burden of care on the families of children with scd and strengthening existing family, social and academic support systems. further studies are therefore necessary to help design, implement and assess the effectiveness of such strategies in this region. l i m i tat i o n s this research was subject to certain limitations. a meta-analysis could not be conducted to determine correlations between variables due to the differences suthan pandarakutty, kamala murali, judie arulappan and sulaiman d. al-sabei review | e287 in statistical analyses across studies. in addition, articles focusing on hrqol outcomes of children and adolescents with scd in the mena region which were published in other languages could not be included in the final analysis, possibly resulting in the lack of inclusion of relevant non-english language studies. conclusion a systematic review of studies assessing the hrqol of children and adolescents with scd in the mena region revealed that the hrqol of this population was poor in comparison to healthy children in all domains including physical, psychological, familial, academic, social and financial functioning. as such, healthcare providers, educators and policymakers should implement strategies to improve the hrqol of this group. the authors recommend the implementation of mandatory awareness and premarital screening programmes, thereby increasing understanding, reducing stigma and minimising the incidence of hereditary diseases such as scd. in addition, interventions such as play therapy may help to encourage socialisation, reduce psychological stress and strengthen familial bonds. finally, existing financial support systems should be strengthened so as to alleviate the economic burden of medical care on affected families. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this research. references 1. yawn bp, buchanan gr, afenyi-annan an, ballas sk, hassell kl, james ah, et al. management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. jama 2014; 312:1033–48. https://doi.org/10.1001/jama.2014.10517. 2. centers for disease control and prevention. data & statistics on sickle cell disease. from: www.cdc.gov/ncbddd/sicklecell/ data.html accessed: apr 2020. 3. lemanek kl, ranalli m. sickle cell disease. in: roberts mc, steele rg, eds. handbook of pediatric psychology, 4th ed. new york, usa: guilford press, 2009. pp. 303–18. 4. mcgann pt, hernandez ag, ware re. sickle cell anaemia in sub-saharan africa: advancing the clinical paradigm through partnerships and research. blood 2017; 129:155–61. https://doi. org/10.1182/blood-2016-09-702324. 5. quinn ct. sickle cell disease in childhood: from newborn screening through transition to adult medical care. paediatr clin north am 2013; 60:1363–81. https://doi.org/10.1016/j. pcl.2013.09.006. 6. aygun b, odame i. a global perspective on sickle cell disease. pediatr blood cancer 2012; 59:386–90. https://doi.org/10.1002/ pbc.24175. 7. makani j, cox se, soka d, komba an, oruo j, mwamtemi h, et al. mortality in sickle cell anemia in africa: a prospective cohort study in tanzania. plos one 2011; 6:e14699. https://doi. org/10.1371/journal.pone.0014699. 8. sack ff, njangtang dm, chemegni bc, djientcheu vd. prev alence of sickle cell disease in newborns in the yaounde central hospital. j med res 2017; 3:277–9. https://doi.org/10.31254/ jmr.2017.3607. 9. macharia aw, mochamah g, uyoga s, ndila cm, nyutu g, makale j, et al. the clinical epidemiology of sickle cell anemia in africa. am j hematol 2018; 93:363–70. https://doi.org/10.1002/ ajh.24986. 10. kauf tl, coates td, huazhi l, mody-patel n, hartzema ag. the cost of health care for children and adults with sickle cell disease. am j hematol 2009; 84:323–7. https://doi.org/10.1002/ ajh.21408. 11. piel fb, hay si, gupta s, weatherall dj, williams tn. global burden of sickle cell anaemia in children under five, 20102050: modelling based on demographics, excess mortality, and interventions. plos med 2013; 10:e1001484. https://doi. org/10.1371/journal.pmed.1001484. 12. world health organization. sickle-cell anaemia: report by the secretariat. from: https://apps.who.int/gb/archive/pdf_files/ wha59/a59_9-en.pdf accessed: apr 2020. 13. dormandy e, james j, inusa b, rees d. how many people have sickle cell disease in the uk? j public health (oxf ) 2018; 40:e291–5. https://doi.org/10.1093/pubmed/fdx172. 14. bouva mj, mohrmann k, brinkman hb, kemper-proper ea, elvers b, loeber jg, et al. implementing neonatal screening for haemoglobinopathies in the netherlands. j med screen 2010; 17:58–65. https://doi.org/10.1258/jms.2010.009075. 15. carey pj. addressing the global health burden of sickle cell disease. int health 2014; 6:269–70. https://doi.org/10.1093/ inthealth/ihu045. 16. piel fb, patil ap, howes re, nyangiri oa, gething pw, dewi m, et al. global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. lancet 2013; 381:142–51. https://doi. org/10.1016/s0140-6736(12)61229-x. 17. mulumba ll, wilson l. sickle cell disease among children in africa: an integrative literature review and global recomm endations. int j africa nurs sci 2015; 3:56–64. https://doi. org/10.1016/j.ijans.2015.08.002. 18. tadmouri go, nair p, obeid t, al ali mt, al khaja n, hamamy ha. consanguinity and reproductive health among arabs. reprod health 2009; 6:17. https://doi.org/10.1186/17424755-6-17. 19. memish za, saeedi my. six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and β-thalassemia in saudi arabia. ann saudi med 2011; 31:229–35. https://doi.org/10.4103/0256-4947.81527. 20. jastaniah w. epidemiology of sickle cell disease in saudi arabia. ann saudi med 2011; 31:289–93. https://doi.org/10.4103/02564947.81540. 21. essawy ma, el sharkawy a, al shabbani z, aziz ar. quality of life of children with sickle cell anemia. iosr j nurs health sci 2018; 7:29–39. https://doi.org/10.9790/1959-0702102939. 22. el-hazmi ma, al-hazmi am, warsy as. sickle cell disease in middle east arab countries. indian j med res 2011; 134:597–610. https://doi.org/10.4103/0971-5916.90984. https://doi.org/10.1001/jama.2014.10517 https://doi.org/10.1182/blood-2016-09-702324 https://doi.org/10.1182/blood-2016-09-702324 https://doi.org/10.1016/j.pcl.2013.09.006 https://doi.org/10.1016/j.pcl.2013.09.006 https://doi.org/10.1002/pbc.24175 https://doi.org/10.1002/pbc.24175 https://doi.org/10.1371/journal.pone.0014699 https://doi.org/10.1371/journal.pone.0014699 https://doi.org/10.31254/jmr.2017.3607 https://doi.org/10.31254/jmr.2017.3607 https://doi.org/10.1002/ajh.24986 https://doi.org/10.1002/ajh.24986 https://doi.org/10.1002/ajh.21408 https://doi.org/10.1002/ajh.21408 https://doi.org/10.1371/journal.pmed.1001484 https://doi.org/10.1371/journal.pmed.1001484 https://doi.org/10.1093/pubmed/fdx172 https://doi.org/10.1258/jms.2010.009075 v v https://doi.org/10.1016/s0140-6736%2812%2961229-x https://doi.org/10.1016/s0140-6736%2812%2961229-x https://doi.org/10.1016/j.ijans.2015.08.002 https://doi.org/10.1016/j.ijans.2015.08.002 https://doi.org/10.1186/1742-4755-6-17 https://doi.org/10.1186/1742-4755-6-17 https://doi.org/10.4103/0256-4947.81527 https://doi.org/10.4103/0256-4947.81540 https://doi.org/10.4103/0256-4947.81540 https://doi.org/10.9790/1959-0702102939 https://doi.org/10.4103/0971-5916.90984 health-related quality of life of children and adolescents with sickle cell disease in the middle east and north africa region a systematic review e288 | squ medical journal, november 2020, volume 20, issue 4 23. rajab a, al rashdi i, al salmi q. genetic services and testing in the sultanate of oman: sultanate of oman steps into modern genetics. j community genet 2013; 4:391–7. https://doi.org/10.10 07/s12687-013-0153-1. 24. alkindi s, al zadjali s, al madhani a, daar s, al haddabi h, al abri q, et al. forecasting hemoglobinopathy burden through neonatal screening in omani neonates. hemoglobin 2010; 34:135–44. https://doi.org/10.3109/03630261003677213. 25. rajab ag, patton ma, modell b. study of hemoglobinopathies in oman through a national register. saudi med j 2000; 21:1168–72. 26. potoka kp, gladwin mt. vasculopathy and pulmonary hyper tension in sickle cell disease. am j physiol lung cell mol physiol 2015; 308:l314–24. https://doi.org/10.1152/ajplung.00252.2014. 27. brousseau dc, owens pl, mosso al, panepinto ja, steiner ca. acute care utilization and rehospitalizations for sickle cell disease. jama 2010; 303:1288–94. https://doi.org/10.1001/jama.2010.378. 28. jastaniah w, abrar mb, khattab t. treatment related mortality of aml pediatric patients in a single center in saudi arabia. blood 2011; 118:4291. https://doi.org/10.1182/blood.v118.21.4291.4291. 29. meier er, miller jl. sickle cell disease in children. drugs 2012; 72:895–906. https://doi.org/10.2165/11632890-000000000-00000. 30. manwani d, frenette ps. vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. blood 2013; 122:3892–8. https://doi.org/10.1182/blood-2013-05-498311. 31. yale sh, nagib n, guthrie t. approach to the vaso-occlussive crisis in adults with sickle cell disease. am fam physician 2000; 61:1349–56. 32. jaiyesimi o, kasem m. acute chest syndrome in omani children with sickle cell disease: epidemiology and clinical profile. ann trop paediatr 2007; 27:193–9. https://doi.org/10.1179/1465328 07x220307. 33. jaiyesimi f, pandey r, bux d, sreekrishna y, zaki f, krishnamoorthy n. sickle cell morbidity profile in omani children. ann trop paediatr 2002; 22:45–52. https://doi.org/10.1179/027249302125000148. 34. lagunju ia, brown bj, sodeinde oo. chronic blood transfusion for primary and secondary stroke prevention in nigerian child ren with sickle cell disease: a 5-year appraisal. pediatr blood cancer 2013; 60:1940–5. https://doi.org/10.1002/pbc.24698. 35. ballas sk, bauserman rl, mccarthy wf, castro ol, smith wr, waclawiw ma. hydroxyurea and acute painful crises in sickle cell anemia: effects on hospital length of stay and opioid utilization during hospitalization, outpatient acute care cont acts, and at home. j pain symptom manage 2010; 40:870–82. https://doi.org/10.1016/j.jpainsymman.2010.03.020. 36. voskaridou e, christoulas d, bilalis a, plata e, varvagiannis k, stamatopoulos g, et al. the effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (lashs). blood 2010; 115:2354–63. https://doi.org/10.11 82/blood-2009-05-221333. 37. angelucci e, matthes-martin s, baronciani d, bernaudin f, bonanomi s, cappellini md, et al. hematopoietic stem cell trans plantation in thalassemia major and sickle cell disease: indic ations and management recommendations from an international expert panel. haematologica 2014; 99:811–20. https://doi.org/1 0.3324/haematol.2013.099747. 38. shahine r, badr lk, karam d, abboud m. educational inter vention to improve the health outcomes of children with sickle cell disease. j pediatr health care 2015; 29:54–60. https://doi. org/10.1016/j.pedhc.2014.06.007. 39. dale jc, cochran cj, roy l, jernigan e, buchanan gr. healthrelated quality of life in children and adolescents with sickle cell disease. j pediatr health care 2011; 25:208–15. https://doi. org/10.1016/j.pedhc.2009.12.006. 40. moher d, shamseer l, clarke m, ghersi d, liberati a, petticrew m, et al. preferred reporting items for systematic review and metaanalysis protocols (prisma-p) 2015 statement. syst rev 2015; 4:1. https://doi.org/10.1186/2046-4053-4-1. 41. wells ga, shea b, o’connell d, peterson j, welch v, losos m, et al. the newcastle-ottawa scale (nos) for assessing the quality of nonrandomized studies in meta-analyses. from: www.ohri.ca/programs/clinical_epidemiology/oxford.asp accessed: apr 2020. 42. pace r, pluye p, barlett g, macaulay ac, salsberg j, jagosh j, et al. testing the reliability and efficiency of the pilot mixed methods appraisal tool (mmat) for systematic mixed studies review. int j nurs stud 2012; 49:47–53. https://doi. org/10.1016/j.ijnurstu.2011.07.002. 43. kambasu dm, rujumba j, lekuya hm, munube d, mupere e. health-related quality of life of adolescents with sickle cell disease in sub-saharan africa: a cross-sectional study. bmc hematol 2019; 19:9. https://doi.org/10.1186/s12878-019-0141-8. 44. alharbi ea, alamri rf, aljerayan es, salawati hs, al-mjershi sm. quality of life assessment for children with sickle cell disease (scd) in mecca region. int j med sci public health 2016; 5:901–5. https://doi.org/10.5455/ijmsph.2016.29122015310. 45. sehlo mg, kamfar hz. depression and quality of life in children with sickle cell disease: the effect of social support. bmc psychiatry 2015; 15:78. https://doi.org/10.1186/s12888015-0461-6. 46. boulassel mr, al-badi a, elshinawy m, al-hinai j, al-saadoon m, al-qarni z, et al. hemoglobin f as a predictor of health-related quality of life in children with sickle cell anemia. qual life res 2019; 28:473–9. https://doi.org/10.1007/s11136-018-2031-0. 47. cevher f, ünal s, küçükkavruk şp, taşdelen b, tunçtan b. quality of life, clinical effectiveness, and satisfaction in pediatric and young adult patients with sickle cell disease receiving hydroxyurea therapy. turk klin j med sci 2018; 38:30–9. https://doi.org/10.5336/medsci.2017-57070. 48. senol sp, tiftik en, unal s, akdeniz a, tasdelen b, tunctan b. quality of life, clinical effectiveness, and satisfaction in patients with beta thalassemia major and sickle cell anemia receiving deferasirox chelation therapy. j basic clin pharm 2016; 7:49–59. https://doi.org/10.4103/0976-0105.177706. 49. al jaouni sk, al muhayawi ms, halawa tf, al mehayawi ms. treatment adherence and quality of life outcomes in patients with sickle cell disease. saudi med j 2013; 34:261–5. 50. amr ma, amin tt, al-omair oa. health related quality of life among adolescents with sickle cell disease in saudi arabia. pan afr med j 2011; 8:10. https://doi.org/10.4314/pamj.v8i1.71057. 51. salih km. the impact of sickle cell anemia on the quality of life of sicklers at school age. j family med prim care 2019; 8:468–71. https://doi.org/10.4103/jfmpc.jfmpc_444_18. 52. menezes as, len ca, hilário mo, terreri mt, braga ja. quality of life in patients with sickle cell disease. rev paul pediatr 2013; 31:24–9. https://doi.org/10.1590/s0103-05822013000100005. 53. adegoke sa, kuteyi ea. psychosocial burden of sickle cell disease on the family, nigeria. afr j prim health care fam med 2012; 4:380. https://doi.org/10.4102/phcfm.v4i1.380. 54. bhatt-poulose k, james k, reid m, harrison a, asnani m. incr eased rates of body dissatisfaction, depressive symptoms, and suicide attempts in jamaican teens with sickle cell disease. pediatr blood cancer 2016; 63:2159–66. https://doi.org/10.1002/pbc.26091. 55. palermo tm, schwartz l, drotar d, mcgowan k. parental report of health-related quality of life in children with sickle cell disease. j behav med 2002; 25:269–83. https://doi.org/10.1 023/a:1015332828213. 56. smith ke, patterson ca, szabo mm, tarazi ra, barakat lp. predictors of academic achievement for school age children with sickle cell disease. adv sch ment health promot 2013; 6:5–20. https://doi.org/10.1080/1754730x.2012.760919. 57. thornburg cd, calatroni a, panepinto ja. differences in health-related quality of life in children with sickle cell disease receiving hydroxyurea. j pediatr hematol oncol 2011; 33:251–4. https://doi.org/10.1097/mph.0b013e3182114c54. https://doi.org/10.1007/s12687-013-0153-1 https://doi.org/10.1007/s12687-013-0153-1 https://doi.org/10.3109/03630261003677213 https://doi.org/10.1152/ajplung.00252.2014 https://doi.org/10.1001/jama.2010.378 https://doi.org/10.1182/blood.v118.21.4291.4291 https://doi.org/10.2165/11632890-000000000-00000 https://doi.org/10.1182/blood-2013-05-498311 https://doi.org/10.1179/146532807x220307 https://doi.org/10.1179/146532807x220307 https://doi.org/10.1179/027249302125000148 https://doi.org/10.1002/pbc.24698 https://doi.org/10.1016/j.jpainsymman.2010.03.020 https://doi.org/10.1182/blood-2009-05-221333 https://doi.org/10.1182/blood-2009-05-221333 https://doi.org/10.3324/haematol.2013.099747 https://doi.org/10.3324/haematol.2013.099747 https://doi.org/10.1016/j.pedhc.2014.06.007 https://doi.org/10.1016/j.pedhc.2014.06.007 https://doi.org/10.1016/j.pedhc.2009.12.006 https://doi.org/10.1016/j.pedhc.2009.12.006 https://doi.org/10.1186/2046-4053-4-1 https://doi.org/10.1016/j.ijnurstu.2011.07.002 https://doi.org/10.1016/j.ijnurstu.2011.07.002 https://doi.org/10.1186/s12878-019-0141-8 https://doi.org/10.5455/ijmsph.2016.29122015310 https://doi.org/10.1186/s12888-015-0461-6 https://doi.org/10.1186/s12888-015-0461-6 https://doi.org/10.1007/s11136-018-2031-0 https://doi.org/10.5336/medsci.2017-57070 https://doi.org/10.4103/0976-0105.177706 https://doi.org/10.4314/pamj.v8i1.71057 https://doi.org/10.4103/jfmpc.jfmpc_444_18 https://doi.org/10.1590/s0103-05822013000100005 https://doi.org/10.4102/phcfm.v4i1.380 https://doi.org/10.1002/pbc.26091 https://doi.org/10.1023/a:1015332828213 https://doi.org/10.1023/a:1015332828213 https://doi.org/10.1080/1754730x.2012.760919 https://doi.org/10.1097/mph.0b013e3182114c54 suthan pandarakutty, kamala murali, judie arulappan and sulaiman d. al-sabei review | e289 58. panepinto ja, o’mahar km, debaun mr, loberiza fr, scott jp. health-related quality of life in children with sickle cell disease: child and parent perception. br j haematol 2005; 130:437–44. https://doi.org/10.1111/j.1365-2141.2005.05622.x. 59. wonkam a, mba cz, mbanya d, ngogang j, ramesar r, angwafo ff. psychosocial burden of sickle cell disease on parents with an affected child in cameroon. j genet couns 2014; 23:192–201. https://doi.org/10.1007/s10897-013-9630-2. 60. andong am, ngouadjeu ed, bekolo ce, verla vs, nebongo d, mboue-djieka y, et al. chronic complications and quality of life of patients living with sickle cell disease and receiving care in three hospitals in cameroon: a cross-sectional study. bmc hematol 2017; 17:7. https://doi.org/10.1186/s12878-017-0079-7. 61. patel ab, pathan hg. quality of life in children with sickle cell hemoglobinopathy. indian j pediatr 2005; 72:567–71. https://doi.org/10.1007/bf02724180. 62. malheiros cd, lisle l, castelar m, sá kn, matos ma. hip dys function and quality of life in patients with sickle cell disease. clin pediatr (phila) 2015; 54:1354–8. https://doi.org/10.1177/00 09922815586051. 63. al-azri mh, al-belushi r, al-mamari m, davidson r, mathew ac. knowledge and health beliefs regarding sickle cell disease among omanis in a primary healthcare setting: cross-sectional study. sultan qaboos univ med j 2016; 16:e437–44. https://doi. org/10.18295/squmj.2016.16.04.006. 64. hijmans ct, fijnvandraat k, oosterlaan j, heijboer h, peters m, grootenhuis ma. double disadvantage: a case control study on health-related quality of life in children with sickle cell disease. health qual life outcomes 2010; 8:121. https://doi. org/10.1186/1477-7525-8-121. 65. pandarakutty s, murali k, arulappan j, thomas ds. effect iveness of nurse led intervention on health related quality of life among children with sickle cell disease in oman: a pilot study. adv hematol 2019; 2019: 6045214. https://doi.org/10.11 55/2019/6045214. https://doi.org/10.1111/j.1365-2141.2005.05622.x https://doi.org/10.1007/s10897-013-9630-2 https://doi.org/10.1186/s12878-017-0079-7 https://doi.org/10.1007/bf02724180 https://doi.org/10.1177/0009922815586051 https://doi.org/10.1177/0009922815586051 https://doi.org/10.18295/squmj.2016.16.04.006 https://doi.org/10.18295/squmj.2016.16.04.006 https://doi.org/10.1186/1477-7525-8-121 https://doi.org/10.1186/1477-7525-8-121 https://doi.org/10.1155/2019/6045214 https://doi.org/10.1155/2019/6045214 department of surgery, college of medicine & allied health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: albusaidimeera@gmail.com overview of assault-induced trauma presenting to a trauma centre in oman *mira al-busaidi, hilal al-miskry, aisha al-harbi, ilyas al-zadjali, firas al-saidi, hani al-qadhi sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 549–553, epub. 25 nov 21 submitted 11 may 20 revisions req. 16 jul & 6 oct 20; revisions recd. 16 aug & 11 oct 20 accepted 14 oct 20 https://doi.org/10.18295/squmj.4.2021.033 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. assault-induc ed tr aum a (ait ) is a potentially life-threatening emergency that often requires a multidisciplinary approach, as it can contribute substantially to illness, disability and early death. victims of such traumatic injuries, who are usually young males, sustain injuries of varying complexities.1,2 the injuries can range from a simple isolated wound to complex injuries involving multiple organs.1 these injuries are commonly caused by the use of bodily force and the use of blunt and sharp objects.2,3 according to the 2016 omani statistics, 1,631 cases of assault were reported in the year 2015.4 contemporary medical literature pertaining to victims of ait is scarce, especially in oman. to the best of the authors’ knowledge, no local literature in this field has been published yet. this study aimed to characterise cases of ait victims presenting to sultan qaboos university hospital (squh), a tertiary care trauma centre in al khoud, muscat, oman. this will aid the analysis of local trends and the improvement of current management methods, thereby encouraging further research and the enhancement of health service delivery. methods this retrospective descriptive study included cases of ait that presented to the emergency department of squh between january 2007 and december 2018. cases of self-inflicted injuries, accidental injuries and patients with insufficient data in their medical records (more than three of the studied variables) were excluded from this study. furthermore, victims of assault who died prior to their arrival at the hospital were also excluded. cases were extracted from the electronic patient record using the hospital information system trakcare® (intersystems corporation, cambridge, massachusetts, usa; his). the data collected from the electronic records of all eligible cases were incorporated into an analysis sheet in the statistical package for the social sciences (spss), version 22 (ibm corp., chicago, illinois, usa). the data obtained included the following variables: incidence of assault per year, victims’ demographic data (age at the time of the assault, gender and nationality) and mode of assault. information regarding triaging abstract: objectives: assault-induced trauma (ait) is a public health concern that must be addressed and acknowledged. this study aimed to characterise cases of ait presenting to sultan qaboos university hospital (squh), muscat, oman. methods: this retrospective descriptive study included patients presenting with ait to the emergency department of squh from january 2007 to december 2018. the data obtained included incidence, patients’ demographics, mode of assault, triaging, management and hospital stay. the data were collected using the hospital’s information system and subsequently analysed. results: a total of 268 cases of ait were identified and 239 fulfilled the study criteria. the highest incidence recorded was in 2018, accounting for 72 cases. the mean incidence of ait was 20 ± 19 per year. the sample was predominantly comprised of males (82.4%) and omani citizens (65.3%). most patients (66.9%) were between the ages of 20 and 39. the most common mode of assault was the use of bodily force (34.7%). additionally, 18.4% were triaged as red cases. in terms of management, 84.5% of the cohort were treated non-surgically. no incidence of in-patient mortality was recorded. conclusion: this study found that the rate of ait averaged at 20 per year with most of the victims being young males. this was the first study that examined ait in oman and its results will aid future research and the estimation of the magnitude of this problem in the community. keywords: trauma; physical violence; demography; oman. advances in knowledge assault-induced trauma (ait) in oman is an uncommon presentation and this was the first study that addressed ait in the sultanate. most ait cases were male, omani citizens and between the ages of 20–39; the most common mode of assault was bodily force. applications to patient care this study shed light on the incidence of ait in oman and helped in assessing the magnitude of the problem in the community. the findings of this study will also form the basis for further research and policy creation. overview of assault-induced trauma presenting to a trauma centre in oman 550 | squ medical journal, november 2021, volume 21, issue 4 at the emergency department was also gathered and classified into red cases or non-red cases, where red cases were defined as cases that required the activation of the trauma team per hospital protocol. details regarding the patients’ hospital stay and management were also collected. the forms of patient management were classified into surgical (defined as any patient requiring a procedure in the operating theatre) and non-surgical management. patients who required non-surgical management were further subdivided into those who required a procedure (e.g. suturing and chest tube insertion) and those who were treated conservatively. missing data were recorded as ‘unknown’. ethical approval was obtained from the ethics committee at the college of medicine and health sciences, sultan qaboos university (ref. no.squ-ec/182/16 mrec#1364). results a total of 268 cases of ait were identified during the study period and 239 fulfilled the study’s criteria and were included. the mean incidence of ait was 20 ± 19 per year. the years 2007 and 2008 had the lowest incidence with three cases each year. in addition, the highest incidence recorded was in the year 2018, which accounted for 72 cases in total. furthermore, since the year 2016, the rate of incidence has shown an annual doubling pattern [figure 1]. there was a predominance of males who represented 197 cases (82.4%) compared to females who represented 42 cases (17.6%). the mean age was 29 ± 11 years with the highest incidence of assault involving victims aged between 20 and 29 (38.5%), followed by those between 30 and 39 (28.5%), while only four (1.7%) cases of assault involving patients below the age of 10 were documented. the majority of the assaults were on omanis compared to nonomanis (65.3% versus 34.7%). the most common mode of assault was the use of bodily force (34.7%) followed by knives (21.3%), blunt objects (18.8%), the use of explosives (1.3%) and sharp objects (1.3%). the mode of assault was not documented in some cases (19.7%). of the total cases of ait identified, 18.4% of the patients were triaged as red cases on arrival at the emergency department. approximately 30.1% of the patients required admission to the in-patient wards with a median length of stay of two days (interquartile range = 3) and three (4.2%) of those patients required intensive care unit admission. regarding the types of management, 15.5% of the patients required surgery. out of the patients who were treated non-surgically, 23% required a procedure (e.g. suturing and chest tube insertion) and 61.5% were only treated with conservative treatment. no cases of in-hospital mortality were documented [table 1]. discussion this study aimed to describe the incidence, demo graphics, mechanisms and management of ait victims presenting to squh. to the best of the authors’ knowledge, this is the first study to provide a detailed description of this type of trauma in oman. in this study, a total incidence of 268 cases was found over 12 years. studies conducted in europe, uk and africa have demonstrated that factors contributing to an increase in assault rates include unemployment, low socioeconomic status, gross income and alcohol consumption. on the other hand, being educated served as a positive protective factor against being assaulted.3,5–7 keeping these factors in mind, it should be noted that the rate of unemployment in oman has continued to decrease, reaching 1.84% of the total labour force in 2019.8 regarding education, oman showed a persistently increasing high gross enrolment rate in primary and secondary education, which reached 102.9% and 107%, respectively.9 furthermore, in march 2020, the national center for statistics figure 1: incidence of assault-induced trauma cases per year at sultan qaboos university hospital in muscat, oman, from 2007–2018 (n = 239). mira al-busaidi, hilal al-miskry, aisha al-harbi, ilyas al-zadjali,firas al-saidi and hani al-qadhi clinical and basic research | 551 and information published that oman has seen an increase in the average monthly income of households over the previous years.10 additionally, a report by the world health organization (who) titled ‘who global information system on alcohol and health (gisah)’, which was last updated in 2018, showed that oman witnessed alcohol consumption of 0.8 l per capita in 2016, which was significantly lower when compared to the global consumption at 6.4 l in the same year.11 considering all this, no obvious reason for this increase could be pinpointed by the current study; thus, this warrants further investigation. regarding the low incidence of assault cases in the years 2007 and 2008, this might not have reflected the true incidence during those years, as the his was in its early stages then. therefore, the retrieval of patients’ electronic medical records from that time was difficult. since 2016, the incidence of assault cases presenting to the emergency department has been doubling each year. wright and kariya’s study included assault patients presenting to the accident and emergency department in a hospital in scotland and it was found that 80% of the assault cases involved males with a mean age of 28 years.12 hadjizacharia et al.’s study explored different types of assault injuries in california, usa, by examining the patients’ outcomes following blunt assault over a period of 13 years; the study found that 89.7% of the cases involved males with a mean age of 36 years.13 el-abdellati et al.’s study, which was conducted in belgium in 2016, discussed the epidemiology and treatment strategies of assaultinduced stab injuries and concluded that 95% of the assaults occurred on men with a mean age of 31 years.14 subba et al.’s 2010 study aimed to establish the patterns of injuries in victims of physical assault presenting to a hospital in western nepal; the study found that the majority of cases (~63%) involved young males between the ages of 16 and 35.15 the present study is in agreement with the international published literature, as males accounted for 82.4% of the total number of cases with a mean age of 29. this establishes that across continents and types of assault injuries, young males are usually targeted. furthermore, subba et al.’s study demonstrated that the male predominance pattern also extended throughout all age groups.15 the most common mechanism of injury in the present study was the use of bodily force (34.7%) followed by the use of knives (21.3%) and blunt objects (18.8%). this was in line with wright and kariya’s study where body force was the most common mechanism, followed by the use of knives.12 mullen et al.’s study, which was conducted in pennsylvania, usa, examined interpersonal violence among youth aged 8–24 years and concluded that the use of bodily force was the most common mechanism.16 the fact that bodily force was used the most might reflect that most cases of assault were impromptu or not premeditated, as the assaulter(s) had not armed themselves beforehand. this is also apparent in the types of weapons commonly used (knives and blunt table 1: characteristics, mode of assault and management approach of assault-induced trauma patients (n = 239) variable n (%) gender male 197 (82.4) female 42 (17.6) age in years 0–9 4 (1.7) 10–19 40 (16.7) 20–29 92 (38.5) 30–39 68 (28.5) 40–49 22 (9.2) 50–59 12 (5.0) ≥ 60 1 (0.4) nationality omani 156 (65.3) non-omani 83 (34.7) mode of assault bodily force 83 (34.7) knife 51 (21.3) unknown 47 (19.7) blunt object 45 (18.8) bite 7 (2.9) explosives 3 (1.3) sharp object 3 (1.3) triage red case 44 (18.4) non-red case 195 (81.6) inpatient management required yes 72 (30.1) no 167 (69.9) management surgical 37 (15.5) procedural 55 (23.0) conservative 147 (61.5) overview of assault-induced trauma presenting to a trauma centre in oman 552 | squ medical journal, november 2021, volume 21, issue 4 objects, e.g. bricks and shoes), which are usually easy to obtain and could have been available on the site of the incident for the perpetrator to utilise. the low incidence of gun use can be attributed to the fact that it is not easy to obtain a gun in oman. to possess a gun, one must go through many legal procedures and protocols, which are monitored by the weapons law of oman. those include and are not restricted to the following: being 25 years of age, passing a physical and mental wellbeing test and having no criminal background.17 in the present study, the median length of stay was two days. o’mullane et al.’s study reviewed cases of assault that took place between 2001 and 2007 (data was obtained from the victorian state trauma registry for assaults). it identified 803 patients and a median length of stay of five days, which was longer compared to the present study.18 el-abdellati et al.’s study focused on assaults by stabbing and they found a median length of stay of three days.14 david-ferdon et al.’s study was conducted in the usa and analysed the trends of non-fatal assault injuries between the years 2001 and 2015 in patients between the ages of 10 and 24; they found that 87% were treated and discharged from the emergency department and did not require inpatient admission.19 the present study found a slightly lower rate of 69.9%; this could be explained by the difference in the age groups included between the two studies. furthermore, it has been established in the literature that great improvement has been made in the past few years in the approach adopted for the treatment of assaulted patients. treatment modalities have shifted toward a more conservative approach than an invasive approach that was practised previously.20 indeed, findings in the present study demonstrated that the main treatment approach was non-surgical in 84.5% of the total cases, out of whom the majority were treated conservatively (72.8%). for the present study, certain limitations should be noted. first, the lack of proper documentation of assault-induced trauma cases, which possibly resulted in missing several cases that had presented within the studied period. second, this study provided an incomplete picture of the magnitude of this problem in oman as it did not include cases that were managed in outpatient clinics and other health facilities. this, in turn, might affect the generalisability of the study’s results. finally, this study did not include those who died before arriving at the hospital and those who did not seek medical attention. conclusion this was the first study that examined ait in oman. it provides an insight into the demographics, mode of assault and the management of assault cases presenting to squh within the 12-year study period. the mean incidence of ait was 20 per year with most of the victims being males (accounting for 82.4%) of young age with a mean age of 29. the results of this study will aid in improving trauma care by providing a basis for future research and an estimation of the magnitude of this problem in the community. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n ma-b and aa-h drafted the proposal and applied for the ethical approval. ma-b, aa-h, ia-z and fa-s collected the data. ha-m and ia-z conducted the data analysis. ha-q supervised the work. ma-b, ha-m and aa-h drafted the manuscript. all authors approved the final version of the manuscript. references 1. kristoffersen s, normann sa, morild i, lilleng pk, heltne jk. the hazard of sharp force injuries: factors influencing outcome. j forensic leg med 2016; 37:71–7. https://doi.org/10.1016/j. jflm.2015.10.005. 2. tingne cv, shrigiriwar mb, ghormade ps, kumar nb. quantitative analysis of injury characteristics in victims of interpersonal violence: an emergency department perspective. j forensic leg med 2014; 26:19–23. https://doi.org/10.1016/j. jflm.2014.06.003. 3. bass p, sanyang e, lin m. risk factors for violent injuries and their severity among men in the gambia. am j mens health 2018; 12:2116–27. https://doi.org/10.1177/1557988318794524. 4. public prosecution (2016). statistics of cases committed to public prosecution. muscat, oman: public prosecution. 5. faergemann c, lauritsen jm, brink o, skov o, mortensen pb. demographic and socioeconomic risk factors of adult violent victimization from an accident and emergency department and forensic medicine perspective: a register-based casecontrol study. j forensic leg med 2009; 16:11–17. https://doi. org/10.1016/j.jflm.2008.05.014. 6. steen k, hunskaar s. violence in an urban community from the perspective of an accident and emergency department: a two-year prospective study. med sci monit 2004; 10:cr75–9. 7. brennan i, moore s, shepherd j. risk factors for violent victimisation and injury from six years of the british crime survey. int rev vict 2010; 17:209–29. https://doi. org/10.1177/026975801001700204. mira al-busaidi, hilal al-miskry, aisha al-harbi, ilyas al-zadjali,firas al-saidi and hani al-qadhi clinical and basic research | 553 8. the world bank. unemployment, total (% of total labor force) (modeled ilo estimate) – oman. from: https://data. worldbank .org/indic ator/sl .u e m.totl .z s?end=2019 accessed: oct 2020. 9. the world bank. countryprofile – oman. from: https:// d at ab a n k . w o r l d b a n k . o rg / v i e w s / re p o r t s / re p o r t w i d ge t . aspx?report_name=countr yprofile&id=b450fd57&tbar =y&dd=y&inf=n&zm=n&country=omn accessed: oct 2020. 10. national center for statistics and information; sultanate of oman. ncsi releases results of household income and expenditure survey. from: https://www.ncsi.gov.om/news/pages/newsc t_20200317104250050.aspx accessed: oct 2020. 11. world health organization. recorded alcohol per capita con sumption, three-year average with 95%ci – by country. from: https://apps.who.int/gho/data/node.main.a1029?lang=en accessed: oct 2020. 12. wright j, kariya a. assault patients attending a scottish accident and emergency department. j r soc med 1997; 90:322–6. https://doi.org/10.1177/014107689709000608. 13. hadjizacharia p, plurad ds, green dj, dubose j, benfield r, shiflett a, et al. outcomes of blunt assault at a level i trauma center. j trauma 2009; 66:1202–6. https://doi.org/10.1097/ ta.0b013e318180f5a0. 14. el-abdellati e, messaoudi n, van hee r. assault induced stab injuries: epidemiology and actual treatment strategy. acta chir belg 2011; 111:146–54. https://doi.org/10.1080/00015458.2011 .11680726. 15. subba sh, binu vs, menezes rg, kumar v, rana ms. physical assault related injuries in western nepal--a hospital based retrospective study. j forensic leg med 2010; 17:203–8. https:// doi.org/10.1016/j.jflm.2010.02.001. 16. mollen cj, fein ja, vu tn, shofer fs, datner em. charact erization of nonfatal events and injuries resulting from youth violence in patients presenting to an emergency department. pediatr emerg care 2003; 19:379–84. https://doi.org/10.1097/0 1.pec.0000101577.65509.95. 17. royal oman police. weapons law. from: https://www.rop.gov. om/pdfs/roplaws/roprule-8.pdf accessed: oct 2020 18. o’mullane pa, mikocka-walus aa, gabbe bj, cameron pa. incidence and outcomes of major trauma assaults: a populationbased study in victoria. med j aust 2009; 190:129–32. https://doi.org/10.5694/j.1326-5377.2009.tb02311.x. 19. david-ferdon cf, haileyesus t, liu y, simon tr, kresnow mj. nonfatal assaults among persons aged 10–24 years – united states, 2001–2015. mmwr morb mortal wkly rep 2018; 67:141–5. https://doi.org/10.15585/mmwr.mm6705a1. 20. bieler d, franke af, hentsch s, paffrath t, willms a, lefering r, et al. [gunshot and stab wounds in germany – epidemiology and outcome: analysis from the traumaregister dgu®]. unfall chirurg 2014; 117:995–1004. https://doi.org/10.1007/s00113014-2647-7. divisions of 1pharmacy, 2respiratory medicine and 3neurology, mito medical centre, university of tsukuba-mito kyodo general hospital, mito; 4division of general medicine, kasama city hospital, kasama; 5department of neurology, university of tsukuba, tsukuba, japan *corresponding author’s e-mail: hirosato@md.tsukuba.ac.jp maintaining weight and nutritional status with ninjin’yoeito in elderly patients with chronic wasting diseases yumi nakagawa,1 katsunori kagohashi,2 ayako shioya,3 kensuke kinoshita,4 hiroshi tsuji,5 *hiroaki satoh2 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 280–282, epub. 26 may 22 submitted 8 dec 20 revisions req. 17 jan & 14 feb 21; revisions recd. 1 feb & 22 feb 21 accepted 26 feb 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.071 brief communication abstract: objectives: this retrospective study aimed to obtain information on the nutritional maintenance effects of ninjin’yoeito (nyt) in elderly patients with chronic wasting diseases. methods: changes in body weight and serum levels of total protein and albumin were investigated in patients who received nyt for chronic wasting diseases for more than six months in mito medical centre, university of tsukuba-mito kyodo general hospital, mito, japan, from april 2009 to october 2019. results: during the study period, 11 patients (median age: 75 years) received nyt for six months or more. the median administration period of nyt was 14 months. the body weight and serum levels of total protein and albumin at the time of the last observation were not significantly different from those at the beginning of nyt administration (p = 0.176, p = 0.766 and p = 0.550, respectively). conclusion: this study suggested the possibility of maintaining nutritional condition by administering nyt in elderly patients with chronic wasting disease of various aetiologies. more evidence will be required to confirm these results. keywords: body weight; nutritional status; ninjin’yoeito; aged; chronic wasting disease. several kampo medicines (japanese traditional herbal medicines) have shown favourable nutritional effects in patients with chronic wasting diseases.1 among kampo medicines, hozai is a term used to refer to any drug that supplements what one is lacking physically and mentally.1 ninjin’yoeito (nyt) is a type of hozai that has been used for improving disturbances and imbalances in the homeostatic condition of the body.2,3 this kampo medicine is comprised of 12 herbs, including ginseng, one of the most famous herbal medicines used to treat chronic wasting disease symptoms.4 it is hypothesised that nyt might be a candidate drug for the treatment of frailty symptoms observed in the elderly.5 a retrospective study was conducted to obtain information on the nutritional maintenance effects of nyt in elderly patients with chronic wasting diseases. methods medical records of all of the patients who received nyt for chronic wasting diseases for more than six months in mito medical centre, university of tsukuba-mito kyodo general hospital, mito, japan, from april 2009 to october 2019 were reviewed. body weight and serum levels of total protein and albumin in these patients were evaluated at the beginning and end of nyt administration. a 2.5 g or 3 g (depending on the manufacturing company) dosage of nyt was orally administered three times per day. to rule out its possible effects on body weight and serum levels of protein and albumin, patients were treated with continuous administration of corticosteroids and those with serum protein transfusion during the study period were excluded from this study. due to the small number of patients who took nyt for a long period, instead of carrying out a background-matched property case-control study, comparisons of body weight and serum levels of total protein and albumin before and after nyt administration were performed for each patient in this study. data were analysed using statistical package for social sciences (spss), version 23 (ibm corporation, armonk, new york). the wilcoxon rank-sum test, a non-parametric test of paired samples, was used to compare the samples. follow-up sessions were conducted with patients for more than six months and it was confirmed that no patients received drugs that might affect the nutrition of the patients after the start of nyt administration. this study was approved by the institutional review board of mito medical centre, university of tsukuba-mito kyodo general hospital (nos. 15– 26). comprehensive written informed consent was obtained from each patient. results for the study period, 11 patients (males = 6, females = 5) who received nyt for six months or more were found in the in-hospital database. the median age was 75 years (56–90 years). all 11 patients had lost https://creativecommons.org/licenses/by-nd/4.0/ yumi nakagawa, katsunori kagohashi, ayako shioya, kensuke kinoshita, hiroshi tsuji and hiroaki satoh brief communication | 281 their appetite and eight of them had general fatigue. the sample’s underlying chronic diseases were as follows: four patients had respiratory diseases (two patients with chronic obstructive pulmonary disease, one with nontuberculous mycobacteriosis and one with combined pulmonary fibrosis and emphysema), four had neurological diseases (two patients with parkinson’s disease and two with polyneuropathy) and three had digestive diseases (two patients with chronic gastritis and one with gastric ulcer). the median administration period of nyt was 14 months (8–61 months). the participants’ body weight at the last observation (median: 47.9 kg, range: 43.5–70.0 kg) was not significantly different from their body weight at the start of administration (median: 48 kg, range: 42.7–70.0 kg; p = 0.176). moreover, there was no statistically significant difference in serum total protein level (median: 7.0 g/dl, range: 5.7–8.2 g/dl versus median: 6.9 g/dl, range: 5.8–7.9 g/dl; p = 0.766). their serum albumin level at the last observation (median: 3.9 g/dl, range: 2.8–4.6 g/dl) was not lower than that at the start of administration (median: 3.9 g/ dl, range: 2.4–4.6 g/dl; p = 0.550). among the male patients, changes in body weight and serum levels of total protein and albumin between the start and end of nyt administration were not statistically significant (p = 0.276). there were no changes in these three indicators between the two measurements in time (p = 0.285) among the female patients either. discussion since the 18th century, nyt has been prescribed in japan according to the original text (wazaikyokuho, héjì júfāng in chinese: a collection of prescriptions for medicines published in china in the 12th century) without any changes.6 nyt is made up of a combination of several crude herbal medicines: rehmannia glutinosa root, japanese angelica root, atractylodes lancea, poria sclerotium, ginseng, cinnamon bark, polygala root, peony root, citrus unshiu peel, astragalus root, glycyrrhiza and schisandra fruit.6 of these herbal medicines, ginseng is one of the most famous herbal medicines and has been administered to patients with chronic wasting diseases.4 nyt has been reported to be effective in treating anorexia in elderly individuals and fatigue in patients with cancer in various organs.2,5 the effects of nyt on frailty, cachexia and sarcopenia in patients with malignant and non-malignant diseases have been studied.2,5 however, in english literature, only a few studies have reported the long-term effects of this kampo medicine on body weight gain in patients with various chronic wasting diseases.2,5 given this background, this study sought to examine the effects of nyt on the maintenance of body weight and nutritional status in elderly patients with chronic wasting diseases. recently, suzuki et al. conducted a postmarketing survey among elderly patients to evaluate the safety and effectiveness of nyt.5 in this survey, the safety and effectiveness of nyt in 808 elderly patients were evaluated. the median age was 78 years and body weights at both baseline and week 24 were analysed in 275 (34.0%) of 808 patients. it was reported that the mean body weight in these 275 patients increased significantly from 49.4 ± 9.0 kg at baseline to 50.0 ± 9.0 kg at week 24 (p <0.01). there was a significant difference in women (p <0.01), but not in men. although body weight increased by 0.6 kg on average, the increment did not apply to all the 808 patients, and body weight was analysed using a paired t-test, which is not a non-parametric test. in addition, serum levels of total protein and albumin were not evaluated in that study.5 it was interesting that the mean or median body weight was around 50 kg in the post-marketing survey as well as in the current study. the differences in changes of body weight in the postmarketing survey and this study could be attributed to the difference in background diseases and the method considered for statistical analysis . a characteristic of the kampo medicinal approach is to deal with anorexia due to different pathologies in an integrated manner, rather than by engaging in comparative analysis using more western medical means. therefore, it would be meaningful to disseminate the information on the treatment results for patients who wish to be treated with herbal medicine. although this is a small-sized study without a comparative group and could not be comprehensive enough to draw generalisable conclusions, the information obtained from this study could help future researchers explore the role of nyt in treatments as an alternative to otherwise mainstream western avenues. conclusion the results obtained in this study suggested the possibility of maintaining nutritional condition by administration of nyt in elderly patients with chronic wasting disease of various aetiologies. as there was no control group in this study, future studies should include a control group to enable a solid conclusion to be drawn. maintaining weight and nutritional status with ninjin’yoeito in elderly patients with chronic 282 | squ medical journal, may 2022, volume 22, issue 2 c o n f l i c t s o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this pilot study. a u t h o r s’ c o n t r i b u t i o n yn, kak and hs designed the study. yn, kak, as, kek, ht and hs collected the data. yn, kak and hs analysed the data and prepared the manuscript. all authors approved the final version of the article. references 1. amitani m, amitani h, sloan ra, suzuki h, sameshima n, asakawa a, et al. the translational aspect of complementary and alternative medicine for cancer with particular emphasis on kampo. front pharmacol 2015; 6:150. https://doi.org/10.3389/ fphar.2015.00150. 2. miyano k, nonaka m, uzu m, ohshima k, uezono y. multi functional actions of ninjinyoeito, a japanese kampo medicine: accumulated scientific evidence based on experiments with cells and animal models, and clinical studies. front nutr 2018; 5:93. https://doi.org/10.3389/fnut.2018.00093. 3. scheid v, bensky d, ellis a, barolet r. chinese herbal medicine formulas and strategies. seattle, usa: eastland press, inc., 2009. pp. 505–618. 4. shergis jl, di ym, zhang al, vlahos r, helliwell r, ye jm, et al. therapeutic potential of panax ginseng and ginsenosides in the treatment of chronic obstructive pulmonary disease. complement ther med 2014; 22:944–53. https://doi.org/10.10 16/j.ctim.2014.08.006. 5. suzuki s, aihara f, shibahara m, sakai k. safety and effectiveness of ninjin’yoeito: a utilization study in elderly patients. front nutr 2019; 6:14. https://doi.org/10.3389/fnut.2019.00014. 6. terasawa, k. japanese and chinese medical practice learned from cases (in japanese). tokyo, japan: igaku-shoin ltd., 1990. https://doi.org/10.3389/fphar.2015.00150 https://doi.org/10.3389/fphar.2015.00150 https://doi.org/10.3389/fnut.2018.00093 https://doi.org/10.1016/j.ctim.2014.08.006 https://doi.org/10.1016/j.ctim.2014.08.006 https://doi.org/10.3389/fnut.2019.00014 departments of 1public health & community medicine, 4physiology and biochemistry, jordan university of science and technology, irbid, jordan; 2department of preventive medicine, jordanian royal medical services, amman, jordan; 3ministry of health, irbid, jordan *corresponding author’s e-mail: rasaadeh@just.edu.jo إصابات اإلبر واألدوات احلادة لدى عمال الرعاية الصحية دراسة إستعادية ملدة ستة سنوات رامي �صعادة، خالد خري اهلل، ح�صني اأبوزيد، ملا الر�صدان، حممود الفقيه، عبيد اهلل اخلطاطبة abstract: objectives: this study aimed to examine the proportion of needle stick and sharp injuries (nssis) among healthcare workers at king hussein medical center (khmc), amman, jordan. methods: all nssi reports referred from departments at khmc to the preventive medicine department between 2013–2018 were retrospectively reviewed. proportion of nssis were calculated and stratified according to age, gender, job title, place and site of injury and the procedure/task during which the injury occurred. results: there were a total of 393 nssis. a significant association was found between the proportion of nssis and all tested variables (p <0.001). the reported proportion of nssis was highest among nurses (39.7%) followed by cleaners (36.3%), physicians (10.4%), other workers (7.4%) and lab technicians (5.9%) during the study’s six-year period. hospital wards were the most common locations (46.1%) where injuries took place. injuries also occurred most frequently during medical waste collection (38.2%). conclusion: the proportion of nssis was highest among nurses and cleaners. safety policies and training among high-risk groups should be reviewed to reduce the risk of nssis. multicentre studies at a national level should be conducted to examine whether this study’s findings reflect national trends. keywords: needlestick injuries; safety; self report; nurses; accident prevention; jordan. امللخ�ص: الهدف: هدفت هذه الدرا�صة اإىل درا�صة حالت الإ�صابة بالإبر والأدوات احلادة بني العاملني يف جمال الرعاية ال�صحية يف مركز امللك ح�صني الطبي، عمان، الأردن. الطريقة: متت مراجعة جميع تقارير الإ�صابة بالإبر والأدوات احلادة املحالة من اأق�صام مركز امللك ح�صني الطبي اإىل ق�صم الطب الوقائي بني 2018-2013 باأثر رجعي. مت ح�صاب معدلت حدوث الإ�صابة بالإبر والأدوات احلادة وكانت املعدلت مق�صمة طبقيا وفقا للعمر واجلن�س وامل�صمى الوظيفي ومكان وموقع الإ�صابة والإجراء الذي وقع خالل الإ�صابة. النتائج: كان هناك ما جمموعه 393 حالة من الإ�صابة بالإبر والأدوات احلادة. مت العثورعلى ارتباط كبري بني حدوث الإ�صابة بالإبر والأدوات احلادة وجميع املتغريات التي مت اختبارها )لكل منها p >0.001(. كانت معدلت الإبالغ عن الإ�صابة بالإبر والأدوات احلادة اأعلى بني املمر�صات )%39.7( يليها اإ�صابة عمال النظافة )%36.3( والأطباء )%10.4( والعاملني الآخرين )%7.4( وفنيي املختربات )%5.9( خالل فرتة الدرا�صة ملدة ستة �صنوات. وكانت اأجنحة ا ب�صكل متكرر اأثناء جمع النفايات الطبية )38.2%(. امل�صت�صفى هي الأماكن الأكرث �صيوًعا حلدوث الإ�صابات )%46.1(. حدثت الإ�صابات اأي�صً اخلال�صة: كانت ن�صبة حدوث الإ�صابة بالإبر والأدوات احلادة اأعلى بني املمر�صات وعمال النظافة. يجب مراجعة �صيا�صات ال�صالمة والتدريب بني الفئات املعر�صة للخطر للحد من خماطر الإ�صابة بالإبر والأدوات احلادة. ينبغي اإجراء درا�صات متعددة املراكز على امل�صتوى الوطني لبحث ما اإذا كانت نتائج هذه الدرا�صة تعك�س الجتاهات الوطنية. الكلمات املفتاحية: اإ�صابات الإبر؛ ال�صالمة؛ تقرير ذاتي؛ املمر�صني؛ الوقاية من احلوادث؛ الأردن. needle stick and sharp injuries among healthcare workers a retrospective six-year study *rami saadeh,1 khaled khairallah,1 hussein abozeid,2 lama al rashdan,3 mahmoud alfaqih,4 obaidallah alkhatatbeh2 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e54–62, epub. 9 mar 20 submitted 26 may 19 revisions req. 15 jul & 8 aug 19; revisions recd. 22 jul & 10 aug 19 accepted 22 aug 19 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.008 clinical & basic research advances in knowledge the current study highlights work-related factors associated with needle stick and sharp injuries (nssis) in settings where a surveillance system does not exist. this study highlights the importance of initiating effective surveillance as well as a reporting system that could contribute to reducing the occurrence of nssis locally and nationally. application to patient care a safe work environment that minimises injuries among healthcare workers provides a higher level of quality care to patients and lower possibility of infectious disease transmission. percutaneous needle stick and sharp injuries (nssis) could be associated with healthcare workers’ (hcws) exposure to hepatitis b (hbv), hepatitis c (hcv) and hiv. more than 20 other infections could be transmitted through nssis, including syphilis, malaria and herpes.1,2 using devices with safety features, promoting health education and implementing safety protocols and https://creativecommons.org/licenses/by-nd/4.0/ rami saadeh, khaled khairallah, hussein abozeid, lama al rashdan, mahmoud alfaqih and obaidallah alkhatatbeh clinical and basic research | e55 training programmes for individuals at risk of nssis are part of national public health policies designed to prevent the transmission of blood-borne pathogens among or to hcws.3 although most nssis occur in developing countries, nssis are still reported in developed countries, indicating that nssis might be a global problem. indeed, although developed countries use prevention measures as advanced as real-time injury monitoring systems coupled with standard operating protocols, nssis still occur.4,5 the prevalence of nssis is higher in developing countries than developed countries.6 however, exp eriences from several developing countries demonstrate that implementing national health policy plans consisting of established safety protocols and offering mandatory training programmes to hcws can be successful in reducing the prevalence of nssis and associated infections.7,8 despite the established safety protocols in some developing countries, compliance with safety protocols is below expectations and nssis often go unreported.9,10 it has been suggested that to improve compliance with guidelines related to infection control practices, a culturally-oriented approach which aims to improve overall community awareness and focuses on both organisational and individual account ability should be developed. however, for this approach to be successful in achieving its goals, it must be supported by establishing policies and surveillance systems and providing adequate training to hcws.11,12 few studies have examined nssis in jordan and most have only included data collected from practicing nurses or nursing students.10,13–15 these studies concluded that nssi rates are high among nurses and nursing students, the level of awareness of universal precaution guidelines is low, reporting occupational exposures to nssis is inadequate and young female nurses with fewer years of experience are more vulnerable to nssis.10,13–15 studies on the proportion of nssis among hcws, except nurses, have not been conducted in jordan. moreover, none of the studies investigated the practices and predisposing factors associated with nssis among affected hcws. thus, further investigations are needed to understand the causes of the high nssi rate and the low level of knowledge of safety practices and precautionary guidelines.16,17 it is difficult to identify the precise reason for the high proportion of nssis; however, by collecting information about the site of injury, the hospital department where the injury took place and the procedure performed by the hcw when the nssi occurred, it may be possible to infer trends. identifying these trends would allow for the development of better preventive measures and programmes. the lack of similar studies in jordan and a shortage of addressing hcws’ safety concerns in public hospitals necessitates efficient, useful and accurate research which may yield possible prevention methods. therefore, this study aimed to measure the proportion of nssis among hcws of the jordanian royal medical services between 2013–2018, to examine the associations of selected factors, including age, gender, job, place and site of injury and type of procedure/task performed when the nssi occurred. methods this retrospective study was conducted at the prev entive medicine department at king hussein medical center (khmc), amman, jordan, between 2013–2018. the preventive medicine department is the site of referral for all injuries from all other departments at khmc and is thus expected to house all injury reports regardless of the department in which they took place. khmc is a medical compound consisting of five hospitals. this centre is one of the major jordanian royal medical services hospitals distributed in different governorates across jordan. injury report forms are housed within the department of preventive medicine at the royal medical services, which covers all hcws. all nssi report sheets were collected and reviewed by a clinical research coordinator and all data used for analysis were extracted directly from the reports. all reported cases that took place between 2013–2018 were included in the study. data collected included age, gender, job, place and site of injury and type of procedure/task being performed at the time of injury. extracted data were entered in excel spreadsheets, version 2010 (microsoft corp., redmond, washington, usa) and then exported into statistical package for the social sciences (spss), version 22 (ibm, corp., armonk, new york, usa), which was used for all analyses. the proportion of nssis was calculated based on age, gender, job, place and site of injury and type of procedure when injury occurred. chi-squared test was used to examine relationships among the above listed variables. a p value <0.05 was considered statistically significant. this study was approved by the institutional review board committee of khmc. needle stick and sharp injuries among healthcare workers a retrospective six-year study e56 | squ medical journal, february 2020, volume 20, issue 1 results a total of 393 nssis were included in this study. more than half of reported injuries were among males (55.5%) and almost two-thirds were among those aged 20–30 years old (66.4%). most reported cases were among nurses (39.7%) and cleaners (36.6%). almost half of reported injuries occurred in hospital wards (46.1%) and more than one-third of reported injuries occurred during medical waste collection (38.2%). injuries occurred mainly in the left and right hand (48.9% and 42.2%, respectively). although injury rates increased from 15.0% in 2013 to 21.1% in 2015, they declined to 13.5% in 2018 [table 1]. all variables were statistically significant according to participants’ job titles (p <0.001 each). most injuries among those 20–30 years old occurred among nurses (59.4%) and cleaners (22.6%). among those older than 30 years, most injuries (68%) were found among cleaners. the majority of reported injuries among males were from nurses (67.4%) and among females, cleaners had the most injuries (66.9%). within laboratory settings, all cases were among nurses and in wards the majority (57.5%) was found among nurses. in the outpatient (op) clinics, almost all injuries were among cleaners (97.9%). right-hand injuries occurred mostly among nurses (68.7%) while left-hand injuries were most common among cleaners (66.1%). although the incidence of nssis during medical waste collection or while giving medication was mainly among nurses, injuries during other procedures occurred most often among cleaners [table 2]. the comparison of nssis by location of injury to all variables was statistically significant (p <0.001 each). in 20–30 years old, most nssis happened in hospital wards (67%) followed by the operating room (or; 20.3%). males reported having more in-ward injuries than females (60.1% versus 28.6%, respectively). most injuries among physicians occurred in the or (85.4%) while injuries among nurses occurred mainly in wards (66.7%), followed by the laboratory (17.3%) and the or (16%). right and left hand injuries were mainly reported in hospital wards (47.6% and 53.1%, respectively) [table 3]. following hospital wards (46.1%), the most frequent place for injuries were other locations (19.6%), ors (15.3%) and op clinics (12.2%) [table 1]. all relationships between nssis by procedure and other independent variables were statistically significant (p <0.001 each). the proportion of nssis during medical waste collection was highest among those aged 20–30 years (54.8%) compared to other age groups. females were more commonly injured during an unusual occurrence (33.1%) or surgical intervention table 1: distribution of needle stick and sharp injuries according to selected variables of healthcare workers in jordan (n = 393) variable n (%) age in years <20 7 (1.8) 20–30 261 (66.4) >30 125 (31.8) gender male 218 (55.5) female 175 (44.5) job title physician 41 (10.4) nurse 156 (39.7) lab technician 23 (5.9) cleaner 144 (36.6) other 29 (7.4) place of injury or 60 (15.3) laboratory 27 (6.9) hospital wards 181 (46.1) op clinic 48 (12.2) other 77 (19.6) site of injury right hand 166 (42.2) left hand 192 (48.9) lower limb 27 (6.9) chest & abdomen 2 (0.5) head & neck 6 (1.5) procedure/task during which injury occurred medical waste collection 150 (38.2) giving medication 41 (10.4) blood sampling 61 (15.5) surgical intervention 59 (15) blood analysis 24 (6.1) unusual occurrence 58 (14.8) year injury reported 2013 59 (15.0) 2014 64 (16.3) 2015 83 (21.1) 2016 77 (19.6) 2017 57 (14.5) 2018 53 (13.5) or = operating room; op = outpatient. rami saadeh, khaled khairallah, hussein abozeid, lama al rashdan, mahmoud alfaqih and obaidallah alkhatatbeh clinical and basic research | e57 (30.3%) than other procedures. it is noteworthy that nssis among physicians occurred mainly during surgical interventions (85.4%). during surgical interventions, the left hand was more commonly injured (30.7%) while the right hand was more commonly injured during medical waste collection (83.1%) [table 4]. regarding the comparison of nssis by site to other independent variables, the site of injury was statistically significant for all variables (p <0.001 each). in op clinics, injuries were reported only in the left hand (100%). moreover, among cleaners (88.2%), females (77.7%) and at hospital wards (56.4%) left hand injuries were the most common. among the procedures/tasks during which an injury occurred, the right hand was most often injured during medical waste collection (92%) [table 5]. discussion nssis are frequent yet preventable occupational hazards among hcws. according to recent world health organization estimates, approximately two million nssi cases are reported annually, but this number could be an underestimation as many cases of nssis are not reported, especially in developing countries.1,11,18 public health sectors are concerned about nssis because they comprise a major source of morbidity and mortality worldwide. it is estimated table 2: comparison of needle stick and sharp injuries by job title to independent variables of healthcare workers in jordan (n = 393) variable n (%) p value physician nurse lab technician cleaner other total age in years <20 6 (85.7) 1 (14.3) 0 (0) 0 (0) 0 (0) 7 (100) <0.001 20–30 29 (11.1) 155 (59.4) 18 (6.9) 59 (22.6) 0 (0) 261 (100) >30 6 (4.8) 0 (0) 5 (4) 85 (68) 29 (23.2) 125 (100) gender male 35 (16.1) 147 (67.4) 9 (4.1) 27 (12.4) 0 (0) 218 (100) <0.001 female 6 (3.4) 9 (5.1) 14 (8) 117 (66.9) 29 (16.6) 175 (100) place of injury or 35 (58.3) 25 (41.7) 0 (0) 0 (0) 0 (0) 60 (100) <0.001 lab 0 (0) 27 (100) 0 (0) 0 (0) 0 (0) 27 (100) hospital ward 0 (0) 104 (57.5) 18 (9.9) 59 (32.6) 0 (0) 181 (100) op clinic 0 (0) 0 (0) 0 (0) 47 (97.9) 1 (2.1) 48 (100) other 6 (7.8) 0 (0) 5 (6.5) 38 (49.4) 28 (36.4) 77 (100) site of injury right hand 35 (21.1) 114 (68.7) 9 (5.4) 8 (4.8) 0 (0) 166 (100) <0.001 left hand 2 (1) 42 (21.9) 14 (7.3) 127 (66.1) 7 (3.6) 192 (100) lower limb 4 (14.8) 0 (0) 0 (0) 9 (33.3) 14 (51.9) 27 (100) chest & abdomen 0 (0) 0 (0) 0 (0) 0 (0) 2 (100) 2 (100) head & neck 0 (0) 0 (0) 0 (0) 0 (0) 6 (100) 6 (100) procedure/task during which injury occurred medical waste collection 35 (23.3) 104 (69.3) 4 (2.7) 7 (4.7) 0 (0) 150 (100) <0.001 giving medication 0 (0) 27 (65.9) 0 (0) 14 (34.1) 0 (0) 41 (100) blood sampling 0 (0) 24 (39.3) 8 (13.1) 29 (47.5) 0 (0) 61 (100) surgical intervention 0 (0) 1 (1.7) 8 (13.6) 50 (84.7) 0 (0) 59 (100) blood analysis 0 (0) 0 (0) 3 (12.5) 18 (75) 3 (12.5) 24 (100) unusual occurrence 6 (10.4) 0 (0) 0 (0) 26 (44.8) 26 (44.8) 58 (100) or = operating room; op = outpatient. needle stick and sharp injuries among healthcare workers a retrospective six-year study e58 | squ medical journal, february 2020, volume 20, issue 1 that nssis account for 16,000, 66,000 and 1,000 annual cases of hcv, hbv and hiv infections, respectively. this may lead to approximately 1,100 deaths or significant disabilities.18 despite the global magnitude of nssi occurrence and the negative impact it has in terms of morbidity and mortality, studies evaluating nssis in jordan are scarce or have not been comprehensive in design or have only focused on the nursing sector.14,16,19–21 although the current study includes only nssi data from one medical centre, all nssi reports referred to the preventive medicine department from 2013–2018 were collected, regardless of the referring party. information related to age, gender and occupation of the nssi referee were also collected. moreover, site of the nssi and the procedure/ task performed by the individual at the time of injury was acquired. this study helps identify potential risk factors, gaps in the current preventive strategies implemented at khmc and may serve as a roadmap for future changes in preventive medicine and public health policies at the institution. although this study was limited in size and only included data collected from one institution, it could serve as a pilot study, and the study design could be easily modified. implementation on a national scale is a future direction anticipated by the authors. analogous to other developing countries, the proportion of nssis among hcws at khmc was relatively high.4,5,7,13,22–26 this finding is in agreement table 3: comparison of needle stick and sharp injuries by location of injury to independent variables of healthcare workers in jordan (n = 393) variable n (%) p value or lab wards op clinic other total age in years <20 7 (100) 0 (0) 0 (0) 0 (0) 0 (0) 7 (100) <0.00120–30 53 (20.3) 27(10.3) 175 (67) 6 (2.3) 0 (0) 261 (100) >30 0 (0) 0 (0) 6 (4.8) 42 (33.6) 77 (61.6) 125 (100) gender male 60 (27.5) 27 (12.4) 131 (60.1) 0 (0) 0 (0) 218 (100) <0.001 female 0 (0) 0 (0) 50 (28.6) 48 (27.4) 77 (44) 175 (100) job title physician 35 (85.4) 0 (0) 0 (0) 0 (0) 6 (14.6) 41 (100) <0.001 nurse 25 (16) 27 (17.3) 104 (66.7) 0 (0) 0 (0) 156 (100) lab technician 0 (0) 0 (0) 18 (78.3) 0 (0) 5 (21.7) 23 (100) cleaner 0 (0) 0 (0) 59 (41) 47 (32.6) 38 (26.4) 144 (100) other 0 (0) 0 (0) 0 (0) 1 (3.4) 28 (96.6) 29 (100) site of injury right hand 60 (36.1) 27 (16.3) 79 (47.6) 0 (0) 0 (0) 166 (100) <0.001 left hand 0 (0) 0 (0) 102 (53.1) 48 (25) 42 (21.9) 192 (100) lower limb 0 (0) 0 (0) 0 (0) 0 (0) 27(100) 27 (100) chest & abdomen 0 (0) 0 (0) 0 (0) 0 (0) 2 (100) 2 (100) head & neck 0 (0) 0 (0) 0 (0) 0 (0) 6 (100) 6 (100) procedure/task during which injury occurred medical waste collection 60 (40) 27(18) 63 (42) 0 (0) 0 (0) 150 (100) <0.001 giving medication 0 (0) 0 (0) 41 (100) 0 (0) 0 (0) 41 (100) blood sampling 0 (0) 0 (0) 57 (93.4) 4 (6.6) 0 (0) 61 (100) surgical intervention 0 (0) 0 (0) 14 (23.7) 33 (55.9) 12 (20.3) 59 (100) blood analysis 0 (0) 0 (0) 5 (20.8) 6 (25) 13 (54.2) 24 (100) unusual occurrence 0 (0) 0 (0) 1 (1.7) 5 (8.6) 52 (89.7) 58 (100) or = operating room; lab = laboratory; op = outpatient. rami saadeh, khaled khairallah, hussein abozeid, lama al rashdan, mahmoud alfaqih and obaidallah alkhatatbeh clinical and basic research | e59 with the results of many studies that found a high incidence rate of nssis among nurses and nursing students.1,15,16,21,23,24,27 the exact cause of the high proportion of nssis among hcws, including nurses, is unknown but could be related to several factors. it is possible that the public in jordan and many other developing countries prefer injections over other methods for the delivery of drugs and pharmaceuticals.11,21 this preference would result in a higher rate of injections in public and private clinics; a higher injection rate could explain the high proportion of injection-related nssis observed in this study. hospitals and other medical centres in jordan, especially those affiliated with the military, are shortstaffed but have a high volume of visitors.14 this high hcw-to-patient ratio results in a high workload among hospital staff, including nurses. high workload was previously shown to be associated with increased frequency of occupational injuries among nurses in jordan.14,16,20,21 indeed, a high incidence of nssis appears to be a global problem as studies from many countries around the world have reported similar findings among nurses.4,10,16,21,28–30 in this study, a higher proportion of nssis was reported among male nurses compared to female nurses. this finding, however, is not in agreement with similar investigations in jordan, saudi arabia, kenya, ethiopia and iran.12,20,22,25,31 these studies reported a higher incidence of nssis among female nurses compared to male nurses. the difference observed in gender distribution of nssis may be attributed to differences in the male-to-female ratio between different hospitals, especially as khmc has table 4: comparison of needle stick and sharps injuries by procedure/task during which the injury occurred to independent variables of healthcare workers in jordan (n = 393) variable n (%) p value medical waste collection giving medication blood sampling surgical intervention blood analysis unusual occurrence total age in years <20 7 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 7 (100) <0.00120–30 143 (54.8) 39 (14.9) 57 (21.8) 18 (6.9) 4 (1.5) 0 (0) 261 (100) >30 0 (0) 2 (1.6) 4 (3.2) 41 (32.8) 20 (16) 58 (46.4) 125 (100) gender male 150 (68.8) 37 (17) 25 (11.5) 6 (2.8) 0 (0) 0 (0) 218 (100) <0.001 female 0 (0) 4 (2.3) 36 (20.6) 53 (30.3) 24 (13.7) 58 (33.1) 175 (100) job title physician 0 (0) 0 (0) 0 (0) 35 (85.4) 0 (0) 6 (14.6) 41 (100) <0.001 nurse 104 (66.7) 27 (17.3) 24 (15.4) 1 (0.6) 0 (0) 0 (0) 156 (100) lab technician 4 (17.4) 0 (0) 8 (34.8) 8 (34.8) 3 (13) 0 (0) 23 (100) cleaner 7 (4.9) 14 (9.7) 29 (20.1) 50 (34.7) 18 (12.5) 26 (18) 144 (100) other 0 (0) 0 (0) 0 (0) 0 (0) 3 (10.3) 26 (89.7) 29 (100) place of injury or 60 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 60 (100) <0.001 laboratory 27 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 27 (100) hospital ward 63 (34.8) 41 (22.7) 57 (31.5) 14 (7.7) 5 (2.8) 1 (0.6) 181 (100) op clinic 0 (0) 0 (0) 4 (8.3) 33 (68.8) 6 (12.5) 5 (10.4) 48 (100) other 0 (0) 0 (0) 0 (0) 12 (15.6) 13 (16.9) 52 (67.5) 77 (100) site of injury right hand 138 (83.1) 18 (10.8) 10 (6) 0 (0) 0 (0) 0 (0) 166 (100) <0.001 left hand 12 (6.2) 23 (12) 51 (26.6) 59 (30.7) 19 (9.9) 28 (14.6) 192 (100) lower limb 0 (0) 0 (0) 0 (0) 0 (0) 5 (18.5) 22 (81.5) 27 (100) chest & abdomen 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (100) 2 (100) head & neck 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 6 (100) 6 (100) or = operating room; op = outpatient; lab = laboratory. needle stick and sharp injuries among healthcare workers a retrospective six-year study e60 | squ medical journal, february 2020, volume 20, issue 1 more male than female nurses, potentially explaining the higher proportion of injuries among males. the current findings indicate that hospital wards were the most common location at khmc where nssis took place. this result is in agreement with the findings of several other studies.27,32 a possible explanation is that this area of the hospital has high foot-traffic as patients enter or leave the ward. moreover, the ward experiences a high daily volume of procedures that require the use of needles and sharp objects.27,32 such procedures are mainly done by nurses, which may explain the significant association of medical ward injuries with occupation, young age and left-hand injuries, which are typical characteristics for young nurses working in a busy hospital. these results also demonstrate that most nssis at the hospital wards were significantly more often acquired during medical waste collection, more frequent among males, more likely to occur to either nurses or cleaners and significantly more likely to occur in the left hand. a possible explanation for the higher frequency of nssis among nurses and cleaners during medical waste collection is that both are involved in disposing needles/syringes, which often requires recapping of the needle. right-handed individuals usually use their right hand to hold syringes or needles and the left hand for recapping. most nurses and cleaners responsible for recapping needles are righthanded.24 this could explain why the majority of nssis were to the left hand. similarly, several studies have table 5: comparison of needle stick and sharp injuries by site of injury to independent variables of healthcare workers in jordan (n = 393) variable n (%) p value right hand left hand lower limb chest & abdomen head & neck total age in years <20 7 (100) 0 (0) 0 (0) 0 (0) 0 (0) 7 (100) <0.00120–30 159 (60.9) 102 (39.1) 0 (0) 0 (0) 0 (0) 261 (100) >30 0 (0) 90 (72) 27 (21.6) 2 (1.6) 6 (4.8) 125 (100) gender male 162 (74.3) 56 (25.7) 0 (0) 0 (0) 0 (0) 218 (100) <0.001 female 4 (2.3) 136 (77.7) 27 (15.4) 2 (1.1) 6 (3.4) 175 (100) job title physician 35 (85.4) 2 (4.9) 4 (9.8) 0 (0) 0 (0) 41 (100) <0.001 nurse 114 (73.1) 42 (26.9) 0 (0) 0 (0) 0 (0) 156 (100) lab technician 9 (39) 14 (60.9) 0 (0) 0 (0) 0 (0) 23 (100) cleaner 8 (5.6) 127 (88.2) 9 (6.3) 0 (0) 0 (0) 144 (100) other 0 (0) 7 (24.1) 14 (48.3) 2 (6.9) 6 (20.7) 29 (100) place of injury or 60 (100) 0 (0) 0 (0) 0 (0) 0 (0) 60 (100) <0.001 laboratory 27 (100) 0 (0) 0 (0) 0 (0) 0 (0) 27 (100) hospital ward 79 (43.6) 102 (56.4) 0 (0) 0 (0) 0 (0) 181 (100) op clinic 0 (0) 48 (100) 0 (0) 0 (0) 0 (0) 48 (100) other 0 (0) 42 (54.5) 27 (35.1) 2 (2.6) 6 (7.8) 77 (100) procedure/task during which injury occurred medical waste collection 138 (92) 12 (8) 0 (0) 0 (0) 0 (0) 150 (100) <0.001 giving medication 18 (43.9) 23 (56.1) 0 (0) 0 (0) 0 (0) 41 (100) blood sampling 10 (16.4) 51 (83.6) 0 (0) 0 (0) 0 (0) 61 (100) surgical intervention 0 (0) 59 (100) 0 (0) 0 (0) 0 (0) 59 (100) blood analysis 0 (0) 19 (79.2) 5 (20.8) 0 (0) 0 (0) 24 (100) unusual occurrence 0 (0) 28 (48.3) 22 (37.9) 2 (3.4) 6 (10.3) 58 (100) or = operating room; op = outpatient. rami saadeh, khaled khairallah, hussein abozeid, lama al rashdan, mahmoud alfaqih and obaidallah alkhatatbeh clinical and basic research | e61 reported that recapping was a significant contributor to nssis.4,24,33 this study highlights the high frequency of nssis and indicates that there is a need for proper intervention measures to reduce this preventable source of morbidity and mortality. as nssis constitute the largest occupational hazard for hcws, the findings of this study should impact local and national healthcare settings. this study’s findings should encourage institutions, with similar occupational settings that have a high proportion of nssis, to revisit their surveillance reporting systems and implement proper educational and training programmes. in addition, since exposure to nssis is often associated with blood-borne pathogens, prevention strategies should not be limited to the population of this study but also extend to include all hcws worldwide. however, this study had some limitations. the data used was self-reported and therefore only included information from individuals familiar with the impact of nssis on the quality of health services and may have only captured those who were wellversed in the importance of reporting nssis. this data may not be representative of all nssi cases that took place within the timeframe set for data collection. the study included data collected from only one healthcare institution in jordan affiliated with the royal medical services. findings of this study require confirmation by using data collected from a larger sample size across multiple public and private healthcare institutions in jordan. nonetheless, the findings of this study will increase knowledge about the factors associated with the occurrence of the nssis and support and contribute to the effort of establishing a national reporting system for nssis in jordan’s public healthcare sector; such a system can be easily adapted in other countries as well. conclusion despite the limitations of this study, it confirms the findings of previous reports that highlighted the high proportion of nssis among hcws in jordan. proper intervention measures, including well-designed training and awareness programmes, should be mandated in all medical institutions in jordan. the success of these interventions could be applicable to other developing countries as well. such a programme should incorporate surveillance techniques that enforce implementation of standard precautions that protect hcws, regardless of their occupation, job title, place of work or socio demographic characteristics. although these precautions should be compulsory for all hcws, additional measures that target high-risk groups, such as nurses and cleaners, should include additional training or awareness prog rammes to ensure their safety. these training or aware ness programmes should focus on the importance of reporting nssis, explaining the objectives of surv eillance systems, outlining available resources, devel oping skills to decrease the incidence of nssis and building leadership capacity for evaluating programmes and training others in the future. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. rapiti e, prüss-üstün a, hutin y. sharp injuries: assessing the burden of disease from sharps injuries to health-care workers at national and local levels. from: https://apps.who.int/iris/ handle/10665/43051 accessed: aug 2019. 2. khabour of, al ali kh, mahallawi wh. occupational infection and needle stick injury among clinical laboratory workers in almadinah city, saudi arabia. j occup med toxicol 2018; 13:15. https://doi.org/10.1186/s12995-018-0198-5. 3. cooke ce, stephens jm. clinical, economic, and humanistic burden of needlestick injuries in healthcare workers. med devices (auckl) 2017; 10:225–35. https://doi.org/10.2147/mder.s140846. 4. jahangiri m, rostamabadi a, hoboubi n, tadayon n, soleimani a. needle stick injuries and their related safety measures among nurses in a university hospital, shiraz, iran. saf health work 2016; 7:72–7. https://doi.org/10.1016/j.shaw.2015.07.006. 5. matsubara c, sakisaka k, sychareun v, phensavanh a, ali m. prevalence and risk factors of needle stick and sharp injury among tertiary hospital workers, vientiane, lao pdr. j occup health 2017; 59:581–5. https://doi.org/10.1539/joh.17-0084-fs. 6. world health organization. protecting healthcare workers from occupational exposure to bloodborne pathogens: the role of worksafebc. from: www.who.int/occupational_health/ publications/newsletter_17_regions/en/index2.html accessed: aug 2019. 7. hanafi mi, mohamed am, kassem ms, shawki m. needlestick injuries among health care workers of university of alexandria hospitals. east mediterr health j 2011; 17:26–35. https://doi. org/10.26719/2011.17.1.26. 8. kakizaki m, ikeda n, ali m, enkhtuya b, tsolmon m, shibuya k, et al. needlestick and sharps injuries among health care workers at public tertiary hospitals in an urban community in mongolia. bmc res notes 2011; 4:184. https://doi.org/10.1186/1756-0500-4-184. 9. singru sa, banerjee a. occupational exposure to blood and body fluids among health care workers in a teaching hospital in mumbai, india. indian j community med 2008; 33:26–30. https://doi.org/10.4103/0970-0218.39239. 10. al jarallah am, ahmed as. risk management approach of needle stick and sharp injuries among nurses, saudi arabia: an interventional study. j arab soc med res 2016; 11:50–5. https://doi.org/10.4103/1687-4293.199300. 11. king kc, strony r. statpearls [internet]. needlestick. treasure island, florida, usa: statpearls publishing llc, 2019. 12. mbaisi em, ng'ang'a z, wanzala p, omolo j. prevalence and factors associated with percutaneous injuries and splash exposures among health-care workers in a provincial hospital, kenya, 2010. pan afr med j 2013; 14:10. https://doi.org/10.11604/ pamj.2013.14.10.1373. https://doi.org/10.1186/s12995-018-0198-5 https://doi.org/10.2147/mder.s140846 https://doi.org/10.1016/j.shaw.2015.07.006 https://doi.org/10.1539/joh.17-0084-fs https://doi.org/10.26719/2011.17.1.26 https://doi.org/10.26719/2011.17.1.26 https://doi.org/10.1186/1756-0500-4-184 https://doi.org/10.4103/0970-0218.39239 https://doi.org/10.4103/1687-4293.199300 https://doi.org/10.11604/pamj.2013.14.10.1373 https://doi.org/10.11604/pamj.2013.14.10.1373 needle stick and sharp injuries among healthcare workers a retrospective six-year study e62 | squ medical journal, february 2020, volume 20, issue 1 13. amini m, behzadnia mj, saboori f, bahadori m, ravangard r. needle-stick injuries among healthcare workers in a teaching hospital. trauma mon 2015; 20:e18829. https://doi.org/10.58 12/traumamon.18829. 14. abozead se, abuhasheesh m, nawafleh ha, kawafha mm, tarawneh o. knowledge and practices of jordanian nurses on needlestick injuries. infec dis clin pract 2015; 23:21–5. https://doi.org/10.1097/ipc.0000000000000159. 15. ghasemi m, khabazkhoob m, hashemi h, yekta a, nabovati p. the incidence of needle stick and sharp injuries and their associations with visual function among hospital nurses. j curr ophthalmol 2017; 29:214–20. https://doi.org/10.1016/j. joco.2017.06.001. 16. suliman m, al qadire m, alazzam m, aloush s, alsaraireh a, alsaraireh fa. students nurses' knowledge and prevalence of needle stick injury in jordan. nurse educ today 2018; 60:23–7. https://doi.org/10.1016/j.nedt.2017.09.015. 17. nawafleh ha, abozead se, al momani mm, aaraj h. invest igating needle stick injuries: incidence, knowledge and percep tion among south jordanian nursing students. j nurs educ prac 2018; 8:59–69. https://doi.org/10.5430/jnep.v8n4p59. 18. goniewicz m, włoszczak-szubzda a, niemcewicz m, witt m, marciniak-niemcewicz a, jarosz mj. injuries caused by sharp instruments among healthcare workers--international and polish perspectives. ann agric environ med 2012; 19:523–7. 19. khuri-bulos na, toukan a, mahafzah a, al adham m, faori i, abu khader i, et al. epidemiology of needlestick and sharp injuries at a university hospital in a developing country: a 3-year prospective study at the jordan university hospital, 1993 through 1995. am j infect control 1997; 25:322–9. https://doi. org/10.1016/s0196-6553(97)90024-9. 20. hassan z, wahsheh m. occupational exposure to sharp injuries among jordanian health care workers. infect dis clin pract 2009; 17:169–74. https://doi.org/10.1097/ipc.0b013e31819b8d10. 21. khraisat fs, juni mh, said sm, abd rahman a, hamdanmansour a. needle stick injuries prevalence among nurses in jordanian hospitals. int j public health clin sci 2015; 2:7–16. 22. jahan s. epidemiology of needlestick injuries among health care workers in a secondary care hospital in saudi arabia. ann saudi med 2005; 25:233–8. https://doi.org/10.5144/02564947.2005.233. 23. rampal l, zakaria r, sook lw, zain am. needle stick and sharps injuries and factors associated among health care workers in a malaysian hospital. eur j soc sci 2010; 13:354–62. 24. askarian m, malekmakan l, memish za, assadian o. prevalence of needle stick injuries among dental, nursing and midwifery students in shiraz, iran. gms krankenhhyg interdiszip 2012; 7:doc05. https://doi.org/10.3205/dgkh000189. 25. bekele t, gebremariam a, kaso m, ahmed k. factors associated with occupational needle stick and sharps injuries among hospital healthcare workers in bale zone, southeast ethiopia. plos one 2015; 10:e0140382. https://doi.org/10.1371/ journal.pone.0140382. 26. khabour of, al ali kh, mahallawi wh. occupational infection and needle stick injury among clinical laboratory workers in almadinah city, saudi arabia. j occup med toxicol 2018; 13:15. https://doi.org/10.1186/s12995-018-0198-5. 27. abdifard e, sepahvand e, aghaei a, hosseini s, khachian a. needle-stick, sharp injuries, and its related factors among nurses of imam reza hospital, kermanshah, iran. j clientcentered nurs care 2015; 1:183–8. https://doi.org/10.15412/j. jccnc.04010403. 28. kebede a, gerensea h. prevalence of needle stick injury and its associated factors among nurses working in public hospitals of dessie town, northeast ethiopia, 2016. bmc res notes 2018; 11:413. https://doi.org/10.1186/s13104-018-3529-9. 29. trinkoff am, le r, geiger-brown j, lipscomb j. work schedule, needle use, and needlestick injuries among registered nurses. infec control hosp epidemiol 2015; 28:156–64. https:// doi.org/10.1086/510785. 30. smith dr, mihashi m, adachi y, nakashima y, ishitake t. epidemiology of needlestick and sharps injuries among nurses in a japanese teaching hospital. j hosp infect 2006;6 4:44–9. https://doi.org/10.1016/j.jhin.2006.03.021. 31. razieh l, gashtasbi a. needle stick and sharps injuries and its risk factors among health center personnel (astara; iran, 2006). j babol univ med sci 2008; 10:71–7. 32. shanks nj, al-kalai d. occupation risk of needlestick injuries among health care personnel in saudi arabia. j hosp infect 1995; 29:221–6. https://doi.org/10.1016/0195-6701(95)90332-1. 33. motaarefi h, mahmoudi h, mohammadi e, hasanpour-dehkordi a. factors associated with needlestick injuries in health care occupations: a systematic review. j clin diagn res 2016; 10:ie1–4. https://doi.org/10.7860/jcdr/2016/17973.8221. https://doi.org/10.5812/traumamon.18829 https://doi.org/10.5812/traumamon.18829 https://doi.org/10.1097/ipc.0000000000000159 https://doi.org/10.1016/j.joco.2017.06.001 https://doi.org/10.1016/j.joco.2017.06.001 https://doi.org/10.1016/j.nedt.2017.09.015 https://doi.org/10.5430/jnep.v8n4p59 https://doi.org/10.1016/s0196-6553%2897%2990024-9 https://doi.org/10.1016/s0196-6553%2897%2990024-9 https://doi.org/10.1097/ipc.0b013e31819b8d10 https://doi.org/10.5144/0256-4947.2005.233 https://doi.org/10.5144/0256-4947.2005.233 https://doi.org/10.3205/dgkh000189 https://doi.org/10.1371/journal.pone.0140382 https://doi.org/10.1371/journal.pone.0140382 https://doi.org/10.1186/s12995-018-0198-5 https://doi.org/10.1186/s12995-018-0198-5 https://doi.org/10.1186/s12995-018-0198-5 https://doi.org/10.1186/s13104-018-3529-9 https://doi.org/10.1086/510785 https://doi.org/10.1086/510785 https://doi.org/10.1016/j.jhin.2006.03.021 https://doi.org/10.1016/0195-6701%2895%2990332-1 https://doi.org/10.7860/jcdr/2016/17973.8221 july 2008.indd sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 243-243 sultan qaboos university© received 12th april 2008 re: prevalence and determinants of waterpipe (‘sheesha’) tobacco use among adolescents in oman to the editor, we write in response to the above mentioned article which appeared in the march 2008 issue of squmj.1 the incidence of this emerging trend of waterpipe use is increasing at an alarming rate.2 concerted efforts need to be made to actively alert young people in oman to the potential hazards of this form of drug abuse. the importance of this should not be underestimated, as the waterpipe could easily become a means of not only tobacco consumption, but also other inhaled drugs of abuse. at squ college of medicine, we have conducted a similar study using an anonymous questionnaire which was distributed to young omanis in different regions of oman. the main difference in our study was that our target group was young omanis, age range 16-26 years as compared to school going adolescents in the above study. participants were squ students, medical students and other young people from elsewhere in oman and the total number was 1,000. overall, our study showed a lower prevalence of sheesha smoking in young people compared to other studies.3 we fully endorse the comments of the authors of the above study regarding introduction of comprehensive tobacco control legislation in oman. can we not campaign to increase awareness of the dangers of sheesha use among the youth of oman? ragini vaishnav department of pharmacology & clinical pharmacy college of medicine & health sciences sultan qaboos university talal al-aghbari, thuraiya al-masoudi, maha al-jabri medical students college of medicine & health sciences sultan qaboos university r e fe r e n c e s 1. al lawati ja, muula as, hilmi sa, rudatsikira e. prevalence and determinants of waterpipe tobacco use among adolescents in oman. squ med j 2008; 8:241-247. 2. barry k, yona amitai. waterpipe (narghile) smoking: an emerging health risk behavior. pediatrics 2005, 116:113-119. 3. maziak w, eisssenberg t, rastam s, hammal f, asfar t, bachir me, et al. beliefs and attitudes related to narghile (waterpipe) smoking among university students in syria. ann epidemiol 2004 oct; 14:646-654. l e t t e r t o t h e e d i t o r departments of 1pathology and 2medicine, king george’s medical university, lucknow, india *corresponding author’s e-mail: aliwahidkgmu@gmail.com expression levels and genetic polymorphism of scavenger receptor class b type 1 as a biomarker of type 2 diabetes mellitus mohd wamique,1 d. himanshu,2 *wahid ali1 clinical & basic research sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 117–122, epub. 28 feb 22 submitted 17 aug 20 revisions req. 10 sep & 12 oct 20; revisions recd. 20 sep & 3 nov 20 accepted 03 nov 20 https://doi.org/10.18295/squmj.4.2021.042 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to determine whether the expression level and genetic polymorphism scavenger receptor class b type 1 (scarb1) rs5888 may be used as biological markers in type 2 diabetes mellitus (t2dm). methods: this case-control study was conducted at king george’s medical university, lucknow, india, from september 2018 to december 2019. blood samples were collected from each individual with t2dm and each healthy individual. total proteins were determined using western blot analysis. additionally, restriction fragment length polymorphism analysis was achieved to detect the incidence of genetic polymorphisms. results: a total of 600 individuals, including 300 individuals with t2dm and 300 healthy individuals, were enrolled in the study. western blot analysis results revealed that the protein expression of srb1 was significantly decreased in t2dm of scarb1 cc variant when compared with controls (p = 0.007). the genotype distribution and the allelic frequencies for the srb1 polymorphism were significantly different between t2dm and controls (p = 0.03). the cc genotype of the scarb1 polymorphism showed a potential association with the incidence of t2dm (odds ratio = 1.19, 95% confidence interval = 0.63–2.25; p = 0.577). conclusion: the expression levels and genetic polymorphisms of the scarb1 cc variant may be potential biomarkers for the occurrence of t2dm. keywords: genetic polymorphism; type 2 diabetes mellitus; human srb1 protein; biomarker; india. advances in knowledge this was the first study to identify the scavenger receptor class b type 1 (scarb1) variant’s association with type 2 diabetes mellitus (t2dm) at the protein level and revealed that the lower expression level of the srb1 protein might be due to variation at the srb1 rs5888 locus. scarb1 gene polymorphism could be considered as an independent risk factor for the development of t2dm and may be used as a biomarker for early diagnosis. application to patient care early identification of disease susceptibility could explain disease risk and prognostics. type 2 diabetes mellitus (t2dm) persists as a major health problem worldwide; it is well accepted that t2dm is a metabolic disorder caused by hyperglycaemia, which arises from insufficient pancreatic insulin secretion to peripheral tissues.1 however, long-term defects in beta-cells could also impair insulin levels and inhibit the production of insulin.2,3 insulin resistance is associated with increased serum insulin and dysfunctional betacells that could result in lipoprotein abnormalities and increased glucose levels.4 furthermore, genetic studies have shown that more than 45 genetic variants are associated with susceptibility to t2dm, including hereditary factors that also play a role in the development of diabetes.5 scavenger receptor class b type 1 (srb1) protein plays a major role in the uptake of cholesteryl ester from high-density lipoprotein (hdl) and it eliminates extra cholesterol from peripheral tissues as bile through the process of reverse cholesterol transport.6,7 lack of srb1 protein can result in an imbalance of cholesterol and dyslipidaemia and eventually lead to insulin resistance.8,9 mccarthy et al. reported that the rs5888 variants of scarb1 were associated with insulin resistance.10 similarly, tetik vardarli et al. found that scarb1 c1050t polymorphism is a risk factor for the development of diabetic dyslipidaemia.11 constantineau et al. studied the effects of c1051t polymorphism on srb1 protein expression and function in an in vitro study.12 moreover, there are numerous specificity protein-1 (sp1) binding positions in this dna region, and previous results designated that the glucose inhibition of srb1 expression is to some extent, intervened by the activation of the p38 mitogen-activated protein kinase (mapk)-sp1 pathway regulatory genes; this inhibits inflammation and other inflammatory signalling pathways such as nuclear factor-κb and arachidonate-signalling.13 as a result, hyperglycaemia could activate the p38 mapk pathway that might considerably add to the development of diabetes. this inhibitory effect of hyperglycaemia on scarb1 promoter activity is https://creativecommons.org/licenses/by-nd/4.0/ expression levels and genetic polymorphism of scavenger receptor class b type 1 as a biomarker of type 2 diabetes mellitus 118 | squ medical journal, february 2022, volume 22, issue 1 mediated by the p38 mapk/sp1 signalling cascade. these findings create the possibility of hyperglycaemia affecting reverse cholesterol transport by controlling sr-bi expression in diabetic patients.13 the current study aimed to determine whether the expression level and genetic polymorphism of scarb1 rs5888 may be used as biological markers in t2dm. methods this case-control study was conducted between september 2018 and december 2019 among the general population presenting at the out-patient department of medicine, king george’s medical university (kgmu), lucknow, india. all participants had to follow a careful screening programme, which involved the determination of clinical and biochemical parameters. following screening, subjects were selected based on the inclusion/exclusion criteria resulting in an equal number of t2dm subjects and control subjects. according to the american diabetes association, t2dm is defined as a fasting plasma glucose level with a fasting blood sugar (fbs) ≥126 mg/dl and glycated haemoglobin (hba1c) ≥6.5%.14 subjects who were diagnosed with t2dm were included in this study. those with congenital disorders, mental disorders, cardiovascular disease, heart failure or diabetes complications were excluded. for the control subjects, apparently healthy participants with no individual or familial history of t2dm or any other serious illness were included. furthermore, those with identified systemic diseases, including t1dm, hypertension, heart disease, liver cirrhosis, renal disease, gastrointestinal disease, pulmonary disease or cancer were excluded. to gather the participant’s demographic characteristics, a prepared questionnaire was administered by qualified staff. the authors preferred two diabetes risk-associated polymorphisms scarb1 rs5888 c > t from 12q24.31 loci with minor allele frequency (maf) > 5%. previous literature reported that this locus is responsible for predisposition to diabetes.15 for analysis, a total of 3 ml of venous blood was withdrawn from each participant under the supervision of a general practitioner. out of this, 1 ml of blood was transferred into ethylenediaminetetraacetic acid (edta) vials, mixed up and down gently and then used for the isolation of genomic dna and genetic analysis. the remaining 2 ml of whole blood was centrifuged at 1,500 rpm for 10 minutes and the isolated serum was used for the analysis of blood sugar and lipid parameters. dna was extracted from peripheral blood leuko cytes (obtained from edta admixed whole blood) using the phenol-chloroform process.16 neb cutter, version 2.0 (new england biolabs, massachusetts, usa), was used to select the restriction enzymes that cut at the sites of single nucleotide polymorphisms (snps). since the molecular weight of the dna fragments digested with restriction enzymes were small (100– 300 bp), they were checked by using 2% agarose gels. gels were prepared in 1× tris-acetate-edta buffer (in diethyl pyrocarbonate water) and stained with 0.5 µg/ml ethidium bromide (etbr). dna samples (2 µl) were mixed with dna loading buffer (xylene cyanole/bromophenol dye), loaded onto the gel and run at 50–70 volts until the dye migrated 3/4 of the way up gel. dna was analysed in a gel documentation system (bio-rad gel doc tm ez imager, bio-rad laboratories inc, hercules, california, usa). scarb1 gene polymorphism was detected by polymerase chain reaction (pcr; applied biosystems™ veriti™ hid 96-well thermal cycler, thermo fisher scientific inc., waltham, massachusetts, usa) followed by restriction fragment length polymorphism. scarb1 gene was amplified by the following pcr conditions: 93°c for 5 minutes, followed by 33 cycles of 91°c for 35 seconds, 61°c for 38 seconds, 69°c for 39 seconds and final elongation at 71°c for 5 minutes with precise scarb1 rs5888 gene forward primer 5’-cttgtttctcctcgacgc-3’ and reverse primer 5’-caccaccccagccagcagc-3’ (eurofins geno mics, ebersberg, germany). amplification was done with a 12 µl pcr mixture comprising 0.5 µl template dna, 0.5 µl of both primers and 2× pcr master mixes (new england biolabs). enzyme digestion was conducted in a 15 μl final volume consisting of 1 unit of the hin1i enzyme (thermo fisher scientific inc.). the reaction was conducted at 37°c overnight and the digested products were separated on 2% agarose gel electrophoresis containing etbr (0.5 μg/ml); agarose gel was observed by gel documentation system (biorad laboratories inc.). the genotypes recognised were labelled according to the presence or absence of the enzyme restriction sites. as a result, the tt genotype was a wild homozygote, the ct genotype was a heterozygote and the cc genotype was a variant homozygote. western blot assay was carried out to assess the protein expression of srb1 in a subset of t2dm cases and controls. the determined protein was then transferred to the polyvinylidene fluoride membrane through a western blot procedure at 30 volts for 120 minutes using a wet electrotransfer apparatus (biorad laboratories inc.). the membrane was blocked for 60 minutes in a tris-buffered saline (tbs) buffer containing 5% skimmed milk powder. the primary polyclonal antibody was added at a 1:1000 dilution in mohd wamique, d. himanshu and wahid ali clinical and basic research | 119 tbs buffer and kept overnight at 4°c. the membrane was washed three times for 5 minutes each in tbs+polysorbate buffer; a secondary antibody (goat anti-mouse immunoglobulin g-alkaline phosphatase [ap]) was added at a 1:1000 dilution in tbs buffer and incubated for 60 minutes at room temperature. detection of ap-conjugated antibody was done by supersignal west pico chemiluminescent substrate (elabscience biotechnology inc., houston, texas,usa; catalogue number: sc-358798). membrane images were examined by a gel documentation system. imagej software was used for the investigation of serum protein bands. the differences between all parametric variables were analysed using the student’s t-test. chi-square test was used to determine the significance of differences in allele and genotype frequency. analysis of variance was used to test for variance in parameters between genotypes. differences were considered statistically significant when p was <0.05. all statistical analyses were performed using the statistical package for the social sciences (spss) software, version 16.0 (ibm corp., chicago, illinois, usa). institutional ethics committee’s at kgmu approved this study (code: 98th ecmiia/p4). all subjects signed the approved consent form. results a total of 663 subjects were recruited for this study but 63 subjects were excluded because they refused to participate or were not willing to provide consent. of the remaining participants, 300 individuals with t2dm and 300 healthy controls were included. no significant differences were observed between the two groups in terms of age and alcohol consumption; however, there were significant differences in smoking table 1: characteristics and biochemical parameters of participants with type 2 diabetes mellitus participants and healthy controls (n = 600) characteristic mean ± sd or (95% ci) p value controls n = 300 t2dm cases n = 300 age in years 47.5 ± 7.3 48.6 ± 9.7 0.11 bmi in kg/m2 23.4 ± 4.90 26.5 ± 5.10 0.02 smoking 1.5 (1.09–2.09) 0.01 yes 169 138 no 131 162 alcohol consumption 1.12 (0.81–1.55) 0.51 yes 165 156 no 135 144 biochemical parameter hdl in mg/ dl 42.3 ± 8.5 46.5 ± 7.9 0.001 ldl in mg/ dl 97.8 ± 12.7 139.2 ± 22.5 0.001 vldl in mg/ dl 44.5 ± 11.3 42.6 ± 8.5 0.001 tg in mg/dl 122.6 ± 11.7 206.2 ± 34.5 0.001 tc in mg/dl 184.4 ± 21.5 215.2±33.4 0.001 fbs in mg/dl 78.4 ± 13.7 133.2 ± 17.4 0.001 hba1c in % 5.6 ± 0.7 7.94 ± 0.99 0.001 sd = standard deviation; or = odds ratio; ci = confidence interval; t2dm = type 2 diabetes mellitus; bmi = body mass index; hdl = high-density lipoprotein; ldl = low-density lipoprotein; vldl =very low-density lipoprotein; tg =triglycerides; tc = total cholesterol; fbs =fasting blood sugar; hba1c =glycated haemoglobin. table 2: association between lipid parameters and scavenger receptor class b type 1 rs5888 polymorphism in participants with type 2 diabetes mellitus compared to healthy controls lipid parameter srb1 rs5888 polymorphism, mean ± sd p value tt ct cc controls number of cases 80 147 73 hdl in mg/dl 43.1 ± 11.5 39.5 ± 9.7 39.7 ± 10.2 0.03 ldl in mg/dl 97.2 ± 27.6 95.2 ± 30.1 104.1 ± 29.4 0.10 vldl in mg/dl 41.4 ± 9.4 40.3 ± 9.1 43.1 ± 10.6 0.12 tg in mg/ dl 144.2 ± 23.5 142.6 ± 33.1 147.5 ± 26.1 0.841 tc in mg/ dl 172.1 ± 39.7 177.2 ± 29.6 176.8 ± 33.8 0.544 t2dm cases number of cases 63 129 108 hdl in mg/dl 35.1 ± 7.5 33.1 ± 12.5 30.3 ± 7.2 0.03 ldl in mg/dl 116.5 ± 22.4 123.7 ± 17.2 130.3 ± 36.4 0.02 vldl in mg/dl 41.4 ± 10.3 43.5 ± 10.2 44.5 ± 12.5 0.31 tg in mg/ dl 179.7 ± 28.2 182.5 ± 29.4 176.3 ± 32.3 0.835 tc in mg/ dl 222 ± 28.1 228.3 ± 21.1 223.5 ± 26.1 0.16 srb1 = scavenger receptor class b type 1; hdl = high-density lipoprotein; ldl = low-density lipoprotein; vldl = very low-density lipoprotein; tg = triglycerides; tc = total cholesterol;t2dm = type 2 diabetes mellitus. expression levels and genetic polymorphism of scavenger receptor class b type 1 as a biomarker of type 2 diabetes mellitus 120 | squ medical journal, february 2022, volume 22, issue 1 behaviour (p = 0.01) and body mass index (bmi; p = 0.02). significantly higher levels of total cholesterol (tc), triglyceride, low-density lipoprotein (ldl), fbs and hba1c and decreased hdl levels were observed in the individuals with t2dm compared to controls (p = 0.001 each) [table 1]. furthermore, the findings also revealed that the scarb1 tt genotype had significantly increased hdl levels when compared to the cc genotype (p = 0.03) [table 2]. in scarb1 rs5888, the frequencies of the cc, tt and ct genotypes in the t2dm group were 36%, 21% and 43%, respectively, while in the control group, these were 24%, 27% and 49%, respectively. the distribution of all genotypes and alleles were in hardy weinberg equilibrium. it was observed that in scarb1 rs5888 polymorphism, the cc genotype was significantly increased in the t2dm group compared to control group (odds ratio [or] = 1.87, χ2 = 7.19, 95% confidence interval [ci]: 1.20–2.92; p = 0.007). the c allele frequency was associated with the t2dm group when compared to the control group (or = 1.41, χ2 = 8.70, 95% ci: 1.12–1.78; p = 0.003) [table 3]. a total of 100 serum samples (n = 50 for each group) were analysed for possible consequences of the scarb1 genetic polymorphism on protein expression levels by western blot analysis. beta-actin was used as an endogenous control. results showed that the protein expression of srb1 was significantly higher in the scarb1 tt variant of healthy controls compared to participants in the t2dm group and the variant might affect srb1 protein expression levels [figure 1]. discussion the results of numerous previous association studies between the scarb1 rs5888 snp and diabetes were not constant between different ethnic groups. therefore, genetic confirmation for an association between the scarb1 snp and diabetes in humans needs to be explored. in the present study, it was observed that the scarb1 cc genotype was significantly associated with an increased t2dm risk, which was in concordance with previous findings that also reported a significant association between the scarb1 polymorphism and t2dm risk.10 in agreement with this, a previous study from the han and guangxi population also showed that scarb1 is significantly associated with an increased risk of t2dm.17 although the precise role of scarb1 rs5888 in regard to t2dm risk is still under investigation, evidence has suggested that the scarb1 gene variants may affect susceptibility to the disease by altering the levels of srb1 that might contribute to the risk of t2dm.13 in the present study, it was noticed that the scarb1 cc variant had decreased srb1 protein expression, which might have been due to the variation in the regulatory region of the scarb1 gene; this could have contributed to the differential expression of srb1, as the variant was located in the promoter region of the gene and could hinder the binding of the transcriptional factor.15 previous reports table 3: comparison of genotype and allele frequencies of scavenger receptor class b type 1 rs5888 in participants with type 2 diabetes mellitus compared to healthy controls (n = 600) srb1 (rs5888) polymorphism n (%) or (95% ci) p value genotype controls n = 300 t2dm cases n = 300 tt 80 (27) 63 (21) reference (1.00) ct 147 (49) 129 (43) 1.11 (0.74–1.67) 0.67 cc 73 (24) 108 (36) 1.87 (1.20–2.92) 0.007 χ2 = 7.19 allele t 307 (51) 255 (43) c 293 (49) 345 (58) 1.41 (1.12–1.78) 0.003 χ2 = 8.70 srb1 = scavenger receptor class b type 1; or =odds ratio; ci =confidence interval. figure 1: a: representative western blot using betaactin as the loading control and protein expression levels of scavenger receptor class b type 1 (srb1) in a healthy control versus a participant with type 2 diabetes mellitus (t2dm). b: protein expression levels of srb1 in a healthy control and a participant with t2dm. *p <0.05. mohd wamique, d. himanshu and wahid ali clinical and basic research | 121 also found that the rs5888 snp affected the scarbi rna secondary structure, which changed its ability to undergo productive protein translation, ultimately leading to significantly lower srb1 protein expression.18 findings indicated that the lower expression level of the srb1 protein might be due to the variation at the rs5888 (exonic c1050t) locus, which affects the functionality and stability of the protein. interestingly, snps located in the exonic region of the gene might manipulate mrna translation, thereby affecting the level of protein expression.19 the involvement of numerous variants in the scarb1 gene and serum lipid profiles has been described in distinct populations worldwide. in the present study, control subjects carrying the scarb1 tt genotype had higher hdl levels compared with the cc genotype. this result was in concordance with a previous study that also revealed that the rs5888 t allele is significantly associated with higher hdl levels among the turkish population.11 additionally, t2dm subjects with the cc genotype had a significantly low level of hdl. this result indicated that patients with t2dm have significantly higher levels of scarb1 and a significantly higher frequency of homozygous cc snps (rs5888). these findings suggest that srb1 may be a potential biomarker for the incidence of t2dm. this study selected control and case groups which is vital for a genetic study, as any systematic error in either groups can result in false-positive and falsenegative results.20 there are several risk factors for t2dm that primarily include increased age, gender, dyslipidaemia, smoking, increased serum tc and ldl. to mitigate the effect of confounders caused by the mismatch between the two included groups, t2dm and control subjects were matched in age, gender and bmi. however, the present study was subject to certain limitations. this study was conducted using a small sample size and was single centric. a study with a large sample size that is multicentric and considers different ethnic groups should be conducted to identify the potential relationship of these loci. conclusion the present study showed an increased number of cc genotype in t2dm participants with reduced srb1 protein expression; this might be associated with the occurrence of t2dm and could be used as a biomarker for early diagnosis. identification of the genes involved will help in better understanding the mechanism of the disease and lead to improved treatment. future efforts should use a genetic approach to increase the functional efficiency of srb1, which could result in a decreased occurrence of t2dm. however, a healthy diet, physical activity and dedication to lifestyle changes could delay or prevent t2dm in individuals with increased risk. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this work was supported by council of science and technology, cstup, lucknow, uttar pradesh (grant no. cst/serpd/d-8423). a c k n o w l e d g e m e n t we are thankful to vice-chancellor of king george’s medical university, lucknow for providing research support and facilities. we would like to acknowledge the efforts and support from zoya shakir, imran ahmad, neha srivastava and shraddha mishra, priyanka singh in completing the research work. a u t h o r s’ c o n t r i b u t i o n mw, wa and dh designed and performed the study. mw and wa analysed the data. mw drafted the manuscript. all authors approved the final version of the manuscript. references 1. knowler wc, pettitt dj, savage pj, bennett ph. diabetes inci dence in pima indians: contributions of obesity and parental diabetes. am j epidemiol 1981; 113:144–56. https://doi.org/10.1 093/oxfordjournals.aje.a113079. 2. oh ys, bae gd, baek dj, park ey, jun hs. fatty acid-induced lipotoxicity in pancreatic beta-cells during development of type 2 diabetes. front endocrinol (lausanne)2018; 9:384. https:// doi.org/10.3389/fendo.2018.00384. 3. himanshu d, ali w, wamique m. type 2 diabetes mellitus: pathogenesis and genetic diagnosis. j diabetes metab disord 2020;19:1959–66. https://doi.org/10.1007/s40200-020-00641-x. 4. wamique m, ali w, rizvi snf. role of free fatty acid and elevated vldl in type ii diabetes mellitus a review. eur j pharm med res 2015; 2:115–19. 5. wamique m, ali w, reddy dh, waseem m, vishwakarma p. association of cholesteryl ester transferyl protein gene (g277a) polymorphism and risk prediction of type 2 diabetes mellitus: a case control study of northern indian population. meta gene 2018; 17:163–6. https://doi.org/10.1016/j.mgene.2018.06.005. 6. wamique m, ali w, rizvi snf, singh p. scarb1 gene poly morphism in type 2 diabetes mellitusa review. j med dent sci res 2015; 2:22–7. 7. shen wj, asthana s, kraemer fb, azhar s. scavenger receptor b type 1: expression, molecular regulation, and cholesterol transport function. j lipid res 2018; 59:1114–31. https://doi. org/10.1194/jlr.r083121. https://doi.org/10.1093/oxfordjournals.aje.a113079 https://doi.org/10.1093/oxfordjournals.aje.a113079 https://doi.org/10.3389/fendo.2018.00384 https://doi.org/10.3389/fendo.2018.00384 https://doi.org/10.1007/s40200-020-00641-x https://doi.org/10.1194/jlr.r083121 https://doi.org/10.1194/jlr.r083121 expression levels and genetic polymorphism of scavenger receptor class b type 1 as a biomarker of type 2 diabetes mellitus 122 | squ medical journal, february 2022, volume 22, issue 1 8. wamique m, ali w, himanshu d. association of srb1 and pon1 gene polymorphisms with type 2 diabetes mellitus: a case control study. int j diabetes dev ctries 2020; 40:209–15. 9. richard e, von muhlen d, barrett-connor e, alcaraz j, davis r, mc arthy jj.modification of the effects of estrogen therapy on hdl cholesterol levels by polymorphisms of the hdl-c receptor, srbi: the rancho bernardo study. atherosclerosis 2005; 180:255–62. https://doi.org/10.1016/j.atherosclerosis.2004.12.013. 10. mccarthy jj,somji a, weiss la, steffy b, vega r, barrettconnor e, et al. polymorphisms of the scavenger receptor class b member 1 are associated with insulin resistance with evidence of gene by sex interaction. j clin endocrinol metab 2009; 94:1789–96. https://doi.org/10.1210/jc.2008-2800. 11. tetik vardarlı a, harman e, bozok çetintaş v, kayıkçıoğlu m, vardarlı e, zengi a, et al.polymorphisms of lipid metabolism enzyme-coding genes in patients with diabetic dyslipidemia. anatol j cardiol 2017; 313–21. https://doi.org/10.14744/anatol jcardiol.2016.7142. 12. constantineau j,greason e, west m, filbin m, kieft js, carletti mz, et al. a synonymous variant in scavenger receptor, class b, type i gene is associated with lower sr-bi protein expression and function. atherosclerosis 2010; 210:177–82. https://doi. org/10.1016/j.atherosclerosis.2009.11.029. 13. murao k,yu x, imachi h, cao wm, chen k, matsumoto k,et al. hyperglycemia suppresses hepatic scavenger receptor class b type i expression. am j physiol endocrinol metab 2008; 294:e78–87. https://doi.org/10.1152/ajpendo.00023.2007. 14. american diabetes association. 2. classification and diagnosis of diabetes: standards of medical care in diabetes-2019. dia betes care 2019; 42:s13–28. https://doi.org/10.2337/dc19-s002. 15. mccarthy jj,somji a, weiss la, steffy b, vega r, barrett-connor e, et al. polymorphisms of the scavenger receptor class b member 1 are associated with insulin resistance with evidence of gene by sex interaction. j clin endocrinol metab 2009; 94:1789–96. https://doi.org/10.1210/jc.2008-2800. 16. green mr, sambrook j. isolation of high-molecular-weight dna using organic solvents. cold spring harb protoc 2017; 2017:pdb.prot093450. https://doi.org/10.1101/pdb.prot093450. 17. wu df, yin rx, yan tt, aung lh, cao xl, miao l, et al. the scarb1 rs5888 snp and serum lipid levels in the guangxi mulao and han populations. int j med sci 2012; 9:715–24. https://doi.org/10.7150/ijms.4815. 18. constantineau j,greason e, west m, filbin m, kieft js, carletti mz, et al. a synonymous variant in scavenger receptor, class b, type i gene is associated with lower sr-bi protein expression and function. atherosclerosis 2010; 210:177–82. https://doi. org/10.1016/j.atherosclerosis.2009.11.029. 19. steri m, idda ml, whalen mb, orrù v. genetic variants in mrna untranslated regions. wiley interdiscip rev rna 2018; 9:e1474. https://doi.org/10.1002/wrna.1474. 20. lewallen s, courtright p. epidemiology in practice: casecontrol studies. community eye health 1998; 11:57–8. https://doi.org/10.1016/j.atherosclerosis.2004.12.013 https://doi.org/10.1210/jc.2008-2800 https://doi.org/10.14744/anatoljcardiol.2016.7142 https://doi.org/10.14744/anatoljcardiol.2016.7142 https://doi.org/10.1016/j.atherosclerosis.2009.11.029 https://doi.org/10.1016/j.atherosclerosis.2009.11.029 https://doi.org/10.1152/ajpendo.00023.2007 https://doi.org/10.2337/dc19-s002 https://doi.org/10.1210/jc.2008-2800 https://doi.org/10.1101/pdb.prot093450 https://doi.org/10.7150/ijms.4815 https://doi.org/10.1016/j.atherosclerosis.2009.11.029 https://doi.org/10.1016/j.atherosclerosis.2009.11.029 https://doi.org/10.1002/wrna.1474   evidence-based medicine: an overview *kamlesh bhargava1, roman jaeschke2 abstrac t. evidence-based medicine (ebm) has been proposed as the most significant intellectual advance in the process of clinical decision-making in the past decade. with more than , medical journals publishing  million articles a year, doctors are unable to cope with the information overload. the principles and practice of ebm show the way to bridge the gap between research and practice. reactions evoked in the medical profession towards this new discipline have been in extremes, from outright rejection to enthusiastic acceptance. the goal of this paper is to familiarise the readers with the ideas and concepts associated with the phrase evidence-based medicine. key words: evidence-based medicine, review, oman 1department of family and community health, college of medicine, sultan qaboos university, p.o.box: , postal code: , al-khod, sultanate of oman. 2department of medicine, mcmaster university, hamilton, ontario, canada. *to whom correspondence should be addressed. e-mail: bhargava@squ.edu.om t  -  ()  appeared in an information document for prospec-tive residents in internal medicine at mcmaster university, canada, in . e relevant passage declared: residents are taught to develop an attitude of “enlightened scepticism” towards the application of diagnostic, therapeutic, and prognostic technologies in their day-to-day management of patients. is approach, which has been called “evidence-based medicine,” is based on principles outlined in the text clinical epidemiology.1 e goal is to be aware of the evidence on which one’s practice is based, the soundness of the evidence, and the strength of inference the evidence permits. e strategy employed requires a clear delineation of the relevant question(s); a thorough search for the relevant information (information in the form of primary evidence and/or in the form of synopsis or summary of such evidence, see further); a critical appraisal of the evidence, and its applicability to the clinical situation; a balanced application of the conclusions to the clinical problem. e fact that the term ebm was coined in  does not mean that its ideas were absent prior to that time. some of ebm’s proponents trace its origins to post-revolutionary paris. e first step in modern clinical trials was the advent of the randomised trial as a methodology for resolving therapeutic dilemmas. subsequent events included the development of the methodology of systematic overviews culminating in the cochrane collaboration, the introduction of informative abstracts specifying the key components of study design and results, and the advent of secondary journals that selectively present results of methodologically sound and clinically relevant articles previously published in primary journals. as practitioners realized that the principles of ebm are as applicable to nursing, podiatry, physiotherapy, occupational therapy and all other fields of healthcare as they are to medicine, the term evidence-based health care (ebhc) has emerged. in the remainder of this article we will address the need for ebm, the principles of evidence-based practice, and the electronic resources to practice ebm. our comments will draw extensively from previous publications.     :   , : , : , – ©                                 /          historically, physiological rationale is the basis for treatment recommendations, but it has repeatedly failed to predict the results of randomized trials as the following examples illustrate. in patients with heart failure, angiotensin-converting enzyme inhibitors have been proved to reduce mortality, whereas other promising vasodilators have had marginal or no effect2 and some agents with vasodilator and ionotropic properties actually increase mortality.3,4 while equally promising cerebrovascular surgical procedures have had no effect or have increased stroke morbidity,5 others have proved dramatically effective in reducing stroke.6 antiarrhythmic agents can obliterate non-lethal cardiac arrhythmias while increasing mortality7 and plasmapheresis confers benefit in some inflammatory conditions, but not others.8,9 chalmers and colleagues conducted meta-analyses of randomized trials of interventions in pregnancy and childbirth and found that  interventions should have been abandoned.10 a second impetus to the rise of evidence-based health care was provided by studies demonstrating that physicians manage similar patients very differently. in results unexplained by differences in patient characteristics or geographical variations, surgeons have chosen widely varying rates of breast-conserving surgical procedures in women with breast cancer,11 the rates of common surgical procedures have varied up to seven-fold among countries,12 the rates of coronary artery bypass surgery have varied more than three-fold among canadian provinces,13 the odds of tonsillectomy during childhood have ranged –, and those of hysterectomy, –.14,15 a study of procedure rates for medicare patients in  large metropolitan areas in north america showed variations of more than  for more than half the procedures.16 such wide variations raise questions about whether the differences might be reduced by appropriate application of research evidence. at some of these variations might lead to additional costs without additional benefit has made the dilemma more intense. is intensity has been further enhanced by the third major stimulus to evidence-based health care: reduced resources for health care delivery.                      how does ebm differ from the traditional approaches to health care? one can view these differences as fundamental or revolutionary, or evolutionary. e former view contends that evidence-based practice represents a shi in the underlying paradigm of healthcare delivery and notes changes in the associated assumptions, while the latter sees ebm as a fine-tuning of approaches and ideas already in wide use. in the old paradigm, healthcare practitioners assumed that (i) observations from day-to-day clinical experience are a valid way of building and maintaining knowledge about patient prognosis, the value of diagnostic tests and the efficacy of treatment, (ii) the study and understanding of basic mechanisms of disease and pathophysiologic principles are an adequate guide for clinical practice, (iii) a combination of traditional medical training and common sense is sufficient to allow evaluation of new tests and treatments, and (iv) content expertise and clinical experience are a sufficient base from where to generate guidelines for clinical practice. according to the old paradigm, clinicians sort out clinical problems by reflecting on their own clinical experience, reflecting on the underlying biology, referring to a textbook, or asking a local expert. reading the introduction and discussion sections is considered adequate for gaining relevant information from a journal article. e old paradigm puts a high value on traditional scientific authority and adherence to standard approaches.17 e evidence-based healthcare paradigm also suggests that clinical experiences, and the development of clinical instincts (particularly with respect to diagnosis) are crucial parts of becoming a competent physician. many aspects of clinical practice cannot be adequately tested because of ethical or practical considerations. clinical experience is particularly important in these situations. in the absence of systematic observation, clinicians must be, however, cautious in interpreting information derived from clinical experience and intuition, for it may be misleading. second, evidence-based healthcare practitioners believe that study and understanding of basic mechanisms of disease are necessary but insufficient guides for practice. ird, understanding rules of evidence is necessary to correctly interpret literature on prognosis, diagnostic tests, and treatment and potentially harmful exposures. finally, when pronouncing their recommendations, clinical experts must refer to the evidence, whether from research studies in the published literature or other sources. an alternative conceptualisation of evidence-based health care sees it as an evolutionary process. while clinicians have always used the healthcare literature to solve patient problems, evidence-based practitioners acknowledge an explicit hierarchy of evidence. for example, in making treatment decisions they may conduct an n of  randomised trial in determining the optimal treatment for an individual patient or seek a systematic review of randomised trials of treatment alternatives.18 if a systematic                 review is not available, they will look for individual randomised trials of relevant management strategies. failing that, they will seek high quality observational studies. if unable to get the desired evidence from the above searches, they will fall back on the underlying biology, and on their own and their colleagues’ clinical experience. ebm emphasizes that the ultimate decision that clinicians make will not flow only from the evidence.19 since all clinical decisions involve tradeoffs, preference or value judgements about the alternatives will always be involved.20 ideally, the values and preferences for decisions about individual patient care will come from the patients themselves. some patients may prefer the traditional parental model of care in which the health worker makes decisions, and the patient’s role is to trust the practitioner and follow instructions. others may insist on a more active role. ideally, we should be striving for evidence-based patient choice; a concept that involves shared decision-making between clinician and patient.21 whether one finds the revolutionary or evolutionary conceptualisation of evidence-based medicine more appealing, they both imply a number of steps in the development of clinical decisions, including clinical policies. ese steps include identifying the relevant research, making an accurate assessment of the validity and the results, developing clinical policies with the best match between the research evidence and the clinical circumstances, and applying the research evidence to individual patients in the right way, place and time.22 e ultimate goal is to provide the practice consistent with the current best evidence. clinicians can achieve evidence based practice in a variety of ways, as we shall describe below.                     e idea of clinical practice consistent with the current best evidence has become an important characteristic of high quality healthcare. providing individual clinicians with the skills required to independently find from primary sources such as medline, embase or hand searching journals, appraise and apply the best evidence (i.e., training evidence-based practitioners), became one way of achieving this goal. a complementary approach creates a practice milieu that facilitates evidence-based care. e skills that an evidence-based practitioner brings to resolving a clinical dilemma include all the above steps (defining the problem; searching for evidence; appraising it; considering that evidence and its implications in the context of patients, circumstances and values). attaining this set of ebm skills requires intensive study and timeconsuming application. us, in a mcmaster training program explicitly committed to creating evidence-based practitioners, we have found that only a minority of trainees are interested in attaining advanced ebm skills.23 our trainees’ responses mirror those of uk general practitioners who, despite using evidence-based summaries generated by others () and evidence-based practice guidelines or protocols (), overwhelmingly () felt that learning the skills of evidence-based medicine was not the most appropriate method for moving from opinion-based to evidence-based medicine.24 at the same time, our residency programme trainees all appear to develop a respect for, and ability to track down, recognise, and use evidence-based sources of information that provide immediately applicable conclusions. having mastered this more restricted set of ebm skills, these trainees (whom we might call evidence users) could become highly competent, up-to-date practitioners capable of delivering evidence-based care. e recognition that trying to train all clinicians to become evidence-based practitioners is not feasible, and that evidence-based practitioners require tools to optimise their efficiency, has led to the development of sources of pre-appraised evidence. ese sources serve the needs of both evidence-based practitioners and clinicians who do not routinely read the methods and results sections of journal articles, yet seek and use evidence-based sources of information. ese evidence-based users may also, when seeking expert advice, confine their attention to opinion leaders who undertake a systematic, explicit critical appraisal of the available evidence before making recommendations. as a result, evidence-using clinicians may achieve evidence-based care with nearly as much consistency, and considerably less effort, than those who spend time searching for and critiquing research evidence. r e s o u r c e s new resources for practising ebm are developing every day; so are the individuals and organizations critically appraising and assimilating best evidence and developments in information technology. brian haines has proposed the s resources (systems, synopses, syntheses and studies), which redefine the earlier primary and secondary resources.25 ese are available as paper journals, cd roms, and on websites. [table .]     (      ) e ideal computerised decision support system (cdss), now in development, would link the patients’ problems to the best available evidence incorporating electronic medical records. trials conducted with limited conditions                        have shown that such systems may improve patient care. is, however, is mostly an issue for the future. available at present are electronic textbooks such as clinical evidence, uptodate and scientific american medicine. ough not integrated with the electronic medical records, these can be used on the same computer. ese databases are focused more on internal medicine and subspecialties, and primary care. clinical evidence precise aims: to provide evidence to assist clinicians in answering the questions most relevant to clinical practice and to highlight areas where such evidence is lacking. e ‘book’ does not aim to make recommendations, nor does it judge effectiveness or cost-effectiveness. both beneficial and harmful effects of therapy are presented, leaving clinicians to translate these effects into an estimate of effectiveness for the individual patient.26 uptodate (www.uptodate.com) aims to provide information that is comprehensive, accurate, verifiable (well-referenced), easy to access, and updated regularly. it encompasses all areas of internal medicine, but the dermatology, oncology, and neurology sections are still under development. it describes most important studies briefly reviews quantitative data. even though uptodate does not give explicit criteria for seeking and appraising evidence, most clinicians have found it relevant and easy to use.      (      ) resources for busy clinicians who do not have the time to read lengthy articles and digest them are available. one such resource for internal medicine and primary care is best evidence, annually produced on cd-rom by the american college of physicians and american society of internal medicine best evidence finds good studies from the top  journals, critically appraises them and gives a one-page synopsis for each, along with a commentary by an expert. e best evidence cd-rom also features the entire contents of acp journal club (acpjc), evidencebased medicine (ebm), and the textbook diagnostic strategies for common medical problems (ds). most of its references are relevant to internal medicine: a reflection of the preponderance of acpjc articles.27        (      ) ese resources include systematic reviews that are summaries of medical literature. ey perform literature searches, critically appraise individual studies and statistically combine the studies, and are available as databases on cd-roms such as cochrane library. e cochrane collaboration (www.updateusa.com/clibip/clib.htm) was established in  to facilitate systematic reviews of randomised controlled trials across all areas of health care.28,29 is international organization aims to help people make well-informed decisions about health care by preparing, maintaining and ensuring the accessibility of systematic reviews of the effects of healthcare interventions. e cochrane library includes (i) e cochrane database of systematic reviews—regularly updated reviews of the effects of health care, (ii) database of abstracts of reviews of effectiveness—critical assessments and structured abstracts of good systematic reviews published elsewhere; (iii) e cochrane controlled trials register —bibliographic information on controlled trials and (iv) other sources of information—the science of reviewing, research and evidence-based health care. e abstracts of the cochrane reviews can be browsed free at www.updatesoware.com/abstracts/titlelist.htm.                 practice guidelines are also being developed by various organizations, some based on the principles of ebm, others not so explicit. ese can be found on the web at sites such as the national guideline clearinghouse and medline.      (     ) original studies form the last resource for finding evidence. ese can be accessed in several ways. for the beginner, sumsearch might be a good starting point. sumsearch is a ‘meta-searching service’ that searches the following resources: (i) merck manual (which it uses as the default textbook), (ii) medline (for original research, review articles and editorials from general journals), (iii) national guideline clearinghouse from the agency for health care policy and research (ahcpr), and (iv) database of abstract of reviews of effectiveness (dare). depending of the focus requested, sumsearch will search pubmed with the highest sensitivity filters developed by haynes et al. for example, if the search were about physical examination, sumsearch would search the database bedside diagnosis.30 another option is to use ‘clinical queries’ in pubmed followed by searching the medline through pubmed. medline, the database maintained by the national library of medicine in bethesda, maryland, usa, is the electronic equivalent of index medicus. it includes more than  million citations dating from , from over , journals. e strength of this database is its relatively comprehensive coverage of medical journals and free accessibility via the internet at www.ncbi.nlm.nih.gov/entrez/query.fcgi.31 e downside is that medline’s sheer size calls for skills and time to retrieve information, and it mostly provides only abstracts with links to full-text sites (, as on january ) that oen need paid subscription. again, the studies thus found need to be critically appraised by the clinician be applying them for patient care. us the utility of medline searches are limited to rare conditions and where the more dedicated resources are unsuccessful. over the last several years the concepts and ideas                      table 1. useful ebm resources source site yearly cost (us $) best evidence www.acponline.org/catalog/electronic/best_evidence.htm 85 cochrane library www.updateusa.com/clibip/clib.htm 235 medline clinical.updateusa.edu/pubmed.htm free uptodate www.uptodate.com 530 sumsearch sumsearch.uthscsa.edu free trip www.tripdatabase.com free scientific american medicine www.samed.com 299 clinical evidence www.evidence.org/index-welcome.htm 110 emedicine www.emedicine.com free scharr netting the evidence www.shef.ac.uk/~scharr/ir/netting/ free acp journal club www.acponline.org/journals/acpjc/jcmenu.htm/wni free bmj www.bmj.com free jama jama.ama-assn.org 125 lancet www.thelancet.com 50 evidence-based medicine: how to practice and teach ebm www.churchillmed.com 31 md consult www.mdconsult.com 219 bandolier www.jr2.ox.ac.uk/bandolier free centre for evidence-based medicine cebm.jr2.ox.ac.uk free mcmaster health information hiru.mcmaster.ca free   attributed to and labelled collectively as ebm became part of daily clinical lives. clinicians hear about evidence-based medicine, eb healthcare, eb guidelines, eb care paths, and eb questions and solutions. e controversy has shied from whether to implement the new concepts to how to do so sensibly and efficiently while avoiding numerous potential problems on the way. ere are many reasons why ebm-related skills and solutions would allow us to function more rationally, and with more satisfaction and fun, in our daily practice. even though original literature keeps spewing forth new evidences that should influence the way we practice, our access to such information is limited, and thereby we risk obsolescence. ebm provides solutions here.32 however, while adopting ebm strategies, clinicians must avoid a series of misconceptions about ebm. some critics have mistakenly suggested that ebm equates evidence with results of randomised trials, statistical significance with clinical relevance, evidence (of whatever kind) with decisions, and lack of evidence of efficacy with the evidence for the lack of efficacy. a final mistaken notion is that ebm is a cost-containment tool, rather than a tool for providing optimal patient care33. each healthcare practitioner needs to decide to what extent she would like to become an ebm practitioner. learning the advanced skills of locating and assessing evidence from the original literature gives the practitioners the skills to judge competing recommendations and alternative courses of action while making healthcare practice more intellectually stimulating and rewarding. ebm skills are very much essential for anyone whose goal is to provide recommendations for optimal practice to others by authoring reviews, editorials or practice guidelines, or as clinical teacher. e advent of ebm has meant that traditional sources of authority such as age and experience must be supplemented by explicit reference to the available valid and clinically relevant literature. awareness of such literature, and of rules that allow one to integrate evidence from multiple sources to draw valid conclusions, are rapidly becoming essential for all teachers. ose without such skills risk missing an important tool for communicating with their learners.becoming an accomplished ebm practitioner comes at the cost of time, effort, and sacrificing other priorities. as pointed out earlier, an equally legitimate alternative for clinicians is to actively seek information from sources that explicitly use ebm tools in their selection and presentation of evidence. even here the clinician requires specific ebm skills to be able to apply the gleaned information to individual patients. for instance, in helping patients weigh the risks and benefits of a treatment they are considering, the clinician must understand the best estimate of the magnitude of the treatment effect, and the precision of that estimate. for the policy decision makers, including regulators and payers, the evolution of ebm provides new opportunities and challenges. e opportunities lie in the fact that, when properly used, ebm tools help generate data to inform and rationalize healthcare decisions. e challenges, even dangers, lie in the superficial use of ebm concepts, hijacking ebm labels to support preconceived ideas and using labels of ebm without actually applying the concepts. for example, in the recent assessment of the methodological quality of  practice guidelines, shaneyfelt et al found that authors described the method of identifying evidence in only , indicated the methods of grading the evidence in , described the role and use of expert opinion in , indicated the role of value judgement in making recommendations in , and graded the strength of recommendations according to the quality of evidence behind them in . even more surprisingly, the purpose of the guideline was specified in only  of the publications, the background and expertise of authors described in only , and the process of external review revealed in only .38 not surprisingly, one can find practice guidelines or care paths supporting all kinds of questionable practices. e findings of this survey are particularly distressing when one considers that practice guidelines may, in some institutions and organizations, acquire the status of practice directives. generating policies or recommendations intended for wide use requires a detailed understanding of the way such                 policies should be constructed, what constitutes ‘admissible’ evidence, how research evidence can be integrated with patients and societal values, and how the strength of a recommendation relates to the quality of underlying evidence and the tradeoffs between risks and benefits.          during –, a survey of  doctors was conducted in oman to assess their knowledge, attitudes and practices of ebm (unpublished data). it showed that  doctors felt that the practice of ebm would improve the standards of care, and help put research findings into practice. even though  had access to computers, the internet, and were aware of medline searches, they never used critically appraised databases like cochrane, best evidence, uptodate, bandolier, clinical evidence or national guideline clearing house. e participants had limited understanding of the basic ebm terms such as numbers needed to treat (nnt), likelihood ratios, odds ratio and relative risk. table 2. steps to practise ebm 1. ask answerable questions 2. translate them to effective searches for the best evidence 3. critically appraise 4. apply the evidence 5. evaluate performance to promote the understanding and practice of ebm, yearly workshops are being conducted in oman. e threeday workshop held in april  involved small group (–) teaching, with two facilitators in each group. e participants were from various specialties and levels of experience. e facilitators represented the major centres of ebm including the mcmaster, canada, the centre of evidence-based medicine in oxford, and a reviewer for the cochrane collaboration. a manual was developed for selfstudy. e focus was on covering the  steps of ebm [table ]. ere were three plenary sessions, two hands-on computer lab sessions, one for medline searches, the other for non-medline searches using databases on cd roms such as best evidence, cochrane and uptodate. questionnaire surveys before and aer the workshop showed that the participants had gained an understanding of ebm and demonstrated that workshops are effective ways to learn the practice of ebm. aer the workshop the participants have been trying to practice themselves and introduce the concepts of ebm in their organizations.                      c o n c l u s i o n e purpose of ebm is to provide healthcare practitioners and decision-makers (physicians, nurses, administrators, regulators) with tools that allow them to gather, access, interpret, and summarize evidence required to buttress their decisions and to explicitly integrate this evidence with patients’ and providers’ values. in this sense, ebm is not an end in itself, but rather a set of principles and tools that helps us distinguish evidence from unsubstantiated opinions, ignorance of evidence from real scientific uncertainty, and ultimately, serves to provide better patient care. r e f e r e n c e s . sackett dl, haynes rd, guyatt gh, tugwell p. in: clinical epidemiology basic science for clinical medicine. boston, little brown, . . mulrow cd, mulrow jp, linn wd, et. al. relative efficacy of vasodilator therapy in chronic congestive heart failure. jama , , –. . packer m, carver jr, rodeheffer rj, ivanhoe rj, dibianco r, zeldis sm et al. effect of oral milrinone on mortality in severe chronic heart failure. n engl j med , , –. . yusuf s, teo kk. inotropic agents increase mortality in patients with congestive heart failure. circulation , , . . e ec/ic bypass study group. failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. n engl j med , , –. . north american symptomatic carotid endarterectomy trial collaborators. beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. n engl j med , , –. . echt ds, liebson pr, mitchell lb, peters rw, obias-manno d, barker ah, et al. mortality and morbidity in patients receiving encainide, flecainide, or placebo. e cardiac arrhythmia suppression trial. n engl j med , , –. . miller fw, leitman sf, cronin me, hicks je, leff rl, wesley r, et al. controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. new engl j med , , –. . lewis ej, hunsicker lg, lan s, rohde rd, lachin jm. a controlled trial of plasmapheresis therapy in severe lupus nephritis. n engl j med , , –. . chalmers i, enkin m, keirse njnc. effective care in pregnancy and childbirth. oxford university press, oxford, , –. . iscoe na, goel v, wu k, fehringer g, holowaty ej, naylor cd. variation in breast cancer surgery in ontario. can med assoc j , , –. . mcpherson k. why do variations occur? in: anderson tf, mooney g (eds.). e challenges of medical practice variations. macmillan, london: , –. . anderson gm, lomas j. regionalization of coronary artery bypass surgery: effects on access. med care , , –. . wennberg j. dealing with medical practice variations: a proposal for action. health aff millwood , , –. . eddy dm. clinical decision making: from eory to practice: a collection of essays from jama. boston: jones & bartlett publishers, .         j       . chassin mr, brook rh, park re, keesey j, fink a, kosecoff j, et al. variations in the use of medical and surgical services by the medicare population. n engl j med , , –. . light dw. uncertainty and control in professional training. j health social behav , , –. . chalmers i. scientific inquiry and authoritarianism in perinatal care and education. birth , , –. . hayward r, wilson mc, tunis sr, bass eb, guyatt gh. how to use clinical practice guidelines. a. are the recommendations valid?e evidence-based medicine working group. jama , , –. . guyatt gh, sackett dl, sinclair j, hayward rs, cook dj, cook rj. users’ guides to the medical literature. ix. a method for grading health care recommendations. jama , , –. . hope t. evidence based patient choice. report to the anglia and oxford health authority into the use of evidence based information for enhancing patient choice. old road, headington, oxford: anglia and oxford regional health authority, . . haynes rb, lomas j, hayward rsa. bridges between healthcare research evidence and clinical practice. j amer med inform assoc , , –. . evidence-based medicine working group. evidence-based medicine: a new approach to teaching the practice of medicine. jama , , –. . mccoll a, smith h, white p, field j. general practitioners’ perceptions of the route to evidence based medicine: a questionnaire survey. bmj , , –. . haynes r b. of studies,syntheses, synopses, and systems: the “s” evolution of services for finding current best evidence. evidence based medicine  march-april. , –. . haynes b, glasziou p, straus s. advances in evidence-based information resources for clinical practice, acp journal club , , a--a-. . straus se, sackett dl. getting research findings into practice. using research findings in clinical practice bmj , , –. . kenneth al. resource corner best evidence . acp journal club.  , a-. chalmers i, dickersin k, chalmers tc. getting to grips with archie cochrane’s agenda. bmj , , –. . editorial. cochrane’s legacy. lancet , , –. . booth a. o’rourke a. resource corner, sumsearch and pubmed:  internet-based evidence-based medicine tools, acp journal club. , , a-. . sackett dl, richardson ws, rosnberg w, haynes rb. evidencebased medicine. how to practice and teach ebm. churchill livingstone, . . sackett dl, rosenberg wmc, gray jam, haynes rb, richardson ws. evidence-based medicine: what it is and what it isn’t. bmj , , –. . shaneyfelt tm, mayo-smith mf, rothwangl jr. are guidelines following guidelines? e methodological quality of clinical practice guidelines in the peer-reviewed medical literature. jama , , –. submitted 19 jan 22 1 revision req. 9 mar 22; revision recd. 24 apr 22 2 accepted 17 may 22 3 online-first: may 2022 4 doi: https://doi.org/10.18295/squmj.5.2022.040 5 6 guillain-barre syndrome associated with sars-cov-2 in two pediatric 7 patients 8 fatema al amrani,1 raghad al-abdwani,2 fatma al rashdi,3 eiman al 9 ajmi,4 *amna al futaisi5 10 11 1pediatric neurology unit and 2pediatric intensive care unit, department of child health 12 and 3pediatric emergency unit, emergency medicine department, sultan qaboos 13 university hospital, mucat, oman; 4department of radiology, sultan qaboos university 14 hospital, mucat, oman; 5pediatric neurology unit, department of child health, college 15 of medicine and health sciences, sultan qaboos university, muscat, oman. 16 *corresponding author’s e-mail: amnaf@squ.edu.om. 17 18 abstract 19 guillain-barre syndrome (gbs) is a recognized complication of severe acute respiratory 20 syndrome coronavirus 2 (sars-cov-2). we report two children with gbs associated with 21 sars-cov-2 presented to a tertiary center in muscat, oman in 2021: the first patient was 22 a 3-month-old female infant who presented with bradypnea, encephalopathy, and 23 generalized weakness that required mechanical ventilation. polymerase chain reaction 24 (pcr) testing of the nasopharyngeal swabs (nps) was positive for sars-cov-2. she had 25 axonal variant gbs based on a nerve conduction study, cerebrospinal fluid analysis, and 26 neuroimaging findings. the second patient was a 6-year-old girl with fever, vomiting, and 27 diarrhea followed by ascending weakness who presented with quadriplegia and facial 28 weakness. subsequently, she developed respiratory muscle weakness and required 29 mechanical ventilation. pcr testing of nps was negative for sars-cov-2, however igg 30 serology analysis was positive. the clinical course of these two patients was rapidly 31 progressive and both of them required mechanical ventilation. the patient with axonal 32 variant gbs made an incomplete recovery. 33 keywords: acute inflammatory demyelinating polyradiculoneuropathy, sars-cov-2, 34 oman. 35 36 introduction 37 a wide array of neurological manifestations is linked to sars-cov-2 involving both the 38 central and peripheral nervous systems.1 these manifestations appear to be a combination 39 of non-specific complications of systemic disease, the effects of direct viral infection, or 40 inflammation of the nervous system and vasculature, which can be para-infectious or post-41 infectious.2 peripheral nervous system is less frequently involved and disorders that are 42 described to be associated with covid-19 include guillain-barre syndrome (gbs), 43 polyneuritis cranialis, myopathy and rhabdomyolysis.1 44 45 gbs is an immune-mediated disorder that can present in either a demyelinating or axonal 46 form.3 the demyelinating variant is characterized by autoantibodies that bind to the myelin 47 sheath of schwann cells and initiate complement activation, leading to a cascade of events 48 resulting in focal destruction of the myelin sheath. in the axonal variant autoantibodies 49 attack the nodal axolemma leading to the formation of membrane attack complex (mac), 50 which subsequently leads to axonal degeneration.3 51 52 similar to adults, gbs is one of the most commonly reported neurological manifestations 53 associated with covid-19 in pediatric populations.4 most children developed gbs after 54 covid-19 but asymptomatic patients were also described. the clinical presentations and 55 electrophysiologic findings are similar to the classic gbs with slight prevalence of acute 56 inflammatory demyelinating polyneuropathy (aidp) over acute motor axonal neuropathy 57 (aman).5 the prognosis is favorable with 70% of patients showing good response to 58 intravenous immunoglobulins. the prognosis is worse in the older age groups which is also 59 similar to the classic gbs. 60 61 we describe two pediatric patients with different variants of guillain-barre syndrome 62 (gbs) associated with sars-cov-2 infection and their clinical course and outcome. 63 64 case reports 65 patient one 66 a 3-month-old female infant born at 34 weeks gestation (corrected 8 weeks) had an 67 uneventful antenatal and postnatal history and adequate growth and development. she 68 presented to the emergency department (ed) with a two-day history of poor feeding, 69 lethargy, shallow slow breathing, and decreased urine output. ten days prior, she had one 70 day of fever, vomiting, and diarrhea. physical examination revealed an encephalopathic 71 infant with a weak cry and glasgow coma scale of e1v2m3. the patient was pale, 72 tachycardic, hypertensive, poorly perfused; in compensated shock, bradypneic with 73 intermittent episodes of apnea requiring intubation and mechanical ventilation. further 74 examination showed hypotonia with lower extremity weakness and absent deep tendon 75 reflexes (dtr). she was resuscitated with fluid and covered with broad-spectrum 76 antimicrobials (ceftriaxone, vancomycin and acyclovir) for the possibility of septic shock 77 and meningoencephalitis. initial testing showed that the nasopharyngeal aspirate (npa) 78 was positive for sars-cov-2, respiratory viral screen was positive for adenovirus and 79 negative for the rest of viruses including parechoviruses, human bocavirus, influenza a & 80 b, parainfluenza 1, 2, 3, 4, rhinovirus, respiratory syncytial virus (rsv), human 81 metapneumovirus, enterovirus and h1n1. npa for mycoplasma pneumoniae polymerase 82 chain reaction (pcr) was negative. pcr for cytomegalovirus (cmv), and epstein barr 83 virus (ebv) from the serum was negative. computed tomography (ct) of the brain was 84 normal; cerebrospinal fluid (csf) analysis showed high protein 0.64 g/l (normal range: 85 0.15–0.45) and glucose 4.1 mmol/l(normal range: 3.3–4.4) with no leucocytes. csf 86 culture showed no growth, and viral pcr for herpes simplex virus (hsv), parechovirus, 87 enterovirus, varicella zoster virus and mumps viruses.was negative. 88 89 the patient remained persistently tachycardic and hypertensive despite hydration and 90 sedation but was controlled with propranolol. renal ultrasound and magnetic resonance 91 angiography of the aorta and renal arteries were normal. echocardiography revealed left 92 ventricular hypertrophy with moderate outflow obstruction. in view of this clinical 93 presentation, magnetic resonance imaging (mri) of the brain was performed which showed 94 leptomeningeal enhancement on the surface of the brainstem and within the internal 95 auditory canals. mri of the spine showed diffuse enhancement of the spinal nerve roots, 96 which was more conspicuous along the cauda equina nerve roots, with surface 97 enhancement of the cord at the conus (figure 1). nerve conduction studies (ncs) showed 98 sensorimotor axonal polyneuropathy. moreover metabolic screen including lactate, 99 ammonia, lactase dehydrogenase, thyroid function test, neonatal metabolic screen and 100 createnine kinase (ck) were normal. furthermore patient had whole exome sequencing 101 (wes) that came negative with no pathogenic variants or variants of unknown significance. 102 103 the patient was diagnosed with gbs based on the results of csf analysis, ncs, and 104 neuroimaging. she was treated with intravenous immunoglobulin (ivig; 2g/kg) followed 105 by plasma exchange (plex; five cycles) and a second dose of ivig. the patient was 106 successfully extubated to bilevel positive airway pressure (bipap) but could not be weaned 107 off due to generalized muscle weakness and bradypnea so we planned for a tracheostomy 108 and home ventilation. however, because of her difficult socioeconomic status, the parents 109 refused tracheostomy, and the patient was eventually discharged home and palliated on 110 continuous bipap and exclusive nasogastric tube feeding. 111 112 patient two 113 a 6-year-old previously healthy girl presented to a community hospital with one week 114 history of fever, vomiting, constipation, and abdominal pain followed by lower extremity 115 weakness on day 7 of illness. the weakness progressed to involve the upper extremities 116 and respiratory muscles requiring intubation and mechanical ventilation. csf analysis 117 revealed cytoalbuminologic dissociation with protein of 0.94 g/l (normal range: 0.15–118 0.45), glucose of 3.93 mmol/l (normal range: 3.3–4.4), wbc of 0 and rbcs of 512. the 119 patient was treated with ivig but showed no major improvement so was transferred to our 120 institution for further management. here, she was found to have bilateral facial weakness as 121 well as axial and appendicular hypotonia with a strength of 1/5 on the right and 0/5 on the 122 left side. dtr were absent, and the plantar flexors showed no clonus. no signs of 123 autonomic involvement were observed. the npa was negative for sars-cov-2, however 124 igg serology testing was positive. poliovirus pcr in the stool was negative. 125 126 the ncs showed a sensorimotor demyelinating polyneuropathy with conduction blocks. 127 the patient underwent plex followed by ivig, and was eventually extubated and 128 discharged home with follow up at four weeks showing normalization to her baseline 129 functional status. 130 131 consents were taken from patients’ parents for these case reports publication. 132 133 discussion 134 gbs is classified as either acute inflammatory demyelinating polyradiculoneuropathy 135 (aidp) or acute axonal neuropathy which is further classified as acute motor axonal 136 neuropathy (aman) or acute motor sensory axonal neuropathy (amsan).3 other gbs 137 variants include miller-fisher syndrome, bickerstaff encephalitis, pharyngeal-cervical-138 brachial variant, and pandysautonomia variant.3 this autoimmune-mediated disorder can be 139 triggered by viruses such as cytomegalovirus, epstein-barr virus (ebv), influenza, 140 hepatitis e, and zika, or by bacteria such as campylobacter jejuni or mycoplasma 141 pneumoniae.5,65 sars-cov-2 has been reported to be a potential trigger that could be 142 associated with gbs. the first case of gbs associated with sars-cov-2 was reported in 143 early 2020 in an adult.2 since this initial report, there have been multiple case reports, case 144 series, and systemic reviews demonstrating this association including in the pediatric 145 population.5,7-12 table 1 summarizes gbs cases associated with sars-cov-2 in pediatric 146 population. 147 148 here, we report two pediatric patients who were diagnosed with gbs and tested positive 149 for sars-cov-2. the first patient is of particular interest because of the age at presentation 150 of 8 weeks. gbs usually occurs after the age of 3 years; onset in infancy is extremely rare. 151 there are reported cases of congenital gbs but the youngest patient reported was 11 152 months old.13, 14 our patient had symptoms of infection such as fever, vomiting, and 153 diarrhea 10 days prior to her presentation to the ed. pcr testing of the nasopharyngeal and 154 throat swabs were positive for sars-cov-2 and adenovirus. pcr testing of the csf for 155 sars-cov-2 was not performed. gbs in our patient was likely triggered by sars-cov-2 156 infection, as this association has been previously reported and adenovirus infection is not 157 among the reported potential infectious triggers of gbs. 5, 7 however, there is a question 158 regarding the possible association between the adenovirus vaccine and gbs as a possible 159 complication.15 sars-cov-2 is likely the potential trigger for gbs, due to either surface 160 epitope mimicry of sars-cov-2 to the antigens on schwann cell myelin sheaths in the 161 demyelinating variant or to the nodal axolemma in the axonal variant.3 this molecular 162 mimicry has been reported with other viruses, such as varicella zoster virus (vzv), ebv 163 and cmv in patients infected with human immunodeficiency virus.16 both patients had 164 cytoalbuminologic dissociation, which has been well documented in previous reports.5, 7 165 the neurophysiological evaluation of our first patient showed a picture suggestive of 166 amsan. the amsan variant has been reported in association with sars-cov-2. in a 167 recent systematic review of different gbs variants, there were seven cases of amsan 168 reported, with an age range of 23–77 years and no cases in the pediatric age group.17 169 recently, akçay et al. reported the first pediatric patient with axonal variant gbs 170 associated with sars-cov-2.10 our patient is the youngest reported pediatric patient with 171 amsan associated with sars-cov-2. the amsan variant of gbs has been reported in 172 children but is mainly associated with c. jejuni gastroenteritis.18 our patient’s diagnosis 173 was based on the presence of sensorimotor axonal polyneuropathy, cytoalbuminologic 174 dissociation in the csf, and cauda equina root enhancement on neuroimaging. 175 furthermore, she had features of dysautonomia, including persistent hypertension that was 176 initially refractory to medical treatment and pupillary abnormalities. the persistent 177 hypertension likely led to a hypertrophic left ventricle. autonomic disturbances are among 178 the clinical features of gbs, especially during the acute clinical presentation. these clinical 179 features may include blood pressure and heart rate instability, sweating disturbances, bowel 180 and bladder retention, incontinence, and vasomotor instability.19 in addition, the presence 181 of dysautonomia correlates with illness severity, and this is particularly true for 182 hypertension and tachycardia.20 moreover, this patient had rapid progression of the disease 183 requiring intubation and mechanical ventilation at the time of presentation, indicating a 184 rapidly progressive course of her illness and a short peak to disability. she required a 185 prolonged period of mechanical ventilation in the picu before weaning to non-invasive 186 ventilation was possible. this course is similar to that of a previously reported pediatric 187 patient with axonal gbs associated with sars-cov-2.10 this patient had multiple poor 188 prognostic factors, including the rapid deterioration of her clinical status requiring 189 mechanical ventilation on presentation, the axonal variant of gbs and the presence of 190 dysautonomia.22, 23 peak disability has been reported as an independent risk factor for 191 outcomes.22 although the combination of gbs and encephalopathy in this patient seems 192 unusal, the early resolution of encephalopathy and longer-persisting neuropathy may permit 193 the consideration of gbs as a possible diagnosis. 194 195 in the second patient, pcr testing of the nps and throat swab were negative for sars-196 cov-2, but igg serology was positive. hence, gbs was likely part of a parainfectious 197 process associated with sars-cov-2. her clinical course was similar to a previously 198 reported case of the demyelinating variant of gbs associated with sars-cov-2.24 her 199 outcome was more favorable than that of the first patient, although her initial presentation 200 was rapidly progressive, and she had a short peak to disability. prognosis was more 201 favorable in the demyelinating variant than in the axonal variant, which is well documented 202 in the literature.25 in addition, this patient did not have dysautonomia, and her period of 203 mechanical ventilation was shorter. given that sars-cov-2 diagnosis in this patient was 204 based on igg serology and that other antimicrobial causes were not excluded, gbs may not 205 be related to sars-cov-2. 206 207 in both cases, the clinical course was severe with rapid progression, which is likely related 208 to the severe autoimmune response that is mounted by the body in response to sars-cov-209 2 infection.26 210 211 conclusion 212 gbs should be considered in the differential diagnosis of any child presenting with acute 213 flaccid paralysis even in patients less than one year of age. there is growing evidence that 214 there is association between sars-cov-2 infection and gbs. 215 216 authors’ contribution 217 aaf conceptualized the idea. faa and aaf drafted the manuscript. far and ra-a drafted 218 the case history. eaa prepared the images, annotation and description. faa, ra-a and 219 aaf revised the manuscript. all authors approved the final version of the manuscript. 220 221 references 222 1. guerrero ji, barragán la, martínez jd, montoya jp, peña a, sobrino fe, et al. 223 central and peripheral nervous system involvement by covid-19: a systematic 224 review of the pathophysiology, clinical manifestations, neuropathology, 225 neuroimaging, electrophysiology, and cerebrospinal fluid findings. bmc infect dis 226 2021; 21:515. https://doi.org/10.1186/s12879-021-06185-6. 227 2. zhao h, shen d, zhou h, liu j, chen s. guillain-barrarryndrome associated with 228 sars-cov-2 infection: causality or coincidence? the lancet neurology. 2020 may 229 1;19(5):383–4. https://doi.org/10.1016/s1474-4422(20)30109-5. 230 3. yuki n, hartung h-p. guillain-barré syndrome. n engl j med. 2012 jun 231 14;366(24):2294–304. https://doi.org/10.1056/nejmra1114525. 232 4. sánchez-morales ae, urrutia-osorio m, camacho-mendoza e, rosales-pedraza g, 233 dávila-maldonado l, gonzález-duarte a et al. neurological manifestations 234 temporally associated with sars-cov-2 infection in pediatric patients in 235 mexico. childs nerv syst. 2021;37(7):2305-2312. https://doi: 10.1007/s00381-021-236 05104-z5 237 5. abu-rumeileh s, abdelhak a, foschi m, tumani h, otto m. guillain-barré syndrome 238 spectrum associated with covid-19: an up-to-date systematic review of 73 cases. j 239 neurol. 2021 apr;268(4):1133–70. https://doi.org/10.1007/s00415-020-10124-x. 240 6. grygorczuk s, zajkowska j, kondrusik m, pancewicz s, hermanowska-szpakowicz t. 241 [guillain-barré syndrome and its association with infectious factors]. neurol 242 neurochir pol. 2005 jun;39(3):230–6. 243 7. sansone p, giaccari lg, aurilio c, coppolino f, esposito v, fiore m, et al. post-244 infectious guillain-barrrr its association to sars-cov-2 infection: a systematic 245 review. life (basel). 2021 feb 21;11(2). https://doi.org/10.3390/life11020167. 246 8. al-zadjali mm, shibli ea, maskari ma, gujjar ar, asmi aa. post covid-19 247 guillain-barré-syndrome (gbs): a case report from oman. sultan qaboos univ med 248 j [internet]. 2021 jun 27 [cited 2021 dec 29]; available from: 249 https://journals.squ.edu.om/index.php/squmj/article/view/4390. 250 https://doi.org/10.18295/squmj.6.2021.090 251 9. curtis m, bhumbra s, felker mv, jordan bl, kim j, weber m, et al. guillain-252 barrrrbarré-syndrome (gbs): a case report from oman. siatrics. 2021;147(4). 253 https://doi.org/10.1542/peds.2020-015115. 254 10. akak42/peds.2020-015115.ker mv, jordan bl, kim j, weber m, et al. guillain-255 barrrrbarré-syndrome (gbs): a case report from oman. siatrics. 2021;147(4). j 256 [internet]. 2021 jun 27 https://doi.org/10.1002/jmv.27018. 257 11. khalifa m, zakaria f, ragab y, saad a, bamaga a, emad y, et al. guillain-258 barrrrrrbarré-syndrome (gbs): severe acute respiratory syndrome coronavirus 2 259 detection and coronavirus disease 2019 in a child. j pediatric infect dis soc. 2020 260 sep 17;9(4):510–3. https://doi.org/10.1093/jpids/piaa086. 261 12. frank chm, almeida tvr, marques ea, de sousa monteiro q, feitoza pvs, borba 262 mgs, et al. guillain-barré syndrome associated with sars-cov-2 infection in a 263 pediatric patient. j trop pediatr. 2021 jul 2;67(3):fmaa044. 264 https://doi.org/10.1093/tropej/fmaa044. 265 13. luijckx gj, vles j, baets m de, buchwald b, tmost j. guillain-barré syndrome in 266 mother and newborn child. the lancet. 1997 jan 4;349(9044):27. 267 https://doi.org/10.1016/s0140-6736(97)24001-8. 268 14. kannan ma, ch rk, jabeen sa, mridula kr, rao p, borgohain r. clinical, 269 electrophysiological subtypes and antiganglioside antibodies in childhood guillain-270 barré syndrome. neurology india. 2011 sep 1;59(5):727. 271 https://doi.org/10.4103/0028-3886.86549. 272 15. mcneil mm, paradowska-stankiewicz i, miller er, marquez pl, seshadri s, collins 273 lc, et al. adverse events following adenovirus type 4 and type 7 vaccine, live, oral in 274 the vaccine adverse event reporting system (vaers), united states, october 275 2011-july 2018. vaccine. 2019 16;37(44):6760–7. 276 https://doi.org/10.1016/j.vaccine.2019.08.087. 277 https://doi.org/10.18295/squmj.6.2021.090 16. gnann jw. varicella-zoster virus: atypical presentations and unusual complications. j 278 infect dis. 2002 oct 15;186 suppl 1:s91-98. https://doi.org/10.1086/342963. 279 17. robinson-papp j, simpson dm. neuromuscular diseases associated with hiv-1 280 infection. muscle nerve. 2009 dec;40(6):1043–53. 281 https://doi.org/10.1002/mus.21465. 282 118. sriwastava s, kataria s, tandon m, patel j, patel r, jowkar a, et al. guillain 283 barrrrmuscle nerve. 2009 dec;40(6):1043–53.s91-98.pe 4 and type 7 vaccine, live, 284 oral in the vaccineand case series. j neurol sci. 2021 15;420:117263. https://doi.org/ 285 10.1016/j.jns.2020.117263. 286 19. heikema ap, islam z, horst-kreft d, huizinga r, jacobs bc, wagenaar ja, et al. 287 campylobacter jejuni capsular genotypes are related to guillainin vaccine, lme. 288 clinical microbiology and infection. 2015 sep 1;21(9):852.e1-852.e9. https://doi.org/ 289 10.1016/j.cmi.2015.05.031. 290 20. zaeem z, siddiqi za, zochodne dw. autonomic involvement in guillain-barrrr al. 291 campylobacter jejuni capsular genotypes are relatedhttps://doi.org/10.1007/s10286-292 018-0542-y. 293 21. dimario fj, edwards c. autonomic dysfunction in childhood guillain-barrrrr al. 294 campylobacter jejuni capsular genotypes 295 arhttps://doi.org/10.1177/0883073811420872. 296 22. kalita j, kumar m, misra uk. prospective comparison of acute motor axonal 297 neuropathy and acute inflammatory demyelinating polyradiculoneuropathy in 140 298 children with guillain-barré syndrome in india. muscle nerve. 2018;57(5):761–5. 299 https://doi.org/10.1002/mus.25992. 300 23. chakraborty t, kramer cl, wijdicks efm, rabinstein aa. dysautonomia in guillain-301 barré syndrome: prevalence, clinical spectrum, and outcomes. neurocrit care. 302 2020;32(1):113–20. https://doi.org/10.1007/s12028-019-00781-w. 303 24. hasan i, saif-ur-rahman km, hayat s, papri n, jahan i, azam r, et al. guillain-barré 304 syndrome associated with sars-cov-2 infection: a systematic review and individual 305 participant data meta-analysis. j peripher nerv syst. 2020;25(4):335–43. 306 https://doi.org/ 10.1111/jns.12419. 307 25. estrade s, guiomard c, fabry v, baudou e, cances c, chaix y, et al. prognostic 308 factors for the sequelae and severity of guillain-barré syndrome in children. muscle 309 nerve. 2019;60(6):716–23. https://doi.org/10.1002/mus.26706. 310 26. garcrc/mus.26706.rd c, fae, inflammation, and the clinical spectrum of covid-19. 311 front immunol. 2020;11:1441. https://doi.org/ 10.3389/fimmu.2020.01441. 312 313 table 1: clinical characteristics of reported pediatric patients with guillian-barre syndrome –associated with sars-cov-2 314 315 abbreviations: yr: age in years, iv: invasive ventilation, d: days, cn: cranial nerves, dx from symp onset: diagnosis from symptom onset, csf: cerebrospinal 316 fluid, ivig: intravenous immunoglobulin, plex: plasma exchange, pcr: polymerase chain reaction, abs: antibodies, aidp: acute inflammatory demyelinating 317 polyradiculopathy, aman: acute motor axonal neuropathy, na: not available 318 author sex age at onset (yr) time to loss functional ability iv dx from symp onset (d) clinical features cn involve ment dysaut onomia csf cytoalb umin dissocia tion ivi g regi men ple x invasi ve ventil ation period (d) nasoph aryngea l sarscov-2 pcr csf sarscov-2 pcr serum sarscov-2 serolog y antigangliosides abs gbs-variant 1 curtis et al 9 m 8 few days + 12 flaccid weakness + 2 g/ kg over 2d 4 + na na aidp 2 khalifa et al 11 m 11 few days 2 distal weakness of the u & le + 2 g/ kg over 2d + na na na aidp 3 frank chm et al 12 m 15 few days na progressi ve u and le weakness + 0.4 g/kg x 5d + + aman 4 akçay et al 10 m 6 4d + 14 flaccid weakness + 2 g/ kg over 2d + 30 + na na aman 319 320 321 figure 1. (a) a gadolinium-enhanced axial t1-weighted image through the posterior fossa shows bilateral enhancement in the internal auditory canals (arrows). (b) an axial t2-weighted image of the lumbar spine doesn’t show abnormal thickening of the cauda equina nerve roots. there is however uniform enhancement of the spinal nerve roots on gadolinium-enhanced axial t1-weighted image (c). (d) the enhancement on the surface of the disatal cord and cauda equina nerve roots is also shown on sagittal post-contrast t1 weighted image (arrows). a b c d submitted 23 jan 23 1 revision req. 8 mar 23; revision recd. 10 apr 23 2 accepted 9 may 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.038 5 6 peri-ictal water drinking in an omani patient with bilateral mesial 7 temporal sclerosis 8 younis al-mufargi,1 *haifa alabri,2 arunodaya r. gujjar3 9 10 departments of 1human clinical anatomy and 3medicine, sultan qaboos university, muscat, 11 oman; 2department of medicine, sultan qaboos university hospital, sultan qaboos university, 12 muscat, oman 13 *corresponding author’s e-mail: jood@squ.edu.om 14 15 abstract 16 peri-ictal water drinking (piwd) is a rare vegetative manifestation of temporal lobe epilepsy 17 without a definite lateralization value. we report a case of piwd in a 22-year-old omani man 18 with post-concussion syndrome and epilepsy presented to a tertiary care hospital in muscat, 19 oman in 2021 for evaluation of paroxysmal events. his behaviour of piwd was misinterpreted 20 by his family until characterized in the epilepsy-monitoring unit as a manifestation of epilepsy 21 that was treated medically. to our knowledge, this is the second reported case in our region. 22 keywords: peri-ictal water drinking, ictal spitting, epilepsy, autonomic 23 24 introduction 25 vegetative manifestations have been well-described in patients with epilepsy during the seizure 26 in both pediatric and adult age groups.1,2 peri-ictal vegetative symptoms (pivs) may occur 27 without any particular relationship to the cause of epilepsy.3 pivs include cardiovascular, 28 respiratory, gastrointestinal, and urinary signs and symptoms. peri-ictal water drinking (piwd) 29 is an infrequently described automatism in an epileptic patient, often among those with temporal 30 lobe epilepsy.3,4 among patients with focal epileptic seizure, 65 cases only are reported to have 31 mailto:jood@squ.edu.om peri-ictal water drinking behavior.4 piwd has been defined as the urge to drink water ictally or 32 up to 2-minute in the post-ictal phase of epileptic seizures.1 peri-ictal water drinking as a 33 manifestation of epileptic seizure signifies a reliable sign of lateralization to a non-dominant 34 temporal lobe.5 35 36 herein, we report a case of peri-ictal water drinking (piwd) in a 22-year-old man with post-37 concussion syndrome with bilateral mesial temporal sclerosis. to our knowledge, this is the 38 second reported case in our region. we found that piwd has localizing but no lateralizing value. 39 40 case report 41 a 22-year-old right-handed man had a road traffic accident at the age of 11 years and suffered a 42 post-concussion syndrome with behavioural changes of impulsiveness and seizures. his seizures 43 were described as chest discomfort followed by lip and hand automatism and excessive water 44 drinking during the event. his family thought that he would drink water to relive his chest 45 discomfort. after that, he was routinely offered a bottle of water whenever his seizure started, in 46 the context of this recurrent habitual behaviour. 47 48 to better characterize his seizure semiology and localize the ictal onset, he was admitted for 3-49 day in the epilepsy monitoring unit at a tertiary care hospital in muscat, oman for long-term 50 eeg evaluation (figure 1). during evaluation, his anti-seizure medications (asm) including 51 lacosamide 200 mg bid, sodium valproate sr 750mg am/1000 mg pm and clobazam 15mg 52 am/20 mg pm were tapered off. his interictal recording showed intermittent slowing in the right 53 temporal chain and bitemporal sharp waves: 80% on the right (maximum at f8>t4), 20% on the 54 left (maximum at f7>t3). he had five seizures of the same semiology. seizures started with him 55 holding his chest, either due to discomfort or as a reaction to a gastric aura. this was followed by 56 swallowing movements and hand automatism. out of 5 seizures, 3 seizures had clear water 57 drinking during the seizure or after the seizure terminated. he would ask for or grab a nearby 58 water bottle to drink multiple times. the water bottles were 500 ml, and he drank almost 2/3 the 59 amount of the bottle in each seizure. during the other 2 seizures, the patient was alone, and his 60 behaviour seemed restless, looking for water through his bed sheets but not found. he would 61 always ask for water and no other types of fluids. 62 63 table 1 summarize the details. (any gross variations in the pattern of seizure may be 64 summarized here in 1-3 sentences. rest of the paragraph may be superfluous. the table gives fair 65 details). in seizure 1, he used his hands to perform body language to his attendant indicating the 66 need to drink. he grabbed the bottle again from his attendant to drink the second and third time 67 after giving it back after first request to drink. in the third time, he pointed to his chest as of 68 explaining the reason for drinking. all 3 events of water drinking in seizure one happened 69 ictally. in seizure 2, he drank twice ictally and 24 seconds post ictally. in both events, he grabbed 70 the water bottle off his attendant’s hand to drink. in seizure 3, the seizure woke him up from 71 sleep while the attendant was not aware of the event. there were no water bottles close to him, 72 so he seemed restless and looking around the room frequently. finally, he got off bed and walked 73 around the bed but that was not visualized by the video. in the 4th seizure, again he was alone and 74 seemed restless when the seizure started as attendant was not around. there was a bottle close to 75 his pillow, but he did not visualize it. he seemed in discomfort and wiping his face and left nose 76 multiple times with his hands. in seizure 5, it started again by chest sensation as he held his 77 hands against his chest then started swallowing movements. his attendant walked into the room 78 and patient pointed by hand gestures that he wants to drink and again pointed to his chest as of 79 explaining his reasoning. he started spitting and he drank all the bottles given to him (~ 400 ml). 80 81 his mri brain showed evidence of bilateral hippocampal atrophy and bilateral mesial temporal 82 sclerosis (figure 2). his pet/ct of brain was unremarkable with no focal hyper or 83 hypometabolism. the patient’s consent was obtained for publication purposes. 84 85 discussion 86 peri-ictal water drinking was first reported upon a statistical review of aura in epilepsy among 87 1359 cases by lennox,6 defined as the urge of drinking water ictally or up to 2-minutes in the 88 post-ictal phase of epileptic seizures.1 seeking water in epileptic patients has been noticed 89 mostly in ictal phase, yet post-ictal water drinking has been reported as well.1 reported cases of 90 piwd in literature remain infrequent all over the world, with around 65 cases have been reported 91 to date, including one case in our region.4,7 92 93 water-seeking behavior has been correlated electro-clinically and neuropathologically with 94 pathologies in the mesial temporal lobe, emphasizing further on the value of localization 95 hypothesis.8 however, a recently published retrospective study in surgically confirmed patients 96 with focal epilepsy in which piwd occurs more often in frontal lobe epilepsy (fle) than 97 temporal lobe epilepsy (tle) indicating that piwd might not be specific symptom of tle.9 the 98 epileptic discharges in our patient’s seizure confirmed the localization hypothesis of temporal 99 lobe origin. the epileptic discharges from the temporal lobe structures propagating to the 100 hypothalamus is proposed to be a stimulus for water-seeking behavior and sense of thirst in 101 epilepsy.8,10 102 103 several cases of peri-ictal water drinking have been published in the literature highlighting the 104 value of lateralization of peri-ictal water drinking in patients with temporal lobe epilepsy. water 105 seeking behavior has been concluded as a sign representing epileptic focus on the non-dominant 106 temporal lobe.11,12 this lateralization may be explained by asymmetrically represented network 107 of central autonomic system implemented in water-seeking behavior, control of fluid and thirst.11 108 however, other studies have shown no consistent lateralization of epileptiform activity in similar 109 cases.3,5,13 in our patient, we could not conclude definite lateralization as he had seizures with 110 water drinking behavior evident in either of the temporal lobes. even though, seizures number 1 111 and 2 that originated from the right temporal lobe started earlier at 12 and 15 seconds compared 112 to seizure number 5 that may argue that it lateralizes to the non-dominant hemisphere. however, 113 we have incomplete data of seizure number 3 and 4 that may change the equation, therefore, the 114 significance of lateralization in patient presenting with peri-ictal water drinking is still uncertain 115 as demonstrated in our case. 116 117 the autonomic manifestations of epilepsy have a risk to progress into status epilepticus as 118 reported in the literature.14 therefore, the importance of detecting other semiologies of epileptic 119 events as autonomic manifestations such as cardiac and respiratory, is very crucial as it may lead 120 to sudden unexpected death in epilepsy (sudep). 121 122 as noticed in our case, the patient had also other epileptic semiologies of temporal origin like 123 post-ictal spitting. spitting as an ictal phenomenon which has been evoked by direct electrical 124 stimulation to temporal lobe in many trials, confirming the value of localization again with no 125 lateralization value.15 126 127 focal epileptic syndromes are estimated to affect 60% of patients with epilepsy, in which 15% of 128 those patients’ condition cannot be controlled by anti-seizure medications adequately and as 129 observed assumption, half of them may be considered potential candidates for a surgical 130 intervention of epilepsy. a published case of middle-aged man diagnosed with epilepsy since 131 childhood with features of peri-ictal water drinking on anti-seizure medications of right temporal 132 lobe origin, remained seizure-free in 1-year follow up after right anterior temporal resection.7 133 moreover, a recent retrospective study discussing occurrence of piwd in focal epilepsy patients 134 with favorable outcome postoperatively, including frontal lobe epilepsy (flp) and temporal lobe 135 epilepsy (tle) signifying the value of preoperative evaluation in patients with focal epileptic 136 syndromes.9 in the present case, the patient had bi-temporal lobe epilepsy secondary to bilateral 137 mesial temporal sclerosis that was better controlled with anti-seizure medications but has 138 significant behavioral issues requiring follow up with psychiatry. a multidisciplinary discussion 139 to consider if he would benefit from surgical management aimed at improvement in both his 140 seizures and behavioral issues is planned. 141 142 conclusion 143 peri-ictal water drinking, and ictal spitting are infrequent vegetative symptoms seen in the 144 temporal lobe epilepsy without a definite lateralization value. 145 146 authors’ contribution 147 ya did the literature review and wrote entire discussion and analysed of the case. ha wrote the 148 case, analysed the eeg findings in detail with tables and supervised the entire paper. ag 149 reviewed the paper. all authors approved the final version of the manuscript. 150 151 reference: 152 1. baumgartner c, koren j, britto-arias m, schmidt s, pirker s. epidemiology and 153 pathophysiology of autonomic seizures: a systematic review. clin auton res. 2019 154 apr;29(2):137–50. https://doi.org/10.1007/s10286-019-00596-x 155 2. fogarasi a, janszky j, tuxhorn i. autonomic symptoms during childhood partial epileptic 156 seizures. epilepsia. 2006 mar;47(3):584–8. https://doi.org/10.1111/j.1528-157 1167.2006.00472.x 158 3. janszky j, fogarasi a, toth v, magalova v, gyimesi c, kovacs n, et al. peri-ictal 159 vegetative symptoms in temporal lobe epilepsy. epilepsy behav. 2007 aug;11(1):125–9. 160 https://doi.org/10.1016/j.yebeh.2007.04.015 161 4. pietrafusa n, trivisano m, de palma l, serino d, moavero r, benvenga a, et al. peri-ictal 162 water drinking: a rare automatic behaviour in temporal lobe epilepsy. epileptic disord. 163 2015 dec;17(4):384–96. https://doi.org/10.1684/epd.2015.0776 164 5. szűcs a, fogarasi a, rásonyi g, kelemen a, narula l, tóth v, et al. peri-ictal water 165 drinking in temporal lobe epilepsy: is it a reliable lateralizing sign? epilepsy behav. 2007 166 dec;11(4):578–81. https://doi.org/10.1016/j.yebeh.2007.07.012 167 6. lennox wg. epilepsy: xiii. aura in epilepsy; a statistical review of 168 1,359 cases. arch neurol psychiatry. 1933 aug 1;30(2):374. 169 https://doi.org/10.1001/archneurpsyc.1933.02240140138007 170 7. alanazi gm. a young man with peri-ictal water drinking. neurosciences. 2021 171 jan;26(1):85–8. https://doi.org/10.17712/nsj.2021.1.20200074 172 8. cascino gd, sutula tp. thirst and compulsive water drinking in medial basal limbic 173 epilepsy: an electroclinical and neuropathological correlation. j neurol neurosurg 174 psychiatry. 1989 may 1;52(5):680–1. https://doi.org/10.1136/jnnp.52.5.680 175 9. tanno y, matsudaira t, usui n, ogawa h, tokumoto k, kawaguchi n, et al. periictal water 176 drinking revisited: occurrence and lateralizing value in surgically confirmed patients with 177 focal epilepsy. epilepsia open. 2023 mar;8(1):173–82. https://doi.org/10.1002/epi4.12690 178 10. denton da, mckinley mj, weisinger rs. hypothalamic integration of body fluid 179 regulation. proc natl acad sci. 1996 jul 9;93(14):7397–404. 180 https://doi.org/10.1073/pnas.93.14.7397 181 11. trinka e, walser g, unterberger i, luef g, benke t, bartha l, et al. peri-ictal water 182 drinking lateralizes seizure onset to the nondominant temporal lobe. neurology. 2003 mar 183 11;60(5):873–6. https://doi.org/10.1212/01.wnl.0000049459.83589.6c 184 12. musilová k, kuba r, brázdil m, tyrlíková i, rektor i. occurrence and lateralizing value of 185 “rare” peri-ictal vegetative symptoms in temporal lobe epilepsy. epilepsy behav. 2010 186 nov;19(3):372–5. https://doi.org/10.1016/j.yebeh.2010.07.010 187 13. remillard gm, andermann f, gloor p, olivier a, martin jb. water-drinking as ictal 188 behavior in complex partial seizures. neurology. 1981 feb 1;31(2):117–117. 189 https://doi.org/10.1212/wnl.31.2.117 190 14. huang s, al-abri h, sachdeva a, alkhachroum am, shatzman s, lüders h. recurrent 191 focal seizures as a feature of status epilepticus presenting as a peri-ictal water drinking. 192 epilepsy behav case rep. 2018;10:129–32. https://doi.org/10.1016/j.ebcr.2018.09.004 193 15. quevedo-diaz m, campo at, vila-vidal m, principe a, ley m, rocamora r. ictal spitting 194 in non-dominant temporal lobe epilepsy: an anatomo-electrophysiological correlation. 195 epileptic disord. 2018 apr;20(2):139–45. https://doi.org/10.1684/epd.2018.0963 196 197 table 1: summary of seizures, eeg onset, duration and details of water drinking phenomenon. 198 sz (seizure), sec (seconds), na (not available). 199 eeg onset sz duration onset of first drinking during a sz number of times drinking during the sz further remarks sz # 1 right temporal 44 sec 12 sec 3 times sz # 2 right temporal 66 sec 15 sec 2 times during a sz and 1 after sz ends (1.5 min after sz ended) sz # 3 left temporal 47 sec na na nocturnal seizure sz # 4 left temporal 54 sec na na left nose wiping sz # 5 left temporal 63 sec 55 sec 1 time post ictal spitting 200 201 202 203 204 figure 1: (a) ictal eeg onset with rhythmic discharges in the right temporal chain, maximum at 205 f8/t4. (b) ictal eeg onset with rhythmic discharges in the left temporal chain, maximum at t3 206 207 208 figure 2: mri brain (a) flair, (b) t2 that both showed evidence of bilateral hippocampal 209 atrophy and mesial temporal sclerosis. 210 december 2008 no white pages.indd abstract atypical lymphocytosis due to infections is classically seen in viral and chronic bacterial infections. a four year old boy with acute streptococcal infection presented at al-nahdha hospital, muscat, oman, with follicular tonsillitis and bilateral cervical lymphadenitis. the blood film showed 33% atypical lymphocytes. serologically, immunoglobulin m (igm) antibodies were positive for cytomegalovirus, herpes simplex virus, and epstein barr virus, but the patient responded dramatically to antibiotics. key words: atypical lymphocytes; acute streptococcal infection; lymphnode; case report; oman. an unusual case of atypical lymphocytosis *suresh venugopal, jessy george, salima s al-harthy sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 353-355 sultan qaboos university© submitted 31st march 2008 accepted 18th august 2008 department of laboratory, al-nahdha hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: sure5155@omantel.net.om فاوِيَّات الال منطية مْ اللِّ ثْرَةُ لكَ اعتيادية غير حالة احلارثي سالم سليمة جورج، جسي فينوجوبال، سوريش أربع عمره ولد حالة هنا ندرج املزمنة. واجلرثومية الفيروسية االلتهابات في يالحظ ما عادة االلتهابات النمطية بسبب الال فاوِيَّات اللِّمْ ثْرَةُ كَ ملخص: الفحص أظهر لقد في اجلهتني. العنقية يَّة فِ اللِّمْ دِ قَ والْتِهابُ العُ اللوزتني في التهاب هيئة على ظهرت والتي يَّات دِ قْ بالعِ حاد بالتهاب مصاب سنوات ، وفيروس الَيا للخَ مُ خِّ ُضَ امل ــروسُ ي للفَ إيجابيا (m) املناعي اجللوبيولني أضداد كان .33% ــة الال منطي ــبة الكريات الليمفاوية نس أن ــريحة لش اهري احليوية. للمضادات كبير املريض بشكل استجاب هذا ومع بار إيبِشتاينالبَسيط ، وفَيروسُ رْبِسٌ الهِ عمان. ، حالة تقرير ، الليمفاوية الغدة احلاد ، يَّات دِ قْ العِ التهاب ، منطية الال الكلمات: اخلاليا الليمفاوية مفتاح acute bacterial infections usually produce neutrophilic leucocytosis. chronic bacte-rial and viral infections typically cause lymphocytosis. however, acute streptococcal infections can lead to atypical lymphocytosis as well as elicit false positive viral antibody results. c a s e r e p o r t a 4 year old boy from barka, oman, came to the ear, nose and throat (ent) department of al-nahdha hospital, muscat, oman, on 4 november 2007 complaining of fever and difficulty in swallowing for the last 4 days. on clinical examination, both the tonsils were huge and studded with follicles. there were bilateral cervical lymphnodes, each measuring 7cm x 6cm, tender, soft and hot. the clinical diagnosis entertained was follicular tonsillitis with bilateral cervical lymphadenitis. the patient was immediately admitted to the ent. a complete blood count (cbc) on admission showed hb = 11.5 g/dl. the total white blood cell count (wbc) count = 7.6 x 109/l and the platelet count = 237x109/l, which was normal, but the erythrocyte sedimentation rate (esr) was 15 mm at 1 hour, which was mildly above the normal range of 10 mm at 1 hour. a sample sent for blood culture subsequently revealed no growth. the throat culture grew normal flora, but the swab showed gram positive cocci. the cbc was repeated 3 days later on 7 november and showed hb = 10 g/dl; total wbc count = 14.7x109/l and platelet count = 141x109/l. a differential wbc count showed 33% atypical lymphocytes. we advised that a monospot test be done and the clinicians put the patient on a course of intravenous augmentin. the same day (7 november), the monospot test results were negative. we immediately requested an epstein barr virus (ebv) immunoglobulin m (igm) antibody test and a torch (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) test. next day, the cmv (cytomegalo virus) igm came out positive. we requested a polymerase chain reaction (pcr) test to detect cmv dna. on 9 november, the herpes simplex igm test came out positive. on 10th november, c a s e r e p o r t s u r e s h ve n u g o pa l , j e s s y g e o r g e a n d s a l i m a s a l h a r t h y 354 the ebv igm antibody test also came out positive. clinically, the patient was afebrile, the lymphnode enlargement on both the sides had vanished, and he had responded very well to antibiotics. he was discharged on the same day. the pcr test result arrived on 12 november and did not detect any cmv dna in the plasma. but an antistreptolysin o (aso) titre done on the sample was increased and measured 400 iu. the boy came for a follow up in december 2007. clinically and haematologically (cbc, differential wbc count and esr) he was absolutely normal. d i s c u s s i o n this 4 year old boy had an acute onset of fever and dysphagia. the dysphagia was due to the severe enlargement of both the tonsils. contributing to the above was bilateral, tender, soft and hot cervical lymph node swellings. his tonsils were studded with follicles and tender soft and hot. a diagnosis of lymphadenopathy fitted well with an acute bacterial infective pathology. sensing the severity of the condition, the boy was admitted to the hospital. the throat swab revealed many gram positive cocci, but the throat swab culture grew normal flora and the blood culture did not reveal any growth. this could be explained by the fact that this patient was referred from barka and was already on oral antibiotic treatment. it is well known that a prior antibiotic treatment can lead to no growth on culture.1 the cbc repeated 2 days later on the automated haematology analyzers revealed mild anaemia, leucocytosis and mild thrombocytopenia. a blood film was prepared. the most striking feature on this film was the presence of numerous atypical lymphocytes with deep basophilic cytoplasm and large, round to oval to indented to irregular nuclei. no blasts were seen [figure 1]. a differential count revealed 16% neutrophils, 51% lymphocytes and 33% atypical lymphocytes. a diagnosis of atypical lymphocytosis was made. viral infections are one of the commonest causes of lymphocytosis and atypical lymphocytosis.2 such a large percentage of atypical lymphocytes made the laboratory entertain the diagnosis of viral infection. we advised a monospot test to rule out infectious mononucleosis, but the clinicians thought and acted otherwise. they were sure that it was an acute bacterial infection and put the patient on a course of intravenous augmentin. to our surprise, the subsequent monospot test result came out negative. we immediately requested an ebv antibody test to increase the specificity of the test and also asked for a torch test. unlike the clinicians, we were pursuing the viral etiology. when cmv igm antibody test came out positive, the laboratory entertained the diagnosis of cervical lymphadenitis due to acute cmv infection and requested a blood pcr test to detect cmv dna. the next day, the herpes simplex virus igm antibody test came positive. we were puzzled. a day later when ebv igm antibody also came positive for this patient, we were confused. a diagnostic dilemma set in. was the patient suffering from cytomegalovirus infection or a herpes simplex virus infection or an ebv infection? we turned our attention to the patient in the ward. we were amazed to see the patient afebrile, with tonsillar and lymphnode enlargement having disappeared, playing in the toy room and ready for discharge. after 7 days of antibiotic treatment, the sick looking boy was perfectly normal. the experience and expertise of the clinicians had won the case. the laborious laboratory scientists looked lost. the pcr test result arrived two days after the patient’s discharge and did not reveal cmv dna in the plasma, confirming that the patient did not have cmv infection. did he have herpes simplex or ebv infection? facilities for doing a pcr test for herpes simplex and ebv were not available. fortunately, one of our scientists had done an aso titre on this patient and it was increased and measured 400 iu. an aso titre of >166 todd units is seen in 80% of children with streptococcal pharyngitis.³ by now, things were getting clearer. we analysed the case comprehensively. here was a patient who prefigure 1: blood smear showing atypical lymphocytes a n u n u s ua l c a s e o f at y p i c a l ly m p h o c y t o s i s 355 sented acutely with fever, swollen, follicle studded tonsils and enlarged bilateral tender, soft and hot cervical lymphnodes. the throat swab had showed numerous gram positive cocci. the aso titre was increased and the patient dramatically and completely responded to antibiotics. taking into consideration, the presenting symptoms and signs, the laboratory data and clinical response, the diagnosis was crystal clear. the patient suffered from an acute streptococcal infection. however, two features demanded explanation. one was the high percentage of atypical lymphocytes in an acute bacterial infection and the second was the cmv igm, herpes simplex igm and ebv igm, all positive in a patient with acute streptococcal infection. lymphocytosis often occurs in young children in response to infections which produce a neutrophil reaction in adults.4 this explains the lymphocytosis and atypical lymphocytes seen in our case with acute streptococcal infection which typically produces a neutrophilic leucocytosis in adults. however, it is worthwhile noting that according to the literature, lymphocytosis is usually rare during such acute bacterial infections except in pertussis.5 the rarity and paucity of literature on this subject prompted the publication of this report. it is well documented in the literature that in response to stress, lymphocytes that are characterised by nuclear and cytoplasmic distortion appear in the blood.5 thus, another explanation for atypical lymphocytosis in this child could be the stress caused by dysphagia. false positive cmv igm can be due to cross-reactions between infections caused by closely related viruses like the acute ebv infection. the cmv igm axsym assay shows a lack of specificity in acute ebv infection hence precautions must be taken when cmv igm results are interpreted.6 the above mentioned published fact, plus the absence of cmv dna in plasma in this patient, proves that the cmv igm result was false positive. acute herpes simplex virus infections typically produce pharyngitis and stomatitis and very rarely lead to such huge bilateral tonsillar enlargement. failure of a patient with suspected streptococcal throat infection to improve within 48 hours should evoke suspicion of infectious mononucleosis, 7 but our patient responded very well to antibiotics thus ruling out a primary infection by ebv. thus in this patient with acute upper respiratory and lymphnode inflammation due to streptococci, well known for its immunological warfare, and taking into consideration the entire clinical, pathological and therapeutic scenario, igm antibodies to cmv, hsv and ebv were false positive. c o n c l u s i o n haematologically, a large number of atypical lymphocytes can be seen in the blood film of a patient with severe, acute upper respiratory streptococcal infection. immunologically, false positive igm antibodies to cmv, hsv and ebv can be observed in patients with such severe acute streptococcal infections. r e f e r e n c e s 1. mims ca, playfair jhl, roitt im, wakelin d, williams r, anderson rm, medical microbiology, part 1. london: mosby, 1993. 2. hoffbrand av, catovsky d, tuddenham egd. postgraduate hematology, 5th ed. oxford: blackwell, 2005. 3. behrman re, vaughan vc. nelson test book of pediatrics, 12th ed. philadelphia: wb saunders company, 1983. 4. hoffbrand av, pettit je, moss pah. essential hematology, 4th ed. oxford: blackwell, 2001. 5. lee gr, foerster j, lukens j, paraskevas f, greer jp, rodgers gm. wintrobe’s clinical hematology, 10th ed. philadelphia: lippincott, williams & wilkins, 1999.. 6. deyi ym, goubau p, bodeus m. false positive igm antibody tests for cytomgalovirus in patients with acute epstein-barr virus infections. eur j clin microbiol infect dis, 2000; 19:557-560. 7. behrman re,vaughan vc. nelson test book of pediatrics, 12th ed. philadelphia: wb saunders company, march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 24-31, epub 16th mar 2009 submitted 27th feb 08 revision req. 20th april 08, revision recd. 26th april 08 accepted 11th june 08 abstract available literature on medical education charts an emerging trend in the field of anatomy. in the past decade, assisted by innovations in informatics and the paradigm shift in medical education, the hands-on experience of cadaver dissection has progressively become a relic of the past. within the context of the situation in gulf cooperation council countries, this paper compares the traditional teaching approach with the modern one that tends to emphasise technical gadgetry, virtual reality and plastic models rather than hands-on-experience to impart knowledge and skill. however, cadaver-based learning is an important building block for the future physician and surgeon since clinical astuteness is likely to rely on skills gained from hands-on experience rather than the tendency to learning through virtual reality found in modern curricula. key words: anatomy teaching; computer-assisted learning; curriculum; cadaver; dissection. the state of human anatomy teaching in the medical schools of gulf cooperation council countries present and future perspectives “anatomy is a science and it owes it to the practice”…. anon. *omar habbal department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: habbal@squ.edu.om التعاون مجلس الطبّ بدول كليّات في التشريح البشريّ مادة تدريس اخلليجيّ للمستقبل الراهن وأمل في الوضع ص تفحّ نظرة احلبَّال مر عُ العقد ففي . الطبي التعليم مجال في مراجع ر من متوفّ هو مما يتضح كما ، ــريح مادة التش مناهج تدريس طرق في متنامية ظاهرة هناك امللخص: املاضي. من ضرباً اجلثة ــريح تش أصبح فبالتدريج ، . الطبيّ التعليم طرق في ل جوهريّ حتوّ حصل ، املعلوماتية عصر ــتجدات مس ــاندة ، ومبس املاضي طرق ــات ملمارس الراهن بالوضع املقال هذا يهتم لذا . التعاون اخلليجي مجلس بدول الطب ــات كلي في املادة تدريس على احلال هذا ــس انعك ــع وبالطب التقنية ــائل على وس ترتكز التي ــتحدثة املس الطرق مقابل ، في واملهارات العلم ــب لكس كطريقة العملية الدروس على واملرتكز التقليدي التدريس علمية بناء كوحدة اجلثة ــول ح املرتكزة ــة الدراس فكرة عن تتغاضى احلديثة فالطريقة ــتيكية. البالس ــمات واس اإللكتروني كالتوضيح ، ــة احلديث في مطروح هو ما بعكس ــبة الضرورية املكتس املهارات هذه تنمي أن ميكن واحلكيمة العملية الطبية اخلبرة وإن ، ــتقبل املس ــية ألطباء وجرّاحي أساس املستحدثة. التشريح مقررات ، تشريح. جثة املنهاج ، احلاسوب ، مبساعدة التعلم ، التشريح تعليم الكلمات: مفتاح teaching anatomy as a medical and clinical science is in a downward spiral. in the past, anatomical skills and knowledge were gained through didactic lectures and complete dissection of the body via personal tuition. this approach has been modernised by the addition of special study modules, problem-based workshops, computers, plastic models and other teaching tools. evidence suggests that, in some centres, dissected cadaver-based anatomy is no longer a priority. the present trend is likely to undermine the vital role of anatomy in life sciences and medical practice. the report entitled “tomorrow’s doctors’1 published by the uk general medical council attempted s p e c i a l c o n t r i b u t i o n th e s tat e o f h u m a n a n at o m y te a c h i n g i n t h e m e d i c a l s c h o o l s o f g u l f c o o p e r at i o n c o u n c i l c o u n t r i e s 25 to address overcrowding of the undergraduate medical curriculum. it recommended a reduction of factual content across the curriculum yet failed to define what constitutes a “core curriculum”.1 by allowing each institution to define its own core material and optional study modules, it paradoxically encouraged the establishment of a variety of curricula, but their suitability has not been scrutinised since there is no benchmark for comparability.2 in gulf cooperation council (gcc) medical schools, there is no unified approach to teaching medicine in general and anatomy in particular. the reduction in the content, depth and breadth of teaching and knowledge of anatomy; changes in basic surgical training; less new graduates adopting anatomy teaching careers, and a change in examination standards, are leading to a likely dire situation where tomorrow’s surgeons and physicians will lack a detailed knowledge of anatomy and have potentially questionable professional capability.3 a primary concern in cadaver-based learning is the difficulty in acquiring enough cadavers. most, if not all, gcc countries do not have a body donor programme so unclaimed bodies are the main source for anatomical dissection. the use of cadavers in human anatomy teaching requires close supervision of students, but there is a worldwide shortage of qualified anatomists. compared to other basic sciences, anatomy teachers have a higher teaching load and, given the current emphasis on research for career development, not surprisingly few graduates choose a career in anatomy. this negatively impacts on basic medical education. teaching the principles of anatomy within the dissecting room introduces students to the reality of death. it also emphasises the concept of biological variation and demonstrates common pathologic changes. with its rich vocabulary, it teaches the basic language of medicine. it also develops manual dexterity. finally, it nurtures the group spirit thus assisting in social bonding and communication.4 the art and science of medicine is to define disease with concision and precision in order to decide on interventions. adequate skills and knowledge of anatomy are therefore indispensable and should be imparted from the onset of medical education.5 the most appropriate method is to show the inner workings of tissues and structures of the human anatomy. however, major criticisms are levelled at anatomy teaching: overcrowded curricula packed with clinically unconnected facts; excessive memorisation; didactic lectures; passive learning and lack of communication with patients. at the same time, computerisation and biomedical informatics have reduced the need for excessive memorisation and actual dissection. this trend has significantly reduced the amount of time students spend learning anatomy.2 in some centres, cadaver-based anatomy is no longer featured in the curriculum regardless of its vocational importance to physicians and surgeons.6 the present fashion to use clinical imaging to help conceptualise anatomical structures, effectively transforms anatomy into a different entity. the new trend is further facilitated with technologies like ultrasound, 3d visualisation, multiaxial computerised image reconstruction, multiplanar magnetic resonance imaging and plastinated prosections.7 running counter to this revolution, some centres are now reverting to classical dissection. medicine is the compassionate art of healing through a detailed understanding of the tissues and structures inside the body, and this is best learnt by dissection.7 although biomedical informatics and new imaging technologies have improved our understanding of anatomic structural organisation, the burning question is still: “is cadaver-based learning in the dissecting room relevant or essential for tomorrow’s doctor?” the answer to this question is addressed in the following discussion. t h e k e y i s s u e l i f e a n d d e a t h some argue that anatomy, as a basic science, lacks connectivity with the living patient; however, changes in the field tend only to embrace the ‘living’ patient thus discounting mortality. many argue that the cadaver is the first patient,8 the moment where students have to face the reality of life, morbidity and mortality and the awesome responsibility of a physician in caring for the patient. beginning with a lifeless cadaver also reduces complexity, giving a good understanding of gross anatomy integrated to structure and function which can then be extrapolated to the living. in the dissection room, the students learn skills by vicarious means. they may experience anxiety and stress, not through detachment or indifference, but as a defence mechanism. this should lead to the compassionate detachment essential for a physician to cope well with death, loss and grief. good medical education involves development of observation, conceptualisation and the formulation of hypotheses in order to produce critical thinking in o m a r h a b b a l 26 tomorrow’s doctors. curricula that demean the importance of dissection are likely to reduce the ability to approach diagnosis and intervention scientifically. this goes against the claims that current reforms are in line with evidence-based medicine.9,10 m a n u a l d e x t e r i t y from the hippocratic tradition, ‘touch’ between physician and patient has always been deemed an essential skill acquired in the dissecting room. hands-on cadaver teaching is the first step towards deciphering the three-dimensional structural organisation of the body.11 even three-dimensional high resolution software, which appears better at visualising human anatomy, still produces a simplistic and distorted picture of the human body.12 amidst the flurry of curricular reforms, students of medicine, and other basic science courses which are also divorcing human touch, have been left with no access to dissection,13 thus mortgaging their future to the whim of technological innovation. this could explain why tomorrow’s doctors are often not even equipped to extract blood. hands-on experience is important for developing the touch-based skills of palpation, percussion and auscultation which can be superior to the new mechanical gadgets. hand dexterity, trained in the dissecting room, is part and parcel of all branches of the medical profession. a n a t o m i c a l v a r i a t i o n biological variation is one of the most important concepts in modern medicine. even a layman knows that no two individuals have identical anatomy and pathoanatomy. as students get exposure to different cadavers, they learn the principles of both anatomical variations and developmental anomalies. thus, the future doctor is likely to acknowledge the complexity and uniqueness of the whole body. this realisation is essential when a doctor is confronted with amorphous clinical entities such as where to localise a hysterectomy or colectomy, and where and how to insert a pacemaker, an artificial joint or a bypass vessel. unfortunately, reduced student exposure to dissection and dissected specimens,14 and anatomy teaching using a computerised and standardised ‘visible man’,15 plastic bones, models and computer-generated simplified images will compromise future doctors’ clinical astuteness a recipe for misdiagnosis and eventual malpractice.16 t e a m s p i r i t although the new information age that is fuelled by fast computers has reduced ‘rote learning’, cognitive skills in anatomical concepts have direct relevance to clinical skills.16 the ability to call on these skills is essential for emergency medicine where, at the spur of the moment, one is required to make a clinical decision that entails life or death, litigation or job satisfaction. group activity is often an inherent feature of the traditional dissection room. in psychological parlance, people working for a common good are likely to benefit from group cohesion and the team-spirit of colleagues.17 d i a g n o s t i c i n n o v a t i o n s powerful tools such as computerised tomography (ct), magnetic resonance imaging (mri) and ultrasound have been developed to assist diagnosticians and surgeons as well as serving the interests of anatomy. there is even a growing hype that one day anatomy will be taught via the ‘cyber cadaver’.18 however, it is clinical astuteness, owing it strength to hands-on experience, that produces highly skilled physicians and surgeons.19 dissection of the cadaver should induct one into topography at the beginning of studies, with the new technology serving to consolidate knowledge. a balance between new and old methodologies can be found in some centres where anatomy is taught both by classic dissections and modern imaging technology. c o m p u t e r a s s i s t e d l e a r n i n g in less than two decades, medicine has witnessed a huge expansion of databases on the cellular and molecular processes of both healthy and diseased states. the instantaneous access, storage, and retrieval of information and hypertext on computers has also reduced the importance of rote learning, while computer-assisted learning is rewarding for problem solving workshops and indeed enhances the integration of basic and clinical sciences. however, our over-dependence on ‘cybernetic’ technology has devalued ‘humanness’ in medical education; machines cannot tell us anything about life or death. according to older,17 ”high technology tends to dehumanise patient care, with a growing rejection by both patients and physicians”. we have yet to be convinced of the effectiveness of ‘computer atlases’ marketed as innovative anatomy teaching. the th e s tat e o f h u m a n a n at o m y te a c h i n g i n t h e m e d i c a l s c h o o l s o f g u l f c o o p e r at i o n c o u n c i l c o u n t r i e s 27 dissected cadaver remains the most powerful means of presenting and learning anatomy as a dynamic basis for solving problems. medicine is a direct dialogue between the patient and physician; therefore, if students only use models, images, audiovisuals or computers, they will not develop the requisite reasoning that comes from investigative dissection of real tissue to acquire knowledge of the living. nor will they have the ability in emergencies to make clinical decisions that entail life or death, litigation or job satisfaction. cognitive ability garnered with hands-on experience is paramount. f i n a n c i a l i m p l i c a t i o n s where institutions focus their expenditure on securing patient service income and funding for research, education lies at the end of the budget queue. there is a temptation among stakeholders to reduce staff and costs and ‘keep pace with the times’ by closing the dissecting room. paradoxically, such a proposal is often mooted just when the number of students is rising.20 p o s t g r a d u a t e s u r g i c a l t r a i n i n g changes in undergraduate medical education have partly influenced new trends in postgraduate surgical training. for example, a surgical fellowship was taken to mean a broad-based examination taken early in training with high standards in basic sciences, a very testing component with essay questions and vigorous vivas. the principle prerequisite was a proficiency in the art and science of anatomy. thereafter, successful candidates became fellows of a royal college and then sought apprenticeship to sharpen their skills and knowledge. during apprenticeship, the qualified candidates were subjected to no further examinations. by the time they became senior registrars, their skills were second to none. 21 however, times have changed with now a membership as an entry examination. essays have been duly replaced by multiple choice computer-marked examinations. this form of assessing skills is a recipe for superficial learning. the viva is now often cursory. in some colleges, there are no prosections or models for surface anatomy. this means that some candidates now have an inferior knowledge of anatomy. although empirical evidence suggests otherwise, the argument goes that a high standard of anatomy will be required at the specialist fellowship exit examination. however, it is unacceptable that young men and women with lack of skills and knowledge of anatomy are recruited for careers as surgeons. the new membership and fellowship examination system was supposed to maintain the previous high standards; however, it is becoming increasingly clear that such ambitions have failed to materialise.17 a background in basic science was previously required as foundation for a successful surgical career. the calman report 21 appears to have had a serious impact on the recruitment of surgical trainees to ‘anatomy demonstrator’ posts. this has triggered a ‘domino effect’ in anatomy departments which can no longer rely on surgical trainees to teach which, in turn, has adversely affected the ability of medical schools to deliver essential skills in anatomy. 21 p r o b l e m b a s e d l e a r n i n g the present trend in anatomy curricula is to include integrated problem-based learning (pbl) and computer assisted teaching leading to a reduction in overall content, didactic lectures and mechanical rote memorisation.22 pbl is credited with heightening and synthesising students’ knowledge of their respective field both in horizontal and vertical integration of different disciplines. in theory, using clinical vignettes, students learn to merge the clinical side with the underlying basic science concepts. however, studies at the university of maastricht in the netherlands have suggested that pbl tends to leave many students dissatisfied with their basic science knowledge, particularly in gross anatomy. during clinical clerkships they expressed a need for more anatomy training.23, 24, 25 in one of the latest twists and turns on pbl, the maastricht group have reported a longitudinal study of fourth year medical students at eight medical schools in the netherlands to find out how pbl and non-pbl teaching methodology was perceived at the start of clinical clerkships. the results showed no significant difference in anatomy knowledge levels between pbl and non-pbl schools. however, the two centres which scored significantly higher in knowledge appeared to adhere to more traditional teaching methods.9 there is evidence that the repetition of topics has a beneficial effect, confirming a fundamental thesis of rote learning. also, there is a discrepancy between what students think they know and what they think they need to know. on the whole, the integrated pbl approach seems to be associated with uncertainty and perceived o m a r h a b b a l 28 deficiencies in basic science. t e a c h e r s o r r e s e a r c h e r s ? some anatomists have total control over teaching content, and methods, but increasingly these are beyond the control of anatomy teaching staff.6 undergraduate programmes are now almost of footnote importance with survival strongly depending on research and the income it generates. amazingly, dedicated career teachers are still to be found taking the teaching load off those more inclined to research. there is a perception that teaching, both basic science and clinical, is less academically valuable. in addition, there is a tendency to offer unattractive salaries to those with clinical qualifications,26 and not to recruit gross anatomists for core teaching.27 most non-medical anatomists cannot build the bridge between basic science and clinical applications; this therefore calls for the reintroduction of medically qualified anatomists to classrooms. some centres have thus recruited retired or semi-retired clinicians or surgeons to teach. a n a t o m y c u r r i c u l a in many gcc countries, the primary goals of teaching anatomy have not been empirically scrutinised before changing the undergraduate programme. for instance, little is known about how to implement a common core curriculum. despite objections in this part of the world and elsewhere, there was no published data on the impact of the general medical council’s ‘ tomorrow’s doctors’ report on anatomy teaching.1 in the absence of comparative research and an agreed regional, let alone national, core curriculum, a variety of new curricula have been introduced over the past few years. there is no common medical licensing examination in the gcc, so medical schools are free to teach anatomy and to assess content and quality as they see fit, independent of external validation. as a result, anatomy teaching is at risk. if the aim is to produce high calibre, caring and compassionate medical practitioners, then abandoning well designed cadaver-based instruction is contrary to achieving such goals. jones et al. have challenged anatomists to gather hard evidence to support the importance of dissection;15 however, its pedagogical merit has passed the test of time. judicious use of dissection, lectures, small group discussion, case studies and living anatomy can be linked with the computer and diagnostic imaging, involving human to human and human to machine interactions, to create an enhanced learning environment. in the present climate of curricular reform, problem-based and system orientated studies, together with gross anatomy, must show affinity and creativity. the debate is raging as to whether pbl will spread rapidly in medical schools or not.28 in pbl there are no common themes and approach to teaching medicine, and gross anatomy in particular.29 some curricula do not include exposure to dissection, but rather just computers and models, meaning that medical students are not exposed to the ‘real thing’ until they enter clinical years under the pretext that “traditional anatomy teaching has negative predictive validity”.30 smithers, well known for his medical education research, has suggested that pbl is a debunked educational school of thought from which children’s schools in the uk are only just being salvaged by literacy and numeracy strategies. he has expressed surprise that medicine “which has at its heart a thorough and detailed understanding of the human body”, should have taken up a method that has failed so spectacularly elsewhere.28 c h a l l e n g e s & o p p o r t u n i t i e s at this juncture, reflection is needed on the failures and successes of anatomy curricula and how to teach the principles of anatomy to tomorrow’ doctors in order to develop their clinical skills. in the nutshell, is the dissecting room a relic of the past or inspiration for the future? some of the dissenting challenges that have to be faced are that: a. anatomy is said to be an exhausted science. b. dissection-based learning is increasingly less popular. c. the contents taught in anatomy are ill-defined. d. the insecurity of cadaveric resources make it risky to maintain cadaver-based teaching. this shortage reinforces the need to take advantage of new technologies and communications. e. teaching methodology and the goals of learning anatomy are discrepant. in many departments, with lecture-based teaching and many hours of dissection, the excessive content prevents students from discerning between what is essential and what is accessory in clinical practice. f. finally, the professional situation of anatomists th e s tat e o f h u m a n a n at o m y te a c h i n g i n t h e m e d i c a l s c h o o l s o f g u l f c o o p e r at i o n c o u n c i l c o u n t r i e s 29 has been devalued. given their often non-medical training background and promotion expectations, anatomy teachers can give more importance to research than to teaching.31 reduction in anatomy instruction currently causes problems for medical professionals when identifying structures, analysing images, choosing surgical approach routes and deciding on possible consequences. in the united states, about one third of resident physicians are insufficiently prepared in anatomy,32 which means that some medical errors must result33 due in part to a lack of anatomical knowledge.34 technology should be incorporated into curricula, but not totally replace cadaver-based teaching, which should take place early in the programme and be clinically orientated as it is a key element at the start of medical education and training. the recommendations mentioned below are meant to keep cadaveric material available for our students. this provides an early, active learning encounter with mortality where facts are verified from the primary source, discoveries enjoyed and checked against the interpretation of others leading to a three-dimensional understanding of the body, its variation and pathology. in the process, students’ manual dexterity and team-work and communication skills will develop and improve. all this will give them confidence and enrich their clinical competence. as a part of a regional centre for the new intercollegiate membership of the royal colleges of surgeons uk examinations (edinburgh), the college of medicine & health sciences at sultan qaboos university, believes that a thorough knowledge of anatomy is essential and mandatory as a preliminary to higher surgical training. the teaching of anatomy in surgical specialities must be improved. does the dissecting room still have a place in educating our underand postgraduate students? our answer is a qualified yes a sound knowledge of anatomy is essential to define accurately and treat successfully the problem presented by patients. dissection remains the most powerful way to learn anatomy as a dynamic basis for solving problems.35 c o n c l u s i o n s a n d r e c o m m e n d a t i o n s 1. we should aim towards a teaching of anatomy that is clinically oriented and as applicable as possible with closer links between basic scientists and clinicians to enhance teaching and research. anatomy is a living subject, not a collection of facts learnt early and then forgotten. retaining anatomical facts requires constant practical application so these must be taught by scientists and clinicians with a clinical perspective. radiologists, for example, can play a key role in teaching anatomy. 2. in our department at squ, to palliate the reduction in hours devoted to anatomy, we use prosections, peer teaching as learning method and the inclusion of other instructional systems, such as multimedia programmes and computer-assisted teaching which offer a clear, renewable, rapid and efficient way of offering 3-d images. we are also introducing newer technologies, such as the readily expandable and understandable streaming media. 3. surgeons must address the problem seriously. detailed knowledge of anatomy can only be obtained by diligent study, preferably as a demonstrator involving six months of learning on prosections and teaching undergraduates, together with master class type anatomical tutorials. a three to six months rotating programme for senior house officers in anatomy would enhance their learning, teaching and communication skills. we would even encourage a gcc interchange programme of demonstrators between anatomy departments. 4. the new membership of the royal colleges of surgeons (uk) contains a rigorous examination in anatomy using dissections, imaging and surface anatomy. this should be mandatory preliminary to entry into higher surgical training. anatomy should not be left to the exit fellowship examinations. this will give us better trained young surgeons. courses in surgical anatomy should be established to attract and train our future surgeons. 5. adaptation to the new curricular demands and objectives. our own experience concurs with that of others,36 that anatomy instructors should preferably be trained physicians so that a clinical orientation can be given to the subject.37 interdepartmental collaboration should also be fostered with the aims of integrating teaching, developing life-long training courses at post-graduate level, and intervening in the training of clinical specialists.38 6. there should be a debate at every level in gcc medical schools. this debate should highlight aro m a r h a b b a l 30 eas of concern, explore in depth and define a common minimum core anatomy curriculum as there is currently no agreement on this at undergraduate level. one way would be to reduce the amount at the start of the course, emphasise surface and radiological anatomy and teach sufficient general anatomy for systems-based courses. teach more anatomy later and throughout the course. but it is rare to have sufficient time later. the perception of the depth of knowledge required by both student and examiner varies widely. 7. teaching must be enhanced with a critical look at both teachers and methods. the dominance of research must be reassessed to establish an equitable cohabitation with teaching. the place of basic science, especially anatomy in basic surgical teaching, must be examined 8. planning strategies to compensate for the acute shortage of cadaveric material in the region because of restrictions imposed by various sources. we feel that we should maintain cadaver-based teaching of anatomy, together with computer-assisted teaching as an adjunct. 9. medical schools that are fortunate enough to have a good bank of cadaveric teaching material are encouraged to develop plastination facilities to make longer and durable use of such resources. such facilities are already available in some gcc schools like squ. we are willing to train interested colleagues from other gcc departments. 10. with increasing pressures to admit more students into medical programmes, the student/staff ratio should be improved so that the quality of small group teaching is maintained. 11. establish a regional anatomical society or body that holds regular scientific meetings, and discusses and publishes anatomical research through the establishment of a regional anatomy journal. this is in line with previous recommendations made by anatomy heads of departments in gcc countries at the first gcc anatomy heads of department meeting held at king faisal university, dammam, kingdom of saudi arabia on 25th april 2000. 12. encourage regional and international links with other anatomical societies, departments or institutes for exchange visits and feedback to keep up with contemporary educational trends in the discipline and to encourage collaborative research. such societies have created a renewed and more dynamic outlook for anatomy. multilateral meetings between anatomists from all over the world are being fostered and the publication of a new edition of anatomical terminology has been promoted. “doctors without anatomy are like moles. they work in the dark and the works of their hands are mounds.” tiedemann, heidelberg, 1781-1861. a c k n ow l e d ge m e n t to all those who, through the spirit of giving, medicine is ever indebted. r e f e r e n c e s 1. general medical council, education committee. recommendations on undergraduate medical education. london: general medical council, 1993. 2. waterston sw, laing mr, hutchison jd. ninteenth century medical education for tomorrow’s doctors. scot med j 2006; 52:45-9. 3. spielmann pm, oliver cw. the carpal bones: a basic test for medical students’ and junior doctors’ knowledge of anatomy. surgeon 2005; 3:257-9. 4. ellis h. teaching in the dissecting room. clin anat 2001; 14:149-51. 5. general medical council. recommendations on basic medical education. london: gmc, 1987. 6. heylings dja. anatomy 1999-2000: the curriculum who teaches it and how. med ed 2002; 36:702-10. 7. hanna sj, freeston je. importance of anatomy and dissection: the junior doctor’s viewpoint. clin anat 2002; 15:377-8. 8. winkelmann a, güldner fh. cadavers as teachers: the dissecting room experience in thailand. brit med j 2004; 329:1455-7. 9. boon jm, meiring jh, richards pa, jacobs cj. evaluation of clinical relevance of problem-oriented teaching in undergraduate anatomy at the university of pretoria. surgical and radiol anat 2001; 23:57-60. 10. walter t. body worlds: clinical detachment and anatomical awe. sociol health & illness 2004; 26:464-88. 11. kaufman mh. anatomy training for surgeons a personal viewpoint. j r coll surg edinb 1997; 42:215-6. 12. garg a, norman gr, spero l, maheshwari p. do virtual computer models hinder anatomy learning? acad med 1999; 74:587-9. 13. de bruxelles s. “medical school consigns cadavers to history”. the times 30 september 2002. p. 3. th e s tat e o f h u m a n a n at o m y te a c h i n g i n t h e m e d i c a l s c h o o l s o f g u l f c o o p e r at i o n c o u n c i l c o u n t r i e s 31 14. spitzer vm, whitlock dg. the visible human dataset: the anatomical platform for human simulation. anat rec (new anat) 1998; 253:49-57. 15. jones na, olafson rp, sutin j. evaluation of gross anatomy programme without dissection. j med educ 1978; 53:198-205. 16. willan p. basic surgical training 2: interactions with the undergraduate medical curriculum. clin anat 1996; 9:167-70. 17. older j. anatomy: a must for teaching the next generation. surg j r coll edinb irel 2004; 2:79-90. 18. rosse c. terminologia anatomica considered from the perspective of next generation knowledge sources. clin anat 2001; 14:120-33. 19. beahers oh. gross anatomy in medicine. clin anat 1991; 4:310-12. 20. dinsmore ce, daugherty s, zeitz hj. teaching and learning gross anatomy: dissection, prosection or “both of the above?” clin anat 1999; 12:110-14. 21. calman k. hospital doctors. the report of the working group on specialist medical training. london: hmso, 1993. 22. prince kjah, van mameren h, hylekema n, drukker j, scherpbier ajja, van der vlenten cpm. does problem-based learning lead to deficiencies in basic science knowledge? an empirical case on anatomy. med educ 2003; 37:15-21. 23. van mameren h, leiner t, wanders a, van der vleuten cpm. students evaluation of anatomy/ embyology teaching at maastricht university. bull med onderwijs 1997; 16:91-100. 24. drukker j, van mamereh h, croonen hghm, wanders ajb, verwijnen gm, van der vleuten cpm. physicians’ restrospective evaluation of anatomy teaching. bull med onderwijs 1999; 18:9-16. 25. prince kjah, van der wiel mwj, scherpbier ajja, van der vleuten cdm, boshuizen hpa. a qualitative analysis of the transition from theory to practice in undergraduate training in a pbl medical school. adv health sci educ 2000; 5:105-16. 26. ellis h. the surgeon as a teacher of anatomy. clin anat 1994; 7:156-61. 27. monkhouse ws. anatomy and the medical school curriculum. lancet 1992; 340:834-5. 28. smithers a. medical training heading for disaster. the independent education supplement 19 september 2002. p. 2. 29. mclaughlan j. anatomy in a new medical school. exeter and plymouth anatomical education: present advances and future developments. report of one day symposium 25 september 2002. p.17-18. 30. monkhouse ws, farrell tb. tomorrow’s doctors: today’s mistakes? clin anat 1999; 12:131-4. 31. willan plt, humpherson jr. concepts of variation and normality in morphology. important issues at risk in modern undergraduate medical courses. clin anat 1999; 12:186-90. 32. cottam ww. adequacy of medical school gross anatomy education as perceived by certain postgraduate residency programs and anatomy course directors. clin anat 1999; 12:55-65. 33. gawande a. when doctors make mistakes. new yorker 1999; 1:40-5. 34. cahill dr, leonard rj and marks sc. a comment on recent teaching of human anatomy in the united states. surg radiol anat 2000; 22:69-71. 35. winkelmann a. anatomical dissection as a teaching method in medical school: a review of the evidence. mel educ 2007; 41:15-22. 36. skandalakis je. the teaching of anatomy: a dialogue with a cell biologist. surg radiol anat 2000; 22:1-2. 37. lockwood am, roberts am. the anatomy demonstrator of the future: an examination of the role of medically-qualified anatomy demonstrator in the context of tomorrow’s doctors and modernizing medical careers. clin anat 2007; 20:455-9. 38. willan plt, humpherson jr. profiles of applicants for junior faculty posts to teach anatomy. clin anat 1999; 12:272-6. neurofibromatosis with bilateral renal artery stenosis and end stage renal disease case report *mohamed al-rawahi,1 dawood al-riyami,1 mahfooz a farooqui,1 and humoud al-duhli2 case report squ med j, august 2009, vol. 9, iss. 2, pp. 167-169, epub 30th june 2009 submitted 4th nov 2008 revision req. 21st dec 08, revision recd. 18th jan 09 accepted 3rd february 09 مرض الورام العصيب الليفي مع تضيق الشرايني الكلوية الثنائية وفشل ُكلِْويٌّ باملَْرَحلَِة النَِّهائِيَّة تقرير حالة محمد الرواحي، داوود الريامي، حمود الذهلي، محفوظ فاروقي امللخص: الورام العصبي الليفي النوع األول هو مرض وراثي ذو صفة وراثية سائدة ، وهو عبارة عن متالزمة عصبية جلدية تصيب مختلف أعضاء أو أجهزة اجلسم بصفة أولية أو ثانوية ، ومن ضمنها اجلهاز القلبي الوعائي. وأكثر األوعية الدموية تأثرا باملرض هي الشرايني الكلوية التي تصاب بالتضيق مما يؤدي إلى ارتفاع ضغط الدم. هنا نعرض تقرير وصفي بحالة مريض في أواسط العمر راجع مستشفى جامعة السلطان قابوس وقد أصيب بفشل كلوي باملرحلة النهائية مصحوبا بارتفاع شديد في ضغط الدم ناجت عن ضيق الشريانني الكلويني جراء اإلصابة مبرض الورام العصبي الليفي. مفتاح الكلمات: مرض الورام العصبي الليفي ، تضيق الشريان الكلوي ، فشل ُكلِْويٌّ باملَرَْحلَِة النَِّهائِيَّة ، ارتفاع ضغط الدم كلوي املنشأ ، غسيل كلوي ، تقرير حالة ، عمان. abstract: neurofibromatosis type 1 )nf-1( is an autosomal dominant, hereditary, neurocutaneous syndrome that may, primarily or secondarily, affect different organs or systems of the body including the cardiovascular system. the most common vascular abnormality in patients with nf-1 is renal artery stenosis. here we report the case of a middleaged gentleman who presented at sultan qaboos university hospital, oman, with end stage renal disease and severe hypertension and was diagnosed to have nf-1 with bilateral renal artery stenosis. he was started on renal replacement therapy. keywords: neurofibromatosis; renal artery stenosis; end stage renal disease; renal hypertension; haemodialysis; case report; oman. department of 1medicine, 2radiology & molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: mohdrawahi@gmail.com type 1 neurofibromatosis (nf-1) is a common genetic disorder, with variable clinical manifestations, which affects at least one million persons throughout the world. although rare, vascular abnormalities are a wellrecognised manifestation of neurofibromatosis and may lead to renal artery stenosis and renovascular hypertension. here, we present the case of a young omani man who presented with end stage renal disease (esrd) and severe hypertension, and was diagnosed to have nf-1 with bilateral renal artery stenosis. case report a 37 years old omani man presented at sultan qaboos university hospital, oman, with a headache of two years duration and was found to be severely hypertensive. upon presentation, his blood pressure was 190/105 mmhg. his past medical history was significant for decreasing hearing in the left ear since early childhood. his family history was significant for neurofibromatosis in one son. the patient was evaluated for the possibility of neurofibromatosis. he was noted to have decreased hearing in the left ear due to mastoid sinus disease and fundoscopy revealed lisch nodules. clinically, the patient had multiple café au lait spots and a neurofibroma in the cervical region. laboratory investigations revealed: creatinine 1387umol/l; urea 71 mmol/l; bicarbonate 7mmol/l and potassium 5.4 mmol/l. the urine dipstick was positive for proteins (+2) and trace red blood cells (rbc). urine microscopy showed few rbcs and numerous neurofibromatosis with bilateral renal artery stenosis and end stage renal disease case report 168 | squ medical journal, august 2009, volume 9, issue 2 granular casts. haemoglobin was 10.1 g/dl; platelets 204 x 109l; serum catecholamines 1 pmol/l; serum calcium 1.89 mmol/l and serum phosphate was 3.81mmol/l. tests for cytoplasmic antibodies (anca), anti-nuclear antibodies (ana), hepatitis b, hepatitis c and hiv 1&2 were negative. an ultrasound of the abdomen demonstrated that both kidneys were small in size with significantly increased cortical echogenicity. the left kidney measured 8.1 cm in length and the right kidney 7.8 cm. a renal magnetic resonance angiography (mra) showed severe proximal bilateral renal artery stenosis [figure 1]. magnetic resonance imaging (mri) of the head showed chronic otitis media with mastoitidis and an intercostal neurofibroma in the cervical area. the patient was started on haemodialysis three times per week with a satisfactory outcome. his blood pressure was controlled on atenolol. an arteiovenous fistula was created for long term renal replacement therapy. he had no potential donor for a kidney transplant. discussion neurofibromatosis is an autosomal dominant neurocutaneous disorder with an incidence of approximately 1 in 3,000 individuals.1 approximately half of the cases are familial and the remainder are due to new mutations.2 the diagnostic criteria developed by the national institutes of health are based upon the presence of specific clinical features, at least two of which must be present to make a diagnosis of nf-1:1 1. six or more café au lait macules >5 mm in diameter in prepubertal and >15 mm in diameter in postpubertal individuals. 2. two or more neurofibromas of any type or one plexiform neurofibroma. 3. freckling in the axillary or inguinal regions. 4. optic glioma. 5. two or more lisch nodules (iris hamartomas) 6. a distinctive bony lesion such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudoarthrosis. 7. a first-degree relative with nf-1 based upon the above criteria. the cardinal features of nf-i in this patient were the presence of lisch nodules and a positive family history. this patient illustrates the complete penetrance of the affected gene. the likelihood is that individuals carrying the mutation will be affected over several generations, but with a variable expression of the disease.3 hypertension is a frequent finding in adults with nf-1 and may develop during childhood. it is found in most cases, but vascular lesions producing renovascular hypertension are more frequent in nf-1 patients.4 renovascular lesions can be detected in patients who are still normotensive; the frequency with which such patients will develop hypertension is not known. coarctation of the aorta is a known cause of hypertension that also tends to occur in nf-1. a much less common cause of hypertension in nf-1 is pheochromocytoma, which has been clinically identified in 0.1 to 5.7% of patients. the mean age at diagnosis was 42 years.5 our patient had hypertension upon presentation and was found to have bilateral proximal renal artery figure 1: minimum intensity projection (mip) of magnetic resonance angiography (mra) of the renal arteries shows severe stenosis of the proximal segments of both renal arteries (arrows). mohamed al-rawahi, dawood al-riyami, mahfooz a farooqui, and hamoud al-duhli case report | 169 stenosis. serum catecholamine levels were normal hence pheochromocytoma was ruled out as a cause of secondary hypertension. most patients with nf-i vascular abnormalities are asymptomatic, but have involvement of multiple vessels.6 the prevalence of vascular lesions is not well known, however, large clinical series estimate them to be around 0.4% to 6.4%.6 symptoms usually occur in childhood or early adulthood. the renal artery is the most frequent site of involvement with a prevalence of 41% of all vascular abnormalities, of which 68% are unilateral. in addition, these lesions are more stenotic than aneurysmal.7 renovascular hypertension is the most common presentation of these vascular abnormalities.8 abdominal aortic coarctation, internal carotid artery aneurysms, and cervical vertebral arteriovenous malformations are other common manifestations.8 end stage renal disease (esrd) has been reported in very few individual case series in the literature due to chronic ischaemia of the kidneys as a result of renal vascular abnormalities. this patient had esrd which was due to bilateral renal artery stenosis and secondary hypertension. his esrd was managed with renal replacement therapy as no suitable donor was found. his hypertension was managed with atenolol with good response. percutaneous transluminal angioplasty (pta) had a limited role for this patient as the blood pressure was well controlled with anti-hypertensive therapy. renal failure would have not improved with pta as both kidneys were small and indicated chronic renal insult. moreover, the success due to the ostial localisation of renal arterial stenosis (ras) and the tough fibrotic tissue involved is often refractory to dilatation.9, 10 nephrectomy would have been a probable choice if blood pressure were difficult to manage medically. conclusion in summary, neurofibromatosis is a disorder usually associated with unilateral ras. we believe that this is the first case report of this condition to present as esrd. all young patients (< 30 year) with hypertension should be clinically screened very early for secondary causes of hypertension including neurofibromatosis so that renal revascularization can be offered before permanent end organ damage has occurred as in this patient. references 1. national institutes of health consensus development conference: neurofibromatoses. arch neurol 1988; 45:575-8. 2. riccardi vm. neurofibromatosis: phenotype, natural history, and pathogenesis. baltimore: johns hopkins university press, 1992. 3. easton df, ponder ma, huson sm, ponder ba. an analysis of variation in expression of neurofibromatosis (nf) type 1 (nf1): evidence for modifying genes. am j hum genet 1993; 53:305. 4. fossali e, signorini e, intermite rc, casalini e. renovascular disease and hypertension in children with neurofibromatosis. pediatr nephrol 2000; 14:806. 5. walther mm, herring j, enquist e, keiser hr, linehan wm. von recklinghausen’s disease and pheochromocytomas. j urol 1999; 162:1582. 6. lin ae, birch p, korf br, tenconi r, niimura m, poyhonen m, et al. cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis type i. am j med genet 2000; 95:108-17. 7. elias dl, ricketts rr, smith rb. renovascular hypertension complicating neurofibromatosis. am surg 1985; 51:97-106. 8. hamilton sj, friedman jm. insights into the pathogenesis of neurofibromatosis 1 vasculopathy. clin genet 2000; 58:341-4. 9. hughes rj, scoble je, reidy jf. renal angioplasty in non-atheromatous renal artery stenosis: technical results and clinical outcome in 43 patients. cardiovasc intervent radiol 2004; 27:435-40. 10. miller ga, ford kk, braun sd, moore av jr, malone r, dunnick nr. percutaneous transluminal angioplasty vs. surgery for renovascular hypertension. ajr 1985; 144:447-50. departments of 1medicine and 2clinical physiology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com estimation of salt intake and its relation to knowledge and attitude regarding the dangers of high salt intake among an urban omani population a pilot study muhammad m. shaikh,1 ali h.z. alkhayari,1 qusay a.k. alabdulsalam,1 khamis alhashmi,2 *sunil k. nadar1 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 486–492, epub. 7 nov 22 submitted 19 may 21 revisions req. 12 jul & 12 aug 21; revisions recd. 22 jul & 17 aug 21 accepted 26 aug 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.134 clinical & basic research cardiovascular diseases (cvds) are a leading cause of death and disability globally, affecting more than 17.5 million people annually.1 this is especially relevant in the middle east region, which has seen dramatic transformations in its socio-economic situation over the last few decades, fuelled by rapid urbanisation, migration and modernisation and accompanied by significant changes to diet and lifestyle. this has led to an increase in the prevalence of cardiovascular risk factors such as diabetes, hypertension and obesity and a high incidence of cvds.2–4 it is estimated that cvds account for more than 34% of the deaths in the middle east.5 hypertension is a major risk factor for cvd and disability and is now considered the number one risk factor attributable to burden of disease quantified by disability adjusted life years (dalys).6 high salt intake is considered to be a major risk factor for hypertension; it is considered to be responsible for around one-third of the hypertension cases worldwide, which amounts to approximately 300 million people.7 in addition to hypertension, high salt intake is also found to be associated with meniere’s disease, osteoporosis and gastric and renal cell cancers. modern western diets, which are high in processed food, tend to have a high salt content and are considered a major global health issue. in fact, the world health organization (who) has listed the reduction of dietary salt intake by 30% as one of its nine global targets to be achieved by the year 2025.8 as specified in the who recommendations, the ideal daily adult salt consumption should be ≤5 g/day. however, data from many countries have consistently shown that the dietary intake of salt far exceeds this amount.9 many countries have implemented abstract: objectives: high salt consumption is a major risk factor for hypertension. studies have shown dietary salt intake to be high in many parts of the world. this study aimed to assess the daily salt consumption of the omani urban population and their knowledge and attitudes regarding dietary salt. methods: this cross-sectional questionnairebased study was conducted in muscat between september and december 2017. participants were recruited from malls, university students and staff, hospital staff and their relatives and relatives of patients. a previously validated questionnaires were used to assess the participants’ salt intake and their knowledge and attitudes regarding salt intake. results: a total of 345 participants were included in this study (response rate: 69%), of which 300 responses (mean age: 27.88 ± 7.9 years, 54.3% male) were included for analysis. overall, 94.3% of the participants agreed that lowering salt in diet is important, and nearly half the participants said that they were taking measures to reduce salt intake. however, the median salt intake was high at 10.5 g/day (interquartile range: 7.3–15.1 g/day), with 90% of the respondents consuming more than the maximum recommended amount of salt per day. salt intake was significantly higher in women and the older age group (>40 years). there did not appear to be any correlation between awareness of the dangers of salt intake and the amount consumed. conclusion: the salt intake in the sampled population in oman was high and did not depend on knowledge. strategies should be designed to reduce salt intake among the urban population, including health education to increase knowledge about the complications of high salt intake. keywords: dietary sodium chloride; knowledge, attitudes and practice; oman. advances in knowledge this study demonstrates that the average salt intake in the omani population is high (more than double the recommended levels). the knowledge regarding the dangers of high salt intake is high but this does not translate into action. application to patient care patients should be advised to reduce their salt intake. patients should be educated about the dangers of high salt in their diet and on different methods for reducing salt intake. https://creativecommons.org/licenses/by-nd/4.0/ muhammad m. shaikh, ali h.z. alkhayari, qusay a.k. alabdulsalam, khamis alhashmi and sunil k. nadar clinical and basic research | 487 community education schemes to educate their population about the harms of high salt intake and the corresponding need to reduce the intake.10–12 dietary sources of sodium differ from one country and culture to another. for example, the top 10 sources in the usa are bread, pizza, sandwiches, cured meat, soup, burritos and tacos, savoury snacks, chicken, cheese and eggs and omelettes, while in some asian countries, soup, rice and yeast bread account for almost a third of the dietary salt sources.13–15 in oman, the prevalence of cardiovascular risk factors is high and it is expected that treatment for cvd will account for 21% of the healthcare budget by 2025.16 hypertension is also fairly common, with a prevalence of 29.8% of the adult population.17 according to the national nutrition survey published in 2004, the average salt intake in the omani population was approximately 11–12 g/day.18 many steps have been taken to try to reduce this intake to recommended levels.19 these include a reduction in the salt content in bottled water and bread as well as public education. however, the effect of these steps is not yet evident. this study aimed to assess the amount of salt intake by the urban population in oman and compare it with the reported levels from 2004. in addition, this study sought to examine the urban population’s knowledge and attitudes regarding salt and whether this has had any impact on their salt consumption. methods this was a cross-sectional questionnaire-based study conducted among the urban population in muscat, oman, between september and december 2017. a convenience sampling method was used for this study. the subjects recruited included visitors to malls (during health promotional activities), university students and staff, hospital staff and their relatives and relatives of patients. omani nationals aged above 18 years, who were normotensive and non-diabetic, had no evidence of cvd and were not taking any medications for hypertension, diabetes or cvd were included. those below 18 years of age, who had hypertension, diabetes or evidence of cvd and those who were taking medications for any of these conditions were excluded. the questionnaire had three parts. the first part comprised the demographic data of the participants including age, educational and employment status and eating habits. the second part of the questionnaire collected data on their knowledge, attitudes and practices regarding salt intake. this part was based on a questionnaire devised by who, which was translated into arabic by a native professional arabic speaker.20 it was then translated back into english to assess consistency. subsequently, it was piloted on non-medical university students to verify whether any questions were confusing. the third part of the questionnaire was derived from a cross-sectional study conducted in south africa.21 this questionnaire was selected, as the dietary habits of south africans are fairly similar to that of omanis. in addition, this questionnaire has been validated and the details are published.21 however, a few changes were made to the questionnaire by deleting some of the food items that are not consumed in oman and substituting them with similar food types. this questionnaire was also translated into arabic and then back-translated into english to assess consistency. this questionnaire is free-to-use and does not require any licence to be used. however, permission was obtained from the authors of the questionnaire prior to the study. based on the responses to the questionnaire, the daily salt intake of every participant was calculated according to the formula devised by charlton et al.21 this was calculated by multiplying the average of the chosen frequency with the sodium (na) content per serving. the sum of the 36 categories would then give the total na intake (mg/day) of a participant. conversion of na (mg/day) to salt (g/day) was obtained by dividing the amount by 1,000 and then multiplying it by 2.5. the equation applied was: where s(g/d) is the daily salt in grams per day, fn is the chosen frequency of the food category ‘n’ and nan is the sodium in one serving of the food category ‘n’. the sample size was calculated based on the formula for calculating the number required for a cross-sectional prevalence study. the sample size was: where (z1-α/2) is the standardised value for the corresponding level of confidence, which is 2.58 for a 99% confidence interval or a 1% type i error, σ is the standard deviation based on previous studies (a value of 5g was used for the present calculations), and d is the margin of error (set at 1g).9 using these values, a sample size of 166 was derived. the data were analysed using the statistical package for the social sciences (spss), version 21 (ibm corp., chicago, illinois, usa). all data are described as either percentages or mean ± standard deviation or median (interquartile range [iqr]). the chi-square test, student’s t-test or non-parametric tests (mann–whitney u test or kruskall–wallis test) s(g/d) = [(fn1×nan1) + (fn2×nan2) + (fn36+nan36)] × 2.5/1000 [equation 1] n = (z1-α/2) 2 (σ)2/d2 [equation 2] estimation of salt intake and its relation to knowledge and attitude regarding the dangers of high salt intake among an urban omani population a pilot study 488 | squ medical journal, november 2022, volume 22, issue 4 were used as appropriate. spearman’s coefficient of correlation was used to assess the correlation between salt intake (non-normally distributed data) and age. a p value of <0.05 was considered to be significant. ethical approval was granted by the medical research ethics committee, college of medicine and health sciences at sultan qaboos university, muscat, oman. before the participants began filling in the questionnaire, the rationale and reason for conducting the study were explained and they were required to sign a consent statement on the questionnaire. results a total of 345 responses were received (response rate: 69%). however, 45 responses were excluded from the study as they were incompletely filled. therefore, responses obtained from 300 participants (mean age: 27.88 ± 7.9 years, range: 18–56) of which the majority were male (54.3%) were included in the final analysis. all the participants were residents of muscat. a total of 46% of the participants had a secondary school degree or a lower qualification, and more than half (54.7%) of the participants were not in active employment (i.e. either a student, unemployed or retired) [table 1]. table 1: charactertistics of the included participants (n = 300) characteristic n (%) age in years 18–28 146 (48.7) 29–39 102 (34.0) ≥40 52 (17.3) mean ± sd 27.88 ± 7.9 gender male 163 (54.3) female 137 (45.7) educational level primary school or below 23 (7.7) secondary school 115 (38.3) diploma 42 (14.0) bachelor’s degree 114 (38.0) master’s degree/phd or higher 6 (2.0) employment status employed 136 (45.3) student 126 (42.0) retired/unemployed 38 (12.7) sd = standard deviation; phd = doctor of philosophy. table 2: responses to attitude, knowledge and practice questions (n = 300) parameter n (%) attitude towards salt intake how important is it to lower the salt/sodium in your diet? not at all important 17 (5.7) somewhat important 165 (55.0) very important 118 (39.3) what is your opinion regarding the amount of salt you consume? too low/low 42 (14.0) just right 196 (65.3) high/too high 40 (13.3) don’t know 22 (7.3) behaviour related to salt intake do you add salt to food at the table? never/rarely 127 (42.3) sometimes 81 (27.0) often/always 92 (30.7) do you add salt while cooking? never/sometimes 33 (11.0) mostly/always 267 (89.0) do you routinely check the salt content on food labels before purchasing them? yes 77 (25.7) no 223 (74.3) do you take any steps on a regular basis to control your salt intake? yes 129 (43.0) no 151 (50.3) don’t know 20 (6.7) knowledge related to salt intake do you think that a high salt diet can cause serious health problems? yes 268 (89.3) no 9 (3.0) don’t know 23 (7.7) can high salt intake cause the following diseases? hypertension 214 (71.3) kidney stones 48 (16.0) osteoporosis 5 (1.7) all of the above 33 (11.0) do you know the recommended maximum salt intake per person per day? yes 23 (7.7) no 277 (92.3) muhammad m. shaikh, ali h.z. alkhayari, qusay a.k. alabdulsalam, khamis alhashmi and sunil k. nadar clinical and basic research | 489 more than half of the participants (55.0%) agreed that lowering the salt/na in their diet is somewhat important. almost half of the participants (42.3%) remarked that they never or rarely added salt to their food at the table. nearly half of the participants said they tried to control their salt consumption on a regular basis (43%). a total of 79.3% of the respondents felt that they were consuming either just the right amount of salt (65.3%) or lower than the recommended level (14.0%). most (89.3%) believed that a high salt diet causes serious health diseases. most of the participants (92.3%) did not know the recommended daily salt intake per person per day. while many (71.3%) believed that excessive salt consumption can cause hypertension, not many were aware of the other conditions that can be caused by excess salt; 16.0% stated that it causes kidney stones, 1.7% stated that it causes osteoporosis and 11.0% thought that it causes all the conditions listed [table 2]. when investigating the factors that contributed to the knowledge regarding salt, it was found that 67% of participants with a master’s/phd degree and 44.0% with a bachelor’s degree thought that lowering salt consumption was very important, while only 27.5% of high school diploma holders or those with a lower qualification thought it was very important to lower salt intake (p = 0.02). similarly, 71.3% of those above 40 years of age said they take actions to control salt consumption compared to 43.5% of participants below the age of 40 (p = 0.005). the median salt intake in the present cohort was 10.5 g/day (iqr: 7.3–15.1 g/day). out of the 300 participants, the salt intake of 270 (90.0%) participants was more than the who recommended amount of 5 g/day, while only 30 (10.0%) had an intake of ≤5 g/day. more males (73.3%), those with a secondary school qualification or below (70.0%) and those who were unemployed (73.3%) had normal salt intake compared to women (26.6%), those who had a diploma degree or higher qualification (30%) and those in active employment (26.7%) [table 3]. the calculated median salt intake by males was 9.9 g/day (iqr: 6.1–14.4 g/day) compared to 11.1 g/ day (iqr: 7.9–15.6 g/day) by females (p = 0.03). a total of 86.3% of male participants had salt intake more table 3: differences among the groups with normal and high salt intake (n = 300) variable total n (%) p value normal salt intake (n = 30) high salt intake (n = 270) mean age ± sd in years 24.5 ± 6.7 28.2 ± 7.9 0.1* gender 0.02† male 163 25 (15.3) 138 (84.7%) female 137 5 (4.4) 132 (95.6%) employment status 0.03† employed 136 8 (5.9) 128 (94.1) student/ retired/ unemployed 164 22 (13.4) 142 (86.6) educational level 0.002† secondary school or below 138 25 (18.1) 113 (81.9) diploma or higher 162 5 (3.7) 157 (96.3) actively takes steps to reduce salt intake 0.43† yes 129 10 (7.8) 121 (92.3) no 151 16 (10.6) 133 (89.5) don’t know 20 4 (20.0) 16 (80.0) aware of the dangers of high salt intake 0.41† yes 268 28 (10.4) 240 (89.6) no/don’t know 32 2 (6.3) 30 (93.8) sd = standard deviation. *using student’s t-test. †using chi-squared test. table 4: comparison of median salt intake across different groups group salt intake in g/day (iqr) p value age group in years 0.01* ≥40 11.8 (9.5–13.4) 30–39 10.6 (7.6–15.8) 18–29 10.3 (7.12–15.2) gender 0.03† male 9.9 (6.1–14.4) female 11.1 (7.9–15.6) educational status 0.4† secondary school or below 10.02 (6.1–15.2) diploma or higher 10.6 (7.6–15.4) employment status 0.8† employed 10.4 (7.1–14.6) unemployed 10.7 (7.8–14.9) iqr = interquartile range. *using kruskal–wallis test. †using mann–whitney test. estimation of salt intake and its relation to knowledge and attitude regarding the dangers of high salt intake among an urban omani population a pilot study 490 | squ medical journal, november 2022, volume 22, issue 4 than the who-recommended amount (≥5 g/day) compared to 94.3% of female participants [table 4]. analysis based on age groups (18–29, 30–39 and ≥40 years) revealed that the salt intake was the highest in the older age group (≥40 years) at 11.8 g/ day (iqr: 9.5–13.4 g/day), and the lowest intake was in the youngest group (18–29 years) at 10.3 g/day (iqr: 7.12–15.2 g/day; p = 0.01). however, there was no overall correlation between age and the amount of salt consumed (spearman’s coefficient of correlation = 0.06; p = 0.27). there was no difference in salt intake between the unemployed and employed groups (10.7 versus 10.4 g/day; p = 0.8). there was also no significant difference between those with a secondary school education or below and those with a diploma or higher qulaifications (10.02 versus 10.6 g/day; p = 0.4). the top three food items contributing the most to salt intake in the sample are, in order, fish biltong (dried salty fish), white bread and soup. the averages of sodium intake in fish biltong, white bread and soup are 469.1 mg/day, 386.8 mg/day and 370.4 mg/day, respectively. discussion this study assessed the amount of dietary salt intake in oman among a healthy population and correlated it with their awareness of the dangers of high salt intake. due to the widespread use of sodium in food processing, extensive distribution of sodium in food, presence of sodium in drinking water and extensive use of table salt, the accurate measurement of salt intake is difficult. the present study found that the median daily salt intake was 10.5 g/day (iqr: 7.3–15.1 g/day), which is consistent with the findings of previous reports and studies from other countries in the arabian gulf region.19,22 the median salt intake of women in the present study was higher than that of men. this is contrary to many other studies that found the salt intake in men to be more than in women.23,24 however, a few studies have shown that women consume more salt than men, such as in japan, while some studies have found no difference between the two genders.25,26 these different results could be because of cultural differences among the different populations or indeed the method used to assess salt intake. eating habits between the genders can vary considerably according to the culture. in some cultures, men tend to eat out more, while women stay at home and tend to eat more home-cooked meals.26 awareness regarding the dangers of salt intake was high in the present study, an observation reflected in other recent studies from the region.22,27 however, this awareness did not translate into actual reductions in the amount of salt consumed. the present study found that the youngest age group (18–28 years) had the lowest salt intake compared to the other two groups, although based on the dietary practices noted in the questionnaire, they were less likely than the older group to take actions to reduce their salt intake. similarly, it was found that participants with a diploma degree or higher qualification claimed to take actions to reduce salt intake, but there was no difference in the amount of salt consumed. though some studies have shown that salt consumption decreases with increasing educational status, most studies show that education or awareness itself is inadequate in reducing salt intake.28,29 similarly, the employed participants tended to have a slightly higher salt intake compared to the unemployed participants. this could be a reflection of the busy lifestyle of the employed participants, who would have had to eat outside, while those at home probably had more home-cooked meals. the current study found that the major food items that contribute to high salt intake are fish biltong, bread and soup. the major processed food items contributing to salt intake vary among populations. for example, in kuwait, the major food items contributing to salt intake are kuwaiti composite dishes, bread and sandwiches and pastries, while in the netherlands, the major sources are bread and cereal products, cheese and meat.19,30 one of the main issues that hinders the reduction of salt intake by the public is their perception of the recommended salt levels and high salt intake. this study found that although almost none of the respondents knew the recommended level of dietary salt intake, most still felt that they were consuming just the right amount of salt or indeed even less, while in reality, they were consuming a high amount of salt. even those who claimed to take steps to reduce their salt intake were consuming a high amount. it is imperative to increase awareness of the presence of high levels of salt in processed food and in other routinely consumed foodstuffs. increasing awareness regarding normal or high dietary salt intake and the importance of avoiding food with high salt content is key to tackling the problem of high dietary salt intake.9,11,12 the major limitation of the present study was the lack of urinary sodium estimation to validate the responses of the individuals, making the findings unreliable. however, the questionnaire that was used was previously validated.21 being a questionnairebased study, one of the inherent limitations is that patients tend to respond based on what they feel they muhammad m. shaikh, ali h.z. alkhayari, qusay a.k. alabdulsalam, khamis alhashmi and sunil k. nadar clinical and basic research | 491 should be doing rather than what they are actually doing.31 hence, the amount of salt consumed might be even higher than the amount obtained via the questionnaire. however, this was a pilot study, and its intention was to obtain a general sense for the amount of salt consumption in the country. another limitations, was that the sample size was small, which would affect the generalisability of the study’s findings. in addition, this survey was limited to the muscat region, which is urban, and did not take into consideration the vast geographical extent of oman. it is highly likely that in rural parts of the country, where the diet is mainly composed of freshly cooked food, the salt content would vary significantly. another limitation is that the questionnaire contained only 36 food categories with 50 mg na/serving or more; many food items that have less than 50 mg na/serving were not included in the questionnaire. therefore, it is likely that the actual salt intake might be higher than the calculated amount. lastly, another possible limitation is that the questionnaire was established with the referenced sodium amount for each serving according to south african food. the omani food and serving size may contain different amounts of sodium, but a reference for the sodium content in omani food was not available. even though it is not possible to categorically state that the salt intake calculated in the present study is accurate, it provides a general idea of the salt intake among the urban population of oman. the present study, along with other similar studies from the region, will help shape future public health initiatives to tackle the problem of high dietary salt. conclusion despite many health education campaigns and public awareness programmes, the level of salt consumption was high among the small sample of this study. the high level of awareness did not translate into action. further education of the public is necessary to help people reduce the amount of salt in their diet. additionally, food manufacturers could be required to reduce the amount of salt in commercially available food. a u t h o r s’ c o n t r i b u t i o n mms was involved in data collection and manuscript writing. ahza and qaka were involved in data collection. ka contributed to manuscript writing. skn was involved in data analysis and manuscript writing. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. roth ga, johnson c, abajobir a, abd-allah f, abera sf, abyu g, et al. global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. j am coll cardiol 2017; 70:1–25. https://doi.org/10.1016/j.jacc.2017.04.052. 2. traina mi, almahmeed w, edris a, murat tuzcu e. coronary heart disease in the middle east and north africa: current status and future goals. curr atheroscler rep 2017; 19:24. https://doi.org/10.1007/s11883-017-0659-9. 3. alhabib kf, batais ma, almigbal th, alshamiri mq, altaradi h, rangarajan s, et al. demographic, behavioral, and cardiovascular disease risk factors in the saudi population: results from the prospective urban rural epidemiology study (pure-saudi). bmc public health 2020; 20:1213. https://doi.org/10.1186/s12 889-020-09298-w. 4. shehab a, bhagavathula as, alhabib kf, ullah a, suwaidi ja, almahmeed w, et al. age-related sex differences in clinical pres entation, management, and outcomes in st-segment-elevation myocardial infarction: pooled analysis of 15 532 patients from 7 arabian gulf registries. j am heart assoc 2020; 9:e013880. https://doi.org/10.1161/jaha.119.013880. 5. bhagavathula as, shehab a, ullah a, rahmani j. the burden of cardiovascular disease risk factors in the middle east: a systematic review and meta-analysis focusing on primary prevention. curr vasc pharmacol 2021; 19:379–89. https://doi.org/10.2174 /1573406416666200611104143. 6. bromfield s, muntner p. high blood pressure: the leading global burden of disease risk factor and the need for worldwide prevention programs. curr hypertens rep 2013; 15:134–6. https://doi.org/10.1007/s11906-013-0340-9. 7. aaron kj, sanders pw. role of dietary salt and potassium intake in cardiovascular health and disease: a review of the evidence. mayo clin proc 2013; 88:987–95. https://doi.org/10.1016/j. mayocp.2013.06.005. 8. world health organisation. salt reduction. from: http:// www.who.int/news-room/fact-sheets/detail/salt-reduction accessed: aug 2021. 9. powles j, fahimi s, micha r, khatibzadeh s, shi p, ezzati m, et al. global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. bmj open 2013; 3:e003733. https://doi.org/10.1136/bmjopen-2013-003733. 10. farrand c, he fj, macgregor ga. reducing population salt intake in the eastern mediterranean region time for urgent action. east mediterr health j 2015; 20:761–4. https://doi.org/10.2 6719/2014.20.12.761. 11. he fj, macgregor ga. a comprehensive review on salt and health and current experience of worldwide salt reduction programmes. j hum hypertens 2009; 23:363–84. https://doi. org/10.1038/jhh.2008.144. 12. macgregor ga, he fj. world action on salt. lancet 2008; 371:471. https://doi.org/10.1016/s0140-6736(08)60228-7. 13. u.s. department of health and human services, u.s. department of agriculture. what we eat in america. from: https ://w w w.ars .usda .gov/ar suserfiles/80400530/p df/ dbrief/sodium_intake_0708.pdf accessed: aug 2021. https://doi.org/10.1016/j.jacc.2017.04.052 https://doi.org/10.1007/s11883-017-0659-9 https://doi.org/10.1186/s12889-020-09298-w https://doi.org/10.1186/s12889-020-09298-w https://doi.org/10.1161/jaha.119.013880 https://doi.org/10.1007/s11906-013-0340-9 https://doi.org/10.1016/j.mayocp.2013.06.005 https://doi.org/10.1016/j.mayocp.2013.06.005 https://doi.org/10.1136/bmjopen-2013-003733 https://doi.org/10.2 6719/2014.20.12.761 https://doi.org/10.2 6719/2014.20.12.761 https://doi.org/10.1038/jhh.2008.144 https://doi.org/10.1038/jhh.2008.144 https://doi.org/10.1016/s0140-6736(08)60228-7 estimation of salt intake and its relation to knowledge and attitude regarding the dangers of high salt intake among an urban omani population a pilot study 492 | squ medical journal, november 2022, volume 22, issue 4 14. batcagan-abueg ap, lee jj, chan p, rebello sa, amarra ms. salt intakes and salt reduction initiatives in southeast asia: a review. asia pac j clin nutr 2013; 22:490–504. https://doi. org/10.6133/apjcn.2013.22.4.04. 15. firestone mj, beasley jm, kwon sc, ahn j, trinh-shevrin c, yi ss. asian american dietary sources of sodium and salt behaviors compared with other racial/ethnic groups, nhanes, 2011–2012. ethn dis 2017; 27:241–8. https://doi.org/10.18865/ ed.27.3.241. 16. al riyami a, elaty ma, morsi m, al kharusi h, al shukaily w, jaju s. oman world health survey: part 1 methodology, socio demographic profile and epidemiology of non-communicable diseases in oman. oman med j 2012; 27:425–43. https://doi. org/10.5001/omj.2012.43. 17. nadar sk, al-riyami h, al-riyami a, al-lawati h, panakkal b, mohammed s, et al. may measurement month 2018; an analysis of blood pressure screening results from oman. eur heart j suppl 2020; 22:h100–3. https://doi.org/10.1093/eurheartj/suaa039. 18. centers for disease control and prevention (cdc), ministry of health (oman), united nations children's fund (unicef), world health organization regional office for the eastern mediterranean (emro-who). oman food fortification study 2004. from: http://ghdx.healthdata.org/record/oman-food-for tification-study-2004 accessed: aug 2021. 19. alhamad n, almalt e, alamir n, subhakaran m. an overview of salt intake reduction efforts in the gulf cooperation council countries. cardiovasc diagn ther 2015; 5:172–7. https://doi. org/10.3978/j.issn.2223-3652.2015.04.06. 20. who attitudes and behaviour towards salt intake 2018. from: http://www.who.int/ncds/surveillance/steps/riskfactor/ steps_saltmodule.pdf accessed: aug 2021. 21. charlton ke, steyn k, levitt ns, jonathan d, zulu jv, nel jh. development and validation of a short questionnaire to assess sodium intake. public health nutr 2008; 11:83–94. https://doi. org/10.1017/s1368980007000146. 22. al-mawali a, d'elia l, jayapal sk, morsi m, al-shekaili wn, pinto ad, et al. national survey to estimate sodium and potassium intake and knowledge attitudes and behaviours towards salt consumption of adults in the sultanate of oman. bmj open 2020; 10:e037012. https://doi.org/10.1136/bmjopen-2020-037012. 23. rezaei s, mahmoudi z, sheidaei a, aryan z, mahmoudi n, gohari k, et al. salt intake among iranian population: the first national report on salt intake in iran. j hypertens 2018; 36:2380–9. https://doi.org/10.1097/hjh.0000000000001836. 24. brown ij, tzoulaki i, candeias v, elliott p. salt intakes around the world: implications for public health. int j epidemiol 2009; 38:791–813. https://doi.org/10.1093/ije/dyp139. 25. sasaki s, yanagibori r, amano k. validity of a self-administered diet history questionnaire for assessment of sodium and potassium: comparison with single 24-hour urinary excretion. jpn circ j 1998; 62:431–5. https://doi.org/10.1253/jcj.62.431. 26. hipgrave db, chang s, li x, wu y. salt and sodium intake in china. jama 2016; 315:703–5. https://doi.org/10.1001/jama.20 15.15816. 27. al-riyami h, al-abdulsalam q, al-khayari l, al-mushrafi h, al-alawi z, al-hashmi k, et al. awareness of the dangers of high salt intake among the urban omani population. sultan qaboos univ med j 2020; 20:e352–6. https://doi.org/10.18295/ squmj.2020.20.03.016. 28. nestle m, wing r, birch l, disogra l, drewnowski a, middleton s, et al. behavioral and social influences on food choice. nutr rev 1998; 56:s50–64. https://doi.org/10.1111/j.1753-4887.1998.tb01732.x. 29. wang x, li x, vaartjes i, neal b, bots ml, hoes aw, et al. does education level affect the efficacy of a community based salt reduction program? a post-hoc analysis of the china rural health initiative sodium reduction study (crhi-srs). bmc public health 2016; 16:759. https://doi.org/10.1186/s12889016-3454-6. 30. temme ehm, hendriksen mah, milder iej, toxopeus ib, westenbrink s, brants ham, et al. salt reductions in some foods in the netherlands: monitoring of food composition and salt intake. nutrients 2017; 9:791. https://doi.org/10.3390/ nu9070791. 31. safdar n, abbo lm, knobloch mj, seo sk. research methods in healthcare epidemiology: survey and qualitative research. infect control hosp epidemiol 2016; 37:1272–7. https://doi. org/10.1017/ice.2016.171. https://doi.org/10.6133/apjcn.2013.22.4.04 https://doi.org/10.6133/apjcn.2013.22.4.04 https://doi.org/10.18865/ed.27.3.241 https://doi.org/10.18865/ed.27.3.241 https://doi.org/10.5001/omj.2012.43 https://doi.org/10.5001/omj.2012.43 https://doi.org/10.1093/eurheartj/suaa039 https://doi.org/10.3978/j.issn.2223-3652.2015.04.06 https://doi.org/10.3978/j.issn.2223-3652.2015.04.06 https://doi.org/10.1017/s1368980007000146 https://doi.org/10.1017/s1368980007000146 https://doi.org/10.1136/bmjopen-2020-037012 https://doi.org/10.1097/hjh.0000000000001836 https://doi.org/10.1093/ije/dyp139 https://doi.org/10.1253/jcj.62.431 https://doi.org/10.1001/jama.2015.15816. https://doi.org/10.1001/jama.2015.15816. https://doi.org/10.18295/squmj.2020.20.03.016 https://doi.org/10.18295/squmj.2020.20.03.016 https://doi.org/10.1111/j.1753-4887.1998.tb01732.x https://doi.org/10.1186/s12889-016-3454-6 https://doi.org/10.1186/s12889-016-3454-6 https://doi.org/10.3390/nu9070791 https://doi.org/10.3390/nu9070791 https://doi.org/10.1017/ice.2016.171 https://doi.org/10.1017/ice.2016.171 1department of medicine, sultan qaboos university hospital, muscat, oman; 2division of medicine, royal darwin hospital, darwin, australia; 3department of endocrinology, metabolism and diabetes, karolinska university hospital, stockholm, sweden; 4department of molecular medicine and surgery, karolinska institute, stockholm, sweden; 5menzies school of health research, darwin, australia *corresponding author’s e-mail: dr.abdullahalalawi@gmail.com محاض كيتوين ناتج من الرضاعة سلسلة حاالت عبد اهلل حممد العلوي، اأ�صامة العامري، وهرنيك فالهمر abstract: lactation ketoacidosis is an extremely rare type of high anion gap metabolic acidosis. we report two lactating women who were diagnosed with lactation ketoacidosis. the first patient presented to the emergency department at royal darwin hospital, darwin, australia, in 2018 with lethargy, nausea and abdominal pain after she commenced a new diet regimen based on three meals of protein per day and free of glucose, gluten and dairy products. the second patient presented to the emergency department at sultan qaboos university hospital, muscat, oman, in 2018 with headache, severe malaise, epigastric pain and worsening of gastroesophageal symptoms. blood investigation results showed that both patients had high anion gap metabolic acidosis, ketosis and hypoglycaemia. the patients responded well to intravenous dextrose and resumption of a balanced diet. both patients were able to continue breastfeeding and remained well on follow-up. keywords: breastfeeding; starvation; hypoglycemia; ketosis; acid-base imbalance; metabolic diseases; ketone bodies; fasting; case series; australia; oman. امللخ�ص: تعد حالة احلما�ض الكيتوين الناجت من الر�صاعة حالة نادرة جدا من اأنواع احلما�ض مرتفع الفارق اليوين. هنا نقوم بت�صجيل حالتني مت ت�صخي�صهما بحالة احلما�ض الكيتوين الناجت من الر�صاعة. ح�رست املري�صة الوىل اإىل ق�صم الطوارئ يف م�صت�صفى رويال داروين، داروين، اأ�صرتاليا، يف عام 2018 ت�صتكي من اخلمول والغثيان واآلم البطن بعد اأن بداأت نظاًما غذائًيا جديًدا يعتمد على ثالث وجبات من الربوتني يومًيا وخالية من اجللوكوز والغلوتني ومنتجات الألبان. املري�صه الثانية مت اح�صارها اىل ق�صم الطوارئ يف م�صت�صفى جامعة ال�صلطان قابو�ض، م�صقط، عمان، يف عام 2018 ت�صتكي من ال�صداع، وال�صعور بالإعياء ال�صديد، والأمل يف املعدة، وتفاقم اأعرا�ض البلعوم املعدي. اأظهرت نتائج فحو�صات الدم اأن كال من املر�صيتني تعاين من احلما�ض الأي�صي مرتفع الفارق اليوين، احلما�ض الكيتوين ونق�ض ال�صكر يف الدم. ا�صتجابت املري�صتينب�صكل جيد ملحلول ال�صكر املعطى عن طريق الوريد املتبوع با�صتئناف نظام غذائي متوازن. متكنت كلتا املري�صتني من موا�صلة الر�صاعة الطبيعية وظلت حالتهما متح�صنة خالل املتابعة. الكلمات املفتاحية: الر�صاع من الثدي؛ اجلوع ال�صديد؛ نق�ض معدل ال�صكر يف الدم؛ اإرتفاع ن�صبة الكيتونات؛ عدم توازن احلم�ض والقاعدة؛ اأمرا�ض اأي�صية؛ الكيتونات؛ ال�صيام؛ �صل�صلة حالت؛ اأ�صرتاليا؛ عمان. lactation ketoacidosis a case series *abdullah m. al alawi,1 usama al amri,1 henrik falhammar2–5 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e359–363, epub. 22 dec 19 submitted 21 jul 19 revisions req. 11 sep & 3 oct 19; revisions recd. 23 sep & 8 oct 19 accepted 24 oct 19 case one a 35-year-old lactating caucasian woman presented to the emergency department at royal darwin hospital, darwin, australia, in 2018 with a four-day history of lethargy and abdominal pain associated with nausea but no vomiting. she denied any history of altered bowel habits, urinary symptoms, fever or cough. she was breastfeeding her five-month-old healthy infant every 4–6 hours. recently, she had changed her diet to a glucose-, glutenand dairy-free diet. her meals consisted of protein shakes three times per day. during the same period, she resumed her work as a fitness instructor and was doing moderate exercise twice per week [table 1]. diabetic ketoacidosis is the most common cause of high anion gap metabolic acidosis. other causes of high anion gap metabolic acidosis include lactic acidosis, renal failure, starvation and toxins (e.g. ethanol, methanol, ethylene glycol and salicylate).1 lactation ketoacidosis is an extremely rare cause of high anion gap metabolic acidosis in humans with the first case described in 1982.2 common precipitating factors include change in diet, commencement of intense exercise, skipping meals or intercurrent illness.3 intravenous dextrose, balanced diet and treatment underlying acute illness are the main treatments for this condition. this condition carries a good prognosis and thus far there is no reported mortality in the literature.3,4 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.012 case report https://creativecommons.org/licenses/by-nd/4.0/ lactation ketoacidosis a case series e360 | squ medical journal, november 2019, volume 19, issue 4 her past medical history included well-controlled asthma and iron-deficiency anaemia for which she had been prescribed a fluticasone propionate inhaler and ferrous sulphate, respectively. she had undergone an emergency lower segment caesarean section (lscs) five months prior due to obstructed labour; the pre and post-natal period were unremarkable. this had been her second lscs for the same indication. there was no history of ethanol consumption, smoking or illicit substance use. on physical examination, she appeared unwell, dehydrated and lethargic but was alert and oriented. her weight was 57.2 kg, blood pressure was 110/68 mmhg and she had a heart rate of 98 beats/minute. oxygen saturation was 100% at room air and she was afebrile. the remaining clinical examination was unremarkable. blood investigations showed high anion gap metabolic acidosis and high capillary ketones [table 2]. she was given 25 ml of 50% dextrose intra venously, followed by 1 l of 5% dextrose infusion. in addition, she was given antiemetics and advised to eat regular meals as tolerated. the patient continued to breastfeed her infant. her symptoms and ketoacidosis improved dramatically over 24 hours and she was table 1: clinical characteristics, presentation and treat ment of two cases diagnosed with lactation ketoacidosis case one case two ethnicity caucasian arab age of the patient in years 35 30 weight of the patient in kg 57.2 63 age of the infant in months 5 12 precipitating factor • protein based diet; free of sugar, dairy products and gluten • exercise • significant reduced oral intake due to worsening of gastroesophageal reflux symptoms • skipped lunch meals presentation lethargy, nausea and abdominal pain headache, severe malaise and epigastric pain treatment intravenous dextrose • intravenous dextrose • proton pump inhibitor duration of recovery in hours 24 24 breastfeeding continued continued table 2: biochemistry results of two cases at initial pre sentation who were diagnosed with lactation ketoacidosis investigation case one case two reference range ph 7.26 7.21 7.3–7.4 bicarbonate in mmol/l 12.3 14.9 21.0–28.0 base excess in mmol/l -13.5 12.6 -2–2 anion gap in mmol/l 20.3 24 8–12 measured serum osmolality in mmol/kg 277.4 275–295 calculated serum osmolality in mmol/kg 284 300 275–295 capillary ketones in mmol/l 4.8 <0.6 urine dipstick +++ ketones 0 lactate in mmol/l 1 0.7 1.5–2.5 glucose in mmol/l 2.9 2.9 3.9–5.8 (fasting) sodium in mmol/l 138 146 135–145 potassium in mmol/l 4.2 4.1 3.5–4.5 chloride in mmol/l 109 108 98–106 urea in mmol/l 4.9 4.7 2.5–7.0 creatinine in µmol/l 74 55 50–100 total carbon dioxide in mmol/l 12 22–32 haemoglobin in g/dl 15.3 10.7 11.5–16.5 platelets in × 109/l 199 302 150–450 white cell count in × 109/l 4.7 7.2 4–11 albumin in g/l 49 37 37–48 corrected calcium in mmol/l 2.28 2.01 2.10–2.60 magnesium in mmol/l 0.81 0.72 0.70–1.10 phosphate in mmol/l 1.31 0.69 0.75–1.50 total bilirubin in µmol/l 20 4 <21 alkaline phosphatase in u/l 91 29 30–110 gamma glutamyl transferase in u/l 10 <43 alanine aminotransferase in u/l 28 14 5–42 total protein in g/l 84 73 64–84 glycosylated haemoglobin in percent 5.4 5.5 4.3–5.7 abdullah m. al alawi, usama al amri and henrik falhammar case report | e361 discharged with the advice to eat regular meals consisting of a balanced diet. her venous blood gas on discharge had almost normalised at ph 7.38 with an almost normal bicarbonate value of 20.4 mmol/l (normal range: 21.0–28.0 mmol/l) and a ketone value of 0.3 mmol/l (normal range: <0.6 mmol/l). after excluding other causes of high anion gap metabolic acidosis, the diagnosis of lactation ketoacidosis was made. she was well and was breastfeeding on followup four weeks later. case two a 30-year-old lactating arab woman presented to the emergency department at sultan qaboos university hospital, muscat, oman, in 2018 with headache, severe malaise and epigastric pain that had persisted for one day. in addition, she had worsening of her gastroesophageal reflux symptoms and significantly reduced oral intake over the preceding four days. she was breastfeeding her 12-month-old infant. her pregnancy had been uneventful and she had delivered a normal baby at full term. she had an abortion two years prior. with regards to her gastrointestinal issue, she had chronic gastroesophageal reflux for more than 10 years that had been treated with antacids previously but had never been investigated thoroughly. the gastroesophageal reflux had worsened over the last four months prior to presentation and she developed dysphagia to solid food. furthermore, she had struggled to swallow a semi-solid and fluid diet for four days prior to presentation. she continued breastfeeding five times per day. in addition, she was employed full-time in an office and she would skip her lunch meals [table 1]. there was no history of alcohol consumption, smoking or illicit substance use. on presentation, she looked dehydrated, was afebrile, alert and oriented. her blood pressure was 125/77, with a heart rate of 92 beats/minute, a respiratory rate of 19 breaths/minute, a weight of 63 kg, a height of 160 cm and a body mass index of 24.6 kg/m2. abdominal examination revealed mild epigastric tenderness, soft abdomen and no organomegaly. otherwise, the clinical examination was unremarkable. blood investigations revealed high anion gap metabolic acidosis, positive urinary ketones and hypoglycaemia [table 2]. other investigations including an electrocardiogram, chest x-ray and urine drug abuse screening were unremarkable. after excluding all causes of high anion gap metabolic acidosis, a diagnosis of lactation ketoacidosis was made and the patient was given 50 ml of 50% dextrose intravenously to treat hypoglycaemia followed by a 10% dextrose infusion. she was admitted to a high dependency unit for close monitoring. her electrolyte derangements were corrected and she was given intravenous esomeprazole to alleviate gastro esophageal symptoms. an upper gastrointestinal scope examination showed severe reflux oesophagitis with ulceration involving the lower third of the oesophagus. the ketoacidosis resolved within 24 hours and the patient had a remarkable improvement in her symptoms (i.e. headache and malaise). however, 10% dextrose infusion was continued for another 72 hours when she was able to tolerate an oral diet. the patient opted to continue breastfeeding due to the infant’s history of cow’s milk formula intolerance. also, she was counselled by a dietician regarding her calorie intake and was advised to have regular meals. the patient was discharged with esomeprazole and a plan for a follow-up upper gastrointestinal scope examination and an oesophageal manometry. the patient remained well and reported an improvement of the gastroesophageal reflux upon follow-up. discussion high anion gap metabolic acidosis is a common manifestation of different diseases. diabetic keto acidosis is the most common cause of high anion gap metabolic acidosis. other causes include renal failure, lactate acidosis, toxins (e.g. ethanol, methanol, ethylene glycol or salicylate) and starvation.5,6 ketone bodies are converted into energy when the body is running short of glucose. there are three types of ketone bodies: 1) acetoacetate; 2) β-hydroxybutyrate; and 3) acetone.7 during a period of fasting, high levels of glucagon and low levels of insulin induce the activity of the enzyme lipoprotein lipase which works on fat stores to release glycerol and long-chain fatty acids.8 those metabolites are processed in the hepatocyte’s mitochondria and converted into acetyl-coenzyme a (acetyl-coa) through hepatic beta-oxidation. due to decreased glucose availability, the acetyl-coa will be largely used in the ketogenic pathway to produce ketone bodies instead of entering the krebs cycle.9 other hormones such as glucagon, cortisol, thyroid hormones and catecholamines facilitate ketogenesis.10 after three days of starvation, the body maximises the ketones body production, however, significant ketoacidosis requires more than 14 days of starvation to occur in otherwise healthy individuals.11 bovine ketoacidosis is a well-known disease in lactating ruminants, especially in dairy cows. it typically occurs during early lactation when the glucose requirement for milk production exceeds the amount lactation ketoacidosis a case series e362 | squ medical journal, november 2019, volume 19, issue 4 of the body’s carbohydrate and glycogen stores.12 as a result, gluconeogenesis accelerates to meet the demand for milk production, especially in high-yield dairy cows.4 cattle with lactation ketoacidosis may show reduced feeding, reduced milk production, hypoactivity, irritability and abnormal licking and chewing.13,14 in cows, intravenous administration of 50% dextrose is a common therapy and associated with rapid recovery.15 however, the effect of dextrose is transit and relapses are common.13 adding intramuscular glucocorticoids to dextrose may result in a more sustainable effect compared to dextrose therapy alone. also, oral propylene glycol, that acts as a glucose precursor, is an effective therapy.13,15 in refractory cases, intramuscular long-acting insulin may improve metabolic acidosis by suppressing ketogenesis and fatty acid mobilisation. however, insulin should be given in combination with dextrose or glucocorticoid to avoid hypoglycaemia. other treatments of refractory lactation ketoacidosis include continuous dextrose infusion and tube feeding.13 a human lactating female requires approximately 500 kcal per day extra to meet additional energy requirements for milk production.16 in humans, lactation ketoacidosis is considered an extremely rare condition; the first case was described by chernow et al. in the usa in 1982.2 they reported a 19-yearold lactating woman who presented to the emergency department with nausea, vomiting and abdominal pain. she was found to have high-anion gap metabolic acidosis and ketonuria. she had been consuming a low energy diet for five weeks prior to presentation and succeeded to loss around 12 kg body weight. in addition, she suffered from a urinary tract infection. she was treated with intravenous normal saline, 5% dextrose and insulin. she was commenced on a 2,500 kcal per day diet and had resolution of ketoacidosis within 24 hours after admission.2 lactation ketoacidosis is a rare condition that occurs in breastfeeding mothers and should be diagnosed after excluding all other causes of high anion gap metabolic acidosis.3 currently, there are 15 cases of lactation ketoacidosis reported in the literature worldwide.2–4,8,17–27 intravenous dextrose, electrolyte replacement and a balanced diet were the main treatments in all previously reported cases; sodium bicarbonate and insulin therapy were used in some cases.3,4,17,19,20 some patients ceased breastfeeding while others managed to continue breastfeeding while receiving treatment for ketoacidosis.3,20,21,24 altered diet and reduced total energy in addition to exercise triggered lactation ketoacidosis in the first case presented while reduced oral intake because of severe gastroesophageal reflux and skipping meals were the precipitating factors in the second case. both cases were treated with intravenous dextrose which resulted in resolution of metabolic acidosis within 24 hours. both patients were able to continue breastfeeding their infants without reoccurrence of the condition. overall, the presentation of these two cases, the rapid response to treatment and the outcomes were consistent with previously reported cases of lactation ketoacidosis.3 the authors have seen several cases of lactation ketoacidosis in their clinical practice and suspect this condition is more common than previously thought and that most cases are not correctly diagnosed. conclusion lactation ketoacidosis is considered an extremely rare cause of high anion gap metabolic acidosis. however, it may be under-diagnosed; therefore, it is important for the physicians and other health professionals to be aware of this condition. a patient may present with non-specific symptoms related to acidosis and hypoglycaemia including lethargy, headache, nausea and loss of energy. a low-energy diet and reduced oral intake due to concurrent illness are common precipitating factors. intravenous dextrose and electrolyte replacement are associated with rapid recovery of the condition. breastfeeding may be resumed after recovery from the metabolic acidosis and when the patient is able to consume a balanced diet. overall, lactation ketoacidosis carries a good prognosis and the condition is very unlikely to recur. references 1. brubaker rh, meseeha m. high anion gap metabolic acidosis. from: www.ncbi.nlm.nih.gov/books/nbk448090/ accessed: oct 2019. 2. chernow b, finton c, rainey tg, o'brian jt. "bovine ketosis" in a nondiabetic postpartum woman. diabetes care 1982; 5:47–9. https://doi.org/10.2337/diacare.5.1.47. 3. al alawi am, falhammar h. lactation ketoacidosis: case presentation and literature review. bmj case rep 2018; 2018. https://doi.org/10.1136/bcr-2017-223494. 4. szulewski a, howes d, morton ar. a severe case of iatrogenic lactation ketoacidosis. bmj case rep 2012;2012. https://doi. org/10.1136/bcr.12.2011.5409. 5. kraut ja, madias ne. differential diagnosis of nongap metabolic acidosis: value of a systematic approach. clin j am soc nephrol 2012; 7:671–9. https://doi.org/10.2215/ cjn.09450911. 6. mubarik a, jupalli a, iqbal am, muddassir s, eddib a. isolated starvation ketoacidosis: a rare cause of severe metabolic acidosis presenting with a ph less than 7. cureus 2019; 11:e4086. https://doi.org/10.7759/cureus.4086. https://doi.org/10.2337/diacare.5.1.47 https://doi.org/10.1136/bcr-2017-223494 https://doi.org/10.1136/bcr.12.2011.5409 https://doi.org/10.1136/bcr.12.2011.5409 https://doi.org/10.2215/cjn.09450911 https://doi.org/10.2215/cjn.09450911 https://doi.org/10.7759/cureus.4086 abdullah m. al alawi, usama al amri and henrik falhammar case report | e363 7. laffel l. ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. diabetes metab res rev 1999; 15:412–26. https://doi.org/10.1002/(sici)15207560(199911/12)15:6<412::aid-dmrr72>3.0.co;2-8. 8. gleeson s, mulroy e, clarke de. lactation ketoacidosis: an unusual entity and a review of the literature. perm j 2016; 20:71–3. https://doi.org/10.7812/tpp/15-097. 9. hammerbeck h, holland mr. starvation ketoacidosis: treatment pitfalls. j intensive care soc 2017; 18:265. https:// doi.org/10.1177/1751143716687593. 10. dhillon kk, gupta s. biochemistry, ketogenesis. from: www. ncbi.nlm.nih.gov/books/nbk493179/ accessed: oct 2019. 11. owen oe, caprio s, reichard ga jr, mozzoli ma, boden g, owen rs. ketosis of starvation: a revisit and new perspectives. clin endocrinol metab 1983; 12:359–79. https://doi.org/10.10 16/s0300-595x(83)80046-2. 12. holtenius p, holtenius k. new aspects of ketone bodies in energy metabolism of dairy cows: a review. zentralbl veterinarmed a 1996; 43:579–87. https://doi.org/10.1111/j.1439-0442.1996. tb00491.x. 13. herdt th. overview of ketosis in cattle. from: www. msdvetmanual.com/metabolic-disorders/ketosis-in-cattle/ overview-of-ketosis-in-cattle accessed: oct 2019. 14. gordon jl, leblanc sj, duffield tf. ketosis treatment in lactating dairy cattle. vet clin north am food anim pract 2013; 29:433–45. https://doi.org/10.1016/j.cvfa.2013.03.001. 15. stone n. acetonaemia (ketosis) of dairy cows. from: http:// agriculture.vic.gov.au/agriculture/pests-diseases-and-weeds/ animal-diseases/beef-and-dairy-cows/acetonaemia-ketosis-ofdairy-cows accessed: oct 2019. 16. dewey kg. energy and protein requirements during lactation. annu rev nutr 1997; 17:19–36. https://doi.org/10.1146/annur ev.nutr.17.1.19. 17. altus p, hickman jw. severe spontaneous 'bovine' ketoacidosis in a lactating woman. j indiana state med assoc 1983; 76:392–3. 18. heffner ac, johnson dp. a case of lactation "bovine" ketoacidosis. j emerg med 2008; 35:385–7. https://doi.org/10.1 016/j.jemermed.2007.04.013. 19. sandhu hs, michelis mf, devita mv. a case of bovine ketoacidosis in a lactating woman. ndt plus 2009; 2:278–9. https://doi.org/10.1093/ndtplus/sfp052. 20. hudak sk, overkamp d, wagner r, häring hu, heni m. ketoacidosis in a non-diabetic woman who was fasting during lactation. nutr j 2015; 14:117. https://doi.org/10.1186/s12937015-0076-2. 21. wuopio j, schiborr r, charalampakis g. [severe ketoacidosis in breastfeeding woman with low energy and carbohydrate intake]. lakartidningen 2015; 112. 22. von geijer l, ekelund m. ketoacidosis associated with lowcarbohydrate diet in a non-diabetic lactating woman: a case report. j med case rep 2015; 9:224. https://doi.org/10.1186/ s13256-015-0709-2. 23. greaney dj, benson p. life-threatening lactation or "bovine" ketoacidosis: a case report. a a case rep 2016; 7:81–4. https://doi.org/10.1213/xaa.0000000000000350. 24. sloan g, ali a, webster j. a rare cause of metabolic acidosis: ketoacidosis in a non-diabetic lactating woman. endocrinol diabetes metab case rep 2017; 2017. https://doi.org/10.1530/ edm-17-0073. 25. azzam o, prentice d. lactation ketoacidosis: an easily missed diagnosis. intern med j 2019; 49:256–9. https://doi.org/10.11 11/imj.14207. 26. nnodum bn, oduah e, albert d, pettus m. ketogenic dietinduced severe ketoacidosis in a lactating woman: a case report and review of the literature. case rep nephrol 2019; 2019:1214208. https://doi.org/10.1155/2019/1214208. 27. seaton c, sutherly k, miller ma. breastfeeding ketoacidosis: a rare but important diagnosis for emergency physicians to recognize. am j emerg med. 2019; 37:374.e1. https://doi.org/10.1 016/j.ajem.2018.10.014. https://doi.org/10.1002/%28sici%291520-7560%28199911/12%2915:6%3c412::aid-dmrr72%3e3.0.co%3b2-8 https://doi.org/10.1002/%28sici%291520-7560%28199911/12%2915:6%3c412::aid-dmrr72%3e3.0.co%3b2-8 https://doi.org/10.7812/tpp/15-097 https://doi.org/10.1177/1751143716687593 https://doi.org/10.1177/1751143716687593 https://doi.org/10.1016/s0300-595x%2883%2980046-2 https://doi.org/10.1016/s0300-595x%2883%2980046-2 https://doi.org/10.1111/j.1439-0442.1996.tb00491.x https://doi.org/10.1111/j.1439-0442.1996.tb00491.x https://doi.org/10.1016/j.cvfa.2013.03.001 https://doi.org/10.1146/annurev.nutr.17.1.19 https://doi.org/10.1146/annurev.nutr.17.1.19 https://doi.org/10.1016/j.jemermed.2007.04.013 https://doi.org/10.1016/j.jemermed.2007.04.013 https://doi.org/10.1093/ndtplus/sfp052 https://doi.org/10.1186/s12937-015-0076-2 https://doi.org/10.1186/s12937-015-0076-2 https://doi.org/10.1186/s13256-015-0709-2 https://doi.org/10.1186/s13256-015-0709-2 https://doi.org/10.1213/xaa.0000000000000350 https://doi.org/10.1530/edm-17-0073 https://doi.org/10.1530/edm-17-0073 https://doi.org/10.1111/imj.14207 https://doi.org/10.1111/imj.14207 https://doi.org/10.1155/2019/1214208 https://doi.org/10.1016/j.ajem.2018.10.014 https://doi.org/10.1016/j.ajem.2018.10.014 1department of radiology, ibri regional hospital, ibri, oman; 2department of radiology and molecular imaging, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asmaalhatmi1989@gmail.com emphysematous gastritis on computed tomography *asma alhatmi,1 sameer b. raniga,2 alok mittal2 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 432–434, epub. 25 aug 22 submitted 13 jul 21 revision req. 2 sep 21; revision recd. 16 sep 21 accepted 13 oct 21 a 67-year-old omani man with multiple comorbidities of diabetes, hypertension, ischaemic heart disease, recurrent uro sepsis and bedridden on permanent suprapubic cathe terisation due to previous history of spinal trauma and surgery presented to the emergency department at a tertiary healthcare centre in muscat, oman, in 2017; he complained of acute onset of severe abdominal pain, abdominal distention and multiple episodes of vomiting for two days. the pain was localised in the epigastric region with mild localised tenderness. his vitals were normal. he had a temperature of 37°c, pulse of 80 beats per minute, blood pressure of 125/75 mmhg and oxygen saturation of 98% on room air. initial work-up showed a white blood cell count of 12,000/μl and normal lipase level. plain radiograph of the abdomen showed a grossly distended stomach without signs of pneumoperitoneum or small bowel obstruction [figure 1]. computed tomography (ct) scan of the abdomen was done to exclude the possibility of gastric outlet obstruction. it showed a grossly distended stomach with mild thickened wall and extensive intramural air involving fundus, body and pyloric region [figures 2a and b]. multiple air loculi were seen within the draining perigastric veins and within the intrahepatic portal vein in the left lobe of the liver [figures 2c and d]. emergent exploratory laparotomy was done as the patient condition deteriorated; this showed a completely gangrenous stomach. a total gastrectomy was performed. the patient, who was kept in the intensive care unit and treated with sepsis protocol, later recovered. the histopathology report revealed emphysematous gastritis with acute ischaemic infarction. literature review shows few case reports of this condition. therefore, we report the ct findings of emphysematous gastritis associated with gastric infarction in a diabetic patient. it is the first case of emphysematous gastritis reported in the presenting healthcare centre using only radiological modality. the reporting of the current case does not contravene with the regulations of the local institutional review board. comment emphysematous gastritis is a rare and potentially lethal condition which requires prompt diagnosis and urgent aggressive management.1 however, the presentation can be similar to other diagnoses this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.10.2021.142 interesting medical image figure 1: plain radiograph of the abdomen of a 67-year-old male patient anteroposterior supine view showing grossly distended stomach (black arrows) without signs of pneumoperitoneum or small bowel obstruction. https://creativecommons.org/licenses/by-nd/4.0/ asma alhatmi, sameer b. raniga and alok mittal interesting medical image | 433 such as gastric emphysema and gastric ischaemia.2 differentiation is very crucial between these as the management and prognosis will also be different. a history of diabetes, ingestion of alcohol or corrosive material, adenocarcinoma of the stomach, peptic ulcer, infarction, trauma or invasion of submucosa by gasforming organism are considered to be predisposing factors to this condition.1,3 the literature shows that commonly isolated organisms are streptococci, escherichia coli, enterobacter and pseudomonas.3 the current patient had two risk factors including history of diabetes and recurrent urosepsis. patients with emphysematous gastritis are usually symptomatic and may present with sudden acute abdominal pain, haematemesis, fever, leukocytosis or septic shock with sign of instability and systemic toxicity.4 emphysematous gastritis is an emergency condition which needs to be considered in the differential diagnosis of acute abdomen especially in presence of risk factors and requires urgent ct scan of the abdomen for early diagnosis and intervention.5 emphysematous gastritis is different from gastric emphysema in which the latter is a benign condition caused by disrupted mucosa and secondary air entry to the wall due to variable causes such as after endoscopy, extension of pneumomediastinum or pneumothorax, severe vomiting or pneumatosis cystoides.2 however, the patient remains asymptomatic and the condition will resolve spontaneously. both emphysematous gastritis and gastric emphysema can be manifested in plain abdominal radiograph as linear thin lucencies along the stomach wall.2,5 ct is the most sensitive method and the best diagnostic modality which helps to differentiate further between these two conditions as emphysematous gastritis is usually associated with thickened gastric mucosal folds and oedema along with cystic pockets of air in the gastric wall and sometimes air in the gastric venous drainage and portal vein in severe conditions.2,4,5 ct also helps to exclude other differential diagnoses of acute abdomen such as acute pancreatitis or perforated viscus.2 plain radiograph of the abdomen of the current patient showed a grossly distended stomach without signs of pneumoperitoneum or small bowel obstruction and a ct scan was done to exclude the possibility of gastric outlet obstruction. it showed extensive intramural air involving the stomach with multiple air loculi seen within the draining perigastric and intrahepatic portal veins. patients with gastric emphysema are usually asymptomatic and have a benign course compared to a patient with emphysematous gastritis; most of the latter patients are clinically ill and need urgent management.2 the mortality rate from emphysematous gastritis is more than 60% and the non-lethal complication rate (e.g. gastric strictures) is up to 25%.1,3 early nonoperative medical management with good hydration, broad-spectrum intravenous antibiotics and bowel rest improve the clinical outcomes.4 surgery is not indicated in an acute setting even in the presence of portal venous air or pneumoperitoneum as it figure 2: non-contrast computed tomography scan of the abdomen of a 67-year-old male patient. a & b: axial image at upper pole of right kidney and coronal image obtained at mid abdomen level showing grossly distended stomach with tiny bubbly intramural air (arrows) and mild perigastric fatty streakiness (arrowheads). c: axial image at mid-renal pole showing minimal air within perigastric draining vein (red arrows). d: axial image obtained at level of gall bladder fossa showing peripheral branching linear lucencies in left lobe of liver consistent with portovenous air (white arrows). emphysematous gastritis on computed tomography 434 | squ medical journal, august 2022, volume 22, issue 3 is associated with increased mortality and postoperative complications such as anastomotic leak and fistula formation. surgery is indicated in case of clinical deterioration, peritonitis, gastric infarction, perforation or failed medical management.2,3 the current patient underwent emergent exploratory laparotomy as his condition deteriorated; this revealed a completely gangrenous stomach for which a total gastrectomy was performed. early detection and management of emphysematous gastritis based on clinical presentation and ct findings will improve the clinical course and reduce the mortality and morbidity.4 a u t h o r s’ c o n t r i b u t i o n s aa collected the clinical data, medical images, did the literature review, wrote the manuscript draft and edited it after review. sbr reviewed the manuscript drafts before submission for error correction. am chose the appropriate images and wrote the captions and citations. allauthors approved the final version od this manuscript. references 1. suwannachod c, rujitanon p. a case report: emphysematous gastritis. int surg j 2017; 4:2819–22. https://doi.org/10.1820 3/2349-2902.isj20173426. 2. matsushima k, won ej, tangel mr, enomoto lm, avella dm, soybel di. emphysematous gastritis and gastric emphysema: similar radiographic findings, distinct clinical entities. world j surg 2015; 39:1008–17. https://doi.org/10.1007/s00268-0142882-7. 3. shipman pj, drury p. emphysematous gastritis: case report and literature review. australas radiol 2001; 45:64–6. https:// doi.org/10.1046/j.1440-1673.2001.00878.x. 4. paul m, john s, menon mc, golewale nh, weiss sl, murthy uk. successful medical management of emphysematous gastritis with concomitant portal venous air: a case report. j med case rep 2010; 4:140. https://doi.org/10.1186/1752-1947-4-140. 5. guniganti p, bradenham ch, raptis c, menias co, mellnick vm. ct of gastric emergencies. radiographics 2015; 23:75–87. https://doi.org/10.1148/rg.2015150062. https://doi.org/10.18203/2349-2902.isj20173426 https://doi.org/10.18203/2349-2902.isj20173426 https://doi.org/10.1007/s00268-014-2882-7 https://doi.org/10.1007/s00268-014-2882-7 https://doi.org/10.1046/j.1440-1673.2001.00878.x https://doi.org/10.1046/j.1440-1673.2001.00878.x https://doi.org/10.1186/1752-1947-4-140 https://doi.org/10.1148/rg.2015150062 departments of 1genetics and 2child health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: khalid.althihli@gmail.com abstract: syndrome of inappropriate antidiuretic hormone (siadh) secretion is a recognisable complication of acute porphyria. we report a nine-year-old female patient with hereditary tyrosinaemia type 1 and poor adherence to nitisinone therapy who presented with acute abdominal pain, vomiting and lethargy at sultan qaboos university hospital, muscat, oman in 2016. she subsequently developed generalised tonic-clonic seizures attributable to severe hyponatremia that met the diagnostic criteria of siadh. the acute porphyria screen also appeared positive. the patient responded well to fluid restriction and was discharged home without immediate neurological sequelae. although acute porphyria is also a recognised complication of uncontrolled tyrosinaemia type 1, to the best of the authors’ knowledge, no patient with tyrosinaemia type 1 has been reported to present with siadh. keywords: tyrosinemia type 1; hyponatremia; inappropriate adh syndrome; case report; oman. syndrome of inappropriate antidiuretic hormone secretion in a patient with uncontrolled tyrosinaemia type 1 abdulhamid al-hinai,1 fathiya al-murshedi,1 dana al-nabhani,2 *khalid al-thihli1 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e312–315, epub. 21 jun 21 submitted 8 apr 20 revision req. 8 jun 20; revision recd. 30 jun 20 accepted 11 aug 20 known complication in patients with uncontrolled tyrosinaemia type 1.7,8 although siadh is a well reported complication of porphyria, it is rarely reported as a complication in a patient with ht-1. this case report describes a nine-year-old female patient, diagnosed at a very young age with ht-1. the patient presented with acute porphyria-like crisis and severe symptomatic hyponatraemia fulfilling the diagnostic criteria of siadh. case report we report a nine-year-old female patient born to consanguineous parents presenting to sultan qaboos university hospital (squh), muscat, oman, in 2016. she had two older siblings diagnosed with tyrosinaemia type 1. following genetic testing for the known familial mutation c.785g>a (p.trp262*) in the fah gene, she was confirmed to have tyrosinaemia type 1 since the age of one month. the patient was reasonably controlled on nitisinone (also known as 2-[2-nitro4-trifluoromethylbenzoyl]-1,3-cyclohexanedione) therapy given at a dose of 1 mg/kg/day in combination with protein restriction. however, the patient’s adherence to therapy started to decline after the age of six years. she started showing measurable succinylacetone in the urine, although it had initially disappeared following initiation of nitisinone therapy. the patient recently presented to a local health care centre with a history of abdominal pain, vomiting, lethargy and undocumented fever for three days. on hereditary tyrosinaemia type 1 (ht-1)is a rare inborn error of the tyrosine metabolism caused by deficiency of the fumarylacetoacetate (faa) hydrolase enzyme in the tyrosine catabolic pathway. the clinical phenotype has been attributed to succinylacetone (sa). the accumulation of toxic metabolites and their derivatives such as faa, maleylacetoacetate, succinyl acetoacetate and succinyl acetone causes the hepatic, renal and neurological complications of ht-1.1,2 uncontrolled tyrosinaemia can lead to hepatic cirrhosis that can further progress to hepatocellular carcinoma. moreover, patients with this diagnosis are also at risk of renal tubular acidosis and progressive renal failure.2 furthermore, the inhibition of delta-5 aminolevulinic acid dehydratase (alad) by sa in the heme biosynthetic pathway leads to acute porphyria, a wellknown complication of ht-1, and the patient typically presents with pain crisis associated with autonomic instability.2,3 syndrome of inappropriate antidiuretic hormone (siadh) is defined by the unsuppressed release of antidiuretic hormone (adh) from the pituitary gland or non-pituitary sources that result in impaired water excretion leading to hyponatraemia with hypervolaemia or euvolaemia.4 hyponatraemia, secondary to siadh, is a common electrolyte disturbance occurring in approximately 30% of hospitalised patients. the diagnosis of siadh is based on the classic schwartz and bartter criteria that were described in 1967.5,6 siadh is most commonly due to secondary systemic causes that are highly heterogeneous. among the aetiologies leading to siadh is porphyria, a wellthis work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.023 case report https://creativecommons.org/licenses/by-nd/4.0/ case report | e313 physical examination, she was conscious, alert and her vital signs were within the normal range. her weight on admission was 21 kg. the patient was noted to be clinically dehydrated and have generalised abdominal tenderness. initial laboratory investigations showed urine ketones at 4+ and normal sodium (142 meq/l; na+), potassium (4.7 meq/l; k+) and bicarbonate (18 mmol/l; hco3 -) levels, with pre-renal azotaemia, urea of 17.6 mmol/l and high creatinine of 114 µmol/l. the patient was subsequently admitted with the clinical impression of acute gastroenteritis with clinical dehydration. she was given two boluses of normal saline (ns), each at a dose of 20 ml/kg/dose. she was also put on dextrose 10% with 0.9% sodium chloride solution (d10%ns) at a one and a half maintenance rate (90 ml/hour). this fluid management continued for approximately 40 hours. after 34 hours of initiating management, the patient developed tonicclonic seizure (tcs) with up-rolling of the eyes. the episode lasted for a minute and a half and was aborted using diazepam (0.2 mg/kg). laboratory investigations showed a sodium concentration of 113 meq/l, chloride concentration of 76 mmol/l, normal creatinine of 39 µmol/l, with normalised urea of 2.4 mmol/l, magnesium of 0.4 mmol/l and phosphate of 0.79 mmol/l. the patient had hypoalbuminaemia with normal albumin-corrected calcium. when the patient was transferred to squh, her glasgow coma scale (gcs) score dropped from 15 to 11 out of 15 and her pupils were dilated at 4–5 mm. her blood pressure was normal for her age and weight (127/94 mmhg) and other vital signs were within the normal range. the patient was well hydrated receiving intravenous d10%ns at a rate of 90 ml/hour. eight hours after admission, the patient developed another episode of tcs which lasted less than a minute and was self-aborted. repeated laboratory investigations showed na+ of 114 meq/l and very low serum osmolality of 236 mosmol/kg. the cortisol level was 488 nmol/l (normal range: 185–624 nmol/l). thyroid function tests, albumin and transaminases were all within the normal range. given the absence of clinical signs of fluid overload and with the patient being euvolaemic, this severe symptomatic hyponatraemia with euvolaemia was most likely due to siadh. the patient was given two boluses of 3% sodium chloride solution (50 ml/ hour) following which the total fluid rate (tfr) was reduced to 20 ml/hour of d10%ns for a rate of 1 ml/kg/hour. the osmolality and na+ concentration improved with fluid restriction [figure 1]. following fluid restriction, the patient developed polyuria and was managed with adjustment of the fluid rate. the plasma amino acid profile showed elevation of tyrosine at 319.8 µmol/l (normal range: 25–115 µmol/l). the succinylacetone assay was not done. the urine porphyria screen was positive with random porphyrin at 427 nmol/l and a urine porphyrin to creatinine ratio of 178 nmol/µmol (normal range: <35 nmol/ µmol) with detectable random porphobilinogen. the patient’s symptoms subsequently improved, sodium concentration normalised, and she was discharged table 1: biochemical profile and fluid management of a nine-year-old patient with hereditary tyrosinaemia type 1 over five days of admission at admission after 8 hours* after 12 hours after 16 hours after 24 hours after three days at discharge serum osmolality in mosmol/kg 236 239 246 267 275 283 na+ in meq/l 113 114 116 128 131 133 137 urine na+ in mmol/l 101 urine osmolality in mosmol/kg 284 213 type of iv fluid d10%ns 3% ns d10%ns + 3% nacl† d10%ns d10%ns d10%ns d10%ns rate of iv fluid‡ tfr 150%, 90 ml/hour two bolus 50 ml each tfr to 50%, 50 ml/hour tfr to 30%, 20 ml/hour tfr as 80%, 50 ml/hour tfr as 80%, 50 ml/hour tfr as 100% urine output 2.6 ml/kg/ hour 6.4 ml/kg/ hour 5.5 ml/kg/ hour 1.5 ml/kg/ hour na+ = sodium; d10% = dextrose 10%; ns = normal saline (0.9% nacl); iv = intravenous; tfr = total fluid rate. *second tonic-clonic seizure occure. †30 ml from d10%ns and 20 ml (1 ml/kg/hour) of 3% nacl. ‡calculated only for the d10%ns (patient’s weight was 20 kg ). abdulhamid al-hinai, fathiya al-murshedi, dana al-nabhani and khalid al-thihli after five days. over the past four years, the patient had not experienced a recurrence of seizures and hyponatraemia when adherent to therapy. however, her adherence with therapy was still suboptimum following discharge and she was admitted with another episode of symptomatic hyponatraemia a few months later. informed consent was obtained from the patient’s uncle (legal guardian) for the purpose of publication. discussion the neurogenic crisis in ht-1 has a wide spectrum of symptoms that include irritability, lethargy and pain crisis that may progress to cause autonomic instability (hyponatraemia and hypertension) and a guillain-barré syndrome-like presentation.9 the pathophysiology of the crisis was attributed to the direct toxic effect of delta 5-aminolevulinic acid and sa on the central nervous system.9 although siadh is a well-reported complication of the acute porphyria crisis, it is not known why only a fraction of patients with acute porphyria crisis develop siadh.8 this may in part reflect the limited understanding of the pathogenesis behind siadh in porphyria crisis, its multifactorial nature or the fact that it may truly be under-reported.10 questions have also been raised about whether some patients with acute intermittent porphyria were truly euvolaemic.11 the pathophysiology of hyponatraemia in acute porphyria, despite being frequently reported in as many as 40% of cases, is still not very well understood.12 while it has been attributed in some reports to the syndrome of inappropriate antidiuresis, there may also be elements of renal or gastrointestinal sodium loss.13 despite the number of patients with tyrosinaemia known worldwide and the likelihood of the existence of non-adherent older patients with complications and morbidities, to the best of the authors’ knowledge, siadh has not been reported among patients with tyrosinaemia type 1. although hyponatraemia was reported in a patient with tyrosinaemia in the past, sufficient data to ascertain whether this was attributed to siadh was not provided or explicitly discussed.7 more recent reviews and clinical guidelines about tyrosinaemia also do not mention or consider siadh as part of complications of this condition.1,2 however, it is of interest to note that tyrosinaemia type 1 has been considered in the diagnostic work-up of an adult patient who presented with siadh for the first time in adulthood.6 the current patient presented with severe symptomatic hyponatraemia and developed seizures as a complication. this indicates that it could be a potentially serious complication in any patient with tyrosinaemia admitted with acute crisis complicating non-adherence to therapy. hyponatraemia secondary to siadh in this patient was diagnosed based on the following criteria:4 (1) hypo-osmolality; (2) inappropriately concentrated urine (>100 mosm/ kg h2o, although usually higher than serum); (3) natriuresis >30 meq/l (depending on sodium intake); (4) reversal of renal sodium wasting and correction of hyponatraemia after water restriction; and (5) normal renal, adrenal, thyroid, cardiac and liver functions and no signs of volume depletion (e.g. absence of diuretic intake). the current patient met the diagnostic criteria of siadh; she was euvolaemic with the hyponatraemia being associated with low osmolality in combination with inappropriately concentrated urine (284 mosmol/ kg) and natriuresis (urine na+ >101 mmol/l). the renal function, thyroid function and cortisol were all within the normal range. this diagnosis was also supported by clinically improved sodium concentration after water restriction following failure of improvement with hypertonic saline (3%) boluses [table 1]. in retrospect, siadh was likely to have complicated the acute porphyria crisis. however, the authors speculate whether recurrent siadh could also be a neurological complication of poorly controlled tyrosinaemia type 1. if siadh is truly an figure 1: the course of sodium, serum osmolality and urine output during admission of a nine-year-old female patient with hereditary tyrosinaemia type 1. syndrome of inappropriate antidiuretic hormone secretion in a patient with uncontrolled tyrosinemia type 1 e314 | squ medical journal, may 2021, volume 21, issue 2 case report | e315 under-recognised or under-reported complication in patients with tyrosinaemia type 1, it may have significant therapeutic implications for such patients admitted with acute porphyria crisis. the management of these crises would typically include increased dextrose concentration delivered in dextrose water solutions at a level more than maintenance need. however, this practice may worsen hyponatremia due to siadh, even in the presence of normal saline added to the solution. in this regard, care should be taken when making a decision on the choice and rate of intravenous fluid administration. this is specifically true when hyponatraemia or borderline low sodium is encountered in patients with tyrosinaemia type 1 presenting with acute porphyria crisis. this would also need to be reflected in future revisions of practice guidelines. conclusion the authors report siadh in a patient with uncontrolled tyrosinaemia type 1. it is proposed that this diagnosis should be taken into consideration when making a decision regarding fluid management of patients admitted with acute crisis. references 1. chinsky jm, singh r, ficicioglu c, van karnebeek cd, grompe m, mitchell g, et al. diagnosis and treatment of tyrosinemia type i: a us and canadian consensus group review and recommendations. genet med 2017; 19. https://doi.org/10.1038/gim.2017.101. 2. de laet c, dionisi-vici c, leonard jv, mckiernan p, mitchell g, monti l, et al. recommendations for the management of tyrosi naemia type 1. orphanet j rare dis 2013; 8:1–9. https://doi. org/10.1186/1750-1172-8-8. 3. sassa s, kappas a. hereditary tyrosinemia and the heme biosynthetic pathway. profound inhibition of δ-aminolevulinic acid dehydratase activity by succinylacetone. j clin invest 1983; 71:625–34. https://doi.org/10.1172/jci110809. 4. yasir m, mechanic oj. syndrome of inappropriate antidiuretic hormone secretion. [updated 2021 mar 21]. in: statpearls [internet]. treasure island, usa: statpearls publishing, 2021. 5. decaux g, musch w. clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. clin j am soc nephrol 2008; 3:1175–84. https://doi.org/10.22 15/cjn.04431007. 6. bartter fc, schwartz wb. the syndrome of inappropriate secretion of antidiuretic hormone. am j med 1967; 42:790–806. https://doi.org/10.1016/0002-9343(67)90096-4. 7. nabin a, thapa lj, paudel r, rana pv. acute intermittent por phyria with siadh and fluctuating dysautonomia. kathmandu univ med j 2012; 10:96–9. https://doi.org/10.3126/kumj.v10i2.7354. 8. muraoka a, suehiro i, fujii m, murakami k. delta-amino levulinic acid dehydratase deficiency porphyria (adp) with syndrome of inappropriate secretion of antidiuretic hormone (siadh) in a 69-year-old woman. kobe j med sci 1995; 41:23–31. 9. yazıcı h, canda e, er e, kılınç ma, uçar sk, karapınar b, et al. tyrosinemia type i and reversible neurogenic crisis after a onemonth interruption of nitisinone. j pediatr res 2018; 5:57–9. https://doi.org/10.4274/jpr42275. 10. suarez ji, cohen ml, larkin j, kernich ca, hricik de, daroff rb. acute intermittent porphyria. clinicopathologic correlation: report of a case and review of the literature. neurol 1997; 48:1678–84. https://doi.org/10.1212/wnl.48.6.1678. 11. bloomer jr, berk pd, bonkowsky hl, stein ja, berlin ni, tschudy dp. blood volume and bilirubin production in acute intermittent porphyria. n engl j med 1971; 284:17–20. https:// doi.org/10.1056/nejm197101072840104. 12. yonatan edel, rivka mamet. porphyria: what is it and who should be evaluated? rambam maimonides med j 2018; 9:e0013. https://doi.org/10.5041/rmmj.10333. 13. anderson ke, bloomer jr, bonkovsky hl, kushner jp, pierach ca, pimstone nr, et al. recommendations for the diagnosis and treatment of the acute porphyrias. ann intern med 2005; 142:439–50. https://doi.org/10.7326/0003-4819-142-6-20050315000010. abdulhamid al-hinai, fathiya al-murshedi, dana al-nabhani and khalid al-thihli https://doi.org/10.1038/gim.2017.101 https://doi.org/10.1186/1750-1172-8-8 https://doi.org/10.1186/1750-1172-8-8 https://doi.org/10.1172/jci110809 https://doi.org/10.2215/cjn.04431007 https://doi.org/10.2215/cjn.04431007 https://doi.org/10.1016/0002-9343%2867%2990096-4 https://doi.org/10.3126/kumj.v10i2.7354 https://doi.org/10.4274/jpr42275 https://doi.org/10.1212/wnl.48.6.1678. https://doi.org/10.1056/nejm197101072840104 https://doi.org/10.1056/nejm197101072840104 https://doi.org/10.5041/rmmj.10333 v v 2008-issue1.indd sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 27-36 sultan qaboos university© submitted 2nd september 2007 accepted 14th january 2008 departments of 1medicine, 2family medicine and public health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3department of quality management, sultan qaboos university hospital, muscat, oman; 4department of information systems, college of commerce and economics, sultan qaboos university, muscat, oman *to whom correspondence should be addressed. email: ikram@squ.edu.om outcome as a measure of quality of care in oncology experience at sultan qaboos university hospital, oman ikram a burney,1 mansour s al moundhri,1 azhar j rizvi,1 shyam s ganguly,2 rashid al abri,3 rafi a ashra 4 abstract objectives: measurement of outcomes is increasingly employed as an indicator of the quality of clinical care. the most commonly measured outcome in many clinical studies, especially in oncology, still remains the overall survival rate. sultan qaboos university hospital (squh), oman, is striving for excellence through quality management. in seeking continual improvement, quality measurement exercises have been initiated throughout the hospital. we present the overall survival rate of four of the ten most common cancers diagnosed in oman. methods: the cancers included non-hodgkin’s lymphoma (nhl), hodgkin’s lymphoma (hl), breast cancer, and stomach cancer. the studies were all retrospective and had been conducted previously. for present purposes, only the overall survival was compared with studies both from the region, and with bench-mark studies. results: for nhl, with a median follow-up of 8 months, the 2-year overall survival rate was 64%; 90% for low risk, 55% for intermediate risk, and 5% for high risk groups. for hl, the 5-year overall survival rate was 64%; 76% for low risk and 42% for high risk. for breast cancer, the 5-year survival rate was 67%; percentages were 88%, 75% and 59% for groups i, ii, and iii respectively. for gastric cancer, the 5-year survival rate was 6.5 %; 24% for the non-metastatic group. conclusion: the outcome of patients with early stages and fewer adverse prognostic factors is comparable to what has been reported in the international literature; however, the outcome is inferior for patients presenting with advanced stage disease and several adverse prognostic factors. key words: oncology; outcome assessment; quality indicators; lymphoma, hodgkin’s; lymphoma, non-hodgkin; cancer, breast; cancer, gastric; oman. السرطان ملرضى جلودة الرعاية كقياس النتائج معطيات السلطان قابوس جامعة جتربة مستشفى رافي اشرفي و العبري راشد شيام جنجولي، أزهر رزفي، ، املنذري برني، منصور إكرام ــريرية الس ــات الدراس في ــا قياس النتائج وأكثر معطيات . الصحية الرعاية جلودة ــر كمؤش النتائج معطيات قياس تطبيق امللخص: الهدف: يتزايد من التميز إلى الوصول أجل من اجلهود كل قابوس السلطان جامعة ــفى مستش وتبذل . احلياة قيد البقاء على معدل هو ــرطان ملرضى الس خاصة البقاء على قيد نعرض هنا معدل أقسام املستشفى. كل في استعملنا مقاييس اجلودة اال هذا في التطوير استمرارية ولتحقيق . اجلودة إدارة خالل املشمولة السرطانية األمراض ــمل الطريقة: تش . عمان في انتشارا األكثر هي ــرطانية س ــرة أمراض عش مجموع من ــرطانية س ألربعة أمراض احلياة وللهدف ، سابقا أجريت االستعادية ــات الدراس هذه . املعدة ــرطان وس الثدي ــرطان وس الهودجكيِنية ومةُ فُ واللِمْ الالهودجكينيَّة ومةٌ فُ بالبحث: اللِمْ الالهودجكينيَّة ومةٌ فُ للِمْ : بالنسبة النتائج . املنطقة وخارج داخل من ــات دراس مع ــات الدراس لهذه احلياة قيد معدل البقاء على مبقارنة قمنا احلالي تِطارٌ املتوسط لالخْ %55 بالنسبة ، ض فِ ُنْخَ امل تِطار لالخْ ــبة %90 بالنس وكان ، 64% بقاء سنتني هو ملعدل ــهر أش ثمانية ملدة املتابعة ــيط كان وس 76% %64 ، حيث كان ــنوات س خمس ملدة احلياة قيد على ــاء البق معدل فكان الهودجكيِنية ــةُ وم فُ للِمْ ــبة أما بالنس . ــي العال ــار تِط و%15 لالخْ النســب: هو%67 وكانت ــنوات أيضا س خمس ملدة ــرطان الثدي كان معدل البقاء على قيد احلياة ولس . العالي تِطار %42 لالخْ و ض فِ ُنْخَ امل تِطار لالخْ %24 . اخلالصة: النقيلي غير ،% 16.5 املعدة خمس سنوات لسرطان ملدة معدل البقاء كان i, ii, , iii . وأخيرا ,%59 للمجموعات 75%, 88% من ذلك أدنى النتائج كانت ولكن ، العاملية لألدبيات مشابهة ، قليلة ضائِرة مآل عوامل مع املبكرة في املراحل مت تشخيصهم الذين املرضى نتائج كانت ضائِرة. عدة عوامل مآل هناك وكان مبكرا تشخيصهم يتم املرضى الذين لم عند عمان. سلطنة الثدي، سرطان املعدة، هودجكن، سرطان ال هودجكن، ملفومة ، اجلودة، مؤشرات النتائج، الكلمات: سرطان، تقييم مفتاح c l i n i c a l a n d b a s i c r e s e a r c h 28 i k r a m a b u r n e y, m a n s o u r s a l m o u n d h r i , a z h a r j r i z v i , s h ya m s g a n g u ly, r a s h i d a l a b r i a n d r a f i a a s h r a f i the need to measure the results of an intervention in medicine has been recognized for a long time. it has been argued that since hospitals work on the premise that patients should derive benefit from the medical care provided, the endresult of interventions should reflect in outcomes.1 it has also been suggested that if the hospitals provided the care, recorded it in a uniform manner, and then published it, comparisons could be made between the outcomes of different health care institutions.1-3 hence, measurement of outcomes is increasingly been employed not only in clinical practice, but also as an indicator of quality of clinical care.4 over the past few decades, scientific methods have been developed to measure the quality of medical care.5-7 more recently, it has been proposed that the quality of care should include dimensions of structure (facilities and organization), process (appropriateness, efficiency, cost-effectiveness) and outcome (mortality, adverse effect, early admissions).8, 9 since many perceive outcomes to be the ultimate validator of the effectiveness and quality of medical care, outcomes research is rapidly gaining attention. outcomes can be measured using several indicators, e.g. alleviation of symptoms and quality of life. however, the most commonly measured outcome in many clinical studies, especially in oncology, continues to remain the overall survival of the patient.10 sultan qaboos university hospital (squh), oman, is on the road to achieving excellence in quality, and has already received iso9001:2000 certification. in an effort to seek continual improvement, quality measurement exercises have been initiated through out the hospital. the section of medical oncology is an integral part of the department of medicine, and endeavors to promote teaching, research and clinical service in accordance with the vision and mission of the hospital. it receives newly diagnosed cancer cases both from within the hospital and referred cases from across the sultanate of oman. breast cancer, gastric cancer, non-hodgkin’s lymphoma (nhl) and hodgkin’s lymphoma (hl) are among the ten most common cancers diagnosed in oman 11 and a substantial number of cases are treated at squh. herein, we report the overall survival of these cancers treated at squh over the past few years, and compare the results with some bench-mark studies, with a view to using outcome quantified in terms of overall survival as a measure of quality of care. m e t h o d s the data on outcomes of nhl, hl, breast cancer, and gastric cancer were collected retrospectively as part of separate studies. the study on nhl aimed to review the clinical features, pathological sub-types (classified according to the recent who classification), response to treatment, disease free survival (dfs) and overall survival (os) of consecutive adult patients (> 14 years of age) diagnosed to have nhl between jan 2003 and dec 2004 and seen at the squh. similarly, the study on hl was aimed to review the clinical features, pathological sub-types, response to treatment, disease free survival (dfs) and overall survival (os) of consecutive adult patients (> 14 years of age) diagnosed to have hl between june 1999 and dec 2005. the study on breast cancer aimed to study clinico-pathological features and outcomes of treatment using patients treated between january 1996 and june 2002. details of the methods can be found elsewhere.12 similarly, the study on gastric cancer aimed to review the clinical features and outcomes of treatment of patients diagnosed between 1993 and 2004. the detailed methods of the study can be found elsewhere.13 a proportion of patients with breast and gastric cancers were diagnosed and treated at the other tertiary care hospital in oman. the staging for both breast and gastric carcinomas was carried out using the american joint committee on cancer tnm (tumour, node, metastasis) cancer staging manual.14 for all four cancer types, the data from the medical charts were extracted on to pre-designed questionnaires and transferred to spss (statistical package for the social sciences) for analyadvances in knowledge this is the first study from oman and one of the few from the region where the outcomes of cancer care, measured in terms of overall survival, have been used to assess the quality of hospital care provided. application to patient care clinical audits of this kind are very important to enhance the quality of care at institutions. 29 o u t c o m e a s a m e a s u r e o f q ua l i t y o f c a r e i n o n c o l o g y sis. survival curves were generated using the method of kaplan and meier.15 only the overall survival data are presented in this paper. details on the rest of the parameters is not within the scope of this paper, and can be found elsewhere.12, 13, 16, 17all retrospective studies were approved by the medical research and ethics committee of squh. r e s u l t s table 1 lists the 10 most common cancers diagnosed in the sultanate of oman during the year 2004. brief description of cancers, together with the overall survival results are presented below: n o n h o d gk i n ’ s ly mph om a over the study period of 2 years, a total of 46 new patients were diagnosed to have nhl. the characteristics are as follows: the median age was 53 (14-77) years; there were 27 males and 19 females. the histological sub-types were as follows: diffuse large b cell lymphoma (dlbcl) 31 (67%); anaplastic large cell lymphoma (alcl) 5 (11%); marginal zone cell lymphoma 3 (one each splenic, cutaneous and intestinal); t-cell acute lymphoblastic lymphoma 2; others 5. overall, 82% of the patients presented with an aggressive histological sub-type. nineteen patients presented with primary extra-nodal disease. thirty-one patients had a high lactate dehydrogenase (ldh). the performance status on the who/ecog (eastern cooperative oncology group) scale was as follows: 0:1:2:3:4 = 3:17:9:8:9. the who/ecog performance status is a grade on a five point scale (range 0 to 4) at the time of investigation in which ‘0’ denotes normal activity and ‘4’ a patient who is 100% bedridden. clinical stages were classified according to the ann-arbor staging system, the most popular system for classifying nhl, from stage 1, limited to one lymph node, to stage 4, extensive in one organ or site. six patients presented with stage i disease, 12 with stage ii, 6 with stage iii, and 22 with stage iv disease. patients with aggressive histological sub-types were uniformly treated with standard doxorubicinbased chemotherapy (chop/r-chop). patients with bulky initial disease, or with residual disease of more than 1 cm after 6-8 cycles of chemotherapy, were also treated with involved field radiation therapy (ifrt) of 36-40 gy. for aggressive lymphomas, the international prognostic index (ipi) score was calculated; 13 patients had 0-1 adverse prognostic factors (low risk = 28%), 7 had 2-3 adverse prognostic factors (intermediate risk = 15%), while 18 patients had 4-5 adverse prognostic factors (high risk = 39%). three patients were lost to follow up, and 16 patients had died at the time of analysis. with a median follow-up of 8 months, the 2-year survival for the entire cohort is 64% (figure 1a); 90% for the low risk, 55% for the intermediate risk, and 15% for the high risk groups (figure 1b). h o d gk i n ’ s ly mph om a over the study period of 6.5 years, a total of 40 adult patients were diagnosed to have hl. the median age was 37 years (range 14-76 years). there were 22 men and 18 women. 75% patients presented with b sympfigure 1a: overall survival (os) of patients treated for nhl. the top line indicates the os of patients diagnosed to have indolent lymphomas. the bottom line indicates os of patients with aggressive lymphomas. figure 1b: overall survival (os) of patients with aggressive nhl according to the international prognostic index. (top line: 0-1 adverse prognostic factors; middle line: 2-3 adverse prognostic factors; lower line: 4-5 adverse prognostic factors) 30 i k r a m a b u r n e y, m a n s o u r s a l m o u n d h r i , a z h a r j r i z v i , s h ya m s g a n g u ly, r a s h i d a l a b r i a n d r a f i a a s h r a f i toms, and nearly half of the patients presented with symptoms of more than 4 months duration. histological subtypes according to the real (revised european-american lymphoma) classification were as follows: nodular sclerosis 17; mixed cellularity 14; lymphocyte predominant 4; not otherwise specified 5. nineteen patients presented with early stage disease (ia-iib), whereas, 13 and 8 patients (total = 21, 52%) presented with stage iiib and ivb disease respectively. eighteen patients had mediastinal involvement; 3 presented with pulmonary parenchymal involvement, and 4 patients presented with primary infra-diaphragmatic disease. fifty percent of patients presented with a high ldh. two patients died before the treatment could be instituted. patients were treated according to the standard chemotherapy with abvd (adriamycin, bleomycin, vinblastine and dtic); copp/abv (cyclophosphamide, oncovin [vincristine], procarbazine, prednisolone/adriamycin [doxorubicin], bleomycin, vp-16[etoposide]); beacopp (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristin [oncovin], procarbazine, prednisone) and vepemb (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone and bleomycin) and with ifrt to the sites of initial bulky or residual disease. there were 38 complete and 2 partial responders. the 2-year overall survival rate was 64% (figure 2a). international prognostic factor score (ipfs) was applied, and the 2 year survival of patients with 0-2 adverse prognostic factors was 76% compared with 32% for those with 3 or more adverse prognostic factors (figure 2b). br e a st c a n c e r over the study period of 6 years, a total of 152 patients were treated for invasive breast cancer. the mean age was 48.5 (sd ± 10.8) years. forty eight percent of the female patients were pre-menopausal and 20.4 % were 40 years of age or younger. the average clinical and pathological sizes of breast tumours were 5.4 cm (sd ± 3.86) and 4.6 cm (sd ± 3.29) respectively. the majority of patients presented with advanced disease: stage iii = 53 (34.9%); stage iv = 24 (15.8%). the receptor status was available for 107 patients (68%) and of these 62 (58%) and 57 (53.3%) expressed estrogen and progesterone receptors respectively. the majority of patients (65.8%) underwent modified radical mastectomy. twenty patients (13.2%) received neo-adjuvant chemotherapy, which represents only 37.7% of 53 patients with locally advanced disease. adjuvant external beam radiotherapy to the breast area was administered to 96 patients (63.1%). during the study period, radiotherapy facilities were not available in oman; hence, radiotherapy was administered in various centres outside oman. with a mean follow-up interval of 35.6 months, there were 37 deaths and 6 patients were lost to follow up. the overall 5-year relapse free survival rate was 62%. the cumulative 5-year relapse free survival rates for stages i, ii, and iii were 87.5%, 71.6%, and 42.7% respectively (data not shown). the overall 5-year survival rate was 67%. the cumulative 5 year survival rate for stages i, ii, iii were 88%, 75%, figure 2a: overall survival (os) of patients treated for hodgkin’s lymphoma figure 2b: overall survival (os) of patients with advanced hodgkin’s lymphoma disease according to international prognostic factor score. the top line indicates os of patients with 0-2 adverse prognostic factors. the bottom line indicates os of patients with three or more adverse prognostic factors 31 o u t c o m e a s a m e a s u r e o f q ua l i t y o f c a r e i n o n c o l o g y and 59%, respectively [figure 3]. g a str i c c a r c i n om a over the study period, clinico-pathological data were available for 339 patients. there were 221 males and 118 females, with an overall mean age of 59.8 years (range: 14–90 years). the predominant tumour was an ulcerative, intestinal adenocarcinoma. at presentation, most of the tumours had deeply penetrated the stomach wall, with t3 and t4 lesions constituting respectively 55.7% and 14.3% of the cases. lymph node involvement was found in 75.9% of patients. advanced stage iii and iv constituted respectively 33.6% and 39.2% of all cases. two hundred and thirty seven patients (69.9%) were subjected to surgery, of which 158 (46.6%) had complete resections. sixty-two (26.2%) patients received additional systemic treatment in the form of neo-adjuvant chemotherapy, adjuvant chemotherapy or chemo-radiotherapy. the mean follow-up time for the entire cohort was 29.3 months (range: 3– 103 months). there were 256 deaths (75.5%), including 11 early post-operative deaths, while 72 patients (21.2%) remained alive. the median survival time for the entire cohort was 12.3 months (95 % ci 9.8–14.8) with a 5-year overall survival rate of 16.5 % [figure 4]. the median survival time for the non-metastatic group was 23.5 months (95 % ci 18.7–28.3) with a 5-year overall survival rate of 24.1 %. d i s c u s s i o n as outcomes research is a broad concept, there is no consensus on its precise definition. on the one hand, all results are outcomes; thus, all research is outcomes research.18 on the other hand, donabedian’s concept of quality includes outcome as a part of the “structure, process, and outcome” paradigm.8 the national library of medicine makes a distinction between health services research and outcome assessment.19 whereas health services research is usually concerned with relationships between need, demand, supply, use, and outcome of health services, outcome research is aimed at assessing the quality and effectiveness of health care as measured by the achievement of a planned end result, improved health, and lowered morbidity or mortality.20 outcome studies have gained attention in oncology literature over the past few years.1, 4, 21, 22 outcome continues to remain the ultimate validator of the effectiveness and quality of care offered to cancer patients.21-23 it is often hard to define and assess quality of care on the basis of main outcomes; frequently, surrogate end points are used to assess the quality of work in daily oncology practice.24 although surrogate outcomes of effectiveness are important and often can not be avoided, these may not be related to the main clinical outcomes. an example is tumour response to chemotherapy or radiotherapy, and the ultimate progression free survival or overall survival. for some cancers there is an association between response rates and survival, for others this relationship is either weak or does not exist. whereas some outcomes are generally unmistakable and easy to measure (death), others are not so clearly defined and can be difficult to measure, e.g. patient attitudes, satisfactions, physical disability etc.18, 22 survival and quality of life are considered the main patient outcomes in oncology practice.21-24 it has figure 3: overall survival (os) of patients treated for breast cancer figure 4: overall survival (os) of patients with gastric cancer 32 i k r a m a b u r n e y, m a n s o u r s a l m o u n d h r i , a z h a r j r i z v i , s h ya m s g a n g u ly, r a s h i d a l a b r i a n d r a f i a a s h r a f i long been suggested that all oncologists should review either their own work or the work in their departments using these two major outcomes.1 we chose to use survival as the measure of outcome. since our work was based on retrospective data, it was difficult to measure quality of life, especially when it was not recorded, or not recorded uniformly. the 2-year survival rate was 64% for patients with nhl. although 2 years is a relatively short period of follow up for aggressive nhl, and relapses continue to occur for further several years, our results at this stage are comparable to what has been reported in the literature.25-29 however, since nhl is a heterogeneous group of lymphomas, with a variable outcome, we sought to study the outcomes according to the risk groups described by ipi (international prognostic index).30 ipi describes 5 independent prognostic factors at presentation known to affect the outcome of aggressive nhl. these include old age, advanced stage, poor performance status, a high ldh, and multiple extra-nodal sites of involvement. analysis of overall survival into the risk categories reveal that, whereas the outcomes for low and intermediate risk is comparable (90% versus 85%, and 55% versus 50% respectively), the outcome for high risk is inferior (15% versus 35%).31 all patients were treated uniformly with anthracyclin based chemotherapy ± rituximab, and ifrt according to the institutional guidelines for patients with initial bulky disease. slow response was defined as less than partial remission after 4 cycles of chemotherapy; residual disease more than 1.5 cm; positive gallium scan after completion of chemotherapy in not more than 1 location. it is clear that the outcomes of patients with fewer risk factors were comparable to the reported figures. at the same time, the outcomes of patients with several risk factors were found to be inferior to the standards. there are several explanations. firstly, the sample size is small. out of a total of 38 patients with aggressive histology, 18 (39%) presented with 4-5 adverse prognostic features. second, it is well known that there are other important prognostic factors, not included in the ipi, which have recently been shown to have an adverse effect on the outcome, such as: bulky disease, lack of expression of bcl-6 protein, presence of cd10 antigen, bcl-2 antigen etc.32 of the high risk group of patients, more than 50% in our series presented with bulky disease, which is significantly higher than what has been reported in the literature. the pattern of expression of the pro-apoptotic and anti-apoptotic genes is currently not known in our group of patients, but the work is still in progress. third, 26% of the patients had co-existing hepatitis b or c virus antibodies. this is significantly higher than the control population in oman, and also significantly higher than what has been reported in the literature. the outcomes of hepatitis virus associated nhl has been reported to be inferior compared to those in which the viruses are not present.33 finally, an impaired immune status confers an inferior long-term disease free survival, and it is plausible that patients with higher percentages of advanced disease (61% versus 30-40%), or extra-nodal disease (48% versus 24-29%), may have an impaired immune status. a study to investigate this particular issue is underway at our institution. for patients with hl, the 5-year survival was 64%. the results are comparable to several reports from around the region.34-38 like nhl, the outcome of hl is variable and depends on several prognostic factors. ipfs describes 7 independent prognostic factors at presentation which are known to affect the outcome of classical hl.39 analysis of overall survival into the risk categories reveals that whereas the outcomes for patients with 0-2 adverse prognostic factors was comparable to the european data (76% versus 78%), 39 the outcome for patients with three or more adverse prognostic factors was inferior (42% versus 55%). like nhl, there are several explanations for this paradox. firstly, the small numbers mean that the difference is not statistically different. second, additional prognostic factors, not included in the ipfs may be present. for example, 70% of the patients in our series presented with b symptoms, compared to about 40% reported leukemia 84 non-hodgkin’s lymphoma 77 breast cancer 66 stomach cancer 49 thyroid cancer 44 lung cancer 36 cancer of the uterine cervix 33 brain tumours 30 hodgkin’s lymphoma 30 prostate cancer 29 table 1: most common cancers diagnosed in the sultanate of oman during 2004. the figures denote the actual number of cases. 33 o u t c o m e a s a m e a s u r e o f q ua l i t y o f c a r e i n o n c o l o g y in the european data which formed the basis for ifps. finally, important differences in the biological nature of the disease are known to exist in hl over different parts of the globe. incorporation of epstein-barr virus (ebv) and the presence of il-10 receptors polymorphisms have been shown to be additional independent prognostic factors, currently unknown in our group of patients.40 for patients with breast cancer, the 5-year survival rate was 67%. a breast cancer study from oman exemplifies the state of breast cancer presentation, care, and outcome in many developing countries.41-46 breast cancer in oman displays established poor prognostic features not only by presenting at a younger age with advanced stage and extensive lymph node involvement, but also with a poor differentiation grade and lack of estrogen and progesterone receptors expression.12 in this series, tumour size of more than 5 cm and tumour differentiation grade were strong predictors of overall survival. in contrast, axillary lymph node status, tumour size of more than 5 cm, and poor differentiation grade were predictors of relapse free survival. tumour size, lymph node involvement, differentiation grade, and estrogen receptor status were tested in multivariate cox’s regression analysis for their relationship with overall survival and relapse free survival. tumour differentiation and 4-9 lymph node involvement retained independent prognostic significance for disease free survival and overall survival respectively12. the survival outcome is worse than for counterparts in the west, but consistent with results from the region. the 5-year survival rate of 67% reported in our series compares favorably with 48% reported by gajalakshmi et al from india, the 10-year survival rate of 55% reported from the eastern province of saudi arabia and a 5-year survival of 68.8% from bahrain.41, 43, 44 there are several explanations. outcomes of breast cancers have been shown to be inferior in patients of lower socio-economic groups, and in under-privileged ethnic minorities.47, 48 for example, o’malley et al have shown the 10-year unadjusted survival rates of 81% for whites, 69% for blacks, 75% for hispanics, and 79% for asians. our results call for immediate steps to increase breast cancer awareness, and introduce breast cancer screening programs in developing countries.49, 50 more importantly, all patients should have easy access to tertiary referring units where multidisciplinary assessment is made on presentation.50 one of the aims should be more breast conserving surgery with greater utilization of neo-adjuvant chemotherapy. research areas exploring cultural, environmental, and genetic issues should be undertaken in an attempt to explain further the above clinical and pathological features.49, 50 for gastric cancer, the 5-year survival was 16%. this figure compares favorably with 5-year survival rates of 21% from jordan, and 15-20% worldwide.14, 53 gastric cancer study exemplifies the issues of presentation, management and prognosis in many developing countries51-55. it exhibits the clinico-pathological features seen in endemic areas where the majority of tumours are likely to be distal, ulcerative, and intestinal adenocarcinomas.56 the most important determinant of outcome is the tnm stage at presentation14. lymph node involvement and overall tnm stage are independent prognostic factors. extended surgical approach and adjuvant treatment may modify the survival outcome, but in the current cohort the advanced stages of most presentations appear to have lessened the survival prospects. this finding emphasises the need for detecting gastric cancer early, either by employing screening programmes or having a lower threshold for initiation of upper gastrointestinal endoscopy, especially for the elderly (who comprised the vast majority of our patients), whilst continuing to adopt the current surgical and medical interventions. whether outcomes research actually affects clinical practice remains open to discussion.57, 58 for example, randomized clinical trials have been shown to have little influence on patterns of care. similarly, consensus development conferences were found to have little effect on medical practice.57 on the other hand, there are examples suggesting the application of outcomes research in routine clinical practice.58 for example, algorithms for evaluation of thyroid nodules or abnormal pap smears, are common in clinical practice. similarly, efforts to assist patients with pancreatic cancers in clarifying their treatment preferences, especially with the use of current palliative chemotherapy, are increasingly been observed.58 at squh, the outcome results have already lead to a study of additional factors which may be responsible for the variable outcomes. although increasingly more research is being carried out using outcomes, there are certain limitations to using outcome as the measure of quality.4 most importantly, the differences in outcomes may reflect variations in the patient population, especially when survival outcomes from one group of patients are com34 i k r a m a b u r n e y, m a n s o u r s a l m o u n d h r i , a z h a r j r i z v i , s h ya m s g a n g u ly, r a s h i d a l a b r i a n d r a f i a a s h r a f i pared with another group, as important biological differences are known to occur, as may be the case here. secondly, measurements of outcome require time delays, and by the time data are available, changes are likely to have occurred either in the treatment of the disease, or in the organisations treating the disease.4 in case of nhl, the significant change in the initial management, has been the addition of rituximab to the combination chemotherapy, which has already been incorporated into the standard of care.59 similarly, adjuvant chemo-radiotherapy became the standard care for completely resected gastric cancers in the recent past, and this modality has been uniformly applied to all patients where it was indicated.60 finally, large sample size may be required to detect small differences in the outcomes, which may occur because of variations in care. c o n c l u s i o n our results suggest that the outcome of patients with early stages and fewer adverse prognostic factors is comparable to what has been reported in the international literature; however, the outcome is inferior for patients presenting with advanced stage disease and several adverse prognostic factors. studies to investigate the reasons for this dichotomy, including the study of additional adverse prognostic factors, are underway. however, because more patients present with advanced stage, bulky disease and in a state where the patients are moribund, with little hope of treatment let alone cure, this means that the necessity for mass education, awareness raising not only for patients, but also for primary health care providers, and surveillance and early detection should be strongly emphasised. a c k n ow l e d ge m e n t s we wish to thank all the physicians, nurses, technical and other staff involved in the care of patients involved in this report. we also acknowledge the grants from sultan qaboos university which supported some of the work presented in this report. r e f e r e n c e s 1. lee s, earle c, weeks j. outcomes research in oncology: history, conceptual framework, and trends in the literature. j natl cancer inst 2000; 92:195-204. 2. clancy cm, eisenberg jm. outcomes research: measure the end results of health care. science 1998; 282:245246. 3. agency for healthcare research and quality. outcomes research fact sheet: what is outcomes research? available at: http://www.ahrq.gov/clinic/outfact/htm. accessed aug 2007. 4. malin jl. moving from guidelines to quality measurement. asco educational book 2004. alexandria, virginia: american society of clinical oncology, 2004. 5. kritchevsky sb, simmons bp. continuous quality improvement: concepts and applications for physician care. jama 1991; 266:1817-1823. 6. brook rh, mcglynn ea, cleary pd. quality of care, part 2 measuring quality of care. n engl j med 1996; 335:966-970. 7. benbassat j, taragin m. what is adequate health care and how can quality of care be improved? int j health care qual assur 1998; 11:58-64. 8. donabedian a. the quality of care: how can it be managed? jama 1988: 260:1743-1748. 9. clifford pi, katsavdakis ka, lyle jl, fultz j, allen jg, graham p. how are you? further development of a generic quality of life outcome measure. j mental health 2002; 11:389-404. 10. fossa s, hjortdahl p. does the service at a large, oncologic out-patient clinic satisfy the patients’ perceived need? int j health care qual assur 1996; 9:24-29. 11. ministry of health oman. cancer incidence in oman 2004. muscat: ministry of health, 2004. 12. al-moundhri m, al-bahrani b, pervez i, ganguly ss, nirmala v, al-madhani a, et al. the outcome of treatment of breast cancer in a developing country-oman. breast 2004; 13:139-145. 13. al-moundhri ms, al-bahrani b, burney ia, nirmala v, al-madhani a, al mawaly k, et al. the prognostic determinants of gastric cancer treatment outcome in omani arab patients. oncology 2006; 70:90-96. 12. greene fl, page dl, fleming id, fritz ag, balch cm, haller dg, et al. ajcc cancer staging handbook. 6th ed. new york: springer, 2002 13. kaplan el, meier p. non-parametric estimation from incomplete observations. j am stat assoc 1958; 53:457481. 14. burney ia, ahmed s, rehman j, al kindi s, nirmala v, al moundhri ms. presentation of non-hodgkin’s lymphoma in oman: a prospective study from a single institute. ann oncol 2005; s5:342. 15. burney ia, ganguly ss, al kindy s, al moundhri ms. outcomes of hodgkin’s lymphoma in oman. ann oncol 2006; s9:212. 16. youngs mt, wingerson l. the 1996 medical outcomes and guidelines source book. new york: faulkner and gray inc, 1995. 17. national library of medicine. medical subject head35 o u t c o m e a s a m e a s u r e o f q ua l i t y o f c a r e i n o n c o l o g y ings. available from: http://www.nlm.nih.gov/mesh. accessed aug 2007. 18. association for health services research. definition of health services research. available from: http://www. ashr.org/hsproj/define.htm. accessed aug 2007. 19. american society of clinical oncology, committee: health series research (hsr): available from: http:// asco.infostreet.com/prof. accessed aug 2007. 20. lipscomb j, donaldson ms. outcomes research at the national cancer institute: measuring, understanding, and improving the outcomes of cancer care. clin ther 2003; 25: 699-712. 21. ayanian jz, chrischilles ea, fletcher rh, fouad mn, harrington dp, kahn kh, et al. understanding cancer treatment and outcomes: the cancer care outcomes research and surveillance consortium. j clin oncol. 2004; 22:2992-2996. 22. national cancer institute. applied research: outcomes research. available from: http://www-ccps.ims.nci.gov/ arb. accessed aug 2007. 23. k.n. naresh, s. advani, m. adde aziz z, banavali s, bhatia k, et al. report of an international network of cancer treatment and research workshop on nonhodgkin’s lymphoma in developing countries. blood cells mol dis 2004; 33:330-337. 24. baker h, al-jarallah m, manguno h, temmim l, madda jp, sinowatz f. clinical characteristics and pathological classification of non-hodgkin’s lymphoma in kuwait. results of a collaborative study with the international lymphoma study group (ilsg). leuk lymphoma 2004; 45:1865-1871. 25. shome dk, george sm, al-hilli f, satir aa. spectrum of malignant lymphomas in bahrain. leitmotif of a regional pattern. saudi med j 2004; 25:164-167. 26. aziz z, sana s, saeed s, akram m. applicability of international prognostic index in non hodgkin’s lymphoma in pakistan. j ayub med coll abbottabad. 2004; 16:15-20. 27. lashari i, memon s, siddique u, gareeb m, islam m, burney ia. outcomes of non-hodgkin’s lymphoma in pakistan: use of international prognostic index. j pak med assoc 2002; 52:23-24. 28. the international non-hodgkin’s lymphoma prognostic factors project. a predictive model for aggressive non-hodgkin’s lymphoma: n eng j med 1993; 329:987994. 29. armitage jo, weisenburger dd. new approach to classifying non-hodgkin’s lymphomas: clinical features of the major histologic subtypes. non-hodgkin’s lymphoma classification project. j clin oncol 1998; 16:27802795. 30. sehn lh. optimal use of prognostic factors in nonhodgkin’s lymphoma. american society of hematology education program book. 2006. p. 295-302. 31. matsuo k, kusano a, suguma a, nakamura s, tajima k, mueller ne. effect of hepatitis c virus infection on the risk of non-hodgkin’s lymphoma: a meta-analysis of the epidemiological studies. cancer sci 2004; 95:745752. 32. al-masri nm. hodgkin’s lymphoma in north jordan. does it have a different pattern? saudi med j 2004; 25:1917-1921. 33. iraj ak. hodgkin’s disease: assessment of treatment and survival rates in iran. asia pacific j cancer prev 2004; 5:397-382. 34. burney ia, rashid s, salam a, siddiqui t. does prognostic score apply to pakistani patients with hodgkin’s disease? ann oncol 2002; 13:123. 35. al diab ai, siddiqui n, sogiawalla ff, fawzy em. the changing trends of adult hodgkin’s disease in saudi arabia. saudi med j 2003; 24:617-622. 36. glaser sl, hsu jl. hodgkin’s disease in asians: incidence, patterns and risk factors in population based data. leukemia res 2002; 26:261-269. 37. hasenclever d, diehl v. a prognostic score for advanced hodgkin’s disease. n eng j med 1998; 339:1506-1514. 38. casasnovas r.-o, mounier n, brice p, divine m, morschhauser f, gabarre j, et al . plasma cytokine and soluble receptor signature predicts outcome of patients with classical hodgkin’s lymphoma. a study from the groupe d’etude des lymphomes de l’adulte. j clin oncol 2007; 25:1732-1740. 39. gajalakshmi ck, shanta v, swaminathan r, sankaranarayanan r, black rj. a population-based survival study on female breast cancer in madras, india. br j cancer 1997; 75:771-775. 40. malik ia. clinico-pathological features of breast cancer in pakistan. j pak med assoc 2002; 52:100-104. 41. ibrahim em, al-mulhim fa al-amri a, al-muhanna fa, ezzat aa, stuart rk, et al. breast cancer in the eastern province of saudi arabia. med oncol 1998; 15:241247. 42. fakhro ae, fateha be, al-asheeri n, al-ekri sa. breast cancer. patient characteristics and survival analysis at salmaniya medical complex, bahrain. east mediterr health j 1999; 5:430-439. 43. ezzat aa, ibrahim em, raja ma, al-sobhi s, rostom a, stuart rk. locally advanced breast cancer in saudi arabia: high frequency of stage iii in a young population. med oncol 1999; 16:95-103. 44. ikpatt of, kuopio t, collan y. proliferation in african breast cancer. biology and prognostication in nigerian breast cancer material. mod pathol 2002; 15:783-789. 45. o’malley cd, le gm, glaser sl, shema sj, west dw. socioeconomic status and breast carcinoma survival 36 i k r a m a b u r n e y, m a n s o u r s a l m o u n d h r i , a z h a r j r i z v i , s h ya m s g a n g u ly, r a s h i d a l a b r i a n d r a f i a a s h r a f i in four racial/ethnic groups: a population-based study. cancer 2003; 97:1303-1311. 46. chu kc, lamar ca, freeman hp. racial disparities in breast carcinoma survival rates. separating factors that affect diagnosis from factors that affect treatment. cancer 2003; 97:2853-2860. 47. sandelin k, apffelstaedt jp, abdullah h, murray em. ajuluchuku eu. breast surgery international breast cancer in developing countries. scand j surg 2002; 91:222-226. 48. anderson bo, braun s, carlson rw, gralow jr, lagios md, lehman c, et al. overview of breast health care guidelines for countries with limited resources. breast j 2003; 9:s42-s50. 49. oluwasola ao, ogunbiyi jo. gastric cancer: aetiological, clinicopathological and management patterns in nigeria. niger j med 2003; 12:177-186. 50. hassan ha, sharma vk, raufman jp. changing trends in gastric carcinoma at a university medical center: a twelve-year retrospective analysis. j clin gastroenterol 2001; 32:37-40. 51. bani-hani ke, yaghan rj, heis ha, shatnawi nj, matalka ii, bani-hani am, et al. gastric malignancies in northern jordan with special emphasis on descriptive epidemiology. world j gastroenterol 2004; 10:21742178. 52. kandasami p, tan wj, norain k. gastric cancer in malaysia: the need for early diagnosis. med j malaysia 2003; 58:758-762. 53. koong hn, chan hs, nambiar r, et al. gastric cancers in singapore: poor prognosis arising from late presentation. aust nz j surg 1996; 66:813-815. 54. stemmermann gn, fenoglio-preiser c. gastric carcinoma distal to the cardia: a review of the epidemiological pathology of the precursors to a preventable cancer. pathology 2002; 34:494-503. 55. kosecoff j, kanouse de, rogers wh, mccloskey l, winslow cm, brook rh. effects of national institute of health consensus development program on physicians practice. jama 1998; 279:1638-1642. 56. weeks jc. outcomes assessment in the nccn. oncology 1997; 11:137-140. 57. macdonald js, smalley sr, benedetti j hundahl sa, estes nc, stemmermann gn, et al. chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. n eng j med 2001; 345:725-730. 58. coiffier b, lepage e, briere j, herbrecht r, tilly h, bouabdallah r, et al. chop chemotherapy plus rituximab compared with chop alone in elderly patients with diffuse large-b-cell lymphoma. n eng j med 2002; 346:235-242. management of diabetes insipidus following surgery for pituitary and suprasellar tumours *mussa h. almalki,1,2 maswood m. ahmad,1 imad brema,1 mohammed almehthel,1,3 khaled m aldahmani,4,5 moeber mahzari,2,6 salem a beshyah7,8 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 354–364, epub. 29 aug 21 submitted 2 jun 20 revision req. 22 jul 20; revision recd. 14 aug 20 accepted 9 aug 20 1obesity, endocrine and metabolism centre, king fahad medical city, riyadh, saudi arabia; 2faculty of medicine, king saud bin abdul aziz university of health sciences, riyadh, saudi arabia; 3division of endocrinology, university of british columbia, vancouver, canada; 4division of endocrinology, tawam hospital, al ain, united arab emirates; 5department of medicine, united arab emirates university, al ain, united arab emirates; 6department of medicine, ministry of national guard health affair, riyadh, saudi arabia; 7department of medicine, dubai medical college, dubai, united arab emirates; 8department of endocrinology, mediclinic airport road, abu dhabi, united arab emirates *corresponding author’s e-mail: m2malki@yahoo.com pituitary adenomas are the third most common intracranial neoplasm which accounts for 10–15% of all diagnosed intracranial tumours and are frequently treated with transsphenoidal surgery (tss), except prolactinomas.1 neurosurgical operations for pituitary and suprasellar tumours may result in postoperative complications due to the crucial anatomical location of these tumours. the resulting postoperative complications can manifest as anterior or posterior pituitary dysfunction, particularly sodium disturbances, due to the changes in antidiuretic hormone (adh) secretion, which remains one of the most frequent postoperative reasons for hospital readmission.2 the patterns of water and electrolyte disorders after tss can be divided into either polyuria or oliguria/hyponatremia, depending on the presence of either low or high levels of adh, respectively.2 some disturbances of water and electrolytes may not reach the level of clinically defined central diabetes insipidus (cdi) or syndrome of inappropriate antidiuretic hormone (siadh). however, they may still require acute or chronic management and are generally divided into six profiles of polyuria or hyponatremia as follows: transient or sustained polyuria, immediate or delayed hyponatremia and biphasic or triphasic diabetes insipidus (di).2,3 cdi manifests as the excretion of large amounts of dilute urine that frequently occurs in the acute phase following surgery for pituitary adenomas, subarachnoid haemorrhage or traumatic brain injury. nonetheless, it occurs rarely in association with large pituitary adenomas before surgical interventions. its occurrence in this setting should question this diagnosis and point towards other diagnoses such as craniopharyngioma or granulomatous diseases.4 serum sodium and osmolality levels are generally maintained within a very narrow range (within 1–2%) despite marked variations in water and salt intake and this is controlled by two mechanisms, namely arginine vasopressin (avp) and thirst. the development of cdi after tss for pituitary adenoma is common, but it is usually transient. most patients who have free access to fluids and have intact thirst mechanisms can maintain normal serum sodium and normal fluid balance, as well as avoid dehydration and hypernatremia that usually result from the development of a significant water deficit. hence, it is exceptionally vital to freq uently monitor the urine output, serum sodium and daily fluid balance in all neurosurgical patients following tss. when patients have impaired levels of consciousness due to various factors, such as sedation, or if the thirst mechanism is impaired, for example in the rare subtype of adipsic di, they can develop significant water deficit and severe hypernatremia.5,6 the measurement of copeptin as a surrogate marker for avp in the diagnostic workup of the three main causes of polyuria (i.e. cdi, nephrogenic review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.010 abstract: central diabetes insipidus (cdi) is a common complication after pituitary surgery. however, it is most frequently transient. it is defined by the excretion of an abnormally large volume of dilute urine with increasing serum osmolality. the reported incidence of cdi after pituitary surgery ranges from 0–90%. large tumour size, gross total resection and intraoperative cerebrospinal fluid leak usually pose an increased risk of cdi as observed with craniopharyngioma and rathke’s cleft cysts. cdi can be associated with high morbidity and mortality if not promptly recognised and treated on time. it is also essential to rule out other causes of postoperative polyuria to avoid unnecessary pharmacotherapy and iatrogenic hyponatremia. once the diagnosis of cdi is established, close monitoring is required to evaluate the response to treatment and to determine whether the cdi is transient or permanent. this review outlines the evaluation and management of patients with cdi following pituitary and suprasellar tumour surgery to help recognise the diagnosis, consider the differential diagnosis, initiate therapeutic interventions and guide monitoring and long-term management. keywords: central diabetes insipidus; polydipsia; polyuria; pituitary adenoma; preoperative risk factor; pituitary surgery; arginine vasopressin; desmopressin; treatment. https://creativecommons.org/licenses/by-nd/4.0/ mussa h. almalki, maswood m. ahmad, imad brema, mohammed almehthel, khaled m aldahmani, moeber mahzari and salem a beshyah review | 355 di and primary polydipsia) has revolutionised the management approach of the patients with these suspected conditions, given its stable assays, high diagnostic accuracy and high specificity.7–10 due to a paucity of studies comparing different treatment and monitoring strategies for acute cdi following transsphenoidal pituitary surgery, there is a general lack of clear guidelines based on grades of evidence for acute di following tss management. nonetheless, there have been increasing adverse events, including death, which have been highlighted in recent years for the patients with established cdi, mainly due to a lack of knowledge among health professionals dealing with this condition.11 hence, there is a need to update the knowledge highlighting all the pitfalls that can lead to adverse patient outcomes. the rationale for this review article is to present updated information regarding the frequency, predictors of occurrence, clinical presentation and diagnostic workup, including the role of measurement of copeptin, which fills an important gap that exists regarding the limitation of water deprivation test in differentiating between cdi and primary polydipsia. the therapeutic interventions for cdi will also be reviewed, including those used for treating the rare and serious subtype of adipsic di, as well as the prognosis of cdi following tss. e p i d e m i o l o g y cdi is a significant complication following pituitary surgery which has been reported in the medical literature. transient diabetes insipidus (tdi) has been reported in 1.6–45.6% of the patients after pituitary surgery with a transnasal microsurgical approach and in 2.5–26% of those who had surgery with the transnasal endoscopic approach.6,21 permanent diabetes insipidus (pdi) is less common and has been reported in 0–10% of patients following the microsurgical approach and in 0–12.5% of patients following the endoscopic approach.12,13 the evidence is inconsistent regarding whether endoscopic tss is associated with a lower incidence of di in comparison to microscopic tss, with some studies showing a lower incidence while others do not.13–15 one study investigated the di following transcranial pituitary surgery and found the incidence of tdi and pdi to be 21.1% and 12.2%, respectively.16 cdi is more common after craniopharyngioma surgery and has been reported in up to 90% of the patients.17 additionally, di occurs in the acute phase of traumatic brain injury (tbi) in approximately 3% and 26% of cases and 15% of cases of subarachnoid haemorrhage (sah).18,19 cdi in the vast majority of cases of tbi and sah is transient. persistent cdi in the setting of tbi and sah is usually a late manifestation of severely raised intracranial pressure and, in this context, has a considerably grave prognosis.18–20 p r e d i c t o r s early detection of cdi can be meaningful to patient care and outcomes following pituitary surgery. di after pituitary surgery is reported to be associated with 3.9-fold increase in patients’ mortality.21 therefore, risk factors for cdi following pituitary surgery have been explored in several studies. the factors that may predict both transient and permanent di include craniopharyngioma, rathke’s cleft cysts, larger tumour size, low postoperative copeptin levels and intraoperative cerebrospinal fluid (csf) leak. other factors that have been shown to predict only tdi include acth-producing adenoma, visual abnormalities on presentation, suprasellar tumour extension, gross total resection, postoperative csf leak and first postoperative serum sodium of >145 mmol/l. in contrast, predictors of pdi only include younger age and reoperation, the former likely due to large tumour mass, while the latter due to possible injury to the neurohypophysis and/ or stalk traction.2,8,22–25 after the transcranial pituitary surgery, the degree of deformation of the third ventricle and hypothalamus as assessed by preoperative magnetic resonance imaging and postoperative haemorrhage was associated with both transient and permanent di.17 presentation and diagnosis c l i n i c a l p r e s e n tat i o n cdi should be considered when a patient excretes large volumes of diluted urine after surgery, typically ranging in 3.5–16.8 l per day, in the presence of high or normal serum sodium and osmolality.26 the onset of polyuria is usually abrupt and occurs within the first 12–24 hours after surgery.27 however, later presentation (two weeks to three months after surgery) has been reported in patients with rathke’s cleft cyst.28 the pathophysiology of this is not well understood but it has been suggested to be resulting from the release of cyst contents, causing inflammation to the infundibulum.29 polyuria is the hallmark of cdi. however, not all patients with polyuria after pituitary surgery have cdi, as polyuria could result from the reactive postoperative diuresis in patients who received excess amounts of intravenous fluids during surgery. it is also essential to rule out other common causes of polyuria such as hyperglycaemia and diuretics use before labelling a patient with cdi. the classic triphasic water dysregulation is rare and occurs in approximately 1.1–3.4% of postoperative patients where transient di, a polyuric phase occurring due to the abrupt cessation of avp release as a result of the temporary hypothalamic dysfunction, is followed by the second management of diabetes insipidus following surgery for pituitary and suprasellar tumours 356 | squ medical journal, august 2021, volume 21, issue 3 phase that resembles siadh, which is caused by the sudden release of avp from the degenerating pituitary. finally, depletion of avp stores leads to permanent cdi.30,31 the onset of polyuria is usually abrupt and occurs within the first 12–24 hours after surgery. the initial transient phase of di happens within 1–3 days after surgery and typically lasts for 5–7 days. the second phase ensues 7–8 days postoperatively and can last 2–14 days if there is no recovery of antidiuretic hormone (adh)-secreting neurons. the third phase occurs when di reappears as a result of depletion of adh stores.32–35 patients with di typically complain of persistent excessive thirst and drink to compensate for the water loss to maintain serum sodium within the normal range. however, patients with limited access to water, impaired consciousness level or impaired thirst sensation may rapidly develop signs of dehydration on physical examination in addition to hypernatremia (serum sodium >145 mmol/l) if free water loss is not replaced.36,37 d i a g n o s t i c w o r k u p the diagnosis of cdi postoperatively begins with the risk assessment using preand intra-operative predictive factors before the patient is transferred from the operation room. excessive thirst and polyuria are the clinical features that typically trigger an evaluation for cdi.38 hence, careful documentation of hourly fluid intake and urine output is essential for the early identification of cdi. it is crucial to note that polyuria may not always be due to di; as seen in cases of mobilisation of intraoperative fluids and hyperglycaemia, it can also be due to a sharp drop of growth hormone level post acromegaly surgery and the use of certain medications such as furosemide or sglt2 inhibitors.39 therefore, documentation of hypotonic polyuria is essential in establishing the diagnosis of di. seckel and dunger criteria to diagnose cdi rely on the presence of hypotonic polyuria (urine osmolality <300 mosmol/kg and urine output more than 2 ml/kg/h) in addition to increased serum osmolality (>300 mosmol/kg) after excluding other causes of polyuria, such as glucosuria.40 in adult patients in particular, urine output of more than 250 ml per hour for two consecutive hours when supplemented with the presence of normal or high serum sodium, normal or high serum osmolality with a urine osmolality of less than 300 mosmol/ kg is highly suggestive of di.41 urine specific gravity is easily assessed at the bedside and could provide a figure 1: post-pituitary-surgery evaluation (risk-based assessment). di = diabetes insipidus; u = urine; s = serum; ddavp = desmopressin; loc = level of consciousness; prn = as needed. di risk: low = no risk factors; high = any di postoperative or intraoperative risk factors. mussa h. almalki, maswood m. ahmad, imad brema, mohammed almehthel, khaled m aldahmani, moeber mahzari and salem a beshyah review | 357 quicker evaluation of urine tonicity, with a value less than 1.005 suggesting low urine osmolality.42 however, despite the availability of these tools, the diagnosis of post-pituitary-surgery cdi could be a challenge due to several factors. first, there is a lack of universal diagnostic criteria for di and enormous variability in the monitoring of patients following pituitary surgery. moreover, the current diagnostic criteria may not apply to patients who are able to consume water and self-manage cdi, especially if the di is partial. furthermore, thin adults could have di, but their urine output is <200 ml/h, which may delay the diagnosis. for such patients, using weightbased criteria to define polyuria (urine output of >2 ml/kg/h or >50 ml/kg/day) would be more accurate. additionally, the frequency of monitoring electrolytes is highly variable among physicians.43 therefore, frequent assessment of electrolytes and osmolality in patients with a decreased level of consciousness or impaired thirst sensation is necessary for early detection of cdi. the difficulty in diagnosing cdi, particularly in the immediate postoperative period, has led to the exploration of other ways to diagnose cdi.44 plasma avp measurement has been explored; however, it could be challenging as its half-life is short (16 minutes) and the avp is usually unstable in collected plasma samples and is affected by many factors leading to its inaccurate level.45–47 moreover, avp measurement with elisa is not usually feasible due to the small size of avp.48 furthermore, avp measurement, usually done by rapid acting insulin and requires a relatively large sample volume, is not available in a timely manner to diagnose di as it requires a relatively long time and specialised labs to process it. for these reasons, avp measurement is rarely useful in the diagnosis of postoperative di. on the other hand, copeptin is the c-terminal peptide of pro-vasopressin, co-secreted with avp in an iso-osmolar manner, and reflects avp level accurately. unlike avp, copeptin measurement is less cumbersome as it remains stable in collected plasma samples for days and its measurement is associated with less preanalytical errors.49,50 it is highly accurate in identifying the aetiology of polyuria in the nonacute setting.51 however, its utility in the postpituitary-surgery setting has been evaluated in only a few studies. a multicentre study, 50 out of 205 patients who developed cdi revealed that a copeptin level of <2.5 pmol/l is accurate in establishing the diagnosis of cdi with a specificity of 97% and positive predictive value of 81% when measured within 24 hours of surgery.52 in contrast, a value of >30 pmol/l almost excluded the diagnosis with a negative predictive value table 1: biochemical parameters in patients with post operative diabetes insipidus parameter description fluid balance variable, usually negative (more output than input) urine output at least >2 ml/kg/h for two consecutive hours in addition to other parameters serum osmolality normal, if the patient has free access to water, or high, >300 mosmol/kg, if the patient has limited access to water serum sodium normal, if the patient has free access to water, or high, >145 mmol/l, if the patient has limited access to water urine osmolality persistently <300 mosmol/l urine specific gravity persistently <1.005 copeptin <2.5 pmol/l table 2: general management strategies for a patient with diabetes insipidus immediate postoperative period • assessment of volume and hydration status; measurement of serum sodium • close monitoring of serum sodium and urine output • optimisation of fluid replacement • consideration of desmopressin therapy in a patient with excessive and inappropriately dilute urine output • titration of desmopressin dose to keep 24-hour urine output above the normal range (15–30 ml/kg/day) after hospital discharge • limiting fluid intake to the amounts required to satisfy thirst • performing electrolyte panel checks in any unwell patient after hospital discharge; close postoperative follow-up • monitoring for water intoxication and hyponatremia • delaying a dose of desmopressin once or twice per week to allow an aquaresis to occur • regular counselling of patient and their family about the principle of the treatment regime table 3: management of hypodipsia/adipsia with central diabetes insipidus • set a target (kg) at the weight the patient is known to be euvolemic and normonatremic • fix 24-hour urine output at 1.5–2 l • determine the obligate fluid intake (approximately 1.5 l) • measure weight daily • daily water intake = obligate volume + (target weight – daily weight) • check plasma sodium weekly • educate patients and their family about the principle of the treatment regime management of diabetes insipidus following surgery for pituitary and suprasellar tumours 358 | squ medical journal, august 2021, volume 21, issue 3 (npv) of 95%. the performance of the test was better when performed <12 hours after surgery with lower accuracy beyond 24 hours. similarly, the test proved superior in predicting persistent rather than transient di (68% versus 32%). another study of eight out of 58 patients with cdi with a standardised copeptin testing time showed that a peak copeptin level of <12.8 pmol/l at 60 minutes post-extubation predicted cdi, while permanent cdi was excluded with 100% npv in those with a level of >4.2 pmol/l.53 interestingly, there was no significant difference in the copeptin level between the two groups in the subsequent post-extubation assessments at 6–48 hours. copeptin is a promising marker that will likely be a routine diagnostic test in the evaluation of cdi in the future. however, presently, the limited number of studies about copeptin use, the uncertainty about the optimal time of its measurement after surgery and the limited availability of the assay are factors limiting its widespread use. table 1 summarises the various parameters that are frequently needed to be evaluated in post-pituitary-surgery patients and the expected changes in these parameters in patients with postoperative di. a risk-based algorithm is proposed on the frequency of laboratory investigation to identify di in the postoperative period [figure 1]. t r e at m e n t although adh secretion impairment and the disturbance of fluid balance often begin during the intraoperative period, cdi usually presents within a few hours after surgery. it is imperative to rule out intraoperative fluid overload and glycosuria as potential causes of polyuria. it is also noteworthy that patients with acromegaly may experience increased urinary output following the resection of their pituitary mass due to diuresis of excess fluid within the soft tissues.54,55 furthermore, approximately 50% and 80% of patients with transient di recover within seven and 90 days of surgery, respectively.56 as such, patients are advised to monitor for the cessation of thirst sensation and resolution of polyuria as potential signs of di recovery. moreover, periodic monitoring of electrolytes can be useful to confirm di recovery, as water deprivation tests are not routinely recommended in this situation.57 an additional advice is to delay desmopressin (ddavp) dose for a few hours to see if increased thirst and polyuria persist.57 patients require continuous monitoring of fluid intake and urine output and frequent assessment of electrolyte. ddavp should be used cautiously as required, especially during the first two weeks postoperatively to avoid hyponatremia due to overreplacement.31 treatment of postoperative cdi is multifaceted and can be divided into acute or chronic phases, depending on the stage of the disease, to restore osmotic equilibrium. although specific guidelines related to the management of postoperative di are unavailable, in the recent past, a disease state review, followed by guidelines on hypopituitarism, was published, offering some guidance to the clinical management.42,58 the general strategies of management of cdi are presented in table 2. the acute phase management covers the first two phases of the triphasic water dysregulation phenomenon. acute management of central diabetes insipidus f r e e wat e r a c c e s s the management is straightforward, provided there is an intact thirst mechanism, i.e. the patient is not receiving fluids for any reason and can drink water at will. water balance can be achieved under such a situation as long as the patient can consume enough fluids.59,60 patients with a decreased level of consciousness and impaired thirst mechanisms or those on intravenous (iv) fluids will require continuous adjustment of iv fluids and pharmacotherapy to maintain adequate hydration and sodium equilibrium. the appearance of hypernatremia and polyuria along with dehydration heralds the onset of cdi. it should be aggressively sought out during the immediate postoperative period as hypernatremia can cause brain shrinkage, leading to vascular rupture and intracranial bleeding, along with other complications.61 the serum sodium level can be normalised safely at a correction rate of 1 meq/l/h without any untoward complications.62,63 hypotonic fluids should be used when intravenous fluids are mandated. the least amount of fluid possible should be used and rapid overcorrection must be avoided as it can lead to cerebral edema.63 va s o p r e s s i n vasopressin is available as an aqueous solution. due to its short half-life of around 20 minutes, it should be administered through iv infusion when acute control of antidiuresis is needed.64 infusion is usually started at a rate of 0.25–1.0 micro unit/kg/h and titrated every half hour after that to maintain the urine output rate at around 100 ml/h and/or urine specific gravity at around 1.010–1.020. d e s m o p r e s s i n ddavp (1-deamino-8-d-arginine vasopressin) is a synthetic analogue of vasopressin, having a prolonged mussa h. almalki, maswood m. ahmad, imad brema, mohammed almehthel, khaled m aldahmani, moeber mahzari and salem a beshyah review | 359 action profile with minimal vasopressor activity. it can be administered orally, intranasally, subcutaneously or intravenously.65 studies have shown a definite relationship between the magnitude and duration of its therapeutic effect and its iv dosage. in patients with cdi, 1 µg iv ‘push’ infusion can increase urine osmolality to a maximum of 700–800 mosmol/ kg.66,67 further increase in dose, from 1 to 8 µg led to prolongation of the duration of action from around 26 hours to 46 hours. the magnitude and duration of its therapeutic effects showed large interindividual variability attributed to individual differences in renal concentration abilities, as it persisted even when the dose was increased to more than 2 µg.67–70 further studies have shown that the antidiuretic efficacy depends on the total dose as well as the rate of increase in plasma ddavp level.71 the human kidney loses concentrating capacity in the absence of vasopressin. therefore, once treatment is initiated, it requires at least eight hours of continued therapy for full recovery.72 according to several studies, the parenteral ddavp can be administered safely to acutely ill patients with cdi. however, the needed dose depends on the individual response, intactness of thirst mechanism and other factors determining fluid intake. in patients with intact thirst mechanisms, a starting dose of 0.25–0.50 µg twice daily as an iv infusion over two hours is usually administered, which is adjusted further to normalise urine output and maintain sodium equilibrium. a smaller dose of 0.06–0.125 µg is usually preferred with further titration to the desired effects for patients who are unable to drink at will or are on iv fluids. although hyponatremia can be a manifestation of excessive ddavp administration, the second phase of the triphasic water dysregulation phenomenon also presents with hyponatremia. both of these have the same underlying mechanism and management principles that require withholding ddavp along with careful electrolyte and fluid balance monitoring. c h r o n i c m a n a g e m e n t o f c e n t r a l d i a b e t e s i n s i p i d u s since cdi rarely remits once established, it requires continuous, complete and around-the-clock manage ment of the polyuria and maintenance of sodium and water equilibrium. hypernatremia rarely goes unnoticed as it is always associated with polyuria and dehydration. management principles of hypernatremia are same as mentioned above; however, in case the duration of hypernatremia cannot be ascertained, the serum sodium level should be corrected at a rate of 0.5 meq/ l/h, with no more than an 8–10 meq/l decrease over 24 hours, while keeping the target sodium level at 145 meq/l.61,63,73 minimising the risk of hyponatremia due to excessive water retention is another critical challenge as it can be occasionally symptomatic and, rarely, lifethreatening. excessive fluid consumption suppresses vasopressin secretion in normal subjects by nonosmotic mechanisms, leading to diuresis and thus preventing over-hydration.74,75 this ‘escape’ mechanism is not possible in patients with cdi as they are on exogenous long-acting desmopressin. consequently, dilutional hyponatremia occurs. a longer-acting form of antidiuretic therapy and limiting fluid intake to the amounts required to satisfy thirst are the possible ways to achieve this goal. titration of antidiuretic dose to keep 24 hours urine output within the normal range (15–30 ml/kg/day) is equally important.76 d e s m o p r e s s i n – n a s a l s p r ay intranasal ddavp has an absorption ratio of around 10–20% when compared to iv preparation in patients with cdi.77 moreover, it has interindividual and intraindividual variability in the magnitude and duration of its antidiuretic effect. the variability is irrespective of age, severity of polyuria or body weight,78,79 leading to the duration of action ranging from 4–18 hours to 8–24 hours seen with 5–10 and 20 µg, respectively.69,80,81 the intranasal preparation is useful as it allows individualisation of treatment and dose titration by metered-dose spray (2.5–10 µg per spray). one must note that the absorption of nasal ddavp may be decreased in the setting of nasal inflammation and rhinorrhoea, such as in upper respiratory tract infections, and therefore patients may need to use extra doses or shift to other routes if polyuria and dehydration are present. d e s m o p r e s s i n o r a l ta b l e t s due to their large molecular size and susceptibility to enzymatic degradation coupled with short plasma halflife, vasopressin and ddavp were initially considered to be unsuitable for oral use. however, despite low oral bioavailability of around 16%,82 a stable antidiuretic effect with a clear dose–response relationship has been observed in clinical trials,83 and preparation strengths (0.1, 0.2 and 0.4 mg) are available for oral use. ddavp oral doses required for equivalent antidiuretic efficacy are around 10–20 times of the intranasal doses; however, the ease of administration makes oral formulations the preferred route of treatment for most patients. although individualisation of therapy and titration of the dose is needed, 0.1–0.2 mg every eight hours is the usual maintenance dose,80 while less frequent dosing, such as once or twice daily, is generally sufficient for infants and children.84 management of diabetes insipidus following surgery for pituitary and suprasellar tumours 360 | squ medical journal, august 2021, volume 21, issue 3 d e s m o p r e s s i n o r a l f o r m u l at i o n s – o r a l m e lt since 2005, ddavp has been available as a sublingual lyophilizate (melt) formulation containing 60, 120 and 240 µg, having bioavailability of around 25%.85 in a recent study, ddavp melt has shown a similar level of antidiuretic control and was found to be as efficacious as intranasal ddavp in both children and adults.86 central diabetes insipidus in specific populations n e o n ata l i n fa n t s/c h i l d r e n the treatment of cdi in this group requires consideration of their diets which contain a proportionally larger amount of water. therefore, to prevent hyponatremia, urine volume must not be reduced too much and careful dose titration with close input/output and plasma sodium monitoring are required. continuous intravenous infusion of low dose ddavp (0.1–0.2 µg s.c./i.m) or arginine adh (0.25–3 mu/kg/h) under intensive monitoring is often used in the first 24–48 hours postoperatively.87,88 once cdi is stable and permanent, regular ddavp can be prescribed. a diluted rhinyl preparation of nasal spray in the amount containing 1–5 µg of ddavp once or twice daily usually provides good control of cdi in infants.89 ddavp can be administered subcutaneously in doses ranging from 0.02 to 0.08 µg once or twice daily.90 children and their parents need to be educated about the features of water intoxication and the hazards of excessive fluid intake. p r e g n a n c y a n d l a c tat i o n ddavp, being resistant to placental leucine amino peptidase, can be administered safely to pregnant women, both for gestational di as well as to patients with pre-existing cdi who become pregnant.91,92 compared to non-pregnant women, the doses needed are usually the same or slightly higher. placental leucine aminopeptidase usually disappears in 4–6 postpartum weeks when ddavp can be discontinued in patients with gestational di. it should be kept in mind during the monitoring of therapeutic effects that serum sodium level during pregnancy decreases typically by approximately 5 mmol/l compared to the nongravid state. as ddavp appears in an infinitesimal amount in breast milk, it can be continued during lactation.93 e l d e r ly as mentioned above, cdi requires lifelong manage ment and, even if the underlying cause is eliminated, cdi once established rarely remits. the treatment of cdi in the elderly does not differ much from that in young adults, though the former faces a higher risk of developing hyponatremia, primarily when intranasal ddavp is used.78 the aetiology is not clear at present. abnormalities of osmoregulation of thirst and fluid intake, along with increased renal sensitivity to ddavp, may be the possible explanation as this population is known to be affected by these factors.94 h y p o d i p s i a/a d i p s i a w i t h c e n t r a l d i a b e t e s i n s i p i d u s anterior hypothalamus injury leading to osmoreceptor damage culminates in the absence or deficiency of thirst and results in the rare occurrence of adipsic di. as a result, these patients have neither of the homeostatic mechanisms required for water balance regulation. consequently, their management becomes difficult and they suffer from wide fluctuation in serum sodium levels.95 in addition, during acute illnesses, patients can develop life-threatening hypernatremia, resulting in somnolence, seizures, hemiplegia, coma and acute renal failure and can experience thrombotic episodes. furthermore, other complications such as obesity and sleep apnoea, which is largely attributed to hypothalamic abnormalities, may be seen in assoc iation with adipsic di; these conditions contribute to the excess morbidity and mortality found in a patient with adipsic di.96 it becomes necessary to prescribe fluid intake on a sliding scale based on daily weight and serum sodium level.97 ddavp, alone or in combination with hydrochlorothiazide, is a useful agent in this regard. an alternative and more practical approach is to set a target weight (kg) at which the patient is known to be euvolemic and normonatremic and maintain fixed urine output at 1.5–2 l with a fixed amount of ddavp. furthermore, daily fluid intake can be titrated as obligate load (1.5 l in temperate climates) + (target weight – daily weight) to maintain volume status, sodium and osmolality within the defined range.98 successful treatment can be achieved through daily measurement of body weight and perhaps weekly serum sodium measurement along with careful monitoring and patient and family education.98 additionally, due to the high rates of venous thrombosis and thrombo embolism in patients with adipsic di, giving low molecular-weight heparin during periods of hyper natremia dehydration is recommended. furthermore, screening for sleep abnormalities is indicated.99 the principles of management of adipsic di are displayed in table 3. mussa h. almalki, maswood m. ahmad, imad brema, mohammed almehthel, khaled m aldahmani, moeber mahzari and salem a beshyah review | 361 conclusion cdi is a frequent complication that occurs in patients who undergo surgery for pituitary and suprasellar tumours and is the commonest leading cause for hospital readmission of these patients. therefore, clinicians dealing with these patients need to perform a thorough preoperative risk assessment in order to identify known predictive factors for cdi, such as in patients with craniopharyngioma and with larger tumours, in order to have clear strategies in place for early diagnosis and management. moreover, postoperative evaluation should be performed in the early and late postoperative periods in order to reduce the risk of complications and unnecessary readmissions to the hospital. while the management of cdi which complicates surgery for pituitary and suprasellar tumours is a commonly encountered topic, it nonetheless remains a challenging area for clinicians and requires high standards of medical knowledge in tandem with superior clinical experience and skills, especially regarding the decision about when to start desmopressin therapy and for how long, as well as planning the long-term follow-up for those who develop permanent cdi. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n mha contributed to study design. all authors contributed to the literature review and data collection. all authors drafted the initial manuscript. mha, mma, and ib edited the manuscript. ma, kmd, mm and sab made critical revision and approved final version. all authors reviewed and approved the final version of the manuscript. references 1. ezzat s, asa sl, couldwell wt, barr ce, dodge we, vance ml, et al. the prevalence of pituitary adenomas: a systematic review. cancer 2004; 101:613–19. https://doi.org/10.1002/cncr.20412. 2. hensen j, henig a, fahlbusch r, meyer m, boehnert m, buchfelder m. prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after trans-sphenoidal surgery for pituitary adenomas. clin endocrinol (oxf ) 1999; 50:431–9. https://doi.org/10.1046/j.1365-2265.1999.00666.x. 3. blair et, clemmer js, harkey hl, hester rl, pruett wa. physiologic mechanisms of water and electrolyte disturbances after transsphenoidal pituitary surgery. world neurosurg 2017; 107:429–36. https://doi.org/10.1016/j.wneu.2017.07.175. 4. thompson cj. polyuric states in man. baillieres clin endocrinol metab 1989; 3:473–97. https://doi.org/10.1016/s0950-351x(89)80012-6. 5. smith d, mckenna k, moore k, tormey w, finucane j, phillips j, et al. baroregulation of vasopressin release in adipsic diabetes insipidus. j clin endocrinol metab 2002; 87:4564–8. https:// doi.org/10.1210/jc.2002-020090. 6. sherlock m, agha a, crowley r, smith d, thompson cj. adipsic diabetes insipidus following pituitary surgery for a macropro lactinoma. pituitary 2006; 9:59–64. https://doi.org/10.1007/s11 102-006-8280-x. 7. szinnai g, morgenthaler ng, berneis k, struck j, muller b, keller u et al. changes in plasma copeptin, the c-terminal portion of arginine vasopressin during water deprivation and excess in healthy subjects. j clin endocrinol metab 2007; 92:3973–8. https://doi.org/10.1210/jc.2007-0232. 8. balanescu s, kopp p, gaskill mb, morgenthaler ng, schindler c, rutishauser j. correlation of plasma copeptin and vasopressin concentrations in hypo-, iso-, and hyperosmolar states. j clin endocrinol metab 2011; 96:1046–52. https://doi.org/10.1210/ jc.2010-2499. 9. katan m, morgenthaler ng, dixit kc, rutishauser j, brabant g, muller b, et al. anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptin assay. j clin endocrinol metab 2007; 92:2640–3. https://doi.org/10.1 210/jc.2006-2046. 10. winzeler b, zweifel c, nigro n, arici b, bally m, schuetz p, et al. postoperative copeptin concentration predicts diabetes insipidus after pituitary surgery. j clin endocrinol metab 2015; 100:2275–82. https://doi.org/10.1210/jc.2014-4527. 11. baldeweg se, ball s, brooke a, gleeson hk, levy mj, prentice m, et al. inpatient management of cranial diabetes insipidus. endocr connect 2018; 7:g8–11. https://doi.org/10.1530/ec18-0154. 12. sheehan jm, sheehan jp, douds gl, page rb. ddavp use in patients undergoing transsphenoidal surgery for pituitary adenomas. acta neurochir (wien) 2006; 148:287–91. https:// doi.org/10.1007/s00701-005-0686-0. 13. goudakos jk, markou kd, georgalas c. endoscopic versus microscopic trans-sphenoidal pituitary surgery: a systematic review and metaanalysis. clin otolaryngol 2011; 36:212–20. https://doi.org/10.1111/j.1749-4486.2011.02331.x. 14. little as, kelly df, white wl, gardner pa, fernandez-miranda jc, chicoine mr, et al. results of a prospective multicenter contr olled study comparing surgical outcomes of microscopic versus fully endoscopic transsphenoidal surgery for nonfunctioning pituitary adenomas: the transsphenoidal extent of resection (transspher) study. j neurosurg 2019; 132:1043–53. https://doi.org/10.3171/2018.11.jns181238. 15. agam ms, wedemeyer ma, wrobel b, weiss mh, carmichael jd, zada g. complications associated with microscopic and endo scopic transsphenoidal pituitary surgery: experience of 1153 consecutive cases treated at a single tertiary care pituitary center. j neurosurg 2018; 130:1576–83. https://doi.org/10.317 1/2017.12.jns172318. 16. wang s, li d, ni m, jia w, zhang q, he j, jia g. clinical predictors of diabetes insipidus after transcranial surgery for pituitary adenoma. world neurosurg 2017; 101:1–10. https:// doi.org/10.1016/j.wneu.2017.01.075. 17. smith d, finucane f, phillips j, baylis ph, finucane j, tormey w, et al. abnormal regulation of thirst and vasopressin secretion following surgery for craniopharyngioma. clin endocrinol (oxf ) 2004; 61:273–9. https://doi.org/10.1111/j.1365-2265.2004.02086.x. 18. agha a, rogers b, mylotte d, taleb f, tormey w, phillips j, et al. neuroendocrine dysfunction in the acute phase of traumatic brain injury. clin endocrinol (oxf ).2004; 60:584–91. https:// doi.org/10.1111/j.1365-2265.2004.02023.x. 19. hannon mj, crowley rk, behan la, o’sullivan ep, o’brien mmc, sherlock m, et al. acute glucocorticoid deficiency and diabetes insipidus are common after acute traumatic brain injury and predict mortality. j clin endocrinol metab 2013; 98:3229–37. https://doi.org/10.1210/jc.2013-1555. https://doi.org/10.1002/cncr.20412 https://doi.org/10.1046/j.1365-2265.1999.00666.x https://doi.org/10.1016/j.wneu.2017.07.175 https://doi.org/10.1016/s0950-351x(89)80012-6 https://doi.org/10.1210/jc.2002-020090 https://doi.org/10.1210/jc.2002-020090 https://doi.org/10.1007/s11102-006-8280-x https://doi.org/10.1007/s11102-006-8280-x https://doi.org/10.1210/jc.2007-0232 https://doi.org/10.1210/jc.2010-2499 https://doi.org/10.1210/jc.2010-2499 https://doi.org/10.1210/jc.2006-2046 https://doi.org/10.1210/jc.2006-2046 https://doi.org/10.1210/jc.2014-4527 https://doi.org/10.1530/ec-18-0154 https://doi.org/10.1530/ec-18-0154 https://doi.org/10.1007/s00701-005-0686-0 https://doi.org/10.1007/s00701-005-0686-0 https://doi.org/10.1111/j.1749-4486.2011.02331.x https://doi.org/10.3171/2018.11.jns181238 https://doi.org/10.3171/2017.12.jns172318 https://doi.org/10.3171/2017.12.jns172318 https://doi.org/10.1016/j.wneu.2017.01.075 https://doi.org/10.1016/j.wneu.2017.01.075 https://doi.org/10.1111/j.1365-2265.2004.02086.x https://doi.org/10.1111/j.1365-2265.2004.02023.x https://doi.org/10.1111/j.1365-2265.2004.02023.x https://doi.org/10.1210/jc.2013-1555 management of diabetes insipidus following surgery for pituitary and suprasellar tumours 362 | squ medical journal, august 2021, volume 21, issue 3 20. qureshi ai, suri mf, sung gy, straw r, yahia am, saad m, et al. prognostic significance of hypernatremia and hyponatremia among patients with aneurysmal subarachnoid hemorrhage. neurosurgery 2002; 50:749–56. https://doi.org/10.1097/000061 23-200204000-00012. 21. barker fg 2nd; klibanski a; swearingen b. transsphenoidal surgery for pituitary tumours in the united states, 1996-2000: mortality, morbidity, and the effects of hospital and surgeon volume. j clin endocrinol metab 2003; 88:4709–19. https:// doi.org/10.1210/jc.2003-030461. 22. ajlan am, abdulqader sb, achrol as, aljamaan y, feroze ah, katznelson l, et al. diabetes insipidus following endoscopic transsphenoidal surgery for pituitary adenoma. j neurol surg b skull base 2018; 79:117–22. https://doi.org/10.1055/s-0 037-1604363. 23. sigounas d, sharpless j, cheng d, johnson t, senior b, ewend m. predictors and incidence of central diabetes insipidus after endoscopic pituitary surgery. neurosurgery 2008; 62:71–8. https://doi.org/10.1227/01.neu.0000311063.10745.d8. 24. nemergut ec, zuo z, jane jr ja, laws jr er. predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients. j neurosurg 2005; 103:448–54. https://doi. org/10.3171/jns.2005.103.3.0448. 25. pratheesh r, swallow dma, rajaratnam s, jacob ks, chacko g, joseph m, et al. incidence, predictors and early postoperative course of diabetes insipidus in paediatric craniopharygioma: a comparison with adults. child’s nerv syst 2013; 29:941–9. https://doi.org/10.1007/s00381-013-2041-8. 26. kristof ra, rother m, neuloh g, klingmüller d. incidence, clinical manifestations, and course of water and electrolyte meta bolism disturbances following transsphenoidal pituitary adenoma surgery: a prospective observational study. j neurosurg 2009; 111:555–62. https://doi.org/10.3171/2008.9.jns08191. 27. prete a, corsello sm, salvatori r. current best practice in the management of patients after pituitary surgery. ther adv endo crinol metab 2017; 8:33–48. https://doi.org/10.1177/204201881 6687240. 28. wedemeyer ma, lin m, fredrickson vl, arakelyan a, bradley d, donoho da, et al. recurrent rathke’s cleft cysts: incidence and surgical management in a tertiary pituitary center over 2 decades. oper neurosurg (hagerstown) 2018; 16:675–84. https://doi.org/10.1093/ons/opy258. 29. hayashi y, aida y, sasagawa y, oishi m, kita d, tachibana o, et al. delayed occurrence of diabetes insipidus after transs phenoidal surgery with radiologic evaluation of the pituitary stalk on magnetic resonance imaging. world neurosurg 2018; 110:e1072–7. https://doi.org/10.1016/j.wneu.2017.11.169. 30. schreckinger m, walker b, knepper j, hornyak m, hong d, kim jung-min, et al. post-operative diabetes insipidus after endoscopic transsphenoidal surgery. pituitary 2013; 16:445–51. https://doi.org/10.1007/s11102-012-0453-1. 31. yuen kcj, ajmal a, correa r, little as. sodium perturbations after pituitary surgery. neurosurg clin n am 2019; 30:515–24. https://doi.org/10.1016/j.nec.2019.05.011. 32. hoorn ej, zietse r. water balance disorders after neurosurgery: the triphasic response revisited. ndt plus 2010; 3:42–4. https://doi.org/10.1093/ndtplus/sfp117. 33. loh ja, verbalis jg. diabetes insipidus as a complication after pituitary surgery. nat clin pract endocrinol metab 2007; 3:489–94. https://doi.org/10.1038/ncpendmet0513. 34. seckl j, dunger d. postoperative diabetes insipidus. bmj 1989; 298:2–3. https://doi.org/10.1136/bmj.298.6665.2. 35. hans p, stevenaert a, albert a. study of hypotonic polyuria after trans-sphenoidal pituitary adenomectomy. intensive care med 1986; 12:95–9. https://doi.org/10.1007/bf00254519. 36. fenske w, allolio b. current state and future perspectives in the diagnosis of diabetes insipidus: a clinical review. j clin endo crinol 2012; 97:3426–37. https://doi.org/10.1210/jc.2012-1981. 37. loh ja, verbalis jg. diabetes insipidus as a complication after pituitary surgery. nat clin pract endocrinol metab 2007; 3:489–94. https://doi.org/10.1038/ncpendmet0513. 38. kiran z, sheikh a, momin sn, majeed i, awan s, rashid o, et al. sodium and water imbalance after sellar, suprasellar, and parasellar surgery. endocr pract 2017; 23:309–17. https://doi. org/10.4158/ep161616.or. 39. gubbi s, hannah-shmouni f, koch ca, verbalis jg. diagnostic testing for diabetes insipidus. in: feingold kr, anawalt b, boyce a, chrousos g, de herder ww, dhatariya k, et al., eds. endotext. south dartmouth: mdtext.com, inc., 2019. 40. seckel j, dunger d. postoperative diabetes insipidus. bmj 1989; 298:2. https://doi.org/10.1136/bmj.298.6665.2. 41. ausiello jc, bruce jn, freda pu. postoperative assessment of the patient after transsphenoidal pituitary surgery. pituitary 2008; 11:391-401. https://doi.org/10.1007/s11102-008-0086-6. 42. woodmansee ww, carmichael j, kelly d. american assoc iation of clinical endocrinologists and american college of endocrinology disease state clinical review: postoperative management following pituitary surgery. endocr pract 2015; 21:832–8. https://doi.org/10.4158/ep14541.dscr. 43. musch w, thimpont j, vandervelde d, verhaeverbeke i, berghmans t, decaux g. combined fractional excretion of sodium and urea better predicts response to saline in hyponatremia than do usual clinical and biochemical parameters. am j med 1995; 99:348–55. https://doi.org/10.1016/s0002-9343(99)80180-6. 44. christ-crain m, fenske w. copeptin in the diagnosis of vaso pressin-dependent disorders of fluid homeostasis. nat rev endocrinol 2016; 12:168. https://doi.org/10.1038/nrendo.2015.224. 45. czaczkes j, kleeman c, koenig m, boston r. physiologic studies of antidiuretic hormone by its direct measurement in human plasma. j clin invest 1964; 43:1625–40. https://doi. org/10.1172/jci105038. 46. ellis mj, livesey jh, evans mj. hormone stability in human whole blood. clin biochem 2003; 36:109–12. https://doi. org/10.1016/s0009-9120(02)00440-x. 47. timper k, fenske w, kühn f, frech n, arici b, rutishauser j, et al. diagnostic accuracy of copeptin in the differential diagnosis of the polyuria-polydipsia syndrome: a prospective multicenter study. j clin endocrinol metab 2015; 100:2268–74. https://doi. org/10.1210/jc.2014-4507. 48. morgenthaler ng, struck j, alonso c, bergmann a. assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressinn. clin chem 2006; 52:112–9. https:// doi.org/10.1373/clinchem.2005.060038. 49. balanescu s, kopp p, gaskill mb, morgenthaler ng, schindler c, rutishauser j. correlation of plasma copeptin and vasopressin concentrations in hypo-, iso-, and hyperosmolar states. j clin endocrinol metab 2011; 96:1046–52. https://doi.org/10.1210/ jc.2010-2499. 50. fenske w, refardt j, chifu i, schnyder i, winzeler b, drummond j, et al. a copeptin-based approach in the diagnosis of diabetes insipidus. n engl j med 2018; 379:428–39. https://doi.org/10.10 56/nejmoa1803760. 51. winzeler b, zweifel c, nigro n, arici b, bally m, schuets p, et al. postoperative copeptin concentration predicts diabetes insipidus after pituitary surgery. j clin endocrinol metab 2015; 100:2275–82. https://doi.org/10.1210/jc.2014-4527. 52. berton am, gatti f, penner f, varaldo e, prencipe n, rumbolo, et al. early copeptin determination allows prompt diagnosis of post-neurosurgical central diabetes insipidus. neuroendocrin ology 2019; 110:525–34. https://doi.org/10.1159/000503145. 53. eisenberg y, charles s, dugas l, agrawal n. clinical practice patterns for postoperative water balance after pituitary surgery. endocr pract 2019; 25:943–50. https://doi.org/10.4158/ep2019-0160. https://doi.org/10.1097/00006123-200204000-00012 https://doi.org/10.1097/00006123-200204000-00012 https://doi.org/10.1210/jc.2003-030461 https://doi.org/10.1210/jc.2003-030461 https://doi.org/10.1055/s-0037-1604363 https://doi.org/10.1055/s-0037-1604363 https://doi.org/10.1227/01.neu.0000311063.10745.d8 https://doi.org/10.3171/jns.2005.103.3.0448 https://doi.org/10.3171/jns.2005.103.3.0448 https://doi.org/10.1007/s00381-013-2041-8 https://doi.org/10.3171/2008.9.jns08191 https://doi.org/10.1177/2042018816687240 https://doi.org/10.1177/2042018816687240 https://doi.org/10.1093/ons/opy258 https://doi.org/10.1016/j.wneu.2017.11.169 https://doi.org/10.1007/s11102-012-0453-1 https://doi.org/10.1016/j.nec.2019.05.011 https://doi.org/10.1093/ndtplus/sfp117 https://doi.org/10.1038/ncpendmet0513 https://doi.org/10.1136/bmj.298.6665.2 https://doi.org/10.1007/bf00254519 https://doi.org/10.1210/jc.2012-1981 https://doi.org/10.1038/ncpendmet0513 https://doi.org/10.4158/ep161616.or https://doi.org/10.4158/ep161616.or https://doi.org/10.1136/bmj.298.6665.2 https://doi.org/10.1007/s11102-008-0086-6 https://doi.org/10.4158/ep14541.dscr https://doi.org/10.1016/s0002-9343(99)80180-6 https://doi.org/10.1038/nrendo.2015.224 https://doi.org/10.1172/jci105038 https://doi.org/10.1172/jci105038 https://doi.org/10.1016/s0009-9120(02)00440-x https://doi.org/10.1016/s0009-9120(02)00440-x https://doi.org/10.1210/jc.2014-4507 https://doi.org/10.1210/jc.2014-4507 https://doi.org/10.1373/clinchem.2005.060038 https://doi.org/10.1373/clinchem.2005.060038 https://doi.org/10.1210/jc.2010-2499 https://doi.org/10.1210/jc.2010-2499 https://doi.org/10.1056/nejmoa1803760 https://doi.org/10.1056/nejmoa1803760 https://doi.org/10.1210/jc.2014-4527 https://doi.org/10.1159/000503145 https://doi.org/10.4158/ep-2019-0160 https://doi.org/10.4158/ep-2019-0160 mussa h. almalki, maswood m. ahmad, imad brema, mohammed almehthel, khaled m aldahmani, moeber mahzari and salem a beshyah review | 363 54. sheehan jm, sheehan jp, douds gl, page rb. ddavp use in patients undergoing transsphenoidal surgery for pituitary adenomas. acta neurochir 2006; 148:287–91. https://doi.org/10.1007/s00 701-005-0686-0. 55. adams jr, blevins ls, allen gs, verity dk, devin jk. disorders of water metabolism following transsphenoidal pituitary surgery a single institution’s experience. pituitary 2006; 9:93–9. https:// doi.org/10.1007/s11102-006-9276-2. 56. adams jr, belvins jr ls, verity dk, devin jk. disorders of water metabolism following transphenoidal pituitary surgery: a single institution’s experience. pituitary 2006; 9:93–9. https:// doi.org/10.1007/s11102-006-9276-2. 57. garrahy a, moran c, thompson cj. diagnosis and management of central diabetes insipidus in adults. clin endocrinol (oxf ) 2019; 90:23–30. https://doi.org/10.1111/cen.13866. 58. fleseriu m, hashim ia, karavitaki n, melmed s, murad mh, salvatori r, et al. hormonal replacement in hypopituitarism in adults: an endocrine society clinical practice guideline. j clin endocrinol metab 2016; 101:3888–921. https://doi.org/10.121 0/jc.2016-2118. 59. dumont as, nemergut ec, jane jr ja, laws jr er. postoperative care following pituitary surgery. j intensive care med 2005; 20:127–40. https://doi.org/10.1177/0885066605275247. 60. makaryus an, mcfarlane si. diabetes insipidus: diagnosis and treatment of a complex disease. cleve clin j med 2006; 73:65–71. https://doi.org/10.3949/ccjm.73.1.65. 61. adrogué hj, madias ne. hypernatremia. n engl j med 2000; 342:1493–9. https://doi.org/10.1056/nejm200005183422006. 62. pfennig cl, slovis cm. sodium disorders in the emergency department: a review of hyponatremia and hypernatremia. emerg med pract 2012; 14:1–26. pmid: 23114652. 63. reynolds rm, padfield p, seckl jr. disorders of sodium balance. bmj 2006; 332:702–5. https://doi.org/10.1136/bmj.332.7543.702. 64. chanson p, jedynak cp, dabrowski g, rohan j, bouchama a, rohan-chabot p, et al. ultralow doses of vasopressin in the management of diabetes insipidus. crit care med 1987; 15:44–6. https://doi.org/10.1097/00003246-198701000-00010. 65. andersson ke, arner b. effects of ddavp, a synthetic analogue of vasopressin, in patients with cranial diabetes insipidus. acta med scand 1972; 192:21–7. https://doi.org/10.1111/j.0954-682 0.1972.tb04772.x. 66. radó jp, marosi j, szende l, borbély l, takó j, fischer j. the antidiuretic action of 1-deamino-8-d-arginine vasopressin (ddavp) in man. int j clin pharmacol biopharm 1976; 13:199–209. 67. radó jp, marosi j, fischer j, takó j, kiss n. relationship between the dose of 1-deamino-8-d-arginine vasopressin (ddavp) and antidiuretic response in man. endokrinologie 1975; 66:184–195. 68. radó jp, marosi j, borbély l, takó j. individual differences in the antidiuretic response induced by single doses of 1-deamino-8-d arginine-vasopressin (ddavp) in patients with pituitary diabetes insipidus. int j clin pharmacol biopharm 1976; 14:259–65. 69. czakó l, mezei g, lászló fa. treatment of diabetes insipidus with 1-deamino-8-d-arginine-vasopressin. acta med acad sci hung 1975; 32:75–84. 70. radó jp, marosi j, fischer j.shortened duration of action of 1-deamino-8-d-arginine-vasopressinn (ddavp) in patients with diabetes insipidus requiring high doses of peroral antidiuretic drugs. j clin pharmacol 1976; 16:518–24. 71. juul kv, bichet dg, norgaard jp. desmopressin duration of antidiuretic action in patients with central diabetes insipidus. endocrine 2011; 40:67–74. https://doi.org/10.1007/s12020011-9492-z. 72. zerbe rl, robertson gl. a comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. n engl j med 1981; 305:1539–46. https:// doi.org/10.1056/nejm198112243052601. 73. kahn a, brachet e, blum d. controlled fall in natremia and risk of seizures in hypertonic dehydration. intensive care med 1979; 5:27–31. https://doi.org/10.1007/bf01738999. 74. thompson cj, burd jm, baylis ph. acute suppression of plasma vasopressin and thirst after drinking in hypernatremic humans. am j physiol 1987; 252:r1138–42. https://doi.org/10.1152/ ajpregu.1987.252.6.r1138. 75. seckl jr, williams td, lightman sl. oral hypertonic saline causes transient fall of vasopressin in humans. am j physiol 1986; 251:r214–17. https://doi.org/10.1152/ajpregu.1986.251.2.r214. 76. kovacs l, rittig s, robertson gl. effect of sustained antidiuretic treatment on plasma sodium concentration and body water homeostasis in healthy humans on ad libitum fluid intake. clin res 1992; 40:165a. 77. andersson ke, arner b. effects of ddavp, a synthetic analogue of vasopressin, in patients with cranial diabetes insipidus. acta med scand 1972; 192:21–7. https://doi.org/10.1111/j.0954-68 20.1972.tb04772.x. 78. aronsen as, andersson ke, bergstrand cg, mulder jl. treatment of diabetes insipidus in children with ddavp, a synthetic analogue of vasopressinn. acta pædiat scand 1973; 62:133–40. https://doi.org/10.1111/j.1651-2227.1973.tb08080.x. 79. becker dj, foley tp jr.1-deamino-8-d-arginine-vasopressinn in the treatment of central diabetes insipidus in childhood. j pediatr 1978; 92:1011–15. https://doi.org/10.1016/s0022-3476 (78)80389-8. 80. robinson ag. ddavp in the treatment of central diabetes insipidus. n engl j med 1976; 294:507–11. https://doi.org/10.10 56/nejm197603042941001. 81. ward mk, fraser tr. ddavp in treatment of vasopressinsensitive diabetes insipidus. br med j 1974; 3:86–9. https://doi. org/10.1136/bmj.3.5923.86. 82. fjellestad-paulsen a, höglund p, lundin s, paulsen o. pharma cokinetics of 1-deamino-8-d-argininevasopressinn after various routes of administration in health volunteers. clin endocrinol (oxf ) 1993; 38:177–82. https://doi.org/10.1111/j.1365-2265.1993. tb00990.x. 83. westgren u, wittström c, harris as. oral desmopressin in central diabetes insipidus. arch dis child 1986; 61:247–50. https://doi.org/10.1136/adc.61.3.247. 84. rivkees sa, dunbar n, wilson ta. the management of central diabetes insipidus in infancy: desmopressin, low renal salt load formula, thiazide diuretics. j pediatr endocrinol metab 2007; 20:459–69. https://doi.org/10.1515/jpem.2007.20.4.459. 85. østerberg o, balchen t, riis a, senderovitz t. pharmacokinetics of desmopressin in children and adults using a new oral lyophilisate. arch dis child 2006; 91:a33. 86. arima h, oiso y, juul kv, nørgaard jp. efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dosetitration study. endocr j 2013; 60:1085–94. https://doi.org/10.15 07/endocrj.ej13-0165. 87. lehrnbecher t, muller-scholden j, danhauser-leistner i, sorensen n, von stockhausen hb. perioperative fluid and electrolyte management in children undergoing surgery for craniopharyn gioma: a 10-year experience in a single institution. childs nerv syst 1998; 14:276–9. https://doi.org/10.1007/s003810050224. 88. mcdonald ja, martha pm, kerrigan j, clarke wl, rogol ad, blizzard rm. treatment of the young child with postoperative central diabetes insipidus. am j dis child 1989; 143:201–4. https://doi.org/10.1001/archpedi.1989.02150140095027. 89. gutmark-little i, repaske dr, backeljauw pf. efficacy and safety of intranasal desmopressin acetate administered orally for the management of infants with neurogenic diabetes insipidus (di). endocrine rev 2010; 31:p3–324. https://doi.org/10.1007/s00701-005-0686-0 https://doi.org/10.1007/s00701-005-0686-0 https://doi.org/10.1007/s11102-006-9276-2 https://doi.org/10.1007/s11102-006-9276-2 https://doi.org/10.1007/s11102-006-9276-2 https://doi.org/10.1007/s11102-006-9276-2 https://doi.org/10.1111/cen.13866 https://doi.org/10.1210/jc.2016-2118 https://doi.org/10.1210/jc.2016-2118 https://doi.org/10.1177/0885066605275247 https://doi.org/10.3949/ccjm.73.1.65 https://doi.org/10.1056/nejm200005183422006 https://doi.org/10.1136/bmj.332.7543.702 https://doi.org/10.1097/00003246-198701000-00010 https://doi.org/10.1111/j.0954-6820.1972.tb04772.x https://doi.org/10.1111/j.0954-6820.1972.tb04772.x https://doi.org/10.1007/s12020-011-9492-z https://doi.org/10.1007/s12020-011-9492-z https://doi.org/10.1056/nejm198112243052601 https://doi.org/10.1056/nejm198112243052601 https://doi.org/10.1007/bf01738999 https://doi.org/10.1152/ajpregu.1987.252.6.r1138 https://doi.org/10.1152/ajpregu.1987.252.6.r1138 https://doi.org/10.1152/ajpregu.1986.251.2.r214 https://doi.org/10.1111/j.0954-6820.1972.tb04772.x https://doi.org/10.1111/j.0954-6820.1972.tb04772.x https://doi.org/10.1111/j.1651-2227.1973.tb08080.x https://doi.org/10.1016/s0022-3476(78)80389-8 https://doi.org/10.1016/s0022-3476(78)80389-8 https://doi.org/10.1056/nejm19760304294100 https://doi.org/10.1056/nejm19760304294100 https://doi.org/10.1136/bmj.3.5923.86 https://doi.org/10.1136/bmj.3.5923.86 https://doi.org/10.1111/j.1365-2265.1993.tb00990.x https://doi.org/10.1111/j.1365-2265.1993.tb00990.x https://doi.org/10.1136/adc.61.3.247 https://doi.org/10.1515/jpem.2007.20.4.459 https://doi.org/10.1507/endocrj.ej13-0165 https://doi.org/10.1507/endocrj.ej13-0165 https://doi.org/10.1007/s003810050224 https://doi.org/10.1001/archpedi.1989.02150140095027 management of diabetes insipidus following surgery for pituitary and suprasellar tumours 364 | squ medical journal, august 2021, volume 21, issue 3 90. blanco ej, lane ah, aijaz n, blumberg d, wilson ta. use of subcutaneous ddavp in infants with central diabetes insipidus. j pediatr endocrinol metab 2006; 19:919–25. https://doi.org/1 0.1515/jpem.2006.19.7.919. 91. durr ja, hoggard jg, hunt jm, schrier rw. diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity. n engl j med 1987; 316:1070–4. https://doi.org/10.1056/nejm198704233161707. 92. barron wm. water metabolism and vasopressin secretion during pregnancy. baillieres clin obstet gynaecol 1987; 1:853–71. https://doi.org/10.1016/s0950-3552(87)80038-x. 93. burrow gn, wassenaar w, robertson gl, sehl h. ddavp treatment of diabetes insipidus during pregnancy and the postpartumm period. acta endocrinol (copenh) 1981; 97:23–5. https://doi.org/10.1530/acta.0.0970023. 94. czernichow p. treatment of diabetes insipidus. in: argente j, ed. diabetes insipidus. madrid, spain: editorial justim, 2010. pp. 107–112. 95. cuesta m, hannon mj, thompson cj. adipsic diabetes insipidus in adult patients. pituitary 2017; 20:372–80. https:// doi.org/10.1007/s11102-016-0784-4. 96. miljic d, miljic p, doknic m, pekic s, stojanovic m, petakov m, et al. adipsic diabetes insipidus and venous thromboembolism (vte): recommendations for addressing its hypercoagulability. hormones (athens) 2014; 13:420–3. https://doi.org/10.14310/ horm.2002.1496. 97. green rp, landt m. home sodium monitoring in patients with diabetes insipidus. j pediatr 2002; 141:618–24. https://doi. org/10.1067/mpd.2002.128544. 98. ball sg, vaidja b, baylis ph. hypothalamic adipsic syndrome: diagnosis and management. clin endocrinol (oxf ) 1997; 47:405–9. https://doi.org/10.1046/j.1365-2265.1997.2591079.x. 99. crowley rk, woods c, fleming m, rogers b, behan la, o'sullivan ep, et al. somnolence in adult craniopharyngioma patients is a common, heterogeneous condition that is potentially treatable. clin endocrinol (oxf ) 2011; 74:750–5. https://doi.org/10.1111/j.1365-2265.2011.03993.x. https://doi.org/10.1515/jpem.2006.19.7.919 https://doi.org/10.1515/jpem.2006.19.7.919 https://doi.org/10.1056/nejm198704233161707 https://doi.org/10.1016/s0950-3552(87)80038-x https://doi.org/10.1530/acta.0.0970023 https://doi.org/10.1007/s11102-016-0784-4 https://doi.org/10.1007/s11102-016-0784-4 https://doi.org/10.14310/horm.2002.1496 https://doi.org/10.14310/horm.2002.1496 https://doi.org/10.1067/mpd.2002.128544 https://doi.org/10.1067/mpd.2002.128544 https://doi.org/10.1046/j.1365-2265.1997.2591079.x https://doi.org/10.1111/j.1365-2265.2011.03993.x clinical practice guidelines for the evaluation and diagnosis of attention-deficit/hyperactivity disorder in children and adolescents a systematic review of the literature *hira abdul razzak,1 nariman ghader,2 ateeq a. qureshi,3 mehnaz zafar,4 jeena f. shaijan,5 muna al kuwari2 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e12–21, epub. 15 mar 21 submitted 14 may 20 revision req. 5 jul 20; revision recd. 20 jul 20 accepted 13 aug 20 1statistics and research center and 2specialized care department, ministry of health & prevention, dubai, united arab emirates; 3department of child & adolescent mental health, maudsley health, dubai, united arab emirates; 4department of psychiatry, al amal psychiatry hospital, dubai, united arab emirates; 5department of psychiatry, nmc medical centre, dubai, united arab emirates *corresponding author’s e-mail: hira.abdulrazzak@mohap.gov.ae attention deficit/hyperactivity disorder (adhd) is a frequently diagnosed, pervasive and controversial neurobehavioural childhood disorder that has received extensive attention from the media, public and researchers.1 adhd makes focusing on everyday requests and routines challenging.2 indiv iduals suffering from adhd often have trouble with focus, organisation, impulsivity and practical planning. they may be noisy, jittery or incapable of adapting to environmental changes.3 it is a chronic impairing disorder that negatively impacts several aspects of a child’s life like social skills, academic attainment, review دالئل إرشادية للممارسة السريرية لتقييم وتشخيص اضطراب فرط احلركة وتشتت االنتباه عند األطفال واملراهقني مراجعة منهجية هريا عبد الرزاق، نارميان غادر، عتيق اأحمد قر�شي، مهناز ظفار، جينا فيجي �شاجان، منى الكواري abstract: this article presents a comprehensive review of clinical practice guidelines (cpgs) for the evaluation and/or diagnosis of attention deficit/hyperactivity disorder (adhd) in children and adolescents. a systematic review was undertaken to summarise the recommendations reported in cpgs. medline® (national library of medicine, bethesda, maryland, usa), cumulative index to nursing and allied health literature® (ebsco information services, ipswich, massachusetts, usa) and other databases were searched to retrieve cpgs. a total of five guidelines were included for analysis. the selected cpgs were appraised independently by five reviewers using the agree ii instrument. the highest total score was achieved by the national institute for health and care excellence guidelines (91.4%) followed by the cpgs from the scottish intercollegiate guidelines network, canadian attention deficit hyperactivity disorder resource alliance, british association of psychopharmacology and the american academy of paediatrics. by appraising current adhd guidelines, clinicians cannot only identify cpgs related to adhd but can also determine which guidelines should be considered of high quality and trustworthy to follow during clinical practice. the researchers recommend using the agree ii instrument for cpg appraisal in healthcare professional education and training. improvements in the applicability of guidelines are warranted in the future to enhance its clinical use and relevance. keywords: attention deficit hyperactivity disorder; practice guidelines; adolescents; children; diagnosis. امللخ�ص: تقدم هذه الدرا�شة مراجعة �شاملة للدالئل االإر�شادية للممار�شة ال�رسيرية عند تقييم وت�شخي�ص ا�شطراب فرط احلركة وت�شتت االنتباه عند االأطفال واملراهقني. مت عمل مراجعة منهجية لتلخي�ص التو�شيات الواردة يف اإر�شادات املمار�شة يف ميد الين medline )مكتبة الطب القومية، بيثثدا، مرييالند، الواليات املتحدة االأمريكية( والفهر�ص الرتاكمي للتمري�ص واالأدبيات ال�شحية امل�شاعدة )خدمات املعلومات ebsco، اب�شوي�ص، ما�شات�شو�شت�ص، الواليات املتحدة االأمريكية( وقواعد بيانات اأخرى مت البحث فيها عما ُن�رس من دالئل اإر�شادية للممار�شة .agree ii ال�رسيرية. وت�شمنت هذه هذه الدرا�شة خم�شة اإر�شادات مت تقييمها من قبل خم�شة مراجعني-ب�شورة م�شتقلة -با�شتخدام اأداة وح�شلت اإر�شادات املمار�شة ال�رسيرية للمعهد القومي لل�شحة والرعاية على اأعلى جمموع نقاط )%91.4(، يليها اإر�شادات املمار�شة ال�رسيرية لل�شبكة االأ�شكتلندية لالإر�شادات امل�شرتكة بني الكليات، وحتالف املوارد الكندي الإر�شادات املمار�شة ال�رسيرية، ثم جمعية علم االأدوية النف�شية، واالأكادميية االأمريكية لطب االأطفال. وعند تقييم الدالئل االإر�شادية ال�شطراب فرط احلركة وت�شتت االنتباه، ال ي�شتطيع الطبيب املعالج فقط التعرف على تلك االر�شادات، بل ميكنه اأن يحدد اأي االر�شادات اأف�شل نوعية وموثقه واأجدر باالتباع يف ممار�شته معاينه املراجعني. ويو�شي الفريق البحثي لهذه الدرا�شة با�شتخدام اأداة agree ii لتقييم الدالئل االإر�شادية للممار�شة ال�رسيرية عند تعليم وتدريب املهنيني العاملني يف جمال الرعاية ال�شحية. ومن الالزم اأي�شا اإحداث حت�شينات يف قابليتها للتطبيق م�شتقبال من اأجل تعزيز مالئمتها وا�شتخدامها عياديا. الكلمات املفتاحية: ا�شطراب فرط احلركة وت�شتت االنتباه؛ الدالئل االإر�شادية للممار�شة ال�رسيرية؛ املراهقون؛ االأطفال؛ الت�شخي�ص. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.003 https://creativecommons.org/licenses/by-nd/4.0/ hira abdul razzak, nariman ghader, ateeq a. qureshi, mehnaz zafar, jeena f. shaijan and muna al kuwari review | e13 child-parent relationship as well as the well being of the entire family. the aetiology of adhd has been linked to genetic factors, potential gene-environment interactions and other environmental risk factors such as toxic metal exposure.4 a study from the united arab emirates (uae) found that increased blood concentrations of lead, manganese and zinc levels were found to be significantly associated with adhd. other potential risk factors include low birth weight, prenatal exposure to alcohol, tobacco use and premature birth.4 adhd is manageable if appropriate treatments are used. while several treatment and management options are available, what works best is mostly based on the individual and their family members. whilst seeking the best treatment/management options, parents should work closely with other people who are involved in a child’s life including therapists, coaches, healthcare providers, educators and other family members. treat ment may consist of medications or behaviour therapy, including training for parents. epidemiological data on adhd are scarce due to the fact that few population-based studies have been conducted globally and also because of changing diagnostic criteria. nevertheless, due to its high prevalence, adhd represents a public health problem.5 this condition manifests in 5.9–7.1% of children and adolescents worldwide.6 several studies have estimated adhd prevalence; it has been reported at 5% in the usa, 7.6–9.5% in korea and 10– 20% in india, whereas the prevalence of hyperactivity symptoms was reported to be 14.9% in the uae.7–10 prevalence rates are markedly different based on the diagnostic criteria utilised, the sample’s origin (i.e. general or clinical population), gender and age of focus and the methodology used. the definition of adhd was amended in the fifth edition of the diagnostic and statistical manual of mental disorders (dsm-5).7 although adhd is a disorder that begins in childhood, it can linger through adulthood. it is often categorised by persistent patterns of impulsivity, hyperactivity and inattention. symptoms are usually present for a minimum of six months and are commonly observed in children below seven years of age; however, normal diagnostic criteria are mostly applicable to children aged 6–12 years.11 the intensity of symptoms of hyperactivity may subside with age or can be replaced in older individuals with restlessness, which is difficult to quantify. characteristics such as organisational dysfunction (i.e. executive function), inattentiveness and impulsivity often persists past the initial diagnosis. adhd diagnosis is complicated by a variety of factors and patients suffering from adhd often present to different medical services for assessment, diagnosis and treatment. application of different diagnostic classification systems, like dsm-iv tr, dsm-5 criteria or icd-10, often tend to present challenges for the practising physicians.7,12,13 these challenges may also include under-diagnosis, high levels of comorbidity, misuse of pharmacological treatments, and the risks of diversion.11 statements about adhd should be developed systematically to information about diagnostic strategies and management of the condition to mental health practitioners, paediatricians and families with children suffering from adhd or with children suspected to have adhd. the evolution of medical understanding of adhd reflects the complicated nature of the condition. the dsm-iv retained adhd terminology and outlined three specific subtypes: hyperactiveimpulsive, inattentive and combined.12 these subtypes are defined by excessive symptoms of hyperactivityimpulsivity and/or inattention. dsm-iv-tr modified the classification of adhd as a disruptive behaviour disorder.12 the dsm-5 saw the addition of the neurodevelopmental disorders category which brought a significant adjustment to adhd classification and resulted in revisions to adhd’s diagnostic criteria;7 the diagnostic criteria of adhd also underwent some revisions in dsm-5. the same 18-symptom criteria were involved as previously, with the addition of specific examples under each criterion, to facilitate classification of the disorder across the individual’s lifespan. the age of adhd onset was also revised to 12 years in the dsm-5 compared to the previous restrictive barrier for diagnosis of seven years of age.11 some of the specifiers were included to designate either hyperactive/impulsive or inattentive adhd presentations. the adult adhd diagnosis criterion endured a symptom threshold variation: adults have a cut-off of five symptoms of hyperactivity or inattention, unlike the six symptoms needed in younger people. hence, the dsm-5 chapter on neurodevelopmental disorders allows for a comorbid adhd diagnosis which had previously not been acceptable under the dsm-iv-tr.4,12 such a diagnosis can currently be made based on the presentation of only mild symptoms or the inability of individuals to compensate for their difficulties through various coping mechanisms. in contrast to the dsm goals, the primary goal of the icd-10 lies in classification instead clinical practice guidelines for the evaluation and diagnosis of attention-deficit/hyperactivity disorder in children and adolescents a systematic review of the literature e14 | squ medical journal, february 2021, volume 21, issue 1 of diagnosis. adhd is found in the icd-10 under the code f90.0.13 consistent clinical guidelines are important for providing better quality care, evidence-based medical practice and cost-efficient services and for improving clinical outcomes, care planning, multidisciplinary communications and resource allocation. such guidelines, however, have limitations. guidelines can become out-dated, be of methodologically poor quality or command unavailable or biased care standards. several international medical societies have targeted different groups of health professionals in their published guidelines on the evaluation and diagnosis of adhd. globally, adhd has been researched extensively because of the potential repercussion it has on children’s families and personal development.11 no agreement, however, exists about which instrument should be utilised in diagnosing children with possible adhd and there are several controversies regarding the criteria currently used for diagnosis. such complications in the diagnostic processes, detection and methodology have given rise to considerable changes (demographic or geographic), mainly leading to overor under-diagnosis of adhd.11 due to a lack of biological markers, adhd diagnosis is mainly clinical. given the large body of international evidence on the topic, healthcare providers working in the fields of psychiatry, psychology, neurology and paediatrics must have practical guidelines on adhd’s diagnosis and evaluation.11 such guidelines should be based on the best scientific evidence and be useful in helping health practitioners select the best options for diagnosis and treatment, support clinical audits and aid in risk management. this article aims to conduct a comprehensive review of cpgs, mainly emphasizing on diagnosis, evaluation and management recommendations. it identifies established differences in practice and standards for the evaluation and diagnosis of adhd by comparing recommendations in the guideline documents. in addition, the methodological quality of the selected adhd guidelines will be further analysed in adolescents and children. this article provides a recommendation about which guidelines will help healthcare professionals provide higher quality care for adolescents and children with adhd and their caregivers. method this literature review used systematic methods to collect secondary data generated between 2008–2018 and critically appraised research studies to synthesise findings on adhd in adolescents and children. medline® (national library of medicine, bethesda, maryland, usa), cumulative index to nursing and allied health literature® (ebsco information services, ipswich, massachusetts, usa), national guideline clearinghouse, nhmrc (the australian national health and medical research council), and the centre for reviews and dissemination of the university of york (university of york, york, uk) figure 1: flowchart showing the process used to identify clinical practice guidelines for the evaluation and diagnosis of attention-deficit/hyperactivity disorder in children and adolescents. hira abdul razzak, nariman ghader, ateeq a. qureshi, mehnaz zafar, jeena f. shaijan and muna al kuwari review | e15 were searched for best practice global evidence and guidelines related to adhd. the following keywords were used: ‘attention deficit hyperactivity disorder’, ‘adhd’, ‘practice guidelines’, “diagnosis” and ‘children and adolescents’ [figure 1]. cross-referencing was also performed to collect further information. cpgs that were conducted exclusively among school-aged children and adolescents with adhd, guidelines that focused on assessment and/or management of adhd, english-language articles and studies conducted by international or national medical societies, health ministries and professional bodies were included. case reports, local protocols, consensus statements, animal studies and previous reviews were excluded. studies not showing results and evidence unrelated to the established objectives were also excluded. the quality of the cpgs was assessed independently by five reviewers, using the appraisal of guidelines for research & evaluation ii (agree ii) tool. agree is an internationally accepted standard for evaluating the methodological quality of all cpgs and was used to assess methodological quality.14 the revised version (agree ii) was launched in 2009. agree ii consists of 23 key items which are rated on a four-point likert scale organised under six domains: applicability, clarity and presentation, rigour of development, stakeholder involvement, scope and purpose and editorial independence. the sum of all domain scores gives a total score. these scores can be presented as a maximum possible percentage for that domain or as a maximum possible total score. the agree ii instrument training manual was used as a resource to guide us. final selection of guidelines was based on the scores on each criterion according to agree-ii instrument.15 the five reviewers performed the scoring and agreed upon the consensus rating for each item score in the cases of initial differences. guidelines that met established inclusion criteria were reviewed and recommendations on assessment/screening and diagnosis were extracted. agree-ii guidelines do not include specific cut-off scores to distinguish between lowor highquality guidelines. to be considered acceptable for this study, a guideline score had to be 60% or above in all domains. these statistics were mainly founded on cutoff scores reported in prior published appraisals of the guidelines.16 scores were calculated as follows: based on the scores, various guidelines were identified as acceptable for the evaluation and diagnosis of adhd. results a total of 18 relevant guidelines were extracted of which five were selected for inclusion: the american academy of paediatrics’ (aap) guidelines, the british association of psychopharmacology (bap) guidelines, the national institute for health and care excellence (nice) guidelines, the scottish intercollegiate guideline network (sign) guidelines and the canadian attention deficit hyperactivity disorder resource alliance (caddra) practice guidelines. table 1 provides an overview of the selected guidelines. the aap (2000, 2001 and 2011) guideline consists of two-parts and were created for primary care physicians by the aap committee on quality improvement.17,18,19 the first part (2000) addressed evaluation and diagnosis and the second part, which was published in 2001, addressed the treatment for uncomplicated adhd cases in 6–12-yearolds presenting to primary care physicians. these guidelines were then updated in 2011. the bap guidelines (2006 and 2014) were the first and foremost adhd guidelines created in the year 2006 and dealt with the management as well as diagnosis of adhd in adolescents and adults who were in a transitional phase to receiving adult services.20,21 the nice guidelines (2008 and 2018) were developed for the national health service (nhs) in wales and england.22,23 these extensive guidelines covered treatment and assessment of patients three years or older. this work was considered to supersede a technology appraisal, which addressed the utilisation of dexamphetamine, atomoxetine and methylphenidate in 2006 among children and adolescents with adhd. for treatment and diagnosis of children over three years of age as well as adults and adolescents suffering from adhd, key priorities were precisely defined. in england and wales, the nice guidelines demonstrated a significant impact on the provision of public health along with extending its influence on some other commonwealth and european countries. this set of guidelines also makes a differential recommendation for adhd pharmacological treatment. nice recommends that pharmacological treatment shall be considered maximum possible score= 7 (strongly agree) × 3 (items) × 5 (appraisers) = 105 [equation 1] minimum possible score= 1 (strongly disagree) × 3 (items) × 5 (appraisers) = 15 [equation 2] scale domain score = × 100 [equation 3]obtained score − minimum possible score maximum possible score clinical practice guidelines for the evaluation and diagnosis of attention-deficit/hyperactivity disorder in children and adolescents a systematic review of the literature e16 | squ medical journal, february 2021, volume 21, issue 1 first-line treatment in adolescents and children and adults with a severe adhd impairment. it should also be part of a comprehensive treatment plan which includes educational, behavioural and psychological interventions. these guidelines additionally recomm end the formation of multiagency groups in all training provisions and localities for teachers or health professionals as well as multidisciplinary specialist adhd clinics or teams. in 2018, these guidelines were updated to improve diagnosis, recommendations table 1: overview of included clinical practice guidelines used for the evaluation and diagnosis of attention-deficit/hyper activity disorder in children and adolescents19,21,23,26,27 clinical practice guideline sign caddra aap bap nice author(s) forbes et al. doron almagor et al. wolraich et al. boleaalamañac baird et al. publication year of latest version 2009 2011 2011 2014 2018 publication year(s) of previous version 2001 2006 and 2008 2001 2006 and 2008 origin scotland canada usa uk uk target group health professional physician primary care clinician gp, paediatrician, camh and psychologist clinician grading of evidence yes yes yes yes yes funding public funding self-funded with individual disclosures unclear pharmaceutical unclear diagnosis yes yes yes yes yes treatment yes yes yes yes yes diagnostic criteria icd-10 and dsm-iv dsm-iv dsm-iv icd-10 and dsm-iv icd-10 and dsm-iv screening yes yes yes yes screening for comorbidities yes yes yes yes yes adhd specialist yes yes yes yes psychiatric interview patient, parents and school patient, parents, school and informants patient, parents, school and informants patient and informants patient and informants questionnaires and rating scales caat to be used optionally: ctrs-r, cprs or ssq-r not recommended for diagnosis: cbcl-r and dsmd–total scale or trf, cprs-r or ctrsrglobal problem index asrs, wurs, bsopa-sc, badds, adhd-rs-iv, asrs-v1.1 or ccsc caadid, conners’ rating scales, sdq or c-gas physical examination yes yes yes yes yes other investigations eeg, blood analysis and brain imaging if essential to exclude underlying medical issues eeg, polysomnography and brain imaging may be indicated thyroid function, blood lead levels, brain imaging, continuous performance tests and eeg not routinely recommended ecg if clinical/ historical indications sign = scottish intercollegiate guideline network; caddra = canadian attention deficit hyperactivity disorder resource alliance; aap = american association of psychopharmacology; bap = british association of psychopharmacology; nice = national institute for health and care excellence; gp = general practitioner; camh = child and adolescent mental health; icd = international classification of diseases; dsm = diagnostic and statistical manual of mental disorders; caat = clinical assessment of attention deficit; ctrs-r = conners’ teacher rating scale-revised; cprs = conners' parent rating scale; ssq-r = school situations questionnaire-revised; cbcl-r = child behaviour checklist-revised; dsmd = deveraux scales of mental disorders; trf = teacher report form; cprs-r = conners' parent rating scale-revised; asrs = adhd self-report scale; wurs = wender utah rating scale; bsopa-sc = barkley self, other and past adhd symptom checklist; badds = brown attention-deficit disorder scales; adhd-rs = adhd rating scale; ccsc = canadian consensus screening checklist; caadid = conners' adult adhd diagnostic interview for dsm-iv; sdq = strengths and difficulties questionnaire; c-gas = children’s global assessment scale; eeg = electroencephalogram; ecg = electrocardiogram. hira abdul razzak, nariman ghader, ateeq a. qureshi, mehnaz zafar, jeena f. shaijan and muna al kuwari review | e17 table 2: pharmacological and psychosocial treatment of attention deficit/hyperactivity disorder recommendations in selected clinical practice guidelines19,21,23,26,27 treatment clinical practice guideline (version) sign (2009) caddra (2011) aap (2011) bap (2014) nice (2018) pharmacological treatment mph flo nrf flo flo flo mph-mr flo flo flo flo flo dexamphetamine flo flo flo flo flo (in young people and children aged five and above) mixed amphetamine nrf flo flo nrf nrf salts lisdexamphetamine nrf flo nrf nrf atomoxetine eflr flo nrf flo flo (in children and adolescents) bupropion eflr eflr os eflr eflr clonidine eflr nrf os eflr eflr guanfacine nrf nrf nrf eflr nrf modafinil eflr nrf eflr eflr pemoline nrf nrf nrf tca eflr eflr os eflr eflr pre-treatment safety measures eflr eflr nrf nrf eflr explicit dose for some agents only eflr eflr nrf eflr titration eflr eflr os nrf eflr monitoring eflr eflr eflr eflr eflr adverse effects eflr eflr eflr eflr eflr contra-indications nrf eflr eflr nrf eflr cost consideration nrf eflr nrf eflr eflr drug holidays nrf nrf (exceptions permitted) nrf nrf nrf (exceptions permitted) psychosocial treatment individual interventions nrf eflr nrf nrf eflr group interventions nrf nrf nrf nrf eflr family-based interventions eflr eflr nrf nrf eflr school-based interventions eflr eflr eflr eflr eflr occupational interventions nrf eflr nrf eflr nrf behavioural training for parents eflr eflr eflr nrf eflr behavioural management nrf eflr nrf nrf eflr psychoeducation eflr eflr eflr eflr eflr family therapy nrf eflr nrf nrf nrf social skills training nrf eflr nrf nrf eflr cognitive therapy nrf nrf nrf nrf cbt nrf eflr nrf eflr sign = scottish intercollegiate guideline network; caddra = canadian attention deficit hyperactivity disorder resource alliance; aap = american association of psychopharmacology; bap = british association of psychopharmacology; nice = national institute for health and care excellence; mph = methylphenidate; flo = first line option; nrf = no recommendation found; mr = modified release; eflr = explicitly favourable recommendation; tca = tricyclic antidepressant; os = outside scope; cbt = cognitive behavioural therapy. clinical practice guidelines for the evaluation and diagnosis of attention-deficit/hyperactivity disorder in children and adolescents a systematic review of the literature e18 | squ medical journal, february 2021, volume 21, issue 1 and quality of care for people with adhd. further clarifications and updates were also made on some of the recommendations, impacts and rationales. both documents (2008 and 2018 versions) have a vibrant cost-effectiveness investigation which addresses the impact of recommendations on the provisions of the healthcare services and healthcare economics. the nice guidelines influence not only adhd care but also the needs for the nhs to offer age-appropriate services for all adhd patients. developed in 2009 to disseminate and develop national cpgs in scotland, the sign (2001, 2005 and 2009) guidelines cover adhd treatment and diagnosis in adolescents and children.24,25,26 sign guidelines play a role in adhd resource allocation and policy-making in scotland’s nhs. in 2011, the caddra practice guidelines for primary care practitioners and specialists were issued both in english and french.27 the guidelines were developed through the consensus of general practitioners, psychiatrists and paediatricians with declared objectives of simplifying care in training and practice and standardising adhd care worldwide. the guidelines are organised based on the complexity of the presenting case and include templates and assessment tools for liaison with and monitoring by external agencies. an online tool kit for primary care practitioners provides free adhd rating scales and structured interview tools for every age group, with precise usage instructions. the caddra guidelines simplify assessment across age groups and allow adhd to be better managed in primary care settings. the most recent versions of the selected guidelines were published between 2009 and 2018. originating from the united kingdom, united states and canada, guidelines showed no significant differences when compared to each other. however, a single particularity was noted for nice and caddra; both guidelines provided recommendations to all age groups, whereas all others focused on only children and adolescents. these guidelines supported the utilisation of categorical diagnostic criteria; the majority recommend using either icd-10 or dsm-iv. recommendations for collateral informants, psychiatric interviews and questionnaire/rating scale use are also provided. all guidelines vary widely in terms of laboratory tests and psychoeducational assessment. neuropsychological evaluation is not essential for establishing an adhd diagnosis through these guidelines. table 2 displays pharmacological and psycho social treatments for adhd. in most guidelines, stimulants constitute the first-line pharmacological choice for the treatment of adhd. caddra (2011) is the only guideline that recommends lisdexam phetamine. in most guidelines, the noradrenaline reuptake inhibitor atomoxetine was considered the preferable treatment option. other drugs, such as tricyclic antidepressants, guanfacine, clonidine and bupropion, are highly recommended for those who have had unsuccessful treatment(s) or suffer any comorbidities, notwithstanding first-line options. pemoline received negative recommendations from aap and bap, based on evidence of liver failure cases. table 2 (cont’d): pharmacological and psychosocial treatment of attention deficit/hyperactivity disorder recommendations in selected clinical practice guidelines19,21,23,26,27 treatment clinical practice guideline (version) sign (2009) caddra (2011) aap (2011) bap (2014) nice (2018) self-help eflr eflr nrf nrf eflr counselling nrf eflr nrf nrf nrf cognitive remediation nrf academic skills nrf nrf nrf carer support eflr eflr eflr nrf nrf other therapies recommended to avoid omega-3 and omega-6 fatty acid supplements, casespecific food additives (þ), zinc supplements, iron supplements, bach flower remedies, antioxidants, neurofeedback, massage therapy and homeopathy anger management, play therapy, interpersonal therapy and expressive arts therapy. play therapy is not recommended nrf elimination and restriction diets not recommended. fatty acid supplements not routinely recommended multimodal interventions eflr eflr eflr nrf eflr sign = scottish intercollegiate guideline network; caddra = canadian attention deficit hyperactivity disorder resource alliance; aap = american association of psychopharmacology; bap = british association of psychopharmacology; nice = national institute for health and care excellence; mph = methylphenidate; flo = first line option; nrf = no recommendation found; mr = modified release; eflr = explicitly favourable recommendation; tca = tricyclic antidepressant; os = outside scope; cbt = cognitive behavioural therapy. hira abdul razzak, nariman ghader, ateeq a. qureshi, mehnaz zafar, jeena f. shaijan and muna al kuwari review | e19 twenty-eight antipsychotics received three positive recommendations in the different guidelines.18,20 a strong disagreement among guidelines related to certain psychosocial interventions for adhd treatment was found. most of the guidelines precisely agreed on the requirements for certain specific forms related to the psychosocial interventions comprising education programmes performed individually with suitable adaptations as required, psychoeducation, support for caregivers and parent training. most of the guidelines recommended that optimal adhd management should usually include some form of psychosocial intervention either with or without medication. table 3 shows the aggregated score results of the five reviewed guidelines. the highest total score was achieved by the nice guidelines followed by the sign, caddra, bap and aap guidelines. all the selected guidelines provide unambiguous and specific recommendations, along with different management options. these recommendations generally yielded scores that reflect clarity in presentation. patient preferences and views were only considered by the nice guidelines. none of the reviewed cpgs was piloted among target users. the documents developed by nice, caddra and sign were revised through an external review process before publication. only the nice guidelines offered a clear timeline and procedure for a continuous revision and considered detailed cost implications of its implementation. two of the guidelines from the uk (i.e. sign and nice) provided materials and criteria for auditing and monitoring purposes mainly derived from their key recommendations. however, only three of the guidelines, caddra (62; 86.6%), sign (62; 86.6%) and bap (60; 83.3%) provided satisfactory information on their editorial independence from the funding body. discussion this comprehensive review of cpgs related to the treatment, management and diagnosis of adhd included five cpgs developed by national medical associations or specialist groups in the uk, usa and canada were reviewed. the reviewed guidelines reflect a diversity of healthcare systems and professionals from primary care to tertiary specialists. the methodol ogical quality of the individual cpgs on the domains of the agree-ii were assessed, allowing for a comparison of cpgs based on these domains. the agree-ii can, therefore, guide clinicians and cpg groups in identifying trustworthy and high-quality evidencebased adhd cpgs using agree-ii criteria.15 the findings of this review can be utilised to inform the development of revised and improved adhd guidelines. most guidelines reviewed describe adhd diagnosis based on a complete clinical interview that comprises impairment assessment, mental state examination, development, family history, comorbidity and physical examination. the child and adolescent adhd guide lines also included a family interview. all guidelines reviewed indicated that clinical interview remains the gold standard of an adhd evaluation. the utilisation of rating scales has improved as has standardised efficiency and their breadth and reliability of assess ment. the importance of excluding psychiatric and physical comorbidity has also been addressed in most of the reviewed guidelines. regarding pharmacological treatment, all the reviewed guidelines suggested utilising stimulants in adolescents and children.19,21,23,25,27 nice recommends prescribing an atypical antipsychotic (i.e. risperidone) along with stimulants for children aged five years and above, young persons and adults with adhd. this recommendation also applies to table 3: aggregated results of selected guidelines according to the appraisal of guidelines for research & evaluation ii tool19,21,23,26,27 category (maximum score) obtained score (%)* sign (2009) caddra (2011) aap (2011) bap (2014) nice (2018) scope and purpose (105) 100 (94.4) 87 (80) 99 (93.3) 87 (80) 105 (100) stakeholder involvement (105) 81 (73.3) 84 (76.6) 87 (80) 84 (76.6) 93 (86.6) rigour of development (280) 240 (83.3) 232 (80) 240 (83.3) 224 (76.6) 264 (93.3) clarity and presentation (105) 90 (83.3) 99 (93.3) 69 (60) 84 (76.6) 102 (96.6) applicability (140) 124 (86.6) 108 (73.3) 100 (66.6) 108 (73.3) 128 (90) editorial independence (70) 62 (86.6) 62 (86.6) 42 (53.3) 60 (83.3) 54 (73.3) total score (805) 693 (83.7%,) 672 (80.7%) 637 (75.6%) 647 (77.1%) 746 (91.4%) sign = scottish intercollegiate guideline network; caddra = canadian attention deficit hyperactivity disorder resource alliance; aap = american association of psychopharmacology; bap = british association of psychopharmacology; nice = national institute for health and care excellence. *the percentages were calculated based on equation 3. clinical practice guidelines for the evaluation and diagnosis of attention-deficit/hyperactivity disorder in children and adolescents a systematic review of the literature e20 | squ medical journal, february 2021, volume 21, issue 1 patients with coexisting pervasive aggression, with rage or irritability causing severe impairment and for those who are inadequately responsive to behavioural interventions.23 moreover, healthcare practice is becoming cons iderably more complex because of several factors. one such aspect is the increasing amount of scientific evidence available. for clinical decisions to be correct, safe and efficient, healthcare providers primarily need to update their knowledge and, to this end, a great deal of effort is being invested in the uae. all cpgs logically defined scope and purpose of the guidelines. caddra and aap guidelines, however, lacked clarity and detail in defining scope and purpose compared to the other included guidelines. the involvement of the patient, family members and other stakeholders at every step of the development process is an essential part of good quality cpgs. such involvement recognises patients as experts and helps develop cpgs that are patient-centred, improving implementation and acceptability.31,32 although all cpgs described stakeholder involvement, this element was not clearly described for every step of the development process; only aap and nice scored ≥80% on this important domain which is a key element of highquality evidence-based cpgs.33 all cpgs, except the bap guidelines, demonstr ated good rigor of development with scores ≥80%. this domain is a strong indicator of overall guideline quality.34,35 three out of the five cpgs scored ≥80% for clarity and presentation, with nice scoring part icularly high; the appraisers’ score for that category in the aap were low (60%), reflecting a lack of clarity in presentation. only the sign and nice guidelines scored >80% on the applicability domain. scores on the applicability domain are a strong indicator of overall quality as well as recommendations for use. low scores on applicability domains for cpgs can raise questions on how recommendations can be implemented.15 the sign, caddra and bap guidelines were scored >80% in the category of editorial independence showing that they are clear and detailed in describing editorial independence. some research has shown that adherence to guidelines by health professionals can be improved by trainings grounded in guideline recommendations.33 this review was subject to certain limitations. one of the limitations of this review is the evaluation of recommendations that do not essentially share a common denominator. moreover, cpgs included were published only in the last ten years and looked at the evidence available at the time, which can explain some of the chronological variability of the recommendations. finally, it is possible that other guidelines might have been missed or may not have been identified. conclusion all cpgs investigated within this systematic review had overall strong scores according to the agreeii instrument. some relevant information such as stakeholder involvement or editorial independence were not always easily accessible or clearly described; future cpg developers should keep these findings in mind. the nice guidelines most recent cpg included, had the highest total score and the highest scores on all domains except editorial independence. the nice guidelines can be used as a model in developing the future adhd guidelines for the uae and globally. cpgs for adhd in the uae must be developed using high quality evidence, while diminishing bias with openness, methodological rigor, stakeholder involvement and transparency. embedding the implementation and use of agree ii for cpgs appraisal in the education and training of healthcare providers is also recommended in future. references 1. barnett r. attention deficit hyperactivity disorder. lancet 2016; 387:737. https://doi.org/10.1016/s0140-6736(16)00332-9. 2. american psychological association. adhd. from: https:// w w w.apa .org/topics/adhd#:~:text=adhd%2c%20or%20 attention%2d defic it%20hy p eractiv ity,plans%20and%20 thinking%20before%20acting accessed: jul 2020. 3. davidovitch m, koren g, fund n, shrem m, porath a. challenges in defining the rates of adhd diagnosis and treatment: trends over the last decade. bmc pediatr 2017; 17:218. https://doi.org/10.1186/s12887-017-0971-0. 4. yousef s, adem a, zoubeidi t, kosanovic m, mabrouk aa, eapen v. attention deficit hyperactivity disorder and environ mental toxic metal exposure in the united arab emirates. j trop pediatr 2011; 57:457–60. https://doi.org/10.1093/tropej/fmq121. 5. herrerias ct, perrin jm, stein mt. the child with adhd: using the aap clinical practice guideline. american academy of pediatrics. am fam physician 2001; 63:1803–10. 6. willcutt eg. the prevalence of dsm-iv attention-deficit/ hyperactivity disorder: a meta-analytic review. neurotherapeutics 2012; 9:490–9. https://doi.org/10.1007/s13311-012-0135-8. 7. american psychiatric association. diagnostic and statistical manual of mental disorders. 5th ed. washington dc, usa: american psychiatric association, 2013. 8. moon s. cultural perspectives on attention deficit hyperactivity disorder: a comparison between korea and the us. j int bus cult stud 2012; 6:1–11. 9. malhi p, singhi p. spectrum of attention deficit hyperactivity disorders in children among referrals to psychology services. indian pediatr 2000; 37:1256–60. 10. bu-haroon a, eapen v, bener a. the prevalence of hyperactivity symptoms in the united arab emirates. nord j psychiatr 1999; 53:439–42. https://doi.org/10.1080/080394899427683. https://doi.org/10.1016/s0140-6736%2816%2900332-9 https://doi.org/10.1186/s12887-017-0971-0 https://doi.org/10.1093/tropej/fmq121 https://doi.org/10.1007/s13311-012-0135-8 https://doi.org/10.1080/080394899427683 hira abdul razzak, nariman ghader, ateeq a. qureshi, mehnaz zafar, jeena f. shaijan and muna al kuwari review | e21 11. crunelle cl, van den brink w, moggi f, konstenius m, franck j, levin fr, et al. international consensus statement on screening, diagnosis and treatment of substance use disorder patients with comorbid attention deficit/hyperactivity disorder. eur addict res 2018; 24:43–51. 12. american psychiatric association. diagnostic and statistical manual of mental disorders. 4th ed, text revision. washington dc, usa: american psychiatric association, 2000. 13. world health organization. icd-10: international statistical classification of diseases and related health problems. 10th revision. from: https://www.who.int/classifications/icd/icd1 0volume2_en_2010.pdf accessed: jul 2020. 14. brouwers mc, kerkvliet k, spithoff k; agree next steps consortium. the agree reporting checklist: a tool to improve reporting of clinical practice guidelines. bmj 2016; 352: i1152. https://doi.org/10.1136/bmj.i1152. 15. hoffmann-eßer w, siering u, neugebauer ea, brockhaus ac, lampert u, eikermann m. guideline appraisal with agree ii: systematic review of the current evidence on how users handle the 2 overall assessments. plos one 2017; 12:e0174831. https://38.doi.org/10.1371/journal.pone.0174831. 16. salarvand s, hemati s, adibi p, taleghani f. a review of the quality of extant clinical practice guidelines in cancer therapy-induced mucositis. international journal of cancer management 2017; 10:e11553. https://doi.org/10.5812/ijcm.11553. 17. american academy of pediatrics (aap), committee on quality improvement subcommittee on attention-deficit/hyperactivity disorder. clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. pediatrics 2000; 105:1158–70. https://doi.org/10.1542/peds.105.5.1158. 18. american academy of pediatrics (aap), committee on quality improvement, subcommittee on attention-deficit/hyperactivity disorder. clinical practice guideline: treatment of the school aged child with attention-deficit/hyperactivity disorder. pediatrics 2001; 108:1033–44. https://doi.org/10.1542/peds.108.4.1033. 19. adhd: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/ hyperactivity disorder in children and adolescents2011. from: https://turnersyndro mefoundation.org/wp-content/uploads/2017/07/adhdguidelines-peds.2011-2654.full.pdf accessed: jul 2020. 20. nutt dj, fone k, asherson p, bramble d, hill p, matthews k, et al. british association for psychopharmacology. evidence based guidelines for management of attention deficit/hyper activity disorder in adolescents in transition to adult services and in adults: recommendations from the british association for psychopharmacology. j psychopharmacol 2007; 21:10–41. https://doi.org/10.1177/0269881106073219. 21. bolea-alamañac b, nutt dj, adamou m, asherson p, bazire s, coghill d, et al. evidence-based guidelines for the pharmacol ogical management of attention deficit hyperactivity disorder: update on recommendations from the british association for psychopharmacology. j psychopharmacol 2014; 28:179–203. https://doi.org/10.1177/0269881113519509. 22. national institute for health and clinical excellence (nice). attention deficit hyperactivity disorder – diagnosis and management of adhd in children, young people and adults. nice clinical guideline 72. london: the british psychological society and the royal college of psychiatrists, 2008. 23. national institute for health and clinical excellence (nice). attention deficit hyperactivity disorder: diagnosis and manage ment. london: national institute for health and clinical excellence, 2018. 24. scottish intercollegiate guidelines network. sign 50: a guideline developers’ handbook. edinburgh, scotland: sign, 2001. 25. the scottish intercollegiate guidelines network (sign): an update. scott med j 2005; 50:51–2. https://doi.org/10.1177/00 3693300505000202. 26. scottish intercollegiate guidelines network (sign) (manage ment of attention deficit and hyperactivity disorders in children and young people – a national clinical guideline. edinburgh: scottish intercollegiate guidelines network (sign). 2009. from: www.argyll-bute.gov.uk/sites/default/files/adhd_informtion.pdf accessed: jul 2020. 27. canadian attention deficit hyperactivity disorder resource alliance (caddra): canadian adhd practice guidelines [internet], 3rd ed. toronto, canada: caddra, 2011. 28. rosh jr, narkewicz ml, birnbaum ah, whitington gl. pemoline associated severe hepatic dysfunction and failure† 509. pediatric res 1997; 41:87. 29. bennett k, gorman da, duda s, brouwers m, szatmari p. practitioner review: on the trustworthiness of clinical practice guidelines a systematic review of the quality of methods used to develop guidelines in child and youth mental health. j child psychol psychiatry 2016; 57:662–73. https://doi.org/10.1111/ jcpp.12547. 30. subcommittee on attention-deficit/hyperactivity disorder; steer ing committee on quality improvement and management; wolraich m, brown l, brown rt, dupaul g, et al. adhd: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. paediatrics 2011; 128:1007–22. https://doi. org/10.1542/peds.2011-2654. 31. van der ham aj, van erp n, broerse je. monitoring and evaluation of patient involvement in clinical practice guideline development: lessons from the multidisciplinary guideline for employment and severe mental illness, the netherlands. health expect 2016; 19:471–82. https://doi.org/10.0000/hex.12370. 32. selva a, sanabria aj, pequeño s, zhang y, solà i, pardohernandez h, et al. incorporating patients’ views in guideline development: a systematic review of guidance documents. j clin epidemiol 2017; 88:102–12. https://doi.org/10.1016/j.jclin epi.2017.05.018. 33. wolraich ml, bard de, stein mt, rushton jl, o’connor kg. pediatricians’ attitudes and practices on adhd before and after the development of adhd pediatric practice guidelines. j atten disord 2010; 13:563–72. https://doi.org/10.1177/108705 4709344194. 34. alonso-coello p, irfan a, solà i, gich i, delgado-noguera m, rigau d, et al. the quality of clinical practice guidelines over the last two decades: a systematic review of guideline appraisal studies. qual saf health care 2010; 19:e58. https://doi.org/10.1 136/qshc.2010.042077. 35. brosseau l, rahman p, poitras s, toupin-april k, paterson g, smith c, et al. a systematic critical appraisal of non-pharma cological management of rheumatoid arthritis with appraisal of guidelines for research and evaluation ii. plos one 2014; 9:e95369. https://doi.org/10.1371/journal.pone.0095369. https://doi.org/10.1136/bmj.i1152 https://38.doi.org/10.1371/journal.pone.0174831 https://doi.org/10.5812/ijcm.11553 https://doi.org/10.1542/peds.105.5.1158 https://doi.org/10.1542/peds.108.4.1033 https://doi.org/10.1177/0269881106073219 https://doi.org/10.1177/0269881113519509 https://doi.org/10.1177/003693300505000202 https://doi.org/10.1177/003693300505000202 https://doi.org/10.1111/jcpp.12547 https://doi.org/10.1111/jcpp.12547 https://doi.org/10.1542/peds.2011-2654 https://doi.org/10.1542/peds.2011-2654 https://doi.org/10.0000/hex.12370 https://doi.org/10.1016/j.jclinepi.2017.05.018 https://doi.org/10.1016/j.jclinepi.2017.05.018 https://doi.org/10.1177/1087054709344194 https://doi.org/10.1177/1087054709344194 https://doi.org/10.1136/qshc.2010.042077 https://doi.org/10.1136/qshc.2010.042077 https://doi.org/10.1371/journal.pone.0095369 1endocrinology & metabolism institute, cleveland clinic, cleveland, oh, usa; 2the university of jordan school of medicine, amman, jordan; 3department of maternal and child health nursing, the university of jordan school of nursing, amman, jordan *corresponding author’s e-mail: borgans@ccf.org attitudes of physicians in jordan towards non-disclosure of health information *saif m. borgan,1 justin z. amarin,2 areej k. othman,3 haya h. suradi,2 yasmeen z. qwaider2 clinical & basic research sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 423–427, epub. 29 aug 21 submitted 22 apr 20 revision req. 21 dec 20; revision recd. 15 aug 20 accepted 20 sep 20 https://doi.org/10.18295/squmj.4.2021.005 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this report aims to investigate the attitudes of physicians in jordan towards non-disclosure of health information among physicians, with a focus on those who are ‘always truthful’ and those who are not. methods: the report is based on the second subset of data from a cross-sectional study—conducted between january and august 2016—of the truth disclosure practices among and attitudes of physicians in jordan. the sample consisted of 240 physicians selected from four major hospitals by stratified random sampling and invited to complete a selfadministered questionnaire regarding truth disclosure attitudes. the attitudes of physicians who were ‘always truthful’ were compared with those who were not. results: a total of 164 physicians (response rate: 68%) completed the questionnaire. of these, 17 (10%) were ‘always truthful’, while the remaining 144 (90%) were not. physicians who were ‘always truthful’ were more likely to indicate that non-disclosure is ‘unethical’ (77% versus 39%; p = 0.009). moreover, physicians who were ‘always truthful’ were more likely to disagree that non-disclosure is beneficial for the physical and psychological health of patients (82% versus 55%; p = 0.03). most of the surveyed physicians agreed that all patients have the right to know their diagnosis, most patients prefer to know their diagnosis and the introduction of legislation to enforce disclosure would positively affect medical practice in jordan. conclusion: the differential attitudes of physicians who were ‘always truthful’ and those who were ‘not always truthful’ suggests a rationale behind independent non-disclosure; namely, that non-disclosure is ethically justifiable and beneficial for the physical and psychological health of patients. keywords: truth disclosure; physicians; attitude; middle east; cross-sectional studies; jordan. advances in knowledge physicians who were ‘not always truthful’ were more likely to agree that non-disclosure is beneficial for the physical and psychological health of patients, which suggests that therapeutic privilege is one possible ethical rationale for non-disclosure. of the physicians who were ‘not always truthful’, 39% indicated that non-disclosure is ‘unethical’, which suggests that these physicians may feel pressured to comply with sociocultural norms that they do not necessarily agree with. application to patient care physicians who were ‘always truthful’ and those who were ‘not always truthful’ generally believed that the introduction of legislation to enforce disclosure would positively affect medical practice (and therefore, patient care) in jordan. non-disclosure of health information was widely prevalent in 20th-century western medicine.1,2 in 1961, oken reported that 90% of a sample of physicians in the united states indicated a preference for not telling cancer patients they have cancer.2 non-disclosure has since dramatically decreased in the united states and is unjustified by contemporary ethics.3,4 in many courts, nondisclosure is considered negligent and illegal and ‘therapeutic privilege’ is not a valid defence because discretion cannot take precedence over informed consent.4 however, non-disclosure remains prevalent in more conservative countries including japan, china, pakistan and many countries in the middle east.5–8 in these countries, multiple factors motivate truth non-disclosure; however, sociocultural factors, such as strong family influence, appear to be the main drivers.9,10 in the context of cancer, for example, families often request non-disclosure because of the associated stigma, misconceptions regarding prognosis and their perceptions of the negative effect of disclosure on patient well-being.7 non-disclosure practices are further propagated by the lack of transparent legislation to protect patient autonomy. from the perspective of physicians, disclosure may theoretically conflict with other ethical principles, such as beneficence and non-maleficence. for instance, some physicians believe that informing patients with a terminal illness of their prognosis results in ‘unnecessary’ psychological suffering and is medically contraindicated.1,11 non-disclosure motivated by this reason is termed ‘therapeutic privilege’.11 similar to other countries in the middle east, jordan’s culture is heavily influenced by family-centred values. the current researchers previously conducted a cross-sectional study to investigate truth disclosure practices of physicians in jordan.10 in 2018, the researchers reported that 23% of physicians do not https://creativecommons.org/licenses/by-nd/4.0/ attitudes of physicians in jordan towards non-disclosure of health information 424 | squ medical journal, august 2021, volume 21, issue 3 usually disclose the truth to a patient with a serious illness and are commonly motivated by a direct request from the patient’s family. however, 15% of physicians who do not usually disclose the truth do so independently—with no impetus from the patient’s family—and current evidence does not explain the rationale behind independent non-disclosure in jordan.10 this study aimed to investigate the attitudes of physicians in jordan towards non-disclosure, with a secondary focus on the differences in attitude between those who are ‘always truthful’ and those who are not. methods the current investigation is based on the second subset of data from a cross-sectional study of truth disclosure practices and attitudes of physicians in jordan, which was conducted between january and august 2016.10 the researchers’ previous report explored the truth disclosure practices of physicians in jordan. in the current study, the attitudes of physicians who always disclose the truth are compared with those who do not. the physicians employed by two of the largest hospitals from each of the public and private sectors in amman, the capital of jordan, were surveyed. the total bed capacity of the four hospitals is 1,524.10 the lists of physicians employed by each hospital were obtained and used to select the preliminary sample by stratified random sampling. paediatricians and psychiatrists were excluded because they deal with unique and specific truth disclosure considerations. sixty participants from each participating hospital were randomly selected using an online random number generator based on atmospheric noise for a total preliminary sample of 240 participants. the participants were approached during office hours, introduced to the study and invited to participate by completing a self-administered questionnaire. a questionnaire developed by hamadeh and adib was modified, following permission, to accommodate the sample.12 the questionnaire includes closed-ended and likert-type questions regarding attitudes towards non-disclosure of health information. the language of complex and ambiguous questions was respectively simplified and clarified, as identified by a pilot sample of 15 physicians employed by a small private hospital in amman. two independent experts were also asked to review the face and content validity of the questionnaire. statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa) was used to perform data analysis. first, descriptive statistics were computed. second, physicians were stratified according to their disclosure policy: ‘always truthful’ versus ‘not always truthful’. physicians whose usual disclosure policy was to ‘informed’ and who reported never making exceptions to their policy were considered ‘always truthful’. physicians who reported a usual ‘do not inform’ policy or those who reported a ‘informed’ policy but reported making exceptions of any frequency were considered ‘not always truthful’. finally, the association between questions concerning disclosure policy and truth disclosure attitude was investigated using pearson’s χ2 test and values of p <0.05 were interpreted as statistically significant. throughout the report, numerical data are presented according to the recommendations of cole.13 the ethics committees of all participating hospitals approved the study protocol and waived the requirement for written consent. verbal consent from each participant was obtained. results out of 240 invitees, 164 (response rate: 68%) completed the questionnaire. the characteristics of the sample have been described previously.10 it was found that 126 physicians (77%) were non-specialists and 38 (23%) were specialists; 113 (69%) were men and 51 (31%) were women; and 95 (58%) worked in the private sector while 69 (42%) worked in the public sector [table 1]. the usual disclosure policy of 127 physicians (77%) was to inform, compared with 37 (23%) whose usual disclosure policy was not to inform. according to their reported disclosure policy, 17 physicians (10%) were ‘always truthful’, while the remaining 147 (90%) were not [table 2]. in total, 19 physicians (12%) indicated that nondisclosure is ethical, 70 (43%) indicated that nondisclosure is unethical and 75 (46%) indicated that it depends on the situation. physicians who were ‘always truthful’ were more likely to indicate that non-disclosure is unethical (77% versus 39%; χ2(2) = 9.3, p = 0.009). notably, none of the physicians who were ‘always truthful’ indicated that non-disclosure is ethical. in addition, 69 physicians (42%) agreed that non-disclosure is beneficial for the physical and psychological health of patients, while 95 (58%) disagreed [table 2]. physicians who were ‘always truthful’ were more likely to disagree (82% versus 55%; χ2(1) = 4.7, p = 0.03). among the physicians belonging to the ‘not always truthful’ group, when asked if they agreed that ‘all patients have the right to know their diagnosis’, 94 (57%) strongly agreed, 61 (37%) agreed, seven (4%) were neutral and two (1%) disagreed. these physicians were also asked if they agreed that ‘most patients prefer to know their diagnosis’ and 59 (36%) strongly agreed, 75 saif m. borgan, justin z. amarin, areej k. othman, haya h. suradi and yasmeen z. qwaider clinical and basic research | 425 (46%) agreed, 16 (10%) were neutral, 10 (6%) disagreed and four (2%) strongly disagreed. the distribution of responses for physicians who were ‘always truthful’ and those who were ‘not always truthful’ are presented in figures 1 and 2. if they were to fall seriously ill, 140 physicians (85%) indicated that they would want to be informed of their diagnosis directly, while 19 (12%) indicated that they would want their family to make the decision to inform them or not and five (3%) indicated that they would not want to be informed at all. the distribution table 1: characteristics of the included physicians from four hospitals in amman, jordan (n = 164) characteristic n (%) age group 20–29 years 97 (59) 30–39 years 41 (25) 40+ years 26 (16) gender male 113 (69) female 51 (31) employment sector public 69 (42) private 95 (58) nationality jordanian 144 (88) other 20 (12) marital status single 85 (52) engaged 8 (5) married 69 (42) other 2 (1) level of specialisation general practitioner 31 (19) resident 95 (58) specialist 38 (23) physician experience 1–5 years 113 (69) 6–10 years 22 (13) >10 years 29 (18) table 2: attitudes towards non-disclosure of medical information among included physicians from four hospitals in amman, jordan attitude n (%) policy on disclosing the diagnosis of ‘serious illness’ directly to a competent adult patient inform 127 (77) do not inform 37 (23) consistency of truthfulness always truthful 17 (10) not always truthful 147 (90) perceived ethics of non-disclosure* ethical 19 (12) unethical 70 (43) depends on the situation 75 (46) perceived physical and psychological benefit of nondisclosure to patients* beneficial 69 (42) not beneficial 95 (58) *statistically significant difference in this attitude between physicians who are ‘always truthful’ and those who are not. figure 1: ratings of 164 physicians from amman, jordan, regarding their perception of a patient’s right to know their diagnosis stratified by disclosure policy using a likert-type scale. figure 2: ratings of 164 physicians from amman, jordan, regarding their perception of a patient’s preference to know their diagnosis stratified by disclosure policy using a likert-type scale. attitudes of physicians in jordan towards non-disclosure of health information 426 | squ medical journal, august 2021, volume 21, issue 3 of responses in favour of direct disclosure was similar for physicians who were ‘always truthful’ and those who were ‘not always truthful’ (94% and 84%, respectively; χ2(1) = 1.2, p = 0.3). finally, 151 physicians (92%) believed that the introduction of legislation to enforce disclosure would positively affect medical practice in jordan, while 12 (8%) did not. once again, the distribution of positive responses was similar for physicians who were ‘always truthful’ and those who were ‘not always truthful’ (94% versus 92%; χ2(1) = 0.1, p = 0.7). compared with physicians working in the private sector, those working in the public sector were more likely to believe that the introduction of legislation to enforce disclosure would positively affect medical practice in jordan (87% versus 99%; χ2(1) = 6.8, p = 0.009). discussion in this study, the attitudes of physicians in jordan towards non-disclosure of health information are explored with a secondary focus on the difference in attitudes between those who were classified as ‘always truthful’ and those who were not. it was found that physicians who were ‘always truthful’—the minority— were more likely to indicate that non-disclosure is unethical and unbeneficial for the physical and psychological health of patients. most of the surveyed physicians (including those who were ‘not always truthful’) indicated that all patients have the right to know their diagnosis, most patients prefer to know their diagnosis and the introduction of legislation to enforce disclosure would positively affect medical practice in jordan. in jordan, non-disclosure of health information is prevalent; the researchers previously reported that the usual policy of 23% of a sample of physicians was not to disclose.10 sociocultural factors are often the drivers of non-disclosure.9,10 however, the attitudes of physicians may also be influential. for example, the researchers also showed that 15% of physicians who do not usually disclose the truth do so independently and that truth disclosure practices vary widely from hospital to hospital and even within the same hospital.10 in this study, it was found that none of the physicians who were ‘always truthful’ indicated that non-disclosure is ethical, which reflects a hard-line, black-and-white stance on truth disclosure. in the grey area, many people in the middle east would not want the truth disclosed to them.8 indeed, in a lebanese study of 498 participants, including patients with cancer, patients with no cancer and healthy people, 42% indicated a preference for non-disclosure.14 however, recent evidence suggests that the attitudes of both physicians and the public are shifting in favour of personal autonomy.8,15 in support, the researchers of the current study also posed a reverse scenario and found that 85% of physicians indicated that they would want to be informed of their diagnosis directly if they were to fall seriously ill. it was also found that most of the physicians surveyed as part of the present investigation, who were ‘not always truthful’, indicated that whether non-disclosure is ethical ‘depends on the situation’. according to previous studies, a physician is less likely to disclose sensitive health information if the patient has a poor prognosis, such as end-stage cancer or limited life expectancy or if the physician is wary of characteristics that signal a limited ability to cope with the truth, such as advanced age or preference for nondisclosure.12,16,17 in these situations, physicians may invoke therapeutic privilege as the ethical rationale for non-disclosure; disclosure may be considered cruel and likely debilitative to patient well-being. indeed, therapeutic privilege may inform the attitudes of both physicians and the public towards non-disclosure.8,16 in support, this study found that physicians who were ‘not always truthful’ were more likely to agree that non-disclosure is beneficial for the physical and psychological health of patients. it was also found that some of the physicians who were ‘not always truthful’ indicated that nondisclosure is ‘unethical’. these physicians may feel pressured to comply with sociocultural norms that they do not necessarily agree with. based on the researchers’ own observations, the repercussions of disclosing the diagnosis of a serious illness against the family’s wishes are grave and the physician-familypatient relationship may break down as a result. in eastern cultures, physicians often make medical decisions with input from the patient’s family.18 hence, they may be compelled to withhold information from the patient for the sake of maintaining the relationship with the family so the patient can continue to receive the necessary treatment. it is not clear whether there is a culturally specific and realistic approach to truth disclosure in the middle east, a deficiency that must be addressed in future studies. while further data are needed to develop an evidence-based approach, culturally specific guidelines based on experience are necessary to support patient autonomy and alleviate the fears and misconceptions of physicians regarding truth disclosure. this study shows that physicians who were ‘always truthful’ and those who were ‘not always truthful’ generally believe that the introduction of legislation to enforce disclosure would positively affect medical practice in jordan. this finding has also been shown in a parallel saif m. borgan, justin z. amarin, areej k. othman, haya h. suradi and yasmeen z. qwaider clinical and basic research | 427 study of physicians in bahrain.19 it is expected that the guidelines will have a bigger impact on the public sector, as supported by the attitudes of physicians, because the private sector in jordan operates under limited governmental and public policy oversight. however, the overwhelming majority of physicians within both sectors believed that introducing truth disclosure legislation would have a positive impact. the main limitations of the current study are potential non-response bias and selection bias. for example, the attitudes of physicians who chose not to participate may be considerably different from those who did. in addition, the four selected hospitals are set in urban areas and the attitudes of physicians in rural areas may also be vastly different. finally, the small number of physicians who were ‘always truthful’— though telling—limits the validity of the comparative analysis. conclusion the differential attitudes of physicians who were ‘always truthful’ and those who were ‘not always truthful’ suggests a rationale behind independent non-disclosure, namely that non-disclosure is ethical and beneficial for the physical and psychological health of patients. regardless of disclosure policy, the introduction of legislation to enforce truth disclosure appears to be welcomed by most physicians. f u n d i n g this work was supported by a grant from the university of jordan deanship of scientific research. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. a u t h o r s’ c o n t r i b u t i o n smb conceived the study. smb and ako designed the study and modified the questionnaire. jza, hhs and yzq collected the data. jza performed the data analysis. smb and jza wrote the manuscript. all authors reviewed and approved the final version of the manuscript. references 1. gillon r. telling the truth and medical ethics. br med j (clin res ed) 1985; 291:1556–7. https://doi.org/10.1136/bmj.291.65 08.1556. 2. oken d. what to tell cancer patients: a study of medical attitudes. jama 1961; 175:1120–8. https://doi.org/10.1001/jama.1961.03 040130004002. 3. fallowfield lj, jenkins va, beveridge ha. truth may hurt but deceit hurts more: communication in palliative care. palliat med 2002; 16:297–303. https://doi.org/10.1191/0269216302pm 575oa. 4. edwin ak. don’t lie but don’t tell the whole truth: the thera peutic privilege – is it ever justified? ghana med j 2008; 42:156–61. 5. uchitomi y, yamawaki s. truth-telling practice in cancer care in japan. ann n y acad sci 1997; 809:290–9. https://doi.org/10.11 11/j.1749-6632.1997.tb48092.x. 6. li s, chou jl. communication with the cancer patient in china. ann n y acad sci 1997; 809:243–8. https://doi.org/10.1111/j.17 49-6632.1997.tb48087.x. 7. malik ia, qureshi af. communication with cancer patients: experiences in pakistan. ann n y acad sci 1997; 809:300–8. https://doi.org/10.1111/j.1749-6632.1997.tb48093.x. 8. bou khalil r. attitudes, beliefs and perceptions regarding truth disclosure of cancer-related information in the middle east: a review. palliat support care 2013; 11:69–78. https://doi.org/10.10 17/s1478951512000107. 9. ni yh, alræk t. what circumstances lead to non-disclosure of cancer-related information in china? a qualitative study. support care cancer 2017; 25:811–6. https://doi.org/10.1007/ s00520-016-3464-z. 10. borgan sm, amarin jz, othman ak, suradi hh, qwaider yz. truth disclosure practices of physicians in jordan. j bioeth inq 2018; 15:81–7. https://doi.org/10.1007/s11673-018-9837-x. 11. richard c, lajeunesse y, lussier mt. therapeutic privilege: between the ethics of lying and the practice of truth. j med ethics 2010; 36:353–7. https://doi.org/10.1136/jme.2009.033340. 12. hamadeh gn, adib sm. cancer truth disclosure by lebanese doctors. soc sci med 1998; 47:1289–94. https://doi.org/10.10 16/s0277-9536(98)00203-2. 13. cole tj. too many digits: the presentation of numerical data. arch dis child 2015; 100:608–9. https://doi.org/10.1136/arch dischild-2014-307149. 14. adib sm, hamadeh gn. attitudes of the lebanese public regarding disclosure of serious illness. j med ethics 1999; 25:399–403. https://doi.org/10.1136/jme.25.5.399. 15. naji f, hamadeh g, hlais s, adib s. truth disclosure to cancer patients: shifting attitudes and practices of lebanese physicians. ajob empir bioeth 2015; 6:41–9. https://doi.org/10.1080/2329 4515.2014.996265. 16. harrison a, al-saadi am, al-kaabi as, al-kaabi mr, albedwawi ss, al-kaabi so, et al. should doctors inform terminally ill patients? the opinions of nationals and doctors in the united arab emirates. j med ethics 1997; 23:101–7. https:// doi.org/10.1136/jme.23.2.101. 17. ozdogan m, samur m, bozcuk hs, coban e, artac m, savas b, et al. “do not tell”: what factors affect relatives’ attitudes to honest disclosure of diagnosis to cancer patients? support care cancer 2004; 12:497–502. https://doi.org/10.1007/s00520-0040633-2. 18. al-bahri a, al-moundhri m, al-azri m. the role of patients’ families in cancer treatment decision-making: perspectives among eastern and western families. sultan qaboos univ med j 2017; 7:e383–5. https://doi.org/10.18295/squmj.2017.17.04.001. 19. jassim, g, alakri, a, alsayegh, r, misselbrook, d. practice and attitudes of physicians regarding disclosure of information to patients with serious illness. glob j health sci 2019; 11:33–40. https://doi.org/10.5539/gjhs.v11n5p33. https://doi.org/10.1136/bmj.291.6508.1556 https://doi.org/10.1136/bmj.291.6508.1556 https://doi.org/10.1001/jama.1961.03040130004002 https://doi.org/10.1001/jama.1961.03040130004002 https://doi.org/10.1191/0269216302pm575oa https://doi.org/10.1191/0269216302pm575oa https://doi.org/10.1111/j.1749-6632.1997.tb48092.x https://doi.org/10.1111/j.1749-6632.1997.tb48092.x https://doi.org/10.1111/j.1749-6632.1997.tb48087.x https://doi.org/10.1111/j.1749-6632.1997.tb48087.x https://doi.org/10.1111/j.1749-6632.1997.tb48093.x https://doi.org/10.1017/s1478951512000107 https://doi.org/10.1017/s1478951512000107 https://doi.org/10.1007/s00520-016-3464-z https://doi.org/10.1007/s00520-016-3464-z https://doi.org/10.1007/s11673-018-9837-x https://doi.org/10.1136/jme.2009.033340 https://doi.org/10.1016/s0277-9536(98)00203-2 https://doi.org/10.1016/s0277-9536(98)00203-2 https://doi.org/10.1136/archdischild-2014-307149 https://doi.org/10.1136/archdischild-2014-307149 https://doi.org/10.1136/jme.25.5.399 https://doi.org/10.1080/23294515.2014.996265 https://doi.org/10.1080/23294515.2014.996265 https://doi.org/10.1136/jme.23.2.101 https://doi.org/10.1136/jme.23.2.101 https://doi.org/10.1007/s00520-004-0633-2 https://doi.org/10.1007/s00520-004-0633-2 https://doi.org/10.18295/squmj.2017.17.04.001 https://doi.org/10.5539/gjhs.v11n5p33 1 submitted 21 dec 22 1 revision req. 13 feb & 26 apr 23; revision recd. 19 mar & 24 may 23 2 accepted 20 jun 23 3 online-first: july 2023 4 doi: https://doi.org/10.18295/squmj.7.2023.044 5 6 expression patterns of er, pr, her-2/neu and p53 in association with 7 nottingham tumor grade 8 a retrospective hospital-based study 9 *kamoru a. adedokun,1 waheed a. oluogun,2 musiliu a. oyenike,3 sikiru o. 10 imodoye,4 lukman a. yunus,2 ismaila a. lasisi,5 ibrahim o. bello,6 ramat t. 11 kamorudeen,7 saheed a. adekola8 12 13 1department of immunology, roswell park comprehensive cancer center, buffalo, new york, 14 usa; 2department of morbid anatomy and histopathology osun state university teaching 15 hospital (uniosunth), osogbo, nigeria; 3department of medical laboratory science, ladoke 16 akintola university of technology, ogbomosho, oyo state, nigeria; 4department of oncological 17 sciences, huntsman cancer institute, university of utah, salt lake city, utah, usa; 5laboratory 18 unit, health centre, osun state polytechnic iree, osun state, nigeria; 6department of biological 19 sciences, southern illinois university at edwardsville, edwardsville, illinois, usa; 7department 20 of public health, university of south wales, pontypridd, uk; 8mbm molecular laboratory, 21 dubai, united arab emirate. 22 *corresponding author’s e-mail: adeolokun@yahoo.com 23 24 abstract 25 objectives: histological grading has been an integral part of cancer diagnosis for a long time. recent 26 molecular studies show that breast cancer is a heterogeneous disease, and several molecular changes 27 may accumulate over time to influence treatment response. as a result, employing reliable molecular 28 biomarkers to monitor these modifications may help deliver personalized treatment. however, this 29 may be unrealistic in the resource-limited parts of the world. thus, we studied the expression pattern 30 of hormone receptors and p53 tumor suppressor using immunohistochemistry (ihc) in breast cancer 31 2 (bc) compared to the traditional tumor grade. methods: two hundred and five (n =205) cases were 32 investigated. the modified bloom-richardson score system was adopted in grading the tumors. 33 tissue sections of the cases were stained with specific primary antibodies (at dilutions of 1:60 for 34 estrogen (er) and progesterone receptors (pr), 1:350 for human epidermal growth factor (her-35 2/neu), and 1:50 for p53. the chi-square test was used to determine the association between the 36 tumor grade and ihc markers. results: invasive ductal carcinoma of no-specific type (190 37 cases;92.7%) was predominant. grade ii tumor (n =146; 71.22%) was the most frequent. hormone 38 receptors (er+; n =227 and pr+; n =145) had 62.0% and 70.7% positive cases; 34.2% (n =70) were 39 positive for her-2/neu, while 76.1% (n =156) were positive for p53. we observed strong associations 40 between nottingham grade and expression patterns of er (p ˂ 0.01), pr (p ˂ 0.001), her-2/neu (p 41 ˂ 0.001), and p53 (p =0.001). conclusion: nottingham grade has a high degree of concordance with 42 the patterns of expression of hormone receptors, her-2/neu, and p53, suggesting that it may play an 43 important role in connection with the predictive and prognostic biomarkers for bc. 44 keywords: breast cancer, her-2/neu, hormone receptor, nottingham grade, p53 mutation. 45 46 advances in knowledge 47 • grade ii tumors displayed higher levels of er and pr expression than grade iii tumors, 48 indicating that as the disease progresses, the proportion of cells expressing er and/or pr steadily 49 declines. 50 • similarly, we observed higher hr positivity than in many black populations, including guinea, 51 ghana, south africa, and mali emphasizing potential identifiable intra-racial factors influencing 52 the diverse variation. 53 • some patients had higher grades in the her-2/neu+ expression group than in the her-2/neu54 expression group but lower in er+ and pr+ expressions compared to erand prof the highest 55 grade iii. 56 • we found a higher her-2+ than the majority of previous studies, but most of these cases co-57 expressed hr+ with her-2/neurather than her-2+ tumors, indicating that the cancer cells are 58 responsive to hormone treatment, have a better prognosis, and are less aggressive, contrary to 59 the common opinion that black population has aggressive breast cancer presentation. 60 • the proportion of tnbc patients was rather low, implying that hormone therapy or targeted 61 therapies targeting at her-2 would benefit the majority of our cancer patients. 62 63 3 application to patient care: 64 • our study shows that cancer phenotype can exhibit location-dependent variations due to several 65 factors including genetic predisposition, lifestyle, and environmental influences. 66 • we observed that the underlying factors for regional, ethnic or racial variation can impact the 67 expression patterns of various biomarkers. 68 • as a result, this study implies that understanding regional variations in cancer phenotype and 69 biomarker expression patterns, as well as tumor grade, can help guide personalized treatment 70 decisions, optimize therapy selection, and perhaps improve patient outcomes. 71 72 introduction 73 cancer continues to be one of the deadliest noncommunicable diseases worldwide.1 although the 74 literature shows that bc is more common in developed countries, a recent globocan estimate 75 shows that africa constitutes a nerve-racking proportion of bc deaths, possibly due to poorer 76 prognosis and limited access to appropriate diagnosis and treatment.2 before the advent of molecular 77 diagnosis, most cases of bc were solely diagnosed using histological methods. yet, the histological 78 method is still commonly and exclusively used, especially in low-resource settings in many african 79 countries.3 80 81 in this new genomic era, molecular markers are gaining wide acceptance as sensitive and inclusive 82 methods to understand the behavior of advanced cancers. specifically, hormone receptors, p53, 83 ki67, and human epidermal growth factor receptor 2 (her-2/neu) are used for the diagnosis, 84 classification, prognosis, and prediction of response to therapy in bc; even so, histological 85 assessment is used primarily.4 each of these biomarkers is important in diagnosing bc and may 86 sometimes correlate with other disease diagnostic indicators. overexpression of her-2/neu has been 87 linked to a higher histological grade, increased tumor size, the number of affected lymph nodes, p53 88 mutation, and lower er expression (or even er expression in some cases).5 similarly, er and pr 89 patterns have been linked to bc grade, potentially influencing treatment options.6,7 furthermore, a 90 mutation in the p53 gene, a tumor suppressor gene, represents a genetic predisposition to cancers 8 91 and has been associated with tumor aggressiveness 9, making them a possible indicator of 92 histological grade. 93 94 4 meanwhile, histological grade enables a description of a tumor's level of aggressiveness and is 95 regarded as a forerunner for morphological evaluation of tumor biological characteristics.10 96 according to a study on gene expression, histological grade reveals information about the molecular 97 makeup of bc in addition to tumor size or lymph node involvement.11 furthermore, evidence from 98 genome-wide microarray-based expression profiling elucidates many characteristics of tumor 99 biology in bc, adding to the evidence that the biological features revealed by histological grade are 100 critical in determining tumor behavior. 10 101 102 the investigation of the connection between histological grade and molecular biomarker expression 103 patterns is thought to add to the body of diagnostic knowledge, particularly in the areas where 104 molecular testing is currently lacking. even though they are complementary, more research is needed 105 to determine the magnitude of the relationship between traditional tumor grading and the more 106 contemporary ihc methodologies, particularly regarding expression patterns. this attempt may 107 highlight the importance of histological grade in low-resource settings as a low-cost, easy, accurate, 108 and validated approach to diagnosing bc. in the present study, we investigated the frequency and 109 patterns of expression of some clinically significant molecular markers in patients with bc. we 110 explored the link between the biomarkers' expression patterns and histological tumor grade to 111 determine their role in disease diagnosis. 112 113 methods 114 study design and patients 115 this investigation was a hospital-based retrospective study. it involved archival tissue blocks and 116 records of female patients older than 18 years referred to lautech hospitals in osogbo and 117 ogbomosho, osun and oyo states, respectively (at the time of the investigation). the study included 118 patients on record between 2005 and 2014 for breast biopsy or surgery diagnosed with bc in their 119 pathology reports. 120 121 slide preparation 122 tissue blocks were retrieved and new thin sections of about 3µm were made using rotary microtome 123 from formalin-fixed paraffin-embedded blocks following a previous method.3 124 125 5 clinicopathological features 126 data vis-à-vis; age, histological grade, nuclear grade, tumor size, and lymph node involvement were 127 extracted from patients’ records. 128 129 tumor classification 130 histological classification of the breast tumor was made following world health organization 131 (who) guidelines. tumor grading was done using nottingham modification of the scarff-bloom-132 richardson (sbr) grading system. tumor staging was done using the tnm system adopted by 133 international union against cancer (uicc) and the american joint committee on cancer and end 134 results reporting (ajc)12. 135 136 immunohistochemical assessment 137 all samples were evaluated by immunohistochemical (ihc) staining under the direct supervision of 138 a chief histopathology scientist and reported by two different consultant pathologists, which were 139 then compared in a blinded fashion. the procedures for ihc staining were performed using the 140 primary antibody specific for er (er6f11) (dako), pr (dako), her-2/neuis (erbb2) (dako), and 141 p53, do-7 (santacruz) at the breast cancer laboratory medical genetic and bioethics research 142 unit, institute for advanced medical research and training (imrat), university college hospital, 143 ibadan. the sections were exposed to the primary antibody (dilutions of 1:60 for er and pr, 1:350 144 for her-2/neu, and 1:50 for p53 for one hour). negative and positive controls were performed by 145 including the control tissues specified by the antibody vendors, respectively. 146 147 scoring of er and pr status 148 the scoring was performed using the modified immunohistochemical score (“quickscore”), a 149 modified semi-quantitative assessment method by allred 13. nuclear staining intensity was scored 150 from 0 to 3+ in combination with the proportion of cells involved to get a range of 0–7 as the final 151 score for er and pr positivity [figure 1]. 152 153 the criteria used are explicitly described as follows: "quickscore" determines the percentage or 154 range of stained cells from 1 to 4 and overall intensity from 1 to 3. the scores are added to give a 155 total maximum score of 7 (table 1). chances of benefit from hormonal therapy were classified as 156 6 follows: 0–1 = no effect; 2–3 = small (20%) chance of benefit; 4–6 = moderate (50%) chance of 157 benefit; 7 = good (75%) chance of benefit. 158 159 scoring of her-2/neu status 160 for her-2/neu expression, the only membrane staining pattern was scored from 0 to 3+, where 0/1+ 161 indicates negative, 2+ stands for equivocal, and 3+ means positive following the standards outlined 162 by ellis et al.14. 163 the criteria used are explicitly described as follows: negative (0 scores): membrane staining <10% 164 of the tumor cells, or no staining detected. negative (1+ score): membrane staining detected in >10% 165 of the tumor cells or faint staining detected. the stain was observed only in some parts of the 166 membrane. equivocal (2+ score): a weak to moderate complete membrane staining was detected in 167 >10% of the tumor cells. positive (3+score): a strong complete membrane staining was detected in 168 >10% of the tumor cells. the molecular classification was based on the positivity and negativity of 169 er, pr, and her-2/neu [figure 1]. 170 171 scoring of p53 status 172 for p53 expression, the nuclear staining pattern was scored from 0, 1+, 2+ to 3+, the numbers 0, 1+, 173 2+, and 3+ were used to describe the intensity of the staining of the p53 protein in the cells (reported 174 by bergh)15. the degree staining was used to determine whether the p53 protein is overexpressed or 175 not. the numbers 0 and 1+ indicated negative staining, while the numbers 2+ and 3+ indicated 176 positive staining, as depicted in figure 1c. the p53 protein is considered negative if it is not 177 overexpressed or mutated. 178 179 statistical analysis 180 data obtained were reported in percentage and proportion using descriptive statistics. no calculation 181 of sample size was done, and all cases with complete information were entered into the study. the 182 chi-square test was used to determine the association between histological tumor grades (i, ii, and 183 iii) against the expression patterns of individual selected molecular markers (for er/pr expression, 184 her-2/neu overexpression, and p53 mutation). a value of p <0.05 was considered statistically 185 significant. 186 187 7 ethical approval and consent 188 ethical approval was obtained from the lautech health research ethics committee. this study 189 posed no risk to the participants and the community at large. data generated were made confidential, 190 and no patients' names were recorded. 191 192 results 193 this was a hospital-based retrospective study involving biopsy/surgical cases of bc recorded over 194 10 years. two hundred and five (n = 205) cases were investigated for ihc markers—hormone 195 receptors (estrogen receptor, er and progesterone receptor, pr), human epidermal growth factor 196 receptor (her-2/neu), and p53 immunomarkers. 197 198 age distribution 199 the age range was 21 and 87 years (mean = 49.30 years) of the total cases. the peak age of this 200 incidence was 50–59 years. 201 202 laterality 203 by laterality, the records showed that bc occurred at nearly the same rate between the left (n = 103 204 cases; 50.2%) and the right (n = 102 cases; 49.8%) breast sides among those with complete records. 205 206 histological type 207 the most frequent histological phenotype of female bc recorded was infiltrating ductal carcinoma 208 (idc) (190 cases: 92.7%). other less frequent types were invasive lobular carcinoma (ilc) (8 cases; 209 3.9%) and medullary carcinoma (3 cases; 1.5%), while the rare frequent phenotypes were mucinous 210 carcinoma, carcinosarcoma, metaplastic carcinoma, and poorly differentiated carcinoma had 1 case 211 each (0.49%), respectively. 212 213 tumor grade 214 using nottingham modification of the bloom-richardson system, the frequency distribution by 215 tumor grade was recorded [table 2]. 216 217 8 tumor size 218 all the cases had specified tumor sizes ranging between 1–22 cm in the widest diameter (mean = 219 5.8 cm). the frequency distribution is shown in table 2. 220 221 lymph node metastasis 222 table 2 also illustrates the degree of lymph node (ln) involvement. ln biopsy was reviewed in the 223 record for a possible note of metastasis in individual cases. the frequency distribution is shown in 224 table 2. 225 226 nottingham prognostic index 227 the nottingham prognostic index (npi) traditionally involves a combination of the assessments of 228 nodal status, tumor size, and histological grade for its potential survival outcome. it is based on a 229 recent prognostic scoring, namely, npi-i (excellent) ≤2.4; npi-ii (good) >2.4 but ≤3.4; npi-iii 230 (moderate) >3.4 but ≤5.4; and npi-iv (poor) >5.4 16. our data showed that out of 205 cases, 63 231 cases (30.7%) indicated a good prognosis, 100 cases (48.7%) signified a moderate prognosis, and 232 42 cases (20.5%) showed a poor prognosis. 233 234 immunohistochemical profile 235 two hundred and five female (n = 205) bc cases were processed and stained for er, pr, her-2/neu 236 antigen, and p53 positivity. 237 two hundred and five female (n = 205) bc cases were immunostained for er and pr. one hundred 238 and twenty-seven cases (n = 127; 62.0%) were positive, er+, while 78 cases (38.0%) were er-. 239 one hundred and forty-five cases (n = 145; 70.7%) were pr+, while 60 cases (29.3%) were pr-. 240 the intensity and its score are shown in table 3a and figure 1. 241 242 two hundred and five cases (n = 205) were immunostained for her-2/neu. seventy cases (n = 70) 243 34.2%) were her-2/neu+, while eighty-one cases (n = 81; 39.5%) were her-2/neu-. fifty-four cases 244 (n = 54; 26.3%) were equivocal. for the equivocal result, the stains were not furthered with 245 fluorescent in situ hybridization (fish) due to limited funding but considered her-2/neu-. 246 247 the staining intensity and the score for her-2/neu are shown in table 4 and figure 1b. 248 9 two hundred and five cases (n = 205) were analyzed for p53 immunostain. one hundred and fifty-249 six cases (n = 156; 76.1%) were p53+, while 49 cases (23.9%) were p53-. the staining intensity and 250 the score for p53 mutation are shown in table 4 and figure 1c. 251 252 immunohistochemical profile and nottingham tumor grade 253 we observed associations between the expression profile of hormone receptors (er and pr), her-254 2/neu, and p53 compared to the nottingham tumor grade. the pattern of expression in er (positivity) 255 showed a significant difference (p ˂ 0.01) compared to the distribution of patients according to 256 tumor grades, in the same way as pr positivity (p ˂ 0.001). likewise, the pattern of her-2/neu 257 expression (connecting positive, negative, and equivocal staining distribution among the incident 258 cases) showed a significant difference (p ˂ 0.001) compared to the nottingham tumor grade pattern. 259 also, the association (p = 0.001) between the p53 expression pattern and the nottingham tumor 260 grade pattern was observed. 261 262 based on the results provided above, we classified the breast cancer subtypes along with their 263 proportions in this study into the following groups: 264 265 er/pr positive, her-2/neu negative cases were 110 (53.6%); this subtype was characterized by the 266 presence of estrogen and progesterone receptors but the absence of her-2 overexpression through 267 er+/pr+, her-2-; er-/pr+, her-2and er+/pr-, her2-. 268 269 er/pr positive, her-2/neu positive cases were 48 (23.4%); this subtype was defined by the 270 presence of both estrogen and progesterone receptors, as well as her-2 overexpression through 271 er+/pr+, her-2+: er-/pr+, her-2+ and er+/pr-, her-2+. 272 273 er/pr negative, her-2/neu positive cases 22 (10.7%); this subtype was identified by the absence 274 of estrogen and progesterone receptors but the presence of her-2 overexpression through er-/pr-, 275 her-2+. 276 277 triple-negative cases were 25 (12.2%): this subtype was specified by the absence of estrogen and 278 progesterone receptors, as well as her-2 overexpression through er-/pr-, her-2and er-/pr-, her-279 2-. 280 10 281 discussion 282 in this study, we retrospectively investigated 205 bc cases in western nigeria for hormone receptor 283 (hr) expression (hr: estrogen receptor [er] and progesterone receptor [pr]), human epidermal 284 growth factor receptor (her-2/neu), and p53 expression profile in terms of pattern and frequency. 285 we explored the expression patterns of these biomarkers in connection with the tumor's 286 aggressiveness using the conventional nottingham grade. 287 288 from our findings, the molecular characteristics of the tumor showed that er and pr were positive 289 in 62% and 70.7% of the total recorded cases, respectively. there were associations between er and 290 pr's expression patterns and the tumor grades' frequency. this is following the report on polish 291 women, which showed an association between tumor grades and hr positivity.17 the present study 292 showed that grade ii tumors had a higher er and pr positive frequency than grade iii. meanwhile, 293 a previous report 18 indicated that the number of cells expressing er and/or pr gradually decreases 294 with disease progression. this was substantiated by the report of badowska-kozakiewicz et al. 17, 295 which showed an inverse correlation between er expression and the size of the primary tumor. in 296 specific terms, in addition to positively predicting therapeutic outcomes, estrogen receptor α (erα) 297 is believed to inhibit epithelial-mesenchymal transition by promoting epithelial phenotype and 298 preventing tumor invasion in breast cancer.19 we observed higher hr positivity than in many 299 african populations, including guinea 20, ghana 21, south africa 22, and mali 23. although there is 300 no specific identifiable factor influencing the diverse variation from one population to another, a 301 previous study suggested that small sample sizes recruited for studies across african countries could 302 be a possible reason.20 even though our study showed higher hr positivity compared to a study of 303 a considerably similar population in nigeria, where a multicentric study involving 507 patients was 304 previously carried out.24 conversely, our data are in tandem with reports involving bc patients in 305 western countries 6 and the saudi population 7, where high hr is also documented. potemski and 306 coworkers 25 reported related results and revealed that the higher the level of receptor expression, 307 the lesser the mortality. in line with their observations, our study also showed that the majority of 308 our incident cases had a moderate prognosis with high hr positivity and lower tumor grades, 309 indicating a possible association between hr expression and tumor grade. 310 311 11 in addition, regarding the her-2/neu expression pattern in this study, some (39.5%) of the cases were 312 negative and were more than the positive (34.2%) outcome, with an unexpected increase in her-2+ 313 proportion than many reported cases. equally, patients were classified histologically as having 314 higher grades in the her-2/neu+ expression group than in the her-2/neuexpression group but lower 315 in er+ and pr+ expressions compared to erand prof the highest grade iii [table 4]. in 316 agreement with our study, arafah 7 reported that the histologic grade of bc was significantly 317 associated with both er and pr expressions but, in turn, found a negative correlation between hr 318 and her-2/neu stains. also, aman et al. 26 recently associated overexpression of her-2/neu with 319 higher nottingham grade in an ivorian population. again, in the literature, concurring with the 320 present study, a study involving the chinese population reported a link between her-2/neu 321 overexpression and a higher histological grade with a higher incidence rate of infiltrating ductal 322 carcinoma, among many other factors.8 although the majority (92.7%) of the incident cases in this 323 study were infiltrating ductal carcinoma, which is in line with the study of ding and his colleagues9, 324 our analysis also showed a strong association between histological grading and the pattern of 325 expression of her-2/neu. however, our observations indicated that her-2/neu overexpression is 326 linked to the aggressive forms of bc, as previously reported by arteaga and his colleagues.27 327 328 moreover, to better understand the therapeutic benefits for the patients, we classified the patients 329 based on histological phenotypes of the hormone receptor and her-2/neu expression patterns. most 330 notably and in agreement with the report of gago et al.28, the majority of our breast cancer patients 331 co-express hr+ with her-2/neurather than her-2+ tumours, indicating that the cancer cells are 332 responsive to hormones such as estrogen and progesterone, better prognosis and also preventing 333 tumour aggressiveness. on the other hand, among the her-2+ category, a smaller number of er/pr-334 her-2/neu+ was observed representing breast cancer cases where both the er and pr are negative, 335 while the her-2/neu is overexpressed. this subtype is commonly known as hormone receptor-336 negative, her-2/neu-positive breast cancer. it suggests that the cancer cells do not respond to 337 hormones and have an overexpression of the her-2/neu gene. more importantly, triple-negative 338 breast cancer (tnbc) is a vastly diverse group of tumours, which represents 15-20% of all breast 339 cancer cases kummel et al.29. the proportion of the tnbc in our study is relatively small suggesting 340 an advantage against the studied population. meanwhile, tnbc is the most difficult to treat among 341 all breast cancer phenotypes because the common hormonal therapy used for the majority of breast 342 12 cancer subtypes is treatment-refractory for tnbc. on the hand, tnbc is often treated in its early 343 stages with surgery, radiation, and chemotherapy. 344 345 furthermore, most of our investigated cases (70.1%) were p53 positive, and there was a strong 346 association between the p53 expression pattern and the nottingham tumor grade. consistent with 347 other studies 5, 30, our findings, therefore, implied that the p53 positivity may have a connection with 348 tumor grade in terms of the frequency of the incident cases. patients in the p53+ expression group 349 were classified histologically as higher grades than those in the p53expression group, similar to the 350 previous report 24 and corresponding to the her-2/neu expression pattern in this investigation. 351 shokouh et al.5 earlier demonstrated that p53 expression had a significant association with the grade 352 of bc. various reports have outlined the functional role of p53 in the progression of bc. 353 mechanistically, p53 activates protein transcriptions involved in the dna repair mechanism. 354 however, if the mechanisms fail due to a defective p53, aberrant cells may proliferate 355 uncontrollably, leading to cancer 31. a report shows that tumors with p53 mutations are more likely 356 to be aggressive and resistant to chemotherapy and radiotherapy.29 in other words, p53 357 immunoreactivity is linked to histologic grade, particularly a tumor's high mitotic index.8 358 359 limitations of the study 360 according to the her-2 testing guidelines of the american society of clinical oncology and the 361 college of american pathologists (asco/cap), breast cancer that is reported 2+ equivocal by 362 ihc should be followed up with in-situ hybridization (ish) testing to confirm the cases for 363 possible gene amplification. however, the current study is limited by the inability to verify the 364 negative (2+ score) results with fluorescence in situ hybridization (fish), and thus considered 365 negative. this could have an impact on the negative result value. 366 367 conclusion 368 our observations suggest that expression patterns of pr, er, her-2/neu, and p53 were influenced 369 by the tumor grade (level of aggressiveness). in other words, there is an association between the 370 tumor grade and expressions of pr, er, her-2/neu, and p53, which suggests that the nottingham 371 grade is still relevant as a reliable prognostic marker for bc. 372 373 13 funding 374 no funding was received for this study. 375 376 conflicts of interest 377 the authors declare no conflicts of interest. 378 379 authors’ contribution 380 kaa, wao, and mao were involved in conceptualization and design of the study. wao, mao, 381 lay, and rtk collected the data. kaa and soi analyzed and interpreted the results. kaa 382 drafted the manuscript. kaa and soi revised the manuscript. kaa, soi, ial, iob and saa 383 joined hands in the literature search. wao carried out clinical studies. all authors approved the 384 final version of the manuscript. 385 386 references 387 1. adedokun ka, imodoye so, bello io, lanihun aa, bello io. therapeutic potentials of 388 medicinal plants for the treatment of cancer and significance of computational tools in anticancer 389 drug discovery. in: egbuna c, rudrapal m, tijjani habibu, eds. elsevier drug discovery update: 390 phytochemistry, computational tools, and databases in drug discovery, 1st ed. amsterdam, 391 netherlands, 2022. pp. 393–4. 392 2. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 393 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 394 countries. ca cancer j clin 2018; 68:394-424. https://doi.org/10.3322/caac.21492 395 3. oluogun wa, adedokun ka, oyenike ma, adeyeba oa. histological classification, 396 grading, staging, and prognostic indexing of female breast cancer in an african population: a 10-397 year retrospective study. int j health sci (qassim) 2019; 13:3-9. pmid: 31341449 398 4. hagemann is. molecular testing in breast cancer a guide to current practices. arch 399 pathol lab med. 2016; 140:815–824. https://doi.org/10.5858/arpa.2016-0051-ra 400 5.shokouh tz, ezatollah a and barand p. interrelationships between ki67, her-2/neu, p53, er, 401 and pr status and their associations with tumor grade and lymph node involvement in breast 402 carcinoma subtypes: retrospective-observational analytical study. feng y, ed. medicine 403 94(32):e1359, 2015. doi: 10.1097/md.0000000000001359 404 https://pubmed.ncbi.nlm.nih.gov/31341449 https://doi.org/10.5858/arpa.2016-0051-ra https://doi.org/10.1097%2fmd.0000000000001359 14 6.lumachi f, brunello a, maruzzo m, basso u, basso sm. treatment of estrogen receptor-405 positive breast cancer. curr med chem. 2013;20(5):596-604. 406 https://doi.org/10.2174/092986713804999303 407 7.arafah m. correlation of hormone receptors with her-2 neu protein expression and the 408 histological grade in invasive breast cancers in a cohort of saudi arabia. turk patoloji derg. 409 2012;28(1):38-43. doi: 10.5146/tjpath.2012.01095. 410 8. oyenike ma, akinbo fo, adedokun ka, ojokuku ho, imodoye so, yunus la, et al. 411 synchronicity of p53 mutation and multiple high-risk hpv genotypes, and the risk of cervical 412 cancer among women in osogbo, nigeria medrxiv 2022.06.28.22277026; doi: 413 https://doi.org/10.1101/2022.06.28.22277026. 414 9. ding l, zhang z, xu y, zhang y. comparative study of her-2, p53, ki-67 expression and 415 clinicopathological characteristics of breast cancer in a cohort of northern china female 416 patients. bioengineered.2017;8(4):383-392. https://doi.org/10.1080/21655979.2016.1235101. 417 10. rakha ea, reis-filho js, baehner f, dabbs dj, decker t, eusebi v, et al. breast cancer 418 prognostic classification in the molecular era: the role of histological grade. breast cancer res. 419 2010;12(4):207. https://doi.org/10.1186/bcr2607. 420 11. eliyatkın n, yalçın e, zengel b, aktaş s, vardar e. molecular classification of breast 421 carcinoma: from traditional, old-fashioned way to a new age, and a new way. j breast 422 health. 2015;11(2):59-66. doi: 10.5152/tjbh.2015.1669. 423 12. hayes df, allred c, anderson bo, et al. breast. in: edge sb, byrd dr, compton cc, 424 editors. american joint committee on cancer (ajcc) cancer staging manual. 7th edn. new 425 york: springer, 2009;347–76. 426 13. allred dc, bustamante ma, daniel co, gaskill hv, cruz ab jr. immunocytochemical 427 analysis of estrogen receptors in human breast carcinomas. evaluation of 130 cases and review of 428 the literature regarding concordance with biochemical assay and clinical relevance. arch surg. 429 1990;125(1):107-113. 430 14. ellis io, bartlett j, dowsett m, humphreys s, jasani b, miller k, pinder se, rhodes a, 431 walker r. best practice no 176: updated recommendations for her2 testing in the uk. j clin 432 pathol. 2004 mar;57(3):233-7. doi: 10.1136/jcp.2003.007724. 433 15. bergh j. analysis of the p53 status of tumors: an overview of methods. methods mol 434 med. 1999; 28:179-199. doi:10.1385/1-59259-687-8:179. 435 https://www.ncbi.nlm.nih.gov/pubmed/?term=lumachi%20f%5bauthor%5d&cauthor=true&cauthor_uid=23278394 https://www.ncbi.nlm.nih.gov/pubmed/?term=brunello%20a%5bauthor%5d&cauthor=true&cauthor_uid=23278394 https://www.ncbi.nlm.nih.gov/pubmed/?term=maruzzo%20m%5bauthor%5d&cauthor=true&cauthor_uid=23278394 https://www.ncbi.nlm.nih.gov/pubmed/?term=basso%20u%5bauthor%5d&cauthor=true&cauthor_uid=23278394 https://www.ncbi.nlm.nih.gov/pubmed/?term=basso%20sm%5bauthor%5d&cauthor=true&cauthor_uid=23278394 https://www.ncbi.nlm.nih.gov/pubmed/23278394 https://doi.org/10.2174/092986713804999303 https://doi.org/10.1186/bcr2607 15 16. blamey rw, ellis io, pinder se, lee ah, macmillan rd, morgan da, et al. survival of 436 invasive breast cancer according to the nottingham prognostic index in cases diagnosed in 1990-437 1999. eur j cancer 2007; 43:1548-55. https://doi.org/10.1016/j.ejca.2007.01.016. 438 17. badowska-kozakiewicz am, patera j, sobol m, przybylski j. the role of oestrogen and 439 progesterone receptors in breast cancer immunohistochemical evaluation of oestrogen and 440 progesterone receptor expression in invasive breast cancer in women. contemp oncol (pozn) 441 2015; 19:220-5. https://doi.org/10.5114/wo.2015.51826. 442 18. allemani c, sant m, berrino f, aareleid t, chaplain g, coebergh jw, et al. prognostic 443 value of morphology and hormone receptor status in breast cancer a population-based study. br j 444 cancer 2004; 91:1263-8. https://doi.org/10.1038/sj.bjc.6602153 445 19. imodoye so, adedokun ka, muhammed ao, bello io, muhibi ma, oduola t et al. 2021. 446 understanding the complex milieu of epithelial-mesenchymal transition in cancer metastasis: new 447 insight into the roles of transcription factors. front. onc. 2021; 11:762817. 448 doi: 10.3389/fonc.2021.76281 449 20. traoré b, koulibaly m, diallo a, bah m. molecular profile of breast cancers in guinean 450 oncological settings. pan afr med j 2019; 33:22. doi: 10.11604/pamj.2019.33.22.18189 451 21. ohene-yeboah m, adjei e. breast cancer in kumasi, ghana. ghana med j 2012; 46:8-13. 452 22. mccormack va, joffe m, van den berg e, broeze n, silva idos s, romieu i, et al. breast 453 cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in 454 soweto, south africa: a case series. breast cancer res 2013;15: r84. doi: 10.1186/bcr3478. 455 https://doi.org/10.1186/bcr3478 456 23. ly m, antoine m, dembélé ak, levy p, rodenas a, touré ba, et al. high incidence of 457 triple-negative tumors in sub-saharan africa: a prospective study of breast cancer characteristics 458 and risk factors in malian women seen in a bamako university hospital. oncology 2012; 83:257–459 63. https://doi.org/10.1159/000341541 460 24. huo d, ikpatt f, khramtsov a, dangou jm, nanda r, dignam j, et al. population 461 differences in breast cancer: survey in indigenous african women reveals over-representation of 462 triple-negative breast cancer. j clin oncol 2009; 27:4515–21. doi: 10.1200/jco.2008.19.6873 463 25. potemski p, kusińska r, kubiak r. the predictive value and prognostic significance of the 464 degree of expression of steroid receptors in breast cancer operation. oncol pol 2007; 10:49–54. 465 https://doi.org/10.1016/j.ejca.2007.01.016 https://doi.org/10.5114/wo.2015.51826 https://doi.org/10.1038/sj.bjc.6602153 https://doi.org/10.3389%2ffonc.2021.762817 https://doi.org/10.11604%2fpamj.2019.33.22.18189 https://doi.org/10.1186/bcr3478 https://doi.org/10.1159/000341541 https://doi.org/10.1200%2fjco.2008.19.6873 16 26. aman na, doukoure b, koffi kd, koui bs, traore zc, kouyate m, et al. her2 466 overexpression and correlation with other significant clinicopathologic parameters in ivorian 467 breast cancer women. bmc clin pathol 2019; 19:1. doi: 10.1186/s12907-018-0081-4 468 27. arteaga cl, sliwkowski mx, osborne ck, perez ea, puglisi f, gianni l. treatment of 469 her2-positive breast cancer: current status and future perspectives. nat rev clin oncol 2012; 470 9:16-32. https://doi.org/10.1038/nrclinonc.2011.177 471 28. gago fe, fanelli ma, ciocca dr. co-expression of steroid hormone receptors (estrogen 472 receptor alpha and/or progesterone receptors) and her2/neu (c-erbb-2) in breast cancer: clinical 473 outcome following tamoxifen-based adjuvant therapy. j steroid biochem mol biol. ;98(1):36-40. 474 doi: 10.1016/j.jsbmb.2005.07.002. 475 29. sporikova z, koudelakova v, trojanec r, hajduch m. genetic markers in triple-negative 476 breast cancer. clin breast cancer. 2018 oct;18(5):e841-e850. doi: 10.1016/j.clbc.2018.07.023. 477 epub 2018 aug 4. pmid: 30146351. 478 30. huszno j, grzybowska e. tp53 mutations and snps as prognostic and predictive factors in 479 patients with breast cancer (review). oncol lett 2018; 16:34-40. 480 https://doi.org/10.3892/ol.2018.8627. 481 31. hafner a, bulyk ml, jambhekar a, lahav g. the multiple mechanisms that regulate p53 482 activity and cell fate. nat rev mol cell biol 2019; 20:199–210. 483 https://doi.org/10.3389/fcell.2021.762651 484 485 https://doi.org/10.1186/s12907-018-0081-4 https://doi.org/10.3389/fcell.2021.762651 17 table 1: scoring guideline (“quickscore”) for er and pr 486 proportion score observation intensity score observation zero zero staining zero no staining of any nuclei even at high magnification 1 1 – 25% 2 26 – 50% 3 51 75% 4 76 – 100% 1 weak staining (only visible at high magnification) 2 moderate staining (readily visible at low magnification) 3 strong staining (strikingly positive even at low magnification) the score for intensity is then added to the score for proportion, giving a range of 0-7. 487 488 table 2: frequency distribution of tumor grade, size, and lymph node involvement in female 489 breast cancers 490 tumor index frequency(%) tumor gradeα i (low) 16 (7.80) ii (intermediate) 146(71.22) iii (high) 43 (20.98) tumor sizeβ pt1 18 (8.78) pt2 106(51.71) pt3 81(39.51) lymph node statusɤ pn0 156(76.1) pn1 46(22.44) pn2 3(1.46) “ɤ”rep.tumor grade(nottingham grade): grade 1 =i; grade 2 =ii; grade 3 =iii 491 “β” rep. lesion size (cm): pt1= ≤ 2 cm; pt2 = 2-5 cm; pt3 = >5cm 492 “ɤ” rep. node positivity: pn0= 0 nodes;pn1 = 1-3 nodes;pn2 = >3 nodes. 493 494 18 table 3: frequency distribution according to er and pr expression status 495 er score frequency (%) cumulati ve pr score frequency (%) cumulati ve interpretation zero 8 (3.9) 78 (38.0) zero 15 (7.3) 60 (29.3) negative 2 70(34.1) 2 45(22.0) negative 3 43 (20.9) 127 (62.0) 3 61 (29.8) 145 (70.7) positive 4 27 (13.2) 4 13 (6.3) positive 5 25 (12.2) 5 55(26.8) positive 6 14(6.8) 6 12 (5.9) positive 7 18(8.9) 7 4(1.9) positive total 205 (100) 205(100) total 205 (100) 205 (100) er -oestrogen receptor; pr progesterone receptor 496 497 table 4: frequency distribution according to her-2/neu and p53 expression status 498 her2/neu score freq. (%) cumulati ve interpreta tion p53 score freq. (%) cumulati ve interpret ation zero 21 (10.2) 81 (39.5) negative zero 13(6.3) 49 (23.9) negative 1+ 60 (29.3) negative 1+ 36(17.6) negative 2+ 54(26.3) 54(26.3) equivocal 2+ 85(41.5) 156 (70.1) positive 3+ 70(34.2) 70(34.2) positive 3+ 71(34.6) positive total 205(100) 205(100) total 205(100) 205(100) her-2/neu – human epidermal growth factor receptor-2 499 500 table 5: expression profile of hormone receptors, her-2/neu and p53 compared to 501 nottingham tumor grade 502 immunohistochemi cal markers nottingham grade χ2, p-value, df grade i grade ii grade iii er+ (%) 10 (7.9) 103(81.1) 14 (11.0) 10.458, ˂0.01, 2 er(%) 3 (3.85) 53 (67.95) 22 (28.21) pr+ (%) 8(5.6) 121 (83.4) 16 (11.0) 18.581, ˂0.001, 2 pr(%) 3 (5.00) 35 (58.33) 22 (36.67) her2/neu+ (%) 4 (5.7) 46(65.7) 20(28.6) 27.317, ˂0.001, 4 her2/neu-ve (%) 31 (38.27) 42 (51.85) 8(9.88) her2/neu-eq (%) 11 (20.37) 28 (51.85) 15 (27.78) p53+ (%) 8 (5.2) 118(75.6) 30 (19.2) 13.381, 0.001, 2 p53(%) 9 (18.37) 38 (77.55) 2 (4.08) er: oestrogenreceptor; pr: progesterone receptor; her2/neu: human epidermal growth factor 503 receptor 2; +: positive; -/-ve: negative; eq.: equivocal 504 19 505 figure 1: a: invasive ductal carcinoma (er-positive x40). note that the tumor cells pick up the 506 stain in the nucleus. the score in this case was 7. b: invasive ductal carcinoma. (her-2/neu 507 positive x40). note that the intensity score for this case was 3. her-2/neu stains in the membrane 508 compared to er/pr which stains in the nucleus. c: invasive ductal carcinoma (p53 positive x40). 509 note that the intensity score for this case is 3. p53 stains in the nucleus like er/pr. 510 peer review of physicians’ performance is it a necessary quality assurance activity? lamk al-lamki squ med j, august 2009, vol. 9, iss. 2, pp. 109-112, epub 30th june 2009 submitted 26th may 08 accepted 29th may 09 هل أن مراجعة الزمالء ألداء األطباء ضرورية لضمان اجلودة ؟ ملك اللمكي editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: mjournal@squ.edu.om to undertake peer review is to “evaluate professionally a colleague’s work”.1 in medicine, peer review is defined as “the objective evaluation of the quality of a physician’s or a scientist’s performance by colleagues”.2 in peer review, physicians professionally and candidly, but confidentially, evaluate each other’s performance, typically at the same institution, but quite often externally. the aim of peer review is not to spy on others, but rather to self-identify openly one’s weakness in the presence of trusted colleagues. peer review is one of the most respected activities in the circles of quality assurance and total quality management. unfortunately, it is not an activity that is particularly favoured by many professionals; it is certainly not well accepted by physicians particularly in eastern countries. physicians have difficulty accepting evaluation of their performance by fellow colleagues even when given equal opportunity to monitor others. peer review is generally more accepted, albeit often with reluctance and reservations, in the united states where it started and in some other western countries. health insurance companies in the usa are now demanding evidence of quality assurance activity among the doctors in an institution prior to entering into a financial arrangement with the group of doctors or with the institution. following the american example, peer review was gradually introduced in the united kingdom by various national health authorities who began demanding some form of medical audit of their doctors.3, 4 a few countries in the east are now introducing peer review among their physicians including the sultanate of oman where the physicians at the sultan qaboos university and its hospital now embrace peer review. this could possibly be a example for the whole region. improving the quality of care to our patients is the main concern of doctors everywhere, whether east or west. there are several ways this can be achieved, but certainly peer review falls among the most important methods once physicians have completed their training. at this stage and having taken the oath to do his utmost for patient welfare, the doctor then has the responsibility of caring for them. whatever specialty the doctor chooses, it is his responsibility to ensure that his management is evidence-based and in keeping with the latest knowledge on the subject. as a corollary to this, it behoves the physician to ensure that his colleagues are also delivering quality care to their patients. it all started with the introduction of quality assurance and continuous quality improvement in medicine after the foundations had been established by the gurus of quality assurance, best exemplified by juran, crosby and deming, and sustained by the requirements of the international organization for standardization (iso), the joint commission international (jci) and similar organisations.5, 6, 7 juran pointed out that “resistance to change” by leaders and managers is what holds back progress in quality assurance. this is indeed an apt description of many physician leaders. the “juran trilogy” states that management for quality consists of a) quality planning, b) quality control and c) quality improvement.5 crosby has pointed out that “defects must be prevented, not inspected out”, and has also highlighted the “cost of non-conformance”; both of these apply today directly to medical errors as well as his philosophy of “zero defects”.6 crosby also introduced the six c’s: comprehension, commitment, competence, communication, correction and continuance7 editorial peer review of physicians’ performance is it a necessary quality assurance activity? 110 | squ medical journal, august 2009, volume 9, issue 2 which are clearly and directly applicable to quality medical care. however, perhaps the greatest impact on medicine comes from several of the 14 points of deming who pointed out the importance of good leadership, “creating constancy of purpose” and “driving out fear” in the process of quality assurance and peer review. he stressed that quality assurance activities must never be used either punitively or for reward. deming also stressed the overwhelming importance of “customer satisfaction” and “measurable data” both of which are still given great importance in medicine and stressed by the jci; in deming’s words, “if we cannot measure it, we cannot manage it”.8 the question that is often asked is what is the relationship of peer review to medical audit and clinical audit? the difference is only a matter of terminology. medical audit is the term that is used more east of the atlantic, in uk and other englishspeaking countries, while the americans use peer review. basically, medical audit is a systematic critical analysis of the quality of medical care and this can be a review of diagnosis, of treatment, of procedures, etc. while strictly speaking peer review, as defined above, is a professional evaluation of colleagues’ work. when medical audit is used as a critical analysis of physicians’ performance by those involved then it is effectively a peer review. then there is clinical audit, which, unlike the above two, is a wider auditing system involving more than physicians although in some countries it is used interchangeably with the terms medical audit or peer review. clinical audit was formally introduced in 1993 in the u.k. national health service and it was defined as “a quality improvement process that seeks to improve patient care and outcomes through systematic review of care against explicit criteria and the implementation of change”.3 in the same reference, peer review is referred to as “an assessment of quality of care provided by a clinical team with a view of improving clinical care”. the question, however, is: “why should we undertake peer review at all?”, given that only 15% of the time a medical error is the result of an individual’s error while 85% of the time it is the result of system errors, as repeatedly shown by deming in his quality assurance quest. the reasons that we, as physicians, need to undertake peer review are many. perhaps the simplest reason is that peer review offers physicians and other medical staff the privilege of participating in shaping the future since we have accepted the responsibility of stewardship of society’s health. we need to encourage our patients to trust us individually and collectively as a medical profession. it is therefore our responsibility to undertake peer review for the collective good. the professional independence that we enjoy as mds is a privilege and not a right. it is a privilege that can easily be lost without self-regulation through peer review. we have been privileged with this professional independence by a society that has always trusted its doctors and expected them to work for its well being. in response to the demands of the public, health authorities will intervene and regulate our practice of medicine unless our self-regulation is satisfactory. the public is now connected to the internet where general education and knowledge are freely available. the public also notes that industry, especially larger organisations such as oil companies, now insists upon peer review among employees. some boards of education and high-quality private education organisations have recently instigated peer review among their staff. why don’t medical schools and medical organisations and institutions follow suit? law makers, prosecutors and defence lawyers are all aware of the various laws passed in several countries such as the “health care quality improvement act of 1986”.9 thus lawyers have become more demanding and so has the public. the demands will likely become unreasonable and society that had previously granted us its trust may suddenly become alienated from us. for those of us who work in a university set-up, we will find that it will be our senior administrators who will be making unreasonable demands of us. to avoid all this, we as keepers of the public’s trust must preserve it by having the foresight to undertake peer review and medical audit as part of good medical practice. practising peer review and consulting each other frequently will stand doctors in good stead with respect to society’s trust and confidence in them as individuals and as an independent professional group. undertaking peer review is simply a way to ensure that both you and your colleagues practice medicine of the highest grade on a par with the rest of the world. in addition, peer review allows you to achieve this without spying on each other, without an authoritarian and demeaning inspection of junior staff by the senior staff or the head of the department. lamk al-lamki editorial | 111 peer review is an act of quality assurance and the principles of quality assurance mean that everybody is concerned not just the privileged few.10 in fact, those who are involved need it most, and can do it best. for example, if a department decides that the interpretation of electrocardiograms (ecgs) is a potential source of errors because of their “high volume”, then every attending staff member must be involved in the double reading (two physicians interpreting the ecg independently and later compare) of ecgs not just a few senior staff. likewise, if a department decides that other potential “problems” such as the reading of cytology slides in pathology, or the reporting of computed tomography (ct) scans in radiology require double reading because of their “high volume” or “high risk” and therefore their potential as “problems”, then these are targets for peer review and a certain percentage of them should be double read by all involved staff, typically 5-10% of the total number of studies performed. the staff members involved are the best people to identify the problem or issue they wish to review. this problem has to be “high volume, high risk or high cost” in their daily medical practice in the department or the institution. the problem chosen also has to have the potential, when solved, to improve the quality of patient care or the potential to raise the level of quality awareness and thus gradually change the culture of the practice and the institution. once the group chooses the problem to peer review, there are 5 or 6 other steps to undertake before the peer review is achieved.10, 11 the initial step is for the participants to decide and formulate criteria and standards based on a review of the literature and on evidence-based medicine as well as on the influence of local practice and culture related to that problem. in other words, the group has to decide what the acceptable level of performance is. the tough decision comes when it is time to collect the data. the participants have to decide on what data are to be collected and how to collect them. “what data?” is a tough decision and a source of major disagreement among medical colleagues; here is where we as medical professionals have to accept compromises because we have to collect data about practices that are dear to us and which we believe are above scrutiny. it is in this component of peer review that the difference between the attitudes of physicians in the east and those in the western countries is most striking. the latter have already more or less accepted the reality and advantages of data collection in peer review. if one’s practice is truly above scrutiny then there should not be any fear to expose it. department members have to find common ground a level of agreement as to what constitutes good practice for the problem that the department has selected. the list of steps that have to be performed as part of good practice for that procedure is drawn up and used as a source of data collection. points of major contention may have to be left out in the initial stages of introducing peer review to an institution or at least until the culture of quality assurance and peer review is more accepted. data collection is followed by team discussion of the results. in these team discussions, tolerance and acceptance of differences of opinion are a basic foundation, in conjunction with constructive criticism and common courtesy; for example, criticism of ideas not individuals has to be one of the rules of conduct. unfortunately after all the effort and compromises, stumbling blocks may still be encountered; for example when the group has to take the next step in peer review i.e. to compare their data with that of other institutions and with the literature. discovery of a wide gap of performance achievement between one’s own level and that of the other institutions and the literature indicates that a change is needed. implementing change maybe another source of disharmony in the group as change is often resisted as shown by juran. unfortunately, unless change is implemented no gain can be obtained. whatever lesson is learnt from the laborious hours of professional effort must result in a fruitful outcome. efforts must also be made to sustain the improvement before engaging in a repeat study effort. the timing and style of the “repeat study” has to be predetermined so that a fair and reasonable insight into the improvements is achieved. the above 6 or 7 steps of peer review from identifying the problem to repeat study will be in accordance with the general guidelines of clinical audit, as originally published at the national institute for clinical excellence (nice).11 these steps basically incorporate several other methods of quality auditing such as focus and deming’s plan-do-check-act cycle (pdca). being a professional can lead to certain types of behaviour and states of mind; thus some steps in the peer review process can be seen as threatening. professionals are often not used to comparing given peer review of physicians’ performance is it a necessary quality assurance activity? 112 | squ medical journal, august 2009, volume 9, issue 2 performance expectations with the achievement of their personal goals; neither are they used to collective responsibility and accountability versus autonomy and individualism. at the same time doctors, because they are professionals, are typically not used to managerial leadership. sometimes professionals have these characteristics, which unfortunately may interfere with the efforts to enhance public confidence and the all-important trust of the patients. we as physicians need a change in our attitude towards peer review, a change in our culture within medicine and a move towards a revolutionary new outlook in our practice of medicine. we need to change certain aspects of our professionalism. we need to focus on the collective good as our goal. n o t e it is with sincere apologies to my female colleagues that in this editorial i refer to the doctor as he. i assure you it is only for simplicity and ease of sentence flow. references 1. wordnet. from http://wordnetweb.princeton.edu/ perl/webwn?s=peer%20review. accessed may 2009. 2. medical dictionary. from http://medical-dictionary. thefreedictionary.com/peer+review. accessed may 2009. 3. clinical audit. from http://www.uhbristol.nhs.uk/ documents/how_to_ca_brief_guide.pdf. accessed may 2009. 4. jones t, cawthorn s. what is clinical audit? from http://www.evidence-based-medicine.co.uk/ ebmfiles/whatisclinaudit.pdf. accessed may 2009. 5. juran jm. the quality trilogy: a universal approach to managing quality. quality progress 1986; 19:1924. 6. crosby pb. the eternally successful organization. new york: mcgraw-hill, 1988. 7. boadu va, martin l. quality management in a changing organizational environment. from http://ageconsearch.umn.edu/bitstream/18091/1/ mi99am02.pdf. accessed may 2009. 8. deming we. the new economics for industry, government, education. cambridge, ma: mit centre for advanced engineering study, 1993. 9. health care quality improvement act of 1986. from http://biotech.law.lsu.edu/books/lbb/x505.htm. accessed may 2009. 10. clinical audit. from http://en.wikipedia.org/wiki/ clinical_audit. accessed may 2009. 11. principls for best practice in clinical audit (2002, nice/chi). from www.nice.org.uk/pdf/ bestpracticeclinicalaudit.pdf. accessed may 2009. december 2008 no white pages.indd sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 356-357 sultan qaboos university© submitted -3rd june 2008 accepted 19th august 2008 right aortic arch with aberrant left subclavian artery *anupam k kakaria,1 sukhpal sawhney,1 rajeev jain2 the patient, a 53 year old man, presented at sultan qaboos university hos-pital, oman, with a history of abdominal pain and alternating constipation and diarrhoea. a الزائغ األيسر الترقوة تحت شريان مع األيمن األبهري القوس جني راجيف ساوهني، سخبال كاكاريا، انوبام i n t e r e s t i n g m e d i c a l i m a g e 1department of radiology & molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman; 2college of medicine and health sciences, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: bittanupam@yahoo.com figure 1: axial contrast enhanced computed tomography scan of the thorax. the left common carotid artery (small arrows in a and b) is the first branch to arise from the right-sided aortic arch (long arrow in b). the left subclavian artery (small arrowheads in a, b and c) is the last branch to arise from kommerell’s diverticulum, a focal dilatation of the arch (large arrowhead in a and b). the black arrowhead points to the left common carotid artery, the black arrow to the right common carotid artery and the medium sized white arrow to right subclavian artery (c). the descending aorta continues inferiorly on the right side of the vertebral column. figure 2: three dimensional representation of the right aortic arch. the left common carotid artery ( thin arrow in a and b) is the first branch and the right common carotid artery (small arrowhead in a and b) is the second branch to arise from the arch. the aberrant left subclavian artery (large arrow in a and d) arises from the kommerell’s diverticulum (large arrowhead in a and d). the relationship of the vessels is shown from the posterior aspect (c). r i g h t a o r t i c a r c h w i t h a b e r r a n t l e f t s u b c l av i a n a r t e r y 357 colonoscopy and a barium enema revealed a short segment of annular narrowing and a large polypoid mass in the rectodigmoid region. subsequent histopathology identified a moderately differentiated adenocarcinoma. computed tomography (ct) scans of the thorax and abdomen were carried out as staging procedures. the ct of thorax demonstrated a right aortic arch. the left common carotid artery, the first major artery to arise from the arch, is followed by the right common carotid, right subclavian and left subclavian arteries. the aberrant left subclavian artery takes its origin from a prominent kommerell’s diverticulum at the distal end of aortic arch. the descending aorta continues inferiorly to the right side of the vertebral column. the findings are consistent with a right arch of aorta with aberrant left subclavian artery [figures 1 and 2]. approximately 0.1% of population has a right sided aortic arch, and about half of these have an aberrant left subclavian artery which may arise either directly from the aorta or from the kommerell’s diverticulum.1 although an aberrant left subclavian artery may occur in isolation, it is the commonest anomaly associated with a right aortic arch. any symptoms, which result from an aberrant left subclavian artery, are associated with compression of the esophagus or trachea and are most likely to occur if its origin is dilated.2, 3 r e f e r e n c e s 1. salanitri j, mr angiography of aberrant left subclavian artery arising from right-sided thoracic aortic arch, br j radiol 2005; 78: 961-966. 2. franquet t, erasmus jj, giménez a, rossi s, prats r, the retrotracheal space: normal anatomic and pathologic appearances. radiographics 2002; 22:s231-246. 3. donnelly lf, fleck rj, pacharn p, ziegler ma, fricke bl, cotton rt. aberrant subclavian arteries: cross sectional imaging findings in infants and children referred for evaluation of extrinsic airway compression. ajr 2002; 178:1269-1274. submitted 11 oct 21 1 revision req. 14 nov 21; revisions recd. 27 dec 21 2 accepted 19 jan 22 3 online-first: february 2022 4 doi: https://doi.org/10.18295/squmj.2.2022.017 5 6 reversible myocarditis following black widow spider (latrodectus spp.) bite in 7 egypt 8 a case report 9 ahmed g. emara,1 abdel-rhman a. aboshady,2 *omar a. aboshady,3 10 mohamed m. shawqi4 11 12 departments of 1cardiology, 2critical care medicine unit and 3clinical pharmacology, faculty 13 of medicine, menoufia university, shebin elkoum, egypt; 4faculty of medicine, benha 14 university, benha, egypt 15 *corresponding author’s email: omr.ali@med.menofia.edu.eg 16 17 abstract 18 black widow spiders (bwss) are poisonous spiders of the arthropoda phylum that live in the 19 mediterranean region. the effects of bws bites ranges from local damage to systemic 20 manifestations including paresthesia, stiffness, abdominal cramps, nausea, vomiting, headache, 21 anxiety, hypertension, and tachycardia. however, cardiac involvement following a bws bite is 22 uncommon. we report a 35-year-old man who developed acute pulmonary edema with 23 electrocardiogram changes that showed st elevation in leads i, avl with reciprocal st segment 24 depression in infero-lateral leads with elevated cardiac biomarkers. echocardiography showed 25 regional wall motion abnormalities with an impaired ejection fraction of 40%. the condition was 26 reversible after one week of supportive treatment, and the patient was discharged from the hospital 27 with normal electrocardiogram, ejection fraction, and negative cardiac markers. a routine cardiac 28 evaluation, serial ecg, serial cardiac markers, and echocardiography follow-up should be 29 considered for any patient exposed to a bws bite for detection of any potentially fatal cardiac 30 abnormalities. 31 keywords: black widow spider; egypt; spider bites; myocarditis; heart failure; kounis 32 syndrome; acute coronary syndrome. 33 34 introduction 35 black widow spiders (bwss) are a rare but very poisonous species of the arthropoda phylum that 36 generally live in moderate climatic conditions.1 these spiders are shiny black with a ventral red 37 hourglass mark on females, while males have various dorsal red marks. their size averages 3-10 38 mm, with females up to 13 mm in length. the spider venom includes a main toxic protein (α-39 latrotoxin) that primarily affects the motor nerve endings, leading to increased catecholamine 40 release and acetylcholine consumption.2 41 42 patients who have been bitten by a bws typically complain of various clinical symptoms that 43 range from local to systemic manifestations; a bws bite can cause soft tissue damage at the site of 44 the bite, with local to generalized pain and/or paresthesia.3,6,7,15,16 in addition, priapism, stiffness, 45 abdominal cramps, nausea, vomiting, headache, tremors, and/or anxiety have been reported.3,5-8 a 46 few patients have hypertension, tachycardia, and/or chest pain.3-6,8,10,16 only one study has 47 reported acute kidney failure and rhabdomyolysis.1 myocardial involvement after bws bites is 48 uncommon, and only a limited number of cases have been recorded with no cases from egypt.3-5,7-49 10,15,16 here, we report on a 35-year-old previously healthy man who developed myocarditis 50 complicated by acute heart failure and pulmonary edema following a bws bite, which is the first 51 case reported from egypt. 52 53 case report 54 a 35-year-old previously healthy man presented to our tertiary hospital 12 hours after having been 55 bitten by a bws on the lateral aspect of his right leg, 15 cm below the knee joint. after being 56 shown various photos of spiders, the patient chose the photo of the bws as the attacker spider. 57 within a few minutes of the bite, he developed local severe burning pain that rapidly involved all 58 of his thigh. fifteen minutes later, he became nauseous with severe diffuse abdominal pain, back 59 pain, dizziness, headache, and severe muscle cramping in his lower limbs. on examination, he had 60 priapism and generalized tremors. 61 62 on admission, he was noted to appear anxious and diaphoretic. his vital signs were as follow: 63 blood pressure 150/100 mmhg, pulse rate 110/min, respiratory rate 40 /min, oxygen saturation 64 98%, and temperature 37.3°c. physical examination revealed a 3 x 2 mm area of erythema at the 65 bite site, board-like abdominal rigidity, and hyperactive stretch reflexes. cardiac examination 66 revealed rapid s1 and s2 with s3, and no murmur or rub. other than a slight leukocytosis (total 67 leucocyte count was 15×103; normal range 4-10×103) with mild elevation in the absolute 68 eosinophilic count (0.9×103/l; normal range 0.0-0.4×103/l), laboratory findings and arterial blood 69 gases were normal. 70 71 the patient was given tetanus prophylaxis with intravenous analgesics, hydrocortisone, anti-72 histamine (pheniramine maleate 22.75 mg/day), and fluids (ringer’s lactate 1.5 l/day). anti-73 venom was not given because it is unavailable in egypt. 74 75 four hours later, the patient developed progressive dyspnea, orthopnea, and retrosternal chest 76 pain. an electrocardiogram was obtained that showed an st-segment elevation of 0.5 mm in leads 77 i, and avl with reciprocal st-segment depression in leads ii, iii, avf, and v2-v6 (figure 1). 78 cardiac biomarkers were ck-mb 89.9 iu/l (0-25 iu/l) and ctni 5.1 ng/ml (0-0.6 ng/ml). a 79 chest radiograph showed exaggerated pulmonary vascular markings consistent with pulmonary 80 edema. echocardiography, done 17 hours of his presentation, revealed impaired left ventricular 81 systolic function, with an ejection fraction of 42%. there were regional wall motion 82 abnormalities, including hypokinesis of the mid-basal anterior, mid-basal posteroseptal, mid-83 lateral, and basal inferior walls, with preserved thickness. in addition, the pericardium was noted 84 to be thickened, with a rim of pericardial effusion on the lateral wall (figure 2). 85 86 the patient was admitted to the intensive care unit and was treated with intravenous furosemide 20 87 mg/8 h, nitroglycerine infusion, intravenous morphine, captopril 12.5 mg/8 h, and prophylactic 88 enoxaparin 80 iu/24 h. later, beta-blocker (bisoprolol 2.5 mg/24 h for 1 month) was added to 89 maintain a heart rate of 60-70 bpm and good coronary perfusion. 90 91 the dyspnea improved rapidly after this supportive therapy. the pain, headache, dizziness, 92 tremors and muscle cramps disappeared after 48 hours. however, hyperreflexia and priapism 93 continued to the fourth day. the patient’s cardiac enzymes, electrocardiogram and echo findings 94 are shown in table 1. he was discharged on the sixth day with resolution of his symptoms. at that 95 point, his electrocardiogram had normalized and the ejection fraction was estimated to be 51% on 96 repeated echocardiography. 97 98 informed written consent for publication of this case report and figures was obtained from the 99 patient. 100 101 discussion 102 our patient had developed the commonly reported symptoms of latrodectism, such as nausea, 103 pain, muscle rigidity, headache, tremors, and muscle cramping.3,5-8,15,16 in addition, a moderate 104 degree of priapism was reported, which is also recorded in the literature.3 the hypertension and 105 tachypnea that our patient developed were similar to previous studies.4,5,8,16 106 107 cardiac involvement following a bws bite is uncommon. only a few cases have been reported in 108 the literature, with effects ranging from reversible myocarditis to acute severe fulminant heart 109 failure and cardiogenic shock.1,4,5,7-10 table 2 summarizes the available reported cases with cardiac 110 involvement after bws bites in the literature. most cases have been reported in males, and most 111 of them had myocarditis after bws bite.3-5,7-10,15,16 the majority of cases presented with chest pain 112 or other manifestations suggesting pulmonary edema or heart failure.3-5,7-10,15,16 eight cases 113 showed elevated levels of cardiac biomarkers.4,5,7-10,15,16 only a few cases showed st segment 114 changes that were similar to our findings.7-10,16 cardiac dysrhythmia, such as atrial fibrillation and 115 incomplete bundle branch block, have also been reported.7,8 116 117 although the underlying mechanism of cardiac affection after a bws bite is still not fully 118 understood, there are many possible explanations, such as the direct toxic effect of α-latrotoxin on 119 cardiomyocytes producing a form of toxic myopericarditis.5,7-10 recently, the hyperadrenergic 120 state was claimed to primarily be involved (broken heart syndrome).4 in addition, α-latrotoxin, 121 which is a foreign protein, might induce an allergic reaction producing a form of hypersensitivity 122 myopericarditis.1 α-latrotoxin also induces inflammatory mediator release, which could induce 123 coronary artery spasm (kounis syndrome).1 124 125 from these proposed mechanisms of cardiac affection, the heart can be affected by two main 126 pathologies: myopericarditis and/or coronary artery spasm. however, the clinical presentation 127 depends on which of the two pathologies predominates. when coronary artery spasm is the 128 dominant pathology, the main presentation is typically chest pain or even acute coronary 129 syndrome. when myopericarditis predominates, however, the main presentation is heart failure 130 and pulmonary edema. in echocardiography, hypersensitivity myopericarditis usually shows 131 heterogeneous segmental wall motion abnormalities. in contrast, coronary artery spasm shows 132 segmental wall motion abnormalities in certain territory. late gadolinium enhancement in cardiac 133 magnetic resonance shows patchy sub-epicardial distribution which is not consistent with any 134 coronary territory. distribution in coronary artery spasm, however, is usually in the sub-135 endocardial and consistent with the infract-related artery. in our case, we suspect the pathology 136 was mostly combined, with greater spasm, which was reflected in the electrocardiogram. 137 138 treatment of the bws bites depends mainly on the severity of presentation.11 most of cases are 139 mild and only require oral pain medication and tetanus prophylaxis. in severe cases, however, 140 parental opioids or/and benzodiazepines might be required.11 antivenom administration is 141 reported to reduce pain duration to less than 24 hours in approximately 80% of cases; it is reported 142 to reduce severity, with home discharge in 90% of patients.11-13 however, allergic reactions, serum 143 sickness, and rare reports of fatalities have been reported from antivenom administration.11,13,14 144 unfortunately, given that bws bites are rare in egypt, we did not have antivenom in our center. 145 146 conclusion 147 to the best of our knowledge, this case is the first to be reported from egypt and to present with 148 electrocardiogram changes typical of acute myocardial infarction in the literature. from this case, 149 clinicians should be aware that reversible myocarditis can occur after a bws bite. moreover, it is 150 recommended that a complete cardiac evaluation be performed for every case of bws bite to 151 screen for myopericarditis and coronary artery spasm. 152 153 authors’ contribution 154 age and aaa managed the case clinically. all authors contributed equally to literature review, 155 drafting, and critically revising the final version of the paper. 156 157 references 158 1. bshabshe a a, alfaifi m, alsayed af. black widow spider bites experience from tertiary care 159 center in saudi arabia. avicenna j med 2017; 7:51. doi: 10.4103/2231-0770.203606. 160 2. ushkaryov y a, volynski k e, ashton a c. the multiple actions of black widow spider toxins 161 and their selective use in neurosecretion studies. toxicon 2004; 43:527–42. doi: 162 10.1016/j.toxicon.2004.02.008. 163 3. bucur i j, obasi o e. spider bite envenomation in al baha region, saudi arabia. ann saudi 164 med 1999; 19:15–9. doi: 10.5144/0256-4947.1999.15. 165 4. dendane t, abidi k, madani n, benthami a, gueddari fz, abouqal r, et al. reversible 166 myocarditis after black widow spider envenomation. case rep med 2012; 2012:4–7. doi: 167 10.1155/2012/794540. 168 5. erdur b, turkcuer i, bukiran a, kuru o, varol i. uncommon cardiovascular manifestations 169 after a latrodectus bite. am j emerg med 2007; 25:232–5. doi: 10.1016/j.ajem.2006.11.005. 170 6. kara h, ak a, bayir a, avci a. case report: reversible myocarditis after spider bite. bmj 171 case rep 2013; 2013. doi: 10.1136/bcr-2013-008957 172 7. levine m, canning j, chase r, ruha a-m. cardiomyopathy following latrodectus 173 envenomation. west j emerg med 2010; 11:521. 174 8. pneumatikos i a, galiatsou e, goe d, kitsakos a, nakos g, vougiouklakis t g. acute fatal 175 toxic myocarditis after black widow spider envenomation. ann emerg med 2003; 41:158. doi: 176 10.1067/mem.2003.32. 177 9. pulignano g, del sindaco d, giovannini m, zeisa p, faia m, soccorsi m, et al. myocardial 178 damage after spider bite (latrodectus tredecimguttatus) in a 16-year-old patient. g ital cardiol 179 1998; 28:1149–1153. 180 10. sari i, zengin s, davutoglu v, yildirim c, gunay n. myocarditis after black widow spider 181 envenomation. am j emerg med 2008; 26:630. doi: 10.1016/j.ajem.2007.09.012. 182 11. clark r f, wethern-kestner s, vance m v, gerkin r. clinical presentation and treatment of 183 black widow spider envenomation: a review of 163 cases. ann emerg med 1992; 21:782–7. doi: 184 10.1016/s0196-0644(05)81021-2. 185 12. ellis r m, sprivulis p c, jelinek g a, banham n d g, wood s v, wilkes g j, et al. a 186 double-blind, randomized trial of intravenous versus intramuscular antivenom for red-back spider 187 envenoming. emerg med australas 2005; 17:152–6. doi: 10.1111/j.1742-6723.2005.00720.x. 188 13. isbister g k, brown s g a, miller m, tankel a, macdonald e, stokes b, et al. a randomised 189 controlled trial of intramuscular vs. intravenous antivenom for latrodectism--the rave study. 190 qjm 2008; 101:557–65. doi: 10.1093/qjmed/hcn048. 191 14. murphy c m, hong j j, beuhler m c. anaphylaxis with latrodectus antivenin resulting in 192 cardiac arrest. j med toxicol 2011; 7:317–21. doi: 10.1007/s13181-011-0183-1. 193 15. piscopo a, massari f, scicchitano p, sanasi m, de palo m, caldarola p, et al. acute 194 myocarditis after black widow spider bite: a case report. cardiol ther 2020; 9:569–75. doi: 195 10.1007/s40119-020-00178-3. 196 16. yaman m, mete t, ozer i, yaman e, beton o. reversible myocarditis and pericarditis after 197 black widow spider bite or kounis syndrome? case rep cardiol 2015; 2015. doi: 198 10.1155/2015/768089. 199 200 table 1: ecg, cardiac enzymes, and ejection fraction findings over the admission period and one 201 week after discharge 202 ecg cardiac enzymes ejection fraction ck-mb (0 25iu/l) ctni (0 0.6 ng/ml) four hours after admission st-segment elevation (0.2 mv) in leads i, avl with reciprocal depression (0.3 mv) in ii, iii, avf and v2-v6 89.9 iu/l 5.1 ng/ml 42% ten hours after admission st-segment elevation (0.1 mv) in leads i, avl with reciprocal depression (0.2 mv) in ii, iii, avf and v2-v6 79.08 iu/l not done not done one day after admission st-segment elevation (0.1mv)in leads i, avlwith reciprocal depression (0.2 mv) in ii, iii, avf and v2-v6 24.07 iu/l 3.2 ng/ml 43% two days after admission normal 6.5 iu/l 0.5 ng/ml 51% one week after discharge normal 6.1 iu/l 0.5 ng/ml 56% 203 table 2: available reported cases with cardiac involvement after bws bites in literature. 204 year age/sex cardiac presentation ecg echocardiography cardiac markers diagnosis piscopo et al., 202015 50/m not mentioned diphasic t wave in the lateral leads at admission. at day 3, ecg showed sinus rhythm and negative t wave in the lateral and inferior leads. -abnormalities in left ventricular wall motions and moderate systolic dysfunction (hypokinesia of lv middle/ basal segment of inferior, lateral and inferior-lateral wall. -lvef= 48% positive acute myocarditis yaman et al., 201516 15/m pulmonary edema/ heart failure st depression in ii, iii, avf, avl and v3-v6 ef=22% global hypokinesia rim of pericardial effusion positive reversible myopericarditis bucur et al., 20124 35/m pulmonary edema/ heart failure sinus tachycardia hyperacute t in v3-v6 ef= 48% septal and lateral wall hypokinesia positive reversible myopericarditis levine et al., 20107 22/m pulmonary edema incomplete right bundle branch block st uptake in v1v6 ef= 35% mild to moderate tricuspid regurg positive reversible myopericarditis sari et al., 200810 65/m chest pain st elevation in ii and avf hyperacute t in v3-v6 normal positive kounis syndrome erdur et al., 20075 22/m chest pain, severe hypertension inverted p in leads ii, iii, avf, avl and v1 ef = 40% anteroseptal wall hypokinesia positive reversible toxic myocarditis pneumatikos et al., 20038 19/f cardiogenic shock atrial fibrillation incomplete right bundle branch block ef = 20 % global hypokinesia positive acute fatal toxic myocarditis bucur et al., june 1988 to may 19973 seven cases (13-57 years) ranging from chest pain to pulmonary edema not mentioned not mentioned not mentioned all cardiac events were reversible pulignano et al., 19989 16/m typical chest pain st-t changes in precordial leads akinesia of interventricular septum depressed left ventricular function positive reversible toxic myocarditis 205 206 207 figure 1: initial electrocardiogram showing st-segment elevation in leads i, avl, and st-208 segment depression in leads ii, iii, avf, and v2–v6. 209 210 211 a b 212 figure 2: (a) echocardiography showing normal left ventricular end-diastolic diameter and 213 impaired left ventricular systolic function with an ejection fraction (ef) of 42%. (b) 214 echocardiography showing thickening of the pericardium with rim of pericardial effusion on 215 lateral wall and right atrium. 216 217 clinical profile of stroke: the experience at king abdulaziz university hospital 35 abstract. objectives : to determine the pattern and risk factors of stroke in saudi nationals and non-saudis, at king abdulaziz university hospital (kauh), in the western province of saudi arabia. method: all cases of stroke admitted to kauh in the period between january 1995 and december 1999 were studied. demographic data of the patients, stroke types, risk factors and mortality were reported. results : of the 103 patients studied, 56% were saudis and 44 % non-saudis with male predominance and mean ages of 66 and 62 years respectively. in saudis, the stroke types were 74% ischemic, 10% hemorrhagic and 16% unspecifi ed, whereas in non-saudis, the fi gures were respectively 62% , 29% and 9% . the frequency of stroke increased steadily with age in saudis but dropped after the sixth decade in nonsaudis. there was no signifi cant difference between the saudis and the non-saudis in the occurrence of risk factors for stroke or in mortality. conclusion: the pattern and risk factors of cases of stroke treated at kauh are similar to those reported from other regions of saudi arabia and other parts of the world. key words : stroke, risk factors, saudis, nonsaudis s troke is one of the leading causes of death, long-term disability, and hospital admission in the industrialized world.1 the loss of the affected individuals from work force and the extended hospitalisation they require during recovery make the economic impact of the disease among the most devastating. in sweden, the prevalence of home-bound stroke victims with residual dysfunctions after an average 95.2 days’ hospitalisation has been estimated at 0.74 per 1000.2 studies in usa suggest an annual cost of at least $ 30–40 billion.3,4 the frequency of different types of stroke, their risk factors and incidence rates vary in different regions of the world.5–11 there are several reports on the pattern and risk factors of stroke in the middle and eastern provinces of saudi arabia.9,12–15 we report our experience regarding saudi nationals and nonsaudis at king abdulaziz university hospital (k auh ) in the western province of saudi arabia. m e t h o d k au h is a teaching hospital with a capacity of 400 beds. the medical charts of all patients admitted to this hospital with a diagnosis of stroke from january 1995 to december 1999 were reviewed. stroke was defi ned as per the world squ journal for scientific research: medical sciences 2001, 1, 35–38 ©sultan qaboos university clinical profi le of stroke: the experience at king abdulaziz university hospital *daad h. akbar, maimona mushtaq department of medicine, king abdulaziz university hospital, jeddah 21415, p.o box 18298 kingdom of saudi arabia. *to whom correspondence should be addressed. .e-mail: daadakb@yahoo.com a k b a r & m u s h t a q36 health organization (who )’s defi nition: rapidly developing clinical signs of focal or global disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than vascular origin.16 findings of brain computerized tomography (ct) scan performed within one week of the onset of stroke were used for classifi cation of the type of stroke. cerebral infarction was diagnosed based on typical ct scan fi ndings of infarct or a normal ct scan when it was performed within two days of the onset of stroke, or the presence of a potential source of cerebral emboli such as the heart or carotid artery relevant to the side of the stroke. patients with cerebral infarction were further classifi ed into lacunar infarct (defi ned as infarct measuring up to 1.5 cm on ct scan of the brain) and non-lacunar infarct (defi ned as infarct measuring >1.5 cm on ct scan of the brain). intracerebral haemorrhage (ich ) or subarachnoid haemorrhage (sah ) was diagnosed based on clinical and ct scan fi ndings. where none of these criteria were fulfi lled, the cause was classifi ed as unspecifi ed type of stroke. in addition to the fi ndings on neurological evaluation at the time of admission, results of clinical and investigative fi ndings of cardiovascular systems were also analysed. patient’s age, sex, nationality, presence of diabetes mellitus (dm ) (defi ned according to the w ho criteria),17 hypertension (defi ned as systolic blood pressure >160 mmhg and /or diastolic blood pressure >95 mmhg at the time of admission and persisted even after that during the hospital stay or if the patient is already known hypertensive), hyperlipidemia (defi ned as total cholesterol >5.2mmol/l, triglyceride >2.3 mmol/l, hdl <0.9 mmol/l, ldl >3.4 mmol/l), history of smoking were recorded as well as history of transient ischemic attacks (ti a), presence of aphasia, loss of consciousness, recurrent stroke, presence of bilateral stroke, stroke in evolution, use of mechanical ventilation and mortality. statistical analysis was done using spss 7.5 software. a two-tailed student’s t-test and chi-square (χ2) were used as appropriate. p <0.05 was considered signifi cant. r e s u l t s a total of 103 patients were studied, out of which 58 (56%) were saudis and 45 (44%) non-saudis with a male:female ratio of 1.4:1 versus 1.6:1 and mean age of 65.8 ± 12.6 years versus 61.75 ± 14.75 years (p 0.7 and 0.1 respectively). in saudis, ischemic stroke constituted the majority of cases, 43/58 (74%), [14/43 (33%) lacunar infarct and 29 /43 (67%) non-lacunar infarct], while hemorrhagic stroke were reported in 6/58 (10%) and unspecifi ed in 9/58 (16%). in non-saudis ischemic stroke constituted 28/45 (62%), [4/28 (14%) lacunar infarct and 24/28 (86%) non-lacunar infarct], hemorrhagic stroke 13/45 (29%), [10/13 (77%) ich and 3/13 (23%) sah ], and unspecifi ed in 4/45 (9%). hemorrhagic stroke was encountered more often in nonsaudis (p 0.03). the incidence of stroke – both ischemic and hemorrhagic – increased progressively after the age of 45 in saudis, while in non-saudis ischemic stroke was mainly in the age group 45–65 and hemorrhagic stroke increased with age [table 1]. risk factors for stroke such as hypertension, dm , hyperlipidemia and smoking were present in both saudis and non-saudis with no signifi cant table1. distribution of stroke type in saudi and nonsaudi by age group stroke type <45 years 45-65 years >65 years total ich s ns 2 (20) 2 (33) 3 (30) 4 (67) 5 (50) 6 10 sah s ns 2 (67) 1 (33) 3 li s ns 1 (7) 7 (50) 4 (100) 6 (43) 14 4 nli s ns 1 (3) 3 (13) 13 (45) 10 (42) 15 (52) 11 (46) 29 24 u s ns 1 (17) 5 (56) 2 (50) 4 (45) 1 (25) 9 4 ich=intracerebral hemorrhage, sah= subarachnoid hemorrhage, li=lacunar infarct, nli= non lacunar infarct, u=unspecified, s= saudi, ns=non-saudi table2. relation between risk factors, stroke type and nationality stroke type total* nationality hbp dm hl smoking ich 6 10 s ns 4 (67) 5 (50) 1 (17) 2 (20) 3 (50) 1 (10) 1 (17) 4 (40) sah 3 s ns 2 (67) 2 (67) 2 (67) li 14 4 s ns 4 (29) 2 (50) 10 (71) 1 (25) 6 (43) 4 (100) 6 (43) 1 (25) nli 29 24 s ns 15 (52) 15 (63) 12 (41) 14 (58) 7 (24) 9 (38) 15 (52) 8 (33) u 9 4 s ns 6 (67) 4 (100) 7 (78) 2 (50) 4 (44) 5 (56) 1 (25) * more than one risk factor in one patient ich= intracerebral haemorrhage, sah= subarachnoid haemorrhage, li=lacunar infarct, nli= non-lacunar infarct, u= unspecified, s=saudi, ns= non-saudi, hbp= hypertension, dm=diabetes mellitus, hl=hyperlipidemia c l i n i c a l p r o f i l e o f s t r o k e 37 difference between the two: 29/58 (50%), 30/58 (52%), 20/58 (35%), 27/58 (47%) in saudis and 28/45 (62%), 21/45 (47%), 14/45 (31%), 16/45 (36%) in non-saudis (p 0.2, 0.6, 0.7, 0.5 respectively). hypercholesterolemia was the commonest type of hyperlipidemia found in our patients in both saudis and non-saudis. while 15/20 (75%) of the saudis had isolated hypercholesterolemia, 3/20 (15%) had mixed hyperlipidemia and 2/20 (10%) had hypertriglyceridemia, the corresponding fi gures for non-saudis were 10/14 (71%), 3/14 (21%) and 1/14 (7%). as shown in table 2, hypertension was the commonest risk factor for both ischemic and hemorrhagic strokes in both saudis and nonsaudis. aphasia and loss of consciousness were reported more frequently in non-saudis while there was no signifi cant difference in the other stroke characteristics between saudis and non-saudis (table 3). parietal area and cerebellum were the areas most often involved in both saudis and non-saudis, 21/58 (36%) and 10/58 (17%) versus 14/45 (31%) and 21/45 (27%) (p 0.5, 0.3 respectively). nine of 58 (16%) of the saudis patients died versus 12/45 (28%) nonsaudis (p 0.16). d i s c u s s i o n our results showed that stroke was more frequent in the sixth decade of life with male predominance in both saudis and non-saudis, a fi nding similar to what has been reported by others.9,10,12,14 ischemic stroke had been reported to be more frequent than hemorrhagic stroke.10,18,19 it accounted for 74% of cases in saudis while ich was more frequent than sah ; both were encountered more in non-saudis, which is consistent with what had been reported from other regions of saudi arabia.12,14,15 the frequency of stroke increased steadily with age in saudis and dropped after the sixth decade in non-saudis, a fi nding in agreement with what had been reported by al-rajeh et al.14 reports from other parts of the world also show that frequency of stroke increases with age.10,19 we reported a mortality of 16% in saudis, which is similar to that reported from riyadh area9 and other parts of the world.19 several risk factors for stroke have been identifi ed, including age, hypertension, dm , cigarette smoking and hyperlipidemia.20–22 the frequency of these risk factors is high in both saudis and non-saudis with hypertension being the commonest in both ischemic and hemorrhagic stroke. hypertension, including borderline hypertension, is probably the most important risk factor for stroke based on the degree of risk and prevalence as described by sacco.23 data from the harvard stroke registry, the stroke data bank, and the new england medical center registries indicate that multiple potential stroke aetiologies are frequent.24–26 among the 407 patients in the new england medical center registry, 20% had two, and 2% had three potential aetiologies for ischemia. the frequent coexistence of more than one and sometimes multiple potential risk factors for stroke is an important factor. all patients who have evidence of potential risk factors for stroke deserve control and modifi cation of these factors when possible. the importance of control of hypertension has to be stressed to the treating physicians. an overview of 14 treatment trials concluded that a long-term (mean fi ve years) 5 to 6 mmhg decrease in the usual diastolic blood pressure was associated with 35-40% reduction in stroke incidence.27 treating hyperlipidemia with h mg coa reductase inhibitor has been described by bucher to reduce the incidence of stroke.28 several studies have reported that physical inactivity increases the risk of stroke and those who participate in leisure-time physical activity have a lower risk.29–32 c o n c l u s i o n this study reveals that the pattern of stroke and its risk factor profi le at k auh , in the western province of saudi arabia, is similar to that reported from other regions of saudi arabia and other parts of the world. r e f e r e n c e s 1. bonita r. epidemiology of stroke. lancet 1992, 339, 342–4. 2. de pedro-cuesta j, sandstrom b, holm m, stawiarz l, widen-holmqvist l, bach-y-rita p. stroke rehabilitation: identifi cation of target groups and planning data. scand j rehabil med 1993, 25, 107–16. table 3. comparison between saudis and non-saudis in relation to some stroke characteristics sign saudi n=58 non-saudi n=45 p value aphasia n (%) 19 (33) 22 (49) 0.09 loss of conciousness n (%) 13 (22) 17 (38) 0.08 rt. hemiplegia n (%) 24 (41) 25 (56) 0.2 bilateral stroke n (%) 10 (17) 6 (13) 0.5 recurrent stroke n (%) 16 (28) 8 (18) 0.2 stroke in evolution n (%) 4 (7) 2 (4) 0.5 transient ischemic attack n (%) 6 (10) 5 (11) 0.9 mechanical ventilation n (%) 5 (9) 1 (2) 0.1 a k b a r & m u s h t a q38 3. matchar db, duncan pw. cost of stroke. clin update 1994, 5, 9–12. 4. taylor tn, davis ph, tomer jc, holmes j, meyer jw, jacobson mf. lifetime cost of stroke in the united states. stroke 1996, 27,1459–66. 5. william gr, jiang jg, matchar db, samas gp. incidence and occurrence of total (fi rst ever and recurrent) stroke. stroke 1999, 30, 2523–8. 6. kurtzke jp, kurland lt. epidemiology of neurological diseases. in: baker ab,joynt rj, ed. clinical neurology, vol 4, philadelphia: harper and row, 1987. 7. matsumoto n, whisnant jp, kurland lt, okazaki h. natural history of stroke in rochester, minnesota, 1955 through 1969: an extension of a previous study, 1945 through 1954. stroke 1973, 4, 20–29. 8. tanaka h, ueda y, date c, baba t, yamashita h, hayashi m et al. incidence of stroke in shibata, japan: 1976–1978. stroke 1981, 12, 460–6. 9. al-rajeh s, awada a,niazi g, larbi e. stroke in a saudi arabian national guard community: analysis of 500 consecutive cases from a population-based hospital. stroke 1993, 24, 1635–9. 10. al jishi aa, mohan pk. profi le of stroke in bahrain. saudi med j 1999, 20, 958–62. 11. jain s, maheshwari mc. cerebrovascular diseases: a review of the indian experience in the last 35 years. neuroepidemiology 1986, 5, 1–16. 12. awada a, al-rajeh s. the saudi data bank. analysis of the fi rst 1000 cases. acta neurol scand 1999, 100, 265–9. 13. yaqub ba, shamena ar, kolawole tm, patel pj. cerebrovascular diseases saudi arabia. stroke 1991, 22, 1173–6. 14. al rajeh s, larbi e, bademosi o, awada a, ismail h, al freihi h, al ghassab g. stroke in a tertiary hospital in saudi arabia: a study of 372 cases. eur neurol 1991, 31, 251–6. 15. al rajeh s, labri e, bademosi o, awada a, ismail h, al freihi h. pattern and ethnic variations in stroke in saudi arabia. j neurol sci 1991, 102, 112–8. 16. world health organization. stroke 1989. recommendations on stroke prevention, diagnosis, and therapy. report of the who task force on stroke and other cerebrovascular disorders. stroke 1989, 20, 1407–31. 17. world health organization. diabetes mellitus: report of a who study group. geneva. who tech rep s no.727 1985, 1–113. 18. yatsu fm, becker c, macleroy kr, coull b, feibel j, howard g et al. community hospital-based stroke program: north carolina, oregon, and new york. stroke 1986, 17, 276–84. 19. kita y, okayama a, ueshima h, wada h, nozaki a, choudhury sr. stroke incidence and case fatality in shiga, japan,1989-1993. int j epidemiol 1999, 28, 1059–65. 20. marmot mg, poulter nr. primary prevention of stroke. lancet 1992, 339, 344–7. 21. neaton jd, blackburn h, jacobs d, kuller l, lee dj, sherwin r et al. serum cholesterol level and mortality fi ndings for men screened in the multiple risk factor intervention trial. multiple risk factor intervention trial group. arch intern med 1992, 152, 1490–500. 22. reed d,yano k,kagan a. lipids and lipoproteins as predictors of coronary heart disease, stroke, and cancer in the honolulu heart program. am j med 1986, 80, 871–8. 23. sacco rl,wolf pa,gorelick pb. risk factors and their management for stroke prevention: outlook for 1999 and beyond. neurology 1999, 53, 15–24. 24. mohr jp, caplan lr, melski jw, goldstein rj, duncan gw, kistler jp et al. the harvard cooperative stroke registry: a prospective registry. neurology 1978, 28, 754–62. 25. foulkes ma, wolf pa, price tr, mohr jp, heir db. the stroke data bank: design, methods, and baseline characteristics. stroke 1988, 19, 547–54. 26. caplan lr. posterior circulation disease: clinical findings, diagnosis and management. cambridge, mass: blackwell science publishers 1996, 179–97. 27. collins r, petro r, macmahon s, hebert p, fiebach nh, eberlein ka et al. blood pressure, stroke and coronary heart disease. part 2: short term reduction in blood pressure: overview of randomised drug trial in their epidemiological contexr. lancet 1990, 335, 827–38. 28. bucher hc, griffi th le, guyatt gh. effect of hmgcoa reductase inhibitors on stroke. a meta analysis of randomized controlled trials. annals intern med 1998, 128, 89–95. 29. kieley dk, wolf pa, cupples la, beiser as, kannel wb. physical activity and stroke risk: the framingham study. am j epidemiol 1994, 140, 608–20. 30. sacco rl, gan r, boden-albala b, lin if, kargman de, hauser wa et al. leisure-time physical activity and ischemic stroke risk: the north manhattan stroke study. stroke 1998, 29, 380–7. 31. lee im, paffenbarger rs jr. physical activity and stroke incidence: the harvard alumni health study. stroke 1998, 29, 2049–54. 32. agnarsson u, thorgeirsson g, sigvaldason h, sigfusson n. effects of leisure-time physical activity and ventilation function on risk of stroke in men: the reykjavik study. annals intern med 1999, 130, 987–90. submitted 21 dec 21 1 revision req. 2 feb 22; revision recd. 6 mar 22 2 accepted 22 mar 22 3 online-first: may 2022 4 doi: https://doi.org/10.18295/squmj.5.2022.041 5 6 haemophilus influenzae empyema in a 2-month-old-infant 7 saif al-yazeedi,1 rima al-farsi,2 hatem al-rawahi,3,4 *laila s. al 8 yazidi3,4 9 10 1medical laboratory department, yanqal hospital, al dahira region, oman; 2radiology 11 department, ibri hospital, al dahira region, oman; 3child health department, sultan 12 qaboos university hospital, muscat, oman; 4oman medical specialty board, muscat, 13 oman. 14 *corresponding author’s e-mail: lailay@squ.edu.om 15 16 abstract 17 empyema can rarely complicate pneumonia in neonates. it carries high morbidity and 18 mortality in this population. we report the case of a 2-month-old healthy term neonate who 19 presented with fever, mild shortness of breath and reduced feeding. investigations revealed 20 the presence of haemophilus influenzae empyema. he was managed with videoassisted 21 thoracoscopic surgery (vats) and prolonged course of antibiotics. a clinic follow-up at the 22 end of the antibiotic course revealed complete symptoms resolution with a repeated cxr 23 showed significant right chest opacity improvement. a baseline immune work-up was done 24 and was reported to be within normal ranges. 25 keywords: empyema, neonate, haemophilus influenzae 26 27 introduction 28 empyema can rarely complicate pneumonia in neonates.1 it carries high morbidity and 29 mortality in this population.1,4,5 it is defined as a progressive pleural pus build up, which is 30 mainly seen as a complication in patients with pneumonia.1-5 empyema can be fatal if sub-31 optimally treated.1 barbosa m et al reported 3 (0.04%) cases of empyema diagnosed out of 32 7,200 nicu admissions over 18 years.2 risk factors of developing empyema in neonates 33 mailto:lailay@squ.edu.om include premature rupture of the membranes, maternal fever during labour, prematurity, 34 extremely low weight birth, viral infection and immunosuppression.1 35 case report 36 a 2-month-old healthy term infant presented to sultan qaboos university hospital 37 emergency department with a 10-day history of fever and runny nose, associated with mild 38 shortness of breath and feeding difficulty on the day of presentation. he received his birth 39 and 2-month vaccinations as per omani immunization schedule. on presentation, his 40 temperature was 37.7c, pulse rate was150 b/min, respiratory rate was 30 breaths /min, with 41 saturation of 94% in room air. his chest examination showed reduced air entry on 42 auscultation with a stony dullness percussion over the right chest. other systemic 43 examinations were unremarkable. laboratory investigations showed leukocytosis of 37.1 x 44 109/l with neutrophilia of 24.7x109/l. the initial chest x-ray showed air space opacities in 45 the right lung with silhouetting of the cardiac border and the right hemidiaphragm. the right 46 costophrenic angle was obliterated, suggestive of right pleural effusion (figure 1). he was 47 started on iv ceftriaxone and clindamycin for a complicated community-acquired 48 pneumonia. ct chest was done and showed a large right-sided pleural effusion which 49 appears to be encysted in apical region, causing compressive atelectasis of right lung and 50 shift of the cardiomediastinal structures to contralateral left side. the right lung appeared to 51 collapse with minimal aeration of the anterior segment of the right upper lobe (figure 2). a 52 video-assisted thoracotomy done and drained a significant amount of pus, with both bacterial 53 culture and viral studies were reported to be negative. a 16s rdna pcr testing from the 54 pleural fluid was processed and reported positive for haemophilus influenzae. he was 55 managed with iv ceftriaxone and clindamycin and then oral co-amoxyclav for a total of 3-4 56 weeks. a clinic follow-up at the end of the antibiotic course revealed complete symptoms 57 resolution with a repeated cxr showed significant right chest opacity improvement. a 58 baseline immune work-up was done and was reported to be within normal ranges. consent 59 for publication has been obtained. here we discuss the causes and management of empyema 60 in infants. 61 62 discussion 63 medical literature on the clinical and laboratory features, and management of neonatal 64 empyema is very limited.1 neonates with empyema have a wide range of symptoms, being 65 asymptomatic to having significant respiratory distress requiring respiratory support.1,4 these 66 patients can present with pallor, jaundice, or poor feeding.1 the mean age of presentation of 67 empyema in one study was 13.5 days (6–38 day).1 68 69 streptococcus pneumoniae, haemophilus influenzae and staphylococcus aureus are the most 70 common causative organisms of empyema in children. drained pus should be sent for 71 biochemistry, microscopy, gram stain, culture, and molecular testing to optimize the 72 identification of the causative organism and guide targeted therapy.4,5 friesen et al reported 2 73 cases and reviewed another 86 cases of neonatal h. influenzae from the literature. they found 74 that 79.6% of these cases were due to non-typeable h. influenzae strains. most of these 75 infections were associated with maternal complications, prematurity, low birthweight, and 76 early onset sepsis.6 sarah collins and her colleagues reported 115 neonates with hi empyema 77 from england and wales over a 5-year period. 96% had non-typable hi and 30 (26%) of 78 these neonates had pneumonia.7 no reported cases of neonatal hi empyema from oman that 79 we can identify. 80 81 managing empyema starts with accurate diagnosis through plain x ray followed by lung 82 ultrasound (us) to obtain further details and characterize the fluid.3 although kurian et al 83 showed that ct chest did not provide additional useful information compared to chest us in 84 their study,8 chest ct has a role in complicated cases and particularly in 85 immunocompromised children where it can reveal other serious clinical problems.9 bacterial 86 culture enables the detection of living bacteria only.10 giving empiric antibiotics can cause 87 sterilization of pleural culture which makes it difficult to identify the offending organism. 88 molecular testing like targeted polymerase chain reaction or broad range 16s rdna pcr 89 have the advantage of detecting viable and nonviable organisms in such cases.10 90 91 the therapeutic course depends on the severity of the empyema and the type of the causative 92 micro-organism. antibiotics and pus drainage, using intercostal chest tube (icd) or video-93 assisted thoracic surgery (vats), are the mainstay of treatment.3 a combination therapy of 94 third generation cephalosporin and vancomycin in areas with high rates of mrsa 95 colonization is the recommended empiric therapy.1 giving antibiotics for 3-4 weeks after 96 adequate drainage of the pus is reasonable and has shown to be effective.1,4 vats is more 97 effective for multiloculated empyema.5,4 follow up with a repeat chest-x-ray after 4-6 weeks 98 is highly recommended.1,5 the prognosis is excellent after proper treatment with no long-99 term complications in the majority of neonates reported in the literature.1 100 101 conclusion 102 in conclusion, early identification of effusion, immediate initiation of antibiotics, and prompt 103 chest tube insertion are the key for successful treatment of this condition. molecular testing 104 of the pus is highly recommended in children with culture negative empyema to optimize the 105 identification of the causative organism and guide targeted therapy. 106 107 conflict of interest 108 the authors declare no conflicts of interest. 109 110 funding 111 no funding was received for this study. 112 113 author contribution: 114 hr and ly conceptualized the idea. sy and rf drafted the manuscript while hr and ly 115 revised the manuscript. all authors approved the final version of the manuscript. 116 117 references 118 1diez jrv, perez mlm, malayan gv, cenabre mvl. loculated empyema in a neonate 119 successfully treated with chest tube thoracostomy and antibiotics. respir med case rep. 120 2020;31:101274. doi:10.1016/j.rmcr.2020.101274 121 2barbosa m., rocha g., flôr-de-lima f., guimarães h. neonatal pleural effusions in a 122 level iii neonatal intensive care unit. j pediatr neonat individual med. 2015;4(1):1. 123 doi: 10.7363/040123 124 3mandal kc, mandal g, halder p, mitra d, debnath b, bhattacharya m. empyema 125 thoracis in children: a 5-year experience in a tertiary care institute. j indian assoc 126 pediatr surg. 2019;24(3):197-202. doi:10.4103/jiaps.jiaps_112_18 127 4s sharma s, sharma a, sharma m, ghosh s. neonatal empyema thoracis. 128 pediatr oncall j. 2018;15: 19-21. doi: 10.7199/ped.oncall.2018.2 129 5kotrashetti v, sonawane vb, bainade k, nair s, bunde s. empyema thoracis in an 130 infant: a case report. indian j child health. 2020; 7(10):427-429 131 6friesen ca, cho ct. characteristic features of neonatal sepsis due to haemophilus 132 influenzae. rev infect dis. 1986 sep-oct;8(5):777-80. doi: 10.1093/clinids/8.5.777. 133 pmid: 3538317. 134 7sarah collins, david j. litt, sally flynn, mary e. ramsay, mary p. e. slack, shamez n. 135 ladhani, neonatal invasive haemophilus influenzae disease in england and wales: 136 epidemiology, clinical characteristics, and outcome, clinical infectious diseases, 137 volume 60, issue 12, 15 june 2015, pages 1786–1792, https://doi.org/10.1093/cid/civ194 138 8kurian j, levin tl, han bk, taragin bh, weinstein s. comparison of ultrasound and 139 ct in the evaluation of pneumonia complicated by parapneumonic effusion in children. 140 ajr am j roentgenol. 2009 dec;193(6):1648-54. doi: 10.2214/ajr.09.2791. pmid: 141 19933660. 142 9balfour-lynn im, abrahamson e, cohen g, et al. bts guidelines for the management of 143 pleural infection in children. thorax. 2005;60 suppl 1(suppl 1):i1-i21. 144 doi:10.1136/thx.2004.030676. 145 10patel a, harris ka, fitzgerald f. what is broad-range 16s rdna pcr? arch dis child 146 educ pract ed 2017;102:261–264. doi:10.1136/archdischild-2016-312049 147 https://doi.org/10.1093/cid/civ194 https://doi.org/10.1093/cid/civ194 148 figure 1: initial chest x-ray which showed air space opacities in the right lung with 149 silhouetting the cardiac border and the right hemidiaphragm. the right costophrenic angle is 150 obliterated. 151 152 figure 2: ct chest showing large right-sided pleural effusion which appear to be encysted in 153 apical region, causing compressive atelectasis of right lung and causing shift of 154 cardiomediastinal structures to contralateral left side. 155 evaluation of different polymerisation methods of ocular prosthesis acrylic resins on subcutaneous tissue inflammatory response in rats emily v.f. da silva,1 *marcelo c. goiato,1 sandro b. bitencourt,1 victor g.b. brito,2 aline s. takamyia,3 paulo a. penitente,1 sandra h.p. de oliveira,2 daniela m. dos santos1 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 233–240, epub. 26 may 22 submitted 20 oct 20 revision req. 11 jan 21; revision recd. 24 jan 21 accepted 10 feb 21 departments of 1dental materials and prosthodontics, 2basic sciences and 3surgery and integrated clinic, school of dentistry, são paulo state university (unesp), araçatuba, brazil *corresponding author’s e-mail: goiato@foa.unesp.br this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.082 clinical & basic research abstract: objectives: this study aimed to evaluate the influence of different polymerisation methods of acrylic resin for ocular prostheses on the subcutaneous tissue inflammatory response of rats. methods: the study was conducted at the basic sciences department, araçatuba dental school, são paulo state university (unesp), brazil, from 2016 to 2018. the samples were prepared by water bath (wb), microwave energy (mw) or autopolymerisation (ap) (n = 20 samples per group). the inflammatory response (cell count and immunohistochemical analysis of interleukin [il]-1β, il-6, tumour necrosis factor [tnf]-α, il-17 and macrophage inflammatory protein-3α) was analysed by the implantation of a sample from each group in the subcutaneous tissue of 20 wistar rats and evaluated after seven, 15, 30 and 60 days. the quantitative and qualitative data were analysed using analysis of variance and tukey tests (p <0.05) and visual comparison, respectively. results: there was a moderate inflammatory infiltrate for the mw and ap groups and a light infiltrate for the wb group after seven days. the inflammatory infiltrate and the immunolabeling of tested targets decreased gradually during the 60-day period. the ap group had the highest immunolabeling of tnf-α (seven days), il-1β and il-17 (at 15 and 30 days) and il-6 (at 30 and 60 days). the wb and mw groups showed greater immunolabeling at 15 and 30 days, while the mw group also had high results at 60 days. conclusion: polymerisation by microwave energy and by chemical activation resulted in a higher inflammatory response. keywords: ocular prosthesis; acrylic resins; biocompatibility testing; wistar rats; polymerization; brazil. advances in knowledge different polymerisation methods of ocular prostheses acrylic resin were analysed. the subcutaneous tissue of wistar rats was assessed for inflammatory response analysis. materials were polymerised according to the manufacturer’s instructions. polymerisation by microwave energy and chemical activation resulted in a higher inflammation. application to patient care the knowledge of ocular prosthesis material’s biocompatibility is important to ensure safe use in patients. the polymerisation by microwave energy and chemical activation resulted in a higher inflammatory response, which is interesting information for clinicians. patients benefit from the identification of the polymerisation method that causes fewer undesirable effects. the use of ocular prostheses to improve the self-esteem of anophthalmic individuals through the re-establishment of facial aesthetics and healthy maintenance of the remaining structures is a viable and safe rehabilitation procedure.1 these prostheses, composed of a larger volume of white acrylic resin (ar) and a smaller volume of colourless resin, can be polymerised in a heated water bath, by microwave energy or chemical activation.2,3 among the factors involved in the success of prosthetic rehabilitation, it is essential that the artificial material used causes no local or systemic undesirable effects in the individual who received it.4 however, there are reports in the literature of irritation associated with the use of ocular prostheses, which may occur when there is an incomplete conversion of methyl methacrylate (mma) monomers into polymers.2,5 this material then releases potentially toxic substances such as formaldehyde, methacrylic acid and residual mma monomers, among others.4,6 in vivo toxicity tests allow the study of the mechanisms of adverse reactions to a material through the analysis of interactions among cells and tissues, simulating a condition similar to what would occur in humans.7,8 the implantation of a sample in the subcutaneous tissue of rats allows for the analysis of local effects of a given stimulus and enables, for example, the identification of inflammatory cells and the analysis of the local tissue response.9,10 an excessive inflammatory response of the organism can promote irreversible damage, so it is important to evaluate the ability of ocular prostheses to induce the release of https://creativecommons.org/licenses/by-nd/4.0/ evaluation of different polymerisation methods of ocular prosthesis acrylic resins on subcutaneous tissue inflammatory response in rats 234 | squ medical journal, may 2022, volume 22, issue 2 pro-inflammatory cytokines and chemokines and to understand their chemotactic activity mechanism.11 these mediators secreted under inflammatory response conditions include two patterns: the t helper type 1 (th1) cytokine pattern, with pro-inflammatory action mainly caused by interleukin (il)-1β, il-6 and tumour necrosis factor (tnf)-α and the th2 pattern, with anti-inflammatory action.12 it is a known fact that human studies involve multiple ethical issues in the performance of certain types of intervention studies. since the results obtained from animal models have acceptable predictability for toxicity in humans (approximately 70–80%),8 being no more resistant than models in humans, the present study can provide useful information for patients and professionals. this study aimed to evaluate the influence of different polymerisation methods of whitecoloured ar for ocular prostheses on the subcut aneous tissue inflammatory response of wistar rats. the null hypothesis is that the different polymerisation methods of white ar tested do not produce inflammatory tissue responses in the subcutaneous tissue. methods the current study was conducted at the basic sciences department, araçatuba dental school, são paulo state university (unesp), brazil, from 2016 to 2018. a total of 60 ar samples in the colour white (artigos odontológicos clássico ltda, são paulo, brazil) were prepared and distributed across three groups (n = 20 each), according to the polymerisation method: thermopolymerised resin in water bath (wb; clássico, artigos odontológicos clássico ltda), thermopolymerised resin by microwave energy (mw; onda cryl, artigos odontológicos clássico ltda) and autopolymerisation (ap; chemically activated) resin (jet, artigos odontológicos clássico ltda).3 samples were obtained from a metallic matrix containing 10 circular compartments (10 mm in diameter and 3 mm in thickness).1,3 the ar was handled according to the manufacturer’s recommendations and inserted into the compartments.13,14 for the wb polymerisation, a flask was immersed in water, heated for 30 min, placed at room temperature for 30 min and boiled at 100 ºc for 1 h. for the microwave energy mw polymerisation, a flask was placed in a microwave for three minutes at 30% power (320 w), four minutes at 0% power (0 w) and three minutes at 60% power (720 w). for ap, an open flask with the required amount of water was placed in a device under 140 kpa for 20 minutes. the samples were then finished with an abrasive drill.3 twenty male albino wistar rats at the age of four months were used. the animals were kept in an environment with controlled temperature and received ad libitum water and food.9,10 initially, samples were washed three times in milli-q water (merck millipore, burlington, massachusetts, usa) and sterilised by exposure to ultraviolet light for 30 minutes per side.15 animals were anesthetised with an intraperitoneal injection of ketamine (25 mg/kg) and xylazine (10 mg/ kg). then, the trichotomy of the dorsal region was performed, followed by asepsis with 5% povidoneiodine solution.9,10 an incision of 2 cm in a head-totail direction was performed in the dorsal region using a no. 15 bard-parker® blade (aspen surgical corp., caledonia, michigan, usa). the connective tissue was laterally divulsed with a blunt-tipped scissor to form three surgical pockets. one sample of each group was inserted in each surgical pocket. it is important to attest that the pockets remained distant from each other. the skin was sutured with a 4.0 silk thread (ethicon inc., raritan, new jersey, us).16 after seven, 15, 30 and 60 days of implantation (n = 5), the animals were euthanised with an overdose of isoflurane, an inhalation agent (cristália, são paulo, brazil). the specimens (samples and adjacent tissues) were removed and fixed in 10% buffered formalin (ph 7.0). for histological processing, the specimens were dehydrated in increasing concentrations of ethyl alcohol (70%, 80%, 90%, 100%-i, 100%-ii, 100%-iii). subsequently, the ar samples were carefully removed from the interior of the tissue, which was diaphanised in a xylol bath and, finally, infiltrated and embedded in paraffin. the specimens were sectioned into 3 μm pieces and stained with haematoxylin and eosin (he) for further microscopic study of their cell count.9,10 the tissue response was classified as 0 (no or few inflammatory cells and no tissue reaction), 1 (less than 25 cells and a mild reaction), 2 (between 25 and 125 cells and a moderate reaction) and 3 (more than 125 cells and a severe reaction). the mean number of cells for each group was obtained from the count of mast cells, eosinophils, lymphocytes, macrophages and neutrophils counted in 10 separate areas (×100 magnification) of one slide by a single evaluator.9,10 representative images for each group were obtained (×40 magnification) [figure 1]. from each group, 25 slides were randomly selected to perform the immunohistochemical (ihc) reactions, where goat primary antibodies (santa cruz biotechnology inc., dallas, texas, usa) were used to detect il-1β, -6 and -17 and rabbit primary antibodies (abcam plc., cambridge, uk) were used to detect tnf-α and macrophage inflammatory emily v.f. da silva, marcelo c. goiato, sandro b. bitencourt, victor g.b. brito, aline s. takamyia, paulo a. penitente, sandra h.p. de oliveira and daniela m. dos santos clinical and basic research | 235 protein 3α (mip-3α/ c-c motif chemokine ligand 20 [ccl20]) (n = 5). these antibodies were selected due to their high performance in inflammatory processes. biotinylated rabbit anti-goat igg antibodies (santa cruz biotechnology inc.) and goat anti-rabbit igg antibodies (abcam plc., cambridge, uk) were used as secondary antibodies. the reactions obtained were amplified with the avidin-biotin complex (vectastain elite abc kit, standard) (vector laboratories, inc., burlingame, california, us) and chromogen diaminobenzidine (dab, dako, glostrop, denmark). following this, the slides were counter-stained by harris haematoxylin for 5 seconds and dehydrated for sealing with a coverslip using dpx mounting medium (sigma aldrich, st. louis, missouri, us). the negative control consisted of the protocol described previously but in the absence of primary antibodies.17,18 photographic recording of the slides was performed at ×20 magnification; except for mip-3α, where a ×10 magnification was used) with an olympus xc50 camera (olympus corp., tokyo, japan) coupled with the olympus bx53 microscope (olympus corp.) further, il-1β, il-6, il-17 and tnf-α were diffuse ihc stained. following this, images were deconvoluted through the fiji image j software, version 2.1.0/1.53c (national institutes of health; bethesda, md, usa), and analysed in a standard colour threshold by a single evaluator. the ihc staining for mip-3α was localised and the stained cells per field were counted. an average value of ihc staining was obtained for each target. the statistical package for the social sciences (spss), version 21.0 (ibm inc., chicago, illinois, usa) was used for data analysis. quantitative data obtained from the evaluation of inflammatory process (he figure 1: hematoxylin and eosin-stained subcutaneous tissue slides at ×40 magnification of three groups of male wistar rats prepared using (a) water bath (wb), (b) microwave energy (mw) and (c) autopolymerisation (ap). the slides show moderate inflammatory infiltrates at seven days for slides prepared using mw and ap (found in sub-images b and c) and light inflammatory infiltrates for all other remaining slides (a, b and c). figure 2: number and standard deviation of mast cells per area for each group of male wistar rats (water bath, microwave energy and autopolymerisation) at four different points of time with different uppercase letters indicating the statistical difference between groups at the same time (p <0.05) and different lowercase letters indicating statistical difference between durations within the same group (p <0.05). evaluation of different polymerisation methods of ocular prosthesis acrylic resins on subcutaneous tissue inflammatory response in rats 236 | squ medical journal, may 2022, volume 22, issue 2 staining) and ihc analysis were submitted for twoway analysis of variance and tukey’s test with a 5% significance level. qualitative data were submitted to visual comparison. the study was approved by the research ethics committee of the school of dentistry, são paulo state university, araçatuba, brazil (process number 005942016). results the specimens stained by he were analysed to evaluate the inflammatory response generated by ar samples implanted in the rats’ subcutaneous tissue. there was a moderate inflammatory infiltrate for the mw and ap groups and a light infiltrate for the wb group after seven days. the characteristics indicative of an inflammatory response gradually decreased over time. no necrosis or formation of granulomas was observed in any of the tested groups [figure 1]. this result is more evident when evaluating the mean number of cells that were attracted to the focus of the inflammatory process. in the first seven days, a larger number of cells (mast cells, eosinophils, lymphocytes and neutrophils) were observed compared to other durations, except for macrophages, which had a greater quantity in 30 days. the mw group exhibited the highest number of inflammatory cells [figures 2–6], while the wb group presented a higher number of eosinophils [figure 3] and lymphocytes [figure 4] after 15 days. in the ap group, a higher number of macrophages and neutrophils were observed after 15 [figure 5] and 60 days [figure 6], respectively. the immunolabeling of different targets was identified through the ihc analysis. in general, when analysed over time, a higher response was verified after seven days of implantation. however, exceptions were verified for the il-1β immunolabeling of the mw (numerical only) and ap groups, where the response was higher after 15 days of implantation, for the il-6 immunolabeling of the ap group, where the response was higher after 30 days and for the mip-3α immunolabeling of the wb and ap groups, where the response was higher after 30 days. however, there was figure 4: number and standard deviation of lymphocytes per area for each group of male wistar rats (water bath, microwave energy and autopolymerisation) at four different points of time with different uppercase letters indicating statistical difference between groups at the same time (p <0.05) and different lowercase letters indicating statistical difference between durations within the same group (p <0.05). figure 3: number and standard deviation of eosinophils per area for each group of male wistar rats (water bath, microwave energy and autopolymerisation) at four different points of time with different uppercase letters indicating statistical difference between groups at the same time (p <0.05) and different lowercase letters indicating statistical difference between durations within the same group (p <0.05). emily v.f. da silva, marcelo c. goiato, sandro b. bitencourt, victor g.b. brito, aline s. takamyia, paulo a. penitente, sandra h.p. de oliveira and daniela m. dos santos clinical and basic research | 237 a decrease in the immunolabeling for all the tested targets in 60 days compared to the previous durations. after seven days of implantation, it was verified that the wb and ap groups presented a higher il1β immunolabeling, with a statistically significant difference when compared to the mw group. however, a higher immunolabeling was verified for the ap group after 15 and 30 days. no statistically significant difference was observed between groups compared to il-6 immunolabeling after seven days of implantation. the ap group presented higher immunolabeling after 30 and 60 days, significantly different from other groups. although the il-6 immunolabeling was reduced after 60 days for this group, it was statistically similar to the number recorded at seven days. the ap group showed the highest il-17 immunolabeling, statistically different from the other groups after 15 and 30 days. regarding tnf-α, the ap group had the highest immunolabeling after seven days of implantation, with a statistically significant difference from the mw group. however, the highest immunolabeling was verified for the wb and mw groups after 15 and 30 days. after 60 days, the mw group exhibited greater immunolabeling than the other groups. for the mip-3α immunolabeling, no statistically significant difference was observed between groups at different durations. discussion the null hypothesis that the different polymerisation methods of white ar do not produce inflammatory tissue responses in the subcutaneous tissue was tested and rejected since differences were observed between groups regarding the number of cells associated with inflammation and immunolabeling of the inflammatory mediators evaluated. in vivo assays involve the complexity of cell-cell and cell-tissue interaction and a variety of cell types and hormonal and systemic effects.8 therefore, it is essential to analyse the local tissue response after the implantation of samples of ar for ocular prostheses on the subcutaneous tissue of rats. considering that biocompatibility is directly dependent on the components released by the ar, a decrease of the figure 5: number and standard deviation of macrophages per area for each group of male wistar rats (water bath, microwave energy and autopolymerisation) at four different points of time with different uppercase letters indicating statistical difference between groups at the same time (p <0.05) and different lowercase letters indicating statistical difference between durations within the same group (p <0.05). figure 6: number and standard deviation of neutrophils per area for each (water bath, microwave energy and autopolymerisation) at four different points of time with different uppercase letters indicating statistical difference between groups at the same time (p <0.05) and different lowercase letters indicating statistical difference between durations within the same group (p <0.05). evaluation of different polymerisation methods of ocular prosthesis acrylic resins on subcutaneous tissue inflammatory response in rats 238 | squ medical journal, may 2022, volume 22, issue 2 inflammatory response was observed over time.19 mast cells, eosinophils, lymphocytes and neutrophils were observed in a greater quantity in the first seven days after implantation, especially for the mw group [figures 1–4 and figure 6]. during the microwave polymerisation, the resin is confined inside the flask and the process is carried out in a dry environment, making it difficult to leach residual monomers and other substances.3 in addition, the microwave energy acts only on the monomer molecules.20 these factors may explain the results found. corroborating these results, da silva et al.found unsatisfactory in vitro results for the mw group, which exhibited slight cytotoxicity on a conjunctival cell line.3 mediators secreted under acute inflammatory conditions include several pro-inflammatory cytokines such as il-1β, il-6 and tnf-α. these cytokines are present in the first hours at the inflammatory site, responsible for the chemotactic activity for different cells in the first days of inflammation, corroborating the present study’s results from the present study.12,13 the wb and ap groups showed a higher il-1β immunolabeling after seven days, whereas the ap group showed a higher tnf-α immunolabeling. these mediators are synthesised by lymphocytes and macrophages, among other cells, and act chemotactically by attracting cells such as lymphocytes to the inflammatory site.21 lymphocytes, whose primary functions are to produce antibodies (b lymphocytes) and induce the inflammatory response (t lymphocytes), were the most recruited cells during the process, mainly in the first seven days [figure 4], followed by mast cells [figure 2] and eosinophils [figure 3].21 smaller amounts of neutrophils and macrophages were found after seven days [figures 5 and 6]. the absence of significant neutrophil invasion in the tissue indicates that there was no severe inflammatory response or necrosis associated with the subcutaneous ar sample, corroborating the findings reported by yokoyama et al.22 these authors found similar results with the implantation of carbon nanofibers in the subcutaneous tissue, stating that a low amount of neutrophils is associated with the presence of a nonacutely toxic material.22 macrophages, on the other hand, were observed in a higher quantity after 30 days [figure 5]. it is possible that macrophage cells were ‘alternatively’ activated (m2) from the stimulus they received and were later attracted to the implantation site.23 in this condition, m2 macrophages promote a th2-type immune response, inducing the process of tissue repair, angiogenesis, extracellular matrix remodelling and anti-inflammatory activity.23 however, it is interesting to note that the ap group showed greater immunolabeling of different inflammatory mediators in greater durations of analysis as follows: il-1β (at 15 and 30 days); il-6 (at 30 and 60 days); il-17 (at 15 and 30 days). this fact can be explained by the low degree of conversion of the ar during the chemically activated polymerisation, resulting in the continuous release of free radicals and unreacted residual monomers during polymerisation.19,24 these are potential tissue irritants and may have influenced the continuous release of pro-inflammatory mediators.24 il-17 has an important role in inducing local tissue inflammation and mip-3α, also known as ccl20, is an inflammatory chemokine that can be secreted or expressed by endothelial cells. further, neutrophils, natural killer cells, th17, b lymphocytes and a variety of other immune system cells are related to a pro-inflammatory or cytotoxic response.15 the wb and mw groups showed a higher tnf-α immunolabeling after 15 and 30 days. these findings corroborate those of the study by gretzer et al.25 these authors observed a greater tnf-α quantity after 21 days and associated this factor with a biphasic response of the tnf-α since there is an initial increase in its amount associated with the sample implantation and an increase of this mediator in the repair stage.25 after 60 days, there was a decrease in the immunolabeling for all ihc targets. however, it is important to note that the mw and ap groups showed a higher immunolabeling of il-6 and tnf-α, respectively, at this time. thus, although the inflammatory response had decreased, its intensity was higher these two groups. one of the limitations of this study was that the durations shorter than seven days were not included in the analysis of the inflammatory response. however, the intent was to avoid the interference of the surgical procedure factor in the results and to allow a sufficient amount of tissue adjacent to the sample for analysis.25 going forward, studies to verify the leaching of residual monomers and other substances after polymerisation of the studied materials should be performed to understand the polymerisation process better. conclusion according to the present study’s results, the different polymerisation methods of white coloured acrylic resin for ocular prostheses resulted in an inflammatory response in the subcutaneous tissue of rats. the polymerisation by microwave energy and by chemical activation resulted in a higher inflammatory response. emily v.f. da silva, marcelo c. goiato, sandro b. bitencourt, victor g.b. brito, aline s. takamyia, paulo a. penitente, sandra h.p. de oliveira and daniela m. dos santos clinical and basic research | 239 a c k n o w l e d g e m e n t s the authors thank the coordination for the improve ment of higher education personnel and fapesp (foundation for support to research of the state of sao paulo; #2015/20221-7) for the scholarship granted to the first author, emily v.f. da silva. the authors thank fapesp (#2016/03455-7) for the financial support granted to daniela m. dos santos. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this work was supported by the coordination for the improvement of higher education personnel and foundation for support to research of the state of sao paulo (#2015/20221-7 and #2016/03455-7, respectively). a u t h o r s’ c o n t r i b u t i o n all authors contributed equally to the work. mcg, dms and shpo participated in the concepts and coordination of the study, performed the study design, and drafted the manuscript. evfs, sbb, pap and vgbb conceived the study, fabricated the samples, and participated in assays, as well helped draft the manuscript. evfs, ast and sbb performed the statistical analysis and participated in interpretation of the data. all authors read and approved the final version of the manuscript. references 1. da silva evf, goiato mc, bonatto ldr, de medeiros ra, santos dmd, rangel ec, et al. toxicity analysis of ocular prosthesis acrylic resin with or without pigment incorporation in human conjunc tival cell line. toxicol in vitro 2016; 36:180–5. https://doi.org/ 10.1016/j.tiv.2016.08.005. 2. canadas md, garcia lf, consani s, pires-de-souza fc. color stability, surface roughness, and surface porosity of acrylic resins for eye sclera polymerized by different heat sources. j prosthodont 2010; 19:52–7. https://doi.org/10.1111/j.1532-849x.2009.00522.x. 3. da silva ev, goiato mc, dos santos dm, bonatto ld, brito vg, de oliveira sh. effect of different methods of polymerizing ocular prosthesis acrylic resin on a human conjunctival cell line. j prosthet dent 2016; 116:818–23. https://doi.org/10.1016/j. prosdent.2016.06.001. 4. ata so, yavuzyilmaz h. in vitro comparison of the cytotoxicity of acetal resin, heat-polymerized resin, and auto-polymerized resin as denture base materials. j biomed mater res b appl biomater 2009; 91:905–9. https://doi.org/10.1002/jbm.b.31473. 5. pine kr, sloan bh, jacobs rj. a proposed model of the response of the anophthalmic socket to prosthetic eye wear and its application to the management of mucoid discharge. med hypotheses 2013; 81:300–5. https://doi.org/10.1016/j.mehy.20 13.04.024. 6. goiato mc, freitas e, dos santos d, de medeiros r, sonego m. acrylic resin cytotoxicity for denture base--literature review. adv clin exp med 2015; 24:679–86. https://doi.org/10.17219/ acem/33009. 7. goldberg m. in vitro and in vivo studies on the toxicity of dental resin. clin oral investig 2008; 12:1–8. https://doi.org/10.1007/ s00784-007-0162-8. 8. ukelis u, kramer pj, olejniczak k, mueller so. replacement of in vivo acute oral toxicity studies by in vitro cytotoxicity methods: opportunities, limits and regulatory status. regul toxicol pharmacol 2008; 51:108–18. https://doi.org/10.1016/j. yrtph.2008.02.002. 9. gomes-filho je, gomes ac, watanabe s, oliveira sh, bernabé pf, percinoto c. evaluation of tissue reaction, cell viability an cyto kine production induced by sealapex plus. j appl oral sci 2011; 19:329–36. https://doi.org/10.1590/s1678-77572011005000006. 10. gomes-filho je, silva fo, watanabe s, cintra lt, tendoro kv, dalto lg, et al. tissue reaction to silver nanoparticles dispersion as an alternative irrigating solution. j endod 2010; 36:1698–1702. https://doi.org/10.1016/j.joen.2010.07.007. 11. maxson s, lopez ea, yoo d, danilkovitch-miagkova a, leroux ma. concise review: role of mesenchymal stem cells in wound repair. stem cells transl med 2012; 1:142–9. https://doi.org/0.5966/ sctm.2011-0018. 12. berger a. th1 and th2 responses: what are they? bmj 2000; 321:424. https://doi.org/10.1136/bmj.321.7258.424. 13. fernandes au, portugal a, veloso lr, goiato mc, santos dm. assessment of the flexural strength of two heat-curing acrylic resins for artificial eyes. braz oral res 2009; 23:263–7. https:// doi.org/10.1590/s1806-83242009000300007. 14. goiato mc, dos santos dm, moreno a, iyda mg, rezende mcra, haddad mf. effect of disinfection and storage on the flexural strength of ocular prosthetic acrylic resins. gerodontology 2012; 29:e838–44. https://doi.org/10.1111/j.1741-2358.2011.00570.x. 15. zhao l, mei s, wang w, chu pk, wu z, zhang y. the role of sterilization in the cytocompatibility of titania nanotubes. biomaterials 2010; 31:2055–63. https://doi.org/10.1016/j.biomat erials.2009.11.103. 16. zaharia c, zecheru t, moreau mf, pascaretti-grizon f, mabilleau g, marculescu b, et al. chemical structure of methylmethacrylate-2[2',3',5'-triiodobenzoyl]oxoethyl methacrylate copolymer, radio opacity, in vitro and in vivo biocompatibility. acta biomater 2008; 4:1762–9. https://doi.org/10.1016/j.actbio.2008.06.009. 17. silva gf, tanomaru-filho m, bernardi mib, guerreiro-tanomaru jm, cerri ps. niobium pentoxide as radiopacifying agent of calcium silicate-based material: evaluation of physicochemical and biolo gical properties. clin oral investig 2015; 19:2015–25. https:// doi.org/10.1007/s00784-015-1412-9. 18. da fonseca ts, da silva gf, tanomaru-filho m, sasso-cerri e, guerreiro-tanomaru jm, cerri ps. in vivo evaluation of the inflammatory response and il-6 immunoexpression promoted by biodentine and mta angelus. int endod j 2016; 49:145–53. https://doi.org/10.1111/iej.12435. 19. urban vm, machado al, oliveira rv, vergani ce, pavarina ac, cass qb. residual monomer of reline acrylic resins. effect of water-bath and microwave post-polymerization treatments. dent mater 2007; 23:363–8. https://doi.org/10.1016/j.dental.20 06.01.021. 20. jorge jb, giampaolo et, vergani ce, machado al, pavarina ac, carlos iz. cytotoxicity of denture base resins: effect of water bath and microwave postpolymerization heat treatments. int j prosthodont 2004; 17:340–4. https://doi.org/0.1016/j.prosdent. 2004.07.003. 21. abbas ak, lichtman ah, pillai s. 2011. cellular and molecular immunology, 7th ed. saint louis, usa: elsevier saunders. pp. 560. https://doi.org/10.1016/j.tiv.2016.08.005 https://doi.org/10.1016/j.tiv.2016.08.005 https://doi.org/10.1111/j.1532-849x.2009.00522.x https://doi.org/10.1016/j.prosdent.2016.06.001 https://doi.org/10.1016/j.prosdent.2016.06.001 https://doi.org/10.1002/jbm.b.31473 https://doi.org/10.1016/j.mehy.2013.04.024 https://doi.org/10.1016/j.mehy.2013.04.024 https://doi.org/10.17219/acem/33009 https://doi.org/10.17219/acem/33009 https://doi.org/10.1007/s00784-007-0162-8 https://doi.org/10.1007/s00784-007-0162-8 https://doi.org/10.1016/j.yrtph.2008.02.002 https://doi.org/10.1016/j.yrtph.2008.02.002 https://doi.org/10.1590/s1678-77572011005000006 https://doi.org/10.1016/j.joen.2010.07.007 https://doi.org/0.5966/sctm.2011-0018 https://doi.org/0.5966/sctm.2011-0018 https://doi.org/10.1136/bmj.321.7258.424 https://doi.org/10.1590/s1806-8324200900030000 https://doi.org/10.1590/s1806-8324200900030000 https://doi.org/10.1111/j.1741-2358.2011.00570.x https://doi.org/10.1016/j.biomaterials.2009.11.103 https://doi.org/10.1016/j.biomaterials.2009.11.103 https://doi.org/10.1016/j.actbio.2008.06.009 https://doi.org/10.1007/s00784-015-1412https://doi.org/10.1007/s00784-015-1412https://doi.org/10.1111/iej.12435 https://doi.org/10.1016/j.dental.2006.01.021 https://doi.org/10.1016/j.dental.2006.01.021 https://doi.org/0.1016/j.prosdent. 2004.07.003 https://doi.org/0.1016/j.prosdent. 2004.07.003 evaluation of different polymerisation methods of ocular prosthesis acrylic resins on subcutaneous tissue inflammatory response in rats 240 | squ medical journal, may 2022, volume 22, issue 2 22. yokoyama a, sato y, nodasaka y, yamamoto s, kawasaki t, shindoh m, et al. biological behavior of hat-stacked carbon nanofibers in the subcutaneous tissue in rats. nano lett 2005; 5:157–61. https://doi.org/10.1021/nl0484752. 23. de carli ml, miyazawa m, nonogaki s, shirata nk, oliveira dt, pereira aa, et al. m2 macrophages and inflammatory cells in oral lesions of chronic paracoccidioidomycosis. j oral pathol med 2016; 45:141–7. https://doi.org/10.0.4.87/jop.12333. 24. urban vm, machado al, vergani ce, giampaolo et, pavarina ac, de almeida fg, et al. effect of water-bath post-polymerization on the mechanical properties, degree of conversion, and lea ching of residual compounds of hard chairside reline resins. dent mater 2009; 25:662–71. https://doi.org/10.0.3.248/j.dental.2008.10.017. 25. gretzer c, emanuelsson l, liljensten e, thomsen p. the inflam matory cell influx and cytokines changes during transition from acute inflammation to fibrous repair around implanted materials. j biomater sci polym ed 2006; 17:669–87. https://doi.org/10.11 63/156856206777346340. https://doi.org/10.1021/nl0484752 https://doi.org/10.0.4.87/jop.12333 https://doi.org/10.0.3.248/j.dental.2008.10.017 https://doi.org/10.1163/156856206777346340 https://doi.org/10.1163/156856206777346340 departments of 1cardiothoracic surgery and 2radiodiagnosis, all india institute of medical sciences, raipur, india *corresponding author’s e-mail: drkleindantis86@gmail.com mediastinal hydatidosis with an unusual presentation a rare case report *klein dantis1 and nilesh gupta2 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 300–303, epub. 26 may 22 submitted 22 dec 20 revision req. 26 jan 21; revision recd. 23 feb 21 accepted 17 mar 21 however, the findings on echocardiogram were normal. the chest x-ray posterior-anterior view showed opacity on the left hemithorax [figure 1]. contrast-enhanced computed tomography (cect) of the thorax showed multiple fluid-filled cystic lesions throughout the mediastinum as well as within the lung parenchyma with atelectasis, with the largest measuring 10 × 7 cm [figure 2]. an incidental hepatic cyst measuring 4 × 3 cm was also noted [figure 2a]. a fibre optic bronchoscopy showed a deviated trachea with compressed left upper lobe bronchus and no endobronchial growth. although the findings were suspicious of hydatid cyst, immunoglobulin g titres for hydatid serology was negative and needle aspiration was inconclusive. therefore, differential diagnosis of various intrathoracic malignancy were considered. the patient underwent left posterolateral thoracotomy under general anaesthesia with a double-lumen intubation. intraoperatively, glistening white fluid filled cystic lesions resembling hydatid cysts were present throughout the lung parenchyma and mediastinum, with dense vascular adhesions between the cyst wall and thoracic cage. parenchymal preserving cyst excision of the lung parenchyma with captionage and cystectomy for the cysts in the mediastinum, diaphragm, pericardium and the chest wall were performed [figure 3a]. histopathology was suggestive of multiple daughter cysts with a germinal layer and scolices suggestive of hydatid disease [figure 3b]. the postoperative course was uneventful and the patient was prescribed albendazole 400 mg twice hydatid disease caused by larval stage of cestode echinococcus is one of the major zoonotic diseases of public health significance with a reported mortality rate of 2–4%.1 although lungs are the second most commonly involved organ, intrathoracic extrapulmonary involvement is uncommon, seen in 5–7% of cases.1,2 we hereby report a rare presentation of mediastinal hydatidosis with extensive lung involvement resembling malignancy. case report a haemodynamically stable, healthy 24-year-old female patient with no significant medical history presented to the department of cardiothoracic surgery at raipur, india in the year 2020 with heaviness and left-sided chest pain for two months. respiratory symptoms—including fever, breathlessness, cough, haemoptysis, dysphagia, or dysphonia—were absent. in addition, the patient’s weight or appetite were unaffected. a decreased left-sided chest movement, deviation of trachea to the right side, dullness over the left hemithorax and decreased vocal fremitus were observed during the chest examination. furthermore, diminished breath sounds with decreased vocal resonance was noted on the left side. routine blood investigations as well as liver and renal function tests were within standard limits. the pulmonary function test showed a restrictive pattern and sinus tachycardia was noted on the electrocardiogram; this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.072 case report abstract: hydatidosis is a common zoonotic disease with a high prevalence in developing countries. while a solitary cyst with unilateral lung involvement is common, bilateral involvement and multiple cysts are rare, only seen in 20% and 30% of the cases, respectively. likewise, extensive involvement of extrapulmonary tissues and mediastinum is rare. we report an unusual case of mediastinal hydatidosis mimicking an intrathoracic malignancy in a 24-year-old female patient. she presented in the year 2020 with a history of left-sided chest pain and heaviness in the left hemithorax for a period of two months. diffuse, multiple fluid-filled cystic lesions with internal echoes throughout the mediastinum, lung, pericardium, diaphragm and chest wall were observed in contrast-enhanced computed tomography of the thorax. an incidental cystic lesion in the liver was also noted. since serology for echinococcosis was negative, a differential diagnosis of intrathoracic malignancy was considered. however, intraoperative and histopathologic findings were suggestive of hydatidosis. keywords: hydatid cyst; diseases thoracic; computed tomography; magnetic resonance imaging; mediastinum; case report. https://creativecommons.org/licenses/by-nd/4.0/ klein dantis and nilesh gupta case report | 301 daily for a period of three months. postoperative chest x-ray as well as a computed tomography scan of the chest after three months of follow-up did not show any recurrence [figure 4]. the patient underwent laparotomy and cyst excision after six months for a hepatic cyst. informed consent was obtained from the patient for publication of this report. discussion hydatidosis is a zoonotic disease transmitted via fecooral route to humans from animal hosts including dogs and sheep. echinococcus granulosus is the most common source of infection accounting for 95% of 2–3 million cases reported globally.3 the infection prevalence varies widely by region, with higher prevalence in mediterranean regions. following the liver, the lungs are the second most common organ involved with a higher predilection for the right lower lobe.4,5 however, in the current case, extensive involvement of left side was present. the cysts are often solitary and unilateral in distribution, while bilateral involvement and multiple cysts are not unusual, seen in 20% and 30% of cases, respectively.5 moreover, extensive mediastinal cystic involvement is rare, seen in less than 4% of cases.6–8 the presenting symptom depends on the size, location of the cyst and degree of compression of the mediastinal structure. vertebral destruction, superior vena cava syndrome and bernard horner’s syndrome have been reported previously with mediastinal cysts.9 apart from the chest pain and heaviness of chest, no other associated symptoms were present in the current patient. considering the age, presence of diffuse involvement of lung parenchyma and opacified left hemithorax on cect thorax and chest x-ray and negative serology for hydatid cyst, a wide variety of differential diagnoses were considered including mediastinal hydatidosis, germ cell tumour, pulmonary sarcoma and diffuse pulmonary metastases.10 high attenuation wall and a low-density content are characteristic of hydatidosis. germ cell tumours constitute 1–3% of intrathoracic malignancies affecting males with a mean age of 25–35 years.11 lobulated heterogeneous mass containing soft tissue elements with fluid and fat has been seen with immature teratoma with calcification in 20–40% of the cases.10,11 on the other hand, pulmonary synovial sarcoma is figure 1: chest x-ray posterior-anterior view showing left opacified hemithorax with contralateral tracheal deviation (arrow). figure 2: a: contrast enhanced computed tomography (cect) thorax coronal view showing multiple intrathoracic cystic lesions with thickened septa (yellow arrows) and hepatic cyst (red arrow). b: cect thorax axial view showing interconnected cystic lesions (arrows) with mediastinal shift to the opposite side. c: axial view of upper lobes with lung window showing consolidation of the left lung (arrow) with minimally visible parenchymal markings. mediastinal hydatidosis with an unusual presentation a rare case report 302 | squ medical journal, may 2022, volume 22, issue 2 characterised by well-circumscribed heterogeneous mass occurring between 16 to 77 years of life with equal sex predilection. although well circumscribed, rounded soft-tissue attenuation noted with diffuse pulmonary metastases was reported in young patients and was considered as a differential diagnosis;12 however, it is unlikely in the current case as the patient did not have any symptoms of metastases or malignant disease. considering the above-mentioned differential diagnoses, posterolateral thoracotomy of the left side was planned. intraoperatively, glistening white fluid filled cystic lesions were noted suggestive of hydatid disease, which was later confirmed by histopathology. although, magnetic resonance imaging (mri) is superior in differentiating between solid and cystic lesions, its role in hydatidosis is very minimal. they appear as low signal intensity on t1-weighted and high signal intensity on t2-weighted images.13 similarly, cystic components of teratoma result in high signal intensity on t2-weighted images and low signal intensity on t1-weighted images with magnetic susceptibility artifacts in the presence of calcification.14 seminomatous germ cell tumours have a hypointense mass on t2-weighted images with relatively homogeneous enhancement.14 in pulmonary synovial sarcoma, there is a heterogeneous signal intensity on t1-weighted images while in pulmonary metastases, diffusion-weighted images show high signal intensity.12 considering the feasibility, mri was not suggestive in this case. surgery is the most accepted treatment of choice for hydatid disease; however, in patients with recurrent cysts, multiorgan disease, poor general conditions and those who refuse to undergo surgery, medical management is the next best option.13 albendazole (10–15 mg/kg/day) is the drug of choice in hydatid disease. it inhibits microtubular assembly within the parasite resulting in glycogen depletion and finally autolysis of the cell.3 preoperatively, albendazole intake helps to soften the cyst and reduce the intracystic pressure while it prevents recurrence of the disease postoperatively. in the current case, albendazole was prescribed postoperatively for three months and no recurrence was observed during follow-up. conclusion due to its variable presentation, diagnosis based only on clinical and radiographic findings of mediastinal hydatidosis can be challenging. although surgical excision remains the treatment of choice without extensive resection, a thorough understanding of all the radiographic differential diagnoses is vital while encountering such an extensive disease of the mediastinum to devise a treatment plan. a c k n o w l e d g e m e n t i would like to thank dr. melisha r pinto, mds (email id: melisha.pinto@gmail.com) for proof reading and editing the manuscript. figure 4: a: immediate postoperative chest x-ray. b: chest x-ray posterior-anterior view at follow-up after three months showing completely resolved cystic lesion. c: computed tomography (ct) of the thorax at the three months follow-up at the level of carina showing no recurrent cystic lesions. d: ct of the thorax at the three months follow-up below the level of carina showing no recurrent cystic lesions. figure 3: a: innumerable hydatid cysts and daughter cysts with typical glistening white appearance. b: hematoxylin and eosin staining at ×50 magnification showing laminated and nucleated germinal layer giving rise to brood capsule. protoscolices are seen within brood capsule (arrows). klein dantis and nilesh gupta case report | 303 a u t h o r s’ c o n t r i b u t i o n kd prepared and drafted the manuscript. ng edited the manuscript. both kd and ng reviewed and approved the final version of the manuscript. references 1. mcmanus dp, gray dj, zhang w, yang y. diagnosis, treatment, and management of echinococcosis. bmj 2012; 344:e3866. https://doi.org/10.1136/bmj.e3866. 2. kabiri eh, el hammoumi m, bhairis m, oukabli m. mediastinal calcified hydatid cyst. acta chir belg 2020; 120:297–98. https:// doi.org/10.1080/00015458.2020.1722932. 3. sarkar m, pathania r, jhobta a, thakur br, chopra r. cystic pulmonary hydatidosis. lung india 2016; 33:179–91. https:// doi.org/10.4103/0970-2113.177449. 4. bin saeedan m, aljohani im, alghofaily ka, loutfi s, ghosh s. thoracic hydatid disease: a radiologic review of unusual cases. world j clin cases 2020; 8:1203–12. https://doi.org/10.12998/ wjcc.v8.i7.1203. 5. bagheri r, haghi sz, amini m, fattahi as, noorshafiee s. pul monary hydatid cyst: analysis of 1024 cases. gen thorac cardiovasc surg 2011; 59:105–9. https://doi.org/10.1007/s11748-010-0690-z. 6. arinc s, kosif a, ertugrul m, arpag h, alpay l, unal o, et al. evaluation of pulmonary hydatid cyst cases. int j surg 2009; 7:192–5. https://doi.org/10.1016/j.ijsu.2008.11.003. 7. msougar y, afandi o, ihfa n, baiz y, rouiessi y, khellouki m, et al. mediastinal hydatid cyst: a case report. j med case rep 2013; 7:236. https://doi.org/10.1186/1752-1947-7-236. 8. polat p, kantarci m, alper f, suma s, koruyucu mb, okur a. hydatid disease from head to toe. radiographics 2003; 23:475–94. https://doi.org/10.1148/rg.232025704. 9. traibi a, atoini f, zidane a, arsalane a, kabiri eh. mediastinal hydatid cyst. j chin med assoc 2010; 73:3–7. https://doi.org/10.1 016/s1726-4901(10)70014-9. 10. moeller kh, rosado-de-christenson ml, templeton pa. media stinal mature teratoma: imaging features. ajr am j roentgenol 1997; 169:985–90. https://doi.org/10.2214/ajr.169.4.9308448. 11. rosti g, secondino s, necchi a, fornarini g, pedrazzoli p. primary mediastinal germ cell tumors. semin oncol 2019; 46:107–11. https://doi.org/10.1053/j.seminoncol.2019.04.001. 12. boulter dj, rosado-de-christenson ml, stevens r, suster s. primary synovial sarcoma of the lung. radiol case rep 2015; 2:82. https://doi.org/10.2484/rcr.v2i4.82. 13. garg mk, sharma m, gulati a, gorsi u, aggarwal an, agarwal r, et al. imaging in pulmonary hydatid cysts. world j radiol 2016; 8:581–7. https://doi.org/10.4329/wjr.v8.i6.581. 14. carter bw, betancourt sl, benveniste mf. mr imaging of mediastinal masses. top magn reson imaging 2017; 26:153–65. https://doi.org/10.1097/rmr.0000000000000134. https://doi.org/10.1136/bmj.e3866 https://doi.org/10.1080/00015458.2020.1722932 https://doi.org/10.1080/00015458.2020.1722932 https://doi.org/10.4103/0970-2113.177449 https://doi.org/10.4103/0970-2113.177449 https://doi.org/10.12998/wjcc.v8.i7.1203 https://doi.org/10.12998/wjcc.v8.i7.1203 https://doi.org/10.1007/s11748-010-0690-z https://doi.org/10.1016/j.ijsu.2008.11.003 https://doi.org/10.1186/1752-1947-7-236 https://doi.org/10.1148/rg.232025704 https://doi.org/10.1 016/s1726-4901(10)70014-9 https://doi.org/10.1 016/s1726-4901(10)70014-9 https://doi.org/10.2214/ajr.169.4.9308448 https://doi.org/10.1053/j.seminoncol.2019.04.001 https://doi.org/10.2484/rcr.v2i4.82 https://doi.org/10.4329/wjr.v8.i6.581 https://doi.org/10.1097/rmr.0000000000000134 1 submitted 9 mar 22 1 revision req. 12 apr & 14 jun 22; revision recd. 11 may & 28 jun 22 2 accepted 5 jul 22 3 online-first: september 2022 4 doi: https://doi.org/ 10.18295/squmj.9.2022.053 5 6 penile girth enhancement using amniotic membrane in a rabbit model 7 a stereological study 8 ali ariafar,1 *saied karbalay-doust,2,3 faisal ahmed,4 ali eslahi,1,5 sona 9 tayebi1 10 11 1department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran; 12 2histomorphometry and stereology research center, shiraz university of medical sciences, 13 shiraz, iran; 3anatomy department, school of medicine, shiraz university of medical sciences, 14 shiraz, iran; 4urology research center, al-thora hospital, department of urology, ibb 15 university of medical sciences, ibb, yemen; 5shiraz geriatric research center, shiraz university 16 of medical sciences, shiraz, iran. 17 corresponding author’s e-mail: karbalas@sums.ac.ir 18 19 abstract 20 objectives: this study aimed to evaluate the efficacy of penile girth enhancement (pge) using 21 amniotic membrane (am) as a graft in a rabbit model. additionally, stereological studies were 22 used to obtain quantitative histological data regarding the structure of the penis. methods: in this 23 study, 20 adult male rabbits of similar age and weight were allocated to two sham and 24 surgery+am groups. both groups underwent surgery by longitudinal ishape midline incision of 25 the tunica albuginea on the dorsal surface of the penis. the surgery +am group underwent pge 26 by am graft. the penile length and mid circumference were measured using a vernier caliper 27 before and two months after the surgery. stereological studies were used to obtain quantitative 28 histological data regarding the structure of the penis. results: the mean total volume and 29 diameter of the penis increased in the surgery +am group (p<0.03 and p<0.04, respectively). 30 2 the stereological evaluation showed a significant increase in the mean volumes of the tunica 31 albuginea and corpora cavernosa in the surgery +am group compared to the sham group 32 (p<0.01, p< 0.03). additionally, the mean volume density of the collagen bundles, muscle fibers, 33 and cavernous sinuses and the total number of fibroblasts and smooth muscle cells increased in 34 the surgery +am group compared to the sham group (p<0.01, p<0.01, p<0.03, p<0.01, and 35 p<0.05, respectively). no infections, bleedings, or other complications were seen. conclusions: 36 am is a method that has appeared promising for material use in penile enhancement. thus, it 37 may be used for pge in the future. 38 keywords: amniotic membrane; histopathology; animal; penile girth enhancement. 39 40 advances in knowledge 41 amniotic membrane is a new method, which has appeared helpful for material use in penile girth 42 enhancement. 43 amniotic membrane may be used for humman penile girth enhancement in future. 44 application to patient care 45 this study aimed to evaluate the efficacy of penile girth enhancement using amniotic membrane 46 as a graft in a rabbit model. 47 48 introduction 49 the penis has historically been considered a sign of masculinity. therefore, its size has become a 50 source of worry for numerous men. today, some men seek for ways to enlarge their penis in order 51 to increase their self-confidence and make their partners more sexually satisfied.1 52 53 penile girth enhancement (pge) is carried out for cosmetic purposes and psychological causes in 54 some patients, similar to breast enlargement amongst females.2 men with a small penis and patients 55 with special urological conditions such as micropenis, peyronie’s disease, and trauma to the penis 56 may benefit from this procedure.3 pge aims at improving the penile function and appearance. 57 nonetheless, there are no suggested guidelines and specific techniques for pge.4 58 59 3 generally, pge can be carried out via such methods as grafts, flaps, fillers, and injections.5 graft 60 procedures are one of the techniques for pge, in which more fat tissue is used.6 other tissues such 61 as small intestinal submucosa and temporalis fascia are also used in graft procedures.3, 7 62 63 many studies have been done regarding the impact of graft fat procedures on the penis and have 64 indicated the effectiveness of graft fat in enhancing the penile girth. for example, zhang et al. 65 (2020) evaluated the effectiveness and safety of human acellular dermal matrix graft in the 66 augmentation phalloplasty method.8 xu et al. (2016) also illustrated the effectiveness and safety 67 of dermal fat graft in augmentation phalloplasty amongst men with a small penis.9 similarly, 68 leungwattanakij et al. (2006) showed the promising effect of using small intestinal submucosa on 69 penis enlargement in a rat model.3 in addition, küçükçelebi et al. (2006) reported that the use of 70 microvascular temporalis fascia strengthened the penis in humans.7 71 considering the social progress, increase in people’s awareness and sexual needs, and increasing 72 demand for surgical treatment to enlarge the penis, researchers have made genuine attempts to 73 develop new and effective methods for this purpose. 74 75 in the last decade, amniotic membrane (am) has been shown to possess many properties that 76 suggest its value in several medical applications. am has also been used in many genitourinary 77 surgeries. 10-13 in the current study, am was used for pge for the first time. am transplantation 78 has been used in surgical procedures in the fields of medicine, ophthalmology, dermatology, 79 plastic surgery, urogenital system, and ent. many researchers have described these applications 80 separately, each having different effects and techniques.14 it is worth mentioning that am is the 81 deepest semitransparent layer of the embryonic membrane, which contains an avascular stromal 82 matrix, a thick collagen layer, an overlying basement membrane, and a single layer of cuboidal 83 epithelium.14 84 85 rabbit has a vascular penis that contains two corpora cavernosa and a corpus spongiosum that 86 encloses the urethra. in addition to the lack of a penile bone, this vascular penis has certain 87 characteristics that make it more similar to human’s penis. therefore, it is a good animal model 88 for studying the structure of the penis.15 stereology techniques have been increasingly applied for 89 determining a variety of morphometric variables of three-dimensional structures.16 to the best of 90 4 our knowledge, no study has evaluated the efficiency of the application of am in pge in a rabbit 91 model using stereological methods in order to obtain quantitative histological data. the chief 92 advantage of stereological methods is the provision of unbiased and precise assessments. thus, 93 the present study aims to investigate whether pge using am accelerates the regeneration of 94 various parts of the penile tissue and leads to an increase in its size. 95 96 methods 97 experimental design 98 a total of 20 adult male new zealand white (oryctolagus cuniculus) rabbits (weight: 1600–2500 99 grams; age: 18 weeks) were obtained from the university’s center of comparative and 100 experimental medicine. the rabbits were kept individually in cages with a 12/12-h light-dark 101 cycle at room temperature of 22–24 °c and humidity of 50% and had access to water and food ad 102 libitum. all animals were kept according to the animal care and ethics committee of the 103 university. the rabbits were divided two sham and surgery +am groups using simple random 104 sampling (n=10). in the both groups, the surgery was done by a longitudinal i-shape midline 105 incision of the tunica albuginea on the dorsal surface of the penis .the second group (surgery +am 106 group) underwent pge using am. 107 108 . all animals underwent the surgical procedure, but only six rabbits in the sham group and seven 109 rabbits in the surgery + am group were included in stereological studies. 110 111 human amniotic membrane preparation 112 human am, provided by burn and wound healing research center, were kept in alcohol (95%) 113 until application. (in this center, am are provided from delivery rooms and are employed as a 114 biological dressing in burn patients).am were gained from women delivery no history of 115 premature rupture of membrane, endometritis, or meconium ileus. all women were seronegative 116 tests for human immunodeficiency virus, hepatitis types b and c, and syphilis.17 117 118 surgical procedure 119 all rabbits were anesthetized using the intramuscular injection of ketamine (10–15 mg/kg) and 120 xylazine (6–10 mg/kg). supplemented doses of ketamine were administered as needed to maintain 121 5 a uniform level of anesthesia. all animals were well shaved and prepared with a povidone iodine 122 topical antiseptic solution and were then draped with sterile sheets. after that, the penis was 123 exposed under aseptic conditions and then, the glans was sutured with 4/0 nylon held with a 124 mosquito clamp under gravity to stretch the penis downward. 125 126 in the both groups, the surgery was done by a longitudinal i-shape midline incision of the tunica 127 albuginea on the dorsal surface of the penis. in the surgery +am group, the am graft (3*15 mm2 128 piece) was placed on the dorsal surface of the penis between the edges of tunica albuginea and 129 over the covernosal tissue in both sides of penis and was sutured with a 6-0 pds (polydioxanone) 130 [figure 1]. 131 132 all rabbits were housed individually and were fed with standard feed throughout the experiment. 133 antibiotics were also administered intramuscularly to all groups for three days. after the operation, 134 the rabbits were observed for bleeding, hematoma, swelling, penile deviation, and other 135 complications. 136 137 the penile length and mid circumference were measured using a digital vernier caliper (accuracy: 138 0.5 mm). the girth of the penis was measured at the mid-penile body in the flaccid state. the 139 penile length during the flaccid state was measured from the palpable lower border of the pubic 140 symphysis to the tip of the glans. the mean length and girth of each rabbit category were 141 determined and compared to those of other rabbit categories.18 142 143 penile tissue preparation 144 after two months, all the rabbits were sacrificed with deep anesthesia. the penis and skin sutures 145 were removed in its entirety by dissecting along the shaft to the crura and separating each cru from 146 its point of attachment at the ischial tuberosity. the penis was divided to 8-12 sections based on 147 length with equal distances between the sections “t” [figure 2 a]. the sections of each penis were 148 processed, embedded, sectioned (4 and 25 µm), and stained (hematoxylin-eosin) [figure 2 b].19 149 150 estimation of the volumes of the penis and its components 151 6 the sections with a 4-µm thickness were used in order to estimate the volume of the penis and the 152 volume density of the penile components. the penis is composed of skin, penile fascias (superficial 153 fascia or dartos fascia and deep fascia or buck’s fascia), tunica albuginea, paired corpora 154 cavernosa, and a single corpus spongiosum that contains a spongy tissue and the urethra. in each 155 penile section, the borders between the regions were identified and characterized [figure 3 a]. the 156 corpora cavernosa contains fibrous tissues (collagen bundles), smooth muscle cells, cavernous 157 sinuses, and vessels.19 the volumes of the fascia (superficial and deep fascia), tunica albuginea, 158 and corpora cavernosa were estimated using a video microscopy system and the software designed 159 at the university’s histomorphometry and stereology research center. the volumes of the penis 160 and its components were estimated by using the “cavalieri method” at 12x magnification [figure 161 3 b]: 162 163 v(penile component) = ∑p × a(p) × t 164 165 where ∑p was the total number of points hitting the structure of interest, a(p) was the area related 166 to every grid point, and “t” was the distance between the sections.19 167 168 estimation of the volume density of the collagen bundles, smooth muscle cells, cavernous sinuses, 169 and vessels of the corpora cavernosa 170 the volume density “vv” of collagen bundles, smooth muscle cells, cavernous sinuses, and vessels 171 was calculated by the “point-counting method” and the following formula19 [figure 4 a]: 172 173 vv(structure / corpora cavernosa) = p(structure) / p(corpora cavernosa) 174 175 where “p(structure)” showed the number of points placed on the mentioned structures and 176 “p(corpora cavernosa)” indicated the number of points superimposed on the corpora cavernosa. 177 the total volume of each structure was calculated by the following formula: 178 179 v(structure) = vv(structure/ corpora cavernosa) × v(corpora cavernosa) 180 181 7 estimation of the numerical density of the fibroblasts and smooth muscle cells in the corpora 182 cavernosa 183 the numerical density “nv(fibroblasts or myocyte / cavernous bodies)” and the total number of 184 fibroblasts and smooth muscle cells were estimated using the “optical disector” technique utilized 185 on 25 µm sections. the optical disector contained an eclipse microscope with a high numerical 186 aperture (na=1.30) ×40 oil-immersion objective lens connected to a video camera that 187 transmitted microscopic live images to a computer monitor and an electronic microcator with 188 digital readout for estimating the number of fibroblasts by moving in the z-direction. the 189 numerical density (nv) of the fibroblasts and smooth muscle cells was estimated using the 190 following formula: 191 192 nv (fibroblasts or myocyte / cavernous bodies) = σq–/ (σp× (a/f) × h) × (t/ba) 193 194 where “∑q” was the number of sampled fibroblasts or myocytes, ”∑p” was the number of 195 disectors, a(f) was the area of the frame, “h” was the height of the disector, and “t” was the mean 196 section thickness. the upper and lower borders of each section were considered guard zones. the 197 total number of fibroblasts or myocytes was estimated by multiplying the numerical density by 198 v(cavernous bodies) [figure 4 b].19 199 200 fibroblasts were recognized by their specific criteria (having plentiful and irregularly branched 201 cytoplasms, a large ovoid euchromatic nucleus, and a prominent nucleolus). smooth muscle cells 202 were also recognized by their spindle shape and single central nucleus.20 203 204 statistics and data analysis 205 graphpad prism software, version 8.0.0 for windows (graphpad software, san diego, california, 206 usa) was applied to analyze the data. the data were compared using mann-whitney u test and 207 were presented as dot plots. p<0.05 was considered statistically significant. 208 209 results 210 the total volume, diameter, and length of the penis 211 8 the total volume, length, and diameter of the penis increased by respectively 26%, 8%, and 4% in 212 the surgery +am group in comparison to the sham group. there was also a significant increase in 213 the mean volume and diameter of the penis in the surgery +am group compared to the sham group 214 (p<0.03 and p<0.04, respectively) [figure 5 a and b]. however, there was no significant difference 215 between the surgery +am and sham groups regarding the mean length of the penis [figure 5 c]. 216 217 the volumes of the fascia, tunica albuginea, and corpora cavernosa of the penis 218 the mean volumes of the fascia, tunica albuginea, and corpora cavernosa increased by respectively 219 15%, 29%, and 40% in the surgery +am group in comparison to the sham group. the results also 220 revealed a significant increase in the mean volumes of tunica albuginea and corpora cavernosa in 221 the surgery +am group compared to the sham group (p<0.01 and p<0.03, respectively) [figure 5 222 e and f]. however, there was no significant difference between the surgery +am and sham groups 223 concerning the mean volume of the fascia [figure 5 d]. 224 225 the volume density of the collagen bundles, smooth muscle cells, cavernous sinuses, and vessels 226 of the corpora cavernosa 227 the mean volume density of the collagen bundles, smooth muscle cells, and cavernous sinuses 228 increased by respectively 24%, 33%, and 32% in the surgery + am group in comparison to the 229 sham group. the results indicated a significant increase in the mean volume density of the collagen 230 bundles, smooth muscle cells, and cavernous sinuses in the surgery +am group compared to the 231 sham group (p<0.01, p<0.01, and p<0.03, respectively) [figure 6 a, b, and c]. however, there was 232 no significant difference between the surgery +am and sham groups in terms of the mean volume 233 of the vessels (figure 6 d). 234 235 the number of fibroblasts and smooth muscle cells of the corpora cavernosa 236 the mean number of fibroblasts and smooth muscle cells increased by 41% and 36%, respectively 237 in the surgery +am group in comparison to the sham group. there was also a significant increase 238 in the mean number of fibroblasts and smooth muscle cells in the surgery +am group compared 239 to the sham group (p<0.01 and p<0.05, respectively) [figure 6 e and f]. 240 241 discussion 242 9 this study aimed to determine the effectiveness of am as a graft in pge in a rabbit model. the 243 results revealed a significant increase in the diameter and volume of the penile corpora cavernosa 244 and the number of fibroblasts and smooth muscle cells in the corpora cavernosa in the animals that 245 had undergone pge surgical procedures. 246 penile enlargement is usually done by auto tissue transplantation, cell injection, or implantation of 247 artificial or natural materials.8 autologous tissue transplantation from the adjacent tissues is one 248 of the most common surgeries performed for pge. autologous fat tissue has also been recently 249 used for pge.8, 21 the utilization of an am graft for pge was first introduced in the present 250 research. 251 252 in the previous studies, different techniques were described for pge and a variety of exogenic 253 materials were utilized in the procedures. however, no standard guidelines are available. 254 moreover, the employed exogenic materials have shown different degrees of success. for example, 255 autologous fat, silicone, and hyaluronic acid gel were injected to the subcutaneous space of the 256 penile body. additionally, dermal fat grafts as well as a cellular dermal matrix derived from a 257 donated human skin tissue (allograft) were used for pge procedures.21,22 in a prior research, 258 dermal cellular porcine grafts were used in 69 participants and the results revealed a promising 259 long-term outcome. after one year of follow-up, the penial circumference increased by 3.1 and 260 2.4 cm during flaccidity and erection, respectively.23 however, the use of pelvicol acellular matrix 261 for pge was not suitable due to the high rate of complications.24 overall, these injectable materials 262 carried a risk of foreign body response, swelling, and penile deviation.25 however, autologous fat 263 grafting reduced the risk of foreign body response and was found to improve pge.26 on the other 264 hand, evidence demonstrated that autologous fat transplantation would lose a large amount of its 265 volume over time and, consequently, needed several procedures to bring about a favorable 266 outcome.25 in the present study, swelling and penile deviation were not observed in the 267 experimental groups. 268 269 am is composed of connective tissue with a significant collagen and extracellular matrix structure. 270 the inner surface is enclosed by a single-layer cubical epithelium, which is avascular, has anti-271 scarring, anti-inflammatory, and antiangiogenic properties, and contains several growth factors. 272 moreover, it has been reported to possess the exclusive quality of avoiding graft versus host disease 273 10 and to facilitate wound healing.27 the mechanism of action of am has been thought to be related 274 to the rich biological construct of the amnion and chorion membranes, which include layers of 275 basement membranes and a variety of intrinsic factors that play a vital role in cell proliferation and 276 differentiation. it has also been reported that the am epithelial cells secrete angiogenic factors.28 277 these properties make human am an ideal tissue graft for reconstruction in different tissues. 278 additionally, am is resistant to rejection and is easy to obtain, derive, and store.27 leungwattanakij 279 et al. studied penile reconstruction using small intestinal submucosa in 20 rats. in that study, pge 280 was performed via the bilateral incision of tunica albuginea and the plane of dissection was 281 between the tunica albuginea and the cavernous tissue. the tunica defect was covered with a piece 282 of small intestinal submucosa. the histological study showed moderate amounts of fibrosis under 283 the graft and the elastic fibers of the graft were oriented in a circular direction.3 in the present 284 study, the same procedure was used and the histological study revealed a significant increase in 285 the mean volumes of the tunica albuginea and corpora cavernosa in the surgery +am group. 286 additionally, the mean volume density of the collagen bundles, smooth muscle cells, cavernous 287 sinuses, and vessels (indicating neovascularization into the graft) and the mean number of 288 fibroblasts and smooth muscle cells increased in the surgery +am group, which represented good 289 tissue acceptance. 290 291 shakeri et al. reported the proper re-epithelialization of the urethra reconstructed with am by 292 transitional epithelium with cytokeratin expression in a rabbit model. however, the fistula was 293 detected in one case (5%) and urethral strictures were seen in two cases (10%).29 in another study, 294 salehipour et al. evaluated the use of human am in the reconstruction of long ureteral defects in 295 a dog model and concluded that am was not useful for long urethral defects (3 cm). they 296 mentioned that the use of am might be studied for shorter defects or as a patch graft.30 salehipour 297 et al. also assessed the efficacy of human am grafting in the canine penile tunica albuginea defect. 298 the results of histopathological examinations showed complete re-epithelialization with squamous 299 epithelium and collagen fiber deposition. besides, no dysplasia was detected.8 300 301 this study had some limitations. firstly, the operation performed in the sham group might induce 302 scaring, which could have affected the final pge and make the comparison more difficult. 303 therefore, a group without surgical procedure (control) had to be added to the group design. 304 11 secondly, the effects of the surgical operation on ejaculation and erection were not evaluated after 305 pge. the third study limitation was the increase in collagen in the penis, which could have affected 306 the function of the penis. therefore, anti-fibrotic drugs can be used to reduce collagen in future 307 studies. 308 309 conclusions 310 am is a new method, which has appeared helpful for material use in pge. hence, it may be used 311 for human pge in future. 312 313 authors’ contribution 314 aa conceptualized and designed the study. fa and ae were involved in the visualization and 315 investigation. st collected the data. sk-d and st drafted the manuscript. sk-d was involved in 316 the validation, review and editing of the manuscript. aa supervised the work. all authors approved 317 the final version of the manuscript. 318 319 acknowledgement 320 the work was performed at the histomorphometry and stereology research center, shiraz 321 university of medical sciences, shiraz, iran. hereby, the authors would like to thank ms. a. 322 keivanshekouh at the research consultation center (rcc) of shiraz university of medical 323 sciences for improving the use of english in the manuscript. 324 325 conflicts of interest 326 the authors declare no conflicts of interest. 327 328 funding 329 this work was financially supported by grant no. 16032-01-01-1396 from shiraz university of 330 medical sciences, shiraz, iran. 331 332 references 333 12 1. al-ansari aa, shamsodini a, talib ra, gul t, shokeir aa. subcutaneous cod liver oil 334 injection for penile augmentation: review of literature and report of eight cases. urology 2010 335 ;75(5):1181-4. https://doi: 10.1016/j.urology.2009.11.023. 336 2. perovic sv, byun js, scheplev p, djordjevic ml, kim jh, bubanj t .new perspectives of 337 penile enhancement surgery: tissue engineering with biodegradable scaffolds. eur urol 338 2006;49(1):139-47. https://doi: 10.1016/j.eururo.2005.08.016. 339 3. leungwattanakij s, pummangura n, ratana-olarn k. penile enhancement using a porcine 340 small intestinal submucosa graft in a rat model. int j impot res 2006 ;18(1):39-43. 341 https://doi:10.1038/sj.ijir.3901358. 342 4. colombo f, casarico a. penile enlargement. curr opin urol 2008 ;18(6):583-8. https://doi: 343 10.1097/mou.0b013e32830fe427. 344 5. vyas ks, abu-ghname a, banuelos j, morrison sd, manrique o. aesthetic augmentation 345 phalloplasty: a systematic review of techniques and outcomes. plast reconstr surg 2020 346 ;146(5):995-1006. https://doi: 10.1097/prs.0000000000007249. 347 6. xu l, zhao m, yang z, chen w, li y, ma n, et al.modified penile augmentation by 348 dermal-fat graft in post-hypospadias adults. aesthetic plast surg 2016 ;40(1):120-9. 349 https://doi: 10.1007/s00266-015-0593-6. 350 7. küçükçelebi a, ertaş nm, aydin a, eroğlu a, ozmen e, velidedeoğlu h. microvascular 351 temporalis fascia transfer for penile girth enhancement. ann plast surg 2001;47(1):86-8. 352 https://doi: 10.1097/00000637-200107000-00016. 353 8. zhang h, jin c, zhang p, wu y, zhang m, bai w, et al.. human acellular dermal matrix 354 augmentation phalloplasty surgery. plast surg (oakv) 2020 ;28(3):161-166. https://doi: 355 10.1177/2292550320928556. 356 9. xu l, zhao m, chen w, li y, yang z, ma n, et al. augmentation phalloplasty with 357 autologous dermal fat graft in the treatment of "small penis". ann plast surg 2016 ;77 suppl 358 1:s60-5. https://doi: 10.1097/sap.0000000000000782. 359 10. wu c, dong y, li y, liu h. the efficacy of amniotic membrane-mediated sequential 360 double-barrier therapy for the treatment of postoperative intrauterine adhesions. 361 medicine (baltimore) 2021;100(15):e25416. https://doi: 10.1097/md.0000000000025416 362 363 https://pubmed.ncbi.nlm.nih.gov/16049525/ https://pubmed.ncbi.nlm.nih.gov/16049525/ https://pubmed.ncbi.nlm.nih.gov/26705273/ https://pubmed.ncbi.nlm.nih.gov/26705273/ 13 11. razzaghi m, rahavian a, fallah karkan m, allameh f, ghiasy s, javanmard b. use of 364 human amniotic membrane repair of anterior urethral defect: first clinical report. 365 int j urol 2020 ;27(7):605-609. https://doi: 10.1111/iju.14257. 366 367 12. barski d, gerullis h, ecke t, boros m, brune j, beutner u, et al.application of dried 368 human amnion graft to improve post-prostatectomy incontinence and potency: a randomized 369 exploration study protocol. adv ther 2020 ;37(1):592-602. https://doi: 10.1007/s12325-019-370 01158-3. 371 13. güneş m, altok m, özmen ö, umul m, güneş a, baş e, et al. a novel experimental 372 method for penile augmentation urethroplasty with a combination of buccal mucosa and 373 amniotic membrane in a rabbit model. urology 2017;102:240-246. https://doi: 374 10.1016/j.urology.2016.10.061. 375 14. jirsova k, jones gla. amniotic membrane in ophthalmology: properties, preparation, 376 storage and indications for grafting-a review. cell tissue bank 2017;18(2):193-204. https://doi: 377 10.1007/s10561-017-9618-5. 378 15. abidu-figueiredo m, ribeiro ic, chagas ma, cardoso le, costa ws, sampaio fj.the 379 penis in diabetes: structural analysis of connective tissue and smooth muscle alterations in a 380 rabbit model. bju int 2011;108(3):400-4. https://doi: 10.1111/j.1464-410x.2010.09944.x. 381 16. rønn lc, ralets i, hartz bp, bech m, berezin a, berezin v, et al.a simple procedure for 382 quantification of neurite outgrowth based on stereological principles. j neurosci methods 2000 383 31;100(1-2):25-32. https://doi: 10.1016/s0165-0270(00)00228-4. 384 17. salehipour m, izadpanah k, safaei a, kamranpoor m, farsiani mr. application of 385 human amniotic membrane in canine penile tunica albuginea defect: first step toward an 386 innovating new method for treatment of peyronie's disease . int braz j urol 2014 ;40(3):400-7. 387 https://doi.org/ 10.1590/s1677-5538.ibju.2014.03.15 388 18. li x, tao l, cao c, shi h, li l, chen l, et al. a new surgical method for penile girth 389 enhancement. int j clin exp med 2015;8(7):10753-9. ecollection 2015. 390 19. eslahi a, shirazi m, khoshnood o, noorafshan a, karbalay-doust s. comparison of the 391 effects of pentoxifylline, simvastatin, tamoxifen, and losartan on cavernous bodies after penile 392 fracture in rats: a stereological study.int j impot res 2020;32(3):338-344. 393 https://doi.org/10.1038/s41443-019-0175-2. 394 https://pubmed.ncbi.nlm.nih.gov/26379868/ https://pubmed.ncbi.nlm.nih.gov/26379868/ 14 20. anthony mescher.junqueira's basic histology: text and atlas, fifteenth edition (15th 395 edition) ,mcgraw-hill education , august, 2018. pp. 96-120 and 197-214 396 21. perovic sv, sansalone s, djinovic r, ferlosio a, vespasiani g, orlandi a. penile 397 enhancement using autologous tissue engineering with biodegradable scaffold: a clinical and 398 histomorphometric study. j sex med 2010 ;7(9):3206-15. https://doi: 10.1111/j.1743-399 6109.2009.01545.x. 400 22. moon dg, kwak ti, cho hy, bae jh, park hs, kim jj. augmentation of glans penis 401 using injectable hyaluronic acid gel. int j impot res 2003; 15(6):456-60. https://doi: 402 10.1038/sj.ijir.3901058. 403 23. alei g, letizia p, ricottilli f, simone p, alei l, massoni f, et al. original technique for 404 penile girth augmentation through porcine dermal acellular grafts: results in a 69-patient series. 405 j sex med 2012; 9(7):1945-53. https://doi: 10.1111/j.1743-6109.2012.02744.x. 406 24. tealab aa, maarouf am, habous m, ralph dj, abohashem s. the use of an acellular 407 collagen matrix in penile augmentation: a pilot study in saudi arabia.arab j urol 2013; 408 11(2):169-73. https://doi: 10.1016/j.aju.2013.02.001 409 25. campbell j, gillis j. a review of penile elongation surgery. transl androl urol 410 2017;6(1):69-78. https://doi: 10.21037/tau.2016.11.19. 411 26. panfilov de. augmentative phalloplasty. aesthetic plast surg 2006 ;30(2):183-97. https:// 412 doi: 10.1007/s00266-004-0153-y. 413 27. leal-marin s, kern t, hofmann n, pogozhykh o, framme c, börgel m, et al. human 414 amniotic membrane: a review on tissue engineering, application, and storage. j biomed mater 415 res b appl biomater 2021 ;109(8):1198-1215. https://doi: 10.1002/jbm.b.34782. 416 28. lei j, priddy lb, lim jj, massee m, koob tj. identification of extracellular matrix 417 components and biological factors in micronized dehydrated human amnion/chorion 418 membrane. adv wound care (new rochelle) 2017 1;6(2):43-53. https://doi: 419 0.1089/wound.2016.0699. 420 29. shakeri s, haghpanah a, khezri a, yazdani m, monabbati a, haghpanah s, et al. 421 application of amniotic membrane as xenograft for urethroplasty in rabbit. int urol nephrol 422 2009;41(4):895-901. https://doi: 10.1007/s11255-009-9532-2. 423 30. salehipour m, mohammadian r, jahanbini s, emadmarvasti v, geramizadeh b, tanideh 424 n. is amniotic membrane a suitable biomaterial for reconstruction of long ureteral defects? 425 https://pubmed.ncbi.nlm.nih.gov/14671667/ https://pubmed.ncbi.nlm.nih.gov/14671667/ https://pubmed.ncbi.nlm.nih.gov/16547638/ https://pubmed.ncbi.nlm.nih.gov/23354211/ 15 saudi j kidney dis transpl 2013 ;24(1):135-8. https://doi: 10.4103/1319-2442.106311. 426 427 428 figure 1: surgical procedure was done by the longitudinal i-shaped midline incision of the tunica 429 albuginea on the dorsal surface of the penis and the placement of the am graft between the tunica 430 albuginea and the corpus cavernosum in both right and left sides of penis. 431 432 433 figure 2: processing technique. the penis was cut into 8-12 sections according to its length (a). 434 the sections were embedded in paraffin blocks, sectioned, mounted on a slide, and stained (b). 435 436 16 437 figure 3: assessment of the rabbit penile tissue. the penile components were indicated on the 438 histological section by arrows (a). the volumes of the penis and penile components were assessed 439 by cavalieri’s technique and point-counting method (b). 440 441 442 figure 4: point-counting method was employed to estimate the volume density of the collagen 443 bundles, smooth muscle cells, cavernous sinuses, and vessels of the corpora cavernosa (a). optical 444 disector technique was used to estimate the numerical density of the fibroblasts and smooth muscle 445 cells. the fibroblasts’ or smooth muscle cells’ nuclei coming into focus through scanning of the 446 height of the disector were recorded (the arrow) (b). 447 448 17 449 figure 5: the aligned dot plots of the total volume (a), diameter (b), and length (c) of the fascia 450 (d), tunica albuginea (e), and corpora cavernosa (f) of the penis in the sham and surgery+am 451 groups. each dot shows an animal and the horizontal bars represent the means of the parameters. 452 the p-values and significant differences have been shown on each dot plot by stars. statistical 453 significance was determined by mann-whitney u test. *p=0.03, **p=0.04, ***p=0.01. 454 18 455 figure 6: the aligned dot plot of the volume density of the collagen bundles (a), smooth muscle 456 cells (b), cavernous sinuses (c), and vessels (d) and number of fibroblasts (e) and smooth muscle 457 cells (f) of the corpora cavernosa in the sham and surgery +am groups. each dot represents an 458 animal and the horizontal bars show the means of the mentioned parameters. the significant 459 differences and p-values have been presented on each dot plot by stars. statistical significance was 460 determined by mann-whitney u test. *p=0.01, **p=0.03, ***p=0.05. 461 screening for gestational diabetes by measuring fasting plasma glucose levels squ journal for scientific research: medical sciences 2003 vol 5, no. –2, 5–8 ©sultan qaboos universit y screening for gestational diabetes by measuring fasting plasma glucose levels *khalil e. rajab1, jonathan h. skerman2, abdulla a. issa1 1department of obstetrics and gynaecology, department of anaesthesia and intensive care, arabian gulf university, college of medicine and medical sciences, salmaniya medical complex, p.o.box 26752, manama, kingdom of bahrain. *to whom correspondence should be addressed. email: yonrajab@batelco.com.bh abstract. objectives: (a) to test the sensitivity and specificity of measuring fasting plasma glucose levels (fpg) as a screening test for gestational diabetes mellitus (gdm). (b) to compare predicting levels of fpg levels with the one-hour, oral 50g non-fasting glucose challenge test (gct) for predicting gdm. methods: one thousand and six hundred pregnant women from the health centres, antenatal clinics and salmaniya medical complex were screened by the gct after 50g of oral glucose during 26–32 weeks gestation, giving a 13.5% incidence of gdm (using the third international workshop cutoff values of 7.8 mmol /l). all patients also had an fpg estimation followed by the threehour oral glucose tolerance test (ogtt). seventy eight percent of the patients were bahraini, 19% asian and 3% other nationalities. their mean age was 27.2+0.2 years. receiver-operating curves (roc) were used to test the ability of the fpg and the ogtt to differentiate patients with gdm and identify the cut off values for predicting a diagnosis of gdm. results: fpg levels of 5.6 mmol /l and 5.4 mmol /l yielded sensitivities and specificities of 94% and 93% respectively. measuring fpg as a screening test required a diagnostic ogtt in 32% compared with 13% when the gct was used. conclusion: using fpg levels at a cutoff value of ≥ 5.5 mmol /l is an easier, more acceptable test for patients compared to the gct. using the fpg levels is also more cost effective and allows nearly 70% of women to avoid the ogtt. key words: gestational diabetes, pregnancy, screening, fasting plasma glucose levels. there is a wide diversity of opinion regard-ing the screening for gestational diabetes melli-tus (gdm). there is no consensus on whether screening is justified,1 who should be screened,2 and what is the optimal method for management after diagnosis.3 in bahrain’s government maternity clinics we have been following the recommendations of the fourth international workshop conference4 for the universal screening of all pregnant women between 26–32 weeks of gestation by use of the non-fasting 50 g oral glucose test (gct). this is followed by the confirmatory 75 g three-hour oral glucose tolerance test (ogtt) in cases of a positive screen which includes fasting plasma glucose levels (fpg). because of the complexity of this test (which requires prior appointments, ingestion of oral glucose, prolonged waiting time and ever increasing costs and pressure on an already over-stretched laboratory service), a search for an easier and less expensive method has been studied. in 997, the american diabetic association5,6 announced new criteria for screening diabetes in nonpregnant patients by measuring a fasting plasma glucose skerman ��������������������������������������������������� ��������������������� �������������������������������������� ��������:�����:�-����������������������������������������������������������������������.�-������ �������������������������������������������������������������������������������������������������)������� �������������������������������������������������������������������������������� .(�������:�������������� ��������������������������������������������������������������������������������������������������� ��������)������������������������������������������������������������ (���������������������������� ��������*%������������� .����������������������������������������������������������������������������� ������������������������������ .������ %��������������������������������� %������������ %��������������� �������������������+������.����������������������������������������������������������������������� ����������������������������������������������������������������� .������� :����������������������� / ������� ��������������������������������������� %�������������� %�������������������������������������� �������������������������������� %��������� %����������������������������������������������������:�� ��������������������� / ���������������������������������������������������������������������������� ���������������������������������������������������������������������������������������������������� %�� ������.������������ : ��������������������������������������������. mailto:yonrajab@batelco.com.bh 6 level (fpg) instead of the oral glucose tolerance test (ogtt). between 999 and 200, progressive population studies by peruccini et al7 in switzerland, agarwal from the uae8 and aguiar9 from brazil have reported successes in the screening of pregnant women for gdm using the measurement of lower fpg levels. our study aimed at evaluating the sensitivity and specificity of using fpg as a screening test for gdm compared to the 50g non-fasting glucose challenge test (gct). m e t h o d s with the purpose of determining a fpg value with good sensitivity and specificity that could identify pregnant women with gdm, we conducted a study between st january and 3st may 2002 in which ,600 pregnant women were screened by gct followed by ogtt. these women were drawn from outpatients and inpatients in salmaniya medical complex, the major referral hospital in bahrain. all patients who were diagnosed to have gdm (by gct testing) had undergone the 75g ogtt which includes the fpg. the major ethnic distribution of the study was 78% bahrainis, 9% asians and 3% from other nationalities. the mean age distribution was 27.2 + 0.2 years, ranging from 7–48. we analysed the data using the med/calc statistical package. a receiver-operating characteristics (roc) curve was constructed in order to compare the ability of the fpg against the gct in discriminating patients with a diagnosis of gdm, and to determine the best cut-off value for fpg levels, which would have the best predictive value for need of ogtt. r e s u lt s the incidence of gdm among the cohort of pregnant women in this study who had undergone the gct followed by ogtt during 26–32 weeks of gestational age was 27 (3.5%) [figure ]. analysis of the results of the gct group was carried out and is reported in table . table 2 shows the analysis of the results of those tested with the fpg. figures 2 and 3 show the fpg level sensitivities and specificities of 94% and 93% respectively, along with the false positives encountered. the area under the curve in figure 3 is 0.962 for fpg. the true positive rates (sensitivity) versus false positive rates (specificity) are plotted for determination of the cut-off value. d i s c u s s i o n gestational diabetes mellitus (gdm) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. this definition applies irrespective of whether insulin or only diet modification is used for treatment, and whether or not the condition persists after pregnancy. it does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy.10 in bahrain, testing pregnant women with 75g threehour ogtt revealed that approximately 7.8% of all pregnancies are complicated by gdm.11 prior to year 2000, r a j a b e t a l table 1. analysis of results of the fasting plasma glucose group using a receiver operating characteristics curve positive group diagnosis “d” sample size 207 negative group diagnosis “nd” sample size 1393 area under roc curve 0.962 standard error 0.017 95% confidence interval 0.948–0.973 at 5.6 mmol/l: sensitivity is 88.9 specificity is 95.0 + lr 14.48 positive likelihood ratio lr 0.0 negative likelihood ratio figure 1. distribution of negative and positive gdms using fasting blood sugar testing under the receiving operating characteristics curve rajab et al 3 figure 1. >5.6 sens: 88.9 spec: 95.0 7 the use of the 50g gct resulted in a higher yield of a 3.5% rate for gdm. currently, approximately 900–200 pregnant women are diagnosed annually to have gdm.12 the prevalence may range from 7% to 4% of all pregnancies based on the ethnic group studied and the diagnostic criteria employed. in bahrain’s government antenatal clinics, the screening test currently used is the 50g gct, performed between 26–32 weeks of gestation. this test involves a prior appointment, ingestion of glucose, nausea after the drink, a waiting time of one hour, and an ever increasing number of patients. more than 30% of those tested would eventually require a full ogtt. to explore new ways for reducing this burden on the laboratory, we should consider a test that is less expensive, more efficient, and more specific. the other option would be the return to clinically selective criteria for patient screening. obviously, the first choice is more attractive. in 997, the american diabetic association announced new diagnostic criteria for diabetic screening, abolishing the use of ogtt, and shifting diagnosis exclusively to the use of fasting glucose.12 in 998, ramachandran et al13 published a paper on using the new diagnostic criteria in an asian population, suggesting the use of fasting glucose level as a screening s c r e e n i n g f o r g e s tat i o n a l d i a b e t e s table 2. analysis of the results of the glucose challenge test group using a receiver operating characteristics curve positive group 217 negative group 1383 area under roc curve 0.964–0.988 sensitivity at 5.4 100% specificity 93.1% positive likelihood ratio 11.36 negative likelihood ratio 0.00 rajab et al 5 figure 3. figure 3. receiver operating characteristics (roc) curve of fasting plasma glucose concentration. rajab et al 4 figure 2. figure 2. sensitivity and specificity of fasting plasma glucose in detecting gestational diabetes mellitus 8 test for diabetes. there was some criticism to the use of fasting glucose instead of ogtt, based on observational studies of long term morbidity of gdm, showing that the glucose level is more accurate than fasting glucose levels in predicting future morbidity.14,15 the use of fasting blood sugar does not carry the same disadvantages, and will not obviate the need for a full gtt if this should be deemed necessary. a few studies on the use of fasting glucose levels in pregnancy have since been published, pointing to the favourable use of fpg as a screening test in obstetrics.16–19 in our series we utilized the receiver-operating curve to test the ability of the fasting plasma sugar and ogtt to identify patients with gdm and find out the cut off value which predicts a gdm diagnosis. fasting plasma glucose levels at 5.6 mmol/l yielded sensitivity and specificity of 94% and 93% respectively. when fasting plasma glucose was used, 3% of the positives required further testing while 32% needed this when the glucose challenge test was used. fpg at a value of 5.5 mmol/l is an easier, more acceptable test for patients compared with the 50g glucose challenge test. using the fpg is more cost effective and allows 70% of women to avoid the challenge test. future collaborative studies, pregnancy outcomes, and metaanalysis will answer all the questions related to the validity of this test. c o n c l u s i o n using fasting plasma glucose levels at cut off values of ≥ 5.5 mol/l (99 mg/dl) as the higher fpg threshold to rule out gdm with a specificity of 95% is an easier, more acceptable test for patients than the 50g glucose challenge test. the fasting blood level test is more cost effective and allows 70% of women to avoid the challenge test. furthermore, 3% more cases of gdm were diagnosed using the fpg criteria compared to the glucose challenge test. r e f e r e n c e s . sacks da, greenspoon js, abu-fadil s, henry hm, woldetsadik g, yao jef. toward universal criteria for gestational diabetes: the 75-gram glucose tolerance test in pregnancy. am j obstet gynecol, 995, 72, 607–64. 2. naylor cd, sermer m, chen e, farine d. selective screening for gestational diabetes mellitus. n engl j med, 997, 337, 59–596. 3. clapp jfiii. effect of dietary carbohydrate on the glucose and insulin response to mixed caloric intake and exercise in both non-pregnant and pregnant women. diabetes care, 988, 2, (suppl 2), b07–2. 4. metzger be, coustan dm. organizing committee. summary and recommendations of the fourth international workshop conference on gestational diabetes mellitus. diabetes care, 998, 2, (suppl 2), b6–67. 5. american diabetes association. report of the expert committees on the diagnosis and classification of diabetes mellitus. diabetic care, 977, 20, 83–97. 6. harris mi, eastman rc, cowie cc, flegal km, eberhardt ms. comparison of diabetes diagnostic categories in the us population according to 997 american diabetes association and 980-985 world health organization diagnostic criteria. diabetes care 997, 20, 859–862. 7. perucchini d, fischer u, spinas ga, huch r, huch a, lehmann r. using fasting plasma glucose concentrations to screen for gestational diabetes mellitus. prospective population study. bmj, 999, 39, 82–85. 8. agarwal mm, hughes pf, ezimokhai h. screening for gestational diabetes in a high-risk population using fasting plasma glucose. int j gynaecol obstet, 2000, 68, 47–48. 9. de aguiar lg, de matos hj, de brito gomes m. could fasting plasma glucose be used for screening high risk outpatients for gestational diabetes mellitus? diabetes care, 200, 24, 954– 955. 0. acog practice bulletin. gestational diabetes—clinical management guideline for obstetricians and gynecologists 2000, 30, –3. . das nf, yousif w. evaluation of gestational diabetes in bahrain. the bahrain conference on diabetes in the in the arab world. abstracts book, 2000, p. 80. 2. department of obstetrics and gynaecology, salmaniya medical complex, kingdom of bahrain. annual report, 2000, p. 2. 3. ramachandran a, snehalatha c, lathe e, vijay v. evaluation of the use of fasting glucose as a new diagnostic criterion for diabetes in the asian indian population. diabetes care, 998, 2, 666–667. 4. the decode-study group. is fasting glucose sufficient to define diabetes? epidemiological data from 20 european studies. european diabetes epidemiology group. diabetes epidemiology: collaborative analysis of diagnostic criteria in europe. diabetologia, 999, 42, 647–654. 5. gourdy p, ruidavets jb, ferrieres j, ducimetiere p, amouyel p, arveiler d, et al. prevalence of type 2 diabetes and impaired fasting glucose in the middle-aged population of three french regions—the monica study 995–97. diabetes metab, 200, 27, 347–358. 6. agarwal mm, hughes pf, punnose j, ezimokhai m, thomas l. gestational diabetes screening of a multiethnic, high-risk population using glycated proteins. diabetes res clin pract, 200, 5, 67–73. 7. hanna fw, peters jr. screening for gestational diabetes, past, present and future. diabet med, 2002, 9, 35–358. 8. reichelt aj, spichler er, branchtein l, nucci lb, franco lj, schmidt mi. fasting plasma glucose is a useful test for detection of gestational diabetes. brazilian study for gestational diabetes (ebdg) working group. diabetes care, 998, 2, 246–249. 9. lucas mj. diabetes complicating pregnancy. obstet gynecol clin north am, 200, 28, 53–536. r a j a b e t a l methods results discussion conclusion references december 2008 no white pages.indd hairy cell leukaemia (hcl) is a rare chronic b lymphoproliferative disorder rep-resenting 2% of all leukaemias.1 the name hcl was coined in 1964 by shrek and donnelly.2 it was first identified as a clinical entity in 1958 and was known as leukaemic reticuloendotheliosis.2 at present the hairy cell has not been identified to have a known normal counterpart in lymphocyte ontogeny. we describe four cases of hairy cell leukaemia, the first to be reported from the sultanate of oman. c a s e 1 an omani male, 61 years of age, presented with recurrent anaemia to another hospital in muscat. he was transfusion dependent and admitted to the royal hospital with fever and pancytopaenia and found to have a splenomegaly of 8cm and hepatomegaly of 6cm. his complete blood count (cbc) showed: hb% 3.2g/dl, hairy cell leukaemia in oman four cases *arundathi kurukulasuriya, asia al-rashdi, muhanna al-muslahi sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 333-338 sultan qaboos university© submitted 12th april 2008 accepted 22nd august 2008 c a s e r e p o r t عمان سلطنة في الشعرية اخلاليا دَّم ابْيِضاضُ أربع حاالت املصلحي مهنا الراشدي، اسيا كوروكوالسوريا، ارونداثي لَة امِ الشَّ رَيَّاتِ الكُ قِلَّةُ العمر. أواسط الذكور في يصيب ما غالبا ومزمن نادر نَسيلِيّ يّ ْفِ ملِّ تَّكاثُريُ اضطراب هو الشعرية اخلاليا دَّم ابْيِضاضُ امللخص: غزير سايتوبالزم الليمفاوية ذو اخلاليا ــاف بواسطة اكتش التشخيص يتم ــارا. انتش ــريرية الس العالمات أكثر من ــيم اجلس حال الطِّ مُ خُّ وتَضَ الدم في جاف. بزل إلى في الغالب العظم تؤدي نقي افَة رُشَ أخذت اسمها. هنا ومن ونقي العظم، ة الدم احمليطي في لُطاخَ شعرية أطراف ــكل ش ــر على ينتش cd103, cd25, fmc7, cd11c منطيا يكون ــيابي االنس الكريات ْرَبَة)، وعد َا) ــل سَ العَ قُرْصُ ــبه مظهر تش خاصة صفات لها ب ِنْقَ امل ةٌ زْعَ خَ لُ بالعامِ ئات البورين املتبوع ضاهِ cd19, cd20, cd79a . مُ الكالسيكية الليمفاوية واصمات اخلاليا مع اخلفيفة ايجابية كابَّا غاما أو لَةُ لْسِ وسِّ املرض من ــنوات خالية س ــر عش ــجيل أمكن تس احلالي. في الوقت األمثل العالج هو احلمى عن الناجت الَت دِ العَ لعالج قِلَّةُ احملببة رات مَ عْ ــتَ سْ للمُ ُنَبِّهُ امل املذكور املرض من حاالت أربع هنا ندرج هذا املرض. لعالج واعدة نتائج أيضا cd22أظهر cd20 و ملضاد التجريبي االستعمال العالج. ذلك بواسطة سلطنة عمان. في املستشفى السلطاني مبسقط في سنتني خالل شخصت عمان. سلطنة حاالت، ، تقرير اللمفي اضطراب التكاثر ، دَّم اخلاليا الشعرية الكلمات: ابْيِضاضُ مفتاح department of haematology & blood transfusion, royal hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: arundathi54@yahoo.com abstract hairy cell leukaemia (hcl) is a rare, clonal, chronic lymphoproliferative disorder commonly seen in males in the middle years of life. pancytopaenia with moderate to massive splenomegaly is the most common clinical presentation. diagnosis is made on detecting the lymphocytes with abundant cytoplasm which spread into hair-like processes on peripheral blood and bone marrow smears, thus giving the name, “hairy cell leukaemia”. the bone marrow aspirate is frequently a dry tap. the trephine biopsy has the characteristic features of a honey comb appearance and flow cytometry is typically cd03, cd25, fmc7, cdc, gamma or kappa light chain positive with the classic b lymphocyte markers cd9, cd20, cd79a. purine analogues followed by granulocyte-colony stimulating factor (g-csf) to manage the febrile neutropenia is currently the treatment of choice. a 0 year disease free survival is recorded with these management strategies. experimental use of anti cd20 and cd22 has also shown promising results in the treatment of this disease. we report four cases of hcl diagnosed in a span of two years at the royal hospital, muscat, oman. key words:: hairy cell leukaemia; lymphoproliferative disorder; case report; oman. a r u n d at h i k u r u k u l a s u r i ya , a s i a a l r a s h d i a n d m u h a n n a a l m u s l a h i 334 white blood cells (wbc) 0.8 x 109/l, absolute neutrophil count (anc) 0.3 x 109/l, platelets 48 x 10 9/l. renal and liver function tests were normal other than for a low serum albumin. the blood picture confirmed the presence of pancytopaenia with no blast cells or dysplastic changes. he was resuscitated with blood transfusion and intravenous antibiotics. nursed in isolation, the bone marrow aspirate was performed once his condition stabilised. the bone marrow aspirate and trephine biopsy showed hairy cells. the cytochemistry was positive with tartrate resistent acid phosphatase (trap). the immunohistochemistry on the trephine biopsy showed the lymphocytes were positive for cd20, cd79a and dba 44. flow cytometry (fcm) on the bone marrow aspirate was positive for cd19, cd20, cd22, cd25, cd103, cd11c, fmc7 and kappa light chain and negative for cd3, cd5, cd7, cd10, cd23, cd38. the diagnosis of hairy cell leukaemia was established, but the patient refused intravenous chemotherapy and received three mega units of interferon alpha subcutaneously thrice a week for six months. he achieved a complete haematological response and his cbc remained stable six months after cessation of therapy. c a s e 2 an omani male, aged 62 years, was referred from another hospital for pancytopaenia, diagnosed with myelodysplasia (mds) and treated with blood transfusions, erythropoietin and granulyte-colony stimulating factor (g-csf) without significant response. he was admitted to the royal hospital with fever, malena, haematemesis and had cervical lymphadenopathy, bilateral basal crepitations with a splenomegaly of 6cm and a hepatomegaly of 4cm. his cbc revealed a severe pancytopaenia with: hb% 3.4 g/dl, wbc – 3.1 x 109/ l, anc -0.4 x 109/l, platelets 5.0 x 109/l. his blood picture and the bone marrow aspirate showed hairy cells positive for trap. the immunohistochemistry was positive on the trephine for cd20, cd79a and dba44 confirming the diagnosis of hairy cell leukaemia. the flow cytometry (fcm) results on the bone marrow aspirate was positive for cd19, cd20, cd22, cd25, cd11c, fmc7 and kappa light chain. he was admitted to the intensive care unit with acute renal failure and septic shock and the blood culture showed a heavy growth of yeast. he succumbed to septicaemia and died a few weeks after admission despite intensive supportive care, broad spectrum antibiotics and antifungal therapy. c a s e 3 an omani male, aged 47 years, a known diabetic on oral hypoglycaemics, was referred from a peripheral hospital for investigation of pancytopaenia, hepatfigure 1: normal lymphocyte in peripheral blood (magnification x 400) figure 2: hairy cell from peripheral blood from patient 1 (magnification x 4000) h a i r y c e l l l e u k a e m i a i n o m a n 335 osplenomegaly and fever. he had diarrhoea positive for salmonella which was treated before he arrived at the royal hospital. he recounted a two month history of backache and fever. he had hepatosplenomegaly with no lymphadenopathy. a computed tomography (ct) scan showed no evidence of mediastinal lymphadenopathy. his cbc revealed an hb% 8.9 g/dl, wbc – 2.6 x109/l, anc 0.4x109/l, platelets – 94.0 x 109/l. the blood picture, bone marrow aspirate and the trephine biopsy showed hairy cells. the trap was unsatisfactory. the marrow aspirate was inadequate for fcm. the trephine biopsy was positive for cd79a, cd20 and dba44. he was treated with cladribine 0.14 mg/kg infusion over two hours for five days. he had two episodes of febrile neutropenia which were treated successfully with intravenous antibiotics. six months later, his blood count improved to hb 10.2 g/dl, wbc 3.1x109/ l, anc 1.9 x109/l and platelets – 141.0 x 109/l. c a s e 4 an iraqi woman, aged 36 years, was referred for pancytopaenia detected on a routine cbc following a lower segment caesarian section. a ct scan showed a para-aortic lymphadenopathy in her chest and moderate hepatosplenomegaly. her haematological parameters confirm the presence of bilineage cytopenia: hb% -12.0 g/dl, wbc 1.7 x10 9/l with anc 0.2x109/l, platelets – 102.0x 10 9/l. the bone marrow aspirate and trephine biopsy showed hairy cells. the trephine biopsy was positive for cd20, cd79a and dba44. the fcm on the bone marrow aspirate was positive for cd19, cd20, cd22, cd25, cd103, fmc7 and kappa light chain. she was treated with intravenous cladribine 0.1mg/ kg continuous infusion for seven days. she continues to be followed up in the region where she lives and her cbc is normal. d i s c u s s i o n middle aged people are more affected by hcl, with a male-female ratio of 5:1.1 three of our patients were male and one was a female. the characteristic presentation is with pancytopaenia in more than 50% of patients, 3 moderate to massive splenomegaly in 85%, with or without hepatomegaly in 40% and bone marrow infiltration. opportunistic infections are common. rare presentations include vasculitis,4 splenic rupture,5 bony involvement,6 neuropathy,7 and autoimmune haemolytic anaemia.8 guillian-barré syndrome has been reported in association with hcl or following cladribine treatment.9, 10 the peripheral blood shows the lymphocytes with shaggy hair like cytoplasmic projections in 90% of patients.3 although it leads to a distinct morphological diagnosis, sometimes a severe pancytopaenia, a dry bone marrow aspirate due to reticulin fibrosis could deprive us of this diagnostic information because of figure 3: tartrate resistent acid phosphatase reaction of hairy cell (patient 2) (magnification x 400) figure 4: trephine biopsy of patient 3 ‘fried egg’ appearance with retraction of cytoplasm around the nucleus (magnification x 400) a r u n d at h i k u r u k u l a s u r i ya , a s i a a l r a s h d i a n d m u h a n n a a l m u s l a h i 336 the paucity of cells. then the diagnosis is often based on the trephine biopsy which shows a patchy, diffuse infiltrate of the hairy cells, described as having a fried egg or honey comb appearance.3 this occurs because the lymphocyte nuclei are spaced far apart due to the retraction of the cytoplasmic processes. the characteristic infiltrate of the spleen is in the red pulp and this is the only small b cell non hodgkin’s lymphoma which infiltrates the red pulp of the spleen.3 if the bone marrow is not infiltrated, the splenic pathology can be used to diagnose the condition. infiltration of the kidneys, colon, adrenal glands, myocardium, meninges, pancreas and connective tissue have been reported.3 cytochemistry and immunohistochemistry play an important role in the diagnosis of hcl. cytochemistry on the hairy lymphocytes in blood or bone marrow aspirate with acid phosphatase is resistant to tartrate (trap). this is also done as immunohistochemistry on the trephine biopsy. there are no specific chromosomal abnormalities or molecular genetic alterations that are diagnostic of this disease.1 thus, morphology, cytochemistry and immunohistochemistry on the trephine biopsy/flow cytometry are useful tools in diagnosis of this uncommon lymphoma in its leukaemic phase. the hairy cells strongly express cd 103, cd25, fmc7, cd11c, and the b cell markers cd20, cd 79a and monoclonal kappa or lambda light chains.1 supportive care with packed red cells and platelets were the mainstay of replacement therapy for the cytopaenias in our patients. the current treatment of hcl is with the purine analogues, 2 chlorodeoxyadenosine (2cda/cladribine) and pentostatin. treatment is indicated for patients with significant cytopaenia, syptomatic splenomegaly, recurrent serious infections and constitutional symptoms. cladribine is used as a single infusion or a course of subcutaneous injections.11 the two widely used infusion regimens are either 0.1 mg/kg continuous intravenous infusion over 24 hours for seven days or 0.14 mg /kg intravenous infusion over two hours for five days, with no statistically significant difference in the rate of response or complications between the two regimens.12, 13 a high incidence of febrile neutropaenia is recorded with this treatment.14-17 g–csf is used to overcome this side effect. it is rare that more than one course of treatment is required. in a recently published randomised study in 132 patients with untreated hcl, one group of patients were treated with the standard regimen of cladribine 0.14mg/kg daily for 5 days, while the other group was treated with a weekly dose of cladribine for six weeks. both regimens where found to be equally effective; the weekly regimen was not, in fact, safer nor did it reduce toxicity or the risk of infections.18 treatment is discontinued once complete remission (cr) or partial remission (pr) is achieved with normalisation of peripheral blood counts.19 cladribine could induce a durable and long lasting remission in the majority of patients with only a single cycle of therapy and the relapsed patients could be treated successfully with a repeated cycle of cladribine.20-22 there is a good correlation between minimal residual disease as demonstrated by dba44 immunostaining and risk of relapse.22 single iv pentostatin is administered intermittently for a longer treatment duration, but may result in a lower incidence of febrile neutropenia. 23, 24 it is usually administered in cycles of 4 mg/m2 twice weekly, repeated every 8 weeks 25 for three cycles. it was found to be highly effective in treating hcl with prolonged remission duration and without an increase in subsequent risk of malignancy.25, 26 most patients remain disease free for ten years following treatment with purine analogues. cr is achieved in 8085% of patients. no patient has been followed up long enough to assess cure.27, 28 the role of consolidation and maintenance therapy in preventing relapse or progression of the disease has not been evaluated. interferon alfa is also used for those patients with intercurrent infections and severe cytopenias.29 cr is seen in 20-30% of patients.30 for patients with severe thrombocytopaenia and massive spleens, splenectomy is considered.31 monoclonal antibodies against cd20 (rituximab) and cd22 have now shown activity against hcl.30 these antibodies seem to achieve good responses in the group relapsing on cladribine; however, its main role maybe useful in combination with purine analogues.30 c o n c l u s i o n hcl manifests in the middle years of life, with a male predominance, characterised by pancytopaenia caused by moderate to massive splenomegaly. it is an easy diagnosis to make on the morphology of well made blood and bone marrow smears. although there are no specific markers for hcl, cytochemistry and flow cytometry readily confirm the diagnosis. this is the first report of hcl in oman. the diagnosis and h a i r y c e l l l e u k a e m i a i n o m a n 337 management was based on current guidelines. the outcome of clinical remission was achieved in 3 patients and one patient succumbed to an opportunistic infection. r e f e r e n c e s 1. feller ac, diebold j, paulli m, le tourneau a. histopathology of nodal and extranodal non hodgkin lymphoma. 3rd ed. new york: springer publishing company, 1992. p. 251-254. 2. shrek r, donnelly wj. hairy cells in blood in lymphoreticular neoplastic disease and flagellated cells of normal lymph nodes. blood 1966; 27:199 –211. 3. bitter ma, knowles dm. hairy cell leukaemia and related disorders. in: neoplastic haematopathology. 2nd ed. philadelphia: lippincott, williams and wilkins. pp. 1531-1547. 4. remkova a, halcin a, stenova e, babal p, kasoerova v, vranovsky a. acute vasculitis as a first manifestation of hairy cell leukemia. eur j intern med 2007; 18:238-240. 5. dalawari p, vandover jc, rosenbaum ra. unusual presentation of spontaneous splenic rupture. del med j 2007; 79:205-208. 6. franco p, filippi ar, fornari a, marinone c, ricardi u. case of bone involvement in hairy cell leukemia successfully treated with radiation therapy. tumori 2006; 92:366-369. 7. rossi d, franceschetti s, cerri m, conconi a, lunghi m, capello d, et al. hairy cell leukaemia complicated by anti-mag paraproteinemic demyelinating neuropathy: resolution of neurological syndrome after cladribrine treatment. leuk res 2007; 31:873-876. 8. mainwaring cj, walewska r, snowden j, winfield da, ng jp, chan-lam d, et al. fatal cord anti-i autoimmune haemolytic anaemia complicating hairy cell leukaemia. br j haematol 2000; 109:641-643. 9. tayal sc, rowbotham ds, bansal sk. guillain-barré syndrome in a patient with hairy cell leukaemia. j r soc med 1991; 84:238-239. 10. sarmiento ma, neme d, fornari mc, bengio rm. guillain-barre syndrome following 2-chlorodeoxyadenosine treatment for hairy cell leukemia. leuk lymphoma 2000; 39:657-659. 11. tallman ms, peterson lc, hakimian d, gillis s, polliack a. treatment of hairy-cell leukaemia. current views semin haematol 1999; 36:155-163. 12. sarmiento ma, neme d, fornari mc, bengio rm. guillain-barre syndrome following 2-chlorodeoxyadenosine treatment for hairy cell leukemia. leuk lymphoma 2000; 39:657-659. 13. robak t, błasińska-morawiec m, błoński j, hellmann a, halaburda k, konopka l, et al. 2 chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia and hairy cell leukemia variant: 7-year experience in poland. eur j haematol 1999; 62:49-56. 14. hoffman ma, janson d, rose e, tai kr. treatment of hairy-cell leukaemia with cladribine: response, toxicity, and long term follow-up. j clin oncol 1997; 15:1138 1142. 15. cheson bd, sorenson jm, vena da, montello mj, barrett ja, damasio e, et al. treatment of hairy cell leukaemia with 2-chlorodeoxyadenosine via the group c protocol mechanism of the national cancer institute: a report of 979 patients. j clin oncol 1998; 16:3007-3015. 16. goodman gr, burian c, koziol ja, saven a. extended follow-up of patients with hairy cell leukaemia after treatment with cladribine. j clin oncol 2003; 21:891896. 17. jehn u, bartl r, dietzfelbinger h, harferlach t, heinemann v. an update: 12 year follow-up of patients with hairy cell leukaemia following treatment with 2-chlorodeoxyadenosine. leukaemia 2004; 18:1476-1481. 18. robak t, jamroziak k, gora-tybor j, blonski jz, kasznicki m, dwilewicz-trojaczek j, et al. cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: final report from the polish adult leukemia group (palg) of a prospective, randomized, multicenter trial. blood 2007; 109:3672-3675. 19. hairy cell leukaemia treatment. national cancer institute, us national institutes of health. from www.cancer.gov/cancer topics/pdq/treatment/hairy cell leukaemia/treatment. accessed september 2007. 20. jehn u, bartl r, dietzfelbinger h. an update: 12-year follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine. leukemia 2004; 18:1476-1481. 21. jehn u, bartl r, dietzfelbinger h, vehling-kaiser u,wolf-hornung b, hill w, et al. long-term outcome of hairy cell leukemia treated with 2-chlorodeoxyadenosine. ann hematol 1999; 78:139-144. 22. bastie jn, cazals-hatem d, daniel mt, d’agay mf, rabian c, glaisner s, et al. five years follow-up after 2chloro deoxyadenosine treatment in thirty patients with hairy cell leukemia: evaluation of minimal residual disease and cd4+ lymphocytopenia after treatment. leuk lymphoma 1999; 35:555-565. 23. ribeiro p, bouaffia f, peaud py, blanc m, salles b, salles g, et al. long term outcome of patients with hairy cell leukaemia treated with pentostatin. cancer 1999; 85:6571. 24. grever m, kopecky k, foucar mk, head d, bennett jm, hutchison re, et al. randomized comparison of pentostatin versus interferon alfa -2a in previously untreated patients with hairy cell leukaemia: an intergroup study. j clin oncol 1999; 13:974-982. 25. johnston jb, eisenhauer e, wainman n. long-term a r u n d at h i k u r u k u l a s u r i ya , a s i a a l r a s h d i a n d m u h a n n a a l m u s l a h i 338 outcome following treatment of hairy cell leukemia with pentostatin (nipent): a national cancer institute of canada study. semin oncol 2000; 27:s32-36. 26. maloisel f, benboubker l, gardembas m, coiffier b, divine m, sebban c, et al. long-term outcome with pentostatin treatment in hairy cell leukemia patients. a french retrospective study of 238 patients. leukemia 2003; 17:45-51. 27. flinn iw, kopecky kj, foucar mk, head d, bennett jm, hutchison re, et al. long term follow up of remission duration, mortality, and second malignancies in hairy cell leukaemia patients treated with pentostatin. blood 2000; 96:2981-2986. 28. chadha p, rademaker aw, mendiratta p, kim b, evanchuk dm, hakimian d, et al. treatment of hairy cell leukaemia with 2chlorodeoxyadenosine(2cda): long term follow-up of the northwestern university. blood 2005; 106:241-246. 29. capnist g, federico m, chisesi t, resegotti l, lamparelli t, fabris p, et al. long term results of interferon treatment in hairy cell leukaemia: italian cooperative group of hairy cell leukaemia (icghcl). leuk lymphoma 1994; 14:457-464. 30. hoffbrand av, catovsky dc, tuddenham egd. postgraduate haematology. 5th ed. oxford: blackwell publishing, 2005. p. 639. 31. golomb hm, vardiman jw. response to splenectomy in 65 patients with hairy cell leukaemia: an evaluation of spleen weight and bone marrow involvement. blood 1983; 61:349-352. department of general surgery, kasturba medical college, manipal academy of higher education, manipal, india corresponding author’s e-mail: gabyrodricks@gmail.com primary ‘false’ enterolith a rare cause of small bowel obstruction radhika salpekar, shrividya rao, chiranth gowda, *gabriel rodrigues sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 587–588, epub. 7 nov 22 submitted 23 may 21 revision req. 25 jul 21; revision recd. 29 aug 21 accepted 29 sep 21 a 72-year-old male who had undergone an open cholecystectomy (uncomplicated with normal small bowel) for calculous cholecystitis in 1999, presented in 2021 at a tertiary care medical college hospital with colicky abdominal pain, bilious vomiting, distension and obstipation (in that order) lasting for four days. a general examination revealed tachycardia and dehydration and perabdominal examination showed a diffusely distended abdomen with no signs of peritonitis. bowel sounds were absent and digital rectal examination revealed a collapsed rectum. a clinical diagnosis of postoperative adhesive small bowel obstruction was made. the blood counts, liver and renal function tests were all normal. an erect abdomen x-ray showed multiple small bowel air-fluid levels and a collapsed large bowel with no cause of obstruction [figure 1a]. hence, a contrast enhanced computed tomography scan of the abdomen was done, which revealed a radio-opaque lesion in the distal ileum with proximally dilated, fluid-filled bowel loops [figure 1b]. there was no pneumoperitoneum or signs of bowel ischaemia. as the patient had dynamic bowel obstruction, he underwent an emergency exploratory laparotomy. intraoperatively, there was a hard, movable lesion in the distal ileum that could not be milked across the ileocaecal valve. hence, an enterotomy was done. a stony hard mass was extracted, proximal bowel decompressed and the enterotomy was closed [figure 2]. rest of the abdominal cavity was normal. postoperatively, he made a good recovery and on follow-up after a year, he appeared to be well. the histopathology of the mass was reported to be an enterolith containing vegetable matter intermingled with calcium. informed consent was obtained from the patient for the publication of the images. comment enteroliths are uncommon entities in the gastrointestinal tract and can be primary or secondary.1,2 the uncommon primary enteroliths, occurring in the small intestine and causing subacute to acute obstruction, are composed of either bile salts, phosphates or calcium oxalate. secondary enteroliths are due to cholelithiasis and present as gallstone ileus.2 while the primary enteroliths are usually located in the proximal small bowel, secondary enteroliths are preferentially found in the distal small bowel owing to the differential acid composition in these regions. existing literature further describes enteroliths as being true (precipitation of intestinal contents) or false (concretion of indigestible materials such as hair and vegetable matter).1,2 stasis of intestinal contents is the major pathophysiology, with aetiologies varying from both benign (infectious or inflammatory) and malignant strictures, congenital or acquired diverticulae and neoplastic growths obstructing the intestinal lumen.2 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.10.2021.143 interesting medical image figure 1: (a) erect abdomen x-ray showing multiple small bowel air-fluid levels; (b) contrast enhanced computed tomography scan of the abdomen showing a radio-opaque lesion obliterating distal small intestinal lumen (arrow). https://creativecommons.org/licenses/by-nd/4.0/ primary ‘false’ enterolith a rare cause of small bowel obstruction 588 | squ medical journal, november 2022, volume 22, issue 4 bile acid-containing stones are classically radiolucent, while calcium-containing are radio-paque. variable imaging features make preoperative diagnosis often difficult and a final diagnosis can be made only at laparotomy for a patient with intestinal obstruction.3 while few stones can be crushed and milked into the large bowel from the distal small intestine, as described for gallstone ileus, larger impacted stones necessitate an enterotomy and extraction. furthermore, complications such as perforation necessitate additional surgical interventions in the form of resection and anastomosis.4 a u t h o r s’ c o n t r i b u t i o n rs and gr conceptualised and designed the work. rs conducted the literature review. sr collected and analysed the data as well as drafted the manuscript. cg and gr reviewed and edited the manuscript. all authors approved the final version of the manuscript. references 1. yadav g, husain s, shukla r, patidar r, luthra r. a rare case of calcified enterolith presenting as subacute intestinal obstruction. indian j surg 2015; 77:327–8. https://doi.org/10.1007/s12262015-1289-5. 2. d’souza c, bhagavan kr, sunil h, mohan r. unusual case of subacute intestinal obstruction due to eosinophilic enteritis with enteroliths. ann trop med public health 2010; 3:83–5. https://doi.org/10.4103/1755-6783.77198. 3. brettner a, euphrat ej. radiological significance of primary enterolithiasis. radiol 1970; 94:283–8. https://doi.org/10.1148/9 4.2.283. 4. kappikeri vs, kriplani am. subacute intestinal obstruction by enterolith: a case study. springerplus 2016; 5:1464. https://doi. org/10.1186/s40064-016-3150-0. figure 2: intraoperative images showing (a) enterotomy and lesion extrusion and (b) enterotomy closure in the abdominal cavity. https://doi.org/10.1007/s12262-015-1289-5 https://doi.org/10.1007/s12262-015-1289-5 https://doi.org/10.4103/1755-6783.77198 https://doi.org/10.1148/94.2.283 https://doi.org/10.1148/94.2.283 https://doi.org/10.1186/s40064-016-3150-0 https://doi.org/10.1186/s40064-016-3150-0 1department of family medicine and public health, sultan qaboos university hospital, muscat, oman; 2department of dermatology, jewish general hospital, mcgill university, montreal, canada *corresponding author’s e-mail: a.alkhalili@hotmail.com linear pigmented purpuric dermatoses ayida al khalili1 and robin billick2 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 593–594, epub. 7 nov 22 submitted 20 sep 21 revision req. 21 nov 21; revision recd. 15 dec 21 accepted 6 jan 22 a 65-year-old female patient presented to a dermatology clinic in montreal in 2014 with slowly progressing asymptomatic pigmentation in both legs. the condition had lasted for the past few years since the time of presentation. patient denied any pigmentation elsewhere. there was no history of chronic use of medications or application of medicated creams and the eruption was also not related to sun exposure. the patient had experienced two episodes of lower extremity superficial thrombophlebitis at ages 20 and 50, for which she subsequently underwent varicose vein ligation and stripping of the left lower extremity. the patient’s medical history also included ulcerative colitis on therapy with mesalazine retention enema and surgically treated renal cell carcinoma. a skin examination revealed linear arrangement of brown, muddy, non-palpable and non-blanchable macules and patches located in the popliteal fossa, bilaterally extending to the thighs. similar macules were seen on both shins scattered with no particular pattern (cayenne pepper appearance) [figure 1]. varicose veins and pitting oedema were also noted and peripheral pulses were easily palpated. the differential diagnoses included pigmented purpuric dermatoses (ppd), diabetic dermatopathy, medication-induced pigmentation and purpuric contact dermatitis. the patient’s complete blood count and coagulation profile were both normal. two skin biopsies were obtained and the histopathology revealed superficial perivascular polymorphous dermatitis with erythrocyte extravasation and hemosiderin deposits. this was consistent with schamberg’s purpura and lichenoid lymphocytic infiltrate with grenz zone and hemosiderin deposition more consistent with lichen aureus [figure 2]. there was no evidence of degeneration in the basal layer of the epidermis. based on the clinical and histological characteristics, a diagnosis of linear ppd most likely due to venous hypertension was made. patient consent was obtained for the publication of these images. comment ppd are a group of chronic relapsing benign cutaneous entities of unknown aetiology that share similar clinical patterns and histological features.1 they generally present as red to purple macules that progressively coalesce and evolve into a golden-brownish colour usually affecting lower extremities. capillaritis with dilated blood vessels, extravasation of erythrocytes, hemosiderin deposition in papillary dermis and perivascular lymphocytic infiltrate are the histological hallmarks of all ppd.1 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.1.2022.004 interesting medical image figure 1: photograph of (a) brownish non-palpable macules and patches arranged bilaterally in a linear distribution on the back of the legs, with macules on the left leg extending into the posterior thigh. prominent varicose veins can also be noted, (b) the magnified linear distribution of the eruption affecting the left leg probably following deep venous system and (c) similarly scattered macules distributed across both shins. https://creativecommons.org/licenses/by-nd/4.0/ linear pigmented purpuric dermatoses 594 | squ medical journal, november 2022, volume 22, issue 4 there are five major clinical variants: schamberg’s disease (the most common of all presentations), pigmented purpuric lichenoid dermatosis of gougerot and blum, purpura annularis telangiectodes of majocchi, eczematid-like purpura of doucas and kapetanakis and lichen aureus.1,2 most ppd are idiopathic, however some are associated with medications or systemic diseases. moreover, predisposing factors that might influence the disease presentation are venous hypertension, exercise and gravitational dependency, capillary fragility, focal infections and chemical ingestion.1,2 linear ppd have been reported previously as a rare form of ppd, even presenting in a unilateral pattern.3,4 the linear array could be blaschkolinear, pseudo-dermatomal or following a deep venous system.3,5 in the current case, it was bilaterally distributed and probably following the deep venous system loosely corresponding to the small saphenous vein. interestingly, the histopathology showed features of both schamberg’s disease and lichen aureus. currently, there is no standard therapy for ppd.6 in asymptomatic patients, conservative management is preferred. other topical and oral therapeutic options can also be tried with a variable response.2 a u t h o r s’ c o n t r i b u t i o n aak was involved in data collection, drafting the manuscript, organising article sections, literature review and agreed to be the corresponding author for this article. rb was involved in helping draft the manuscript, interpretation of data, reviewing the content of the article and approving the version of the article to be published. all authors approved the final version of the manuscript. references 1. sardana k, sarkar r, sehgal vn. pigmented purpuric dermatoses: an overview. int j dermatol 2004; 43:482–8. https://doi.org/10.1 111/j.1365-4632.2004.02213.x. 2. spigariolo cb, giacalone s, nazzaro g. pigmented purpuric dermatoses: a complete narrative review. j clin med 2021; 10. https://doi.org/10.3390/jcm10112283. 3. ruiz-esmenjaud j, dahl mv. segmental lichen aureus: onset associated with trauma and puberty. arch dermatol 1988; 124:1572–4. https://doi.org/10.1001/archderm.1988.01670100070024. 4. taketuchi y, chinen t, ichikawa y, ito m. two cases of unilateral pigmented purpuric dermatosis. j dermatol 2001; 28:493–8. https://doi.org/10.1111/j.1346-8138.2001.tb00018.x. 5. hoesly pm, cappel ma, sluzevich jc. persistent dermatomal eruption on a leg. dermatol online j 2019; 25:13030/qt2k49 w08d. https://doi.org/10.5070/d32510045824. 6. plachouri km, florou v, georgiou s. therapeutic strategies for pigmented purpuric dermatoses: a systematic literature review. j dermatol treat 2019; 30:105–9. https://doi.org/10.108 0/09546634.2018.1473553. figure 2: haematoxylin and eosin stains at (a) ×40 magnification showing dermal licheniod lymphocytic infiltrate with grenz zone with hemosiderin deposition and no evidence of degeneration in the basal layer of the epidermis and (b) ×200 magnification showing polymorphous perivascular infiltrate with prominent hemosiderin deposition. https://doi.org/10.1111/j.1365-4632.2004.02213.x https://doi.org/10.1111/j.1365-4632.2004.02213.x https://doi.org/10.3390/jcm10112283 https://doi.org/10.1001/archderm.1988.01670100070024 https://doi.org/10.1111/j.1346-8138.2001.tb00018.x https://doi.org/10.5070/d32510045824 https://doi.org/10.1080/09546634.2018.1473553 https://doi.org/10.1080/09546634.2018.1473553 abstract: objectives: the aim of the current study was to describe covid-19’s epidemiological characteristics in oman during the initial stages of the outbreak and compare findings with other countries’ reports. methods: data were drawn from a descriptive, records-based review of reported cases of covid-19 collected through the national covid-19 surveillance system from february to april 2020. results: a total of 2,443 confirmed cases were reported during the study period. the overall first-time testing rate for this period was 851.7 per 100,000, the positivity rate was 53.1 (confidence intervals [ci]: 51.0–55.2) and the death rate was 0.32 (ci: 0.20–0.54) per 100,000 population, respectively. the overall national positive ratio was 5.7% and ranged from 2.2–7.1% across various governorates. muscat governorate had the highest positive ratio (12.5%). people in the 51–60 year old age group (rr = 1.97), males (rr = 1.24), non-omanis (rr = 2.33) and those living in muscat (rr = 2.14) emerged as categories with significant demographic risk for covid-19 cases when compared to the national average. the mean age was 35.6 ± 13.4. asymptomatic cases accounted for nearly 16%. conclusion: the overall rate of covid-19 cases and deaths were low in oman compared to the rest of the world during the study period. keywords: coronavirus; covid-19; sars-cov2; epidemiology; pandemic; oman. epidemiological characteristics of pandemic coronavirus disease (covid-19) in oman bader al-rawahi,1 *prakash k. p.,1 adil al-wahaibi,1 amina al-jardani,1 khalid al-harthy,1 padmamohan j. kurup,1 ali al-moqbali,2 mohammad al-tubi,3 zayid al-mayahi,4 amal al-maani,1 seif al-abri1 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e195–202, epub. 21 jun 21 submitted 31 aug 20 revisions req. 7 oct & 10 nov 20; revisions recd. 17 oct & 19 nov 20 accepted 24 nov 20 directorate general of diseases surveillance & control, ministry of health, 1muscat and 2sohar, oman; department of disease surveillance and control, ministry of health, 3nizwa and 4rustaq, oman *corresponding author’s e-mail: drprakashkp@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.007 clinical & basic research advances in knowledge this study showed the incidence of covid-19 and the resulting death rate is low in oman compared to the rest of the world. this study also identified the various high-risk groups, such as the elderly, those with co-morbidities, the expat population and those living in certain geographic areas, associated with the increased risk of having covid-19 infection in oman. application to patient care incidence, positivity and death rates help assess the magnitude of the covid-19 problem in oman. improved understanding of incidence rates and positive-to-negative ratio of covid-19 in oman can prompt resource allocation and preparedness activities. gender, nationality and governorate analysis help in allocating resources and contribute to implementing prevention and lockdown strategies. epidemiological information will aid in establishing covid-19 patient care centres and quarantine strategies. clinical presentations will help modify case definitions and the application of infection control measures accordingly. coronaviruses are a group of related ribonucleic acid (rna) viruses present in mammals, birds and bats, with bats being particularly known as reservoirs of sars-like coronaviruses. these viruses can cause respiratory tract infections that range from mild to severe in humans. several coronaviruses—229e, hku1, nl63 and oc43—are known to cause mild respiratory disease like the common cold among humans.1 however, the recently detected sars-cov (2002) and mers-cov (2012) viruses have been known to cause severe acute respiratory syndrome and community and healthcare setting outbreaks.2 the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was first identified in wuhan city in china’s hubei province. the world health organization (who) designated the disease as covid-19.3 it spread rapidly, resulting in an epidemic within china, and later spread to other countries. the l type of sars-cov-2 predominated during the early days of the epidemic in china within the wuhan city boundaries.4 the virus has shown an affinity for cell entry through the angiotensinconverting enzyme 2 (ace2).5 the who declared the outbreak a public health emergency of international concern on 30 january 2020 and on march 11, it was declared a pandemic.3,6,7 as per an 11 may 2020 situation report, nearly four million cases had been reported across 187 countries and territories, resulting in more than 279,000 deaths worldwide. globally, the case fatality rate was 3.4% of reported covid-19 cases. at the time of writing, the european region had the highest number of cases followed by the americas. the usa had the greatest https://creativecommons.org/licenses/by-nd/4.0/ epidemiological characteristics of pandemic coronavirus disease (covid-19) in oman e196 | squ medical journal, may 2021, volume 21, issue 2 number of cases (1.2 million) and 76,916 deaths.8 worldwide numbers varied by region and country and were influenced by the volume of testing, healthcare system quality, treatment options, time since initial outbreak and population characteristics. the first case was confirmed in oman on 24 february 2020 when two citizens tested positive for covid-19 after returning from iran. the main objective of this article is to describe the epidemiological characteristics of covid-19 during the study period of the pandemic and compare the findings with other countries to facilitate prevention and control measures. methods this record-based description reports covid-19 cases occurring throughout oman between 1 february and 30 april 2020. a person with laboratory confirmation of the sars-cov2 virus causing covid-19 infection, irrespective of clinical signs and symptoms, was considered a confirmed case. all epidemiological and clinical events related to covid-19 patient characteristics such as age, gender, nationality, clinical features and geographic distribution were considered. the data were collected electronically as part of oman’s ministry of health’s national covid-19 surveillance system. standard case definitions were used and all cases were included without any exclusion criteria. all serious events, including clusters, were investigated within a realistic timeframe. cases were entered into the electronic system by doctors, nursing staff, regional epidemiologists and/ or public health staff on possible exposures along with epidemiological investigations. comorbid conditions were recorded as self-reported patient medical history. disease severity was classified as mild/moderate, severe or critical based on the clinical and laboratory findings.9 the voluntarily reported start of symptoms of either fever and/or cough, based on the date of onset, was used to draw the epidemiological curve. cases in oman were categorised by province. asymptomatic cases were defined as people not showing any covid-19 symptoms such as fever and respiratory symptoms and were identified largely through close contact screening. respiratory samples were collected from all suspected cases by trained health care personnel and placed immediately into a sterile transport tube containing 2–3 ml of viral transport medium or universal transport medium. the sample was immediately stored at a 2–8˚c cold chain and transported within 24–72 hours to the central public health laboratory in muscat. the samples then went through reverse transcription polymerase chain reaction (rt-pcr) testing using different kits following an extraction and amplification process. microsoft excel (microsoft, redmond, washington, usa) was used for data compilation and analysis was performed using statistical package for the social sciences (spss), version 21.0 (ibm, corp., armonk, new york, usa). oman’s estimated 2018 population was used to calculate the average annual population-based rates for different variables.10 mean ± two standard deviations (sd) was calculated for continuous variables such as age. positivity rate was recorded as positive cases per 100,000 population. the positive ratio was considered the number of positive cases divided by the number tested. case fatality rates (proportion, %) were calculated as the total number of deaths divided by the total number of cases. using the national average as a reference, the confidence interval (ci) for the difference between proportions calculated was used to compare the group variables and relative risk (rr). additionally, a 95% ci was also calculated using the following website: https://www.pedro.org.au/ wp-content/uploads/cicalculator.xls. an rr >1 was considered statistically significant. the director general for disease surveillance and control of the ministry of health of oman approved the study. results in total, 41,831 suspected cases were identified through oman’s national covid-19 surveillance system during the study period. a total of 1,220 (2.9%) samples were excluded from the analysis because they did not meet the case definition for testing. in total, 2,656 samples (6.5%) were identified for repeat testing. of the 39,195 non-repeat samples tested, the positive ratio was 5.7%. the majority, 94.2%, tested negative for sars-cov-2 ribonucleic acid (rna) by polymerase chain reaction (pcr). inconclusive results were seen in 0.1% of suspected cases. the overall first-time testing rate (excluding repeat testing for the same patient) for this period was 851.7, and the positivity rate was 53.1 (ci: 51.0–55.2). the death rate from covid-19 was 0.32 (ci: 0.20– 0.54) per 100,000 total population. the testing covered nationals and non-nationals from 97 countries with the majority of the non-nationals being working residents from asian countries. the positive ratio was higher (13.3%) among non-nationals compared to the omani population (2.8%). the positive ratio according to the international organization for standardization (iso) week number bader al-rawahi, prakash k. p., adil al-wahaibi, amina al-jardani, khalid al-harthy, padmamohan j. kurup, ali al-moqbali, mohammad al-tubi, zayid al-mayahi, amal al-maani and seif al-abri clinical and basic research | e197 and governorate from the beginning of the outbreak is shown in figures 1 and 2. as shown in figure 1, the positive ratio started to peak during week 10 and reached around 6.9% by week 16. the positive ratio ranged from 0.7–12.5% in different governorates. muscat governorate had the highest positive ratio (12.5%), whereas the lowest was in buraimi (0.7%). of the total tested samples, 87.9% and 12.1% were tested within 24 hours and two days of sample collection, respectively. the results were reported within 24 hours from receiving samples in 84.7% of cases, within two days in 11.6% of cases and after two days in 3.7% of cases. a total of 2,443 covid-19 (sars-cov-2 rna by pcr) confirmed cases were reported during the study period from 40,611 suspected tested cases reported through the covid-19 surveillance system. the male-to-female ratio was 3.9:1. the frequency distribution of cases by age, gender and governorate is shown in table 1. the maximum number of cases were among those aged 31–40 years (36.2%), followed by 21–30 (24.2%) and 41–50 years (17.7%). males (79.6%), non-omanis (61.5%) and people from the muscat governorate (71.5%) were the most commonly affected groups. the reporting rate was significantly higher among those in the 31–70-year-old age groups (73.1–85.4/100,000 population) compared with the national average (53.1/100,000 population). certain populations, such as those in the 51–60 year old age group (rr = 1.33, 95% ci: 1.09–1.61), males (rr = 1.24, 95% ci: 1.17–1.32), non-omanis (rr = 2.33, 95% ci: 2.19–2.47) and those living in muscat (rr = 2.14, 95% ci: 2.02–2.27) emerged as significant risk demographic categories for covid-19 cases in oman when compared to the national average [table 1]. the frequency age (years) distribution of covid-19 cases in oman indicates that middle aged individuals were most commonly affected at the time of writing. the mean and median ages were 35.6 ± 13.4 years and 34.0 years, respectively. table 2 depicts the number of covid-19 cases according to clinical features. asymptomatic individuals accounted for 16% of the cases in oman. the most common symptoms were fever, cough, sore throat and/or runny nose. fever and cough were reported in about 55% of the symptomatic cases each. gastrointestinal symptoms such as nausea, vomiting, abdominal pain, diarrhoea and constipation were seen figure 1: covid-19 testing positivity ratio by the international organisation for standardisation (iso) week number in oman between february and april 2020. figure 2: covid-19 testing positivity rates by governorate in oman between february and april 2020. epidemiological characteristics of pandemic coronavirus disease (covid-19) in oman e198 | squ medical journal, may 2021, volume 21, issue 2 in about 2.4% of cases. anosmia (loss of smell and taste) was present in 2.0% of the cases. of the total covid-19 cases reported, 7% (171/2,443) had a history of travel to affected countries. this finding was common at the beginning of the outbreak and before the restrictive travel guidelines were enacted. nearly 34% (n = 830) had a history of travel to the uk followed by the united arab emirates (n = 357; 14.6%), the usa (6.4%), iran (6.4%), saudi arabia (5.3%), pakistan (4.7%) and tanzania (4.1%). table 1: descriptive statistics of covid-19 cases according to age, gender, nationality and governorate in oman bet ween february and april 2020 variable covid-19 cases per 100,000 total populationa covid -19 cases per 1,000 samples tested sars-2 test result rr (95% ci) positive negative % total positive age in years 1–10 11.1 14.1 87 6083 3.6 0.22 (0.18–0.28) 11–20 16.7 31.2 84 2610 3.4 0.50 (0.40–0.62) 21–30 55.9 62.4 592 8890 24.2 1.00 (0.92–1.10) 31–40 73.1 76.4 885 10692 36.2 1.23 (1.14–1.33)* 41–50 73.9 82.3 432 4816 17.7 1.33 (1.20–1.46)* 51–60 84.4 108.8 228 1867 9.3 1.97 (1.73–2.24)* 61–70 85.4 82.4 96 1069 3.9 1.33 (1.09–1.61)* 71–80 59.6 42.8 30 671 1.2 0.69 (0.48–0.98) ≥81 32.9 27.4 9 283 0.4 0.42 (0.22–0.81) gender male 65.4 77.2 1944 23249 79.6 1.24 (1.17–1.32)* female 30.7 34.9 499 13780 20.4 0.56 (0.51–0.62) nationality omani 36.5 32.4 941 28123 38.5 0.52 (0.48–0.56) nonomani 74.3 144.3 1502 8906 61.5 2.33 (2.19–2.47)* governorate muscat 120.1 132.7 1747 11422 71.5 2.14 (2.02–2.27)* south batinah 59.4 54.8 253 4363 10.4 0.88 (0.78–1.00) south sharqiyah 39.5 58.3 125 2018 5.1 0.94 (0.79–1.12) dakhiliyah 23.7 21.1 112 5185 4.6 0.34 (0.28–0.41) north batinah 12.2 12.3 94 7540 3.8 0.19 (0.16–0.24) dhahira 22.2 31.9 49 1489 2.0 0.51 (0.38–0.67) north sharqiyah 11.8 15.9 33 2043 1.4 0.20 (0.63–0.81) dhofar 3.7 8.9 17 1887 0.7 0.14 (0.08–0.23) musandam 11.1 9.1 5 546 0.2 0.14 (0.06–0.35) buraimi 4.3 18.1 5 271 0.2 0.29 (0.12–0.69) al wusta 6.3 11.2 3 265 0.1 0.18 (0.05–0.55) total 53.1 61.9 2443 37029 100 rr = relative risk, ci = confidence interval. a2018 population estimate. *statistically significant. bader al-rawahi, prakash k. p., adil al-wahaibi, amina al-jardani, khalid al-harthy, padmamohan j. kurup, ali al-moqbali, mohammad al-tubi, zayid al-mayahi, amal al-maani and seif al-abri clinical and basic research | e199 others had travelled to various asian, middle eastern and european countries. the majority of the patients’ occupational information was not available (83%). migrant resident labourers who were living in company accommodations or together in densely populated spaces or who operated small businesses in crowded designated marketplaces, such as the souq in the muttrah district of muscat governorate, represented the majority of cases. healthcare workers directly or indirectly involved in hospital care settings (clinics, hospitals, pharmacy, laboratory, etc.) accounted for 2.5% (62/2,443) of the cases. nearly all patients were advised to quarantine at home, followed by institutional (3.7%) and hospital (0.8%) quarantine. in the majority of cases, the place/ source of contact was not known (59.3%). the place of contact with known covid-19 cases was in workplaces (12.9%) followed by among family contacts (12.3%). the outbreak in oman started when the first imported case—an individual with a history of travel to iran—was diagnosed on 2 february 2020. while the epidemic curve peaked in april 2020 [figure 3], the number of cases remained constant throughout april. of the covid-19 patients, 7% approximately (n = 172) had comorbidities. however, 36.6% (n = 894) of recorded cases included no information on associated illnesses. of the comorbid conditions, hypertension (htn) accounted for 21.2% (n = 518) and diabetes mellitus (dm) for 18% (n = 440) and dm and htn coexisted in 25.5% of cases (n = 623). eleven patients were pregnant at the time of diagnosis. cancer as well as renal and cardiac disease each coexisted in about 2% of cases (n = 49 each). a total of 15 deaths occurred among the 2,443 confirmed cases at the time of writing. the overall case fatality rate was found to be 0.61% or 0.32 per 100,000 population. discussion a highly infectious disease, covid-19 spread very quickly, taking only 30 days to be transmitted from hubei to the rest of mainland china and then throughout the world within the next couple of months. in oman, as per ministry of health policy, the notification of all priority infectious diseases within 24 hours, including rare and novel infections, is mandatory.11 the covid-19 reporting rate per 100,000 population was 53.1. the reporting rates were significantly higher among the 31–70-year-old age groups, males, non-omanis and those living in the muscat governorate. given that covid-19 is a new disease, there is not enough published scientific data to compare with other countries as per the population rates at this point in time. the incidence of covid-19 figure 3: confirmed covid-19 cases by date of onset in oman between february and april 2020. table 2: distribution of covid-19 cases according to the type of clinical presentation in oman february to april 2020 type of clinical findings clinical findings n (%) asymptomatic 391 (16.0) symptomatic* 2052 (84.0) fever 1148 (55.9) cough 1135 (55.3) shortness of breath 113 (5.5) other respiratory symptoms (i.e. sore throat, running nose, sneezing) 958 (46.7) general symptoms (i.e. headache, myalgia, fatigue) 260 (12.7) gastrointestinal symptoms (i.e. nausea, vomiting, diarrhoea, abdominal pain) 50 (2.4) anosmia (i.e. loss of smell and taste) 42 (2.0) others (i.e. renal, cardiac diseaserelated) 5 (0.2) *these numbers exceed 100% because each patient can have more than one symptom. epidemiological characteristics of pandemic coronavirus disease (covid-19) in oman e200 | squ medical journal, may 2021, volume 21, issue 2 which is confirmed based on rapid testing(rt-) pcr is influenced by the testing countries’ criteria and guidelines. in a passive surveillance system, under-reporting can be an important factor and the true extent of the spread of the disease can only be known by the seroprevalence studies using antibody testing. seroprevalence studies in iran and california have shown a higher prevalence than reported in this study.12,13 similar to studies from china, the middle-aged population (aged 31–70 years) in oman was more commonly affected by covid-19 compared to children and young adults.14,15 the infection rates were low (0.8%–4.0%) among children and young adults in turkey which is comparable to the current study.16 the positive ratio varied according to the iso week [figure 1]. this wide variation and decrease or increase in trend is because of testing policy change during these periods such as lockdown, case definition changed by the policy makers. the number of covid-19 cases was significantly higher among males than females and this is similar to a report from china.9 in the current study, 16% of the sars-cov2 positive patients were asymptomatic. a similar observation was made in studies by chinese researchers.16,17 in the diamond princess cruise ship study in japan, asymptomatic cases accounted for 18% of those tested.18 however, according to two chinese studies, the asymptomatic infection rate was 5% and 1%, which is low compared to the current study.15,19 asymptomatic cases in oman resulted from familial clusters or institutional outbreaks. a large number of migrant workers live in company accommodations (camps) similar to the setting reported by the study of zhang et al.20 this variation in asymptomatic cases is due to the testing policy and the demographic characteristics of the country’s population. in oman, nearly 44% of residents are part of the expatriate working population and are largely middle aged and residing in muscat governorate. crowded living conditions and the presence of this demographic could explain the greater number of covid-19 cases from muscat governorate and in non-omanis. additionally, some healthcare facilities tested all close contacts of confirmed sars-cov2 cases irrespective of signs and symptoms. the overall global case fatality rate was 6.3% as per the world health organization (who) situation report.21 however, the mortality rates varied between countries.8 it was noted that the rate was higher in countries with a higher proportion of older individuals. in italy, the median age of those who died was 78 years, whereas the median age of omani cases was 62.22 in turkey, the case fatality rate is 2.1%. hence, covid-19 mortality is multifactorial. the presence of underlying disease or healthcare burden and age demographics could be related to higher mortality rates.23 a meta-analysis reported that common comor bidities like htn, cardiovascular disease, dm, smoking, chronic obstructive pulmonary disease, malignancy and chronic kidney disease were associated with covid-19 morbidity and mortality.14,24,25 similarly in the current study, the most common comorbidity was htn (21.2%), followed by dm (17%) and cardiovascular diseases (11.9%), which is a similar finding to numerous studies.24,26,27 the most common symptoms in this study included fever (55.9%) and cough (55.3%); these symptoms are similar to those found in other viral respiratory diseases. however, the presentation of myalgia, sore throat, nausea, vomiting and diarrhoea may suggest other coexisting infections. viral respiratory coinfection was found to be rare.24,28–32 the outbreak resulted in an unprecedented chain of events in oman in terms of prevention and control measures such as cancellation of air travel, restriction of people’s movements and closure of nonessential services and places of mass congregation. the pandemic has also caused healthcare delivery and communicable disease surveillance and control systems to be stretched to the limit. many other risk factors for covid-19 such as comorbidity and occupation were not studied due to limitations around the availability of detailed data in the initial stages of the pandemic. it is anticipated that the current study’s results reflect the true picture and scale of the pandemic covid-19 outbreak in oman. these findings will help determine future courses of action and guidelines in controlling and/or preventing future epidemics in oman. because the covid-19 outbreak has yet to end, updates should be closely monitored including the disease and risk factors as well as treatment options. conclusions this study described the epidemiological charact eristics during the initial phase of the covid-19 pandemic in oman. fortunately, the disease rate and mortality are low in oman and the majority affected are asymptomatic or have only mild symptoms, are middle-aged or are previously healthy people without any underlying chronic diseases. a c k n o w l e d g e m e n t s the authors are appreciative of all the doctors, nurses, laboratory staff and governorate public health staff who participated in the reporting and investigation of covid-19 cases. all the disease surveillance and bader al-rawahi, prakash k. p., adil al-wahaibi, amina al-jardani, khalid al-harthy, padmamohan j. kurup, ali al-moqbali, mohammad al-tubi, zayid al-mayahi, amal al-maani and seif al-abri clinical and basic research | e201 control staff at the national level and at the governorate level are thanked for the compilation of data. the researchers express their gratitude to all the private and non-moh organisations for actively contributing to surveillance system reporting. their sincere thanks also go to the information technology staff for their continuous support of the health information system. the following authors has also contributed to this work: fatma al-yaquobi,1 sulien al-khalili,1 samir shah,1 zeyana al-habsi,1 sabria al-marshoudi,1 abdullah al-manji,1 hanan al-kindi,1 azza alrashdi,1 intisar al-shukri,1 samira al-mahrooqi,1 weam nazer,1 lamia al-balushi,2 salim al-katheri,2 sultan al-busaidi,2 mahmood al-skaiti,2 nawal alshehhi,2 issam murqos,2 iyad omer,2 ahmed albalushi2. lastly, all those who have directly or indirectly contributed to this study deserve recognition and thanks. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. fung ts, liu dx. human coronavirus: host-pathogen inter action. annu rev microbiol 2019; 73:529–57. https://doi.org/10.1 146/annurev-micro-020518-115759. 2. bulut c, kato y. epidemiology of covid-19. turk j med sci 2020; 50:563–70. https://doi.org/10.3906/sag-2004-172. 3. world health organization. director-general's remarks at the media briefing on 2019-ncov 2. centers for disease control and prevention. 2019 novel coronavirus, wuhan, china. inform ation for healthcare professionals. from: www.cdc.gov/corona virus/2019-ncov/hcp/index.html accessed: nov 2020. 4. jin y, yang h, ji w, wu w, chen s, zhang w, et al. virology, epidemiology, pathogenesis, and control of covid-19. viruses 2020; 12:372. https://doi.org/10.3390/v12040372. 5. zhou p, yang xl, wang xg, hu b, zhang l, zhang w, et al. a pneumonia outbreak associated with a new coronavirus of probable bat origin. nature 2020; 579:270–3. https://doi. org/10.1038/s41586-020-2012-7. 6. world health organization. statement on the second meeting of the international health regulations (2005) emergency committee regarding the outbreak of novel coronavirus (2019-ncov). from: www.who.int/news-room/detail/30-012020-statement-on-the-second-meeting-of-the-internationalhealth-regulations-(2005)-emergency-committee-regardingthe-outbreak-of-novel-coronavirus-(2019-ncov) accessed: nov 2020. 7. world health organization. press release 11 march 2020. from: www.who.int/emergencies/diseases/novel-coronavirus-2019/ events-as-they-happen accessed: nov 2020. 8. world health organization. coronavirus disease (covid-19) situation report–112. from: www.who.int/docs/default-sour ce/coronav ir use/situation-rep or t s/20200511-cov id-19sitrep-112.pdf?sfvrsn=813f2669_2 accessed: nov 2020. 9. the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19)– china. china cdc weekly 2020; 2:113–22. from: weekly. chinacdc.cn/ en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a 8f51 accessed: nov 2020. 10. annual health report. demographic features, introduction chapter one. muscat: ministry of health, oman, 2018. pp. 1–10. 11. manual on communicable diseases manual. directorate general for disease surveillance and control (dgdsc), 2017, introduction chapter, 3rd ed. muscat: ministry of health, oman, 2017. pp. 14–34. 12. shakiba m, hashemi nazari ss, mehrabian f, rezvani sm, ghasempour z, heidarzadeh a. sero-prevalence of covid-19 virus infection in guilan province, iran. from: https://doi.org/1 0.1101/2020.04.26.20079244 accessed: nov 2020. 13. bendavid e, mulaney b, sood n, shah s, ling e, bromleydulfano r, et al. covid-19 antibody sero-prevalence in santa clara county, california. from: doi.org/10.1101/2020.04.14.20 062463 accessed: nov 2020. 14. yang j, zheng y, gou x, pu k, chen z, guo q, et al. prevalence of comorbidities in the novel wuhan coronavirus (covid-19) infection: a systematic review and meta-analysis. int j infect dis 2020; 94:91–5. https://doi.org/10.1016/j.ijid.2020.03.017. 15. wu z, mcgoogan jm. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72,314 cases from the chinese center for disease control and prevention. jama 2020; 7:1239–42. https://doi.org/10.1001/jama.2020.2648. 16. dong y, mo x, hu y, qi x, jiang f, jiang z, et al. epidemiology of covid-19 among children in china. pediatrics 2020; 145:e20200702. https://doi.org/10.1542/peds.2020-0702. 17. hu z, song c, xu c, jin g, chen y, xu x, et al. clinical characteristics of 24 asymptomatic infections with covid-19 screened among close contacts in nanjing, china. sci china life sci 2020; 63:706–11. https://doi.org/10.1007/s11427-0201661-4. 18. mizumoto k, kagaya k, zarebski a, chowell g. estimating the asymptomatic proportion of coronavirus disease 2019 (covid-19) cases on board the diamond princess cruise ship, yokohama, japan, 2020. euro surveill 2020; 25. https://doi.org/10.2807/15 60-7917.es.2020.25.10.2000180. 19. tian sj, hu n, lou j, chen k, kang x, xiang z, et al. charact eristics of covid-19 infection in beijing. j infect 2020; 80:401–6. https://doi.org/10.1016/j.jinf.2020.02.018. 20. zhang j, tian s, lou j, chen y. familial cluster of covid-19 infection from an asymptomatic. crit care 2020; 24:119. https://doi.org/10.1186/s13054-020-2817-7. 21. world health organization. coronavirus disease 2019 (covid-19) situation report–84. from: www.who.int/docs/default-source/ coronaviruse/situation-reports/20200413-sitrep-84-covid-19. pdf?sfvrsn=44f511ab_2 accessed: may 2020. 22. istituto superiore di sanità (2020). characteristics of covid-19 patients dying in italy (based on available data on april 2, 2020). from: www.epicentro.iss.it/en/coronavirus/bollettino/reportcovid-2019_2_april_2020.pdf accessed: nov 2020. 23. ji y, ma z, peppelenbosch mp, pan q. potential association between covid-19 mortality and health-care resource availability. lancet glob health 2020; 8:e480. https://doi. org/10.1016/s2214-109x(20)30068-1. 24. siordia ja jr. epidemiology and clinical features of covid-19: a review of current literature. jr j clin virol 2020; 127. https:// doi.org/10.1016/j.jcv.2020.104357. https://doi.org/10.1146/annurev-micro-020518-115759 https://doi.org/10.1146/annurev-micro-020518-115759 https://doi.org/10.3906/sag-2004-172 https://doi.org/10.3390/v12040372 https://doi.org/10.1038/s41586-020-2012-7 https://doi.org/10.1038/s41586-020-2012-7 https://doi.org/10.1016/j.ijid.2020.03.017 https://doi.org/10.1001/jama.2020.2648 https://doi.org/10.1542/peds.2020-0702 https://doi.org/10.1007/s11427-020-1661-4 https://doi.org/10.1007/s11427-020-1661-4 https://doi.org/10.2807/1560-7917.es.2020.25.10.2000180 https://doi.org/10.2807/1560-7917.es.2020.25.10.2000180 https://doi.org/10.1016/j.jinf.2020.02.018 https://doi.org/10.1186/s13054-020-2817-7 https://doi.org/10.1016/s2214-109x%2820%2930068-1 https://doi.org/10.1016/s2214-109x%2820%2930068-1 https://doi.org/10.1016/j.jcv.2020.104357 https://doi.org/10.1016/j.jcv.2020.104357 epidemiological characteristics of pandemic coronavirus disease (covid-19) in oman e202 | squ medical journal, may 2021, volume 21, issue 2 25. emami a, javanmardi f, pirbonyeh n, akbari a. prevalence of underlying diseases in hospitalized patients with covid-19: a systematic review and meta-analysis. arch acad emerg med 2020; 8:e35. 26. guan wj, ni zy, hu y, liang wh, ou cq, he jx, et al. clinical characteristics of 2019 novel coronavirus infection in china. n engl j med 2020; 382:1708–20. https://doi.org/10.1056/ nejmoa2002032. 27. huang c, wang y, li x, ren l, zhao j, hu y, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet 2020; 395:497–506. https://doi. org/10.1016/s0140-6736(20)30183-5. 28. zhao x, zhang b, li p, ma c, gu j, hou p, et al. incidence, clinical characteristics and prognostic factor of patients with covid-19: a systematic review and meta-analysis. from: www.medrxiv.org/content/10.1101/2020.03.17.20037572v1. full.pdf accessed: nov 2020. 29. woelfel r, corman vm, guggemos w, seilmaier m, zange s,\ mueller ma, et al. clinical presentation and virological assess ment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. from: https://www.med rxiv.org/content/10.1101/2020.03.05.20030502v1 accessed: nov 2020. 30. ai jw, chen j, wang y, liu x, fan w, qu g, et al. the crosssectional study of hospitalized coronavirus disease 2019 patients in xiangyang, hubei province. medrxiv 2020. from: https:// www.medrxiv.org/content/10.1101/2020.02.19.20025023v1 accessed: nov 2020. 31. chen x, zheng f, qing y, ding s, yang d, lei c, et al. epidemiological and clinical features of 291 cases with coronavirus disease 2019 in areas adjacent to hubei, china: a double-center observational study. from: https://www.medrxiv.org/content/10. 1101/2020.03.03.20030353v1 accessed: nov 2020. 32. lin d, liu l, zhang m, hu y, yang q, guo j, et al. co-infections of sars-cov-2 with multiple common respiratory pathogens in infected patients. sci china life sci 2020; 63:606–9. https:// doi.org/10.1007/s11427-020-1668-5. https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.1016/s0140-6736%2820%2930183-5 https://doi.org/10.1016/s0140-6736%2820%2930183-5 https://doi.org/10.1007/s11427-020-1668-5 https://doi.org/10.1007/s11427-020-1668-5 1national hyperbaric medicine center, the royal hospital, muscat, oman; 2department of family medicine, ministry of health, north al batinah, oman; 3department of family medicine & public health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: asmaa_9988@hotmail.com evaluating trauma care capabilities using the essential trauma care guidelines of the world health organization cross-sectional study of primary health centres in muscat, oman aisha al balushi,1 zaleikha al belushi,2 *asma a. al salmani3 clinical & basic research sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 58–64, epub. 28 feb 22 submitted 21 jul 20 revision req. 12 oct 20; revision recd. 9 nov 20 accepted 8 dec 20 https://doi.org/10.18295/squmj.4.2021.057 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to evaluate trauma care capabilities at the primary care level in muscat, oman, using world health organization guidelines. methods: this descriptive cross-sectional study was conducted between january and march 2015 at eight primary health centres in seeb. an english-language questionnaire was distributed to the medical officer or nurse in-charge at each centre to determine the number of staff, total population being served, number of emergency trauma cases and availability of ambulances. subsequently, 10 doctors from each health centre were randomly selected to assess the availability of physical resources as well as their trauma skills and knowledge. results: there were limited physical and human resources for the management of trauma and a complete absence of trauma administrative functions, such as local trauma registries or quality improvement activities. conclusion: this study highlighted the need to introduce national guidelines and improve the delivery of trauma services in oman. keywords: primary healthcare; trauma; emergency medicine; capacity building; health resources; delivery of health care; oman. advances in knowledge there is limited physical and human resources for the management of trauma cases in primary healthcare centres. there is a need for trauma administrative functions such as trauma registries. application to patient care evaluation of trauma capabilities in primary healthcare suggest that patients with serious trauma should be directed to a trauma centre. trauma is a major cause of death and disability worldwide, with the majority of preventable deaths occurring in primary care settings.1,2 in particular, road traffic crashes (rtcs) are a common yet avoidable cause of trauma and represent a considerable economical and logistical burden on the healthcare system.2 according to a report by the world health organization (who), the total number of rtc-related deaths worldwide was 1.35 million in 2018.3 moreover, the risk of dying due to a road traffic injury was highest in the african, south-east asian and eastern mediterranean regions at 26.6, 20.7 and 18 deaths per 100,000 individuals, respectively.3 in 2004, the who published a set of international guidelines for essential trauma care (etc), resulting in a checklist of 260 items outlining the personnel-related (i.e. training, skills and sufficient staffing) and physical (i.e. equipment and supplies) resources necessary for the delivery of high-quality trauma care.4,5 these guidelines provide a standardised template to assess trauma care capabilities in nations worldwide. various countries have since adopted these guidelines in an attempt to identify affordable and sustainable methods to strengthen their capabilities and improve national trauma systems.6,7 in oman, healthcare services are provided in a three-tiered-system at the primary (i.e. primary health centres providing both, acute and chronic care), secondary (i.e. regional referral hospitals) and tertiary care levels (i.e. tertiary referral hospitals and one university hospital in muscat, the capital city). in 2016, oman had a total of 108 primary care centres, of which 28 were located in muscat; however, the majority of these centres in oman do not have beds or intensive care units.8 each centre is staffed by a variety of healthcare personnel, including general practitioners (gps), nurses, dentists, laboratory technicians, pharmacists and paramedical staff.8 in terms of trauma management, primary health centres provide initial care and stabilisation before referring cases to secondary or tertiary hospitals.9 as with other gulf cooperation council countries, oman has a high rtc-related death rate with 16.1 deaths per 100,000 individuals.3 a recent pilot study also showed that the https://creativecommons.org/licenses/by-nd/4.0/ aisha al balushi, zaleikha al belushi and asma a. al salmani clinical and basic research | 59 distribution and quality of trauma centres in oman was inadequate in terms of their proximity to highincidence rtc sites.10 currently, no unified national guidelines regarding trauma treatment exist in oman, with each individual centre or hospital following its own policies based on different international guidelines. moreover, to the best of the authors’ knowledge, no studies on national trauma care capabilities have been conducted at the primary care level yet. this study, therefore, aimed to assess trauma care capabilities with regards to the who guidelines for etc at selected primary health centres in muscat.5 these findings may be useful in informing the planning and allocation of health resources in oman. methods this cross-sectional study was conducted from january to march 2015 at eight primary care centres in muscat governorate. overall, this governorate consists of six wilayats (counties); of these, seeb was selected because it was the most populated, had the highest speed limit compared to the other wilayats (120 km/hour) and had the greatest number of primary centres (n = 8). a convenience sample of 10 doctors of any nationality or specialty were recruited from each healthcare centre. three english-language data collection tools were used to evaluate the current status of trauma care capabilities at the selected primary care centres. the first tool was a structured seven-item questionnaire distributed to the medical officer or nurse in-charge at each health centre. the aim of the questionnaire was to determine general demographic information as well as the number of staff, total population being served, number of emergency cases (especially trauma cases) and availability of ambulances at each centre. the second tool consisted of a modified 32item version of the who etc checklist to assess the availability of equipment required for managing trauma cases.5 each item was rated from 0 to 3 as either not applicable at that level (n/a), absent but should be present (score of 0), inadequate (score of 1), partially adequate (i.e. present but not assured, consistently available or readily available; score of 2) or adequate (i.e. present and used appropriately; score of 3).5 the third tool consisted of a modified 15-item version of the who etc checklist to evaluate skills and knowledge regarding trauma emergency management among the sample of recruited doctors.5 in order to ensure the reliability of the responses, participants were advised not to discuss the questions among themselves to avoid peer influence. a pilot study was conducted in another wilayat in the same governorate in order to ensure the validity of the tools and the level of understanding of the rating scale. follow-up interviews with the medical officers and nurses incharge at each centre were also conducted to ensure their understanding of the rating scale as well as to cross-validate the collected data. the data analysis was performed using the statistical package for the social sciences (spss), version 25.0 (ibm corp., armonk, new york, usa). the results were presented using descriptive statistics. means and standard deviations were reported for continuous variables, while frequencies and percentages were reported for categorical variables. the association of the independent variables with the outcome variables was estimated using kruskalwallis and mann-whitney-u tests. the two-tailed significance level was set at p ≤0.050. ethical approval for this study was obtained from the research ethics committee of the directorate general of health services of the ministry of health in muscat. informed consent was obtained from the participants prior to taking part in the study. moreover, confidentiality of the collected data and anonymity of the participants was ensured at all times. results the total population being served at each centre ranged from 25,000–145,000 individuals. the number of patient visits ranged from 67,000–93,755 per year; of these, approximately 800–1,810 were emergency visits, including trauma cases [table 1]. in terms of the availability of physical resources for basic airway management and breathing, none of the health centres reported shortages of advanced airway breathing devices, including endotracheal tubes (75%), bag valve masks (63%) and laryngoscopes (63%). however, pulse oximeters were available at only three centres (38%) and none of the centres had arterial blood gas analysers, chest tubes, cricothyrotomy sets or ventilators [figure 1a]. with regards to equipment for circulation management, all centres had intravenous access sets and fluids (i.e. crystalloids); however, there was a lack of resources for venous surgical (25%) and interosseous access devices (13%) [figure 1b]. moreover, even where this equipment was available in two and one health centre, respectively, it had never been used. this was reported to be due to the lack of staff experience with such devices. in addition, there was a deficit of physical resources for basic trauma investigations. for example, evaluating trauma care capabilities using the essential trauma care guidelines of the world health organization cross-sectional study of primary health centres in muscat, oman 60 | squ medical journal, february 2022, volume 22, issue 1 each health centre had only one electrocardiography (ecg) machine which was deemed only partially adequate to meet demand due to frequent breakdown. moreover, although all of the centres had haemoglobin assays, only 13% reported this to be adequate, with 63% deeming this resource as only partially adequate because it was not available at all times. the availability of splints for fracture immobilisation was high; however, 58% of centres reported their availability to be only partially adequate. in addition, electrolyte assays, blood transfusion equipment and fluid warmers were not available at any of the centres. only 87% of the centres had adequate urinary catheters. while plain radiography technology was present in all centres, 75% reported it to be inadequate with a complete lack of portable x-ray machines. similarly, while all of the centres had ultrasound machines, these were not used for trauma investigation or treatment purposes. subsequently, 10 doctors at each health centre were surveyed to determine their skills in handling trauma cases. of the 80 doctors assessed, 66 (82%) were female and 14 (18%) were male. the majority were of omani nationality (81%). in terms of their medical certifications, 69% had a doctor of medicine degree, 14% had a bachelor of medicine and bachelor of surgery degree and 17% had a membership of the royal college of general practitioners qualification. in addition, 45% and 55% of the doctors were certified in basic life support and advanced cardiac life support, respectively. however, only one doctor had valid qualifications for paediatric advanced life support and advanced trauma life support (atls). a total of 46 doctors (58%) declared that they had previously taken part in trauma-related continuing medical education activities. in terms of basic airway management and breathing skills, most doctors were consistently able to administer supplemental oxygen (88%), perform chin lift/jaw thrust manoeuvres (71%), put patients in the recovery position (68%), perform assisted ventilation (68%), insert an oropharyngeal airway (52%) and perform a log roll (43%). however, very few were consistently able to practise endotracheal intubation (8%), perform needle thoracotomy (4%) or insert a chest tube (3%) [figure 2a]. critically, some of the doctors reported that they lacked any knowledge of how to perform a needle thoracostomy (18%) or a log roll (15%) or insert a chest tube (10%), while 1% could not put patients in the recovery position or insert an oropharyngeal airway [figure 2b]. regarding the doctors’ circulation management skills, the majority could consistently insert iv access devices (91%), monitor circulation (82%) and assess shock (79%). nevertheless, most were unable to use intraosseous vascular access devices or perform peripheral venous cutdown procedures, with the exception of five and three doctors, respectively. only four doctors (5%) were able to control external haemorrhage by deep wound packing or knew how to wrap potential pelvic fractures [figure 3]. basic orthopaedic skills (i.e. fracture immobilisation) were present in 47% of doctors; however, none could perform more advanced orthopaedic interventions. the majority of the doctors (82%) were familiar with the glasgow coma scale score and could recognise altered mental status. however, 10% did not know table 1: general status of primary health centres in seeb, muscat, oman (n = 8) indicator range doctors per health centre 11–16 specialists per health centre 2–3 nurses per health centre 14–20 ambulances* 0–6 patient visits per year 67,000–93,755 total population 25,000–145,000 emergency† visits per year 800–1,810 *ambulances covering seeb region and sent to specific health centres on demand. †comprising all emergency cases, including trauma. figure 1: frequency of availability of physical resources for (a) basic airway management and breathing and (b) circul ation management at primary health centres in seeb, muscat, oman (n = 8). o2 = oxygen. aisha al balushi, zaleikha al belushi and asma a. al salmani clinical and basic research | 61 how to monitor changes in gcs and 25% did not know how to perform a surgical thoracotomy or undertake surgical neck exploration. overall, 73 doctors (91%) were involved in the management of trauma cases; however, there was no specialised trauma registry or database for them to record the details or handling of these cases. moreover, 80% and 84% reported that their health centres did not have local trauma guidelines or manuals, respectively. finally, 72 participants (90%) reported that there were no trauma committees, trauma simulation activities, trauma rooms or alarm criteria in the health centres where they worked. discussion in most healthcare systems worldwide, trauma centres are designated at different levels according to their capacity to treat critically injured patients, with level i centres typically being considered most capable and level iii centres being least capable.9 generally, higherlevel trauma centres provide the greatest level of care and have access to specialised trauma surgeons (i.e. neurosurgeons and orthopaedic surgeons) and nurses as well as trauma-specific diagnostic equipment. in contrast, lower-level centres may only be able to provide limited initial care for patients with traumatic injuries (i.e. stabilisation), before arranging for the cases to be transferred to higher levels of care.9 according to the findings of the current study, the availability of physical resources for basic airway management was fairly good at the primary care level in oman, with none of the eight primary health centres reporting major deficiencies in advanced airway and breathing devices. similarly, the availability of intravenous access devices was adequate. however, most centres lacked the equipment needed for intraosseous and venous surgical access. in oman, primary care generalists usually undertake the initial assessment of trauma cases and then, if the necessary equipment for management is unavailable, transfer them to the nearest hospital or trauma centre for stabilisation. in fact, the medical officers and nurses incharge at centres in which intraosseous access devices were available admitted that this was because they had needed these devices in the past. this indicates that this type of equipment can be supplied to primary care centres if requested. while basic laboratory equipment such as haemoglobin tests were available at the primary health figure 2: frequency of (a) consistent knowledge and (b) complete lack of knowledge of basic airway management and breathing procedures among doctors working at primary health centres in seeb, muscat, oman (n = 80). o2 = oxygen; cl/jt = chin lift/jaw thrust; opa = oropharyngeal airway; et = endotracheal tube. figure 3: frequency of consistent knowledge of circulation management and other trauma management procedures among doctors working at primary health centres in seeb, muscat, oman (n = 80). pvc = peripheral venous cutdown; dwp = deep wound packing ; io = intraosseous; iv = intravenous. evaluating trauma care capabilities using the essential trauma care guidelines of the world health organization cross-sectional study of primary health centres in muscat, oman 62 | squ medical journal, february 2022, volume 22, issue 1 centres, electrolyte assays were not; in addition, all of the health centres lacked the physical resources and supplies necessary to perform blood transfusions. moreover, while ecg machines were available in all health centres, they were deemed inadequate because of frequent malfunctioning. plain radiography machines were present and widely used at all of the health centres, although there were some complaints that the equipment was non-portable. however, while ultrasonography facilities were available, this technology was not used for trauma investigation purposes. in addition, despite the presence of diagnostic equipment, such resources were considered either only partially adequate or inadequate by the respondents. as such, additional training of physicians regarding the use of radiological investigations and prioritising the maintenance of existing equipment to avoid frequent breakdowns would help reduce the number of referrals to trauma centres. in oman, primary care centres do not provide in-patient or specialised care and would, therefore, transfer trauma cases requiring such services to nearby hospitals or trauma centres. in addition, most members of the public are aware of the limited capabilities of care provided at primary centres and, in contrast, the availability of high-level services at trauma centres. moreover, emergency medical services are often the first point-of-care for critically injured patients and would transfer such patients immediately by ambulance to a trauma centre.9 these factors might thus partly explain the lack of availability of certain types of equipment in primary health care centres. nevertheless, in many trauma cases, immediate management can mean the difference between life or death.1,11 as such, it is important that necessary trauma equipment be provided to primary care centres for emergency situations in which timely transfer to a designated trauma centre is unfeasible or impossible. in the present study, the majority of the primary care doctors surveyed demonstrated adequate knowledge and skills concerning airway and breathing management. as such, this finding indicates that related equipment can be supplied to the centres so that doctors can stabilise trauma cases before referring them to a tertiary hospital. however, in-service handson courses should be provided to all generalists and staff working at these centres to ensure that all practitioners hold the necessary knowledge and skills to correctly utilise these resources. in contrast, gps or generalists in other countries are often not expected to perform specialised procedures such as endotracheal intubations. moreover, certain procedures, such as intravenous access, pelvic wrapping, logrolling and oxygen administration, would be performed by nurses more often. as such, further research should seek to determine the capabilities of nurses in trauma care in oman. early definitive treatment is a major determinant of outcome in cases of severe trauma; as such, the method and time period in which the patient is transported to a medical facility is key.1,5,11 while oman has had an emergency medical services (ems) system in place since 2004, previous research indicates that it may be underutilised for a variety of reasons.12,13 a retrospective study by al-shaqsi et al. found that only 66.7% of rtc-related trauma cases over a one-year period were transported by ambulance.13 however, the analysis showed that while there was a 36% reduction in mortality with ems-transported cases compared with those transported in private vehicles, this difference was not statistically significant (p = 0.13). the researchers also noted that the private transport of trauma patients was likely to continue and therefore recommended that members of the public undergo first aid training in order to reduce rates of related mortality and morbidity in oman.13 a systematic review and meta-analysis carried out in north america reported a 15% reduction in mortality among severely injured patients treated in trauma centres following the establishment of a trauma system.11 within this type of system, a trauma registry with severity scoring is a key component of quality improvement, outcome evaluation and monitoring the process of care; moreover, trauma registries are invaluable during healthcare policymaking, auditing and resource allocation.9,14,15 at most of the studied health centres, there was no specific register or database for trauma cases, although there was one for referred cases which indirectly showed the number of cases referred to trauma centres. with appropriate organisation, planning and the allocation of resources, the authors believe that most primary health centres in oman will be capable of delivering etc services, thus reducing the burden on trauma centres and tertiary hospitals. moreover, a set of national guidelines should be developed in order to standardise the provision of trauma care in oman. education is of paramount importance to the success of a national trauma care system, not only on the part of formal healthcare practitioners such as physicians and nurses, but also for members of the public. the who guidelines for etc highlight the importance of trauma training both during basic medical undergraduate and postgraduate education as well as via continuous education activities in order to update and maintain vital trauma-related knowledge and skills.5 moreover, if provided with education aisha al balushi, zaleikha al belushi and asma a. al salmani clinical and basic research | 63 in basic life support (bls), members of the public – including bystanders, family members or other nearby individuals with minimal medical training – can provide simple yet effective prehospital trauma care, thereby aiding the subsequent efforts of professional healthcare providers and potentially saving lives.16 this study was subject to certain limitations. while the study focused on physical resources, human resources and administrative functions related to etc and outcome measures were not assessed. in addition, the study was only carried out in muscat; as other regions of oman were not included, the results cannot be generalised to a national level. furthermore, the study focused primarily on doctors and did not include nurses. in oman, nurses are not required to be certified in advanced cardiovascular life support or atls, with bls certifications considered sufficient. therefore, doctors take the lead in trauma cases most often. therefore, further research is recommended to determine nurses’ trauma capability in oman as these individuals play an essential role in trauma care. finally, data regarding the etc skills and knowledge of the doctors working in primary care centres depended primarily on self-reported responses; this measure could be subjective and lead to participants overestimating or over-reporting their capabilities. as such, future quantitative and qualitative research to evaluate trauma care in oman is necessary. conclusion this study investigated the trauma care capabilities of eight primary health centres in muscat. although the centres had the basic facilities needed for trauma care, their capacity was limited and both, human and physical resources, were lacking. several centres reported shortages of equipment (i.e. airway breathing devices) and many doctors lacked in-service training in trauma care. moreover, all of the centres had inadequate physical and human resources for managing head, neck and chest injuries. these deficits should be rectified and certain administrative functions implemented including trauma registries, quality improvement programmes and in-service training for practitioners at all healthcare levels. the authors recommend that national standardised guidelines be developed in order to determine necessary improvements to the provision of trauma care in oman. a u t h o r s’ c o n t r i b u t i o n ab, zb conceptualised and designed the study. ab and zb collected the data. ab, zb and as analysed and interpreted the results. ab, zb and as drafted the manuscript. all authors reviewed the results and approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. injuries and violence: the facts 2014. from: https://apps.who.int/iris/bitstream/handle/1066 5/149798/9789241508018_eng.pdf?sequence=1 accessed: nov 2020. 2. world health organization. the global burden of disease: a comprehensive assessment of mortality and disability from dis eases, injuries, and risk factors in 1990 and projected to 2020. from: https://apps.who.int/iris/handle/10665/41864 accessed: nov 2020. 3. world health organization. global status report on road safety 2018. from: https://www.who.int/publications/i/item/9 789241565684 accessed: nov 2020. 4. mock c, joshipura m, goosen j, maier r. overview of the essential trauma care project. world j surg 2006; 30:919–29. https://doi.org/10.1007/s00268-005-0764-8. 5. world health organization. guidelines for essential trauma care. from: https://www.who.int/violence_injury_prevention/ publications/services/en/guidelines_traumacare.pdf accessed: nov 2020. 6. aboutanos mb, mora f, rodas e, salamea j, parra mo, salgado e, et al. ratification of iatsic/who’s guidelines for essential trauma care assessment in the south american region. world j surg 2010; 34:2735–44. https://doi.org/10.1007/s00268-0100716-9. 7. arreola-risa c, mock c, vega rivera f, romero hicks e, guzmán solana f, porras ramírez g, et al. evaluating trauma care capabilities in mexico with the world health organization’s guidelines for essential trauma care publication. rev panam salud publica 2006; 19:94–103. https://doi.org/10.1590/s102049892006000200004. 8. oman ministry of health. annual health report 2016. from: w w w.moh.gov.om/en_us/web/statistics/annual-reports accessed: nov 2020. 9. al-kashmiri a. trauma care in oman: where do we stand and where should we be heading? sultan qaboos univ med j 2017; 17:e386–8. https://doi.org/10.18295/squmj.2017.17.04.002. 10. al-kindi sm, naiem aa, taqi km, al-gheiti nm, al-toobi is, al-busaidi nq, et al. distribution of trauma care facilities in oman in relation to high-incidence road traffic injury sites: pilot study. sultan qaboos univ med j 2017; 17:e430–5. https:// doi.org/10.18295/squmj.2017.17.04.009. 11. celso b, tepas j, langland-orban b, pracht e, papa l, lottenberg l, et al. a systematic review and meta-analysis comparing out come of severely injured patients treated in trauma centers following the establishment of trauma systems. j trauma 2006; 60:371–8. https://doi.org/10.1097/01.ta.0000197916.99629.eb. 12. al-shaqsi sz. ems in the sultanate of oman. resuscitation 2009; 80:740–2. https://doi.org/10.1016/j.resuscitation.2009.04.011. 13. al-shaqsi s, al-kashmiri a, al-hajri h, al-harthy a. emergency medical services versus private transport of trauma patients in the sultanate of oman: a retrospective audit at the sultan qaboos university hospital. emerg med j 2014; 31:754–7. https://doi.org/10.1136/emermed-2013-202779. https://doi.org/10.1007/s00268-005-0764-8 https://doi.org/10.1007/s00268-010-0716-9 https://doi.org/10.1007/s00268-010-0716-9 https://doi.org/10.1590/s1020-49892006000200004 https://doi.org/10.1590/s1020-49892006000200004 https://doi.org/10.18295/squmj.2017.17.04.002 https://doi.org/10.18295/squmj.2017.17.04.009 https://doi.org/10.18295/squmj.2017.17.04.009 https://doi.org/10.1097/01.ta.0000197916.99629.eb https://doi.org/10.1016/j.resuscitation.2009.04.011 https://doi.org/10.1136/emermed-2013-202779 evaluating trauma care capabilities using the essential trauma care guidelines of the world health organization cross-sectional study of primary health centres in muscat, oman 64 | squ medical journal, february 2022, volume 22, issue 1 14. mann nc, mullins rj, mackenzie ej, jurkovich gj, mock cn. systematic review of published evidence regarding trauma system effectiveness. j trauma 1999; 47:s25–33. https://doi. org/10.1097/00005373-199909001-00007. 15. tallon jm, fell db, karim sa, ackroydstolarz s, petrie d. influence of a province-wide trauma system on motor vehicle collision process of trauma care and mortality: a 10-year follow-up evaluation. can j surg 2012; 55:8–14. https://doi. org/10.1503/cjs.016710. 16. world health organization. prehospital trauma care systems. from: https://apps.who.int/iris/bitstream/handle/10665/43167 /924159294x.pdf?sequence=1 accessed: nov 2020. https://doi.org/10.1097/00005373-199909001-00007 https://doi.org/10.1097/00005373-199909001-00007 https://doi.org/10.1503/cjs.016710 https://doi.org/10.1503/cjs.016710   thyrotoxicosis in pregnancy: a case report *bola r kamath1, kamla j rao1, adikari ak mayadunne2 abstrac t. there are various causes of hyperthyroidism in pregnancy such as graves’ disease and gestational thyrotoxicosis. the thyroid stimulation results from the excessive levels of circulating human chorionic gonadotropin (hcg) produced by the trophoblastic tissue in both hydatidiform moles and choriocarcinoma. we present a pregnant patient with hydatidiform mole who presented with hyperthyroidism that resolved after evacuation of the mole. keywords: thyrotoxicosis, hydatidiform mole, pregnancy, hcg 1department of medicine and 2obstetrics & gynæcology, armed forces hospital, p.o.box , postal code , seeb, sultanate of oman. *to whom correspondence should be addressed. e-mail: rajkamat@omantel.net.om t     -nancy is reported in the range of .–.. e majority of the patients have graves’ disease while other causes of hyperthyroidism occur much less frequently. data accumulated indicate that human chorionic gonadotropin (hcg) has weak thyroid stimulating activity. besides its contribution to hyperthyroidism in patients with trophoblastic tumours, the clinical significance of the thyrotrophic action of hcg is now also recognized in normal pregnancy and hyperemesis gravidarum.1 t h e c a s e a -year-old -weeks pregnant woman was admitted to the armed forces hospital on june ,  with history of abdominal pain, vomiting and bleeding per vagina, as well as the history of two previous missed abortions. clinical examination showed she had tachycardia (/min). no goitre was seen. otherwise the vital signs were stable. pelvic scan was suggestive of molar pregnancy with bilateral ovarian theca lutial cyst. liver enzymes were raised. serum bhcg was , miu/l. yroid function test (tft) showed ft > pmol/l and tsh . uiu/ml. ecg showed sinus tachycardia. she was treated with propranolol  mg , neomercazole  mg , lugol’s iodine . ml , and supportive care. nine days aer admission, she had an incomplete abortion aer which an evacuation of retained product of conception (erpc) �������������������������������������������������������� �������������� � � ������ �������� ����� ��������� ���� ��������� ����� �������� ������������� ���� ������ �������� ��������� �������� �������� ��� ��� ��� �������� ��������� ����� ��� ������ �������� �������� ��� ��� ��� ��������� ������ ������ ��� ������ �������� ������ ����� ����� ������ �������� � ����� ����� ����� ���������������������������������������������������������������������������� ������������������������������������������������� � ������������������������������������������������ � ������������������������� ������������������������ ������������������ ��������������������� ��������������������� ������������ ��������������� ��������������������������������� ����������� ������������������ ������������������������ ����������������������������� ������� ������������������������ �������������������������������� �������������������� �������������� ����������������� � ����������������� � � �     :   , : , : , – ©   thyrotoxicosis in pregnancy ����� �� ������ ������: ���� ����� ������ ���� � ��� ���� ����� ��� ������:������ ������ � ����� ��� ��� ����� ����� ������� ���� ����� ����� ��������� ���� .������ �� ������� ����� ����� ���� ��������� ��������� �������� ����� �� �� �� ������� ������ ����� �� ������ � ���� �� ���������� ����� ����� ����� .��� ���� ��� ���� � �������� ������ ����� ���� ����� ������ ������� ������� ����� �� ���������� ����� ��� ������ ��� ���� ��.   was performed. histopathology of the endometrium confirmed hydatidiform mole. e anti-thyroid medications were stopped. all the features of hyperthyroidism resolved when the hydatidiform mole was evacuated. a repeat tft two weeks later showed results within normal limits, and the bhcg level dropped down to . miu/l. when the patient was reviewed  months later, she remained asymptomatic and a repeat tft was normal. d i s c u s s i o n graves’ disease is the commonest cause of hyperthyroidism in pregnancy while other causes occur much less frequently [table ].11 in patients with hyperthyroidism caused by trophoblastic tumours, serum hcg levels usually exceed  u/ ml. however, thyrotrophic potency of hcg varies among its different isoforms, which explains why some patients with trophoblastic tumours and very high serum hcg levels do not manifest hyperthyroidism.4 both hcg and thyroid stimulating hormone (tsh) are glycoproteins, which are composed of a common alpha-subunit and a non-covalently linked hormone-specific beta-subunit. is structural homology suggests the basis for cross-reactivity of hcg with the tsh receptor.3 e diagnosis of hyperthyroidism is established by finding elevated serum free t and t levels, and suppressed tsh concentration. in most instances, a patient with molar pregnancy has mild hyperthyroidism with a small goitre, and the hyperthyroidism resolves rapidly aer surgical removal of the hydatidiform mole. conversely, patients with choriocarcinoma who manifest hyperthyroidism usually have a large mass, and antithyroid therapy may be required in addition to chemotherapy for the tumour.5 e term gestational thyrotoxicosis refers to a subset of hyperemetic patients with clinical and biochemical hyperthyroidism in early pregnancy.1 it is believed to result from circulating hcg with high biological activity. it usually resolves spontaneously in the latter half of pregnancy. women with gestational thyrotoxicosis may be differentiated from those with graves’ disease by the absence of goitre and negative antithyroid antibodies whose titre decreases from mid trimester onwards. as gestational thyrotoxicosis is mediated by hcg, no thyroid antibodies should be present. hyperthyroidism is transient and self-limiting in this condition, and specific antithyroid treatment is not required. hyperemesis gravidarum occurs in about – of pregnancies and most investigators believe in the putative role of hcg in cases of hyperemesis and hyperthyroidism. circulating free t and free t levels were frequently elevated in hyperemetic patients suggesting a relationship between the severity of the hyperemesis and the biochemical evidence of hyperthyroidism. however, the hcg levels in women with hyperemesis compared to those without emesis are similar, but the former have increased serum thyroid stimulating activity. kimura et al hypothesized that the hyperemetic patients produce molecular variants of hcg with increased thyroid stimulating activity.1 graves’ disease oen remits in mid-trimester and recurs aer delivery. if untreated, this condition can lead to significant morbidity and mortality in both mother and fetus. beta blockers are effective in controlling hypermetabolic symptoms and may be used in combination with thionamides until the symptoms abate. propylthiouracil and carbimazole are similarly effective in (blocking thyroid hormone synthesis.7 propylthiouracil appears to have some advantage over carbimazole as it inhibits the peripheral conversion of t to t, crosses the placenta less than methimazole does and is less readily secreted in breast milk. ey should be administered in the lowest possible dose to target maternal serum free t concentration in the upper limits of normal as both the drugs can cross the placenta and can cause fetal goitre and hypothyroidism. block-replacement regimen is contraindicated in pregnancy because thyroxine crosses the placenta less well than carbimazole and foetal goitre and hypothyroidism may result and the mother must also be given more methimazole if maternal hyperthyroidism is to be prevented. further, the rare congenital abnormality of congenital aplasia cutis congenita may be associated with the use of methimazole in pregnancy. dosage of thionamides should be reduced progressively in anticipation of the usual steady amelioration in the disease as pregnancy advances and treatment can eventually be discontinued in approximately  of patients.6 surgery is reserved for patients who are �������������������������������������������������������� �������������� � � ������ �������� ����� ��������� ���� ��������� ����� �������� ������������� ���� ������ �������� ��������� �������� �������� ��� ��� ��� �������� ��������� ����� ��� ������ �������� �������� ��� ��� ��� ��������� ������ ������ ��� ������ �������� ������ ����� ����� ������ �������� � ����� ����� ����� ���������������������������������������������������������������������������� ������������������������������������������������� � ������������������������������������������������ � ������������������������� ������������������������ ������������������ ��������������������� ��������������������� ������������ ��������������� ��������������������������������� ����������� ������������������ ������������������������ ����������������������������� ������� ������������������������ �������������������������������� �������������������� �������������� ����������������� � ����������������� � � �            not responding to antithyroid drugs because of non-compliance or allergy to both the drugs. yroidectomy can be safely performed in the second trimester. radioactive iodine therapy is contraindicated in pregnancy because of potential congenital malformations or congenital hypothyroidism.8 hyperthyroid pregnant patients should be seen at –weeks intervals, with a collaborative effort between the treating physician and obstetrician. yroid-stimulating immunoglobulin (tsi) titres obtained in the last trimester may predict the likelihood of neonatal hyperthyroidism. any newborn from a mother who has a history of hyperthyroidism should be observed for this possibility, due to the transplacental transfer of tsi. e earliest clinical sign of fetal thyrotoxicosis is fetal tachycardia [>/min]. serum thyroid stimulating hormone and yroxine concentration should be measured in neonates whose mothers have or have ever had grave’s disease. postpartum thyroiditis (ppt) is an autoimmune condition that occurs in approximately  of women during the first year of postpartum. e well-recognized improvement in clinically overt and biochemically proven autoimmune thyroid disease in pregnancy is due to the state of relative immune suppression in the mother. is is characterized by a rebound in antibody activity in the postpartum period. is is frequently associated with hyperthyroid phase occurring in the first  months of postpartum, followed by hypothyroid phase between  to  months aer delivery with spontaneous recovery in the majority of patients.9 yrotoxocosis in postpartum thyroiditis (ppt) is usually mild and self-limiting (–weeks duration) and is distinguished from grave’s disease by a low radio active iodine uptake[raiu] (study contraindicated if the mother is breast-feeding). beta-blockers can be administered if symptoms are severe. antithyroid drugs are not useful in ppt because thyrotoxicosis is secondary to hormone release from the damaged gland9. e importance of recognition of this syndrome is two fold: (i) a clear association has been established between the development of this syndrome and alteration in the mood and behaviour that occurs during postpartum period. (ii) ere is clear evidence that in a significant number of women the transient syndrome may go onto permanent hypothyroidism.10 c o n c l u s i o n yroid problem is the most common pre-existing endocrine disorder during pregnancy reflecting in part a predilection for thyroid problems in women of childbearing age. maternal thyrotoxicosis occurs about once in every  pregnancies, and the diagnosis may be difficult because the increase in cardiac output, tachycardia, skin warmth and heat intolerance typical of pregnancy can mimic hyperthyroidism. e diagnosis of thyroid disease is complicated by many important physiological changes in thyroid metabolism and laboratory values observed in pregnancy. measurement of tsab concentration in women with active grave’s disease in late pregnancy or with previous ablative therapy for graves’ disease is useful to predict neonatal graves’ disease. also, systemic thyroid autoantibody screening in the early stages of gestation may improve obstetric outcome and identify women at risk of ppt. proper understanding of all this is essential for the effective management of thyroid disease in pregnancy.              we thank the director of medical services, forced medical services, royal army of oman, for the permission to publish this case report . r e f e r e n c e s . kimura m, amino n tamaki h, ito e, mitsuda n, miyai k et al. gestational thyrotoxicosis and hyperemesis gravidarum, possible role of bhcg with higher stimulating activity clin endocrinol , , –. . yoshimura m, hershnan jm. yrotropic action of human chorionic gonadotropin. yroid , , –. . yoshimura m, pekary ae, pang xp, berg l, cole la, kardana a et al. effect of peptide nicking in the human chorionic gonadotropin beta-subunit on stimulation of recombinant human thyroid-stimulating hormone receptors. eur j endocrinol , , –. . pekary ae, jackson im , goodwin tm goodwin tm, pang xp, hein md et al. increased in vitro thyrotropic activity in partially sialated human chorionic gonadotropin extracted from hydatidiform moles of patients with hyperthyroidism. j clin endocrinol metab , , –. . good tm, heshman jm. hyperthyroidism due to inappropriate production of human chorionic gonadotropin. clin obstet gynecol , , –. . inzucchi se, comite f, burrow gn. graves’ disease and pregnancy. endocr pract , , –. . wing da, miller lk, koonings pp montoro mn, mestman jh. a comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. am j obstet gynecol , , –. . stoffer ss,hamburger ji. inadvertent 131i therapy for hyperthyroidism in the first trimester of pregnancy. j nucl med , , –. . gerstein hc. how common is postpartum thyroiditis? a methodologic review of the literature. arch intern med , , –. . othman s, phillips di, parks ab, richards cj, harris b, fung h et al. a long-term follow up of postpartum thyroiditis. clin endocrinol (oxf ) , , –. . loh kc, chee yc. pregnancy and the thyroid: a clinical review. proceedings of the royal college of physicians of edinburgh , , –.                          acute idiopathic pulmonary haemorrhage in a 2 month old infant case report and review of the literature salem al-tamemi, *hussein al-kindi case report squ med j, august 2009, vol. 9, iss. 2, pp. 170-174, epub 30th june 2009 submitted 16th sep 08 revision req. 21st mar 09, revision recd. 29th apr 09 accepted department of child health, sultan qaboos university hospital, muscat, oman *email: husseink@squ.edu.om pulmonary haemorrhage (ph) and haemoptysis are rare in children and more so in healthy infants.1 ph may be due to very rare conditions such as pulmonary-renal syndromes and idiopathic pulmonary haemosiderosis (iph); it can be dangerous and life-threatening.2 it is also very challenging when presenting acutely in a baby who was previously well and found by parents to be covered with blood on face or nose and struggling to breathe. these infants need immediate medical attention, often ventilatory support and extensive investigations to find out the source of the bleeding and the cause.3 following a report from cleveland, ohio, usa,4 acute idiopathic pulmonary haemorrhage (aiph) in infancy was, in 2004, recognised as a diagnosis of exclusion by the us centers for disease control (cdc). the current report is of a two month old infant who presented at the emergency department of sultan qaboos university hospital, oman, with the clinical and radiological features of acute idiopathic pulmonary haemorrhage. case report the male infant was born at 34 weeks of gestation and had an uneventful perinatal period. there was no family history of bleeding or rheumatologic disorders. at 2 months, the mother got up at 5 am to breast feed the baby who was sleeping next to her and found his face and clothing covered with blood. he was unresponsive, with shallow breathing, نزيف رئوي حاد جمهول السبب عند طفل رضيع عمره شهرين تقرير حالة مع مراجعة أدبيات سالم التميمي ، حسني الكندي امللخص: عادة ما يكون النزيف الرئوي بسبب مرض يصيب عدة أجهزة في اجلسم يؤثر على الرئة ، وقد يكون في الرئة وحدها أو مبشاركة أجهزة اخرى. من جهة أخرى يكون تشخيص نزف الرئة اجملهول بواسطة استبعاد األسباب األخرى ، وهو مرض نادر كما جاء وصفه في األدبيات الطبية. في تقريرنا هذا نصف حالة طفل يبلغ من العمر شهرين، أحضر إلى قسم الطوارئ مبستشفى جامعة السلطان قابوس )عمان( في حالة فشل تنفسي مصحوبة بحالة صدمة من جراء نزيف شديد وحاد في الرئة. بعد التحري الدقيق في مختلف أجهزة اجلسم لم جند سببا لهذا النزيف. هذه احلالة بعرضها السريري وصورها الشعاعية تشبه ما هو موجود في املراجع مبا يسمي النزيف الرئوي مجهول السبب. العالج بالستيرويدات القشرية نتج عن شفاء عاجل من حالته التنفسية احلرجة. مفتاح الكلمات: داء هيموسيديريني ، فشل تنفسي ، صدمة ، ستيرويدات قشرية ، تقرير حالة ، عمان. abstract: pulmonary haemorrhage is usually secondary to a systemic disease affecting the lung with or without other organ involvement. idiopathic pulmonary haemorrhage is a diagnosis of exclusion; as described in the literature, it is a rare disease. we report a two months old infant who presented at the emergency department of sultan qaboos university hospital, oman, with respiratory failure and shock secondary to an acute severe pulmonary haemorrhage. detailed investigations for pulmonary, cardiovascular, renal and systemic inflammatory causes were negative. his clinical presentation and radiological imaging were consistent with idiopathic pulmonary haemorrhage. treatment with corticosteroids resulted in a remarkable and fast recovery from his critical respiratory status. keywords: haemosiderosis; respiratory failure; shock; corticosteroids; case report; oman. salem al-tamemi and hussein al-kindi case report | 171 up-rolling of the eyes and stiff limbs. the parents rushed him to the emergency department of sultan qaboos university hospital. on examination, he was still unresponsive with shallow breathing, the room air pulse oxymetry being 84% saturation. a chest examination showed bilateral diffuse crackles, with signs of respiratory failure and shock. his face and clothes were blood stained with no skin bruises, petechiae, or apparent vascular malformations. he was intubated and fresh blood was noted coming through the endotracheal tube. after resuscitation with intra-venous saline boluses, a first dose of broad spectrum antibiotics was given and he was transferred to the paediatric intensive care unit. he was ventilated with high pressure settings and 100% oxygenation. the arterial blood gas after intubation and ventilation showed severe metabolic acidosis and low pco2 due to hyperventilation (ph = 7.2; po2 = 38.5 kpa; pco2 = 2.9 kpa, hco3 = 8.3, mmol/l, be =18). the metabolic acidosis was corrected with the intravenous (iv) fluids and iv sodium bicarbonate. investigations included: complete blood count (cbc) which showed leukocytosis of 33.8 x 109/l; lymphocytosis of 26.2 x 109/l; a neutrophil count of 7.2 x 109/l; platelets 555 x 109/l; haemoglobin 9.8 g/dl; haematocrit 31.6%; reticulocyte 1.4%; mean cell volume 75.2 fl; mean cell haemoglobin 23.3 pg and red cell distribution width 18.4. his coagulation profile showed a mildly elevated prothrombin time (pt) of 15.8 sec (normal range 10.5-14.9); activated partial thromboplastin time (aptt) 40 sc (range 25.0-39.0) and international normalised ratio (inr) 1.3 (range 0.800-1.200) that corrected when mixed with normal plasma. the liver enzymes were slightly raised: serum aspartate aminotransferase (s-asat) was 153 u/l (normal range 22-58); serum alanine aminotransferase (s-alat) 54 u/l (range 11-39); serum alkaline phosphatase (s-alp) 176 u/l (n range 110-302); serum bilirubin 44 umol/l (range 4-17); total protein 62 g/l (range 64-83); serum albumin 40 g/l (35-50); serum ferritin 162ng/ml (range 20-300); plasma ammonia 56 umol/l (range 11-35), and serum lactic acid 1.44 mmol/l (range 0.50-2.20). his urea at 4.5 mmol/l (range 2.5-6.4) and creatinine at 43 umol/l (range 27-53) were both normal; the urine analysis was negative for blood. he received fresh frozen plasma, packed red blood cell transfusion and vitamin k. his chest x-ray showed a bilateral ground glass appearance [figure 1]. a computed tomography (ct) scan of the chest showed bilateral alveolar opacities [figure 2]. the ct scans of the brain and abdomen were normal. the electroencephalogram (eeg) did not show any epileptic activities. both the electrocardiogram (ecg) and echocardiography were normal. blood, sputum, urine and stool cultures were negative for bacteria and fungus. the auto-antibodies screen was negative including for anti-nuclear antibodies, rheumatoid factor, anti-mitochondrial antibodies, anti-smooth muscle antibodies, antireticulin antibodies, anti-neutrophil nuclear anti-bodies (c-anca), myloperioxidase (mpoanca) and proteinase-3 (pr3-anca). a specific immunoglobulin e (ige) to cow’s milk was negative, an igg to cow’s milk was not feasible. haemosiderin laden macrophages were negative on the gastric aspirate that was done on day 9 of the illness. an interview with both parents showed that there were no smokers at home or a source of moulds since they live in a new house with no water leakage or heating system. during the first 36 hours of admission, the child was treated with parenteral antibiotics and mechanical ventilatory support, however, he continued to be critically sick with fresh blood coming through the endotracheal tube. a bronchoscopy could not be performed because of his critical status, but it was clinically clear that he had a pulmonary haemorrhage with no identifiable cause. as it was suspected that he might have an figure 1: chest x-rays showing bilateral diffuse opacification of both lung fields, ground glass appearance suggestive of pulmonary hemorrhage acute idiopathic pulmonary haemorrhage in a 2 month old infant case report and review of the literature 172 | squ medical journal, august 2009, volume 9, issue 2 idiopathic pulmonary haemorrhage, he was started on methylprednisolone 2mg/kg/day iv divided into 4 doses every 6 hours for 3 days. within few hours of the second dose there was a clear response to steroids seen in a decrease in oxygen need from 70% to 30% and a decrease in mechanical ventilation pressures. he was extubated on the fourth day of admission and was discharged on the ninth day on oral prednisone that was tapered over a 6 month period. no follow-up bronchoscopy was done because the child remained well. a cbc done one month after the illness showed a normal hb of 12.0 g/dl; white blood count (wbc) 15.3 x 109/l, and platelets were 535 x 109/l. there were no more bleeding episodes on subsequent clinic visits up to two years of age; however, he had viral induced wheezes several times between the age of 9 months and 14 months which are now resolved. discussion pulmonary haemorrhage and haemoptysis in children are uncommon. in a major case review by coss-bu et al.,1 it was found that among 228 children and young adult patients, who presented to texas children’s hospital over 10 years, 65% had cystic fibrosis and 16% had congenital heart disease and the remaining 19% had a range of other causes. pulmonary haemosiderosis is defined as an abnormal accumulation of haemosiderin in the lungs that results from a diffuse alveolar haemorrhage. it may occur as a primary process in the lung (idiopathic) or secondary to cardiac diseases, bleeding disorders, collagen vascular diseases, or systemic vasculitis.2 idiopathic pulmonary haemosiderosis (iph) is a rare diagnosis of exclusion. it is distinct from the pulmonary-renal syndrome in that the pathology is confined to the lungs and there is no renal or systemic involvement.2 the incidence in paediatric age groups has been estimated to be very low; for example, during the three decades 1950-1979, iph occurred in 10 swedish children which indicates that the yearly risk of onset is 0.24 case per million children.5 in japan, there were 39 cases of iph in children in a 20 year time span (1974-1993) which gives an incidence of 1.23 cases/year per million children.6 the diagnosis is suggested by the symptom triad of haemoptysis, anaemia and pulmonary infiltrates and is secured by the finding of haemosiderin-laden macrophages (siderophages) in bronchoalveolar lavage fluid (bal).7 in the years 1993-2000, there were reports of an epidemic of an unusual form of iph which affected 30 very young infants in cleveland, ohio. these babies mostly presented with severe diffuse alveolar haemorrhage; 75% of them required blood transfusion and ventilatory support in the acute stage. all known causes of pulmonary haemorrhage were excluded by investigations. in most of the infants, the bleeding either stopped or lessened with the use of steroids.3 following these reports, the us cdc investigated the cases and came up with a recommendation of figure 2: computed tomography scans of the chest showing bilateral alveolar opacities salem al-tamemi and hussein al-kindi case report | 173 case definition in their 2004 report 4,8 as a clinically confirmed case of “acute idiopathic pulmonary haemorrhage”(aiph). this was defined as an illness in a previously healthy infant aged < 1 year with a gestational age of > 32 weeks, no history of neonatal medical problems that might cause pulmonary haemorrhage, and whose illness is consistent with the following criteria: 1. abrupt or sudden onset of overt bleeding or frank evidence of blood in the airway. 2. severe presentation leading to acute respiratory distress or respiratory failure resulting in hospitalisation in a paediatric intensive care unit with intubation and mechanical ventilation. 3. diffuse, bilateral pulmonary infiltrates on a chest radiograph or computed tomography of the chest. it has been suggested by some authors that iph can be due to immunological causes.9-11 yao et al. stated in their case report that a positive perinuclear neutrophil cytoplasmic antibody (p-anca) at the initial assessment may indicate the presence of alveolar capillary or glomerular vasculitis which may be a sign of poor prognosis, and that a measurement of anti-neutrophil cytoplasmic antibodies (anca) is recommended for all patients with pulmonary alveolar haemorrhagic syndromes.11 in our patient, an extensive immune workup did not reveal any evidence of autoimmune disease. environmental or toxic factors may precipitate the disease in genetically predisposed individuals. haemolysin stachylysin, a toxin produced by the fungus stachybotrys chartarum, was associated with pulmonary haemorrhage/haemosiderosis in 10 infants of cleveland community;6 however, an actual cause-and-effect relationship between it and pulmonary haemorrhage has not been definitively established.8,12,13 and the significance of stachylysin in iph is still under investigation.13,14 in our case, we did not make a home visit; however, the interview with the parents did not reveal any source of toxins in the home environment. conclusion our patient met the criteria defined by the cdc for iph. he was two months old at presentation and his gestational age was 34 weeks. he was normal until the day of presentation when he was found to be covered with blood on his face and was in respiratory failure when presented to the hospital for which he was immediately intubated and mechanically ventilated. he had clear evidence of pulmonary haemorrhage: the frank blood in the endotracheal tube and the findings in both the plain and ct chest radiography. our patient responded very well to methylprednisolone 2mg / kg/day iv, which resulted in fast improvement and probably prevented further pulmonary bleeding as in many of the patients reported from cleveland.6 a bronchoscopy to obtain bronchoalveolar lavage could not be done because of the critical status of the patient during the first 72 hours and then we had to extubate him since he responded very dramatically to the steroids. a follow-up bronchoscopy may well have detected continued low grade alveolar bleeding, but it was not done since he was doing well and his haemoglobin remained normal. during the two years of follow up he had no recurrence of pulmonary haemorrhage. in summary, this two months old patient presented as a typical case of acute pulmonary haemorrhage as defined by the cdc criteria and has done very well with corticosteroid therapy for 6 months with no clinical recurrence in 2 years. references 1. coss-bu ja, sachdeva rc, bricker jt, harrison gm, jefferson ls. hemoptysis: a 10-year retrospective study. pediatrics 1997; 100:e7. 2. godfrey s. pulmonary hemorrhage/hemoptysis in children. pediatr pulmonol 2004; 37:476-84. 3. dearborn dg, smith pg, dahms bb, allan tm, sorenson wg, montana e, et al. clinical profile of 30 infants with acute pulmonary hemorrhage in cleveland. pediatrics 2002; 110:627-37. 4. centers for disease control and prevention. investigation of acute idiopathic pulmonary hemorrhage among infants in massachusetts, december 2002-june 2003. mmwr morb mortal wkly rep 2004; 53:817-20. 5. kjellman b, elinder g, garwicz s, svan h. idiopathic pulmonary haemosiderosis in swedish children. acta paediatr scand 1984; 73: 584-8. 6. ohga s, takahashi k, miyazaki s, kato h, ueda k. idiopathic pulmonary haemosiderosis in japan: 39 possible cases from a survey questionnaire. eur j pediatr 1995; 154:994-8. 7. nuesslein tg, teig n, rieger chl. pulmonary haemosiderosis in infants and children. paediatr acute idiopathic pulmonary haemorrhage in a 2 month old infant case report and review of the literature 174 | squ medical journal, august 2009, volume 9, issue 2 respir rev 2006; 7:45-8. 8. centers for disease control and prevention. acute idiopathic pulmonary hemorrhage among infants: recommendations from the working group for investigation and surveillance. mmwr cdc 2004; 53:rr-2. 9. green rj, ross sj, kraft sa, duncan sr, berry gj, raffin ta. pulmonary capillaritis and alveolar hemorrhage. update on diagnosis and management. chest 1996; 110:1305-16. 10. ayman h. acute idiopathic pulmonary haemorrhage in infancy: case report and review of the literature. j paediatr child health 2005; 41:532-3. 11. yao tc, hung ij, jaing th, yang cp. pitfalls in the diagnosis of idiopathic pulmonary haemosiderosis. arch dis child 2002; 86:436-8. 12. montana e, etzel ra, allan t, horgan te, dearborn dg. environmental risk factors associated with pediatric idiopathic pulmonary hemorrhage and hemosiderosis in a cleveland community. pediatrics 1997; 99:117-124. 13. etzel ra, montaña e, sorenson wg, kullman gj, allan tm, dearborn dg, et al. acute pulmonary hemorrhage in infants associated with exposure to stachybotrys atra and other fungi. arch pediatr adolesc med 1998; 152:757-62. 14. elidemir o, colasurdo gn, rossmann sn, fan ll. isolation of stachybotrys from the lung of a child with pulmonary hemosiderosis. pediatrics 1999; 104:964-6. march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 32-36, epub 16th mar 2009 submitted 28th july 08 revision req. 21st aug 08, revision recd. 26th aug 08 accepted 28th aug 08 quality of diabetes care: a cross-sectional observational study in oman *ahmed al-mandhari,1 ibrahim al-zakwani,2 omayma el-shafie,3 mohammed al-shafaee,4 nicholas woodhouse5 عمان في وصفية مقطعية دراسة : السكر لداء الرعاية جودة وودهاوس نيكوالس الشافعي، محمد الشفيع، أميمه الزكواني، ابراهيم املندري، أحمد عدد نصف اختيار فيها مت مقطعية ــة دراس الطريقة: هذه عمان. في ــكر الس داء املقدمة ملرضى الرعاية الصحية جودة ــة: الهــدف: تقييم اخلالص لتبيان ــتخدم اإلحصاء الوصفي اس . منهجية 2005 بصورة عام من ــو يوني ــهر ش خالل األولية الصحية للرعاية ــتة مراكز س راجعوا الذين ــى املرض عمر متوسط كان . (-61% 263 امرأة (منهم 430 مريضا الدراسة هذه شملتهم الذين السكر بداء املصابني املرضى عدد بلغ املعطيات. النتائج: 169) 39% مقابل الدم ، لسكر الفحص العشوائي مت (171 مريضا) 40% فقط في . 84 سنة 6 إلى املدى بني كان بينما 12 ± 52 سنة العينة أو عشوائيا ذلك سواء كان الدم السكر في فحص على حصلوا (339 مريضا) 79% أن يعني .وهذا عندهم على الريق فحص سكر الدم مت مريضا) ثافة بينما الكَ فيضُ خَ يُّ مِ حْ الشَّ والبروتنيُ السكري الهيموغلوبني مت فحص ( (317 مريضا كما يلي: 74% فكانت األخرى الفحوص أما . الريق على وشــملت: (249 مريضا) العينة %58 من في كاملة الفحوص كانت . (409 مريضا) %95 منهم في ــاطي االنقباضي واالنبس الدم ضغط قياس مت ثافَة الكَ عُ رْتَفِ مُ يُّ مِ حْ الشَّ البروتنيُ و ثافة فيضُ الكَ يُّ خَ مِ ــحْ الشَّ والبروتنيُ الكلي ــتيرول والكوليس الدم ضغط وقياس ــكري الس الهيموغلوبني فحص (7%>) ــكري الهيموغلوبني الس مقياس من الطبيعية احلدود ضمن نتائج 249 مريضا) ــوع (6 من مجم 2.4% فقط لدى كان . ــة الثالثي ــون والده ثافَة الكَ عُ رْتَفِ مُ يُّ مِ ــحْ الشَّ البروتنيُ و (>3.5مم/ل) ثافة الكَ ــضُ في خَ يُّ مِ ــحْ و البروتنيُ الشَّ (>5.2مم/ل) ــترول و الكوليس (80/130=<) الدم ــط وضغ ذلك من الرغم على اجلودة. لتقييم املستخدمة املؤشرات جيدا لقيم تدوينا كان هناك اخلالصة: (>1.8مم/ل). الدهون الثالثية و (<-1.1>1.68مم/ل) جدا. منخفضة عامليا الطبيعية املعروفة احلدود في يقعون الذين املرضى %2.4 من تعتبر نسبة . عمان ، املؤشرات ، السكر داء الكلمات: اجلودة ، مفتاح 1department of family medicine & public health, sultan qaboos university hospital, muscat, oman; 2department of pharmacy, sultan qaboos university hospital, muscat, oman; 3department of medicine, sultan qaboos university hospital; 4department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 5department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; *to whom correspondence should be addressed. email: manar96@yahoo.com abstract objectives: the objective of this study was to evaluate the quality of diabetes care in oman. methods: this was a crosssectional observational study. fifty percent of all those attending six general health centres in june 2005 were systematically selected for the study. descriptive statistics were used to describe the data. results: a total of 430 diabetic subjects were included. just over 6% percent of the subjects were female (n = 263). the overall mean age of the cohort was 52 ± 2 years ranging from 6 to 84 years. only 40% (n = 7) and 39% (n = 69) of the diabetics had their random blood sugar (rbs) and fasting blood sugar (fbs) documented, respectively. however, 79% (n = 339) had either rbs or fbs done according to the records. documentation for the other measurements ranged from 74% (n = 37) for hbac and ldl (low density lipoproteins)-cholesterol to 95% (n = 409) for systolic and diastolic blood pressure (sbp/dbp) readings. a total of 58% (n = 249) of patients had non-missing values of hbac, sbp/dbp, total cholesterol, ldl-cholesterol, hdl (high density lipoproteins)-cholesterol, and triglycerides. only 2.4% (6 out of 249 diabetics) were simultaneously within goal for hbac (<7%), sbp/dbp (<=30/80mmhg), total cholesterol (<5.2mmol/l), ldl-cholesterol (<3.3mmol/l), hdl-cholesterol (>. <.68mmol/l), and triglycerides (<.8mmol/l). conclusion: there was good documentation of values for the indicators used in the assessment of quality. however, the proportion (2.4%) of those meeting internationally recognised goals for the three diabetes-related factors was extremely low. key words: quality; diabetes; indicators; oman. c l i n i c a l a n d b a s i c r e s e a r c h q ua l i t y o f d i a b e t e s c a r e : a c r o s s s e c t i o n a l o b s e r vat i o n a l s t u d y i n o m a n 33 diabetes mellitus is a major health problem that is associated with significantmorbidity and mortality. the estimated number of diabetics world wide is greater than 240 million, with 1 of them dying every 10 seconds. the number of affected individuals is increasing rapidly from 94 million in 2003 to 246 million in 2007 representing 6.0% of the adult population. in 2025, the projected prevalence is estimated to be 308 million.1 these startling figures are due mainly to a massive increase in the worldwide prevalence of obesity. in the usa, 75% of adults will be overweight and 41% obese by 2025 if its citizens continue to gain weight at the current rate.2 diabetes also imposes a huge cost burden on the patients, families and health care systems. in 2007, the cost of diabetes mellitus (dm) in the usa alone was estimated to be 232 billion usd.1 these problems are also reflected in the middle east where the prevalence of obesity is also increasing along with that of diabetes mellitus 2 (dm2), which in 2007 varied between 3.4% in the yemen to 19.5% in the uae in patients between 20-79 years of age. in oman, the 2007 figure was 14% and is expected, as in other countries, to increase sharply in the next 25 years.1 given the high prevalence rates of diabetes and the direct link between its poor control and significant morbidities such as blindness, myocardial infarction and renal failure, it is essential to assure delivery of high quality care. ultimately, this would help in reducing the cost of managing such complications and improve the quality of life of diabetic patients. furthermore, primary health care centres play a major role in the management of chronic illnesses. therefore, assessing the quality of care provided by these centres is essential for improving such care. the aim of this study was to assess the quality of diabetic care in the primary health care centres in oman. m e t h o d s out of 26 primary health care centres in muscat, six centres were specifically selected for the study based on their distance from the university hospital. these centres were representative of the muscat region in terms of population covered and type of services provided.3 the target population was 860 patients who visited the six centres during the month of june 2005. every second patient attending the clinics was selected for the study. this produced data on 50% of the total number of patients from each centre. a checklist of indicators was developed based on the omani ministry of health guidelines for the management of diabetes mellitus in primary health care centers.4 the variables assessed included recorded hba1c, triglycerides, total cholesterol, low density lipoproteins-cholesterol (ldl), high density lipoproteins-cholesterol (hdl), systolic and diastolic blood advances in knowledge • this is the first study to highlight the quality of diabetes care in a regions where diabetes is becoming an important factor in regional health problems. applications to patient care given the background of a less than desirable quality of care in oman, more vigilance is required to improve the care of diabetes in oman. the following are recommended: self-management support to patients. maintenance of disease registries. monitoring compliance at the point of care with active follow-up to ensure the best outcome. general practitioners should be aggressive in controlling risk factors associated with diabetes • the nurse’s role in diabetes care should be enhanced. • evidence-based guidelines should be integrated into care, and supported by provider education, links with specialty expertise, and reminder systems. • interventions should focus on patient education, training of primary care physicians and other patient care providers in behavioural change and redesign of local systems of delivering care. • the chronic care model (ccm) provides a blueprint for changing office systems to improve chronic patient care. a h m e d a l m a n d h a r i , i b r a h i m a l z a k wa n i , o m ay m a e l -s h a f i e , m o h a m m e d a l -s h a fa e e a n d n i c h o l a s wo o d h o u s e 34 table 1: demographic, diabetic, blood pressure and lipid profiles of the study cohort stratified by gender (n = 430) characteristic number (%) of documentation in file all male female p-value gender, n (%) 430 (100%) 430 (100%) 167 (39%) 263 (61%) age, mean ± sd, years 430 (100%) 52 ± 12 53 ± 12 51 ± 11 0.120 random blood sugar (rbs),mmol/l 171 (40%) mean ± sd 11.4 ± 4.2 11.0 ± 3.5 11.8 ± 4.7 0.186 patients at goal, 4.4-< = 10, n (%) 72 (42%) 33 (44%) 39 (41%) 0.657 fasting blood sugar (fbs),mmol/l 169 (39%) mean ± sd 9.3 ± 3.1 8.9 ± 3.5 9.5 ± 2.9 0.184 patients at goal, 4.4-< = 7, n (%) 40 (24%) 20 (34%) 20 (18%) 0.022 presence of either rbs or fbs value, n (%) 339 (79%) 339 (79%) 134 (80%) 285 (78%) 0.571 hba1c, % 317 (74%) mean ± sd 8.7 ± 2.4 8.8 ± 2.4 8.7 ± 2.3 0.264 hba1c, %, <8.0% 146 (46%) 59 (48%) 87 (45%) 0.515 hba1c, %, <7.0% 77 (24%) 35 (29%) 42 (22%) 0.149 hba1c, %, <6.5% 45 (14%) 23 (19%) 22 (11%) 0.060 hba1c, %, <5.7% 13 (4%) 9 (7%) 4 (2%) 0.020 systolic blood pressure (sbp), mmhg 409 (95%) mean±sd 133 ± 17 133 ± 17 133 ± 17 0.945 patients at goal, < = 135, n (%) 236 (58%) 92 (58%) 144 (57%) 0.947 patients at goal, < = 130, n (%) 235 (57%) 91 (57%) 144 (58%) 0.849 patients at goal, < = 125, n (%) 138 (34%) 51 (32%) 87 (35%) 0.522 patients at goal, < = 120, n (%) 138 (34%) 51 (32%) 87 (35%) 0.522 diastolic blood pressure (dbp), mmhg 410 (95%) mean±sd 82 ± 9 82 ± 9 82 ± 9 0.704 patients at goal, < = 80, n (%) 273 (67%) 110 (69%) 163 (65%) 0.457 patients at goal, n (%) sbp/dbp, mmhg, < = 135/< = 80 409 (95%) 199 (49%) 77 (48%) 122 (49%) 0.863 sbp/dbp, mmhg, < = 130/< = 80 409 (95%) 198 (48%) 76 (48%) 122 (49%) 0.768 sbp/dbp, mmhg, < = 125/< = 80 409 (95%) 131 (32%) 48 (30%) 83 (33%) 0.481 sbp/dbp, mmhg, < = 120/< = 80 409 (95%) 131 (32%) 48 (30%) 83 (33%) 0.481 total cholesterol,mmol/l 386 (90%) mean ± sd 5.41 ± 1.16 5.47 ± 1.38 5.37 ± 1.01 0.412 patients at goal, <6.5, n (%) 326 (84%) 125 (84%) 201 (85%) 0.809 patients at goal, <5.2, n (%) 153 (40%) 58 (39%) 95 (40%) 0.821 ldl-cholesterol,mmol/l 317 (74%) mean ± sd 3.56 ± 0.95 3.55 ± 1.01 3.57 ± 0.92 0.860 patients at goal, <4.13, n (%) 233 (74%) 85 (71%) 148 (75%) 0.401 patients at goal, <3.3, n (%) 119 (38%) 44 (37%) 75 (38%) 0.802 patients at goal, <2.59, n (%) 46 (15%) 21 (17%) 25 (13%) 0.238 hdl-cholesterol,mmol/l 324 (75%) mean ± sd 1.12 ± 0.68 1.05 ± 0.46 1.16 ± 0.78 0.136 patients at goal, >0.9 <1.2, n (%) 132 (41%) 50 (40%) 82 (41%) 0.830 patients at goal, >1.1 <1.68, n (%) 105 (32%) 31 (25%) 74 (37%) 0.020 triglycerides,mmol/l 346 (80%) mean ± sd 1.68 ± 1.40 1.76 ± 1.35 1.60 ± 1.43 0.309 patients at goal, <4.44, n (%) 333 (96%) 129 (94%) 204 (98%) 0.099 patients at goal, <1.80, n (%) 234 (68%) 89 (65%) 145 (69%) 0.391 total no. of non-missing values of hba1c, sbp/dbp, total cholesterol, ldl-cholesterol, hdl-cholesterol, and triglycerides 249 (58%) 6 (2.4%) *** sd = standard deviation; ***only 6 (out of 249 diabetic patients = 2.4%) were within goal of hba1c (<7.0%), sbp/dbp (< = 130/< = 80 mmhg), total cholesterol (<5.2mmol/l), ldl-cholesterol (<3.3mmol/l), hdl-cholesterol (>1.1 to <1.68mmol/l), and triglycerides (<1.8mmol/l). q ua l i t y o f d i a b e t e s c a r e : a c r o s s s e c t i o n a l o b s e r vat i o n a l s t u d y i n o m a n 35 pressure as well as fasting and/or random blood sugar measurement during the most recent visit. this retrospective research was done by third and fourth year medical students. in order to secure quality data collection, the students were supervised by the first author after a three day training course on how to extract data from patient records. descriptive statistics were used for the data. for categorical variables, frequencies and percentages were reported. differences between groups were analysed using pearson’s χ2 tests (or fisher’s exact test for cells less than 5). for continuous variables, means and standard deviations (±sd) were presented and analyses were conducted using the student’s t-test. an a priori two-tailed level of significance was set at 0.05. r e s u l t s a total of 430 diabetic subjects were included in the study from six health centres in various sections of the capital city, muscat. the demographic, diabetic, blood pressure and lipid profiles of the study cohort, stratified by gender, are shown in table 1. just over 61% percent of the subjects were females (n = 263). the overall mean age of the cohort was 52 ± 12 years ranging from 6 to 84 years. only 40% (n = 171) and 39% (n = 169) of the diabetics had their random blood sugar (rbs) and fasting blood sugar (fbs) documented, respectively. however, 79% (n = 339) had either rbs or fbs done according to the records. documentation for the other measurements ranged from 74% (n = 317) for hba1c and ldl-cholesterol to 95% (n = 409) for blood pressure readings. a total of 58% (n = 249) of the patients had nonmissing values of hba1c, sbp/dbp, total cholesterol, ldl-cholesterol, hdl-cholesterol, and triglycerides. overall, there were only 2.4% (6 out of 249 diabetic patients) that were simultaneously within goal for hba1c (<7%), systolic and diastolic blood pressure (sbp/dbp) (< = 130/80mmhg), total cholesterol (<5.2mmol/l), ldl-cholesterol (<3.3mmol/l), hdl-cholesterol (>1.1 <1.68mmol/l), and triglycerides (<1.8mmol/l). d i s c u s s i o n more than 70% of the patients had their blood pressure, fasting or random blood sugar and hba1c levels measured regularly; however, the proportion of those meeting the expected goals of risk factor control was much lower. more disappointing was the very low number of those (6 out of 249 = 2.4 %) who achieved internationally recognised goals for all 6 diabetes related factors, namely a hba1c <7.0%, bp ≤130/80, total cholesterol <5.2mmol/l, ldl <3.3mmol/l, hdl-cholesterol >1.1 <1.68mmol/l and triglycerides <1.8mmol/l. 5-11 our disappointment is, however, tempered by a recent report form the usa concerning 36 academic, university, non-general practice clinics who reported a success rate of only 10% in achieving these goals.12 the challenge for diabetes care is that treatment of this complex disease requires multiple key processes and resources involving both provider and patient.13 interventions should focus on patient education, training of primary care physicians and other patient care providers in behavioural change and redesign of local systems of delivering care. the chronic care model (ccm) provides a blueprinting for changing office systems to improve chronic care.14 in a study that examined the effect of the chronic care model in a small independent practice, often without major structural change in the practice, nutting et al. showed an association with higher levels of process measures and intermediate outcomes for diabetes care.15 c o n c l u s i o n in conclusion, poor control of high blood sugar levels is linked with microand macrovascular complications such as blindness, renal failure, myocardial infarction and cerebrovascular accidents. ultimately, these have direct impact on the economic state of patients and families as well as being a burden on health care systems. therefore, given the high prevalence of diabetes and its complications with the increasing cost of health care services, assuring high quality care to diabetic patients becomes imperative. this should be achieved through offering self-management support to patients, maintaining disease registries, and monitoring compliance at the point of care with active followup to ensure the best outcome. moreover, the role of nurses in diabetes care should be enhanced. evidencebased guidelines should be integrated into care, and supported by provider education, links with specialty expertise, and reminder systems. furthermore, larger scale studies to assess the quality of diabetes care at the primary, secondary and tertiary health care institution levels are recommended. this would help in identifying opportunities for improvements thus reducing the social and economic burden of the disease on the society. a h m e d a l m a n d h a r i , i b r a h i m a l z a k wa n i , o m ay m a e l -s h a f i e , m o h a m m e d a l -s h a fa e e a n d n i c h o l a s wo o d h o u s e 36 a c k n ow l e d ge m e n t s the authors would like to thank the staff at all the health centres who participated in the study as well as ibtisam al-shaili, amal al-nabhani, khalsa al-khanbashi, iman al-lawati, third year medical students at sultan qaboos university, who were involved in the data collection. c o n fl i c t o f i n t e r e st : none s o u r c e o f f u n d i n g : sultan qaboos university r e f e r e n c e s 1. international diabetes federation (idf). diabetes atlas. from http://www.eatlas.idf.org/ accessed january 2008. 2. wang y, baydoun m. the obesity epidemic in the united states gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. epidemiol rev 2007; 29:6-28. 3. ministry of health oman. annual health report. muscat: ministry of health, 2005. 4. ministry of health oman. diabetes mellitus: management guidelines for primary health care. 2nd edition. muscat: ministry of health, 2003. 5. saydah s, fradkin j, cowie cc. poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. jama 2004; 291:335-42. 6. grant rw, cagliero e, dubey ak, gildesgame c, chueh hc, barry mj, et al. clinical inertia in the management of type 2 diabetes metabolic risk factors. diabet med 2004; 21:150-5. 7. grant rw, pirraglia pa, meigs jb, singer de. trends in complexity of care from 1991 to 2000 for patients with diabetes. arch intern med 2004; 164:1134-9. 8. narayan km, boyle jp, thompson tj, sorensen sw, williamson df. lifetime risk for diabetes mellitus in the us. jama 2003; 290:1884-90. 9. gaede p, vedel p, larsen n. multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. new engl j med 2003; 348:383-93. 10. brown jb, harris sb, webster-bogaert s, wetmore s, faulds c, stewart m. the role of patient, physician and systemic factors in the management of type 2 diabetes mellitus. fam pract 2002; 19:344-9. 11. uk prospective diabetes study (ukpds) group. intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (ukpds 33). lancet 1998; 352:837-53. 12. grant rw, buse jb, meigs jb. quality of diabetes care in the us academic medical centers; low rates of medical regimen change. diabetes care 2005; 28:337-442. 13. american diabetes association. clinical practice recommendations 2000. diabetes care 2000; 23:s1-116. 14. wagner eh, austin bt, von korff m. improving outcomes in chronic illness. manag care q 1996; 4:12-25. 15. nutting pa, dickinson wp, dickinson lm, nelson cc, king dk, crabtree bf, et al. use of chronic care model elements is associated with higher quality care for diabetes. ann fam med 2007; 5:14-20. december 2008 no white pages.indd sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 358-359 sultan qaboos university© submitted 5th april 2008 accepted 25th july 2008 steroid cell tumor abdul al-farsi, *ayman al-talib a 42-year-old woman presented with abdominal pain, increasing hirsutism and clitoromegaly [figure 1]. her plasma testosterone levels were very high (total testosterone: 33.3 ng/ml, free testosterone: 912 pg/ml) and the canver antigen 125 (ca-125) test was 120 u/ml. the computed tomography showed a large, 12.7 x 7.2 cm, lobulated, enhancing mass with central necrosis originating from the right ovary with a moderate amount of ascites. the preoperative diagnosis was sertoli-leydig cell tumor. the patient had an exploratory laparatomy where a total hysterectomy, bilateral salpingooopherectomy, lymph nodes dissection and omentectomy were performed [figure 2]. the tumour, which was removed, was confined to the right ovary and there was no evidence of adjacent structures involvement. no ascites was seen. during the surgery, the patient’s blood pressure went up to 240/140 mmhg. postoperatively, the patient was doing well though her blood pressure was uncontrolled so was started on الستيرويدية اخللية ورم الطالب أمين عبدول الفارسي، i n t e r e s t i n g m e d i c a l i m a g e department of obstetrics and gynaecology, mcgill university, montreal, canada *to whom correspondence should be addressed. email: ayman.altalib@gmail.com figure 1: clitoromegaly figure 2: steriod cell tumor gross appearance figure 3: histological appearance of cell tumor 359 s t e r o i d c e l l tu m o r micardis® (telmisartan). serum levels of testosterone returned to normal a few weeks after the surgery. the histopathological diagnosis was a steroid cell tumor, not otherwise specified [figure 3]. steroid cell tumours of the ovary account for approximately 0.1% of all ovarian tumours and are subdivided into 3 subtypes: stromal leuteomas, leydig cell tumours, and steroid cell tumours, not otherwise specified (nos). the steroid cell tumour (nos) is the most common of the 3 subtypes, accounting for approximately 60% of these tumors and the majority of them show virilisation,1, 2 25-45% of which are clinically malignant.2, 3 estrogen secretion occurs in 6% to 23% of the tumors, which may be associated with menorrhagia, postmenopausal bleeding, or even endometrial adenocarcinoma. cushing’s syndrome occurs in 6% to 10% of the cases. approximately 25% of the cases of steroid cell tumours (nos) are not associated with hormonal disturbances.4 they can occur at any age, but usually develop in adults with an average age of 43 years. 1 steroid cell tumours often present as unilateral solid tumours and occasionally as cystic tumours. necrosis or calcification is frequently associated. 5 ovarian steroid cell tumours are characterised by cells with abundant intracellular lipids, which are similar to adrenocortical cells. 6 the classical gross finding of steroid cell tumor (nos) is a solid, well-circumscribed ovarian mass. microscopic findings include diffusely arranged cells, although tumor cells may be present in nests, clusters, cords, or columns. the stroma is most commonly scant, but may be prominent and can occasionally be fibromatous, edematous, or myxoid. the cells are polygonal to round, with distinct cell borders and central nuclei, and they often have prominent nucleoli. the cytoplasm varies from spongy in lipid-rich cells to granular and eosinophilic in lipid-poor or lipid-free cells [figure 3]. the mainstay of ovarian steroid cell tumor is surgery. careful follow-up evaluation should include a measurement of sex hormone levels, particularly for those patients who demonstrated elevated levels before removal of the primary tumor. r e f e r e n c e s 1. kim yt, kim sw, yoon bs, kim sh, kim jh, kim jw, et al. an ovarian steroid cell tumor causing virilization and massive ascites. yonsei med j. 2007; 48:142-146. 2. veras e, deavers mt, silva eg, malpica a. ovarian steroid cell tumor, not otherwise specified: a clinicopathologic study. zhonghua bing li xue za zhi 2007; 36:516-520. 3. liu ax, sun j, shao wq, jin hm, song wq. steroid cell tumors, not otherwise specified (nos), in an accessory ovary: a case report and literature review. gynecol oncol 2005; 97:260-262. 4. malaika w, sathima natarajan. pathologic quiz case: a rare tumor of the ovary. arch pathol lab med 2003; 127:890–892. 5. faraj g, di gregorio s, misiunas a, faure en, villabrile p, stringa i, et al. virilizing ovarian tumor of cell tumor type not otherwise specified: a case report. gynecol endocrinol 1998; 12:347-352. 6. hayes mc, scully re. ovarian steroid cell tumors (not otherwise specified). a clinicopathological analysis of 63 cases. am j surg pathol. 1987; 11:835-845. 1department of general surgery, al rustaq hospital, al rustaq, oman; departments of 2dental & maxillofacial surgery and 6radiology & molecular imaging, sultan qaboos university hospital, muscat, oman; 3oral and maxillofacial surgery program, oman medical specialty board, muscat, oman; 4department of dental and maxillofacial surgery, al nahda hospital, muscat, oman; 5department of radiology, khoula hospital, muscat, oman *corresponding author’s e-mail: dr.noorjabbar@ymail.com متدد كاذب للشريان الفكي العلوي كإحدى مضاعفات إصابات الوجه والفكني تقرير ثالث حاالت مع مراجعة أدبية نور جبار ال�صاعدي، عبد العزيز باكثري، علي امل�صايخي، اأحمد الها�صمي، اأحمد احلب�صي، في�صل العزري abstract: traumatic maxillary artery pseudoaneurysm is an uncommonly reported complication in the field of oral and maxillofacial surgery. it is usually discovered incidentally, either early after trauma or weeks-to-months later. quick recognition and prompt management are essential to avoid devastating consequences. in this paper, we report three uncommon cases of maxillary artery pseudoaneurysm recognised during the surgical management of maxillofacial injuries in muscat, oman. all cases presented as sudden brisk bleeding during the intraoperative surgical repair and were subsequently diagnosed and successfully managed by endovascular embolisation with platinum coils. this case report highlights the clinical presentation, diagnosis and management of maxillary artery pseudoaneurysm, in addition to a brief review of the literature. keywords: maxillofacial injuries; maxillary artery; pseudoaneurysm; mandibular condyle; angiography; therapeutic embolization; case report; oman. امللخ�ص: يعترب التمدد الكاذب لل�رسيان الفكي العلوي من امل�صاعفات الغري �صائعة يف جمال جراحة الفم والوجه والفكني. والتي عادة ما يتم اكت�صافها عر�صا، اإما يف وقت مبكر بعد الإ�صابة اأو بعد اأ�صابيع اإىل اأ�صهر لحقا. الت�صخي�ض واملعاجلة ال�رسيعة مهم جدا لتفادي امل�صاعفات الوخيمة لهذه احلالة. نعر�ض يف هذا التقرير ثالث حالت غري ماألوفة لتمدد كاذب لل�رسيان الفكي العلوي والتي مت ت�صخي�صها اأثناء املعاجلة اجلراحية لإ�صابات الوجه والفكني. جميع احلالت تعر�صت لنزف حاد ومفاجئ اأثناء العالج اجلراحي لهذه احلالت والتي مت بعد ذلك ت�صخي�صها ومعاجلتها بنجاح عن طريق غلق التمدد الكاذب لل�رسيان من خالل و�صع الو�صائع داخل الأوعية الدموية با�صتخدام اأ�صالك البالتني الناعم. يناق�ض هذا التقرير الأعرا�ض ال�رسيرية بالإ�صافة اإىل الت�صخي�ض والعالج املنا�صب حلالت التمدد الكاذب لل�رسيان الوجهي مع مراجعة اأدبية خمت�رسة. الكلمات املفتاحية: اإ�صابات الوجه والفكني؛ ال�رسيان الفكي العلوي؛ متدد كاذب؛ لقمة الفك ال�صفلي؛ ت�صوير الأوعية؛ الن�صمام العالجي؛ تقرير حالة؛ عمان. maxillary artery pseudoaneurysm as a complication of maxillofacial injuries report of three cases and literature review *noor j. al-saadi,1 abdulaziz bakathir,2 ali al-mashaikhi,3 ahmed al-hashmi,4 ahmed al-habsi,5 faisal al-azri6 sultan qaboos university med j, november 2019, vol. 19, iss. 4, pp. e364–368, epub. 22 dec 19 submitted 28 may 19 revision req. 8 jul 19; revision recd. 26 aug 19 accepted 19 sep 19 trauma is a leading cause of various forms of arterial injuries, including intimal injury, rupture, thrombosis, arteriovenous fistula, true aneurysm, pseudoaneurysm and dissecting aneurysm.1 maxillofacial arterial pseudoaneurysms have rarely been reported in the scientific literature.1–10 a pseudoaneurysm usually occurs following an incomplete tear of an arterial wall. while the inner most layer of the artery and the blood flow are maintained, haemorrhage from the outer two layers occurs into the adjacent soft tissues. this leads to the formation of a haematoma that later organises and, with the continuous arterial pressure, creates an endothelial-lined sac in continuity with the arterial wall, which has the potential to expand further and rupture.4–6 this case report describes three cases of max illary artery pseudoaneurysm (map) encountered during surgeries involving the mandibular condyle and coronoid processes as part of the management of maxillofacial injuries. all cases presented intraoperatively with brisk bleeding and were diagnosed and successfully managed by angiography and endovascular embolisation with platinum coils. case one a 32-year-old male patient was referred to the oral & maxillofacial surgery unit at al-nahda hospital, muscat, oman, in 2013 with a prolonged mandibular dislocation for five months following a motor vehicle collision (mvc). clinical examination and computed tomography (ct) scan revealed bilateral anterior mandibular dislocation and a malunion of a mandibular symphyseal fracture. manual reduction of the dislocated mandible, aided by a muscle relaxant this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2019.19.04.013 case report https://creativecommons.org/licenses/by-nd/4.0/ noor j. al-saadi, abdulaziz bakathir, ali al-mashaikhi, ahmed al-hashmi, ahmed al-habsi and faisal al-azri case report | e365 he sustained a head injury with a fracture in the base of the skull and cavernous avf, which was managed by coil embolisation. in 2016, he presented to the oral & maxillofacial surgery unit at al-nahda hospital with a chief complaint of limited mouth opening. clinical and ct findings revealed coronoid pseudoankylosis with the base of the skull; subsequently, the patient underwent surgical release of the pseudoankylosis through a transoral approach. during the surgical removal of the left coronoid process a sudden severe haemorrhage was encountered. the bleeding was controlled with surgical packing and the surgery was abandoned. the patient was then transferred to the radiology department at khoula hospital. an urgent dsa revealed a left map and the patient underwent platinum coil embolisation with complete resolution of the lesion [figure 2]. the surgical packing was removed and the mandibular surgery was completed with no bleeding. subsequently, the patient’s mouth opening improved significantly. case three a 32-year-old male patient presented to the oral & under general anaesthesia, was unsuccessful. subseq uently, through a transoral approach, a bilateral coro noidectomy was performed and the condylar necks were exposed in an attempt to reduce the dislocated condyles surgically. intraoperatively, a sudden episode of massive bleeding was encountered on the right side, which was controlled initially with suture ligation and surgical packing. the patient was then transferred to the radiology department at khoula hospital, muscat, oman. digital subtraction angiography (dsa) was promptly performed revealing a large lobulated map arising just posterior to the neck of the right condyle with early filling of the jugular vein indicating an arteriovenous fistula (avf) [figure 1a]. at the same setting, endo vascular embolisation was conducted using platinum coils and complete resolution of the map and the avf was achieved [figure 1b]. the surgical wound was subsequently closed uneventfully. case two a 24-year-old male patient initially presented at khoula hospital in 2015 with a history of mvc, where figure 1: digital subtraction angiography images of the anterior-posterior view of the right external carotid artery (eca) of a 32-year-old male patient showing (a) right maxillary artery pseudoaneurysm (map; white arrow) with early filling of the right internal jugular vein indicating an arteriovenous fistula (avf; red arrow) and (b) the eca after platinum coil embolisation showing the resolution of the map and avf (white arrow). figure 2: digital subtraction angiography images of the lateral view of the left external carotid artery of a 24-year-old male patient showing (a) an artefact area (asterisk) representing a gauze pack used for packing the bleeding site and just posterior to it an area of dilatation representing maxillary artery pseudoaneurysm (map; white arrow). previous coiling of direct carotid-cavernous fistula on the day of a motor vehicle accident is visible (red arrow). (b) coil embolisation led to complete resolution of the map (white arrow). maxillary artery pseudoaneurysm as a complication of maxillofacial injuries report of three cases and literature review e366 | squ medical journal, november 2019, volume 19, issue 4 maxillofacial surgery unit at al-nahda hospital in 2015 with a history of mvc. the patient complained of limited mouth opening and deranged occlusion. clinical and radiographic examinations revealed a medially displaced right mandibular subcondylar fracture. subsequently, the patient underwent open reduction and internal fixation of the fracture through a retromandibular approach. during the reduction stage, a sudden episode of massive bleeding was encountered from and around the posterior-superior margin of the mandibular ramus. the bleeding was initially controlled with pressure packs and the surgery was abandoned. the patient was then transferred to the radiology department at khoula hospital where he underwent urgent dsa, which revealed an map just inferior to the right condylar head [figure 3a]. the pseudoaneurysm was successfully embolised with platinum coils [figure 3b]. subsequently, the right subcondylar fracture was reduced and fixed through the previous approach uneventfully. discussion most of the reported vascular aneurysms in the head and neck region tend to occur intra-cranially; only a small percentage reside in the extra-cranial part of the carotid and vertebral arteries.11 there is a scarcity of head and neck pseudoaneurysm reports in the literature, with the majority of data based on case reports and case series; this supports the relatively rare occurrence of these lesions.1–5 head and neck pseudoaneurysms have been reported to occur spontaneously or as a complication of surgical or traumatic injuries, chemoradiotherapy, carcinomas, arteriosclerotic disease and infections.1–10 mycotic aneurysms caused by infections were the most common form of extra-cranial carotid artery aneurysms in the past.9 however, with advances in infection control and antimicrobial therapy, aneurysms caused by infections are uncommon nowadays.9 trauma, penetrating or blunt, is currently the most common cause of head and neck pseudoaneurysms, representing nearly half of the reported cases.12–14 pseudoaneurysms occurring as a consequence of surgical procedures such as orthognathic, temporomandibular joint (tmj), dental and ear, nose and throat surgeries have been reported in recent years as iatrogenic causes of maxillofacial pseudoaneurysms.4–6,10,11,15–18 generally, branches of the external carotid artery are well protected from external insults. nevertheless, some branches are more prone to trauma due to their anatomical location; for example, the superficial temporal artery is vulnerable to both penetrating and blunt trauma due to its superficial location.15 in addition, facial fractures involving the mandibular condyle may contribute to vascular injury of the maxillary artery due to its close proximity, making it vulnerable to injury by the fracture fragments during the initial trauma or during surgical reduction.7,18 orthognathic and tmj surgeries are the most common procedures performed close to the infra-temporal region, which poses a risk to the maxillary artery; however, vascular injuries during these surgeries are uncommonly reported.11,14 pseudoaneurysms of the external carotid artery, facial and palatine arteries have also been reported in association with maxillofacial trauma or surgeries.16–18 given the large volume of maxillofacial trauma, surgical management of facial fractures, orthognathic and tmj surgeries performed at al-nahda and khoula hospitals over the past 25 years, only the current three cases of map were diagnosed.19,20 this confirms the relatively rare occurrence of this complication. the clinical presentation of facial pseudo aneurysms is variable and depends on the location of figure 3: digital subtraction angiography images of the lateral view of the right external carotid artery (eca) of a 32-year-old male patient showing (a) a small maxillary artery pseudoaneurysm (map; white arrow) and a small focal narrowing due to spasm of the eca close to the pseudoaneurysm (red arrow). (b) the map was completely resolved using coil embolisation. noor j. al-saadi, abdulaziz bakathir, ali al-mashaikhi, ahmed al-hashmi, ahmed al-habsi and faisal al-azri case report | e367 access surgically, in addition to the precise localisation and selective occlusion of the lesion.12,25 although coils are the most commonly used embolisation material, stents and liquid agents (such as glues and thrombin) have also been used.25 in the current cases, the minimally invasive endovascular embolisation technique was used utilising platinum coils with no complications and good outcomes. conclusion maxillary artery pseudoaneurysm is an unusual complication of maxillofacial trauma. while operating in the area of this artery, a surgeon must maintain a high level of suspicion if an intraoperative brisk or massive bleeding event is encountered. utilisation of interventional radiology techniques in the management of these lesions can be accomplished with minimal complications. references 1. sclafani ap, sclafani sj. angiography and transcatheter arterial embolization of vascular injuries of the face and neck. laryngo scope 1996; 106:168–73. https://doi.org/10.1097/00005537-199 602000-00012. 2. esteller e, león x, de juan m, quer m. delayed carotid blowout syndrome: a new complication of chemoradiotherapy treatment in pharyngolaryngeal carcinoma. j laryngol otol 2012; 126:1189–91. https://doi.org/10.1017/s0022215112001910. 3. cheng ky, lee kw, chiang fy, ho ky, kuo wr. rupture of radiation-induced internal carotid artery pseudoaneurysm in a patient with nasopharyngeal carcinoma--spontaneous occlusion of carotid artery due to long-term embolizing performance. head neck 2008; 30:1132–5. https://doi.org/10.1002/hed.20753. 4. lanigan dt, hey j, west ra. hemorrhage following mandibular osteotomies: a report of 21 cases. j oral maxillofac surg 1991; 49:713–24. https://doi.org/10.1016/s0278-2391(10)80235-6. 5. lanigan dt, hey jh, west ra. major vascular complications of orthognathic surgery: false aneurysms and arteriovenous fistulas following orthognathic surgery. j oral maxillofac surg 1991; 49:571–7. https://doi.org/10.1016/0278-2391(91)90337-l. 6. elton vj, turnbull iw, foster me. an overview of the management of pseudoaneurysm of the maxillary artery: a report of a case following mandibular subcondylar osteotomy. j craniomaxillofac surg 2007; 35:52–6. https://doi.org/10.1016/j. jcms.2006.11.002. 7. yeo ms, goh tl, nallathamby v, cheong ec, lim tc. maxillary artery injury associated with subcondylar mandible fractures: a novel treatment algorithm. craniomaxillofac trauma reconstr 2012; 5:83–8. https://doi.org/10.1055/s-0032-1313353. 8. kamath g, naalla r, pai vb, narayanan r. left maxillary artery pseudoaneurysm: a rare and late postoperative complication after head and neck cancer treatment. bmj case rep 2014; 13:2014. https://doi.org/10.1136/bcr-2013-203078. 9. dunn gp, uppaluri r, hessler jl, layland mk, derdeyn cp, sunwoo jb. mycotic pseudoaneurysm of the internal maxillary artery: case report and review of the literature. arch otol aryngol head neck surg 2007; 133:402–6. https://doi.org/10.10 01/archotol.133.4.402. the involved vessel; in most cases, these lesions are asymptomatic.13,14 clinical signs and symptoms may occur immediately or weeks-to-months following the initial vascular insult.13,14 headache, facial and neck pain, pulsatile mass, local nerve compression, vascular thromboembolism and vascular rupture have been reported as clinical features of maxillofacial pseudo aneurysms.13 vascular thromboembolism as a compl ication of pseudoaneurysm has also been clinically reported as monocular blindness, transient ischaemic attack and stroke.13 vascular ruptures usually present as brisk bleeding either spontaneously or following an insult.16–18 diagnosis of arterial pseudoaneurysm in the facial region requires careful assessment. ultrasonography has a limited role in areas obscured by bone and thicker fatty tissues, such as the mandible, where visualisation becomes more difficult and less reliable.21 computed tomographic angiography and magnetic resonance angiography are non-invasive and highly defined imaging studies that provide detailed information about the aneurysm. nowadays, angiography is the gold standard for diagnosis and a minimally invasive modality for treating pseudoaneurysms.13,19,21 in the literature, there is no consensus or criteria on vascular pseudoaneurysm repair. treatment should be tailored for each case depending on the size and location of the lesion and the fitness of the patient. treatment options include medical management, surgical excision and endovascular embolisation.6,11–13,22–25 spontaneous thrombosis of the aneurysmal sac has been reported in literature, yet the frequency and period at which this occurs is unpredictable.23,25 lotina et al. presented a case series of 12 patients with 13 extra-cranial carotid aneurysms.23 intraoperative findings revealed one complete and 11 partial thromboses of the aneurysmal sac and only one case underwent surgical intervention.23 other studies have demonstrated that spontaneous thrombosis may occur in up to 89% of vascular pseudoaneurysms in 5–90 days.24 in contrast, yi et al. reported an increased morbidity, risk of bleeding and other complications in observational cases of pseudoaneurysms.24 a mortality rate of 70% for non-operated cases of carotid artery aneurysms has been reported.23 therefore, due to the unforeseeable nature of these lesions, many experts advocate prompt treatment.7,12,15 medical management in terms of antiplatelet and anticoagulant therapies is recommended for small lesions in high-risk patients who are unfit for surgical interventions.24 endovascular embolisation of the facial pseudo aneurysms is superior to surgical treatment as it provides direct access to areas that might be difficult to https://doi.org/10.1097/00005537-199602000-00012 https://doi.org/10.1097/00005537-199602000-00012 https://doi.org/10.1017/s0022215112001910 https://doi.org/10.1002/hed.20753 https://doi.org/10.1016/s0278-2391%2810%2980235-6 https://doi.org/10.1016/0278-2391%2891%2990337-l https://doi.org/10.1016/j.jcms.2006.11.002 https://doi.org/10.1016/j.jcms.2006.11.002 https://doi.org/10.1055/s-0032-1313353 https://doi.org/10.1136/bcr-2013-203078 https://doi.org/10.1001/archotol.133.4.402 https://doi.org/10.1001/archotol.133.4.402 maxillary artery pseudoaneurysm as a complication of maxillofacial injuries report of three cases and literature review e368 | squ medical journal, november 2019, volume 19, issue 4 10. zachariades n, skoura c, mezitis m, marouan s. pseudo aneurysm after a routine transbuccal approach for bone screw placement. j oral maxillofac surg 2000; 58:671–3. https://doi. org/10.1016/s0278-2391(00)90165-4. 11. cameron jl, cameron am. current surgical therapy. 12th ed. philadelphia, usa: elsevier, 2017. 12. yousuf km, khan fh. pseudoaneurysm of head and neck vessels has been frequently observed in road side bomb blast victims. surgeon 2016; 14:142–6. https://doi.org/10.1016/j.sur ge.2014.09.004. 13. hong jt, lee sw, ihn yk, son bc, sung jh, kim is, et al. traumatic pseudoaneurysm of the superficial temporal artery treated by endovascular coil embolization. surg neurol 2006; 66:86–8. https://doi.org/10.1016/j.surneu.2005.10.022. 14. ribeiro ribeiro al, brasil da silva w, alves-junior sde m, de jesus viana pinheiro j. giant life-threatening external carotid artery pseudoaneurysm caused by a mandibular condylar fracture. oral surg oral med oral pathol oral radiol 2015; 119:e95–100. https://doi.org/10.1016/j.oooo.2014.08.017. 15. silva ac, o’ryan f, beckley ml, young hy, poor d. pseudoaneurysm of a branch of the maxillary artery following mandibular sagittal split ramus osteotomy: case report and review of the literature. j oral maxillofac surg 2007; 65:1807–16. https://doi.org/10.1016/j.joms.2005.12.040. 16. madani m, veznedaroglu e, pazoki a, danesh j, matson sl. pseudoaneurysm of the facial artery as a late complication of bilateral sagittal split osteotomy and facial trauma. oral surg oral med oral pathol oral radiol endod 2010; 110:579–84. https://doi.org/10.1016/j.tripleo.2010.03.021. 17. fernández-prieto a, garcía-raya p, burgueño m, muñoz-caro j, frutos r. endovascular treatment of a pseudoaneurysm of the descending palatine artery after orthognathic surgery: technical note. int j oral maxillofac surg 2005; 34:321–3. https://doi.org/10.1016/j.ijom.2004.06.007. 18. hwang sh, joo yh, seo jh, kang jm. proximity of the maxillary artery to the mandibular ramus: an anatomic study using three-dimensional reconstruction of computer tomography. clin anat 2014; 27:691–7. https://doi.org/10.1002/ca.22329. 19. bakathir aa, margasahayam mv, al-ismaily mi. removal of bone plates in patients with maxillofacial trauma: a retro spective study. oral surg oral med oral pathol oral radiol endod 2008; 105:e32–7. https://doi.org/10.1016/j.tripleo.2008.01.006. 20. al-hashmi ak, al-ismaily mi, goss an. a comparative study of the etiology of adult mandibular fractures in the sultanate of oman and south australia. saudi med j 2008; 29:1828–30. 21. lönn l, olmarker a, geterud k, risberg b. prospective rand omized study comparing ultrasound-guided thrombin injection to compression in the treatment of femoral pseudoaneurysms. j endovasc ther 2004; 11:570–6. https://doi.org/10.1583/03-1181.1. 22. bouloux gf, perciaccante vj. massive hemorrhage during oral and maxillofacial surgery: ligation of the external carotid artery or embolization? j oral maxillofac surg 2009; 67:1547–51. https://doi.org/10.1016/j.joms.2009.03.014. 23. lotina s, davidović l, kostić d, sternić n, velimirović d, stojanov p, et al. [aneurysms of the carotid arteries]. srp arh celok lek 1997; 125:141–53. 24. yi ac, palmer e, luh gy, jacobson jp, smith dc. endovascular treatment of carotid and vertebral pseudoaneurysms with covered stents. ajnr am j neuroradiol 2008; 29:983–7. https://doi.org/10.3174/ajnr.a0946. 25. fankhauser gt, stone wm, fowl rj, o'donnell me, bower tc, meyer fb, et al. surgical and medical management of extracranial carotid artery aneurysms. j vasc surg 2015; 61:389–93. https://doi.org/10.1016/j.jvs.2014.07.092. https://doi.org/10.1016/s0278-2391%2800%2990165-4 https://doi.org/10.1016/s0278-2391%2800%2990165-4 https://doi.org/10.1016/j.surge.2014.09.004 https://doi.org/10.1016/j.surge.2014.09.004 https://doi.org/10.1016/j.surneu.2005.10.022 https://doi.org/10.1016/j.oooo.2014.08.017 https://doi.org/10.1016/j.joms.2005.12.040 https://doi.org/10.1016/j.tripleo.2010.03.021 https://doi.org/10.1016/j.ijom.2004.06.007 https://doi.org/10.1002/ca.22329 https://doi.org/10.1016/j.tripleo.2008.01.006 https://doi.org/10.1583/03-1181.1 https://doi.org/10.1016/j.joms.2009.03.014 https://doi.org/10.3174/ajnr.a0946 https://doi.org/10.1016/j.jvs.2014.07.092 december 2007 vol 8 after meeting.indd the learning organisation and health care education *rashid k al-abri and intisar s al-hashmi the ‘learning organisation’ is a concept that is becoming an increasingly widespread philosophy in modern health care institutions. what is achieved by this philosophy depends considerably on one’s interpretation of it and commitment to it. much has been written about the concept of a learning organisation1,2 and some attempts, such as those by critten, and other writers 3 have been made to translate the concept into practice. according to peter senge, learning organisations are: …organisations where people continually expand their capacity to create the results they truly desire, where new and expansive patterns of thinking are nurtured, where collective aspiration is set free, and where people are continually learning to see the whole together.4 so, the concept of the learning organisation is that any successful organisation must continually learn in order to adapt to changes in the environment and grow. any organisation that wants to implement a learning organisation philosophy requires an overall strategy with clear, well defined goals. once these have been established, the tools needed to facilitate the strategy must be identified. the building blocks of a learning organisation are, initially, individuals and then teams, who create, share and act on collective learning. such an organisation operates an organisational learning cycle where quality management department, sultan qaboos university hospital, p.o.box 38, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: ralabri@hotmail.com sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 207-214 sultan qaboos university© submitted 16th july 2007 accepted 19th september 2007 s p e c i a l c o n t r i b u t i o n الصحية الرعاية وتعليم التعلم مؤسسة الهاشمي محمد بنت إنتصار العبري˛ خلفان بن راشد االبداع أجل من قدراتهم وتعزز مستمرة بصورة الناس فيها يتعلم ــة كمؤسس ــينج، س بيتر من وصفه أول هو مفهوم التعلم" ــة "مؤسس امللخص: هذه املنظم. والتفكير ــخصي الش االتقان الذهنية، النماذج املشتركة، الرؤية الفريق، تعلم ــية: رئيس أقسام ــة من خمس التعلم ــة تتكون مؤسس . املعرفة التي بأنه ويوصف احلقيقية، التعلم ملؤسسة ــاس األس احلجر املنظم التفكير يعتبر البعض. بعضها وتتفاعل مع ــة حركية اخلمس ــام األقس ذي موظفني انتاج أجل ــن م احلديثة باملعلومات اعضائه ــد تزوي الى الصحية الرعاية ــدف تعليم يه ــة التعلم. مؤسس في العلوم لتنفيذ ــتعمل تس أهمية النظرية التي لها والنماذج التعليم مفاهيم لذلك هناك بعض اضافة الصحية. الرعاية خدمات نوعية تدعيم مبقدورهم كفاءة وأمانة، يكون بالتفصيل. وصفها يتم التعلم سوف مؤسسة اساسيات للحصول على املراحل الالزمة االدارية. للقرارات وتستطيع تزويد أرضية التعلم، ــة ملؤسس سلبيني. مستلمني ابدا يبقون وال البيئة لتحسني باستمرار يتعلمون اعضاءا التعلم مؤسسة يدعم الذي اتمع في نرى قيادة. ممارس، طبيب الرعاية املستمرة، األدبيات ، الكلمات: مراجعة مفتاح abstract the ‘learning organisation’ is a concept first described by peter senge as an organisation where people continuously learn and enhance their capabilities to create. it consists of five main disciplines: team learning, shared vision, mental models, personal mastery and systems thinking. these disciplines are dynamic and interact with each other. system thinking is the cornerstone of a true learning organisation and is described as the discipline used to implement the disciplines. in a learning organisation, health care education aims to educate its members with up to date knowledge to produce competent and safe personnel, who can promote quality in health care services. in addition, there are some educational concepts and theoretical models, which are of relevance to the learning organisation, and can provide a framework for managerial decisions. the stages required to achieve the principles of a learning organisation will be described in detail. moreover, in a proper culture which supports the learning organisation, members continuously learn to improve the environment and never remain passive recipients. keywords: learning organisation; healthcare education; leadership. r a s h i d k a l a b r i a n d i n t i s a r s a l h a s h m i 208 new knowledge is created, captured, shared and implemented.5, 6 in a learning organisation, managers supported by human resources department professionals have a key role in creating opportunities for individuals and /or teams to learn and sharing learning in work. 7, 8 t h e l e a r n i n g o r g a n i s a t i o n c h a r a c te r i sti c s o f su c c e s sf ul te a m s an organisation development plan is the process through which an organisation develops the internal capacity to be optimally effective in its work and to sustain itself over the long term. organisation development interventions are divided into two basic groups: diagnosis and action or process. team building is one type of process intervention. team work is considered as the fundamental unit and the building block of the learning organisation. teams and team work have been studied by many writers looking for the characteristics that make for success. larson and lafasto looked at high performance groups as diverse as a championship football team and a heart transplant team and found eight characteristics that are always present.9 they are listed below: 1. a clear, elevating goal 2. a results-driven structure 3. competent team members 4. unified commitment 5. a collaborative climate 6. standards of excellence 7. external support and recognition 8. principled leadership te a m f o r m ati o n before a team can learn, it has to be formed. in the 1970s, psychologist b. w. tuckman identified four stages that teams had to go through to be successful. they are: 1. forming: when a group is just learning to deal with one another; a time when minimal work gets accomplished. 2. storming: a time of stressful negotiation of the terms under which the team will work together; a trial by fire. 3. norming: a time in which roles are accepted, team feeling develops and information is freely shared. 4. performing: when optimal levels are finally reached in productivity, quality, decision making, allocation of resources, and interpersonal interdependence.9 fi v e d i s c i pl i n e s c ru c i a l to a l e a r n i n g o r g a n i sati o n there are five disciplines which are crucial to a learning organisation and should be encouraged at all times.4,10 these are as follows, as shown in figure 1. team learning teams, not individuals, are the fundamental learning units and unless a team can learn the organisation cannot learn. consequently, team learning focuses on the learning ability of the group. mature people learn best from each other by reflecting on how they are addressing problems, questioning assumptions and receiving feedback from their team and from their results. through team learning, the learning ability of the group becomes greater than the learning ability of any individual in the group. the discipline of team learning starts with ‘dialogue’, the capacity of members of a team to suspend assumptions and enter into a genuine ‘thinking together’. to the greeks dialogos meant a free-flowing of meaning through a group, allowing the group to discover insights not attainable individually. it also involves learning how to recognize the patterns of interaction in teams that undermine learning.4 shared visions in order to generate a shared vision, large numbers of people within the organisation must draft it, thus empowering them to create a single image of the future. to become reality all members of the organisation must understand, share and contribute to the vision. people will then do things out of personal commitment, not because of external pressure. mental models these are deeply ingrained assumptions, generalisations, or even pictures and images, that influence how we understand the world and how we take action.4 every human being has an internal image of the world, with deep-rooted assumptions. therefore, individuals will behave according to the true mental model that they subconsciously hold and usually not th e l e a r n i n g o r g a n i s at i o n a n d h e a lt h c a r e e d u c at i o n 209 according to the theories in which they claim to believe. if group members can constructively challenge each others’ ideas and assumptions, they can begin to recognise their mental models and to change these to construct a shared mental model for the team. this is essential as the individual’s mental model will control what they think can or cannot be done. personal mastery personal mastery is one of the core disciplines for building a learning organisation. it refers to an individual commitment to life-long learning; it is a continuous and never-ending process. 4 personal mastery can be defined as the process of continually clarifying and deepening an individual’s personal vision. this is a matter of personal choice for the individual and involves persistently assessing in an objective manner the gap between their current and desired proficiencies, and practising and refining skills until they are internalised. this would develop selfesteem and creates the confidence to deal with new challenges. personal mastery has three important elements: commitment to truth, personal vision and creative tension. personal mastery allows individuals to look at their current reality and desired future (commitment to truth and reality), continually focus and clarify their personal vision for the desired future (personal vision) and use these gaps to create the dynamic energy to get to their desired future (creative tension). systems thinking the foundation of any learning organisation is the fifth discipline systems thinking. this is the ability to see the bigger picture, to look at the interrelationships of a system as opposed to simple cause-effect chains thus allowing continuous processes to be studied rather than single snapshots. also, this discipline shows us that the essential properties of a system are not determined by the sum of its parts, but by the process of interactions between those parts. this is why systems thinking is fundamental to any learning organisation as it is the discipline used to implement the disciplines. without it, each of the disciplines would be isolated and consequently not achieve their objective. systems thinking enables the formation of an integrated system, whose properties exceed the sum of its parts. nevertheless, all of the other four disciplines mentioned above are required to successfully implement systems thinking. system thinking is the mainstay of a true learning organisation, integrating the above disciplines and is a way of discovering solutions to complex problems. this discipline enables interrelationships between systems and teams; at the same time, it allows the organization, through linear and logical thinking, to understand the source of and the solutions to modern problems. in summary, the five factors identified are dynamic in the way they interact with each other. for instance, when people are given genuine freedom and are trusted to handle their jobs through adequate support from other team members and appropriate resources, innovation and diversity of ideas will increase.11 this will cultivate a sense of the bigger picture and increase their capacity to know and act upon the events. figure 1: the five disciplines of a learning organisation r a s h i d k a l a b r i a n d i n t i s a r s a l h a s h m i 210 t h e l e a r n i n g o r g a n i s a t i o n a n d h e a l t h c a r e e d u c a t i o n the aim of professional health care education is to educate health care personnel with up to date knowledge and skills, either by theoretical learning through attending courses or practical through training programmes. the core purpose of health care education is to promote quality in health care service by having competent and safe personals. tr a i n i n g a n d l e a r n i n g i s sue s training can help shape ideas and aspirations, because it involves learning new things. depending on the type of training, it can be the most effective way of learning. the difference between training and learning is that individuals are different when it comes to learning. this can lead to a number of unpredictable outcomes, such as increased motivation and self-confidence, changing attitudes and insights which shape future actions.12, 13 e d u c ati o n a l c o n c e p ts a n d th e o r e ti c a l mo d e l s the use of the term theory in education does not need to imply something remote from the day to day experience of the teacher. it is suggested that there is no real dichotomy between theory and practice. also, to some extent, theory serves to provide a rationale for decision-making. managerial activity is enhanced by an explicit awareness of the theoretical framework underpinning practice in educational institutions.14 theory is useful as long as it has relevance to practice in education. theodossin clarifies that academics tends to want understanding for knowledge, while managers seek understanding for action.15 in discussing the relevance of educational concepts to the learning organisation the following should be taken into account:16, 17 awareness organisations must be aware that learning is necessary and must take place at all levels, not just the management level. once the educational institution has accepted the need for change, it is then responsible for creating the appropriate environment in order for this change to occur. environment centralised, mechanistic structures do not create a good environment as individuals do not have a comprehensive picture of the whole organisation and its goals. this causes political and parochial systems to be set up which stifle the learning process. therefore a more flexible and a flatter structure, which encourages innovations, would be more suitable. the flatter structure also promotes the passing of information between workers, so creating a more informed work force. it is necessary for management to embrace a new philosophy: to encourage openness, reflectivity and accept error and uncertainty. staff members need to be able to question decisions without the fear of reprimand. this questioning can often highlight problems at an early stage and reduce time consuming errors. one way of overcoming this fear is to introduce anonymity so that questions can be asked or suggestions made, but the source is not necessarily known. leadership in a learning organisation, leaders are designers, stewards and teachers. they are responsible for building organisations.4 leaders should promote the systems thinking concept and encourage learning to help both the individual and the organisation in learning. it is the leader’s responsibility to help change the individual views of team members. for example, they need to help the teams understand that competition is a form of learning, not a hostile act. management must provide commitment for longterm learning in the form of resources. the amount of resources available (money, personnel and time) determines the quantity and quality of learning. this means that the organisation must be prepared to support this. leaders have to generate and manage creative tension – especially around the gap between vision and reality. mastery of such tension allows for a fundamental shift. it enables the leader to see the truth in changing situations. empowerment ( flatter hierarchies) empowerment has been variously defined, but its core idea is based on creating an environment where others are equipped and encouraged to make decisions in autonomous ways and to feel that they are in control of the outcomes for which they have accepted responsibility. the locus of control shifts from managers to workers (‘empowerment’) thus making workers responsible for their actions, but the managers do not lose their involvement. they still need to encourage, enthuse and co-ordinate the workers. empowerment can help organisations tackle the uncertainties of today’s changing world by drawing out the creative potential of the people who make up the organisation. th e l e a r n i n g o r g a n i s at i o n a n d h e a lt h c a r e e d u c at i o n 211 learning from mistakes staff members need to find out what failure is like so that they can learn from their mistakes in the future. the managers are then responsible for setting up an open, flexible atmosphere in their organisations to encourage their workers to follow their learning example. anonymity can be achieved through electronic conferencing; this type of conferencing can also encourage different sites to communicate and share knowledge. finally, the fifth discipline (systems thinking) has close theoretical linkages with single-loop (adaptive) and double-loop (generative) learning.18 adaptive learning routines can help health care professionals to follow pre-set pathways, detect and correct errors. this is also referred to as single-loop learning, an example being the clinical audit. single-loop learning is the method of learning where you find a better way to do a process and it is comparable to the idea of continuous quality improvement. double-loop learning goes a step further and asks, ‘why are we doing the process in the first place?’ the self-generating behaviour resulting from adaptive learning is determined by the operating norms or standards that guide it. developing evidence-based practitioners may be one way to facilitate double-loop learning.19 the learning-loop concept takes into account the cognitive and behavioural aspects of human development; together they form the theoretical foundation of the organisational learning framework.20 at the centre of these approaches is the importance of promoting creative individualism within organisations, so as to make people feel empowered. consequently, employees will be challenged to find better ways of meeting organisational goals and values.21, 22 h e a lth c a r e pr o fe s si o n a l s ’ f o r m s o f k n ow l e d ge a n d h e a lth c a r e q ua l i t y organisational learning and knowledge management are two concepts that have developed in parallel and are often linked in their definitions and practice.23 organisational learning is referred to as changes in the state of knowledge and involves knowledge acquisition, dissemination, refinement, creation and implementation: the ability to acquire diverse information and to share common understanding so that this knowledge can be exploited.24, 25 organisational knowledge is stored partly in individuals in the form of experience, skills and personal capability, and partly in organisations, in the form of documents, records, rules, regulations and standards, etc.26 therefore, the main task for the management is to create a learning environment between individuals and the organisation in order to facilitate the interaction and strengthening of each other’s knowledge.27 thus, organisational learning is collective learning. health care professionals are obligated both to acquire and maintain the expertise needed to undertake their professional tasks. additionally, they are also obligated to undertake only those tasks that are within their competence and to acquire technical knowledge in their field of work. other forms of knowledge (list adapted from nutley and davies,19) which can be gained by health care professionals (hcp) from their learning organisation are: 1. formal knowledge, such as structured programmes and written procedures. this can be gained through attending courses, conferences and workshops. 2. informal knowledge, such as that learned from different informal situations. also, people learn skills and acquire knowledge beyond their specific job requirements. this enables them to appreciate or perform other roles and tasks. 3. tacit knowledge arising from the capabilities of people, particularly the skills that they have developed over time. 4. cultural knowledge relating to the customs, values and relationships with clients and other stakeholders. these are: celebration of success, absence of complacency, tolerance of mistakes, recognition of tacit knowledge, mutual trust, belief in human potential and staff empowerment. by being aware of their role and importance in the whole organisation, the workers are more motivated to ‘add their bit’. this encourages creativity and free-thinking, hence leading to novel solutions to problems. all in all, there is an increase in job satisfaction and health care quality standards. other important issues related to knowledge and high quality service are: 5. flexibility at work allows workers to move freely within departments and enables them to choose their own speciality, whilst at the same time it removes the barriers associated with rigidly structured training programmes and promotes creativity. 6. knowledge and accountability. denyes et al.28 state that scientific accountability is a characteristic of a profession. knowledge, skill and attitude are considered the most basic pre-requisites for r a s h i d k a l a b r i a n d i n t i s a r s a l h a s h m i 212 accountability. responsibility must be given or taken to carry out an action and then authority is legitimised power, i.e. the legal right to carry out the responsibility.29 an example of this is the implementation of a staff appraisal system. 7. knowledge and empowerment equal participation must be allowed at all levels so that members can learn from each other simultaneously. in the uk, the government ensures that the national quality standards are applied consistently within local practice or units through a system of clinical governance. the key characteristics of clinical governance are the importance and interaction of extended life-long learning and modernised professional selfregulation.30, 31, 32 the combination of all three working well will serve good clinical practice and deliver the requirements of the general medical council for good medical practice.33 first, clinical governance is a process by which each part of the uk national health service (nhs) quality-assures its clinical decisions, backed by a new statutory duty of quality. second, lifelong learning allows nhs staff to identify the training needs across professions to aid clinical team working. third, professional self-regulation provides clinicians with the opportunity to help set standards. the concept has some parallels with the more widely known corporate governance, in that it addresses those structures, systems and processes that assure quality, accountability and proper management of an organisation’s operation and delivery of service. however, clinical governance applies only to health and social care organisations, and only to those aspects of such organisations that relate to the delivery of care to patients and their carers; it is not concerned with the other business processes of the organisation, except in so far as they affect the delivery of care. the concept of ‘integrated governance’ has emerged to refer jointly to the corporate governance and clinical governance duties of healthcare organisations.34 c r e a t i n g a c u l t u r e t h a t s u p p o r t s t h e l e a r n i n g o r g a n i s a t i o n learning organisations embrace change and constantly create the reference points to precipitate an everevolving structure that has a vision of the future built in to it. according to richard karash, learning organisations are healthier places to work because they: 1. garner independent thought 2. improve quality 3. develop a more committed work force 4. increase our ability to manage change 5. give people hope that things can get better 6. stretch perceived limits 7. are in touch with a fundamental part of our humanity.35 one of the biggest challenges that must be overcome in any organisation is to identify and breakdown the ways people reason defensively. everyone must learn that the steps they use to define and solve problems can be a source of additional problems for the organisation.36 h o w t o a c h i e v e t h e p r i n c i p l e s o f a l e a r n i n g o r g a n i s a t i o n the first step is to create a timeline to initiate the types of changes that are necessary to achieve the principles of a learning organisation; these changes are described in details by gaphart as follows:37 sta ge o n e to create a communication system to facilitate the exchange of information, which is the basis on which any learning organisation is built. the use of technology has and will continue to alter the workplace by enabling information to flow freely and to “provide universal access to business and strategic information.” sta ge t wo to organize a readiness questionnaire, which acts as a tool to assess the distance between where an organisation is and where it would like to be, in terms of the following seven dimensions: 1. providing continuous learning 2. providing strategic leadership 3. promoting inquiry and dialogue 4. encouraging collaboration and team learning 5. creating embedded structures for capturing and sharing learning 6. empowering people toward a shared vision 7. making systems connections the questionnaire is completed by all employees or a th e l e a r n i n g o r g a n i s at i o n a n d h e a lt h c a r e e d u c at i o n 213 sample of them; its results are then analysed to form an assessment profile, used to design the learning organisation initiative. sta ge th r e e to commit to developing, maintaining and facilitating an atmosphere that garners learning. sta ge f o ur with the help of all employees, is to create a vision of the organisation and write a mission statement. sta ge fi v e through training and awareness programmes, is to try to expand employees’ behaviours to develop skills and understanding attitudes needed to reach the goals of the mission statement, including the ability to work well with others, become more verbal, and network with people across all departments within the organisation.38 sta ge si x to communicate a change in the company’s culture by integrating human and technical systems. sta ge se v e n to initiate the new practices by emphasizing team learning and contributions because employees will then become more interested in self-regulation and management, and be more prepared to meet the challenges of an ever-changing workplace. sta ge e i gh t to allow employees to question key business practices and assumptions. sta ge n i n e to develop workable expectations for future actions.38 sta ge te n to remember that becoming a learning organisation is a long process and that small setbacks should be expected. c o n c l u s i o n a learning organisation encourages its members to improve their personal skills and qualities, so that they can learn and develop. they benefit from their own and other people’s experience, whether they are positive or negative. in a learning organisation, there are more opportunities to be creative and this helps ensure that any individual will be able to cope rapidly with a changing environment and move freely within the organisation. effective leadership is the foremost requirement for the creation of a learning organisation, which is not based on traditional hierarchy, but based on a mix of different people from all levels of the system leading in different ways.39 technological development may replace human resources in some other sectors, but not in the health sector. in the health field, there are very few options for equipment to replace humans. this is one of the explanations for the perpetually high demand for skilled health care professionals all over the world. another factor necessitating the continuous development of health professionals is the nature of their duties. since they are dealing with sick human beings, poor performance can cost lives. r e f e r e n c e s 1. burgoyne j, pedler m, boydell t. towards the learning company: concepts and practices. london: mcgrawhill, 1994. 2. gordon a, parsons d, richards d. employer strategies and investors in people. horsham: labour market intelligence unit, 1994. 3. critten p. investing in people: towards corporate capability. oxford: butterworth-heinemann, 1994. 4. senge p m. the fifth discipline: the art and practice of the learning organisation. london: random house, 1990. 5. nonaka i. the knowledge-creating company. harvard business review 1991; 69:96-104. 6. dixon n. the organisational learning cycle. maidenhead: mcgraw-hill, 1994. 7. garavan t. strategic human resource development. j europ industr train 1991; 15:17-31. 8. watkins ke, ellinger ad. building learning organisation: new roles for managers and human resource developers, professors’ forum, iftdo conference, dublin, 1998. 9. larson c, lafasto f. teamwork: what must go right, what can go wrong. california, newbury park: sage publications, 1989. p.98. 10. senge p, cambron-mccabe n, lucas t, smith b, dutton j, kleiner a. schools that learn. a fifth discipline field book for educators, parents, and everyone who cares about education. new york: doubleday, 2000. 11. harung hs, heaton dp, alexander cn. evolution of organisations in the new millenium. leadership & organis develop j 1999; 20:198-207. 12. dephillps fa, berliner wm, gribbin, jj. management r a s h i d k a l a b r i a n d i n t i s a r s a l h a s h m i 214 of training programmes. new york: richard irwin, 1960. 13. antonagopoulou ep. do individuals change from learning as well as learn from changing? proceedings of the 2nd international organisational learning conference, lancaster, uk, july 1996. 14. bush t. theories of educational management. 2nd ed. london: paul chapman publishing, 1995. 15. theodossin e. management education and management theory. coombe lodge reports, 1982; 15:137-148. 16. dodgson m. organisational learning: a review of some literature. organisation studies 1993; 14:375-394. 17. mabey c, salaman g, storey j. human resources management: a strategic introduction. oxford: blackwell, 1998. 18. senge pm. the fifth discipline. the art and practice of the learning organisation. london: century business, 1992. 19. nutley sm, davies hto. developing organisational learning in the nhs. med educ 2001; 35:35-42. 20. yeo r. from individual to team learning: practical perspectives on the learning organisation. team perform managt j 2002; 8:157-170. 21. schein eh. empowerment, coercive persuasion and organisational learning: do they connect? the learning organis 1999; 6:163-172. 22. robbins sp. management. 4th ed. englewood cliffs, nj: prentice-hall, 1994. 23. wang cl, ahmed pk. organisational learning: a critical review. the learning organisation 2003; 10:8-17. 24. lyles m. learning among joint venture sophisticated firms. managt internat review 1998; 28:85-98. 25. fiol m. consensus, diversity, and learning in organisation. the learning organisation 1994; 4:149-158. 26. weick k, roberts k. collective mind in organisations. heedful interrelating of flight decks. admin sci quart 1993; 38:357-381. 27. alder ps, goldoftas b, levine, di. flexibility versus efficiency? a case study of model changeovers in the toyota production systems. organis sci 1999; 10:43-68. 28. denyes mj, connor na, oakley d, ferguson s. integrating nursing theory: practice and research through collaborative research. j advan nurs 1998; 14:141-145. 29. manley k. knowledge for nursing practice. in: jolley a, ed. nursing: a knowledge base for practice. london: edward arnold, 1991. 30. headrick la, wilcox pm, batalden pb. inter-professional working and continuing medical education. bmj 1998; 316:771-774. 31. holm ha. quality issues in continuing medical education. bmj 1998; 316. 32. british medical association, academy of medical royal colleges copmed, committee of undergraduate deans, london. making self-regulation work at local level. london: bma, 1998. 33. general medical council. maintaining good medical practice. london: gmc, 1998. 34. clinical governance. from: http://en.wikipedia.org/ wiki/clinical_governance. accessed august 2007. 35. mason mk. new directions: the learning organization. www.moyak.com. accessed june 2007. 36. argyris c. teaching smart people how to learn. harvard business review; 1991; 69:99-109. 37. gephart m a, marsick vj, van buren me, spiro ms. learning organisations come alive. train & develop, 1996; 50:35-45. 38. navran associates newsletter. from: http://www.navran.com. accessed august 2007. 39. senge p. leading learning organization. training & develop 1996; 50:36-37. the emergence of surgical expertise in the care of the critically injured patient in the arab gulf states john d s reid editorial squ med j, august 2009, vol. 9, iss. 2, pp. 113-115 , epub 30th june 2009 invited article, submitted 26th apr 09, accepted 23rd may 09 بزوغ اخلربة اجلراحية يف حالة رعاية املريض املصاب بدرجة حرجة يف دول اخلليج العربي جون دي اس ريد department of surgery, st paul’s hospital, vancouver, canada email: jreid@providencehealth.bc.ca the arab gulf states have undergone a rapid emergence from a rural society into modern urbanisation in a relatively short period of time. in the past century, the world’s hunger for petroleum products has accelerated the interaction with arabian society and brought new dangers, the most striking being the introduction of the automobile. according to world health organization statistics,1 the death rate on the roads is approximately four-fold greater in the gulf states than in europe or america and the financial cost is in the billions of dollars.2 in response to this epidemic, extensive prevention programmes have been initiated, aimed at curbing the volume of violent road injuries and death. an example of this is the salim and salimah, safe and soundtm campaign in oman,3 which targets the unsafe practice of children riding, unrestrained, in the laps of adults and promotes the use of child car-safety seats. while the prevention of road injury and death is a major societal challenge for the gulf states, so also is the response of the trauma system to the patient, once injured. the goal is the reduction of further harm and the delivery of optimal care. the principles of care have been promulgated worldwide, including the gulf states, by the american college of surgeons (acs), committee on trauma, through the advanced trauma life support course. the acs has also published the details of the infrastructure thought necessary for this care in resources for optimal care of the injured patient.4 the move towards western-style health care began with medical missionary work. in oman, the reformed church of america established early hospitals.5 with the stimulus of petroleum resource development, it was the vision of the leaders that was instrumental in bringing modernised health care to the people. by 1947, king abdul aziz ibn saud of saudi arabia saw the need for modern medicine in his country. the extensive health programme there today had humble beginnings with the king purchasing four complete ‘packaged’ hospitals from american army surplus to begin to serve the needs of his people.6 over the ensuing years, a system of both privately and publicly funded hospitals has been built up to the extent that the gulf states now have excellent medical facilities.7 today, oman has 58 hospitals, 49 of which are directly administered by the ministry of health.8 this rapid development of modern medical care necessitated the importation of both technology and personnel to the middle east. in addition, some medical care has been, and continues to be outsourced. the outsourcing can occur between the gulf states, but also to other states in the middle east, or farther afield to europe, britain, india and america. the challenge for the gulf states is sustainability. the importation and exportation of medical care is costly and consumes resources that could be used in establishing a cost-effective system of care for their populations. governments are now attuned to the problem and are currently directing the emergence of surgical expertise in the care of the critically injured patient in the arab gulf states 114 | squ medical journal, august 2009, volume 9, issue 2 efforts at limiting the tenure of foreign doctors9 while stimulating the importation of expertise through medical and fellowship training by their own citizens in the west. trainees in all areas of medical and surgical specialisation have travelled to centres of excellence around the world. their return has resulted in the gulf states accruing an ever-expanding pool of well-trained caregivers.10 despite the development of excellent education systems and medical specialty boards, this pool of citizen-physicians is in the minority and in oman remains small.11 for the returning trainee, there can be a number of impediments. there is a need to establish a viable practice and maintain the valuable skills learned elsewhere. a burden of administrative work is counterproductive to this occurring, but with the returning trainee who brings new ideas and enthusiasm there can be a natural tendency assign to them the tasks associated with change initiatives. this can hamper the early development of the newly returned doctor. conflicts with the status quo of the established patterns of practice may lead to frustration when models of care, learned at a centre of excellence elsewhere, cannot be quickly and easily initiated at home. it is important for leadership to recognise these challenges to the new doctors and to ameliorate the frustrations while using the opportunity to benefit from their newly acquired expertise. while the difficulty of fitting into the system is common to many practitioners returning from overseas training, it is particularly important in the context of the surgeon caring for the injured patient. not only must they bring their skills to the operating room, but also it is incumbent upon the trauma surgeon to participate in the wider arena of trauma care from injury to outcome. apart from often being a surgical challenge, the treatment of injury is a system problem and requires a systematic response to obtain optimal results. in his landmark studies, trunkey demonstrated this fact leading to organised trauma centres resulting in improved care when measuring preventable death.12 he also described the need for trauma system development.13 the major trauma outcome study14 established the benchmarks for trauma care and permitted refinement of the evaluation of trauma systems such that the performance of a hospital could be judged against known standards. trauma centres and trauma systems can now be evaluated in the context of an accreditation process when combined with an audit process of trauma outcomes. with time, the role of the system in the care of the trauma patient is being refined.15-17 more work needs to be done in developing standards that will evaluate the continuum of care from injury through to rehabilitation of the patient and not just the crude outcome measure of mortality. it is necessary to know if we are also achieving the optimal quality of life possible for the patient given the nature and severity of their injury. audits and accreditation related to trauma injury may not be well developed in the gulf states,11 but they are a necessary component of care. the full spectrum of individuals involved in the care of the trauma patient should be engaged in this process, and it is especially important that surgical expertise be included. the focus of the trauma surgeon is evolving and recent trainees in surgery are aware of this fact. in a recent survey, fewer than 100 residents in the entire united states chose to pursue additional training in trauma and critical care.18 the reasons are likely multifaceted, but current thinking suggests that the increase in non-surgical management of patients, because of improved diagnostics with computed tomography scanning and protocols of nonoperative management, are rendering the specialty less attractive to surgeons. the american association for the surgery of trauma has convened an ad hoc committee to define the future role of the trauma surgeon.19 the solution includes training which many returning gulf state surgeons have acquired. it includes expertise in trauma surgery as well as acute-care surgery and most importantly surgical critical care. this reorganised specialty encompasses areas of practice that have been traditionally a part of surgical training and expertise, but have been fragmented as general surgery moved into many subspecialties and away from acute medicine. it is hoped that this reorganisation of the specialty will revitalise the practice of trauma surgery to make it attractive to those choosing career paths. this challenge is not limited to the west, but also is a challenge for the gulf states. if surgeons cannot be attracted into the management of trauma, society as a whole will suffer through the loss of expert care for the injured patient. john d s reid editorial | 115 care of the injured patient in the arab gulf states has a special significance for the population, particularly because of the high incidence of motor vehicle-related trauma. while efforts are being directed towards primary prevention and, in many ways, the greatest gain from morbidity and mortality can be achieved here, there is a need to craft a system that minimises the outcome of the injury when it does occur. not only does this require system organisation, but also it is essential that the expertise gained abroad by surgeons training in trauma and critical care be incorporated into the system. references 1. world heath organization, global burden of disease, 2008. from http://www.who.int/healthinfo/ global_burden_disease/en/. accessed april 2009. 2. martin j. arab traffic jam: road traffic accidents are costing arab states billions of dollars annually, not to mention the catastrophic loss of life. the middle east. ic publications ltd., march 2005. 3. salim and salimah, safe and sound. from http:// www.salimandsalimah.org. accessed april 2009 4. committee on trauma. resources for optimal care of the injured patient: 2006. chicago: american college of surgeons, 2006. 5. de novo ja. american interests and policies in the middle east 1900 -1939. minneapolis: university of minnesota press, 1963. 6. sanger rh. ibn saud’s program for arabia. middle east j 1947; 1:180-90. 7. el-bushra, el-sayed. health care pattern and planning in saudi arabia. geojournal 1989; 18:361-8. 8. sultantate of oman, ministry of health. from http:// www.moh.gov.om. accessed april 2009. 9. arabian business.com. saudi blocks employment for foreign doctors. from http://www.arabianbusiness. com. accessed april 2009. 10. mufti hs. healthcare development strategies in the kingdom of saudi arabia. new york: kluwer academic/plenum publishers 2000. 11. al dhawi aa, west jw jr, spinelli rj, gompf ta. the challenge of sustaining healthcare in oman. health care manag 2007; 26:19-30. 12. west jg, trunkey dd, lim rc. systems of trauma care. a study of two counties. arch surg 1979; 114:455-60. 13. cales rh, trunkey dd. preventable trauma deaths. a review of trauma care systems development. jama 1985; 254:1059-66. 14. champion hr, copes ws, sacco wj, lawnick mm, keast sl, bain lw jr, et al. major trauma outcome study: establishing norms for trauma care. j trauma 1990; 30:1356-65. 15. simons r, kirkpatrick a. assuring optimal trauma care: the role of trauma centre accreditation. can j surg 2002; 45:288-95. 16. chiara o, cimbanassi s. organized trauma care: does volume matter and do trauma centers save lives. curr op crit care 2003; 9:510-14. 17. liberman m, mulder d, lavoie a, sampalis js. trauma care systems: evolution through evaluation j trauma 2004; 56:1330-5. 18. spain da, miller, fb. education and training of the future trauma surgeon in acute care surgery: trauma, critical care, and emergency surgery. am j surg 2005; 190:212-7. 19. the committee to develop the reorganized specialty of trauma, surgical critical care, and emergency surgery. acute care surgery: trauma, critical care, and emergency surgery. j trauma 2005; 58:614-6. 1department of child health, royal hospital, muscat, oman; 2department of child health, sohar hospital, sohar, oman; 3department of child health, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: nawal.almaskari@gmail.com abstract: on 27 april 2020, the national health service england issued an emergency alert for a new condition owing to the observation of an increasing number of cases of a covid-19-related hyperinflammatory syndrome termed multisystem inflammatory syndrome in children (mis-c). some of the presenting symptoms appeared similar to the kawasaki disease and toxic shock syndrome. we report the cases of six children fitting the criteria of mis-c, admitted to royal hospital and sohar hospital, oman, between the months of june and july in 2020. four of these patients required admission at the paediatric intensive care unit for inotropic support while two were admitted to the paediatric ward on suspicion of appendicitis. mis-c has been reported in a small number of individuals below the age of 21 years with a median age of 9–10 years. five of the current patients were aged less than the median age reported in the existing literature. all of the patients showed complete recovery with supportive management, intravenous immunoglobulin and steroids, with one patient requiring interleukin-6 inhibitor (tocilizumab). keywords: covid-19; sars-cov-2; kawasaki disease; multisystem inflammatory syndrome in children; toxic shock syndrome; case report; oman. sars-cov-2-related multisystem inflammatory syndrome in children a case series *nawal al maskari,1 kholoud al mukhaini,1 safiya al abrawi,1 mohammed al reesi,2 juhaina al abulsalam,1 nagi elsidig3 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e302–307, epub. 21 jun 21 submitted 19 aug 20 revision req. 22 oct 20; revision recd. 27 oct 20 accepted 2 dec 20 unique features including older age at onset with a median age of 10 years, abdominal symptoms and predominant cardiac manifestations.7 with only a few initial cases being reported from europe and the united states,3 much remains to be understood about this syndrome. in this regard, there is a paucity of publications describing this syndrome in the middle east with only one reported case of a female saudi child with mis-c who died following rapidly-developing multi-organ failure.8 the total population of oman has been estimated at 5,149,271. at the time of writing this case report, 68,400 cases of covid-19 had been reported, out of which 4,379 were children accounting for approximately 6.6% of the total number of cases.9 to the best of the authors’ knowledge, this case series, describing the characteristics and outcomes of six children who were diagnosed with mis-c in oman, is the first of its kind in the middle east. the current patients fit the criteria for case definition of the mis-c syndrome. five of them were less than seven years of age at the time of presentation and were therefore younger than the reported international median age of 8.3 years.10 this report also aimed to emphasise the early detection of clinical manifestations of the inflammatory response of the digestive system to prevent unnecessary surgical intervention. additional clinical and epidemiological studies are needed to measure the true prevalence of this disease as the country continues to witness an increase in covid-19 infections. covid-19 infections have been shown to occur less frequently in children and is usually associated with a milder clinical course among them.1 however, recent studies from europe and the united states reported a surge of a covid19-related hyperinflammatory multisystem syndrome in individuals below the age of 21 years termed multisystem inflammatory syndrome (mis-c).2,3 the national health service (nhs) england described this new severe inflammatory syndrome on 27 april 2020.4 mis-c can be diagnosed at any time during the course of a covid19 infection. it mostly occurs 1–6 weeks following the infection. it may overlap with an acute covid-19 presentation.5,6 the following are the current national guidelines for the diagnosis of mis-c in oman as per case definition by the who: patients must be <19 years of age with fever lasting longer than 3 days; any two of the following conditions must also be fulfilled: (1) any of the subconditions of (i) mucocutaneous manifestations, (ii) hypotension, (iii) myocardial dysfunction (echocardiography findings or elevated troponin), (iv) evidence of coagulopathy, (v) acute gi; (2) a high amount of inflammatory markers; (3) no other apparent microbes; (4) evidence of covid-19 (reverse transcription polymerase chain reaction, serology) or contact. mis-c appears to share many symptoms with kawasaki disease (kd) such as mucocutaneous manifestations and high inflammatory markers. however, mis-c is characterised by certain this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.021 case series https://creativecommons.org/licenses/by-nd/4.0/ case series | e303 ta bl e 1: c lin ic al fe at ur es o f s ix c hi ld re n ag ed 1 – 11 y ea rs w it h m ul ti sy st em in fla m m at or y sy nd ro m e ad m itt ed to a te rt ia ry c ar e ho sp it al in o m an c as e c li n ic al fe at ur es a ge (i n ye ar s) g en de r pi c u / h d u ad m is si on sy m pt om s fe ve r du ra ti on in d ay s a bd om in al pa in d ia rr ho ea c on ju nc ti vi ti s/ ra sh ly m ph ad en op at hy ex tr em it y oe de m a h ep at os pl en om eg al y a lt er ed m en ta l st at us sh oc k r es pi ra to ry sy m pt om s c as e 1 1 m ye s 6 ye s/ 4 d ye s/ 4 d ye s/ 4 d n o ye s ye s n o n o n o c as e 2 3 m ye s 6 ye s ye s ye s ye s ye s n o ye s ye s ye s c as e 3 6 m n o 1 ye s n o n o n o n o n o n o n o n o c as e 4 5 m ye s 6 ye s n o n o n o n o ye s n o ye s n o c as e 5 4 f n o 7 n o n o ye s ye s ye s n o ye s n o ye s c as e 6 11 f ye s 5 n o n o ye s ye s ye s n o n o ye s n o pi c u = p ae di at ri c i nt en siv e c ar e u ni t; h d u = h ig h de pe nd en cy u ni t . ta bl e 2: l ab or at or y te st fi nd in gs o f s ix c hi ld re n ag ed 1 – 11 y ea rs w it h m ul ti sy st em in fla m m at or y sy nd ro m e (m is -c ) a dm itt ed to a te rt ia ry c ar e ho sp it al in o m an c as e l ab or at or y te st (n or m al r an ge ) n p sa r s c ov 2 p c r sa r sc ov -2 ig g a ss ay -a bb ot la bo ra to ri es (< 1. 4) c r p in m g/ dl (< 10 m g/ dl ) fe rr it in in n g/ m l (1 3. 7– 78 .8 ng /m l) il -6 in p g/ m l (0 –7 p g/ m l) tr op on in in pc /m l (< 4 pg /m l) w b c (4 .3 –1 1. 0 × 10 3 / µl ) a lc (1 .9 –9 .8 × 1 03 / µl ) d -d im er in m g/ l (0 .1 –0 .5 m g/ l) so di um in m m ol /l (1 36 –1 45 m m ol /l ) a lt in u /l (1 0– 35 u /l ) c as e 1 po si tiv e po si tiv e 19 9 27 7 23 5 8 19 .5 1. 5 n ot d on e 13 3 17 c as e 2 po si tiv e po si tiv e 24 0 27 7 85 18 8. 5 2. 4 3. 6 12 7 10 0 c as e 3 po si tiv e po si tiv e 59 33 6 48 8 29 5. 5 12 .4 4 13 7 17 c as e 4 po si tiv e po si tiv e 15 8 40 0 n a 12 3. 8 0. 84 4. 64 12 8 97 c as e 5 po si tiv e po si tiv e 18 4 53 8 n a 15 3. 4 1. 4 7. 5 13 6 75 c as e 6 n eg at iv e po si tiv e 21 9 26 3 30 0 64 3. 2 0. 2 4 13 6 30 n p = na so ph ar yn ge al ; s a rs -c ov -2 = se ve re a cu te re sp ira to ry sy nd ro m e c or on av ir us -2 ; p c r = po ly m er as e c ha in re ac tio n; ig g = im m un og lo bu lin g ; c rp = c -r ea ct iv e p ro te in ; i l6 = in te rl eu ki n6; w bc = w hi te b lo od ce ll co un t; a lc = ab so lu te ly m ph oc yt e c ou nt ; a lt = a la ni ne a m in ot ra ns fe ra se ; n a = n ot a va ila bl e. nawal al maskari, kholoud al mukhaini, safiya al abrawi, mohammed al reesi, juhaina al abulsalam and nagi elsidig case one a 22-month-old male child from barka was admitted to the paediatric intensive care unit (picu) at royal hospital on 6 july 2020 with a fever and other kdlike symptoms followed by gastrointestinal (gi) symptoms. the father of the child had tested positive for covid-19 five weeks earlier. on examination, the current patient was febrile and had mucocutaneous manifestations. abdominal examination revealed ascites with the liver measuring 3 cm below the costal margin. information on other specific symptoms and systemic laboratory findings are presented in tables 1 and 2. nasopharyngeal (np) genexpert sars-cov-2 pcr (e gene: 0, n2 gene: 42; cepheid, sunnyvale, california, usa) and igg (4.7 optical density [od]) were positive on day eight of the illness. while the respiratory viral panel and other laboratory profiles were normal, an abdominal ultrasound (us) revealed hepatosplenomegaly with moderate ascites. the chest x-ray (cxr) and echocardiography were normal. the patient showed improvement within 24 hours of treatment [table 3] and was discharged on day 12. the results obtained from repeated tests and echocardiography taken two weeks later were normal. case two a three-year-old male child from sohar was admitted to the picu of sohar hospital on 7 july 2020 for inotropic support on suspicion of mis-c with toxic shock syndrome. the patient had a fever, acute gastroenteritis and mucocutaneous manifestations with a history of exposure to covid-19 eight weeks prior to presentation. he was febrile, sleepy and in shock. the other systemic examinations were standard. laboratory investigations were recorded as shown in table 2 with positive np genexpert sarscov-2 pcr (e gene: 34.2, n2 gene: 38.8; cepheid) and serology on day six of the illness. the patient was then started on treatment. the initial cxr was ta bl e 3: m an ag em en t a nd o ut co m es o f s ix c hi ld re n ag ed 1 – 11 y ea rs w it h m ul ti sy st em in fla m m at or y sy nd ro m e ad m itt ed to a te rt ia ry c ar e ho sp it al in o m an c as e m an ag em en t r es pi ra to ry su pp or t in ot ro pi c su pp or t st er oi d iv ig im m un om od ul at or a nt ib io ti cs a sp ir in a nt ic oa gu la nt o ut co m e c as e 1 n o n o m pr ed 1 do se n o c t x ye s n o di sc ha rg ed c as e 2 v en til at io n ye s m pr ed 1 do se to ci liz um ab c t x & v a n ye s ye s di sc ha rg ed c as e 3 n o n o m pr ed 1 do se n o ta zo ci n ye s ye s di sc ha rg ed c as e 4 n o ye s m pr ed 1 do se n o c t x ye s ye s di sc ha rg ed c as e 5 n o n o m pr ed 1 do se n o c t x n o ye s di sc ha rg ed c as e 6 n o n o m pr ed 1 do se n o c t x ye s n o di sc ha rg ed iv ig = in tr av en ou s i m m un og lo bu lin ; m pr ed = m et hy lp re d; c t x = co -t ri m ox az ol e; v a n = v an co m yc in . figure 1: chest x-rays of a three-year-old male child (case two) with sars-cov-2 related multisystem inflammatory syndrome showing (a) acute respiratory distress syndrome on day one of picu admission (b) complete resolution after five days of treatment. sars-cov-2-related multisystem inflammatory syndrome in children a case series e304 | squ medical journal, may 2021, volume 21, issue 2 case series | e305 normal and echocardiograpgy showed minimal pericardial effusion with an ejection fraction of 65%. on day two of admission, the patient started to have respiratory distress requiring ventilation. the liver was 3 cm below the costal margin. repeated troponin was increased to 87 pg/ml. while repeated cxr demonstrated pulmonary oedema with infiltrates [figure 1a], echocardiography demonstrated depressed left ventricular function at 46%. in view of his worsening condition, the patient was started on tocilizumab as anakinra was unavailable. a us of the abdomen revealed moderate ascites. the patient showed gradual improvement with ventilation and inotropic support. he was extubated on day five and transferred to the paediatric ward (pw) on day six. repeated investigation demonstrated a decrease in inflammatory markers and improvement in the cxr [figure 1b]. the patient was discharged on day 10 with follow-up appointments. case three a six-year-old male child from al seeb was admitted to the pw of royal hospital on 10 july 2020 on the suspicion of acute appendicitis. on examination, he was febrile with tenderness in the right iliac fossa. an appendectomy was performed and the histopathology showed no evidence of inflammation. the patient continued to have a persistent fever with abdominal pain and developed hypotension. a diagnosis of mis-c was suspected based on the history of fever, abdominal pain, hypotension, evidence of coagulopathy and elevated inflammatory markers with positive np genexpert sars-cov-2 (e gene: 34.3, n2 gene: 36.3; cepheid) and igg (4.97 od) done on day one of symptom presentation, along with a history of exposure to covid-19 four weeks prior to presentation at the hospital [tables 1 and 2]. the echocardiography was standard. the patient showed clinical resolution within 48 hours of treatment and was discharged with follow-up appointments. case four a five-year-old male child from wadi bani khalid was admitted to royal hospital on 21 july 2020 with the impression of acute appendicitis in combination with exposure to an individual with covid-19 four weeks prior to presentation. on examination, he was febrile, hypotensive and required picu care for inotropic support. an abdominal us revealed mesenteric lymphadenitis. mis-c was suspected based on the patient’s history of hypotension, elevated inflammatory markers and coagulopathy with evidence of positive np genexpert sars-cov-2 pcr (e gene: negative), n2 gene: 43; cepheid) and igg (3.67 od) on day six of the illness [table 2]. the echocardiography was normal and the patient showed improvement within 24 hours of treatment [table 3]. he was discharged on day five of admission and repeated echocardiography during follow-up was normal. case five a four-year-old female child from al seeb was admitted to royal hospital on 22 july 2020 with a fever associated with mucocutaneous manifestations and evidence of covid-19 exposure one month prior to presentation. on examination, she was febrile with tachycardia and hepatosplenomegaly. mis-c was suspected based on the history, elevated inflammatory markers and coagulopathy with evidence of positive np genexpert sars-cov-2 pcr (e gene: 0, n2 gene: 38.7; cepheid) and igg (3.65 od) on day five of symptoms [tables 1 and 2]. the echocardiography showed mild pericardial effusion. the patient received treatment leading to clinical resolution within 24 hours [table 3]. she was discharged on day four of admission with follow-up appointments. case six an 11-year-old female patient from al amirat was admitted to royal hospital on 23 july 2020 with a fever and mucocutaneous manifestations. the patient was confirmed to have had covid-19 exposure and subsequently tested positive, four weeks prior to presentation of the current symptoms. however, repeated testing for covid-19 on the day of admission for the current symptoms showed a negative result. on examination, the patient was febrile, tachycardic, hypotensive and required inotropic support. the results of the laboratory investigations are presented in table 2. the echocardiography was normal. the patient showed improvement within 72 hours of treatment [table 3] and she was discharged with follow-up appointments. the reporting of the current cases does not contravene with the regulations of the local institutional review board. discussion to the best of the authors’ knowledge, the current case series is the first of its kind to be reported in the middle east. the authors describe six children, five of nawal al maskari, kholoud al mukhaini, safiya al abrawi, mohammed al reesi, juhaina al abulsalam and nagi elsidig whom were omani and one of whom was of indian origin. all six of the patients were previously healthy with negative blood cultures. testing for viral studies was limited during the reported period unless there were a strong need for further testing, which could have change the management plan. five patients tested positive for covid-19 via pcr testing. these patients also had a history of contact with indexed cases four to eight weeks before the onset of symptoms, in keeping with the trends in reported literature supporting the hypothesis that this syndrome is driven by a delayed immunological response following a covid-19 infection. despite the similarities between the clinical features of both kd and mis-c, there are observed differences in favour of a mis-c diagnosis, including the prominent cardiac dysfunction and gi manifestations. while existing research has indicated that 10% of mis-c cases had rare presentations mimicking acute appendicitis and peritonitis, the high incidence of gi involvement in mis-c cases still remains unclear.11 it is noteworthy that two of the six currently reported patients presented with an acute surgical abdomen denoting the broad clinical manifestations of this condition. studies have shown that mis-c can lead to multi-organ failure requiring intensive care with 44–80% of patients needing admission to the picu. treatment procedures for these patients included inotropic support (47%) and invasive ventilation (20–43%).4,10,11 cardiac involvement in this condition typically included impairment in ventricular ejection, pericardial effusion and other coronary abnormalities.7,10 five of the patients in the current case series required picu admission with three of them requiring inotropic and respiratory support. belhadjer et al. described 35 children with mis-c, all of whom required intensive care including extracorporeal membrane oxygenation support which was needed in 28% of the patients.7 all 35 patients included in this study survived and were discharged. notwithstanding the critical nature of this syndrome, the reported survival rates remain high.4,7,10 cardiac involvement in this syndrome is thought to be secondary to inflammatory cell infiltration of the myocardium leading to transient cardiac injury and dysfunction. this is in contrast to myocardial necrosis or fibrosis found in viral myocarditis.12 the nhs england issued an emergency alert in april 2020 with regard to patients under 19 years of age who were admitted to hospitals with fever, shock, cardiac dysfunction and abdominal symptoms and tested positive for covid-19 via pcr testing.13 previous reports were found in nonasian populations, with a median age range of 8–10 years. this is in contrast to kd, wherein the condition occurs predominately in children less than five years of age.3,6,7 interestingly, five of the patients included in the current case series were aged below the reported median age for mis-c [table 1]. mis-c often occurs 1–6 weeks following infection and may overlap with respiratory covid-19 infection.3 the other difference between the two syndromes is the typical presentation of haemodynamic failure in mis-c versus kd, a condition in which a minority of patients present with shock.14 cardiac manifestations of kd typically include a dilated coronary artery and rare decrease in ventricular function. due to the high risk of cardiac involvement in mis-c, patients require frequent assessment during fluid resuscitation.3 as the features of mis-c overlap with bacterial infections, antibiotics should be initiated. ceftriaxone is often suggested for milder illness while metronidazole can also be included in case of gi manifestations. vancomycin and clindamycin are also recommended in case of severe illness.3 the hypothesis that mis-c is not the result of acute viral infection but is rather a post-infectious immune response linked to igg antibody-mediated intensification of disease remains to be understood.14 what is certainly known is that a multi-disciplinary team is required in the management of such patients when considering the various organs involved in this disease.3 this was the approach that was taken for all of the patients included in this case series. given the excessive c-reactive protein levels, interleukin-6 (il-6) may be involved in the myocardial depression.13 the majority of patients in the current report received therapies that have been used for the treatment of kd including intravenous immunoglobulin and methylprednisolone with an excellent clinical and laboratory response. biological drugs such as tocilizumab were used only in one patient to combat the indication of progressive respiratory failure and acute respiratory distress syndrome [figure 1b]. once the patient showed clinical improvement, he was extubated following 72 hours of invasive ventilation after receiving tocilizumab, an il-6 inhibitor. all of the patients were discharged from the hospital in good condition with follow-up appointments [table 3]. conclusions the clinical presentation of sars-cov-2-related mis-c is broad with some patients presenting with features of acute abdomen. leading to severe and life-threatening manifestations, this syndrome can steer patients into rapid clinical deterioration. therefore, early diagnosis sars-cov-2-related multisystem inflammatory syndrome in children a case series e306 | squ medical journal, may 2021, volume 21, issue 2 case series | e307 and referral to centres equipped with the required subspecialties are recommended. it should be noted that the severity of this disease is transient, usually resulting in high survival rates with proper supportive treatment. a good evaluation of the possibility of acute abdomen related to mis-c is essential to prevent unnecessary surgical intervention. references 1. qiu h, wu j, hong l, luo y, song q, chen d. clinical and epidemiological features of 36 children with coronavirus disease 2019 (covid-19) in zhejiang, china: an observational cohort study. lancet infect dis 2020; 3:689–96. https://doi. org/10.1016/s1473-3099(20)30198-5. 2. toubiana j, poirault c, corsia a, bajolle f, fourgeaud j, angoulvant f, et al. kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: a prospective observational study. bmj 2020; 6:1–5. https://doi.org/10.1136/bmj.m2094. 3. hennon tr, penque md, abdul-aziz r, alibrahim os, mcgreevy mb, prout aj, et al. covid-19 associated multisystem inflammatory syndrome in children (mis-c) guidelines; a western new york approach. prog pediatr cardiol 2020;101232. https://doi.org/10.1016/j.ppedcard.2020.101232. 4. whittaker e, bamford a, kenny j, kaforou m, jones ce, shah p, et al. clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2. jama 2020; 324:259–69. https://doi.org/10.10 01/jama.2020.10369. 5. debiasi rl, song x, delaney m, bell m, smith k, pershad j, et al. severe covid-19 in children and young adults in the washington, dc metropolitan region. j pediatr 2020; 223:199–203. https://doi.org/10.1016/j.jpeds.2020.05.007. 6. verdoni l, mazza a, gervasoni a, martelli l, ruggeri m, ciuffreda m, et al. an outbreak of severe kawasaki-like disease at the italian epicenter of the sars-cov-2 epidemic: an observ ational cohort study. lancet 2020; 395:1771–8. https://doi.org/10.10 16/s0140-6736(20)31103-x. 7. belhadjer z, méot m, bajolle f, khraiche d, legendre a, abakka s, et al. acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sarscov-2 pandemic. circulation 2020;142:429–36. https://doi. org/10.1161/circulationaha.120.048360. 8. al-aamri ma, al-khars ft, alkhwaitem sj, alhassan ak, al aithan am, alkhalifa fh, et al. a saudi g6pd deficient girl died with pediatric multisystem inflammatory syndromecovid-19. medrxiv [preprint] 2020. https://doi.org/10.1101/ 2020.07.08.20137497. 9. al yazidi ls, al hinai z, al waili b, al hashami h, al reesi m, al othmani f, et al. epidemiology, characteristics and outcome of children hospitalized with covid-19 in oman: a multi center cohort study. int j infect dis. 2021 mar;104:655-660. https://doi.org/10.1016/j.ijid.2021.01.036. 10. feldstein lr, rose eb, horwitz sm, collins jp, newhams mm, f son mb, et al. multisystem inflammatory syndrome in the us. children and adolescents. n engl j med 2020; 383:334–46. https://doi.org/10.1056/nejmoa2021680. 11. chen th, kao wt, tseng yh. gastrointestinal involvement in children with covid-related multisystem inflammatory syndrome. gastroenterol 2020; 120:1887–8. https://doi.org/10.10 53/j.gastro.2020.06.084. 12. blondiaux e, parisot p, redheuil a, tzaroukian l, levy y, sileo c, et al. cardiac mri of children with multisystem inflammatory syndrome (mis-c) associated with covid-19. radiol 2020; 297:e283–8. https://doi.org/10.1148/radiol.2020202288. 13. pouletty m, borocco c, ouldali n, caseris m, basmaci r, lachaume n, et al. paediatric multisystem inflammatory syndr ome temporally associated with sars-cov-2 mimicking kawasaki disease (kawa-covid-19): a multicentre cohort. ann rheum dis 2020; 79:999–1006. https://doi.org/10.1136/annrheumdis-2 020-217960. 14. kabeerdoss j, pilania rk, karkhele r, kumar ts, danda d, singh s. severe covid-19, multisystem inflammatory syndrome in children, and kawasaki disease: immunological mechanisms, clinical manifestations and management. rheumatol int 2021; 41:19–32. https://doi.org/10.1007/s00296-020-04749-4. nawal al maskari, kholoud al mukhaini, safiya al abrawi, mohammed al reesi, juhaina al abulsalam and nagi elsidig https://doi.org/10.1016/s1473-3099%2820%2930198-5 https://doi.org/10.1016/s1473-3099%2820%2930198-5 https://doi.org/10.1136/bmj.m2094 https://doi.org/10.1016/j.ppedcard.2020.101232 https://doi.org/10.1001/jama.2020.10369 https://doi.org/10.1001/jama.2020.10369 https://doi.org/10.1016/j.jpeds.2020.05.007 https://doi.org/10.1016/s0140-6736%2820%2931103-x https://doi.org/10.1016/s0140-6736%2820%2931103-x https://doi.org/10.1161/circulationaha.120.048360 https://doi.org/10.1161/circulationaha.120.048360 https://doi.org/10.1101/2020.07.08.20137497 https://doi.org/10.1101/2020.07.08.20137497 https://doi.org/10.1016/j.ijid.2021.01.036 https://doi.org/10.1056/nejmoa2021680 https://doi.org/10.1053/j.gastro.2020.06.084 https://doi.org/10.1053/j.gastro.2020.06.084 https://doi.org/10.1148/radiol.2020202288 https://doi.org/10.1136/annrheumdis-2020-217960 https://doi.org/10.1136/annrheumdis-2020-217960 https://doi.org/10.1007/s00296-020-04749-4 departments of 1ear, nose & throat, 2paediatrics and 3pathology, chacha nehru bal chikitsalaya, new delhi, india *corresponding author’s e-mail: nehaajmera84@gmail.com varied clinical presentation and management of paediatric vallecular cyst jyoti singh,1 *neha jain,1 mamta jajoo,2 suparna roy,1 ekta narang,1 nidhi mahajan3 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 639–643, epub. 25 nov 21 submitted 1 jun 20 revision req. 9 aug 20; revision recd. 31 aug 20 accepted 23 sep 20 he presented to the clinic. his oral examination was normal. flexible naso-pharyngo-laryngoscopy showed a pale pink-coloured swelling over the lingual surface of the epiglottis [figure 1a]. the contrast-enhanced computed tomography (cect) scan showed an ovoid non-enhancing cystic lesion at the level of the epiglottis [figure 2]. an endoscopy-assisted cyst excision was performed via the trans-oral route under general anaesthesia using cold instruments and electrical cautery [figure 1b]. the histopathological examination revealed a cyst lined by pseudostratified columnar epithelium with dense lymphocytic infiltrate within the sub-epithelium [figure 1c]. analgesics, antibiotics and dexamethasone were administered in the postoperative period and the patient was discharged after 72 hours. no sign of local recurrence was seen during follow-up at two years. case two an 11-month-old male infant presented to the chacha nehru bal chikitsalaya hostpital, new delhi, india in 2019 with respiratory distress, choking spells and frequent regurgitation of feeds. the child had noisy breathing since one month of age and keeping laryngomalacia as a possible diagnosis in mind, the primary hospital had planned for conservative management. the patient did well till eight months of age. during an examination, the patient got agitated, had an apnoeic spell requiring resuscitation and was subsequently intubated. an urgent computed tomography (ct) scan was performed to evaluate a vallecular cyst is a unilocular cystic mass which contains clear and non-infected fluid.1 vallecular cysts are rare anomalies presented with respiratory distress, dysphagia and failure to thrive and they can lead to potentially lifethreatening conditions and sudden airway obstruction.2 symptoms such as chest retraction, apnoeic/cyanotic episodes, choking, postprandial vomiting, coughing and hoarse cry are also seen occasionally.1,3 any infant showing such symptoms should be considered to be having laryngomalacia, upper airway anatomical anomalies or upper airway obstructive lesions such as haemangioma, cystic hygroma, teratoma, hamartoma, dermoid cyst, thyroglossal duct cyst or thyroid remnant.1 nasopharyngolaryngoscopy and imaging are required to confirm the diagnosis and to observe the extension of the cyst.1 the treatment options include cyst aspiration, marsupialisation deroofing of the cyst wall and complete excision.4 this case series details the presentation and management of vallecular cysts in three paediatric cases. informed consent was taken from all the three patients for publication of the article. case one a four-year-old male child presented to the ear nose throat (ent) clinic at the chacha nehru bal chikitsalaya hospital, new delhi, india in 2018, with progressive deglutition problems, intermittent odynophagia and persistent dry cough for a year before this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.013 case report abstract: the current article aims to highlight the varied presentation and management of vallecular cysts. we report three children, aged four years, 11 months and three days, diagnosed with vallecular cyst presenting to the chacha nehru bal chikitsalaya hospital, new delhi, india in 2018 and 2019. they were reviewed retrospectively for clinical presentation, diagnostic tools and treatment options. all three cases had respiratory and feeding difficulties. the diagnosis in all of the three cases was made with laryngoscopy (flexible/direct) and imaging. all three patients were treated with the transoral approach aimed at the excision of the cyst using cold instruments. the postoperative period was uneventful. no recurrences were observed during the long-term follow-up. vallecular cysts should be considered as one of the differentials in children with respiratory distress and dysphagia despite being a rare anomaly. a direct transoral approach is recommended for the excision of the vallecular cyst as it is a safe and reliable method with no recurrences to date. keywords: benign cyst; dyspnea; dysphagia; laryngoscopy; case report; india. varied clinical presentation and management of paediatric vallecular cyst 640 | squ medical journal, november 2021, volume 21, issue 4 the upper airway and a cystic mass, 17 × 8.9 mm in diameter, was seen embedded in the base of the tongue [figure 3]. the patient was shifted to the operation theatre (ot). general anaesthesia was administered and when direct laryngoscopy was performed, a large cystic swelling was found at the base of the tongue. the molar retractor was positioned and retraction sutures were placed to retract the tongue. deroofing of the cyst wall was done and the remnant of the cyst wall was cauterised. the patient was extubated and observed overnight in the intensive care unit (icu). the histopathological examination confirmed the diagnosis of a benign cystic lesion. the child recovered well with no recurrence during the two-year followup. case three a full-term, three-day-old male neonate was referred to the ent clinic from the neonatal icu at the chacha nehru bal chikitsalaya hospital, new delhi, india in 2019 with a history of inspiratory stridor, choking and difficulty in feeding since birth. on examination, the neonate was found to be in respiratory distress. the patient was kept on continuous positive airway pressure and saturation was maintained above 95%. the oral examination was normal. a gentle laryngoscopic figure 2: contrast-enhanced computed tomography (cect) scans of a four-year-old child showing an ovoid cystic mass at the base of the tongue and epiglottis. a: a lateral cect slice showing minimal narrowing of the airway. b: an axial cect slice showing the cyst on the lingual surface of the epiglottis. figure 3: computed tomography scans of an 11-monthold male infant showing (a) an axial view of a cystic ovoid mass measuring 17 × 8.9 mm embedded in the base of the tongue and (b) a lateral view revealing compromised airway due to tongue base cystic lesion. figure 4: images of a full-term, three-day-old male neonate including (a) a computed tomography scan showing the ovoid non-enhancing cyst attached to the right lateral wall of the vallecula, causing airway narrowing and (b) a clinical image showing cyst removal via the trans-oral approach wherein the tongue is retracted and the vallecular cyst is clasped with forceps. figure 1: a: flexible nasopharyngolaryngoscopy scans of a four-year-old child showing a pale pink-coloured swelling over the lingual surface of the epiglottis. b: postoperative endoscopy scan showing excision of the cyst with a cold instrument and the base cauterised. c: microscopic section at x40 magnification showing a cyst lined by stratified squamous epithelium and the cyst wall showing mucous glands with no detection of nuclear atypia. jyoti singh, neha jain, mamta jajoo, suparna roy, ekta narang and nidhi mahajan case report | 641 examination showed a huge vallecular cyst obscuring the endo-larynx. the urgent ct scan that was performed confirmed the origin and extension of the cyst [figure 4a]. antibiotics, dexamethasone and histamine-2 blockers were given in the preoperative period. the patient was taken to the ot, but the endolarynx was difficult to visualise with awake fibreoptic intubation due to the presence of a large cyst and anteriorly placed larynx. two ml of fluid was then aspirated from the cyst which aided in successful intubation. surgery was planned to be performed via the transoral route. the tongue was retracted with sutures (silk 2-0) and the hopkins 30-degree endoscope was used. the cyst was clasped with forceps and excised [figure 4b]. complete excision of the cyst could not be ascertained due to the attachment of the cyst to the lateral wall of the vallecula and inadequate exposure. the base of the cyst was cauterised and the wound was left to heal by secondary intention. the neonate was shifted back to the icu and observed overnight.. the very next day, the neonate was extubated and significant improvement was observed as far as the patient’s respiratory distress was concerned. the diagnosis of a cyst with columnar epithelial lining was confirmed on biopsy. there was no recurrence during 10 month follow up after the surgical procedure. informed written consent was obtained for all surgical procedures and for publication of case series without disclosing patient identity . records are kept in the medical record department of our institute. discussion this article described three cases of paediatric vallecular cysts with varied presentations: a newborn infant presenting with inspiratory stridor and failure to thrive, a child on conservative treatment for laryngomalacia and a toddler presenting with chief complaints of dysphagia. abercrombie described vallecular cysts in 1881.5 vallecular cysts have been given various names such as congenital and ductal cyst, mucus retention cyst, epiglottic cyst and base of tongue cyst.3,6 the incidence of laryngeal cysts is approximately 5% of all benign laryngeal lesions and vallecular cysts make 10.5% of all congenital laryngeal cysts.7,8 thus, a vallecular cyst is a rare entity.9 laryngeal cysts have been classified into ductal, saccular and thyroid foraminal subtypes by de santo.6 ductal cysts are the most common and are frequently found in the vallecula and true vocal cords. cysts can be further classified based on their histology and location as congenital cysts, retention cysts, inclusion cysts and lymphoepithelial cysts.8 vallecular cysts can be found at any age, but their presentation differs depending on an individual’s age and cyst size. they are usually asymptomatic when small in size; however, when they increase in size and/or become infected, they may cause respiratory, feeding and speech difficulties.10 inspiratory stridor and dyspnoea are most commonly seen after birth, and failure to thrive with feeding difficulties is more commonly noted among older children.11 symptoms such as chest retraction, apnoeic/cyanotic episodes, choking, postprandial vomiting, coughing and hoarse cry are also seen occasionally.1–3 vallecular cysts may also cause supraglottic obstruction due to their mass effect and, more importantly, by displacement of the epiglottis posteriorly and inferiorly which may present as episodes of apnoea and cyanosis.12 increased size of these cysts progressively interferes with swallowing, subsequently leading to poor weight gain and failure to thrive.13 due to the anatomical location of the cyst and the small airway in the case of an infant, there is a higher risk of sudden airway obstruction.14 around 12–45% of patients with laryngomalacia may have coexisting airway abnormalities such as a laryngeal cyst.15 subsequent increase in inspiratory negative pressure leads to supraglottic prolapse and the development of laryngomalacia.2 hence, vallecular cyst should be considered in the differential diagnosis of congenital stridor in infants along with laryngomalacia, vocal cord palsy and subglottic haemangioma.11–14,16 a combination of a detailed history and radiological and endoscopic assessment provides the necessary information that can confirm the diagnosis of vallecular cyst.3 lateral radiography, flexible nasopharyngolaryngoscopy, direct laryngoscopy, ct, magnetic resonance imaging (mri) and ultrasonography (usg) of the neck are helpful tools in the assessment of vallecular cyst.3 flexible endoscopy is an initial screening tool. direct laryngoscopy is used in securing the airway, detection of other lesions and surgical management.3 cect scan or mri are essential to determine the size, site, anatomic dimensions and extension of the cyst so that the surgical resection can be planned. mri is a diagnostic modality of choice, but it is time-consuming, requires sedation and is expensive because of which it is not widely used in children with compromised airways obstruction.17 laryngoscopy (flexible/direct) was performed in each of the said three cases to confirm the diagnosis along with a cect scan to determine the dimensions varied clinical presentation and management of paediatric vallecular cyst 642 | squ medical journal, november 2021, volume 21, issue 4 and location of each cyst before planning the respective surgeries. it is to be noted that prenatal diagnosis of this condition is possible with ultrasound scanning or foetal mri which can help surgeons secure the infant’s airway during birth.3 a limited number of case reports and series of vallecular cysts have been published stating different treatment modalities. surgical options for dealing with vallecular cysts in infants and children include cyst aspiration, marsupialisation (i.e. deroofing) and extirpation (i.e. resection and excision).4 however, aspiration of cyst is not advocated for its high recurrence rate.9 hence, aspiration should be considered either as a palliative procedure or as an initial step in cases of difficult intubation for decompression of the cyst.9,12 a definitive treatment of vallecular cyst is marsupialisation or extirpation.4,9 in a retrospective analysis, li et al. found successful outcomes from marsupialisation using micro-instruments, electrocautery, potassium-titanyl-phosphate (ktp) laser and micro-debrider and a 15% recurrence rate.3 gutierrez et al. reported success and safety with marsupialisation using cup forceps and co2 laser. 1 hsieh et al. used a co2 laser in for treating vallecular cysts of 33 patients with successful outcomes and no recurrence.18 the use of a co2 laser is recommended because these are less invasive and if these are used, the healing can be fast.18 a vallecular cyst may often be approached via the direct transoral route or by using suspension laryngoscopy. it is only in rare cases that an external approach is required because recurrent lesions and large cysts need to be extirpated.3 this article has described a simple, direct and transoral approach for managing vallecular cyst without any special equipment. this approach can be safely adopted for infants and the recurrence rate consequent to using this approach is minimal. chen et al. found no recurrence in seven patients who underwent complete cyst excision via the transoral surgical approach.19 similarly, in the above-described cases too, no recurrence has been observed so far during the follow-up period of the three cases which has ranged from 10 months to two years. in the currently reported case series, oral fibreoptic intubation was done in case one and case two was intubated in an emergency. in case three, fibreoptic intubation was difficult, so the cyst was aspirated with a large-bore needle, following which the child was intubated orally. however, in general, it must be noted that tracheostomy may be needed in a few cases to secure the airway.9 conclusion vallecular cysts are rare and the challenge in making an early diagnosis, keeping laryngomalacia in mind, has been ascertained in the above case series. it is important to state that each case requires an individualised approach. the direct transoral approach for excision of the vallecular cyst is recommended as a safe and reliable method based on our experience of with no recurrences to date. further randomised studies are required to determine the best diagnostic and treatment options for this vallecular cysts. a u t h o r s’ c o n t r i b u t i o n s js and nj collected the data. nj drafted the manuscript and handled the designing and formatting. en formulated the abstract. js and sr revised the manuscript while mj and en proofread the manuscript. all authors approved the final version of the manuscript. references 1. gutierrez jp, berkowitz rg, robertson cf. vallecular cysts in newborns and young infants. pediatr pulmonol 1999; 27:282–5. https://doi.org/10.1002/(sici)1099-0496(199904)27:4<282::aidppul10>3.0.co;2-g. 2. yao tc, chiu cy, wu kc, wu lj, huang jl. failure to thrive caused by the coexistence of vallecular cyst, laryngomalacia and gastroesophageal reflux in an infant. int j pediatr otorhinolaryngol 2004; 68:1459–64. https://doi.org/10.1016/j. ijporl.2004.06.004. 3. li y, irace al, dombrowski nd, perez-atayde ar, robson cd, rahbar r. vallecular cyst in the pediatric population: evaluation and management. int j pediatr otorhinolaryngol 2018; 113:198–203. https://doi.org/10.1016/j.ijporl.2018.07.040. 4. hsieh ws, yang ph, wong ks, li hy, wang ec, yeh tf. vallecular cyst: an uncommon cause of stridor in newborn infants. eur j pediatr 2000; 159:79–81. https://doi.org/10.1007/ pl00013809. 5. abercrombie j. congenital cyst in larynx. trans pathol soc lond 1881; 32:33–4. 6. de santo lw, devine kd, weiland lh. cysts of the larynxclassification. laryngoscope 1970; 80:145–76. https://doi. org/10.1288/00005537-197001000-00013. 7. ramesar k, abizzati c laryngeal cysts :clinical relevance and mod ified working classification. j laryngotol 1988; 102: 923-925. 8. arens c, glanz h, kleinsasser o. clinical and morphological aspects of laryngeal cysts. eur arch otorhinolaryngol 1997; 254:430–6. https://doi.org/10.1007/bf02439974. 9. mitchell db, irwin bc, bailey cm, evans jn. cysts of the infant larynx. j laryngol otol 1987; 101:833–7. https://doi. org/10.1017/s0022215100102828. 10. berger g, averbuch e, zilka k, berger r, ophir d, saba k. adult vallecular cyst: thirteen-year experience. otolaryngol head neck surg 2008; 138:321. https://doi.org/10.1016/j. otohns.2007.12.008. jyoti singh, neha jain, mamta jajoo, suparna roy, ekta narang and nidhi mahajan case report | 643 11. tuncer u, aydogan lb, soylu l. vallecular cyst: a cause of failure to thrive in an infant. int j pediatr otorhinolaryngol 2002; 65:133–5. https://doi.org/10.1016/s0165-5876(02)00078-2. 12. labagnara j. cysts of the base of the tongue in infants: an unusual cause of neonatal airway obstruction. otolaryngol head neck surg 1989; 101:108–11. https://doi.org/10.1177/0194 59988910100119. 13. gluckman pgc, chu twf, van hasselt ca. neonatal vallecular cysts and failure to thrive. j laryngol otol 1992: 106:448–9. https://doi.org/10.1017/s0022215100119796. 14. lewison mm, lim dt. apnea in the supine position as an alerting symptom of a tumor at the base of the tongue in small infants. j pediatr 1965; 60:1092–3. https://doi.org/10.1016/ s0022-3476(65)80096-8. 15. mancuso rf, choi ss, zalzal gh, grundfast km, laryngomalacia. the search for the second lesion, arch. oto laryngol. head neck. surg. 122 1996; 302—306. 16. holinger ld. etiology of stridor in the neonate, infant and child. ann otol rhinol laryngol 1980; 89:397–400. https://doi. org/10.1177/000348948008900502. 17. weber pc, kenna ma, casselbrant ml. laryngeal cysts: a cause of neonatal airway obstruction. otolaryngol head neck surg 1993; 109:129–34. https://doi.org/10.1177/01945 9989310900124. 18. hsieh lc, yang cc, su ch, lee ks, chen bn, wang lt. the outcomes of infantile vallecular cyst post co2 laser treatment. int j pediatr otorhinolaryngol 2013; 77:424–8. https://doi. org/10.1016/j.ijporl.2013.01.005. 19. chen ey, lim j, boss ef, inglis jr af, ou h, sie kc. transoral approach for direct and complete excision of vallecular cysts in children. int j pediatr otorhinolaryngol 2011; 75:1147–51. https://doi.org/10.1016/j.ijporl.2011.06.007. submitted 21 apr 22 1 revision req. 21 jul 22; revision recd. 2 aug 22 2 accepted 24 aug 22 3 online-first: september 2022 4 doi: https://doi.org/10.18295/squmj.9.2022.055 5 6 imaging features of dyke-davidoff-masson syndrome 7 asma alhatmi,1 talal almashaikhi,2 *eiman al ajmi3 8 1department of radiology, ibri hospital, ibri, oman; departments of 2clinical physiology and 9 3radiology and molecular imaging, sultan qaboos university hospital, muscat, oman 10 *corresponding author’s e-mail: ealajmi@squ.edu.om 11 12 introduction 13 a 42-year-old man presented to the adult epilepsy clinic in 2019 at sultan qaboos university 14 hospital, muscat, oman, with right motor seizures with occasional generalization and loss of 15 consciousness, right-side hemiparesis, and low intellectual capacity since early childhood. the 16 patient had perinatal hypoxic ischemic injury due to a difficult delivery, which resulted in spastic 17 cerebral palsy. his developmental history revealed delayed milestones and learning difficulties at 18 school. his seizure episodes have increased in frequency over the years, requiring treatment with 19 multiple antiepileptics. despite being on four antiepileptic drugs, the patient continued to 20 experience very frequent seizures. on examination, he had slurred speech and right facial 21 deviation. he was able to walk without support, with a circumduction gait. there was right-sided 22 spastic hemiparesis with brisk tendon reflexes and an extensor plantar response. 23 24 an electroencephalogram (eeg) was done and showed left hemispheric cerebral dysfunction 25 with left hemispheric onset focal motor seizures. computed tomography (ct) and magnetic 26 resonance imaging (mri) of the brain were done and revealed atrophy of the left cerebral 27 hemisphere with ipsilateral compensatory thickening of skull bones and hyperpneumatization of 28 the left frontal and sphenoidal sinuses. the diagnosis of dyke-davidoff-masson (ddm) 29 syndrome was made based on clinical and radiological findings. the patient was managed with 30 antiepileptic medications, muscle relaxants, and physiotherapy. due to his intractable seizures, 31 mailto:ealajmi@squ.edu.om he was offered surgical intervention at an outside facility. we present a case of ddm syndrome 32 with characteristic clinical and radiological findings. it is a rare entity with few reported cases in 33 literature. to best of our knowledge, this is the first case to be reported in our institution. 34 35 informed patient consent for publication was obtained. 36 37 comment 38 ddm syndrome is a rare condition that was described for the first time in 1933 by dyke, 39 davidoff, and masson.1,2 those researchers described the plain skull radiograph features of nine 40 patients who presented with seizures, hemiparesis, facial asymmetry, and mental retardation.1 41 42 there are two types of ddm syndrome: congenital and acquired.2 the congenital or infantile 43 type presents early in infancy, secondary to previous intrauterine brain insults like vascular 44 occlusion or anomaly of the middle cerebral artery mainly.2,3 the acquired type occurs later in 45 childhood secondary to variable causes affecting brain perfusion like infection, prolonged febrile 46 seizure, trauma, hemorrhage, or ischemia.2 our patient presented with hemiplegia and seizures 47 since childhood, which is likely due to the hypoxic ischemic injury that he sustained during the 48 perinatal period. the classical imaging features of this condition are unilateral cerebral atrophy 49 with ipsilateral calvarial thickening and hyperpneumatization of the ipsilateral frontal sinus.1,3 50 other reported findings are ipsilateral falcine displacement, elevation of the petrous ridge and 51 wing of sphenoid bone, atrophy of ipsilateral basal ganglia and brainstem and contralateral 52 cerebellum, and hyperpneumatization of ipsilateral mastoid air cells.2 53 54 our patient has the classic clinical and imaging features described in the literature for ddm 55 syndrome. he had ct [figure 1] and mri [figure 2] of the brain, which revealed unilateral left-56 sided cerebral atrophy with ipsilateral compensatory hypertrophic thickening of skull bones. 57 there was also hyperpneumatization of the left frontal and sphenoidal sinuses and the left 58 mastoid process. atrophy of the ipsilateral thalamus, cerebral peduncle, and falttending of the 59 left anterior surface of the pons and medulla in keeping with wallerian degeneration, and 60 contralateral cerebellar atrophy were present. on time-of-flight mr angiogram [figure 3], the 61 left middle cerebral artery and its branches were smaller compared to the right side. it is 62 noteworthy to mention that the imaging findings of cerebral hemiatrophy, features of wallerian 63 degeneration, and cossed cerebellar diaschisis due to impaired neuronal connections can be seen 64 after various major cerebral inulsts, commonly infarcts, at any time in life. the presence of the 65 findings varies depending on the severity of the insults. the presence of skull and sinus 66 hypertrophy is seen, however, in insults that happen early in life, as classically described in 67 ddm syndrome. 68 69 the most common differential diagnosis for this syndrome is chronic rasmussen encephalitis, 70 sturge-weber syndrome, basal ganglia germinoma, and fishman syndrome.1,2 however, 71 differentiation between them can be made by clinical and radiological findings. for example, 72 chronic rasmussen encephalitis is a rare progressive inflammatory disease affecting children 73 who usually present with seizures and cognitive impairment. imaging findings show unilateral 74 cerebral atrophy without associated skull changes.1 patients with sturge-weber syndrome 75 usually present with seizures, mental retardation, and a typical port wine stain on the face in the 76 distribution of the ophthalmic division of the trigeminal nerve. on imaging, there will be 77 unilateral cerebral atrophy with increased angiomatosis and sometimes ipsilateral cortical tram 78 track calcifications.2,3 ddm syndrome has a wide spectrum of presentation, ranging from mild 79 symptoms to severely disabling symptoms. 80 81 refractory seizures remain the most challenging complaint.4,5 patients with refractory seizures 82 may benefit from surgical interventions like functional hemispherectomy, with a reported 83 success rate of 85% in selected cases.1,4 however, it is highly associated with long term adverse 84 effects like obstructive hydrocephalus and chronic subdural hygromas.2,4 hemispherotomy is 85 another surgical option that is also effective and associated with fewer complications. 86 rehabilitation, physiotherapy, speech therapy, and occupational therapy are important to 87 improve the quality of life.4,5 our patient was managed with antiepileptic medications, muscle 88 relaxants, and physiotherapy. due to his intractable seizures, he was offered surgical intervention 89 at an outside facility. 90 91 references: 92 1.arora r, rani jy. dyke-davidoff-masson syndrome: imaging features with illustration of two 93 cases. quant imaging med surg 2015;5(3):469-471. doi: 10.3978/ j.issn.2223-4292.2014.11.17 94 2.ayas zö, asil k, öcal r. the clinico-radiological spectrum of dyke-davidoff-masson 95 syndrome in adults. neurol sci. 2017;38(10):1823-1828. doi:10.1007/s10072-017-3074-7 96 3.gökçe e, beyhan m, sade r. radiological imaging findings of dyke-davidoff-masson 97 syndrome. acta neurol belg. 2017;117(4):885-893. doi:10.1007/s13760-017-0778-7 98 4.kim js, park ek, shim kw, kim ds. hemispherotomy and functional hemispherectomy: 99 indications and outcomes. j epilepsy res. 2018;8(1):1-5. published 2018 jun 30. 100 doi:10.14581/jer.18001 101 5.kumar nv, gugapriya ts, guru at, kumari sn. dyke-davidoff-masson syndrome. int j 102 appl basic med res. 2016;6(1):57-59. doi:10.4103/2229-516x.174016 103 104 105 106 figure 1: axial unenhanced ct of the brain with brain and bone windows shows (a) severe left-107 side cerebral atrophy with ex-vacuo dilatation of the ipsilateral lateral ventricle, (b) left-side 108 compensatory calvarial hypertrophy (arrows), (c) hyperpneumatization and enlargement of the 109 left frontal sinus (long arrow) and left mastoid air cells (short arrow). 110 111 112 113 a b c 114 figure 2: axial (a,b) and coronal (c) t2 weighted images demonstrate severe atrophy of the 115 left cerebral hemisphere with (a) left thalamic atrophy (arrow), (b) left cerebral peduncle 116 atrophy (arrow) and (c) contralateral cerebellar atrophy (arrow). 117 118 119 120 figure 3: coronal time-of-flight mr angiogram: the left main cerebral artery and its branches 121 are smaller than the right side. (arrow). 122 submitted 11 nov 21 1 revision req. 12 dec 21; revisions recd. 26 dec 21 2 accepted 1 feb 22 3 online-first: february 2022 4 doi: https://doi.org/10.18295/squmj.2.2022.018 5 6 dermatological lesions of cholesterol embolization syndrome and kaposi 7 sarcoma mimic primary systemic vasculitis 8 case report study 9 abdulmohsen s. alqurashi,1 mohammed h. aly,2 abdulghaffar mohammed,2 10 walaa a. ahmed,1 abdullah m. alhazmi,1 amal a. ahmed,3 abdulrahman a. 11 alshehri,4 *abdulrahman m. almalki1 12 13 1college of medicine, umm al-qura university, makkah, saudi arabia; departments of 14 2internal medicine, 3histopathology and 4rheumatology, security forces hospital, makkah, 15 saudi arabia. 16 *corresponding author’s e-mail: amalki2023@gmail.com 17 18 abstract 19 primary systemic vasculitis can present with a wide spectrum of manifestations ranging from 20 systemic non-specific features such as fever, malaise, arthralgia, and myalgia to specific organ 21 damage. we describe two cases of cholesterol embolization syndrome and kaposi sarcoma 22 mimicking primary systemic vasculitis, both of which were characterized by features such as 23 livedo reticularis, blue toe syndrome, a brown, purpuric skin rash, and positive p-anca 24 associated with kaposi sarcoma. establishing the right diagnosis was challenging, and thus 25 we aim in this study to highlight the possible ways to distinguish them from primary systemic 26 vasculitis. 27 keywords: dermatological lesions, cholesterol embolization syndrome, kaposi sarcoma, 28 vasculitis mimic 29 30 introduction 31 vasculitis is an inflammatory process affecting the blood vessels, causing destruction that leads 32 to ischemia, hemorrhage, or both (1). it has a wide spectrum of manifestations ranging from 33 systemic non-specific features such as fever and a loss of appetite or weight to specific organ 34 damage such as kidney and/or cutaneous damage manifested by purpura nodules, purpuric 35 urticaria, livedo reticularis, and skin ulcers (2,3). thus, non-specific diverse manifestations can 36 be mistaken for other conditions. we report two cases of the rare presentation of cholesterol 37 embolization syndrome (ces) and kaposi sarcoma (ks) mimicking vasculitis. we aim to 38 prompt their recognition and distinguish them from vasculitis. 39 40 case presentation 41 case one 42 a 65-year-old man, a known case of triple coronary artery vessel disease based on a coronary 43 angiogram performed a week before, presented to our hospital with abdominal pain and vomiting 44 for a day. physical examination revealed a skin rash, livedo reticularis, and the blue discoloration 45 of the toes, which suggested blue toe syndrome (figure 1). all other physical examinations were 46 unremarkable. 47 48 the patient was admitted, and laboratory investigations showed the following results: white 49 blood cell count of 14/mm3 with neutrophiles 53%, eosinophile 9%, and lymphocytes 32%; 50 hemoglobin 11.1 g/dl; platelets 144 × 10³/mm³; erythrocyte sedimentation rate 32 mm/h; c-51 reactive protein 35 mg/l; creatinine 2.4 mg/dl; and urea 43 mg/dl; aspartate aminotransferase 52 36 u/l (normal range, 10–41 u/l); alanine aminotransferase 31 u/l (normal range,10–40 u/l); 53 total cholesterol 209 mg/dl; high-density lipoprotein 42 mg/dl; low-density lipoprotein 138 54 mg/dl; triglyceride 140 mg/dl; serum iron 64lg/dl (normal range, 50–140 lg/dl); serum ferritin 55 138 ng/ml (normal range, 15–300 ng/ml); transferrin iron binding capacity 238 lg/dl (normal 56 range, 130–350 lg/dl). the urinary protein level was 600 mg/dl and the microscopic urinary 57 examination was negative for cells and casts. serological testing for anti-nuclear antibodies, 58 anti-neutrophil cytoplasmic antibodies, hepatitis c virus, and hepatitis b surface antigen all were 59 negative. 60 on abdominal ultrasound, both kidneys were within normal size with no other remarkable 61 findings. transthoracic echocardiography showed the left ventricle normal in size with an 62 ejection fraction of 57%, no intramural thrombus, or any evidence of infective endocarditis. 63 multiple biopsies of the affected skin and kidney were arranged but, unfortunately, were refused 64 by the patient. 65 66 case two 67 an 86-year-old woman presented with intermittent fever, dyspnea, a dry cough, and a loss of 68 weight for two months. physical examination revealed a bilateral brown/purple ill-demarcated 69 plaque over the tibia and dorsum of the feet (figure 2). laboratory investigation revealed mild 70 thrombocytopenia (124×10³/mm³), anemia (10.6 g/dl), high erythrocyte sedimentation rate (55 71 mm/h), and high c-reactive protein (42 mg/l); serological testing was positive for perinuclear 72 anti-neutrophil cytoplasmic antibodies (p-anca), and enzyme-linked immunoassay testing 73 revealed positive anti-myeloperoxidase with a titre of 512 aau/ml (normal: 0-150 aau/ml), 74 and negative for anti-proteinase 3. all other investigations were within the normal range 75 including coagulation profile, renal function, and hbv and hcv testing. multiple biopsies of 76 lesions were taken and these showed areas of hemorrhage, a vague network of connecting 77 channels, and positive human herpesvirus-8 on immunohistostaining (figure 3), which is 78 consistent with ks. human immunodeficiency virus testing was carried out and was negative. 79 80 declaration of patient consent 81 the authors certify that they obtained all appropriate patient consent forms. in the form, patients 82 provided consent for their images and other clinical information to be reported in the journal. 83 they understand that their names and initials will not be published, and due efforts will be made 84 to conceal their identity, but anonymity cannot be guaranteed. 85 86 discussion 87 multiple conditions can injure or occlude the blood vessels and mimic the clinical picture of 88 vasculitis. the location and size of the affected vessel determine the clinical manifestations of 89 the vascular injury more than the underlying cause. for example, damage to small cutaneous 90 vessels is manifested by palpable purpura, urticaria, livedo reticularis, papulovesicular lesions, 91 and nodules. similarly, damage can arise in the heart, kidney, gastrointestinal tract, and brain (4). 92 these diseases are not necessarily associated with blood wall inflammation. however, they 93 might have the same findings of vasculitis in clinical, laboratory, radiographic and/or pathologic 94 settings, which leads to diagnostic confusion (5). 95 96 ces is a great mimic, which makes it confusing for the diagnosis of vasculitis. a purpuric rash, 97 livedo reticularis, myalgia, and acute renal failure are some of the symptoms that can occur. 98 cholesterol emboli can complicate cardiac catheterization and arteriography; moreover, this can 99 happen spontaneously, even in individuals who have never suffered previous vascular disease 100 (6). in our first case, the patient developed manifestations that mimic the typical features of 101 churg–strauss vasculitis such as livedo reticularis, purpura, skin ulceration, and infarction and 102 eosinophilia (6). 103 104 moreover, renal failure can be found in both syndromes. while this can mask diagnosis, multiple 105 biopsies of affected sites (skin, kidney, and muscle) can identify the characteristics of ces, 106 namely, occluded small arteries and arterioles characterized by a lance-shaped cleft (dissolution 107 of cholesterol crystals) (7). unfortunately, our patient refused the biopsy and the diagnosis was 108 made based on clinical pictures. 109 110 the other case is ks mimicking vasculitis at the time of presentation. ks is a malignant tumor 111 that affects immunocompromised patients such as those infected with hiv, those who receive 112 immunosuppressants drugs, and those with congenital causes (8). ks skin lesions manifest as 113 red, purple, and brownish patches and dots, which can be misidentified as malignant or vascular 114 lesions in some phases due to the rise in superficial vascularity (9). 115 116 p-anca, an important marker for anca-associated vasculitis, has been found to be 91% 117 specific (10). the clinical pictures of a brown, purpuric rash on the lower limbs, as in our case, in 118 addition to positive p-anca are highly suggestive of vasculitis. a previously reported case of 119 ks and positive p-anca was due to existing vasculitis (11). in fact, the patient developed ks 120 after receiving an immunosuppression agent to treat vasculitis. but our case is unique in that p-121 anca was positive at the time of presentation with no existent vasculitis. however, the 122 possibility of incidental finding or our patient could develop vasculitis later is possible. to the 123 best of our knowledge, there are no reported cases in the literature of ks associated with positive 124 p-anca with no existing vasculitis. further studies, which take these variables into account, 125 will need to be undertaken. 126 127 conclusion 128 many conditions can mimic the clinical and laboratory features of vasculitis. herein, we present 129 two cases of ces and ks as mimics that might delay the correct diagnosis. however, a previous 130 history of angiography catheterization and biopsy would cut doubt with certainty. this study 131 aims to raise awareness of the possible differential diagnoses of vasculitis. further studies are 132 needed to investigate the relation between positive p-anca in patients and ks. 133 134 acknowledgement 135 the authors appreciate the research code team (rct) at umm al-qura university (uqu) for their 136 valuable contribution and efforts in supervising this research project. 137 138 authors’ contribution 139 asa is responsible for the majority of the work. amam drafted the manuscript and handled the 140 designing and formatting. waa and amah collected the clinical information and wrote the initial 141 manuscript. amaa provided the histopathology results. amam formulated the abstract. mha, am, and 142 abaa were the treating physicians. all authors approved the final version of the manuscript. 143 144 references 145 1. chen kr, carlson ja. clinical approach to cutaneous vasculitis. am j clin dermatol. 146 2008;9(2):71–92. 147 2. shavit e, alavi a, sibbald rg. vasculitis—what do we have to know? a review of 148 literature. int j low extrem wounds [internet]. 2018;17(4):218–26. available from: 149 https://doi.org/10.1177/1534734618804982 150 3. mishra a, iyadurai r, george a, rajdurai e, surekha v. etiological and 151 clinicopathological study of secondary small vessel vasculitis in elderly: a case series of 152 12 patients. j fam med prim care. 2017;6(1):106. 153 4. sack ke. the difficulties of differentiating vasculitis from its mimics. cleve clin j med. 154 1998;65(10):550–2. 155 5. molloy es, langford ca. vasculitis mimics. curr opin rheumatol. 2008;20(1):29–34. 156 6. fegan cd. lesson of the week: any questions. bmj. 1995;310(6979):580. 157 7. maningding e, kermani ta. mimics of vasculitis. rheumatol (united kingdom). 158 2021;60(1):34–47. 159 8. vangipuram r, tyring sk. epidemiology of kaposi sarcoma: review and description of 160 the nonepidemic variant. int j dermatol. 2019;58(5):538–42. 161 9. marušić z, billings sd. histopathology of spindle cell vascular tumors. surg pathol 162 clin. 2017 jun;10(2):345–66. 163 10. guchelaar nad, waling mm, adhin aa, van daele pla, schreurs mwj, rombach sm. 164 the value of anti-neutrophil cytoplasmic antibodies (anca) testing for the diagnosis of 165 anca-associated vasculitis, a systematic review and meta-analysis. autoimmun rev. 166 2021 jan;20(1):102716. 167 11. fatma l ben, rais l, mebazza a, azzouz h, beji s, krid m, et al. saudi journal of 168 kidney diseases and transplantation. saudi j kidney dis transplant [internet]. 2013 169 [cited 2021 nov 9];24(6):1199. available from: 170 https://www.sjkdt.org/article.asp?issn=1319-171 2442;year=2013;volume=24;issue=6;spage=1199;epage=1202;aulast=fatma 172 173 174 figure 1: the dermatological findings at presentation in case 1 175 176 177 figure 2: the dermatological findings at presentation in case 2. 178 179 180 figure 3: a: shows areas of hemorrhage and vague network of connecting channels, dilated 181 channels lined by small hyperchromatic nuclei b: hhv-8 immunohistostaining shows positive 182 granular nuclear staining 183 1department of medical education and 2centre for health education research & innovation, institute of education in medical & dental sciences, university of aberdeen, aberdeen united kingdom; 3aberdeen business school, robert gordon university, aberdeen, united kingdom *corresponding author’s e-mail: dr-hamad-007@hotmail.com استكشاف ثقافة سالمة املريض يف مرافق الرعاية الثانوية الكويتية دراسة نوعية حمد �لقطان، جينيفر كليالند، زوي موري�سون، �إيزبيل كامريون abstract: objectives: qualitative studies can improve understanding of patient safety culture (psc), which has been relatively neglected by researchers in the gulf cooperation council context. this study employed a qualitative approach to explore healthcare staff and patients’ perceptions of psc and how it can be improved. methods: this qualitative study was conducted in a public hospital in kuwait. individual face-to-face interviews were used to understand the experience of healthcare staff and patients concerning psc. after obtaining the required ethical approvals, maximum variation sampling was used. interviews were recorded and transcribed. the analysis was inductive and thematic. results: a total of 51 participants were included in this study (35 healthcare professionals and 16 patients). data analysis revealed four overarching themes relevant to the research question: (1) workload; (2) communication; (3) environmental constraints; and (4) incident reporting. these issues were interrelated in practice. kuwaiti and non-kuwaiti participants held different views, particularly about the response to errors and expatriate staff members’ clinical skills. conclusion: this study revealed multiple factors related to workload, communication, healthcare environment and incident reporting, which hindered the promotion of positive psc in the included department. the presence of numerous constraints suggests that multiple interventions which target both individual and organisational levels should be implemented. keywords: health services research; patient safety; safety culture; kuwait. امللخ�ص: الهدف: ميكن للدر��سات �لنوعية حت�سني فهمنا لثقافة �سالمة �ملري�س و�لتي �أهملها �لباحثون ن�سبيا يف �سياق دول جمل�س �لتعاون �خلليجي. ��ستخدمت هذه �لدر��سة نهجا نوعيا ال�ستك�ساف ت�سور�ت طاقم �لرعاية �ل�سحية و�ملر�سى عن ثقافة �سالمة �ملري�س وكيف ميكن حت�سينها. الطريقة: �أجريت هذه �لدر��سة يف �أحد �مل�ست�سفيات �حلكومية �لعامة يف �لكويت. مت ��ستخد�م �ملقابالت �ل�سخ�سية وجًها لوجه مت �ملطلوبة، �الأخالقية �ملو�فقات على �حل�سول بعد �ملري�س. �سالمة ثقافة بـخ�سو�س و�ملر�سى �ل�سحية �لرعاية طاقم جتربة لفهم ��ستخد�م �أق�سى تباين الأخذ �لعينات. مت ت�سجيل �ملقابالت ون�سخها. كان �لتحليل ��ستقر�ئًيا ومو�سوعًيا. النتائج: متت م�ساركة ما جمموعة ا(. ك�سف حتليل �لبيانات عن �أربعة مو��سيع �ساملة ذ�ت �سلة ا يف �لرعاية �ل�سحية و 16 مري�سً 51 م�سارًكا يف هذه �لدر��سة )35 متخ�س�سً مب�ساألة �لبحث: )1( عبء �لعمل؛ )2( �لتو��سل؛ )3( �لقيود �لبيئية؛ و )4( االإبالغ عن �حلو�دث. كانت هذه �لق�سايا مرت�بطة يف ميد�ن �لعمل. كان للم�ساركني �لكويتيني وغري �لكويتيني وجهات نظر خمتلفة، ال �سيما حول �ال�ستجابة لالأخطاء و�ملهار�ت �ل�رسيرية للموظفني �لغري كويتيني. اخلال�صة: �أظهرت هذه �لدر��سة عن عو�مل متعددة تتعلق بعبء �لعمل، و�لتو��سل، وبيئة �لرعاية �ل�سحية، و�الإبالغ عن �حلو�دث، و�لتي �أعاقت تعزيز ثقافة �سالمة �ملري�س يف �لق�سم �مل�سمول. وجود �لعديد من �لقيود ي�سري�إىل �رسورة تنفيذ مبادر�ت متعددة ت�ستهدف �مل�ستويني �لفردي و�لتنظيمي. الكلمات املفتاحية: بحوث �خلدمات �ل�سحية؛ �سالمة �ملري�س؛ �لثقافة ؛ �ل�سالمة؛ �لكويت. exploring patient safety culture in a kuwaiti secondary care setting a qualitative study *hamad alqattan,1 jennifer cleland,2 zoe morrison,3 isobel m. cameron2 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e77–85, epub. 15 mar 21 submitted 4 feb 20 revision req. 17 jun 20; revision recd. 25 jun 20 accepted 14 jul 20 https://doi.org/10.18295/squmj.2021.21.01.011 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge this study found that the obstacles that prevent an optimal patient safety culture (psc) in a hospital setting in kuwait are associated with workload, communication, environmental constraints and incident reporting. application to patient care the healthcare environment and how the staff behaves and communicates with patients play a crucial role in determining patients’ perceptions of the department’s psc. many patient safety culture (psc) studies have been carried out in kuwait and other gulf cooperation council (gcc) countries using the hospital survey on patient safety culture (hospsc).1,2 collectively, these studies found that the overall punitive response to errors, shortness of staff and lack of open communication hindered the development of optimal psc among https://creativecommons.org/licenses/by-nd/4.0/ exploring patient safety culture in a kuwaiti secondary care setting a qualitative study e78 | squ medical journal, february 2021, volume 21, issue 1 healthcare professionals.2 the presence of a culture which promotes patient safety is critical for improving patients’ outcomes in healthcare organisations. however, research suggests that psc differs across countries.3 it was also evident from the literature that psc has been studied in greater depth in some countries than others. for example, a narrative synthesis of 22 qualitative and mixed methods psc studies revealed that none had been conducted in arab contexts.4 since this review, only one qualitative study in the arab/gcc context was published.5 this recent study explored doctors’ and nurses’ psc perspectives in two public hospitals in kuwait. the authors concluded that participants had a good understanding of the concept of psc and that appropriate leadership support, resources and response to errors were required to achieve optimal psc levels in the studied context.5 surveys describe a phenomenon at a particular point in time. still, they cannot provide an under standing as to ‘why’, i.e. gaining an understanding of how healthcare staff and patients experience psc in the day-to-day world of healthcare delivery. however, such knowledge can help decision-makers identify factors that may hinder safe healthcare services and reveal areas to target for intervention.6 while a quantitative study can identify and measure psc issues, qualitative ones can explore specific factors contributing to these issues and potential ways to address them.7 patient perspectives were seldomly considered in psc studies.4 however, patients are at the centre of the service delivery process and are an ideal source of information on psc.8 patients also see psc from a different perspective than healthcare professionals.9 this different perspective suggests that obtaining the views, attitudes and experiences of both healthcare professionals and patients may provide a more comprehensive picture of psc in a hospital setting. although there have been many psc studies, this area has been relatively neglected in gcc contexts, particularly through qualitative approaches. this study aimed to identify and explore staff and patient perceptions of factors that hinder optimal psc implementation and how these factors might be addressed. this study builds on an earlier survey of staff perceptions of psc.10 methods this qualitative study was conducted using face-toface interviews with participants from the medical department of a public hospital in kuwait between june and august 2018. this department was selected as it provides a wide range of medical services, has employees of different nationalities, and was working to implement the kuwaiti national patient safety standards at the time of the study.11 maximum variation purposive sampling was employed to include a wide range of healthcare professionals and patients. healthcare professionals who had worked in the department for less than a year were excluded to ensure participants had had sufficient experience with and knowledge about the department to engage fully with the research questions. patients who were admitted to the medical wards or visited the medical outpatients’ clinics were also interviewed. participants were given interviews in either arabic or english to ensure the most comprehensive dialogue possible based on the participants’ preference.12 it should be noted that english was not the first language of all participants. the relevant department heads nominated a facilitator whose role was to explain the study’s aim and voluntary nature to their department’s staff and patients and coordinate interviews. the first author conducted all interviews. before starting the interviews, he reiterated the study’s purpose, invited questions and obtained written consent. potential participants were reassured that they had the right to withdraw from the study at any time without prejudice or consequence. interview questions were drawn from the psc literature in the field and informed by an earlier survey conducted in the same department.4,10 openended questions about factors affecting psc in the department were used to guide the discussions, with follow-up questions from the researcher to obtain a deeper understanding of the participants’ views. participants were also asked to speculate on strategies to improve psc. interviews continued until each participant felt they had sufficiently shared their experiences. notes and audio recordings were reviewed after each interview so that the content of earlier interviews could expose further questions for later interviews.13,14 this process was used to check for data saturation, which was estimated to have occurred after interviews with 25 healthcare professionals and 16 patients; however, 10 further healthcare professionals were interviewed to ensure a full range of views across all professional groups.15 the interview recordings were transcribed verbatim. the recordings and transcribed data were stored on a password-protected university computer, while written notes and data were stored in a locked cabinet on university premises. only the authors/ research team had access to the data. hamad alqattan, jennifer cleland, zoe morrison and isobel m. cameron clinical and basic research | e79 the qualitative content analysis approach of graneheim and lundman guided the data analysis.16 as is typical for qualitative data analysis, the approach was non-linear. the researchers moved back and forth through the analytical stages of specifying and defining the unit of analysis, sorting the unit of analysis into content areas, dividing content areas into meaning units, labelling meaning units with codes, clustering the coded meaning units into subthemes and clustering the subthemes into themes.16 the first step was to read the transcripts several times to become familiar with the data. the unit of analysis was the text obtained from the interviews’ transcripts. using microsoft word 365 (microsoft, corp., redmond, washington, usa), the text was sorted into two content areas based on two research questions: (1) “what factors hamper promoting psc?”; and (2) “what interventions might improve psc?”. arabic texts within each content area were first translated into english and then entered into nvivo, version 11 (qsr international, doncaster, australia) for data management and to facilitate data coding and analysis. each content area was then divided into meaning units. to standardise coding meaning units across the entire text, the researchers carried out the process in two phases. in the first phase (i.e. preliminary coding), they analysed three interview transcripts to develop an initial coding framework. in the second phase, they applied these finalised codes across the entire text. the whole context was considered while applying the codes to the meaning units. after coding, the researchers searched the meaning units for similarities and differences and clustered them into subthemes. the codes were discussed and reviewed at regular intervals among the researchers to identify and develop themes as well as minimise individual researcher influence during analysis. coding disagreements were resolved through team discussions. coding and interpretation occurred iteratively and inductively, focusing through out on the research aim. in this study, the credibility and dependability of the findings were improved by obtaining the views of a wide range of participants to help provide more substantial evidence and a better description of the results.17 audio-recordings and transcribing interviews verbatim improved accuracy and precision in presenting participants’ views. the transferability of this study was addressed by providing detailed descriptions of the data collection and analysis processes.18 in addition, the study’s findings were frequently discussed among the research team, which ensured to draw conclusions only once consensus was achieved to guarantee the findings’ confirmability.17 written ethical approval was obtained from the ministry of health of kuwait, the hospital director and the departments’ heads (2017/582). informed consent was also obtained from all participants. results in total, 35 healthcare professionals and 16 patients were interviewed for this study. most healthcare professionals were non-kuwaitis (n = 21) and male (n = 19). conversely, most patients were kuwaiti (n = 14) and female (n = 13). most participants preferred to be interviewed in arabic (n = 34) [table 1]. the average interview duration was 30 minutes. data analysis revealed four predominant themes relevant to the research question: (1) workload; (2) communication; (3) environmental constraints; and (4) incident reporting [table 2]. all staff participants raised the issue of heavy workloads hindering the provision of safe medical services in the department. the data indicated the presence of four major factors contributing to the table 1: characteristics of included healthcare professionals and patients at a public hospital in kuwait (n = 51) participant jobs number nationality gender language of interviews kuwaiti non-kuwaiti male female arabic english medical doctor 6 2 4 6 0 5 1 registered nurse 13 2 11 8 5 3 10 physiotherapist 4 1 3 2 2 2 2 pharmacist 5 3 2 2 3 5 0 nuclear medicine doctor 3 3 0 0 3 2 1 laboratory technician 4 3 1 1 3 2 2 patients 16 14 2 3 13 15 1 total 51 28 23 22 29 34 17 exploring patient safety culture in a kuwaiti secondary care setting a qualitative study e80 | squ medical journal, february 2021, volume 21, issue 1 table 2: summary of participants’ concerns and suggested solutions from a public hospital in kuwait themes concerns suggested solution(s) supporting quotes workload number of staff (s) increase numbers of staff provide paid overtime establish another hospital to serve as a catchment area – “our number is less than what is required for this health region. indeed we have a shortage of staff” (md2). – “i told you we are running here. so better they can supply some staff” (rn5). professional competence (s+p) ongoing staff orientation on patient safety assess pre-employment competency in patient safety for medical department staff offer competitive wages and incentives – “when the nurse came to me, she did not know where to insert the needle. i have bruises on my both arms” (patient 11). – “i will try to improve education for the whole staff, involving them in more regular courses or lectures in hospitals. make sure every staff is involved in orientations” (lab2). – “the employment board should be reformed as it is responsible for contracting with expat staff” (md4). impact of visitors (s) implement strict ward visiting hours for patient families – “this is madness, why visitors are here for 24 hours. i cannot provide good care in such an atmosphere” (rn5). – “we can give visiting time between 11 to 12 like that relatives will come, doctor, is there” (rn11). appropriateness of admissions (s) establish intermediate care units/wards – “most of the patients are either bedridden or in mechanical ventilation who are unable to help themselves” (rn7). – “it is icu patients. ventilator patients mean it should be icu. so in icu, they are taking one nurse to one. so one ventilator patient means one staff will take care of the patient in the whole shift” (rn7). communication interdepartmental cooperation (s) develop interdepartmental policies – “we have regimens for some medications differ from those with doctors. that is why we clash with them” (ph3). – “i think there should be frequent meetings between the different healthcare professionals to support multidisciplinary teamwork” (ph4). appropriateness of documentation (s) offer ongoing staff orientation on appropriate documentation – “most of the prescriptions we receive here in the pharmacy lack some important patients’ information, like patient weight” (ph1). – “the doctor’s handwriting is not clear. usually, i cannot read what is written in the file, so i need to chase the doctor the whole day” (rn3). reliance on junior staff (s) assign only senior/ experienced staff for consultations with other staff – “the trainees should not be dealt with as a competent doctor. they are still under training. we know that it is very risky to rely on them. however, on busy days, we are forced to” (md5). – “any consultation to be sent should be seen by the senior registrar at least. not allowed to send someone a junior or assistant or registrar to come” (md3). healthcare professionals’ behaviour (p) offer ongoing staff training on communication skills – “the doctors, i do not see them, and even when they come, i cannot get what they say” (patient 4). – “somebody should keep reminding them about how to deal with patients” (patient 8). environmental constraints hygiene (s+p) clean and maintain facilities regularly/frequently – “even the place is not clean enough. in the past, when we go to hospitals, the smell of dettol was very clear, but nowadays it is not” (patient 2). – “i think it is the role of supervisors to come and see the condition of the wards themselves” (ph5). appropriateness of facilities (s) expand the department’s facilities – “the toilet smells very bad. the washing sink is leaking. i told them about it two days ago, but nobody cares” (patient 14). – “we said to the nurses that these medications should be stored in a room temperature of between 20˚c and 25˚c. however, they always say that air conditioning is not working well, and nobody fixes it yet” (ph4). s = indicated by staff participants; md = medical doctor; rn = registered nurse; s+p = indicated by staff and patient participants; lab = laboratory technician; icu = intensive care unit; ph = pharmacist; p = indicated by patient participants; pt = physiotherapist; nm = nuclear medicine doctors. hamad alqattan, jennifer cleland, zoe morrison and isobel m. cameron clinical and basic research | e81 heavy workload. three of these were raised by staff participants, not patients: (1) number of staff; (2) the impact of visitors; and (3) the appropriateness of admissions. professional competence was raised as a factor contributing to the heavy workload by both staff and patients. the staff believed it was difficult to provide medical services at the required standard with the current staff-to-patient ratio. this challenging ratio had been exacerbated by many healthcare personnel, particularly the nursing staff, either resigning or being transferred to other departments without replacement. the combination of high patient numbers and staff shortages was considered relevant to patient safety since the staff discussed how they were forced to take short-cuts to finish their tasks on time. to address this challenge, the staff suggested that the hospital administration prioritise increasing staff numbers. paid overtime was additionally seen as a possible solution. some even suggested the need for another hospital to assist in providing healthcare services in the region and alleviating heavy workloads. both kuwaiti patients and staff expressed the opinion that expatriate staff lacked basic clinical skills. this perceived lack of skills and underperformance meant kuwaiti staff members thought it was easier to do tasks themselves rather than engaging with an expatriate staff member. a related issue was high staff turnover, particularly the nursing staff, as new staff would lack familiarity with work procedures. this lack of familiarity could mean additional burden for staff members who had been in the department longer to do most tasks themselves and spend most of their time training new staff on work procedures. training and orientation were seen by the staff as a potential solution to this problem, as well as offering competitive wages and incentives to attract more competent staff. performing a pre-employment competency assessment with the medical staff was seen by many patients as a potential solution. table 2 (cont’d): summary of participants’ concerns and suggested solutions from a public hospital in kuwait themes concerns suggested solution(s) supporting quotes environmental constraints availability of equipment and supplies (s+p) make equipment and supplies consistently available – “we need some important equipment which is not available in medical wards like some special beds and lifters. so, we are always forced to transfer patients from medical building to our department in the old building” (pt1). – “once, we waited for around three months to get ink, and now we are almost out of a4 papers” (md5). privacy and security (p) increase the number of private rooms – “i am not safe here. the next patient always cough. my health is deteriorating here” (patient 2). – “i want a private room. i do not want to bother anybody and do not want anybody to bother me” (patient 16). incident reporting response to errors (s+p) promote/reward staff who participate in quality improvement and patient safety initiatives – “completing an incident report may ruin my relationship with my friends and colleagues” (lab2). – “i am threatened by the aggressive attitude of the patients and those responsible for them. i always feel that i am guilty, and they are so motivated to complain” (rn5). – “we never punish anyone in here – when our staff make mistakes, we talk with them in a friendly way” (nm3). – “yesterday, nurses forgot to give me the medication. she should be fired” (patient 3). – “as a leader, i should be the first one to attend patient safety lectures. i will not ask the staff to attend without my presence. i should be there to support the staff ” (rn9). feedback and follow-up after reporting incidents (s) simplify the incident report form establish a system of feedback after reporting an incident – “we do not know what the reaction is because we completed many forms since one year, but we did not see any reaction” (rn7). – “we never heard about what happened afterwards, so i wrote the paper, the paper was written, it was forwarded, full stop” (rn1). appropriateness of documentation (s) offer ongoing staff orientation on appropriate documentation – “most of the prescriptions we receive here in the pharmacy lack some important patients’ information, like patient weight” (ph1). – “the doctor’s handwriting is not clear. usually, i cannot read what is written in the file, so i need to chase the doctor the whole day” (rn3). s = indicated by staff participants; md = medical doctor; rn = registered nurse; s+p = indicated by staff and patient participants; lab = laboratory technician; icu = intensive care unit; ph = pharmacist; p = indicated by patient participants; pt = physiotherapist; nm = nuclear medicine doctors. exploring patient safety culture in a kuwaiti secondary care setting a qualitative study e82 | squ medical journal, february 2021, volume 21, issue 1 the nursing staff and those working in the wards stressed the importance of implementing strict visiting hours for patients’ families. they claimed that the presence of patients’ relatives and family members after visitation hours was detrimental to good quality care, causing loss of concentration and delay in services. the nature of patient presentations was cited as contributing to heavy staff workloads. staff participants believed that many patients needed constant close observation and special care, which added to the nursing staffs’ workload. to address this problem, many staff participants suggested providing an intermediate critical care unit for suitable admissions. three interrelated issues were reported as negatively affecting communication across the different professional groups. the first issue was that different professional groups had conflicting policies and procedures, which resulted in frequent disagreements and delays in service provision including laboratory results and medication administration. the second issue raised was the lack of appropriate record-keeping and documentation, which hindered communication between the staff members. the third issue was related to an overreliance on inexperienced junior staff for consultations because of staff shortages. this issue meant that staff members were expected to work above their level of competence. staff participants reported that developing interdepartmental policies and communication systems, such as regular meetings, ongoing staff orientation on appropriate documentation in the medical records and assigning only senior/experienced staff members for consult ations, would improve cooperation between the different specialities and support multidisciplinary healthcare provision. several patients commented on staff behaviour, reporting, for example, that staff did not take into consideration patient preferences and that patients were not reasonably involved in healthcare plans. moreover, patients complained about some doctors’ and nurses’ rude attitudes. patients believed that these issues could be addressed by better departmental leadership, intensifying staff orientation and offering ongoing training, particularly in staff-patient comm unication skills. both the staff and patients frequently raised their dissatisfaction with the healthcare environment. participants mentioned numerous problems related to the healthcare environment including hygiene, facilities, equipment, supplies and privacy. all patients and some staff members thought that the medical wards were not sufficiently clean. there was a shortage of essential equipment including beds and physiotherapy kits and necessary supplies such as hand sanitisers and patient diapers. furthermore, existing facilities were poorly maintained and much of the equipment was broken. both the staff and patients reported that these problems could be overcome through regular and frequent cleaning and maintenance and ensuring consistent availability of equipment and supplies. space was also an issue for the staff, particularly those working in outpatient clinics. both the lack of clinical space and the inappropriateness of available space was noted. according to staff members, the lack of such special rooms in the medical facility made the process of taking care of patients overwhelming for both patients and healthcare professionals. they believed that a large expansion, which included all the department’s premises, should be initiated to overcome this problem. many patients admitted to the medical wards’ shared rooms expressed deep upset and distress at disturbances caused by nearby patients and their relatives. they also worried about getting hospitalacquired infections from other patients in the same room due to the environment’s poor cleanliness. for these reasons, increasing the number of private rooms in the medical wards was seen by patients as the ideal solution to their privacy and security problems. many non-kuwaiti staff members stated that the working atmosphere in the medical department did not support incident reporting. they felt that neither the hospital leadership nor the laws and regulations supported non-kuwaiti healthcare professionals when mistakes occurred. the reporting culture was seen as punitive by non-kuwaitis, yet as overly permissive of mistakes by the kuwaiti staff members and patients. patients thought that there was a lack of responsibility and accountability in the department and that managers responded very permissively to staff mistakes. to encourage incident reporting and learning from errors, the staff generally suggested promoting/rewarding staff members participating in any quality improvement or patient safety initiatives rather than focusing on each error as a disciplinary issue. lack of proper feedback and follow-up by management after submitting an incident report was declared the main factor contributing to incidents not being reported. staff were not motivated to report incidents as doing so was seen as not leading to significant departmental improvements. the staff believed that the incident reporting system should be reformed to support communication with departmental management and shortand long-term improvements to quality and safety. some participants also emphasised the importance of simplifying the hamad alqattan, jennifer cleland, zoe morrison and isobel m. cameron clinical and basic research | e83 incident report form as they believed that completing the current form required excessive administrative efforts from them. discussion this qualitative study provides insight into the psc in one kuwaiti medical department and, uniquely in the arab/gcc countries context and incorporates multiple healthcare professional groups and patients’ views. the data obtained suggests multiple constraints on psc promotion in the department, specifically related to workload, communication, the healthcare environment and incident reporting. kuwaiti and nonkuwaiti participants held different views about the department’s response to errors and expatriate staff members’ clinical skills. participant suggestions as to how the diverse constraints of psc implementation could be addressed included interventions at the indiv idual (e.g. training and orientation) and organisational (e.g. increasing staff numbers, providing paid overtime and developing interdepartmental policies) levels. the current staff members’ perspectives were similar to those reported by a recent qualitative study conducted in two accredited public hospitals in kuwait.5 for example, both studies suggested that patient safety was not prioritised in daily practice due to staff and resource shortages. however, unlike that study, the staff and patients in the current study suggested more training and orientation to improve staff awareness of patient safety. this difference in findings may be attributed to accountability differences between the two settings—the hospitals studied by al hamid et al. were accredited, while the hospital in the current study was not.5 another difference of note involved the presence (or lack thereof ) of supportive leadership. whether by implementing an accreditation programme, offering supportive leadership or targeting other factors, it seems that healthcare organisations with a positive psc have mechanisms that support decisive action.19 the perspectives of the current staff members were also more wide-spread. for example, studies conducted in hospitals in the usa have identified significant associations between low staff numbers (and associated increases in work demand) and adverse patient outcomes.20 maintaining optimal communication levels between healthcare staff members was found to be a key determinant of the psc in hospital settings in a chinese study.21 in addition, the healthcare environment’s key role in promoting psc has been emphasised in many studies.22,23 other studies have suggested that feedback should be routine after incidents have been reported and should include information regarding response to the report in question.24,25 this study’s findings also suggest that the surrounding healthcare environment and how staff behave and communicate with the patients played a crucial role in determining patient perceptions of departments’ psc. this finding is not confined to this study; previous studies conducted in other settings have revealed similar results. for example, a study conducted in oncology care settings found that patients valued the physical environment as an essential factor in having a safe healthcare experience.26 another study investigating psc in outpatient clinics in china reported that most participants linked poor organisational safety culture with the presence of a poor staff-patient relationship.27 a novel aspect of this study was the fact that it explored differences in how kuwaiti and nonkuwaiti participants perceive responses to errors and expatriate staff ’s clinical skills. it seems that the damaged relationship and trust between citizens and expatriates in kuwait caused by recently increasing public and political demands to control the number of expatriates in the workforce might influence the way psc is perceived in the department by different national groups.28 this pattern has been seen elsewhere. for example, a study conducted in a university hospital in the conflict-ridden eastern democratic republic of congo also found that national politics affected healthcare.29 it is critical to examine differences between these groups given the large number of expatriate healthcare professionals in kuwait. evidence strongly suggests that an organisational safety culture is constituted by a mixture of safety subcultures and that the presence of contrasting views between these subcultures can compromise the achievement of organisation-wide safety goals.30,31 this evidence suggests that the differences between kuwaiti and expatriate healthcare professionals should be explored more in-depth to identify how these differences might influence working practices. this information should be used to inform developing interventions to address cultural differences as part of psc initiatives.32,33 this study showed that no single measure could work as a panacea for promoting psc in this department. in this context, policymakers should think about interventions that target reform at different levels and include concerns about the healthcare system in general, specific staff behaviours and the healthcare environment. these interventions should be carried out in a coordinated manner to implement the kuwaiti national patient safety standards against a backdrop of solidly-established psc. future research exploring patient safety culture in a kuwaiti secondary care setting a qualitative study e84 | squ medical journal, february 2021, volume 21, issue 1 should focus on evaluating the approaches suggested by the study participants. this is no simple task and attention must be paid to both the outcomes and process of change. this study has several strengths. participants included a range of healthcare professionals and patients. while both groups’ views were similar in many ways, patient participants focused more on issues related to the healthcare environment and staff behaviour. another strength of this study is the iterative analysis of field notes and audio recordings throughout data collection, which allowed the researchers to adapt the semi-structured interview schedule for later interviews based on discussions in earlier interviews. the interviewer’s status as both ‘insider’ and ‘outsider’ may have both helped and hindered the interviews.34 since the interviewer previously worked in the hospital, he had good connections and relationships with the hospital leadership. these relationships facilitated obtaining ethical approval and access to the study’s participants. on the contrary, the interviewer’s former employment as a hospital council member may have prompted participants to conceal some of the system’s weaknesses. the interviewer’s ‘insider’ status may have been an issue in data analysis regarding potential preconceived assumptions about the department’s psc status. furthermore, the interviewer’s kuwaiti nationality may have negatively affected the openness of the interviews conducted with non-kuwaiti participants. these hindrances were mitigated via the team’s balance and reflective team discussions, which encouraged the constant considerations of alternative explanations in data interpretation. as a qualitative study, participant views cannot be considered generalisable, but they provide insight into perceptions and attitudes in the context under investigation. english was the second language for all participants, except for those who only spoke arabic. this fact may have affected their ability to express their views about the department’s psc. despite these limitations, faceto-face interviews enabled the participants to express their opinions about patient safety in their own words and gave them privacy to share their personal stories.17 conclusion to the best of the researchers’ knowledge, this qualitative study is the first to consider both patients’ and a wide range of healthcare professionals’ perspectives of psc in a gcc hospital setting. this study revealed multiple factors related to workload, communication, the healthcare environment and reporting incidents that hinder promoting a positive psc in the studied departments. the presence of numerous constraints suggests that multiple inter ventions should be implemented that target both individual and organisational levels to promote psc in the department. further research is required to examine the effectiveness as well as the practicality of the suggested interventions. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g the first author received a scholarship from the government of kuwait to do this work. references 1. agency for healthcare research and quality. hospital survey on patient safety culture: user’s guide. rockville, usa: us department of health and human services. 2016. 15(16)-0049-ef. 2. elmontsri m, almashrafi a, banarsee r, majeed a. status of patient safety culture in arab countries: a systematic review. bmj open 2017; 7:e013487. https://doi.org/10.1136/ bmjopen-2016-013487. 3. najjar s, baillien e, vanhaecht k, hamdan m, euwema m, vleugels a, et al. similarities and differences in the associations between patient safety culture dimensions and self-reported outcomes in two different cultural settings: a national cross sectional study in palestinian and belgian hospitals. bmj open 2018; 8:e021504. https://doi.org/10.1136/bmjopen-2018-021504. 4. alqattan h, morrison z, cleland j. a narrative synthesis of qualitative studies conducted to assess patient safety culture in hospital settings. sultan qaboos univ med j 2019; 19:91–9. https://doi.org/10.18295/squmj.2019.19.02.002. 5. al hamid a, malik a, alyatama s. an exploration of patient safety culture in kuwait hospitals: a qualitative study of healthcare professionals’ perspectives. int j pharm pract 2020; 28:617–25. https://doi.org/10.1111/ijpp.12574. 6. nieva vf, sorra j. safety culture assessment: a tool for improving patient safety in healthcare organisations. qual saf health care 2003; 12:ii17–23. https://doi.org/10.1136/qhc.12.suppl_2.ii17. 7. listyowardojo t, ray-sannerud b, turk e, lyons m, pytte m, leyshon s, et al. mixed methods: improving the assessment of safety culture in healthcare. from: www.dnvgl.us/publications/ mixed-methods-improving-assessment-of-safety-culture-inhealthcare-109113 accessed: jun 2020. 8. king e, coldham t. patients and carers can be our service design consultants. from: www.england.nhs.uk/blog/tina-coldham/ accessed: jun 2020. 9. davis re, sevdalis n, neale g, massey r, vincent ca. hospital patients’ reports of medical errors and undesirable events in their health care. j eval clin pract 2013; 19:875–81. https://doi. org/10.1111/j.1365-2753.2012.01867.x. 10. alqattan h, cleland j, morrison z. an evaluation of patient safety culture in a secondary care setting in kuwait. j taibah univ med sci 2018; 13:272–80. https://doi.org/10.1016/j.jtum ed.2018.02.002. 11. ministry of health, kuwait. accreditation standards for hospitals in kuwait. medical care version 5. from: cdhpage.com/wpcontent/uploads/2015/12/check-the-medical-care-nationalaccreditation-standards-for-hospitals.pdf accessed: jun 2020. https://doi.org/10.1136/bmjopen-2016-013487 https://doi.org/10.1136/bmjopen-2016-013487 https://doi.org/10.1136/bmjopen-2018-021504 https://doi.org/10.18295/squmj.2019.19.02.002 https://doi.org/10.1111/ijpp.12574 https://doi.org/10.1136/qhc.12.suppl_2.ii17 https://doi.org/10.1111/j.1365-2753.2012.01867.x https://doi.org/10.1111/j.1365-2753.2012.01867.x https://doi.org/10.1016/j.jtumed.2018.02.002 https://doi.org/10.1016/j.jtumed.2018.02.002 hamad alqattan, jennifer cleland, zoe morrison and isobel m. cameron clinical and basic research | e85 12. malterud k, siersma vd, guassora ad. sample size in qualitative interview studies: guided by information power. qual health res 2016; 26:1753–60. https://doi.org/10.1177/1049732315617444. 13. josselson r. interviewing for qualitative inquiry: a relational approach. new york, usa: guilford press, 2013. 14. maxwell ja. qualitative research design: an interactive approach, 3rd ed. thousand oaks, usa: sage publications, 2013. 15. saunders b, sim j, kingstone t, baker s, waterfield j, bartlam b, et al. saturation in qualitative research: exploring its concep tualization and operationalization. qual quant 2018; 52:1893–907. https://doi.org/10.1007/s11135-017-0574-8. 16. graneheim uh, lundman b. qualitative content analysis in nursing research: concepts, procedures and measures to achieve trustworthiness. nurse educ today 2004; 24:105–12. https://doi.org/10.1016/j.nedt.2003.10.001. 17. hays dg, singh aa. qualitative inquiry in clinical and educational settings. new york, usa: guilford press, 2011. 18. korstjens i, moser a. series: practical guidance to qualitative research. part 4: trustworthiness and publishing. eur j gen pract 2018; 24:120–4. https://doi.org/10.1080/13814788.2017. 1375092. 19. wachter rm, pronovost p, shekelle p. strategies to improve patient safety: the evidence base matures. ann intern med 2013; 158:350–2. https://doi.org/10.7326/0003-4819-158-5-201303050-00010. 20. carayon p, gurses ap. nursing workload and patient safety—a human factors engineering perspective. in: hughes rg, ed. patient safety and quality: an evidence-based handbook for nurses. rockville, usa: agency for healthcare research and quality, 2008. 21. zhu j, li l, li y, shi m, lu h, garnick dw, et al. what constitutes patient safety culture in chinese hospitals? int j qual health care 2012; 24:250–7. https://doi.org/10.1093/ intqhc/mzs010. 22. pelzang r, johnstone m-j, hutchinson am. culture matters: indigenizing patient safety in bhutan. health policy plan 2017; 32:1042–8. https://doi.org/10.1093/heapol/czx042. 23. wang y, liu w, shi h, liu c, wang y. measuring patient safety culture in maternal and child health institutions in china: a qualitative study. bmj open 2017; 7:e015458. https://doi. org/10.1136/bmjopen-2016-015458. 24. antonacci ac, lam s, lavarias v, homel p, eavey rd. benchmarking surgical incident reports using a database and a triage system to reduce adverse outcomes. arch surg 2008; 143:1192–7. https://doi.org/10.1001/archsurg.143.12.1192. 25. francis r. report of the mid staffordshire nhs foundation trust public inquiry: executive summary. london, uk: the stationery office, 2013. 26. browall m, koinberg i, falk h, wijk h. patients’ experience of important factors in the healthcare environment in oncology care. int j qual stud health well-being 2013; 8:20870. https:// doi.org/10.3402/qhw.v8i0.20870. 27. liu c, liu w, wang y, zhang z, wang p. patient safety culture in china: a case study in an outpatient setting in beijing. bmj qual saf 2014; 23:556–64. https://doi.org/10.1136/bmjqs-20 13-002172. 28. toumi h. deep rifts emerge in kuwait over expatriates’ status. from: gulfnews.com/world/gulf/kuwait/deep-rifts-emerge-inkuwait-over-expatriates-status-1.1964054 accessed: jun 2020. 29. labat f, sharma a. qualitative study exploring surgical team members’ perception of patient safety in conflict-ridden eastern democratic republic of congo. bmj open 2016; 6:e009379. https://doi.org/10.1136/bmjopen-2015-009379. 30. xuanyue m, yanli n, hao c, pengli j, mingming z. literature review regarding patient safety culture. j evid based med 2013; 6:43–9. https://doi.org/10.1111/jebm.12020. 31. sutcliffe km, paine l, pronovost pj. re-examining high reliability: actively organising for safety. bmj qual saf 2017; 26:248–51. https://doi.org/10.1136/bmjqs-2015-004698. 32. doval e, doval o. issues of standardisation concerning organ isational culture in change management. 32nd annual congress of ara proceedings 2008; 978:374–7. 33. mannion r, davies h. understanding organisational culture for healthcare quality improvement. bmj 2018; 363:k4907. https:// doi.org/10.1136/bmj.k4907. 34. tinker c, armstrong n. from the outside looking in: how an awareness of difference can benefit the qualitative research process. qual rep 2008; 13:53–60. https://doi.org/10.1177/1049732315617444 https://doi.org/10.1007/s11135-017-0574-8 https://doi.org/10.1016/j.nedt.2003.10.001 https://doi.org/10.1080/13814788.2017.1375092 https://doi.org/10.1080/13814788.2017.1375092 https://doi.org/10.7326/0003-4819-158-5-201303050-00010 https://doi.org/10.1093/intqhc/mzs010 https://doi.org/10.1093/intqhc/mzs010 https://doi.org/10.1093/heapol/czx042 https://doi.org/10.1136/bmjopen-2016-015458 https://doi.org/10.1136/bmjopen-2016-015458 https://doi.org/10.1001/archsurg.143.12.1192 https://doi.org/10.3402/qhw.v8i0.20870 https://doi.org/10.3402/qhw.v8i0.20870 https://doi.org/10.1136/bmjqs-2013-002172 https://doi.org/10.1136/bmjqs-2013-002172 https://doi.org/10.1136/bmjopen-2015-009379 https://doi.org/10.1111/jebm.12020 https://doi.org/10.1136/bmjqs-2015-004698 https://doi.org/10.1136/bmj.k4907 https://doi.org/10.1136/bmj.k4907 1department of pharmacology & toxicology, madonna university, nigeria; 2department of science, university of benin, benin, nigeria; departments of 3civil & environmental engineering and 4experimental pharmacology & toxicology and 5african centre of excellence for public health and toxicological research, university of port harcourt, port harcourt, nigeria *corresponding author’s e-mail: orishebere@gmail.com تقييم خطر وجود االملنيوم والزرنيخ والزئبق يف مكونات أغذية الرّضع الصناعية يف نيجرييا بالنسبة للصحة العامة واألطفال زيلنجو اقويز، او�صازاو اختور، اآيفي نواقازي، اأور�س ابري اأوري�صاكوي abstract: objectives: infant formulas are useful alternatives to breast milk in many circumstances but may pose health risks to infants and children due to contamination by potentially toxic metals. this study aimed to determine the aluminium, arsenic and mercury concentrations and carry out an exposure health risk assessment in commonly consumed infant formulas in nigeria. methods: different brands of both locally manufactured and imported infant formulas were purchased in march 2017 from stores in port harcourt, nigeria. analysis of metals in the samples was performed by atomic absorption spectrophotometry. the health risk was assessed by comparing estimated daily intake of aluminium, arsenic and mercury with the provisional tolerable daily intake acceptable by the joint food and agricultural organization/world health organization expert committee on food additives (jecfa). results: a total of 26 infant formulas were analysed. the levels of arsenic were higher in cereal-based formulas compared to milkbased formulas, but the difference was not significant (p >0.05). the intake levels of aluminium, arsenic and mercury in infant formulas were found to be 8.02–14.2%, 437.1–771% and 23.7–41.8% of the provisional tolerable daily intake jecfa threshold values, respectively. conclusion: commonly consumed infant formulas in nigeria may add to the body burden of arsenic in children. keyword: infant formulas; toxicity test; aluminum; arsenic; mercury; health risk appraisal; child health; nigeria. امللخ�ص: الهدف: اأغذية الر�صع ال�صناعية ت�صكل بدائل مفيدة حلليب الأم يف كثري من احلالت. غري اأنها قد ت�صكل خطرا على الر�صع والأطفال ب�صبب تلوثها مبعادن قد تكون �صامة. تهدف هذه الدرا�صة لقيا�س تركيز الأملنيوم والزرنيخ والزئبق يف تركيبات اأغذية الر�صع امل�صتخدمة بكرثة يف نيجرييا، وتقييمخطر وجودها فيها. الطريقة: مت �رشاء اأنواع خمتلفة من اأغذية الر�صع التجارية مبدينة بورت هاركورت بنيجرييا يف مار�س من عام 2017م. ومت إجراء القيا�صات عن طريق جهاز المت�صا�س الذري الطيفي. مت تقييم املخاطر ال�صحية من خالل مقارنة الكمية املقدر تناولها يوميا من الملنيوم والزرنيخ والزئبق، بالكمية اليومية امل�صموح بها واملقبوله مبدئيا من ِقَبل جلنة اخلرباء امل�صرتكة بني منظمة الأغذية والزراعة ومنظمة ال�صحة العاملية املعنية باملواد امل�صافة اإىل الأغذية. النتائج: مت حتليل 26 عينة من تركيبات حليب الر�صع. وكان تركيزات الزرنيخ فيها اأعلى يف الرتكيبات القائمة على احلبوب، مقارنة بتلك القائمة على احلليب، ولكن مل يكن ذلك الفرق معتد به اح�صائيا )p <0.05(. وتراوحت تركيزات الملنيوم والزرنيخ والزئبق يف العينات بني %14.2–8.02، %771–437.1 و %41.8–23.7، على التتابع، من القيم العتبية التي و�صعتها جلنة اخلرباء امل�صرتكة بني منظمة الأغذية والزراعة ومنظمة ال�صحة العاملية املعنية باملواد امل�صافة اإىل الأغذية. اخلال�صة: قد تزيد مكونات اأغذية الر�صع الوا�صعة ال�صتخدام يف نيجرييا من اخلطر الرتاكمي للزرنيخ عند الأطفال. الكلمات املفتاحية: مكونات اأغذية الر�صع؛ اختبار ال�صمّية؛ األملنيوم؛ الزرنيخ؛ الزئبق؛ تقييم اخلطر ال�صّحي؛ �صحة الأطفال؛ نيجرييا. public health and paediatric risk assessment of aluminium, arsenic and mercury in infant formulas marketed in nigeria zelinjo n. igweze,1 osazuwa c. ekhator,2 ify nwaogazie,3 *orish e. orisakwe4,5 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e63–70, epub. 9 mar 20 submitted 2 may 19 revisions req. 23 jun & 30 jul 19; revisions recd. 8 jul & 2 aug 19 accepted 5 sep 19 advances in knowledge infant formula consumption in nigeria may add to children’s body burden of arsenic. food regulatory agencies in developing nations should maintain regular and periodic checks of foods to ensure permissible limits of contaminants. application to patient care heavy metals may be implicated in the aetiology of certain diseases. physicians should be mindful of dietary sources of heavy metals in the diagnosis and management of diseases. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.009 clinical & basic research breastfeeding is the best adapted-food for infants and imparts health benefits due to its composition which reduces the risk of disease and strengthens the infant’s immune system.1 infant formulas are alternatives to breast milk specially produced to completely satisfy the nutritional needs of infants during their first months of life and until appropriate complementary feeding https://creativecommons.org/licenses/by-nd/4.0/ public health and paediatric risk assessment of aluminium, arsenic and mercury in infant formulas marketed in nigeria e64 | squ medical journal, february 2020, volume 20, issue 1 can be introduced.2 although infant formulas are beneficial and generally considered safe, they may be a source of contaminants, including heavy metals, which bioaccumulate to pose health risks to infants.3 as infancy is characterised by high growth and development rates, infants are susceptible to noxious chemical contaminants due to their special physiology, toxicokinetics and body weight (bw) ratio. earlier reports on dairy-based milk powder and infant formulas have cited contamination by toxic metals.4 to ensure safety, various regulatory agencies have set threshold intake levels of heavy metals for infants, including aluminium, arsenic and mercury.5 aluminium is a widely distributed element in the earth's crust and was long considered safe for humans because of its relatively low bioavailability.6 this safety has been questioned, however, by epidemiological reports that link chronic aluminium exposure to alzheimer's disease.7 chronic dietary aluminium exposure, especially in susceptible individuals with impaired renal function, often leads to adverse neurologic, skeletal, haemato poietic, immunologic and other health effects.7 the joint food and agricultural organization/world health organization (who) expert committee on food additives (jecfa), based on experimental bioavailability and toxicological data, established a provisional tol erable weekly intake (ptwi) of aluminium at 2 mg/kg bw/week.8 the use of arsenic in agriculture has led to severe soil contamination, thus constituting immediate human health risks due to contaminated dust, soil particles or water.9 in particular, rice has high grain arsenic but is still used to fortify many infant foods due to its high fibre content.10 despite the wide use of rice in infant formulas, arsenic levels in baby foods has received little attention.11 arsenic’s classification as a human carcinogen correlates with skin, lung, bladder, kidney and liver cancers and is capable of influencing neurological, respiratory, cardiovascular, immunological and endocrine systems. as a result, the jecfa estimated that the benchmark dose lower confidence limit for inorganic arsenic species should be no more than 2.1 μg/kg bw/day.12,13 the toxicity of mercury depends on its chemical form. inorganic mercury is mainly associated with renal damage, but methylmercury crosses the placenta and blood-brain barriers to cause irreversible neuronal damage in the fetus and growing children.14 even organic produce cannot confer protection, as reports have found that both organic and conventional produce can be prone to heavy metal contamination.15 the upper limits of estimates of average dietary exposure to total mercury from foods other than fish and shellfish for children was set at 4 μg/kg bw/week by jecfa.13 the actual dietary intake of aluminium, arsenic and mercury can be estimated and compared with corresponding toxicological reference intakes such as the provisional tolerable daily intake (ptdi) and ptwi to assess the risk to children’s health arising from the presence of contaminants in food. there is a paucity of information on children’s exposure to metals through food because of a scarcity of child-specific data on food consumption. in developing countries, including nigeria, there is lean data on contamination of infant food.4 this study aimed to determine the aluminium, arsenic and mercury concentrations and conduct an exposure health risk assessment in commonly consumed infant formulas in nigeria. the infant’s aluminium, arsenic and mercury daily intakes were calculated to provide context of such exposure to both the inter national dietary aluminium, arsenic and mercury reg ulations and the values reported in the literature from similar studies. this study also employed principal comp onent analyses (pca) of heavy metal concentrations in three types of infant formulas: milk-based (m), cerealbased (c) and a mixture of cereal and milk-based (cm). methods this study was conducted on samples of both locally manufactured and imported brands of commonly consumed formulas for infants ranging in age from birth to beyond the first year of life. this sample represented approximately 75% of infant formulas avail able on the nigerian market and were purchased from stores in port harcourt, rivers state, nigeria, in march 2017. the infant formulas were divided into three groups: m1–9, c1–7 and cm1–10 [table 1]. these products consisted of infant formulas and follow-on formula samples which were soy-based; milk and ricebased; rice, wheat and mixed cereal gruel (all sold as powder); vegetable meals; and fruit-based desserts. the infant formula samples (1–2 g) were weighed with plastic materials to prevent contamination with metals. the samples were then digested using hot-block digestion as in a previous procedure.15 approximately 9 ml of 65% concentrated nitric acid and 3 ml of perchloric acid were added in a ratio of 3:1 prior to heating and the solution was transferred to a hot plate and heated to 120°c for approximately five hours. the samples were then placed in an oven where the temperature was gradually increased by 10°c every 60 minutes until reaching 450°c. after 18 hours, the samples had been converted to white ash and were left to cool. the white ash was then dissolved in 5 ml of 1.5% nitric acid and a final volume of 25 ml was made by the addition of deionised water. metal con zelinjo n. igweze, osazuwa c. ekhator, ify nwaogazie and orish e. orisakwe clinical and basic research | e65 centrations were assayed with atomic absorption spectroscopy (model 205, buck scientific, east norwalk, connecticut, usa). samples were analysed in triplicate.16 the instrument was recalibrated after every 10 runs. the analytical procedure was checked using the spike recovery method. a known standard of the metals was introduced into already-analysed samples and reanalysed. results of recovery studies for aluminium, arsenic and mercury found a recovery rate of more than 97%.16 the relative standard deviation (sd) between replicate analyses was less than 4%. the limit of detection for aluminium, arsenic and mercury were 0.005, 0.001 and 0.001 mg/kg, respectively, with blank values reading as 0.00 mg/kg for all the metals in deionised water with an electrical conductivity of less than 5 μs/cm. the limit of quantification was 0.04 mg/kg. the jecfa ptdi values were used as threshold values for the consumption of aluminium, arsenic and mercury.8,13 to assess aluminium exposure in children through the consumption of commonly used infant formulas in nigeria, a jecfa ptdi of 286 μg/kg bw/day and a ptwi of 2,000 μg/kg bw/week were considered threshold values. in assessing infants’ arsenic intake, a ptdi of 2.1 μg/kg bw/day and a ptwi of 15 μg/kg bw/week was considered acceptable. the threshold values for children’s exposure to mercury was set at a ptdi of 0.57 μg/kg bw/day and a ptwi of 4.0 μg/kg bw/week. the exposure health risks of aluminium, arsenic and mercury from consumption of infant formulas were based on estimated daily intake (edi) and comp ared with the jecfa ptdi.17,18 where edi is the estimated daily intake of aluminium, arsenic and mercury (mg/kg/day), c is the mean concentration of aluminium, arsenic or mercury in infant formula samples (mg/kg), ir is the intake of infant formula (kg/bw/day) and bw is the infant’s body weight. the edi of aluminium, arsenic and mercury in different infant formulas was calculated using the actual aluminium, arsenic and mercury levels from this study to multiply the recommended consumption/intake rate by manufacturers divided by bw [equation 1]. the edi was calculated for 0–12 month old infants with a bw of 3.5–10.5 kg.19 the daily consumed powder formula, according to the infants’ mean bw, were obtained from feeding tables and dosages recommended by manufacturers. for an exposure assessment of aluminium, arsenic and mercury in infant formulas, the percentage of aluminium, arsenic and mercury according to ptdi was calculated using the lowest and highest edi [equation 2]. all the calculated ptdis were based on data appropriate for infants of various ages and bws. the edi was compared with the jecfa ptdi for aluminium, arsenic and mercury. the highest and lowest edi values from all three types of infant formula were used to calculate the percentages of alum inium, arsenic and mercury that contributed to ptdi. percentages of aluminium, arsenic and mercury in infant formulas were calculated using the following equation: statistical analysis was carried out using graphpad prism, version 6.5 (graphpad software inc., san diego, california, usa). all results were expressed as mean ± sd. the data were analysed using one-way analysis of variance and tukey’s post-hoc test at a 95% confidence level. a p value of <0.05 was considered statistically significant. pca was applied to reduce the number of variables and extract as much information as possible. this study was approved by the ethics committee on research at the university of port harcourt, rivers state, nigeria. results a total of 26 infant formulas were analysed in this study. the concentrations of aluminium, arsenic and mercury varied from 0.41–2.47, 0.02–1.56 and 0.000–0.050 mg/kg, respectively. mercury was not detected in 19.2% of the tested formulas. the highest and lowest detected values of mercury were observed in m6 (0.050 mg/kg) and c2 (0.001 mg/kg), respectively. arsenic was detected in all analysed formulas, with the highest value detected in c2 (1.56 mg/kg) and the lowest values in cm2, 4 and 5 (0.02 mg/kg each). aluminium was found to be present in all analysed formulas, with the highest and lowest values observed in m4 (2.47 mg/kg) and c5 (0.41 mg/kg), respectively [table 1]. the mean mercury concentration in all three types of infant formula was 0.01 mg/kg. the mean arsenic concentration in cereal-based infant formula was higher compared to milk-based and a mixture of cereal and milk-based formula (0.68 ± 0.67 versus 0.33 ± 0.26 and 0.46 ± 0.52 mg/kg, respectively); these differences were not statistically significant (p >0.05). the highest mean concentration of aluminium was found in the milk-based infant formula compared to cereal-based and a mixture of cereal and milk-based formula (1.70 ± 0.49 versus 1.52 ± 0.6 and 1.17 ± 0.56 mg/kg, respectively); these differences were also not statist ically significant (p >0.05) [table 2]. c × ir [equation 1] [equation 2] bw edi × 100% of ptdi = ptdi edi = public health and paediatric risk assessment of aluminium, arsenic and mercury in infant formulas marketed in nigeria e66 | squ medical journal, february 2020, volume 20, issue 1 table 1: concentrations of aluminium, arsenic and mercury found in different brands of infant formulas in nigeria (n = 26) sample code brand name manufacturer (country) packaging type aluminium in mg/kg arsenic in mg/kg mercury in mg/kg m1 pre nan nestle (nigeria) aluminium tin 1.92 0.83 0.020 m2 sma wyeth nutritionals (south africa) aluminium tin 1.39 0.05 0.010 m3 peak baby friesland campina (nigeria) aluminium tin 1.02 0.29 0.000 m4 lactogen 1 nestle (nigeria) aluminium tin 2.47 0.16 0.020 m5 nutristart laffort (france) hard cardboard exterior with formula in aluminium foil 1.86 0.03 0.001 m6 sma pro nestle (nigeria) aluminium tin 1.08 0.39 0.050 m7 sma pro wyeth nutritionals (south africa) aluminium tin 2.07 0.24 0.001 m8 cowbell tina cowbell (nigeria) aluminium tin 1.43 0.34 0.003 m9 my boy eldorin pocket friendly (nigeria) aluminium tin 2.03 0.61 0.020 c1 nestle cerelac nestle (nigeria) aluminium tin 1.53 1.50 0.010 c2 nestum baby cereal nestle (nigeria) hard cardboard exterior with formula in aluminium foil 1.97 1.56 0.001 c3 golden country baby cereal sun mark ltd. (england) aluminium tin 1.43 0.08 0.010 c4 friso gold friso gold (singapore) aluminium tin 1.54 0.26 0.000 c5 cerelac infant cereal na aluminium tin 0.41 0.15 0.010 c6 pediasure: grow and gain na hard cardboard exterior with formula in aluminium foil 2.35 1.02 0.003 c7 aptamil: organic rice na hard cardboard exterior with formula in aluminium foil 1.39 0.17 0.002 cm1 nutriban nutrimental (brazil) hard cardboard exterior with formula in aluminium foil 0.73 1.27 0.014 cm2 ridielac (vina milk) vietnam dairy products (vietnam) hard cardboard exterior with formula in aluminium foil 2.07 0.02 0.003 cm3 nutriben alter farmacia (spain) hard cardboard exterior with formula in aluminium foil 0.45 0.33 0.000 cm4 ninolac ninolac maroc sarl (luxembourg) hard cardboard exterior with formula in aluminium foil 0.58 0.02 0.002 cm5 gerber nestle (nigeria) plastic 2.04 0.02 0.003 cm6 heinz dinners heinz (usa) hard cardboard exterior with formula in aluminium foil 1.52 0.10 0.030 cm7 gerber oatmeal gerber (usa) plastic 1.16 0.11 0.000 cm8 heinz summer fruits nestle (nigeria) plastic with aluminium lining 1.26 0.79 0.004 cm9 nutrilac infant cereal wyeth nutritionals (south africa) hard cardboard exterior with formula in aluminium foil 0.92 1.32 0.000 cm10 cerelac infant cereal friesland campina (nigeria) aluminium tin 0.99 0.60 0.012 m = milk-based sample; c = cereal-based sample; cm = a mixture of cereal and milk-based sample; na = not available. zelinjo n. igweze, osazuwa c. ekhator, ify nwaogazie and orish e. orisakwe clinical and basic research | e67 the edi of aluminium, arsenic and mercury in milk based infant formula ranged from 0.023–0.040, 0.005– 0.008 and 1.4 × 104–2.4 × 104 mg/kg bw/day, respectively. in cereal-based infant formula, the edi of aluminium, arsenic and mercury ranged from 0.021–0.036, 0.009– 0.016 and 1.4 × 104–2.4 × 104 mg/kg bw/day, respectively. the edi of aluminium, arsenic and mercury in a mixture of cereal and milk-based infant formula ranged from 0.016–0.025, 0.006–0.011 and 1.4 × 104–2.4 × 104 mg/kg bw/day, respectively [table 3]. compared to the ptdi jecfa threshold values there was an intake range of 8.02–14.2% for aluminium, 437.1–771% for arsenic and 23.7–41.8% for mercury [table 4]. the pca for the three variables (aluminium, arsenic and mercury) resulted in a biplot with alum inium in the first quadrant alongside milk-based formulas [figure 1]. this finding suggests that aluminium is the principal component with an eigenvalue of 2.956 and corresponding variability of 98.55%. table 2: mean concentrations of aluminium, arsenic and mercury in three different groups of infant formulas in nigeria (n = 26) infant formula type mean concentration ± sd in mg/kg (range) aluminium arsenic mercury m1–9 1.70 ± 0.49 (1.02–2.47) 0.33 ± 0.26 (0.03–0.83) 0.01 ± 0.02 (0.00–0.05) c1–7 1.52 ± 0.6 (0.41–2.35) 0.68 ± 0.67 (0.08–1.56) 0.01 ± 0.00 (0.00–0.01) cm1–10 1.17 ± 0.56 (0.45–2.07) 0.46 ± 0.52 (0.02–1.32) 0.01 ± 0.01 (0.00–0.03) sd = standard deviation; m = milk-based sample; c = cereal-based sample; cm = a mixture of cereal and milk-based sample. table 3: estimated daily intake of aluminium, arsenic and mercury in different groups of infant formulas in nigeria infant formula type and infant age dir in kg bw in kg edi in mg/kg bw/day aluminium arsenic mercury milk-based age 0–2 weeks 0.075 3.5 0.036 0.007 2.1 × 104 2–4 weeks 0.100 4.2 0.040 0.008 2.4 × 104 2 months 0.110 4.7 0.040 0.008 2.3 × 104 4 months 0.145 6.5 0.038 0.007 2.2 × 104 6 months 0.135 7.5 0.031 0.006 1.8 × 104 6–12 months 0.135 10 0.023 0.005 1.4 × 104 cereal-based age 0–2 weeks 0.075 3.5 0.032 0.015 2.1 × 104 2–4 weeks 0.100 4.2 0.036 0.016 2.4 × 104 2 months 0.110 4.7 0.035 0.016 2.3 × 104 4 months 0.145 6.5 0.033 0.015 2.2 × 104 6 months 0.135 7.5 0.027 0.012 1.8 × 104 6–12 months 0.135 10 0.021 0.009 1.4 × 104 mixture of cereal and milk-based age 0–2 weeks 0.075 3.5 0.021 0.010 2.1 × 104 2–4 weeks 0.100 4.2 0.025 0.011 2.4 × 104 2 months 0.110 4.7 0.020 0.011 2.3 × 104 4 months 0.145 6.5 0.023 0.010 2.2 × 104 6 months 0.135 7.5 0.016 0.008 1.8 × 104 6–12 months 0.135 10 0.016 0.006 1.4 × 104 dir = daily intake rate; bw = body weight; edi = estimated daily intake. table 4: percentage of the joint food and agricultural org anization/world health organization expert committee on food additives provisional tolerable daily intake of aluminium, arsenic and mercury found in analysed infant formulas in nigeria aluminium arsenic mercury jecfa ptwi in μg/kg bw/week 2000 15 4.0 jecfa ptdi in μg/kg bw/day 286 2.1 0.57 age percentage of jecfa ptdi 0–2 weeks 12.7 693.9 37.6 2–4 weeks 14.2 771 41.8 2 months 13.9 757.9 41.1 4 months 13.3 722.3 39.1 6 months 10.7 582.9 31.6 6–12 months 8.02 437.1 23.7 jecfa = joint food and agricultural organization/world health organ ization expert committee on food additives; ptwi = provisional toler able weekly intake; bw = bodyweight; ptdi = provisional tolerable daily intake. figure 1: biplot of principal component analysis. public health and paediatric risk assessment of aluminium, arsenic and mercury in infant formulas marketed in nigeria e68 | squ medical journal, february 2020, volume 20, issue 1 discussion the present study showed the presence of aluminium, arsenic and mercury in infant formulas sold in nigeria. aluminium and mercury levels were within per missible limits, but arsenic concentrations in the infant formulas exceeded established safe limits. the mean concentrations of aluminium and mercury were highest in milk-based infant formulas compared to other types of infant formulas, whereas arsenic was lowest in milkbased infant formulas compared to other analysed types. the mean arsenic concentration in this study was higher than the threshold value of 0.14 mg/kg.20 the detected aluminium concentrations in the current study was higher than those reported earlier in nigeria but this level of contamination is not con sidered a health concern.21 aluminium in infant formulas marketed in nigeria may be considered safe because, contrary to expectations and given the ubiquity of aluminium in the environment and fortification of formulas with iron and other ingredients, the aluminium in all the infant-based formulas were under the ptdi threshold value and the edi for children aged 0–12 month. in this study, aluminium levels in milk-based infant formulas were higher compared to cerealbased formulas (1.70 ± 0.49 versus 1.52 ± 0.6 mg/kg, respectively). these aluminium levels were also higher than those reported by koo et al. for both milk-based and soy-based infant formulas (14–565 µg/l and 455–2346 µg/kg, respectively).22 aluminium can have plant and animal origins, with the former reflecting the content in the soil and in the water resulting from carry-over or run-off. the produce used as raw materials for these infant formulas may have been grown in contaminated soil or produced with aluminium contaminated water.23 baxter et al. reported that soya-based formulas usually contained higher concentrations of aluminium than milk-based formulas although there is evidence that some manufacturers can lower concentrations of aluminium in soy-based formulas.23 high levels of aluminium disrupt enzyme activities and impairs mitochondrial functions in many organs, especially the haemopoietic system, nervous system and bones, which are especially important in growing infants and children.24 according to the committee on nutrition of the american academy of pediatrics, aluminium content should not exceed 30,000 ng/kg of bw/day for infants and children, with chronic renal failure requiring phosphate binders.25 the jecfa, based on the experimental bio availability and toxicological data, reduced the ptwi of aluminium from 7,000 to 2,000 µg/kg of bw for humans. interestingly, according to the same committee, estimates of dietary exposure of children to aluminium containing food additives, including high dietary exposures, can exceed ptwi by up to two-fold.14 this study found an aluminium intake range of 8.02–14.2% for full-term 0–12-month-old infants (3.5–10 kg bw) of the jecfa ptdi for the analysed infant formulas. these levels are within the ptwi of aluminium established by the jecfa.8 however, this aluminium content of infant formulas is higher than the aluminium content of breast milk, which is usually approximately 15–30 μg/l.26 this may be of concern in infants with impaired renal function and premature infants who should be on infant formula with an aluminium level of less than 100 ng/g.27 fat concentrates, lactose and mineral mixtures have been reported as contributing to the total aluminium content in infant formulas and could be reduced by over 70% by replacing these components with low-aluminium equivalents.27 more than 90% of the infant formulas in this study were packaged in some form of aluminium. migration of aluminium from the packaging may have contributed to the presence of aluminium in the infant formulas in this study.25 arsenic can cause cancer in many organs, including the skin, lungs, bladder, kidney and liver; it is also capable of influencing the neurological, respiratory and cardiovascular systems.13 arsenic has also been implicated in diabetic pathophysiology and reproductive toxicity.13 this study found an arsenic intake range of 437.1–771% of the jecfa ptdi for infant formulas. recent research has shown that infant formulas, specifically rice-based infant food, contains arsenic which can be traced to the natural raw materials used for processing.28,29 currently, there is no guideline for arsenic content in baby food, including infant formulas, but the food industry has been advised to adhere to a 0.2 mg/kg arsenic level to ensure the safety of infants and young children.29,30 infant formulas derived from rice have been shown to contain arsenic, which potentially has health risks for infants due to long-term exposure starting at a young age.30 in this study, the cereal-based infant formulas showed the highest levels of arsenic at 0.68 ± 0.67 mg/kg. although some work has reported that infant formula contributes minimally to overall inorganic arsenic exposure in children and does not pose a significant public health concern, the edi of arsenic in all infant formulas in the current study exceeded the infant age group ptdi of 2.1 µg/kg bw/day set by the jecfa.30 the arsenic levels in the present study are general measurements and not representative of any specific type of arsenic. although the main dietary source of mercury in humans is fish, non-fish sources can also contain mercury.24 this study found an intake range of 23.7–41.8% of the ptdi for the analysed infant formulas. edi of zelinjo n. igweze, osazuwa c. ekhator, ify nwaogazie and orish e. orisakwe clinical and basic research | e69 mercury in infant formula was found to be under the ptdi value recommended by the jecfa.31 mercola showed that high-fructose corn syrups may be a source of mercury in infant formulas.32 in addition, there are many instances at which metals can enter infant formulas, such as through metal, plastic or glass containers used for storing formula, through washing or leaching from lids and/or through equipment and processes used for filling these containers. this study was subject to some limitations. due to financial constraints, this study only focused on a small sample. it is possible that the levels of metals in the samples may be due to batch contamination. in addition, metal speciation could not be performed. further studies with larger sample sizes including metal speciation analyses will shed more light on the public health impact of infant formula consumption in nigeria conclusion feeding infants and children in nigeria with commonly available infant formulas may pose a risk to infants and add to their body burden of arsenic. although exceeding the ptwi occasionally may not indicate a health risk, the assessed content of arsenic in the infant formulas was much higher than the ptdi and ptwi recommended by the jecfa, suggesting a cause for public health concern. notwithstanding the lack of legislation on mercury content in infant and baby foods, manufacturers are advised to be more circumspect in their choice of raw materials, and more studies should be conducted to justify the need for legislation concerning levels of total mercury (metal speciation) in infant and baby foods. food regulatory agencies in developing nations should periodically conduct targeted analyses of all infant formula types to ensure that the permissible limits of contaminants are not exceeded and no processes or ingredients have been inadvertently introduced which would accidentally contaminate the product. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. hörnell a, lagström h, lande, b thorsdottir, i. breastfeeding, introduction of other foods and effects on health: a systematic literature review for the 5th nordic nutrition recommendations. food nutr res 2013; 57:1–27. https://doi.org/10.3402/fnr.v57i0.20823. 2. codex alimentarius commission. standard for infant formula and formulas for special medical purposes intended for infants. rome: food and agriculture organization of the united nations and world health organization, 1981. codex stan 72-1981. 3. domínguez a, paz s, rubio c, gutiérrez a, gonzález-weller d, revert c, et al. essential and toxic metals in infant formula from the european community. open access j toxicol 2017; 2:1–8. https://doi.org/10.19080/oajt.2017.02.555585. 4. european environment and health information system. exposure of children to chemical hazards in food. from: www.euro.who. int/__data/assets/pdf_file/0003/97446/4.4.pdf accessed: aug 2019. 5. chemlinked. gb 2762-2012 national food safety standard maximum levels of contaminants in foods. from: https:// food.chemlinked.com/node/3441 accessed: aug 2019. 6. gupta n, gaurav ss, kumar a. molecular basis of aluminium toxicity in plants: a review. am j plant sci 2013; 4:21–37. https://doi.org/10.4236/ajps.2013.412a3004. 7. bondy sc. low levels of aluminum can lead to behavioral and morphological changes associated with alzheimer's disease and age-related neurodegeneration. neurotoxicology 2016; 52:222–9. https://doi.org/10.1016/j.neuro.2015.12.002. 8. osman na, zaki a, agmay nf, shehata gm. aluminum in food: dietary exposure among adolescent residents in the food catering establishments in alexandria, egypt. glob j pharm educ res 2017; 6:1–6. 9. rintala em, ekholm p, koivisto p, peltonen k, venäläinen er. the intake of inorganic arsenic from long grain rice and ricebased baby food in finland low safety margin warrants follow up. food chem 2014; 150:199–205. https://doi.org/10.1016/j. foodchem.2013.10.155. 10. jackson bp, taylor vf, punshon t, cottingham kl. arsenic concentration and speciation in infant formulas and first foods. pure appl chem 2012; 84:215–23. https://doi.org/10.1351/pac con-11-09-17. 11. ljung k, palm b, grandér m, vahter m. high concentrations of essential and toxic elements in infant formula and infant foods a matter of concern. food chem 2011; 127:943–51. https://doi.org/10.1016/j.foodchem.2011.01.062. 12. international agency for research on cancer. arsenic and arsenic compounds. from: https://www.ncbi.nlm.nih.gov/books/nbk3 04380 accessed: aug 2019. 13. food and agriculture organization of the united nations, world health organization. safety evaluation of certain contaminants in food: prepared by the seventy-second meeting of the joint fao/who expert committee on food additives (jecfa). from: https://apps.who.int/iris/handle/10665/44520 accessed: aug 2019. 14. bose-o’reilly s, mccarty km, steckling n, lettmeier b. mercury exposure and children’s health. curr probl pediatr adolesc health care 2010; 40:186–215. https://doi.org/10.1016/j.cppeds.2010.07.002. 15. tobin r, larkin t, moane s. the irish organic food market: shortfalls, opportunities and the need for research. j sci food agric 2011; 91:2126–31. https://doi.org/10.1002/jsfa.4503. 16. orisakwe oe, igweze zn, udowelle na. candy consumption may add to the body burden of lead and cadmium of children in nigeria. environ sci pollut res int 2019; 26:1921–31. https://doi.org/10.1007/s11356-018-3706-3. 17. poitevin e. official methods for the determination of minerals and trace elements in infant formula and milk products: a review. j aoac int 2016; 99:42–52. https://doi.org/10.5740/ jaoacint.15-0246. 18. bargellini a, venturelli f, casali e, ferrari a, marchesi i, borella p. trace elements in starter infant formula: dietary intake and safety assessment. environ sci pollut res int 2018; 25:2035–44. https://doi.org/10.1007/s11356-016-8290-9. https://doi.org/10.3402/fnr.v57i0.20823 https://doi.org/10.19080/oajt.2017.02.555585 https://doi.org/10.4236/ajps.2013.412a3004 https://doi.org/10.1016/j.neuro.2015.12.002 https://doi.org/10.1016/j.foodchem.2013.10.155 https://doi.org/10.1016/j.foodchem.2013.10.155 https://doi.org/10.1351/pac-con-11-09-17 https://doi.org/10.1351/pac-con-11-09-17 https://doi.org/10.1016/j.foodchem.2011.01.062 https://doi.org/10.1016/j.cppeds.2010.07.002 https://doi.org/10.1002/jsfa.4503 https://doi.org/10.1007/s11356-018-3706-3 https://doi.org/10.5740/jaoacint.15-0246 https://doi.org/10.5740/jaoacint.15-0246 https://doi.org/10.1007/s11356-016-8290-9 public health and paediatric risk assessment of aluminium, arsenic and mercury in infant formulas marketed in nigeria e70 | squ medical journal, february 2020, volume 20, issue 1 19. onayade aa, abiona tc, abayomi io, makanjuola ro. the first six month growth and illness of exclusively and non-exclusively breast-fed infants in nigeria. east afr med j 2004; 81:146–53. https://doi.org/10.4314/eamj.v81i3.9145. 20. bratakos sm, lazou ae, bratakos ms, lazos es. aluminium in food and daily dietary intake estimate in greece. food addit contam part b surveill 2012; 5:33–44. https://doi.org/10.1080/ 19393210.2012.656289. 21. ikem a, nwankwoala a, odueyungbo s, nyavor k, egiebor n. levels of 26 elements in infant formula from usa, uk, and nigeria by microwave digestion and icp-oes. food chem 2002; 77:439–47. https://doi.org/10.1016/s0308-8146(01)00378-8. 22. koo ww, kaplan la, krug-wispe sk. aluminum contamination of infant formulas. jpen j parenter enteral nutr 1988; 12:170–3. https://doi.org/10.1177/0148607188012002170. 23. baxter mj, burrell ja, massey rc. the aluminium content of infant formula and tea. food addit contam 1990; 7:101–7. https://doi.org/10.1080/02652039009373826. 24. bundesministerium für gesundheit. aluminium: toxikologie und gesundheitliche aspekte körpernaher anwendungen. from www.sozialministerium.at/themen/gesundheit/verbrauch e r g e s u n d h e i t / s t u d i e a l u m i n i u m -to x i k o l o g i e u n d gesundheitliche-aspekte-k%c3%b6rpernaher-anwendungen-. html accessed: aug 2019. 25. american academy of pediatrics committee on nutrition: aluminum toxicity in infants and children. pediatrics 1986; 78:1150–4. 26. fernandez-lorenzo jr, cocho ja, rey-goldar ml, couce m, fraga jm. aluminum contents of human milk, cow’s milk and infant formulas. j pediatr gastroenterol nutr 1999; 28:270–5. https://doi.org/10.1097/00005176-199903000-00011. 27. dabeka r, fouquet a, belisle s, turcotte s. lead, cadmium and aluminum in canadian infant formulae, oral electrolytes and glucose solutions. food addit contam part a chem anal control expo risk assess 2011; 28:744 –53. https://doi.org/10. 1080/19393210.2011.571795. 28. carignan cc, cottingham kl, jackson bp, farzan sf, gandolfi aj, punshon t, et al. estimated exposure to arsenic in breastfed and formula-fed infants in a united states cohort. environ health perspect 2015; 123:500–6. https://doi.org/10.1289/ehp.1408789. 29. shibata t, meng c, umoren j, west h. risk assessment of arsenic in rice cereal and other dietary sources for infants and toddlers in the us. int j environ res public health 2016; 13:361. https://doi.org/10.3390/ijerph13040361. 30. cubadda f, jackson bp, cottingham kl, van horne yo, kurzius-spencer m. human exposure to dietary inorganic arsenic and other arsenic species: state of knowledge, gaps and uncert ainties. sci total environ 2017; 579:1228–39. https://doi.org/10.1 016/j.scitotenv.2016.11.108. 31. joint fao/who expert committee on food additives. safety evaluation of certain food additives and contaminants: prepared by the seventy fourth meeting of the joint fao/who expert committee on food additives ( jecfa) . from: https://apps. who.int/iris/handle/10665/44813 accessed: aug 2019. 32. mercola j. this common food ingredient can really mess up your metabolism. from: https://clareswinney.wordpress.com/2010 /01/28/this-common-food-ingredient-can-really-mess-upyour-metabolism/ accessed: aug 2019. https://doi.org/10.4314/eamj.v81i3.9145 https://doi.org/10.1080/19393210.2012.656289 https://doi.org/10.1080/19393210.2012.656289 https://doi.org/10.1016/s0308-8146%2801%2900378-8 https://doi.org/10.1177/0148607188012002170 https://doi.org/10.1080/02652039009373826 https://doi.org/10.1097/00005176-199903000-00011 https://doi.org/10.1080/19393210.2011.571795 https://doi.org/10.1080/19393210.2011.571795 https://doi.org/10.1289/ehp.1408789 https://doi.org/10.3390/ijerph13040361 https://doi.org/10.1016/j.scitotenv.2016.11.108 https://doi.org/10.1016/j.scitotenv.2016.11.108 1department of family medicine, sultan qaboos university hospital, muscat, oman; 2department of family medicine and public health, sultan qaboos university, muscat, oman; 3department of medical services, royal guard of oman, muscat, oman *corresponding author’s e-mail: yaqoubs@squ.edu.om knowledge, attitudes and practices of primary care physicians regarding tobacco dependence treatment in muscat governorate, oman a cross-sectional study *yaqoub alsaidi,1 buthaina almaskari,2 moon fai chan,2 sanaa al sumri,2 hajer alhamrashdi3 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 563–571, epub. 25 nov 21 submitted 23 jun 20 revision req. 14 sep 20; revision recd. 30 sep 20 accepted 1 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.034 clinical & basic research abstract: objectives: this study aimed to assess the knowledge, attitudes and practices (kaps) of primary care physicians (pcps) regarding tobacco dependence treatment (tdt) and to identify barriers to tdt practice in muscat, oman. methods: this cross-sectional study was carried out from september 2019 to december 2019 at all 27 health centres in muscat. all 313 pcps working in these health centres were invited to participate. an adapted version of a previously validated 36-item questionnaire was used to assess kaps regarding tdt services. results: a total of 255 pcps completed the survey (response rate: 81.5%) and they demonstrated poor knowledge (40%) but positive attitudes (60%) about tdt services. of these, the majority were female (85.9%), had never smoked (99.2%) and were general practitioners (64.3%). the mean age was 34.3 ± 6.3 years. only 28.2% had previously received tdt training and less than half displayed accurate tdt-related knowledge, with undergraduate medical school representing the main source of such knowledge (58.8%). while 96.9% of the pcps agreed on the importance of tdt, only 28.6% reported feeling sufficiently confident to provide such services themselves. lack of training (83.5%) and time (71.4%) were the main barriers to tdt practice. conclusion: overall, pcps in muscat demonstrated poor knowledge but positive attitudes with regard to tdt; however, further knowledge and training is required in order to ensure the effective and accurate provision of tdt services. these findings provide baseline data which may be of value for further research and in overcoming barriers to tdt practice in oman; for instance, establishing cessation services as part of the package of care in primary health centres could address the time constraints barriers identified by the pcps. keywords: tobacco dependence; smoking cessation; primary care physicians; health knowledge, attitudes, practice; oman. advances in knowledge omani primary care physicians (pcps) in muscat demonstrated poor knowledge about (40%) but positive attitudes (60%) towards tobacco dependence treatment (tdt) services. a high proportion of respondents (71.8%) had never received basic tdt training which would explain why lack of training was identified as a major barrier to tdt practice. application to patient care the positive attitudes among pcp towards the provision of tdt to their smoking patients provides an opportunity to pilot cessation services in primary care centres in muscat. establishing cessation services as part of the package of care in primary health centres could address the time constraint barriers identified by the pcps. tobacco use is a major modifiable risk factor for non-communicable diseases and is responsible for six million deaths annually.1 worldwide, there are approximately 1.3 billion tobacco users, of which an alarmingly high proportion consist of men in the eastern mediterranean (emr) region.2,3 while many smokers find it difficult to quit, evidence-based research has shown that support from healthcare providers can increase cessation rates by up to 66–84%.4,5 moreover, a meta-analysis found that tobacco dependence treatment (tdt) interventions significantly reduced tobacco use in the short term while maintaining cessation efforts over time.6 the world health organization (who) framework convention on tobacco control stipulates that nations should address tobacco dependence by promoting cessation services.7,8 common interventions include counselling through regular health services, telephone quitlines and access to pharmacological therapy. furthermore, specialised tdt clinics should be established and staffed by trained physicians in order to provide appropriate knowledge, attitudes and practices of primary care physicians regarding tobacco dependence treatment in muscat governorate, oman a cross-sectional study 564 | squ medical journal, november 2021, volume 21, issue 4 motivational counselling and prescriptions for nicotine replacement therapy (nrt), most forms of which are usually available over the counter.7,8 in june 2019, the price of tobacco products doubled due to the addition of tax; this change is expected to increase demand for tobacco cessation services, particularly in lowand middle-income countries.3,9 assorted tobacco control measures have been implemented in the gulf cooperation council (gcc) region with varying degrees of success.10 overall, the majority of gcc countries have made important strides in tobacco control in recent years, such as implementing bans on the advertisement or marketing of tobacco products; moreover, all gcc states, apart from bahrain, have a national body dedicated to tobacco control measures.11 however, there is some concern that clinical tdt interventions may not be as effective for arab populations compared to western populations.12 this is possibly because traditional tdt interventions do not take into account the sociocultural norms of this region, such as the strong influence of friends and family members on lifestyle choices.13 moreover, tdt measures can be prohibitively expensive; heydari et al. observed that the mean cost of accessible tdt services in the emr region, such as those involving nrt, was much higher than the price of common tobacco products such as cigarettes.14 in oman, the prevalence of tobacco use among men aged ≥15 years old was estimated to be 17.9% in 2010; without additional tobacco control measures, this rate is expected to increase to 33.3% by 2025.15 moreover, the global youth tobacco survey showed an alarming level of tobacco use among adolescents in oman, with 17.8% of boys and 11.3% of girls using various types of tobacco products.16 the national tobacco control committee is responsible for developing and implementing national policies, laws and regulations for tobacco control as well as raising awareness and supporting tdt-related training and research.17 in oman, three smoking cessation clinics offering nrt and psychological motivational therapy were established in muscat, nizwa and in the primary health care centre at the main public university in muscat in 2006, 2009 and 2015, respectively.15 primary care providers (pcps) are in an ideal position to support tobacco cessation efforts as they represent the first point-of-care for the majority of tobacco users.5,18 in oman, health centres are the cornerstone for primary care and provide both preventive and curative services; while primary care services are also provided at renal dialysis units, polyclinics, offices of the centers for disease control and prevention and small primary hospitals, patients must first be referred from local health centres. most pcps are either non-certified general practitioners (gps), family medicine residents or certified family physicians. according to statistics from the ministry of health (moh), there were 432 omani and non-omani physicians working in primary healthcare institutions in muscat in 2018, of which approximately 313 pcps worked in local health centres.19 although tobacco use is a growing problem in gcc countries, few studies have sought to assess knowledge, attitudes and practices (kaps) and barriers to providing tdt services among pcps. a recent study from saudi arabia showed that, despite their positive attitudes, pcps had poor knowledge and unsatisfactory practices with regards to smoking cessation counselling.20 another study conducted in armenia found that smoking cessation was limited by several factors, including subpar knowledge and skills.21 to the best of the authors’ knowledge, no previous studies on this topic have been conducted in oman. as such, this study aimed to identify the kaps of pcps in muscat with regards to the provision of tdt services, determine associations with sociodemographic variables and explore possible barriers to tdt practice. methods this cross-sectional study was carried out from september 2019 to december 2019 at all 27 health centres in muscat, oman. all pcps working at these health centres were included in the study. the required sample size was calculated to be 243 using the nquery advisor® software, version 19 (statistical solutions ltd., boston, massachusetts, usa), assuming a margin of error of 0.03 and a confidence interval level of 95%.22 in order to account for missing responses and attrition, all 313 pcps currently working at the health centres were invited to participate in the study. a modified version of a previously published semistructured 36-item questionnaire was utilised to collect data from the participants.20 this self-administered questionnaire comprised of three domains, with the first section collecting sociodemographic information, the second assessing responses to items related to tdt-related knowledge (n = 12), attitudes (n = 7) and practices (n = 7) and the third identifying self-reported barriers to tdt practice. the inter-rater reliability of the kap subscales in the modified instrument was high (cronbach’s alpha: 0.88–0.92). to ensure a high response rate, the research team contacted the heads or deputies of each health centre to ask them to distribute the questionnaire to the members of their teams and encourage them to take part in the study. a reminder yaqoub alsaidi, buthaina almaskari, moon fai chan, sanaa al sumri and hajer alhamrashdi clinical and basic research | 565 was sent to submit the completed questionnaires within a three-week period. completed questionnaires were returned to the heads of the health centres before being collected by the research team. in terms of scoring, correct answers to knowledge items received 1 point, while incorrect answers received 0 points. attitude items were rated in terms of agreement on a 5-point likert scale with responses of ‘strongly agree’, ‘agree’, ‘neither agree nor disagree’, ‘disagree’ and ‘strongly disagree’. positive attitudes (indicated by responses of ‘strongly agree’ or ‘agree’) were assigned 1 point, while neutral or negative attitudes (indicated by responses of ‘neither agree nor disagree’, ‘disagree’ or ‘strongly disagree’) received 0 points. finally, practice items were rated in terms of frequency on a 4-point likert scale with responses of ‘always’, ‘sometimes’, ‘rarely’ and ‘never’. satisfactory practices (represented by responses of ‘always’ or ‘sometimes’) were assigned 1 point, while unsatisfactory practices (represented by responses of ‘rarely’ and ‘never’) received 0 points. responses were grouped in this way to give a clearer indication of positive/satisfactory attitudes and practices. percentage mean scores were then calculated for each of the knowledge, attitude and practice subscales. the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa) was used for data analysis. descriptive statistics (e.g. frequencies, percentages, means and standard deviations) were used to describe the basic sociodemographic characteristics of the respondents. as appropriate, chi-squared, fisher’s exact and student’s t-tests were used to test for any significant differences or associations between gender and other sociodemographic factors. subsequently, either an independent t-test or analysis of variance was utilised to determine significant differences in kap with regards to sociodemographic variables. a post-hoc test was performed for pair comparisons. all tests were set at the 5% level of significance (p <0.05). ethical approval for this study was obtained from the local research ethics committee of the moh (moh-dgs-mg-46/2019). written informed consent was provided by all pcps prior to their participation in the study. identifying information was not collected to ensure privacy and confidentiality. results of the 313 pcps invited to take part in the study, 255 completed the questionnaire (response rate: 81.5%). the mean age was 34.3 ± 6.3 years, with 56.6% of the participants being between 31–45 years of age. the majority of the participants were female (85.9%). in terms of position, most were non-certified gps (64.3%), followed by family medicine residents (14.9%) or family medicine specialists (11.4%). interestingly, only two male physicians were ex-smokers of cigarettes (0.8%). moreover, only 28.2% of the participants had previously received training in tdt services [table 1]. the main source of tdt-related information was undergraduate medical school training (58.8%), followed by the internet (55.7%), textbooks (39.2%), postgraduate studies (37.6%), medical colleagues (37.6%), research studies (28.2%), workshops (20.0%) table 1: sociodemographic characteristics of primary care physicians in muscat, oman (n = 255) characteristic n (%) p value* total male (n = 36) female (n = 219) age in years† 0.278 ≤30 76 (33.6) 10 (27.8) 66 (34.7) 31–45 128 (56.6) 20 (55.6) 108 (56.8) >45 22 (9.7) 6 (16.7) 16 (8.4) mean ± sd 34.3 ± 6.3 36.9 ± 8.8 33.8 ± 5.5 0.064 current position 0.713 gp 164 (64.3) 22 (61.1) 142 (64.8) fm resident 38 (14.9) 6 (16.7) 32 (14.6) fm specialist 29 (11.4) 6 (16.7) 23 (10.5) fm senior specialist 20 (7.8) 2 (5.6) 18 (8.2) fm senior consultant 4 (1.6) 0 (0.0) 4 (1.8) previously received tdt training 0.125 yes 72 (28.2) 14 (38.9) 58 (26.5) no 183 (71.8) 22 (61.1) 161 (73.5) smoking status 0.019 non-smoker 253 (99.2) 34 (94.4) 219 (100.0) ex-smoker 2 (0.8) 2 (5.6) 0 (0.0) smoker 0 (0.0) 0 (0.0) 0 (0.0) type of tobacco used cigarettes 2 (0.8) 2 (5.6) 0 (0.0) shisha 0 (0.0) 0 (0.0) 0 (0.0) midwakh 0 (0.0) 0 (0.0) 0 (0.0) chewable tobacco 0 (0.0) 0 (0.0) 0 (0.0) other 0 (0.0) 0 (0.0) 0 (0.0) sd = standard deviation; gp = non-certified general practitioner; fm = fam ily medicine. *calculated using a chi-squared (χ2) test, student’s t-test or fisher’s exact test, as appropriate. †missing data for this variable were reported for 29 participants. knowledge, attitudes and practices of primary care physicians regarding tobacco dependence treatment in muscat governorate, oman a cross-sectional study 566 | squ medical journal, november 2021, volume 21, issue 4 and conferences (14.1%). crucially, most knowledge questions were answered correctly by less than half of the participants; furthermore, a large proportion indicated that they did not know the correct response to certain questions. most pcps were aware of the firstline treatment for tobacco dependency (88.2%) and the best methods for longand short-term cessation success (80.4%). moreover, only 118 participants (46.3%) were familiar with the ‘ask, advise, assess, assist and arrange’ (5as) approach; however, 29 (24.6%) of them could not accurately identify the five individual components of this approach [figure 1]. in terms of attitudes, most pcps (96.9%) agreed on the importance of providing tdt counselling services for their patients; however, only 28.6% felt sufficiently confident to perform such counselling themselves. furthermore, while the majority of pcps agreed that they should ask patients about their smoking status (83.9%) and advice patients to quit tobacco use routinely (90.6%), 57.6% of the participants expressed dissatisfaction with their own tdt knowledge and skills [figure 2]. concerning actual tdt practices, 38.0% of the pcps reported always asking and documenting their patients’ smoking status; however, only 13.3% continued updating this information on a regular basis. most pcps (99.2%) explained the health-related consequences of tobacco use to their patients and encouraged them to stop smoking. in contrast, few participants (14%) provided information regarding smoking cessation and helped their patients to make plans to quit. just under half of the pcps had never prescribed pharmacological tdt agents (48.2%) or scheduled follow-up tdt appointments (45.5%). the two most commonly reported barriers to tdt practice included a lack of training and time (83.5% and 71.4%, respectively). moreover, failure to follow up cessation efforts was considered a barrier to tdt practice by 51.4% of participants. other less commonly identified barriers to providing tdt services included withdrawal symptoms, relapses and the patients’ desire to smoke. most pcps recommended that adding tobacco status as a mandatory field in electronic health information systems or to the patient’s figure 1: knowledge regarding tobacco dependence treatment among primary care physicians in muscat, oman (n =255). sr = sustained-release ; nrt = nicotine replacement therapy ; tdt = tobacco dependence treatment ; 5as = ask , advise , assess, assist and arrange . figure 2: attitudes towards tobacco dependence treatment among primary care physicians in muscat, oman (n = 255). tdt = tobacco dependence treatment; pcps = primary care physicians. yaqoub alsaidi, buthaina almaskari, moon fai chan, sanaa al sumri and hajer alhamrashdi clinical and basic research | 567 vital signs would encourage more physicians to provide tdt services (73.7% and 65.1%, respectively). a comparison of mean kap scores according to sociodemographic characteristics is shown in tables 2 to 4. overall, the percentage mean scores for the knowledge, attitude and practice subscales were 39.8% ± 18.8%, 59.1% ± 19.6% and 60.0% ± 25.2%, respectively. there were no statistically significant differences in mean scores between the different age groups with regards to attitude (f = 0.990; p = 0.373) or practice (f = 1.669; p = 0.191). however, there was a significant difference in knowledge according to age (p = 0.002). according to the post-hoc analysis, participants aged ≤30 years had significantly lower mean knowledge scores compared to those aged 31–45 years (33.3% ± 14.3% versus 43.2% ± 20.9%; p <0.001). in terms of position, specialists and senior specialists/consultants achieved the highest mean knowledge (56.9% ± 20.5%) and practice (75.8% ± 18.9%) scores, respectively. moreover, there was a statistically significant difference in both knowledge (f = 22.892; p <0.001) and practice (f = 14.609; p <0.001) according to position. however, there was no statistically significant difference in attitude (f = 0.152; p = 0.928). a post-hoc test indicated that gps had significantly lower mean knowledge scores compared to both specialists and senior specialists/consultants (34.7% ± 16.8% versus 56.9% ± 20.5% and 56.3% ± 16.7%; p <0.001 each). in addition, gps also had significantly lower mean practice scores compared to residents, specialists and senior specialists/consultants (52.9% ± 24.3% versus 69.5% ± 23.6%, 74.8% ± 21.3% and 75.8% ± 18.9%; p ≤0.001 each). with regard to gender, there was no significant difference between males and females in terms of either attitude (t = 0.139; p = 0.890) or practice (t = 1.275; p = 0.203). however, male physicians had significantly higher mean knowledge scores compared to female physicians (47.7% ± 21.0% versus 38.5% ± 18.2%; t = 2.743; p = 0.007). previous tdt training was found to significantly affect mean scores for the knowledge and practice subscales. in comparison to untrained physicians, trained physicians demonstrated significantly higher mean scores for knowledge (54.4% table 3: mean attitude scores regarding tobacco depen dence treatment according to sociodemographic vari ables among primary care physicians in muscat, oman (n = 255) characteristic percentage mean score ± sd in % f or t value p value age in years 0.990 0.373 ≤30 56.8 ± 13.4 31–45 60.6 ± 22.2 >45 59.7 ± 13.7 gender 0.139 0.890 male 59.5 ± 21.7 female 59.0 ± 19.2 previously received tdt training 1.953 0.052 yes 62.9 ± 19.9 no 57.6 ± 19.3 current position 0.152 0.928 gp 59.0 ± 18.5 fm resident 57.9 ± 17.9 fm specialist 61.9 ± 24.7 fm senior specialist/ consultant 58.6 ± 22.9 sd = standard de viation ; gp = non-certified general practitioner ; fm = family medicine. table 2: mean knowledge scores regarding tobacco dep endence treatment according to sociodemographic vari ables among primary care physicians in muscat, oman (n = 255) characteristic percentage mean score ± sd in % f or t value p value age in years 6.684 0.002 ≤30 33.3 ± 14.3* 31–45 43.2 ± 20.9 >45 37.9 ± 19.7 gender 2.743 0.007 male 47.7 ± 21.0 female 38.5 ± 18.2 previously received tdt training 7.534 <0.001 yes 54.4 ± 21.1 no 34.1 ± 14.3 current position 22.892 <0.001 gp 34.7 ± 16.8† fm resident 39.6 ± 13.5‡ fm specialist 56.9 ± 20.5 fm senior specialist/ consultant 56.3 ± 16.7 sd = standard de viation ; gp = non-certified general practitioner ; fm = family medicine. *the difference in mean knowledge scores between participants aged ≤30 versus 31–45 years (p <0.001) was statistically significant. †the difference in mean knowledge scores between gps versus specialists (p <0.001) and gps versus senior specialists/consultants (p <0.001) was statistically sig nificant. ‡the difference in mean knowledge scores between residents ver sus specialists (p <0.001) and residents versus senior specialists/consultants (p <0.001) was statistically significant. knowledge, attitudes and practices of primary care physicians regarding tobacco dependence treatment in muscat governorate, oman a cross-sectional study 568 | squ medical journal, november 2021, volume 21, issue 4 ± 21.1% versus 34.1% ± 14.3%; t = 7.534; p <0.001) and practice (69.7% ± 26.5% versus 56.2% ± 23.7%; t = 3.956; p <0.001), but not for attitude (62.9% ± 19.9% versus 57.6% ± 19.3%; t = 1.953; p = 0.052). discussion the current study was performed in order to assess the kaps of pcps in muscat with regard to the provision of tdt services, determine associations with sociodemographic variables and explore possible barriers to tdt practice. overall, pcps demonstrated poor knowledge, satisfactory practices and positive attitudes concerning tdt services. certain variables were significantly associated with kap scores including age, gender, position and previous tdt training. the two major barriers to tdt practice identified by the respondents included a lack of training and time. these findings represent a baseline for further research exploring additional barriers to providing such services in oman as well as potential measures to circumvent these obstacles. the proportion of participants in the current study who had never received basic tdt training was alarmingly high (71.8%). al hosani et al. reported that a similar proportion (72.1%) of personnel working in primary care centres in the united arab emirates (uae) had not received specific training on smoking cessation.23 these findings can be explained by the dearth of properly structured postgraduate tdt training programmes for pcps in the gcc region. this is an area of training which is paramount to support regional tobacco cessation efforts. according to a previous meta-analysis, healthcare professionals who receive tdt training are more likely to perform smoking cessation tasks compared to untrained controls.6 indeed, the present study found that trained physicians scored significantly higher compared to those without training in terms of both tdt-related knowledge and practice. a similar finding was reported in armenia in which trained physicians were twice as likely to provide assistance to tobacco users compared to non-trained physicians.24 overall, 40% of the pcps demonstrated poor knowledge of tdt (mean score: 39.8% ± 18.8%). aljdani et al. documented a comparable level of knowledge among primary healthcare providers in saudi arabia (mean score: 35.25% ± 18.40%).20 this finding is unsurprising, given that most physicians in the present study reported relying on their undergraduate medical education or the internet as their primary sources of information regarding tdt. similar results have been reported in saudi arabia with regard to the popularity of online sources of tdt information among primary healthcare professionals.18,20 in addition, surrati et al. identified a significant association between source of tdt information and awareness of smoking cessation measures.18 in contrast, al-turkstani et al. reported that the majority of pcps (74.4%) in makkah, saudi arabia, were knowledgeable with regard to smoking cessation measures.25 this may be due to the larger proportion of current or ever-smokers in the latter study (26%); however, this is unlikely to have had an effect as non-smoker physicians were found to demonstrate significantly greater knowledge compared to smokers.25 knowledge of tdt services was significantly affected by several factors in the current study including age, gender and position. overall, pcps aged ≤30 years demonstrated significantly lower knowledge scores compared to those aged 31–45 years. similarly, al-turkstani et al. noted that pcps aged 36–45 and >55 years were significantly more likely to exhibit correct knowledge compared to those aged 25–35 years old.25 in the present study, male physicians exhibited significantly better knowledge table 4: mean practice scores regarding tobacco depend ence treatment according to sociodemographic variables among primary care physicians in muscat, oman (n = 255) characteristic percentage mean score ± sd in % f or t value p value age in years 1.669 0.191 ≤30 55.5 ± 25.9 31–45 62.2 ± 25.5 >45 60.0 ± 20.5 gender 1.275 0.203 male 65.0 ± 22.2 female 59.2 ± 25.6 previously received tdt training 3.956 <0.001 yes 69.7 ± 26.5 no 56.2 ± 23.7 current position 14.609 <0.001 gp 52.9 ± 24.3* fm resident 69.5 ± 23.6 fm specialist 74.8 ± 21.3 fm senior specialist/ consultant 75.8 ± 18.9 sd = standard de viation ; gp = non-certified general practitioner ; fm = family medicine. *the difference in mean practice scores between gps versus residents (p = 0.001), gps versus specialists (p <0.001) and gps versus senior specialists/consultants (p <0.001) was statistically significant. yaqoub alsaidi, buthaina almaskari, moon fai chan, sanaa al sumri and hajer alhamrashdi clinical and basic research | 569 compared to females. al-turkstani et al. reported the opposite to be true among pcps in makkah, where females were significantly more knowledgeable than males.25 finally, job position was significantly linked with tdt knowledge in the present study, with gps demonstrating significantly lower mean knowledge scores compared to physicians in other positions. while al-jdani et al. also found position to be significantly related to knowledge scores, dentists were found to be least knowledgable.20 position was not found to be significantly associated with knowledge among pcps in makkah, while al-jdani et al. reported that neither age nor gender significantly affected tdtrelated knowledge among healthcare practitioners in western saudi arabia.20,25 despite their low levels of knowledge, approx imately 60% of the pcps demonstrated positive attitudes and satisfactory practices with regard to tdt services (mean scores: 59.1% ± 19.6% and 60.0% ± 25.2%, respectively). al-jdani et al. and alateeq et al. also documented positive attitudes and satisfactory practices among pcps in saudi arabia.20,22 variables which were found to affect tdt practices in the current study included position and previous tdt training; however, none of the studied sociodemographic variables were found to affect attitudes. in contrast, previous research has found that attitudes towards smoking cessation among healthcare providers in western saudi arabia are significantly impacted by gender and position.20 the generally positive attitudes towards tdt services demonstrated by pcps in the present study may have something to do with the low prevalence of current smokers in the cohort (0.8%). indeed, alsaqry et al. reported that smoker and non-smoker pcps in northern saudi arabia displayed significantly different attitudes with regard to certain tobacco control measures, such as the prohibition of smoking in certain areas, increasing taxes on tobacco products and the routine provision of smoking cessation advice, although not with regard to the prohibition of tobacco advertisements.26 in contrast, al hosani et al. noted that the majority of primary care personnel in the uae (82.8%) had positive attitudes towards smoking cessation services, regardless of their smoking status.23 smoker and non-smoker pcps in makkah also reported similar tdt attitudes in most regards, except one; there was a significant discrepancy in agreement with the idea that physicians should speak to community groups about smoking (88.2% versus 97.9%; p = 0.001).25 it is possible that the participants in the present study did not reveal true details of their smoking habits for various reasons. a previous study conducted by allawati et al. concluded that the prevalence of tobacco use in oman was 16.4% among male physicians and dentists; this is much higher compared to the current study in which only 5.6% of male pcps admitted to a history of smoking.27 however, it is important to note that male physicians represented only 14.1% of the present cohort. cigarette smoking by women is generally frowned upon in gcc countries and is seen as socially undesirable.25,26,28 in accordance with this cultural norm, al-lawati et al. noted that less than 1% of female physicians in oman were tobacco users.27 the who framework convention on tobacco control recognises the discrepancy in smoking rates among men and women in certain regions and therefore advocates for gender-specific strategies in the implementation of tobacco control measures.7 a lack of training and time were the two major barriers to tdt practice reported by the participating physicians in the current study. healthcare providers in northern saudi arabia have identified a lack of skills and facilities (e.g. medical resources) to be frequent reasons for not implementing smoking cessation interventions.26 monshi et al. also underlined that a lack of time, training and resources on the part of clinicians were important barriers to smoking cessation efforts in gcc countries, alongside perceptions of responsibility and discrepancies in tdt-related knowledge.13 these findings emphasise the importance of providing additional postgraduate tdt training to all pcps. moreover, as yet no official guidelines or policies have been published with regards to a national tobacco control programme in oman. furthermore, establishing tdt services in primary care provides the necessary grounds to apply the pcp’s undergraduate and postgraduate knowledge in daily practice that can enhance their hands on experience and confidence in the field. until cessation services become a routine part of health service delivery throughout government facilities, it will be difficult for individual practitioners to provide this service. in 2017, it was projected that providing tdt services on its own can influence the prevalence of smoking in oman by 3.5% in 5 years and 8.7% by 40 years averting 8,870 deaths in 40 years.15 if combined with the implementation of the complete set of the who’s 6-points mpower initiative, the prevalence will reduce by 35.8% in 5 years and 54.1% in 40 years, saving up to 55,395 lives in 40 years.15 further research is recommended to assess the tdt-related kaps of pcps in other regions of oman. despite the limited existing tobacco cessation services in oman, their presence gives a valuable opportunity to study their effectiveness, strengths and limitations that can represent a local view of the overall experience providing essential context-specific knowledge, attitudes and practices of primary care physicians regarding tobacco dependence treatment in muscat governorate, oman a cross-sectional study 570 | squ medical journal, november 2021, volume 21, issue 4 evidence. the importance of this view is raised by the emerging concerns that traditional tdt interventions are not as effective for arab populations compared to western populations.12 exploring this unique experience will serve as a guide for implementing any further developments in this area in oman. moreover, it would be worthwhile to determine the effectiveness of tailored tdt interventions in improving kaps among physicians, members of the public and tobacco users. this study was hindered by certain limitations. as the data were collected using a self-administered questionnaire, the results may have been affected by response bias. moreover, no pilot study was performed to assess the face validity, reliability or comprehensibility of the modified questionnaire or to determine the effect of any relevant cultural issues. in addition, the scoring system used in the present study differed from that employed by the original authors of the questionnaire tool, limiting comparison of the results with previous research.20 finally, as the study was conducted in a single governorate of oman, the generalisability of the results may be limited. however, the current study adds new information to the existing literature regarding the kaps of pcps towards tdt services in oman and reveals commonly reported barriers to tdt practice. these findings may be of use to policymakers and healthcare administrators in the development of a targeted tdt training programme. conclusion despite displaying positive attitudes and satisfactory practices, pcps in muscat displayed poor knowledge with regards to tdt services. this urgently needs to be addressed in order to ensure the provision of effective tdt services to tobacco users in this region. furthermore, both lack of training and time were noted to be barriers to tdt practice. establishing cessation services as part of the package of care in primary health centres could address the time constraint barriers identified by the pcps. in addition, the latter barrier could be overcome by allotting adequate time during appointment slots for known tobacco users or implementing weekly clinics especially for tdt services. this study is intended as a baseline for further research in oman focusing on tdt services. these findings will hopefully aid decision-makers and primary healthcare authorities in the implementation of targeted tdt training programmes to enable pcps to effectively help patients with their tobacco cessation efforts. a c k n o w l e d g e m e n t s permission was obtained from the original authors to use their previously validated questionnaire in the current study. in addition, the authors would like to thank all of the participants, as well as the heads of the local health centres for their support during data collection. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n ya conceptualised the study. ya and ba performed the literature review and drafted the manuscript. mf designed the methodology and reviewed the results. ba, sas and ha collected the data. ya analysed the data while ha performed the data entry. mf and sas performed the final review of the manuscript. all authors approved the final version of the manuscript. references 1. thakur js, garg r, narain jp, menabde n. tobacco use: a major risk factor for non communicable diseases in south-east asia region. indian j public health 2011; 55:155–60. https:// doi.org/10.4103/0019-557x.89943. 2. wipfli h, samet jm. global economic and health benefits of tobacco control: part 1. clin pharmacol ther 2009; 86:263–71. https://doi.org/10.1038/clpt.2009.93. 3. oman ministry of health. regional workshop discusses implementation of tobacco taxes. from: www.moh.gov.om/ en/-/---935 accessed: sep 2020. 4. taylor gmj, dalili mn, semwal m, civljak m, sheikh a, car j. internet-based interventions for smoking cessation. cochrane database syst rev 2017; 9:cd007078. https://doi. org/10.1002/14651858.cd007078.pub5. 5. stead lf, buitrago d, preciado n, sanchez g, hartmannboyce j, lancaster t. physician advice for smoking cessation. cochrane database syst rev 2013; 2013:cd000165. https://doi. org/10.1002/14651858.cd000165.pub4. 6. carson kv, verbiest me, crone mr, brinn mp, esterman aj, assendelft wj, et al. training health professionals in smoking cessation. cochrane database syst rev 2012; 5:cd000214. https://doi.org/10.1002/14651858.cd000214.pub2. 7. world health organization. who framework convention on tobacco control. from: www.who.int/fctc/text_download/en/ accessed: sep 2020. 8. piné-abata h, mcneill a, raw m, bitton a, rigotti n, murray r. a survey of tobacco dependence treatment guidelines in 121 countries. addiction 2013; 108:1470–5. https://doi. org/10.1111/add.12158. 9. blecher eh, van walbeek cp. an international analysis of cigarette affordability. tob control 2004; 13:339–46. https:// doi.org/10.1136/tc.2003.006726. yaqoub alsaidi, buthaina almaskari, moon fai chan, sanaa al sumri and hajer alhamrashdi clinical and basic research | 571 10. heydari g, talischi f, masjedi mr, alguomani h, joossens l, ghafari m. comparison of tobacco control policies in the eastern mediterranean countries based on tobacco control scale scores. east mediterr health j 2012; 18:803–10. https:// doi.org/10.26719/2012.18.8.803. 11. awan kh, hussain qa, khan s, peeran sw, hamam mk, hadlaq ea, et al. accomplishments and challenges in tobacco control endeavors report from the gulf cooperation council countries. saudi dent j 2018; 30:13–18. https://doi. org/10.1016/j.sdentj.2017.08.003. 12. alzahrane a, west r, ubhi hk, brown j, abdulqader n, samarkandi o. evaluations of clinical tobacco cessation interventions in arab populations: a systematic review. addict behav 2019; 88:169–74. https://doi.org/10.1016/j.addbeh.2018.08.017. 13. monshi ss, halpern mt. factors associated with smoking cessation and smoking cessation interventions in the gulf cooperation council countries. saudi med j 2019; 40:119–25. https://doi.org/10.15537/smj.2019.2.23904. 14. heydari g, talischi f, mojgani n, masjedi mr, algouhmani h, lando ha, et al. status and costs of smoking cessation in countries of the eastern mediterranean region. east mediterr health j 2012; 18:1102–6. https://doi.org/10.26719/2012.18.11.1102. 15. al-lawati j, mabry rm, al-busaidi zq. tobacco control in oman: it’s time to get serious! oman med j 2017; 32:3–14. https://doi.org/10.5001/omj.2017.02. 16. world health organization. oman: global youth tobacco survey 2007. from: https://extranet.who.int/ncdsmicrodata/ index.php/catalog/316/related_materials accessed: sep 2020. 17. oman ministry of health. 15th symposium of the gcc on tobacco and trade. from: www.moh.gov.om/en_us/-/15th-symposiumof-the-gcc-on-tobacco-and-trade accessed: apr 2020. 18. surrati am, alhazmi bh, abass zj, alahmary ta, almohammadi ms. knowledge and practice of smoking cessation among physicians in madinah, 2016. int j med res prof 2017; 3:27–33. https://doi. org/10.21276/ijmrp.2017.3.1.005. 19. oman ministry of health. statistical reports. from: www.moh. gov.om/en/web/statistics/annual-reports accessed: sep 2020. 20. al-jdani s, mashabi s, alsaywid b, zahrani a. smoking cessation counseling: knowledge, attitude and practices of primary health care providers at national guard primary healthcare centers, western region, saudi arabia. j family community med 2018; 25:175–82. https://doi.org/10.4103/jfcm.jfcm_142_17. 21. abrahamyan a, harutyunyan a, petrosyan v. primary healthcare physicians’ knowledge, attitude and practice towards smoking cessation in armenia. eur j public health 2016; 26:51. https:// doi.org/10.1093/eurpub/ckw165.025. 22. alateeq m, alrashoud am, khair m, salam m. smoking cessation advice: the self-reported attitudes and practice of primary health care physicians in a military community, central saudi arabia. patient prefer adherence 2016; 10:651–8. https:// doi.org/10.2147/ppa.s103010. 23. al hosani s, al ali m, al-marashda k, al-shamsi n, alansari t, al-behandy a, et al. smoking prevalence, attitudes and behaviors of primary healthcare providers and its impact on their smoking cessation counseling practices. ibnosina j med biomed sci 2015; 7:47–55. https://doi.org/10.4103/1947489x.210270. 24. harutyunyan a, abrahamyan a, hayrumyan v, petrosyan v. perceived barriers of tobacco dependence treatment: a mixedmethods study among primary healthcare physicians in armenia. prim health care res dev 2019; 20:e17. https://doi.org/10.10 17/s1463423618000828. 25. al-turkstani ahm, alkail ba, hegazy aa, asiri si. knowledge, attitude, and practice among primary health-care physicians toward smoking cessation in makkah, saudi arabia. int j med sci public health 2016; 5:714–24. https://doi.org/10.5455/ijmsph.20 16.13112015224. 26. alsaqry as, dar uf, banday ah, alsharari tm, alrushaydan ak. comparison of smoking cessation practices among smoker and non-smoker health care providers: a kap study in northern saudi arabia. egypt j hosp med 2018; 72:5673–8. https://doi.org/10.21608/ejhm.2018.11547. 27. al-lawati ja, nooyi sc, al-lawati am. knowledge, attitudes and prevalence of tobacco use among physicians and dentists in oman. ann saudi med 2009; 29:128–33. https://doi.org/10.41 03/0256-4947.51803. 28. borgan sm, jassim g, marhoon za, almuqamam ma, ebrahim ma, soliman pa. prevalence of tobacco smoking among health-care physicians in bahrain. bmc public health 2014; 14:931. https://doi.org/10.1186/1471-2458-14-931. department of rheumatology, mongi slim hospital, la marsa, tunisia; university of tunis el manar, tunis, tunisia *corresponding author’s e-mail: yasmine.mkhlouf@gmail.com validity of remission criteria in rheumatoid arthritis compared to ultrasound-defined remission kawther ben abdelghani, saoussen miladi, *yasmine makhlouf, alia fazaa, mariem sallemi, leila souebni, kmar ouenniche, selma kassab, selma chekili, kamel ben salem, leith zakraoui, ahmed laatar sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 554–560, epub. 7 nov 22 submitted 25 may 21 revision req. 25 jul 21; revision recd. 11 aug 21 accepted 1 sep 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.128 clinical & basic research abstract: objectives: remission is the ultimate purpose of treatment in rheumatoid arthritis (ra). however, even when the most stringent composite scores are used, structural damages can occur; hence, ultrasonography (us) appears to be the best way to assess real remission. this study aimed to investigate the validity of different ra remission scores using us as a reference. methods: an analytic diagnostic study, of 30 ra patients in remission (according to the disease activity score in 28 joints [das28]) and a control group with active ra, was conducted between january and october 2018 at mongi slim hospital in tunis, tunisia. among them, patients in remission were identified according to their simple disease activity index (sdai), clinical disease activity index (cdai) and the boolean american college of rheumatology/european league against rheumatism activity index (acr/eular) remission scores. the validity of each activity score for remission was calculated by considering the absence of power doppler (pd) signals as a gold standard. results: all patients were in remission according to the das28, with an average score of 2.03 (1.1–2.6). us examination showed pd signals in 57% of patients. a total of 26 patients were in remission according to the cdai; a doppler signal was detected in 58% of those cases. sdai remission was accomplished in 19 patients, with pd activity in 53% of cases. of the 14 patients in remission according to the boolean acr/eular criteria, synovial hyper-vascularisation was found in 64%. considering true remission as the absence of pd signals, the most sensitive and specific score was the das28 (93% and 68%, respectively). conclusion: considering remission in ra as the absence of vascularised synovitis, the das28 is the most sensitive and most specific score. keywords: rheumatoid arthritis; ultrasonography; doppler; reproducibility of results; tunisia. advances in knowledge various composite outcome measures exist, but structural damage can occur even when the most stringent ones are used. using the most reliable composite score is important to achieve low disease activity and remission as a part of a treat-to-target strategy. finding the most reliable score using ultrasonography as a reference will facilitate the management of patients with rheumatoid arthritis and would help determine further scores that are more stringent. application to patient care considering true remission as the absence of a power doppler (pd) signal, it is important to assess the validity of each disease activity score in obtaining remission. the disease activity score in 28 joints score seems to be the most valid score for assessing remission when the absence of a pd signal is taken as a reference. achieving remission is the ultimate goal of treatment in rheumatoid arthritis (ra). in the past few decades, new therapeutic modalities and strategies have increased the potential to achieve low disease activity and remission by halting the inflammatory process. indeed, a specific strategy of treating early ra, which is adapted to each patient, includes close follow-ups and aims for less disease activity and lower cost, called ‘treat-totarget’ and ‘treat-to-budget’, is now being adopted.1 however, the concept of remission is complex, as there is no consensus on its definition.2 based on clinical and biological criteria, several composite scores are available in daily practice; however, structural damage can occur even when the most stringent ones are used. this is because some patients in clinical remission do not experience an absence of disease activity but exhibit a low level of inflammation that is not easily detectable by clinical examination or reflected in laboratory results. the disease activity score in 28 joints (das28) is the most calculated score used in daily practice. this composite score includes objective, subjective and biological data. other lesser used scores include the simple disease activity index (sdai), the clinical disease activity index (cdai) and the boolean american college of rheumatology/european league against rheumatism activity index (acr/eular) remission criteria. all these composite indices differ when considering remission according to their specific cut-offs. indeed, in the same group of ra patients, the number of those in remission according to the das28 was found to be higher compared to other remission https://creativecommons.org/licenses/by-nd/4.0/ kawther ben abdelghani, saoussen miladi, yasmine makhlouf, alia fazaa, mariem sallemi, leila souebni, kmar ouenniche, selma kassab, selma chekili, kamel ben salem, leith zakraoui and ahmed laatar clinical and basic research | 555 scores such as the sdai.3,4 thus, the das28 may not be considered the most suitable score to diagnose remission. owing to recent technical advances, musculo skeletal ultrasound of the joints now has an important role in the quantification of synovitis. moreover, it can provide important information for the diagnosis, monitoring and management of ra.5 the adoption of this tool as an extension to clinical and biological data may be instrumental in the assessment of remission.6 correspondingly, the present study aimed to invest igate the validity of different ra disease activity scores to assess remission by using ultrasonography (us) as the reference. methods this is an analytic, diagnostic monocentric study carried out in the rheumatology department of mongi slim hospital in tunis, tunisia, between january and october 2018. a total of 30 patients with established ra, meeting the criteria of acr 1987 and in remission according to the eular definition (das28 score ≤2.6), were included.7 the inclusion criteria were ra evolving for more than six months, age at the time of diagnosis greater than 16 years and a state of remission (das28 ≤2.6) diagnosed for at least three months. patients who had a therapeutic adjustment, flare disease or joint steroid injection in the three months prior to the study date were excluded. a control group (active-ra group) was established to compare the validity of the various criteria for remission. it encompassed 37 patients with active established ra (das28 >3.2). at inclusion, clinical data including the age of onset of the disease, duration of morning stiffness, number of night awakenings, visual analogic scale (vas) of pain and patient and physician global assessment (pga and phga) were recorded. a tender and swollen joints count (tjc and sjc) over 66 joints was assessed by the physician who performed the investigation. laboratory markers, including c-reactive protein (crp) and erythrocyte sedimentation rate (esr) levels, were obtained on the same day. immunological assessment of the rheumatoid factor (rf), anticitrullinated peptide antibodies (anti-ccps) and antinuclear antibodies (anas) was collected from the recorded data. the functional impact of the disease was assessed using the health assessment questionnaire. das28 is a composite ra activity score of the tjc, sjc, pga and levels of esr and crp.7 the eular cut-off for disease activity was used and the study group was found to have a das28 score of ≤2.6 and the control group, a das28 score of >3.2. other established scores considered in this study were the sdai, cdai and boolean acr/eular remission criteria.8–10 the cdai includes only clinical parameters: tjc, sjc, pga and phga. the sdai includes all the aforementioned parameters as well as the crp levels. the remission cut-offs considered were cdai ≤2.8, sdai ≤3.3 or the boolean acr/eular remission criteria of, for example, tjc ≤1, sjc ≤1, crp ≤10 mg/l and pga ≤10.11 us of the hands and the wrists was performed for each patient with a delay not exceeding 30 minutes after the clinical examination and the biological sampling. the us examination was performed by a rheumatologist with expertise in musculoskeletal us and at least 10 years of field experience. the operator was blinded to the study group and all other study findings. the equipment used was mylab™ 60 (esaote, genoa, italy) with a 6–18 mhz linear array probe. when using power doppler (pd), the pulse repetition frequency was adjusted at 500–750 hz and the receiver gain was adjusted to eliminate the artefact. overall, 22 joints were scanned bilaterally per patient, including the wrists, metacarpophalangeal joints (mcp) and proximal interphalangeal joints (pip). the wrists and mcp were studied on the dorsal side and pip on their palmar side. the semi-quantitative szkudlarek scale was used in grey-scale (gs) imaging evaluation for synovial hypertrophy (sh) and in pd.11 the sum of grades obtained for each joint and each us mode was established such that it ranged from 0 to 66 for gs and pd. ultrasound detection of erosions was not included in this study, as erosions primarily reflect cumulative lesions related to previous history rather than an ongoing inflammation. to study the validity of the various criteria, the absence of a doppler signal on the sonogram was considered as the gold standard to define us remission. sensitivity, specificity and positive and negative predictive values were calculated and compared between the different remission scores using us remission as a reference. considering us remission, a new threshold for the quantitative scores (das28, cdai, and sdai) was assessed using a receiver operating characteristic (roc) curves. following this, the validity of each score was calculated using the new values. the concordance between the das28 and the other ra activity assessment scores (cdai, sdai and acr/eular remission) was assessed based on the kappa coefficient using us assessment as a reference. validity of remission criteria in rheumatoid arthritis compared to ultrasound-defined remission 556 | squ medical journal, november 2022, volume 22, issue 4 the data were transcribed using excel and analysed using the statistical package for the social sciences (spss), version 12.0 (ibm corp., chicago, illinois, usa). the simple frequencies and relative frequencies (percentages) of the qualitative variables were calculated. similarly, the averages and standard deviations were calculated and the extent of the quantitative variables (extreme values: minimum and maximum) was determined. comparisons of two independent series averages were made using the mann–whitney non-parametric test. the independent series percentage comparisons were made using pearson’s chi-squared test. comparisons of two percentages on paired series were made using mcnemar’s test. the links between the two quantitative variables were studied using spearman’s rank correlation coefficient and the differences were found to be significant: p < 0.05. the agreement between two qualitative variables was measured by cohen’s kappa coefficient. the thresholds for interpreting the kappa coefficient, as determined by landis and koch, were as follows: a κ of 0–0.20 was considered poor, 0.20–0.40 was fair, 0.40–0.60 was moderate, 0.60–0.80 was good and 0.80–1 was excellent. written consent was obtained from the participants. this study was conducted in accordance with the ethical principles of the declaration of helsinki and was approved by the human research ethics committee at mongi slim hospital. results overall, 67 patients with ra were included in the study. the participants of the study group (n = 30) were in remission according to the das28 for a mean period of 16 months (range: 3–72 months). half of the patients were under corticosteroids, with an average dosage of 3.75 mg/day (range: 5–10 mg/ day). conventional disease-modifying anti-rheumatic drugs alone were prescribed for 80% of patients and biotherapies for 20% of patients. the study group and the control group were comparable for demographic data. in the study group, rf and anti-ccp positivity were found in 60% and 66% of patients, respectively. anas were available in 23 patients and positive in 10% of them, with a mean titre of 1/160 (range: 1/80–1/320). in the active ra group (control group; n = 37), rf and anti-ccp positivity were observed in 79.8% and 73.6% of patients, respectively. anas were positive in 6% of the cases [table 1]. table 1: comparison of the demographic and clinical characteristics of 67 patients with rheumatoid arthritis variable mean (range) p value patients (n = 30) controls (n = 37) age in years ± sd 48 ± 8.98 (33–67) 52.4 ± 10.3 (30–70) 0.38 gender ratio 0.20 0.15 0.5 disease duration in years ± sd 8 ± 4.9 (1–23) 10 (0.5–38) 0.12 night awakenings 1 (0–1) 1.23 (0–4) 0.001 morning stiffness in minutes 2 (0–30) 37.7 (0–240) 0.001 tender joint count* 0 (0–1) 7 (0–27) 0.001 swollen joint count* 0.3 (0–9) 6 (0–17) 0.001 vas pain† 6 (0–10) 57 (10–100) 0.012 pga† 3 (0–5) 5 (20–100) 0.025 esr in mm/h ± sd 16.7 ± 10.4 (2–40) 46 ± 25 (15–110) 0.001 crp in mg/l ± sd 3.1 ± 3.7 (0–19) 16.8 ± 15 (5–59) 0.005 das28 ± sd 2.03 (1.1–2.6) 5.2 (3.11–8.6) 0.001 haq 0.12 (0–1) 1.7 (0–2.62) 0.001 sd = standard deviation; vas = visual analogue scale; pga = patient global assessment; esr = erythrocyte sedimentation rate; crp = c-reac tive protein; das28 = disease activity score 28 joints; haq = health assessment questionnaire. *can range from 0–28. †can range from 0–100. figure 1: ultrasound scans of a rheumatoid arthritis patient in clinical remission in power doppler mode showing (a) a persistent power doppler image and (b) an image after the power doppler signal was abolished. kawther ben abdelghani, saoussen miladi, yasmine makhlouf, alia fazaa, mariem sallemi, leila souebni, kmar ouenniche, selma kassab, selma chekili, kamel ben salem, leith zakraoui and ahmed laatar clinical and basic research | 557 with regard to the study group, among the 660 joints studied, sh was detected in 14% of joints and pd signals in 7%. the most affected joints were the wrists. when considering the patient scale, synovitis was present in 80% of patients and pd in 57% of them [figure 1]. in the active ra group, among the 814 joints studied using the ultrasonographic scans, sh was found in 44% and pd in 36% of joints; both tended to occur in the wrists. considering the patient scale, all the patients had sh, with at least one vascularised joint. when comparing the two groups, a significant difference was noted in both the gs and pd modes. grade 0 was more frequent in the study group, while grade 3 was more frequent in the active ra (control) group across both modes [table 2]. the validity of different remission criteria was assessed by considering the absence of any doppler signals on ultrasonographic scans as the gold standard for defining ‘real remission’. the absence of doppler signals was found in 13 patients in remission and in one patient in the active ra group. the das28 was the most sensitive (93%) and the most specific (68%). when considering the state of ‘real remission’, the thresholds that corresponded to the best sensitivity-specificity couple were 3.2 for the das28, 8 for the cdai and 6.5 for the sdai. the validity of the different disease activity scores and each score using new limits according to roc curves are presented in tables 3 and 4, respectively. in gs, synovitis was detected in 80%, 81%, 79% and 78% of patients, using the das28, cdai, sdai and acr/eular remission criteria, respectively. in the pd mode, vascularised synovitis was present in 57%, 58%, 53% and 64% of patients considering the das28, cdai, sdai and acr/eular remission criteria, respectively. there was no significant correlation between any of the remission criteria used and the us findings either in gs or in pd mode [table 5]. among the patients in remission, 26 (87%) were in remission according to the cdai, 19 (63%) were in remission according to the sdai and 14 (47%) were in remission according to the acr/eular criteria. the agreement between das28 remission and cdai was excellent (κ = 0.88), while that between das28 and sdai was good (κ = 0.66). furthermore, the agreement between das28 and acr/eular remission criteria was moderate (κ = 0.47). discussion to the best of the authors’ knowledge, this is the first study that investigates the validity of four different clinical remission scores in ra patients using ultrasonographic remission as a gold standard. in this study, the das28 was the most sensitive score (93%), followed by the cdai (92%), sdai (90%) and acr/eular remission criteria (83%). the das28 was also the most specific (68%), followed by the cdai (65%), sdai (63%) and, finally, acr/eular criteria (59%). only one previous study assessed the validity of the sdai as opposed to that of us in ra patients. table 2: comparison of the ultrasound grades between the study group and the control group grade characteristic n (%) p value study group (n = 660) control group (n = 814) gs grade 0 571 (86) 458 (56) 0.001 grade 1 52 (8) 146 (18) 0.001 grade 2 31 (5) 154 (19) 0.001 grade 3 6 (1) 56 (7) 0.001 pd grade 0 616 (93) 518 (64) 0.001 grade 1 17 (3) 9 (11) 0.001 grade 2 17 (3) 114 (14) 0.001 grade 3 10 (0.1) 93 (11) 0.001 gs = grey scale; pd = power doppler. table 3: reliability of the different scores of remission in the study group remission score % sensitivity specificity ppv npv das28 93 68 43 97 cdai 92 65 37 97 sdai 90 63 33 97 acr/eular 83 59 17 97 ppv = positive predictive value; npv = negative predictive value; das28 = disease activity score 28 joints; cdai = clinical disease activity index; sdai = simplified disease activity index; acr/eular = american college of rheumatology/european league against rheumatism. table 4: validity of the different scores of remission after receiver operating characteristic curve thresholds were applied in the study group remission score threshold % p value sensitivity specificity das28 threshold of 3.2 100 65.4 0.0001 cdai threshold of 8 100 79.1 0.0001 sdai threshold of 6.5 85.7 79.2 0.0001 das28 = disease activity score 28 joints; cdai = clinical disease activity index; sdai = simplified disease activity index. validity of remission criteria in rheumatoid arthritis compared to ultrasound-defined remission 558 | squ medical journal, november 2022, volume 22, issue 4 in that study, balsa et al. showed that when the cut-off was set to 5, the sensitivity of sdai was 65.5%, and the specificity was 55%.12 the specificity of this score was 74.4% when the cut-off was set to 3.3.12 the authors concluded that an sdai ≤3.3 seemed to be a more specific criterion of true remission that is aimed for by different therapeutic strategies than the das28. indeed, when the das28 score was used, a patient could be diagnosed in remission even when they had up to five swollen joints. however, the definition is more stringent with the sdai, which allows for the presence of either two painful or swollen joints or one painful joint and one swollen joint.13 however, based on the present study’s results, it was concluded that the das28 was more specific than the sdai and therefore even better suited to assess true remission. the cdai, which includes only clinical parameters, was found to be more specific than the sdai for assessing remission. the authors did not find any previous study with similar findings. among the multitude of definitions and scores proposed to assess remission, the present study included four, which can be easily used in daily practice. a das28 of ≤2.6 was considered the inclusion criteria, as it is the most used score in daily practice. the concordance between the different ra remission scores compared with the das28 was excellent (0.88) for the cdai, good (0.66) for the sdai and moderate (0.47) for the acr/eular remission criteria. in a study by hmamouchi et al., the agreement of the different scores calculated for patients in remission in the french cohort espoir was moderate between the das28 and the sdai remission (0.54) and poor between the das28 and the acr/eular remission criteria (0.44).14 in another study by chandrashekara and priyanka including 100 ra patients in remission, no agreement was found between the das28 and acr/eular (r = −0.16).15 however, overall, the present study noted good agreement between the different scores; the differences with other studies could be related to patient selection. there is no consensus on the number of joints and sites to be assessed by us to evaluate ra activity. many scores have been proposed for evaluating remission by us. taking into account the conclusions of various authors, the present study evaluated 22 joints: the wrists, the mcp and the pip of both hands. in the current study, 80% of patients had synovitis in gs and 57% had vascularised ones. although heterogeneity was found in published studies, it could be attributed to a different methodology and remission criteria. however, all the studies agreed on the persistence of us activity among patients in remission despite the score used. in a systematic review by ben abdelghani et al. comprising 12 studies of ra in remission, synovitis was detected in 50.7–95% in gs and 14.7–57.4% in pd.16 the detection of synovitis was particularly important, as this infra-clinical activity was responsible for a lownoise evolution during remission.17 importantly, the us scoring system utilized by the current study was the szkudlarek scale instead of the eular as this study was conducted before the validation of the eular score. furthermore, as sh can be seen in many other diseases and even in healthy subjects, the lack of any doppler signal was considered as the real remission state in the present study. no correlation between the das28 and us score was found in the present study either in the gs or pd mode. only one previous study assessed the link between the das28 and us scores; balsa et al. observed a positive correlation between das28 and pd (r = 0.17; p = 0.043).12 the differences between the study by balsa et al. and the present study are probably due to the methodologies used. first, the number of patients in remission included in the two studies was different (74 versus 30). second, inclusion criteria and cut-off values used for assessing remission were different. finally, these differences could mainly be due to the number of joints evaluated in the us. the strength of the present study is that it assessed remission scores that are easily used in current practice. moreover, a control group was included to calculate the validity of the various ra activity scores. however, the current study also suffered from some limitations. the duration of remission, set to three months at inclusion, may be considered insufficient as the persistence of us synovitis was demonstrated in these patients. in the literature, the minimum duration of remission varied in the range of 3–18 months.18 when the duration of remission was prolonged to 12 months, pd was observed in 47.1% of patients.19 another limitation was that the performance of the us examination depended on the technical characteristics of the device and the operator. in the current study, a single operator performed all the us scanning. it would be interesting to perform the us assessments on two separate occasions and by a second sonologist for better validity of the present results. however, the operator in this study was an expert in us and good intraand inter-observer reproducibility of the pd had been confirmed by several studies, making its use by a single operator reliable. another limitation concerns the use of corticosteroids in the remission group; however, the majority of them were treated with low dosages (<7.5 mg/day) and were in remission for 16 months. kawther ben abdelghani, saoussen miladi, yasmine makhlouf, alia fazaa, mariem sallemi, leila souebni, kmar ouenniche, selma kassab, selma chekili, kamel ben salem, leith zakraoui and ahmed laatar clinical and basic research | 559 finally, the absence of the pd in us was considered a state of ‘real remission’ in the present study. this choice was based on the results in the literature, which provided evidence that subclinical disease (a persistent pd signal in clinical remission) is predictive of acute flares in ra and even of future structural damage. it is a very stringent criterion; however, this choice could be discussed as a limitation, as, on the one hand, there is no clear consensus on the definition of ultrasound remission and on the other, the implementation of us in everyday practice as well as in follow-ups has been reconsidered in the recent past. indeed, some authors do not currently support the routine use of us assessment as part of an enhanced treat-to-target strategy recommended by eular.20–22 according to the results of the aiming for remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a clinical tight control regimen (arctic) trial, the tight control strategy of us did not show additional effect compared to the conventional tight control strategy.22 the results of the targeting synovitis in early rheumatoid arthritis (taser) study are in line with these findings.23 indeed, aiming for a total pd joint count of ≤1 as part of the ultrasonographic treat-to-target strategy led to more intensive treatment with no better clinical or imaging outcomes when compared to the das28-driven strategy (das28 <3.2).24 furthermore, raising the level of requirement in treating ra using us as a reference did not augur well for the treat-to-budget concept. more studies are therefore needed to assess the role of us in evaluating disease activity and tailoring treatment in patients with ra.22 conclusion the das28 and, subsequently, the cdai seem to be the most specific scores for assessing remission in ra. this is because, compared to other composite scores, they appear to provide the closest possible indicator of the absence of inflammatory activity when considering true remission as the absence of pd signals in us. the findings of the present study could be the basis for further research, which should be conducted with a larger sample to draw effective conclusions. a u t h o r s’ c o n t r i b u t i o n sm, ym, ko, sk, sc and lz conceptualised and designed the study. sm and ym collected the data. ka, af, ms, ls, ko, sk, sc, ks, lz and al analysed and interpreted the data. ks performed the statistical analysis. ym performed the literature review and drafted the manuscript. sm edited the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this work received no funding. references 1. sacristán ja, díaz s, de la torre i, inciarte-mundo j, balsa a. treat-to-target and treat-to-budget in rheumatoid arthritis: measuring the value of individual therapeutic interventions. rheumatol ther 2019; 6:473–7. https://doi.org/10.1007/s4074 4-019-00178-3. 2. paulshus sundlisæter n, olsen ic, aga ab, hammer hb, uhlig t, van der heijde d, et al. predictors of sustained remission in patients with early rheumatoid arthritis treated according to an aggressive treat-to-target protocol. rheumatology (oxford) 2018; 57:2022–31. https://doi.org/10.1093/rheumatology/key202. 3. khanna d, oh m, furst de, ranganath v, gold rh, sharp jt, et al. evaluation of the preliminary definitions of minimal disease activity and remission in an early seropositive rheumatoid arthritis cohort. arthritis rheum 2007; 57:440–7. https://doi. org/10.1002/art.22619. 4. smolen js, aletaha d. activity assessments in rheumatoid arthritis. curr opin rheumatol 2008; 20:306–13. https://doi. org/10.1097/bor.0b013e3282fbd382. 5. wang x, qian g, duan h. diagnostic value of musculoskeletal ultrasound in rheumatoid finger arthritis. j coll physicians surg pak 2020; 30:617–21. https://doi.org/10.29271/jcpsp.2020.06.617. 6. boylan m. should ultrasound be used routinely in the diagnosis of rheumatoid arthritis? ir j med sci 2020; 189:735–48. https:// doi.org/10.1007/s11845-019-02096-3. 7. van der heijde dm, van’t hof m, van riel pl, van de putte lb. development of a disease activity score based on judgment in clinical practice by rheumatologists. j rheumatol 1993; 20:579–81. 8. aletaha d, smolen js. the simplified disease activity index (sdai) and clinical disease activity index (cdai) to monitor patients in standard clinical care. best pract res clin rheumatol 2007; 21:663–75. https://doi.org/10.1016/j.berh.2007.02.004. 9. smolen js, breedveld fc, schiff mh, kalden jr, emery p, eberl g, et al. a simplified disease activity index for rheumatoid arthritis for use in clinical practice. rheumatology (oxford) 2003; 42:244–57. https://doi.org/10.1093/rheumatology/keg072. 10. felson dt, smolen js, wells g, zhang b, van tuyl lh, funovits j, et al. american college of rheumatology/european league against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. ann rheum dis 2011; 70:404–13. https://doi.org/10.1136/ard.2011.149765. 11. felson dt, smolen js, wells g, zhang b, van tuyl lh, funovits j, et al. american college of rheumatology/european league against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. ann rheum dis 2011; 70:404–13. https://doi.org/10.1136/ard.2011.149765. 12. balsa a, de miguel e, castillo c, peiteado d, martin-mola e. superiority of sdai over das-28 in assessment of remission in rheumatoid arthritis patients using power doppler ultra sonography as a gold standard. rheumatology (oxford) 2010; 49:683–90. https://doi.org/10.1093/rheumatology/kep442. 13. smolen js, aletaha d. activity assessments in rheumatoid arthritis. curr opin rheumatol 2008; 20:306–13. https://doi. org/10.1097/bor.0b013e3282fbd382. 14. hmamouchi i, combe b, fautrel b, rincheval n, lukas c. prevalence and concordance of early and sustained remission assessed by various validated indices in the early arthritis “espoir” cohort. j bone spine 2014; 81:409–15. https://doi. org/10.1016/j.jbspin.2014.02.007. https://doi.org/10.1007/s40744-019-00178-3 https://doi.org/10.1007/s40744-019-00178-3 https://doi.org/10.1093/rheumatology/key202. https://doi.org/10.1002/art.22619 https://doi.org/10.1002/art.22619 https://doi.org/10.1097/bor.0b013e3282fbd382 https://doi.org/10.1097/bor.0b013e3282fbd382 https://doi.org/10.29271/jcpsp.2020.06.617 https://doi.org/10.1007/s11845-019-02096-3 https://doi.org/10.1007/s11845-019-02096-3 https://doi.org/10.1016/j.berh.2007.02.004 https://doi.org/10.1093/rheumatology/keg072 https://doi.org/10.1136/ard.2011.149765 https://doi.org/10.1136/ard.2011.149765. https://doi.org/10.1093/rheumatology/kep442. https://doi.org/10.1097/bor.0b013e3282fbd382 https://doi.org/10.1097/bor.0b013e3282fbd382 https://doi.org/10.1016/j.jbspin.2014.02.007. https://doi.org/10.1016/j.jbspin.2014.02.007. validity of remission criteria in rheumatoid arthritis compared to ultrasound-defined remission 560 | squ medical journal, november 2022, volume 22, issue 4 15. chandrashekara s, priyanka b. remission in rheumatoid arthritis by different criteria does not converge over the inflammatory markers. int j rheum dis 2013; 16:291–6. https://doi.org/10.111 1/1756-185x.12091. 16. ben abdelghani k, miladi s, souabni l, kassab s, chekili s, laatar a, et al. role of ultrasound in assessing remission in rheumatoid arthritis. diagn interv imaging 2015; 96:3–10. https://doi.org/10.1016/j.diii.2014.07.006. 17. vergara f, ruta s, rosa j, marín j, garcía-mónaco r, soriano er. the value of power doppler ultrasound in patients with rheumatoid arthritis in clinical remission: reclassifying disease activity? reumatol clin (engl ed) 2018; 14:202–6. https://doi. org/10.1016/j.reuma.2017.01.007. 18. aletaha d, funovits j, breedveld fc, sharp j, segurado o, smolen js. rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment. arthritis rheum 2009; 60:1242–9. https://doi.org/10.1002/art.24433. 19. peluso g, michelutti a, bosello s, gremese e, tolusso b, ferraccioli g. clinical and ultrasonographic remission deter mines different chances of relapse in early and long standing rheumatoid arthritis. ann rheum dis 2011; 70:172–5. https:// doi.org/10.1136/ard.2010.129924. 20. nessrine a, siham d, meryem b, samira ef, taoufik h. should the ultrasound of hands be a component of rheumatoid arthritis remission criteria? curr rheumatol rev 2019; 15:312–5. https://doi.org/10.2174/1573397115666181231115233. 21. simpson e, hock e, stevenson m, wong r, dracup n, wailoo a, et al. what is the added value of ultrasound joint examination for monitoring synovitis in rheumatoid arthritis and can it be used to guide treatment decisions? a systematic review and cost-effectiveness analysis. health technol assess 2018; 22:1–258. https://doi.org/10.3310/hta22200. 22. smolen js, landewé rbm, bijlsma jwj, burmester gr, dougados m, kerschbaumer a, et al. eular recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. ann rheum dis 2020; 79:685–99. https://doi.org/10.1136/ annrheumdis-2019-216655. 23. dale j, stirling a, zhang r, purves d, foley j, sambrook m, et al. targeting ultrasound remission in early rheumatoid arthritis: the results of the taser study, a randomised clinical trial. ann rheum dis 2016; 75:1043–50. https://doi.org/10.1136/ annrheumdis-2015-208941. 24. haavardsholm ea, aga ab, olsen ic, lillegraven s, hammer hb, uhlig t, et al. ultrasound in management of rheumatoid arthritis: arctic randomised controlled strategy trial. bmj 2016; 354:i4205. https://doi.org/10.1136/bmj.i4205. https://doi.org/10.1111/1756-185x.12091 https://doi.org/10.1111/1756-185x.12091 https://doi.org/10.1016/j.diii.2014.07.006 https://doi.org/10.1016/j.reuma.2017.01.007 https://doi.org/10.1016/j.reuma.2017.01.007 https://doi.org/10.1002/art.24433 https://doi.org/10.1136/ard.2010.129924 https://doi.org/10.1136/ard.2010.129924 https://doi.org/10.2174/1573397115666181231115233. https://doi.org/10.3310/hta22200 https://doi.org/10.1136/annrheumdis-2019-216655 https://doi.org/10.1136/annrheumdis-2019-216655 https://doi.org/10.1136/annrheumdis-2015-208941 https://doi.org/10.1136/annrheumdis-2015-208941 https://doi.org/10.1136/bmj.i4205 1oman college of health sciences, north sharqyia, oman; 2directorate of nursing, directorate general of health services, ministry of health, nizwa, oman; 3department of nursing affairs, ministry of health, izki, oman *corresponding author’s e-mail: mohammed.almaskari20@gmail.com جودة احلياة العملية بني املمرضني دراسة حالة من حمافظة الداخلية، عمان حممد عامر امل�سكري، جونا�س ا�سبال دوبو، نا�رص خلفان ال�سليمي abstract: objectives: quality of work life (qwl) is an important indicator of job-related satisfaction among nurses; however, there is little information regarding the qwl of nurses in oman. therefore, this study aimed to explore factors affecting qwl among nurses working in governmental health institutions in ad dakhiliyah governorate, oman. methods: this descriptive cross-sectional study was conducted between september and november 2018 at 29 governmental health institutions in ad dakhiliyah governorate. a total of 374 nurses employed at these institutions were recruited via stratified random sampling. a demographic questionnaire incorporating brooks’ quality of nursing work scale was used to collect data. results: a total of 345 nurses participated in the study (response rate: 92.2%). the mean age was 33.3 ± 5.1 years and the majority were female (90.7%), married (88.7%), of omani nationality (70.1%) and had a diploma degree (70.7%). overall, the nurses demonstrated moderate levels of qwl (mean total score: 179.99 ± 24.17). both job designation and nationality were found to be significant predictors of qwl (p = 0.041 and <0.001, respectively). conclusion: the findings of this study represent a baseline for further research on this important topic. as with all healthcare professionals, the qwl of nurses indirectly affects quality of patient care and associated health outcomes. as such, identifying areas of poor qwl among nurses can help in the development of initiatives to improve their professional satisfaction, thereby enhancing job performance and employee retention. keywords: nursing; quality of life; work satisfaction; occupational burnout; workload; motivation; health workforce; oman. القليل هناك ذلك، ومع املمر�سات؛ و املمرضني بني الوظيفي للر�سا مهًما موؤ�رًصا )qwl( العملية احلياة جودة تعد الهدف: امللخ�ص: احلياة جودة على توؤثر التي العوامل ا�ستك�ساف اإىل الدرا�سة هذه هدفت لذلك، عمان. يف التمري�سي للكادر qwl حول املعلومات من العملية )qwl( بني الكادر التمري�سي العامل يف املوؤ�س�سات ال�سحية احلكومية يف حمافظة الداخلية، عمان. الطريقة: اأجريت هذه الدرا�سة املقطعية الو�سفية بني �سهري �سبتمرب ونوفمرب 2018 يف 29 موؤ�س�سة �سحية حكومية يف حمافظة الداخلية. مت تعيني ما جمموعه 374 ا يعملون يف هذه املوؤ�س�سات عن طريق اأخذ العينات الع�سوائية الطبقية. مت ا�ستخدام ا�ستبيان يحتوي اسئلة دميوغرافية على مقيا�س ممر�سً بروك�س جلودة عمل التمري�س جلمع البيانات. النتائج: �سارك يف الدرا�سة 345 ممر�سة )معدل اال�ستجابة: %92.2(. بلغ متو�سط العمر 5.1 ± 33.3 �سنة غالبيتهم من االإناث )%90.7(، متزوجني )%88.7(، عمانيني اجلن�سية )%70.1( وحا�سلني على دبلوم )%70.7(. ب�سكل عام، اأظهر املمر�سون و املمر�سات م�ستويات معتدلة من qwl )متو�سط الدرجة االإجمالية: 24.17 ± 179.99(. مت العثور على كل من تعيني الوظيفة واجلن�سية ليكونا تنبوؤات مهمة جلودة احلياة العملية )على التوايل، 0.001< و p = 0.041(. اخلال�صة: متثل نتائج هذه الدرا�سة اأ�سا�ًسا ملزيد من البحث حول هذا املو�سوع املهم. كما هو احلال مع جميع املتخ�س�سني يف الرعاية ال�سحية، توؤثر qwl للكادر التمري�سي ب�سكل غري qwl مبا�رص على جودة رعاية املر�سى والنتائج ال�سحية املرتبطة بها. على هذا النحو، و اأي�سا ميكن اأن ي�ساعد حتديد جماالت �سعف بني الكادر التمري�سي يف تطوير مبادرات لتح�سني ر�ساهم املهني، وبالتايل تعزيز االأداء الوظيفي واالحتفاظ باملوظفني. الكلمات املفتاحية: الكادر التمري�سي؛ جودة احلياة العملية؛ الر�سا عن العمل؛ االإرهاق املهني وعبء العمل؛ التحفيز؛ القوى العاملة ال�سحية؛ عمان. quality of work life among nurses a case study from ad dakhiliyah governorate, oman *mohammed a. al-maskari,1 jonas u. dupo,2 nasser k. al-sulaimi3 sultan qaboos university med j, november 2020, vol. 20, iss. 4, pp. e304–311, epub. 21 dec 20 submitted 13 nov 19 revisions req. 1 jan & 4 mar 20; revisions recd. 13 feb & 22 mar 20 accepted 2 apr 20 https://doi.org/10.18295/squmj.2020.20.04.005 clinical & basic research advances in knowledge this study found that nurses in ad dakhiliyah governorate, oman, demonstrated moderately high levels of quality of work life (qwl). nationality and job designation were significant predictors of qwl, with nurses in high leadership positions and omani nurses reporting greater qwl compared to general nurses and non-omani nurses. there is a need for further research to explore factors influencing the qwl of nurses in oman. application to patient care improving the qwl of nurses can indirectly influence the quality of patient care, thereby promoting better healthcare outcomes. as such, the findings of this study underline the need for strategies to improve the qwl of nurses in the ad dakhiliyah region. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ mohammed a. al-maskari, jonas u. dupo and nasser k. al-sulaimi clinical and basic research | e305 nurses currently comprise the largest proportion of the healthcare workforce, with employment in this field expected to continue to rise over the next few years.1 this specialty encompasses a myriad of functions, from direct primary and preventative care, education, quality assurance and case management to specialised care in a myriad of areas such as family medicine, obstetrics and gynaecology, neurology, surgery, oncology, anaesthesiology, paediatrics and geriatric medicine.1 nurses also face many challenges in the workplace including staff shortages, low salary, burnout and work overload; as a result, the rate of staff turnover among experienced nurses is high.2,3 consequently, these factors may affect the provision of high-quality nursing care and lead to poor productivity.4 it is therefore integral to explore factors affecting job-related satisfaction in the nursing sector, particularly as high rates of job satisfaction help increase employee retention and improve patient outcomes. quality of work life (qwl) is a measurement of the degree of satisfaction of an employee with regards to the fulfilment of personal and professional needs and demands in the workplace.4 the philosophy behind the concept of qwl posits that every employee deserves the opportunity to contribute meaningfully to their organisation and improve their professional growth and career. as such, assessing qwl allows employers to recognise challenges or obstacles within a work environment that affect issues such as the job satisfaction or retention of their employees.4 globally, the majority of nurses report low-tomoderate qwl.5,6 in the gulf region, kaddourah et al. reported that more than half of nurses (54.7%) employed at two tertiary healthcare institutions in riyadh, saudi arabia, were dissatisfied with their work life; moreover, 94% of participants indicated their intent to resign from their current roles.7 despite the importance of qwl among nurses, little attention has been paid to this topic in oman. oman is divided into 11 governorates comprising 61 wilayats (counties) served by a total of 65 hospitals, 242 health centres and 974 private clinics.8 as in other governorates in oman, nurses in the ad dakhiliyah governorate face many challenges that can affect their qwl. a better understanding of factors affecting the qwl of nurses in this region is crucial in order to develop strategies to improve their motivation, job performance and retention, thereby indirectly improving the quality of patient care.9 accordingly, this study aimed to explore factors affecting the qwl of nurses working in governmental health institutions in ad dakhiliyah governorate, oman. methods this descriptive cross-sectional study was conducted between september and november 2018 at 29 governmental health institutions in ad dakhiliyah governorate. all registered full-time nurses with at least six months of experience who were involved in direct patient care and who spoke, read and could write in english were included in the study. the nurses were recruited from all departments including medical/ surgical wards, outpatient departments and paediatric, maternity and critical care units. however, nurses with less than six months of experience, those not directly involved in patient care (e.g. those working in infection control and quality assurance departments, excluding those in leadership positions such as head nurses or nurse supervisors) and those who were on leave during the study period were excluded. participants were recruited using a stratified random sampling technique in order to ensure that variability within subgroups was low compared to that which might ensue from targeting the entire population.10 according to data from the ministry of health, the total number of nurses working in governmental healthcare institutions in the ad dakhiliyah governorate in 2018 was 1,259, including 622 nurses at nizwa hospital and 637 at the other 28 health institutions in the region (i.e. local hospitals, polyclinics and health centres).11 using slovin’s formula, the required sample size was calculated to be 374 participants (including 185 respondents from the tertiary hospital and 189 from other healthcare institutions), based on an a priori power of 0.80, medium effect size of 0.50 and a one-tailed p value of ≤0.050.12 a nine-item english-language questionnaire was designed to collect information regarding the participants’ sociodemographic characteristics incl uding institution, age, gender, marital status, education level, number of years of experience, job designation, nationality and ward assignment. in addition, brook’s quality of nursing work life (bqnwl) scale was incorporated into this survey; this scale consists of 42 items in four dimensions including home or work life (eight items), work design (10 items), work context (20 items) and work world (four items).4 the bqnwl scale has been confirmed to have acceptable construct validity (cronbach’s alpha = 0.89) and testretest reliability (intraclass correlation coefficient = 0.9).4–7 according to the flesch-kincaid formula, the readability of the scale is ranked at the seventh grade level with an estimated time of completion of 9–13 minutes.4,10 quality of work life among nurses a case study from ad dakhiliyah governorate, oman e306 | squ medical journal, november 2020, volume 20, issue 4 for the purposes of the current study, each item of the bqnwl tool was scored on a 6-point likert scale, with 1 indicating strongly disagree and 6 strongly agree, for a total score ranging from 42–252. total scores of 42–112, 113–182 and 183–252 were considered to indicate low, moderate and high qwl, respectively.4 the full version of the questionnaire was piloted among 20 nurses from nizwa polyclinic to assess the clarity of the instrument and time needed for completion, as well as to explore suggestions for improvement. based on the participants’ feedback, several modifications were made to the questionnaire. the internal consistency of the final version of the questionnaire was high (cronbach’s alpha = 0.889). a total of 374 questionnaires were distributed at all governmental healthcare institutions in ad dakhiliyah governorate. beforehand, the institutions were contacted individually to inform them of the study, specifying that a random sampling method would be used so that every nurse had an equal chance of participating. heads of nursing departments and nurses-in-charge were requested to help disseminate the necessary information to all staff nurses working at these institutions. in addition, research assistants were recruited and trained to facilitate the distribution and collection of hard copies of the questionnaires. the statistical package for the social sciences, version 23.0 (ibm corp., armonk, new york, usa) was used for the data analysis. results were reported using descriptive and inferential statistics including percentages, means and standard deviations and frequency distributions. a multiple regression analysis was conducted to examine relationships between bqwnl scores and sociodemographic characteristics (e.g. age, gender, ward assignment, marital status, nationality, job designation, institution, education level and number of years of experience). a p value of ≤0.050 was considered statistically significant. this study received ethical approval from the research and ethical review and approval committee of the ministry of health, oman. informed consent was granted by all participants prior to the administration of the questionnaire. all data were kept anonymous and the nurses were assured that participation in the study was voluntary. results of the 374 questionnaires distributed, 29 were excluded due to incomplete data. the final analysis therefore consisted of 345 complete questionnaires (response rate: 92.2%). of the 345 nurses who submitted completed questionnaires, the majority worked at nizwa hospital (53.6%) and were female (90.7%), table 1: sociodemographic characteristics of nurses working in governmental health institutions in ad dakh iliyah governorate, oman (n = 345) characteristic n (%) gender (n = 345) male 32 (9.3) female 313 (90.7) age in years (n = 339) 21–30 117 (34.5) 31–40 196 (57.8) 41–50 24 (7.1) 51–55 2 (0.6) type of institution (n = 345) tertiary hospital (i.e. nizwa hospital) 185 (53.6) local hospital 67 (19.4) polyclinic 34 (9.9) health centre 59 (17.1) marital status (n = 345) single 33 (9.6) married 306 (88.7) widowed 3 (0.9) divorced 3 (0.9) education level (n = 345) diploma 244 (70.7) post-diploma 30 (8.7) bsn 68 (19.7) msn 3 (0.9) job designation (n = 345) general nurse 329 (95.4) nurse-in-charge/ward-in-charge 10 (2.9) head of nursing 2 (0.6) supervisor 4 (1.2) nationality (n = 345) omani 242 (70.1) indian 50 (14.5) filipino 49 (14.2) tunisian 1 (0.3) sri lankan 1 (0.3) bangladeshi 2 (0.6) number of years of experience (n = 345) 1–5 44 (12.9) 6–10 122 (35.2) 11–15 103 (29.9) 16–20 57 (16.4) 21–25 18 (5.3) ≥25 1 (0.3) bsn = bachelor of science in nursing ; msn = master of science in nursing. *not including the 59 nurses working at health centres who were not assigned to a specific ward or department. mohammed a. al-maskari, jonas u. dupo and nasser k. al-sulaimi clinical and basic research | e307 married (88.7%) and of omani nationality (70.1%). the mean age was 33.3 ± 5.1 years. additionally, 244 nurses (70.7%) held a diploma in nursing and 329 (95.4%) were general nurses. most had between 6–10 (35.2%) or 11–15 (29.9%) years of experience [table 1]. with regards to individual items on the bqnwl scale, nurses most highly ranked the importance of private break areas for nursing staff (mean score: 5.34 ± 1.15), followed by their ability to communicate well with nurse managers or supervisors (mean score: 5.08 ± 1.08) and friendships with their co-workers (mean score: 5.08 ± 1.21). on the other hand, items which were ranked lowest included the negative effect of rotating schedules (mean score: 3.08 ± 1.59), followed by the sufficiency of registered nurses in the work place (mean score: 3.28 ± 1.56) and having energy left after work (mean score: 3.32 ± 1.59) [table 2]. according to the total bqnwl scores for specific subscales, the score for the work context subscale was high compared to the other three subscales which received moderate scores. the overall mean bqnwl score was 179.99 ± 24.17, thereby indicating a moderate level of qwl [table 3]. a multiple linear regression analysis was conducted to examine relationships between bqwnl scores and sociodemographic characteristics. the overall model explained 6.8% of the variability in bqwnl scores (r2 change = 0.068; p = 0.005). job table 2: scores for individual items assessing quality of work life* among nurses working in governmental health institutions in ad dakhiliyah governorate, oman (n = 345) item mean score ± sd i receive a sufficient amount of assistance 3.57 ± 1.38 i am satisfied with my job 4.77 ± 1.23 my workload is too heavy 4.27 ± 1.39 in general, society has an accurate image of nurses 3.86 ± 1.26 i am able to balance my work with my family needs 4.17 ± 1.25 i have the autonomy to make patient care decisions† 4.42 ± 1.21 i am able to communicate well with my nurse manager/supervisor† 5.08 ± 1.08 i have adequate patient care supplies and equipment 3.73 ± 1.38 my nurse manager/supervisor provides adequate supervision 4.54 ± 1.22 it is important for a hospital to offer employees on-site childcare services 4.66 ± 1.32 i perform many non-nursing tasks 4.09 ± 1.41 i have energy left after work 3.32 ± 1.59 friendships with my co-workers are important to me 5.08 ± 1.21 my work setting provides career advancement opportunities 4.02 ± 1.40 there is teamwork in my work setting 4.76 ± 1.15 i experience many interruptions in my daily work routine† 4.05 ± 1.34 i have enough time to do my job well† 3.93 ± 1.34 there are enough rns in my work setting 3.28 ± 1.56 i feel a sense of belonging in my workplace 4.40 ± 1.29 rotating schedules negatively affect my life† 3.08 ± 1.59 i am able to communicate with other therapists (i.e. physical, respiratory, etc.) 4.76 ± 1.17 i receive feedback on my performance from my nurse manager/supervisor 4.27 ± 1.27 i am able to provide good-quality patient care 5.05 ± 1.06 my salary is adequate for my job, given the current job market conditions† 4.15 ± 1.62 my organisation’s policy on family leave time is adequate 3.73 ± 1.52 i am able to participate in decisions made by my nurse manager/ supervisor 4.27 ± 1.27 sd = standard deviation; rn = registered nurse. *assessed using the 42 item brook’s quality of nursing work life scale.4 each item was rated on a 6-point likert scale from 1 (strongly disagree) to 6 (strongly agree). †missing data were reported for this item. table 1 (cont’d): sociodemographic characteristics of nurses working in governmental health institutions in ad dakhiliyah governorate, oman (n = 345) characteristic n (%) ward assignment (n = 286)* accident and emergency 25 (8.7) burns 6 (2.1) coronary care 13 (4.5) delivery 28 (9.8) general 18 (6.3) outpatient 37 (12.9) intensive care 27 (9.4) obstetric and maternity 23 (8.0) medical 15 (5.2) surgical 18 (6.3) operating theatre 13 (4.5) paediatric 28 (9.8) renal medicine 12 (4.2) special baby care 16 (5.6) other (i.e. supervisory position) 7 (2.4) bsn = bachelor of science in nursing ; msn = master of science in nursing. *not including the 59 nurses working at health centres who were not assigned to a specific ward or department. quality of work life among nurses a case study from ad dakhiliyah governorate, oman e308 | squ medical journal, november 2020, volume 20, issue 4 designation (p = 0.041) and nationality (p <0.001) were the only significant predictors of qwl among the nurses. other variables including institution, age, gender, marital status, education level, number of years of experience and ward assignment did not add any value to the prediction model [table 4]. multicollinearity was not a concern (variation inflation factor = 2.031). discussion this study provides an initial baseline understanding of the overall level and factors affecting qwl among nurses in ad dakhiliyah governorate, an important issue which has not been adequately assessed in oman. understanding this issue is vital in order to establish strategies and policies to improve qwl among nurses, thereby eventually leading to an improvement in the quality of patient care.9 moreover, the findings of this study add to the existing body of knowledge related to qwl among nurses in the gulf region. overall, nurses in the current study demonstr ated moderate-to-high qwl. in contrast, comparable studies conducted in jordan, iran and bangladesh reported the qwl of nurses to be low-to-moderate.6,13–15 in addition, much lower bqnwl scores have been reported among nurses in nepal in comparison to those in the present study (mean score: 100.5 ± 57.88 versus 179.99 ± 24.17).16 of the four subscales of the bqnwl tool, the work context subscale received the highest score in the current study. brooks and anderson intended items in this subscale to evaluate the actual settings in which nurses worked and practised and to explore the impact of the work environment on both nurses and patients.4 in a similar study in saudi arabia, the highest and lowest mean scores were observed on the work life/home life and work world subscales, findings which contrast with those of the present study.17 recent implementation by oman’s ministry of health of strategies to improve working conditions in the healthcare sector over the last three years may have affected the findings of the current study. these initiatives have included increasing salaries, restricting working hours to seven-hour shifts in the morning and afternoon and 10-hour shifts at night-time and the provision of a mandatory day off per night duty. in addition, the directorate of nursing affairs in ad dakhiliyah governorate have also begun to conduct motivational seminars and workshops for nursing professionals. such strategies may have increased motivation and job satisfaction among nurses in the present study, thereby increasing their qwl. a comprehensive literature review found that continuing education activities, opportunities to enhance intercolleague relationships, stress reduction exercises and increases in salary were among the factors most likely to increase qwl among nurses in canada and the usa.18 in addition, a recent unpublished study indicated that nurses in ad dakhiliyah governorate have moderate-to-low levels of burnout and moderateto-high retention compared to other countries.19 table 2 (cont’d): scores for individual items assessing qual ity of work life* among nurses working in governmental health institutions in ad dakhiliyah governorate, oman (n = 345) item mean score ± sd it is important for a hospital to offer employees on-site day care facilities for elderly patient† 4.47 ± 1.38 i feel respected by physicians in my work setting† 4.57 ± 1.28 it is important to have a designated private break area for nursing staff 5.34 ± 1.15 it is important to me to have a nursing degree-granting programme available at my hospital 4.93 ± 1.18 i receive support to attend inservices and continuing education programmes 3.86 ± 1.54 i communicate well with the physicians in my work setting† 5.04 ± 1.05 i am recognised for my accomplishments by my nurse manager/supervisor 4.38 ± 1.20 nursing policies and procedures facilitate my work 4.54 ± 1.22 the security department provides a secure environment† 3.60 ± 1.55 it is important for a hospital to offer employees on-site childcare services for ill children 4.85 ± 1.55 i would be able to find the same job in another organisation with about the same salary and benefits 3.77 ± 1.61 i feel safe from personal harm (either physical, emotional or verbal) at work 3.92 ± 1.48 i believe my job is secure† 4.27 ± 1.48 upper level management has respect for nurses 4.29 ± 1.37 my work impacts the lives of patients/ families 4.74 ± 1.19 i receive quality assistance from unlicensed support personnel (i.e. dietary aides, housekeepers and nursing assistants) 3.79 ± 1.39 sd = standard deviation; rn = registered nurse. *assessed using the 42 item brook’s quality of nursing work life scale.4 each item was rated on a 6-point likert scale from 1 (strongly disagree) to 6 (strongly agree). †missing data were reported for this item. mohammed a. al-maskari, jonas u. dupo and nasser k. al-sulaimi clinical and basic research | e309 job designation was found to be a significant predictor of qwl among nurses in ad dakhiliyah governorate. this indicated that nurses with more elevated job titles, such as nurse-ward-in-charge, head of nursing or supervisor, demonstrated a greater level of satisfaction in terms of their qwl compared to general nurses. one possible reason for this finding is that more advanced job designations may offer a supervisory role compared to staff nurses who are mainly on the frontline of patient care and dealing directly with patients and their attendants, an often stressful experience. however, suleiman et al. reported contradictory findings indicating that nurses-in-charge in jordan had significantly higher qnwl scores compared to both junior and senior staff nurses.6 however, further research in this context is necessary in light of the fact that most studies on qwl focus only on general nurses and not on nurse managers. the second significant predictor of qwl in the current study was nationality, with omani nurses exhibiting higher levels of qwl compared to non-omani nurses. this finding is supported by a study in saudi arabia in which saudi nationality was identified as a predictor of qwl among nurses working in jeddah.20 in contrast, alharbi et al. found that the opposite was true, with non-saudi nationality significantly associated with higher bqnwl scores.21 nationality may play a role in promoting qwl in the sense that local nurses may demonstrate higher morale compared to foreign nurses at the thought of serving their own country and taking care of their own people. besides morale, other factors potentially based on nationality—such as culture, religion and salary—may also be linked to qwl and job-related satisfaction. other sociodemographic variables in the current study had no significant association with qwl, including age, gender, and marital status. kelbiso et table 3: overall scores for quality of work life* among nurses working in governmental health institutions in ad dakhiliyah governorate, oman (n = 345) subscale possible score range actual score range mean score ± sd assessment of qwl work life/home life† 7–42 9–41 28.26 ± 5.10 moderate work design‡ 10–60 16–59 41.21 ± 6.08 moderate work context§ 20–120 27–118 89.69 ± 13.94 high work world¶ 5–30 5–30 20.79 ± 4.01 moderate/high overall// 42–252 63–232 179.99 ± 24.17 moderate sd = standard deviation; qwl = quality of work life. *assessed using the 42-item brook’s quality of nursing work life scale.4 †scores of 7–18, 19–29 and 30–42 were considered low, moderate and high, respectively. ‡scores of 10–26, 27–44 and 45–60 were considered low, moderate and high, respectively. §scores of 20–38, 39–77 and 78–100 were considered low, moderate and high, respectively. ¶scores of 5–12, 13–20 and 21–30 were considered low, moderate and high, respectively. //overall, total scores of 42–112, 113–182 and 183–252 were considered low, moderate and high, respectively. table 4: predictors of quality of work life among nurses working in governmental health institutions in ad dakhiliyah governorate, oman (n = 345) variable* unstandardised coefficients standardised coefficients p value b se beta t value constant 158.470 18.289 8.665 <0.001 institution 1.088 1.264 0.051 0.861 0.390 age 0.076 0.539 0.016 0.141 0.888 gender −2.838 4.510 −0.034 −0.629 0.530 marital status 2.003 3.758 0.030 0.533 0.594 education level −0.688 1.906 −0.024 −0.361 0.718 job designation 7.256 3.536 0.116 2.052 0.041 nationality 7.323 2.056 0.254 3.561 <0.001 number of years of experience −0.136 0.530 −0.030 −0.256 0.798 ward assignment 0.273 0.332 0.046 0.822 0.412 *overall quality of work life was the dependent variable. quality of work life among nurses a case study from ad dakhiliyah governorate, oman e310 | squ medical journal, november 2020, volume 20, issue 4 al. and thakre et al. similarly reported no significant relationships between bqnwl scores and age, gender or marital status among nurses in ethiopia and india, respectively.5,22 in contrast, kowitlawkul et al. demonstrated that age and marital status were predictors for qwl among nurses in singapore.23 the present study also revealed no significant association between qwl and type of healthcare institution (e.g. regional hospital, polyclinics, local hospitals and health centres) or ward assignment. however, kelbiso et al. reported working unit and working environment to be significant predictors of qwl among ethiopian nurses, with nurses working in outpatient settings more likely to have higher qwl compared to those in inpatient settings.5 a possible explanation could be that nurses working in outpatient settings usually have fewer responsibilities in comparison to those in inpatient settings. however, much like the present study, nagammal et al. reported no significant rela tionship between unit assignment and qwl among a cohort of nurses working in an oncology care centre in qatar.24 the findings of this study should be considered in the light of certain limitations. first, the study was set in a single region of oman; as such, the results cannot be generalised on a national level. second, although the bqnwl scale is a valid and reliable tool for assessing qwl, there was a risk of response bias due to the self-reported of the responses.4–7 third, the questionnaire was administered in english which was a second language for most of the respondents; therefore, some nurses may have had difficulty understanding and answering certain questions. third, the regression model explained only 6.8% of the variability in bqnwl scores, a factor which requires further exploration. finally, monthly salary, a variable not assessed in the present study, has previously been observed to affect perception of qwl among nurses.15,18,22 conclusion in the nursing sector, qwl is a challenging issue which can affect the quality of care provided to patients. as such, it is important to explore this topic further in order to plan strategies to increase motivation and retention. the current study demonstrated that nurses in ad dakhiliyah governorate had moderately high levels of qwl; moreover, nationality and designation were the only significant predictors of qwl, with nurses in high leadership positions and omani nurses reporting greater qwl compared to general nurses and non-omani nurses. these findings provide a baseline for future studies to examine the issue of qwl among all types of healthcare professionals and across multiple regions of oman. a c k n o w l e d g e m e n t s the authors are grateful to the original developers for granting permission to use the qnwl tool in this study. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest f u n d i n g no funding was received for this study. references 1. american association of colleges of nursing. nursing fact sheet. from: www.aacnnursing.org/news-information/factsheets/nursing-fact-sheet accessed: mar 2020. 2. bradley s, kamwendo f, chipeta e, chimwaza w, de pinho h, mcauliffe e. too few staff, too many patients: a qualitative study of the impact on obstetric care providers and on quality of care in malawi. bmc pregnancy childbirth 2015; 15:65. https://doi.org/10.1186/s12884-015-0492-5. 3. scanlan jn, still m. relationships between burnout, turnover intention, job satisfaction, job demands and job resources for mental health personnel in an australian mental health service. bmc health serv res 2019; 19:62. https://doi.org/10.1186/ s12913-018-3841-z. 4. brooks ba, anderson ma. nursing work life in acute care. j nurs care qual 2004; 19:269–75. https://doi.org/10.1097/00001786200407000-00014. 5. kelbiso l, belay a, woldie m. determinants of quality of work life among nurses working in hawassa town public health facilities, south ethiopia: a cross-sectional study. nurs res pract 2017; 2017:5181676. https://doi.org/10.1155/2017/5181676. 6. suleiman k, hijazi z, al kalaldeh m, abu sharour l. quality of nursing work life and related factors among emergency nurses in jordan. j occup health 2019; 61:398–406. https://doi. org/10.1002/1348-9585.12068. 7. kaddourah b, abu-shaheen ak, al-tannir m. quality of nursing work life and turnover intention among nurses of tertiary care hospitals in riyadh: a cross-sectional survey. bmc nurs 2018; 17:43. https://doi.org/10.1186/s12912-0180312-0. 8. al-maskari ma. omani staff nurses’ and nurse leaders’ attitudes towards and perceptions of barriers and facilitators to the implementation of evidence-based practice. phd. thesis, 2017, widener university, chester, pennsylvania, usa. 9. al sabei sd, labrague lj, ross am, karkada s, albashayreh a, al masroori f, et al. nursing work environment, turnover intention, job burnout, and quality of care: the moderating role of job satisfaction. j nurs scholarsh 2020; 52:95–104. https:// doi.org/10.1111/jnu.12528. 10. grove sk, burns n, gray jr. the practice of nursing research: appraisal, synthesis, and generation of evidence, 7th ed. philadelphia, pennsylvania, usa: saunders, 2012. 11. oman ministry of health. annual health report 2018. from: www.moh.gov.om/en/web/statistics/annual-reports accessed: mar 2020. 12. ellen s. slovin’s formula sampling techniques. from: https:// sciencing.com/slovins-formula-sampling-techniques-5475547. html accessed: mar 2020. https://doi.org/10.1186/s12884-015-0492-5 https://doi.org/10.1186/s12913-018-3841-z https://doi.org/10.1186/s12913-018-3841-z https://doi.org/10.1097/00001786-200407000-00014 https://doi.org/10.1097/00001786-200407000-00014 https://doi.org/10.1155/2017/5181676 https://doi.org/10.1002/1348-9585.12068 https://doi.org/10.1002/1348-9585.12068 https://doi.org/10.1186/s12912-018-0312-0 https://doi.org/10.1186/s12912-018-0312-0 https://doi.org/10.1111/jnu.12528 https://doi.org/10.1111/jnu.12528 mohammed a. al-maskari, jonas u. dupo and nasser k. al-sulaimi clinical and basic research | e311 13. raeissi p, rajabi mr, ahmadizadeh e, rajabkhah k, kakemam e. quality of work life and factors associated with it among nurses in public hospitals, iran. j egypt public health assoc 2019; 94:25. https://doi.org/10.1186/s42506-019-0029-2. 14. sadat z, aboutalebi ms, alavi nm. quality of work life and its related factors: a survey of nurses. trauma mon 2017; 22:e31601. https://doi.org/10.5812/traumamon.31601. 15. akter n, akkadechanunt t, chontawan r, klunklin a. factors predicting quality of work life among nurses in tertiary-level hospitals, bangladesh. int nurse rev 2018; 65:182–9. https:// doi.org/10.1111/inr.12401. 16. ghimire s. quality of nursing work life among nurses working in nobel medical college, biratnagar. cliff nurs j kathmandu univ 2018; 1:38–43. 17. alsadah zo. exploring the relationship between the quality of nurses’ work life and nurses’ work engagement in hospitals in the eastern province of saudi arabia. ph.d. thesis, 2017, pennsylvania state university, university park, pennsylvania, usa. 18. nowrouzi b, giddens e, gohar b, schoenenberger s, bautista mc, casole j. the quality of work life of registered nurses in canada and the united states: a comprehensive literature review. int j occup environ health 2016; 22:341–58. https:// doi.org/10.1080/10773525.2016.1241920. 19. al toubi m, dupo j. the relationships of ethical climate and burnout towards nursing retention index among nurses in al dakhliyah governorate, oman. [unpublished]. 20. ibrahim nk, alzahrani na, batwie aa, abushal ra, almogati gg, sattam ma, et al. quality of life, job satisfaction and their related factors among nurses working in king abdulaziz university hospital, jeddah, saudi arabia. contemp nurse 2016; 52:486–98. https://doi.org/10.1080/10376178.2016.1224123. 21. alharbi mf, alahmadi ba, alali m, alsaedi s. quality of nursing work life among hospital nurses in saudi arabia: a cross‐sectional study. j nurs manag 2019: 27:1722–30. https://doi.org/10.1111/jonm.12863. 22. thakre sb, thakre ss, thakre sn. quality of work life of nurses working at tertiary health care institution: a cross sectional study. int j community med public health 2017; 4:1627–36. https://doi.org/10.18203/2394-6040.ijcmph20171775. 23. kowitlawkul y, yap sf, makabe s, chan s, takagai j, tam ww, et al., investigating nurses’ quality of life and work-life balance statuses in singapore. int nurs rev 2019; 66:61–9. https://doi. org/10.1111/inr.12457. 24. nagammal s, nashwan aj, nair sl, susmitha a. quality of working life among nurses in a tertiary care center in qatar. glob j med public health 2017; 6:1–9. https://doi.org/10.1186/s42506-019-0029-2 https://doi.org/10.5812/traumamon.31601 https://doi.org/10.1111/inr.12401 https://doi.org/10.1111/inr.12401 https://doi.org/10.1080/10773525.2016.1241920 https://doi.org/10.1080/10773525.2016.1241920 https://doi.org/10.1080/10376178.2016.1224123 https://doi.org/10.1111/jonm.12863 https://doi.org/10.18203/2394-6040.ijcmph20171775 https://doi.org/10.1111/inr.12457 https://doi.org/10.1111/inr.12457 2008-issue1.indd prevalence and determinants of waterpipe tobacco use among adolescents in oman *jawad a al-lawati,1 adamson s muula,2, 3 sahar a hilmi,4 emmanuel rudatsikira5 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 37-43 sultan qaboos university© submitted 24th july 2007 accepted 15th december 2007 c l i n i c a l a n d b a s i c r e s e a r c h الوبائية ومحدداتها مان عُ في املُراهقني بني الشيشة تدخني انتشار روديتسكيرا حلمي، امينيويل عبده سحر مووال، آدمسون اللواتي، أحمد جواد هذه . الطريقة: أجريت مان ــلطنة عُ س ُراهقني في امل الطالب بني النرجيلةِ أو ــة ــتعمال الشيش اس ــار ومحددات مدى انتش تَقييم امللخص: الهدف: من املشاركني طلبنا . الشباب عند التبغ الشامل الستخدام املسح من كجزء من عمان مناطق تسع 2003 في سنة املدارس في املقطعية الدراسة . التدخني في واألصدقاء األبوين وعادات السجائر تدخني واملواقف جتاه ، املاضي واحلاضر الشيشة في ــتعمال واس دميغرافية صفات يحوي ــتبيان ملء اس .95% وفترة الثقة األرجحية نسبة على للحصول (االمدادي) اللوجستي وُّف حتليل التَّحَ استخدم االنتشار ، كما معدالت حلساب النسب استخدمت (26%) خمسمائة واثنان وعشرون . 13 – 16 سنة %88 بني سن ، (51.2%) 1005 طالبا ، منهم 1962 طالبا وطالبة الدراسة في النتائج: شارك يدخنون (2.6%) 24 طالبة و (15.5%) 155طالبا . الشيشة حاليا يدخنون بأنهم (9.6%) 189 بينما أفاد ، حياتهم الشيشة في دخنوا قالوا انهم املراهقون أقل يكون . ــجائر الس يدخن األصدقاء الوالدين أو أحد كان ــة إذا الشيش ــتعمال الس أكثر عرضة يكونون الطالب أن تبني . ــة حاليا الشيش لتدخني الشيشة احتماال أكثر يكونون أكثر باليوم أو 500 بيزة يأخذون الذين الطالب . للصحة ضار الدخان أن اعتقدوا ما إذا الشيشة لتدخني عرضة ــبة نس أن االختالفات متعدد وجدنا في التحليل . (4.6 2.3 %95 بني فترة الثقة ، 3.3 األرجحية ــبة (نس ذلك املبلغ أقل من مقارنة بالذين يأخذون يكون عندما األرجحية ــبة نس 2.38 8.35)، بينما بني %95 هو الثقة (فترة 4.46 ــو ه باإلناث مقارنة ــة للشيش ليكون مدخنا للذكور ــة األرجحي أن يعتقدون الذين الطالب . (11.13 2.87 بني %95 هو الثقة (فترة 5.65 ال يدخنون بالذين مقارنة املدخنني للسجائر من األصدقاء كل أو معظم 95% الثقة 0.31 وفترة األرجحية (نسبة للصحة ضار يتصورون أن التدخني ال الذين من ــة ــتعمال الشيش الس احتماال أقل هم للصحة ضار التدخني بني الشيشة تدخني 1.5 -( 3.2. اخلالصة: يعتبر %95 بني الثقة 2.2 وفترة األرجحية (نسبة أكثر أو 500 بيزة يأخذون 0.29 ( 0.92 والذين بني يجب وكذلك ، ــلوك الس لهذا املرافقة العوامل نحو املراهقني اجلهود الالزمة ملنع توجه أن ينبغي ولهذا ، صاعدة صحية ــكلة مش املراهقني العمانيني . التبغ أنواع كل تشمل أن عمان. ، الشيشة ، مراهقون ، الكلمات: التبغ مفتاح 1department of non-communicable diseases, ministry of health, muscat, oman; 2department of community health, college of medicine, university of malawi, blantyre, malawi; 3department of epidemiology, school of public health, university of north carolina at chapel hill, usa; 4department of school health, ministry of health, muscat, oman; 5department of global health, school of public health, loma linda university, california, usa. * to whom correspondence should be addressed. email: jallawat@yahoo.com abstract: objective: to assess the prevalence and determinants of waterpipe use among school-going adolescents in oman. methods: a cross-sectional, school-based study was conducted in 2003 involving 9 regions of oman, as part of the global youth tobacco survey. participants were requested to complete an anonymous questionnaire containing demographic characteristics, current and previous use of waterpipe tobacco, attitudes towards cigarette smoking, parents’ and friends’ cigarette smoking habits. proportions were used to calculate prevalence rates and logistic regression analysis to obtain odds ratio (or) and 95% confidence interval (ci). results: ,962 students participated of whom ,005 (5.2%) were males. eighty-eight percent were between 3 and 6 years of age. five hundred and twenty-two (26.6%) reported ever smoking waterpipe tobacco while 89 (9.6%) were current users. among males, 55 (5.5%) were current users while among females only 24 (2.6%) smoked currently. study participants were more likely to use waterpipe if they had a parent or friend who smoked cigarettes. adolescents were, however, less likely to use waterpipe tobacco if they believed that cigarette smoking was harmful to health. students who were receiving 500 baisas (us$ .3) or more per day pocket money were more likely to use waterpipe tobacco compared to those receiving less (or 3.3, 95% ci 2.3 to 4.6). in multivariate analysis, the or for males being a smoker of waterpipe tobacco compared to females was 4.46 (95% ci, 2.38 to 8.35); while the or for most or all friends smoking cigarettes compared to non-smoking was or 5.65 (95% ci 2.87 to .3). study participants who perceived smoking as harmful to health were less likely to use waterpipe tobacco compared to those who did not believe smoking was harmful (or 0.3, 95% ci 0.29 to 0.92) and those receiving 500 baisas or more (or 2.2, 95% ci .5 to 3.2). conclusion: waterpipe smoking among omani adolescents is an emerging public health concern. efforts to prevent adolescent smoking should be designed with knowledge of associated factors of such behaviour and should include all forms of tobacco. key words: tobacco; waterpipe; adolescents; oman. j awa d a a l l awat i , a d a m s o n s m u u l a , s a h a r a h i l m i a n d e m m a n u e l r u d at s i k i r a 38 globally, tobacco use is a major cause of preventable morbidity and mortality.1 in developing countries and emerging economies, adolescents are particularly likely to initiate and maintain cigarette smoking as the public health and legal infrastructure may not be effective in preventing its use. cigarette manufacturing firms have specifically targeted adolescents and young adults.2, 3 while there has been a longstanding recognition in health literature of adolescent cigarette smoking, public health concerns about the prevalence and determinants of other forms of smoked tobacco use, such as the use of waterpipe, (also known as shishah, narghile, hookah or hubble-bubble), is a relatively recent phenomenon.4-6 this interest has been galvanized by the world health organization’s study group on tobacco product regulation (tobreg) 2005 advisory note, waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators.7 daily waterpipe use can produce nicotine absorption of a magnitude similar to that produced by daily cigarette use thus resulting in adverse effects to health similar to those resulting from nicotine obtain from cigarette smoking;8 however, many people perceive waterpipe smoking as less harmful than cigarette smoking.4, 9 nonetheless, waterpipe use may result in similar pulmonary disease, coronary heart disease, and pregnancy related complications to those associated with cigarette smoking.6 earlier studies have reported the prevalence of tobacco use among omani adults and noted that the majority of current smokers smoked manufactured cigarettes (82.9%), while 6.4% smoked shisha (contemporary type of waterpipe), 7.9% smoked gadou (old fashioned waterpipes), 7.7% smoked a pipe, and 4.5% used other tobacco products such as chewing tobacco.10 there is, however, a paucity of data on the use of waterpipes among adolescents in oman. we therefore set out to assess the prevalence of waterpipe tobacco use among school-going adolescents and the factors associated with its use. m e t h o d s we conducted a secondary analysis of the omani global youth tobacco survey (gyts). this cross-sectional study was conducted in 2003 among school-going adolescents in 9 out of the 11 administrative regions of oman. the regions surveyed were muscat, dakhliyah, north batinah, south batinah, north sharqiyah, south sharqiyah, north dhahirah, south dhahirah and dhofar. the survey targeted students in classes 8-10 (usually aged 13-15 years) and was part of the gyts. a comprehensive description of an equivalent study methodology has been reported elsewhere.11 in brief, a multistage sample design was used in which schools were selected proportional to their enrollment sizes. in any selected school, classrooms were chosen randomly and all students within the selected classes were eligible for participation regardless of their actual ages, i.e. even though the study aimed to recruit students 13 to 15 years, younger or older students were still allowed to participate as long as they belonged to the selected classes (8 -10). at the initial stage of sampling, a list of governmental schools eligible to participate in the survey was collected in coordination with the ministry of education (moe). private schools were excluded mainly because of the smaller number of students in these schools and various logistical arrangements. the student enrolment numbers were obtained for each of the schools. from the list of schools, a sample was drawn with a probability proportional to enrolment size (i.e. large schools with more students were more likely to be selected than smaller ones). a total of 50 schools were selected with no replacement for schools that did not agree to participate. as there were low student numbers in some regions (al-wusta and musandam), only nine out of eleven educational regions were included in the sample. advances in knowledge • illustrates the emergence of a new tobacco related epidemic in youth of an arabian gulf developing country. • shows the determinants of waterpipe tobacco use among youth in oman • determines a baseline for waterpipe use among youth in oman for monitoring future tobacco use among same groups. applications to patient care • data could be used to educate adolescents, youth, patients and parents p r e va l e n c e a n d d e t e r m i n a n t s o f wat e r p i p e to b a c c o u s e a m o n g a d o l e s c e n t s i n o m a n 39 st udy q ue sti o n n a i r e the omani version of the gyts questionnaire had 72 questions. the questionnaire consisted of core components (similar to other gyts questionnaires) and an optional component. the core component allowed for comparison with other countries which conducted the gyts. the optional component included issues specific to the situation in oman and the research needs of the omani ministry of education. the questionnaire was translated into arabic and reviewed by the technical office at the ministry of education. subsequently, it was piloted tested in two schools which did not participate in the survey. the self-administered questionnaire was completed anonymously by the students and took between 30 and 40 minutes to complete. for the purposes of this paper, the following information was obtained: demographic characteristics, current and previous use of waterpipe tobacco, attitudes towards cigarette smoking; whether the study participant had a parent or friend who was a cigarette smoker. current waterpipe use was defined as having ever used waterpipe in the preceding 30 days including the questionnaire completion date. having ever used water was defined as having ever actively inhaled smoke from water-pipes even once. we also aimed to determine whether the amount of pocket money the study participant received on a daily basis was associated with waterpipe use. for this variable, the amount of money was categorized as a binary variable (0, 1), the cut-off being pocket money ≥ 500 baisa (us $1.3) versus <500 baisa daily. there are 1,000 baisa in one omani riyal which is equivalent to us $2.6. permission to conduct the study was obtained from the relevant authorities within the ministries of health and education. participation by eligible students was voluntary. data collection was supervised in schools by trained assistants, who in turn were supervised by school-health doctors without the presence of teachers. however, the research assistants’ role was only limited to ensuring that questionnaires were distributed and then collected and to answering related questions. parents of the students provided written permission while the study participants themselves assented to participate in the study. the sudaan 9.0 software package (research triangle institute, research triangle park, usa) was used for data analysis. proportions and 95% confidence intervals (ci) were obtained to estimates prevalence rates. bivariate logistic regression analysis was used to determine odds ratios (or) between current waterpipe use and other relevant variables selected according to the literature.12-16a weighting structure to account for the study design and non-response was employed using the following formula: w = w1 * w2 * f1 * f2 *f3 *f4 where w1 = the inverse of the probability of selecting the school; w2 = the inverse of the probability of selecting the classroom within the school; fl = a school-level non-response adjustment factor calculated by school size category (small, medium, large); f2= a class-level non-response adjustment factor calculated for each school; f3 = a student-level non-response adjustment factor calculated by class; f4 = a post stratification adjustment factor calculated by grade. r e s u l t s a total of 2,024 students were eligible to participate; however, only 1,962 (96.9%) students participated in the study, of whom 1,005 (51.2%) were males, and 44 (2.2%) had missing data. the overall response rate was 96.6%. the mean age of participants was 15 years (sd ±1.50). of the 1,614 study participants who reported their ages, 15.8% were 13 years old or younger, 25.2% were 14 years, 26.6% were 15 years, 20.1% were 16 years, and 12.3% were 17 years or older. over a quarter (522) of students (26.6%; 95% ci 24.6% to 28.6%) reported to have ever used waterpipe tobacco while 1 in 10 (9.6%; 95% ci 8.3% to 11.0%) were current users. there were 155 (15.4%; 95% ci 13.8% to 17.0%) male users of waterpipe tobacco and 24 (2.6%; 95% ci 1.8% to 3.4%) female users, p<0.001. ten smokers of waterpipe did not report their gender. over half of current waterpipe users (50.3%; 95% ci 42.4% to 58.2%) were also current cigarette smokers. of the current waterpipe users, 11.6% reported using it on 20 or more days in a month, 5.8% used it on 10 to 19 days and 82.6% had used a waterpipe on less than 10 days in the previous month. the association between selected variables and waterpipe use was assessed using bi-variate and multivariate logistic regression analysis. we present the results of both bivariate and multivariate analysis in table 1. male gender was positively associated with smoking waterpipes in the multivariate analysis (or 4.46; 95% ci, 2.38-8.35). smoking in some and most/all friends was also positively associated with waterpipe tobacco use or 3.76 (95% ci 2.28 to 6.22) and 5.65 (95% ci 2.87 to 11.13) respectively. study participants who believed j awa d a a l l awat i , a d a m s o n s m u u l a , s a h a r a h i l m i a n d e m m a n u e l r u d at s i k i r a 40 that smoking was harmful were less likely to have been users of waterpipe or 0.31 (95% ci, 0.29 to 0.92). the amount of pocket money received by the adolescent each day was strongly associated with waterpipe tobacco use. in a bivariate logistic regression analysis, the or for using waterpipe for adolescents receiving 500 baisa or more (us $1.3) per day compared to those receiving less than 500 baisa was 3.3 (95% ci 2.3 to 4.6). in a multivariable logistic regression in which adjustment for sex, friends smoking status, fathers smoking and mothers smoking status were made, the or was 2.2 (95% ci 1.5 to 3.2). d i s c u s s i o n this study presents the prevalence of waterpipe use among school-going adolescents in oman. our study is among just a few others from the eastern mediterranean region which investigated the use of this emerging form of tobacco among adolescents in the region. it shows that at least 1 in 4 omani students have ever tried this form of tobacco use while 1 in 10 is a regular user of this form of tobacco smoking. like cigarettes smoking, waterpipe use appears to be a gender-specific habit with males being 7 times more likely to be waterpipe users than girls. zoughaib et al, in a study of waterpipe use in lebanon also reported a male predominance in its use.17 maziak et al, suggested that this gender-gap is declining with a ratio of 1.9:1.0 for male to female waterpipe use compared to the ratio of 4.3:1.0 for cigarettes smoking.6 pooled data from 76 countries involved in the gyts showed no gender difference in the use of tobacco products other than cigarettes.11 other studies have reported male predominance and suggested that predominance of one gender over another in waterpipe use is location and context-specific and can not be generalized.4 we found 26.6% of adolescents in oman were ever users of waterpipe. rice et al18, reported a similar prevalence (27%) of waterpipe among arab american adolescents. the high percentage of experimenters with waterpipe may be attributed to this form of smoking being viewed as a trendy part of youth lifestyle.19 the prevalence of current waterpipe use in our study was much lower than that reported from neighbouring gulf nations of bahrain (18.2%) and kuwait (24.1%) gyts.20, 21 however, the latter figures were reported as “use of other forms of tobacco” than cigarettes and thus may have included oral or snuff tobacco use. nonetheless, waterpipe was reported as the “predominant” form in this category. lower prevalence of tobacco use has characteristics waterpipe user (%) bivariate odds ratios (95% ci) multivariate odds ratios (95% ci) gender female 2.6 1.00 1.00 male 16.5 7.37 (4.65 to 11.67) 4.46 (2.38 to 8.35) parental smoking status none 8.2 1.00 1.00 one or both parents smokers 14.2 1.84 (1.30 to 2.62) 1.25 (0.75 to 2.09) best friend smokers none 4.4 1.00 1.00 some 22.8 6.40 (4.42 to 9.27) 3.76 (2.28 to 6.22) most or all 30.3 9.40 (5.97 to 14.80) 5.65 (2.87 to 11.13) perception that smoking is harmful no 19.3 1.00 1.00 yes 6.8 0.31 (0.19 to 0.48) 0.51 (0.29 to 0.92) receiving pocket money < us 1.3 per day 1410 1.00 1.00 > = us 1.3 per day 552 3.3 (95% ci 2.3 to 4.6). 2.2 (95% ci 1.5 to 3.2) table 1: factors associated with current smoking of waterpipe among adolescents in oman p r e va l e n c e a n d d e t e r m i n a n t s o f wat e r p i p e to b a c c o u s e a m o n g a d o l e s c e n t s i n o m a n 41 been a consistent finding in oman when compared with other arabian gulf states. this may be attributed to the fact that oman’s recent development started later (in 1970 following a régime change) than other gulf states, and thus opened up to world markets, including tobacco trade, relatively later than other gulf states such as kuwait, bahrain and saudi arabia. in addition, tobacco use has been traditionally viewed as a taboo in oman’s non-costal areas, together with the strict ruling by the religious authorities that have long declared tobacco as haram (religiously forbidden). main stream tobacco smoke from waterpipes contains large amounts of heavy metals such as arsenic, cobalt, chromium, and lead.22 this form of tobacco use is also known to increase the risk of many chronic diseases including oral and lip cancer and obstructive lung disease.23 hadidi and mohammed5 have assessed the content of smoke from waterpipe tobacco and concluded that, in relation to nicotine exposure and dependence, smokers of them are not at a lesser health risks than cigarette smokers. chaouachi, however, has argued that many factors, such as aspiration speed, pressure, water solubility of certain substances, volume of the bowl, the amount and temperature of the water, added substances and the length of the aspiration hose, need to be taken into consideration in comparing the harmful substances inhaled from waterpipe as compared to cigarettes.4 as yet, global health institutions have failed properly to address the health risks associated with this form of tobacco use, and thus there is an urgent need to establish solid knowledge of the health risks associated with tobacco use in the form of waterpipes.6 we found that at least 50% of current waterpipe smokers were also current cigarette smokers. arab american teenagers who smoked waterpipes were found to be twice as likely to have smoked cigarettes in the previous 30 days and 8 times more likely to be ever cigarette smokers compared to teenagers not smoking waterpipes.18 faeh et al, have reported on the clustering of unhealthy behaviours such as illicit drug use, cigarette smoking and alcohol use among young people.24 adolescents using waterpipes may also have other unhealthy habits, such as cigarette smoking, that compounds the deleterious health effect from a single substance. further, the dual use of waterpipe and cigarettes illustrates the need to control for the confounding effect of cigarette smoking when attempting to study specific effects of waterpipe use. we also found that having a parent who was a cigarette smoker was associated with being a waterpipe user. kelishadi et al, have reported similar findings with current smoking being associated with having a closer relative who was also a smoker.25 in our study, though, participants were not asked about waterpipe use among their relatives, but rather cigarette smoking, yet it is likely that having a relative who was a cigarette smoker may influence waterpipe use adolescents of the family. adolescents who received pocket money of more than 500 baisa (us $1.3) per day had higher odds of being current waterpipe users than if their pocket money was lower. this may suggest that having more money may have encouraged the adolescents to initiate and maintain their smoking habit. studies have shown that price increase is a very effective measure to reduce tobacco consumption. a 10% increase in the real (inflation adjusted) price of cigarettes reduces their consumption by 4-8% in low and middle income countries.26, 27 currently, the price of one waterpipe is only one omani rial (us $2.6) and taxes on tobacco have remained static since the year 2000 in oman and other gulf states. the same trend applies to local municipal taxes on cafes serving this product. thus applying price measures such as tax increases, could significantly contribute to halting the waterpipe epidemic and its increasing trend in the arab world in general. l i mi tati o n s our study has several limitations. first, data collected was based on self-administered questionnaires; this may have contributed to a reporting bias especially in terms of understanding specific questions. to minimize this bias, explanatory notes were given at the beginning of the questionnaires. they were also completed anonymously with reasonable confidentiality. secondly, smoking history or lack of it, was not corroborated with biochemical markers such blood nicotine or cotinine levels or their metabolites.28, 29 thirdly, the study involved only in-school adolescents in oman thus the results can not be generalized to all adolescents in the entire country as adolescents out of school may differ from those still in school. however, we believe that out of school adolescents are more likely to be waterpipe users than those still in school. if that is the case, then our estimates are likely to be lower than the actual situation. furthermore, the gyts j awa d a a l l awat i , a d a m s o n s m u u l a , s a h a r a h i l m i a n d e m m a n u e l r u d at s i k i r a 42 only surveys students who are present in school on the day the questionnaire is administered. we did not follow-up students who may have not been in class on that day. in the omani gyts, 2,024 persons were eligible as in-school adolescents in the selected school with a high participation rate (96.6%). finally, despite the fact that the research assistants’ responsibility was limited to supervising the students without influencing any responses, it is possible that some students may have completed the questionnaires in a different way given the presence of such a person. we however, believe this was unlikely to have influenced the findings to any appreciable degree. c o n c l u s i o n waterpipe smoking among omani adolescents is an emerging public health concern. public health interventions against tobacco should be directed not only towards cigarette smoking, but also other forms of tobacco use including the use of waterpipes, especially in the light of oman being party to the world health organization’s framework convention on tobacco control. one of the effective instruments to curb smoking in general is the introduction of comprehensive tobacco control legislation, which oman most urgently needs. a c k n ow l e d ge me n ts the study used the global youth tobacco survey data (gyts). the gyts is a collaborative project of the who and the centers for disease control and prevention (cdc)/participating countries. analyses of gyts data are not necessarily endorsed by the who/cdc/ participating countries. r e f e r e n c e s 1. peto r, lopez ad, boreham j, thun m, heath c, jr. mortality from tobacco in developed countries: indirect estimation from national vital statistics. lancet 1992; 339:1268-1278. 2. sargent jd, dalton m, beach m, bernhardt a, heatherton t, stevens m. effect of cigarette promotions on smoking uptake among adolescents. prev med 2000; 30:320-327. 3. lavato c, linn g, stead lf, best a. impact of tobacco advertising and promotion on increasing adolescent smoking behaviours. cochrane database syst rev 2003; 4:cd003439. 4. chaouachi k. a critique of the who tobreg’s “advisory note” report entitled: “waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators”. j negat results biomed 2006; 5:17. 5. hadidi ka, mohammed fi. nicotine content in tobacco used in hubble-bubble smoking. saudi med j 2004; 25:912-917. 6. maziak w, ward kd, afifi soweid ra, eissenberg t. tobacco smoking using a waterpipe: a re-emerging strain in a global epidemic. tob control 2004; 13:327-333. 7. world health organization (tobacco free initiative). advisory note waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators 2005. from http://www.who.int/tobacco/ global_interaction/tobreg/en/. accessed 25 december 2006. 8. neergaard j, singh p, job j, montgomery s. waterpipe smoking and nicotine exposure: a review of the current evidence. nicotine tob res 2007; 9:987-994. 9. smith sy, curbow b, stillman fa. harm perception of nicotine products in college freshmen. nicotine tob res 2007; 9:977-982. 10. al riyami aa, afifi m. smoking in oman: prevalence and characteristics of smokers. east mediterr health j 2004; 10:600-609. 11. global youth tobacco survey collaborating group. differences in worldwide tobacco use by gender: findings from the global youth tobacco survey. j sch health 2003; 73:207-215. 12. rozi s, akhtar s. prevalence and predictors of smokeless tobacco use among high-school males in karachi, pakistan. east mediterr health j 2007; 13:916-924. 13. bricker jb, andersen mr, rajan kb, sarason ig, peterson av, jr. the role of schoolmates’ smoking and nonsmoking in adolescents’ smoking transitions: a longitudinal study. addiction 2007; 102:1665-1675. 14. reddy p, resnicow k, omardien r, kambaran n. prevalence and correlates of substance use among high school students in south africa and the united states. am j public health 2007;97:1859-1864 from http://www.cdc. gov/tobacco/global/gyts/reports/emro/2001/kuwait_ 2001.htm. accessed 29 december 2006. 15. rudatsikira e, abdo a, muula as. prevalence and determinants of adolescent tobacco smoking in addis ababa, ethiopia. bmc public health 2007; 7:176. 16. siziya s, rudatsikira e, muula as, ntata pr. predictors of cigarette smoking among adolescents in rural zambia: results from a cross sectional study from chongwe district. rural remote health 2007; 7:728. 17. zoughaib ss, adib sm, jabbour j. prevalence and determinants of waterpipe or narghile use among students in beirut’s southern suburbs. j med liban 2004; 52:142148. 18. rice vh, weglicki ls, templin t. predictors of arab american adolescent tobacco use. merrill palmer q (wayne state univ press) 2006; 52:327-342. 19. maziak w, eissenberg t, rastam s, hammal f, asfar t, p r e va l e n c e a n d d e t e r m i n a n t s o f wat e r p i p e to b a c c o u s e a m o n g a d o l e s c e n t s i n o m a n 43 bachir me, et al. beliefs and attitudes related to narghile (waterpipe) smoking among university students in syria. ann epidemiol 2004; 14:646-654. 20. public health department, ministry of health kingdom of bahrain. from http://www.cdc.gov/tobacco/global/ gyts/reports/emro/2003/bahrain_2003_ermo.htm. accessed 29 december 2006. 21. el-nasser s. report on the results of the global youth tobacco survey in kuwait. 2001. from http://www.cdc. gov/tobacco/global/gyts/reports/emro/2001/kuwait_ report.htm. accessed 29 december 2006. 22. shihadeh a. investigation of mainstream smoke aerosol of the argileh waterpipe. food chem toxicol 2003; 41:143-152. 23. el-hakim ie, uthman ma. squamous cell carcinoma and keratoacanthoma of the lower lip associated with quot & shisha smoking. int j dermatol 1999; 38:108-110. 24. faeh d, viswanathan b, chiolero a, warren w, bovet p. clustering of smoking, alcohol drinking and cannabis use in adolescents in a rapidly developing country. bmc public health 2006; 6:169. 25. kelishadi r, ardalan g, gheiratmand r, majdzadeh r, delavari a, heshmat r, et al. smoking behavior and its influencing factors in a national-representative sample of iranian adolescents: caspian study. prev med 2006; 42:423-426. 26. jha p, chaloupka f, eds. tobacco control in developing countries. new york: oxford university press, 2000. 27. abedian i, van der merwe r, wilkins n, jha p, eds. the economics of tobacco control: towards an optimal policy mix. cape town: applied fiscal research centre, university of cape town, 1998. 28. jenkins ra, counts rw. personal exposure to environmental tobacco smoke: salivary cotinine, airborne nicotine, and nonsmoker misclassification. j expo anal environ epidemiol 1999; 9:352-363. 29. mulcahy m, evans ds, hammond sk, repace jl, byrne m. secondhand smoke exposure and risk following the irish smoking ban: an assessment of salivary cotinine concentrations in hotel workers and air nicotine levels in bars. tob control 2005; 14:384-388. whole1.indd abstract objective: endeavor to improve (i) the quality of primary eye care with the aid of an eye health care programme and (ii) the resourcing primary eye care in ministry of health institutions in 200. method: in this descriptive study, staff were randomly selected from 84 health institutions and representing 36 primary health institutions to carry out quality assurance procedures. ophthalmologists trained in this evaluation were field staff who evaluated the resource status, such as health staff, space for eye care delivery, instruments, materials for health education, referring cases (for continuous medical education of the primary health staff ), drugs for eye care, etc., in each health institution. in addition to availability, the standards of eye care delivery were also estimated. results: the health institutes of oman have adequate resources for primary eye care. additional requirement of ophthalmic loupes and medicaments would further improve primary eye care in oman. conclusion: it is recommended that such a review of the health care programme and its resources and quality be periodically conducted as a part of a system of quality assurance in primary health care. key words: primary health centers, oman, eye health care program, quality assurance, quality improvement. health facilities for primary eye care in sultanate of oman primary eye care study 2000 *rajiv khandekar1, ali j mohammed2 sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© primary prevention of common eye dis-eases and early detection of sight-threatening eye diseases are possible with the existing primary health care (phc) services of our country. periodic evaluation of available resources for primary eye care would strengthen the endeavor of national health care programmes to attain the goal of quality primary health initiatives.1 the sultanate of oman is a country in the arabian peninsula. health services provided to the citizens of oman are universally free. it is one of the landmark achievements in last two decades. eye care is an important part of the health initiatives in the sultanate. blindness is prevalent at a rate of 1.1%, and 80% of cases were due to preventable causes or curable diseases.2 it is crucial that the existing phc practitioners detect common and sight threatening eye diseases at early stages. the ministry of health (moh) has prioritized eye problems in a ‘specific disease control program’ in the next five-year plan.3 thus the commitment to strengthen the phc will be stronger in the next ten years. since 1991, primary eye care was offered to all the schools in oman through eye health care programme. trained school health staff annually screened students 1 eye & ear care department, dsdc, dgha, ministry of health (hq), sultanate of oman, 2 director general of health affairs, ministry of health (hq), sultanate of oman *to whom correspondence should be addressed. email: rajshpp@omantel.net.om o r i g i n a l s t u d y عمان سلطنة في األولية العني لرعاية الصحية اإلمكانيات ٢٠٠٠ األولية العني رعاية دراسة وزارة منشآت في األولية" "رعاية العني موارد و(٢) العني، صحة رعاية برنامج مبساعدة األولية العني (١) رعاية حتسني امللخص: الهدف: محاولة ١٣٦ مركزا صحيا متثل صحية ٨٤ منشاة من عشوائية بصورة اختيروا عاملني تقييم الوصفية، مت الدراسة هذه الطريقة: في الصحة لسنة ٢٠٠١. في العاملني مثل املورد، حالة تقييم احلقل في هذا في املدربون العيون أطباء قام عالي. معيار الدراسة ذو أن من للتأكد اجلودة ضمان عبر طرق أوليا (للتعليم الطبي املستمر احلاالت إحالة الصحي، التثقيف املستخدمة في املواد األجهزة، بالعني، خدمات العناية لتقدمي مساحة توفير الصحة، مجال من التأكد مت فقد ذلك، إلى توفر إضافة صحية. مؤسسة كل في العيون..الخ. في طب املستعملة األدوية ، األولية) الصحية الرعاية في للعاملني إضافة جهاز ." للعني األولية "الرعاية ل الكافية املوارد متتلك عمان سلطنة في النتائج: املؤسسات الصحية العني. رعاية في اخلدمات تقدمي مستوى الصحية الرعاية كهذا لبرنامج تقييم أن يجرى اخلالصة: نوصي عمان. في " للعني األولية "الرعاية أكثر ستحسن واألدوية (loupe) للعني خاص األولية. الصحية الرعاية جودة لضمان النظام من كجزء دورية بصورة والنوعية واملوارد r a j i v k h a n d e k a r , a l i j m o h a m m e d 22 from the 1st primary, 4th primary, 1st preparatory and 1st secondary classes in order to detect and manage common eye diseases and provide visual assessment.4 in 1995, the primary eye care was initiated in 136 moh institutions all over oman with the help of a regional cadre of program managers using standard tools.5 this study was accomplished with the objective of evaluating the available resources for primary eye care at moh health institutions (hi) of oman and recommending policies for further strengthening it. m e t h o d facilities for primary eye care exist in 136 moh hi in 10 health regions in the sultanate. an estimated representative sample with 95% confidence intervals, 5% possible errors and 80% of primary health institutions (his), have facilities to provide standard eye care; 88 his were enumerated. these samples were further stratified by region. then the regional proportion of hi (related to eye care) was used as a sample (mentioned in the “annual statistical report 1999” of moh)6 to calculate the sub-sample. using all listed institutions from the random number table gave the required samples for primary eye care evaluation. ten selected ophthalmologists acted as field investigators. the details of health institution staff and the population of the catchment areas were obtained from the hi authorities and the references were collected by using health documents. then the information on the availability of resources was gathered through personal observation and interviews with the health staff on duty and by recording their performance using a specifically-devised pre-tested standard data collection form. in case of non-availability of required resources for eye care, the official in-charge had to furnish details of action to procure them. to ensure a high quality survey, various steps of randomization, the use of instruction manuals, conducting training and standardizing workshops, a pilot study and the auditing of data collection forms were carried out. during pilot stage inter-observer variations were verified. the data collection form and computer format were matched prior to the field work. the forms were audited in the regions and then forwarded to the data manager for computing. complete data was input in a specially-designed software termed epi6. with the range of through checking and random variable tabulation, the process of sorting of data was carried out. the analysis was carried out using the statistical package for social studies (spss 9). the frequency and percentage proportions of important results were calculated. verbal consent of regional and local health administrators was taken for the study. the results and recommendations were given to the regional administrators for further improvement of resources and eye care delivery at primary health centers. r e s u l t s sample profile: of 88 samples enumerated, 84 hi were examined in this study. due to logistic problems, 4 could not be examined. the coverage rate was 96%. as to the human resources for primary eye care qualified graduate medical doctors provided eye care at these institutions. the nursing staff of the his were graduate nurses. these staff had limited training in eye care during their studies so additional training was given after they joined the moh in the sultanate. the catchment area population reported was based on mid1999 population projections.6 the number and ratio to population is specified in table 1. space for eye care: most of the his have separate doctor’s examination rooms, nursing stations, waiting areas for male and female patients and a pharmacy for dispensing medications. also, 73 his (87%) were with adequate space for vision assessment and other activities related to standard eye care. in eight his (9.5%), visual testing was performed in the corridor or waiting area if the doctor thought it essential. in three his (3.5%), this facility was missing. hi with information on human resource related to eye care 84 primary eye care doctors 167 primary eye care nursing sta 725 population of catchment area 960, 625 doctor: population ratio 1:5, 752 nursing staff: population ratio 1:1, 325 primary eye care staff: population ratio 1:1, 077 table 1. human resource for primary eye care (primary eye care study 2000) h e a lt h fa c i l i t i e s f o r p r i m a r y e y e c a r e i n s u lta n at e o f o m a n ( p r i m a r y e y e c a r e s t u d y 2 0 0 0 ) 23 instruments for primary eye care: torches: all 84 his used torches to examine eye cases. however, only 68 (81%) of them had torches with good focus; in the remaining 16 hi (19%), the torches had either poor illumination or poor focus. snellen’s distant vision chart: of 84 his, 76 (91%) had snellen’s distant vision “e” chart and 9% his did not have vision charts. among those having these charts, 56 his (74%) were displayed properly, while 20 his (26%) did not display them as per the recommended standards. ophthalmoscope: although it is not an essential instrument for primary eye care, all hid were provided with a diagnostic set having a combined ophthalmoscope and otoscope. out of 84 hs, 73 (86%) had this instrument; in 11 his (11%) it was not available. among 69 his with this instrument, 60 (95%) had them in working condition, while in 4 his (5%) they were not working. ophthalmic loupe: an ophthalmic loupe is an asset to primary staff to diagnose minute details of ocular tissue, especially for accurately diagnosing trachoma. health staff of presbyopic age would benefit if an ophthalmic loupe were available. only 2 his (2%) had an ophthalmic loupe. in 82 his, (98%) it was not available. material for health education on eye care: for the eye health care program (ehcp), moh had prepared and supplied four posters to all moh institutions in 1999. these posters are related to ocular hygiene, vision hygiene, cataract and “nutrition and eye health”. health staff used the posters for promoting safe preventive practices for eye care. they are in local language and have self-explanatory pictures. of 84 his, 79 (94%) had posters on eye care, while in 5 his (6%) these posters were not available. among those hi having the posters, 49 his (58%) had all four posters, 9 his (11%) had three, 15 his (18%) had two and 11 his (13%) had only one poster displayed properly. reference material on eye care for health staff: for the ehcp, the moh had prepared and supplied flow charts to guide the trained health staff in policies for eye care for common eye diseases. the standard operating procedures and policies of moh for eye care in oman are stipulated in the eye health care (ehc) manuals – 1st and 2nd editions. ophthalmologists reviewed the availability of these reference materials. this information is given in table 2. drugs for primary eye care: the moh has stipulated for his a drug policy on primary eye care. the ophthalmologists collected information on available medicines in the his. if medicines other than those recommended in drug policy were present in the hi, the staff provided the reason for keeping them. the profile of drugs and disposables for primary eye care is shown in table 3. d i s c u s s i o n primary eye care as an integral part of primary health care, is a key strategy that is adopted by national health programs on recommendation of the world health organization (who). it includes promotion of eye health and provision of basic preventive items yes no missing at hi for each sta both # % # % # % # % # % flowchart 45 54 14 17 29 30 eye health care manual 1st edition 57 68 9 11 17 20 1 1 eye health care manual 2nd edition 45 54 5 6 12 14 22 26 table 2. reference material for primary eye care (primary eye care study 20004,5) r a j i v k h a n d e k a r , a l i j m o h a m m e d 24 and/or curative treatment for common eye disorders. the sultanate of oman in its five-year health plans has stressed this strategy since 1990. the national survey for blindness and common eye diseases, which was conducted in oman in 1996-97, suggested that oman had prevalence rates of blindness, which is less than other developing countries but more than industrialized countries. more than ¾ of the blindness was reported to be due to either curable or preventable causes. the communicable eye disease, trachoma, was prevalent at a rate of 2.2%. further strengthening of primary eye care would enable to further reduce blindness and communicable eye diseases. providing the required resources for effective primary eye care has enabled the moh to consolidate primary eye care at all moh institutions since 1995. our assessment on the results of five years of establishing primary eye care should be useful for health planners to formulate future strategies for human resource development and further strengthening of primary eye care in the sultanate. our sample has an adequate unbiased representation. with the random selection procedures adopted, all his had an equal chance of being assessed. thus, the results of this assessment represent the overall situation of primary eye care facility in the sultanate of oman. qualified medical graduates provide the eye services in oman at primary health centers. a large proportion of the professionals is hired from other countries. graduate nursing staff provides the nursing care to eye patients, many of whom graduated in oman. however, the distribution of omani nursing staff is not uniform. in small his, the nursing staff manage eye patients in the absence of doctors. thus, they also are important primary care staff. the moh has provided training to health staff in primary eye care since 1995 with the help of mid-level managers of the eye health care program in all regions. the who has recommended increasing the population of ophthalmic nurse in asian countries from 1: 200,000 in 2000 to 1:50,000 by 2020.7 the study has shown that the primary eye care doctor to population ratio in oman is nearly 1: 5,750, while the nursing staff to population is 1: 1,350. the ratio of primary eye care staff to population is 1: 1,100. in view of the low proportion of skilled omani health staff, this ratio is misleading as far as sustained health services are concerned. the calibre of these primary health staff is of paramount importance for quality eye care. efforts to continuously improve their calibre through training and supervision are the responsibility of the regional eye care program management. health centers have been established in all health regions of oman in the last 20 years. the buildings have standard health care facilities. required alterations to provide standard primary eye care were made within the existing facilities in 1995. this study showed that nearly 90% had adequate space for providing standard eye care. in the remaining his, arrangements are made to assess the visual acuity on a need basis and provide eye care without compromising quality. lack of space in these institutions could discourage health staff from assessing visual acuity in all eye patients. some of the patients with visual impairment but without symptoms could be missed in such circumstances. the cases referred from these institutions on an emergency basis for further care at secondary level will also be without standard vision assessment and this may cause medico-legal problems. simple tools for standard eye examination are necessary to accurately diagnose eye conditions and prono. of hi % chloramphenicol eye drops available 82 97.6 not available 2 2.4 tetracycline eye ointment available 84 100.0 antihistamine eye drops available 74 88.0 not available 10 12.0 azithromycin suspension/tablet available 13 15.5 not available 68 81.0 missing info. 3 3.5 fluoresciene strip available 23 27.4 not available 59 70.2 missing info. 2 2.4 eye pad & dressing material available 57 68.0 not available 26 31.0 missing info. 1 1.0 eye wash facility available 73 87.0 not available 9 11.0 missing info. 2 2.0 extra medication available 31 37.0 not available 53 63.0 table 3. drugs for primary eye care (primary eye care study 2000) h e a lt h fa c i l i t i e s f o r p r i m a r y e y e c a r e i n s u lta n at e o f o m a n ( p r i m a r y e y e c a r e s t u d y 2 0 0 0 ) 25 vide quality eye care. for example, a torch with poor illumination or without good focus, can cause misdiagnosis especially of trachoma and small foreign bodies etc. the majority of his had good torchs. the rest should procure them as soon as possible through their regional administrators. hi staff should also ensure good maintenance and supply of spare batteries in order to keep them in good working condition. distant vision is tested in the sultanate by using snellen’s illiterate‘e’ chart. they are periodically provided by the programme in the required number. placement of the chart is of paramount importance. the regional ophthalmologists during their hi visits should demonstrate the use and positioning of the ‘e’ chart to obtain standard results in vision testing. because oman is a trachoma endemic country, primary health staff should treat active trachoma cases frequently. to differentiate the follicles of trachoma and allergic conjunctivitis and to locate foreign bodies on the cornea etc., it is essential that eyes be examined using magnification. ophthalmic loupes would be useful for this purpose. all his should be provided with ophthalmic loupes in the required quantity. ophthalmoscopy is a skilled procedure and primary staff would take a long time to be proficient in this procedure, hence it is not recommended as a standard operating procedure. however, the medical graduates in their curriculum are trained to use ophthalmoscopes. they could evaluate the hypertensive, diabetic and disc changes in intra-cranial lesions. in the present study, this tool was found to be underutilized in most of the his. promotion of safe preventive practices is part of primary eye care. the eye health care program provided posters for public display at his. only 60% of his had all posters. all had at least one poster displayed. the policy of framing posters before display in his of some regions was responsible for not having these posters properly displayed. a large number of posters to be displayed by different programs have made it impossible for the hi to have all posters displayed at a time. use of handouts, as done for the eye changes of diabetes, trachoma, cataract etc., could be an alternative to poster display. the health staff had sufficient reference material for eye care. this material was used extensively in the initial part of launching the program. periodic reading in clinical meetings or journal clubs would ensure proper utilization of these reference materials. medicines for primary eye care were available in the required quantity in all his. in the year 2001, azithromycin is to be supplied to all hi to treating active trachoma cases. the consumption of tetracycline will reduce in future. all hi should be provided with fluorescein strips for detecting foreign bodies and diagnosing corneal ulcers. the medicines prescribed by ophthalmologists to chronic eye patients are being collected from the parent his. this was the main reason for keeping extra eye medication at some his. regional procurement of sulphacetamide and the provision of it to his should be checked. drug policy for local antibiotics for eye care should be reviewed periodically. reccommendations based on the evaluation, the following recommendations were proposed. ophthalmic loupes should be provided to all institutions. all new his should have standard eye care facilities. antihistamine eye drops, azithromycin suspension/capsule and fluoresceine strips should be supplied to all his. health staff should use reference material for eye care in the journal clubs and when holding periodical clinical meetings. the national and regional health managers should review the constraints and solve them so that posters on eye care can be displayed in waiting areas. pamphlets on common eye diseases should be distributed to interested clients at all his. strict policies for vision testing should be implemented for all cases that are referred to ophthalmologists for further care. the literature does not report the criteria of accreditation of health institutions for primary eye care. however, the model of labeling his as baby friendly institutions and breast feeding health initiatives at moh institutions of oman could also be applied for the accreditation for eye care. in the present study, the distribution of human resources, the availability of materials for eye care and the level of trained staff were measured. however, such point evaluation may have to be supplemented with additional indicators, which could be assessed periodically and with uniform standards. the criteria of measuring the level of his ‘eye care delivery and patients’ satisfaction should also be included as a part of system for quality assurance and quality improvement procedures. r a j i v k h a n d e k a r , a l i j m o h a m m e d 26 c o n c l u s i o n • the assessment suggests that most of the resources for primary eye care are available as per the national policy in oman and resource constraints are not a barrier for providing standard primary eye care. • such a review should be caried out periodically for resources and quality, in order to improve primary health care. acknowledgements we acknowledge the cooperation of primary health staff, the ophthalmologists who worked as field investigators, the staff of the regional directorate and the moh and for their constant encouragement in all steps of this study. the who provided financial support. we are also thankful to all the epidemiologists who assisted in the analysis part of this study. r e f e r e n c e s 1. issues in health services delivery. in: world health organization, who/eip/00.1; 3-4. 2. khandekar r, mohammed aj, negrel ad, riyami aa. the prevalence and causes of blindness in the sultanate of oman: the oman eye study (oes). br j ophthalmol 2002; 86:957-962. 3. fifth 5-year health development plan. in: ministry of health, sultanate of oman, 1996; 32-36. 4. eye health care program. in: oman & unicef ‘eye health care manual 1st edition: ministry of health, 1995; 55-57. 5. oman & who ‘eye health care manual 2nd edition’. in: eye health care program: ministry of health, 2000; 9-10. 6. annual statistical report for year 1999. in: ministry of health, oman, 2000; 2-4. 7. issues in health services delivery. in: world health organization, who/eip/00.1; 24-25. metered-dose inhaler technique among healthcare providers practising in oman 39 abstract. objective : to evaluate the correctness of metered-dose inhaler (mdi) technique in a sample of healthcare providers practising in oman, considering that poor inhaler technique is a common problem both in asthma patients and healthcare providers, which contributes to poor asthma control. method: a total of 150 healthcare providers (107 physicians, 33 nurses and 10 pharmacists) who were participants in symposia on asthma management conducted in fi ve regions of oman, volunteered for the study. after the participants answered a questionnaire aimed at identifying their involvement in mdi prescribing and counselling, a trained observer assessed their mdi technique using a checklist of nine steps. results : of the 150 participants, 148 (99%) were involved in teaching inhaler techniques to patients, and 103 of 107 physicians (96%) had prescribed inhaled medications. however only 22 participants (15%) performed all steps correctly. physicians performed signifi cantly better than non-physicians (20% vs. 2% , p <0.05) among the physicians, internists performed better (26%) than general practitioners (5%) and accident and emergency doctors (9%). conclusion: the majority of healthcare providers responsible for instructing patients on the correct mdi technique were unable to perform this technique correctly indicating the need for regular formal training programmes on inhaler techniques. key words: metered-dose inhaler, asthma management, inhaler technique a sthm a is one of the most common chronic conditions affecting both adults and children and there is evidence that its prevalence and severity are increasing.1 despite the recent advances in the understanding of its pathophysiology and the availability of effective treatment, asthma continues to be a major cause of morbidity leading to a signifi cant economic burden to indi viduals and societies.2 poor asthma control has been related to several common and important problems.1 these include: underdiagnosis and inadequate treatment,1 poor patient understanding of the disease and its treatment,3,4 non compliance,5 and incorrect use of inhaler devices.6,7 inhaled medications form the cornerstone of asthma treatment.6 however, incorrect patient inhaler technique has been identifi ed as a common and persistent problem by many studies worldwide.8–12 up to 90% of adult patients have been reported to have inadequate inhaler technique with higher rates of errors in children and old patients.8–13 poor inhaler technique reduces the drug delivery to the airways, decreasing the effi ciency of the inhaled drug.6,14 the high prevalence of incorrect inhaler technique by patients has been explained by several factors.15,16 most squ journal for scientific research: medical sciences 2001, 1, 39 –43 ©sultan qaboos university metered-dose inhaler technique among healthcare providers practising in oman sawsan a. baddar1, omar a. al-rawas2, kassim a. al-riyami1, elizabeth a. wor thing1, yolande i. hanssens1 aqeela m. taqi1, *bazdawi m.s. al-riyami2 1department of pharmacy, sultan qaboos university hospital, p.o. box: 38, al-khod 123, muscat, sultanate of oman. 2department of medicine, college of medicine, sultan qaboos university, p.o. box: 35, al-khod 123, muscat, sultanate of oman. *to whom correspondence should be addressed. e-mail: bazdawi@squ.edu.om b a d d a r e t a l40 healthcare providers do not spend suffi cient time educating patients on the correct use of the inhalers.17 another problem is the lack of regular periodic assessment of patients’ inhaler technique, essential to ensure proper use.12 more importantly, studies show that most providers themselves have poor inhaler technique.18–27 thus, they may give incorrect instructions to patients.26,27 in addition, the correct use of inhalers has been shown to be infl uenced by patients’ characteristics, such as their age,13 literacy,28 and their understanding of asthma and its treatment.6 therefore, the magnitude of the problem may vary in different populations. furthermore, formal training and demonstration of the correct use of inhalers have been shown to improve the skills of inhaler use in both patients and healthcare providers.29–33 local baseline information is, therefore, essential for each country to develop its own asthma care services and educational programmes targeted at their specifi c problems and needs.1 asthma is common in oman36 and most inhaler devices including m di and dry powder inhalers (rota halers disk halers and turbohalers) are available for its treatment. however, there are no published data on the ability of patients and healthcare providers in oman to use these inhalers correctly. this study, accordingly, aimed to evaluate the ability of healthcare providers in oman to demonstrate the correct mdi technique. m e t h o d t h e pa rt i c i pa n t s between december 1998 and november 1999, the respiratory units at sultan qaboos university hospital and royal hospital conducted a series of symposia on asthma management guidelines in fi ve different regions of oman (muscat, dakhiliya, north batinah, south batinah, and dhofar). all healthcare providers were invited to attend. attendees included physicians (general practitioners, internists, paediatricians, and accident and emergency doctors), nurses and pharmacists. as part of the symposia activities, all at tendees were asked and encouraged to volunteer to demonstrate their inhaler technique without prior knowledge of the purpose of the study. p r o t o c o l after answering a brief verbal questionnaire aimed at identifying involvement in asthma management and m di technique counselling, each participant was asked to demonstrate the use of the m di by taking two puffs from a placebo m di device (glaxo/welcome inc. u k). one trained observer (a respiratory nurse with extensive involvement in the assessment and teaching of inhalers technique to both patients and healthcare providers) using a checklist of nine steps graded the correctness of each participant technique. the nine steps [table 2] were based on manufacturer’s instructions and international clinical guidelines on the mdi technique.37 steps 1 and 4–6 were considered essential for proper delivery of the inhaled medications and the remaining steps were classifi ed as recommended for optimal delivery but not essential. verbal questionnaire this consisted of three questions: (1) what is your specialty? (2) do you counsel patients on the use of inhalers? (3) do you prescribe inhaler medications? steps of mdi technique the acceptability of each step was defi ned as follows:37 the participant must shake the canister vigorously and breathe out slowly and completely before each puff. positioning was considered correct if the canister was held in the upright position and either inserted between closed lips or up to four centimetres in front the open mouth. the participant must then begin a slow inhalation just before depressing the canister once (actuation). the timing of actuation (co-ordination) was considered correct if it occurred anywhere during the fi rst third of the slow inspiration including simultaneously with the start of inhalation. the slow inspiration must continue to total lung capacity after which the inhaler is removed and the lips kept closed, with breath-holding for at least ten seconds. finally, the participants must wait at least 30 seconds before starting the second puff. table 1. participants’ specialties and involvement in mdi prescribing and counselling total number of participants 150 a. physicians 107 adult internists 27 paediatricians 19 general practitioners 39 accident and emergency physicians 11 other physicians 11 number of physicians prescribing mdi 103 (96%) b. non-physicians 43 nurses 33 pharmacists 10 total number of participants who counsel patients on mdi use 148 (99%) m e t e r e d d o s e i n h a l a t i o n t e c h n i q u e 41 data presentation and analysis data were analysed using a statistical software (spss for windows) and presented in terms of frequencies. the different groups of participants were compared using the chisquare (χ2 ) test and p <0.05 was considered signifi cant. r e s u l t s t h e pa rt i c i pa n t s table 1 shows the number of participants and their specialties. 148/150 (99%) participants reported involvement in teaching patients on the use of inhalers. the entire group consisted of three categories of healthcare providers: 107 physicians (71%), 23 nurses (22%) and 10 pharmacists (7%). because of their small number, the nurses and the pharmacists were analysed as a single group: ‘non-physicians’. the physicians group was heterogeneous consisting of internists, paediatricians, general practitioners, and a& e doctors. ninety-six percent of the physicians acknowledged having prescribed inhaled medications. i n h a l e r t e c h n i q u e table 2 lists the nine steps of correct mdi technique and the percentage of healthcare providers who had the correct technique for each step. except for step 3 (holding the inhaler in upright position), the frequency of correct technique was low (27–67%). the frequency of participants who made errors was similar for both essential and preferred steps. of the essential steps, shaking the inhaler and co-ordination (steps 1 and 6) had the highest frequency of errors (41 and 40% respectively), whereas inadequate breath-holding and waiting before starting a second puff (steps 8 and 9) were the most frequent non-essential (preferred) steps in error (36 and 27% respectively). figure 1 shows the frequency of participants’ correct inhaler technique. only 22/150 (15%) participants performed all steps correctly. when only essential steps were considered, the overall performance increased to 28/150 (19%). physicians performed signifi cantly better than nonphysicians for all steps (20% vs. 2%, p < 0.05) and essential steps (22% vs. 9%, p < 0.05). only one of the 43 nonphysicians performed all steps correctly. figure 2 shows the frequency of physicians with correct inhaler technique according to their specialty. while the overall performance was very poor, internists (in both general medicine and paediatrics) performed relatively better table 2. the nine steps of correct metered-dose inhaler technique and the percentage of healthcare providers performing each step correctly step procedure % correct 1* remove cap and shake the inhaler vigorously 41 2 breathe out slowly and completely 51 3 hold the inhaler in the upright position 93 4* insert the mouthpiece into mouth between closed lips 67 5* depress the canister once and … 58 6* … at the same time begin slow deep inhalation (co-ordination) 40 7 remove the inhaler with closed lips 42 8 hold breath for 10-15 seconds 36 9 wait for 20-30 seconds before starting the second puff 27 *the essential steps. % o f p ar tic ip an ts w ith co rr ec t t ec hn iq ue figure 1. percentage of health care providers who performed mdi steps correctly 0% 5% 10% 15% 20% 25% physicians n=107 non-physicians n=43 all participants n=150 all steps essential steps figure 2. percentage of physicians in different specialities who performed all mdi steps correctly 0 5 10 15 20 25 30 gps (n=39) a&e (11) paed (19) med (27) others (11) % o f p ar tic ip an ts w ith c or re ct te ch ni qu e b a d d a r e t a l42 (26% each) than accident and emergency physicians (9%) and general practitioners. d i s c u s s i o n the change from oral to inhaled medications as the preferred route of administration has been one of the most important developments in asthma treatment.1 inhaler therapy is now the preferred mode of delivery of many drugs used in the treatment of asthma and chronic obstructive pulmonary disease.6,11 it is the only way to deliver some drugs such as anticholenergics and sodium cromoglycate and is the preferred mode of delivery for b-agonists and cortico steroids. the major advantage of inhalation therapy is the direct delivery of medications in much smaller effective doses compared to systemic routes, thus reducing sideeffects.11 in addition, inhaled bronchodilators act more quickly.11 the important limitation of inhaler devices is that they are more diffi cult to use and less convenient than tablets. each inhaler device has its own specifi c sequence of steps for optimal drug delivery and it is therefore necessary to give careful and correct instruction to patients.1 mdi , the most commonly used device, requires the patient to co-ordinate inhalation with action of the device (actuation) which can be diffi cult for some.6,16 patients with asthma have been shown to have poor inhaler technique, an important cause of poor asthma control.8–14 the problem is common in both children and adults affecting as many as 60 to 90% patients.8,15,16,25 as a result, international asthma management clinical guidelines emphasise the importance of demonstrating the correct inhaler technique at initial diagnosis and correcting patient performance at each follow-up visit.1 unfortunately, numerous studies consistently show that healthcare providers have poor inhaler technique.18–27 the reported rate of correct inhaler technique among various groups of physician is in the range of 28–69% in different studies with respiratory specialist and internists performing relatively better than others.21–27 for nurses, the reported rate of correct inhaler technique is in the range of 15–66%.20,27 in one study, respiratory therapists performed better than physicians.21 in another study, asthmatic patients performed better than both physicians and nurses.27 however, this universal problem have been shown to improve by formal and regular training of both patients and healthcare providers.30–36 asthma is common in oman.36 the present study is part of a comprehensive project evaluating the different aspects of asthma in this country to design a national programme for the management of asthma. the results of this study show that poor m di technique was very common in this sample of healthcare providers. despite being involved in patients counselling on inhalers, only 15% of the participants were able to perform all steps correctly, which was substantially lower than reports from the literature. in addition, errors were equally frequent for both essential and non-essential (preferable) steps. of the essential steps, the greatest number of errors occured in shaking the inhaler and co-ordination (steps 1 and 6), whereas inadequate breath-holding and waiting before a second puff (steps 8 and 9) were the most frequent non-essential steps in error. although internists performed relatively better than other participants (26% had correct technique), this was still unacceptably low. of special concern was the very poor performance of general practitioners, accident and emergency doctors, nurses and pharmacists. the burden of asthma has become so big that general practitioners and accident emergency doctors are the frontline physicians looking after asthmatic patients with the responsibility to teach them the correct use of inhalers. because of their position, nurses and pharmacists also have opportunity to educate patients on this. it is therefore essential that all providers master the correct technique. training programmes involving instructions and demonstration of the inhaler technique have been shown to improve the skills of patients and providers.29–35 the very poor inhaler technique observed in our study is most probably due to the lack of any formal training for healthcare providers on the correct use of inhalers. c o n c l u s i o n healthcare providers’ skill in the m di technique in oman is very limited, indicating the need for establishing regular educational programmes for both patients and providers. in addition, our results indicate that inhaler technique training programmes for healthcare providers must include not only the specialist, but also general practitioners, accident and emergency physicians, nurses, pharmacists and health educators. special attention should be given to correct the errors in the essential steps of inhaler technique. r e f e r e n c e s 1. scheffer al (ed). global strategy for asthma management and prevention. nhlb/who workshop report. national institute of health, bethesda md, 1995, publication no.95, 3659. 2. bousquet, j. a physician’s view of health economics in asthma. eur respir re 1995, 5, 30, 275–8. 3. ellis me, friend jar . how well do asthma clinic patients understand their asthma? br j dis chest 1985, 79, 43–8. 4. lim sh, goh dy, tan ay, lee bw. parents’ perception towards their child’s use of inhaled medication for asthma therapy. j paeditr child health 1996, 32, 306–9. m e t e r e d d o s e i n h a l a t i o n t e c h n i q u e 43 5. cochrane mg, bala mw, downs ke, mauskpf j, benjoseph rh. inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique. chest 2000, 117, 542–50. 6. self th, rumbak mj, kelso tm. correct use of metereddose inhalers and spacer devices. poatgrad med 1992, 92, 95–6. 7. cockcroft, dw. practical issues in asthma management: correct use of inhalation devices. ann allergy 1993, 71, 83–4. 8. de blaquiere p, christensen, db, carter wb, martin tr. use and misuse of metered-dose inhalers by patients with chronic lung disease. am rev respir dis 1989, 140, 910–6. 9. hilton s. an audit of inhaler technique among asthma patients of 34 general practitioners. br j gen pract 1990, 40, 505–6. 10. thompson j, irvine t, grathwohl k, roth mb. misuse of meter-dose inhalers in hospitalised patients. chest 1994, 105, 715–7. 11. pedersen s, frost l, arnfred t. errors in inhalation technique and effi ciency in inhaler use in asthmatic children. allergy 1986, 41, 118–24. 12. kamps aw, van ewijk b, roorda rj, brand pl . poor inhalation technique, even after inhalation instructions, in children with asthma. pediatr pulmonol 2000, 29, 39–42 13. allen sc, prior a. what determines whether an elderly patient can use meter-dose inhaler correctly? br j dis chest 1986, 8, 45–9. 14. lindgren s, bake b, larsson s. clinical consequences of inadequate inhalation technique in asthma therapy. eur j respir dis 1987, 70, 93–8. 15. horsley mg, bailie gr. risk factors for inadequte use of pressurised aerosol inhalers. j clin pharmacol ther 1988, 13, 139–43. 16. crompton gk. problems patients have using pressurised aerosol inhalers. eur j respir dis 1982, 63, 101–4. 17. mickle tr, self th, farr ge, bess dt, tsiu sj, caldwell fl. evaluation of pharmacists’ practice in patients education when dispensing a metered-dose inhaler. dicp 1990, 24, 927–30. 18. kelling js, strohl kp, smith rl, altose md. physician knowledge in the use of canister nebulisers. chest 1983, 83, 612–4. 19. guidry gg, brown wd, stogner sw, george rb. incorrect use of metered dose inhalers by medical personnel. chest 1992, 101, 31–3. 20. self th, kelso tm, arheart kl, morgan jh, umberto mg. nurses’ performance of inhalation technique with metered dose inhaler plus spacer device. ann pharmacother 1993, 27, 185–7. 21. hanania na, wittman r, kesten s, chapman kr. medical personnel’s knowledge of and ability to use inhaling devices. chest 1994, 105, 111–6. 22. benjaponpitak s. kraisarin c, direkwattanachai c, sasisakunporn c. incorrect use of metered dose inhaler by paediatric residents. j med assoc thai 1996, 79, 122–6. 23. o’donnell j. birkinshaw r, burke v, driscoll pa. the ability of a & e personnel to demonstrate inhaler technique. j accid emerg med 1997, 14, 163–4. 24. tsang kw, lam wk, ip m, kou m, yam l, cheung m et al. inability of physicians to use metered-dose inhalers. j asthma 1997, 34, 493–8. 25. plaza v, sacnchis j and cesea group. medical personnel and patients skill in the use of meter dose inhalers: a multi-centric study. respiration 1998, 65, 195–8. 26. interiano b, guntupalli kk. meter dose inhalers: do healthcare providers know what to teach? arch intern med 1993, 153, 81–5. 27. jones js, holstege cp, riekse r, white l, bergquist t. meter-dose inhalers: do emergency healthcare providers know what to teach? ann emerg med 1995, 26, 308–11. 28. williams mv, baker dw, honig eg, lee tm, nowlan a. inadequate literacy is a barrier to asthma knowledge and self-care. chest 1998; 114, 1008–15. 29. o’bey ka, jim lk, gee jp, cowen me, quingley ae. an education programme that improves the psychomotor skills needed for metaproterenol inhaler use. dicp 1982, 16, 945–8. 30. verver s, peolman m, bogels a, chilsolm sl, dekker fw. effects of instruction by practice assistants on inhaler technique and respiratory symptoms of patients. a controlled randomised videotaped intervention study. fam pract 1996, 13, 35–40. 31. van der palen j, klein jj, kerkhoff ah, van herwaarden cl, zielhuis ga, seydel er. inhalation technique of 166 adult asthmatics prior to and following a self-management programme. j asthma 1999, 36, 441–7. 32. gracia–antequera m, morales suarez-varela m. an intervention to improve the inhalatory technique of children and adolescents with asthma. allergol immunopathol 1999, 27, 255–60. 33. shrestha m, parupia h, andrews b, kim sw, martin ms, park di et al. metered-dose inhaler technique of patients in an urban ed: prevalence of incorrect technique and attempt at education. am j emerg med 1996, 14, 380–4. 34. self th, brooks jb, lieberman p, ryan mr. the value of demonstration and the role of pharmacist in teaching the correct use of pressurised bronchodilators. can med assoc j 1983, 128, 129–31. 35. jackevicius ca, chapman kr. inhaler education for hospital–based pharmacists: how much is required? can respir j 1999, 6, 237–44. 36. the international study of asthma and allergies in childhood (isaac) steering committee. worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: isaac. lancet 1998, 351, 1220–1. 37. whellan am, hanhn nw. optimising drug delivery from metered-dose inhalers. drug intel clin pharm 1991, 25, 638–45. december 2008 no white pages.indd women’s health a practical guide for healthcare professionals sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 360-361 sultan qaboos university© submitted 18th august 2008 the guru of french feminism and existentialist ethics, simone de beauvoir, epitomised the view that biology is not destiny. she remarked, “one is not born, but rather becomes, a woman”. simone de beauvoir would turn in her grave if she knew about sarah bekaert’s volume, women’s health: a practical guide for healthcare professionals. the very fact that it focuses on women’s health appears to challenge simone de beauvoir’s premises about gender and identity. of course, the world has changed since simone de beauvoir’s heyday. the discussion as to whether culture or biology plays the major role in the development of womanhood has been relegated to a trivial footnote by our contemporaries. the spirit of this age, as encapsulated in the sarah bekaert’s volume, emphasises the fact that females are different from males. as if to vandalise simone de beauvoir’s legacy, the view that biology is destiny has been firmly embraced by mainstream medical culture. this has grown out of increased interest in what makes women tick in health related matters, so that tailoredmade and evidence-based etiology, prevention and treatment for women can be consolidated. this wind of change has found important allies. in the past decade, the office on women’s health in the us department of health and human services has been established. several publications have also emerged focusing on solely on women’s health. the academic approach in this endeavour includes scholarly publications such as health care for women international, women & aging, women & therapy, to name just a few. there is also the new harvard guide to women’s health. other ivy league universities have joined the bandwagon, churning out many books on similar issues, further testifying to the current relevance of this issue. in this context, sarah bekaert’s volume brings fresh insight into a field that has been progressively nurtured by her experienced as a paediatric nurse with degrees in gynaecology and reproductive health and membership of the british association for sexual health and hiv. the volume aims to familiarise the practitioner with the disorders and conditions that manifest differently or exclusively in women. thus, if the knowledge it contains is applied properly, it may be the best way to ensure proper health care for women. b o o k r e v i e w النساء صحة الرعاية الطبية في العملي للمهنيني الدليل بيكارت سارة املؤلف: author: sarah bekaert pub. date: october 2007 publisher: radcliffe publishing, oxford & new york, 2007. no. of pages 200 isbn-978 1 84619 029 2 orders: http://www.radcliffe-oxford.com b o o k r e v i e w : wo m e n s h e a lt h 361 the volume is a practical guide addressing the unique, multidisciplinary aspects of women’s health issues. the goal of the author is to offer the practitioner a quick reference guide to possible diagnosis according to symptoms, and the tests that could be performed with to reach a diagnosis. in order to provide a comprehensive guide, brief descriptions of the conditions and tests are included for the convenience of the reader. the chapters are grouped in to five sections: symptom sorter, conditions, tests and procedures, contraception and sexually transmitted infections. the first chapter provides a comprehensive view of the possible signs and symptoms of common female health concerns. it is intended only as a guide and should not be a substitute for communication and liaison with colleagues. the author presents and discusses almost all areas of women’s health including menstrual symptoms, hormonal changes, sexual health, pelvic conditions, pregnancy and infertility, in addition to breast symptoms, urinary symptoms and weight. the chapter on tests and procedures gives an idea about those commonly used in relation to women’s health. it includes the physical examination, blood tests, imaging and samples. the reader would be particularly impressed with the final two chapters which deal with contraception and sexually transmitted infections because of their significance in many women’s lives. all five chapters are brief overviews of medical issues relevant to women. the selection of topics is very extensive. is this volume is a retreat from the hard won advances of feminism? it maybe so for madame simone de beauvoir’s ‘diehards’. this book is, however, not a challenge to such classic treatises, but simply a teaching manual with high-quality graphics and photographs accompanied by a generous number of tables. it is easy to read because it maintains a simple structure. the strength of the volume is that women’s health issues are simplified. the book provides basic information on conditions, tests required and links to useful related resources. thus, it will be useful for medical students, interns and residents. because of the simple language used it can also be used by a layperson concerned about women’s health. the book would be an essential guide for all medical practitioners, but more so for female practitioners with specific interest in women’s health. its audience could even include males who are well known to dwell at the lower end of evolutionary ladder in term of their understanding of the female body and health. the take home message is that women’s health should require special consideration. the book departs from the previous chauvinistic approach and teleological debate as to whether or not biology is destiny. r e v i e w e r rahma al-kindi department of family medicine and public health, college of medicine and health sciences, sultan qaboos university, muscat, sultanate of oman email: rkindi@squ.edu.om departments of 1microbiology and 3child health, royal hospital, muscat, oman; 2department of clinical microbiology, oman medical specialty board, muscat, oman *corresponding author’s e-mail: hussain.mohsin2@outlook.com early disseminated mycobacterium abscessus complex infection in an infant with coexisting cystic fibrosis and progressive familial intrahepatic cholestasis case report and literature review sanjeewani a. weerakoon,1 maya al salti,2 jalila mohsin,1 hilal al hashami,3 tawfiq al lawati,3 *hussain mohsin3 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 295–299, epub. 26 may 22 submitted 10 nov 20 revisions req. 11 jan & 21 mar 21; revisions recd. 16 feb & 4 apr 21 accepted 14 apr 21 the age of two months with a chronic cough for one month and failure to thrive. he was diagnosed with cf based on elevated sweat chloride level (>60 mmol/l) and genetic testing that confirmed the presence of a homozygous 3120 + 1g >a cystic fibrosis transmembrane conductance regulator (cftr) gene mutation. the infant received intravenous antibiotics therapy and was started on pancreatic enzymes and fat-soluble vitamins. his throat swab culture was negative and he was discharged with an outpatient follow-up. at the age of five months, the infant was admitted through the paediatric emergency department with a two-day history of fever, cough and difficulty in breathing. at the time of presentation, the infant was in respiratory failure with a respiratory rate of 70 breaths per minute, low oxygen saturation of 76% in room air, bilateral diffused crackles and wheezing. he required immediate tracheal intubation and mechanical ventilation. the infant looked icteric with a palpable liver 4–5 cm below the costal margin with no splenomegaly. other systemic examinations were unremarkable. the initial laboratory tests revealed a haemoglobin level of 12.1 g/dl with leukocytosis (predominantly neutrophils) at 26.2 × 109 cells/l. he had elevated liver enzymes including alanine transaminase of 460 iu/l, aspartate aminotransferase of 768 iu/l and alkaline phosphatase of 316 iu/l. the total bilirubin was 159 µmol/l (conjugated bilirubin at 121 μmol/l) mycobacterium abscessus complex (mabsc) belongs to a group of rapidly growing mycobacteria (rgm) that can be clinically significant. diseases caused by rgm have been increasingly reported during the past few decades due to various factors including improvement of molecular diagnostic methods and the increase in population at risk for non-tuberculous mycobacterial (ntm) diseases.1 mabsc is implicated in causing a wide range of clinical diseases including localised skin and soft tissue infections and disseminated infections such as osteomyelitis, lymphadenitis, cutaneous, lung and bloodstream infections, particularly in an immunocompromised host.1–3 the presence of underlying chronic lung diseases predisposes an individual to pulmonary infections.2 ntm has been increasingly reported as a significant pathogen among cystic fibrosis (cf) patients and has been linked to poor prognosis among this group.4–7 progressive familial intrahepatic cholestasis (pfic) is an autosomal recessive liver disease that can present with early-onset progressive liver failure.8 herein, we report a case of disseminated infection due to m. abscessus in an infant with coexisting cf and pfic. case report a full-term male infant who has a 10-year-old sibling with cf, was referred to a tertiary care hospital at this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.089 case report abstract: mycobacterium abscessus complex (mabsc) is a rapidly growing mycobacterium and may rarely cause disseminated infections in immunocompromised patients. in patients with cystic fibrosis (cf), it peaks between the ages of 11 and 15 years. we present a five-month-old infant with coexisting cf and progressive familial intrahepatic cholestasis (pfic) who had pulmonary and cutaneous dissemination of mabsc infection. the management of this disseminated infection in an infant with two coexisting chronic diseases was challenging and resulted in the rapid deterioration of lung function and progression of pfic to liver cirrhosis with a fatal outcome. keywords: cystic fibrosis; atypical mycobacterium; mycobacterium abscessus complex; progressive familial intrahepatic cholestasis; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ early disseminated mycobacterium abscessus complex infection in an infant with coexisting cystic fibrosis and progressive familial intrahepatic cholestasis case report and literature review 296 | squ medical journal, may 2022, volume 22, issue 2 reaction (pcr) were all negative. the infant continued to experience low-grade fever over the second week and had progressive worsening of his respiratory parameters which prompted performing a flexible bronchoscopy and obtaining bronchoalveolar lavage (bal) fluid. the bal sample was sent for bacterial, mycobacterium and fungal cultures and extended viral pcrs. the bal sample microscopy showed a positive result for acid fast bacilli (afb) through ziehl-neelson staining, while the tuberculosis pcr test done using genexpert (cepheid, sunnyvale, california, usa) was negative, raising the suspicion of ntm. a computed tomography (ct) scan of the chest showed bilateral cystic bronchiectasis and nodules [figure 1]. given the lack of improvement on broadspectrum antibiotics, the isolation of ntm from bal and the ct changes, the child met the american thoracic society and the infectious diseases society of america (ats/idsa) diagnostic criteria for nontuberculous mycobacterial pulmonary disease.6 on day 20 of admission, anti-tuberculous drugs—rifampicin (15 mg/kg/dose once daily), ethambutol (20 mg/kg/ dose once daily), clarithromycin (7.5 mg/kg/dose twice daily)—were commenced while meropenem was continued. the child developed a confluent macular-papular skin rash involving the face, trunk, limbs, palms and soles but sparing the mucus membranes. there was neither evidence of desquamation, erythroderma or angioedema clinically nor any blood eosinophilia. disseminated cutaneous infection due to atypical mycobacteria was highly suspected after excluding other causes including drug-related hypersensitivity reaction. around the same time, the afb positive peripheral blood culture was also positive for grampositive bacilli [figure 2]. these were subsequently and serum albumin level was normal. the infant’s coagulation profile was normal. chest x-ray showed hyperinflated lungs, peribronchial wall thickening and bilateral lower lobe consolidations. the infant was started on intravenous piperacillin-tazobactam (90 mg/kg/dose four times daily), gentamicin (10 mg/kg/dose once daily) and oral oseltamivir (30 mg/dose twice daily) for the management of severe pneumonia and cystic fibrosis pulmonary exacerbation. although the infant did not have a previously positive respiratory culture to guide antibiotic choice, his sibling was known to have chronic pseudomonas aeruginosa airway infection. hence, his sibling’s chronic p. aeruginosa infection status was taken into consideration when choosing antibiotics to ensure adequate coverage. during the first week of his stay at the paediatric intensive care unit (picu), there was a deterioration in the infant’s clinical condition, therefore the medication was changed from piperacillin-tazobactam to meropenem (40 mg/kg/dose thrice daily). initial blood cultures and respiratory samples (obtained via an endotracheal tube) for bacterial and fungal cultures and respiratory viral panel polymerase chain figure 2: (a) gram stain at ×100 (oil immersion) magnification showing thin, beaded gram-positive bacilli and (b) ziehl-neelson stain at ×100 (oil immersion) magnification showing acid fast bacilli in a five-month old infant. figure 1: computed tomography scans of the chest of a five-month old infant performed (a) before and (b) three months after the initiation of non-tuberculous mycobacterial treatment showing progressive bilateral cystic bronchiectasis. sanjeewani a. weerakoon, maya al salti, jalila mohsin, hilal al hashami, tawfiq al lawati and hussain mohsin case report | 297 identified as m. abscessus by matrix-assisted laser desorption ionisation-time of flight mass spectrometry (maldi-tof ms). the central line blood culture remained negative for bacterial growth. the bal culture was identified as m. abscessus through the line probe assay method using inno-lipa (lipa innogenetics, ghent, belgium). azithromycin-based combination therapy with parenteral amikacin (18 mg/kg/dose once daily) and meropenem (imipenem was not available) was started as an intensive phase regimen based on the us cystic fibrosis foundation (cff) and european cystic fibrosis society (ecfs) recommendations for eight weeks.9 the isolate was not tested for standard drug sensitivity due to technical limitations. subsequently, the treatment was switched to the continuation phase that included oral azithromycin (10 mg/kg/dose once daily), levofloxacin (10 mg/kg/dose twice daily) and nebulised amikacin (250 mg/dose twice daily). furthermore, the infant had progressive cholestasis with elevated conjugated bilirubin and transaminitis. based on a family history of pfic in his first degree cousins, he underwent a liver biopsy which showed cholestatic hepatitis with fibrosis. a wholeexome sequence sample was sent to centogene labs (centogene n.v., rostock, germany), which found a homozygous mutation in the atp binding cassette subfamily b member 11 (abcb11) gene, confirming the diagnosis of autosomal recessive pfic type 2 in addition to cf. given the early onset of ntm lung disease and the disseminated infection, the patient was extensively investigated for primary immunodeficiency disorders (pids) including mendelian susceptibility to mycobacterial disease. however, no pids were found. during his five-month stay in the hospital, the infant remained on respiratory support; mostly noninvasive ventilation with recurrent icu admissions requiring intubation and mechanical ventilation. multiple respiratory cultures obtained through the endotracheal tube and bal remained negative for m. abscessus over the initial three months of treatment. however, a repeat bal sample once again showed a positive result for m. abscessus in the fourth month of treatment. two samples were positive for aspergillus species with no other laboratory findings suggestive of allergic bronchopulmonary aspergillosis. the infant received four weeks of voriconazole (10 mg/kg/dose twice daily) that was switched to amphotericin b due to transaminitis. despite being on ursodeoxycholic acid, his liver cirrhosis progressed and he developed portal hypertension. despite receiving anti-bacterial and antituberculous therapy and the supportive picu care, the infant developed an acute-on-chronic deterioration of respiratory status. this led to rapid respiratory failure and death after five months of inpatient hospital stay. discussion disseminated infections due to m. abscessus are rare and occur mostly in immunocompromised patients.10,11 the current patient was investigated thoroughly for pids but none were found. to the best of the authors’ knowledge, cases of coexisting conditions of cf and pfic have never been reported before. although cf is a known risk factor for ntm lung disease, it is not usually associated with disseminated ntm infection. additionally, the onset of ntm lung disease in the infant was much earlier than what has been reported in the cf literature.12,13 pfic type 2 typically results from a failure in the bile salt exporter pump (bsep) protein which is responsible for exporting bile acids from the hepatocyte into canaliculi. this results in early-onset and progressive liver failure.8 reviewing the literature, in general, pfic or liver cirrhosis has not been shown to increase the susceptibility to ntm infection. it is possible that the coexistence of these two conditions resulted in a secondary immunodeficiency status which led to this disseminated infection. however, this conclusion cannot be made based on this single case. the presence of at least one of the following characteristics would define the disseminated disease: cutaneous manifestations, involvement of more than one organ with or without cutaneous involvement, involvement of more than two groups of lymph nodes or positive blood culture.12 cutaneous presentations can manifest as skin infections with discrete nodules, ulceration, multiple abscesses, diffuse maculopapular eruptions or, in contrast, as reactive skin lesions such as erythema nodosum, pustular psoriasis, generalised pustulosis and acute febrile neutrophilic dermatosis (sweet syndrome).14 the current patient did have maculopapular skin eruptions; however, though the lesions were not biopsied, the patient showed dramatic improvement after the commencement of anti-ntm agents. lymphadenitis is the most common presentation of ntm in immunocompetent children.12 ntm infects patients with underlying chronic lung diseases such as bronchiectasis, emphysema and healed tuberculosis. it has emerged as a frequently isolated pathogen among cf patients over the past few decades with prevalence rates of up to 20% in usa and 13% in europe.4,5 according to the us cff registry data (2016), m. abscessus was found to be the second most common isolate after m. avium complex accounting for 16% and 72% of positive cultures respectively.15 the isolation of m. abscessus from early disseminated mycobacterium abscessus complex infection in an infant with coexisting cystic fibrosis and progressive familial intrahepatic cholestasis case report and literature review 298 | squ medical journal, may 2022, volume 22, issue 2 the ats/idsa 2007 guideline recommends a multidrug, macrolide-based regimen along with surgical resection, if possible, for both pulmonary and extrapulmonary infections.6 as per the us cff and ecfs consensus recommendations, the treatment is divided into an initial intensive phase (which can range from three to 12 weeks) followed by a continuation phase.9 the intensive phase includes an oral macrolide, intravenous amikacin and one or more of the following: intravenous tigecycline, imipenem or cefoxitin. the decision to switch to the continuation phase should depend on the response to treatment, the severity of infection and if the regimen is tolerated by the patient. the continuation phase includes an oral macrolide, inhaled amikacin and two to three out of the following antibiotics: minocycline, clofazimine, moxifloxacin and linezolid.9 antibiotic choices should be guided but not dictated by drug susceptibility testing.17 inducible resistance to clarithromycin is another challenge and it is due to the presence of the erythromycin ribosome methyltransferase (erm) gene in two of the m. abscessus sub-species: m abscessus subsp. abscessus and m. abscessus subsp. bolletii. in comparison, m. abscessus subsp. massiliense does not have inducible resistance to clarithromycin due to the non-functioning erm gene, making therapeutic response to macrolide-based therapy more effective and efficient.2,21,22 unavailability of recently validated techniques such as multi-locus sequence typing of hsp65, rpob and seca genes for differentiation into sub-species levels, was an additional limitation in optimising antibiotic treatment in our case.23 conclusion the current case report describes a fatal case of disseminated m. abscessus infection in an infant who had two chronic comorbid conditions of cf and pfic along with the diagnostic and therapeutic challenges associated with case management. this report highlights the importance of having a high index of suspicion for ntm infection in children with cf presenting with early deterioration of lung function. more research with regard to the optimal management of ntm infection in this young population is required. a u t h o r s’ c o n t r i b u t i o n sw and mas drafted the initial manuscript focusing on the microbiology aspect. hm added the clinical presentation and discussion sections. hah reviewed the manuscript and updated the infectious disease aspect. jm reviewed and updated the microbiology aspect. tal wrote and reviewed the liver disease aspects. all authors approved the final version of the manuscript. sputum culture does not necessarily indicate infection. accurate differentiation of lung infection from lung colonisation is challenging but important since the infection contributes to a more fulminant disease outcome in cf patients.7 furthermore, the recovery of m. abscessus from routine bacterial cultures is often masked and easily missed due to overgrowth of other common respiratory tract pathogens and colonising bacteria. in order to diagnose ntm lung disease, the following criteria should be fulfilled: clinical (persistent respiratory symptoms), radiological (nodular and/ or cavitary opacities on radiograph or bronchiectasis with nodules on ct scan) and microbiological evidence.6 microbiological diagnostic criteria for ntm lung disease requires persistent growth of ntm in respiratory specimens: one positive afb culture results in either two separate expectorated sputum samples or in one bronchial wash or lavage.6 the presence of a central venous catheter is a common predisposing factor for m. abscessus bloodstream infections.16 identification of the ntm from blood culture may be difficult and often misdiagnosed with corynebacterium spp. which are usually considered to be skin contaminants.16 this case highlights the importance of careful interpretation of gram-positive bacilli which helps in the timely management of ntm disseminated infections. accurate and urgent identification of ntm down to the species level is important in deciding the correct antibiotic choice. different laboratory methods are used for the identification of ntm including biochemical tests, high-performance liquid chromatography and molecular tests.6,9 a reverse hybridisation assay such as ‘inno-lipa mycobacteria v2’ (lipa innogenetics) is designed to amplify the mycobacterial 16s–23s rrna internal transcribed spacer region. however, it cannot differentiate m. abscessus on a sub-species level.9,17 a recent study shows that maldi-tof ms can be used with promising results to identify ntm species including m. abscessus (concordance results with a reverse hybridisation-based assay showing 96.9% agreement).18 management of pulmonary and extra-pulmonary mabsc infection is faced with multiple challenges including intrinsic resistance to the common, standard anti-tuberculous agents, discordant in vitro susceptibility and clinical response, limited provento-be-effective drugs, serious side-effects and the long duration required for clinical and microbiological cure.19 to overcome these difficulties, a multidisciplinary team which includes a chest physician, infectious disease expertise, clinical microbiologist, clinical pharmacist, physiotherapist, community nurse, the patient and his/her family is needed.20 sanjeewani a. weerakoon, maya al salti, jalila mohsin, hilal al hashami, tawfiq al lawati and hussain mohsin case report | 299 references 1. brown-elliot ba, wallace jr rj. infections due to nontuberculous mycobacteria other than mycobacterium avium-intracelluare. in mandell gl, bennett je, dolin r, eds. mandell, douglas and bennet's principles and practice of infectious diseases. 7th ed. philadelphia: elsevier, 2010. pp. 3191–8. 2. de groote ma, huitt g. infections due to rapidly growing myco bacteria. clin infect dis 2006; 42:1756–63. https://doi.org/10.10 86/504381. 3. sfeir m, walsh m, rosa r, aragon l, liu sy, cleary t, et al. mycobacterium abscessus complex infections: a retrospective cohort study. open forum infect dis 2018; 5:ofy022. https:// doi.org/10.1093/ofid/ofy022. 4. cystic fibrosis foundation. cystic fibrosis foundation patient registry 2016 annual data report. from: https://prod-test.cff. org/research/researcher-resources/patient-registry/2016patient-registry-annual-data-report.pdf accessed: apr 2021. 5. valenza g, tappe d, turnwald d, frosch m, könig c, hebestreit h, et al. prevalence and antimicrobial susceptibility of microor ganisms isolated from sputa of patients with cystic fibrosis. j cyst fibros 2008; 7:123–7. https://doi.org/10.1016/j.jcf.2007.06.006. 6. griffith de, aksamit t, brown-elliott ba, catanzaro a, daley c, gordin f, et al. an official ats/idsa statement: diagnosis, treat ment, and prevention of nontuberculous mycobacterial diseases. am j respir crit care med 2007; 175:367–416. https://doi. org/10.1164/rccm.200604-571st. 7. esther cr jr, henry mm, molina pl, leigh mw. nontuber culous mycobacterial infection in young children with cystic fibrosis. pediatr pulmonol 2005; 40:39–44. https://doi.org/10.10 02/ppul.20222. 8. srivastava a. progressive familial intrahepatic cholestasis. j clin exp hepatol 2014; 4:25–36. https://doi.org/10.1016/j.jceh.20 13.10.005. 9. floto ra, olivier kn, saiman l, daley cl, herrmann jl, nick ja, et al. us cystic fibrosis foundation and european cystic fibrosis society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. thorax 2016; 71:i1–i22. https://doi.org/10.1136/thoraxjnl-2015-207360. 10. gardner ai, mcclenaghan e, saint g, mcnamara ps, brodlie m, thomas mf. epidemiology of nontuberculous mycobacteria infection in children and young people with cystic fibrosis: analysis of uk cystic fibrosis registry. clin infect dis 2019; 68:731–7. https://doi.org/10.1093/cid/ciy531. 11. zimmermann p, curtis n, tebruegge m. nontuberculous myco bacterial disease in childhood update on diagnostic approaches and treatment. j infect. 2017 jun; 74:s136–42. https://doi. org/10.1016/s0163-4453(17)30204-9. 12. chetchotisakd p, mootsikapun p, anunnatsiri s, jirarattanapochai k, choonhakarn c, chaiprasert a, et al. disseminated infection due to rapidly growing mycobacteria in immunocompetent hosts presenting with chronic lymphadenopathy: a previously unrec ognized clinical entity. clin infect dis 2000; 30:29–34. https:// doi.org/10.1086/313589. 13. roux al, catherinot e, ripoll f, soismier n, macheras e, ravilly s, et al. multicenter study of prevalence of nontuberculous myco bacteria in patients with cystic fibrosis in france. j clin microbiol 2009; 47:4124–8. https://doi.org/10.1128/jcm.01257-09. 14. lee mr, sheng wh, hung cc, yu cj, lee ln, hsueh pr. mycobacterium abscessus complex infections in humans. emerg infect dis 2015; 21:1638–46. https://doi.org/10.320 1/2109.141634. 15. olivier kn, weber dj, wallace rj jr, faiz ar, lee jh, zhang y, et al. nontuberculous mycobacteria. i: multicenter prevalence study in cystic fibrosis. am j respir crit care med 2003; 167:828–34. https://doi.org/10.1164/rccm.200207-678oc. 16. el helou g, viola gm, hachem r, han xy, raad ii. rapidly growing mycobacterial bloodstream infections. lancet infect dis 2013; 13:166–74. https://doi.org/10.1016/s1473-3099(12)7 0316-x. 17. suffys pn, da silva rocha a, de oliveira m, campos ce, barreto am, portaels f, et al. rapid identification of mycobacteria to the species level using inno-lipa mycobacteria, a reverse hybridization assay. j clin microbiol 2001; 39:4477–82. https:// doi.org/10.1128/jcm.39.12.4477-4482.2001. 18. mediavilla-gradolph mc, de toro-peinado i, bermúdez-ruiz mp, garcía-martínez mde l, ortega-torres m, montiel quezelguerraz n, et al. use of maldi-tof ms for identification of nontuberculous mycobacterium species isolated from clinical specimens. biomed res int 2015; 2015:854078. https://doi. org/10.1155/2015/854078. 19. tippett e, ellis s, wilson j, kotsimbos t, spelman d. mycobac terium abscessus complex: natural history and treatment out comes at a tertiary adult cystic fibrosis center. int j mycobacteriol 2018; 7:109–16. https://doi.org/10.4103/ijmy.ijmy_55_18. 20. harris ka, kenna dtd. mycobacterium abscessus infection in cystic fibrosis: molecular typing and clinical outcomes. j med microbiol 2014; 63:1241–6. https://doi.org/10.1099/jmm.0.077164-0. 21. zelazny am, root jm, shea yr, colombo re, shamputa ic, stock f, et al. cohort study of molecular identification and typing of mycobacterium abscessus, mycobacterium massiliense, and mycobacterium bolletii. j clin microbiol 2009; 47:1985–95. https://doi.org/10.1128/jcm.01688-08. 22. rubio m, march f, garrigó m, moreno c, español m, coll p. inducible and acquired clarithromycin resistance in the myco bacterium abscessus complex. plos one 2015; 10:e0140166. https://doi.org/10.1371/journal.pone.0140166. 23. m macheras e, konjek j, roux al, thiberge jm, bastian s, leão sc, et al. multilocus sequence typing scheme for the myco bacterium abscessus complex. res microbiol 2014; 165:82–90. https://doi.org/10.1016/j.resmic.2013.12.003. https://doi.org/10.1086/504381 https://doi.org/10.1086/504381 https://doi.org/10.1093/ofid/ofy022 https://doi.org/10.1093/ofid/ofy022 https://doi.org/10.1016/j.jcf.2007.06.006 https://doi.org/10.1164/rccm.200604-571st https://doi.org/10.1164/rccm.200604-571st https://doi.org/10.1002/ppul.20222 https://doi.org/10.1002/ppul.20222 https://doi.org/10.1016/j.jceh.2013.10.005 https://doi.org/10.1016/j.jceh.2013.10.005 https://doi.org/10.1136/thoraxjnl-2015-207360 https://doi.org/10.1093/cid/ciy531 https://doi.org/10.1016/s0163-4453(17)30204-9 https://doi.org/10.1016/s0163-4453(17)30204-9 https://doi.org/10.1086/313589 https://doi.org/10.1086/313589 https://doi.org/10.1128/jcm.01257-09 https://doi.org/10.3201/2109.141634 https://doi.org/10.3201/2109.141634 https://doi.org/10.1164/rccm.200207-678oc https://doi.org/10.1016/s1473-3099(12)70316-x https://doi.org/10.1016/s1473-3099(12)70316-x https://doi.org/10.1128/jcm.39.12.4477-4482.2001 https://doi.org/10.1128/jcm.39.12.4477-4482.2001 https://doi.org/10.1155/2015/854078 https://doi.org/10.1155/2015/854078 https://doi.org/10.4103/ijmy.ijmy_55_18 https://doi.org/10.1099/jmm.0.077164-0 https://doi.org/10.1128/jcm.01688-08 https://doi.org/10.1371/journal.pone.0140166 https://doi.org/10.1016/j.resmic.2013.12.003 2nd multidisciplinary scientific conference ibri regional hospital, ibri, oman 31 december 2022 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 276–283, epub. 31 may 23 https://doi.org/10.18295/squmj.5.2023.039 conference abstracts first clinical case of vim-1-producing leclercia adecarboxylata: a case report and literature review *mohammed abdullah al shuhoumi,1–3 abdulrahman al mhrooqi,1 azza al-rashdi,4 rajesh kumar,5 ahood al-jabri,5 amal al-kalbani,5 amina al-jardani6 1laboratory department, ibri hospital, ibri, oman; 2academic lecturer, oman college of health sciences, muscat, oman; 3center of studies and research, muscat, oman; 4central public health laboratories, directorate general of disease surveillance and control (dgdsc), muscat, oman; 5central public health laboratory, muscat, oman; 6who collaborating center for emerging & re-emerging infections, central public health laboratories, dgdsc, ministry of health, muscat, oman. *corresponding author’s e-mail: mls971.ihs@gmail.com leclercia adecarboxylata is a recently recognised emerging pathogen. we describe the first emergence of l. adecarboxylata generating vim-1 in an immunocompetent 63-year-old female patient with an abrupt intracerebral haemorrhage. this case report aimed to narrate the course of infection, management, outcomes and the unique morphological and molecular characteristics of the vim-1-producing l. adecarboxylata. the local laboratory used api e to identify the multi-drug resistant strain in the patient's sample. it was identified using vitek 2, maldi-tof ms and 16s rrna sequencing after being sent to the central public health laboratory. vitek 2 was used to conduct antimicrobial susceptibility testing (ast), which employed the ast gn card 215 and the e test. the clinical and laboratory standards institute served as the foundation for the data interpretation. to validate the isolate's phenotype as a carbapenem producing enterobacterals (cpe), the modified hodge test and the modified carbapenem inactivation technique were used. furthermore, multiplex pcr targeting blaoxa-48, blandm, blakpc, blaimp and blavim was used to characterise the cpe genes on a molecular level. finally, the sanger cycle sequencing technique (bigdyetm terminator v3.1 cycle sequencing) was used for vim amplicon to confirm vim-1. the strain was incorrectly classified as citrobacter koseri by api e (99.9%) and pantoea species by vitek 2, however l. adecarboxylata was verified by maldi-tof ms (score 2) and 16s ribosomal rna analysis. the existence of two populations of resistance genes, vim1 and oxa-48, was detected using conventional pcr. accuracy of whole blood for bedside pregnancy test *khadija h. al shukaili,1 khalfan d. al amrani,2 umaima al wahaibi3 1emergency department, ibri hospital, ibri, oman; 2emergency department, sultan qaboos university hospital, sultan qaboos university, muscat, oman; 3general surgery program, oman medical specialty board, muscat, oman. *corresponding author’s e-mail: khadijashukaili@gmail.com objectives: the primary aim of the study was to assess the sensitivity, specificity, negative predictive value (npv) and positive predictive value (ppv) of whole blood in bedside pregnancy tests at three levels of serum human chorionic gonadotropin (hcg) (5, 10 and 25 miu/ ml). the secondary aim was to determine the reading time difference using whole blood versus laboratory serum hcg. methods: this study was conducted between january 2018 and july 2018 at the emergency department of sultan qaboos university hospital, muscat, oman, and included healthy females who required a pregnancy test. a triage nurse or phlebotomist drew blood from the patients. a few drops were applied to a standard diagnosis (sd) bioline bedside hcg test. the remaining blood was processed in the laboratory. the beside whole blood test results were compared according to three quantitative serum hcg levels. results: of the 278 patients included, 130 patients had a serum hcg level of ≥5 miu/ml, 125 had a serum hcg level ≥10 miu/ml and 123 had a serum hcg level ≥25 miu/ ml. the sensitivity and npv was 90% and 91.93%, respectively, at serum hcg levels ≥5 miu/ml. at serum beta hcg level of 10 miu/ ml, the sensitivity and npv was 93.6% and 95%, respectively. the specificity and ppv was 100% at three level of serum hcg. the savings time was 70 minutes with the use of whole blood (p <0.05). conclusion: the sd bioline hcg whole blood test can rapidly detect early pregnancy with high sensitivity, specificity, npv and ppv with threshold of 10 miu/ml. genetic basis of early-onset breast cancer in oman *waleed s. al amri,1 thomas a. hughes,2 zakiya al ajmi,1 fatma al lawati1 1department of histopathology & cytopathology, the royal hospital, muscat, oman; 2school of medicine, university of leeds, leeds, uk. *corresponding author’s e-mail: waleedsaid.alamri@ moh.gov.om objectives: more than 50% of all breast cancer (bc) patients diagnosed during the period of 1999–2015 in oman were below the age of 45. by contrast, early-onset of breast cancer (eobc) accounted for only 10.3% in usa, 9% in uk and 16% in canada. the causes for this unprecedented high incidence of eobc in oman is not known. brca1/2 gene mutations are known to be associated with eobc. however, the prevalence of brca1/2 mutations and whether they are responsible for eobc in omani population remains unknown. this study aimed to assess the prevalence of brac1/2 mutations and investigate whether they are main causative factors for eobc in omani population. methods: breast tissue samples and associated clinical data for patients treated at royal hospital, muscat, oman, between 2010–2020 were collected and analysed. germ-line brca1/2 gene mutations were identified using oncomine brca assay (thermofisher scientific, usa). correlation analysis was performed to correlate brca1/2 genes mutation status with patients age and family history. results: a total of 1,336 patients were included in the study; 611 patients (45.7%) were aged <45 years at diagnosis and 725 (54.3%) were ≥45 years old. data for brca1/2 mutations were available for 262 patients. no significant correlation was found between brca1/2 genes mutation status and age (p = 0.229). however, brca1/2 genes mutation status correlated significantly with family history (p = 0.017). conclusion: eobc is not associated with germ-line brca1/2 gene mutations. the majority of eobc (73.4%) have no family history of breast cancer, indicating that early-onset of the disease is unlikely to be caused by inherited germline mutations, but rather caused by acquired somatic mutations. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. 31 december 2022 conference abstracts | 277 utilization of echocardiography in detection of intracardiac masses in the setting of emergency medicine: a case series *mohammed al shukaili,1 ahmed al salmi,2 ammar al rahbi,3 amal al mandhari,4 mahmood al jufaili4 1,2,3oman medical specialty board, muscat, oman; 4emergency department, sultan qaboos university hospital, sultan qaboos university, muscat, oman *corresponding author’s e-mail: modizoom@gmail.com identification of intracardiac masses in an emergency setting can be tricky and requires expert skills. once done with proper technique, it can dramatically change the line of diagnosis and management and direct the patient to the recommended specialised care. we report three cases. case 1 is a young female patient, 8-weeks post-partum with an uneventful pregnancy, presenting with epigastric pain. examinations showed significant fluid overload. bedside echocardiography showed a left atrial mass and departmental echocardiography confirmed a left atrial myxoma. the patient was admitted, operated on and discharged in good condition. myxoma was confirmed by histopathology. case 2 is a 47-year-old male patient, on dialysis from a central line, who was planned for central line removal. he presented with ascites and palpitation. bedside echocardiography showed vegetation at the tip of the catheter in the right atrium; these findings were confirmed with official echocardiography. case 3 is a 67-year-old female patient with ischaemic heart disease and who had had covid one month prior. she presented with syncope, tachypnoea and chest discomfort. bedside echocardiography showed a large mobile clot migrating between the right ventricle and right atrium (clot-in-transit). ct scan confirmed a sub-massive pulmonary embolism. the patient was thrombolysed and admitted to the intensive care unit. in conclusion, using point of care ultrasound in the emergency department for patients with cardiac complaints can guide a physician’s decision and excludes critical presentations. unexpected intracardiac mass findings can change the diagnosis and alter patient outcome. trends and characteristics of emergency department visits during ramadan: a retrospective study *mohammed alshukaili,+ badria alhatali,2 naeema alhinai3 1emergency medicine department, ibri regional hospital, ibri, oman; 2poison center, ministry of health, muscat, oman; 3emergency medicine departmetn, the royal hospital, muscat, oman. *corresponding author’s e-mail: modizoom@gmail.com objective: this study aimed to explore the trends and characteristics of emergency department visits during the month of ramadan compared to the rest of the year. methods: a retrospective analysis was performed using data collected from a tertiary hospital from january 2017 to 31st december 2019. the data included age, gender, the hourly number of visits, triage categorisation, presenting complaint to emergency department, provisional diagnosis and disposition plan from the emergency department. results: a total of 109,967 visits to the emergency department were recorded. the daily average during ramadan was lower compared to one month before and one month after (p <0.0001). patient attendance was lower between 17:00 and 20:00 and the highest was between 23:00 and 01:00, as compared to non-ramadan months, which tended to be lowest at late night and highest during the daytime (p <0.008). there were no statistical differences in the initial triage categories, most common medical conditions, rate of admission, categories of disposition, or mortality rates in the emergency department compared with non-ramadan months. conclusion: in this study, there is a significant variation in patient presentation during ramadhan compared to other months. we suggest better preparedness and resource allocation will help improve patient care and optimise patient flow in the emergency department. maximising result of bedsore prevention in a mechanically ventilated patient abeer al ghafri,1 asad al ghafri,2 *mohammed abdullah al shuhoumi3,4 1covid-19 department, ibri regional hospital, ibri, oman; 2center of studies and research, directorate general of health services, muscat, oman; 3laboratory department, ibri hospital, ibri, oman; 4oman college of health sciences, muscat, oman. *corresponding author’s e-mail: mls971.ihs@gmail.com objective: there are various preventative measures for pressure ulcers, according to the clinical practice guideline, including a comprehensive initial evaluation after admission to identify risk factors, education about pus, repositioning and nutritional assistance. although there hasn't been much studied, hydrocolloid dressings have been used to prevent bed sores in a few locales. this study aimed to determine whether there is a link between hydrocolloid dressing and the prevention of bedsores in ventilated patients. method: this retrospective observational study included patients on mechanical ventilation. participants were selected from the covid-19 ward of ibri regional hospital, ibri, oman. preand post-test studies were conducted utilising conventional or conventional treatment with preventative hydrocolloid dressing. staff recordings and evaluations in the alshifa 3 plus program were used to acquire information. result: a total of 74 patients were included. the pre-test comprised forty patients who received only conventional care, while the posttest included 34 patients who had both conventional therapy and hydrocolloid dressing. the number of bedsores decreased from 22 (55%) in the pre-test to 5 (15%) at the post-test. the most common bedsore stage in the post-test was stage one (4 out of 34) and was mostly associated with individuals with comorbidities. conclusion: this study showed a significant difference between the post-test and pus variable of employing cc+hd (p <0.05), which reduces patient harm. it is critical to encourage experiments that compare various preventative interventions. association of pre-gestational diabetes mellitus (type 1 & type 2), gestational diabetes and pre-eclampsia with preterm birth among omani women zainab k. al maqbali nursing programme, oman college of health science, muscat, oman. author’s e-mail: alrabee33@hotmail.com objectives: this study aimed to determine if and to what extent rates of pre-gestational diabetes mellitus, gestational diabetes mellitus and pre-eclampsia differ between omani women who deliver preterm infants and omani women who deliver term infants. shonkoff ’s bio-developmental framework provided the theoretical foundation for this study. methods: this quantitative retrospective crosssectional study used secondary data. data were gathered from a simple random sample of 400 women who delivered preterm or term infants between 2015 and 2017 at ibri hospital, ibri, oman. the control group included 200 women with full-term infants and the other group consisted of 200 cases of women with pre-term infants. after data extraction and cleaning, descriptive analyses and chi-square tests of independence were conducted. results: a total of 400 randomly selected participants (mean age = 29.26 ± 5.75 years) were included in the study. results indicated no differences in rates of pre-gestational diabetes mellitus, gestational diabetes, or 2nd multidisciplinary scientific conference ibri regional hospital, ibri, oman 278 | squ medical journal, may 2023, volume 23, issue 2 pre-eclampsia between mothers of preterm infants and term infants. however, results indicated differences involving selected clinical and demographic variables including education level, multiple pregnancies complications in current pregnancy, and maternal history of gestational diabetes, gestational hypertension and obesity. the findings reveal the significance of social determinants of health, including specific clinical and demographic factors, in predicting preterm birth for omani women. conclusion: according to the results, the researcher recommends addressing the current study’s limitation of omani specific results in broader studies covering a greater population and diverse population demographics and to be applied to nursing practice and education by training nurses and nursing students to identify factors in patient family histories which might suggest high risk pregnancies. characteristics and trend of breast cancer in al-dahirah region: a retrospective study of cases diagnosed in ibri hospital from 2014–2022 aziza al ghafri department of radiology, ibri regional hospital, ibri, oman. author’s e-mail: alazhar23@yahoo.co.uk objectives: this study aimed to determine the trend and prevalence of breast cancer in the al-dahirah governorate and to assess the clinical characteristics of breast cancer in the region. methods: this retrospective cross-sectional study included 137 patients diagnosed with breast cancer from january 2014 to december 2022 in al-dahirah region (ibri hospital, ibri, oman). data were collected on age at presentation, family history, pregnancy status and breastfeeding status. other clinical parameters were also studied, such as presenting symptom, disease characteristics and metastatic status on diagnosis. results: the number of women diagnosed with breast cancer in al-dahirah region had increased steadily from 2014 to 2022. most cases presented with lumps (75.9%) followed by screening (12.41%) and 28.47% of the cases were less than 40 years. most cases (90.51%) had no family history of breast cancer. despite the increase in the number of breast cancer cases in the region, most cases presented with less advanced disease. ductal carcinoma was the most common type in histopathology diagnosis. almost one-quarter (23.36%) of the total cases were lactating mothers and six cases had a previous history of in-vitro fertilisation. conclusion: the study highlights an increase in the prevalence of breast cancer in al-dahirah region and emphasises the importance of educating women on the importance of home self-examination as a continuous screening tool at younger ages. this research also highlights the need for further research on the relation of breast cancer and breastfeeding and the relation of breast cancer with in-vitro fertilisation. routine annual mammogram screening from 40 years onwards should be considered a must. patient-centered care, diabetes self-management and glycaemic control among omani patients with type-2 diabetes *abdullah s. al mahrouqi,1 r. kevin mallinson,2 kyeung mi oh,2 ali a. weinstein3 1oman college of health sciences, muscat, oman; 2school of nursing and 3department of global and community health, george mason university, fairfax, usa. *corresponding author’s e-mail: mahrooqi76@gmail.com objectives: an estimated 350,000 omanis will be living with type-2 diabetes mellitus (t2dm) by 2050. the role of the nurse in primary healthcare in promoting diabetes self-management (dsm) in a patient-centered care (pcc) model is unexplored. this study examined the relationships between pcc, dsm and selected outcomes (glycaemic control [a1c] and quality of life) for omani patients with t2dm in diabetes clinics. methods: correlational cross-sectional surveys were administered to 237 omani patients with type-2 diabetes. hierarchical regression analyses were used to investigate the relationships between the study variables. results: nearly a decade (mean = 9.68 ± 6.11) since being diagnosed with t2dm, the sample’s a1c was high (mean = 8.8 ± 2.4). pcc was positively associated with dsm but not glycaemic control or quality of life. however, in the regression model, pcc was positively associated with physical and mental aspects of health-related quality of life after controlling demographic and clinical characteristics. in the final model, dsm significantly predicted both glycaemic control and both physical and mental aspects of health-related quality of life after controlling for demographic and clinical characteristics and pcc. conclusions: the findings support the idea of using individualised care to improve the self-management of chronic conditions. to achieve the best outcome, providers may need to effectively assess patients’ challenges and motivations. increasing dsm may improve the quality of life and reduce diabetes complications. patients’ and nurses’ perceptions of diabetes self-management in oman: a qualitative study *abdullah s. al mahrouqi,1 r. kevin mallinson,2 kyeung mi oh,3 ali a. weinstein4 1oman college of health sciences, muscat, oman; 2school of nursing and 3department of global and community health, george mason university, fairfax, usa. *corresponding author’s e-mail: mahrooqi76@gmail.com objectives: type-2 diabetes mellitus (t2dm) is an emerging public health issue in the oman. primary health care (phc) nurse’s role in promoting diabetes self-management (dsm) within a patient-centered care (pcc) model in the gulf region is unexplored. this study explored the perceptions of omani patients with t2dm and their nurses on the nurses’ role in promoting dsm within a pcc approach. methods: a descriptive qualitative design was used to conduct individual interviews to gather patient and nurses’ perceptions regarding the delivery of dsm and pcc in the clinical setting. standard qualitative probes were used to elicit elaboration, clarification and sequencing in the gathered narratives. the interview was iterative and field notes and reflective notes were recorded after each interview to enhance data analysis. results: the thematic analysis of the data from individual interviews with patients (n = 24) revealed two themes: patients experienced “missteps on an unclear path” and “nurses doing their best”. patients struggled to find treatment goals and had difficulty adopting dsm behaviors. nurse narratives (n = 21) showed that very few nurses were aware of the pcc model and their role was perceived as task-oriented. a theme appeared of nurses “needing a new perspective” to transition their care delivery to align with the pcc philosophy. nurses missed opportunities for assessment, engagement and collaborative problem-solving while meeting patients. conclusion: moving to a patient-centered primary care delivery system may require nurses to engage more effectively with patients, collaborate on individualised treatment plans and empower them to adopt self-management. 31 december 2022 conference abstracts | 279 investigation the impact of clinical pharmacist-led discharge counselling on the 30-day readmission rate of patients with heart failure at sultan qaboos university hospital: a single-centre non-randomised interventional cohort sameh al maqbali ibri polyclinic, ibri, oman. author’s e-mail: s.s.k.al-maqbali@rgu.ac.uk objectives: there is currently no data on the impact of clinical pharmacist discharge counselling on heart failure (hf) patients in oman. this study aimed to critically investigate the impact of clinical pharmacist-led discharge counselling on the 30-day readmission rate of hf patients. method: this prospective cohort study was conducted at sultan qaboos university hospital, muscat, oman. patients admitted with hf were divided into intervention and control groups. the intervention group (patients who received intensive discharge counselling by a clinical pharmacist using a medication calendar tool) was reviewed prospectively and the control group was reviewed retrospectively. the rate of hospital readmission within 30 days post-discharge was compared between the intervention and the control group. results: a total of 23 patients were recruited for the intervention group and 81 patients were included in the control group. patients had a mean age of 68.05 ± 14.28 years 57.7% were male. the intervention group had a 13% readmission rate compared with 32% in the control group, however, this was not statistically significant (p = 0.31). conclusion: this is the first study conducted in oman to investigate the impact of clinical pharmacist-led discharge counselling. the study demonstrated that this intervention improved patient outcomes and reduced the 30-day readmission rate of hf patients, highlighting the importance of implementing discharge counselling in the healthcare system. wandering spleen with infarction in a non-symptomatic patient *aziza al-ghafri, farida ambusaidi, mohammed kotb, wael moustafa department of radiology, ibri regional hospital, ibri, oman. *corresponding author’s e-mail: alazhar23@yahoo.co.uk one or more of the ligaments that keep the spleen in its natural location in the left upper quadrant are weak or absent in wandering spleen, a relatively uncommon abnormality. the symptoms that a patient experiences vary and might be completely asymptomatic, the sensation of an abdominal mass, or abrupt, mild to severe abdominal pain brought on by myocardial infarction. clinical diagnosis might be difficult due to the wide range of non-specific symptoms; thus, imaging is crucial in the diagnosis. splenic torsion, the main side effect of wandering spleen, is what causes acute abdomen. we present a case of an asymptomatic patient’s torn wandering spleen with infarction that was unintentionally found after a history of minor trauma. multiple stomach varices and portal hypertension were the results of the splenic vein thrombosis, which appeared to be persistent. on the basis of computed tomography and ultrasonography, a preoperative diagnosis was determined. surgery later verified the findings. the patient received a successful laparoscopic splenectomy. females had a worse t-score at lumbar region and males had a worse t-score at femoral region among chronic kidney disease hilal al kalbani,1 *issa al salmi,2 fatma al rahbi,2 sumaiya al siyabi,3 suad hannawi4 departments of 1rheumatology, 2renal medicine and 3nuclear medicine, the royal hospital, muscat, oman; 4department of medicine, ministry of health and prevention, dubai, united arab emirates.*corresponding author’s e-mail: isa@ausdoctors.net objetcives: this study aimed to assess bone turnover indicators and bone mineral density (bmd) as measured by dual energy x-ray absorptiometry (dexa) in individuals with chronic kidney disease (ckd). methods: this clinical observational study included all patients who underwent dexa scans in 2018. according to the world health organization's definition of osteoporosis, all individuals with poor bone density or osteoporosis were included. results: a total of 87.3% of the 505 individuals with abnormal bmd had early ckd stages i to ii, 8.5% had stages iii to v and 4.2% had no renal testing. a mean age of 57.0 years was recorded for 95 (18.8%) men and 55.8 years for 410 (81.2%) females. patients over 65 years of age showed lower t-scores than patients under 65 years. patients with latestage ckd (stages iii to v) showed lower t-scores and fewer bmd assessments than those with early-stage ckd (stage i ii). the lower t-score and parathyroid hormone (pth) level showed a strong positive association. the t-score of the female was lower than the male's in the lumbar and femoral regions, respectively. the t-score did not significantly differ between men and women at the hip region. conclusion: the distribution of aberrant bmd among various age, sex and ckd groups is noticable. dexa bmd measurements might be a helpful diagnostic tool to identify osteoporosis in ckd patients. however, dexa might not be able to identify osteoporosis in the lumbar region of ckd patients. femoral and total hip regions were more impacted. patients with more severe ckd and older patients have lower t-scores. the amount of bone loss is proportionately correlated with pth level. to effectively manage ckd patients, a multidisciplinary team approach must be used for early intervention and care. mucolipidosis type iv in omani families with a novel mcoln1 mutation: search for evidence of founder effect badriya al-alawi,1 beena harikrishna,2 khalid al-thihli,3 sana al zuhabi,2 anuradha ganesh,2 zainab al hashami,4 zeyana al dhamhmani,4 razan zadjali,4 nafila b. al riyami,4 *fahad zadjali4 1clinical biochemistry program, oman medical specialty board, muscat, oman; departments of 2ophthalmology and 3genetics, sultan qaboos university hospital, sultan qaboos university, muscat, oman; 4department of clinical biochemistry, college of medicine and health sciences, sultan qaboos university, muscat, oman.*corresponding author’s e-mail: fahadz@squ.edu. om objectives: this study aimed to carry out mutation analysis of the mcoln1 gene in two families with mucolipidosis type iv (mliv) and to screen for the identified mutation in the omani general population coming from the same region of the identified families in order to determine carrier frequency. methods: patients and families were ascertained clinically through the genetic and developmental medicine clinic at the sultan qaboos university hospital, muscat, oman. patients underwent clinical evaluation and laboratory investigations. they had corneal haziness; histologically intracytoplasmic inclusion bodies were found. their mri showed thinning of the corpus callosum. results: a novel mutation was identified (c.237+5 g>a) in all affected individuals, even though they are unrelated. the novel mutation was not detected through screening 1,280 individuals from the same geographical regions of the two families using hrmpcr, therefore mutation age could not be calculated. conclusion: a novel mliv causative mutation was found in the omani population. the absence of this variant among 1,280 healthy individuals from the same region support this variant being pathogenic. 2nd multidisciplinary scientific conference ibri regional hospital, ibri, oman 280 | squ medical journal, may 2023, volume 23, issue 2 inability to detect the mutation among screened individuals from the same region does eliminate the possibility of a founder effect, given the rarity of this disorder, yet with the same mutation implication in both unrelated families. the skin speaks inflammatory bowel disease said al farsi ibri regional hospital, ibri, oman. author’s e-mail: saeedalfarsi@gmail.com cutaneous manifestations of inflammatory bowel disease (ibd) are relatively common, although they vary widely. the presentation of only a skin lesion, for many years without gastrointestinal manifestation, make the diagnosis of ibd really challenging and delays proper management chances. studies of such presentations need to be addressed in different scientific areas. a case study from a gi clinic for prolonged skin manifestations of crohn’s disease (a type of ibd) was used, based on qualitative material, observation, testing and examinations, with review of literature. the study also used patient file documents from different health facilities over a period of six years prior to diagnosis, with the use of laboratory studies and imaging. finally, a review of the biopsy samples taken during the period of illness was undertaken. the case study of a 25-year-old patient who manifested with a skin disorder over six years and underwent multiple laboratory and imaging studies with the use of endoscopy service, was later diagnosed with systemic ibd. the use of tissue biopsy during colonoscopy was the cornerstone for diagnosing the patient’s disease, who was successfully treated using biological therapy which led to the resolution of her symptoms. this is a case of cutaneous crohn’s disease, which was missed due to a rare presentation and manifestation of the disease. a complete change in management plan was needed to treat such a case. the use of colonic biopsy eases the diagnosis and may initiate a new treatment plan. cardiopulmonary resuscitation-induced consciousness: case series report and ethical, legal and social aspects overview nasser alazri, khadija alshukaili, noora alsukaiti, *waleed alsukaiti, emergency department, ibri regional hospital, ibri, oman. *corresponding author’s e-mail: waleed.als.uk.aiti@gmail.com death is a unique human experience that is flooded with very strong emotions and carries many ethical, legal and social aspects (elsa) with it; cardiac arrest is a significant public health concern whether it’s outor in-hospital cardiac arrest, with approximately 500,000 cases reported annually in the usa. we report two cases of cardiopulmonary resuscitation–induced consciousness (cpric) that presented to the emergency department of a secondary hospital over a period of one year. a 57-year-old female presented with a one-hour history of typical chest pain. manual cpr was immediately started as per the advanced cardiac life support protocol. approximately five seconds after receiving the first direct current (dc) shock, the patient opened her eyes, started to move both arms in an attempt to push the rescuers away and she was biting the tube while endotracheal intubation was attempted. the ‘consciousness manifestations’ during cpr lasted for no longer than five seconds; cpr was continued for 20 mins but no return of spontaneous circulation was achieved. a 54-year-old male was escorted from a general practitioner clinic to the emergency department with 2-hour duration of central chest pain. his electrocardiogram (ecg) showing inferior st-segment elevation myocardial infraction. after the ecg, the patient’s blood pressure dropped and he became unconscious with no pulse. cpr started and dc shock delivered for ventricular fibrillation. the patient regained ‘consciousness’ and flexed his upper limbs and tried to push the face mask away. chest compressions were stopped immediately and carotid pulse was checked. he was pulseless and the patient stopped moving shortly after stopping the chest compressions. cpric is still under reported. this phenomenon needs to be properly understood in terms of its elsa aspects. such events should be reported during cpr as this will aid in further investigation and literature enrichment. blood supply chain: an analysis of diverse clinical conditionsin light of the importance of laboratory techniques and transfusion issues a retrospective analysis of hospital-based incidents amani al waili1 and *mohammed a. al shuhoumi2–4 1laboratory department, khoula hospital, muscat, oman; 2laboratory department, ibri hospital, ibri, oman; 3oman college of health sciences, muscat, oman; 4center of studies and research, muscat, oman. *corresponding author’s e-mail: mls971.ihs@gmail.com a blood transfusion is a medical treatment that has the potential to save a person's life. errors and consequences in blood transfusion can occur at any stage, from blood collection through to the blood transfusion itself; laboratory practices are critical in preventing such negative results. this case study aimed to give an analysis of diverse clinical scenarios based on clinical history and blood inventory. two instances had clinically significant antibodies (anti-d and anti-fy), indicating a high risk of developing haemolytic disease of the fetus and newborn or delayed haemolytic transfusion reaction. other situations were compounded by pre-existing irregularities. the findings demonstrated that laboratory techniques have a high benefit in decreasing and avoiding transfusion-related adverse outcomes. evidence stresses the need of continual development, technical training and adherence to all hospital departments’ directives in the complex pathway of blood delivery. improving blood transfusion safety for thalassaemia patients with frequent adverse reaction by using leukocyte reduced red cell transfusion: case series *said al sawafi,1 latifa al mamari2 1laboratory department and 2pediatric ward, ibri regional hospital, ibri, oman. *corresponding author’s e-mail: saeedalsawafi@hotmail.com objectives: patients on regular blood transfusion have frequent transfusion adverse reactions associated with fever and some other allergic symptoms such as anaphylaxis. this study aimed to investigate the use of leukoreduction of red blood cells (rbcs) which are considered one of the common blood component modifications that help to reduce the risk of a post-transfusion reaction among patients on regular transfusion. methods: a group of thalassaemic patients who had multiple episodes of post-transfusion adverse reactions, were monitored in each transfusion event; including the period of transfusion with unfiltered rbcs and the period of transfusion 31 december 2022 conference abstracts | 281 with several units of leukocyte-reduced rbcs in a secondary healthcare institution. the monitoring included current observation by the medical care team; during and after transfusion and home care observation. the study took place over 48 months and data were collected from blood bank monitoring modules of the alshifa 3plus programme, post-transfusion incident reports and clinical information collected by clinicians and the medical care team. results: the incidents of post-transfusion adverse reactions dropped to 16% with the use of leukocyte-reduced rbcs. particularly, the incidence associated with patients who were expected to have febrile nonhaemolytic transfusion reactions in which the reaction incidence decreased to 0%. furthermore, allergic reactions significantly reduced after receiving leukocyte-reduced rbcs. conclusion: these findings suggest that the use of leukocyte-reduced rbcs can provide safe blood transfusion for patients on regular transfusion associated with multiple episodes of post-transfusion adverse reactions. what is the risk of lower gastrointestinal bleeding associated with selective serotonin reuptake inhibitors? bushra al jassasi pharmacist, ibri regional hospital, ibri, oman.author’s e-mail: bushra.aljssasi@gmail.com paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-ht, serotonin) uptake and its antidepressant action. serotonin is associated with increased bleeding tendency. selective serotonin reuptake inhibitors (ssris) would deplete platelet serotonin, leading to a reduced ability to form clots and a subsequent increase in the risk of bleeding. we report the case of a 37-year-old female with no medical history other than psychiatric disorders, presenting with lower gastrointestinal bleeding after four months of paroxetine use. a retrospective analysis of patient records available via alshifa plus-3 programme was undertaken. informed consent was obtained from the closest next ken of the patient. the scarce literature available suggests that paroxetine in particular, increases the risk of lower gastrointestinal bleeding. interestingly, this case was found in consistency with the reported literature, the termination of ssri resulted in full recovery of the patient. thus, strengthening the available evidence that ssri may result in lower gastrointestinal bleeding. to conclude, lower gastrointestinal bleeding is rarely reported; careful monitoring is highly recommended during the initial period of use. autologous platelet-rich plasma therapy for diabetic foot ulcer: case series amr elborgy1 and *said al sawafi2 1surgical and 2laboratory department, ibri regional hospital, ibri, oman. *corresponding author’s e-mail: saeedalsawafi@hotmail.com objectives: over recent years, great progress has made in the techniques of wound healing, for example via autologous platelet-rich plasma (prp). the growth factors are able to produce granulation tissue and to induce epithelialisation by the production of neo-vessels, attraction of fibroblasts and mesenchymal cells, secretion of collagen fibres and by proliferation of keratinocytes. this study aimed to evaluate the effect of concentrated prp on diabetic foot ulcer (dfu) healing. methods: this study included six patients with chronic diabetic foot ulcer; type 1 and type 2 diabetes patients who controlled their diabetes by either medication or insulin were included. grade 1a wound without tendon, capsule, or bone involvement and also without association infection or ischaemia were targetted. prp was prepared by isolation from the patient’s peripheral blood into multiple citrated vacutainers. prp was injected to the edge of the ulcer and covered with sterile dressing. all patients were monitored once in a week. the rate of healing of the ulcer was determined by measuring the ulcer’s dimensions via metric tapes at initial visit and at each visit. results: more than 80% (n = 5) of the ulcers were completely healed after approximately four weeks of prp therapy. all treated patients developed granulation tissue and, ultimately, the wound at the ulcer site closed. no adverse effect or re-infection was reported after each prp administration. conclusion: prp is a effective method which can be used to treat dfu; it can be considered as the most promising method to treat a dfu in terms of healing rate. multi-drug resistant organism prevalence: a five years’ experience from a secondary healthcare institution covering all clinical samples *mohammed a. al shuhoumi,1–3 suleiman al ghafri,1 fareed j. hameed,1 asma al hinai,1 abir al ghafri,1 sathiya raj mony,1 bader al swawafi,1 gopinath govindaraj,1 asma al yaqoobi,1 abdulrahman al mhrooqi1 1laboratory department, ibri hospital, ibri, oman; 2oman college of health sciences, muscat, oman; 3center of studies and research, muscat, oman. *corresponding author’s e-mail: mls971.ihs@gmail.com objectives: this study aimed to describe the prevalence and trends of multi-drug resistant organisms (mdros) from clinical samples at ibri hospital, ibri, oman, from 2017–2021. methods: this retrospective cohort study gathered data extracting laboratory culture results for all clinical samples from hospital information system. all non-clinical samples (i.e. screening) were excluded. only mdros were included and used for calculation of prevalence per 1,000 admissions to the hospital. ethical approval was obtained from the regional research ethical committee. results: the overall mdros per 1,000 admission was 25.7 in 2017 which steadily increased until it reached 31.6 in 2021. the gram-negative bacteria continued to be the majority of all mdro cases over the five-year study period with approximately 80% with gram-positive constituting approximately 20%. extended spectrum beta-lactamase (esbl) escherichia coli was the leading mdros and was approximately twice a frequent as the next mdro species. e.coli was followed by mdr acinetobacter and esbl klebsiella pneumoniae in prevalence. vancomycin-resistant enterococci were extremely rare until a spike was seen in 2021 due to an outbreak during the covid-19 pandemic but this returned to its baseline after the height of the pandemic. conclusion: antimicrobial resistance is a growing problem in healthcare. we reported prevalence of mdros at a secondary care hospital. there were much more mdros than gram-positive. e. coli remains the leading mdro at the current hospital. blood transfusion errors, could be eradicated? improving transfusion safety: a case report *mohammed a. al shuhoumi,1–3 said al sawafi,1 bader al sawafi,1 badryia al alawi1 1laboratory department, ibri hospital, ibri, oman; 2oman college of health sciences, muscat, oman; 3center of studies and research, muscat, oman; *corresponding author’s e-mail: mls971.ihs@gmail.com an old practice was carried on that allows nurses to enter the laboratory to retrieve blood units, where blood issuing services was 2nd multidisciplinary scientific conference ibri regional hospital, ibri, oman 282 | squ medical journal, may 2023, volume 23, issue 2 an attached unit with blood bank crossmatching, and other essential testing procedures on the same working bench. therefore, it is essential to establish a more safe and confusion-free transfusion process. this report used four tools: spaghetti diagram, 5s audit, 8 types of waste and a survey. the first three tools provided a holistic view of the current lab deficiencies so problems can be detected, traced and solved. the circulated survey was used to test the degree of satisfaction among laboratory and nursing staff. after the goals of the initiation were fulfilled, blood bank issuing services are now physically separated near the laboratory’s reception without having to go inside the laboratory; this allows for a more sustainable plan. there is a rapid and confusion-free issuing process, biohazard related contact of external staff is reduced to a minimum and more space is saved allowing the laboratory to upgrade and expand services. this evidence emphasises the importance of continuous development, operational training, compliance to instructions of all healthcare workers in the complex pathway of blood delivery and the attempt to create a safe environment even with limited resources despite advanced technologies that are meant to streamline transfusion practices. anti-inflammatory effects of n-3 polyunsaturated fatty acids in thp-1 macrophages: promising in-vitro insights hamed s. al hinai,1 sam hooper,2 steve potter,2 sulaiman a. al alawi,3 *mohammed a. al shuhoumi,4–6 dorel anna2 1laboratory department, ibri hospital, ibri, oman; 2cardiff metropolitan university, cardiff, uk; 3ministry of health chemical pathology laboratory, royal hospital, muscat, oman; 4laboratory department, ibri hospital, ibri, oman; 5oman college of health sciences, muscat, oman; 6center of studies and research, muscat, oman. *corresponding author’s e-mail: mls971.ihs@ gmail.com objectives: this study aimed to determine how eicosapentaenoic acid (epa) and docosahexaenoic (dha), two polyunsaturated fatty acids (pufas), affect the inflammatory responses in lps-stimulated thp-1 macrophages. methods: epa and dha were treated with cells for 24 and 48 hours, respectively. to ascertain the vitality of cells both before and after incubation, cell viability tests were utilised. the expression levels of inflammatory cytokines were examined using an enzyme-linked immunosorbent assay and dose amounts of 0.09 and 0.45 mm for both epa and dha. all data were given as sem, submitted to the anderson and pearson tests for normality; a one-way analysis of variance test was used to assess the statistical significance of the difference. results: in lps-stimulated thp-1 cells treated with 0.09 mm dha, there was a drop in the levels of il-6; this reduction was higher at 0.45 mm dha (p = 0.001). additionally, dha did not significantly alter the inflammatory cytokines tnf-alpha compared to cells alone (p = 0.001). when exposed to epa, lps-stimulated thp-1 cells only significantly decreased interleukin-6 and tumour necrosis factor-alpha at the higher dosage and did not exhibit a statistically significant change at 0.09 mm (p = 0.001). conclusion: pufas, such as epa and dha, might inhibit the production of inflammatory cytokines. dha is a more effective anti-inflammatory drug, suggesting that it may be a useful marker in the battle against chronic illnesses. the effectiveness of intrauterine blood transfusion in treating haemolytic disease of the fetus and newborn caused by red blood cell alloimmunisation *mohammed a. al shuhoumi,1–3 suleiman s. al ghafri,1 sumayia s. al mamri4 1laboratory department, ibri hospital, ibri, oman; 2oman college of health sciences, muscat, oman; 3center of studies and research, muscat, oman; 4laboratory department, saham hospital, saham, oman. *corresponding author’s e-mail: mls971.ihs@gmail.com objectives: due to maternal red cell alloimmunisation, haemolytic disease of the fetus and newborn (hdfn) spread widely around the world, leading to an increase in death and morbidity rates. by giving the fetal blood that is compatible with it, intrauterine transfusion (iut) is one of the treatments used to treat fetuses with hdfn and therefore enhances the likelihood of survival. this study used a systematic assessment of published studies to assess the efficiency of iut in relation to the likelihood that afflicted fetuses would survive and the occurrence of hydrops. methods: this systematic review included four powerful studies from pubmed that were further validated by a quality assessment tool. results: with the availability and use of iut, the prognosis of hdfn and neonatal outcomes improved dramatically. the survival percentage improved dramatically from the numerous trials considered in this research and varied between 81% and 100%. in competent hands, procedure-related problems are as low as 1.2% per surgery, with a 0% loss rate. nonetheless, fetal loss prevention can be technically tackled in situations requiring early intravascular iut, and methods for early referral identification and antibody detection must be built to avoid or decrease the severity of hydrops. conclusion: intrauterine blood transfusion is regarded as a safe and effective treatment for treating hdfn induced by red cell alloimmunisation, resulting in improved neonatal outcomes due to decreased incidence of procedure-related complications. use of castor beans as laxatives: case series and visits to herbal stores *waleed s. al sukaiti,1 amani al kalbani,1 suad al abri2 1emergency department, ibri regional hospital, ibri, oman; 2sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: waleed.als.uk.aiti@gmail.com castor beans, which are known as a traditional treatment for constipation, are easily available at herbal shops. these beans contain ricin in their pulp. ricin is one of the most toxic substances known to human. it was hypothesised that the use of castor beans for treating constipation is broadly practiced under uncontrolled measures and by inadequately educated herbal sellers. we report two cases of ricin toxicity following castor bean ingestion at two centers in oman. additionally, five herbal stores were visited seeking constipation treatment. the two cases showed signs of intoxication within the first hour of ingestion. three out of five herbal stores offered castor beans as laxatives without offering poisoning education. these findings support that castor beans are frequently used in the community as a treatment for constipation, with the failure to provide th necessary precautions by the provider. severe anticholinergic toxicity from datura stramonium: case report azza al qamshouai, talal m. al abri, *waleed s. al sukaiti emergency department, ibri regional hospital, ibri, oman. *corresponding author’s e-mail: waleed.als.uk.aiti@gmail.com datura stramonium (also known as jimsonweed) is a poisonous plant which grows all over the world. it has been used in alternative medicine, especially in ayuvada, in the formulation of many drugs. the seeds and the flower are toxic in nature; it contains a variety of poisonous substances such as tropane, alkaloids, atropine, hyoscyamine and scopolamine. we report a 65-year-old patient who was brought to the emergency department with acute mental status changes after consumption of two entire fruits of jimsonweed in a 31 december 2022 conference abstracts | 283 trial attempt for treatment of his high blood pressure. the patient presented with confusion, tachycardia and tachynpnoea with high blood pressure and raised body temperature. the patient was clearly showing an acute presentation of anticholinergic toxidrome due to jimsonweed and was subsequently admitted and started on multiple doses of benzodiaspines and hydration therapy which led to recovery. this plant contains anticholinergic alkaloids which act on acetylocholine at the postganglionic parasympathetic muscarinic receptor in salivary glands, smooth muscle, heart, eye and central nervous system. the management of jimsonweed toxicity is mainly supportive. consumption of local plants are not uncommon as alternative medicine. the recognition of toxicity from such plants is important to guide therapy. biofilm formation and antibiotic resistance: an ongoing challenge? amani al waili1 and *mohammed a. al shuhoumi2,3,4 1laboratory department, khoula hospital, muscat, oman; 2laboratory department, ibri hospital, ibri, oman; 3oman college of health sciences, muscat, oman; 4center of studies and research, muscat, oman. *corresponding author’s e-mail: mls971.ihs@gmail.com objectives: in order to reduce the process and have an efficient therapy, biofilms appear to be a crucial virulence factor that strengthens bacterial colonisation in medical devices and live tissues. this study aimed to examine the relationship between antibiotic susceptibility and biofilm development. methods: a total of 96-well-plate assays were used to evaluate biofilm formation in five different organisms. one-way analysis of variance and the tukey post-test were used in statistical analysis to highlight significant differences between the tested bacterial strains. antibiotic susceptibility testing was conducted using the european committee on antimicrobial susceptibility testing (eucast) disk diffusion test. results: the study showed variation in biofilm formation by a large number of bacteria; it also looked at the similarities between clinical and laboratory standards institute (clsi) and eucast during the experiment which demonstrated equivalent antimicrobial susceptibility testing (ast) breakpoints across eucast and clsi which found in consistency with the literature. due to the fact that eucast is publicly available, it makes it simple for laboratories in underdeveloped regions and with limited funding to use. conclusion: due to the heightened prevalence of antibiotic resistance, biofilms now present a serious problem for microbiologists and public health. patients with indwelling devices are shown to be complicated by it. therefore, a better understanding of biofilms and their role in infectious illnesses can enhance clinical decision-making. retrieval of dislodged central venous pressure catheters early experience with three case presentations *hafidh al-hadi,1 mansour sallam,1, 2 case report squ med j, august 2009, vol. 9, iss. 2, pp. 175-179, epub 30th june 2009 submitted 9th nov 08 revision req. 21st mar 09, revision recd. 4th may 09 accepted 11th may 09 اسرتجاع اجلزء املنفصل من قساطر الضغط الوريدية املركزية اخلربة األولية مع تقرير لثالث حاالت حفيظ الهادى، منصور سالم حالة وفى القسطرة، هذه من جزء ينفصل ما السريرية. نادرا الطبية املمارسة فى بكثرة املركزية الوريدية الضغط قساطر تستخدم امللخص: فشل استرجاع هذا اجلزء املنفصل بواسطة القسطرة القلبية عن طريق اجللد ، فان جراحة القلب املفتوح تكون ضرورية السترجاع هذا اجلزء املكسور لتجنب حدوث مضاعفات محتملة. هذا التقرير يصف خبرتنا األولية في مستشفى جامعة السلطان قابوس باسترجاع اجلزء املكسور من قساطر الضغط الوريدية املركزية عن طريق ثالث طرق مختلفة: األولى، عن طريق القسطرة القلبية باستخدام الشراك )الفخ(، والثانية عن طريق جراحة الصدر فقط ، أما الثالثة فتكون عن طريق جراحة القلب املفتوح أثناء عمل توصيالت للشرايني التاجية. نود أن نذكر هنا بامكانية استرجاع األجزاء املنفصلة من قساطر الضغط الوريدية املركزية التي تستقر في اجلهة اليمنى من القلب أو الشريان الرئوي عن طريق القسطرة القلبية باستخدام الشراك. مفتاح الكلمات: قساطر الضغط الوريدية املركزية ، انفصال، القسطرة القلبية، الشراك، أشعة الصدر، الشريان الرئوي، تَْخطيُط َصَدى الَقلْب،تَْنظيٌر تَأَلُِّقّي، تقرير حالة. abstract: central venous catheters )cvp( are frequently used in clinical practice. occasionally, catheters may become dislodged. if percutaneous retrieval fails, then cardiothoracic surgery is necessary to retrieve the fractured catheter and avoid potential complications. this report describes early experiences of three different modes of broken catheter retrieval: the first by use of a snare catheter; the second by surgery and the third during bypass surgery. we conclude that broken fragments of catheters that lodge in the right side of the heart or pulmonary circulation can be retrieved most of the time percutaneously by snare catheters. keywords: central venous pressure )cvp(; dislodgement, percutaneous; snare catheter; chest x-ray, pulmonary; 2d echocardiography; fluoroscopy; case report. 1department of medicine, sultan qaboos university hospital, muscat, sultanate of oman; 2al-azhar university, al-hussein hospital, cairo, egypt. *to whom correspondence should be addressed. email: halhadi@hotmail.com central venous pressure (cvp) catheters are frequently used in clinical practice to monitor and guide further management of sick patients in coronary care units (ccus) or intensive care units (icus). this is essential to balance fluid and drug requirements. breakage of the catheters with the intravascular fragment migrating centrally as a foreign body embolus has been reported and is associated with potentially serious complications.1-3 fortunately this is usually a rare incidence. 4 most often, the intravascular fragments become lodged within the right side of the heart where they may induce sepsis, thrombosis, perforation, or endocarditis.4-5 in other instances, the intravascular fragment lodges more distally within the main pulmonary artery or one of its branches carrying the risk of pulmonary infarction.5 many intravascular techniques have been developed to retrieve fractured catheters such as intravascular forceps and basket retrievals; however, the most commonly used device is the intravascular snare.6-7 snares and baskets have the ability to grasp the catheter fragment firmly and securely allowing it to be pulled out percutaneously through the access site. failure of such intravascular techniques to retrieve the fracture catheters results in surgical interventions to avoid the potential complications.7 this report describes our early experience in this rare complication of catheter dislodgement and the different modes of their restoration. retrieval of dislodged central venous pressure catheters early experience with three case presentations 176 | squ medical journal, august 2009, volume 9, issue 2 case one a male patient, 45 years old, was admitted with symptoms of heart failure to the ccu for the purpose of close haemodynamic monitoring. a central venous pressure (cvp) catheter was inserted via the right subclavian vein. after haemodynamic improvement, an attempt to remove the cvp catheter was done. however, the hub totally separated from the shaft of the catheter and migrated to the right ventricle as proved by urgent chest x-ray. within one hour, the patient was shifted to the catheterisation laboratory. fluoroscopy proved the fast migration of the fractured catheter into the main shaft of right pulmonary artery. the patients’ right common femoral vein was accessed and a 6f 13cm long sheath was inserted. a 6f right judkin’s guiding catheter was advanced over a 0.035 inch guide wire to the right pulmonary artery. then the guide wire was withdrawn. a ‘noose neck nitinol snare retrieval catheter (microvena, minnesota) [figure 1] was introduced through the right judkin’s catheter. the snare was manipulated to the distal end of the dislodged catheter. after three attempts, the snare successfully caught the dislodged catheter fragment. the snare together with the secured catheter fragment was pulled back to the guiding catheter then to the level of femoral sheath. the vascular sheath, guiding catheter and the snared catheter fragment were then withdrawn as a unit out through the skin of the right groin and haemostasis was achieved manually. the retrieved fragment catheter was 9 cm long. fluoroscopic examination of the inferior vena cava, heart and pulmonary arteries revealed no residual catheter fragments. the entire procedure was accomplished successfully in 25 minutes. case two a female patient, 55 years old and a known diabetic with hypertension and chronic renal failure, was on regular haemodialysis. she was referred from a secondary hospital with a history of a right subclavian cvp catheter dislodged 6 hours previously. a chest x-ray confirmed that the dislodged catheter had impacted in the left pulmonary artery. immediately, the patient was transferred to the catheterisation laboratory. initial fluoroscopic imaging with small amounts of contrast showed that the fractured catheter was deeply impacted in the subpulmonic branches of the left pulmonary artery. using the same technique described above, many attempts were made to snare the fractured catheter, none of them successful. a 6f pigtail catheter was also used to attempt to free the catheter from its impacted position without success [figure 2]. after approximately two hours, all attempts to free the broken fragment had failed. the guiding catheter was withdrawn followed by the snare catheter and then the vascular sheath; haemostasis was achieved manually. after explaining the risks of an impacted fractured catheter and the risks of surgical removal through thoracotomy, the patient and family agreed to an attempt to retrieve it surgically. this was accomplished successfully with no complications. the surgical report confirmed that the fractured catheter, which was 13 cm long, was deeply impacted in the small branches of the left pulmonary artery and so it was theoretically very difficult to retrieve it with a percutaneous snare. figure 1: shows snare catheter, which is the most common technique used to retrieve broken catheter fragments figure 2: shows standard 6f pigtail catheter, which is used sometimes to dislodge deeply impacted or entrapped fragments of broken catheters. hafidh al-hadi and mansour sallam case report | 177 case three a male patient, 62 years old, was a known hypertensive, diabetic, dyslipidaemic and a heavy smoker. he was referred from a district general hospital for coronary angiography after an attack of acute myocardial infarction complicated by left ventricular failure one month prior to his admission in our hospital. the patient gave a history suggestive of cvp catheter insertion through the right jugular vein for a few days during admission in the district hospital. he was asymptomatic at rest and was haemodynamically and clinically stable, but had mild effort-induced chest pain and shortness of breath. surprisingly, a routine chest x-ray did not reveal the broken catheter [figure 3]. the terminal catheter position was confirmed by 2d echocardiography which showed a radio-opaque indwelling catheter tip protruding into the posterior aspect of the right atrium (ra) [figure 4]. coronary angiography fluoroscopic imaging clearly showed a long catheter that moved with each heart beat with its superior end originating from the superior vena cava and inferior edge ends in the ra [figure 5]. during coronary angiography, we noticed the ’unusual’ frequent catheter thrombosis that required a generous 7000 units of intravenous heparin and catheter exchange. coronary angiography revealed extensive multiple vessel coronary artery diseases (cad) requiring bypass surgery. it was decided to retrieve the catheter fragment surgically for the following reasons: 1) the catheter has been dislodged for more than a month and could be adherent to the posterior aspect of the ra; 2) the possibility of significant thrombus formation around the catheter could not be ruled out, which would make it difficult and hazardous to snare; 3) the patient was asymptomatic, and 4) he anyway required emergency coronary artery bypass surgery (cabg) during the index admission. during the bypass surgery, the surgeon retrieved the broken catheter through a small incision in the right atrium. the catheter, which was 12 cm long, was surprisingly not adherent to the myocardial tissue and was retrieved successfully and intact [figures 5 & 6]. discussion many techniques have been developed to retrieve intravascular fragments from fractured central venous catheters. the most commonly used techniques are the use of an intravascular snare to capture and retrieve the loose catheter fragment [figure 1]. this minimally invasive technique is feasible when at least one free end of a fractured catheter is accessible. in some cases, snare removal of a foreign body may be extremely difficult, especially when both ends are fixed or entrapped and thus impossible to grasp. in such instances, one may attempt to release one end of the impacted catheter by using another catheter with a bent tip e.g. a pigtail catheter [figure 2]. if, however, both ends of the dislodged catheter are adherent to the vessel wall or are fixed inside a thrombus, then technically successful retrieval may not be possible figure 3: there was no obvious foreign body that could be identified with any certainty on this routine chest x-ray. figure 4: this is a modified echocardiographic view showing the radio-opaque catheter tip protruding into the posterior aspect of the right atrium. the arrow points to the tip of the catheter fragment. retrieval of dislodged central venous pressure catheters early experience with three case presentations 178 | squ medical journal, august 2009, volume 9, issue 2 and the alternative safer option is surgical removal. the broken catheter of the first patient had been notified immediately within one hour and the intravascular retrieval attempt was carried out successfully. the time factor seems to be of paramount importance. however, as shown in the second and third cases, it is not the only factor. the size of the broken catheter and the distance it can migrate distally, i.e. become impacted, can also have an important influence. the second patient represented a challenge despite the relatively short time (6 hours) after the incident. the many intravascular attempts failed to retrieve the damaged catheter. unfortunately, major surgery thoracotomy had to be undertaken to remove the catheter. during surgery, the broken catheter was found to be deeply impacted into the branches of the left pulmonary artery. in the third patient, the dislodged catheter was discovered accidentally. he was lucky enough, in the sense that he had not suffered major complications such as thrombotic embolism or serious infection. he also had another indication for a thoracotomy which was the planned cabg due to his extensive multi-vessel coronary artery disease (cad). owing to the long duration of the dislodgement (one month), there was some concern that the fragment could have caused significant in-situ thrombosis or might be quite brittle and subject to additional breakage when tension was applied to the snare. consequently, to avoid such complications and as the patient was planned for open heart surgery anyway, a direct visual removal of the impacted catheter was seen as the right option. conclusion broken cvp lines are fortunately a rare incidence; however, their occurrence is associated with significant morbidity and mortality. all intravascular cvp catheters should be removed gently and the terminal end inspected carefully to avoid missing dislodged fragments. if identified, such complications should be notified immediately. foreign bodies that break and lodge accidentally in the right side of the heart or in the pulmonary vasculature can be retrieved through percutaneous approaches. if these methods fail, then surgical removal via thoracotomy is the alternative option. the time lapse from catheter dislodgement to retrieval is of paramount importance to avoid figure 6: shows a picture of the fractured cvp catheter recovered after surgery. figure 5: the position of the broken catheter is pointed out with an arrow in these two different angiographic view. hafidh al-hadi and mansour sallam case report | 179 adhesions or thrombus formation and the occurrence of distal migration or deep impaction. our cases show that when broken catheters are identified early, percutaneous or surgical retrieval is a feasible option. references 1. thomas j, sinclair-smith b, bloomfield d, davachi a. non-surgical retrieval of a broken segment of steel spring guide from the right atrium and inferior vena cava. circulation 1964; 30:106-8. 2. doering rb, stemmer ea, connally je. complications of indwelling venous catheters with particular reference to catheter embolus. am j surg 1964; 114:259-66. 3. wellman kf, reinhard a, salazar ep. polyethylene catheter embolization. circulation 1968; 37:380-92. 4. simon-fayard ee, kroncke rs, solarte d, peverini r. nonsurgical retrieval of embolized umbilical catheters in premature infants. j perinatol 1997; 17:143-7. 5. massin m, lombet j, rigo j. percutaneous retrieval of broken silastic catheter from the left atrium in a critically ill premature infant. catheter cardiovasc diagn 1997; 42:409-11. 6. weisel ab, moschos cb, levinson el, regan tj. snaring of a broken sommer pacemaking electrode. ann intern med 1970; 72:695-7. 7. abbruzzese pa, chiappa e, murru p, stefanini l, longo s, balagna r. surgical retrieval of an embolized central venous catheter in a premature baby. ann thorac surg 1998; 66:938-9.  foreign bodies in the upper aero-digestive tract * mur ty psn, vijendra s ingle, ramakrishna s, fahim a shah, varghese philip department of ent, ibri regional referral hospital, p.o. box , p.c: , ibri, sultanate of oman. *to whom correspondence should be addressed. e-mail: sumam@omantel.net.om abstrac t. foreign bodies in the upper aero-digestive tract pose major challenges to the otolaryngologist in both diagnosis and management. aspirated and ingested foreign bodies are often emergencies, leading to inadequate study and poorly prepared, improper attempts at removal. the authors share their experience in managing upper aero-digestive tract foreign bodies in omani population at a district hospital, present a statistical review of  cases, and highlight certain critical scenarios as well as cultural variations specific to the region. keywords: foreign body, aero-digestive tract, bronchoscopy, oesophagoscopy, oman a       the upper aero-digestive tract, either acciden-tally or deliberately, oen constitute otolaryngologic emergencies. e type of the foreign body and the site of obstruction depend on various factors. foreign body aspiration is commonly seen in children. e cases present with a wide spectrum of clinical problems. in general the treatment of a foreign body in the upper aero-digestive tract is a reasonably prompt endoscopic removal under conditions of maximum safety and minimum trauma.1 e authors, working in a district level hospital, retrospectively reviewed cases of  patients who underwent peroral endoscopy under general anaesthesia for the retrieval of foreign bodies for alleged aspiration or swallowing, from june ,  to may , . e findings of the review are tabulated in tables –. from among these, the more challenging cases and culturally specific ones are highlighted below. • two cases involved sharp and irregular foreign bodies detected below the cricopharyngeus—a glass piece and a thick bone—which could not be negotiated through sphincter because of their size, shape and possible trauma     :   , : , : , – ©   figure . radiograph showing a coin in the food passage.   to the mucosa. since shears were not available, the authors took the decision to push these objects under vision into the stomach. ey were able to do this without untoward complication. • another case where the right equipment was not available was that of a two-year-old boy. at neonatal stage, the child had undergone repair of a tracheo-oesophageal fistula, which now presented with bolus obstruction in the oesophagus over an acquired stricture at the site of repair. a  mm bronchoscope, for want of an oesophagoscope, was passed and the bolus was removed piecemeal from the oesophagus. • a one-year-old child was admitted with complaints of dysphagia and change in the voice since  days. as there was no history of foreign body aspiration, she was treated conservatively with antibiotics and steroids. non-response to medications prompted the authors to conduct an endoscopic examination that revealed a pistachio shell seed in the postcricoid area. it was removed. • a -year-old child was admitted with recurrent lower respiratory tract infections. clinical and radiological examination confirmed a right-sided lung collapse. bronchoscopy under general anaesthesia showed a watermelon seed in the right main bronchus, which was successfully removed. • among the cases involving adults was that of an expatriate, a known diabetic, who presented with a fishbone impaction in the hypopharynx, associated with a retropharyngeal abscess. e abscess was drained endoscopically and the foreign body removed. four days aer the operation he had a re-collection in the retropharyngeal space, necessitating a repeat endoscopic drainage. • in another adult case, a -year-old woman was brought in cyanosed. immediate resuscitation was attempted. laryngoscopy showed a mutton bone impaction in the hypopharynx, which was removed. e patient subsequently developed pulmonary oedema and was intubated and put on ventilator. she was slowly weaned off the ventilator and extubated. • ingestion of scarf pins, used to keep head-scarves in place, is peculiar to the region. eight cases of scarf pins ( in the airway and one in the stomach) were encountered in this study [figures  and ]. in one case the radiography showed the presence of the pin in the trachea. bronchoscopy and oesophagoscopy did not show any foreign body. on the table, c-arm exposure revealed the scarf pin to be in the stomach, and it successfully went through the digestive tract.               tracheobronchial foreign bodies were commonly seen in children whereas the food passage hosted foreign bodies in all the age groups. e right bronchus was more likely to have a foreign body than the le. scarf pins were the commonest. oesophagus had more foreign bodies than the hypopharynx. one out of  bronchoscopies (.) and / oesophagoscopies (.) were negative for the presence of foreign bodies. foreign body related complications such as retropharyngeal abscess, pulmonary oedema and lung collapse were seen in three patients (.). no complications accountable to endoscopy were encountered. d i s c u s s i o n foreign bodies cause problems if the site of their impaction is at the narrowest regions such as the glottis and the � �������������������������������������������������������������� ������������� ������� ������������� ������ ������ ��� ��� ��� ������ ��� ��� ��� ������ �� ��� ��� ������ �� ��� ��� ����� �� ��� ��� ������ ��� ��� ��� ������������������������������������������ ������� � ������������� �������� �� � ������������� ��� ����������� �� � ����������� �� ������������ �� � ������ �� ������� �� � ���������� �� ������ �� � ���������������� �� � � � �������������� �� � � � ������������� �� � � � ������������ �� ������ ��� � ������ ��� � ����������������������������� ������� � ������������� ��������������� �� � ����������� ��� �������������� �� � �������������� ������������� ��� �������� �� � ���������� �� ������ ��� � ������ ��� � �            cricopharyngeal sphincter. aspirated and ingested foreign bodies can lead to potential complications because of their shape, size and site of impaction. as we encountered ourselves, foreign body aspiration is much more common in children, with a peak incidence in the third year. oesophageal foreign bodies are more likely in adults. both males and females are equally affected.2 various factors can be responsible for the aspiration or swallowing of foreign bodies. e increased incidence in small children could be due to their natural propensity to gain knowledge by putting things in the mouth, inability to masticate well and inadequate control of deglutition, as well as the tendency to cry, shout, laugh or play during eating. psychological factors like mental retardation, behavioural disorders, anxiety neurosis and hyperkinetic syndrome also can compound the problem.3 e maturity of an adult larynx may account for the relatively lower incidence of tracheobronchial foreign bodies, but possibly increases their chance of slipping into the oesophagus. significantly, / of our patients with oesophageal foreign bodies were aged >. edentulousness and poor masticating habits are also predisposing factors.         foreign body aspiration is the most common cause of home deaths in children under the age of . e highest incidence of aspiration occurs between – years.4 e patients oen present to the emergency room with acute respiratory distress or even in a cyanosed state. at the other end of the spectrum is the patient who walks in with nothing more than a history of aspiration and on investigation is found to have a foreign body in the bronchus. in between are a whole range of patients with persistent cough, pneumonitis or non-resolving lung pathology. e authors removed a range of foreign bodies from the airway, such as nuts, seeds, whistles and metallic objects. scarf pins were rather unusual foreign bodies—and specific to the region—to be found in the tracheobronchial tree.5 small and smooth-walled objects tend to pass into trachea and bronchi whereas larger ones can cause acute laryngeal obstruction.6 e symptoms and the course of illness depends grossly on the type of the object and the length of its stay at the site of obstruction. most foreign bodies are found on the right side since the right main bronchus is wider, shorter and straighter than the le, and also because the interbronchial septum projects to the le.7 hassan et al opined that anatomical and aerodynamic considerations determine the site of final impaction.7 our clinical experience was an equal incidence in the right and le sides of the airway. a positive history, detailed clinical examination and radiographic search oen lead to a diagnosis, while negative history and/or normal chest radiographs can be misleading. successful retrieval of foreign bodies requires excellent teamwork between the endoscopist, anaesthetist and the nursing staff because the airway of the patient is tended by all these personnel. a well ventilated, unconscious and relaxed patient affords the best prospects for the successful removal of a foreign body from the airway. rigid bronchoscopy using ventilation bronchoscopes offers good visualization and is the preferred mode of treatment. as reported, flexible fibre-optic bronchoscopes also have good rate of success.8 e authors, however, have not used these.        foreign bodies can be impacted in the pharynx and the oesophagus mainly because of their size, shape and anatomical narrow segments. e oesophagus is a passive and unadaptable organ and its peristalsis is not strong enough to prevent its retaining certain types of swallowed objects.10 more adults than children tend to have impaction of bones in the pharynx and oesophagus. impacted coins, however, were more seen in children in this study. ingestion of dentures due to poor masticatory habits is usually seen in old age. patients usually present with history of swallowing a foreign body, dysphagia and/or odynophagia. plain radiographs of neck, chest and abdomen identify radio-opaque                                       figure 2. radiograph showing a scarf pin in the left main bronchus.  foreign bodies, while fluoroscopy using thin barium may be required to delineate non radio-opaque objects. potential complications include oesophageal perforation, mediastinitis, cervical or mediastinal abscess, emphysema, oesophago-tracheal fistula and septic complications.10 however, the authors did not encounter any of these. because the pharyngeal constrictors are usually strong enough to propel an object through the sphincter, and the oesophageal muscles are relatively weaker at pushing it downwards, foreign bodies usually impact below the cricopharyngeal sphincter. predisposing factors such as stricture, neuromuscular disturbance,11 hiatus hernia, peptic strictures, achalasia cardia or carcinoma oesophagus can oen present with foreign body impaction as their first symptom. ere was a child in this series who had a stricture formed aer the correction of a tracheo-oesophageal fistula. endoscopic removal of the foreign body to prevent complications is the first step in such cases. an impacted foreign body should be removed as soon as the diagnosis is made, because: (i) the chance of spontaneous passage is less for an impacted object, (ii) oedema due to local trauma tends to grip the object more firmly, making later manipulation increasingly difficult, and (iii) perforation of the oesophagus is much more serious and dangerous complication. c o n c l u s i o n from their experience, the authors recommend that no foreign body in the upper aero-digestive tract should be le alone with the hope that it will come out spontaneously. all the impacted foreign bodies should be, removed via peroral endoscopy as soon as possible. for the trauma and dangers caused by the foreign bodies can be minimised if parents are made aware of the risks and taught paediatric home care. a successful example is that of israel, where an intensive educational campaign through the media and community paediatric care, reduced foreign body aspiration by .12 r e f e r e n c e s . holinger ld. management of sharp and penetrating foreign bodies of the upper aero-digestive tract. ann otol rhinol laryngol , , –. . biswas b, datta r. retained oesophageal foreign bodies—report of three cases. indian journal of otolaryngology and head and neck surgery , spl no. on foreign bodies,–. . banerjee s. concept of the foreign body—its past and present. indian journal of otolaryngology and head and neck surgery. spl no. on foreign bodies, –. . brown da, clark cm. inhaled foreign bodies in children. med j aust , , –. . murthy psn et al. sharp foreign bodies in the tracheobronchial tree. am j otolaryngol (in press). . banerjee a, rao ks, khanna sk, narayanan ps, gupta bk, sekar jc et al. laryngo-tracheo-bronchial foreign bodies in children. j laryngol otol , , –. . hassan am, ghosh p, menon psn, kaul hl, mukhopadhaya s. changes in tracheobronchial angles as a function of age. indian journal of otolaryngology and head and neck surgery , , –. . cunanan os. e flexible fibreoptic bronchoscope in foreign body removal. experience in  cases. chest , , –. . nandi p, ong gb. foreign body in the oesophagus: review of  cases. br j surg , , –. . wilson rt, dean pj, lewis m. aortoesophageal fistula due to a foreign body. gastrointest endosc , , –. . bakara a, bikhazi g. oesophageal foreign bodies. bmj , , –. . sadan n, ras a, wolach b. impact of community educational programmes on foreign body aspiration in israel. eur j pediatr , , –.         the coronavirus disease 2019 (covid-19) pandemic has brought an unimaginable crisis to healthcare systems worldwide. the sarscov-2 virus is highly potent in transmission among community and healthcare settings. the cases of covid-19 have rapidly increased worldwide. the data reveals an average of 200,000 new cases every day and a global death toll of over 2.5 million at the time of writing this article.1,2 like other countries, oman has confirmed at least 143,955 cases and over 1,500 deaths in march 2021.2 restrictive measures such as physical distancing, visitor restrictions in healthcare facilities and burial and funeral restrictions have been implemented and strictly monitored. magnitude of the problem it is well-recognised that, sadly, many patients did not survive this pandemic.2 physical distancing and a hospital ban on visits make patients' death especially difficult; they suffer the disease alone and die in the hospital without their relatives' support. news of death is often regarded as the most painful event a family will receive and it is the start of the grief and grieving process.3–5 healthcare providers lack the knowledge and skills to provide care to grieving families. relatives are often found isolated and crying during the terminal phases of their loved one’s life.6 the increasing demand for palliative care palliative care, according to the world health organi zation, is: “an approach that improves the quality of life of patients and their families facing the problems associated with a life-threatening illness, through the prevention and relief of suffering by means of early ident ification and impeccable assessment, and treatment of pain and other problems: physical, psychosocial and spiritual”.7 the effectiveness and cost-effectiveness of palliative care, both in the hospital and at home, are well documented. it preserves patients’ rights and promotes patient-centred care.8,9 experts from king’s college london have produced worldwide projections of the future of palliative care. it is estimated that by 2060, 48 million people per year will die from severe health-related illnesses and 83% of these individuals will be from low and middle-income nations.10 during the pandemic, it became more evident that palliative care is an ethical imperative. it is globally recognised that palliative care is a health system strengthening intervention. evidence suggest that palliative care services have a role to play in supporting the wider health system and a survey in the middle-east region has shown that palliative care services have the capacity to support the wider health system with additional support and resources.11,12 palliative care successfully supports the acute medical management plan by addressing the collective suffering of covid-19 patients and tailoring curative options according to the needs of the individuals. in particular, those who rapidly deteriorate and those who are not suitable for admission to the intensive care unit, all being attained within a context of maintaining human rights.13,14 moreover, the large disease burden of covid-19 and implementation of restrictive measures to contain the spread of coronavirus also have complicated issues of grief and bereavement process for patients, their families and healthcare providers. attending to these issues is where palliative care has made the most significant impact.15,16 all of these challenges amplify the importance of developing an evidence based approach to provide palliative care during pandemics. in oman, palliative care is currently provided for patients in the national oncology centre, which is limited to pain management and control of symptoms. some initiatives have been taken to promote the service. oman cancer association in partnership with the ministry of health trained 360 omani nurses and directorate general of planning and studies, ministry of health, muscat, oman e-mail: challenger.777@hotmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. integrating palliative care services in pandemics and emergencies preparedness and response plans time for action in oman aisha al saadi editorial sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 5–7, epub. 28 feb 22 submitted 27 dec 20 revision req. 1 mar 21; revision recd. 10 mar 21 accepted 24 mar 21 https://doi.org/10.18295/squmj.5.2021.100 https://creativecommons.org/licenses/by-nd/4.0/ integrating palliative care services in pandemics and emergencies preparedness and response plans time for action in oman 6 | squ medical journal, february 2022, volume 22, issue 1 20 primary care physicians in palliative care from april 2013 to february 2017. furthermore, a website called oman palliative care was created for palliative care in 2019. however, the service is still in its early stages and it should be strengthened to provide different palliative care models and expanded to all medical conditions. this paper has suggested two recommendations to improve provision of palliative care in oman during pandemics and healthcare emergencies. integration of palliative care into preparedness and response plans challenges have emerged during the covid-19 pandemic. these include rationing care when resources are limited and withholding non-beneficial treatment and palliative treatment options to treat breathlessness and other distressing symptoms of covid-19. palliative care services provide an extra layer of support to manage these challenges.11,12 integrating palliative care services into preparedness and response plans would require appropriate guidelines to standardise care, adequate policies and legislations, capacity building of healthcare workers in palliative care, accredited training and degree programmes; it would also require an advanced approach to deliver the service during a pandemic.17,18 a d va n c e d a p p r o a c h e s t o d e l i v e r palliative care during a pandemic tele-palliative medicine there is strong support for maximising the use of telemedicine in the provision of palliative care for inpatients, outpatients and patients at home; successful implementation requires robust health infrastructure support and technical expertise.19–24 tele-palliative care allows for remote delivery of palliative care services such as symptom assessments, discussion of goals of care as well as counselling and bereavement support. this approach minimises exposure to the infection, reduces personal protective equipment use and reconnects the patient with clinicians and their family during the challenging times brought on by the covid-19 pandemic.18,20 a 24/7 hotline access to the palliative care team applying creative interventions during a crisis situation are beneficial in reducing emotional distress and facil itating a supportive transition throughout the grieving process for patients as well as the bereaved families.25,26 launching a 24/7 hotline access to the palliative care team was one of the interventions implemented during the covid-19 crisis in the health system of mount sinai in new york city. the help line provides two support services: teleconsultation (physicianto-physician support) and telemedicine (palliative medicine-to-family). telephonic support by a palliative care team assisted clinicians in conducting complex goals-of-care discussion and symptoms management during the peak of the covid-19 pandemic in new york city and helped families to receive clear and timely information about their loved one’s condition, enabled patients and families to participate in decision-making, increased the development of trust and facilitated the process of grieving and healing.27 developing hotline access to palliative care teams in oman will allow provision of palliative care services in clinical sites in the highest need of support during pandemics and healthcare emergencies. this service will provide coverage of palliative care to all hospitals which lack hospital-based palliative care services. home-based palliative care evidence has shown that home palliative care progr ammes provide better management of distressing symp toms of dying patients.28 however, there is a lack of data on how this could be done during a pandemic. one study recommended availability of mobile palliative care teams for the covid-19 patients who would prefer to die at home.17 many studies have found clear benefits of interdisciplinary palliative care teams, because each discipline will have a unique role to function in the realm of psychosocial and spiritual care.28 globally, the demand for home-based palliative care will substantially increase in the future.10 developing this service in oman is subjected to certain limitations. the greatest of which is the restrictive policies concerning pain medication that requires changing legislation by raising awareness within the community to allow people to be cared for at home. over the years, it is reasonable to expect that other pandemics or healthcare emergencies will emerge. therefore, integration of palliative care into preparedness and response plans is a priority to alleviate suffering. palliative care service should be considered as a critical component of a health system disaster response and a part of the global commitment to the universal health coverage (uhc), which considers palliative care as an essential health service. it is suggested that integrating palliative care into response plans would foster reaching the uhc goals. developing a national policy on palliative care will resolve many barriers to palliative care in general and will allow expansion of this service during pandemics and healthcare emergencies. references 1. adams jg, walls rm. supporting the health care workforce during the covid-19 global epidemic. jama. 2020; 323:1439–40. https://doi.org/10.1001/jama.2020.3972. https://doi.org/10.1001/jama.2020.3972 aisha al saadi editorial | 7 2. coronavirus disease (covid-19) situation reports. from: https://www.who.int/emergencies/diseases/novel-coronavir us-2019/situation-reports accessed: mar 2021. 3. kübler-ross e. on death and dying. new york, usa: the macmillan company, 1969. 4. carey s, cosgrove j. cultural issues surrounding end-of-life care. curr anaesth crit care 2006; 17:263–70. https://doi.org/10.1 016/j.cacc.2006.10.002. 5. carvalheiro am, faria c, semeão i, martinho sm. caring for end-of-life patients and their families, during life, and mourning, in the covid-19 era-the experience of a palliative care team in portugal. front psychiatry 2021; 12:624665. https://doi. org/10.3389/fpsyt.2021.624665. 6. parkes cm. love and loss: the roots of grief and its complications. new york, usa: routledge. 2009. 7. who. who definition of palliative care. from: https://www. who.int/cancer/palliative/definition/en/ accessed: mar 2021. 8. bajwah s, oluyase ao, yi d, gao w, evans cj, grande g, et al. the effectiveness and cost-effectiveness of hospital-based spec ialist palliative care for adults with advanced illness and their caregivers. cochrane database syst rev 2020; 9:cd012780. https://doi.org/10.1002/14651858.cd012780.pub2. 9. gomes b, calanzani n, curiale v, mccrone p, higginson ij. effectiveness and cost-effectiveness of home palliative care services for adults with advanced illness and their caregivers. cochrane database syst rev 2013; 6:cd007760. https://doi. org/10.1002/14651858.cd007760.pub2. 10. sleeman ke, de brito m, etkind s, nkhoma k, guo p, higginson ij, et al. the escalating global burden of serious health-related suffering: projections to 2060 by world regions, age groups, and health conditions. lancet glob health 2019; 7:e883–92. https://doi.org/10.1016/s2214-109x(19)30172-x. 11. etkind sn, bone ae, lovell n, cripps rl, harding r, higginson ij, et al. the role and response of palliative care and hospice services in epidemics and pandemics: a rapid review to inform practice during the covid-19 pandemic. j pain symptom manage 2020; 60:e31–40. https://doi.org/10.1016/j.jpainsymman.2020.03.029. 12. boufkhed s, harding r, kutluk t, husseini a, pourghazian n, shamieh o. what is the preparedness and capacity of palliative care services in middle-eastern and north african countries to respond to covid-19? a rapid survey. j pain symptom manage 2021; 61:e13–50. https://doi.org/10.1016/j.jpainsymman.2020.10.025. 13. arya a, buchman s, gagnon b, downar j. pandemic palliative care: beyond ventilators and saving lives. cmaj 2020; 192:e400–4. https://doi.org/10.1503/cmaj.200465. 14. ting r, edmonds p, higginson ij, sleeman ke. palliative care for patients with severe covid-19. bmj 2020; 370:m2710. https://doi.org/10.1136/bmj.m2710. 15. kokou-kpolou ck, fernández-alcántara m, cénat jm. prolonged grief related to covid-19 deaths: do we have to fear a steep rise in traumatic and disenfranchised griefs. psychol trauma 2020; 12:s94–5. https://doi.org/10.1037/tra0000798. 16. eisma mc, tamminga a, smid ge, boelen pa. acute grief after deaths due to covid-19, natural causes and unnatural causes: an empirical comparison. j affect disord 2020; 278:54–6. https://doi.org/10.1016/j.jad.2020.09.049. 17. janssen dja, ekström m, currow dc, johnson mj, maddocks m, simonds ak, et al. covid-19: guidance on palliative care from a european respiratory society international task force. eur respir j 2020; 56:2002583. https://doi.org/10.1183/1399 3003.02583-2020. 18. fadul n, elsayem af, bruera e. integration of palliative care into covid-19 pandemic planning. bmj support palliat care 2021; 11:40–4. https://doi.org/10.1136/bmjspcare-2020-002364. 19. calton b, abedini n, fratkin m. telemedicine in the time of coronavirus. j pain symptom manage 2020; 60:e12–14. https://doi.org/10.1016/j.jpainsymman.2020.03.019. 20. humphreys j, schoenherr l, elia g, saks nt, brown c, barbour s, et al. rapid implementation of inpatient telepalliative medicine consultations during covid-19 pandemic. j pain symptom manage 2020; 60:e54–9. https://doi.org/10.1016/j.jpainsymm an.2020.04.001. 21. funderskov kf, boe danbjørg d, jess m, munk l, olsen zwisler ad, dieperink kb. telemedicine in specialised palliative care: health care professionals' and their perspectives on video consultations a qualitative study. j clin nurs 2019; 28:3966–76. https://doi. org/10.1111/jocn.15004. 22. hancock s, preston n, jones h, gadoud a. telehealth in palliative care is being described but not evaluated: a systematic review. bmc palliat care 2019; 18:114. https://doi.org/10.1186/s12904-0 19-0495-5. 23. jess m, timm h, dieperink kb. video consultations in palliative care: a systematic integrative review. palliat med 2019; 33:942–58. https://doi.org/10.1177/0269216319854938. 24. tasneem s, kim a, bagheri a, lebret j. telemedicine video visits for patients receiving palliative care: a qualitative study. am j hosp palliat care 2019; 36:789–94. https://doi.org/10.1177/104 9909119846843. 25. wakam gk, montgomery jr, biesterveld be, brown cs. not dying alone modern compassionate care in the covid-19 pandemic. n engl j med 2020; 382:e88. https://doi.org/10.1056/ nejmp2007781. 26. strupp j, groebe b, knies a, mai m, voltz r, golla h. evaluation of a palliative and hospice care telephone hotline for patients severely affected by multiple sclerosis and their caregivers. eur j neurol 2017; 24:1518–24. https://doi.org/10.1111/ene.13462. 27. delima thomas j, leiter re, abrahm jl, shameklis jc, kiser sb, gelfand sl, et al. development of a palliative care toolkit for the covid-19 pandemic. j pain symptom manage 2020; 60:e22–5. https://doi.org/10.1016/j.jpainsymman.2020.05.021. 28. o’connor m, fisher c, guilfoyle a. interdisciplinary teams in palliative care: a critical reflection. int j palliat nurs 2006; 12:132–7. https://doi.org/10.12968/ijpn.2006.12.3.20698. https://doi.org/10.1 016/j.cacc.2006.10.002 https://doi.org/10.1 016/j.cacc.2006.10.002 https://doi.org/10.3389/fpsyt.2021.624665 https://doi.org/10.3389/fpsyt.2021.624665 https://doi.org/10.1002/14651858.cd012780.pub2 https://doi.org/10.1002/14651858.cd007760.pub2 https://doi.org/10.1002/14651858.cd007760.pub2 https://doi.org/10.1016/s2214-109x(19)30172-x https://doi.org/10.1016/j.jpainsymman.2020.03.029 https://doi.org/10.1016/j.jpainsymman.2020.10.025 https://doi.org/10.1136/bmj.m2710 https://doi.org/10.1037/tra0000798 https://doi.org/10.1016/j.jad.2020.09.049 https://doi.org/10.1183/13993003.02583-2020 https://doi.org/10.1183/13993003.02583-2020 https://doi.org/10.1136/bmjspcare-2020-002364 https://doi.org/10.1016/j.jpainsymman.2020.03.019 https://doi.org/10.1016/j.jpainsymman.2020.04.001 https://doi.org/10.1016/j.jpainsymman.2020.04.001 https://doi.org/10.1111/jocn.15004 https://doi.org/10.1111/jocn.15004 https://doi.org/10.1186/s12904-019-0495-5 https://doi.org/10.1186/s12904-019-0495-5 https://doi.org/10.1177/0269216319854938 https://doi.org/10.1177/1049909119846843 https://doi.org/10.1177/1049909119846843 https://doi.org/10.1056/nejmp2007781 https://doi.org/10.1056/nejmp2007781 https://doi.org/10.1111/ene.13462 https://doi.org/10.1016/j.jpainsymman.2020.05.021 https://doi.org/10.12968/ijpn.2006.12.3.20698 submitted 6 oct 21 1 revisions req. 13 dec 21 & 27 feb 22; revisions recd. 30 jan & 9 mar 22 2 accepted 22 mar 22 3 online-first: april 2022 4 doi: https://doi.org/10.18295/squmj.4.2022.029 5 6 cilia ultrastructure associated with primary ciliary dyskinesia in omani 7 patients 8 *kawther al adawi,1 taher baomar,2 marwa al riyami,1 nawal al 9 shamli,3 khoula al shidhani,4 aliya al ansari,2 hussein al kindi3 10 11 1department of pathology, sultan qaboos university hospital, muscat oman; 2department 12 of biology, college of science and 3department of child health, college of medicine & 13 health sciences, sultan qaboos university, muscat, oman; 4department of child health, 14 the royal hospital, ministry of health, muscat, oman 15 *corresponding author’s e-mail: kawthara@squ.edu.om 16 17 abstract 18 objectives: primary ciliary dyskinesia (pcd) is a disorder affecting the structure and function 19 of motile cilia. transmission electron microscopy is one method that can be used to examine 20 ciliary ultrastructure in airway biopsies. although the role of ultrastructural findings in pcd 21 has been described in the literature, this role has not been well studied in the middle east or, 22 by extension, oman. this study aims to describe ultrastructural features in omani patients with 23 high suspicion of pcd. methods: this retrospective cross-sectional study included 129 24 adequate airway biopsies obtained between 2010–2020 from omani patients suspected of 25 having pcd. results: ciliary ultrastructural abnormalities in our study population were outer 26 dynein arm associated with inner dynein arm defects (8%), microtubular 27 disorganisation associated with inner dynein arm defect (5%), and isolated outer dynein arm 28 defect (2%). most of the biopsies sowed normal ultrastructure (82%). conclusion: in omani 29 patients suspected to have pcd, normal ultrastructure was the commonest feature. 30 keywords: cilia; primary ciliary dyskinesia; airway biopsy; transmission electron 31 microscopy; ultrastructure; oman. 32 33 mailto:kawthara@squ.edu.om advances in knowledge 34  transmission electron microscopy (tem) is a feasible diagnostic tool for primary 35 ciliary dyskinesia (pcd). 36  normal ciliary ultrastructure features are common finding when using tem. 37 applications to patient care 38  a normal ciliary ultrastructure finding does not exclude pcd in omani patients. 39  other tests need to be considered, including genetic testing, if a ciliary ultrastructure 40 finding is normal. 41 42 introduction 43 primary ciliary dyskinesia (pcd) is a hereditary disorder affecting the structure and/or 44 function of motile cilia.1,2 pcd is particularly challenging to manage and research, and 45 diagnosis is typically delayed due to shared clinical features with other diseases, including 46 cystic fibrosis (cf), immunodeficiency, chronic pulmonary aspiration, asthma and recurrent 47 respiratory viral infection.2–4 48 49 the symptoms of pcd are initially observed in organs in which cilia motility is essential for 50 normal function and manifest in organs outside the respiratory tract as well as in sinuses and 51 the lungs.3 in the respiratory system, pcd-related mucociliary clearance impairment can 52 cause chronic wet cough, recurrent respiratory tract infections, bronchitis and 53 bronchiectasis.4–7 the effects may vary between patients but are common in that they never 54 fully resolve despite using systemic antibiotics.4 outside the respiratory system, pcd patients 55 can suffer from fertility issues and hearing difficulties due to glue ear, and approximately 45–56 50% have situs inversus.5,7,8 pcd patients also can have inborn heart defects due to situs 57 ambiguuus.6 58 59 the official american thoracic society (ats) clinical practice guidelines for the diagnosis 60 of pcd recommend testing for pcd if two clinical pcd phenotypes are present.4 the 61 recommended testing methodologies are the examination of ciliary ultrastructure using tem, 62 genetic testing, nasal nitric oxide (nno) measurement in children five years of age or older 63 and high-speed video microscopy (hsvm).3,7,8 although hsvm is useful for accessing 64 ciliary beat frequency and its pattern and length, such testing is limited to specialised pcd 65 centres.4 66 67 ultrastructural studies of ciliary axonemes by tem remains one of the most widely used and 68 reliable diagnostic methods for pcd.9 using this diagnostic process, however, is challenging, 69 because obtaining an adequate sample with a sufficient number of cilia that are technically 70 acceptable for interpretation is not easy.3,10 however, using tem to identify a consistent 71 ultrastructural abnormality within the ciliary axoneme helps to expedite disease management 72 as it indicates a definite diagnosis.11 ciliary ultrastructural features, including the location of 73 the central pair complex, the availability of the dynein arms, orientation of peripheral 74 microtubules (mts), and epithelial cells abnormalities are definitive clues leading to pcd 75 diagnosis.5,10,12 76 77 international guidelines for reporting pcd using tem were established to regulate and direct 78 the diagnostic efforts.10 according to these guidelines, ciliary ultrastructure can be classified 79 as normal, or as class 1 or class 2 defects.10 normal ultrastructure is defined as the presence 80 of the well-known 9 + 2 axonemal structure with a clear identification of outer dynein arms 81 (oda), inner dynein arms (ida) and the central microtubules in the middle of the axoneme 82 [figure 1].10 class 1 findings are considered as hallmark defects ( i.e. diagnostic) while class 2 83 defects may possibly be used to indicate a diagnosis of pcd if it is consistent across multiple 84 samples.10 in this case, and if clinical symptoms are persistent, it is required to confirm the 85 diagnosis using another mode of testing like for example high-speed video microscopy or 86 genetic testing.10 87 88 class 1, or hallmark defects, can include isolated loss of oda or combined oda and ida 89 absence from > 50% of cross-sections. however, when it is < 50 % ( i.e. 20 -50%) it is 90 referred to as class 2 defects. in addition, microtubular disorganisation combined with ida 91 defects is considered a class 1 defect, while microtubular disorganisation when ida is present 92 is referred to as class 2 defect. .10 moreover, central complex defect and the mislocalisation of 93 basal bodies with few or no cilia are also considered class 2 defects.10 94 95 pcd is no longer considered a mild disease, and more research is needed to expedite pcd 96 management in order to prevent complications from the disease. the objective of this study, 97 therefore, was to determine the most common ciliary ultrastructural defects in omani pcd 98 patients and use those results to assist in patient management. 99 100 all airway biopsies sent to the electron microscopy unit (emu) at sultan qaboos university 101 (squ) from 2010–2020 were included in this study. this sample included biopsies from all 102 omani patients who were highly suspected of having pcd based on clinical phenotypes and 103 symptoms. specimens were taken from patients between one month and 70 years of age. 104 these patients had presented to clinics suffering from at least two out of four ats-defined 105 pcd symptoms. these symptoms included recurrent chest infections; wet, productive cough; 106 the presence of laterality defects and neonatal respiratory distress.4 107 108 methods 109 medical ethics approval was obtained to include all airway biopsies for ciliary ultrastructural 110 examination from 2010–2020 in squ’s emu. the research was approved by the medical 111 research ethics committee (mrec), college of medicine and health sciences at sultan 112 qaboos university (mrec #2089) and the scientific research committee (src) at the 113 royal hospital, ministry of health, sultanate of oman (src #23/2020). 114 115 araldite blocks from samples of patients attending pulmonary clinics at sultan qaboos 116 university hospital (squh) and the royal hospital (rh) that had been received in the 117 emu, department of pathology at squ were collected retrospectively. in addition, two 118 adequate normal control samples were obtained from two healthy adult candidates. 119 120 samples were considered adequate if 50 cross cilia were possible to screen using tem. 121 samples of adequate airway biopsies from highly suspected pcd omani patients were all 122 included if they met the inclusion criteria. they were included if patients had presented with 123 at least two of the following symptoms: recurrent chest infections with no response to 124 antibiotics; laterality defects; respiratory distress during early infancy, year-round wet cough. 125 126 all inadequate samples were excluded as were samples from patients diagnosed with 127 conditions other than pcd after reviewing patients’ clinical charts. 128 129 samples had been collected using the following steps: nasal airway biopsies were taken in 130 outpatient clinics. the clinicians obtained the specimens by scraping the nasal inferior 131 turbinate using either a brush or rhino pro curette. specimens were received in karnovsky’s 132 fixative and then transferred into sodium cacodylate buffer and kept at 4° c. specimens were 133 then fixed in osmium tetroxide, washed in distilled water and dehydrated in a series of graded 134 acetone. the dehydrated specimens were infiltrated in a mixture of acetone and araldite resin, 135 embedded in freshly prepared pure araldite resin and polymerised at 60° c overnight. control 136 specimens were processed following the same protocol that was used for the retrospectively 137 collected specimens. 138 139 the blocks containing ciliated cells were cut using a diamond knife, and thin sections were 140 placed on copper grids. sections were stained using supersaturated uranyl acetate and 141 reynolds’ lead citrate. in total, 50 cross cilia from each sample were screened at high 142 magnification using a jeol jem-1230 tem at 80 kv (jeol, ltd. tokyo, japan). images 143 were captured using a gatan msc si003 1 digital camera system (gatan, inc., pleasanton, 144 california, usa) and analysed. 145 146 results 147 a total of 421 airway biopsies were received and processed during the study period, out of 148 which 129 biopsies (30%) were adequate. from the adequate samples, 114 were from 149 individuals between 1 month and 18 years old, and only 15 were from patients above 18 150 years old. these samples were of patients from different regions in the country. a sample 151 was considered adequate when 50 cross cilia could be examined and photographed with a 152 tem. 153 154 image analysis was done following ats international guidelines for reporting pcd using 155 tem. 10 out of the 129 adequate samples, 23 (18%) showed alterations in the ciliary 156 ultrastructure [table 1]. the absence of oda and ida was the most frequently observed 157 abnormality in the studied group (n = 10; 8%) [figure 2] followed by the microtubular 158 disorganisation associated with an ida defect (n = 6; 5%). both of these abnormalities are 159 considered class 1 defects. the least common class 1 ultrastructural defects were the isolated 160 absence of oda (n = 3; 2%) [figure 3]. additionally, 3 samples (n = 3; 2%) showed central 161 complex defects [figure 4] and one sample (n = 1) showed microtubular disorganisation 162 without ida defect. these types of defects are classified as class 2 defects and would require 163 another mode of testing (e.g., testing for genetic mutations) to confirm pcd diagnosis. 164 165 most of the sample (n = 106; 82%) showed normal ultrastructure of the ciliary axoneme 166 [figure 5]. on review, it was found that all of these individuals had fulfilled the ats clinical 167 criteria for testing. pcd was highly suspected due to their presentation with at least two out 168 of four pcd clinical phenotypes. furthermore, 65 patients (50%) from this group had 169 negative sweat chloride test, and 57 (44%) had a negative workup for immunodeficiency. 170 however, 37 patients (29%) were not tested for immunodeficiency or sweat chloride for 171 clinical reasons. 172 173 discussion 174 ciliary ultrastructure analysis requires special expertise. analysts require knowledge of 175 normal versus abnormal ciliary structures and tem availability.13 it is important that 176 healthcare institutions overcome these challenges, however, because this type of analysis is 177 essential to the process of diagnosing pcd.8,9 tem is feasible in about 70% of pcd patients, 178 but tem alone is not sufficient to achieve reliable diagnosis.14 in this study, most of the 179 current studied sample showed normal ultrastructure on tem (n = 106; 82%). other 180 researchers have achieved similar findings.7,13,14 in their study, papon et al. found that more 181 than half of their pcd-positive sample showed normal ultrastructure.14 182 183 other researchers’ findings and those of the current study suggest the potential role of gene 184 mutations in causing normal ciliary ultrastructure.7,11,15–17 dnah11 gene mutations, for 185 example, have been found to cause pcd but are associated with normal ciliary 186 ultrastructure.16 these mutations affect the structural proteins and subsequently the function 187 of oda, but the structure still looks normal through a tem.16 the hydin autosomal 188 recessive gene mutation is also associated with normal ultrastructure.18 this gene is involved 189 in the production of proteins for the central pair complex.18 190 191 due to high rates of consanguinity in oman, it is expected that certain pcd-associated genes 192 are predominant in the omani population. if the most common pcd-associated gene 193 mutations in this region are associated with normal ciliary ultrastructure, then this may 194 explain the current study results. genetic testing, however, is needed to confirm this 195 theory. in omani cases of suspected pcd, it is recommended to re-evaluate clinical 196 phenotypes in individuals who show repetitive normal ciliary ultrastructure. if symptoms of 197 pcd persist, then other diagnostic investigations are highly recommended to confirm pcd. a 198 similar recommendation should be followed if ultrastructural features suggest class 2 defects. 199 as with class 1 defects, a final diagnosis of class 2 defects requires confirmation of disease 200 by applying, for example, genetic testing.10 201 202 defects of oda and ida and microtubular disorganisation combined with ida defects were 203 among the ciliary ultrastructural abnormalities reported in the current study. both of which 204 are considered class one defects and confirm pcd.10 in the current study, oda associated 205 with an ida defect was reported in 10 patients (8%), and microtubular disorganisation 206 associated with an ida defect was reported in seven patients (5%). on the other hand, an 207 isolated oda defect was reported in only 2% (n = 3) of the studied group. in these cases, 208 pcd diagnosis was confirmed by tem, and testing for gene mutations causing these 209 abnormalities become an option but were not a priority.10 210 211 the high inadequacy rate of samples submitted for tem analysis was a challenge in the 212 current study. however, inadequacy might also indicate a specific cause of pcd. it is now 213 well known that if multiple specimens from the same patient all show a low percentage of or 214 no cilia in the epithelial cells, then it may indicate specific pcd gene mutations.18 this type 215 of finding suggests that something is not right in the ciliogenesis process. in such cases, re-216 evaluating the clinical presentation is highly recommended. if symptoms persist with no other 217 explanation, then genetic testing for pcd to explore certain gene mutations as in the protein 218 coding ccno or mcidas genes may be considered.18 future research should examine 219 possible genetic mutations in omani pcd patients and correlate them with the clinical and 220 ultrastructural phenotypes of patients. 221 222 conclusion 223 the current research group recommends ciliary ultrastructural studies for pcd patients in 224 oman. if class 1 defects are identified, early pcd management might limit or even prevent 225 lung damage due to disease complications. in this case, genetic testing is optional and may 226 not be necessary unless it is required for family planning. the percentage of cases diagnosed 227 using tem is not high, but tem cannot exclude pcd upon normal ultrastructure findings 228 nor when multiple specimen inadequacy is observed within the same patient. at this time, a 229 combination of tests are required to confirm pcd including tem, genetic testing, nno and 230 hsvm. 231 232 conflict of interest 233 the authors declare no conflicts of interest. 234 235 236 funding 237 no funding was received for this study. 238 239 acknowledgment 240 the authors would like to acknowledge the electron microscopy team at squ for their help in 241 providing the specimens and equipment used in this research and in special ms. marwa al 242 shukri for the great help in producing the diagrams of the abnormal cilia. 243 244 authors’ contribution 245 kaa carried out the electron microscopy laboratory work related to this research and 246 prepared the samples. then screened them, captured the images and analyzed the results of 247 the research under the supervision of the team. tb was the main supervisor for this research 248 and reviewed the ultrastructure of cilia and helped in the results analysis. mar authorized 249 the final reports of the ultrastructure for the patients included in this research. aaa and hak 250 were the co-supervisors for this research and participated in the analysis of results. hak is 251 also one of the clinicians who participated in the analysis of the clinical features for the 252 patients included in this research. nas and kas were the clinicians who reviewed the 253 clinical features and participated in the setup of this research. all authors approved the final 254 version of this manuscript. 255 256 references 257 1. lee sl, o’callaghan c, lau yl, lee cwd. functional analysis and evaluation of 258 respiratory cilia in healthy chinese children. respir res. 2020 oct 9;21(1):259. doi: 259 10.1186/s12931-020-01506-w.. 260 2. rubbo b, lucas js. clinical care for primary ciliary dyskinesia: current challenges and 261 future directions. eur respir rev. 2017 sep 6;26(145):170023. doi: 10.1183/16000617.0023-262 2017. 263 3. stillwell pc, wartchow ep, sagel sd. primary ciliary dyskinesia in children: a review for 264 pediatricians, allergists, and pediatric pulmonologists. . pediatr allergy immunol pulmonol. 265 2011 dec;24(4):191-196. doi: 10.1089/ped.2011.0099. 266 4. shapiro aj, davis sd, polineni d, manion m, rosenfeld m, dell sd, et al. diagnosis of 267 primary ciliary dyskinesia: an official american thoracic society clinical practice guideline. 268 am j respir crit care med. 2018 jun 15;197(12):e24-e39. doi: 10.1164/rccm.201805-269 0819st. 270 5. o’callaghan c, rutman a, williams g, kulkarni n, hayes j, hirst ra. ciliated conical 271 epithelial cell protrusions point towards a diagnosis of primary ciliary dyskinesia. respir res. 272 2018 jun 25;19(1):125. doi: 10.1186/s12931-018-0782-3. 273 6. horani a, ferkol tw, dutcher sk, brody sl. genetics and biology of primary ciliary 274 dyskinesia. . paediatr respir rev. 2016 mar;18:18-24. doi: 10.1016/j.prrv.2015.09.001. 275 7. knowles mr, zariwala m, leigh m. primary ciliary dyskinesia. clin chest med. 2016 276 sep;37(3):449-61. doi: 10.1016/j.ccm.2016.04.008. 277 8. tang d, sha y, gao y, zhang j, cheng h, zhang j, et al. novel variants in dnah9 lead to 278 nonsyndromic severe asthenozoospermia. reprod biol endocrinol. 2021 feb 20;19(1):27. 279 doi: 10.1186/s12958-021-00709-0. 280 9. thomas b, rutman a, o’callaghan c. disrupted ciliated epithelium shows slower ciliary 281 beat frequency and increased dyskinesia. eur respir j. 2009 aug;34(2):401-4. doi: 282 10.1183/09031936.00153308. 283 10. shoemark a, boon m, brochhausen c, bukowy-bieryllo z, de santi mm, goggin p, et al. 284 international consensus guideline for reporting transmission electron microscopy results in 285 the diagnosis of primary ciliary dyskinesia (beat pcd tem criteria). eur respir j. 2020 286 apr 16;55(4):1900725. doi: 10.1183/13993003.00725-2019. 287 11. olin jt, burns k, carson jl, metjian h, atkinson jj, davis sd, et al. diagnostic yield of 288 nasal scrape biopsies in primary ciliary dyskinesia: a multicenter experience. pediatr 289 pulmonol. 2011 may;46(5):483-8. doi: 10.1002/ppul.21402. 290 12. li f-q, siller ss, takemaru k-i. oncotarget basal body docking in airway ciliated cells. 291 oncotarget. 2015 aug 21;6(24):19944-5. doi: 10.18632/oncotarget.4609. 292 13. haarman eg, schmidts m. accuracy of diagnostic testing in primary ciliary dyskinesia: are 293 we there yet? eur respir j. 2016 mar;47(3):699-701. doi: 10.1183/13993003.01914-2015. 294 14. papon jf, coste a, roudot-thoraval f, boucherat m, roger g, tamalet a, et al. a 20-year 295 experience of electron microscopy in the diagnosis of primary ciliary dyskinesia. eur respir 296 j. 2010 may;35(5):1057-63. doi: 10.1183/09031936.00046209. 297 15. shapiro aj, zariwala ma, ferkol t, davis sd, sagel sd, dell sd, et al. diagnosis, 298 monitoring, and treatment of primary ciliary dyskinesia: pcd foundation consensus 299 recommendations based on state of the art review. pediatr pulmonol. 2016 feb;51(2):115-32. 300 doi: 10.1002/ppul.23304. 301 16. knowles mr, leigh mw, carson jl, davis sd, dell sd, ferkol tw, et al. mutations of 302 dnah11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. 303 thorax. 2012 may;67(5):433-41. doi: 10.1136/thoraxjnl-2011-200301. 304 17. shoemark a, burgoyne t, kwan r, dixon m, patel mp, rogers a v., et al. primary 305 ciliary dyskinesia with normal ultrastructure: three-dimensional tomography detects absence 306 of dnah11. eur respir j. 2018 feb 21;51(2):1701809. doi: 10.1183/13993003.01809-2017. 307 18. shapiro aj, leigh mw. value of transmission electron microscopy for primary ciliary 308 dyskinesia diagnosis in the era of molecular medicine: genetic defects with normal and non-309 diagnostic ciliary ultrastructure. ultrastruct pathol. 2017 nov-dec;41(6):373-385. doi: 310 10.1080/01913123.2017. 311 312 table 1: shows the ultrastructure detected by tem from 2010 to 2020 313 ultrastructural defect number of specimens class 1 defect oda + ida defects 10 (8%) microtubular disorganisation with ida defect 7 (5%) oda defect ) 2 (2%) class 2 defect central complex defect 3 (2%) microtubular disorganisation with ida present 1 (1%) normal ultrastructure 106 (82%) total adequate airway biopsies 129 314 315 316 317 318 319 320 321 322 323 324 figure 1: a schematic diagram of the cross section of a motile cilium illustrating the normal 325 9+2 microtubular structure. the 9 fused doublet microtubules with outer and inner dynein 326 arms are arranged in the outer periphery surrounding a pair of singlet microtubules in the 327 middle of the ciliary axoneme. the central pair is surrounded by a central sheath and radial 328 spokes are radiating between them and the outer doublets. diagram was taken from: 329 ishikawa, h., & marshall, w. f. (2017). intraflagellar transport and ciliary dynamics. cold 330 spring harb perspect biol. 2017; 9(3):a021998. published 2017 mar 1. 331 https://doi.org/10.1101/cshperspect.a021998 332 333 334 335 336 337 338 339 340 341 342 figure 2: (a) an electron micrograph of a class 1 defect showing the absence of both oda 343 & ida in the 9+2 ultrastructure of the ciliary axoneme from an adequate patient’s sample. 344 (b) a schematic diagram of the cross section of a motile cilium illustrating the absence of 345 both oda + ida. 346 347 348 figure 3: (a) an electron micrograph showing a class 1 defect, oda is missing from the ciliary 349 axoneme, while ida (black arrow) can be identified. (b) a schematic diagram of the cross 350 section of a motile cilium illustrating the absence of oda. 351 a b a b 352 353 figure 4: (a) electron micrograph of a class 2 defect. the majority of the cilia in this sample 354 showed the absence of central complex (black arrows). however, oda & ida can be 355 identified in those cilia. (b) a schematic diagram of the cross section of a motile cilium 356 illustrating the absence of the central complex. 357 358 359 figure 5: electron micrograph showing normal 9+2 ultrastructure of the ciliary axoneme from 360 an adequate patient’s sample, oda (elbow arrow), ida (arrow) & central complex ( arrow 361 head) are identified in this image. 362 a b family medicine practice in oman present and future mohamed al-shafaee squ med j, august 2009, vol. 9, iss. 2, pp. 116-118, epub 30th june 2009 invited article, submitted 23 may 2009 revision req. 25th may 2009, revision recd. 31st may 2009 accepted 1 june 2009 ممارسة طب األسرة يف ُعمان اآلن ويف املستقبِل محمد بن علي الشافعي department of family medicine & public health, college of medicine & health sciences, muscat, sultanate of oman email: shafaee4@omantel.net.om the european definition of the discipline and speciality of general practice/family medicine, as defined in 2005 states: “general practice/family medicine is an academic and scientific discipline and a clinical specialty with its own educational content, research and evidence base and clinical activity, orientated to primary care”. according to this definition general practitioners/ family doctors are “specialist physicians trained in the principles of the discipline”.1 the two terms “general practice” and “family medicine” were synonymous in this context. family medicine has accomplished a great deal and grown significantly since its birth worldwide. the strongest proof of its importance and contribution to health care is demonstrated by looking at how strongly western countries depend on family physicians. international evidence indicates that health systems based on effective primary care, with highly trained generalist physicians (family doctors) practising in the community, provide better clinical and more cost-effective care than those with a low primary care orientation.2 therefore, family physicians are a fundamental force and as such, they are in a unique position to influence muchneeded changes in health care. other countries and systems have already taught us that societies fare better when they have a strong, structured, accessible and affordable primary care system, to provide at least some minimum level of care. in her extensive studies of primary care around the world over many years, barbara starfield has found that countries with strong primary care have lower overall health care costs, improved health outcomes, and healthier populations.³ studies have shown also that the higher the family physician-to-population ratio in an area, the lower the hospitalisation rates for both adults and children.4 in oman, the department of family and community medicine (famco) was established in 1987 at the college of medicine, sultan qaboos university to teach undergraduates. family medicine was considered a major discipline like medicine, paediatrics, surgery and obstetrics and gynecology. in 1994, a formal structured four-year postgraduate training programme was started in family medicine. in 2001, this programme was recognised by the royal college of general practitioners (uk) and oman was the first country in the world to conduct the mrcgp (int) examination. up to 2009, about 110 omanis have graduated as family physicians; most of them are employed by the ministry of health in various capacities ranging from medical officers to directors of medical services in various wilayats (districts). these specialists are also providing useful input in defining teaching, training and evaluation so that the postgraduate programme becomes increasingly indigenous, precisely targeting the needs of the country. since 2007, this postgraduate programme has been run under the auspices of the oman medical specialty board which has not only involved local experts, but also collaborated with other training programmes in the region and in north america, europe, india and australia. the family physicians emerging from a residency programme of this type possess the credentials of adequate preparation and the capacity for professional action. these are keys to status, self-esteem and public trust. so far primary health care in oman has been managed mostly by a variety of graduate and postgraduate doctors from various parts of the special contribution mohamed al-shafaee special contribution | 117 world, specially the subcontinent, who do not have formal training in general practice/family medicine. this has led to wide variations in the quality of patient care and the status of general practice in the country. we need to provide high quality and valued services that are safe, evidenced-based and grounded in the needs of the community. there is a need to standardise the care being provided not only by the residency training program, but also through continuous professional development activities. given the current intake of about 10 residents per year and the existing 110, in the next 5 years there could be a family physician for each of the 159 health centres. to have an average of four family physicians for each health centre will take many years. to monitor and ensure the standards of knowledge, skills and attitudes, regular audits and peer review are required. these should be nonpunitive exercises. resources the complexity of caring for patients with acute and chronic problems over time and managing preventive services for populations of patients requires the involvement of many health care professionals working in well-organized systems and supported by information technology.5 the ability of family physicians to provide quality service is also dependant on their skills, knowledge, professionalism and the resources available. the resources include appropriate facilities, equipments, diagnostic tools, medications and accessibility to secondary care. currently there is a global problem of matching resources to the needs. there is a continuous increase in costs due to newer diagnostic and therapeutic options. one of the current challenges in oman, faced by the doctors in primary care, is the availability of the range of medications needed to treat common conditions like diabetes. to overcome this problem we need to develop guidelines with the active involvement of family physicians and there should be regular audits to see that the guidelines are implemented and there is optimal utilisation of resources. oman is on a par with the rest of the world in the availability of information technology, but family physicians do not have internet and electronic databases available at the point of primary care, which becomes one of the barriers for continuing professional development. training the residency training should focus on the following five competency areas as the foundation of education and training: 1) patient-centered care, 2) interdisciplinary team work, 3) evidencedbased practice, 4) quality improvement, and 5) medical informatics. these attributes are central to the new vision of family medicine education globally. furthermore, training should emphasize the biopsychosocial model, cultural proficiency and practice-based research.6 the best way to ensure that family physicians are able to deliver the core attributes of the specialty throughout their careers is to develop a comprehensive lifelong learning programme. this will be based on continuous personal, professional, and clinical practice assessment and improvement. professionalism family medicine as a medical profession is a recent dicipline in oman. we need to be part of and contribute to the development of the overall medical profession and work with the other medical disciplines to ensure that the services provided to the population are of the highest standard. the professionalism expected from family physicians includes certain skills, attitudes and behaviours during the practice of their profession. concepts such as maintenance of competence, ethical behavior, integrity, honesty, service to others, adherence to professional codes, justice, respect for others, self regulation will have to be emphasised and developed.7 this will be achieved not only by individual efforts, but also by professional bodies like the omani society of family medicine. these values can not be imported from anywhere in the world, but have to be developed indigenously taking into consideration the unique circumstances in oman including religious, social and cultural values. family physicians have to set high standards of professionalism to gain the confidence and trust not only of their patients, but also of society in general and peers in particular. the family medicine team which includes nurses, pharmacists, health educators, and administrators family medicine practice in oman present and future 118 | squ medical journal, august 2009, volume 9, issue 2 working in primary care need to take a more active role in delivering health care. this will help the doctors to concentrate more on addressing activities such as assessment and management of poorly differentiated symptoms. conclusion family medicine is a new specialty in oman; it needs to be nurtured well so that not only the individuals, but also the specialty achieves global standards. this requires constant evaluation and updating of the undergraduate and postgraduate teaching and training programmes. the needs of trained family physicians also need to be identified and addressed by constant monitoring including audits and peer reviews. there should be a constant review of resource allocation so that quality primary care is provided in the most cost effective manner. references 1. european definition of the discipline and speciality of general practice/family medicine. from http:// www.woncaeurope.org/definition%20gp-fm.htm 2. starfield b. primary care: balancing health needs, services and technology. oxford: oxford university press, 1998. 3. starfield b. new paradigms for quality in primary care. br j gen pract 2001; 51:303-9. 4. parchman m, culter s. primary care physicians and avoidable hospitalization. j fam pract 1994; 39:123-6. 5. bates dw, ebell m, gotlieb e, zapp j, mullins hc. a proposal for electronic medical records in u.s. primary care. j am med inform assoc 2003; 10:110. 6. future of family medicine project leadership committee. the future of family medicine: a collaborative project of the family medicine community. ann fam med 2004; 2:s1-s32. 7. canmeds 2000: professional role document. ottawa: royal college of physicians and surgeons of canada, 2000. available from http://rcpsc.medical. org/english/publications/roles_e.html. accessed may 2009. department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: sunilnadar@gmail.com characteristics and outcomes of critically ill patients with raised cardiac troponins admitted in the intensive care unit a single centre experience from oman *sunil k. nadar, muhammad m. shaikh, muhammad a. khatri, wael a. abdelmottaleb, sheeraz ahmed, abdulhakeem alhashim, mujahid albusaidi, fahad alkindi sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 37–44, epub. 28 feb 22 submitted 5 aug 20 revision req. 6 oct 20; revision recd. 2 nov 20 accepted 3 dec 20 https://doi.org/10.18295/squmj.4.2021.060 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. the use of high-sensiti ve c ardiac troponin (hs-ctn) assays has made it possible to identify previously unrecognised patients with myocardial injury in a variety of clinical settings.1,2 the heart, like any other organ, can be affected by systemic illnesses and although hs-ctn is highly specific to cardiac muscle, it does not differentiate between the aetiologically diverse types of myocardial infarction (mi) or non-mi-related myocardial injury.2,3 therefore, the fourth universal definition of mi includes the conditions of myocardial injury without infarction and states criteria to help differentiate between infarction and injury.4 indeed, in the definition, five subtypes have been introduced to account for the various pathophysiological processes involved. type 1 mi is the subtype commonly referred to as a ‘heart attack’ or an atherothrombotic mi due to plaque rupture. conversely, type 2 mi is associated with a demand–supply mismatch and is commonly found in critically ill patients admitted into the intensive care unit (icu) and in patients with other severe systemic illnesses. the other types of mi are those occurring in special circumstances, such as after an angioplasty, a coronary artery bypass grafting or a cardiac arrest. in critically ill patients, especially those who have had multi-organ failure and are hypotensive or hypoxic, the myocardium, along with other organs, is affected by the associated decreased perfusion. this leads to a demand–supply mismatch, which is exacerbated in the presence of coronary atheroma.5 abstract: objectives: critically ill patients have raised troponins. this study aimed to assess the incidence of myocardial injury in the intensive care unit (icu) at a tertiary care hospital and assess the management and prognosis. methods: this retrospective study included adult patients who were admitted to the icu of sultan qaboos university hospital, muscat, oman, between january and december 2019 and had undergone a highsensitive cardiac troponin (hs-ctn) assay. patients admitted with a primary diagnosis of myocardial infarction were excluded. results: a total of 264 patients had their hs-ctn measured during the study period. of these, 128 (64.3 ± 17.1 years; 58.6% male) had elevated levels, giving an incidence rate of approximately 48.5%. those with raised troponin were older and had more co-morbidities. these patients were also more critically ill with lower blood pressure, higher heart rates and increased hypotensive episodes. of these, 47 were treated for acute coronary syndrome, 32 underwent coronary angiography and only three required stenting. patients with raised troponin had a poor outcome with only 45 (35.2%) surviving to discharge compared to 101 (74.3%) with normal troponin. patients with raised troponin had shorter hospital stays than those with normal troponin (16 versus 19 days; p = 0.017). conclusion: a high proportion of critically ill patients showed evidence of myocardial injury without significant coronary artery disease, which is associated with a poor prognosis. further prospective studies are required to ascertain the best course of treatment for these patients. keywords: troponin; biomarkers; intensive care; myocardial infarction; oman advances in knowledge results show that the incidence of type 2 myocardial infarction (mi) in critically ill patients is relatively high and that of coronary artery disease is low. this is the first study of its kind from oman and describes the incidence of type 2 mi in the intensive care setting at a single tertiary care centre in oman. application to patient care the study shows that the probability of occurrence of type 1 mi in critically ill patients is low. these patients can be managed conservatively without the need for invasive tests until they are stable enough for further cardiac investigations. https://creativecommons.org/licenses/by-nd/4.0/ characteristics and outcomes of critically ill patients with raised cardiac troponins admitted in the intensive care unit a single centre experience from oman 38 | squ medical journal, february 2022, volume 22, issue 1 in milder forms, there could be a hypoxic myocardial injury, but in severe cases, the decreased perfusion could lead to muscle necrosis and infarction even in the absence of plaque rupture, ultimately leading to type 2 mi. previous studies have demonstrated a poorer prognosis in critically ill patients with raised troponin, either with or without features of type 2 mi.6,7 there are no clear guidelines on the management of the conditions of these patients; the management often varies from institution to institution and, indeed, sometimes even within an institution. this study aimed to assess the clinical features, treatment and prognosis of critically ill patients admitted to the icu with non-cardiac issues and raised troponin levels. in addition, this study sought to assess the angiographic results of these patients to evaluate the true incidence of coronary artery disease (cad) in this patient population. methods this retrospective study was conducted at the sultan qaboos university hospital, muscat, oman, from january to december 2019 and included patients who were admitted to the icu within the one-year study period. all patients above the age of 18 years at the time of admission to the icu during this period were eligible for inclusion. those who were admitted primarily with an mi (either with or without stsegment elevation on their electrocardiogram [ecg]) and those who did not have a troponin test done during their stay in the icu were excluded. electronic case records of eligible patients were reviewed for data retrieval. according to the fourth universal definition of mi, a patient is diagnosed as having a mi if their troponin levels increase by more than 20% from the baseline value (with at least one value above the 99th percentile) and the patient has chest pain, new ecg changes or new regional wall motion abnormality on echocardiogram.4 during the current study, if a patient exhibited a significant troponin rise with no other associated feature, a diagnosis of myocardial injury was made. statistical analysis was performed using the statistical package for the social sciences (spss), version 22.0 (ibm corp., chicago, illinois, usa). all data were presented as number (percentage) and mean ± standard deviation if normally distributed or median (interquartile range [iqr]) if not normally distributed. analysis was done using student’s t-test, mann-whitney u test or chi-square test, as appropriate. logistic regression was performed with inpatient death as the outcome variable and the various comorbid onditions, blood investigations and clinical parameters as the input variables. p <0.05 was considered to be statistically significant. ethical approval was obtained from the hospital under concern prior to the commencement of the study (squh 1461). as this was a retrospective study, patient consent was not required. results a total of 352 patients above the age of 18 were admitted to the icu at the sultan qaboos university hospital during the study period. of these patients, 264 had a troponin test done. the results of 128 patients showed raised troponin levels, resulting in a prevalence rate of approximately 48.5%. no gender-based difference was table 1: demographic and clinical characteristics of patients who underwent a high-sensitive cardiac troponin assay and were admitted to the intensive care unit at sultan qaboos university hospital, muscat, oman, between january and december 2019 (n = 264) demographic characteristic n (%) p value* troponin not raised (n = 136) troponin raised (n = 128) mean age in years ± sd 54.6 ± 19.3 64.3 ± 17.1 <0.001 gender 0.87 male 81 (59.6) 75 (58.6) female 55 (40.4) 53 (41.4) clinical characteristic hypertensive 51 (37.5) 83 (64.8) <0.001 diabetic 35 (25.7) 55 (43.0) 0.003 dyslipidaemia 19 (14.0) 37 (28.9) 0.003 smoker 14 (10.3) 4 (3.1) 0.02 known ihd 9 (6.6) 22 (17.2) 0.008 known ckd 36 (26.5) 56 (43.8) 0.003 mean sbp on admission in mmhg ± sd 123.1 ± 22.6 115.7 ± 28.4 0.014 mean dbp on admission in mmhg ± sd 74.8 ± 13.2 65.3 ± 16.1 <0.001 mean hr on admission in bpm ± sd 92.4 ± 17.3 96.2 ± 23.0 0.07 hypotensive episodes 46 (33.8) 92 (71.9) <0.001 sd = standard deviation; ihd = ischaemic heart disease; ckd = chronic kidney disease; sbp = systolic blood pressure; dbp = diastolic blood pressure; hr = heart rate; bpm =beats per minute. *using student t-test and chi-square test, as appropriate. sunil k. nadar, muhammad m. shaikh, muhammad a. khatri, wael a. abdelmottaleb, sheeraz ahmed, abdulhakeem alhashim, mujahid albusaidi and fahad alkindi clinical and basic research | 39 found between the patients with raised troponin and those with normal troponin. however, those who had a raised troponin level were significantly older (64.3 ± 17.1 versus 54.6 ± 19.3 years; p <0.001) and had more co-morbidities compared to those whose with normal troponin levels. in addition, those who had a raised troponin level had lower systolic (115.7 ± 28.4 versus 123.1 ± 22.6; p = 0.014) and diastolic blood pressure (65.3 ± 16.1 versus 74.8 ± 13.2; p <0.001) at the time of admission to the icu compared to those with normal troponin levels. furthermore, patients with raised troponin levels were more likely to have at least one hypotensive episodes (defined as one sustained episode of mean arterial pressure of <60 mmhg that lasts for 30 minutes; 71.9% versus 33.8%; p <0.001) [table 1]. those with normal troponins were more likely to have normal ecg or sinus tachycardia (75.7%), while those with raised troponins were more likely to have abnormalities such as st elevation or depression (25.0%), t wave inversions (15.6%) and bundle branch block (14.8%). the ejection fraction, as measured by echocardiography, was lower in patients with raised troponins; however, none had been diagnosed with stress-induced cardiomyopathy. patients with raised troponins also had lower haemoglobin and glomerular filtration rates, along with higher serum creatinine, c-reactive protein, n-terminal pro-brain type natriuretic peptide and troponins [table 2]. of the patients with raised troponins, 110 were referred to the cardiology department for specialist’s opinion. the treatment for acute coronary syndrome (acs)—dual antiplatelet and therapeutic anticoagulation therapy—was initiated for 47 of these. acs management was not started in the remaining patients for the following reasons: the rise was estimated to not be related to a cardiac condition in 44 patients, including six who were diagnosed with table 2: laboratory results of patients on admission to the intensive care unit who were tested for cardiac troponin levels (n = 264) n (%) p value* troponin not raised (n = 136) troponin raised (n = 128) ecg changes <0.001 not done 11 (8.1) 0 (0.0) normal 66 (48.5) 43 (33.6) sinus tachycardia 37 (27.2) 47 (36.7) bbb 21 (15.4) 19 (14.8) st depression 1 (0.7) 26 (20.3) t wave inversion 0 (0.0) 20 (15.6) frequent pvc† 0 (0.0) 10 (7.8) atrial fibrillation 0 (0.0) 13 (10.2) st elevation 0 (0.0) 6 (4.7) heart block 0 (0.0) 1 (0.8) other findings ejection fraction 55 ± 9 48 ± 15 <0.001 admission hb in g/dl 10.8 ± 1.5 10.3 ± 1.9 0.013 lowest hb in g/dl 9.3 ± 1.8 8.2 ± 1.7 <0.001 median admission creatinine in µmol/l (iqr) 65 (48–88) 76 (57–120) 0.004 median peak creatinine in µmol/l (iqr) 84 (68–104) 124 (76–250) <0.001 median gfr on admission to icu in ml/min (iqr) 90 (65–90) 81 (46–90) <0.001 median lowest gfr in ml/min (iqr) 75 (55–90) 45 (21–82) <0.001 median first troponin in ng/l (iqr) 17 (13–24) 50 (21–130) <0.001 median peak troponin in ng/l (iqr) 17 (12–22) 274 (99–756) <0.001 median crp in mg/l (iqr) 110 (54–238) 179 (99–290) 0.004 median d-dimer μg/lfeu (iqr) 2.5 (1.1–6.2) 4.5 (1.2–10.2) 0.21 mean total cholesterol in mmol/l ± sd 3.9 ± 1.2 3.9 ± 1.7 0.9 mean ldl in mmol/l ± sd 2.2 ± 1.05 1.7 (1.3–2.7) 0.28 mean hdl in mmol/l ± sd 0.99 ± 0.38 1.1 ± 0.4 0.3 median triglycerides in mmol/l (iqr) 1.4 (0.97–2.11) 1.2 (0.8–1.5) 0.37 median ldh in u/l (iqr) 439 (223–942) 405 (226–569) 0.43 median ntprobnp in pg/ml (iqr) 1,270 (280–3,379) 3,855 (1,479–11,571) 0.003 ecg = electrocardiogram; bbb = bundle branch block; pvc = premature ventricular contractions; hb = haemoglobin; iqr = interquartile range; gfr = glomerular filtration rate; icu = intensive care unit; crp = c-reac tive protein; feu = fibrinogen equivalent units; sd = standard deviation; ldl = low-density lipoprotein; hdl = high-density lipoprotein; ldh = lactic dehydrogenase; nt-probnp = n-terminal pro-brain-type natri uretic peptide. *using student’s t-test, chi-square test or mann–whitney u test, as appropriate. †frequent pvcs were defined as more than 10 pvcs per minute. characteristics and outcomes of critically ill patients with raised cardiac troponins admitted in the intensive care unit a single centre experience from oman 40 | squ medical journal, february 2022, volume 22, issue 1 a pulmonary embolus; 13 were designated as ‘not for resuscitation’ and six had significant bleeding. patients in whom acs treatment was initiated did not have significantly different troponin values or ecg changes as compared to those for whom acs treatment was not initiated. a coronary angiogram was performed in 30 of the 47 patients who were treated for acs. the reason for not performing angiogram in the remaining 17 was that seven patients were designated as ‘not for resuscitation’, six were very unstable and critical and, hence, not fit for invasive procedures and four did not give their consent. there were another two patients for whom acs treatment was not initiated but an angiogram was performed due to their clinical condition. of the 32 on whom angiogram was performed, 24 were normal, two had mild disease, three had longstanding chronic total occlusions and only three had a significant disease that required stenting. regarding the treatments received by the patients, those with raised troponins were more likely to receive therapeutic anticoagulation and dual antiplatelet therapy. they were also more likely to undergo dialysis and be started on inotropes (62.5% versus 29.4%; p <0.001) [table 3]. patients with raised troponins were more likely to have a diagnosis of sepsis, heart failure or pulmonary embolism, while those with normal troponins received diagnoses that included a central nervous system cause, malignancy, trauma and gastrointestinal bleed [table 4]. there were 46 patients (age 67.2 ± 14.2 years; n = 28 males) who fulfilled the criteria for a type 2 mi. although not statistically significant, these patients tended to be older than those who had myocardial injury without infarction; there was also a trend of them having more comorbidities, higher peak creatinine and troponin, higher mortality rates and shorter hospital stays. however, none of these parameters were found to be statistically significant [table 5]. patients with raised troponins had a shorter length of hospital stay than those with normal troponins (16 [range: 8–25] versus 19 [range: 13–28] days; p = 0.017). moreover, the in-hospital mortality rate of those with raised troponin was 64.8% compared to 26.5% for those with normal troponin levels. patients with raised troponins had a poor outcome, with only 45 (35.2%) surviving to discharge compared to 74.3% for those with normal troponin [table 6]. table 3: treatment/management of the patients who under went a high-sensitive cardiac troponin assay and were admitted to the intensive care unit at sultan qaboos uni versity hospital, muscat, oman, between january and december 2019 (n = 264) treatment/ management n (%) p value* troponin not raised (n = 136) troponin raised (n = 128) dialysis 23 (16.9) 38 (29.7) 0.01 therapeutic anticoagulation 0 53 (41.4) <0.001 prophylactic anticoagulation 86 (63.2) 43 (33.6) <0.001 any anticoagulation 86 (63.2) 96 (75.0) 0.51 antibiotics 99 (72.8) 116 (90.6) 0.01 inotropes 40 (29.4) 80 (62.5) <0.001 dual antiplatelet agents 0 (0.0) 47 (36.7) <0.001 single antiplatelet therapy 21 (15.4) 27 (21.1) 0.07 any antiplatelet therapy 21 (15.4) 74 (57.8) <0.001 cardiology consultation 17 (12.5) 110 (85.9) <0.001 *using chi-square test. table 4: final diagnosis of patients who underwent a high sensitive cardiac troponin assay and were admitted to the intensive care unit at sultan qaboos university hospital, muscat, oman, between january and december 2019 (n = 264) final diagnosis* n (%) p value† troponin not raised (n = 136) troponin raised (n = 128) sepsis 46 (33.8) 75 (58.6) <0.001 heart failure 10 (7.4) 38 (29.7) <0.001 pulmonary embolus 0 (0.0) 6 (4.7) 1.000 central nervous system cause 31 (22.8) 12 (9.4) <0.001 respiratory failure 18 (13.2) 2 (1.6) malignancy 22 (16.2) 12 (9.4) trauma 12 (8.8) 2 (1.6) ohca 3 (2.2) 10 (7.8) ckd 1 (0.7) 3 (2.3) gi cause 14 (10.3) 10 (7.8) others‡ 7 (5.1) 2 (1.6) ohca = out of hospital cardiac arrest; ckd = chronic kidney disease; gi = gastrointestinal. *values add up to more than the number of patients as some patients had more than one diagnosis. †analysis by chi-square test. ‡includes anaphylaxis, mesenteric ischaemia, poisoning and diabetic ketoacidosis. sunil k. nadar, muhammad m. shaikh, muhammad a. khatri, wael a. abdelmottaleb, sheeraz ahmed, abdulhakeem alhashim, mujahid albusaidi and fahad alkindi clinical and basic research | 41 another three patients with raised troponins out of the 45 who were discharged alive died at one month compared to none for the patients with normal troponins. however, there were more hospital readmissions within one month among the group with normal troponin levels. underlying malignancy was found in 12 of the 17 patients without raised troponins, and they were readmitted for a worsening condition/ sepsis; 10 of these patients died during the second admission. the remaining five patients were admitted for worsening renal functions and required dialysis. all three of the patients with raised troponins who were readmitted had presented with signs of sepsis. all three died during the second admission. the probability of death for people with a raised troponin level was calculated at 5.32 (95% confidence interval: 3.14–9.03). based on binary logistic regression, the factors that predicted in-hospital deaths were age (p = 0.01), peak troponin (p = 0.004), lowest haemoglobin (p = 0.01), peak serum creatinine and glomerular filtration rates (p = 0.02) and hypotensive episodes (p <0.001). the other parameters were not predictive. discussion raised cardiac troponins, in the absence of significant cad, have been described in many clinical scenarios, including sepsis, renal failure, generalised or localised infections and post-operative states and especially in critically ill patients.1 previous studies have stated a median value of 43% (iqr: 21–59%) of icu patients exhibiting raised troponin levels, with the figure rising to more than 60% for those with sepsis or septic shock.8,9 the mortality rate of these patients has also shown to be higher than those with normal troponin values.8 the findings of the current study are largely consistent with the published data and results showed that troponin levels were raised in 48.5% of those who were tested, with 58.6% of these patients having sepsis. the mortality rate of those with raised troponins was five times higher compared to those with normal levels. patients with raised troponin levels were generally more ill, are more likely to be on inotropes and have multi-organ failure and sepsis, which explains the higher mortality rate. the reasons for the raised troponins in the absence of cad range from myocardial inflammation (as seen in sepsis) to myocardial injury due to hypoxia, hypoperfusion and decreased excretion of the molecule, table 5: characteristics of patients with type 2 myocardial infarction versus myocardial injury without infarction (n = 128) characteristic n (%) p value* myocardial injury without infarction (n = 82) type 2 mi (n = 46) mean age in years ± sd 62.6 ± 18.1 67.2 ± 14.2 0.14 male:female ratio 47:35 28:18 0.69 alive on discharge 33 12 0.12 median peak troponin in ng/l (iqr) 262 (96–690) 351 (118–899) 0.32 median peak creatinine in µmol/l (iqr) 118 (72–211) 132 (83–281) 0.43 haemoglobin in g/l ± sd 10.3 ± 1.7 10.1 ± 2.3 0.91 hypertensive 51 (62.2) 32 (69.6) 0.41 diabetic 32 (39.0) 23 (50.0) 0.23 previous ihd 11 (13.4) 11 (23.9) 0.76 sepsis 48 (58.5) 27 (58.7) 0.18 median los in days (iqr) 17 (10–27) 12 (5–22) 0.13 mi = myocardial infarction; sd = standard deviation; iqr = interquartile range; ihd = ischaemic heart disease; los = length of hospital stay. *using student’s t-test, chi-square test or mann–whitney u test, as appropriate. table 6: outcomes at discharge and at one month of patients who underwent a high-sensitive cardiac troponin assay and were admitted to the intensive care unit at sultan qaboos university hospital, muscat, oman, between january and december 2019 (n = 264) n (%) p value* troponin not raised (n = 136) troponin raised (n = 128) median los in days (iqr) 19 (13–28) 16 (8–25) 0.017 alive at discharge 101 (73.5) 45 (35.1) <0.001 status at one month for patients discharged alive with follow-up 92 (67.4) 39 (30.5) alive† 75 (81.5) 33 (84.6) dead† 0 (0.0) 3 (7.7) readmitted† 17 (18.5) 3 (7.7) 0.001* no follow-up† 9 6 0.001† los = length of hospital stay; iqr = interquartile range. *using chi-square test. †percentage calculated out of the patients discharged alive with follow-up. characteristics and outcomes of critically ill patients with raised cardiac troponins admitted in the intensive care unit a single centre experience from oman 42 | squ medical journal, february 2022, volume 22, issue 1 as seen in the case of renal failure.2 many precipitants of myocardial injury in critically ill patients have been described such as tachycardia, anaemia, sepsis and hypotension; indeed, the current study confirms that those with raised troponin had a higher mean heart rate on admission, lower haemoglobin values, lower blood pressure and at least one hypotensive episode.10 stress-induced cardiomyopathy is also another entity that can occur in these patients and is not always identified on echocardiography.11 raised troponin levels alone are not diagnostic of an acute mi; patients need to fulfil the criteria, as described earlier. distinguishing between myocardial injury and either type 1 or type 1 mi is often difficult in the icu setting.12–14 inability to get a proper history of chest pain, lack of ‘baseline’ ecg and echocardiogram in many cases and lack of specificity of ecg and echocardiogram changes add to this diagnostic diff iculty.15,16 coronary angiographies are frequently required to differentiate between a type 1 and type 2 mi and further tools such as intravascular ultrasound or optical coherent tomography might be required to assess whether the atheroma is stable or unstable.5,17 physicians tend to err on the side of caution and there is a tendency to over-diagnose mi; indeed, postmortem studies suggest that the rate of type 2 mi is not as high as it is suspected clinically.16,18 one suggestion to help differentiate myocardial injury from mi is to use different thresholds for the troponin values.19 this approach, however, is unlikely to be effective, as the amount of troponin leak would depend on multiple factors, such as the underlying health condition of the myocardium (previous mi, cardiomyopathy, etc.) and the presence of non-obstructive atheroma. there are no clear guidelines regarding the management of patients with myocardial injury or type 2 mi, given the paucity of trial data. all the guidelines on acs management are for type 1 mi patients (either with or without st-segment elevation) who present with chest pain. the management of patients with type 2 mi is often left to the individual treating clinician. one of the approaches that many physicians take is to treat all patients with raised troponins as acs, unless there is a clear precipitating cause for non-ischaemic myocardial injury, and perform a coronary angiogram once the patient has been stabilised. however, many constraints often prevent this. many patients are hypotensive on inotropic support, and as such, antiischaemic measures such as beta-blockers or nitrates might not be appropriate. bleeding issues prevent the initiation of dual antiplatelet therapy.20 moreover, many patients with multiple underlying conditions and poor pre-morbid state are labelled ‘not for resuscitation’, and hence, invasive procedures may be deemed inappropriate in these situations. indeed, in the study’s cohort, only 47 out of the 128 patients were given treatment for acs management. as in other studies, the researchers found that a large proportion of the patients having raised troponins were not treated for acs.6,21–23 clear triggering factors for a demand–supply mismatch and alternative diagnosis such as heart failure or pulmonary embolism were the reasons in the current study. even where acs was considered, other factors such as altered coagulation profile, bleeding complications and general conditions prevented the initiation of acs management, thereby reflecting the complex nature of these patients and the practical difficulties encountered in their management in a realworld setting. although acs management might be ineffective in non-coronary-related myocardial injury or type 2 mi, evidence suggests that aspirin, beta-blockers and statin might improve prognosis.24 it has been postulated that serious or critical illness might trigger a hypercoagulable state and this is countered with the aspirin.25 beta-blockers have been suggested to help by reducing the cardiac workload and reducing the heart rate, thereby reducing oxygen demand.5 however, these data are derived from retrospective studies; prospective studies are required to conclusively show the benefit of this method. subjecting these critically ill patients to an invasive coronary angiogram is debatable. previous studies have shown quite a variable rate of angiography in these patients, with many studies showing a high prevalence of normal coronaries or non-obstructive lesions in patients with sepsis and raised troponins.21 in the current study, a high proportion of patients treated for acs underwent a coronary angiogram, with only three patients having significant coronary artery disease (suggesting a type 1 mi) that required stenting. the management of patients with coincidental coronary atheroma is controversial. it has been suggested that relieving this obstruction may benefit the patient, as in the presence of coronary atheroma, the threshold for the cause of a demand–supply mismatch is lower. removing this obstruction could theoretically increase the threshold for myocardial injury.5 however, there are no trials to prove this, and this potential improvement in the flow could be offset by an increased risk of bleeding.5 the appropriateness of coronary investigation in myocardial injury and type 2 mi trial is an ongoing randomised trial that compares invasive coronary angiography (or coronary computed tomography angiogram) with conservative management on two-year all-cause mortality, which sunil k. nadar, muhammad m. shaikh, muhammad a. khatri, wael a. abdelmottaleb, sheeraz ahmed, abdulhakeem alhashim, mujahid albusaidi and fahad alkindi clinical and basic research | 43 the researchers hope would provide insights into the management of these patients.26 in keeping with other studies, the current study found that patients with raised troponins had a higher mortality rate (five-fold) than those with normal troponin values. these patients had a lower length of stay in the hospital, presumably since many died early during the hospital stay. the reason for this increased mortality could be the severe nature of the underlying illness. in the current study, the majority of the patients with raised troponin had sepsis, and, indeed, many had experienced at least one hypotensive episode and needed inotropes, reflecting the serious nature of their illness. the current study, being retrospective in nature, is characterised by limitations that are inherent to such types of studies. the quality of the data obtained depends on the quality of the electronic records. in most cases, all of the required information could be extracted. follow-up information, however, was lacking in a small number of patients. the group considered to be type 2 mi was not analysed separately due to the difficulty in making that diagnosis, which is similar to the approach of other published studies on the topic.6,7,8,9 it is likely that the hs-ctn assays in this study picked up a higher number of myocardial injury without mi. indeed, in the cohort, only 48 of the 128 patients with raised troponin fulfilled the criteria for type 2 mi, and it is probable that only a smaller number of these would have had histopathological changes of mi. despite these limitations, the data are important, as they provide information about myocardial injury in the icu setting in oman. in addition, this study is the first of its kind from the region. conclusion a large proportion of critically ill patients admitted to the icu had evidence of myocardial injury and/ or mi. these patients had a worse prognosis and treating them for acs did not appear to improve their prognosis. thus, more research is required to fully understand the pathophysiology and management of these patients. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n mms, mak, waa, sa, aa, ma and fa collected the data. skn analysed the data. ma, fa and skn drafted the manuscript. all authors approved the final version of the manuscript. references 1. giannitsis e, katus ha. cardiac troponin level elevations not related to acute coronary syndromes. nat rev cardiol 2013; 10:623–34. https://doi.org/10.1038/nrcardio.2013.129. 2. mueller m, vafaie m, biener m, giannitsis e, katus ha. cardiac troponin t: from diagnosis of myocardial infarction to cardiovascular risk prediction. circ j 2013; 77:1653–61. https:// doi.org/10.1253/circj.cj-13-0706. 3. de lemos ja, drazner mh, omland t, ayers cr, khera a, rohatgi a, et al. association of troponin t detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. jama 2010; 304:2503–12. https:// doi.org/10.1001/jama.2010.1768. 4. thygesen k, alpert js, jaffe as, chaitman br, bax jj, morrow da, et al. fourth universal definition of myocardial infarction (2018). circulation 2018; 138:e618–51. https://doi.org/10.1161/ cir.0000000000000617. 5. defilippis ap, chapman ar, mills nl, de lemos ja, arbabzadeh a, newby lk, et al. assessment and treatment of patients with type 2 myocardial infarction and acute nonischemic myocardial injury. circulation 2019; 140:1661–78. https://doi. org/10.1161/circulationaha.119.040631. 6. alatassi a, habbal m, tamim h, sadat m, al qasim e, arabi ym. association between troponin-i levels and outcome in critically ill patients admitted to non-cardiac intensive care unit with high prevalence of cardiovascular risk factors. bmc anesthesiol 2018; 18:54. https://doi.org/10.1186/s12871-018-0515-7. 7. saaby l, poulsen ts, diederichsen ac, hosbond s, larsen tb, schmidt h, et al. mortality rate in type 2 myocardial infarction: observations from an unselected hospital cohort. am j med 2014; 127:295–302. https://doi.org/10.1016/j.amjmed.2013.12.020. 8. lim w, qushmaq i, devereaux pj, heels-ansdell d, lauzier f, ismaila as, et al. elevated cardiac troponin measurements in critically ill patients. arch intern med 2006; 166:2446–54. https://doi.org/10.1001/archinte.166.22.2446. 9. bessière f, khenifer s, dubourg j, durieu i, lega jc. prognostic value of troponins in sepsis: a meta-analysis. intensive care med 2013; 39:1181–9. https://doi.org/10.1007/s00134-013-2902-3. 10. sandoval y, smith sw, thordsen se, apple fs. supply/demand type 2 myocardial infarction: should we be paying more attention? j am coll cardiol 2014; 63:2079–87. https://doi. org/10.1016/j.jacc.2014.02.541. 11. roffi m, patrono c, collet jp, mueller c, valgimigli m, andreotti f, et al. 2015 esc guidelines for the management of acute coronary syndromes in patients presenting without persistent stsegment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation of the european society of cardiology (esc). eur heart j 2016; 37:267–315. https://doi.org/10.1093/ eurheartj/ehv320. 12. gard a, lindahl b, batra g, hadziosmanovic n, hjort m, szummer ke, et al. interphysician agreement on subclassif ication of myocardial infarction. heart 2018; 104:1284–91. https://doi.org/10.1136/heartjnl-2017-312409. 13. shah as, mcallister da, mills r, lee kk, churchhouse am, fleming km, et al. sensitive troponin assay and the classification of myocardial infarction. am j med 2015; 128:493–501.e3. https://doi.org/10.1016/j.amjmed.2014.10.056. 14. fernandes cj jr, akamine n, knobel e. cardiac troponin: a new serum marker of myocardial injury in sepsis. intensive care med 1999; 25:1165–8. https://doi.org/10.1007/s001340051030. https://doi.org/10.1038/nrcardio.2013.129 https://doi.org/10.1253/circj.cj-13-0706 https://doi.org/10.1253/circj.cj-13-0706 https://doi.org/10.1001/jama.2010.1768 https://doi.org/10.1001/jama.2010.1768 https://doi.org/10.1161/cir.0000000000000617 https://doi.org/10.1161/cir.0000000000000617 https://doi.org/10.1161/circulationaha.119.040631 https://doi.org/10.1161/circulationaha.119.040631 https://doi.org/10.1186/s12871-018-0515-7 https://doi.org/10.1016/j.amjmed.2013.12.020 https://doi.org/10.1001/archinte.166.22.2446 https://doi.org/10.1007/s00134-013-2902-3 https://doi.org/10.1016/j.jacc.2014.02.541 https://doi.org/10.1016/j.jacc.2014.02.541 https://doi.org/10.1093/eurheartj/ehv320 https://doi.org/10.1093/eurheartj/ehv320 https://doi.org/10.1136/heartjnl-2017-312409 https://doi.org/10.1016/j.amjmed.2014.10.056 https://doi.org/10.1007/s001340051030 characteristics and outcomes of critically ill patients with raised cardiac troponins admitted in the intensive care unit a single centre experience from oman 44 | squ medical journal, february 2022, volume 22, issue 1 15. ver elst km, spapen hd, nguyen dn, garbar c, huyghens lp, gorus fk. cardiac troponins i and t are biological markers of left ventricular dysfunction in septic shock. clin chem 2000; 46:650–7. https://doi.org/10.1093/clinchem/46.5.650. 16. saaby l, poulsen ts, hosbond s, larsen tb, pyndt diederichsen ac, hallas j, et al. classification of myocardial infarction: frequency and features of type 2 myocardial infarction. am j med 2013; 126:789–97. https://doi.org/10.1016/j.amjmed.2013.02.029. 17. kubo t, imanishi t, takarada s, kuroi a, ueno s, yamano t, et al. assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. j am coll cardiol 2007; 50:933–9. https://doi.org/10.1016/j.jacc.20 07.04.082. 18. berlot g, vergolini a, calderan c, bussani r, torelli l, lucangelo u. acute myocardial infarction in non-cardiac critically ill patients: a clinical-pathological study. monaldi arch chest dis 2010; 74:164–71. https://doi.org/10.4081/ monaldi.2010.257. 19. lindahl b, baron t, erlinge d, hadziosmanovic n, nordenskjöld a, gard a, et al. medical therapy for secondary prevention and long-term outcome in patients with myocardial infarction with nonobstructive coronary artery disease. circulation 2017; 135:1481–9. https://doi.org/10.1161/circulationah a.116.026336. 20. ammann p, maggiorini m, bertel o, haenseler e, joller-jemelka hi, oechslin e, et al. troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. j am coll cardiol 2003; 41:2004–9. https://doi.org/10.1016/s07351097(03)00421-2. 21. baron t, hambraeus k, sundström j, erlinge d, jernberg t, lindahl b, et al. type 2 myocardial infarction in clinical practice. heart 2015; 101:101–6. https://doi.org/10.1136/heartjnl-2014-3 06093. 22. furie n, israel a, gilad l, neuman g, assad f, ben-zvi i, et al. type 2 myocardial infarction in general medical wards: clinical features, treatment, and prognosis in comparison with type 1 myocardial infarction. medicine (baltimore) 2019; 98:e17404. https://doi.org/10.1097/md.0000000000017404. 23. rothenberg fg, clay mb, jamali h, vandivier-pletsch rh. systematic review of beta blocker, aspirin, and statin in critically ill patients: importance of severity of illness and cardiac troponin. j investig med 2017; 65:747–53. https://doi. org/10.1136/jim-2016-000374. 24. jackson sp, darbousset r, schoenwaelder sm. thromboin flammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. blood 2019; 133:906–18. https://doi.org/10.1182/blood-2018-11-882993. 25. altmann dr, korte w, maeder mt, fehr t, haager p, rickli h, et al. elevated cardiac troponin i in sepsis and septic shock: no evidence for thrombus associated myocardial necrosis. plos one 2010; 5:e9017. https://doi.org/10.1371/journal.pone.0009017. 26. lambrakis k, french jk, scott ia, briffa t, brieger d, farkouh me, et al. the appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (act-2): a randomized trial design. am heart j 2019; 208:11–20. https://doi.org/10.1 016/j.ahj.2018.09.016. https://doi.org/10.1093/clinchem/46.5.650 https://doi.org/10.1016/j.amjmed.2013.02.029 http://v http://v https://doi.org/10.4081/monaldi.2010.257 https://doi.org/10.4081/monaldi.2010.257 https://doi.org/10.1161/circulationaha.116.026336 https://doi.org/10.1161/circulationaha.116.026336 https://doi.org/10.1016/s0735-1097(03)00421-2 https://doi.org/10.1016/s0735-1097(03)00421-2 https://doi.org/10.1136/heartjnl-2014-306093 https://doi.org/10.1136/heartjnl-2014-306093 https://doi.org/10.1097/md.0000000000017404 https://doi.org/10.1136/jim-2016-000374 https://doi.org/10.1136/jim-2016-000374 https://doi.org/10.1182/blood-2018-11-882993 https://doi.org/10.1371/journal.pone.0009017 https://doi.org/10.1016/j.ahj.2018.09.016 https://doi.org/10.1016/j.ahj.2018.09.016 covid-19 associated pneumonia a review of chest radiograph and computed tomography findings *rashid s. al-umairi, joukha al-kalbani, saqar al-tai, ahmed al-abri, faiza al-kindi, atheel kamona sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e4–11, epub. 15 mar 21 submitted 7 may 20 revision req. 29 jul 20; revision recd. 12 sep 20 accepted 17 oct 20 department of radiology, royal hospital, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com in december 2019, an outbreak of severepneumonia of unknown aetiology emerged in wuhan, china; by january 2020, the infectious illness was termed covid-19 and the causative virus identified as a novel strain of betacoronavirus, specif ically severe acute respiratory syndrome (sars) coronavirus 2 (cov-2).1 since then, cases of covid-19 have rapidly spread worldwide as a result of humanto-human transmission, with a total of 2,668,135 confirmed cases and 190,236 deaths globally as of april 2020.2 common clinical symptoms of covid-19 include coughing and fever, while other symptoms such as chest pain, muscle ache, abdominal pain or diarrhoea, pharyngeal discomfort, headaches and dizziness are less frequent.3–5 in most cases, a diagnosis of covid-19 is based on a combination of clinical findings and positive results from a real-time polymerase chain reaction (rt-pcr) assay of specimens and aspirates from the upper respiratory tract, bronchia or trachea.6 however, medical imaging modalities, including chest radiography and computed tomography (ct), have proven to hold high diagnostic sensitivity and can act as a supplement to rt-pcr testing in establishing the diagnosis.7 moreover, such imaging is essential in monitoring disease progression during the admission period. this article provides an overview of the available evidence regarding characteristic chest radiograph and ct findings among patients with covid-19 associated pneumonia, illustrated by cases from the authors’ own experience at the royal hospital, muscat, oman. methods this non-systematic narrative review was performed in april 2020. a search was conducted of the google scholar (google llc, mountain view, california, usa) and medline® (national library of medicine, bethesda, maryland, usa) databases to identify all englishlanguage research studies reporting chest radiograph and ct findings of patients with confirmed diagnoses of covid-19 associated pneumonia. articles were review االلتهاب الرئوي املصاحب لكوفيد-19 مراجعة حبثية لنتائج التصوير أبشعة اكس واألشعة املقطعية را�صد �صيف العمريي، جوخة الكلباين، �صقر الطائي، احمد العربي، فايزة الكندي، اثيل كمونه abstract: medical imaging, including chest radiography and computed tomography, plays a major role in the diagnosis and follow-up of patients with covid-19 associated pneumonia. this review aims to summarise current information on this topic based on the existing literature. a search of the google scholar (google llc, mountain view, california, usa) and medline® (national library of medicine, bethesda, maryland, usa) databases was conducted for articles published until april 2020. a total of 30 articles involving 4,002 patients were identified. the most frequently reported imaging findings were bilateral ground glass and consolidative pulmonary opacities with a predominant lower lobe and peripheral subpleural distribution. keywords: covid-19; viral pneumonia; diagnostic imaging; x-ray computed tomography; radiography; review. امللخ�ص: يلعب الت�صوير الطبي، مبا يف ذلك الت�صوير باأ�صعة اك�ص والأ�صعة املقطعية، دورا رئي�صيا يف ت�صخي�ص ومتابعة املر�صى امل�صابني باللتهاب الرئوي املرتبط بفريو�ص كوفيد-19. تهدف هذه املراجعة البحثية اىل تلخي�ص املعلومات احلالية حول هذا املو�صوع بناء على الأدبيات املوجودة. مت البحث يف قواعد بيانات جوجل العلمي )�رشكة جوجل كاليفورنيا، الوليات املتحدة المريكية( والببميد )من املكتبة الوطنية للطب، ماريالند، الوليات املتحدة الأمريكية( عن املقالت املن�صورة حتى ابريل 2020. مت ت�صمني ما جمموعه 30 مقالة يف هذه املراجعة البحثية، �صمت ماعدده 4,002 مري�ص. اأظهرت هذه املراجعة البحثية ان اأكرث نتائج الت�صور �صيوعا التي مت الإبالغ عنها هي ت�صلد الزجاج املطحون وعتامة الرئة والتي عادة ما ي�صيب الرئتني معا وبتوزيع �صائد لأطراف الرئتني وللف�صني ال�صفليني. الكلمات املفتاحية: كوفيد-19؛ التهاب رئوي فريو�صي؛ الت�صوير الت�صخي�صي؛ الأ�صعة املقطعية؛ الت�صوير ال�صعاعي؛ مراجعة. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.002 https://creativecommons.org/licenses/by-nd/4.0/ rashid s. al-umairi, joukha al-kalbani, saqar al-tai, ahmed al-abri, faiza al-kindi and atheel kamona review | e5 identified using a combination of search terms inc luding “coronavirus”, “sars-cov-2”, ”covid-19”, “computed tomography” and “chest radiograph”. following the initial search, the titles and abstracts of all articles were screened for eligibility by two reviewers [figure 1]. only peer-reviewed studies published in english as of april 2020 with extractable full texts and conducted on humans were included in the review. studies with no medical imaging findings, those focusing on paediatric populations and those involving fewer than 10 cases were excluded, as were case reports, editorials, letters to the editor and systematic and pictorial reviews. subsequently, important data regarding chest radiograph and ct findings were extracted from the studies, including lung parenchymal findings (i.e. the presence of ground glass opacities [ggos], consolidation, crazy paving, interstitial thickening/ reticulation and fibrotic streaks/lineal opacities), pleural findings (i.e. the presence of pleural effusion and pleural thickening/retraction) and lymph node findings (i.e. the presence of lymphadenopathy). results a total of 30 studies involving the chest radiograph and ct findings of patients with covid-19 associated pneumonia were identified and included in the analysis.8–37 overall, these studies involved a total of 4,002 patients with confirmed covid-19 diagnoses. the mean age was 49.6 years.8–37 figure 1: flowchart showing the selection process used to identify articles included in the qualitative synthesis. table 1: review of chest radiograph findings in studies of patients with covid-19 (n = 2)21,29 author and year of publication sample size mean/ median age in years male/female distribution chest radiograph findings,n (%) no abnormality cons ggo increased hazy opacity pe distribution/ predominance lomoro et al.21 (2020) 32* 66.3 36/22* 5 (15.6) 15 (46.9) 12 (37.5) • bilateral: 25 (78.1) • unilateral: 2 (6.2) • neither bilateral nor unilateral: 5 (15.6) wong et al.29 (2020) 64 56 26/38 13 (20.3) 30 (47) 21 (33) 2 (3) • bilateral: 32 (50) • unilateral, right lung: 10 (16) • unilateral, left lung: 9 (14) • peripheral: 26 (41) • perihilar: 6 (9) • neither peripheral nor perihilar: 19 (30) • lower zone: 32 (50) cons = consolidation; ggo = ground glass opacity; pe = pleural effusion. *out of a total of 58 patients, including 22 who underwent chest ultraso nography, 32 who underwent chest radiography and 42 who underwent computed tomography. covid-19-associated pneumonia a review of chest radiograph and computed tomography findings e6 | squ medical journal, february 2021, volume 21, issue 1 chest radiograph findings were reported in only two studies [table 1].21,29 lomoro et al. confirmed bilateral lung consolidation to be the most common chest radiograph finding among 32 patients with covid-19.21 similarly, wong et al. found bilateral and lower lung peripheral consolidation to be most frequent among 64 patients.29 in contrast, chest ct findings were reported in 29 studies [table 2].8–28,30–37 the most common ct findings were ggos followed by consolidation.8–28,30–37 such features were usually bilateral with predominant lower lobe and peripheral subpleural distribution. another common finding was crazy paving (5– 70.6%).9–11,14,17–21,24,30,32,34,37 notably, pleural effusion and lymphadenopathy were reported in a minority of patients (1–13.9% and 1–14.3%, respectively).9–11,19–21,26,27,30–34,36,37 other uncommon manifestations included interstitial thickening/reticulation, linear opacities/fibrotic streaks, pleural thickening, reverse halo signs, pulmonary nodules, air bronchograms and vascular enlarge ment.8,10,11,13,16,22,25–27,31,32,34,36,37 discussion medical imaging can help to supplement rt-pcr assay results in the diagnosis of covid-19 by showing characteristic imaging findings. in fact, fang et al. demonstrated that the sensitivity of chest ct imaging was actually higher than that of rt-pcr assay results (98% versus 71%).15 similarly, in a recent meta-analysis, kim et al. reported that chest ct had a high sensitivity in the diagnosis of covid-19 (rate: 94%, 95% confidence interval: 91–96%).38 falaschi et al. also reported the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of ct imaging in the identification of sarscov-2 infections to be 90.7%, 78.8%, 86.4%, 85.1% and 85.9%, respectively.7 moreover, chest ct scans have been able to detect covid-19 associated lung changes even in asymptomatic patients.18 nevertheless, it is important to note that routine ct screening is not currently recommended as a method of identifying covid-19 infections. according to a statement issued by the fleischner society in april 2020, the use of imaging is not indicated for the purposes of triaging asymptomatic or mildly symptomatic patients; instead, chest ct is advocated only for covid-19 patients with worsening respir atory statuses or those with moderate to severe symptoms, regardless of rt-pcr test results.39 c h e s t r a d i o g r a p h f i n d i n g s there is evidence to demonstrate that chest radiography is less sensitive in the early stages of covid-19 compared to ct.29 however, due to issues related to infection control while transporting patients to the ct room and the lack of availability of ct equipment in many parts of the world, chest radiography is widely accepted as an alternative imaging modality for the identification and follow-up of lung abnormalities.40 moreover, portable x-ray machines can be used to image infected patients in isolation rooms, thereby lowering the risk of avoidable infectious exposure along the transport route. in addition, the low radiation dose involved in radiography compared to ct makes it an ideal imaging modality for follow-up purposes.41 in covid-19 cases, the appearance of lung changes on chest radiography is dependent on the stage of disease. initially, chest radiographs are usually insensitive to mild changes in patients with early disease; however, at later or more advanced stages, radiograph abnormalities are usually apparent.29 based on the results of the current review, the most common radiograph findings in patients with covid-19 assoc iated pneumonia included consolidation, ggos or increased hazy opacity, most frequently bilateral with a lower lobe and peripheral subpleural predominance [figure 2].21,29 however, these findings can overlap with those observed in other forms of viral pneumonia; as such, chest radiograph findings should be interpreted in view of the specific clinical context of the patient.42 c h e s t c o m p u t e d t o m o g r a p h y f i n d i n g s as demonstrated by the present review, a wide variety of ct findings for covid-19 have been reported in the literature.8–28,30–37 of these, the most frequently reported were ggos, either as an isolated abnormality or combined with other features such as consolidation, crazy paving, interstitial thickening/reticulation and linear opacities/fibrotic streaks.8–28,30–37 such findings tended to be bilateral, multifocal and with a lower lobe peripheral subpleural predominance [figure 3]. in contrast, pleural effusion, pleural thickening and lymphadenopathy were uncommon ct findings in patients with covid-19 associated pneumonia.9–11,19–21, 26,27,30–34,36,37 other rare findings reportedly include organising pneumonia and both reversed halo and halo signs; however, such features have been reported in only a few case series and are not specific to covid-19 associated pneumonia.43–45 the underlying pathological mechanism of such findings is unclear; however, it is thought that they represent the healing process of lung injuries related to covid-19 infection. as with radiography, ct findings in covid-19 patients appear to vary according to different disease stages.24,27 typical ct manifestations in the ultra-early stage (i.e. 1–2 weeks after exposure, when patients are rashid s. al-umairi, joukha al-kalbani, saqar al-tai, ahmed al-abri, faiza al-kindi and atheel kamona review | e7 table 2: review of computed tomography findings in studies of patients with covid-19 (n = 29)8–28,30–37 author and year of public ation sample size mean/ median age in years male/ female distrib ution ct findings, n (%) cons ggo both cons and ggo crazy paving itr fs or linear opacity pe pt or retraction lap distribution/ predominance ai et al.8 (2020) 888 51 447 (50) 409 (46) 8 (1) • bilateral: 801 (90) bai et al.9 (2020) 219 45 119/100 150 (69) 200 (91) 11 (5) 111 (51) 9 (4) 32 (15) 6 (3) • unilateral: 41f (19) • bilateral: 165 (75) • central: 3 (1) • peripheral: 176 (80) • both central and peripheral: 31 (14) bernheim et al.10 (2020) 121 45 61/60 2 (2) 41 (34) 50 (51) 6 (5) 9 (7) 1 (1) • bilateral: 73 (60) • peripheral: 63 (52) chate et al.11 (2020) 12 4 (33) 12 (100) 7 (58) 1 (8) • bilateral: 11 (92) • peripheral: 9 (75) • lower lobes: 8 (67) chen et al.12 (2020) 99 55.5 67/32 14 (14) • bilateral: 74 (75) • unilateral: 25 (25) cheng et al.13 (2020) 11 50.4 8/3 6 (54.5) 11 (100) 9 (81.8) 2 (18.2) • peripheral: 11 (100) • right lower lobe: 8 (72.7) • left lower lobe: 7 (63.6) chung et al.14 (2020) 21 51 13/8 12 (57) 6 (29) 4 (19) 3 (14) • bilateral: 16 (76) • unilateral: 2 (10) • peripheral: 7 (33) fang et al.15 (2020) 51 45 29/22 36 (71) • peripheral: 36 (51) • lower lobes: 36 (51) guan et al.16 (2020) 1,099 47 640/459 409 (37.2) 550 (50) 143 (13) • bilateral: 505 (46) han et al.17 (2020) 108 45 38/70 6 (6) 65 (60) 44 (41) 43 (40) • peripheral: 97 (90) • central: 2 (2) • both peripheral and central: 9 (8) inui et al.18 (2020) 104 62 54/50 22 (21) 30 (29) 11 (11) • peripheral: 35 (34) • central: 4 (4) • mixed: 24 (23) li et al.19 (2020) 83 45.5 44/39 53 (63.9) 81 (97.6) 30 (36.1) 54 (65.1) 7 (8.4) • bilateral: 79 (95.2) • lower lobes: 80 (96.4%) li et al.20 (2020) 51 58 28/23 3 (5.9) 18 (35.3) 28 (54.9) 36 (70.6) 1 (2) • peripheral and subpleural: 49 (96.1) lomoro et al.21 (2020) 42* 66.3* 36/22* 15 (35.7) 25 (59.5) 24 (57.1) 21 (50) 3 (7.1) 6 (14.3) • peripheral: 27 (64.3) • central: 1 (2.4) • peripheral and central: 12 (28.6) • neither peripheral nor central: 2 (4.8) meng et al.22 (2020) 58 42.6 26/32 3 (5.2) 30 (51.7) • bilateral: 24 (41.4) • peripheral: 44 (75.9) • central: 14 (24.1) ng et al.23 (2020) 21 56 13/8 13 (62) 18 (86) • peripheral: 18 (86) • perihilar: 1 (5) pan et al.24 (2020) 21 40 6/15 19 (90) 15 (71) 4 (19) • peripheral: 13 (62) • random: 7 (33) • diffuse: 1 (4.8) pan et al.25 (2020) 63 44.9 33/30 12 (19) 54 (85.7) 11 (17.5) shi et al.26 (2020) 81 49.5 42/39 14 (17.3) 53 (65.5) 3 (3.7) 4 (4.9) 26 (32.1) 5 (6.2) • unilateral: 17 (21) • bilateral: 64 (79) • central: 10 (12.4) • peripheral: 44 (54.3) • both central and peripheral: 27 (33.3) song et al.27 (2020) 51 49 25/26 28 (55) 39 (77) 30 (59) 1(2) 4 (8) 3 (6) • bilateral: 44 (86) • lower lobes: 46 (90) • peripheral: 44 (86) wang et al.28 (2020) 138 56 75/63 138 (100) • bilateral: 138 (100) wu et al.30 (2020) 80 44 42/38 50 (63) 73 (91) 23 (29) 5 (6) • subpleural: 42 (53) • diffuse: 7 (9) • peribronchial: 3 (4) • mixed: 24 (30) ct = computed tomography; cons = consolidation; ggo = ground glass opacity; itr = interstitial thickening or reticulation; fs = fibrotic streaks; pe = pleural effusion; pt = pleural thickening ; lap = lymphadenopathy; inc. = including. *out of a total of 58 patients, including 22 who underwent chest ultrasonography, 32 who underwent chest radiography and 42 who underwent ct. †within the lobes of 41 moderate/severe/critically ill patients. covid-19-associated pneumonia a review of chest radiograph and computed tomography findings e8 | squ medical journal, february 2021, volume 21, issue 1 table 2 (cont’d): review of computed tomography findings in studies of patients with covid-19 (n = 29)8–28,30–37 author and year of public ation sample size mean/ median age in years male/ female distrib ution ct findings, n (%) cons ggo both cons and ggo crazy paving itr fs or linear opacity pe pt or retraction lap distribution/ predominance xu et al.32 (2020) 90 50 39/51 12 (13) 65 (72) 11 (12) 33 (37) 55 (61) 4 (4) 50 (56) 1 (1) • peripheral: 46 (51) • bilateral: 53 (59) • lower lobes: 47 (52) • upper lobes: 40 (44) xu et al.33 (2020) 50 43.9 29/21 15 (30) 30 (60) 25 (50) 4 (8) • peripheral†: 39 (95.1) • central†: 19 (46.3) • peripheral involving central†: 23 (56.1) • symmetrical†: 26 (63.4) zhang et al.34 (2020) 120 45.4 43/77 62 (52) 107 (89) 30 (25) 75 (63) 9 (8) 5 (4) • bilateral: 68 (57) • peripheral: 109 (91) • central: 39 (33) zhao et al.35 (2020) 19 48 11/8 17 (89.47) • bilateral: 15 (78.95) zhao et al.36 (2020) 101 44.44 56/45 44 (43.6) 87 (86.1) 65 (64.4) 49 (48.5) 14 (13.9) 1 (1) • unilateral: 10 (9.9) • bilateral: 83 (82.2) • peripheral: 88 (87.1) • lower lobes: 55 (54.5) • upper lobes: 6 (5.9) zhou et al.37 (2020) 62 52.8 39/23 21 (33.9) 25 (40.3) 39 (62.9) 35 (56.5) 6 (9.7) 35 (56.5) • peripheral: 48 (77.4) • both peripheral and central: 14 (22.6) ct = computed tomography; cons = consolidation; ggo = ground glass opacity; itr = interstitial thickening or reticulation; fs = fibrotic streaks; pe = pleural effusion; pt = pleural thickening; lap = lymphadenopathy; inc. = including. *out of a total of 58 patients, including 22 who underwent chest ultrasonography, 32 who underwent chest radiography and 42 who underwent ct. †within the lobes of 41 moderate/severe/critically ill patients. figure 2: chest x-rays of (a) a 67-year-old man with covid-19 showing bilateral consolidation with a predominant peripheral distribution (arrows) and (b) a 44-year-old women with covid-19 showing bilateral consolidation with a predominant lower lobe and peripheral distribution (arrows). figure 3: high-resolution axial chest computed tomography scans of (a) a 35-year-old male patient with covid-19 showing right lower peripheral subpleural consolidation and ground glass opacity (ggo; arrows), (b) a 46-year-old male patient with covid-19 showing bilateral predominant peripheral subpleural consolidation and ggo (arrows), (c) a 62-year-old male patient with covid-19 showing bilateral lower lobe consolidation (arrows) and (d) a 67-year-old male patient with covid-19 showing bilateral predominant peripheral subpleural consolidation and ggo (arrows) and interlobular septal thickening with crazy paving involving the lingula (arrowhead). rashid s. al-umairi, joukha al-kalbani, saqar al-tai, ahmed al-abri, faiza al-kindi and atheel kamona review | e9 usually asymptomatic) include patchy consolidation and air bronchograms, nodules surrounded by ggo and single or multifocal ggos, progressing to single or multiple patchy ggos or ggos associated with interlobular septal thickening in the early stage (i.e. 1–3 days after the onset of symptoms).46 during the rapid progression stage (i.e. 3–7 days after the onset of symptoms), ct findings include large areas of consolidation with air bronchograms. in the consolidation stage (i.e. 7–14 days after the onset of symptoms), the size and density of this consolidation appears to regress. finally, during the dissipation stage (i.e. 2–3 weeks after the onset of symptoms), ct imaging shows further regression of the consolidation seen in the earlier stages, with a few residual patchy and scattered areas associated with interlobular septal thickening and the strip-like twisting of the bronchial wall.46 pan et al. noted that 85% of 63 patients who underwent follow-up chest ct scans within two weeks of the initial scan showed signs associated with disease progression, such as an increase in ggos, consolidative opacities, interstitial septal thickening and pulmonary nodules.25 in humans, coronaviruses can cause a variety of respiratory illnesses ranging from the common cold to severe pneumonia, including sars and middle east respiratory syndrome (mers).47,48 chest ct findings in covid-19 cases can imitate manifestations of both infectious and non-infectious disease, especially those observed in other viral pneumonias. according to a recent meta-analysis, altmayer et al. found that both covid-19 associated and other types of viral pneumonia had overlapping ct findings, except for a higher prevalence of peripheral distribution and involvement of the upper and middle lobes.42 both sars and mers share common findings with covid-19 due to their similar pathogenesis.47,48 however, ct changes related to sars and mers are commonly unifocal, as opposed to the multifocal changes usually seen in covid-19. moreover, reversed halo signs and pulmonary nodules have been described in covid-19 cases, but not in sars and mers.5,47,48 similarly, several non-infectious conditions can have similar ct manifestations to covid-19, such as organising pneumonia and interstitial lung changes related to drug toxicity and radiation therapy.49 therefore, both radiologists and clinicians should remain aware of common conditions that can simulate the appearance of covid-19 associated pneumonia on chest ct scans. in order to help decrease variability and reduce uncertainty in reporting ct findings and to allow for the better integration of such findings into clinical decision-making, the radiological society of north america have proposed four categories for reporting ct findings in covid-19 cases: (1) typical appearance; (2) indeterminate appearance; (3) atypical appearance; and (4) negative for pneumonia.50 it is important to acknowledge growing concern that the increase in the utilisation of radiation-based imaging during the current covid-19 pandemic could increase the radiation dose burden of the population; this is particularly concerning because ionising radiation increases the lifetime likelihood of developing cancer.51 therefore, as suggested by the international commission on radiological protection, the alara principle of reducing risk (i.e. “as low as reasonably achievable”) should be followed in the daily practice of radiology, even in the setting of epidemic events.52 moreover, this approach does not necessarily reduce diagnostic efficacy, as recent research has shown that low-dose chest ct scans can be used with reliable sensitivity in the detection of intrathoracic abnormalities including covid-19 associated pneumonia.53 l i m i tat i o n s this review is subject to certain limitations. first, most of the studies included in the analysis were descriptive, non-blinded and heterogeneous in terms of sample size, methodological quality and data availability, potentially resulting in bias. second, case series and reports involving <10 patients were excluded, a factor which might have precluded rare imaging findings seen in covid-19 patients. finally, studies focusing on the paediatric population were excluded; as such, it is possible that chest ct and radiograph findings among children may differ to those seen in the adult population. conclusion medical imaging is a critical component in the diagnosis and follow-up of patients with covid-19 associated pneumonia. current evidence indicates that the most common chest radiograph and ct findings are bilateral predominant lower lobe peripheral subpleural ggos, with or without accompanying consolidation. awareness of these characteristic imaging features is essential to ensure the appropriate integration of such findings into the clinical management of affected patients. a c k n o w l e d g e m e n t s ethical approval to publish the x-ray and ct images included in this article was provided by the institutional ethics and research committee of the royal hospital (src#52/2020). covid-19-associated pneumonia a review of chest radiograph and computed tomography findings e10 | squ medical journal, february 2021, volume 21, issue 1 c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this research. references 1. rothan ha, byrareddy sn. the epidemiology and pathogenesis of coronavirus disease (covid-19) outbreak. j autoimmun 2020; 109:102433. https://doi.org/10.1016/j.jaut.2020.102433. 2. world health organization. rolling updates on coronavirus disease (covid-19). from: www.who.int/emergencies/diseas es/novel-coronavirus-2019/events-as-they-happen accessed: apr 2020. 3. singhal t. a review of coronavirus disease-2019 (covid-19). indian j pediatr 2020; 87:281–6. https://doi.org/10.1007/s12 098-020-03263-6. 4. huang c, wang y, li x, ren l, zhao j, hu y, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet 2020; 395:497–506. https://doi.org/10.1016/s014 0-6736(20)30183-5. 5. yang w, cao q, qin l, wang x, cheng z, pan a, et al. clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (covid-19): a multi-center study in wen zhou city, zhejiang, china. j infect 2020; 80:388–93. https:// doi.org/10.1016/j.jinf.2020.02.016. 6. udugama b, kadhiresan p, kozlowski hn, malekjahani a, osborne m, li vy, et al. diagnosing covid-19: the disease and tools for detection. acs nano 2020; 14:3822–35. https://doi. org/10.1021/acsnano.0c02624. 7. falaschi z, danna psc, arioli r, pasché a, zagaria d, percivale i, et al. chest ct accuracy in diagnosing covid-19 during the peak of the italian epidemic: a retrospective correlation with rt-pcr testing and analysis of discordant cases. euro j radiol 2020; 130: 109192. https://doi.org/10.1016/j.ejrad.2020.109192. 8. ai t, yang z, hou h, zhan c, chen c, lv w, et al. correlation of chest ct and rt-pcr testing for coronavirus disease 2019 (covid-19) in china: a report of 1014 cases. radiology 2020; 296:e32–40. https://doi.org/10.1148/radiol.2020200642. 9. bai hx, hsieh b, xiong z, halsey k, choi jw, tran tml, et al. performance of radiologists in differentiating covid-19 from non-covid-19 viral pneumonia at chest ct. radiology 2020; 296:e46–54. https://doi.org/10.1148/radiol.2020200823. 10. bernheim a, mei x, huang m, yang y, fayad za, zhang n, et al. chest ct findings in coronavirus disease-19 (covid-19): relationship to duration of infection. radiology 2020; 295:20 0463. https://doi.org/10.1148/radiol.2020200463. 11. chate cr, fonseca ekun, passos rbd, teles gbds, shoji h, szarf g. presentation of pulmonary infection on ct in covid-19: initial experience in brazil. j bras pneumol 2020; 46:e20200121. https://doi.org/10.36416/1806-3756/e20200121. 12. chen n, zhou m, dong x, qu j, gong f, han y, et al. epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study. lancet 2020; 395:507–13. https://doi.org/10.1016/s01406736(20)30211-7. 13. cheng z, lu y, cao q, qin l, pan z, yan f, et al. clinical features and chest ct manifestations of coronavirus disease 2019 (covid-19) in a single-center study in shanghai, china. ajr am j roentgenol 2020; 215:121–6. https://doi.org/10.2214/ ajr.20.22959. 14. chung m, bernheim a, mei x, zhang n, huang m, zeng x, et al. ct imaging features of 2019 novel coronavirus (2019ncov). radiology 2020; 295:202–7. https://doi.org/10.1148/rad iol.2020200230. 15. fang y, zhang h, xie j, lin m, ying l, pang p, et al. sensitivity of chest ct for covid-19: comparison to rt-pcr. radiology 2020; 296:e115–17. https://doi.org/10.1148/radiol.2020200432. 16. guan wj, ni zy, hu y, liang wh, ou cq, he jx, et al. clin ical characteristics of coronavirus disease 2019 in china. n engl j med 2020; 382:1708–20. https://doi.org/10.1056/nejmoa200 2032. 17. han r, huang l, jiang h, dong j, peng h, zhang d. early clin ical and ct manifestations of coronavirus disease 2019 (covid-19) pneumonia. ajr am j roentgenol 2020; 215:338–43. https:// doi.org/10.2214/ajr.20.22961. 18. inui s, fujikawa a, jitsu m, kunishima n, watanabe s, suzuki y, et al. chest ct findings in cases from the cruise ship diamond princess with coronavirus disease (covid-19). radiol cardiothorac imaging 2020; 2:e200110. https://doi.org/10.1148/ryct.2020200110. 19. li k, wu j, wu f, guo d, chen l, fang z, et al. the clinical and chest ct features associated with severe and critical covid-19 pneumonia. invest radiol 2020; 55:327–31. https://doi.org/10.10 97/rli.0000000000000672. 20. li y, xia l. coronavirus disease 2019 (covid-19): role of chest ct in diagnosis and management. ajr am j roentgenol 2020; 214:1280–6. https://doi.org/10.2214/ajr.20.22954. 21. lomoro p, verde f, zerboni f, simonetti i, borghi c, fachinetti c, et al. covid-19 pneumonia manifestations at the admission on chest ultrasound, radiographs, and ct: single-center study and comprehensive radiologic literature review. eur j radiol open 2020; 7:100231. https://doi.org/10.1016/j.ejro.2020.100231. 22. meng h, xiong r, he r, lin w, hao b, zhang l, et al. ct imaging and clinical course of asymptomatic cases with covid-19 pneu monia at admission in wuhan, china. j infect 2020; 81:e33–9. https://doi.org/10.1016/j.jinf.2020.04.004. 23. ng my, lee eyp, yang j, yang f, li x, wang h, et al. imaging profile of the covid-19 infection: radiologic findings and literature review. radiol cardiothorac imaging 2020; 2:e200034. https://doi.org/10.1148/ryct.2020200034. 24. pan f, ye t, sun p, gui s, liang b, li l, et al. time course of lung changes at chest ct during recovery from coronavirus disease 2019 (covid-19). radiology 2020; 295:715–21. https://doi.org/10.1 148/radiol.2020200370. 25. pan y, guan h, zhou s, wang y, li q, zhu t, et al. initial ct findings and temporal changes in patients with the novel coronavirus pneumonia (2019-ncov): a study of 63 patients in wuhan, china. eur radiol 2020; 30:3306–9. https://doi. org/10.1007/s00330-020-06731-x. 26. shi h, han x, jiang n, cao y, alwalid o, gu j, et al. radiological findings from 81 patients with covid-19 pneumonia in wuhan, china: a descriptive study. lancet infect dis 2020; 20:425–34. https://doi.org/10.1016/s1473-3099(20)30086-4. 27. song f, shi n, shan f, zhang z, shen j, lu h, et al. emerging 2019 novel coronavirus (2019-ncov) pneumonia. radiology 2020; 295:210–17. https://doi.org/10.1148/radiol.2020200274. 28. wang d, hu b, hu c, zhu f, liu x, zhang j, et al. clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china. jama 2020; 323:1061–9. https://doi.org/10.1001/jama.2020.1585. 29. wong hyf, lam hys, fong ah, leung st, chin tw, lo csy, et al. frequency and distribution of chest radiographic findings in patients positive for covid-19. radiology 2020; 296:e72–8. https://doi.org/10.1148/radiol.2020201160. 30. wu j, wu x, zeng w, guo d, fang z, chen l, et al. chest ct findings in patients with coronavirus disease 2019 and its relationship with clinical features. invest radiol 2020; 55:257–61. https://doi.org/10.1097/rli.0000000000000670. 31. xiong y, sun d, liu y, fan y, zhao l, li x, et al. clinical and high-resolution ct features of the covid-19 infection: comparison of the initial and follow-up changes. invest radiol 2020; 55:332–9. https://doi.org/10.1097/rli.0000000000000674. https://doi.org/10.1016/j.jaut.2020.102433 https://doi.org/10.1007/s12098-020-03263-6 https://doi.org/10.1007/s12098-020-03263-6 https://doi.org/10.1016/s0140-6736%2820%2930183-5 https://doi.org/10.1016/s0140-6736%2820%2930183-5 https://doi.org/10.1016/j.jinf.2020.02.016 https://doi.org/10.1016/j.jinf.2020.02.016 https://doi.org/10.1021/acsnano.0c02624 https://doi.org/10.1021/acsnano.0c02624 https://doi.org/10.1016/j.ejrad.2020.109192 https://doi.org/10.1148/radiol.2020200642 https://doi.org/10.1148/radiol.2020200823 https://doi.org/10.1148/radiol.2020200463 https://doi.org/10.36416/1806-3756/e20200121 https://doi.org/10.1016/s0140-6736%2820%2930211-7 https://doi.org/10.1016/s0140-6736%2820%2930211-7 https://doi.org/10.2214/ajr.20.22959 https://doi.org/10.2214/ajr.20.22959 https://doi.org/10.1148/radiol.2020200230 https://doi.org/10.1148/radiol.2020200230 https://doi.org/10.1148/radiol.2020200432 https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.2214/ajr.20.22961 https://doi.org/10.2214/ajr.20.22961 https://doi.org/10.1148/ryct.2020200110 https://doi.org/10.1097/rli.0000000000000672 https://doi.org/10.1097/rli.0000000000000672 https://doi.org/10.2214/ajr.20.22954 https://doi.org/10.1016/j.ejro.2020.100231 https://doi.org/10.1016/j.jinf.2020.04.004 https://doi.org/10.1148/ryct.2020200034 https://doi.org/10.1148/radiol.2020200370 https://doi.org/10.1148/radiol.2020200370 https://doi.org/10.1007/s00330-020-06731-x https://doi.org/10.1007/s00330-020-06731-x https://doi.org/10.1016/s1473-3099%2820%2930086-4 https://doi.org/10.1148/radiol.2020200274 https://doi.org/10.1001/jama.2020.1585 https://doi.org/10.1148/radiol.2020201160 https://doi.org/10.1097/rli.0000000000000670 https://doi.org/10.1097/rli.0000000000000674 rashid s. al-umairi, joukha al-kalbani, saqar al-tai, ahmed al-abri, faiza al-kindi and atheel kamona review | e11 32. xu x, yu c, qu j, zhang l, jiang s, huang d, et al. imaging and clinical features of patients with 2019 novel coronavirus sars-cov-2. eur j nucl med mol imaging 2020; 47:1275–80. https://doi.org/10.1007/s00259-020-04735-9. 33. xu yh, dong jh, an wm, lv xy, yin xp, zhang jz, et al. clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by sars-cov-2. j infect 2020; 80:394–400. https://doi.org/10.1016/j.jinf.2020.02.017. 34. zhang r, ouyang h, fu l, wang s, han j, huang k, et al. ct features of sars-cov-2 pneumonia according to clinical presentation: a retrospective analysis of 120 consecutive patients from wuhan city. eur radiol 2020; 30:4417–26. https://doi.org/10.1 007/s00330-020-06854-1. 35. zhao d, yao f, wang l, zheng l, gao y, ye j, et al. a comparative study on the clinical features of coronavirus 2019 (covid-19) pneumonia with other pneumonias. clin infect dis 2020; 71:756–61. https://doi.org/10.1093/cid/ciaa247. 36. zhao w, zhong z, xie x, yu q, liu j. relation between chest ct findings and clinical conditions of coronavirus disease (covid-19) pneumonia: a multicenter study. ajr am j ro entgenol 2020; 214:1072–7. https://doi.org/10.2214/ajr.20.22976. 37. zhou s, wang y, zhu t, xia l. ct features of coronavirus disease 2019 (covid-19) pneumonia in 62 patients in wuhan, china. ajr am j roentgenol 2020; 214:1287–94. https://doi. org/10.2214/ajr.20.22975. 38. kim h, hong h, yoon sh. diagnostic performance of ct and reverse transcriptase polymerase chain reaction for coronavirus disease 2019: a meta-analysis. radiology 2020; 296:e145–55. https://doi.org/10.1148/radiol.2020201343. 39. rubin gd, ryerson cj, haramati lb, sverzellati n, kanne jp, raoof s, et al. the role of chest imaging in patient management during the covid-19 pandemic: a multinational consensus statement from the fleischner society. radiology 2020; 296:172–80. https://doi.org/10.1148/radiol.2020201365. 40. american college of radiology. acr recommendations for the use of chest radiography and computed tomography (ct) for suspected covid-19 infection. from: www.acr.org/advoca c y a n d e c o n o m i c s / a c r p o s i t i o n s t a t e m e n t s / re commendations-for-chest-radiography-and-c t-forsuspected-covid19-infection accessed: sep 2020. 41. brady z, scoullar h, grinsted b, ewert k, kavnoudias h, jarema a, et al. technique, radiation safety and image quality for chest x-ray imaging through glass and in mobile settings during the covid-19 pandemic. phys eng sci med 2020; 43:765–79. https://doi.org/10.1007/s13246-020-00899-8. 42. altmayer s, zanon m, pacini gs, watte g, barros mc, mohammed tl, et al. comparison of the computed tomo graphy findings in covid-19 and other viral pneumonia in immunocompetent adults: a systematic review and metaanalysis. eur radiol 2020; 30:6485–96. https://doi.org/10.1007/ s00330-020-07018-x. 43. wang y, jin c, wu cc, zhao h, liang t, liu z, et al. organizing pneumonia of covid-19: time-dependent evolution and outcome in ct findings. plos one 2020; 15:e0240347. https:// doi.org/10.1371/journal.pone.0240347. 44. shaghaghi s, daskareh m, irannejad m, shaghaghi m, kamel ir. target-shaped combined halo and reversed-halo sign, an atypical chest ct finding in covid-19. clin imaging 2021; 69:72–4. https://doi.org/10.1016/j.clinimag.2020.06.038. 45. li x, zeng x, liu b, yu y. covid-19 infection presenting with ct halo sign. radiol cardiothorac imaging 2020; 2:e200026. https://doi.org/10.1148/ryct.2020200026. 46. jin yh, cai l, cheng zs, cheng h, deng t, fan yp, et al. a rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-ncov) infected pneumonia (standard version). mil med res 2020; 7:4. https://doi.org/10.1186/s407 79-020-0233-6. 47. world health organization. summary of probable sars cases with onset of illness from 1 november 2002 to 31 july 2003 december 31, 2003. from: www.who.int/csr/sars/country/ table2004_04_21/en/ accessed: sep 2020. 48. world health organization. middle east respiratory syndrome coronavirus (mers-cov). from: www.who.int/emergencies/ mers-cov/en/ accessed: sep 2020. 49. raptis ca, hammer mm, short rg, shah a, bhalla s, bierhals aj, et al. chest ct and coronavirus disease (covid-19): a critical review of the literature to date. ajr am j roentgenol 2020; 215:839–42. https://doi.org/10.2214/ajr.20.23202. 50. simpson s, kay fu, abbara s, bhalla s, chung jh, chung m, et al. radiological society of north america expert consensus statement on reporting chest ct findings related to covid-19: endorsed by the society of thoracic radiology, the american college of radiology, and rsna. radiol cardiothorac imaging 2020; 2:e200152. https://doi.org/10.1148/ryct.2020200152. 51. gilbert es. ionising radiation and cancer risks: what have we learned from epidemiology? int j radiat biol 2009; 85:467–82. https://doi.org/10.1080/09553000902883836. 52. yeung aw. the “as low as reasonably achievable” (alara) principle: a brief historical overview and a bibliometric analysis of the most cited publications. radioprotection 2019; 54:103–9. https://doi.org/10.1051/radiopro/2019016. 53. tabatabaei sm, talari h, gholamrezanezhad a, farhood b, rahimi h, razzaghi r, et al. a low-dose chest ct protocol for the diagnosis of covid-19 pneumonia: a prospective study. emerg radiol 2020; 27:607–15. https://doi.org/10.1007/s10140-020-01838-6. https://doi.org/10.1007/s00259-020-04735-9 https://doi.org/10.1016/j.jinf.2020.02.017 https://doi.org/10.1007/s00330-020-06854-1 https://doi.org/10.1007/s00330-020-06854-1 https://doi.org/10.1093/cid/ciaa247 https://doi.org/10.2214/ajr.20.22976 https://doi.org/10.2214/ajr.20.22975 https://doi.org/10.2214/ajr.20.22975 https://doi.org/10.1148/radiol.2020201343 https://doi.org/10.1148/radiol.2020201365 https://doi.org/10.1007/s13246-020-00899-8 https://doi.org/10.1007/s00330-020-07018-x https://doi.org/10.1007/s00330-020-07018-x https://doi.org/10.1371/journal.pone.0240347 https://doi.org/10.1371/journal.pone.0240347 https://doi.org/10.1016/j.clinimag.2020.06.038 https://doi.org/10.1148/ryct.2020200026 https://doi.org/10.1186/s40779-020-0233-6 https://doi.org/10.1186/s40779-020-0233-6 https://doi.org/10.2214/ajr.20.23202 https://doi.org/10.1148/ryct.2020200152 https://doi.org/10.1080/09553000902883836 https://doi.org/10.1051/radiopro/2019016 https://doi.org/10.1007/s10140-020-01838-6 january 2007 vol 7 correct a.indd abstract objectives: to determine the prevalence and intensity of infection with schistosomiasis among school children and to evaluate the efficacy of praziquantel in normalizing the levels of some haematological and biochemical blood constituents. methods: a total of 346 school children, aged 7-3 years, from el-kriab primary school, near the el-seleit irrigation scheme east of khartoum, sudan, were screened for schistosomiasis. all 36 children infected with schistosoma haematobium and/or s. mansoni were clinically investigated and treated with a single oral dose of praziquantel (40 mg/kg body weight). results: in 74% out of 97 children infected with s. haematobium the egg count exceeded 500 eggs/0 ml of urine and they had high level of eosinophilia and leukocyte counts, high globulin and calcium levels and low potassium. the serum total proteins, globulins, albumin and urea showed statistically significant differences between control and patients and between patients before and after treatment, although the levels were within the normal reference range. praziquantel treatment was highly effective as proved by a (58%) cure rate, a (98%) reduction in egg count and normalization of the examined blood parameters six weeks post-treatment. conclusion: infection with s. haematobium influenced the normal levels of certain blood constituents and treatment with praziquantel normalized the physiological conditions. according to who guidelines, regular mass treatment with praziquantel and health education are recommended as part of the primary health care programme in areas of hight prevalence and intensity of s. haematobium infection. keywords: blood, egg count, electrolytes, praziquantel, prevalence, schistosoma haematobium, sudan. haematological and biochemical morbidity of schistosoma haematobium in school children in sudan *elagba ha mohammed¹, mohamed eltayeb², hikmat ibrahim1 ¹natural history museum, faculty of science, university of khartoum. p. o. box 321, khartoum, sudan. ²national health laboratory, ministry of health, sudan. p. o. box 22, khartoum, sudan. *to whom correspondence should be addressed. email: elagba2000@yahoo.com املدارس تالميذ دم بعض مكونات بالبلهارسيا البولية على اإلصابة أثر السودان اإلبتدائية في البرازكوانتل بعقار العالج تقييم وكذلك املدارس، ألطفال الدم مكونات بعض على ذلك وأثر مبرض البلهارسيا اإلصابة معدل امللخص: الهدف: حتديد الكرياب مدرسة من سنة (13-7) بعمر 346 تلميذا من مكونة عينة ــح مت مس الطريقة: الطبيعية. املعدالت إلى الدم مكونات ــني وحتس العالج في (بنوعيها)، بالبلهارزيا مصابا 56 تلميذة) و (80 تلميذا 136 على الكشف مت اخلرطوم. مدينة شرق الزراعي ــليت الس ــروع من مش االبتدائية بالقرب مصابون و33 تلميذة) (64 تلميذا 28% النتائج: وجد أن ــم). من وزن اجلس كجم (40 جم/ البرازكوانتل من واحدة بجرعة ــم ومعاجلته ــم، وفحصه و البيضاء، الدم كريات ــاع عدد اإلصابة بارتف حدة ارتبطت من البول. 10 مل / 500 بيضة ــض فاق عدد البي %74 منهم ــي وف ــة، البولي ــيا بالبلهارس 98%) البيض عدد في انخفاض مع ، 58% الشفاء نسبة كانت ــيوم. والبوتاس األلبيومني ــيوم وانخفاض والكالس القلوبيولني و مصل الدم بروتينات لألطفال العامة الصحة على البولية بالبلهارسيا الدراسة تأثير حدة اإلصابة اخلالصة: أثبتت ــابيع. 6 أس بعد لألطفال الصحية احلالة ــنت وحتس ، ( التثقيف باإلضافة إلى األولية الصحية الرعاية برنامج ضمن للبرازكوانتيل الدوري باالستخدام الدراسة توصي العالج. في البرازكوانتل عقار وفعالية املنطقة. في الصحي الصرف ووسائل النقي املاء الصحي وتوفير السودان. البلهارزيا البولية ، انتشار ، ، برازيكوانتال ، حساب البيض ، املفردات املفتاحية: دم schistosomiasis is a serious public health and socio-economic problem in sudan.1 infec-tion with schistosoma haematobium and/or s. mansoni is widespread among the entire population, with a prevalence range of 57-79%.2 the spread of the disease is associated with the establishment of irrigation schemes and the flow of migrant labourers in the country.2-3 praziquantel was introduced in sudan in the early 80s to treat patients infected with urinary and/or intestinal schistosomiasis in gezira and proved to be an efficient drug.4-5-6 in 1992, a new focus of s. haematobium was reported as a public health prob sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© o r i g i n a l s t u d y e l a g b a h a m o h a m m e d , m o h a m m e d e ltay e b a n d h i k m at i b r a h i m 60 lem after the establishment of the el-seleit irrigation scheme in eastern khartoum state. although a high prevalence of s. haematobium infection was recorded among school children in the area (unpublished data), no effective control measures were taken by the authorities. the epidemiology of urinary schistosomiasis in the sudan was extensively studied, but the clinical, haematological and biochemical aspects of the disease have received little attention.2 haematological and biochemical morbidity studies are needed to understand better the public health significance of urinary schistosomiasis. accordingly, this study was conducted to determine the prevalence of s. haematobium among the pupils of el-kriab primary school, aged (7-13) years, who live near el-seliet agricultural scheme. the other objectives of this study were to investigate the clinical, haematological and biochemical effects of s. haematobium before and six weeks after treatment with praziquantel. since praziquantel has been established as an efficient drug for treatment of schistosomiasis in sudan, it was thus used in the present study. m e t h o d s st udy a r e a a n d sub je c ts this study was carried out in el-kriab village, 20 km east of khartoum in el-seleit agricultural scheme on the blue nile. most of the residents had originally come from an endemic schistosomiasis area in western sudan. the environmental sanitation and health services are below standard in the village, where more than 50% of the villagers have no latrines at home and 10% of them depend completely on the irrigation canals for their water supply. both s. haematobium and s. mansoni were first reported a few years after the establishment of el-seleit and other agricultural schemes in the area. the pupils of el-kriab primary school were selected in the present study. c l i n i c a l a n d pa r a si to l o gi c a l e x a mi n ati o n a total of 346 students were screened with the filtration technique7 or stool examination for s. haematobium and s. mansoni, respectively. ninty seven children (64 males and 33 females) infected with s. haematobium only were selected for preand posttreatment analysis. the initial screening survey of infected children included a clinical examination according to standard protocols8 as well as grading and measuring of liver and spleen sizes. abdominal pain and headache were reported and urinary blood was detected by chemical reagent strips.9 concurrent bacterial or parasitic infections (chest infection, malaria, typhoid…etc) were also reported. urine was collected from patients shortly before midday. the number of eggs per 10ml urine was determined for each patient. 10 h a e m ato l o gi c a l a n d bi o c h e mi c a l e x a mi n ati o n a blood sample was taken from each patient, as well as a control group of 20 non-infected school children. half of each sample was kept in a tube containing an anticoagulant and used for a full blood analysis including haemoglobin, haematocrit and differential and total leukocyte counts.11 the other half was used to determine the serum levels of total proteins, albumin, globulin, urea, uric acid, sodium, potassium and calcium.12 all patients were treated with a single oral dose of 40 mg/kg body weight of praziquantel, according to who guidelines13, under the supervision of a medical doctor and after family consent was obtained. none of them has had a previous history of antischistosomal therapy. for no obvious reason, 47 of the s. haematobiums patients, previously treated did not come for follow up examination, so only 50 were considered in this study. clinical, parasitological, haematological and biochemical examinations were repeated six weeks after the treatment with praziquantel. stati sti c a l a n a ly si s data analysis was carried out by the statistical package for social sciences (spss/pc, ver. 4.1). all continuous data are represented as mean ± standard deviation (sd). for comparisons of means students t-test was used. r e s u l t s the children examined, including the control group, were 7 to 13 years old, with a mean body weight of 20 kg (range: 15-45 kg). clinical examination revealed a wide spectrum of the clinical forms of the disease. thirty-four percent of the children complained of abdominal pain, while 30% had haematuria and 9% had dysuria and/or diarrhea. hepatomegaly was not encountered in any of the patients and splenomegaly was detected in three females only. table 1 shows significant increase (p < 0.01) in eosinophilia and leukocyte counts in s. haematobium inh a e m at o l o g i c a l a n d b i o c h e m i c a l m o r b i d i t y o f s c h i s t o s o m a h a e m at o b i u m i n s c h o o l c h i l d r e n i n s u d a n 61 fected children and a haemoglobin level below 12 g/dl for both the patients and the control group. there was no relationship between the level of haemoglobin and the intensity of the infection. haematocrit was within the normal range. elevated levels of serum total protein and globulin and decreased serum albumin were observed in infected children. no significant change in the level of urea and uric acid or sodium content was observed. serum potassium was significantly decreased and calcium was significantly increased (p < 0.01). a cure rate of 58 % (56 % of the males and 61 % of the females) was obtained. although 42 % (66.7 % of the males and 33.3 % of the females), including 76.2 % of the age group ≤10 years, had some schistosome eggs after treatment, a 98 % reduction in the intensity of infection (egg output) was recorded (p < 0.01). both sexes followed the same pattern of improvement independent of the intensity of infection. a significant improvement (p < 0.05) in most of the clinical symptoms was observed six weeks after treatment. this was associated with an improvement in the levels of all the tested blood parameters [table 1]. d i s c u s s i o n clinical observations noted among the s. haematobium infected children agreed with some authors.8 haematuria and dysuria are common clinical consequences of urinary schistosomiasis.9 hepatomegaly and splenomegaly were not common among our patients. relationships between hepatomegaly and splenomegaly with s. haematobium infection and regression in both organs after treatment were previously documented.14 the absence of enlarged liver and spleen in our patients is not surprising, because the prevalence of these clinical forms of the disease was found to be associated with the intestinal rather than urinary schistosomiasis.15 the biochemical results indicated that eosinophilia and raised leukocyte counts were related to the intensity of infection, while haemoglobin level was not. low haemoglobin concentrations were observed, a cut-off point suggested for anaemia.13 this corresponded with the findings of some authors,16-17 but differed from table 1: biochemical and haematological features of blood from children infected with s. haematobium, before and after praziquantel treatment (mean ± standard deviation) blood indices control group (n=20) infected subjects (n = 50) (p value)* before treatment after treatment haemoglobin(g/dl) 11.2 ± 0.2 10.7 ± 0.2 11 ± 0.2 ns heamatocrit 33 ± 0.7 31 ± 0.5 33 ± 0.5 ns leukocytecount(/mm3) 5100 ± 82 10184 ± 30 5260 ± 95 p<0.01 lymphocytes(/mm3) 2096 ± 58 321 ± 61 2374 ± 74 p<0.01 neutrophils(/mm3) 2454 ± 76 3886 ± 89 3645 ± 53 p<0.01 eosinophils(/mm3) 359 ± 82 1572 ± 90 435 ± 50 p<0.00 monocytes(/mm3) 103 ± 27 363 ± 59 139 ± 7 p<0.01 total protein(g/dl) 6.8 ± 0.1 7.6 ± 0.1 7.4 ± 0.1 p<0.05 globulin(g/dl) 3.4 ± 0.1 4.4 ± 0.1 3.7 ± 0.1 p<0.05 albumin(g/dl) 3.8 ± 0.1 3.2 ± 0.1 3.6 ± 0.1 p<0.05 urea(mg/dl) 22 ± 0.7 26 ± 0.9 22 ± 0.8 p<0.05** uric acid(mg/dl) 3.5 ± 0.1 3 ± 0.1 3 ± 0.1 ns sodium(meq/l) 138 ± 0.6 137 ± 0.7 138 ± 0. ns potassium(meq/l) 4 ± 0.1 3.7 ± 0.1 4.5 ± 0.1 p<0.05 calcium(mg/dl) 9 ± 0.2 9.7 ± 0.2 8.8 ± 0.2 p<0.01 ns: not significant * infected vs. control & infected vs. treated ** statistically significant, but clinically below the normal clinical range e l a g b a h a m o h a m m e d , m o h a m m e d e ltay e b a n d h i k m at i b r a h i m 62 those of others.14 in kenyan school children infected with s. haematobium, the low level of haemoglobin did not recover until six weeks after treatment,18 despite its significant relationship to the intensity of infection and there was no significant difference between infected and non-infected or treated children with s. haematobium infection from east cameroon.19 heavy infections with s. haematobium are known to cause iron deficiency anaemia due to urinary iron loss and red cells haemolysis by the spleen.14-18 treatment of the infection was expected to result in a significant increase in haemoglobin levels of anaemic children, but no improvement was noted. interestingly, haemoglobin in the control group was also below the normal limits. this could probably be due to malnutrition and/or poor quality of food for the whole community of children in the area and not necessarily due to s. haematobium infection. in addition, treated children were not given any supplementary food or iron therapy. a significant rise in the level of total leukocyte counts could be attributed to the rise in eosinophils, but likewise a significant rise was encountered in monocytes, lymphocytes and neutrophils. this indicated a general immunological response. a number of systems employing antibodies and/or eosinophils, neutrophils, monocytes were produced to kill schistosomes. a significant relationship was observed between the degree of eosinophilia and the intensity of infection.16 however, the significant reduction observed in the circulating leukocytes and eosinophils after treatment indicates that this immunological cell response was due to s. haematobium infection, as the level remained high in the patients still passing eggs after treatment, unlike patients with other parasitic infections. we found significant abnormalities in serum total protein, albumin, globulin, urea, potassium and calcium ions in infected subjects (p<0.05). serum sodium and uric acid levels were normal. the increase of serum total proteins and globulin and the decrease of serum albumin may have been due to liver dysfunction or to a poor nutritional status or both. the increased levels of serum total proteins and globulin, associated with the intensity of infection, could also have been due to immunological reactions and the production of immunoglobulin, which occurred before treatment. the low level of serum albumin could also be explained by high protein loss due to heavy infection. urinary protein excretion is known to interfere with the concentration of serum proteins, which may contribute to hypoproteinemia in cases of marginal protein supply.20 it was obvious, following treatment, that there was a significant improvement in the levels of these indices, which indicates recovery of some liver functions. low levels of serum proteins and albumin in s. mansoni infection, but no change in pure s. haematobium infection was observed.21 low levels of serum total proteins and albumin in s. haematobium patients was observed by some authors,22 while others23 found normal level of serum proteins before and after treatment. the significant increase in urea with intensity of infection contrasted with some researchers,22-23 who found urea to be within the normal limits for both s. mansoni and s. haematobium infected subjects. the increase found in our study could be explained either by an excessive production of amino acids, due to an increased breakdown of proteins and the production of urea, and/or an abnormal function of the kidneys and their inability to excrete urea. uric acid decreased slightly after treatment, but did not show a significant difference between preand post-treated subjects. the change observed in the serum electrolytes could be due to their influence in cellular metabolism, particularly in enzyme regulation. the decrease in potassium level of infected children might be due to an excessive urinary and gastric excretion of potassium (gastro-intestinal disorder) and/or decreased gut potassium absorption.24 the significant increase in calcium level before treatment could be explained by an increased intestinal absorption of dietary calcium and/or by a decreased urinary excretion. increased resorption of calcium from bone could be another cause. elevated calcium is believed to result from an increase of vitamin d, 1/25-(oh)2 vit d, which is necessary for the response of the gut to the parathyroid hormones. this in turn promotes calcium absorption from the gut and increases its resorption from bone.25 macrophages and other cells associated with granulomatous deposits are believed to synthesize 1/25-(oh)2 vit d, and schistosome eggs initially evoke a granulomatous response, which probably caused elevation in serum calcium in our subjects. hypercalcemia might also alter the renal function due to calcium deposits in renal tubules and interstitial areas of the kidneys.22 all electrolytes normalized in both sexes after treatment. h a e m at o l o g i c a l a n d b i o c h e m i c a l m o r b i d i t y o f s c h i s t o s o m a h a e m at o b i u m i n s c h o o l c h i l d r e n i n s u d a n 63 c o n c l u s i o n this study showed that s. haematobium infection can influence the normal levels of some haematological and biochemical constituents of the blood and treatment with praziquantel proved to be effective in normalizing these parameters. we recommend the following control strategies: community-based screening, largescale treatment with praziquantel and health education, as well as permanent improvement in water supply and sanitation. previous studies on schistosomiasis among school children in sudan produced the same recommendations. a k n ow l e d ge me n ts the authors would like to thank the postgraduate college, university of khartoum for financing this work. our thanks also go to the technical staff of the national health laboratory, ministry of health, sudan. our gratitude is also due to dr. e. scrimgeour, department of medicine, college of medicine and health sciences, sultan qaboos university for valuable comments on the manuscript. r e f e r e n c e s 1. blue nile health project. editorial. lancet 1985; 326, 1166-1167. 2. bella h, marshall tfc, omer ahs, vaughan jp. migrant workers and schistosomiasis in the gezira, sudan. trans r soc trop med hyg 1980; 74:36-39. 3. el-gaddal aa. the blue nile health project: a comprehensive approach to the prevention and control of water-associated disease in irrigated schemes of the sudan. j trop med hyg 1985; 88:47-56. 4. el-tayeb m, daffalla aa, kardaman mw. praziquantel and oltipraz: the treatment of schoolchildren infected with schistosoma mansoni and/or s. haematobium in gezira, sudan. ann trop med parasitol 1988; 82:5357. 5. kardaman mw, amin ma, fenwick a, cheesmond ak, dixon hg. a field trial using praziquantel (biltricider) to treat schistosoma mansoni and s. haematobium infection in gizera, sudan. ann trop med parasitol 1983; 77:297-304. 6. kardaman mw, fenwick a, el-agail ab, el-tayeb m. daffalla aa, dixon hg. treatment with praziquantel of schoolchildren with concurrent schistosoma mansoniand s. haematobium infections in gezira, sudan. j trop med hyg 1985; 88:105-109. 7. feldmeier h, bienzle u, dietrich m, sievertse hj. combination of viability test and a quantification method for schistosoma haematobium eggs (filtration-trepan bluestaining technique). tropenmed parasitol 1979; 30:417 422. 8. mott ke, dixon h, sci-tuta eo, england ec. relationship between intensity of schistosoma haematobium infection and clinical haematuria and proteinuria. lancet 1983; 321:10051008. 9. holzer b, saladin k, degremont a. the impact of schistosomiasis among rural populations in liberia. acta trop 1983; 40:239-259. 10. bradley dj. a simple and rapid method for counting schistosome eggs in urine. trans r soc trop med hyg 1964; 58:291-295. 11. dacie jv, lewis sm. practical haematology 4th ed. london: j and a churchill, 1968. 12. varley h, gowenlock ah, bell m. practical clinical biochemistry. volume 1, 5th ed. london: william heinemann medical books ltd, 1980. 13. world health organization (who). the control of schistosomiasis: who expert committee report. no. 910, geneva: who tech rep ser, 2002 . 14. stephenson ls, kinot sn, latham mc, kruz km, kyobe j. single dose metrifonate or praziquantel treatment in kenyan children: effects on schistosoma haematobium, hookworm, haemoglobin levels, splenomegaly, and hepatomegaly. am j trop med hyg 1989; 41:436444. 15. razdan s, vlachiotis jd, edelstein ra, krane ra, siroky mb. schistosomal myelopathy as a cause of neurogenic bladder dysfunction. urology 1997; 49:77-80. 16. davis a, biles je, urich am, dixon h. tolerance and efficacy of praziquantel in phase iia and iib therapeutic trials. arzneimittel forschung res 1981; 33:568-582. 17. prual a, daouda h, develoux m, sellin b, galan p, hercberg s. consequences of schistosoma haematobium infection on the iron status of school children in niger. am j trop med hyg 1992; 47:291-297. 18. latham mc, stephenson ls, kurz km, kinoti sn. metrifonate or praziquantel treatment improves physical fitness and appetite of kenyan schoolboys with schistosoma haematobium and hookworm infections. am j trop med hyg 1990; 43:170-179. 19. mengue rnb, ratard rc, alessandro ad, rice j, mengue rb, kouemeni le, cline bl. the impact of schistosoma haematobium and of praziquantel treatment on the growth of primary school children in bertoua, cameroon. j trop med hyg 1993; 96:225-230. 20. doehring e, erich jhh, vester h, feldmeir u, poggensee u, brodehl h. proteinuria, hematuria and leukocyturia in children with mixed urinary and intestinal schistosomiasis. kid intes 1985; 28:520-525. 21. pope rt, cline bl, el alamy ma. evaluation of schistosomal morbidity in subjects with high intensity of infection in qalyub, egypt. am j trop med hyg 1980; 29:416-425. 64 22. el sharabasy mmh, shaban ia, mansour ma, el gammal mi. biochemical effect of praziquantel on bilharzial patients. egyp j bilharz 1994; 15:135-143. 23. kaiser c, doehring se, abdel rahim m, et al. renal function and morphology in sudanese patients with advanced hepatosplenic schistosomiasis and portal hypertension. am j trop med hyg 1989; 40:179-185. 24. habib ya, kira lh, el sherbini ha, asser la, el shamy ea, hatem ya. role of arterial natriuretic factors in sodium and water retention in patients with schistosomal hepatic fibrosis. am j trop med hyg 1991; 94:272276. 25. dorothy es. endocrine system. in: lowenthal dt ed, essentials of biochemistry, philadelphia fa davis company, 1988; 455-460. e l a g b a h a m o h a m m e d , m o h a m m e d e ltay e b a n d h i k m at i b r a h i m december 2007 vol 8 after meeting.indd abstract symptoms of angina pectoris can present with the typical specific symptoms, which are easy to recognize, or vague symptoms like chills, nausea, dizziness, belching and mild chest pain. both the typical and atypical forms of angina symptoms may rarely be associated with or masked by predominantly extra cardiac manifestations, which are occasionally referred to the abdomen. we report here an unusual presentation of angina. a 62 years old male who had been healthy all his life, presented at sultan qaboos university, oman, with a two month history of belching episodes as the chief and the only complaint. he was found to have angina pectoris, although there were no classical symptoms or signs to suggest it. he was treated successfully by surgery. it is concluded that belching can be a presenting symptom of angina. keywords: angina pectoris, symptoms; eructation; case report; oman. belching as a presenting symptom of angina pectoris kawther el-shafie sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 257-259 sultan qaboos university© submitted 13th june 2007 accepted 12th september 2007 in the age of technology, simple historical features of pathologic processes are often over-looked as diagnostic aids. to most patients, belching, chills and fatigue do not sound like symptoms of heart attack. as a result, many sufferers do not seek medical attention, or they delay it, which can result in permanent damage to the heart muscle or even death.1 a recent research study indicated that most patients with recent heart attacks had symptoms different from those they expected.2 as a result, medical treatment was significantly delayed. there is increasing awareness that associated symptoms of anginal chest pain, do not reliably distinguish between cardiac and gastrointestinal origins of chest pain, which can coexist in up to 35% of patients. belching or painful swallowing are suggestive of esophageal disease, although belching and indigestion may be seen with myocardial ischaemia.3,4,5 belching as an isolated symptom of angina without chest pain, have not been reported before, and was not included as a common presenting symptom of angina pectoris in the standard textbooks of medicine and cardiology. we report an otherwise healthy middle aged man with a typical anginal symptom that presented with belching and was treated successfully by surgery. c a s e r e p o r t a 63 years old male, who had had normal health all his life, presented at sultan qaboos university, oman, with a history of belching episodes following a sensation of gas in the stomach for two months duration. he noticed these symptoms only during physical effort department of family health and community medicine, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman email: kawther@squ.edu.om c a s e r e p o r t الصدرية كعرض للذبحة ؤ شُّ التَجَ ظاهرة الشفيع طه كوثر الغثيان ، مثل القشعريرة واضحة غير بأعراض أو ، ــخيصها تش ــهل الس من والتي املعروفة باألعراض تظهر أن ميكن الصدرية الذبحة امللخص: أعراض منطقة البطن. تظهر في أحيانا والتي القلب خارج أعراض عليها تطغى أو تصاحبها ما احلالتني نادرا وكلتا بالصدر. خفيف وألم ــؤ شُّ التَجَ ، الدوخة ، ؤ شُّ التَجَ نوبات من بدأ يشكو طوال حياته ، مرض من يعاني يكن اثنان وستون عاما، لم العمر من يبلغ رجل الصدرية. للذبحة معتادة غير حاله هنا نورد تدل التي املعهودة أو العالمات األعراض وجود عدم من الرغم على الصدرية الذبحة يعانى من وجد أنه قد ــيه. وأساس وحيدة ــكوى ــهرين كش وملدة ش للذبحة الصدرية. عرضا تكون أن ؤ ميكن شُّ التَجَ نستنتج أن ظاهرة ميكن أن هنا ومن اجلراحة. بواسطة بنجاح عالجه مت على ذلك. عمان. حالة؛ ، تقرير ؤ شُّ التَجَ ، ، أعراض الصدرية الكلمات: الذبحة مفتاح k aw t h e r e l -s h a f i e 258 such as walking, going up the stairs or with emotional stress. it was not associated with chest pain or any other gastrointestinal symptom. the belching was not related to eating meals and was absent at rest. there was no past history of epigastralgia or chest pain. he had no prior history of surgery. he had not used any medication recently and had no drug allergy. the general physical examination was normal, including pulse and blood pressure. his body mass index (bmi) was 25. investigations done, including complete blood count, electrolytes, creatinin, liver function tests, lipids and glucose were normal. a resting electrocardiogram was normal. a stress test electrocardiogram was strongly positive for angina pectoris. coronary angiography showed 50% narrowing at the left anterior descending (lad), both branches of the circumflex artery and 98% blockage of the right coronary artery (rca) and its branch, the posterior descending artery (pda). the patient underwent coronary artery bypass grafting (cabag) surgery and was put on statins and aspirin medication. since then he has remained asymptomatic and his bmi has not changed. d i s c u s s i o n the only explanation for the cause of belching in this patient was angina pectoris. he had no other risk factors relating to a gastric problem such as drugs, relation to meals or stressful events.6 the symptoms were confined mainly to effort and emotions, which were the clues for the diagnosis. the diagnosis was confirmed by a strongly positive stress test during which he experienced the same symptoms without chest pain, besides an abnormal coronary angiography and the disappearance of the symptom after surgery. our patient did not present with the typical specific symptoms of myocardial ischaemia, which are easy to recognize, but he presented with an atypical symptom which can easily be missed.1 belching, chills and fatigue do not sound like symptoms of heart attack to most patients; as a result many sufferers do not seek medical attention or they delay it, which can result in damage to the heart muscle and even death.1 the relative infrequency or lack of specificity of this symptom reduces its value in diagnosing ischaemic heart disease. a good history taking helped in the diagnosis and early intervention for this patient. most studies report the association of belching with the chest pain of myocardial infarction, but none figure 1: a normal ecg record for the patient during rest b e l c h i n g a s a p r e s e n t i n g s y m p t o m o f a n g i n a p e c t o r i s 259 relates the symptom either exclusively to or associated with the pain of angina.7, 8 previous studies reported the association of belching with inferior myocardial infarction.9 another noticed its association with q wave infarction and the predictive value for belching with infarction is 72%.7 these patients could have been diagnosed earlier by the general practitioner before presenting to the accident and emergency department. sweating is not the only symptom, other than chest pain, which predicts infarction.10 others have reported an association of nausea, vomiting and belching.8,11, this symptom can certainly also be associated with non cardiac causes of chest discomfort (such as aerophagia or peptic ulcer),12 but when it is associated with coronary artery disease, it always indicates inferior wall ischaemia.9 the mechanism may be the marked vagal stimulation associated with inferior infarction causing gastric distress and subsequent gas formation.8 the association of belching with inferior infarction suggests an enhanced autonomic response to ischaemic heart disease at this site.9 the predominance of our patient’s symptom can be explained by inferior wall ischaemia induced by an almost occluded pda, which probably masked other symptoms induced by the other partially narrowed coronary vessels. c o n c l u s i o n the diagnosis of angina pectoris by the nature of resultant pain or discomfort is unreliable. while a number of associated symptoms, particularly belching, do have a higher predictive value, our report reinforces the need for a good history taking and earlier objective electrocardiographic information to prevent cardiac muscle damage and even death. r e f e r e n c e s 1. biggers v. heart attack: what you don’t know can hurt. home care provid. 1996; 1:149-150. 2. johnson ja, king kb. influence of expectations about symptoms on delay in seeking treatment during a myocardial infarction. am j crit care 1995; 4:29-35. 3. davis ha, jones db, rhodes j, newcombe rg angina like esophageal pain differentiation from cardiac pain by history. j clin gastroenterol 1985; 7:477-481. 4. ros e, armengol x, grande l, toledopimentel v, lacima g, sanz g. chest pain at rest in patients with coronary artery disease, (myocardial ischaemia, esophafigure 2: a stress test ecg record for the patient, which shows a strongly positive test with reversible horizontal st depression in the inferior and lateral leads k aw t h e r e l -s h a f i e 260 geal dysfunction, or panic disorder?) dig dis sci 1997; 42:1344-1353. 5. voskuil jh, cramer mj, breumelhof r, timmer r, smout aj. prevalence of esophageal disorders in patients with chest pain newly referred to the cardiologist. chest 1996; 109:1210-1214. 6. roth jl. the symptom patterns of gaseousness. ann n y acad sci 1968; 150:109-126. 7. logan rl, wong f, barclay j. symptoms associated with myocardial infarction: are they of diagnostic value? n z med j 1986; 99:276-278. 8. darsee jr. eructonesius with inferior myocardial infarction. nz med j 1978; 99:276-278. 9. culic v, miric d, eterovic d. correlation between symptomatology and site of acute myocardial infarction. int j cardiol 2001; 77:163-168. 10. goldman i, weinberg m, weisberg m, ohlshen r, cook ef, sargent rk et al. a computer derived protocol to aid in the diagnosis of emergency room patients with acute chest pain. n engl j med 1982; 307:588-596. 11. ingram da, fulton ba, portal bv, aber cp. vomiting as a diagnostic aid in acute ischaemic cardiac pain. bmj 1980; 281:636-637. 12. bauman d. partial relief of anginal chest pain by belching. jama1977; 238:481. submitted 7 jul 21 1 revision req. 7 sep 21; revision recd. 2 nov 21 2 accepted 25 nov 21 3 online-first: jan 2022 4 doi: https://doi.org/10.18295/squmj.1.2022.005 5 6 comparison of tissue adhesive glue with subcuticular absorbable suture 7 for skin closure following thyroid surgery 8 a single blinded randomized controlled trial 9 aditya musham,1 evangeline m.k. samuel,2 ashok k. sahoo,3 10 *elamurugan tp,2 manwar a.s.4 11 12 1department of paediatric surgery, lady hardinge medical college, new delhi, india; 13 2department of surgery, jawaharlal institute of postgraduate medical education and 14 research, pondicherry, india; 3department of surgery, s.c.b medical college and hospital, 15 cuttack, india; 4department of surgery, all india institute of medical sciences, 16 bhuvaneshwar, india. 17 *corresponding author’s e-mail: elamurugantp@gmail.com 18 19 abstract 20 objectives: the objective of this study was to compare the skin closure time, postoperative 21 pain and the scar outcome between tissue adhesive and sub-cuticular sutures in thyroid 22 surgery. methods: this was a prospective, single-blinded, randomized controlled trial. a 23 sample size of 64 in each group was calculated. adult patients undergoing thyroid surgery 24 were included while those with previous neck surgery, history of keloids/hypertrophic scars 25 and those undergoing concomitant neck dissections were excluded. following platysma 26 closure, they were randomised into two groups tissue adhesive or subcuticular sutures, using 27 serially numbered opaque sealed envelopes technique. the primary outcome was the skin 28 closure time. the secondary outcomes were postoperative pain at 24 hours and scar scoring at 29 1st and 3rd post-operative month. statistical analysis was done using spss software version 30 19.0 for windows. results: the median skin closure time and postoperative pain was 31 significantly lower in the tissue adhesive group as compared to the suture group (p<0.01). 32 however, there was no statistically significant difference in scar outcome at 1st month 33 mailto:elamurugantp@gmail.com (p=0.088) and in 3rd month (p=0.137) between the two groups. there were no wound-related 34 complications in either group. it was seen on a subgroup analysis that there was no difference 35 in the scar outcome or wound-related complications in patients with comorbidities. there 36 were no instances of allergic contact dermatitis to the tissue adhesive. conclusion: the use 37 of tissue adhesive leads to lower operative time and less post-operative pain in thyroid 38 surgeries. the scar outcome is comparable between tissue adhesives and subcuticular sutures. 39 keywords: thyroidectomy; scar; tissue glue; subcuticular sutures 40 41 advances in knowledge 42  there is a decrease in operating time when tissue adhesive is used for skin closure as 43 compared to sutures 44  there is lower immediate postoperative pain when tissue adhesive is used, as 45 compared to sutures. 46  there is no difference in scar outcome or wound complications between tissue 47 adhesive and sutures, irrespective of patients’ comorbidities 48  there is an increase in cost when tissue adhesives are used. 49 50 applications to patient care 51  during thyroidectomy, tissue adhesive can be an attractive option to use, instead of 52 sutures, in order to decrease operative time and post-operative pain. 53  the patient must be counselled that the scar outcome is not likely to improve by using 54 tissue adhesive as compared to sutures. 55  the patient must be made aware of the increase in cost, if tissue adhesives are used. 56 57 introduction 58 thyroid diseases are more common in women and in younger age groups, which makes them 59 the main population group to undergo thyroid surgeries.1 conventional thyroid surgeries are 60 done via a collar-neck incision, which is in the anterior aspect. such incisions have the 61 potential to leave a conspicuous scar, if skin closure is not optimal. advances such as 62 minimally invasive thyroidectomies were designed in order to achieve a better cosmesis.2 63 however, these surgeries require sophisticated surgical equipment and expertise.3,4 hence, 64 conventional thyroid surgery is still the standard procedure in most patients. 65 66 the ideal method of skin closure is a rapid, easy-to-apply technique with a good cosmetic 67 outcome. initially, simple sutures were used, but was found to have a poor scar outcome due 68 to railroad tracking.6 subsequently, subcuticular sutures were used, which showed a better 69 scar outcome with less post-procedure pain.6 however, it needs meticulous work, time to gain 70 expertise7,8 and has the risk of needlestick injuries9. 71 72 tissue adhesive glue was introduced as an ideal system of wound closure.10 it is composed of 73 monomeric cyanoacrylate which polymerizes on contact with moisture to form an adhesive 74 layer over the skin.10 it is an attractive choice for thyroidectomies as it is easy to apply8 and 75 takes less time. its main disadvantage is contact dermatitis11, which has been purported to 76 vary with the climate.12 this is because the antigen presenting cells identify the monomeric 77 form of cyanoacrylate. in arid climates, it takes time for polymerization thus increasing the 78 chance of reaction.12 79 80 studies have been performed, comparing subcuticular sutures to tissue adhesives in thyroid 81 surgeries but differences in postoperative pain, wound dehiscence rates and operative time 82 has not been clearly elucidated. in our study, we aim to study the effects of both methods of 83 repair on post-thyroidectomy patients in a south asian country, with equatorial climate as 84 well as a wide variation in the skin type of its population. 85 86 methodology 87 study design 88 the study was designed as a prospective, single-blinded, randomized controlled trial. it was 89 conducted from march 2017 to december 2019 in the department of general surgery in a 90 tertiary care hospital after obtaining approval from institute ethics committee 91 (jip/iec/2017/0213) and registration in ctri (ctri/2018/02/011698). 92 93 sample size and patient enrolment 94 the sample size was calculated based on a similar study conducted by consorti et al.13 using 95 open epi software, a sample size of 64 in each group was calculated, taking the difference in 96 time required for skin closure as the primary criterion, with level of significance as 5% and 97 the power of study set to 90% expecting a dropout rate of 10%. all patients between 18 to 80 98 years of age undergoing thyroid surgery during the study period were included. patients with 99 previous neck surgery, history of keloids or hypertrophic scars and those undergoing 100 concomitant neck dissections were excluded. written informed consent was obtained from 101 the participants. 102 103 all patients received an intravenous dose of prophylactic antibiotic (inj. cloxacillin 500mg) 104 within 30 minutes from the time of skin incision, as per the departmental policy at our centre. 105 the surgery was done as per the standard operating procedure. once the resection was done, 106 a 14 f closed-suction drain was placed in all patients, which is part of the operative policy at 107 our centre. the strap muscles and platysma were approximated using 2-0 and 3-0 round-108 bodied vicryl simple sutures respectively. following platysma closure, the patients were 109 randomised into the two groups. tissue adhesive (octyl 2-cyanoacrylate)dermabond® 110 from ethicon inc, johnson and johnson (san lorenzo, puerto rico) was used in the study 111 while 3-0 sized monocryl suture, from lotus surgicals pvt limited (uttarakhand, india) was 112 used for subcuticular suturing. for each patient, one unit was used, according to the group 113 allotted. 114 115 postoperative analgesia was standardized in both groups, with all patients receiving 116 intravenous tramadol and ketorolac alternately every 4th hourly for first 24 hours in the 117 postoperative period. scar assessment was done at the first and third postoperative month. 118 119 randomisation details 120 randomisation was done using computer generated random numbers and allocation was done 121 using serially numbered opaque sealed envelopes (snose) technique, which were opened 122 after platysma closure. 123 124 outcome assessment 125 the primary outcome measured was the skin closure time (minutes). in the tissue adhesive 126 group (group a), after closing the platysma, the skin closure start time was noted once the 127 skin edges were dry. the tissue adhesive was applied slowly in 2 layers, using a brushing 128 motion. a gap of 15 seconds was given between the applications and the adhesive was 129 allowed to set for 60 seconds, at which point the skin closure end time was noted. dressing 130 was not applied. 131 132 in the subcuticular suture group (group b), after closing the platysma, the skin closure start 133 time was noted. the skin was closed by subcuticular absorbable suture and a dressing was 134 applied. once done, the skin closure end time was noted. 135 136 the secondary outcomes measured were postoperative pain at 24 hours and scar scoring at 137 1st and 3rd post-operative month. post-operative pain was assessed using a 10-point visual 138 analog scale.14 the scar cosmesis was assessed by a person who was blinded regarding the 139 method of skin closure, using the manchester scar scale.15 the cost per unit used was also 140 compared between the two groups. 141 142 statistical analysis 143 statistical analysis was done using spss software version 19.0. continuous variables were 144 expressed as mean or median based on the distribution. ordinal variables were expressed as 145 median. categorical variables were expressed as proportions, frequencies or percentages. 146 continuous variables were compared using unpaired t-test. ordinal variables were tested 147 using pearson chi-square test. the difference of medians of skin closure time, pain, scar 148 scores at 1st and 3rd postoperative months between both the groups were tested using mann-149 whitney u test. 150 151 results 152 among the 143 patients who underwent thyroid surgery during this study period, 124 patients 153 were included in the study based on the inclusion criteria. the schematic representation of the 154 study as per the consort 2010 (consolidated standards of reporting trials) flow diagram 155 is shown in figure 1. as shown in table 1, the baseline characteristics were comparable 156 between the two groups. the mean age of patients in the suture group was 42.62 ± 12.28 157 years and of tissue adhesive group was 42.03 ± 11.8. the majority of the study participants 158 were female, both in the suture group and in the tissue adhesive group (72.13% and 82.53% 159 respectively). the preoperative diagnosis distribution and type of surgery done in both the 160 groups were similar. 161 162 the median skin closure time in suture group and the adhesive group was 390 and 250 163 seconds respectively and the difference was found to be statistically significant (p<0.01) by 164 mann-whitney test, as shown in table 2. the median pain score between the two groups also 165 showed significant difference (p<0.01), as shown in table 3. however, there was no 166 statistically significant difference in scar outcome at 1st month (p=0.088) and in 3rd month 167 (p=0.137) between both the groups, as shown in table 4 and table 5. there were no wound-168 related complications in either group. the cost of one unit of tissue adhesive was found to 169 2000 inr and one unit of suture was 899 inr. 170 171 discussion 172 the use of tissue adhesives has gained significance in recent days owing to the concept of no-173 suture cosmetic surgery. previously, subcuticular suturing was a standard technique used for 174 skin closure especially in areas of cosmetic interest. studies comparing subcuticular suturing 175 and tissue adhesive are few in number with contradicting results. therefore, we conducted 176 this study to add to the body of existing knowledge. 177 178 the present study showed that there was a significant difference in skin closure time between 179 the tissue adhesive group and suture group. tissue adhesive reduced skin closure time by 180 36% to that of subcuticular suture. saving theatre time is essential to avoid wastage of 181 hospital resources and to avoid dissatisfaction of staff, which would affect the quality of 182 work.16 bozkurt17 and consorti13 also came to the same conclusion as this study. 183 184 postoperative pain between the two groups has been analysed in our study, which showed a 185 significant difference on the first postoperative day between the suture and tissue adhesive 186 group, which is a novel finding. in the available literature, there is no clear evidence that 187 postoperative pain in affected by using tissue adhesive, as compared to sutures. in a 188 randomized cohort study by chamariya et al in 2016, it was found that using a tissue 189 adhesive causes less pain after closure of the episiotomy wound as compared to suturing.18 190 however, the skin closure technique was mattress suturing and the area of interest was the 191 perineum. with respect to thyroid surgeries, pronio et al20 mentioned that 26.3% of 192 patients in the control group and 9.3% of the study group, which was a significant difference; 193 however, they compared between staples and tissue adhesives. amin et al21 compared pain 194 at first and tenth postoperative day using the visual analogue scale and concluded that there 195 is no difference between both the groups (p=0.829 and p=0.931). our findings can be 196 explained by the fact that there was a lower amount of tissue handling and dissection, no 197 needle pricks and no suture lying within the skin postoperatively in the tissue adhesive 198 group. 199 200 scar outcome is one another important factor for assessing a skin closure technique. 201 consorti13 have assessed scar outcome at 6 weeks using patient and observer scar 202 assessment scale (posas) score. based on observer assessment, subcuticular suture was 203 favoured above tissue adhesive, but there was no difference on the patients’ assessment. this 204 study was, however, criticized for assessing scars at 6 weeks as it may be too early to assess 205 scar outcome with most surgical scars taking an optimal time of 3 months to mature. ciufelli 206 et al concluded that there was better scar in tissue adhesive group than suture group at tenth 207 day, but at three months, there was no difference.19 pronio20, amin21 and yang22 also showed 208 that there was no significant difference in the scar outcome at the 3rd month between both the 209 groups. we found concordant results in our study with there being no difference in the scar 210 outcome both at 1st month and at 3rd month between the groups. 211 212 in the cochrane review published by dumville, it was stated that sutures were significantly 213 better than tissue adhesives for minimising dehiscence, but the available evidence was of a 214 low quality. a need to study a subset of the population that have comorbidities that influence 215 the rates of wound breakdown was also noted.9 in our present study, we have tried to bridge 216 this gap in knowledge by taking comorbidities into account with 16.39% patients in suture 217 group and 15.87% patients in the tissue adhesive group having comorbidities. it was seen on 218 a subgroup analysis that there was no difference in the scar outcome or wound-related 219 complications in these patients. however, the validity of this statement was questionable due 220 to the small subgroup size (15-16%) and this statement requires larger studies to reinforce 221 this conclusion. 222 223 regarding the time for closure of the skin incision, it would depend on the skin incision 224 length which depends on the extent of surgery. pronio20 and ciufelli19 did not differentiate 225 between the different types of thyroid surgeries. consorti13 had only taken patients 226 undergoing total thyroidectomy patients, whereas bozkurt17 had taken all head and neck 227 surgeries into account. in our study, we have taken patients undergoing different extents of 228 thyroid surgeries and randomized them into both groups, and as table 1 demonstrates, were 229 equally distributed into either arm. our study shows that hemithyroidectomy took 230 significantly less time in both groups, which may be attributed to the incision length. as all 231 types of thyroid surgeries were included in our study, this was prevented from being a 232 confounding factor. 233 234 in the present study, each patient required one package of 3-0 monocryl suture which costs 235 899 inr or one vial of tissue adhesive which costs 2000 inr. this showed that the tissue 236 adhesive was twice as expensive as a suture. however, there was no need of dressing or 237 follow-up visits for suture removal in tissue adhesive. hence, the overall cost involved in 238 both groups was difficult to estimate and compare. bozkurt and saydam17 also had similar 239 results in their study done in 2008. 240 241 the disadvantages of cyanoacrylate were mainly technical, and care should be taken to 242 prevent them. in literature, it was seen that the adhesive can seep into the wound edges, 243 impairing the wound healing and affecting the scar cosmesis by causing a foreign body 244 reaction.23 asai et al reported that 9/577 patients had developed allergic contact dermatitis 245 after the first application of cyanoacrylate tissue adhesive.11 bitterman et12 reported a 246 papulovesicular rash at the application site, 2 weeks postoperatively, which on close 247 examination, showed residual glue found at the incision site, which improved once the glue 248 was washed off. none of these effects were noted in any of our patients. 249 250 another advantage of tissue adhesive is the antimicrobial nature. cyanacrylate, in the 251 unused form, is manufactured in the monomeric state. when it encounters moisture, it 252 polymerizes forming a layer of waterproof material, which forms a physical barrier to the 253 entry of microbes, obviating the need for dressing. it can also inhibit microbial growth in 254 vitro. this is thought to be due to high electronegative charge on the cyanoacrylate monomer 255 which reacts with the positively charged polysaccharide capsule of organisms.24 256 257 the present study was not without limitations of its own. it was a single institutional study. 258 the skin closure was not done by a single surgeon in all patients. thus, the experience of the 259 surgeon with the technique may have affected our results especially skin closure time and 260 scar outcome. the length of the skin incision was not measured which can affect the skin 261 closure time. scar outcome was assessed by a blinded observer using manchester scar score 262 which is a subjective score. patient satisfaction and their assessment of the scar were not 263 evaluated which can tell us the patient’s preference which may affect the choice of skin 264 closure. 265 266 conclusion 267 tissue adhesive is faster to apply than subcuticular sutures in all types of thyroid surgeries. 268 they also result is less immediate postoperative pain and the two groups have a comparable 269 scar cosmesis. there was no difference seen in the wound-related complications between the 270 two groups, even among patients with comorbidities. however, the cost involved in tissue 271 adhesives is significantly higher as compared to sutures. hence, we propose that the use of 272 tissue adhesives can replace subcuticular sutures in thyroid skin closure, if the patient is able 273 to afford it. 274 275 conflict of interest 276 the authors declare no conflicts of interest. 277 278 funding 279 no funding was received for this study. 280 281 authors’ contribution 282 am was involved in the formulation of the protocol and of its execution. emks was 283 involved in the data collection and the writing of the final manuscript. aks was involved in 284 protocol creation and the editing of the manuscript. etp and mas were involved in the 285 overall process of supervising the study and editing the manuscript. 286 287 references 288 1. taylor pn, albrecht d, scholz a, gutierrez-buey g, lazarus jh, dayan cm, et al. 289 global epidemiology of hyperthyroidism and hypothyroidism. nat rev endocrinol. 290 2018 may;14(5):301–16. https://doi.org/10.1038/nrendo.2018.18 291 2. ohgami m, ishii s, arisawa y, ohmori t, noga k, furukawa t, et al. scarless 292 endoscopic thyroidectomy: breast approach for better cosmesis. surgical 293 laparoscopy endoscopy & percutaneous techniques. 2000 feb;10(1):1–4. 294 pmid: 10872517 295 3. lang bh-h, wong k-p. a comparison of surgical morbidity and scar appearance 296 between gasless, transaxillary endoscopic thyroidectomy (gtet) and minimally 297 invasive video-assisted thyroidectomy (vat). ann surg oncol. 2013 feb;20(2):646–298 52. https://doi.org/10.1245/s10434-012-2613-y 299 https://doi.org/10.1038/nrendo.2018.18 4. stalberg p, delbridge l, van heerden j, barraclough b. minimally invasive 300 parathyroidectomy and thyroidectomy--current concepts. surgeon. 2007 oct;5(5):301–301 8. https://doi.org/ 10.1016/s1479-666x(07)80029-1 302 5. lombardi cp, bracaglia r, revelli l, insalaco c, pennestrì f, bellantone r, et al. 303 [aesthetic result of thyroidectomy: evaluation of different kinds of skin suture]. ann ital 304 chir. 2011 dec;82(6):449–55; discussion455-456. pmid: 22229233 305 6. swanson na, tromovitch ta. suture materials, 1980s: properties, uses, and abuses. int 306 j dermatol. 1982 sep;21(7):373–8. https://doi.org/ 10.1111/j.1365-4362.1982.tb03154.x 307 7. singer aj, hollander je, valentine sm, thode hc, henry mc. association of training 308 level and short-term cosmetic appearance of repaired lacerations. acad emerg med. 309 1996 apr;3(4):378–83. https://doi.org/ 10.1111/j.1553-2712.1996.tb03454.x 310 8. singer aj, quinn jv, clark re, hollander je, traumaseal study group. closure of 311 lacerations and incisions with octylcyanoacrylate: a multicenter randomized controlled 312 trial. surgery. 2002 mar;131(3):270–6. https://doi.org/ 10.1067/msy.2002.121377 313 9. dumville jc, coulthard p, worthington hv, riley p, patel n, darcey j, et al. tissue 314 adhesives for closure of surgical incisions. cochrane database syst rev. 2014 nov 315 28;(11):cd004287. https://doi.org/ 10.1002/14651858.cd004287.pub4 316 10. trott at. cyanoacrylate tissue adhesives: an advance in wound care. jama. 1997 317 may 21;277(19):1559–60. https://doi.org/ 10.1001/jama.1997.03540430071037 318 11. asai c, inomata n, sato m, koh n, goda s, ishikawa h, et al. allergic contact 319 dermatitis due to the liquid skin adhesive dermabond® predominantly occurs after the 320 first exposure. contact dermatitis. 2021;84(2):103–8. https://doi.org/ 321 10.1111/cod.13700 322 12. bitterman a, sandhu k. allergic contact dermatitis to 2-octyl cyanoacrylate after 323 surgical repair: humidity as a potential factor. jaad case rep. 2017 nov;3(6):480–1. 324 https://doi.org/ 10.1097/00006534-199811000-00022 325 13. consorti f, mancuso r, piccolo a, pretore e, antonaci a. quality of scar after total 326 thyroidectomy: a single blinded randomized trial comparing octyl-cyanoacrylate and 327 subcuticular absorbable suture. isrn surg. 2013;2013:270953. https://doi.org/ 328 10.1155/2013/270953 329 14. hayes mh. experimental developement of the graphics rating method. physiol bull. 330 1921;18:98–9. https://doi.org/ 331 15. beausang e, floyd h, dunn kw, orton ci, ferguson mw. a new quantitative scale for 332 clinical scar assessment. plast reconstr surg. 1998 nov;102(6):1954–61. https://doi.org/ 333 https://doi.org/10.1016/s1479-666x(07)80029-1 https://doi.org/10.1111/j.1365-4362.1982.tb03154.x https://doi.org/10.1111/j.1553-2712.1996.tb03454.x https://doi.org/10.1067/msy.2002.121377 https://doi.org/10.1002/14651858.cd004287.pub4 https://doi.org/10.1111/cod.13700 https://doi.org/10.1097/00006534-199811000-00022 https://doi.org/10.1155/2013/270953 16. huskisson ec. measurement of pain. lancet. 1974 nov 9;2(7889):1127–31. 334 https://doi.org/ 10.1016/s0140-6736(74)90884-8 335 17. bozkurt mk, saydam l. the use of cyanoacrylates for wound closure in head and neck 336 surgery. eur arch otorhinolaryngol. 2008 mar;265(3):331–5. https://doi.org/ 337 10.1007/s00405-007-0454-2 338 18. chamariya s, prasad m, chauhan a. comparison of dermabond adhesive glue with skin 339 suture for repair of episiotomy. international journal of reproduction, contraception, 340 obstetrics and gynecology. 2016 dec 15;5(10):3461–5. 341 http://dx.doi.org/10.18203/2320-1770.ijrcog20163423 342 19. alicandri-ciufelli m, piccinini a, grammatica a, molteni g, spaggiari a, di matteo s, 343 et al. aesthetic comparison between synthetic glue and subcuticular sutures in thyroid 344 and parathyroid surgery: a single-blinded randomised clinical trial. acta 345 otorhinolaryngol ital. 2014 dec;34(6):406–11. pmid: 25762833 346 20. pronio a, filippo add, narilli p, caporillli d, vestri a, ciamberlano b, et al. closure 347 of cutaneous incision after thyroid surgery: a comparison between metal clips and 348 cutaneous octyl-2-cyanoacrylate adhesive. a prospective randomized clinical trial. 349 european journal of plastic surgery. 2010; https://doi.org/10.1007/s00238-010-0477-6 350 21. amin m, glynn f, timon c. randomized trial of tissue adhesive vs staples in 351 thyroidectomy integrating patient satisfaction and manchester score. otolaryngol head 352 neck surg. 2009 may;140(5):703–8. https://doi.org/10.1016/j.otohns.2009.01.003 353 22. yang y-l, xiang y-y, jin l-p, pan y-f, zhou s-m, zhang x-h, et al. closure of skin 354 incision after thyroidectomy through a supraclavicular approach: a comparison between 355 tissue adhesive and staples. scand j surg. 2013;102(4):234–40. 356 https://doi.org/10.1177/1457496913490610 357 23. elmasalme fn, matbouli sa, zuberi ms. use of tissue adhesive in the closure of small 358 incisions and lacerations. j pediatr surg. 1995 jun;30(6):837–8. https://doi.org/ 359 10.1016/0022-3468(95)90760-2 360 24. mizrahi b, weldon c, kohane d. tissue adhesives as active implants. in: active 361 implants and scaffolds for tissue regeneration. 2011. p. 39–56. https://doi.org/ 362 10.1007/8415_2010_48 363 364 https://www.ncbi.nlm.nih.gov/pubmed/25762833 https://doi.org/10.1007/s00238-010-0477-6 https://doi.org/10.1016/j.otohns.2009.01.003 https://doi.org/10.1177/1457496913490610 https://doi.org/10.1016/0022-3468(95)90760-2 http://dx.doi.org/10.1007/8415_2010_48 365 figure 1: consort 2010 flow diagram 366 367 table 1: demographic and clinical parameters comparison between the two groups 368 parameters subcuticular suture tissue adhesive p value mean age 42.62 ± 12.28 42.03 ± 11.8 0.785 gender male [n(%)] 17(27.87) 11(17.46) 0.166 female [n(%)] 44(72.13) 52(82.54) preoperative diagnosis benign [n(%)] 44(72.13) 46(73.02) 0.912 malignant [n(%)] 17(27.86) 17(26.98) type of surgery hemithyroidectomy [n(%)] 29(47.54) 30(47.62) 0.993 subtotal and total thyroidectomy [n(%)] 32(52.46) 33(52.38) 369 table 2: comparison of skin closure time in each group 370 group median (in seconds) minimum (in seconds) maximum (in seconds) p-value# suture 390 130 750 <0.01* tissue adhesive 250 90 720 #mann-whitney u test 371 *statistically significant with 1% level of significance 372 373 table 3: comparison of post-operative pain score in each group 374 group median minimum maximum p-value# suture 6 1 9 <0.01* tissue adhesive 5 1 9 #mann-whitney u test 375 *statistically significant with 1% level of significance 376 377 table 4: comparison of scar score in the 1st postoperative mont 378 group median minimum maximum p-value# suture 10 6 15 0.088 tissue adhesive 9 5 15 #mann-whitney u test 379 380 table 5: comparison of scar score in the 3rd postoperative month in each group 381 group median minimum maximum p-value# suture 8 6 13 0.137 tissue adhesive 8 5 13 #mann-whitney u test 382 secondary infertility due to fetal bone retention a systematic literature review *arjola agolli,1 jannel a. lawrence,2 upasana maskey,2 hanyou loh,2 charmy parikh2 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 448–454, epub. 7 nov 22 submitted 9 jan 22 revision req. 3 apr 22; revision recd. 22 apr 22 accepted 2 jun 22 1department of family and community medicine, pennsylvania state univeristy, pennsylvania, usa; 2division of clinical & translational research, larkin health system, south miami, usa *corresponding author’s e-mail: aagolli@pennstatehealth.psu.edu according to the united nations mediumvariant projection, the global fertility rate declined from 3.2 live births per woman in 1990 to 2.5 in 2019 and is expected to reach 2.2 live births per woman in 2050 and 1.9 in 2100.1 each year, more than 227 million women become pregnant worldwide, out of which roughly two-thirds deliver live infants, while the remaining one-third end in miscarriage, stillbirth or induced abortion.2 globally, one in four pregnancies (25%) end in abortion, of which nearly half (45%) are unsafe abortions.3 worldwide, 8–12% of couples of reproductive age are affected by infertility.4 it is estimated that one in four couples in developing countries and one in seven couples in developed countries suffer from infertility. the prevalence of infertility in some parts of the world, such as south and central asia, the middle east, north africa, subsaharan africa and central and eastern europe, is as high as 30%.5 in the usa, about 1.3 million women are treated annually for infertility, while 2% undergo treatment with assisted reproductive technology.6 secondary infertility is the most common form of infertility. it is commonly seen in areas with unsafe abortion practices and maternity care, which are often associated with increased chances of infection.7 postabortion infection can lead to future fertility problems resulting from damage to the fallopian tubes or direct damage to the endometrial lining leading to adhesions (asherman’s syndrome). rarely, surgical midtrimester abortions can lead to retained fetal bones and cause subfertility.8 as reported by izhar et al., prolonged intrauterine retention of any fetal bone can lead to secondary infertility.9 although rare, retained fetal bones are more commonly seen in an anomalous uterus.10 the exact incidence remains unclear; however, the incidence was reported to be 0.15% among 2000 diagnostic hysteroscopies.9,11 apart from subfertility, retained fetal bones may also present with chronic pelvic pain, dysmenorrhoea, abnormal uterine bleeding and dyspareunia.10 prolonged retention of fetal bones may lead to chronic inflammation and endometrial damage, making it harder to achieve fertility.10 the present review was focused on outlining the pathophysiology, clinical presentations, diagnostic modal ities and treatment options and outcomes in patients with secondary infertility due to fetal bone retention. sometimes, patients with this condition are asympto matic and fetal bones can be found as an incidental finding on an ultrasound or hysteroscopy, as part of the infertility workup.10 a high level of suspicion is nec essary to diagnose this rare condition; hence, this review aimed to raise awareness among obstetric/ gynaecologists about the possibility of this condition. pat h o p h y s i o l o g y a n d h y p o t h e s i s o f s e c o n d a r y i n f e r t i l i t y d u e t o f e ta l b o n e r e t e n t i o n prolonged intrauterine retention of any fetal bone can lead to secondary infertility. the earliest report of calcified tissue of fetal origin in utero goes back to 1966.12 these calcified tissues, when deeply embedded in the uterine mucosa, may present with the same contraceptive effect as an intrauterine contraceptive device, thereby causing secondary infertility.13,14 on imaging, these tissues usually present as echogenic review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2022.042 abstract: prolonged intrauterine retention of fetal bones during an abortion procedure can lead to secondary infertility. this review aimed to raise awareness among obstetric/gynaecologists about the possibility of this condition. a total of 17 case reports, seven case series and one retrospective study were included in this review, with 75 patients in total. overall, 60% had a pregnancy termination in the second trimester, while 20% had a termination during the first trimester. hysteroscopic resection was used to remove the intrauterine fetal bones in 69% of patients. in total, 59% of patients conceived following the procedure, 1% conceived despite the presence of intrauterine bones, 24% could not conceive at the time of the study and 16% had an unknown outcome. transvaginal ultrasound was used for diagnosis in 41 (55%) patients, while pelvic ultrasound was used in 21 (28%) patients. in conclusion, secondary infertility is a common occurrence after a dilation and curettage procedure partially due to fetal bone retention. the gold standard for an accurate diagnosis and treatment is hysteroscopy. keywords: incomplete abortion; abortion; therapeutic abortion; miscarriage; infertility. https://creativecommons.org/licenses/by-nd/4.0/ arjola agolli, jannel a. lawrence, upasana maskey, hanyou loh and charmy parikh review | 449 foci partially embedded in the endometrial lining, an intrauterine foreign body, thin plates of bone or many fetal bones with a nearly intact morphology.9,12,15,16 microscopic examinations have revealed necrotic bony trabeculae, bone marrow and chronic inflammation in the intervening spaces within the endometrium during its proliferative phase.16,17 in 1982, dawood et al. posited that the presence of the fetal bones can act as uterine synechiae or an intrauterine device (iud) and thus could prevent pregnancy. according to their study, fetal bones near the fundal region also elevated the concentration of endometrial prostaglandin f2 alpha in that region, leading to infertility.18 in addition, lewis et al. discov ered that the pattern of prostanoid increase was similar to that seen in iud users.19 another pathogenesis for this condition is endometrial osseous metaplasia, a rare entity.20 however, a previous pregnancy history is reported in >80% of these cases.21 there are two theories regarding the origin of osseous metaplasia: 1) persistence of embryonic bones that keep developing after curettage; and 2) induction of a process of osteogenesis by one’s embryonal cells, provoking the osseous differentiation of hypothetical pluripotent endometrial cells. this process can be differentiated from retained fetal bones by comparing the patient’s short tandem repeats and the bony sample.22 in a study by wani et al., histopathological exam ination of retrieved endometrial tissue from 10 patients revealed nonspecific lymphocytic infiltrate with interspersed lamellar bone in six (42.8%) patients and trabecular bone in four (28.5%) patients with scanty endometrial glands and stroma in various hormonal phases. these results confirmed the diagnosis of osseous metaplasia of the endometrial lining.23 methods p r o t o c o l this systematic review consists of analysis from published case reports, case series and retrospective studies. it was conducted according to the standards and guidelines established in the preferred reporting items for systematic reviews and meta-analysis (prisma) guidelines. s e a r c h s t r at e g y a systematic literature search of four academic databases was conducted in october 2021: pubmed (national library of medicine, maryland, usa), sciencedirect (elsevier, amsterdam, netherlands), cochrane (cochrane library, london, england) and google scholar (google, california, usa). the search included all relevant articles from inception up to october 2021. regular terms used were ‘infertility’ and ‘retained fetal bones’. terms used from the medical subject headings database were ‘infertility, female’ and/or ‘retained’ and/or ‘fetal bones’ and/or ‘abortion’. the search terms were kept broad to encompass all possible relevant studies. inclusion and exclusion criteria were then applied. the first and second authors screened the title and abstract, then the full paper was read to determine its relevance. at the end of the search, any duplicate articles were eliminated using microsoft excel. all selected articles reporting patients with retained fetal bones from a previous pregnancy termination who presented with infertility were included in the analysis. s t u d y s e l e c t i o n, e x t r a c t i o n a n d a n a ly s i s the literature search yielded 1,119 studies. study selection was completed by three independent, parallel reviewers and performed in two separate stages: (1) title/abstract screening, followed by (2) full-text screening. data extraction was performed by three investigators, who resolved discrepancies via consensus. a total of 410 duplicates were manually removed and the three investigators independently reviewed all titles and abstracts. subsequently, 600 studies were deemed irrelevant and excluded after screening their titles and abstracts. the full texts of the articles regarded as potentially eligible for consideration were extracted and screened for further analysis based on the predefined inclusion and exclusion criteria. finally, 25 studies were selected for inclusion in the review after the full-text screening [figure 1]. disagreements between the authors were resolved through consensus and active discussion. i n c l u s i o n /e x c l u s i o n c r i t e r i a the eligibility criteria were determined following the patient, intervention, comparison and outcome approach. the following inclusion criteria were considered: participants of all ages, articles published in and after 1982, human subjects and articles written in english. the exclusion criteria consisted of review articles, animal studies, studies published in a language other than english and the absence or unclear reporting of the infertility complication status in post-abortion patients. q u a l i t y a p p r a i s a l the first and second authors performed quality appraisals. a total of 17 case reports, seven case series and one retrospective study were included in the review, comprising a total of 75 patients. secondary infertility due to fetal bone retention a systematic literature review 450 | squ medical journal, november 2022, volume 22, issue 4 results c l i n i c a l m a n i f e s tat i o n s overall, 25 published papers with a total of 75 cases of retained fetal bones were included. in all 75 cases, women presented with infertility after the termination of pregnancy in either the first or second trimester. other presenting symptoms included dysmenorrhoea, menorrhagia, chronic pelvic pain, dyspareunia and vaginal discharge. the comprehensive literature review concluded that most patients had a previous pregnancy termination during the second trimester. a total of 45 (60%) cases had a termination in the second trimester, while 15 (20%) had a pregnancy termination during the first trimester. the exact date of termination was unknown for 15 (20%) patients. the interval between termination and reporting of symptoms varied. the shortest interval recorded was 12 months and the longest was 180 months.24,25 in a study by petrakis et al., a patient presented with chronic pelvic pain and infert ility 12 months after a miscarriage at 19 weeks gestation due to placental abruption.24 a summary of cases with retained fetal bones seen in patients presenting with infert ility after either a spontaneous or induced pregnancy termination is provided in table 1.8–10,13,14,16,18,24–41 d i a g n o s i s pelvic ultrasound proved to be an excellent imaging tool for diagnosis in any female with infertility; transvaginal and abdominal ultrasound was used in 41 (55%) and 21 (28%) of the 75 patients, respectively. areas of interest during the transvaginal ultrasound (tvs) included the patency of fallopian tubes, the size of the uterus and the presence of echogenic areas suggestive of fetal bones in the endometrial cavity. one (1%) patient had a saline infusion sonography (sis) procedure performed in addition to a tvs, in which highly echogenic areas in the anterior wall of the uterus were visualised.9 hysterosalpingogram (hsg) was another method used in seven (9%) patients, which looks for filling defects and space-occupying irregularities in the uterine cavity and fallopian tubes. additionally, hysteroscopy provided both diagnostic and therapeutic benefits in five (7%) patients. t r e at m e n t a n d o u t c o m e a hysteroscopic resection alone was performed in 52 patients (69%), while it was performed along with dilation and curettage (d&c) in two (3%) patients. petrakis et al. presented a case where one (1%) patient had a hysteroscopy scheduled but did not comply with treatment recommendations.25 other treatment methods used included d&c without hysteroscopy in 17 (23%) patients and dilation and evacuation (d&e) in three (4%) patients. hysteroscopic resection was used most frequently for the removal of intrauterine fetal bones [table 1]. regarding patients experiencing a successful pregnancy post-treatment, the review revealed that 44 (59%) patients conceived following the removal of retained intrauterine fetal bones. one (1%) case was identified in which a patient conceived despite the presence of intrauterine bone fragments.24 in comparison, 18 (24%) patients had not conceived at the time of the study. the remaining 12 (16%) patients either were not followed up for infertility or had other outcomes, or the details of their follow-up are unknown. other outcomes following treatment that were reported included the patient’s return to a normal menstrual cycle and the resolution of presenting symptoms. discussion although rare, the intrauterine retention of fetal bones is a potential complication following an abortion, often in the second or third trimester.34 abortions occurring in the first trimester, when fetal bone ossification has not yet completely occurred, could involve dystrophic calcification of retained products that could also lead to intrauterine bone formation.10 however, it could also occur secondary to osseous figure 1: prisma flow diagram depicting search strategy of all relevant articles from inception up to october 2021. arjola agolli, jannel a. lawrence, upasana maskey, hanyou loh and charmy parikh review | 451 table 1: summary of cases of retained fetal bones seen in patients presenting with infertility after either a spontaneous or induced pregnancy termination8–10,13,14,16,18,24–41 authors and year of public ation number of cases presenting with infertility age in years interval between top or miscarriage and diagnosis in months gestational age at top or miscarriage in weeks clinical presentation diagnostic imaging method treatment outcome srofenyoh et al.8 (2006) 3 35 30 42 nk 16 (n = 2); nk (n = 1) chronic pelvic pain (n = 1); dyspareunia (n = 1); secondary infertility (n = 1) pelvic ultrasound d&e conceive (n = 2); had not conceived (n = 1) izhar et al.9 (2015) 1 36 nk 20 secondary infertility transvaginal ultrasound and sis d&c scheduled for repeat sis and kept on high-dose oestrogen. has not conceived gainder et al.10 (2018) 18 nk >24 (n = 5); 24–36 (n = 6); >36 (n = 7) first trimester (n = 5); second trimester (n = 13) secondary infertility; menorrhagia (n = 5); amenorrhoea (n = 2); metrorrhagia (n = 4); chronic pelvic pain (n = 2) pelvic ultrasound (n = 17); hysteroscopy (n = 1) hysteroscopy (n = 15); d&c (n = 3) conceived (n = 5); had not conceived (n = 7); not followed up for conception (n = 6) lanzarone and pardey14 (2009) 1 36 nk nk secondary infertility hysteroscopy hysteroscopy sis determined a normal cavity patil et al.13 (2013) 1 28 nk 6 menorrhagia hysteroscopy hysteroscopy nk dajani and khalaf16 (1985) 1 26 18 18 secondary infertility hysterosal pingogram d&c conceived dawood and jarrett18 (1982) 1 22 72 10 secondary infertility hysterosal pingogram hysteroscopy with d&c had not conceived. petrakis et al.24 (2019) 1 28 12 19 chronic pelvic pain transvaginal ultrasound hysteroscopy scheduled but did not comply. conceived without removal of fetal bones. moon et al.25 (1997) 11 26–37 12–60 (n = 10); 180 (n = 1) 16–24 secondary infertility transvaginal ultrasound d&c conceived (n = 10); bilateral tubal obstruction. had not conceived (n = 1) melius et al.26 (1991) 1 33 108 nk secondary infertility hysterosal pingogram hysteroscopy had not conceived. chan27 (1996) 1 34 108 16 secondary infertility, dysmenorrhoea transvaginal ultrasound hysteroscopy returned to a normal menstrual cycle. not followed up for conception. arora et al.28 (1998) 2 28 27 case 1: 48 case 2: nk case 1: 16 case 2: 12 secondary infertility hysterosal pingogram hysteroscopy case 1: returned to a normal menstrual cycle case 2: conceived tulandi and sammour29 (2001) 1 33 96 6 secondary infertility hysterosal pingogram hysteroscopy nk elford and claman30 (2003) 1 36 15 late first trimester secondary infertility pelvic ultrasound hysteroscopy with d&c conceived goldberg and roberts31 (2008) 1 32 nk 22 secondary infertility transvaginal ultrasound hysteroscopy conceived top = termination of pregnancy; nk = not known; d&e = dilation and evacuation; sis = saline infusion sonography; d&c = dilation and curettage. secondary infertility due to fetal bone retention a systematic literature review 452 | squ medical journal, november 2022, volume 22, issue 4 metaplasia due to the chronic inflammation of the endometrium.34 hypercalcaemia, hyperphosphatemia and hypervitaminosis d are rarer causes of this endometrial calcification.10 the incidence of this complication is thought to be underestimated, as symptoms experienced by patients are not readily attributed to the abortion, leading to a considerable delay between the abortion and diagnosis.42 retained fetal bones exert an intrauterine device (iud)-like effect, resulting in secondary infertility, and their removal could reverse this effect.34 as seen from the outcomes of included case reports, d&c procedures for the evacuation of the prior non-viable fetus had preceded secondary infertility and the removal of retained fetal bones, most commonly via hysteroscopy, allowed these patients to conceive.6,16,24,25,30–36 the present review found that hysteroscopic removal was performed in 69% of patients, enabling 59% to conceive after the procedure. other treatment methods used included d&c without hysteroscopy in 23% of patients and d&e in 4% of patients. in a study by gainder et al., the data of 6,435 patients who visited a fertility clinic in india were retrospectively reviewed, out of which 18 patients received ‘retained fetal bone’ as the sole diagnosis for their infertility.10 all patients underwent diagnostic hysteroscopy and had the bony fragments removed via hysteroscopy (n = 15) or d&c (n = 3). despite following up on 12 of the 18 patients for up to 6 years, spontaneous conception was only noted in five patients. it must be noted that these five patients had presented for secondary infertility within 3 years of their previous abortion, while the remaining seven had presented after >3 years. this finding led the authors to conclude that any changes associated with the retention of bony fragments are expected to regress with a return of fertility only if the bony fragments are removed quickly and provided there table 1 (cont’d.): summary of cases of retained fetal bones seen in patients presenting with infertility after either a spontaneous or induced pregnancy termination8–10,13,14,16,18,24–41 authors and year of public ation number of cases presenting with infertility age in years interval between top or miscarriage and diagnosis in months gestational age at top or miscarriage in weeks clinical presentation diagnostic imaging method treatment outcome kramer and rhemrev32 (2008) 1 32 96 12 secondary infertility hysteroscopy hysteroscopy conceived singla et al.33 (2012) 1 23 36 10 secondary infertility transvaginal us hysteroscopy advised a hysterosal pingogram for tubal patency. had not conceived. xiao et al.34 (2014) 1 30 108 15 secondary infertility hysteroscopy hysteroscopy conceived mishra et al.35 (2018) 1 28 60 15 secondary infertility transvaginal ultrasound hysteroscopy conceived mahdavi et al.36 (2019) 1 25 24 15 secondary infertility hysterosal pingogram hysteroscopy conceived graham et al.37 (2000) 11 23–36 24–144 10 (n = 2), 12 (n = 1), 14 (n = 3), 16 (n = 2), 20 (n = 1), 24 (n = 1), 26 (n = 1) secondary infertility transvaginal ultrasound hysteroscopy conceived (n = 8); had not conceived (n = 2); nk (n = 1) pereira et al.38 (2014) 7 24–40 nk nk secondary infertility transvaginal ultrasound (n = 5); hysteroscopy (n = 2) hysteroscopy conceived (n = 5); did not conceive (n = 2) grigore et al.39 (2014) 2 41 34 nk nk secondary infertility transvaginal ultrasound hysteroscopy case 1: conceived; case 2: resolution of symptoms bozdag et al.40 (2015) 1 30 10 nk secondary infertility transvaginal ultrasound hysteroscopy conceived awowole et al.41 (2021) 4 nk nk nk secondary infertility transvaginal ultrasound hysteroscopy conceived top = termination of pregnancy; nk = not known; d&e = dilation and evacuation; sis = saline infusion sonography; d&c = dilation and curettage. arjola agolli, jannel a. lawrence, upasana maskey, hanyou loh and charmy parikh review | 453 is no tubal damage or formation of uterine synechiae following the abortion. the long-term presence of bony fragments in the endometrial cavity could have led to endometritis, thus accounting for persistent infertility. the authors also postulated that a few bony fragments could have become so deeply embedded in the endometrium that they could not be successfully removed; thus, these could have continued to act as foreign bodies, preventing intrauterine pregnancy.10 petrakis et al. similarly reported that achieving childbearing is possible, with spontaneous conception and a high live birth rate, once bony fragments have been removed from the uterine cavity. however, petrakis et al. also reported the case of a successful live pregnancy, conceived spontaneously and carried to term, in a patient with calcium salt deposits in the placenta and the intrauterine retention of fetal bones from a previous miscarriage at 19 weeks gestation a year prior.24 to date, this is the only reported case where a patient could conceive despite the presence of intrauterine fetal bones. in addition to secondary infertility, intrauterine fetal bones could also cause abnormal uterine bleeding, menorrhagia, dysmenorrhea, chronic pelvic pain and abnormal vaginal discharge.34 it was suggested that pelvic pain and dysmenorrhoea could be due to an increase in the levels of prostaglandins from the inflammatory reaction.10 removal of bony fragments could thus reverse these symptoms.8,10,15,27 pelvic ultrasounds, pelvic x-rays, hysterosalpingo grams and hysteroscopies have been used to detect intrauterine bony fragments.10,37 shadows observed on ultrasonography are often not definitive for diagnosis but could guide the hysteroscopic removal of these bony fragments.10 a report of calcifications in the endo metrium by radiologists is also not definitive for diagnosis. however, it should still raise suspicion about retained fetal bones, especially when coupled with a history of prior abortion.11 an accurate diagnosis is best obtained via hysteroscopy, which will reveal osseous fragments embedded within the endometrium. although d&c may also be employed to remove these bony fragments, it is a less commonly choice for treatment. hysteroscopy plays a vital role as a management option, as bony fragments may simul taneously be retrieved during the procedure.10 conclusion secondary infertility is a common occurrence after a d&c procedure. in second-trimester abortions, fetal bone retention could be one of the causes of secondary infertility. the theories discussed in the studies of infertility due to fetal bone retention included elevated endometrial prostaglandin f2, osseous metaplasia and chronic inflammation. to achieve another pregnancy, removal of these retained bones is recommended. the sooner the removal is made, the better are the chances of achieving a future pregnancy. very rarely has there been reported conception despite the fetal bones retained in the uterine cavity. besides secondary infertility, patients can also present with dysmenorrhea, menorrhagia, chronic pelvic pain, dyspareunia and vaginal discharge. the gold standard for an accurate diagnosis is hysteroscopy, which provides the added benefit of removing these fragments at the same sitting. therefore, to improve outcomes and restore fertility in women presenting with secondary infertility after having a prior abortion, physicians must be wary of the possibility of fetal bone retention. a u t h o r s’ c o n t r i b u t i o n s aa conceptualised and designed the work. aa and jal collected, analysed and interpreted the data. aa, um, hl and cp drafted the manuscript. all authors critically revised the manuscript and approved the final version. a c k n o w l e d g e m e n t the contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by hrsa, hhs, or the u.s. government. for more information, please visit hrsa.gov. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this work is supported by the health resources and services administration (hrsa) of the u.s. department of health and human services (hhs) as part of an award totaling $473,925 with 15% financed by non-governmental sources. references 1. united nations department of economic and social affairs, population division. world fertility and family planning 2020: highlights. new york, usa: united nations. 2020. 2. mesce d. abortion facts and figures 2021. washington, dc, usa: population reference bureau. 2021. 3. singh s, remez l, sedgh g, kwok l, onda t. abortion worldwide 2017: uneven progress and unequal access. new york: guttmacher institute. 2018. 4. ombelet w, cooke i, dyer s, serour g, devroey p. infertility and the provision of infertility medical services in developing countries. hum reprod update 2008; 14:605–21. https://doi. org/10.1093/humupd/dmn042. https://doi.org/10.1093/humupd/dmn042 https://doi.org/10.1093/humupd/dmn042 secondary infertility due to fetal bone retention a systematic literature review 454 | squ medical journal, november 2022, volume 22, issue 4 5. mascarenhas mn, flaxman sr, boerma t, vanderpoel s, stevens ga. national, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. plos med 2012; 9: e1001356. https://doi.org/10.1371/journal.pmed.1001356. 6. katz p, showstack j, smith jf, nachtigall rd, millstein sg, wing h, et al. costs of infertility treatment: results from an 18-month prospective cohort study. fertil steril 2011; 95:915–21. https://doi.org/10.1016/j.fertnstert.2010.11.026. 7. inhorn mc, patrizio p. infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. hum reprod update 2015; 21:411–26. https:// doi.org/10.1093/humupd/dmv016. 8. srofenyoh e, addison m, dortey b, kuffour p. intrauterine retained fetal bones as a cause of secondary infertility. ghana med j 2006; 40:105–9. https://doi.org/10.4314/gmj.v40i3.55262. 9. izhar r, husain s, tahir s, husain s. secondary infertility due to retained fetal bones diagnosed via saline sonography. j coll physicians surg pak 2016; 26:861–2. 10. gainder s, arora p, dhaliwal lk. retained intrauterine bony fragments as a cause of secondary infertility in a tertiary level indian hospital. j hum reprod sci 2018; 11:286–90. https://doi. org/10.4103/jhrs.jhrs_33_18. 11. makris n, stefanidis k, loutradis d, anastasiadou k, hatjipappas g, antsaklis a. the incidence of retained fetal bone revealed in 2000 diagnostic hysteroscopies. jsls 2006; 10:76–7. 12. roth e, taylor hb. heterotopic cartilage in the uterus. obstet gynecol 1966; 27:838–44. 13. patil sb, narchal s, paricharak dg, more ss. endometrial osseous metaplasia: case report with literature review. ann med health sci res 2013; 3:s10–2. https://doi.org/10.4103/2141-9248.121209. 14. lanzarone vf, pardey jm. retained intrauterine fetal bone as a rare cause of secondary infertility. aust n z j obstet gynaecol 2009; 49:700–1. https://doi.org/10.1111/j.1479-828x.2009.01072.x. 15. cepni i, kumbak b, ocal p, idil m, aksu f. infertility due to intra uterine residual fetal bone fragments: retained intrauterine fetal bone fragments. j clin ultrasound 2004; 32:253–5. https://doi. org/10.1002/jcu.20028. 16. dajani yf, khalaf sm. intrauterine bone contraceptive device: an accident of nature. fertil steril 1985; 43:149–50. https://doi. org/10.1016/s0015-0282(16)48335-4. 17. usha kiran ts, bhal ps. the potential consequence of early recognition and treatment of retained fetal bony fragments. j obstet gynaecol 2002; 22:443–4. https://doi.org/10.1080/01 4436102320261177. 18. dawood my, jarrett jc 2nd. prolonged intrauterine retention of fetal bones after abortion causing infertility. am j obstet gynecol 1982; 143:715–17. https://doi.org/10.1016/0002-9378 (82)90120-x. 19. lewis v, khan-dawood f, king m, beckmann c, dawood my. retention of intrauterine fetal bone increases menstrual prostaglandins. obstet gynecol 1990; 75:561–3. 20. umashankar t, patted s, handigund rs. endometrial osseous metaplasia: clinicopathological study of a case and literature review. j hum reprod sci 2010; 3:102–4. https://doi.org/10.41 03/0974-1208.69329. 21. magudapathi c, anathakrishnan r, kalargala h. osseous meta plasia of the endometrium: a rare entity. j obstet gynaecol india 2015; 65:342–5. https://doi.org/10.1007/s13224-014-0589-1. 22. cayuela e, perez-medina t, vilanova j, alejo m, cañadas p. true osseous metaplasia of the endometrium: the bone is not from a fetus. fertil steril 2009; 91:1293.e1–4. https://doi.org/10.10 16/j.fertnstert.2008.12.026. 23. wani ah, parry ah, feroz i, jehangir m, rashid m. imaging of endometrial osseous metaplasia—an uncommon but treatable cause of infertility. middle east fertil soc j 2020; 25:35. https:// doi.org/10.1186/s43043-020-00045-0. 24. petrakis e, chatzipapas i, papapanagiotou ik, fotinopoulos p, siemou p, ntzeros k, et al. a successful pregnancy despite the presence of an intrauterine fetal bone fragment. case rep obstet and gynecol 2019; 2019:3064727. https://doi.org/10.11 55/2019/3064727. 25. moon hs, park yh, kwon hy, hong sh, kim sk. iatrogenic secondary infertility caused by residual intrauterine fetal bone after midtrimester abortion. am j obstet gynecol 1997; 176:369–70. https://doi.org/10.1016/s0002-9378(97)70500-3. 26. melius fa, julian tm, nagel tc. prolonged retention of intra uterine bones. obstet gynecol 1991; 78:919–21. 27. chan ns. intrauterine retention of fetal bone. aust n z j obstet gynaecol 1996; 36:368–71. https://doi.org/10.1111/j.1479-828 x.1996.tb02733.x. 28. arora p, sharma rk, sodhi b, chattopadhayay ab. foetal bones causing secondary infertility. med j armed forces india 1998; 54:282–3. https://doi.org/10.1016/s0377-1237(17)30570-1. 29. tulandi t, sammour a. retained fetal bones in the uterine cavity. j am assoc gynecol laparosc 2001; 8:179–80. https:// doi.org/10.1016/s1074-3804(05)60574-9. 30. elford k, claman p. novel treatment of a patient with secondary infertility due to retained fetal bone. fertil steril 2003; 79:1028–30. https://doi.org/10.1016/s0015-0282(02)04919-1. 31. goldberg jm, roberts s. restoration of fertility after hystero scopic removal of intrauterine bone fragments. obstet gynecol 2008; 112:470–2. https://doi.org/10.1097/aog.0b013e318173fd4c. 32. kramer hmc, rhemrev jpt. secondary infertility caused by the retention of fetal bones after an abortion: a case report. j med case rep 2008; 2:208. https://doi.org/10.1186/1752-1947-2-208. 33. singla a, gupta b, guleria k. first trimester abortion: a rare cause of intrauterine bony spicules. case rep obstet gynecol 2012; 2012:701021. https://doi.org/10.1155/2012/701021. 34. xiao s, tian q, xue m. infertility caused by intrauterine fetal bone retention: a case report. j med case rep 2014; 8:177. https://doi.org/10.1186/1752-1947-8-177. 35. mishra n, bharti r, mittal p, suri j, pandey d. retained intra uterine foetal bones resulting in secondary infertility: a case report. cureus 2018; 10:e2575. https://doi.org/10.7759/cureus.2575. 36. mahdavi a, kazemian s, koohestani e. secondary infertility due to intrauterine fetal bone retention: a case report and review of the literature. int j reprod biomed 2019; 17:591–4. https://doi. org/10.18502/ijrm.v17i8.4825. 37. graham o, cheng l, parsons j. the ultrasound diagnosis of retained fetal bones in west african patients complaining of infertility. bjog 2000; 107:122–4. https://doi.org/10.1111/j.1471-0528.20 00.tb11588.x. 38. pereira mc, vaz mm, miranda sp, araújo sr, menezes db, das chagas medeiros f. uterine cavity calcifications: a report of 7 cases and a systematic literature review. j minim invasive gynecol 2014; 21:346–52. https://doi.org/10.1016/j.jmig.2013.1 1.001. 39. grigore m, blidaru i, iordache f. intrauterine foreign bodies, other than contraceptive devices and systems, may affect fertility – report of two very different cases. eur j contracept reprod health care 2014; 19:141–3. https://doi.org/10.3109/1362518 7.2013.856406. 40. bozdag g, mumusoglu s, dogan s, esinler i, gunalp s. osseous metaplasia and subsequent spontaneous pregnancy chance: a case report and review of the literature. gynecol obstet invest 2015; 80:217–22. https://doi.org/10.1159/000439529. 41. awowole i, badejoko o, ayegbusi e, allen o, loto o. infertility due to prolonged retention of fetal bones: a case series. j gynecol surg 2021; 38:107–10. https://doi.org/10.1089/gyn.2021.0045. 42. rådestad a, flam f. intrauterine retention of fetal bones after abortion. acta obstet gynecol scand 1995; 74:662–4. https:// doi.org/10.3109/00016349509013487. https://doi.org/10.1371/journal.pmed.1001356 https://doi.org/10.1016/j.fertnstert.2010.11.026 https://doi.org/10.1093/humupd/dmv016 https://doi.org/10.1093/humupd/dmv016 https://doi.org/10.4314/gmj.v40i3.55262 https://doi.org/10.4103/jhrs.jhrs_33_18 https://doi.org/10.4103/jhrs.jhrs_33_18 https://doi.org/10.4103/2141-9248.121209 https://doi.org/10.1111/j.1479-828x.2009.01072.x https://doi.org/10.1002/jcu.20028 https://doi.org/10.1002/jcu.20028 https://doi.org/10.1016/s0015-0282(16)48335-4 https://doi.org/10.1016/s0015-0282(16)48335-4 https://doi.org/10.1080/014436102320261177 https://doi.org/10.1080/014436102320261177 https://doi.org/10.1016/0002-9378(82)90120-x https://doi.org/10.1016/0002-9378(82)90120-x https://doi.org/10.4103/0974-1208.69329 https://doi.org/10.4103/0974-1208.69329 https://doi.org/10.1007/s13224-014-0589-1 https://doi.org/10.1016/j.fertnstert.2008.12.026 https://doi.org/10.1016/j.fertnstert.2008.12.026 https://doi.org/10.1186/s43043-020-00045-0 https://doi.org/10.1186/s43043-020-00045-0 https://doi.org/10.1155/2019/3064727 https://doi.org/10.1155/2019/3064727 https://doi.org/10.1016/s0002-9378(97)70500-3 https://doi.org/10.1111/j.1479-828x.1996.tb02733.x https://doi.org/10.1111/j.1479-828x.1996.tb02733.x https://doi.org/10.1016/s0377-1237(17)30570-1 https://doi.org/10.1016/s1074-3804(05)60574-9 https://doi.org/10.1016/s1074-3804(05)60574-9 https://doi.org/10.1016/s0015-0282(02)04919-1 https://doi.org/10.1097/aog.0b013e318173fd4c https://doi.org/10.1186/1752-1947-2-208. https://doi.org/10.1155/2012/701021 https://doi.org/10.1186/1752-1947-8-177 https://doi.org/10.7759/cureus.2575 https://doi.org/10.18502/ijrm.v17i8.4825 https://doi.org/10.18502/ijrm.v17i8.4825 https://doi.org/10.1111/j.1471-0528.2000.tb11588.x https://doi.org/10.1111/j.1471-0528.2000.tb11588.x https://doi.org/10.1016/j.jmig.2013.11.001 https://doi.org/10.1016/j.jmig.2013.11.001 https://doi.org/10.3109/13625187.2013.856406 https://doi.org/10.3109/13625187.2013.856406 https://doi.org/10.1159/000439529 https://doi.org/10.1089/gyn.2021.0045 https://doi.org/10.3109/00016349509013487 https://doi.org/10.3109/00016349509013487 march 2007 vol 7 isuue 1 final without suicide .indd abstract objective: transvaginal sonography (tvs) is being used in the investigation of postmenopausal bleeding (pmb). the bleeding could be the result of a number of factors; endometrial polyps are one of the common findings in these patients. the aim was to compare the findings of tvs and hysteroscopy to determine the sensitivity of each method in detecting endometrial polyps. methods: this was a retrospective study, designed to investigate the sensitivity and specificity of transvaginal sonography in the detection of endometrial polyps. this study was conducted from july 992 to july 999 and identified from the record 37 patients with pmb referred for transvaginal sonography, hysteroscopy and biopsy investigations. results: thirty-seven patients with pmb were scanned using tvs and hysteroscopy. the result was not specific or sensitive when using tvs alone. tvs showed 3.52 % sensitivity, hysteroscopy/biopsy showed 00% sensitivity. tvs p>0.06 was not significant. conclusion: using tvs alone to diagnose polyps in pmb patients is not sensitive, especially when the polyps are smaller than 6 mm. if it is combined with hysterscopy, the reliability and s sensitivity are significantly improved. keywords: endometrial polyps, transvaginal sonography, postmenopausal bleeding, hysteroscopy the relationship between hysteroscopy, endometrial biopsy andthe results of transvaginal sonography in assessing endometrial polyps *saad r i al-kubaisi *ultrasound supervisor, high level general hospital, p o box 1462, hight level, alberta, canada, toh 1z0 canada email: saa3d@hotmail.com طيطٌ ونتائج َالتخْ بطانة الرحم ة زْعَ الرحم، خَ بني تنظير العالقة يَّة مِ الرَحِ البِطانَّةٌ الَئِلُ سَ تقييم في املهبل عبر اتِيِّ وَ التَصْ الكبيسي سعد البطانة ــالئل س منها عدة، لعوامل والذي يكون لليأس، التالي النزف ــقصاء اس في املهبل وَاتِيِّ عبر التَصْ طيطٌ َالتخْ ــتعمل امللخص: الهدف: يس ــية والقيمة احلساس لتحديد تنظير الرحم، الطريقة مع نتائج نتائج تلك مقارنة هو ــة الدراس من الهدف عند املريضات. توجد بكثرة ــي الت ــة الرحمي التخطيط التصواتي ونوعية حساسية لدراسة صممت ــة استعادية دراس الطريقة: هذه الرحم. بطانة ــالئل س ــاف اكتش في طريقة لكل التنبؤية للتخطيط احيلت ،1999 سنة 1992 الى من سنة التالي لليأس من النزف 37 حالة تعاني دراسة مت الرحم. بطانة ــالئل س ــاف اكتش في املهبل عبر التصواتي بالتخطيط لليأس التالي النزف من تعاني 37 مريضة فحص النتائج: مت الرحم. بطانة خزعة وفحص الرحم وتنظير املهبل عبر التصواتي لديها احلاالت كان %82.85 من مبفرده. التصواتي التخطيط فحص ــتخدم اس ــة حني حساس أو نوعية ــت ليس النتيجة . الرحم وتنظير املهبل عبر لوحده، بينما املهبل عبر التصواتي التخطيط بواسطة تشخيصها يتم لم (62.8%) السالئل 22 من 4 ملم). من (أكثر العام الرحم بطانة تضخم املهبل عبر التصواتي التخطيط استعمال يكفي اخلالصة: ال .(100%) سالئل بطانة الرحم قاطبة حااالت كل اكتشاف من الرحم تنظير استطاع ، وعندما ترفق 6 ملم من أقل السليلة تكون عندما خاصة لليأس، التالي النزف من املريضات الالتي يعانني عند الرحم بطانة سالئل حاالت لتشخيص ملموس. بشكل واحلساسية املعولية تتحسن تنظير الرحم مع التالي لليأس، تنظير الرحم. النزف املهبل، عبر التصواتي التخطيط الرحم، بطانة الكلمات: سالئل مفتاح sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© c l i n i c a l & b a s i c r e s e a r c h postmenopausal bleeding (pmb) is a relatively common presentation that can be a source of anxiety because it is a symptom common to both benign and malignant conditions. men-opause is the permanent cessation of menstruation resulting from the loss of follicular ovarian activity.1 s a a d r i a l k u b a i s i 52 generally, pmb is regarded as bleeding from the genital tract one or many years following the cessation of menses.2 pmb has no organic cause and some form of further investigation is required in order to exclude the possibility of malignancy3 or to identify the existence of benign conditions such as endometrial hyperplasia or polyps. pmb is regarded as an indicator to perform invasive procedures to obtain histological samples for diagnosis, such as hysteroscopy, endometrial biopsy 4 or dilation and curettage (d&c). 5, 6 tvs is a non-invasive technique that can be assessed for this purpose. endometrial polyps are common finding in 10% of pre and postmenopausal women and it is important they are diagnosed as the main source for the bleeding and the presence of any malignant lesion excluded.7 histologically, the endometrial polyps are composed of a fine fibrous core of stroma and glands and are invariably benign. they may be asymptomatic and cause abnormal uterine bleeding.8 malignant endometrial conditions are diagnosed only in a minority of women with pmb. the risk remains sufficiently high, however, that the patients require further investigation. therefore, there is a need for a less invasive test, which is well tolerated by patients and relatively inexpensive.8, 9 the identification or exclusion of an endometrial malignancy is the primary goal of scanning this group of pmb patients. 4, 9 studies have favoured the use of transvaginal ultrasound as an initial investigation for women with pmb; this may raise the need for more invasive d&c, hystereroscopy or biopsy.4, 10 it is important to know which modality to use to find more diagnostic details. the aim of this study was to analyze the patients with pmb and compare the results from tvs and hysteroscopy. many sonographers will assert that the presence of polyps can be both confirmed and excluded using transvaginal sonogram. various criteria have been hypothesized as indicating the presence of polyps in the endometrium cavity, including endometrial thickness (et), intracavitary fluid and the density of endometrial echoes. studies have demonstrated the limited ability of the transvaginal sonogram to discriminate polyps in both preand postmenopausal women.9, 11&12 m e t h o d s this was a retrospective study. thirty-seven patients with pmb were examined by tvs, followed by a hysteroscopy and biopsy at three hospitals, in canada and brunei, without selection bias. twenty patients were examined in canada and 17 in brunei. various ultrasound machines were used, such as atl ultra mark 3000, hdi 5000, diasonic 1000, sonoline and aligant 4500 scanning machines, with a 7.5 mhz transvaginal and 3.5 mhz trans-abdominal transducers. the machines were top of the range and the differences did not influence the results, as tvs transducers with the same frequencies (5 to 10) mhz were used. the author did all the ultrasound examinations and measurements. the patients had signed a consent form approved by the hospitals’ ethics committees. the patients had attended outpatient clinics between july 1992 and july 1999 with post-menopausal bleeding and been referred for a tvs, followed by hysteroscopy and biopsy investigation. the patient ages ranged from 40 to 80 years (median was 60 years). tvs of the uterus were done in both sagittal and coronal planes. the american institute of ultrasound use in medicine criteria were used. the following criteria were recorded: patient age at menopause, endometrial thickness (et), the presence of abnormal echoes of fluid within the endometrium, the presence of any other uterine or ovarian pathology, whether the patient was taking hormone replacement therapy (hrt) or tamoxifen. the results for the biopsies and hysteroscopy were collected from the pathology departments. any intracavitary fluid detected was subtracted from the overall thickness of the endometrium. the endometrial texture differentiation was homogeneous, heterogeneous or cystic. the presence of submucosal myomas (fibroids) or focal polyps was documented. the presence and position of myometrial myomas (fibroids) was noted. any adnexal pathology such as dermoid was recorded. the ultrasound reports were then compared with hysteroscopy and histology findings. the comparison was done by the departmental radiologist. female nurses chaperones were asked to be in the ultrasound room when the tvs was conducted. r e s u l t s thirty-seven patients with pmb were scanned using tvs. hysteroscopy and histological results were obtained from the pathology departments upon request. endometrium thickness (et) of 4 mm was found in eight cases using tvs with no sign of polyps, and using hysteroscopy four polyps were detected. et of 5 to 6 mm was found in 22 cases. using tvs, 8 fibroids were suspected within the myometrium and one polyp noted. hysteroscopy results confirmed the presence th e r e l at i o n s h i p b e t w e e n h y s t e r o s c o p y, e n d o m e t r i a l b i o p s y a n d th e r e s u lt s o f tr a n s va g i n a l s o n o g r a p h y i n a s s e s s i n g e n d o m e t r i a l p o ly p s 53 of 22 polyps and one fibroid was found. seven cases measured an et of 7 to 8 mm; tvs found four polyps and hysteroscopy results confirmed the presence of seven polyps. the results were tabulated according to the et and the findings from tvs, hysterscopy, and biopsy results [table 1]. d i s c u s s i o n when taking an endometrium thickness 5 to 8 mm the prevalence of polyps using tvs was 17.25 % as a positive diagnosis. the predictive value of tvs was less sensitive and less specific than the predictive value of hysteroscopy, especially in et less than 6 mm. the ability of tvs to identify correctly the endometrial pathology can be affected by a number of factors. during tvs, sonographers often obtain detailed images showing clearly defined polyps within the endometrium. this leads to the general idea that the majority of polyps can be detected by transvaginal sonogram. however, results from this study indicated that very few polyps could be detected in this way.9, 11, 12 subsequent hysteroscopy examination identified sizeable and numerous small polyps less than 5 mm, which had not been noted sonographically. the use of saline contrast (sonohysterography) 12 may well improve the detection of endometrial polyps; however the widespread use of hysteroscopy has now generally obviated the use of this technique. essentially this comes down to how much reliability a gynecologist should place on a negative ultrasound report for endometrial polyps in a patient with postmenopausal bleeding. the predictive value of tvs for screening endometrial polyps is much lower than the use of hysteroscopy. ultrasound equipment has improved dramatically over the past several years, particularly with the development of endo vaginal transducers with multi frequencies, harmonic imaging and 3d sonography. these features can increase the specificity and negative predictive value, thus decreasing the need for invasive procedures. hysterscopy confirmed the presence of endometrial lesions in 100% of cases in this study. tvs failed in 75.67 % of the case to confirm the presence of endometrial lesions. tvs was sensitive in 24.33 % of the cases. when the endometrium thickening (et) was 7 mm and larger, tvs was sensitive in 57.15 % of the cases. tvs was not sensitive in 95.45 % of the cases when et was 5 to 6 mm. using tvs alone it was difficult to differentiate between polyps and subserosal fibroids with false positive reporting. in et 4mm and less, tvs missed four polyps, which were found by hysteroscopy and biopsy. the result of this study suggests that the diagnosis of endometrial polyps is not specific using tvs alone and it was not significant, (p>0.06), especially when the et is 5 mm or less. while some polyps are readily identifiable, other polyps fail to present any specific features. 78.38 % of the cases presented with endometrial thickening. the sensitivity increased to 100% when a combination of tvs and hysteroscopy were used: p<0.01 and better than 95% confidence interval was obtained. tvs failed in 95.5 % of the cases to detect polyps in 5 to 6 mm et. therefore, the negative reports on the four cases done by tvs with an et of 4 mm and less was coincidence and not reliable. tvs depends upon sonographer skills and training and the type of ultrasound equipment being used. if the equipment and the tvs transducers were equipped with 3-d, harmonic fusion, angio colour doppler, gain suppression and focal strength capabilities, the detection of these lesions might be more successful. l i m i t a t i o n s a prospective study would have greater validity because all subjects would be required to have a hysterosnumber of patients endometrial thickening (et) t.v.s finding sensitivity hysteroscopy finding sensitivity biopsy finding sensitivity 8 4mm normal inconclusive 0% 4 polyps 4 normal 100% 4 polyps; benign 100% 22 5 to 6 mm 8 fibroids 1 polyp 4.5% 1 fibroid 22 polyps 100% 22 polyps; 21 benign, 1 malignant 100% 7 7 to 8 mm 4 polyps, 3 normal 57.15% 7 polyps 100% 7 polyps benign 100% tvs= transvaginal sonography table 1the sensitivity of tvs versus hysteroscopy and biopsy to detect endometrial polyps. s a a d r i a l k u b a i s i 54 copy regardless of the tvs findings, whereas in other cases, only those with abnormal tvs will be referred for hysteroscopy. in that case, those with endometrial lesion, but missed by tvs, would not be identified by hysteroscopy. it was difficult in some cases to obtain consent forms from the patients when they are older than 70 years. most patients over the age of 70 asked their family members. they consented to the tvs after the radiologist and their physician explained the benefit of this procedure to them. the advanced ultrasound machines are expensive and required trained skillful sonographers to operate them. c o n c l u s i o n using tvs alone to detect endometrial lesions is not sensitive and reliable enough. using tvs with hysteroscopy together with tvs increases the sensitivity to 100%. tvs was not sensitive and unreliable in 86.48 % of the cases in this study. hysteroscopy is the method of choice to be used in pmb cases if the tvs shows a normal result, as it could be a false negative result. advanced ultrasound equipment and multi frequency transducers are necessary to increase the sensitivity of the examination. r e f e r e n c e s 1. research on the menopausal in the 1990s report of who scientist group. world health organization who technical report series no 866, 1996. 2. smith p, bakos o, heimer g, ulmsten u. transvaginal ultrasound for identifying endometrial abnormalities. acta obstet gynecol scand, 1991; 70:591-594. 3. choo yc, mak kc, hsu c, wong ts, ma hk. postmenopausal uterine bleeding of non-organic cause. obstet gynecol 1985; 66:225-228. 4. investigation of post menopausal bleeding. scottish intercollegiate guidelines network, royal college of physicians, 9 queen st edinburgh www.sign.ac.uk. accessed: september 2002 5. weber g, merz f, bahlmann e, rosch b. evaluation of different transvaginal sonographic diagnostic parameters in women with postmenopausal bleeding. ultrasound obstet gynecol 1998; 12:265-270. 6. stovall t, salomon s, ling f. endometrial sampling prior to hysterectomy. obstet gynec 1989; 73:405-409 7. karlson b, granberg s, wikland m, et al. endovaginal scanning of the endometrium in women with postmenopausal bleeding. a nordic multicenter study. am j obstet gynecol 1995; 172:1488-1494. 8. gredmark t, kvint s, havel g, mattsson la. histopatholgical findings in women with postmenopausal bleeding. br j obstet gynaecol 1995; 102:133-136. 9. gibbs v, henson j, hawkins k. a retrospective analysis of the role of transvaginal sonographgy in the evaluation of patients with abnormal postmenopausal bleeding. br med ultrasound soc bulletin 2004; 12:218-221. 10. jones k, bourne t. the feasibility of one stop ultrasound-based clinic for the diagnosis and management of abnormal uterine bleeding. ultrasound obstet gynecol 2001; 17:517-521. 11. epstein e, ramirez a, skoog l, valentin l. transvaginal sonography, saline contrast sonohysterography and hysterography for the investigation of women with postmenopausal bleeding and endometrium >5mm. ultrasound obstet gynecol 2001; 18:157-162. 12. kazandi m, aksehirli s, cirpan t, akerhan f. transvaginal sonography combined with saline contrast sonohysterography to evaluate the uterine cavity in patients with abnormal uterine bleeding and postmenopausal endometrium more than 5mm. eur j gynaecol oncol 2003; 24:185-190. march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 37-41, epub 16th mar 2009 submitted 21st may 08 revision req. 4th aug 08, revision recd. 4th nov 08, accepted 23rd dec 08 department of chemical pathology, royal hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: drsharef@omantel.net.om serum myoglobin in patients with thyroid dysfunction *waad-allah s mula-abed, sawsan s al-sinani, huda s al-hashmi abstract objectives: to assess the pattern of change in serum myoglobin concentration in subjects with thyroid dysfunction. methods: serum samples were selected from 50 subjects with suspected thyroid disorder who were referred to the royal hospital, muscat, oman. the subjects were 35 males and 5 females, aged 4-56 years with mean ± sd of 34.3 ± 2.7 years. they were classified on the basis of thyroid stimulating hormone (tsh) and free thyroxine (ft4) into 3 groups, each consisting of 50 subjects: hypothyroid, hyperthyroid, and euthyroid subjects. results: the mean serum myoglobin concentration was higher in hypothyroid patients compared to hyperthyroid and euthyroid subjects (mean ± sd was 38.5 ± 23. µg/l in hypothyroid; 8. ± 7.0µg/l in hyperthyroid; 7.4 ± 5.7µg/l in euthyroid). there was a significant difference in myoglobin concentration between hypothyroid and euthyroid groups (f = 36., p <0.00), however, there was no significant difference between the hyperthyroid and euthyroid groups. when the mean ± 2sd for myoglobin in euthyroid subjects was calculated, the reference range was 6-29 µg/l. of the hypothyroid subjects, 29 (58%) had high myoglobin and 2 (42%) had normal myoglobin level. no significant correlation was noticed between tsh or ft4 and myoglobin in all studied subjects. conclusion: raised serum myoglobin may be observed in patients with hypothyroidism. hence hypothyroidism should be considered in the differential diagnosis of patients with raised serum myoglobin concentration. key words: myoglobin; hypothyroidism. باضطراب الدم لدى املرضى املصابني مصل �مايوغلوبني الدرقية الغدة وظيفة الهاشمي سعيد هدى السناني، سالم سوسن عبد، مال شريف اهللا وعد فحص الطريقة: مت . الدرقية ــدة وظيفة الغ باختالل املرضى املصابني لدى الدم مصل ــتوى مايوغلوبني في مس التغير منط تقييم امللخــص: الهــدف: (سلطنة السلطاني مبسقط املستشفى إلى احملولني من الدرقية وظيفة الغدة باختالل مصابا و115 أنثى) (35 ذكرا 150 مريضا من للمصل عينات فحص نتائج وفق املرضى تصنيف مت . ــنة) 34.3 ± 12.7 س االنحراف املعياري ± املعدل (كان ــنة 14 56 س يتراوح بني أعمارهم كان مدى عمان). وظيفة بانخفاض املصابون :( منها لكل (50 شخصا مجاميع ثالث إلى احلر) الدرقية وهرمون الدرقية للغدة املنبه الهرمون الوظيفية الدرقية الغدة مايوغلوبني مستوى متوسط النتائج: كان . الدرقية للغدة الطبيعية الفعالية ذوي واألشخاص الدرقية نشاط الغدة بفرط املصابون ، الدرقية الغدة املتوسط (كان األصحاء ــخاص واألش الدرقية الغدة ــاط نش بفرط باملصابني مقارنة الدرقية وظيفة الغدة بانخفاض املصابني مرتفعا لدى الدم مصل إحصائيا معتدا فرقا هناك وكان ، /لتر) 5.7 + 17.4 مايكروغرام +7.0 18.1 و +23.1 38.5 مقابل بالتعاقب للمايوغلوبني املعياري االنحراف + معتد إحصائيا فرق أي لم يالحظ ، بينما واألصحاء الدرقية الغدة وظيفة بانخفاض املايوغلوبني بني املصابني متوسط ((f= 36.1, p < 0.001 في املدى كان األصحاء عند للمايوغلوبني معياريني انحرافني + ــاب املتوسط حس مت عندما . األصحاء ومجموعة الدرقية الغدة ــاط بفرط نش املصابني بني تركيز لديهم كان الدرقية ــدة الغ وظيفة بانخفاض املصابني من (58%) ــا 29 مريض أن أيضا ــة أظهرت الدراس ليتر. غرام/ ــرو 6-29 مايك ــي املرجع للغدة الدرقية املنبه الهرمون بني إحصائيا معتدا ارتباطا يالحظ لم . (42%– (21 مريضا اآلخرين لدى تركيزه طبيعيا كان بينما عاليا ، املايوغلوبني بانخفاض املصابني معظم لدى الدم مصل مايوكلوبني اخلالصة: لوحظ ارتفاع . حتت الدراسة األشخاص عند كل واملايوغلوبني احلر الدرقية هرمون أو لديهم الذين يكون ــخاص لألش التفريقي ــخيص التش الدرقية ضمن الغدة وظيفة بوضع انخفاض جديا التفكير يجب ولهذا ، الدرقية الغدة وظيفة . املايوغلوبني في مصولهم تركيز في ارتفاعا الدرقية. الغدة انخفاض وظيفة ، الكلمات: مايوغلوبني مفتاح c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • elevated myoglobin values can occur following muscle involvement or damage in patients with myopathy or transiently following cardiac ischaemia. 38 wa a d a l l a h s m u l a a b e d , s aw s a n s a l -s i n a n i a n d h u d a s a l h a s h m i myoglobin is a cytoplasmic protein in striated cardiac and skeletal muscula-ture that is involved in oxygen transport and storage within the myocytes. besides troponin, myoglobin determination in serum may play a contributing step in the diagnosis of myocardial ischaemia particularly acute myocardial infarction.1, 2 elevated myoglobin values can also occur after skeletal muscle damage in patients with myopathy and in those with marked renal impairment.3 disorders of thyroid function are common and are now considered in the differential diagnosis of patients with a wide variety of symptoms. the prevalence of hypothyroidism was 3.7% and that of hyperthyroidism was 0.5% in the united states general population in a 1999-2002 survey.4 the prevalence of thyroid dysfunction is even higher in the elderly,5 many having subclinical thyroid dysfunction with controversial recommendations for treatment thresholds balanced on the risk to target organs particularly the heart and bone.6 hence, screening for thyroid problems is now commonly followed in clinical practice.7 however, although biochemical screening for thyroid disorders is usually followed, particularly in the elderly, the clinical diagnosis of hypothyroidism should also be considered in patients with unexplained persistent elevations of serum muscle enzymes. a significant increase in these enzymes may occur in basal conditions and is gradually normalised by substitution therapy.8, 9 the objective of this study was to assess the pattern of change in serum myoglobin concentration in patients with thyroid disorders, both hypothyroidism and hyperthyroidism, and to compare them with euthyroid subjects. m e t h o d s in this study, 150 tests from routine sampling were selected on the suspicion of thyroid disorders and underwent a thyroid function test (tft), which included measurement of free thyroxine (ft4) and thyroid stimulating hormone (tsh). the study was a naturalistic observation, an integral part of routine clinical procedure. the blood samples for these subjects were selected from those referred to the department of chemical pathology, royal hospital, muscat, oman, for tft during a period of 6 months (1 jan to 30 june 2007). the criteria for selection included patients with no other diseases or abnormal clinical or laboratory tests other than thyroid related problems. of these subjects, 32 were referred from the outpatient department at the royal hospital and 118 were from primary health centres within the muscat region. the subjects were 35 males and 115 females, aged 14-56 years with mean ± sd of 34.3 ± 12.7 year. they included 50 patients with hypothyroidism (12 males, 38 females, aged 20-56 years, 38.0 ± 13.9 years), 50 patients with hyperthyroidism (15 males, 35 females, aged 14-56 years with 34.0 ± 10.6 years), and 50 subjects with euthyroid state (8 males, 42 females, • myopathy may develop due to a variety of diseases including endocrine dysfunction such as hypothyroidism. • thyroid dysfunction is common and screening for it is now commonly followed in clinical practice. • hypothyroidism should be considered in the differential diagnosis of patients with myopathy or raised serum myoglobin concentration. applications to patient care • patients with hypothyroidism may rarely develop muscle damage in the form of asymptomatic elevation of muscle markers, myopathy or even rhabdomyolysis. • this involvement may occur especially in undiagnosed cases, those with poor drug compliance, or in combination with other aggravating factors such as statin therapy. • such a link is of particular consideration due to the large number of patients taking statin drugs nowadays. • hypothyroidism should be considered in the differential diagnosis of patients with myopathy or raised serum myoglobin concentration, even if there is another disease, mechanism or therapy explaining its elevation. 39 s e r u m my o g l o b i n i n pat i e n t s w i t h th y r o i d d y s f u n c t i o n aged 15-54 years, 32 ± 12.4 year). hypothyroidism was defined as raised tsh (>10.0 mu/l) with low (or lownormal) ft4, while hyperthyroidism was defined as suppressed tsh (<0.010) with raised ft4. 10 all serum samples were assayed for ft4 and tsh, and following the definition of the subject as hypothyroid, hyperthyroid or euthyroid, serum was then assayed also for myoglobin. serum ft4 and tsh were measured by a chemiluminescent microparticle immunoassay (cmia) on the architect 2000 system (abbott, usa).11, 12 the tsh assay is an ultrasensitive third generation assay with analytical sensitivity of 0.003 mu/l. serum myoglobin was measured by an electrochemiluminescence immunoassay (eclia) on the roche cobas e 411 immunoassay analyser (roche/ hitachi, germany).13 the statistical methods included descriptive statistical analyses that comprise the mean, standard deviation (sd), and range (minimum-maximum). onesample kolmogorov-smirnov analysis was used for identifying the pattern of distribution of myoglobin in each group while one way anova (one way analysis of variance) was used to compare the differences in the means of myoglobin concentrations between the groups. a correlation study was also done to compare between myoglobin and tsh or ft4 concentrations.14 statistical significance was assigned for p <0.05. r e s u l t s the results of data analysed are presented according to the grouping of subjects based on tft as in table 1. the use of one-sample kolmogorov-smirnov analysis revealed a normal distribution in serum myoglobin concentration in each of the three groups. one way anova revealed a significant difference (f = 36.1, p <0.001) in means of myoglobin concentrations between the hypothyroid (38.5 ± 23.1 µg/l) and euthyroid (17.4 + 5.7 µg/l) groups. however, there was no significant difference in mean serum myoglobin concentration between the hyperthyroid and euthyroid groups. when the mean + 2sd for myoglobin concentration in the euthyroid subjects was calculated (figure 1), the reference range was 6-29 µg/l. of the hypothyroid subjects, 29 (58%) had a high myoglobin and 21 (42%) had a normal myoglobin level. no significant correlation was noticed between tsh or ft4 and myoglobin in all studied subjects (p> 0.05). the distribution of serum myoglobin in the studied subjects is shown in figure 1. d i s c u s s i o n biochemical screening using different organ profiles, including tft, is frequently performed for patients consulting clinics or hospitals as part of health care provision. subclinical or overt hypothyroidism or hyperthyroidism are commonly diagnosed in clinical practice.4, 5, 7 in this study, hypothyroid patients showed signifitable 1: serum thyroid stimulating hormone (tsh), free thyroxine (ft4) and myoglobin in the studied groups. analyte euthyroid hypothyroid hyperthyroid mean standard deviation mean standard deviation mean standard deviation tsh (mu/l) 1.339 0.958 71.113 32.323 0.0036 0.0023 ft4 (pmol/l) 14.00 2.26 6.52 2.149 40.57 17.04 myoglobin (µg/l) 17.4 5.7 38.5 23.1 18.1 7.0 100.0 75.0 50.0 25.0 euthyroidism hyperthyroidism hypothyroidism m yo gl ob in (u g/ l) figure 1: distribution of myoglobin in euthyroid, hypothyroid, and hyperthyroid groups (bars represent mean ± 1sd). 40 wa a d a l l a h s m u l a a b e d , s aw s a n s a l -s i n a n i a n d h u d a s a l h a s h m i cantly higher mean myoglobin levels in comparison with hyperthyroid or euthyroid subjects. serum myoglobin levels were higher than the reference range in the euthyroid group in 58% of the hypothyroid patients. this may be explained on the basis that, depending on the degree of hormone deficiency, skeletal muscle involvement may occur in hypothyroidism. creatine kinase and myoglobin have been proved to be useful indicators of myopathy including that due to hypothyroidism.15, 16 they are sensitive for the early detection of muscle involvement due to the metabolic disorder and are closely correlated with the metabolic states of patients.16 another possible mechanism for raised myoglobin in patients with hypothyroidism may be explained by an underlying autoimmune process whereby muscle protein antibodies, especially to myoglobin, myosin and troposin, are frequently present in patients with autoimmune thyroid disease leading to muscle damage.17 in comparison with other studies, mortino et al.18 observed significantly higher serum myoglobin levels in long-term and short-term hypothyroid patients (examined 20 days after withdrawal of thyroid replacement therapy) than normal controls, with a significant inverse correlation between thyroid hormones and myoglobin levels in long-term, but not short-term, hypothyroids. normalisation of myoglobin levels following thyroxine replacement was achieved earlier than serum tsh, hence, the duration and severity of hypothyroidism are important factors in the rise of myoglobin. roti et al.19 also reported high and low serum concentrations of myoglobin, creatine kinase and lactate dehydrogenase in hypothyroid and hyperthyroid patients respectively. they confirmed that the muscle (not cardiac) isoenzymes are the source of increased enzyme activity, a finding that was also confirmed by giampietro et al.16 in our study, as in other reports,16, 20 despite the high serum myoglobin concentrations observed in hypothyroidism, no significant correlation was noted between tsh and the muscle markers, creatine kinase or myoglobin. also, in our study, the hyperthyroid patients clearly exhibited myoglobin levels very approximate (with no significant difference) to those of euthyroid subjects. however, this finding was not in accord with that of wan nazainmoon et al. 21 who found that in both overt and subclinical hyperthyroid patients, serum creatine kinase levels were significantly lower than euthyroid or hypothyroid patients. it seems that patients with hypothyroidism may occasionally be prone to muscle damage leading to myopathy or even rhabdomyolysis which can be attributed to undiagnosed hypothyroidism. the spectrum of presentation, as a consequence of muscle involvement, may be in the form of asymptomatic elevation of muscle markers, myopathy, rhabdomyolysis or even acute renal failure. muscle functions usually completely recover with thyroxine therapy.22, 23, 24 studies, such as those reported by sekine et al. 25 suggest that rhabdomyolysis could also occur in patients with hypothyroidism, especially those with poor drug compliance, in combination with other aggravating factors such as exercise. recently, kursat et al.26 and kiernan et al..27 reported an important link between statin induced rhabdomyolysis and hypothyroidism, both overt and occult forms. such a link or aggravating factor is of particular concern due to the large number of patients taking statin drugs nowadays worldwide. hence, statin, when prescribed as a hypolipidaemic drug for patients with dyslipidaemia and an associated or underlying hypothyroidism, may raise their risk for muscle involvement, which is a recognised side effect of statin,28, 29 and also may rarely raise their requirement for thyroxine therapy.27 c o n c l u s i o n raised serum myoglobin may be observed in patients with hypothyroidism. hence, hypothyroidism should be considered in the differential diagnosis of patients with raised serum myoglobin concentration, even if there is another disease, mechanism or therapy explaining its elevation. a c k n ow l e d ge m e n t s the authors gratefully acknowledge the support of the royal hospital, muscat, for their research. c o n fl i c t o f i n t e r e st : none r e f e r e n c e s 1. mair j, puschendorf b. current aspects in the laboratory diagnosis of acute myocardial infarction. lab med 1995; 19:304-18. 2. bakker aj, koelemay mj, gorgels jp, van vlies b, smits r, tijissen jg, et al. troponin t and myoglobin at admission: value of early diagnosis of acute myocardial infarction. eur heart j 1994; 15:45-53. 3. ohman em, casey c, bengston jr, pryor d, tormey w, horgan jh. early detection of acute myocardial infarction: additional diagnostic information from serum 41 s e r u m my o g l o b i n i n pat i e n t s w i t h th y r o i d d y s f u n c t i o n concentrations of myoglobin in patients without st elevation. br heart j 1990; 63:335-8. 4. aoki y, belin rm, clickner r, jeffries r, phillips l, mahaffer kr. serum tsh and total t4 in the united states population and their association with participant characteristics: national health and nutrition examination survey (nhanes 1999-2002). thyroid 2007; 17:121123. 5. empson m, flood v, ma g, eastman cj, mitchell p. prevalence of thyroid disease in an older australian population. intern med j 2007; 37:448-55. 6. biondi b, cooper ds. the clinical significance of subclinical thyroid dysfunction. endocr rev 2008; 29:76131. 7. vanderpump mpj, tunbridge wmg, french jm, appleton d, bates d, clark f, et al. the incidence of thyroid disorders in the community; a twenty-year follow up of the whickham survey. clin endocrinol (oxf ) 1995; 43:55-68. 8. burnett jr, crooke mj, delahunt jw, feek ck. serum enzymes in hypothyroidism. n z med j 1994; 107:3556. 9. minutiello l. the enzymatic and electrocardiographic changes falsely indicative of an acute myocardial infarct during hypothyroidism. minerva cardioangiol 1993; 41:597-602. 10. ladenson pw, singer pa, ain kb, bagchi n, bigos st, levy eg, et al. american thyroid association guidelines for detection of thyroid dysfunction. arch intern med 2000; 160:1573-5. 11. sturgess ml, weeks i, evans pj, mpoko cn, laing i, woodhead js. an immunochemiluminometric assay for serum free thyroxine. clin endocrinol 1987; 27:38393. 12. hay id, klee gg. linking medical needs and performance goals: clinical and laboratory perspectives on thyroid disease. clin chem 1993; 39:1519-24. 13. lee hs, cross sj, garthwaite p, dickie a, ross i, walton s, et al. comparison of the value of novel rapid measurement of myoglobin, creatine kinase, and creatine kinase mb with the electrocardiogram for the diagnosis of acute myocardial infarction. br heart j 1994; 71:3115. 14. hill ab, hill id. bradford hill’s principles of medical statistics. 12th ed. london: hodder arnold, 1991. 15. finsterer j, stollberger c, corossegger c, kroiss a. hypothyroid myopathy with unusually high serum creatine kinase values. horm res 1999; 52:205-8. 16. giampietro o, clerico a, buzzigoli g, del chicca mg, boni c, carpi a. detection of hypothyroid myopathy by measurement of various serum muscle markersmyoglobin, creatine kinase, lactate dehydrogenase and their isoenzymes. correlations with thyroid hormone levels (free and total) and clinical usefulness. horm res 1984; 19:232-42. 17. ruchala m, kasowicz j, baumann-antczak a, skiba a, zamyslowska h, sowinski j. the prevalence of autoantibodies to: myosin, troponin, tropomyosin and myoglobin in patients with circulating triiodothyronine and thyroxine autoantibodies. neuro endocrinol lett 2007; 28:259-66. 18. mortino e, sardano g, vaudagna g, bambini g, breccia m, motz e, et al. serum myoglobin in primary hypothyroidism and effect of l-thyroxine therapy. j nucl med 1982; 23:1088-92. 19. roti e, bandini p, robuschi g, emanuele r, ciarlini e, buzzonetti p, et al. serum concentrations of myoglobin, creatine kinase, lactate dehydrogenase and cardiac isoenzymes in euthyroid, hypothyroid and hyperthyroid subjects. ric clin lab 1980; 10:609-17. 20. mula-abed ws, al-naemi ah. validity of serum creatine kinase activity in the diagnosis of thyroid disorders. j bahrain med soc 2005; 17:14-17. 21. wan nazainmoon wn, siaw fs, sheriff ih, faridah i, khalid bak. serum creatine kinase: an adjunct biochemical index of subclinical thyrotoxicosis. ann clin biochem 2001; 38:57-8. 22. kisakol g, tunc r, kaya a. rhabdomyolysis in a patient with hypothyroidism. endocr j 2003; 50:221-3. 23. kar pm, hirani a, allen mj. acute renal failure in a hypothyroid patient with rhabdomyolysis. clin nephrol 2003; 60:428-9. 24. birewar s, oppenheimer m, zawada et jr. hypothyroid acute renal failure. s d j med 2004; 57:109-10. 25. sekine n, yamamoto m, michikawa m, enomoto t, hayashi m, ozawa e, et al. rhabdomyolysis and acute renal failure in a patient with hypothyroidism. intern med 1993; 32:269-71. 26. kursat s, alici t, colak hb. a case of rhabdomyolysis induced acute renal failure secondary to statin-fibratederivative combination and occult hypothyroidism. clin nephrol 2005; 64:391-3. 27. kiernan tj, rochford m, mcdermott jh. simvastatin induced rhabdomyolysis and an important clinical link with hypothyroidism. int j cardiol 2007; 119:374-6. 28. harper cr, jacobson ta. the broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. curr opin lipidol 2007; 18:401-8. 29. kobayshi m, chisaki i, narumi k, hidaka k, kagawa t, itagaki s, et al. association between risk of myopathy and cholesterol-lowering effects: a comparison of all statins. life sci 2008; 82:969-75. abstract: objectives: this study aimed to examine acceptance levels of and attitudes towards telemedicine among users in the united arab emirates (uae) and assess associations between perceived usefulness (pu), perceived ease of use (peou), attitudes towards use (atu) and behavioural intention of use (biu) in relation to telemedicine technology. methods: this cross-sectional study used a simple random sampling design to obtain an appropriate sample from throughout the uae. the technology acceptance model (tam) and rogers’ diffusion of innovations (doi) theory were applied as the conceptual basis for this study. an arabic/english version of the questionnaire was distributed via email to physicians and nurses, members of the public (including patients), healthcare directors and information technology professionals. data were collected from 1st march to 30th august 2019 and analysed using statistical package for the social sciences (spss). results: a total of 330 participants were included (response rate: 85.7%). biu and pu were considered important elements of tam in the adoption of telemedicine services compared to the other variables. the association between peou (beta = 0.033, p = 0.692), pu (beta = 0.034; p = 0.679) and atu (beta = 0.055; p = 0.421) in relation to telemedicine were positive but not significant. however, biu was found to be a strong significant predictor of actual usage (beta = 0.224; p = 0.003). conclusion: this study confirms tam’s applicability in the adoption of telemedicine services in the uae. the results show that users’ perceptions were significantly related to their behavioural intention to use telemedicine. factors influencing telemedicine technology are likely to vary as technology acceptance in other geographical areas may differ from the sample presented here. keywords: telemedicine; patient acceptance of healthcare; attitude; behaviour; intention; united arab emirates. user acceptance level of and attitudes towards telemedicine in the united arab emirates a quantitative study *shaikha abdool,1 sherief abdallah,2,3 suhair akhlaq,1 hira abdul razzak1 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e203–209, epub. 21 jun 21 submitted 21 apr 20 revision req. 10 jun 20; revision recd. 15 jul 20 accepted 19 aug 20 1statistic & research center, ministry of health & prevention, dubai, united arab emirates; 2department of computer science, university of massachusetts amherst, united states of america; 3department of information technology, british university in dubai, dubai, united arab emirates *corresponding author’s e-mail: shaikha.abdool@hotmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.008 clinical & basic research advances in knowledge the technology acceptance model and rogers’ diffusion of innovations theory were effective in this study to evaluate acceptance of telemedicine in the united arab emirates (uae). key elements such as participants’ attitudes towards telemedicine impacted technology acceptance and usage. the findings of the study will enable healthcare organisations to identify current levels of acceptance of telemedicine. this study contributes to the body of work associated with technology in healthcare. to the best of the authors’ knowledge, this study is a first in the uae and one of the few in the gulf cooperation council that examined telemedicine based on sociotechnical analysis. application to patient care the study improves understanding of patients’ acceptance of telemedicine, in which patients can receive healthcare via telecommunication means. patients’ acceptance of telemedicine is affected in part by their perceived ease of use of the technology surrounding telemedicine. telemedicine’s diffusion in the uae will be impacted by patients’ acceptance of technology. patient care can be optimised through telemedicine. forecasting users’ acceptance before fully deploying technology may reduce the risk of rejection, allow a technology’s design to be modified and establish trust in order to prepare patients for virtual care. telemedicine has been defined as an exchange of medical information from a distance and the use of communications and electronic technologies to support and provide healthcare when distance separates the participants.1 the information exchanged in telemedicine can be image-based, voice files, a series of commands to a surgical robot or elements of medical records.2 in the past, telemedicine focused exclusively on comm unication between medical experts in remote geo graphical locations. at present, though, telemedicine programmes are going beyond their traditionally educational roles and have shifted into the arena of clinical care to improve overall healthcare outcomes. although the application of this technology is still in its infancy, the medical community is enthusiastic about using telemedicine with patients throughout the united arab emirates (uae).3 https://creativecommons.org/licenses/by-nd/4.0/ user acceptance level of and attitudes towards telemedicine in the united arab emirates a quantitative study e204 | squ medical journal, may 2021, volume 21, issue 2 telemedicine has great potential to support healthcare for disease management. medical care delivered through telemedicine will reduce length of stay (los), visits and related costs of the healthcare institutions.4 the technology behind telemedicine is multifaceted and requires in-depth evaluation. to ensure acceptance and diffusion of telemedicine, vast human and capital resources and effort are needed to comprehend it appropriately. tam was developed by fred davis in the late 1980s and is mainly used in the information systems discipline to address users’ acceptance and use of technology. doi theory was developed by everett rogers in 1962 and has been used in multiple disciplines, including sociology and anthropology.5 the aim of the doi theory is typically to help researchers understand the spread of a new idea or technology by answering how, why and what. tam and the doi theory have been used together in research in medical and non-medical fields. for instance, cowen applied tam to evaluate computed radiography systems, while mutahar et al. addressed mobile banking services in yemen by applying tam and the doi theory.6,7 tam includes perceived usefulness (pu) and perceived ease of use (peou) leading to attitudes towards use (atu), behavioural intention to use (biu) and actual use (au). telemedicine has a number of advantages over traditional face-to-face approaches to medicine. but it is nonetheless essential to examine users’ opinions and knowledge regarding this technology before starting a telemedicine programme.8,9 additionally, healthcare professionals’ perceptions and knowledge are essential influencers of a programme’s success.10–12 previous studies have revealed that a lack of training and skills in healthcare providers and a lack of knowledge among users are barriers to telemedicine utilisation.13,14 initial costs and a deficiency of technical expertise and reimbursement of capital costs have also emerged as obstacles in utilisation of telemedicine.15 additionally, appropriate telemedicine technological understanding specifically by healthcare professionals is required for successfully implementing and deploying technology.9 the more capabilities with and knowledge of telemedicine users have, the more optimistic they are about such technology.16 previous studies have demonstrated an underst anding of telemedicine among patients and clinical staff. meher et al. suggested that patients and physicians should increase their awareness and utilisation of telemedicine.17 el gatit et al. found that 48.8% of patients had a fair understanding of telemedicine, 12.2% of the physicians had limited knowledge of telemedicine and 39% had a higher level of telemedicine-related understanding.18 the familiarity of professionals regarding telemedicine impacted their attitudes towards the utilisation of telemedicine technology.19 this study aimed to evaluate the user’s acceptance level and attitudes towards telemedicine in the uae along with studying the association between peou, pu, atu and biu and the actual usage of telemedicine technology. the results of the study will be valuable for practitioners in the uae and can also be used in fields outside healthcare. methods this cross-sectional study was conducted from 1st march to 30th august 2019 using a simple random sampling approach design throughout the uae. using this technique, every member of the population had the same probability of being selected and is an appropriate approach when inferences are to be made from a large population. the randomly selected target population included physicians and nurses (n = 98), members of the public including patients (n = 215) and healthcare directors and information technology professionals (n = 17). the sample size was calculated using a raosoft calculator (raosoft, inc., seattle, washington, usa) and the services of select statistical services limited (exeter, uk). sample size was calculated based on a population size of 8,093,766 (ages 18+) with a 5% margin of error at a 95% confidence interval (ci). therefore, the recommended sample size was 385 participants. this study included participants who were ≥18 years old, spoke both arabic and english, were competent enough to participate without any assistance and had proper intellectual and mental capabilities. critically ill patients were excluded from the study. tam and the doi theory were applied to this study. doi theory elements were added to the tam as external factors impacting telemedicine acceptance. the implementation of models and theories in this research followed prototype testing/system selection procedures. the resulting arabic/english language questionnaire was distributed via email and evaluated the participants’ reactions to the telemedicine technology via a series of questions which were designed to measure possible users’ demand for telemedicine, acceptance level of technology use, attitude and biu towards telemedicine, as well as pu and peou because these constructs have been identified as accurate predictors of users’ intention to use technology.20 usage frequency was also measured. validated questions from previous research were adapted to measure the applied model and theory in this research.19,20 cronbach alpha of 0.8 indicated an acceptable level of reliability. a five-point shaikha abdool, sherief abdallah, suhair akhlaq and hira abdul razzak clinical and basic research | e205 likert-scale questionnaire was designed on the basis of the literature review. the scale ranged from strongly disagree (1) to strongly agree (5). based on participants’ agreement levels on a likert scale, responses were pooled during analysis as ‘strongly agree’ and ‘agree’ indicating agreement; ‘strongly disagree’ and ‘disagree’ indicating disagreement and neutral responses were kept as it is. scores for all questions for each perceived telemedicine attribute were averaged to generate a precise mean score. ibm statistical package for the social sciences (spss), version 25.0, new york, united states was used to analyse descriptive statistics. mean ± standard deviation (sd) was calculated for continuous variables, while percentages and frequencies were calculated for categorical variables. multiple linear regression was performed to measure the association between actual usage and pu, peou, atu and biu. regression analysis was carried out to determine statistical significance and examine the predictability potential of the independent variables (pu, peou, atu and biu) on the dependent variable (au). stepwise model selection was used. a p value ≤0.05 was considered statistically significant. the p values provided helpful information in choosing a model. the potential collinearity among variables using variance inflation factors (effect modifiers) was tested for assumptions. the uae’s ministry of health and prevention research ethics committee (approval reference no: mohp/rec-3/2018) and the british university in table 2: knowledge of, acceptance of (i.e. perceived usefulness and perceived ease of use), attitude towards and behav ioural intention to use telemedicine (n = 330) category statement n (%) mean ± sd strongly disagree and disagree neutral strongly agree and agree general there is evident use of advanced technology in the uae. 30 (9.1) 34 (10.3) 266 (80.6) 4.04 ± 1.08 telemedicine is a well-known concept. 162 (49.1) 71 (21.5) 97 (29.4) 2.73 ± 1.14 demand there is a need for telemedicine in the uae. 42 (12.7) 54 (16.4) 234 (70.9) 3.71 ± 1.02 pu telemedicine would allow tasks to be accomplished more quickly than traditional care. 30 (9.1) 53 (16.1) 247 (74.8) 3.83 ± 0.91 using telemedicine would improve healthcare performance. 32 (9.7) 79 (23.9) 219 (66.4) 3.69 ± 0.91 telemedicine would be useful. 22 (6.7) 57 (17.3) 251 (76.1) 3.91 ± 0.90 peou i would find telemedicine flexible to interact with. 41 (12.4) 97 (29.4) 192 (58.2) 3.52 ± 0.92 it would be easy for me to become skilful at using telemedicine. 41 (12.4) 77 (23.3) 212 (64.3) 3.62 ± 0.99 telemedicine would be easy to use. 41 (12.4) 101 (30.6) 188 (56.9) 3.55 ± 0.92 atu telemedicine would be better than traditional medical care delivery. 110 (33.3) 89 (27.0) 131 (39.7) 3.05 ± 1.15 biu i will use telemedicine on a regular basis. 85 (25.8) 108 (32.7) 137 (41.5) 3.17 ± 0.99 sd = standard deviation; uae = united arab emirates; pu = perceived usefulness; peou = perceived ease of use; atu = attitude towards use; biu = behavioural intention of use. table 1: demographic characteristics of the study popul ation (n = 330) characteristic n (%) gender male 152 (46.1) female 178 (53.9) age group in years 18–25 29 (8.8) 26–35 124 (37.6) 36–45 118 (35.8) 46–55 44 (13.3) 56–65 15 (4.5) nationality emirati 162 (49.1) non-emirati 168 (50.9) education basic education 30 (9.1) undergraduate 215 (65.2) postgraduate 85 (25.8) place of residence dubai 136 (41.2) sharjah 78 (23.6) ajman 43 (13.0) abu dhabi 34 (10.3) umm al quwain 13 (3.9) ras al khaimah 10 (3.0) fujairah 16 (4.8) user acceptance level of and attitudes towards telemedicine in the united arab emirates a quantitative study e206 | squ medical journal, may 2021, volume 21, issue 2 dubai research ethics committee granted ethical approvals. prior to completing the questionnaire, individuals signed a consent form. participation was completely voluntary with no obligations, penalties or risks for participation or withdrawal from the study. confidentiality and anonymity of the participants was maintained. results a total of 330 participants completed the questionnaire (response rate: 85.7%) and were included in this study with a mean age of 37.56 ± 9.43 years (range: 18–65). in total, 152 (46.1%) males and 178 (53.9%) females were included. there was an almost equal distribution of emiratis and non-emiratis who participated (49.1% versus 50.1%, respectively). most of the respondents were 26–35 years old (n = 124; 37.6%) followed by those aged 36–45 years old (n = 118; 35.8%). in terms of education levels, most of the participants had completed undergraduate education (n = 215; 65.2%) followed by those who had earned a post-graduate degree (n = 85; 25.8%). a minority (n = 30; 9.1%) of participants had only completed basic education. participants from dubai formed the majority of the sample (n = 136; 41.2%) followed by sharjah (n = 78; 23.6%), ajman (n = 43; 13.0%), abu dhabi (n = 34; 10.3%), al-fujairah (n = 16; 4.8%), umm al-quwain (n = 13; 3.9%) and ras al-khaimah (n = 10; 3.0%) [table 1]. the highest mean score for general knowledge of telemedicine was recorded for the statement “there is evident use of advanced technology in the uae” (4.04 ± 1.08). the lowest mean score for general knowledge was for the statement “telemedicine is a well-known concept” (2.73 ± 1.14). the majority of participants (80.6%) agreed “there is evident use of advanced technology in the uae”. the statement “there is a need for telemedicine in the uae” received a mean score of 3.71 ± 1.02 with most respondents (70.9%) agreeing with the statement [table 2]. with respect to the au of telemedicine, participants responded most frequently that they would use it often (n = 88; 26.7%) or did not know whether they would use it (n = 80; 24.2%). less frequently, users indicated that they would use telemedicine rarely (n = 72; 21.8%), not at all (n = 64; 19.4%) or regularly (n = 26; 7.9%). almost half of participants (n = 162; 49.1%) indicated that online help would be the telemedicine feature table 3: distribution of responses to statement/questions regarding the use of telemedicine in the united arab emirates (n = 330) statement/question n (%) frequency of telemedicine use regularly 26 (7.9) often 88 (26.7) rarely 72 (21.8) not at all 64 (19.4) don’t know 80 (24.2) which of telemedicine’s features have you mostly used or will probably use?* reports generation 120 (36.4) scheduler 87 (26.4) export/import files 116 (35.2) online help 162 (49.1) other 6 (1.8) what features of telemedicine do you most like?* virtual communication 135 (40.9) sharing reports 117 (35.5) booking an appointment without visiting the hospital 180 (54.5) accessing personal medical record 152 (46.1) other 8 (2.4) what features of telemedicine do you most dislike?* risk of sudden internet disconnection 163 (49.4) user interface 66 (20.0) language 94 (28.5) technical skills required 125 (37.9) other 17 (5.2) *participants could choose multiple options. table 4: correlation matrix of the study variables pu peou atu biu au pu 1.000 peou 0.741* 1.000 atu 0.437 0.488* 1.000 biu 0.577 0.597 0.608* 1.000 au 0.212 0.219 0.222 0.297* 1.000 telemedicine acceptance (pu and peou) 0.488 0.597 0.219 mean ± sd 3.81 ± 0.82 3.56 ± 0.83 3.05 ± 1.15 3.17 ± 0.99 pu = perceived usefulness; peou = perceived ease of use ; atu = attitude towards use ; biu = behavioural intention of use ; au = actual usage ; sd = standard deviation. *correlation is significant at p ≤0.01 (two-tailed). shaikha abdool, sherief abdallah, suhair akhlaq and hira abdul razzak clinical and basic research | e207 most likely to be used, whereas the most liked features included booking an appointment easily without visiting the hospital (n = 180; 54.5%), accessing personal medical records (n = 152; 46.1%), communicating virtually (n = 135; 40.9%) and sharing reports (n = 117; 35.5%). most respondents (n = 163; 49.4%) indicated that fear of sudden internet disconnection was the most disliked aspect of telemedicine [table 3]. the mean score for peou was 3.56 ± 0.83, suggesting that telemedicine would be easy to use. the mean score for the question of whether delivering care via telemedicine would be better than care delivered traditionally was 3.05 ± 1.15 (atu) and participants indicated that they would use telemedicine on a regular basis with a mean score of 3.17 ± 0.99 (biu). a strong significant positive correlation was detected between peou and pu (r = 0.741; p <0.01). this finding indicates that when users find the system easy to use, then the pu of that system intensifies. similarly, a significant strong positive correlation was found between peou and atu (r = 0.488; p <0.01). atu and biu also demonstrated a strong positive correlation (r = 0.608; p <0.01). a weak but still significant positive relationship was found between biu and au (r = 0.297; p <0.01) [table 4]. the model of regression found biu was a strong significant predictor of au (beta = 0.224; p = 0.003). peou (beta = 0.033; p = 0.692), pu (beta = 0.034; p = 0.679) and atu (beta 0.055; p = 0.421) were not significant predictors of au. the results indicate that the variables that were measured describe 8.2% of the dependent variable for actual usage [table 5]. in terms of characteristics associated with acceptance of telemedicine, there were no significant differences between age groups. emirati participants had a 1.379 probability of accepting telemedicine and had a positive attitude (95% ci: 0.867–2.193), positive behavioural intention (odds ratio [or]: 1.301, 95% ci: 0.780–2.170) and effective usage (or: 1.359, 95% ci: 0.861–2.145); however, there was no statistically significant difference. furthermore, being male and having a higher level of education was found to have no effect on the association between a positive attitude, positive behavioural intention and effective use of telemedicine on the acceptance of telemedicine. however, participants had a greater probability for table 5: multivariate regression analysis of the study variables model* unstandardised coefficients standardised coefficients t value p value b se beta (constant -actual use) 0.244 0.338 0.722 0.471 pu 0.053 0.128 0.034 0.415 0.679 peou 0.052 0.131 0.033 0.397 0.692 atu 0.062 0.077 0.055 0.806 0.421 biu 0.292 0.099 0.224 2.963 0.003 pu = perceived usefulness; peou = perceived ease of use; atu = attitude towards use; biu = behavioural intention of use; se = standard error. *r2 = 0.093 and adjusted r2 = 0.082; dependent variable was the frequency of actual use. table 6: characteristics associated with acceptance of telemedicine among users in the united arab emirates characteristic or (95% ci) p value or (95% ci) p value or (95% ci) p value positive attitude positive behavioural intention effective use 18–30 years old 2.167 (0.803–5.844) 0.127 1.716 (0.583–5.051) 0.327 1.885 (0.709–5.016) 0.204 31–40 years old 1.866 (0.735–4.735) 0.189 1.423 (0.517–3.916) 0.494 1.522 (0.606–3.827) 0.372 41–50 years old 1.426 (0.528–3.855) 0.484 0.890 (0.300–2.645) 0.834 1.138 (0.426–3.043) 0.797 male 0.871 (0.548–1.385) 0.559 0.959 (0.575–1.601) 0.874 0.853 (0.542–1.345) 0.853 emirati 1.379 (0.867–2.193) 0.174 1.301 (0.780–2.170) 0.313 1.359 (0.861–2.145) 0.187 basic education 1.117 (0.462–2.704) 0.805 1.573 (0.599–4.133) 0.358 1.469 (0.611–3.534 0.391 undergraduate education 0.725 (0.423–1.242) 0.242 0.805 (0.443–1.461) 0.476 0.844 (0.500–1.427) 0.527 diffusion of innovations 4.805 (2.855–8.085) <0.001 3.851 (2.201–6.736) <0.001 5.743 (3.411–9.668) <0.001 or = odds ratio; ci = confidence interval. user acceptance level of and attitudes towards telemedicine in the united arab emirates a quantitative study e208 | squ medical journal, may 2021, volume 21, issue 2 the confounding variable of diffusion of innovation when they responded with strongly agree or agree to accept telemedicine (or = 4.805, 95% ci: 2.855–8.085; p <0.001). in addition, diffusion of innovations had a statistically significant relationship with positive behavioural intention (or = 3.851, 95% ci: 2.201–6.736; p <0.001) or effective use of telemedicine (or = 5.743, 95% ci: 3.411–9.668; p <0.001) [table 6]. discussion this study assessed users’ acceptance levels of and attitudes towards telemedicine in the uae and determined the association between peou, pu, atu and biu towards the au of telemedicine. the results of this study indicate a strong positive correlation between pu and peou. this finding implies that the easier users find the system to use, the more they consider it beneficial and vice versa. previous studies found a similar correlation between peou and pu.6,19,21 furthermore, this finding suggests that the tam tends to position peou and pu as two different antecedents towards using technology due to their positive correlation. a significant positive correlation was found between peou and atu. respondents were more likely to form a positive attitude towards utilising the system when it was confirmed as useful through practice and vice versa. these findings were consistent with previous findings that indicated that equal acceptance was associated with attitude.22 previous studies have also found that pu was highly correlated with attitude, but peou had a relationship that did not reach statistical significance.19,21 the findings of the current study revealed that atu and biu demonstrated a strong positive correlation. this suggests that if users tend to have positive attitudes towards utilising the system, then actual system usage becomes much easier. this attitude is a factor contributing to biu telemedicine and was also evident in previous studies.22,23 a weak positive relationship was also observed in the current study between biu and au. this relationship between biu technology and au requires further exploration to rectify the high level of focus on biu, otherwise known as the ‘bottleneck’ problem.24 results of the current study on the regression model presented 8.2% of the observed variance in actual usage being a dependent variable. this study’s findings were contrary to those of a previous study which stated that in any organisation, a system can be adopted if it is considered to be useful and offers direct benefits, regardless of attitudes.25 thus, if new technology is useful compared to what the users have been using to perform their daily activities then other factors such as peou and attitudes are considered secondary.26 these findings are contrary to the results of prior research in which attitude emerged as the most authoritative predictor of system use.27 the results of the study suggest that telemedicine can be introduced in the uae if key elements are considered to ensure acceptance and effective usage. however, decision-makers need to consider other aspects of technology including its strengths and obstacles to increase acceptance. while this research had strengths, it also had limitations. while the cross-sectional design was useful for the uae’s context, evaluating technology at a single point in time means that it is highly likely that people’s attitude towards and acceptance of technology may change or have changed over time. this possibility is especially prevalent after a period of technology exposure. conclusion this research examined telemedicine acceptance in the uae. the associations peou and atu in relation to telemedicine technology tested were found to be positively correlated. biu was considered the strongest predictor of telemedicine au compared to atu and peou. in addition, results suggest that biu is essential but the usefulness of a system is even more important and should not be ignored. an individual’s perception of the ease of using telemedicine is significantly associated with their intention to use telemedicine. further empirical studies should measure telemedicine technology’s impact on patients’ health outcomes and expenditures over time. moreover, a combination of models (e.g. tam and task-technology fit) should be applied to future research to understand and classify common aspects along with the underlying determinants of behavioural intentions to compare the results of the models used. future researchers should attempt to analyse and gather both data for objective use and self-reported perceptions. these types of data will further guide solving lingering questions with respect to tam constructs along with their relationship to past tam research. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. shaikha abdool, sherief abdallah, suhair akhlaq and hira abdul razzak clinical and basic research | e209 references 1. chen et. improving patient care with telemedicine technology. in: mchaney rw, reychev i, azuri j, mchaney me, moshanov r. impacts of information technology on patient care and empowerment. 1st ed. pennsylvania: igi global, 2019. pp. 1–18. 2. shah tk, tariq t, phillips r, davison s, hoare a, hasan ss, et al. health care for all: effective, community supported, healthcare with innovative use of telemedicine technology. j pharm policy pract 2018; 11:3. https://doi.org/10.1186/s40545018-0130-5. 3. al-qirim n. realizing telemedicine advantages at the national level: cases from the united arab emirates. telemed j e health 2007; 13:545–55. https://doi.org/10.1089/tmj.2006.0087. 4. armaignac dl, saxena a, rubens m, valle ca, williams lm, veledar e, gidel lt. impact of telemedicine on mortality, length of stay, and cost among patients in progressive care units: experience from a large healthcare system. crit care med 2018; 46:728. https://doi.org/10.1097/ccm.0000000000002994. 5. kaminski j. diffusion of innovation theory. can j nurs inform 2011; 6:1–6. 6. cowen jb. the influence of perceived usefulness, perceived ease of use, and subjective norm on the use of computed radiography systems: a pilot study. from: www.kb.osu.edu/ dspace/bitstream/handle/1811/36983/?sequence=1 accessed: jul 2020. 7. mutahar am, daud nm, thurasamy r, isaac o, abdulsalam r. the mediating of perceived usefulness and perceived ease of use: the case of mobile banking in yemen. int j technol diffusion (ijtd) 2018; 9:21–40. https://doi.org/10.4018/ijtd.2018040102. 8. hayavi hmh, alipour j, mastaneh z, mouseli l. feasibility study of telemedicine implementation in hormozgan university of medical sciences. hormozgan med j 2011; 15:128–37. 9. judi hm, razak aa, sha’ari n, mohamed h. feasibility and critical success factors in implementing telemedicine. inf technol j 2009; 8:326–32. https://doi.org/10.3923/itj.2009.326.332. 10. au l. assessing the potential needs for telehealth in papua new guinea (png). msc thesis, 2009, university of canterbury, canterbury, new zealand. 11. ibrahim mi, phing cw, palaian s. evaluation of knowledge and perception of malaysian health professionals about telemedicine. j clin diagn res 2010; 4:2052–6. 12. macneill v, sanders c, fitzpatrick r, hendy j, barlow j, knapp m, et al. experiences of front-line health professionals in the delivery of telehealth: a qualitative study. br j gen pract 2014; 64:e401–7. https://doi.org/10.3399/bjgp14x680485. 13. almathami hk, win kt, vlahu-gjorgievska e. barriers and facilitators that influence telemedicine-based, real-time, online consultation at patients’ homes: systematic literature review. j med internet res 2020; 22:e16407. 14. scott kruse c, karem p, shifflett k, vegi l, ravi k, brooks m. evaluating barriers to adopting telemedicine worldwide: a systematic review. j telemed telecare 2018; 24:4–12. 15. khammarnia m, torani s, mohamadi r. feasibility of remote medical consultation implementation in iran university of medical sciences. eur j med res 2010; 15:199 16. hu pjh, chau pyk, sheng orl. adoption of telemedicine technology by health care organizations: an exploratory study. j org comp elect com 2002; 12:197–221. https://doi. org/10.1207/s15327744joce1203_01. 17. meher sk, tyagi rs, chaudhry t. awareness and attitudes to telemedicine among doctors and patients in india. j telemed telecare 2009; 15:139–41. https://doi.org/10.1258/jtt.2009.003011. 18. el gatit am, tabet as, sherief m, warieth g, abougharsa m, abouzgaia h. effects of an awareness symposium on perception of libyan physicians regarding telemedicine. east mediterr health j 2008; 14:926–30. 19. davis fd, bagozzi rp, warshaw pr. user acceptance of computer technology: a comparison of two theoretical models. manage ment sci 1989; 35:982–1003. https://doi.org/10.1287/mnsc.35.8.982. 20. mutahar am, norzaidi md, ramayah t, isaac o, alrajawy i. integration of innovation diffusion theory (idt) and technology acceptance model (tam) to understand mobile banking acceptance in yemen: the moderating effect of income. int j soft comput 2017; 12:164–77. 21. jensen sj. an evaluation of geobest contingency beddown planning software using the technology acceptance model. from: https://scholar.afit.edu/etd/4426/ accessed: jul 2020 22. liu zy. an analysis of technology acceptance model—exploring user acceptance and intension of taxi-hailing app in shanghai. from: https://gupea.ub.gu.se/bitstream/2077/38592/1/gupea_2 077_38592_1.pdf accessed: jul 2020. 23. hussein z. leading to intention: the role of attitude in relation to technology acceptance model in e-learning. procedia comput sci 2017; 105:159–64. https://doi.org/10.1016/j.procs.2017.01.196. 24. sniehotta ff. towards a theory of intentional behaviour change: plans, planning, and self-regulation. br j health psychol 2009; 14:261–73. https://doi.org/10.1348/135910708x389042. 25. davis f. perceived usefulness, perceived ease of use, and user acceptance of information technology. mis quarterly 1989; 13:319–40. https://doi.org/10.2307/249008. 26. aboelmaged mg. predicting e-procurement adoption in a dev eloping country: an empirical integration of technology accep tance model and theory of planned behavior, college of business administration, ajman university of science and technology, ajman, united arab emirates. ind manage data syst 2010; 110:392–414. https://doi.org/10.1108/02635571011030042. 27. chau pyk, hu pj. examining a model of information technology acceptance by individual professionals: an exploratory study. j manag inf syst 2002; 18:191–229. https://doi.org/10.1080/0742 1222.2002.11045699. https://doi.org/10.1186/s40545-018-0130-5 https://doi.org/10.1186/s40545-018-0130-5 https://doi.org/10.1089/tmj.2006.0087 https://doi.org/10.1097/ccm.0000000000002994 https://doi.org/10.4018/ijtd.2018040102 https://doi.org/10.3923/itj.2009.326.332 https://doi.org/10.3399/bjgp14x680485 https://doi.org/10.1207/s15327744joce1203_01 https://doi.org/10.1207/s15327744joce1203_01 https://doi.org/10.1258/jtt.2009.003011 https://doi.org/10.1287/mnsc.35.8.982 https://doi.org/10.1016/j.procs.2017.01.196 https://doi.org/10.1348/135910708x389042 https://doi.org/10.2307/249008 https://doi.org/10.1108/02635571011030042 https://doi.org/10.1080/07421222.2002.11045699 https://doi.org/10.1080/07421222.2002.11045699 1department of family medicine and public health, sultan qaboos university hospital, muscat, oman; departments of 2family medicine & public health and 4radiology, ministry of health, muscat, oman; 3college of medicine, sultan qaboos university, muscat, oman *corresponding author’s e-mail: asmaa_9988@hotmail.com inflammatory markers as a predictor of postmenopausal osteoporosis cross-sectional study from sultan qaboos university hospital *asma al salmani,1 asma al shidhani,1 nouf m. al-alawi,2 arwa a. al sulaimi,3 maha a. al-hashemi4 clinical & basic research sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 508–514, epub. 7 nov 22 submitted 5 jul 21 revision req. 29 aug 21; revision recd. 16 sep 21 accepted 13 oct 21 https://doi.org/10.18295/squmj.11.2021.145 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: postmenopausal osteoporosis is a progressive metabolic bone disease resulting from oestrogen deficiency. due to the silent nature of the disease, there is an urgent need for a simple, early predictive marker. this study aimed to assess the potential of three factors—neutrophil-to-lymphocyte ratio (nlr), monocyteto-lymphocyte ratio (mlr) and platelet-to-lymphocyte ratio (plr)—as inflammatory markers of bone mineral density (bmd) loss. methods: a retrospective cross-sectional study was conducted among 450 postmenopausal omani women undergoing dual-energy x-ray absorptiometry at the sultan qaboos university hospital, muscat, oman, from january 2017 to december 2019. the participants were allocated to groups based on lumbar spine bmd t-score values. a receiver operating characteristic curve was used to determine the area under the curve (auc). multivariate logistic regression was performed to identify independent predictors of low bmd. results: a total of 65 (14.4%), 164 (36.4%) and 221 (49.1%) women were allocated to the control, osteopenia and osteoporosis groups, respectively. no significant differences in plr, mlr and nlr values were observed among the groups. bmd t-score values were reversely correlated with age (p = 0.007) and plr (p = 0.004) and positively correlated with body mass index (bmi; p <0.001). the auc was 0.59. the independent predictors of low bmd were age (>65 years) and bmi (<25 kg/m2). conclusion: none of the three inflammatory biomarkers studied were found to be useful prognostic indicators of bone loss. further research is recommended to reject or support theories regarding the role of inflammatory status in the pathogenesis. keywords: postmenopausal woman; bone mineral density; osteoporosis; oman. advances in knowledge platelet-to-lymphocyte ratio was found to be a poor indicator of bone loss in postmenopausal women. as such, evaluation of this marker would have minimal use from a prognostic or diagnostic perspective. although neither neutrophil-to-lymphocyte ratio nor monocyte-to-lymphocyte ratio values were found to be correlated with lumbar spine bone mineral density (bmd) t-score values and bmd group allocation, these findings cannot be used to either support or reject current theories related to the role of inflammation in the pathogenesis of postmenopausal osteoporosis (pmop). application to patient care based on the findings, bone mineral densitometry remains the best prognostic indicator of pmop. osteoporosis is a chronic progressive metabolic bone disease, affecting approximately 10% of the global population.1,2 the progressive systemic disease is characterised by low bone mass and microarchitectural impairment of the bone tissue.3 the prevalence of osteoporosis is significantly higher among postmenopausal women and men over 70 years of age.1,4 primary osteoporosis is classified into types 1 and 2, also referred to as oestrogen-related postmenopausal osteoporosis (pmop) and age-related senile osteoporosis, respectively.5 the pathogenesis of pmop is mainly related to the sudden onset of hypoestrogenemia at menopause, which has both a direct and indirect effect on bone resorption. indirectly, impaired t-cell function increases the recruitment and lifespan of osteoclasts by releasing pro-inflammatory cytokines such as interleukin (il)1 beta, il-6, il-11, il-15, il1-7 and tumour necrosis factor alpha (tnf-α).6 prolonged exposure to these pro-inflammatory cytokines induces receptor activator of nuclear factor kappa β ligand (rankl) and suppresses osteoprotegerin (opg). moreover, oestrogen deficiency also influences the release of high levels of rankl by b and t lymphocytes.7 increased expression of rank results in increased interaction between rank and rankl, thereby increasing osteoclast bone resorption activity and osteoclast precursor cell differentiation and inhibiting osteoclast apoptosis.8 this overactive osteoclastic status results in the greater resorption of trabecular than cortical bone.9 clinically, pmop increases the risk of asympt omatic vertebral compression fractures as well as symptomatic fractures such as colles fractures or those of the wrist or hip.10 mild compression fractures are usually painless with no obvious clinical symptoms. however, most patients diagnosed with osteoporosis https://creativecommons.org/licenses/by-nd/4.0/ asma al salmani, asma al shidhani, nouf m. al-alawi, arwa a. al sulaimi and maha a. al-hashemi clinical and basic research | 509 present with osteoporotic fractures usually following trauma. as such, the disease accounts for a considerable medical and socioeconomic burden. in 2010, there were an estimated 2.7 million hip fractures worldwide, of which 50% were attributable to osteoporosis and, thus, preventable.11 risk factors for pmop include age, genetic factors, calcium and vitamin d deficiency, use of corticosteroids and anticancer drugs, hormonal levels, physical inactivity and low peak bone mass.1,5,12 however, previous studies have shown that the prevalence of osteoporosis among women aged over 50 years varies widely (10.3–34.8%).13,14 in particular, omani women may be at a higher risk of pmop as a consequence of calcium and vitamin d deficiency and inactive lifestyles.15,16 according to the diagnostic criteria of the world health organization, osteopenia and osteoporosis should be considered in young adult females if their bone mineral density (bmd) is 1–2.5 or ≥2.5 standard deviations (sds) below the mean, respectively.3 although various methods can be used to assess bmd, dual-energy x-ray absorptiometry (dexa) is the gold standard, particularly to calculate bone mineral content of the lumbar spine, hip bone and femur neck.12 the often delayed presentation and serious complications exhibited by osteoporotic patients underline the need for an early, rapid and simple predictive marker. despite the predictive role of levels of certain inflammatory cytokines in the blood, such as rankl and opg, these markers are not often used due to the complex nature of such laboratory monitoring.17 previous research has confirmed that serum inflammatory markers can play a diagnostic role in various diseases, with researchers reporting an association between inflammatory response and potential loss of bone mass.9 however, few studies have assessed the predictive role of inflammatory markers such as neutrophil-tolymphocyte ratio (nlr), monocyte-to-lymphocyte ratio (mlr) and platelet-to-lymphocyte ratio (plr). moreover, the results of such studies have been conflicting. ye et al. reported a correlation between increased bone loss and osteoporosis severity with low lymphocyte and high neutrophil and monocyte ratios among 487 patients at a hospital in china.17 yilmaz et al. found a significant negative correlation between nlr and lumbar spine bmd values, concluding that nlr might be a better predictor of pmop than c-reactive protein (crp) level.18 in a cross-sectional study of 252 postmenopausal women in turkey, eroglu and karatas reported that the osteoporotic group demonstrated a significantly higher plr; however, no association was noted with nlr.19 in contrast, a cross-sectional study of 407 postmenopausal women in korea conducted by lee et al. found that nlr was significantly higher in the pmop group, but not plr.20 two other studies conducted in china confirmed that bmd was negatively correlated with nlr among 233 postmenopausal women and 316 osteoporotic patients.21,22 as the onset of osteoporosis lacks obvious disease characteristics, it is difficult to diagnose it early; once a patient has visible changes in body shape or bone pain, the lesion has already entered an accelerated phase. at present, clinical diagnostic methods primarily include osteoporosis screening tools such as the frax® tool (university of sheffield, sheffield, uk), bone turnover markers and bmd detection technologies, with the latter being some of the most common methods. an objective and non-invasive diagnostic predictor at an earlier disease stage is needed. for instance, peripheral blood markers are newly proposed inflammatory factors with various advantages over other modalities, such as simplicity, cost-effectiveness and non-invasiveness. as such, this study aimed to clarify the association between inflammatory markers—specifically nlr, plr and mlr values— and lumbar spine bmd t-score values in a cohort of postmenopausal omani women. assessment of these simple inflammatory serum markers may help in the early diagnosis of osteoporosis, thus precluding the development of serious complications such as asymptomatic compression fractures. ideally, the results of this study can add to existing knowledge in the literature and may inform future systematic reviews and meta-analyses designed to conclude on the effectiveness of these markers. methods this retrospective cross-sectional study was conducted among postmenopausal women who underwent dexa scanning from january 2017 to december 2019 at the sultan qaboos university hospital in muscat, oman. a non-probability convenience sampling strategy was used to recruit all women presenting to this hospital during the above-mentioned period who were either ≥50 years of age or <50 years of age if postmenopausal status was confirmed. however, women with a history of menopause of less than a year in duration were excluded, as were women with conditions or factors thought to affect immunoinflammatory response, including those with hepatic, renal, oncological, haematological or rheumatologic diseases. similarly, women with a history of steroid use, trauma, hospitalisation over the preceding six months and blood transfusions over the last 12 months were also excluded. inflammatory markers as a predictor of postmenopausal osteoporosis cross-sectional study from sultan qaboos university hospital 510 | squ medical journal, november 2022, volume 22, issue 4 data were collected from the database of the electronic hospital information system. information regarding the demographic characteristics of the participants was collected including age, weight and height. the body mass index (bmi) of each participant was calculated as follows: in addition, various laboratory results from the participants’ most recent blood tests were collected, including their haemoglobin (hb) level, mean cell volume, platelet count, neutrophil count, lymphocyte count and monocyte count. inflammatory markers plr, nlr and mlr were subsequently calculated using the following formulae: finally, bmd t-score values were obtained from dexa imaging of the lumbar spine, femoral neck or hip bone. these values were then used to allocate the participants to control, osteopenia or osteoporosis group. for the purposes of the analysis, the participants in the osteopenia and osteoporosis groups were combined to draw comparisons between those with normal and low bmd values. data calculations and statistical analyses were performed using the statistical package for the social sciences (spss) software, version 25 (ibm corp., armonk, ny, usa). age and bmi were expressed as means ± sds, while all other continuous variables were expressed as means and ranges, including hb levels and plr, nlr and mlr values. the onesample kolmogorov–smirnov test was conducted to determine the normality of continuous variables, with all variables found to be non-normally distributed. non-parametric tests such as the mann–whitney u and kruskal–wallis tests were performed to determine the difference between two groups or more than two groups, respectively. associations were determined between bmd group allocation and selected variables including age, bmi, hb levels and plr, nlr and mlr values. spearman’s correlation test was applied to evaluate the significance of correlations between age; bmi; hb level; plr, nlr and mlr values and lumbar spine bmd t-score values. a receiver operating characteristic (roc) curve analysis was employed to find the area under the curve (auc) and determine the plr cut-off value. the multivariate logistic regression analysis was performed to identify the strongest independent predictors of osteoporosis. a p value of <0.05 was considered statistically significant. the medical research and ethics committee of the college of medicine and health sciences, sultan qaboos university, approved this study. results a total of 450 women were included in the study. the mean age was 63.69 ± 8.23 years, with the majority (56.7%) being 50–65 years old, followed by >65 years (40.2%) and <50 years (2.9%). the mean bmi was 29.24 ± 5.93 kg/m2. based on their bmd values, 65 (14.4%), 164 (36.4%) and 221 (49.1%) women were allocated to the control, osteopenia and osteoporosis groups, respectively. the mean ages of women in these groups were 59.80 ± 8.66, 62.71 ± 6.90 and 65.76 ± 8.29 years, respectively. age was significantly higher in the osteoporosis group (p <0.001), while bmi was significantly higher in the control group (p <0.001) [tables 1 and 2]. no significant differences in mean plr, mlr and nlr values were observed between women with normal bmd values and those with low bmd values (p >0.05 each) [table 1]. furthermore, no significant differences were noted in mean plr, mlr and nlr values between the control, osteopenia and bmi = weight in kg/(height in m)2 [equation 1] plr = platelet count/lymphocyte count [equation 2] nlr = neutrophil count/lymphocyte count [equation 3] mlr = monocyte count/lymphocyte count [equation 4] table 1: comparison of age, haemoglobin levels, body mass index and platelet-to-lymphocyte ratio, neutrophil-tolymphocyte ratio and monocyte-to-lymphocyte ratio values between subjects with normal and low bone mineral density values (n = 450) variable mean (range) p value normal bmd group (n = 65) low bmd group (n = 385) mean age in years ± sd 59.80 ± 8.66 64.50 ± 7.88 <0.001 mean bmi in kg/m2 ± sd 32.66 ± 4.94 28.64 ± 5.89 <0.001 hb level in g/dl 12.59 (11.0–14.7) 12.41 (10.3–15.3) 0.218 plr 122.93 (59.68–245.00) 127.68 (39.74–256.92) 0.311 nlr 1.22 (0.36–2.93) 1.18 (0.20– 4.43) 0.263 mlr 0.194 (0.08–0.37) 0.212 (0.09–0.65) 0.182 bmd = bone mineral density; sd = standard deviation; bmi = body mass index; hb = haemoglobin; plr = platelet-to-lymphocyte ratio; nlr = neutrophil-to-lymphocyte ratio; mlr = monocyte-to-lymphocyte ratio. asma al salmani, asma al shidhani, nouf m. al-alawi, arwa a. al sulaimi and maha a. al-hashemi clinical and basic research | 511 osteoporosis groups (p >0.05 each) [table 2]. similarly, differences in hb level among the groups were nonsignificant (p >0.05) [tables 1 and 2]. according to the correlation analysis, lumbar spine bmd t-score values were inversely correlated with age (p = 0.007) and plr values (p = 0.004) and positively correlated with bmi (p <0.001). however, no significant correlations were observed with hb levels and nlr or mlr values (p >0.05) [table 3]. the plr cut-off value was estimated to be 117.11. an roc curve analysis indicated that the auc was 0.59, which was significant for plr values only [figure 1]. age was positively correlated with all three inflammatory markers: nlr (p = 0.001), plr (p = 0.031) and mlr (p <0.001). in addition, age was inversely correlated with bmi (p = 0.046) and hb levels (p = 0.002). there was also a positive correlation between all three of the inflammatory markers studied (p <0.001). based on the logistic regression analysis, an age >65 years (p = 0.023) and a bmi <25 kg/m2 (p = 0.004) were identified as independent predictors of low bmd [table 4]. discussion serum inflammatory markers are considered indicators of many chronic inflammatory diseases, with both plr and nlr values reported as indicators of severity in ulcerative colitis and acute pancreatitis as well as various neoplastic conditions such as hepatocellular carcinoma and colorectal, breast and lung cancer.6,23 similarly, there is strong evidence to support the association between systemic inflammatory status and osteoporosis, with pro-inflammatory markers, hormones and growth factors all playing a role in the table 3: correlations between lumbar spine bone mineral density t-score values and age, body mass index, haemoglobin levels and platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio values variable age bmi hb level plr nlr mlr lumbar spine bmd t-score values correlation coefficient -0.150 0.345 0.032 -0.160 -0.003 -0.087 p value 0.007 <0.001 0.571 0.004 0.963 0.119 bmi = body mass index; hb = haemoglobin; plr = platelet-to-lymphocyte ratio; nlr = neutrophil-to-lymphocyte ratio; mlr = monocyte-to-lymphocyte ratio; bmd = bone mineral density. table 4: logistic regression analysis of age and body mass index as potential predictors of low bone mineral density risk factor or (95% ci) p value age ≥65 years 1.942 (1.10–3.44) 0.023 bmi <25 kg/m² 8.419 (2.01–35.20) 0.004 or = odds ratio; ci = confidence interval; bmi = body mass index. figure 1: receiver operating characteristic curve analysis for platelet-to-lymphocyte ratio. area under the curve = 0.59; platelet-to-lymphocyte ratio cut-off = ~117.11. table 2: comparison of age, haemoglobin levels, body mass index and platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio values between the control, osteopenia and osteoporosis groups variable mean (range) p value control group (n = 65) osteopenia group (n = 164) osteoporosis group (n = 221) mean age in years ± sd 59.80 ± 8.66 62.71 ± 6.90 65.76 ± 8.29 < 0.001 mean bmi in kg/m2 ± sd 32.66 ± 4.94 30.38 ± 5.73 27.47 ± 5.72 < 0.001 hb level in g/dl 12.59 (11.0–14.7) 12.47 (10.3–15.3) 12.37 (10.3–15.0) 0.313 plr 122.93 (59.68–245.00) 122.36 (46.30–240.00) 131.47 (39.74–256.92) 0.186 nlr 1.22 (0.36–2.93) 1.17 (0.38–4.21) 1.19 (0.20–4.43) 0.534 mlr 0.194 (0.08–0.37) 0.204 (0.09–0.47) 0.218 (0.10–0.65) 0.268 sd = standard deviation; bmi = body mass index; hb = haemoglobin; plr = platelet-to-lymphocyte ratio; nlr = neutrophil-to-lymphocyte ratio; mlr = monocyte-to-lymphocyte ratio. inflammatory markers as a predictor of postmenopausal osteoporosis cross-sectional study from sultan qaboos university hospital 512 | squ medical journal, november 2022, volume 22, issue 4 pathogenesis of the disease.6,24 various epidemiological studies have shown an increased risk of osteoporosis in chronic inflammatory conditions, such as systemic lupus erythematosus, ankylosing spondylitis, crohn’s disease, rheumatoid arthritis and ulcerative colitis.21,25 in addition, a previous study reported a negative correlation between low bmd and nlr, crp and erythrocyte sedimentation rate in elderly people.6 while the role of inflammation in osteoporosis has been proven by many studies at the molecular level, there is still insufficient evidence to support the relationship between serum levels of these inflammatory markers and degree of bone loss. this may be because serum levels of inflammatory markers may not always reflect the processes happening at the tissue level. a prospective case-cohort study reported a correlation between certain serum inflammatory markers—specifically il-6 and its soluble receptor (sr) and tnf sr1 and tnf sr2—and an increased risk of hip fractures.26 alternatively, other research has shown no correlation between il-6 and osteoporosis.6 the present cross-sectional study sought to assess the relationship between bmd and three serum inflammatory markers—nlr, plr and mlr values— among a cohort of 450 postmenopausal omani women. no significant differences with regard to nlr, plr and mlr values were noted among the participants according to their allocation into normal and low bmd groups. likewise, there were no significant differences in these markers when the participants were further subcategorised into control, osteopenia and osteoporosis groups. moreover, a correlation analysis of lumbar spine bmd t-score values indicated no significant correlations with nlr and mlr values. overall, plr was the only studied inflammatory marker found to be significantly correlated with bmd t-score values, with plr values inversely correlated with lumbar spine bmd t-scores. these results confirm findings reported from a similar study performed in turkey, wherein plr was the only inflammatory marker found to be negatively correlated with lumbar spine bmd t-score values.19 accordingly, plr can be considered an indicator of bmd in postmenopausal women and may even reflect the degree of osteoporosis when correlated with lumbar spine bmd t-score values. however, an roc curve analysis revealed that plr failed to predict osteoporosis in the present study and appeared to be a poor test for low bmd in a previous study conducted in turkey.19 based on the findings of the present study, neither nlr nor mlr values can be considered predictive markers of osteoporosis as they do not appear to directly indicate osteoporotic risk. these findings may be explained by the large number of factors affecting white blood cells, such as infection, cardiovascular diseases, ulcerative colitis, acute appendicitis, metabolic syndrome, malignancy, pharmacological agents and non-alcoholic fatty liver disease.6,27,28 however, conflicting findings regarding the relationship between nlr and bmd values have been reported. three cross-sectional studies demonstrated negative correlations in different populations in east asia.20,22,29 additionally, one of those studies found a negative correlation between mlr and bmd values.22 in contrast, neither the present study nor a previous one conducted in turkey reported correlations between bmd and nlr or mlr values.19 these differences could be attributed to varying ethnicity or genetic and environmental factors, particularly when comparing differences between east asian and middle eastern populations. regardless, further research is necessary to either support or reject current theories regarding the role of inflammatory status in the pathogenesis of osteoporosis. in the current study, both age and bmi were significantly associated with group allocation based on bmd values, with the logistic regression analysis indicating that advanced age and low bmi were independent predictors of low bmd. in addition, age was negatively correlated with lumbar spine bmd t-score values. these findings were expected given that osteoporosis is a progressive age-related disease, with old age considered the greatest risk factor for the disease.13 in contrast, bmi was positively correlated with both lumbar spine bmd t-score values and bmd group allocation, with women in the control group having a significantly greater bmi than those in the low bmd groups. this finding can be explained by the loss of muscle and adipocyte replacement due to lack of physical activity in the osteoporosis group, especially for those with osteoporotic fractures, as well as the minimal loss of bone weight due to the osteoporosis.30 nevertheless, high bmi cannot be considered a protective factor for osteoporosis, as obesity is associated with both physical inactivity and low bone quality.31 daytime variation of haematological parameters can also affect plr, nlr and mlr values, particularly with regard to neutrophil, monocyte and lymphocyte percentages. conversely, red blood cells, platelets and other related parameters have been found to exhibit less frequent daytime variation.32 bektas et al. emphasised that chronic inflammatory status and the dysregulation of proinflammatory markers correlate with the natural ageing process in all species, resulting in the elevation of inflammatory markers such as crp, il-6, il-8 and tnf-α.33 the findings of the present study confirm this concept, as all three asma al salmani, asma al shidhani, nouf m. al-alawi, arwa a. al sulaimi and maha a. al-hashemi clinical and basic research | 513 of the inflammatory markers studied were found to be positively correlated with age. such factors may have resulted in the non-significant capacity of these plasma inflammatory markers to indicate low bmd, considering the inability to separate two intertwined factors, namely age and low oestrogen levels. the current study was subject to certain limitations. first, as a convenience sampling strategy was employed, no minimum sample size was calculated. as such, it was not possible to determine the representativeness of the cohort to the population being studied. second, all patients with medical conditions known to interfere with nlr, mlr and plr values could not be excluded due to insufficient patient medical information and the huge number of conditions known to affect these factors.27 third, all secondary causes of osteoporosis could not be excluded. finally, as the study was conducted at a single centre using a cross-sectional design, longitudinal changes in nlr, mlr and plr values could not be determined in the study population. as such, the role of these serum inflammatory markers in the pathogenesis of osteoporosis could not be assessed. further longitudinal studies are recommended to determine changes in these serum inflammatory markers among women in the early postmenopausal period. moreover, additional research is recommended to assess more specific markers of pmop inflammation in this population, including cytokines such as interferon (ifn) α-2, ifn-γ, il-12p70, il-33 and monocyte chemoattractant protein 1.24 conclusion plr was found to be a poor indicator of bone loss in postmenopausal women in this study. as such, evaluation of this marker would have minimal use from a prognostic or diagnostic perspective. although neither nlr nor mlr values were found to be correlated with lumbar spine bmd t-score values and bmd group allocation, these findings cannot be used to either support or reject current theories related to the role of inflammation in the pathogenesis of pmop. further research is recommended and should focus on other specific serum inflammatory markers for osteoporosis. a u t h o r s’ c o n t r i b u t i o n aasa was involved in question formulation, methodology designing, data cleaning and manuscript writing, submission and revision. aash was involved in question formulation and methodology designing. nma-a contributed to data analysis and manuscript writing. aaas contributed towards data collection, data analysis and manuscript writing. maa-h was involved in data collection and manuscript writing. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. references 1. bijelic r, milicevic s, balaban j. risk factors for osteoporosis in postmenopausal women. med arch 2017; 71:25–8. https://doi. org/10.5455/medarh.2017.71.25-28. 2. dixit p, waliullah s, jafar t. osteoporosis: a major health problem. era j med res 2020; 7:134–42. https://doi.org/10.24 041/ejmr2020.22. 3. kanis ja. assessment of osteoporosis at the primary healthcare level: report of a who scientific group. from: www.shef. ac.uk/frax/pdfs/who_technical_report.pdf accessed: oct 2021. 4. tian l, yang r, wei l, liu j, yang y, shao f, et al. prevalence of osteoporosis and related lifestyle and metabolic factors of postmenopausal women and elderly men. medicine (baltimore) 2017; 96:e8294. https://doi.org/10.1097/md.0000000000008294. 5. hawkins f, garla v, allo g, males d, mola l, corpas e. senile and postmenopausal osteoporosis: pathophysiology, diagnosis, and treatment. in: corpas e, ed. endocrinology of aging: clinical aspects in diagrams and images. amsterdam, netherlands: elsevier, 2021. pp. 147–89. https://doi.org/10.1016/b978-0-12819667-0.00005-6. 6. öztürk za, yesil y, kuyumcu me, bilici m, öztürk n, yeşil nk, et al. inverse relationship between neutrophil lymphocyte ratio (nlr) and bone mineral density (bmd) in elderly people. arch gerontol geriatr 2013; 57:81–5. https://doi.org/10.1016/j.arch ger.2013.02.005. 7. fujiwara y, piemontese m, liu y, thostenson jd, xiong j, o’brien ca. rankl (receptor activator of nfκb ligand) produced by osteocytes is required for the increase in b cells and bone loss caused by estrogen deficiency in mice. j biol chem 2016; 291:24838–50. https://doi.org/10.1074/jbc. m116.742452. 8. kohli ss, kohli vs. role of rankl–rank/osteoprotegerin molecular complex in bone remodeling and its immun pathologic implications. indian j endocrinol metab 2011; 15:175–81. https://doi.org/10.4103/2230-8210.83401. 9. fuggle nr, westbury ld, syddall he, duggal na, shaw sc, maslin k, et al. relationships between markers of inflammation and bone density: findings from the hertfordshire cohort study. osteoporos int 2018; 29:1581–9. https://doi.org/10.1007/ s00198-018-4503-z. 10. rosen cj. the epidemiology and pathogenesis of osteoporosis. in: feingold kr, anawalt b, boyce a, chrousos g, de herder ww, dhatariya k, et al., eds. endotext. south dartmouth, massachusetts, usa: mdtext.com, 2020. 11. odén a, mccloskey ev, johansson h, kanis ja. assessing the impact of osteoporosis on the burden of hip fractures. calcif tissue int 2013; 92:42–9. https://doi.org/10.1007/s00223-0129666-6. 12. bjelica a, vučaj-ćirilović v, tomašević-todorović s, filipović k. postmenopausal osteoporosis. med pregl 2018; 71:201–5. https://doi.org/10.2298/mpns1806201b. https://doi.org/10.5455/medarh.2017.71.25-28 https://doi.org/10.5455/medarh.2017.71.25-28 https://doi.org/10.24041/ejmr2020.22 https://doi.org/10.24041/ejmr2020.22 https://doi.org/10.1097/md.0000000000008294 https://doi.org/10.1016/b978-0-12-819667-0.00005-6 https://doi.org/10.1016/b978-0-12-819667-0.00005-6 https://doi.org/10.1016/j.archger.2013.02.005 https://doi.org/10.1016/j.archger.2013.02.005 https://doi.org/10.1074/jbc.m116.742452 https://doi.org/10.1074/jbc.m116.742452 https://doi.org/10.4103/2230-8210.83401 https://doi.org/10.1007/s00198-018-4503-z https://doi.org/10.1007/s00198-018-4503-z https://doi.org/10.1007/s00223-012-9666-6 https://doi.org/10.1007/s00223-012-9666-6 https://doi.org/10.2298/mpns1806201b inflammatory markers as a predictor of postmenopausal osteoporosis cross-sectional study from sultan qaboos university hospital 514 | squ medical journal, november 2022, volume 22, issue 4 13. choi mh, yang jh, seo js, kim yj, kang sw. prevalence and diagnosis experience of osteoporosis in postmenopausal women over 50: focusing on socioeconomic factors. plos one 2021; 16:e0248020. https://doi.org/10.1371/journal.pone.0248020. 14. wright nc, looker ac, saag kg, curtis jr, delzell es, randall s, et al. the recent prevalence of osteoporosis and low bone mass in the united states based on bone mineral density at the femoral neck or lumbar spine. j bone miner res 2014; 29:2520–6. https://doi.org/10.1002/jbmr.2269. 15. al-habsi a, kilani h. lifestyles of adult omani women: crosssectional study on physical activity and sedentary behaviour. sultan qaboos univ med j 2015; 15:e257–65. 16. al-kindi mk. vitamin d status in healthy omani women of childbearing age. sultan qaboos univ med j 2011; 11:56–61. 17. ye x, jiang h, wang y, ji y, jiang x. a correlative studies between osteoporosis and blood cell composition: implications for auxiliary diagnosis of osteoporosis. medicine (baltimore) 2020; 99:e20864. https://doi.org/10.1097/md.0000000000020864. 18. yilmaz h, uyfun m, yilmaz ts, namuslu m, inan o, taskin a, et al. neutrophil-lymphocyte ratio may be superior to c-reactive protein for predicting the occurrence of postmenopausal osteoporosis. endocr regul 2014; 48:25–33. https://doi.org/10.4 149/endo_2014_01_25. 19. eroglu s, karatas g. platelet/lymphocyte ratio is an independent predictor for osteoporosis. saudi med j 2019; 40:360–6. https:// doi.org/10.15537/smj.2019.4.24009. 20. lee sh, ryu sy, park j, shin mh, han ma, choi sw. the relationship of neutrophil-lymphocyte ratio and platelet-lympho cyte ratio with bone mineral density in korean postmenopausal women. chonnam med j 2019; 55:150–5. https://doi.org/10.40 68/cmj.2019.55.3.150. 21. fang h, zhang h, wang z, zhou z, li y, lu l. systemic immune inflammation index acts as a novel diagnostic biomarker for postmenopausal osteoporosis and could predict the risk of osteo porotic fracture. j clin lab anal 2020; 34:e23016. https://doi. org/10.1002/jcla.23016. 22. gao k, zhu w, liu w, ma d, li h, yu w, et al. the predictive role of monocyte-to-lymphocyte ratio in osteoporosis patient. medicine (baltimore) 2019; 98:e16793. https://doi.org/10.1097/ md.0000000000016793. 23. jeong y, jeon sr, kim hg, moon jr, lee th, jang jy, et al. the role of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in ulcerative colitis. intest res 2021; 19:62–70. https://doi.org/10.5217/ir.2019.09156. 24. ilesanmi-oyelere bl, schollum l, kuhn-sherlock b, mcconnell m, mros s, coad j, et al. inflammatory markers and bone health in postmenopausal women: a cross-sectional overview. immun ageing 2019; 16:15. https://doi.org/10.1186/s12979-019-0155-x. 25. pietschmann p, mechtcheriakova d, meshcheryakova a, föger-samwald u, ellinger i. immunology of osteoporosis: a mini-review. gerontology 2016; 62:128–37. https://doi. org/10.1159/000431091. 26. barbour ke, lui ly, ensrud ke, hillier ta, leblanc es, ing sw, et al. inflammatory markers and risk of hip fracture in older white women: the study of osteoporotic fractures. j bone and miner res 2014; 29:2057–64. https://doi.org/10.1002/jbmr.2245. 27. bedel c, korkut m, armağan hh. nlr, d-nlr and plr can be affected by many factors. int immunopharmacol 2021; 90:107154. https://doi.org/10.1016/j.intimp.2020.107154. 28. yu xy, li xs, li y, liu t, wang rt. neutrophil-lymphocyte ratio is associated with arterial stiffness in postmenopausal women with osteoporosis. arch gerontol geriatr 2015; 61:76–80. https://doi.org/10.1016/j.archger.2015.03.011. 29. huang c, li s. association of blood neutrophil lymphocyte ratio in the patients with postmenopausal osteoporosis. pak j med sci 2016; 32:762–5. https://doi.org/10.12669/pjms.323.10292. 30. kim ys, han jj, lee j, choi hs, kim jh, lee t. the correlation between bone mineral density/trabecular bone score and body mass index, height, and weight. osteoporos sarcopenia 2017; 3:98–103. https://doi.org/10.1016/j.afos.2017.02.001. 31. shapses sa, sukumar d. bone metabolism in obesity and weight loss. ann rev nutr 2012; 32:287–309. https://doi.org/10.1146/ annurev.nutr.012809.104655. 32. yang d, zhou y, yang c. daytime biological variation of hemato logical parameters in a healthy chinese population. int j lab hematol 2017; 39:e37–40. https://doi.org/10.1111/ijlh.12569. 33. bektas a, schurman sh, sen r, ferrucci l. aging, inflammation and the environment. exp gerontol 2018; 105:10–18. https:// doi.org/10.1016/j.exger.2017.12.015. https://doi.org/10.1371/journal.pone.0248020 https://doi.org/10.1002/jbmr.2269 https://doi.org/10.1097/md.0000000000020864 https://doi.org/10.4149/endo_2014_01_25 https://doi.org/10.4149/endo_2014_01_25 https://doi.org/10.15537/smj.2019.4.24009 https://doi.org/10.15537/smj.2019.4.24009 https://doi.org/10.4068/cmj.2019.55.3.150 https://doi.org/10.4068/cmj.2019.55.3.150 https://doi.org/10.1002/jcla.23016 https://doi.org/10.1002/jcla.23016 https://doi.org/10.1097/md.0000000000016793 https://doi.org/10.1097/md.0000000000016793 https://doi.org/10.5217/ir.2019.09156 https://doi.org/10.1186/s12979-019-0155-x https://doi.org/10.1159/000431091 https://doi.org/10.1159/000431091 https://doi.org/10.1002/jbmr.2245 https://doi.org/10.1016/j.intimp.2020.107154 https://doi.org/10.1016/j.archger.2015.03.011 https://doi.org/10.12669/pjms.323.10292 https://doi.org/10.1016/j.afos.2017.02.001 https://doi.org/10.1146/annurev.nutr.012809.104655 https://doi.org/10.1146/annurev.nutr.012809.104655 https://doi.org/10.1111/ijlh.12569. https://doi.org/10.1016/j.exger.2017.12.015 https://doi.org/10.1016/j.exger.2017.12.015 distribution of arylamine n-acetyltransferase 2 (nat2) genotypes among omanis distribution of arylamine n-acetyltransferase 2 (nat2) genotypes among omanis *musbah o. m. tanira1, mehmet simsek2, khalid al balushi1, khulood al lawatia2 hameedah al barawani2, and riad a. bayoumi2 abstrac t. objective: to determine the genotypes of arylamine n-acetyltransferase (nat2) among 127 unrelated apparently healthy omanis. method: identify the most common known polymorphisms of nat*2 gene namely, g191a, c282t, c341t, c481t, g590a, a803g and g857a using pcr-rflp analysis. results: eleven allele variants (3 alternative) and 30 different genotypes were determined. the commonest alleles were found to be nat*5b, nat2*6a and nat*4 with corresponding frequencies of 0.362, 0.248 and 0.189 respectively. the overall frequency of rapid acetylator alleles was 0.25. conclusion: a new allele variant containing g590a, c282t and t341c polymorphisms was found in one subject (was named nat2*5j). the commonest genotypes were found to be 5b/5b, 5b/6a, 4/5b, 4/6a with frequencies 0.165, 0.157, 0.118, 0.110 and 0.079 respectively. keywords: omani, n-acetyltransferase (nat2), genotyping departments of 1pharmacology and 2biochemistry, college of medicine & health sciences, sultan qaboos university, p o box 35, al khod 123, sultanate of oman. *to whom correspondence should be addressed. email: tanira@squ.edu.om there is ample evidence to support the concept that the inter-ethnic genetic variation may be accountable, at least in part, for the variability in drug response.1,2 genetic polymorphism that may influence a drug’s response may exist in drug metabolizing enzyme genes3,2 and/or drug receptor genes.4,5 drug metabolizing enzyme (dme) polymorphisms play a significant role in determining the outcome of using drugs in therapy and may be a risk factor in some human diseases.6,7,3 genetic polymorphism of n-acetyltransferase (nat) is among the most studied dme polymorphism. nat has two isoenzymes (nat and nat2) that have been identified in humans and animals. both genes are single, intronless protein coding exons with 870 bp open reading frames encoding 290 amino acids protein that exhibit polymorphism.8 in a recent review, hein et al,9 and hein10 presented the most significant information on the molecular genetics and cancer epidemiology of nat. the authors also provided a list of reviews published in the past years, which dealt with this topic. furthermore, they included an updated nomenclature for nat and nat2 based on a consensus system published by vatsis et al11 and the international nat nomenclature committee guidelines.12 a few reports have been published on nat genotyping of arab populations. those available are on egyptians,13 emiratis,14 lebanese,15 and saudis,16,17 all of which are suggestive of different patterns of polymorphism. no information is available on omanis of arab descent in this respect. in this work we present the first report on nat2 genotyping of apparently healthy omani adults. m a t e r i a l s a n d m e t h o d s the research and ethics committee of the college of medicine, sultan qaboos university, approved this study. blood from 27 apparently healthy unrelated nat� tanira et al �� ������ ������� ������ �����nat���������� ��� ���� ���� ������ ���������� ���� ��������� ����� ��������� ���� �������� ���� � ��������:����� :�� ������ �������� ������� ������ �����nat��� ����� ������ ����������� ��� ������ � �����. �������:��� ������� ���� �������� ������� ���� ����� �����g���a, c���t, c���t, c���t g���a, a���g, g���a������� ����� ������ � ��������pcr-rflp .�������:������ �� ����� ������ ���� �� ������� �����nat*�b, nat�*�a ,nat*����� ������ ��������� , �����,������������ ��� .������� ���� ������ ����� ������ ������� ������� ���� ���������� ����������� ��������� ����� �� ������� .������:������� ��� ����� ����� ������ ���� �� ���� ���� ������ ��g���a, c���t ,t���c� ������ ���nat�*�j . �� ����� ����� ������� ������ �����b/�b, �b/�a, �/�b, �/�a���� ������ ��������� ,����� ,����� ,�����,�����. keys squ journal for scientific research: medical sciences 2003 vol 5, no. –2, 9–4 ©sultan qaboos universit y mailto:tanira@squ.edu.om 0 omani adults (males and females; age range 20–30 years) was used. polymer ase chain re ac tion (pcr) amplifying 999 bp segment of nat2* gene sequence genomic dna was obtained from the buffy coat of whole blood samples of subjects by phenol/chloroform extraction. amplification was carried out by pcr using 0.2 µm of oligonucleotide primers, nat-hu 4 (forward primer; 5’-gac att gaa gca tat ttt gaa ag3’) and nat-hu 6 (reverse primer; 5’-gat gaa agt att tga tgt tta gg-3’) described by hickman and sim (99) in a 00 µl mixture of 0.0 m tris buffer (ph 8.3), mgcl2 2.5 m, dntp .25 µm, taq polymerase .25 u, and genomic dna  µl. reagents and mixture were kept on ice during preparation. negative control (dna not added) was used for quality control. amplification conditions were denaturation  cycle at 95°c for 5 min, 35 cycles (94°c 30 sec, 56°c  min, 72°c 2 min), then  cycle 72°c 8 min. amplifying 360 bp and 683 segments from the 999 bp of nat2* gene sequence two other pcrs were performed to amplify 683 bp and 360 bp sequences from the 999 bp product of genomic dna. forward primers ms 34cc-m (5’-cac ctt ctc ctg cag gtg acc cc-3’) and ms 342rc (5’cga caa tgt aat tcc tgc cgt cc-3’) were used respectively. nat hu 6 was the reverse primer in both cases. the nat2 gene amplification product (999 bp) was diluted :00 and used as a template. pcr conditions were similar to the above. the 360 bp fragment was used for t341c polymorphism detection, whereas the 683 bp fragment was used to confirm genotyping as explained below. pcr was performed using hybaid omnigene or perkin elmer system 480. restric tion fr agment length polymorphism (rflp) the presence of polymorphisms g191a, c282t, c481t, g590a, a803g, g857a on nat2 gene was determined by rflp using the restriction endonucleases msp i, fok i, kpn i, taq i, dde i and bam hi respectively. the presence of polymorphism t341c was determined using nco i enzyme as described by simsek et al.18 the method is based on mutagenesis-directed pcr to create an nco i site for the wild-type allele. enzymatic digestion was carried out in a total volume of 5 μl using 0 μl of the nat2 gene amplification product (999 bp), the appropriate restriction enzyme (0 u) and its buffer. distilled water was added to bring the final volume to 5 μl. digestion was carried overnight at 37°c for all enzymes but at 56°c for taq i, under mineral oil. digested dna (0 μl) was separated by electrophoresis on 2% agarose or 0% polyacrylamide gel (90v cm–1 for 90 min or 80 min respectively) with dna molecular size marker. bands were visualised with ethidium bromide and uv transillumination. dna sequencing an amplified 998 bp fragment of nat2 gene from a new variant (5j) was sequenced in both chains (forward and reverse) using the dideoxy termination method on an abi-30 dna sequencer. the sequencing primers utilized were nat hu 4 for the forward sequencing, and nat hu 6 for the reverse. nomencl ature using rflp analysis, the presence/absence of polymorphism(s) in each dna sample was identified. accordingly, the genotype of each subject was determined as per the nat nomenclature scheme published by hein et al.9 and the website (http://www.louisville. edu/medschool/pharmacology/nat.html).19 allelic linkage analysis in 4 dna samples, the detected combination of polymorphisms matched more than one genotype. for these samples, polymorphism linkage analysis was performed to confirm their genotype using method detailed in cascorbi’s et al.20 the details of polymorphisms, and alternative genotypes of these samples are listed in table . reagents were purchased from gibcobrl. taq polymerase was from pharmacia. r e s u l t s the summary of the rflp data, which follows, is presented by the name of enzyme followed by the size of produced fragments (in parentheses), the type of the digested allele and lastly the size of the initial pcr segment size used for rflp. msp i (80 bp and 89 bp, wild allele, 999 bp segment), fok i (269 bp and 9 bp, wild allele; 360 bp segment), kpn i (52 bp and 478 bp, wild allele, 999 bp segment), taq i (359, bp, 244 bp, 226 bp and 70 bp, wild allele, 999 bp segment), dde i (345 bp, 278 bp, 203 bp, 50 bp and 23 bp, mutant allele, 999 bp segment), bam hi (853 bp and 46 bp, wild allele, 999 bp segment) and nco i (98 bp, 36 bp and 23 bp wild allele; 360 bp segment). cutting sites other than polymorphism site were due to the presence of naturally existing nonpolymorphic restriction sites. the latter was found in cases of taq i, dde i and nco i enzymatic digestion. ta n i r a e t a l  table 1. combination of polymorphisms detected in 41 dnas and their nat2* genotypes or alternative genotype among 127 unrelated healthy omani subjects. group number of dnas polymorphisms genotype alternative genotype 1 14 341, 481, 803 nat2*4 / nat2*5b nat2*5a / nat2*12a or nat2*5d/nat2*12c 2 14‡ 282, 590 nat2*4 / nat2*6a nat2*6b / nat2*13 3 4 282, 341, 481, 803 nat2*5b / nat2*13 nat2*5a / nat2*12b 4 3 341, 803 nat2*4 / nat2*5c nat2*5d / nat2*12a 5 3 282, 857 nat2*4 / nat2*7b nat2*7a / nat2*13 6 2 341 (m/m), 481, 803 nat2*5a / nat2*5c nat2*5b / nat2*5d 7 1 341, 381, 803 (m/m) nat2*5b / nat2*12a nat2*5c / nat2*12c note: linkage analysis was performed using cascorbi et al 1995 method. ‡ linkage analysis in these 14 samples could not be performed. all enzymes except dde i cut the wild allele. hence, the presence of the 999 bp fragment (undigested initial pcr product) marked the presence of polymorphisms g191a, c481t and g857a. similarly, a 360 bp fragment indicated the presence of c282t polymorphism. however, for polymorphisms c341t, g590a and a803g, the presence of a 22 bp, 396 bp and 203 bp fragment, respectively, was diagnostic. a new allele variant, containing c282t, t341c, and g590a, was characterized using both automated dna sequencing and two different rflp methods. identical genotyping results were obtained for the c282t and g590a polymorphism by the sequencing and rflp methods. however, the genotyping results at the t341c polymorphic site were different. two independent rflp methods showed presence of a heterozygosity (t/c) at the t341c site, while dna sequencing detected no heterozygosity in this position (mainly t in the forward, and a in the reverse sequencing). the discrepancy about the t341c site is elaborated in the discussion section. the distribution of seven investigated nat2* gene polymorphisms is detailed in table 2. none of the tested alleles was found to contain g191a polymorphism, indicating the absence of this polymorphism in our examined population. all polymorphism distribution was in hardy-weinberg equilibrium. polymorphisms with the highest frequency (0.44) were c341t and a803g whereas the g857a polymorphism was least frequent (0.04) and was found in heterozygote but not in homozygote dnas. polymorphisms c481t, c282t, g590a were found in 39%, 33% and 27% of all alleles, respectively. the allele identification as per hein et al,9 showed that the frequency of various alleles among our studied samples of omanis is as represented in table 3. alleles *5b *6a and *4 (89, 63 and 45 alleles respectively) were repeated in more than 0.78 of the sample size. the least frequent allele was a previously non-reported variant. it contained polymorphisms g590a, c282t and c341t. alleles 5d, 5f, 6c, 6d, 7a and 4 a were not detected. table 4 summarises the frequency of genotype distribution. the commonest genotypes were found to be 5b/5b, 5b/ 6a, and 4/6a (2, 20 and 5 individuals respectively) reflecting the abundance of their alleles in the studied population. d i s c u s s i o n this is the first report on nat2* genotyping of an arab population in which all known seven polymorphisms of this gene have been fully and thoroughly tested. for example, the detection method for polymorphism c481t, which was not previously detected in an arab population, was based on two different complementing rflp procedures.21 also, in a number of samples, direct automated dna sequencing18 confirmed the presence/ absence of some polymorphisms. furthermore, when combination of polymorphisms theoretically matched more than one genotype, further rflp procedures were developed to identify the correct genotype. hence, when hardy-weinberg equation was applied, the number of observed alleles (254) exactly matched the expected number in all polymorphisms except for polymorphisms c282t and c481t where the expected number was 253 and 255 respectively. in complementation to our experimental work, we used the latest published nat2* nomenclature system for allele nomenclature as per the nat website.19 the distribution of polymorphisms in our studied population appears to be similar to that in other ethnically n at 2 g e n o t y p e s i n o m a n i s 2 related arab populations, especially in the neighbouring countries such as the united arab emirates.14 however, no g191a polymorphism (the “african polymorphism”) was found in our group, whereas two individuals having this polymorphism were identified in the uae study. this may be explained by the fact that our omani population was sampled from the “internal” omani region and it was ensured by pedigree experts of the area to have not mixed with other ethnic groups. in addition, we found an allele variant that was not reported in hein et al.9 it contained the following polymorphisms c282t, t341c, and g590a. the suggested name of the new allele, nat2*5j, has been accepted by the nat2 nomenclature committee. the allele has been listed at the nat web site, with a note “the snps on nat2*5j were determined by rflp methods which are indirect”.19 (this note will be removed once a direct approach is applied to identify the snps in the allele.) all three polymorphic changes (c282t, t341c, and g590a) in our new variant were characterized independently both by automated dna sequencing and two different rflp methods. dna sequencing of a 999 bp fragment of the nat2 gene confirmed the genotyping results obtained by rflp methods at the c282t, and g590a sites. however, there was a discrepancy for the genotyping results at the t341c site, where two independent rflp methods detected heterozygosity (t/c) at the 34 site while dna sequencing showed a main peak signal for t and a small peak, less than 0% for c. since the threshold value for heterozygote detection is usually set at 30% in sequencing, the presence of heterozygosity at the t341c site was missed by automated dna sequencing. a similar conflicting result between dna sequencing and rflp methods has recently been described by simsek et al18,21 who showed that two complementary pcr-rflp methods are better than automated dna sequencing for the detection of heterozygotes in the nat2 gene. almost all groups with published work on nat2, subdivide nat2* phenotypes to either “slow” or “rapid” acetylators. however, a third type of acetylators, namely “intermediate” is also mentioned in hein8 and hein et al.9 the genotype/phenotype relationship is thoroughly discussed by these authors. one added evidence to support ta n i r a e t a l table 2. distribution of 7 polymorphisms in the nat2* gene among 127 unrelated healthy omani subjects g191a c282t c341t c481t g590a a803g g857a frequency 0.00 0.33 0.44 0.39 0.27 0.44 0.04 # % # % # % # % # % # % # % w/w 127 100 60 47 42 33 51 40 71 56 44 35 117 92 w/m 0 0 50 39 57 45 53 42 43 34 55 43 10 8 m/m 0 0 17 13 28 22 23 18 13 10 28 22 0 0 # number of polymorphism per dna. % percentage (total may not add up to 100 because figures were rounded to the nearest integer.) * percentage of mutant allele from total alleles, i.e., 254 alleles. table 3. frequency of various nat2* gene allele variants among 127 unrelated healthy omani subjects allele variant predicted phenotype number frequency *4 r 45 0.177 *5a s 8 0.031 *5b s 89 0.350 *5c s 9 0.035 *5e s 1 0.004 *6a s 63 0.248 *6b s 4 0.016 *7b s 10 0.039 *12a r 6 0.024 *12b r 4 0.016 *12c r 3 0.012 *13 r 6 0.024 *5j? s 1 0.004 total 254 1.000 * total value adds up to higher than 1.000 due to rounding to the third decimal point. 3 their view can be lent from an experimental observation reported by cascorbi et al.6 these authors unequivocally showed that individuals carrying a homozygote rapid genotype present with statistically significant higher acetylation capacities than those who are heterozygotes, i.e., slow/rapid genotype. the predicted phenotype in our study was deduced from genotypes as three sub-types of acetylators as adopted from hein et al.9 a slow acetylator was predicted if the genotype was comprised of 2 slow alleles; a rapid acetylator genotype would consist of 2 rapid alleles and an intermediate acetylator would be predicted if its genotype contained one slow and another rapid acetylator alleles. the alleles considered rapid were the wild (nat2*4) ones and those containing polymorphisms c282t (nat2*3) and a803g (nat2*2). all other alleles were considered slow acetylators.6,9 accordingly, the prevalence rate of genotypes (and hence the predicted phenotype) was 0.57, 0.38 and 0.05 for slow, intermediate and rapid acetylators. as mentioned earlier, most published data classify nat2* acetylators into two (slow and rapid) subtypes. having our population classified into three subtypes makes it difficult to compare our nat2* genotype/phenotype prevalence with that of other studies. c o n c l u s i o n our data are in line with the published data from populations of similar ethnic background. however, we detected a new allele variant in one subject whose other allele was found to be nat2*6a. the new allele, nat2*5j, has been accepted by the nat2 nomenclature committee, and listed at the nat web site.19 in addition, from our experience, we suggest a re-visit of all published data on nat2* genotyping and phenotyping in such a way that addresses two issues, first to name alleles according to the latest published nomenclature system9 and second, to re-classify phenotypes as three, rather than two sub-types. this may help in making the published work on nat2* correlating and more efficacious. acknowledgement we would like to acknowledge mr. s. muralitharan, department of biochemistry, sultan qaboos university hospital, for his help in performing a confirmatory sequencing of the new allele variant, nat2*5j. r e f e r e n c e s . evans dap, mcleoud hl, pritchard s, tariq m, mubarak a. ethnic difference in drug response. new directions in pharmacogenetics & ecogenetics conference, university of michigan. ann arbor, october 999. presented by edap. 2. nebert dw. pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? clin genet, 999, 56, 247–258. 3. ingelman-sundberg m, oscarson m, lellan ra. polymorphic human cytochrome p450 for individualised drug treatment. tips, 999, 20, 342–349. 4. liggett sb, wagoner le, craft ll, hornung rw, hoit bd, mcintosh tc, et al. the he 64 ß2–adrenergic receptor polymorphism adversely affect the outcome of congestive heart failure. j clin invest, 999, 62, 534–539. 5. lima jj, thomason db, mohamed mhn, eberle lv, self th, johnson ja. impact of genetic polymorphism of the ß2adrenergic receptor on albuterol bronchodilator pharmacodynamics. clin pharmacol therap, 999, 65, 59–525. 6. cascorbi i, brockmöller j, mrozikiewicz pm, müller a, roots i. arylamine n-acetyltransferase activity in man. drug metab rev, 999, 3, 489–502. n at 2 g e n o t y p e s i n o m a n i s table 4. frequency of various nat2* genotypes among 127 unrelated healthy omani subjects genotype predicted phenotype number‡ frequency 5b/5b s 21 0.165 5b/6a s 20 0.157 4/5b i 15 0.118 4/6a i 14 0.110 6a/6a s 10 0.079 5a/12b i 4 0.031 5b/7b s 4 0.031 4/4 r 3 0.024 4/7b i 3 0.024 5b/5c s 3 0.024 5d/12a i 3 0.024 6a/13 i 2 0.016 6a/6b s 2 0.016 5b/12a i 2 0.016 5b/5d s 2 0.016 5c/6a s 2 0.016 5c/5c s 2 0.016 5c/12c i 2 0.016 total 127 1.000 ‡nat2* genotypes, 4/5a, 4/6b, 4/12a, 4/12c, 4/13, 5a/5a, 5c/6a, 5b/6b, 6b/6b, 5e/6a, 7b/13, 13/13, ?/6a were detected in only 1 subject each (frequency 0.008). i = intermediate; r = rapid; s = slow. 4 7. ingelman-sundberg m. functional consequences of polymorphism of xenobiotic metabolising enzymes. tox lett, 998, 02–03, 55–60. 8. hein dw. n-acetyltransferase genetics and their role in predisposition to aromatic and heterocyclic amine-induced carcinogenesis. tox lett, 2000, 2–3, 349–356. 9. hein dw, doll ma, fretland aj, leff ma, webb sj, xiao gh, et al. molecular genetics and epidemiology of the nat and nat2 acetylation polymorphism. cancer epidemiology, 2000, 9, 29–42. 0. hein dw. molecular genetics and function of nat and nat2: role in aromatic amine metabolism and carcinogenesis. mutat res, 2002, 30, 506–507, 65–77. . vatsis kp, weber ww, bell da, dupret jm, price-evans da, grant dm, hein dw, et al. 995. nomenclature for nacetyltransferase. pharmacogenetics, 995, 5, -7. 2. ilett kf, kadllubar ff, minchin rf. meeting on arylamine nacetyltransferase: synopsis of the workshop on nomenclature, biochemistry, molecular biology, interspecies comparisons, the role in human disease risk. drug metab dispos, 999, 27, 957–959. 3. anwar wa, abdel-rahman sz, el-zein ra, mostafa hm, au ww. genetic polymorphism of gstm, cyp2e and cyp2d6 in egyptian bladder cancer patients. carcinogenesis 996, 7, 923–929. 4. woodhouse nm, qureshi mm, bastaki sma, patel m, abdulrazzaq y, bayoumi r. polymorphic n-acetyltransferase (nat2) genotyping of emiratis. pharmacogenetics, 997, 7, 73–82. 5. dhaini hr, levy gn. arylamine n-acetyltransferase  (nat) genotypes in a lebanese population. pharmacogenetics, 2000, 0, 79–83. 6. evans dap, krahn p, narayanan n. the mephenytoin (cytochrome p450 2c 9) and dextromethorphan (cytochrome p450 2d6) polymorphisms in saudi arabians and filipinos. pharmacogenetics, 995, 5, 64–7. 7. mclellan ra, oscarson m, seidegard j, evans da, ingelman-sundberg m. frequent occurrence of cyp2d6 gene duplication in saudi arabians. pharmacogenetics, 997, 7, 87– 9. 8. simsek m, tanira mom, al-baloushi ka, al-barawani h, lawatia k, bayoumi ral. improved detection of t341c polymorphism in human n-acetyltransferase gene using a two complementary pcr-rflp methods: better than automated dna sequencing for detection of heterozygotes. clin biochem, 2000, 33, 585–588. 9. http://www.louisville.edu/medschool/pharmacology/nat. html. 20. cascorbi i, drakoulis n, brockmöller j, maurer a, sperling k, roots i. arylamine n-acetyltansferase (nat2) polymorphisms and their alleleic linkage in unrelated caucasian individuals: correlation with phenotypic activity. am j hum genetics 995, 57, 58–592. 2. simsek m, tanira om, al-baloushi ka, al-barawani h, lawatia k, bayoumi, ral. a precaution in the detection of heterozygotes by 7 sequencing: comparison of automated dna sequencing and pcr-restriction fragment length polymorphism methods. clin chem, 200, 47, 34–37. ta n i r a e t a l distribution of arylamine n-acetyltransferase 2 (nat2) genotypes among omanis materials and methods polymerase chain reaction (pcr) amplifying 999 bp segment of nat2* gene sequence amplifying 360 bp and 683 segments from the 999 bp of nat2* gene sequence restriction fragment length poly­morphism (rflp) dna sequencing nomenclature allelic linkage analysis results discussion conclusion acknowledgement references 1 submitted 27 may 21 1 revision req. 25 jul 21; revision recd. 12 aug 21 2 accepted 9 sep 21 3 online-first: september 2021 4 doi: https://doi.org/10.18295/squmj.9.2021.138 5 6 progressive dilatation as a successful treatment for y duplication of urethra 7 a case report 8 *akash pati, subrat k. sahoo, bikasha b. tripathy 9 10 department of pediatric surgery, all india institute of medical sciences, bhubaneswar, odisha, 11 india 12 *corresponding author’s e-mail: patiakash.ap@gmail.com 13 14 abstract 15 duplication of urethra is a rare congenital anomaly that has been reported in case reports and 16 case series. a y-shaped urethral duplication is the rarest variant as per the classification 17 suggested and hence lacks a standardized treatment option. we report a case of y-duplication of 18 urethra diagnosed during neonatal age and presented to us at nine years of age. the patient had 19 undegone a vesicostomy at seventh day of life for passing urine per anus and was lost to follow 20 up thereafter. an attempt at disconnection of the duplicated urethral tract to anus after 21 colostomy, at eight years of age had failed. the patient was managed successfully by progressive 22 dilatation of the orthotopic urethra, which required multiple stages, followed by separation of the 23 urethra from the rectum. at three years follow up the patient is continent and asymptomatic. 24 keywords: y duplication of the urethra; padua technique; rectourinary fistula; urethral 25 duplication. 26 27 introduction 28 duplication of the urethra is a rare congenital anomaly of the lower urinary tract, occurring more 29 commonly in males. multiple variants of duplication anomalies have been described for lower 30 urinary tract. duplication of the urethra can occur along with the bladder or in isolation. when it 31 2 affects the urethra alone, it usually occurs in the sagittal plane on a single phallus. several types 32 of anatomic variations in the duplicated urethra have been identified. the accessory urethra may 33 be incomplete or complete, opening in the midline at normotopic, episapdaic, hypospadiac or 34 perineoanal region. there is no standard treatment described for the condition as it is rare. the 35 progressive augmentation by dilating the urethra anterior (padua) technique was used 36 successfully for urethral hypoplasia,1 but promising results have not been described for its use in 37 “y duplication” of urethra. we describe a case, where the padua technique has been used to 38 successfully manage the y duplication of urethra and have discussed the possible reason for our 39 successful outcome. 40 41 case report 42 a nine-year-old male child presented to us with a cutaneous vesicostomy, and right transverse 43 loop colostomy done elsewhere. the child was passing urine per anus at birth, and was unable to 44 pass urine per urethra, for which a vesicostomy was done at seventh day of life. an 45 ultrasonogram of the abdomen done during neonatal age was suggestive of left ectopic kidney in 46 midline, sub umbilical position and healthy right kidney and bladder. following the vesicostomy 47 the patient was lost to follow up. at eight years of age, the patient again presented to a surgeon 48 and had underwent a right transverse colostomy. as per the records, an attempted surgical 49 disconnection between the urethra and anal orifice through the perineal approach had failed. 50 51 at the time of presentation to us, the patient was passing most of the urine per vesicostomy and 52 was occasionally dribbling drops of urine per anus. a small pit-like opening was present on the 53 tip of the glans. the rest of the genitalia and abdominal examination was unremarkable. on 54 digital rectal examination, anal opening of the fistula was palpable anteriorly just inside the anal 55 verge. a functional nuclear imaging revealed a small ectopic kidney in the left lower abdomen, 56 contributing to 23% of total renal function, and there was no morphological or functional 57 abnormality in the right kidney. a voiding cystourethrogram done after blocking the 58 vesicostomy demonstrated a very thin caliber anterior urethra and a normal posterior urethra. the 59 urinary bladder was smooth in outline and of small volume with bilateral grade two 60 vesicoureteric reflux. during micturition, the dye was flowing into the rectum. the distal 61 colostogram was unremarkable. 62 3 63 cystoscopy performed through the vesicostomy revealed a small capacity bladder with a smooth 64 wall. the left ureteric orifice was ectopic, opening medially on the trigone while the right 65 ureteric orifice was orthotopic. bladder neck was regular, and scope could be negotiated through 66 the bladder neck into the posterior urethra. there was a fistulous opening seen in the posterior 67 wall of the posterior urethra distal to the veru. a standard 0.018” straight tip guidewire inserted 68 through the fistulous opening in the posterior urethra was retrieved from the anal canal. 69 70 there was a small pit at the tip of the glans resembling a stenotic meatus. a 0.018” straight 71 flexible tip guidewire introduced through this meatal pit and was retrieved at the stoma of the 72 vesicostomy under guidance of a cystoscope inserted through the vesicostomy. a well lubricated 73 three french gauge (fr) ureteral catheter was inserted over the guidewire smoothly and was 74 retrieved through the vesicostomy. the catheter was left indwelling, with a plan for weekly 75 dilatation. every week, after adequate lubrication, a progressively larger catheter was passed 76 gently over a guidewire and left indwelling as a ring stent. this mode of progressive dilation 77 continued for several weeks until a dilatation of 16 fr was achieved. [figure 1]. a voiding 78 cystourethrogram after blocking the vesicostomy [figure 2 a] was performed which confirmed 79 good caliber of the orthotopic urethra. 80 81 the fistulous connection between the posterior urethra and anal canal was closed via a perineal 82 approach. the perineal body muscles were interposed between the anterior wall of the rectum 83 and the urethra to prevent a recurrence. the colostomy and vesicostomy were reversed after four 84 weeks. postoperatively, the indwelling bladder catheter was kept for ten days and on removal, 85 the patient could pass urine per urethra. the patient was on clean intermittent self-catheterization 86 and a weekly calibration schedule until six months following vesicostomy closure. 87 88 a good urethral caliber was seen on voiding cystourethrogram, performed after closing the 89 vesicostomy and at six months follow up. [figure 2b&c]. uroflowmetry done immediately after 90 the vesicostomy closure had a flow rate of 5ml/sec which increased to 12 ml/sec at six months 91 follow-up and there was no post void residue. at three years follow up, the patient is continent 92 4 with a normal voiding stream. the parents of the patient provided informed consent for 93 publication of this case. 94 95 discussion 96 y duplication of the urethra occurs when the prostatic urethra splits into two channels with one 97 coursing to the glans, and the other more functional one extends ventrally to the perineal area 98 near the anus. less than 50 cases of y duplication of urethra have been described in english 99 literature.2 the orthotopic urethra is characteristically stenotic. this form of aberration is usually 100 associated with other congenital anomalies in the genitourinary and gastrointestinal tract. in the 101 present case described, there was an associated left ectopic kidney with bilateral vesicoureteric 102 reflux. 103 104 being a rare condition there is no standardized method of treatment for the anomaly. several 105 surgeons have mobilised the perineal urethra to the scrotal skin level and laid open the 106 orthotopic stenoptic urethra 3,4. at a second stage they have performed a urethroplasty. singh and 107 rawat have also performed a similar method, but they have completely excised the orthotopic 108 urethra and have tried to reconstruct the neourethra from locally available healthy tissue.5 sinha 109 et al have tried to reinforce the urethra by strips of mucosa from the anterior anorectum.6 110 passerini – glazel et al have successfully managed the orthotopic urethral hypopalasia by 111 padua technique.1 the authors have reported a slow progressive dilatation of the hypoplastic 112 urethra to be successful in 6 out of 8 cases. we have employed the same method of gradual 113 progressive dilatation of anterior urethra in the case of y duplication of the urethra. some 114 authors do not agree with the padua technique of dilatation, as repeated trauma leads to 115 stricture formation and the hypoplastic urethra is not usable.5 lima et al have reported, padua 116 technique, to be ineffective in two cases of y duplication of urethra as both the cases have 117 developed urethral stenosis.7 118 119 the urethra is a distensible structure and probably remains hypoplastic because of the presence 120 of a low-pressure channel to the rectum. as a result, the anterior urethra is not challenged by the 121 voiding pressure and urinary stream and remains hypoplastic in cases with y duplication. the 122 cause of failure of the padua technique, as mentioned by different authors can be summarized 123 5 as multiple injuries to the hypoplastic urethra resulting in stricture. a gentle progressive 124 dilatation is likely to have less trauma on the orthotopic urethra. hence, a smooth progressive 125 dilatation will give a successful result without a stricture of the urethra. the procedure of 126 dilatation is such that the catheter is large enough to fill the lumen of the urethra but not forced.1 127 128 conclusion 129 we could successfully manage the patient using the padua technique described for urethral 130 hypoplasia. the patient had a good urinary stream from the orthotopic meatus and had no post 131 void residue. gentle progression of the dilatation was the key to success. however, more cases 132 of y duplication of urethra should be managed by slow progressive dilatation of the hypoplastic 133 orthotopic urethra before any definite conclusion is formulated. 134 135 authors’ contribution 136 ap conceptualized the report. ap, sks and bbt were involved in data collection and 137 acquisition, preparation of the original manuscript and revision of the manuscript. all authors 138 approved the final version of the manuscript. 139 140 references 141 1. passerini-glazel g, araguna f, chiozza l, artibani w, rabinowitz r, firlit cf. (1998)the 142 p.a.d.u.a. (progressive augmentation by dilating the urethra anterior) procedure for the 143 treatment of severe urethral hypoplasia. journal of urology. 140(5 part 2):1247–9. 144 2. wagner jr, carr mc, bauer sb, et al. congenital posterior urethral perineal fistulae: a unique 145 form of urethral duplication. urology 1996; 48:277 80. 146 3. podesta miguel l., medel ricardo, castera roberto, duarte adolfo c. (1998)urethral 147 duplication in children: surgical treatment and results. journal of urology. 160(5):1830–3. 148 4. wakhlu a, wakhlu ak. (1998)management of h-type urethral duplication. journal of 149 pediatric surgery. 33(8):1238–42. 150 5. singh s, rawat j. y-type urethral duplication in children: management strategy at our 151 center.(2013) j indian assoc pediatr surg. 18(3):100–4. 152 6 6. sinha s, sen s, chacko j, thomas g, karl s, mathai j. (2006)y-duplication of the male 153 urethra: use of anterior anorectal wall for posterior urethral lengthening. ped surgery int. 154 22(6):529–31. 155 7. m. lima, f. destro, m. maffi, d. persichetti proietti, g. ruggeri. (2017)practical and 156 functional classification of the double urethra: a variable, complex and fascinating 157 malformation observed in 20 patients. journal of pediatric urology, 13(1): 42.e1-42.e7 158 159 160 figure1: ring stent (black arrow) of 16 fr kept indwelling passing through orthotopic 161 urethra and exiting through vesicostomy. 162 7 163 figure 2: voiding cystourthrogram done after blocking the vesicostomy (a), immediately 164 after closing the vesicostomy(b) and at 6 months follow up (c). 165 tuberculosis (tb) remains a global public health issue with an estimated 10 million cases reported in 2020 despite international efforts to combat the problem. it remains the leading cause of death from a single infectious agent worldwide and the leading cause of death among people living with hiv.1 the covid-19 pandemic has had a severe impact on tb services such as tb notification and death across many countries which necessitates urgent resource reprioritisation to manage expected tb resurgence.2 the world health organization (who) vision for the post-2015 global tb strategy is “a world free of tb”, also expressed as “zero deaths, disease and suffering due to the disease”. the goal is to end the global tb epidemic by reducing global tb incidence and mortality rates by 80% and 90%, respectively, in 2030 compared to 2015.3 however, despite progress made by the united nations in bringing countries together to set goals and the development of the who end tb strategy, the world is still not on track and efforts are required to amplify and expand the tb curative and preventive treatments to meet upcoming targets.3 oman is a low tb incidence country with an annual incidence rate of less than 7.0 cases per 100,000 in 2020. out of a total population of 4.6 million, 38% are expatriates from south east asia who travel to oman for employment.4 the epidemiology of tb in oman follows that of low incidence countries and active tb is mainly diagnosed in the expatriate community arriving from south east asia as a result of reactivation of latent tb infection (ltbi) acquired in their country of origin.5 the end tb strategy – oman considering the current national incidence rate, oman is positioned to achieve the pre-elimination phase (<1 case per 100,000) by 2035. this requires a reduction in the incident rate of 10% per year and it should take into consideration the risk of importation of active tb cases from high burden countries [figure 1]. such a rate will not be reached unless a new innovative approach is implemented. therefore, oman adopted the end tb strategy aimed at strengthening detection using molecular diagnostics, optimising disease management through a patient-centred approach, focusing on prevention by expanding on ltbi management, promoting community awareness and intensifying research.6 end tb strategic pillars oman launched its national end tb strategy during world tb day on 24th of march 2021, the strategy was endorsed by who as oman is set to be one of the pathfinders for the global tb elimination initiative. in this editorial, we will summarise oman’s end tb strategy and the opportunities and challenges in meeting its targets before 2035. oman’s end tb strategy is articulated into four pillars – detect, treat, prevent and promote. this editorial will highlight key interventions under each pillar we believe to be steps to quality improvement in the tb programme that impact the progression towards end tb targets. p i l l a r 1: d e t e c t tb in expatriates constitutes the majority of tb cases in oman, 68% and 70% in 2019 and 2020, respectively.1 these cases are detected during medical fitness screening for residency. though pre-entry screening is the norm, it does not necessitate ltbi screening. this creates a challenge as the majority of expatriates come from tb endemic countries, such as bangladesh, india, pakistan and philippines, with incidence rates of over 150/100,000.1 in individuals exposed to the disease in their home countries, the risk of reactivation to active tb upon arrival to oman due to many factors such as socioeconomic stress, is increased. in a study conducted in expatriates new to oman in north batinah governorate using interferon gamma reaction assay (igra); 22.4% (30.9% were of african and 21.2% of asian descent) tested positive for directorate general of disease surveillance and control, ministry of health, oman *corresponding author’s e-mail: salabri@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. oman, a pathfinder towards tuberculosis elimination the journey begins fatma al yaquobi and *seif al-abri editorial sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 1–4, epub. 28 feb 22 submitted 29 sep 21 revision req. 1 nov 21; revision recd. 1 dec 21 accepted 19 dec 21 https://doi.org/10.18295/squmj.2.2022.019 https://creativecommons.org/licenses/by-nd/4.0/ oman, a pathfinder towards tuberculosis elimination the journey begins 2 | squ medical journal, february 2022, volume 22, issue 1 ltbi. of these, 24.7% of participants had strong igra positivity defining a sub-population with an increased risk of progression to active disease within two years of arrival.7 many studies have compared tests for detecting ltbi such as the igra and the mantoux test.8 the latest modelling study using oman’s data showed that the use of igra and three months of preventive treatment with rifapentine and isoniazid is the most cost-effective intervention.9 therefore, while the strategy continues to strengthen screening contacts for ltbi, it also aims to identify those who are at an increased chance of reactivation using a mycobacterium tb-specific test. igra is the test best suited as it only requires one visit and can easily be integrated into the migrant screening protocol. oman is considering the implementation of this strategy through a public-private mixed approach under monitoring and governance as part of the fitness testing programme to avoid the load on the healthcare system. such a strategy is thought to break the cycle of sustaining the tb rate in the community. for active tb detection, oman has achieved several milestones in the diagnostic pathway. rapid molecular diagnostic testing was introduced in 2014; initially, it was set-up to confirm acid fast bacilli positive samples and was subsequently introduced to all governorates. the national policy for tb testing was updated so that rapid molecular tests became the initial diagnostic test for all presumptive tb cases. this strategy aims to expand the utilisation of molecular techniques, such as genome sequencing, from its limited use as part of outbreak investigation to routine confirmation tools. in addition, the notification system has been upgraded to an electronic platform to link all presumptive and confirmed cases in government and private health care institutions to treatment facilities and initiate contact tracing. digital surveillance will also allow monitoring and evaluation of all tb programme activities at the governorate and national levels which will ensure achieving the targets of tb elimination such as 100% contact-screening and an over 90% treatment success rate. p i l l a r 2: t r e at given the continuous influx of expatriates to oman from high tb burden countries (600,000 yearly), the risk of importation will continue during their initial years of arrival. ltbi prevalence is probably higher in some migrant populations, which could drive higher active tb incidence within these populations.6 moreover, treatment initiation, follow-up and completion is challenge, especially with this higher number of expatriates. there is more than sufficient evidence that prev entive treatment of ltbi should be part of a comprehen sive and epidemiologically sound strategy for tb elim ination.10 the who has published a recommendation for low incidence countries to consider systematic ltbi testing and treatment in expatriates;11 consequently, many countries have adapted this recommendation for expatriates from high tb endemic countries alongside other high-risk groups. integrating the treatment initiation to the subset of expatriates with positive igra test results (priority for those originating from highly endemic countries) should be undertaken as part of the expansion of the tb programme for ltbi care. a recent systematic review has shown tb prev entive treatment, initiation and completion in expatriates has improved from 2010 to 2020. data from expatriates who tested positive and were initiated on treatment showed that the pooled estimate for the true pro portion of positive ltbi initiated on treatment was 69% and those who completed treatment was 74%.12 the availability of shorter regimens were found to have similar effectiveness to sixto nine-month isoniazid treatments.13,14 based on these concepts, the ltbi management guidelines in oman have been updated to include additional shorter therapy which can improve compliance, reduce complications and figure 1: projected 10% reduction (compared to 2015) in tuberculosis incidence rate (icr) versus actual icr. icr = incidence rate. fatma al yaquobi and seif al-abri editorial | 3 side effects, and ultimately have a positive effect on treatment completion rates. many factors throughout the cascade of care of ltbi management can influence the effectiveness of screening and treatment programmes involving expatriates; therefore, understanding these barriers, to identify where to target interventions to improve the outcome, is essential. regarding an active tb in-hospital treatment approach, although it meets the standards for direct observation therapy (dot), factors such as the cost of hospitalising patients for two months and the risk of the exposure to hospital-acquired pathogens make community dot (cdot) preferred for providing tb care in oman. furthermore, considering the deficiency of hospital beds and isolation rooms for tb, which the covid-19 pandemic illuminated, cdot is the more realistic and achievable approach. the strategy of cdot, while providing universal access to tb care and support within the universal health coverage (uhc) concept, provides social protection and addresses social determinants of tb for expatriates as an important at-risk group. the ministry of health in oman is in the process of establishing a public–private partnership between the government and the private health sector; this includes igra testing of all expatriates on arrival and will link those with igra-positive tests with healthcare institutions to initiate treatment for ltbi under the universal health approach. p i l l a r 3: p r e v e n t ltbi in expatriates will continue to fuel the tb burden in low incidence countries. the stable incidence rate for expatriates and the slow decrease for nationals in the last 10 years potentially reflects the mycobacterium tb transmission from the expatriate population.15 yet, a recent study from europe did not show a clear pattern between tb transmission and immigration. however, a significant positive correlation between migration and tb was seen in germany, italy and norway.16 in oman only close contacts and people living with hiv (plhiv) are currently screened for tb. the rate of ltbi screening in plhiv is improving dramatically and reached 86% in 2020 (unpublished data from national aids programme). therefore, scaling up ltbi screening and prev ention by expanding the at-risk group to healthcare workers and expatriates while strengthening household contacts screening is predicted to reduce the incidence of new active cases especially among expatriates during the first two years of arrival with subsequent reduction of community transmission to the local population. however, the decision to screen should be a decision to treat in order to meet the proposed national incidence target rate. a national policy for screening and vaccination of healthcare workers was issued in february 2021, and the screening and treatment for ltbi has already been rolled out for all healthcare workers including students and subcontractors. to support this intervention, several studies provide strong evidence of the cost effectiveness of screening for ltbi in expatriates arriving from high endemic countries.17,18 p i l l a r 4: p r o m o t e oman’s tb programme database has been maintained in electronic form and used for routine programme evaluation. additionally, several studies have been published addressing the burden of disease and mapping at-risk groups, but the kind of intensified research required to accelerate the process for ending tb are lacking and therefore require strong leadership, including from the governorates as well as financial investment, coordination and collaboration between stakeholders such as the private sector. during the 73rd world health assembly in 2020, member states adopted the global strategy for tb research and innovation to support efforts by governments and partners to accelerate tb research and innovation as well as to improve equitable access to the benefits of research in line with the commitments made in the who end tb strategy.19 another example from oman involves allocation of budgets to fund innovative tb research as a priority in areas such as molecular epidemiology and geospatial data addressing tb transmission between different tb communities in order to stop this cycle and achieve end tb strategy targets. therefore, creating a research-enabling environment and enforcing the priority for budget allocation for tb research and identifying resources is a quality improvement step in the tb programmes by identifying gaps and bridging them with the best evidence-based approach. conclusion oman’s aim is to use this adaptation of the end tb strategy to understand the current gaps in its tb programme at all levels using innovative measures to make a significant shift in tb incidence. this decision relies on a strong political commitment and universal government-funded healthcare coverage and strong surveillance, quality and rational use of medicines, and infection prevention and control. this can be achieved by strengthening the detection using molecular testing, treatment with a patient-centred approach, a focus on prevention (particularly in expatriates ltbi screening oman, a pathfinder towards tuberculosis elimination the journey begins 4 | squ medical journal, february 2022, volume 22, issue 1 using igra) and treatment using a short regimen containing rifamycin alongside the expansion on screening and treatment of at-risk groups. additionally, partnership with other stakeholders including private sector institutions is a crucial step in implementing these strategies to meet tb elimination targets. although the continuous influx of expatriates might challenge these interventions, choosing an appropriate cascade of care in an evidence-based approach through intensifying research and promoting community awareness using innovative and new technology in addition to having a strong monitoring and evaluation system will facilitate a firmer implementation of the strategic plan. this approach will ensure meeting uhc targets by providing quality and equity in tb care and by effective implementation of key interventions of the end tb strategy which would position oman as a pathfinder towards tb elimination and make it a role model for the region and the world. a u t h o r s’ c o n t r i b u t i o n fay and sa-a contributed to the conceptualisation, drafting and editing of the manuscript. both authors approved the final version of the manuscript references 1. world health organization. global tuberculosis report 2020. from: https://www.who.int/publications/i/item/97892400131 31 accessed: dec 2021 2. migliori gb, thong pm, alffenaar jw, denhom j, marina t, alyaquobi f, et al. gauging the impact of the covid-19 pan demic on tuberculosis services: a global study. eur respir j 2021; 58:2101786. https://doi.org/10.1183/13993003.01786-2021. 3. world health organization. the end tb strategy. global strategy and targets for tuberculosis prevention, care and control after 2015. from: https://www.who.int/teams/global-tuberculosisprogramme/the-end-tb-strategy accessed: dec 2021. 4. national center of statistics and information. sultanate of oman. from: https://www.ncsi.gov.om/pages/ncsi.aspx accessed: sep 2021. 5. lönnroth k, mor z, erkens c, bruchfeld j, nathavitharana rr, van der werf mj. tuberculosis in migrants in low-incidence countries: epidemiology and intervention entry points. int j tuberc lung dis 2017; 21:624–36. https://doi.org/10.5588/ ijtld.16.0845. 6. national strategic plan (nsp) for tb elimination. 2021-2025. https://www.moh.gov.om/ar/web/directorate-general-ofdisease-surveillance-control/resources accessed: dec 2021. 7. alyaquobi f, almaqbali aa, al-jardani a, ndunda n, al rawahi b, alabri b, et al. screening migrants from tuberculosis high-endemic countries for latent tuberculosis in oman: a cross sectional cohort analysis . travel med infect dis 2020; 37:101734. https://doi.org/10.1016/j.tmaid.2020.101734. 8. zwerling a, van den hof s, scholten j, cobelens f, menzies d, pai m. interferon-gamma release assays for tuberculosis screening of healthcare workers: a systematic review. thorax 2012; 67:62–70. https://doi.org/10.1136/thx.2010.143180. 9. al abri s, kowada a, yaqoubi f, al khalili s, ndunda n, petersen e. cost-effectiveness of igra/qft-plus for tb screening of migrants in oman. int j infect dis 2020; 92:s72–7. https://doi. org/10.1016/j.ijid.2020.03.010. 10. rangaka mx, cavalcante sc, marais bj, thim s, martinson na, swaminathan s, et al. controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection. lancet 2015; 386:2344–53. https://doi.org/10.1016/s0140-6736(15)00323-2. 11. world health organization. latent tuberculosis infection: updated and consolidated guidelines for programmatic management. from: https://apps.who.int/iris/handle/10665/26 0233 accessed: dec 2021. 12. rustage k, lobe j, hayward se, kristensen kl, margineanu i, stienstra y, et al. initiation and completion of treatment for latent tuberculosis infection in migrants globally: a systematic review and meta-analysis. lancet infect dis 2021; 21:1701–12. https://doi.org/10.1016/s1473-3099(21)00052-9. 13. menzies d, adjobimey m, ruslami r, trajman a, sow o, kim h, et al. four months of rifampin or nine months of isoniazid for latent tuberculosis in adults. n engl j med 2018; 379:440–53. https://doi.org/10.1056/nejmoa1714283. 14. diallo t, adjobimey m, ruslami r, trajman a, sow o, obeng baah j, marks gb, et al. safety and side effects of rifampin versus isoniazid in children. n engl j med 2018; 379:454–63. https://doi.org/10.1056/nejmoa1714284. 15. aldridge rw, zenner d, white pj, williamson ej, muzyamba mc, dhavan p, et al. tuberculosis in migrants moving from highincidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to england, wales and northern ireland. lancet 2016; 388:2510–18. https://doi.org/10.1016/s0140-6736(16)31008-x. 16. boudville da, joshi r, rijkers gt. migration and tuberculosis in europe. j clin tuberc other mycobact dis 2020; 18:100143. https://doi.org/10.1016/j.jctube.2020.100143. 17. abubakar i, drobniewski f, southern j, sitch aj, jackson c, lipman m, et al. prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (uk predict tb): a prospective cohort study. lancet infect dis 2018; 18:1077–87. https://doi.org/10.1016/ s1473-3099(18)30355-4. 18. zenner d, hafezi h, potter j, capone s, matteelli a. effectiveness and cost-effectiveness of screening migrants for active tuber culosis and latent tuberculous infection. int j tuberc lung dis 2017; 21:965–76. https://doi.org/10.5588/ijtld.16.0935. 19. world health organization. 73rd world health assembly decisions 7 august 2020. from: https://reliefweb.int/report/ world/73rd-world-health-assembly-decisions-7-august-2020 accessed: dec 2021. https://doi.org/10.1183/13993003.01786-2021 https://doi.org/10.5588/ijtld.16.0845 https://doi.org/10.5588/ijtld.16.0845 https://doi.org/10.1016/j.tmaid.2020.101734 https://doi.org/10.1136/thx.2010.143180 https://doi.org/10.1016/j.ijid.2020.03.010 https://doi.org/10.1016/j.ijid.2020.03.010 https://doi.org/10.1016/s0140-6736(15)00323-2 https://doi.org/10.1016/s1473-3099(21)00052-9 https://doi.org/10.1056/nejmoa1714283 https://doi.org/10.1056/nejmoa1714284 https://doi.org/10.1016/s0140-6736(16)31008-x https://doi.org/10.1016/j.jctube.2020.100143 https://doi.org/10.1016/s1473-3099(18)30355-4 https://doi.org/10.1016/s1473-3099(18)30355-4 https://doi.org/10.5588/ijtld.16.0935 july 2008.indd st international conference on quality management in health care sultan qaboos university, sultanate of oman 19th 23rd january 2008 sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 245-254 sultan qaboos university© f u t u r e l e a n h o spi ta l s (i n t r o du c t i o n o f t h e c o n c e p t o f l e a n h o s pi ta l s t o g c c) mohamed buheji, itqan management consultancy, oman. it is about time to try to transfer the concept of ‘lean management’ to the gcc. all healthcare organisations are challenged to put performance excellence into practice through being as safe, thorough, productive, cost-effective, efficient and accurate as possible. that is really a challenge and, while many organisations are striving to achieve this goal, how they get there differs a lot from one healthcare organisation to the next. lean management – kaizen – and toyota principles have managed to spread across many world-class hospitals which have tried different means to address the issue of quality-cost-delivery. many projects undertaken in our hospitals fail or do not achieve results because they depend on sustainability, top management commitment, resource availability and staff culture. the good thing about the lean concept is that we can reduce the impact of these factors and still establish the lean processes. we present the principle of lean management in healthcare and how we expect future lean hospitals to look in practice i.e. how they deal with lengthy waiting lists, inefficient processes for discharging inpatients, delayed admissions, bottle necks between urgently needed surgeries, limitations of operating theatres and long waits at the pharmacy, or the challenge of enhancing bed occupancy rates for one day surgery. we will also discuss the importance of mapping and understanding and observing the process through teams. elements of lean thinking were combined with this map to help identify “muda” (a japanese word for waste). to understand which steps were not contributing to timely discharge, aspects of the existing process are categorised as value-added, non-value-added and waste. fa l l s a k e y p e r f o r m a n c e i n d i c at o r phang ah looi, nursing directorate, sultan qaboos university hospital, muscat, oman. falls in healthcare settings are among the serious risk management issues facing the healthcare industry. prevention of falls among patients and residents in acute and long term care healthcare settings requires a multifaceted approach and challenges healthcare providers to create a safe environment. in 2005, the incidence of falls in sultan qaboos university hospital squh was found to be the second highest amongst incidences reported. a survey was done and presented to nursing management in february 2006. a reduction target of reduction in falls by 10% by december 2006 was set and an action plan implemented. a re-survey was carried out in early 2007 and a comparison was done for the years 2006 and 2007. findings revealed a reduction in falls in 2006 by 12.5% compared to 2005. in-depth analysis showed that in 2005 there were 24 falls out of 17,239 total admissions with a percentage of 0.14 % and in 2006 there were 21 falls out of 18,491 total admissions with a percentage of 0.11%. o u t c om e a s a m e a su r e o f q ua l i t y o f c a r e i n o n c o l o g y : s q u h e x pe r i e n c e ikram a burney, mansour s al moundhri, azhar j rizvi, shyam s ganguly, rashid al abri, rafi a ashrafi. departments of medicine, family medicine and public health, and quality management, sultan qaboos university hospital, and college of commerce and economics, sultan qaboos university, muscat, oman. email: ikramburney@hotmail.com measurement of outcomes is increasingly been employed not only in clinical practice but also as an indicator of quality of clinical care. the most commonly measured outcome in oncology practice remains overall survival rate. squh is on road to achieving excellence through quality and has already received iso 9001:2000 certification. in an effort to seek continual improvement, quality measurement exercises have been initiated through out the hospital. the section of medical oncology is an integral part of the department of medicine, and endeavours to promote teaching, research and clinical service in accordance with the vision and mission of the university hospital. herein, we present the overall survival of four of the ten most common cancers diagnosed in the sultanate of oman. these include, in the order of occurrence, non-hodgkin’s lymphoma (nhl), breast cancer, stomach cancer and hodgkin’s lymphoma (hl). the studies were all retrospective in nature. the overall survival was compared with studies both from within the region, and with bench-mark studies. for nhl, with a median follow-up of 8 months, the 2-year survival was 64%; 90% for the low risk, 55% for the intermediate risk, and 15% for the high risk groups according to the international prognostic index (ipi). for hl, the 2-year overall survival was 64% according to the international prognostic factor project (ipfp), the survival was 76% for 0-2 risk factors and 32% for three or more risk factors. for breast cancer, the 5-year survival rate was 67%; were 88%, 75% and 59% for stages i, ii, and iii respectively. for gastric cancer, the 5-year survival rate was 16.5 %; 24% for the non-metastatic group. the long-term outcomes of patients with nhl, hl, breast cancer and gastric cancer are generally comparable with published reports. note: this study was published in full in squmj, vol. 8, issue 1, p. 21-36. available at: www.squ.edu.om/squmj a b s t r a c t s 1 s t i n t e r n at i o n a l c o n f e r e n c e o n q ua l i t y m a n a g e m e n t i n h e a lt h c a r e 246 m o n i t o r i n g c l i n i c a l c a r e w i t h i n d i c at o r s shahnaz wasti, division of obstetrics & gynaecology, royal hospital, muscat, oman. quality improvement is not a goal it is a continuous process and requires planning, control and teamwork. monitoring clinical care with indicators offers an opportunity for improvement in clinical care given to patients. the objective of initiating this programme in the department of obstetrics & gynaecology in khoula hospital was to monitor care in an efficient and systematic manner and to match care with the standards that were set. our aim was to assess the trends and traits of indicators before and after implementation of a specific intervention. indicators were selected from the american college of obstetrics and gynaecology manual of obstetric care. every indicator had a standard against which it was matched. these indicators were presented in the departmental meeting and consensus was obtained regarding implementation of this programme. the programme was initiated in january 2002 and results up to 31 january 2003 are presented. avoidable factors were ascertained, guidelines were reviewed and a plan of management was formulated. main outcome measures were trends of clinical indicators and the effect of educational measures, presentations and discussions on clinical care. improvement in clinical care resulted in the following indicators: 1) in hospital maternal red blood cell transfusion rate; 2) in hospital initiation of antibiotics 24 hours or more so after term vaginal delivery; 3) unplanned readmissions within 14 days of discharge; 4) rate of caesarean section showing an increase; 5) repeat caesarean section rate increased from 17.5% to 20%; 6) post-partum unplanned return to operation theatre or delivery room showing a downward trend; 7) laparoscopic surgery performed during this period monitored with indicators. an effective quality improvement can be established and implemented in a clinical department with existing resources. the observed changes presented were a direct result of monitoring clinical care with indicators on an ongoing basis. commitment to the cause is important. ‘ wa l ki n ’ pat i e n t s a pa r a d i g m s h i f t i n m e e t i n g cu st om e r ne e d s : a st u dy o n pat i e n t s w h o “ wa l k e d i n ” w i t h o u t a pp o i n tm e n t s a n d pat i e n t s w h o d e fau lt e d o n t h e i r a pp o i n tm e n t s bala al-marimutu, nursing services; department of behavioural medicine, sultan qaboos university, muscat, oman and lead auditor quality management department, sultan qaboos university, muscat, oman. the psychiatric outpatients clinic at sultan qaboos university hospital (squh) oman, is a referral clinic and operates on all five weekdays. all new and follow-up patients are given appointment dates for consultations and review, however, the increasing number of patients walkingin without appointments and the high number of patients not attending the clinic as per appointments was causing disruption to the effective implementation of the appointment system where resources could be planned and managed according to expected workload to provide quality patient-care. a 12-month retrospective study was carried to measure the prevalence of patients who ‘walk-in’ for consultation and patients who did not keep their appointments. the objectives were to identify any trend or pattern of patients who ‘walk-in’ without appointments and non-compliant behaviour of patients who did not attend given appointments. the accumulated data could be used to understand and possibly initiate a customer friendly outpatient’s consultation system without compromising on quality customer service. the study was carried from 1 january to 31 december 2006. the study revealed that 33.2% of patients walked-in without prior appointments and 34.4 % patients did not keep their appointments. the number of ‘walk-in’ appears to be related to the number of patients who did not keep their appointments. it is postulated that patients who did not turn-up for the appointments most probably turned up later as walk-ins. psychiatric patients by virtue of their illness do relapse and need immediate interventions to prevent exacerbation of their illness. accommodating ‘walk-in’ patients enables patients to have consultations at their own convenience with little disruptions to their work and social obligations. clinics must meet customer needs or else these patients may default on medication and relapse or may seek alternative care elsewhere. the department of behavioural medicine in squh in initiating a process for accommodating ‘walk-ins’ contributes positively towards meeting customer needs. a paradigm shift amongst health care managers is imminent. r e q u i r e m e n t s o f a dv e r se e v e n t s r e p o rt i n g syst e m : a pat i e n t s a fe t y c h a l l e n ge i n o m a n i h o spi ta l s amr m taman, faculty of medicine, univeristy of cairo, cairo, egypt and quality management consultant, head quarters, ministry of health, oman. reporting adverse events is an essential component of patient safety enhancement. the present cross-sectional study examined the perspectives of physicians and nurses working in two omani hospitals regarding the requirements of reporting adverse events. data were collected using a pre-tested self-administered anonymous questionnaire that included doctors’ and nurses’ opinions regarding the preferred model and requirements of an adverse events reporting system. most respondents (67.65%) confirmed the presence of a reporting system of adverse events in their department. nearly 60% did not accept the anonymous model, whereas the majority (91.5%) preferred the confidential one. most respondents wished the recipient to belong to their own profession and over half (51.4%) admitted that they were reluctant to provide information about adverse events. the highest percentages claimed they did not report adverse events so as not to appear incompetent or incur negative consequences on their future career. most respondents (71.8%) expected to receive a rebuke face to face and be closely watched in the future by their leader if they made an error. the majority of respondents mentioned that it is important to give the patient an expression of regret and an explanation of why the error happened (90.6%) as well as the hospital acknowledging its responsibility. the majority (more than 93%) perceived that it is important to offer support and professional help to colleagues who have been involved in adverse events. nearly two-thirds strongly agreed that their wards are good at learning from errors, whereas about half stated that their wards are careful and thorough when giving information to patients after events. more than half confirmed that the mistake makes them try never to leave risky and demanding tasks to their colleagues or inclines them to change their work, whereas, only 39.6% expressed that it is distressing them. the study recommended confidentiality, protection of reporters and discretionary reporting of adverse events with guidelines, as well as an open and participative climate in which education is emphasised. the hospital should acknowledge its responsibilities and offer support, feedback and professional help to the staff who have been involved in adverse events. 247 a b s t r a c t s tota l q ua l i t y st r at e g y i n h e a lt h c a r e : o m a n e x pe r i e n c e amr m taman, faculty of medicine, university of cairo, cairo, egypt and quality management consultant, head quarters, ministry of health, oman. over the last three decades, the sultanate of oman has achieved exponential strides in health development, reflected in the widely acclaimed rapid improvement in health indicators and the building of a comprehensive modern health infrastructure. however, the challenge facing the omani health system is to sustain its success and continue improvement. therefore, the issue of health care quality assurance/improvement assumed a pivotal importance for future health development prospects and is placed high on the omani ministry of health agenda. the presentation will highlight the practical methodology for establishing quality management systems (qmss) in public healthcare (phc) facilities and the different strategies, challenges and future perspectives of the national quality assurance/improvement program in phc in oman. g u i d e l i n e s f o r tota l q ua l i t y m a n a ge m e n t i n h e a lt h c a r e ali al-qahtani, department of ent, college of medicine, king khalid university, saudi arabia email:saeed1994@hotmail.com quality of healthcare is a concern in any health organisation. quality is defined as best practice or customer satisfaction when the patients get what they need within the available facility. it is a broad management philosophy ensuring quality and leadership commitment which provide the energy and the rationale for the implementation of the process of continuous quality improvement. the quality system has three important areas: system improvement, system control and system development. the main component of each system will be discussed. a quality system is team-work for planning, implementing, monitoring and evaluating what we do in each department. all staff must be consulted and there must be the use of incentive and motivation. quality is detailed procedures requiring top management commitment and system control by job description and policy procedures guidelines based on statistics. benchmarking and self-assessment are important factors to improve the system. a blame free reporting culture should exist. finally, quality is the responsibility of every staff member. h e a lt h c a r e a c c r e d i tat i o n i n a c o r p o r at e o r g a n i sat i o n waleed albedaiwi, national guard health affairs, riyadh, saudi arabia. email: bedaiwiw@ngha.med.sa we have just finished the long trip toward (jci) joint commission international accreditation and achieved this important goal at the national guard health affairs (ngha), saudi arabia (a corporate four hospital, 2,000 bed organisation). this process was full of challenges (systematic i.e. structural, and process challenges) as ngha is uniquely a coprporate organisation rather than a single hospital. the presentation will cover the following topics: experience of a corporate 4 hospital, 2,000 bed organisation in jci accreditation; understanding; structure; process per set of standards/team/function; timeline; other activities. h e a lt h te c h n o l o g y a s se s sm e n t & m a n a ge m e n t i n i r a n ahmad moslemi, ministry of health, tehran, iran. email: ah1mos@yahoo.com in this study, first the definition and history of health technology assessment (hta) and the stages of hta development around the world are explained. then the different uses of hta in healthcare systems are studied. the methodology of hta is explained then a model of hta in medical equipment offered. the following topics are covered: 1. assessment and selection of health technology (a) what is hta? (b) developing stages of hta (c) hta methodology (d) application of hta in different levels of healthcare systems (e) management of health technology (medical equipment management). 2. study methods (a) study specification (b) method of data gathering and analysis. 3. results: review of existing state of selection and use of medical devices; stakeholders in medical devices field; new technologies; model of medical devices acquisition; main participants in acquisition of medical devices; planning and financing. 4. need assessment. 5. selection. 6. safety and performance. 7. standardization. 8. procurement. 9. vendors and supply. 10. importation. 11. installation and commissioning: utilisating quality assurance. training; safety; maintenance and repair. 12. optimized model of hta. 13. conclusion. mu lt i d i s c i pl i n a ry a ppr oa c h t o c r i t i c a l a n a lysi s o f h o spi ta l o u t pat i e n t a pp o i n tm e n t syst e m by u t i l i z i n g i sh i k awa ( fi sh b o n e , c au se e ffe c t) d i a gr a m shakil ahmad, health authority abu dhabi, abu dhabi, united arab emirates. email: shak966@hotmail.com our objective was to analyse critically the outpatient appointment system, identify areas for improvement and recommend solutions to the management. in a hospital, outpatient patient appointments form a significant part of the system. a system may be defined as, “a set of functions or activities within an organisation that work together for the aim of the organisation”. consequently, the main focus of this case study is how a quality tool, ‘cause effect diagram’ is utilised for critical analysis of the outpatient appointment system. a multidisciplinary group (doctor, nurse, receptionist, outpatient department (opd) manager) was formed that brainstormed and used the cause – effect diagram to pursue the following: 1a) problem identification: we analysed the data of customer complaints received at the hospital related to outpatient services and found that 70% of patients complained about the inefficiency of the opd appointment system and were dissatisfied with it; 1b) identification of root causes: after discussion the team agreed to examine six main factors: resources, people, environment, equipment, policies, procedure; 1c) causes identified after identifying the main factors: a detailed brainstorming to discover possible causes related to each factor. 2. results of brainstorming: (a) policies 18 out of 20 policies had not been updated; ambiguous job descriptions resulting in confusion and conflicts etc; (b) procedures, old patient file retrieval system; inadequate queuing system etc; (c) people: training – 8 out of 10 frontline staff were not fully computer literate causing data entry delay; language barriers – 7 out of 10 receptionists knew only arabic resulting in miscommunication, transaction delays between patient and receptionist etc; (d) equipment (lack of addressograph machine; no token system etc; (e) resources: lack of staff (doctors, porters, clerks), lack of sitting space; (f ) environment: housekeeping – no written schedule for cleaning resulted in erratic cleaning and thus the whole place appeared untidy; designated smoking area – none for visitors who smoke, exposing 1 s t i n t e r n at i o n a l c o n f e r e n c e o n q ua l i t y m a n a g e m e n t i n h e a lt h c a r e 248 non-smokers and children to passive smoking; 3. urgent and non-urgent recommendations to the hospital management. 4. conclusion: this study helped to confirm that (a) there were numerous correctable causes plaguing the appointment system; (b) the project was able to achieve its objective of identifying causes using the ishikawa diagram and make evidence-based recommendations; (c) the project proved that the multidisciplinary approach and usage of quality tools can help to improve quality in healthcare and may be used in problem solving for other healthcare issues as well. st r at e gi c m a n a ge m e n t a n d q ua l i t y wafaa h jad, king abdulaziz university hospital, jeddah, saudi arabia. email: wafaa_jad@hotmail.com in pursuit of excellence, today’s managers are challenged to manage and improve the existing system at the same time as rebuilding and renovating towards the future system. this is a difficult, but not impossible, task given pro-active thinking, strategic planning and good managment of their organisations. making the right decisions at the right time is vital. following through on those decisions is the challenge. strategic management, through its different phases, is the right approach for managers to make the right decisions at the proper time (planning ahead), following through on them (operating and measuring performance), and guiding their organisations to success (monitored through the balanced scorecard). in short, ‘strategic management’ is the proper management approach and technique for policymakers, executives, and mangers seeking excellence. ways t o i m pr ov e pat i e n t s a fe t y wafaa h jad, king abdulaziz university hospital, jeddah, saudi arabia. email: wafaa_jad@hotmail.com healthcare providers have always considered the provision of safe patient care essential. now, however, there is an increased emphasis on looking at the processes of care, and how healthcare organisations can identify patient safety risks and reduce the occurrence of medical errors. studies of adverse patient incidents have heightened our awareness of the need to redesign processes to prevent human errors. it is time for organisations to use cognitive ergonomics and increase focus on human factors analysis to make health care services safer for patients. we will focus anther following questions: “how can safety be improved? are there other mistake-proofing techniques? can barriers or safeguards prevent untoward events? where are patients at risk? where to start?” we will also emphasise: everyone has a role in patient safety; proactive and reactive actions to be taken to reduce risk; sharing safety improvement ideas with example of a sentinel event; examining the safety of processes; redesigning the process for safety improvement and how to test the redesigned process. pat i e n t s a fe t y a n d nu r si n g e d u c at i o n girija kalayil, nursing program, sultan qaboos university, muscat, oman. km_girija@yahoo.com the challenge of achieving significant improvements in patient safety is one of the key tasks facing healthcare at the start of the 21st century. patient safety is the foundation of healthcare practice and education internationally. quality education is essential to ensure the continuous provision of safe and competent health professionals entering the workforce. the role of education in creating a safety culture through the inclusion of issues such as human factors theory from the outset of the practitioner preparation programme is explored. a patient safety incident was defined by the national patient safety agency (npsa), in 2004 as, “any unintended or unexpected incident which could have or did lead to harm for one or more patients receiving nhs funded care”. npsa issued a seven steps to patient safety guide: 1. build a safety culture. 2. lead and support your staff. 3. integrate your risk management activity. 4. promote reporting. 5. involve and communicate with patients and the public. 6. learn and share safety lessons. 7. implement solutions to prevent harm. steps 1, 6, 7, are relevant to healthcare education. concerns about the quality and safety of health care have changed practice expectations and created a mandate for change in the preparation of health care professionals. quality and safety education for nurses (qsen) derived 6 core quality and safety competencies as follows: patient-centred care; teamwork and collaboration, evidence-based practice; quality improvement; safety, and informatics. the new emphasis on patient safety demands attention to both individual and system errors. individual errors are of concern regarding nursing education and patient safety. educators are encouraged to engage in a culture shift whereby student error is considered from an education systems perspective. educators and schools are challenged to look within and systematically review how programme structures and processes may be contributing to student error and undermining patient safety. training students by simulation based teaching and objective structured clinical evaluation reduces the risk and assures patient safety. educators must address discontinuities between education and practice. structures and processes for student supervision in clinical learning include: legislation of nursing; regulatory structures within health sectors and educational institutions; communication, collaboration and adequate preparation of staff to supervise students. safe and competent practice is reliant on clearly articulated structures and operationalising processes between the health sector and higher educational institutions that can assist staff and students to meet the requisite standards of practice. i n n ovat i v e q ua l i t y h e a lt h c a r e a c t i v i t y by q ua l i t y i m pr ov e m e n t c om m i t t e e o f a l na h d h a h o spi ta l , o m a n suresh venugopal, al nahdha hospital, muscat, oman. email: sure5155@omantel.net.om the quality improvement committee of al nahdha hospital, oman, conceived and conducted an innovative healthcare activity in 2007. a comprehensive preventive health check up of 100 omani health care personnel from 25 departments/sections of al nahdha hospital for body mass index, blood pressure, fasting blood sugar and cholesterol was done. the results were: 90% of staff tested was between 20 and 40 years of age. twenty-eight % were obese and 30% were overweight; 28% had hypercholesterolemia; 20% had prediabetes and 3% were diabetics; 35% had prehypertension and 10% had hypertension. a synopsis of this study was distributed to the director general, the executive director and all the heads of department. “are you waiting for the first heart attack to change your lifestyle? change your lifestyle today!” was the clear 249 a b s t r a c t s message to all. this innovative activity helped the staff understand the concept that ‘quality of healthcare begins with me’. it also established a feeling (inexplicable in words) that the hospital committee cares for the health of its staff. l e a r n i n g fr om a dv e r se c l i n i c a l o u t c om e s – r o ot c au se a n a lysi s veena paliwal, ministry of health, salalah, oman email: paliwal@omantel.net.om the objectives of the study were to learn from root cause analysis of adverse pregnancy outcome cases and to improve the quality of service and patient safety. the study was done at sultan qaboos hospital, salalah, from may to october 2007. root cause analysis is a part of clinical risk management done in cases of patient complaints, critical events, near misses and poor neonatal out comes or still births. we present the results of important problems over a period of 6 moths where we could make reasonable changes. problems which were studied were either very serious or repetitive. as reported in earlier studies, communication was the biggest factor especially over the weekends. in high risk cases, especially in diabetes with still birth/shoulder dystocia, noncompliance was an important factor. this was dealt with more aggressively by providing dedicated clinic and health educators. wound infection morbidity was dealt with by doctor and staff training in aseptic techniques. management of massive obstetric haemorrhage was dealt with by putting stricter guidelines of blood loss management along with the audit for correct estimation of blood loss. we conclude that vigilance about adverse outcomes gives us feedback on our services. we can learn from our mistakes and take appropriate measures to prevent or dilute their effects on patients’ conditions. this also gives us guidelines to improve services and patient safety. stress is put on team work, good communication and adequate supervision of new or junior doctors. reminders are given to doctors and staff to follow guidelines and to consult senior doctors whenever required. high-quality healthcare requires a balance of risks, benefits, and patients’ preferences, not necessarily rigid adherence to clinical guidelines. te c h n o l o g y i m pa c t o n pat i e n t s a fe t y a n d q ua l i t y i m pr ov e m e n t : o pp o rt u n i t y c o st s ve r su s o pp o rt u n i t i e s l o st rejeanna freij hunter, solumedix management consultancy, abu dhabi, uae. email: rejifreij@solumedix.com opportunity cost is defined as the value of foregone opportunities or alternatives unable to be achieved because of time or money utilised or dedicated towards some other option. ultimately, it is the net balance or total of opportunity costs sustained, either tangible or intangible, in not taking certain opportunities and the costs of making alternative decisions. because of the increased demand on limited resources, healthcare providers are increasingly required to make choices among competing claims. opportunity cost as applied to healthcare also raises the issue of the quality or quantity of life. part of the opportunity cost in resisting investment in technology solutions for healthcare organisations is increased patient safety. how is that measured? number of lives? number of near misses (if they are reported)? the bottom line? the universal existence of patient safety initiatives indicates that patient safety is an issue at the forefront of healthcare organisations and that priority of investment needs to be taken to address it. clear communication and appropriate decision-making among clinical staff often aided by technology and computer systems are crucial elements to delivering the right care to the right patient at the right time. in the 2003 healthcare information and management systems society (himss) patient safety survey, nearly all respondents indicated that technology can address at least one patient safety issue and 93% reported that technology is likely to play a significant role in reducing medication errors. other areas of potential improvement cited included: the reduction of excessive time spent on administrative tasks; the improvement of the quality of care provided, and the increased consistency of care provided. these survey findings support what might be expected in any industry: information technology (it) improves both quality and efficiency. healthcare industry leaders and policy experts report that rapidly adopting information technology is the most effective cure for costly and harmful medical errors and increased patient safety. it is important for healthcare executives to recognise the importance of linking it strategy and patient safety strategies. like clinical expertise, it expertise and the investment in it solutions is required to produce the best patient safety solutions. th e e ffe c t o f d o u b l e c h e c k i n g o f fi l l e d p r e s c r i p t i o n s i n r e d u c i n g p ot e n t i a l d i spe n si n g e r r o r s at o u t pat i e n t p h a r m a c y i n s u lta n qa b o o s un i v e r si t y h o spi ta l , o m a n waiel al-naeem, pharmacy department, squh, muscat, sultanate of oman. email: wadalnaeem@hotmail.com sultan qaboos university hospital (squh) is a government funded tertiary care teaching hospital. outpatient pharmacy dispensing is one of the major activities at the squh pharmacy. it dispenses an average of 350 outpatient prescriptions daily. in 2005, a total of 146,989 prescriptions containing 353,336 items were dispensed to outpatients. it is policy to double check all prepared prescriptions before handing the medications to the patient. the policy’s aims are to minimize dispensing errors, optimise pharmacotherapy and comply with good pharmacy practice. at squh, no previous study had looked into the number and types of dispensing errors detected by the double-checking of filledprescriptions in the outpatient setting and whether there is any association with time of dispensing. this study was part of the continual improvement process in the pharmacy and will be used for educational purposes. the objectives were: 1. to establish data on number and types of potential dispensing errors detected while double checking and identify if there is any relationship between dispensing errors and time of dispensing. 2. to identify the factors leading to dispensing errors and propose solutions. 3. to evaluate the clinical significance of the documented dispensing errors. a four week prospective interventional study was conducted at the outpatient pharmacy in squh from 11 november 11 december 2006. the study included all prescriptions prepared by the pharmacy staff members and found to have a dispensing error. data was captured in the data collection form. two clinical pharmacists independently evaluated the clinical significance. during the study period, 180 potential dispensing errors were discovered. seventy-four percent of theses errors were in adult patients’ prescriptions and 26% in paediatric patients’ prescriptions (<12 years old). seventy-eight percent of the errors took place between 10:00 hr and 14:30 hr. in 34% of the cases, the error was dispensing of inappropriate quantity of medicines to patients. errors due to improper labelling of medicines were found in 15% of the prescriptions. in 11% of the cases, a wrong medicine was prepared, 6% of them were due to similar sounding names and the other 5% were due to similar looking medicines. thirteen percent of the errors were due to dispensing a medicine of a wrong strength. eightyfour percent of the dispensing errors were detected by pharmacists responsible for double checking prescriptions before handing medicines to patients and 16% were detected by pharmacy technicians. the potential clinical significance showed reduced effectiveness in 43% of the cases, 1 s t i n t e r n at i o n a l c o n f e r e n c e o n q ua l i t y m a n a g e m e n t i n h e a lt h c a r e 250 increased toxicity in 27%, reduced effectiveness and/or increased toxicity in 14% and unknown in 16%. the grading of clinical significance showed that the double-checking prevented potential fatality or end organ damage in 2% of the cases and were of major clinical significance in 45%, moderate in 31%, minor in 6% and unknown in 16%. the double-checking of filled-prescriptions led to the correction of prescriptions with different dispensing-related problems. it contributed positively to the quality of pharmacotherapy and also prevented potentially fatal or end-organ damage in 2% of cases. th e e ffe c t i v e n e s s o f e sta b l i sh i n g a pat i e n t s a fe t y c e n t e r i n t h e m i n i st ry o f h e a lt h , s au d i a r a b i a saeed al qahtani, mazaya office for health consultations, riyadh, saudi arabia. email: saeed1994@hotmail.com it is very important to establish a patient safety centre (psc) in saudi arabia to help all hospitals to promote the patient safety concept and reduce medical errors, through submitting sentinel reports. indeed, without a psc, we can not plan for health care services, especially for reducing medical errors. the psc also encourages training, research, continuous quality improvement and communication among hospitals. the target clients in this survey were governmental, private and military hospitals and ministry of health staff. the objectives were: 1. to measure the feasibility of a psc. 2. to find factors that support the patient safety culture in the saudi health care system. 3. to assess the commitment of leadership toward a psc. 4. to find major barriers to prevent the establishment of a psc in the ministry of health. 5. to know the impact of communication among hospitals. 6. to determine the relationship between the types of reporting systems (voluntary, mandatory) and the success of a psc. 7. to find factors that help and sustain the psc structure. 8. to specify a suitable structure for the psc. 9. to determine systematic surveillance for potential hazards through the psc. we used a stratified sample from five regions in saudi arabia in order to receive various suggestions, ideas and comments from different respondents regarding feasibility, appropriate structure and leadership commitment to a psc to reach our goal. the data collection tool was a questionnaire to study the impact of some factors in establishing a psc: 1. staff safety culture. 2. communication among hospitals. 3. chain of command and hiring new staff 4. implementing computerized physician order entry. 5. use of the incident reporting system. many outcomes, comments and recommendations were extracted to help in establishing a psc in saudi arabia such as strengthening communication among health care providers and setting up a database to enhance accurate decision making. d e l i v e r i n g h i gh q ua l i t y c a r e : wh o se r e sp o n si b i l i t y ? rabie’e kayid al-rashdy, armed forces medical services, muscat, oman. email: abukamal@omantel.net.om quality refers to the characteristics of and the pursuit of excellence. excellence, on the other hand, is established by determining whether the outcomes of whatever we do favourably compare to the standards that we set. within healthcare settings, quality is defined as the degree to which the provisions of our health services meet the needs and expectations of our patients and clients. in other words, it is the degree to which the services we offer for the individuals and population increase the likelihood of desired health outcomes and are consistent with current professional knowledge, standards and research evidence. but whose responsibility is it to deliver a high standard of care? is it the government, professional agencies, structure, healthcare organisations, groups or individual healthcare workers? in this presentation, the aim is to define and highlight the importance of high quality care from the perspectives of various stakeholders and to present the role and responsibility of all concerned in the delivery of high standards of care. furthermore, the presentation addresses issues or challenges within omani society that could hinder the delivery of high quality care. m a n a gi n g c h a n ge i n h e a lt h c a r e rashid k al-abri, quality management department, sultan qaboos university hospital, muscat, oman. email: ralabri@hotmail.com one of the key concerns in healthcare management is the management of change. with healthcare professionals obligated to acquire and maintain the necessary professional expertise. change occurs continuously around us. we may want to support it, be indifferent to it, and be passive or participate in it. managing change is about handling the complexity of the process: evaluating, planning and implementing operations, tactics and strategies and making sure that the change is worthwhile and relevant. effective change has been characterized as unfreezing old behaviours, introducing new ones, and re-freezing them. change may be continuous, sporadic, or rare and either predictable or not. the only sustainable competitive advantage today is the ability to change, adapt, and evolve and to do it better than the competition. failure comes from lack of vision and commitment from senior management, limited integration with other systems and processes in the organisation, and ill-conceived implementation plans. employees want to understand why change is happening and how they will be affected. promoting change is both demanding and fatiguing, needing a proactive attitude. bringing about change requires: challenging precedents, persevering against established habits, focussing on key valves and time. organisations will not perform well if they become overly bureaucratic and hierarchical as they will be less flexible, less amenable to change and less likely to empower staff. leaders need to understand the change process, overcome obstacles and cope with chaos in order to have the capability to lead and manage change effectively. leaders should help employees and other stakeholders structure and build effective teams. establishing a clear vision about the direction of the change process as well as measuring and monitoring are key elements for assuring successful change. changes in healthcare practice are welcome if they improve quality and safety, or save money. however, it is important to tailor healthcare delivery to the needs of the local population so awareness programmers and clear communication between the public and the organisation is essential. l e a r n i n g o r g a n i sat i o n a n d h e a lt h c a r e e d u c at i o n rashid k al-abri, intisar m al-hashmi, quality management department, sultan qaboos university hospital, muscat, oman. email: ralabri@hotmail.com the learning organisation is a concept first described by peter senge as an organisation where people continuously learn and enhance their 251 a b s t r a c t s capabilities to create. it consists of five main disciplines; team learning, shared vision, mental models, personal mastery and systems thinking. these disciplines are dynamic and interact with each other. systems thinking is the cornerstone of a true learning organisation and it is describes as the discipline used to implement the disciplines. in a learning organisation, health care education aims to educate their members with up to date knowledge to produce competent and safety conscious personnel who could promote quality in healthcare services. in addition, there are some educational concepts and theoretical models which are of relevance to the learning organisation and can provide a framework for managerial decisions. stages required to achieve the principles of a learning organisation are described in detail. moreover, in a proper culture which supports the learning organisation, members continuously learn to improve the environment and never remain passive recipients note: this study was published in full in squmj, vol. 7, issue 3, p. 207-214. available at: www.squ.edu.om/squmj s q u h j o u r n e y towa r d s a c c r e d i tat i o n yasmeen s al hatimy, quality management department, sultan qaboos university hospital, muscat, oman email: yaz4me2@yahoo.ca sultan qaboos university hospital (squh) is regarded as the sultanate of oman’s model healthcare institution, after having in 2005 been internationally recognised with iso 9001:2000 certification, which stimulated the country’s interest and participation in quality healthcare. it is known as the national leading tertiary teaching hospital in the sultanate of oman. squh aims to provide continual improvement in health service provision and delivery. this presentation explores the preliminary approach squh is taking towards introducing hospital accreditation as a quality improvement approach and how the successful achievement of a certified quality management system (qms) and its contributing factors influence and positively support this process. a n a n a lysi s o f s q u h sta ff p e r c e p t i o n o n i n t r o d u c i n g h o spi ta l a c c r e d i tat i o n yasmeen s al hatimy, quality management department, sultan qaboos university hospital, muscat, oman. email: yaz4me2@yahoo.ca squh is a national leading tertiary teaching hospital in the sultanate of oman, internationally recognised with iso 9001:2000 certification. it is an institution which provides quality patient care, education and research. this paper focuses on the willingness and readiness of squh to consider introducing hospital accreditation. the initial survey questionnaire seeks perceptions of staff (clinicians, administrators, nurses, technicians and top management) to identify the aspects of accreditation that are considered important, timely and relevant to the hospital, and where they may not be. combined with a strengths weaknesses opportunities and threat (swot) analysis drawn up by the quality team, in addition to contextual information, it then analyses the data to decide if or if not squh is willing and prepared to consider introducing hospital accreditation. furthermore, following an accreditation workshop recently held at squh, an additional survey questionnaire attempts to capture the respondents’ view on the reasons for participation, but also what benefits are hoped to be gained by implementing hospital accreditation, as well as anticipated difficulties squh may face. c o n fi d e n t i a l i t y o f pat i e n t s’ i n f o r m at i o n ahmed al-barwani, quality management department, sultan qaboos university hospital, muscat, oman. email: ahbarwani@hotmail.com confidentiality, defined as the principle which protects personal writing and all other personal productions, not against theft and physical appropriation, but against publication in any form, is in reality not the principle of private property, but that of an inviolate personality. duties of confidentiality arise when a person discloses information to another in circumstances where it is reasonable to expect that the information will be held in confidence. protecting patient information is the duty of each individual working in a health organisation, and it is the organisation’s role to set policies to protect the confidentiality of patient information. confidentiality has become as a major aspect in health care organisation because of the following points: a) privacy is the right of individuals to control disclosure of their personal information; b) it is a key element in the quality of a health service; c) it creates trust in the clinical relationship; d) it builds reflect patient satisfaction and trust; e) confidentiality is an ethical concept; f ) data security is an key to quality healthcare. et h i c a l p r i n c i pl e s a ppl i e d t o e l e c t r o n i c pat i e n t r e c o r d s ahmed al-barwani, quality management department, sultan qaboos university hospital, muscat, oman. email: ahbarwani@hotmail.com advances in health care technology have raised big concerns about medical ethics. many discussions were held prior to implementing electronic patient records (epr). some people are in favour of implementing this technology and others are against because of ethical issues. this presentation will draw an attention to the following points: 1.the importance of epr (supporting medical ethics). 2. ethical requirements for implementing epr: a) maintaining confidentiality; b) consumer consent and control of records; c) security and authentication; d) messaging and communication; f ) telecommunications; g) imaging and audio standards; h) protecting integrity; i) ensuring availability; j) demonstrating accountability. 3. recommendations. te l e h e a lt h a s a ne w i n n ovat i o n f o r o m a n jamal al-busaidi, hospital information system, sultan qaboos university hospital, muscat, oman. email: amalsat@squ.edu.om telehealth is an electronic audio-visual contact between a patient and healthcare practitioner relating to the healthcare diagnosis or treatment of the patient. telehealth is a new innovation in healthcare services in the sultanate of oman. the presentation covers anticipated government involvement in supporting telehealth, evaluation efforts to date for such technology and, finally, concerns that need to be addressed in designing an affordable internet-based technology and economic-based framework to evaluate the use and benefit of information and communication technology (internet, mobile phones and wireless communication) especially to rural communities. telehealth could be of major 1 s t i n t e r n at i o n a l c o n f e r e n c e o n q ua l i t y m a n a g e m e n t i n h e a lt h c a r e 252 benefit to oman given the problems of rural areas: limited physical access to primary health care and recruitment and retention of healthcare personnel. pa r a m o u n t i m p o rta n c e o f h e a lt h i n f o r m at i o n syst e m s i n h e a lt h c a r e jamal al-busaidi, health information system, sultan qaboos university hospital, muscat, oman. email: jamalsat@squ.edu.om changes in the demand and supply sides of healthcare information and communications technologies (ict) have been gathering momentum in recent years in most parts of the world and promise to be more vibrant in future. a hospital information system (his) is an organised procedure or method to collect and store data. it can be an electronic (software) system and/or paper based. hospital information systems are the driving force in healthcare organisations. a radical shift in the his market is expected which, according to new research, will result in stronger and more prolonged growth. for example, according to hbs-tekplus consultants in healthcare and it, “the european his market is predicted to grow by a compound annual growth rate of 4.5 percent, from $2.69 billion in 2001 to $3.2 billion in 2005”. the major drivers in the hospital information systems market include: a) the public’s demand for politicians and hospitals to improve healthcare quality; b) hospitals beginning to understand the concept of return on investment; c) his becoming part of a wider healthcare it integration. the success or failure of a new his depends on some components including: change management; failure to take account of the local healthcare culture; understanding the complexity of healthcare processes; staff turn-over; failure to learn lessons from past projects; staff shortages; responsibility of professional staff, etc. a r e v i e w st u dy o f t h e e ffe c t i v e n e s s o f b i om e d i c a l e n gi n e e r i n g sta n da r d s i n i n c r e a si n g pat i e n t s a fe t y abdullah al-hashmi, sultan qaboos university hospital, muscat, oman. biomedical equipment and devices are often identified as contributors to patient safety. a literature review was conducted for the role of biomedical engineering standards in increasing patient safety. implementation of these standards was assessed in critical clinical areas to find out how these standards are contributing to increasing patient safety. this evaluation study indicated a need for further improvement in periodic preventive maintenance programmes, equipment safety standards awareness and introducing error recovery systems. this study highlighted the role of biomedical engineering standards in increasing patient safety. a m o d e l o f i n t e gr at i n g t h e r a d i o l o g y i n f o r m at i o n syst e m a n d c a r d i o l o g y e q u i pm e n t w i t h t h e h o spi ta l i n f o r m at i o n syst e m , b a se d o n a n i n t e gr at i n g h e a lt h c a r e e n t e r pr i se s a ppr oa c h abdullah al-hashmi, sultan qaboos university hospital, muscat, oman. email: amhashmi@squ.edu.om integrating healthcare enterprises (ihe) is an initiative by healthcare professionals and industry to improve the way computer systems in healthcare share information. the ihe approach models were established to integrate radiology and cardiology equipment with the squ hospital information system (his). it was suggested that by using a health level seven (hl7) interface the communication and data transfer between the radiology or cardiology information system and the his is achievable. however the study evaluated the difficulties in implementing such integrations. j o b s at i sfa c t i o n o f h e a lt h c a r e p r o fe s si o n a l s i n o m a n amr m taman, faculty of medicine, cairo, egypt; quality management consultant, ministry of health, muscat, oman. job satisfaction among health care professionals has become a pertinent issue because of its relationship with three major concerns of health administration: absenteeism, turnover and performance. this study aimed to measure the level of job satisfaction of primary healthcare (phc) staff in oman and to determine factors influencing it. a cross sectional study was conducted among phc staff (390 respondents) in two regions in oman. data were collected using a pre-tested, self-administered and anonymous questionnaire sheet that included personal data, overall staff satisfaction with the profession and working in their facility and staff rating of 10 domains of the job: resources, pay, work content, autonomy, supervision, opportunity for advancement, job security, status/prestige, professional relationships and patient relationships. the overall staff satisfaction with their professions was 79.44%. staff satisfaction scores were lower regarding availability of supplies and equipment for their practice (69.28%); pay and incentives (66.9%); opportunity to learn new skills and abilities (66.05%); amount of proper work (64.62%); workload (68.21%); their input in to organisational decisions (70.51%); opportunities for promotion and further studies (58.23%); job security (66.56%) and relationships with patients (68.2%); they expressed higher scores regarding safety and cleanliness of the working environment (80.87%); the importance of their work (85.64%) and status/prestige in belonging to the job (82.65%);the overall job satisfaction scores were significantly higher among nurses than physicians, among expatriates than the nationals, among females, older and married staff and among those who had graduated more than 10 years ago. the following recommendations are suggested to improve job satisfaction: provide the necessary supplies and equipment for proper practice; implement an appointment system in phc facilities to help in managing the workload; ensure administrative support, job security and clinical autonomy; encourage staff input in organisational decisions; provide incentives, recognise and acknowledge good work; and provide the opportunity to learn new skills and abilities and develop basic communication skills to improve provider-user relationships. d i s c u s si o n o n p r a c t i c a l a ppl i c at i o n s o f m e d i c a l i n f o r m at i c s dhananjaya bulathwatta, bukha hospital, ministry of health, musandam, sultanate of oman. email: dbulathwatta@gmail.com this presentation will discuss the pros and cons of using multiuser medical clinic software. this particular interface module, which was created by the presenter, can be used in a private local area network of computers. its use in the fields of medical statistics and its research and 253 a b s t r a c t s economic benefits, data accuracy and durablity and protection of patient privacy will be discussed. a st u dy o n o u t pat i e n t s at i sfa c t i o n at a l na h d h a h o spi ta l , o m a n i n 2 0 0 6 suresh venugopal, nahdha hospital, muscat, oman. email: sure5155@omantel.net.om a study on outpatient satisfaction at al-nahdha hospital, muscat, oman, was conducted by its quality improvement committee in 2006. a total of 500 patients were studied for patient satisfaction from the dermatology, ent, eye, dental and medical outpatient departments (100 each) by way of questionnaires in arabic and english. they were analysed with the epi info software package. the results were as follows: the male to female ratio was almost equal; 62% of patients were in their 20s and 30s; 49% had secondary school education and 13% were uneducated; 55% were employed and almost 45% unemployed (including females and children); 42% of patients waited for less than 29 minutes after the scheduled appointment time; 52% of patients spent 10 minutes or more with doctor; 33% of patients spent between 5 and 9 minutes and the rest less than 5 minutes. there were three main reasons for the visits: a) follow up (28%); b) chronic illness (24%); c) surgery (14%). in conclusion, the total overall patient satisfaction among outpatients was 94% of which 54% were highly satisfied and 40% were satisfied. the two main recommendations to improve patient satisfaction were a further reduction in the waiting time of patients after the scheduled appointment time and an increase in the time spent with doctor, from less than 10 minutes to more than 10 minutes for all patients. c l i n i c a l r i sk m a n a ge m e n t i n o b st e t r i c s veena paliwal, ministry of health, salalah, oman. email: paliwal@omantel.net.om clinical risk management (crm) is one approach to improve the quality of care, which places special emphasis on care episodes with unexpected outcomes where patients may have been harmed or disturbed. this approach to risk management entails doing a detailed study of adverse events to promote reflective practice and improve subsequent care rather than the litigation management approach. obstetrics is the highest risk area and generates the most adverse events. the leading causes of litigation in maternity services are mental handicap, intrapartum stillbirth, erb’s palsy and missed congenital anomalies. risk management can, therefore, be seen as the identification, analysis and control of risk. clinical risk management, if practised, will be useful in giving highest possible quality care. crm includes not only cases with a poor outcome, but also the near miss incidents where, despite good outcomes, more effective clinical management would have prevented a potentially dangerous situation developing in the first place. this strategy helps to change the focus from, “why an error was made” to, “why the relevant procedures did not prevent the error”. a n t i c i pat i n g a n d r e sp o n d i n g t o o b st e t r i c e m e r ge n c i e s veena paliwal, ministry of health, salalah, sultanate of oman email: paliwal@omantel.net.om improving emergency obstetric care is critical to improving global obstetric safety. high quality emergency obstetric care is the most important strategy to reduce global maternal mortality dramatically. in last 10 years, international attention has focused on the importance of medical errors and safety. effective and efficient care is essential for good outcomes and safety. obstetrics has the lowest rate of serious adverse events due to errors (1.5%), but the highest rate of negligent care (38.3%) as seen in the confidential enquiries in to stillbirths and deaths in infancy (cesdi) survey. suboptimal care leads to two thirds of intrapartem foetal deaths. mothers and infants at risk is a global safety issue. the labour room is a complex and dynamic place: highly trained professionals of many disciplines all work in a fast-paced, unpredictable environment. time, critical decision making, team communication and cooperation can make the difference between life and death. quick identification of obstetrical emergencies and a rapid coordinated response is essential to good outcomes. awareness, knowledge, and training for responding to obstetric emergencies is essential for anyone who cares for pregnant women. rapid coordinated teamwork can save lives in obstetrics emergencies. simulation can help to retain and enhance knowledge and skill that are not used frequently, see www.obsafety.org. obstetric emergencies are the leading cause of maternal mortality and morbidity. expect the unexpected. fire drills are recommended to improve effectiveness and efficiency in response to obstetric emergencies. clinical team drills may improve care process, guideline adherence and clinical outcomes. s at i sfa c t i o n s u rv e y o f pat i e n t s at t e n d i n g s u lta n qa b o o s un i v e r si t y h o spi ta l p h a r m a c y, o m a n waiel al-naeem, pharmacy department, sultan qaboos university hospital, muscat, sultanate of oman. email: wadalnaeem@hotmail.com sultan qaboos university hospital (squh) is a government-funded tertiary care teaching hospital. the outpatient pharmacy in squh dispenses an average of 350 prescriptions daily. in the year 2005, a total of 146,989 prescriptions containing 353,336 items were dispensed at the outpatient pharmacy. a 1998 survey showed an 80% patient satisfaction rate. the objectives of this survey were: 1. to assess the patients’ satisfaction rate. 2.to evaluate the clarity of written and verbal information. 3. to identify current strengths and weaknesses. a two week survey was conducted in may 2006 by a structured questionnaire to all patients presenting their prescriptions. a total of 328 filled questionnaires were returned, out of which 316 (96.3%) could be included in the analysis. fifty percent of the participants were male. the age distribution was 63% between 15-35 years and 29% between 36-64 years. the majority (75%) were of secondary school or university level. the analysis showed 92% found that they were treated professionally and respectfully by the pharmacists. twenty one percent of the participants reported they were notified about the approximate waiting time, while 19% reported that this was never done. the pharmacy waiting area was evaluated as comfortable by 64%, not comfortable by 23%. the waiting time in the pharmacy was considered intolerable by 17%, long by 51% and reasonable by 27%. eighty-six percent of the participants said they got information and clear answers to questions about their medications, while 1% said they never got answer to their queries. eighty eight percent reported difficulties in reading the instructions written on the medicines. seventythree percent of the participants reported satisfaction with the pharmacy services. current strengths are professionalism and respectfulness and clarity of written and verbal information. areas needing improvement are: advance notification on waiting time, reducing waiting time 1 s t i n t e r n at i o n a l c o n f e r e n c e o n q ua l i t y m a n a g e m e n t i n h e a lt h c a r e 254 and making waiting area more comfortable. o u t pat i e n t p h a r m a c i st s’ i n t e rv e n t i o n s i n s u lta n qa b o o s un i v e r si t y h o spi ta l , o m a n waiel al-naeem, pharmacy department, sultan qaboos university hospital, muscat, sultanate of oman. email: wadalnaeem@hotmail.com sultan qaboos university hospital (squh) is a government-funded tertiary care teaching hospital. the outpatient pharmacy in squh dispenses an average of 350 prescriptions daily. in the year 2004, a total of 144,807 prescriptions containing 343,222 items were dispensed. through their interventions, pharmacists ensure the accuracy of prescriptions and collaborate with doctors to optimise pharmacotherapy. however, no previous comprehensive study has attempted to determine the number and types of pharmacist interventions in an outpatient setting. a two week prospective interventional study, conducted at outpatient pharmacy in squh in 2004, established data on: 1) number and types of interventions in the outpatient area; 2) time involved in such interventions and 3) clinical significance of the interventions. the study included all prescriptions received at the outpatient pharmacy with an intervention. during the study period 2,475 prescriptions were received, of which 103 required an intervention. in these 103 prescriptions, 201 interventions were made. fifty-one percent of the interventions were administrative and 49% were clinical. in 52% of the administrative interventions the doctor’s contact number was not on the prescriptions and 4% of the prescriptions were without doctor’s signature. seventy-six percent of the clinical interventions were problems in the drug’s regimen and 24% due to the choice of drug. the pharmacist had to call the prescribers in 61% of the cases, another pharmacy colleague in 16%, and to consult the patient in 15%. the prescriptions were corrected and finally dispensed in 83% of the cases. sixty percent of the interventions took < 10minutes, while 17% took > 20 minutes to be solved. the total time spent on interventions during the study period was 39 hours which exceeds the weekly working hours (37 hours) of a full-time pharmacist. the potential clinical significance showed improved effectiveness in 58% of the cases, reduced effectiveness in 2%, avoidance of toxicity in 32%, increased toxicity in 1% and unknown in 7%. the grading of clinical significance showed that interventions prevented potential fatality or end-organ damage in 4% of the cases and were of major clinical significance in 34%, moderate in 48% and detrimental in 1%. pharmacist interventions therefore led to modifications of prescriptions for different drug-related problems and contributed positively to the quality of pharmacotherapy. they prevented potentially fatal or end-organ damage in 4% of the cases. if a pharmacist were posted in clinics, most of these problems could have been averted 76%. l e a r n i n g fr om o u r ow n m i sta k e s : te n ox i c a m a n d ta m ox i fe n badriya al-zadjali, pharmacy department, sultan qaboos university hospital, muscat, sultanate of oman. email: zadjal@squ.edu.om a computer-generated prescription was received in the pharmacy department for a 64 year old female. she was prescribed tenoxicam tablets 20mg once daily. the pharmacy technician prepared the prescription and it was checked and dispensed by another technician. the patient discovered that tenoxicam tablets were missing and tamoxifen tablets 20mg were dispensed instead of tenoxicam. she did not take any of the medications since she was fully aware of her disease, condition and medications and returned them to the pharmacy where the error was corrected. medication error has occurred between tenoxicam and tamoxifen despite their use to treat different conditions and different storage shelves in the pharmacy. from our perspective, the similarities between the names, in addition to similarities in the route of administration, dosage form and dosage quantity may further increase the risk of confusion between tenoxicam and tamoxifen, particularly if healthcare providers are not educated concerning this potential for confusion. clearly, patients with rheumatic disease or breast cancer who mistakenly receive an incorrect medication could experience severe health consequences, in addition to not receiving the appropriate life saving medication. a study reported that 83% of errors are discovered during counselling and corrected before the patient leaves the pharmacy. medication errors caused by similar drug names may result in adverse events that cause harm to the patient, especially when two products have different uses. people who are especially vulnerable are the old, those on polypharmacy or those with concomitant medical conditions. however, few procedures exist to ensure safety. therefore drug appropriate solutions must be identified to reduce the potential for confusion between products with similar names. patient counselling plays an important role in preventing and reducing medication errors. december 2008 no white pages.indd men’s health how to do it sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 362-363 sultan qaboos university© submitted 20th may 2008 in the age of emerging objectification of the male gender, perhaps heralding female he-gemony but yet in patrilineal terrains, there is a consensus that masculinity may be a curse in disguise. consider the headlines: females are outshining males in college entrance examinations and a yobbo is seen as the archetypal source of all social ills. in the medical fraternity, the trend is catching on fast. academic publishers are churning out books on men’s health. the message is becoming clear: modern males are either an endangered species or endangering the status quo of the world. unless rescue measures are undertaken, the consequences will be dire. imagine the world without males? even in matrilineal societies this idea appears to be an alarming proposition. david conrad and alan white have edited men’s health: how to do it. the volume is mantled with the assumption that typical macho cholos, or so called ‘y chromosome owners’ are reluctant to seek care in medical settings. males tend to abhor hospitals, hiding their miseries in vanity. in the final analysis, the inevitable would become inevitable. being both reluctant to introspect and resistant to external pressure, males are in the top of the list of those who fall prey to many types of ill-health. this is testified to by the silent epidemic of male gender related diseases, disabilities and untimely deaths often occurring at tender ages. with various authors contributing to the 16 chapters, conrad and white have produced a ‘dirty hands manual’ offering tips on how to approach males about health and educate them to curb the negative sequelae of their masculine lifestyles. the manual is divided into three parts with ample summary boxes, vignettes and cartoon-like illustrations; reader friendly tables and figures are also available. in the spirit of simplicity, the chapters are embedded with subheadings. some sections are narrated with questions and answers. the first part of the volume comes with a catchy title: “men’s health – what’s it all about?” part two of the book starts with abbreviations that have not cropped up earlier, but still within the spirit of simplicity. some ‘hints’ and ‘warnings’ are highlighted on many pages. fancy titles have not been spared either, including: “erectile dysfunction and male incontinence clinics”, “sex and relationship education in schools with boys”. these chapters are a mishmash of information with antics like ‘anti-bullying work’. the final part, far from being anti-climax, describes the history of men’s health. some tips and personal testimonies on how to be a men’s health worker are vividly chronicled. the impression is given that men’s health should be supplied as a standard manual for health workers. the theme of the volume is obviously orthogonal to arnold schwarzenegger’s image of macho masculinity. like anything in life, there is the other side of the story but, for this volume, it is not hyperbole. the إليها؟ الوصول كيف الرجال صحة وايت واالن كونارد ديفيد املؤلفون: editors: david conrad and alan white publisher: radcliffe publishing, oxford & new york, 2007. no. of pages 180 isbn: 13 9781846191923 orders: http://wwww.radcliffe-oxford.com b o o k r e v i e w b o o k r e v i e w : m e n ’ s h e a lt h h o w t o d o i t ? 363 writing is simple but, like sudoku, one needs to be very attentive to grasp the flow of information. many abbreviations crop up without explanation. despite its practical application, the book overlooks the role of women in the lives of men. therefore it disregards the statement that behind every strong man is a stronger woman. another source of attrition is the explicit ‘medicalisation’ of all that it takes to be a ‘y chromosome owner’. medicalisation is a sociological concept that misconstrues mundane characteristics such as baldness or socially constructed misbehaviours as ‘diseases’ which should naturally call for medical attention. from this perspective, the volume fails to differentiate between social deviance, illness and endowments that are natural to man. isn’t masculinity and all that it entails part and parcel of the y chromosome? but why should the blueprint of masculinity be medicalised? to paraphrase arthur schopenhauer, isn’t struggling with difficulties as natural to a man as grubbing in the ground to a mole? related to medicalisation, there emerges the issue of a self-fulfilling prophecy. as social psychologists would confess, if negative labels are assigned to certain traits of masculinity, even a wrong assumption about a particular event or behaviour can breed itself into a new entity that is consistent with the original faulty assumption. what is often overlooked in this context is that the behaviour of modern day ‘y chromosome owners’ may be deeply rooted in socialisation forces. in many paternalistic societies, boys are differently socialised. in the arab part of the world, daredevil (shuja’a) masculine behaviour is encouraged by society. this view echoes the roman philosopher, marcus cicero’s, notion that “a man’s chief quality is courage”. in such an atmosphere, risk taking or, in its extreme form poor impulse control, is paradoxically intrinsically sanctioned. it is no wonder therefore that men, with their socially patterned risk taking propensities, are likely to succumb to drug addiction and other health risky behaviours. therefore, unless wordsworth’s euphemism, “the child is father of the man” is considered as a part of the equation, all the efforts to curb the dark side of masculinity would likely to end in vain or as empty rhetoric. finally, although the volume should be applauded for its audacity in formulating the protocol for addressing male problems, scant attention is paid to methods of measuring the outcomes of such an undertaking. who should read this book? the authors unabashedly propose that all healthcare professionals, health managers or simply all aspirants in the emerging field of men’s health should read this volume. the strength of this book is that it is a manual filled with anecdotes, cartoons and, for brevity, at the end of each chapter references, an index and appendices are provided to consolidate the message. the manual does not pretend to be anything more than a practical approach to the development and implementation of a men’s health program for the situation in the uk. unlike other previous approaches, the message has ecological validity in that it aims to reach the culprits on their own turf, be it in the tavern or on the football pitch. samir al-adawi department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: adawi@squ.edu.om risk factors for ischaemic stroke in an omani community a case-control study shyam s. ganguly,1 *arunodaya r. gujjar,2 hasina al harthi,1 amal al hashmi,3 sanjay jaju,1 abdulaziz al-mahrezi,1 abdullah r. al-asmi2 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 585–590, epub. 25 nov 21 submitted 18 aug 20 revision req. 28 sep 20; revision recd. 3 nov 20 accepted 28 nov 20 departments of 1family medicine & public health and 2medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3department of neurology, khoula hospital, muscat, oman *corresponding author’s e-mails: arunoday@squ.edu.om and grarunoday@hotmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.043 clinical & basic research abstract: objectives: stroke is recognised as the third most common cause of mortality and it has an increasing incidence in developing countries. recognition and control of risk factors are of prime importance in the prevention of stroke. this study aimed to examine the characteristics of ischaemic stroke (is) patients in oman and quantify its various risk factors using a case-control model. methods: this case-control study was conducted from january 2012 to march 2013 at sultan qaboos university hospital and royal hospital, muscat. adult omani patients with is who were admitted to either hospital were compared to ageand gender-matched controls. demographic factors and frequency of various conventional risk factors were documented. univariate and stepwise multivariate logistic regression analyses were performed to evaluate the risk factors associated with is. results: a total of 255 patients and age-and gender-matched controls were included in this study. the mean age was 62.2 ± 13.2 years and 63.14% were male. most cases (89.02%) were above 45 years of age. cardio-embolism (31.76%) was the commonest mechanism of is. stepwise multiple logistic regression model revealed that family history of stroke was the strongest independent risk factor, followed by hypertension and high-density lipoprotein levels (odds ratio: 10.10, 5.17 and 3.34, respectively; p <0.01 each). conclusion: cardio-embolism was the predominant mechanism of is in this study. family history of stroke, hypertension and reduced high-density lipoprotein were the leading independent risk factors. strong emphasis on screening for risk factors, control of hypertension and lifestyle modification for those with a family history of stroke would be expected to emerge as the major stroke-preventive measures in oman. keywords: ischemic stroke; risk factors; case-control study; oman. advances in knowledge in the context of the rising prevalence of stroke in many developing countries, recognition of the predominant risk factors in a community is of prime importance. in this study, cardio-embolism was observed to be the predominant cause of ischaemic stroke (is) in omani subjects and a family history of stroke, hypertension and dyslipidemia were the most prevalent risk factors. applications to patient care is in omani population shows a significant association with a family history of stroke and hypertension, which are predominant risk factors. since cardio-embolism is a major mechanism of is in oman, investigations to recognise cardiac dysrhythmias and valvular heart diseases should be a routine part of stroke evaluation. preventive measures aimed at reducing the incidence of is in oman should focus on modifiable risk factors such as hypertension, dyslipidaemia and lifestyle modification (e.g. control of smoking and increasing physical activity). the global burden of stroke is increasing despite the declining stroke mortality rates. a more comprehensive approach to primary prevention of stroke, which targets individuals at all levels of risk and is integrated with prevention strategies for other diseases that share common risk factors, is required.1 ischaemic stroke (is) is a heterogeneous multifactorial disorder that is identified by the sudden onset of neurologic deficits secondary to vascular obstruction and its varied manifestations are determined by the location of injury in the brain. while the burden of is is gradually reducing in several developed nations, most developing countries have an increasing incidence. the high domestic and global burden of is makes it an important public health concern.2 stroke-related deaths in oman contribute to approximately 6.58% of the total deaths, with the age-adjusted mortality rate being 39.08 per 100,000. it is the third leading cause of mortality in oman after coronary heart disease and diabetes mellitus.3 oman, similar to the middle eastern population, has a relatively higher load of conditions that predispose one to cardiovascular disease – hypertension, obesity, diabetes mellitus and dyslipidemia.4 preliminary observations from hospital-based stroke registries in oman as well as in the gulf cooperation council (gcc) countries suggest that stroke occurs about risk factors for ischaemic stroke in an omani community a case-control study 586 | squ medical journal, november 2021, volume 21, issue 4 a decade earlier in the omani population when compared to western cohorts.5,6 in this context, it is important to examine the actual risk factors of stroke in this population in order to identify the preventive measures that might need to be pursued with a greater emphasis for the prevention of stroke. to the best of the authors’ knowledge, no study has addressed the prevalence of is or a formal quantification of risk factors associated with is in oman. this hospitalbased study aimed to study the characteristics of is as well as to investigate and quantify the risk factors associated with is among omani patients using a case-control design. methods this prospective, hospital-based case-control study was conducted from january 2012 to march 2013 on omani patients with is who were admitted to two premier hospitals in oman – sultan qaboos university hospital (squh) and royal hospital, muscat. both the hospitals serve as national referral centres for specialised treatment of all types of stroke from all over oman and have similar referral patterns. participants aged ≥18 years who were newly diagnosed with is and admitted to the hospital were recruited as ‘cases’. is was defined as the occurrence of acute focal neurologic deficits due to a vascular insult as confirmed by clinical examination and brain computed tomography and/ or magnetic resonance imaging.7 is subtypes were defined according to the trial of org 10172 in acute stroke treatment (toast) criteria.8 this is a widely used classification with good reliability and high sensitivity and specificity.9 five subtypes of is were recognised: large-artery atherosclerosis, small-vessel disease or lacunar stroke, cardio-embolic stroke (ce), stroke of other defined aetiologies or stroke of other undetermined aetiology.8,10 conditions that mimic is, such as intracerebral haemorrhage, cerebral venous sinus thrombosis, brain tumours and a demyelinating condition, were excluded. the control subjects included patients admitted to the same hospitals with non-medical conditions or for elective non-neurologic surgeries such as hernia and cataracts. none of the controls had a history of stroke according to a detailed documented medical evaluation. the controls were matched for age (±2 years) and gender. the information collected from cases included demographic characteristics, is subtypes, risk factors, medical comorbidities, laboratory tests, duration of hospital admission and outcomes such as death, survived or left against medical advice. face-to-face interviews of admitted subjects or knowledgeable relatives (or telephonic interviews as required) helped to complete any missing information. information obtained from control subjects included demographics and the presence of risk factors. sample sizes for the cases and controls were estimated using the method suggested by schlesselman.11 this study considered the prevalence of hypertension as prime exposure rate in controls as 20% as well as the risk of developing stroke in exposed subjects with an odds ratio (or) of 2.0 with 95% confidence interval (ci) and 80% power; the sample sizes for the cases and controls were estimated at 255 each. the risk factors of is included hypertension, diabetes mellitus, dyslipidaemia, cardiac diseases, family history, smoking, alcohol, physical activity and obesity. conventional definitions of risk factors were used in this study.8,12,13 they can be briefly described as follows: (1) hypertension was defined as systolic blood pressure of ≥140 mmhg and/or diastolic blood pressure of ≥90 mmhg or current use of antihypertensive table 1: baseline and clinical characteristics of ischemic stroke patients in oman (n = 255) characteristic n (%) mean age in years sd 62.2 ± 13.2 gender male 161 (63.14) female 94 (34.86) age group in years 18–45 28 (10.98) 46–65 117 (45.88) >65 110 (43.14) ischaemic stroke sub-type laa 72 (28.24) ce 81 (31.76) ls 61 (23.92) od 6 (2.35) ud 35 (13.73) mortality in hospital prior to discharge 8 (3.14) documented within three months postdischarge 23 (9.02) total 31 (12.16) previous history of tia 37 (14.51) previous history of stroke 91 (35.69) laa = large artery atherosclerosis; ce = cardio-embolism; ls = lacunar stroke ; od = other determined cause ; ud = undetermined cause ; tia = transient ischaemic attack. shyam s. ganguly, arunodaya r. gujjar, hasina al harthi, amal al hashmi, sanjay jaju, abdulaziz al-mahrezi and abdullah r. al-asmi clinical and basic research | 587 medicines; (2) individuals who were on anti-diabetic drugs or had a fasting blood glucose of ≥7.0 mmol/l or a glycated haemoglobin of >6.5 were considered to have diabetes mellitus; (3) dyslipidaemia was defined as the presence of one or more of the following: (a) total cholesterol (tc) ≥5.2 mmol/l; (b) high-density lipoprotein cholesterol (hdl-c) <1.03 mmol/l; (c) low-density lipoprotein cholesterol (ldl-c) ≥3.4 mmol/l; or (d) triglycerides (tg) ≥1.7 mmol/l; (4) cardiac disease was defined as the presence (in the past or currently) of a cardiac condition such as atrial fibrillation, ischaemic heart disease, cardiomyopathy or valvular heart disease, which is considered a risk factor for is; (5) family history of is was recognised when the subject had a first-degree relative (maternal, paternal or sibling) with a diagnosis of stroke; (6) individuals who were not doing regular exercise for at least 20 minutes three times a week were considered as lacking physical exercise; (7) body mass index (bmi) was calculated as weight/height2 (kg/m2) and being overweight meant having a bmi ≥30 kg/m2; and (8) a history of smoking and alcohol consumption history were classified as binary exposure variables based on any use currently or in the past versus never having smoked or consumed alcohol. continuous variables were expressed as means and standard deviations; categorical variables were expressed as numbers and percentages. significant differences between cases and controls for various categorical variables were explored using a chi-square test. the relationships between the different risk factors and the development of stroke were estimated using univariate analysis and expressed in terms of crude ors with their 95% cis. a multivariable logistic regression model was fitted to investigate the association between the significant factors found under the univariate analysis; the adjusted ors with their 95% cis were obtained using a backward conditional multiple logistic regression analysis. the analyses were carried out using statistical package for the social sciences (spss), version 23 (ibm corp., armonk, new york, usa).14 a p value of <0.05 (2-tailed tests) was considered statistically significant. the medical research and ethics committee of the college of medicine and health sciences, sultan qaboos university approved the study. all participants provided their written informed consent prior to participating in the study. results the ratio of males to females among cases was 1.7:1. their ages ranged from 22 to 90 years with a mean of 62.2 ± 13.2 years. male and female patients were comparable in their mean ages (p = 0.54). a majority of the cases (89.02%) were in the age group table 2: prevalence of risk factors of ischaemic stroke and their crude odds ratios among cases of ischaemic stroke and controls in oman (n = 255 each) risk factor n (%) or (95% ci) p value cases controls hypertension 202 (79.22) 108 (42.35) 5.18 (3.50–7.67) <0.001 diabetes mellitus 159 (62.35) 114 (44.7) 2.05 (1.44–2.92) <0.001 dyslipidaemia 173 (67.84) 111 (43.5) 2.73 (1.91–3.93) <0.001 chronic kidney disease 16 (6.27) 13 (5.1) 1.24 (0.58–2.64) 0.566 heart disease 67 (26.27) 30 (11.8) 2.67 (1.66–4.24) <0.001 smoking (n = 210) 69 (27.06) 43 (16.86) 1.84 (1.18–2.87) 0.006 no regular exercise (n = 204) 123 (48.24) 76 (9.80) 2.54 (1.70–3.78) <0.001 alcohol consumption (n = 205) 30 (11.76) 15 (5.88) 2.17 (1.13–4.17) 0.020 bmi of ≥30 in kg/m2 (n = 107) 40 (15.69) 55 (21.57) 1.32 (0.80–2.19) 0.275 family history of stroke (first-degree relatives) (n = 201) 45 (17.65) 7 (2.75) 8.08 (3.54–18.41) <0.001 tc of ≥5.2 in mmol/l (n = 226) 108 (42.35) 80 (31.37) 1.68 (1.15–2.45) 0.007 hdl-c of <1.03 in mmol/l (n = 225) 119 (46.67) 59 (23.14) 3.18 (2.14–4.72) <0.001 ldl-c of ≥3.4 in mmol/l (n = 223) 112 (43.92) 72 (28.24) 2.12 (1.44–3.11) <0.001 tg of ≥1.7 in mmol/l (n = 225) 50 (19.61) 41 (16.08) 1.29 (0.81–2.05) 0.281 or = odds ratio; ci = confidence interval; bmi = body mass index; tc = total cholesterol; hdl-c = high-density lipoprotein cholesterol; ldl-c = low density lipoprotein cholesterol; tg = triglycerides. risk factors for ischaemic stroke in an omani community a case-control study 588 | squ medical journal, november 2021, volume 21, issue 4 above 45 years. a total of 234 (91.76%) patients were recruited from royal hospital and 21 (8.24%) from squh. among patients with is, cardio-embolism was the commonest mechanism (31.76%) followed by large artery atherosclerosis (28.24%) [table 1]. on subgroup analysis, cardio embolic stroke was found to be the predominant subtype among those <65years old (34.50%), followed by stroke due to small artery occlusion in 26.20% of subjects. in contrast, among older patients, large artery atherosclerosis was the main subtype, accounting for 37.30% of the cases. among the cases of is, 14.51% had a history of transient ischaemic attack (tia). the prevalence of tia was 15.00% among males and 16.70% among females with no significant difference (p = 0.73). almost one-third of the patients (35.69%) had a previous history of one or more episodes of stroke. family history of stroke in first-degree relatives was the strongest independent risk factor with an or of 8.08 (95% ci: 3.54–18.41) followed by hypertension with an or of 5.18 (95% ci: 3.50–7.67). decreased levels of hdl-c (or = 3.18; 95% ci: 2.14–4.72) and higher ldl-c (or = 2.12; 95% ci: 1.44–3.11) and tc levels (or = 1.68; 95% ci: 1.15–2.45) were noted among the cases when compared to the controls (p <0.01 each). however, the level of tg was not significantly associated with is (p = 0.28). other risk factors, namely ischaemic heart disease (or = 2.67; 95% ci: 1.66–4.24) and diabetes mellitus (or = 2.05; 95% ci: 1.44–2.92) were also found to be associated with is. among lifestyle practices, lack of physical exercise (or = 2.54; 95% ci: 1.70–3.78), history of alcohol consumption (or = 2.17; 95% ci: 1.13–4.17) and history of smoking (or = 1.84; 95% ci: 1.18–2.87) were observed to be more prevalent among the cases when compared to the control subjects (p <0.05 each) [table 2]. estimation of adjusted ors based on stepwise multiple logistic regression analysis reconfirmed that a family history of stroke (or = 10.10; 95% ci: 3.41–29.98) was the strongest independent risk factor followed by hypertension (or = 5.17; 95% ci: 2.92– 9.14) and hdl-c (or = 3.34; 95% ci: 1.93–5.78; p <0.01 each) [table 3]. discussion stroke is a common non-communicable disease that has a variable profile of risk factors among different communities. the use of a case-control model, as in the current study, is a valid method of exploring the risk factors of stroke and provided an opportunity to quantify the burden of the various risk factors present in patients with stroke compared to controls in terms of or; it is also an inexpensive and easier approach. in contrast, a cross-sectional study would have entailed the study of a larger number of patients but would have provided prevalence measures though with poorer differentiation of the cause-effect relationship. several of the observations in this study were comparable to those present in the recently published literature on is within the region. the mean age of is cases in the current study was similar to that observed in the outcomes in patients with tia and cerebrovascular disease (optic) registry (64.1 ± 10.4 years) and the prevention of cerebrovascular and cardiovascular events of ischaemic origin with terutroban in patients with a history of ischaemic stroke or transient ischaemic attack (perform) study.14 although is due to cardio embolism was more prevalent in the current study compared to the rates reported in other arab studies, the prevalence of heart disease and atrial fibrillation were found to be similar.6,11 large artery stroke is often the more prevalent subtype; however, it had a slightly lower prevalence than ce in the current study.5,6 the most likely reason for this discrepancy may have been sampling bias. most patients with is underwent tests for the identification of a cardio-embolic source (viz. holter study and echocardiography). data also revealed that cardio-embolism had the worst outcomes among is and was associated with a higher fatality. this was also recognised in several earlier studies and this is mainly related to its pathophysiology.15–17 specifically, cardioembolic stroke is often associated with relatively larger infarctions consequent to major vessel occlusion by the thrombus.18 modifiable risk factors play an important role in the development of stroke.19 the prevalence of different risk factors of is varies among populations. the overall prevalence of risk factors in the current study appeared to be similar to those reported by a table 3: results of multiple logistic regression analysis exploring the relationship of ischaemic stroke risk factors in oman factor or (95% ci) p value family history 10.10 (3.41–29.98) <0.001 hypertension 5.17 (2.92–9.14) <0.001 no regular exercise 2.65 (1.56–4.50) <0.001 alcohol consumption 2.28 (0.88–5.91) 0.090 hdl-c 3.34 (1.93–5.78) <0.001 ldl-c 2.96 (1.72–5.09) <0.001 or = odds ratio; ci = confidence interval; hdl-c = high-density lipoprotein cholesterol; ldl-c = low-density lipoprotein cholesterol. shyam s. ganguly, arunodaya r. gujjar, hasina al harthi, amal al hashmi, sanjay jaju, abdulaziz al-mahrezi and abdullah r. al-asmi clinical and basic research | 589 stroke registry cohort from oman as well as in the gcc region.5,6 in agreement with the gcc registry, the current study showed that hypertension and dyslipidaemia had a higher prevalence in is compared to controls.6 hypertension was nearly two times more prevalent among is patients when compared to controls. this exceeds the range reported by other arab countries but is comparable to stroke patients from other asian populations such as pakistan.20 in contrast, though diabetes mellitus was observed to be significantly associated with is on conducting a univariate analysis, it did not emerge as a significant risk factor on conducting a multivariate analysis in this study. a possible reason for this was the overall higher prevalence of diabetes mellitus in the control population as well. this observation could be supported by reports of a relatively high prevalence of diabetes mellitus among adults in oman.21 in the current study, the strongest risk factor for is was observed to be a family history of stroke in first degree relatives, with a proportion nearly similar to that observed in studies from the united arab emirates (20%) and saudi arabia (14.1%).22 the relatively higher proportion of consanguinity in oman may explain this observation.23 this observation may have several implications. the relatively high familial burden of stroke noted in this study may indeed point to specific genetic factors underpinning atherosclerotic disease in the omani population. other possibilities are a stronger genetic predisposition to vascular risk factors such as hypertension or dyslipidaemias, indirectly influencing stroke incidence or, rarely, the prevalence of one or more specific single-gene mutations that are associated with stroke. this observation also suggested that studies utilising a genome-wide analysis involving a significantly large number of families with stroke burden may have a reasonable chance of recognising such factors. indeed, a few large and well-powered genome-wide association study analyses have uncovered significant associations in is.2 the findings of a prospective hospital-based registry that collected data from four arabian gulf countries also supports the concept that is is a poly-aetiologic disease and that race/ethnic differences and genetic factors may be the reasons for the differences between arab and western populations.6 an effort towards exploring the genetic basis of is has been initiated at our centre in the form of genetic analysis of apolipoprotein profile using a case-control design. an ongoing stroke registry also aims to include genetic studies. many factors ranging from differences in physical activity and nutrition patterns to genetic predisposition are likely to contribute to the higher prevalence of diabetes and obesity in this region.24,25 the large, multinational optic registry and perform trial observed the trend of a higher frequency of conventional risk factors for stroke as well as inadequately managed diabetes mellitus, hypertension and tobacco smoking in patients from arab countries.14 though a significantly higher prevalence of diabetes mellitus among is cases was noted in this study, diabetes mellitus and smoking were not found to be important risk factors on conducting a logistic regression analysis. earlier studies have observed a younger age of occurrence of stroke in arab countries.14 while 89.02% of the cases in the present study were in the age group above 45 years, the mean age of is patients was at least a decade less than that reported in western populations. a larger study may be required to provide a plausible explanation for these findings related to diabetes, smoking and younger age among the cases in this study. this study had several limitations. a relatively small number of patients were sourced from two major health care institutions in the country, both located in the same city; this may limit the generalisability of the observations to more distant communities of the country. however, as both institutions serve the same population and have similar referral practices, they were unlikely to recruit different patterns of cases for the study. familial occurrence of stroke could not be explored in detail with regard to patterns of inheritance, relation to risk factors, etc. in addition, patients with tia who were discharged early for outpatient follow-up could not be objectively assessed. while heart disease (inclusive of different conditions) as a risk factor was studied, certain risk factors such as atrial fibrillation or other specific heart diseases were not addressed in this study. further well-designed comparative studies of arabian populations including other ethnic communities are required to explore these concepts. conclusion in the omani population, is was found to have a significant association with a family history of stroke and hypertension, which are the predominant risk factors. since cardio embolism is a major mechanism of is in oman, investigations to recognise cardiac dysrhythmias and valvular heart diseases should be a routine part of stroke evaluation. preventive measures aimed at reducing the incidence of is in oman should focus on modifiable risk factors such as hypertension, dyslipidaemia and lifestyle modification (e.g. for control of smoking, improving physical activity, etc.). further studies that explore the familial burden of stroke in oman with the help of modern genetic risk factors for ischaemic stroke in an omani community a case-control study 590 | squ medical journal, november 2021, volume 21, issue 4 studies may provide an insight into possible genebased interventions for the prevention of stroke as well as other related non-communicable disorders. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was supported by an internal grant (ig/ med/famco/13/01) at sultan qaboos university. a u t h o r s’ c o n t r i b u t i o n ssg and arg conceptualised and designed the study. ssg, arg, ah, am and ara supervised the work. hh developed the proposal and ssg acquired the ethical approval and funding. arg, hh, ah and ara collected the data, while ssg and sj analysed the data. ssg, arg and sj drafted the manuscript, while all authors proofread the article. all authors approved the final version of the manuscript. references 1. hankey gj. stroke. lancet 2017; 389:641–54. https://doi. org/10.1016/s0140-6736(16)30962-x. 2. favate as, younger ds. epidemiology of ischemic stroke. neurol clin 2016; 34:967–80. https://doi.org/10.1016/j.ncl.2016.06.013. 3. world health rankings. oman: life expectancy. from: www. worldlifeexpectancy.com/oman-life-expectancy accessed: sept 2021. 4. ng sw, zaghloul s, ali hi, harrison g, popkin bm. the prevalence and trends of overweight, obesity and nutrition‐ related non-communicable diseases in the arabian gulf states. obes rev 2011; 12:1–13. https://doi.org/10.1111/j.1467-789x.20 10.00750.x. 5. gujjar ar, nandhagopal r, ganguly ss, shoaib r, al-asmi ar. ischemic stroke outcomes in oman: experience of a university hospital based stroke registry. neurol 2017; 88:278. 6. deleu d, inshasi j, akhtar n, ali j, vurgese t, ali s, et al. risk factors, management and outcome of subtypes of ischemic stroke: a stroke registry from the arabian gulf. j neurol sci 2011; 300:142–7. https://doi.org/10.1016/j.jns.2010.08.023. 7. wittenauer r, smith l. ischaemic and hemorrhagic stroke. from: www.who.int/medicines/areas/priority_medicines/bp6_ 6stroke.pdf accessed: nov 2020. 8. adams hp jr, bendixen bh, kappelle lj, biller j, love bb, gordon dl, et al. classification of subtypes of acute ischemic stroke. definitions for use in a multicenter clinical trial. stroke 1993; 24:35–41. https://doi.org/10.1161/01.str.24.1.35. 9. kolominsky-rabas pl, weber m, gefeller o, neundoerfer b, heuschmann pu. epidemiology of ischemic stroke subtypes according to toast criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a populationbased study. stroke 2001; 32:2735–40. https://doi.org/10.1161/ hs1201.100209. 10. zhou h, li jj, wang yj. [the reliability of ischemic stroke subtype classification using the toast criteria]. zhonghua nei ke za zhi 2005; 44:825–7. 11. schlesselman jj. case-control studies. design, conduct, analysis. oxford, uk: university press, 1982. 12. ganguly ss, al-shafaee ma, al-maniri aa. some risk factors for coronary heart disease among omani males: a matched case-control study. sultan qaboos univ med j 2008; 8:45–51. 13. al-riyami a, abdelaty ma, jaju s, morsi m, alkharusi h, al-shekaili w. world health survey 2008. muscat, oman: ministry of health, 2012. 14. abboud h, sissani l, labreuche j, arauz a, bousser mg, bryer a, et al. specificities of ischemic stroke risk factors in arabspeaking countries. cerebrovasc dis 2017; 43:169–77. https:// doi.org/10.1159/000454776. 15. hong ks, lee j, bae hj, lee js, kang dw, yu kh, et al. greater stroke severity predominates over all other factors for the worse outcome of cardioembolic stroke. j stroke cerebrovasc dis 2013; 22:e373–80. https://doi.org/10.1016/j. jstrokecerebrovasdis.2013.04.008. 16. stead lg, gilmore rm, bellolio mf, jain a, rabinstein aa, decker ww, et al. cardioembolic but not other stroke sub types predict mortality independent of stroke severity at presentation. stroke res treat 2011; 2011:281496. https://doi. org/10.4061/2011/281496. 17. grau aj, weimar c, buggle f, heinrich a, goertler m, neumaier s, et al. risk factors, outcome, and treatment in subtypes of ischemic stroke: the german stroke data bank. stroke 2001; 32:2559–66. https://doi.org/10.1161/hs1101.098524. 18. arboix a, alió j. cardioembolic stroke: clinical features, specific cardiac disorders and prognosis. curr cardiol rev 2010; 6:150–61. https://doi.org/10.2174/157340310791658730. 19. world health organization. chronic diseases and their common risk factorsfrom: http://www.who.int/chp/chronic_ disease_report/media/factsheet1.pdf accessed: nov 2020. 20. shah sm, shah sm, khan s, rehman s, khan z, ahmed w, et al. “addressing the impact of stroke risk factors in a case control study in tertiary care hospitals”: a case control study in tertiary care hospitals of peshawar, khyber phukhtoonkhwa (kpk) pakistan. bmc res notes 2013; 6:268. https://doi. org/10.1186/1756-0500-6-268. 21. al-lawati ja, panduranga p, al-shaikh ha, morsi m, mohsin m, khandekar rb, et al. epidemiology of diabetes mellitus in oman: results from two decades of research. sultan qaboos univ med j 2015; 15:e226–33. 22. tadmouri go, nair p, obeid t, al ali mt, al khaja n, hamamy ha. consanguinity and reproductive health among arabs. reprod health 2009; 6:17. https://doi.org/10.1186/17424755-6-17. 23. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571–94. https://doi.org/10.1017/s0021932012000016. 24. rahim hf, sibai a, khader y, hwalla n, fadhil i, alsiyabi h, et al. non-communicable diseases in the arab world. lancet 2014; 383:356–67. https://doi.org/10.1016/s0140-6736(13)62383-1. 25. meyer bf, alsmadi o, wakil s, al-rubeaan k. genetics of type 2 diabetes in arabs: what we know to date. int j diabetes mellit 2009; 1:32–4. https://doi.org/10.1016/j.ijdm.2009.03.003. whole1.indd abstract background: haemoglobinopathies are a major cause of morbidity in the sultanate of oman and premarital screening is being encouraged in order to reduce the number of affected births. the identification of β-thalassaemia carrier status is an essential prerequisite of any screening programme. however, the level of haemoglobin (hb) a2, which is used to detect β-thalassaemia carriers, can be affected by other factors including iron deficiency, concurrent α thalassaemia and the type of dna mutation present. objectives: the following study was undertaken to ascertain if the hb a2 level is an appropriate tool for the identification of β-thalassaemia carriers in the omani population. method: hb a2 was measured by high performance liquid chromatography (hplc) in 60 obligate carriers of β-thalassaemia. 58 subjects had hb a2 levels above 3.5% indicating β-thalassaemia trait. two subjects had slightly lower levels and were found to be iron deficient. after therapy both these subjects’ hb a2 levels increased to above 3.5%. conclusion: in the absence of iron deficiency, hb a2 is an accurate marker for the presence of β-thalassaemia trait in the sultanate of oman. key words: hb a2 , β-thalassaemia trait, sultanate of oman diagnosis of beta-thalassaemia carriers in the sultanate of oman *shahina daar1, david gravell2 sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© in the normal population haemoglobin a2 (α2δ2) is physiologically unimportant as it is present in very small quantities (<3% of total haemoglobin). however, the carrier state for β-thalassaemia is characterised by an increased level of hb a2 above 3.5%, low mean cell volume (mcv) and low mean cell haemoglobin (mch).1 exceptions to this are a group of heterozygotes that may have normal hb a2 levels; these include the ‘silent’ thalassaemias and coinheritance of δ-thalassaemia.2 the mechanism underlying the increase in hb a2 appears to be through increased αδ-dimer formation. in a normal red cell, α chains will preferentially combine with β chains rather than δ chains which are more positively charged; however, in the presence of a reduced quantity of β chains and a relative excess of α chains as found in β-thalassaemia, more hb a2 will be formed.3 beta-thalassaemia heterozygotes are usually clinically asymptomatic. although there is a decrease in β globin gene output, there is very little ineffective erythropoiesis, with the proteolytic mechanisms within the red cell having the capacity to deal with this degree of chain imbalance. thus, in presence of the normal 1 department of haematology, sultan qaboos university, college of medicine and health sciences, p.o.box 35, al-khod, muscat 123, sultanate of oman, 2 department of haematology, sultan qaboos university hospital, p.o.box 35, al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. email: asdoc@omantel.net.om o r i g i n a l s t u d y سلطنة (β-thalassaemia) في ثاالسيميا البيتا حاملي تشخيص عمان قبل ما (غربلة) تقصي تشجيع مت وقد عمان، سلطنة في للمراضة االسباب الرئيسية من (الهيموجلوبني) املقدمة: امراض خضاب الدم امللخص: حال، أية على للتقصي. ألي برنامج جوهري مطلب هو البيتا ثاالسيميا حاملي على التعرف أن بهذه األمراض. املصابني األطفال والدة لتقليل الزواج α) ، ووجود الفا ثاالسيميا احلديد كعوز اخرى بعوامل يتأثر أن ميكن ثاالسيميا ، البيتا حاملي لكشف واملستخدم (hb a٢) الدم خضاب مستوى hb a٢ خضاب الدم مستوى كان ملعرفة فيما إذا هذه الدراسة أجريت dna). ألهدف: ) (دي ان أي) ال في طفرة حالة في thalassemia ) وكذلك ل (hplc) الفعالية عالي خاص حتليل جهاز hb a٢ بواسطة قياس الطريقة: مت عمان. في ثاالسيميا البيتا حاملي على للتعرف مناسبة وسيلة كان واثنني فقط ، ٣٫٥ من مستوى hb a٢ أعلى لديهم كان ١٥٨ شخصا في صفات البيتا ثاالسيميا مت كشف ثاالسيميا. للبيتا مؤكد ١٦٠ حامل يكون عوز احلديد غياب ٣٫٥. اخلالصة: في hb a٢ الى أعلى من مستوى ارتفع العالج، بعد بعوز احلديد. انهما مصابني ذلك واكتشف أقل من لديهم عمان. سلطنة في ثاالسيميا البيتا صفة hb a٢ مؤشرا دقيقا لوجود s h a h i n a d a a r , d av i d g r av e l l 28 complement of α chains, most β-thalassaemia heterozygotes can be diagnosed by an increase in hb a2. however, the presence of coexistent α-thalassaemia could theoretically lower the hb a2 level. the omani population is known to have a high prevalence of α-thalassaemia and a substantial number of the population are carriers of either haemoglobin s or βthalassaemia.4,5 pre-marital screening and counselling are now encouraged. all blood samples at the sultan qaboos university hospital (squh) that have a low mcv and mch are routinely analysed by high performance liquid chromatography (hplc). for these reasons, it is important to know the range of hb a2 among β-thalassaemia carriers in this population and, in particular, to observe if the presence of α-thalassaemia has lowered the levels hb a2 to overlap with the normal range. this study also compared hb a2 levels in β0 and β+ heterozygotes. m e t h o d dna analysis (for beta globin gene mutations and αthalassaemia) had previously been performed on 117 unrelated omani patients with homozygous β thalassaemia being treated at squh in the sultanate of oman.6 for the present study, blood samples from 160 omani obligate carriers (parents of known β-thalassaemia homozygotes) were collected into k edta and analysed by hplc biorad variant, β-thalassaemia ‘short’ programme. the samples included 28 parents heterozygous for hb dhofar (β58 c-g, β29 c-t) a known β-thalassaemia mutation, 86 from parents of patients homozygous for either β0 or β+ mutations and 46 parents of patients who were compound heterozygotes for β0/ β+. 40 of these samples had been previously analysed for the presence of α thalassaemia. ten (25%) had no α-thalassaemia, 14 (35%) had a single gene deletion and 16 (40%) had two alpha genes deleted.7 r e s u l t s 158 of 160 samples from obligate β-thalassaemia carriers, including hb dhofar, had hb a2 levels above 3.5% (mean 4.8%, range 3.6%-6.7%) (figure 1). the two exceptions had hb a2 levels of 3.4%; they were both found to be severely iron deficient and after six months of treatment with haematinics, the hb a2 levels had risen to 3.6% and 3.5% respectively. hb dhofar elutes in the ‘d’ window, very close to hb a2 and raises the baseline of hb a2 resulting in a falsely low reading (figure 2). in these cases an accurate value for hb a2 was obtained by elution after electrophoresis on cellulose acetate. the range of hb a2 in hb dhofar simple heterozygotes was 3.6%-5.5%, (mean 4.5%± 0.47%). of the 160 samples, 69 were from known β+ heterozygotes and 26 from known β0 heterozygotes. of the sixtynine β+ samples, all but two had an hb a2 level above 3.5% (range 3.6%-6.5%); the two exceptions were found to have iron deficiency. the mean level in this group was 4.9% ± 0.65%. the range of hb a2 in the twenty-two β 0 samples was 3.7% 7.1% (mean 4.9% ± 0.62%). mutations no. alleles % total type ivs 1-5 (g-c) 146 62.4 β+ codon 44 –c 26 11.1 β0 hb dhofar (β29 β58) 17 7.3 β+ ivs 1-3 –25bp 14 6.0 β0 619 del 8 3.4 β0 ivs ii –1 (g-a) 7 3.1 β0 218 93.3 β0 the remaining 16 alleles were spread between 10 mutations found in very low frequency, namely, ivs 1-1( g-a) (βo), codon 39 (c-t) (βo), codon 5 –ct (βo), hbe (β+), ivs1-110( g-a) (βo), codon 15 ( g-a) (βo), codon 30 ( g-c) (βo), codon 36/37 -t(βo), codon 37( g-a) (βo), ivs 1-128 ( g-a) (β+) table 1. analysis of β-thalassaemia mutations in omanis (234 alleles from 117 unrelated homozygous beta thalassaemia individuals) d i a g n o s i s o f b e ta -th a l a s s a e m i a c a r r i e r s i n t h e s u lta n at e o f o m a n 29 d i s c u s s i o n a large number of β-thalassaemia mutations have been identified worldwide; some of these result in a total absence of beta globin chain production (β0 mutations) while others cause a variable decrease in beta globin chain production (β+ mutations). in the present study, there was no significant difference in hb a2 levels between the carriers of β+, β0 or hb dhofar. this concurs with the separate findings of investigators who have found that despite the immense heterogeneity of β-thalassaemia mutations, the level of hb a2 in heterozygotes is remarkably similar. huisman analysed data from six hundred β-thalassaemia heterozygotes and found hb a2 levels to be between 4.5% and 5.5% in persons with β0 or severe β+ thalassaemia and between 3.6% and 4.2% in those with milder mutations.2 altay and gurgey obtained similar data from turkish individuals.8 it is only when very mild β+ alleles are present that the hb a2 level may drop. other than the single allele of hb e, (which poses no diagnostic difficulty), none of the mutations thus far identified in the sultanate can be classified as mild table 1.6 however, it should be noted that our studies have all been hospital based; there may be a number of milder beta thalassaemia mutations in the general population that have yet to be identified. a complicating issue in the accurate identification of β-thalassaemia trait is that the coexistence of iron deficiency may suppress the level of hb a2 leading to misdiagnosis. the association of iron deficiency with lowered hb a2 is not a constant finding. wasi et al 9 describe normal levels of hb a2 in β-thalassaemia trait individuals who were also iron deficient but alperin et al10 found that the more severe the anaemia the lower the hb a2 level. in contrast, madan found the mean hb a2 to be significantly higher in those patients with iron deficiency anaemia than in those without in a group of indian β-thalassaemia heterozygotes.11 our results suggest that iron deficiency lowers the hb a2 level in some individuals. the effect of concurrent α-thalassaemia on hb a2 is also a potential pitfall in the diagnosis of the β-thalassaemia carrier state, as in parts of the world where βthalassaemia is found, α-thalassaemia is often present in high prevalence.12-14 martinez and menendez have shown that lower amounts of hb a2 may be formed when the supply of α chains is limited15 but a recent study in singapore has shown that routine haematological tests can confirm β-thalassaemia carrier status in the simultaneous presence of α and β-thalassaemia.16 in addition, the results of a study in sardinian children conducted by galanello et al showed that when αthalassaemia coexists with β-thalassaemia, although the mean cellular volume (mcv) and mean cellular haemoglobin (mch) in heterozygote β-thalassaemics may fall within the normal range, the levels of hb a2 are always increased compared to the normal.17 thus, in regions where both α and β-thalassaemia are prevalent the diagnosis of heterozygous β-thalassaemia should not be excluded on the basis of normal indices figure 1. hb a2 in oblgate β-thalassaemia carriers s h a h i n a d a a r , d av i d g r av e l l 30 and hb a2 must always be evaluated. statistically, at least 75% of omanis are expected to have either single gene or two-gene deletional αthalassaemia.4 the same ratio was found in a study group of omani thalassaemia major patients, with 36% having no α-thalassaemia, 32% having a single alpha gene deletion and 32% having two alpha genes deleted.7 a smaller study of 40 of the obligate carriers showed 10 (25%) to have no α-thalassaemia, 14 (35%) with a single gene deletion and 16 (40%) with two alpha gene deletion. the results of the present study show that, other than the two carriers with iron deficiency, all the obligate carriers had hb a2 levels over the diagnostic range for β-thalassaemia trait. c o n c l u s i o n for the purposes of genetic screening and premarital counselling it is reassuring to find that, despite the high prevalence of α-thalassaemia in the omani population, the levels of hb a2 in β-thalassaemia carriers are above the normal range and that β-thalassaemia trait in omanis can be diagnosed by the presence of hb a2 equal to or above 3.5% as long as there is no concomitant iron deficiency. in order to minimise false negatives, all individuals with hb a2 of 3.3%-3.4%, or who have anemia, should be screened for iron deficiency; if this is present, the hb a2 level should be repeated after adequate treatment with hematinics. r e f e r e n c e s 1. kunkel hg, ceppellini r, muller-eberhard u, et al. observations on the minor basic hemoglobin component in the blood of normal individuals and patients with thalassemia. j clin invest 1957; 36: 1615-1625. 2. huisman t. levels of hba2 in heterozygotes and homozygotes for beta-thalassemia mutations: influence of mutations in the caccc and ataaa motifs of the beta-globin gene promoter. acta haematol 1997; 98: 187-194. 3. steinberg mh, adams jg iii. hemoglobin a2: origin, evolution, and aftermath. blood 1991; 78: 2165-2177. 4. white jm, christie bs, nam d, daar s, higgs dr. frequency and clinical significance of erythrocyte genetic abnormalities in omanis. j med genet 1993; 30: 396400. 5. al-riyami aa, suleiman aj, afifi m, al-lamki zm and daar s. a community –based study of common figure 2. hplc of hb dhofar trait analyte id % time a0 76.9 2.40 a2 1.7 3.65 d-window 11.3 4.04 d i a g n o s i s o f b e ta -th a l a s s a e m i a c a r r i e r s i n t h e s u lta n at e o f o m a n 31 hereditary blood disorders in oman. east mediterr health j 2001; 7(6): 1004-1011. 6. daar s, hussein hm, merghoub t and krishnamoorthy r. spectrum of ‚ β-thalassemia mutations in oman. ann n y acad sci 1998; 850: 404-406. 7. daar s. md thesis haemoglobinopathies in the sultanate of oman. in: university of bristol uk, 2000. 8. altay c, gurgey a. β-thalassemia intermedia in turkey. ann n y acad sci 1990; 612: 81-89. 9. wasi p, disthasongchan p, na-nakorn s. the effect of iron deficiency on the levels of hemoglobins a2 and e j. lab clin med 1968; 71: 85-91. 10. alperin jb, dow pa, petteway mb. hemoglobin a2 levels in health and various hematologic disorders. am j clin pathol 1977; 67: 219-226. 11. madan n, sikka m, sharma s, rusia u. phenotypic expression of hemoglobin a2 in β-thalassemia trait with iron deficiency. ann hematol 1998; 77: 93-96. 12. ganeshaguru k, acquaye jk, samuel ap, et al. prevalence of thalassaemias in ethnic saudi arabians. trop geogr med 1987; 39: 238-243. 13. el-kalla s, mathews ar. a significant‚ β-thalassemia heterogeneity in the united arab emirates. hemoglobin 1997; 21:237-247. 14. el-kalla s, baysal e. α-thalassemia in the united arab emirates. acta haematol 1998; 100: 49-53. 15. martinez g, menendez r. differences in affinity of β and δ hemoglobin chains for α chains. biochim biophys acta 1983; 743: 256-259. 16. law hy, chee mkl, tan gp, ng isl. the simultaneous presence of α and β thalassaemia alleles: a pitfall in thalassaemia screening. community genet 2003; 6: 14-21. 17. galanello r, lilliu f, bertolino f, et al. percentile curves for red cell indices of β0-thalassaemia heterozygotes in infancy and childhood (1991). eur j paediatr; 150: 413-415. december 2007 vol 8 after meeting.indd a 58 year old male patient was admitted with a two month history of short-ness of breath and left hypochondral pain. the plain radiograph of the chest [figure 1] showedlarge left pleural effusion. computed tomography (ct)of the chest [figure 2] confirmed the presence of a large left pleural effusion. in addition, it showed circumferential nodular masses involving the left parietal pleura. the gallium scan showed diffuse circumferential uptake in the left thoracic cavity. fused ct/ga-67 spect image, using syngo fusion software (siemens medical solutions), allowed the precise localization of the gallium uptake to the left pleura [figure 2]. the patient underwent pleural biopsy, which showed a diffuse large b cell lymphoma. most of the tumours involving the pleura invade the pleura secondarily. the usual primary tumours are bronchogenic carcinoma, breast cancer, lymphoma, and ovarian or gastric tumours.1 primary benign and malignant tumours of the pleura are uncommon. primary malignant pleural neoplasms can present as solitary nodular mass or diffuse infiltrating tumour.2 fused ct/ga-67 spect images for detection of pleural lymphoma *khalid alsaadi,1 *humoud al-dhuhli,1 samir hussain,1 ikram burney2 sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 261-262 sultan qaboos university© submitted 3rd june 2007 accepted 1st september 2007 i n t e r e s t i n g m e d i c a l i m a g e اجلَنَب اللمفاويه اورام ct/ga67 spect لكشف صور دمج برني اكرام حسني، ، سامر الذهلي حمود ، خالد السعدي 1department of radiology and microbiology, sultan qaboos university hospital, p. o. box 38, al-khod 123, muscat, sultanate of oman; 2department of medicine, sultan qaboos university hospital, p. o. box 38, al-khod 123, muscat, sultanate of oman *to whom correspondence should be addressed. email: alzuhli@hotmail.com figure 1: fused ct/ga-67 spect image. enhanced axial ct image at level of the lower thorax shows circumferential nodular pleural thickening. note pleural effusion. the ga-67 spect image of the chest shows circumferential high uptake along the left pleural cavity. the fused ct/ ga-67 spect image clearly demonstrates the high uptake in the pleural masses shown on the ct figure 1: frontal chest radiograph shows almost complete opacification of the left hemithorax with shift of the mediastinum to the right a l s a a d i k h a l i d , a l d h u h l i h u m o u d , s a m i r h u s s a i n a n d i k r a m b u r n e y 262 primary pleural lymphoma is rare. it occurs in both hodgkin’s and non hodgkin’s disease. the lymphomatous deposits arise from lymphatic channels and lymphoid aggregates in the subpleural connective tissue below the visceral pleura. associated pleural effusion is attributed to obstruction of lymphatic channels by mediastinal lymphadenopathy.3 although primary pleural lymphoma as the only initial site of malignancy is rare, lymphomatous involvement of the pleura not uncommonly occurs secondarily. in this circumstance, it appears associated with mediastinal lymphadenopathy or pulmonary parenchymal lymphoma or develops as a manifestation of recurrent disease.4 the standard non-invasive radiological examinations include plain radiograph and computed tomography. ct scans help in deciding the location and the extent of the tumour. gallium scans play a complementary role in diagnosis and staging. ct/67ga spect fusion imaging allowed precise localization of gallium uptake and correct attribution to the viscera involved, thereby altering the diagnosis in 20%-25% of studies in comparison with ct and 67ga spect analyses alone. ct/67ga spect fusion therefore appears valuable in facilitating the interpretation of 67ga scintigraphy and it is recommend for use in patients with lymphoma when ct and 67ga scintigraphy are planned.5 r e f e r e n c e s 1. bonomo l, feragalli b, sacco r, merlino b. storto ml. malignant pleural disease. eur radiol 2000; 34;98-118. 2. shuman ls, libshitz hi. solid pleural manifestations of lymphoma. am j roentgenol 1984; 142:269-273. 3. malatskey am, fields s, lisbon e. ct appearance of primary pleural lymphoma. compute med imaging graph 1989; 13:165-167. 4. dynes mc, white em, fry wa, ghahremani gg. imaging manifestation of pleural tumours. radiographics 1992; 12:1191-1201. 5. bernstine h, bar-sever z, ekstein j, hardoff r. ga-67 scintigraphy in a rare case of primary hodgkin’s lymphoma. clin nucl med 1999; 24:880-881. معدل االنتشار والعوامل املؤثرة يف استخدام األدوية العشبية أثناء احلمل يف حائل باململكة العربية السعودية دراسة مستعرضة حممد اجلوفان و �صهيب اخلماي�صة abstract: objectives: the increasing prevalence of herbal medicine use is a global public health concern. critically, many women continue to use herbal medicines during pregnancy despite potential maternofetal risks. the current study aimed to determine the prevalence of and factors associated with herbal medicine use during pregnancy in saudi arabia. methods: this cross-sectional study was conducted between february and may 2017. an arabic-language 33item survey assessing herbal medicine use was designed and distributed to 879 random women attending outpatient clinics at governmental and private hospitals in hail, saudi arabia. only women who were pregnant or had been pregnant in the previous 10 years were included. results: the mean age of the participants was 29.5 years, with 49% under 30 years old. overall, 33% of the respondents claimed to have used herbal medicines during pregnancy. the most common reasons for doing so were to improve lactation (73%), improve the course of the pregnancy (56%) and facilitate labour (49%). women who worked full-time and those with high school diplomas or above were significantly more likely to use herbal medicines during pregnancy (p <0.001 each). conclusion: to the best of the authors’ knowledge, this is the first study to determine the prevalence and associated factors of herbal medicine use during pregnancy in hail. the results showed a high prevalence of herbal medicine use among pregnant women in the region. healthcare providers should therefore ensure that patients disclose the use of herbal medicines during pregnancy to avoid treatment complications or adverse herb-drug interactions. keywords: herbal medicine; plant preparations; pregnancy; complementary therapies; health behaviors; prevalence; herb-drug interactions; saudi arabia. امللخ�ص: الهدف: يعترب تزايد معدل انت�صار ا�صتخدام الأدوية الع�صبية م�صدر قلق عاملي على ال�صحة العامة. وب�صكل حرج توا�صل العديد من الن�صاء ا�صتخدام الأدوية الع�صبية اأثناء احلمل على الرغم من املخاطر الأُموِمية اجَلنيِنّية املحتملة. هدفت الدرا�صة احلالية اإىل حتديد الدرا�صة هذه اأجريت الطريقة: ال�صعودية. العربية اململكة يف احلمل اأثناء بها املرتبطة والعوامل الع�صبية الأدوية ا�صتخدام انت�صار مدى الع�صبية الأدوية ا�صتخدام لتقييم بندا 33 من مكونا العربية باللغة ا�صتبيان ت�صميم مت .2017 ومايو فرباير بني الفرتة يف امل�صتعر�صة ووزع ع�صوائيا على 879 امراأة يف العيادات اخلارجية يف امل�صت�صفيات احلكومية واخلا�صة يف مدينة حائل باململكة العربية ال�صعودية. و�صمل ح�رشا الن�صاء احلوامل اأو الالئي كن حوامل يف ال�صنوات الع�رش املا�صية. النتائج: كان متو�صط عمر امل�صاركات 29.5 �صنة و كان عمر %49 منهن اأقل من 30 �صنة. عموما زعمت %33 من امُل�صَتطلعات اأنهن ا�صتخدمن الأدوية الع�صبية اأثناء احلمل. وكانت اأكرث الأ�صباب �صيوًعا للقيام بذلك هي زيادة تدفق احلليب )%73(، وحت�صني م�صار احلمل )%56( وت�صهيل املخا�س )%49(. كانت الن�صاء الالئي يعملن بدوام كامل والالتي يحملن �صهادات الثانوية العامة او �صهادات اأعلى هن الأرجح وب�صكل ملحوظ يف القدام على ا�صتخدام الأدوية الع�صبية اأثناء احلمل )p >0.001(. اخلال�صة: وفقا لأف�صل ما لدينا من معلومات تعترب هذه الدرا�صة الأوىل لتحديد مدى انت�صار ا�صتخدام الأدوية الع�صبية والعوامل املرتبطة بها اأثناء احلمل يف حائل. اأظهرت النتائج ارتفاع معدل ا�صتخدام الأدوية الع�صبية بني الن�صاء احلوامل يف هذه املنطقة. لذا يتوجب على مقدمي الرعاية ال�صحية التاأكد من اف�صاح املري�صات عن ا�صتخدام الأدوية الع�صبية اأثناء احلمل لتجنب م�صاعفات العالج اأو التفاعالت بني الأدوية الع�صبية والعقاقري. والعقاقري؛ الع�صبية الأدوية تفاعالت انت�صار؛ معدل �صحية؛ �صلوكيات تكميلية؛ عالجات حمل؛ نباتية؛ م�صتح�رشات ُع�صبي؛ دواء املفتاحية: الكلمات اململكة العربية ال�صعودية. prevalence and factors influencing use of herbal medicines during pregnancy in hail, saudi arabia a cross-sectional study *mohamad aljofan1 and suhaib alkhamaiseh2,3 sultan qaboos university med j, february 2020, vol. 20, iss. 1, pp. e71–76, epub. 9 mar 20 submitted 15 apr 19 revision req. 13 jun 19; revision recd. 19 jun 19 accepted 21 jul 19 advances in knowledge to the best of the authors’ knowledge, this is the first study to determine the prevalence of herbal medicine use during pregnancy in hail, saudi arabia. the findings of this study may improve understanding of factors which influence the use of herbal medicines during pregnancy, particularly those related to local cultural beliefs, such as the belief in the safety and efficacy of herbal medicine. 1department of biomedical sciences, school of medicine, nazarbayev university, astana, kazakhstan; 2department of clinical pharmacy, university of hail, hail, saudi arabia; 3department of pharmaceutical chemistry, college of pharmacy, jerash university, jordan *corresponding author’s e-mail: m.aljofan@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2020.20.01.010 clinical & basic research https://creativecommons.org/licenses/by-nd/4.0/ prevalence and factors influencing use of herbal medicines during pregnancy in hail, saudi arabia a cross-sectional study e72 | squ medical journal, february 2020, volume 20, issue 1 the results of the current study provide insight into the specific characteristics of herbal medicine users in hail. herbal medicine users are likely to have at least 12 years of education and be working full-time. application to patient care healthcare providers should encourage pregnant patients to disclose any herbal medicine use and ensure that such individuals are aware of potential interactions with prescription and over-the-counter drugs prior to the initiation of treatment. herbal medicine use refers to the use of plant-derived materials or preparations to treat, diagnose and prevent illnesses and maintain well-being.1 the use of herbal medicine is a common practice in different parts of the world, particularly in developing countries, despite limited scientific evidence establishing the safety and efficacy of such products.2,3 according to the world health organization, an estimated 40% of all healthcare services in china comprise traditional medicines and up to 80% of africans still use traditional medicine to meet their healthcare needs.4 such treatments are also rapidly gaining momentum in more developed countries where they are referred to under the umbrella term of complementary alternative medicine (cam).5–9 according to eisenberg et al., approximately onethird of american adults in a national sample reported using at least one unconventional therapy in the past year.5 in australia, maclennan et al. reported that 48.5% of individuals used at least one non-medicallyprescribed alternative medicine, excluding calcium, iron and prescribed vitamins.7 moreover, results from the 2007 national health interview survey indicated that approximately 38% of adults and 12% of children in the usa were using cam in some form that year.8 another study in the usa estimated that one in five american adults take herbal products.9 the unregulated use of herbal medicines during pregnancy presents a high risk for pregnant women and the developing fetus.10 alarmingly, despite the lack of scientific evidence to support its use, there is an increasing trend in the prevalence of herbal medicine use during pregnancy.11 kim sooi and lean keng found that 34% of pregnant malaysian women used herbal medicines during their pregnancy.12 in the usa, an estimated 6–9% of pregnant women use herbal medicines, with this statistic increasing to an alarming 69% in russia.13,14 like many countries in the region, the use of herbal medicine in saudi arabia is high; a recent study reported that 94% of 1,300 respondents from northern regions of the country had a history of herbal product use.15 however, to the best of the authors’ knowledge, no previous study has assessed the use of herbal medicines among pregnant women in the hail region of northern saudi arabia. the current study therefore aimed to determine the prevalence of and factors influencing the use of herbal medicines during pregnancy in hail. as the prevalence of herbal medicine use is fairly high in this region, it was hypothesised that there would be a similarly high frequency of herbal product use during pregnancy, particularly in the early stages to alleviate symptoms of nausea and vomiting. methods this cross-sectional questionnaire-based study was carried out between february and may 2017 at various govern mental and private hospitals in hail. a convenience sampling methodology was used to randomly recruit women from the outpatient clinics of hail maternal hospital, general hail hospital and salamat private hospital, as well as other participating health centres. only adult women, ≥18 years of age, who were currently or had previously been pregnant in the last 10 years were included in the study. those who were mentally handicapped were excluded from the study. in order to determine the prevalence of herbal medicine use among the pregnant population in the region, the minimum sample size needed was calculated according to the following equation:15 where z is the z statistic (2.576) at a 99% confidence interval (ci), p is the standard deviation (0.5) and d is the margin of error (0.05). this resulted in a value of 663.57, which was rounded up to 664 individuals at a 99% ci with a margin of error of 1% [equation 1]. however, in order to ensure that the sample was truly representative, a total of 879 women were recruited to participate in the study. an english-language questionnaire was developed to assess the prevalence of herbal medicine use during pregnancy, reasons for use and knowledge regarding potential health risks. the questionnaire contained 33 items divided into four different sections, including a section to assess the participants’ demographic charact eristics as well as knowledge, attitudes and practices regarding herbal medicine use during pregnancy. subsequently, the questionnaire was translated into arabic by proficient arabic-language speakers and revised to be suitable for use in the general population. z2 × p × (1-p) [equation 1] d2 n = mohamad aljofan and suhaib alkhamaiseh clinical and basic research | e73 a pilot study of 21 randomly selected women was performed to validate the questionnaire. the participants included 14 pregnant women attending the outpatient department of the hail maternal hospital, five employees from the same institution and two participants from the university of hail. after corrections were made based on feedback from the pilot study, the final questionnaire was distributed to the participants by research assistants who met the participants at the outpatient departments of each of the participating hospitals. data were recorded using a data collection form and entered into an excel spreadsheet, version 2010 (microsoft corp., redmond, washington, usa). stat istical analysis was conducted using the statistical package for the social sciences (spss), version 21.0 (ibm corp., armonk, new york, usa). a chi-squared test was used to test associations between variables. an a priori level of p <0.010 was considered statistically significant. this study received ethical approval from the scientific research ethical committee of the university of hail (h-2017-015). all procedures were performed in accordance with the revised declaration of helsinki. informed consent was obtained from all participants subsequent to the provision of full details regarding the study and its intended purpose. in addition, all of the women were made aware that their participation was voluntary and that no identifying information would be collected. during the study period, the data collection forms were kept in a secure environment, accessible only to the principal investigator and were destroyed following completion of the study. results the mean age of the study participants was 29.5 years, with 49% under the age of 30 years old. in terms of education level, the vast majority (96%) had a high school diploma or above. approximately half of the respondents (49%) were working full-time, while the remainder were housewives. at the time of the survey, 623 (71%) participants were pregnant and 256 (29%) were not currently pregnant but had had full-term pregnancies in the past 10 years. most of the participants (62%) lived in urban areas, while the remaining participants (38%) lived in rural areas outside of hail city [table 1]. overall, 712 women (81%) reported that they had used herbal medicine regularly before their pregnancies. in addition, 294 women (33%) admitted to using such products during pregnancy [figure 1]. among the 294 respondents who had used herbal medicines while pregnant, 59 (20%) had used herbal products during the first trimester, 132 (45%) during the second trimester and 103 (35%) during the third trimester. among the 256 women who were not currently pregnant at the time of the survey, 217 (85%) admitted to using herbal medicines during the lactation period (p <0.001) [figure 2]. the most commonly reported reasons for using herbal medicines during pregnancy were to increase milk supply during the lactation period (73%), to improve the course of the pregnancy (56%) and to facilitate labour (49%) [figure 3]. in terms of their figure 1: prevalence of herbal medicine use before and during pregnancy among women attending outpatient clinics in hail, saudi arabia (n = 879). table 1: demographic characteristics of women attending outpatient clinics in hail, saudi arabia (n = 879) variable n (%) age in years 18–29 432 (49) 30–39 291 (33) 40–49 135 (15) ≥50 21 (2) mean ± sd (range) 29.5 ± 6.6 (18–53) education level none* 39 (4) high school diploma 461 (52) college 379 (43) place of residence urban 544 (62) rural 335 (38) pregnancy status currently pregnant 623 (71) previously pregnant 256 (29) employment status housewife 451 (51) working full-time 428 (49) *less than 12 years of formal study. prevalence and factors influencing use of herbal medicines during pregnancy in hail, saudi arabia a cross-sectional study e74 | squ medical journal, february 2020, volume 20, issue 1 knowledge of health risks, most respondents (74%) believed that the moderate consumption of herbal medicines would affect neither the mother nor the fetus. however, the women believed that excessive use would lead to negative outcomes such as miscarriage (41%), premature labour (33%), birth defects (12%), long-term maternal health effects (9%) and stillbirth (5%) [table 2]. after adjusting for potential confounders, a multi variable linear regression model was used to identify factors influencing herbal medicine use during pregnancy. women with a high school diploma or above (β = 0.361, 95% ci: 0.230–0.344; p <0.001) and those working full-time (β = 0.271, 95% ci: 0.485–0.592; p <0.001) were significantly more likely to use herbal medicines during pregnancy [table 3]. discussion in many developed countries, herbal medicines are strictly regulated by legislation to ensure the quality, safety and efficacy of these therapeutic products.3,16,17 in contrast, herbal medicines in developing countries such as saudi arabia are usually unregulated and form ulated without rigorous scientific testing or physician consultation. this increases the risk of abnormal pathologies or toxicities, especially among vulnerable groups such as children, the elderly, pregnant women and developing fetuses.10,18 this is particularly worrisome as there is also a high rate of non-compliance with regulations that control the dispensing of prescriptiononly medications in community pharmacies in saudi arabia.19 therefore, there is an urgent need to establish a national regulating body to monitor the use of herbal medicine to avoid adverse herb-drug interactions. to the best of the authors’ knowledge, the current study represents the first in the hail region to determine the prevalence of and associated factors influencing herbal medicine use during pregnancy. the results indicated a high percentage of herbal medicine use, both prior to and during pregnancy (81% and 33%, respectively). al-ghamdi et al. similarly reported that 25.3% of pregnant women from the central region of saudi arabia used herbal products during pregnancy.20 in the current study, pregnant participants reported taking herbal medicines during all three stages of pregnancy, in the first (20%), second (45%) and third (35%) trimesters. however, a significantly greater pro portion of the respondents (85%) reported using herbal medicines during the lactation period. other researchers have reported similar results in other parts of saudi arabia and in nearby countries such as palestine.20–23 in the present study, women with a high school diploma or higher (i.e. those with at least 12 years of formal education) and women who were working full-time were significantly more likely to use herbal figure 2: patterns of herbal medicine use during pregnancy among women attending outpatient clinics in hail, saudi arabia (n = 294). *significant at p <0.010. figure 3: reasons for herbal medicine use during pregnancy among women attending outpatient clinics in hail, saudi arabia (n = 294)*. *respondents were permitted to select more than one reason for use. table 2: beliefs regarding the risks of excessive herbal medicine use during pregnancy among women attending outpatient clinics in hail, saudi arabia (n = 879) risk n (%)* birth defects 106 (12) miscarriage 360 (41) premature labour 290 (33) stillbirth 44 (5) long-term maternal health effects 79 (9) *percentages do not add up to 100% as respondents were permitted to select more than one risk. table 3: associations between herbal medicine use during pregnancy and demographic variables among women attending outpatient clinics in hail, saudi arabia (n = 879) variable β (95% ci) p value age 0.566 (0.506–0.491) 0.151 education level 0.361 (0.230–0.344) <0.001* place of residence 0.125 (0.385–0.377) 0.235 employment status 0.271 (0.485–0.592) <0.001* ci = confidecne interval. *significant at p <0.010. mohamad aljofan and suhaib alkhamaiseh clinical and basic research | e75 medicines during pregnancy compared to their less educated and unemployed counterparts. this contr adicts the widespread assumption that the most likely users of risky and untested products, such as herbal products, are uneducated housewives in rural areas. nevertheless, this finding is consistent with those of a previous study investigating the prevalence of herbal medicine use and costs in australia, which reported that educated women were more likely to use herbal medicine.7 with regards to their knowledge of the risks associated with herbal medicine use during pregnancy, the majority of respondents in the current study believed that excessive consumption, although not explicitly defined, during pregnancy can cause various health risks to both the mother and child, including birth defects, miscarriage, premature labour, stillbirth and negative long-term effects on the mother’s health. indeed, some of these risks have scientific basis; for example, the consumption of moderate amounts of fenugreek during pregnancy purportedly increases milk production, whereas large quantities can cause uterine contractions, miscarriage or premature labour.24 however, while the exact sources of the respondents’ knowledge regarding the health risks of herbal products were not determined, such assertions are likely based on hearsay and local cultural beliefs and practices. when asked about their reasons for using herbal medicines during pregnancy, the majority of women in the present study believed that herbal medicines would generally improve their pregnancy, facilitate labour and increase milk supply. such reasoning is probably based on cultural beliefs and practices.20,25 interestingly, the latter two reasons may in part explain the increase in herbal medicine use during the second trimester and lactation period. the current study was subject to certain limitations. although there are no significant differences in traditional practices between different areas of saudi arabia, the current study was only conducted in one region; as such, the findings cannot be deemed reflective of the entire saudi population. this study did not evaluate specific forms or methods of herbal product use or the prevalence of side-effects following usage, as such variables were deemed beyond the scope of the study. some of the participants were not pregnant at the time of the survey and were therefore reporting experiences and practices from their last pregnancy; in some cases, this may have occurred as much as a decade beforehand. this could have resulted in recall bias for some of the responses, particularly those assessing herbal medicine use during the lactation period. this may have had an impact on the generalisability of the results. conclusion to the best of the authors’ knowledge, this is the first study to investigate the prevalence of herbal medicine use among pregnant women in hail, saudi arabia. the findings indicate a high prevalence of herbal medicine use during pregnancy in the region, most likely influenced by local cultural practices. therefore, urgent measures are needed to raise public awareness regarding the risks of herbal medicine use without professional advice. in addition, healthcare providers should ensure that pregnant patients disclose inform ation concerning herbal product use in order to avoid health complications and drug interactions during treatment. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. legal status of traditional medicine and complementary/alternative medicine: a worldwide review. from: www.who.int/iris/handle/10665/42452 accessed: jun 2019. 2. aljofan m, netter hj, aljarbou an, hadda tb, orhan ie, sener b, et al. anti-hepatitis b activity of isoquinoline alkaloids of plant origin. arch virol 2014; 159:1119–28. https://doi.org/10. 1007/s00705-013-1937-7. 3. bent s. herbal medicine in the united states: review of efficacy, safety, and regulation grand rounds at university of california, san francisco medical center. j gen intern med 2008; 23:854–9. https://doi.org/10.1007/s11606-008-0632-y. 4. world health organization. who traditional medicine strategy: 2002–2005. from: www.wpro.who.int/health_technology/boo k _ w h o _ t r a d i t i o n a l _ m e d i c i n e _ s t r ate g y _ 2 0 0 2 _ 2 0 0 5 . p d f accessed: jun 2019. 5. eisenberg dm, kessler rc, foster c, norlock fe, calkins dr, delbanco tl. unconventional medicine in the united states: prevalence, costs, and patterns of use. n engl j med 1993; 328:246–52. https://doi.org/10.1056/nejm199301283280406. 6. nissen n. practitioners of western herbal medicine and their practice in the uk: beginning to sketch the profession. comple ment ther clin pract 2010; 16:181–6. https://doi.org/10.1016/j. ctcp.2010.06.001. 7. maclennan ah, wilson dh, taylor aw. prevalence and cost of alternative medicine in australia. lancet 1996; 347:569–73. https://doi.org/10.1016/s0140-6736(96)91271-4. 8. national center for complementary and integrative health. the use of complementary and alternative medicine in the united states. from: https://nccih.nih.gov/research/statistics/2007/ca msurvey_fs1.htm accessed: jun 2019. 9. barnes pm, powell-griner e, mcfann k, nahin rl. comple mentary and alternative medicine use among adults: united states, 2002. adv data 2004; 343:1–19. https://doi.org/10.1016/ j.sigm.2004.07.003. 10. ekor m. the growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. front pharmacol 2014; 4:177. https://doi.org/10.3389/fphar.2013.00177. https://doi.org/10.1007/s00705-013-1937-7 https://doi.org/10.1007/s00705-013-1937-7 https://doi.org/10.1007/s11606-008-0632-y https://doi.org/10.1056/nejm199301283280406 https://doi.org/10.1016/j.ctcp.2010.06.001 https://doi.org/10.1016/j.ctcp.2010.06.001 https://doi.org/10.1016/s0140-6736%2896%2991271-4 https://doi.org/10.1016/j.sigm.2004.07.003 https://doi.org/10.1016/j.sigm.2004.07.003 https://doi.org/10.3389/fphar.2013.00177 prevalence and factors influencing use of herbal medicines during pregnancy in hail, saudi arabia a cross-sectional study e76 | squ medical journal, february 2020, volume 20, issue 1 11. holden sc, gardiner p, birdee g, davis rb, yeh gy. complementary and alternative medicine use among women during pregnancy and childbearing years. birth 2015; 42:261–9. https://doi.org/10.1111/birt.12177. 12. kim sooi l, lean keng s. herbal medicines: malaysian women’s knowledge and practice. evid based complement alternat med 2013; 2013:438139. https://doi.org/10.1155/2013/438139. 13. broussard cs, louik c, honein ma, mitchell aa; national birth defects prevention study. herbal use before and during pregnancy. am j obstet gynecol 2010; 202:443.e1–6. https://doi.org/10.1016/j.ajog.2009.10.865. 14. kennedy da, lupattelli a, koren g, nordeng h. herbal medicine use in pregnancy: results of a multinational study. bmc comple ment altern med 2013; 13:355. https://doi.org/10.1186/14726882-13-355. 15. alkhamaiseh si, aljofan m. prevalence of use and reported side effects of herbal medicine among adults in saudi arabia. complement ther med 2020; 48:102255. https://doi.org/10.10 16/j.ctim.2019.102255. 16. calapai g. european legislation on herbal medicines: a look into the future. drug saf 2008; 31:428–31. https://doi.org/10.21 65/00002018-200831050-00009. 17. briggs dr. the regulation of herbal medicines in australia. toxicology 2002; 181–2:565–70. https://doi.org/10.1016/s0300 483x(02)00483-3. 18. paule s, aljofan m, simon c, rombauts lj, nie g. cleavage of endometrial α-integrins into their functional forms is mediated by proprotein convertase 5/6. hum reprod 2012; 27:2766–74. https://doi.org/10.1093/humrep/des203. 19. alshammari tm, alhindi sa, alrashdi am, benmerzouga i, aljofan m. pharmacy malpractice: the rate and prevalence of dispensing high-risk prescription-only medications at community pharmacies in saudi arabia. saudi pharm j 2017; 25:709–14. https://doi.org/10.1016/j.jsps.2016.10.001. 20. al-ghamdi s, aldossari k, al-zahrani j, al-shaalan f, al-sharif s, al-khurayji h, et al. prevalence, knowledge and attitudes toward herbal medication use by saudi women in the central region during pregnancy, during labor and after delivery. bmc complement altern med 2017; 17:196. https://doi.org/10.1186/s12906-0171714-3. 21. elolemy at, albedah am. public knowledge, attitude and practice of complementary and alternative medicine in riyadh region, saudi arabia. oman med j 2012; 27:20–6. https://doi. org/10.5001/omj.2012.04. 22. shraim ny, shawahna r, sorady ma, aiesh bm, alashqar gs, jitan ri, et al. community pharmacists’ knowledge, practices and beliefs about complementary and alternative medicine in palestine: a cross-sectional study. bmc complement altern med 2017; 17:429. https://doi.org/10.1186/s12906-017-1940-8. 23. suleiman ak. attitudes and beliefs of consumers of herbal medicines in riyadh, saudi arabia. j community med health educ 2014; 4:269. https://doi.org/10.4172/2161-0711.1000269. 24. laelago t. herbal medicine use during pregnancy: benefits and untoward effects. in: builders p, ed. herbal medicine. rijeka, croatia: intechopen, 2018. https://doi.org/10.5772/intechopen. 76896. 25. rassool gh. cultural competence in nursing muslim patients. nurs times 2015; 111:12–15. https://doi.org/10.1007/978-1137-35841-7. https://doi.org/10.1111/birt.12177 https://doi.org/10.1155/2013/438139 https://doi.org/10.1016/j.ajog.2009.10.865 https://doi.org/10.1186/1472-6882-13-355 https://doi.org/10.1186/1472-6882-13-355 https://doi.org/10.1016/j.ctim.2019.102255 https://doi.org/10.1016/j.ctim.2019.102255 https://doi.org/10.2165/00002018-200831050-00009 https://doi.org/10.2165/00002018-200831050-00009 https://doi.org/10.1016/s0300-483x%2802%2900483-3 https://doi.org/10.1016/s0300-483x%2802%2900483-3 https://doi.org/10.1093/humrep/des203 https://doi.org/10.1016/j.jsps.2016.10.001 https://doi.org/10.1186/s12906-017-1714-3 https://doi.org/10.1186/s12906-017-1714-3 https://doi.org/10.5001/omj.2012.04 https://doi.org/10.5001/omj.2012.04 https://doi.org/10.1186/s12906-017-1940-8 https://doi.org/10.4172/2161-0711.1000269 https://doi.org/10.5772/intechopen.76896 https://doi.org/10.5772/intechopen.76896 https://doi.org/10.1007/978-1-137-35841-7 https://doi.org/10.1007/978-1-137-35841-7 absence of left pulmonary artery case report *dilip sankhla, samir hussein, jojy george, ranjan william, sinan al-azawi, badriya al-qassabi case report squ med j, august 2009, vol. 9, iss. 2, pp. 180-183, epub 30th june 2009 submitted 1st feb 09 revision req. 22nd apr 09, revision recd. 3rd may 09 accepted 17th may 09 department of radiology and molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman. to whom correspondence should be addressed. email: sankhladilip@gmail.com the unilateral absence of a pulmonary artery is a rare condition with diverse clinical presentations. routine investigations including chest x-rays and echocardiography may suggest the diagnosis of absence of a pulmonary artery, but confirmation requires computed tomography (ct) scans and magnetic resonance angiography (mra). an early diagnosis of a unilateral absence of pulmonary artery and appropriate intervention may significantly improve the outcome. we report a rare case of a young woman with a unilateral absence of the left pulmonary artery who presented with a recent history of shortness of breath and chronic cough. case report a 21 year old lady was admitted to sultan qaboos university hospital, oman, via its outpatient clinic, for the evaluation of a small left hemithorax and a mild cough. she had a history of mild attacks of shortness of breath, especially after exertion, and occasional left-sided chest pain. her symptoms had got worse during the previous year. there was no history of associated fever, sweating, chills, loss of appetite or weight loss. there was no past history of allergy or contact with patients with pulmonary tuberculosis. on examination, she was observed to be in good condition and her vital signs were within normal ranges. examination of the respiratory system showed a tracheal shift to the left, reduced left chest movements and reduced breath sounds and dull percussion in the left lung. her chest x-ray [figure 1] showed evidence of volume loss in the left hemithorax, a mediastinal shift to the left and crowding of the left ribs. the right lung showed compensatory hyperinflation. the left lung showed less vascular marking compared to the right side. the right main pulmonary artery غياب الشريان الرئوي األيسر تقرير حالة دليب شنكال، سامر حسني، جوجي جورج، راجنان وليم، سنان العزاوي، بدرية القصابي عن العيوب اخللقية عادة ما يكون نادر الذكر في التقارير الطبية. يتم تشخيص الناجت األيسر الرئوي الشريان منَو وقصور تخلق امللخص: عدم معظم احلاالت في مرحلة الطفولة، وأحيانا ما تكون هذه احلاالت بدون أعراض ويتم التعرف عليها للمرة األولى في سن البلوغ من خالل أشعة الصدر. نعرض هنا حالة مريضة تبلغ من العمر واحدا وعشرين عاما تعاني من عدم تخلق الشريان الرئوي األيسر الذي كان بدون أعراض حتى البلوغ ، حيث بدأت تعاني من أعراض بسيطة في اجلهاز التنفسي وكانت صورة األشعة السينية للصدر غير طبيعية. ساعد االْسِتْعزازٌ الَتبايُِنّي للتَّْصويُر املَْقَطِعيُّ امُلَوَسب في تأكيد التشخيص. من اجلدير ذكره أن التشخيص املبكر لهذة احلالة املرضية ضروري لتجنب املضاعفات التي ميكن أن تكون قاتلة. مفتاح الكلمات: عدم تخلق الشريان الرئوي وحيد اجلانب ، الشريان الرئوي األيسر ، العيوب اخللقية . تقرير حالة ، عمان. abstract: agenesis and hypoplasia of left-sided pulmonary artery anomalies have been infrequently reported. the majority of cases are diagnosed in childhood, but occasionally some asymptomatic cases are first recognised in adulthood when detected by an abnormal chest radiograph. we report a twenty-one year old female patient with left pulmonary artery agenesis who was asymptomatic till adulthood, but presented with mild respiratory symptoms and an abnormal chest x-ray. a contrast enhanced computerised tomography )cect( scan helped to establish the diagnosis. early diagnosis of this condition is essential to avert potentially lethal complications. keywords: unilateral pulmonary artery agenesis; left pulmonary artery; congenital abnormalities; case report; oman. dilip sankhla, samir hussein, jojy george, ranjan william, sinan al-azawi and badriya al-qassabi case report | 181 was normal and the left was not seen. these findings were suggestive of either a hypoplastic left lung or secondary to chronic obstruction in the left main bronchus. bronchoscopy, however, revealed normal carina and main bronchi. a pool of secretions was noted in left main bronchus. the bronchial aspirate was negative for acid fast bacilli and its culture was negative. a contrast enhanced computerised tomography (cect) scan [figure 2], was performed on this patient to visualise the pulmonary vasculature. it revealed the absence of her left pulmonary artery, a right-sided aortic arch and a dilated main pulmonary artery with evidence of collaterals at the left hilum and in the apical region. the lung parenchyma was normal apart from volume loss of the left lung with compensatory hyperinflation of the right lung. the bronchi on either side were patent. a perfusion-ventilation scan (v/q) [figure 3] was also performed. the perfusion scan showed normal perfusion of the right lung and no uptake in the left lung. the ventilation scan showed hypoventilation in the left lung and a normally ventilated right lung. these findings led to the diagnosis of left pulmonary artery agenesis. discussion the unilateral absence of a pulmonary artery is a rare condition and is believed to originate from a single embryological defect in the proximal sixth aortic arch. it refers to proximal interruption of those vessels, but the vessels are usually intact in the lungs. the incidence is about 1 in 200,000. left-sided pulmonary artery anomalies have been reported even less frequently. right pulmonary artery agenesis is twice as common as left pulmonary artery agenesis.1, 2 the majority of cases are diagnosed in childhood, but occasionally some cases with very few symptoms are first recognised in adulthood through the detection of an abnormal chest radiograph. chest x-rays frequently show a decreased size of the affected hemithorax, compensatory hyperinflation of the contralateral hemithorax, elevation of the ipsilateral hemidiaphragm, absent ipsilateral and enlarged contralateral pulmonary artery shadow, figure 1: chest x-ray posterior anterior view shows hypoplastic left lung, decreased vascular markings with ipsilateral mediastinal shift legend: rpa = right main pulmonary artery; mpa = main pulmonary artery; aa = aorta figures 2a & 2b: contrast enhanced computed tomography axial image (a) and reformatted coronal image (b) shows absence of left pulmonary artery and right-sided aortic arch. absence of left pulmonary artery case report 182 | squ medical journal, august 2009, volume 9, issue 2 a right-sided aortic arch and an ipsilateral shift of the mediastinum.2, 3, 4 most of these findings were present in the chest x-ray of our patient. fallot’s tetralogy, intracardiac septal defects, coarctation of aorta, right aortic arch and eisenmenger’s syndrome are associated with left pulmonary artery atresia (75%).5 the most common presenting symptoms in patients with pulmonary atresia are recurrent pulmonary infection, mild dyspnea and decrease exercise tolerance.5 our patient had no major complaints until a year before her admission. in these asymptomatic patients, the blood supply distal to the interruption is provided by a patent ductus arteriosus, bronchial collaterals, and an artery arising directly from the aorta or, less commonly, by transpleural intercostal collaterals.6 many bronchial collaterals were visible on the cect of our patient. the presence of a hypoventilated left lung with no perfusion on that side also explains the presence of collateral vessels supplying the left lung. diminished or total absence of ipsilateral perfusion and normal or mildly reduced ventilation has been reported in the literature.3 this also explains the late onset of her symptoms. the unilateral absence of the pulmonary artery (uapa) may be suspected by the presence of recurrent respiratory infections, haemoptysis, bronchiectasis or pulmonary hypertension in the absence of other known causes. the parenchymal abnormality is extremely rare. the diagnosis of uapa can be made by chest radiography and echocardiography. the definitive diagnosis, anatomic details and the presence of hilar collaterals, however, can be discerned by cect scanning and mr angiography.7, 8 cardiac angiography and pulmonary venous wedge angiography have been considered in establishing the diagnosis of uapa and identifying collateral vessels. however, with the advent of cect and mr angiography, cardiac catheterisation should be reserved for patients requiring embolisation for recurrent haemoptysis or being considered for revascularisation surgery.4, 5 if sufficiently large hilar arteries are found, revascularisation may significantly improve the outcome. however, large collateral arteries can also lead to pulmonary hypertension or haemoptysis which may require embolisation. the early diagnosis of uapa and management can avert the above complications and it can also avert the potentially devastating effects of high altitude or pregnancy. conclusion agenesis of the left pulmonary artery is a rare anomaly and the patient may remain asymptomatic till adulthood. imaging plays a major role in the diagnosis and detecting the associated findings in heart and lungs. for patients who present with a unilateral small hemithorax, recurrent chest infections and an abnormal chest x-ray, a uapa anomaly should be considered in the differential diagnosis. an early diagnosis can avert serious complications. references 1. fraser rs, müller nl, colman n, pare pd. developmental anomalies affecting the pulmonary vessels. in: fraser rs, pare pd, eds. fraser and pare’s perfusion anterior view ventilation anterior view ventilation posterior view figure 3: perfusion and ventilation scans. the perfusion scan shows no activity in the left lung and normal activity in right lung. ventilation scans display mild activity in the left lung and normal activity in right lung dilip sankhla, samir hussein, jojy george, ranjan william, sinan al-azawi and badriya al-qassabi case report | 183 diagnosis of disease of the chest. 4th ed. philadelphia: wb saunders company, 1999. pp. 637-5. 2. bouros d, paré p, panagou p, tsintiris k, siafakas n. the varied manifestation of pulmonary artery agenesis in adulthood. chest 1995; 108:670-6. 3. harris km, lloyd dcf, morrissey b, adams h. the computed tomographic appearances in pulmonary artery atresia. clin radiol 1992; 45:382-6. 4. griffin n, mansfield l, redmond kc, dusmet m, goldstraw p, mittal tk, et al. imaging features of isolated unilateral pulmonary artery agenesis presenting in adulthood: a review of four cases. clin radiol 2007; 62:238-44. 5. ten harkel ad, blom na, ottenkamp j. isolated unilateral absence of a pulmonary artery: a case report and review of the literature. chest 2002; 122:1471-7. 6. morgan pw, foley dw, erickson sj. proximal interruption of a main pulmonary artery with transpleural collateral vessels: ct and mr appearances. j comput assist tomogr 1991; 15:311-3. 7. lynch da, higgins cb. mr imaging of unilateral pulmonary artery anomalies. j comput assist tomogr 1990; 14:187-91. 8. debatin jf, moon re, spritzer ce, spritzer c, macfall j. mri of absent left pulmonary artery. j comput assist tomogr 1992; 16:641-5. submitted 30 may 22 1 revision req. 6 jul 22; revision recd. 1 aug 22 2 accepted 31 aug 22 3 online-first: september 2022 4 doi: https://doi.org/10.18295/squmj.9.2022.056 5 6 the role of hyposthenuria in enuresis among paediatric patients 7 with sickle cell disease 8 *jasim n. al‑asadi,1 alyaa m. radhi,2 dhuha s. jumaa,2 meaad k. 9 hassan2 10 11 departments of 1family & community medicine and 2pediatrics, college of 12 medicine, university of basrah, basrah, iraq 13 *corresponding author’s e-mails: jnk5511@yahoo.com and 14 jasim.naeem@uobasrah.edu.iq 15 16 abstract 17 objectives: enuresis in children with sickle cell disease (scd) is common. many risk 18 factors have been postulated but its relation to hyposthenuria is debatable. this study 19 aims to determine the prevalence of enuresis inchildren with scd in basrah, iraq and 20 to examine its relation with hyposthenuria. methods: a cross-sectional 21 epidemiological study was performed on children with scd who met the inclusion 22 criteria at the basrah center for hereditary blood diseases over the period from the 23 first of december 2020 through may 2021. a questionnaire was used to collect 24 relevant data. blood samples were tested for hemoglobin genotype, certain blood 25 indices, and serum hemoglobin. urine was tested for albumin and creatinine, and the 26 specific gravity was measured using urine dipsticks. the relationships between 27 enuresis and various sociodemographic and clinical variables were assessed. binary 28 logistic regression analysis was done to examine the independent risk factors of 29 enuresis. results: out of 200 eligible children, 161 were studied after exclusion of 39 30 based on the exclusion criteria, yielding an 80.5% response rate, 60.9% of them were 31 males. the mean age of the participants was 10.9 ± 2.9 years. enuresis was reported 32 in 50 (31.1%) patients. the independent risk factors for enuresis were; family history 33 mailto:jnk5511@yahoo.com mailto:jasim.naeem@uobasrah.edu.iq of enuresis (or, 5.94; 95% ci, 2.54-13.89; p<0.001), hyposthenuria (or, 3.76, 95% 34 ci, 1.25-11.30; p= 0.018), and sleep disorders (or, 2.90; 95% ci, 0.19-7.06; p= 35 0.019). conclusion: enuresis is common among children with scd. hyposthenuria 36 was significantly associated with enuresis. family history of enuresis, and sleep 37 disorders were also found to be significantly related to enuresis. 38 keywords: enuresis, sickle cell disease, children, prevalence, hyposthenuria 39 40 advances in knowledge 41 enuresis is prevalent in sickle cell disease children (scd). the role of hyposthenuria 42 as a determinant of enuresis is controversial. this study revealed hyposthenuria as 43 significant predictor of enuresis in children with scd. 44 45 to the best of the authors’ knowledge, this study is the first in iraq that attempts to 46 examine the association between hyposthenuria and enuresis in scd children. 47 48 application to patient care 49 the results of this study may help understand the mechanisms underlying the enuresis 50 in children with scd. 51 52 introduction 53 sickle cell disease (scd), an autosomal-recessive hemoglobin disorder, is one of the 54 most common heritable diseases in the world.1 some eastern mediterranean countries, 55 including iraq, have also reported the disease. in basrah, iraq, 6.48% of the 56 population has the sickle cell trait. 2 enuresis is more common in children with scd 57 than in those with normal hemoglobin; however, prevalence rates vary widely, 58 ranging from 26.4% to 51% depending on study methodology and enuresis definition 59 criteria.3 60 61 scd is a multisystem disease, with one of the most typically afflicted organs being 62 the kidneys due to medullary ischemia and infarction. the underlying etio63 pathogenesis of enuresis in scd is not fully known. it has been related to tubular 64 dysfunction manifested as defects in urinary concentration (hyposthenuria) and 65 acidification, 4 low functional bladder capacity and high overnight urine volume, 3,5 66 glomerular hyperfiltration caused by increased prostaglandin production. 6 eneh et al, 67 on the other hand, revealed that enuresis in children with scd is related to other 68 causative variables that are common in the general population rather than 69 hyposthenuria. 7 similarly, other studies revealed that potential mechanisms 70 underlying nocturnal enuresis in patients with normal hemoglobin genotype 71 (hemoglobin aa) are equally relevant in scd patients. 5,8 72 73 the debatable role of hyposthenuria as a predictor of enuresis in scd patients, as well 74 as the lack of studies on the subject in basrah, iraq justified the conduct of this study, 75 which aimed to verify the role of hyposthenuria in enuresis among scd children. 76 77 methods 78 study setting, design, and patients 79 this was an analytical cross-sectional study including a non-probability convenient 80 sample of 200 children with steady state scd consecutively attending the basrah 81 center for hereditary blood diseases during the period from the first of december 82 2020 through may 2021. subjects having diabetes mellitus, epilepsy, features of 83 urinary tract infection, isolated daytime incontinence, known renal dysfunction/ 84 impairment, diabetes insipidus, and on desmopressin or diuretic medication were 85 excluded from the study. of the 200 eligible children, 34 children were excluded 86 because they either reported a history of recurrent urinary tract infection or were 87 proven to have it by urine analysis. other exclusion criteria led to the exclusion of 88 five more children. the final studied sample size is made up of the remaining 161 89 children (80.5%). 90 91 data collection & definition of variables 92 patients and / or their parents were interviewed using a structured questionnaire that 93 was developed for this study and completed by one of the researchers. it consisted of 94 two parts; the first part contained information about the child's and parents' 95 sociodemographic features (age, sex, and birth order of the child, exposure to stressful 96 life event such as death or divorce of parents, number of siblings, parental level of 97 education, and monthly family income). parents were asked if any of the following 98 life events had occurred in the family within the last 12 months; death or divorce of 99 parent, death of someone in close proximity, child moving to another address or 100 school, conflicts with neighbors or friends, financial problems.9 the second part 101 sought information on enuresis (type, time, and frequency or severity of enuresis), 102 family history of enuresis, and medical history of the child including sleep disorders 103 including disorders in initiating and maintaining sleep (like snoring, difficult arousal, 104 sleep breathing disorders, and insomnia). parents were told that any information 105 received would be kept private and anonymous. two pediatric experts and two 106 community medicine consultants in the field of research methodology validated the 107 questionnaire. 108 109 the type of scd was recorded for all patients depending on baseline hemoglobin 110 electrophoresis and / high performance liquid chromatography (hplc) results. 111 blood samples were collected for complete blood count using automated hematology 112 analyzer. the urine samples sent for analysis were the first-voided morning, clean113 catch mid-stream samples. specific gravity was measured using dipstick urinalysis 114 (acon laboratories, inc., usa). a urinalysis was done to check for urinary tract 115 infection, and those with positive results were sent for urine culture and sensitivity. 116 urine albumin was determined using immunoturbidimetric assay. urinary creatinine 117 was measured by the alkaline picrate method. the urinary albumin/creatinine ratio 118 (acr) was computed and classified as normal when it was less than 30mg/g, 119 microalbuminuria (acr= 30-300 mg/g), or macroalbuminuria (acr more than 300 120 mg/g). 10 121 122 the way of urine collection was explained to the parents/ caregivers and older 123 participants. 124 125 enuresis was applied when the child has a "repeated involuntary or unintentional 126 urine voiding into the bed or clothes that occurs exclusively during sleeping periods 127 and not related to medication by the age of five years or older, with a minimum 128 frequency of once monthly for at least three consecutive months" 3,11,12 secondary 129 enuresis is reserved for children who have been dry for more than 6 months. 130 otherwise, it is referred to as primary enuresis. 12 hyposthenuria was defined as urine 131 specific gravity <1.010 on dipstick analysis. 13 132 133 statistical analysis 134 data were compiled and analyzed by the spss version 23.0 software (ibm corp, 135 armonk, new york, usa). the t-test, chi square test, or fisher’s exact test were 136 used for comparison of covariates where applicable. binary logistic regression 137 analysis was done to look for the possible independent risk factors associated with 138 enuresis. the level of significance was chosen at a p-value of <0.05. 139 140 ethical consideration 141 the ethical committee of the college of medicine, university of basrah authorized 142 this study. before the children were included in the research, their parents provided 143 informed consent. 144 145 results 146 out of 200 eligible children, 161 were studied after exclusion of 39 based on the 147 exclusion criteria, yielding an 80.5% response rate, with 98 (60.9%) males and 63 148 (39.1%) females; their mean age was 10.9±2.9 years (10.9±2.8 for males and 11.0±3.1 149 for females). of the participants, children 50 (31.1%) were found to have enuresis. of 150 enuretic children, 45 (90%) had primary enuresis and 5 (10%) had secondary enuresis. 151 diurnal enuresis was reported in 4 (8%), nocturnal in 33 (66%), and both diurnal and 152 nocturnal in 13 (26%). daily enuresis was found in 22 (44%) children, several 153 times/week in 15 (30%), once/week in 5 (10%), and once or more per month in 8 154 (16%). [table 1] 155 156 no significant difference was noticed between children with and without enuresis 157 regarding age, sex, birth order, family income, stressful life events, and parents' level 158 of education. however, family history of enuresis, and higher number of siblings were 159 found to be significantly associated with enuresis [table 2]. 160 161 all children included in the study have sickle cell anemia and sickle/ βthalassemia. 162 none was found to have other types of scd. in univariate analysis, children with 163 enuresis exhibited a significantly higher proportion of hyposthenuria than those 164 without enuresis (24.0% vs. 6.3%, p=0.002). although enuretic children had a higher 165 percentage of sleep disorders and hospitalization rate and frequency during the 166 previous 12 months than non-enuretic, the difference was not found to be significantly 167 different. furthermore, hemoglobin genotype, albuminuria, and serum hemoglobin 168 level, and red blood indices values (mch, mcv, and mchc values) were not 169 significantly different between the two groups [table 3]. 170 171 among scd studied patients, three variables were found to be independent predictors 172 of enuresis. these were family history of enuresis (odd ratio (or), 5.94; 95% ci, 173 2.54-13.89; p<0.001), hyposthenuria (or, 3.76; 95% ci, 1.25-13.30; p=0.018) and 174 sleep disorders (or, 2.90; 95%ci, 1.19-7.06; p= 0.019) [table 4]. in contrast, none 175 of the other investigated variables was shown to be independent predictors of 176 enuresis. 177 178 discussion 179 our study has revealed that prevalence rate of enuresis was 31.1% among sickle cell 180 disease pediatric patients. other studies have reported varying rates of enuresis in this 181 group of patients; in the united kingdom, london (35.7%), 14 sudan (38%), 15, 182 saudi arabia (48.6%), 16 and nigeria (49.4%). 11 such variation in the prevalence 183 rates might be due to disparities in the definition of enuresis, sampling method, 17 184 socio-cultural differences, and study design whether population or health institute 185 based studies. 18 earlier studies in iraq showed lower prevalence of enuresis among 186 children without scd, which ranges from 7.5% 29.5%. 18-20 many studies have 187 consistently found a strong relationship between sickle cell disease and enuresis. 21,22 188 sickle cell disease significantly affects renal structure and function, reflected in a 189 variety of renal syndromes and diseases including abnormal hemodynamics, 190 glomerulopathies, and hyposthenuria (impaired urinary concentrating ability). 23 191 192 the logistic regression analysis showed that hyposthenuria was independently and 193 significantly associated with enuresis (or, 3.76; 95% ci, 1.25-11.30; p= 0.018). a 194 long before, 24 hyposthenuria-induced nocturnal polyuria was thought to be the cause 195 of nocturnal enuresis in sickle cell anemia (sca) patients. this theory is reinforced 196 by the fact that hyposthenuria is a common and early infarction-related renal 197 complication. 25 ugwu et al. later demonstrated the same results. 26 however, eneh et 198 al. 7 and readett et al. 27 found no association between enuresis and hyposthenuria, 199 and after water deprivation, scd children with enuresis had the same maximum 200 voided urine volume as those without enuresis. they attributed enuresis to reduced 201 functional bladder capacity and other factors such as social and environmental 202 influences and decreased arousal during sleep. 7,27 203 204 factors other than hyposthenuria were found to be significantly and independently 205 associated with enuresis. family history of enuresis was found to be an independent 206 predictor of enuresis with an adjusted odds ratio of 5.94 (95% ci, 2.54-13.89; 207 p<0.001). a result, that has been reported before. 18,28 such association highlights the 208 importance of genetic roots in the etiology of enuresis. 28 209 210 although the rate of sleep disorders was higher in enuretic children (30.0%) compared 211 to 17.1% in non-enuretic children in univariate analysis, the difference was not 212 significant (p=0.064). however, after adjustment for other variables, sleep disorders 213 were observed to be an independent predictor for enuresis (adjusted or, 2.90; 95% 214 ci, 1.19-7.06; p=0.019). other studies have found that children with scd are more 215 likely to have sleep difficulties, which cause them to be unable to awaken from sleep 216 in response to a full bladder, resulting in enuresis. 29,30 a variety of factors, including 217 pain, environmental, psychological, and treatment factors (which were not 218 investigated in this study), have been reported to influence sleep disorders. 31 these 219 factors might confound such relationship. the precise relationship between sleep 220 disorders and enuresis needs to be further investigated. furthermore, the absence of 221 polysomnography and parents' reported data made defining sleep problems difficult. 222 lehmann et al who reported an association between sleep disorders and enuresis 223 recommended that children with scd and enuresis have to be referred to the 224 pulmonologist for the evaluation of sleepdisordered breathing. 32 225 226 nocturnal enuresis in individuals with airway obstruction is thought to be caused by 227 increased synthesis of atrial natriuretic peptide, which raises the arousal threshold 228 during sleep. 33 229 230 the aggregation of two or all of the three independent risk factors mentioned above 231 was significantly higher in enuretic children than in non-enuretic children. in the 232 enuretic children, 37 (74.0%) had 0-1 risk factor of the three independent risk factors, 233 11 (22.0%) had 2 risk factors, and 2 (4.0%) had all three factors, compared to 109 234 (98.2%) who had 0-1 risk factor, 2 (1.8%) had 2 risk factors, and none (0.0%) had all 235 three factors (p <0.001). 236 237 family income, parents' level of education, and birth order did not affect the 238 association with enuresis, a result that agrees with many previous studies.20,34 239 however, other studies reported a significant impact of socio-economic status on 240 enuresis prevalence rates. 15,35 thus, it seems that there is no agreement on the 241 significance of socio-economic status as a risk factor for enuresis. this could be 242 attributed to the relative inaccuracy of social basic facilities in determining social rank 243 or it might reflect the increased knowledge and awareness regarding health and 244 health-related issues among all socioeconomic groups. 27 245 246 our findings revealed that the well-documented decrease in enuresis prevalence with 247 age in children without scd 20,36 was less evident in children with scd, implying 248 that some scd-related morbidities, such as intravascular sickling and vaso-occlusion, 249 improved less spontaneously in children with scd. 25,37 this result is consistent with 250 what other researchers have found. 11,37 although enuresis is frequently reported to be 251 more prevalent in boys than girls in children without scd, 34 gender was not 252 associated with enuresis in our study. this finding is consistent with the findings of 253 esezobor et al. 11 according to one possible theory, several sickle cell-related 254 characteristics may be related to enuresis. readett et al. 27 observed a higher rate of 255 enuresis in children with hemoglobin ss, as well as a lower fetal hemoglobin level. in 256 agreement with esezobor et al., 11 no association was identified between enuresis and 257 history of hospitalization during the 12 months preceding the study. 258 259 though the number of siblings had a significant association with enuresis in 260 univariate analysis (p= 0.018), the logistic regression analysis revealed no effect after 261 adjusting for other variables. this result is consistent with that reported by others. 38 262 our study is limited in that it was a cross-sectional study; thus, no causal relationships 263 between variables could be established. furthermore, polysomnography was not done 264 to assess the pattern of sleep disordered breathing. recall bias cannot be entirely 265 eliminated. the form and content of questions, as well as connecting exposure to 266 specific life events, may all have an impact on recall accuracy. scd impacts the 267 psychosocial and quality of life in general, therefore, parents who have children with 268 the disease are more likely to recall previous exposure of their children. 269 270 the study's strength is that it is the first in iraq to measure the prevalence and 271 determinants of enuresis in children with scd, with special emphasis on the most 272 controversial determinant, hyopsthenuria. 273 274 conclusions 275 enuresis is common in pediatric patients with sickle cell disease. hyposthenuria, 276 family history of enuresis, and sleep disorders were significant independent predictors 277 of enuresis. children with sickle cell disease, especially those with a family history of 278 enuresis, should be assessed frequently for enuresis and kidney function. 279 280 authors’ contributions 281 jn, mk and am designed and planned the study. am and ds collected the data. jn 282 and mk contributed to the data analysis and drafting of the manuscript. all authors 283 reviewed and approved the final version of the manuscript. 284 285 conflict of interest 286 the authors declare no conflicts of interest. 287 288 funding 289 no funding was received for this study. 290 291 rerferences 292 1. xu jz, thein sl. the carrier state for sickle cell disease is not completely 293 harmless. haematologica 2019; 104: 1106–11.doi: 10.3324/haematol.2018.206060. 294 2. hassan mk, taha jy, al-naama lm, widad nm, jasim sn. frequency of 295 haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in basra. 296 east mediterr health j 2003;9:45–54. 297 3. uwaezuoke sn, eneh ci, ezenwosu ou, ndu ik. nocturnal enuresis in children 298 with sickle cell anemia. in: zakaria m, hassan t. contemporary pediatric 299 hematology and oncology [internet]. london: intech open; 2019, pp: 824–33. [cited 300 2022 feb 16]. available from: https://www.intechopen.com/books/7084 doi: 301 10.5772/intechopen.73875. 302 4. hariri e, mansour a, el alam a, daaboul y, korjian s, bahous sa. sickle cell 303 nephropathy: an update on pathophysiology, diagnosis, and treatment. int urol 304 nephrol. 2018;50:1075–83. doi: 10.1007/s11255-018-1803-3. 305 5. wolf rb, kassim aa, goodpaster rl, debaun mr. nocturnal enuresis in sickle 306 cell disease. expert rev hematol. 2014;7:245–54. 307 doi:10.1586/17474086.2014.892412. 308 6. da silva gb jr, libório ab, daher ede f. new insights on pathophysiology, 309 clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. ann 310 hematol. 2011;90:1371–9. doi: 10.1007/s00277-011-1327-8. 311 7. eneh ci, ikefuna an, okafor hu, uwaezuoke sn. nocturnal enuresis in school312 aged children with sickle-cell anemia: any relationship with hyposthenuria?. niger j 313 clin pract 2017;20:215–20.doi: 10.4103/1119-3077.187326. 314 8. uwaezuoke sn, eneh ci, ndu ik. nocturnal enuresis in children with sickle-cell 315 anemia: global prevalence rates, gender bias and hypotheses on pathogenesis. internal 316 medicine review 2016, 11 pages doi: 10.18103/imr.v0i5.119. 317 9. fang y, raat h, windhorst da, fierloos in, jonkman h, hosman cmh, crone 318 mr, jansen w, van grieken a. the association between stressful life events and 319 emotional and behavioral problems in children 0-7 years old: the cikeo study. 320 int j environ res public health. 2022;19:1650. doi: 10.3390/ijerph19031650. 321 10. kwak bo, chung s,kim ks. microalbuminuria in children with urinary tract 322 infection. korean j pediatr. 2010; 5: 840–44.doi: 10.3345/kjp.2010.53.9.840.z 323 11. esezobor ci, akintan p, nwaogazieu, akinwunmi e, temiye e, akinsulie a, et 324 al. enuresis in children and adolescents with sickle cell anaemia is more frequent and 325 substantially different from the general population. plos one 2018;13:e0201860. 326 doi: 10.1371/journal. pone.0201860. 327 12. austin pf, bauer sb, bower w, chase j, franco i, hoebeke p, et al. the 328 standardization of terminology of lower urinary tract function in children and 329 adolescents: update report from the standardization committee of the international 330 children’s continence society. neurourol. urodynam. 2015;9999:1–11. doi: 331 10.1002/nau.22751 332 13. cheesebrough m. examination of urine. in: district laboratory practice in 333 tropical countries. england: cambridge university press; 2002. p. 711–2. 334 14. chakravorty s, de la fuente j, mohammed a. prevalence of nocturnal enuresis 335 and proteinuria in children with sickle cell disease and its relation to severity of 336 painful crises. blood 2013;122:4693. doi: 10.1182/blood.v122.21.4693.4693. 337 15. ahmed fe, salim ee, salih km. nocturnal enuresis among sudanese children 338 with sickle cell disease. curr pediatr res 2016; 20: 294–300. 339 16. alzhrani fs, alsadiq sa, ghaith mm, simsim nn, kommosani nh, al-qahtani 340 wh, et al. enuresis in children and adolescents with sickle cell anemia is more 341 frequent and substantially different from the general population. curr pediatr res 342 2020; 24:298–302. 343 17. bakhtiar k, pournia y, ebrahimzadeh f, farhadi a, shafizadeh f, hosseinabadi 344 r. prevalence of nocturnal enuresis and its associated factors in primary school and 345 preschool children of khorramabad in 2013. int j pediatr. 2014;2014:120686. doi: 346 10.1155/2014/120686. 347 18. saleh aa, al-saffar aj. nocturnal enuresis and its relation to child’s behavior 348 in a sample of children from baghdad, iraq. iraqi jms 2015;3:7–13 349 19. abed ah, habib os, majeed mn. prevalence of enuresis in nassiriyah city 350 thiqar governorate. med j basrah univ 2009;27:42–5. 351 20. murad mc, obaid aa, ali fm. prevalence of nocturnal enuresis and its 352 associated ultrasonic findings in children of wasit. sys rev pharm 2020;11:120–2. 353 21. portocarrero ml, portocarrero ml, sobral mm, lyra i, lordelo p, barroso u jr. 354 prevalence of enuresis and daytime urinary incontinence in children and adolescents 355 with sickle cell disease. j urol 2012;187:1037–40. doi: 10.1016/j.juro.2011.10.171 356 22. ekinci o, celik t, ünal ş, oktay g, toros f, ozer c. nocturnal enuresis in sickle 357 cell disease and thalassemia major: associated factors in a clinical sample. int j 358 hematol 2013;98:430–6. doi: 10.1007/s12185-013-1422–9. 359 23. nath ka, hebbel rp. sickle cell disease: renal manifestations and mechanisms. 360 nat rev nephrol. 2015;11:161–71. doi:10.1038/nrneph.2015.8. 361 24. noll jb, newman aj, gross s. enuresis and nocturia in sickle cell disease. j 362 pediatr 1967;70:965–7. 363 25. reid cd. renals. in: bertnam l, reid cd, charache c, lubin b, editors. 364 management and therapy of sickle cell disease. 3rd ed. maryland: nih publication; 365 1995. pp. 95–100. 366 26. ugwu ro, eke fu. urinary abnormalities in children with sickle cell anaemia. 367 port harcourt med j 2007;2:45–50. doi: 10.4314/phmedj.v2i1.38892. 368 27. readett dr, morris j, serjeant gr. determinants of nocturnal enuresis in 369 homozygous sickle cell disease. arch dis child 1990;65:615–8. 370 28. fockema mw, candy gp, kruger d, haffejee m. enuresis in south african 371 children: prevalence, associated factors and parental perception of treatment. bju int. 372 2012;110:e1114–20. doi:10.1111/j.1464-410x.2012.11416.x 373 29. sharma s, efird jt, knupp c, kadali r, liles d, shiue k, boettger p, quan sf. 374 sleep disorders in adult sickle cell patients. j clin sleep med 2015;11:219–23. doi: 375 10.5664/jcsm.4530. 376 30. daniel lc, grant m, kothare sv, dampier c, barakat lp. sleep patterns in 377 pediatric sickle cell disease. pediatr blood cancer. 2010;55:501-7. doi: 378 10.1002/pbc.22564. 379 31. hassan mam, darwish mm, abd el-samed ma. factors causing sleep 380 disturbances among school age children with sickle cell disease. med. j. cairo univ. 381 2019;87:1805–15. doi: 10.21608/mjcu.2019.54023 382 32. lehmann gc, bell tr, kirkham fj, gavlak jc, ferguson tf, strunk rc, et al. 383 enuresis associated with sleep disordered breathing in children with sickle cell 384 anemia. j urol. 2012;188: 1572–76.doi: 10.1016/j.juro.2012.02.021. 385 33. sakellaropoulou av, hatzistilianou mn, emporiadou mn, aivazis vt,goudakos 386 j, markou k, et al. association between primary nocturnal enuresis and habitual 387 snoring in children with obstructive sleep apnoea-hypopnoea syndrome. arch med 388 sci 2012;8:521–7.doi: 10.5114/aoms.2012.28809. 389 34. eneh ci, okafor hu, ikefuna an, uwaezuoke sn. nocturnal enuresis: 390 prevalence and risk factors among school-aged children with sickle-cell anaemia in a 391 south-east nigerian city. ital. j. pediatr 2015;41:66. doi: 10.1186/ s13052-015-0176-392 9. 393 35. lee ja, johns ts, melamed ml, tellechea l, laudano m, stern jm, et al. 394 associations between socioeconomic status and urge urinary incontinence: an 395 analysis of nhanes 2005 to 2016. j urol. 2020;203:379–84.doi: 396 10.1097/ju.0000000000000542 397 36. huang hm, wei j, sharmas,bao y, li f, song jw, et al. prevalence and risk 398 factors of nocturnal enuresis among children ages 5–12 years in xi’an, china: a cross-399 sectional study. bmc pediatr 2020;20:305. doi: 10.1186/s12887-020-02202-w 400 37. nelli am, mrad fcc, alvaia ma, maia haads, guimarães cos, carvalho 401 ess, et al. prevalence of enuresis and its impact in quality of life of patients with 402 https://dx.doi.org/10.21608/mjcu.2019.54023 sickle cell disease. int braz j urol 2019;45:974–80. doi: 10.1590/s1677-403 5538.ibju.2019.0026. 404 38. yousef ka , basaleem ho , taher bin yahiya m. epidemiology of nocturnal 405 enuresis in basic schoolchildren in aden governorate, yemen. saudi j kidney dis 406 transplant 2011;22:167–73. 407 408 table 1: types of enuresis reported among studied scd patients 409 variable no. % onset of enuresis primary secondary 45 5 90 10 time of enuresis diurnal nocturnal both 4 33 13 8 66 26 frequency daily several times/ week once/week once or more/month 22 15 5 8 44 30 10 16 total 50 100 410 table 2: association of enuresis with socio-demographic characteristics 411 variable enuresis no enuresis pvalue age (years), mean ±sd 10.4±2.8 11.2±2.9 0.119 age (years) 6-7 8-9 10-11 12-13 14-15 9 (18.0) 11 (22.0) 10 (20.0) 11 (22.0) 9 (18.0) 21 (18.9) 13 (11.7) 20 (18.0) 24 (21.6) 33 (29.7) 0.369 male sex, no. (%) 34 (68.0) 64 (57.7) 0.228 no. of siblings, no. (%) 0 1 2 3 4 5 & more 4 (8.0) 2 (4.0) 5 (10.0) 9 (18.0) 12 (24.0) 18 (36.0) 1 (0.9) 11 (9.9) 21 (18.9) 33 (29.7) 18 (16.2) 27 (24.3) 0.018 birth order, no. (%) first second third fourth 12 (24.0) 11 (22.0) 12 (24.0) 5 (10.0) 37 (33.3) 33 (29.7) 22 (19.8) 7 (6.3) 0.316 fifth or higher 10 (20.0) 12 (10.8) family history of enuresis, no. (%) yes no 24 (48.0) 26 (52.0) 16 (14.4) 95 (85.6) <0.001 per capita family monthly income (iqd), no. (%) <2500,000 250,000 -500,000 > 500,000 33 (66.0) 15 (30.0) 2 (4.0) 84 (75.2) 22 (19.8) 5 (4.5) 0.402 father's education (years) < 12 ≥ 12 41 (82.0) 9 (18.0) 83 (74.8) 28 (25.2) 0.418 mother's education (years) < 12 ≥ 12 37 (74.0) 13 (26.0) 89 (80.2) 22 (19.8) 0.412 stressful life's event yes no 15 (30.0) 35 (70.0) 20 (18.0) 91 (82.0) 0.101 total 50 (31.1) 111 (68.9) no.= number, iqd= iraqi dinar 412 413 table 3: association of enuresis with certain clinical characteristics 414 variable enuresis n= 50 no enuresis n= 111 p value hemoglobin genotype, no. (%) sca sc/ thalassemia 23 (46.0) 27 (54.0) 52 (46.8) 59 (53.2) 0.999 hyopsthenuria, no. (%) 12 (24.0) 7 (6.3) 0.002 sleep disorders, no. (%) 15 (30.0) 19 (17.1) 0.064 hospitalization during the last year, no. (%) 42 (84.0) 78 (72.2) 0.115 frequency of hospitalization, no. (%) no 1-3 times 4-6 times >6 times 8 (16.0) 13 (26.0) 14 (28.0) 15 (30.0) 33 (29.7) 33 (29.7) 29 (26.1) 16 (14.5) 0.068 albuminuria (mg/g), no. (%) < 30 30 -300 >300 43 (86.0) 2 (4.0) 5 (10.0) 89 (80.2) 13 (11.7) 9 (8.1) 0.296 hb (g/dl) 9.4 ± 1.7 9.4 ± 0.9 0.954 mch (pg/cell), mean± sd 25.5±5.0 26.9±3.6 0.579 mcv (fl), mean± sd 75.5±11.4 80.8±9.7 0.408 mchc (gm/dl), mean± sd 33.5±1.7 33.2±1.2 0.742 no.= number, sca= sickle cell anemia, sc= sickle cell, hb= hemoglobin, mch= 415 mean corpuscular hemoglobin, mcv= mean corpuscular volume, mchc= mean 416 corpuscular hemoglobin concentration 417 418 table 4: logistic regression analysis 419 parameter β coefficient or 95% ci for or p-value lower upper family history of enuresis 1.781 5.94 2.54 13.89 <0.001 hyposthenuria 1.326 3.76 1.25 11.30 0.018 sleep disorders 1.066 2.90 1.19 7.06 0.019 420 departments of 1infectious disease and 3gastroenterology, royal hospital, muscat, oman; 2department of medicine, ibri hospital, ibri, oman *corresponding author’s e-mail: cgolchin@gmail.com amoebic liver abscess a disease native to oman? nenad pandak,1 *sirous golchinheydari,1 asmaa s. mahdi,1 ali al majrafi,2 stephen s. deenadayalan,3 faryal khamis1 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 253–256, epub. 26 may 22 submitted 17 nov 20 revision req. 11 jan 21; revision recd. 7 mar 21 accepted 14 apr 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.083 clinical & basic research abstract: objectives: amoebic liver abscess (ala) is endemic to many areas of the world. this study sought to investigate the epidemiology, presentation, laboratory tests and imaging characteristics of ala in oman and ultimately determine whether it is native to oman or originated abroad. methods: this case series study was conducted at the royal hospital, muscat, oman, from january 2013 to december 2017 with patients older than 13 years and having a discharge diagnosis of ala. patient data were extracted from the royal hospital patient database. results: 22 patients were included in the study—18 omani patients and four expatriates. only two omanis had a history of traveling abroad. there were 15 male patients and seven were female with an average age of 45.2 years. the most common presentation was abdominal pain, which was seen in 17 patients. fever was seen in 13 patients. alanine transferase was found to be elevated in 13 patients. the majority of patients (90%) had no symptomatic infections prior to developing ala. conclusion: the data suggests that ala is endemic to oman, considering the high number of local patients and lack of travel abroad in this population. as the number of patients treated for ala is rather small, it can be concluded that the occurrence of ala is much lower in oman than in other endemic areas. the majority of patients had no prior symptomatic infections; thus, a method of control involves screening to prevent amoebic spread. keywords: amoebic liver abscess; amoebiasis; liver abscess; entamoeba histolytica; oman. advances in knowledge amoebic liver abscess is endemic to oman. a large proportion of patients are asymptomatic carriers in oman. this study’s results are contrary to what other countries in the region with a similar migrant population have reported. application in patient care healthcare professionals should actively look for and treat infected patients to limit the amoebic spread. amoebic liver abscess (ala) is a secondaryresult of amoebiasis caused by entamoeba histolytica, a protozoan transmitted mainly through the faecal–oral route. this can occur through the ingestion of water or food that is contaminated with cysts excreted via faeces.1 amoebic infections are mostly asymptomatic, but invasive intestinal disease can occur in the colon when the invasive trophozoite form invades colonic mucosa and activates a strong immune response, thus causing further tissue damage.2 access to mesenterial vessels can result in haematogenous amoebic dissemination to extra-intestinal sites, potentially causing a liver abscess.3 ala is the most common extra-intestinal manifestation and has a widespread global impact; it primarily affects developing countries with poor hygiene and inadequate sanitation.4 high rates of ala are seen in the indian subcontinent, east asia, africa and central and south america.5 immigration is an important factor for cases discovered in non-endemic areas. despite the above, ala reports from countries in the arabian peninsula are scarce. studies in saudi arabia and qatar show that a very large proportion of ala patients are either foreigners or local citizens that have travelled to endemic areas.6,7 to the best of the authors’ knowledge, the epidemiological situation related to ala in oman remains unknown. similar to other gulf countries, oman has a large migrant worker community from endemic areas in asia and as of 2020, they account for approximately 40% of the population.8 it is, therefore, natural to assume that the majority of ala patients would also be migrants. accordingly, this retrospective study aimed to establish the epidemiological and clinical characteristics of ala cases in oman and determine if oman is a region endemic to ala or if most of the cases originate elsewhere. methods this study was carried out at the royal hospital in muscat, oman and data was extracted from the hospital database. patients older than 13 years of age who were diagnosed with ala and admitted to the royal hospital between january 2013 and december 2017 were included. the diagnosis was confirmed via https://creativecommons.org/licenses/by-nd/4.0/ amoebic liver abscess a disease native to oman? 254 | squ medical journal, may 2022, volume 22, issue 2 the commercial immunoglobulin g (igg) anti-amoebic assay (r-biopharmag, darmstadt, germany). the extracted data included patient biodata and history, comorbidities, laboratory values, radiological imaging reports and procedures carried out. these were analysed using descriptive statistical methods with microsoft office word, version 2017 (microsoft corp., redmond, washington, usa). ethical approval was obtained from the royal hospital scientific research committee (code: src#32/2018). results during the five-year period considered for this study, 75 patients were treated for liver abscess. of these, 53 were confirmed to have pyogenic liver abscess and 22 patients were confirmed and treated for ala. eighteen patients were omanis and four were expatriates; of the latter, three were from india and one was from pakistan. there were 15 (68%) male patients and seven (32%) were female. the patient ages ranged from 16 to 77 years and the average age was 45.2. the average age of the men was higher (47.4) than the women (40.6). the most common presentation, as seen in 17 (77%) patients, was abdominal pain. fever was a common symptom in 13 patients (59%), while jaundice was far less common and presented only in three (14%) patients. diabetes mellitus was the most common comorbidity found in patients with ala. a total of seven patients had comorbidities, out of which five (71%) had diabetes mellitus while the rest had hepatobiliary disease. all but one patient was admitted to the general ward, while that one patient was admitted to the icu. none of the patients required urgent surgery and none presented with sepsis or septic shock. laboratory testing was done for alanine amino transferase (alt), bilirubin, albumin, leukocyte and platelet levels. a significant number of patients (n = 13; 59%) presented with above-normal alt, while nine (41%) patients presented with normal alt levels. however, bilirubin did not follow the same trend. the majority of patients (n = 13; 59%) had normal bilirubin levels, while nine (41%) had raised bilirubin levels. albumin levels were similar to bilirubin; it was normal in the majority of patients (n = 20; 91%) and only two (9%) had abnormal albumin levels. as expected, most patients presented with leukocytosis. exactly half (50%) the patients had leukocyte counts in the range of 10–20/µl of blood, while seven (32%) patients had counts of more than 20/µl of blood. only one (4%) patient had an abnormal platelet count. the anatomical position of the abscess was established for each patient using multiple radiological imaging techniques. a total of 19 (86%) patients were found to have an abscess in the right lobe, while three (14%) patients had bilateral abscesses. the presentation of a single abscess was found in 15 (68%) patients, while multiple abscesses were found in seven (32%). percutaneous drainage was done for 18 patients (82%). no prior infections were found in 90% of patients. the remaining 10% had previously had gastrointestinal infections. this shows that the majority were asymptomatic carriers. the outcome of all the patients was good. none of the patients died and they were all cured and discharged from the hospital. discussion the available data show that a significant number of liver abscesses are reported to be pyogenic in origin and not amoebic.9 invasive amoebiasis, such as ala, is attributed to 50 million infections worldwide.2 the incidence rate in the us is 8.5/100,000 hospital admissions, with extremely low mortality.10 the known endemic area of sri lanka has reported an incidence of 3–9/10,000 hospital admissions.11 taiwan, another known endemic area, has attributed the sharp drop in the high prevalence rate of ala to improved sanitation.12,13 at the same time, the mortality rate was reported to be 2.4%. to the best of the authors’ knowledge, there is no data about the prevalence of ala in oman and its neighbouring countries in the arabian peninsula. it can be assumed that ala occurrence in oman is low and, as shown by this study, the mortality rate is considerably lower when compared to the regions indicated in other studies. notably, the present study was conducted at a single centre, the royal hospital in muscat, and does not represent the incidence of ala in oman. however, the royal hospital is a tertiary care centre and the biggest hospital in the country, containing the largest infectious diseases department in the country. immunocompromised hosts are prone to developing ala.14 it is well known that diabetes mellitus is the most common predisposing factor to pyogenic liver abscess, but no such conclusion seems to have been drawn about ala.6,7 the data from the present study suggest that diabetes mellitus is also a major risk factor for ala, as approximately 71% of the patients with comorbidities had diabetes mellitus. it is also well known that the ala is more common in men and, as one study from india showed, that the gender nenad pandak, sirous golchinheydari, asmaa s. mahdi, ali al majrafi, stephen s. deenadayalan and faryal khamis clinical and basic research | 255 proportion of men can rise up to 93%.15 similarly, a report from qatar showed that only 9% of their ala patients were female.7 in the present study, about twothirds of the patients were male, but this proportion could be biased due to the cohort size. it has previously been reported that ala most often occurs in the age group of 18–50 years and the present study’s data is in agreement with this.16 in the us, most of the ala cases are found among the immigrant population, mostly from mexico.17,18 reports from qatar and saudi arabia show that the majority of patients are either expatriates or had a history of travel to endemic areas.6,7 in contrast, most of the patients in the present study were locals and only two of them had a history of travel. one travelled to pakistan three months prior to his illness and the other one visited india a year before the onset of his illness. this indicates that, unlike saudi arabia and qatar, ala is indigenous to oman. coinciding with the study data, abdominal pain in the right upper quadrant and fever have been reported to be the most common forms of presentation.17 septic shock or admission to the icu, which can be used as a parameter of disease severity, does not seem to be common among ala patients as this is not addressed in the existing literature. the present study’s results were similar, although one of the 22 patients was admitted and treated in the icu. the majority of the patients (86%) in the present study had abscesses in the right liver lobe and the left lobe was involved only in patients with bilateral abscesses. other studies have showed that about half of ala cases involve the right lobe and the rest are left-sided or bilateral.9 the right lobe of the liver has more blood supply, which may explains why more lesions are found on the right side of the liver. it has been reported that a rather small number of patients have bilateral lesions; this aligns with the present study’s data, which shows that 14% of the patients had bilateral lesions.13 previously published studies state that ala cases usually involve single abscesses, as was found in the present study’s cohort. amoebiasis occurs after the ingestion of e. hystolitica cysts found in faecally contaminated water or food. the cyst migrates to the colon and undergoes excystation, releasing trophozoites that can penetrate colonic mucosa and the hepatic portal circulation, resulting in haematogenous spread. this spread often leads to ala formation, but in rare cases, the trophozoite can even spread to other organs.2 almost 90% of infected patients are asymptomatic and fewer than 1% of patients with amoebic colitis have associated extra-intestinal disease manifestation, most often ala.11 this explains why only 10% of the study patients previously had a history of intestinal infection and it also indicates that, prior to the ala, these asymptomatic patients represented a significant risk to their environment. it is estimated that e. hystolitica globally affects around 50 million people every year, causing more than 10,000 deaths in 2013.2 this includes occurrences of intestinal and extra-intestinal amoebiasis. mortality varies around the world and depends on whether the country is in an endemic area as well as the quality of and access to healthcare. there is no data regarding the ala mortality rate of countries in the arabian peninsula. notably, there were no fatal outcomes connected to ala treatment in the present study, most probably because of easy access to high-quality healthcare facilities in oman. the main limitation of this study is its singlecentre design and rather small sample size. due to this, it is not representative of the ala epidemiology in oman, but it provides good insights into the epidemiological situation in the country and serves as a good starting point for further studies. conclusion as the majority of the study patients were omanis without any history of travel to ala endemic areas, it can be concluded with high certainty that oman is an endemic area but with considerably lower ala occurrence than other endemic areas close by. in addition, the majority of patients were asymptomatic cyst passers prior to their diagnosis and represented a significant risk for others; therefore, it is important to actively look for infected persons and begin early treatment to prevent the amoebic spread. c o n f l i c t o f i n t e r e s t the authors of this article declare that there is no conflict of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n np and sg designed the research. data collection was carried out by all authors. sg analysed the results and drafted the manuscript. all authors contributed with suggestions and amendments to the initial version of the manuscript. all authors approved the final version of the manuscript. amoebic liver abscess a disease native to oman? 256 | squ medical journal, may 2022, volume 22, issue 2 references 1. kantor m, abrantes a, estevez a, schiller a, torrent j, gascon j, et al. entamoeba histolytica: updates in clinical manifestation, pathogenesis, and vaccine development. can j gastroenterol hepatol 2018; 2018:1–6. https://doi.org/10.1155/2018/4601420. 2. tharmaratnam t, kumanan t, iskandar m, d’urzo k, gopeeramanan p, loganathan m, et al. entamoeba histolytica and amoebic liver abscess in northern sri lanka: a public health problem. trop med health 2020; 48:1–13. https://doi.org/10.1 186/s41182-020-0193-2. 3. drinić m, raninger a, zraunig a, astelbauer f, leitsch d, obwaller a. activity of methylgerambullin from glycosmis species (rutaceae) against entamoeba histolytica and giardia duodenalis in vitro. int j parasitol drugs drug resist 2019; 10:109–17. https://doi.org/10.1016/j.ijpddr.2019.08.001. 4. torre a, kershenobich d. amebic liver abscess. ann hepatol 2002; 1:45–7. https://doi.org/10.1016/s1665-2681(19)32192-1. 5. chou a, austin rl. entamoeba histolytica. treasure island, usa: statpearls publishing, 2020. 6. albenmousa a, sanai fm, singhal a, babatin ma, alzanbagi aa, al-otaibi mm, et al. liver abscess presentation and manage ment in saudi arabia and the united kingdom. ann saudi med 2011; 31:528–32. https://doi.org/10.4103/0256-4947.84635. 7. abbas m, khan f, muhsin s, al-dehwe b, abukamar m, elzouki a. epidemiology, clinical features and outcome of liver abscess: a single reference center experience in qatar. oman med j 2014; 29:260–3. https://doi.org/10.5001/omj.2014.69. 8. national centre for statistics and information. from: https:// www.ncsi.gov.om/pages/ncsi.aspx accessed: mar 2021 9. akhondi h, sabih de. liver abscess. treasure island, usa: statpearls publishing, 2020. 10. seeto rk, rockey dc. amebic liver abscess: epidemiology, clinical features, and outcome. west j med 1999; 170:104–9. 11. kannathasan s, murugananthan a, kumanan t, de silva n, rajesh kannan n, haque r, et al. epidemiology and factors associated with amoebic liver abscess in northern sri lanka. bmc public health 2018; 18:1–8. https://doi.org/10.1186/s12889-018-5036-2. 12. chuah sk, chang-chien cs, sheen is, lin hh, chiou ss, chiu ct, et al. the prognostic factors of severe amebic liver abscess: a retrospective study of 125 cases. am j trop med hyg 1992; 46:398-402. https://doi.org/10.4269/ajtmh.1992.46.398. 13. chen h, lin i, wu c, lee y, bair m. clinical manifestations and risk factors of amebic liver abscess in southeast taiwan compared with other regions of taiwan. am j trop med hyg 2013; 89:1214–18. https://doi.org/10.4269/ajtmh.13-0300. 14. sayek i, onat d. pyogenic and amebic liver abscess. in: holzheimer rg, mannick ja, eds. surgical treatment: evidence-based and problem-oriented. munich, germany: zuckschwerdt, 2001. 15. singh a, banerjee t, kumar r, shukla s. prevalence of cases of amebic liver abscess in a tertiary care centre in india: a study on risk factors, associated microflora and strain variation of entamoeba histolytica. plos one 2019; 14:e0214880. https:// doi.org/10.1371/journal.pone.0214880. 16. prakash v, jackson-akers jy, oliver ti. amebic liver abscess. treasure island, usa: statpearls publishing, 2019. from: https ://europepmc .org/article/nbk/nbk430832#impact accessed: mar 2021. 17. giorgio a, esposito v, farella n, di sarno a, liorre g, de stefano m, et al. amebic liver abscesses: a new epidemiological trend in a non-endemic area? in vivo 2009; 23:1027–30. 18. hoffner r, kilaghbian t, esekogwu v, henderson s. common presentations of amebic liver abscess. ann emerg med 1999; 34:351–5. https://doi.org/10.1016/s0196-0644(99)70130-7. https://doi.org/10.1155/2018/4601420 https://doi.org/10.1186/s41182-020-0193-2 https://doi.org/10.1186/s41182-020-0193-2 https://doi.org/10.1016/j.ijpddr.2019.08.001 https://doi.org/10.1016/s1665-2681(19)32192-1 https://doi.org/10.4103/0256-4947.84635 https://doi.org/10.5001/omj.2014.69 https://doi.org/10.1186/s12889-018-5036-2 https://doi.org/10.4269/ajtmh.1992.46.398 https://doi.org/10.4269/ajtmh.13-0300 https://doi.org/10.1371/journal.pone.0214880 https://doi.org/10.1371/journal.pone.0214880 https://doi.org/10.1016/s0196-0644(99)70130-7 the arab board of health specializations, amman, jordan author e-mail: oalrawas@arab-board.org this work is licensed under a creative commons attribution-noderivatives 4.0 international license. in memory of professor bazdawi al-riyami, md omar a. al-rawas obituary sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 513, epub. 25 nov 21 https://doi.org/10.18295/squmj.11.2021.146 it is a great privilege to reflect on my association with the mentor and colleague, professor bazdawi al-riyami who passed away on september 28, 2021. i first met prof. bazdawi in 1984 in glasgow, scotland, during my undergraduate studies at the university of glasgow, where he was doing his ph.d. in respiratory medicine. i have been privileged to have him as a great coach who has contributed to shaping my professional development throughout my career. he was generous with his time, knowledge and spirit and was always ready to share his experience with remarkable wisdom, humility and encouragement. he was a role model to many healthcare providers in oman. prof. bazdawi completed his medical degree at the university of baghdad, iraq, and started his career as a junior doctor at salalah hospital, dhofar region, in 1972. two years later, he received a government scholarship to complete his general professional training in the united kingdom. he acquired the membership of royal colleges of physicians in 1976 and returned to oman in 1977 to work as a senior specialist in the ministry of health. in 1984, he joined the sultan qaboos “university project” and was awarded another scholarship for higher professional training. he obtained his ph.d. degree from the university of glasgow in 1988 and the same year he was elected a fellow of the royal colleges of physicians and surgeons of glasgow; he then rejoined sultan qaboos university (squ) as an associate professor in the college of medicine and health sciences (com-h) and a consultant in squ hospital (squh). he was promoted to full professor in 2004. prof. bazdawi was instrumental in advancing teaching and research at squ. for this, he was the primary mover and shaker of introducing a new curriculum that resonated with the situation on the ground. oman at that time was witnessing a rapid social and economic transformation coinciding with the al nahda era or renaissance. when this era is gleaned via the theory of demography in transition, oman was experiencing all the key components of the ‘second phase’ of demography transition—a decline in maternal and child mortality and the traditional enemy of health (communicable diseases). however, rising living standards have led to new challenges, namely the rise of non-communicable diseases. therefore, the existing model of health services in oman—top-down, professionallydriven and cure-oriented—was becoming incapable to withstand the vagary of a new assortment of health problems. within such a sociodemographic trend and the disease pattern in the country, prof. bazdawi embarked to revise the curriculum and research to better fit these changes. on the teaching front, the new curriculum was patched-up with the sole aim of addressing the demographic trend and emergence of diseases of affluence. he has been instrumental in expanding the scope of the com-h by establishing a full-fledged bsc in biomedical sciences and the college of nursing. thus, the medical school becomes com-h. corollary to this, research infrastructure was established under his leadership to kick-start medical research at squ—the establishment of squmj as well as an institutional review board to the squ that adheres to an evidence-based ethical approach. to date, seeds planted in teaching and research by prof. bazdawi have come to fruition. the curriculum he established has produced a new breed of competent physicians in the country. the research he has orchestrated has improved by leaps and bounds. as a result, squ is increasingly becoming a hub of international research collaboration and excellence in teaching. prof. bazdawi's contribution to healthcare in oman emerged by his personality marked with dedication, passion, patience, wisdom and thoughtfulness. the country and medical fraternity is saddened by the loss of one of the finest physicians, leader and team-maker. his legacy will remain an inspiration for generations to follow. he is survived by his beloved companion, his wife (muheira nasser al mugheiri), his daughters (nafila, hanan and maryam), his sons (usama, ahmed and mohamed) and his grandchildren. 1department of physiology, college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia; 2department of hematology, temar diagnostics, rawalpindi, pakistan; 3department of surgery, doctors hospital, lahore, pakistan *corresponding author’s e-mail: doctorfarrukhmajeed@gmail.com sleep patterns and their association with blood pressure and heart rate variability parameters in young saudi females *farrukh majeed,1 rabia latif,1 aamna latif,2 rehma bibi3 clinical & basic research sultan qaboos university med j, august 2021, vol. 21, iss. 2, pp. 394–402, epub. 29 aug 21 submitted 31 may 20 revisions req. 16 jul & 8 sep 20; revisions recd. 15 aug & 17 sep 20 accepted 29 sep 20 https://doi.org/10.18295/squmj.4.2021.014 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: disturbed sleep patterns might alter the autonomic tone and lead to various cardiovascular morbidities. this study aimed to determine sleep patterns (quality, duration, efficiency and daytime sleepiness) and explore their association with blood pressure (bp) and heart rate variability (hrv) in apparently healthy, young saudi females. methods: this cross-sectional study was conducted in the department of physiology, imam abdulrahman bin faisal university, saudi arabia between march 2019 and december 2019. self-reported pittsburgh sleep quality index and epworth sleepiness scale questionnaires were used to collect data. in addition, the participants’ bp and hrv was measured. based on the cut-off values of sleep quality, duration, efficiency and daytime sleepiness scores, participants were categorised into groups. hrv and bp were compared between the groups by a t-test/one-way anova. results: a total of 98 participants were included in this study (response rate: 72.6%). poor sleep patterns (quality, duration and efficiency) were observed, but no association was found with bp and hrv parameters among groups with different sleep quality, duration and efficiency. systolic bp was significantly increased in the moderate to severe daytime sleepiness group (p = 0.039). dozing off as a passenger in a car, in the afternoon and after lunch were negatively correlated with hrv parameters (p <0.05). conclusion: sleep quality, duration and efficiency were not found to be statistically significant, but various dozing-off situations were associated with fluctuations in hrv parameters. daytime sleepiness may augment sympathetic responses in apparently healthy female participants. keywords: sleep; daytime sleepiness; blood pressure; autonomic nervous system; sleeping habits; sleepiness; saudi arabia. advances in knowledge the current study provides a platform for education on students’ sleep health. to the best of the authors’ knowledge, this is the first study to report altered blood pressure and heart rate variability parameters in young, apparently healthy female students with daytime sleepiness and in dozing-off situations. application to patient care disturbed sleep patterns and daytime sleepiness alters the autonomic tone and may lead to various cardiovascular morbidities, affecting health and academic performance. the results of this study raise awareness regarding the potentially harmful effects of disturbed sleep patterns on health. sleep is a natural, calming mechanism of all bodies and its alteration produces multiple deleterious effects such as disturbed cognition and behaviour, mental stress and chronic fatigue.1 changes in sleep patterns might alter the autonomic tone and lead to various cardiovascular morbidities. short sleep duration and poor sleep quality both have been associated with numerous cardiovascular disease (cvd) risk factors such as hypertension, diabetes, obesity, coronary artery diseases and myocardial infarction.2 young adults (20–25 years old) are recommended to have at least six hours of sleep per day.3 women are more likely than men to report poor sleep quality, long sleep latency, short sleep duration and daytime somnolence. this not only affects their quality of life but also leads to associated morbidities.4,5 university students have reported at least twice as many sleep difficulties as the general population.6 according to a study from king khalid university (kku) in saudi arabia, medical students have poor sleep quality, longer sleep latency, shorter sleep duration and the majority go to sleep after midnight.7 gender differences have also been reported in sleep quality and other sleep variables among the student population. female students have longer sleep latency, more awakenings and poorer sleep quality than male students.8,9 many instruments have been developed to measure sleep quality, sleep patterns and daytime sleepiness. two of the most widely used instruments are the pittsburgh sleep quality index (psqi) and the epworth sleepiness scale (ess). the psqi is a 19https://creativecommons.org/licenses/by-nd/4.0/ farrukh majeed, rabia latif, aamna latif and rehma bibi clinical and basic research | 395 item self-reported questionnaire designed to measure subjective sleep quality and sleep disturbances over a one-month period. these 19 items produce a global sleep quality score. global psqi scores greater than five are consistent with clinically disturbed or poor sleep quality. the ess assesses the participant’s daytime sleepiness. it consists of eight items of daily routine (e.g. sitting and reading, watching tv, etc.) in which participants most likely doze off. these items are answered using a 4-point likert scale ranging from 0 (never doze off ) to 3 (high chance of dozing).10,11 poor sleep quality was significantly associated with elevated levels of stress. previous studies confirm that augmented stress response is always associated with sympathetic stimulation.12 the precise involvement of autonomic modulation in sleep-deprived participants is still debatable. a sympathetic predominance was observed in participants with acute sleep deficiency.13 contrarily, an increased parasympathetic tone was also observed after sleep deprivation.14 heart rate variability (hrv) is a non-invasive technique to measure autonomic modulation in various basic and clinical setups.15 the electrocardiograph (ecg) record can be used to measure both the time domain and the frequency domain parameters of hrv. in the time-domain analysis, average heart rate and mean of the normal-to-normal heartbeats (nn) reveal total hrv. the standard deviation of the normal-to-normal heartbeats (sdnn) indicates autonomic effects, while the square root of the mean squared differences of successive nn intervals (rmssd) reveals the parasympathetic influence of the autonomic system and hrv. in the frequency-domain analysis, low-frequency power (lf) is an indicator of sympathetic activity whereas high-frequency power (hf) reflects parasympathetic (vagal) activity. the ratio of lf/hf reflects sympathovagal balance (i.e. a larger lf/hf ratio indicates a predominance of sympathetic activity over vagal control of the heart).16 despite innumerable research on autonomic modulation and cvd, there is a lack of studies that identify the segment of the autonomic nervous system modulated by sleep quality, sleep duration, sleeps efficiency and chances of dozing off, particularly in young, apparently healthy individuals. the purpose of the present study was to determine sleep patterns (sleep quality, duration, efficiency and daytime sleepiness) in young female students through validated questionnaires and to explore any association/correlation of bp and hrv parameters with sleep patterns. the authors hypothesised that the hrv and the bp will differ significantly in participants having poor vs normal sleep quality, short vs normal sleep duration, low vs normal sleep efficiency and normal vs moderate-severe daytime sleepiness; these sleep variables will be associated/ correlated to the bp and hrv. methods a cross-sectional study was conducted between march 2019 and december 2019 at the department of physiology, imam abdulrahman bin faisal university, saudi arabia. healthy female students from the university aged 18–22 years were included. those who had a past or present history of any chronic medical or psychological conditions, smoking, pregnancy and menstruating either on the day of the experiment or one week before it, were excluded. furthermore, students who had a regular consumption of diet supplements, medications such as birth control pills and caffeine intake of more than three cups/day were excluded. additionally, trained athletes or regularly exercising participants were also excluded. study’s participants were invited through an advertisement in a whatsapp (facebook inc., menlo park, california, usa) group for the university students. raosoft® software (raosoft, inc., seattle, washington, usa) was used to calculate the sample size. keeping the margin of error as 5% and the confidence interval as 95%, a population size of 200 students (female medical students registered in year 1 and year 2 in the 2019–2020 academic year) with a response distribution of 50% resulted in a recommended sample size of 132. participants were instructed to fast for 12 hours before their allotted time. to avoid any confounding factors, the body mass index (bmi; weight in kilogram/height in meter squared) was first measured. participants who had a bmi of more than 24.9 kg/m2 were excluded as high bmi is related to the higher sympathetic and lower parasympathetic activity of the heart.17 on experiment day (i.e. the allotted day for ecg and blood pressure measurement of the participants), three ecg electrodes were used: one on each wrist around the radial artery and one on the left foot. these electrodes were connected through the ecg box to a dual bio amplifier and a powerlab (adinstruments®, australia). the powerlab settings (as suggested by the manufacturer for hrv recording from ecg signals) were set at a range of 10–20 mv, sampling rate of 400–1 khz, high pass filter of 0.3 hz (to minimise iso-electric artifacts) and low pass filter of ≤25–50% sampling rate (typically 200–1 khz low-pass).18 a finometer® cuff (fms, the netherlands) was placed on the middle phalanx of a middle finger to obtain continuous finger arterial bp, i.e. systolic blood pressure (sbp), diastolic blood pressure (dbp), mean sleep patterns and their association with blood pressure and heart rate variability parameters in young saudi females 396 | squ medical journal, august 2021, volume 21, issue 3 arterial blood pressure (mabp) and the pulse pressure were calculated afterwords.19 calibration was done after proper placement of the finger bp sensor and ecg leads. after five minutes of stabilisation, a 5-minute ecg recording was done in the supine position for hrv, based on the european society task force recommendation.20 from the ecg record, labchart® software (adinstruments®, australia) was used to derive both time-domain and frequency-domain parameters of hrv.20 to assess sleep patterns, the following sleep variables were determined: (1) sleep quality; (2) sleep duration; and (3) sleep efficiency. sleep quality was assessed using the psqi. in this 19-item questionnaire, the first four items inquire about bedtimes, wake times, sleep latency and sleep duration. the next 15 items examine how often participants experience certain symptoms such as ‘cannot get to sleep in less than 30 minutes’ or ‘just get up to use the bathroom’, etc. these 19 items produce a global sleep quality score that dichotomised the participants (those with scores ≥5 have poor sleep quality and those with scores <5 have normal sleep quality).10 sleep duration was estimated using the psqi question: ‘during the past month, how many hours of actual sleep did you get at night?’. based on sleep duration, students were divided into table 1: characteristics of apparently healthy female saudi arabian students included in the current study (n = 98) characteristic mean ± sd age in years 20.4 ± 0.5 bmi in kg/m2 22.1 ± 2.4 blood pressure parameters using finometer® systolic blood pressure in mmhg 122.6 ± 11.9 diastolic blood pressure in mmhg 67.1 ± 8.0 pulse pressure in mmhg 55.5 ± 8.9 arterial blood pressure in mmhg 85.6 ± 8.5 heart rate variability parameters using ecg avg rate in beats/minute 80.5 ± 8.9 nn mean in milliseconds 736.2 ± 111.3 sdnn in milliseconds 62.4 ± 18.8 rmssd in milliseconds 55.7 ± 25.8 lf/hf 1.43 ± 1.02 lf in normalised units 50.6 ± 15.6 hf in normalised units 43.5 ± 13.1 sleep-related characteristics bed time using 24-hour clock 13.8 ± 10.7 fall sleep in minutes 23.4 ± 15.6 time morning wakeup in am ± hour 6.1 ± 1.2 sleep duration in hours 5.8 ± 1.6 time in bed in hours 6.4 ± 2.1 pittsburgh sleep quality index score 8.2 ± 4.0 epworth sleepiness scale score 8.1 ± 5.2 sd = standard deviation; bmi = body mass index; ecg = electrocardio graph; nn mean = mean of the normal-to-normal heart beats; sdnn = standard deviation of the normal-to-normal heartbeats; rmssd = square root of the mean squared differences of successive nn intervals; lf = low frequency power; hf = high frequency power. table 2: comparison of blood pressure and heart rate var iability parameters between participants having normal or poor sleep quality sleep quality status* mean ± sd p value† blood pressure parameters using finometer® systolic blood pressure in mmhg normal 122.1 ± 9.6 0.820 poor 122.7 ± 12.8 diastolic blood pressure in mmhg normal 66.5 ± 8.5 0.688 poor 67.3 ± 7.8 pulse pressure in mmhg normal 55.6 ± 9.0 0.954 poor 55.4 ± 8.9 mean arterial blood pressure in mmhg normal 85.1 ± 7.8 0.720 poor 85.8 ± 8.8 heart rate variability parameters using ecg average heart rate in beats/minute normal 79.7 ± 8.9 0.576 poor 80.8 ± 8.9 nn mean in milliseconds normal 748.0 ± 115.2 0.496 poor 731.1 ± 109.9 sdnn in milliseconds normal 59.9 ± 13.3 0.397 poor 63.4 ± 20.6 rmssd in milliseconds normal 51.2 ± 20.2 0.262 poor 57.6 ± 27.7 lf/hf normal 1.33 ± 0.86 0.542 poor 1.47 ± 1.08 lf in normalised units normal 49.7 ± 15.0 0.737 poor 50.9 ± 15.9 hf in normalised units normal 44.3 ± 12.4 0.697 poor 43.2 ± 13.4 sd = standard deviation; ecg = electrocardiograph; nn mean = mean of the normal-to-normal heart beats; sdnn = standard deviation of the normal-to-normal heartbeats; rmssd = square root of the mean squared differences of successive nn intervals; lf/hf = lf/hf ratio; lf = low frequency power; hf = high frequency power. *29 participants had normal sleep quality and 69 had poor sleep quality. †using t-test. farrukh majeed, rabia latif, aamna latif and rehma bibi clinical and basic research | 397 two groups: short sleep duration, consisting of those with <6 hours of sleep, and normal sleep duration, consisting of those with ≥6 hours.21 sleep efficiency was calculated using the ratio of total sleep time and time in bed (multiplied by 100 to yield a percentage) from the psqi questionnaire. based on sleep efficiency, students were categorised as having either low sleep efficiency (<85%) or normal sleep efficiency (≥85%).22 ess assesses the participant’s daytime sleepiness in recent times. it consists of eight items of daily routine in which participants have high chances of dozing off (e.g. sitting and reading, watching tv, etc.). this scale uses a 4-point likert scale ranging from 0 which is ‘never doze off ’ to 3 which is ‘high chance of dozing off ’.11 based on the levels of sleepiness, students were categorised into 0–10 as normal daytime sleepiness, 11–12 as mild daytime sleepiness and ≥13 as moderate to severe daytime sleepiness. statistical package for the social sciences (spss), version 21 (ibm corp., armonk, new york, usa) was used for statistical analysis. the normality of data was tested by the shapiro-wilk test. cronbach’s alpha was table 3: comparison of blood pressure and heart rate var iability parameters between participants having normal or short sleep duration sleep duration status* mean ± sd p value† blood pressure parameters using finometer® systolic blood pressure in mmhg short 124.2 ± 14.8 0.256 normal 121.4 ± 9.0 diastolic blood pressure in mmhg short 68.2 ± 8.3 0.202 normal 66.1 ± 7.7 pulse pressure in mmhg short 55.9 ± 10.1 0.714 normal 55.2 ± 8.0 mean arterial blood pressure in mmhg short 86.9 ± 9.8 0.182 normal 84.6 ± 7.2 heart rate variability parameters using ecg average heart rate in beats/minute short 79.4 ± 8.5 0.318 normal 81.2 ± 9.1 nn mean in milliseconds short 746.6 ± 108.0 0.423 normal 728.3 ± 113.9 sdnn in milliseconds short 64.9 ± 20.0 0.259 normal 60.5 ± 17.7 rmssd in milliseconds short 58.5 ± 28.7 0.349 normal 53.6 ± 23.4 lf/hf short 1.36 ± 1.10 0.595 normal 1.47 ± 0.96 lf in normalised units short 49.0 ± 16.3 0.402 normal 51.7 ± 15.0 hf in normalised units short 45.3 ± 13.6 0.255 normal 42.2 ± 12.7 sd = standard deviation; ecg = electrocardiograph; nn mean = mean of the normal-to-normal heart beats; sdnn = standard deviation of the normal-to-normal heartbeats; rmssd = square root of the mean squared differences of successive nn intervals; lf/hf = lf/hf ratio; lf = low frequency power; hf = high frequency power. *42 participants had a short sleep duration and 56 had a normal sleep duration. †using t-test. table 4: comparison of blood pressure and heart rate var iability parameters between participants having low or normal sleep efficiency sleep efficiency status* mean ± sd p value† blood pressure parameters using finometer® systolic blood pressure in mmhg low 124.7 ± 14.6 0.187 normal 121.4 ± 9.9 diastolic blood pressure in mmhg low 68.2 ± 8.3 0.286 normal 66.4 ± 7.8 pulse pressure in mmhg low 56.4 ± 10.6 0.428 normal 54.9 ± 7.8 mean arterial blood pressure in mmhg low 87.0 ± 9.6 0.198 normal 84.7 ± 7.7 heart rate variability parameters using ecg average heart rate in beats/minute low 82.1 ± 7.5 0.174 normal 79.5 ± 9.5 nn mean in milliseconds low 734.1 ± 82.0 0.893 normal 737.3 ± 125.7 sdnn in milliseconds low 64.1 ± 22.4 0.493 normal 61.4 ± 16.3 rmssd in milliseconds low 55.7 ± 31.0 0.994 normal 55.7 ± 22.6 lf/hf low 1.62 ± 1.2 0.015 normal 1.31 ± 0.82 lf in normalised units low 53.0 ± 15.9 0.235 normal 49.1 ± 15.3 hf in normalised units low 42.3 ± 14.2 0.486 normal 44.2 ± 12.5 sd = standard deviation; ecg = electrocardiograph; nn mean = mean of the normal-to-normal heart beats; sdnn = standard deviation of the normal-to-normal heartbeats; rmssd = square root of the mean squared differences of successive nn intervals; lf/hf = lf/hf ratio; lf = low frequency power; hf = high frequency power. *36 participants had low sleep efficiency and 62 had normal sleep efficiency. †p value obtained from t-test. sleep patterns and their association with blood pressure and heart rate variability parameters in young saudi females 398 | squ medical journal, august 2021, volume 21, issue 3 0.709 and 0.741 for the psqi and ess questionnaires, respectively. an independent sample t-test was performed for the comparison of the two groups while one-way anova with post hoc bonferroni was employed, after being adjusted for multiple testing. pearson’s or point-biserial correlation was applied to check the relationship between variables. p <0.05 was regarded as statistically significant. the participants were briefed about the study’s purpose and informed consent was acquired during familiarisation sessions. permission and ethical approval for this study were acquired from the deanship of scientific research, imam abulrahman bin faisal university, saudi arabia (irb-2019-01-402). results a total of 98 participants were included in this study (response rate: 72.6%). of the 135 students that initially enrolled, 105 students completed the questionnaires; furthermore, seven participants either didn’t appear on an experiment day or had insufficient ecg recordings, resulting in a final sample of 98. the participants had a mean age of 20.4 ± 0.5 years and a bmi of 22.1 ± 2.4 kg/m2. mean sbp was 122.6 ± 11.9 mmhg, dbp was 67.1 ± 8.0 mmhg and mabp was 85.6 ± 8.5 mmhg. the mean of various hrv parameters such as sdnn and lf/hf ratio was 62.4 ± 18.8 milliseconds and 1.43 ± 1.02, respectively. an average of 23.4 ± 15.6 minutes was taken to fall asleep; the average morning wake-up time was 6:00 am ± 1.24 hours. the mean sleep duration of the participants was 5.8 ± 1.6 hours and their total time in bed was 6.4 ± 2.1 hours. the mean psqi score was 8.2 ± 4.0 and the mean ess score was 8.1 ± 5.2 [table 1]. a comparison of bp and hrv parameters between participants based on normal or poor sleep quality showed no statistically significant difference (p >0.05) [table 2]. a comparison of bp and hrv parameters between short or normal sleep duration revealed no statistically significant differences between the two sleep quality groups (p >0.05) [table 3]. a comparison of bp and hrv parameters between participants with low or normal sleep efficiency showed no statistically significant difference (p >0.05) [table 4]. a comparison of bp and hrv parameters between participants based on the ess score using a one-way anova revealed that sbp was significantly increased (f = 3.37; p = 0.039) in the moderate to severe daytime sleepiness group compared to the mild daytime sleepiness group (with bonferroni p = 0.035) [table 5]. table 5: comparison of blood pressure and heart rate variability parameters between participants with daytime sleepiness based on epworth sleepiness scale score normal daytime sleepiness mean ± sd (n = 66) mild daytime sleepiness mean ± sd (n = 11) moderate to severe daytime sleepiness mean ± sd (n = 21) *p value blood pressure parameters using finometer® systolic blood pressure in mmhg 122.9 ± 10.5 114.7 ± 11.5 125.8 ± 14.6 0.039† diastolic blood pressure in mmhg 66.9 ± 7.7 63.5 ± 6.1 69.2 ± 9.4 0.156 diastolic blood pressure in mmhg 55.9 ± 9.0 51.1 ± 8.4 56.5 ± 8.8 0.226 mean arterial blood pressure in mmhg 85.6 ± 7.6 80.6 ± 7.3 88.2 ± 10.6 0.057 heart rate variability parameters using ecg average heart rate in beats/minute 80.3 ± 9.3 80.9 ± 9.1 80.9 ± 7.6 0.935 nn mean in milliseconds 735.3 ± 115.4 749.1 ± 100.4 732.2 ± 107.4 0.915 sdnn in milliseconds 64.8 ± 19.6 60.4 ± 21.2 55.8 ± 12.7 0.150 rmssd in milliseconds 59.1 ± 27.2 50.4 ± 25.5 47.8 ± 19.4 0.172 lf/hf ratio 1.45 ± 1.04 1.28 ± 1.08 1.44 ± 0.96 0.884 lf in normalised units 50.7 ± 15.5 49.2 ± 15.6 50.8 ± 16.4 0.957 hf in normalised units 42.8 ± 12.6 47.8 ± 13.5 43.5 ± 14.5 0.504 sd = standard deviation; ecg = electrocardiograph; nn mean = mean of the normal-to-normal heart beats; sdnn = standard deviation of the normal to-normal heartbeats; rmssd = square root of the mean squared differences of successive nn intervals; lf/hf = lf/hf ratio; lf = low frequency power; hf = high frequency power. *using one-way anova. †post hoc with bonferroni. farrukh majeed, rabia latif, aamna latif and rehma bibi clinical and basic research | 399 correlation among the psqi parameters of sleep quality, sleep duration and sleep efficiency were not statistically significant with hrv and bp variables. however, there were point biserial correlations of hrv parameters with various dozing-off situations (measured by the ess). dozing off as a passenger in the car was negatively correlated with the average heart rate (r = -0.206, p = 0.042). dozing off in the afternoon was also negatively correlated with the average heart rate (r = −0.251; p = 0.013), but was positively correlated to the mean nn (r = 0.285; p = 0.005). dozing off after lunch was negatively correlated with sdnn (r = −0.256, p = 0.011) and rmssd (r = −0.241, p = 0.017) [figure 1]. discussion this study found that hrv parameters and bp measurements do not differ among young, apparently healthy female participants with various sleep patterns (sleep quality, duration and efficiency). moreover, there is no correlation between these sleep patterns and hrv parameters. however, daytime sleepiness may influence sbp, as some of the dozing-off situations were correlated with low hrv and decreased parasympathetic control. the current study is novel in presenting the association of moderate to severe daytime sleepiness with high bp and various dozingoff situations with low hrv parameters. students all over the world are prone to develop disturbed sleep patterns due to demanding academic studies. a comprehensive meta-analysis of 57 studies on chinese university students revealed a mean sleep duration of seven hours/day, a bedtime of approximately 1 am and an average time of 17 minutes to fall asleep.23 another study involving american college students revealed mean psqi scores of 6.34 ± 4.5, and mean ess scores of 8.6 ± 3.7.24 a study from kku, saudi arabia, reported mean psqi scores of 10.50 ± 2.58, with a sleep duration of 7.83 ± 2.88 and 30 minutes to fall asleep.7 all sleep parameters in that study are slightly higher compared to the current study. the underlying reason might be that the studied university has a more competitive environment compared to kku. these study results are contrary to dettoni et al., who reported reduced hrv in experimentally induced sleep-deprived participants.25 similarly, virtanen et al. observed harmful effects of acute total sleep deficit on the autonomic nervous system.13 conflicting results observed in this study could be because of the initial response to acute sleep deprivation is sympathetically induced decreased hrv. chronic sleep deprivation causes protective parasympathetic stimulation that buffers the sympathetic response in the absence of any figure 1 (a–e): point biserial correlations of heart rate variability parameters with various doze-off situation using the epworth sleepiness scale (n = 98). sleep patterns and their association with blood pressure and heart rate variability parameters in young saudi females 400 | squ medical journal, august 2021, volume 21, issue 3 other morbidity, as evident in these apparently healthy study participants.26,27 bp variables did not differ significantly in partic ipants with poor sleep vs normal sleep quality. compar able to this study’s results, kato et al. and muenter et al. witnessed no differences in bp parameters in sleepdeprived participants.28,29 consistent with this, tracey postulated activation of an efferent activity of the vagus nerve to peripheral organs, particularly toward the heart, via nicotinic acetyl-choline receptors on tissue macrophages, which prevents the pro-inflammatory cytokines from inducing peripheral inflammation and possible sympathetic stimulation.30 similar to the current study, goldstein et al. found higher sbp in apparently healthy subjects with higher chances of daytime sleepiness and reported higher levels of anger, depression and anxiety. their study participants were more likely to be diagnosed with hypertension in the following five years.31 feng et al. also observed a positive correlation of excessive daytime sleepiness with bp in their patients suffering from obstructive sleep apnea.32 similar observations have been made by stock et al. and taranto montemurro et al.; notably, they witnessed a reduction in bp parameters after improvement in sleep duration.33,34 similar to the current study’s observations related to hrv changes with ess score, bisogni et al. didn’t find any significant changes in hrv parameters concerning excessive daytime sleepiness. they concluded that excessive daytime sleepiness is not associated with sympathetic nervous system activation.35 however, this study’s results showed that the participants having higher chances of dozing off in the car as a passenger, in the afternoon and after lunch have negative correlations with the average heart rate, sdnn and rmssd and a positive correlation with mean nn, reflecting decreased hrv and parasympathetic responses, pointing toward underlying autonomic modulation in apparently healthy participants. the mechanism by which hrv is transiently reduced following dozing off situations is not yet defined but it is likely to involve derangements in the neural activity of cardiac origin by disturbed daytime sleep patterns. one hypothesis is that sleep deprivation-induced stress can augment the sympathetic autonomic response.36 to the best of the authors’ knowledge, no research so far has explored the association of hrv with daytime somnolence in healthy individuals. this study is the first to explore this association in young, apparently healthy females, principally from a student population. despite this strength, there are certain limitations to the present study. self-reporting of sleep patterns by the participants may involve some degree of recall errors. actigraphy is a suitable tool for sleep parameters but due to the unavailability of actigraphy at the institute, it could not be employed. in addition, many people in the middle east take daytime naps that were not considered when calculating the total sleep duration. furthermore, this was a cross-sectional study, observing participants only at a single point in time. the groups were made based on the cutoff levels of sleep pattern variables and without the power. the unequal number of study participants in the groups may affect type 1 error rates. the narrow age range of the study’s population was also an important limitation. another limitation is that the probable impact of sleep patterns on the autonomic nervous system in young individuals may be mistaken by the apparently healthy nervous system. this study’s participants were only female and recruited from a single university which may limit the generalisability of the results. in the future, studies with a large cohort and from different student population groups of both genders should be planned. conclusion the current study has shown that bp and hrv parameters do not differ among young, apparently healthy female students with various sleep patterns (sleep quality, duration and efficiency). moreover, there is no relationship between sleep patterns and hrv parameters. moderate to severe daytime sleepiness increases sbp and various dozing off situations may have a negative correlation with hrv parameters, directed towards an overall decrease in the hrv (average heart rate, sdnn) and a decrease in the parasympathetic autonomic control (rmssd). daytime somnolence may be a useful tool to detect early hrv changes that were otherwise masked in healthy subjects. early detection of autonomic dysfunction may be beneficial in identifying future cardiovascular morbidities in a healthy generation. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n fm and rl conceptualized the idea and collected the data. acquisition, interpretation and analysis of the data were done by fm, rl, al and rb. fm, rl, al and rb drafted and revised the manuscript. all authors approved the final version of the manuscript. farrukh majeed, rabia latif, aamna latif and rehma bibi clinical and basic research | 401 references 1. tufik s, andersen ml, bittencourt lr, mello mt. paradoxical sleep deprivation: neurochemical, hormonal and behavioral alterations. evidence from 30 years of research. an acad bras cienc 2009; 81:521–38. https://doi.org/10.1590/s000137652009000300016. 2. tobaldini e, costantino g, solbiati m, cogliati c, kara t, nobili l, et al. sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases. neurosci biobehav rev 2017; 74:321–9. https://doi.org/10.1016/j.neubiorev.2016.07.004. 3. zhu g, catt m, cassidy s, birch-machin m, trenell m, hiden h, et al. objective sleep assessment in >80,000 uk mid-life adults: associations with sociodemographic characteristics, physical activity and caffeine. plos one 2019; 14:e0226220. https://doi. org/10.1371/journal.pone.0226220. 4. baldwin cm, kapur vk, holberg cj, rosen c, nieto fj; sleep heart health study group. associations between gender and measures of daytime somnolence in the sleep heart health study. sleep 2004; 27:305–11. https://doi.org/10.1093/sleep/27.2.305. 5. nowakowski s, meers j, heimbach e. sleep and women's health. sleep med res 2013; 4:1–22. https://doi.org/10.17241/smr.2013.4.1.1. 6. felix va, campsen na, white a, buboltz wc. college students’ prevalence of sleep hygiene awareness and practices. adv soc sci 2017; 4. https://doi.org/10.14738/assrj.44.2767. 7. siddiqui af, al-musa h, al-amri h, al-qahtani a, al-shahrani m, al-qahtani m. sleep patterns and predictors of poor sleep quality among medical students in king khalid university, saudi arabia. malays j med sci 2016; 23:94–102. https://doi.org/10.21315/ mjms2016.23.6.10. 8. sweileh wm, ali i, sawalha af, abu-tah as, zyoud sh, al-jabi sw. gender differences in sleep habits and sleeprelated problems in arab palestinian university students. int j disabil hum dev 2012; 11:289–93. https://doi.org/10.1515/ ijdhd-2012-0041. 9. tsai ll, li sp. sleep patterns in college students: gender and grade differences. j psychosom res 2004; 56:231–7. https://doi. org/10.1016/s0022-3999(03)00507-5. 10. buysse dj, reynolds cf, monk th, berman sr, kupfer dj. the pittsburgh sleep quality index: a new instrument for psychiatric practice and research. psychiatry res 1989; 28:193–213. https:// doi.org/10.1016/0165-1781(89)90047-4. 11. janssen kc, phillipson s, o'connor j, johns mw. validation of the epworth sleepiness scale for children and adolescents using rasch analysis. sleep med 2017; 33:30–5. https://doi. org/10.1016/j.sleep.2017.01.014. 12. alotaibi ad, alosaimi fm, alajlan aa, bin abdulrahman ka. the relationship between sleep quality, stress, and academic perf ormance among medical students. j family community med 2020; 27:23–8. https://doi.org/10.4103/jfcm.jfcm_132_19. 13. virtanen i, kalleinen n, urrila as, leppänen c, polo-kantola p. cardiac autonomic changes after 40 hours of total sleep depriv ation in women. sleep med 2015; 16:250–7. https://doi.org/10.10 16/j.sleep.2014.10.012. 14. vaara j, kyröläinen h, koivu m, tulppo m, finni t. the effect of 60-h sleep deprivation on cardiovascular regulation and body temperature. eur j appl physiol 2009; 105:439–44. https://doi. org/10.1007/s00421-008-0921-5. 15. taralov zz, terziyski kv, kostianev ss. heart rate variability as a method for assessment of the autonomic nervous system and the adaptations to different physiological and pathological conditions. folia med (plovdiv) 2015; 57:173–80. https://doi. org/10.1515/folmed-2015-0036. 16. bilchick kc, berger rd. heart rate variability. j cardiovasc electrophysiol 2006; 17:691–4. https://doi.org/10.1111/j.15408167.2006.00501.x. 17. fatima y, doi sa, mamun aa. sleep quality and obesity in young subjects: a meta-analysis. obes rev 2016; 17:1154–66. https://doi.org/10.1111/obr.12444. 18. ecg/ekg signals. from: https://www.adinstruments.com/sig nal/ecg accessed: sep 2020. 19. guelen, i, westerhof be, van der sar gl, van montfrans ga, kiemeneij f, wesseling kh, et al. finometer, finger pressure meas urements with the possibility to reconstruct brachial pressure. blood press monit 2003; 8:27–30. https://doi.org/10.1097/001260 97-200302000-00006. 20. radespiel-tröger m, rauh r, mahlke c, gottschalk t, mückweymann m. agreement of two different methods for measure ment of heart rate variability. clin auton res 2003; 13:99–102. https://doi.org/10.1007/s10286-003-0085-7. 21. chen hc, hsu nw, chou p. the association between extreme sleep duration and cardiac autonomic control in communitydwelling older adults: the yilan study, taiwan. j gerontol a biol sci med sci 2017; 72:929–36. https://doi.org/10.1093/gerona/ glx045. 22. matthews ee, schmiege sj, cook pf, berger am, aloia ms. adherence to cognitive behavioral therapy for insomnia (cbti) among women following primary breast cancer treatment: a pilot study. behav sleep med 2012; 10:217–9. https://doi.org/1 0.1080/15402002.2012.666220. 23. li l, wang yy, wang sb, li l, lu l, ng ch, et al. sleep duration and sleep patterns in chinese university students: a comprehensive meta-analysis. j clin sleep med 2017; 13:1153–62. https://doi.org/10.5664/jcsm.6760. 24. dietch jr, taylor dj, sethi k, kelly k, bramoweth ad, roane bm. psychometric evaluation of the psqi in u.s. college students. j clin sleep med 2016; 12:1121–9. https://doi.org/10.5664/ jcsm.6050. 25. dettoni jl, consolim-colombo fm, drager lf, rubira mc, souza sb, irigoyen mc, et al. cardiovascular effects of partial sleep deprivation in healthy volunteers. j appl physiol (1985) 2012; 113:232–6. https://doi.org/10.1152/japplphysiol.01604.2011. 26. pagani m, pizzinelli p, traon ap, ferreri c, beltrami s, bareille mp, et al. hemodynamic, autonomic and baroreflex changes after one night sleep deprivation in healthy volunteers. auton neurosci 2009; 145:76–80. https://doi.org/10.1016/j.autneu.2008.10.009. 27. quintana ds, elvsåshagen t, zak n, norbom lb, pedersen pø, quraishi sh, et al. diurnal variation and twenty-four hour sleep deprivation do not alter supine heart rate variability in healthy male young adults. plos one 2017; 12:e0170921. https://doi. org/10.1371/journal.pone.0170921. 28. kato m, phillips bg, sigurdsson g, narkiewicz k, pesek ca, somers vk. effects of sleep deprivation on neural circulatory control. hypertension 2000; 35:1173–5. https://doi.org/10.116 1/01.hyp.35.5.1173. 29. muenter nk, watenpaugh de, wasmund wl, wasmund sl, maxwell sa, smith ml. effect of sleep restriction on orthostatic cardiovascular control in humans. j appl physiol (1985) 2000; 88:966–72. https://doi.org/10.1152/jappl.2000.88.3.966. 30. tracey kj. the inflammatory reflex. nature 2002; 420:853–9. https://doi.org/10.1038/nature01321. 31. goldstein ib, ancoli-israel s, shapiro d. relationship between daytime sleepiness and blood pressure in healthy older adults. am j hypertens 2004; 17:787–92. https://doi.org/10.1016/j.amjhy per.2004.05.009. 32. feng j, he qy, zhang xl, chen by; sleep breath disorder group, society of respiratory medicine. epworth sleepiness scale may be an indicator of blood pressure profile and prevalence of coronary artery disease and cerebrovascular disease in patients with obstructive sleep apnea. sleep breath 2012; 16:31–40. https://doi.org/10.1007/s11325-011-0481-5. https://doi.org/10.1590/s0001-37652009000300016 https://doi.org/10.1590/s0001-37652009000300016 https://doi.org/10.1016/j.neubiorev.2016.07.004 https://doi.org/10.1371/journal.pone.0226220 https://doi.org/10.1371/journal.pone.0226220 https://doi.org/10.1093/sleep/27.2.305 https://doi.org/10.17241/smr.2013.4.1.1 https://doi.org/10.14738/assrj.44.2767 https://doi.org/10.21315/mjms2016.23.6.10 https://doi.org/10.21315/mjms2016.23.6.10 https://doi.org/10.1515/ijdhd-2012-0041 https://doi.org/10.1515/ijdhd-2012-0041 https://doi.org/10.1016/s0022-3999(03)00507-5 https://doi.org/10.1016/s0022-3999(03)00507-5 https://doi.org/10.1016/0165-1781(89)90047-4 https://doi.org/10.1016/0165-1781(89)90047-4 https://doi.org/10.1016/j.sleep.2017.01.014 https://doi.org/10.1016/j.sleep.2017.01.014 https://doi.org/10.4103/jfcm.jfcm_132_19 https://doi.org/10.1016/j.sleep.2014.10.012 https://doi.org/10.1016/j.sleep.2014.10.012 https://doi.org/10.1007/s00421-008-0921-5 https://doi.org/10.1007/s00421-008-0921-5 https://doi.org/10.1515/folmed-2015-0036 https://doi.org/10.1515/folmed-2015-0036 https://doi.org/10.1111/j.1540-8167.2006.00501.x https://doi.org/10.1111/j.1540-8167.2006.00501.x https://doi.org/10.1111/obr.12444 https://doi.org/10.1097/00126097-200302000-00006 https://doi.org/10.1097/00126097-200302000-00006 https://doi.org/10.1007/s10286-003-0085-7 https://doi.org/10.1093/gerona/glx045 https://doi.org/10.1093/gerona/glx045 https://doi.org/10.1080/15402002.2012.666220 https://doi.org/10.1080/15402002.2012.666220 https://doi.org/10.5664/jcsm.6760 https://doi.org/10.5664/jcsm.6050 https://doi.org/10.5664/jcsm.6050 https://doi.org/10.1152/japplphysiol.01604.2011 https://doi.org/10.1016/j.autneu.2008.10.009 https://doi.org/10.1371/journal.pone.0170921 https://doi.org/10.1371/journal.pone.0170921 https://doi.org/10.1161/01.hyp.35.5.1173 https://doi.org/10.1161/01.hyp.35.5.1173 https://doi.org/10.1152/jappl.2000.88.3.966 https://doi.org/10.1038/nature01321 https://doi.org/10.1016/j.amjhyper.2004.05.009 https://doi.org/10.1016/j.amjhyper.2004.05.009 https://doi.org/10.1007/s11325-011-0481-5 sleep patterns and their association with blood pressure and heart rate variability parameters in young saudi females 402 | squ medical journal, august 2021, volume 21, issue 3 33. stock aa, lee s, nahmod ng, chang am. effects of sleep ext ension on sleep duration, sleepiness, and blood pressure in college students. sleep health 2020; 6:32–9. https://doi.org/10.1016/j. sleh.2019.10.003. 34. taranto montemurro lt, floras js, picton p, kasai t, alshaer h, gabriel jm, et al. relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure. j clin sleep med 2014; 10:271–6. https://doi.org/10.566 4/jcsm.3526. 35. bisogni v, pengo mf, drakatos p, maiolino g, kent b, rossitto g, et al. excessive daytime sleepiness does not correlate with symp athetic nervous system activation and arterial stiffening in patients with mild-to-moderate obstructive sleep apnoea: a proof-ofprinciple study. int j cardiol 2017; 236:458–61. https://doi.org/1 0.1016/j.ijcard.2017.01.149. 36. lombardi c, parati g, cortelli p, provini f, vetrugno r, plazzi g, et al. daytime sleepiness and neural cardiac modulation in sleep-related breathing disorders. j sleep res 2008; 17:263–70. https://doi.org/10.1111/j.1365-2869.2008.00659.x. https://doi.org/10.1016/j.sleh.2019.10.003 https://doi.org/10.1016/j.sleh.2019.10.003 https://doi.org/10.5664/jcsm.3526 https://doi.org/10.5664/jcsm.3526 https://doi.org/10.1016/j.ijcard.2017.01.149 https://doi.org/10.1016/j.ijcard.2017.01.149 https://doi.org/10.1111/j.1365-2869.2008.00659.x 2008-issue1.indd abstract objectives: evaluation of some of the leading risk factors for coronary heart disease (chd) among males in oman. methods: we conducted a hospital-based pair-wise matched case-control study among omani chd patients admitted in the sultan qaboos university hospital and the royal hospital located in muscat, oman. the cases were matched with an equal number of controls in respect of age and hospital. the information was collected from the cases and controls based on an interview and review of the medical records of the admitted chd patients. the odds ratios (ors) were estimated under univariate as well as multivariate situations using conditional multiple binary logistic regression model. results: the analysis revealed that 74 percent of the cases were of angina pectoris. the majority of the cases (96%) were above 40 years of age. the prevalence of sedentary life style was predominant (88.0%). hypertension, diabetes, family history of chd and a sedentary occupation were the most significant risk factors for the development of the disease. the estimated values of the adjusted ors were found to be 9.98, 2.74, 28.9 and 3.00 respectively (p<0.05). conclusion: individuals with hypertension, diabetes mellitus, a family history of chd and with sedentary occupations are to be considered at high risk of developing chd. such individuals should be provided with appropriate health education along with close monitoring for symptoms and signs of chd. key words: coronary heart disease; risk factors; males; case-control study; oman. some risk factors for coronary heart disease among omani males a matched case-control study shyam s ganguly, mohammed aal-shafaee, abdullah a al-maniri department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: ganguly@squ.edu.om : الذكور العمانيني عند التاجي القلب ملرض االختطار عوامل بعض د توافقية واهِ وشَّ حاالَتِ ةُ دِراسَ املنيري اهللا عبد ، الشافعي محمد ، شيام جنجلي التوافقية ــواهد والش احلاالت ــة دراس . الطريقة: أجرينا في عمان عند الذكور التاجي القلب ملرض االختطار عوامل بعض امللخص: الهدف: تقييم بني بعمل توافق قمنا . ــلطاني الس ــفى واملستش قابوس ــلطان الس جامعة ــفى مستش من في كل والراقدين القلب التاجي املصابني مبرض للمرضى املعنيني ــطة مقابلة بواس الضابطة العينة في وأقرانهم املرضى من املعلومات أخذت . ــفى واملستش العمر حيث من الضابطة والعينة املرضى عدد الثنائي اللوجستي باستخدام برنامج االنحدار املتغيرات وذلك ومتعدد أحادي من كال بواسطة األرجحية ــبة نس قدرت . ــجالت الطبية الس ومراجعة فوق كان (96%) احلاالت أغلب في املرضى وأن عمر ، الصدرية من الذبحة تعاني احلاالت كانت %74 من بني التحليل أن . النتائج: ــرطي الش املتعدد هي إحصائيا معتدة بصورة التاجي القلب مبرض ــببة املتس عوامل االختطار كانت .(88%) كبيرا احلركة اخلالي من احلياة منط ــار انتش و كان األربعني لنسب املصححة املقدرة القيم كانت . من احلركة العمل اخلالي وطبيعة األسرة في التاجي القلب مرض حاالت السكر ووجود وداء الدم ارتفاع ضغط في توجد والتي ، ــكر الس وداء ضغط الدم بارتفاع املصابون ــخاص اخلالصة: يعتبر األش .(p<0.05) (3.00 , 28.19 ,2.74 هي: (9.98, االختطار األمور الضرورية من . التاجي القلب مبرض لإلصابة اختطارا أكثر احلركة وقلة بالركود تتميز أعماال يزاولون والذين ، التاجي مرض القلب حاالت أسرهم . التاجي لديهم القلب مرض وعالمات أعراض لظهور دقيقة مراقبة عمل وكذلك األشخاص هؤالء ملثل بالتثقيف الصحي القيام عمان. ، وشواهد ، دراسة حاالت االختطار عوامل ، التاجي القلب مرض الكلمات: مفتاح sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 45-51 sultan qaboos university© submitted 5th august 2007 accepted 13th february 2008 c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • the findings of the article have important implications in the primary prevention of chd. • the study indicated major risk factors for chd among males in oman. • the hypertension, diabetes mellitus, family history of chd and sedentary type of occupation were found to be the most contributing factors in the causation of chd. s h ya m s g a n g u ly, m o h a m m e d a a l -s h a fa e e , a b d u l l a h a a l m a n i r i 46 an estimated 16.7 million or 29.2% of total global deaths result from the various forms of cardiovascular disease, many of which are preventable. out of the 16.7 million deaths, 7.2 million are due to coronary heart disease (chd). moreover, 56% of these deaths occur before the age of 75 years.1 at least twenty million people survive heart attacks and strokes every year, their treatment requiring costly clinical care and so placing a huge financial burden on the individual as well as on the nation.1 heart disease has no geographic, gender or socio economic boundaries.1, 2 the world health organization (who) has drawn attention to the fact that (chd) is a modern epidemic. in the eastern mediterranean region, cardiovascular diseases (cvd) and stroke account for 31% of mortality.3 in oman, chronic non-communicable diseases related to lifestyle, namely coronary heart diseases, hypertension, diabetes mellitus and cancer, are now emerging as new health challenges for the country.4 the chd made up nearly 10.5% of all deaths for adults aged 45–60 years and 31.5% for these above 60 years. in various studies carried out in the omani population, hypertension, diabetes, dyslipidaemia, sedentary occupations and smoking have been reported to be the major cardiovascular risk factors.5, 6 moreover, consanguinity is quite common with 34 percent of women married to first cousins and 20% married to other relations.7 this cultural practice may have resulted in an increased prevalence of hypertension and diabetes.8, 9 although there are many risk factors related to chd in our population, we focused on some of the leading risk factors, namely hypertension, diabetes mellitus, sedentary occupations, lack of physical exercise and a family history of chd and diabetes. as the prevalence of chd risk factors in the omani population is high, so the present study aimed to quantify the degree and extent of association between chd and such risk factors in terms of ors under univariate and multivariate situations. m e t h o d s a hospital-based pair-wise matched case control study was carried out among the omani male chd patients admitted and treated in the cardiac care units (ccu) of sultan qaboos university hospital (squh) and the royal hospital, muscat. patients were identified from the ccu register and information was extracted from the medical records. an equal number of controls (i.e. either noncoronary patients or any asymptomatic individual) were matched in respect of the confounding variables namely, age (± 2yrs) and hospital. following the method as described by schlesselman,10 a total of 100 case-control pairs constituted an adequate sample size for carrying out the study. a questionnaire was developed and pilot testing was conducted with 20 subjects. after the pretesting, the relevant information on the risk factors of interest (including level of physical activity) in 200 subjects was recorded based on interviews. the study subjects gave informed consent before participation in the study. the study was conducted based on the necessary permission from the concerned authorities of both hospitals. the various levels/degrees of chd risk factors used in this study were as follows: h y pe rte n si o n the standard definition of hypertension was considered as systolic blood pressure ≥ 140 mm hg and/or diastolic blood pressure ≥ 90 mm hg or current use of any hypertensive medicines.11 d i a be te s me l l i t us individuals who were on anti diabetic drugs or having fasting blood glucose level ≥ 7.0 mmol/l were considered havings diabetes.12 fa mi ly h i sto ry o f c h d individuals who responded to a history of angina on exertion, myocardial infarction, diagnosis of chd or sudden death among first degree relatives were considered to have a positive family history of chd. se d e n ta ry o c c upati o n the individuals who were working in an office at a job without much movement were classified as sedentary. fa mi ly h i sto ry o f d i a be te s individuals who responded to a history of diagnosis of diabetes among first degree relatives were considered applications to patient care • data could be used for appropriate health education to patients as well as the community in oman. s o m e r i s k fa c t o r s f o r c o r o n a r y h e a r t d i s e a s e a m o n g o m a n i m a l e s 47 to have a positive family history of diabetes. l a c k o f ph y si c a l e x e r c i se this was classified as individuals who were not doing at least 150 minutes of moderate intensity aerobic physical activities or at least 90 minutes of vigorous exercise per week. smo k i n g the matched pairs were classified into ever smoker and non-smoker groups. the ever smokers were individuals who were irregular or regular were considered at risk. stati sti c a l a n a ly si s the percentages were calculated to summarize the various socio-demographic characteristics of the patients. the data on all the risk factors included in the study were coded “1” if the respondent was found to be in the exposure category and “0’ if the individual was not in the exposure category. the mcnemar chisquare test13 was used for testing the significance of association under univariate analysis. the data were entered and the univariate analysis was carried out using the statistical package for the social sciences (spss) software version 10.0. to estimate the ors for each of the risk factors, a 2x2 table was formed representing the results of matched case-control study designed to assess the relationship between a single dichotomous risk factor and chd. denoting an exposed individual by (+) and an unexposed individual by (-), we obtained the discordant pairs of observations in the resulting cells of the table corresponding to (+ -) and (+). considering b and c as the discordant pairs, the estimated values of the ors were obtained by the relation or= b/c and their 95% confidence limits were obtained by: or x exp [± 1.96 x √{(1/b)+(1/c)}] th e c o n d i ti o n a l l o gi sti c r e gr e s si o n me th o d consider x= (x1,……., x7) a vector of risk factor variables for an individual under study. each of the variables entering in the conditional logistic regression analysis is defined in table 1. the parameters βj (j = 1…,7) and their asymptotic standard errors were estimated using conditional likelihood procedure.14, 15 variable definition disease status (d) 0 1 noncoronary patient/asymptomatic individual a case of chd hypertension (x1) 0 1 <140mm hg systolic and < 90mm diastolic ≥ 140mm hg systolic and/or ≥90mm hg diastolic diabetes mellitus (x2) 0 1 < 7.0 mmol/l ≥ 7.0 mmol/l family history of chd (x3) 0 1 absence of family history presence of family history type of occupation (x4) 0 1 active sedentary family history of diabetes (x5) 0 1 absence of family history presence of family history physical exercise (x6) 0 1 at least 90 minutes vigorous exercise weekly less than the above smoking (x7) 0 1 nonsmoker smoker table 1: summary of variables used in the analysis of coronary heart disease data s h ya m s g a n g u ly, m o h a m m e d a a l -s h a fa e e , a b d u l l a h a a l m a n i r i 48 the ors for each of the risk factors were estimated by ψj=exp(βj), j=1,… ,7. the asymptotic variances of the estimated ors were obtained by the use of delta method 16 and is given by v(ψj)=[ψj] 2 v[βj], j= 1, ……, 7 the tests of significance of the parameters involved in the model were carried out using the wald test. the conditional multiple logistic regression model was fitted using egret, version 2.0.31 software. the level of p <0.05 was considered as cut-off value of statistical significance. r e s u l t s table 2 shows that the mean age was 56.24 years (± 10.37) with 96 percent above 40 years of age. the literacy rate was 39 percent. the majority (73%) was married. the prevalence of a sedentary life style was very high (88.0%). the break-up of the 100 cases according to the type of chd diagnosed revealed that the largest number of cases were of angina pectoris (74%) followed by acute myocardial infarction (15%) and chronic chd (11%). un i va r i ate a n a ly si s the results from univariate analysis for each risk factor are shown in table 3. it is evident that an individual with a history of hypertension has 7 times more chance of developing chd as compared to a person without hypertension (p< 0.01). the risk of developing chd was 3 times higher for a diabetic patient as compared to a nondiabetic person (p<0.05). a family history of chd was found more frequent among the cases as compared to controls with an or of 5.0, but this was not statistically significant (p>0.05). the ors of suffering from chd for a person with a sedentary type of occupation as compared to an individual with a non-sedentary occupation was found to be 3.14 (p<0.01). a family history of diabetes, lack of physical exercise and the smoking habits of the individual also contributed to the incidence of the disease, with ors of 1.71, 1.43 and 1.15 respectively, but these were not statistically significant (p>0.05). multi va r i ate a n a ly si s the pair-wise matched case-control data set, for which the univariate analysis was carried out, was also considered for multivariate analysis. for this, conditional logistic regression analysis was used. all seven risk factors, which were entered in the analysis, provided the estimated values of ors controlled for other variables included in the model. the maximum likelihood estimates of the parameters, the standard errors of the estimates and the estimated values of ors with their standard errors under the model, are shown in table 4. it is observed that, out of the seven risk factors, hypertension status, diabetes mellitus, a family history of chd and sedentary type of occupation of the individual are the main modifiable factors in the development of chd in this community (p<0.05). the estimated odds of developing chd for an individual with hypertension, after adjusting the effect of other risk factors, was about 10 times higher as compared to a normal person. the adjusted or for chd due to diabetes mellitus was found to be 2.74. the odds of suffering from the disease for an individual with the presence of family history of chd after adjusting the effect of other factors, was found to be very high as compared to an individual who did not have a family history (p<0.05). moreover, the analysis also revealed that an indicharacteristics n % age range < 40 40 – 49 50 – 59 ≥ 60 4 21 32 43 4.0 21.0 32.0 43.0 education illiterate koran elementary & above 61 28 11 61.0 28.0 11.0 marital status single married divorced widowed 2 73 3 22 2.0 73.0 3.0 22.0 type of occupation active sedentary 12 88 12.0 88.0 category of chd acute chronic angina pectoris 15 11 74 15.0 11.0 74.0 table 2: distribution of 100 cases according to the socio-demographic characteristics and type of coronary heart disease diagnosed s o m e r i s k fa c t o r s f o r c o r o n a r y h e a r t d i s e a s e a m o n g o m a n i m a l e s 49 vidual with a sedentary occupation had 3 times the risk of developing chd as compared to a person with an occupation involving physical activity (p<0.05). the chance of developing chd among the individuals with the family history of diabetes was found to be about 2.7 times more as compared to the individuals without family history of diabetes mellitus but this was not statistically significant (p>0.05). in the case of the other two risk factors, namely lack of physical exercise and smoking, the risk of developing the disease were found to be approximately the same as found under the univariate analysis. d i s c u s s i o n by the end of twentieth century, most developing countries, including oman, experienced a major surge in life expectancy due to a decline in various mortality indicators and an improvement in overall socioeconomic development. the demographic shift has increased the number of older adults thus providing longer exposure to risk factors of chd. the medical and socioeconomic consequences of an increase in the burden of chd will be disastrous for most of the countries as costly interventions and drugs may not be affordable.17 strategies to prevent the acquisition or augmentation of chd risk factors will be a combination of primordial prevention and primary preventive action to reverse and reduce the elevation of risk factors. most researchers suggest that overweight/obesity increased serum total cholesterol, low density lipoprotein cholesterol and decreased high density lipoprotein cholesterol are well established risk factors for coronary heart diseases.18, 19 in our study, we excluded these factors since they have been well uninvesigated in this part of the world. our study has reported that the average age of the patients was 56.2 ±10.4 years ranging from 36 years to 80 years. al adsani et al20, in their study carried out in kuwait on a similar population to ours, found that the average age of male patients of chd was 52.4 ± 10.4. the results from both univariate and multivariate analyses indicate that hypertension, diabetes mellitus and sedentary occupations contributed significantly to the development of chd (p< 005). yusuf et al21 in their interheart study in 52 countries reported the strength of association between hypertension and acute myocardial infarction in men and women after adjustment for age, sex, and geographical region with an or of 2.95 (95% ci 2.59, 3.39). in the present study, it was found that hypertension was present in 61% of the cases against 23% in the control (p<0.001). a family history of cvd reflects genetic, environmental and behavioural elements and interactions between them. the relative risk ranges from 2.0 to 9.0 among persons who report a family history of cvd, depending on the type and number of relatives considered.22 in this study, the family history of chd is associated with the development of the disease (p<0.05). ganguly et al23 in their study reported that smoksl. no. risk factor no. of discordant pairs odds ratio 95% confidence limits p (+ -) (+) 1 hypertension 44 6 7.33 3.12, 17.20 0.008 2 diabetes mellitus 23 7 3.29 1.34, 8.40 0.010 3 family history of chd 5 1 5.00 0.58, 42.79 0.230 4 sedentary occupation 22 7 3.14 1.50, 6.58 0.006 5 family history of diabetes 12 7 1.71 0.67, 4.34 0.359 6 lack of physical exercise 10 7 1.43 0.54, 3.78 0.630 7 smoking habit 15 13 1.15 0.55, 2.52 0.850 table 3: the estimated values of odds ratios and their 95 percent confidence limits for the various risk factors s h ya m s g a n g u ly, m o h a m m e d a a l -s h a fa e e , a b d u l l a h a a l m a n i r i 50 ing increases by threefold the chances of developing chd as compared to nonsmokers (p<0.001). in this study, no significant association between smoking history and development of disease was found (p>0.05). this may be due to reluctance to provide a correct history of smoking habits because of religious and cultural taboos. it can be observed that the ors computed using univariate analysis and multivariate analysis differ. in univariate analysis, we estimate the ors for each factor independently, whereas, under the conditional logistic regression model, the estimation of ors depends upon the regression coefficients, which in turn were estimated by simultaneously considering all the factors included in the model. thus we can always expect differences in conclusions based on the two procedures. c o n c l u s i o n from the above study, it can be concluded that individuals above 40 years of age with hypertension, diabetes mellitus, a family history of chd and a sedentary life style should be considered at high risk for developing chd. they should be provided with intensive health education along with close monitoring to detect the emergence of the symptoms and signs of chd. a c k n ow l e d ge me n ts the authors would like to thank the squh and royal hospital authorities for providing the necessary data and squ students, sh al-busaidi and aa al-muniri, who assisted with the research. r e f e r e n c e s 1. world health organization. cardiovascular disease: prevention and control. who, 2007. from www.who. int/dietphysicalactivity/publications/facts/cvd/en/. accessed 22 may 2007. 2. lozano r, murray cjl, lopez ad, satoh t eds. miscoding and misclassification of ischemic heart disease mortality. geneva: who, 2001. 3. world health organization eastern mediterranean regional office. annual report of regional director 2004, cairo: who, 2005. 4. hill ag, chen lc. oman’s leap to good health: a summary of rapid health transition in the sultanate of oman. muscat: who, unicef, 1996. 5. al-riyami aa, afifi m. clustering of cardiovascular risk factors among omani adults. east mediterr health j 2003; 9:893-903. 6. mehta fr, jaffer a, suleiman m, lambourne a, alaufy s. assessment of some cardiovascular risk factors during the pre-haj medical examinations in oman. east mediterr health j 1995; 1:223-229. 7. sulaiman ajm, al-riyami a, farid sm ed. oman famvariable xj estimate of the parameter βj standard error se(βj) odds ratio (adjusted) ψj=exp(βj) standard error se(ψj) hypertension, β1 2.301 0.519 9.98** 5.17 diabetes, β2 1.010 0.530 2.74** 1.45 family history of coronary heart disease, β3 3.39 0.615 28.19* 17.33 sedentary occupation, β4 1.100 0.553 3.00* 1.65 family history of diabetes, β5 0.978 0.691 2.66 1.83 lack of physical exercise, β6 0.548 0.655 1.73 1.13 smoking, β7 0.295 0.505 1.34 0.67 **p<0.01, *p < 0.05 table 4: the estimated values of odd ratios for the risk factors under conditional logistic regression model s o m e r i s k fa c t o r s f o r c o r o n a r y h e a r t d i s e a s e a m o n g o m a n i m a l e s 51 ily health survey, muscat: ministry of health, sultanate of oman, 2000. 8. al-moosa s, allin s, jemiai n, al-lawati j, mossialos e. diabetes and urbanization in omani population: an analysis of national survey data. popul health metr 2006; 4:5-12. 9. hasab aa, jaffer a, hallaj z. blood pressure patterns among omani population. east mediterr health j 1999; 5:46-54. 10. schlesselman jj. case-control studies; design, conduct, analysis, new york: j wiley and sons, 1982. 11. world health organization/international society of hypertension writing group. guidelines for management of hypertension. j hypertens 1999; 17:151-182. 12. world health organization. definition, diagnosis and classification of diabetes mellitus and its complications. part 1: diagnosis and classification of diabetes mellitus, report of a who consultation. geneva: department of noncommunicable disease surveillance, world health organization, 1999. 13. mcnemar q. note on the sampling error of the differences between correlated proportions or percentages. psychometrika 1947; 12:153-157. 14. holford tr, white c, kelsey jl. multivariate analysis for matched case-control studies. am j epidemiol 1978; 107:245-256. 15. hosmer dw, lemeshow s. applied logistic regression. new york: j wiley and sons, 1989. 16. ganguly ss, naik nimbalkar uv. analysis of ordinal data in a study of endometrial cancer under a matched pairs case-control design. stat med1995; 14:1545-1552. 17. reddy ks, yusuf salim. emerging epidemic of cardio vascular disease in developing countries. circulation 1998; 97:596-601. 18. aghaeishahsavari m, noroozianavval m, veisi p, parizad r, samadikhah j. cardiovascular diseases risk factors in patients with confirmed cardiovascular disease. saudi med j 2006; 27:1358-1361. 19. achari v, thakur ak, sinha ak. the metabolic syndromeits prevalence and association with coronary artery disease in types 2 diabetes. j indian acad clin med 2006; 7:32-38. 20. al adsani a, memon a, peneva a, baidas g. clinical epidemiology of acute myocardial infarction in kuwait. acta cardiol 2000; 55:17-23. 21. yusuf s, hawken s, ounpuu s, dans t, avezum a, lanas f, et al. effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the interheart study): case-control study. lancet 2004; 6:937-952. 22. mccusker me, yoon pw, gwinn m, malarcher am, neff l, khoury mj. family history of heart disease and cardiovascular disease risk reducing behaviors. genet med 2004; 6:153-158. 23. ganguly ss, dutta pk, tilak vw. evaluation of some risk factors for ischemic heart disease under a matched pairs case-control design. indian j med res 1997; 150:278-82. march 2007 vol 7 isuue 1 final without suicide .indd pulmonary infarction a rare case of adrenal carcinoma *sukhpal sawhney1, ikram burney2, rajeev jain1 الرِّئَة تِشاءُ احْ ر ظْ الكُ رَطانَة سَ من نادرة حالة جني وراجيف بورني اكرام سوهني، سخبال انسداد مع املشخص غير الكظر سرطانة الدم، وكان لديها ضغط انخفاض لعدة مرات بسبب للمستشفى أدخلت شابة تقرير حالة امللخص: هذا األمين البطني األَميَن، ، األُذَينُ لِيّ ــفْ وَفُ السُّ الوَريدُ األَجْ إلى ممتدة اليمنى الكظر غدة في كبيرة كتلة أظهر ــب احملوس املقطعي التصوير الرئوي. ــريان الش املصابني املرضى عند األمين واألذين السفلي األجوف الوريد من كال توثق خثرة من تقارير حلاالت العديد هناك األدبيات الطبية، في األمين. الرئوي والشريان الرئوي. الشريان إلى الورم امتداد نتيجة الرئوي االحتشاء خاصة بصورة توثق هذه أول حالة علمنا حسب الكظر. بسرطانة عمان. حالة، تقرير ب، َوْسَ يُّ احملُ عِ طَ َقْ امل وِيْرُ التَّصْ الرئة، احتشاء الكظر، سرطانة الكلمات: مفتاح 1department of radiology and molecular imaging, sultan qaboos university hospital, p. o. box 35, al-khod 123, sultanate of oman 2department of medicine, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: sukh@squ.edu.om sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© we report a case of a previously well young girl with newly diagnosed adrenal carcinoma, who presented with a pulmonary infarction due to a tumour thrombus extending in-continuity from the inferior vena cava to the right atrium, right ventricle and pulmonary artery. she did not have any clinical or imaging studies in the past. there have been no previous reports specifically documenting pulmonary embolism from a tumour thrombus of adrenal carcinoma, though there are many reports in literature documenting inferior vena cava and right atrial thrombus in patients with adrenal carcinoma. this is the first reported case of adrenal cortical carcinoma presenting as pulmonary infarction in which a computed tomography (ct) scan established the diagnosis. c a s e r e p o r t a 15-year-old girl was referred to a tertiary hospital in urban oman with a two-month history of sudden onset of hirsutism, acne, and a three-day history of episodes of prolonged hypotension, with blood pressure dropping to 90/60 mmhg. her past medical history was not significant for medical or surgical illness. however, the menstrual history was significant, in that she had not attained menarche. on examination, she had a pulse rate of 138/min, blood pressure of 110/70mmhg, had a coarse voice, hirsutism, acne, ascites, and bilateral c a s e r e p o r t abstract a case report of unsuspected adrenal carcinoma with pulmonary artery obstruction in a young girl who was admitted with recurrent episodes of hypotension is presented. computed tomography (ct) scans demonstrated a large right adrenal mass extending into the inferior vena cava (ivc), right atrium, right ventricle and right pulmonary artery. there are many case reports in literature documenting ivc and right atrial thrombus in patients with adrenal carcinoma. to our knowledge, this is the first case report specifically documenting pulmonary infarction secondary to tumour extension into the pulmonary artery. keywords: adrenal carcinoma, pulmonary infarction, computed tomography , case report, oman. s u k h pa l s aw h n e y, i k r a m b u r n e y, r a j e e v j a i n 56 pitting edema. her external genitalia were normal. the oxygen saturation was 95%, and blood gases revealed ph 7.42, pco2 2.4 kpa, po2 11.9 kpa, hco3 11.9 mmol/l. the results of the full blood count were as follows: hb 16.1 g/dl, wbc 16.8x109/1, cytology platelets 208 x 109 / l. ascitic tap revealed lymphocytic exudates, with a protein content of 22.8gm/l. serum cortisol levels were 6284 nanomol/l. a ct scan of her abdomen and chest was performed. a contrast enhanced ct scan (cect) of the abdomen showed a large enhancing mass in the right adrenal gland. the mass was extending into and within the extrahepatic and intrahepatic course of the inferior vena cava. the liver showed features of budd-chiari syndrome in the form of an enlarged liver with areas of patchy parenchymal enhancement and multiple enhancing regenerative nodules. hepatic veins could not be identified [fig 1]. a cect scan of her chest at the level of the heart showed a mass in the right atrium extending into the right ventricle [fig 2]. the ct scan at the level of the main pulmonary arteries showed a extension of the tumour in the right main pulmonary artery, with diminished perfusion of the lung distally [fig 3]. the patient died on the third day after admission, before any surgical intervention could be contemplated. d i s c u s s i o n this is the first reported case of an adrenal tumour with an ivc thrombus extending into the pulmonary artery. the estimated incidence of adrenocortical carcinomas in patients younger than 20 years of age is three per million of the population.1 of adrenal tumours in children, adrenocortical neoplasms are far less common than neuroblastomas, but more common than pheochromocytomas.2 it is now recognized that most children with an adrenocortical neoplasm show clinical evidence of an endocrine abnormality, in contrast to the behaviour of adrenocortical neoplasms in adults.3 although the commonest cause of inferior vena cava extension of a tumour is from renal cell carcinoma, various other tumours, such as leiomyosarcomas of the inferior vena cava, adrenal cortical carcinomas, pheochromocytoms, neuroblastomas, transitional cell carcinomas of the renal pelvis, metastatic small cell carcinomas and wilms tumours have been described to extend into the inferior vena cava.4 pulmonary artery tumour thrombus has been reported in patients with renal cell carcinomas,5,6 but to our knowledge there is no reported case of an adrenal carcinoma with tumour thrombus extension into the pulmonary artery. adrenal carcinomas may extend into the renal veins and inferior vena cava, and are usually accompanied by a thrombus.7 right atrial involvement is very rare.7 evidence suggests that as many as a third of primary figure 1: contrast-enhanced ct scan of upper abdomen shows an enhancing mass in the right adrenal gland (arrowheads), extending into the intrahepatic inferior vena cava (ivc) see arrows. geographic hepatic parenchymal enhancement together with ivc occlusion by enhancing tumour thrombus indicates hepatic venous outflow obstruction (budd-chiari syndrome) figure 2: contrast-enhanced ct scan of chest at the level of the right ventricle shows a large tumour thrombus as a filling defect in the right atrium and ventricle (arrowheads). hardly any enhancing pulmonary arteries are identified on the right side p u l m o n a r y i n fa r c t i o n 57 adrenocortical cancers may develop a tumour thrombus within the inferior vena cava.8 the thrombus may be asymptomatic or may become manifest as ascites, nephrotic syndrome, hepatomegaly, acute tricuspid valve failure or the budd-chiari syndrome.9 a limitation of this case report is the lack of availability of a tissue diagnosis. the patient was very ill at presentation, in a state of hypotension and pursued a rapid downhill course, succumbing to the disease within three days of admission. however, virilising clinical features, a very high serum cortisol, together with a radiological picture of an adrenal mass with extension into the ivs, right atrium and right pulmonary artery are highly suggestive of an adrenal carcinoma. c o n c l u s i o n patients with adrenocortical carcinomas may have an extensive inferior vena caval tumour thrombus, which can extend into the right cardiac chambers and occasionally into the pulmonary arteries. such patients may present with clinical features of pulmonary infarction. alternatively, cardiac and/or pulmonary extensions of tumour thrombi may be overlooked, if not assiduously looked for. therefore, a complete evaluation of a patient with adrenocortical carcinoma should include an evaluation of the cardiac chambers with echocardiography or contrast-enhanced ct scans. r e f e r e n c e s 1. lack ee, mulvihill jj, travis wd, kozakewich hp. adrenal cortical neoplasms in the pediatric and adolescent age group: clinicopathologic study of 30 cases with emphasis on epidemiological and prognostic factors. pathol ann 1992; 27:1-53. 2. stewart dr, jones ph, jolleys a. carcinoma of the adrenal gland in children. j pediatr surg 1974; 9:59-67. 3. lack ee. adrenal cortical neoplasms in childhood. in lack ee, ed. atlas of tumors of the adrenal gland and extra adrenal paraganglia,. fasc 19, ser 3. washington, dc: armed forces institute of pathology, 1997. p. 153168. 4. chesson jp, theodorescu. adrenal tumor with caval extension. case report and review of the literature. scand j urol nephrol 2002; 36: 71-73 5. g gayer, s. mini, d. olchovosky, et al. pulmonary embolism the initial manifestation of renal cell carcinoma in a young woman. emerg. radiol 2003; 10:43-45. 6. wieder ja, laks h, freitas d, marmureanu a, belldegrun a. renal cell carcinoma with tumor thrombus extension into the proximal pulmonary artery. j urol 2003; 169: 2296-2297. 7. rosen b, rozenman y, harpaz d. extension of adrenocortical carcinoma into the right atrium-echocardiographic diagnosis; a case report. cardiovas ultrasound 2003; 16:5. 8. radecka e, brekkan e, juhlin c, sundin a, magnusson a. an unusual case of tumor thrombus in the inferior vena cava. acta radiol 2003; 44:160-161 9. hugh tb, jones rm, shanahan mx. intra-atrial extension of renal and adrenal tumors: diagnosis, management, and prognosis. world j surg 1986; 10:496-500. figure 3: contrast-enhanced ct scan of chest demonstrates a thrombus in the right main pulmonary artery (arrowheads) with diminished arterial perfusion of the right lung. 1departments of community-based initiatives, 3investment and financing alternatives, ministry of health, muscat, oman; 2office of the world health organization, muscat, oman; 4department of architecture and urban planning, german university of technology, muscat, oman *corresponding author’s e-mail: rmmabry@gmail.com adaptation of the physical activity neighborhood environment scale in oman huda al siyabi,1 *ruth mabry,2 mosa al subhi,3 gustavo de siqueira4 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 626–631, epub. 25 nov 21 submitted 30 jun 20 revision req. 3 sep 20; revision recd. 9 oct 20 accepted 4 nov 20 methods the adaptation process followed a methodology similar to a previous study carried out in nigeria.11 it was conducted in three phases between september 2016 and august 2017 in oman: (1) revision by local experts in muscat, (2) arabic translation and cognitive testing in muscat and (3) test-retest reliability testing with a sample of omani women and men in nizwa, a city 130 km from the capital city, muscat. the 17 items of the panes tool measured the perceived attributes of the neighbourhood environment including residential density (1 item), access to destinations (3 items), paedestrian and bicycling facilities (4 items), recreational facilities (1 item), visual qualities (1 item), social environment (1 item), street connectivity (1 item), traffic safety (2 items), crime safety (2 items) and household motor vehicles (1 item). perceptions were measured using a 4-point scale ranging from strongly disagree to strongly agree, except for two items. response options for the residential density item ranged from singlefamily detached homes to apartments; the question about the number of vehicles was open-ended.10 the tool was reviewed by seven experienced experts from a variety of backgrounds [table 1]. the experts worked independently, and they were requested to propose replacements for items that were not relevant to the omani environment. these replacements needed to be culturally appropriate equivalents. the experts suggested additional items physical inactivity is one of the 10 leading risk factors for mortality; it causes 3.2 million deaths each year globally.1 the built environment of an area is associated with the physical activity levels of a population. increased street connectivity, residential density and accessibility of mixed destinations are some of the environmental attributes that support physical activity.2–5 research on the built environment’s influence on physical activity in oman and neighbouring countries is needed to guide public health policy.6 reliable and valid measures of the built environment are available for conducting such research; however, they have not been tested for cities in the arab world, including in the countries of the arabian peninsula.7–9 the physical activity neighborhood environment scale (panes), developed by the international physical activity prevalence study group, is a comprehensive yet brief measure of the perceived environment. this 17-item tool assesses adults’ perceptions of the built environment’s ability to support physical activity such as walking and bicycling in terms of land use mix, residential density, pedestrian infrastructure, aesthetic qualities and safety from traffic and crime.10 studies that have used this tool have demonstrated associations of the built environment with physical activity in the lower, middleand high-income countries on all five continents.9,11 the current study, the first in a two-part series, aimed to describe the adaptation of the panes to the omani context to assess the test-retest reliability of the omani version. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.035 brief communication abstract: objectives: this study aimed to adapt the physical activity neighborhood environment scale (panes), which is a 17-item tool for assessing environmental factors relevant for walking and bicycling in the community, to the omani context. methods: the adaptation process was conducted in three steps: (1) revision by local experts, (2) arabic translation and cognitive testing and (3) test-retest reliability testing with a sample of 33 omani women and men, between september 2016 and august 2017. results: four of the 17 items of the panes were modified and one was removed, resulting in a 16-item panes, oman (panes-o) questionnaire. the test-retest reliability scores ranged from 0.436–1.000; scores for more than half (n = 9) were almost perfect (0.8–1.0), demonstrating a good level of consistency and good psychometric performance similar to other studies. conclusion: the panes-o demonstrated good test-retest reliability and appears to be a promising tool for assessing environmental perceptions related to physical activity in oman. however, construct validity should be confirmed before wider use. keywords: physical activity; built environment; exercise; health promotion; policy; transportation; urban planning; oman. huda al siyabi, ruth mabry, mosa al subhi and gustavo de siqueira brief communication | 627 that were to be included if not already reflected. feedback was provided to the research team on a separate form. the panes questionnaire was revised based on the suggestions provided by the experts. the revised english version, panes oman (panes-o), was translated into the arabic language by an omani english language teacher and reviewed by the research team. six public health experts were invited to a meeting to review the arabic panes-o. during the meeting participants were briefed about the background of the panes including its development in australia and the usa and its adaptation in nigeria and oman.9–11 the research team then facilitated a discussion about the clarity and relevance of each item including appropriate wording in the local arabic dialect. their suggestions for improvement were welcomed and items were rephrased as needed. the test-retest reliability testing was carried out using a convenience sample of 50 women and men from different neighbourhoods and socioeconomic statuses (educational level and employment status) in nizwa. participants were approached directly to take part in the study from their home, college or place of work. eligibility criteria included being between 18–60 years old, not having any disability and being willing to complete the survey in arabic. participants completed the questionnaire in the presence of a researcher twice, at a seven-day interval. sociodemographic characteristics (age, gender, education and marital status) were included in the initial data collection. all participants provided informed consent. test-retest reliability was assessed using a oneway model single-measure intraclass correlation coefficient (icc) to ascertain consistency across multiple observers along with a 95% confidence interval. the test-retest reliability of each of the environmental variables was also conducted. agreement ratings followed landis and koch’s proposal, which was used in the nigerian adaptation: poor (0.0–0.2), fair (0.2–0.4), moderate (0.4–0.6), substantial (0.6–0.8) and almost perfect (0.8–1.0).11 the statistical package for the social sciences (spss), version 16 (spss inc., chicago, illinois, usa) was used for statistical analysis. this study was designed and conducted in adherence to the requirements of the declaration of helsinki. results out of the 17 items of the panes, four were modified and one was removed. the responses to item 1 (“what is the main type of housing in your neighbourhood?”) were changed. item 10 (“the crime rate in my neighborhood makes it unsafe to go on walks during the day”) was changed to ‘walking during the day is safe in my neighborhood’, item 11 (“the crime rate in my neighbourhood makes it unsafe to go on walks at night”) was changed to ‘walking at night is unsafe in my neighbourhood’ and item 16 (“there are many four-way intersections in my neighbourhood”) was modified to ‘there are many cross-junctions in my neighborhood’. item 17 (“how many motor vehicles in working orders [e.g. cars, trucks and motorcycles] are there at your household?”) was deleted because of broad car ownership in the country [table 2]. during the meeting with experts on the arabic translation of panes-o, the participants confirmed the clarity of the questions and their relevance to the table 1: characteristics of the local experts in oman who reviewed the physical activity neighborhood environment scale questionnaire no. gender workplace position at work education work experience in years 1 male college of education, sultan qaboos university, muscat head of physical education phd ≥20 2 male college of applied science, rustaq assistant professor of physical activity phd ≥20 3 male ministry of housing, muscat geographic master’s degree 15 4 male ministry of environment, muscat director of environmental affairs bachelor’s degree ≥20 5 male capital market authority, muscat expert on oman centre for governance and sustainability master’s degree ≥20 6 female college of agriculture, sultan qaboos university, muscat assistant professor phd ≥20 7 female petroleum development oman, muscat dietician master’s degree 15 adaptation of the physical activity neighborhood environment scale in oman 628 | squ medical journal, november 2021, volume 21, issue 4 table 2: adaptation of the physical activity neighborhood environment scale questionnaire in oman item no. original panes question local expert’s comments in % changes made by experts panes-o item relevant modify not relevant residential density 1 what is the main type of housing in your neighbourhood? 66.6 33.3 0.0 options rephrased what is the main type of housing in your neighbourhood? a.one-floor villa b.more than a one-floor villa c.more than a one-floor villa c.apartment d.detached single-family housing access to destinations 2 many shops, stores, markets or other places to buy things i need are within easy walking distance from my home. 100.0 0.0 0.0 unchanged many shops, stores, markets or other places to buy things i need are within easy walking distance from my home. 3 there are many places to go within easy walking distance from my home. 85.7 14.2 0.0 examples added there are many places to go within easy walking distance from my home, such as mosques, schools, health institutions, workplaces, markets and parks. 4 it is within a 10–15-minute walk to a transit stop (such as bus, taxi, train, trolley or tram) from my home. 14.2 57.1 28.5 item rephrased it is within easy walking distance from my home to access the public transport and taxi in the main road of my neighbourhood. neighbourhood infrastructure 5 there are sidewalks on most of the streets in my neighbourhood. 100.0 0.0 0.0 unchanged there are sidewalks on most of the streets in my neighbourhood. 6 there are facilities to bicycle in or near my neighbourhood, such as special lanes, separate paths or trails and shared-use paths for cycles and pedestrians. 57.1 14.2 28.5 unchanged there are facilities to bicycle in or near my neighbourhood, such as special lanes, separate paths and shared-use paths for cycles and pedestrians. 7 places for bicycling (such as bike paths ) in and around my neighbourhood are well maintained and not obstructed. 71.4 28.5 0.0 unchanged places for bicycling (such as bike paths) in and around my neighbourhood are well maintained and not obstructed. 8 my neighbourhood has several free or lowcost recreation facilities, such as parks, walking trails, bike paths, recreation centres, playgrounds, and public swimming pools. 57.1 42.9 0.0 item rephrased my neighbourhood has several places such as open fields, parks, a sea, clubs and gymnasiums for exercising and playing football and other sports. 9 the sidewalks in my neighbourhood are well maintained (paved, with few cracks ) and not obstructed. 100 0.0 0.0 unchanged the sidewalks in my neighbourhood are well maintained (paved, with few cracks) and not obstructed. neighbourhood safety 10 the crime rate in my neighbourhood makes it unsafe to go on walks during the day. 28.5 57.1 14.2 item rephrased walking during the day is safe in my neighbourhood. 11 the crime rate in my neighbourhood makes it unsafe to go on walks at night. 28.5 57.1 14.2 item rephrased walking at night is unsafe in my neighbourhood. 12 there is so much traffic on the streets that it makes it difficult or unpleasant to walk in my neighbourhood. 85.7 14.2 0.0 options rephrased there is so much traffic on the streets that it makes it difficult or unpleasant to walk in my neighbourhood. 13 there is so much traffic on the streets that it makes it difficult or unpleasant to ride a bicycle in my neighbourhood. 71.4 28.5 0.0 unchanged there is so much traffic on the streets that it makes it difficult or unpleasant to ride a bicycle in my neighbourhood. neighbourhood social environment 14 i see many people being physically active in my neighbourhood and doing things like walking, jogging, cycling or playing sports and active games. 100.0 0.0 0.0 unchanged i see many people being physically active in my neighbourhood and doing things like walking, jogging, cycling or playing sports and active games. neighbourhood aesthetics 15 there are many interesting things to look at while walking in my neighbourhood. 85.7 14.2 0.0 appropriate examples added there are many interesting things to look at while walking in my neighbourhood, such as shady trees, building variety and a beautiful beach. huda al siyabi, ruth mabry, mosa al subhi and gustavo de siqueira brief communication | 629 country except for item 1. for item 1 (“what is the main type of housing in your neighbourhood?”), the housing options were changed. although participants were concerned about the applicability of the items about neighbourhood infrastructure (such as sidewalks and bicycle pathways), they agreed to retain these items. a total of 33 participants (response rate: 66%), with a mean age of 35.9 ± 10.2 years, completed the test-retest reliability survey. a majority were married (78.8%), two-thirds of the participants were women (66.7%) and the same percentage had at least a high school education. the results of the test-retest reliability were good overall with icc scores ranging from 0.436–1.000. of the 16 items, nine had an almost perfect agreement (icc = 0.8–1.0) with one item on the neighbourhood infrastructure (“there are facilities to bicycle in or near my neighbourhood, such as special lanes, separate paths and shared-use paths for cycles and pedestrians”) having a perfect score (icc = 1.0) of the remaining seven items, five showed substantial agreement (icc = 0.6–0.8), and two items that were related to the neighbourhood social environment and aesthetics showed moderate agreement (icc = 0.4–0.6). for four items, a substantial proportion (25–50%) of the participants reported that they did not know and/or the item was not applicable; three were related to the neighbourhood infrastructure and one was related to the neighbourhood social environment [table 3]. discussion the adaptation of the panes instrument to the omani context showed promise in terms of assessing perceptions about the built environment in oman. a high portion of non-responses to items related to the neighbourhood infrastructure and social environment possibly reflected the development patterns and cultural context of oman and the city of nizwa in particular. oman has developed rapidly in the past 50 years following a western planning model of functional spatial segregation and dispersal of low-density settlements.12,13 newer communities are not designed to be supportive of walking and cycling.14 although older parts of nizwa follow traditional designs that may be more supportive of active travel, like muscat, the challenges respondents faced in completing certain items may have reflected their experience in the newer neighbourhoods. in addition, cultural perceptions have altered people’s attitudes towards walking and bicycling, especially among the younger population.12–16 the test-retest reliability scores ranged from 0.436–1.000 and scores for more than half of the items were almost perfect (0.8–1.0), demonstrating a good level of consistency and good psychometric performance similar to those reported in other studies.10,11 all items assessing residential density, access to destinations, neighbourhood safety and street connectivity had higher reliability coefficients (>0.650) compared to items on social environment and aesthetics. neighbourhood social environment, the item with the lowest score, was also the item that the largest number of participants did not respond to; this may have reflected both the negative socio-cultural perceptions towards active travel and an unsupportive built environment.6,13–15 further research is needed to confirm retention and possible rewording of items that scored poorly or received a limited response. the main strength of this study was the systematic adaptation of this internationally validated tool. however, the modest non-representative sample size from one city limited its generalisability despite the demographic diversity of the sample in terms of age, gender and educational level. selecting samples from a variety of neighbourhood environments would help in better measuring the variability in perceptions about the built environment and confirming the utility of this tool in the omani context.10 table 2 (cont’d): adaptation of the physical activity neighborhood environment scale questionnaire in oman item no. original panes question local expert’s comments in % changes made by experts panes-o item relevant modify not relevant street connectivity 16 there are many four-way intersections in my neighbourhood. 57.1 28.5 14.2 item rephrased there are many cross-junctions in my neighbourhood. motor vehicle 17 how many motor vehicles in working orders (e.g. cars, trucks and motorcycles) are there at your household? 100.0 0.0 0.0 unchanged – deleted how many motor vehicles in working orders (e.g. cars, trucks and motorcycles) are there at your household? adaptation of the physical activity neighborhood environment scale in oman 630 | squ medical journal, november 2021, volume 21, issue 4 table 3: intraclass correlation coefficients of the test-retest reliability of the adapted physical activity neighborhood environment scale, oman (n = 33) item no. adapted item total icc (95% ci) number of responses excluded from icc analysis residential density don’t know not applicable for the respondent’s neighborhood 1 what is the main type of housing in your neighbourhood? 0.868 (0.750–0.933) 0 0 access to destinations 2 many shops, stores, markets or other places to buy things i need are within easy walking distance from my home. 0.851 (0.720–0.924) 0 0 3 there are many places to go within easy walking distance from my home, such as mosques, schools, health institutes and workplaces. 0.928 (0.854–0.965) 3 0 4 it is within easy walking distance from my home to access the public transport such as bus and taxi in the main road of my neighbourhood. 0.954 (0.909–0.977) 0 0 neighbourhood infrastructures 5 there are sidewalks on most of the streets in my neighbourhood. 0.948 (0.896–0.974) 1 0 6 there are facilities to bicycle in or near my neighbourhood, such as special lanes, separate paths and shared-use paths for cycles and pedestrians. 1.000 (1.000–1.000) 1 7 7 places for bicycling (such as bike paths) in and around my neighbourhood are well maintained and not obstructed. 0.791 (0.446 – 0.931) 16 4 8 my neighbourhood has several places such as open fields, parks, a beach, clubs, and gymnasiums for exercising and playing football and other sports. 0.802 (0.636–0.897) 0 0 9 the sidewalks in my neighbourhood are well maintained (paved, with few cracks) and not obstructed. 0.611 (0.230–0.830) 2 12 neighbourhood safety 10 walking during the day is safe in my neighbourhood. 0.767 (0.574–0.879) 1 0 11 walking at night is safe in my neighbourhood. 0.663 (0.418–0.818) 0 0 12 there is so much traffic on the streets that it makes it difficult or unpleasant to walk in my neighbourhood. 0.855 (0.684–0.937) 2 5 13 there is so much traffic on the streets that it makes it difficult or unpleasant to ride a bicycle in my neighbourhood. 0.870 (0.745–0.936) 3 0 neighbourhood social environment 14 i see many people being physically active in my neighbourhood and doing things like walking, jogging, cycling or playing sports and active games. 0.436 (0.114–0.695) 11 0 neighbourhood aesthetics 15 there are many interesting things to look at while walking in my neighbourhoods, such as shades and trees, building variety and a beautiful beach. 0.598 (0.320–0.781) 1 0 street connectivity 16 there are many cross-junctions in my neighbourhood. 0.666 (0.412–0.824) 2 0 icc = intraclass correlation coefficient; ci = confidence interval huda al siyabi, ruth mabry, mosa al subhi and gustavo de siqueira brief communication | 631 conclusion this study supported the view that panes is a promising measure of perceptions of the built environment related to physical activity. specifically, the panes-o demonstrated good test-retest reliability. phase two of this study will examine the construct validity of this tool. further research to confirm these findings using objective measures and respondents from a variety of neighbourhoods is needed before wider use. a c k n o w l e d g e m e n t s the authors acknowledge the support of national experts who reviewed the panes and the participants who field-tested the tool. the views expressed in this paper are those of the authors and do not necessarily reflect those of the world health organization. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n ha and rm conceived the study and planned the project. ha and ma carried out the field work and data analysis. rm took the lead in preparing the manuscript. all authors provided critical feedback and approved the final version of the manuscript. reference 1. world health organization. global status report on noncommunicable diseases 2014. geneva: world health organization, 2014. 2. sallis jf, floyd mf, rodríguez da, saelens be. role of built environments in physical activity, obesity, and cardiovascular disease. circulation 2012; 125:729–37. https://doi.org/10.1161/ circulationaha.110.969022. 3. ding d, gebel k. built environment, physical activity, and obesity: what have we learned from reviewing the literature? health place 2012; 18:100–5. https://doi.org/10.1016/j. healthplace.2011.08.021. 4. durand cp, andalib m, dunton gf, wolch j, pentz ma. a systematic review of built environment factors related to physical activity and obesity risk: implications for smart growth urban planning. obes rev 2011; 12:e173–82. https://doi. org/10.1111/j.1467-789x.2010.00826.x. 5. gul y, sultan z, johar f. effects of neighborhood’s built environment on physical activities in gated communities: a review. international journal of built environment and sustainability 2016; 3. https://doi.org/10.11113/ijbes.v3.n1.112. 6. mabry r, koohsari mj, bull f, owen n. a systematic review of physical activity and sedentary behaviour research in the oil-producing countries of the arabian peninsula. bmc public health 2016; 16:1003. https://doi.org/10.1186/s12889-016-3642-4. 7. brownson rc, hoehner cm, day k, forsyth a, sallis jf. measuring the built environment for physical activity: state of the science. am j prev med 2009; 36:s99–123.e12. https://doi. org/10.1016/j.amepre.2009.01.005. 8. cerin e, conway tl, cain kl, kerr j, de bourdeaudhuij i, owen n, et al. sharing good news across the world: devel oping comparable scores across 12 countries for the neighbor hood environment walkability scale (news). bmc public health 2013; 13:309. https://doi.org/10.1186/1471-2458-13-309. 9. ding d, adams ma, sallis jf, norman gj, hovell mf, chambers cd, et al. perceived neighborhood environment and physical activity in 11 countries: do associations differ by country? int j behav nutr phys act 2013; 10:57. https://doi. org/10.1186/1479-5868-10-57. 10. sallis jf, kerr j, carlson ja, norman gj, saelens be, durant n, et al. evaluating a brief self-report measure of neighborhood environments for physical activity research and surveillance: physical activity neighborhood environment scale (panes). j phys act health 2010; 7:533–40. https://doi.org/10.1123/ jpah.7.4.533. 11. oyeyemi al, sallis jf, oyeyemi ay, amin mm, de bourdeaudhuij i, deforche b. adaptation, test-retest reliability, and construct validity of the physical activity neighborhood environment scale in nigeria (panes-n). j phys act health 2013; 10:1079–90. https://doi.org/10.1123/jpah.10.8.1079. 12. al-gharibi h. urban growth in muscat from patchwork to sustainability. ph.d. thesis, 2014, technical university, berlin, germany. 13. nebel s, von richthofen, eds. urban oman, trends and perspectives of urbanisation in muscat capital area. zurich, switzerland: lit verlag, 2016. 14. jafari m, scholz w. towards sustainable urban development: challenges and chances of climate-sensitive urban design in muscat/oman. in: azar e, raouf ma, eds. sustainability in the gulf: challenges and opportunities. london, uk: routledge, 2018. pp. 103–122. 15. mabry rm, al siyabi h, kannan m, al siyabi a. physical activity and the built environment: perceptions of policymakers in oman. health promot int 2020: 35;762–70. https:// doi.org/10.1093/heapro/daz066. 16. mabry rm, winkler ea, reeves mm, eakin eg, owen n. correlates of omani adults' physical inactivity and sitting time. public health nutr 2013; 16:65–72. https://doi.org/10.1017/ s1368980012002844. prerequisite for enhancing student learning outcomes in medical education c b hazlett special contribution squ med j, august 2009, vol. 9, iss. 2, pp. 119-123, epub 30th june 2009 invited article, submitted 1st may 09 accepted 19th may 09 department of educational services, the chinese university of hong kong, hong kong sar, china email: shazlett@shaw.ca most medical students have been exposed at some point to teaching that requires them to be passive learners. the classical example occurs in the lecture theatre in which the instructor, with or without audio-visual aids, addresses the class from a lectern and students take notes. occasional questions may be raised, but often the goal is to cover as much material as possible within the scheduled time, and thus question periods and discussions are minimised. most learning that occurs in the lecture theatre is simply an orientation to subject matter that the instructor considers worthwhile and that the students assume may be assessed in a subsequent examination. both experiential and experimental research has established that passive learning modalities are the least effective, not only in terms of the amount of material that can be learned by students, but also in terms of acquisition efficiency and in the length of time that the material will be retained. teaching modalities that require students to be actively involved in learning new knowledge and skills have been shown to be ten to sixteen times more effective.1 active learning there are three principal features to active learning: the new material needs to be constructed, contextualized, and cooperatively acquired. these three components will be described and followed with some illustrative examples. if new subject matter is presented in a manner where the learner can logically organise it, i.e., build upon previously learned content and skills, then the learning is said to be constructed.2 no matter how novel and unique the material being taught, an instructor needs to present information so that the learner can make a logical connection to what s/he has previously learned. if this is done, the learner will be able mentally to organise the new information within a personalised, conceptual framework. subsequently, this framework is easier to recall than any of the details that have been organised into the framework. after the framework is recalled, retrieval of the specific details within the framework is facilitated. if new subject matter is presented in a manner that the learner can determine how the content will be relevant to one’s work or experience, then it is said to be contextualised.3 in terms of medical education, students need to املستلزمات املطلوبة لتعزيز نتائج تعلم الطالب بالتعليم الطيب سي بي هازيلت امللخص: كل من يحصل على درجة )أ( يعني أنه عمل مبستوى جيد جدا ، بينما يستخدم مؤشر )أ( الثالثي في بعض األحيان لتمييز األشخاص فائقي تعلم بأن تؤكد التي األدلة من الكثير مؤشر )أ( الثالثي. هناك على للحصول البالغني تساعد التي التعليم تقنيات الورقة هذه في االداء. نناقش الطالب يجب أن يكون فعاال ومقيما وعلى الطريق الصحيح من أجل أن يحصل على تلك املرتبة. مفتاح الكلمات : التعليم ، طبي ، تعلم فعال. abstract: anyone achieving a grade of “a” has performed at a very good level. the label, “triple a”, is sometimes used to distinguish those who are particularly outstanding. in this paper, teaching techniques that facilitate adults becoming triple a learners are discussed. a large volume of evidence has established that, in order to achieve this rating, student learning must be active, assessed and aligned. keywords: education, medical; active learning prerequisite for enhancing student learning outcomes in medical education 120 | squ medical journal, august 2009, volume 9, issue 2 see in which practice environment, with which type of patient or at which disease stage new information will have its use. for example, basic medical science content can be presented by illustrating how the underlying mechanisms for a disease stage work; or new social sciences material is illustrated by how one’s clarity of communication or the impact of interacting with patients can be enhanced; new clinical science material is presented by clarifying its applicability for patient assessment, interpreting laboratory findings, making a diagnosis, managing care or projecting a prognosis. consider the following seemingly random pieces of information: standing sometimes helps. rain adds danger. leaning forward helps a lot but leaning a lot in other directions can hinder. you can’t go backwards easily. nails are obstacles. trying to remember this information is obviously difficult. however, if you are informed that these are factors that one needs to remember in learning how to ride a bicycle, the information is much easier to learn. that is, the information can be attached to previous experience of seeing people on bicycles; and if one is intending to learn how to ride this form of transportation, the relevance of each point is enhanced. without accompanying constructed and contextualised data, the myriad of basic science information encountered in a medical programme (physiology, biochemistry, anatomy, pharmacology, biostatistics) can appear to students as disjointed and difficult to remember as the isolated details initially illustrated for riding a bicycle safely. lastly, if new subject matter is addressed by cooperatively working together in groups, it is said to be cooperative.4 world-wide, over 900 investigations have been done on cooperative learning; those rigorously conducted (randomised trials) number more than 160. a meta-analysis of these latter studies found cooperative learning to be more effective than independently learning new material as competitive individuals. the margin of gain was statistically significant and educationally meaningful. the benefit was evident across gender, social class, culture, ethnicity, geographic regions and the subject matter taught.5 in cooperative learning, members of the group must take responsibility for teaching each other, raising and answering questions that lead to insightful discussions such as how the new information can be addressed when the underlying mechanism of disease, disease stage, type of patient, or practice environment are modified. success by any one individual depends on all group members being successful in the course. assessed learning the literature repeatedly notes the influential role that assessments have on students and the outcomes of their learning: a. to change student learning, change the methods of assessment6,7 b. assessment is a potent agent for enhancing or injuring the quality of higher education8 c. assessment dominates students’ thinking and how they approach their learning9 d. what students learn well is not what is taught, but what is tested.10 there are two principle types of assessments: summative and formative. tests designed to determine if one should pass, be promoted, obtain a degree or qualify for professional licensure are summative assessments.11 the information from high stakes tests are primarily designed for third parties (teachers, professional bodies, society) so that decisions about a candidate’s qualifications can be made. given the consequence of these decisions for the candidates, summative assessments normally serve as a significant motivator for the candidates to prepare by studying and practising. formative assessments have a different purpose. they are designed to provide the student with assistance before a summative test is taken so that they can independently determine, at anytime, how they are progressing. the goal is for the learners to be able to confirm for themselves how well they are or are not progressing and make adjustments, if needed, to their learning strategies (e.g. less time in the library and more time on the wards or in discussions with their peers or clinical supervisors).12 certain prerequisites have to be implemented for an assessment to be formative.13 first, provision of timely, appropriate feedback after an assessment is a necessity. second, the feedback must be appropriately designed. feedback has limited usefulness if it only c b hazlett special contribution | 121 indicates that an answer is or is not correct. this form of feedback can help a candidate remember the answer to the same question, but will not be useful if a summative question incorporates variations. for example, a summative item may address similar signs and symptoms, as was assessed in a formative assessment, but the disease stage or type of patient is modified. third, to aid in developing life-long, self-learning skills, appropriate feedback needs to provide information for the student to reflect meaningfully on the answer they have given.15 for example, if the answer was incorrect, an explanation is provided why the answer could not be correct and sometimes followed with an indication of a new direction for the candidate to consider. depending on the test’s format, the feedback may suggest further reading materials, relevant case notes or patients to clerk. thus, the feedback does not provide the correct answer, but rather information for the student to discover independently or deduce the correct response or action. fourth, frustration develops if the student has to spend an inordinate amount of time researching every one of the incorrect answers made on a formative assessment. thus, across the entire formative assessment, some feedback will be more prescriptive. in any case, provided the student has at least partial knowledge, the feedback should help the candidate solve the problem after reflecting on his or her previous incorrect response. for example, consider the following on-line question (developed at the university of the witwatersrand) that was submitted to ideal consortium’s formative item bank.16 “a 32-year-old diabetic patient wishes to have a second child. she developed gestational diabetes during her first pregnancy. her blood glucose is now well controlled with insulin therapy. what is the best treatment during this time? a. insulin lispro administered with insulin glargine. b. inhaled insulin. c. intraperitoneal insulin with the implantable pump. d. daily dosing with insulin dettimer insulin aspart (subcut).” the feedback appropriately varies, being matched to the answer specified by each candidate. “a. tight glycaemic control is not achieved with this treatment. b. variability on absorption, tight glycaemic control not achieved. c. tight glycaemic control is achieved and thus is recommended in pregnancy. d. insulin dettimer is a long-acting preparation and will not confer tight glycaemic control. e. insulin aspart is an ultra-short acting insulin preparation that is used preprandially.” lastly, performance on formative assessments should not be incorporated into determining a candidate’s course mark or pass-fail status. if marks on a formative assessment are used for assigning grades, students will try to conceal their deficiencies in skill or understanding (since this will negatively impact their grade).17 to be useful, formative assessments need to be seen as having a positive, not a negative, consequence. that is, students will be candid about any of their difficulties if the feedback aids in adjusting their learning strategies and further teaching is appropriately informed by the information gleaned from the formative exercise. thus, both forms of assessment are needed: summative assessments will motivate because they focus on the amount of learning, while formative assessments are aids for learning. if only summative assessments are used, the second criterion for active learning will not be met. aligned learning the final requirement for generating triple a learners is alignment.18 the principle components in delivering a medical education programme need to be logically aligned and consistent: the curriculum designed by the college; the course objectives set by the year coordinators; the teaching methods utilised by the teachers; the climate created for interaction among students and with teachers; the assessments used for and of learning; the feedback provided after tests are taken and sthe institutional policies and procedures that students and teachers have to follow. examples of misalignment in medical education prerequisite for enhancing student learning outcomes in medical education 122 | squ medical journal, august 2009, volume 9, issue 2 include: a. programme and course objectives not being matched to material addressed in classes and rotations (often because the curriculum is not owned by the college, but by individual departments and instructors who may focus on other content and skills than those designated by the college). b. an inordinate amount of material is required by the curriculum which in turn prevents teachers from ensuring that there is adequate time for questions and answers and in-depth, relevant discussions. c. formative assessments are omitted or no feedback is provided after a formative assessment. d. summative assessments are not matched to course objectives or the content and skills that were taught in classes and rotations. e. teachers have little incentive to expend the time and effort to learn and use active learning modalities because the university does not reward the use of active learning modalities (or conversely, does not penalise teachers who only use less effective passive learning modalities). f. the college provides little or no teaching enhancement support for its academic staff. the inconsistencies evident in these types of misalignments interfere with successfully introducing and maintaining active learning; this in turn leads to students learning less, less quickly and less well. conversely, if there is an appropriate and adequate amount of alignment, the medical programme will find that: a. teachers exhibit a professional approach to student learning, i.e., accepting responsibility for teaching not only medical knowledge and clinical skills, but also the skill of how-to-learn (i.e. self-learning or life-long learning skills). b. courses and rotations include a range of assessments and students are exposed to increasingly sophisticated levels of tasks that require integrating skills and knowledge. c. teachers allocate time for and make the needed effort to produce and provide timely and appropriate feedback. d. teachers are supported by their department in terms of reserved time and resources for learning and using active learning techniques. e. the university provides incentives and faculty enhancement support for teachers to pursue and achieve enhanced student learning outcomes. conclusion to summarise the key messages, consider the following questions and answers. q: what is active learning in medicine? a: new information is presented and acquired in a manner that is constructed, contextualised and cooperative. q: who is an excellent medical teacher? a: one who facilitates students learning more, learning more quickly, learning more permanently. q: what is an excellent medical education? a: students learn (i) important medical knowledge and clinical skills, but also, (ii) how-to-learn skills so that they can teach themselves and remain effective practitioners throughout their medical careers. q: how is an excellent medical education delivered? a: student learning is active, assessed and aligned in the pursuit of new information and how-tolearn skill. medical academics have the responsibility and honour to help prepare future medical practitioners. these teachers only have access to their charges at the very beginning of the students’ medical careers. if teachers simply prepare students for the beginning of these careers, then they do their students a disservice. if the students are also taught how to learn more, more quickly and more permanently, the additional life-long learning skills will enable the novice medical doctors to remain up-to-date, i.e. keeping pace with on-going developments in medical practice after leaving medical school. more importantly, patients treated by these doctors will c b hazlett special contribution | 123 more likely receive care that meets a rating of triple a in terms of quality of service. references 1. lowery ll. average retention rate: learning pyramid. bethel: national training labortories, 2002. from: http://tamu.edu/teaming/morgan. accessed march 2009. 2. jonassen dh. evaluating constructive learning. in: duffy tm, jonassen dh, eds. constructivism and the technology of instruction: a conversation. new jersey: lawrence erlbaum associates, 1992. pp. 12148. 3. mikkelsen j, holm ha. contextual learning to improve health care and patient safety. education for health, 2007; 20:124. 4. johnson dw, johnson rt. learning together and alone: cooperative, and individualistic learning. boston: allyn & bacon, 1999. 5. springer l. effects of small-group learning on undergraduates in science, mathematics, engineering, and technology: a meta-analysis. review educ res 1999; 69: 21-51. 6. brown g, bull j, pendlebury m. assessing student learning in higher education. london: routledge, 1997. 7. laurillard d. rethinking university teaching. london: routledge, 1993. 8. ramsden p. learning to teach in higher education. london: routledge, 1992. 9. gibbs g, simpson c. conditions under which assessment supports students’ learning. learning & teaching higher educ 2005;1:3-31. 10. schuwirth lw, van der vleuten cpm. different written assessment methods: what can be said about their strengths and weaknesses. med educ 2004; 38:974-9. 11. miller ah, imrie bw, cox k. student assessment in higher education: a handbook for assessing performance. london: kogan page, 1998. pp. 33-4. 12. miller ah, imrie bw, cox k. student assessment in higher education: a handbook for assessing performance. london: kogan page, 1998. pp. 32-3. 13. morgan c, dunn l, parry s, o’reilly m. the student assessment handbook: new directions in traditional and online assessment. london: routledge falmer, 2004. p.18. 14. brown g, bull j, pendlebury m. assessing student learning in higher education. london: routledge, 1997. ch. 4. 15. hazlett cb, yip s, nicholls j, au w, tan j. idealhktm: intranet users’ guide: instructors and system administrators. hong kong: don bosco, 2008. 16. kvale s. contradictions of assessment for learning in institutions of higher learning. in: boud d, falchiko n, eds. rethinking assessment in higher education: learning for the longer term. london: routledge, 2007. 17. biggs j. enhancing teaching through constructive alignment. higher education. 1996; 32:347-64. 2008-issue1.indd sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 83-87 sultan qaboos university© submitted 7th october 2007 accepted 5th february 2008 department of medicine, nizwa hospital, nizwa, sultanate of oman *to whom correspondence should be addressed. email: fatemimi@omantel.net.om a case of castor bean poisoning *faisal a al-tamimi, ahmad e m hegazi abstract castor beans, sometimes used in traditional therapies, contain ricin one of the most toxic substances known. it may cause an acute and potentially fatal gastroenteritis in addition to neurological and ophthalmological lesions. poisoning may also lead to delayed visceral damages; however, the latter is quite rare. the toxicity is dose related and depends on the amount of castor beans ingested. there is no specific treatment and symptomatic management to reduce the load of the toxin needs to be initiated quickly and early when a case of poisoning is suspected so that serious complications will be avoided. increasing the awareness of the population to the dangers of ricin would be a way to avoid the utilisation of castor seeds in traditional therapies. here we are reporting a case of mild poisoning after ingestion of a single castor bean. the patient, who presented at nizwa hospital, oman, fortunately recovered completely as the ingested dose was quite small. key words: castor beans; poisoning; ricin; case report; oman. اخلروع ببذور تسمم حالة حجازي محمد السيد التميمي، أحمد عبداهللا فيصل بذور تناول يؤدي فقد . سمية املعروفة املواد أكثر من على الريسني الذي يعتبر حتتوي ، الشعبي الطب في أحيانا تستعمل التي اخلروع : بذور امللخص نادرا) (ولو ــبب تس قد وكذلك والعني. العصبي في اجلهاز آفات الى باالضافة ، املوت الى يفضي أن ميكن والذي ، احلاد واالمعاء املعدة التهاب الى اخلروع بذور بتناول التسمم حلالة عالج نوعي اليوجد تناولها. التي مت بذوراخلروع جرعة على ــمم التس شدة تعتمد ــوية. احلش ــم اجلس أجهزة في متأخرا تلفا إن زيادة كما املتوقع حدوثها. واملضاعفات اجلسم في السم لتقليل كمية التسمم حالة في الشك عند العام البدء مبكرا بالعالج يجب ولكن اخلروع تقرير نثبت هنا التسمم. وتالفي حاالت ــعبي في الطب الش ــتعمالها اس يقلل من ــعبية قد الش االدوية في اخلروع بذور تناول عن مخاطر العام الوعي اجلرعة لكون الشفاء التام املصاب اكتسب احلظ وحلسن فقط حبة واحدة بعد تناول بذور اخلروع مبادة ــيطة بس ــمم تس حالة عن نزوى ــفى مستش من قليلة. املتناولة the castor oil plant (ricinus communis l), is a plant species of the family euphorbiaceae and the sole member of the genus ricinus and of the subtribe ricininae.1 the castor plant is native to the ethiopian region of east africa. it grows in tropical and warm temperate regions throughout the world and is becoming an abundant weed in the southwestern united states. ricinus communis is a perennial, erect, branched, herb, typically less than 2 meters in height.2 the beans are oblong and light brown, mottled with dark brown spots. the seed is only toxic if the outer shell is broken or chewed. ricin is contained in the bean pulp following the separation of the oil from the beans. no ricin is thought to remain in the oil, and it is inactivated during extraction if done under heated conditions. ingested castor beans are generally toxic only if the ricin is released through mastication. reports on the ricin content of castor beans vary, but it is probably in the range of 1% to 5%.3 purified ricin is a white powder that is soluble in water and stable over a wide ph range. 4 it is a protein toxin (toxalbumin).5 it is a glycoprotein lectin composed of 2 chains, a and b, linked by a disulfide bond.6 the b chain is a lectin and binds to galactose-containing glycoproteins and glycolipids expressed on the surface of cells, facilitating the entry of ricin into the cytosol.7 the a chain inhibits protein synthesis by irreversibly inactivating eukaryotic ribosomes through removal of a single adenine residue from c a s e r e p o r t 84 fa i s a l a . a l -ta m i m i , a h m a d e m h e g a z i the 28s ribosomal rna loop contained within the 60s subunit. this process prevents chain elongation of polypeptides and leads to cell death.8 toxicity results from the inhibition of protein synthesis, but other mechanisms are noted including apoptosis pathways, direct cell membrane damage, alteration of membrane structure and function, and release of cytokine inflammatory mediators.9 the castor bean plant also contains another glycoprotein lectin, the ricin communis agglutinin, which, unlike ricin, is not directly cytotoxic, but does have affinity for the red blood cell, leading to agglutination and subsequent haemolysis. ricin communis agglutinin is not significantly absorbed from the gut and causes clinically significant haemolysis only after intravenous administration.10 there are no literature reports of poisoning from ingesting purified ricin. all clinical reports with regard to poisoning refer to castor bean ingestion. documented mild to lethal clinical symptoms may result from ingesting one half to 30 beans.11 two castor oil beans were the minimum number found to be associated with death.12 symptom onset after ingestion is usually within 4 to 6 hours but may be as late as 10 hours.13 initial symptoms are nonspecific and may include colicky abdominal pain, vomiting, diarrhoea, heartburn, and oropharyngeal pain. haematemesis and melena are reported less commonly.14 fluid losses may lead to electrolyte imbalances, dehydration, hypotension, and circulatory collapse.15 laboratory abnormalities may include leukocytosis, elevated transaminases and creatinine kinase, hyperbilirubinemia, renal insufficiency, and anaemia.16 information on allergic reactions to ricin is primarily from persons working in or living near castor bean processing plants.17 allergy patch testing reveals an ige–mediated inflammatory reaction to ricin although other allergens may be present in the castor bean dust.18 castor beans have been used traditionally by women in many countries for birth control.19 the use of castor seed oil in india has been documented since 2000 bc for use in lamps and in local medicine as a laxative, figure 1: ecg showing normal sinus rhythm & t wave inversion in lii, liii, avf 85 a c a s e o f c a s t o r b e a n p o i s o n i n g purgative, and cathartic in unani, ayurvedic and other ethnomedical systems. castor seed and urine have also been used in china for centuries, mainly prescribed in local medicine for internal use or use in dressings.1 castor beans have been found in ancient egyptian tombs dating back to 4000 b.c. according to the ebers papyrus, an egyptian medical text from 1500 bc, egyptian doctors used castor oil to protect the eyes from irritation. the oil from the bean was used thousands of years ago in facial oils and in wick lamps for lighting.20 in oman, this is the first patient we have receive in the last 10 years who used castor beans as a traditional treatment for a cough. c a s e r e p o r t a 51 year-old omani man, neither diabetic nor hypertensive and not on any regular medication, was brought to the accident & emergency department of nizwa hospital, oman, by his son. he was in a confused state after ingesting three hours previously one green fruit of castor bean, as stated by the son. he had vomited once at home. there were no other complaints. on examination the patient was confused, disoriented as to time and place, and was afebrile. his pulse was 108/min regular, blood pressure was 110/68 mmhg and the respiratory rate was 22 per minute. examinations of the chest, cardiovascular system and abdomen were unremarkable. he had dryness of mouth and the pupils were bilaterally dilated with sluggish reaction to light. the patient was admitted to the medical ward and treated symptomatically and with activated charcoal. his initial laboratory results showed normal results for renal function tests, electrolytes, liver function tests, coagulation profile, cardiac enzymes, full haemogram and routine urine tests. an initial electrocardiogram showed normal sinus rhythm with t wave inversion in leads ii, iii and avf [fig. 1]. a repeat ecg after 6 hours showed sinus bradycardia with t inversion in inferior leads as well [fig. 2]. computed tomography of the brain was normal. he stayed in hospital for two days which were uneventful. his pulse rate returned gradually to normal and his conscious level improved and he was discharged in a good condition with the advice to evaluate his cardiac status with an echocardiogram and treadmill test at a later date. d i s c u s s i o n in various countries castor beans are the base of many traditional remedies. our patient believed that they could treat his cough. ingested castor beans are generally toxic only if ricin is released through mastication or maceration.11 the toxicity results from the inhibition of protein synthesis, but other mechanisms are noted as well.9 the clinical effects of castor bean ingestion can be classified as acute and late effect. in the acute phase, figure 2: ecg of patient showing sinus bradycardia & t wave inversion lii, liii, avf 86 fa i s a l a . a l -ta m i m i , a h m a d e m h e g a z i the patient usually develops a gastrointestinal manifestation, while the late phase reflects the cytotoxic effect on liver, kidney, and the adrenal gland, which typically starts 2 to 5 days after exposure. the ricin toxicity affects many of the body systems, and fever may be the major presenting clinical picture.21 the fever may start 30 minutes to two hours after ingesting 1 to 4 beans.22 the ricin may cause miosis14 or mydriasis23; both have been reported. in our patient, the abnormality was a mydriasis. it is also reported that the ricin can produce central nervous system depression, somnolence and loss of consciousness.24 gastrointestinal haemorrhage due to sloughing of tissue may also be seen in intoxicated persons,21 and vomiting and abdominal pain are frequently reported symptoms.14, 25 elevated liver enzymes and a transient rise in blood sugar were reported earlier too,26 as well as haematuria, fluid and electrolyte disturbance in association with severe vomiting and diarrhoea.14 a weak pulse is commonly seen, and cardiovascular shock is the commonest cause of death with no direct cardiotoxic effects, but usually secondary to fluid and electrolyte loss.11 our patient developed somnolence, mydriasis and vomiting, all of them expected symptoms; fortunately, they were mild followed by full recovery. the t inversion in his ecg is most probably not related to the ricin toxicity, but the bradycardia that occurred, may be due to the beta blocking effect of ricin that was reported only once in 1974.23 gastrointestinal decontamination for potentially toxic ingestions includes the use of activated charcoal. treatment in general is supportive and symptomatic.27 c o n c l u s i o n castor beans contain ricin, one of the most toxic substances known. they may cause an acute and potentially fatal gastroenteritis. delayed visceral damage is another serious complication; however, the latter is quite rare. the toxicity is dose related and depends on the amount of castor beans ingested. there is no specific treatment and supportive management needs to be started early to reduce the load of the toxin so as to avoid serious complications. although this is the first case in the last 10 years admitted to nizwa hospital with signs and symptoms of castor bean toxicity, there is no database about its prevalence. however, increasing the awareness of the population would be a way to avoid the utilisation of castor seeds in traditional therapies. r e f e r e n c e s 1 castor oil plant. from http://en.wikipedia.org/wiki/ castor_bean. accessed jan 2008. 2 morton jf. major medicinal plants. in: morton jf ed. botany. springfield, illinois: cc thomas, 1977. 3 bradberry sm, dickers kj, rice p, griffiths gd, vale ja. ricin poisoning. toxicol rev 2003; 22:65-70. 4 cope ac, dee j, cannan rk, renshaw b, moore s, et al. chemical warfare agents and related chemical problems part i: summary technical report of division 9. washington, dc: national defense research committee, 1945. p. 179-203. 5 parker dt, parker ac, ramachandran ck. joint technical data source book. vol 6. part 3. us dugway proving ground, utah: joint contact point directorate, 1996. dgp no. dpgjcp-961007, p.1-38. 6 ishiguro m, tomi m, funatsu g, funatsu m. isolation and chemical properties of a ricin variant from castor bean. toxicon 1976; 14:157-165. 7 sandvig k, van deurs b. entry of ricin and shiga toxin into cells: molecular mechanisms and medical perspectives embo j 2000; 19:5943-5950. 8 olsnes s. the history of ricin, abrin and related toxins. toxicon 2004; 44:361-370. 9 day pj, pinheiro tj, roberts lm, lord jm. binding of ricin a-chain to negatively charged phospholipids vesicles leads to protein structural changes and destabilizes the lipid bilayer. biochemistry 2002; 41:2836-2843. 10 hegde r, podder sk. studies on the variants of the protein toxins ricin and abrin. eur j biochem 1992; 204:155164. 11 challoner kr, mccarron mm. castor bean intoxication: review of reported cases. ann emerg med 1990; 19:1177-1183. 12 rauber a, heard j. castor bean toxicity reexamined: a new perspective. vet hum toxicol 1985; 27:498-502. 13 klaim gj, jaeger jj. castor seed poisoning in humans: a review: technical report #453. san francisco, ca: letterman army institute of research, january 1990. 14 malizia e, sarcinelli l, andreucci g. ricinus poisoning: a familiar epidemy. acta pharmacol toxicol (copenh) 1977; 41:351-361. 15 koch la, caplan j. castor bean poisoning. am j dis child 1942; 64:485-486. 16 wedin gp, neal js, everson gw, krenzelok ep. castor bean poisoning. am j emerg med 1986; 4:259-261. 17 layton ll, yamanaka e, green tw. multiple allergies 87 a c a s e o f c a s t o r b e a n p o i s o n i n g to the pollen and seed antigens of ricinus communis (castor bean). j allergy 1962; 33:232-235. 18 metz g, bocher d, metz j. ige-mediated allergy to castor bean dust in a landscape gardener. contact dermatitis 2001; 44:367. 19 salhab as, issa aa, alhougog i. pharmaceut biol 1997; 35:63–65. 20 castor oil. in: longe jl project ed. gale encyclopedia of alternative medicine. 2nd ed. 2005. p. 369-372. 21 pillay vv, bhagyanathan pv, krishnaprasad r, rajesh rr, vishnupriya n. poisoning due to white seed variety of abrus precatorius. j assoc physicians india 2005; 53:317-319. 22 kulkarni ml, sreekar h, keshavmurthy ks, shenoy n. jatropha curcas poisoning. indian j pediatr 2005; 72:75-76. 23 balint ga. ricin: the toxic protein of castor oil seeds. toxicology 1974; 2:77-102. 24 lampe kf, fagerstorm r. plant toxicity and dermatitis. baltimore, md: lippincott williams & wilkins, 1968. 25 tenenbein m, cohen s, sitar ds: efficacy of ipecac-induced emesis, orogastric lavage, and activated charcoal for acute drug overdose. ann emerg med 1987; 16:838841. 26 kaszas t. papp g: ricinussamen-vergiftung von schulkindern (poisoning of castor oil seeds in schoolchildren). arch toxikol 1960; 18:145-150. 27 behrman re, kliegman rm, jenson hb. nelson textbook of pediatrics. 17th ed. philadelphia: wb saunders, 2003. p. 2375. december 2008 no white pages.indd the world financial crisis and human health in the last issue of this journal,1 i briefly discussed the impact of one natural disaster on our health namely, ‘climate change’. little did i realize that in this issue, i might have to discuss the effect of another natural disaster on our health, i.e. the impact of the current of world financial crisis. i refer to it as a “natural disaster” because it is a “disaster” to the health of most of the world’s population and it is “natural” because it has been expected by financial experts as a natural consequence of the loose-ending policies of the major institutions in the rich nations in the west that lead the world economy and the over-inflated stock markets. be that as it may, our concern in the medical profession should be focused on the consequences of the current downturn of the economy on our health. some health consequences are very obvious while others are more subtle. any individual who has a major portion of his wealth in the stock market, in effect suddenly became 20 25% poorer, just in the first 10 days of october 2008. this is not just limited to the investments of individuals, but also affected the major companies that employ thousand of people and the pension plans of several institutions. many large firms in oman have their pension funds invested in the stock markets of the world. how does this impact our health and what is health? according to the alma-ata declaration of 1978, “health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity”. this is according to the international conference on primary health care at alma-ata in present kazakhstan (former sovient union) on 6th december 1978. it declared that health, as per the above definition, “is a fundamental human right and that the attainment of the highest possible level of health is the most important world-wide, social goal whose realization requires the action of many other social and economic sectors in addition to the health sectors”.2. the current financial crisis deprives many of us of this “fundamental human right” e.g. it is not surprising that the suicide rate has significantly risen in japan.3 in oman, perhaps, we have not been as greatly affected by this economic downturn as some other countries, but the food prices here have risen significantly lately. this will naturally impact on the health of the less fortunate in our society who may not be able to afford a square meal at the new prices. food prices are still rising in many countries and there is a worldwide “food crisis”. there are 850 million people going hungry each day despite a huge surplus of food production in some countries.4 around 24,000 hungry people perish each day in an endless wait for food.5 physicians can speak out on behalf of these hungry millions. we stand facing a hungry planet and the threat of “financial armageddon”.4 apart from this food crisis, we also have evidence that the financial crisis can cause an increase in cardiovascular events, including myocardial infarcts. studies conducted at the university of chicago have shown evidence of increased stress hormones and aggravated atheroscolerotic plaques.6 this study also indicted that job lay-offs from the economic crisis lead to a two-fold increase in subsequent heart attacks and cerebrovascular events.6 a study reported from duke university workers has also shown that ex-smokers are more likely to relapse, drinkers drink more, and people eat less heart-healthy foods during financial crises. the message is clear, “if you do not have the money to pay the bills, you are stuck.” 6 historically, there are several other health consequences of the financial downturn such as the vaccinations decline of the late 90s, an increase in child infections7 and the stagflation of the 1970’s that ended the economic model of keynesianism.8 now, it threatens our mental health as per the who’s evaluation.9 families in the usa now have to struggle with tough financial decisions needing a sacrifice of their health care.10 rising unemployment and soaring drug and hospital costs impact the health care of canadians also.11 medical societies and associations have a moral responsibility to act collectively to reduce the adverse health effects of the economic downturn by a premeditated plan of preventative medicine and close monitoring. governments equally have the obligation to avert the health effects of such a crisis by preventive measures and by acting to prevent more financial crises and not only provide ‘bailout’ solutions. action is needed to neutralise the sting of this financial crisis, the food m e s s a g e f r o m t h e e d i t o r i n c h i e f 259 260 m e s s a g e f r o m t h e e d i t o r i n c h i e f crisis, and the subsequent health crisis. the health consequences of this world financial crisis can be physical and mental, acute and chronic, immediate and remote, all of them needing our attention. prof. muhammad yunus, a bangladeshi banker and economist, led the world in solving one financial lending dilemma and thus improved the lives of millions while writing a new chapter in the history of solutions for financial crises and human suffering. he was also awarded a 2006 nobel peace prize for pioneering the use of micro-credit to benefit the poor. this should act as an inspiration for financial gurus and economic academicians in oman to strive for a solution to this financial crisis and thus its health consequences. squmj is encouraging the publication of any scientific endeavour from any of the squ colleges or elsewhere in search for a solution to this intertwined problem of health and financial crisis. lamk al-lamki md, frcpc, facr, facnm editor-in-chief email: mjournal@squ.edu.om tel. number: (+968) 2414 3457 r e f e r e n c e s 1. al lamki l. physicians, climate change and human health message from the editor-in-chief. squ med j 2008; 8:125127. 2. declaration of alma-ata: international conference on primary health care, alma ata, ussr, 6-12 september 1978. from http://www.who.int/hpr/nph/docs/declaration_almaata.pdf. accessed october 2008. 3. hogg c. downturn stirs japan suicide fears. from http://news.bbc.co.uk/2/hi/asia-pacific/7651518.stm. accessed october 2008. 4. shattuck a. the financial crisis and the food crisis: two sides of the same coin. from http://www.stwr.org/food-security-agriculture/the-financial-crisis-and-the-food-crisis-two-sides-of-the-same-coin.html. accessed october 2008. 5. sharma d. global priorities: feeding markets, starving the hungry. from .http://www.stwr.org/global-financial-crisis/ global-priorities-feeding-markets-starving-the-hungry.html. accessed october 2008. 6. o’connor a. how the financial crisis could break your health, literally? from http://living.health.com/2008/09/25/howthe-financial-crisis-could-break-your-heart-literally/. accessed october 2008. 7. who. vaccinations may decline due to financial crisis. from http://www.who.int/inf-pr-1998/en/pr98-83.html. accessed october 2008. 8. parsons aw. food and markets: a crisis of faith. from http://www.stwr.org/food-security-agriculture/food-and-markets-a-crisis-of-faith.html. accessed october 2008 . 9. who. economic downturn poses a threat to mental health. from http://www.cbc.ca/health/story/2008/10/10/mentalhealth-economy.html. accessed october 2008. 10. collins s. losing ground: how the loss of adequate health insurance is burdening working families. from http://ccf.georgetown.edu/index/research-economic-downturn. accessed october 2008 . 11. canadian medical association journal, www.cmaj.ca/reprint166. december 2008 no white pages.indd hazardous waist tackling male weight problems sultan qaboos university medical journal november 2008, volume 8, issue 3, p.364-365 sultan qaboos university© submitted 4th september 2008 if you think that your dishdasha*, after tucking your khanjar** around it, is helping you hide your extended waistline, you may actually be hiding something of sinister consequence to your health. male fatness, or android obesity, that manifests as an expanded waistline is now perceived in the medical profession as an key precursor of many intractable illnesses from diabetes to cancer, as well as a myriad of others that lead to poor quality of life, disability or simply shortened lives. of course, this is not new; the ‘father’ of medicine, hippocrates, long ago indicated that corpulence leads to untimely death. this view has been recently resurrected in the volume, hazardous waist: tackling male weight problems. when one sees the title of this book, it appears that it is one of those ‘self-help’ books with directions on how to curb one’s mass of adiposis tissue. the title appears to suggest new age themes like those of dr. deepak chopra, (indian medical doctor and popular writer on spirituality and diverse topics in mind-body medicine), but browsing through the pages, we realize that this book is no ‘psycho babble’ or esoteric book enticing people to recharge their ‘chakra’. the volume is neither reminiscing of ‘gutbuster’ exercise or drugs that often appears as e-mail spam. alan white and maggie pettifer have edited chapters from presentations previously conducted under the auspices of the men’s health forum which took place from 2004 in the uk. it synthesises the literature and all that the services of weight problems entail among the male population. the statistics are staggering and the situation is overwhelming bleak. males are more gluttonous and sedentary and are unlikely to be unaware of their belly fat or simply deny its size. more dishearteningly, males are less likely to do something about it than females. most demoralising, males with central obesity have a higher risk of succumbing to illeffects of obesity. although there are many academic publications highlighting the global epidemic of obesity, this volume uniquely focuses on the male gender. the motto of the book is the formula that what works for females may not be the best solution to preventing the rising tide of hazardous waist among males. then, you may wonder, in the age of ‘schism’ and ‘ism’, is this book just dangerously revamping and evoking ‘gender wars’ and اخلطر اخلصر لدى الذكور الوزن معاجلة مشاكل بيتيفر وماجي وايت االن : املؤلفون editors: alan white and maggie pettifer publishers: radcliffe publishing, oxford & new york, 2007. no. of pages 225 isbn: 10 1846191033 orders: www.radcliffe-oxford.com b o o k r e v i e w * traditional omani men’s robe ** traditional omani dagger b o o k r e v i e w : h a z a r d o u s wa i s t 365 stereotypes? is a thin veneer of health-speak actually just masking male bashing? the answer is emphatically no. the book simply raises awareness of male weight problems and it is built around the theme that the waist’s circumference in males has reached the danger zone and that this trend is taking on epidemic proportions. the first part of the volume addresses the challenges of male weight problems. under this heading, there are six chapters synthesising the multidisciplinary and gender sensitive approach to central obesity and its impact on psychological, medical and social outcomes. the second part of the book, divided into fifteen chapters, addresses how to tackle male weight problems. it highlights the important roles of primary health care, community and an ‘obesogenic’ environment in the effort to confront the health risks posed by obesity in men. although eating disorders are becoming global challenges, the book derives its database from the uk and australian populations. both of them are a heterogeneous collection of different ethnic groups, so the book does transcend the white middle class situation. references to the world health organization also crop up on many occasions. scholarly work and statistics on the prevalence of obesity in minorities and even a chapter featuring the situation among south asian men are given audience in this volume. despite the well established association between genetic factors and obesity, it is the socio-cultural context that is central to the predisposition, onset, course and outcome of obesity and more importantly, biopsychosocial factors that are of major importance in designing interventions and obesity management plans. whereas the lower classes are increasingly succumbing to obesity in western europe and north america, in the arabian gulf its first victims are urban elites who are likely to live a sedentary life with no physical activity to balance out its effects. related to this, in many societies, is the message that obesity is bad for health would likely go unheeded. there many societies where thinness is perceived as socially undesirable whereas plumpness is regarded as a status symbol and beautiful. there is also the perception that the ‘cult of thinness’ pervading our media is deeply rooted in a western-centric perspective on body-image. against this background, unless cultural forces are employed as catalysts for curbing obesity, health education among different ethnic groups will have a limited impact due to their different concepts of health and body image. as this volume does discuss the situation in some sub-cultural groups in the uk, its message can be applied to situations elsewhere. reading between the lines, however, this volume appears to be insidiously polemical, trumpeting great tribulation. the argument is that if no urgent measures are taken, obesity will be equivalent to the mediaeval bubonic plague or other more recent scourges that have decimated humanity. as any fear monger or student of social stigmatisation would attest, the consequence of grandiloquent rhetoric can be the birth of negative perceptions which can in turn cause the intended message to trigger a boomerang effect. it is widely known that any social construct or culturally devalued phenomenon that is labelled as negative is likely to go underground only to resurface later when the condition has reached a stage of irreversible deterioration. despite this caveat, the chapters are well-written, backed up with citations and fully indexed. although the book has as many as twenty-five authors, we do not find the common rumblings often come across in books authored by many contributors. the approach of this volume is to give balanced practical guidance to individuals, institutions and all the stake-holders, derived from empirical and evidence-based research as well as personal experience. the book is technical and yet any avid reader could grasp its content. most of the jargon is well defined. the book draws its expertise from the myriad talents of professors of men’s health, dieticians, sociologists, psychologists and others. this is indeed a multidisciplinary endeavour. this volume should be on the reading list for all health care practitioners, nutritionists and other professionals who are advancing the cause of health education. if there is no steadfast effort to curb the obesity of their husband and boys in the household, women would also benefit from reading it to know why their husbands are likely to leave them as widows. r e v i e w e r samir al-adawi department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: adawi@squ.edu.om january 2007 vol 7 correct a.indd abstract objectives: (a) to determine the natural infection rate of bulinus truncatus and biomphalaria pfeifferi snails with trematodes’ cercariae. (b) to determine the emergence and rhythmicity of cercariae. (c) to elucidate the high-risk time for man and other animals to acquire infection. methods: snails were collected from dawar el mahadi agricultural scheme, khartoum state, identified in the laboratory, kept at room temperature and fed on lettuce. the snails were screened weekly for six weeks for natural infection and infected snails were kept in the dark. the swimming patterns and resting position of the freshly emerged cercariae were studied using a stereomicroscope. the rhythmicity of the different types of cercariae was studied by screening three sets of 5 naturally infected snails under fluorescent light from 07.00 to 9.00 and similar sets from 9.00 to 07.00. results: out of ,257 screened bulinus truncatus, 87 (4.9%) shed four types of cercariae. the highest prevalence of natural infection (9.5%) was by schistosome cercariae followed by amphistome (2.5%), xiphidiocercariae (2.4%) and lastly by avian cercariae (0.5%). however, out of 200 screened b. pfeifferi, 22 (%) shed only xiphidiocercariae. the rhythmicity studies showed that the emergence of schistosome cercariae increased steadily from 07.00 to reach its peak at .00-3.00. the emergence rhythms of avian cercariae are similar to those of the schistosome, but with an early peak at 09.00-.00. the xiphidiocercariae and amphistome cercariae started with high rate of emergence at 07.00. and decreased gradually to very low levels or complete disappearance, respectively, around sunset. conclusion: information on cercarial rhythmicity and chronobiological characteristics are thought to be useful in avoiding water contact during high-risk time of infection and may be helpful in the identification of closely related species and strains of cercariae. key words: bulinus, biomphalaria, prevalence, cercarial rhythms, schistosomes, amphistome, avian, xiphidiocercariae. laboratory studies on the prevalence and cercarial rhythms of trematodes from bulinus truncatus and biomphalaria pfeifferi snails from khartoum state, sudan abdel aziz m ahmed1, nidal a ibrahim1, *mohamed a idris2 في املثقبة الديدان ذوانب (تواتر) نسبة ونظم لدراسة جتارب مختبرية ترنكيتص البولينص قواقع حتديد خروج . (ب) املثقبة الديدان بذوانب فايفري ــا وبيومفيالري ترنكيتص البوالينص قواقع في الطبيعية االصابة ــبة نس (أ)حتديد ــص: الهدف: امللخ املهدي دوار من القواقع ــات عين الطريقة: جمعت . املثقبة ــدان الدي لالصابة بذوانب خطورة ــر االكث الوقت حتديد املثقبة. (ج) ــدان الدي ــب ذوان ــم ونظ ، ــابيع اس ــتة ولفترة س ــبوعيا اس القواقع قمنا بفحص . باخلس البلهارزيا ومتت تغذيتها مبختبر القواقع ــظ وحف وتصنيف ــرز ف ومت ، ــوم ــة اخلرط بوالي بفحص ثالث اتلفة الذوانب نظم بدراسة قمنا م. َسِّ ُا باهر اتلفة الذوانب وجلوس سباحة دراسة أجرينا . في الظالم املصابة القواقع وحفظنا 7 مساء الى من الساعة فحصنا مجموعات متشابهه و كذلك ، 7 مساء الى 7 صباحا من الساعة ــية الفلورنس االضاءة حتت ــية خماس مجموعات البلهارزيا ذوانب وسجلت ، 1257 مجموع من الذوانب من أنواع بأربعة مصابة بوالينص ترنكيتص (14.9%) 187 ألنتائج: وجدنا . 7 صباحا الساعة 200 بايومفيالريا مجموع ومن .(5%) الطيور ذوانب وأخيرا (2.4%) ــركاريا ، والذيفيدوس (2.5%) ــتوم االمفيس ذوانب (%9.5)، تلتها ــبة نس أعلى 7 صباحا الساعة من اخلروج بدأت البلهارزيا ذوانب أن بينت نظم الذوانب ــة دراس . ــركاريا الذيفيدوس بذوانب فقط مصابة (11%) 22 ان وجد فايفري وصلت لكن ، البلهارزيا ذوانب لنظمية متشابهة كانت الطيور ذوانب نظمية أن كما 11صباحا الى الواحدة بعد الظهر. الساعة بني ما ذروتها لتصل تدريجيا تناقصت ثم 7 صباحا الساعة خروجها معدالت اعلي بدات ــتوم ــيركاريا واالمفيس ذوانب الذيفيدوس أما . 9-11 صباحا ــاعة الس بني ذروتها التعرض لعدم فائدة كبيرة ذو املثقبة الديدان سلوك ذوانب حول املعلومات اخلالصة: توفر . غروب الشمس مع بالتوالي توقفت متاما قليلة أو العداد في تصنيف تساعد قد والنظم اخلروج دراسة أن كما . الذوانب أثناء ذروة وجود االبتعاد عن املياه امللوثة طريق عن ذلك و البلهارزيا ، خاصة ، بها لالصابة . الذوانب لهذه املتشابهة واالنواع االجناس 1schistosomiasis research laboratory, faculty of science, university of khartoum, sudan, 2department of microbiology & immunology, college of medicine & health sciences, sultan qaboos university, p.o. box 35, al khod 123, muscat, sultanate of oman *to whom correspondence should be addressed. email: midris@squ.edu.om sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© o r i g i n a l s t u d y a b d e l a z i z m a h m e d , n i d a l a i b r a h i m a n d m o h a m e d a i d r i s 66 schistosomes are helminthes of the class trematoda that alternate generations, with a sexual phase in definitive mammalian hosts and an asexual phase in intermediate snail hosts. in humans, these blood flukes reside in the mesenteric and vesical venules. they have a life span of many years and daily produce large numbers of eggs, which must traverse the gut and bladder tissues on their way to the lumens of excretory organs. to understand the transmission dynamics of the disease, it is necessary to highlight essential segments in the process of acquiring an infection. thus, knowledge of cercarial infection rates, not only in individual habitats and the area as a whole, but also in relation to seasonal population changes, is crucial.1,2 other segments like the susceptibility of the snail to infection and the effects of such infection, the pattern and number of cercarial production and the factors influencing cercariae are of paramount importance in aspects related to the transmission of schistosomiasis. as relatively few studies were conducted on the production and dynamics of trematodes cercariae in africa, the main objectives of this study were to determine the prevalence, highlight the cercarial emergence of trematodes from naturally infected snails and to elucidate the high risk time for man and other animals to acquire infection. m e t h o d s sn a i l c o l l e c ti o n four field surveys were conducted for systematic snail sampling. a standardized scoop was used for sampling some minor canals in dawar el mahadi agricultural scheme, khartoum state. in each field survey, the collected snails were pooled in plastic bowls and lined by grass cover from the canals. the collected snails were transported to the schistosomiasis research laboratory, university of khartoum, where different snail species were isolated, cleaned and a series of laboratory experiments were conducted. pr e va l e n c e o f n at ur a l i n fe c ti o n the collected snails were screened weekly, for six weeks, for the presence of trematodes natural infection. patches of (20-30) cleaned snails were put in small glass containers containing about 20 ml of warm water (30-38°c) and placed under artificial light from 10:00 to 13:00 to enable cercarial emergence. the glass containers showing cercariae were identified and the snails were screened individually for cercarial shedding. snails (bulinus and biomphalaria) observed to shed any trematode cercariae were placed in separate plastic bowls containing 5 liters of dechlorinated water and kept in the dark at room temperature (30-35°c). o b se rvati o n o f l i v i n g un sta i n e d c e r c a r i a e immediately after cercarial shedding the snails that liberated the same type of cercaria were placed in the same plastic bowls. the different freshly emerged cercarial specimens were placed, separately, in a water volume sufficient to allow their normal behavioural pattern. the swimming patterns and resting position of the cercariae were observed using a stereomicroscope of 8-40 times of magnification. to observe the cercarial developmental pattern, a piece of cellophane was introduced to enable cercarial encystation on external substrate (if any). the identification of cercariae to the major type level was carried out by transferring living and unstained cercariae onto a glass slide. a cover slip was added and excess water was drawn off by applying a strip of filter paper to one side of the cover slip. sta i n i n g a n d i d e n ti fi c ati o n o f c e r c a r i a e the different types of cercariae were collected from naturally infected snails by emergence then prepared in permanent slides using ehrlich’s haematoxylin and were identified following frandsen and christensen.3 it was observed that the morphological features in the stained cercariae are more easily observable than in unstained ones. the diagnostic characteristics used in the identification of the cercariae included: general appearance, tegument, body suckers, alimentary system, excretory system, gland cells, genital primordium and cercarial tail. four types of cercariae (human schistosome, xiphidiocercaria, amphistome and avian) were identified. c e r c a r i a l e me r ge n c e a n d ry th mi c i t y of each cercarial type, three sets of five naturally infected snails were placed in small beakers each with 15 ml of warm water (34-40°c) and placed under fluorescent light from 07:00 to 19:00. the water with cercariae was changed in concurrent sets every two hours. three samples, 50 micro litres each, of the cercarial suspension in the beaker, were taken by a finn pipette into small petri dishes. drops of iodine were added to kill and stain the cercariae, which were then counted l a b o r at o r y s t u d i e s o n t h e p r e va l e n c e a n d c e r c a r i a l r h y t h m s o f t r e m at o d e s f r o m b u l i n u s tr u n c at u s a n d b i o m p h a l a r i a p f e i f f e r i s n a i l s f r o m k h a r t o u m s tat e , s u d a n 67 under a dissecting microscope. averages of the cercarial numbers in the 3 samples were calculated. then the total numbers of cercariae in the suspension were calculated as follow the mean number of cercariae in 50 microlitres x 20 x volume of suspension in millilitres. other similar sets, replications and calculations were carried for cercarial emergence from 19:00 to 07:00. stati sti c a l a n a ly si s based on the distribution of the observation, paired t-test and wilcoxon matched pairs, signed ranks tests were used to determine the level of significance in the differences of related samples of paired observations. in addition, all normally distributed related samples of more than two observations were treated with friedman twoways anova. r e s u l t s pr e va l e n c e o f n at ur a l i n fe c ti o n out of 1,257 screened b. truncatus snails, 187 (14.9%) shed four different types of cercariae. the highest prevalence of natural infection was shown by schistosome cercariae (9.5%) followed by amphistome (2.5%), xiphidiocercariae (2.4%) and lastly by avian cercariae (0.5%). the observed differences in the snails’ infection rates were found to be statistically significant (p < 0.05). out of 200 b. pfeifferi screened snails, 22 (11%) liberated only xiphidiocercariae. c e r c a r i a l pr o d u c ti o n table 1 shows the means and the ranges of cercarial production from naturally infected b. truncatus snails. the number of xiphidiocercariae liberated daily was more than 62% of the total cercariae. at the very commencement point, xiphidiocercariae were more than twice the total number of other emerging cercariae, as shown in table 2. amphistome cercariae were the least observed in both aforesaid parameters. statistical analysis revealed high significant differences (p < 0.001) in the rate of different cercarial emergence. further analysis, via scheffe test, reassured that such differences were mainly attributed to xiphidiocercariae. i n n ate r h y th m s tables 2 summarises the patterns of innate diurnal rhythms of the four types of cercariae, liberated from naturally infected b. truncatus. the individual types of cercariae showed a remarkable constant daily periodicity, though day-to-day irregularity in numbers of cercariae shed was observed. in the naturally infected snails, cercariae emergence began at sunrise, around 07:00. in schistosome cercariae, the emergence increased to reach a peak at 11:00-13:00 and gradually decreased to disappear around sunset at 19:00. the avian and xiphidiocercariae were like the schistosome in the general pattern, but with an early peak at 09:0011:00. however, avian cercariae showed substantial nocturnal emergence. on the other hand, the amphistome cercariae started from the highest rate of emergence at sunrise to sharp decrease at early afternoon and to complete disappearance around sunset. d i s c u s s i o n the full understanding of the transmission pressure of a trematode infection in a given area must include knowledge of cercarial production and dynamics. the present study emphasized that the local strain of b. truncatus is susceptible to the local s. haematobium strain. also, to the best of our knowledge a single study was conducted more than 20 years ago in north gezira, sudan and gave 3.3% patent infection of b. truncatus by s. haematobium4 which is much lower than the 9.5% reported in this study. the reported natural infection (0.2%) of b. pfeifferi snails by s. mansoni in the sudan was by far less,5,6 but comparable to the prevalence of natural infection (7.9%),7 in b. arabica, a strain of b. pfeifferi,8 from the sultanate of oman. cercarial emergence is the final product of many biotic and abiotic factors.9 productivity also depends on the host-parasite compatibility.10 if a strain of snail is very receptive, the parasitic process will be longer and the cercarial productivity greater.11,12 the maximum mortality rate was observed among snails with high natural infection, immediately after the first trial for cercarial shedding. the intensity of the snails’ natural infection was expressed in their multiple infections as well as the high frequent shedding of cercariae. such a mortality rate was expected, since infected snails are comparatively more sensitive to environtable 1: means and ranges of cercarial emergence from naturally infected b. truncatus (snail/day) type of cercariae means and ranges schistosome cercariae 135 (53 252) xiphidiocercariae 827 (198 2430) amphistome cercariae 82 (14 106) avian cercariae 285 (274 291) a b d e l a z i z m a h m e d , n i d a l a i b r a h i m a n d m o h a m e d a i d r i s 68 mental changes than non-infected snails. it seems that the temperature and the water quality are the factors behind the increased death rates among the naturally infected snails.12 the longevity of infected snails in the field is determined by different factors such as: age of the snail, super-infection and effect of schistosome miracidia and other parasites. however, the lifespan of the naturally infected snails could not be elucidated in the field, since the date on which the snails became infected was not known.9 studies on trematode emergence in freshwater systems suggest that the larval emergence from snails varies according to the circadian cycle and is optimized to enhance the probability of successful transmission.13-17 the present study proved that the cercarial shedding pattern of s. haematobium, although it peaked early (11:00-13:00), does not differ from those reported by other workers. cercariae of s. mansoni in the gunaid scheme peaked 13:00-15:00,3,9 while the same species in the gezira scheme peaked 12:00-14:00.1 it seems that the peak of the s. haematobium cercarial rhythm coincides with the peak of human water-contact activities during the day. the cercariae aves are like schistosomes in this manner, but with an earlier peak, 09:0011:00, moving to a complete disappearance around dusk time. the cercarial emergence rhythm is closely correlated with periods of activity of the most permissive host. human schistosomes have a diurnal emergence rhythm. s. rodhaini, which infects wild rodents, has a nocturnal emergence. the ultradian emergence rhythm of s. margrebowiei, which peaks at dawn and dusk, is thus perfectly adapted to antelopes coming to water pools early in the morning and late in the evening. this variability of emergence rhythms, documented at the interspecific level, was recently observed at intraspecific level by the discovery of chronobiological polymorphism in populations of s. mansoni from a single endemic area.18 in sudan, the schistosome cercarial emergence peaks vary over an interval of twelve hours from one scheme to another, between 6:00 to 18:00, depending on the schistosoma population considered.1 findings on cercarial emergence rhythmicity might reveal micro-evolutionary shifts taking place in schistosome populations. obviously, data on cercarial chronobiological characteristics may well prove of value for the identification of closely related species and strains.8 thus, thorough systematic observations are crucial to elucidate these characteristics. furthermore, such studies might explain the role of different factors affecting the cercarial rhythmicity and production dynamics, especially in the field. a c k n ow l e d ge me n ts we would like to thank with great appreciation professor e. b. taha, minster of science and technology, for a generous financial support for the schistomiasis research laboratory. we are also grateful to the laboratory staff for their cooperation. r e f e r e n c e s 1. ahmed aa. micro epidemiological factors influencing transmission pressure of schistosomiasis in gunaid scheme, sudan. j natl sci 2002; 2:22-32. 2. ahmed aa. schistosomiasis in sugar cane schemes, sudan. j natl sci 2003; 3:9-17. 3. frandsen f, christensen no. an introductory guide to the identification of cercariae from african freshwater snails with special reference to cercariae of trematode species of medical and veterinary importance. acta tropica 1984; 41:181-202. 4. babiker sm, blankespoor hd, wassila m, fenwick a, daffalla aa. transmission of schistosoma haematotable 2: emergence rhythms of cercariae from naturally infected b. truncatus time of day(hours) number and types of cercariae schistosome cercariae xiphidio-cercariae amphistome cercariae avian cercariae 07:00 09:00 140 ± 24 1430 ± 51 264 ± 33 293 ± 29 09:00 11:00 160 ± 9 1849 ± 108 118 ± 26 570 ± 32 11:00 01:00 220 ± 43 421 ± 84 21 ± 3 201 ± 26 13:00 15:00 140 ± 11 236 ± 47 6 ± 2 163 ± 9 15:00 17:00 12 ± 3 115 ± 23 2 ± 0.3 110 ± 6 17:00 19:00 2 ± 0.5 86 ± 17 0.0 90 ± 8 19:00 07:00 60 ± 3 2.0 ± 0.3 230 ±24 2480 ± 92 l a b o r at o r y s t u d i e s o n t h e p r e va l e n c e a n d c e r c a r i a l r h y t h m s o f t r e m at o d e s f r o m b u l i n u s tr u n c at u s a n d b i o m p h a l a r i a p f e i f f e r i s n a i l s f r o m k h a r t o u m s tat e , s u d a n 69 bium in north gezira, sudan. j trop med hyg 1985; 88 :65-73. 5. ahmed aa, babiker a, el tash la, shiff cj. development of a modified baited trap for detection of schistosome cercariae in sudanese irrigation canal systems. acta tropica 2002; 82:363-368. 6. hilali ah. transmission of schistosoma mansoni in the managil area, sudan. ph.d. thesis, department of zoology, faculty of science, university of khartoum, 1992 7. mone h, mouahid g, shaban ma, et al. ecological and molecular studies on emerging schistosomiasis mansoni in dhofar governorate, sultanate of oman. trop med int health 2003; 8:269-276. 8. dejong rj, morgan ja t, wilson wd, et al. phylogeography of biomphalaria glabrata and b. pfeifferi, important intermediate hosts of schistosoma mansoni in the new and old world tropics. j molec eco 2003; 12:30413056. 9. ahmed aa. epidemiological observations of intestinal schistosomiasis in the gunaid sugar cane scheme, central state, sudan. ph.d thesis, 1998, department of zoology, faculty of science, university of khartoum. 10. niemann gm, lewis f a. schistosoma mansoni: influence of biomphalaria glabrata size on susceptibility to infection and resultant cercarial production. exp parasitol 1990; 70:286-292. 11. barbosa fs. survival and cercariae production of bilharzian biomphalaria glabrata and b. straminea infected with schistosoma mansoni. j parasitol 1975; 61: 151-152. 12. mouahid a, coombes c. genetic variability of schistosoma bovis cercarial production according to miracidial dose. j helminth 1987; 61:89-94. 13. pages j r, theron a. analysis and comparison of cercarial emergence rhythms of schistosoma haematobium, schistosoma intercalatum, schistosoma bovis, and their hybrid progeny. int j parasitol 1990; 20:193-198. 14. combes c, fournier a, mone, h, theron a. behaviors in trematode cercariae that enhance parasite transmission: patterns and processes. parasitol 1994; 109:s3s13. 15. pechenik ja, fried b. effect of temperature on survival and infectivity of echinostoma trivolvis cercariae: a test of the energy limitation hypothesis. parasitol 1995; 111: 373-378. 16. n’goran e, bremond p, sellin e. intraspecific diversity of schistosoma haematobium in west africa: chronobiology of cercarial emergence. acta tropica 1997; 66: 35-44. 17. fingerut tj, zimmer ac, zimmer kr. patterns and processes of larval mergence in an estuarine parasite system. biol bull 2003; 205:110-120. 18. shiff jc. population genetics of schistosoma haematobium. measurement of parasite diversity using rapdpcr. exp parasitol 2000; 96:47-51. growth pattern of primary schoolchildren in benghazi, libya 45 abstract. objective : to fi nd the growth trends in a sample of schoolchildren in benghazi (libya), and to compare it with international and other local growth charts, as a step for setting the national curves. method: from 25th february to 31st october 1993, a sample of 2,022 pupils (1,160 boys and 862 girls) were randomly selected from three public primary schools in three different socio-economic areas in benghazi. a questionnaire consisting of social and scholastic items was distributed to teachers a few days before the examination. the height and weight of all the pupils were measured according to the standards of jellife, gorstein, who, and de onis. data were analysed and compared with both the reference standard of the united states national center for health statistics (nchs-usa), and the local standards of tripoli-1986. results : the boys and girls in the lowest age-group had a pattern similar to that of the reference population for both height/age and weight/age, but it dropped sharply from mid-school years. the benghazi curves were consistently higher than those of tripoli, particularly for height/age. conclusion: the nutritional status of these children, which was good before the beginning of schooling, was negatively affected during the school years. this could be attributed either to births in the family and consequent neglect, or to the school’s negative effects on the child, such as lack of appetite created by anxiety or other factors. further studies from dif ferent regions of the country are needed to set national growth curves. key words : anthtropometric measurements, child, growth, nutrition, benghazi, libya, nchs-usa. i t h as been long r ecognized that environ mental infl uences – especially nutrition and socio-economic status – are more important than genetics in determining the somatic growth of children, particularly during the early childhood when growth is rapid.1 this is supported by recent community-based researches on child growth in uk,8 hong kong,9 argentina,10 usa11–14 and other countries.15 therefore, the growth pattern of children is a good indicator of their nutritional status, health and socioeconomic level. nutritional anthropometric measurements are useful for measuring such growth patterns. their simplicity belies their ability to refl ect the pattern of physical growth and development of a population.16,17 in spite of the tediousness in the preparation of growth charts,1,18 it is advisable to have local charts developed in the community itself, as the charts pertaining to the well-nourished children in developed countries may not be quite valid in developing ones.1,3 charts developed using local data are valuable not only for assessing the current nutritional status but also for detecting future changes, such as improved nutritional awareness, better health status by implementation of health education programmes, prevention and effective treatment of diseases, vaccination programmes etc., or a downslide, as in famine, epidemics or war. ideally both cross-sectional and longitudinal serial squ journal for scientific research: medical sciences 2001, 1, 45–49 ©sultan qaboos university growth pattern of primary schoolchildren in benghazi, libya *mar wan m. al-sharbati1, ameer a. younan2, omar h. sudani3 1department of behavioural medicine college of medicine, sultan qaboos university p.o. box 35, al-khod 123, muscat, sultanate of oman. 2department of nutrition, college of public health al-arab medical university, benghazi, libya. 3dean, college of public health, al-arab medical university, benghazi, libya. *to whom correspondence should be addressed. e-mail: marwan@squ.edu.om a l s h a r b a t i e t a l46 measurements are needed for growth assessment of children, however, only cross-sectional measurements were practical for this study, as they were quickly obtained, gave information on the prevailing state of nutrition, and did achieve the general objectives.1,3 although many countries have charted their growth reference standards,19–22 in libya, such studies were few. prior to us, only two studies had been performed: (1) in 1979 in benghazi on preschoolers,23,24 and (2) in 1986 in tripoli on schoolchildren.7 lack of growth data for children in benghazi, an important port city in north eastern libya and the second biggest city in libya after tripoli, obliged us to conduct this study. the study aimed to prepare local growth curves (weight/age and height/age) for a representative sample of benghazi schoolchildren, till a countrywide study could be performed for a larger, representative sample of both urban and rural pupils, to set the national curves. m e t h o d this cross-sectional study was conducted between 25th february and 31st october 1993 by taking physical measurements of 2,022 pupils (1,160 boys and 862 girls) aged 6–12 years, living in benghazi. public primary schools in three areas of the city of different socio-economic levels: alfwehat al-sharqiya (high class area), al-slawi (middle class area) and al-mheshi (lower class area)25 were listed, and one school was randomly selected from each area: school-h from the high class area, school-m from the middle class area, and school-l from the lower class area. we excluded private schools because their children comprised a small fraction of the total population of schoolchildren, and because of the possibility that their inclusion in the sample might create bias. all the pupils were examined in the school-h and school-m, but systematic sampling was done in school-l due to the large number of classes there. using this method we examined 3–4 classes in every grade, in every school. p r o c e d u r e the internists who worked under our supervision were fully instructed about the aim and the procedure of the research, and were frequently changed to prevent possible bias.3 the administrations of the schools, teachers and the children were also clearly informed about the nature and objectives of the research. we distributed a questionnaire (which sought information social variables related to each child, such as the date of birth, parents’ education level and occupation, family size, etc.) to teachers a few days before the physical examination of the children. in most cases the schools were able to obtain this information from the pupils’ fi les; wherever such information was lacking it was obtained from the child’s parents by sending a slip of paper with the child, to be returned the next day. m e a s u r e m e n t s for each child we measured height to the nearest 0.1cm, and weight to the last 100 g. for measuring height, we fi xed a calibrated ruler to the wall. as the child stood barefoot with his/her heel, back and head touching the wall with the head in the frankfurt plane, a thin wooden plate was placed above the head perpendicular to the ruler and parallel to the ground to measure the height accurately. weight was measured using a portable weighing machine3 that was standardized regularly, the child being barefoot and wearing light clothes. all the anthropometric measurements were carried out as stipulated by jellife et al,1 gorstein et al,2 w ho 3,4 and de onis et al.5 the data were analysed statistically using harvard graphics statistical package. the results were compared with the reference nchs-usa standards and with the local standards of tripoli (1986).6,7 r e s u l t s table 1 shows the composition of the sample according to age, sex and school. a total of 2,022 pupils (1,160 boys and 862 girls) were examined, among whom 855 pupils were from school-h (473 boys and 382 girls), 524 pupils from school-m (281 boys and 243 girls), and 643 pupils from school-m (406 boys and 237 girls). figure 1 shows the benghazi boys’ height percentiles compared with the boys’ medians of height (of the same age) for both the reference population of nchs-usa standards,6 and the standards of tripoli.7 the median of height for benghazi boys starts off at the same level as the reference median during the younger ages. however, by the age of nine, differences start to appear, when the benghazi median starts defl ecting downward. indeed, at the age of 12, the reference median curve approaches the 75th percentile curve of benghazi. however, median height of benghazi boys remains consistently higher than the tripoli median throughout the school years. in fact, the latter reaches only the 25th percentile of benghazi boys’ height. figure 2 shows the weight/age of benghazi boys compared with the nchs-usa reference and the tripoli curves. here the median weight for benghazi boys, which, at the age of 6 years remains just below but very close to the reference median, starts declining by the age of 9 and by the end of school age the reference median approaches the 75th percentile. as for tripoli median, it remains slightly lower than the benghazi median throughout. girls’ height percentiles are plotted with the median g r o w t h pa t t e r n o f s c h o o l c h i l d r e n 47 height of both nchs -usa reference and tripoli medians in figure 3. here also, the difference between benghazi girls’ median height and reference population is minimal during the early years of the school, but it starts to appear at the age of eight years, and the curve goes down sharply at the age of 11. the reference median height actually crosses the 75th percentile of that of benghazi girls at the highest age. tripoli median for girls’ height remains lower than that of benghazi, and it corresponds to the 25th percentile during the school years. weight/age for benghazi girls is shown in figure 4, compared with the medians of both the reference population and tripoli girls of comparable age. here also benghazi girls’ median weight simulates that of the reference median of nchs-usa at the age of six years, but deviates down in mid-school age. the tripoli girls’ median weight, however, is similar with that of benghazi at the beginning of the school age, but dips down between the ages of 8–11 years, to again rise to the level of benghazi at 12 years. d i s c u s s i o n this study demonstrates that the growth pattern (height/ age and weight/age) of the public primary schoolchildren aged six to twelve years in benghazi in the year 1993 was similar to the international standards at early school years for both sexes (which is different from other studies)21,22 but it dropped down with the advance of the age, (which is in accordance with other studies).7,26,27 the picture is clear enough for boys, where the relative decline started from the age of nine, while in girls it began at the age of eight or even earlier. the minimal differences in height and weight between benghazi schoolchildren and the reference population at the start of the school indicates the satisfactory nutritional status of the former at preschool age. that state of good nutrition has been possibly affected negatively at midschool period, possibly either by reduced attention from mother as it diverted toward newborns or younger children in the family, or by the pressures of school life affecting health and nutrition. we must also keep in mind the here ditary and environmental factors that affect the growth spurt in both sexes. this may be responsible for the big difference between benghazi children and the reference population at mid-school age; the americans possibly started their adolescent growth spurt earlier than the libyans. the higher curves of growth seen in our group compared to that of tripoli for both boys and girls, specially for height, indicates better nutritional status in the fi rst few years of schooling in benghazi than in tripoli, as it is well known that the height is a good indicator of nutrition in the past.17 the difference in weight curves in favour of benghazi, although less marked than the height, perhaps indicates improved nutrition in 1993 compared to 1986, when table 1. the composition of the sample of school children examined for growth pattern according to age and sex, benghazi (1993) school-h (high class neighbourhood) school-m (middle class neighbourhood) school-l (lower class neighbourhood) grand total age (y) boys girls total boys girls total boys girls total boys girls total 6 74 55 129 45 23 68 50 36 86 169 114 283 7 83 56 139 26 39 65 58 53 111 167 148 315 8 69 68 137 47 29 76 58 39 97 174 136 310 9 89 56 145 39 42 81 76 35 111 204 133 337 10 63 70 133 36 36 72 47 13 60 146 119 265 11 69 66 135 42 50 92 57 19 76 168 135 303 12 17 6 23 23 19 42 36 25 61 76 50 126 13 5 5 10 16 3 19 15 11 26 36 19 55 14+ 4 4 7 2 9 9 6 15 20 8 28 total 473 382 855 281 243 524 406 237 643 1160 862 2022* *2088 questionnaire sheets were distributed; however, 66 pupils were absent during the physical examination. the age-groups 13 and 14+ are not considered in the charts because their numbers were very small. a l s h a r b a t i e t a l48 the tripoli curves were drawn. the improvement of the socio-economic status, earlier diagnosis and treatment of diseases, and better awareness of people regarding nutrition probably achieved this result. this emphasises the importance of reviewing and updating growth charts periodically, especially in developing countries to assess the effi cacy of national health programs.21,28,29 though our study had limitations, the present charts figure 3. benghazi girls' height percentiles (cm) according to age, compared with nchs-usa and tripoli medians figure 4. benghazi girls' weight percentiles (kg) according to age, compared nchs-usa and tripoli medians 100 110 120 130 140 150 160 6 7 8 9 10 11 12 age (years) he ig ht (c m ) bengh 25th bengh 50th bengh 75th us 50th tripoli 50th 15 25 35 45 6 7 8 9 10 11 12 age (years) w eig ht (k g) bengh 25th bengh 50th bengh 75th us 50th tripoli 50th figure 1. benghazi boys' height percentiles (cm) according to age, compared with nchs-usa and tripoli medians figure 2. benghazi boys' weight percentiles (kg) according to age, compared nchs-usa and tripoli medians 100 110 120 130 140 150 160 6 7 8 9 10 11 12 age (years) he ig ht (c m ) bengh 25th bengh 50th bengh 75th us 50th tripoli 50th 15 25 35 45 6 7 8 9 10 11 12 age (years) w eig ht (k g) bengh 25th bengh 50th bengh 75th us 50th tripoli 50th g r o w t h pa t t e r n o f s c h o o l c h i l d r e n 49 are more suited for local use, instead of foreign ones. however, further studies on larger samples representing schoolchildren of the whole country (urban and rural) are needed on a nation-wide level, to set up the fi nal national libyan growth charts. c o n c l u s i o n this study has shown that benghazi public primary schoolchildren had more or less a similar pattern of growth with the reference population at the start of the school, but it dropped below that during the school years. on the other hand, benghazi children’s growth pattern is higher than that of tripoli children as measured in 1986, especially the height curves, which is probably an indication of better nutritional status of school-children of benghazi in their preschool period compared to the tripoli schoolchildren. a c k n ow l e d g e m e n t we are grateful to the ministry of education, government of libya for permitting us to do this research. we would like also to express our thanks to the directors, social workers, teachers, parents and pupils who helped us in carrying out this study. we greatly value the efforts of all the internists who showed high motivation and precision while working with us on this study. r e f e r e n c e s 1. jellife db. the assessment of the nutritional status of the community (with special reference to fi eld surveys in developing regions of the world) who, geneva 1966, 50–1. 2. gorstein j, sullivan k, yip r, de onis m, trowbridge f, fajans p et al. issues in the assessment of nutritional status using anthropometry. bull world health organ 1994, 72, 273–83. 3. world health organization. measuring change in nutritional status. who, geneva 1983. 4. world health organization. physical status: the use and the interpretation of anthropometry: report of a who expert committee. who technical report series no. 854 geneva 1995. 5. de onis, yip r. the who growth chart: historical considerations and current scientifi c issues. bibl nutr dieta 1996, 53, 74–89. 6. united states public service, health resources administration. nchs growth charts, rockville, md, 1976 (hra 76-1120, 25, 3). 7. abounaja ss. anthropometric standards for libyan children aged 6–17 years. unpublished manuscript, glasgow university 1986. 8. kelly am, shaw nj, thomas am, pynsent pb, baker dj. growth of pakistani children in relation to the 1990 growth standards. arch dis child 1997, 77, 401–5. 9. leung ss, lau jt, tse ly, oppenheimer sj. weight-forage and weight-for-height references for hong kong children from birth to 18 years. j pediatr child health 1996, 32, 103–9. 10. lomaglio db. growth assessment in school children of villa cubas, catamarca argentine. rev fac cien med univ nac cordoba 1997, 55, 39–45. 11. miller je, korenman s. poverty and the children’s nutritional status in the united states. am j epidemiol 1994, 140, 233–43. 12. reed ba, habicht jp, niameogo c. the effects of maternal education on child nutritional status depend on socio-environmental conditions. int j epidemiol 1996, 25, 585–92. 13. lewit em, kerrebrock n. population based growth stunting. future child 1997, 7, 149–56. 14. flegal km. curve smoothing and transformations in the development of growth curves. am j clin nutr 1999, 70(s), 163–5. 15. frongillo ea, hanson km. determinants of variability among nations in child growth. ann hum biol 1995 22, 395–411. 16. waterloo jc, buzina r, keller w, lane jm, nichaman mz, tanner jm. the presentation and use of height and weight data for comparing the nutritional status of groups of children under the age of 10. bull world health organ 1977, 55, 489–98. 17. graitcer pl, gentry em, nichman mz, lane mj. anthropometric indicators of nutrition status and morbidity. j trop pediatr 1981, 28, 292–8. 18. al-sekait ma, al-nasser an, bamgboye ea. the growth pattern of schoolchildren in saudi arabia. saudi med j 1992, 13, 141–6. 19. lingreen g. height, weight and menarche in swedish urban schoolchildren in relation to socio-economic and regional factors. ann hum biol 1976, 3, 501–28. 20. seth v, rai a, gupta m, semwal op, patnaik kk, sundaram kr. construction of growth reference standards for urban slum children in developing countries. indian pediatr 1990, 27, 1081–7. 21. jamal aa, abolfotouh ma, badawi ia, al-najjar y. growth of normal urban saudi schoolboys aged 6–13 years in the southwestern region of saudi arabia. saudi med j 1995, 16, 513–5. 22. taghi ayatollahi sm, carpenter rg. growth of school children of southern iran in relation to the nchs standard. ann hum biol 1991, 18, 515–22. 23. abudejaja a, singh r, amanullah khan m, gupta bs. anthropometric measurements in children up to 5 years 50 of age in bouhadema area, benghazi. garyounis medical journal 1980, 3, 163–73. 24. tajouri re. cross sectional study of growth in urban preschool children in libya. unpublished manuscript 1979. 25. al-sharbati m, younan a, sudani o. behavioral problems among pupils. saudi med j 1998,19, 776–80. 26. kanawati aa, mclaren ds, abu jawdeh i. failure to thrive in lebanon i: experience with some simple somatic measurements. acta paediatr scand 1971, 60, 309–16. 27. waterloo jc. observation of nutritional history of stunting. in: 14th nestle workshop on linear growth retardation in less developed countries, cha-am, thailand, march 11–13,1986, bienne, switzerland: nestle nutrition 1987. 28. abounaja ss, gilmour wh. standards for height and weight of libyan children aged 6–17 years. arab j med, 1985, 4, 13–18. 29. ljung bo, bergsten-brucefors a, lindgren g. the secular trend in physical growth in sweden. ann human biol 1974,1, 245–56. submitted 29 dec 21 1 revision req. 15 feb 22; revisions recd. 27 feb 22 2 accepted 23 mar 22 3 online-first: april 2022 4 doi: https://doi.org/10.18295/squmj.4.2022.030 5 6 idiopathic granulomatous mastitis 7 a six-years’ experience and the current evidence in literature 8 *mahmood m. al awfi1 and salim k. al rahbi2 9 10 1department of general surgery, oman medical specialty board, muscat, oman; 2department 11 of surgery, the royal hospital, muscat, oman 12 *corresponding author’s e-mail: mahmood.alawfi@gmail.com 13 14 15 abstract 16 objective: this study aims to retrospectively describe the clinicopathological pattern and 17 management experience of idiopathic granulomatous mastitis in women attending care at royal 18 hospital, a tertiary care center at sultanate of oman. then to compare our experience with the 19 current literature trends. methods: the data of patient were retrospective reviewed from 1st of 20 january 2012 to 31st of december 2017, after receiving ethical approval from the center of studies 21 and research. results: sixty-four patients were conformed to have idiopathic granulomatous 22 mastitis. all of our patients were in the premenopausal phase with only one being nulliparous. 23 mastitis was the most common clinical diagnosis and half of them had a palpable mass. most of 24 our patient had received antibiotics during their treatment span. drainage procedure was done in 25 73% of the patient, whereas excisional procedure was done for 38.7%. only 52.4% of our patient 26 were able to achieve complete clinical resolution within 6 months of follow-up. conclusion: there 27 is no standardized management algorithm, due to the paucity of high-level evidence comparing 28 different modalities. however, steroids, methotrexate and surgery are all considered to be 29 effective and acceptable treatments. moreover, current literature tends towards multi-modality 30 treatments planned tailed case-to-case based on the clinical context and patient’s preference. 31 keywords: granulomatous; mastitis; chronic breast infection. 32 33 advancement in knowledge 34  the clinicopathological characteristics of omani women’s care similar to the international 35 community. 36  multi-modality management of idiopathic granulomatous mastitis tend to have the best 37 clinical outcome. 38 application to patient care 39  immunosuppressive therapy is important to ensure low-rate reoccurrence. 40  management plan should be tailored case-by-case, given the pros and cons of each 41 treatment modality, according to patients’ need and expectations. 42 43 introduction 44 granulomatous mastitis is a relatively uncommon category of inflammatory breast conditions. 45 granuloma based inflammation is the defining character of this inflammatory process. this entity 46 can be further classified as specific or idiopathic (1). specific granulomatous mastitis is 47 subcategorized as per the causative process to the granulomatous inflammatory reaction, which 48 could be infections, autoimmunity or duct ectasis (2). whereas, if no cause was identified, then it 49 is considered as idiopathic granulomatous mastitis (igm). 50 51 kessler and wolloch were the first to set the bases of this diagnostic entity in 1972 through 52 reporting a series of five cases (3). this condition tends to mimic inflammatory breast cancer and 53 infectious breast conditions in the clinical presentation. hence, igm is a diagnosis of exclusion 54 and histopathology examination is the gold standard to conform the diagnosis. igm represent 1.8% 55 of all benign breast conditions biopsied (4). this condition was found to predominantly occur in 56 childbearing age women. pregnancy and lactation history were noted in majority to proceed the 57 occurrence of igm (5). 58 59 idiopathic granulomatous mastitis is an evolved term to declare the enigma behind its real etiology. 60 however, there have been some cases reported igm patients with common autoimmune clinical 61 manifestation such as erythema nodosum and arthritis (6). however, altintoprak f and colleagues 62 observed no association between igm patients and autoantibodies (7). accordingly, those reported 63 autoimmune related clinical manifestation could be attributed to another undiagnosed condition. 64 otherwise, the granulomatous mastitis is just the first manifestation of autoimmune condition yet 65 to flare completely (8). 66 67 etiology guided management is the standard of treatment for specific type granulomatous mastitis. 68 whereas, the idiopathic type treatment is controversial. however, immunosuppressive treatment 69 has lately merged to be the mainstay of treatment. the role of surgical management is debatable. 70 yet, it is a vital option as solo or combination therapy tailored to case base (9). 71 72 the aim of this study is to retrospectively describe the clinicopathological pattern and management 73 experience of idiopathic granulomatous mastitis in women attending care at royal hospital, a 74 tertiary care center at sultanate of oman. 75 76 methods 77 patient records were retrospectively reviewed from 1st of january 2012 to 31st of december 2017, 78 after receiving ethical approval from the center of studies and research. data collected included, 79 demographic data, past medical history, obstetric and gynecological history, clinical manifestation 80 history, radiological findings, microbiological findings, medical and surgical treatment along with 81 the treatment outcome. 82 83 data were obtained from patient medical records system, plus from phone calls to complete 84 missing history related information. epidata software v4.4.2.1 was used for data entry and spss 85 statistics software v25 used for statistical analysis. categorical variables were expressed in 86 percentages whereas, continuous variables were expressed in mean with its’ standard deviation. 87 88 results 89 our search reviled a total of 65 patients with histopathological diagnosis of granulomatous 90 mastitis. one case was excluded from the analysis as granulomatous mastitis was due to 91 mycobacterium tuberculosis infection. the remaining 64 patients were conformed to be idiopathic 92 granulomatous mastitis by exclusion. 96.8% of the woman responded to the phone calls inquiry 93 form. the mean age of our population was 35.56 ± 6.75 years old. 95.3% of patients were omani’s. 94 the regional distribution of our patients was as follow, al bitanah 40.6%, muscat 28.1%, al 95 sharqiyah & al dakhilia 10.9%, al dhahirah 6.3%, al buraimi & dhofar 1.6%. 96 97 none of our patients had previous history of tuberculosis infection. only one patient had a resolved 98 past diagnosis of autoimmune condition, which was reactive arthritis. diabetes mellites was found 99 in 10.9% of the patients. there was no history of smoking among our patients but 22% gave history 100 of 2nd hand smoking. all of the woman was premenopausal, 10.9% were pregnant and 31.3% were 101 lactating at time of presentation. only one woman was nulliparous. the median number of parities 102 was four. history of abortion was present in 45.2% and still birth in 6.5%. seventy six percent 103 have breastfed their children. hormonal contraceptive was used by 51.7% of woman (table 1). 104 105 the mean time to diagnosis was 11.44±22.99 weeks. the most common clinical presentation was 106 mastitis. all of our patient had a single breast affected and almost equally distributed between each 107 side. half of our patients had a mass clinically and radiologically (table 2). about two thirds had 108 a surgical biopsy during a surgical intervention. bacteriology testing done and only 10.9% had a 109 concomitated bacterial infection. methicillin-sensitive staphylococcus aureus was the most 110 common isolated organism. gram-negative organisms were isolated in two cases only which were 111 klebsiella pneumoniae and proteus mirabilis. antibiotics were used in 93.8% of our patients, 112 whereas only 15.6% were treated with steroids. severe inflammation was treated with 60 113 milligrams once per day of prednisolone for a week then gradually tapered as per patient response 114 and tolerance. it would be stopped once patient reach clinical resolution or could not tolerate the 115 treatment. while, mild to moderate inflammation the starting dose was 20 milligram once per day 116 of prednisolone. severity assessment was subjective to the treating surgeon. drainage was done to 117 73% patients. one third of patients had an excisional procedure (table 3). 118 119 twenty-two patients have lost follow up during the first 6 months. out of 42 patients, 52.4% 120 showed complete resolution, 23.8 % had partial resolution and 23.8% had persistence of disease. 121 122 discussion 123 granulomatous mastitis is an infrequent diagnosis reached by exclusion of other more common 124 breast condition with similar clinical manifestation. to diagnose a patient with idiopathic 125 granulomatous mastitis, every effort should be made to exclude known cause of granulomatous 126 infection, as treatment will depend on it. moreover, till date the trigger of this granulomatous 127 inflammation in this subset of patient population is unknown. 128 129 granulomatous inflammation is a chronic inflammatory process due to ongoing cellular injury 130 from a trigger, leading to granuloma formation with macrophages and multinucleated giant cells 131 being the predominant inflammatory cells (10). this pathohistological features explain the natural 132 presentation of the disease as chronic, recurrent and remittent infection. plus, they tend to present 133 with breast inflammation or mass or the combination of both. 134 135 igm affects the premenopausal childbearing woman. this was noticed in almost all studies as well 136 in our cohort. the reason behind it is not clear yet, but those women breast features and cyclic 137 changes are unique and defiantly has a vital environmental role for disease onset. furthermore, it 138 rarely affects the nulliparous woman. most studies reported the disease inception was few years 139 after pregnancy, but there were few cases where disease onset was during pregnancy or lactation 140 period (4-5). there were few reported cases where non-gestational/non-lactational related 141 hyperprolactinemia were responsible for the igm which have resolved after normalization of 142 prolactin level (11). this all suggest that a full mature breast is the best medium of disease onset 143 and elevation of prolactin level have a triggering role. 144 145 diabetes mellitus have not been reported to have any association between it and the occurrence of 146 igm. instead, the presence of diabetes should stimulate the physician to rule out diabetic 147 mastopathy, which is an important differential diagnosis of specific granulomatous mastitis to 148 exclude (12). autoimmunity features and autoantibodies are found is some patients with igm 149 occasionally as stated earlier, therefore excluding autoimmune disease is essential (6-8). 150 additionally, autoimmune disease is known to occur more in childbearing age women and that 151 abortions and still births are known to be of frequent occurrence in them (13). furthermore, we 152 found in our igm cohort to have a significate percentage of overall fetal loss reaching to 51.6%. 153 looking at the similarities between igm patient and autoimmune disease patient, give the 154 indication that igm probably is a disease under the same umbrella that is yet not well understood. 155 156 there is no known association between breastfeeding, oral contraceptive use, smoking and igm. 157 our cohort similar rate of breastfeeding compared to other studies but a higher percentage of oral 158 contraceptive than other studies, which could be due to culture different preference only (4-5, 7). 159 most patients tend to present with mastitis with or without abscess as seen in our cohort. moreover, 160 they are diagnosed late because of significant overlap with acute bacterial mastitis. 161 162 the radiological findings of igm patient are non-specific with wide range of findings. on 163 ultrasonography, the breast tends to have an altered echotexture with the presence of a single or 164 multiple hypoechoic mass with single or multiple collections. in our cohort abscess was found 165 more commonly than a mass. in mammography, abnormal asymmetrical density is the most 166 common finding (14). 167 168 the usual microbiological work-up for granulomatous mastitis is to rule out fungal infection and 169 tuberculosis infection, because those are the most common infections causing granulomatous 170 reaction. recent data is recommending routine testing to rule out corynebacterium infections as 171 well due its association with special type of recurrent granulomatous mastitis called, cystic 172 neutrophilic granulomatous mastitis (cngm). this recommendation was based on the fact that, 173 those types of infections require special antibiotics ragmen for longer duration. this type of 174 organisms is difficult to be detect, whoever new technology made it easy, using 16s rna 175 sequencing and matrix-assisted laser desorption ionization–time of flight mass spectrometry 176 (maldi-tof ms) (15). once those cultures came to be negative then igm diagnosis can be 177 established, however it’s not uncommon to have a secondary bacterial infection (5). we have also 178 demonstrated secondary bacterial infection and it was noted to be more common during the follow 179 up period. for that reason, bacterial cultures are needed on first encounter at every relapse as well, 180 in order to treat as well. 181 182 igm diagnosis is a difficult to reach, as a result most of patient on their first encounter are treated 183 with antibiotics plus aspiration or surgical drainage. only when the patient does not respond to 184 treatment or has reoccurrence, this diagnostic entity is thought off. this is clearly noted in our 185 cohort, as 93.8% received antibiotic and 73% had drainage procedure. 186 187 however, the current literature is supporting the use of immunosuppression for the treatment of 188 igm, such as corticosteroid or other immunomodulatory such as methotrexate (16-17). pandey et 189 al (16), have reported 80% of patients had complete resolution on systemic steroids only. 190 additionally, montazer et al (18), have reported in a small randomized clinical trial that high dose 191 steroids have achieved 93.3% remission rate with 0% reoccurrence within 12 months follow-up 192 period. interestingly, tang et al (19) have also reported the effectiveness of intralesional steroid 193 injection. steroid’s effectiveness was also demonstrated in another randomized clinical trial by 194 çetin et al (20) to be above 80% with reoccurrence rate of near 20%. they have demonstrated in 195 their trial that topical steroids are as effective as systemic steroids in terms of response rate, but 196 with prolonged recovery period and lesser side effect profile. 197 198 non-steroidal immunosuppressive/steroid-sparing therapy have emerged to overcome the 199 systemic steroids side-effect from prolonged use. of those group, methotrexate so far have proven 200 efficacy as monotherapy and as combination therapy. as monotherapy, papila kundaktepe et al 201 (17), reported a complete recovery rate of 81.25%, which similar to the reported rates of steroidal 202 treatment, with low acceptable side-effect profile compared to steroid. furthermore, kehribar et 203 al (21), have demonstrated a remission rate of 87.9% with combination therapy of steroids and 204 methotrexate with zero relapse during 24-months follow-up period. unfortunately, in our cohort 205 the use of immunosuppressive medications was decimal because it was only recently introduced 206 to the unit and this could explain the poor remission rates. 207 208 on the other hand, surgical treatment is also an effective method to reach remission. zhou et al 209 (22), have demonstrated in their systematic review of 10 studies (1101 patients), that there is no 210 significant difference between non-surgical (includes; oral steroids, mtx, antibiotics, and 211 observation and surgical (includes; excisional and drainage procedures) when comparing 212 remission and relapse rates. nevertheless, lei et al (23), reported in their meta-analysis of 15 213 studies that surgical treatment (excisional & drainage) had the highest complete remission rate and 214 the lowest reoccurrence rate. ma et al (24), is another recent systematic review and meta-analysis 215 of 21 publications, that reported surgical treatment is superior to non-surgical management. 216 though, to reach to this high remission rate with low reoccurrence rate in surgical management, 217 the patient would have to go for an excisional procedure with negative surgical margin for active 218 disease (25). this will lead to large breast tissue volume loss with large surgical scar, which would 219 be considered disfiguring in some cases. thus, excisional procedures should be left for cases failed 220 medical management, not willing for medical management or patients asking for a quick fix. in 221 our cohort, 38.7% had excisional procedure. 222 223 fascinatingly, there are studies that have demonstrated that igm is self-limiting and can be 224 observed only without treatment. bouton et al (26), have reported the largest cohort of patients 225 subjected to observation only, where 72% of patients achieved remission during an average time 226 of 7.4 months, with 11% reoccurrence rate. those outcomes are comparable to some studies 227 outcome from the use of steroids. 228 229 those are the reasons why the treatment is still not standardized. therefore, patient is best treated 230 with multimodality treatment and those treatments are selected patient-to-patient base (27). for 231 this reasons, latest publications have looked into multi-modality treatments. for example, wang 232 j., and colleagues have reported best clinical outcome in patients treated with surgery after steroid 233 therapy (28). akcan et al (29), is another example, where they have reported superiority of wide 234 local excision after steroidal therapy when compared to surgery alone. likewise, godazandeh g, 235 and colleagues have reported in their recent systematic review and meta-analysis, that steroids with 236 surgery is superior to steroids alone (30). the combination therapy dose not only improve the 237 remission rate and reduce the reoccurrence rate, but they also reduce the breast tissue volume loss 238 and the surgical scar. 239 240 conclusion 241 triple breast assessment is a necessity in all patients with breast complain in order not to miss or 242 delay a diagnosis of cancer or a chronic breast inflammatory disorder. moreover, recurrent breast 243 inflammation with or without mass should raise the suspicion of granulomatous mastitis and 244 comprehensive work-up is essential. once the diagnosis of idiopathic granulomatous mastitis has 245 been established and other differential diagnoses were ruled out, an agreed multi-modality 246 treatment plan should be commenced according to patient needs and preference. 247 248 authors’ contribution 249 mma and skr conceptualized and designed the study. mma collected the data and drafted the 250 manuscript. mma and skr edited and revised the manuscript. both authors approved the final 251 version of the manuscript. 252 253 conflict of interest 254 the authors declare no conflicts of interest. 255 256 funding 257 no funding was received for this study. 258 259 reference 260 1. binesh f, kargar s, zahir st, behniafard n, navabi h, et al. (2014) idiopathic 261 granulomatous mastitis, a clinicopathological review of 22 cases. j clin exp pathol 4: 262 157. 263 2. altintoprak f, kivilcim t, ozkan ov. aetiology of idiopathic granulomatous mastitis. 264 world j clin cases. 2014 dec 16; 2(12):852-8. 265 3. kessler e, wolloch y. granulomatous mastitis: a lesion clinically simulating carcinoma. 266 am j clin pathol. 1972 dec; 58(6):642-6. 267 4. prasad s, jaiprakash p, dave a, pai d. idiopathic granulomatous mastitis: an institutional 268 experience. turk j surg. 2017 jun 1; 33(2):100-103. 269 5. uysal e, soran a, sezgin e; granulomatous mastitis study group. factors related to 270 recurrence of idiopathic granulomatous mastitis: what do we learn from a multicentre 271 study? anz j surg. 2018 jun;88(6):635-639. 272 6. saba zabetian, ben jacob friedman, and chauncey mchargue. a case of idiopathic 273 granulomatous mastitis associated with erythema nodosum, arthritis, and reactive cough. 274 jaad case rep. 2016 mar; 2(2): 125–127. 275 7. altintoprak f, karakece e, kivilcim t, dikicier e, cakmak g, celebi f, ciftci ih. 276 idiopathic granulomatous mastitis: an autoimmune disease? scientificworldjournal. 2013 277 sep 4; 2013:148727. 278 8. sellitto a, santoriello a, de fanis u, benevento r, perna g, rossiello r, maio md, 279 giunta r, canonico s, lucivero g, romano c. granulomatous lobular mastitis: another 280 manifestation of systemic lupus erythematosus? breast j. 2013 may-jun;19(3):331-2. 281 9. lei x, chen k, zhu l, song e, su f, li s. treatments for idiopathic granulomatous 282 mastitis: systematic review and meta-analysis. breastfeed med. 2017 sep;12(7):415-283 421. 284 10. shah k.k., pritt b.s., alexander m.p. histopathologic review of granulomatous 285 inflammation. j clin tuberc other mycobact dis 2017; 7:1–12. 286 11. nikolaev a, blake cn, carlson dl. association between hyperprolactinemia and 287 granulomatous mastitis. breast j. 2016 mar-apr;22(2):224-31. 288 12. fong d, lann ma, finlayson c, page dl, singh m. diabetic (lymphocytic) mastopathy 289 with exuberant lymphohistiocytic and granulomatous response: a case report with review 290 of the literature. am j surg pathol. 2006 oct;30(10):1330-6. 291 13. jones wr. autoimmune disease and pregnancy. aust n z j obstet gynaecol. 1994 292 jun;34(3):251-8. 293 14. fazzio rt, shah ss, sandhu np, glazebrook kn. idiopathic granulomatous mastitis: 294 imaging update and review. insights imaging. 2016 aug;7(4):531-9. 295 15. wu jm, turashvili g. cystic neutrophilic granulomatous mastitis: an update. j clin pathol. 296 2020 aug;73(8):445-453. 297 16. pandey ts, mackinnon jc, bressler l, millar a, marcus ee, ganschow ps. idiopathic 298 granulomatous mastitis--a prospective study of 49 women and treatment outcomes with 299 steroid therapy. breast j. 2014 may-jun;20(3):258-66. 300 17. papila kundaktepe b, velidedeoğlu m, mete b. the effect of methotrexate monotherapy 301 on treatment-resistant idiopathic granulomatous mastitis patients. surgeon. 2021 apr 6: 302 s1479-666x (21)00065-2. 303 18. montazer m, dadashzadeh m, moosavi toomatari se. comparison of the outcome of 304 low dose and high-dose corticosteroid in the treatment of idiopathic granulomatous 305 mastitis. asian pac j cancer prev. 2020 apr 1;21(4):993-996. 306 19. tang a, dominguez da, edquilang jk, green aj, khoury al, godfrey rs. 307 granulomatous mastitis: comparison of novel treatment of steroid injection and current 308 management. j surg res. 2020 oct; 254:300-305. 309 20. çetin k, sıkar he, göret ne, rona g, barışık nö, küçük hf, gulluoglu bm. comparison 310 of topical, systemic, and combined therapy with steroids on idiopathic granulomatous 311 mastitis: a prospective randomized study. world j surg. 2019 nov;43(11):2865-2873. 312 21. kehribar dy, duran ti, polat ak, ozgen m. effectiveness of methotrexate in idiopathic 313 granulomatous mastitis treatment. am j med sci. 2020 nov;360(5):560-565. doi: 314 10.1016/j.amjms.2020.05.029. epub 2020 may 29. 315 22. zhou f, liu l, liu l, yu l, wang f, xiang y, zheng c, huang s, cai h, yu z. 316 comparison of conservative versus surgical treatment protocols in treating idiopathic 317 granulomatous mastitis: a meta-analysis. breast care (basel). 2020 aug;15(4):415-420. 318 23. lei x, chen k, zhu l, song e, su f, li s. treatments for idiopathic granulomatous 319 mastitis: systematic review and meta-analysis. breastfeed med. 2017 sep;12(7):415-320 421. 321 24. ma x, min x, yao c. different treatments for granulomatous lobular mastitis: a 322 systematic review and meta-analysis. breast care (basel). 2020 feb;15(1):60-66. 323 25. yabanoğlu h, çolakoğlu t, belli s, aytac ho, bolat fa, pourbagher a, tezcaner t, 324 yildirim s, haberal m. a comparative study of conservative versus surgical treatment 325 protocols for 77 patients with idiopathic granulomatous mastitis. breast j. 2015 jul-326 aug;21(4):363-9. 327 26. bouton me, jayaram l, o'neill pj, hsu ch, komenaka ik. management of idiopathic 328 granulomatous mastitis with observation. am j surg. 2015 aug;210(2):258-62. 329 27. maione c, palumbo vd, maffongelli a, damiano g, buscemi s, spinelli g, fazzotta s, 330 gulotta e, buscemi g, lo monte ai. diagnostic techniques and multidisciplinary approach 331 in idiopathic granulomatous mastitis: a revision of the literature. acta biomed. 2019 jan 332 23;90(1):11-15. 333 28. wang j, zhang y, lu x, xi c, yu k, gao r, bi k. idiopathic granulomatous mastitis 334 with skin rupture: a retrospective cohort study of 200 patients who underwent surgical 335 and nonsurgical treatment. j invest surg. 2019 dec 10:1-6. 336 29. akcan a, oz ab, dogan s, akgün h, akyüz m, ok e, gök m, talih t. idiopathic 337 granulomatous mastitis: comparison of wide local excision with or without 338 corticosteroid therapy. breast care (basel). 2014 may;9(2):111-5. 339 30. godazandeh g, shojaee l, alizadeh-navaei r, hessami a. corticosteroids in idiopathic 340 granulomatous mastitis: a systematic review and meta-analysis. surg today. 2021 feb 15. 341 342 table 1: demographic and baseline characteristics of our igm patients 343 patient’s characteristics n (%) or mean ± sd age at diagnosis in years 35.56 ± 6.75 omani nationality 61 (95.3%) diabetes mellitus 7 (10.9%) autoimmune disease 1 (1.6%) history of tuberculosis 0 (0%) history of 1st hand smoking 0 (0%) history of 2nd had smoking 13 (22%) history of abortion 28 (45.2%) history of stillbirth 4 (6.5%) use of hormonal contraceptive 31 (51.7%) hormonal treatment 3 (5.1%) breastfeeding 48 (76.2%) infertility treatment 7 (11.9%) premenopausal 64 (100%) time to diagnosis in weeks 11.44 ± 22.99 pregnancy at presentation 7 (10.9%) lactate at presentation 20 (31.3%) 344 table 2: clinical and radiological characteristics of our igm patients 345 patient’s characteristics n (%) or mean ± sd breast affected left breast 31 (48.4%) right breast 33 (51.6%) clinical examination mastitis 46 (71.9%) abscess 29 (45.3%) mass 44 (68.8%) ultrasonography* mastitis 42 (85.7%) abscess 31 (63.3%) mass 28 (56.0%) *14 patients had missing data 346 347 table 3: diagnostic work-up and management of our igm patients 348 patient’s characteristics n (%) or mean ± sd type of biopsy core needle 25 (39.1%) surgical 39 (60.9%) positive bacterial culture* first culture 5 (10.9%) during follow-up 11 (23.4%) medical management antibiotics 60 (93.8%) steroids 10 (15.6%) surgical management drainage** 46 (73.0%) excision*** 24 (38.7%) *18 patients had missing data; **1 patient had missing data; ***2 patients had missing data 349 december 2007 vol 8 after meeting.indd congenital right coronary artery fistula *hilal alsabti,1 madan m maddali2 sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 263-264 sultan qaboos university© submitted 17th june 2007 accepted 1st september 2007 i n t e r e s t i n g m e d i c a l i m a g e االمين التاجي للشريان الناسوراخللقي مادالي موهان مادان و السبتي علي هالل 1department of surgery, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman; 2department of anesthesia, royal hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: alsabti@hotmail.com artery (rca) was dominant with no lesion, but a fistula was seen connecting the rca to the main pulmonary artery (pa) [figure 1]. a congenital coronary artery fistula (caf) is a rare identity defined as an abnormal communication between the coronary artery and either cardiac chambers, great vessels, coronary sinus or other close structures bypassing the myocardial capillary network.1 the most common symptoms and complications of caf include fatigue, dyspnea, orthopnea, angina, endocarditis, myocardial ischaemia and myocardial infarction.2 despite coronary angiography being the gold standard3 for the diagnosis of a caf, echocardiography helps in localizing the orifice, course and drainage of a fistula. multi-slice computed tomographic (msct) imaging along with ecg gated angiography can be very helpful in the precise evaluation of the malformation.4 closure of the caf is highly recommended because of the risk of endocarditis and other complications, especially as closure is safe and effective either through surgery or a transcatheter intervention.5 r e f e r e n c e s 1. levin dc, fellows ke, abrams hl. hemodynamically significant primary anomalies of the coronary arteries: angiographic aspects. circulation 1978; 58:25-34. 2. gowda rm, vasavada bc, khan ia. coronary artery fistulas: clinical and therapeutic consideration. int j cardiol 2006; 107:7-10. 3. vavuranakis m, bush ca, boudoulas h. coronary artery fistulas in adults: incidence, angiographic characteristics, natural history. cathet cardiovasc diagn 1995; 35:116-120. a fifty-one year old lady with a his-tory of dyslipidemia presented to the royal hospital, muscat, oman, with progressive exertional dyspnea and angina (class i of canadian cardiovascular society) of one year’s duration. at physical examination, a mild continuous murmur could be heard mainly at the level of the second intercostal space of the left parasternal area. the coronary angiogram showed a normal left anterior descending artery and a left circumflex artery. the right coronary figure 1: coronary angiogram showing the coronary artery fistula (c af) arising from the right coronary artery (rc a) to the main pulmonary artery( mpa) h i l a l a l s a b t i , a n d m a d a n m o h a n m a d d a l i 2 264 4. utsunomiya d, nishiharu t, urata j, ino m, nakao k, awai k et al. coronary arterial malformation depicted at multi-slice ct angiography. int j cardiovasc imaging. 2006; 22:547-551. 5. perry sb, rome j, keane jf, baim ds, lock ie. transcatheter closure of coronary artery fistulas. j am coll cardiol 1992; 20:201-209. 1oman medical specialty board, muscat, oman; departments of 2family medicine & public health and 4microbiology & immunology, sultan qaboos university hospital, muscat, oman; 3department of family medicine & public health, university of bristol, bristol, united kingdom *corresponding author’s e-mail: rkindi@squ.edu.om prevalence of coeliac disease in omani adults with iron deficiency anaemia of unknown cause case-finding study safa ambusaidi,1 al manar al busaidi,1 asma al salmani,2 robin davidson,3 jalila alshekaili,4 mahmood al kindi,4 *rahma al kindi2 clinical & basic research sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 262–267, epub. 26 may 22 submitted v revision req. 31 mar 21; revision recd. 8 apr 21 accepted 27 apr 21 https://doi.org/10.18295/squmj.5.2021.101 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to estimate the serological prevalence of coeliac disease in patients with iron deficiency anaemia (ida) of unknown cause at a primary healthcare facility in oman. methods: this prospective case-finding study was conducted at the primary care clinics in sultan qaboos university hospital, muscat, oman from september 2018 to june 2020. patients aged 18 to 55 years, with a haemoglobin (hb) level <11.5 g/dl for males and <11.0 g/dl for females and a ferritin level <30 ng/ml for males and <13 ng/ml for females, were included in the study. blood samples were obtained for initial serological screening using serum immunoglobulin (ig)a level; those samples with normal levels of iga, iga anti-tissue transglutaminase antibody (ttg) and iga anti-deamidated gliadin peptide (dgp) were determined. positive iga-ttg test was confirmed using iga-endomysial antibodies. patients with low iga levels were tested using igg-ttg and igg-dgp. results: a total of 104 patients participated in this study. eight patients (7.7%) were found to have a positive serological screening result for coeliac disease; of these patients, three (37.5%) had a positive iga-ttg result. two of those three (66.7%) had a positive iga-endomysial antibody. the iga-dgp result was positive in seven (6.7%) of the 104 patients. out of those seven patients, two also had a positive iga ttg. conclusion: coeliac disease is not a rare disorder. there is a need to increase awareness among healthcare professionals about coeliac disease and its non-classical manifestations such as ida. keywords: celiac disease; iron-deficiency anemia; serological testing; tissue transglutaminase antibody; deamidated gliadin peptide; oman. advances in knowledge this study is the first to report the prevalence of coeliac disease (cd) serology in omani adults with iron deficiency anaemia (ida) of unknown cause presenting to primary healthcare. application in patient care cd is not a rare disorder and should be considered a possibility in patients with anaemia, especially when there is a positive family history of the disease. this can be diagnosed easily by an assessment of the patient’s immunoglobulin (ig )a level followed by a combination of anti-tissue transglutaminase antibody and endomysial antibody tests and anti-deamidated gliadin peptide tests based on the iga deficiency status. the findings of this study highlight the growing need to increase awareness among healthcare professionals about cd and its nonclassical manifestations such as ida. the findings encourage the development of guidelines for the investigation of cd in general and in patients with unexplained ida specifically. these measures will not only benefit patients with cd but also significantly improve the healthcare system overall. coeliac disease (cd) is a chronic autoimmune disorder of the small bowel that is triggered by exposure to dietary gluten. the dietary sources of gluten include wheat, rye, barley and possibly oats.1 cd causes chronic mucosal inflammation, villous atrophy and crypt hyperplasia.2 the main intervention for cd is a lifelong commitment to a gluten-free diet. multiple serological approaches have been described to help in the diagnosis of cd, including assessments of the immunoglobulin a (iga)-endomysial antibody (ema), iga-tissue transglutaminase antibody (ttg) and iga-deamidated gliadin peptide antibody (dga).3 in general, studies have shown that serum iga-ema and iga-ttg testing offer the highest diagnostic accuracy levels, with a sensitivity of 95% and a specificity close to 100%.2 however, there are variations reported between different laboratories.4 the newer anti-deamidated gliadin peptide (dgp) assays display higher diagnostic accuracy than the older anti-gliadin antibody assays.5 moreover, iga deficiency is commonly seen in patients with cd. therefore, a test of igg against ttg and dgp is employed for cd screening in at-risk patients. in addition, genetic testing for the human leukocyte antigens human leukocyte antigen (hla)-dq2 and hla-dq8 can help resolve cases with high clinical suspicion but doubtful or discrepant serology or histology.3 for a definitive https://creativecommons.org/licenses/by-nd/4.0/ safa ambusaidi, al manar al busaidi, asma al salmani, robin davidson, jalila alshekaili, mahmood al kindi and rahma al kindi clinical and basic research | 263 diagnosis, upper esophagogastroduodenoscopy with a small bowel biopsy should be performed for any patient with positive serology or a high probability of having the disease (>5%), regardless of the serology results.6 the clinical manifestations of cd depend on the age of the patient.7 in the paediatric age group, common intestinal manifestations include diarrhoea, abdominal pain, distension, loss of appetite, weight loss and failure to thrive. however, later in life, many patients present with subtle symptoms, including irritable bowel syndrome (ibs)-like presentation with alternating bowel habits, nausea and vomiting. up to 60% and 62% of paediatric and adult patients, respectively, present with extra-intestinal manifestations.8 examples of such presentations include poor growth, anaemia, elevated liver enzymes, arthralgia, decreased bone mineral density and dermatitis herpe tiformis.9 similar to intestinal manifestations, the presence of some of these manifestations depends on age. for instance, poor growth is purely a paediatric presentation, whereas osteoporosis and dermatitis herpetiformis are adult manifestations.10,11 mass screening for cd in four general european populations revealed a prevalence of 1% in 2010.12 on the other hand, information about the prevalence of cd among arab populations is sparse and based on small-scale studies.13 a recent study in saudi arabia reported a prevalence of positive cd serology of 1.5% among adult blood donors.14 anaemia is a unique presentation of cd. up to 40% of patients with cd can present with anaemia.11 conversely, a good proportion of patients with cd present only with iron deficiency anaemia (ida). at the tertiary level of care, the prevalence of cd among patients presenting with ida at a haematology clinic was found to be 14.6%, with 4% prevalence among caucasian patients and 0% among non-caucasians.15,16 more specifically, the prevalence of cd among iranian and indian patients presenting with ida was found to be 10.4% and 11%, respectively.17,18 in oman, the frequency was found to be 4% among patients with ida at the haematology clinic of a tertiary care facility.19 primary healthcare workers in western countries often fail to test for cd in patients presenting with extra-intestinal manifestations such as ida, leading to diagnostic delays.20,21 the same scenario is expected to be present in middle eastern and arab countries. therefore, this study aimed to estimate the prevalence of cd among omani adults with ida of unknown cause. methods a prospective case-finding study was conducted at the students’ and family medicine clinics in sultan qaboos university hospital (squh) from september 2018 to june 2020. these two clinics are both under the department of family medicine and public health; they provide primary care services to all sultan qaboos university (squ) students and staff, as well as their families from all over oman. therefore, the sample included patients from different regions of the country. the hospital health information system (his) was searched for data on all patients with ida at both clinics for the four-year period from 2016 to 2019. the target population for this study comprised omani adults aged 18–55 years with a haemoglobin (hb) level <11.5 g/dl for males and <11.0 g/dl for females and a ferritin level <30 ng/ml for males and <13 ng/ ml for females (according to the local laboratory reference ranges). patients with a known cause of ida (i.e. a history of haematemesis, melena, menorrhagia, frequent blood donation or post-bariatric surgery) or women who were pregnant, two months postpartum or lactating were excluded from the study. a total of 451 patients were identified through the his to have ida of which 282 patients met the inclusion criteria. of these, 104 patients agreed to participate in the study. all the participants were given general information about the research project including the proposed blood test, the targeted disease and the possible outcomes and treatment options. the study was anonymous, confidentiality was assured and emphasised and all participants were given a study number, which was used for data analysis. the participants’ socio-demographic details, including age, gender, past medical and surgical history, medication history and smoking and alcohol consumption history, were gathered. further information on hb level, ferritin level, mean corpuscular volume (mcv), mean corpuscular haemoglobin (mch) and red cell distribution width (rdw) was also obtained for each patient. blood samples were sent for initial serological screening tests using the total level of iga on an spa plus machine (binding site group, uk). if total iga was normal, iga-ttg and iga-dgp were assessed using the euroimmun analyzer i (euroimmun, germany). positive test of iga-ttg was confirmed using igaendomysial antibodies (euroimmun). patients with low iga level were tested using igg-ttg and iggdgp (euroimmun). confirmed patients were then offered follow-up appointments with their respective prevalence of coeliac disease in omani adults with iron deficiency anaemia of unknown cause case-finding study 264 | squ medical journal, may 2022, volume 22, issue 2 treating doctors and a referral for further investigation with the gastroenterologist at the squh. those who refused the referral were offered an appointment with the dietician to start a gluten-free diet. the statistical analyses were conducted using the statistical package for the social sciences (spss), version 23.0 (ibm spss inc., chicago, il, usa). descriptive statistics were used to describe the sample’s characteristics and frequencies; percentages were reported for categorical variables. the study was approved by the medical research ethics committee of the college of medicine and health sciences, squ, oman in 2018 (#squ-ec/221/18). written informed consent with a statement of confidentiality was obtained from each participant and their privacy was maintained throughout the study. the patients were all informed that their participation was voluntary and that they had the right to withdraw from the study at any time. results a total of 451 patients with ida were identified over the four-year period from 2016 to 2019; 282 patients were eligible for the study, of which 104 patients agreed to participate in the study. all of the participants who consented were female and their ages ranged from 18 to 48 years (mean age: 28.2 ± 8.4 years). none of the participants drank alcohol or smoked. the mean hb level was 10.6 ± 0.7 g/dl (range: 8.2–10.9), ferritin level was 9.2 ± 3.5 μg/l (range: 1.0– 13.0), mcv level was 71.4 ± 6.6 fl (range: 57.6–100 fl), mch level was 22.2 ± 2.4 pg (range: 16.9–31.5 pg) and rdw was 15.8 ± 2.5 × 1012/l (range: 11.8–22.5 × 1012/l). iga levels were normal (median = 2.4 g/l, reference range: 0.85-4.9 g/l) in the vast majority of the participants (n = 103; 99.0%) and only one patient (1.0%) had a low level of iga (<0.02 g/l). out of those with normal iga, eight patients (7.8%) were positively screened for cd. the mean age of these eight patients was 28.0 ± 8.6 years, mean hb was 10.9 ± 0.0 g/dl, ferritin was 7.4 ± 4.6 μg/l, mcv was 77.7 ± 5.8 fl, mch was 24.4 ± 2.5 pg and rdw was 15.15 ± 2.0 ×1012/l. three of the eight patients (37.5%) had positive iga-ttg results with a mean concentration of 84.5 iu/l and median of 140 (reference range: 0–20 iu/l). two out of these three patients (66.7%) tested positive for iga-endomysial antibodies. iga-dgp was positive in seven patients (87.5%), with a mean concentration of 44.7 iu/l and median of 113.5 (reference range: 0–25 iu/l). of these seven patients, two also had a positive iga-ttg [figure 1]. discussion the current study is the first to report a 7.8% prevalence of cd serology in omani adults with ida of unknown cause at a primary healthcare centre. a study in the uk previously reported that the most common mode of presentation of cd is anaemia with varying degrees of severity and recommended that cd should be considered in patients with anaemia, especially when there is a positive family history of the disease.22 cd can be easily screened by assessing the patient’s iga level, followed by a combination of the highly sensitive and specific ttga and ema tests and dgp based on the iga deficiency status.23 few studies have been conducted in the middle east using cd-associated antibodies and the combination of anti-ttga and ema for screening.24 pelkowski and viera reported that ida refractory to oral supplementation was strongly associated with cd; 10% of the study population had cd, which is comparable to the present study.23 furthermore, a study conducted in the uk found that approximately one in 30 patients with ida and 1 in 200–300 of the general population had cd.14,25 a study on students at squ showed that anaemia is common in oman, as 40% of them had ida. it was noted that 21% of those with ida who agreed to be treated with oral iron therapy figure 1: flowchart showing the results of the serologic tests for coeliac disease in adult omani patients ig = immunoglobulin; ttg = anti-tissue transglutaminase; dgp = anti-deamidated gliadin peptide. safa ambusaidi, al manar al busaidi, asma al salmani, robin davidson, jalila alshekaili, mahmood al kindi and rahma al kindi clinical and basic research | 265 for three months failed to respond to treatment.26 this suggests that such patients should be screened for cd. although individuals with cd typically present with intestinal symptoms such as malabsorption and diarrhoea, occult forms of the disease with nonspecific extra-intestinal symptoms, such as fatigue and isolated ida, have been recognised in the last few years.22,27 the continuing use of rice as the primary source of dietary carbohydrates in oman explains the lack of overt disease in adults, but this may change with the increasing import of wheat-containing foods, as is the case in jordan.28 there are multiple community characteristics as well as genetic and environmental factors that affect the prevalence of cd.29 genetic factors can significantly increase the risk of developing cd, especially the presence of the hla.30 a familial aggregation is found in 5–15% of patients with cd.31 consanguinity is very common in oman at a rate of more than 50%. in total, 39% of omanis are married to their first cousins; oman ranks among the top seven arab countries in terms of consanguinity rates.32,33 consanguineous marriages can result in an increased expression of rare genetic disorders. changes in dietary habits constitute another factor that may contribute to the increased prevalence of cd; the younger generation tends to consume more gluten-containing foods than the older generation that depends mainly on rice. in the literature, multiple environmental factors other than gluten have been researched as possible contributing factors that reduce gluten tolerance; these include early infant feeding, the spectrum of intestinal microorganisms and how they change over time, intestinal infections and stressors in general.34 in the present study, all the participants were female. two male patients met the inclusion criteria, but they declined to participate in the study. a study by jansson-knodell et al. revealed that anaemia is more common among women but not at a statistically significant level; approximately 37% of the women and 25% of the men in their study had anaemia.35 the predominance of women in the present study was surprising. it may be because female students are more likely to seek medical attention at the clinic than male students or this may reflect differences in diet and nutrition between men and women in the study population. multiple factors contribute to the underrecognition of cd in general and in patients with ida in particular, especially in the primary care setting. the first and foremost cause is the lack of awareness among healthcare professionals about the non-classical manifestations of cd. another reason is the lack of continuity of care in primary care settings. to overcome this gap in healthcare, it is necessary to disseminate relevant information to the concerned physicians through regular continuing medical education, updates and conferences. establishing well-structured services based on continuous and comprehensive follow-ups would also be helpful. there are some limitations to the present study, namely the small sample size used for the statistical calculations. however, this is acceptable as a starting point since research on this condition from the middle east is rare. the study reported the prevalence of cd among at-risk subjects with ida. investigation of cd among healthy subjects and others at risk, such as patients with osteoporosis, is recommended in the future. it would be helpful to study genetic predisposition to cd by considering hla-dq2 or hla-dq8 or both. this can pave the way for larger prevalence studies in the general population. additionally, all the participants in the present study were female patients and the study was conducted at a single institution with a small sample size; therefore, the results may not be generalised to other regions of the country. a large-scale community-based study that includes all omani governorates, various age groups and both genders would overcome some of these limitations. conclusion cd is not a rare disorder as it was previously thought to be. there is a need to increase awareness among healthcare professionals about cd and its nonclassical manifestations such as ida. the present study’s findings enable the development of guidelines and protocols for the routine investigation of cd in general and in patients with unexplained ida specifically. these measures will not only benefit cd patients but also significantly improve the healthcare system overall. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g this project was funded by an internal grant from the college of medicine and health sciences at sultan qaboos university, muscat, oman (rf/med/ famco/20/1). a u t h o r s’ c o n t r i b u t i o n sa, amb, as, rd and rk conceived the research idea and performed the literature review. sa and amb— under the supervision of rd, as and rk—designed prevalence of coeliac disease in omani adults with iron deficiency anaemia of unknown cause case-finding study 266 | squ medical journal, may 2022, volume 22, issue 2 the research methodology and the data collection sheet. sa, amb, ja and mk were involved in the data collection and date entry. sa, amb, as, ja, mk and rk analysed and interpreted the results. sa, amb, as and rk had a major contribution in drafting the manuscript in consultation with rd, ja and mk. rk was the research supervisor who guided sa and amb throughout the project. all authors read and approved the final version of the manuscript. references 1. malalgoda m, simsek s. celiac disease and cereal proteins. food hydrocoll 2017; 68:108–113. https://doi.org/10.1016/j. foodhyd.2016.09.024. 2. rostom a, dube c, cranney a, aloojee n, sy r, garritty c, et al. celiac disease: summary. in: ahrq evidence report summaries prepared by the university of ottawa evidencebased practice center. rockville, md: agency for healthcare research and quality, 2004. 3. husby s, koletzko s, korponay-szabó r, mearin ml, philips a, shamir r, et al. european society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. j pediatr gastroenterol nutr 2012; 54:136–60. https://doi.org/10.1097/mpg.0b013e31821a23d0. 4. abrams ja, brar p, diamond b, rotterdam h, green ph. utility in clinical practice of immunoglobulin a anti-tissue transglutaminase antibody for the diagnosis of celiac disease. clin gastroenterol hepatol 2006; 4:726–30. https://doi.org/10.1 016/j.cgh.2006.02.010. 5. national institutes of health consensus development conference statement on celiac disease, june 28–30, 2004. gastroenterology 2005;128:s1–9. https://doi.org/10.1053/j.gastro.2005.02.007. 6. casella s, zanini b, lanzarotto f, villanacci v, ricci c, lanzini a. celiac disease in elderly adults: clinical, serological, and histolo gical characteristics and the effect of a gluten-free diet. j am geriatr soc 2012; 60:1064–9. https://doi.org/10.1111/j.15325415.2012.03997.x. 7. fasano a. clinical presentation of celiac disease in the pediatric population. gastroenterology 2005; 128:s68–73. https://doi. org/10.1053/j.gastro.2005.02.015. 8. jericho h, guandalini s. extra-intestinal manifestation of celiac disease in children. nutrients 2018; 10:755. https://doi.org/10.3 390/nu10060755. 9. nih consensus development conference on celiac disease. nih consens state sci statements 2004; 21:1–23. 10. laurikka p, nurminen s, kivelä l, kurppa k. extraintestinal manifestations of celiac disease: early detection for better long term outcomes. nutrients 2018; 10:1015. https://doi.org/10.33 90/nu10081015. 11. mahadev s, laszkowska m, sundström j, björkholm m, lebwohl b, green phr, et al. prevalence of celiac disease in patients with iron deficiency anemia-a systematic review with meta-analysis. gastroenterology 2018; 155:374–82.e1. https://doi.org/10.105 3/j.gastro.2018.04.016. 12. mustalahti k, catassi c, reunanen a, fabiani e, heier m, mcmillan s, et al. the prevalence of celiac disease in europe: results of a centralized, international mass screening project. ann med 2010; 42:587–95. https://doi.org/10.3109/07853890. 2010.505931. 13. saadah oi. celiac disease in children and adolescents at a single center in saudi arabia. ann saudi med 2011; 31:51–7. https:// doi.org/10.4103/0256-4947.75779. 14. khayyat ym. serologic markers of gluten sensitivity in a healthy population from the western region of saudi arabia. saudi j gastro enterol 2012; 18:23–5. https://doi.org/10.4103/1319-3767.91733. 15. zamani f, mohamadnejad m, shakeri r, amiri a, najafi s, alimohamadi s, et al. gluten sensitive enteropathy in patients with iron deficiency anemia of unknown origin. world j gastroenterol 2008; 14:7381–5. https://doi.org/10.3748/wjg.14.7381. 16. murray ja, mclachlan s, adams pc, eckfeldt jh, garner cp, vulpe cd, et al. association between celiac disease and iron deficiency in caucasians, but not non-caucasians. clin gastro enterol hepatol 2013; 11:808–14. https://doi.org/10.1016/j.cgh.2 013.02.009. 17. baghbanian m, farahat a, vahedian h a, sheyda e, zarekhormizi mr. the prevalence of celiac disease in patients with iron-deficiency anemia in center and south area of iran. arq gastroenterol 2015; 52:278–82. https://doi.org/10.1590/s000428032015000400006. 18. kavimandan a, sharma m, verma ak, das p, mishra p, sinha s, et al. prevalence of celiac disease in nutritional anemia at a tertiary care center. indian j gastroenterol 2014; 33:114–18. https://doi.org/10.1007/s12664-013-0366-6. 19. fraser js, woodhouse nj, el-shafie ot, al-kindy ss, ciclitira pj. occult celiac disease in adult omanis with unexplained iron deficiency anemia. saudi med j 2003; 24:791. 20. spencer m, lenhart a, baker j, dickens j, weissman a, read aj, et al. primary care physicians are under-testing for celiac disease in patients with iron deficiency anemia: results of a national survey. plos one 2017; 12:e0184754. https://doi.org/10.1371/ journal.pone.0184754. 21. paez ma, gramelspacher am, sinacore j, winterfield l, venu m. delay in diagnosis of celiac disease in patients without gastro intestinal complaints. am j med 2017; 130:1318–23. https:// doi.org/10.1016/j.amjmed.2017.05.027. 22. hin h, bird g, fisher p, mahy n, jewell d. coeliac disease in primary care: case finding study. bmj 1999; 318:164–7. https:// doi.org/10.1136/bmj.318.7177.164. 23. pelkowski td, viera aj. celiac disease: diagnosis and manage ment. am fam physician 2014; 89:99–105. 24. al-sinani s, sharef sw, al-yaarubi s, al-zakwani i, al-naamani k, al-hajri a, et al. prevalence of celiac disease in omani children with type 1 diabetes mellitus: a cross sectional study. oman med j 2013; 28:260–3. https://doi.org/10.5001/omj.2013.73. 25. al-lawati tt, al-musawi hs. celiac disease in oman: a tertiary centre experience. oman med j 2013; 28:70–2. https:// doi.org/10.5001/omj.2013.17. 26. alkindi s, al musalami a, al wahaibi h, al senani a, al ghammari n, panjwani v, et al. iron deficiency and iron deficiency anemia in the adult omani population. j appl hematol 2018; 9:11–15. https://doi.org/10.4103/joah.joah_65_17. 27. johnston sd, watson rg, mcmillan sa, sloan j, love ah. celiac disease detected by screening is not silent-simply unrecognized. qjm 1998; 91:853–60. https://doi.org/10.1093/qjmed/91.12.853. 28. rawashdeh mo, khalil b, raweily e. coeliac disease in arabs. j pediatr gastroenterol nutr 1996; 23:415–18. https://doi. org/10.1097/00005176-199611000-00009. 29. lionetti e, catassi c. the role of environmental factors in the development of celiac disease: what is new? diseases 2015; 3:282–93. https://doi.org/10.3390/diseases3040282. 30. abadie v, sollid l m, barreiro lb, jabri b. integration of genetic and immunological insights into a model of celiac disease pathogenesis. annu rev immunol 2011; 29:493–525. https:// doi.org/10.1146/annurev-immunol-040210-092915. 31. wolters vm, wijmenga c. genetic background of celiac disease and its clinical implications. am j gastroenterol 2008; 103:190–5. https://doi.org/10.1111/j.1572-0241.2007.01471.x. https://doi.org/10.1016/j.foodhyd.2016.09.024 https://doi.org/10.1016/j.foodhyd.2016.09.024 https://doi.org/10.1097/mpg.0b013e31821a23d0 https://doi.org/10.1016/j.cgh.2006.02.010 https://doi.org/10.1016/j.cgh.2006.02.010 https://doi.org/10.1053/j.gastro.2005.02.007 https://doi.org/10.1111/j.1532-5415.2012.03997.x https://doi.org/10.1111/j.1532-5415.2012.03997.x https://doi.org/10.1053/j.gastro.2005.02.015 https://doi.org/10.1053/j.gastro.2005.02.015 https://doi.org/10.3390/nu10060755 https://doi.org/10.3390/nu10060755 https://doi.org/10.3390/nu10081015 https://doi.org/10.3390/nu10081015 https://doi.org/10.1053/j.gastro.2018.04.016 https://doi.org/10.1053/j.gastro.2018.04.016 https://doi.org/10.3109/07853890.2010.505931 https://doi.org/10.3109/07853890.2010.505931 https://doi.org/10.4103/0256-4947.75779 https://doi.org/10.4103/0256-4947.75779 https://doi.org/10.4103/1319-3767.91733 https://doi.org/10.3748/wjg.14.7381 https://doi.org/10.1016/j.cgh.2013.02.009 https://doi.org/10.1016/j.cgh.2013.02.009 https://doi.org/10.1590/s0004-28032015000400006 https://doi.org/10.1590/s0004-28032015000400006 https://doi.org/10.1007/s12664-013-0366-6 https://doi.org/10.1371/journal.pone.0184754 https://doi.org/10.1371/journal.pone.0184754 https://doi.org/10.1016/j.amjmed.2017.05.027 https://doi.org/10.1016/j.amjmed.2017.05.027 https://doi.org/10.1136/bmj.318.7177.164 https://doi.org/10.1136/bmj.318.7177.164 https://doi.org/10.5001/omj.2013.73 https://doi.org/10.5001/omj.2013.17 https://doi.org/10.5001/omj.2013.17 https://doi.org/10.4103/joah.joah_65_17 https://doi.org/10.1093/qjmed/91.12.853 https://doi.org/10.1097/00005176-199611000-00009 https://doi.org/10.1097/00005176-199611000-00009 https://doi.org/10.3390/diseases3040282 https://doi.org/10.1146/annurev-immunol-040210-092915 https://doi.org/10.1146/annurev-immunol-040210-092915 https://doi.org/10.1111/j.1572-0241.2007.01471.x safa ambusaidi, al manar al busaidi, asma al salmani, robin davidson, jalila alshekaili, mahmood al kindi and rahma al kindi clinical and basic research | 267 32. hamamy ha. oman: a model for the integration of community genetic services into primary health. from: pdfs.semanticscholar. org/50e2/1afdb1db76addc78f5a73e1db98b044607ef.p df accessed: apr 2021. 33. islam mm. the practice of consanguineous marriage in oman: prevalence, trends and determinants. j biosoc sci 2012; 44:571–94. https://doi.org/10.1017/s0021932012000016. 34. lionetti e, catassi c. new clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. int rev immunol 2011; 30:219–31. https://doi.org/10.3109/08830185. 2011.602443. 35. jansson-knodell cl, king ks, larson jj, van dyke ct, murray ja, rubio-tapia a. gender-based differences in a populationbased cohort with celiac disease: more alike than unalike. dig dis sci 2018; 63:184–92. https://doi.org/10.1007/s10620-0174835-0. https://doi.org/10.1017/s0021932012000016 https://doi.org/10.3109/08830185.2011.602443 https://doi.org/10.3109/08830185.2011.602443 2008-issue1.indd 1 molecular imaging bridging imaging and biology in this issue, samir hussein et al present a case of recurrent breast cancer in which anatomical imaging, i.e. mammography, was equivocal, but functional imaging, i.e. tc-99m sestamibi, detected the recurrent breast cancer which was later confirmed surgically.1 this is a good example of the utility of functional imaging. we also hope to publish in the next issue the outcome of oman’s first international radiology conference on the topic of magnetic resonance imaging (mri) held at sultan qaboos university 20-22 february 2008. this conference discussed papers on mri and functional mri(fmri) which is a stepping stone to molecular imaging. functional imaging has moved forward by leaps and bounds in the last few years. it started off with planar nuclear imaging moving to single photon emission computed tomography (spect) and spect-ct followed by the introduction of positron emission tomography (pet) imaging. pet functional imaging humbly started with f-18 fluorodeoxyglucose (fdg) and was widely accepted as a major advancement in oncology, cardiology and neurology. however, the demand for non-invasive exploration of the biology of tumours, myocardial metabolism and brain function, led to the invention of other pet imaging agents which explored the molecular events. this further widened the vista of the new science of molecular imaging. for example, in oncology, pet imaging using c-11 methionine can study the biological behaviour of protein synthesis in multiplying cancer cells; f-18 fluorothymidine (f-18 flt) is used for evaluating dna synthesis in cancer, f18-fluoro-isomidazole for studying hypoxic areas in cancer. in cardiology, c-11 palmitate can study the fatty acid metabolism in the myocardium, and c-11 acetate the oxidative metabolism of myocardium. in neurology, c-11 methyl-spiperone or f-18-altenserin can study serotonin-2a receptors in the brain, while c-11 raclopride can probe into the behaviour of dopamine d2 in various psychiatry disorders and also monitor their treatment. experimentally, molecular imaging used micro-pet for tissue biological studies and for metabolic studies in small animals. after pet and micro-pet in molecular imaging came optical imaging which includes. these are all very useful in imaging biological processes, e.g. the changing concentration of enzymes, but unfortunately, in most cases, they are restricted to small organs or disorders near the surface of the body. small organs that have benefited include the eye and lately the breast. on clinical trial is equipment such as softscan which uses laser light to send pulses of near infrared (nir) light at four frequencies; the light transmitted through the breast is then detected digitally to create an image.2 malignant lesions absorb more light (vascularity) and will appear as dark spots. another optical molecular imaging technique using nir light has been incorporated in the breast coil of mri, thus resulting in fused images of the breast-both mri and optical images,3, 4 two very sensitive techniques available in the study of breast cancer and its biology. a third type of molecular imaging using nir incorporates ultrasound in the same probe giving a fused anatomic/functional image.5 there are many other new imaging tools and techniques which fall into the category of molecular imaging and explore the biology of disease and normal tissues e.g. humanised antibodies and their fragments as well as some of the fmri studies: dynamic contrast-enhanced magnetic resonance imaging (dce-mri) to evaluate tumour angiogenesis, and integrin-targeted nanoparticles for mri imaging of angiogenesis. in the near future, most of the molecular imaging, including optical imaging and pet, that uses the metabolicm e s s a g e f r o m t h e e d i t o r i n c h i e f 2 specific radiopharmaceuticals will be available for phase 3 clinical trials and also for use in clinical practice. it is our responsibility to ensure that the public and in particular our patients in oman and the gcc countries benefit from these. we need to ensure that these tools and facilities are available in oman and the gulf states; get ourselves involved in the available phase 3 clinical trials and introduce them into our practice as soon as they are available for clinical use. our patients deserve the best available medical and molecular imaging that is currently available. those researchers who are involved in the clinical use of molecular imaging or in clinical trials are encouraged to submit their experience/research for publication in squmj. we encourage the invigoration of medical research and its publication in keeping with his majesty sultan qaboos’ vision. let there be a new dawn in bridging medical imaging and biology in this age of ‘targeted and personalized therapy’. lamk al-lamki md, frcpc, facr, facnm editor-in-chief email: mjournal@squ.edu.om tel. number: (+968) 2414 3457 r e f e r e n c e s 1 hussein s, sawhney s, al jarrah a. tc-99m tetrofosmin scintimammography for the detection of recurrent breast cancer in a patient with equivocal mammography study. sultan qaboos univ med j 2008; 8:79-81. 2. optical imaging may improve breast cancer detection. from http://www.cadth.ca/index.php/en/hta/reports-publications/health-technology-update/issue4/optical. accessed february 2008. 3. concurrent mr-nir imaging for breast cancer diagnosis. from http://www.stinet.dtic.mil/oai/oai?verb=getrecord&m etadataprefix=html&identifier=ada438601. accessed february 2008. 4. breast cancer diagnosis from combined mri-optics method. from http://www.huliq.com/18532/breast-cancer-diagnosis-from-combined-mri-optics-method accessed on 16th feb.2008 accessed february 2008. 5. optical imaging added to ultrasound improves breast cancer diagnosis. from http://www.sciencedaily.com/releases/ 2005/09/050928085420.htm. accessed february 2008. submitted 16 jun 21 1 revision req. 22 aug 21; revision recd. 10 oct 21 2 accepted 7 nov 21 3 online-first: jan 2022 4 doi: https://doi.org/10.18295/squmj.1.2022.006 5 6 acquired uterine vascular anomaly 7 experience from a tertiary care center in pakistan 8 kulsoom fatima,1 mustafa b.a. zubairi,2 muhammad azeemuddin,1 *raza 9 sayani1 10 11 1department of radiology, aga khan university hospital and 2medical college, dow university 12 of health sciences, karachi, pakistan 13 *corresponding author’s e-mail: sayani_raza@yahoo.com 14 15 abstract 16 objective: to retrospectively review imaging findings and the outcomes of uterine artery 17 embolization (uae) in symptomatic uterine vascular anomalies. methods: we identified 15 18 cases of acquired uterine vascular anomaly from 2010 to 2020 who were evaluated with 19 ultrasound, computed tomography, and magnetic resonance imaging, either alone or in 20 combination. all patients had history of dilatation and curettage or uterine instrumentation. they 21 underwent angiography and embolization of the uterine arteries. primary outcome post 22 embolization was assessed clinically and/or in combination with ultrasound. post procedure 23 pregnancies were also recorded. results: non-invasive imaging was abnormal in all patients, 24 however this pre intervention imaging was unable to accurately classify the type of vascular 25 anomaly except in the case of pseudoaneurysm. conventional angiography showed uterine artery 26 hyperemia in 6, arteriovenous malformation in 7 and pseudoaneurysm in 2 patients. the 27 technical success rate was 100% with no repeat embolization needed. follow up ultrasound in 12 28 patients revealed resolution of abnormal findings, remaining three were normal on clinical 29 follow up. seven patients (46.7%) had a normal pregnancy, 15.7 months after the procedure 30 mailto:sayani_raza@yahoo.com (range 4-28 months). conclusion: uae is a safe and effective management option for intractable 31 severe bleeding in patients with uterine vascular anomaly post instrumentation and is seen not to 32 impair future pregnancy. 33 keywords: uterine artery embolization; pseudoaneurysm; arteriovenous malformation; 34 ultrasound; computed tomography; magnetic resonance imaging. 35 36 advances in knowledge 37  all hypervascular lesions in the uterus on ultrasound are not true arteriovenous 38 malformations. placental subinvolution theory should be kept in mind when assessing 39 patients for suspected uterine vascular anomaly post-abortion on imaging. 40 41 application to patient care 42  pelvic artery embolization prevents hysterectomy in cases of severe vaginal bleeding. 43 embolization of the uterine artery does not preclude successful future pregnancy 44 45 introduction 46 uterine vascular anomalies (uva) are classified into two main types, a) vascular malformations, 47 and b) vascular neoplasms, according to the international society for the study of vascular 48 anomalies classification system.1 the first category includes several entities such as venous 49 malformations, arteriovenous fistulas, pseudoaneurysms, arteriovenous malformations (avms), 50 and rarely a combination of pseudoaneurysm and avm. 1-3 avms are the most reported uterine 51 vascular anomaly although their true incidence is unknown.4,5 these may be either congenital or 52 acquired, the latter being far more common.4,6 acquired uterine avms are most commonly 53 secondary to uterine trauma, such as curettage or uterine surgery, which results in abnormal 54 communication of uterine artery branches with the myometrial venous plexus and lack a true 55 nidus.4,7,9 56 57 rare causes of uterine avm include endometrial or cervical carcinoma, leiomyoma, uterine 58 infection, gestational trophoblastic diseases or endometriosis.9-11 direct communication between 59 artery and vein results in arteriovenous fistulas.1,12 pseudoaneurysms constitute another rare 60 acquired vascular anomaly. these are focal areas of confined defects communicating with the 61 vessel lumen through a traumatic defect, frequently post pelvic/uterine surgery or a curettage 62 procedure, and lack a true wall.2 patients with acquired uterine vascular anomaly present with 63 acute heavy bleeding, which may be intermittent or continuous.5,8 other symptoms such as lower 64 abdominal pain, urinary frequency or incontinence, dyspareunia, and hypotension or 65 hypovolemia secondary to blood loss have also been described.11 all suspected cases of uterine 66 avm initially undergo ultrasound evaluation for diagnosis, supplemented by computed 67 tomography (ct) or magnetic resonance imaging (mri) in cases where ultrasound is 68 inconclusive.8,12 although conventional angiography is the gold standard for diagnosis, it is 69 reserved for cases that are unresponsive to conservative management and in whom a therapeutic 70 embolization is planned.13-16 71 72 the purpose of our study was to review the diagnostic accuracy of imaging in identifying uterine 73 vascular anomalies in symptomatic patients and to assess the technical success of percutaneous 74 uterine artery embolization (uae) in the management of this patient cohort. 75 76 methods 77 this study was a retrospective analysis conducted at the aga khan university hospital (akuh), 78 karachi after taking approval from the institute’s ethical review committee (ethical review 79 number: erc # 2020-3690-10189). we searched our radiology database for patients 80 undergoing uae from january 2010 to may 2020. after excluding patients with known uterine 81 tumors, retained products of conception, gestational trophoblastic disease, and post-partum 82 hemorrhage, we identified 15 cases suspected of uterine vascular anomaly clinically and on 83 imaging. 84 85 a pre-structured proforma was used to record patient demographics including age, parity, 86 pattern, and volume of vaginal bleeding, history of uterine surgery or dilatation and curettage 87 (d&c), time interval since the intervention, findings on imaging and angiography, and patient 88 outcome. the duration of hospital stays, post-procedure complication, follow-up ultrasound 89 findings, and post-embolization fertility/pregnancy were also recorded. the patient’s imaging 90 was reviewed on picture archiving and communication system (pacs), rogan delft view pro-91 x, while additional data was collected from the health information management services 92 (hims). 93 94 the pre angiography imaging modality was chosen at the discretion of the referring physician, 95 which included ultrasonography with color doppler imaging, pelvic mri, and ct, either alone 96 or a combination. the referring physician decided on embolization after consulting with the 97 interventional radiologist. in the angiographic suite of aga khan university hospital, 98 interventional radiologists performed embolization procedures. consent was taken in every case 99 to explain the benefits and risks. under local anesthesia, the procedure was performed on a flat 100 panel monoplane digital subtraction angiography machine axiom-artis, siemens. the femoral 101 artery was punctured and a 4f vascular access sheath was inserted. a 4fr simmons (sim 1) 102 catheter (cordis), or a cobra (c1) angiographic catheter (cordis) was advanced over a 0.035-103 inch guidewire. an angiographic run was performed after selective catheterization of the uterine 104 artery, followed by super-selective cannulation using a microcatheter (progreat terumo) which 105 was placed coaxially as near as possible to the feeder vessel. the embolization materials used 106 were polyvinyl alcohol particles (pva), size 355-500 µm, gel foam, glue, and coil, either in 107 combination or isolation. in a few cases, the ovarian artery was also embolized. clinical success 108 was defined as resolution of vaginal bleeding and/or abnormal imaging findings on post 109 embolization follow-up. 110 111 spss version 20 was used for statistical analysis. quantitative data were expressed as mean ± 112 standard deviation; qualitative data were expressed using frequencies (percentages). descriptive 113 analysis was done for all variables, including the demographic variables as well as the other 114 categorical variables, and frequencies, proportions, and percentages were reported. 115 116 results: 117 the mean patient age was 28.2 years (range: 20-35 years). fourteen patients had undergone a 118 prior uterine procedure. twelve patients had a prior d&c, one patient had a repair of a uterine 119 rupture and one patient had a c-section. the patient without prior d&c or surgery had a history 120 of medical termination of pregnancy. 121 122 the clinical features are shown in table 1. main presenting complain was abnormal pervaginal 123 bleeding. it was considered mild if there was only spotting, when there was continuous bleeding 124 but no clots it was labelled as moderate and severe when there was passage of clots. the mean 125 time interval of patient presentation after the intervention was 64.6 days (range: 1-365 days). 126 all patients underwent pre-embolization us except one, who underwent only mri examination. 127 greyscale ultrasound identified an abnormal area in the myometrium in 12 patients (85.7%) and 128 an abnormal area in the endometrium in 2 patients. on doppler imaging, eight patients showed 129 mixed arterial/venous flow. six of the eight were confirmed as avm on angiography (figure 1) 130 while the other two showed only uterine hyperemia on angiography. four patients showed focal 131 increased vascularity within the myometrium, one turned out to be an avm on angiography 132 while the other three just showed uterine artery hyperemia. two patients showed 133 pseudoaneurysms on doppler that were confirmed on pre-embolization ct and angiography 134 (figure 2). two other patients had abnormal focal vascularity on arterial phase with prominent 135 veins on pre-embolization ct suggesting avm. among these, one proved avm on angiography 136 (figure 3) while the other showed uterine hyperemia only. 137 138 six out of 15 patients underwent pre-embolization mri. mri findings demonstrated abnormal 139 signal intensity areas in either the myometrium or endometrium with abnormal enhancement and 140 multiple flow voids suggesting avm. three of these were confirmed as avm (figure 4) on 141 angiography, while the other three showed enlarged, prominent uterine arteries. 142 the details of the angiographic findings and procedures are shown in table 2. 143 144 the embolization procedure was technically successful in all 15 patients, and none required a 145 repeat embolization or post embolization transfusion. none of the patients had an on-table 146 procedure-related or puncture site complication. the mean duration of hospital stay was 2.73 147 days, (range: 2 4 days). nine out of fifteen patients had mild bleeding at the time of discharge 148 from the hospital which resolved by the next clinic visit. two patients had an episode of per 149 vaginal bleeding a month later which responded to conservative management. 150 151 twelve patients underwent follow-up ultrasound examinations. the mean time of the follow-up 152 ultrasound, after embolization, was 40.6 days (range15 to 90 days). in five patients, the follow-153 up ultrasound was completely normal. five patients showed persistent greyscale findings, 154 however, abnormal vascularity had resolved. one patient showed a decrease in size of the 155 abnormal area on ultrasound with persistent mild vascularity, although she was asymptomatic. in 156 another patient, both greyscale and doppler abnormality was demonstrated on initial follow-up 157 ultrasound, but it resolved completely on repeat ultrasound two months later. three patients did 158 not have any follow-up imaging but were clinically asymptomatic. 159 160 seven patients (46.7%) had normal pregnancies that carried to term after the procedure. the 161 mean time interval between the procedure and the pregnancy was 15.7 months (range4 to 28 162 months). the remaining eight did not conceive to our knowledge. 163 164 discussion 165 our retrospective study at a tertiary referral center reviewed the spectrum of imaging findings in 166 patients with suspected acquired vascular uterine anomalies and the outcomes of super-selective 167 uae. we found true avms in seven cases including one arteriovenous fistula. additional 168 anomalies that we found were uterine hyperemia and pseudo-aneurysm. timmerman et al 169 studied 30 cases of suspected uterine vascular malformations out of which eight underwent 170 angiography. their study showed true avms in three patients while the rest had only abnormal 171 arterial blush.17 occasionally, the number of avms is purportedly higher on (conventional) 172 angiography. hugues et al did a study on 26 cases of suspected uterine avms, of which about a 173 quarter showed uterine hyperemia, whilst true avms were observed in the remaining cases.18 174 also, a study of iatrogenic uterine arterial injuries, which were treated by uae, found avms in 175 the majority of cases (15 out of 24), either alone or in combination with pseudoaneurysm.2 176 177 all of our cases showed abnormalities on both greyscale and color doppler ultrasound 178 examinations. both pseudoaneurysms were accurately identified. pseudoaneurysms appear as 179 cystic spaces on greyscale ultrasound which show swirling multidirectional flow on color 180 doppler with varying degrees of turbulence, allowing for correct identification in most cases.1,2 181 the greyscale appearances of avms, on the other hand, are non-specific, ranging from subtle 182 myometrial inhomogeneity to linear, anechoic spaces in the myometrium which show color 183 filling on doppler interrogation with a mosaic pattern.12,19 the specificity is increased by duplex 184 us/ spectral analysis which reveals high velocity, low resistance arterial flow.17 185 186 unfortunately, the spectral analysis findings were not available in all our cases as mostly 187 greyscale and color doppler evaluation was done. it has been seen that low resistance abnormal 188 vascularity often persists in the myometrium at the site of trophoblast/placental implantation and 189 takes time to resolve.1,11 this has been referred to as sub-involution of placental bed and may 190 account for abnormal findings on ultrasound and mri as seen in some of our cases which 191 subsequently demonstrated only uterine hyperemia on angiography with no avm. nevertheless, 192 angioembolization was justified as these patients presented with moderate to severe bleeding that 193 had been resistant to conservative management. symptoms completely resolved following a 194 single session of embolization, with no discernable adverse effects. 195 196 currently, digital subtraction angiography (dsa) is the gold standard for the diagnosis of uterine 197 vascular anomalies; however, its use is not justified unless it is the precursor to an embolization. 198 the management of uterine vascular anomalies depends on the clinical presentation as well as 199 the severity of the anomaly. patients who have minimal symptoms and/or are hemodynamically 200 stable may be followed clinically and by ultrasound. bleeding usually resolves spontaneously 201 within weeks to months in milder cases. 20 uae is offered to patients with severe intractable or 202 recurrent bleeding. it avoids hysterectomy preserving chances of future fertility. uae may 203 theoretically result in reduced vascular supply to the uterus; however, the presence of rich 204 collaterals prevents uterine infarction.13 many case reports and studies have shown successful 205 pregnancy outcomes post angioembolization.13,20,21 nearly half of our cases had pregnancies that 206 carried to term, post embolization. 207 208 several embolic agents have been used for the treatment of uvas. these include gel foam, pva 209 particles, glue, coil, or a combination 13,15,16,18,22,23. in our study, pva particles were the most 210 used embolization material, used in thirteen out of fifteen cases. it was the sole embolic agent in 211 ten cases and used in combination with gel foam in one case and combination with histoacryl 212 glue and coil in two patients. gel foam was used as the sole embolic agent in one case. one 213 patient with a right uterine artery pseudoaneurysm was embolized with cyanoacrylate glue. the 214 reported complication rate of pelvic artery embolization is low.23 215 216 minor complications such as puncture site pain or hematoma, fever, and transient lower limb and 217 buttock claudication are more frequent than rare severe complications such as iatrogenic rupture 218 of a pelvic artery, sloughing of perineal skin, vesicovaginal fistula, or major distal 219 ischemia.13,22,23 we did not encounter any major post-procedural complications. only three 220 patients experienced mild abdominal pain not requiring any treatment while fever was observed 221 in two patients which resolved before discharge. 222 223 conclusion 224 ultrasound is the first-line imaging modality employed for the diagnosis of uterine vascular 225 anomaly. it has high specificity for pseudoaneurysms but lacks specificity for avms. it is 226 important to consider placental bed sub-involution whilst diagnosing avms on non-invasive 227 imaging in cases with a history of a recent miscarriage. in summary, uae is a safe and effective 228 management option for intractable severe bleeding in patients with uterine vascular anomaly post 229 instrumentation and does not limit future pregnancy outcomes. 230 231 conflict of interest 232 the authors declare no conflicts of interest. 233 234 funding 235 no funding was received for this study 236 237 author contributions 238 kf, rs and ma conceived the idea, kf and mz collected the data, kf, mz and rs analysed 239 and interpreted the data, kf, rs and mz drafted the article, ma critically reviewed the 240 manuscript and supervised the study. all authors approved the final draft. 241 242 references: 243 1. vijayakumar a, srinivas a, chandrashekar bm, vijayakumar a. uterine vascular 244 lesions. rev obstet gynecol 2013; 6:69-79. https://doi.org/10.3909/riog0207 245 2. kwon jh, kim gs. obstetric iatrogenic arterial injuries of the uterus: diagnosis with us 246 and treatment with transcatheter arterial embolization. radiographics 2002; 22:35-46. 247 https://doi.org/10.1148/radiographics.22.1.g02ja0735 248 3. mammen t, shanthakumari h, gopi k, lionel j, ayyappan ap, kekre a. iatrogenic 249 secondary post-partum hemorrhage: apropos of two uncommon cases. australas radiol 250 2006; 50:392-4. https://doi.org/10.1111/j.1440-1673.2006.01609.x 251 4. o'brien p, neyastani a, buckley ar, chang sd, legiehn gm. uterine arteriovenous 252 malformations: from diagnosis to treatment. j ultrasound med 2006; 25:1387-253 92. https://doi.org/10.7863/jum.2006.25.11.1387 254 5. kim th, lee hh. presenting features of women with uterine arteriovenous 255 malformations. fertil steril 2010; 94:2330.e7-10. 256 https://doi.org/10.1016/j.fertnstert.2010.03.031 257 6. vogelzang rl, nemcek aa jr, skrtic z, gorrell j, lurain jr. uterine arteriovenous 258 malformations: primary treatment with therapeutic embolization. j vasc interv radiol 259 1991; 2:517-22. https://doi.org/10.1016/s1051-0443(91)72234-3 260 7. hoffman mk, meilstrup jw, shackelford dp, kaminski pf. arteriovenous 261 malformations of the uterus: an uncommon cause of vaginal bleeding. obstet gynecol 262 surv 1997; 52:736-40. https://doi.org/10.1097/00006254-199712000-00004 263 8. cura m, martinez n, cura a, dalsaso tj, elmerhi f. arteriovenous malformations of the 264 uterus. acta radiol 2009; 50:823-9. https://doi.org/10.1080/02841850903008792 265 9. fleming h, ostör ag, pickel h, fortune dw. arteriovenous malformations of the 266 uterus. obstet gynecol 1989; 73:209-14. https://pubmed.ncbi.nlm.nih.gov/2643064/ 267 10. cockshott wp, hendrickse jp. persistent arteriovenous fistulae following chemotherapy 268 of malignant trophoblastic disease. radiology 1967; 88:329-33. 269 https://doi.org/10.1148/88.2.329 270 11. timmerman d, van den bosch t, peeraer k, debrouwere e, van schoubroeck d, 271 stockx l, et al. vascular malformations in the uterus: ultrasonographic diagnosis and 272 conservative management. eur j obstet gynecol reprod biol 2000; 92:171-8. 273 https://doi.org/10.1016/s0301-2115(00)00443-7 274 file:///c:/users/raza.sayani/downloads/%20https:/doi.org/10.3909/riog0207 https://doi.org/10.1148/radiographics.22.1.g02ja0735 https://doi.org/10.1111/j.1440-1673.2006.01609.x https://doi.org/10.7863/jum.2006.25.11.1387 https://doi.org/10.1016/j.fertnstert.2010.03.031 https://doi.org/10.1016/s1051-0443(91)72234-3 https://doi.org/10.1097/00006254-199712000-00004 https://doi.org/10.1080/02841850903008792 https://doi.org/10.1148/88.2.329 https://doi.org/10.1016/s0301-2115(00)00443-7 12. polat p, suma s, kantarcý m, alper f, levent a. color doppler us in the evaluation of 275 uterine vascular abnormalities. radiographics 2002; 22:47-53. 276 https://doi.org/10.1148/radiographics.22.1.g02ja0947 277 13. ghai s, rajan dk, asch mr, muradali d, simons me, terbrugge kg. efficacy of 278 embolization in traumatic uterine vascular malformations. j vasc interv radiol 2003; 279 14(11):1401-8. https://doi.org/10.1097/01.rvi.0000096761.74047.7d 280 14. lin ac, hung yc, huang lc, chiu th, ho m. successful treatment of uterine 281 arteriovenous malformation with percutaneous embolization. taiwan j obstet gynecol 282 2007; 46(1):60-3. https://doi.org/10.1016/s1028-4559(08)60109-6 283 15. salazar gm, petrozza jc, walker tg. transcatheter endovascular techniques for 284 management of obstetrical and gynecologic emergencies. tech vasc interv radiol 2009; 285 12(2):139-47. https://doi.org/10.1053/j.tvir.2009.08.007 286 16. kim t, shin jh, kim j, yoon hk, ko gy, gwon di, et al. management of bleeding 287 uterine arteriovenous malformation with bilateral uterine artery embolization. yonsei 288 med j 2014; 55(2):367-73. https://doi.org/10.3349/ymj.2014.55.2.367 289 17. timmerman d, wauters j, van calenbergh s, van schoubroeck d, maleux g, van den 290 bosch t, et al. color doppler imaging is a valuable tool for the diagnosis and 291 management of uterine vascular malformations. ultrasound obstet gynecol 2003; 292 21(6):570-7. https://doi.org/10.1002/uog.159 293 18. hugues c, le bras y, coatleven f, brun jl, trillaud h, grenier n, et al. vascular 294 uterine abnormalities: comparison of imaging findings and clinical outcomes. eur j 295 radiol 2015; 84(12):2485-91. https://doi.org/10.1016/j.ejrad.2015.10.005 296 19. müngen e. vascular abnormalities of the uterus: have we recently over-diagnosed them? 297 ultrasound obstet gynecol 2003; 21(6):529-31. https://doi.org/10.1002/uog.163 298 20. poppe w, van assche fa, wilms g, favril a, baert a. pregnancy after transcatheter 299 embolization of a uterine arteriovenous malformation. am j obstet gynecol 1987; 300 156(5):1179-80. https://doi.org/10.1016/0002-9378(87)90136-0 301 21. chow tw, nwosu ec, gould da, richmond dh. pregnancy following successful 302 embolization of a uterine vascular malformation. br j obstet gynaecol 1995; 102(2):166-303 8. https://doi.org/10.1111/j.1471-0528.1995.tb09075.x 304 https://doi.org/10.1148/radiographics.22.1.g02ja0947 https://doi.org/10.1097/01.rvi.0000096761.74047.7d https://doi.org/10.1016/s1028-4559(08)60109-6 https://doi.org/10.1053/j.tvir.2009.08.007 https://doi.org/10.3349/ymj.2014.55.2.367 https://doi.org/10.1002/uog.159 https://doi.org/10.1016/j.ejrad.2015.10.005 https://doi.org/10.1002/uog.163 https://doi.org/10.1016/0002-9378(87)90136-0 https://doi.org/10.1111/j.1471-0528.1995.tb09075.x 22. sidhu hk, prasad g, jain v, kalra j, gupta v, khandelwal n. pelvic artery embolization 305 in the management of obstetric hemorrhage. acta obstet gynecol scand 2010; 306 89(8):1096-9. https://doi.org/10.3109/00016349.2010.481015 307 23. grönvall m, tikkanen m, metsätähti m, loukovaara m, paavonen j, stefanovic v. 308 pelvic arterial embolization in severe obstetric hemorrhage. acta obstet gynecol scand 309 2014; 93(7):716-9. https://doi.org/10.1111/aogs.12376 310 311 table 1. baseline characteristics of the study population 312 age years (mean) 28.2, range (20-35) parity 0 3 1-2 7 >3 5 history of d&c 12 time since d&c, days (mean) 42.6, range (1-60) history of uterine surgery 2 history of mtp 1 amount of bleeding moderate 6 (40%) severe 9 (60%) pattern of bleeding intermittent 9 (60%) continuous 6 (40%) d&c: dilatation and curettage, mtp: medical termination of pregnancy 313 314 table 2. details of the embolization procedure 315 case angiographic finding vessels embolized embolization material used complications duration of hospital stay post embolization pregnancy 1 hyperemia b/l uterine artery pva none 2 no 2 hyperemia b/l uterine artery pva none 3 no 3 hyperemia b/l uterine artery pva + gel foam none 2 yes 4 hyperemia u/l uterine artery pva fever 3 no 5 hyperemia b/l uterine artery pva none 4 yes https://doi.org/10.3109/00016349.2010.481015 https://doi.org/10.1111/aogs.12376 6 hyperemia b/l uterine artery pva none 4 no 7 avm b/l uterine artery pva none 2 no 8 avm b/l uterine artery pva none 4 yes 9 avm b/l uterine artery pva none 2 no 10 avm b/l uterine artery gel foam none 3 yes 11 avm b/l uterine artery pva fever 4 yes 12 avm b/l uterine artery pva none 2 no 13 avm b/l uterine artery+ ovarian pva + coil + glue none 2 no 14 pseudoaneurysm u/l uterine artery glue none 2 yes 15 pseudoaneurysm b/l uterine + ovarian pva + coil + glue none 2 yes avm: arteriovenous malformation, b/l: bilateral, u/l: unilateral, pva: polyvinyl alcohol 316 317 318 figure 1: a 25-year-old with moderate vaginal bleeding. (a) doppler ultrasound shows a 319 mosaic color pattern in the myometrium on the right side extending into endometrium indicating 320 both arterial and venous flow (arrow), (b) digital subtraction angiography (dsa) image shows 321 the avm supplied by right uterine artery, (c) dsa image shows the early draining vein (black 322 arrow), (d) post embolization shows resolution of the avm. 323 324 figure 2: a 29-year-old with moderate vaginal bleeding post uterine surgery. (a) greyscale 325 transvaginal ultrasound image shows an irregular anechoic area in the myometrium (arrow) with 326 the turbulent arterial flow on spectral analysis, (b) doppler image shows heterogeneous color 327 filling in the pseudoaneurysm, (c) and (d) digital subtraction angiographic images, left uterine 328 artery (long white arrow) and left ovarian artery (black arrow) supplying the pseudo-aneurysm. 329 330 331 figure 3: a 25-year-old with continuous vaginal bleeding. transvaginal ultrasound doppler 332 images (a) show abnormal vascularity in the uterine myometrium, (b) coronal contrast-333 enhanced ct image confirms abnormal myometrial vascularity and dilated draining gonadal vein 334 (white arrow), (c) dsa image shows an abnormal bunch of vessels supplied by right uterine 335 artery, (d) post embolization image showing complete resolution of the avm 336 337 338 339 figure 4: a 31-year-old with severe vaginal bleeding. (a) t2 weighted sagittal mri shows a 340 heterogeneous bulging mass with serpentine signal voids involving the lower uterine cavity and 341 anterior myometrium (white arrow). no myometrium is seen between the urinary bladder and 342 this mass. (b) coronal t2 weighted image shows multiple serpentine signal voids (white arrow). 343 (c) digital subtraction angiographic image shows dilated tortuous right uterine artery supplying 344 avm (d) post embolization image showing complete resolution of the avm. 345 3rd resuscitation and research conference sultan qaboos university, muscat, oman (virtual) 17–18 october 2021 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 159–161, epub. 28 feb 22 https://doi.org/10.18295/squmj.2.2022.021 conference abstracts health-related stigma, social support, self-efficacy and self-care actions among adults with sickle cell disease in oman *huda al ruqaishi,1 mohammed al qadire,2 omar al zaabi,2 omar al omari2 1department of emergency medicine, sultan qaboos university hospital, muscat, oman; 2college of nursing, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: alruqaishi@squ.edu.om objectives: this study aimed to examine the associations between stigma, social support, self-efficacy and self-care actions among adult patients with sickle cell disease (scd) in oman. methods: a cross-sectional, descriptive correlational design using standardised questionnaires about stigma, self-efficacy, social support and self-care actions was used. a stratified random sample of 264 adult omanis with scd was recruited from two tertiary hospitals in muscat. both descriptive statistics (mean ± standard deviation, frequencies and percentages) and inferential statistics (independent t-test, the mann-whitney u test and pearson correlation) were used to analyse the data. results: findings indicated that patients with scd in oman had health-related stigma with mean 28.1 ± 12.9 out of 66. however, the mean total scores for social support, self-efficacy and self-care actions were 4.8 ± 1.5, 28.3 ± 7.5 and 27.3 ± 4.2, respectively. there were significant negative relationships between social support, self-efficacy, self-care actions and stigma. further, this study showed that the length of hospital stay was positively correlated with stigma, but not significantly correlated with social support, self-efficacy or self-care actions. participants with a high level of education had significantly higher self-care action scores. conclusion: health-related stigma is a challenge for scd patients. it has a detrimental impact on the health status of patients with scd and on their families. therefore, strategies for managing scd and preventing complications are urgently needed. understanding factors that affect stigma is essential when implementing effective strategies to improve the quality of care of individuals with scd. an overview of legal aspects of resuscitation and do not resuscitate orders under omani law nasser h. al-azri ibri hospital, ministry of health, ibri, oman. email: dralazri@yahoo.com resuscitation has become an integral part of the standard of care in modern healthcare practice over the last half a century. yet, death, and hence decisions on resuscitation, remain a complex issue with certain dilemmas encountered in many cases. likewise, healthcare has become a regulated discipline with more legislative mandates in healthcare practice. resuscitation touches on a crucial religious, cultural and human values of life and death, and law has become more involved in its regulation. this presentation attempts to shed a light on aspects of resuscitation regulated by omani law. it covers, from a legal perspective, three stages surrounding the death in relation to the practice of resuscitation. the first is the stage of end of life care and advanced decisions of resuscitation and do not resuscitate orders. the second stage is the practice of resuscitation at the time of death. lastly, the third stage is the stage following the resuscitation and death of the patient. all these stages carry religious, social, ethical and legal values and concerns. healthcare providers need to be aware of these values and concerns, not the least the legal framework that governs their practice in order to ensure safe and legitimate practice. use of simulation in team based learning to enhance the performance of undergraduate medical students in emergency medicine care at sultan qaboos university: students’ perception. *fatma a. y. al rajhi,1 amal al-mandhari,2 aisha h. al khamisi2 1college of medicine and health sciences, sultan qaboos university, muscat, oman; 2department of emergency medicine, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: s124411@student.squ.om objectives: team-based learning (tbl) and simulation have been proven to be effective educational approaches. however, the impact of combining these methods as part of undergraduate emergency medicine education has not been reported before. this study assessed the use of simulation as a tool in tbl in emergency medicine education. it aimed to compare preand post-confidence level in knowledge of undergraduates in myocardial infarction and anaphylaxis as emergency medicine presentations using simulation-tbl methods at sultan qaboos university hospital (squh), muscat, oman. it also evaluated students' satisfaction towards this method. methods: this cross-sectional study used a convenience sample that included senior medical students who rotated through the emergency medicine department at squh from april 2020 to march 2021. preand post-confidence level in knowledge and students’ satisfaction were evaluated using a validated self-developed likert-scale questionnaire. wilcoxon signed‐rank test was used to compare preand post-confidence level in knowledge and descriptive statistics were used to evaluate students’ satisfaction. results: a total of 54 students attended tbl and high-fidelity simulator sessions and completed the questionnaire. results showed that 38.89% of students in acute coronary syndrome topic and 42.59% of students in anaphylaxis topic had a significant increase in their level of confidence. the highest increase in students' confidence was noticed in managing acute emergency situations. agreement percentage of 86% towards the method was noted. students were satisfied with this method’s ability to link knowledge to practice and align with learning and availability of appropriate scenarios for their level of competence. conclusion: simulation combined with tbl is an effective educational method in enhancing students' confidence with a high level of students’ satisfaction. it is recommended to implement this method in undergraduate emergency medicine education. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://creativecommons.org/licenses/by-nd/4.0/ 3rd resuscitation and research conference sultan qaboos university, muscat, oman (virtual) 160 | squ medical journal, february 2022, volume 22, issue 1 overview of assault induced trauma presenting to a trauma centre in oman mira al-busaidi, hilal al-miskry, aisha al-harbi, ilyas al-zadjali, *firas al-saidi, hani al qadhi department of surgery, college of medicine and health sciences, sultan qaboos university, muscat, oman. *corresponding author’s e-mail: frs.alsaidi@gmail.com objectives: assault induced trauma (ait) is a public health concern that must be addressed and acknowledged. to the best of the authors’ knowledge, in oman, this issue has not been studied before. this study aimed to characterise cases of ait presenting to sultan qaboos university hospital (squh), muscat, oman. methods: this is a retrospective descriptive study of patients presenting with ait to the emergency department of squh from january 2007 to december 2018. data obtained included incidence, patients’ demographics, mode of assault, triaging, management and hospital stay. the data were collected using the hospital information system ‘trakcare’ and analysed using statistical package for the social sciences. results: the total number of cases of ait identified was 268 cases and 239 fulfilled the study criteria. the highest incidence recorded was in 2018 accounting for 72 cases. the sample was predominantly composed of males at 82.4% and 65.3% of the total cases were omani citizens. in addition, 66.9% of the total sample cases were between the age of 20 and 39. the most common mode of assault implicated was the use of bodily force (34.7%). additionally, 18.4% were triaged as red cases. in terms of management, 84.5% of the cohort was treated non-surgically. no incidence of in-patient mortality was recorded. conclusion: this is the first study that looked into ait in oman. results of this study will aid in providing basis for future research and estimation of the magnitude of this problem in the community. please note that the highlighted numbers were updated per the published version (https://doi.org/10.18295/squmj.4.2021.033). coagulopathy in trauma: causes and preventive implementations at sultan qaboos university hospital maather al abri,1 *tamadher al barhi,2 esraa al yaqoub,3 hani al qadhi4 4department of surgery, 1sultan qaboos university hospital, muscat, oman; 2oman medical specialty board, muscat, oman; 3mubarak alkabeer hospital, jabriya, kuwait. *corresponding author’s e-mail: albar7i95@gmail.com objectives: trauma is the leading cause of death in people less than 40 years old worldwide. the trauma triad of death is composed of acidosis, hypothermia and coagulopathy. coagulopathy is found in 24.5% of trauma patients, mainly with severe injury. mechanisms of coagulopathy in trauma include: protein c activation, endothelial injury, coagulation factor deficiency, hyperfibrinolysis and many others. appropriate management and resuscitation decrease mortality significantly. methods: there are multiple markers used to detect coagulopathy in trauma. viscoelastic methods (vem) are used to measure the whole blood viscoelastic properties during clot formation. they provide information about clot initiation, strength and fibrinolysis. based on these values, a goal-oriented management of coagulopathy can be achieved at sultan qaboos university hospital (squh), muscat, oman, for trauma patients. there are two evidence devices available for vem: thromboelastography (teg) and rotational thromboelastometry (rotem). these devices will provide fast bedside results in squh’s emergency department within 10 minutes compared to 45 minutes with the conventional test. results: teg measures the entire life cycle of a clot and it gives an estimation of clot strength. the values of teg help guide the management of coagulopathy. coagulopathy types that are discussed are factor deficiency, low platelet function, low fibrinogen, increased fibrinolysis, hyper-coagulation status and hyper-coagulation with primary fibrinolysis. conclusion: implementing the teg and rotem devices in squh’s emergency department will help manage coagulopathy in trauma by delivering the best option of treatment according to the patients need. hypoglycaemia in emergency medicine department: incidence, epidemiological profile, aetiology and mortality at sultan qaboos university hospital. *walaa al hinai,1 mahmood aljufaili,2 abdulla al futaisi3 1sultan qaboos university, muscat, oman; departments of 2emergency medicine and 3internal medicine, sultan qaboos university hospital, muscat, oman. *corresponding author’s e-mail: s115872@student.squ.edu.om objective: this study aimed to estimate the incidence of hypoglycaemia in patients admitted to the emergency department (ed) of sultan qaboos university hospital (squh), muscat, oman, and to describe the epidemiological characteristics, aetiology, mortality and treatment options for hypoglycaemic patients. methods: this is a cross sectional retrospective study on patients admitted with hypoglycaemia to ed at squh. patients aged 15 years or more at the time of arrival to the ed with random blood glucose level of ≤3.9mmol/l in the period of january 2010 to january 2017 are included in the study. results: a total of 242 patients were admitted to the ed with hypoglycaemic episode. the incidence of hypoglycaemia increased, mainly from 2013 to 2016. the most common symptoms were abnormal heart rate (27%), followed by drowsiness (17.77%), gastrointestinal symptoms (14.88%), motor deficit (10.74%) and altered conscious status (10.33%). the most common aetiologies in diabetics were insulin use (76.2%), cardiovascular disease (71.2%), use of oral hypoglycaemic agents (26.6%) and infection/sepsis (12.4%). while in non-diabetics, cardiovascular diseases and infection/sepsis were the main causes with (38.2%) and (25.5%), respectively. the other causes in non-diabetics were liver disease (14.5%), malignancies (10.9%) and drugs/toxins (9.1%). no mortality was reported due to hypoglycaemia. the most common intervention for hypoglycaemia was intravenous dextrose (81.78%). conclusion: overall, the incidence of hypoglycaemia at the ed of squh increased during the study period. aetiology of hypoglycaemia was linked mainly with insulin use in diabetics and cardiovascular disease in non-diabetics. the most used treatment was intravenous dextrose. cardio pulmonary respiratory refresher role in retaining psychomotor skills *hajar al jadidi1 and mahmood al jufaili2 1emergency medicine training programme, oman medical specialty board, muscat, oman; 2emergency medicine department, sultan qaboos university hospital, muscat, oman. *corresponding author’s email: hajar.j@resident.omsb.org objectives: this study aimed to determine whether the six months cardiopulmonary resuscitation (cpr) refresher training would maintain the psychomotor skills of high-quality cpr. methods: this prospective single-centre non-blinded randomised controlled study was conducted at sultan qaboos university hospital, oman, from february 2018 to august 2020. all enrolled participants were assessed for their baseline knowledge and skills of cpr including chest compression, chest recoil, chest release, ventilation 17–18 october 2021 conference abstracts | 161 and interruption time. they received training for cpr at the same time. six months later, participants were divided randomly into intervention group, who received a refresher training of cpr, and control group who received no training. performance was assessed for both groups after 12 months, from the date of enrolment. a p <0.050 was considered statistically significant. results: a total of 38 healthcare providers, 19 in each group, were enrolled in this study. results showed comparable findings in terms of knowledge. one year post-enrolment, the intervention group showed an improvement in their performance in terms of ventilation (p = 0.028), interruption time (p = 0.020) and overall performance (p = 0.010). conclusion: a short-time refresher cpr training program six months after the initial training can help trainees retain cpr skills for up to one year. validation of heart score in a tertiary care hospital in oman *mohammed al-oraimi1 and saad al-juma2 1accident and emergency department, sur hospital, oman; 2department of emergency medicine, royal hospital, muscat, oman. *corresponding author’s email: dr.mohammed.s.j.o@gmail.com objectives: accurate risk stratification by emergency physicians for patients presenting to the emergency department (ed) with chest pain is critical. the heart score predicts the incidence of major adverse cardiac events (mace) within six weeks of patient’s presentation to ed with chest pain. in addition, the heart score is an accurate and fast prognostic tool. this study aimed to conduct an external prospective validation study of the heart score among ed patients. methods: this prospective crosssectional study included all patients who presented to the ed of royal hospital, oman, with chest pain from may to november 2018. data were collected from the alshifa 3+ electronic health system and data sheets filled by the treating physicians. the primary outcome was a composite of all-cause mortality, myocardial infarction or unscheduled coronary revascularisation at six weeks of presenting to ed. results: this study enrolled 300 patients but 50 patients were excluded due to missing data. among the 250 patients, 56 (22.4%) patients had mace within six weeks. the 250 patients were categorised based on heart score as low risk (n = 122, 48.8%), followed by intermediate (n = 91, 36.4%) and high risk (n = 37, 14.8%). seven patients of low risk had mace. so, 5.7 % of low risk had mace. the area under the curve was 0.775. conclusion: the results of this external validation study show poor prognostic accuracy of the heart score for six-week mace. epidemiology of spinal fractures due to motor vehicle collisions at a tertiary care hospital in oman *haya s. al-hasani,1 rajinder kumar,2 ghusn al sideiri1 1department of surgery, sultan qaboos university hospital, muscat, oman; 2all india institute of medical sciences, new delhi, india. *corresponding author’s email: haya.alhassani@gmail.com objectives: spinal fractures are one of the injuries that are potentially disabling. the leading cause of these fractures is motor vehicle collisions (mvcs) worldwide. however, there is a lack of data regarding the epidemiology of spinal fractures in oman. this study aimed to determine the incidence of spinal fractures and to study the pattern of these injuries in trauma patients due to mvcs presented at sultan qaboos university hospital (squh), oman. methods: this retrospective observational study included all the trauma patients due to mvcs who presented at squh between january and june 2017. the baseline demographic, clinical and radiological data of the patients were analysed. results: a total of 815 trauma patients were identified during the study period. the incidence of spinal fractures was 5.1% (n = 42). of these, 78.6% were males and 71.4% were from the younger age group (20–39 years). the most common anatomical region of fractures were in the lumbar region (28.6%), mainly spinal levels l1 and l2 (53.1%). of the patients, 7.1% sustained neurological deficits and 9.5% required surgical interventions. drivers sustained more spinal fractures (45.2%) compared to second seat passengers (14.3%). in addition, the restrained group sustained more cervical fractures (50%) and the non-restrained group sustained more thoracic fractures (50%). conclusion: this study provides baseline spine trauma epidemiological data at squh. future studies and collaborations between trauma centres in oman can guide efficient resource allocations for the management of spine trauma. family medicine academy, qassim health cluster, buraydah, saudi arabia *corresponding author's e-mail: abdullaziz5333@gmail.com انتشار حاالت السقوط وعوامل اخلطورة املرتبطة هبا بني كبار السن يف مدينة عنيزة ابململكة العربية السعودية عبد العزيز العبد القادر وأنيب رباين abstract: objectives: falls and fall-related consequences are a major public health problem in the elderly. this study aimed to measure the prevalence of falls and fall-related risk factors among elderly individuals in saudi arabia. methods: this cross-sectional study was conducted between january and october 2019 among 280 elderly patients aged >60 years old attending 10 randomly selected primary healthcare centres in unaizah city, qassim province, saudi arabia. data were collected using the validated 10-item missouri alliance for home care (mahc-10) fall risk assessment tool. results: a total of 269 participants were included in the study (response rate: 96.1%). the prevalence of falls over the preceding year was 31.6%. females fell more frequently than males (34.5% versus 28.5%) and most falls occurred indoors (84.7%). various risk factors were associated with fall risk including being aged >80 years (adjusted odds ratio [aor]: 5.17, 95% confidence interval [ci]: 1.66–16.14), polypharmacy (aor: 2.40, 95% ci: 1.01–5.71) and environmental factors (aor: 2.79, 95% ci: 1.24–6.28). however, more educated participants had a lower risk of falling (aor: 0.26, 95% ci: 0.09–0.77). there was also a significant association with the mahc-10 fall risk score (p = 0.043). conclusion: there was a high prevalence of falls among the elderly in unaizah city. various factors were associated with falls including advanced age, polypharmacy, age-related changes and environmental factors. as the majority of fall events occurred indoors, home safety improvements are recommended. moreover, additional larger-scale research is necessary regarding fall-related risk factors and fall prevention initiatives among elderly individuals in saudi arabia. keywords: elderly; falls; geriatrics; public health; prevalence; risk factors; saudi arabia. هذه هدفت ال�سن. كبار لدى العامة ال�سحة م�ساكل من رئي�سية م�سكلة عليها املرتتبة والعواقب ال�سقوط حاالت ت�سكل امللخ�ص: الهدف: الدرا�سة اإىل قيا�س مدى انت�سار حاالت ال�سقوط بني كبار ال�سن وعوامل اخلطورة املرتبطة بها يف اململكة العربية ال�سعودية. الطريقة: اأجريت ا م�سًنا تزيد اأعمارهم عن 60 عاًما ممن ح�رضوا اىل 10 مراكز رعاية �سحية هذه الدرا�سة املقطعية بني يناير واأكتوبر 2019 على 280 مري�سً اأولية مت اختيارها ع�سوائًيا يف مدينة عنيزة، منطقة الق�سيم، اململكة العربية ال�سعودية. مت جمع البيانات با�ستخدام اأداة تقييم خماطر ال�سقوط املوؤلفة من بنود حتالف مي�سوري للرعاية املنزلية الع�رض. النتائج: �سملت هذه الدرا�سة ما جمموعه 269 م�سارًكا )معدل اال�ستجابة: %96.1(. بلغ معدل انت�سار حاالت ال�سقوط خالل العام ال�سابق %31.6. كان معدل �سقوط االإناث اأكرث من الذكور )%34.5 مقابل 28.5%( وحدثت معظم حاالت ال�سقوط داخل املنازل )%84.7(. ارتبطت عوامل خطورة خمتلفة بخطر ال�سقوط، مبا يف ذلك العمر 80> عاًما )16.14 – 1.66 :فا�سل الثقة %95، 5.17 :ن�سبة االأرجحية املعدلة(، تعدد االأدوية )5.71 – 1.01 :فا�سل الثقة %95، 2.40 :ن�سبة االأرجحية املعدلة( والعوامل البيئية )6.28 – 1.24 :فا�سل الثقة %95، 2.79 :ن�سبة االأرجحية املعدلة(. ومع ذلك، كان امل�ساركني االأكرث تعليمًا اأقل عر�سة ا ارتباطا كبريا مع حا�سل جمموع البنود الع�رض لل�سقوط )0.77 – 0.09 :فا�سل الثقة %95، 0.26 :ن�سبة االأرجحية املعدلة(. كان هناك اأي�سً لتحالف مي�سوري للرعاية املنزلية امل�ستخدمة لتقييم خطر ال�سقوط )p = 0.043(. اخلال�صة: هناك ارتفاع مبعدل انت�سار حاالت ال�سقوط بني كبار ال�سن يف مدينة عنيزة. ارتبطت عوامل خمتلفة بحاالت ال�سقوط، مبا يف ذلك تقدم العمر، وتعدد االأدوية، والتغريات املرتبطة بالعمر والعوامل البيئية. نظًرا الأن غالبية اأحداث ال�سقوط حدثت داخل املنازل، يو�سى باإجراء حت�سينات على �سالمة املنزل. عالوة على ذلك، من ال�رضوري اإجراء املزيد من االأبحاث على نطاق وا�سع فيما يتعلق بعوامل اخلطورة املرتبطة بحاالت ال�سقوط ومبادرات الوقاية من �سقوط االأفراد امل�سنني يف اململكة العربية ال�سعودية. الكلمات املفتاحية: كبار ال�سن؛ �سقوط؛ طب ال�سيخوخة؛ ال�سحة العامة؛ انت�سار؛ عوامل اخلطورة؛ اململكة العربية ال�سعودية. prevalence and risk factors of falls among the elderly in unaizah city, saudi arabia *abdullaziz alabdullgader and unaib rabbani clinical & basic research sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e86–93, epub. 15 mar 21 submitted 28 apr 20 revisions req. 9 jun & 1 jul 20; revisions recd. 14 jun & 5 jul 20 accepted 14 jul 20 https://doi.org/10.18295/squmj.2021.21.01.012 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge this study adds important information to fill the gap in the existing literature regarding the burden of falls among the elderly in the middle east. the results indicated that females have a higher prevalence of falls than males and most falls occur indoors. age-associated decline in function due to gait changes, visual impairment, memory loss and chronic pain was a significant predictor of falling, as were environmental factors such as high door sills, inadequate lighting and uneven flooring. https://creativecommons.org/licenses/by-nd/4.0/ abdullaziz alabdullgader and unaib rabbani clinical and basic research | e87 application to patient care due to increasing life expectancy, the proportion of the elderly patient population is growing, resulting in a greater burden of care required for this high-risk group. based on this study's findings, targeted health promotion and fall prevention education interventions are needed to ensure healthy ageing and reduce fall-related injuries in saudi arabia. the 10-item missouri alliance for home care fall risk assessment tool can be used in routine primary care practice to screen elderly patients and identify fall-related predisposing factors. this tool would help inform individualised care and provide targeted health education initiatives to prevent fall-related injuries. the world health organization defines a fall as "an event which results in a person coming to rest inadvertently on the ground, floor or other lower level".1 in the usa, falls are a leading cause of morbidity and mortality among older adults.2 falls among the elderly can result in a myriad of adverse consequences including disability, loss of independence, decreased daily functioning and increased mortality and fear of falling.3–5 in most developed countries, old age is usually defined as beginning from 60 or 65 years, roughly equivalent to the retirement age.6 according to the united nations, 60 years of age is used as a reference point for someone to be described as elderly.7 a number of fall-related risk factors among elderly individuals have been reported in the existing literature including age, comorbidities, lack of physical activity and urinary incontinence.1,8 age, gender and race are non-modifiable risk factors. in contrast, modifiable factors include polypharmacy, excessive alcohol consumption, lack of exercise and environmental risks such as poor interior design, insufficient lighting and uneven flooring or surfaces.1 while obesity appears to be associated with a greater risk of falling, a body mass index (bmi) of ≥40 kg/m2 may reduce the risk of fall-related injury due to mobility limitations.9 comorbidities such as hypertension (htn) and diabetes mellitus (dm) also increase the risk of falling, as do impaired balance and visual and gait disorders.2,10,11 a review of fall-related risk factors reported that a history of previous falls was also a risk factor among the elderly.12 a meta-analysis indicated that falls were most strongly associated with a history of falls, gait problems, use of walking aids, vertigo, parkinson's disease and antiepileptic drug use.13 various researchers worldwide have studied falls among the elderly. in the usa, the annual prevalence of falls is 22%.14 other studies from elsewhere have estimated the prevalence of falls each year to be 16.5– 37.4% worldwide, including ecuador, japan, ethiopia, india and the uk.8,15–19 in canada, a recent study showed that the prevalence of falls in the past one year was 34.5%, while the rate of seeking medical attention for falls was 20.2% and fear of falling was 38.8%.20 similarly, other researchers have reported that 26.9% and 43.3% of japanese men and women, respectively, have a fear of falling.21 in italy, cesari et al. reported that the rate of falls among frail elderly people living in the community was 35.9%, with falls frequently correlated with modifiable factors such as wandering off, gait problems, depression and environmental hazards.22 unfortunately, there is a lack of literature regarding falls among elderly individuals in the middle east. in the united arab emirates (uae), one study demonstrated that approximately 50% of elderly participants had experienced a fall incident in the preceding two years, with females and those aged ≥70 years more likely to fall compared to their male and younger counterparts, respectively.23 only two previous studies have sought to assess falls among the elderly in saudi arabia.24,25 almegbel et al. found that the yearly prevalence of falling among elderly individuals in riyadh was 49.9%, with medications, walking aids, cerebrovascular accidents, poor vision and back pain strongly associated with falls.24 in turn, alshammari et al. reported that 57.7% of elderly participants in riyadh had a history of falls, with significant associations noted for advanced age, female gender, impaired health and environmental hazards.25 as with other places worldwide, countries in the middle east are currently experiencing a demographic transition wherein increasing life expectancy is contributing to an increase in the elderly proportion of the population.7,26 estimating the burden and risk factors of falls among older individuals is an important step towards preventing this problem.2,3 however, there appears to be a wide variation in the burden of falls due to differences in environmental and populationbased characteristics including specific fall-related risk factors.12 given the paucity of literature regarding falls among the elderly in the middle eastern region, the current study aimed to measure the prevalence of falls and fall-related risk factors among elderly individuals in qassim province, saudi arabia. prevalence and risk factors of falls among the elderly in unaizah city, saudi arabia e88 | squ medical journal, february 2021, volume 21, issue 1 methods this cross-sectional study was conducted between january and october 2019 among elderly patients aged ≥60 years visiting primary healthcare centres (phcs) in unaizah city, the second-largest city in qassim province with an estimated elderly population of 10,642 (~6.5% of the total population).27 the necessary sample size was calculated to be 257 participants at a 95% confidence level with a 5% bound on error and an expected prevalence of 22%.14 the aforementioned local studies were not used for sample size determination due to methodological differences and limitations.24,25 to account for attrition and missing data, 28 consecutive elderly patients were recruited from each of the 10 out of 19 phcs in unaizah city selected via simple random sampling, resulting in a total of 280 subjects. data were collected from the participants using a structured arabic-language questionnaire developed from a review of the literature. the final version of the questionnaire was reviewed by family and community medicine consultants for face validity— the questionnaire comprised two sections. the first part assessed demographic data (i.e. age, gender, education level, income and smoking status) and the second explored fall prevalence in the prior three and 12 months. in addition, fall-related risk factors were assessed using the 10-item missouri alliance for home care (mahc-10), a standardised, validated tool which explores 10 variables of fall risk including advanced age (>65 years), comorbidities (>3 medical diagnoses), a history of falls within the last three months, incontinence, vision impairment, impaired functional mobility, polypharmacy (≥4 concurrent medications), cognitive impairment, chronic pain affecting the level of function (i.e. knee pain) and environmental hazards (i.e. poor illumination, equipment tubing, inappropriate footwear, pets, hard-to-reach items, uneven/cluttered floor surfaces and outdoor entry and exit points).28,29 in terms of scoring, each item received a score of one if present and zero if absent, with total scores of ≥4 indicating an increased risk of falling.28 as no validated arabic translation of the mahc-10 tool was readily available, the principal investigator performed the translation of the original english-language questionnaire. the translated version was subsequently back-translated to english by two independent bilingual translators and then cross-checked with the original version to ensure the accuracy of the translation. data were analysed using the statistical package for the social sciences (spss), version 21.0 (imb corp., armonk, new york, usa). results were presented as frequencies and proportions for categorical variables and means with standard deviations for continuous variables. univariate and multivariate logistic regression analyses were conducted to assess associations between falls and sociodemographic and other variables. crude and adjusted odds ratios (aors) along with 95% confidence intervals (cis) were calculated for fall-related risk factors. all variables were included in the univariate logistic regression model. subsequently, those found to be significant or non-significant but biologically important were included in the multivariate model. correlations between variables were assessed using pearson's and spearman's correlation coefficients and cramer's v and phi statistics. if variables were correlated with each other, only one was retained in the regression model. variables were included in the final model based on associated changes in -2log likelihood ratios. a p value of <0.050 was considered statistically significant. this study was reviewed and approved by the qassim regional bioethics committee of the ministry of health in saudi arabia (approval no.: 1440-1411549). permission to conduct the study was also sought from the unaizah health sector office, which oversees the governorate's primary healthcare services. informed consent was obtained from all elderly individuals prior to their participation in the study. table 1: sociodemographic characteristics of elderly patients attending primary healthcare centres in unaizah city, saudi arabia (n = 269) characteristic n (%) gender male 133 (49.4) female 136 (50.6) age in years 60–69 155 (57.6) 70–79 78 (29) ≥80 36 (13.4) education level uneducated 104 (38.7) up to middle school 98 (36.4) high school and above 67 (24.9) income in sar <500 76 (28.3) 500–1,000 148 (55) >2,000 45 (16.7) sar = saudi arabian riyal. abdullaziz alabdullgader and unaib rabbani clinical and basic research | e89 results of the 280 elderly patients recruited for inclusion in the study, 274 (97.9%) consented to participate; however, five (1.8%) were excluded due to incomplete information. as such, a total of 269 participants were included in the final analysis (response rate: 96.1%). the participants ranged in age from 60–90 years, with a mean age of 70.3 ± 8.18 years and 68.6 ± 6.8 years for males and females, respectively. the majority (57.6%) were aged 60–70 years, while 13.4% were ≥80 years old. approximately a quarter (24.9%) of the participants had been educated to the high school level or higher, whereas 38.7% were uneducated. a greater number of female participants were uneducated compared to male participants (48.5% versus 28.6%). more than half of the cohort (55%) received a moderate income of 5,000–1,000 saudi arabian riyals [table 1]. in terms of fall-related risk factors, the prevalence of obesity (i.e. a bmi of ≥30 kg/m2) was 30.9%. a total of 22 participants (8.2%) were inactive. only 31.6% regularly performed physical exercise and 8.6% were smokers. most participants had chronic diseases, including htn (20.8%), dm (18.2%) or both htn and dm (38.2%). polypharmacy was prevalent in 58% of the cohort and 11.2% used ambulatory aids. visual table 2: fall-related risk factors among elderly patients attending primary healthcare centres in unaizah city, saudi arabia (n = 269) factor n (%) bmi category normal 70 (26) overweight 116 (43.1) obese 83 (30.9) activity status active 247 (91.8) inactive 22 (8.2) regular physical exercise yes 85 (31.6) no 184 (68.4) smoking status smoker 23 (8.6) non-smoker 246 (91.4) age-related factors* gait impairment 26 (9.7) visual impairment 42 (15.6) memory loss 20 (7.4) incontinence 21 (7.8) chronic pain 32 (11.9) chronic disease* 222 (82.5) htn 159 (59.1) dm 152 (56.5) arthritis 54 (20.1) cva 21 (7.8) polypharmacy yes 156 (58) no 113 (42) environmental factors* poor lighting 26 (9.7) inappropriate footwear 17 (6.3) pets 15 (5.6) uneven floor surfaces 38 (14.1) high door sills 51 (19) bmi = body mass index; htn = hypertension; dm = diabetes mellitus; cva = cerebrovascular accident. *percentages do not add up to 100% as more than one variable may have identified in certain cases. table 3: fall prevalence, location and risk category among elderly patients attending primary healthcare centres in unaizah city, saudi arabia (n = 269) variable n (%) history of falls over the last three months 23 (8.6) over the last year 85 (31.6) location of falls* indoors 72 (84.7) bedroom 12 (16.7) washroom 20 (27.8) stairs 18 (25) kitchen 9 (12.5) front doorstep 11 (15.3) other 2 (2.8) outdoors 13 (15.3) masjid (n = 13) 3 (23.1) street (n = 13) 8 (61.5) other (n = 13) 2 (15.4) fall risk category† at risk 93 (34.6) no risk 176 (65.4) *calculated out of the total number of patients with a history of falls over the preceding year. †based on scores from the validated 10-item missouri alliance for home care fall risk assessment tool.28,29 scores of ≥4 were considered to indicate an increased risk of falling.28 prevalence and risk factors of falls among the elderly in unaizah city, saudi arabia e90 | squ medical journal, february 2021, volume 21, issue 1 impairment, gait problems, memory loss, incontinence and chronic pain were reported in 15.6%, 9.7%, 7.4%, 7.8% and 11.9% of participants, respectively. at least one environmental risk factor was present in 52% of the cohort, with the most frequent hazards being high door sills (19%), uneven floor surfaces (14.1%) and poor lighting (9.7%) [table 2]. the prevalence of falls over the preceding year was 31.6%, with a higher rate of falls among females than males (34.5% versus 28.5%). the three-month prevalence of falls was 8.6%. of the 85 participants who had fallen during the preceding year, 84.7% had fallen indoors, with the most frequent locations being in washrooms (27.8%) and on stairs (25%). outdoor falls occurred among 15.3% of those with a history of falls over the last 12 months, most of which happened on the street (61.5%). a total of 93 participants (34.6%) were categorised as being at high risk of falling based on their mahc-10 fall risk scores [table 3]. of these, 64 (68.8%) had fallen during the preceding year, with a significant association between fall risk score and history of falls (p <0.001). according to the multivariate logistic regression analysis, there was a strong association between advanced age and fall risk; individuals aged ≥80 years were five times more at risk of falling compared to younger participants (aor: 5.17, 95% ci: 1.66–16.14; p = 0.005). polypharmacy (aor: 2.40, 95% ci: 1.01–5.71; p = 0.046), age-related changes (aor: 2.77, 95% ci: 1.14–6.73; p = 0.024) and environmental factors (aor: 2.79, 95% ci: 1.24–6.28; p = 0.013) also significantly increased falling risk, particularly poor lighting, table 4: risk factors associated with falls and fall risk score among elderly patients attending primary healthcare centres in unaizah city, saudi arabia (n = 269) variable unadjusted or (95% ci) p value adjusted or (95% ci) p value age in years 60–69 1 1 70–79 3.5 (1.91–6.42) <0.001 1.61 (0.70–3.69) 0.259 ≥80 8.02 (3.62–17.74) <0.001 5.17 (1.66–16.14) 0.005 education level uneducated 1 1 up to middle school 0.39 (0.21–0.70) 0.002 0.46 (0.20–1.03) 0.060 high school and above 0.16 (0.07–0.37) <0.001 0.26 (0.09–0.77) 0.015 bmi category 9 (12.5) normal 1 1 overweight 1.39 (0.70–2.78) 0.337 1.47 (0.57–3.80) 0.419 obese 2.46 (1.21–4.99) 0.013 2.32 (0.86–6.31) 0.096 polypharmacy no 1 1 yes 5.03 (2.89–8.77) <0.001 2.40 (1.01–5.71) 0.046 age-related changes no 1 1 yes 11.08 (6.07–20.22) <0.001 2.77 (1.14–6.73) 0.024 environmental factors absent 1 1 present 4.72 (2.64–8.44) <0.001 2.79 (1.24–6.28) 0.013 fall risk category* no risk 1 1 at risk 16.28 (8.65–30.66) <0.001 3.07 (1.03–9.10) 0.043 or = odds ratio; ci = confidence interval; bmi = body mass index. *based on scores from the validated 10-item missouri alliance for home care fall risk assessment tool.28,29 scores of ≥4 were considered to indicate risk of falling.28 abdullaziz alabdullgader and unaib rabbani clinical and basic research | e91 uneven floor surfaces and high door sills. in addition, participants categorised as being at risk of falling based on their mahc-10 scores were at three times greater risk than those in the no-risk group (aor: 3.07, 95% ci: 1.03–9.10; p = 0.043). educated participants were at less risk of falling compared to those who were uneducated (aor: 0.26, 95% ci: 0.09–0.77; p = 0.015). other factors such as obesity, inappropriate footwear and having pets were not related to falling risk [table 4]. discussion the current study aimed to assess the prevalence of falls and fall-related risk factors among elderly individuals in a saudi arabian province. the prevalence of falls over the preceding year in this population group was 31.5%, a rate much higher than those reported from the usa and japan (22% and 16.5%, respectively).14,15 similarly, studies from ecuador, ethiopia and the uk have also indicated slightly lower rates of falls among the elderly (30.3%, 28% and 28%, respectively).8,16,18 on the other hand, local research has indicated much higher prevalence rates of falls among the elderly according to two previous studies conducted in riyadh (49.9% and 57.7%).24,25 there are several reasons which could potentially explain these differences in fall prevalence rates across studies. for example, it is possible that the lower prevalence of falls in the current study compared to other studies from saudi arabia may be attributed to differences in lifestyle factors, while the higher burden of falls compared to international studies could be due to the influence of comorbid conditions and polypharmacy, both of which are known to increase the risk of falling.8,24 indeed, the prevalence of comorbidities and polypharmacy was lower in the cohorts from ecuador and the uk, while medication use was higher among participants from one of the studies from riyadh.8,18,24 additionally, differences in environmental conditions may also contribute to diff erences in fall prevalence across different settings.12,13 in the present study, the prevalence of falls was higher among elderly women compared to elderly men (34.5% versus 28.5%); this is in accordance with findings reported by a similar study from the uk which indicated that the overall ratio of male to female fallers was 1:2.7.19 this could be due to fact that there were more uneducated female than uneducated male participants (48.5% versus 28.6%), with educated participants being at significantly less risk of falling compared to those who were uneducated. a study from the uae also found a higher proportion of fall events among illiterate individuals and those with lower education levels.23 in addition, age has consistently been reported to be a risk factor for falling.15,24,25 there was a strong association between advanced age and fall risk in the present study, with those aged 80 years or more being five times more likely to fall compared to younger individuals. this can be attributed to an age-induced decline in physical, sensory and cognitive function, as well as an increase in the number of comorbid conditions. indeed, age-related factors in the current study such as gait, visual impairment, memory loss, incontinence and chronic pain affecting the level of function (e.g. knee pain) were found to increase fall risk by more than two. this is similar to previous local findings. almegbel et al. reported that elderly individuals living in riyadh who had good vision were less likely to experience falls than those with poor vision.24 while all classes of obesity (bmi of ≥30 kg/m2) have been shown to be associated with increased risk of falling, class iii obesity (bmi of ≥40 kg/m2) has been found to result in a lower risk of fall-related injury.18 however, no significant association was observed between fall risk and bmi category in the current study. this may be due to the use of a single category of obesity (bmi ≥30 kg/m2) instead of subclasses to avoid insufficient numbers for the statistical analysis. however, polypharmacy (defined as ≥4 concurrent medications) was prevalent in 58% of the cohort and was found to double the risk of falling. this is similar to findings from a previous study from riyadh, which reported that the lack of medications was significantly related to fewer falls.24 the link between polypharmacy and fall risk could be due to the presence of multiple comorbidities leading to the use of a greater number of medications. alternatively, both comorbidities and multiple medications could result in fall events because of general poor health and drug-drug interactions or drug-related side-effects, respectively. a significant correlation (0.81) was observed in the present study between the number of comorbidities and number of medications (data not shown). such findings have important implications for clinical practice. firstly, healthcare providers must assess all elderly patients' medication history to confirm whether these medications are prescribed or are over-the-counter (otc) to inform patients regarding the appropriate use and possible side effects of otc medications. secondly, healthcare providers should counsel elderly patients taking multiple medications and their family members to take extra care to prevent falls. medication consultation practices have been found to be an effective method of reducing falls among the elderly.30 prevalence and risk factors of falls among the elderly in unaizah city, saudi arabia e92 | squ medical journal, february 2021, volume 21, issue 1 the majority of falls in the current study were found to occur indoors (84.7%), most frequently in the washroom, stairs and bedroom (27.8%, 25% and 16.7%, respectively). a previous study conducted by alshammari et al. in riyadh also reported that most falls occurred at home (72.8%) with the most frequent location being the bathroom (35.7%).25 in turn, the present study found that environmental factors were strongly associated with fall risk, particularly poor lighting, uneven floor surfaces and high door sills; however, inappropriate footwear and the presence of pets were not significantly related. lim and sung revealed that poor night lighting and protruding door sills were predictors of accidental falls among older women in south korea, along with physical inactivity.31 finally, mahc-10 fall risk score was significantly linked with an increased risk of falling in the current study. a previous saudi arabian study also showed a significant association between documented history of falls and mahc-10 fall risk score.25 certain limitations should be considered when interpreting the results of the present study. first, due to the cross-sectional study design, temporal relationships could not be established. second, the study targeted patients attending a random selection of phcs in unaizah city who may have had chronic diseases and other illnesses; thus, the findings may not be representative of the general population. third, because of time and resource constraints, the questionnaire could not be pilot-tested to ensure its reliability; however, the translated version was reviewed for face validity. an internationally validated tool was used to assess fall risk factors.28,29 fourth, the true prevalence of falls may have been underreported by the participants, especially as memory impairment is a common concern among elderly people.32,33 finally, the necessary sample size for the study was powered for prevalence alone; as such, the sample size may not have been adequate for determining associations with fall risk. conclusion this study found a high prevalence of falls among elderly patients attending phcs in unaizah city. most of the falls occurred indoors, thereby highlighting the need for improvements in home design and safety. in addition, various factors were found to be significantly associated with risk of falling including advanced age, polypharmacy, age-related changes and environmental factors. healthcare providers should screen elderly patients for these risk factors and provide targeted advice and care to prevent falls. additional research conducted on a larger scale is recommended to further evaluate fall-related risk factors and fall prevention strategies among elderly individuals residing in saudi arabia. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. world health organization. who global report on falls prevention in older age. from: www.who.int/ageing/public ations/falls_prevention7march.pdf accessed: jul 2020. 2. rubenstein lz. falls in older people: epidemiology, risk factors and strategies for prevention. age ageing 2006; 35:ii37–41. https://doi.org/10.1093/ageing/afl084. 3. oliver d. development of services for older patients with falls and fractures in england: successes, failures, lessons and controversies. arch gerontol geriatr 2009; 49:s7–12. https:// doi.org/10.1016/s0167-4943(09)70005-6. 4. sekaran nk, choi h, hayward ra, langa km. fall-associated difficulty with activities of daily living in functionally independent individuals aged 65 to 69 in the united states: a cohort study. j am geriatr soc 2013; 61:96–100. https://doi.org/10.1111/ jgs.12071. 5. stel vs, smit jh, pluijm sm, lips p. consequences of falling in older men and women and risk factors for health service use and functional decline. age ageing 2004; 33:58–65. https://doi. org/10.1093/ageing/afh028. 6. gorman m. development and the rights of older people. in: randel j, german t, eds. the ageing and development report: poverty, independence and the world's older people. 1st ed. routledge, 1999. pp. 3–21. https://doi.org/10.4324/978131 5071541. 7. united nations population fund. ageing in the twenty-first century: a celebration and a challenge. from: www.unfpa.org/ public/home/publications/pid/11584 accessed: jul 2020. 8. orces ch. prevalence and determinants of falls among older adults in ecuador: an analysis of the sabe i survey. curr gerontol geriatr res 2013; 2013: 495468. https://doi. org/10.1155/2013/495468. 9. himes cl, reynolds sl. effect of obesity on falls, injury, and disability. j am geriatr soc 2012; 60:124–9. https://doi. org/10.1111/j.1532-5415.2011.03767.x. 10. maurer ms, burcham j, cheng h. diabetes mellitus is associated with an increased risk of falls in elderly residents of a long-term care facility. j gerontol a biol sci med sci 2005; 60:1157–62. https://doi.org/10.1093/gerona/60.9.1157. 11. vestergaard p, rejnmark l, mosekilde l. hypertension is a risk factor for fractures. calcif tissue int 2009; 84:103–11. https:// doi.org/10.1007/s00223-008-9198-2. 12. ambrose af, paul g, hausdorff jm. risk factors for falls among older adults: a review of the literature. maturitas 2013; 75:51–61. https://doi.org/10.1016/j.maturitas.2013.02.009. 13. deandrea s, lucenteforte e, bravi f, foschi r, la vecchia c, negri e. risk factors for falls in community-dwelling older people: a systematic review and meta-analysis. epidemiology 2010; 21:658–68. https://doi.org/10.1097/ede.0b013e3181e89905. https://doi.org/10.1093/ageing/afl084 https://doi.org/10.1016/s0167-4943%2809%2970005-6 https://doi.org/10.1016/s0167-4943%2809%2970005-6 https://doi.org/10.1111/jgs.12071 https://doi.org/10.1111/jgs.12071 https://doi.org/10.1093/ageing/afh028 https://doi.org/10.1093/ageing/afh028 https://doi.org/10.4324/9781315071541 https://doi.org/10.4324/9781315071541 https://doi.org/10.1155/2013/495468 https://doi.org/10.1155/2013/495468 https://doi.org/10.1111/j.1532-5415.2011.03767.x https://doi.org/10.1111/j.1532-5415.2011.03767.x https://doi.org/10.1093/gerona/60.9.1157 https://doi.org/10.1007/s00223-008-9198-2 https://doi.org/10.1007/s00223-008-9198-2 https://doi.org/10.1016/j.maturitas.2013.02.009 https://doi.org/10.1097/ede.0b013e3181e89905 abdullaziz alabdullgader and unaib rabbani clinical and basic research | e93 14. stevens ja, ballesteros mf, mack ka, rudd ra, decaro e, adler g. gender differences in seeking care for falls in the aged medicare population. am j prev med 2012; 43:59–62. https:// doi.org/10.1016/j.amepre.2012.03.008. 15. niino n, tsuzuku s, ando f, shimokata h. frequencies and circumstances of falls in the national institute for longevity sciences, longitudinal study of aging (nils-lsa). j epidemiol 2000; 10:s90–4. https://doi.org/10.2188/jea.10.1sup_90. 16. janakiraman b, temesgen mh, jember g, gelaw ay, gebremeskel bf, ravichandran h, et al. falls among community-dwelling older adults in ethiopia: a preliminary cross-sectional study. plos one 2019; 14:e0221875. https://doi.org/10.1371/journal. pone.0221875. 17. joseph a, kumar d, bagavandas m. a review of epidemiology of fall among elderly in india. indian j community med 2019; 44:166–8. https://doi.org/10.4103/ijcm.ijcm_201_18. 18. gale cr, cooper c, sayer aa. prevalence and risk factors for falls in older men and women: the english longitudinal study of ageing. age ageing 2016; 45:789–94. https://doi.org/10.1093/ ageing/afw129. 19. blake aj, morgan k, bendall mj, dallosso h, ebrahim sb, arie th, et al. falls by elderly people at home: prevalence and associated factors. age ageing 1988; 17:365–72. https://doi. org/10.1093/ageing/17.6.365. 20. pirrie m, saini g, angeles r, marzanek f, parascandalo j, agarwal g. risk of falls and fear of falling in older adults residing in public housing in ontario, canada: findings from a multisite observational study. bmc geriatr 2020; 20:11. https:// doi.org/10.1186/s12877-019-1399-1. 21. tomita y, arima k, tsujimoto r, kawashiri sy, nishimura t, mizukami s, et al. prevalence of fear of falling and associated factors among japanese community-dwelling older adults. medicine (baltimore) 2018; 97:e9721. https://doi.org/10.1097/ md.0000000000009721. 22. cesari m, landi f, torre s, onder g, lattanzio f, bernabei r. prevalence and risk factors for falls in an older communitydwelling population. j gerontol a biol sci med sci 2002; 57:m722–6. https://doi.org/10.1093/gerona/57.11.m722. 23. sharif si, al-harbi ab, al-shihabi am, al-daour ds, sharif rs. falls in the elderly: assessment of prevalence and risk factors. pharm pract (granada) 2018; 16:1206. https://doi. org/10.18549/pharmpract.2018.03.1206. 24. almegbel fy, alotaibi im, alhusain fa, masuadi em, al sulami sl, aloushan af, et al. period prevalence, risk factors and consequent injuries of falling among the saudi elderly living in riyadh, saudi arabia: a cross-sectional study. bmj open 2018; 8:e019063. https://doi.org/10.1136/bmjopen-2017-019063. 25. alshammari sa, alhassan am, aldawsari ma, bazuhair fo, alotaibi fk, aldakhil aa, et al. falls among elderly and its relation with their health problems and surrounding environ mental factors in riyadh. j fam community med 2018; 25:29–34. https://doi.org/10.4103/jfcm.jfcm_48_17. 26. hajjar rr, atli t, al-mandhari z, oudrhiri m, balducci l, silbermann m. prevalence of aging population in the middle east and its implications on cancer incidence and care. ann oncol 2013; 24:vii11–24. https://doi.org/10.1093/annonc/mdt268. 27. saudi arabia general authority for statistics. sixteenth services guide 2017: qassim region. from: www.stats.gov.sa/ sites/default/files/al-qaseem_region_ar.pdf accessed: jul 2020. 28. missouri alliance for home care. mahc 10: fall risk assessment tool. from: www.homecaremissouri.org/projects/falls/docume nt s/o ct2012fin alvalidate dfallr iska ssessmentto ol.p df accessed: jul 2020. 29. calys m, gagnon k, jernigan s. a validation study of the missouri alliance for home care fall risk assessment tool. home health care manag pract 2013; 25:39–44. https://doi. org/10.1177/1084822312457942. 30. blalock sj, casteel c, roth mt, ferreri s, demby kb, shankar v. impact of enhanced pharmacologic care on the prevention of falls: a randomised controlled trial. am j geriatr pharmacother 2010; 8:428–40. https://doi.org/10.1016/j.amjop harm.2010.09.002. 31. lim ym, sung mh. home environmental and health-related factors among home fallers and recurrent fallers in community dwelling older korean women. int j nurs pract 2012; 18:481–8. https://doi.org/10.1111/j.1440-172x.2012.02060.x. 32. barker a, jones r, jennison c. a prevalence study of ageassociated memory impairment. br j psychiatry 1995; 167:642–8. https://doi.org/10.1192/bjp.167.5.642. 33. larrabee gj, crook th 3rd. estimated prevalence of ageassociated memory impairment derived from standardised tests of memory function. int psychogeriatr 1994; 6:95–104. https://doi.org/10.1017/s1041610294001663. https://doi.org/10.1016/j.amepre.2012.03.008 https://doi.org/10.1016/j.amepre.2012.03.008 https://doi.org/10.2188/jea.10.1sup_90 https://doi.org/10.1371/journal.pone.0221875 https://doi.org/10.1371/journal.pone.0221875 https://doi.org/10.4103/ijcm.ijcm_201_18 https://doi.org/10.1093/ageing/afw129 https://doi.org/10.1093/ageing/afw129 https://doi.org/10.1093/ageing/17.6.365 https://doi.org/10.1093/ageing/17.6.365 https://doi.org/10.1186/s12877-019-1399-1 https://doi.org/10.1186/s12877-019-1399-1 https://doi.org/10.1097/md.0000000000009721 https://doi.org/10.1097/md.0000000000009721 https://doi.org/10.1093/gerona/57.11.m722 https://doi.org/10.18549/pharmpract.2018.03.1206 https://doi.org/10.18549/pharmpract.2018.03.1206 https://doi.org/10.1136/bmjopen-2017-019063 https://doi.org/10.4103/jfcm.jfcm_48_17 https://doi.org/10.1093/annonc/mdt268 https://doi.org/10.1177/1084822312457942 https://doi.org/10.1177/1084822312457942 https://doi.org/10.1016/j.amjopharm.2010.09.002 https://doi.org/10.1016/j.amjopharm.2010.09.002 https://doi.org/10.1111/j.1440-172x.2012.02060.x https://doi.org/10.1192/bjp.167.5.642 https://doi.org/10.1017/s1041610294001663 identification of remarkable dimensions in management and evaluation of non-communicable disease programmes a systematic review and meta-synthesis leila vali,1 *fatemeh ataollahi,2 mohammadreza amiresmaili,3 nouzar nakhaee4 sultan qaboos university med j, august 2021, vol. 21, iss. 3, pp. 365–372, epub. 29 aug 21 submitted 10 jun 20 revisions req. 11 aug & 6 oct 20; revisions recd. 5 sep & 28 oct 20 accepted 17 nov 20 1environmental health engineering research center, 2faculty of management and medical informatics, 3department of health economics and management, 4kerman neuroscience research center, kerman university of medical sciences, kerman, iran *corresponding author’s e-mail: ataollahi.f@gmail.com in recent decades, one of the leading global challenges in the health system has been non-communicable diseases (ncds).1 this results in poor health, economic loss, life loss, diminished quality of life and poor social development.2 ncds are expected to account for over 70% of all deaths globally based on the prediction of the world health organization (who).3 it is estimated that 41 million people in countries with low-resource potential will die from ncds mainly due to cardiovascular diseases (cvds; 48%), cancers (21%), chronic respiratory diseases (12%) and diabetes (3%).3 the who has predicted that appropriate inter ventions will prevent the spread of ncds.4 coping strategies for ncds include interventions to reduce risks to the general public. these interventions change health behaviours by providing interactions among health care providers and recipients of these services through legislation, financial and tax incentives and public health promotion.5 in this regard, organisations are responsible for managing and controlling ncds. despite these undertakings in the field of ncds, the incidence and prevalence of these diseases have not yet decreased significantly.6 a systematic approach to prioritising, decisionmaking and managing and improving interventions and community-based strategies is necessary to develop a programme for managing ncds considering the limited resources available in developing countries.7 managerial bodies in the field of ncds have to adopt a participatory approach relying on sound scientific evidence to merge information and set long-term plans.8 developing a proper plan depends on setting goals and priorities and the way they are shaped to draw up a clear vision of the future. to this end, development plans are based on such factors as awareness of the external environment, the parent organisation and the necessary mechanisms.9 one of the important tasks within the process of programme development is determining the success rate of the programme goal achievement. furthermore, to influence activities and actions, developing the programme requires continuous monitoring and evaluation and optimising the movement within the designated framework.10 dimensions of programme management and evaluation include raising community awareness, improving indicators, performing special interventions to reduce risk factors for ncds, conducting applied research, improving cooperation and participation and establishing a system to track and evaluate progress in the field of control and prevention of ncds.11 evaluation helps to compare actual situations with expected outcomes of managers and policymakers towards goals and objectives.12 different assessment patterns can be applied in the health system, including time-cost models (such as halflife chart – score model), models of organisational excellence and self-evaluation (such as deming model, quality audit model, malcolm baldridge quality model and organisation excellence model) and integrated models (such as smart system, performance charter model, modelling model, goal-based management review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.011 abstract: objectives: this study aimed to identify indicators of proper programme development in the field of non-communicable diseases through the systematic review of existing literature. methods: in this systematic review, a search was conducted through pubmed, scopus, embase, web of science, google scholar, cochrane library, proquest and grey literature. the search was limited to literature published between january 2000 and january 2019. results: a total of 36 articles were found relevant to the study objectives. data were obtained through these articles based on the context, input, process and product (cipp) model. seven subsets for context, five subsets for input, four subsets for process and six subsets for the product were identified. conclusion: according to cipp subsets, indicators such as programme definition, appropriate organisational culture, structure and evaluation must be considered to develop an appropriate programme to improve health services. keywords: disease management; program evaluation; health status indicators; program development. https://creativecommons.org/licenses/by-nd/4.0/ identification of remarkable dimensions in management and evaluation of non-communicable disease programmes a systematic review and meta-synthesis 366 | squ medical journal, august 2021, volume 21, issue 3 model, hoshin management system model, balanced scorecard and donabedian framework).13 the context, input, process and product (cipp) model is a comprehensive, functional model that considers all aspects of the programme or system.14 this evaluation model is one of the most recommended frameworks for the conception, design, implementation and assessment to improve decisions emphasising constructive eval uation during the evolutionary steps of a programme.11 the four components of this model include context, input, process and product. the model contributes to the programme evaluators by collecting regular information during development and implementation.15 despite the prevalence of ncds and the problems caused by the chronic, progressive and debilitating nature of the diseases and various responses from the health system to focus on prevention with ncd priority, programmes in this field have not been very successful in their implementation.6 to develop a suitable programme, aspects such as accessibility, quality, efficiency and equity, that lead to the promotion of health services and a healthier community, were considered. therefore, this study aimed to identify significant dimensions of developing programmes for the management and evaluation of ncds through a systematic review of existing literature. methods the present study is a systematic review of existing literature that aimed to identify dimensions of management and evaluation of ncds. two questions were chosen for the study: 1) what remarkable dimensions should be considered for the management of programmes for ncds?; 2) what dimensions should be considered for the evaluation of programmes for ncds? to identify relevant studies, selected keywords were searched in pubmed, scopus, embase, web of science, google scholar, cochrane library and proquest. grey literature, searched through cochrane library and proquest, pertained to the period from january 2000 to january 2019. after eliminating articles that met the exclusion criteria, to increase the sensitivity and to identify all relevant studies, the references were checked, which finally led to the inclusion of three more articles. keywords used to search the relevant literature included ‘evaluation or assessment or appraisal or measurement or audit or accreditation’, ‘developing programme’, ‘noncommunicable disease or health system’, ‘framework or model or scheme or pattern or mechanism or system’, ‘non-communicable disease or diabetes or respiratory disease or heart disease or cancer disease’ and ‘management model or management pattern or management framework or management theory of diseases or disease management policy’. the following inclusion criteria were used to select relevant studies: (1) articles published between january 2000 and january 2019 in english; (2) studies that focused on the management and development of programmes in the ncd field; (3) studies related to the evaluation of the health and national plans for the evaluation and management of ncds; and (4) studies that employed evaluating models for the health services. the following exclusion criteria were used to eliminate studies: (1) studies published in other languages; (2) studies in the area of programme implementation; (3) performance evaluation studies unrelated to the research question; and (4) studies that were published before 2000. the selected keywords were fed into the database search boxes and, in some databases, the search was limited to abstracts and titles. search results of keywords were checked by a team member for the inclusion criteria; in cases of uncertainty, decisions were made based on consensus. after identifying unrelated articles and eliminating duplicated ones, the titles of the selected articles were imported into an excel spreadsheet. the abstracts that met the inclusion criteria and were closely related to the aims of the present study were reviewed and unrelated ones were excluded. closely related articles were included in the final step of analysis after obtaining a minimum quality score based on the ‘strengthening the reporting of observational studies in epidemiology’ (strobe) statement. finally, the full text of selected articles was downloaded; in case an article was not for free access, it was purchased by the kerman university of medical sciences central library. qualitative evaluation, selection of related articles and data collection were performed by two researchers separately (fa and lv). selected articles were quali tatively evaluated by researchers using the strobe checklist.16 any disagreement between the two evaluators was referred to a third researcher (ma). the checklist consists of 22 different sections, following which various aspects of methodology were evaluated including sampling methods, measuring variables, statistical analysis, modifiers of confounders, validity and reliability issues of the tools used and study objectives. since not all articles exactly adhered to the strobe checklist, scores were calculated as a percentage and the acceptance threshold was considered to be a minimum score of 65%. accordingly, studies that acquired the minimum score (65%) from the checklist questions were included and the related data extracted to perform the meta-synthesis. leila vali, fatemeh ataollahi, mohammadreza amiresmaili and nouzar nakhaee review | 367 for each study, data pertaining to the article title, first author, year of publication, place of the study and the prerequisites for programme development were extracted and manually entered into the excel spreadsheet. meta-synthesis was performed by collecting data from articles based on the dimensions of the cipp model. this study is a part of a phd thesis in healthcare management at kerman university of medical sciences that has not yet been completed. it was approved by the research ethics committee of kerman university of medical sciences (code: ir.kmu.rec.1399.272). results a total of 6,633 articles were extracted during the initial search of electronic resources. of these, 1,835 duplicated articles were removed, 4,798 relatively related articles retained and 3,035 studies excluded after evaluating the titles and abstracts; 1,763 potentially related studies remained and 706 articles were excluded after the restricting search. this restriction was done by setting a time limit, restricting keywords and searching only titles and abstracts. subsequently, 1,057 studies were selected for text retrieval, following which 1,003 were removed; 54 studies were selected for the evaluation of the inclusion and exclusion criteria, following which 18 articles were set aside. finally, 36 studies were selected for the analysis process [figure 1]. based on the above-described process, 36 articles were reviewed. of these, five were national programmes. a total of 113 authors’ participation was recorded. five articles were from the united states, four from south africa, three from iran and three from bangladesh, published across 29 journals. the first paper was published in 2005 and the latest one in 2018; while the highest frequency of publication was in 2017 and 2018 with six articles each year. meta-synthesis was performed according to the cipp model. first, the content of the articles and documents was analysed and all components related to management and evaluation of ncd programmes were placed based on the relationships among the four dimensions: context, input, process and product. finally, seven sub-categories in the context dimension, five sub-categories in the input dimension, four subcategories in the process dimension and six subcategories in the product dimension were identified. meta-synthesis was conducted based on the cipp model, relying on which programme development precondition was extracted. according to the above model, prerequisites for programme development comprise four dimensions: input, context, product and process [table 1]. subcategories and preconditions were taken into account for these four dimensions. it is noteworthy that dimensions, subcategories and prerequisites are related to the definitions of the cipp model. in the context dimension, the relevant elements were placed as an attempt to identify problems, needs and opportunities in the field.17 input was evaluated to specify and assess the existing capabilities, possible programme strategies for goal achievement, intended methods for implementing strategies, organisations and other resources, including budget and time.18 process evaluation is done to identify or predict executive problems in the field of ncds and the desirability of the process of implementing these activities.18 in the output evaluation, the results were figure 1: flow diagram of study selection. identification of remarkable dimensions in management and evaluation of non-communicable disease programmes a systematic review and meta-synthesis 368 | squ medical journal, august 2021, volume 21, issue 3 table 1: context, input, process and product dimensions necessary for plan developing dimension subset subcategory prerequisites context objective stages of development considering the process of forming a team, identifying dimensions of the programme, drafting, feedback to members and developing final goals clarity considering realistic, clear trends in goal development feasibility of implementation feasibility of implementation via considering adequate resources coverage achieving health system goals, improving community health, reducing health inequality, identifying budgets and creating accountable systems international databases and targets, surveillance organisation, non-communicable disease control and prevention centres programme development partnerships, clear policies, specific strategies and activities, stakeholders, outcomes, evaluation criterion and resource coverage developing intervention programmes developing an operational plan and roadmap developing programmes at national and international levels nature covering long-term, short-term and mid-term standards in the fields of home, school and workplace health mission developing policies and documents aimed at capacity building, accessibility enhancement, cost reduction, careful monitoring and evaluation, multi-dimensionality, political commitment and prioritisation. guidelines developing guidelines in the areas of managerial, economic, social, legal and goal-based protocols technology information technology and tools application of multilateral information and communication technology, management and decision support system, metadata technology and data integration and media usable technology technology in the field of people and culture and community national and international collaborative innovative approaches culture motivation attention to organisational incentives and creating a reward system to encourage initiatives and increase stakeholder confidence culture investigating beliefs, ethnography and identifying the impact of cultural factors on risk factors organisation accessibility access to diagnostic, treatment and essential medicines geographical access access to the right budget prioritisation participatory prioritisation considering environmental, social and cultural, legal and political contexts prioritisation through motivating, successful processes, stakeholder engagement and coordination prioritisation through infrastructure identification and priority mechanisms (process, tool, method), use of evidence and public values input executive strategies developing international and national clinical guidelines to reduce disability, mortality, disease burden and appropriate design of intervention packages developing comprehensive interdisciplinary guidelines to implement effective, integrated, sustainable and evidence-based policies, human resources mobilisation, research, monitoring and managing complex cases developing comprehensive interdisciplinary guidelines to implement effective, integrated, sustainable and evidence-based policies, human resources mobilisation, research, monitoring and managing complex cases developing strategies to improve municipal performance (commitment to create public services for recreational spaces and parks), transportation, education (promoting healthy programmes in healthy school food distribution), tax and food industry (use of native agricultural products and natural foods) developing global marketing strategies, trade liberalisation, foreign investment and legal strategies to reduce demand (through price, tax) resources human resource mobilisation and investment coordination to strengthen the human resources system upgrading the capacity of specialist staff such as managers, physicians, nurses, health care staff and volunteers equipment proper investment in equipment financial economic and financial tools to fund equity in sectors structure physical health service provider centres, provincial regional hospitals, educational consulting centres, diagnostic and pharmaceutical centres programmatic redesigning the system with the aim of socialising and collaborating, accessing services, supporting clinical information, self-management, managing and supporting technology and equipment and creating an organisational structure consisting of different stakeholders promoting capacity building in prevention and control in governmental and non-governmental service organisations teaching increasing awareness through the authority delegated to local organisations to increase education and information for stakeholders and patients national and international training programmes for professionals, students, policymakers and clients and building up of a comprehensive participatory approach to developmental aid in education and knowledge, beliefs, attitudes and skills for individuals learning developing scientific and evidence-based knowledge with the help of specialised public and private institutions to create a favourable environment for empowerment leila vali, fatemeh ataollahi, mohammadreza amiresmaili and nouzar nakhaee review | 369 measured against the goals of the programme and the relationship between expectations and actual results. in this study, the findings were categorised based on the definitions of the four dimensions. the context dimension showed the subsets of the context for programme development. they include the objective (stages of development, clarity, feasibility of implementation and coverage), programme (development, coverage and nature), mission, guidelines, technology, culture and organisation. the input dimension includes executive strategies, resources (human, equipment and financial), structure (physical and programmatic), teaching and learning. the process dimension includes responsibilities, communications, management and leadership. the product dimension includes the benefits of change table 1 (cont’d): context, input, process and product dimensions necessary for plan developing dimension subset subcategory prerequisites process responsib ilities responsibility at the global, regional and national level for quality of service, patient safety and service effectiveness proper accountability for noncommunicable diseases through collaboration commitment communi cations individuals and stakeholders shared responsibility and proper communication among the stakeholders to develop the plan (stakeholders include community members, health professionals and non-health organizations, health and non-health associations, municipalities, the private sector, religious leaders, nongovernmental and local leaders and the education and training sector) levels of service provision control mechanisms through communication at the service level cross-sectoral communication communication at different levels of society, family and individuals, agriculture, environment, industry (coordination of administrative and non-administrative structure of tobacco laws, alcohol), education, economy, nutrition, media, urban planning, ministry of information (for information), collaboration between various departments of the ministry of health, religious organisations, trade unions, the insurance industry (private and public), universities, policymakers and community leaders professional involvement of the national and international community in development, including engagement of community, health professionals, volunteers, advisory committees and health professionals management strong leadership aimed at creating comprehensive policies (national and international) and monitoring activities clear governance and leadership in every part of the programme managing and leading services such as screening, diagnosis, treatment, follow-up, case management, referral, counselling, motivating, lifestyle changes, standard treatment protocol, team-based care, access to core data sets, supervision, patient empowerment, social participation and policy interventions management in programme development to identify potential benefits, global coverage, multilateral actions, definition of multi-sectoral relationships (involvement of all aspects of private / public / industry / civil society / university), reduction of risk factors, coordination and cooperation leadership level of service coverage, prevention in society, the time between diagnosis and treatment, survival rate and quality of life product benefits of change in the organisation use of scientific evidence and dissemination of information, goals, attention to multidisciplinary and stakeholder environments, fairness of integrated actions and essential interventions appropriate interventions and accountability, promoting services based on available resources and infrastructure, resuscitation and reorganisation of health services, early diagnosis and integrated care, documentation and monitoring of activities, multi-sectoral participatory interventions, support and sensitisation of policy planners and programme managers and providers health promotion development of operational plans, implementation strategies and roadmaps promotion of fiscal policy through tax, subsidies and system to encourage healthy nutrition increasing the role of the government as a supervisor of efficient and integrated prevention and control policies, allocating multilateral resources and plans and monitoring framework for plans and guidelines resource use effectiveness assessment cost effectiveness of resources, national health reporting system (annually, monthly and periodically) evaluation of programme results and programme performance based on international strategies systematic evaluation and monitoring through review of the number of patients admitted, follow-up, treatment (improved, died, stopped treatment, stopped follow-up) and transfer to other health care centres documentation and policy evaluation process people assessment feedback of evaluation results to contacts assessment of trends and outcomes of interventions at the individual, social and environmental level work progress assessment evaluation and monitoring of the priorities identified and work progress, integrated disease management and making the best decision evaluation of facilities for diagnosis and treatment assessment of cultural issues in prevention and control in society evaluation and implementation of community-based activities and community initiatives evaluating the impact of programmes on reducing disease risk factors information system evaluation monitoring through ncd information and data strengthen monitoring and evaluation in the area of education, research and regional strategies identification of remarkable dimensions in management and evaluation of non-communicable disease programmes a systematic review and meta-synthesis 370 | squ medical journal, august 2021, volume 21, issue 3 in the organisation, health promotion, resource use effectiveness assessment, people assessment, work progress assessment and information system evaluation. discussion this study attempted to identify crucial and effective components for management and evaluation of the programmes in the field of ncds and the creation of a responsive system. the findings were synthesised based on the cipp model. in the context dimension, factors such as the objective, development and coverage programme, mission, guidelines, technology, culture and organisation were studied. in this dimension, one of the prerequisites was to consider the process of developing programme objectives appropriately as well as checking clarity, feasibility of implementation and coverage. peykari et al. stated that clear and appropriate goals should be considered in developing national plans. referring to a national programme for the management and control of risk factors, they suggest that developing an operational plan and roadmap, as well as providing accountability through political commitment, is one of the success factors.1 the category of technology can be considered to be an appropriate mode in the development of the programme. in this regard, sankaranarayanan et al. have indicated that most technological responses to address personnel shortages and problems of access to health services focus on ncd programmes. for example, they demonstrated the effectiveness of using cellphone applications to check patients’ compliance with medication regimens for managing diabetes and asthma.19 in the input section, some dimensions including executive strategies, resources, structure, teaching and learning have been presented. in developing ncd programmes, one of the aspects to be considered is the resource (e.g. human, equipment and financial). nishtar suggests that a focus on human resources for health (hrh) in the context of ncd control could have been a lever for health system change after 2015, which led to the measures designed to improve health systems more broadly.20 hrh is also an important lever in the post-2015 efforts for the attainment of universal health coverage (uhc). of all the health system resources, the most strategic ones are human, physical, technological and financial. human resources can implement changes in the health system on a collective or individual basis.20 in programme development, providing an appropriate physical and programmatic structure is required, such as municipal commitment to creating public services, providing services centres and creating an organisational structure. in this regard, the planning commission of india (2003) states that, to achieve maximum impact on ncds, programmes that are both horizontal (such as concerning public health and social welfare) and vertical (strategies focusing on populations such as controlling risk factors) should be integrated.21 the process dimension includes responsibilities, communications, management and leadership. one of the prerequisites for programme development is that communications and multi-sectoral collaborations are taken into account. the political statement of the united nations (2012) stated that since ncds resulted in higher costs and lower productivity for families, individuals and societies, coordination and multi-sector communications are essential to resolve the problems through promoting tools to identify and mobilise sufficient funds.2 moreover, the australian national preventive health agency (2010) stated that cooperation in health matters was important and one should draw a distinction between processes designed for cross-sectional coordination and the official means of increasing involvement of different sectors.22 the management of programme development includes detecting, screening and treating the diseases and providing access to palliative care for people in need. sarink et al. concluded that coronary artery disease (cad) could be controlled by engaging the public in policy-making, organising, coordinating and financing.23 public involvement can be evaluated in making policies by rules and regulation. hence, a management framework comprising legislation, regulations and screening, as well as public education, seems necessary for preventing and controlling cardiovascular diseases.23 the product dimension includes the benefits of change in the organisation, health promotion, resource use effectiveness assessment and assessment of people, work progress and information systems. monitoring through the information system and data on ncds was found important in programme development. the strategic plan of bangladesh (2007–2010) claimed that it would emphasise ncd surveillance mechanism through the national health information system which generates data and publish them in database form which provides access to information for policymakers, public health managers and researchers globally.24 one of the prerequisites in the product dimension is the issue of health promotion which can be met through appropriate interventions and accountability, promoting available resources and infrastructure, integrated care, documentation and monitoring of activities and multi-sectoral support of policymakers, programme managers and providers. in a study by diem et al., the role of capacity building leila vali, fatemeh ataollahi, mohammadreza amiresmaili and nouzar nakhaee review | 371 was established through a comprehensive approach to public health interventions such as creating processes of improvement, knowledge production, increasing need evaluation, examining the characteristics of the target population and identifying the resources and required procedures.25 mondal et al. stated that, through appropriate approaches towards interdisciplinary leadership, the shift from treatment to prevention, guideline development on interdisciplinary communication education, community access and investment within the world framework have adopted a healthier approach to accountability.26 it is worth noting that in programme development, it is crucial to have common responsibility and proper communication among the stakeholders including community members, health professionals and nonhealth organisations, municipalities, the private sector, religious leaders, nongovernmental and local leaders and the ministry of education. today, global health due to the prevalence and incidence of ncds is in a state of crisis and the health system is trying to respond to this crisis.2 proper planning and management are essential at all levels (primary, secondary and tertiary) in all types of organisations (public, private and non-profit). therefore, to develop, implement and evaluate the appropriate programme, a framework and a collective approach should be considered in a comprehensive view of all effective factors to promote community health. this study systematically considered the components of appropriate programme development. although existing literature has already considered the dimensions of developing a programme in detail, a comprehensive review did not exist. therefore, this study improves the current knowledge of this field by collecting and categorising all necessary dimensions for developing a programme. in this article, data were collected based on the cipp model. it is acknowledged that other models are available for this purpose; using any other model may change the results. moreover, limited access to the full text of some articles and documents could be the reason that some studies have not been reviewed. the fact that less robust evidence was reviewed for developed national and strategic programmes could be regarded as another limitation of the present study. however, this study offered an opportunity to study substantial plans and valuable insights. conclusion certain dimensions are essential for programme development, including engaging all key stakeholders, providing required resources and addressing cultural issues. furthermore, a proper development of prog rammes should take into account such issues as developing, implementing and evaluating programmes and all components such as context, input, process and product factors. this study thereby provides valuable information for policy-makers and planners to develop appropriate programmes in a sound and cost-effective manner. a u t h o r s’ c o n t r i b u t i o n lv and fa conceptualized the idea, while lv, fa and ma designed the study. lv, fa and nn collected the data. lv, fa and ma provided analysis and interpretation of the data. lv and fa provided the first draft of manuscript. lv, fa and ma revised the manuscript. all authors approved the final version of this manuscript. references 1. peykari n, hashemi h, dinarvand r, haji-aghajani m, malekzadeh r, sadrolsadat a, et al. national action plan for non-communicable diseases prevention and control in iran: a response to emerging epidemic. j diabetes metab disord 2017; 16:3. https://doi. org/10.1186/s40200-017-0288-4. 2. political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases. new york: united nations; 2011 (66/2; http://www.who. int/nmh/events/un_ncd_summit2011/en/ accessed: oct 2020. 3. world health organization. noncommunicable diseases (ncd). from: https://www.who.int/gho/ncd/mortality_morbidity/en/ accessed: oct 2020. 4. ruby a, knight a, perel p, blanchet k, roberts b. the effect iveness of interventions for non-communicable diseases in human itarian crises: a systematic review. plos one 2015; 10:e0138303. 5. mannava p, abdullah a, james c, dodd r, annear pl. health systems and noncommunicable diseases in the asia-pacific region: a review of the published literature. asia pac j public health 2015; 27:np1–np19. https://doi.org/10.1177/1010539513500336. 6. organization who. global status report on noncommunicable diseases 2014: world health organization; 2014. 7. mendis s, davis s, norrving b. organizational update: the world health organization global status report on noncommunicable diseases 2014; one more landmark step in the combat against stroke and vascular disease. stroke 2015; 46:e121–2. https:// doi.org/10.1161/strokeaha.115.008097. 8. geneau r, stuckler d, stachenko s, mckee m, ebrahim s, basu s, et al. raising the priority of preventing chronic diseases: a political process. lancet 2010; 376:1689–98. https://doi.org/10.1016/ s0140-6736(10)61414-6. 9. doulabi rz, asnaashari e. identifying success factors of healthcare facility construction projects in iran. procedia eng 2016; 164:409–15. https://doi.org/10.1016/j.proeng.2016.11.638. 10. woodward m. epidemiology: study design and data analysis. boca raton: chapman and hall/crc, 2013. 11. world health organization. prevention and control of noncommunicable diseases: implementation of the global strategy. from: www.apps.who.int/gb/ebwha/pdf_files/eb126/ b126_12-en.pdf/ accessed: oct 2020. https://doi.org/10.1186/s40200-017-0288-4 https://doi.org/10.1186/s40200-017-0288-4 https://doi.org/10.1177/1010539513500336 https://doi.org/10.1161/strokeaha.115.00809 https://doi.org/10.1161/strokeaha.115.00809 https://doi.org/10.1016/s0140-6736(10)61414-6 https://doi.org/10.1016/s0140-6736(10)61414-6 https://doi.org/10.1016/j.proeng.2016.11.638 identification of remarkable dimensions in management and evaluation of non-communicable disease programmes a systematic review and meta-synthesis 372 | squ medical journal, august 2021, volume 21, issue 3 12. valmohammadi c, ahmadi m. the impact of knowledge manage ment practices on organizational performance: a balanced scorecard approach. j enterp inf manag 2015; 28:131–59. https://doi.org/10.1108/jeim-09-2013-0066. 13. anh vtk. evaluation models in educational programme: strengths and weaknesses. vnu j foreign stud 2018; 34. https://doi.org/10.25073/2525-2445/vnufs.4252. 14. stufflebeam dl, madaus gf, kellaghan t. evaluation models: viewpoints on educational and human services evaluation. springer science & business media, 2006. 15. zhang g, zeller n, griffith r, metcalf d, williams j, shea c, et al. using the context, input, process, and product evaluation model (cipp) as a comprehensive framework to guide the planning, implementation, and assessment of servicelearning programs. journal of higher education outreach and engagement. 2011; 15:57–84. 16. von elm e, altman dg, egger m, pocock sj, gøtzsche pc, vandenbroucke jp, et al. the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies. lancet 2007; 370:1453–7. https://doi.org/10.1016/s0140-6736(07)61602-x. 17. stufflebeam, d. l. the cipp model for evaluation. in: stuffle beam dl, kellaghan t, eds., the international handbook of educ ational evaluation. boston: kluwer academic publishers, 2003. 18. stufflebeam dl, shinkfield, aj. evaluation theory, models, & applications. san francisco: jossey-bass, 2007. 19. sankaranarayanan r, nene bm, shastri ss, jayant k, muwonge r budukh am, et al. hpv screening for cervical cancer in rural india. n engl j med 2009; 360:1385–94. https://doi.org/10.1056/ nejmoa0808516 pmid: 19339719. 20. nishtar s. choked pipes: reforming pakistan’s health system. oxford: oxford university press, 2010. https://doi.org/10.2471/ blt.10.079285. 21. planning commission of india. public health care system (chapter viii), 2000. from: https://niti.gov.in/planningcommi ssion.gov.in/docs/aboutus/committee/strgrp/stgp_fmlywel/ sgfw_ch8.pdf accessed: oct 2020. 22. federal register of legislation. australian national preventive health agency act 2010. from: https://www.legislation.gov.au/ details/c2016c00720 accessed: oct 2020. 23. sarink d, nedkoff l, briffa t, shaw je, magliano dj, stevenson c, et al. projected ageand sex-specific prevalence of cardiovas cular diseases in western australian adults from 2005-2045. eur j prev cardiol 2016; 23:23–32. https://doi.org/10.1177/204 7487314554865. 24. bangladesh, ministry of health and family welfare. strategic plan for surveillance and prevention of non-communicable diseases in bangladesh 2011-2015. dhaka: directorate general of health services, ministry of health and family welfare, 2007. 25. diem g, brownson rc, grabauskas v, shatchkute a, stachenko s. prevention and control of noncommunicable diseases through evidence-based public health: implementing the ncd 2020 action plan. glob health promot 2016; 23:5–13. https://doi. org/10.1177/1757975914567513. 26. mondal s, van belle s. india’s ncd strategy in the sdg era: are there early signs of a paradigm shift? global health 2018; 14:1–9. https://doi.org/10.1186/s12992-018-0357-6. https://doi.org/10.1108/jeim-09-2013-0066 https://doi.org/10.25073/2525-2445/vnufs.4252 https://doi.org/10.1016/s0140-6736(07)61602-x https://doi.org/10.1056/nejmoa0808516 pmid: 19339719 https://doi.org/10.1056/nejmoa0808516 pmid: 19339719 https://doi.org/10.2471/blt.10.079285 https://doi.org/10.2471/blt.10.079285 https://doi.org/10.1177/2047487314554865 https://doi.org/10.1177/2047487314554865 https://doi.org/10.1177/1757975914567513 https://doi.org/10.1177/1757975914567513 https://doi.org/10.1186/s12992-018-0357-6 december 2007 vol 8 after meeting.indd sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 197-206 sultan qaboos university© submitted 2nd april 2007 accepted 19th june 2007 1department of family medicine and public health, college of medicine and health sciences, sultan qaboos university, oman. 2academic unit of primary care, university of leeds, uk. 3department of general practice, north wales clinical school, cardiff university, uk. 4centre for research in primary care, university of leeds, uk. *to whom correspondence should be addressed. email: mhalazri@squ.edu.om continuity of care literature review and implications *mohammed alazri,1 philip heywood,2 richard d neal,3 brenda leese4 r e v i e w abstract continuity of care is widely regarded as a core value of primary care. the objective of this article is to explore the literature about the concept of continuity of care focusing on factors that influence continuity; advantages and disadvantages of continuity and the effect of continuity on outcomes, hence on the quality of care. electronic databases and other websites were searched for relevant literature. the results of this review showed that continuity of care is influenced by demographic factors, factors related to patients and healthcare professionals, patient-healthcare professional relationship, inter-professional factors, role of receptionists and organisational factors. several advantages were found to be associated with most types of continuity in various medical disciplines preventive medicine, general health, maternity and child health, mental and psychosocial health, chronic diseases and costs of care. various factors influenced different types of continuity. most types of continuity were associated with good outcomes, hence indirectly affecting the quality of care. health care professionals and policy makers should be aware of the effect of continuity on quality of care and of the factors that influence continuity if they wish to preserve it as a core value of primary care. keywords: continuity of care; general practitioner; literature review املستمرة �الرعاية ياتها تَضَ قْ ومُ األدبيات مراجعة ليز برندا نيل، ريتشارد هيود، فيليب العزري، محمد والتركيز ــتمرة املس مفهوم الرعاية ملعرفة األدبيات مراجعة املقال هو هذا هدف إن األولية. الرعاية ــيات أساس من ــتمرة املس الرعاية امللخص: تعتبر املعطيات مراجعة متت الرعاية. جودة ــى عل ، ومن ثم النتائج على تأثيرها وكذلك ، ــلبياتها وس وإيجابياتها ــتمرارية، االس تؤثر على التي ــى العوامل عل الدميوغرافية بالعوامل الرعاية املستمرة تتأثر أن املراجعة هذه نتائج أظهرت العالقة. ذات على األدبيات حتتوي التي الدولية الشبكة ومواقع اإللكترونية أنفسهم الطب مهنة في العاملني بني والعالقة في مهنة الطب العاملني املريض مع الطب وعالقة حقل في والعاملني باملريض تتعلق التي والعوامل الطبية التخصصات مجاالت في عديدة للرعاية املستمرة إيجابيات وجود أظهرت الدراسة التنظيمية. الشؤون وكذلك ــتقبال االس موظفي وتصرف هناك الرعاية. وكذلك تكاليف املزمنة، ــراض واألم والعقلية ــية النفس والصحة األمومة والطفولة وصحة العامة والصحة الوقائي ــة كالطب اتلف لذلك ـ الرعاية نوعية على ــر مباش ــكل غير بش تؤثر ولهذا جيدة نتائج لها ــتمرة املس معظم أنواع الرعاية ــتمرة. الرعاية املس على عوامل تؤثر عدة يريدون كانوا إذا عليها تؤثر والعوامل التي للرعاية اإليجابية النتائج تلك مالحظة وواضعي السياسة الصحية الطبي احلقل في على العاملني يتحتم . للرعاية املستمرة كأساس احملافظة عليها ممارس. طبيب ، املستمرة الرعاية ، األدبيات الكلمات: مراجعة مفتاح continuity of care has been regarded as one of the core values of primary care and as a fundamental part of the work of the general practitioner (gp).1 evidence from international literature has shown that the strength of a country’s primary care system is associated with improved population health outcomes.2 continuity is a complex concept because it means several different things; hence many types of continuity have been identified, which are defined in table 1. throughout the world, good quality primary care improves health outcomes for the population;6 continuity powerfully affects patient-focused outcomes.7, 8 however, in many countries, enormous changes are occurring in primary care organisations, such as increasing care team membership of professionals allied m o h a m m e d a l a z r i , p h i l i p h e y w o o d , r i c h a r d d n e a l a n d b r e n d a l e e s e 198 to medicine.9 thus, patients can consult several health care professionals and may be given conflicting advice by different team members.10 where services are not available in primary care, patients may move to secondary care, potentially affecting the continuity and hence the quality of care. furthermore, the information in clinical records may be incomplete or incorrect and problems may be compounded between care settings.11 gps are thus faced with a challenge to provide good services, including continuity, to ensure good quality of care. the aim of this paper is to provide an overall review of the literature for the concept of continuity of care, focusing on factors that influence continuity, advantages and disadvantages of continuity and how continuity affects the outcomes and hence the quality of care. l i t e r a t u r e r e v i e w s o u r c e s the electronic databases searched were medline/ pubmed (from 1966), embase (from 1980), cinahl (from 1981), psycinfo (from 1967), and web of science citation (from 1981). other websites were also searched, including the cochrane library, science direct and ingenta. the search terms used were “continuity”, “coordinated care”, and “seamless care” in combination with “factors”, “process”, “outcomes”, “patients”, “general practitioners”, “family doctors”, “family practitioners”, “primary care practitioners”, “family physicians” and “gps”. the literature review was not limited to particular countries, but only included literature published in english. abstracts of retrieved references were studied; copies of original articles were requested if they could not be obtained electronically. r e v i e w r e s u l t s fa c to r s w h i c h i n flue n c e c o n ti nui t y a number of factors identified from the literature influence each type of continuity as outlined in table 1; these include demographic factors, patient and healthcare professional factors, patient-healthcare professional relationships, inter-professional factors, the role of receptionists and organisational factors. demographic factors in the usa, a study found that the majority of patients intended to stay with their doctors as long as they could travel to the practice.12 in contrast, another study in australia showed that geographical distance was not the sole, nor even the most important, determinant of choice of general practice or of a doctor with whom patients felt more comfortable.13 indeed, people who are more mobile and have frequent changes of address are less likely to keep in contact with the same doctor; hence they are less likely to be followed up by the same doctor.14 patient and healthcare professional factors patients sometimes wish to exercise choice of healthcare professional because of the particular nature of their problem. a female patient might choose a female doctor for a gynaecological problem, or a doctor with manipulation skills for back pain.15 patients also want to be able to choose a doctor with whom they have a rapport and whom they could entrust with their confidences.16 studies have shown that a high level of continuity is more important for certain conditions than others. schers et al.17 found in the netherlands that although patients felt it was important for them to see their personal doctor, fewer did so for minor problems than for family problems or to discuss the future when they were seriously ill. kearley et al.18 found in the uk that the majority of patients highly rated relational continuity, particularly for more serious conditions such as cancer, psychological problems, and family problems. however, relational continuity had much less value for minor and acute illnesses such as cough and cold, itchy rash, painful knee and contraceptive advice. patients of full-time gps experience higher levels of continuity than patients of part-time gps.19 however, healthcare professionals in different countries are increasingly taking on other responsibilities, such as management and teaching, which reduce their availability to patients.20 consequently, patients may find that their chosen doctor is only available on some days or at particular times of the day; therefore, their attachment to a particular doctor may decrease.21 whilst gps regard continuity as an important aspect of patient care and would like to be available to see every patient at every consultation, they feel that this is an unrealistic expectation and that continuity could be provided by different doctors within the same practice (team continuity) if they have good working relationships.22 patient-healthcare professional relationship patients who exhibit trust are more likely to have had a longer relationship with their doctor.23 lack of trust or confidence could lead to conflict between patients and doctors which enhanced movement of patients from 199 c o n t i n u i t y o f c a r e one doctor to another.24 patient satisfaction has been regarded as an important measure of good quality of care; continuity has been associated with increased patient satisfaction.20, 25 patients who experienced relational continuity were more likely to be satisfied with their consultation than those who had seen different gps, thus, reinforcing longitudinal continuity might be one way of increasing quality of care.26 inter-professional factors inter-organisational communication (continuity of information) among multiple providers is the core function of consistency and has been regarded as central to continuity of patient care.15 however, healthcare professionals must accept responsibility for overall coordination, including responsibility to communicate, in order for coordination to occur.27 cross-boundary continuity between the practice and the hospital needs effective communication and problems in communication between different services disrupt crossboundary continuity.28 role of receptionists the behaviour of receptionists tends to vary with the size of the practice; as the organisation becomes more complex, the accessibility to a named healthcare professional is reduced. therefore, patient criticism of receptionists becomes more frequent as the organisation becomes bigger and more complex, as patients find it more difficult to access the doctor of their choice.29 kibbe et al.30 in the usa, recognised the role of the receptionist in making it easier for patients to see their usual doctor; they therefore emphasised the importance of training receptionists to help in this respect. organisational factors studies have consistently shown that longitudinal continuity is higher in smaller than in larger group practices and that patients registered with doctors in large practices are usually not guaranteed to see either the same doctor or their doctors of choice.20 in countries such as the uk, the netherlands, and denmark, where patients are registered with a named doctor, longitudinal continuity might be promoted.31 however, in other parts of the world, particularly where primary care services are provided privately, it can be difficult for patients to maintain longitudinal continuity. for example, in the usa where primary care is frequently provided by health maintenance organisations, health insurance has led to increased access to care being accompanied by an interest in reducing costs. thus, patients have to enrol with a new doctor annually if their company’s insurer swaps policies in response to market competition; this affects both relational and longitudinal continuity.16 • experienced continuity the patient’s judgement of co-ordinated and smooth progression of care.3 • relational (interpersonal) continuity *an ongoing therapeutic relationship between a patient and one or more providers. 3, 4 • team continuity care obtained from a group of healthcare professionals working in either primary or secondary care settings, providing consistent communication and co-ordination of care for their patients. • cross-boundary continuity care that follows the patient across settings (e.g. from primary care to hospital or vice versa).3 • longitudinal continuity*care from the same healthcare professional or as few professionals as possible, consistent with other needs.3 • flexible continuityservices that are flexible and adjusted to the needs of the individual over time.3 • management continuity a consistent and coherent approach to the management of a health condition that is responsive to a patient’s changing needs.4 • geographic continuity care that is given or received in person on one site (office, home, hospital, etc).4, 5 • informational continuity information transfer that follows the patient.3 * relational continuity and longitudinal continuity are not easy to distinguish from each other and are therefore often regarded as one type of continuity.4 table 1: definitions of different types of continuity as emerged from the literature m o h a m m e d a l a z r i , p h i l i p h e y w o o d , r i c h a r d d n e a l a n d b r e n d a l e e s e 200 advantages of continuity continuity of care has been regarded as a crucial component of quality of care,32 as it influences both the process (interactions between users and services) and outcomes of care.33 furthermore, continuity of care has been evaluated concerning the extent to which it has an impact on healthcare outcomes, such as prevention or reduction of physical, mental, and social disabilities, increased patient satisfaction and reduced aggregate healthcare spending. 34 table 2 summarises the advantages of different types of continuity within various medical disciplines. the details of the association between different types of continuity and outcomes of care for the various medical disciplines will each be presented in turn. preventive medicine and general health steven et al. 35 in australia found that patients, who only visited one practice on a regular basis, were significantly more likely to report for blood pressure, cholesterol screening, and cervical cytology testing, and to follow smoking cessation, exercise and dietary advices.32 devroey et al.36 found in belgium that patients without a named gp were less likely to have a healthy lifestyle than those who had a named gp. they were more likely to smoke, be less physically active, less concerned about the calories in their food, and have their blood pressure and cholesterol checked less frequently. mainous et al.37 found in the usa that having a regular doctor was associated with a higher likelihood of attempted weight loss among obese patients. furthermore, it has been shown that continuity with a table 2: summary of the advantages of different types of continuity area/ discipline type of continuity advantages preventive medicine and general health geographic patients reported better screening of blood pressure, cholesterol, and cervical cytology. they reported ease of following advice for smoking cessation, exercise and diet longitudinal • improvement in control of hypertension and more compliance with medication • blood pressure and cholesterol are checked regularly • decrease in illness visits • improvement in diagnosis of bacterial meningitis • fewer missed appointments • less smoking, more exercise and weight control maternity and child health relational (midwife) • reduced risk of white coat hypertension, pre-eclampsia and use of epidural anaesthesia • low rates of episiotomy, perineal lacerations and electronic foetal monitoring team (midwifery) • low rate of caesarean section and reduction in analgesic requirements during delivery. • higher birth weight of infants and fewer admissions of infants to a neonatal intensive care unit longitudinal • good maintenance of the child’s develop-mental and immunisation profile • reduced incidence of rheumatic fever in children behavioural, mental and psycho-social health team • reduced risk of re-admission of psychiatric patients and risk of suicide relational • increased trust, confidence, and rapport between the patient and the healthcare professional; patient discloses psychosocial problems • greater enablement in the consultation and increased patient satisfaction • patients less likely to have drug and alcohol abuse behaviour • healthcare professionals became better at understanding patients’ social and family context; they becomes better at identifying patients’ psychosocial problems and unspecific symptoms cancer geographic • better screening of cervical cytology longitudinal • better cancer screening asthma relational • better emotional and mental well-being longitudinal • good communication with the healthcare professional diabetes relational • better emotional and mental well-being longitudinal • good preventive measurements (more foot examinations, blood glucose monitoring, retinal examinations, etc.) and usually better diabetic control team • good diabetic control 201 c o n t i n u i t y o f c a r e gp for hypertensive patients is associated with a lower chance of developing hypertension-related complications, such as stroke, congestive heart failure and acute myocardial infarction.38 women who experienced longitudinal continuity over one year were more than four times as likely to have had a papanicolaou smear test for early diagnosis of cervical cancer, twice as likely to have had a breast examination, and three times as likely to have had a mammogram compared with those without. 39 maternity and child health a known midwife has been found to reduce the likelihood of white coat hypertension, decrease the risk of pre-eclampsia, reduce the use of epidural anaesthesia during delivery, and is associated with lower rates of episiotomy, perineal lacerations and electronic foetal monitoring.40 if women have continuity in the midwifery team during the antenatal period, there is a reduced rate of caesarean section, a lower risk of miscarriage and more likelihood that labour and delivery occur without intervention.41 on the other hand, midwifery team continuity seems to have no effect on improving psychological outcomes, such as improved postpartum depression.42 in child health, the records of physical problems in children, as well as immunisation and developmental profiles, are more likely to be maintained with longitudinal continuity.43 psychosocial problems in children are more likely to be recognised if the children are evaluated by their usual gp.44 mental and psychosocial health patients who had a usual gp are less likely to misuse drugs and alcohol and have a better emotional status and mental well-being than those without.45 moreover, there is a widespread belief that failure to provide continuity of care may increase the likelihood of untoward incidents such as suicide.46 relational continuity is commonly associated with increased patient satisfaction with the consultation and services provided in primary care,26, 47 trust in the usual doctor and midwife, 23 familiarity with and confidence in the usual doctor,12 and easy communication with the usual doctor.48 lack of relational continuity, on the other hand, is associated with an increased number of relationship problems between the patient and the doctor, including ‘difficult’ consultations, nonattendances and communication problems.49 chronic diseases the willingness to undertake cancer screening is higher in patients with a regular care provider and longitudinal continuity has been associated with stricter adherence to recommended screening among patients with colorectal cancer.50, 51 love et al.52 assessed the role of relational continuity in predicting the perceptions of the physician-patient relationship held by patients with asthma. they found that for these patients continuity of care was an important factor, which contributed to good communication with the usual doctor. in type 2 diabetes, relational and longitudinal continuity could decrease diabetes-related complications and improve the quality of life53; however, another study showed that longitudinal continuity was associated with significantly more diabetic complications.52 c o sts o f c a r e people who see the same doctor (relational and longitudinal continuity) have fewer and shorter hospitalisations, decreased use and utilisation of emergency departments, fewer operations, fewer duplicate diagnostic tests, decreased use of open access clinics and hence reductions in resource utilisation and costs.49, 54 d i sa dva n ta ge s o f c o n ti nui t y a study has shown that continuity could sometimes waste resources by increasing prescribing, referral, and the issuing of sickness certificates.55 patients who knew their doctors well, sometimes persuaded them to do more because they felt more empowered, and these doctors responded by trying to do more for such patients; thus, rational continuity in such circumstances is not cost effective.56 sometimes, a gp who frequently sees the same patient might miss the slow development of disease, while another gp who has not previously seen the patient might recognise it.57 for example, patients with chronic, recurring depression, who received care from their primary care physician, continued to be distressed with unrelieved symptoms.58 in diabetes, longitudinal continuity has been associated with worsening diabetic control and increased risk of complications.53 within the context of team continuity, there might be a problem in the relationships between team members or between any member of the team and the patient.59 availability of medical records, including electronic records (continuity of information), is particularly important when a different healthcare profesm o h a m m e d a l a z r i , p h i l i p h e y w o o d , r i c h a r d d n e a l a n d b r e n d a l e e s e 202 sional needs to know what is already known, or has been deduced, about the patient. nevertheless, the security and confidentiality of electronic information cannot be guaranteed, particularly if the information is shared in a network between different healthcare organisations.60 d i s c u s s i o n the purpose of this integrated literature review is to explore the concept of continuity of care, with particular emphasis on factors that promote or inhibit continuity, the advantages and disadvantages of continuity and the effect of continuity on outcomes, hence on the quality of care. several factors were found to influence continuity of care. the development of primary care organisations is an essential process of modernisation that goes with the development of society and technology; however, this development could harm some types of continuity, hence indirectly affecting the quality of care. many gps now work in teams with nurses, receptionists, and other professionals allied to medicine.9 however, there might be concern that patients will get confused within the context of team continuity, if management is inconsistent, hence the quality of care provided for patients might be affected. indeed, it is damaging to patient confidence if one member of the team, for example, is known to act differently in certain situations.15 nevertheless, being registered in a large practice is usually not a guarantee that the patient will see the same gp consistently, as the practice’s systems may not promote longitudinal continuity. 61 unavailability of the patient’s usual gp could interfere with continuity;3 indeed, many patients still prefer small practices rather than larger ones because they perceive that larger practices offer less relational and longitudinal continuity.62 thus, this component of quality, ‘personal care’, could be affected. patients in primary care could move between different care settings and consult specialists at the hospital. as a result, they may be given conflicting advice. poor communication with hospitals caused difficulties, which were a source of dissatisfaction in primary care leading sometimes to poor quality of care provided for patients. 63 medical records may be incomplete, not recorded sufficiently or recorded incorrectly. furthermore, doctors and nurses who treat patients do not always have the information needed for the consultation, and patients may thus have to repeat the same information to different healthcare professionals. the problem may be worse if patients move between primary and secondary care settings, especially if the transfer of information between the two settings is delayed, thus potentially affecting the quality of care. electronic communication may be important to avoid duplication of services.64 relational continuity improved the relationship with the named professional.65 a doctor who knew the patient was more likely to identify appropriate therapies.66 also, knowing the patient contributes to quality of care by ensuring that patients are treated as individuals; it is associated with increased knowledge which can inform decision-making and may be a factor that improves patient outcomes.16 the potential risk of familiarity leading to misdiagnosis may occur in relational continuity because gps may assume that they are already aware of everything significant and may not conduct more important investigations.67 misdiagnosis is one indicator of poor quality. indeed, patients reported benefits of consulting an unfamiliar doctor, such as early detection of diabetes.62, 68 however, unfamiliar doctors may not show a personal interest and be more likely to provide physical rather than psychosocial care as the length of contact is usually short.18 although quality of care is a complicated concept meaning different things to managers, patients and practitioners, who may each use different methods for its measurement, continuity of care has been regarded as a crucial component of good quality care.69 team continuity has been found to provide good quality care;70 there were fewer short and long-term complications of chronic diseases in large practices that implemented a team approach.69 this might indicate that the “physical” care provided by team continuity, rather than “personal” care accruing in relational continuity, plays a role in achieving good outcomes. on the other hand, certain elements in relational continuity (trust, confidence, good communication, good rapport) can make patients adhere better to recommendations leading to improved outcomes.71 also, the usual healthcare professional may understand the patients’ views of the diseases better, thus influencing self-care and, thereby, improving outcomes.33 however, sometimes healthcare professionals may be concerned that circumstances promoting relational continuity could impede their developing skills to manage 203 c o n t i n u i t y o f c a r e chronic diseases.72 i mpl i c ati o n s o f fi n d i n g s f o r pr a c ti c e , p o l i c y a n d r e se a r c h several recommendations have emerged from this review for policy makers and researcher at primary care level to improve quality of care. whilst there are some advantages in consulting an unfamiliar doctor, patients’ priorities and requirements should be paramount. patients may seek relational continuity in a practice where organisational factors prevent them from accessing their usual healthcare professional. healthcare professionals must be aware that the continuing relationship between patients and their usual healthcare professionals should not be threatened. indeed, relational continuity appears to be important for providing more “psychosocial” than “physical” care. therefore, if healthcare professionals and policy makers wish to preserve continuity as a core value of primary care, they should be aware of the threat to relational continuity as future policy is developed. it seems that there is more need for effective communication between the practice and hospital to improve cross-boundary continuity and thus to improve the quality of care. healthcare professionals should be aware that poor communication between primary and secondary care may impede cross-boundary continuity. better implementation of technology, such as computer links and e-mails to improve communication between the practice and the hospital, should improve cross-boundary continuity thus indirectly improving quality. receptionists have a role in determining some aspects of continuity in primary care; hence the training of receptionists could be targeted to emphasise the importance of patients seeing their usual healthcare professional, whenever that is possible and appropriate. as stated previously, there are enormous changes occurring in primary care organisations as part of development and “modernisation”, but this has affected continuity of care. therefore, in the light of these changes, future research is needed to explore how patients and healthcare professionals experience continuity of care in primary care. c o n c l u s i o n several factors have emerged from the literature which has influenced the various types of continuity, these include demographic factors, factors related to patients and healthcare professionals, patients-healthcare professional relationships, inter-organisational communication, the role of receptionists and factors related to the structure and function of primary care organisations. most types of continuity were found to be associated with improving outcomes of care, hence indirectly affecting the quality of care. continuity of care was found to improve outcomes in preventive medicine and general health, maternity and child health, mental and psychosocial health, management of chronic diseases and cost of care. however, there were a few disadvantages associated with certain types of continuity, such as misdiagnosis occurring in relational continuity, problems in delivering consistency of care in team continuity, and the security and confidentiality of electronic information in providing continuity of information. f un d i n g b o dy sultan qaboos university in the sultanate of oman funded dr alazri as part of his post-graduate education in the uk. this review was part of a phd thesis at the university of leeds, uk. c ompe ti n g i n te r e sts none a c k n ow l e d g me n ts the author would like to express great thanks to sultan qaboos university for sponsoring his post-graduate education in the uk. also, he would like to thank his supervisors who are co-authors of this paper. r e f e r e n c e s 1. royal college of general practitioners. the educational needs of the future general practitioner. j r coll gen pract 1969; 18:358-360. 2. starfield, b. is primary care essential? lancet 1994; 344:1129-1133. 3. freeman g, shepper s, robinson i, ehrich k, richards s. continuity of care: report of a scoping exercise for the national co-ordinating centre for nhs service delivery and organisation r&d (nhsccsdo). london: nccsdo 2001. from http://www.sdo.lshtm. ac.uk/continuityofcare.htm. accessed on jan 2006. 4. haggerty jl, reid rj, freeman gk, starfield bh, adair ce, mckendry r. continuity of care: a multidisciplinary review. bmj 2003; 327:1219-1221. 5. saultz jw. defining and measuring interpersonal continuity of care. ann fam med 2003; 1:134-143. m o h a m m e d a l a z r i , p h i l i p h e y w o o d , r i c h a r d d n e a l a n d b r e n d a l e e s e 204 6. starfield b. primary care. participants or gatekeepers? diabetes care 1994; 17:12-17. 7. koopman rj, mainous ag, iii, baker r, gill jm, gilbert ge. continuity of care and recognition of diabetes, hypertension, and hypercholesterolemia. arch intern med 2003; 163:1357-1361. 8. cabna md, jee sh. does continuity of care improve patient outcomes? j fam pract 2004; 53:974-980. 9. stevenson k, baker r, farooqi a, sorrie r, khunti k. features of primary health care teams associated with successful quality improvement of diabetes care: a qualitative study. fam pract 2001; 18:21-26. 10. constantino m, hoskins pl, fowler pm, pech c, mcfarlane r, flack jr. interaction between diabetic patients, their general practitioners and a hospital diabetic clinic. med j aust 1991; 155:515-518. 11. mageean rj. study of “discharge communications” from hospital. bmj 1986; 293:1283-1284. 12. gabel ll, lucas jb, westbury rc. why do patients continue to see the same physician? fam pract res j 1993; 13:133-147. 13. humphreys js, mathews-cowey s, weinand hc. factors in accessibility of general practice in rural australia. med j aust 1997; 166:577-580. 14. farrell sp, blank m, koch jr, munjas b, clement dg. predicting whether patients receive continuity of care after discharge from state hospitals: policy implications. arch psychiatr nurs 1999; 13:279-285. 15. fleming dm. continuity of care: a concept revisited. eur j gen pract 2000; 6:140-145. 16. emanuel ej, dubler nn. preserving the physician-patient relationship in the era of managed care. jama 1995; 273:323-329. 17. schers h, webster s, van den hoogen h, avery a, grol r, van den bosch w. continuity of care in general practice: a survey of patients’ views. br j gen pract 2002; 52:459-462. 18. kearley ke, freeman gk, heath a. an exploration of the value of the personal doctor-patient relationship in general practice. br j gen pract 2001; 51:712-718. 19. murray a, safran dg, rogers wh, inui t, chang, montgomery je. physician workload and patient-based assessments of primary care performance. arch fam med 2000; 9:327-332. 20. baker r, streatfield j. what type of general practice do patients prefer? exploration of practice characteristics influencing patient satisfaction. br j gen pract 1995; 45:654-659. 21. harris mf, frith jf. continuity of care: in search of the holy grail of general practice. med j aust 1996; 164:456-457. 22. sturmberg jp, schattner p. personal doctoring. its impact on continuity of care as measured by the comprehensiveness of care score. aust fam physician 2001; 30: 513-518. 23. kao ac, green dc, davis na, koplan jp, cleary pd. patients’ trust in their physicians: effects of choice, continuity, and payment method. j gen intern med 1998; 13:681-686. 24. levinson w, stiles wb, inui ts, engle r. physician frustration in communicating with patients. med care 1993; 31:285-295. 25. weyrauch kf. does continuity of care increase hmo patients’ satisfaction with physician performance? j am board fam med 1996; 9:31-36. 26. hjortdahl p, laerum e. continuity of care in general practice: effect on patient satisfaction. bmj 1992; 304:1287-1290. 27. owen c. coordination and continuity of care. aust fam physician 1996; 25:1009. 28. taylor d, cameron p. continuity of care in the transition from emergency department to general practitioner: is it adequate? emerg med 1999; 11:244-249. 29. arber s, sawyer l. changes in general practice: do patients benefit? bmj 1981; 283:1367-1370. 30. kibbe dc, bentz e, mclaughlin cp. continuous quality improvement for continuity of care. j fam pract 1993; 36:304-308. 31. buetow sa. what do general practitioners and their patients want from general practice and are they receiving it? a framework. soc sci med 1995; 40:213-221. 32. campbell sm, roland mo, buetow sa. defining quality of care. soc sci med 2000; 51:1611-1625. 33. o’connor pj, desai j, rush wa, cherney lm, solberg li, bishop db. is having a regular provider of diabetes care related to intensity of care and glycemic control? j fam pract 1998; 47:290-297. 34. gonnella js, herman mw. continuity of care. jama 1980; 243:352-354. 35. steven id, dickens e, thomas sa, browning c, eckerman e. preventive care and continuity of attendance. is there a risk? aust fam physician 1998; 27:s44-s46. 36. devroey d, coigniez p, vandevoorde j, kartounian j, betz w. prevention and follow-up of cardiovascular disease among patients without a personal gp. fam pract 2003; 20:420-424. 37. mainous ag, koopman rj, gill jm, baker r, pearson ws. relationship between continuity of care and diabetes control: evidence from the third national health and nutrition examination survey. am j public health 2004; 94:66-70. 38. lackland d, egan bm. lack of continuous care is asso205 c o n t i n u i t y o f c a r e ciated with higher rates of stroke in hypertensive medicaid beneficiaries. am j hypertens 2002; 15:a142. 39. ettner, s. l. the timing of preventive services for women and children: the effect of having a usual source of care. am j public health 1996; 86:1748-1754. 40. flint c, poulengeris p, grant a. the ‘know your midwife’ scheme a randomised trial of continuity of care by a team of midwives. midwifery 1989; 5:11-16. 41. homer cs, davis gk, brodie pm, sheehan a, barclay lm, wills j, chapman, mg. collaboration in maternity care: a randomised controlled trial comparing community-based continuity of care with standard hospital care. br j obstet gynaecol 2001; 108:16-22. 42. marks mn, siddle k, warwick c. can we prevent postnatal depression? a randomized controlled trial to assess the effect of continuity of midwifery care on rates of postnatal depression in high-risk women. j matern fetal neonatal med 2003; 13:119-127. 43. christakis da, mell l, koepsell td, zimmerman fj, connell fa. association of lower continuity of care with greater risk of emergency department use and hospitalization in children. pediatrics 2000; 103:524-529. 44. kelleher kj, childs ge, wasserman rc, mcinerny tk, nutting pa, gardner wp. insurance status and recognition of psychosocial problems: a report from the pediatric research in office settings and the ambulatory sentinel practice networks. arch pediatr adolesc med 1997; 151:1109-1115. 45. ettner s. l. the relationship between continuity of care and the health behaviors of patients: does having a usual physician make a difference? med care 1999; 37:547555. 46. hulten a, wasserman d. lack of continuity a problem in the care of young suicides. acta psychiatr scand 1998; 97:326-333. 47. morgan ed, pasquarella m, holman jr. continuity of care and patient satisfaction in a family practice clinic. j am board fam med 2004; 17:341-346. 48. freeman gk, richards sc. is personal continuity of care compatible with free choice of doctor? patients’ views on seeing the same doctor. br j gen pract 1993; 43:493-497. 49. sweeney kg, gray dp. patients who do not receive continuity of care from their general practitioner are they a vulnerable group? br j gen pract 1995; 45:133-135. 50. o’malley as, mandelblat, j, gold k, cagney ka, kerner j. continuity of care and the use of breast and cervical cancer screening services in a multiethnic community. arch intern med 1997; 157:1462-1470. 51. kelly rb, shank jc. adherence to screening flexible sigmoidoscopy in asymptomatic patients. med care 1992; 30:1029-1042. 52. love mm, mainous ag, talbert jc, hager gl. continuity of care and the physician-patient relationship: the importance of continuity for adult patients with asthma. j fam pract 2000; 49:998-1004. 53. hanninen j, takala j, keinanen-kiukaanniemi s. good continuity of care may improve quality of life in type 2 diabetes. diabetes res clin pract 2001; 51:21-27. 54. raddish m, horn sd, sharkey pd. continuity of care: is it cost effective? am j manag care 1999; 5:727-734. 55. hjortdahl p, borchgrevink cf. continuity of care: influence of general practitioners’ knowledge about their patients on use of resources in consultations. bmj 1991; 303:1181-1184. 56. freeman g, hjortdahl p. what future for continuity of care in general practice? bmj 1997; 314:1870-1873. 57. freeman g. continuity of care in general practice: a review and critique. fam pract 1984; 1:245-252. 58. schwenk t, evans d, laden s, lewis l. treatment outcome and physician-patient communication in primary care patients with chronic, recurrent depression. am j psychiatry 2004; 161:1892-1901. 59. feron jm, cerexhe f, pestiaux d, roland m, giet d, montrieux c, paulus d. gps working in solo practice: obstacles and motivations for working in a group? a qualitative study. fam pract 2003; 20:167-172. 60. sullivan f, wyatt j. how computers help make efficient use of consultations. bmj 2005; 331:1010-1012. 61. freeman gk, horder jp, howie jgr, hungin ap, hill ap, shah nc. evolving general practice consultation in britain: issues of length and context. bmj 2002; 324:880882. 62. alazri mh, neal rd, heywood p, leese b. patients’ experiences of continuity in the care of type 2 diabetes: a focus group study in primary care. br j gen pract. 2006; 56:488-495. 63. pierce m, agarwal g, ridout d. a survey of diabetes care in general practice in england and wales. br j gen pract 2000; 50:542-545. 64. branger pj, van der wouden jc, schudel br, verboog e, duisterhout js, van der lei j et al. electronic communication between providers of primary and secondary care. bmj 1992; 305:1068-1070. 65. tarrant c, stokes t, baker r. factors associated with patients’ trust in their general practitioner: a cross-sectional survey. br j gen pract 2003; 53:798-800. 66. schers h, van den hh, bor h, grol r, van den bw. familiarity with a gp and patients’ evaluations of care. a cross-sectional study. fam pract 2005; 22:15-19. 67. broom dh. familiarity breeds neglect? unanticipated benefits of discontinuous primary care. fam pract 2003; 20:503-507. m o h a m m e d a l a z r i , p h i l i p h e y w o o d , r i c h a r d d n e a l a n d b r e n d a l e e s e 206 68. tandeter hb,vinson dc. transient discontinuity of care. others seeing what we have missed. j fam pract 1998; 47:423-424. 69. campbell sm, hann m, hacker j, burns c, oliver d, thapar a, et al. identifying predictors of high quality care in english general practice: observational study. bmj 2001; 323:784-787. 70. mccann tv, baker h. models of mental health nursegeneral practitioner liaison: promoting continuity of care. j adv nurs 2003; 41:471-479. 71. banahan bfj, banahan bf. continuity as an attitudinal contract. fam pract 1981; 12:767-768. 72. alazri mh, heywood p, neal rd, leese b. uk gps’ and practice nurses’ views of continuity of care for patients with type 2 diabetes. fam pract 2007; 24:128-137. departments of 1radiology, 3medicine and 4anaesthesia, royal hospital, muscat, oman; departments of 2research section and 5radiology, oman medical specialty board, muscat, oman *corresponding author’s e-mail: alumairi1@yahoo.com covid-2019 pneumonia severity and distribution of lung changes observed on the initial chest x-ray as an indicator of final outcomes *rashid s. al umairi,1 ishaq al salmi,1 jokha al kalbani,1 atheel kamona,1 saqar al tai,1 faiza al kindi,1 sachin jose,2 faryal khamis,3 huda al khalili,4 mohammed al busaidi5 clinical & basic research sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 98–105, epub. 28 feb 22 submitted 8 aug 20 revisions req. 14 oct & 20 dec 20; revisions recd. 10 nov & 28 dec 20 accepted 24 jan 21 https://doi.org/10.18295/squmj.4.2021.061 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to assess the correlation between the severity of the initial chest x-ray (cxr) abnormalities in patients with a confirmed diagnosis of covid-19 and the final outcomes. methods: this retrospective study was conducted at the royal hospital, oman between mid-march and may 2020 and included patients who had been admitted with a confirmed diagnosis of covid-19 and had a final outcome. serial cxrs were identified and examined for presence, extent, distribution and progression pattern of radiological abnormalities. each lung field was divided into three zones on each cxr and a score was allocated for each zone (0 is normal and 1–4 is mild–severe). the scores for all six zones per cxr examination were summed to provide a cumulative chest radiographic score (range: 0–24). results: a total of 64 patients were included; the majority were male (89.1%) and the mean age was 50.22 ± 14.86 years. the initial cxr was abnormal in 60 patients (93.8%). the most common finding was ground glass opacity (n = 58, 96.7%) followed by consolidation (n = 50, 83.3%). most patients had bilateral (n = 51, 85.0%), multifocal (n = 57, 95.0%) and mixed central and peripheral (n = 36, 60.0%) lung abnormalities. the median score of initial cxr for deceased patients was significantly higher than recovered patients (17 versus 11; p = 0.009). five cxr evolution patterns were identified: type i (initial radiograph deteriorates then improves), type ii (fluctuate), type iii (static), type iv (progressive deterioration) and type v (progressive improvement). conclusion: a higher baseline cxr score is associated with higher mortality rate and poor prognosis in those with covid-19 pneumonia. keywords: sars-cov-2; covid-19; x-ray film; pneumonia; prognosis; oman. advances in knowledge the findings of this study demonstrate that severe lung abnormalities on chest radiographs are associated with poor clinical outcome prognosis and increased mortality. application to patient care this study highlights the importance of chest radiographs in the initial diagnosis, follow-up and prediction of clinical course/outcome of patients with covid-19. in wuhan, china in december 2019, several cases of severe pneumonia of unknown aetiology were admitted to the hospitals. by january 2020, the cause was identified as a novel coronavirus that was called severe acute respiratory syndrome coronavirus 2 (sars-cov-2) by the international committee on taxonomy of viruses on february 22, 2020. the disease was named covid-19 by the world health organisation (who) on the same day.1–3 since then, the virus has spread worldwide and the who classified it as a pandemic on march 11, 2020.4 covid-19 is diagnosed based on the clinical findings and real-time polymerase chain reaction (rtpcr) assay of specimens obtained from the respiratory tract.5,6 medical imaging, including chest computed tomography (ct) and chest x-rays (cxr), plays an important role in its diagnosis and disease progression monitoring upon admission.7–22 in the muscat governorate of oman, the royal hospital is the main referral hospital for the majority of patients with covid-19 pneumonia who require admission; cxr is the main imaging modality for diagnosis and follow-up. quantification of radiographic findings at initial presentation and follow-up can help determine the appropriate management of patients with covid-19 pneumonia. therefore, this study aimed to quantify the severity of the cxr findings using a scoring system and to examine the relationship between the severity of the lung changes on the baseline cxr and the final outcomes to determine its prognostic value. secondly, this study aimed to evaluate the evolution pattern of follow-up cxrs of patients admitted with covid-19 pneumonia. https://creativecommons.org/licenses/by-nd/4.0/ rashid s. al umairi, ishaq al salmi, jokha al kalbani, atheel kamona, saqar al tai, faiza al kindi, sachin jose, faryal khamis, huda al khalili and mohammed al busaidi clinical and basic research | 99 methods this retrospective study included all patients with confirmed diagnosis of covid-19 who were admitted to the royal hospital in muscat, oman, between midmarch and may 2020 and had a final outcome. the covid-19 diagnosis was made based on a positive rt-pcr for sars-cov-2 of specimens obtained from the nasopharynx and oropharynx of all patients. medical records of all patients were reviewed and demographic characteristics, presenting symptoms, vital signs, comorbidities, serum reactive protein, white blood count (wbc) and estimated glomerular filtration rate were obtained. the duration of hospitalisation, admission to the intensive care unit (icu), history of intubation and the final outcome (death or recovery) were also documented. all patients had initial frontal cxrs on the day of admission and follow-up cxrs during hospitalisation, obtained in the posteroanterior (pa) projection for those who were able to stand and anteroposterior projection for patients not able to stand. all cxrs were acquired using machines with digital radiography systems using standard techniques (mobilet mira max, siemens medical solution diagnostic ltd. europe, dublin, ireland; drx-revolution, carestream health, rochester, new york, usa). baseline and follow-up cxrs were reviewed retrospectively in consensus by three radiologists with 8–15 years of experience, with all three unaware of final patient outcomes. all cxrs were viewed using a dedicated radiology picture archiving and communication system and were assessed for the presence, distribution and extent of lung abnormalities, including consolidation, ground glass opacity (ggo), cavitation and pleural effusion. distribution was considered peripheral if the changes were predominantly in the lateral half of the lung fields and central if they were predominantly in the medial half. for the assessment of the severity of lung changes, each lung field was divided into three equal zones. this was due to technical reasons as most of the cxrs were taken bedside for critically ill patients and it was difficult to identify some anatomical landmarks. each zone was assigned a score from 0–4 based on the percentage of lung involved (0 = no abnormality, 1 = <25% of the zone involved, 2 = 25–50% involved, 3 = 51–75% involved and 4 = >75% involved). the scores for all six zones of each cxr examination were summed to provide a cumulative chest radiographic score (range, 0–24) [figure 1]. evolution patterns of lung changes on serial cxrs were classified into five patterns: i) progression of cxr findings followed by an improvement; ii) fluctuation of cxr findings with at least two cxr peaks and an intervening, mild improvement of more than 25% from the overall mean of cxr scores; iii) static cxr findings with no peaks or improvement of more than 25% from the overall mean of cxr scores; iv) progressive deterioration of cxr scores; and v) progressive improvement of cxr scores. patients were divided into two groups according to the final outcome: the deceased group and the recovered group. continuous and discrete data were summarised using the median and interquartile range (iqr). categorical data were summarised using freq uency and percentage. the chi-squared test (fisher’s exact test/likelihood ratio) was used to test the association between the categorical variables. the mann-whitney u test was used to compare nonnormally distributed continuous and discrete variables. spearman’s rank correlation coefficient was used to assess the correlation between the non-normally distributed continuous variables. kolmogorov-smirnov tests were performed to check normal distribution of continuous variables between the groups. demographic characteristics, cxr scores, comorbidities and other important clinical features were also compared between the groups. a multivariate binary logistic regression analysis was performed to determine the independent predictors of mortality. a p value <0.05 was considered statistically significant. all statistical analyses were performed using statistical package for the social sciences (spss), version 25 (ibm corp., chicago, illinois, usa). the scientific research committee at the royal hospital approved this retrospective, single institution study and waived informed consent (src# 59/2020). results a total of 64 patients were included, 57 men and seven women. the mean age was 50.22 ± 14.86 years. of those, 29 patients (45.3%) had no comorbidities, 16 patients (25.0%) had a single comorbidity and 19 patients (29.7%) had multiple comorbidities. the duration of hospitalisation ranged between 7–19.5 days with a median of 11.5 days. of the 64 patients, 44 (68.8%) were admitted to the icu, 31 (48.4%) required intubation, 17 (26.6%) patients died and 47 (73.4%) recovered. the median duration of icu admission was 11 days (iqr: 5.3–14.8 days). the median duration of intubation was 10 days (iqr: 7–16.8 days). the fatality rate among patients admitted to the icu was 38.6% (n = 17) [table 1]. the initial cxrs were acquired at a median of seven days (iqr: 5–8 days) from the onset of covid-2019 pneumonia severity and distribution of lung changes observed on the initial chest x-ray as an indicator of final outcomes 100 | squ medical journal, february 2022, volume 22, issue 1 symptoms and were abnormal in 93.8% of the patients (n = 60). the most common finding was ggo (n = 58, 96.7%), followed by consolidation (n = 50, 83.3%). pleural effusion was a rare finding (n = 2, 3.3%) and none of the patients had cavitation. bilateral lung involvement (n = 51, 85.0%) was more common than unilateral involvement (n = 9, 15.0%). the right lower (n = 50, 83.3%) and left lower (n = 51, 85.0%) zones were more commonly affected than the right middle (n = 45, 75.0%), left middle (n = 42, 70.0%), right upper (n = 35, 58.3%) and left upper (n = 28, 46.7%) zones. mixed central and peripheral distribution was the table 1: characteristics of patients with a confirmed diag nosis of covid-19 who were admitted to the royal hospital, oman between mid-march and may 2020 (n = 64) characteristic n (%) gender male 57 (89.1) female 7 (10.9) age in years mean ± sd 50.22 ± 14.86 median (min–max) 46.5 (22–78) symptom fever 47 (73.4) runny nose 7 (10.9) cough 40 (62.5) sob 41 (64.1) headache 4 (6.3) vomiting 1 (1.6) nausea 4 (6.3) dizziness 1 (1.6) muscle ache/body ache 6 (9.4) malaise 0 (0) lethargy 8 (12.5) phalangeal discomfort/pain 11 (17.2) chest pain 5 (7.8) pleuritic chest pain 1 (1.6) abdominal pain 0 (0) diarrhoea 12 (18.8) haemoptysis 0 (0) anorexia 3 (4.7) comorbidity no comorbidity 29 (45.3) single comorbidity 16 (25) multiple comorbidity 19 (29.7) diabetes mellitus 27 (42.2) ischemic heart disease 2 (3.1) hyperlipidaemia 5 (7.8) chronic kidney disease 6 (9.4) hypertension 19 (29.7) duration of hospital stay and disease course median days of hospitalisation (iqr)* 11.5 (7.0–19.5) number of patients admitted to the icu 44 (68.8) median days of icu admission (iqr) 11 (5.3–14.8) number of patients intubated 31 (48.4) median days of intubation (iqr) 10 (7.0–16.8) final outcome recovered (i.e. discharged) 47 (73.4) deceased 17 (26.6) *hospitalisation duration was from the day of the admission to the day of discharge or death. sd = standard deviation; sob = shortness of breath; iqr = interquartile range; icu = intensive care unit. table 2: radiological findings of patients with confirmed diagnosis of covid-19 included in this study (n = 64) finding n (%) abnormal cxr at admission 60 (93.8) median days since symptoms started and the cxr was acquired (iqr) 7 (5–8) abnormal cxr findings (n = 60) consolidation 50 (83.3) ggo 58 (96.7) cavitation 0 (0) central 4 (6.7) peripheral 20 (33.3) mixed central and peripheral 36 (60.0) unilateral 9 (15.0) bilateral 51 (85.0) unifocal 3 (5.0) multifocal 57 (95.0) pleural effusion 2 (3.3) total score of the baseline cxr mean ± sd 11.91 ± 7.84 median (iqr) 12.5 (4–18) cxr = chest x-ray; sd = standard deviation; iqr = interquartile range; ggo = ground glass opacity. rashid s. al umairi, ishaq al salmi, jokha al kalbani, atheel kamona, saqar al tai, faiza al kindi, sachin jose, faryal khamis, huda al khalili and mohammed al busaidi clinical and basic research | 101 predominant distribution (n = 36, 60.0%), followed by peripheral (n = 20, 33.3%) and central distribution (n = 4, 6.7%). multifocal distribution was more common (n = 57, 95.0%) than unifocal distribution (n = 3, 5.0%) [table 2]. table 3: association between initial chest x-ray score and patient characteristics variable total baseline cxr score median score (iqr) p value* age group in years 20–29 10 (0.5–19.5) 0.296 30–39 13 (4–16) 40–49 14 (4–22) 50–59 7.5 (2.5–11.5) 60–69 13.5 (6.3–22.8) ≥70 12 (5–17) diabetes mellitus yes 13 (7–19) 0.149 no 11 (2.5–17.5) hypertension yes 11 (5–18) 0.797 no 13 (4–18.5) ischaemic heart disease yes 6.5 (0–13) 0.288 no 12.5 (4–18.3) chronic kidney disease yes 3.5 (0.8–7.3) 0.010† no 13 (4.8–19) hyperlipidaemia yes 13 (3–24) 0.625 no 12 (4–18) icu admission yes 14 (12–21) 0.0001† no 2.5 (1–5) intubation yes 16 (13–21) 0.0001† no 5 (1.5–12.5) outcome recovered 11 (4–16) 0.009† deceased 17 (12–22.5) cxr = chest x-ray; iqr = interquartile range; icu = intensive care unit. *using mann-whitney u test. †statistically significant. table 4: association between patients’ clinical and laboratory findings and final outcome variable total n (%) p value recovered deceased gender male 57 42 (73.7) 15 (26.3) 1.000 female 7 5 (71.4) 2 (28.6) mean age in years ± sd 46.57 ± 13.57 60.29 ± 13.91 0.001* diabetes mellitus yes 27 16 (59.3) 11 (40.7) 0.044* no 37 31 (83.8) 6 (16.2) ischemic heart disease yes 2 2 (100) 0 (0) 1.000 no 62 45 (72.6) 17 (27.4) hyperlipidaemia yes 5 4 (80.0) 1 (20.0) 1.000 no 59 43 (72.9) 16 (27.1) chronic kidney disease yes 6 6 (100) 0 (0) 0.182 no 58 41 (70.7) 17 (29.3) hypertension yes 19 12 (63.2) 7 (36.8) 0.236 no 45 35 (77.8) 10 (22.2) wbc count normal 44 36 (81.8) 8 (18.2) 0.034* abnormal 20 11 (55.0) 9 (45.0) crp in mg/l <10 1 1 (100) 0 (0) 0.137 10–50 15 14 (93.3) 1 (6.7) 50–100 17 13 (76.5) 4 (23.5) 100–150 9 6 (66.7) 3 (33.3) >150 22 13 (59.1) 9 (40.9) lymphocyte normal 21 16 (76.2) 5 (23.8) 1.000 abnormal 43 31 (72.1) 12 (27.9) neutrophils normal 22 (84.6) 4 (15.4) 0.149 abnormal 25 (65.8) 13 (34.2) sd = standard deviation; wbc = white blood cell; crp = c-reactive protein; egfr = estimate glomerular filtration rate; ggo = ground glass opacity. *statistically significant. covid-2019 pneumonia severity and distribution of lung changes observed on the initial chest x-ray as an indicator of final outcomes 102 | squ medical journal, february 2022, volume 22, issue 1 the median score of initial cxr for deceased patients was significantly higher than for those who recovered (17 versus 11; p = 0.009). in addition, there was a higher median score for initial cxrs for those who were admitted to the icu than those who were not admitted to the icu (14 versus 2.5; p = 0.0001). similarly, higher median scores of the initial cxrs were observed for those who were intubated compared to those who were not intubated (16 versus 5; p = 0.0001) [table 3]. a significant positive correlation was found between the duration of hospitalisation and the score of the initial cxr (correlation coefficient = 0.381; p = 0.002). there was no significant correlation between the initial cxr and duration of icu admission or intubation. upon review of the follow-up cxrs, five evolution patterns were identified: type i (initial deterioration followed by improvement), type ii (fluctuate), type iii (static), type iv (progressive deterioration) and type v (progressive improvement). type iii and iv progr ession patterns were the most frequent among the deceased group. age (p = 0.001), diabetes mellitus (p = 0.044) and wbc count (p = 0.034) were significantly associated with the final outcomes of the patients in the univariate analysis [table 4]. there was a statistically significant difference in the mortality rate between the comorbidity groups (p = 0.004). the mortality rate among patients who had no comorbidity was 10.3% (n = 3), whereas the mortality rates among single comorbidity and multiple comorbidity groups were 56.3% (n = 9) and 26.3% (n = 5), respectively. a multivariate binary logistic regression was performed to determine the effects of age, baseline cxr score, diabetes mellitus and wbc count on the likelihood of mortality among patients with covid-19 pneumonia. the logistic regression model was statistically significant (χ2 [4] = 24.130; p = 0.0001). the model explained 45.8% (nagelkerke r2) of the variance in the outcome mortality and correctly classified 87.5% of cases. increasing age (odds ration [or] = 1.085, 95% confidence interval [ci]: 1.027– 1.147; p = 0.004) and baseline cxr score (or = 1.113, table 4 (cont’d.): association between patients’ clinical and laboratory findings and final outcome variable total n (%) p value egfr in ml/min/1.73m2 ≥90 40 31 (77.5) 9 (22.5) 0.132 60–90 16 11 (68.8) 5 (31.3) 30–60 4 3 (75.0) 1 (25.0) 15–30 2 0 (0) 2 (100) <15 2 2 (100) 0 (0) consolidation yes 50 34 (68.0) 16 (32.0) 0.089 no 14 13 (92.9) 1 (7.1) ggo yes 58 42 (72.4) 16 (27.6) 1.000 no 6 5 (83.3) 1 (16.7) pleural effusion yes 2 1 (50.0) 1 (50.0) 0.464 no 62 46 (74.2) 16 (25.8) progression pattern initial deterio ration followed by improve ment (type i) 11 9 (81.8) 2 (18.2) 0.014* fluctuation (type ii) 1 1 (100) 0 (0) static (type iii) 18 11 (61.1) 7 (38.9) progressive deterio ration (type iv) 12 5 (41.7) 7 (58.3) progressive improve ment (type v) 18 17 (94.1) 1 (5.9) sd = standard deviation; wbc = white blood cell; crp = c-reactive protein; egfr = estimate glomerular filtration rate; ggo = ground glass opacity. *statistically significant. table 5: multivariate binary logistic regression analysis to determine the independent predictors of mortality variable b p value or (95% ci) age 0.082 0.004* 1.085 (1.027–1.147 total baseline cxr score 0.107 0.044* 1.113 (1.003–1.236) diabetes mellitus no (reference) yes 0.936 0.207 2.550 (0.595–10.928) wbc count normal (reference) abnormal 1.420 0.065 4.138 (0.916–18.700) or = odds ratio; ci = confidence interval; cxr = chest x-ray; wbc = white blood cell. *statistically significant. rashid s. al umairi, ishaq al salmi, jokha al kalbani, atheel kamona, saqar al tai, faiza al kindi, sachin jose, faryal khamis, huda al khalili and mohammed al busaidi clinical and basic research | 103 95% ci: 1.003–1.236; p = 0.044) were significantly associated with an increased likelihood of mortality [table 5]. discussion a combination of clinical suspicion, rt-pcr and cxr and ct imaging is used to diagnose covid-19.5,23 although cxr is less sensitive when compared to ct, as well as due to the infection control issues and lack of availability of ct machines in many parts of the world, cxr is an alternative imaging modality that can be used for identification and follow-up of lung abnormalities in patients with covid-19.11,24 in the current study, ggo was the most common cxr manifestation of covid-19 pneumonia (96.7%), followed by consolidation (83.3%). mixed peripheral and central distribution of lung abnormalities was the most common distribution (60.0%) followed by peripheral distribution alone (33.3%). predilection for lower lung zones involvement was another feature of covid-19 pneumonia on cxr. pleural effusion was rare as it was seen in only two patients. the absence of cavitation is an important negative finding that, when present, requires consideration of an alternative diagnosis or co-existing or added superinfection. the current study’s results are consistent with the findings reported in several recent studies.11,12 cxr findings of covid-19 pneumonia can overlap with other viral pneumonias, in particular, other coronavirus infections, due to the similar pathogenesis of viruses belonging to the same family. for example, sars and middle east respiratory syndrome (mers) share common cxr manifestations with covid-19.17 therefore, these findings need to be interpreted in combination with the clinical context of patients. the cxr score was found to be an independent predictor of mortality and morbidity of admitted patients with covid-19 pneumonia in the current study. a higher cxr score is associated with increased duration of hospitalisation, rate of icu admission and intubation along with increased fatality. borghesi et al. used a different scoring system to quantify the severity of cxr findings of patients with covid-19 pneumonia. each cxr was divided into three zones and each zone was given a score as follows: 0 was no lung abnormality, 1 was intestinal infiltrates, 2 was intestinal and alveolar infiltrates (interstitial predominance) and 3 was intestinal and alveolar infiltrates (alveolar predominance). findings indicated that a high cxr score is associated with higher inhospital mortality.25,26 regarding the temporal evaluation of lung abnormalities in the current study, progressive deterioration (type iv pattern) and static findings figure 1: chest x-rays (cxrs) showing the division of each lung divided into three equal zones with each zone given a score from 0 to 4 based on the percentage the lung involved. a: initial frontal chest radiograph of 40-year-old man with covid-19 showing clear lung filed (cxr score =0). b: initial frontal cxr of a 57-year-old male with covid-19 showing right middle zone consolidation along with ground-glass opacities in left lower lung zone (cxr score = 2). c: initial frontal cxr of a 64-year old male with covid-19 showing right and left middle zones ground-glass opacity, right and left lower zones consolidation as well as ground-glass opacity (cxr score = 7). d: follow-up frontal cxr of a 67-year old male with covid-19 showing bilateral diffuse consolidation and ground-glass opacities (cxr score = 24). rulz = right upper lung zone; rmlz = right middle lung zone; rllz = right lower lung zone; lulz = left upper lung zone; lmlz = left middle lung zone; lllz = left lower lung zone. covid-2019 pneumonia severity and distribution of lung changes observed on the initial chest x-ray as an indicator of final outcomes 104 | squ medical journal, february 2022, volume 22, issue 1 (type iii pattern) were the most common evolution patterns among the deceased group, whereas the progressive improvement pattern was the most frequently observed pattern among recovered patients. wong et al. studied the pattern of progression of 138 patients with sars and found the most common pattern was initial radiographic deterioration to peak level followed by radiographic improvement.27 das et al. studied the progression pattern in 55 patients with mers and found that progressive deterioration was the most common progressive pattern.28 this study is an adjunct to the current literature since it proposes another quantifying method to assess the severity of cxr findings in patients with covid-19 that can help stratify patients and plan their management. older age and diabetes mellitus were significantly associated with an increased likelihood of mortality. these findings are consistent with results from prior studies.29 this study was subject to certain limitations. first, this study had a small sample size. second, due to this study’s retrospective nature, some important clinical information might not be well documented (for example, viral load, oxygen saturation and detailed symptoms at presentation). lastly, visual estimation of the lung zones and percentage of lung involvement are subjective; therefore, the percentage of lung involvement might be overor under-estimated. conclusion a high score of the initial cxr in patients with covid-19 pneumonia, accompanied by increased age, diabetes mellitus and increased wbc count, were associated with a poor prognosis and higher mortality. this information could help clinicians stratify and manage patients with covid-19 pneumonia better. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n rsu and mab collected the data. rsu, ias and jak reviewed the chest x-ray. rsu drafted the manuscript. sj performed the statistical analysis and wrote the statistical section. ak, sat, fak, fk and hak reviewed the manuscript and provided intellectual input. all authors approved the final version of the manuscript. references 1. de jaegere tmh, krdzalic j, fasen bacm, kwee rm; covid-19 ct investigators south-east netherlands (cisen) study group. radiological society of north america chest ct classification system for reporting covid-19 pneumonia: interobserver variability and correlation with reverse-transcription poly merase chain reaction. radiol cardiothorac imaging 2020; 2:e200213. https://doi.org/10.1148/ryct.2020200213. 2. ge h, wang x, yuan x, xiao g, wang c, deng t, et al. the epidem iology and clinical information about covid-19. eur j clin microbiol infect dis 2020; 39:1011–19. https://doi.org/10.1007/ s10096-020-03874-z. 3. chen n, zhou m, dong x, qu j, gong f, han y, et al. epidem iological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study. lancet 2020; 395:507–13. https://doi.org/10.1016/s0140-6736(20)30211-7. 4. world health organization. coronavirus disease 2019 events as they happen 2020. from: https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/events-as-they-happen accessed: dec 2020. 5. udugama b, kadhiresan p, kozlowski hn, malekjahani a, osborne m, li vyc, et al. diagnosing covid-19: the disease and tools for detection. acs nano 2020; 14:3822–35. https://doi.org/10.10 21/acsnano.0c02624. 6. rothan ha, byrareddy sn. the epidemiology and pathogenesis of coronavirus disease (covid-19) outbreak. j autoimmun 2020; 109:102433. https://doi.org/10.1016/j.jaut.2020.102433. 7. ai t, yang z, hou h, zhan c, chen c, lv w, et al. correlation of chest ct and rt-pcr testing for coronavirus disease 2019 (covid-19) in china: a report of 1014 cases. radiology 2020; 296:e32–40. https://doi.org/10.1148/radiol.2020200642. 8. liu j, yu h, zhang s. the indispensable role of chest ct in the detection of coronavirus disease 2019 (covid-19). eur j nucl med mol imaging 2020; 47:1638–9. https://doi.org/10.1007/s00259020-04795-x. 9. bai hx, hsieh b, xiong z, halsey k, choi jw, tran tml, et al. performance of radiologists in differentiating covid-19 from non-covid-19 viral pneumonia at chest ct. radiology 2020; 296:e46–54. https://doi.org/10.1148/radiol.2020200823. 10. fang y, zhang h, xie j, lin m, ying l, pang p, et al. sensitivity of chest ct for covid-19: comparison to rt-pcr. radiology 2020; 296:e115–17. https://doi.org/10.1148/radiol.2020200432. 11. wong hyf, lam hys, fong ah, leung st, chin tw, lo csy, et al. frequency and distribution of chest radiographic findings in patients positive for covid-19. radiology 2020; 296:e78–8. https://doi.org/10.1148/radiol.2020201160. 12. lomoro p, verde f, zerboni f, simonetti i, borghi c, fachinetti c, et al. covid-19 pneumonia manifestations at the admission on chest ultrasound, radiographs, and ct: single-center study and comprehensive radiologic literature review. eur j radiol open 2020; 7:100231. https://doi.org/10.1016/j.ejro.2020.100231. 13. cheng z, lu y, cao q, qin l, pan z, yan f, et al. clinical features and chest ct manifestations of coronavirus disease 2019 (covid-19) in a single-center study in shanghai, china. ajr am j roentgenol 2020; 215:121–6. https://doi.org/10.2214/ajr.20.22959. 14. chung m, bernheim a, mei x, zhang n, huang m, zeng x, et al. ct imaging features of 2019 novel coronavirus (2019-ncov). radiology 2020; 295:202–7. https://doi.org/10.1148/radiol.202 0200230. 15. han r, huang l, jiang h, dong j, peng h, zhang d. early clinical and ct manifestations of coronavirus disease 2019 (covid-19) pneumonia. ajr am j roentgenol 2020; 215:338–43. https:// doi.org/10.2214/ajr.20.22961. https://doi.org/10.1148/ryct.2020200213 https://doi.org/10.1007/s10096-020-03874-z https://doi.org/10.1007/s10096-020-03874-z https://doi.org/10.1016/s0140-6736(20)30211-7 https://doi.org/10.1021/acsnano.0c02624 https://doi.org/10.1021/acsnano.0c02624 https://doi.org/10.1016/j.jaut.2020.102433 https://doi.org/10.1148/radiol.2020200642 https://doi.org/10.1007/s00259-020-04795-x https://doi.org/10.1007/s00259-020-04795-x https://doi.org/10.1148/radiol.2020200823 https://doi.org/10.1148/radiol.2020200432 https://doi.org/10.1148/radiol.2020201160 https://doi.org/10.1016/j.ejro.2020.100231 https://doi.org/10.2214/ajr.20.22959 https://doi.org/10.1148/radiol.2020200230 https://doi.org/10.1148/radiol.2020200230 https://doi.org/10.2214/ajr.20.22961 https://doi.org/10.2214/ajr.20.22961 rashid s. al umairi, ishaq al salmi, jokha al kalbani, atheel kamona, saqar al tai, faiza al kindi, sachin jose, faryal khamis, huda al khalili and mohammed al busaidi clinical and basic research | 105 16. li k, wu j, wu f, guo d, chen l, fang z, et al. the clinical and chest ct features associated with severe and critical covid-19 pneumonia. invest radiol 2020; 55:327–31. https://doi.org/10.10 97/rli.0000000000000672. 17. li y, xia l. coronavirus disease 2019 (covid-19): role of chest ct in diagnosis and management. ajr am j roentgenol 2020; 214:1280–6. https://doi.org/10.2214/ajr.20.22954. 18. ng my, lee eyp, yang j, yang f, li x, wang h, et al. imaging profile of the covid-19 infection: radiologic findings and liter ature review. radiol cardiothorac imaging 2020; 2:e200034. https://doi.org/10.1148/ryct.2020200034. 19. wu j, wu x, zeng w, guo d, fang z, chen l, et al. chest ct findings in patients with coronavirus disease 2019 and its relationship with clinical features. invest radiol 2020; 55:257–61. https://doi.org/10.1097/rli.0000000000000670. 20. xiong y, sun d, liu y, fan y, zhao l, li x, et al. clinical and high-resolution ct features of the covid-19 infection: comp arison of the initial and follow-up changes. invest radiol 2020; 55:332–9. https://doi.org/10.1097/rli.0000000000000674. 21. xu x, yu c, qu j, zhang l, jiang s, huang d, et al. imaging and clinical features of patients with 2019 novel coronavirus sarscov-2. eur j nucl med mol imaging 2020; 47:1275–80. https:// doi.org/10.1007/s00259-020-04735-9. 22. xu yh, dong jh, an wm, lv xy, yin xp, zhang jz, et al. clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by sars-cov-2. j infect 2020; 80:394–400. https://doi.org/10.1016/j.jinf.2020.02.017. 23. singhal t. a review of coronavirus disease-2019 (covid-19). indian j pediatr 2020; 87:281–6. https://doi.org/10.1007/s120 98-020-03263-6. 24. american college of radiology. acr recommendations for the use of chest radiography and computed tomography (ct) for suspected covid-19 infection. from: https://www.acr.org/ ad v o c a c y a n d e co n o m i c s / ac rpo s i t i o n -s t at e m e nt s / re commendations-for-chest-radiography-and-c t-forsuspected-covid19-infection accessed: dec 2020. 25. borghesi a, zigliani a, golemi s, carapella n, maculotti p, farina d, et al. chest x-ray severity index as a predictor of inhospital mortality in coronavirus disease 2019: a study of 302 patients from italy. int j infect dis 2020; 96:291–3. https://doi. org/10.1016/j.ijid.2020.05.021. 26. borghesi a, maroldi r. covid-19 outbreak in italy: experi mental chest x-ray scoring system for quantifying and monit oring disease progression. radiol med 2020; 125:509–13. https:// doi.org/10.1007/s11547-020-01200-3. 27. wong kt, antonio ge, hui ds, lee n, yuen eh, wu a, et al. severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients. radiology 2003; 228:401–6. https://doi.org/10.1148/radiol.2282030593. 28. das km, lee ey, al jawder se, enani ma, singh r, skakni l, et al. acute middle east respiratory syndrome coronavirus: temporal lung changes observed on the chest radiographs of 55 patients. ajr am j roentgenol 2015; 205:w267–74. https:// doi.org/10.2214/ajr.15.14445. 29. lu l, zhong w, bian z, li z, zhang k, liang b, et al. a comp arison of mortality-related risk factors of covid-19, sars, and mers: a systematic review and meta-analysis. j infect 2020; 81:e18–25. https://doi.org/10.1016/j.jinf.2020.07.002. https://doi.org/10.1097/rli.0000000000000672 https://doi.org/10.1097/rli.0000000000000672 https://doi.org/10.2214/ajr.20.22954 https://doi.org/10.1148/ryct.2020200034 https://doi.org/10.1097/rli.0000000000000670 https://doi.org/10.1097/rli.0000000000000674 https://doi.org/10.1007/s00259-020-04735-9 https://doi.org/10.1007/s00259-020-04735-9 https://doi.org/10.1016/j.jinf.2020.02.017 https://doi.org/10.1007/s12098-020-03263-6 https://doi.org/10.1007/s12098-020-03263-6 https://doi.org/10.1016/j.ijid.2020.05.021 https://doi.org/10.1016/j.ijid.2020.05.021 https://doi.org/10.1007/s11547-020-01200-3 https://doi.org/10.1007/s11547-020-01200-3 https://doi.org/10.1148/radiol.2282030593 http://v http://v https://doi.org/10.1016/j.jinf.2020.07.002 laboratory diagnosis of viral hepatitis c laboratory diagnosis of viral hepatitis c the sultan qaboos university hospital experience *said h s al dhahry1, jameel c nograles2, situsekara m w w b rajapakse2, fadhila s s al toqi2, geraldine z kaminski2 squ journal for scientific research: medical sciences 2003 vol 5, no. –2, 5–20 ©sultan qaboos universit y abstrac t. objectives: a retrospective study was carried out to assess the performance of hepatitis c diagnostic assays in our laboratory, and to determine the prevalence of hepatitis c among blood donors at the sultan qaboos university hospital. methods: from 1991 to 2001, approximately 55,000 serum samples collected from blood donors and patients were submitted to our laboratory for testing. all sera were screened for antibodies to hepatitis c virus (hcv) by three successive generations of the enzyme-linked immunosorbent assay (elisa). anti-hcv positive sera were further tested by recombinant immunoblot assay (riba). reverse-transcriptase polymerase chain reaction (rtpcr) for hcv rna was carried out on a limited number (241) of elisa positive samples. results: out of 30012 samples from blood donors that were screened for anti-hcv, 272 (0.91%) were positive. of these, 46.5% were confirmed positive by riba. the proportion of patient sera that were confirmed positive varied from 95% among intravenous drug users to 81% in patients with hepatitis to 70% in those with haemoglobinopathies. hcv rna was detected in 67%, 6%, and 0% of the riba positive, indeterminate and negative samples respectively. conclusions: based on riba, the prevalence of anti-hcv among blood donors in oman is close to 0.5%. in our experience, riba-positivity is predictive of hcv infection in two thirds of subjects, and hcv infection is highly unlikely in those who are riba-negative. the experience at squh with three types of hcv assays has enabled the laboratory to develop a test algorithm, starting with screening anti-hcv elisa. key words: hepatitis c virus, elisa, riba, polymerase chain reaction. 1department of microbiology and immunology, college of medicine and health sciences, sultan qaboos university, p o box 35, al khod, muscat-123, sultanate of oman 2department of microbiology and immunology, sultan qaboos university hospital, p o box 38, al khod-123, muscat, sultanate of oman *to whom correspondence should be addressed. email: sdhahry@squ.edu.om hepatitis c virus (hcv) is a blood-borne pathogen that appears to be endemic in most parts of the world. it is estimated by the world health organization that there are 70 million hcvinfected persons worldwide.1 currently, hcv is the leading cause of post-transfusion hepatitis and end-stage liver disease requiring liver transplantation.2 the disease it causes is characterised by silent onset, a high rate of viral persistence, and the potential for development of chronic liver disease, ranging from chronic hepatitis to cirrhosis and occasionally hepatocellular carcinoma.3 the discovery of the genome of hcv in 989 by choo et al4 paved the way for development of serological and molecular assays for viral hepatitis c. in the first generation of an enzyme-linked immunosorbent assay (elisa), wells of microtitre plates were coated with purified recombinant antigen c00-3 that was derived from the non-structural 4 (ns4) region of the hcv genome [figure ]. however, elisa- was associated with a high percentage (50% to 70%) of false positive results among low-risk blood donors and in the presence of hyperglobulinemia.5 thus, second-generation anti-hcv elisas were developed. elisa-2 by ortho diagnostics contained recombinant antigens from the core (c22-3), ns3 region (c33c), and ns4 region (c00-3) as well as a part of c00-3, named 5-- [figure ]. third generation antihcv elisa was introduced in europe in 993 and in the usa in 996. in addition to the antigens of elisa-2, third-generation anti-hcv elisa uses an antigen of the ns5 region of the viral genome. however, synthetic pepsaid dhahri �����������������������������������: ���������������������������� ������������������������������������������������������������������������� ��������:�����:�������������������������������������������������������������������������������������� �������������������������������������������������������������������������������:-�������������������� ����������������������������������������������������������elisa.������������������������������������ riba.������������������������������������������������)rt-pcr(.�������:������������������������������� �����)���� (%�������������������������������%����������������������riba.����������������������������� ������������������������������������������%��� %���%��������.������������������������������������������ �������������������riba���������%�� %�� %��������.������:������������������������������������������ ��������������������������������������� %������riba.�������������������������������������������������������� ��������������������riba.������������ :����� ������ ��������� ������ ������������������������������� 6 d h a h r y e t a l tide antigens (c22 and c-00) replaced recombinant antigens of elisa-2 [table , figure ]. other manufactures, for example abbott diagnostics, used recombinant antigens derived from the same regions of hcv genome. despite increased sensitivity and specificity with each generation of elisa, false-positive antibody results continue to be observed, particularly among low-risk blood donors.6 thus, supplemental or confirmatory assays were developed in parallel with elisa. the recombinant immunoblot assay (riba) has been used extensively to confirm presence or absence of antibody to hcv epitopes. in riba recombinant or peptide hcv antigens are blotted as separate bands onto a nitrocellulose strip flanked by a weak-positive (level i) and a moderately positive (level ii) strip control [figure 2]. although technically more demanding than elisa, the riba identifies antibodies to individual hcv antigens and therefore has higher specificity than elisa.7 since elisa and riba are antibody tests, positivity of either one or both does not necessarily indicate current hcv infection as patients who have recovered from infection may remain anti-hcv positive for many years.7 conversely, during seroconversion, antibody tests may be negative.8 the direct molecular qualitative detection of hcv rna by reverse-transcriptase polymerase chain reaction (rt-pcr) is considered the gold standard for the diagnosis of hcv infection.6 testing for hcv was introduced at the sultan qaboos university hospital (squh) in 99, starting with the first-generation elisa. in subsequent years, new generations of both elisa and riba were used as they became commercially available. the rt-pcr was introduced in the year 2000. we report here our results and experience in testing blood donors, patients suspected to have viral hepatitis, and other subjects from 99 to 200. m a t e r i a l s a n d m e t h o d s sera. serum samples for hcv testing were collected from blood donors and patients mainly at squh. a few were sent from other hospitals within the capital area table 1. antigens incorporated in serological assays (elisa and riba) for hepatitis c. assay elisa riba first generation c100-3 c100-3 5-1-1 second generation c100-3 c100-3 c22-3 5-1-1 c33c c22-3 c33c third generation c100-3 c100-3/5-1-1 (peptide) c200 (c100-3 + c33c) c22-3 (peptide) c22-3 c33c ns5 recombinant antigen ns5 recombinant antigen figure 1. genome organization of hcv and antigens licensed for diagnostic use. 7 of muscat. in 99, approximately ,350 sera were tested. in 992, the figure had trebled, and by 200, it reached 6,500. over a period of  years, approximately 55,000 serum samples were submitted for hcv testing. screening for anti-hcv. all sera were first screened for the presence of antibodies to hcv. in 99, the mictotitre-based, first-generation elisa (hcv c00-3 elisa, ortho diagnostic systems, raritan, nj) was used. between 992 and 996, different formats of secondgeneration enzyme immunoassays (abbott diagnostic division, germany) were used in the following chronological order: hcv eia on quantum™ instrument, micro particle enzyme immunoassay on imx,™ and micro particle enzyme immunoassay on axsym™ analyser. the three analysers were from abbott laboratories, diagnostic division, usa. from 997 to 200, sera were screened by a third-generation micro particle enzyme immunoassay on the axsym.™ samples that were initially reactive by elisa were retested in duplicate, and results were interpreted according to manufacturers’ instructions. supplementary assay. the second-generation recombinant immunoblot assay (riba hcv 2, chiron corp., emeryville, ca) was introduced in our laboratory in mid994, and was replaced by third generation assays (riba hcv 3, chiron and hcv blot, genelab diagnostics, singapore) by the end of 996. all sera that were repeatedly reactive in elisa were subjected to supplemental testing by riba according to manufacturers’ recommendations. in these assays specimens were considered positive if they demonstrated reactivity to two or more antigen bands at an intensity greater than, or equal to the weak positive control. specimens reacting with a single antigen band were classified as indeterminate and specimens producing no reactive bands or bands with an intensity less than the weak positive control were classified as negative. hcv rna detection. hcv rna was assayed on plasma or serum samples using the hcv monitor (v2.0) rtpcr kit on the cobas amplicor system (roche diagnostics, switzerland). data storage. demographic, clinical and laboratory data of all subjects whose samples tested positive for anti-hcv by elisa were kept in a microsoft access database for retrieval and analysis. r e s u l t s of the approximately 55,000 serum samples that were screened for anti-hcv antibodies from 99 to 200, 30,02 were from blood donors. the annual anti-hcv positivity rate among blood donors varied from .4% l a b o r at o r y a n a ly s i s o f v i r a l h e pat i t i s c table 2. prevalence of antibodies to hepatitis c virus among blood donors year no. tested no. positive % positive 1991* 668 6 0.9 1992 2596 34 1.3 1993 3584 51 1.4 1994 2033 23 1.1 1995 2330 20 0.86 1996 2637 25 0.95 1997 2638 26 0.99 1998 2817 20 0.71 1999 2996 19 0.63 2000 3290 23 0.7 2001 4423 25 0.57 *first, second and third generation anti-hcv elisas were used to screen blood donors in 1991, 1992–1996, and 1997 –2001, respectively. figure 2. identity and location of hcv antigens on a nitrocellulose strip of the recombinant immunoblot assay 8 in 993 to 0.57% in 200, and the mean rate was 0.9% [table 2]. on average, proportionately more samples tested positive in second generation elisa than in third generation. of a total of 2,039 sera that were reactive by elisa from 994 to 200, ,457 (7.5%) were tested by riba [table 3]. the proportion of samples confirmed positive for anti-hcv antibodies varied widely. it was high among intravenous drug users (95.5%) and patients with liver disease (80.9%), intermediate in patients with haemoglobinopathies, and low among blood donors (46.5%) [table 3]. the majority of patients with liver disease had hepatitis, liver cirrhosis or hepatocellular carcinoma. the impact of changing from second to third generation assays is summarized in table 4. although third generation riba confirmed more positive samples than second generation riba, it was also associated with slightly more indeterminate results. plasma samples from 24 elisa positive subjects were assayed by hcv rt-pcr. these samples were collected in 2000 and 200. overall hcv rna was detected in (49.8 %) of the subjects. when results were analysed according to riba-3 status, 67.4%, 5.7% and 0% of the riba positive, inderterminate and negative subjects respectively had hcv rna [table 5]. d i s c u s s i o n the introduction of anti-hcv elisa to screen blood donors has led to a dramatic reduction in post-transfusion non-a non-b hepatitis, and the detection of antibodies to hcv has become the most practical means of diagnosing infection.5 over a period of  years, three generations of elisa were used at squh to screen healthy subjects, particularly blood donors, and patients for anti-hcv and two generations of riba as supplementary test. based on elisa, the prevalence of hcv among blood donors in oman is close to %. however, since only about half of these were confirmed by riba, the true prevalence is about 0.5%. on the basis of studies among blood donors that used both elisa and supplemental testing the lowest anti-hcv prevalence rates (0.0– d h a h r y e t a l table 3. confirmatory assay of anti-hcv elisa positive samples from blood donors and patients. clinical category no. samples elisa positive no. tested by riba % riba positive % riba indeterminate % riba negative liver disease 406 340 80.9 13.8 5.3 thalassaemia 840 628 69.6 19.8 10.7 sickle cell disease 126 111 71.2 17.1 11.7 intra-venous drug abuse 25 22 95.5 4.5 0 other diseases 133 107 61.7 27.1 11.2 disease not specified 237 105 60.9 25.7 13.3 blood donors 272 144 46.5 23.6 29.9 total 2039 1457 69.3 19.3 11.5 table 4. comparison of detection rates of anti-hcv antibodies by second and third generation serological assays generation elisa and system % riba-2 % riba-3 positive indeterminate negative positive indeterminate negative elisa-3 quantum (n=117) 61.5 12.8 25.6 –* – – elisa-2 imx(n=222) 59.8 21.0 19.2 – – – elisa-2 axsym(n=249) 54.2 13.3 32.5 – – – elisa-3 axsym(n=869) –* – – 69.9 20.8 9.3 *elisa-positive samples were re-tested by either second, or third generation riba. none of the samples was tested by both riba-2 and riba-3. 9 0.%) have been reported from the united kingdom9 and scandinavia.10 low but slightly higher rates (0.2– 0.5%) have been reported from western europe, north america, most areas of central and south america, and limited regions of africa.2 the rate reported here for oman falls into this group. intermediate rates of anti-hcv prevalence (–5%) have been found in other countries, including neighbouring yemen11 and saudi arabia.12 the proportion of anti-hcv elisa positive samples that were confirmed by either riba-2 or riba-3 varied from 47% in blood donors to 80% in patients with a clinical diagnosis of hepatitis. these findings are consistent with reports by other investigators.13–15 in populations at low risk for hepatitis c, such as blood donors, the proportion of samples confirmed positive by riba is low, and varies from 7% to 37%.9,13,14 on the other hand, most (80%–90%) of elisa-2 or elisa-3 positive patients with chronic liver disease are riba positive.13,15–17 the introduction of third generation riba was reported to have resolved many of the indeterminate samples of riba-2.14,18,19 in our experience, this was not the case. the proportion of indeterminate samples remained at about 20% when the laboratory changed from second to third generation assays. the results presented here show that hcv rna was detectable in 67% of riba-positive samples, in 6% of riba-indeterminates and in none of the samples that were riba negative. the mean detection rate was close to 50%. although our data is based on a small number of subjects, it is comparable to data from larger studies involving blood donors and individuals with normal alanine aminotransferase (alt) levels.7 in these subjects, the percentage that have detectable hcv rna in serum when tested by pcr assay varies from 70% to 80% for those who are riba positive to 2% to 40% for those who are riba indeterminate, to none among those who are riba negative, giving an overall detection rate of 35% to 45%. three types of assays (elisa, riba and pcr) were used at squh to test for hcv infection. do diagnostic laboratories need to use all three? different diagnostic algorithms have been proposed which reflects different opinions on this subject.5–7 there can be no question on the utility of elisa as a screening test for all subjects. the need for and the choice of supplementary and confirmatory tests depend on the clinical setting and the likelihood of a true-positive elisa result. in general, qualitative pcr assay for serum or plasma hcv rna is the best confirmatory assay and should be used in elisa positive patients who present with chronic liver disease. there is no need for doing riba in such cases. however, elisa-positive blood donors and individuals with normal alt levels may be evaluated by riba first, pcr for hcv rna being performed only on those who are riba positive or indeterminate. c o n c l u s i o n s at squh, we have used elisa and riba to detect antibodies to hcv as means of diagnosing hepatitis c. these two tests are relatively easy to perform. the recent introduction of hcv pcr assay has provided the laboratory with the tool to confirm presence of the virus, either in those who have anti-hcv antibodies, or those who lack antibodies but are suspected to be infected. acknowledgement we thank prof. mohammed idris for reviewing the manuscript. r e f e r e n c e s . world health organization. hepatitis c—global prevalence (update). wkly epidemiol rec, 999, 74, 425–427. 2. wasley a, alter mj. epidemiology of hepatitis c: geographic differences and temporal trends. sem liver dis, 2000, 20, – 6. 3. alter hj, seef lb. recovery, persistence, and sequelae in hepatitis c infection: a perspective on long-term outcome. sem liver dis, 2000, 20, 7–35. 4. choo ql, kuo g, weiner aj, overby lr, bradley dw, houghton m. isolation of a cdna clone derived from a bloodborne non-a, non-b viral hepatitis genome. science, 989, 244, 359–362. 5. de medina m, schiff er. hepatitis c: diagnostic assays. sem liver dis, 995, , 33–40. 6. schiff er, de medina m, kahn rs. new perspectives in the diagnosis of hepatitis c. sem liver dis, 999, 9, 3–5. 7. lok asf, gunaratnam nt. diagnosis of hepatitis c. hepatology, 997, 26(suppl ), 48–56s. 8. galel sa, strong dm, tegtmeier ge, holland pv, kuramoto ik, kemper m, et al. comparative yield of hcv rna testing in blood donors screened by 2.0 versus 3.0 antibody assays. transfusion, 2002, 42, 507–53. l a b o r at o r y a n a ly s i s o f v i r a l h e pat i t i s c table 5. comparison of third generation riba and pcr riba-3 results % pcr positive % pcr negative positive(n=175) 67.4 32.6 indeterminate(n=35) 5.7 94.3 negative(n=31) 0 100 20 9. dow bc, coote i, munro h, mcomish f, yap pl, simmonds p, et al. confirmation of hepatitis c virus antibody in blood donors. j med virol, 993, 4, 25–220. 0. nørdoy i, schrumpf, e, elgjo, k, flesland ø, andersen glende j, ørjasæter h et al. liver disease in anti-hepatitis c virus-positive norwegian blood donors. scand j gastroenterol, 994, 29, 77–8. . el guneid, am, gunaid, aa, o’neill, am, zureikat ni, coleman jc, murray-lyon im. prevalence of hepatitis b, c, and d virus markers in yemeni patients with chronic liver disease. j med virol, 993, 40, 330–333. 2. al-faleh fz, ramia s, arif m, ayoola ea, al-rashed rs, aljeffry m, et al. profile of hepatitis c virus and the possible modes of transmission of the virus in the gizan area of saudi arabia: a community-based study. ann trop med parasitol 995, 89, 43–437. 3. bresters d, zaaijer hl, cuypers htm, reesink hw, winkel in, van exel-oehlers aaj, et al. recombinant immunoblot assay reaction patterns and hepatitis c rna in blood donors and non-a, non-b hepatitis patients. transfusion, 993, 33, 634–638. 4. damen m, zaaijer hl, cuypers htm, vrielink h, van der poel, reesink hw et al. reliability of third-generation recombinant immunoblot assay for hepatitis c. transfusion, 995, 35, 745–749. 5. chemello l, cavalleto d, pontisso p, bortolotti f, donada c, donadon v, et al. patterns of antibodies to hepatitis c virus in patients with chronic non-a, non-b hepatitis and their relationship to viral replication and liver disease. hepatology, 993, 7, 79–82. 6. schrötter m, schäffer p, zöllner b, polywka s, laufs r, feucht h. strategies for reliable diagnosis of hepatitis c infection: the need for serological confirmatory assay. j med virol, 200, 64, 320–324. 7. polywka s, schrötter m, feucht h, zöllner b, laufs r. relevance of reactivity in commercially available hepatitis c virus antibody assays. j clin microbiol, 200, 39, 665–668. 8. uyttendaele s, claeys h, mertens w, verhaert h, vermylen c. evaluation of third-generation screening and confirmatory assays for hcv antibodies. vox sang, 994, 66, 22–29. 9. soffredini r, rumi m, lampertico p, aroldi a, tarantino a, ponticelli c. increased detection of antibody to hepatitis c virus in renal transplant patients by third generation assays. amer j kid dis, 996, 28, 437–440. d h a h r y e t a l laboratory diagnosis of viral hepatitis cthe sultan qaboos university hospital experience *said h s al dhahry1, jameel c nograles2, situsekara m w w b rajapakse2, fadhila s s al toqi2, geraldine z kaminski2 materials and methods results discussion conclusions acknowledgement references 1department of dermatology, hospital regional universitario de málaga, málaga, spain; 2department of dermatology, hospital clínico universitario virgen de la arrixaca, murcia, spain *corresponding author’s e-mails: anaseor95@gmail.com and ana.serrano.ordonez.sspa@juntadeandalucia.es porphyria cutanea tarda in a patient with myelofibrosis *ana serrano-ordóñez,1 daniel j. godoy-díaz,1 miguel lova-navarro2 sultan qaboos university med j, may 2023, vol. 23, iss. 2, pp. 274–275, epub. 31 may 23 submitted 27 nov 22 revision req. 24 jan 23; revision recd. 30 jan 23 accepted 5 feb 23 a 63-year-old male patient presented toa dermatology department with a four-month history of erosions affecting the dorsum of the hands. his medical history was remarkable for primary myelofibrosis on treatment with hydroxyurea and supportive transfusions for anaemia and thrombo cytopenia. he also reported high alcohol consumption. physical examination showed ruptured blisters with signs of superinfection. bacterial culture was positive for staphylococcus aureus and the patient received treatment with oral antibiotics. one week later, he reported improvement of the erosive lesions but also new blistering lesions on the dorsum of the hands [figure 1]. in addition, the patient also reported generalised skin hyperpigmentation in the last months. based on the suspicion of porphyria cutanea tarda (pct), we observed urine through wood’s light, which revealed bright red-pink fluorescence [figure 2]. laboratory tests revealed elevated serum ferritin and decreased haemoglobin and platelets. blood and urine porphyrines determination were compatible with pct. skin histology showed subepidermal blister formation and deposits of igg in the dermal-epidermal junction. the patient was treated with periodic phlebo tomies, with a good clinical response. patient consent was obtained for the publication of these images. comment pct is the most common human porphyria, due to a deficit in or inactivation of the uroporphyrine decarboxylase (urod) enzyme, which leads to accumulation of photosensitive metabolites. the accumulated uroporphyrines and intermediates spill over into the blood circulation and are excreted in the urine.1,2 it usually happens in adulthood and there are several known triggers, such as viral hepatitis, alcohol, hormone therapies, haemodialysis and condition leading to iron overload. it has also been reported to be associated with haematological disorders, mainly with thalassaemia, multiple myeloma, hairy cell leukaemia, acute myeloblastic leukaemia, chronic lymphocytic leukaemia and chronic myeloid leukaemia.3 there are a few reported cases of pct in association with myelofibrosis, yet the mechanism by which this occurs this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.1.2023.007 interesting medical image figure 1: tense bullae on the dorsal right hand and erosive lesions with milia and scarring on the dorsal left and right hand. marked skin hyperpigmentation. ana serrano-ordóñez, daniel j. godoy-díaz and miguel lova-navarro interesting medical image | 275 is unknown. one hypothesis suggests that myelofibrosis could induce hepatotoxicity leading to liver disfunction and pct.3 in the current case, the patient required multiple blood transfusions for treating anaemia caused by myelofibrosis. this situation provoked an iron overload and he finally developed pct. urine examination through wood’s lamp is a simple, fast and economic method that supports the diagnosis and can be performed immediately in the consultation room. treatment consists of removing probable sec ondary disease triggers, photoprotection, phlebotomy as an effective treatment of iron removal, resulting in improvement of hepatic urod activities and the use of hydroxychloroquine.1−3 here we report a case of pct in a patient with idiopathic myelofibrosis and we suggest the use of wood’s light as a tool to aid diagnosis of such cases. a u t h o r s’ c o n t r i b u t i o n all authors have contributed equally to the conception and design of the work, in drafting the manuscript and revising it critically. all authors approved the final version of the manuscript. references 1. singal ak. porphyria cutanea tarda: recent update. mol genet metab 2019; 128:271–81. https://doi.org/10.1016/j. ymgme.2019.01.004. 2. jin mf, wieland cn. porphyria cutanea tarda. mayo clin proc 2021; 96:1248–9. https://doi.org/10.1016/j.mayocp.20 20.12.025. 3. lee sc, yun sj, lee jb, lee ss, won yh. a case of porphyria cutanea tarda in association with idiopathic myelofibrosis and crest syndrome. br j dermatol 2001; 144:182–5. https://doi. org/10.1046/j.1365-2133.2001.03971.x. figure 2: urine sample fluorescing bright red-pink under wood’s light examination. march 2007 vol 7 isuue 1 final without suicide .indd sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© ovarian vein thrombophlebitis an unusual cause of postpartum fever and abdominal pain *anupam k kakaria pain in the lower abdomen in female patients can be a confusing problem at the best of times. in the immediate postpartum period, the situation is worsened as the list of possible diagnoses expands to include problems peculiar to the puerperal state like adnexal torsion, broad ligament hematoma and abscesses, in addition to the usual causes of pain like acute appendicitis,1 diverticulitis etc. the post partum state is characterized by many physiological changes including ligamentous laxity, hypercoagulability and other changes peculiar to this particular physiological event. it may be further compounded by bacterial inoculum caused by complicated parturition. post partum ovarian vein thrombophlebitis is an uncommon, potentially serious puerperal complication, unless it is diagnosed and treated promptly. prior to the introduction of cross sectional imaging, the diagnosis and management were often delayed. as the clinical examination and laboratory investigations are not able to delineate the problem clearly and provide a definitive diagnosis, imaging plays an important role in diagnosis and management of these patients. imaging can now provide an accurate and reliable method for the diagnosis and follow up of these patients. this may lead to early surgery if required. on the other hand, an alternative diagnosis can lead to medical management and obviate the need for unnecessary exploration. this complication is reported in 1 in 600 to 1 in 2,000 deliveries.2 *department of radiology, armed forces hospital, po box 726, pc 111, cpo seeb, muscat email: bittanupam@gmail.com abstract ovarian vein thrombophlebitis is an uncommon, but potentially serious, complication of complicated deliveries. prolonged rupture of membranes prior to delivery is a pre-disposing factor. we report a case of a patient with prolonged ruptured membranes, who developed right ovarian vein thrombophlebitis. the patient was managed medically and responded favourably to treatment. keywords: prolonged ruptured membranes, ovrarian vein thrombophlebitis, postpartum fever, case report, oman c a s e r e p o r t املبيض وريد في اخلثاري االلتهاب الوالدة بعد البطن وألم حلمى اعتيادية غير حالة كاكاريا كومار انوبام العوامل يكون أحد الوالدة طويلة من قبل فترة ــية األغش متزق املعقدة. الوالدات في خطيرة لكنها حالة نادرة، املبيض لوريد اخلُثارِيّ امللخص: االلتهاب املريضة عوجلت املبيض. اخلُثارِيّ لوريد االلتهاب حصول إلى الوضع، والذي أدى فترة طويلة من قبل األغشية متزق حالة يصف التقرير هذا لذلك. املسببة ملموس. بشكل وحتسنت باألدوية حالة، عمان. تقرير الوالدة، بعد ما حمى املبيض، لوريد اخلُثارِيّ طويلة، االلتهاب األغشية لفترة الكلمات: متزق مفتاح a n u pa m k k a k a r i a 60 c a s e r e p o r t the patient was a 26 year old female who presented to the antenatal clinic of the armed forces hospital, muscat, at a gestation age of 30 weeks. she was gravida three, para two with two living children. she presented with the chief complaint of liquid leaking from the vagina. on examination, the fundal height was consistent with the gestational age. an ultrasound revealed a normal for age fetus, but with reduced amniotic fluid. in view of the diagnosis of spontaneous rupture of membranes and the early gestational age, the patient was admitted and started on three antibiotics prophylactically (a third generation cephalosporin, an aminoglycoside and an antianerobic antibiotic) and dexamethasone. this was standard practice by gynecologists in this hospital for prolonged rupture of membranes. in spite of all efforts to prolong the gestation, the patient delivered spontaneously, vaginally on the 9th day of admission. although triple antibiotics were administered, the patient started to have spikes of fever reaching up to 39° c from the 11th day of admission. the white blood cell count was 12 x 109/l with 85% polymorphonuclear cells, and she started to complain of pain in the right iliac fossa from the 13th day of admission. on examination, there was tenderness on deep palpation of the right iliac fossa. mild rebound tenderness could be elicited. clinically acute appendicitis was suspected and the patient was referred for ultrasound examination. evaluation of the right iliac fossa revealed a long, tubular, non compressible aperistaltic structure located to the right of the inferior vena cava (ivc). the ultrasound findings and the clinical review did not produce a good fit for acute appendicitis and the patient was subjected to a computed tomography (ct) scan for further evaluation. contrasted enhanced ct identified a round lesion in the right paracaval region, with central hypodensity and marginal enhancement. the lesion veered towards the right iliac fossa on caudal scans. on cranial scans, the lesion indented and then projected into the lumen of the ivc [figs. 1 & 2]. a coronal reformat showed better the course of the lesion away from the cecum and pointing towards the ivc. the findings were consistent with the diagnosis of right ovarian vein thrombosis. the diagnosis had not been considered and came as a surprise. with this diagnosis in mind, two of the antibiotics (the aminoglycoside and the anti anaerobic antibiotic) were stopped empirically on the basis of the prevalent flora in the hospital at the time) and the patient was started on iv low molecular weight heparin. the patient, who had continued to be febrile on three antibiotics, improved significantly with the introduction of low molecular weight heparin and was afebrile within 48 hrs. the patient continued i/v heparin for 7 days after which she was put on oral anti coagulation titrated to keep inr of around 2-2.5. she continued oral anticoagulation for four weeks after which she was lost to follow up. further investigations for thrombophilia were not done in view of clear precipitating factors for the thrombophlebitis (prolonged rupture of membranes) and no previous history of thrombotic events in the previous pregnancies or otherwise. d i s c u s s i o n post partum ovarian vein thrombosis is an uncommon, but potentially serious, complication of post partum sepsis.3 ovarian vein thrombosis has an incidence of 1:600 to 1:2,000 deliveries.4 virchow’s triad is closely related to the pathogenesis of the puerperal vein thrombosis. the virchow’s triad consists of (a) change in circulating coagulation factor levels, (b) alterations in the vein walls, (c) stasis of blood flow. pregnancy and puerperium fulfill the first and the third criteria and the venous walls may be altered by the surgical trauma and bacterial insult to the endothelium. in addition, high thromboplastin levels in placenta and amniotic fluid may gain access to maternal circulation during parturition. right ovarian vein is involved in 80-90% of patients.2, 3 the increased incidence of the right vein involvement may be partly due to dextrorotaion of the enlarging uterus which compresses the right ovarian vein at the pelvic brim and partly due to retrograde flow from the left ovarian and uterine veins into the right system, which increases the size of the bacterial inoculum in the right ovarian vein. in addition, the increased length of the right ovarian vein and presence of multiple incompetent valves are contributory factors.5 the patients complain of pyrexia starting 2-4 days postpartum or post operatively. lower quadrant pain on right or the left side, depending on the side of vein involved, may be associated with chills, tachycardia, nausea, and vomiting.5, 6, 7 acute appendicitis, adnexal torsion, abscess, pyelonephritis are the differential diagnoses. ultrasound is the initial imaging investigation of choice and usually can suggest the correct diagnosis. o va r i a n ve i n th r o m b o p h l e b i t i s 61 in cases of ambiguity, ct with contrast can help in resolving this dilemma. due to flow sensitivity and ability to assign the age to the venous clot, the mri may be of use in difficult cases. surgical ligation of the ovarian vein was sometimes used in the past for controlling a possible pulmonary embolism. currently, the management is mainly medical. there is no standard protocol for the duration of anticoagulation or conversion to warfarin.2 surgical excision may have to be resorted to in cases of failure of medical management and pulmonary embolism.8 c o n c l u s i o n recognition and adequate treatment of this rare but significant complication of pregnancy is critical as it can lead to significant maternal morbidity.9 since the clinical and laboratory parameters are non-specific and there is no clear set of predisposing factors, the diagnosis of ovarian vein thrombosis remains difficult. this mandates a high index of suspicion and ovarian vein thrombosis should be in the list of differential diagnoses in post partum patients undergoing evaluation for abdominal pain and fever in spite of adequate antibiotic treatment. r e f e r e n c e s 1. jinxing yu, fulcher as, turner ma, halvorsen ra. am j roentgenol. helical ct evaluation of acute right lower quadrant pain: part ii, uncommon mimics of appendicitis 2005; 184:1143-1149. 2. dähnert w. radiology review manual, 5th ed. philadelphia: lippincott, williams & wilkins, 2003. p. 1050 3. gourlay m, gutierrez c, chong a, robertson r. group a streptococcal sepsis and ovarian vein thrombosis after an uncomplicated vaginal delivery. j am board fam pract 2001; 14:375-80. 4. jain ka, jeffrey rb jr. gonadal vein thrombosis in patients with acute gastrointestinal inflammation: diagnosis with ct. radiology1991; 180:111-113. 5. savader sj, otero rr, savader bl. puerperal ovarian vein thrombosis: evaluation with ct, us and mr imaging. radiology 1988; 167:637-639. 6. munsick ra, gillanders la. a review of the syndrome of puerperal ovarian vein thrombophlebitis. obstet gynecol surg 1981;36:57-66. 7. duff p, gibbs r. pelvic vein thrombophlebitis: diagnostic dilemma and therapeutic challenges. obstet gynecol surg 1983; 38:365-373. 8. carr s. surgical treatment of ovarian vein thrombosis. vasc endovascular surg 2007; 40:505-508. 9. kominiarek ma, hibbard ju. post partum ovarian vein thrombosis: an update. obstet gynecol surv 2006; 61:337-442. figure 1: cect shows a round hypodense lesion to the right of the ivc with marginal enhancement figure 2: cranially the lesion extends upto the ivc, indents it and projects into the lumen of ivc 1dermatology department, bahla polyclinic, ministry of health, bahla, oman; 2dermatology department, barka polyclinic, ministry of health, barka, oman *corresponding author’s e-mail: mhhh1414@gmail.com intralesional measles-mumps-rubella vaccine for genital warts report of two cases with a review of literature *al-mu'tasim al-qassabi,1 fahad al-farsi2 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 413–416, epub. 25 aug 22 submitted 16 feb 21 revision req. 29 mar 21; revision recd. 22 apr 21 accepted 20 may 21 more than two months. he noted that the lesions were increasing in size. upon examination, there were multiple skincolored flat and verrucous papules coalescing into plaques over the pubic area and shaft of the penis [figure 1a]. the koebner phenomenon was also observed, since some of the lesions appeared in a linear fashion due to hair removal with a razor. laboratory investigations were negative for human immunodeficiency virus (hiv), venereal disease research laboratory (vdrl) test, treponema pallidum hemagglutination (tpha), hepatitis c and hepatitis b surface antigen. the patient was diagnosed with genital warts based on the typical clinical presentation. a plan of treatment was discussed with the patient and he agreed to try cryotherapy at two-week intervals with koh 5% solution application at home twice daily. after six sessions, there was no significant improvement and so the patient was offered ablative radiofrequency. two sessions were performed one month apart; however, there was a recurrence after a few weeks. finally, an intralesional mmr injection was offered considering prior vaccination with mmr as per the national programme. the two biggest warts were chosen to be injected with 0.3 ml of mmr solution (m-m-r® ii 0.5 ml vial, merck sharp & dohme corp., new jersey, usa), once every two weeks with no other modalities of treatment. a total of four sessions were required to achieve complete resolution of the warts without any reported side effects [figure 1b]. to enhance the efficacy, the patient was given two sessions of cryotherapy after the third session of intralesional mrr injection. there was no recurrence on follow-up after three and six months. genital warts, also known as anogenital warts and condylomata acuminata, are fleshy growths affecting the genital and anal area and are caused by the human papilloma viruses (hpvs). more than 200 hpv subtypes have been identified, with hpv subtypes 6 and 11 being considered low risk, while subtypes hpv 16 and 18 are considered high risk as they are associated with cervical dysplasia.1 genital warts are transmitted through sexual contact; however, vertical transmission and autoinoculation have also been reported.2,3 the treatments for genital warts focus on removing the warty growths, rather than eradicating the virus. many treatment modalities are available, including topical agents (e.g. imiquimod ointment), destructive methods (e.g. cryotherapy or lasers) and immunomodulators (e.g. interferons). recently, immunotherapy with intralesional agents such as the measles, mumps and rubella (mmr) vaccine, purified protein derivative (ppd) and the bacillus calmette-guérin (bcg) vaccine have been shown to be efficient with good tolerability in the treatment of warts, especially refractory ones.4 we report two cases of recalcitrant genital warts that were treated successfully with intralesional immunotherapy using the mmr vaccine, along with a literature review for the use of this treatment method on genital warts. case one a 23-year-old male patient presented to the dermatology department at barka polyclinic in 2020 with multiple papules over the groin area lasting for this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.093 case report abstract: genital warts are caused by several strains of human papilloma viruses. although asymptomatic in most cases, they can be psychologically and physically distressing for patients. recently, intralesional immunotherapy using different antigens—such as bacille calmette–guerin vaccine, candida antigen and measles, mumps, and rubella (mmr) vaccine—have shown promising efficacy in the treatment of genital warts. we report two cases in omani males who presented to the dermatology department at barka polyclinic with recalcitrant genital warts that resolved completely with intralesional injection of the mmr vaccine. keywords: genital warts; immunotherapy; measles-mumps-rubella vaccine; venereal warts; oman. https://creativecommons.org/licenses/by-nd/4.0/ intralesional measles-mumps-rubella vaccine for genital warts report of two cases with a review of literature 414 | squ medical journal, august 2022, volume 22, issue 3 case two a 25-year-old male patient presented to the dermatology department at barka polyclinic in 2020 with extensive anogenital warts for more than 18 months [figure 2a]. he was seen in different skin clinics and had received multiple treatments, including topical imiquimod cream 5%, cryotherapy sessions, electrocautery and radiofrequency treatments with no successful results as the warts were reoccurring. the patient was counselled on potential treatment using immunotherapy via mmr injections as he was already vaccinated with the same as per the national programme and he agreed to proceed with the immunotherapy. prior to the injection, he was tested for hiv, hbsag, hepatitis c virus, antinuclear antibodies test, tpha and vdrl, which were all negative. the patient was given a total of seven sessions of mmr injections (merck sharp & dohme corp.), two weeks apart, with four sites injected in each session and 0.3 ml of mmr per site. in addition, the patient started cryotherapy after the third session of mmr injections, once every two weeks, receiving a total of five sessions. the patient had significant improvement after completing the course of treatment with no reported side effects [figure 2b]. there was no figure 1: a: a 23-year-old male patient with genital warts before treatment with an intralesional measles, mumps and rubella injection. b: affected area after the fourth session of immunotherapy showing complete regression with postinflammatory hypopigmentation. figure 2: a: a 25-year-old male patient with extensive genital warts. b: complete resolution after seven sessions of intralesional measles, mumps and rubella injection. table 1: summary of published literature on the use of intralesional measles, mumps and rubella for genital warts study type no. of patients dose and number of mmr sessions combination treatment used results side effects meena et al.9 case report 2 0.5 ml into biggest wart every three weeks complete response for the 1st patient after two sessions, 2nd patient had almost complete response after a single session pain during procedure sharma et al.8 open label study 35 0.5 ml into biggest wart every three weeks for a maximum of three injections 98% improvement at nine weeks swelling following injection (18.2%) present cases case report 2 case one: total of 0.6 ml of mmr every two weeks case two: total of 1.2 ml of mmr every two weeks cryotherapy complete resolution after four and seven sessions for patients one and two, respectively mmr = measles, mumps and rubella. al-mu'tasim al-qassabi and fahad al-farsi case report | 415 recurrence on follow-up at eight weeks and most of the inflammation marks were resolved. the authors have obtained patient consent prior to publication. the patients have given their consent for the use of their images and other clinical information for publication purposes. discussion several treatments for genital warts are available, including medical agents (e.g. imiquimod cream and podophyllotoxin), destructive methods (e.g. cryotherapy, electrocautery and lasers) or surgical excision. these options are limited by a high rate of recurrence and side effects, such as pain and scarring.5 immunotherapy is becoming more popular for the treatment of warts, especially for genital and refractory warts.4 commonly used agents include the mmr vaccine, ppd, the bcg vaccine and the candida antigen. among these, the mmr vaccine and ppd have been shown to be the most effective in achieving complete primary and long-term recovery, reducing the recurrence rate at the same site compared with cryotherapy and other immunotherapeutic modalities.6 additionally, combining intralesional immunotherapy with a destructive method may enhance the efficacy and reduce treatment duration.6 there are no clear guidelines on when to use immunotherapy; however, it is generally used on extensive, recurrent and refractory warts in difficult to treat areas, such as the periungual area.4 the exact mechanism of intralesional immuno therapy is not entirely understood. a postulated mode of action includes the release of different immunoregulatory cytokines such as interleukins 2 and 12 and interferon-c that stimulate a strong immune response against hpv.7 furthermore, antigen injection is associated with proliferation of peripheral blood mononuclear cells that promotes t-helper 1 cytokine responses to eradicate hpv-infected cells.8 it is used to treat genital warts at a dose of 0.3 to 0.5 ml injected into the biggest wart at three week intervals. to date, there are no randomised clinical trials evaluating the efficacy of intralesional mmr vaccines in the treatment of genital warts nor clear guidelines as to when to use them. a review of the literature showed a dearth of research evaluating the use of mmr vaccines to treat genital warts [table 1]. in an open-label study, sharma et al. evaluated the use of the mmr vaccine on 35 patients using a 0.5 ml dose given at three week intervals.9 the treatment response rate was nearly 98% after a period of nine weeks. meena et al. reported two cases of genital warts that had an excellent response to a 0.5 ml intralesional injection of the mmr vaccine at a similar interval.10 side effects were minimal and temporary, however, with flu-like symptoms being the most common side effect reported from studies of intralesional mmr vaccines to treat extra-genital warts.11 in the current cases, a slightly higher dose (0.6 ml and 1.2 ml, respectively) of the mmr vaccine was used, as the patients had extensive bilateral warts. a combination with a destructive method (i.e. cryotherapy) was also utilised to enhance the resolution of stubborn lesions. intralesional mmr vaccine is currently not routinely used for genital warts. the present cases along with the previously reported cases draw attention to the need for further randomised clinical trials to establish the potential role of mmr vaccine immunotherapy in the management of anogenital warts. compared with current modalities of treatments, the mmr vaccine offers low recurrence, less side effects and an easy-touse therapeutic method. conclusion intralesional immunotherapy with the mmr vaccine seems to be a safe and effective treatment modality for recalcitrant genital warts and can save the patients and doctors a long treatment time, noted using other methods. further large sample studies are needed to establish this modality of treatment for genital warts. a u t h o r s’ c o n t r i b u t i o n s aq and ff were involved in the literature review process. aq drafted the manuscript. ff contributed with the evaluation of the cases. both authors approved the final version of the manuscript. a c k n o w l e d g e m e n t the authors would like to thank the patients for giving consent to publish the cases. references 1. tyring sk. human papillomavirus infections: epidemiology, pathogenesis, and host immune response. j am acad dermatol 2000; 43:s18–26. https://doi.org/10.1067/mjd.2000.107807. 2. mayeaux ej jr, dunton c. modern management of external genital warts. j low genit tract dis 2008; 12:185–92. https:// doi.org/10.1097/lgt.0b013e31815dd4b4. 3. hernandez by, shvetsov yb, goodman mt, wilkens l, thompson p, zhu x, et al. genital and extra-genital warts increase the risk of asymptomatic genital human papillomavirus infection in men. sex transm infect 2011; 87:391–5. https://doi.org/10.1136/ sti.2010.048876. 4. thappa dm, chiramel mj. evolving role of immunotherapy in the treatment of refractory warts. indian dermatol online j 2016; 7:364–70. https://doi.org/10.4103/2229-5178.190487. https://doi.org/10.1067/mjd.2000.107807. https://doi.org/10.1097/lgt.0b013e31815dd4b4. https://doi.org/10.1097/lgt.0b013e31815dd4b4. https://doi.org/10.1136/sti.2010.048876 https://doi.org/10.1136/sti.2010.048876 https://doi.org/10.4103/2229-5178.190487 intralesional measles-mumps-rubella vaccine for genital warts report of two cases with a review of literature 416 | squ medical journal, august 2022, volume 22, issue 3 9. sharma s, agarwal s. intralesional immunotherapy with measles mumps rubella vaccine for the treatment of anogenital warts: an open-label study. j clin aesthet dermatol 2020; 13:40–4. 10. meena d, sharma s, chauhan p. measles, mumps, and rubella vaccine in genital warts: a case report of two patients. indian j sex transm dis aids 2018; 39:133–5. https://doi.org/10.4103/ ijstd.ijstd_44_16. 11. nofal a, nofal e, yosef a, nofal h. treatment of recalcitrant warts with intralesional measles, mumps, and rubella vaccine: a promising approach. int j dermatol 2015; 54:667–71. https:// doi.org/10.1111/ijd.12480. 5. bacelieri r, johnson sm. cutaneous warts: an evidence-based approach to therapy. am fam physician 2005; 72:647–52. 6. salman s, ahmed ms, ibrahim am, mattar om, el-shirbiny h, sarsik s, et al. intralesional immunotherapy for the treatment of warts: a network meta-analysis. j am acad dermatol 2019; 80:922–30.e4. https://doi.org/10.1016/j.jaad.2018.07.003. 7. king m, johnson sm, horn td. intralesional immunotherapy for genital warts. arch dermatol 2005; 141:1606–7. https://doi. org/10.1001/archderm.141.12.1606. 8. horn td, johnson sm, helm rm, roberson pk. intralesional immunotherapy of warts with mumps, candida, and tricho phyton skin test antigens: a single-blinded, randomized, and controlled trial. arch dermatol 2005; 141:589–94. https://doi. org/10.1001/archderm.141.5.589. https://doi.org/10.4103/ijstd.ijstd_44_16 https://doi.org/10.4103/ijstd.ijstd_44_16 https://doi.org/10.1111/ijd.12480 https://doi.org/10.1111/ijd.12480 https://doi.org/10.1016/j.jaad.2018.07.003. https://doi.org/10.1001/archderm.141.12.1606 https://doi.org/10.1001/archderm.141.12.1606 https://doi.org/10.1001/archderm.141.5.589 https://doi.org/10.1001/archderm.141.5.589 enemy within? the silent epidemic of substance dependency in gcc countries the use of naturally occurring moodaltering substances is deeply rooted in the tradi-tions and cultures of many communities worldwide. as documented in other societies and historical records,1,2 various compounds have been employed for altering consciousness and for their curative effects.3 two substances traditionally used in the middle east include hashish and khat.4 hashish, as cannabis, has been known in the region since ancient times.5 khat, also known as chat, derived from the leaves and young shoots of the khat plant (catha edulis), is used for its stimulant effect.6 technological advances that enable high purification of drugs and transporting them fast, and increasing urbanisation, have caused these mood altering substances to be taken out of their traditional role in societies and have come to pose new, complex and challenging threats.7 these threats have been manifested in two important ways: () wider use of drugs, and (2) a shift from natural drugs to the more potent purer forms. globally, illegal money derived from illicit drug transactions amounts to 400 billion dollars annually, and is second only to the arms trade.8,9 the countries of the arabian gulf co-operation council (gcc) offers an interesting study area because their diverse cultures have experienced rapid acculturation, a phenomenon often equated with a rise in psychosocial stress.10 psychosocial stress has often been associated with vulnerability to self-poisoning11 and substance abuse.12 although there are no adequate statistical studies to indicate the incidence of substance dependency in the gcc, it is clear that substance abuse is not a minor problem considering the number of reported enemy within? the silent epidemic of substance dependency in gcc countries abdullah al-harthi1, *samir al-adawi2 1royal oman police, p.o. box 2, muscat 113, sultanate of oman. 2department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, p.o. box 35 al-khod -123, muscat, sultanate of oman. *to whom correspondence should be addressed. email: adawi@squ.edu.om e d i t o r i a lsqu journal for scientific research: medical sciences 2002, vol. 4, no. –2, –7 ©sultan qaboos universit y drug seizures by the authorities.13 in real terms, the drugs seized by law enforcement authorities constitute only 5–0 percent of the actual quantity.14 comprehensive data on the pattern of substance dependency is hampered by the criminal and moral stigma associated with substance dependency. whatever the real number of people afflicted with addiction, substance dependency is a severe problem when considered in terms of personal distress, family disruption and interference with productivity and economic growth. efforts have been undertaken in gcc countries to reduce the demand for drugs and to prevent drug abuse before it occurs. these efforts are coordinated through the demand reduction committee, created in 200 with members from all countries of the gcc. the committee provides leadership in coordinating and facilitating strategies in this area including law enforcement, rehabilitation and leading and assisting the community in the task of education and prevention of substance abuse. some studies have suggested that substance dependency occurs in adolescents in all strata of the society.14–16 however, these studies are limited to self-report questionnaires based on secondary school students. although peer pressure is likely to play a significant part in the initiation of substance abuse,16 the subsequent heavy abuse is often associated with various psychosocial factors. it has been suggested that of all the social factors that predispose individuals to substance abuse, boredom is the most significant.14,17 the recent affluence and modernisation of the gcc societies have led many people to have a lot of spare time, as household chores are carried out by expatriate servants.14 the detrimental effects of such a lifestyle, including substance dependency, have been samir editorial ����� �����! ���� ����������� ������� ���� ��� �� �������� ��� �� ������ ���� � ������� �� ��� 2 a l h a rt h i & a l a d aw i speculated in the literature.13,18–21 in a study cited by alharthi14 of personality profiles and descriptive analyses of typical substance users enrolled in a treatment centre in riyadh, saudi arabia, the most frequently stated reason for indulging in drugs was to escape boredom. this view, though substantiated by other studies in the region,22,23 has not taken into account the relationship of individual temperament to substance abuse. recent studies have suggested that phenotypical “risk takers” or “sensation seekers” are often not inhibited from yielding to various illicit practices including substance abuse.24 future studies in the region should examine the association between personality types, risk taking behaviour and boredom. the premise that the rise in substance dependency might be precipitated by erosion of traditional family networks and skewed social expectations might be relevant to gcc countries. al-hashmi18 has suggested that modernisation has resulted in the omani family becoming nuclear at the cost of the traditional extended family. concurrently, domestic servants brought from overseas, often illiterate in the dominant language, are providing much of the socialisation to children. reinforced by frequent international travelling, satellite televisions and the internet, acculturation appears to have occurred too quickly in gcc societies. smith has remarked that these changes have brought these communities development that took a thousand years in europe in less than 20 years.25 studies from other parts of the world that have experienced similar rapid pace of modernisation have shown disintegration of native culture and identity as well as dissolution of the social network, to which individuals had previously turned for help when in trouble.26 in addition, the spread of education have resulted in higher levels of expectations. in the new social order, individuals in the region tend to regard employment opportunities, guaranteed higher levels of income, and especially, higher social standing, as acquired rights. frustration of the desire to climb the social ladder leads to social insecurity.14 the present situation of society in transition fits with the classical sociological observations of ibn khaldun and emile durkheim: rapid transformation leads to breakdown of traditional social cohesion.14as a result, the sense of belonging becomes a luxury, leading to social drift, alienation, and the proliferation of social misfits. the society itself may become anomic. the relationship between acculturation, anomie and drug taking has received empirical support.27 the present tendency is to view substance abuse in its psychosocial context rather than on moral terms. while more studies that are comprehensive are needed to examine the pattern of use and misuse of drugs in the gcc countries, there are various reasons to assume that substance dependency is likely to continue to pose a problem in the region. first, the geography helps both trafficking and consumption. gcc countries are located close to the “golden triangle” or “drug belt”, a part of asia where underdevelopment and political instability have fuelled drug driven economies. second, being on a major route for international airlines and sea routes by virtue of being in the middle of the world, gcc countries are at constant risk of being used as trans-shipment points for drug trafficking. the arabian peninsula has a vast coastline with its horizon overlooking major sea routes to different continents. even if vigilance to guard its borders is heightened, such a long coastline would remain porous. moreover, effective surveillance would require more allocation of resources and work force, drawing vital resources away from establishing essential remedial and rehabilitation services for the victims of substance abuse. thirdly, the increasing number of visitors and the presence of foreign labour in the gcc also help make the “gulf route” a crossroad for trans-world drug supplies. some individuals may fall prey to the fallouts from these passing illegal shipments even though they may be destined elsewhere. it is also possible that an increase in consumption of illicit substances among the local population has in itself escalated the demand. in support of the latter view are the rising statistics on the mortality related to drug abuse and the number of clients seeking treatment in rehabilitation centres in the gcc states.15,28 dispensing accurate information on issues related to substance abuse is a key component to fighting drug abuse. studies are needed to illuminate the effect of substance dependency in the ggc countries as the mass media often tends to downplay the risks of drug use, or sometimes even glamorises it. evidence is emerging on the personal consequences of substance dependency. okasha, in the context of egypt, has demonstrated that substance dependency is likely to lead to underachievement at school or work and exacerbate family stress, financial burdens and exposure to criminal activity.29 however, literature does not discern whether these social problems are the cause or the effect of the substance dependency. substance dependency is often associated with psychiatric morbidity30 but it is not clear whether this is cause or effect. karam et al in their report from lebanon suggest a strong relationship between addiction to substances of abuse and psychiatric diagnoses.31 these authors further suggest that certain personality types 3s u b s ta n c e d e p e n d e n c y i n t h e g c c often abuse specific substances. however, such a simplistic view appears to be merely reiterating the chickenor-the-egg argument. some authors have suggested that substance dependency is a form of self-medication, which implies that individuals with substance dependency have high levels of psychosocial distress and use illicit drugs in an attempt to alleviate their distress. this is relevant to the suggestion that some psychiatric symptoms may mimic withdrawal effects of chronic substance dependency and withdrawal symptomatology co-varies with cognitive and psychological functioning.32 in addition to psychiatric illness, substance dependency has been seen to increase the risk of adverse drug reactions. a well-known complication of substance dependency is the risk of transmission of human immunodeficiency virus and other infections.33 v i s i b l e p a t t e r n s i n t h e g c c the discovery of oil in the gcc has brought rapid modernisation as well as unprecedented material progress and economic security.34 although gcc nationals, like other cultural groups in developing countries, are thought to have beliefs that protect them against developing substance dependency, such beliefs appear to be eroding with the rising tide of acculturation and economic restructuring. demographic factors such as the preponderance of adolescents in the population will continue to elude those advocating demand reduction policies even if harsher penalties are decreed for traffickers and users. approximately 60% of the population in the region are less than 20 years old.35 as reported elsewhere, 36 adolescents are prone to risk taking behaviour, a temperament that has been associated with developmental milestones including the underdevelopment of the orbital-frontal cortex.34 in gcc countries, the rate of juvenile delinquency has, in a span of 0 years, increased approximately by 400%. unless the needs of such a large and important segment of society as its young people are addressed, this may present a demographic time-bomb with unpredictable social consequences. with a fast growing population, competitions for social and occupational roles are likely to be more intense, leaving many failed individuals behind. with such a demographic trend, it is likely that many individuals carry a greater risk of developing various adjustment difficulties including substance dependency.37 data emanating from other developing countries suggest that drug peddlers tend to target the poor and the unemployed. whereas substance dependency in other parts of the world is often associated with economic and social breakdown,38 no study has examined whether substance dependency in the gcc countries follows the same pattern.39 preliminary observations in oman suggest that there is relationship between unemployment and propensity for substance abuse.14 interestingly, the study suggests that addiction to illicit drugs is likely to interfere with employment, often rendering some individuals to lose their jobs. in the midst of such conflicting views, further studies are needed to ascertain the conditions that trigger drug dependency in the community.40 while more information is needed in order to make an informed policy on substance dependency, there is some evidence pointing to which substances are widely abused in gcc countries. first, clinical reports suggest that solvent misuse is extensive although no formal studies have been conducted. hafeiz41 has suggested that abuse of solvents often occurs in order to overcome the boredom of modern living. there is also increasing evidence to suggest that some of these agents cause mental disorders42 as well as neurological complications.43 the chemicals in question include glues, liquid shoe polish, deodoriser, petrol, cologne and insecticides.44,45 a special pattern of substance dependency associated with social deviancy and delinquency also involves a homemade mixture of dates and ointments as well as inhalation of intoxicating fumes derived from burning the wings of cockroaches and ants with volatile substances. habitual inhaling of these substances is often associated with a failure to thrive.42 secondly, inhaling smoke derived from nicotine based substances is now common in many gcc countries.46,47 tobacco is often chewed, snuffed or smoked either in cigarettes or in sheesha. the latter (also known as hookah) is a smoking device, widely used in some communities of the arabian peninsula, to smoke jurak, a cooked tobacco-fruit mixture, and burnt by an electrical device or by charcoal. the produced smoke passes through the water at the base of the sheesha and then a long-tube before it is inhaled. though most smokers consider sheesha less harmful to health than cigarette smoking,48 this has not been substantiated in regional studies.48,49 experimental and clinical studies have found that nicotine, an active ingredient of both sheesha and cigarettes, not only triggers cardiovascular diseases, but also predisposes frequent users to various neuropsychiatric disorders.50 the question remains whether smoking triggers mental illness or people with mental illness are more likely to smoke.51 pharmacological studies have 4 unequivocally shown that nicotine is as addictive as other well-known psychoactive drugs such as cocaine and amphetamines.52 however, gcc countries have given a low priority to this a public health issue. demand for nicotine has been falling in industrialised nations, 53 but a similar picture is not emerging from middle and low income countries. cigarette companies are now targeting the developing world.53 moreover, cigarette companies are manufacturing products of differing quality for sale in different markets. it has been shown that cigarettes of the same brand sold in developing countries have higher tar content than in the country of origin.54 some studies have suggested that certain cigarettes are made from more potent, hence, more addictive, nicotine.53,55 as there is no known effective program to educate people about the dangers of smoking, prevention and smoking cessation appear to an unattainable goals. to compound the problem, some proponents of the “gateway phenomenon” suggest that smoking is a springboard to hard drugs such as cocaine and heroin, 56 though there is also evidence to contradict this view.57 the social problems precipitated by alcoholism have not yet been reported in the gcc countries though some reports suggest that drinking problems are proliferating.13,44,58 the world health organisation59 estimates that more then 5 million people are disabled because of alcohol use, making it the fourth leading cause of worldwide disability. theobald has suggested that approximately 0% of alcohol consumers will at some time experience serious health problems related to their drinking habit.60 as many individuals are now facing the daily challenges of modern living and the pressures of modern life, alcohol abuse is thought to be one of the elusive antidotes to modern insecurity.17 some recent findings suggest that individuals who have a high subjective level of insecurity in their lives are likely to abuse alcohol to ward of their psychosocial stress. interestingly, people with such attributes have been seen to have refractory types of alcoholism.61 alcohol syndromes such as delirium tremens and korsakoff ’s psychosis are known to occur among people who consume it regularly.50 persons at risk of drinking problems cannot be reliably identified in the population; therefore the pattern of drinking and its psychosocial correlates are indicated for the gcc countries. the bulk of the studies21,45,58 have focused solely on exploring the validity of research instruments on crosscultural application of drinking attitude and behaviour. little is known on the effect of alcohol repackaged as “cologne” available in some gcc countries.62,63 colognes or ethyl alcohol-containing perfume and after-shave are sometimes ingested as an alcohol substitute.64 relevant to this, it would be important to determine whether the availability of alcohol and other soft drugs deters people from going into narcotics that are more dangerous. one suggestion is that in those societies of gcc where there is a relaxed attitude towards alcohol, there are fewer propensities towards heroin and other dangerous drugs.14 it also not clear how such information would be helpful in planning intervention programs in gcc countries, as the experiences from other societies suggest a complex relationship between alcohol and substance abuse. the “gateway theory” would suggest that using alcohol leads people to use harder drugs like cocaine and heroin.65 there is also scant information on the pattern and psychosocial correlates of over-the-counter medications in the gcc countries. though generally viewed as harmless, many of them have the potential for abuse, particular those that are considered to be amphetaminelike stimulants.66 these includes nasal decongestants, bronchodilators, appetite suppressants and energy pills and drinks. while there is no evidence to suggest that cocaine and hallucinogens are widely consumed in the gcc countries, 13 the story of opiate use is somewhat different. historical documents suggest that opium was considered as a medicinal substance in the middle east. it was recommended by various towering arab figures such as ibn sina.1 more recently, however, its semi-synthetic counterpart, heroin, far removed from its cultural context, is becoming the drug of choice for addicts in the gcc countries. being close to heroin producing regions of the world, gcc appears to be the trafficker’s place of choice. being capable of causing compulsive dependency within a short time, heroin has a devastating effect on the user and society in general. to those who are addicted to heroin, it appears the habit leaves them little time for meaningful life. to compound the problem, as 90% of gcc heroin addicts use it intravenously, sharing of contaminated needles causes infections of human immune deficiency virus and a high incidence of other infections.33 similarly, the number of cases of heroin addiction is often directly related to the number of crimes.27 despite stringent regulations to reduce the supply and demand, the habit proliferates. judging from the quantities of drugs seized by the authorities, the last decade has witnessed a dramatic increase in the number of cases of heroin addiction, the number of addicts seeking rehabilitation, and death due to heroin overdose.13,14,33 a l h a rt h i & a l a d aw i 5 p r o s p e c t s f o r t h e f u t u r e rehabilitation for addiction is often in the hands of psychiatric or penitentiary services though some specialised centres have emerged in some gcc countries.16 culturally sensitive interventions seem to be often relegated to fringe importance. medical interventions are likely to grow considering the many claims about new pharmacological tools that take advantage of the chemical properties of alcohol and other drugs. however, drug treatment for substance dependency should not hold up the search for psychosocial predisposing factors, which, in turn, could be a springboard for educational strategies to reduce demand. indeed, blind adherence to pharmacological intervention not only seems similar to drug peddling, but also may be counterproductive in the long term. a biomedical explanatory model of substance dependency may lead to stigma, and lessen the individual and societal accountability in tackling compulsive dependency. stressing personal responsibility, on the other hand, motivates one to change, as well as help one understand the challenges ahead and evolve coping mechanisms.67 as distress and stress are experienced in a socio-cultural context, rehabilitation services should avoid committing what kleinman has called a “category fallacy”, where a view of human nature developed for one cultural group is uncritically applied to members of another group for whom its validity has not been established.68 according to kleinman, this results in a “distortion of pathology” rather than a critical understanding of the ways in which the members of a different cultural group perceive, experience and communicates beliefs and distress. one of the essential grounds for formulating enlightened policies toward drug dependency is to consider the society’s outlook towards mood altering substances. despite the documented frequency of substance abuse in gcc countries, a review of the literature reveals no objective studies on knowledge, attitude and perception. opinion towards substance dependency among citizens of gcc countries is likely to have a wide-ranging influence, affecting issues as diverse as personal consequences of substance dependency, prevention, care and management of people with substance abuse. historical and cross-cultural studies have suggested that individuals with substance dependence are likely to encounter active discrimination and harassment which, in turn, exacerbates their psychosocial predicament and perpetuates their relapse into drug taking.37 similarly, it has been suggested that social attitudes can be more devastating than the addiction itself, and the addict’s family suffers as well.69 although many victims of substance dependency could benefit from treatment, attitudes of society towards them is likely to hamper their seeking rehabilitation. as a result, many are likely to stay underground until addiction has reached an advanced stage of irreversible pathology. this not only increases pessimism of the victims and those around them but also shatters the prospect of recovery. therefore, more research in gcc countries should be conducted in order to shed light on socio-cultural factors that precipitate individuals to succumb to substance abuse. this would open the door for contemplating strategies to achieve a reasonable level of prevention as well as to prioritise which aspects of services are pertinent to the region. grinspoon and bakalar have suggested that of all the mistakes repeated, the most serious is trying to free society of drugs via legislation and regulation.70 indeed, many studies1 suggest that no punitive measure deters availability and abuse of drugs.14 it appears that financial gain is one of the strongest determining factors. globally, though consensus from the experts in the field suggests that substance dependency is a disease, public opinion often considers it a form of moral degeneracy that can destroy social values. as a result, victims of substance dependency are sent to the prison. many countries have pursued the idea of creating a national consensus towards zero tolerance for substance abuse and death penalty for drug traffickers. the policies fluctuate between curbing trafficking, reducing demand and decriminalisation of certain classes of drugs.71 some countries have considered decriminalizing soft drugs and the debate continues on the rationale of dispensing heroin to heroin-addicts.72 although more time is needed to assess the long-term outcome of these new programs, history has shown that none of the previous campaigns to curb the spread of substance misuse has worked. instead, the situation appears to be summed up in bob marley’s lyric, “so you think you have found the solution; but it’s just another illusion”. c o n c l u s i o n the problem of drug abuse in the gcc is a multidimensional one without easy solutions. this paper has touched upon several of these issues. even though for zero tolerance to substance dependency is advocated, no program has been found to be universally successful in reducing drug dependence. historically, many societies have tried both criminalisation and decriminalisation but to no avail. despite all the technologies to monitor and legal authority to bring the drug traffickers to justice, s u b s ta n c e d e p e n d e n c y i n t h e g c c 6 including the threat of death penalty, dealing with substances that cause addiction is becoming a global challenge of ever increasing magnitude. more discouraging, the problem has even affected societies where one would expect cultural factors to protect them from the attraction of drugs. the purpose of this paper, thus, is to “point a finger to the moon”, the moon symbolising the complexity of substance dependency. one should not confuse the moon with the finger that points to it. r e f e r e n c e s . mckim wa. drugs and behavior: an introduction to behavioral pharmacology. (5th edition). new jersey: prentice hall, 2003. 2. maccoun rj, reuter p. drug war heresies: learning from other vices, times, and places: rand studies in policy analysis. cambridge, uk: cambridge university press, 200. 3. davenport-hines r. the pursuit of oblivion: a global history of narcotics, 500–2000 . phoenix: phoenix press, 2002. 4. nahas gg. hashish in islam 9th to 18th century. bull n y acad med, 982, 58, 84–83. 5. hamarneh s. pharmacy in medieval islam and the history of drug addiction. med hist, 972, 6, 226–237. 6. kalix p. catha edulis, a plant that has amphetamine effects. pharm world sci, 996, 8, 69–73. 7. costa e, silva ja. evidence-based analysis of the worldwide abuse of licit and illicit drugs. hum psychopharmacol, 2002, 7,3–40. 8. williams s, milani c. globalization of the drug trade. sources, 999, , 4–5. 9. levi m. money laundering and its regulation. ann am acad polit ss, 2003, 582, 8–94. 0. ghubash r, hamdi e, bebbington p. the dubai community psychiatric survey: acculturation and the prevalence of psychiatric disorder. psychol med, 994, 24, 2–3. . zaidan za, burke dt, dorvlo as, al-naamani a, al-suleimani a, et al. deliberate self-poisoning in oman. trop med int health, 2002, 7, 549–556. 2. cherpitel cj, borges g. substance use among emergency room patients: an exploratory analysis by ethnicity and acculturation. am j drug alcohol abuse, 2002, 28, 287–305. 3. younis yo, saad ag. a profile of alcohol and drug misusers in an arab community. addiction, 995, 90, 683–684. 4. al-harthi a. drug abuse in the gulf states/oman: an evaluation of the death penalty as a deterrent. unpublished thesis, university of manchester, manchester, uk, 999. 5. abdelkarim ao. sustance abuse among patients attending a psychiatric hospital in jeddah: a descriptive study. ann saudi med, 992, 2, 289–293. 6. abalkhail ba. social status, health status and therapy response in heroin addicts. east mediterr health j, 200, 7, 465–472. 7. monteiro mg. a world health organization perspective on alcohol and illicit drug use and health. eur addict res, 200, 7, 98–03. 8. al-hashmi s. effect of urbanization and modernization on family structure in oman. unpublished thesis, portland university, 99. 9. joyce m. the sultanate of oman: a twentieth century history. london, praeger, 995. 20. alnajjar a, al-hilawani y. delinquency and social changes in united arab emirates: a comparison study between delinquent males and females on the family functioning questionnaire. int j rehabil res, 999, 22, 99–206. 2. al-ansari ea, negrete jc. screening for alcoholism among alcohol users in a traditional arab muslim society. acta psychiatr scand, 990, 8, 284–288. 22. demerdash am, mizaal h, el farouki s, el mossalem h. some behavioural and psychological aspects of alcohol and drug dependence in kuwait psychiatric hospital. acta psychiatr scand, 98, 63, 73–85. 23. chinnian rr, taylor lr, al-subaie a, sugumar a, al-jumaih aa. a controlled study of personality patterns in alcohol and heroin abusers in saudi arabia. j psychoactive drugs, 994, 26, 85–88. 24. oetting er, deffenbacher jl, donnermeyer jf. primary socialization theory. the role played by personal traits in the etiology of drug use and deviance. ii. subst use misuse, 998, 33, 337–366. 25. smith r. oman: leaping across the centuries. bmj, 988, 297, 540–544. 26. kleinman a, cohen a. psychiatry’s global challenge. sci am, 997, 276, 86–89. 27. inciardi ja, pottieger ae. drug use and street crime in miami: an (almost) twenty-year retrospective. subst use misuse, 998, 33, 839–870. 28. al-amal hospital. official publication of the ministry of health, riyadh, saudi arabia, ministry of health, 1997. 29. okasha a. young people and the struggle against drug abuse in the arab countries. bull narc, 985, 37, 67–73. 30. gataa r. kamikazes: youth serving youth in a dangerous climate. algeria. plan parent chall, 995, , 39–40. 3. karam eg, yabroudi pf, melhem nm. comorbidity of substance abuse and other psychiatric disorders in acute general psychiatric admissions: a study from lebanon. compr psychiatry, 2002, 43, 463–468. 32. al-adawi s, powell j. the influence of smoking on reward responsiveness and cognitive functions: a naturalistic experiment. addiction, 997, 92, 1773–782. 33. shawky s, ghabrah tm, abalkhail ba, soliman nk. hepatitis c infection among drug addicts. saudi med j, 999, 20, 877–88. 34. al-adawi s, burke dt. revamping neurorehabilitation in oman. squ j sci res: med sci, 200, 3, 6–64. 35. al-qudsi s. the demand for children in arab countries: evidence from panel and count data models. j popul econ, 998, , 435-452. 36. ross mh, yurgelun-todd da, renshaw pf, maas lc, mendelson jh, et al. age-related reduction in functional mri response to photic stimulation. neurology, 997, 48, 73–76. 37. al-adawi s, dorvlo ass, burke d, al-bahlani s, martin rg a l h a rt h i & a l a d aw i 7 et al. presence and severity of anorexia and bulimia among male and female omani and non-omani adolescents. j am acad child adolesc psychiatry, 2002, 4, 24–3. 38. liu x, weiss f. additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropinreleasing factor and opioid mechanisms. j neurosci, 2002, 22, 7856–786. 39. macgregor s. drug treatment systems and policy frameworks: a comparative social policy perspective. eur addict res, 999, 5, 8–25. 40. draine j, salzer ms, culhane dp, hadley tr. role of social disadvantage in crime, joblessness, and homelessness among persons with serious mental illness. psychiatr serv, 2002, 53, 565–573. 4. hafeiz hb. socio-demographic correlates and pattern of drug abuse in eastern saudi arabia. drug alcohol depend, 995, 38, 255–259. 42. baasher t. drug and alcohol problems and the developing world. special issue: psychiatry and the addictions. int rev psychiatr, 989, , 3–6. 43. deleu d, hanssens y. toluene induced postural tremor. j neurol neurosurg psychiatry, 2000, 68, 8. 44. chaleby k. a comparative study of alcoholics and drug addicts in an arabian gulf country. soc psychiatry, 986, 2, 49–5. 45. amir t. personality study of alcohol, heroin, and polydrug abusers in an arabian gulf population. psychol rep, 994, 74, 55–520. 46. musaiger ao. diet and prevention of coronary heart disease in the arab middle east countries. med prin pract, 2002, , 9–6. 47. al-faris ea. smoking habits of secondary school boys in rural riyadh. public health, 995, 09, 47–55. 48. zahran fm, ardawi sm, attallah aa. hazards of smoking sheesha in saudi arabia. riyadh. king abdulaziz city for science and technology, 988. 49. sajid km, akhter m, malik gq. carbon monoxide fractions in cigarette and hookah (hubble-bubble) smoke. jpma, 993, 43, 79–82. 50. brust jc. neurologic complications of substance abuse. j acquir immune defic syndr, 2002, 3, s29-34. 5. de leon j, becona e, gurpegui m, gonzalez-pinto a, diaz fj. the association between high nicotine dependence and severe mental illness may be consistent across countries. j clin psychiatry, 2002, 63, 82–86. 52. pontieri fe, tanda g, orzi f, di chiara g. effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. nature, 996, 382, 206-207. 53. american public health association. trust fund for developing countries to meet national commitment under the who framework convention for tobacco control. am j public health, 200, 9, 520. 54. hamadeh rr, mcpherson k, doll, r. tobacco consumption and chemical analysis of cigarettes in bahrain. int j addict, 994, 29, 325–337. 55. fisher be. turning over a new leaf. tobacco. environ health perspect, 999, 07, 206–209a. 56. lai s, lai h, page jb, mccoy cb. the association between cigarette smoking and drug abuse in the united states. j addict dis, 2000, 9, –24. 57. beenstock m, rahav g. testing gateway theory: do cigarette prices affect illicit drug use? j health econ, 2002, 2, 679–698. 58. bilal am, kristof j, el-islam mf. a cross-cultural application of a drinking behavior questionnaire. addict behav, 987, 2, 95–0. 59. world health organization. trends in substance abuse and associated health problems. geneva, world health organization, 996 (fact sheet no. 27). 60. theobald h, johansson se, bygren lo, engfeldt p. the effects of alcohol consumption on mortality and morbidity: a 26-year follow-up study. j stud alcohol, 200, 62,783–789. 6. willinger u, lenzinger e, hornik k, fischer g, schonbeck g, aschauer hn, et al. anxiety as a predictor of relapse in detoxified alcohol-dependent patients. alcohol alcohol, 2002, 37, 609–62. 62. world health organization. world health day 200: country profile: oman. world health organization. eastern mediterranean regional office, 200, alexandria, egypt. 63. yayci n, agritmis h, turla a et al. fatalities due to methyl alcohol intoxication in turkey: an 8-year study. forensic sci int, 2003, 3, 36–4. 64. the arab news. four die in asir after drinking cologne. arab news, august 20, 2002. 65. golub a, johnson bd. the shifting importance of alcohol and marijuana as gateway substances among serious drug abusers. j stud alcohol, 994, 55, 607–64. 66. tinsley ja, watkins dd. over-the-counter stimulants: abuse and addiction. mayo clin proc, 998, 73, 977–982. 67. al-adawi s, al-salmy, h, martin rg, al-naamani a, prabhakar s, deleu d. patient’s perspective on epilepsy: self-knowledge among omani. seizure, 2003, 2, –9. 68. kleinman a. depression, somatization and the new cross-cultural psychiatry. soc sci med, 977, , 3–0. 69. copello a, orford j. addiction and the family: is it time for services to take notice of the evidence? addiction, 2000, 97, 36–363. 70. grinspoon l, bakalar jb. the war on drugs and a peace proposal. n engl j med, 994, 330, 357–360. 7. haden m. illicit i.v. drugs. a public health approach. can j public health, 2002, 93, 43–434. 72. copeman m. heroin prescription for opioid addicts. lancet, 2002, 359, 889–890. s u b s ta n c e d e p e n d e n c y i n t h e g c c 1 submitted 27 jan 22 1 revisions req. 17 mar & 22 may 22; revisions recd. 20 apr & 3 jun 22 2 accepted 16 jun 22 3 online-first: june 2022 4 doi: https://doi.org/10.18295/squmj.6.2022.045 5 6 inappropriate hospital stay of patients admitted under care of 7 general medicine units 8 a retrospective study 9 10 ahmed al-yarabi,1,2 huriya al balushi,2 khaloud al hatmi,2 reem al yahyaie,2 11 *abdullah m. al alawi,1,3 khalfan al zeedy,1,3 hatem al farhan1,3 12 13 1oman medical specialty board, muscat, oman; 2national cardiology center, muscat, oman; 14 3department of medicine, sultan qaboos university hospital, muscat, oman. 15 *corresponding author’s e-mail: dr.abdullahalalawi@gmail.com 16 17 abstract 18 objective: this study aims to assess the incidence of inappropriate hospital stay and to identify 19 reasons behind inappropriate hospitalisation. methods: the study was a retrospective cohort 20 study included patients admitted under the care of general internal medicine. first, we 21 calculated the average length of hospital stay for all included patients, and then we used 22 appropriateness evaluation protocol to examine admissions that exceeded the average length of 23 hospital stay and then identify reasons for the inappropriate hospital stay. results: there were 24 854 admissions during the study period. in this cohort, 53.1% were men, and the median age was 25 64 (iqr:44-75) years. there was a total of 6785.4 hospitalization days, and the average length of 26 hospital stay was 5 (iqr:3-9) days. 31.9% of admissions (n=272 admissions) included 27 inappropriate hospitalization days. 9.9 % (n=674 days) of hospitalization days were classified as 28 inappropriate. delay in complementary tests (29.0%), and unavailability of extra-hospital 29 resources (21.7%) were the most common reasons associated with inappropriate hospital stay. 30 mailto:dr.abdullahalalawi@gmail.com 2 old age was associated with increased inappropriate hospital stay. conclusion: a significant 31 proportion of hospitalisation days were inappropriate due to hospital related factors. therefore, 32 auditing hospital services, and investing in home-based care are among the top strategies which 33 are likely to improve early discharge and minimize inappropriate hospital bed occupancy. 34 keywords: hospital stay; hospitalization, patient discharge; general internal medicine 35 36 advances in knowledge: 37  a significant proportion of hospital stay is inappropriate primarily due to hospital-related 38 factors. 39 40 application to patient care: 41  auditing healthcare services, implementing programs to lean process of tests and 42 procedures execution, and investing in subacute health services and home-based care 43 programs are essential steps to improve early discharges and minimize inappropriate 44 hospital stay. 45 46 introduction 47 inappropriate hospital stay has been used widely in the medical literature to describe any hospital 48 stay with no clinical indication resulting from the suboptimal use of health care services.1, 2 the 49 inappropriate days of hospitalization may undermine the effort to improve medical health care 50 quality due to the increased risk of iatrogenic complications such as healthcare-associated 51 infection, deep vein thrombosis, depression, and loss of physical dependence. in addition, 52 inappropriate length of hospital stay is associated with a substantial increase in morbidity and 53 mortality.2, 3 54 55 reducing healthcare costs and optimizing the utilization of the current healthcare facilities, 56 including hospital beds, are among the best ways to increase the efficiency of healthcare 57 resources. nevertheless, studies showed that more than 20% of hospital beds are used 58 inappropriately, resulting in a waste of resources, and increased iatrogenic risks for patients.4, 5 59 60 3 previous studies have shown that between 20-and 40% of hospital days were inappropriate 61 stays.1, 6-8 delay in performing and reporting diagnostic tests, delay in consultation, delay in 62 performing procedures are among the most common causes of inappropriate hospital stay.1, 7, 9, 10 63 old age, prolonged length of hospital stay, and medical admissions were associated with an 64 increased inappropriate hospital stay.8, 11, 12 in general, implementing quality improvement 65 projects including routine auditing hospital services, multidisciplinary team approach, 66 engagement of discharge planners early on admission, and improving home-based services have 67 been shown to reduce inappropriate hospital stay.6, 13 68 69 studies assessing factors associated with inappropriate hospital stay in the middle eastern 70 region are sparse. the study's findings will assess the extent of inappropriate hospital stay and 71 identify reasons for the inappropriate hospital stay. also, it will guide hospital managers, and 72 stakeholders to put strategies and implement measures to optimize health care resources 73 utilization without the need for additional financial investment. 74 75 methods 76 study setting 77 oman's population is rising at more than 9% per year, making it one of the most growing 78 populations globally. according to the latest united nations figures, oman’s current population 79 is around 5 million people, and more than 1.4 million live in muscat governorate.14, 15 80 socioeconomic growth coupled with a remarkable improvement in the health care system in 81 oman has resulted in an increased birth rate and decreased mortality rate, hence causing an 82 accelerated population expansion which continues to put a tremendous strain on the healthcare 83 system resources.16 84 85 one of the indicators of the quality of health service delivery is the number of hospital beds. 86 according to the ministry of health's annual report in 2020, there were 15.6 hospital beds 87 available for every 10,000 individuals in oman.17 similarly, hospital beds available for every 88 10,000 individuals range from 12.5 to 22 beds in the gulf cooperation countries (gcc). while 89 in the united states, there are 28.7 beds for every 10,000 of the population.16, 18 90 91 4 the study was a retrospective cohort study conducted at sultan qaboos university hospital 92 (squh), a 500-bed multispecialty tertiary referral hospital with several unique services and 93 certain specialized medical facilities. in addition, it is a major teaching hospital for medical and 94 nursing students at the college of medicine and health sciences and college of nursing. also, it 95 is a major training centre for medical interns, general foundation program trainees and residents 96 of the oman medical speciality board. 97 98 the general internal medicine unit receives around 70-80% of medical patients admitted 99 through the emergency department. the range of patients varies between patients with single 100 organ system disease -e.g. pneumonia-and patients with complex diseases or undifferentiated 101 illnesses. besides medical admissions, the general internal medicine unit provides admission 102 services to patients with immunological, genetic, and metabolic diseases due to the lack of 103 admission services for these specialities. 104 105 there are two main medical wards with a total bed capacity of 45 beds and ten beds in the high 106 dependency unit. in addition, general medical patients may be admitted to other non-medical 107 wards during busy periods. 108 109 data sources 110 we included patients admitted under the care of the general internal medicine unit from the 1 of 111 january 2020 until the 30 of june 2020. patients admitted with covid-19 infection were 112 excluded from the study. trained medical doctors collected relevant demographic and clinical 113 data from patients' electronic records. length of hospital stay counted as difference between the 114 time and date of admission and the time and date of discharge primary diagnoses were coded 115 and classified according to the 10th revision of the international statistical classification of 116 diseases and related health problems (icd-10). 117 118 hospital stay appropriateness measurement tool and procedure 119 the appropriateness evaluation protocol (aep) is the most widely used instrument for 120 evaluating the appropriateness of hospitalizations in various countries. gertman and restuccia 121 developed aep in 1981, and the original version contains 27 criteria for use in internal medicine 122 5 and surgical departments to evaluate the appropriateness of hospital admission and 123 hospitalization days.19 reasons for inappropriate hospital stay-according to aepinclude 124 inappropriate date of discharge, delay related to awaiting complementary tests, delay related to 125 awaiting the results of complementary tests, awaiting surgical procedures, delay related to 126 awaiting consultations, delays related to poor planning for discharge, delay related to unavailable 127 extra-hospital resources (e.g. palliative care, and rehabilitation services), delay related to 128 unavailable intensive care bed, or delay related to inadequate family support.20 129 130 aep has been used across many countries, and it was modified many times to adapt to various 131 health care settings.21 in addition, previous studies have proven that aep is highly reliable and 132 valid modality to provide an objective assessment for inappropriate hospital stay.21, 22 133 134 we have used a modified version of aep that includes 27 objective criteria items related to 135 medical and nursing services, extra-hospital resources, and patient-related factors. if one of the 136 criterion is fulfilled, the hospital days are considered appropriate, and if none are met, then the 137 days are considered inappropriate.20, 23 138 139 a team of four trained medical doctors who were not involved directly in patient care reviewed 140 all included patient medical records – patient electronic medical recordsin detail. each 141 admission was assessed independently by at least two medical doctors to assess the 142 appropriateness of hospital stay. the previously reported average length of hospital stay for 143 patients admitted under the care of the general internal medicine unit at squh and the 144 calculated average length of hospital stay for our cohort was five days. hence, any admission 145 that exceeded five days was reviewed to assess the appropriateness of the hospital stay. 146 uncertainty regarding the appropriateness of hospital stay was discussed among team members 147 until consensus was achieved. 148 149 statistical analysis 150 categorical variables (e.g. sex) were reported as numbers and percentages, and differences 151 between groups were assessed using the chi-square test or fisher's exact as appropriate. we 152 report continuous variables (e.g. age) as mean ± sd for normally distributed values or median 153 6 (iqr) for non-normally distributed values. in addition, differences between groups (3 or more) 154 were assessed using one-way anova for normally distributed continuous variables or kruskal–155 wallis rank test for non-normally distributed continuous variables. finally, we conducted a 156 regression analysis to identify patient-related factors associated with an increased risk of the 157 inappropriate hospital. stata v. 17.0 software package (statacorp llc, usa) was utilized to 158 perform statistical calculations, and p-values <0.05 were considered statistically significant. 159 160 ethical approval 161 the study was approved by the medical research ethics committee (mrec) of the college of 162 medicine and health sciences at our institution. 163 164 results 165 there were 855 admissions under the care general internal medicine unit during the study 166 period. in this cohort, 53.1% were men, and the median age was 64 (iqr:44-75) years. there 167 were 6785.4 hospitalization days, and the average length of hospital stay was 5 (iqr:3-9) days. 168 31.8% of admissions (n=272 admissions) included inappropriate hospitalization days. 9.9 % 169 (n=674 days) of hospitalization days were classified as inappropriate. there were 29 mortalities 170 during the study period (table 1). 171 172 diseases of the circulatory system (22.4%) and respiratory systems (22.0%) were the most 173 common class of primary diagnoses for patients admitted under the care of the general internal 174 medicine unit. in addition, neoplasms and diseases of the skin and subcutaneous tissue had a 175 longer hospital stay than other classes of primary diagnoses-i.e. 8 and 7, respectively (table 2). 176 177 pneumonia (14.0%), heart failure (3.8%), transient ischemic attack (tia) and stroke (8.0%), 178 exacerbations of chronic lung diseases (6.3%), sepsis (4.6%), admissions related to drug and 179 alcohol (4.2%), and urinary tract infection (4.1%) were the most common primary diagnoses. 180 drug and alcohol-related admissions occurred mainly in young and male patients. admission 181 due to tia and stroke (42.7%), exacerbations of chronic lung disease (42.6%) and urinary tract 182 infections (42.9%) were likely to result in an inappropriate hospital stay. also, tia and stroke 183 diagnoses (3 {1-3} days) were associated with prolonged length of inappropriate hospital stay. 184 7 sepsis was associated with an increased inpatient mortality rate (12.8%) (table 3). 185 186 delay in complementary tests (29.0%), unavailability of extra-hospital resources (21.7%), and 187 delay in the results of the complementary tests (18.8%) were the most common reasons 188 associated with inappropriate hospital stay (table 4). 189 190 in terms of patient’s related factors, a regression analysis showed that old age was associated 191 with an increased risk of inappropriate stay (p= 0.007; odds ratio [or]: 0.020 per 10-year 192 increase in age, 95% confidence interval ci: 0.006-0.036). 193 194 discussion 195 this study assessed inappropriate hospital stay in a region with a rapidly expanding population 196 that overstrained health care system resources. it showed that around 10% of hospital bed-day 197 were wasted. waiting for complementary tests, awaiting results of complementary tests and lack 198 of extra-hospital resources were the most common causes of inappropriate hospital stay. in 199 addition, old age and specific diagnoses such as stroke and chronic respiratory diseases are more 200 likely to result in an inappropriate hospital stay. 201 202 in this study, the overall average length of hospital stay for patients admitted to the general 203 internal medicine unit was five days which is higher than the average length of stay (3.9 days) in 204 a similar health care setting in oman,17 but is below the average length of stay reported in 205 different asian & european countries (6.4-7.8 days).24 a study from thailand reported a length 206 of hospital stay of 25.9 days for patients admitted under the care of the general medicine 207 department.25 this probably is due to the inclusion of subacute admissions (e.g. palliative care, 208 rehabilitation services) under the internal medicine department. in contrast, a study from 209 australia has shown the length of hospital stay of patients admitted under the care of general 210 medicine was 3.7 days.26 the variations in the reported length of hospital stay could be explained 211 by multiple factors, including accessibility to diagnostic and therapeutic services, availability of 212 subacute medical services and home-based services. 213 214 according to appropriateness evaluation protocol criteria, 31.9% of hospitalization (n=272) 215 8 included inappropriate hospital days, causing a waste of around 9.9% of total hospital bed-days 216 (n=674). the rate of inappropriateness has been reported in various international studies with 217 significant variation across countries, hospitals, and clinical departments. however, studies 218 conducted to assess the utilization of beds in internal medicine departments over the past 20 219 years concluded the rate of inappropriateness ranges between 20 to 41%. 27-30 a study from 220 netherland showed that more than 20% of hospital stay was inappropriate and old age, lack of 221 home-based care and specialized medical services were associated with an increased risk of 222 inappropriate hospital stay.28 223 224 the disparity in the rate of inappropriate hospitalization between these studies is significant, 225 which could be due to differences in admission and discharge protocols, geographic areas, or bed 226 occupancy rates of different hospitals. in addition, differences in methodology, including 227 sampling methods, aep modifications, options used to justify hospitalization days, and the 228 quality of medical records are important factors that might have contributed to the differences in 229 the previously reported rate of inappropriate hospital stay.28, 31 our rate is lower than the reported 230 rate in a similar setting, probably because we have only included admissions that exceeded the 231 calculated average length of hospital stay (i.e. five days). 232 233 the most common reasons for the inappropriate hospital stay in the current study mainly were 234 related to the hospital system factors, including delay of complementary tests or awaiting its 235 results. in our institution, a routine imaging request is usually carried out in 1-3 days, and the 236 official report may require up to 2 days following the procedure. as a tertiary and university 237 hospital receiving many undiagnosed cases from different regional hospitals for expert opinion, 238 diagnostic workup represents a significant part of patient's hospitalization period. hence, 239 institutional arrangements should be initiated, including the execution of a program for request 240 justification, scheduling and reporting procedures.9 241 242 in addition, extra-hospital care, including the availability of long-term or palliative care beds and 243 rehabilitation services, accounted for around 21% of inappropriate hospital stay. this result 244 highlights the lack of adequate rehabilitation services, home-based care and nursing homes, 245 resulting in inappropriate hospitalization and utilization of acute health resources in oman. 246 9 247 around 17% of inappropriate hospital stays were due to waiting for specialist consultation. 248 general internal medicine routinely admits patients with multiple complex issues; hence other 249 specialities consultation is vital. creating an efficient consultation process and improving 250 communication between teams might decrease inappropriate hospital stays. 32, 33 251 252 in term of patients’ related factors, previous studies have shown that old age, patient with 253 multiple comorbidities including chronic heart failure, stroke, and soft tissue infection at 254 increased risk of prolonged length of hospital stay.34, 35 255 256 our study has shown that the majority of patients were hospitalized with circulatory and 257 respiratory systems diseases. pneumonia and exacerbations of chronic lung disease were among 258 the most common diagnoses, with a median length of hospital stay of 6 days, which is higher 259 than the reported length of hospital stay in similar health settings (i.e. five days).36 this could be 260 explained by the fact that our cohort of patients had advanced chronic pulmonary diseases, and 261 many were on long-term oxygen therapy and mechanical ventilatory support. 262 263 acute decompensated heart failure was the second most common diagnosis in our study, with a 264 median length of hospital stay of 5.5 days (iqr: 4-9), consistent with international studies, 265 which reported a median of 6 days (iqr 4-9).34, 37 this is due to the nature and complexity of 266 managing heart failure leading to an increased rate of admission and readmission, the need for 267 intravenous diuretics and the possible development of complications like renal injury.38 heart 268 failure was also associated with increased length of inappropriate hospital stay, which might be 269 due to the delay in performance of cardiac-specific imaging, the interpretation of these 270 investigations, and lack of multidisciplinary heart failure service. 271 272 neoplasm’s class of diagnoses had the most extended length of hospital stay and the highest total 273 number of inappropriate hospitalization days, which is likely due to the time needed to perform 274 diagnostic investigations to confirm the diagnosis and arrange the appropriate transfer of care to 275 oncological specialities. diseases of the skin and subcutaneous tissue had an increased length of 276 inappropriate hospital stay, possibly due to delay diagnosis and delayed specialist consultation. 277 10 278 around 43% of admission due to stroke and tia contains inappropriate hospital days. this was 279 mainly due to delays in performing relevant investigations such as magnetic resonance imaging 280 (mri), holter monitoring, and echocardiography. in addition, the absence of a dedicated stroke 281 unit and inpatient rehabilitation service contributed to inappropriate hospitalization of patients 282 with acute stroke. 283 284 logistic regression analysis demonstrated that old age was associated with an increased 285 inappropriate hospital stay. this could be explained by the increased burden of comorbidity and 286 high prevalence of geriatric syndromes in elderly patients.39 dementia, poor pre-morbid 287 functional status were found to be associated with prolonged length of hospital stay in elderly 288 patients in previous studies.40 289 290 many previous studies identified strategies and interventions to promote early discharge and 291 reduce inappropriate hospital stay. auditing clinical and procedural services, physicians' 292 accountability, coordinating patient care early on admission, establishing a discharge planning 293 unit, investing in home-based care, nursing home and rehabilitation services were effective 294 strategies to minimize inappropriate hospital stay.5, 9, 41, 42 295 296 also, geriatric assessment for old patients, implementing of clinical pathways for management of 297 common diagnoses such as heart failure, medications for patients with polypharmacy, and case 298 management may reduce length of hospital stay.34, 43 299 300 this study has many strengths. it is one of the few studies from the middle east region where 301 the expanding population puts extreme pressure on health care systems. the study identified 302 several hospital-related factors causing the prolongation of inappropriate hospital stay. also, it 303 provides stakeholders and hospital managers with insights about the waste in acute hospital beds 304 and potential services to target to reduce inappropriate hospital stays. 305 306 the limitation of the study includes the retrospective nature of the study that reports data from a 307 single centre. also, only we reviewed admissions that exceeded the average length of hospital 308 11 stay, which might underestimate the wasted hospital beds. due to the study's retrospective nature 309 and lack of billing information -free of cost health care system for citizenswe could not 310 estimate the financial implication of inappropriate hospital stay. 311 312 conclusion 313 a significant proportion of hospital stays are deemed inappropriate primarily due to hospital-314 related factors, including in-hospital delay procedures and the inability to discharge patients to 315 subacute hospital care settings. therefore, auditing hospital services to minimize the time 316 between test request and completion of the test (performance and reporting), monitoring the 317 quality of consultation services, establishing rehabilitation services and investing in home-based 318 care are among the top strategies which are likely to improve early discharge and minimize 319 inappropriate hospital bed occupancy. 320 321 conflicts of interest 322 the authors declare no conflict of interests. 323 324 funding 325 no funding was received for this study. 326 327 author contributions 328 ahmed al-yarabi was involved in study conception and design, data collection, and draft 329 manuscript preparation. huriya al balushi, khaloud al hatmi and reem al yahyaie were 330 involved in data collection, and draft manuscript preparation. abdullah m. al alawi was 331 involved in study conception and design, analysis and interpretation of results, revision, and final 332 editing of the manuscript. khalfan al zeedy and hatem al farhan were involved in study 333 conception and design. 334 335 references 336 1. liu w, yuan s, wei f, yang j, zhu c, yu y, et al. inappropriate hospital days of a 337 tertiary hospital in shanghai, china. int j qual health care. 2017;29:699-338 704.https://doi.org/10.1093/intqhc/mzx091 339 https://doi.org/10.1093/intqhc/mzx091 12 2. silva sa, valacio ra, botelho fc and amaral cf. reasons for discharge delays in 340 teaching hospitals. rev saude publica. 2014;48:314-21.https://doi.org/10.1590/s0034-341 8910.2014048004971 342 3. anderson p, meara j, brodhurst s, attwood s, timbrell m and gatherer a. use of 343 hospital beds: a cohort study of admissions to a provincial teaching hospital. bmj. 344 1988;297:910-2.https://doi.org/10.1136/bmj.297.6653.910 345 4. smith he, pryce a, carlisle l, jones jm, scarpello j and pantin c. appropriateness of 346 acute medical admissions and length of stay. j r coll physicians lond. 1997;31:527-32 347 5. caminiti c, meschi t, braglia l, diodati f, iezzi e, marcomini b, et al. reducing 348 unnecessary hospital days to improve quality of care through physician accountability: a cluster 349 randomised trial. bmc health serv res. 2013;13:14.https://doi.org/10.1186/1472-6963-13-14 350 6. li h, tao h and li g. predictors and reasons for inappropriate hospitalization days for 351 surgical patients in a tertiary hospital in wuhan, china: a retrospective study. bmc health serv 352 res. 2021;21:900.https://doi.org/10.1186/s12913-021-06845-y 353 7. barisonzo r, wiedermann w, unterhuber m and wiedermann cj. length of stay as risk 354 factor for inappropriate hospital days: interaction with patient age and co-morbidity. j eval clin 355 pract. 2013;19:80-5.https://doi.org/10.1111/j.1365-2753.2011.01775.x 356 8. soria-aledo v, carrillo-alcaraz a, campillo-soto a, flores-pastor b, leal-llopis j, 357 fernandez-martin mp, et al. associated factors and cost of inappropriate hospital admissions and 358 stays in a second-level hospital. am j med qual. 2009;24:321-359 32.https://doi.org/10.1177/1062860609337252 360 9. dizdar o, karadag o, kalyoncu u, kurt m, ulger z, sardan yc, et al. appropriate 361 utilization of hospital beds in internal medicine: evaluation in a tertiary care hospital. j eval clin 362 pract. 2007;13:408-11.https://doi.org/10.1111/j.1365-2753.2006.00724.x 363 10. ou l, young l, chen j, santiano n, baramy ls and hillman k. discharge delay in 364 acute care: reasons and determinants of delay in general ward patients. aust health rev. 365 2009;33:513-21.https://doi.org/10.1071/ah090513 366 11. chopard p, perneger tv, gaspoz jm, lovis c, gousset d, rouillard c, et al. predictors 367 of inappropriate hospital days in a department of internal medicine. int j epidemiol. 368 1998;27:513-9.https://doi.org/10.1093/ije/27.3.513 369 https://doi.org/10.1590/s0034-8910.2014048004971 https://doi.org/10.1590/s0034-8910.2014048004971 https://doi.org/10.1136/bmj.297.6653.910 https://doi.org/10.1186/1472-6963-13-14 https://doi.org/10.1186/s12913-021-06845-y https://doi.org/10.1111/j.1365-2753.2011.01775.x https://doi.org/10.1177/1062860609337252 https://doi.org/10.1111/j.1365-2753.2006.00724.x https://doi.org/10.1071/ah090513 https://doi.org/10.1093/ije/27.3.513 13 12. majeed mu, williams dt, pollock r, amir f, liam m, foong ks, et al. delay in 370 discharge and its impact on unnecessary hospital bed occupancy. bmc health serv res. 371 2012;12:410.https://doi.org/10.1186/1472-6963-12-410 372 13. tavakoli n, hosseini kasnavieh sm, yasinzadeh m, amini m and mahmoudi nejad m. 373 evaluation of appropriate and inappropriate admission and hospitalization days according to 374 appropriateness evaluation protocol (aep). arch iran med. 2015;18:430-375 4.https://doi.org/0151807/aim.007 376 14. united nations doeasa, population division (2019). world population prospects 2019. 377 2019;2021. 378 15. information tncfsa. popoulation 379 clock.from:https://www.ncsi.gov.om/pages/ncsi.aspx .accessed:08/12/2021. 380 16. oman's health care system increasingly ready to meet the population's needs. oxford 381 bussines group 2021. 382 17. statistics doi.annual health report 383 2020.from:https://www.moh.gov.om/en/web/statistics/-/-2020.accessed: 384 18. li r, rivers c, tan q, murray mb, toner e and lipsitch m. estimated demand for us 385 hospital inpatient and intensive care unit beds for patients with covid-19 based on 386 comparisons with wuhan and guangzhou, china. jama netw open. 387 2020;3:e208297.https://doi.org/10.1001/jamanetworkopen.2020.8297 388 19. gertman pm and restuccia jd. the appropriateness evaluation protocol: a technique for 389 assessing unnecessary days of hospital care. med care. 1981;19:855-71 390 20. selker hp, beshansky jr, pauker sg and kassirer jp. the epidemiology of delays in a 391 teaching hospital. the development and use of a tool that detects unnecessary hospital days. med 392 care. 1989;27:112-29.https://doi.org/10.1097/00005650-198902000-00003 393 21. lang t, liberati a, tampieri a, fellin g, gonsalves mda l, lorenzo s, et al. a 394 european version of the appropriateness evaluation protocol. goals and presentation. the 395 biomed i group on appropriateness of hospital use. int j technol assess health care. 396 1999;15:185-97.https://doi.org/10.1017/s0266462399152784 397 22. sanchez-garcia s, juarez-cedillo t, mould-quevedo jf, garcia-gonzalez jj, contreras-398 hernandez i, espinel-bermudez mc, et al. the hospital appropriateness evaluation protocol in 399 https://doi.org/10.1186/1472-6963-12-410 https://doi.org/0151807/aim.007 https://www.ncsi.gov.om/pages/ncsi.aspx https://www.moh.gov.om/en/web/statistics/-/-2020.accessed https://doi.org/10.1001/jamanetworkopen.2020.8297 https://doi.org/10.1097/00005650-198902000-00003 https://doi.org/10.1017/s0266462399152784 14 elderly patients: a technique to evaluate admission and hospital stay. scand j caring sci. 400 2008;22:306-13.https://doi.org/10.1111/j.1471-6712.2007.00528.x 401 23. brabrand m, knudsen t and hallas j. the characteristics and prognosis of patients 402 fulfilling the appropriateness evaluation protocol in a medical admission unit; a prospective 403 observational study. bmc health serv res. 2011;11:152.https://doi.org/10.1186/1472-6963-11-404 152 405 24. length of hospital stay. 2021, 10.1787/8dda6b7a-en 406 25. ruangkriengsin d and phisalprapa p. causes of prolonged hospitalization among general 407 internal medicine patients of a tertiary care center. j med assoc thai. 2014;97 suppl 3:s206-15 408 26. gilfillan c, newnham e, nagappan r, evans j and compton j. a 7-day team-based 409 model of care in general medicine: implementation and outcomes at 12 months. intern med j. 410 2016;46:79-85.https://doi.org/10.1111/imj.12913 411 27. panis lj, verheggen fw and pop p. to stay or not to stay. the assessment of appropriate 412 hospital stay: a dutch report. int j qual health care. 2002;14:55-413 67.https://doi.org/10.1093/intqhc/14.1.55 414 28. panis lj, gooskens m, verheggen fw, pop p and prins mh. predictors of inappropriate 415 hospital stay: a clinical case study. int j qual health care. 2003;15:57-416 65.https://doi.org/10.1093/intqhc/15.1.57 417 29. mozes b, schiff e and modan b. factors affecting inappropriate hospital stay. qual 418 assur health care. 1991;3:211-7.https://doi.org/10.1093/intqhc/3.3.211 419 30. siavashi e, kavosi z, zand f, amini m and bordbar n. inappropriate hospital stays and 420 association with lack of homecare services. east mediterr health j. 2021;27:656-421 664.https://doi.org/10.26719/2021.27.7.656 422 31. hwang ji, kim j, jang w and park jw. inappropriate hospitalization days in korean 423 oriental medicine hospitals. int j qual health care. 2011;23:437-424 44.https://doi.org/10.1093/intqhc/mzr028 425 32. emes m, smith s, ward s and smith a. improving the patient discharge process: 426 implementing actions derived from a soft systems methodology study. health syst (basingstoke). 427 2019;8:117-133.https://doi.org/10.1080/20476965.2018.1524405 428 https://doi.org/10.1111/j.1471-6712.2007.00528.x https://doi.org/10.1186/1472-6963-11-152 https://doi.org/10.1186/1472-6963-11-152 https://doi.org/10.1111/imj.12913 https://doi.org/10.1093/intqhc/14.1.55 https://doi.org/10.1093/intqhc/15.1.57 https://doi.org/10.1093/intqhc/3.3.211 https://doi.org/10.26719/2021.27.7.656 https://doi.org/10.1093/intqhc/mzr028 https://doi.org/10.1080/20476965.2018.1524405 15 33. rohatgi n, kane m, winget m, haji-sheikhi f and ahuja n. factors associated with 429 delayed discharge on general medicine service at an academic medical center. j healthc 430 qual. 2018;40:329-335.https://doi.org/10.1097/jhq.0000000000000126 431 34. siddique sm, tipton k, leas b, greysen sr, mull nk, lane-fall m, et al. interventions 432 to reduce hospital length of stay in high-risk populations: a systematic review. jama netw 433 open. 2021;4:e2125846.https://doi.org/10.1001/jamanetworkopen.2021.25846 434 35. aubert ce, schnipper jl, fankhauser n, marques-vidal p, stirnemann j, auerbach ad, 435 et al. association of patterns of multimorbidity with length of stay: a multinational observational 436 study. medicine (baltimore). 2020;99:e21650.https://doi.org/10.1097/md.0000000000021650 437 36. angelillo if, ricciardi g, nante n, boccia a, bianco a, la torre g, et al. 438 appropriateness of hospital utilisation in italy. public health. 2000;114:9-14 439 37. kul s, barbieri a, milan e, montag i, vanhaecht k and panella m. effects of care 440 pathways on the in-hospital treatment of heart failure: a systematic review. bmc cardiovasc 441 disord. 2012;12:81.https://doi.org/10.1186/1471-2261-12-81 442 38. martin-sanchez fj, carbajosa v, llorens p, herrero p, jacob j, miro o, et al. [length of 443 stay in patients admitted for acute heart failure]. gac sanit. 2016;30:191-444 200.https://doi.org/10.1016/j.gaceta.2016.01.003 445 39. bo m, fonte g, pivaro f, bonetto m, comi c, giorgis v, et al. prevalence of and factors 446 associated with prolonged length of stay in older hospitalized medical patients. geriatr gerontol 447 int. 2016;16:314-21.https://doi.org/10.1111/ggi.12471 448 40. lisk r, uddin m, parbhoo a, yeong k, fluck d, sharma p, et al. predictive model of 449 length of stay in hospital among older patients. aging clin exp res. 2019;31:993-450 999.https://doi.org/10.1007/s40520-018-1033-7 451 41. coffey a, leahy-warren p, savage e, hegarty j, cornally n, day mr, et al. 452 interventions to promote early discharge and avoid inappropriate hospital (re)admission: a 453 systematic review. int j environ res public health. 454 2019;16.https://doi.org/10.3390/ijerph16142457 455 42. yu sy, ko is, lee sm, park yw and lee c. a unit-coordinator system: an effective 456 method of reducing inappropriate hospital stays. int nurs rev. 2011;58:96-457 102.https://doi.org/10.1111/j.1466-7657.2010.00850.x 458 https://doi.org/10.1097/jhq.0000000000000126 https://doi.org/10.1001/jamanetworkopen.2021.25846 https://doi.org/10.1097/md.0000000000021650 https://doi.org/10.1186/1471-2261-12-81 https://doi.org/10.1016/j.gaceta.2016.01.003 https://doi.org/10.1111/ggi.12471 https://doi.org/10.1007/s40520-018-1033-7 https://doi.org/10.3390/ijerph16142457 https://doi.org/10.1111/j.1466-7657.2010.00850.x 16 43. hammond cl, pinnington ll and phillips mf. a qualitative examination of 459 inappropriate hospital admissions and lengths of stay. bmc health serv res. 460 2009;9:44.https://doi.org/10.1186/1472-6963-9-44 461 462 table 1: patients' characteristics and admission data 463 characteristic total (n= 855) age (years)-median (iqr) 64 (44-75) female-no (%) 401(46.9%) male -no (%) 454 (53.1%) the average length of hospital stays (days)-median (iqr) 5 (3-9) total hospitalisation days (n) 6785.4 admissions with appropriate date of discharge no (%) 583 (68.2%) admissions included inappropriate hospitalization days -no (%) 272 (31.9%) total number of inappropriate hospitalization days (days) 674 mortalityno (%) 29 (3.4%) 464 table 2: the length of hospital stay according to the primary diagnosis classified according to 465 icd-10 466 the average length of hospital stay; median (iqr) total (n= 855) classification of primary diagnosis according to icd-10 6 (3-10) 46 (5.4%) infectious disease (a00-b99) 8 (5-14) 18 (2.1%) neoplasms (c00-d48) 4 (3-7) 29 (3.4%) haematological diseases (d50-d89) 4.5 (3-6) 70 (8.2%) endocrine, nutritional, and metabolic diseases (e00-e90) 4 (2-6) 25 (2.9%) mental and behavioural disorders (f00-f99) 5 (3.5-8) 44 (5.2%) diseases of the nervous system (g00-g99) 3 (2-5) 7 (0.8%) diseases of the ear and mastoid process (h60-95) 6 (4-10) 191 (22.4%) diseases of the circulatory system (i00-i99) 6 (3-10) 188 (22.0%) diseases of the respiratory system (j00-j99) 4 (3.5-7) 60 (7.0%) diseases of the digestive system (k00-k93) 7 (3.5-11) 20 (2.3%) diseases of the skin and subcutaneous tissue (l00-l99) https://doi.org/10.1186/1472-6963-9-44 17 6 (3-16) 12 (1.4%) diseases of the musculoskeletal system and connective tissue (m00-m99) 6(5-8) 55(6.4%) diseases of the genitourinary system (n00-n99) 6(4-8) 69 (8.1%) symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified (r00-r99) 5 (2-13) 7 (0.8%) injury, poisoning and certain other consequences of external causes (s00-t98) 3 (2-5) 13 (1.5%) factors influencing health status and contact with health services (z00-z99) icd-10: the 10th revision of the international statistical classification of diseases and related health problems 467 468 18 table 3: patients' characteristics and admission data of the most common diagnoses characteristic pneumonia heart failure stroke & tia exacerbation of chronic lung diseases* sepsis drugs & alcohol urinary tract infection others p-value admissions (total n=855) 120 (14.0%) 118 (13.8) 68 (8.0%) 54 (6.3%) 39 (4.6%) 36 (4.2%) 35(4.1%) 385 (45.0%) age (years) 68 (43.575) 70 (6177) 67 (5676) 67.5 (53-76) 75 (6484) 38 (29.547.0) 71 (48-79) 57 (35-72) 0.0043* female (n) 49 (40.9%) 61 (51.7%) 28 (41.2%) 31 (57.4%) 17 (43.6%) 7(19.4%) 22(62.9%) 186 (48.3%) 0.0034** male (n) 71(59.2%) 57 (48.3%) 40 (58.8%) 23 (42.6%) 22 (56.4%) 29 (80.6%) 13(37.1%) 199(51.7%) 0.0034** average length of hospital stay (days) 6 (3-10) 5.5 (4-9) 5.5 (4-8) 6(3-8) 6 (4-10) 4 (3.0-6.5) 6 (5-8) 5 (3-8) 0.0751* admissions with appropriate date of discharge (n) 77 (64.2%) 72 (61.0%) 39 (57.4%) 31(57.4%) 31 (79.5%) 28(77.8%) 20 (57.1%) 285(74.0%) 0.0023** admissions with inappropriate hospital stay (n) 43 (35.8%) 46 (39.0%) 29 (42.7%) 23(42.6%) 8 (20.5%) 8 (22.2%) 15(42.9%) 11(26.0%) 0.0023** total number unnecessary hospital stay days (n=674 days) 120 (17.8%) 103 (15.3%) 72 (10.7%) 49 (7.3%) 12 (1.8%) 21 (3.1%) 40 (5.9%) 257 (38.1%) 0.0411** 19 average length of inappropriate hospitalization (days) 2 (1-3) 2 (1-3) 3 (1-3) 2 (1-3) 1(1-2) 2 (1.5-4) 2 (2-3) 2 (1-3.5) 0.0043* mortality (n) 2 (1.7%) 1 (0.9%) 1(1.5%) 0 5 (12.8%) 0 0 20 (5.2%) 0.0016** tia: transient ischemic attack. *chronic obstructive lung disease, interstitial lung disease, bronchiectasis, bronchial asthma. *p-value for differences between continuous variables groups using kruskal–wallis rank test. ** p-value for differences between categorical variables groups using chi-square test. table 4: reasons for the inappropriate hospital stay20 reasons for the inappropriate hospital stay total admissions n=272 awaiting complementary tests 79 (29.0%) awaiting the results of complementary tests 51(18.8%) awaiting surgical procedures 3 (1.1%) awaiting specialist consultations 48 (17.6%) awaiting extra-hospital care to be arranged & unavailable extra-hospital resources, including the availability of long-term or palliative care beds or rehabilitation 59 (21.7%) patients awaiting transfer to intensive care or admission to another program or in-home care or awaiting transfer to other departments within the same hospital 3 (1.1%) inadequate family support 29 (10.7%) departments of 1adult health & critical care, 2statistics and 3fundamentals & administration, sultan qaboos university, muscat, oman; 4community and mental health nursing, oman college of health sciences, muscat, oman; 5department of plastic & reconstructive surgery, university of toronto, toronto, canada; 6national heart centre, royal hospital, muscat, oman *corresponding author’s e-mail: joyk@squ.edu.om nursing students’ perceived disaster preparedness and response pilot study in oman *joy k. kamanyire,1 ronald wesonga,2 susan achora,1 leodoro l. labrague,3 anju malik,4 sultan alshaqsi,5 jamila a.s. alhabsi6 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 621–625, epub. 25 nov 21 submitted 25 aug 20 revisions req. 06 oct & 01 dec 20; revisions recd. 16 nov & 15 dec 20 accepted 23 dec 20 methods this pilot study was conducted between may and june 2019, with the target population being nursing students enrolled in a degree program at two government nursing education institutions (sultan qaboos university and oman college of health sciences) located in muscat, oman. using a stratified cluster sampling method, with the clusters being the academic or cohort years, a random sample size of 51 students was selected across all the years of study. the participants responded to a questionnaire containing items related to demographic data, types of disasters experienced, personal and institutional disaster preparedness and willingness to volunteer during a disaster. other questions were adopted from the disaster preparedness evaluation tool (dpet) and the disaster response self-efficacy scale (drses).10,11 the dpet comprises 47 items assessing disaster preparedness, which are categorised into three subscales (post-disaster management, disaster knowledge and skills) using a 6-point likert scale (1 is strongly disagree and 6 is strongly agree). the tool was reported to have acceptable validity and high internal consistency with a cronbach’s alpha of 0.90. the drses examines the self-efficacy in disaster response using 19 items that are categorised into four due to its geographical location in the arabian peninsula, oman has been reportedly experiencing a natural disaster every three to five years, especially earthquakes and tropical cyclones that result in flash floods.1,2 the national committee for civil defence oversees the management of disasters in oman; they have also outlined the importance of training, education, public awareness and volunteerism during an emergency.1 nurses constitute the largest group of responders when disasters strike. however, nursing schools have been reported to omit disaster training from their curricula, thereby leaving an untapped workforce of nursing students that can be utilised while dealing with disasters.3 studies have documented the lack of knowledge on disaster preparedness and management among nursing students though they possess a positive attitude to volunteering during disasters.4–6 disaster education and simulated drills have proven to enhance disaster preparedness and confidence among nursing students.7–9 the ability of nursing students in oman to handle disasters is unknown. therefore, this study aimed to describe the level of disaster preparedness and response among nursing students in oman as well as their level of perceived confidence in handling disasters. to the best of the authors’ knowledge, this is the first study to do so in oman. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.074 brief communication abstract: objectives: this study aimed to assess the perceived level of disaster preparedness and response among nursing students in oman, as the country is disaster prone and experiences disasters every three to five years. methods: a descriptive cross-sectional pilot study was conducted from may to june 2019 using a stratified cluster sampling method among nursing students recruited from two government nursing colleges in muscat, oman. the disaster preparedness evaluation tool and disaster response self-efficacy scale were used to assess the knowledge, skill, disaster management and self-efficacy in handling disasters. results: a total of 51 students participated in this study. most students (78.4%) had experienced a disaster while at home. overall, the students had moderate levels of knowledge (3.17 ± 1.49), skill (3.12 ± 1.52), post-disaster management (3.22 ± 1.44) and self efficacy in responding to disaster (2.93 ± 1.16). conclusion: nursing students in oman have experienced disasters and are willing to respond when called upon though they possess moderate knowledge and confidence in handling disasters. keywords: disasters; nursing students; pilot study; oman. nursing students’ perceived disaster preparedness and response pilot study in oman 622 | squ medical journal, november 2021, volume 21, issue 4 subscales (assessment, on-site rescue, psychological nursing and role quality and adaptation) and uses a 5-point likert scale (1 is no confidence at all and 5 is complete confidence). the scale was reported to have excellent validity and reliability with a cronbach’s alpha of 0.912. the original english versions of the tools were used in this study. the statistical software table 1: characteristics of nursing students, personal and institutional disaster plans and disasters likely to occur in muscat, oman (n = 51) characteristic n (%) gender male 2 (3.9) female 49 (96.1) marital status single 49 (96.1) married 2 (3.9) year of study year 1 6 (11.8) year 2 33 (64.7) year 3 11 (21.6) year 4 1 (2) attendance of special courses/education on disaster yes 14 (27.5) no 37 (72.5) attendance of disaster course outside their university/ institution yes 16(31.4%) no 35(68.6%) consider taking another disaster course in the future yes 29 (56.9) no 11 (21.6) undecided 11(21.6) knowledge on the disaster preparedness of his/her university yes 22 (43.1) no 21 (41.1) undecided 8 (15.7) knowledge on the availability of his/her university’s disaster management plan yes 19 (37.3) no 15 (29.4) don’t know 17 (33.3) opinion on the need for a structured disaster management plan in the university yes 38 (74.5) no 5 (9.8) don’t know 8 (15.7) have specific delineated roles to perform during a disaster yes 6(11.8%) no 16(31.4%) unsure 29(56.9%) perceived disaster role based on university disaster plan caregiver 28 (54.9) triage 9 (17.6) manager 10 (19.6) perceived role that could be performed yes 13 (25.5%) no 38 (74.5%) role of institution in disaster preparedness provide disaster specific course/education 46 (90.2%) others 5 (11.8%) personal experience with disaster at home 40 (78.4) at work 3 (5.9) travelled to respond to a disaster 3 (5.9) no 5 (9.8) willingness to report to the university as a volunteer during disaster not at all 11 (21.6) probably not 4 (7.8) possibly 28 (54.9) probably 5 (9.8) definitely 3 (5.9) requirements for being available to report to the university during a disaster* transport 31 (60.8) communication 39 (76.5) compensation 28 (54.9) type of disaster likely to occur* infectious disease outbreaks (severe acute respiratory syndrome/avian flu, tuberculosis) 41 (80.4) extreme weather conditions (heat or cold waves) 41 (80.4) food poisoning by human causes 41 (80.4) drought 43 (84.3) typhoon/hurricane/cyclone 45 (88.2) *percentages do not add up to 100% as multiple options could be chosen. joy k. kamanyire, ronald wesonga, susan achora, leodoro l. labrague, anju malik, sultan alshaqsi and jamila a.s. alhabsi brief communication | 623 students (78.4%) had experienced a disaster while at home [table 1]. overall, the participants had moderate knowledge of disaster management (3.17 ± 1.49), moderate skill in handling disaster management (3.12 ± 1.52) and moderate preparedness of post-disaster management (3.22 ± 1.44). overall, the level of disaster preparedness and management of the students was at a moderate level (3.18 ± 1.48). all participants had moderate confidence in disaster assessment competency (2.87 ± 1.08), disaster emergency rescue competency (2.92 ± 1.15), disaster psychological nursing competency (2.86 ± 1.19) and disaster role quality and adaption competency (3.09 ± 1.25), which translated into an overall moderate self-efficacy in disaster response (2.93 ± 1.16) [table 2]. discussion the majority of the nursing students in this study had experienced a disaster while at home with cyclones/hurricanes/typhoons being reported as the main disasters experienced, thereby affirming earlier reports that oman is indeed a disaster-prone area.1–3 consequently, almost all students wanted their institution to add a disaster course to their curriculum as reported in another study.12 nursing educators have been encouraged to prepare degree nurses with the minimal knowledge and skill appropriate for disaster response by adjusting their curricula and meeting the increased need for education and training in disaster nursing.7,8,13 stata®, version 13 (stata corporation, texas, usa) was used to generate frequencies, means and standard deviations. approval for the study was obtained from the institutional review boards of both institutions (rec 2017-2018/10 and moh/csr/18/9479). all participants consented voluntarily with knowledge of the study, protection of their privacy through the use of coded numbers and no foreseeable risks for participating in the study. results a total of 51 students participated in this study. the majority were female (96.1%) and had an average age of 25 years. most of the participants were single (96.1%) and in their second year of study (64.7%). the majority of the participants (88.2%) reported that hurricanes/ typhoons/cyclones were the disasters that were most likely to occur. most participants (72.5%) had never participated in any course or received education in disaster preparedness. only 27.5% had ever attended a special course on disaster management and 31.4% had ever attended a disaster course outside their institution. yet, most were willing to take a course in disaster management (56.9%) if they were given the opportunity and some (43.1%) stated that their institution had information on how to prepare for a disaster. only 37.3% reported the presence of a disaster management plan in their institution, while 29.4% denied the existence of such a plan; 33.3% were unsure whether their institution had a disaster management plan. most participants (74.5%) affirmed that their institution needed a structured disaster management plan. the majority of participants (52.9%) had no information on preparing themselves for a disaster; neither were they (56.9%) even sure of which role they could play in the case of a disaster. however, 54.9% felt that they could perform the role of a caregiver, 17.6% felt that they could perform a triage role and only 19.6% believed that they could perform a managerial role. the majority (74.5%) reported that they were unable to perform any role during a disaster. almost all participants (90.2%) reported that their institution should offer a disaster-specific course to prepare them for disasters. most of the participants (70.6%) were willing to report to the university as a volunteer during a disaster. however, 60.8% reported needing transport, while 76.5% reported that they would require communication equipment to stay in touch with their family; 54.9% reported that they would require compensation if they were to volunteer in a disaster response. it was also observed that the majority of the table 2: participants’ overall responses to the disaster preparedness evaluation tool and disaster response self-efficacy scale dpet subscale mean ± sd post-disaster management 3.22 ± 1.44 disaster knowledge 3.17 ± 1.49 disaster skill 3.12 ± 1.52 dpet composite score 3.18 ± 1.48 drses subscale disaster assessment competency 2.87 ± 1.08 disaster emergency rescue competency 2.92 ± 1.15 disaster psychological nursing competency 2.86 ± 1.19 disaster role quality and adaptation competency 3.09 ± 1.25 drses composite score 2.93 ± 1.16 dpet = disaster preparedness evaluation tool; sd = standard deviation; drses = disaster response self-efficacy scale. reproduced with permission from al khalaileh et al. and li et al.10,11 nursing students’ perceived disaster preparedness and response pilot study in oman 624 | squ medical journal, november 2021, volume 21, issue 4 coincidentally, most of the students reported their willingness to report to the university as volunteers during a disaster as noted in other studies.4,6,13 academic and clinical disaster preparedness is critical to enhancing the safety and competence of students, which directly affects their willingness to participate in an emergency. however, over half of the nursing students wanted compensation for volunteering in a disaster. it was found that not all nursing students are willing to respond to chemical, biological or radiological disasters due to fear of personal risk, personal priorities and the unavailability of personal protective equipment, education and prior disaster training.7,12,13 overall, the participants reported having a moderate level of knowledge, skill and preparedness for dealing with disasters and their management, which was similar to a previous study.14 specifically, they had low knowledge of emergency planning in their community and low awareness about classes on disaster preparedness and management being offered at their institute; furthermore, they also lacked skills in using the local emergency response systems. studies have demonstrated the effectiveness of relevant knowledge and skill acquired by nursing students after disaster training, thereby highlighting the need to include it in nursing curricula.3,7 most participants denied or were unaware of the presence of an institutional disaster management plan. subsequently, the nursing students also stated that they did not have a personal/family emergency plan as similarly reported in another study.10 this combination predisposes the nursing students to a high-risk situation. information dissemination and plan translation is a significant aspect of disaster planning even for students and this should be emphasised. generally, the nursing students had a moderate level of self-efficacy in disaster management; moderate levels of self-efficacy were seen across all three subscales of the dpet. based on social cognitive theory, previous performances and vicarious experiences in certain tasks such as disaster response are important for gaining a sense of self-confidence.15 in the current study, a lower rating was expected since most of the participants were in the early years of nursing education and had never personally handled a disaster. disaster self-efficacy is an important predictor of actual disaster response; thus, measures to increase disaster self-efficacy in nursing students are warranted. nursing education plays an important role in fostering disaster competence and confidence in responding to emergency and disastrous events by incorporating disaster-related content into the nursing curriculum using simulated disaster drills, first aid and life support training.3,7,16 in oman, there is a wellestablished emergency medical service. however, nursing students can be modelled as future responders by their faculty and clinical preceptors during disaster drills to provide them with an opportunity for selfpreparedness. this study may serve as a platform for future research in a nation that is increasingly experiencing natural storms, such as oman, which was previously ill-prepared to handle the cyclone gonu that ravaged the country. conclusion nursing students in oman have experienced disasters, especially cyclones. despite this, they have moderate disaster preparedness and confidence to volunteer as responders. though they are willing to respond, they lack vital information and skills that are not incorporated into their nursing curriculum. it is imperative that nursing students are included in regular disaster drills and simulations to familiarise themselves with institutional and personal disaster preparedness. the practice of volunteering during disasters without the need for compensation in any form should be strongly emphasised during training since nursing is grounded in altruism, compassion and care. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study received an internal grant from sultan qaboos university (grant number: ig/con/ ahcc/19/02). a u t h o r s’ c o n t r i b u t i o n jkk, sa and lll conceived the original idea of the study, rw performed the computations and analysis of the data. jkk, rw, sa, lll, am, sas and jasa contributed to the discussion of results, provided critical feedback and shaped the final version of the manuscript. jkk supervised the project. all authors approved the final version of the manuscript. references 1. al-shaqsi sz. emergency management in the arabian peninsula: a case study from the sultanate of oman. from: http://pacdaoman.gov.om/images/pdf/research/drsultan-alshaqsi.pdf accessed: dec 2020. 2. al-shaqsi s. care or cry: three years from cyclone gonu. what have we learnt? oman med j 2010; 25:162–7. https://doi. org/10.5001/omj.2010.50. joy k. kamanyire, ronald wesonga, susan achora, leodoro l. labrague, anju malik, sultan alshaqsi and jamila a.s. alhabsi brief communication | 625 10. al khalaileh ma, bond ae, beckstrand rl, al-talafha a. the disaster preparedness evaluation tool: psychometric testing of the classical arabic version. j adv nurs 2010; 66:664–72. https://doi.org/10.1111/j.1365-2648.2009.05208.x. 11. li hl, bi rx, zhong ql. the development and psychometric testing of a disaster response self-efficacy scale among undergraduate nursing students. nurse educ today 2017; 59:16–20. https://doi.org/10.1016/j.nedt.2017.07.009. 12. gershon rr, magda la, canton an, riley he, wiggins f, young w, et al. pandemic-related ability and willingness in home healthcare workers. am j disaster med 2010; 5:15–26. https://doi.org/10.5055/ajdm.2010.0002. 13. liou sr, liu hc, lin cc, tsai hm, cheng cy. an exploration of motivation for disaster engagement and its related factors among undergraduate nursing students in taiwan. int j environ res public health 2020; 17:3542. https://doi.org/10.3390/ ijerph17103542. 14. cusack l, arbon p, ranse j. what is the role of nursing students and schools of nursing during disaster? a discussion paper. collegian 2010; 17:193–7. https://doi.org/10.1016/j. colegn.2010.09.006. 15. bandura a. self-efficacy: toward a unifying theory of behavioral change. psychol rev 1977; 84:191–215. https://doi. org/10.1037//0033-295x.84.2.191. 16. kılıç n, şimşek n. the effects of psychological first aid training on disaster preparedness perception and self-efficacy. nurse educ today 2019; 83:104203. https://doi.org/10.1016/j. nedt.2019.104203. 3. achora s, kamanyire jk. disaster preparedness: need for inclusion in undergraduate nursing education. sultan qaboos univ med j 2016; 16:e15–19. https://doi.org/10.18295/ squmj.2016.16.01.004. 4. yonge o, rosychuk rj, bailey tm, lake r, marrie tj. willingness of university nursing students to volunteer during a pandemic. public health nurs 2010; 27:174–80. https://doi. org/10.1111/j.1525-1446.2010.00839.x. 5. schmidt ck, davis jm, sanders jl, chapman la, cisco mc, hady ar. exploring nursing students’ level of preparedness for disaster response. nurs educ perspect 2011; 32:380–3. https:// doi.org/10.5480/1536-5026-32.6.380. 6. özpulat f, kabasakal e. knowledge levels of nursing students on disaster nursing and their state of disaster preparedness. int j med res & health sci 2018; 7:165–74. 7. alim s, kawabata m, nakazawa m. evaluation of disaster preparedness training and disaster drills for nursing students. nurse educ today 2015; 35:25–31. https://doi.org/10.1016/j. nedt.2014.04.016. 8. grochetdreis t, de jong n, harenberg n, görres s, schröderbäck p. nurses’ roles, knowledge and experience in national disaster pre-paredness and emergency response: a literature review. south east eur j public health 2016; 7:1–19. https:// doi.org/10.4119/unibi/seejph-2016-133. 9. kalanlar b. effects of disaster nursing education on nursing students’ knowledge and preparedness for disasters. int j disaster risk reduct 2018; 28:475–80. https://doi.org/10.1016/j. ijdrr.2017.12.008. 2008-issue1.indd the icu book sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 95-96 sultan qaboos university© submitted 7th november 2007 the book, running to more than 1000 pages, has 53 chapters in 16 sections covering: basic science review; preventive practices in the critically ill; vascular access; haemodynamic monitoring; disorders of circulatory flow; critical care cardiology; acute respiratory failure; mechanical ventilation; acid base disorders; renal and electrolyte disorders; transfusion practices in critical care; disorders of body temperature; inflammation and infection in the icu; nutrition and metabolism; critical care neurology; toxic ingestions.the appendices include units and conversions, selected reference ranges and clinical scoring systems. the icu book is excellent reference material for all physicians, not just intensivists. it is a valuable resource for any health professional, from medical student to experienced physicians and a must for anyone entering critical care medicine, anaesthesia, accident and emergency, medicine or surgery and even for critical care nurses as well. it provides a superior review for residents preparing for board examinations and the essential background for icu rotations. the icu book is a very complete overview of fundamentals and the physiology behind patient care presented in a succinct manner. the latest complex physiological findings are broken down into simple concepts, accompanied by important straight to the point facts and easy to understand illustrations. the short paragraphs prevent you from getting lost in the subject. the text is brilliantly written and easy to read and learn from, with simple english for those who speak english as a foreign language; every nurse can follow it as well. the emphasis on managing critically ill patients in a simple manner with the support of evidence-based medical literature is also useful for patient care outside the icu. b o o k r e v i e w املركزة العناية وحدة �كتاب مارينو ال. بول : املؤلف author: paul l marino publisher: lippincott williams and wilkins. third edition 2007 isbn: 13: 9 78-0-07817-4802-5 price: or 24 available at: al manahil educational email: manahil@omantel.net.om au th o r i n f o r m ati o n dr. marino is chairman of the department of medicine and critical care director of saint vincent’s midtown hospital in new york city. he is also clinical associate professor of new york medical college in valhalla. the third edition of the icu book welcomes dr. kenneth sutin, department of anaesthesiology and surgery at bellevue hospital centre and associate professor of anaesthesiology and surgery at university school of medicine in new york city, who adds his expertise to the final 13 chapters of the book. th e i c u b o o k 96 the icu book covers a broad spectrum of critical care topics. the third edition has undergone extensive revision in content and most of the chapters have been rewritten. newly renamed and refocused chapters on hot topics are: acute coronary syndromes, severe airflow obstruction and anaemia and red blood cell transfusion in the icu. additional new chapters include hyperthermia and hypothermia syndromes and infection control in the icu. close to 400 new tables and figures including radiographs, ct scans, electrocardiograms and microscopic images have been added to provide visual references, which aid in comprehension of the text. the editor is to be congratulated on enforcing the original aim to produce a book that is well organised, with topics that are easy to find for quick reference and exam review. the majority of chapters make good use of tables and figures. critical points and controversies are bold faced throughout the text. most chapters include a so-called final word with an important take-home message. each chapter has an extensive and generally up-to-date reference list, subdivided into specific topics as an easy link to further readings, and with emphasis on evidence-based clinical practice guidelines. in general, the icu book has good quality paper and binding. the large print and solid text unbroken by illustrations and brilliant simple figures with great message make the book pleasant to read. a future edition should not be any larger so that the book retains its handy portability. however, i found there were too few details about non-invasive–ventilation. also the ramsay score, which assesses the level of icu sedation, although described in the text, should be included in the appendix of clinical scoring systems. as an owner of the previous edition and the german translation, i am even more impressed with this third edition. the icu book has been always a great guide for my everyday practice as anaesthetist and i highly recommend this excellent reference book, available at a reasonable price that will disappoint nobody. r e v i w e r karin nollain department of anesthesia and intensive care unit, sultan qaboos university hospital, muscat, sultanate of oman email: karin@squ.edu.om december 2008 no white pages.indd riding the diabetes rollercoaster a new approach for health professionals, patients and carers sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 366-367 sultan qaboos university© submitted 20th may 2008 the book provides a new approach in looking at diabetes as a health problem with complex dimensions affecting patients, their families and health professionals. the authors have adopted a particular approach to diabetes, starting with a brief introduction to diabetes, outlining some of its main aspects and charting historical developments to show why it is such a perfect example of a complex system. they highlight the growing number of patient with diabetes worldwide, now reaching epidemic proportions, and the consequent social and economic impacts. in the second chapter, they introduce the reader to the basics of complexity science. using a historical approach, the authors chart the pathways of complexity’s emergence out of the natural sciences in the early twentieth century and its spilling over into the medical and social sciences at the end of that century. following this historical and theoretical exposé, they apply different concepts of complexity to the management of diabetes. diabetics run the additional risk of developing psychological problems; indeed, the prevalence of mental health problems in people with diabetes exceeds that found in general populations. therefore, in chapter 4, the authors approach the psychological aspects of the problem of balancing patients’ mood swings due to the anxieties caused by diabetes. they also discuss negative attitudes, coping difficulties, eating disorders, depressions, anxiety and other disorders which frequently complicate the health care of diabetics and are often missed. poor psychological functioning causes suffering, can seriously interfere with daily diabetes self-management, and is associated with poor medical outcomes and high costs. they highlight the need to integrate personal experiences into the educational process, so acknowledging the expertise the patient develops from living with diabetes. in chapter 5, the authors discuss the complexity of the management of diabetes viewing, on the one hand, the medical expert’s emphasis on the importance of glucose control. on the other hand, they discuss the patient’s viewpoint on living with diabetes on a day-to-day basis and so acquiring valuable knowledge and experience of their condition and its management. ultimately, they therefore become experts in living with their disease. the authors also contrast the hierarchical with the interactive approach to the management of diabetes. the emphasis is on how to help diabetics of all ages to understand and communicate what is happening to السكر لداء (القطار السريع) ركوب يرعاهم ومن واملرضى في القطاع الصحي للمهنيني جديدة طريقة جيير وروبرت كوبر هيلني املؤلفون: authors: helen cooper and robert geyer publisher: radcliffe publishing, oxford & new york, 2007. no. of pages 115 isbn: 978 1 84619 045 2 orders: http://www.radcliffe-oxford.com b o o k r e v i e w b o o k r e v i e w r i d i n g t h e d i a b e t e s r o l l e r c o a s t e r 367 them. the design of interactive counselling and learning aids is also discussed; for example, three `diabetes boxes`, each one a three-dimensional hand-made cube, can be used to stimulate discussions and to help people to develop knowledge and understanding of the biological and psychological concepts relating to diabetes, and help them to understand and express their feelings about having the disease. each box relates to a specific theme. the idea of the three-dimensional diabetes boxes is to encourage people to make their own box modelled on their own particular needs or situation. the sixth chapter discusses diabetes as a cascade of complexity. it is presented as a gateway event for anyone developing the disease since it combines new regularities (monitoring diet, exercise, blood glucose levels, etc.) with the new, unpredictable events (integrating one’s lifestyle with new regularities, personal reactions, patient-career relationships, family responses, etc.). once someone passes through the gateway, they can not go back. the main point of this chapter is that helping patients to make most of their walk is the truly caring approach expected from health professionals and others. in chapter 7, there is an emphasis on the management of diabetes through complementary therapies. it covers lifestyle therapies such as medications and relaxations; eastern therapies such as chinese medicine and acupuncture; natural therapies such as herbalism and homeopathy; manipulative therapies such chiropratic and osteopathy; mind therapies such as hypnotherapy and spiritual healing, and the arts such as dance, music, and art. combining modern and complementary medicine provides the best of both approaches and would seem to be common sense. however, the scientific barrier that lies between them is both a lack of research to prove the effectiveness of complementary therapies and the difficulty of applying the methods of conventional medical research to such treatments. notwithstanding, relaxation therapy is presented as a widely used and scientifically proven diabetic therapy. the final chapter of this book summarises for the reader the effectiveness of the complexity approach for dealing with diabetes: the recognition of the importance of the interwoven physical and mental aspects of diabetes. it argues that if one is going to support people with diabetes effectively the health system must pay more attention to and spend more money on mental health aspects. similarly, complementary therapies that have been shown to have an impact on mental health must be researched to support their common use in medical practice. the complexity approach, which was outlined in this book, is a radical new approach to understanding and managing diabetes that embraces its challenges and uncertainties using the latest advances in complexity theory. from this perspective, the diabetes rollercoaster is a normal curve and is a mirror of life itself. learning this tool may alter the approach to diabetes. this book is a good and interesting read for anybody dealing with diabetes, including health professionals, careers, families and patients themselves. ali al mamari department of medicine, sultan qaboos university hospital, sultan qaboos university, muscat, sultanate of oman email: amamari@squ.edu.om synchronous bilateral endometrioid ovarian cancer and uterine adenocarcenoma in a young woman 51 t he pr esence of simulta neous c a rcinom as involving both the ovary and uterine corpus is relatively uncommon, and only 0.7–10% of patients with epithelial ovarian or uterine cancers have been found to have simultaneous tumours in large series.1 however, these synchronous tumours represent a diagnostic and therapeutic challenge, particularly if they have a similar histology. here we present the case of a 34-year-old woman with endometrioid cancers of both ovaries and adenocarcinoma of the uterus. c a s e r e p o r t the patient was referred to our hospital because of metrorrhagia and lower abdominal pain of six months duration. she had started to menstruate at the age of 14 and her periods were irregular, occurring every 2–3 months, but with no associated abdominal pain. five years earlier she had a spontaneous abortion during the12th week of gestation and evacuation had been done. six months earlier, she had begun to experience excessive vaginal bleeding with severe abdominal pain. findings of clinical examination were normal apart from mobile uterus just above the symphysis pubis. the vaginal examination revealed an ir regularly enlarged uterus of 10 weeks gestation size, with mobile fornices. ultrasound scan of abdomen revealed a bulky, multifi broid uterus, with bilateral ovarian masses. her laboratory investigations were all within the normal squ journal for scientific research: medical sciences 2001, 1, 51–53 ©2001 sultan qaboos university synchronous bilateral endometrioid ovarian cancer and uterine adeno carcinoma in a young woman *mansour al-moundhri1, mariam mathew2, andrzej krolikowski2 abstract. synchronous carcinomas involving both the ovary and uterine corpus are relatively uncommon. these tumours represent a diagnostic and therapeutic challenge, particularly if they have similar histology. here we present the case of a 34-year-old woman with bilateral endometrioid cancers of both ovaries and adenocarcinoma of the uterus. 1departments of medicine and 2obstetrics and gynae cology, sultan qaboos university hospital, p.o. box: 38, al-khod 123, muscat, sultanate of oman *to whom correspondence should be addressed figure 1. the ruptured right ovarian tumour and the enlarged uterus a l m o u n d h r i e t a l52 limits apart from high levels of cancer cell surface antigen 125 (ca125 ) of 322 i u /l. an explorative laparotomy showed a large, ruptured right ovarian tumour measuring 12 × 10 × 8 cm, a smaller but similar left ovarian tumour measuring 7 × 6 × 5 cm and a bulky uterus [figure1]. there was a single deposit on the anterior wall of the uterus and multiple deposits on the omentum. the largest of these deposits was <2 cm in diameter. however, the bowels, paracolic gutter, liver, and diaphragm were clear. frozen sections of both the ovaries revealed endometrioid carcinomas. therefore, total abdo minal hysterectomy, bilateral salpingo-oophorectomy, appendectomy and total omentectomy were performed. histopathological examination showed well-differentiated bilateral endometrioid ovarian carcinomas with focal squamoid differentiation in the right ovarian tumour [figures 2 and 3] and moderately differentiated adenocarcinoma of uterus infi ltrating up to two-thirds of the depth of uterine wall [figure 4]. there were multiple neoplastic omental lesions. fallopian tubes and appendix were normal. the clinical and histological picture was suggestive of at least two synchronous primaries: (1) fédération internationale de gynécologie et d’obstétrique (figo ) stage iiib ovarian cancer with bilateral, large, diffuse, well differentiated endometrioid ovarian cancers with focal squamoid differentiation in right ovary; (2) figo stage ic uterine adenocarcinoma extending up to two-thirds of myometrium, with no associated endometrial hyperplasia. the patient made an uncomplicated recovery following her surgery. six weeks after surgery, her ca125 level decreased to 40 i u /l. she received six cycles of carboplatinum and paclitaxel chemotherapy, which resulted in further decline in her ca125 levels [figure 5]. subsequently she received 5000 cgy whole pelvis external radiotherapy, in 25 fractions through 15mv photons over fi ve weeks, followed by whole vaginal intracavitary radio therapy. ten months after the diagnosis, she remains in clinical remission with ca125 of 1.7 i u /l. figure 2. photomicrograph of endometrioid carcinoma of the right ovary with squamoid differentiation figure 3. photomicrograph of endometrioid carcinoma of left ovary figure 4. photomicrogaph of moderately differentiated adenocarcinoma of uterus s y n c h r o n o u s o va r i a n a n d u t e r i n e c a n c e r s 53 d i s c u s s i o n the si multaneous presence of carcinoma in the endometrium and in the ovary may indicate either metastatic disease or independently developing neoplasms. the classifi cation of these lesions either as two separate primary tumours, or as a single primary tumour with a metastasis has implications for patient prognosis and recommendations for therapy. several large retrospective studies of ovarian endometrioid cancers have demonstrated that the presence of co-existing endometrial adenocarcinoma was not detrimental to the prognosis of patients: in fact it has been suggested that they may indicate better prognosis.2,3,4 although several morphological criteria have been proposed as guidelines for classifi cation of these lesions, certain cases remain diffi cult to classify. eifel et al suggested that if both the tumours were of endometrioid type, the neoplasms represented two separate primaries, and the patient had good prognosis. in contrast, histology of papillary, clear-cell or mucinous type suggested two separate primaries of different morphology, with poorer prognosis. ulbright showed that concomitant endometrioid carcinoma of the ovary and adenocarcinoma of the endometrium, if moderately or well differentiated, was possibly independent in origin, whereas the poorly differentiated ones were possibly metastatic.6 more recently it was suggested that molecular analysis might be useful in determining the relationship of synchronous uterine and ovarian endometrioid neoplasms. emmert-buck et al reported loss of heterozygosity in chromosomes 17q21.3-22 or 11q13 in 10 out of 13 patients who presented with endometrioid tumours in both uterus and ovary. however, eight cases had selective local osteolytic hypercalcemia (loh ) for one tumour site only, suggesting two separate primary tumours.7 similarly, lin et al reported high incidence mutations of the human putative protein tyrosine phosphatase (pten / m m ac1) gene at chromosome in synchronous endometrial and ovarian carcinomas.8 the mainstay of the treatment is aggressive surgical cytoreduction with total abdominal hysterectomy, bilateral salpingo-oophorectomy, appendectomy and total omentectomy, followed by adjuvant treatment. as with other types of ovarian tumours, the treatment with platinum based chemotherapy has been shown to improve survival in simultaneous tumours. on the other hand, the admini stration of adjuvant radiotherapy to isolated figo stage ic uterine adenocarcinoma has been shown to improve outcome. however, it is not clear from the literature whether administration of radiotherapy infl uences prognosis where concomitant lesions exist c o n c l u s i o n this case illustrates the issues raised by presentation of concomitant ovarian and uterine endometrioid cancers and the fact that it may affect relatively younger women, often requiring extensive surgery and adjuvant chemotherapy. r e f e r e n c e s 1. zaino rj, ungar er, whitney c. synchronous carcinomas of the uterine corpus and ovary. gynecol oncol 1984, 19, 329–35. 2. tidy j, mason wp. endometrioid carcinoma of ovary: a retrospective study. br j obstet gynaecol 1988, 95, 1165–9. 3. czernobilsky b, silverman bb, mikuta jj. endometrioid carcinoma of the ovary. a clinicopathologic study of 75 cases. cancer 1970, 26, 1141–52. 4. pearl ml, johnson cm, frank ts, roberts ja. synchronous dual primary ovarian and endometrial carcinomas. int j gynaecol obstet 1993, 43, 305–12. 5. eifel p, hendrickson m, ross j, ballon s, martinez a, kempson r. simultaneous presentation of carcinoma involving the ovary and the uterine corpus. cancer 1982, 50, 163–70. 6. ulbright tm, roth lm. metastatic and independent cancers of the endometrium and ovary: a clinicopathologic study of 34 cases. hum pathol 1985, 16, 28–34. 7. emmert-buck mr, chuaqui r, zhuang z, nogales f, liotta la, merino mj. molecular analysis of synchronous uterine and ovarian endometrioid tumors. int j gynecol pathol 1997, 16, 143–8. 8. lin wm, forgacs e, warshal dp, martin js, ashfaq r et al. loss of heterozygosity and mutational analysis of the pten/mmac1 gene in synchronous endometrial and ovarian carcinomas. clin cancer res 1998, 4, 2577–83. 0 1 0 2 0 3 0 0 1 0 2 0 3 0 4 0 5 0 ca 1 25 u /m l t i m e ( w e e k s ) figure 5. decline in ca125 with chemotherapy 1department of medicine, school of medicine & medical sciences, holy spirit university of kaslik, jounieh, lebanon; 2inspect-lb: national institute of public health, clinical epidemiology and toxicology, beirut, lebanon; 3department of neurology, notre-dame des secours university hospital, byblos, lebanon; 4 these authors contributed equally to this work *corresponding author’s e-mail: souheilhallit@hotmail.com abstract: objectives: this study aimed to determine the incidence and post-discharge resolution of new-onset insomnia in hospitalised patients with no previous history of insomnia, as well as to define major correlates of in-hospital insomnia. methods: this prospective observational study was conducted between november 2019 and january 2020 at a tertiary care centre in lebanon. all hospitalised patients >18 years of age with no history of insomnia were screened for new-onset insomnia using the insomnia severity index (isi) scale. subsequently, patients were re-assessed two weeks after discharge to determine insomnia resolution. results: a total of 75 patients were included in the study. of these, nine (12%) had no insomnia, 34 (45.3%) had subthreshold insomnia, 22 (29.3%) had moderate insomnia and 10 (13.3%) had severe insomnia. the mean isi score was 14.95 ± 6.05, with 88% of patients having isi scores of >7 (95% confidence interval: 0.822–0.965). the frequency of new-onset insomnia was significantly higher among patients who shared a room compared to those in single-bed rooms (95.7% versus 75%; p = 0.011). other factors were not found to be associated with new-onset insomnia, including the administration of medications known to cause insomnia, in-hospital sedative use, overnight oxygen, cardiac monitoring and self-reported nocturnal toilet use. overall, insomnia resolution occurred in 78.7% of patients two weeks after discharge. conclusion: there was a high incidence of acute new-onset insomnia among hospitalised patients at a tertiary centre in lebanon. additional research is recommended to further examine inhospital sleep disturbance factors and to seek convenient solutions to limit insomnia. keywords: sleep wake disorders; insomnia; hospitalization; incidence; risk factors; lebanon. incidence of and factors associated with new-onset insomnia among lebanese hospitalised patients a single-centre study nour sakr,1 *souheil hallit,1,2,4 hanna mattar1,3,4 clinical & basic research sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e210–220, epub. 21 jun 21 submitted 13 apr 20 revision req. 9 jun 20; revision recd. 19 jul 20 accepted 18 aug 20 https://doi.org/10.18295/squmj.2021.21.02.009 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge this study provides important information regarding the incidence of new-onset insomnia among hospitalised patients, as well as associated factors and resolution rates. to the best of the authors’ knowledge, only one previous study on this topic has been reported in the literature. in particular, sharing a room was an extrinsic factor found to be associated with the development of new-onset insomnia among hospitalised patients. although the rate of in-hospital new-onset insomnia was high, the majority of cases resolved within two weeks of discharge, thus confirming that the onset of the insomnia was related to the hospitalisation. application to patient care the findings of this study underline the importance of making environmental improvements to hospitals in order to enhance sleep quality among inpatients, for instance by separating patients into single-bed rooms. this would lead to fewer sleep disturbances during hospital stays, thereby potentially resulting in better outcomes in terms of patient satisfaction and wellbeing. the supr achiasmatic hypothal amic nucleus of the brain is responsible for regulating circadian rhythm by synchronising the body’s internal clock to the light-dark cycle, thus helping to determine sleep-wake patterns.1 however, environmental factors such as changes in season, temperature and feeding schedules, as well as deregulations to this biological clock, can disrupt sleep physiology by altering several circadian clock genes present in the suprachiasmatic nucleus, potentially resulting in sleep disorders.1 insomnia is the most common of all sleep disorders and represents a significant public and mental health concern.2,3 however, defining and evaluating the prevalence of this disorder is challenging due to its heterogeneity in terms of duration, type and aetiology.3 as a result, the estimated prevalence of insomnia in the general population varies widely from 10–40%.4,5 according to the diagnostic and statistical manual of mental disorders, insomnia is defined as “dissatisfaction with sleep quantity or quality, with one or more of the following symptoms: difficulty in initiating sleep, maintaining sleep, and earlymorning awakening with inability to return to sleep”.6,7 https://creativecommons.org/licenses/by-nd/4.0/ nour sakr, souheil hallit and hanna mattar clinical and basic research | e211 moreover, it may cause significant impairment in daytime functioning, as indicated by: “fatigue or low energy, daytime sleepiness, cognitive impairment, mood disturbance, behavioral difficulties, impaired occupational or social function, and negative effect on caregiver or family functioning”.6,7 insomnia is also categorised based on duration into acute/shortterm, intermittent or chronic types. chronic insomnia occurs at least three nights per week for at least three months, despite adequate opportunity for sleep.8,9 various risk factors for insomnia have been identified including gender, age, depression, regular use of sedative-hypnotic drugs, the onset of menses, previous insomnia complaints, snoring, low levels of physical activity, comorbidities and nocturnal micturition.4,9–13 hospitalisation can often result in a period of acute sleep deprivation.10 multiple factors have been found to interfere with inpatient sleep including patient-related factors such as pre-existing anxiety, schizophrenia and depression, illness-related factors such as pain, hyperarousal, whole-body metabolic rate and circadian deregulation and environmental factors such as noise and lighting.1,4,7–9,14–17 several studies have confirmed that hospitalisation can have a major impact on sleep quality and quantity. for example, talih et al. found that 67.4% of hospitalised psychiatric patients had insomnia.9 other studies conducted in hospital settings have reported rates of insomnia ranging from 50–73%, with sleep complaints persisting for several months to 11 years post-discharge.11,18 however, to the best of the authors’ knowledge, only one previous study has sought to assess the incidence of new-onset insomnia in patients admitted to general medical wards without a prior history of insomnia.8 as such, the current study aimed to determine the incidence of new-onset insomnia among hospitalised patients at a tertiary care centre in lebanon with no history of insomnia, define the major correlates of in-hospital insomnia and report the rate of insomnia resolution after discharge. methods this prospective observational study was conducted from november 2019 to january 2020 at the notre dame des secours university hospital (chu-nds) in byblos, lebanon. all arabic-speaking patients aged >18 years old admitted to various medical and surgical wards at chu-nds during this period were included in the study. only patients staying in the hospital for a minimum of two days were included in the study to ensure at least one night of in-hospital sleep. patients with cognitive impairment, delirium, major hearing loss and infectious diseases were excluded, as were those who were immune-compromised, intubated or who used sleep-aid medications or sedatives. an arabic-language questionnaire was used to collect data from potential participants. the first section incorporated an arabic version of the 7-item insomnia severity index (isi) scale to assess the severity of sleep-onset, sleep-maintenance and earlyawakening insomnias as well as satisfaction with current sleep patterns, interference with daytime functioning, noticeability of impairment to others and level of distress caused by the sleep problem.19,20 the isi scale has been previously validated in lebanon and measures insomnia severity on a 5-point likert scale ranging from 0 (not at all severe) to 4 (very severe).19,20 total scores range from 0–28, with scores of 0–7, 8–14, 15–21 and 22–28 deemed indicative of no clinically significant insomnia, subthreshold insomnia, moderate insomnia and severe insomnia, respectively.19 the internal consistency of this section was acceptable (cronbach’s alpha: 0.88). subsequently, at follow-up, patients with new-onset insomnia were contacted by telephone two weeks after discharge, with isi scores of <7 deemed indicative of insomnia resolution. the second section of the questionnaire comprised an arabic version of the validated 19-item pittsburgh sleep quality index (psqi) scale.21,22 items in this scale are combined to form seven component subscales assessing subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications and daytime dysfunction.21 each subscale is scored from 0 to 3, with total scores ranging from 0–21. higher scores are indicative of poorer sleep quality, with a cut-off value of ≥5 distinguishing poor sleepers.21 this was used to exclude patients with a positive history of insomnia prior to admission. arabic versions of both the isi and psqi scales were used for the purposes of the current study, since arabic is the native language in lebanon. these translated versions have been validated in previous studies.22,23 finally, the third part of the questionnaire collected information regarding selected variables in order to compare associations with the distribution of insomnia. this information included the participants’ gender, age, basic sociodemographic characteristics, education level, assigned ward, drugs taken during admission, use of overnight oxygen, cardiac monitoring, type of hospital room (i.e. single-bed or shared), hospitalisation date and overall hospital stay duration. factors deemed to affect sleep included interruptions by nurses to draw blood or check vital signs, noise incidence of and factors associated with new-onset insomnia among lebanese hospitalised patients a single-centre study e212 | squ medical journal, may 2021, volume 21, issue 2 and lighting, lack of familiarity with the hospital environment, pain and other disease symptoms and anxiety and stress. data were retrieved from the patients’ medical records to determine eligibility for participation in the study. in order to provide adequate power for bivariate and multivariate analyses, the necessary sample size was calculated to be 72 using epi info™ software tools (centers for disease control and prevention, atlanta, georgia, usa), based on a total number of hospital beds of 90, a frequency of insomnia incidence of 36% and at a 95% confidence interval.8 initially, a total of 223 medical records were reviewed, after which 89 patients were excluded due to not meeting the inclusion criteria. the remaining 134 patients completed the questionnaire during 10-minute bedside face-to-face interviews with a single researcher in order to decrease interrater variability and prevent any confusion, omission or misunderstanding regarding the questions. thereafter, 59 patients with psqi scores of ≥5 were excluded due to a past history of insomnia in the month prior to their hospitalisation.21 as such, 75 patients with psqi scores of <5 were included in the final analysis [figure 1]. no significant differences were observed between eligible patients with and without a prior history of insomnia, except for body mass index (bmi) [table 1]. data were analysed using the statistical package for the social sciences (spss), version 25.0 (ibm corp., armonk, new york, usa). since the sample was not normally distributed, non-parametric tests were used. mcnemar’s test was used to compare categorical variables, while a mann-whitney u test was used to compare two means. a wilcoxon signedrank test was used to compare mean isi scores during hospitalisation and post-discharge. multinomial logistic regression analysis was conducted, using categories of insomnia as the dependent variable with the absence of insomnia as the reference category. subsequently, all significant variables were included in the bivariate analysis as independent variables. a repeated-measures analysis of variance (anova) was conducted to determine factors influencing the resolution of insomnia after discharge, after adjusting for sociodemographic variables. a p value of <0.050 was considered statistically significant. ethical approval for this study was obtained from the institutional ethics committee of chu-nds. written informed consent was obtained from each patient prior to participation in the study. results of the 75 patients included in the final analysis, nine (12%) had no insomnia, 34 (45.3%) had subthreshold insomnia, 22 (29.3%) had moderate insomnia and 10 (13.3%) had severe insomnia. the mean isi score was 14.95 ± 6.05. in total, 66 patients had isi scores of >7 (95% confidence interval [ci]: 0.822–0.965), resulting in an overall rate of new-onset insomnia of 88%. figure 1: diagram showing the inclusion of patients in the current study. *assessed using an arabic version of the 19-item pittsburgh sleep quality index scale.22,23 scores of ≥5 were considered indicative of a past history of insomnia.22 †assessed using an arabic version of the 7-item insomnia severity index.19,20 scores of >7 were considered indicative of new-onset insomnia.19 nour sakr, souheil hallit and hanna mattar clinical and basic research | e213 table 1: differences between hospitalised patients with and without a prior history of insomnia at a tertiary care centre in lebanon (n = 134) variable hospitalised patients, n (%) p value without a prior history of insomnia (n = 75) with a prior history of insomnia* (n = 59) mean age in years ± sd 52.37 ± 18.41 55.12 ± 16.27 0.554 mean bmi in kg/m2 ± sd 28.15 ± 4.92 25.85 ± 4.28 0.006† mean hospital stay ± sd assumed hospital stay in days 6.16 ± 3.51 6.68 ± 4.53 0.893 actual hospital stay in days 4.07 ± 2.99 4.49 ± 3.46 0.674 gender 0.775 male 35 (54.7) 29 (45.3) female 40 (57.1) 30 (42.9) type of insurance 0.340 no coverage 4 (80) 1 (20) coop 3 (33.3) 6 (66.7) army 14 (56) 11 (44) moph 5 (50) 5 (50) nssf 23 (50) 23 (50) private 26 (66.7) 13 (33.3) monthly salary in usd 0.289 none 29 (58) 21 (42) <1,000 22 (66.7) 11 (33.3) 1,000–2,000 22 (45.8) 26 (54.2) >2,000 2 (66.7) 1 (33.3) education level 0.447 illiterate/ primary school 5 (38.5) 8 (61.5) elementary 7 (46.7) 8 (53.3) secondary 19 (59.4) 13 (40.6) university 44 (59.5) 30 (40.5) hospital ward 0.276 surgery 11 (45.8) 13 (54.2) cardiology 7 (38.9) 11 (61.1) internal medicine 20 (57.1) 15 (42.9) first-class 17 (77.3) 5 (22.7) icu 2 (50) 2 (50) gynaecology/ obstetrics 15 (60) 10 (40) haematology/ oncology 3 (50) 3 (50) type of hospital room 0.056 single-bed 28 (68.3) 13 (31.7) shared 47 (50.5) 46 (49.5) sd = standard deviation; bmi = body mass index; coop = cooperative insurance; moph = ministry of public health; nssf = national social security fund; usd = united states dollars; icu = intensive care unit. *assessed using an arabic version of the 19-item pittsburgh sleep quality index scale.22,23 scores of ≥5 were considered indicative of a past history of insomnia.22 †statistically significant at p <0.050. table 2: bivariate analysis of factors associated with new onset insomnia among hospitalised patients without a prior history of insomnia at a tertiary care centre in lebanon (n = 75) variable hospitalised patients, n (%) p value without new-onset insomnia (n = 9) with new-onset insomnia* (n = 66) mean age in years ± sd 51.00 ± 17.03 52.56 ± 18.70 0.769 mean bmi in kg/m2 ± sd 27.45 ± 5.45 28.25 ± 4.88 0.068 mean hospital stay ± sd assumed hospital stay in days 6.00 ± 7.26 5.94 ± 2.91 0.234 actual hospital stay in days 4.44 ± 5.57 3.99 ± 2.50 0.514 mean number of awakenings per night ± sd 0.78 ± 1.09 3.85 ± 2.80 <0.001† gender >0.999 male 3 (10.7) 25 (89.3) female 6 (12.8) 41 (87.2) insurance 0.407 no 1 (25) 3 (75) yes 8 (11.3) 63 (88.7) monthly salary in usd 0.423 none 5 (20.8) 19 (79.2) <1,000 1 (4.5) 21 (95.5) 1,000–2,000 3 (11.5) 23 (88.5) >2,000 0 (0) 3 (100) sd = standard deviation; bmi = body mass index; usd = united states dollars; icu = intensive care unit. *assessed using an arabic version of the 7-item insomnia severity index.19,20 scores of >7 were considered indicative of new-onset insomnia.19 †statistically significant at p <0.050. incidence of and factors associated with new-onset insomnia among lebanese hospitalised patients a single-centre study e214 | squ medical journal, may 2021, volume 21, issue 2 table 3: bivariate analysis of factors perceived to influence new-onset insomnia among hospitalised patients without a prior history of insomnia at a tertiary care centre in lebanon (n = 75) perceived impact hospitalised patients, n (%) p value without new-onset insomnia (n = 9) with new-onset insomnia* (n = 66) environmental changes 0.060 none/little 8 (21.1) 30 (78.9) mild/ moderate 1 (4.8) 20 (95.2) severe/very severe 0 (0) 16 (100) nurse-related factors 0.104 none/little 7 (17.9) 32 (82.1) mild/ moderate 2 (13.3) 13 (86.7) severe/very severe 0 (0) 21 (100) disease and pain 0.119 none/little 7 (18.4) 31 (81.6) mild/ moderate 2 (11.1) 16 (88.9) severe/very severe 0 (0) 19 (100) respiratory symptoms 0.683 none/little 9 (14.1) 55 (85.9) mild/ moderate 0 (0) 2 (100) severe/very severe 0 (0) 9 (100) noise and light disturbances 0.636 none/little 8 (15.4) 44 (84.6) mild/ moderate 0 (0) 9 (100) severe/very severe 1 (7.1) 13 (92.9) stress and anxiety 0.231 none/little 7 (14.9) 40 (85.1) mild/ moderate 2 (16.7) 10 (83.3) severe/very severe 0 (0) 16 (100) sharing a room 0.272 none/little 9 (16.1) 47 (83.9) mild/ moderate 0 (0) 10 (100) severe/very severe 0 (0) 9 (100) *assessed using an arabic version of the 7-item insomnia severity index.19,20 scores of >7 were considered indicative of new-onset insomnia.19 table 2 (cont’d): bivariate analysis of factors associated with new-onset insomnia among hospitalised patients without a prior history of insomnia at a tertiary care centre in lebanon (n = 75) variable hospitalised patients, n (%) p value without new-onset insomnia (n = 9) with new-onset insomnia* (n = 66) education level 0.259 illiterate/ primary 2 (40) 3 (60) elementary 0 (0) 7 (100) secondary 2 (10.5) 17 (89.5) university 5 (11.4) 39 (88.6) hospital ward 0.167 surgery 0 (0) 12 (100) cardiology 3 (33.3) 6 (66.7) internal medicine 2 (13.3) 13 (86.7) first-class 3 (25) 9 (75) icu 0 (0) 2 (100) gynaecology/ obstetrics 1 (5.3) 18 (94.7) haematology/ oncology 0 (0) 6 (100) type of hospital room 0.011† single-bed 7 (25.0) 21 (75.0) shared 2 (4.3) 45 (95.7) self-reported nocturnal toilet use 0.407 no 8 (11.3) 63 (88.7) yes 1 (25) 3 (75) night oxygen use >0.999 no 8 (12.1) 58 (87.9) yes 1 (11.1) 8 (88.9) cardiac monitoring >0.999 no 9 (12.3) 64 (87.7) yes 0 (0) 2 (100) in-hospital sedative use >0.999 no 9 (12.7) 62 (87.3) yes 0 (0) 4 (100) sd = standard deviation; bmi = body mass index; usd = united states dollars; icu = intensive care unit. *assessed using an arabic version of the 7-item insomnia severity index.19,20 scores of >7 were considered indicative of new-onset insomnia.19 †statistically significant at p <0.050. nour sakr, souheil hallit and hanna mattar clinical and basic research | e215 among patients in this category, the average score for each component in the isi scale was as follows: 2.76 for difficulty falling asleep, 3.13 for maintaining asleep, 2.69 for waking up too early, 2.55 for sleep satisfaction, 1.68 for noticeability of impairment to others, 1.44 for being worried about insomnia and 1.88 for interference with daytime functioning. the bivariate analysis showed that a significantly higher percentage of patients in shared rooms devel oped new-onset insomnia compared to those admitted to single-bed rooms (95.7% versus 75%; p = 0.011). in addition, patients with new-onset insomnia had a higher mean number of awakenings during the night compared to those who did not (3.85 ± 2.80 versus 0.78 ± 1.09 awakenings; p <0.001). however, no significant differences were noted with regards to any of the other variables assessed [tables 2 and 3], including the administration of medications known to cause insomnia [table 4]. patients with subthreshold insomnia were signif icantly older (mean age: 57.85 ± 18.75 years; p = 0.041) and had longer hospital stays (mean stay duration: 4.41 ± 2.74 days; p = 0.050) compared to those with other categories of insomnia. in addition, a significantly higher percentage of individuals in this category had insurance (47.9% versus 11.3–29.6%; p = 0.039). moreover, patients with subthreshold insomnia more frequently perceived environmental changes (52.4% versus 4.8–28.6%; p = 0.045), nurse-related factors (46.7% versus 0–40%; p = 0.003) and stress and anxiety table 4: bivariate analysis of medications associated with new-onset insomnia among hospitalised patients without a prior history of insomnia at a tertiary care centre in lebanon (n = 75) medication taken hospitalised patients, n (%) p value without newonset insomnia (n = 9) with new-onset insomnia* (n = 66) corticosteroids 1 no 8 (12.9) 54 (87.1) yes 1 (7.7) 12 (92.3) levothyroxine 1 no 9 (12.5) 63 (87.5) yes 0 (0) 3 (100.0) proton pump inhibitors 0.720 no 5 (10.6) 42 (89.4) yes 4 (14.3) 24 (85.7) anti-viral medications 1 no 9 (12.9) 61 (87.1) yes 0 (0) 5 (100.0) carbapenems 0.549 no 8 (11.6) 61 (88.4) yes 1 (16.7) 5 (83.3) cephalosporins 0.674 no 8 (13.8) 50 (86.2) yes 1 (5.9) 16 (94.1) paracetamol 1 no 8 (13.1) 53 (86.9) yes 1 (7.1) 13 (92.9) non-steroidal anti-inflammatory drugs 0.588 no 9 (13.6) 57 (86.4) yes 0 (0) 9 (100.0) betablockers 0.344 no 7 (10.8) 58 (89.2) yes 2 (20.0) 8 (80.0) diuretics 0.294 no 7 (10.6) 59 (89.4) yes 2 (22.2) 7 (77.8) pregabalin 1 no 9 (12.7) 62 (87.3) yes 0 (0) 4 (100.0) anti-spasmodic drugs 1 no 9 (12.5) 63 (87.5) yes 0 (0) 3 (100.0) statins 1 no 9 (12.5) 63 (87.5) yes 0 (0) 3 (100.0) anti-emetic drugs 1 no 9 (12.7) 62 (87.3) yes 0 (0) 4 (100.0) quinolones 0.227 no 8 (11.0) 65 (89.0) yes 1 (50.0) 1 (50.0) bronchodilators 1 no 9 (12.9) 61 (87.1) yes 0 (0) 5 (100.0) allopurinol 1 no 9 (12.3) 64 (87.7) yes 0 (0) 2 (100.0) *assessed using an arabic version of the 7-item insomnia severity index.19,20 scores of >7 were considered indicative of new-onset insomnia.19 incidence of and factors associated with new-onset insomnia among lebanese hospitalised patients a single-centre study e216 | squ medical journal, may 2021, volume 21, issue 2 (50% versus 16.7%; p = 0.003) to have only a mild/ moderate effect on their insomnia, whereas patients with moderate insomnia more frequently perceived noise and light disturbances to have a mild/moderate effect (66.7% versus 0–33.3%; p = 0.001). finally, patients with severe insomnia more frequently awoke during the night (mean number of awakenings: 5.30 ± 2.06; p <0.001) [tables 5 and 6]. of the 66 patients diagnosed with new-onset inhospital insomnia, follow-up isi scores two weeks after discharge indicated insomnia resolution in 52 (78.7%). there was a significant decrease in mean isi scores post-discharge (2.08 versus 14.95 ± 6.05; t = 15.57; degrees of freedom = 48; p <0.001). according to the repeated-measures anova, no factors were associated with the decrease in mean isi score. a multinomial logistic regression analysis indicated that number of awakenings per night was significantly associated with the likelihood of subthreshold insomnia (adjusted odds ratio [aor] = 2.30, 95% ci: 1.35–3.93; p = 0.002), moderate insomnia (aor = 2.76, 95% ci: 1.60–4.75; p <0.001) and severe insomnia (aor = 2.90, 95% ci: 1.67–5.03; p <0.001). no other variables entered into the model were significant including age, bmi, assumed duration of hospital stay and the perceived impact of environmental changes, noise and light disturbances, nurse-related factors and stress and anxiety. discussion this prospective observational study aimed to document the incidence, resolution and factors associated with the development of new-onset insomnia in hospitalised patients at a tertiary care centre in lebanon. to the best of the authors’ knowledge, this is only the second study worldwide to assess the development of newonset insomnia among inpatients with no prior history of insomnia.8 overall, the rate of new-onset insomnia in the current study was 88%, with 45.3% of patients having subthreshold insomnia and 42.7% having clinically significant moderate or severe insomnia. however, in a comparable study, ho et al. reported a much lower overall incidence rate of 36%, with 26% of patients having subthreshold insomnia and only 10% suffering from moderate or severe insomnia.8 various factors could be responsible for this difference in findings. for instance, the present study included patients admitted to various medical and surgical wards, including the internal medicine, cardiology, haematology/oncology, first-class and gynaecology/obstetrics wards as well as the intensive care unit (icu). in contrast, ho et al. included only patients admitted to medical wards.8 however, all 12 patients (100%) admitted to the surgical ward in the current study developed new-onset insomnia, representing the highest rate of all wards and hospital areas outside of the icu. it is therefore possible that the inclusion of such patients contributed to an increase in the incidence of new-onset insomnia in the current study in comparison to previous research.8 moreover, it is important to mention that the rate of new-onset insomnia reported by ho et al. is low in comparison to findings from other studies (38–57%).8,10,11,13 finally, the present study utilised a validated translated version of the psqi in order to exclude patients with a prior history of insomnia, in contrast to the previous study which did not make use of a validated index to exclude patients.8,22 lack of use of a psqi cut-off score could have resulted in fewer excluded patients, thus opening the sample selection to bias. sharing a room was found to result in significantly greater odds of developing new-onset insomnia compared to those in single-bed hospital rooms. in comparison, this variable did not appear to be statistically significant in the previous study by ho et al.8 the most probable explanation for this finding is that most patients at chu-nds are usually accompanied by a family member or other caregiver who also occupies the same room, thus making shared rooms even more crowded with an average of four people in a normally dual room. this would likely cause more frequent sleep disturbances to those in shared rooms. similarly, the present study found that patients with new-onset insomnia had a significantly higher mean number of awakenings during the night (0.78 versus 3.85 awakenings; p <0.001), a finding in agreement with previous research (0.9 versus 1.35 awakenings; p = 0.027).8 as would be expected, this factor also significantly influenced insomnia category, with patients with severe insomnia more frequently waking at night (5.30 versus 0.78–4.36 awakenings; p <0.001). no significant differences were noticed between patients with and without new-onset insomnia in terms of sociodemographic parameters such as gender and age. these findings are comparable to those reported by ho et al., apart from a slight difference in mean age in which patients with insomnia appeared to be younger (61 versus 63 years; p = 0.038).8 in contrast, other researchers have shown that older adults suffer from increased sleep disturbances, particularly as they are usually more easily roused by increased noise or light, stimuli which commonly occur in a hospital environment.10 in the current study, other factors—such as the administration of medications known to cause insomnia, sedative use, overnight oxygen use, cardiac monitoring, self-reported nocturnal toilet use and nour sakr, souheil hallit and hanna mattar clinical and basic research | e217 table 5: bivariate analysis of factors associated with insomnia categories among hospitalised patients without a prior history of insomnia at a tertiary care centre in lebanon (n = 75) variable category of insomnia* n (%) p value none (n = 9) subthreshold (n = 34) moderate (n = 22) severe (n = 10) mean age in years ± sd 51.00 ± 17.03 57.85 ± 18.75 43.41 ± 17.80 54.70 ± 13.51 0.041† mean bmi in kg/m2 ± sd 27.45 ± 5.45 27.34 ± 4.48 30.58 ± 4.98 26.21 ± 4.42 0.106 mean hospital stay ± sd assumed hospital stay in days 6.00 ± 7.26 6.47 ± 2.95 5.27 ± 2.51 5.60 ± 3.47 0.093 actual hospital stay in days 4.44 ± 5.57 4.41 ± 2.74 3.13 ± 1.72 4.40 ± 2.80 0.050† mean number of awakenings per night 0.78 ± 1.09 3.09 ± 1.56 4.36 ± 4.05 5.30 ± 2.06 <0.001† gender 0.468 male 3 (10.7) 11 (39.3) 8 (28.6) 6 (21.4) female 6 (12.8) 23 (48.9) 14 (29.8) 4 (8.5) insurance 0.039† no 1 (25) 0 (0) 1 (25) 2 (50) yes 8 (11.3) 34 (47.9) 21 (29.6) 8 (11.3) monthly salary in usd 0.277 none 5 (20.8) 12 (50) 5 (20.8) 2 (8.3) <1,000 1 (4.5) 13 (59.1) 6 (27.3) 2 (9.1) 1,000–2,000 3 (11.5) 9 (34.6) 8 (30.8) 6 (23.1) >2,000 0 (0) 0 (0) 3 (100) 0 (0) education level 0.566 illiterate/primary 2 (40) 2 (40) 1 (20) 0 (0) elementary 0 (0) 4 (57.1) 1 (14.3) 2 (28.6) secondary 2 (10.5) 10 (52.6) 4 (21.1) 3 (15.8) university 5 (11.4) 18 (40.9) 16 (36.4) 5 (11.4) hospital ward 0.419 surgery 0 (0) 4 (33.3) 6 (50) 2 (16.7) cardiology 3 (33.3) 5 (55.6) 1 (11.1) 0 (0) internal medicine 2 (13.3) 6 (40) 4 (26.7) 3 (20) first-class 3 (25) 7 (58.3) 2 (16.7) 0 (0) icu 0 (0) 1 (50) 1 (50) 0 (0) gynaecology/obstetrics 1 (5.3) 9 (47.4) 5 (26.3) 4 (21.1) haematology/oncology 0 (0) 2 (33.3) 3 (50) 1 (16.7) type of hospital room 0.505 single-bed 3 (9.7) 12 (38.7) 10 (32.3) 6 (19.3) shared 6 (13.6) 22 (50.0) 12 (27.3) 4 (9.1) self-reported nocturnal toilet use 0.365 no 8 (11.3) 31 (43.7) 22 (31) 10 (14.1) yes 1 (25) 3 (75) 0 (0) 0 (0) night oxygen use 0.903 no 8 (12.1) 30 (45.5) 20 (30.3) 8 (12.1) yes 1 (11.1) 4 (44.4) 2 (22.2) 2 (22.2) cardiac monitoring 0.528 no 9 (12.3) 33 (45.2) 22 (30.1) 9 (12.3) yes 0 (0) 1 (50) 0 (0) 1 (50) sd = standard deviation; bmi = body mass index; usd = united states dollars; icu = intensive care unit. *assessed using an arabic version of the 7-item insomnia severity index.19,20 scores of 0–7, 8–14, 15–21 and 22–28 were considered indicative of no clin ically significant insomnia, subthreshold insomnia, moderate insomnia and severe insomnia, respectively.19 †statistically significant at p <0.050. incidence of and factors associated with new-onset insomnia among lebanese hospitalised patients a single-centre study e218 | squ medical journal, may 2021, volume 21, issue 2 respiratory symptoms—were not found to interfere significantly with the development of new-onset insomnia. ho et al. reported similar findings.8 in the present study, patients with new-onset insomnia frequently reported the negative impact of various factors on their sleep including environmental changes, nurse-related disturbances (i.e. frequent interruptions to draw blood or check vital signs), disease and pain, noise and brightness, stress and anxiety and sharing a room. nevertheless, the effect of such disturbances were also reported by patients who did not have insomnia; as such, these factors could not be deemed to significantly affect the development of new-onset insomnia. ho et al. similarly found that 36% of hospitalised patients with new-onset insomnia attributed staff disturbances and disease symptoms to be the most common causes of sleep disruption.8 table 6: bivariate analysis of factors perceived to influence insomnia according to insomnia category among hospital ised patients without a prior history of insomnia at a tertiary care centre in lebanon (n = 75) perceived impact category of insomnia,* n (%) p value none (n = 9) subthreshold (n = 34) moderate (n = 22) severe (n = 10) environmental changes 0.045† none/little 8 (21.1) 19 (50) 8 (21.1) 3 (7.9) mild/moderate 1 (4.8) 11 (52.4) 6 (28.6) 3 (14.3) severe/very severe 0 (0) 4 (25) 8 (50) 4 (25) nurse related factors 0.003† none/little 7 (17.9) 21 (53.8) 9 (23.1) 2 (5.1) mild/moderate 2 (13.3) 7 (46.7) 6 (40) 0 (0) severe/very severe 0 (0) 6 (28.6) 7 (33.3) 8 (38.1) disease and pain 0.120 none/little 7 (18.4) 20 (52.6) 8 (21.1) 3 (7.9) mild/moderate 2 (11.1) 8 (44.4) 5 (27.8) 3 (16.7) severe/very severe 0 (0) 6 (31.6) 9 (47.4) 4 (21.1) respiratory symptoms 0.159 none/little 9 (14.1) 31 (48.4) 17 (26.6) 7 (10.9) mild/moderate 0 (0) 0 (0) 2 (100) 0 (0) severe/very severe 0 (0) 3 (33.3) 3 (33.3) 3 (33.3) noise and light disturbances 0.001† none/little 8 (15.4) 30 (57.7) 10 (19.2) 4 (7.7) mild/moderate 0 (0) 0 (0) 6 (66.7) 3 (33.3) severe/very severe 1 (7.1) 4 (28.6) 6 (42.9) 3 (21.4) stress and anxiety 0.003† none/little 7 (14.9) 26 (55.3) 9 (19.1) 5 (10.6) mild/moderate 2 (16.7) 6 (50) 2 (16.7) 2 (16.7) severe/very severe 0 (0) 2 (12.5) 11 (68.8) 3 (18.8) sharing a room 0.161 none/little 9 (16.1) 28 (50) 14 (25) 5 (8.9) mild/moderate 0 (0) 3 (30) 4 (40) 3 (30) severe/very severe 0 (0) 3 (33.3) 4 (44.4) 2 (22.2) *assessed using an arabic version of the 7-item insomnia severity index.19,20 scores of 0–7, 8–14, 15–21 and 22–28 were considered indicative of no clinically significant insomnia, subthreshold insomnia, moderate insomnia and severe insomnia, respectively.19 †statistically significant at p <0.050. nour sakr, souheil hallit and hanna mattar clinical and basic research | e219 the current study found a significant decrease in mean isi score two weeks post-discharge, with the insomnia resolving in 78.7% of patients initially found to have new-onset insomnia. this result is consistent with ho et al.’s study in which 75% of patients not lost to follow-up reported resolution of their insomnia.8 transient insomnia is defined as insomnia that resolves after removal of the stressor or adaptation of the individual to the nuisance.24 such dramatic rates of resolution therefore support the notion that sudden cases of new-onset in-hospital insomnia are closely tied to factors related to the hospital environment. sleep is essential to the process of recovery, with research showing that acute sleep loss in the hospital may be associated with the development of chronic insomnia after discharge, as well as poor longterm health outcomes.10 policymakers and hospital authorities should therefore be vigilant of the need to promote better quality of sleep among inpatients, for instance by optimising hospital rooms and procedures to reduce the frequency and occurrence of sleep disturbances.4 such measures could also potentially improve the recognition and treatment of previously undiagnosed insomnia.10 one study indicated that healthcare providers often neglect the evaluation of sleeping hospitalised patients, resulting in frequent sleep disturbances, with the primary reasons for this lack of efficient sleep care being the absence of standardised assessments, poor communication and inadequate comprehension of the importance of sleep to the recovery process.24 certain limitations were encountered in the present study. the inclusion of patients from a single centre in lebanon could have resulted in selection bias. residual confounding bias is also possible since the study did not take all factors associated with insomnia into consideration. moreover, information bias could have occurred since patients often tend to overor underestimate their symptoms. nevertheless, the study also had several strengths. although the sample size was low, it met the necessary number of patients needed for statistical power. furthermore, an internationally recognised and validated screening tool was used to determine the incidence of insomnia. in addition, this study was the first to exclude patients with a history of insomnia using a validated and translated questionnaire. finally, an analysis of included and excluded patients showed that they did not appear to differ significantly in terms of sociodemographic characteristics, apart from a higher bmi, thus limiting the likelihood of selection bias. conclusion the incidence of new-onset hospital-related insomnia among hospitalised patients at a tertiary centre in lebanon was 88%, with resolution observed two weeks after discharge in 78.7%. the likelihood of new-onset insomnia was significantly greater among patients who shared a room compared to those in single-bed rooms. patients with new-onset insomnia also had a greater number of night awakenings compared to patients without sleep disturbances, with the number of night awakenings linked to insomnia severity. further research is recommended to evaluate factors affecting in-hospital sleep disturbances and to develop appropriate solutions to limit insomnia in this population. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. zaki nf, yousif m, bahammam as, spence dw, bharti vk, subramanian p, et al. chronotherapeutics: recognizing the importance of timing factors in the treatment of disease and sleep disorders. clin neuropharmacol 2019; 42:80–7. https:// doi.org/10.1097/wnf.0000000000000341. 2. lipton j, becker re, kothare sv. insomnia of childhood. curr opin pediatr 2008; 20:641–9. https://doi.org/10.1097/mop.0b 013e32831897cb. 3. lichstein k, taylor d, mccrae c, ruiter me. insomnia: epidemiology and risk factors. in: kryger mh, roth t, dement wc (eds). principles and practice of sleep medicine, 5th ed. philadelphia, pennsylvania: saunders, 2010. pp. 827–37. 4. mai e, buysse dj. insomnia: prevalence, impact, pathogenesis, differential diagnosis, and evaluation. sleep med clin 2008; 3:167–74. https://doi.org/10.1016/j.jsmc.2008.02.001. 5. colten hr, altevogt bm. improving awareness, diagnosis, and treatment of sleep disorders. in: sleep disorders and sleep deprivation: an unmet public health problem. washington d.c., usa: national academies press, 2006. 6. reynolds cf 3rd, redline s. the dsm-v sleep-wake disorders nosology: an update and an invitation to the sleep community. j clin sleep med 2010; 6:9–10. https://doi.org/10.5664/jcsm.27703. 7. reynolds cf 3rd, o’hara r. dsm-5 sleep-wake disorders classification: overview for use in clinical practice. am j psy chiatry 2013; 170:1099–101. https://doi.org/10.1176/appi.ajp.20 13.13010058. 8. ho a, raja b, waldhorn r, baez v, mohammed i. new onset of insomnia in hospitalized patients in general medical wards: incidence, causes, and resolution rate. j community hosp intern med perspect 2017; 7:309–13. https://doi.org/10.1080/ 20009666.2017.1374108. 9. talih f, ajaltouni j, ghandour h, abu-mohammad as, kobeissy f. insomnia in hospitalized psychiatric patients: prevalence and associated factors. neuropsychiatr dis treat 2018; 14:969–75. https://doi.org/10.2147/ndt.s160742. https://doi.org/10.1097/wnf.0000000000000341 https://doi.org/10.1097/wnf.0000000000000341 https://doi.org/10.1097/mop.0b013e32831897cb https://doi.org/10.1097/mop.0b013e32831897cb https://doi.org/10.1016/j.jsmc.2008.02.001 https://doi.org/10.5664/jcsm.27703 v v https://doi.org/10.1080/20009666.2017.1374108 https://doi.org/10.1080/20009666.2017.1374108 https://doi.org/10.2147/ndt.s160742 incidence of and factors associated with new-onset insomnia among lebanese hospitalised patients a single-centre study e220 | squ medical journal, may 2021, volume 21, issue 2 10. stewart nh, arora vm. sleep in hospitalized older adults. sleep med clin 2018; 13:127–35. https://doi.org/10.1016/j. jsmc.2017.09.012. 11. smith mt, klick b, kozachik s, edwards re, holavanahalli r, wiechman s, et al. sleep onset insomnia symptoms during hospitalization for major burn injury predict chronic pain. pain 2008; 138:497–506. https://doi.org/10.1016/j.pain.2008.01.028. 12. knutson kl, van cauter e. associations between sleep loss and increased risk of obesity and diabetes. ann n y acad sci 2008; 1129:287–304. https://doi.org/10.1196/annals.1417.033. 13. gambhir is, chakrabarti ss, sharma ar, saran dp. insomnia in the elderly: a hospital-based study from north india. j clin gerontol geriatr 2014; 5:117–21. https://doi.org/10.1016/j. jcgg.2014.05.005. 14. ellis jg, gehrman p, espie ca, riemann d, perlis ml. acute insomnia: current conceptualizations and future directions. sleep med rev 2012; 16:5–14. https://doi.org/10.1016/j.smrv.20 11.02.002. 15. macfarlane m, rajapakse s, loughran s. what prevents patients sleeping on an acute medical ward? an actigraphy and qualitative sleep study. sleep health 2019; 5:666–9. https://doi. org/10.1016/j.sleh.2019.06.012. 16. axén i. pain-related sleep disturbance: a prospective study with repeated measures. clin j pain 2016; 32:254–9. https:// doi.org/10.1097/ajp.0000000000000249. 17. dijk dj, archer sn. light, sleep, and circadian rhythms: together again. plos biol 2009; 7:e1000145. https://doi. org/10.1371/journal.pbio.1000145. 18. lawrence jw, fauerbach j, eudell e, ware l, munster a. the 1998 clinical research award: sleep disturbance after burn injury a frequent yet understudied complication. j burn care rehabil 1998; 19:480–6. https://doi.org/10.1097/00004630199811000-00005. 19. bastien ch, vallières a, morin cm. validation of the insomnia severity index as an outcome measure for insomnia research. sleep med 2001; 2:297–307. https://doi.org/10.1016/s13899457(00)00065-4. 20. hallit s, haddad c, hallit r, al karaki g, malaeb d, sacre h, et al. validation of selected sleeping disorders related scales in arabic among the lebanese population. sleep biol rhythms 2019; 17:183–9. https://doi.org/10.1007/s41105-018-0196-0. 21. buysse dj, reynolds cf 3rd, monk th, berman sr, kupfer dj. the pittsburgh sleep quality index: a new instrument for psy chiatric practice and research. psychiatry res 1989; 28:193–213. https://doi.org/10.1016/0165-1781(89)90047-4. 22. suleiman kh, yates bc, berger am, pozehl b, meza j. translating the pittsburgh sleep quality index into arabic. west j nurs res 2010; 32:250–68. https://doi.org/10.1177/0193945909348230. 23. suleiman kh, yates bc. translating the insomnia severity index into arabic. j nurs scholarsh 2011; 43:49–53. https://doi. org/10.1111/j.1547-5069.2010.01374.x. 24. chokroverty ms, sahota mp (eds). acute and emergent events in sleep disorders. oxford, uk: oxford university press, 2011. https://doi.org/10.1093/med/9780195377835.001.0001. https://doi.org/10.1016/j.jsmc.2017.09.012 https://doi.org/10.1016/j.jsmc.2017.09.012 https://doi.org/10.1016/j.pain.2008.01.028 https://doi.org/10.1196/annals.1417.033 https://doi.org/10.1016/j.jcgg.2014.05.005 https://doi.org/10.1016/j.jcgg.2014.05.005 https://doi.org/10.1016/j.smrv.2011.02.002 https://doi.org/10.1016/j.smrv.2011.02.002 https://doi.org/10.1016/j.sleh.2019.06.012 https://doi.org/10.1016/j.sleh.2019.06.012 https://doi.org/10.1097/ajp.0000000000000249 https://doi.org/10.1097/ajp.0000000000000249 https://doi.org/10.1371/journal.pbio.1000145 https://doi.org/10.1371/journal.pbio.1000145 https://doi.org/10.1097/00004630-199811000-00005 https://doi.org/10.1097/00004630-199811000-00005 https://doi.org/10.1016/s1389-9457%2800%2900065-4 https://doi.org/10.1016/s1389-9457%2800%2900065-4 https://doi.org/10.1007/s41105-018-0196-0 https://doi.org/10.1016/0165-1781%2889%2990047-4 https://doi.org/10.1177/0193945909348230 https://doi.org/10.1111/j.1547-5069.2010.01374.x https://doi.org/10.1111/j.1547-5069.2010.01374.x https://doi.org/10.1093/med/9780195377835.001.0001 1department of family medicine and public health, college of medicine and health sciences, sultan qaboos university, muscat, oman; 2sultan qaboos comprehensive cancer care & research centre, muscat, oman; 3college of medicine and health sciences, sultan qaboos university, muscat, oman. 4research section, medical simulation and skills development centre, oman medical specialty board, muscat, oman *corresponding author’s e-mail: mhalazri@squ.edu.om the unmet supportive care needs of omani women diagnosed with breast cancer *mohammed al-azri,1 khalid al-bimani,2 al-anoud al-maqbali,3 hala al-riyami,3 al-kuthar al-shabnooti,3 sathiya m. panchatcharam,4 sanjay jaju1 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 515–524, epub. 7 nov 22 submitted 8 jun 21 revision req. 5 aug 21; revision recd. 8 aug 21 accepted 24 aug 21 https://doi.org/10.18295/squmj.9.2021.135 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. supportive care refers to a patient-centred approach to care in which necessary services are provided to meet the emotional, social, informational and spiritual needs of patients with serious illnesses.1,2 patient-centred care is recognised as a benchmark of quality in cancer care, with the delivery of supportive care services deemed just as important as that of curative or palliative cancer treatments.3 thus, while cancer treatment is essential to cure the patient and increase their likelihood of survival, supportive care is considered necessary to improve their quality of life. in recent years, there has been a shift in focus from treatment to supportive care to help patients cope with the experience of living with cancer.3,4 the supportive care requirements of cancer patients have been categorised into six domains: health system and information, patient care, treatment, psychosocial, sexual and financial needs.5 a greater understanding of the supportive care needs of cancer patients can help to identify specific challenges and concerns.6 on the other hand, failure to meet these needs can interfere with the patient’s comfort, quality of life, treatment decision-making abilities and adherence to treatment.7 abstract: objectives: this study aimed to assess the unmet supportive care needs of omani women with breast cancer (bc). methods: this cross-sectional study was conducted from november 2020 to february 2021 among 250 adult omani women diagnosed with bc at sultan qaboos university hospital, muscat, oman. an arabic version of the 34-item supportive care needs survey-short form tool was used to determine perceived unmet supportive care needs across five domains. results: a total of 181 women participated in the study (response rate: 72.4%). the domain with the highest mean score per item was health system and information (mean score: 3.33), with the greatest unmet need in this domain being information about what the patient could do to help themselves get well (40.9%). the domain with the second highest mean score per item was patient care and support (mean score: 3.04), with the greatest unmet need being for clinicians to be more sincere with the patient (36.5%). higher total mean scores were reported by women who had visited the hospital four times or more over the two months preceding the study (p = 0.045), those with stage 3 or 4 cancer (p = 0.047) and those who had recently undergone radiotherapy or chemotherapy (p = 0.014). conclusion: most unmet supportive care needs fell under the health system and information domain. healthcare providers in oman should explore patient concerns and provide sufficient information at various stages of the care process to decrease the anxiety associated with living with cancer. keywords: breast neoplasms; needs assessment; palliative supportive care; women; oman. advances in knowledge to the best of the authors’ knowledge, this is the first study to assess the unmet supportive care needs of omani women diagnosed with breast cancer (bc). the most frequently reported unmet supportive care needs were informational in nature, while the greatest unmet psychological need was how to deal with the fear of cancer recurrence. women most frequently reported needing greater sincerity from their clinicians and more help with sleeping issues but were less concerned regarding unmet sexual needs. significantly higher unmet supportive care needs were reported by women who had recently received radiotherapy or chemotherapy. application to patient care the findings of this study indicate an urgent need to improve existing informational support services for omani women with bc and to incorporate psychological support services into routine oncology practice. clinicians should consider improving patient-clinician communication and adopting a patient-centred care approach during consultations to help address the unmet care needs of women with bc in oman. this may help reduce the rate of related psychological comorbidities such as depression, anxiety and stress. https://creativecommons.org/licenses/by-nd/4.0/ the unmet supportive care needs of omani women diagnosed with breast cancer 516 | squ medical journal, november 2022, volume 22, issue 4 a study on chinese patients with breast and colorectal cancer showed that both types of patients most commonly experienced unmet needs in the health system and information domains, with younger patients having more frequent unmet needs in the sexual and health system and information domains.6 on the other hand, a recent study conducted in the united arab emirates (uae) showed that the most prevalent unmet supportive care needs rated at a moderate-to-high level by patients with different cancers were in the psychological domain, while needs in the sexual domain were least frequently reported.8 in oman, breast cancer (bc) is a leading cause of death and disability, accounting for 12.79% of all cancers and 24.50% of all female cancers.9 as a result of increased life expectancy, urbanisation and the adoption of more westernised lifestyles, the incidence of bc in oman has almost doubled over the last two decades.10 moreover, most women with bc in oman are diagnosed at a younger age and at a later stage compared to those in western countries, with an average five-year survival rate of 63%.10,11 previous studies have shown that omani women diagnosed with bc are at risk of adverse physical and psychosocial morbidities.4,12,13 however, no study has yet attempted to assess the unmet supportive care needs of omani women diagnosed with bc. identifying and addressing the unmet supportive care needs of cancer patients is imperative to help improve their quality of life.6 methods this cross-sectional questionnaire study was conducted from november 2020 to february 2021 at the sultan qaboos university hospital (squh), muscat, oman, a referral teaching and training hospital that provides comprehensive oncological treatment to bc patients. adult omani women aged ≥18 years who had been diagnosed with any stage of bc over the past five years at squh were identified from the electronic hospital information system. according to official data from the ministry of health, there were 274 bc cases in oman in 2017.14 thus, assuming a prevalence of 50% of unmet supportive care needs in five domains, with a precision rate of 5% and desired confidence interval of 95%, the necessary sample size for the study was calculated to be 170 participants. however, to compensate for non-respondents, a total of 250 patients were invited to participate in the study via telephone or e-mail according to the contact information available in the system. a previously validated arabic version of the 34-item supportive care needs survey-short form (scns-sf34) was used to collect data regarding the respondents’ unmet supportive care needs.8 the original scns-sf34 is a validated instrument used as part of routine cancer care to measure cancer patients’ perceived unmet supportive care needs across five domains, including psychological (10 items), health system and information (8 items), patient care and support (6 items), physical and daily living (5 items), sexuality (2 items) and other (3 items) needs.15 originally, the data were intended to be collected using a paper-based questionnaire; however, due to the ongoing covid-19 pandemic, research assistants were prohibited from entering squh and having direct contact with patients to minimise the risk of transmission. thus, the arabic version of the scnssf34 tool was modified so that it could be accessed and completed electronically by literate participants. for illiterate participants, the questionnaires were completed by a researcher based on the information collected during telephone interviews. participants were asked to rate their perceived level of need for additional support for each item on a five-point scale. the internal consistency of the original scns-sf34 tool has been found to be high (cronbach’s alpha coefficient range: 0.86–0.96).15 in addition, the tool has been translated into various languages and used in different populations worldwide.5,16,17 nair et al. translated the scns-sf34 into arabic for use in the uae, a neighbouring country to oman.8 in addition, a pilot study was conducted on the first 30 participants to determine the reliability and clarity of the arabic version of the scns-sf34 questionnaire used in the present study. this revealed cronbach’s alpha coefficients of 0.90, 0.92, 0.83, 0.87 and 0.94 for the psychological, health system and information, patient care and support, physical and daily living and sexuality domains of unmet supportive care needs, respectively. collected data were analysed using the statistical package for the social sciences (spss), version 25.0 (ibm corp., armonk, new york, usa). for descriptive purposes, categorical variables were presented as numbers and percentages, while continuous variables were presented as means and standard deviations or standard errors of measurement. frequencies of ratings for individual items were calculated to determine the items most and least commonly reported to have a high level of unmet need in each domain. associations between continuous and categorical variables were compared using an independent t-test or analysis of variance. a p value of <0.05 was considered statistically significant. the study has been approved by the medical research and ethics committee of the college mohammed al-azri, khalid al-bimani, al-anoud al-maqbali, hala al-riyami, al-kuthar al-shabnooti, sathiya m. panchatcharam and sanjay jaju clinical and basic research | 517 of medicine and health sciences, sultan qaboos university (mrec #2189). all study procedures conformed to the tenets of the declaration of helsinki. written informed consent was obtained from all respondents prior to their participation in the study. results of the 250 women with bc invited for the study, a total of 181 agreed to participate (response rate: 72.4%). the mean age was 47.5 ± 10.6 years, with most participants being 41–50 years old (44.4%), married (72.9%) and educated to the university level or higher (40.3%). most women were unemployed (58.0%) and had a monthly household income of ≤500 omani rials (56.4%). over one-third (35.9%) were residents of muscat and a quarter (25.4%) reported a family history of bc. the majority of women (70.2%) had been diagnosed with bc more than two years prior and at an advanced stage (stage 3 or 4; 42.2%). a total of 78 (44.1%) patients had recently undergone chemotherapy or immunotherapy [table 1]. across the five domains of unmet supportive care needs, the domain with the highest mean score per item was health system and information (3.33 ± 0.09), followed by patient care and support (3.04 ± 0.08), physical and daily living (2.90 ± 0.08), psychological (2.77 ± 0.08) and sexuality (2.27 ± 0.10) [table 2]. the mean total score for items in the psychological domain was 27.70 ± 10.33. overall, the item most frequently perceived by respondents as associated with a high level of unmet need in this domain was fears about cancer recurrence (34.3%), followed by fears about cancer spreading (33.7%) and fears about children or people close to the patient (32.6%). the least frequently reported items included fears about the patient’s loss of independence (5.0%), concerns regarding the ability of those close to the patient to cope with their care (11.6%) and thoughts about death (11.6%). the mean total score for items in the physical and daily living domain was 14.51 ± 5.40. items most frequently reported as having a high level of unmet need included not sleeping well (16.0%) and not being able to continue with the activities that the patient had engaged in before being diagnosed with cancer (15.5%). in contrast, fewer participants reported a high level of unmet need for items such as pain (9.9%) and nausea/vomiting (9.9%). the mean total score for items in the health system and information domain was 26.64 ± 9.42. the need to be informed about what the patient could do to help themselves get well was most frequently found to be unmet at a high level (40.9%), followed by the table 1: sociodemographic and clinical characteristics of omani women diagnosed with breast cancer (n = 181) characteristic n (%) age in years* ≤30 10 (5.6) 31–40 30 (16.7) 41–50 80 (44.4) 51–60 41 (22.8) >60 19 (10.6) education level† illiterate (cannot read or write) 28 (15.5) completed primary school (grade 6) 10 (5.5) completed intermediate school (grade 9) 13 (7.2) completed secondary school (grade 12) 57 (31.5) completed university 63 (34.8) completed postgraduate/doctorate 10 (5.5) marital status married 132 (72.9) single 13 (7.2) widowed 12 (6.6) divorced 24 (13.3) place of residence muscat 65 (35.9) south al batinah 16 (8.8) north al batinah 27 (14.9) a’dakhiliyah 38 (21.0) south ash sharqiyah 6 (3.3) north ash sharqiyah 10 (5.5) dhofar 6 (3.3) ad dhahirah 12 (6.6) al buraimi 1 (0.6) employment status unemployed 105 (58.0) employed 41 (22.7) retired 35 (19.3) monthly family income in omr ≤500 102 (56.4) 501–1,000 52 (28.7) 1,001–2,000 26 (14.4) ≥2,001 1 (0.6) omr = omani rials; bc = breast cancer *information from one patient is missing (n = 180). †according to the educ ation system in oman. ‡information from four patients are missing (n = 177). the unmet supportive care needs of omani women diagnosed with breast cancer 518 | squ medical journal, november 2022, volume 22, issue 4 need to be informed about available treatments and their benefits and side effects (39.8%), the need to be given an explanation about any tests conducted on the patient (35.9%), the need for more information about the patient’s diagnosis and prognosis (33.7%) and the need to talk to someone who understood and had experience with the patient’s case (31.5%). the least frequently reported items with high unmet needs in this domain included the need for access to professional counselling (22.7%), the need to be informed about support groups (26.5%) and the need for information about how to manage the patient’s illness and side effects at home. the mean total score for items in the patient care and support domain was 18.23 ± 6.55. the most frequently reported unmet needs rated highly by the participants included the need for clinicians to be more sincere with the patient (36.5%), followed by the need for the hospital to protect the patient’s privacy (32.6%) and the need for clinicians to show sensitivity to the patient’s emotional needs (30.4%). items for which fewer participants reported a high level of unmet needs included more choices regarding which hospital to attend (18.2%) and increased waiting time for a clinic appointment (19.3%). the mean total score for items in the sexuality domain was 4.53 ± 2.67. overall, few respondents reported a high level of unmet needs regarding changes in sexual feelings (9.9%) and sexual relationships (9.9%). other items rated by participants as having a high level of unmet need included the need to receive less commiseration from other people (27.1%), the need for economic help (18.2%) and the need to talk to other people who had experience with cancer (10.5%) [table 3]. significant associations were observed between total mean scores and certain sociodemographic and clinical variables. higher mean scores were reported by women who had visited the hospital four or more times over the two months preceding the study (p = 0.045), those diagnosed with stage 3 or 4 cancer (p = 0.047) and those who had received radiotherapy or chemotherapy over the past two months (p = 0.014) [table 4]. discussion to the best of the authors’ knowledge, this is the first study conducted in oman to evaluate the unmet supportive care needs of omani women diagnosed with bc. in general, supportive care services— table 1 (cont’d.): sociodemographic and clinical character istics of omani women diagnosed with breast cancer n = 181) characteristic n (%) family history of bc no 135 (74.6) yes 46 (25.4) number of hospital visits in the last two months 1 79 (43.6) 2 36 (19.9) 3 21 (11.6) 4 17 (9.4) >4 28 (15.5) time since diagnosis in years ≤2 54 (29.8) >2 127 (70.2) stage of cancer at diagnosis* 1 52 (28.9) 2 52 (28.9) 3 or 4 76 (42.2) treatment received in the last two months‡ chemotherapy 45 (15.4) immunotherapy 33 (18.6) radiotherapy 10 (5.6) surgery 10 (5.6) combined treatment 18 (10.2) hormonal therapy 25 (14.1) other 26 (14.7) none 10 (5.6) omr = omani rials; bc = breast cancer *information from one patient is missing (n = 180). †according to the educ ation system in oman. ‡information from four patients are missing (n = 177). table 2: mean score per item for each domain of perceived unmet supportive care needs* among omani women diagnosed with breast cancer (n = 181) domain number of items per domain mean score per item ± sem† psychological 10 2.77 ± 0.08 physical and daily living 5 2.90 ± 0.08 health system and information 8 3.33 ± 0.09 patient care and support 6 3.04 ± 0.08 sexuality 2 2.27 ± 0.10 sem = standard error of measurement *self-assessed using a previously validated arabic version of the 34-item supportive care needs survey-short form.8 items were scored in terms of perceived level of need for additional support on a 5-point scale as either 1 (no need/not applicable), 2 (no need/satisfied), 3 (low need), 4 (moderate need) or 5 (high need).15 †score range: 1.0–5.0. mohammed al-azri, khalid al-bimani, al-anoud al-maqbali, hala al-riyami, al-kuthar al-shabnooti, sathiya m. panchatcharam and sanjay jaju clinical and basic research | 519 table 3: perceived level of unmet supportive care needs* in each domain among omani women diagnosed with breast cancer (n = 181) domain item n (%) perceived level of unmet need no need/ not applicable no need/ satisfied low moderate high psychological fears about loss of independence 73 (40.3) 38 (21.0) 33 (18.2) 28 (15.5) 9 (5.0) feeling depressed/sad 64 (35.4) 30 (16.6) 35 (19.3) 25 (13.8) 27 (14.9) fears about pain 37 (20.4) 28 (15.5) 50 (27.6) 43 (23.8) 23 (12.7 fears about cancer spreading 30 (16.6) 22 (12.2) 32 (17.7) 36 (19.9) 61 (33.7) fears about cancer recurrence 28 (15.5) 28 (15.5) 31 (17.1) 32 (17.7) 62 (34.3) accepting changes to your body/ appearance 22 (12.2) 82 (45.3) 24 (13.3) 28 (15.5) 25 (13.8) thinking about death 69 (38.1) 47 (26.0) 20 (11.0) 24 (13.3) 21 (11.6) fears about lifestyle changes 54 (29.8) 42 (23.2) 39 (21.5) 24 (13.3) 22 (12.2) concerns regarding the ability of those close to you to cope with your care 73 (40.3) 37 (20.4) 33 (18.2) 17 (9.4) 21 (11.6) fears about your children or those close to you 43 (23.8) 23 (12.7) 26 (14.4) 30 (16.6) 59 (32.6) physical and daily living pain 28 (15.5) 39 (21.5) 50 (27.6) 46 (25.4) 18 (9.9) tiredness 19 (10.5) 38 (21.0) 48 (26.5) 53 (29.3) 23 (12.7) nausea/vomiting 65 (35.9) 26 (14.4) 36 (19.9) 36 (19.9) 18 (9.9) not sleeping well 42 (23.2) 22 (12.2) 41 (22.7) 47 (26.0) 29 (16.0) not able to do the things that you could before the cancer diagnosis 38 (21.0) 34 (18.8) 41 (22.7) 40 (22.1) 28 (15.5) health system and information need to talk to someone who understands and has experience with your case 19 (10.5) 41 (22.7) 34 (18.8) 30 (16.6) 57 (31.5) need for more information about your diagnosis and prognosis (i.e. your future condition) 19 (10.5) 48 (26.5) 20 (11.0) 33 (18.2) 61 (33.7) need to be informed about available treatments and their benefits and side effects 14 (7.7) 44 (24.3) 22 (12.2) 29 (16.0) 72 (39.8) need for information about how to manage your illness and side effects at home 26 (14.4) 34 (18.8) 31 (17.1) 40 (22.1) 50 (27.6) need for an explanation regarding any tests that you undergo 15 (8.3) 47 (26.0) 21 (11.6) 33 (18.2) 65 (35.9) need to be informed about what you can do to help yourself get well 19 (10.5) 40 (22.1) 20 (11.0) 28 (15.5) 74 (40.9) need to be informed about support groups 35 (19.3) 32 (17.7) 31 (17.1) 35 (19.3) 48 (26.5) need for access to professional counselling 51 (28.2) 31 (17.1) 32 (17.7) 26 (14.4) 41 (22.7) patient care and support need for promptness in clinical appointments 44 (24.3) 50 (27.6) 29 (16.0) 23 (12.7) 35 (19.3) need for the hospital to protect your privacy 18 (9.9) 70 (38.7) 10 (5.5) 24 (13.3) 59 (32.6) *self-assessed using a previously validated arabic version of the 34-item supportive care needs survey-short form.8 items were scored in terms of perceived level of need for additional support on a 5-point scale as either 1 (no need/not applicable), 2 (no need/satisfied), 3 (low need), 4 (moderate need) or 5 (high need).15 the unmet supportive care needs of omani women diagnosed with breast cancer 520 | squ medical journal, november 2022, volume 22, issue 4 incorporating the social, spiritual, educational and informational needs of cancer patients—require a substantial improvement in most healthcare systems; moreover, until such services are easily available and accessible, the needs of cancer patients will continue to go unfulfilled.3 nonetheless, although there were slight variations between different domains of supportive care needs in this study, the omani women demonstrated a need for additional support across most domains, with the greatest unmet needs attributed to the domain of health system and information. when a domain is reported to have a high prevalence of unmet needs, the provision of related services in this area is commonly perceived to be insufficient; therefore, future work should be aimed at improving these services for the population.18 cancer patients often report high levels of unmet supportive care needs concerning information and communication; in particular, many patients express a desire for further information regarding the shortand long-term implications of cancer, the management of their illness and the effectiveness and side-effects of potential treatments.7,19,20 similarly, many of the women in the current study reported high unmet needs for more information regarding what they could do to help themselves and further explanation regarding tests, disease prognosis and the benefits and side-effects of different treatment options. in general, cancer patients often seek additional information to assuage anxiety associated with the uncertainty of living with cancer, particularly concerning the type of cancer, its stage and potential side effects of cancer prognosis and management.20 several factors have been found to influence cancer patients’ needs for cancer-related information, including time since diagnosis, the chosen treatment, cancer stage, disease severity and the role of the patient in the treatment decision-making process.20 approximately one-third of patients in the present study expressed fear regarding cancer recurrence and spread as well as fear for their children and loved ones, ranking these unmet needs highest in the psychological domain. failure to identify and address topics of concern among cancer patients through informational support and resource availability can result in depression, anxiety and feelings of fear.18,21 insufficient time for adequate information provision during consultations may also exacerbate unmet supportive care needs in the information and psychological domains.19 patient–physician interaction is central to the process of healthcare delivery, in conjunction with adequate informational support associated with various desirable health outcomes for cancer patients.22 in addition, good physician–patient communication helps ensure an effective working relationship.23 however, patients in the current study reported a high table 3 (contd.): perceived level of unmet supportive care needs* in each domain among omani women diagnosed with breast cancer (n = 181) domain item n (%) perceived level of unmet need no need/ not applicable no need/ satisfied low moderate high patient care and support need for more choice about which hospital you attend 41 (22.7) 56 (30.9) 26 (14.4) 25 (13.8) 33 (18.2) need for clinicians to attend promptly to your physical needs 23 (12.7) 67 (37.0) 15 (8.3) 27 (14.9) 49 (27.1) need for clinicians to show sensitivity to your emotional needs 19 (10.5) 65 (35.9) 12 (6.6) 30 (16.6) 55 (30.4) need for clinicians to be more sincere with you 20 (11.0) 62 (34.3) 13 (7.2) 20 (11.0) 66 (36.5) sexuality changes in your sexual feelings 73 (40.3) 42 (23.2) 29 (16.0) 19 (10.5) 18 (9.9) changes in your sexual relationship 79 (43.6) 35 (19.3) 25 (13.8) 24 (13.3) 18 (9.9) other needs need to talk with other people who have experienced cancer 41 (22.6) 58 (32.0) 31 (17.1) 32 (17.7) 19 (10.5) need for economic help 75 (41.4) 28 (15.5) 23 (12.7) 22 (12.2) 33 (18.2) need to receive less commiseration from other people 69 (38.1) 32 (17.7) 19 (10.5) 12 (6.6) 49 (27.1) *self-assessed using a previously validated arabic version of the 34-item supportive care needs survey-short form.8 items were scored in terms of perceived level of need for additional support on a 5-point scale as either 1 (no need/not applicable), 2 (no need/satisfied), 3 (low need), 4 (moderate need) or 5 (high need).15 mohammed al-azri, khalid al-bimani, al-anoud al-maqbali, hala al-riyami, al-kuthar al-shabnooti, sathiya m. panchatcharam and sanjay jaju clinical and basic research | 521 level of unmet needs in the patient care and support domain, especially in terms of the clinicians’ lack of sincerity and sensitivity to their emotional needs. the interpersonal relationship between healthcare providers and patients plays a major role in shaping perceptions of service quality.24 moreover, patients who feel that their treating physician is not capable of addressing the broader aspects of their care may seek information, help and advice from other sources.23 few women in the present study prioritised certain needs related to the sharing of their experiences with others, including the need to be informed about support groups, to talk with other cancer patients/ survivors or for access to professional counselling services. in western countries, support groups are often perceived by cancer patients to be very important, as they provide many benefits, including a greater sense of control over cancer and its treatment.19 on the other hand, cancer patients in oman and other arab islamic countries often rely more heavily on family members to support them, especially when dealing with the side-effects of chemotherapy.3,4 in general, family members in oman demonstrate a greater degree of involvement in the treatment decision-making process, a finding which may be table 4: associations between sociodemographic and clinical variables and total mean score for perceived unmet supportive care needs* among omani women diagnosed with breast cancer (n = 181) variable mean score ± sem p value age in years 0.855 ≤40 100.98 ± 27.79 41–50 99.51 ± 25.34 51–60 96.17 ± 31.98 >60 101.26 ± 26.13 education level† 0.800 illiterate (cannot read or write) 99.50 ± 22.85 completed primary school (grade 6) 105.70 ± 28.38 completed intermediate school (grade 9) 97.08 ± 26.21 completed secondary school (grade 12) 99.37 ± 28.28 completed university 97.18 ± 29.17 completed postgraduate/ doctorate 109.40 ± 26.03 marital status 0.509 married 100.50 ± 27.75 single 94.00 ± 31.27 widowed 89.58 ± 24.33 divorced 100.92 ± 24.78 employment status 0.209 unemployed 99.45 ± 26.99 employed 104.39 ± 26.91 retired 93.23 ± 28.66 monthly family income in omr 0.136 <500 103.02 ± 25.50 501–1,000 92.31 ± 31.06 1,001–2,000 98.62 ± 25.25 family history of bc 0.297 no 100.61 ± 27.86 yes 95.72 ± 25.91 number of hospital visits in the last two months 0.045‡ 1 94.62 ± 27.27 2 101.61 ± 25.54 3 93.14 ± 29.20 4 112.82 ± 26.38 >4 106.36 ± 26.34 time since diagnosis in years 0.403 ≤2 101.98 ± 25.95 >2 98.25 ± 28.01 stage of cancer at diagnosis 0.047‡ 1 92.11 ± 30.24 2 99.50 ± 23.47 3 or 4 104.32 ± 27.24 treatment received in the last two months 0.014‡ chemotherapy 109.76 ± 24.49 immunotherapy 102.52 ± 26.38 radiotherapy 110.70 ± 24.66 surgery 82.30 ± 24.51 combined treatment 88.44 ± 26.99 hormonal therapy 94.48 ± 30.48 other 96.27 ± 26.62 none 93.50 ± 25.19 sem = standard error of measurement; omr = omani rials; bc = breast cancer. *self-assessed using a previously validated arabic version of the 34-item supportive care needs survey-short form.8 items were scored in terms of perceived level of need for additional support on a 5-point scale as either 1 (no need/not applicable), 2 (no need/satisfied), 3 (low need), 4 (moderate need) or 5 (high need).15 †according to the education system in oman. ‡significant at p <0.05. the unmet supportive care needs of omani women diagnosed with breast cancer 522 | squ medical journal, november 2022, volume 22, issue 4 exacerbated by the patients’ poor communication with their oncologists.25 in western countries, women with bc have reported feelings of fear, anxiety and guilt during and after cancer treatment, which affects communication with their partners and interferes with sexual activity.26 however, few omani women in the current study perceived a high level of unmet need for additional support in the sexuality domain, despite previous research indicating that women in this population are concerned with potential bodily disfigurement, alopecia and loss of femininity as a result of surgical intervention and chemotherapy.12 however, previous studies conducted in other islamic countries such as malaysia and the uae have similarly found the sexuality domain to be ranked low in terms of priority compared to other domains.8,16 as in other conservative communities, omani women are often embarrassed and reluctant to explore their sexual needs and concerns with healthcare professionals, as such topics are considered taboo due to cultural norms.27 furthermore, it is not considered routine practice to assess the sexual well-being of cancer patients in oman. healthcare professionals may not have the knowledge and skills necessary to do so; moreover, some may believe that such issues fall outside the scope of their professional responsibilities and could carry legal ramifications.26 the present study reported significant assoc iations between total mean scores and various sociodemographic and clinical variables. in particular, women who had visited the hospital more frequently in the two months preceding the study, those diagnosed with bc at more advanced stages and patients receiving chemotherapy or radiotherapy demonstrated significantly higher total mean scores for unmet supportive care needs compared to their respective counterparts. previous studies have shown that most unmet supportive care needs for cancer patients occur during the treatment phase.5,28 surgical or medical treatments for cancer often result in serious physical side-effects and complications as well as negative psychosocial outcomes.29 moreover, if their informational needs are not met, cancer patients are more likely to become anxious and depressed, which can worsen their health status.30 thus, adequate informational and psychosocial support should be provided to cancer patients to help them cope with symptoms at different stages of treatment.28 certain limitations to the current study should be acknowledged. first, although the questionnaire used in this study was originally intended to be selfcompleted by the participants or administered by research assistants to illiterate participants, due to the risk of covid-19 cross-infection, the tool was modified so that it could be administered online. this could have impacted the patients’ responses. moreover, the occurrence of a global pandemic and disruptions to normal cancer service provisions at the time of the study may have affected perceptions of unmet supportive care needs among the respondents. second, although the current study reported a significant association between women who received chemotherapy or radiotherapy and higher total mean scores for unmet supportive care needs, other factors may have played a role in these findings. psychological or emotional distress, as well as other variables such as age, education level, family history of bc, access to information and financial status might all have a strong bearing on a patient’s perceptions and concerns regarding their unmet needs. thus, further research utilising more objective measures and evaluation tools and with a larger sample size is needed to rule out such negative associations. third, future research evaluating the unmet supportive care needs of women with bc in oman should consider the impact of their level of involvement in the decision-making process and the influence and perceptions of other family members, particularly male family members, as well as other psychosocial aspects of attitudes to health, such as the stigma associated with a bc diagnosis and the patient’s own level of knowledge regarding their diagnosis, stage of disease and health outcome. finally, participants were recruited from one of two main oncology treatment centres in oman; therefore, differences in findings between the two centres cannot be ruled out. conclusion despite slight variations between different domains, this study found that the majority of unmet supportive care needs among omani women with bc were informational in nature. as such, there is an urgent need to improve informational support services at squh. in addition, physicians should consider adopting a patient-centred care approach during consultations. this should include exploring the concerns and expectations of the patient at various stages of the cancer care process, including the short and long-term implications of cancer, their prognosis, potential side-effects of treatment and the risk of cancer among family members. moreover, additional training should be provided to improve language barriers between patients and non-arabic–speaking providers. mohammed al-azri, khalid al-bimani, al-anoud al-maqbali, hala al-riyami, al-kuthar al-shabnooti, sathiya m. panchatcharam and sanjay jaju clinical and basic research | 523 a u t h o r s’ c o n t r i b u t i o n ma, ka, aaa, ha and aka conceived the design of the study. aaa, ha and aka collected the data, while smp and sj analysed the data. all authors participated in drafting the manuscript. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t s permission to use the arabic version of the scnssf34 tool utilised in this study was granted by nair et al.8 the authors would like to thank the participants for taking part in this study as well as the authorities at the squh for allowing this study to be conducted. c o n f l i c t s o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2018; 68:394–424. https://doi.org/10.3322/caac.21492. 2. maguire r, kotronoulas g, simpson m, paterson c. a systematic review of the supportive care needs of women living with and beyond cervical cancer. gynecol oncol 2015; 136:478–90. https://doi.org/10.1016/j.ygyno.2014.10.030. 3. harrison jd, young jm, price ma, butow pn, solomon mj. what are the unmet supportive care needs of people with cancer? a systematic review. support care cancer 2009; 17:1117–28. https://doi.org/10.1007/s00520-009-0615-5. 4. al-azri mh, al-awisi h, al-rasbi s, al-moundhri m. coping with a diagnosis of breast cancer among omani women. j health psychol 2014; 19:836–46. https://doi.org/10.1177/13591053134 79813. 5. chou yh, hsieh vcr, chen xx, huang ty, shieh sh. unmet supportive care needs of survival patients with breast cancer in different cancer stages and treatment phases. taiwan j obstet gynecol 2020; 59:231–6. https://doi.org/10.1016/j.tjog.2020.01.010. 6. li wwy, lam wwt, au ahy, ye m, law wl, poon j, et al. interpreting differences in patterns of supportive care needs between patients with breast cancer and patients with colo rectal cancer. psychooncology 2013; 22:792–8. https://doi. org/10.1002/pon.3068. 7. al-bahri a, al-moundhri m, al-mandhari z, al-azri m. role of the family in treatment decision-making process for omani women diagnosed with breast cancer. patient educ couns 2019; 102:352–9. https://doi.org/10.1016/j.pec.2018.08.026. 8. nair sc, jaafar h, jaloudi m, qawasmeh k, almarar a, ibrahim h. supportive care needs of multicultural patients with cancer in the united arab emirates. ecancermedicalscience 2018; 12:838. https://doi.org/10.3332/ecancer.2018.838. 9. al-lawati na, al-bahrani bj, al-raisi ss, al-lawati ja. twenty-year trends of cancer incidence in omanis, 1996-2015. oman med j 2019; 34:361–87. 10. al-lawati ja, al-zakwani i, fadhil i, al-bahrani bj. cancer incidence in oman (1996-2015). oman med j 2019; 34:271–3. https://doi.org/10.5001/omj.2019.55. 11. al-azri m, al-baimani k, al-awaisi h, al-mandhari z, alkhamayasi j, al-lawati y, et al. knowledge of symptoms, time to presentation and barriers to medical help-seeking among omani women diagnosed with breast cancer: a cross-sectional study. bmj open 2021; 11:e043976. https://doi.org/10.1136/ bmjopen-2020-043976. 12. al-riyami a, abdulhadi nn, al-azri m. understanding the perceptions of omani women regarding life after a breast cancer diagnosis. sultan qaboos univ med j 2020; 20:e360–7. https://doi.org/10.18295/squmj.2020.20.04.013. 13. al-azri m, al-awisi h, al-rasbi s, el-shafie k, al-hinai m, al-habsi h, et al. psychosocial impact of breast cancer diagnosis among omani women. oman med j 2014; 29:437–44. https:// doi.org/10.5001/omj.2014.115. 14. oman ministry of health. cancer incidence in oman 2017. from: www.moh.gov.om/en/-/-20-10 accessed: aug 2021. 15. boyes a, girgis a, lecathelinais c. brief assessment of adult cancer patients’ perceived needs: development and validation of the 34-item supportive care needs survey (scns-sf34). j eval clin pract 2009; 15:602–6. https://doi.org/10.1111/j.13652753.2008.01057.x. 16. edib z, kumarasamy v, binti abdullah n, rizal am, aldubai sar. most prevalent unmet supportive care needs and quality of life of breast cancer patients in a tertiary hospital in malaysia. health qual life outcomes 2016; 14:26. https://doi. org/10.1186/s12955-016-0428-4. 17. heckel l, fennell km, reynolds j, osborne rh, chirgwin j, botti m, et al. unmet needs and depression among carers of people newly diagnosed with cancer. eur j cancer 2015; 51:2049–57. https://doi.org/10.1016/j.ejca.2015.06.129. 18. moghaddam n, coxon h, nabarro s, hardy b, cox k. unmet care needs in people living with advanced cancer: a systematic review. support care cancer 2016; 24:3609–22. https://doi. org/10.1007/s00520-016-3221-3. 19. ussher j, kirsten l, butow p, sandoval m. what do cancer support groups provide which other supportive relationships do not? the experience of peer support groups for people with cancer. soc sci med 2006; 62:2565–76. https://doi.org/10.1016/j.socsci med.2005.10.034. 20. mekuria ab, erku da, belachew sa. preferred information sources and needs of cancer patients on disease symptoms and management: a cross-sectional study. patient prefer adherence 2016; 10:1991–7. https://doi.org/10.2147/ppa.s116463. 21. hawkins na, pollack la, leadbetter s, steele wr, carroll j, dolan jg, et al. informational needs of patients and perceived adequacy of information available before and after treatment of cancer. j psychosoc oncol 2008; 26:1–16. https://doi.org/10.13 00/j077v26n02_01. 22. maly rc, leake b, silliman ra. health care disparities in older patients with breast carcinoma: informational support from physicians. cancer 2003; 97:1517–27. https://doi.org/10.1002/ cncr.11211. 23. adamson m, choi k, notaro s, cotoc c. the doctorpatient relationship and information-seeking behavior: four orientations to cancer communication. j palliat care 2018; 33:79–87. https://doi.org/10.1177/0825859718759881. 24. padma p, rajendran c, lokachari ps. service quality and its impact on customer satisfaction in indian hospitals: perspectives of patients and their attendants. benchmarking 2010; 17:807–41. https://doi.org/10.1108/14635771011089746. 25. al-bahri a, al-moundhri m, al-mandhari z, al-azri m. the role of patients’ families in treatment decision-making among adult cancer patients in the sultanate of oman. eur j cancer care (engl) 2018; 27:e12845. https://doi.org/10.1111/ ecc.12845. 26. stilos k, doyle c, daines p. addressing the sexual health needs of patients with gynecologic cancers. clin j oncol nurs 2008; 12:457–63. https://doi.org/10.1188/08.cjon.457-463. https://doi.org/10.3322/caac.21492. https://doi.org/10.1016/j.ygyno.2014.10.030 https://doi.org/10.1007/s00520-009-0615-5 https://doi.org/10.1177/1359105313479813. https://doi.org/10.1177/1359105313479813. https://doi.org/10.1016/j.tjog.2020.01.010 https://doi.org/10.1002/pon.3068 https://doi.org/10.1002/pon.3068 https://doi.org/10.1016/j.pec.2018.08.026 https://doi.org/10.3332/ecancer.2018.838 https://doi.org/10.5001/omj.2019.55 https://doi.org/10.1136/bmjopen-2020-043976 https://doi.org/10.1136/bmjopen-2020-043976 https://doi.org/10.18295/squmj.2020.20.04.013 https://doi.org/10.5001/omj.2014.115 https://doi.org/10.5001/omj.2014.115 https://doi.org/10.1111/j.1365-2753.2008.01057.x https://doi.org/10.1111/j.1365-2753.2008.01057.x https://doi.org/10.1186/s12955-016-0428-4 https://doi.org/10.1186/s12955-016-0428-4 https://doi.org/10.1016/j.ejca.2015.06.129 https://doi.org/10.1007/s00520-016-3221-3 https://doi.org/10.1007/s00520-016-3221-3 https://doi.org/10.1016/j.socscimed.2005.10.034 https://doi.org/10.1016/j.socscimed.2005.10.034 https://doi.org/10.2147/ppa.s116463 https://doi.org/10.1300/j077v26n02_01 https://doi.org/10.1300/j077v26n02_01 https://doi.org/10.1002/cncr.11211 https://doi.org/10.1002/cncr.11211 https://doi.org/10.1177/0825859718759881 https://doi.org/10.1108/14635771011089746 https://doi.org/10.1111/ecc.12845 https://doi.org/10.1111/ecc.12845 https://doi.org/10.1188/08.cjon.457-463 the unmet supportive care needs of omani women diagnosed with breast cancer 524 | squ medical journal, november 2022, volume 22, issue 4 27. wahba m. adolescents’ sexual and reproductive health in the arab world. in: laher e (ed). handbook of healthcare in the arab world. berlin, germany: springer, 2019. pp. 1–25. https:// doi.org/10.1007/978-3-319-74365-3_100-1. 28. smith a, hyde ym, stanford d. supportive care needs of cancer patients: a literature review. palliat support care 2015; 13:1013–17. https://doi.org/10.1017/s1478951514000959. 29. walker lg, eremin o. psychological assessment and intervention: future prospects for women with breast cancer. semin surg oncol 1996; 12:76–83. https://doi.org/10.1002/(sici)1098-2388(1 99601/02)12:1<76::aid-ssu11>3.3.co;2-y. 30. whelan tj, mohide ea, willan ar, arnold a, tew m, sellick s, et al. the supportive care needs of newly diagnosed cancer patients attending a regional cancer center. cancer 1997; 80:1518–24. https://doi.org/10.1002/(sici)1097-0142(199 71015)80:8<1518::aid-cncr21>3.0.co;2-7. https://doi.org/10.1007/978-3-319-74365-3_100-1 https://doi.org/10.1007/978-3-319-74365-3_100-1 https://doi.org/10.1017/s1478951514000959 https://doi.org/10.1002/(sici)1098-2388(199601/02)12:1<76::aid-ssu11>3.3.co;2-y https://doi.org/10.1002/(sici)1098-2388(199601/02)12:1<76::aid-ssu11>3.3.co;2-y https://doi.org/10.1002/(sici)1097-0142(19971015)80:8<1518::aid-cncr21>3.0.co;2-7 https://doi.org/10.1002/(sici)1097-0142(19971015)80:8<1518::aid-cncr21>3.0.co;2-7 submitted 15 apr 22 1 revision req. 15 jun 22; revision recd. 25 jul 22 2 accepted 7 sep 22 3 online-first: september 2022 4 doi: https://doi.org/10.18295/squmj.9.2022.057 5 6 effect of erector spinae block and pecs block on quality of recovery 7 and analgesia after modified radical mastectomy 8 a randomised controlled study 9 md hammad mohsin,1 *reetu verma,2 hemlata,2 dinesh singh,2 sarita 10 singh,2 kulranjan singh3 11 12 1department of anaesthesiology, all india institute of medical sciences, patna, india; 13 departments of 2anaesthesiology and 3endocrine surgery, king george's medical university, 14 lucknow, india. 15 *corresponding author’s e-mail: reetuverma1998@gmail.com 16 17 abstract 18 objectives: postoperative pain after modified radical mastectomy ranges from moderate to 19 severe. pectoralis block in comparison to erector spinae block have been found better in 20 reducing pain scores and reducing consumption of rescue analgesic in postoperative period. 21 this study aimed to compare the effect of erector spinae block and pectoralis block on 22 quality of recovery after modified radical mastectomy using qor-40 score. methods: after 23 general anaesthesia, patients were given block according to computer generated 24 randomization. group-i-pectoralis block including pec i and pec ii(pecs), group-ii-25 erector spinae block(esp) and group iii-control group (no intervention). quality of 26 recovery (qor-40) score was observed on morning of surgery and at 24 hrs. time to rescue 27 analgesia and total consumption of rescue analgesia in first 24 hrs. were also observed. 28 results: in the postoperative period at 24 hrs. global qor-40 scores were 183.64±6.36 in 29 pecs group, 179.68± 6.38 in esp group and 171.37±6.88 in control group. (p<0.0001) but, 30 there was no statistically significant difference between qor score of pecs & esp group 31 patients(p=0.0551). the total requirement of rescue analgesic was significantly lesser in 32 pecs group (137.28±31.46 mg) in comparison to esp group(189.46±42.98mg) and control 33 mailto:reetuverma1998@gmail.com group (229.57±46.80 mg). (p<0.0001). time to first rescue analgesia was significantly higher 34 in pecs group (6.53±2.78 hrs) in comparison to esp (4.05±2.91 hrs) and control group 35 (2.15±1.51 hrs). (p<0.0001) conclusion: both erector spinae block and pectoralis block are 36 effective for improving qor score and reducing consumption of rescue analgesic after 37 modified radical mastectomy. 38 keywords: breast surgery, cancer, postoperative recovery, postoperative pain 39 40 advances in knowledge 41  both erector spinae block and pecs block have been shown very promising 42 results in providing postoperative analgesia after breast surgery. our study based 43 on these blocks helped us to get more data and knowledge as well as getting 44 accustomed about these blocks. 45 46 application to patient care 47  these blocks providing post-operative analgesia resulted in patients being more 48 comfortable post operatively, having a better feel of general over all wellbeing as 49 well as better post operative outcomes. 50 51 introduction 52 in year 2020 female breast cancer was diagnosed as most common cancer worldwide.1,2 53 radical or modified radical mastectomy (mrm) is main treatment option for locally 54 advanced lesions of breast.3 mrm is usually done under general anaesthesia. incidence 55 of severe post-operative pain on the first post-operative day after mrm has been 56 reported to be 60%.4 poor management of pain in the postoperative period may produce 57 various acute and chronic detrimental effects.5,6 so, adequate control of pain in 58 postoperative period is very important to alleviate these detrimental effects. also, getting 59 adequate pain management is fundamental right of every patient. 7 moreover, adequate 60 control of pain in postoperative period can also have an impact on quality of recovery of 61 patients.8 qor-40 score is a global score for assessing the status of recovery after 62 anaesthesia and surgery. it includes 40 questions covering five domains: patient’s 63 psychological support, emotional status, physical comfort, physical independence in 64 doing his work and severity of pain. in a number of surgical settings, the qor-40 score 65 has been shown to be a valid, and sensitive method, for measuring the dynamic and 66 multidimensional process of post-operative recovery.9-11 nair et al., in their study found 67 that patients who received regional blocks during breast surgery had higher 68 postoperative qor scores.11 yao y et al. also observed that preoperative esp block 69 improves postoperative qor score and postoperative analgesia in patients undergoing 70 mrm.12 sinha c et al compared pecs block and esp after mrm and observed that 71 pecs block patients had lower pain scores and consumptions of analgesics in the 72 postoperative period in comparison to esp block.13 so we hypothesized that pecs 73 block patient would also have better quality of recovery in comparison to esp, and this 74 study was done to compare the effect of esp block and pecs block on post-operative 75 quality of recovery after mrm using qor-40 score. the primary objective of the study 76 was to compare the quality of recovery score (qor-40) at 24 hrs. after surgery. the 77 secondary objectives were total consumption of analgesics in the first 24hrs, time to 78 rescue analgesia, postoperative vas score and to compare intraoperative hemodynamic. 79 80 methods 81 this randomized control study was conducted adhering to the helsinki declaration, 82 consort recommendations for rct from 20/12/2020 to 20/12/2021 after approval from 83 the institutional ethical committee (***) and after clinical trial registry (***) in department of 84 anaesthesia. 85 86 this study included patients between 18-60 years female with asa grade i &ii, who 87 were planned for unilateral modified radical mastectomy for breast cancer. written 88 informed consent was obtained from all patients. exclusion criteria were patient refusal, 89 endocrine disorders (including i and ii type of diabetes mellitus), any coagulation 90 disorders, cognitive inability to understand qor-40 questionnaire and allergies to local 91 anaesthetics. 105 patients were assessed for eligibility. (figure 1) patients were 92 randomly allocated to one of the following three groups using computer-generated 93 random numbers. group-i-pectoralis block (pecs block), group-ii-erector spinae block 94 (esp block) & group iii-control group. qor-40 score was noted on the morning of 95 surgery in each patient. after taking the patients in operation theatre, monitors were 96 attached. the patients were monitored for heart rate, bp (sbp, dbp & map), spo2, and 97 ecg. after that intravenous line was taken in arm contralateral to surgery planned and 98 an intravenous fluid was started. preoxygenation was done for 3 mins and after that 99 patient were induced with injection fentanyl 1ug/kg, injection propofol 2-2.5 mg/kg and 100 after confirming adequate bag and mask ventilation injection vecuronium 0.1mg/kg was 101 given. after three minutes, either second generation supraglottic airway device or 102 endotracheal tube was inserted. after confirmation of adequate ventilation by 103 auscultation and capnography patients were put on volume-controlled ventilation mode. 104 anaesthesia was maintained with o2: n20(50:50) and sevoflurane. after that patient 105 received respective block according to randomization. 106 107 the blocks were performed with stimuplex® needle a100 (0.80 x 100mm (21g x 4”) 108 and toshiba usg machine with a high frequency linear probe 38mm, 6-13 mhz. hydro 109 dissection (saline) was used to identify the correct position and plane before injecting the 110 local anesthetic. 111 pectoralis block 112 the patient was positioned supine, with the arm ipsilateral to surgery site abducted to 90 113 degrees. the skin was prepared with 10% betadine solution. the sterile usg probe was 114 put longitudinally at the mid clavicular level just below clavicle and was adjusted to 115 identify axillary artery and vein. after that caudal edge of probe was turned laterally and 116 usg probe was moved downwards to identify third rib, fourth rib, pectoralis major 117 muscle, pectoralis minor muscle and serratus anterior muscle. the needle was introduced 118 through an in-plane technique from cranial edge of probe and advances to lie in 119 interfascial plane between pectoralis minor and serratus anterior muscle and 20 ml of 120 .25% bupivacaine was administered (pecs ii). after giving pecs ii block, the needle 121 was withdrawn slowly and adjusted to lie between pectoralis major and minor muscle 122 and after confirmation by hydro dissection, 10 ml of 0.25% bupivacaine was deposited 123 there (pecs i). 124 125 erector spinae block 126 the patient was placed in lateral decubitus position and, following aseptic precautions, 127 sterile usg probe was put longitudinally paramedian to thoracic spine and t4 transverse 128 process was identified. superficial to transverse process erector spinae, rhomboid major 129 and trapezius muscles were identified. the needle was introduced through an in-plane 130 cephalocaudal approach till the needle tip contacts the transverse process and after 131 confirmation of correct plane by hydro dissection 20ml of 0.25% bupivacaine was given 132 superficial to the transverse process and beneath the erector spinae muscle. 133 134 this study was double blinded as the patients were not aware of the intervention, they had 135 received and the observer who observed the patient and collected data was also not aware of 136 intervention each patient has received. 30 minutes before completion of surgery each patient 137 was given pcm 1gm i.v. and thereafter 1gm i.v. at every 6 hours. if any patient had vas 138 score > 3 in postoperative period, rescue analgesic injection of tramadol (100mg) i.v. was 139 given. time duration between two injection of tramadol was kept >4 hrs. hemodynamic 140 variables (heart rate, map, sbp, dbp, & spo2) were recorded before surgery and after that 141 every 15 minutes till completion of surgery. time to rescue analgesia and total consumption 142 of rescue analgesia in 1st 24 hrs. were also observed. quality of recovery (qor-40) score was 143 observed again at 24 hrs. qor-40 questionnaires were filled by observer who verbally 144 translated the questionnaire to patients into the regional language. 145 146 statistical analysis 147 sample size is calculated on the basis of pilot study done on 10 patients in which sd was 148 7.12 for qor-40 in control group. assuming a difference of 10 would be clinically 149 significant, minimum sample size was calculated to be 28 in each group. we took 30 patients 150 in each group with the possibility of loss to follow up. statistical analysis was performed 151 using spss software (15.0 version). the continuous variables were evaluated by mean and 152 standard deviation.. the dichotomous variables were presented in number and were analysed 153 using chi-square or fisher extract test. to compare the means between the two groups, 154 student t-test and for comparing three groups anova tests were used. a p-value of < 0.05 155 was regarded as significant. 156 157 results 158 in our study all groups had comparable demographic profile. (table no.1) on 159 comparing mean average global qor-40(0-200) score preoperatively, there was no 160 statistically significant difference between three groups (p =0.8360). at 24 hrs there 161 was a significant difference between three groups. in our study at 24 hours, global 162 qor-40(0-200) score was highest in pecs group followed by erector spinae group 163 and control group patients. the difference between three groups were statistically 164 significant(p<0.0001). but difference between pecs & erector spinae group patients 165 was not significant statistically(p=0.0551). (table no.2) 166 167 the requirement of rescue analgesic was significantly lower in pecs group in comparison to 168 erector spinae group and control group patients(p<0.0001). time to first rescue analgesic 169 was significantly higher in pecs group in comparison to other two groups. (table 3) 170 the gradual increase in vas score was observed in all the three groups after surgery. vas 171 score was lowest in pecs group. the difference between groups was statistically significant 172 at 6 hours, 12 hours and 24 hours. (table-4) 173 174 there was no clinically significant difference between haemodynamic in three groups 175 intraoperatively. (fig 2,3) 176 177 discussion 178 after mrm, patients report moderate to severe postoperative pain and various drugs and 179 regional analgesic techniques are being used for providing postoperative pain relief. opioids 180 are the drugs which are most commonly used for providing postoperative analgesia but using 181 opioid in cancer patients is related to suppression of cellular immunity and increase in cancer 182 recurrence.14 nsaids are the other class of drugs which are also commonly used for 183 postoperative analgesia but their efficacy is limited to mild to moderate pain. also, patients 184 with mrm has high incidence of postoperative nausea and vomiting and using opioids and 185 nsaids may increase the incidence of ponv.15 transdermal patch is a non-invasive 186 method of providing postoperative analgesia and they have been found very effective in 187 reducing pain scores in postoperative period in various other surgeries. but transdermal 188 patches generally contain opioids and nsaids which can again increase the incidence of 189 nausea and vomiting after mrm surgery. so, regional analgesia is best modality for 190 providing postoperative analgesia in mrm patients. further, it has also been found that using 191 regional analgesia also decreases the incidence of chronic pain. 16 192 193 among, regional analgesia thoracic epidural and paravertebral blocks are still gold 194 standard analgesic techniques.17-19 but, sometimes it may be difficult to give thoracic 195 epidural and paravertebral block and they are also associated with complications such 196 as pneumothorax, vascular puncture, or nerve injury. so, there is always a need to find 197 alternatives to these blocks, which are easy to give, having a higher safety profile and 198 can provide equivalent pain relief. both pecs block and esp block are blocks which 199 are easy to perform and with very less complications in expert hands. they also reduce 200 the requirement of analgesia in postoperative period with decrease in pain scores. 20,21 201 202 quality of recovery of any patient after surgery may be related to quality of 203 perioperative analgesia. myles ps et al in their study observed that patient’s quality of 204 recovery after anaesthesia and surgery can be assessed effectively by using qor-40 205 score.10 206 207 in our study at 24 hours, the global qor-40 score was 183.64±6.36 in pecs group, 179.68± 208 6.38 in esp group, and 171.37±6.88 in control group and the inter mean difference between 209 groups was statistically significant at 24 hours global qor-40(0-200) (p<0.0001). however, 210 the difference between pecs group and esp group was statistically insignificant. kamiya y 211 et al studied the effect of pecs block on postoperative pain and qor score in breast cancer 212 surgery patients and observed that pain score in pecs group was lower than control group 213 till 24 hrs. 22 but there was no statistically significant difference between requirement of 214 rescue analgesic and qor-40 score in their study. in our study, we reported a significant 215 difference between pecs and control group in requirement of rescue analgesic and qor 216 score. it may be because of that for pecs ii block kamiya y,. et al injected the drug deep to 217 serratus anterior muscle and in our study drug was administered superficial to serratus 218 anterior muscle. 219 220 in a study conducted by yao y et al,. it was also found that esp block improves pain score 221 qor score in the postoperative period.12 222 223 similar to our study sinha et al,. also observed that pecs block administered prior to mrm 224 leads to decreased requirement of postoperative analgesics in first 24 hours. the mean 225 duration of analgesia was 7.26 ±0. 69 hrs in patients with pecs block and 5.87 ±1.47 hrs in 226 individuals with esp block.13 227 228 similar to our study altiparmak b et al, also observed that pecs group patients had lower 229 consumption of tramadol in postoperative period. in their study consumption of tramadol was 230 132.78 ± 22.44 mg in pecs group and 196 ± 27.03 mg in esp group (p = 0.001).23 231 232 gad m et al also observed that patients in pecs group had lower consumption of morphine 233 in postoperative period in comparison to esp block patients.24 234 235 regarding complications, we have not encountered any procedure related complications in 236 any of group which is similar to other studies. 237 238 the limitation of our study is that we used original version of qor-40 score which is in 239 english and score was filled by clinician verbally translating it into regional language. so it 240 might have affected the interpretation of score. other limitations of our study were its small 241 sample size and single-centric approach. another limitation was that the block was given 242 after inducing the patients so we could not access the level of sensory block. 243 244 conclusion 245 to conclude, both erector spinae and pectoralis blocks in comparison to control group are 246 effective for improving postoperative quality of recovery after modified radical mastectomy. 247 but, in pectoralis blocks group time to first rescue analgesic was higher and requirement of 248 rescue analgesic was lesser in comparison to erector spinae block. as our study is single 249 centred, a multicentric study with large sample size is required for generalizability of results. 250 251 conflicts of interest 252 the authors declare no conflict of interests. 253 254 funding 255 no funding was received for this study. 256 257 author contributions 258 collection of data and drafting the manuscript was done by mhm. analysis and 259 interpretation of data were handled by mhm and rv. rv, h, ds, ss and ks contributed to 260 the concept and design as well as the critical revision of the manuscript. all authors approved 261 the final version of the manuscript. 262 263 references 264 1. ferlay j, soerjomataram i, dikshit r, eser s, mathers c, rebelo m, et al. cancer 265 incidence and mortality worldwide: sources, methods and major patterns in 266 globocan 2012. int j cancer. 2015;136(5):e359–86. 267 2. sung, h, ferlay, j, siegel, rl, laversanne, m, soerjomataram, i, jemal, a, bray, 268 f. global cancer statistics 2020: globocan estimates of incidence and mortality 269 worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021: 71: 209249. 270 3. bland ki, de la torre ji, copeland em, klimberg vs, boneti c, vasconez lo. general 271 principles of mastectomy: evaluation and therapeutic options. in the breast: 272 comprehensive management of benign and malignant diseases. elsevier inc. 2018. p. 273 386-421 274 4. fecho k, miller nr, merritt sa, klauber-demore n, hultman cs, blau ws. acute and 275 persistent postoperative pain after breast surgery. pain med. 2009 may-jun;10(4):708 276 5. kehlet h, jensen ts, woolf cj. persistent postsurgical pain: risk factors and prevention. 277 lancet. 2006 may;367:1618-25. 278 6. gan tj. poorly controlled postoperative pain: prevalence, consequences, and prevention. 279 j pain res. 2017 sep 25;10:2287-2298. 280 7. brennan f, carr db, cousins m. pain management: a fundamental human right. anesth 281 analg. 2007 jul;105(1):205-21. 282 8. onaka h, ishikawa m, mizuguchi y, et al. evaluation of postoperative pain control and 283 quality of recovery in patients using intravenous patient-controlled analgesia with 284 fentanyl: a prospective randomized study. j nippon med sch 2016; 83:158–166. 285 9. myles ps, weitkamb b, jones k, melick j, hensen s. validity and reliability of a post-286 operative quality of recovery score: the qor-40. br j anaesth 2000;84:11-5. 287 10. myles ps, hunt jo, fletcher h, solly r. relation between quality of recovery in 288 hospital and quality of life at 3 months after cardiac surgery. anesthesiology 289 2001;95:862-7. 290 11. nair g, wong dj, chan e, alexander t, jeevananthan r, pawa a. mode of 291 anesthesia and quality of recovery after breast surgery: a case series of 100 292 patients. cureus. 2021 mar 11;13(3):e13822. 293 12. yao y, li h, he q, chen t, wang y, zheng x. efficacy of ultrasound-guided erector 294 spinae plane block on postoperative quality of recovery and analgesia after modified 295 radical mastectomy: randomized controlled trial. reg anesth pain med. 2019 nov 296 2:rapm-2019-100983. 297 13. sinha c, kumar a, kumar a, prasad c, singh pk, priya d. pectoral nerve versus 298 erector spinae block for breast surgeries: a randomised controlled trial. indian j 299 anaesth 2019; 63:617-22 300 14. kaye ad, patel n, bueno fr, hymel b, vadivelu n, kodumudi g, et al.effect of 301 opiates, anesthetic techniques, and other perioperative factors on surgical cancer 302 patients. ochsner j. 2014;14(2):216-28. 303 15. xu l, xie x, gu x. dexamethasone for preventing postoperative nausea and vomiting 304 after mastectomy. medicine (baltimore). 2020 jul 24;99(30):e21417. 305 16. poleshuck el, katz j, andrus ch, hogan la, jung bf, dworkin rh. risk factors for 306 chronic pain following breast cancer surgery: a prospective study. j pain 2006;7:626-34 307 17. schnabel a, reichl su, kranke p, pogatzki-zahn em, zahn pk. efficacy and safety of 308 paravertebral blocks in breast surgery: a meta-analysis of randomized controlled trials. br 309 j anaesth. 2010;105(6):842-52. 310 18. doss nw, ipe j, crimi t, rajpal s, cohen s, fogler rj, et al. continuous thoracic 311 epidural anesthesia with 0.2% ropivacaine versus general anesthesia for 312 perioperative management of modified radical mastectomy. anesth analg. 313 2001;92:1552–7. 314 19. smith c. manion, timothy j. brennan, bruno riou; thoracic epidural analgesia and 315 acute pain management. anesthesiology 2011; 115:181–188. 316 20. bashandi gm, abbas dn. pectoral nerves i and ii blocks in multimodal analgesia 317 for breast cancer surgery: a randomized clinical trial. reg anesth pain med 2015; 40: 318 68-74. 319 21. ultrasound guided erector spinae plane block reduces postoperative opioid consumption 320 following breast surgery: a randomized controlled study. j clin anesth. 2018 nov;50:65-321 68. 322 22. kamiya y, hasegawa m, yoshida t, takamatsu m, koyama y. impact of pectoral nerve 323 block on postoperative pain and quality of recovery in patients undergoing breast cancer 324 surgery: a randomised controlled trial. eur j anaesthesiol. 2018 mar;35(3):215-223 325 23. altıparmak b, korkmaz toker m, uysal ai̇, turan m, gümüş demirbilek s 326 comparison of the effects of modified pectoral nerve block and erector spinae plane 327 block on post-operative opioid consumption and pain scores of patients after radical 328 mastectomy surgery: a prospective, randomized, controlled trial. j clin anesth. 329 2019 may;54:61-65. 330 24. gad m, abdelwahab k, abdallah a, abdelkhalek m, abdelaziz m. ultrasound-331 guided erector spinae plane block compared to modified pectoral plane block for 332 modified radical mastectomy operations. anesth essays res. 2019;13(2):334-339. 333 334 figure 1: consort flow chart 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 assessed for eligibility (n= 105 ) randomized(n=90) excluded(n=15) not meeting exclusion criteria(n=10) declined to participate(n=5) allocated to pecs block(n= 30 ) received pecs block (n= 30 ) did not receive pecs block (n= 0) allocated to erector spinae block(n= 30 ) received erector spinae block (n= 30 ) did not receive erector spinae block (n= 0 ) lost to follow-up (n= 0) discontinued intervention (n= 0 ) lost to follow-up (n= 0) discontinued intervention (n= 0 ) analysed (n= 30 ) excluded from analysis (n= 0 ) allocated to control group (n= 30 no intervention (control group) (n= 30 ) analysed (n= 30 ) excluded from analysis (n= 0 ) lost to follow-up (n= 0) analysed (n= 30 ) excluded from analysis (n= 0 ) table 1: demographic profiles 369 group-i(pecs group) [n=30] group-ii(esp group) [n=30] groupiii(control group) [n=30] p-value age(in years) 43.52±9.6 42.26±7.64 44.13±8.9 f=0.3563 p=0.7013# weight (in kg) 59.4±9.1 57.2±5.28 56.71±8.1 f=1.048 p=0.3551# height (in cms) 162.6±7.6 159.0±46.5 156.21±3.9 f=0.4132 p=0.66283# bmi(kg/m2) 22.5±3.8 23.9±3.6 22.0±3.1 f=1.118 p=0.21963# asa i:ii 24:6 26:4 25:5 x=0.48 p=0.7866# duration of anaesthesia(in minutes) 86.8±18.1 89.4±19.4 87.7±17.5 f=0.1553 p=0.8564# *p value< 0.05= significant, #p value> 0.05= non-significant 370 371 table 2: tabular presentation of mean global qor-40(0-200) of group-i, group-ii and 372 group-iii patients 373 global qor-40 (0-200) group-i(pecs group) [n=30] group-ii(esp group) [n=30] groupiii(control group) [n=30] p-value pre-op 186.63±7.78 185.53±6.73 186.34±7.56 f=0.1795 p=0.8360 ¥p=0.8322, €p=0.9873,£p=0.9051 at 24 hrs 183.64±6.36 179.68± 6.38 171.37±6.88 f=27.47 p<0.0001* ¥p=0.0551,€p<0.0001*,£p<0.0001* *p value< 0.05= significant, #p value> 0.05= non-significant 374 ¥group-i vs group-ii, € group-i vs group-iii, £ group-ii vs group-iii 375 376 377 378 379 380 381 382 383 table 3: time to first rescue analgesic requirement and total rescue analgesic in first 24 hrs 384 groupi(pecs group) [n=30] group-ii(esp group) [n=30] groupiii(control group) [n=30] p-value time to first rescue analgesics requirement(hrs) 6.53±2.78 4.05±2.91 2.15±1.51 f=23.5 p<0.0001* ¥p=0.0006*,€p<0.0001*,£p=0.0108* total rescue analgesics requirement (in mg) in first 24 hrs 137.28±31.46 189.46±42.98 229.57±46.80 f=38.34 p<0.0001* ¥p<0.0001*,€p<0.0001*,£p=0.0008* *p value< 0.05= significant, #p value> 0.05= non-significant, 385 ¥group-i vs group-ii, € group-i vs group-iii, £ group-ii vs group-iii 386 387 table 4: tabular presentation of mean vas score of group-i, group-ii and group-iii 388 patients 389 vas score groupi(pecs group) [n=30] groupii(esp group) [n=30] groupiii(control group) [n=30] p-value at 1 hour 0±0 0±0 0±0 -- at 2 hour 0±0 0±0 0±0 -- at 4 hour 0.52±0.37 0.54±0.82 0.59±0.21 f=0.1371 p=0.8721 at 6 hour 1.04±0.19 2.01±0.54 4.13±1.45 f=92.48 p<0.0001* at 12 hour 1.44±0.54 2.28±0.90 4.80±1.09 f=120.2 p<0.0001* at 24 hour 2.10±1.14 3.41±1.19 4.94±1.95 f=27.9 p<0.0001* *p value< 0.05= significant, #p value> 0.05= non-significant, 390 ¥group-i vs group-ii, € group-i vs group-iii, £ group-ii vs group-iii 391 392 393 394 395 396 397 398 399 figure 2: mean pulse rate in beats per minute between three groups 400 401 402 figure 3: mean arterial pressure in mm of hg between three groups 403 2008-issue1.indd efficacy and safety of selective laser trabeculoplasty as a primary procedure for controlling intraocular pressure in primary open angle glaucoma and ocular hypertensive patients mohamed a-m s mahdy1, 2 1department of ophthalmology, rustaq hospital, sultanate of oman; 2department of ophthalmology, al-hussein university hospital, al-azhar university, cairo, egypt email: mmahdy67@gmail.com sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 53-58 sultan qaboos university© submitted 18th october 2007 accepted 26th january 2008 c l i n i c a l a n d b a s i c r e s e a r c h عالجى االنتقائى كاجراء الليزر باستخدام التَّرْبيق ْبُ رَأ وأمان فعالية الضغط مرتفع الزاوية مفتوح الزَرَق فى العني ضغط للتحكم فى اولى العني ضغط ارتفاع ومرضى السيد مهدى املنعم عبد محمد ومرضى (مرتفع الضغط) الزاوية مفتوح االولي للزَرَق أولى كعالج اإلنتقائى الليزر ــتخدام بإس التَّرْبيق ــالمة رَأْبُ وس فعالية امللخص: الهدف: تقييم 2005 يناير من الفترة خالل (25 مريضا) 35 عينا التدخلية على االستباقية الطولية الدراسة هذه في البحث الطريقة: اجرى العني. ضغط إرتفاع عن وافية معلومات بعد اعطاء من املرضى ــتنيرة املس املوافقة اخذت . (مصر) بالقاهرة العني مركز الليزر في كل عمليات .أجريت 2006 اكتوبر الى 7 مرضى و ــط املتوس الضغط اخلفيف الى ذات الزاوية مفتوح الزرق من يعانون (25 عينا) 18 مريضا البحث ــمل ش . التربيق رأب في البحث طريقة الغربالية للزاوية بالطبقة ثقوب بإستخدام الليزر اإلنتقائى إلحداث املذكورين للمرضى التربيق رأب إجراء مت العني. ضغط إرتفاع من يعانون (10 عيون) للعملية. احملتملة االختالطات ومعرفة بعد العملية ، ضغط العني لتقييم انخفاض 12 شهرا على مدى املرضى متابعة و متت 180 درجة مدى على زئبقى 19.34±1.89 ملم إلى العملية قبل زئبقي 26.78±3.13 ملم من املعياري) االنحراف ± (املتوسط العني ضغط إنخفاض النتائج: لوحظ الثقة (فترة زئبقي 7.44 ملم ــهرا ش عشر اجلراحة بإثنى بعد العني ضغط إنخفاض ــط متوس وكان .(p<0.001) ــهرا ش ــر عش بإثنى بعد العملية 30% ≤ ب العني ضغط فيهم إنخفض (22 عينا) ــاالت احل %62.9 من ــهرا) (12 ش نهاية فترة املتابعة فى . زئبقي) ــم 6.45 8.41 مل ــني %95 ب التربيق اخلالصة: رأب . قيمته قبل العملية ≥%25 من ب العني ضغط فيهم إنخفض ــا) (27 عين احلاالت %77.1 من و العملية, قبل ــه قيمت ــن م إرتفاع ومرضى الزاوية مفتوح ــزرق ال مرضى عالج في أولى ــتخدامه كإجراء اس العني، وميكن ضغط خلفض فعالة طريقة اإلنتقائى ــزر ــتخدام اللي باس وميكن آمنة طريقة رأب التربيق في اإلنتقائى الليزر ــتعمال اس أن ــتنج نس البحث أثناء لوحظت التى القليلة اجلانبية األعراض ضوء العني.وفى ضغط . العني ضغط إرتفاع ومرضى الزاوية مفتوح الزرق ملرضى العني ضغط خلفض أولي بديل كعالج استعماله التربيق. رأب ، إرتفاع ضغط العني الليزر, جراحة ، العني ضغط ، الزاوية الكلمات: الزرق مفتوح مفتاح abstract objective: assessment of the potential efficacy and safety of selective laser trabeculoplasty (slt) as a primary therapeutic modality for lowering the intraocular pressure (iop) in high tension open angle glaucoma (oag) and ocular hypertensive patients (oht). methods: twenty five patients (35 eyes) were enrolled in this prospective interventional longitudinal clinical study, undertaken during the period january 2005 to october 2006. all the laser procedures were done in the oyoon eye center in cairo, egypt. informed consent was taken from the patients after explanation of the procedure. eighteen patients (25 eyes) had mild to moderate high tension open angle glaucoma, and there were 7 ocular hypertensive patients (0 eyes). participants underwent selective laser trabeculoplasty (slt) 80 degrees and followed up over a period of 2 months to assess the intraocular pressure lowering effect after slt. possible complications of the procedure were reported. results: the intraocular pressure (mean ± standard deviation [stdev]) decreased from baseline pre-operative value of 26.78±3.3 mm hg to 9.34±.89 mm hg 2 months after slt (p<0.00). the average reduction in intraocular pressure (iop) was 7.44 mm hg (95% confidence interval 6.45 8.4 mm hg). by the end of the follow up period (2 months), 62.9% of cases (22 eyes) showed iop decrease by ≥ 30% from the baseline value, and 77.% of cases (27 eyes) m o h a m e d a m s m a h d y 54 intraocular pressure (iop) is one of the most challenging issues in ophthalmology. for a long time, primary control of iop in primary open angle glaucoma (poag) was medical. laser treatment was indicated in case of a noncompliant patient, or with the aim of cutting down the cost of medications, or to convert the noncompliant patient with multiple topical medications to a compliant one with one topical medication. for these cases, argon laser trabeculoplasty (alt) was introduced by wise and witter as early as 1979.1 eyes that were treated with alt tended to have better results, in terms of lower iop and better functional and morphometric status, than medically treated eyes;2 however, late failure was common. clinical as well as histological studies of alt demonstrated that late failure of alt was due to destruction of the uveoscleral meshwork with surrounding thermal damage which, in addition to membrane formation over the meshwork by migrating endothelial cells, leads to long term loss of effect.3, 4 other types of laser treatment modalities, including diode laser, were tried, but with limited success.3 in 1998, a new laser trabeculoplasty treating modality was introduced by marc latina and his colleagues.4 in this modality of selective laser trabeculoplasty (slt), a 532 nm, q switched, frequency doubled, neodymium:yittrium-aluminium-garnet (nd:yag) laser is used. slt selectively targets pigmented tm cells (sparing the non-pigmented cell) producing selective photolysis without causing structural or coagulative damage. absorption of radiant energy by melanosomes of the pigmented tm cells leads to rupture of these melanosomes and celluar destruction (photolysis). the ruptured melanosomes liberate metalloproteasis and other proteolytic enzymes. these liberated enzymes, as well as other factors, trigger an inflammatory response mediated by macrophages and other phagocytic cells. the phagocytic action in and around the trabecular meshwork is responsible for increased aquous outflow with reduction of iop.4 encouraging results, with moderate iop reduction and minimal side effects had been shown.7, 8 since there is practically no thermal coagulative damage to the trabecular meshwork, it might be possible to repeat slt in eyes previously treated with alt or slt. m e t h o d s the objective of the study was to assess the potential efficacy of selective laser trabeculoplasty (slt) as a primary therapeutic modality for lowering the inadvances in knowledge • selective laser trabeculoplasty is a new modality of laser treatment for lowering intraocular pressure both in high tension glaucoma and ocular hypertension. • selective laser trabeculoplasty has lesser side effects as compared to the other laser therapeutic modalities. • a target intraocular pressure lowering effect of 25-30 % can be reached and maintained over a period of one year in a good percentage of cases (62.9% to 77.1% of cases). applications to patient care • selective laser trabeculoplasty is a safe and easy primary therapeutic modality for treatment of open angle glaucoma and ocular hypertensive patients. • selective laser trabeculoplasty can be used as a safe alternative to argon laser trabeculoplasty and medical treatment of open angle glaucoma and ocular hypertensive patients. • if we consider the relative easiness of selective laser trabeculoplasty procedure and its safety, the costs of glaucoma patients’ care (antiglaucoma medications) can be minimized and complications of surgical treatment can be avoided or at least delayed. showed iop decrease by ≥ 25% of baseline iop. conclusion: selective laser trabeculoplasty is an effective iop lowering modality. it can be used as a primary treatment for open angle glaucoma and ocular hypertensive patients. if the minimal side effects reported are considered, it can be concluded that slt has a potential safety to be used as primary alternative treatment for open angle glaucoma and ocular hypertensive patients. keywords: glaucoma, open-angle; intraocular pressure; laser surgery; ocular hypertension; trabeculoplasty. e f f i c a c y a n d s a f e t y o f s e l e c t i v e l a s e r tr a b e c u l o p l a s t y a s a p r i m a r y p r o c e d u r e f o r c o n t r o l l i n g i n t r a o c u l a r p r e s s u r e i n p r i m a r y o p e n a n g l e g l au c o m a a n d o c u l a r h y p e r t e n s i v e pat i e n t s 55 traocular pressure (iop) in high tension open angle glaucoma (oag) and ocular hypertensive patients (oht). also complications of this procedure are reported. the main outcome measure was the intraocular pressure before and after slt. in this prospective clinical study, twenty five patients (35 eyes) were enrolled: 18 patients (25 eyes) with mild to moderate high tension open angle glaucoma, and 7 ocular hypertensive patients (10 eyes). all these patients were treated at the oyoon eye center in cairo, egypt, during the period january 2005 to october 2006. informed consent was taken from each patient after explanation of the procedure high tension glaucoma patients were defined as those with the following characteristics: 1) intraocular pressure (iop) ≥ 22 mmhg on at least two measurements, measured on at least two separate occasions; 2) visual field changes (in standard achromatic automated perimetry) that fulfilled the minimal criteria for glaucomatous visual field (vf) damage according to hodapp, parrish and anderson;5 3) optic nerve head and/or retinal nerve fiber layer changes characteristic for glaucoma, based on clinical stereobiomicroscopic slit lamp examination: excavation; notching; focal or diffuse atrophy of neuro-retinal rim area; vertical cup/ disc ratio more than 0.6; cup/disc asymmetry between fellow eyes greater than 0.2 and/or localized slit; or wedge defect; or generalized atrophy of the retinal nerve fiber layer as seen with slit lamp biomicroscopy. all patients had open anterior chamber angle. ocular hypertensives were defined as those subjects with elevated iop ≥ 22 mmhg, on at least two measurements, measured on at least two separate occasions. in addition, patients should have no visual field (vf) changes as mentioned in the glaucoma group, and no optic nerve head or retinal nerve fiber layer changes suggestive of glaucoma. all patients enrolled in the study were subjected to full ophthalmic assessment including visual acuity, iop measurements, slit lamp biomicrospcopic optic nerve head assessment, and gonioscopy to assure that the anterior chamber was opened, in addition to visual field examination (standard achromatic perimetry). the surgical procedure was done in all cases with a coherent selecta 7000 laser system (lumenis, coherent, inc, ca, usa). this is a frequency doubled, q-switched nd:yag laser wavelength 532 nm, with a fixed pulse duration of 3 ns, and spot size of 400 µm. the laser system is coupled to a slit lamp delivery system with a helium-neon laser (hene) aiming beam. for preoperative preparation, the eye was anaesthetised with topical anaesthesia (novesine hydrochlototal number: patient (eyes) 25 (35) primary open angle glaucoma 13 (15) pseudoexpholiation 3 (6) pigmentary glaucoma 2 (4) ocular hypertensive 7 (10) age: mean (stdev) 57.44 (8.99) sex: number (percentage) male 14 (56%) female 11 (44%) vertical cp/disc ratio, mean (range) primary open angle glaucoma 0.64 (0.4 0.8) ocular hypertensive 0.42 (0.2 0.6) pre-operative intraocular pressure, mean (sd) 26.8 (3.25) pre-operative best corrected visual actuity, mean (sd) 0.84 (0.18) vf characteristics for the open angle glaucoma group, mean (sd) mean defect (md) -5.19 (2.69) pattern standard deviation (psd) 6.66 (3.65) table 1: preoperative demographic characteristics and data figure 1: mean ± stdev of pre-operative intraocular pressure and 12 months post-operative after slt in mmhg m o h a m e d a m s m a h d y 56 ride). no alpha agonist was used as a routine preoperative preparation. the procedure was as follows: with the patient seated at the slit lamp, a three mirror gonio-lens was placed on the eye, while methylcellulose was used as a coupling medium between the lens and the eye. then, the laser was focused on the trabecular meshwork using the hene aiming beams. with the 400 µm spot size, the inferior half of the trabecular meshwork was irradiated with laser pulses, starting at the three o’clock position and proceeding till nine o’clock. the laser energy was initially set at 0.8 mj. if a cavitation bubble appeared (overexposure) the laser energy was reduced by 0.1 mj steps until no bubble formation was observed and treatment was continued at this energy level. if no cavitation bubble was observed, the pulse energy was increased by of 0.1 mj steps until bubble formation was observed then decreased again by 0.1 mj. during whole laser application, bubble formation was monitored with each pulse for the appearance of a bubble; if a bubble appeared, the pulse energy was decreased as described above. non-overlapping 46–55 laser spots were applied over the entire inferior 180 degrees of the trabecular meshwork. at the end of the laser procedure, a single drop of prednisolone acetate 1% was instilled into the eye. postoperatively, the patients were prescribed dexamethasone 0.1% eye drops 4 times a day for 7 days. then the patients were examined at 1 hour, 1 day, 1 week and followed up at 1, 3, 6, and 12 months intervals. at each visit, patients underwent a full ophthalmic examination, which included visual acuity measurement, slit lamp biomicroscopy. goldmann applanation tonometry, gonioscopy, and funduscopy were performed at 12 months. any symptoms of ocular complications were reported. in case of failure to reach an adequate iop lowering effect after 3 months, an additional session of slt was done or medical treatment was resorted to according to the surgeon’s decision. stati sti c a l a n a ly si s spss 11.01 was used and a paired student’s t-test was used for comparison between preand postoperative intraocular pressure values. a p value of <0.05 was considered statistically significant. r e s u l t s in 35 eyes with high tension oag and ocular hypertensive patients (25 patients, 14 males and 11 females), slt was done and the patients followed up over a pefigure 2: the mean intraocular pressure changes over time during the follow up period e f f i c a c y a n d s a f e t y o f s e l e c t i v e l a s e r tr a b e c u l o p l a s t y a s a p r i m a r y p r o c e d u r e f o r c o n t r o l l i n g i n t r a o c u l a r p r e s s u r e i n p r i m a r y o p e n a n g l e g l au c o m a a n d o c u l a r h y p e r t e n s i v e pat i e n t s 57 riod of 12 months. the demographic characteristics for these patients are shown in table 1. after slt, the iop (mean ± stdev) decreased from baseline preoperative value of 26.78±3.13 mm hg to 19.34±1.89 mm hg 12 months after slt (p<0.001) as shown in figure 1. the mean iop lowering effect was 7.44 mm hg (95% confidence interval 6.45 8.41 mm hg). by the end of follow up period (12 months), 62.9% of cases (22 eyes) showed iop decrease by ≥ 30% from the baseline value, and 77.1% of cases (27 eyes) showed iop decrease by ≥ 25% of baseline iop. the mean iop changes during the follow up period are shown in figure 2. it has been reported that 5 cases (14.3%) exhibited < 20% reduction of iop; one of them did not show any decrease in iop from the baseline measurement. in case of failure to reach 25% reduction of baseline iop after 3 months (6 eyes 17.1%), the slt procedure was repeated in the superior 180 degrees. three cases failed to complete the 12 months follow up period. some complications occurred with this procedure. iop spikes of 4-7mm hg at 1 hour post-op was detected in 5 cases (14.3%). mild uveitis was reported with mild ac flare and cells in 25 cases (71.4%); this was controlled with topical steroid within 24-96 hours. ocular discomfort, pain and conjunctival redness were detected in 23 cases (65.7%). there were no differences in terms of mean snellen equivalent, best corrected visual acuities, measured cup/disc ratios and average values of mean defects (decibels). d i s c u s s i o n in this prospective study, slt demonstrated an effective iop lowering effect. it lowers the iop (mean ± stdev) from baseline pre-operative value of 26.78±3.13 mm hg to 19.34±1.89 mm hg 12 months after slt (p<0.001). the magnitude of iop lowering effect was 7.44 mm hg. this is in agreement of the results reported by melamed et al.6 their results demonstrated an iop lowering effect of 7.7 ±3.5 mmhg in a similar mixed group of oag and oht patients. another study published by nagar et al,7 showed that the iop lowering effect in 180º slt treated group was significantly less than in their medically treated group, to whom latanoprost was administered; however, the difference between the 360º treated group and the latanoprost group did not reach a statistical significance level, both of the treatment modalities showing similar results. also they showed an iop reduction by >30% from the baseline value in 59% of cases, which is in agreement with our study results. these showed an iop decrease by ≥ 30% from the baseline value in 62.9% of cases, while 77.1% of cases showed an iop decrease by ≥ 25% of baseline iop. mcilraith et al in 2006, reported similar results of a 31% reduction of baseline iop as compared to 30% reduction with latanoprost.8 contradictory results were reported in a retrospective study by song et al.9 they showed a high failure rate in slt treated patients, as 86% of cases showed <20% iop reduction. the explanation for this is that the studied group of patients was not treated similarly; some of them underwent 180º while other patients were treated with 90º. also, most of them had a lower baseline iop before treatment which was a predictor for failure. their observation that lower baseline iop is a predictor for failure is in agreement with our study results, which showed that 5 cases (14.3%) exhibited < 20% reduction of iop, while one of them did not show any decrease in iop from the baseline measurement. these cases in our study were those who had lower iop values and some of them (2 eyes) were patients with pseudoexfoliation glaucoma for whom slt was repeated. this is in agreement with the study of gracner, who demonstrated a poor response of patients with capsular glaucoma to slt.10 in contrast to this, patients with pigmentation of the drainage angle (pigmented races, capsular glaucoma and pigment dispersion syndrome) showed better responses to alt as compared to slt.11 this is logical with alt where coagulative damage is known to occur. however, in slt the mechanism is suggested to be at a cellular level and debris in the drainage angle in terms of iris pigment and pseudoexfoliation material may prevent adequate laser tissue interaction. c o n c l u s i o n in view of the results of our study, which showed that 77.1% of cases showed iop decrease by ≥ 25% of baseline iop, we can conclude that slt is an effective iop lowering modality. it can be used as a primary treatment for open angle glaucoma and ocular hypertensive patients. if we consider the minimal side effects reported in our study and also in other studies published before, minimal or no coagulative damage is produced, so no subsequent trabecular meshwork fibrosis is produced. it can therefore be concluded that slt is a safe alternative to alt and medical treatment m o h a m e d a m s m a h d y 58 of open angle glaucoma and ocular hypertensive patients. r e f e r e n c e s 1. wise jb, witter sl. argon laser therapy for open angle glaucoma: a pilot study. arch ophthalmol 1979; 97:319322. 2. the glaucoma laser trail research group. the glaucoma laser trail (glt) and glaucoma laser trial follow up study: 7 results. am j ophthalmol. 1995; 120:718731. 3. mchugh d, marshall j, ffytche tj, hamilton pa, raven a. diode laser trabeculoplasty (dlt) for primary open angle glaucoma and ocular hypertension. br j ophthalmol 1990; 74:743-747. 4. latina ma, park c. selective targeting of trabecular meshwork cells: in vitro studies of pulsed and cw laser interactions. exp eye res 1995; 60:359-371. 5. hodapp e, parrish rk, anderson dr. clinical decisions in glaucoma. st. louis mo: cv mosby, 1993. 6. melamed s, ben simon gj, levkovitch-verbin h. selective laser trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. arch ophthalmol 2003; 121:957-960. 7. nagar m, ogunyomade a, o’brart dp, howes f, marshall j. a randomised, prospective study comparing selective laser trabeculoplasty with latanoprost for the control of intraocular pressure in ocular hypertension and open angle glaucoma. br j ophthalmol 2005; 89:1413-1417. 8. mcilraith i, strasfeld m, colev g, hutnik cm. selective laser trabeculoplasty as initial and adjunctive treatment for open-angle glaucoma. j glaucoma 2006; 15:124130. 9. song j, lee pp, epstein dl, stinnett ss, herndon lw, jr, asrani sg, et al. high failure rate associated with 180 degrees selective laser trabeculoplasty. j glaucoma 2005; 14:400-408. 10. gracner t. intraocular pressure response of capsular glaucoma and primary open-angle glaucoma to selective nd:yag laser trabeculoplasty: a prospective, comparative clinical trial. eur j ophthalmol 2002; 12:287292. 11. ederer f, gaasterland da, dally lg, kim j, vanveldhuisen pc, blackwell b et al. the advanced glaucoma intervention study group (asis): 13. comparison of treatment outcomes within race: 10-year results. ophthalmology 2004; 111:651-664. whole1.indd abstract objective: it has been postulated that geographical locations of the herbs affect the constituents of their essential oils and thus the degree of their antimicrobial action. this study examine two samples of clove obtained from sri lanka and zanzibar and two samples of thyme from iran and oman to determine the antimicrobial potential of their extracted oils. method: the active agents in each plant were extracted by steam distillation and by boiling. the antimicrobial activities of the extracts were determined at neat and by two-fold dilutions in well agar diffusion technique using staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, streptococcus pyogenes, corynebacterium species, salmonella species, bacteroides fragilis and candida albicans. results: all oil extracts possessed antimicrobial activity against all bacteria and yeast tested. their water extracts exhibited lower antimicrobial activity, though thyme aqueous extract was active only against s. aureus. the lowest concentration of antimicrobial activity (0.% i.e., :024) was obtained with thyme oil extract using candida albicans. there was no significant difference in antimicrobial activity between clove obtained from sri lanka or zanzibar or thyme obtained from iran or oman. conclusion: our experiment showed that the country of origin of the herbs has no effect on their antimicrobial activity. however, further work is necessary to ascertain why candida albicans displayed remarkable degree of sensitivity with the extracts than all the other organisms test. keywords: thyme, clove, oil, extract, antimicrobial, oman, iran, sri lanka, zanzibar. antimicrobial activities of clove and thyme extracts *b c nzeako, zahra s n al-kharousi and zahra al-mahrooqui sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© the essential oil of thyme (thymus vul-garis) is utilized as a flavour enhancer in awide variety of foods, beverages, confectionery products and in perfumery for the scenting of soaps and lotions.1 it possesses some antiseptic, bronchiolytic, antispasmodic and antimicrobial properties that make it popular as a medicinal herb and as a preservative for foods.2,3 the therapeutic potential of thyme rests on its contents of flavonoids, thymol, eugenol, aliphatic phenols as well as saponins, luteolin and tetramethoxylated flavones.4,5 clove (syzygium aromaticum) on the other hand, is a plant widely cultivated in spice islands, indonesia, pemba and zanzibar, though earlier production of the plant was in china. like thyme, it is used in the seasoning of food.4,6 its antimicrobial potential was established when its essential oil extracts killed many gram department of microbiology and immunology, sultan qaboos university, college of medicine and health sciences, p.o.box 35, al-khod, muscat 123, sultanate of oman *to whom correspondence should be addressed. email: basil @squ.edu.om o r i g i n a l s t u d y والسعتر القرنفل ملشتقات للجراثيم املضادة الفعاليات درجة فعاليتها على يؤثر بدوره و هذا زيوتها اجلوهرية تؤثر على مكونات لألعشاب اجلغرافية أن املناطق مؤداها نظرية هناك املقدمة: كانت أمللخص: املضادة ملعرفة القابلية وعمان إيران من السعتر من وعينتني وزجنبار، النكا سري من كل من القرنفل من عينتني الهدف: اختبار للجراثيم. املضادة املضادة الفعاليات وحددت والغليان. التقطير بواسطة نبات كل من الفعالة العناصر استخلصت ألطريقة: املستخلصة. زيوتها في للجراثيم staphylococcus aureus pseudomonas) باستعمال (agar) آجر انتشار في تقنية الثنائي احمللول تخفيف بواسطة للمستخلص للجراثيم aeruginosa, escherichia coli, streptococcus pyogenes, corynebacterium species, salmonella species, bacteroides الدراسة. قيد كانت التي واخلمائر البكتريا لكل مضادة فعالية على حتتوي املستخلصات النتائج: كل .(fragilis and candida albicans فقط. الذهبية العنقودية جراثيم ضد فعالية لديه فكان املائي السعتر مستخلص أما اجلراثيم، ضد أقل فعالية لديها كان املائية املستخلصات الفعالية في معنوي فرق يوجد ال .(candida albicans) للسعتر باستخدام املشتق الزيتي في (٠٫١٪ أي ١:١٠٢٤) ضد اجلراثيم أقل فعالية وجدت اجلغرافية املنطقة أن جتربتنا أوضحت أخلالصة: عمان. أو ايران من املأخوذ السعتر وبني الزجنباري أو النكي السري القرنفل بني للجراثيم املضادة candida) تكون ملاذا ملعرفة أخرى بأعمال القيام الضروري من حال، على كل للجراثيم. املضادة فعاليتها على تؤثر ال األعشاب فيها تعيش التي اختبارها. مت التي الدقيقة األحياء كل من أكثر للمستخلصات ملموسة حساسية ذو (albicans b c n z e a k o , z a h r a s n a l k h a r o u s i a n d z a h r a a l m a h r o o q u i 34 positive and gram negative organisms including some fungi.6,7 the antimicrobial activity of clove is attributable to eugenol, oleic acids and lipids found in its essential oils.8 thyme oil extract failed to kill staphylococcus aureus, salmonella choleraesuis or klebsilela pneumoniae but stopped the growth of pseudomonas aeruginosa and candida albicans. while clove extracts were found to inhibit the growth of pseudomonas aeruginosa, candida albicans, staphylococcus aureus, salmonella choleraesuis, klebsiella pneumoniae,3 arora and kaur8 found the aqueous extracts of clove to possess no antimicrobial activity against pseudomonas aeruginosa, staphylococcus aureus or escherichia coli but possessed some activity against shigella flexneri. dorman and deans7 assessed the antibacterial activity of thyme, clove and other medicinal plants against 25 different genera of bacteria including animal and plant pathogens, food poisoning and spoilage bacteria using iso-sensitest agar. they found all the organisms tested against clove and thyme to be sensitive, with thyme exhibiting more antibacterial effect than clove. from the work of other investigators, it is observed that oil and water extracts of both clove and thyme kill many microorganisms. however, it is said that differences in major oil constituents and thus in antimicrobial effect is affected by differences in the geographical areas from where the plants were grown.9-11 thyme and clove are routinely used as food additives in omani food menus. the aim of this project is to assess the antimicrobial activity of water and oil extracts of thyme from oman and iran and clove from sri lanka and zanzibar using standard laboratory procedures. we hope to establish if differences exist in their respective abilities to exhibit some antimicrobial action since they come from various parts of the world. m e t h o d sources of thyme and clove thyme (thymus vulgaris) thyme used in this experiment came from oman and iran. the parts of the plant employed for the distillation of essential oils were leaves, stems and flowers. clove ( syzygium aromaticum) the buds were used and they came from zanzibar and sri lanka. extraction of essential oils about 20g of each herb soaked in distilled water was distilled in a stove still (steam distiller, locally fabricated). the volatile vapour that condensed at water temperature of 80oc was called essential oils. the clove buds were distilled in the same way as the thyme. the distilled oils were labeled and placed in a fridge until ready for use. extraction of essential oils by boiling about 20g of each herb were soaked in 50ml of distilled water and were subsequently boiled at 100oc for 15 minutes. the boiled extracts were allowed to cool at room temperature after which they were left at fridge temperature overnight to allow the solute particles to settle. the aqueous phases were pipetted, labeled and called aqueous extracts. they were kept in the fridge until ready for use. media diagnostic sensitivity test (dst, oxoid, uk) agar plates were used for the determination of zones of inhibition produced by each extract on the control and test organisms. blood agar were used for the preparation of pure cultures of bacteria while sabouraud plates (oxoid, uk) were used for c. albicans. control organisms the control organisms used for screening the extracts for the presence of antimicrobial activities were: staphylococcus aureua (nctc 6571), pseudomonas aeruginosa (nctc 10662) and escherichia coli (nctc 10418). these bacteria are routinely used in our laboratory as control organisms for antibiotic sensitivity testing of bacterial isolates from clinical specimens and they are usually sensitive to most antibiotics. test organisms the test bacteria were organisms kept as stock cultures in our laboratory and was made of: • streptococcus pyogenes • corynebacterium spp • salmonella spp • bacteroides fragilis • candida albicans inoculum prepar ation the control and test organisms were each plated on blood agar and incubated overnight at 37oc except c. albicans which was plated on sabouraud medium and incubated for 48 hours. suspensions of pure colonies in broth at 106 cfu/ml from growth on the plates a n t i m i c r o b i a l a c t i v i t i e s o f c l o v e a n d th y m e e x t r a c t s 35 were made using mcfarland’s turbidity standards (tube 0.5). screening of oil and aqueous extr ac ts oil extracts one hundred microlitres (100µl) of each oil extract were added to 100µl of 5% dimethylsulphoxide (dmso) to solubilize the extracts.3,9 the aqueous extracts were used without solubilization. each control organism (s. aureus (nctc 6571), p. aeruginosa (nctc 10662), e. coli (nctc 10418) was spread on dst agar using an inoculating rotator (bbl, usa ). wells of 4 mm were bored into each plate with sterile un-drawn. pasteur pipette and plugs were removed with sterile tips.5 one hundred microlitres (100µl) of each extract were put in triplicates into each plate of media. the plates were kept at room temperature for 15 minutes to allow the extracts to seep into the media. they were subsequently incubated at 37oc overnight. the concentration of organisms used for screening the extracts were cross checked using visible count method in which 3.3µl (3mm diameter loop) was plated on plates of blood agar in triplicates. counts were made after incubation at 37oc overnight. control for dmso made up of equal volumes of dmso and saline was put up as in the test. zones of inhibition or no inhibition produced by each extract were measured and average zone size was taken. determination of the antimicrobial concentration of each oil and water extracts the concentration end-points of the activity of the extracts were done using the organisms listed above. two-fold dilutions of the extracts except water extracts were first made in 5% (dmso) and were subsequently diluted in sterile saline using equal volumes of the extracts and saline to 0.1% (1:1024) dilution. twofold dilutions of aqueous extracts were made in saline. all dilutions were prepared fresh each time they were to be used. wells of 4 mm diameter were made on dsts which were swabbed with the appropriate organism at 106 cfu/ml as previously described. each well was separately filled with 100µl of each dilution in triplicates. controls for dmso were put up as previously described. the plates were incubated aerobically at 37oc overnight except for b. fragilis which were incubated anaerobicaly. zones of inhibition were measured and the average zone size of each dilution was taken. the end-point of activity for each extract was defined as the lowest dilution of the extract showing growth inhibition of the organisms. r e s u l t s screening of oil and aqueous extr ac ts dmso the dmso control showed no growth inhibition with any of the microorganism including c. albicans. control bacteria the zones of inhibition produced by the oil extracts with the control organisms varied from 14.7mm (p. aeruginosa) to 33.7mm (s. aureus). their water extracts produced zones between 10mm (e. coli) and 34.3mm (s. aureus). zone of 15.7mm was obtained with p. aeruginosa. determination of the antimicrobial concentr ation oil and water extr ac ts figures 1 represents the zones of inhibition produced by omani thyme oil (anticlockwise direction) at 0.78% (128) and 0.39% (256) against escherichia coli while figure 2 represents that of zanzibar clove oil at 1.56% (64) and 0.78% (128) against staphylococcus aureus. figure 3 shows zones of inhibition produced against pseudomonas aeruginosa by zanzibar (right) and sri lanka (left) clove water extracts at no dilutions. table 1 and figure 4 represent the concentration end-points of the antimicrobial activities of thyme and clove extracts using various organisms. all essential oils possessed antimicrobial activity against all bacteria and yeast tested. the sri lankan clove oils had concentration end points at 0.2% (512) with c. albicans while omani and iranian thymes oils had 0.1% (1024) respectively. however, the concentration end-points for the oils for various bacteria varied from 0.39% (256) to 1.56% (64) with corynebacteria spp. 0.39% (256), e. coli 0.78% (128), s. pyogenes 0.78% (128), p. aeruginosa 1.56% (64) to b. fragilis 1.56% (64) respectively. sri lankan and zanzibar clove oils had concentration end points of 1.56% (64) and 0.78% (128) respectively with s. aureus and salmonella spp while omani and iranian thymes had end-points of 0.39% (256) respectively. table 2, figure 5 show the antibacterial and antifungal activities of clove and thyme water extracts which were demonstrable only at neat dilutions for b c n z e a k o , z a h r a s n a l k h a r o u s i a n d z a h r a a l m a h r o o q u i 36 corynebacterium spp., e. coli and salmonella spp. no inhibition zones were demonstrable with c. albicans, s. pyogenes or b. fragilis. however, omani and iranian thyme water extracts each showed of some least activities at 25% (4) with s. aureus while sri lanka and zanzibar clove water extracts showed activities each at 6.25% (16) dilution. d i s c u s s i o n thyme and clove oil extracts are known to possess some antimicrobial activities and are used in various food preparations as flavour enhancers and in herbal medicine.1-3 though the modes of action of the extracts are not known, their antimicrobial agents include thymol, terpenes, eugenol, flavones, glycosides of phenolic monoterpenoids and aliphatic alcohols among other elements.4,5,8 these substances acting alone or in combination may result in a broad spectrum of antimicrobial activity exhibited for both bacteria and fungi. thyme and clove oils possess antimicrobial activity against s. aureus, e. coli, p. aeruginosa as well as against s. pyogenes, corynebacterium, salmonella, bacteroides and c. albicans at various dilufigure 1. zones of inhibition produced by omani thyme oil (anticlockwise direction) against e. coli at 0.78% (128) and 0.39% (256) dilutions plant extract staphylococcus aureus streptococcus pyogenes corynebacterium spp escherichia coli pseudomonas aeruginosa salmonella spp bacteroides fragilis candida albicans clove (sri lanka) 1.56 (64) 0.78 (128) 0.39 (256) 0.78 (128) 1.56 (64) 0.78 (128) 1.56 (64) 0.20 (512) clove (zanzibar) 1.56 (64) 0.78 (128) 0.39 (256) 0.78 (128) 1.56 (64) 0.78 (128) 1.56 (64) 0.20 (512) thyme (oman) 0.39 (256) 0.78 (128) 0.39 (256) 0.78 (128) 1.56 (64) 0.39 (256) 1.56 (64) 0.10 (1024) thyme (iran) 0.39 (256) 0.78 (128) 0.39 (256) 0.78 (128) 1.56 (64) 0.39 (256) 1.56 (64) 0.10 (1024) ( ) double dilution end-points table 1. the end point of antimicrobial activity of clove and thyme oils at % v/v dilution. figure 2. zones of inhibition produced by clove oil (clockwise direction) against s. aureus, 1.56% (64) and 0.78% (128) dilutions a n t i m i c r o b i a l a c t i v i t i e s o f c l o v e a n d th y m e e x t r a c t s 37 tions of the extracts [table 1, figure 4]. these findings agree with the work of other workers.7-9 in this study, c. albicans was found to be the most susceptible to thyme and clove oil with concentration end-points of 0.1% (1024) and 0.2% (512) respectively. similar findings were reported by other workers.9,12,13 therapeutic agents with high killing propensity for fungi are few. the reason why yeast is more susceptible to the extracts than bacteria is unclear but it may be that at any given time, these oils may break up the structural integrity of c. albicans faster than they dissociate bacteria. in this study, the incubation time and temperature were the same for bacteria and fungi. the inhibition zones obtained with thyme oil against p. aeruginosa, salmonella spp and s. aureus were greater than those obtained by other workers3,14. the differences may be due to the methods used in solubilizing the oils to obtain hydrophilic molecules. we observed that dissolving the extracts in dmso produced higher zones than using tween 20, though hili et.al.9 obtained faster killing of bacteria in the absence of dmso. the study, using t-test at 95% level, demonstrates that there is no significant difference (p< 0.05) in antimicrobial activities of cloves obtained from sri lanka and zanzibar or between thyme from oman and iran [table 1, figure 4]. the activities of water extracts differed from that of oil extracts where all the organisms tested produced zones of inhibition [table 2, figure 5]. clove water extract showed inhibitions with all the organisms tested except with s. pyogenes, b. fragilis and c. albicans. thyme water extract possessed antimicrobial activity only against s. aureus. it is therefore an extract with figure 4. the end point of antimicrobial activity of clove and thyme oils at v/v dilution figure 3. zones of inhibition produced by zanzibar (right) and sri lanka (left) clove water extracts against pseudomonas aeruginosa b c n z e a k o , z a h r a s n a l k h a r o u s i a n d z a h r a a l m a h r o o q u i 38 limited or narrowed antimicrobial activity. this observation is in contrast with the finding of gislene15 where extracted materials contained agents that killed salmonella, c. albicans, p. aeruginosa and e. coli. the difference in the individual findings may be due to the differences in the methods of extraction. in our study, water was used for the extraction whereas in gislene’s15 study, ethanol was used. moreover, the water extraction method in our finding was not as good as extraction by distillation method [table 1, figure 4] where the extracted oils contained antimicrobial agents for all the organisms tested. the reason for poor antimicrobial activity exhibited by the water extracts is attributable to the evaporation of the essential active agents during boiling. there was no significant difference using student ttest at 95% level (p<0.05) between clove water extract from sri lanka and zanzibar or thyme water extract from oman and iran [table 2, figure 5]. in summary, our work showed that differences in antimicrobial activities do not exist between thyme (thymus vulgaris) obtained from oman and iran or clove (syzygium aromaticum) obtained from sri lanka and zanzibar. however, our work does not rule out differences in the constituents of oils within species. besides possession of antimicrobial action, essential oils of herbs function as phytoprotective agents, defending the plant from herbivores and lethal pathogens.16 plant extract staphylococcus aureus streptococcus pyogenes corynebacterium spp escherichia coli pseudomonas aeruginosa salmonella spp bacteroides fragilis candida albicans clove (sri lanka) 6.25% (16) neat neat 6.25 (16) neat clove (zanzibar) 6.25% (16) neat neat 6.25 (16) neat thyme (oman) 25.00 %(4) thyme (iran) 25.00 %(4) ( ) double dilution end-points figure 5. the end point of antimicrobial activity of clove and thyme water extract at v/v dilution table 2. the end point of antimicrobial activity of clove and thyme water extracts at % v/v dilution a n t i m i c r o b i a l a c t i v i t i e s o f c l o v e a n d th y m e e x t r a c t s 39 r e f e r e n c e s 1. arora d, kaur j. antimicrobial activity of spices. int j antimicrob agents 1999; 12: 257-262. 2. briozzo j, nunez l, chirife j, herszage l, d’aquino m. antimicrobial activity of clove oil dispersed in a concentrated sugar solution. j appl bact 1989; 66: 69-75. 3. cosentino s, tubeerso cig, pisano b, satta m, mascia v, arzedi e, palmas f. in-vitro antimicrobial activity and chemical composition of sardinian thymus essential oils. lett appl microbiol 1999; 29: 130-135. 4. deans sg, ritchie ga. antimicrobial properties of plant essential oils. int j food microbiol 1987; 5: 165180. 5. dorman hgd, deans sg. antimicrobial agents from plants: antibacterial activity of plant volatile oils. j appl microbiol 2000; 88: 308-316. 6. gijzen m, efraim l, savage t, croteau r. bioactive volatile compounds from plants. in: teranishi r, buttery rg, sugisawa h, ed. conifer monoterpenes: biochemistry and bark beetle chemistry ecology. ch. 2 ed. washington dc: american chemistry society, 1991. 7. gislene gf, paulo c, giuliana l. antibacterial activity of plant extracts and phytochemicals on antibiotic resistant bacteria. braz j microbiol 2000; 31: 314-325. 8. hammer ka, carson cf, riley tv. antimicrobial activity of essential oils and other plant extracts. j appl microbiol 1999; 86: 985-990. 9. hili p, evans cs, veness rg. antimicrobial action of essential oils: the effect of dimethylsulphoxide on the activity of cinnamon oil. lett appl microbiol 1997; 24: 269-275. 10. janssen am, sheffer jjc, baerheim sa. antimicrobial activity of essential oils: a 1976-1986 literature review aspects of the test methods. planta medica 1987; 53: 395-398. 11. manoui, bouillard l, devleeschouwer mj, barel ao. evaluation of the preservative properties of thymus vulgaris essential oil in topical applied formulations under challenge. j appl microbiol 1998; 84: 368-376. 12. panizzi l, flamini g, cioni pl, morelli i. composition and antimicrobial properties of essential oils of four mediterranean lamiaceae. j ethnopharmacol 1993; 39: 167-170. 13. piccaglia r, marotti m, giovanelli e, deans sg, eaglesham e. antibacterial and antioxidant properties of mediterranean aromatic plants. indust crops prod 1993; 2: 47-50. 14. singh sangwan n, abdad faruoqi ah, singh sanwan r. effect of drought stress on growth and essential oil metabolism in lemongrass. new phytologist 1994; 128: 173-178. 15. smith palmer a, stewart j, fyfe l. antimicrobial properties of plant essential oils and essences against five important food-borne pathogens. lett appl microbiol 1998; 26: 118-122. 16. van den broucke co, lemli ja. pharmacological and chemical investigation of thyme liquid extracts. planta medica 1981; 41: 129-135. submitted 25 jan 22 1 revision req. 13 mar 22; revisions recd. 15 mar 22 2 accepted 27 mar 22 3 online-first: april 2022 4 doi: https://doi.org/10.18295/squmj.4.2022.031 5 6 evolution of minimally invasive adrenal surgery at a tertiary care centre 7 in oman 8 najeeb abudraz,1 mohamed s. al-masruri,1 ghalib al badaai,1 yamam al-9 shamari,1 omayma elshafie,2 *khurram m. siddiqui1 10 11 1urology division, department of surgery, sultan qaboos university, oman; 2endocrinology 12 division, department of medicine, sultan qaboos university, oman. 13 *corresponding author’s e-mail: kmsiddiqui4@gmail.com 14 15 abstract 16 objective: we reviewed the case records of adrenalectomy cases at our institution between 17 january 2010 and december 2020 and report the outcomes of both open and laparoscopic 18 adrenalectomy (la). methods: this retrospective study included patients who underwent 19 adrenal surgery from january 2010 to december 2020. we recorded demographic details, 20 indications, surgical approach, intra operative data and complications. the final pathology and 21 outcome at the last follow up was also documented. data was analyzed through the spss 22 program. results: fifty two patients underwent 61 adrenalectomy procedures. six patients had 23 bilateral procedure and 3 patients underwent redo surgery accounting for 55 subjects. open 24 adrenalectomy (oa) was performed on 11 patients and 44 patients underwent la. majority of 25 the patients (27) were obese having bmi > 30. functional adenoma was excised in 36 patients 26 with final diagnosis of conn’s syndrome in 15, pheochromocytoma in 13 and cushing syndrome 27 in 9 patients. five patients had surgery for oncological indications. nonfunctional adenoma was 28 excised in 13 patients, with a mean size of 8.9 cm (range 4-15 cm). the mean duration of surgery 29 was less in laparoscopic procedure (199 min) compared to open (246 min). the mean estimated 30 mailto:kmsiddiqui4@gmail.com blood loss in la was significantly less (108ml vs 450 ml, p-value < 0.05). out of 55 subjects 31 only 1 patients developed clavien-dindo grade 2 complication. conclusion: at our institution 32 both laparoscopic and open adrenalectomy were safely performed. there is a trend to perform 33 la and with experience the duration of surgery and ebl are demonstrating positive trend. 34 keywords: adrenal gland surgery; laparoscopic adrenalectomy; open adrenalectomy; 35 pheochromocytoma; adrenal metastasis; nonfunctional adrenal tumors; oman. 36 37 advances in knowledge 38  this study looks at the transition of adrenal surgery from open approach to minimally 39 invasive approach at our center. 40  it provides objective evidence that adrenal surgery is feasible in oman. 41  this study demonstrates that laparoscopic adrenalectomy is being performed with good 42 results comparable to any other good center in the world. 43 application to patient care 44  adrenal gland is located in a difficult to access location and required large surgical incision. 45 laparoscopic surgery for adrenal gland has the unique advantage of providing excellent 46 exposure without large incision. the advancements in surgical techniques for 47 adrenalectomy and the results of laparoscopic adrenalectomy at our center provide an 48 opportunity for our patients to benefit. 49  this study shows that less blood loss, operative time and better cosmetic results of 50 laparoscopic adrenalectomy make it the standard of care for most patient requiring adrenal 51 surgery 52  the complication rate is well within internationally acceptable range 53 54 introduction 55 laparoscopic adrenalectomy (la) is now recognized as the gold standard approach for adrenal 56 pathology. the post-operative analgesics requirements, hospital stay, surgical morbidity and better 57 cosmetic results are the main driving forces.1, 2, 3 la was first described by ganger et al in 1992 58 for cushing disease, since then the list of indications have now expanded to include almost all 59 benign and malignant adrenal neoplasms.4 the growing experience and systematic training 60 programs have resulted in marked reduction in the duration of surgery and morbidity.5 in this study 61 we reviewed our 10-years’ experience of open and transperitoneal laparoscopic adrenalectomy 62 procedures at our institution. to our knowledge this is the first large case series from oman 63 comparing the open and laparoscopic approach for adrenalectomy. 64 65 methods 66 ethics review committee approval was obtained from our institution to conduct a retrospective 67 chart review of all the adult patients undergoing adrenal surgery our institution. ten-year period 68 from january 2010 to december 2020 was selected and using electronic medical record (emr) of 69 the hospital information system (trakcare® united health care systems) we identified 55 eligible 70 subjects. 71 72 collected data included patient demographic features, comorbidities, body mass index (bmi), 73 preoperative diagnosis, intraoperative details including surgical approach (open/laparoscopic), 74 duration of surgery, estimated blood loss, pathological diagnosis. the post-operative 75 complications were also recorded and graded according to clavien-dindo classification system. 76 data was analyzed using spss program version 21.0. the analysis was done using variable graph, 77 pie-chart and frequency tables. frequency tables provides information about mean, median and 78 standard deviation. a p-value of <0.05 was considered as statistically significant. 79 80 results 81 fifty two patients underwent 61 adrenalectomy procedures. six patients had bilateral procedure 82 and 3 patients underwent redo surgery accounting for 55 subjects. open adrenalectomy (oa) was 83 performed on 11 patients and 44 patients underwent la. there were 13 male and 39 female 84 patients. the mean age was 44 years (range 15-70 years). 85 86 majority of the patients (36) underwent adrenalectomy for functional tumors. five patients had 87 surgery for oncological indication including two for metastasis from other organs. the frequency 88 of distribution of final diagnosis is illustrated in fig1. 89 90 the median tumor size was slightly larger in the open surgery group (5 cm vs. 6.5 cm). the details 91 of difference in size are illustrated in table 1. nonfunctional adenoma was excised in 13 patients, 92 with a mean size of 8.9 cm (range 4-15 cm). 93 94 asa 2 was the most common category in 63% patients. majority of the patient were obese with 95 52% having bmi > 30, the frequency of american society of anesthesia (asa) score and bmi 96 groups is shown in the figure 2. 97 98 laparoscopic adrenalectomy was performed in 44 patients and 11 underwent open adrenalectomy. 99 the mean duration of open surgery was 246 min (median 241 min) vs. 189 min (median 197 min) 100 in the laparoscopic group. in patient undergoing open surgery the estimated mean blood loss (ebl) 101 was 450 ml (100 to 1000 ml) vs. 108 ml (range 50 ml to 500 ml) in the laparoscopic group (p=0.05). 102 we also independently analyzed the unilateral adrenalectomy group and found similar trend. the 103 mean duration of surgery and ebl in unilateral laparoscopic vs. unilateral open adrenalectomy 104 were 198 min vs. 248 min and 108 ml vs. 245 ml respectively. 105 106 we used operating time as a surrogate maker to reflect the surgical expertise. after january 2017, 107 we transitioned to a subspecialty based approach and all adrenal procedures were referred to 108 urology service having a lead surgeon with dedicated interest in adrenal surgery. to assess the 109 impact of this intervention we created two groups, time period 1(before december 2017) and 110 time period 2 (after january 2017). we found that the mean duration of surgery reduced from 111 mean of 206 min to 145 min only. 112 113 there were no complications in majority of patients. one patient developed diarrhea related to 114 clostridium infection and 3 patients developed paralytic ileus (2 in open and 1 in laparoscopic 115 group). the frequency of complications according clavien-dindo system of classification of 116 surgical complications is shown in table 2. 117 118 three patient were treated for recurrence of disease. two of them belong to a family with von 119 hippel-lindau (vhl) abnormality where the recurrence is not unexpected over a period of time. in 120 one patient there was a suspicion of cancer on the histopathology and the patient underwent 121 revision la with free margins and is doing well after 4 years of follow up. 122 123 discussion 124 adrenal surgery for a functional tumor like cushing’s disease and pheochromocytoma is 125 exceptionally rewarding in terms of the physiological outcomes. the additional benefits of 126 minimally invasive approach in terms of cosmetics, minimal blood loss, lesser analgesic 127 requirement, hospital stay and higher patient satisfaction have certainly placed laparoscopic 128 adrenalectomy (la) at the pedestal of gold standard.6, 7, 8 in this study we looked at the safety and 129 efficacy of intraperitoneal laparoscopic adrenalectomy at our institution and how it has evolved to 130 be now a routine surgical procedure. 131 132 functional adrenal tumors present multiple challenges in the peri operative period. significant 133 number of patients are also obese. in our study 52% of our patients had bmi of > 30, which is well 134 known to be associated with intraoperative difficulties.9, 10 secondary hypertension is also one of 135 the common presentation of adrenal tumors. studies have shown that almost two third of the 136 indications of surgery are for functional tumors exhibiting hypertension.11 in our study 67% 137 patients had secondary hypertension related to either cushing disease, pheochromocytoma or 138 conn’s disease. post operatively all patients were successfully weaned off the antihypertensive 139 medications. 140 141 the evolution of laparoscopic adrenal surgery has witnessed an expansion of indications. 142 functional tumors like pheochromocytoma which were initially regarded as out of bound are now 143 routinely treated by key-hole surgery.12 in our series we successfully performed la on 13 patient 144 with pheochromocytoma. laparoscopic treatment of conditions like adrenocortical neoplasm has 145 also been reported with comparable oncologic outcome.13 we performed la in 3 cases of primary 146 adrenocortical neoplasm with adequate surgical margins and acceptable oncologic control. 147 adrenalectomy for metastatic disease is increasing performed and can be considered as standard 148 of care for some cancers with solitary adrenal metastasis.14 we performed laparoscopic 149 metastatectomy in 2 patients with adrenal metastasis. one of them relapsed within one year but 150 the other patient has no evidence of disease with more than 3 years of follow up. the limit of size 151 of the gland to undergo la has always been debatable and some authorities have recommended 152 the upper limit as > 6cm.15 technical difficulty and suspicion of malignancy are regarded as factors 153 responsible to cap the size limit.16 in our study we have performed la for tumors up to 15 cms 154 with no significant increase in operating time or blood loss. in these cases we did not encounter 155 any incidental finding of cancer, in our opinion the advancements in radiology have increased our 156 confidence. modern ct scan and mri of the adrenal gland using specific protocols now have 157 excellent ability to predict the final pathology.17 in our cohort of la for non-functional adenoma 158 the mean size of the gland removed was 5.8cm. 159 160 in our series the la had also retained the advantage of shorter operative time with the mean 161 duration of la as 189 min compared to open adrenalectomy with the mean of 246 min. the ebl 162 in la is significantly less with the mean of 170ml comparing with 450ml in open procedure, with 163 the significant p-value < 0.001. 164 165 we also looked a two time periods for la, before december 2017 and after january 2017. this 166 division was created to assess the impact of change in the referral system at our institution as from 167 january 2017 onwards all cases of adrenal tumor were referred to a team dedicated to do la. we 168 found that the mean duration of surgery reduced from 206 min to 145 min. we must acknowledge 169 the limitation here as the cases were not controlled for complexity of procedure. 170 171 the overall rate of complications of adrenalectomy, both open and laparoscopic was very low at 172 our institution. majority of patients did not have any complications. out of 55 subjects one 173 developed grade 2 clavien-dindo complications. there we no grade 3 or above complications. 174 during follow up 3 patients had disease recurrence and underwent redo surgery. two of them 175 belonged to a family of patients with vhl abnormality and were predisposed to high risk of 176 recurrence. one patient had suspicious pathology for adrenocortical cancer and had revision 177 surgery. 178 179 conclusion 180 both laparoscopic and open adrenalectomy have been performed safely at our institution with low 181 morbidity. the benefits of minimally invasive approach clearly favor laparoscopic approach 182 especially in term of duration of surgery and estimated blood loss. however in selected cases there 183 is still a role of open approach. 184 185 authors’ contribution 186 na and kms designed the study. na, msm and ys collected the data. na, msm, gb and 187 kms performed the statistical analysis. na and msm drafted the manuscript. gb, oe and kms 188 critically reviewed the manuscript and revised the manuscript. all authors approved the final 189 version of the manuscript. 190 191 conflict of interest 192 the authors declare no conflicts of interest. 193 194 funding 195 no funding was received for this study. 196 197 references 198 1. lee j, el-tamer m, schifftner t, turrentine fe, henderson wg, khuri s et al. open and 199 laparoscopic adrenalectomy: analysis of the national surgical quality improvement 200 program. j am coll surg. 2008 206(5):953-9. doi: 10.1016/j.jamcollsurg.2008.01.018. 201 2. elfenbein dm, scarborough je, speicher pj, scheri rp. comparison of laparoscopic 202 versus open adrenalectomy: results from american college of surgeons-national surgery 203 quality improvement project. j surg res. 2013;184 (1):216-220. 204 doi:10.1016/j.jss.2013.04.014 205 3. eichhorn-wharry li, talpos gb, rubinfeld i. laparoscopic versus open adrenalectomy: 206 another look at outcome using the clavien classification system. surgery. 2012;152 207 (6):1090-1095. doi:10.1016/j.surg.2012.08.020 208 4. gagner m, lacroix a, bolté e. laparoscopic adrenalectomy in cushing’s syndrome and 209 pheochromocytoma. n engl j med. 1992;327(14):1033. 210 doi:10.1056/nejm199210013271417 211 5. al-qurayshi z, robins r, buell j, kandil e. surgeon volume impact on outcomes and cost 212 of adrenal surgeries. eur j surg oncol. 2016;42(10):1483-1490. 213 doi:10.1016/j.ejso.2016.06.392 214 6. thompson gb, grant cs, van heerden ja, et al. laparoscopic versus open posterior 215 adrenalectomy: acase-control study of 100 patients. surgery 1997;122: 1132–6. 216 7. terachi t, matsuda t, terai a, ogawa o, kakehi y, kawakita m, et al. transperitoneal 217 laparoscopic adrenalectomy: experience in 100 patients. j endourol 1997;11:361–5. doi: 218 10.1089/end.1997.11.361. 219 8. assalia a, gagner m. laparoscopic adrenalectomy.br j surg 2004;91:1259–74. 220 9. dancea hc, obradovic v, sartorius j, woll n, blansfield ja. increased complication rate 221 in obese patients undergoing laparoscopic adrenalectomy. jsls. 2012;16(1):45-222 49.doi:10.4293/108680812x13291597715862 223 10. kazaure hs, roman sa, sosa ja. obesity is a predictor of morbidity in 1,629 patients 224 who underwent adrenalectomy. world j surg. 2011;35(6):1287-1295. 225 doi:10.1007/s00268-011-1070-2 226 11. gumbs aa, gagner m. laparoscopic adrenalectomy. best pract res clin endocrinol 227 metab 2006;20:483–99. 228 12. thomson bn, moulton ca, davies m. laparoscopic adrenalectomy for 229 phaeochromocytoma: with caution. anz j surg 2004;74:429–33. doi: 10.1111/j.1445-230 1433.2004.03024.x. 231 13. moinzadeh a, gill is. laparoscopic radical adrenalectomy for malignancy in 31 patients. 232 j urol 2005;173:519–25. 233 14. solaini, l., ministrini, s., tomasoni, m, g merigo, g gaverini, g p bertoloni et al. 234 adrenalectomy for metastasis: long-term results and predictors of survival. endocrine 235 2015(50), 187–192 . https://doi.org/10.1007/s12020-015-0596-8 236 15. n tsuru, k suzuki, t ushiyama, s ozono. laparoscopic adrenalectomy for large adrenal 237 tumors. j endourol 2005;19(5). doi.org/10.1089/end.2005.19.537 238 16. qureshi ah, junejo nn, siddiqui k, zaidi sz. adrenocortical oncocytoma. j coll 239 physicians surg pak. 2014 dec;24(12):947-8. doi: 08.2014/jcpsp.947948. 240 17. wang, f., liu, j., zhang, r., bai, y., li, c., li, b., liu, h., & zhang, t. (2018). ct and 241 mri of adrenal gland pathologies. quantitative imaging in medicine and surgery, 8(8), 242 853–875. https://doi.org/10.21037/qims.2018.09.13 243 244 245 figure 1: the distribution of frequency of diagnosis for adrenalectomy 246 247 248 figure 2: the distribution of body mass index (bmi) and american society of 249 anesthesiologist (asa) of the patients undergoing adrenalectomy 250 https://doi.org/10.21037/qims.2018.09.13 table 1: the distribution of tumor size in the two groups 251 laparoscopic adrenalectomy n=44 open adrenalectomy n=11 mean size in cm 5.8 6.8 median size in cm 5 6.5 range 1.5-15 3.8-11 standard deviation 3.49 2.22 252 table 2: the frequency of surgical complications in the two groups 253 clavien-dindo grade total n=55 laparoscopic adrenalectomy open adrenalectomy 0 51 0 0 1 3 1 2 2 1 1 0 3 0 0 0 254 submitted 11 sep 22 1 revisions req. 23 oct 22 & 4 jan 23; revisions recd. 14 dec 22 & 18 jan 23 2 accepted 6 feb 23 3 online-first: february 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.012 5 6 a rare case of lung hypoplasia, cardiac anomalies and ovarian 7 tumour in a patient with mrkh syndrome 8 pratap upadhya,1 arpitha a.,2 *sivaselvi c.,1 dasari papa,2 vignesh k.1 9 10 departments of 1pulmonary medicine and 2obstetrics and gynaecology, jawaharlal institute 11 of postgraduate medical education & research, puducherry, india. 12 *corresponding author’s e-mail: sivaselvisaran33@gmail.com 13 14 abstract 15 hypoplasia of the lung is an uncommon congenital abnormality of the respiratory system in 16 contrast to pulmonary agenesis. mayer-rokitansky-küster-hauser (mrkh) syndrome is the 17 congenital absence of the upper two-thirds of the vagina and uterus with normal secondary 18 sexual characteristics, ovary, and normal karyotype. here we describe a case of left lung 19 hypoplasia and congenital cardiac malformations with mrkh syndrome and leiomyoma of 20 the ovary. a 31-year-old female presented with cough with expectoration, left side chest pain 21 and breathlessness for four years to jawaharlal institute of postgraduate medical education 22 and research (jipmer). she was evaluated for amenorrhea and diagnosed as mrkh 23 syndrome and the patient underwent right side oophorectomy for right ovarian torsion with a 24 tumour. computed tomography pulmonary angiogram (ctpa) and fiberoptic endoscopy 25 were suggestive of left lung hypoplasia, and the patient was advised symptomatic treatment 26 for lung hypoplasia and planned for vaginoplasty. 27 keywords: pulmonary hypoplasia, infertility, mullerian aplasia, congenital bronchiectasis, 28 left-sided superior vena cava, ovarian leiomyoma. 29 30 introduction 31 pulmonary hypoplasia is a developmental lung anomaly characterized by a decrease in the 32 number of airway, alveoli and lung cells leading to a net reduction in the lung's size and 33 weight. it can be either unilateral or bilateral.1 estimated prevalence of pulmonary 34 hypoplasia is 1-2 per 12000 births although the exact prevalence is not well known.2 35 pulmonary hypoplasia usually presents with other associated cardiovascular,gastrointestinal, 36 and genitourinary tract anomalies. the onset of clinical manifestations usually depends upon 37 the degree of hypoplasia.3 38 39 mayer-rokitansky-küster-hauser (mrkh) syndrome is a rare congenital problem in women 40 and it is characterized by failure of the appropriate development of the uterus and the vagina 41 with normal external genitalia and normal ovarian function. they develop secondary sexual 42 characteristics during puberty (e.g., breast development and pubic hair) but present with 43 primary amenorrhea. the estimated incidence of mayer-rokitansky-küster-hauser syndrome 44 (mrkh syndrome) is 1 in 4500 female births.3 most cases are sporadic. autosomal 45 dominance with an incomplete degree of penetrance and variable expressivity is the mode of 46 inheritance in this syndrome. here, we are report a rare left lung hypoplasia case associated 47 with cardiac anomalies, with mrkh. 48 49 case report 50 a 31-year-old unmarried female patient presented with four years of cough with whitish 51 expectoration, left side dull aching chest pain, and difficulty in breathing. breathlessness 52 progressed from modified medical research council grade 1 to 3 over these four years and 53 was not associated with palpitations, wheeze, or orthopnea. she had no history of loss of 54 weight, loss of appetite, abdominal distension, bilateral leg swelling, or reduced urine output. 55 history of pulmonary tuberculosis at the age of 2 years with an intake of antituberculosis 56 drug therapy was there but no documentation available regarding treatment. 57 58 she also had a history of amenorrhea but with no family history suggestive of mullerian 59 tract/cardiac/renal/ lung/ skeletal anomalies. initially patient underwent traditional medicine 60 treatment for amenorrhea after that patient went to another hospital to evaluate amenorrhea in 61 2017.then she was referred to our institute for further evaluation. 62 63 during the evaluation, blind vaginal pouch with an absent uterus with a normal ovary found 64 in the ultrasound abdomen and pelvis. in view of suspecting mrkh syndrome following 65 investigations was done. karyotyping 46xx, fsh (follicle stimulating hormone) =5.7 iu/l 66 (normal range-1.5-12.4 iu/l), lh (luteinizing hormone) =7.25 iu/l (1.09-9.2 iu/l), 67 prolactin= 18ng/ml (normal range<25ng/ml), testosterone= 0.7 nmol/l (normal range 68 0.5-2.4 nmol/l) and estrogen 118 pg/ml(normal range 30-400pg/ml) and advised about 69 vaginoplasty and surrogacy. but patient did not come for a follow-up after that,in 2021 70 patient presented to the obstetrics department with abdominal pain with outside magnetic 71 resonance imaging (mri) film, which showed right sided ovarian tumor with torsion and 72 features of mrkh syndrome such as absence of the uterus, hypoplastic vaginal canal with 73 normal bilateral kidney. 74 75 the patient underwent emergency laparotomy for ovarian torsion and the right ovary was 76 removed with a tumor followed by peritoneal cytology, and infracolic-omentectomy. ovarian 77 tumour histopathology was a benign spindle cell tumor suggestive of leiomyoma with 78 torsion-related changes. 79 80 she had no pallor, clubbing, or clinically palpable generalized lymphadenopathy on 81 examination. her room air saturation was 96%, her blood pressure was 110/70 mm of hg, 82 and her pulse rate was about 95/min. she had tanner grade 4 pubic hairs and breasts. 83 examination of external genitalia showed a blind vagina. on chest examination, she had left 84 side tracheal deviation with the same side decreased vesicular breath sounds with biphasic 85 coarse inspiratory crepitations. chest x-ray revealed cystic changes on the left side with 86 ipsilateral mediastinal and tracheal shift with compensatory hyperinflation on the right side 87 (figure 1 a). severe restrictive abnormality (fev1/fvc-0.85, fvc-43%, fev1-50% of the 88 predicted value) was found in spirometry. given all these clinical and imaging features, a left 89 lung developmental anomaly was suspected and a contrast-enhanced pulmonary angiogram 90 (ctpa) done for the left main pulmonary artery size. ctpa showed left lung volume loss 91 with multiple thin and thick-walled cystic areas connected to lobar bronchus with no 92 evidence of lung parenchyma. herniation of right upper lobe parenchyma into left hemi 93 thorax and small caliber of left main pulmonary artery [0.67cm], lobar and segmental arteries 94 than right side suggestive of left lung hypoplasia with cystic bronchiectasis with left superior 95 vena cava (figure 1 b) and right aortic arch (figure 1c) was noted. fiber optic bronchoscopy 96 showed right side and left lower lobe were normal bronchopulmonary segment with left side 97 upper lobe bronchus does not sudivide further (figure 2 a&b). this confirmed our suspicion 98 of left lung developmental anomaly, and a diagnosis of left lung hypoplasia (grade 3 monaldi 99 classification of hypoplasia) was made. 2d echocardiography was done, which showed 100 moderate tricuspid regurgitation with dilated coronary sinus and left-sided superior vena 101 cava. patient was advised for pulmonary rehabilitation (breathing exercises, active cycle 102 breathing technique and postural drainage for left lung), pneumococcal and influenza 103 vaccination and advised for pneumonectomy. however, the patient was not willing to 104 undergo for surgical procedure. the patient was explained about vaginoplasty and surrogacy 105 in view of mrkh but patient was not willing to undergo surgical procedures. 106 107 informed consent was obtained for publication of the patient’s clinical images and history. 108 109 discussion 110 two types of mayer-rokitansky-küster-hauser (mrkh) syndrome are there which include 111 type i (isolated) or rokitansky sequence and type ii or murcs association (mullerian duct 112 aplasia, renal dysplasia, and cervical somite anomalies.4the association of mrkh with lung 113 malformation mimicking bronchiectasis and heart malformations is very uncommon. severe 114 cardiac defects evocating holt-oram or velocardiofacial-like syndromes requiring surgery 115 were reported in other case studies. the reported malformations were conotruncal defects 116 such as pulmonary valvular stenosis,5 aortopulmonary window.6but in our case presented 117 with left superior vena cava. 118 119 in most studies, uterine leiomyoma was found in patients with mrkh syndrome but very 120 rarely was ovarian leiomyoma. ovarian tumour is difficult to examine in mrkh, mainly in 121 patients without vaginal reconstruction. hence appropriate imaging is also needed to look for 122 pelvic mass during mrkh evaluation.7pulmonary hypoplasia is defined as reduced lung 123 tissue with hypo-plastic bronchi and vessels of varying degrees. lung development starts 124 from the 26th day of intrauterine life and is completed in the early post-natal period.8 125 pulmonary hypoplasia may be primary or secondary. primary pulmonary hypoplasia is an 126 intrinsic defect in lung development with an incidence of 1-2 cases per 12,2000 live births. 127 several mechanisms, like decreased hemi thoracic volume, decreased pulmonary vascular 128 perfusion, fetal movements, and lung fields are implicated in secondary pulmonary 129 hypoplasia. they are frequently associated with other congenital anomalies involving 130 urogenital, cardiovascular system, central nervous system, and musculoskeletal abnormalities 131 of the thoracic cage.9 lung developmental disorders constitute three main categories 132 according to boyden, which include agenesis (complete absence of the lung tissue), aplasia 133 (absent lung tissue with rudimentary bronchus ), and hypoplasia (reduced lung tissues).10 134 pulmonary hypoplasia has a spectrum of clinical manifestations from asymptomatic to 135 respiratory failure.11 most patients will develop respiratory distress as a newborn. however, 136 our patient presented with respiratory symptoms at the age of 2 years but was diagnosed with 137 pulmonary tuberculosis and treated; since then, the patient has had recurrent respiratory 138 infections, which led us to think of bronchiectasis as the primary lung pathology. 139 140 diagnosis of pulmonary hypoplasia with mrkh syndrome is rare in adulthood. left lung 141 hypoplasia is more common than right, and in our patient, a chest x-ray was suggestive of 142 decreased volume loss with increased opacity on the affected side. a severe restrictive 143 pattern was seen in spirometry, and computed tomography pulmonary angiography (ctpa) 144 was used to diagnose pulmonary hypoplasia. before diagnosing pulmonary hypoplasia, we 145 must evaluate for other conditions similar to hypoplasia, including non-cystic bronchiectasis, 146 and congenital airway malformations, and sequestration.12 in all these scenarios, the usually 147 standard caliber/size of same side pulmonary artery size will be expected. 148 149 treatment for lung hypoplasia in adults were mainly supportive measures which include 150 recurrent infection control measures, expectorants for symptomatic management, and 151 management of other complications. prophylaxis treatment for pneumococcus, respiratory 152 syncytial virus (rsv), and influenza is recommended. prognosis in such cases is based on the 153 remaining lung parenchyma and the presence of associated anomalies. 13 154 155 cases with polycystic ovaries and ovarian tumors have been described in women presenting 156 otherwise with the usual 46, xx karyotype. in yalavarthi s et al. study, the case of 157 sertoliform endometrioid carcinoma associated with mrkh syndrome is reported.14 158 in mrkh syndrome 40% of upper urinary tract malformations are found which includes 159 ectopia of one or both kidneys (17%), unilateral renal agenesis (23–28%), horseshoe kidney, 160 renal hypoplasia (4%), and hydronephrosis. in murcs patients 10–25% of them had 161 auditory defects or deafness and 30–40% of the skeletal abnormalities of the spine were also 162 found in these cases.15 163 164 case reports by bach et al16 described the association of mrkh syndrome with pulmonary 165 agenesis. however, our case report is left lung hypoplasia with cardiac anomalies and mrkh 166 syndrome with ovarian leiomyoma. 167 168 169 170 conclusion 171 pulmonary hypoplasia affects the lung and airways and can be easily missed, especially in 172 those with previous pulmonary tuberculosis treatment history, unless the treating physician 173 has a high index of suspicion. we must evaluate anyone with recurrent respiratory symptoms 174 since childhood and primary amenorrhea for the congenital lung anomaly and other system 175 congenital malformations. urinary anomalies are the most common anomaly associated with 176 mrkh syndrome, but lung hypoplasia association is infrequent. once suspected, it would be 177 easy to diagnose with available investigations and further follow-ups in those with lung 178 hypoplasia with mrkh syndrome. 179 180 authors’ contribution 181 pu made the diagnosis in pulmonary medicine part and helped in writing the case report. aa 182 diagnosed mrkh and helped in revising case report. sc wrote the paper and followed the 183 case and collected details. dp helped in drafting article and images. vk helped in writing 184 report. all authors approved the final version of the manuscript. 185 186 references 187 1. laudy ja, wladimiroff jw. the fetal lung. 2: pulmonary hypoplasia. ultrasound obstet 188 gynecol. 2000;16:482–94. doi: 10.1046/j.1469-0705.2000.00252.x 189 2. kant s. unilateral pulmonary hypoplasia – a case report. lung 190 india . 2007;24:69–71. doi: 10.4103/0970-2113.44215 191 3. griffin je, edwards c, madden jd, harrod mj, wilson jd. congenital absence of the 192 vagina. the mayer-rokitansky-kuster-hauser syndrome. annals of internal medicine. 193 1976;85:224–36. doi: 10.7326/0003-4819-85-2-224 194 4. opitz jm. vaginal atresia (von mayer-rokitansky-küster or mrk anomaly) in 195 hereditary renal adysplasia (hra). american journal of medical genetics. 196 1987;26:873–6. doi: 10.1002/ajmg.1320260414 197 5. kula s, saygili a, tunaoğlu fs, olguntürk r. mayer-rokitansky-küster-hauser 198 syndrome associated with pulmonary stenosis. acta paediatr. 2004;93:570–2. 199 doi: 10.1080/08035250310023773 200 6. ulrich u, schrickel j, dorn c, richter o, lewalter t, lüderitz b, et al. mayer-von 201 rokitansky-küster-hauser syndrome in association with a hitherto undescribed variant 202 https://doi.org/10.1046/j.1469-0705.2000.00252.x https://doi.org/10.7326/0003-4819-85-2-224 https://doi.org/10.1002/ajmg.1320260414 https://doi.org/10.1080/08035250310023773 of the holt-oram syndrome with an aorto-pulmonary window. human reproduction. 203 2004;19:1201–3. doi: 10.1093/humrep/deh198 204 7. miao y, wen j, huang l, wu j, zhao z. diagnosis and management of ovarian tumor 205 in mayer-rokitansky-küster-hauser (mrkh) syndrome. biomed research 206 international . 2018 ;2018:2369430. https://doi.org/10.1155/2018/2369430 207 8. papadopoulos d, misthos p, chorti m, skopas v, nakou a, karagianidis n, et al. 208 unilateral pulmonary hypoplasia in an adult patient. monaldi archives for chest 209 disease. 2018;88. doi: 10.4081/monaldi.2018.829 210 9. liners j, médart dl, collignon l. primary pulmonary hypoplasia. journal of the 211 belgian society of radiology . 2019 ;103. doi: http://doi.org/10.5334/jbsr.1717 212 10. boyden ea. developmental anomalies of the lungs. the american journal of surgery. 213 1955;89:79–89. doi: 10.1016/0002-9610(55)90510-9 214 11. gülen f, kar s, midyat l, demir e, özyurt s, özyürek ar, et al. a rare clinical 215 presentation of pulmonary hypoplasia. open journal of pediatrics. 2011;01:75–8. 216 doi:10.4236/ojped.2011.14018 217 12. 3d imaging in unilateral primary pulmonary hypoplasia in an adult: a case report. 218 https://www.hindawi.com/journals/crira/2011/659586/ 219 13. thomas rj, lathif hc, sen s, zachariah n, chacko j. varied presentations of unilateral 220 lung hypoplasia and agenesis: a report of four cases. pediatric surgery international. 221 1998;14:94–5. doi: 10.1007/s003830050447 222 14. yalavarthi s, jadhav va, kumar ss, pavani m. mayer–rokitansky–kuster–hauser 223 syndrome: syndrome of mullerian agenesis – a report of two cases. medical journal of 224 dr dy patil university . 2017;10:207. doi: 10.4103/0975-2870.202095 225 15. morcel k, watrin t, pasquier l, rochard l, le caignec c, dubourg c, et al. utero-226 vaginal aplasia (mayer-rokitansky-küster-hauser syndrome) associated with deletions 227 in known digeorge or digeorge-like loci. orphanet journal of rare disease. 2011 ;6:9. 228 16. bachh aa, pulluri s, beigh a, raju c, deshpande r. pulmonary aplasia with unusual 229 associations in a woman. iranian journalof medical sciences. 2014;39:148–51. 230 pmid: 24644386 231 232 https://doi.org/10.1093/humrep/deh198 https://doi.org/10.1155/2018/2369430 https://doi.org/10.4081/monaldi.2018.829 http://doi.org/10.5334/jbsr.1717 https://doi.org/10.1016/0002-9610(55)90510-9 http://dx.doi.org/10.4236/ojped.2011.14018 https://doi.org/10.1007/s003830050447 https://pubmed.ncbi.nlm.nih.gov/24644386 233 figure 1: a: chest x-ray demonstrating a mediastinal shift to the left with crowding of ribs 234 on the left with hypolucent opacity with ectatic changes on the left side. b: ctpa showing a) 235 left lung volume loss with multiple thin and thick-walled intercommunicating cystic areas 236 and b) decreased caliber of the left main pulmonary artery (0.67mm) and left superior vena 237 cava (asterisk), (c) ctpa showing right aortic arch(asterisk) 238 239 figure 2: a: fibreoptic bronchoscopy shows the main carina with bilateral patent bronchi. b: 240 left side secondary carina with lobar bronchi (white arrow showed left upper lobe single 241 bronchial opening without subdivision) 242 1department of health sciences, college of health & rehabilitation sciences, princess nourah bint abdulrahman university, riyadh, saudi arabia; 2health education department, saudi alzheimer’s disease association, riyadh, saudi arabia *corresponding author’s e-mail: amalhashem@pnu.edu.sa stigmatisation of covid-19 in riyadh, saudi arabia a cross-sectional study fatmah almoayad,1 samira mahboub,1 lujain bin amer,2 alaa alrabiah,1 *anwar alhashem1 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 525–531, epub. 25 nov 21 submitted 25 aug 20 revision req. 22 oct 20; revision recd. 11 nov 20 accepted 24 nov 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.044 clinical & basic research abstract: objectives: infectious diseases are the most common cause of disease stigmatisation, which can lead to a denial of healthcare, education, housing and employment as well as physical violence. such stigmatisation is common during pandemics. this study aimed to examine the social stigmatisation of covid-19 among residents of riyadh, saudi arabia. methods: a cross-sectional descriptive study was conducted in riyadh in may 2020. non-probability convenient sampling was used to recruit 847 participants through social media platforms, including whatsapp. the data were analysed using descriptive statistics, the pearson correlation coefficient and the chi-squared test were used along with a multiple linear regression model. results: there was a high level of stigma among 21% of the participants and an intermediate level in almost 49% of the participants. low stigma was indicated among 30% of the study’s sample. a highly significant association existed between stigma, on the one hand, and older age groups, being married and lower levels of education, on the other. conclusion: future awareness programmes should educate patients and their families about stigma as well as the consequences of stigmatising covid-19. stigma eradication policies and interventions should be implemented to avoid potentially harmful consequences for public health. keywords: social stigma; covid-19; pandemic; saudi arabia. advances in knowledge this study found that covid-19-related stigmatisation exists at moderate to high levels among more than two-thirds of the residents of riyadh, saudi arabia. general knowledge about covid-19 was not found to be associated with social stigma. the factors significantly associated with the high stigma scores among the studied sample were the following : old age, being married, low educational level, not working in the healthcare field, not being exposed to infection previously, high level of knowledge about preventive measures, low perceived susceptibility and high perceived severity of the disease. applications to patient care the findings of this study might guide health educators in designing educational campaigns that focus on perceived susceptibility, which was found to be significantly associated with low stigma towards covid-19. specifically, such campaigns should raise people’s awareness about the likelihood of becoming infected with covid-19. stigma eradication policies and interventions should be implemented to avoid potentially harmful public health consequences. stigma is defined as “a simplified, standardised image of the disgrace of certain people that is held in common by a community at large”.1 stigmatisation of diseases is considered the foremost barrier deterring people from seeking treatment.2,3 in many instances, this is caused by the perceived risk of stigma outweighing the perceived benefit of healthcare-seeking behaviour.2 infectious diseases have been considered the most common cause of disease stigmatisation.4 historically, many infectious diseases have been stigmatised.5 a review of major studies in this area confirmed that there is a statistically significant relationship between newly emerging infectious diseases and stigma.5–8 the involved stigmatisation leads not only to denial of healthcare, education, housing and employment but also to physical violence.9 for example, the severe acute respiratory syndrome (sars) epidemic resulted in a significant reduction in the public’s healthcare-seeking behaviour.10 after the ebola and sars outbreaks, social stigma was attached to healthcare workers, as people feared being infected by them. if a person is infected, the social stigma attached to the individual and those who live around them continues even after the quarantine period when there is no further risk of spreading the virus.8 moreover, stigma has been commonly recorded during pandemic outbreaks.4 the covid-19 pandemic has caused individual fear and community panic.11,12 this is considered a natural response to the rapidly changing and uncertain conditions in which people find themselves.9,13 this is particularly true for people who are more vulnerable to covid-19, namely older people, immunocompromised people, family members of infected patients and residents of high-incidence stigmatisation of covid-19 in riyadh, saudi arabia a cross-sectional study 526 | squ medical journal, november 2021, volume 21, issue 4 areas as well as those with severe underlying medical conditions.14,15 moreover, people’s fear of and anxiety about unknown/unexpected diseases provide a rationale for exclusion and rejection.14 for instance, the fear of covid-19 gave rise to mutual discrimination in china (i.e. discrimination within the asian/chinese communities).15 all of this could lead to ‘social stigmatisation’ that makes an individual hide the disease to avoid discrimination, inhibits them from adopting healthy behaviours and prevents them from seeking healthcare.5,7,8 some people who face social stigma as a result of covid-19 are those of asian descent, those who have travelled and healthcare practitioners.15 a health stigma and discrimination framework developed by stangl et al. provided an approach for planning for and responding to health-related stigma.13 their framework is comprehensive and applicable to a broad range of health conditions; it highlights how stigma feeds upon socio-ecological factors related to health and national economic status. the process can be divided into a series of phases, including drivers and facilitators, stigma ‘making’ and stigma manifestations, which affect the outcomes of health in society.13 evidence has shown that the fear and stigmatisation related to previous epidemics, namely sars and ebola, led to negative consequences; this may also be the case if covid-19 is similarly stigmatised.8 stangl et al. recommended early intervention to reduce the public stigma of health conditions to reach optimal health and quality healthcare.13 it is extremely important to increase people’s knowledge about the disease, its prevention and its treatment to prevent social exclusion and reduce stigma.5 in addition to facilitating support by family and healthcare teams, knowledge improves the commitment to healthcare.3 this highlights the role of public health practitioners and health educators who need to intensify their efforts and use rapid and effective ways to raise community awareness.5 this is highly important during a pandemic in which stigmatisation can also affect healthcare practitioners and public health workers, undermining their efforts.4 with the ultimate aim of helping to minimise the public health consequences of stigmatisation during the latest pandemic, this study was conducted to examine the social stigmatisation of covid-19 among riyadh’s residents and the factors affecting it. riyadh was chosen as the first location in a series of studies to assess and compare stigmatisation of covid-19 across the country. it was chosen due to its status as the capital of saudi arabia, the country’s largest and most diverse city with more than seven million residents. the findings of this study are expected to help in understanding the stigma around covid-19 to inform public health research and practices to eradicate it. methods this research is part of a project to study the stigmatisation of covid-19. in the first part of the project, a cross-sectional descriptive study was conducted in riyadh, saudi arabia, in may 2020. nonprobability convenience sampling was used to recruit residents. an electronic survey created with the help of microsoft forms (microsoft corp., redmond, washington, usa) was distributed via social media and whatsapp groups. only respondents who were residents of riyadh and over 18 years of age were included, regardless of their gender, race or nationality. the study sample was estimated to consist of a minimum of 385 participants out of the total of more than five million adult residents of riyadh.16 this number was estimated to have a confidence level of 95% and a real value within ±5%. on the whole, 886 people participated in the survey. of these, 39 participants were excluded for being under 18 years old. thus, the sample size was 847, raising the confidence level to 98% and ensuring a real value within ±4%. the research instrument consisted of five sections: socio-demographic characteristics, knowledge, attitude, practice and stigmatisation. this article is focused on stigmatisation; the findings on knowledge, attitudes and preventive practices regarding covid-19 have been published separately.17 however, data concerned with knowledge (symptoms, risk groups and preventive measures) and participants’ perceptions of severity and susceptibility were used to examine their correlations with stigma. the socio-demographic characteristics and general data of the participants included age, gender, level of education, workplace, the existence of chronic diseases and personal experience(s) with covid-19. questions about public stigma towards covid-19 patients were adopted from an unpublished stigmatisation tool developed by the team that worked on this research. the questions included in the questionnaire were intended to measure public attitudes towards stigma. seven questions were included in this section, which asked about participant perceptions of the following: (1) whether people with covid-19 have low personal hygiene; (2) whether people with covid-19 deserve to get infected because of their lifestyle during the pandemic; (3) whether a person with covid-19 is not as responsible as others; (4) whether people who have had covid-19 fatmah almoayad, samira mahboub, lujain bin amer, alaa alrabiah and anwar alhashem clinical and basic research | 527 previously are obligated to disclose this information; (5) whether the participant keeps a physical distance from people who have recovered from covid-19; (6) whether the participant avoids socialising with people who have had covid-19 even after the latter’s recovery; and (7) whether low-income individuals are the reason the infection is spreading. questions were evaluated based on a five-point likert scale ranging from 1–5, where 5 represented ‘strongly agree’ and 1 represented ‘strongly disagree’.18 the total possible score was 35 and was interpreted based on quartiles as follows: ≤18 = low stigma, 19–24 = intermediate stigma and >24 = high stigma. the questionnaire was developed based on an extensive review of relevant literature and guidelines. it was translated from english to arabic using the forward-backward method. the final arabic questionnaire was tested for face validity by experts in the field of community medicine and public health which resulted in some minor modifications. reliability and validity tests were run and two questions were removed. after removal of the two questions, all of the questions had a significant positive correlation with the total stigma score; the r-value was above 0.4 and cronbach’s α was 0.73. the data were analysed using jmp, version 14.2 (sas institute inc., cary, north carolina, usa). descriptive statistics were used to represent sociodemographic characteristics, exposure to covid-19 table 1: socio-demographic characteristics of residents from the city of riyadh, saudi arabia (n = 847) characteristic n (%) gender female 673 (79) male 174 (21) age group in years 18–25 207 (24) >25–35 219 (26) >35–45 270 (32) >45–60 131 (15) >60 20 (2) marital status married 524 (62) not married 323 (38) education less than a college degree 121 (14) college degree 577 (68) postgraduate degree 149 (18) working status working 457 (54) not working 338 (40) retired 52 (6) are you a health practitioner? yes 217 (26) no 630 (74) figure 1: percentage of the responses of residents in riyadh, saudi arabia, to statements regarding covid-19 stigmatisation (n = 847). stigmatisation of covid-19 in riyadh, saudi arabia a cross-sectional study 528 | squ medical journal, november 2021, volume 21, issue 4 and stigmatisation of covid-19. the pearson correl ation coefficient and chi-squared test were used to assess the correlation between stigma and sociodemographic factors, exposure to covid-19, perception and knowledge. a multiple linear regression model was performed to determine stigma predictors. ethical approval (irb number: 20-0176) was obtained from princess nourah bint abdulrahman university. an informed consent statement was displayed at the start of the survey, which briefed the participants on the aim of the study and the confidentiality of the data. the statement also informed them that the data about them would only be used for research purposes. results a total of 847 adults in riyadh were included in this study with 79% of the participants being female. the participants in the >35–45 years category formed the largest component (32%); 62% of the study sample were married and 68% had a college degree. moreover, 54% were employed and only 26% worked in the healthcare field [table 1]. the questions concerned with exposure revealed that 10% of the participants had been infected or knew someone who had been infected with covid-19. meanwhile, 3% of the participants knew someone who had died as a result of covid-19. only 5% of the participants had been in contact with a covid-19 patient. the study revealed a high level of stigma among 21% of the participants and an intermediate level in 49%of the participants. low stigma was indicated among 30% of the study sample. the majority of the sample (69%) maintained a physical distance from people who had recovered from covid-19 infection and 88% agreed that people who have had covid-19 should disclose this information. almost half of the participants would avoid socialising with people who have had covid-19 even if the latter had recovered (49%) [figure 1]. strong associations were found between stigma towards covid-19 and many of the included factors. there was a highly significant association between stigma and older age groups. none of those aged 60 years or above had low stigma scores and 30% of them had a high level of stigma (p <0.001). stigmatisation scores were significantly higher among individuals who were married than among those who were not (26% versus 12%, respectively; p <0.001). stigmatisation was also higher among participants with lower education levels than those with higher education levels (35% versus 18%, respectively; p <0.003) and among those who did not work as health practitioners than those who did (23% versus 15%, respectively; p <0.001). low stigma was found to be significantly more prevalent among those who had been infected or knew someone who had been infected by covid-19 (41% versus 29%, respectively; p <0.010) [table 2]. moreover, a weak significant positive correlation was found between covid-19 stigma and both perceived severity and knowledge about prevention and control measures (r = 0.247 and 0.131, respectively; p <0.001). on the contrary, a weak significant negative table 2: factors influencing covid-19 stigmatisation among residents in riyadh, saudi arabia (n = 847) characteristic level of stigmatisation n (%) p value high stigma intermediate stigma low stigma gender 0.900 female 140 (21) 331 (49) 202 (30) male 37 (21) 83 (48) 54 (31) age group in years <0.001 18–25 26 (13) 98 (47) 83 (40) >25–35 41 (19) 93 (42) 85 (39) >35–45 67 (25) 144 (53) 59 (22) >45–60 37 (28) 65 (50) 29 (22) >60 6 (30) 14 (70) 0 (0) marital status <0.001 married 138 (26) 259 (49) 127 (24) not married 39 (12) 155 (48) 129 (40) education <0.003 less than a college degree 42 (35) 53 (44) 26 (21) college degree 108 (19) 288 (50) 181 (31) postgraduate degree 27 (18) 73 (49) 49 (33) working status 0.100 working 86 (19) 218 (48) 153 (33) not working 77 (23) 168 (50) 93 (28) retired 14 (27) 28 (54) 10 (19) are you a health practitioner? <0.001 yes 34 (15) 92 (42) 91 (42) no 143 (23) 322 (51) 165 (26) have you or anyone you know been infected with covid-19? <0.010 yes 9 (11) 39 (48) 34 (41) no 168 (22) 375 (49) 222 (29) fatmah almoayad, samira mahboub, lujain bin amer, alaa alrabiah and anwar alhashem clinical and basic research | 529 correlation between covid-19 stigma and perceived susceptibility was found (r = −0.080; p = 0.021). however, the total knowledge score, which includes symptoms, risk groups and preventive measures, was not correlated with stigma [table 3]. to find predictors of stigma, a multiple linear regression model was applied. the variables entered into the model were age, marital status, educational level, whether the respondent was a health practitioner, whether they had been exposed to infection, knowledge about preventive measures, perceived susceptibility and perceived severity of the disease. all of these variables significantly predicted the stigma score, except being a health practitioner. the probability was <0.010 for all of them and the whole model. the variables with the strongest regression weight on stigma were perceived severity of the disease, knowledge about preventive measures, not having previous exposure to the disease and low education level [table 4]. discussion the study found that stigma exists in moderate to high levels among more than two-thirds of riyadh’s residents. this supports the findings of previous studies that reported a statistically significant positive correlation between many infectious diseases, including those caused by the influenza a virus (h1n1/h3n1/h5n1) and social stigma.2 notably, there is limited literature concerning stigmatisation of infectious diseases in saudi arabia. however, several studies have indicated that hiv/aids has been stigmatised.19,20 a qualitative study involving patients who recovered from the middle east respiratory syndrome coronavirus in saudi arabia revealed that they experienced social stigmatisation, alienation and rejection.21 the high rate of stigmatisation among the study participants highlights the importance of apt interventions to avoid the potentially harmful consequences of healthcare avoidance and healthy behaviours. to the best of the authors’ knowledge, this is the first study that assesses public stigmatisation towards covid-19 in saudi arabia. in addition, the current investigation was carried out during the time of the pandemic thereby providing more accurate insight into the phenomenon being studied. it must be stated here that a full covid-19 stigma scale is under development by the present research team. for this study, the part of the scale concerned with public stigmatisation was used and it showed good reliability and validity. several studies have identified a strong relationship between the stigma of infectious disease and education, profession, income, health status, age and perceived risk factors such as residential location.2 the present study found the stigma towards covid-19 to be strongly associated with older age, lower education levels, being married and not being a healthcare professional. thus, the interventions to reduce covid-19 stigma should suitably target these groups. the present study also found that general knowledge about covid-19 was not associated with stigma. the lack of a relationship between stigma and knowledge is common in infectious diseases; however, table 3: correlation between covid-19 stigmatisation and perception and knowledge about the disease among residents in riyadh, saudi arabia (n = 847) variable correlation with stigma p value perceived susceptibility -0.080 0.021 perceived severity 0.247 <0.001 knowledge about prevention and control measures 0.131 <0.001 total knowledge 0.009 0.789 table 4: multiple linear regression predicting stigma against covid-19 infection among 847 residents from the city of riyadh, saudi arabia variable estimate se t ratio prob>|t| intercept 12.173 1.408 8.65 <0.001 age 0.052 0.016 3.21 <0.001 marital status [married] 0.490 0.189 2.60 <0.010 educational level [college degree or higher] -0.628 0.221 -2.85 <0.005 are you a health practitioner? [no] 0.255 0.184 1.39 0.166 have you or anyone you know been infected with covid-19? [no] 0.701 0.255 2.74 0.006 total knowledge about measures for prevention and control 0.721 0.217 3.33 <0.001 perceived susceptibility -0.600 0.140 -4.25 <0.001 perceived severity 1.037 0.148 7.02 <0.001 se = standard error; prob>|t| = two sample t-test. stigmatisation of covid-19 in riyadh, saudi arabia a cross-sectional study 530 | squ medical journal, november 2021, volume 21, issue 4 a rational explanation for this is still elusive.2 notably, this study did find a correlation between stigma and specific knowledge about preventive measures and practices. this could be related to the nature of preventive behaviours which involve, to a large extent, personal hygiene, perhaps causing people to consider this infection to be a consequence of poor hygiene. on the other hand, it must be noted that these findings contradict those regarding the stigmatisation of hiv/ aids in saudi arabia; the studies concerning the latter have found a negative correlation between knowledge and stigma.19,20 this contradiction could be because of the differences concerning the nature of these diseases and the different attitudes towards their respective causative behaviours. stigma was also higher among those who had not been exposed to covid-19 infection previously. a similar finding was reported in cases of other newly emerging diseases—especially when quarantine was required—where, despite having recovered, those who had been quarantined were stigmatised.7 stigma was low among people with high perceived susceptibility, which could be because they expect to become infected themselves. on the other hand, stigmatisation was high among people with high perceived severity which could be attributed to their heightened fear of becoming infected. the findings reported for hiv/ aids have been similar.22 however, a study of another respiratory infectious pandemic—namely the h1n1 virus—did not find an association between perceived severity and stigma.4 thus, it is important to intervene early to erad icate disease stigma and promote healthcare access.13 while education can improve preventive practices, the accompanying study conducted by the current team shows that on its own, education could increase stigma.17 consequently, educational campaigns should focus on perceived susceptibility which was found to be significantly associated with low stigma towards covid-19. specifically, campaigns should raise people’s awareness of the likelihood of getting infected with covid-19. relevant literature has shown that stigmatisation of an infectious disease leads to abstention from testing and healthcare and this would certainly have a substantial impact on the quality of life of the individual concerned. as suggested by mahajan et al. concerning hiv/ aids stigma, it is recommended to develop and reinforce a social and legal framework to reduce the consequences of stigmatisation.23 there is a need for an in-depth qualitative study to explore the experience of stigma among covid-19 patients and healthcare workers who come in contact with covid-19 patients. as part of the larger research project, a covid-19 stigma scale is being developed. it is recommended to be used for future research on this subject to explore not only the experiences of patients and healthcare practitioners as carriers of stigma but also the consequences of stigmatising covid-19 in various contexts. convenience nonprobability sampling that was used for this study was a limitation in as much as it prevented generalisability of this study’s findings. however, the large sample size increased the confidence level to 98% and the real value was within ±4% of the surveyed value. conclusion the present study revealed that the prevalence of stigma against the covid-19 infection is high among 21% of riyadh’s adult population. the factors that were significantly associated with the high stigma scores generated among the studied sample were old age, being married, low educational level, not working in the healthcare field, not being exposed to the infection previously, high knowledge about preventive measures, low perceived susceptibility and high perceived severity of the disease. all of these factors, except working in the healthcare field, could significantly predict stigma against covid-19. the saudi health authorities need to direct educational campaigns towards increasing the perception of susceptibility and awareness regarding the high chance of getting infected. it is also recommended that stigma eradication policies and interventions be implemented to avoid public health consequences. c o n f l i c t o f i n t e r e s t the authors report no conflicts of interest. f u n d i n g this research was funded by the deanship of scientific research at princess nourah bint abdulrahman university through the fast-track research funding program. a u t h o r s’ c o n t r i b u t i o n all authors (fa, sm, lab, ala, ana) have substantially contributed to the design of the study, data collection, drafting the manuscript and approved the final version for submission. fa, lab, ana contributed in the literature review and discussing the results. sm, ala contributed to data analysis and interpretation. fatmah almoayad, samira mahboub, lujain bin amer, alaa alrabiah and anwar alhashem clinical and basic research | 531 references 1. neuberg sl, smith dm, asher t. why people stigmatize: toward a biocultural framework. in t. f. heatherton, r. e. kleck, m. r. hebl, & j. g. hull (eds.), the social psychology of stigma. new york, usa: guilford press, 2000. pp. 31–61. 2. williams j, gonzalez-medina d, le q. infectious diseases and social stigma. med health sci j 2011; 4:58–70. https://doi. org/10.15208/mhsj.2011.127. 3. de vries sg, cremers al, heuvelings cc, greve pf, visser bj, bélard s, et al. barriers and facilitators to the uptake of tuberculosis diagnostic and treatment services by hard-toreach populations in countries of low and medium tuberculosis incidence: a systematic review of qualitative literature. lancet infect dis 2017; 17:e128–43. https://doi.org/10.1016/s14733099(16)30531-x. 4. mccauley m, minsky s, viswanath k. the h1n1 pandemic: media frames, stigmatization and coping. bmc public health 2013; 13:1116. https://doi.org/10.1186/1471-2458-13-1116. 5. brooks sk, webster rk, smith le, woodland l, wessely s, greenberg n, et al. the psychological impact of quarantine and how to reduce it: rapid review of the evidence. lancet 2020; 395:912–20. https://doi.org/10.1016/s0140-6736(20)30460-8. 6. chew nw, lee gk, tan by, jing m, goh y, ngiam nj, et al. a multinational, multicentre study on the psychological outcomes and associated physical symptoms amongst healthcare workers during covid-19 outbreak. brain behav immun 2020; 88:559–65. https://doi.org/10.1016/j.bbi.2020.04.049. 7. des jarlais dc, galea s, tracy m, tross s, vlahov d. stigmatization of newly emerging infectious diseases: aids and sars. am j public health 2006; 96:561–7. https://doi. org/10.2105/ajph.2004.054742. 8. person b, sy f, holton k, govert b, liang a, garza b, et al. fear and stigma: the epidemic within the sars outbreak. emerg infect dis 2004; 10:358–63. https://doi.org/10.3201/ eid1002.030750. 9. hatzenbuehler ml, phelan jc, link bg. stigma as a fundamental cause of population health inequalities. am j public health 2013; 103:813–21. https://doi.org/10.2105/ ajph.2012.301069. 10. chang hj, huang n, lee ch, hsu yj, hsieh cj, chou, yj. the impact of the sars epidemic on the utilization of medical services: sars and the fear of sars. am j public health 2004; 94:562–4. https://doi.org/10.2105/ajph.94.4.562. 11. world health organization. coronavirus. from: https://www. who.int/health-topics/coronavirus accessed: may 2020. 12. world health organization. mental health and psychological resilience during the covid-19 pandemic. from: http:// www.euro.who.int/en/health-topics/health-emergencies/ coronavirus-covid-19/news/news/2020/3/mental-healthand-psychological-resilience-during-the-covid-19-pandemic accessed: may 2020. 13. stangl al, earnshaw va, logie ch, van brakel w, simbayi lc, barré i, et al. the health stigma and discrimination frame work: a global, crosscutting framework to inform research, intervention development, and policy on health-related stigmas. bmc medicine 2019; 17:31. https://doi.org/10.1186/s12916-019-1271-3. 14. center for disease control and prevention. reducing stigma. from: https://www.cdc.gov/coronavirus/2019-ncov/daily-lifecoping/reducing-stigma.html accessed may 2020. 15. lin cy. social reaction toward the 2019 novel coronavirus (covid-19). soc health behav 2020; 3:1–2. https://doi.org/10.4 103/shb.shb_11_20. 16. general authority for statistics. annual yearbook 2015. saudi statistical yearbook 51. from: https://www.stats.gov.sa/en/411; 2015 accessed may 2020. 17. almoayad fa, bin-amer la, mahboub s, alrabiah am, alhashem am. preventive practices against covid-19 among residents of riyadh, saudi arabia. j infect dev ctries 2021; 15:780–6. https://doi.org/10.3855/jidc.13175. 18. likert r. a technique for measurement of attitudes. arch psychol 1932; 140:5–55. 19. badahdah am. stigmatization of persons with hiv/aids in saudi arabia. j transcult nurs 2010; 21:386–92. https://doi. org/10.1177/1043659609360873. 20. raheel h. stigma towards people living with hiv/aids (plwas) among adolescents of riyadh, kingdom of saudi arabia. j aids clin res 2016; 7:612. https://doi.org/10.4172/2155-6113.1000612. 21. almutairi af, adlan aa, balkhy hh, abbas oa, clark amj. “it feels like i’m the dirtiest person in the world.”: exploring the experiences of healthcare providers who survived mers-cov in saudi arabia. j infect public health 2017; 11:187–91. https:// doi.org/10.1016/j.jiph.2017.06.011. 22. limage-pierre m. phd thesis. walden university, columbia, usa: 2016. stigma and hiv testing among african american women in new jersey. 23. mahajan ap, sayles jn, patel va, remien rh, ortiz d, szekeres g, et al. stigma in the hiv/aids epidemic: a review of the literature and recommendations for the way forward. aids 2008; 22:s67–79. https://doi.org/10.1097/01. aids.0000327438.13291.62. 2008-issue1.indd abstract washing machines are part of every household and there are various reports of upper extremity injuries due to inadequate safety precautions while operating the machine. most of the injuries occur when an attempt is made to remove the clothes from the machine and the hand gets caught in the spinning machine. the presentation can vary from minor soft tissue injuries to a mangled upper extremity. the chance of neurovascular damage resulting in compartment syndrome is very high. the author reports three cases of washing machine injuries to draw attention to this not so uncommon injury. the relevant literature is also considered. keywords: injury, arm; fracture; child injuries; washing machines; case report; oman. washing machine injuries of the upper extremity case reports with a review of the literature s s suresh department of orthopaedics, ibri regional referral hospital, sultanate of oman email: dr.s.s.suresh@gmail.com مع حاالت تقرير الغسيل مكائن عن الناجتة اصابات الطرف العلوي مراجعة أدبيات اس سوريش اس الالزمة السالمة أخذ احتياطات لعدم نظرا تقارير عديدة ألصابات الطرف العلوي وهناك ، من اثاث البيت مهما جزءا الغسيل امللخص: تعتبر مكائن خفيفة االصابة تكون أن ــن ميك . املاكنة في اليد حصر ــي ف ــبب تتس والتي منها املالبس رفع محاولة عند حتصل االصابات ــم معظ ــغيلها. تش ــاء أثن متالزمة عنها ينتج واألوعية الدموية والتي األعصاب الصابة كبير هناك احتمال . شديدة أخرى حاالت في بينما تكون فقط ، الرخوة االنسجة وتشمل ذات األدبيات الى أيضا التطرق مت . ــادرة الن غير االصابات هذه التوعية لتفادي أجل من ــيل الغس ماكنات الصابات حاالت لثالث هنا وصفا ــدم نق . ــز احلي . العالقة عمان. حالة ، تقرير الغسيل، مكائن اصابات اليد، كسر, ذراع، اصابة، الكلمات: مفتاح sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 89-92 sultan qaboos university© submitted 4th september 2007 accepted 22th january 2008 there have been various reports of washing machine related injuries ever since maccollum first published on ‘wringer arm’ injuries in 1938. 1, 2 he described the ‘wringer arm’ as an avulsion injury to the arm caused by the wringer washing machines that were popular at that time.1, 2 most of the washing machine related injuries were not clinically significant as most of the sufferers required only outpatient management, but a few were serious requiring inpatient management for many days. as the design of washing machine has changed in the recent times, most of the reports are of injuries caused by wringer washing machines. in support of this view, according to the united states consumer product safety commission, 3 there were 19,109 injuries from 1993 till year 2000 due to washing machines. most of the reported cases of washing machine injuries come from north america and were often due to a design that is now defunct. the present study documents three cases of injuries to the upper extremities caused by washing machines of more modern design. these were caused when the children were trying to unload the contents while the machine was still spinning, with or without their parents’ permission. c a s e 1 a 10 year old girl was admitted to ibri hospital, oman, in september 2004 following injury to her right forec a s e r e p o r t s s s u r e s h 90 arm when she attempted to remove the clothes from a washing machine while the machine was spinning. she sustained a closed fracture of the radial and ulnar bones of the forearm. there was gross oedema of the forearm and she was hospitalized for observation. the position was not acceptable after closed manipulation and hence she was taken for closed intramedullary fixation. the fracture united in six weeks time and she regained full range of movements and full recovery of function [figs. 1 & 2]. c a s e 2 a five year old boy presented to the orthopaedic department of ibri hospital in march 2007 with swelling of the right arm after it had been trapped in a spinning washing machine. he was diagnosed to have a closed comminuted fracture of the shaft of the right humerus which was treated conservatively. there was no neurovascular compromise in the extremity. the arm was immobilized in a back slab. the boy was admitted for three days to observe for compartment syndrome. there was uneventful healing of the fracture with normal elbow and hand function [figs. 3 & 4]. c a s e 3 a 14 year old boy presented in the accident and emergency department of ibri hospital in may 2007 with pain of his right middle finger. the injury was sustained while attempting to remove the clothes from the washing machine while the machine was still spinning. he had sustained a closed undisplaced fracture of the proximal phalanx of his middle finger, which was managed conservatively by strapping it to the neighbouring finger. at follow up he had full range of movements without residual deformity [fig. 5]. d i s c u s s i o n washing machines have been part of the household ever since the earliest washing machine, ‘the scrub board’, was invented in 1797. injuries occur when attempts are made to remove clothes from the machine and the hand gets entangled in the spinning laundry, leading to soft tissue injuries and fractures. in the previously reported studies, this occurs most in children. this present study is consonant with this view. it has been speculated that such vulnerability is probably due to parental negligence. figure 1: (case 1) fracture of the humerus figure 2: (case 1) post operative x-ray showing intramedullary k wires in situ wa s h i n g m a c h i n e i n j u r i e s o f t h e u p p e r e x t r e m i t y 91 in most machines there is a safety mechanism to stop the drum from spinning once the loading door is opened. there should be two safety features in the machine: one to keep the door shut and locked during the operation and the other to stop the machine from spinning when the door is opened. but usually there is a time delay and the machine continues to spin even when the door is open. to prevent injury, the washing machine lid, which blocks access to the spinning drum, should be locked in the closed position during the wash and spin cycles; however, most machines continue to spin even when the lid is open causing injury to people trying to remove clothes. a time-delay feature in the lid lock using a thermal element4 is a recently patented improved safety feature. previous wringer machines had ‘instinctive’ release mechanisms which stopped the machine to prevent hand injuries. usually, when the arm is trapped, an attempt is made to pull out the arm instead of activating the safety release. the severity of the injury, which occurs due to mechanical and thermal damage, is not obvious initially, but only a few hours later. these children need to be hospitalised and observed for soft tissue injuries and compartment syndromes.1, 5 the vascular status of the extremity has to be periodically assessed and fasciotomy done if required. in rare cases, a child can present with degloving or mangled extremity. many authors recommend hospitalization for 48 hours since the magnitude of the soft tissue injury is not obvious at presentation, with initial assessment of neurovascular integrity and radiological survey to rule out skeletal injuries.1, 5 simple elevation compared to compression dressings is found to be effective in preventing vascular compromise. in an animal study by adams and fowler,6 they found maximum damage to tissues at 24 hours, although it began at three to five hours. in their study, striated muscle was found to have the maximum injury. injuries that can occur include: friction injuries; compression causing contusion of skin and muscles; fractures and haematomas, and degloving injuries.5 deshmukh in 2005, 7 reported a case of irreducible volar subluxation of the proximal interphalangeal joint of the index finger in a woman, sustained when she attempted removal of clothes while the washing machine was slowing down. most of the injuries caused now are due to automatic machines as the united states stopped production of wringer machines in 1983.3 the injuries in the present series were due to top loaded machines which figure 3: (case 2) post operative x-ray showing fractured humerus figure 4: (case 2) x-ray showing united fracture s s s u r e s h 92 are popular in oman. the injuries occurred during the spin cycle when patients tried to remove clothes while the machine was still running. front loading machines use 40-60% less water and 30-50 % less energy than top-loaders, but are expensive. child injury could be due to specific preventable factors and inadequate child supervision. there should be attentive supervision around known hazards that are frequent sites of injury. 5, 8-10 c o n c l u s i o n given the risk, there are various measures that would prevent washing machine injuries to children. parents should be counselled regarding the proper location of the machine; the need to keep it unplugged to prevent injury and better child supervision. injuries could also be prevented by improved safety features such as a triggering system, sensitive enough to detect even a small opening of the lid. a further improvement would be a list of safety features and measures clearly displayed in arabic on a visible area of the machine. r e f e r e n c e s 1. posch jl, weller cn. mangle and severe wringer injuries of the hand in children. j bone joint surg 1954; 36:57-63. 2. kwan mk, saw a, ahmad ts. automatic top loader washing machine related injury. a report of four cases with serious injury. med j malaysia march 2005; 60:112-114. 3 warner bl, kenney bd, rice m. washing machine related injuries in children: a continuing threat. inj prev 2003; 9:357-360. 4. osvatic ms. washing machine lid lock with memory wire actuator. new patent. from http://www.freepatentsonline.com/20060101869.html 18/5/2006. accessed aug 2007. 5. golden gt, fisher jc, edgerton mt. wringer arm reevaluated a survey of current surgical management of upper extremity compression injuries. ann surg 1973; 177:362-369. 6. adams jp, fowler fd. observations in wringer injuries an experimental study. j bone joint surg 1961; 43:1179-1186. 7. deshmukh nv, sonanis sv, stothard j. irreducible volar dislocations of the proximal interphalangeal joint. emerg med j 2005; 22:221-223. 8. landen mg, bauer u, kohn m. inadequate supervision as a cause of injury deaths among children in alaska and louisiana. pediatrics 2003 feb; 111:328-331. 9. press e, lederer m, o’shoughnessy, andelman sl. wringer washing machine injuries. am j public health 1964; 54:812-822. 10. hyder aa. childhood injuries (guest editorial). inj prev 2003; 9:292. figure 5: (case 3) fracture of proximal phalanx a 30 year old multigravida presented to the gynecology department of sultan qaboos university hospital, oman, at 32 weeks pregnancy. both parents were healthy and the marriage was nonconsanguineous. there was no familyhistory of birth defects. an antenatal ultrasound study, prenatal mri image of a fetus with semilobar holoprosencephaly *sukhpal sawhney,1 lovina machado,2 rajeev jain1 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 93-94 sultan qaboos university© submitted 2nd july 2007 accepted 21st november 2007 i n t e r e s t i n g m e d i c a l i m a g e جنني عند الفصي نصف الدِّماغ مِ دَّ قَ مُ اجُ مَ ِالنْدِ صور الرنني املغناطيسي احلمل أثناء جني راجيف لوفينا ماجادو˛ سخبال سوهني˛ 1department of radiology and molecular imaging, sultan qaboos university hospital, muscat, oman; 2department of gynecology and obstetrics, sultan qaboos university hospital, muscat, oman; 3department of radiology and molecular imaging, sultan qaboos university, college of medicine & health sciences, muscat, oman *to whom correspondence should be addressed. email: sukh@squ.edu.om 1a. coronal plane at the level of the thalami: central horseshoe-shaped single monoventricle (arrows) with absent frontal horns, absent anterior midline falx and inter-hemispheric fissure, absent septum pellucidum with failure of cleavage of frontal and parietal lobes anteriorly; rudimentary temporal horns (arrowheads); thalami are partially separated with rudimentary third ventricle (marked *) 1b. sagittal plane: corpus callosum (arrow) is absent in the uncleavaged frontal region. temporal horn (arrowhead) is identified. note the proptosis. figure 1a: heavily t2w (haste) images in the fetal cranial coronal and sagittal planes. s u k h pa l s aw h n e y, l o v i n a m a c h a d o a n d r a j e e v j a i n 94 at 32 weeks pregnancy, raised the suspicion of a brain malformation, but it was suboptimal due to maternal habitus. an mri of the fetus, at 34 weeks pregnancy, demonstrated semilobar holoprosencephaly. the baby was born at term with microcephaly, proptosis, and dysmorphic features. the diagnosis was confirmed by a postnatal computed tomography (ct) scan. c o m m e n t holoprosencephaly (hp) is a congenital anomaly characterized by lack of cleavage of the prosencephalon. although relatively rare, it is the most common anomaly that involves both the brain and the face. prenatal diagnosis of this anomaly using ultrasonography, particularly of the less severe forms, is difficult. magnetic resonance imaging (mri) has recently become an important complement to ultrasound in prenatal diagnosis of central nervous system anomalies.1 hp is the most common anomaly affecting the ventral forebrain, occurring in 1/250 embryos and 1/830016,000 live births.2, 3 hp refers to a spectrum of disorders resulting from absent or incomplete cleavage of the forebrain (prosencephlon) during early embryologic development (days). hp is usually categorized as alobar, semilobar or lobar depending on the degree of forebrain cleavage. 4 alobar is the most severe form with complete failure of cleavage of the two cerebral hemispheres. it results in a monoventricular cavity; fusion of the thalami; absence of the corpus callosum; falx cerebri; optic tracts and olfactory bulbs. semilobar hp shares many of these same features, but demonstrates partial segmentation of the ventricles and incomplete fusion of thalami. septo-optic dysplasia, the least severe type of hp, results in separation of the ventricles and thalami and absence of the septum pellucidum.5 the advent of high-resolution real-time ultrasound imaging equipment has allowed detection of the group of holoprosencephalies, but lack of familiarity with uncommon forms may lead to diagnostic confusion. coronal sonograms of the fetal head, in addition to standard axial projections, should be performed whenever an intracranial cystic abnormality is identified.6 several characteristic midline facial malformations are associated with holoprosencephaly, including hypotelorism. the degree of facial dysmorphism tends to parallel the severity of holoprosencephaly and, therefore, sonographic evaluation of facial morphology may aid in prenatal diagnosis.7 recently, diffusion tensor imaging and fiber tracking have revealed white matter structures not apparent on routine mri imaging sequences, which are in agreement with pathologic descriptions of the holoprosencephalic brain.8 r e f e r e n c e s 1. wong alex mc, bilaniuk lt, ng kk, chang yl, chao as, wai yy. lobar holoprosencephaly: prenatal diagnosis with post natal mr correlation. prenat diagn 2005; 25:296-299. 2. roessler e, muenke m. holoprosencephaly: a paradigm for the complex genetics of brain development. j inher metab dis 1998; 21:481-497. 3. golden ja. towards a greater understanding of the pathogenesis of holoprosencephaly. brain dev 1999; 21:513-521. 4. de myer w. holoprosencephaly (cyclopia arhinencephaly). in: yinken pj, bruyn gw, eds. handbook of clinical neurology, vol 30. amsterdam: netherlands. 1977. p. 431-478. 5. byrd se, harwood-nash dc, fitz cr, rogovitz dm. computed tomography evaluation of holoprosencephaly in infants and children. j comput assist tomogr 1997; 1:456-463. 6. cayea pd, balcar i, oswaldo a jr, jones tb. prenatal dithe icu book sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 95-96 sultan qaboos university© submitted 7th november 2007 the book, running to more than 1000 pages, has 53 chapters in 16 sections covering: basic science review; preventive practices in the critically ill; vascular access; haemodynamic monitoring; disorders of circulatory flow; critical care cardiology; acute respiratory failure; mechanical ventilation; acid base disorders; renal and electrolyte disorders; transfusion practices in critical care; disorders of body temperature; inflammation and infection in the icu; nutrition and metabolism; critical care neurology; toxic ingestions.the appendices include units and conversions, selected reference ranges and clinical scoring systems. the icu book is excellent reference material for all physicians, not just intensivists. it is a valuable resource for any health professional, from medical student to experienced physicians and a must for anyone entering critical care medicine, anaesthesia, accident and emergency, medicine or surgery and even for critical care nurses as well. it provides a superior review for residents preparing for board examinations and the essential background for icu rotations. the icu book is a very complete overview of fundamentals and the physiology behind patient care presented in a succinct manner. the latest complex physiological findings are broken down into simple concepts, accompanied by important straight to the point facts and easy to understand illustrations. the short paragraphs prevent you from getting lost in the subject. the text is brilliantly written and easy to read and learn from, with simple english for those who speak english as a foreign language; every nurse can follow it as well. the emphasis on managing critically ill patients in a simple manner with the support of evidence-based medical literature is also useful for patient care outside the icu. b o o k r e v i e w املركزة العناية وحدة �كتاب مارينو ال. بول : املؤلف author: paul l marino publisher: lippincott williams and wilkins. third edition 2007 isbn: 13: 9 78-0-07817-4802-5 price: or 24 available at: al manahil educational email: manahil@omantel.net.om au th o r i n f o r m ati o n dr. marino is chairman of the department of medicine and critical care director of saint vincent’s midtown hospital in new york city. he is also clinical associate professor of new york medical college in valhalla. the third edition of the icu book welcomes dr. kenneth sutin, department of anaesthesiology and surgery at bellevue hospital centre and associate professor of anaesthesiology and surgery at university school of medicine in new york city, who adds his expertise to the final 13 chapters of the book. th e i c u b o o k 96 the icu book covers a broad spectrum of critical care topics. the third edition has undergone extensive revision in content and most of the chapters have been rewritten. newly renamed and refocused chapters on hot topics are: acute coronary syndromes, severe airflow obstruction and anaemia and red blood cell transfusion in the icu. additional new chapters include hyperthermia and hypothermia syndromes and infection control in the icu. close to 400 new tables and figures including radiographs, ct scans, electrocardiograms and microscopic images have been added to provide visual references, which aid in comprehension of the text. the editor is to be congratulated on enforcing the original aim to produce a book that is well organised, with topics that are easy to find for quick reference and exam review. the majority of chapters make good use of tables and figures. critical points and controversies are bold faced throughout the text. most chapters include a so-called final word with an important take-home message. each chapter has an extensive and generally up-to-date reference list, subdivided into specific topics as an easy link to further readings, and with emphasis on evidence-based clinical practice guidelines. in general, the icu book has good quality paper and binding. the large print and solid text unbroken by illustrations and brilliant simple figures with great message make the book pleasant to read. a future edition should not be any larger so that the book retains its handy portability. however, i found there were too few details about non-invasive–ventilation. also the ramsay score, which assesses the level of icu sedation, although described in the text, should be included in the appendix of clinical scoring systems. as an owner of the previous edition and the german translation, i am even more impressed with this third edition. the icu book has been always a great guide for my everyday practice as anaesthetist and i highly recommend this excellent reference book, available at a reasonable price that will disappoint nobody. r e v i w e r karin nollain department of anesthesia and intensive care unit, sultan qaboos university hospital, muscat, sultanate of oman email: karin@squ.edu.om december 2007 vol 8 after meeting.indd sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 215-218 sultan qaboos university© submitted 14th april 2007 accepted 19th september 2007 1faculty of medicine, cairo university, cairo, egypt; 2pharmacy department, sultan qaboos university hospital, muscat, oman; 3royal hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: ial_zakwani@yahoo.com hypoparathyroidism in adult patients with beta-thalassemia major gihan ali a m sleem,1 *ibrahim s al-zakwani,2 muhanna almuslahi3 abstract objective: to evaluate the prevalence of hypoparathyroidism in adult transfusion-dependent patients with beta-thalassemia major in a teaching referral hospital in oman. methods: all adult (>3 years) patients with beta-thalassemia major seen at royal hospital in oman between 2004 and 2006 were studied. demographic, pharmaceutical, clinical and biochemical data were collected for all the subjects. analyses were performed using both descriptive and univariate statistics. results: a total of 3 patients were included into the study with an overall mean age of 9±3 years ranging from 4 to 30 years. just over half of the subjects were males (n=6; 52%). all the patients were on hypertransfusion and combined chelation therapy with desferrioxamine 40-60 mg/kg 5 days per week and deferiprone 75 mg/kg/day. three of the patients had low levels of parathyroid hormone (<.6 pmol/l). a further three patients had normal levels of parathyroid hormone (.6 – 9.3 pmol/l) in the presence of low serum calcium levels (<2. mmol/l). these patients (with normal hypoparathyroid hormone levels, but lower calcium levels) were also defined to have hypoparathyroidism bringing the total prevalence of hypoparathyroidism in this cohort of adult patients with beta-thalassemia major to 9% (6 out of 3). the patients with hypoparathyroidism had statistically significantly lower levels of parathyroid hormone (2.7 versus 5.3 pmol/l; p=0.03) and serum calcium (.7 versus 2.3 pmol/l; p=0.004) compared to those without hypoparathyroidism. conclusion: the prevalence of hypoparathyroidism in adult beta-thalassemia major patients at this referral center was significantly higher (9%) than those reported elsewhere (2.5 and 0.7%). keywords: hypoparathyroidism; thalassemia major; beta-thalassemia; oman. الدم ثالسيميا مبرض املصابني البالغني املرضى لدى رَيْقات الدُّ صورُ قُ بيتا نوع الرئيسي املصلحي مهنا ، الزكواني سعود إبراهيم ، سليم عبداملولى جيهان علي نقل على واملعتمدين بيتا نوع ــي الدم الرئيس ــيميا ثالس مبرض املصابني املرضى البالغني لدى رَيْقات قُصورُ الدُّ ــار إنتش معدل امللخص: الهدف: تقييم مبرض واملصابني 13 سنة) من (أكثر املرضى البالغني جميع املقطعية الدراسة هذه الطريقة: شملت مان. عُ في مستشفى تعليمي مرجعي في الدم الدميغرافية املعطيات جمع مت .2006 – 2004 بني ما مان للفترة عُ في السلطاني املستشفى في العالج تلقوا ممن بيتا نوع الرئيسي الدم ثالسيميا االحادي. واملتغير الوصفي االحصائي التحليل ــتخدام باس البيانات حتليل مت املرضى. جلميع احليوية بالكيمياء املتعلقة واملعلومات ــريرية والدوائية والس بقليل النصف من أكثر الذكور عدد كان ــنة. 14 30 س ، ومداها مابني ــنة 19 ± 3 س أعمارهم ــط متوس 31 مريضا ــة الدراس ــملت النتائج: ش 40-60 ملجرام/ ديسفيروكسامني اخلَلْب باستخدام لعالج باالضافة ، مفرط بشكل الدم نقل لعملية املرضى جميع خضع (%52) (16 مريضا). 1.6 (أقل من 3 مرضى ــي ف منخفضاً ة كان رَيقَ الدُّ ــون هرم وجد أن معدل يومياً. ــم 75 ملجرام/كج وديفيربرون ــبوعياً ، أس ــة أيام خمس ــم ملدة كج 2.1 (أقل من الدم لكالسيوم منخفض معدل مع (1.6 9.3 بيكومول/لتر) آخرين 3 مرضى لدى طبيعياً الهرمون معدل كان بينما بيكومول/لتر)، من يعانون كمرضى الدم) ــيوم لكالس منخفض ومعدل الدريقة غدد هرمون من عادي معدل لديهم (ممن الثالثة املرضى هؤالء تعريف مت لتر). ملمول/ يصل الرئيسي بيتا نوع الدم ثالسيميا مبرض واملصابني البالغني املرضى من اموعة هذه في املرض إنتشار معدل يجعل مما الدريقة نشاط غدد إنخفاض معدل منخفض لديهم املصابني أن وجد املصابني, ــع غير م الدريقة غدد ــاط بانخفاض نش املصابني املرضى مقارنة عند .(31 أصل (6 من 19% ــى إل كانت . 2.3 بيكومول/لتر) (1.7 مقابل لكالسيوم الدم ومعدل منخفض ((p=0.031 5.3 بيكومول/لتر) (2.7 مقابل الغدد تلك هرمون من نوع الرئيسي الدم ثالسيميا مبرض واملصابني البالغني املرضى في الدريقة غدد نشاط إنخفاض إنتشار معدل اخلالصة: أن قيمة احصائية. النتائج ذات .(10.7% (2.5 و أماكن أخرى في املسجلة من املعدالت بوضوح أعلى وهو ،(19%) هو املرجعي املركز هذا في بيتا . عمان ، بيتا نوع ثالسيميا الدم ، الرئيسي الدم ثالسيميا رَيْقات ، الدُّ الكلمات: قُصورُ مفتاح c l i n i c a l a n d b a s i c r e s e a r c h 216 g i h a n a l i a b d u l m aw l a s l e e m , i b r a h i m s au d a l z a k wa n i a n d m u h a n n a a l m u s l a h i beta-thalassemia major, first described by cooly and lee in 1925,1 is a haemoglob-inopathy caused by a defect in the production of the b globin chain. the disease is manifested by anaemia, hepato-splenomegaly, growth retardation, bone changes and jaundice. the combination of regular blood transfusion and chelation has extended the life span of these patients.2, 3 however, despite chelation therapy, regular blood transfusion led to iron overload, that resulted in frequent endocrine complications including hypogonadism, diabetes mellitus, hypothyroidism and hypoparathyroidism.4 hypoparathyroidism secondary to siderosis, first described by gabriele in 1971,5 is now a well recognized complication of regular blood transfusion occurring in the second decade of life; however, the incidence of hypoparathyroidism varies from centre to centre.6 asymptomatic hypocalcaemia is common in these patients and may be missed for some; thus it is important to check for hypocalcaemia in the presence of mild hypoparathyroidism, especially in the second decade of life. improvement in chelation therapy has largely resulted in the reduction of the prevalence of hypoparathyroidism, but has yet to eliminate it entirely.7, 8 the current study was conducted to determine the prevalence of hypoparathyroidism as well as the description of the various clinical and biochemical parameters in a group of adult patients with beta-thalassemia major at the royal hospital, a tertiary care hospital in muscat, sultanate of oman. m e t h o d s the study included all adult patients (>13 years) with beta-thalassemia major being treated at the royal hospital in oman. all the patients were on a hypertransfusion regimen and combined chelation therapy with desferrioxamine 40-60 mg/kg 5 days per week and deferiprone 75 mg/kg/day. the demographic and clinical data of all the patients studied were obtained including age, sex, height, body weight, age at first blood transfusion , age at start of regular desferrioxamine chelation, duration of iron chelation, compliance, history of splenectomy and laboratory investigations, including average serum ferritin level in the last year and hepatitis c virus (hcv) seropositivity. all patients were tested to detect whether they are hypoparathyroid. the tests included serum calcium (total), phosphorus, alkaline phosphatase and parathyroid hormone levels. hypoparathyroidism was defined as low levels of parathyroid hormone (<1.6 pmol/l) or normal levels of parathyroid hormone (1.6-9.3 pmol/l) in the presence of low serum calcium levels (<2.1 mmol/l). r e s u l t s a total of 31 patients were included in the study. the demographic and clinical characteristics of the study cohort are shown in table 1. just over half of the patients were males (n=16; 52%). the overall mean age of the cohort was19±3 years; the age range being from 14 to 30 years. the mean age at first blood transfusion and start of iron chelation therapy was 18±18 months and 9±6 years, respectively. less than half of the cohort had good compliance with iron chelation therapy (n=13; 42%). nearly two thirds of the cohort had hepatitis c antibodies (n=18; 58%), while just under a third of the patients had had their spleens removed (n=9; 29%). three of the patients had low levels of parathyroid hormone (<1.6 pmol/l). a further three patients had normal levels of parathyroid hormone (1.6-9.3 pmol/l) in the presence of low serum calcium levels (<2.1 mmol/l). these were also considered to be in a advances in knowledge despite the small sample size, this study provides the only available published literature on the prevalence estimate of hypoparathyroidism in adult patients with beta-thalassemia major in the arabian gulf. it also adds to the current scant evidence that no correlation exists between serum ferritin and parathyroid hormone levels. application to patient care because of its significant prevalence (19%), all adult beta-thalassemia major patients should be routinely monitored for any signs and symptoms of hypoparathyroidism. serum ferritin is not a good or reliable indicator of the development of hypoparathyroidism. it is therefore recommend that the parathyroid function be tested periodically, particularly when iron overload-associated complications occur. 217 h y p o pa r at h y r o i d i s m i n a d u lt pat i e n t s w i t h b e ta -th a l a s s e m i a m a j o r hypoparathyroidism state bringing the total prevalence of hypoparathyroidism in this cohort of major beta-thalassemia patients to 19% (6 out of 31). the patients with hypoparathyroidism had statistically significantly lower levels of parathyroid hormone compared to those without hypoparathyroidism, (2.7 versus 5.3 pmol/l; p=0.031). all the patients in the hypoparathyroidism group had hepatitis c antibodies compared to only 48% in the cohort without hypoparathyroidsm, and this difference was statistically significant (100% versus 48%; p=0.025). the cohort with hypoparathyroidism also had statistically significantly lower levels of serum calcium than those without hypoparathyroidism (1.7 versus 2.3 pmol/l; p=0.004). the hypoparathyroidism group had also higher levels of serum ferritin (5967 versus 5340 mcg/l; p=0.788), phosphorous (2.1 versus 1.6 mmol/l; p=0.072), and alkaline phosphatase (182 versus 124 iu/l; p=0.182). however, the differences were not statistically significant. furthermore, there was also no correlation between serum ferritin levels and parathyroid hormone levels (r=-0.015; p=0.935). d i s c u s s i o n endocrinopathies, of which hypoparathyroidism is one of the most common, are a well recognized complication of beta-thalassemia major due to chronic anaemia, hypoxia and iron overload.9, 10 the prevalence of hypoparathyroidism in our study was 19%, which is significantly higher compared to other studies (2.5% and 10.7%).11, 12 one of the possible explanations of this finding is the older age at which regular home chelation by desferrioxamine was initiated in our patients. contrary to expectations of a positive correlation between serum ferritin levels and hypoparathyridism, there were no significant differences in serum ferritin levels between those with hypoparathyridism and those without hypoparathyridism. several explanations can be put forth for this finding. the serum ferritin level can be subjected to changes with intercurrent infection and hence it is not a reliable indicator of the development of hypoparathyroidism. another explanation is the individual susceptibility to iron toxic effect or the development of organ damage by severe iron overload in the many years preceding the initiation of chelation therapy. angelopoulos et al.13 also found no correlation between serum ferritin levels and hypoparathyroidism. they went on to recomcharacteristic all (n=31) hypoparathyroidism* no (n=25) yes (n=6) p-value age, years, mean±sd 19±3 18±3 21±5 0.172 male gender, n (%) 16 (52%) 13 (54%) 3 (43%) 1.000 age at first blood transfusion, months, mean±sd 18±18 14±11 31±30 0.170 age at start of iron chelation therapy, years, mean±sd 9±6 8±5 10±8 0.297 number of patients with good compliance**, n (%) 13 (42%) 11 (44%) 3 (43%) 1.000 ferritin, mcg/l, mean±sd 5461±3268 5271±2775 5340±2738 0.788 calcium, mmol/l, mean±sd 2.2±0.26 2.3±0.08 1.7±0.28 0.005 phosphorous, mmol/l, mean±sd 1.7±.35 1.6±0.26 2.1±0.47 0.072 alkaline phosphatase, iu/l, mean±sd 135±58 125±44 182±91 0.182 parathyroid hormone, pmol/l, mean±sd 4.8±2.1 5.3±1.7 2.7±2.2 0.031 hepatitis c infection, n (%) 18 (58%) 11 (46%) 6 (100%) 0.028 splenectomized, n (%) 9 (29%) 6 (25%) 3 (50%) 0.320 *hypoparathyroidism was defined as those who had low levels of parathyroid hormone (<1.6 pmol/l) or those with normal levels of parathyroid hormone (1.6 – 9.3 pmol/l), but with lower levels of serum calcium (<2.1 mmol/l). **good compliance was defined as the regular use of subcutaneous desferrioxamine in a dose of 40-60 mg/kg 5 times per week. sd = standard deviation; percentages are column percents; p-values were generated using student’s t-tests, pearson’s χ2test, and fisher’s exact test whenever appropriate. table 1: demographic and clinical characteristics of the major beta-thalassemia cohort stratified by hypoparathyroidism* status (n=31) 218 g i h a n a l i a b d u l m aw l a s l e e m , i b r a h i m s au d a l z a k wa n i a n d m u h a n n a a l m u s l a h i mend that the parathyroid function to tested periodically, particularly when other iron overload-associated complications occur. several studies have implicated genetic risk factors in the development of chronic complications of beta-thalassemia major. filosa et al. 14 have shown that hypogonadism and severity of osteoporosis in patients with transfusion dependant beta-thalassemia major are related to the haematologic phenotype; patients with b0/b0 phenotype presented more frequently with hypogonadism and severe osteoporosis. previous published reports have already demonstrated a reasonable correlation between hypoparathyroidism and other endocrinopathies; 15, 16 therefore, it is reasonable to assume that the beta-thalassemia genotype is also responsible for the expression of endocrinopathies. however, this is only an assumption and further studies are needed to corroborate this hypothesis. the results of this study should only be applied in the context of its limitations, namely: small sample size, testing of b0/b0 genotyping, as well as lack of the details of some of laboratory measurements such as vitamin d and magnesium. a c k n ow l e d ge me n t the authors would like to thank mr. waiel al-naeem for his help in providing the arabic translation. r e f e r e n c e s 1. cooly tb, lee p. a series of cases of splenomegaly in children with anaemia and peculiar bone changes. trans am pediatr soc 1925; 37:29-30. 2. zurlo mg, de stefano p, borgna-pignatti c, di palma a, piga. a, melevendi c, et al. survival and cases of death in thalassemia major. lancet 1989; 2:27-30. 3. borgna-pignatti c, rugolloto s, de stefano p, piga a, di gregorio f, gamberini mr, et al. survival and disease complication in thalassemia major. ann ny acad sci 1998; 850:227-231. 4. italian working group on endocrine complications in non endocrinal diseases. multicentre study on prevalence of endocrine complications in thalassemia major. clin endocrinol 1995; 42:581-586. 5. gabriele of. hypoparathyroidism associated with thalassemia. south med j 1971; 64:115-116. 6. chern jp, lin kh. hypoparathyroidism in transfusion dependent patients with betathalassemia. j pediatr haematol oncol 2002; 24:291-293. 7. olivieri nf. medical progress: the beta-thalassemias. n engl j med 1999; 341:99-109. 8. rund d, rachmilewitz e. thalassemia major 1995: older patients, new therapy. blood rev 1995; 9:25-32. 9. oerter ke , kamp ga, munson pj, nienhis aw, cassorla fg, manasco pk. multiple hormone deficiencies in children with haemochromatisis. j clin endoc metab 1993; 76:357-361. 10. sonakal d. endocrine pathology. in: brancati c, ed. thalassemia, endocrine disorders. berlin: springerverlag, 1995. p. 75-82. 11. gabutti v, piga a. results of long-term iron–chelating therapy. acta hematol 1996; 95:6-36. 12. chern jp, lin kh. hypoparathyroidism in transfusiondependent patients with beta-thalassemia. j pediatr hematol oncol 2002; 24:291-293. 13. angelopoulos ng, goula a, rombopoulos g, kaltzidou v, katounda e, kaltsas d, et al. hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. j bone miner metab 2006; 24:138-145. 14. filosa a, di maio s, vocca s, saviano a, esposito g, pagano l et al. longitudinal monitoring of bone mineral density in thalassemic patients: genetic structure and osteoporosis. acta paediatr 1997; 86:342-346. 15. borgna-pignatti c, de stefano p, zonta l, vullo c, de sanctis v, melevendi c, et al. growth and sexual maturation in thalassemia major. j pediatr 1985; 106;150155. 16. aydinok y, dacran s, plat a, kavakli k, nigli g, coker m, et al. endocrine complications in patients with betathalassemia major. j trop pediatr 2002; 48:50-54. december 2008 no white pages.indd sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 261-265 sultan qaboos university© submitted 16th september 2008 accepted 24th september 2008 medical practice in the twenty-first century what, if anything, will doctors be doing? des gorman the ability of governments to identify, fund and deliver desirable health services will be increasingly challenged by ageing populations, escalating costs of health-related technology and by increasing consumer expectations. current health costs are unsustainable. the usa ‘healthspend’ is about 16% of gross domestic product (gdp); about 31% of this is consumed by bureaucracy and up to 45 million citizens have little or no access to health care.1, 2 almost 10% of australians are employed as health workers and health care costs about 10% of the australian gdp.3 the latter is increasing by 0.5% per annum such that it will double in less than 20 years. the new zealand treasury has made a similar forecast,4 which is in line with nobel laureate robert fogel’s prediction that western economies will spend about 20% of gdp on health by 2020.5 the context of this increase is that of relatively fewer tax payers in australasia as the “baby-boomer generation” leaves the workforce.6,7 the who estimates a global shortage of 4.3 million health workers for the decade 2006-16.8 it is noteworthy then that countries such as australia, new zealand and oman, which are heavily reliant on recruiting overseas trained doctors,9 are counting on remaining attractive to international health workers at a time of severe global shortage. this reliance will be variously threatened by indo-asian doctors “staying at home” to attend to an increasing affluent middle class and by the related recent decision by the indian government to recognise foreign trained doctors,10 and by an enlarging and increasingly specialised health workforce in the usa.11, 12, 13 in this context, a cautious response is probably advisable to any recommendation to address shortfalls in the medical workforce by re-training nurses or other existing health workers given the generic nature of current and predicted shortages.6, 7 this is not to argue that health provider roles will or should not change, but rather that there is a need to encourage health work careers and to create new and satisfying roles for any consequent recruits. health workforce planning is both complex and difficult; probably the only truism is that any plan is inevitably wrong. the effective variables are plentiful and comprise cultural and social changes, which include the demand-side effects of ageing and the supply-side effects of feminisation and generational changes; macro-and micro-economic changes; new biomedical technologies, pharmaceutical and health-disease industry developments and marketing; changes in the balance of power between health ‘accountants’, public health advocates and clinicians; changes in relative remuneration between and within school of medicine of the university of auckland, consultant physician to the royal navy of oman email: d.gorman@auckland.ac.nz e d i t o r i a l القرن الواحد والعشرين املمارسة الطبية في األطباء؟ سيفعل ماذا جورمان ديس d e s g o r m a n 262 the medical profession and other groups; successful trials of alternative health service models versus the power of established models and guilds; migration, recruitment and retention and international and private versus public recruitment changes; changes in medical indemnity; and, other changes in those factors that influence clinical decision making. 6, 7 , 14, 15, 16, 17, 18, 19 a change in work hours for doctors illustrates the problems for planners. the effect of every doctor in new zealand working one hour less per week is the same as 300 doctors leaving the health system completely. the inevitable conclusion is that health professionals must be able to be rapidly crossand retrained and re-deployed. recognition of this intrinsic uncertainty also supports an emphasis on generalist and inter-professional training in all health disciplines and the need for new educational models. we have previously proposed four categories of solution to shortfalls in health workforces: 20 the compression of the years of morbidity in later life; a better alignment of the elements of the medical education and health systems with each other and with patient care needs; an increase in the percentage of the community employed in health services and greater output from the current workforce; and, the identification and employment of disruptive innovations.16 compressing morbidity in later life will be difficult in the context of epidemics such as obesity and diabetes and will be opposed by increasing health service consumption by the affluent “well-worried-sick”. the commercial investment in this anxiety is considerable.19, 21 in australia and new zealand, there will be relatively fewer workers, and individual productivity gains will be opposed by generational phenomena and the effect of feminisation, work life balances, litigation and practice safety, unionisation, indebtedness, demographic changes, profitable low utility practice, and by practitioner emigration. indeed, it is probably wise that health planners begin with an assumption of an average 37.5 hour working week.22 the proposals likely to be most useful are based on the elements of the education and health systems being better aligned with each other, to increase health literacy, and with patient care needs, and on the identification and employment of disruptive innovations.16 a reasonable first step for a health planner is to debate the role that doctors should play in a health service. in the context of the increasing recognition that health costs are increasingly unsustainable, the only justification for a health service provider that takes 15 years to train to individual competency, and at a considerable cost, is the need for patient differentiation and care planning and oversight. these functions must be of high quality if a health service is to be outcome-focussed and cost-effective. if doctors in 2025 are to be employed to sclerose varicose veins, then all communities will need many times more than the current number of medical graduates.9 by contrast, if doctors are to be employed in a narrower range of predominantly cognitive roles, then the non-medical trained-for-purpose workforce will have to be extensive and adaptable. to paraphrase jean-paul sartre, you cannot choose not to choose; that is, to do nothing is to select the status quo of medical education and practice. we have argued previously that time in training is a poor facsimile of competency determination and that direct measures are needed.23 the utility of such a time-independent approach has been demonstrated by the faculty of occupational medicine of the royal australasian college of physicians. the acknowledged preface to such a system is agreement on the intended role of the worker group and consequent essential competencies (“attributes”). this editorial then will present some generic doctor ‘attributes’ that are likely to be agreed upon and sufficiently robust to stand the test of time. these should be debated vigorously as they will determine learning outcomes and responsive curricula and pedagogies. the doctor of the future should be professional. effective medical practice is contingent upon skills in the professional domains of communication, quality and safety, teaching and learning, cultural competency, ethics, clinical decision-making, leadership and management, and health advocacy.24, 25 the doctor of the future should be re-deployable. as cited above, given the uncertainty about what society might be like in 2025, let alone what the health needs and resources of that time might be, the only truism for planning the future health workforce is that the planners will ‘almost certainly get it wrong’. the inevitable conclusion then is that the doctor of the future must be able to be crossand re-trained and re-deployed. the doctor of the future should be able to recognise and employ suitable innovative disruptions, even if they result in personal role change. this is not the m e d i c a l p r a c t i c e i n t h e tw e n t y f i r s t c e n t u r y w h at, i f a n y t h i n g , w i l l d o c t o r s b e d o i n g ? 263 usual case, nor is it the common history of innovations that disrupt established groups and technologies outside the health sector.16 one previous development that illustrates both these perspectives is the nurse practitioner. this innovative disruption was predictably opposed by doctors on the grounds that doctor roles and status were threatened. in the case of obstetric services in new zealand, the result of the consequent turf war is an apparent increase in autonomy for pregnant new zealand women, which may have been gained at the expense of quality of care.26 the initial enthusiasm of employers for nurse practitioners to undertake both general and limited scopes of practice has dissipated somewhat with the realisation that there are usually only marginal savings in time to train, and in cost to employ and deploy. in part, this occurred because nursing authorities chose to follow traditional and time-punitive pathways for aspirants to obtain the new ‘higher’ qualifications. an opportunity for innovation was lost. in retrospect, it should not have been such a surprise that changing the name of a task-oriented practitioner would not significantly change the time it took or the cost of training and employing them unless the training was genuinely innovative, or unless there was a reduction in the quality or the quantity of the tasks undertaken. although this threat to doctors may have been somewhat averted, nonsensical concepts persist, such as the use of nurses to triage undifferentiated patients for doctors, rather than the other way around. the practice of differentiation is one of the few reasons why it is possible to argue that the medical section of the health workforce should be strongly rooted in science and so slow and expensive to train. the reaction of the doctors to the threat of being disrupted by nurse practitioners was understandable, given the way in which the disruption was often presented to them. it was also predictable on the basis of the history of the profession and the reaction of any community to such innovations.16 finally, it was reactionary and unhelpful. a sensible engagement of nurse practitioners and doctors has been put off by the response. the doctor of the future should be a physician-scientist. the history of medicine shows a persistently elevated status and consequent privileges for doctors.27 comparison with other health providers suggests that the basis of that status and privilege is the scientific predication and evidence base of medical practice. accordingly, contractions of training time and revisions of training for doctors should not be at the expense of scientific education; however, there is a reasonable argument that this should be predominantly clinically-oriented science. within the sciences there is a need for some rationalisation. organ anatomy is often taught in great detail, although such knowledge serves the interest of relatively few future proceduralists, in contrast to the often neglected teaching of surface anatomy, which is important to almost all doctors. similarly, teaching should focus on pathophysiology as compared to physiology per se. personal interests of basic scientists should not be allowed to dictate medical curricula. the doctors of the future should be resilient and sceptical, and will need to be if they are to remain scientific. already, the pharmaceutical industry exerts undue influence on health service expenditure and potentially distorts professional judgment.28 this is not accidental; in the usa, this industry spends about as much as the combined budgets of all the medical schools on direct doctor-propaganda.29 there are many examples of health-disease industry marketing triumphing over scientific practice; one is the use of mri images to determine surgical interventions for back surgery at a time when the ‘normal’ findings in people who did not have back pain were unknown. inevitably, escalating health costs must be curtailed. doctors with training and attributes for effective clinical decision making will be best prepared to assist with the difficult decisions regarding limiting applications of expensive health technologies. the ability to tolerate clinical uncertainty will also become increasingly important. resilience will have to be taught and reinforced through continuing medical education programmes. such programmes do exist and have reasonable track records. scepticism will also need to become a cornerstone of teaching. this will require a major change in examination techniques,23 as current recall-based assessments strongly reinforce the evolution of what are ephemeral hypotheses into “life long facts”.21, 23 the doctor of the future should have skills in and an understanding of health psychology, and of anthropology and sociology. there is widespread agreement that the future role of the doctor will be increasingly that of generalist individual health care within a population health approach;30 however, other than being taught statistical and epidemiological princid e s g o r m a n 264 ples, modern graduates are generally poorly equipped for effective preventive medicine. to do so requires education in health psychology, anthropology and sociology. mindful of the marketing success of water bottlers, who have convinced the consumer to pay three times more for their water than for petrol, there is clearly great potential for modifying health-at-risk perceptions, beliefs and behaviours. the doctor of the future should have a cognitive and general scope of practice. there is a strong financial and health outcome basis for arguing that doctors should, as much as possible, be employed in general scopes of practice.17, 31 we have already opined that a cognitively-oriented practice is the only one that would sustain critical public scrutiny in terms of how much and how long it takes us to educate doctors. to this must now be added a shift in emphasis from acute to chronic disease management. the opposite is occurring. in our medical school, about 10% of graduates have a strong interest in becoming general practitioners. unfortunately, more exposure to general practice does not translate into more inclination; the key issue is the quality and not the quantity of the exposure. nevertheless, there is evidence that “immersion programmes” do work, and particularly in respect to graduates selecting rural medical careers.32, 33 the disinclination to general medical practice is in part maintained by the significant distortion of medical career choice and practice that we have described beforehand.21 this arises from the perverse and now 70 year old actuarial decision to fund medical units of practice rather than time expended. the failure of “generalism” is global.11, 13 bodenheimer reports that less than half the training positions in family medicine in north america are taken up by local graduates. in the same edition of the new england journal of medicine, woo cites a decline in us medical graduates filling training positions, in the period from 1998 to 2006, of 51% in family medicine, 18% in internal medicine, 16% in obstetrics and gynaecology, 8% in paediatrics and of 4% in general surgery.13 to a large extent, these declines are explained by relative levels of remuneration. to the acceptance of medical education, designed to show-case general scopes of practice, must then be added the need for an urgent relative values study and realignment of remuneration and need. fear of waiting-list blow-outs and other undesirable outcomes has prevented any such political bravery in the past; the current and emergent crisis in medical workforce disposition may warrant greater fortitude now. another consideration in the context of generalism is the feminisation of the medical workforce. in new zealand, women now comprise over 50% of undergraduates and junior doctors, but only 31% of specialists, including gps.34 with respect to the future roles of doctors, there are positives to this demographic change as the cognitive and flexible generalist roles, which many of us advocate, appeal more to women. there has been much made of the fact that women work around eight fewer hours per week, 34 yet analysis of these new zealand data shows this differential is not present in the early post graduate years, or past the age of 70, although there are, as yet, few practitioners in this latter age group. there is also a suggestion that women doctors may have longer working lives;35 however, if women are to lead a generalist revival, ways must be found to make working and training more flexible, especially through the years of specialty training and early specialist practice. this should be accompanied by a revaluing of the skills needed to effect quality chronic and integrated care, so crucial to the health of society and to controlling health costs.14, 36 the future, female dominated, medical profession will need sufficient status to exert the necessary influences to maintain high standards of patient care.35, 36 along with redefining the role of a doctor, some thought must be given to addressing what will be regarded as ‘success’ in the medical profession in 2025. c o n c l u s i o n the doctor of the future is already in training. the health system that they will inherit, the health problems of that day, and the technology, which will be available to them, can only be guessed at. the reality of the latter must underpin the outcomes, which are adopted for each stage of medical training, and the curricula and pedagogies that are consequently derived. the debate about these competencies and who decides them needs to begin. r e f e r e n c e s 1. the lancet. where health care is not a right. the lancet 2002; 359:1871. 2. woolhandler s, campbell t, himmelstein du. costs of health care administration in the united sates and canada. n engl j med 2003; 349:768-775. m e d i c a l p r a c t i c e i n t h e tw e n t y f i r s t c e n t u r y w h at, i f a n y t h i n g , w i l l d o c t o r s b e d o i n g ? 265 3. the australian institute of health and welfare. australian health 2006. canberra: aihw, 2006. p. 315. 4. gorman df, kolbe j, callaghan k, scott pj. on the elusive grail of health service quality. intern med j 2008; 38:5-7. 5. fogel rw. the escape from hunger and premature death 1700-2100. cambridge: cambridge university press, 2004. 6. schofield dj. replacing the projected retiring baby boomer nursing cohort 2001-2026. bmc health serv res 2007; 7:87. 7. schofield d, beard j. baby boomer doctors and nurses: demographic change and transitions to retirement. med j aust 2005; 183:80-83. 8. the world health organisation. working together for health. who world health workforce report. geneva: who, 2006. 9. zurn p, dumont j-c. health workforce and international migration: can new zealand compete? oecd health working paper #33. who: delsa/hea/wd/ hwp (2008)3. 10. value md. facing a doctor shortage india will recognise foreign trained medical degrees. from www.medical schools forum.htm 09 august 2008 chronicle.com/ news/artcle/4209/ accessed september 2008. 11. bodenheimer t. primary care – will it survive? n engl j med 2006; 355:861-864. 12. weiner jp. expanding the us medical workforce: global perspectives and parallels. bmj 2007: 335:236-238. 13. woo b. primary care – the best job in medicine? n engl j med 2006; 355:864-866. 14. baicker k, chandra a. medicare spending, the physician workforce, and beneficiaries quality of care. data watch, 07 april 2004; w4184-197. 15. brooks pm, lapsley hm, butt db. medical workforce issues in australia: “tomorrow’s doctors too few, too far”. med j aust 2003; 179:206-208. 16. christensen cm, bohmer r, kenagy j. will disruptive innovations cure health care? harvard business review sept-oct 2000; 102-111. 17. gorman df, scott pj. on the case that the new zealand public health system is subject to government as compared to governance. n z med j 2008; 121:9-14. 18. gorman df, scott pj, poole p. on the maldistribution of the medical workforce. intern med j 2007; 37:669-671. 19. gorman df, scott pj, poole p. on the future role of the doctor. intern med j 2007; 37:145-148. 20. gorman df, brooks pm. on solutions to shortfalls in local health workforces. (paper in progress). 21. gorman df, scott pj. the social distortion of medical practice. medicine today 2003; 4:75-77. 22. grunstein rr, rogers nl. medical work hours: time for a maggie’s law for doctoring? intern med j 2005; 35:269-271. 23. gorman df, scott, pj. time for a medical educational change in time. intern med j 2006; 36:687-689. 24. cooke m, irby dm, sullivan w, ludmerer km. american medical education 100 years after the flexner report. n engl j med 2006; 355:1339-1344. 25. racp draft professional qualities curriculum july 2006. available from http://www.racp.edu.au/members/edu/curriculum/prof_qual_curr.pdf.accessed october 2006. 26. ferguson w. the decline of gp involvement in maternity care and its possible consequences for maternal and infant health. n z med j 1999; 112:24-25. 27. porter, r. the greatest benefit to mankind: a medical history of humanity from antiquity to the present. london: harper collins, 1997. 28. breen kj, rogers w. on the need for probity when physicians interact with industry (correspondence). intern med j 2006; 36:265-269. 29. hoffman jr, wilkes m. direct to consumer advertising of prescription drugs: an idea whose time should not come. bmj 1999; 318:1301-1302. 30. gorman df, scott, pj, poole p. dilemma for medical education revisited. intern med j 2005; 35:507-509. 31. gorman df, scott, pj. is a concentration on generalist medical practitioners the solution to the new zealand health workforce crisis? n z fam physician 2005; 32:368-371. 32. dunbabin js, mcewin k, cameron i. postgraduate medical placements in rural areas: their impact on the rural medical workforce. rural remote health 2006; 6:481. epub. 2006 apr 4. 33. rourke jt, incitti f, rourke ll, kennard m. relationship between practice location of ontario family physicians and their rural background or amount of rural medical education experience. can j rural med 2005; 10:231-240. 34. the new zealand medical workforce in 2004. available from http://www.mcnz.org.nz/portals/0/publications/ workforce_2004.pdf. accessed october 2006. 35. levinson w, lurie n. when most doctors are women: what lies ahead? ann intern med 2004; 141:471-474. 36. rcp women in medicine: college statement. available from http://www.rcplondon.ac.uk/news/statements/ womenmed_keyissues.asp. accessed october 2006. 1department of internal medicine, kasr alainy university hospital, cairo, egypt; 2department of nephrology, theodor bilharz institute, cairo, egypt *corresponding author’s e-mail: taroukah5070@kasralainy.edu.eg this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to determine the incidence and factors associated with complications for kidney biopsy. percutaneous kidney biopsy is a useful diagnostic procedure. haemorrhagic complications may occur following the procedure. methods: the present study retrospectively analysed the records of patients who had percutaneous renal biopsy between march 2013 and march 2018. the cohort included both native kidney and native transplant biopsies. we have included only the first biopsy for each patient; repeat biopsies were excluded from the analysis. results: a total of 1,198 patients (332 transplant recipients and 886 native kidney patients) were included in this study. major complications occurred in 1.5% (n = 18) of patients (1.4% in native kidney biopsies versus 1.6% in kidney transplant recipients). adequate renal tissue (core of >6 glomeruli) was obtained in 91% of the patients. data analysis revealed that the incidence of major complications in the native kidney biopsy increase with an age >65 years (odds ratio = 2.4; 95% confidence interval [ci] = 1.5–5.6), estimated glomerular filtration rate (egfr) <30 ml/min/m2 (odds ratio = 9.7; 95% ci = 3.4–18.2) and anaemia (odds ratio = 3.2; 95% ci = 1.7–5.2). in transplant recipients kidney biopsy, the incidence of complications was increased with age >65 years (odds ratio = 2.8; 95% ci = 1.7–7.3), egfr <30 ml/min/m2 (odds ratio = 11.3; 95% ci = 3.5–16.8) and anaemia (odds ratio = 2.4; 95% ci = 1.4–4.7). conclusion: the incidence of major complications following kidney biopsy was 1.5% for a cohort of native kidney biopsy and kidney transplant biopsies. age >65 years, lower egfr <30 ml/min/m2 and anaemia were independent risk predictors for the occurrence of major complications in both native and transplant kidney biopsies. keywords: biopsy; biopsy, needle; complications; safety; kidney. incidence and determinants of complications of percutaneous kidney biopsy in a large cohort of native kidney and kidney transplant recipients moataz fatthy,1 ahmed saleh,1 reham a. ahmed,1 sameh abouzeid,2 seham bakry,1 *tarek abdelaziz1 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 268–273, epub. 26 may 22 submitted 26 jan 21 revisions req. 15 mar & 6 may 21; revisions recd. 13 apr & 9 may 21 accepted 18 may 21 https://doi.org/10.18295/squmj.5.2021.107 clinical & basic research advances in knowledge the incidence of major complications of percutaneous kidney biopsy is low (1.5%) in the present cohort. there are a number of factors that predict safety of kidney biopsy; most importantly, age, estimated glomerular filtration rate and anaemia. application to patient care some factors should be taken into consideration while deciding on a kidney biopsy to maximise safety. some factors are correctable (anaemia) and some other factors are not correctable (age and estimated glomerular filtration rate). renal biopsy is a procedure that has been in practice for more than 100 years.1 the technique has seen substantial evolution since the introduction of percutaneous renal biopsy in the 1940s.2,3 the main aim of the technique and needle development is to increase diagnostic yield while simultaneously decreasing the rate of complications. a percutaneous approach to obtain the kidney tissue is now considered the standard of care. the technique involves obtaining the biopsy sample using ultrasound guidance under local anaesthesia. the needles that are used during the procedure have variable gauges (14g, 16g and 18g), the outer diameter of which are 2.11, 1.65 and 1.27 mm, respectively. spring-loaded automatic needles have almost completely replaced the older true-cut® needles (merit medical®, south jordan, utah, usa) in most centres. a number of studies have suggested the superiority of automatic needles over tru-cut® needles (merit medical®) in obtaining adequate renal tissue while decreasing the rate of complications. thus, automatic spring-loaded needles have been the standard of care in most centres.4 various major complications may occur after a percutaneous renal biopsy procedure. those include massive bleeding requiring red blood cells (rbcs) transfusion, the requirement of angiographic embolisation to control the bleeding, nephrectomy or death. the incidence of major complications in native kidney biopsies is 2–8% as reported in the literature.5 other less serious compilations include renal hematoma following renal biopsy and macroscopic haematuria. a satisfactory diagnostic yield is achieved in 90–95% of cases with the use of automatic needles and obtaining 10–20 glomeruli is usually sufficient to make a pathological diagnosis. https://creativecommons.org/licenses/by-nd/4.0/ moataz fatthy, ahmed saleh, reham a. ahmed, sameh abouzeid, seham bakry and tarek abdelaziz clinical and basic research | 269 this study aimed to determine the incidence and factors associated with complications for kidney biopsy. methods the records of the renal division of kasr-alainy university hospitals were reviewed. the investigators have reviewed all the records that were available regarding patients who had undergone renal biopsy between march 2013 and march 2018. the renal division in kasr-alainy centre is a large tertiary care centre; percutaneous renal biopsies are performed on regular weekly slots. all biopsies were performed using ultrasound guidance. the cohort included both, native kidney and kidney transplant recipients. the authors have included only the first biopsy for each patient; repeat biopsies were excluded from the analysis. the recorded data include epidemiological data such as age, gender, estimated glomerular filtration rate (egfr), haemoglobin level, needle gauge and style. in the authors’ centre, it is contraindicated to perform a kidney biopsy on patients with platelets <100.000/cc (or international normalised ratio [inr] >1.00). it is also contraindicated to perform kidney biopsy when patients’ haemoglobin is <9 mg/dl as per protocol. any uncorrected bleeding diathesis was considered a contraindication for renal biopsy. desmopressin is not routinely used as a premedication in kidney biopsies as per the protocol in the investigators’ institution. all patients were required to stop anti-platelets one week before renal biopsy. patients on oral anticoagulants were required to be switched to unfractionated heparin which was held at least 12 hours before attempting renal biopsy. kidney biopsies were all performed by one investigator. to make analysis less complex, each patient had only one entry into the study. the statistical package for the social sciences (spss) version 21 (ibm corp., chicago, illinois, usa) was used to perform the statistical analysis. categorical variables were compared using the chi-squared test. continuous variables were expressed as a mean and standard deviation. the group means were compared using the mann-whitney u test. logistic regression was used to create a model to predict the development of major complications of percutaneous renal biopsy. a forward stepwise method was used in the binary table 1: patient characteristics at the time of percutaneous kidney biopsy (n = 1,198) characteristic unit native kidney transplant recipient *p value age in years mean ± sd 48 ± 17 45 ± 14 0.24 gender percentage of males 61 60 0.31 nephrotic range proteinuria ≥3 gm percentage 35 31 0.03 aki percentage 30 27 0.04 haematuria percentage 61 57 0.02 proteinuria ≥0.3 gm percentage 84 79 0.001 table 3: incidence of complications for native versus kidney transplant recipients (n = 1,198) complication n (%) p value total (n = 1,198) native kidney (n = 886) kidney transplant recipients (n = 312) gross haematuria 34 (2.8) 25 (2.8) 9 (3) 0.1 major complications 18 (1.5) 13 (1.5) 5 (1.6) 0.15 surgery 4 (0.3) 3 (0.3) 1 (0.3) 0.91 arterial embolization 3 (0.3) 2 (0.2) 1 (0.3) 0.54 need for packed rbcs transfusion 16 (1.3) 12 (1.4) 4 (1.3) 0.23 rbcs = red blood cells. table 2: gross haematuria by needle gauge in patients who underwent percutaneous kidney biopsy (n = 1,198) gross haematuria total *p value no yes 0.008 needle-gauge 14 277 16 293 16 445 9 454 18 442 9 451 total 1164 34 1198 *obtained using kruskal-wallis test. incidence and determinants of complications of percutaneous kidney biopsy in a large cohort of native kidney and kidney transplant recipients 270 | squ medical journal, may 2022, volume 22, issue 2 logistic regression. this research was conducted in accordance with the declaration of helsinki. written informed consent was obtained from all the patients. this study protocol was approved by the kasr-alainy research ethics committee (approval number ka-19-134). results there were a total of 1,198 patients who had undergone renal biopsy during the study period. the rate of major complications of the patients (including patients with repeated renal biopsies) was the same as the rate in the authors’ cohort (including only the first renal biopsy for all patients). we can conclude that this was not a source of bias. what has been included in the analysis was only the first biopsy of every patient. baseline patients characteristics of both native and transplant recipient kidney biopsies were obtained [table 1]. the biopsy was considered adequate and repre sentative if 6–10 glomeruli were obtained successfully. the overall diagnostic yield of the needles of different gauges revealed a high adequacy rate (88–96%) among all gauges [figure 1]. table 4: predictors of occurrence of major complications in native kidney biopsy (n = 886) unadjusted analysis adjusted analysis odds ratio (ci) p value odds ratio (ci) p value age in years 18–65 1.00 (reference) <0.001 1.00 (reference) <0.001 >65 2.7 (1.7–5.7) 2.4 (1.5–5.6) gender male 1.15 (0.97– 1.9) 0.71 1.1 (0.9–1.7) 0.64 female 1.00 (reference) 1.00 (reference) egfr in ml/min/m2 ≥60 1.00 (reference) <0.001 1.00 (reference) <0.001 30–59 4.7 (1.6– 12.1) 4.5 (2.3–13.4) <30 11.1 (2.6– 17.1) 9.7 (3.4–18.2) proteinuria in g/24 hours <3 1.00 (reference) 0.61 1.00 (reference) 0.54 ≥3 1.5 (0.9–3.9) 1.3 (0.9–2.7) needle gauge 14 1.5 (0.87– 2.7) 0.53 1.3 (0.85–2.1) 0.7316 1.4 (0.9–2.1) 1.1 (0.7–1.9) 18 1.00 (reference) 1.000 (reference) haemoglobin in mg/dl >13 1.00 (reference) 0.003 1.00 (reference) 0.00311–13 1.8 (1.5–5.9) 2.39 (1.5–4.5) 9–11 2.65 (1.8–6.4) 3.2 (1.7–5.2) platelets per cm3 >150,000 1.00 (reference) 0.47 1.00 (reference) 0.56 100,000–150,000 1.6 (0.9–2.3) 1.5 (0.9–2.6) aki yes 2.30 (0.7–3.6) 0.37 1.9 (0.8–5.5) 0.46 no 1.00 (reference) 1.00 (reference) glomerulonephritis yes 1.02 (0.9–2.4) 0.25 1.03 (0.9–2.6) 0.29 no 1.00 (reference) 1.00 (reference) pre-biopsy blood pressure in mmhg <140 1.00 (reference) 0.79 1.00 (reference) 0.81140–159 1.24 (0.7–6.03) 1.2 (0.31–5.6) ≥160 2.84 (0.8–9.9) 2.3 (0.55–8.6) referral critical care area 1.3 (0.8–1.9) 0.43 1.2 (0.97–1.5) 0.53non-critical care ward 1.00 (0.75–1.2) 1.00 (0.92–1.1) outpatient 1.00 (reference) 1.00 (reference) ci = confidence interval; egfr = estimated glomerular filtration rate. moataz fatthy, ahmed saleh, reham a. ahmed, sameh abouzeid, seham bakry and tarek abdelaziz clinical and basic research | 271 macroscopic haematuria occurred in 2.8% of patients (n = 34). the occurrence of macroscopic haematuria was significantly higher with the use of 14g needles [table 2]. major complications were defined as either the need for blood transfusion or the need for surgical procedure/angiographic embolisation to stop the bleeding following the biopsy procedure. the variables were adjusted for age while age was adjusted for egfr. there were 132 patients with more than one renal biopsy; however, repeat biopsies have not been included in the analysis. a total of 18 patients (1.5%) had major complications [table 3]. furthermore, predictors of occurrence of major complications following renal biopsy in native kidney biopsy and transplant, respectively, have also been tabulated [tables 4 and 5]. discussion this study included 1,198 patients who underwent percutaneous renal biopsy; this included 332 transplant recipients and 886 native kidney patients. major complications, defined as either the need for blood transfusion, surgery or arterial embolisation, figure 1: adequacy of renal tissue by needle gauge. *adequate refers to successfully obtaining 6–10 glomeruli while inade quate refers to failure to obtain 6 glomeruli. table 5: predictors of occurrence of major complications in kidney transplant recipient biopsy (n = 312) unadjusted analysis adjusted analysis odds ratio (ci) p values odds ratio (ci) p value age in years 18–65 1.0 (reference) <0.001 1.0 (reference) <0.001 >65 3.1 (1.7–5.7) 2.8 (1.7–7.3) gender male 0.8 (0.7–2.9) 0.55 0.8 (0.9–1.7) 0.83 female 1.0 (reference) 1.0 (reference) egfr in ml/min/m2 ≥60 1.0 (reference) <0.001 1.0 (reference) <0.001 30–59 5.3 (2.4–14.3) 5.1 (2.7–13.8) <30 12.9 (3.8–18.3) 11.3 (3.5–16.8) proteinuria in g/dl <3 1.0 (reference) 0.42 1.0 (reference) ≥3 1.3 (0.8–1.7) 1.4 (0.9–1.9) needle gauge 14 1.1 (0.6–1.9) 0.71 1.1 (0.8–2) 0.84 16 1.2 (0.6–1.6) 1.1 (0.7–1.9) 18 1.0 (reference) 1.0 (reference) haemoglobin in mg/dl <13 1.0 (reference) <0.001 1.0 (reference) <0.001 11<13 1.8 (0.8–5.9) 1.7 (0.9–4.5) 9–11 2.8 (1.3–5.9) 2.4 (1.4–4.7) platelets >150,000 1.0 (reference) 0.46 1.0 (reference) 0.75 100,000–150,000 1.3 (0.7–1.9) 1.4 (0.8–2) aki yes 1.5 (0.8–2.2) 0.42 1.3 (0.8–4.1) 0.34 no 1.0 (reference) 1.0 (reference) chronic allograft nephropathy yes 1.7 (0.6–2.2) 0.24 1.4 (0.6–1.8) 0.35 no 1.0 (reference) 1.0 (reference) pre-biopsy blood pressure in mmhg <140 1.0 (reference) 0.07 1.0 (reference) 0.17 140–159 2.1 (0.8–5.3) 1.8 (0.7–5.1) ≥160 3.5 (0.8–4.1) 3.3 (0.9–7.2) ci = confidence interval; egfr = estimated glomerular filtration rate. incidence and determinants of complications of percutaneous kidney biopsy in a large cohort of native kidney and kidney transplant recipients 272 | squ medical journal, may 2022, volume 22, issue 2 occurred in 1.5% of patients. gross haematuria occurred in only 2.8% of patients. this emphasises the overall safety of the percutaneous renal biopsy procedure, a finding that has been demonstrated by previous reports.6,7 adequate renal tissue was obtained in 91% of patients. there were a number of factors that predicted the development of complications. age >65 years, egfr <30 ml/min/m2 and anaemia (haemoglobin <9 mg/dl) were associated with an increased risk of developing major complications. the incidence of major complications was not statistically significant among different needle gauges. the use of either 14g or 16g was associated with more adequate renal tissue, which was statistically significant (p = 0.001). this study is one of the largest reports of kidney biopsy safety and complications in a cohort of both native kidneys and kidney transplant recipients. complications after the procedure of percut aneous renal biopsy included the observation of peri-nephric hematomas, which had an incidence of 60–70% in previous reports. nevertheless, on most occasions, peri-nephric hematomas are not clinically meaningful and thus should not be regarded as an alarming complication.8 there are a number of other haemorrhagic complications, which include macroscopic haematuria, major bleeding requiring surgery or angiographic embolisation. a number of factors have been suggested to be associated with the potential haemorrhagic complications that can be divided into procedure-related factors and patientrelated factors. patient related factors include age >40 years, female gender, elevated serum creatinine and lower haemoglobin level at the time of the procedure.5,9,10 the main procedure related factor was the use of 14g needles. it was observed that the increased number of passes due to the use of smaller diameter needles did not lead to increased haemorrhagic complications.11,12 many previous studies have found that the complication rates were lower with the use of small diameter biopsy needles.6,13–15 in a nationwide registry in norway, the incidence of major complications was found to be 0.9%.16 in the current study, the incidence of major complications was not affected by needle gauge; however, the use of 18g was associated with the occurrence of more frequent gross haematuria. the explanation for this observation was that the small gauge needles allowed easy deviation of the needle towards the high-density vessels in the pelvis. in another small cohort of 86 patients, the use of 14g needles was associated with more frequent hematoma following the percutaneous renal biopsy procedure.17 a large meta-analysis of more than 9,000 patients who underwent percutaneous native kidney biopsy found that the use of 14g needles was associated with a higher incidence of packed rbcs transfusion.5 the incidence of haemorrhagic complications, as reported in this meta-analysis, was macroscopic haematuria in 3.5% and the requirement for packed rbcs transfusion in 0.9% of patients. anaemia is another important predisposing factor for the occurrence of post procedure haemorrhagic complications. this has been evident in previous reports.16 data on kidney transplant biopsy complications stratified by needle gauge is scarce. however, one prospective randomised trial found no statistically significant difference between the three needle diameters (14g, 16g and 18g) in the incidence of major complications. the use of 14g needles was associated with more pain.18 however, that study was limited by the small sample size; the present study cohort provides a larger sample of transplant patients. one of the strengths of the current study is that the cohort included both, native and renal transplant recipient patients. different needle gauges are well represented in the sample. nevertheless, the study has a number of limitations. firstly, the number of needle passes for each biopsy could not be determined. secondly, this is a single centred study; a multi-centred study would provide more data about the difference in operators’ expertise. thirdly, the incidence of post-biopsy renal hematoma was not reported in the present study as the records did not provide sufficient data to include this complication in the analysis. lastly, the study protocol specified recording only the first biopsy for every patient. this is closely comparable to the rate of major complications in the main cohort. we therefore do not count this as a major source of bias. conclusion the incidence of major complications following kidney biopsy was 1.5% for a cohort of patients undergoing native kidney biopsy and age >65 years, lower egfr (<30 ml/min/m2) and anaemia (haemoglobin <9 mg/dl) were independent risk predictors for the occurrence of major complications in both native and transplant kidney biopsies. c o n f l i c t s o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. moataz fatthy, ahmed saleh, reham a. ahmed, sameh abouzeid, seham bakry and tarek abdelaziz clinical and basic research | 273 a u t h o r s’ c o n t r i b u t i o n mf, as and ta contributed to research idea development, data collection and data analysis. all authors contributed to the drafting of the manuscript, while sa, sb and raa revised manuscript. all authors approved the final version of the manuscript. references 1. cameron js, hicks j. the introduction of renal biopsy into nephrology from 1901 to 1961: a paradigm of the forming of nephrology by technology. am j nephrol 1997; 17:347–58. https://doi.org/10.1159/000169122. 2. iversen p, brun c. aspiration biopsy of the kidney. am j med 1951; 11:324–30. https://doi.org/10.1016/0002-9343(51)90169-6. 3. alwall n. aspiration biopsy of the kidney, including i.a. a report of a case of amyloidosis diagnosed through aspiration biopsy of the kidney in 1944 and investigated at an autopsy in 1950. acta med scand 1952; 143:430–5. 4. riehl j, maigatter s, kierdorf h, schmitt h, maurin n, sieberth hg. percutaneous renal biopsy: comparison of manual and automated puncture techniques with native and transplanted kidneys. nephrol dial transplant 1994; 9:1568–74. 5. corapi km, chen jl, balk em, gordon ce. bleeding complic ations of native kidney biopsy: a systematic review and meta analysis. am j kidney dis 2012; 60:62–73. https://doi.org/10.105 3/j.ajkd.2012.02.330. 6. manno c, strippoli gf, arnesano l, bonifati c, campobasso n, gesualdo l, et al. predictors of bleeding complications in percu taneous ultrasound-guided renal biopsy. kidney int 2004; 66:1570–7. https://doi.org/10.1111/j.1523-1755.2004.00922.x. 7. korbet sm. percutaneous renal biopsy. semin nephrol 2002; 22:254–67. https://doi.org/10.1053/snep.2002.31713. 8. doyle aj, gregory mc, terreros da. percutaneous native renal biopsy: comparison of a 1.2-mm spring-driven system with a traditional 2-mm hand-driven system. am j kidney dis 1994; 23:498–503. https://doi.org/10.1016/s0272-6386(12)80370-2. 9. whittier wl, korbet sm. timing of complications in percut aneous renal biopsy. j am soc nephrol 2004; 15:142–7. https:// doi.org/10.1097/01.asn.0000102472.37947.14. 10. joseph aj, compton sp, holmes lh, annand a, self se, fitzgibbon wr, et al. utility of percutaneous renal biopsy in chronic kidney disease. nephrology (carlton) 2010; 15:544–8. https://doi.org/10.1111/j.1440-1797.2010.01293.x. 11. constantin a, brisson ml, kwan j, proulx f. percutaneous us guided renal biopsy: a retrospective study comparing the 16-gauge end-cut and 14-gauge side-notch needles. j vasc interv radiol 2010; 21:357–61. https://doi.org/10.1016/j.jvir.2009.11.005. 12. burstein dm, korbet sm, schwartz mm. the use of the automatic core biopsy system in percutaneous renal biopsies: a comparative study. am j kidney dis 1993; 22:545–52. https:// doi.org/10.1016/s0272-6386(12)80927-9. 13. eiro m, katoh t, watanabe t. risk factors for bleeding complic ations in percutaneous renal biopsy. clin exp nephrol 2005; 9:40–5. https://doi.org/10.1007/s10157-004-0326-7. 14. parrish ae. complications of percutaneous renal biopsy: a review of 37 years' experience. clin nephrol 1992; 38:135–41. 15. briganti em, dowling j, finlay m, hill pa, jones cl, kincaid-smith ps, et al. the incidence of biopsy-proven glomerulonephritis in australia. nephrol dial transplant 2001; 16:1364–7. https:// doi.org/10.1093/ndt/16.7.1364. 16. tøndel c, vikse be, bostad l, svarstad e. safety and complic ations of percutaneous kidney biopsies in 715 children and 8573 adults in norway 1988-2010. clin j am soc nephrol 2012; 7:1591–7. https://doi.org/10.2215/cjn.02150212. 17. hogan jj, mocanu m, berns js. the native kidney biopsy: update and evidence for best practice. clin j am soc nephrol 2016; 11:354–62. https://doi.org/10.2215/cjn.05750515. 18. nicholson ml, wheatley tj, doughman tm, white sa, morgan jdt, veitch ps, et al. a prospective randomized trial of three different sizes of core-cutting needle for renal transplant biopsy. kidney int 2000; 58:390–5. https://doi.org/10.1046/j.1523-1755.2000.00177.x. https://doi.org/10.1159/000169122 https://doi.org/10.1016/0002-9343(51)90169-6 https://doi.org/10.1053/j.ajkd.2012.02.330 https://doi.org/10.1053/j.ajkd.2012.02.330 https://doi.org/10.1111/j.1523-1755.2004.00922.x https://doi.org/10.1053/snep.2002.31713 https://doi.org/10.1016/s0272-6386(12)80370-2 https://doi.org/10.1097/01.asn.0000102472.37947.14 https://doi.org/10.1097/01.asn.0000102472.37947.14 https://doi.org/10.1111/j.1440-1797.2010.01293.x https://doi.org/10.1016/j.jvir.2009.11.005 https://doi.org/10.1016/s0272-6386(12)80927-9 https://doi.org/10.1016/s0272-6386(12)80927-9 https://doi.org/10.1007/s10157-004-0326-7 https://doi.org/10.1093/ndt/16.7.1364 https://doi.org/10.1093/ndt/16.7.1364 https://doi.org/10.2215/cjn.02150212 https://doi.org/10.2215/cjn.05750515 https://doi.org/10.1046/j.1523-1755.2000.00177.x december 2008 no white pages.indd sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 368-369 sultan qaboos university© received 21st september 2008 re: physicians, climate change & human health to the editor, i congratulate you for having chosen a very pertinent topic for your message from the editor-in-chief, in the july 2008 issue of squmj.1 this is a global issue which has vast and long term effects on everyone in every region of the world. it is even more gratifying to note that you want physicians in all capacities to be aware of the issue and contribute to solutions in whatever capacity that they can. perhaps an equally if not more important theme and, in my opinion, the most important health matter today from the prevention point of view, is that of unhealthy lifestyles. this is again an issue of worldwide importance, but of special significance to this region and this country in particular where we are experiencing a flood of its after-effects. vast masses of the population, especially young children and youth are being adversely affected by this scourge, due probably to wealth and easy access to every amenity of life, many of which are not being used judiciously. it is therefore of special relevance to all physicians with the need for them to be pro-active rather than reactive. lifestyle is important to us as individuals, families and as communities, as we all in our turn contribute to overall national health. unfortunately, this subject has not yet been the focus of any world health day. unhealthy lifestyles are perhaps equally if not much more dangerous and devastating than climate change, especially for our most vital resource, our new generation, which carries the hopes and aspirations of every country. if the effects of climate change will affect the lives of millions, unhealthy lifestyles trap billions. every branch of medicine will face the consequences and they will pose a gradually increasing burden and challenge for them in the coming decades, with, unfortunately, with little hope of successful solutions, if present trends continue and the world clings to unhealthy lifestyles as the dearest, most cherished and attractive thing on earth. excuse me for my rather strongly expressed sentiments, but this is a reality and it needs expressing in clear and strong words for the world and to those who can make the most difference: parents, teachers and doctors, all of whom are presently playing a rather passive instead of a strong and proactive role. in oman and other gulf states, we already have certain adverse factors, such as a high proportion of consanguinity and genetic defects which gives us little chance of escape from many health problems. we therefore have no choice but to choose, establish and propagate this golden option: a healthy lifestyle. this is a strong, cost-effective preventive strategy against the fury of many modern diseases, many of them incurable and life-long afflictions which top the global list of causes of morbidity and mortality and to which we are unfortunately and helplessly both succumbing and contributing. this region has innumerable risks and dangers knocking at its door, waiting to enter and afflict the lives of us and our families. we can and have imported the best hospitals of the world, but this will never improve the overall general health of the nation. hospitals are meant for the sick and those who are lucky enough to be aware of their disease and have it detected. unawareness of health problems has unfortunately become rampant in the modern world, even though we are saturated with information and information technology. we know everything that goes on in the most distant corners of the world, but give little importance and time to what is going on within our bodies and our families. in oman, we have provided the very best of everything to our most loved ones, our children, right from birth, keeping them safe and on the road to health. why do we then allow them as they grow older to take on our unhealthy lifestyle, most of it imported from the knowledgeable west, and allow them to contribute further to our already high national health risks? why do we allow them detour off the road to health and safety? this is exactly what we are doing, of course unknowingly and maybe unintentionally. are they immune to the health risks of adult life? do they have to experience the same fate as we and others and run these risks till their old age and death? l e t t e r t o t h e e d i t o r r e : p h y s i c i a n s , c l i m at e c h a n g e & h u m a n h e a lt h 369 can we not change the present environment and scenario? why cannot we as parents, teachers and doctors be good, healthy and responsible role models so making a healthy lifestyle a social norm and a mass movement? we certainly can do it if we control our gradually increasing desires, strengthen our will power and, most important of all, give deep and serious thought to the future of our children, our families and our nation. mushtaq a khan department of family medicine & public health college of medicine & health sciences sultan qaboos university r e fe r e n c e s 1. al lamki l. physicians, climate change and human health message from editor-in-chief. squ med j 2008; 8:125-127 july 2008.indd control and management of hypertension at a university health centre in oman abdulaziz almahrezi,1 *ibrahim al-zakwani,2 ayman al-aamri,3 samia al-khaldi,3 nisrin al-zadjali,3 mohammed al-hatali,3 abdullah al-shukeili3 sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 179-184 sultan qaboos university© submitted 4th march 2008 accepted 21st april 2008 جامعي صحي وعالجه مبركز ضغط الدم ارتفاع مرض على السيطرة عمان في عبداهللا ، الهطالي محمد ، الزدجالي ، نسرين اخلالدي ، ساميه العامري الزكواني ، أمين ، إبراهيم احملرزي عبدالعزيز الشكيلي عمان. في قابوس في مركز صحي بجامعة السلطان عالجه وطرق عليه والسيطرة الدم ضغط ارتفاع مرض انتشار معدل امللخص: الهدف: تقييم والذين ، أكثر أو ــنة 18 س الدم البالغة أعمارهم ارتفاع ضغط املصابني مبرض املرضى جميع ــتعادية االس املقطعية ــة الدراس هذه ــملت الطريقة: ش ــاطي الدم االنقباضي واالنبس ضغط قيم حتليل مت .2002 1998 و بني عامي ما الفترة خالل قابوس ــلطان الس بجامعة الصحي املركز مبراجعة قاموا (التقرير الدم ضغط ارتفاع وعالج وتقييم ــف وكش ملنع املشتركة الوطنية اللجنة معايير ــتخدام اس مت للمركز. األخيرة الثالثة الزيارات في ــجلة املس البيانات حتليل مت االنبساطي. للضغط زئبقي و90 مليمتر االنقباضي للضغط زئبقي 140 مليمتر ,أقل من بالضغط التحكم درجة لتعريف السابع) ) هو الدم ضغط ارتفاع ــار مرض انتش معدل أن وجد ، طبيا ــجال 7702 س مراجعة النتائج: بعد األحادي. املتغير اإلحصائي ذو التحليل ــتخدام باس العمانيني من كانوا املرضى أغلب %54 101 مريضة). ) بلغت النساء ــبة نس ــنة. 55±11 س للعينة العمر ــط متوس كان %2.4 187 مريضا). على ضغط ــيطرة الس درجة أن لوحظ (41 % 77 مريضا). ــت كان ــيطرة الس املصابني بضغط الدم حتت ــى املرض ــبة نس ــا). (66 % 123 مريض كانوا املرضى معظم .(p= 0.017 , % 53 ــع م (35 % مقارنة إحصائيا معتدة ــورة بص العمانيني مع غير مقارنة العمانيني ــدى ل أقل ــت ــدم كان ال حتويل ومثبطات البيتا محصرات أدوية كانت . ــن بدواءي يعاجلون %27 50 مريضا) ) بينما كان هناك %70 131 مريضا). ) ــد ــدواء واح ب ــون يعاجل أدوية كانت املزدوج العالج أدوية فيما يخص . التوالي على %25 47 مريضا) و %34 64 مريضا ) أحادية كأدوية شيوعا األكثر األجنيوتينسن أنزمي األكثر هي %24 12 مريضا) ) للبول املدرة األدوية مع البيتا ومحصرات %28 14 مريضا) ) البيتا محصرات مع األجنيوتينسن انزمي حتويل مثبطات أن الدراسة هذه أظهرت الوطني. املتوسط مع منخفضا باملقارنة يعد العينة هذه في الدم ارتفاع ضغط مرض ــار انتش معدل اخلالصة: إن ــيوعا. ش دول أخرى. في املسجلة النسب ولكنه أعلى من األمثل ليس هو الدم ارتفاع ضغط على السيطرة درجة عمان. املرض ، ، عالج الوقاية والسيطرة ، ضغط الدم ارتفاع الكلمات: مفتاح departments of 1family medicine & public health; 2pharmacy, sultan qaboos university hospital, muscat, sultanate of oman; 3medical students college of medicine & health sciences, sultan qaboos university, muscat, oman *to whom correspondence should be addressed. email: ial_zakwani@yahoo.com abstract objectives: to evaluate the prevalence of hypertension, its control and management at sultan qaboos university (squ) health centre, oman. methods: this was a retrospective cross-sectional study, in which were enrolled all the subjects (≥8 years), with the diagnosis of essential hypertension, who attended the squ health centre between 998 and 2002. the systolic and diastolic blood pressure (bp) values of the last three visits were used for analysis. bp control was defined using the joint national committee (jnc-7) criteria, <40 mmhg and <90 mmhg for systolic and diastolic bps, respectively. analyses were performed using univariate statistics. results: among the 7,702 medical records reviewed, the prevalence of hypertension was 2.4% (n = 87). the overall mean age of the cohort was 55± years, 54% (n = 0) were females, and majority of the subjects were omanis (n = 23; 66%). the proportion of subjects who had their bp controlled was 4% (n = 77) with omanis significantly less likely to have their bp controlled compared to non-omanis (53% versus 35%; p = 0.07). the majority of the subjects were on mono (n = 3; 70%) followed by dual (n = 50; 27%) anti-hypertensive therapies. the most frequent mono anti-hypertensive therapies were b-blockers (n = 64; 34%) and angiotensin-converting enzyme (ace) inhibitors (n = 47; 25%). among the dual combination therapies, the most common prescribed regimens were ace inhibitor plus b-blocker (n = 4; 28%) and b-blocker plus diuretic (n = 2; 24%). conclusion: the prevalence of hypertension in this patient population was low compared to the national average. this study shows that control of hypertension is not optimal, but higher than those reported elsewhere. key words: hypertension; prevention and control; disease management; oman. c l i n i c a l a n d b a s i c r e s e a r c h a b d u l a z i z a l m a h r e z i , i b r a h i m a l z a k wa n i , ay m a n a l a a m r i , s a m i a a l k h a l d i , n i s r i n a l z a d j a l i , m o h a m m e d a l h ata l i a n d a b d u l l a h a l -s h u k e i l i 180 hypertension is a common disease with significant morbidity and mortality. it is theleading diagnosis made in physician offices in the united states.1 twenty-six percent of the world adult population has hypertension.2 moreover, the proportion is expected to rise further in 2025 to 29.2% with an estimated total number of 1.56 billion affected adults.2 the reported prevalence varies around the world with the lowest prevalence in rural india (3.4% in men and 6.8% in women) and the highest prevalence in poland (68.9% in men and 72.5% in women).3 in oman, a community based survey conducted in 2000 estimated the prevalence of hypertension to be 33%.4 high blood pressure (bp) leads to an increasing risk of stroke, myocardial infarction and cardiovascular disease, all of which cause mortality.5, 6, 7 furthermore, hypertension contributes to the prevalence of other cardiovascular risk factors, such as insulin resistance, lipid abnormalities, changes in renal function, obesity, left ventricular hypertrophy, diastolic dysfunction, and abnormalities in vascular structure.8 clinical trials have unequivocally shown that lowering bp reduces cardiovascular morbidity and mortality in patients with hypertension of all degrees of severity.8 despite the significance of the problem with respect to overall health, control of high blood pressure (bp < 140/90 mmhg while on antihypertensive medication) is far from being optimal. data from the usa (the national health and nutrition survey) have shown that those achieving target bp account only for 36% of the hypertensive population.9 a control rate of 25% was reported from a primary health care in saudi arabia.10 researchers from bahrain have reported a control rate of 16.5%.11 similar data on hypertension control from oman is lacking. the aim of this study was to determine the prevalence of hypertension, its control and management at sultan qaboos university (squ) health centre in muscat, oman. the squ health centre provides free health care services to all university employees and their dependants. m e t h o d s this study included all patients, 18 years and above, who were documented to have “essential hypertension” in their medical records at the health centre. the cohort had to have a minimum period of one year follow up. the charts reviewed were of those patients attending the health centre over a five-year period between january 1st 1998 and december 31st 2002. the following information was collected: age, gender, nationality (omani, non-omani), the three most recent bp readings, medications, current smoking status (yes, no), body mass index (bmi), the frequency of attendance at the outpatient clinic (within 3 months, 3-6 months, > 6 months), associated chronic diseases and the presence of any complications secondary to advances in knowledge blood pressure (bp) control in this cohort was low. diabetics, in particular, had a much lower bp control. omanis were significantly less likely to achieve bp targets compared to non-omanis. the majority of the subjects were on mono anti-hypertensive therapy. beta-blockers were the most commonly used monotherapy followed by angiotensin-converting enzyme (ace) inhibitors. the most commonly prescribed dual anti-hypertensive regimens were ace inhibitor plus beta-blocker and beta-blocker plus diuretic. application to patient care physicians should be more aggressive in controlling hypertension. physicians should continually update their knowledge with the latest treatment guidelines. combination therapies should be prescribed more often, particularly in diabetics. close attention should be paid to omanis in order to improve their bp control. c o n t r o l a n d m a n a g e m e n t o f h y p e r t e n s i o n at a u n i v e r s i t y h e a lt h c e n t r e i n o m a n 181 hypertension. descriptive statistics were used to describe the data. for categorical variables, frequencies and percentages were reported. differences between groups were analyzed using pearson’s χ2 tests or fisher’s exact tests (for cells less than 5). for continuous variables, means and standard deviations (±sd) were presented. mean differences between groups were analysed using unpaired student’s t-tests. an a priori two-tailed level of significance was set at the 0.05 level. statistical analyses were performed using stata version 9.2 software (statacorp 2006, stata statistical software; release 9.2, college station, tx, usa). table 1: demographic, clinical, healthcare resource use, and pharmaceutical characteristics of the study cohort stratified by blood pressure (bp) goal attainment as per the joint national committee ( jnc-7) recommendations characteristic blood pressure goal attainment as per jnc-7 no (n = 110) yes (n = 77) p-value demographic age, mean±sd, in years 54±11 55±11 0.546 female gender, n (%) 57 (52%) 44 (57%) 0.472 omani national, n (%) 80 (73%) 43 (56%) 0.017 bmi, mean±sd, in kg/m2 30±5.7 31±6.4 0.558 smoking status, n (%) 8 (7.3%) 4 (5.2%) 0.764 clinical dyslipidaemia, n (%) 44 (40%) 34 (44%) 0.571 diabetes mellitus, n (%) 34 (31%) 25 (32%) 0.821 cardiac disease, n (%) 13 (12%) 5 (6.5%) 0.315 diabetic nephropathy, n (%) 4 (3.6%) 1 (1.3%) 0.650 diabetic retinopathy, n (%) 3 (2.7%) 0 (0%) 0.269 stroke, n (%) 3 (2.7%) 0 (0%) 0.269 healthcare resource use attendance of opd visits, n (%) 0.955 within 3 months, n (%) 91 (83%) 63 (82%) between 3-6 month, n (%) 13 (12%) 10 (13%) after 6 months, n (%) 6 (5.5%) 4 (5.2%) pharmaceutical not on anti-hypertensive, n (%) 4 (3.6%) 2 (2.6 %) 0.894 monotherapy beta-blocker, n (%) 35 (32%) 29 (38%) acei, n (%) 23 (21%) 24 (31%) arb, n (%) 7 (6.4%) 1 (1.3%) ccb, n (%) 4 (3.6%) 1 (1.3%) diuretic, n (%) 5 (4.6%) 2 (2.6%) dual therapy acei + beta-blocker, n (%) 9 (8.2%) 5 (6.5%) acei + ccb 3 (2.7%) 1 (1.3%) acei + diuretic 2 (1.8%) 1 (1.3%) acei + arb 1 (1.0 %) 0 (0%) beta-blocker + diuretic, n (%) 7 (6.4%) 5 (6.5%) beta-blocker + ccb, n (%) 3 (2.7%) 2 (2.6%) beta-blocker + arb, n (%) 2 (1.8%) 2 (2.6%) diuretic + arb 2 (1.8%) 1 (1.3%) ccb + arb, n (%) 2 (1.8%) 0 (0%) ccb + diuretic, n (%) 1 (1.0%) 1 (1.3%) sd = standard deviation; bmi = body mass index; opd = outpatient department; acei = angiotensin converting enzyme inhibitor; arb = angiotensin receptor blocker; ccb = calcium channel blocker; bp control was defined as casual bp of <140 (systolic) and <90 mmhg (diastolic) as per the jnc-7; percents are column percents; differences between groups were analyzed using unpaired student’s t-test, pearson’s χ2 test, and fisher’s exact test whenever appropriate. a b d u l a z i z a l m a h r e z i , i b r a h i m a l z a k wa n i , ay m a n a l a a m r i , s a m i a a l k h a l d i , n i s r i n a l z a d j a l i , m o h a m m e d a l h ata l i a n d a b d u l l a h a l -s h u k e i l i 182 r e s u l t s among the 7,702 charts reviewed, the prevalence of hypertension was 2.4% (n = 187). the characteristics of the study cohort are shown in table 1. the overall mean age of the cohort was 55±11 years, 54% (n = 101) were females, and majority of the subjects were omanis (n = 123; 66%). the proportion of subjects who had their bp controlled was 41% (n = 77) with omanis significantly less likely to have their bp controlled compared to non-omanis (35% versus 53%; p = 0.017). omanis were also slightly more obese compared to the non-omanis (bmi was 31 versus 29 kg/m2; p = 0.091). the proportion of diabetic subjects who had their bp controlled (<130 mmhg systolic and <80 mmhg diastolic) was only 10% (n = 6 out of 59 diabetics) [table 1]. males were more likely to be smokers than females (12% versus 2%; p = 0.013). furthermore, females were also more obese than their male counterparts (bmi was 31 versus 29 kg/m2; p = 0.048). however, there was no statistical difference in hypertension goal attainment between the genders (39% male versus 44% female; p = 0.472). the majority of the subjects were on monotherapy (n = 131; 70%) followed by dual regimens (n = 50; 27%). the most frequent mono anti-hypertensive therapies were b-blockers (n = 64; 34%) and angiotensin-converting enzyme (ace) inhibitors (n = 47; 25%). among the dual combination therapies, the most common prescribed regimens were ace inhibitor plus b-blocker (n = 14; 28%) and b-blocker plus diuretic (n = 12; 24%). those on dual therapies were less likely to attain their goal than those on monotherapies (36% versus 44%; p = 0.359; power 12%). however, the dual regimen group also consisted of more diabetics (38% versus 27%; p = 0.169; power 25%) as well as those with dyslipidaemia (54% versus 37%; p = 0.043). d i s c u s s i o n the three main findings in our study were the following: the majority of our subjects (59%) were not treated so as to achieve their target bp, particularly diabetics; omanis were less likely to have their bp controlled compared to non-omanis, and the majority of our patients were on monotherapy. research conducted worldwide points clearly to the difficulty in achieving satisfactory bp control in a large proportion of treated patients. worldwide, control rates vary from as low as 5.4% in korea to as high as 58% in barbados.3 numerous factors may contribute to ineffective hypertension control.12 nonadherence with medication is very common amongst hypertensive patients. it has been reported that up to 60% of patients discontinue their anti-hypertensive medications within the first 12 months.13 reasons include complex medication regimens, adverse effects, convenience factors such as dosing frequency, personal health beliefs, and attitudes regarding treatment of an often asymptomatic condition.14 physician behaviour could also be a major obstacle to the successful achievement of target bp goals. the major concern relates to the reluctance of physicians to change treatment when bp control is inadequate.15 the physician might not also be aware of the recent treatment guidelines. for example, a study from the usa reveals that 41% of physicians have not heard of or are not familiar with the reports of the joint national committee (jnc), detection, evaluation, and treatment of high blood pressure and their hypertension treatment guidelines.16 patients who have both diabetes and hypertension are at a higher risk of cardiovascular events compared to non-diabetics.17 the united kingdom prospective diabetes study (ukpds) suggests that tight control of bp prevents the development of microvascular and macrovascular complications in patients with type 2 diabetes.18 the guidelines of the seventh report of the jnc recommend a target bp of 130/80 in patients who have concomitant diabetes. 19 physicians, however, appear to be doing a poor job of helping patients with diabetes achieve this goal. in a study by abbott and colleagues, only 11% of the diabetic patients treated for hypertension were reported to have achieved the systolic bp goal of <130 mmhg.20 in our study, the bp control in diabetics was similar (10%); furthermore, only 27% (16 out of 59) of the diabetics were on dual anti-hypertensive therapies in our study. this is against the jnc19 recommendations, which clearly state that diabetics be treated with at least two anti-hypertensive medications to obtain optimal bp control. possible reasons for the poor control of bp among omanis are ethnicity, higher prevalence of male gender (55% versus 45%; p = 0.003) and obesity (31 versus 29 kg/m2; p = 0.091). racial differences have been documented as a cause for differences in the prevalence, course, and control of hypertension.21 for instance, african-americans were reported to have an increased prevalence of hypertension, higher mean bp levels, and higher morbidity and mortality rates attributable c o n t r o l a n d m a n a g e m e n t o f h y p e r t e n s i o n at a u n i v e r s i t y h e a lt h c e n t r e i n o m a n 183 to hypertension, compared to white americans.21 hypertensive blacks have a higher incidence of left ventricular dysfunction, stroke, and renal damage, but a lower incidence of ischaemic heart disease, than do hypertensive whites.22 hypertensive blacks also have lower rates of bp control.21 furthermore, the two races respond differently to anti-hypertensive medications. blacks respond well to thiazide diuretics, but poorly to b-blockers and angiotensin-converting enzyme (ace) inhibitors compared to whites.23 pathophysiological differences between the two populations such as salt sensitivity, rennin levels and dopamine response to a salt load might be responsible for the differences in effectiveness.22 recent clinical trials have shown that effective bp control can be achieved in most hypertensive patients, but to do so requires two or more antihypertensive drugs for most patients.24, 25, 26 thirty to 60% of patients will be controlled with a single drug regimen, while two drugs in combination are likely to improve control rates in 80 to 85%; three or more drugs will provide control in 90 to 95% of patients.27 most of our patients were on monotherapy. in fact, this might have contributed to unsatisfactory bp control in our subjects. in addition, diuretics which are widely recommended as a first line therapy were only rarely used in our cohort (3.7%) [table 1]. this low use could be due to the fact that the pharmaceutical industry promotes the use of newer and more expensive alternatives. this study has two major limitations. the study population is highly educated, and the treatment of hypertension may not be representative of those experienced by the general population. the ideal setting at the university which ensures the availability of a wide variety of anti-hypertensive medications and easy access to the facilities of a tertiary care hospital differ widely from the setting and population in the general community. c o n c l u s i o n in conclusion, hypertension is not adequately controlled in our cohort particularly in diabetics. the racial background was a significant factor correlating with bp control. anti-hypertensive medications were mainly used as monotherapy in contrast to the recent hypertension guidelines as recommended by jnc-7. further research in a community setting is needed in order to draw more accurate conclusions about the state of hypertension control in oman. r e f e r e n c e s 1. hing e, cherry dk, woodwell da. national ambulatory medical care survey: 2004 summary. adv data 2006; 374:1-33. 2. kearney pm, whelton m, reynolds k, muntner p, whelton pk, he j. global burden of hypertension: analysis of worldwide data. lancet 2005; 365:217-223. 3. kearney pm, whelton m, reynolds k, whelton pk, he j. worldwide prevalence of hypertension: a systematic review. j hypertens 2004; 22:11-19. 4. al riyami aa, afifi mm. hypertension in oman: distribution and correlates. j egypt public health assoc 2002; 77:383-407. 5. staessen ja, gasowski j, wang jg, thijs l, den hond e, boissel jp, et al. risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. lancet 2000; 355:865-872. 6. lewington s, clarke r, qizilbash n, peto r, collins r. age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. lancet 2002; 360:1903-1913. 7. psaty bm, furberg cd, kuller lh, cushman m, savage pj, levine d, et al. association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. arch intern med 2001; 161:1183-1192. 8. messerli fh, williams b, ritz e. essential hypertension. lancet 2007; 370:591-603. 9. ong kl, cheung bm, man yb, lau cp, lam ks. prevalence, awareness, treatment, and control of hypertension among united states adults 1999-2004. hypertension 2007; 49:69-75. 10. al-rukban mo, al-sughair am, al-bader bo, altolaihi ba. management of hypertensive patients in primary health care setting, auditing the practice. saudi med j 2007; 28:85-90. 11. al khaja ka, sequeira rp, damanhori ah. treatment of hypertension in bahrain. ann pharmacother 2003; 37:1511-1517. 12. vidt dg. new strategies for blood pressure control. j hum hypertens 2002; 16:s124-127. 13. esposti ld, di martino m, saragoni s, sgreccia a, capone a, buda s, et al. pharmacoeconomics of antihypertensive drug treatment: an analysis of how long patients remain on various antihypertensive therapies. j clin hypertens (greenwich) 2004; 6:76-84. 14. osterberg l, blaschke t. adherence to medication. n engl j med 2005; 353:487-497. 15. hyman dj, pavlik vn, vallbona c. physician role in lack of awareness and control of hypertension. j clin hypertens (greenwich) 2000; 2:324-330. a b d u l a z i z a l m a h r e z i , i b r a h i m a l z a k wa n i , ay m a n a l a a m r i , s a m i a a l k h a l d i , n i s r i n a l z a d j a l i , m o h a m m e d a l h ata l i a n d a b d u l l a h a l -s h u k e i l i 184 16. hyman dj, pavlik vn. self-reported hypertension treatment practices among primary care physicians: blood pressure thresholds, drug choices, and the role of guidelines and evidence-based medicine. arch intern med 2000; 160:2281-2286. 17. casiglia e, zanette g, mazza a, donadon v, donada c, pizziol a, et al. cardiovascular mortality in non-insulin-dependent diabetes mellitus. a controlled study among 683 diabetics and 683 ageand sex-matched normal subjects. eur j epidemiol 2000; 16:677-684. 18. tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: ukpds 38. uk prospective diabetes study group. bmj 1998; 317:703-713. 19. chobanian av, bakris gl, black hr, cushman wc, green l a, izzo jl jr, et al. the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the jnc 7 report. jama 2003; 289:2560-2572. 20. abbott k, basta e, bakris gl. blood pressure control and nephroprotection in diabetes. j clin pharmacol 2004; 44:431-438. 21. bosworth hb, dudley t, olsen mk, voils ci, powers b, goldstein mk, et al. racial differences in blood pressure control: potential explanatory factors. am j med 2006; 119:70 e9-15. 22. eisner gm. hypertension: racial differences. am j kidney dis 1990; 16:35-40. 23. seedat yk. varying responses to hypotensive agents in different racial groups: black versus white differences. j hypertens 1989; 7:515-518. 24. fox jc, leight k, sutradhar sc, demopoulos la, gleim gw, lewin aj, et al. the jnc 7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy. j clin hypertens (greenwich) 2004; 6:437-442; quiz 43-44. 25. jamerson k, bakris gl, dahlof b, pitt b, velazquez e, gupte j, et al. exceptional early blood pressure control rates: the accomplish trial. blood press 2007; 16:8086. 26. neutel jm, smith dh, weber ma, schofield l, purkayastha d, gatlin m. efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the systolic evaluation of lotrel efficacy and comparative therapies (select) study. j clin hypertens (greenwich) 2005; 7:641-646; quiz 7-8. 27. moser m, pickering t, sowers jr. combination drug therapy in the management of hypertension: when, with what, and how? j clin hypertens (greenwich) 2000; 2:94-98. 2008-issue1.indd skandalakis’ surgical anatomy the embryology and anatomic basis of modern surgery sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 97-98 sultan qaboos university© submitted 28th september 2007 the book is based on the half-century experi-ence of the editor-in-chief in teaching anat-omy. the purpose of the book is to provide brief facts on embryology and surgical anatomy with special reference to their surgical implications. the contents come in two volumes with a total 29 chapters. the book contains many good cadavaric illustrations of anatomy and drawings of embryology to illustrate the text. also there are tables to summarize historical aspects of anatomy and surgery. a large number of references are also given for those wishing to further explore any given subject. every chapter has the same well organised, logical format i.e.: i) history ii) embryogenesis iii) surgical anatomy, with the help of illustrations and land marking and some flow charts. in some sections, there are also descriptions of histology and minimally invasive surgery. chapter 1 describes the neck and its important anatomical triangles with its surgical implications, and the following chapters the thoracic wall, breast, mediastinum with its related organs, the respiratory system, the heart and the great thoracic vessels and the diaphragm in the same format. in chapter 9, the anatomy of the abdominal wall is described enabling the reader to fully understand the inguinal anatomy and, thus, how inguinal hernias arise. this chapter also covers the laparoscopic aspect of hernia surgery. the following two chapters cover the peritoneum and retro-peritoneum with tabulation of omental development from childhood to adulthood. he describes the peritoneal spaces, internal herniation, and its good anatomical relation. next, there is an excellent description of the aorta and the inferior vena cava. the course and variation of the vessels is described. also various vessel injuries are classified with related degrees of ischemia, the anatomical relations and other surgical complications. the pharynx follows and then a detailed description of the esophagus with emphasis on the التشريحي واألساس األجنة علم لسكاندالكيز اجلراحي التشريح احلديثة للجراحة سكاندالكيز اي. التحرير: جون رئيس editor: john e skandalakis publisher: paschalidis medical publication ltd. international student edition, two volumes, 2004. isbn: 960-399-199-8 orders: paschalidis@medical-books.gr au th o r i n f o r m ati o n the editor-in-chief of this book, prof. skandalakis, is a greek-american academic scholar from emory university, atlanta, georgia, usa. he has published a vast number of scientific publications and books. several recognized other scholars from around the world have contributed in writing the different chapters. b o o k r e v i e w s k a n d a l a k i s ’ s u r g i c a l a n at o m y 98 surgical importance of sphincter, and the esophageal stabilizing structure. various open or laparoscopic surgical options are discussed. in the chapter on the stomach, the emphasis is on vascular and lymphatic supply and its importance regarding the metastasis of tumours. the peptic ulcer with its contributing factors and different surgical options in this context are also mentioned. chapters 16, 17 and 18 are devoted to the small intestine, the appendix and the colon, respectively. the liver is described in detail with variations in arterial supply, bile duct, hepatic, venous anatomy as well as the segmental anatomy of the liver. all of this is well illustrated and the facts are nicely tabulated. injuries to the liver are also mentioned as well as anatomical complications of liver transplantation. the author then focuses on the gall bladder with the treacherous variations of bile duct anatomy and discusses important points on how to avoid complications. in the subsequent chapters the spleen, the kidneys, the ureter, the urinary bladder, the male and female genital system, the adrenal gland, the perineum and the lymphatic system are also described. this book would be a helpful reference book for the surgical resident and would also serve as a quick anatomical refresher for the practicing surgeon. the medical student or intern aiming at a surgical career, would be well served reading selected chapters from this book before assisting in surgeries. the author covers all important and relevant aspects of the embryology and surgical anatomy. new interventions, such as minimally invasive surgery, are also included to some extent. all topics and material are in proper, logical sequence and well integrated. the contents and the layout of the book, make it highly appropriate to the target readership, surgical residents, practising surgeons, interns and medical students. in summary, this is an excellent book. although not unique, it is well-written and graphically palatable for any surgeon, present or prospective, wishing to get a better understanding of human anatomy and thus avoid the pitfalls and improve the chances of surgical success. r e v i e w e r s zia aftab department of surgery, sultan qaboos university hospital, muscat, sultanate of oman email: surgeonziaaftab@yahoo.com andreas wladis karolinska institutet, stockholm, sweden email: awladis@gmail.com march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 42-52, epub 16th mar 2009 submitted 21st june 08 revision req. 3rd sept 08, revision recd. 7th dec 08 accepted 21st dec 08 qualitative study on the community perception of the integrated management of childhood illness (imci) implementation in lahej, yemen *huda o basaleem,1 rahmah m amin2 c l i n i c a l a n d b a s i c r e s e a r c h املتكامل العالجي التدبير حول تصورات اتمع عن دراسة نوعية اليمن حلج ألمراض الطفولة في محمد أمني رحمة باسليم، هدى عمر منذ اليمن حلجفي ــل الطف صحة يخص ما اتمع في وأداء ــة حول اخلدمات الصحي واألمهات اتمع ــادة ق تصورات ــتطالع اس ــص: الهدف: امللخ اتمع قادة من ــتة س مع وجهاً لوجه مقابالت معمقة إجراء الطريقة: مت .2003 في الطفولة ألمراض املتكامل التدبير العالجي ــتراتيجية اس تطبيق تبد مجموعتا الدراسة إدراك لم النتائج: اليمن. في حلج مبحافظة ــتراتيجية االس تلك تطبق التي الثالثة 2007 في املديريات في عام ــبع أمهات وس اتمع" ــاركة ومش الصحية اللجان دور من متيقنني "غير اتمع قادة كان فيما املقدمة. اخلدمات حول أبدوا تصورات إيجابية ولكنهم ــتراتيجية االس العيش موارد "قلة األمهات أكدت كما ــر". أكب دوراً تلعب أن يجب الصحية "القيادات وأن مختلفة" بطرق ــاركة املش ميكنه "اتمع ــدوا أن أك ــم إال أنه ــتراتيجية الس اتمعي اجلاد للمكون للتبني ــة ماس احلاجة اخلالصة: أن البارزة لهن". التثقيفية ــورة املش ــائل رس وصول "عدم و والظروف البيئية" والتي الطفل صحة لدعم اتمعية املبادرات ــوائية وعش والبيئية ــية املعيش الظروف ــدة وطأة لش نظراً الطفولة ألمراض املتكامل العالجي التدبير الكافي. غير احلكومي الدعم تطبيقها عطل اليمن. ، النوعية الدراسة ، اتمعية ، املبادرات ألمراض الطفولة املتكامل العالجي التدبير استراتيجية الكلمات: مفتاح 1department of community medicine and public health, faculty of medicine and health sciences, aden university, yemen; 2department of community health, university kebengsaan malaysia (ukm), ukm medical centre, kuala lumpur, malaysia. *to whom correspondence should be addressed. email: hudabasaleem92@hotmail.com abstract objectives: this qualitative study was aimed at exploring the perceptions of community leaders and mothers about health services and community actions pertaining to child health in lahej, yemen since the implementation of integrated management of childhood illnesses (imci) in 2003. methods: face-to-face, semi-structured, in-depth interviews were conducted with six community leaders and seven mothers in 2007 in the three districts of lahej governorate, yemen, that are implementing imci. results: neither group was aware of imci, but had “positive perception to the services.” community leaders expressed “uncertainty about the role of health committees and community participation,” and said, “people can contribute in different ways” and “health authorities must play a more active role.” the mothers emphasised, “poor livelihood and environmental conditions” and “salient counselling messages not received.” conclusion: the pressing needs for effective community-imci is obvious owing to the appalling toll on child health of unfavourable livelihood and environmental conditions and disorganised community initiatives. thus, for effective imci implementation, governmental support needs to be strengthened. key words: integrated management of childhood illness; community initiatives; qualitative study; yemen. advances in knowledge • this is the first study on imci in yemen in general and its community component in particular. • despite some improvement, suboptimal family practices pertaining to child health in yemen still prevail. • the study revealed appreciation for the positive role of child health services staff despite the complaints about the insufficient governmental support. • also revealed were a diminished role of community-based health workers and poor community initiatives to support child health. q ua l i tat i v e s t u d y o n t h e c o m m u n i t y p e r c e p t i o n o f t h e i n t e g r at e d m a n a g e m e n t o f c h i l d h o o d i l l n e s s ( i m c i ) i m p l e m e n tat i o n i n l a h e j , ye m e n 43 the integrated management of childhood illnesses (imci) is a broad strategy developed in the mid-1990s designed to reduce child morbidity and mortality and improve the growth and development of children under five in developing countries. it encompasses three components aiming at improving: skills of health providers, the health system, and family and community practices. however, the community component of the imci strategy (c-imci) was globally introduced later than the health worker training and health system components. experience has been gained only recently on how to adapt and implement c-imci interventions effectively.1 besides focusing on a set of family practices that are important for child health and development, c-imci encourages the development and implementation of community and household-based interventions. these increase the proportion of children exposed to these practices,2 and creates a groundswell of community involvement and commitment to sustain initiatives for health.3 the c-imci was initiated based upon the realisation that a facility-based strategy would not reach significant portions of the population that did not have access to or chose not to use a health facility.4 evidence has shown that up to 80% of deaths of children under five years of age may occur at home with little or no contact with health providers care even though the large majority were living within a few kilometres of health facilities.3 in its essence, c-imci attempts to coordinate health services initiatives with actions carried out in the community, involving all possible actors and sectors at the local level, in order to promote family and community practices for the care and protection of children in the home and community. the family itself and the social networks are the main target of the interventions being developed.4 advocates of imci argue that, if c-imci is to be effective, sustainable communities need to be empowered to take responsibility for their own health. for c-imci, this means that communities must develop a sense of ownership of the twelve key practices that cover promotion of growth and development, disease prevention and appropriate home management and care-seeking outside the home and assume the responsibility for practising and promoting them over the long term.5 in yemen, the imci strategy started in 2000.6 so far, scarce data are available about imci implementation in yemen. this study was aimed at exploring the perception of community leaders (cls) and mothers about health services and community actions pertaining to child health in the lahej governorate of yemen since imci implementation in 2003. m e t h o d s st u dy se t t i n g lahej is a yemeni governorate located in south-western yemen with a total population of 722,694 inhabitants and an area of 13,046 sq. km.7 ninety five percent of the population lives in rural areas and works in agriculture. the governorate consists of 15 districts most of them located in coastal areas. lahej was selected because it is one of the most effective yemeni governorates in terms of implementation of health programmes. it also has good supervision, by the central health office in the governate’s capital city, al-hawta, of the activities in the peripheral districts. furthermore, the researcher was familiar with this governorate after working and living in it for three years. the application to patient care • integrated management of childhood illness (imci) providers should employ proper counselling and effective communication skills when approaching mothers. • strengthening health system support is a must to maximise the benefit from the comprehensive effect of imci on child health. • the role of health committees, community-based health workers and community initiatives to support child health need to be increased. • innovative approaches such as the positive deviance technique could be very helpful in enhancing the role of imci in child health improvement. h u d a o b a s a l e e m a n d r a h m a h m a m i n 44 study was conducted in the three districts of lahej that had been implementing imci since 2003 (tor albaha, al-madhareba-ras-al-ara, and al-melah).8 pa rt i c i pa n t e n r o l m e n t this qualitative study targeted cls and mothers of children aged 2-23 months. they were purposively identified in the course of a quantitative study assessing child health indicators of c-imci conducted during the period january-september 2007. a purposive sample is a non-probability non-representative sample commonly used in qualitative inquiries targeting a particular group of people in the community thought to be difficult to locate and recruit.9 potential cls were first identified by the health providers in the three districts. later, a snowballing technique, particularly useful in hard-to-track populations, was used to identify additional members to be included in the sample, by requesting further names from those cls who responded.9,10 cls and mothers who were available in the study period and agreed to participate were interviewed. six community leaders (two from each district) and seven mothers (two from each of two districts and three from one district) were included. the basic characteristics of the participants are summarised in table 1. data c o l l e c t i o n & a n a ly si s individual face-to-face, semi-structured, in-depth interviews using an interview guide were conducted by the first author [tables 2 & 3]. the purpose of the study was explained at the start of the interview, each respondent’s written or oral consent obtained and confidentiality assured. free expression was encouraged and probing used when necessary to elicit deeper understanding of issues. the researchers audio-taped the interviews and any relevant contextual remarks were recorded. interviews were 60-75 minutes for cls and 50-70 minutes for mothers. the study was approved by the institutional research and ethics committee of the universiti kebengsaan, malaysia. data analysis took place alongside data collection to allow questions to be refined, and new avenues of inquiry to develop and shape the ongoing data collection. interview tapes were transcribed within 48 hours of the interview. to ensure data credibility and dependability,10 the textual data were translated separately into english language by the two researchers, then reviewed together and triangulated to reach better understanding. a content analysis was used to interpret the findings7 whereby the transcript was read repeatedly and then categorised into words and phrases to find meaningful relationships between the themes that emerged. table 1: characteristics of the interviewees age (years) education status community leaders 34 secondary school member of the local council for 6 years, head of planning, development and financial committee in the local council. 37 secondary school teacher in basic school, member of the health committee for 4 years. 50 basic school sheikh of a district, member of the local council. 42 basic school merchant in the fishing sector, new member of the local council. 35 bachelor of history teacher and director of youth and sport office in a district. 47 secondary school sheikh of a district, member of the local council. mothers 31 secondary school teacher in basic school, 3 children, youngest 2 years. 33 secondary school teacher in basic school, 5 children, youngest 3 years. 26 5 years basic school housewife, 1 child aged 17 months, 2 children died, currently pregnant. 19 9 years basic school housewife, 2 children, youngest 6 months. 35 4 years basic school housewife, 8 children, youngest 18 months, currently pregnant. 26 illiterate housewife, 5 children, youngest 18 months. 28 9 years basic school housewife, 5 children, youngest 9 months. q ua l i tat i v e s t u d y o n t h e c o m m u n i t y p e r c e p t i o n o f t h e i n t e g r at e d m a n a g e m e n t o f c h i l d h o o d i l l n e s s ( i m c i ) i m p l e m e n tat i o n i n l a h e j , ye m e n 45 r e s u l t s the results of the analysis of each group are presented separately. altogether, 14 themes emerged from the analysis: six from community leaders and eight from mothers. i n t e rv i e w s w i t h c om mu n i t y l e a d e r s theme : not aware of imci but positive perception of child health services the cls interviewed were not aware of any strategy to improve child health. however, they said that there was noticeable support for child health: “improvement in child health services,” “starting distribution of mosquito bed nets” and “improvement in child health status.” they gave examples: “we do not hear anymore about some diseases like judari (smallpox), shalal alatfal (poliomyelitis), or hasbah (measles).” theme 2: the community had various different perceptions of the care provided cls had different views on how the community perceived the health care services and explained varying degrees of community dependence on the health facilities. the first type of response was the most positive one and expressed by the two sheikhs in the study: “people are dependent on the services provided by the health facility”; “people appreciate the improvement in health services especially home visits”; “the relation between the community and the hospital is good despite the shortage of drugs and doctors.” a somewhat different response was given by others: “people have no choices because they are poor.” (a merchant and new member of the local council); “people do not complain because health providers are very cooperative. if they do not find the expected care, they go to another place” (old member of the local council). a completely different response was also provided by the two teachers: “the community is not totally dein your opinion, how could you evaluate the current level of child health services and child health status? what could be done at the level of the household and community to help in reducing child morbidity and mortality in the community? how could you work to support such activities? in your opinion, to what extent is the community involved in the work of the health facility? how do you think the community could be involved in providing feedback on the quality of care and in the actual management of the health facility? what could be your role in strengthening community involvement in the provided health care? what is your opinion about the current level of community-based health related initiatives? what could be your role in supporting such care? generally, what are the possible ways of improving the health status of children? table 2: assessment of child health indicators of the community integrated management of childhood illness (c-imci) and its determinants in imci and non-imci districts in lahej, yemen 2a: interview questions for community leaders: 2b: interview questions for mothers: assessment of child health indicators of the community integrated management of childhood illness (c-imci) and its determinants in imci and non-imci districts in lahej, yemen to what extent do you think the current level of availability of medicines, vaccines, and supplies are satisfying the needs of the community? what is your opinion about the way the health workers deal with you? do you feel that you are treated with respect? why? what do you think about the way the health workers communicate health messages to you? to what extent could you freely communicate your ideas, concerns and expectation about the health of your children to them? to what extent would you be able to communicate your opinion about health services? what activities do you do at home that could help in improving your children health? what encourages you to seek care from the governmental health facility in your area? do you think there is any difference in seeking care for your youngest child compared to an older one (3 years ago)? what are these differences? in your opinion, what are the positive aspects of seeking care from the governmental health facility? in your opinion, what are the negative aspects of seeking care from the governmental health facility? h u d a o b a s a l e e m a n d r a h m a h m a m i n 46 pendent on our health facility due to lack of a laboratory which is necessary for malaria and faker al-dam (anaemia) investigation. people use the facility mainly as first aid.” theme 3: different ways to improve the health of the family in general and of children in particular families have an important role in the health of children as agreed by cls who believed in: “the necessity to do something for the communities.” different responses were expressed. a new member of the local council said: “i will work when it becomes possible. only i participated in the planning and distribution of the mosquito bed nets.” a teacher in one village expressed what he did and was intending to do: “i am trying to communicate advice on how to avoid malaria in schools. unfortunately, there is no child-to-child programme to communicate educational messages. i will try to adopt this programme through the health committee.” a sheikh of an area stated: “i am working through the health committee to improve the health services and the relation between the community and the health facility.” on the other hand, the role of the volunteers and their home visits was greatly appreciated although, as the cls explained, it was restricted to immunisation and reproductive health services. volunteers are usually trained by imci health providers who tried through personal initiative to train unpaid volunteers in issues related to child and maternal health. however, such initiatives are not universal in all areas. in addition, the follow-up of these volunteers and their reports was performed in an unorganised way. in a parallel context, the united nation’s children’s fund (unicef) conducted a training course for 36 women as community communicators in one district in imci related issues. the training was aimed at building a volunteer health education team to educate mothers at homes and social gatherings like funeral and wedding ceremonies. however, there was no agreement on the selection mechanism of the community communicators and no organised ways on how to communicate the information later to the community. on the other hand, four cls agreed that: “the role of civil society organisations is either absent or not noticeable and not respected by the community as these organisations are not present on a continuous base and consist of non-trustworthy persons”. it was only in one area (ras-al-ara) that the local organisation of fishermen was greatly appreciated and complimented by the cls for its role in providing a partial supply of water and electricity to the area from its profit. theme 4: uncertainty about the role of community participation with regards to community participation, different responses were reported. a local council member expressed his idea: “the only form of community participation is buying drugs from the drug fund.” a teacher had a contradictory opinion: “people do not exhibit any community participation even financial support. the person responsible for this is the director of the health facility and the health committee because they do not arrange meetings and ignore the role of the local council.” a positive form of community behaviour was explained: “community participation in health is not clear, but it is noticeable in other issues. for example, the community participated with 10% financing of the unicef water project and 10% of the world bank project for building a secondary school” (sheikh in one district). “the civil society organisation helped to ensure water and electricity to the hospital” (sheikh in another district). however, almost all cls argued that community participation could be more effective if people were more informed and involved in the community and health facility problems: “people do not know what to do because we do not tell them. the picture might be different if they knew.” theme 5: no consensus about the role of health committees there is a health council at the district centre and health committees at the village level. each usually consists of four to five influential persons in the community like teachers, the sheikh, the imam, or a representative of the local authority beside the director of the health facility. the health committee is the “connecting body” between the health facility and the community members. cls’ evaluations of the role of the health committees differed. while a teacher confirmed: “there is no role for the health committees and i never heard about them”, a member of a health committee expressed his feeling: “the role of health committees must be strengthened and people should select them from more respectable persons to make it easy for people to accept them. in the committee, q ua l i tat i v e s t u d y o n t h e c o m m u n i t y p e r c e p t i o n o f t h e i n t e g r at e d m a n a g e m e n t o f c h i l d h o o d i l l n e s s ( i m c i ) i m p l e m e n tat i o n i n l a h e j , ye m e n 47 we report the obstacles facing better delivery of health services to the higher levels, but no one responds to our reports.” other cls had different opinion about their health committee: “it plays an important role in connecting people with the health facility. currently, the committee is playing an important role in malaria control by putting in bed net distribution and spraying of mosquito breeding sites.” theme 6: health authorities must play a more active role cls’ opinions on how to improve community health status were focused on the role of the health facilities: “health status can not be improved unless health services are improved by increasing its financial resources. home visitors should receive some incentives and be allowed to give drugs” (sheikh in one district). “upgrading health personnel and offering doctors and laboratories” (sheikh in another district).“building health facilities in the very remote areas, training midwives for these areas and health education in schools and mosques” (teacher with a bachelor’s degree). “strengthening the role of health committees to improve the dialogue between the health facility and the community” (another teacher). “more integration between the health facilities and the community. health facilities need to involve the communities in their work by regularly allowing cls to attend their meetings” (old member of the local council). “civil society organisations and non governmental organisations (ngos) should have a stronger role” and “improving the living conditions particularly the insufficient and bad quality of water”(new member of the local council). i n t e rv i e w s w i t h m ot h e r s the mean age of interviewed mothers was 28.3 years. the mean years of schooling among literate mothers were 8.5 years. the interview results can be summarised in eight themes as follows: theme : unfavourable livelihood and environmental conditions all mothers began their talk hoping for future help. they explained about: “poor status”; “poor living conditions”; “lack of money”; “poor markets that lack essential foods”; “lack of continuous supply of water and electricity”; “no fish, fresh vegetable or fruits. our children depend on rice and potatoes”; and “no secondary schools for girls.” theme 2: health staff kind, but only provides basic treatment mothers agreed that, despite the positive role of health providers, there were deficiencies in the services. the majority agreed they were receiving first aid only, nothing more. a 31 year old teacher stated one deficiency: “health workers are very cooperative, but the health facility provides only simple drugs, not strong antibiotics (injections). ”another teacher (33 years old) was more specific: “health workers are doing their best. they can come to any house even at midnight. however, they haven’t many things to provide such as investigation for faker al-dam (anaemia) or malaria, ashiah (x-rays), labour facilities, vitamins or supplementary foods”. theme 3: there is improvement but more is needed mothers’ evaluations of the changes in the health care for the youngest child compared with the oldest children (within the last three years) differed. while two of them stated: “the care is sawa sawa (the same),” others had different opinions: “vaccines became more available and there is more education. family planning methods are always available” (31 year old teacher). “there is improvement in simple services. we are much better here than many neighbouring villages” (19 year old housewife). “there is improvement, but it is not enough” (33 year old teacher). “there is noticeable improvement in the care provided. they come to our homes to vaccinate children or send announcements to attend on certain time” (33 year old housewife with 8 children, and 28 years old housewife with 5 children). on the other hand, three mothers mentioned home visits, but what happen in these visits was differently explained: “volunteers came to weigh children” (illiterate mother). “they did not speak about how to take care of my children, but motivated me to go to the health unit if there is any problem” (33 year old teacher). “home visitors speak about maternal health and breastfeeding.” (19 year old housewife). another woman said that she had never been visited by home visitors: “i live a little bit far from the health unit. no health volunteers had come to me except two persons from the health committee to follow up the water project” (31 year old teacher). however, all mothers stated that: “we do not feel the role of the local council members.” h u d a o b a s a l e e m a n d r a h m a h m a m i n 48 theme 4: no point complaining, find alternatives mothers gave different responses about their ability to communicate any ideas or comments about the provided care: “we can complain, but i did not hear of any previous complaints” (33 year old teacher). “we can speak with health workers, but if there is no improvement we go to the nearby district” (31 year old teacher). “we cannot complain. if they deliver care we gratefully accept it, if not, we do not say anything and we go to aden” (illiterate mother). “we do not feel there is a need to complain” (remaining four mothers). theme 5: salient counselling messages not received educational messages from health providers were mentioned by all interviewed mothers although some messages appeared not clearly understood: “they always advise us to take care of our children, particularly breastfeeding and vaccination. sometimes they explain when we need to bring our children to the health facility” (all mothers). “health workers try to speak with me and to give me time, but sometimes i cannot understand what they said” (illiterate mother). “they emphasised the importance of breastfeeding. therefore, i exclusively breastfed my youngest child for six months. however, there is some advice that i do not follow. for example, they said i need not to give water to the newborn after delivery and during the first six months, but i gave because i do not know why. later, i gave the artificial milk through bottle because i am working; however, i insisted on breastfeeding for three years.” (31 year old teacher). “they always explain the role of exclusive breastfeeding, and accordingly, i breastfed exclusively for the first six months, but other things, i cannot follow” (28 year old housewife). educational messages were delivered verbally and on a collective base. only one mother received the mother’s counselling card. another mother said that she saw the card while they were explaining to her the importance of breastfeeding. the other five mothers said that they did not see or hear about it despite their regular use of the facility. theme 6: mothers’ concerns about basic services mothers had different views about the advantages and disadvantages of using the health facilities in their areas. perceived advantages were: 1. education about maternal and child health; 2. first aid service; 3. midwives from the community in some areas; 4. kindness of health providers; 5. free vaccines and some drugs; 6. free supplementary food for mothers and children (only in one area). perceived disadvantages were: 1. lack of laboratory investigations and important drugs; 2. lack of labour facilities in all health facilities except one, and of specialists particularly paediatricians and gynaecologists; 3. ineffective control of malaria. theme 7: consensus about the important role of families in child health the mothers expressed a common idea that care at home is the most important factor for children’s health. some family practices were given special emphasis: “good diet, cleanliness, use of fumes or bed nets to control mosquitoes” (all mothers). “breastfeeding for the first 4-6 months followed by family foods and fruits between meals. foods like cheese and eggs are good but not artificial milk” (31 year old teacher). “giving breast milk only in the first six months followed by good food like goat milk, cake and fruits and family food by one year of age” (19 year old housewife). however, traditional practices such as applying oil on the child’s body at night and protective measures against cold as wrapping the child with heavy clothes were also mentioned by almost all mothers. mothers’ responses clearly indicated that there is inadequate awareness about the whole range of the key family practices promoted by the imci strategy. theme 8: insufficient knowledge to recognise signs of immediate care-seeking mothers expressed different reasons for immediate care-seeking. four mothers said: “when the child is sick” without further explanation. two teachers specified some signs: “when the child has fever or is unable to breathe easily”; “if the child can not eat or breastfeed, having fever, or becomes seriously sick.” on the other hand, another mother said: “i live alone with my children. therefore, i used to come urgently if my children have anything.” d i s c u s s i o n through its community component, the imci has helped to reinforce beneficial home-based child care through active family and community participation, which, through intersectoral work coordinated at the local level, makes it possible to reach the most vulnerable population groups.5 in the absence of private health services, the study communities were dependent on their local governmental health facilities. the presence of such a trusting q ua l i tat i v e s t u d y o n t h e c o m m u n i t y p e r c e p t i o n o f t h e i n t e g r at e d m a n a g e m e n t o f c h i l d h o o d i l l n e s s ( i m c i ) i m p l e m e n tat i o n i n l a h e j , ye m e n 49 relationship is very important to improve child-care practices and the uptake of health services.11 the interviewees appreciated the kindness of the health providers and the improvement in health services and child health status after imci implementation. such appreciation for imci is documented in many studies.2,12,13 however, complaints about the provided services were raised. the complaints of lack of doctors might not mean low competence of the paramedical providers. instead, it might be related to the deeply rooted belief that “adequate” health care can be provided only by doctors,14 or that the relation between the community and the health providers was so intimate that the community considered these providers as less credible providers of quality professional healthcare. alternatively, the community preference for doctors might be attributed to the laboratory investigations which doctors order compared to the “syndromic approach” of imci or to the attractively packaged medication doctors prescribe compared to those freely distributed from the imci health facility. the literature gives examples of good work performance among imci trained paramedical providers. trained imci nurses showed good competence in south africa,15 and performed as well as, and sometimes better than, doctors in brazil16 and tanzania.17 the presence of disease “warning signs”, should lead the caregivers to seek care from a health provider outside the home.18,19 in the present study, mothers only recognised four out of the eight warning signs present in the yemeni mother’s counselling card. such poor recognition could be attributed to the fact that only one mother had received this card and another one only saw it whereas the other five have no idea about it. alternatively, the inability of mothers to recognise these signs could be attributed to the failure of health providers to communicate such information. imci devoted increasing attention to training health providers on how to teach mothers about disease warning signs.20 ineffective counselling and suboptimal use of the mother’s counselling card might in part be responsible for the inability of mothers to realise some important child care messages. simple, pictorial cards reminding the mother of several home care messages, and the signs indicating the need to return immediately to the health facility (hf) are being developed in many countries including yemen.21 in rural areas of developing countries, several reasons support the use of community health workers (chws). compared with the hfs, chws are geographically closer and available when health facilities are closed. in addition, chws can help ensure that treatment at home is appropriate and function as a bridge between hf and households.22 in ethiopia, chws diagnose and treat fever,23 while in pakistan, lady health workers are a pivotal component of the national health system.24 furthermore, chws have shown to have great potential in extending the imci strategy into the community in india and nepal.25 the present study explored difficulties facing the experience of chws. first, chws were not present in every locality visited. their home visits were restricted to reproductive health and immunisation except in some villages where some women were trained as community communicators. secondly, their training was usually done by external bodies without involving the local health providers which might not result in work integration between health facility providers and chws. thirdly, there was no continuing system of recruitment, training, and supervision of a cadre of volunteers to meet health care needs. fourthly, many of the chws were unpaid volunteers that began their work enthusiastically, regularly sending reports to the health committee, but later their role gradually weakened. it was reported that of 1,200 trained community communicators in imci-yemen, only 10%-20% were still reporting to the nearest health facilities.26 the literature also discusses ways to improve the sustainability of chws 3,5,25 that could be applicable to our yemeni context. a community will appreciate chws’ contributions more if it has participated in their selection, training and supervision. this may engender a willingness to motivate and reward chws. some non-monetary incentives were proposed including support from both the formal health system and the community. these include elevated community status and personal growth through the acquisition of new skills. health facility staff can also motivate chws through supportive supervision and recognition (i.e. attending community meetings with the chws and allowing them to refer cases and distribute basic medicines). in el salvador, non-monetary incentives were found to be insufficient to combat the marketability of the lucrative new skills of the chws. some programmes, have decided to integrate income-generating activities into the set of interventions to allow for community reward of the chws.4 in the present study, the need for monetary incentive for the chws h u d a o b a s a l e e m a n d r a h m a h m a m i n 50 was indicated, perhaps, due to the poor economic status encountered in the study districts. mobilisation of all community actors could have a positive influence on the health of community members. this is a process through which health improvement actions are stimulated, planned, carried out, and evaluated by a community’s individuals, groups and organisations on a participatory and sustained basis.27 it begins with creating a fuller community understanding of the goals of health programmes and moves on to increased community involvement in health decision-making and management.3 in the study areas, community-based activities appeared to be patchy and ineffective. although communities were participating in some activities like water and electricity projects and building schools, their participation in hf issues was not significant perhaps due to insufficient linkage between the hfs and their communities. on the other hand, the mechanism of member selection for health committees was unclear in contrast to what is seen in the literature. conventionally, health committees consist of influential people elected by their communities to be responsible for management of village health-related activities.4 substantive collaboration between many sectors is needed to influence the health of a community. the advocates of c-imci provided several frameworks for its implementation all emphasising the importance of a multisectoral approach for supporting sustainable child health. the multisectoral platfrom (msp) addresses social, economic and environmental factors that facilitate or hinder the adoption of the key family practices,5 the logic behind it being that people may find it difficult or impossible to adopt new behaviours if other problems that they face, such as food insecurity or lack of access to clean water, are not also addressed.4 given the level of community initiatives encountered in our districts, it could be reasonable to conclude that the poor level of living conditions will continue to have a detrimental effect on child’s health unless sustainable improvement is ensured. this cannot be achieved without serious adoption of c-imci as shown by examples from many countries.24 in the eastern mediterranean region, a number of community-based interventions are being implemented to address health, poverty and development. the basic development needs programme is a useful example; it seeks to promote a comprehensive approach for development to meet community priority needs including health, education, means of livelihood, water supply, sanitation, improved roads, provision of electricity, etc. it yielded promising success in afghanistan and somalia.22 non-governmental organisations (ngos) are important stakeholders to promote child health. through the msp, ngos focus on strategies for linking broader development activities with child health improvement by working with families in the context of community health education, literacy classes, micro-enterprise and environmental sanitation.5 yemen could benefit from the example of ghana where an ngo has made a link between social and economic development activities and the promotion of specific health behaviours. the programme combined village bank services for women with education in breastfeeding, child nutrition, diarrhoea control, immunisation, and family planning. the combination of credit with education resulted in better food security, better breastfeeding practices and improved nutritional status, particularly of young children.3 however, the yemeni cls in the areas studied believed that their communities did not get the maximum benefits they deserved from the ngos. it is striking to note that the local civil society organisations and initiatives were either absent or only had a weak role. furthermore, the community’s lack of trust towards these bodies was noticeable in all areas except one. fortunately, c-imci is unrestrictive and involves many innovative approaches.3,4,27 one of these approaches could be the “child-to-child” programme which was mentioned by a teacher in this study: children could be given the knowledge and tools to disseminate health messages within the community and households since older siblings have a role in educating and caring for younger ones.3 schools are good places for communicating such health messages and ‘advertising’ healthy practices because of the potential for learning and modelling during the formative years.28 teachers could help to integrate basic health messages within the school curriculum. c o n c l u s i o n the pressing need for effective c-imci is obvious. this is clear from the appalling toll on child health of poor livelihood and environmental conditions and disorganised community initiatives, which are further hampered by insufficient governmental support. strengthening community mobilisation and capacity-building q ua l i tat i v e s t u d y o n t h e c o m m u n i t y p e r c e p t i o n o f t h e i n t e g r at e d m a n a g e m e n t o f c h i l d h o o d i l l n e s s ( i m c i ) i m p l e m e n tat i o n i n l a h e j , ye m e n 51 activities to enhance the commitment of community members towards health improvement and ensuring their effective involvement in both facility and community health initiatives are mandatory. additionally, the study found suboptimal family health practices in the districts visited. the solution would be to strengthen counselling mechanisms through effective communication techniques. innovative approaches such as positive deviance (pd) could be helpful as it has given promising results in more than 20 developing countries. pd is based on the premise that in communities where everyone faces serious resource limitations, some families still find a way to keep their children healthy.29 thus, imci staff and community members could identify the unique practices of some community members (positive deviants) that enable them to cope more successfully within the same resource-base. once identified, staff and community can develop strategies to enable all members of the community to learn about these practices and to adopt them. this can improve care-giving, nutrition and hygiene and other practices that contribute to child health. a c k n ow l e d ge m e n t s & s o u r c e o f f u n d i n g the study was approved by the institutional research and ethics committee of the universiti kebengsaan, malaysia. dated 29th december 2006, project code: ff265-2006. the authors would like to acknowledge the financial and spiritual support for this study by the third world organisation of women in science and technology (twows). c o n fl i c t o f i n t e r e st : none declared r e f e r e n c e s 1. unicef. the state of the world children 2008: child survival. new york: oxford university press, 2008. pp. 31-5. 2. victora cg, adam t, bryce j, evans db. integrated management of the sick child. in: jamison dt, breman jg, measham ar, alleyne g, claeson m, evans db et al. eds. disease control priorities in developing countries, 2nd ed. new york: oxford university press and the world bank publication, 2006. pp. 1177-92. 3. child survival collaborations and resources group, who, unicef. child health in the community. imci briefing package for facilitators. geneva world health organisation, 2004. 4. winch p, le ban k, kusha b. advancing pvo/ngo technical capacity and leadership for household and community integrated management of childhood illness. paper presented at the workshop “reaching communities for child health”. baltimore, maryland, 2001. 5. winch p, le ban k, casazza l, walker l, pearcy k. an implementation framework for household and community integrated management of childhood illness. hlth policy plan 2002 17:345-53. 6. ministry of public health & population. the annual report of child health directorate. sana’a, yemen: ministry of public health and population, 2004. 7. yemeni population and housing census. sana’a, yemen, 2005. 8. ministry of public health & population. the annual report of lahej governorate, 2004. sana’a, yemen: ministry of public health and population, 2005. 9. patton mq. qualitative evaluation and research methods. 3rd ed. thousand oaks, ca: sage publications incorporation, 2002. pp. 9-35. 10. pope c, ziebland s, mays n. qualitative research in healthcare: analysing qualitative data. br med j 2000; 320:114-16. 11. ministry of health & population egypt, egypt health facility survey on outpatient child-care (imci) services. geneva: who, 2003 (who-em/cah/o12/e/ g). 12. bradley j, igras s. improving the quality of child health services: participatory action by providers. int j qual hlth care 2005; 17:391-99. 13. naimoli jf, row a, lyaghfour a, larbi r, lamrani la. effect of the integrated management of childhood illness strategy on healthcare quality in morocco. int j qual hlth care 2006; 18:134-44. 14. hansen pm, peters dh, viswanathan k, rao kd, mashkoor a, burnham g. client perceptions of the quality of primary care services in afghanistan. int j qual hlth care 2008; 20; 384-91. 15. chopra m, patel s, cloete k, sanders d, peterson s. effect of an imci intervention on quality of care across four districts in cape town, south africa. arch dis child 2005; 90:397-401. 16. amaral j, gouws e, bryce j, leite aj, cunha aj, victora cg. effect of integrated management of childhood illness (imci) on health worker performance in northeast-brazil. cad saúde pública rio de janeiro 2004, 20:209-19. 17. imci documentation in tanzania experiences, progress and lessons learnt. from http://www.afro.who.int/ whd2005/imci/tanzania-imci-edit-ginny111104.pdf. accessed 25 december 2007. 18. who. world health report 2005: make every mother h u d a o b a s a l e e m a n d r a h m a h m a m i n 52 and child count. geneva: world health organisation, 2005. 19. sreeramareddy ct. care-seeking behaviour for childhood illness a questionnaire survey in western nepal. bmc int hlth human rights 2006; 6:7-12. 20. who, unicef. integrated management of childhood illness information. geneva: world health organisation, 1999 (who/chs/cah/98). 21. who, unicef. imci adaptation guide. a guide to identifying necessary adaptations of clinical policies and guidelines, and to adapting the charts and modules for the who/unicef course. protocol for designing and pretesting an adapted mother’s card. geneva: world health organisation, 2002. 22. who, regional office for the eastern mediterranean region (emro). planning and implementation of the integrated management of childhood illness community child care component in five countries in the eastern mediterranean region. report of conference cairo, 29 june 4 july, 2002. cairo: world health organisation, 2003 (who-em/cah/008/e/l). 23. ghebreyesus ta. the community-based malaria control programme in tigray, northern ethiopia. a review of programme set-up, activities, outcomes and impact. parassitologia 2000; 42:255-90. 24. ministry of health pakistan. evaluation of the prime minister’s programme for family planning and primary healthcare. oxford policy management. from www. emro.who.int/rc51/media/emrc5112.pdf. accessed 20 march 2008. 25. kelly lm, black re. research to support community integrated management of childhood illness. report of a meeting to support household and community integrated management of childhood illness, 22-24 january, 2001, maryland, baltimore, usa. j hlth popul nutr 2001; 19:111-54. 26. al-serouri aw. consultancy report on development of monitoring and evaluation system for integrated management of childhood illnesses in yemen. sana’a, yemen: ministry of public health & population, child health directorate, 2007. 27. who, regional office for the western pacific region (wpro). regional committee, report of fifty-fourth session. wpr/rc54/11/ provisional agenda item 17. manila, philippines 8-12 september, 2003. from http:// www.wpro.who.int/nr/rdonlyres/f1c46e42-d9824724-b00f-39af8d1463cd/0/rc5411.pdf. accessed january 2008. 28. ahmed c. bridging the gap between community health and k-12 schools. int quar comm hlth edu 2006; 24:161-66. 29. lorraine wo sterling bs, hoke mm, dearden ka. applying the concept of positive deviance to public health data: a tool for reducing health disparities. public hlth nurs 2007; 24:571-6. 1universidad industrial de santander, school of medicine, bucaramanga, santander, colombia; 2department of surgery, university of texas rio grande valley, edinburg, texas, usa; 3hospital internacional de colombia, piedecuesta, santander, colombia *corresponding author’s e-mail: jhonfreddymartinez@hotmail.com giant gastroduodenal duplication cyst with juxta-pancreatic communication a rare intraoperative finding *jhon f. martinez-paredes,1,2 daniel g. plata-diaz,1 adriana pinilla3 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 417–420, epub. 25 aug 22 submitted 26 jan 21 revision req. 14 mar & 11 may 21; revision recd. 12 apr & 20 may 21 accepted 10 jun 21 tomography (ct) scan of the abdomen was done. a huge hypodense cystic mass with the dimensions of 11 × 12.8 × 6 cm and an approximated volume of 320 cc was documented [figure 1b]. the patient underwent surgical exploration through a midline vertical incision after considering a mesenteric cyst versus an enteric duplication cyst as a possible diagnosis. during surgery, a giant boot-shaped cystic mass with a diameter of 15 × 12 cm occupying approximately 70% of the abdomen was found [figure 2a]. the mass was adherent to the greater curvature of the stomach, sharing the serosa and muscular layers. it was hyper-vascularised, with blood supply from the left gastric artery, gastroepiploic artery, splenic artery, short gastric arteries and the pancreatic artery. although a normal pancreatic duct was found, an aberrant duct communicating the cystic mass with the pancreas was also identified. the juxta-pancreatic communication was confirmed by intraoperative cholangiogram. intraoperative process included the dissection of the giant enteric duplication cyst by layers and the ligation of contiguous vessels related to the cyst. the mass was disconnected from the greater curvature without compromise of the muscular and the mucosa layer of the stomach. after removing this giant mass, no evidence of loss to the greater curvature of the stomach or the pancreas was identified. normal perfusion of the stomach was also confirmed. additionally, ligation of the aberrant communication was performed using a 4-0 polypropylene suture after a normal intraoperative cholangiography that verified a normal transit of the contrast to the duodenum [figures 2b and c]. gross examination revealed a mass with an approximate dimension of 10 × 10 × 5 gastrointestinal tract duplications or enteric duplication cysts are rare congenital malformations formed during the embryonic development of the digestive system with an incidence of 1:4,500 births. these malformations most frequently occur in the oesophagus, jejunum, ileum, colon and stomach.1 the involvement of the pancreas is very rare.2 the clinical presentation of these malformations has a wide diversity of signs and symptoms including abdominal pain and distension, gastrointestinal bleeding, obstruction or intussusceptions.3–5 urgent surgical intervention is needed when the severity of symptoms and signs involve significant complications such as massive bleeding or perforation of the intestine.3 we present a case of a giant gastroduodenal duplication cyst with a juxta-pancreatic communication, a rare intraoperative finding that was successfully treated surgically. case report a 2-month-old boy arrived at the paediatric emergency department (ed) of a tertiary care centre in bucaramanga, colombia, in 2016, with vomiting after feeds, abdominal distention and an abdominal mass found by his mother. the patient had a history of suspected duodenal atresia by antenatal ultrasounds (double bubble sign found). however, this congenital malformation was ruled-out postnatally after a normal upper gastrointestinal series test and in the absence of vomiting or gastric aspirates in the neonatal period. physical examination at the ed revealed a giant abdominal mass located in the hypogastrium [figure 1a]. given the clinical context, a contrasted computed this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.095 case report abstract: enteric duplication cysts are rare congenital malformations with a low incidence and there are only a few reports in the literature. their clinical presentation varies according to the location and the type of duplication. their overall prognosis is good if early surgical intervention is provided. we report a 2-month-old boy who presented with a case of a giant gastroduodenal duplication cyst with a juxta-pancreatic communication and was successfully treated surgically. it is imperative to be aware of this rare congenital malformation that can present clinically with a wide range of non-specific symptoms that can cause significant morbidity and mortality if the treatment is delayed. keywords: pancreatic duct; congenital abnormalities; intestinal diseases; newborn; case report; colombia. https://creativecommons.org/licenses/by-nd/4.0/ giant gastroduodenal duplication cyst with juxta-pancreatic communication a rare intraoperative finding 418 | squ medical journal, august 2022, volume 22, issue 3 cm. a final diagnosis of a gastroduodenal duplication with a juxta-pancreatic communication was made. histopathological examination showed the wall of the cyst composed of the muscular layers with extensive atrophic changes. although the mucosa architecture was distorted, paneth cells and enteric cells were identified. the submucosa and the muscularis layer were also documented [figure 3]. the patient was evaluated in postoperative follow-up visits at one, two and six months. his recovery was uneventful. prenatal ultrasounds were also reviewed while writing this report. the authors did not find evidence of images suggesting an enteric duplication cyst. no maternal polyhydramnios was documented during antenatal follow-ups. informed consent from the patient's guardian was obtained for publication purposes. discussion this is a case report of a giant gastroduodenal duplication cyst with juxta-pancreatic communication in a 2-month-old boy with vomiting after feeds, abdominal distention and an abdominal mass in the hypogastrium. gastrointestinal tract duplications are rare anomalies that are usually found in early childhood but can remain asymptomatic until adulthood. clinical presentation of this abnormality has a wide range of signs and symptoms from non-bilious vomiting to severe abdominal pain due to fluid leakage or rupture of the cyst.2,6 most enteric duplications become symptomatic as a result of the obstruction of the gastrointestinal tract by external pressure, distention of the cystic mass or bleeding.2 the embryogenesis of the enteric duplications remains unclear. however, several hypotheses including canalisation impairment, intrauterine vascular accident, cellular migration defects and diverticulisation have been postulated.7 furthermore, in those cases with an associated figure 3: haematoxylin and eosin stain at ×10 magnification of the excised cyst wall showing gastric and duodenal mucosa, submucosa, and muscle coats consistent with an enteric duplication cyst. figure 1: a: photograph of a 2-month-old boy showing giant abdominal mass. b: contrasted computed tomography scan of the patient’s abdomen showing a 11 × 12.8 × 6 cm mass with an approximated volume of 320 cc. figure 2: a: intraoperative photograph of the current patient showing a boot-shaped giant mass occupying 70% of the abdomen. b: intraoperative photograph of the same giant mass showing juxta-pancreatic communication. c: normal intraoperative cholangiography showing normal transit of the contrast to the duodenum. jhon f. martinez-paredes, daniel g. plata-diaz and adriana pinilla case report | 419 pancreatic communication, the mechanism of embryonic maldevelopment is thought to be more complicated.8 the anatomy of gastrointestinal tract duplications usually includes a hollow, epithelial-lined and cystic or tubular mass attached to the wall of the gut and supplied by contiguous blood vessels. however, in the current case, the enteric duplication was sharing a blood supply of arteries with a common embryonic origin, there is no clear literature about this relationship.7 regarding location, the gastroduodenal region is a rare site for enteric duplication to occur (10% of cases), and only approximately 20% of cases at this level have an associated pancreatic communication. from those cases involving the stomach, approximately 66% of gastroduodenal duplications occur at the greater curvature.9,10 a case series by lopez-fernandez et al. presented a total of 11 cases of pyloroduodenal duplication cysts treated over 26 years of practice. from those cases, only three corresponded to an enteric duplication with pancreatic communication.11 therefore, the current case represents to a rare entity with a very low incidence (a giant enteric duplication cyst with an aberrant pancreatic duct). radiologic studies, including abdominal ultrasono graphy, magnetic resonance imaging or abdominal ct scan, are usually needed for antenatal or postnatal diagnosis.12 an abdominal ct scan is recommended for postnatal diagnosis due to its ability to document the anatomical relationship with the surrounding structures.2 as previously mentioned, the current patient had an antenatal diagnosis of duodenal atresia by ultrasound that was ruled-out postnatally. interestingly, in a case report by okamoto et al., a gastrointestinal mass found antenatally was diagnosed as a duplication cyst postnatally.13 it should be noted that the case reported by okamoto et al. and the current case reinforces the need for a complete evaluation of the newborn as well as radiologic studies in the postnatal period in patients with antenatal images suggesting intra-abdominal cystic masses or congenital abnormalities of the intestines; this would enable an early and accurate diagnosis and prevent complications. the surgical approach of enteric duplications varies according to location and type of duplication. surgical management for asymptomatic cases is controversial.4 it has been suggested that enteric duplications should be excised not only due to the symptoms but also for the risk of developing adenocarcinoma within the cyst.2 in those cases with a precise preoperative diagnosis, a laparoscopic approach is recommended.14 the presence of an aberrant pancreatic communication and its risk of postoperative pancreatitis makes a radiological evaluation imperative and an intraoperative endoscopic retrograde cholangiopancreatography is usually recommended to avoid morbidity.15 in the current case, adequate diagnosis and surgical treatment led to a satisfactory outcome. this case describes an uncommon condition that paediatricians and paediatric surgeons should be aware of as part of the differential diagnoses that must be ruled-out during postnatal evaluations when intra-abdominal cystic lesions are documented antenatally. this also shows how an abnormality in the embryogenesis of the gastrointestinal tract can manifest in an infant. conclusion gastrointestinal tract duplications are rare conditions. the current case describes a giant enteric duplication cyst that presented as an abdominal mass associated with abdominal distention and vomiting. complete radiologic evaluation of patients with antenatally documented intra-abdominal cystic masses must be performed to pursue an early diagnosis and prevent complications of undiagnosed pathologies. additionally, in the event of an abnormal pancreatic communication, the evaluation of the integrity of the pancreatic drainage during the procedure and the careful resection with preservation of adjacent structures is essential. it is imperative to be aware of this rare congenital malformation that can present clinically with a range of non-specific symptoms that can cause significant morbidity and mortality if treatment is delayed. a u t h o r s’ c o n t r i b u t i o n jfmp and ap were involved in conceptualisation, writing and editing of final manuscript. dgpd was involved in the histopathological examination as well as writing the manuscript. all authors approved the final version of this article. references 1. holcomb gw 3rd, gheissari a, o'neill ja jr, shorter na, bishop hc. surgical management of alimentary tract duplications. ann surg 1989; 209:167–74. https://doi. org/10.1016/0002-9610(64)90210-7. 2. fujishiro j, kaneko m, urita y, hoshino n, jinbo t, sakamoto n, et al. enteric duplication cyst of the pancreas with duplicated pancreatic duct. j pediatr surg 2011; 46:e13–16. https://doi. org/10.1016/j.jpedsurg.2011.04.056. 3. sharma s, yadav ak, mandal ak, zaheer s, yadav dk, samie a. enteric duplication cysts in children: a clinicopathological dilemma. j clin diagn res 2015; 9:ec08–11. https://doi. org/10.7860/jcdr/2015/12929.6381. https://doi.org/10.1016/0002-9610(64)90210-7. https://doi.org/10.1016/0002-9610(64)90210-7. https://doi.org/10.1016/j.jpedsurg.2011.04.056 https://doi.org/10.1016/j.jpedsurg.2011.04.056 https://doi.org/10.7860/jcdr/2015/12929.6381. https://doi.org/10.7860/jcdr/2015/12929.6381. giant gastroduodenal duplication cyst with juxta-pancreatic communication a rare intraoperative finding 420 | squ medical journal, august 2022, volume 22, issue 3 10. stringer md, spitz l, abel r, kiely e, drake dp, agrawal m, et al. management of alimentary tract duplication in children. br j surg 1995; 82:74–8. https://doi.org/10.1002/bjs.1800820126. 11. lopez-fernandez s, hernandez-martin s, ramírez m, ortiz r, martinez l, tovar ja. pyloroduodenal duplication cysts: treatment of 11 cases. eur j pediatr surg 2013; 23:312–16. https://doi.org/10.1055/s-0033-1333640. 12. gałązka p, redloch k, kroczek k, styczyński j. minimally invasive surgery for congenital abdominal cystic lesions in newborns and infants. in vivo 2020; 34:1215–21. https://doi. org/10.21873/invivo.11895. 13. okamoto t, takamizawa s, yokoi a, satoh s, nishijima e. completely isolated alimentary tract duplication in a neonate. pediatr surg int 2008; 24:1145–7. https://doi.org/10.1007/ s00383-008-2220-y. 14. nobuhara kk, gorski yc, la quaglia mp, shamberger rc. bronchogenic cysts and esophageal duplications: common origins and treatment. j pediatr surg 1997; 32:1408–13. https:// doi.org/10.1016/s0022-3468(97)90550-9. 15. christians kk, pappas s, pilgrim c, tsai s, quebbeman e. duplicate pancreas meets gastric duplication cyst: a tale of two anomalies. int j surg case rep 2013; 4:735–9. https://doi. org/10.1016/j.ijscr.2013.05.005. 4. liu r, adler dg. duplication cysts: diagnosis, management, and the role of endoscopic ultrasound. endosc ultrasound 2014; 3:152–60. https://doi.org/10.4103/2303-9027.138783. 5. banerjee r, singh g, aggarwal sk. a rare presentation of y-duplication of the pancreatic tail with enteric duplication cyst as intussusception in a child: a case report. int j surg case rep 2021; 78:96–8. https://doi.org/10.1016/j.ijscr.2020.11.131. 6. hishiki t, saito t, terui k, mitsunaga t, nakata m, matsuura g, et al. a rare presentation in a case of gastric duplication cyst communicating to the pancreatic duct: coincidental detection during pyloromyotomy for hypertrophic pyloric stenosis. j pediatr surg 2008; 43:e1–3. https://doi.org/10.1016/j.jpedsu rg.2008.04.009. 7. mandhan p, ehsan t, al-sibai s, khan am, sankhla d. noncommunicating multiple intra-abdominal enteric duplication cysts. afr j paediatr surg 2014; 11:276–8. https://doi.org/10.4 103/0189-6725.137344. 8. shinde t, lindner j, silverman j, agrawal r, dhawan m. gastric-duplication cyst with an aberrant pancreatic-ductal system: an unusual cause of recurrent abdominal pain. gastrointest endosc 2009; 69:377–9. https://doi.org/10.1016/j. gie.2008.04.059. 9. hoffman m, sugerman hj, heuman d, turner ma, kisloff b. gastric duplication cyst communicating with aberrant pancreatic duct: a rare cause of recurrent acute pancreatitis. surgery 1987; 101:369–72. https://doi.org/10.1002/bjs.1800820126. https://doi.org/10.1055/s-0033-1333640. https://doi.org/10.21873/invivo.11895 https://doi.org/10.21873/invivo.11895 https://doi.org/10.1007/s00383-008-2220-y https://doi.org/10.1007/s00383-008-2220-y https://doi.org/10.1016/s0022-3468(97)90550-9 https://doi.org/10.1016/s0022-3468(97)90550-9 https://doi.org/10.1016/j.ijscr.2013.05.005 https://doi.org/10.1016/j.ijscr.2013.05.005 https://doi.org/10.4103/2303-9027.138783. https://doi.org/10.1016/j.ijscr.2020.11.131 https://doi.org/10.1016/j.jpedsurg.2008.04.009. https://doi.org/10.1016/j.jpedsurg.2008.04.009. https://doi.org/10.4103/0189-6725.137344. https://doi.org/10.4103/0189-6725.137344. https://doi.org/10.1016/j.gie.2008.04.059. https://doi.org/10.1016/j.gie.2008.04.059. magnitude and determinants of exodontia in south batinah region of oman magnitude and determinants of exodontia in south batinah region of oman a cross sectional study *rajiv khandekar1, zina fouad2, aliya m al-khusaibi3 squ journal for scientific research: medical sciences 2003 vol 5, no. –2, 2–25 ©sultan qaboos universit y abstrac t. objectives: to estimate the magnitude, determinants and causes of exodontia presented at all the three dental units of south batinah region of oman. methods: this is a cross sectional study of 8,963 samples representing dental cases reported at the three dental units for 12 weeks in year 2000. the information on patients undergoing exodontia and its indications were collected from their case files. standard definitions were used to categorise causes of exodontia. mid 2000 population was used as reference for calculating rates. age-sex standardisation and 95% confidence interval of the exodontia rates were calculated for statistical validation. results: the annual exodontia rate was 16.67 per 1,000 population (ci95% 16.52, 16.82). the rate in males was 11.56 (ci95% 11.40, 11.73) and and in females, 40.04 (ci95% 39.73, 40.34). the rate in the 12+ age group was significantly higher than that in the 0–12 age group. the rates showed geographic differences. conclusions: the exodontia rates were high in the study area. exodontia rates were significantly higher in females, persons older than 12 years, and those living in the coastal areas of south batinah. based on the exodontia rates, the impact on the oral health services was reviewed and recommendations for improving the dental care were proposed. key words: exodontia, dental caries, oral health programmme, oman 1specific diseases control programme, dsdc, dgha, ministry of health, p.o.box 393, muscat-113, sultanate of oman, 2dental department, rustaq hospital, south batinah region, ministry of health, sultanate of oman, 3oral health program, ministry of health, sultanate of oman. *to whom correspondence should be addressed. email: rajshpp@omantel.net.om dental care is one of the important health initiatives in oman.1 rapid economic development in the middle east has resulted in changes in the dietary pattern, especially among children. large arid area of oman has water supply either through pipelines from desalination plants or from wells, using tankers. the fluorine content of water supplied to the population varies considerably in different areas. personal hygiene habits of the population are changing but changing attitudes would take long time. thus the risk of dental caries seems to be high in oman. the ministry of health has prioritized oral health in the national five year health plan. the problem of dental caries is addressed through the oral and dental health program and it has adopted the strategies of early detection of dental caries and prevention of dental caries through prophylactic intervention, increasing awareness for oral hygiene and promoting water fluoridation by regional authorities. the survey conducted to estimate the dental status of 6 year old school children reported dmf rate of 4.6.2 the rate in 2 to 3 year-olds in 2000 was .53%.3 thus dental caries seems to be a major public health problem in school children of oman. qualified dentists at dental clinics and mobile dental units provide dental care to the population in all health regions. south batinah region has both costal and mountainous moh dental �� ��� ������� �������� ����� �� ������� ���� ����� �� ���� ����� ����� ��������� ��������� ������������ ����� ��������:�����:�������� ����� ������ ������ ��� ��������� ��� �� ������� ���� ����� �� ������ ��� ����� ����� . �������:��� ����� ���� ����� ���� ��� ��������������� ���� ����������� ������ �������� ������ ������ ��� �������� �������� �� ����������.������ ������ ��� ��������� ������ ���� ����� �� �������� ��������� ����� �� .�������� � �������� ���������������� ������� ������������������������������� ���� �������� ������ ����� ������ ����� ������� � ������.���������� ����� �������� ���������%�� .�������:��������������� �������������������� �� ����)ci��� ��, ��–����� (���������������)(ci��������, �����–���������� �� �(ci��� ����� , �����) �����.��� ������ ������ ���� ������� ��� ����� ���� ������������������� ���������.������ ������ ���� ������ �����.������:�������������� ������ ���� ������� ���������������� ����� ������� ���������� ���� �� �������� �������.���� ��� ����� ����� �� ��� ��� ����� ������� ������ ��������.������� ������ :������� ���� � ������ �� ,���� ��� ������. 22 k h a n d e k a r e t a l terrain. three static dental units at the health institutions at rustaq, musanna and barka and one mobile unit cater to nearly 205,000 omani population.4 exodontia (dental extraction) is an indicator of the dental caries problem and status of oral health of a population. limited information is available in the literature on the magnitude and determinants of exodontia in oman and other middle eastern countries. as this information is crucial for improving the dental services and determining the risk factors of this problem, a study was undertaken in south batinah region to review exodontia cases seen at three dental units. based on the results of the study recommendations to improve dental services in the regions were proposed. m e t h o d this was a cross sectional type of descriptive study. mid2000 population of south batinah region was the reference population.4 the cases of patients visiting the dental units of rustaq hospital, barka and musanna health centres from st april 2000 to 2st june 2000 (2 weeks) and had tooth extraction were included in the study. seven dentists comprised the field staff. a detailed dental examination and recording of the findings as present in the case file was undertaken as per the standard operating procedures.5 details such as gender, age and causes of dental extraction were also collected. where a patient had teeth with completely missing crown due to destruction by dental caries with remaining root embedded in the alveolar bone, the condition was grouped under “remaining roots indicated for extraction”. cases of caries teeth unfit for any type of conservation, were grouped under ‘gross dental caries with no dental salvation.’ patients were grouped into ‘deciduous teeth problem’ if (a) the deciduous teeth were mobile and near shedding and parent requested for their removal, (b) deciduous teeth were over-retained and permanent successors had appeared in mal-positions, or (c) deciduous teeth needed extraction before shedding time to avoid overcrowding of the erupting permanent teeth. the group for ‘prosthetic treatment’ included cases which had tooth extraction to give space for orthodontic treatment, tooth with chronic periodontitis and tooth removed for prosthetic treatment. the cases undergoing tooth extraction of posterior multi rooted teeth that were badly destructed and could not be restored by endodontic treatment were grouped under exodontias for ‘exposed teeth’. those with history of trauma were placed under ‘exodontia following trauma.’ quality assurance procedures, such as the use of standard definitions, pre tested form for collecting data, and mode of diagnosis and treatment as per the standard operating procedure stipulated in oral health manual, were performed in this study. the data were collected using standardised form and computed using pre-tested format on microsoft excel software. two entries were performed and matched to correct discrepancies. double entry system was utilized for correct entry of the data. the frequency and percentage proportion of the cases of exodontia per cause were calculated. for statistical validation, the results were adjusted using indirect standardization method. the population proportion by age group, gender and wilayat (mid 2000 population) were referred for this purpose. the population proportions by age group, gender and wilayat (mid 2000 population) were referred for this purpose2 by age, gender and location. by using population preparations of region as gold standard, the results in subgroups were compared. 95% confidence interval (ci95%) was calculated for the important results. based on the outcome of 2 weeks, annual extraction rates were calculated by using factor 52.5/2. the participants gave their verbal consent for tooth extraction as per the protocol of the ministry of health. consent of the regional and hospital authorities was obtained. the feedback of the study was provided with the recommendations for improving dental care. the annual dental screening for st primary students is undertaken between october and may. therefore students identified with problem and referred for the dental care could constitute a larger proportion of the cases requiring exodontia among deciduous teeth. r e s u l t s the characteristics of the population of the south batinah region and of the examined sample are given in table . proportion of the study population and the examined sample differed markedly suggesting the need for standardisation before generalising the outcome to the population. the exodontia and risk factors. the frequency of exodontia cases crude and adjusted rates per 000 population and their 95% ci were calculated for different variants [table 2]. the exodontia rates suggested need for dental extraction in 6 out of ,000 population. females, those above 2 years and those residing in the costal areas of barka and musanna wilayats had significantly higher rates of exodontia. causes of exodontia. the cases of exodontia were grouped according to the causes and their proportion [table 3]. nearly half of the dental extractions were due to the caries patients who had come in advanced stages 23 where salvation was not possible. the proportion of exodontia due to other causes such as periodontitis, secondary caries, trauma, exposed pulp and deciduous teeth was low and statistically not significant. table 1. profile of the study population and examined sample (south batinah dental study 2000) epidemiological sub-groups study population (mid 2000) examined sample (for 12 weeks) # % # % gender male 142,185 58.4 3,668 40.9 female 101,408 41.6 5,295 59.1 age-group 0–12 72,461 29.7 2,184 24.4 13+ 171,132 70.3 6,779 75.6 area barka 76,146 31.3 2,676 29.9 musanna 56,195 23.1 2,298 25.6 rustaq 111,252 45.7 3,989 44.5 total 243,593 100.0 8,963 100.0 table 2. rate of exodontia by variants (south batinah dental study 2000) frequency crude rate adj rate ci 95% gender male 1,703 11.98 11.56 11.40, 11.73 female 2,491 24.56 40.04 39.73, 40.34 age group <12 1,319 18.20 17.34 17.06, 17.62 13+ 2,875 16.80 19.82 19.63, 20.01 institution barka ehc 1,098 14.42 16.25 15.99, 16.51 musanna ehc 903 16.07 21.03 20.69, 21.36 rustaq hospital 2,193 19.71 14.75 14.54, 14.96 total 4,194 17.22 16.67 16.52, 16.82 d i s c u s s i o n the study addressed the important issue of exodontia. limited information is available in oman on the magnitude of exodontia, especially in adult population. the result of the present study could be useful to reorganise the oral health services in the study area. the sample covered all the cases of patients visiting dental units of south batinah. as dental services are offered free of cost in oman, it is likely that the study covered majority of the symptomatic cases of dental problem. those without symptoms may not have visited the health institution and some with symptoms may have visited private dental clinics. however, costly private dental services for dental extraction purpose constitute less than 0% of total cases of exodontia, as was revealed by personal communication with the dentists of the region. since areas of barka and musanna had overlapping catchment area, some of the dental cases might have visited the dental units of neighbouring regions. however, since similar patients from the neighbouring suwaiq wilayat are known to visit musanna extended health centre and rustaq hospital, the number of cross-regional cases is likely to be constant. private clinics might have been visited by the comparatively affluent, mainly for prosthetic treatment, since these services are not provided in the regional ministry of health institutions. thus the study results could be generalised to the entire population, with caution. table 3. causes of exodontia (south batinah dental study 2000) gross dental caries with no salvation possible 2,176 51.9% deciduous teeth with problem 837 20.0% remaining teeth to be extracted 590 14.1% for prosthetic treatment 431 10.3% for exposed teeth 114 2.7% secondary caries 43 1.0% secondary to trauma 3 0.1% total 4,194 100.0% with the inclusion of the data of all the cases visiting the three dental units of the region for 2 weeks of the study period and with such a large sample, the rates of the exodontia are likely to be true values and less likely to be observation by chance. since the proportion of the study population and examined population differed, standardisation was carried out. this also enabled to minimize the effects of age, gender, geographic distribution and other unknown confounders on the exodontia rates. the quality assurance procedures minimized the observation and misclassification bias. the hospital records were used, hence recall bias is less likely. since the participating dentists were aware of the study, observer bias, especially for exodontias, could be possible. the annual rate of dental extraction in region during study period closely matched the rate during the other months of the same year.2 the study in 993 conducted to determine the main demand of dental patients showed large proportion of clinics having patients attending 27 private clinics with first choice of extraction.6 therefore e x o d o n t i a i n s o u t h b at i n a h 24 an overestimation of exodontia due to observer’s bias, even if it exists, would be marginal, and is unlikely to have given spurious results. the details of exodontia in relation to the type of teeth were not collected in this study. therefore causes in different groups of teeth could not be assessed. extraction rates per attendance of the dental clinic have been reported in different studies.8,9,11 among highly educated and health conscious population, such hospital based rates might reflect the situation in overall population. but such calculation would not give true rates in developing countries where access to the dental services is limited and dental care awareness in the population is low. the exodontia rates in this study in relation to the dental consultations ranged from 40% to 50%. in view of over utilization of health services in oman,7 the possibility of multiple visits for different episodes, such denominator may be misleading. therefore, the rates of exodontia in relation to the population were calculated in this study. dental caries and its complications constituted more than 95% of the exodontia cases among the study population. more than half of them consulted the dentists at a stage when salvation of the caries tooth was not possible. this is a matter of concern. screening of high risk population, implementing preventive measures and promotion of health education for early and periodic dental check ups are the strategies that need to be vigorously implemented. the study in usa showed that in spite of improved paediatric oral health, dental caries and its sequel remained the most common reason for extraction of primary teeth.8 developed countries such as the uk9,10 and norway11 also showed similar trends of high proportion of dental caries as cause for dental extractions. gender difference of tooth extraction was not found in usa.8 but females were at more risk for tooth loss in kenya compared to male and the trend was observed of more male having exodontia due to periodontal diseases.12 in oman, male-female population ratio is 03:00.2 the health services are easily accessible at nominal cost of less than half dollar. in this situation, the gender difference observed for high dental extraction among females needs further study to confirm the findings and determine the underlying causes of the gender variation. in this study, 20% of the exodontia was for deciduous teeth of under 2-year-olds. however, detailed age grouping was not carried out in this study. the causes of exodontia by age group, mainly focusing the geriatric age groups, therefore could not be studied. a national study with sound epidemiological methodology and adding the information on tooth involved should be undertaken. the results suggest that 7 persons per ,000 population underwent dental extraction. based on this rate, the resources for providing dental services could be planned. currently seven dentists in three dental units provide care for exodontia. during the study period, each dentist attended about ten cases of exodontia in the seven hours of a working day. estimating an average 20 minutes per procedure per patient, each dentist would be occupied for 3½ hours on exodontia services. this may compromise their other work of screening, counselling and specialised orthodontic work. due to a lack of skilled manpower to undertake endodontic treatment at the regional centres, caries patients requiring conservative treatment have to be referred to a tertiary dental care unit at muscat. if such conservative treatment requires multiple visits, patients usually refuse and do not comply for the complete treatment. in such situation, the dentist might opt for dental extraction, which might also contribute to increase the rate of exodontias. further studies to determine the advice to dental caries patients prior to exodontias would help to understand the magnitude of additional exodontias than those actually needed. acknowledgements the authors thank all the dentists of the study area for actively participating in the study. the support of regional and national health administration for the study is also appreciated. we also thank all the omani dental patients who had participated in this study. the advice of mrs. ruth al mabry in finalizing the article was very useful. r e f e r e n c e s . ministry of health. specific disease control program—dental caries. 5th five year health plan of the ministry of health, sultanate of oman. 995, pp: 67–78 2. ministry of health, world health organization. national dmf survey of st primary school children in oman. 3. ministry of health, world health organization. national dmf survey of st preparatory school children in oman. 4. ministry of health. annual health report 2000. muscat, oman. pp: -, 9. 5. oral health care manual st edition, ministry of health, sultanate of oman, golden printers, muscat, oman 998. 6. hassan f. evaluation of dental care at private dental clinic in oman. 993 (unpublished document of the ministry of health, sultanate of oman) 7. tjam fs. a report on referral activities in healthcare sector of k h a n d e k a r e t a l 25 oman world health organization (unpublished), 996, 8–9. 8. alsheneifi t, hughes cv. reasons for dental extractions in children. pediatr dent, 200, 23,09–2. 9. agerholm d. reasons for extraction by dental practioners in england and wales: a comparison with 986 and variations between regions. j dent, 200, 4, 237–24. 0. mc caul lk, jenkins wm, kay ej. the reasons for the extraction of various tooth types in scotland: a 5 year followup. j dent, 200, 29, 40–407. . trovik ta, klock ks, haugejorden o. trends in reasons for tooth extraction in norway from 968 to 998. acta odontol scand, 2000, 58, 89–96. 2. manji f, baelum v, fejeskov o. tooth mortality in an adult rural population in kenya. j dent res, 988, 67, 496–500. e x o d o n t i a i n s o u t h b at i n a h magnitude and determinants of exodontia in south batinah region of oman a cross sectional study *rajiv khandekar1, zina fouad2, aliya m al-khusaibi3 method results discussion acknowledgements references percutaneous septal reduction therapy in a patient with severely symptomatic hypertrophic obstructive cardiomyopathy an experience from a tertiary care centre *hatim al lawati, sunil k. nadar, adil b. al riyami sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 443–447, epub. 7 nov 22 submitted 7 nov 21 revisions req. 16 dec 21 & 1 feb 22; revisions recd. 4 jan & 24 feb 22 accepted 6 mar 22 department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: hatim.al.lawati@gmail.com hypertrophic cardiomyopathy (hcm) isa heterogeneous group of genetically-transmitted diseases characterised by abnormal hypertrophy and disarray of the cardiomyocytes.1 the hypertrophy is usually asymmetricly affecting the basal septum, though other morphological variants such as apical or mid-septal which are also not uncommon. although the global prevalence of hcm is reported to be around 0.16-0.29% (approximately 1 in 344–625) of the general adult population.1 the true prevalence is likely higher as many patients with hcm are asymptomatic and diagnosed during family screening or late in adult life once symptoms begin.2,3 with increased awareness of the disease, improved cardiac imaging modalities and increased availability of genetic screening of families, the reported prevalence appears to be increasing and it is now estimated that around 0.6% of the population carry hcm-related genes.4 patients usually present with symptoms late in adult life. the more severe forms may present in early childhood or the teenage years. the symptoms include dyspnoea related to the diastolic dysfunction or left ventricular outflow tract (lvot) obstruction, anginalike chest pain due to oxygen demand supply mismatch caused by the severe hypertrophy or light-headedness, syncope or palpitations due to the lvot obstruction or arrhythmias. lvot obstruction at rest occurs in around a third of patients with hcm while another third has provocable obstruction. the remaining third have hypertrophy without obstruction.1 management of patients with hcm can be challenging and depends on the symptoms experienced by the patient. pharmacological management with negative inotropic and negative chronotropic agents such as beta-blockers, calcium channel blockers and disopyramide helps alleviate symptoms by improving left ventricular diastolic filling and systolic stroke volume, but is achieved in only 50% of the cases.5 additional interventional treatment strategies should be considered early during the course of the disease. outcomes of randomised studies on dual-chamber electrosystolic stimulation with a dual chamber pace maker have been disappointing.6 implantable cardio verter-defibrillators should be considered for those at high risk for sudden cardiac death. for patients with significant lvot obstruction, septal reduction strategies in the form of surgical septal myectomy (sm) or alcohol septal ablation (asa) should be considered. these alternative therapeutic modalities are supported by a large body of evidence confirming positive shortand long-term outcomes in symptomatic patients.1 the open-heart surgical approach was the only treatment option available until the early 90s. this commentary offers a description of the authors’ experience with treating a severely symptomatic middle-aged female patient with obstructive hcm. the patient did not respond to medical therapy and successfully underwent asa at a tertiary care hospital in muscat, oman in 2017. to the best of the authors’ knowledge, this is the first such experience from the country. an exemplary case from the authors’ service a 51-year-old active, obese female patient (bmi 36.8 kg/m2) with sjögren’s syndrome, dyslipidaemia, fatty liver and obstructive sleep apnoea presented to a tertiary care hospital in muscat, oman, in 2017 with worsening exertional dyspnoea. she had been investigated previously and had an echocardiogram a few years earlier which was reported as good left ventricular function with concentric left ventricular hypertrophy (lvh). a 12-lead electrocardiogram (ecg) revealed sinus rhythm with lvh and secondary repolarisation abnormalities [figure 1a]. a gated cardiac computed tomographic study showed normal coronary arteries. the investigations for a possible respiratory cause were unremarkable. in view of the worsening dyspnoea and possible pulmonary hypertension, the patient underwent a repeat comment this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.3.2022.020 https://creativecommons.org/licenses/by-nd/4.0/ percutaneous septal reduction therapy in a patient with severely symptomatic hypertrophic obstructive cardiomyopathy an experience from a tertiary care centre 444 | squ medical journal, november 2022, volume 22, issue 4 echocardiogram. the echocardiogram revealed moderate asymmetrical septal hypertrophy (ash) with an interventricular septal (ivs) diastolic dimension of 21 mm (normal: <11 mm) and a posterior left ventricular wall diastolic dimension of 10 mm (normal: <11 mm; ivs/posterior wall ratio: 2.1). systolic anterior motion (sam) of the anterior mitral valve leaflet was noted with a resting left ventricular mid-cavitary gradient of 42 mmhg that accentuated to 51 mmhg with the valsalva manoeuvre. there was mild concomitant mitral regurgitation with a normal-appearing mitral valve apparatus. there was no evidence of pulmonary hypertension. the patient’s previous echocardiogram, from approximately five years earlier, was reviewed and confirmed the absence of ash or sam. the patient was started on oral bisoprolol up to a dose of 10 mg once daily, with modest symptomatic improvement. an exercise-stress echocardiogram was performed while on maximum treatment. she was only able to exercise for 5.02 minutes on the standard bruce protocol attaining a total of seven metabolic equivalents (mets). her blood pressure dropped from 146/68 mmhg to 135/37 mmhg at peak stress. the test was stopped due to severe dyspnoea. no significant arrhythmias were documented. however, the echocardiogram at peak exercise recorded a significant gradient of 80 mmhg across the midfigure 3: haemodynamics obtained at the time of first, left heart catheterisation showing (a) a significant pressure gradient between the left ventricular (lv) apex and lv outflow tract with no gradient between the outflow tract and the aorta, (b) the classic brockenbrough-braunwald-morrow sign with a marked post-extra systolic accentuation of the peak to peak pressure and mean gradients, (c) septal ischaemia resulting from balloon-occlusion of the septal perforator branch, (d) a significant 100 mmhg gradient measured between the lv and aorta using simultaneous pressure tracings from both chambers (e) marked reduction in the resting pressure gradient after injection of 100% ethanol into the target septal perforator and (f) complete elimination of post-extra-systolic accentuation after alcohol injection. figure 1: baseline standard 12-lead electrocardiogram of a 51-year-old female patient showing (a) normal sinus rhythm and voltage criteria for left ventricular hypertrophy with secondary repolarisation abnormalities seen in the lateral leads and (b) complete right bundle branch with st elevation in v1/v2 consistent with a septal infarction taken after alcohol septal ablation. the atrio-ventricular conduction time is also normal. figure 2: selective coronary angiogram of the left coronary system in the cranial projection laying out the course of the left anterior descending coronary artery of a 51-year-old female patient. the dominant septal perforator branch (arrows) arising from the proximal segment, which was the target for balloon occlusion and subsequent alcohol injection, can also be seen. hatim al lawati, sunil k. nadar and adil b. al riyami comment | 445 left ventricular cavity with mild mitral regurgitation and normal pulmonary artery pressure. a detailed discussion was undertaken about the patient’s options for septal reduction therapy in view of the failure of medical therapy and the worsening of symptoms and the presence of severe lvot obstruction at rest which was accentuated on provocation. the patient consented to asa. an initial coronary angiogram demonstrated angiographically normal coronary arteries and delineated one dominant septal perforator (sp) branch in the proximal left anterior descending (lad) coronary artery [figure 2]. the initial resting left-ventricular-aortic mean pressure gradient was measured at 38 mmhg through a gradual pull-back performed using an end-hole catheter [figure 3a]. the post-extra-systolic beat showed a dramatic accentuation of the peak pressure gradient to 160 mmhg and the mean pressure gradient to 100 mmhg indicating severe dynamic mid-cavity obstruction, which is the classic brockenbrough-braunwaldmorrow sign of dynamic lvot obstruction [figure 3b]. balloon occlusion of the dominant sp for two minutes resulted in a remarkable diminution of the lv gradient down to 22 mmhg [figure 3c]. a contrast-enhanced echocardiogram was performed using agitated saline and iodinated contrast mixture and definity® [lantheus medical imaging, billerica, usa] ultrasound contrast administered through a microcatheter in the target sp branch, revealed a very focal area of opacification in the septum at the point of anterior mitral valve leaflet-septal contact and the aliasing zone on colour doppler images [figure 4]. a standard coronary guide wire was secured into the distal lad and a stiffer support-type coronary guide wire, in the dominant sp branch. a coronary microcatheter was advanced into the side branch. this was intended for local alcohol delivery. after excluding the sp from the lad with a 2.5 × 9.0 mm semicompliant balloon, 100% ethanol was injected into the sp in 0.5 ml aliquots to a total amount of 2 ml. the resting mean pressure gradient eventually decreased to 21 mmhg with no post-extra-systolic accentuation [figures 3d–f]. the procedure was well-tolerated and no significant arrhythmias or heart blocks were encountered [figure 1b]. she experienced mild, manageable chest pain and transient complete heart block that resolved with an otherwise unremarkable hospital stay. the immediate post ablation transthoracic echocardiogram demonstrated only a 5 mmhg gradient across the mid-lv cavity both at rest and post valsalva. there was now an absence of sam of the anterior mitral valve leaflet and only trivial mitral regurgitation. similar findings were documented on an echocardiographic study done 10 days later, at which point the patient had already resumed her daily activities without any symptoms. a stress echocardiogram was repeated eight weeks after the intervention (off bisoprolol). at this time the patient’s exercise duration had increased significantly to 8.1 minutes attaining 10 mets with a normal blood pressure response. both the resting and immediate post-exercise echocardiogram revealed no midcavitary gradient. at two-year follow up, the patient was off-treatment and remained asymptomatic with a good exercise tolerance. the authors confirm that written consent for submission and publication of this work, including images and associated tests, has been obtained from the patient. the patient had no objection to the publication, provided her identifying details were anonymised. author reflections asa has been gaining favour worldwide as the procedure of choice in managing patients with hcm and lvot obstruction, who fail medical therapy. the first septal ablation was performed by urlich sigwart in 1994.7 he described three patients with severe dynamic subaortic obstruction. all three patients responded to a trial of balloon occlusion of the target sp branch, following which injection of absolute alcohol completely abolished the outflow tract gradient within seconds of alcohol delivery and remained eliminated figure 4: echocardiographic scans of the 51-yearold female patient obtained during alcohol septal ablation (a) with agitated saline and iodinated contrast mixture and (b) with ultrasound-enhancing agent. note the focal opacification in the target area in the mid-interventricular septum (asterisk) without right ventricular extension or involvement of the papillary muscle. percutaneous septal reduction therapy in a patient with severely symptomatic hypertrophic obstructive cardiomyopathy an experience from a tertiary care centre 446 | squ medical journal, november 2022, volume 22, issue 4 even at 12 months of follow-up. the procedure aims to induce a controlled chemical infarction of left ventricular septal myocardium at the point of septal-mitral leaflet contact. it is not uncommon to see a resurgence in gradient after days or weeks due to local myocardial oedema. once necrosis and fibrosis set in, thinning and fibrotic retraction of the basal septum results in a more gradual reduction in outflow gradient.8 the effect is augmented by mild left ventricular dilatation and regression of hypertrophy due to afterload reduction. clinical and echocardiographic outcomes after asa appear comparable to sm. early observational studies comparing outcomes after asa and sm, showed a significant reduction in lv gradient and a marked improvement in functional status without a significant difference in in-hospital mortality.9 in a meta-analysis of twelve observational studies, investigators from the cleveland clinic showed no difference in short term (3-month) and long term (5-year) mortality.10 asa produced a significant improvement in new york heart association functional class, post-procedural reduction in septal thickness and lvot gradient. there was no difference in post-procedural lv ejection fraction and degree of mitral regurgitation. patients undergoing asa very commonly developed right bundle branch block after septal ablation and were more likely to require permanent pacemaker implantation (odds ratio [or] = 2.57, 95% confidence interval [ci]: 1.68–3.93; p <0.001) and had higher residual gradients.9 another concern about asa was the hypothetical risk of scar-related ventricular arrhythmias and increased risk of sudden cardiac death. one systematic review addressing this concern, reported similar rates of all-cause mortality and sudden cardiac death in patients treated with asa and sm.11 furthermore, when adjusted for baseline characteristics, the odds ratio for treatment effect on all-cause mortality was 12.5% lower in the asa-treated patients (or = 0.28, 95% ci: 0.16–0.46) compared to those who underwent sm (or = 0.32, 95% ci: 0.11–0.97).11 the annual risk of sudden cardiac death after asa is reported to be 0.5% per year, which is comparable to the general population.12–14 conclusion asa is a viable alternative to surgical myectomy in symptomatic patients with hypertrophic obstructive cardiomyopathy. the procedure results in a significant improvement in functional status and carries favourable short-term and long-term outcomes. the current authors’ experience has shown a favourable immediate and long-term outcome for this condition in the first case treated with asa in oman at a tertiary care hospital. extant literature suggests that it is relatively safe, less invasive and cheaper than open heart myomectomy which should be performed by experienced surgeons in specialised centres capable of performing high risk procedures. the successful outcome of this endeavour opens up a treatment option to patients in oman that was not previously readily available to them. a u t h o r c o n t r i b u t i o n s all authors have contributed equally in writing the manuscript, verifying the scientific contents and preparing its final version after review for publication. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t s authors would like to acknowledge the cardiology unit in the department of medicine, the nursing personnel and the cardiovascular technologists in the cardiac catheterisation laboratory and echocardiography laboratory for their valuable clinical input. references 1. marian aj, braunwald e. hypertrophic cardiomyopathy: genetics, pathology, clinical manifestations, diagnosis and therapy. circ res 2017; 121:749–70. https://doi.org/10.1161/circresaha.117.31 1059. 2. maron bj, gardin jm, flack jm, gidding ss, kurosaki tt, bild de. prevalence of hypertrophic cardiomyopathy in a general popul ation of young adults. echocardiographic analysis of 4111 subjects in the cardia study. coronary artery risk development in (young) adults. circulation 1995; 92:785–9. https://doi.org/10.11 61/01.cir.92.4.785. 3. moon i, lee sy, kim hk, han kd, kwak s, kim m, et al. trends of the prevalence and incidence of hypertrophic cardiomyopathy in korea: a nationwide population-based cohort study. plos one 2020; 15:e0227012. https://doi.org/10.1371/journal.pone.0227012. 4. semsarian c, ingles j, maron ms, maron bj. new perspectives on the prevalence of hypertrophic cardiomyopathy. j am coll cardiol 2015; 65:1249–54. https://doi.org/10.1016/j.jacc.2015.01.019. 5. spaziano m, sawaya fj, lefevre t. alcohol septal ablation for hypertrophic obstructive cardiomyopathy: indications, technical aspects and clinical outcomes. j invasive cardiol 2017; 29(12): 404-410. pmid: 29207362. 6. nishimura ra, trusty jm, hayes dl, ilstrup dm, larson dr, hayes sn, et al. dual-chamber pacing for hypertrophic cardio myopathy: a randomized, double-blind, crossover trial. j am coll cardiol 1997; 29:435–41. https://doi.org/10.1016/s0735-1097(9 6)00473-1. 7. sigwart u. non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. lancet 1994; 346:211–14. https:// doi.org/10.1015/s0140-6736(95)91267-3. 8. veselka j. twenty years of alcohol septal ablation document more than a history of a single interventional procedure. cor et vasa 2015; 57:e16–27. https://doi.org/10.1016/j.crva sa.2014.12.004. https://doi.org/10.1161/circresaha.117.311059 https://doi.org/10.1161/circresaha.117.311059 https://doi.org/10.1161/01.cir.92.4.785 https://doi.org/10.1161/01.cir.92.4.785 https://doi.org/10.1371/journal.pone.0227012 https://doi.org/10.1016/j.jacc.2015.01.019 https://doi.org/10.1015/s0140-6736(95)91267-3 https://doi.org/10.1015/s0140-6736(95)91267-3 https://doi.org/10.1016/j.crva sa.2014.12.004 https://doi.org/10.1016/j.crva sa.2014.12.004 hatim al lawati, sunil k. nadar and adil b. al riyami comment | 447 9. agarwal s, tuzcu em, desai my, smedira n, lever hm, lytle bw, et al. updated meta-analysis of septal alcohol ablation versus myomectomy for hypertrophic cardiomyopathy. j am coll cardiol 2010; 55:823–34. https://doi.org/10.1016/j.jacc.2009.09.047. 10. alam m, dokainish h, lakkis nm. hypertrophic obstructive cardiomyopathy alcohol septal ablation vs. myomectomy: a meta analysis. eur heart j 2009; 30:1080–7. https://doi.org/10.1093/ eurheartj/ehp016. 11. leonardi r, kransdorf ep, simel dl, wang a. meta-analyses of septal reduction therapies for obstructive hypertrophic cardio myopathy: comparative rates of overall mortality and sudden cardiac death after treatment. circ cardiovasc interv 2010; 3:97–104. https://doi.org/10.1161/circinterventions.109.916676. 12. jensen mk, prinz c, horstkotte d, van buuren f, bitter t, faber l, et al. alcohol septal ablation in patients with hypertrophic obstr uctive cardiomyopathy: low incidence of sudden cardiac death and reduced risk profile. heart 2013; 99:1012–17. https://doi. org/10.1136/heartjnl-2012-303339. 13. veselka j, lawrenz t, stellbrink c, zemanek d, branny m, januska j, et al. early outcomes of alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a european multicenter and multi national study. catheter cardiovasc interv 2014; 84:101–7. https://doi.org/10.1002/ccd.25236. 14. veselka j, jensen mk, liebregts m, januska j, krejci j, bartel t, et al. long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the euro-asa registry. eur heart j 2016; 37:1517–23. https://doi. org/10.1093/eurheartj/ehv693. https://doi.org/10.1016/j.jacc.2009.09.047 https://doi.org/10.1093/eurheartj/ehp016 https://doi.org/10.1093/eurheartj/ehp016 https://doi.org/10.1161/circinterventions.109.916676 https://doi.org/10.1136/heartjnl-2012-303339 https://doi.org/10.1136/heartjnl-2012-303339 https://doi.org/10.1002/ccd.25236 https://doi.org/10.1093/eurheartj/ehv693 https://doi.org/10.1093/eurheartj/ehv693 january 2007 vol 7 correct a.indd abstract objective: this project aimed to assess the antibacterial potential of various brands of honey sold in muscat area on some isolates of h. pylori and to determine if there is any synergy between honey and amoxycillin or clarithromycin used in the treatment of h. pylori gastritis and duodenal ulcer. methods: eight samples of commercial honey were used in the experiment after they were checked for purity by sub-culturing on blood agar and incubating for 48 hours at 370c. honey samples showing gross contamination were discarded. purified culture isolates of h. pylori from our laboratory stock cultures were swabbed on chocolate plate using x 04 cfu/ml. one hundred microlitres (00µl) of various honey samples were placed on each plate which was subsequently incubated microaerophilically at 37ºc for 3 days. the presence or absence of growth inhibition zones on each plate was noted and an average zone size of each honey was taken. honey samples with high zone sizes were further diluted from :2-:8 to find the end-points of their growth inhibition concentrations and the experiment was repeated in triplicates. the synergistic effect between honey, amoxycillin and clarithromycin was done in triplicates by placing honey at various distances between each antibiotic after swabbing chocolate agar with x 04 cfu/ml of h. pylori. the plates were incubated as before. results: all honey samples produced growth inhibition zones with h. pylori no at dilution of honey but had different zone sizes at :2–:8 dilutions. black forest honey had the highest antibacterial activity followed by langnese honey. none of the honeys had a synergistic effect with either clarithromycin or amoxycillin. conclusion: we conclude that, in vitro, some honey brands possess antibacterial activity against h. pylori and that no synergy or antagonism was observed between honey and clarithromycin or honey and amoxicillin using h. pylori as a test organism. though no synergy or antagonism was observed between honey, amoxicillin or clarithromycin, it has been suggested that the use of honey with triple therapy regimen may help shorten the time required to eliminate h. pylori from stomach lining of patients with gastritis or duodenal ulcer caused by h. pylori infection key words: antibacterial, amoxicillin, clarithromycin, honey, h. pylori, triple therapy, synergy the antibacterial activity of honey on helicobacter pylori *basil c nzeako, faiza al-namaani department of microbiology and immunology, sultan qaboos university, college of medicine and health sciences, p.o.box 35, al-khod, muscat 123, sultanate of oman *to whom correspondence should be addressed. email: basil @squ.edu.om البوابية العطيفة جلرثومة املضادة فعالية العسل اذا هناك فيما وملعرفة البَوَّابِيَّة، ةُ طيفَ العَ ضد جرثومة حيوي مسقط كمضاد أسواق في املتوفر العسل من أنواع عدة تقييم فاعلية امللخص: الهدف: تسببها التي عشري االثني وقرحة املعدة التهاب في عالج التي تستعمل ( ــ أو الكالريثرومايس ــلني (االموكسيس احليوية املضادات وبني بينه مؤازرة 48 الدم ملدة في آغار زراعتها ــطة بواس نقائها من التثبت مت بعد ان ــل العس من عينات ثماني على البحث هذا ألطريقة: اجري ــورة. املذك ــة اجلرثوم (1x104 cfu/ml)بتركيز الكاكاو صحون مختبرنا في في املتوفرة البَوَّابِيَّة ــةُ طيفَ العَ جرثومة زرعت . ثالثة أيام ملدة 37 مئوية حرارة ــة بدرج ــاعة س بعدها لوحظ قليل. هواء بوجود أيام ثالثة ملدة 37 مئوية حرارة درجة حفظ الصحون في ومت صحن، كل الى العسل عينات من (µl 100) اضافة ومتت لفاعلية االدنى التركيز تقييم مت ذلك بعد أنواع العسل. من نوع التثبيط لكل منطقة معدل اخذ بعد عينات العسل اتلفة في اجلرثومة منو تثبيط مؤازرة دراسة مت كما ثالثا. التجربة هذه كررنا وقد ،1:8 1:2 الى من بتخفيفها وذلك اجلرثومة منو تثبيط في كبيرة فاعلية أظهرت التي العسل عينات في البَوَّابِيَّة ةُ طيفَ العَ من (1x104 cfu/ml) بعد زرع احليوية املضادات بني العسل عينات بوضع وذلك والكالريثرومايسني لألموكسيسيلني العسل بدرجات متفاوتة ولكن البَوَّابِيَّة ةُ طيفَ العَ منو كبحت العسل عينات النتائج: كل أيام. ثالتة ملدة 37 مئوية حرارة درجة في وحفظها الكاكاو صحون وتبني . الالجننيس ــل يليه عس ، االعلى هي اجلرثومة ضد ــوداء الس ــل الغابة عس فاعلية أن ــة الدراس 1:8 . وأثبتت 1:2 الى العينات من عند تخفيف خواصا للعسل أن البحث هذا اخلالصة: أثبت أعاله. في املذكورة احليوية واملضادات عينات العسل املستعملة بني مؤازرة وجود عدم الدراسة من هذه لكن ، اخرى جهة من ــني والكالريثرومايس ــيلني االموكسيس من جهة وكال من ــل العس بني تضادد أو تآزر يظهر لم أنه ولو ، ةُ البَوَّابِيَّة طيفَ للعَ مضادة للعالج. الالزم الوقت من يقصر قد البَوَّابِيَّة ةُ طيفَ تسببها العَ التي االمعاء وقرحة اللتهاب املعدة الثالثي العالج العسل مع استعمال ، تآزر. العالج الثالثي ، البوابية العطيفة ، عسل ، ، كالريثرومايسني اموكسيسيللني ، جرثومي املفردات املفتاحية: مضاد sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© o r i g i n a l s t u d y b a s i l c n z e a k o , fa i z a a l n a m a a n i 72 the history of helicobacter pylori dates back to 1875 when the german scien-tists first found spiral bacteria in the lining of the human stomach.1 walery in 1899 published a paper on spiral shaped bacteria from the sediment of human gastric washings, but his publication was in polish so it attracted little or no attention.2 the work of the german and polish scientists was not rediscovered till 1979 when warren saw curved and spiral bacteria in the biopsy material from gastric mucosa. he and marshall isolated and cultured the organism and named it campylobacter pyloridis.3 they contended that most stomach ulcers and gastritis were caused by colonization with this bacterium. following dna sequences, the organism in 1989 was renamed helicobacter pylori by warren and marshall.4 however, the association of h. pylori with gastritis or ulcers was distrusted since it was believed that no bacterium could survive for long in the acid ph of the stomach. to prove their point, marshall infected himself and had gastritis. the organism was subsequently isolated from his stomach lining.5 marshall and warren were awarded the nobel prize in medicine in 2005 for their discovery of h. pylori and its role in gastritis and peptic ulcer disease.6 currently, it is estimated that half the world’s population harbours h. pylori and that while it exits as normal flora in some people, in others, it causes gastritis and ulcers.7 malfertheiner et al.8 recommended the use of triple therapy which includes an anti-ulcer agent such as ranitidine, bismuth citrate, or a proton pump inhibitor, omeprazol or pantoprazole and a combination of two antibiotics from either metronidazole, clarithromycin or amoxicillin for elimination of h. pylori from the stomach. though this recommendation was made and is applied in the treatment of h. pylori infection, a significant problem associated with the treatment is the organism’s increasing resistance to antibiotics and the failure of the clinicians to follow up the course of treatment with repeated isolations and sensitivity pattern of the original isolate. hiyana9 in japan found most of his h. pylori isolates to be resistant to clarithromycin and metronidazole while crone et al.10 isolates from children and adolescent , in vitro, showed resistance to clarithromycin. honey has been used as a medicine since ancient times in many countries.11,12,13 its use is recorded in sumerian clay tablets estimated to be 4000 years old and in egyptian papyri from 1900 to 1250 b.c.11 the revelation in the holy koran and documentation in the hadith clearly referred to the effectiveness of honey in the healing of diseases for mankind.14 abu taib et al.14 reported that growth of h. pylori was inhibited by 20% concentration of natural honey while al somal et al,15 mcgovern et al.16 found, in vitro, that manuka honey solution possessed antibacterial properties against h. pylori. our project aimed to determine the antibacterial potential of various brands of honey sold in muscat area on h. pylori and to find out if there is synergy between honey and amoxycillin or clarithromycin which are two antibiotics currently in use in the treatment of h. pylori infection in sultan qaboos university hospital (squh). table 1: honey samples and their sources honey sample sources black forest germany langnese forest germany langnese natural bee germany black forest germany blossom bee honey switzerland al-shifa natural honey iran al-nada chestnut honey oman al-nada clove honey oman figure 1: zone of inhibition of honey on staphylococcus aureus (nctc6571). th e a n t i b a c t e r i a l a c t i v i t y o f h o n e y o n h e l i c o b a c t e r p y l o r i 73 m e t h o d s c ult ur e s o f h e l ic o b ac t e r p y lo r i these were provided from departmental stock cultures. the organisms were checked for purity by inoculating them onto campylobacter and chocolate agar media and incubating microaerophilically (co2 10%, oxygen 10%, nitrogen 80%) for 5 days at 370c. grown colonies were gram stained and observed for spiral shape, oxidase and urease activities. spiral shaped, urease and oxidase positive colonies typical of h. pylori were used in the experiment. h o n e y sa mpl e s thirteen brands of commercial honey available in muscat area of oman were collected for the study. they were checked for purity by inoculating onto blood agar and incubating aerobically at 37°c for 48 hours. samples showing growth of bacteria or growth of more than 4-5 colonies of yeasts were excluded from the study. only eight samples were found good for our study [table 1]. c h e c k i n g th e h o n e y sa mpl e s f o r a n ti b a c te r i a l a c ti v i t y the honeys were initially checked for antibacterial activity by using staphylococcus aureus (nctc 6571) as a control organism. this strain of s. aureus is known to be sensitive to most antimicrobial agents and is used in our laboratory for the control of our antibiotic sensitivity pattern. an inoculum containing 1x104 cfu/ml of the organism was prepared using mcfarland tube 0.5. a dry swab immersed into it was pressed on the side of the bottle to remove excess fluid and was subsequently used to swab a dry diagnostic sensitivity test (dst, oxoid, uk) plate. one hundred microlitres (100µl) of honey was placed on the surface of each plate using a chipped sterile tip. this process was applied for each honey sample. the plates were incubated at 37˚c overnight and zones of growth inhibition produced by each honey with the test organism were subsequently taken. d e te r mi n ati o n o f a n ti b a c te r i a l a c ti v i t y o f h o n e y o n h . p y lo r i inocula containing 1x 104 cfu/ml of each h. pylori were prepared and smeared on chocolate as done with s. aureus control. one hundred microliters (100µl) of each individual honey were placed on the surface of each plate using a chipped sterile tip as before. the plates were incubated microerophilically (co2 10%, oxygen 10%, nitrogen 80%) at 37˚c for 3 days. honey samples producing zones of inhibition of more than 8mm were double diluted from 1:2 to 1:8 to obtain the final end-points of antibacterial activity. s y n e r gi sti c te st be t w e e n h o n e y a n d s ome a n ti bi oti c s the antibiotics used in this experiment were those used for the treatment of cases of h. pylori infection at squh. amoxycillin (panpharma, france) and clarithromycin (panpharma, france) obtained from the pharmacy department of the squh at concentrations of 250mg powder were diluted to 10µg and table 2: the zone of growth inhibition of the honey samples on h. pylori code honey samples zone of inhibition (mm) at various dilutions neat 1:2 1:4 1 black forest 25 19 18 2 langnese forest 25 17 17 3 langnese natural bee honey 28 11 zero 4 black forest 25 zero zero 5 blossom bee honey 15 nd* nd 6 al-shifa natural honey 17 nd nd 7 al-nada clove honey 29 zero zero 8 al-nada chestnut honey 26 nd nd * not done (insufficient amount of honey) figure 2: zone of inhibition of honey on helicobacter pylori on chocolate agar. b a s i l c n z e a k o , fa i z a a l n a m a a n i 74 15µg respectively using sterile distilled water. these concentrations are contained in the antibiotic discs routinely used at sultan qaboos university hospital for the determination of h. pylori sensitivity. efforts to obtain the antibiotics as pure liquid concentrates proved impossible. two isolates of h. pylori out of five used in this experiment were employed. an inoculum of each h. pylori was prepared and smeared on plates as mentioned earlier in the text. fifty microlitres (50µl) of honey and antibiotics were placed at 15, 20 and 25mm apart from each other using three sets of plates per distance and for each antibiotic. they were allowed to seep into the media and incubated microaerophilically (co2 10%, oxygen 10%, nitrogen 80%) at 37ºc for 3 days. synergy exists if the growth inhibition zone produced by honey in combination with any of the antibiotics is greater than growth inhibition zones produced by either alone.17 r e s u l t s table 1 shows the types of honey and their sources while figure 1 is a micrograph of the growth inhibition zones produced by some honey on s. aureus (control organism). table 2 shows the inhibition zone sizes produced by various honeys at various dilutions of the honeys. the highest growth inhibition zone was produced by black forest (sample 1) followed by langnese honey and natural honeys (samples 2 and 3). other honeys used in the investigation produced zones only at no dilution. figure 2 represents the micrograph of the growth inhibition zones produced by some of the honey samples on h. pylori on chocolate agar. no synergy was observed between honey and clarithromycin or honey and amoxicillin. d i s c u s s i o n honey is known to possess antimicrobial activity and has been used to cure many skin infections.11,12,13,18,19 in our experiment, we observed that all the honey samples examined possessed antibacterial activity against h. pylori with the natural black forest honey from the black forest in germany showing the highest antibacterial activity. this is followed by langnese honey also from germany. the elements responsible for the antibacterial activity of honey are not fully known, but have been attributed to various polyphenolic compounds found in honey (propolis, flavonoids, flavones, tannins) and to glucose oxidase and osmosis.11 honey is a product of various plant nectars and differences exist between one nectar and the other based on plant species, the season of the year and the geographical location of the plant.11 molan11,19 attributed the antibacterial activity of honey to its content of glucose oxidase, which liberates hydrogen peroxide when it is diluted. the hydrogen peroxide so liberated is antibacterial besides encouraging epithelial proliferation. burdon20 emphasized that the normal route of wound healing is the stimulation of the growth of fibroblasts and epithelial cells by the hydrogen peroxide produced as a result of injury or infection. somerfield21, condon22 and osato23 ascribed the antibacterial effect of honey to the osmotic effect of its sugar content. honey contains 38% fructose, 31% glucose and 17% water while its ph is 3.9.24 its low content of water encourages wound healing by hygroscopic absorption of water molecules on wound surfaces and by soothing of the wound.12,13 the findings of our work agree with the observation of many earlier researchers14,15,16,19,23,25 who, in vitro, found honey to possess antibacterial activity against h. pylori. in squh, amoxicillin and clarithromycin are used in the treatment of helicobacter infection using triple regimen.26 the use of triple regimen is based on the fact that antibiotics will eliminate h. pylori allowing gastric or duodenal ulcers to heal naturally.8 this condition is not always obtained for some patients fail to comply with the treatment regimen, thereby creating a lack of sufficient concentration of antibiotics in the stomach over a period required to eliminate the organism. in addition, there is an increase in gastric ph which affects the activity of some of the drugs. the low content of the drugs in the stomach results in bacterial mutation, increase of bacterial load and subsequent emergence of intracellular and dormant forms of the bacterium which renders the drugs ineffective.27 though in our experiment, we found no synergy existing between amoxicillin or clarithromycin and honey, suggestions were made that the combination of triple regimen with any of the agents known, in vitro, to have antibacterial effect against h. pylori could help eliminate the organism from the stomach.19,27 in this respect, suggestions were advanced of combining the triple therapy regimen with fresh or fermented milk, propolis, broccoli sprouts, ginger, honey, or mangavath e a n t i b a c t e r i a l a c t i v i t y o f h o n e y o n h e l i c o b a c t e r p y l o r i 75 brava.27,28,29,30,31,32,33 fresh milk contains lactoferrin, fermented milk (lactoferrin and lactobacilli), propolis (polyphenols), broccoli sprouts (sulforaphane) ginger (gingerols), honey (glucose oxidase and polyphenols), mangava-brava (ellagic acid). these substances, individually, are antibacterial and are known in vitro, to stop the growth of h. pylori, but whether, in combination with the triple therapy, more effective elimination of h. pylori is ensured is subject to further experiment, though synergy has been shown to exists between honey and some antibiotics.34 however, the advantage which honey has over other substances suggested is that honey has a ph of 3.9.24 and its dilution by gastric juices in the stomach will activate its glucose oxidase content. the glucose oxidase so activated will liberate hydrogen peroxide which is both antibacterial and an activator of fibroblasts and epithelial cells needed in the healing process of the ulcer caused by h. pylori. helicobacter pylori thrives in acid ph, but produces infection under alkaline ph due to its ability to hydrolyze urea from mucosa cells liberating ammonia27. the acid ph of honey can neutralize this thereby helping the healing process of ulcer caused by the organism. the drawback is that it is difficult to quantify the dosage, but it is worth experimenting on. in our experiment, we found the use of the surface diffusion method better than well diffusion. in surface diffusion, contaminants in honey had more surface area for growth and were clearly visible as contaminants but this was absent in the well diffusion method. moreover, viscous honey samples diffused poorly in the well diffusion method resulting in little or no growth inhibition zones being produced. c o n c l u s i o n in summary, we have tried to show that in vitro many honey samples sold in muscat area of oman possess antibacterial activity against h. pylori and that the degree of this antibacterial activity varies from sample to sample. the differences in antibacterial activity, in our opinion, are dependent on where the nectars were obtained by the bees, the mode of preparation and preservation of the honeys and how long the honeys stayed on the shelves before use. we found that no synergy existed between honey and amoxicillin or clarithromycin used in the treatment of h. pylori infection. though no synergy was observed between honey and the antibiotics used in our experiment, we suggest that honey used in combination with triple therapy may help speed up the rate of elimination of h. pylori from cases of gastritis and duodenal ulcer patients. a c k n ow l e d ge me n t the authors are most grateful to dr. akbar rafay for providing all the stock cultures of h. pylori used in the experiment, the pharmacy department of squh for providing the antibiotics for synergy experiment and to the staff of microbiology and immunology for their cooperation through out the period of the investigation. r e f e r e n c e s 1 blasser mj. an endangered species in the stomach. sci am 2005; 292:38-45 2 konturek jw. discovery by jaworski of helicobacter pylori and its pathogenic role in peptic ulcer, gastritis and gastric cancer. j physiol pharmacol 2003; 54:23-41 3 marshall bj unidentified curved bacilli on gastric epithelium in active chronic gastritis. lancet 1983; 1:12731275. 4 marshall bj, warren jr. unidentified curved bacilli in the stomach patients with gastritis and peptic ulceration. lancet 1984; 1:1311-1315. 5 helicobacter pylori in peptic ulcer disease nih consensus statement online jan 7, 1994; 12:1023. 6 the nobel prize in physiology or medicine awarded to marshall bj and warren jr “for their discovery of the bacterium helicobacter pylori and its role in gastritis and peptic ulcer disease”. nobelprize.org/med/ laureates/2005/index.html, accessed 9th september 2006. 7 angela cm and charles wp. helicobacter pylori. in: max sussman ed. molecular medical microbiology, london: academic press 2002; 1331-1347. 8 malfertheiner p, megraud f, o’morain c, et al. current concepts in the management of helicobacter pylori infection: the maastricht 2-2000 consensus report. aliment pharmacol ther 2002; 16:167-80. 9 hiyana t, tanaka s, masuda h, et al. prevalence of helicobacter pylori resistance to clarithromycin and metronidazole determined by 23s ribosomal rna and rdxa gene analyses in hiroshima, japan. j gastroenterol hepatol 2003; 18:1202-1207. 10 crone j, granditsch g, huber wd et al. helicobacter pylori in children and adolescent: increase of primary clarithromycin resistance 1997-2000. j paediatr gastreenterol nutr 2003; 36:368-371. 11 molan pc. the antibacterial activity of honey: 1 the nature of the antibacterial activity. j bee world 1992; 73: 5-28. b a s i l c n z e a k o , fa i z a a l n a m a a n i 76 12 efem se. recent advances in the management of fournier’s gangrene: preliminary observations. j surg 1993; 113:200-204. 13 efem se. clinical observation on the wound healing properties of honey br j surg 1988; 75:679-681 14 abu taib mm, chowdhury mn, al-humayyd m. inhibitory effect of natural honey on helicobacter pylori. trop gastroenterol 1991; 12:139-143. 15 al-somal n, coley ke, molan pc, hancock bm. susceptibility of helicobacter pylori to the antibacterial activity of manuka honey. j royal soc med 1994; 87:9-13. 16 mc-govern pb, abbas sz, vivian g, dalton hr. manuka honey against helicobacter pylori. j royal soc med 1999; 92:439. 17 miles rs and amyes sgb. laboratory control of antimicrobial therapy. in: collee jg, fraser ag, marmion bp, simmons a. eds. mackie and mccartney, practical medical microbiology. 14th ed. edinburgh: churchill livingstone, 1996: 175. 18 dunford c, cooper ra, molan pc. using honey as a dressing for infected skin lesions. nurs 2000; 96:7-9. 19 molan pc. why honey is effective as a medicine:the scientific explanation of its effects. bee world 2001; 82:22-40. 20 burdon rh. superoxide and hydrogen peroxide in relation to mammalian cell proliferation. free radic biol med 1995; 18:775-794. 21 somerfield sd. honey and healing. j r soc med. 1991; 84:179. 22. condon re. curious intersections of bugs and bees. surg 1993; 113:234-235. 23 osato ms, reddy sg, graham dy. osmotic effect of honey on growth and viability of helicobacter pylori. dig dis sci 1999; 44:462-464. 24 white jw et al. composition of american honeys usda tech bull 1962; 1261. 25 ali at, chowdhury mn, al humayyd ms. inhibitory effect of honey on helicobacter pylori trop gastroenterol 1991; 12:139-143. 26 scrimgeour em, alexander pc, akbar rafay, kassin alriyami. antibiotic handbook, 6th ed. oman: courtesy of glaxo smith kline, 2003. 27 mcloughlin r, racz i, buckley m, o’connor hj, o’morain c. therapy of helicobacter pylori. helico. 2004; 9:42-49. 28 da mota menezea v, atallah an, lapa aj, catapani wr assessing the therapeutic use of lafoensia pacari st. hil. extract (mangavabrava) in the eradication of helicobacter pylori: double blind randomized clinical trial helico 2006; 11:188-95. 29 pantoflickova d, corthesy-theulaz i, dorta g, et al. favourable effect of regular intake of fermented milk containing lactobacillus johnsonii on helicobacter pylori associated gastritis. aliment pharmacol ther 2003; 18:805-813. 30 di mario f, aragona g, bo nd ingegnoli a, cavestro gm et. al. use of lactoferin for helicobacter pylori eradication. aliment pharmacol ther 2003; 17:125-129. 31 boyanova l, dereji s, koumanova r, katsarov n, gergova g, mitov i, nikolov r, krastev z. inhibition of helicobacter pylori growth in vitro by bulgarian propolis: preliminary report. j med microbiol 2003; 52:417419. 32 mahady gb, pendland sl, yun gs, lu zz, stoia a. ginger (zingiber officinale roscoe) and the gingerols inhibit the growth of caga+ strains of helicobacter pylori. anticancer res 2003; 23:3699-3702. 33 galan mv, kishan aa, silverman al oral broccoli sprouts for the treatment of helicobacter pylori infection: a preliminary report. dig dis sci 2004; 49: 10881090. 34 al jabri aa, al hosni sa, nzeako bc, al mahrooqi zh, nsanze h. antibacterial activity of omani honey alone and in combination with gentamicin. saudi med j 2005; 26:767-771. 2008-issue1.indd a 30 year old multigravida presented to the gynecology department of sultan qaboos university hospital, oman, at 32 weeks pregnancy. both parents were healthy and the marriage was nonconsanguineous. there was no familyhistory of birth defects. an antenatal ultrasound study, prenatal mri image of a fetus with semilobar holoprosencephaly *sukhpal sawhney,1 lovina machado,2 rajeev jain1 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 93-94 sultan qaboos university© submitted 2nd july 2007 accepted 21st november 2007 i n t e r e s t i n g m e d i c a l i m a g e جنني عند الفصي نصف الدِّماغ مِ دَّ قَ مُ اجُ مَ ِالنْدِ صور الرنني املغناطيسي احلمل أثناء جني راجيف لوفينا ماجادو˛ سخبال سوهني˛ 1department of radiology and molecular imaging, sultan qaboos university hospital, muscat, oman; 2department of gynecology and obstetrics, sultan qaboos university hospital, muscat, oman; 3department of radiology and molecular imaging, sultan qaboos university, college of medicine & health sciences, muscat, oman *to whom correspondence should be addressed. email: sukh@squ.edu.om 1a. coronal plane at the level of the thalami: central horseshoe-shaped single monoventricle (arrows) with absent frontal horns, absent anterior midline falx and inter-hemispheric fissure, absent septum pellucidum with failure of cleavage of frontal and parietal lobes anteriorly; rudimentary temporal horns (arrowheads); thalami are partially separated with rudimentary third ventricle (marked *) 1b. sagittal plane: corpus callosum (arrow) is absent in the uncleavaged frontal region. temporal horn (arrowhead) is identified. note the proptosis. figure 1a: heavily t2w (haste) images in the fetal cranial coronal and sagittal planes. s u k h pa l s aw h n e y, l o v i n a m a c h a d o a n d r a j e e v j a i n 94 at 32 weeks pregnancy, raised the suspicion of a brain malformation, but it was suboptimal due to maternal habitus. an mri of the fetus, at 34 weeks pregnancy, demonstrated semilobar holoprosencephaly. the baby was born at term with microcephaly, proptosis, and dysmorphic features. the diagnosis was confirmed by a postnatal computed tomography (ct) scan. c o m m e n t holoprosencephaly (hp) is a congenital anomaly characterized by lack of cleavage of the prosencephalon. although relatively rare, it is the most common anomaly that involves both the brain and the face. prenatal diagnosis of this anomaly using ultrasonography, particularly of the less severe forms, is difficult. magnetic resonance imaging (mri) has recently become an important complement to ultrasound in prenatal diagnosis of central nervous system anomalies.1 hp is the most common anomaly affecting the ventral forebrain, occurring in 1/250 embryos and 1/830016,000 live births.2, 3 hp refers to a spectrum of disorders resulting from absent or incomplete cleavage of the forebrain (prosencephlon) during early embryologic development (days). hp is usually categorized as alobar, semilobar or lobar depending on the degree of forebrain cleavage. 4 alobar is the most severe form with complete failure of cleavage of the two cerebral hemispheres. it results in a monoventricular cavity; fusion of the thalami; absence of the corpus callosum; falx cerebri; optic tracts and olfactory bulbs. semilobar hp shares many of these same features, but demonstrates partial segmentation of the ventricles and incomplete fusion of thalami. septo-optic dysplasia, the least severe type of hp, results in separation of the ventricles and thalami and absence of the septum pellucidum.5 the advent of high-resolution real-time ultrasound imaging equipment has allowed detection of the group of holoprosencephalies, but lack of familiarity with uncommon forms may lead to diagnostic confusion. coronal sonograms of the fetal head, in addition to standard axial projections, should be performed whenever an intracranial cystic abnormality is identified.6 several characteristic midline facial malformations are associated with holoprosencephaly, including hypotelorism. the degree of facial dysmorphism tends to parallel the severity of holoprosencephaly and, therefore, sonographic evaluation of facial morphology may aid in prenatal diagnosis.7 recently, diffusion tensor imaging and fiber tracking have revealed white matter structures not apparent on routine mri imaging sequences, which are in agreement with pathologic descriptions of the holoprosencephalic brain.8 r e f e r e n c e s 1. wong alex mc, bilaniuk lt, ng kk, chang yl, chao as, wai yy. lobar holoprosencephaly: prenatal diagnosis with post natal mr correlation. prenat diagn 2005; 25:296-299. 2. roessler e, muenke m. holoprosencephaly: a paradigm for the complex genetics of brain development. j inher metab dis 1998; 21:481-497. 3. golden ja. towards a greater understanding of the pathogenesis of holoprosencephaly. brain dev 1999; 21:513-521. 4. de myer w. holoprosencephaly (cyclopia arhinencephaly). in: yinken pj, bruyn gw, eds. handbook of clinical neurology, vol 30. amsterdam: netherlands. 1977. p. 431-478. 5. byrd se, harwood-nash dc, fitz cr, rogovitz dm. computed tomography evaluation of holoprosencephaly in infants and children. j comput assist tomogr 1997; 1:456-463. 6. cayea pd, balcar i, oswaldo a jr, jones tb. prenatal dieffect of pegylated interferon 9 effect of pegylated interferon on non-responders and relapsers with interferon *hisham o. akbar, mahmoud s. al ahwal abstrac t. objectives: to assess whether a combination of pegylated interferon (interferon conjugated with polyethylene glycol) and ribavirin can improve the response rate in patients with chronic hepatitis c who either did not respond to (non-responders), or had relapsed after responding to (relapsers) standard interferon and ribavirin combination therapy. patients and methods: in this prospective study, 20 chronic hepatitis c patients (comprising 16 non-responders and 4 relapsers to previous treatment with alpha interferon and ribavirin), were treated with pegylated interferon-2b weekly and ribavirin daily for one year. eleven patients had genotype 4, eight were of genotype 1 and one patient had genotype 3. response to treatment was determined based on normalisation of liver enzymes and negative viral load (assessed using qualitative hcv rna pcr) at end of treatment (etr) and 6 months off treatment (svr). results: seven patients (35%) achieved normalisation of liver enzymes and negative viral load at the end of treatment. however, only 2 patients (10%) managed to retain these levels after six months off treatment. the latter two patients had been previous relapsers. conclusion: combination of pegylated interferon and ribavirin may be beneficial in previous relapsers with standard interferon-ribavirin combination therapy, but is unlikely to achieve sustained virological response in non-responders. key words: pegylated interferon, ribavirin, hepatitis c virus, non-responders, relapsers department of medicine, king abdulaziz university hospital, jeddah p.o.box 80215, jeddah 21589, saudi arabia. *to whom correspondence should be addressed. email: gastro20000@yahoo.com feron. several studies have shown pegylated interferon’s superiority in improving response rate in naïve patients, alone or in combination with ribavirin.6–9 this additional effect is yet to be proven on previous non-responders or those who relapsed after combination therapy with ribavirin and interferon. p a t i e n t s a n d m e t h o d s : patients who had been treated earlier with combination therapy (interferon and ribavirin) for one year and did not respond or had relapsed off treatment, were considered for this study. non-responders were defined as those patients who, during treatment, had increased liver enzymes (ast/alt) and persistent detectable viral load, measured using qualitative hcv rna pcr (roche t re atment of hepatitis c virus (hc v) infections has been a subject of different studies. alpha-interferon was the first drug approved for treatment of hcv. initially interferon monotherapy for 6 months was a common practice but it was associated with high relapse rates.1 extended treatment with interferon for one year was found to decrease the relapse rate and increase sustained response.2,3 subsequently ribavirin was approved for treating hcv in combination with interferon. one year-long interferon-ribavirin combination therapy resulted in higher response.4,5 despite such improvement, there are many patients who do not respond to treatment or relapse off treatment. recently, pegylated interferon has been approved for treatment of patients with chronic hcv. attachment of polyethylene glycol molecule to interferon (pegylation) has the advantage of prolonged action as compared to regular intersqu journal for scientific research: medical sciences 2002, vol. 4, no. –2, 9–3 ©sultan qaboos universit y interferon �� ��� ������ ���������� ����� ����� ������������ � ��� ������ ������� �� �������� ���������� �������� ����� ����� ����� ���� �������� :�����:�������� ������ � ��� ������ ������� ������ ������ ���� ��� ������ ���������� ������ �� ������ �������� ���������� .������� :��� ������ �� �������� ���� ����������� �� ������ ���������� ����� ���������� ���� ����� ������ �����.�������:��������� ���� ����� ����� ������ �� ���� ��� ��� ��� ������ ������� ������� ����� ����� �� ���� � ����� �� ���� ����� ����������� ����� ����� �� ���������������� ��� �������.������:����� ���� ���� ������ ���������� ��� �� �������� ���������� ��� �� ��������� ����� �� ����� ������. 0 diagnostics). relapsers were those patients who had normal liver enzymes and undetectable viral load (hcv rna pcr-qualitative) at end of treatment that was not persistent 6 months after stopping combination therapy. all patients were at least 6 months and not more than 2 years off-treatment. end of treatment response (etr) was defined as normalisation of liver enzymes and negative hcv rna pcr (qualitative) at end of treatment. sustained virologic response (svr) was defined as persistent normalisation of liver enzymes and negative hcv rna pcr (qualitative) 6 months off treatment. spss statistical package was used for analysis. descriptive statistics were done. pvalue was set at <0.05 for statistical significance. patient characteristics twenty patients, comprising 6 non-responders and 4 relapsers (to a previous combination treatment) were included in the study. the patients were followed for the period from march 2000 to november 200 at king abdulaziz university hospital, jeddah, saudi arabia. before treatment, complete blood count (cbc), liver function test (lft), prothrombin time (pt), thyroid function test (tft/t4, tsh), quantitative hcv rna pcr (roche diagnostics), gastroscopy and abdominal ultrasound were conducted. quantitative hcv rna pcr results were grouped into low (<06 copies/ml), moderate (06–07 copies/ml) and high (>07 copies/ ml). previous liver biopsy results before treatment with combination therapy were considered while assessing patient response to pegylated interferon. histological severity using grading for necroinflammatory activity and staging for degree of fibrosis was reported as mild hepatitis (grade 2, stage ), moderate hepatitis (grade>2, stage 2), severe hepatitis (grade>2, stage 3) and liver cirrhosis (stage 4). patients included in the study were started on pegylated interferon-2b (schering plough usa) 00 mcg subcutaneously weekly, together with ribavirin (400 mg) twice daily for one year. cbc and lft were repeated weekly for the first month and then monthly until the end of treatment. tft and qualitative hcv rna pcr were repeated after 6 months, end of treatment (2 months) and 6 months off treatment together with lft. the patients had given their written consent. female patients were instructed to practise contraception during childbearing period. fourteen patients (70%) were male and 6 (30%) were female. their mean age was 4 years (29–6 years), and average weight, 74.4 kg (53–94 kg). none of the patients had esophageal varices, and their abdominal ultrasound did not show evidence of ascites, splenomegaly or focal liver lesions. viral load was low in three patients (5%), moderate in 6 patients (80%), and high in one patient (5%). eleven patients (55%) were of genotype 4, five patients (25%) had genotype a, three patients (5%) had genotype b, and one patient (5%) had genotype 3 (consistent with the most prevalent genotypes among this community where genotypes  and 4 account for > 86.4%). two patients (0%) had mild hepatitis, 8 patients (40%) had moderate hepatitis, 6 patients (30%) had severe hepatitis and 4 patients (20%) had liver cirrhosis. r e s u l t s seven patients (35%) achieved etr with pegylated interferon and ribavirin, and 3 of them had low viral load and 4 had moderate viral load; 2 patients had mild hepatitis and 4 had moderate hepatitis. four patients had already achieved etr with previous treatment with regular interferon combination therapy, but were relapsers, and 3 patients were non-responders. two patients (0%) had svr (genotype a,3) while another patient, of genotype 4, had persistent normal ast level with positive hcv rna pcr 6 months off treatment (sustained biochemical response – sbr). all patients who had svr or sbr were relapsers [table ]. patients who achieved etr with the current treatment had already negative hcv rna pcr (qualitative) after 6 months during treatment (p<0.05). two patients (one with low and another with moderate viral load) had achieved svr (p>0.05). these two patients had respectively mild and moderate hepatitis (p>0.05). seventeen patients (85%) had leucopoenia (4 patients had wbc 3.4×09/l, 3 patients had wbc 2.3×09/l) and 3 patients (5%) had thrombocytopoenia (<50×09/l) during current treatment. on reviewing these patients’ previous cbc results while they were on regular interferon combination therapy, it was found that 6 of them (30%) had leucopoenia (5 patients had wbc 3.4×09/l, table 1. comparison of responses to treatment with pegyalated and non-pegylated interferons drug used number of patients who responded etr svr sbr interferon and ribavirin 4 (20%) 0 0 pegylated interferon and ribavirin 7 (35%) 2 (10%) 1 (5%) etr: end of treatment response svr: sustained virologic response sbr: sustained biochemical response a k b a r & a l a h wa l  and one had 2.3×09/l) and none had thrombocytopoenia (p>0.05). one patient was hypothyroid on replacement therapy from previous interferon treatment; however l-thyroxin requirement of this patient did not increase during the current treatment with pegylated interferon and ribavirin. none of the other patients developed denovo thyroid dysfunction. none of the patients experienced significant subjective constitutional symptoms with the current therapy as compared to previous therapy of regular interferon-ribavirin combination. d i s c u s s i o n since the discovery of hcv, treatment of patients chronically infected with this virus was continuously modified to achieve higher response rates. several variables were found to affect treatment response, including age at infection, gender, viral load, virus genotype, stage of liver fibrosis and patient’s immunity status.4,5,10– 13 iron overload was found to decrease patient response to treatment; however iron reduction via phlebotomy did improve the response.14,15 response to treatment in hcv patients is assessed by the normalisation of liver enzymes and decrease in viral load beyond detection level (qualitative hcv rna pcr <00 copies/ml). hence non-responders and relapsers represent the same group of patients where both groups have persistent viraemia at end of treatment with the difference in the load being above or below detection level depending on the test used. with the improvement of viral load assays with lower limit detection level, more cases of true non-responders rather than relapsers should be diagnosed in future. non-responders or relapsers to old treatment regimen have been candidates in different controlled studies for new regimens to improve their response as compared to naïve patients. extended and higher dose treatment with interferon monotherapy was associated with decreased relapse rate and sustained response rate in 20–40% of cases.16 introduction of combination therapy was more effective than interferon monotherapy in naïve patients. however, results were disappointing with re-treatment in patients who did not respond to initial interferon monotherapy (3– 29%) and was associated with sustained response in 46–58% in selected group of relapsers.17–19 viral mutation and development of quasispecies in response to standard interferon regimen together with pre-treatment patients and viral demographics may explain the response failure in the majority of patients infected with hcv to interferon monotherapy or combination therapy (>50%).20 long-acting pegylated interferon, which is associated with constant levels between consecutive doses, was found to be more effective than regular interferon in naïve patients.6–9 in our study, more patients had etr with pegylated interferon combination therapy as compared to previous regular interferon combination therapy (7 versus 4 patients). this effect was influenced by the viral load (p<0.05) rather than by the degree of fibrosis (p=0.056). unfortunately this response was not durable after stopping treatment where only 2 patients (0%) had svr and 5 patients relapsed off treatment (7.4%). svr was only achieved in a subset of patients that had viral load below detectable level with previous standard combination therapy (relapsers). this additional effect of pegylated interferon is probably through decreasing viral mutation or development of less quasispecies strains. though pegylated interferon was slightly superior to regular interferon in this group of patients, this effect is modest since it does not change most of pre treatment host and viral factors that also influence patient response. in a similar study by afdahl et al using pegylated interferon alfa-2a plus ribavirin only preliminary etr was reported. etr was 6% in relapsers and 25% in non-responders.21 different other combinations were used with pegylated interferon including mycophenolate mofetil and amantadine. the highest etr reported was 7% in relapsers and 40% in non-responders upon adding amantadine to pegylated interferon and ribavirin.21 in our study etr was 00% in relapsers and 8.7% in non-responders, however svr was 50% in relapsers and 0% in non-responders. other dugs have been used as adjuvant or alternative therapy including ursodeoxycholic acid,22 nonsteroidal anti inflammatory drugs,23 thymosin,24 isis 4803 (anti-sense therapy),25 histamine dihydrochloride (maxamine)26 and interlukins 0 and 2,27,28 none of them improved viral response rates. new investigational agents such as proteinase inhibitors, albuferon, vx-497 and ribozyme therapy may prove to be beneficial in future.29–31 currently there is no solid consensus regarding treatment of non-responders or relapsers after standard interferon-ribavirin combination therapy. however it seems that relapsers may benefit from pegylated interferon combination therapy. further studies are required to assess whether prolonged or maintenance pegylated interferon alone or in combination with other anti viral agents can improve response in this group of patients. e f f e c t o f p e g y l at e d i n t e r f e r o n 2 c o n c l u s i o n this study suggests that therapy with pegylated interferon in combination with ribavirin may be beneficial in patients with hcv who relapsed after initially clearing hcv rna during previous treatment with standard interferon-ribavirin combination therapy. patients with persistent viral load during previous standard combination therapy are unlikely to respond to pegylated interferon-ribavirin combination therapy and should be enrolled in more clinical trials with different drugs and regimen to achieve a better response. r e f e r e n c e s . davis gl, balart la, schiff er, lindsay k, bodenheimer hcjr, perrillo rp, et al. treatment of chronic hepatitis c with recombinant interferon alfa. n engl j med, 989, 32, 50–506. 2. poynard t, bedossa p, chevalier m, mathurin p, lemonnier c, trepo c, et al. a comparison of three interferon alpha-2b regimens for the long term treatment of chronic non a, non b hepatitis. n engl j med, 995, 332, 457–463. 3. poynard t, leroy v, cohard m, thevenot t, mathurin p, opolon p, et al. meta-analysis of interferon randomized trials in the treatment of viral hepatitis: effects of dose and duration. hepatology, 996, 24, 778–789. 4. mchutchinson jg, gordon sc, schiff er, shiffman ml, lee wm, rustgi vk, et al. interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis c. n engl j med, 998, 339, 485–492. 5. poynard t, marcellin p, lee ss, niederau c, minuk gs, ideo g, et al. randomized trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis c virus. lancet, 998, 352, 426–432. 6. glue p, rouzier-panis r, raffanel c, sabo r, gupta sk, salfi m, et al. a dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis c. the hepatitis c intervention therapy group. hepatology, 2000, 32, 647–653. 7. manns mp, mchutchinson jg, gordon s, rustgi v, shiffman ml, lee wm, et al. peg interferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis c. 24 weeks treatment analysis of a multicenter, multinational phase iii randomized controlled trial. hepatology, 2000, 32, 297a. 8. reddy kr, wright tl, pockros pj, shiffman m, everson g, reindollar r, et al. efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis c. hepatology, 200, 33, 433–438. 9. heathcote ej, shiffman ml, cooksley wg, dusheiko gm, lee ss, balart l, et al. peg interferon alfa-2a in patients with chronic hepatitis c and cirrhosis. n engl j med, 2000, 343, 673–680. 0. martinot-peignoux m, marcellin p, pouteau m, castelnau c, boyer n, poliquin m, et al. pre-treatment serum hepatitis c virus rna and genotype are the main and independent prognostic factors of sr to interferon alfa therapy in chronic hepatitis c. hepatology, 995, 22, 050–056. . indilman r, maria n, colantoni a, dokmeci a, vanthiel dh. interferon treatment for cirrhotic patients with chronic hepatitis c. j viral hepat, 997, 4, 8–9. 2. soriano v, garcia-samaniego j, bravo r, castro a, odriozola pm, gonzalez j, et al. efficacy and safety of alfa interferon for chronic hepatitis c in hiv-infected patients. j infect, 995, 3, 9–3. 3. poynard t, mchutchinson j, goodman, ling mh, albercht j. is an “ā la carte” combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis c? hepatology, 2000, 3, 2–28. 4. olynyk jk, reddy r, di bisceglie m, jeffers lj, parker ti, radick jl, et al. hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis c. gastroenterol, 995, 08, 04–09. 5. fontana rj, israel j, leclair p, banner bf, tortorelli k, grace n, et al. iron reduction before and during interferon therapy of chronic hepatitis c: results of a multicenter, randomized, controlled trial. hepatology, 2000, 3, 730–736. 6. alberti a, chemello l, noventa f, cavalletto l, desalvo g. therapy of hepatitis c: re-treatment with alpha interferon. hepatology, 997, 26, s37–42. 7. schalm s, weiland o, hansen be, milella m, lai my, hollander a, et al. interferon-ribavirin for chronic hepatitis c with and without cirrhosis: analysis of individual patient data of six controlled trials: gastroenterol, 999, 7, 408–43. 8. heathcote ej, keefe eb, lee ss, feinman sv, tong mj, reddy kr, et al. re-treatment of chronic hepatitis c with consensus interferon. hepatology, 998, 27, 36–43. 9. davis gl, esteban-mur r, rustgi v, hoefs j, gordon sc, trepo c, et al. interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis c. international hepatitis interventional therapy group. n engl med j, 998, 339, 493–499. 20. nakazawa t, kato n, ohkoshi s, shibuya a, shimotohno k. characterization of the 5’ noncoding and structural region of the hepatitis c virus genome from patients with non-a, nonb hepatitis responding differently to interferon treatment. j hepatol, 994, 20, 623–629. 2. afdhal n, flamm s, imperial j, malet p, tong m, herrine sk, et al. analysis of 40 kda peg interferon alfa-2a in combination with ribavirin, mycophenolate mofetil, amantadine or amantadine plus ribavirin in patients that did not respond to rebetron therapy: a report of two randomized, multicenter, efficacy and safety trials. hepatology, 200, 34, 243a. 22. boucher e, jouanolle h, andre p, ruffault a, guyader d, moirand r, et al. interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral c hepatitis: results from controlled randomized trial in 80 patients. hepatology, 995, 2, 322–327. 23. zarski jp, maynard-muet m, chousterman s, baud m, barnoud r, abergel a, et al. tenoxicam, a non-steroid antiinflammatory drug, is unable to increase the response rate in a k b a r & a l a h wa l 3 patients with chronic hepatitis c treated by alpha interferon. hepatology, 998, 27, 862–867. 24. sherman k, sherman sn. interferon plus thymosin for treatment of chronic hepatitis c infection: a meta analysis. ther for viral hepat, 998, 48, 379–383. 25. mchutchinson jg, pockros p, nyberg l, kwoh tj, dorr fa. a dose escalation study of isis 4803, an anti sense inhibitor of hcv, in chronic hepatitis c patients. hepatology, 200, 34, 350a. 26. lurie y, pakula r, malnick s, beer-gabel m, israel r, gehlsen kr. efficacy and safety of the combination of histamine dihydrochloride and interferon alfa-2b in a phase 2 trial in naïve patients with chronic hepatitis c. hepatology, 200, 34, 350a. 27. mchutchinson jg, giannelli g, nyberg l, blatt lm, waite k, mischkot p, et al. a pilot study of daily subcutaneous interleukin-0 in patients with chronic hepatitis c. j interferon cytokine res, 999, 9, 265–269. 28. pockros pj, mchutchinson jg, o’brien c, tong m, smith c, rustgi v, et al. a phase 2 randomize, double blind, placebo controlled, multicenter trial of recombinant human interleukin-2 for the treatment of chronic hepatitis c virus infection in patients non-responsive to previous treatment with or without ribavirin. hepatology, 200, 34, 350a. 29. de francesco r, steinkuhler c. structure and function of hepatitis c virus ns3-ns4a serine proteinase. curr top microbiol immunol, 2000, 242, 49–52. 30. kwong ad. vx-497 a novel impdh inhibitor is a broad spectrum antiviral agent with superior activity compared to ribavirin against selected dna and rna viruses in vitro. hepatology, 999; 30, 26a. 3. macejak dg, jensen kl, jamison sf, domenico k, roberts ec, chaudhary n, et al. inhibition of hepatitis c virus (hcv)rnadependant translation and replication of a chimeric poliovirus using synthetic stabilized ribozymes. hepatology, 2000, 3, 769–776. e f f e c t o f p e g y l at e d i n t e r f e r o n bacterial keratitis: perspective on epidemiology, clinico-pathogenesis, diagnosis and treatment *abdullah al-mujaini, nadia al-kharusi, archana thakral, upender k wali continuing medical education squ med j, august 2009, vol. 9, iss. 2, pp. 184-195, epub 30th june 2009 submitted 25th oct 08 revision req. 23rd nov 08 & 21st mar 09 revision recd. 30th nov 08 & 15th apr 09 accepted 10th may 09 التهاب القرنية اجلرثومي: األبعاد الوبائية، املرضية السريرية، التشخيصية والعالجية عبد اهلل اجمليني، نادية اخلروصي، أركانا ثاكرال، أوبيندار والي امللخص: التهاب القرنية اجلرثومي قد يكون حادا أو مزمنا، عابرا أو متكررا يصيب املناطق اخملتلفة من القرنية مثل الوسطية أو امليطية . وقد يكون خطرها في تهديد البصر كامنا ، وتنتج عن عوامل مؤهبة أكثرها انتشارا استعمال العدسات الالصقة . املعطيات الوبائية تشير إلى انتشارها بشكل شامل . مع التقدم احلاصل في عوامل اإلِْمراض والفحوص اخملبرية مثل املناعة الكيميائية النسيجية واجملهر املتألق واملقايسة املناعية وعلم األحياء اجلزيئي ووجود اجليل الرابع من املضادات احليوية ، كلها أثرت بشكل إيجابي على النتيجة النهائية اللتهاب القرنية اجلرثومي. يجب االنتباه بشكل خاص لتلك احلالة وذلك الحتمال تطورها بشكل سريع مما يؤدي إلى تلف القرنية بصورة كاملة خالل 24 48 ساعة . التشخيص املبكر وهو سريري بصورة أولية مدعوما باملعطيات اجملهرية الدقيقة والعالج السريع مهم جدا لتقليل احتمالية فقدان البصر الدائمي والضرر البنيوي للقرنية . مفتاح الكلمات : التهاب القرنية ، السموم ، عدسات الصقة. abstract: bacterial keratitis is an acute or chronic, transient or recurrent infection of the cornea with varying predilection for anatomical and topographical parts of the cornea like marginal or central. it is a potentially sight-threatening corneal infection in humans that is generally found in eyes with predisposing elements, the most common of which is contact lens wear. the epidemiological data reveals the universal occurrence of this disease. with advances in the understanding of its pathogenesis, laboratory investigations like immunohistochemistry, fluorescent microscopy, enzyme immunoassays and molecular biology, and the availability of fourth generation antibiotics, the overall visual outcome in bacterial keratitis has improved with time. particular attention should be given to this condition as it can progress very rapidly with complete corneal destruction occurring within 24-48 hours. early diagnosis, which is primarily clinical and substantiated largely by microbiological data, and prompt treatment are needed to minimise the possibility of permanent visual loss and reduce structural damage to the cornea. keywords: keratitis; toxins; contact lens department of ophthalmology, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: mujainisqu@hotmail.com bacterial keratitis is an acute or chronic, transient infection of the cornea with varying predilection for anatomical, topographical and geographic parts of the cornea. it can be of a slowly progressive or rapidly deteriorating suppurative type involving any part of the cornea. a variety of pathogens like bacteria, fungi, viruses and protozoa can infect the cornea, but bacteria top the list in causing vision threatening keratitis. as the number of contact lenses users increases globally, the incidence of corneal infection increases proportionately. in spite of advances in clinical diagnosis, molecular laboratory investigations, and the availability of potent antibiotics, visual morbidity continues to be high in underdeveloped countries. the importance of this disease can be judged by the fact that bacterial keratitis remains one of the most common global causes of irreversible blindness due to corneal diseases. the aim of this article is to review the recently available perspectives on the epidemiology, pathogenesis, clinical presentations, diagnosis and treatment modalities of bacterial keratitis. epidemiology since keratitis is not included in the five target diseases of who for blindness prevention, most of the data regarding keratitis is from individual publications.1 bacterial keratitis is one of the most important causes of corneal opacifications, which is the second common cause of legal blindness world-wide after cataracts. the pattern of microbial keratitis varies with geographic region and according to the local climate. the bacteriological profile in keratitis shows huge disparities amongst populations living abdullah al-mujaini, nadia al-kharusi, archana thakral and upender k wali continuing medical education | 185 in both western2,3 and in developing countries.4 the incidence varies considerably between western and developing countries due to the fact that less industrialised countries have significantly lower number of contact lens users, hence fewer contact lenses related infections. for example, usa has an incidence of 11 per 100,000 persons5 for microbial keratitis as compared to 799 per 100,000 persons in nepal.6 ormerod et al. described the staphylococcal species, pseudomonas aeruginosa and streptococcus pneumoniae as major isolates in microbial keratitis in north america.7 in sweden, neuman and sjostrand found staphylococcus aureus and staphylococcus epidermidis were the most common gram-positive bacteria in central microbial keratitis while pseudomonas aeruginosa was the most common gram-negative bacteria.8 factors which influence the aetiology and pathogenesis of bacterial keratitis vary. they include: use of contact lenses, ocular surface diseases, corneal trauma, use of immunosuppressive medications and postocular surgery especially corneal graft. contact lens related corneal ulcers in the general population have increased from almost 0% in the 1960s to 52% in the 1990s. erie et al. 5 in minnesota, usa, gave an incidence of ulcerative keratitis as 5.3 per 100,000 people per year, revealing an increase in incidence of 435% from the 1950s to the 1980s. erie’s study revealed contact lens wear as the most important risk factor. epidemiology, regarding contact lenses as significant risk factor for bacterial corneal infections, is very significant. the annual incidence of ulcerative keratitis in contact lens wearers is 4-21 per 10,000 daily wear and extended wear soft contact lens wearers.9 extended wear soft contact lens users have a higher annual incidence of ulcerative keratitis than daily wear soft contact lenses. this was confirmed by poggio et al.,9 who, in a case control study of ulcerative keratitis in soft contact lens wearers, found overnight use of contact lenses as the most important risk factor for ulcerative keratitis. the study provided the interesting revelation that smokers are three times more prone to develop keratitis than non-smokers. the rate of ulcerative keratitis is 1 in 2,500 daily wear contact lens users as compared to 1 in 500 extended wear contact lens users per year. pathogenesis several factors can be attributed to the onset of bacterial keratitis. bialasiewicz et al. reported that trachoma, trauma and contact lens overwear are significant risk factors for infectious keratitis in oman.10 in almost all situations, it is the break in the continuity of the epithelium that starts the bacteriopathological process of keratitis. in penetrating keratoplasty, 12% of patients develop corneal infections.11 these eyes have predisposing risk factors like corticosteroids, sutures, epithelial defects and contact lens wear for developing post-operative infections. both gram-positive and gram-negative organisms are involved.12,13 g e n e r a l b a c t e r i o pat h o l o g y i n m i c r o b i a l k e r at i t i s eighty percent of bacterial corneal ulcers are caused by staphylococcus aureus, streptococcus pneumoniae and pseudomonas species. pseudomonas aeruginosa is the most frequent and the most pathogenic ocular pathogen which can cause corneal perforation in just 72 hours. bacteria causing keratitis may be gram-positive or gram-negative. the ability of an organism to adhere to the edge or base of an epithelial defect signatures its pathogenicity. such an organism has the ability to invade stroma despite adequate hostdefenses.14 staphylococcus aureus, streptococcus pneumoniae and pseudomonas aeruginosa have such an ability.15,16 membrane appendages such as fibrillae in gram-positive organisms, fimbriae and glycocalyx in gram-negative bacteria help these organisms adhere to damaged epithelial cells14 and stroma. bacteria loose their glycocalyx envelope once inside the stroma. pseudomonas aeruginosa and neisseria gonorrhea utilise glycocalyx to adhere to each other and to diseased epithelial cells17 and contact lenses.18 the adhering quality of pseudomonas aeruginosa19 is due to its pili containing calcium and magnesium. pseudomonas aeruginosa gets attached to both contact lenses and epithelial breaks17 due to its biofilm, a coating around the organism. during bacterial corneal infections, there is activation of plasminogen to plasmin which is active proteolytically. protease, chymase and tryptase cause epithelial microlesions and healing is delayed bacterial keratitis: perspective on epidemiology, clinico-pathogenesis, diagnosis and treatment 186 | squ medical journal, august 2009, volume 9, issue 2 due to the degradation of adhesive glycoproteins by proteolytic enzymes.19 some bacteria improve their chances of survival and become more pathogenic by producing a chemical slime which even resists phagocytosis and the bacteria can decrease their metabolic demand.20 proteases and certain lytic enzymes can help organisms like neisseria gonorrhea, corynebacteium diphtheriae, and listeria, shigella and koch-weeks bacilli to produce keratitis even through the intact epithelium. proteases attack peptide bonds to dissolve elastin. certain bacterial strains like pneumococci resist ocular lysozyme and phagocytosis by forming polysaccharide capsules around them. there are certain bacterial toxins and enzymes, including enzymes produced by polymorph nuclear cells, which help in the digestion and degradation of the corneal matrix. these include exotoxins produced by actively multiplying bacteria, endotoxins produced by organisms after their death, proteases, collagenases, coagulases, lipases and fibrinolysins. endotoxins are lipopolysaccharides within the cell wall of gram-negative bacteria. they are responsible for corneal ring infiltrates which are polymorph nuclear cells in stroma attracted by c-pathway and properdin activated chemotoxins. ring infiltrates are believed to be antigen-antibody precipitates and are also seen on viral, fungal and acanthamoeba infections. the immune response does not have an established role in suppurative keratitis. c o n ta c t l e n s a s s o c i at e d pat h o g e n e s i s contact lens wearers are more prone to bacterial infection, especially with gram-negative organisms. the contact lens induces hypoxia, increases corneal temperature and decreases tear flow over the corneal surface. the adhering 21 of microorganisms (staphylococci, moraxella, candida) to the contact lens and epithelium 22-24 is aided by mucus and proteins. the risk of developing corneal infections is 9-15 times greater with overnight use of contact lenses compared to daytime use. aphakic eyes are more prone to microbial keratitis with extended wear soft contact lenses. there is a higher risk of bacterial keratitis with disposable contact lenses used overnight.24 the most common organisms associated with contact lens related bacterial keratitis are pseudomonas aeruginosa and staphylococci. bandage soft contact lenses are more often associated with polymicrobial infections (staphylococci, streptococci, serratia). extended wear soft cosmetic lenses are more prone to pseudomonas infections.25 while gram-negative organisms like pseudomonas, haemophilus and moraxella cause infectious keratitis in extended wear cosmetic contact lens users, therapeutic soft contact lens wearers on the other hand are prone to corneal ulcers caused by gram-positive bacteria especially streptococci. clinical presentation the overall clinical course in bacterial keratitis is acute in onset with features relating to visual and sensory functions. lid and conjunctival oedema, reduced vision, pain, redness, photophobia and discharge form the commonly presenting signs and symptoms. the severity of signs and symptoms depends on the virulence of the organism, the host immune status, any prior disease of the cornea, any previous therapy with corticosteroids and the duration of the infection. the conjunctival reaction may be non-specific. gonococcal, haemophilus and pneumococcal corneal infections may have associated moderate to severe conjunctivitis with chemosis and sometimes pseudomembranes. the clinical signs and symptoms in bacterial keratitis may be altered or difficult to interpret if the cornea has had previous pathology like stromal inflammation, necrosis or opacification. slit-lamp biomicroscopy shows cells and debris in the precorneal tear film and meniscus, absent corneal epithelium over an area of infection and focal suppurative process. it is important to document the size of any epithelial and stromal defect in at least two meridians. several authors have given grading systems in corneal ulcers, creating some difficulty in following them on an individual basis. for the sake of convenience, the following overall guidelines, can be employed for clinical diagnosis, treatment and follow-up: 1) mild reaction: focal, superficial suppuration; 2) moderate reaction: suppuration confined to superficial two-third of the cornea; 3) severe reaction: suppuration confined to posterior one-third of the cornea and may present as a ring abscess, scleral suppuration and impending abdullah al-mujaini, nadia al-kharusi, archana thakral and upender k wali continuing medical education | 187 perforation. overall gram-positive cocci form localised, round or oval, gray-white lesions with clear margins, minimal surrounding epithelial oedema and stromal infiltrates. staphylococcal ulcers are more often found in compromised corneas like bullous keratopathy, dry eyes, chronic herpetic keratitis, atopic disease and rosacea keratitis. staphylococcus aureus is found in 15% of cultures from lids of normal persons. this pathogen produces more severe corneal infiltration than staphylococcus epidermidis. both these strains frequently produce indolent lesions with distinct borders, nonoedematous surrounding stroma and they tend to be localised. long standing staphylococcal ulcers dig deep into the stroma producing intra-stromal abscesses and sometimes perforation. occasionally multiple satellite stromal microinfiltrates may be seen. there may be radiating folds in the descemet’s membrane due to loss of stromal substance. coagulase-negative staphylococcal corneal infections are usually associated with surgical procedures, foreign bodies and intraocular prosthetic devices. streptococcal bacterial keratitis has a rapid course. streptococcus viridans keratitis is characterised by a distinct, non-inflammatory, indolent crystalline keratopathy. this entity is typically seen after penetrating keratoplasty. clinically, one may find epithelial defects and loose sutures and there may be history of contact lens use and corticosteroids, resulting in a chronic infective process of the cornea. bacillus cereus, a large aerobic gram-positive rod is extremely virulent. it causes rapid and devastating bacterial keratitis, starting as a ring infiltrate in the cornea away from the site of the injury and rapidly progresses to abscess formation often with corneal perforation. other pathogens which produce ring infiltrates and ring abscesses in cornea are proteus, pseudomonas aeruginosa, streptococcus and listeria monocytogenes. most of the ring abscesses develop following penetrating injuries at the limbus.26 mycobacterium,27 nocardia28 and actinomyces species are gram-positive branching filamentous bacteria found in soil. the keratitis follows soil contaminated corneal injury and produces an indolent ulcer with elevated hyphate edges, often with satellite lesions, mimicking a fungal ulcer. the cornea has a typical cracked windshield appearance. gram-negative corneal bacterial infections, on the other hand, are mostly rapid in onset and progress fast due to lytic enzymes like protease, lipase and elastase. these infections can lead to corneal perforation and the loss of an eye. the most common and virulent gram-negative ocular pathogens belong to pseudomonas species. pseudomonas can contaminate ophthalmic solutions like fluorescein, ocular cosmetics like mascara and any substance containing traces of organic carbon. transmission electron microscopy29 has shown that pseudomonas can infect stroma within one hour of adhering to an injured corneal epithelium. within 6-8 hours, it produces grayish superficial epithelial and stromal microinfiltration with oedema at the edge of the injury. during the next 18-24 hours, the stromal infiltration extends horizontally and vertically. there is a severe anterior chamber reaction with hypopyon. the symmetric and concentric extension involves the whole width and depth of the cornea. there is a characteristic diffuse grayish, epithelial inflammation and infiltration away from the main corneal lesion. during the next 48-96 hours, if untreated, a ring infiltration develops with scleral and corneal melting associated with greenish yellow mucopurulent discharge adhering to the ulcer. within 2-5 days, an untreated corneal ulcer may lead to descemetocele formation and perforation of the cornea.30 moraxella species,30 a gram-negative diplobacillus, causes infective keratitis in debilitated patients with a history of alcoholism, diabetes mellitus and chronic malnutrition. trauma is an important predisposing factor. typically, the location is paralimbal or paracentral, involving the inferior cornea. the lesion is oval, grayish white, shallow, irregular and indolent with mild to moderate anterior chamber reaction. the inflammation often remains localised, but if untreated, can spread to deep stroma 31 leading to endothelial decompensation and severe stromal and anterior chamber reactions. klebsiella, escherichia coli and proteus keratitis are common in compromised corneas with chronic epithelial disease, often without any history of trauma. a typical lesion has an indolent course with mild anterior chamber reaction. the non-spore forming anaerobes like peptococci, peptostreptococci and propionibacterium form a broad group of gram-positive and grambacterial keratitis: perspective on epidemiology, clinico-pathogenesis, diagnosis and treatment 188 | squ medical journal, august 2009, volume 9, issue 2 negative rods, found in mixed infections of the cornea. they are active and invasive under compromised conditions like trauma, surgery, corticosteroids and antibiotics. diagnosis c o l l e c t i o n a n d p r o c e s s i n g o f c l i n i c a l s a m p l e s undoubtedly, microbiology remains the critical tool in the diagnosis of bacterial keratitis. clinical acumen, though valuable, may falter in cases where keratitis has atypical manifestations due to prior therapy or certain ulcers. the rule however remains that wherever and whenever possible, a meticulous microbiological workup of bacterial keratitis should be done before therapy is initiated. smears, culture and sensitivity to antimicrobials form the three fundamental tools of diagnosis. cultures should always be preferred to smears as they are more specific and information yielding. the culture positive rate in bacterial keratitis and ulcers is 40-73%31,32 as compared to 0-57% in gram’s staining.31,33-34 thirty-two percent of patients with bacterial keratitis have two or more bacteria. in polymicrobial keratitis,34-36 gram’s staining is not of much value in identifying the causative pathogen. an infection that is deteriorating despite antibiotic therapy yields a poor bacterial count for examination and diagnosis. it is important to know that, while positive cultures and smears are very useful for diagnosis, negative results may not rule out corneal infection, especially where antibiotics have already been given. in this situation, a corneal biopsy may be mandatory to establish diagnosis or the suspension of the antibiotic therapy for 72 hours to enable a repeat culture. it is wise to obtain cultures from lids and conjunctiva of both eyes, even if there is unilateral bacterial keratitis, and use blood and chocolate agar plates. in spite of clinical evidence of bacterial keratitis, a methodology for diagnosis should be used. this should include aerobic bacteria, anaerobe non-spore forming bacteria, filamentous fungi and yeasts. there are occasions when preliminary fungal ulcers are infected secondarily by bacterial pathogens. mycobacteria (acid fast), actinomyces (non-acid fast) and nocardia (variable) can be identified by carbol-fuchsin or ziehl-nelson stains. mycobacteria can also be identified by fluorochrome stain and fluorescence microscopy. immunological techniques available for the detection of bacterial antigens include direct immunofluorescence, immunoelectrophoresis, immunohistochemistry, fluorescent microscopy, enzyme immunoassays, agglutination, radioimmunoassay and molecular techniques. it is important to remember that the topographical importance of the site of lesion chosen for smear taking is important for an effective yield of the bacteria, e.g. streptococcus pneumoniae are more active near edge of the ulcer while the crater gives better yield for moraxella. in the presence of deep ulcers and abscesses without surface suppuration, it may be necessary to obtain corneal fragments with a blade, microsurgical scissors or a trephine. these fragments can be crushed on a glass slide for staining and also inoculated in thioglycolate and brain heart infusion (bhi). all corneal lesions due to contact lenses should be presumed to be infectious in origin, unless proved otherwise. it is mandatory to send the contact lenses, contact lens solutions and the carrying cases for laboratory cultures. preservatives in topical anesthetics may be bacteriostatic or bactericidal and may interfere with the results, besides which the drops may also be contaminated. proparacaine is the least bactericidal and is recommended. usually corneal specimens contain small numbers of organisms, especially with prior antibiotic therapy. under such circumstances, it is mandatory to inoculate the specimen material directly into the culture media and avoid carrier and transport media. debris from the corneal ulcer can be inoculated on the same blood agar plates which have the lid and conjunctival inoculates. the scraping from the advancing edge and center of the infected ulcer can be done using a modified kimura platinum spatula. a large gauge disposable needle is a possible alternative. the use of a slit-lamp makes the procedure more scientific. the material thus obtained is to be streaked on blood agar in a c shape. growth along the c streak is microbiologically significant while any growth away from the c streak is probably a contamination. additional specimens should be reserved for chocolate agar and sabouraud agar without cycloheximide. chocolate agar provides hemin (x-factor) and v-factor, essential for growth of haemophilus and is ideal for isolation of neisseria abdullah al-mujaini, nadia al-kharusi, archana thakral and upender k wali continuing medical education | 189 and moraxella. for anaerobic pathogens, it is ideal to use chopped meat glucose broth or thioglycolate medium with vitamin k. thioglycolate broth also provides basic nutrients for aerobic organisms. its sulfhydryl (sh) compound acts as an oxygen reducing agent which is suitable for anaerobic bacteria. bhi is valuable if a poor yield of organisms is expected as in patients on prior antibiotics. in patients with any signs or symptoms of dacryocystitis, fluid expressed from the lacrimal sac should be cultured. overall, gram’s stain is appropriate for bacteria and can also show dimorphic fungi in the yeast phase; however, cellular details appear better with a giemsa stain. gram-positive bacteria appear blue-purple and retain gentian violet while gramnegative bacteria lose gentian violet and appear pink with safranin. if done meticulously, gram’s stain can identify the pathogen (single organism) in 75% of cases and in 37% of cases having mixed bacterial infections.37 giemsa can distinguish noninfectious keratitis by the type of inflammatory cells. in indolent corneal infections, it may be necessary to use acid fast stains for mycobacterium, nocardia and actinomyces species. in order to get the maximum information, the sample should cover an area approximately 1cm in diameter on the glass slide. excessive decolorisation should be avoided and immersion of the slide in 95% methanol or cold acetone for 5-10 minutes is preferable to heat fixation in maintaining the morphology and staining characteristics of the pathogens. in addition to gram’s and giemsa stains, an extra slide and some specimen material should be reserved for special stains like periodic acid schiff, calcofluor, gomori, acid fast bacilli and methenamine silver. all refrigerated media should be warmed to room temperature before inoculation to prevent fatal cold shock to the organisms. i n t e r p r e tat i o n o f c u lt u r e m e d i a though pathogens can be identified within 1215 hours of inoculation, most aerobic bacteria in microbial keratitis appear only within 48 hours on standard culture media. the plates should be examined on daily basis and liquid media observed for turbidity. blood agar is best for isolation of aerobic bacteria. anaerobes are slow growing; therefore, cultures should be incubated for at least 10 days. the most common combination found in polymicrobial keratitis is aerobic gram-positive coccus plus gram-negative rod,35 followed by fungus plus bacteria.36 there are no established criteria for true diagnosis of corneal infections. one of the authentic criteria was put forward by jones35 which includes clinical signs of infection and isolation of ten or more colonies of bacteria on one solid medium and one additional medium in presence of a positive smear. it is unusual to find gram-positive rods or gramnegative cocci or when two or more organisms are found in smears or cultures, so one should be cautious when such a result is obtained. such observations are not correct in 75% cases. the reasons for poor or negative results could be prior antibiotic therapy; an insufficient sample; excessive heat fixation; mechanical damage to cell wall architecture and a reluctance to examine the whole slide. management g e n e r a l c o n s i d e r at i o n s bacterial keratitis is a rapidly destructive form of microbial keratitis. any doubtful microbial keratitis should be treated as bacterial keratitis unless proven otherwise. some preventive approaches would go a long way towards minimising bacterial keratitis and its sequelae. though the expanded range of antibiotics has made the treatment of bacterial keratitis easy, at times it may be devastating to loose an eye despite having dozens of anti-microbial drugs at our disposal. eighty seven percent of bacterial corneal ulcers are caused by four groups of organisms, but no single antibiotic is effective against all organisms. baum and barza have provided a historical review of current therapy of bacterial keratitis.37 in the usa, patients of bacterial keratitis are treated on an outpatient basis, while in the uk such patients are usually admitted. gram’s stain is a quick and helpful means of starting antibiotic therapy, however, there is a poor correlation between gram’s stain and culture results38 and hence one should not rely too heavily on gram’s results. gram’s and giemsa stain results may be nondiagnostic or inaccurate 30% of the time. it is ethical to start with wide spectrum antibiotics in corneal infections until culture reports and sensitivities are available, keeping in view the seriousness of the bacterial keratitis: perspective on epidemiology, clinico-pathogenesis, diagnosis and treatment 190 | squ medical journal, august 2009, volume 9, issue 2 disease and the few side effects of the drugs. an ideal antibiotic should be bactericidal, least allergic, and least toxic with good ocular penetration. the main aims of treatment of bacterial keratitis should be bacterial inhibition, healthy epithelialisation and prevention of complications. one of the impressive antibiotics in the treatment of corneal infections has been ciprofloxacin (0.3%). it covers virtually all common corneal pathogens and has an edge over a combination therapy of aminoglycosides and cephalosporins in that ciprofloxacin is effective against many strains of aminiglycoside resistant pseudomonas39 and methicillin-resistant staphylococcus aureus (mrsa).40 the drug is also very effective against neisseria species. ciprofloxacin eye drops are very well tolerated; however, precipitate formation in the area of an epithelial defect occurs in 16% of cases, which usually resolves in spite of continued treatment.41 ofloxacin (0.3%) can be substituted for ciprofloxacin as a monotherapy in situations of unknown organisms or a new case or where there is no growth on first culture. increasing resistance to the fourth generation fluoroquinolones has been reported amongst staphylococcus species in the usa, and pseudomonas species in india.42 new generation fluoroquinolones like moxifloxacin and gatifloxacin have been introduced to treat such cases.43-46 one of the best combinations in the treatment of bacterial keratitis has been that of cefazolin 5% and tobramycin or gentamicin 2% fortified. cefazolin (cephalosporin) covers gram-positive cocci and some gram-negative rods while tobramycin (aminoglycoside) covers most gram-negative rods including pseudomonas and some gram-positive pathogens. tobramycin is three times more potent than gentamycin against pseudomonas aeruginosa, has good corneal penetration and less epithelial and conjunctival toxic than gentamycin. in vitro resistance to antibiotics may not hold true under clinical conditions where a very high concentration of drugs is used in the form of topical drops. acquired antibiotic resistance in bacterial keratitis is a problem with nosocomial infections in intensive care units and burn units. the availability of single, broad spectrum antibiotics has made it possible to treat even moderate to severe infections of the cornea on an outpatient basis due to better drug compliance. daily follow-up and frequent (up to 55 drops per day) drug instillation can take care of the patient satisfactorily. clinical trials have shown that monotherapy with fluoroquinolones is as effective as combination therapy, with less toxicity.47alexandrakis et al. have reported that fortified antibiotic preparations may be helpful in situations like advanced bacterial keratitis and resistance to fluoroquinolones.48 new generation broad spectrum penicillin drugs such as ticarcillin and piperacillin are undoubtedly potent weapons against certain corneal pathogens. ticarcillin is 2-4 times more active against pseudomonas aeruginosa than carbenicillin. piperacillin has very high activity against klebsiella and pseudomonas, but should be combined with aminoglycosides to avoid the development of resistance. the incidence of allergic reaction to ticarcillin and piperacillin is 3.5% in the general population and 10% in penicillin treated patients. ten percent mortality during anaphylaxis has been reported.49 b a c t e r i a l k e r at i t i s u n d e r s p e c i a l c i r c u m s ta n c e s there are moments when there is no response to first line of treatment, neither can any organisms be identified. here a second line of broad spectrum antibiotics should be started including vancomycin 5% (50 mg/ml), amikacin 5% (50 mg/ml) and trimethoprim 0.1% (16mg/ml). this combination kills resistant streptococci, nocardia and mycobacterium as well. erythromycin (0.5%) or rifampicin (2.5%) ointment may be used at night. mycobacterium chelonae used to be the cause of severe and chronic keratitis after radial keratotomy. the pathogen is sensitive to topical amikacin 5%. nocardia can be responsible for refractory keratitis. it may respond to topical amikacin 5% and erythromycin 0.5% with or without vancomycin 5% and trimethoprim 0.1%. surgical debridement of the lesion helps in early recovery. the role of enzyme inhibitors like disodium edentate (0.05 m), acetylcysteine (20%), heparin (2%) has not been proven clinically in bacterial keratitis. c o r t i c o s t e r o i d s i n b a c t e r i a l k e r at i t i s at cellular level, corticosteroids can be accepted as damage reducing agents in bacterial keratitis. corticosteroids have two important actions: abdullah al-mujaini, nadia al-kharusi, archana thakral and upender k wali continuing medical education | 191 first to decrease polymorphonuclear leukocyte activity at the level of ingestion and degranulation and, second, to reduce inflammation initiated by dividing bacteria and their toxins, host enzymes and hydrolytic enzymes from polymorphonuclear leucocytes. overall, steroids have a conflicting role in bacterial keratitis.50 davis et al.51 have reported no adverse effect on bacterial status in keratitis due to pseudomonas and staphylococcus aureus when corticosteroids were given under cover of fortified bactericidal antibiotics. smolin et al.52 reported delayed eradication of corneal infection with combined treatment of corticosteroids and antibiotics, while harbin53 reported relapse of pseudomonas keratitis in a corticosteroid treated patients. it can be said that since there is no conclusive evidence about the efficacy of corticosteroids in bacterial keratitis, they should not be used at the commencement of therapy and may be used with caution under cover of antibiotics. one justifiable indication for steroids could be stromal necrosis due to gram-negative bacilli to reduce the destructive components of inflammation. a d j a c e n t t h e r a p y i n b a c t e r i a l k e r at i t i s adjacent therapy includes treatment of those extra-corneal factors which directly or indirectly initiate or enhance keratitis. entropion, trichiasis, lagophthalmos and dry eyes should be treated meticulously. all of the following contribute significantly to effective treatment of bacterial keratitis: analgesics; control pf glaucoma; cycloplegics; patching for epithelial defects (only after elimination of bacterial infection); bandage soft contact lenses for indolent epithelial defects; extensive stromal ulcerations and microperforations. 54 s u r g i c a l m a n a g e m e n t o f b a c t e r i a l k e r at i t i s a n d i t s c o m p l i c at i o n s small corneal perforations and descemetoceles can be treated with cyanoacrylate tissue glue adhesive. it helps to restore anterior segment integrity, but it is not a permanent solution. the glue just supports the eye to a later safe stage when surgery may help. the stromal ulcer bed should be debrided before applying glue and a contact lens should be used over it. cyanoacrylate is toxic to endothelium and the lens.49 a patch graft can be an alternative to cyanoacrylate glue, but it may be destroyed by bacteria, hence it should only be used after effective antimicrobial therapy. a conjunctival flap should never be used over active infected necrotic tissue or the flap will become necrosed. the flap can be used to promote healing over a debrided corneal ulcer bed, especially for peripheral ulcers. penetrating keratoplasty (pk) is indicated in about 10% of cases of bacterial keratitis. the pathogens frequently involved in such an indication include; streptococcus pneumoniae, staphylococcal species, pseudomonas aeruginosa, moraxella, betahemolytic streptococci55 and pseudomonas species. the main indications for pk in bacterial keratitis49 are large corneal perforations; small corneal perforations with consistent bacterial growth and progressive suppuration including scleral involvement despite antibiotic therapy. the main objectives of pk in bacterial keratitis are to eliminate the infection load, restore corneal integrity and preserve vision.49 the outcome of pk in bacterial keratitis depends upon any previous herpes simplex virus keratitis, the severity of the stromal inflammation, the size and location of the graft and any prior therapeutic measures like contact lenses or glues. the best chance of success for pk is when the procedure is done after a total bacterial kill has been achieved and before corneal vascularisation appears. oral corticosteroids are given 24 hours before and seven days after a pk to curtail inflammation. to prevent suture erosion, a relapse of keratitis and wound dehiscence after pk, it is important to prepare a healthy recipient edge by debriding all necrotic corneal tissue. bites should be taken through healthy recipient corneal tissue and excised infected cornea sent for a laboratory workup to guide post pk antimicrobial therapy. gudmundsson et al.56 have reported that less than 50% patients treated by pk for bacterial keratitis achieve a visual acuity better than pregraft vision. the university eye hospital erlangennuremberg evolved a triple therapeutic approach for the treatment of keratitis in 223 eyes: 1) topical and systemic antibiotics; 2) antibiotics and corticosteroids; 3) antibiotics, corticosteroids and early tectonic penetrating keratoplasty. patients with keratoplasty had the shortest hospital stay while bacterial keratitis: perspective on epidemiology, clinico-pathogenesis, diagnosis and treatment 192 | squ medical journal, august 2009, volume 9, issue 2 visual rehabilitation was better in the corticosteroid group and best in the keratoplasty group.57 clinical course and prognosis even with an armamentarium of highly selective and broad spectrum antimicrobials in the therapy of bacterial keratitis, 24% of patients develop vision threatening complications like descemetoceles, perforations, endophthalmitis, atrophy and disorganisation of the affected eye. an eye with bacterial keratitis may heal with minimal or no opacification, vascularisation or visual deficit; however, inadequately, ignorantly or late treated bacterial keratitis can have an extremely dangerous clinical course because of corneal opacification, secondary glaucoma, scleral extension of infection and anterior segment disorganisation. there may be scarring of the cornea with hyalinisation, calcium and lipid deposits. prognosis is poor in corneal infections due to streptococcus pneumoniae unless treatment begins rapidly. with increasing age and debility, the prognosis is not good. destruction of the corneal lamella leads to corneal thinning and ectasia. corneal fistulae, anterior synechiae due to a fibrinous anterior chamber reaction, seclusion pupillae, cataract, secondary glaucoma, panophthalmitis and pthisis bulbi can be the sequale of bacterial keratitis. amongst gram-negative infections of the cornea, moraxella keratitis has a good visual prognosis. healing may be with scar formation, usually away from the visual axis. in mixed or polymicrobial infections, perforation and pthisis may develop. pseudomonas infections invariably lead to corneal perforation and loss of the eye if untreated, especially in immunocompromised patients with a history of contaminated traumatic bacterial keratitis. shah et al. have suggested vision improvement following prompt and standard treatment of contact lens induced severe keratitis.58 conclusion despite all the advances in the diagnosis and treatment of bacterial keratitis, it remains the most aggressive and destructive pathogen invading the cornea and is responsible for sight threatening corneal scarring and vascularisation. on the one hand, the expansion of contact lenses wear has increased the worldwide incidence of bacterial keratitis, while, on the other hand, newer methods of diagnosis, aided by more specific laboratory investigations and newer antibiotics have revolutionised the visual outcome in these patients. modern surgery has also contributed significantly towards minimising ocular morbidity. an early diagnosis, repetitive cultures and smears, and professional management go a long way towards preventing the complications of bacterial keratitis. references 1. bialasiewicz aa, schonherr u, schmitt t, naumann goh. triple therapeutic approach for keratitis. in: bialasiewicz aa, schaal kp, eds. infectious diseases of the eye. buren: aeolus press, 1985. p. 266. 2. schaefer f, bruttin o, zagrafos l, guex-corsier y. bacterial keratitis: a prospective clinical and microbiological study. br j ophthalmol 2001; 85:842-7. 3. bernet ha, hay j, kirkness cm. antimicrobial management of presumed microbial keratitis: guidelines for treatment for central and peripheral ulcers. br j ophthalmol 1998; 82:137-45. 4 vajpayee rb, dada t, saxena r, vajpayee m, taylor hr, venkatesh p, et al. study of the first contact management profile of cases of infective keratitis: a hospital based study. cornea 2000; 19:52-6. 5. erie jc, nevitt mp, hodge do, ballard dj. incidence of ulcerative keratitis in a defined population from 1950 through 1988. arch ophthalmol 1993; 111:1665-71. 6. upadhyay mp, karamcharya pc, koirala s, shah dn, shakya s, shrestha jk, et al. the bhaktapur eye study: ocular trauma and antibiotic prophylaxis for the prevention of corneal ulcers in nepal. br j ophthalmol 2001; 85:388-92. 7. ormerod ld, hertzmark e, gomez ds, stabiner rg, schanzlin dj, smith re. epidemiology of microbial keratitis in southern california. ophthalmology 1987; 94:1322-33. 8. neumann m, sjostrand j. central microbial keratitis in a swedish city population. acta ophthalmol copenh 1993; 71:160-4. 9. poggio ec, glynn rj, schein od, seddon jm, shannon mj, scardino va, et al. the incidence of ulcerative keratitis among users of daily wears and extended wear soft contact lenses. n engl j med 1989; 321:779-83. 10. bialasiewicz a, shenoy r, thakral a, al-muniri a, shenoy u, al-mughairi z. microbial keratitis: a 4 year study of risk factors and traditional/ abdullah al-mujaini, nadia al-kharusi, archana thakral and upender k wali continuing medical education | 193 complementary medicine in oman. ophthalmologe 2006; 103:682-7. 11. al-hazzaa saf, tabbara kf. bacterial keratitis after penetrating keratoplasty. ophthalmology 1988; 95:1504. 12. tuberville aw, wood to. corneal ulcers in corneal transplantation. curr eye res 1981; 8:479. 13. badenoch pr, aggarwal rk, coster dj. clostridium perfringens keratitis after penetrating keratoplasty. aust nz j ophthalmol 1995; 23:245. 14. synder rw, hyndiuk ra. mechanisms of bacterial invasion of the cornea. in: tasman w, jaeger ea, eds. duane‘s foundations of clinical ophthalmology. philadelphia: j b lippincott & co., 1990. pp. 11-44. 15. reichart r, stern ga. qualitative adherence of bacteria to human corneal epithelial cells. arch ophthalmol 1984; 102:1394. 16. panjwani n, clerk b, cohen m, barza m, baum j. differential binding of ps. aeruginosa and staph. aureus to corneal epithelium in culture. invest ophthalmol vis sci 1990; 31:696. 17. klotz sa, an yk, misra rp. a partial thickness epithelial defect increases adherence of ps. aeruginosa to the cornea. invest ophthalmol vis sci 1989; 30:1069. 18. john t, refojo mf, hanninen l, leong fl, medina a, kenyon kr. adherence of viable and non-viable bacteria to soft contact lenses. cornea 1989; 8:21. 19. stern ga, lubiniewski a, allen c. the interaction between ps. aeruginosa and the corneal epithelium. arch ophthalmol 1985; 103:1221. 20. speziale p, raucci g, visai l, switalski lm, timpl r. binding of collagen to staph. aureus. j bacteriol 1986; 167:77-81. 21. slusher mm, myrvik qn, lewis jc, gristina ag. extended wear lenses, biofilm and bacterial adhesion. arch ophthalmol 1987; 105:110. 22. aswad mi, barza m, baun j. effect of lid closure on contact lens associated ps. keratitis. arch ophthalmol 1989; 107:1667. 23. miller mj, wilson la, ahearn dg. adherence of ps. aeruginosa to rigid gas permeable contact lenses. arch ophthalmol 1991; 9:1447. 24. mathews td, frazer dg, minassian dc. risks of keratitis and patterns of use with disposable contact lenses. arch ophthalmol 1992; 110:1559. 25. ormerod ld, smite re. contact lens associated microbial keratitis. arch ophthalmol 1986; 104:7. 26. o’day dm, ho pc, andrews js. mechanisms of tissue destruction in ocular bacillus cereus infections. in: roper t, ed. the cornea in health and disease. san diego: academic press, 1981. p. 403. 27. turner l, stinson i. mycobacterium fortuitum as a cause of corneal ulcer. am j ophthalmol 1965; 60:329. 28. sridhar ms, sharma s, garg p, rao gn. treatment and outcome of nocardia keratitis. cornea 2001; 20:458-62. 29. hyundik ra. experimental pseudomonas keratitis. trans am ophthalmol soc 1981; 79:541-624. 30. ostler hb, thygeson p, okumoto m, weddell j. opportunistic ocular infections. am fam physician 1978; 17:134-40. 31 asbell p, stenson s. ulcerative keratitis survey of 30 years laboratory experience. arch ophthalmol 1982; 100:77. 32. groden lr, rodnite j, brinser jh, genvert gi. acridine orange and gram‘s stain in infectious keratitis. cornea 1990; 9:122-4. 33. wahl jc, katz hr, abrams da. infectious keratitis in baltimore. ann ophthalmol 1991; 23:234. 34. jones db. initial therapy of suspected microbial corneal ulcers ii. specific antibiotic therapy based on corneal scrapings. surv ophthalmol 1979; 24:97. 35. jones db. polymicrobial keratitis. trans am ophthalmol soc 1981; 79:153. 36. liesegang tj, forster rf. spectrum of microbial keratitis in southern florida. am j ophthalmol 1980; 90:38. 37. baum j, barza m. the evolution of antibiotic therapy of bacterial conjunctivitis and keratitis: 1970-2000. cornea 2000; 19:659-72. 38. jones db. a plan for antimicrobial therapy in bacterial keratitis. trans am acad ophthalmol otolaryngol 1975; 79:95. 39. reidy jj, hobden ja, hill jm, forman k, o’callaghan rj. the efficacy of topical ciprofloxacin and norfloxacin in the treatment of experimental pseudomonas keratitis. cornea 1992; 10:25. 40. insler ms. successful treatment of mrsa keratitis with topical ciprofloxacin. ophthalmology 1991; 98:1690. 41. kaatz gw, seo sm. mechanism of ciprofloxacin resistance in pseudomonas aeruginosa. j infect dis 1988; 58:537. 42. jhanji v, sharma n, satpathy g, tityal j. fourth generation fluoroquinolone-resistant bacterial keratitis. j cataract & refract surg 2007; 33:1488-9. 43. kaliamurthy j, jesudasan can, geraldine p, parmar p. comparison of in vitro susceptibilities of ocular bacterial isolates to gatifloxacin and other topical antibiotics. ophthalmic res 2005; 37:117-22. 44. parmar p, salman a, kalavathy cm, kaliamurthy j, prasanth da, thomas pa et al. comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis. am j ophthalmol 2006; 141:282-6. 45. michael kj, richard gf. selecting between gatifloxacin and moxifloxacin drops in ambulatory ophthalmic surgery. am j health syst pharm 2006; bacterial keratitis: perspective on epidemiology, clinico-pathogenesis, diagnosis and treatment 194 | squ medical journal, august 2009, volume 9, issue 2 63:637-40. 46. callegan mc, ramirez r, kane st, cochran dc, jensen h. antibacterial activity of the fourth generation fluoroquinolones gatifloxacin and moxifloxacin against ocular pathogens. adv ther 2003; 20:246-52. 47. lehokar s, sidhu n, mirdha br. comparison of topical 0.3% ofloxacin to fortified tobramycincefazolin in the therapy of bacterial keratitis. infection 2000; 28:149-52. 48. alexandrakis g, alfonso ec, miller d. shifting trends in bacterial keratitis in s. florida and emerging resistance to fluoroquinolones. ophthalmology 2000; 107:1497-502. 49. baum j. bacterial keratitis. in: schlossberg d, ed. current therapy of infectious disease. philadelphia: w.b. saunders company, 2002. 50 stern ga, buttross m. use of corticosteroids in combination with antimicrobials in the treatment of infections and corneal diseases. ophthalmology 1991; 98:847. 51 davis sd, sarff ld, hynduik ra. corticosteroids in experimentally induced pseudomonas keratitis. arch ophthalmol 1987; 96:126. 52. smolin g, okumoto m, leongsit l. combined gentamicin, tobramicin, corticosteroid treatment ii: effect on gentamicin resistant ps keratitis. arch ophthalmol 1980; 98:473. 53. harbin t. recurrence of a corneal pseudomonas infection after topical steroid therapy: case report. am j ophthalmol 1964; 58:670. 54. coster dj, bodenoch pr. host, microbial and pharmacological factors affecting the outcome of suppurative keratits. br j ophthalmol 1987; 71:96. 55. ormerod ld, hertzmark e, gomez ds, stabiner rg, schanzlin dj, smith re. epidemiology of microbial keratitis in southern california. ophthalmology 1987; 94:1322-33. 56. gudmundsson og, ormerod ld, kenyon kr, glynn rj, baker as, haaf j, et al. factors influencing predilection and outcome of bacterial keratitis. cornea 1989; 8:115. 57. klauss v, scaller uc, bialasiewicz aa. antiseptic prophylaxis and therapy in ocular infections. in: kramer a, behrens-baumann w, eds. infectious eye diseases. 1st ed. basel: s. karger ag, 2002. pp. 14590. 58. shah r, shah m, khandekar r, al-raisi a. contact lens induced corneal ulcer management in a tertiary eye unit in oman a descriptive study. squ med j 2008; 8:283-90. abdullah al-mujaini, nadia al-kharusi, archana thakral and upender k wali continuing medical education | 195 cme quiz questions 1. which type of contact lens is responsible for the highest incidence of ulcerative keratitis? a. hard contact lenses b. disposable contact lenses used overnight c. day wear soft contact lenses d. polymethyl metha-acrylate lenses 2. the most pathogenic ocular pathogen which can cause corneal perforation in just 72 hours is: a. staph.aureus b. strep. pneumoniae c. pseudomonas d. neis. gonorrhea 3. the ring infiltrates seen in the corneal ulcer are: a. damaged epithelial cells b. polymorph nuclear cells in stroma c. multiplying bacteria d. nothing but collection of the mucus 4. if the eye with keratitis has greenish discharge the most likely causing organism is: a. moraxella species b. klebsiella c. e. coli d. pseudomonas 5. the culture positive rate of the bacterial keratitis and ulcers is: a. 40-73% b. 50 -77% c. 20-30% d. >80% 6. the most common combination of organisms found on culture in polymicrobial keratitis is: a. aerobic gram-positive coccus plus gram-negative rod b. fungus plus bacteria c. acanthoemeba d. none of the above 7 the staining used for identification of gram-positive and gram-negative bacteria is: a. gram stain b. hematoxylin c. eosin d. naoh (sodium hydroxide) 8 corneal infections associated with surgical procedures, foreign bodies and intra-ocular prosthetic devices are usually caused by: a. coagulase-negative staphylococcus b. strep. pneumoniae c. pseudomonas d. neis. gonorrhea 9 the most potent antibiotic against pseudomonas is: a. ofloxacin b. gentamicin c. piperacillin d. cefazoline 10. the incidence of developing vision threatening complications like descematoceles, perforations, endophthalmitis, as a sequel of keratitis is: a. 24% b. 10% c. 30-40 % d. <15% answers: 1 b; 2 c; 3 b; 4 d; 5 a; 6 a; 7 a; 8 a; 9 c; 10 a submitted 6 oct 21 1 revision req. 11 nov 21; revision recd. 30 nov 21 2 accepted 12 dec 21 3 online-first: jan 2022 4 doi: https://doi.org/10.18295/squmj.1.2022.007 5 6 knowledge, attitudes and practices regarding traditional and 7 complimentary medicine in oman 8 hassan al-riyami,1 ahmed al-maskari,1 *sunil k. nadar,2 mohammed 9 almaskari3 10 11 1directorate of nursing and 2department of medicine, sultan qaboos university hospital, 12 muscat, oman; 3oman college of medical sciences, north sharqiyah, ibra, oman 13 *corresponding author’s e-mail: sunilnadar@gmail.com 14 15 abstract 16 objectives: the aim of the study was to assess the knowledge, attitudes and practices with 17 regards to traditional medicine in oman and to assess the factors that lead to its use. methods: 18 this was a cross sectional questionnaire-based study. all omani nationals above the age of 18 19 were eligible to be enrolled. the questionnaire consisted of questions regarding the knowledge, 20 attitudes and use of traditional medicine. results: there were 598 (out of 700) responses to the 21 questionnaire (response rate of 85.4%) of which 552 (mean age 33.6±7.7 years; 345 or 62.5% 22 male) were complete. majority of the respondents (90%) are aware of the different types of 23 traditional medicine(tm). a high percentage (81.5%) feel that it is effective. 67.8% had tried at 24 least one method. these were older (34.5±7.8 years vs 31.8±7.2 years, p<0.001) and mostly male 25 (72.1% vs 42.1%, p<0.001) and in full time employment (73% vs 27%). herbal medications 26 (65.7%) and traditional massage (60.4%) were the most common form of tm that was practiced. 27 women tended to go more for herbal medications (69.2%) and massage (63.4%), while, for men 28 cupping was the most popular (65.1%) followed by herbal medications (64.4%) and massage 29 (59.2%). back pain was the most common condition for which tm was used with only a small 30 mailto:sunilnadar@gmail.com percentage reporting any side effects. conclusion: there is widespread use of tm among the 31 urban population in oman. better understanding of their benefits will help incorporate them into 32 modern health care services. 33 keywords: traditional and complementary medicine; knowledge and attitudes 34 35 advances in knowledge 36  this study is the first in the region to evaluate the knowledge attitudes and practices of 37 traditional medicine among the urban population in oman 38  it shows that traditional medicine is still widely practiced in oman 39 40 application to patient care 41  understanding the use of traditional medicinal practices will help physicians evaluate 42 patients better and helps get better histories from patients when they present in hospitals 43 with side effects or complications related to any of these practices 44  this will help to formulate plans from a governmental level to try to integrate better these 45 traditional practices with modern health care 46 47 introduction 48 traditional medicine (tm) is a term broadly used to refer to various forms of indigenous medicine 49 that are practiced by communities native to a particular region, such as the traditional chinese 50 medicine system, the indian ayurvedic system and the greco-arabian unani system of medicine. 51 the who defines tm as health practices, approach, knowledge, and beliefs incorporating plant, 52 animal, and mineral based medicines, spiritual therapies, manual techniques, and exercises applied 53 singularly or in combination to treat, diagnose, and prevent illness or maintain wellbeing.1;2 the 54 terms “complementary” and “alternative” medicine are used to refer to a broad set of health care 55 practices that are not part of a country’s own tradition, or not integrated into its dominant health 56 care system, but part of another countries traditional practices.1 for example, acupuncture and 57 indian ayurvedic practices are part of traditional chinese and indian medicine respectively, but 58 many western countries consider them as a complimentary or alternative practice as it is not part 59 of their own traditional practices. traditional, complementary and alternative health practices are 60 very common and the who estimates that around 70-80% of the population in both developing 61 and developed countries use it either on its own or alongside modern therapies.2 62 63 the use and form of tm practices varies from country to country and indeed even between regions 64 in a particular country.3 it forms part of the culture in many asian and african countries.3;4 many 65 of these practices like the indian ayurvedic system or the african or chinese systems are centuries 66 old and have been handed down from generation to generation either by word of mouth or by 67 written script. some of these practices are related to the use of herbs or animal or plant products 68 or might be related to physical practices such as traditional massages, acupuncture, exercises, or 69 other practices such as cupping and branding.2;4 in the past, in many developing countries, 70 practitioners of tm were the only source of health care in remote villages due to poor access to 71 modern hospitals and doctors which were expensive and at times miles away.5 with improved 72 access to modern health care in developing countries, the number of these practitioners of tm has 73 dwindled considerably.6 despite this, many of these practices are embedded in the culture and 74 customs of many communities and these traditional practices coexist along with modern hospitals 75 and modern medicine.4 76 77 there is now a renewed interest in traditional and complementary practices in the western world 78 and indeed even in many developing countries.4;7 they are considered to be more natural and 79 therefore free from side effects of harmful chemicals. patients also tend to turn to them for chronic 80 conditions such as diabetes, hypertension or chronic aches and pains typically back pain. even a 81 decade ago, a study from australia suggested that around 70% of the population has used at least 82 one form of complementary medication with an estimated annual expenditure of more than us 83 dollars 3 billion in 2007 on traditional and complementary medications.8 more recently, in the 84 united states around 32 billion dollars were spent on complimentary medicine in 2012 and it is 85 expected to reach around 60 billion dollars in 2021.(7) the global market for complimentary 86 medicines is estimated to be around 100 billion us dollars and expected to rise to more than 400 87 billion us dollars in 2028.9 88 89 in oman, there is a rich heritage in the use of traditional health medicine which has been practiced 90 for centuries.10 oman has a rich biodiverse flora and fauna due to its varied terrain of mountains, 91 deserts and river beds (wadis) which has led to herbal medications that are unique to this region.11 92 they have also been influenced greatly by their historic ties with other civilisations. oman has a 93 history of trade for many centuries with countries in africa, the indian subcontinent and even far 94 off places such as europe and china. as a result, some of the traditional practices in oman have 95 derived important aspects from these civilisations.11;12 some of the common practices in oman 96 include traditional massages with herbal oils, branding (known locally as wassam), cupping 97 (known locally as hijama), herbal medications and more recently acupuncture.12 98 99 with urbanisation of the omani population and the improved access to modern health care even 100 in rural areas of the country, it is not clear whether patients still seek out these traditional practices. 101 the aim of this study is to assess the knowledge, attitudes, and practices among the general omani 102 population with regards to the traditional medical practices. we also sought to find out the factors 103 that affect the utilisation of these practices. the findings of this study can help governmental 104 institutions devise strategies to control and incorporate the use of traditional practices in modern 105 medicine. 106 107 methods 108 patient recruitment: 109 this was a cross-sectional questionnaire based study conducted among general population in 110 muscat, oman. ethical approval was granted by the medical research ethics committee, college of 111 medicine and health sciences at sultan qaboos university prior to commencing the study. the 112 study was conducted between november 2019 and march 2020. all adults above the age of 18 113 were eligible to take part in the study. we excluded those under the age of 18 and those not willing 114 to participate. a convenience sampling method was employed. the subjects were recruited from 115 malls and public places during health promotion events. it was also posted as a link and circulated 116 on social media. prior to filling in the questionnaire, the rationale and reason for conducting the 117 study was explained to the participants and they signed a consent statement on the questionnaire. 118 those filling in the electronic questionnaire had to tick a box stating that they have read the 119 rationale for the study and understood it and consented to taking part. 120 121 questionnaire development: 122 the questionnaire was self-developed and derived from other similar studies.6, 8, 13, 14, 15 it consisted 123 of 21 items in two sections. the first part comprised of the demographic data of the participants 124 and consisted of five questions. the second part of the questionnaire (16 items) collected data 125 about the participants’ knowledge, attitudes and practices with regards to the traditional medical 126 practices. to test knowledge, each participant was asked five (yes or no) questions about the use 127 of the tms, potential risks of tms, side effects of tms, and the need of tms training. the 128 respondents' attitudes and practices were measured using 11 (yes or no) questions that focussed on 129 the history of tm use, promoting these methods to others, method efficacy, and desire to use it 130 again. this questionnaire was devised in arabic, and was modified, reviewed and adjusted based 131 on interviewing lay members of the public regarding the various traditional practices that are 132 available in oman. it was piloted on 50 volunteers and minor adjustments were made to the 133 language to remove ambiguity and improve clarity and used in the final questionnaire. no 134 questions were deleted following the pilot. the final chronbachs alpha was around 0.78, 0.83 and 135 0.79 for the knowledge, attitude and practice questions respectively with the overall alpha value 136 of 0.81, which is acceptable level of reproducibility. 137 138 statistics: 139 sample size estimations were made according recommendations for population based cross 140 sectional questionnaire studies, where a minimum of 384 to 400 participants are required for a 141 standard error of 5%.16 the data were analyzed using spss version 21 software (ibm corp. 142 armonk, newyork usa). all data are described as either percentages or mean ± standard 143 deviation or median (interquartile range). students t test, mann-whiney u test or chi-square test 144 were used as appropriate. binary logistic regression was used to predict use of any tm practice as 145 a whole or individually. the demographic factors were used as predictors. a p value of <0.05 was 146 considered to be significant. the data has been stored securely in a password protected file that is 147 only accessible by the investigators. 148 149 results 150 a total of 700 questionaires were distributed of which 598 replies were received (response rate of 151 85.4%), of which 46 were incomplete. therefore 552 (mean age 33.6±7.7 years; 345 or 62.5% 152 male) responses were included in the final analysis. there were 32 diabetics (5.8%), 22 (4%) 153 hypertensive, 14(2.5%) with heart disease. majority of the respondents (491 or 88.4%) who did 154 not have any of these risk factors. most of the respondents were in full time employment (78.1%) 155 with another 3.4% in full time education. nearly three quarters of the respondents had completed 156 a university diploma degree or higher [table 1]. 157 158 table 2 shows the results of the general knowledge and attitudes towards traditional medicine 159 practices. majority of people know about/are aware of the different types of traditional methods 160 such as wassam – 476 (86.2%), cupping 495(89.7%), traditional massage 427 (77.4%) herbal 161 medications 461 (83.5%) and acupuncture 384 (69.6%). although most feel that traditional 162 medicine is not better than modern medicines (80.3%), a high percentage (81.5%) feel that it is 163 effective and around two-thirds (374 or 67.8%) said that they had tried at least one traditional 164 method. of those who had tried it, majority (310 out of 374 or 82.8%) found it was useful with 165 only a small percentage 31 out of 374(8.2%) saying they had some form of side effects. 166 167 most of those who had used it said they would try it again (85.2%), though only a small percentage 168 said they would recommend its use to others(36.1%). of those who have not tried it, most did not 169 have any specific reason for not trying, but 30.8% said that they did not know enough of it to try 170 it. there was no significant difference between the attitudes and practices between men and women 171 apart from the fact that there was a significant higher proportion of men who had tried some form 172 of traditional medicine than women(p<0.001), with men also more likely to try it again (p<0.001). 173 174 those who had tried at least one traditional practice were older (34.5±7.8 years vs 31.8±7.2 years, 175 p<0.001) and mostly male (72.1% vs 42.1%, p<0.001) as compared to those who did not try it 176 [table 3]. 78.2% of males had tried some form of traditional medicine as compared to 50.2% of 177 women. most of those who had tried a traditional practice were in active employment (73% of 178 those employed) with only a third of those in full time education and just over half of those who 179 were unemployed or retired. however, there was no difference with regards to educational status. 180 similarly having any cardiovascular risk factor also did not influence their use of tm practices. 181 182 the type of tm practice utilised did not vary according to age, sex employment status or 183 educational status [table 4]. herbal medications (65.7%) and traditional massage (60.4%) were 184 the most common form of tm that was practiced. women tended to go more for herbal 185 medications (69.2%) and massage (63.4%) rather the other forms of tca (cupping 29.8%, wassam 186 24%, and acupuncture 11.5%). meanwhile, more than half of men have tried all forms of tm 187 practices apart from wassam (46.6%) and acupuncture (21.8%), with cupping being the most 188 common (65.1%) followed by herbal medications (64.4%) and massage (59.2%). a high 189 proportion of patients with diabetes (66.6%) and hypertension (72%) have tried herbal 190 medications, with a high proportion saying that they specifically used it to lower blood sugar 191 (56.2%) or blood pressure (77.2%). 192 193 table 5 shows the distribution of the type of tca practice with the condition treated. back pain 194 was the most common condition for which tm was used and majority had tried traditional massage 195 (74.2%), cupping (69.3%) and herbal medications (62.3%) for this. acupuncture was the least 196 common practice, and again, when tried, was mainly for back pain. the other conditions for which 197 tm was used were headache, abdominal pain, “nerve” pain and swelling. 198 199 binary logistic regression revealed that age (p<0..001) and gender (p<0.001) strongly predicted 200 the use of any traditional practice. the other factors such as educational or employment status were 201 not predictive. gender also specifically predicted the use of wassam (p<0.001), cupping 202 (p<0.001), and acupuncture (p>0.001). knowledge regarding a specific practice predicted their 203 use in wassam (p=0.04), cupping (p<0.001), massage (p<0.001) and herbal medications (p<0.001). 204 employment status was only predictive of the use of herbal medication (p=0.01) 205 206 discussion 207 in oman, there appears to be continued widespread use of tm practices for a range of ailments. 208 the proportion of people who had used some form of tm in this study is 67.8% which is similar 209 to that reported in other studies from countries such as ethiopia,13 nigeria,14 ghana,15 india,6 210 china,17 and south africa.18 as in other countries, it is usually used mainly for chronic conditions 211 that do not respond to modern medications or for which there is no cure such as diabetes, low back 212 pain, muscular pain etc. it is interesting that many of those who have used it say that they tolerated 213 it well and found it useful and would recommend its use. patterns of use however suggest that the 214 more physical forms of traditional practices such as massage, acupuncture, branding and cupping 215 are used more by men, whilst women tend to use herbal medications more than other forms. this 216 is consistent across different cultures.6, 13-18 217 218 consistent with other studies, herbal therapy was the most common form of tm that was utilised 219 in this study group.15;19 herbal medications can be used for a wide variety of ailments and are 220 considered to be safe and generally free from side effects as it is derived from naturally occurring 221 plants and herbs. traditional herbal therapy is common in many cultures usually with the 222 indigenous herbs and plants that are unique to that particular country or region. studies from the 223 middle-east have demonstrated a high level of use of herbal medications for many ailments and 224 especially during pregnancy. 20,21 many of the traditional omani herbal medications contain rose 225 water, lime and local honey which are plentiful in the hilly ranges of jebal akhdar.11;12 the leaves, 226 resin, bark and sap of plants found in these hills are also used extensively in the herbal preparations. 227 11;12 in addition, the dhofar region of oman is famous for frankincense which has been used for 228 centuries as an incense as well as for its medicinal properties.22 frankincense forms a part of many 229 of the omani herbal medications, both as a paste, as an inhalant, an ointment or even for ingestion. 230 in view of this abundance of local medicinal herbs and plants, it is therefore not surprising that 231 this was the most common form of tm in this study. the use of herbal medications is widespread 232 and generally unregulated in most countries and although they appear to be well tolerated in the 233 current study, patients may develop unexpected side effects especially with prolonged or excessive 234 use. it is therefore recommended to include a history of ingestion of herbal medications as part of 235 the routine work up of patients. 21 236 237 traditional massage therapy is common all over the world and is used for a variety of conditions. 238 it has been shown to decrease muscular and joint pain, labour pain, improve mood, reduce anxiety, 239 improve quality of sleep and reduce blood pressure in the short term,23 although data on long term 240 benefits are lacking.24 however, it is readily available, presumed safe and often has an immediate 241 effect on pain and mood and hence its popularity.25 there are various mechanisms to explain the 242 effects of massage on pain and mood. the pressure and local heat caused by rubbing and 243 massaging improves blood flow and local vasodilatation. there are also neuro-hormonal changes 244 such as increased dopamine and decreased noradrenaline levels, changes in parasympathetic 245 activity, and changes in neuronal excitability after massage.26 this was the second most common 246 form of tm practice among the current study population. however as with the other forms of tm, 247 it appears to be predominantly used by males and employed individuals. it was the second most 248 common form of tm used by women. and used for most indications. 249 250 branding is a common practice among many countries.27 this involves applying a hot metal object 251 to the affected part of the body and the third degree burns so caused are considered to be a form of 252 counter irritant to the original disease. although this is dangerous and potentially harmful,28 it is 253 widely practiced in many countries and known by different names such as “wassam” in oman, 254 “guboow” in somalia, “kaiy” in libya etc.27 despite its popularity, there have been many case 255 reports of complications related to branding.12;28 it was not the most commonly used practice in 256 the present study cohort and was used mainly by older men. however, interestingly, almost half 257 of the men who had practiced some form of tm said that they had used it, suggesting that it is still 258 popular despite the pain and the potential harm. 259 260 cupping therapy is another common traditional physical method of treatment in many parts of 261 asia and the middle-east and is growing in popularity in the west. there are two types of cupping 262 either wet cupping (or hijama as it is known in oman)or dry cupping. it involves the application 263 of a bamboo, glass or plastic cup at the area of treatment. vacuum is then created either manually 264 or by electromagnetic suction inside the cup to draw the skin into the cup. in wet cupping, blood 265 is drawn into the cup via a small incision made prior to the application of the cup, while in dry 266 cupping, no blood is drawn. the mechanism of action of cupping is not clear, and many theories 267 have been proposed. some suggest that it acts by triggering a diffuse noxious inhibitory control or 268 by the removal of oxidants and the decrease of oxidative stress locally. others hypothesise that 269 this therapy drains excess fluids; increases blood flow to skin and muscles; and stimulates the 270 peripheral nervous, neurohormone, circulatory, and immune systems.29 there are numerous 271 clinical trials and meta-analysis of its use in a variety of conditions such as back pain, neck pain 272 migraine, hypertension and chronic obstructive pulmonary disease.29-31 the results are variable, 273 with some studies showing benefit compared to placebo or standard therapy whilst others did not. 274 interest in cupping has increased after some celebrity athletes have been shown to use it.32 in this 275 cohort, less than half of those who had used some form of tm had used cupping, similar to 276 wassam, demonstrating that there is still considerable interest in this form of therapy. 277 278 acupuncture was the least common of the tm utilised in this study. acupuncture is a chinese tm 279 practice that involves the placing of needles in special locations that can affect the pain sensations. 280 it is suggested that by affecting afferent nerve signalling, acupuncture can lead to the release of 281 endogenous opioids and thereby reduce pain.33 although it has been around in chinese traditional 282 practice for many centuries, it is only within the last few decades that it has been gaining popularity 283 and acceptance in much of the western world.34 inconsistent clinical results, limited availability 284 (as it has to be provided by specially trained professionals) and misconceptions about its use such 285 as pain and other complications limit its availability and overall appeal as compared to other forms 286 of tm.35 it is interesting to note that other “painful” and potentially harmful practices such as 287 wassam (branding) were more popular than acupuncture. this could be due to familiarity with 288 wassam as it has been practiced in the region for a long time. 289 290 there were no clear demographic factors that could predict the use of tm. as in other studies from 291 the region, massage therapy and herbal medications were used by both men and women, while 292 men also used the more “painful” physical therapies such as wassam, cupping and acupuncture.19 293 tm was used by a high proportion of those in active employment as compared to students and 294 those not in active employment, perhaps reflecting the cost implications of using tm. 295 296 one of the limitations of this study was that this was confined to the urban areas of the capital city 297 of muscat in oman. the use and views of the population living in rural areas might be different. 298 similarly, the present cohort had a high proportion of young, educated and employed individuals 299 suggesting a higher socioeconomic status (although we did not collect data on household income). 300 the views and practices of those who are older and who have not got formal education beyond 301 primary school might be different and are not represented in the current survey. similarly, the 302 practices and attitudes towards traditional medicine in the rural areas of oman, might be different. 303 despite these limitations, the sample size of this study was high and it gives an insight into the 304 knowledge, attitudes and practices relating to traditional medicine in modern day oman. 305 additionally this is the first study to assess the attitudes of the omani population regarding 306 traditional medical practices. 307 308 this study has demonstrated the widespread use of tm practices among the urban population in 309 oman. the use of tm practices is deeply embedded in the social culture of the population with 310 many using it and feeling benefit. in many countries, efforts have been undertaken to try and 311 integrate these practices to complement modern health care.2,3,5,6 although this study has given an 312 insight into the practices and attitudes, more research is required to help understand the local tm 313 practices better, so that they can be fully integrated into the local health care. many patients seem 314 to find benefit in these traditional practices, and utlising them to complement modern health care 315 can go a long way in improving the overall health of the population. care should also be given to 316 educate the population regarding the ill effects of some of the poorly understood practices such as 317 branding or untested herbal concoctions, which can give rise to serious complications 318 319 conclusion 320 despite the availability and ease of access to modern health care, there is still widespread use of 321 traditional medicinal practices alongside modern medicine in urban oman. traditional practices 322 are part of the culture and heritage of various communities, though these practices appears to be 323 used less frequently by the younger age group as compared to the older population. more needs to 324 be done to educate the public regarding the ill effects of some of the more harmful methods of tm, 325 while at the same time a better understanding of the mechanisms underlying the benefits of some 326 of these practices is needed to help integrate them better into the local health services. 327 328 conflict of interest 329 the authors declare no conflicts of interest. 330 331 funding 332 no funding was received for this study. 333 334 authors’ contribution 335 har and aam collected the data. aam, sn and mam contributed to the manuscript writing. 336 sn analysed the data. 337 338 references 339 (1) traditional medicine: definitions. 2021. 22-5-2021. availabe at 340 https://www.who.int/traditional-complementary-integrative-medicine/en/ accessesd 341 on 14 july 2021 342 (2) who: traditional medicine strategy 2014-2023. 2021. availabe at who traditional 343 medicine strategy: 2014-2023 accessesd on 14 july 2021 344 (3) oyebode o, kandala nb, chilton pj, lilford rj. use of traditional medicine in middle-345 income countries: a who-sage study. health policy plan 2016 oct;31(8):984-91. 346 (4) who global report on traditional complimentary and integrative medicine 2019. 2021. 347 availabe at https://www.who.int/traditional-complementary-integrative-348 medicine/whoglobalreportontraditionalandcomplementarymedicine2019.pdf 349 accessesd on 14 july 2021 350 (5) birhan w, giday m, teklehaymanot t. the contribution of traditional healers' clinics to 351 public health care system in addis ababa, ethiopia: a cross-sectional study. j ethnobiol 352 ethnomed 2011 dec 2;7:39. 353 (6) angmo k, adhikari bs, rawat gs. changing aspects of traditional healthcare system in 354 western ladakh, india. j ethnopharmacol 2012 sep 28;143(2):621-30. 355 (7) the state of the nutritional supplements market. 2021. availabe at nutritional 356 supplements flexing muscles as growth industry (forbes.com) accessesd on 14 july 357 2021 358 (8) xue cc, zhang al, lin v, da cc, story df. complementary and alternative medicine 359 use in australia: a national population-based survey. j altern complement med 2007 360 jul;13(6):643-50. 361 (9) complementary and alternative medicines market report. 2021. availabe at 362 https://www.grandviewresearch.com/industry-analysis/complementary-alternative-363 medicine-market accessesd on 14 july 2021 364 (10) azaizeh h, saad b, cooper e, said o. traditional arabic and islamic medicine, a re-365 emerging health aid. evid based complement alternat med 2010 dec;7(4):419-24. 366 (11) divakar mc, al-siyabi a, varghese ss, rubaie ma. the practice of ethnomedicine in 367 the northern and southern provinces of oman. oman med j 2016 jul;31(4):245-52. 368 (12) shenoy r, bialasiewicz a, khandekar r, al bb, al bh. traditional medicine in oman: 369 its role in ophthalmology. middle east afr j ophthalmol 2009 apr;16(2):92-6. 370 https://www.who.int/publications/i/item/9789241506096 https://www.who.int/publications/i/item/9789241506096 https://www.forbes.com/sites/davidlariviere/2013/04/18/nutritional-supplements-flexing-their-muscles-as-growth-industry/?sh=2b63cd068845 https://www.forbes.com/sites/davidlariviere/2013/04/18/nutritional-supplements-flexing-their-muscles-as-growth-industry/?sh=2b63cd068845 (13) wassie sm, aragie ll, taye bw, mekonnen lb. knowledge, attitude, and utilization 371 of traditional medicine among the communities of merawi town, northwest ethiopia: 372 a cross-sectional study. evid based complement alternat med 2015;2015:138073. 373 (14) aina o, gautam l, simkhada p, hall s. prevalence, determinants and knowledge about 374 herbal medicine and non-hospital utilisation in southwest nigeria: a cross-sectional study. 375 bmj open 2020 sep 10;10(9):e040769. 376 (15) sato a. revealing the popularity of traditional medicine in light of multiple recourses and 377 outcome measurements from a user's perspective in ghana. health policy plan 2012 378 dec;27(8):625-37. 379 (16) sample size calculations for questionairre based studies. 2015. 380 https://issuu.com/medecinsdumonde/docs/47-the-kap-survey-model-knowledge-a/9 381 accessed on 19 august 2021 382 (17) xin b, mu s, tan t, yeung a, gu d, feng q. belief in and use of traditional chinese 383 medicine in shanghai older adults: a cross-sectional study. bmc complement med ther 384 2020 apr 28;20(1):128. 385 (18) nxumalo n, alaba o, harris b, chersich m, goudge j. utilization of traditional healers 386 in south africa and costs to patients: findings from a national household survey. j public 387 health policy 2011;32 suppl 1:s124-s136. 388 (19) albedah am. use of complementary and alternative medicine by cancer patients in 389 saudi arabia: a paradox in healthcare. j altern complement med 2013 nov;19(11):918-390 9. 391 (20) aljofan m, alkhamaiseh s. prevalence and factors influencing use of herbal medicines 392 during pregnancy in hail, saudi arabia: a cross-sectional study. sultan qaboos univ 393 med j. 2020;20(1):e71-e76. doi:10.18295/squmj.2020.20.01.010 394 (21) alkhamaiseh si, aljofan m. prevalence of use and reported side effects of herbal medicine 395 among adults in saudi arabia. complement ther med. 2020 jan;48:102255. doi: 396 10.1016/j.ctim.2019.102255 397 (22) al-yasiry ar, kiczorowska b. frankincense--therapeutic properties. postepy hig med 398 dosw (online ) 2016 jan 4;70:380-91. 399 (23) boyd c, crawford c, paat cf, price a, xenakis l, zhang w. the impact of massage 400 therapy on function in pain populations-a systematic review and meta-analysis of 401 randomized controlled trials: part iii, surgical pain populations. pain med 2016 402 sep;17(9):1757-72. 403 (24) krinock m, goyal d, goel h, nadar sk. wanted: long term studies on massage therapy 404 in hypertension. j hum hypertens 2020 nov;34(11):741-4. 405 (25) perlman a, fogerite sg, glass o, bechard e, ali a, njike vy, et al. efficacy and safety 406 of massage for osteoarthritis of the knee: a randomized clinical trial. j gen intern 407 med 2019 mar;34(3):379-86. 408 (26) nelson nl. massage therapy: understanding the mechanisms of action on blood pressure. 409 a scoping review. j am soc hypertens 2015 oct;9(10):785-93. 410 (27) ghazanfar sa. wasm: a traditional method of healing by cauterisation. j ethnopharmacol 411 1995 jul 28;47(3):125-8. 412 (28) raza s, mahmood k, hakeem a, polsky s, haemel a, rai s, et al. adverse clinical 413 sequelae after skin branding: a case series. j med case rep 2009 jan 23;3:25. 414 (29) kaki a, sawsan r, samiha m, al js, elalah ma, ibrahim n. wet cupping reduces pain 415 and improves health-related quality of life among patients with migraine: a 416 prospective observational study. oman med j 2019 mar;34(2):105-9. 417 (30) kim s, lee sh, kim mr, kim ej, hwang ds, lee j, et al. is cupping therapy effective 418 in patients with neck pain? a systematic review and meta-analysis. bmj open 2018 nov 419 5;8(11):e021070. 420 (31) moura cc, chaves ecl, cardoso aclr, nogueira da, correa hp, chianca tcm. 421 cupping therapy and chronic back pain: systematic review and meta-analysis. rev lat 422 am enfermagem 2018 nov 14;26:e3094. 423 (32) increased interest in cupping after celebrity use. 2021. availabe at 424 https://www.theguardian.com/sport/2016/aug/08/cupping-therapy-interest-spikes-425 michael-phelps-rio-olympics accessesd on 14 july 2021 426 (33) vanderploeg k, yi x. acupuncture in modern society. j acupunct meridian stud 2009 427 mar;2(1):26-33. 428 (34) hao jj, mittelman m. acupuncture: past, present, and future. glob adv health med 2014 429 jul;3(4):6-8. 430 (35) deng s, zhao x, du r, he si, wen y, huang l, et al. is acupuncture no more than a 431 placebo? extensive discussion required about possible bias. exp ther med 2015 432 oct;10(4):1247-52. 433 434 table 1: demographic features of the respondents 435 numbers (%) age (years) 33.6±7.7 gender male female 345 (62.5) 207(37.5) diabetic 32 (5.8) hypertensive 22 (4) heart disease 14 (2.5) no cardiovascular risk factors 491 (88.9) employment student full time employed retired/unemployed 19 (3.4) 431 (78.1) 102 (18.5) educational status less than secondary school completed secondary school diploma or higher 24 (4.3) 118(21.4) 410 (74.3) 436 table 2: knowledge and attitudes regarding traditional and complementary medicine practices 437 number (%) male (n=345)(%) female(n=207)(%) p value are you aware of: wassam cupping massage herbal medications accupuncture 476 (86.2) 495 (89.7) 427 (77.4) 461(83.5) 384 (69.6) 291(84.3) 314(91) 253(73.3) 286(82.8) 232(67.2) 185(89.3) 181(87.4) 174(84.1) 175(84.5) 152(73.4) 0.09 0.1 0.04 0.6 0.1 do you feel traditional medicine is effective? 450 (81.5) 291(84.3) 159(76.8) 0.02 do you think it is better than modern medicine? 109 (19.7) 69(20) 40(19.3) 0.8 have you ever tried any? 374 (67.8) 270(78.2) 104(50.2) <0.001 did you try it for hypertension (n=22) 17 (77.2) (n=15) 13(86.6) (n=7) 4 (57.1) 0.1 did you try it for reducing blood sugar (n=32) 18 (56.2) (n=17) 10(58.8) (n=15) 8(53.3) 0.6 for those who had tried it (n=374) was it useful? did you have any side effects? will you try it again in future did you use it alongside modern medications would you recommend its use 315 (84.2) 31 (8.2) 319 (85.2) 186 (49.7) 135 (36.1) (n=270) 228(84.4) 21(7.7) 163(78.7) 125(60.3) 103(49.7) (n=104) 87(83.6) 10(9.6) 89(85.5) 61(58.6) 31(29.8) 0.5 0.6 <0.001 0.07 0.1 if you have not used any, why not? (n=178) not effective don’t know where available expensive don’t know enough of it no specific reason 67 (37.6) 4(2.2) 8(4.4) 55 (30.8) 168 (94.3) (n=75) 37(49.3) 4(5.3) 7(9.3) 32(42.6) 70(93.3) (n=103) 30(29.1) 0 1(0.9) 23(22.3) 98(95.1) 0.04 analysis by chi-square test 438 439 table 3: characteristics of respondents who have tried any form of traditional treatment 440 not tried (n=178)(%) tried (n=374)(%) p value age (years) 31.8±7.2 34.5±7.8 <0.001* sex male female 75 (42.1%) 103(57.9%) 270 (72.1%) 104 (27.9%) <0.001 employment status student employed unemployed/retired 13(7.3%) 116(65.1%) 49 (27.6%) 6 (1.6%) 315(84.2%) 53 (14.2%) <0.001 educational status primary school or less secondary school diploma or higher 8(4.4%) 34(19.1%) 138(76.5%) 18(4.8%) 84(22.4%) 272(72.8%) 0.4 co-morbidites diabetes hypertension heart disease 7(3.9%) 7(3.9%) 3(1.6%) 15(4%) 25(6.6%) 11(2.9%) 0.9 0.19 0.38 analysis by chi-square test, except * which is by students t-test 441 442 table 4: characteristics of those trying each different modality of traditional practice (n=374). 443 tried wassam (n=151) tried cupping (n=207) tried massage (n=226) tried herbal (n=246) tried acupuncture (n=71) age (years) 34.6±7.8 34.8±7.5 34.2±8.2 34.9±8.5 35.9±9.4 sex male(n=270) female(n=104) 126(83.4%) 25(16.6%) 176(85%) 31(15%) 160(70.7%) 66(29.3%) 174(70.7%) 72(29.3%) 59(83%) 12(17%) employment status student employed unemployed 2(1.3%) 135(89.4%) 14 (9.3%) 2 (0.9%) 180 (86.9%) 25 (12.2%) 3(1.3%) 192(84.9%) 31(13.8%) 3(1.3%) 199(80.8%) 44 (17.9%) 0 62(87.3%) 9(12.7%) educational status primary school or less secondary school diploma or higher 6 (3.9%) 40 (26.4%) 105(69.7%) 13(6.2%) 53(25.6%) 141(68.2%) 10(4.4%) 62(27.4%) 154(68.2%) 16(6.5%) 50(20.3%) 170(69.2%) 5(7%) 20(28.1%) 46(64.2%) diabetic (n=15) 7 (4.6%) 7 (3.3%) 6(2.6%) 10(4%) 3(4.2%) hypertensive (n=25) 7 (4.6%) 17(8.2%) 14(6.1%) 18(7.3%) 6(8.4%) heart disease (n=11) 7 (4.6%) 7 (3.3%) 5(2.2%) 7(2.8%) 3(4.2%) 444 table 5: distribution of the traditional practice with the symptom 445 wassam (n=151) cupping (n=207) traditional massage (n=226) herbal medications (n=246) acupuncture (n=71) for headache (n=110) 44 77 69 73 28 for backpain (n=202) 75 140 150 126 43 for abdominal pain (n=126) 55 43 67 100 10 for nerve pain (n=147) 57 97 106 103 31 for jaundice (n=62) 48 34 25 31 7 for swelling (n=36) 19 18 22 29 4 446 a       —and the gulf region in general—is the sharp rise in traffic accidents and the consequent head injuries, which render many young people to severe morbidity and mortality.1 head injuries result in  of global mortality and are responsible for more years of life lost than most diseases or medical conditions.2,3 ough oman is a world leader in health care, facilities for rehabilitation of the brain injured remain minimal.4–6 until recently this was understandable and perhaps excusable, since experts previously considered it impossible to regenerate or anatomically reorganize the adult nervous system, once damaged.7 is may no longer be the case. research in the nineties—the decade of the brain—has brought new insights into the pathophysiology, impairments, functional limitations and disabilities involved in brain injury. ese may provide a better understanding of the mechanisms of functional recovery following brain damage, and have kindled hopes for more effective rehabilitation.7, 8 it is instructive to review some of the pertinent medical history and then the recent medical progress in our understanding of the response of the brain to injury. e belief in irreversibility of neural damage probably goes back to the spanish anatomist and nobel laureate, santiago ramony cajal. in his  book        he declared, ‘once development is completed, the sources of growth and regeneration of axons and dendrites are irrevocably lost. in the adult brain, nervous pathways are fixed and immutable; everything may die, nothing is regenerated’ (p ).9 for decades, his influential words kept health planners in inertia under the impression that it was pointless to try to develop training or rehabilitation programmes to promote something that could not happen. cajal’s pessimistic views were seriously challenged only in the last two decades. we now know not only that there is continuous growth of brain tissue, but have also begun to recognize that the brain, when injured, begins a process of healing which involves intrinsic growth, reorganization, adaptation and environmental interaction that reverses many of the pessimistic connotations of cajal’s lament. e understanding of the mechanisms of plasticity was an important development.10 plasticity refers not only to possible cortical changes aer injuries but also to a wide variety of biological processes relevant to rehabilitation.11 among the models and mechanisms suggested to explain plasticity is vicarience, which infers that different areas of the brain have the potential to take over specific functions of damaged tissues. e parallel term in modern neuropsychology is equipotentiality, the ability of healthy nerve cells to take over the functions of their damaged counterparts. vicarience has been supported by many experiments. among these are the longitudinal studies on monkeys and rats by merzenich et al and more recently, by al-adawi.12–13 following median nerve transection and ligation, the researchers completely deafferented the animals’ limbs, thus severing all sensory nerves. subsequently, ‘new’ inputs formed in the brain’s receptive field of deafferented limbs, suggesting that the brain possesses an inherent capacity for reorganization, leading to functional recovery and possibly, rehabilitation. similar reorganization has also been reported in humans. mogilner showed somatotopic reorganization in two adult subjects who were scanned using magnetoencephalography before and aer surgical separation of syndactyly (webbed fingers).14 e presurgical maps had displayed shrunken and nonsomatotopic hand representation. within weeks of surgery, however, cortical reorganization occurred up to  mm from the revamping neurorehabilitation in oman *samir al-adawi1, david t. burke2 1department of behavioural medicine, college of medicine, sultan qaboos university, p.o. box: , al-khod , muscat, sultanate of oman. 2department of physical medicine and rehabilitation, spaulding rehabilitation hospital, harvard medical school,  nashua street, boston, ma , usa. *to whom correspondence should be addressed. e-mail: adawi@squ.edu.om             :   , : , : , – ©   squ medical sciences journal ���� (�) issue editorial ���� ����������� ������ ����� �� ���� ������ ��� �� ������� ����� �   site of the original area of representation, reflecting the new functional status of the separated digits. ere are more experimental and clinical reports that reaffirm the mechanism of vicarience.15 interestingly, neuropsychological plasticity, rather than being limited by certain critical periods of development, can occur at any age.15 e second popular concept of how recovery might occur is based on the notion that the brain evolves ‘backup’ or ‘fail-safe systems’ to be activated when something goes wrong. is is similar to backup computers or second brake systems in vehicles, where the standby facility automatically assumes the functions of the damaged system. in neuropsychology, such compensatory mechanism is termed redundancy. in the s, wall and his colleagues demonstrated redundancy by showing that previously silent fibre pathways in the brain stem could become immediately active when the primary sensory fibres in the spinal cord were cut.16 since the appearance of activity occurred soon aer the injury, wall proposed that the new pathways were there all the time, but had been masked or inhibited by the active primary sensory fibres. redundancy (or unmasking) in the nervous system is oen used to explain how a patient can retain function aer suffering major trauma to the brain.17 such recoveries could also be explained as being due to functional substitution, where part of the brain is considered ‘reprogrammed’ to take charge of the functions of the damaged area. recovery is explained not so much by the restoration of normal behaviour as by the development of alternative behaviour that permit patients to achieve certain goals in everyday life, though not as efficiently as before.18 examples of functional substitution are demonstrated by individuals such as physicist stephen hawking who lost his ability to speak but learned to communicate by using a keyboard. in this conceptual model of rehabilitation, behavioural substitution is expected to be accompanied by structural reorganization of the nervous system itself.19,20 e third concept that has received renewed attention is diaschisis, which postulates that when injury or disease has disturbed a part, the resultant trauma can affect other quite distant parts. diaschisis is thought to be a temporary block of function produced by damage or irritation to brain tissue.21 recent preliminary studies suggest that aer injury, areas of the brain distant from the actual damage site could become depressed.7 ese studies provide evidence that focal subcortical lesions can result in cortical dysfunction in patients even though the cortex is intact, and vice versa. is may explain why non-specific brain injuries sometimes lead to impairments. in addition to these suggested mechanisms of injury and recovery, another possible mechanism of injury at neurochemical level has begun to emerge.22 experiments over the past decades indicate that when a healthy brain is suddenly injured, neurotransmitter activity tends to change.23 ere is consensus that at the earliest phase of a lesion, the injured, traumatized and dying cells become unable to control their fluid and ion balance, and release their stores of amino acid neurotransmitters and calcium ions.24 e consequent excitotoxicity weakens and ‘burns out’ the neurons, which eventually die.19 it is through the understanding of these processes that we now realize that there is a cascade of chemical processes that must occur for a brain cell to die. e understanding of these processes has given us a realization that there may be a number of opportunities to affect the process by which cells die, and perhaps by doing so affect the magnitude of the injury itself. while some of the early studies suggest that there may be a limited window of opportunity during which we may affect these processes, this remains a very fertile area for research and a potentially significant means by which we may reduce the morbidity of our patients. each of the areas outlined suggest a response by a medicinal/rehabilitation team that, if not pursued, represent a failure of our medical system to apply the knowledge gained over the past decade to the lives of the citizens who depend on our vigilance. each advance in knowledge invites more than our passive observation. first, as we discuss the concept of vicarience, we must not view this as an internal process separate from environmental influences. biernaskie & corbett have noted that the process of reorganization seems to be heavily influenced by the stresses on the organism as it attempts to engage the damaged neural tissue. 25 for instance, if the damage in the brain results in paralysis of the le arm, it seems the attempt to use the le arm stimulates the organism to more fully reorganize this area of the brain. without this stress, the reorganization will be less complete. efforts in rehabilitation elsewhere in the world, which have addressed this, have focused on the forced use of the impaired portion of the brain. ere are entire programs that focus on this forced use concept, which are unique to the process of rehabilitation. e second concept discussed suggests that a redundancy of the brain allows for the ‘awakening’ of area of the brain when other primary areas have been injured. a point that may be lost in these relatively recent discoveries is that once these areas have been brought “on line” and thus are available for a new function, there is need for this tissue to be trained. if we step back and review the development of the primary tissue, it is clear that there are years of train              ing during which this tissue originally obtained its facility of function. it is not surprising therefore that there needs to be a process of focused ‘rehabilitation’ of this new tissue that allows us to maximize its function. indeed, over the last few years, more cases of functional recovery aer cerebral injury and disease have been published than anytime before.26 e pathways of neurotransmitters involved have been well charted and the safety of the drugs which influence these transmitters has been relatively well established.12 it is important to note that although these drugs have helped to tease out neurochemical and pathophysiology behind neurocognitive impairment following brain damage, the traditional role of retraining and remediation (in other words, rehabilitation) plays a central role. in a way, the drug appears to kick-start the system so the retraining or remediation can occur in tandem.21, 27 we now know that if an area of the brain has been injured that there is a change in the neurochemistry that affects the function of that tissue. if we study the involved neurochemistry, a number of medications are suggested that can introduce or enhance the chemicals that have been altered. with severe injury, the focus of the rehabilitation may be to enhance the ability to attend to the environment. of the medications most oen employed in rehabilitation, neurostimulants are oen mentioned prominently. ese allow the individual to begin or to maximize his ability to focus on the environment and on the process of rehabilitation. with better focus and longer attention to the learning process the elements of reorganization and teaching of the reorganized tissue can be maximized. eses are not independent issues. one must be attended while the other is ongoing. is illustrates the new, complex process of neurorehabilaitation. how practical are the above behavioural and neurochemical descriptions of the mechanisms of injury and recovery? ey do suggest that the brain can heal, or be induced to heal, aer injury. e individual then can regain self-sufficiency and self worth while he or she is eased into independent living. if one ponders on the practice and services of rehabilitation in oman, a sense of helplessness would likely take hold, for the field and practice have been largely disregarded, and worse, there is no such endeavour on the horizon. each year, .–. of the population of oman is estimated to incur brain injury, principally from road traffic accidents, domestic accidents and falls from date palms.28–30 another major cause of brain injuries in oman are the ‘diseases of affluence’—diabetes, hypercholesteremia, and obesity—that lead to strokes.31, 32 for victims of these, the protocol has limited itself to reducing mortality. with a ‘low child, low adult’ mortality stratum, oman’s population has an extremely large youth base, with  below .33 recklessness, novelty seeking and proneness to accidents peak in adolescence, the underdeveloped frontal cortex in young people being cited as one of the many reasons for this.34 an unusual trend in oman is reckless driving in young women. whereas studies from elsewhere place road traffic accidents in the ‘male turf ’, for reasons not yet apparent, females in oman have managed to blur such demarcation.35 with the advent of effective emergency care, faster transportation and acute medical management, the mortality rate among the brain-injured has decreased in oman. however, merely saving lives and leaving them at that may result in a most distressing quality of life for the survivors who are even incapable of self-care. prevention being infinitely superior to rehabilitation, the youth of oman should be intensely targeted from their early teens, and the dangers of reckless driving should become an important part of the campaign to reduce injuries and discourage lifestyle conducive to the ‘diseases of affluence.’ in ,  people per , vehicles were either maimed or killed in traffic accidents.3 psychosocial studies should be carried out to delineate behavioural factors leading to injuries and tease out culture-specific factors responsible for accidents.36 as youth oen occurs with a sense of invincibility, those more sober forces of society must assist in the prevention of the catastrophic. traffic surveillance should be stepped up, backed by stiff and inescapable fines. programmes should be evolved to wean away youngsters from the thrill of fast cars to sports or other healthier forms of catharsis relevant for youth. in spite of best efforts at prevention, the numbers of cases of brain damage will keep rising at least in the short and medium term. during just one year from  to , debilitating injuries in oman increased by . 3 as we have discussed, emerging evidence gives hope that these unfortunate people can indeed be rehabilitated to regain selfsufficiency. is needs now to be a priority for healthcare planners in oman who are urged to review and revamp the policies and facilities for rehabilitating the victims of physical, sensory, cognitive, developmental or emotional disabilities that have occurred due to brain injuries. we must move not one but two steps ahead of our current practices. we must encourage the primary prevention of the injuries, and then bring to bear the full weight of our medical system to address the issues described above. we can and should see each individual as having a weakened neurochemical system that can be strengthened, as having rescue mechanisms that can be coerced                          to accelerate, and once introduced, as having new tissue available which must be trained towards maximal function. ese processes require medical diligence. it is time the healthcare system of oman rose to the occasion and gave due importance to the rehabilitation of those with brain injury. r e f e r e n c e s . ansari s, akhdar f, mandoorah m, moutaery k. causes and effects of road traffic accidents in saudi arabia. public health , , –. . deeen jl, vos t, huttly sra, tulloch j. injuries and non-communicable diseases: emerging health problems of children in developing countries. b world health orgn , , –. . traffic and congestion. world development indicators , –. . al-dhahry shs, al-awaidy st, al-busaidy sm, koul rl, alkhusaiby sms, suleman ajm. poliomyelitis in oman. ii. toward eradication. acta trop , , –. . smith r. oman: leaping across the centuries. bmj , , –. . e world health report . world health organization, geneva. . stein dg, brailosky s, will b. brain repair. oxford: oxford university press, . . selzer me. neural plasticity and repair in rehabilitation. neurorehab neural re , , –. . defelipe j, jones eg. cajal’s degeneration and regeneration of the nervous system. new york: oxford university press, . . yuste r, bonhoeffer t. morphological changes in dendritic spines associated with longterm synaptic plasticity. annu rev neurosci , , –. . hodge cj, boakye m. biological plasticity: e future of science in neurosurgery. neurosurgery , , –. . merzenich mm, kaas jh, wall jt, sur m, nelson rj, felleman dj. progression of change following median nerve section in the cortical representation of the hand in area b and area  in adult owl and squirrel monkeys. neuroscience , , –. . al-adawi s. e role of cortical plasticity and ascending noradrenergic innervation in autotomy aer sciatic and saphenous nerve transection in the rat. unpublished thesis, university of surrey. . mogilner a, grossman ja, ribary u, joliot m, volkmann j, rapaport d, beasley rw, llinas rr. somatosensory cortex cortical plasticity in adult humans revealed by magnetoencephalography. pro natl acad sci , , –. . ramachandran vs. behavioural and magnetoencephalographic correlates of plasticity in the adult human brain. pro natl acad sci , , –. . wall d. e presence of ineffective synapses and the circumstances which unmask them. philos trans r soc lond b biol sci , , –. . powell j, al-adawi s, morgan j, greenwood rj. motivational deficits aer brain injury: effects of bromocriptine in  patients. j neurol neurosurg psychiatry , , –. . dobkin bh. functional rewiring of brain and spinal cord aer injury: the three rs of neural repair and neurological rehabilitation. curr opin neurol , , –. . zarei m, al-adawi s, dawe gs, bonner a, stephenson jd. role of sm and the effect of central noradrenergic blockade on autotomy behaviour in rat. eur j neurosci ,  (suppl. s), a. . schoups a, vogels r, qian n, orban g. practising orientation identification improves orientation coding in v neurons. nature , , –. . sultzer dl, mahler me, cummings jl, vangorp wg, hinkin ch, brown c. cortical abnormalities associated with subcortical lesions in vascular dementia—clinical and positron emission tomographic findings. arch neurol , , –. . al-adawi s, dawe gs, bonner a, stephenson jd, zarei m_. central noradrenergic blockade prevents autotomy in rat: implication for pharmacological prevention of postdenervation pain syndrome. brain res, in press. . al-adawi s, dawe gs, al-hussaini a. aboulia: neurobehavioral dysfunction of dopaminergic system? med hypotheses , , –. . lee jm, zipfel gj, choi dw. e changing landscape of ischaemic brain injury mechanisms. nature ,  (suppl. s), a–a. . biernaskie j, corbett d. enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth aer focal ischemic injury. neurosci , , –. . karli dc, burke dt, kim hj, calvanio r, fitzpatrick m, temple d, et al. effects of dopaminergic combination therapy for frontal lobe dysfunction in traumatic brain injury rehabilitation. brain inj , , –. . rossetti y, rode g, pisella l, farne a, li l, boisson d, perenin mt. prism adaptation to a rightward optical deviation rehabilitates le hemispatial neglect. nature , , –. . ministry of health (). head injury conference, muscat, sultanate of oman. . bener a, elrufaie oe, alsuweidi ne. pediatric injuries in an arabian gulf country. inj prev , , –. . lithander j, al kindi h, tonjum am. loss of visual acuity due to eye injuries among  school children in the sultanate of oman. acta ophthalmol scand , , –. . kamoopuri h. diabetes, stress, obesity rising in oman. oman daily observer,  nov . . hasab aa, jaffer a, hallaj z. blood pressure patterns among the omani population. east mediterr health j , , –. . ministry of national economy. statistical year book : sultanate of oman. (th edition), muscat, information and publication centre, . . spear lp. e adolescent brain and age-related behavioural manifestations. neurosci biobehav r , , –. . odero w, garner p, zwi a. road traffic injuries in developing countries: a comprehensive review of epidemiological studies. trop med int health , , –. . petridou e, moustaki m. human factors in the causation of road traffic crashes. eur j epidemiol , , –.             the use of medicines in oman public knowledge, attitudes and practices ahmed abdo-rabbo, manal al-ansari, *brian c gunn, batool j suleiman clinical & basic research squ med j, august 2009, vol. 9, iss. 2, pp. 124-131, epub 30th june 2009 submitted 7th jan 2009 revision req. 22nd mar 09, revision recd. 22nd april 09 accepted 6th may 09 directorate of rational use of medicines, ministry of health, muscat, sultanate of oman *to whom correspondence should be addressed. email: gunnbc@gmail.com advances in knowledge 1. this is the first study in oman to assess the knowledge, attitudes and current practices of patients towards medicine seeking and using behaviour. 2. the results of this study will help to provide a strong platform for future regional and national interventions to improve the use of medicines and to reduce wastage. application to patient care 1. omani patients need to be given more information about their medication by their health providers. 2. omani patients need to be encouraged to ask health workers more questions about their medication. 3. a public education campaign on the rational use of medicines (rum) should be conducted at the national level 4. the knowledge obtained from this survey will serve as a base for preparing local public educational materials and help in promoting public education in the appropriate use of medicines in oman. استعمال األدوية يف عمان معرفة ومواقف وممارسات اجملتمع أحمد عبدربه، منال االنصاري، براين جن، بتول جعفر هذه أجريت استعمالها. الطريقة: وترشيد حتسني أجل من وذلك عمان في الشائعة األدوية استعمال مشاكل على التعرف الهدف: امللخص: الدراسة االرتيادية املقطعية باستخدام استبيان مكتوب مت تعبئته من قبل 6675 مريضا عمانيا خالل ترددهم على املراكز الصحية األولية. النتائج: 66 % من املراجعني زاروا أكثر من مركز صحي في نفس الوقت لنفس املرض، و51 % ال يعودون إلى نفس املرفق الصحي للمتابعة. كما أن 39 % ال يقبلون العالج بدون أدوية وأن 30 % من املراجعني يفضلون ثالثة أدوية أو أكثر عند كل زيارة. كثير من املرضى ال يسألون الطبيب عن كيفية اخذ العالج وتوقيته وال عن مكان تخزينه في املنزل ، كما انهم ال يذكرون أسماء األدوية التي يستخدمونها. 70 % من املراجعني يتوقفون عن استعمال أدويتهم عند اختفاء األعراض. تبني أن 62 % من املراجعني ليست لديهم معرفة بأن لألدوية تأثيرات جانبية وأن 61 % ال يعرفون أن احلقن أكثر خطورة من حيث اجلرعة. 54 % منهم يفضلون لون وطعم محدد للدواء بينما يقوم 43 % منهم باملداواة الذاتية و68 % ال يستشيروا الصيدلي. يختار 36 % من املراجعني األدوية التي جربوها و33 % يتبادلون األدوية فيما بينهم . يخزن 55 % من املرضى كافة األدوية في الثالجة و17 % منهم ال يتأكدون من تاريخ نفاد صالحية الدواء. 45 % يرموا األدوية غير املستعملة و41 % يحتفظوا بها للمستقبل و16 % يعيدوها للصيدلية أو املركز الصحي. في املعرفة لدى الناس حول االستخدام الرشيد واألمثل للدواء. بعض املواقف واملعتقدات ميكن أن تؤدي إلى أخطار نقصا هناك أن اخلالصة: تبني صحية وهدر مالي غير مبرر. الكثير من هذه النتائج ميكن حتسينها بواسطة حملة توعوية صحية جماهيرية ذات أهداف محددة. مفتاح الكلمات: بالغ ، معرفة ومواقف وممارسات صحية ، استبيان ، مستحضرات صيدالنية ، ُعمان abstract: objectives: the objective of this study was to identify the common problems of medicine use in oman in order to improve the appropriate use of medicines. methods: a cross-sectional, pilot-tested questionnaire was administered to 6,675 omani patients or their carers on exit from primary health care centres. results: 66% of respondents visited multiple facilities on the same date for the same complaint and 51% failed to go for follow up to the same facility. 39% did not accept non-drug therapy and 30% preferred prescription of 3 or more medicines per visit. many failed to ask how or when to take the medicines, where to store them at home and did not mention any current therapies they were taking. a total of 70% stopped taking their medicines when symptoms disappeared; 26% were unaware that most medicines have side-effects and 61% did not realise that injections are the riskiest dosage form. a total of 54% had definite colour and taste preferences; 43% practised self-medication and 68% never consulted the dispenser; 36% chose medicines based on previous experience and 33% exchanged medicines with others; 55% stored all their medicines in a fridge and 17% did not check the expiry date; 45% threw unused medicines away; 41% kept them for future use and only 12% returned them to a pharmacy or health facility. conclusions: there is a widespread lack of knowledge about the appropriate use of medicines in oman. certain attitudes and beliefs can contribute to health risks and unnecessary expenditure. many of these results could be improved by a well-targeted public education campaign. keywords: adult; health knowledge, attitudes and practice; questionnaires; pharmaceutical preparations; oman. ahmed abdo-rabbo, manal al-ansari, brian c gunn and batool j suleiman clinical and basic research | 125 in the year 2000, oman was the first country in the world to establish a national body dedicated to the rational use of medicines (rum). the oman national drug policy (ondp), also formulated in 2000, contains guidelines for the rational use of medicines by both health care providers and the public.1,2 while rum by health providers has received high priority, investigations of medicine use in the community and public education have received very little attention and have often not been allocated the necessary human and financial resources. although health care providers play an important role in the use of medicines, patients are equally important. public knowledge, attitudes and perceptions (kap) regarding the use of medicines influences the decision to seek health care, the choice of care provider, the use of medicines and, ultimately, the success of treatment. as defined by the who, rum means that patients receive medications appropriate to their clinical needs, in doses that meet their individual requirements, for an adequate period of time, and at the lowest cost to them and their community.3 in oman, health care and medicines are free at source in all ministry of health facilities for omanis and for expatriates working for the government. everyone pays a nominal fee of one omani rial (or) to register at a facility of their choice annually, plus there is a token fee of 200 baizas per visit (1 or = 1,000 baizas = $2.60). very few studies have documented kap on medicine use problems in the community in oman and other gulf countries;4,5 therefore, research studies into medicine use in the community should be conducted as a priority and used in the development and implementation of community-based regional and national interventions to improve the appropriate use of medicines by the population. the world health organisation (who) produced a guide on how to investigate the use of medicines by consumers.6 this guide is intended to provide researchers, administrators of health programmes and health workers with simple research methods to identify problems in the provision and use of drugs at the community level of health care. the aim of this study was to assess the knowledge, attitude and practice of patients about medication use in order to identify the common problems in the community. the results should provide the focus for an effective public education campaign to improve medicine use and increase public awareness about certain irrational practices. methodology a baseline survey was conducted in the 10 health regions of oman during the year 2006-2007. a written questionnaire in arabic was designed, field tested, revised and finalised (see table 1 for english translation). the pilot study tested the questionnaire for reliability, comprehension, question design and length. the questionnaire, composed entirely of closed questions, covered the following aspects: a) characteristics of the respondents; b) patient visits to health facilities and drug therapy; c) patient-health care provider communication; d) patient adherence and perception; e) self-medication; f ) storage, expiry date and disposal of unused medicines. respondents from each of the selected 75 public primary health care facilities from 10 different health regions, including urban and rural areas, were selected by random sampling and interviewed (approximately 100 per facility). the total number of collected questionnaires was 6,675, representing an estimated 26% of the daily visits to those public (government) primary health care facilities. the respondents included the patients who visited the studied health facilities or their carers who accompanied them in the case of the elderly or disabled patients. the study method was essentially a structured interview using the described questionnaire. respondents were interviewed as they left the out-patient clinics, i.e. at the patient exit and they were allowed to ask for clarification. the answers obtained were filled immediately into the questionnaire forms by the research assistants who were mainly health educators, assistant pharmacists and nurses. all researchers were pre-trained, involved in the pilot test and given written guidelines to conduct the survey properly. field supervisors and data collectors from the 10 health regions received training in order to standardise the procedures, ensure proper handling of the questionnaire and understanding of its contents. any weaknesses found were addressed before the full study started. the data were processed and analysed, by use of the statistical package for social sciences (spss version 10, spss inc.), for each health region and for the country as a whole. the mean percentage results, representing the use of medicines in oman public knowledge, attitudes and practices 126 | squ medical journal, august 2009, volume 9, issue 2 the whole country, were used in analysing the data. the ministry of health and the health services in all health regions were informed before the study began. all respondents were assured of anonymity and informed that only aggregate data would be reported and that they were free to refuse to participate at any time. results the majority of the respondents were female (63%), young adults from 15 to 30 years old (59%) and either uneducated or with only general education (12 years of instruction) (78%). table 2 shows the results of the survey. a high percent of the respondents (66%) mentioned that they visited more than one health facility on the same day for the treatment of the same ailment. about half (51%) said they did not return for follow-up to the same health facility if they did not feel better within the time they expected. more than one third (39%) stated they would not accept it if only advice and assurance were given and if no medicines were prescribed for them. about one third (30%) reported that they preferred to have three or more drugs prescribed per consultation. almost a quarter of respondents (26%) said they did not inform the prescriber or the dispenser about the medicines they were already using, including any traditional medicines. a few respondents said that they did not ask the prescriber or the dispenser to explain about the prescribed medicines, particularly how (18%) and when (12%) to take the medicines i.e. before or after food. just under half (43%) of those surveyed reported that they did not ask and were not told how to store their medicines properly at home. more than one third (34%) reported that they did not ask the prescriber or dispenser about any possible side effects of the prescribed and dispensed medicines. more than two thirds (70%) of the respondents said they discontinued their treatment course when they felt that the symptoms disappeared or if they felt better. almost one quarter (26%) of those surveyed reported that they did not know that all medicines have side effects which could influence their compliance. about two-thirds (61%) reported that they did not know that injections are the riskiest dosage form and 14% said they preferred to take their medicines in injectable form. more than half (54%) of those surveyed reported that their acceptance was influenced by the colour and/or taste of the medicine. just under half of respondents (43%) mentioned that they practised self-medication, while approximately one third (32%) of them consulted and sought help from dispensers in choosing the appropriate treatment. more than one third (36%) said they chose their medicines on the basis of previous experience, i.e. a trial and error process. one third (33%) admitted to sharing or exchanging medicines with others. more than half (55%) of the respondents said they stored all medicines at home in a fridge and about one fifth (17%) admitted to using medicines without checking their expiry dates. almost half (45%) said they discarded prescribed medicines after use in the waste bin. about two-fifths (41%) kept any left-over medicines for future use by themselves or others, but a small number (12%) reported that they return the unused medicines to a pharmacy or health facility. discussion pat i e n t s’ v i s i t s t o h e a lt h fa c i l i t i e s a n d d r u g t h e r a p y although omani patients have the right to seek treatment anywhere they choose, they are not encouraged to visit more than one governmental health facility for the treatment of the same illness on the same day. they should preferably return to the same health facility if there is no improvement in their symptoms within a time agreed with the doctor. if follow-up is necessary, they should avoid going to another facility or switching doctors or going to traditional healers or taking self-medication for the same condition. an exception, perhaps, would be if a patient felt strongly about the need for a second opinion for an intractable condition. patients should not believe in ‘a pill for every ill’ and should accept non-medicine therapy when only advice and assurance are decided on by the provider and not insist on polypharmacy. omani residents receive health care, including the provision of prescription medication from governmental health facilities, free of charge. one of the problems associated with the provision of free medications, in certain countries, is frequent switching by the patient from one ahmed abdo-rabbo, manal al-ansari, brian c gunn and batool j suleiman clinical and basic research | 127 facility to another or multiple visits to one facility and demanding multiple medicines. cost sharing or cost recovery and a drug revolving fund have been implemented in some developing countries to improve drug availability and the quality of care.7,8 it has been reported by prescribers that many patients in oman believe the 200 baizas (50 cents) fee collected per visit is a charge for medicines. table 1: questionnaire for survey of public knowledge, attitudes and practices towards use of medications a. personal data 1 sex: male  female  2 age: 15 30  > 30 40  > 40 -50  > 50 60  > 60  3 level of education: uneducated  general education  undergraduate  postgraduate  b. characteristics of visits and drug therapy question answer 1 have you visited more than one health facility on the same day for the same illness? yes  no  2 if you don’t get better within the time expected, where will you go for follow up? return to the same facility  go to another facility  3 do you accept if no medicines prescribed for you and only advice and assurance are provided? yes  no  4 how many drugs do you prefer to have per consultation in general? 1  2  3  >3  c. communication between patient and health provider question answers 1 do you inform the prescriber and dispenser about the drugs you are using currently? yes  no  2 do you ask the prescriber or dispenser about the side effects of the prescribed drugs? yes  no  3 do you request the prescriber or dispenser to explain how to take the prescribed drugs? yes  no  4 do you ask the prescriber or dispenser when to take the drug (before or after meals)? yes  no  5 do you ask the prescriber or dispenser where to store the prescribed drug at home? yes  no  d. patient concordance with treatment and perceptions question answers 1 do you know that all drugs have side effects? yes  no  2 do you stop taking the prescribed drug when you feel better or the symptoms disappear? yes  no  3 what is the riskiest dosage form? syrup  tablet  injection  don’t know  4 what is the route of administration you prefer? oral  injectable  5 does the colour or taste of the drug influence your acceptance? yes  no  e. self-medication question answer 1 have you practised self-medication? yes  no  2 do you exchange medicines with others? yes  no  3 how do you choose self-medication? according to: experience  advice from others  promotion  advice from dispenser  f. storage and disposal of medicines question answer 1 do you store all medicines in the fridge? if no, in which of the following places: wardrobe  medicine’s box  on a shelf  in a drawer  in a bag  another place  (mention ………………..…..) yes  no  2 do you check the expiry date before using the medicines? yes  no  3 how do you deal with left-over medicine? keep it for future use by myself or others  return it to the pharmacy  throw it  note: the answers of the respondents will be filled in by data collectors the use of medicines in oman public knowledge, attitudes and practices 128 | squ medical journal, august 2009, volume 9, issue 2 pat i e n t-h e a lt h p r o v i d e r c o m m u n i c at i o n the interaction between the patient and the health provider (prescriber and dispenser) is clearly critical to health care delivery and the proper use and understanding of medicines. training in communication skills frequently receives low priority in the medical curricula and in some health training institutions it is not covered at all. health care providers should ask appropriate questions and give patients the information they need in a language they understand and the patients should also be encouraged to communicate properly. patients should tell the prescriber about any conventional and traditional medicines they are using currently, and ask about the possible side effects and how and when to take the prescribed medicines, i.e. before or after food. finally, they should know where to store them in the home. pat i e n t a d h e r e n c e a n d p e r c e p t i o n s many patients decide by themselves whether to continue taking the prescribed medicines if the symptoms disappear. they should continue their treatment as instructed by the health provider even if they feel better or the symptoms disappear. it is presently unclear how much advice is freely given by prescribers to patients in oman. most of the patients surveyed did not know that all medicines have side effects and injections are the riskiest dosage form or that the colour or taste of a medicine is largely irrelevant to the action of the medicine. therefore, patients should ask about the side effects and not insist on having injections. they should leave the health provider to choose the appropriate dosage form and not refuse a medicine of different colour or taste than what they have taken before. when people experience side effects such as nausea, vomiting or dizziness, it is usually thought to be a worsening of the illness. there are many examples in the news and literature where patients are apparently not using medicines in the way table 2: main results of survey of public knowledge, attitudes and practices towards use of medications identified attitudes and behaviour percentage of total respondents 95% ci characteristics of visits and drug therapy visit more than one health facility on the same date 66 65.07 67.35 do not return to the same health facility for follow up 51 48.80 52.22 do not accept non-drug therapy 39 38.27 40.63 prefer 3 or more drugs per consultation 30 28.79 31.00 communication between patient & health provider do not inform the provider about the medicines they are using 26 24.60 26.71 do not ask the providers how to take their medicines 18 17.89 19.99 do not ask the providers when to take their medicines 12 11.70 13.30 do not ask the provider about the side effects of prescribed drugs 34 32.40 34.67 do not ask the providers where to store their medicines at home 43 42.15 44.54 patient concordance with treatment and perceptions discontinue treatment when they feel better or symptoms disappear 70 68.47 70.69 do not know that medicines have side effects 26 25.30 27.43 do not know that injections are the riskiest dosage form 61 59.43 61.79 prefer to take their medicines by injection 14 12.96 14.63 influenced by the colour or taste of the medicine 54 52.77 55.18 self medication practise self-medication 43 42.06 44.45 do not consult dispensers when practising self-medication 68 67.17 69.42 choose medicines according to previous experience 36 34.51 36.82 exchange medications with others 33 32.17 34.45 storage & disposal store all their medicines in a fridge 55 55.87 56.27 use the medication without checking its expiry date 17 16.27 18.09 throw out left-over medicines 45 44.33 46.73 keep any left-over medicines for future use 41 40.25 42.63 return left-over medicines to pharmacy 12 11.20 12.77 ahmed abdo-rabbo, manal al-ansari, brian c gunn and batool j suleiman clinical and basic research | 129 intended by the health providers based on the amount and nature of unused medicine gathered. some studies have shown low levels of adherence to medical regimens.9 research in the gulf region suggests that as many as 50% of patients are non-adherent with the dosing regimens of their prescription.4 in a household survey conducted in gezira state, sudan, 71% of all households reported poor compliance.10 p r a c t i s i n g s e l f-m e d i c at i o n self-medication can be a problem in many countries. in certain countries, over 80% of all medicines are purchased by individuals for themselves or for a family member without a prescription. in a pilot study with small sample size interviewed at a local health centre, 65% of the respondents used nonprescription drugs, while a community study in thailand described the overuse of analgesics in rural communities.11,12 in a household survey conducted in saudi arabia and other gulf countries, 43.5% of all households purchased drug products based on the advice of friends and relatives.4 in another recent study conducted in eastern province of saudi arabia, self-medication was widespread among female school students.13 in sudan, a survey of households from khartoum state showed that 81.8% of the study population had used medicines, including herbal remedies, without a medical consultation within 2 months prior to the study period.14 another household survey, conducted in gezira state, found that all respondents had at least one pharmaceutical product stored at home, with around a half of all households reporting self-medication, re-use of stored medicines and exchange of drugs between family members.10 patients should avoid practising self-diagnosis and self-medication. however, if they do, they should at least consult with the dispenser/ pharmacist to ensure effective and safe treatment. patients should not rely upon their past experience and advice of friends and relatives in dealing with health problems and they should never exchange medicines with others. s t o r a g e, e x p i r y d at e a n d d i s p o s a l o f m e d i c at i o n s in our study, as well as in a pilot study conducted in one health facility, more than half of the respondents stored all of their medicines in a fridge.11 the perception that all medicines should be stored in a fridge is wrong, but is enforced by the very hot and humid climate of oman. the appropriate place for storing most of the medicines at home is in a medicine box, on a high shelf or hung high in a room or in a locked cabinet. many homes now have air conditioning which keeps the indoor climate at a reasonable temperature and humidity. medicines should always be kept out of the reach of children. it is very important to check the expiry date when receiving and before using any medicine. a total of 37% of saudi patients interviewed indicated that they never checked the expiry date of a medication prior to consumption.4 in two surveys of uk households, 51% of medicines in the households were not in current use and of these, 40% were expired. 15,16 medication wastage is defined as any drug product either dispensed by a prescription or purchased over-the-counter that is never fully consumed. it is an important factor that contributes to escalating health care costs.17,18 in another study conducted at primary health care facilities in oman, one third of medicines prescribed were refused or rejected. the main reason for rejection (57%) was that patients had a stock of the same or similar drugs at home.19 many patients do not know what to do with any medicine that remains unused. the availability of unused medicines in the home may constitute a source of material for irrational use and intentional or accidental poisoning. in the majority of cases, any unused medicine should not be kept for future use. it is very important to consult a dispenser on how to deal with these medicines as there is no regulation at present in oman regarding the disposal of medicines by patients and public. in a recent study conducted in kuwait, almost all respondents (95.7%) reported that they had medicines in the home which they wished to dispose of.20 the most common method of disposal of unwanted medicines reported in the same study was to discard them in the waste bin (87.7%), a figure which is almost double that of this current study (45%). only 11.9% of the respondents returned them to a pharmacy which is similar to the result found in this study. the impact of inappropriate medicine disposal by patients is a serious environmental issue.21 therefore guidelines on safe disposal of unwanted medicines are required and an organised method of collecting unused medication needs to be introduced. the use of medicines in oman public knowledge, attitudes and practices 130 | squ medical journal, august 2009, volume 9, issue 2 l i m i tat i o n s for reasons of convenience, this study was conducted at health facilities only, so there is a chance that the clinical setting influenced some interviewees. a household survey is currently underway which may address this issue. the questionnaire, which was designed by the authors, was not psychometrically evaluated and no reliability index is currently available. conclusion the patient’s own practices in using medicines are an important part of the quality use of medicines, as well as the prescribing habits and patient care practices by health workers. unfortunately, health policy makers generally focus more on the provision and regulation of medicines and on efforts to improve health workers’ prescribing skills, rather than on efforts to ensure rational use of medicines by consumers.22 public education on the appropriate use of medicines is of crucial importance; therefore, well focussed campaigns could definitely bring about positive changes. these campaigns should include patient instruction at the time of illness in the appropriate use of medicines and instruction of the public at large, or of specific target groups, in the principles and practical application of appropriate use of medicines and other therapies. therefore it is important to plan, develop, implement, monitor, evaluate and reassess effective public education programmes on rum. the educational activities should be focussed on those people or groups whose medicine use patterns are in most need of change, taking into account the cultural and social context in which the beliefs and practices have developed. it is important to use a multi-educational aid approach in order to reach more people in the community and the necessary resources need to be allocated for this purpose. the who has published resource materials for educating the community on the rational use of medicines.23 health care providers play a pivotal role in rum activities. they have a professional obligation to avoid the undesirable consequences of inappropriate practice and improve the quality of patient care. collaborating institutions such as the department of health education and information, nongovernmental organisations (ngos), professional associations, religious groups, development agencies such as the world health organization (who), united nations children’s fund (unicef), health action international (hai) and others have important roles to play. they can enhance the visibility of any public education campaign, potentially increase its impact and promote rational medicine use concepts. it is very important that public education should be accompanied by supportive legislation and regulation on promoting rum in the community along with appropriate enforcement. the directorate of rational use of medicines in the oman ministry of health has a major campaign planned for promoting rational use of medicines by the community. the campaign started in april 2009 with a nationwide household survey. the results of the current study suggest a certain lack of knowledge and information about the proper use of medicines by the public as well as highlighting some unsound medicine use behaviour and inappropriate practices. attitudes and beliefs have been revealed which contribute to increasing health risks, and potentially needless expenditure. this evidence makes the need to promote rum in the community more compelling. acknowledgements we would like to express our high appreciation and deep gratitude to the directors general, directors and supervisors of pharmacy and medical supply, data collectors and respondents from all the ten health regions of oman for their cooperation and contribution towards the success of this work which was carried out in 2006-2007 and to the mininstry of health, oman for funding their study. without them this study would not have been possible. conflict of interest the authors report no conflit of interest. references 1. ministry of health, oman. oman national drug policy. sultanate of oman, ministry of health, the directorate general of pharmaceutical affairs and drug control, 2000. 2. who/dap (world health organization/action programme on essential drugs). how to develop and implement a national drug policy. 2nd ed. geneva: who/dap, 2001. ahmed abdo-rabbo, manal al-ansari, brian c gunn and batool j suleiman clinical and basic research | 131 3. who/dap (world health organization/action programme on essential drugs). rational drug use: education and information. who/dap/mac 8/96.6. geneva: who/dap, 1996. 4. abou-auda hs. an economic assessment of the extent of medication use and wastage among families in saudi arabia and arabian gulf countries. clin ther 2003; 25:1276-92. 5. ali sa. an analysis of communication and promotional strategies for patients and staff education regarding rational use of medicinal drugs in health care facilities belonging to muscat health region, muscat, oman. mba thesis. university of lincolnshire & humberside, uk, 1999. 6. chetley a, hardon a, hodgkin c, haaland a, fresle d. how to investigate the use of medicines by consumers. (who/psm/par/2007.2). geneva: world health organisation, 2007. 7. newbrander w, quick jd, waddington c. drug financing strategies. in: quick jd et al., eds. managing drug supply. 2nd ed. west hartford: kumarian press, 1997. 8. uzochukwu bsc, onwujekwe oe, akpala co. effect of the bamako-initiative drug revolving fund on availability and rational use of essential drugs in primary health care facilities in south-east nigeria. health policy plan 2002; 17:378-83. 9. homedes n, ugalde a. patient’s compliance with medical treatments in the third world. what do we know? health policy plan 1993; 7:291-314. 10. yousif ma. in-home drug storage and utilization habits: a sudanese study. east mediterr health j 2002; 8:422-31. 11. al-araimi ms. kap survey on the community concepts of drug use at a local health centre in south sharqiyah region, sultanate of oman. pharmaco logical (newsletter of directorate of rational use of medicines, moh, oman) 2005; 1:10. 12. sringernyuang l. availability and use of medicines in rural thailand. academisch proefschrift, university of amsterdam, netherlands, 2000. 13. abahussain ea, taha az. knowledge and attitudes of female school students on medications in eastern saudia arabia. saudi med j 2007; 28:1723-7. 14. awad ai, eltayeb ib, capps p. self-medication practices in khartoum state, sudan. eur j clin pharmacol. 2006; 62:317-24. 15. all-party pharmacy group. concordance and wasted medicines. london: royal pharmaceutical society of great britain, 2002. 16. skinner rf, shave jhl, harris jm. a survey of medicines in patients’ homes. presentations at british pharmaceutical conference, coventry, uk, 10-13 september 1998. 17. al-siyabi k, al-riyami k. value and types of medicines-returned by patients to sultan qaboos university hospital pharmacy, oman. squ med j 2007; 7:109-16. 18. boivin m. the cost of medication waste. can pharm j 1997; 130:32-9. 19. gunn bc, wysse a-r, suleiman bj. rejection of prescription medicines at out-patient departments. pharmaco logical (newsletter of directorate of rational use of medicines, moh, oman) 2005; 1:4-5. 20. abahussain ea, ball ed, matowe cw. practice and opinion towards disposal of unused medication in kuwait. med princ pract 2006; 15:352-7. 21. kolpin dw, furlong et, mayer mt, thurman em, zaugg sd, barber lb et al. pharmaceutical, hormones, and other organic wastewater contaminants in u.s. streams, 1999-2000: a national reconnaissance. environ sci technol 2002; 36:1202121. 22. chetley a, hardon a, hodgkin c, haaland a, fresle d. how to improve the use of medicines by consumers. (who/psm/par/2007.2). geneva: world health organisation, 2007. 23. fresle d. rational drug use: consumer education and information. (dap/mac/(8)96.6). geneva: world health organisation, 1996. 1department of urology, university of miami hospital, miami, florida, usa; 2department of pediatric urology, nicklaus children's hospital, miami, florida, usa *corresponding author’s e-mail: rubenblachman@gmail.com aphallia associated with anorectal malformation *ruben blachman-braun,1 cinthia galvez,2 christian guevara,2 raquel quintanilla,2 alireza alam2 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 428–429, epub. 25 aug 22 submitted 22 jun 21 revision req. 8 aug 21; revision recd. 19 aug 21 accepted 8 sep 21 a 3-year-old hispanic male infant was admitted to the paediatric urology department at a children’s hospital in florida, usa, with a febrile urinary tract infection and constipation. the patient’s perinatal history included c-section delivery due to premature membrane rupture (g1, p1) at the gestational age of 36 weeks. the patient was born in nicaragua with anorectal malformation and without fistula, aphallia and a perineal urethra. the infant underwent colostomy during the neonatal period followed by posterior-sagittal anorectoplasty, perineal urethral closure and suprapubic catheter (spc) placement. six months following colostomy closure at two years of age, the patient arrived at the current institution in the usa. on physical examination, an spc to gravity in the suprapubic region and normally descended testicles along with an absence of phallus were observed. the neo-anus was well-located and there were no abnormalities in the sacral region. there were also no deformities in the extremities [figure 1]. the renal and bladder ultrasound showed malrotated kidneys and magnetic resonance imaging showed no visualisation of the corpora cavernosa or corpus spongiosum, normal sacrum and spinal cord [figure 2]. following multidisciplinary evaluation and shared decision-making with the patient and the family, the current team will consider performing a neophalloplasty in the future. informed consent was obtained from the patient’s mother for the publication of the case and the associated images. comment aphallia is an extremely rare sporadic genitourinary malformation with less than 100 cases reported worldwide.1–3 it is defined as an absent phallus with complete absence of the two corpora cavernosa and the corpus spongiosum. in addition, it is usually associated with an ectopic and short urethral opening to the rectum or anus and a well-formed scrotum with both testes descended. aphallia may also occur in female patients since it is the absence of corporal tissue that is considered the defining factor of the aphallia, although this is less common and more difficult to diagnose.4 during the fourth week of gestation, a mesenchymal prominence within the cloacal membrane proliferates to form the genital tubercle, which then develops into a penis or clitoris. it is hypothesised that aphallia results from the developmental failure or absence of the genital tubercle. animal models suggest that abnormalities in the sonic hedgehog (shh) gene— critical in normal bladder and bowel development— this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.139 interesting medical image figure 1: frontal clinical image of the lower abdomen showing total absence of penis and normal scrotum with both descended testicles. a suprapubic tube with a 10 fr foley catheter draining urine and old surgical scars on the left hemiabdomen can also be observed. https://creativecommons.org/licenses/by-nd/4.0/ ruben blachman-braun, cinthia galvez, christian guevara, raquel quintanilla and alireza alam interesting medical image | 429 may be linked to aphallia.4 shh knockout mice demonstrate genital tubercle agenesis, most likely through impaired signalling of the fibroblast growth factor. these models also suggest that impaired retinoic acid signalling within the shh molecular pathway may also be the cause of genital tubercle agenesis via inhibited vasculogenesis.4 furthermore, abnormalities in the shh pathway are also critical in the explanation of the high incidence of concomitant anorectal malformations seen in aphallia. it is possible that polymorphism located in 9qh+ might be part of the underlying aetiology as well.4,5 in over 50% of patients, aphallia presents as a symptom of a broader spectrum of congenital malformations; renal, urinary tract and anorectal malformations are frequently associated with each other. however, aphallia may also present as an isolated disorder, such as in cases where the genitourinary system has a normal configuration.2 most children with this disorder of sex development have 46,xy karyotype; however, it may also be seen in patients with congenital adrenal hyperplasia and 46,xx karyotype. the differential diagnoses include concealed penis, intra-uterine amputation of the penis or 46,xy disorders of sex differentiation. aphallia may be classified in numerous ways: using skoog’s anatomical classification, based on the position of the ectopic urethra in relation to the anus and the number of associated anomalies.2 using skoog’s anatomical classification, aphallia may be subclassified as pre-sphincteric, post-sphincteric or urethral atresia, with this last being the least common (12% of cases) and uniformly fatal. evans’ prognostic classification, solely based on the presence or absence of major associated anomalies, may be used as well.2 the management approaches are divided into short, intermediate and long-term treatment phases. while short-term treatment involves dealing with any life-threatening complications and associations of aphallia that may present in the neonatal period, intermediate-term treatment typically consists of division of the urethrorectal fistula with perineal urethrostomy. finally, long-term treatment commits to the creation of a neophallus that will allow the patient to appear outwardly male and be able to void while standing up.2 in conclusion, aphallia is an extremely rare sporadic genitourinary malformation. it is characterised by the absence of the two corpora cavernosa and the corpus spongiosum, usually the scrotum is well-formed, the urethra is ectopic, short and frequently opens in the rectum or anus. it is hypothesised that aphallia results from the absence or developmental failure of the genital tubercle and the exact aetiology still need to be elucidated. a multidisciplinary evaluation and shared decision-making with the patient and the family are needed to provide optimal outcomes. a u t h o r s’ c o n t r i b u t i o n aa and rb-b conceptualised and designed the work. rb-b, cig, chg, rq and aa were involved in data acquisition, analysis and interpretation. all authors contributed equally to drafting the manuscript and approved the final version of this manuscript. references 1. talebpour amiri f, nasiry zarrin ghabaee d, naeimi ra, seyedi sj, mousavi sa. aphallia: report of three cases and literature review. int j reprod biomed 2016; 14:279–84. https:// doi.org/10.29252/ijrm.14.4.279. 2. gabler t, charlton r, loveland j, mapunda e. aphallia: a review to standardize management. pediatr surg int 2018; 34:813–21. https://doi.org/10.1007/s00383-018-4271-z. 3. oliveira de, da cruz ml, liguori r, garrone g, leslie b, ottoni sl, et al. neophalloplasty in boys with aphallia: a systematic review. j pediatr urol 2016; 12:19–24. https://doi.org/10.1016/j. jpurol.2015.10.003. 4. friedman aa, zelkovic pf, reda ef, franco i, palmer ls. male and female aphallia associated with severe urinary tract dysplasia. j pediatr urol 2016; 12:268.e1–7. https://doi. org/10.1016/j.jpurol.2016.04.040. 5. qiang s, li fy, zhou y, yuan y, li q. congenital absence of the penis (aphallia): a rare case report. medicine (baltimore) 2019; 98:e15129. https://doi.org/10.1097/md.0000000000015129. figure 2: a: magnetic resonance imaging (mri) scan in a sagittal view of the lower abdomen and pelvis showing an under distended bladder, a suprapubic catheter and no cavernosa bodies, corpus spongiosum or urethra. the sacrum and spinal cord show no abnormalities. b: mri scan in an axial view showing no cavernosa bodies, corpus spongiosum or urethra. https://doi.org/10.29252/ijrm.14.4.279 https://doi.org/10.29252/ijrm.14.4.279 https://doi.org/10.1007/s00383-018-4271-z https://doi.org/10.1016/j.jpurol.2015.10.003 https://doi.org/10.1016/j.jpurol.2015.10.003 https://doi.org/10.1016/j.jpurol.2016.04.040 https://doi.org/10.1016/j.jpurol.2016.04.040 https://doi.org/10.1097/md.0000000000015129 التجربة احلية لضحااي آتكل الكارثي للساحل دائرة التأثري والنتائج والتعايف رينجوالل يسودهاران، تيسي تريسا خوسيه، إران جوديث روتش abstract: objectives: environmental hazards are part of the earth’s natural cycle and are ongoing within human history. when vulnerable situations meet environmental hazards, disasters occur where human and natural costs could be enormous. this study aimed to explore the experiences of the victims of coastal erosion during the monsoon season. methods: seven victims of catastrophic coastal erosion in the kollam district of kerala, india, were interviewed from december 2013 to february 2014. the study followed edmond husserl’s descriptive phenomenological method. result: these interviews constituted the primary data source. three main themes with eleven subthemes emerged from these data. the main themes were impact, consequences and recovery. the subthemes were living in constant fear, escaping from the catastrophe; cataclysmic sea waves and their tumultuous behaviour, instant damage and destruction, the epoch of losses; agony and suffering; homelessness-helplessness-sleeplessness mixed with fear; government aid only in dreams; haunting memories; never-ending daily needs; first home and native land; and the desire to go back to the site of the disaster. conclusion: from the derived themes, a phenomenon associated with coastal erosion evolved. the phenomenon is termed “catastrophic coastal erosion: a cycle of impact, consequences, and recovery.” keywords: disaster victims; ecological and environmental phenomena; natural disasters; oceans and seas; quality of life; qualitative research; tsunamis; india. اله�شة الظروف تواجه عندما الب�رشية. تاريخ يف وم�شتمرة للأر�ض الطبيعية الدورة من جزًءا البيئية املخاطر تعترب الهدف: امللخ�ص: خماطر بيئية، حتدث الكوارث التي من املمكن اأن توؤدي اإىل تكاليف ب�رشية وطبيعية �شخمة. يهدف هذا البحث اإىل درا�شة جتربة �شحايا االجنراف ال�شاحلي خلل مو�شم الرياح املو�شمية. الطريقة: متت مقابلة �شبعة من �شحايا التاآكل ال�شاحلي الكارثي يف منطقة كوالم بوالية �شكلت النتائج: الظاهرية. الو�شفية هو�رشل اإدموند طريقة الدرا�شة اتبعت .2014 فرباير اإىل 2013 دي�شمرب من الفرتة يف بالهند كرياال املقابلت امل�شدر الرئي�شي للبيانات. نتج عن هذه الدرا�شة ثلثة موا�شيع رئي�شية و اأحد ع�رش م�شاألة فرعًية. كانت املو�شوعات الرئي�شية هي التاأثري والعواقب والتعايف. واملوا�شيع الفرعية متحورت حول العي�ض يف خوف م�شتمر ،الهروب من الكارثة، موجات البحر الكارثية وا�شطرابها، الدمار واالأ�رشار الفورية، حقبة اخل�شائر ، االأمل واملعاناة، الت�رشد، العجز، االأرق املمزوج باخلوف، امل�شاعدة احلكومية الغري الكارثة. موقع اإىل العودة يف والرغبة االأ�شلية؛ واالأر�ض االأول املنزل تنتهي؛ ال التي اليومية واالحتياجات املوؤملة الذكريات متحققة؛ اخلال�صة: من املو�شوعات امل�شتقة، ن�شاأت ظاهرة مرتبطة بتاآكل ال�شواحل. ت�شمى "تاآكل ال�شواحل الكارثي: دورة من التاأثريات والعواقب والتعايف". الكلمات املفتاحية: �شحايا الكوارث؛ الظواهر البيئية والبيئية؛ الكوارث الطبيعية؛ املحيطات والبحار؛ جودة احلياة؛ البحث النوعى؛ ت�شونامي. الهند. the lived experience of victims of catastrophic coastal erosion a cycle of impact, consequence and recovery renjulal yesodharan,1 tessy t. jose,1 *erna j. roach2 sultan qaboos university med j, february 2021, vol. 21, iss. 1, pp. e94–102, epub. 15 mar 21 submitted 5 jan 20 revision req. 9 mar 20; revision recd. 7 apr 20 accepted 11 jun 20 1manipal college of nursing, manipal academy of higher education, udupi, india; 2department of maternal & child health, sultan qaboos university, muscat, oman *corresponding author’s email: erna@squ.edu.om this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.01.013 clinical & basic research advances in knowledge the study helps understand the nature and dynamics of catastrophic coastal erosion and the problems encountered. the study’s findings enhance understanding of how disaster management practices emerge. critical analysis of the study might improve the implementation of disaster management strategies. this study can serve as a resource for researchers who are interested in exploring and describing this social phenomenon. the new dimensions and insights provided by this study could contribute to an in-depth study of coastal erosion. application to patient care this study helps create awareness and the early recognition of psychological trauma and the subsequent need for counselling services to address mental distress in victims of catastrophic coastal erosion. there is a need to integrate disaster management into primary healthcare and inculcate a minimum requirement of disaster management competencies and skills in healthcare professionals. such skills would help them deal with vulnerable populations during the cycle of impact, consequences and recovery that result from catastrophic coastal erosion. https://creativecommons.org/licenses/by-nd/4.0/ renjulal yesodharan, tessy t. jose and erna j. roach clinical and basic research | e95 coastlines are famous for their natural beauty and abundance of recreational opportunities. half of the world’s population is settled along shorelines and the number of people living along the coast is likely to rise in the coming decades.1 in addition to inhabited settlements, coastlines also include trade establishments, agriculture and industry. communities that reside along coastlines are exposed to specific coastal hazards such as coastal erosion, tsunamis, coastal flooding, hurricanes and the spread of infectious diseases.2 coastal erosion mainly occurs due to massive storms, strong wave action, rising sea levels and flooding. human activities, including inappropriate and indiscriminate use of land, landscape alterations and the use of shore protection structures, are major triggers of erosion.3–5 additionally, the sea level rise and shifts in global climate have been found to increase global coastal erosion, resulting in the loss of valuable coastal land.6,7 india has a coastline of about 7,500 km of which 23–26% is eroding, with an average sea-level rise of 1.30 mm/year.8–10 a 590-km stretch of the state of kerala lies along india’s southwest coast; 218 km of this coastline is eroding.11 this stretch of kerala has 221 marine and 113 inland fishing villages with an average population density of approximately 2,000 people/km2, making it highly vulnerable to coastal erosion.12 erosion destabilises and regularly destroys houses, businesses and community infrastructure, leading to long-standing economic and social consequences.13 the vulnerability of beaches to erosion-associated catastrophe is higher in the monsoon months, and the intensity and frequency of such extreme events have increased due to climate change.14,15 an impact assessment study conducted by the national institute of oceanography showed that the 2004 tsunami devastated the low-lying coastal areas of kollam, alleppey and ernakulam, kerala, leading to a loss of life and property. due to the coast’s geographical orientation, geomorphology of the landmass and the shallow water’s bathymetry, the maximum intensity of the tsunami was observed in the kollam district.16 trauma, which is a stressor involving actual or threatened death, severe injury and loss of physical property, can be a direct result of catastrophic coastal erosion. it also threatens individuals’ physical integrity.17 the post-catastrophe symptoms of trauma include irritability, angry outbursts, recklessness, self-destructive behaviour, hypervigilance, problems with concentration, sleep disturbance, persistent exaggerated negative beliefs, diminished interest in performing activities and the inability to remember important aspects of the traumatic event. the victims of a catastrophe also can display intrusion symptoms, namely recurrent and involuntary distress memories of the event, recurrent distressing dreams and flashbacks.18,19 research on victims’ suffering after a major catastrophe is scarce. this research explores lived experiences after catastrophic coastal erosions during the monsoon season in india. methods a descriptive phenomenological approach was chosen to guide this study due to its support of exploring lived experiences through an in-depth examination of people’s realities.20,21 this study aimed to gather insights from those affected by catastrophic coastal erosion by detailing their lived experiences. through an in-depth analysis of the data collected in this study, researchers can better understand the experiences of suffering in the aftermath of catastrophic coastal erosion events. the researchers conducted in-depth interviews with seven families’ elders who were affected by coastal erosion in the areas of chavara and panmana grama panchayat in kollam, india from december 2013 to february 2014. the five female and two male leaders of the families spoke at length about their experiences during catastrophic erosion events. through the phenomenological inquiry method, knowledge of people’s values, humanistic under standing and unique experiences is accessible through dialogue.20 bracketed interviews were used to mitigate the effects of personal ideas and assumptions regarding the effects of coastal erosion and separate the researchers from the participants’ descriptions. in phase one of the study, 100 heads of families in the affected area were surveyed using the quality of life rating scale (qolrs), which the primary author developed to identify information-rich cases for phase two. the purpose of phase one was to validate the developed scale for the second phase. qolrs is a 33item three-point self-administered rating scale, which measures domains such as life satisfaction, material well-being, health, productivity, safety, family and social relation, support system and emotional wellbeing of the families residing in the coastal area. the this study can advise dialogue between decision-makers and vulnerable populations. the findings indicate a need for early crisis management and disaster mental health in the catastrophe-affected areas on a long-term basis. the lived experience of victims of catastrophic coastal erosion a cycle of impact, consequence and recovery e96 | squ medical journal, february 2021, volume 21, issue 1 minimum and maximum possible scores were 33 and 99, respectively. the final content validity index of the qolrs was 1 and the reliability coefficient was calculated by computing the cronbach’s alpha, which yielded 0.892. participants were considered for inclusion in the study if they could speak and understand malayalam, the official language of kerala, india. the qolrs was given to the participants for self-rating. for those who could not read or comprehend, the items were read aloud and explanations were provided on how to score each item. after administration, the scores were arranged in ascending order and the heads of the family who obtained scores between 33–66 on the qolrs were determined to reflect a poor qol. in total, 48% of these respondents were recruited into the sample pool for phase two. a purposive sampling technique with set criteria helped to choose information-rich participants for phase two.22 in phase two, seven interviews were conducted with five female and two male heads of families. a priori sample size calculation was not used for phase two, as the study’s design was emergent. data saturation was noticed during the interview of the seventh participant; hence, the researchers stopped further data collection. all interviews were done in the participants’ residence and the verbatims of the participants were recorded using a sony-ic recorder (sony, tokyo, japan), a portable digital recording and playing device. the interviews were conducted with the help of a semistructured interview guide, which was developed by the researchers for the purpose of this study; the interview lasted for an average of one hour. the data were analysed using colaizzi’s pheno menological method of data analysis.23 based on colaizzi’s strategy, face-to-face interviews were conducted using a pre-prepared interview guide. the participants were encouraged to express and articulate their experiences and recount incidents they underwent during the catastrophic event. the researchers listened to audio data on the sony-ic recorder (sony) using headphones and transcribed them verbatim. another researcher transcribed and compared the data for possible deviations, thus establishing the validity of data transcription. the statements in malayalam were translated into english. the researchers analysed each participant’s verbatim account separately by reading the transcript thoroughly to extract the interview’s general sense and significant statements about the catastrophic coastal erosion. the extracted statements were used to formulate the meaning of the phenomenon, and the researchers used this meaning to derive the code and categories for specific participants. after analysing each participant’s data individually, the researchers looked for possible connections in the categories across the participants and derived themes to describe the phenomenon. lincoln and guba’s trustworthiness criteria were used to establish the rigour of this study; the trust worthiness criteria involve determining credibility, trans ferability, dependability and confirmability.24 the researchers conducted both of the phases of the study in the same locality, which helped maintain a rapport and mutual trust with the participants. the researchers spent more than one month in the field, observing various aspects of the research setting. they interacted with a broad range of people including political party leaders, voluntary self-help group members, nongovernmental organisation (ngo) members, local self-government authorities and community leaders. the transcripts were categorised and then coded accordingly to ensure credibility. the data scripts were reviewed by two community psychiatry and nursing experts, respectively, and the researchers met the experts in person and reached an agreement on the core categories and theme. the researchers also did a member-check formally and informally with the participants to check the categories, interpretation and conclusion with their original data. ethical approval (iec 528/2013) for the study was obtained from the institutional ethics committee of kasturba hospital of the manipal academy of higher education in india. participants were given detailed information sheets that summarised the study’s purpose and methods, the participants’ roles and responsibilities and issues related to consent, confidentiality and the right to withdraw. the forms also stated that the research centred on the experience of the victims of catastrophic coastal erosion. results the demographic characteristics in phase one of the study showed that the mean age of the participants was 54.19 ± 12.59 and only two did not have any formal education. most of the families were nuclear (90%), and 68% stayed in tiled houses, while the rest were in concrete-roofed houses. the researchers interviewed seven participants (two males and five females) in phase two of the study. all participants were from low socioeconomic strata with a monthly income of less than 2,000 rupees. among the participants, two were widows and the other five had a living spouse. all participants had primary education and did not have any formal occupation. only one male participant was working as a fisherman, and the other female participants were housewives. all the participants lived in tiled houses, making them vulnerable to the renjulal yesodharan, tessy t. jose and erna j. roach clinical and basic research | e97 effects of coastal erosion. in this study, the victims reported their experiences with catastrophe; these accounts constituted the primary data. three main themes with eleven subthemes emerged from this data and were grouped under three themes: impact, consequences and recovery. significant statements are in table 1 and the subthemes derived from the data follow: living in constant fear on the kerala coast, monsoons often bring fear to residents. even though monsoons are seasonal, memories of past events have created a feeling of constant fear. the participants mentioned that they experience fear even at night and escaping from it is an enormous task. at the time of the 2004 tsunami, participants’ houses were either thatched or tiled, making them vulnerable to rough waves. additionally, walls and doors were not built to stop water from entering houses, so flooding affected those who slept on the floor. additionally, the previous impact of tidal waves had caused ongoing fear in participants’ minds. one participant mentioned that the loud sounds of high tide waves caused tremendous fear, affecting her sleep during most monsoon nights. the fear created by the catastrophe affected them so severely that some of the participants would send their children to sleep in other houses at a greater distance from the coastline. this fear impacted participants’ lives to such an extent that the family’s seniors indicated taking turns watching the sea for rising waters. escaping from the catastrophe all the participants expressed experiencing the effects of coastal erosion over an extended time, and they took extra precautions during the monsoon season. they expressed difficulties and highlighted the additional health demands of escaping the effects of coastal erosion. rising waters often occurred suddenly, and most participants did not have enough time to defend themselves. they were also aware that the extent of damage caused by the violent waves could be severe and life-threatening. one participant said that one time the waves had entered their house, and they had to seek safe shelter. most participants expressed shock at seeing seawater come inside their houses, leaving them with no option but to abandon their homes, leave behind belongings and stay in temporary camps during the monsoon season. cataclysmic sea waves and their tumultuous behaviour although people escaped from the rising waters, the sea waves encroached beyond the immediate coast and deposited sand in the surrounding areas, including coastal inhabitants’ homes. in a few areas, the sea walls were not built to stop strong waves, which one participant mentioned had grown increasingly violent and rough in recent years. additionally, she mentioned that she had never witnessed disasters of this extent in the past. one participant mentioned that coastal erosion was rarely reported in the past and this violent, catastrophic form of erosion is a recent phenomenon along the coast of kollam. another participant said that the sea waves used to dump soil inside their houses and that sand mining is one reason for the encroachment of sand. at times, the sea became so violent that participants could hardly sleep at night. all the respondents lived near the sea since their childhood and they knew the sea and its general nature. it was only in the last few years that the sea had become violent and caused damage to livelihood. one participant recollected that once the waves rose to the height of his tiled house roof and damaged the roof and windows. the waves were seen as unpredictable and tumultuous. damage and destruction in the bat of an eye— the epoch of losses the damage and destruction caused by the sea waves was swift, sometimes destroying properties in seconds. the waves were described as taking away almost everything in their path. people indicated not having time to retrieve valuables, so they lost their houses and household articles, clothes, pets, cattle and important documents. after the initial wave-based damage, coconut trees were often uprooted due to strong currents. some people even became homeless. one participant expressed that he lost everything he had earned from fishing. the loss was so devastating that the entire family lost hope and expected death at any moment. all participants described property damage as instantaneous and causing massive losses. all of them had lost their homes and had to seek refuge and safe shelters. agony and suffering participants indicated going to safe shelters when the destructive waves struck. however, witnessing the loss of their homes and their belongings caused tremendous mental stress for the victims. they suffered great distress as they also had to carry older family members and children to safety. in one particular instance, a participant describing trying to take her ill mother to the nearest safe place, but her mother wanted to urinate on the way. this task proved difficult as they had lost their house along with its attached toilets. the situation proved similarly difficult for many female participants as they could not find private places to urinate or meet their bodily needs. the lived experience of victims of catastrophic coastal erosion a cycle of impact, consequence and recovery e98 | squ medical journal, february 2021, volume 21, issue 1 table 1: subthemes and themes derived from codes and selected participant quotes (n = 7) theme subtheme participants’ quotes impact living in constant fear participant 1: (…) the sea used to become violent many times a year. high tide used to hit our houses (…) it was a serious issue. we could not do any work at house calmly. we had a fear always. participant 3: (…) the sea came violently even inside our house. we were afraid. participant 4: (…) when i go for fishing, there will be my wife and children at home. they could not sleep as i was out in the sea. we sent our kids to some houses in the east. the rest of us would sit and watch the sea to find if the waves are coming. escaping from the catastrophe participant 1: we were running, carrying that old mother (pause). when it came suddenly, we felt that anything might happen (pause) (…), so we thought about running to somewhere. participant 7: we were running for our life. we did not have a place to go with our children. participant 3: when the waves came suddenly inside our house, we were shocked and thought, “what is this?” (pause) we lost everything (crying) (pause). we ran away from there. cataclysmic sea waves and its tumultuous behaviour participant 2: before, that is when the seawall was not built, violent sea waves used to come towards the shore frequently and destroy our houses; the waves used to hit our house. participant 3: (…) the sea came violently even inside our house. we were afraid. participant 7: (…) we were afraid to see the sea at that time. the sea will not be like this at that time. the water will rise and come towards the shore, taking away the sand. we are not new to this place. our ancestors too lived here. the sea was not violent like this earlier. participant 4: (…) the leading cause of the sea becoming violent is these two companies. these companies were taking soil. as a result, the soil on top of the land started going down. the sea waves covered our house with soil (...) at night; we were able to hear loud sounds. we could not sleep at night. participant 6: (…) suddenly, it comes inside. our plates, glasses utensils were floating on water. it happened at night. consequences damage and destruction in the bat of an eye—the epoch of losses participant 2: (…) the waves used to hit our house. we lost the windows, our roof everything in a second. participant 3: (…) the sea came violently even inside our house. we were afraid. our house was destroyed. coconut trees fell. participant 4: (…) we lost everything; we felt that there is no need for living. we were waiting for death that was about to come at any time (pause). we lost everything that we earned from the sea. can we control the sea or wind? participant 7: (…) it destroyed everything. the sea took all our belongings (silence). agony and suffering participant 1: (…) when we left our house, my mom said: “i want to go to the toilet,” (pause) the pain i felt that time (silence) (crying). it cannot be expressed through words. unless we experience such a situation, we will not understand it—the pain (crying). participant 3: (…) our mental state at that time (silence) it cannot be expressed through words. participant 4: (…) just imagine our state of mind during that period when we lost all our belongings. we felt that there is no need for living. homeless, helpless, sleepless and blended with fear participant 3: (…) we lost everything. i do not even want to recollect the experiences we had at that time. we lost everything (silence). participant 4: (…) at night we were able to hear loud sounds. we could not sleep at night. they could not sleep as i was out in the sea. when we lost our belongings and equipment, we were much worried and concerned about our future. i did not know what was going to happen. for many days we slept in our relation’s house near the bank of the river. participant 6: when we had to run from our home, we had no idea about where to go (silence). recovery governmental aid only in dreams participant 2: after one week, when the sea withdraws, we would come back. the government also would forget about us. participant 3: (…) we did not get any help from the government; we did not get even a loan from the bank. renjulal yesodharan, tessy t. jose and erna j. roach clinical and basic research | e99 some participants mentioned that the mental pain they had suffered could not be explained and one could only understand their pain if they had undergone such situations in their own lives. most of the participants described experiencing mental pain when they lost their houses or moved to a safe place. some participants suffered from physical injuries while trying to rescue others and some participants described psychological pain when what they had earned in their lives was taken away by the sea. in both cases, agony and suffering deepened when they had full cognisance of the extent of their loss. uncertainty prevailed and it was the start of their suffering. homelessness, helplessness and sleeplessness blended with fear the participants were rendered homeless and expressed feeling perplexed and helpless. most of the survivors initially went to a nearby convent or church and stayed the night. most eventually left to stay in relatives’ houses near the other side of the beach. some participants expressed confusion about whether to remain in temporary living situations or go back to their own places. the roar of the sea interfered with sleep and frightened participant. male members of the family described sitting outside temporary shelters holding vigil over the sea’s condition. most of the participants and their families had been earning a living by fishing, and they had to go back out to sea at night, all the time worrying about their family members who were in safe shelters. similarly, those in shelters were afraid for the men who went fishing in the rough seas. the participants were mainly concerned and worried about their future. some participants said that they did not want to recollect their experiences concerning homelessness and feelings of helplessness. governmental aid—only in dreams most of the participants described believing that government agencies would help them reconstruct their lost houses, and they applied for government assistance. however, the district administration evacuated the victims to safe shelters with minimal facilities and allowed them to come back to their houses only when the sea became calm. the participants eventually returned to the coast and rebuilt their houses with their own money. haunting memories the events’ memories were often disturbing and haunted the victims after years, even when they were out of danger. one participant mentioned that recollecting the experiences was painful and that they intentionally suppressed the images of the catastrophe. the events were so traumatic and painful that one of the part icipants mentioned in his statement that presently he is afraid to even look at the sea. down and out—never-ending daily needs most of the participants had been earning money from fishing, and they did not have any savings for the future. with the ocean encroachment and resulting erosion, they lost their houses, fishing equipment, boats and personal belongings and were forced to spend money to build a new house. they had to borrow money from others to meet their daily needs. first home and native land—a desire to go back most of the participants said that they wanted to go back to their previous homes and they were not accustomed to their current place of living. one participant mentioned that she wanted to die on the land where she was born. the participants were affectionate towards their homeland and some regretted leaving their homes. table 1 (cont’d): subthemes and themes derived from codes, and selected participant quotes (n = 7) theme subtheme participants’ quotes recovery haunting memories participant 3: i do not want to recollect the experiences we had that time. participant 6: i am afraid to look at the sea now. participant 1: even now, our thoughts are about the place and the church (...) it is so painful. the pain is heart breaking. down and out— never-ending daily needs participant 1: (…) we do not have money to spend every day. participant 4: “(…) we are short of money. we lost everything that we earned from the sea (sigh). we spend everything on our new house and medicines. first home and native land—a desire to go back participant 1: (…) we are not able to adjust to this place even now. kovilthottam was good. participant 2: (…) we are missing kovilthottam a lot now. we still wish to live there. it was the land of holy mary. participant 6: (…) sometimes i regret leaving that place. we did not wish to sell our land and come here. our land was good for everything. participant 7: (…) i left my house unwillingly. i wished to die living there. even though all the others sold their property, i did not. the lived experience of victims of catastrophic coastal erosion a cycle of impact, consequence and recovery e100 | squ medical journal, february 2021, volume 21, issue 1 the phenomenon that emerged from the analysis of the themes was ‘catastrophic coastal erosion: a cycle of impact, consequences, and recovery’. discussion this study explored the experiences of victims of catastrophic coastal erosion during the monsoon season on the southern coast of kerala. the study provides details of the impact of coastal erosion and sea-level rise and the consequences of and recovery from sea encroachment on a vulnerable population. the findings reveal that the people residing along kerala’s coast live under constant fear. a previous study reported ongoing fear of sea rise through the theme “experience of physical impact”.25 the participants in that study said they were afraid and worried every time they saw ocean levels rise. a quantitative component of the research also found that 91% of the participants were worried about rising sea levels.25 vulnerability mapping and risk assessment of disaster-prone areas in the affected districts as well as awareness campaigns to sensitise vulnerable populations to what should and should not be done during disasters can reduce fear.26 such a training should focus on search and rescue, emergency first aid, temporary shelter, food safety, water and environmental sanitation, removal of dead bodies and carcasses, epidemic control, preparation of household kits and restoration of communication channels, roads and transport. the erosion that occurs in coastal regions usually progresses to catastrophic levels. the impact of sea encroachment is beyond human imagination, and it only leaves devastation in its wake, causing immense loss of life and livelihood. the most devastating losses associated with sea rise are within communities that live along the coast among people who fish for a living; participants in this study described the challenging nature of ocean waves and the magnitude of the damage caused by them.27 these findings are similar to a study conducted by roxberg et al., who found that the tsunami waves on boxing day in the indian ocean were powerful and destroyed the coastal population.28 in 2018, nair et al. found that almost 60% of kerala’s coastline was eroding, warranting immediate protective measures.29 in order to minimise the consequences of future disasters, steps need to be taken to reduce the vulnerability of the coastal population by strength ening structures’ disaster-resilient features, constructing permanent multipurpose shelters, conducting exercises related to lessons learned and revising standard operation protocols based on past experiences.27 a study cond ucted by abushandi and abualkishik in oman stressed the importance of detecting shoreline changes using new technologies and projecting possible future changes in the coastline based on the acquired data.30 such an approach is critical to managing disasters associated with coastal erosion effectively. coastal populations are vulnerable to natural disasters, and the resulting suffering is an added consequence of these catastrophes. the current study’s findings are similar to those of hatthakit and thaniwathananon who described tsunami victims’ suffering in terms of physical pain, anxiety, depression and post-traumatic stress disorder.31 one of the themes identified in the present research, (haunting memories) describes victims’ re-traumatising experience when reflecting on past incidents. hatthakit and thani wathananon also found that traumatic experiences often come back in thoughts, memories and dreams.31 traumatic reminders include photographs and the occurrence of similar catastrophes and both were found to trigger unpleasant memories. the current study also highlighted the theme ‘damage and destruction in the bat of an eye—the epoch of losses’. this theme reflects the extent of damage and destruction made by catastrophic waves and is similar to the theme “back to zero,” which was derived by hatthakit and thaniwathananon.31 in their study, the researchers found that buddhist tsunami survivors whose houses and businesses were destroyed harboured feelings of having nothing or even less than nothing.31 baum and fleming reported in their study that most people recovered fully from moderate stress reactions within 6–16 months.32 the present study’s findings, however, suggests that haunting memories and retraumatising experiences persist, even after several years. the current participants carried the burden of the experience with them and were sad whenever they talked about or remembered the traumatising events. in reflection of the importance of mental health support for helping victims recover from trauma, raphael and wooding discussed the need for readily available mental health services.33 according to the centre for mental health of the new south wales institute of psychiatry, speedy recovery in individuals affected by natural disasters relies on psychological first aid, triage, debriefing, identification of risk factors and strengths, screening for psychopathology, interventions for stress syndromes and long-term follow-up.34 the health professionals caring for disaster-affected individuals require an in-depth understanding of victims’ lived experiences. a systematic review conducted by labrague et al. reported that nurses generally lack awareness of disaster management and are ill-prepared for disaster response.35 many health professionals still lack the necessary knowledge and skills to deal with disasters, pointing to an urgent need for disaster renjulal yesodharan, tessy t. jose and erna j. roach clinical and basic research | e101 preparedness content in the undergraduate curriculum and specialised training for healthcare professionals.36 when disasters strike, many factors determine how successfully the individuals and their communities recover. physical, socio-psychological and political factors affect the impact of the catastrophe and influence people’s recovery. conclusion the study results indicate that the trauma of cata strophic coastal erosion follows a cycle of reactions to the event’s immediate impact, followed by dealing with the event’s consequences and recovery. if the disaster’s initial impact is controlled, the consequences can be minimised, leading to faster recovery. under standing the nature and dynamics of catastrophic coastal erosion along with mental preparedness of the vulnerable population is crucial to reducing the risk associated with the impact. training and capacity building of all stakeholders involved in disaster manage ment are essential for limiting natural disasters. appropriate training needs should be provided to local self-help groups, ngos and community representatives to reduce the severity of natural disasters’ impacts. specialised disaster management training for healthcare professionals needs to be included in their regular work. integrating disaster management in primary healthcare settings and inculcating disaster management competencies and skills will help healthcare professionals deal with vulnerable populations. such a move is crucial in minimising long-term consequences of natural disasters. early recognition of psychological trauma and providing immediate counselling services will prevent unnecessary suffering in victims of catastrophic coastal erosion. the findings also suggest the need for ongoing, early crisis management and mental health support in catastrophe-affected areas. the practical implementation of disaster management practices requires frequent dialogue between decision-makers and vulnerable populations. c o n f l i c t o f i n t e r e s t authors declared no conflict of interest. f u n d i n g no funding was received for this study. references 1. the national academies. ocean science series coastal hazards. from: https://dels.nas.edu/resources/static-assets/osb/miscell aneous/coastal_hazards.pdf accessed: apr 2020. 2. the united states agency for international development (usaid). concepts and practices of “resilience”: a compilation from various secondary sources. from: https://pdf.usaid.gov/ pdf_docs/pnady190.pdf accessed: apr 2020. 3. mangor k, drønen nk, kærgaard kh, kristense se. the shoreline management guideline. 4th ed. from: www. d h i g r o u p . c o m / u p l o a d / c a m p a i g n s / s h o r e l i n e / a s s e t s / s h o r e l i n e m a n a g e m e n t g u i d e l i n e s _ fe b 2 0 1 7 -to c . p d f accessed: apr 2020. 4. eurosion. living with coastal erosion in europe: sediment and space for sustainability part iv – a guide to coastal erosion management practices in europe: lessons learned. from: www. eurosion.org/reports-online/part4.pdf accessed: apr 2020. 5. marchand m. concepts and science for coastal erosion management concise report for policy makers. delft; 2010. from: www.conscienceeu.net/documents/concise-report-final. pdf accessed: apr 2020. 6. nicholls rj, wong pp, burkett v, codignotto j, hay j, mclean r, et al. coastal systems and low-lying areas. from: http://ro.uow. edu.au/scipapers/164 accessed: may 2017. 7. zhang k, douglas bc, leatherman sp. global warming and coastal erosion. clim change 2004; 64:41–58. https://doi.org/10.1 023/b:clim.0000024690.32682.48. 8. space applications centre-isro. coastal zones of india. from: http://www.keralaczma.gov.in/pdfs//coastal_zones_of_india. pdf accessed: may 2017. 9. asian development bank (adb). technical assistance com pletion report. from: www.adb.org/sites/default/files/projectdocument/67861/39135-ind-tcr.pdf accessed: apr 2020. 10. unnikrishnan as, nidheesh ag, lengaigne m. sea-level-rise trends off the indian coasts during the last two decades. curr sci 2015; 108:966–71. 11. rajawat as, chauhan hb, ratheesh r, rhode s, bhanderi rj, mahapatra m, et al. assessment of coastal erosion along indian coast on 1:25,000 scale using satellite data. int arch photogramm remote sens spat inf sci 2014; xl:119–25. https://doi.org/10.51 94/isprsarchives-xl-8-119-2014. 12. national centre for sustainable coastal management (ncscm). coastal issues and concerns: challenges for the research community. from: https://ncscm.res.in/cms/more/pdf/downl o a d / c o a s t a l % 2 0 i s s u e s % 2 0 a n d % 2 0 c o n c e r n s % 2 0 % 2 0 challenges%20for%20the%20research%20community.pdf accessed: apr 2020. 13. partnerships in environmental management for the seas of east asia (pemsea). integrating climate change and disaster risk scenarios into coastal and sea use planning in manila bay. from: www.pemsea.org/sites/default/files/climate-change-manila -bay.pdf accessed: apr 2020. 14. banholzer s, kossin j, donner s. the impact of climate change on natural disasters. in: singh a, zommers z, eds. reducing disaster: early warning systems for climate change. berlin, germany: springer publishing, pp. 21–49. 15. united nations office for disaster risk reduction (unisdr). global assessment report on disaster risk reduction 2013 from shared risk to shared value: the business case for disaster risk reduction search. from: www.preventionweb.net/english/hyogo /gar/2013/en/home/download.html accessed: apr 2020. 16. rasheed kaa, das vk, revichandran c, vijayan pr, thottam tj. tsunami impacts on morphology of beaches along south kerala coast, west coast of india. sci tsunami hazards 2006; 24. 17. american psychiatric association (apa). the diagnostic and statistical manual of mental disorders (dsm-5). 5th ed. arlington, usa: american psychiatric publishing, 2013. p. 271. 18. shalev a, liberzon, i, marmar, c. post-traumatic stress disorder. n engl j med 2017; 376:2459–69. https://doi.org/10.1056/nej mra1612499. https://doi.org/10.1023/b:clim.0000024690.32682.48 https://doi.org/10.1023/b:clim.0000024690.32682.48 https://doi.org/10.5194/isprsarchives-xl-8-119-2014 https://doi.org/10.5194/isprsarchives-xl-8-119-2014 https://doi.org/10.1056/nejmra1612499 https://doi.org/10.1056/nejmra1612499 the lived experience of victims of catastrophic coastal erosion a cycle of impact, consequence and recovery e102 | squ medical journal, february 2021, volume 21, issue 1 19. fenster rj, lebois lam, ressler kj, suh j. brain circuit dys function in post-traumatic stress disorder: from mouse to man. nat rev neurosci 2018; 19:535–51. https://doi.org/10.1038/s415 83-018-0039-7. 20. carr d. the crisis of european sciences and transcendental phenomenology: an introduction to phenomenology. evanston, usa: northwestern university press, 1970. 21. lopez ka, willis dg. descriptive versus interpretive pheno menology: their contributions to nursing knowledge. qual health res 2004; 14:726–35. https://doi.org/10.1177/104973230 4263638. 22. patton mq. qualitative research and evaluation methods. 3rd ed. thousand oaks, usa: sage publications, 2002. 23. colaizzi pf. psychological research as the phenomenologist views it. in: valle rs, king m, eds. existential-phenomenological alternatives for psychology. oxford, uk: oxford university press, 1978. p. 6. 24. lincoln ys, guba eg. naturalistic inquiry. 1st ed. thousand oaks, usa: sage publications, 1985. p. 416. 25. asugeni j, maclaren d, massey pd, speare r. mental health issues from rising sea level in a remote coastal region of the solomon islands: current and future. australas psychiatry 2015; 23:22–5. https://doi.org/10.1177/1039856215609767. 26. achutha menon centre for health science studies. coastal disaster management plan—for local self-government. from: https://sctimst.ac.in/post-flood-management/resources/ resources/disaster-management_comprehensive-plan.pdf accessed: apr 2020. 27. kerala state emergency operations centre. kerala state disaster management plan 2016. from: https://sdma.kerala.gov.in/ wp-content/uploads/2018/11/kerala%20state%20disaster%20 management%20plan%202016.pdf accessed: apr 2020. 28. roxberg ås, burman m, guldbrand m, fridlund b, barbosa da silva a. out of the wave: the meaning of suffering and relieved suffering for survivors of the tsunami catastrophe. a hermeneutic phenomenological study of tv-interviews one year after the tsunami catastrophe, 2004. scand j caring sci 2010; 24:707–15. https://doi.org/10.1111/j.1471-6712.2009.00767.x. 29. nair ls, prasad r, rafeeque mk, prakash tn. coastal mor phology and long-term shoreline changes along the southwest coastal morphology and long-term shoreline changes along the southwest coast of india. 2018; 92:588–95. https://doi.org/10.10 07/s12594-018-1072-x. 30. abushandi e, abualkishik a. shoreline erosion assessment modelling for sohar region: measurements, analysis, and scenario. sci rep 2020; 10:4048. https://doi.org/10.1038/s41598-020-61033-y. 31. hatthakit u, thaniwathananon p. the suffering experiences of buddhist tsunami survivors. int j hum caring 2007; 11:59–66. https://doi.org/10.20467/1091-5710.11.2.59. 32. baum a, fleming i. implications of psychological research on stress and technological accidents. am psychol 1993; 665–72. https://doi.org/10.1037/0003-066x.48.6.665. 33. raphael b, wooding s. early mental health interventions for traumatic loss in adults. in: litz bt, eds. early intervention for trauma and traumatic loss. new york, usa: guilford press, 2004. pp. 147–78. 34. new south wales (nsw). department of health. centre for mental health. disaster mental health response handbook: an educational resource for mental health professionals involved in disaster management/nsw health. north sydney, australia: nsw health, 2000. pp. 170. 35. labrague lj, hammad k, gloe ds, mcenroe-petitte dm, fronda dc, obeidat aa, et al. disaster preparedness among nurses: a systematic review of literature. int nurs rev 2018; 65:41–53. https://doi.org/10.1111/inr.12369. 36. achora s, kamanyire jk. disaster preparedness: need for inclusion in undergraduate nursing education. sultan qaboos univ med j 2016; 16:e15–19. https://doi.org/10.18295/squmj.2 016.16.01.004. https://doi.org/10.1038/s41583-018-0039-7 https://doi.org/10.1038/s41583-018-0039-7 https://doi.org/10.1177/1049732304263638 https://doi.org/10.1177/1049732304263638 https://doi.org/10.1177/1039856215609767 https://doi.org/10.1111/j.1471-6712.2009.00767.x https://doi.org/10.1007/s12594-018-1072-x https://doi.org/10.1007/s12594-018-1072-x https://doi.org/10.1038/s41598-020-61033-y https://doi.org/10.20467/1091-5710.11.2.59 https://doi.org/10.1037/0003-066x.48.6.665 https://doi.org/10.1111/inr.12369 https://doi.org/10.18295/squmj.2016.16.01.004 https://doi.org/10.18295/squmj.2016.16.01.004 eosinopenia is associated with a high risk of serious disease during infection with the severe acute respiratory syndrome coronavirus 2, the causative agent of covid-19. persistent eosinopenia correlates with low rates of recovery, while the resolution of eosinopenia predicts improvement.1 eosinophils have an important role in the pathogenesis of chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (copd). in copd, eosinopenia is associated with poorer patient outcomes and short-term readmission after discharge.2 eosinophils also play a key role in allergic diseases, including asthma. moreover, many patients with asthma can have intentionally induced eosinopenia by biological drugs. in addition, persistent peripheral eosinopenia indicates poor survival in sepsis.3 in this context, the role of eosinophils remains a puzzle in covid-19, especially among those with severe disease or an associated obstructive lung disease. it is unclear if they directly play a pathobiological role in sepsis and lung injury or whether they are just sentinel cells that are harbingers of danger. the incidence of eosinopenia in covid-19 patients has been shown to vary from 50.8% to 94%.3–5 a lower prevalence of 26.93% was noted in a study from spain, possibly due to a large sample size and the study period spanning through the course of the pollen season.6 eosinopenia on admission is associated with a higher risk of severe disease and intensive care unit admissions. yan et al. noted that eosinophil levels were significantly low in covid-19 patients with critical disease and the eosinophil counts remained low or progressively declined in those with fatal outcomes.7 similarly, in another study, maximum reduction in eosinophils was observed on the fourth day from onset and these patients with low eosinophil counts were more likely to have fever, fatigue, dyspnoea and worse lesions in their computed tomography scan than those with normal counts.8 peripheral eosinophil counts typically return to near normal levels as patients recover from moderate-to-severe infection suggesting that normalisation of the blood eosinophil count indicates recovery.9 on admission, a low eosinophil count was found to improve continuously, reaching significantly higher levels in survivors than among non-survivors with a greater increase indicating a better outcome.10 surprisingly, the prognostic utility of peripheral eosinophil counts varied with patient race and ethnicity.11 in contrast, increased levels of eosinophils were noted among patients with severe covid-19 in a large cohort. however, this observation cannot be generalised as a different technique was used and low density eosinophils were counted.12 thus, the current evidence suggests a protective role for eosinophils in mortality and length of hospital stay among patients with covid-19. there is mixed evidence regarding the prevalence of asthma in patients with covid-19 or the effect of asthma and its treatment on the progression of the disease.13 theoretically, patients with asthma could be at a higher risk considering their increased susceptibility to common respiratory virus-associated exacerbations. the prevalence of asthma was markedly lower among those diagnosed with covid-19 compared to the general population of wuhan, china.14 in a group of 140 hospitalised patients from wuhan, no cases of asthma and allergic rhinitis were reported while the prevalence of asthma and allergic rhinitis in the province was 4.2% and 9.7%, respectively.5 a low incidence of 2.1% was noted in severe asthma patients from belgium and none of them experienced a severe disease course or death.15 similarly low incidence was reported from italy, russia and australia.16 however, contradictory data were reported from germany and the united states, where higher asthma prevalence was noted among patients with covid-19.16 though asthma was not a risk factor for poor prognosis, higher mortality was observed among those who had experienced an acute exacerbation in the previous year.17 since eosinopenia is a biomarker for the severity of covid-19, the eosinophil reduction/ depletion induced by anti-interleukin (il)-5 and antiil-5 receptor blocking monoclonal antibodies raises a real concern. however, reports on the safety of 1division of pulmonology, sultan qaboos comprehensive cancer care and research centre, muscat, oman; 2department of medicine, division of respirology, st joseph’s healthcare and professor of medicine, mcmaster university, hamilton, ontario, canada *corresponding author’s e-mail: drjayakrish@hotmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. covid-19, obstructive airway disease and eosinophils a complex interplay b. jayakrishnan1 and parameswaran nair2 editorial sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 163–166, epub. 26 may 22 submitted 16 aug 21 revision req. 21 oct 21; revision recd. 2 nov 21 accepted 24 nov 21 https://doi.org/10.18295/squmj.1.2022.001 https://creativecommons.org/licenses/by-nd/4.0/ covid-19, obstructive airway disease and eosinophils a complex interplay 164 | squ medical journal, may 2022, volume 22, issue 2 patients using the monoclonal antibodies for asthma or atopic dermatitis are reassuring.14,15,18 a study from spain on 545 patients receiving different biologics for severe asthma found no increased risk, no greater disease severity or higher mortality.18 a large study on asthmatics, with infection confirmed by polymerase chain reaction testing, did not find anti-il-5 biologics to increase the risk of infection or worsen outcomes. in contrast, systemic corticosteroids were an independent risk factor for the highest covid-19 severity and allcause mortality.19 nevertheless, there is clear evidence that asthma presents a lesser risk for developing severe covid-19 and the current medications, including inhaled corticosteroids and biologics, remain safe for use.9,15,18 available data certainly suggests a higher risk for severe covid-19 in copd patients. an early case series on covid-19 from china reported a higher prevalence of copd in patients with severe presentation and worse outcomes.20 a meta-analysis of studies in chinese and english languages showed that the pre-existing copd is associated with a four-fold increase in the risk of developing severe covid-19.21 the prevalence of copd among hospitalised covid-19 patients ranges from 0% to 10% in china, 2.4% to 14% in new york city and 5.6% to 9.2% in italy.22 in copd, higher blood eosinophil counts predict a positive response to corticosteroids and eosinopenia is associated with worsening of symptoms and severity of exacerbations.2 eosinophils remain in the blood only for about 8 to 12 hours before they migrate into tissues, where they are active for several days.9 they have potent proinflammatory effects and participate in inflammation, immunoregulation and provide a defence against many diseases including viral infections.4 proliferation, development and activation of eosinophils are controlled by il-5, il-3 and granulocyte-macrophage colony-stimulating factor (gm-csf).23 the immune mechanism of eosinopenia in covid-19 remains unclear. it is likely to be multifactorial, involving inhibition of the main steps in the eosinophil life cycle, apoptosis induced by type 1 interferon during acute infection or association with eosinophil consumption by their antiviral actions.1,24 it is also unclear if it is indeed eosinopenia that leads to poor outcomes or if eosinopenia is a manifestation of impaired gmcsf signalling, il-33 secretion or the diminished expression of its receptor, st2, in the airway epithelium.25 thus, eosinopenia could either be the sign of host exhaustion trying to clear the covid-19 virus or a primary risk factor for a severe infection.24,26 it is not clear whether the covid-19 virus could involve the bone marrow and cause the decrease of peripheral blood eosinophils. nevertheless, increased production of neutrophils in bone marrow leading to a reduction in eosinophil production has also been reported.8,27 to re-iterate, it is still not clear whether eosinopenia is the result of direct virus targeting or the result of generally impaired immunity.14 considering the anti-viral effects of eosinophils, the reported eosinopenia in covid-19 patients is of special interest.28 studies have indicated a potential role of eosinophils in promoting viral clearance and antiviral host defence. respiratory virus infections are associated with asthma exacerbation in children and adults, among which rhinovirus is the most common agent.14 asthma was identified as the single most common comorbid condition among hospitalised individuals with influenza a virus subtype haemagglutinine-1 neuraaminidase-1 (h1n1) infection, with rates of asthma ranging from 10% to 32%.29 interestingly, there are no reports regarding asthma exacerbation due to covid-19. there were only a few reports on asthma exacerbation during the severe acute respiratory syndrome and middle east respiratory syndrome epidemics as well. though biological agents that induce eosinopenia reduce asthma exacerbations, patients enduring these conditions have not been reported to have increased viral infections.1 in fact, a large population-based cohort study showed that patients with nonallergic asthma had a higher risk of severe covid-19 when compared to those with allergic asthma.30 eosinophils in the respiratory tract might represent a “doubleedged sword”—promoting antiviral responses on the one hand and resulting in an exaggerated host response leading to tissue damage on the other.9 this lack of susceptibility to covid-19 in patients with pre-existing asthma and allergic airway disease appears in contrast with the established link between these chronic respiratory conditions and susceptibility to common respiratory viruses, especially rhinoviruses.6 however, rhinoviruses use intercellular adhesion molecule-1 as an entrance into respiratory epithelial cells which is overexpressed in allergic airways. in contrast, corona viruses use another host cell receptor, the angiotensin-converting enzyme 2 (ace2). the expression of ace2 on ace inhibitors is increased in patients with copd, diabetes mellitus and hypertension explaining their higher risk of developing covid-19. on the other hand, lower expression of ace has been noted in the airways of asthmatic patients which reduces the chances of a covid-19 infection. moreover, inhaled steroids can down regulate ace2 receptors and suppress cytokine production and corona virus replication.31 the use of inhaled corticosteroids was found to be associated b. jayakrishnan and parameswaran nair editorial | 165 with a decreased level of ace2 and transmembrane protease serine 2 gene expression from sputum in asthmatic patients.32 an inhaled steroid, ciclesonide, reduced severe acute respiratory syndrome coronavirus 2 (sars-cov-2) ribonucleic acid replication as well as host inflammation in the lungs in in-vitro studies.33 conclusion eosinopenia, that might also represent a low t2 immune status, is associated with poor outcomes in asthmatic and possibly in non-asthmatic copd patients. however, it is unclear if the eosinophils directly contribute to the pathobiology of sars-cov2 lung injury or not. there is even less clarity around the role of lung eosinophils as this has not been extensively investigated. eosinophils are unlikely to be directly involved in lung injury as the use of antieosinophil biologics has not been associated with poor outcomes in asthma patients with covid-19. eosinophil numbers in peripheral blood are likely to be just a biomarker of the biological activity of t helper 2 cytokines. there is very little information on their numbers or activity in the airways in patients with covid-19. the general consensus is to continue to manage airway diseases, both asthma and copd, as per current guidelines with the appropriate use of corticosteroids and bronchodilators and judicious use of biologics as indicated. a u t h o r s’ c o n t r i b u t i o n s bj conceptualised and wrote out the draft of the initial manuscript. bj and pn contributed to the literature review. pn performed a critical review and both the authors approved the final version of the manuscript. references 1. lindsley aw, schwartz jt, rothenberg me. eosinophil responses during covid-19 infections and coronavirus vaccination. j allergy clin immunol 2020; 146:1–7. https://doi.org/10.1016/j. jaci.2020.04.021. 2. kerkhof m, chaudhry i, pavord id, miravitlles m, kook rhee c, halpin dmg, et al. blood eosinophil count predicts treatment failure and hospital readmission for copd. erj open res 2020; 6:00188–2020. https://doi.org/10.1183/23120541.00188-2020. 3. al duhailib z, farooqi m, piticaru j, alhazzani w, nair p. the role of eosinophils in sepsis and acute respiratory distress syndrome: a scoping review. can j anesth/j can anesth 2021; 68:715–26. https://doi.org/10.1007/s12630-021-01920-8. 4. soni m. evaluation of eosinopenia as a diagnostic and prognostic indicator in covid-19 infection. int j lab hematol 2021; 43:137–41. https://doi.org/10.1111/ijlh.13425. 5. zhang jj, dong x, cao yy, yuan yd, yang yb, yan yq, et al. clinical characteristics of 140 patients infected with sarscov-2 in wuhan, china. allergy 2020; 75:1730–41. https://doi. org/10.1111/all.14238. 6. valverde-monge m, canas ja, barroso b, betancor d, ortegamartin l, gómez-lópez a, et al. eosinophils and chronic respiratory diseases in hospitalized covid-19 patients. front immunol 2021; 12:1–10. https://doi.org/10.3389/fimmu.2021.66 8074. 7. yan b, yang j, xie y, tang x. relationship between blood eosinophil levels and covid-19 mortality. world allergy organ j 2021; 14:1–12. http://doi.org/10.1016/j.waojou.2021.100521. 8. xie g, ding f, han l, yin d, lu h, zhang m. the role of peripheral blood eosinophil counts in covid-19 patients. allergy 2021; 76: 471–82. https://doi.org/10.1111/all.14465. 9. rosenberg hf, foster ps. eosinophils and covid-19: diagnosis, prognosis, and vaccination strategies. semin immunopathol 2021; 43: 383–92. https://doi.org/10.1007/s00281-021-00850-3. 10. chen r, sang l, jiang m, yang z, jia n, fu w, et al. longitudinal hematologic and immunologic variations associated with the progression of covid-19 patients in china. j allergy clin immu nol 2020; 146: 89–100. https://doi.org/10.1016/j.jaci.2020.05.003. 11. glickman jw, pavel ab, guttman-yassky e, miller rl. the role of circulating eosinophils on covid-19 mortality varies by race/ethnicity. allergy 2021; 76: 925–7. https://doi.org/10.1111/ all.14708. 12. lucas c, wong p, klein j, castro tbr, silva j, sundaram m, et al. longitudinal analyses reveal immunological misfiring in severe covid-19. nature 2020; 584:463–9. https://doi.org/10.10 38/s41586-020-2588-y. 13. garcia-moguel i, diaz campos r, alonso charterina s, fernandez rodriguez c, fernandez crespo j. covid-19, severe asthma, and biologics. ann allergy asthma immunol 2020; 125:357–9.e1. https://doi.org/10.1016/j.anai.2020.06.012. 14. liu s, zhi y, ying s. covid-19 and asthma: reflection during the pandemic. clin rev allergy immunol 2020; 59:78–88. https://doi.org/10.1007/s12016-020-08797-3. 15. hanon s, brusselle g, deschampheleire m, louis r, michils a, peché r, et al. covid-19 and biologics in severe asthma: data from the belgian severe asthma registry. eur respir j 2020. 56:1–4. https://doi.org/10.1183/13993003.02857-2020. 16. ramakrishnan rk, al heialy s, hamid q. implications of pre existing asthma on covid-19 pathogenesis. am j physiol lung cell mol physiol 2021; 320: l880–91. https://doi.org/10.1152/ ajplung.00547.2020. 17. lee sc, son kj, han ch, jung jy, park sc. impact of comorbid asthma on severity of coronavirus disease (covid-19). sci rep 2020; 10:1–9. https://doi.org/10.1038/s41598-020-77791-8. 18. rial mj, valverde m, del pozo v, gonzález-barcala fj, martínez rivera c, muñoz x, et al. clinical characteristics in 545 patients with severe asthma on biological treatment during the covid-19 outbreak. j allergy clin immunol pract 2021; 9:487–9.e1. https://doi.org/10.1016/j.jaip.2020.09.050. 19. adir y, humbert m, saliba w. covid-19 risk and outcomes in adult asthmatic patients treated with biologics or systemic corticosteroids: nationwide real-world evidence. j allergy clin immunol 2021; 148:361–7.e13. https://doi.org/10.1016/j.jaci. 2021.06.006. 20. guan wj, ni zy, hu y, liang wh, ou cq, he jx, et al. clinical characteristics of coronavirus disease 2019 in china. n engl j med 2020; 382:1708–20. https://doi.org/10.1056/nej moa2002032. 21. zhao q, meng m, kumar r, wu y, huang j, lian n, et al. the impact of copd and smoking history on the severity of covid-19: a systemic review and meta-analysis. j med virol 2020; 92: 1915–21. https://doi.org/10.1002/jmv.25889. 22. leung jm, niikura m, yang cwt, sin dd. covid-19 and copd. eur respir j 2020; 56:1–9. https://doi.org/10.1183/13 993003.02108-2020. 23. aoki a, hirahara k, kiuchi m, nakayama t. eosinophils: cells known for over 140 years with broad and new functions. allergol int 2021; 70: 3–8. https://doi.org/10.1016/j.alit.2020.09.002. https://doi.org/10.1016/j.jaci.2020.04.021 https://doi.org/10.1016/j.jaci.2020.04.021 https://doi.org/10.1183/23120541.00188-2020 https://doi.org/10.1007/s12630-021-01920-8 https://doi.org/10.1111/ijlh.13425 https://doi.org/10.1111/all.14238 https://doi.org/10.1111/all.14238 https://doi.org/10.3389/fimmu.2021.668074 https://doi.org/10.3389/fimmu.2021.668074 http://doi.org/10.1016/j.waojou.2021.100521 https://doi.org/10.1111/all.14465 https://doi.org/10.1007/s00281-021-00850-3 https://doi.org/10.1016/j.jaci.2020.05.003 https://doi.org/10.1111/all.14708 https://doi.org/10.1111/all.14708 https://doi.org/10.1038/s41586-020-2588-y https://doi.org/10.1038/s41586-020-2588-y https://doi.org/10.1016/j.anai.2020.06.012 https://doi.org/10.1007/s12016-020-08797-3 https://doi.org/10.1183/13993003.02857-2020 https://doi.org/10.1152/ajplung.00547.2020 https://doi.org/10.1152/ajplung.00547.2020 https://doi.org/10.1038/s41598-020-77791-8 https://doi.org/10.1016/j.jaip.2020.09.050 https://doi.org/10.1016/j.jaci.2021.06.006 https://doi.org/10.1016/j.jaci.2021.06.006 https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.1056/nejmoa2002032 https://doi.org/10.1002/jmv.25889 https://doi.org/10.1183/13993003.02108-2020 https://doi.org/10.1183/13993003.02108-2020 https://doi.org/10.1016/j.alit.2020.09.002 covid-19, obstructive airway disease and eosinophils a complex interplay 166 | squ medical journal, may 2022, volume 22, issue 2 24. tanni f, akker e, zaman mm, figueroa n, tharian b, hupart kh. eosinopenia and covid-19. j am osteopath assoc 2020; 120:504–8. https://doi.org/10.7556/jaoa.2020.091. 25. krishack pa, hollinger mk, kuzel tg, decker ts, louviere tj, hrusch cl, et al. il-33-mediated eosinophilia protects against acute lung injury. am j respir cell mol biol 2021; 64:569–78. https://doi.org/10.1183/23120541.00188-2020. 26. jesenak m, banovcin p, diamant z. covid-19, chronic inflam matory respiratory diseases and eosinophils-observations from reported clinical case series. allergy 2020; 75:1819–22. https:// doi.org/10.1183/23120541.00188-2020. 27. huang c, wang y, li x, ren l, zhao j, hu y, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet 2020; 395:497–506. https://doi. org/10.1016/s0140-6736(20)30183-5. 28. phipps s, lam ce, mahalingam s, newhouse m, ramirez r, rosenberg hf, et al. eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. blood 2007; 110:1578–86. https://doi.org/10.1182/blood-2007 01-071340. 29. santillan salas cf, mehra s, pardo crespo mr, juhn yj. asthma and severity of 2009 novel h1n1 influenza: a population-based case-control study. j asthma 2013; 50:1069–76. https://doi.org/ 10.3109/02770903.2013.834505. 30. zhu z, hasegawa k, ma b, fujiogi m, camargo ca, jr., liang l. association of asthma and its genetic predisposition with the risk of severe covid-19. j allergy clin immunol 2020; 146: 327–9.e4. https://doi.org/10.1016/j.jaci.2020.06.001. 31. lovinsky-desir s, deshpande dr, de a, murray l, stingone ja, chan a, et al. asthma among hospitalized patients with covid-19 and related outcomes. j allergy clin immunol 2020; 146:1027–34.e4. https://doi.org/10.1016/j.jaci.2020.07.026. 32. peters mc, sajuthi s, deford p, christenson s, rios cl, montgomery mt, et al. covid-19-related genes in sputum cells in asthma. relationship to demographic features and corticosteroids. am j respir crit care med 2020; 202:83–90. https://doi.org/10.1164/rccm.202003-0821oc. 33. matsuyama s, kawase m, nao n, shirato k, ujike m, kamitani w, et al. the inhaled steroid ciclesonide blocks sars-cov-2 rna replication by targeting the viral replication-transcription complex in cultured cells. j virol 2021; 95:e01648–20. https:// doi.org/10.1128/jvi.01648-20. https://doi.org/10.7556/jaoa.2020.091 https://doi.org/10.1183/23120541.00188-2020 https://doi.org/10.1183/23120541.00188-2020 https://doi.org/10.1183/23120541.00188-2020 https://doi.org/10.1016/s0140-6736(20)30183-5 https://doi.org/10.1016/s0140-6736(20)30183-5 https://doi.org/10.1182/blood-2007-01-071340 https://doi.org/10.1182/blood-2007-01-071340 https://doi.org/10.3109/02770903.2013.834505 https://doi.org/10.3109/02770903.2013.834505 https://doi.org/10.1016/j.jaci.2020.06.001 https://doi.org/10.1016/j.jaci.2020.07.026 https://doi.org/10.1164/rccm.202003-0821oc https://doi.org/10.1128/jvi.01648-20 https://doi.org/10.1128/jvi.01648-20 whole1.indd adult onset still’s disease in oman *faisal a al-temimi, prasad george sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© george frederic still described a form of chronic joint disease in childhood in 1897.1 this syndrome originally consisted of fever, arthritis, lymphadenopathy and splenomegally which may be associated with skin rash.2 the rash is characterized by red evanescent macules with distinct borders and may be associated with isomorphic (koebner) phenomena.3 the adult form was recognized for the first time in 1967.4 it is primarily a disease of young adults, rarely diagnosed after the age of thirty five,5 although it has been reported affecting patients in their seventh decade of life.6,7 arthralgias are present nizwa hospital, p.o. box 1222, pc 611, nizwa, sultanate of oman *to whom correspondence should be addressed. email: fatemi@omantel.net.om abstract objective: to . highlight the demographic characteristics, clinical features, laboratory investigations and outcome if possible of a relatively rare disease (adult onset still’s disease {aosd}) and 2. to compare our results with those reported earlier by others. method: a retrospective review of the clinical, laboratory and radiological manifestations in 6 patients admitted with aosd. data were collected from clinical summary of each case highlighting the demographic, clinical features and relevant investigation. the diagnosis was made on clinical base and supported by the laboratory and radiological examinations to confirm the diagnosis and/or exclude other differential diagnoses. results: mean age of patients (2.6), presence of fever (80.2%) and its pattern, skin rash (80.2%), arthralgia(00%), arthritis(66.65%), and the duration of morning stiffness, all these findings were compatible with earlier results. however young adult females constitute (80.2%) of our small group, which is quite high in comparison with others. splenomegaly (33.3%), hepatomegaly(6.6%), and lymphadenopathy(6.6%) were less than that reported by others who have more serious intra-abdominal visceral involvement. one patient (6.65%) had a fatal pulmonary embolism, although usually pulmonary involvement is a mild one. none of our patients had neurological, ophthalmological or hearing involvement. the results of the investigations and radiological findings are more or less similar to those in other series. conclusion: the clinical and laboratory characteristics of our small number of patients are more or less consistent with findings of others. it is important to keep in mind that aosd is an uncommon syndrome with a range of signs and symptoms which are non-specific and may simulate a variety of connective tissue and general medical problems. differences in the expression of aosd were found between patients from different locations and the disease can be responsible for life-threatening complications. o r i g i n a l s t u d y الكبار عند يّ عِ اليَفَ لِ الرُّوماتويديّ فاصِ املَ الْتِهابُ روماتزمي ملرض ذلك) أمكن إن ) باملرض اإلصابة وحصيلة اتبرية واملتغيرات والسريرية الدميوغرافية على اخلصائص الضوء الهدف: إلقاء امللخص: سابقا. الطريقة: متت مسجل هو ما مع نحصل عليها التي النتائج ومقارنة الكبار. عند يّ عِ الرُّوماتويديّ اليَفَ لِ َفاصِ امل الْتِهابُ وهو نسبيا احلدوث نادر طريق مراجعة عن الكبار عند يّ عِ اليَفَ الرُّوماتويديّ لِ َفاصِ بالْتِهابُ امل املصابني من املرضى لستة واالشعاعية اتبرية التحاليل السريرية، احلالة دراسة مدعوما السريرية واألعراض العالمات على املرض اعتمادا تشخيص مت العالقة. الفحوصات ذات ونتائج السريرية، احلالة عن تفاصيل يحتوي ملخص (٢١٫٦) املرضى عمر معدل بلغ النتائج: األخرى. التفاضلية التشخيصات استبعاد أو التشخيص إلثبات والاشعاعية اتبرية الفحوصات بنتائج املرضى قيد لدى الصباحي التصلب ومدة (٪٦٦٫٦٥) املفاصل التهاب ،(٪١٠٠) املفاصل ألم ،(٪٨٠٫٢) وجود الطفح اجللدي ،(٪٨٠٫٢) احلرارة ارتفاع سنة، عدد نسبة أما السابقة. الدراسات مع باملقارنة نسبيا عالية وهي ،(٪٨٠٫٢) النساء من املرضى غالبية كانت سابقا. مسجل هو ملا مطابقة الدراسة األخرى. مع الدراسات قورنت ما قليلة إذا كانت فقد (٪١٦٫٦) اللمفاوية والغدد ،(٪١٦٫٦) والكبد ،(٪٣٣٫٣) الطحال بتضخم اإلصابة وشدة املصابني على تأثيرات أية تسجل لم الرئوية. اإلصابات بساطة هو عليه املتعارف أن ولو المرضى عند أحد (٪١٦٫٦) مميتة رئوي جتلط حالة حدوث سجل اآلخرون. أخلالصة: بينت الباحثون سجله ملا مطابقة بأنها بينت واإلشعاعية اتبرية نتائج الفحوص دراسة السمع والبصر. وكذلك اجلهاز العصبي، لِ َفاصِ امل الْتِهابُ أن ذكر املهم ومن سابقا. مسجل ملا هو لدرجة ما مطابقة والاشعاعية الفحوصات اتبرية ونتائج السريرية األعراض بأن الدراسة اختالفات وجود سابقا لوحظ األخرى. األمراض من الكثير يشابه جتعله املرض وعالمات أعراض تعدد ولكن احلدوث الكبار نادر عند يّ عِ اليَفَ الرُّوماتويديّ تهديد إلى تؤدي مضاعفات عن مسؤوال املرض يكون وقد ، اجلغرافية املواقع تبعا الختالف الكبار يّ عند عِ اليَفَ الرُّوماتويديّ لِ َفاصِ امل في سمات الْتِهابُ أحيانا. املصاب حياة fa i s a l a a l -te m i m i , p r a s a d g e o r g e 42 in virtually all patients with the fever spikes. chronic arthritis with disability may be a sequel in up to 20% of cases.8-10 myocardial11 and endocardial12 involvement are rarely seen. pulmonary involvement is usually transient and mild but severe restrictive lung disease has been observed.13-15 neurological,16,17 hepatic,9,18 ophthalmological involvement19-21 and hearing loss22 have been reported too. in rare cases renal disease may occur.23 several sets of diagnostic criteria have been proposed24-26 for the diagnosis; however, cush et al24 criteria are a practical guide. here we present a personal experience of the clinical characteristics for 6 patients with adult onset still’s disease (aosd). the objective was to study the natural history of our patients inflicted with this relatively rare disease, which may mimic many other diseases, and to compare our results with those reported by others. m e t h o d this is a review of the clinical, laboratory and radiological manifestations in 6 patients admitted under care of one of the authors (faisal al-temimi) over 10 years time (1992-2002) with aosd. data were collected from the clinical summary of each case highlighting the demographic, clinical features and relevant investigation. the diagnosis was made on a clinical basis and supported by the laboratory and radiological examinations to confirm the diagnosis and/or exclude other differential diagnoses. r e s u l t s five patients were females and one was a male. demographic characteristics were as shown in table 1. duration of the disease was from 3 months to 7 years, symptoms and/or signs of patients were as shown in table 2. d i s c u s s i o n aosd is a cause of fever of unknown origin, and frequently diagnosis may have missed in its early stage. the diagnosis depends predominantly on clinical features. the combination of hectic temperature and the salmon pink colored skin rash should always raise the possibility. our small group which consists of 6 patients illustrates many of the features of aosd (5 females (80.2%)and 1 male (16.65%)), while 51% were females in ohta a et al reviewed groups.27 the mean age of our patients was 21.6% (19-24), which is compatible with what had been reported.5 however, an s. no age (years) sex marital state occupation pregnancy 1 19 f married house wife no 2 20 f single student \ 3 22 f single house wife \ 4 22 f single teacher \ 5 23 f married house wife no 6 24 m single p g student \ table 1. demographic characteristics of 6 patients with adult onset still’s disease presenting symptons/signs no. of patients % fever > 39oc 3 50.0 fever < 39oc 2 33.3 no fever 1 16.65 continous 2 33.3 night fever 2 33.3 hectic 1 16.65 fever & chills 1 16.65 skin rash 5 80.2 pruritc 1 16.65 non pruritc 4 66.6 trunk 4 66.6 trunk & legs 1 16.65 arthralgia 6 100.0 arthritis 4 66.6 morning stiffness (30 mins 2hours) 4 66.6 shortness of breath, cough 2 33.3 sore throat 3 50.0 tachycardia (> 100/min) 4 66.6 splenomegally 2 33.3 hepatomegally 1 16.65 pericardial effusion 2 33.3 lymphadenopathy 1 16.65 mouth ulcers 1 16.65 menstrual disturbance 1 20.00 hair loss 1 16.65 upper gastrointestinal bleeding 1 16.65 table 2. symptoms and signs a d u lt o n s e t s t i l l’ s d i s e a s e 43 onset up to the 7th decade of life has been described also.6,7 of 6 patients 5 (80.2%) patients febrile at presentation and 2 (33.3%) patients had temperatures of more than 39oc, while one patient had a hectic temperature, this is compatible with that of pouchot et al,10 but slightly less than that of ohta et al.27 salmon pink, macular, or maculopapular skin rash was perceived in 5 (80.2%) patients. only one (16.65%) patient suffered from pruritis. rashes were present on the trunk in all the 5 patients, and involved the legs in one. this is in agreement with what has been reported earlier.28.29 in aosd, the systemic complaints may overshadow the joints manifestations, actually joints involvement may develop 2 years after the initial onset of the disease.6 in our group arthralgia was present in all patients especially during febrile episodes. arthritis was seen in 4 (66.6%) patients only. one (16.65%) of the patients had persistent chronic arthritis; this is consistent with findings in patients reviewed by ohta et al27 and others.8-10 the main joints affected [table 3] joints no. of patients % both knees 4 66.6 ankles 3 50.0 wrists 3 50.0 elbows 2 33.3 hips 2 33.3 cervical spine 2 33.3 metacarpophalangeal joints 1 16.65 metatarsophalangeal joints 1 16.65 shoulders 1 16.65 acromioclavicular joints 1 16.65 sternoclavicular joints 1 16.65 polyarthritis 4 66.6 arthralgia 6 100.0 table 3. joints involved and their frequency in 6 patients adult onset still’s disease test no. of patients % cbc haemoglobin < 11gms 4 66.3 > 11gms 2 33.3 hypo microcytic rbc’s 3 50.0 hypo normocytic rbc’s 3 50.0 wcc > 11000/dl 4 66.6 < 11000/dl 2 33.3 neutrophil leucocytosis > 80% 4 66.6 platelets count > 400, 000/mm3 2 33.3 elevated erythrocyte sedimentation rate(esr) 5 80.2 elevated liver enzymes 2 33.3 raised c-reactive protein 4/4 100.0 negative rheumatoid factor 6 100.0 negative antinuclear antibody(ana) 5 80.2 abnormal urine routine examintion (pyuria,albuminuria) 2 33.3 negative vdrl 6 100.0 chest x ray cardiomegally 1 13.65 joints x-ray osteopenia 2 33.3 decreased j. space 2 33.3 sclerosis and, subchondral & cyst formation 1 16.65 echocardiography study (echo) rv enlargement 1 16.65 pericardial effusion 2 33.3 table 4. laboratory and radiological findings fa i s a l a a l -te m i m i , p r a s a d g e o r g e 44 were those of the lower limbs, the knees in 4 (66.6%) patients, followed by ankles in 3 (50%) patients, wrists in 3 (50%) patients, then elbows. the axial joints and joints of the upper limbs are affected to lesser extent as shown in table 3. a polyarticular pattern was seen in all 4 patients with arthritis. significant (30 minutes-2 hours) morning stiffness was present in 4 (66.6%) patients. two (33.3%) patients had cough and shortness of breath, one was an acute episode consistent with a pulmonary embolism which unfortunately led to death. it has been showned that mild transient pulmonary involvement not unusual the and severe restrictive lung disease has been observed.13,14 fifty percent of our patients had sore throats. this figure is lower than that in ohta et al27 series (92%). the prevalence of pericarditis, was similar to that seen in children with still’s disease and may occur in adults too, early in the course of the disease and in association with systemic exacerbations.30,31 in our patients, 4 (66.6%) patients had significant tachycardia, and 2 patients proved to have pericardial effusion by echocardiography, one of whom had right ventricular enlargement too (this patient had pulmonary embolism). however, echocardiography study was not performed for others who had asymptomatic cardiac involvement. electrographic examination showed nonspecific asinus tachycardia. splenomegaly was seen in 2 (33.3%) patients, one (16.65%) patient had hepatomegaly and lymphadenopathy. these are lower than the figures of ohta et al,27 which were 52%, 42% and 63% respectively. raised liver enzymes were present in 2 (33.3%) patients and serum albumin was normal in all our patients in comparison to raised enzymes in 73% and a serum albumin below 3.5 gm/dl in 81% of ohta et al’s reviewed patients.27 menstrual disturbance was seen in 20% of females. diffuse hair loss and mouth ulceration were each seen in one (16.65%) patient only. alopecia was seen in 24% of pouchot et al group.10 upper gastrointestinal bleeding was a presenting problem in one case (16.65%), after aspirin ingestion for high fever. no neurological, ophthalmological or hearing problems were present in our patients. raised esr was present in 5 (80.2%) patients in comparison to 99% of cases reviewed by ohta et al.27 the explanation for this is that one of our patients was in remission from the disease. four (66.6%) patients had their haemoglobin levels below 11 gm and wbc more than 11000/dl while the platelets count was more than 400,000/dl in 2 (33.3). the rbcs were hypochromic normocytic in 3 (50%) patients and hypochromic microcytic in the other 3 (50%) patients. more than 80% had leucocytes, which were predominantly neutrophils in 4 (66.6%) of patients. the c-reactive protein was measured in 4 patients only and was found raised in all. the rheumatoid factor was negative in all patients, and the ana was positive in one patient. in the patient with positive ana there were no other supportive criteria to diagnose sle and the anti ds-dna was not present. this autoantibody profile is consistent with findings of others.27 the chest x-ray was normal in all except one which showed cardiomegaly, while articular x-rays showed osteopenia and decreased joint space in 2 (33.3%) patients, one of these two has long standing disease with joint sclerosis also. c o n c l u s i o n the clinical and laboratory characteristics of our small number of patients are more or less consistent with the findings of others. it is important to keep in mind that aosd is an uncommon syndrome with a range of signs and symptoms which are non specific and may simulate a variety of connective tissue and general medical problems. however, a physician should keep a high index of suspicion and the combination of hectic temperature and salmon coloured skin rash should suggest the diagnosis. it is important to reemphasize the fact raised by bujack et al19 that not all manifestations of the syndrome may be present with each febrile episode and careful collection of long term historical data can be of great assistance in making the diagnosis. r e f e r e n c e s 1. still g. on a form of chronic joint disease in childhood. med chir trans 1897; 88: 47-49. 2. boldero m. a case of still’s disease. medical society transaction 1933; 16: 55. 3. bywaters e. still’s disease in adult. ann rheum dis 1971; 30: 133. 4. sunderkotter c, frieling u, nashan d , metze d. adult onset still’s disease and its characteristic rash. hautarzt 1988; 49: 920-924. 5. esdaile jm, tannebaum h, hawkins d. adult still’s disease. am j med 1980; 68: 825-830. 6. steffe la, cooke cl. still’s disease in a 70 year old women. jama 1963; 249: 2062-2063. 7. wonters jmgw, van rijswyk mh, van de putte lba. a d u lt o n s e t s t i l l’ s d i s e a s e 45 adult onset still’s disease in the elderly: a report of two cases. j rheumatol 1985; 12: 4791-4793. 8. elkon k. adult onset still’s disease: twenty-years follow up and further studies of patients with active disease. arthritis rheum 1982; 25: 647-654. 9. cabane j, michon a, ziza jm, bourgeois p, bletry o, godeau p, et al. comparison of long term evolution of adult onset and juvenile onset still’s disease, both followed up for more than 10 years. ann rheum dis 1990; 49: 283-285. 10. pouchot j, sampalis js, beaudet f, carette s, decary f, salusinsky-sternbach m, et al. adult still’s disease: manifestations, disease course, and outcome in 62 patients. medicine 1991; 70: 118-136. 11. sachs rn, talvard o, lanfranchi j. myocarditis in adult still’s disease. int j cardiol 1990; 27: 377-380. 12. taillan b fj, vinti h, casterla j, pesce a, meyer p, et al. adult onset still’s disease complicated by endocarditis with fatal evolution. clin rheumatol 1989; 8: 541. 13. corbett aj, zizic tm, stevens mb. adult onset still’s disease with an associated severe restrictive pulmonary defect: a case report. ann rheum dis 1983; 42: 452-454. 14. cantor jp, pitcher wd, hurd e. severe restrictive pulmonary defect in a patient with adult onset still’s disease. chest 1987; 92: 939-940. 15. cheema gs, quismorio fp. pulmonary involvement in adult onset still’s disease. curr opin pulm med 1999; 5: 305-309. 16. wouters jm, van de putte lb. adult onset still’s disease: clinical and laboratory features, treatment and progress of 45 cases. q j med 1986; 61: 1055-1065. 17. denault a, dimopoulos ma, fitzcharles ma. meningoencephalitis and peripheral neuropathy complicating adult still’s disease. j rheumatol 1990; 17: 698700. 18. esdaile jm, tannenbaum h, lough j, hawkins d. hepatic abnormalities in adult onset still’s disease. j rheumatol 1979: 673-679. 19. bujak js, aptekar rg, decker jl, wolff sm. juvenile rheumatoid arthritis presenting in adult as fever of unknown origin. medicine 1973; 52: 431-444. 20. cush jj, leibowtiz ih, friedman sa. adult onset still’s disease and inflammatory orbital pseudotumor. n y state j med 1985; 85: 110-111. 21. kuafman ld, sibony pa, anand ak, gruber bl. superior orbital tenosynovitis (brown’s syndrome) as a manifestation of adult still’s disease. j rheumatol 1987; 14: 625-627. 22. markusse hm, stolk b, van der mery ag, de jongebok jm, heering kj. sensorineural hearing loss in adult onset still’s disease. ann rheum dis 1988; 47: 600-602. 23. wedling d, hory b, blanc d. adult still’s disease and mesangial glomerulonephritis: a report of two cases. clin rheumatol 1990; 9: 95-99. 24. cush jj, medsger ta jr, christy wc, herbert dc, cooprestein la. adult-onset still’s disease: clinical course and outcome. arthritis rheum 1987; 30: 186194. 25. yamaguchi m, ohta a, tsunematsu t, kasukawa r, mizushima y, kashiwagi h, et al. preliminary criteria for classification of adult still’s disease. j rheumatol 1992; 19: 424-430. 26. masson c, le loet x, liote f, et al. comparative study of 6 types of criteria in adult still’s disease. j rheumatol 1996; 23:495-497. 27. ohta a, yamaguchi m, kaneoka h, nagayoshi t, hiida m. adult still’s disease: review of 228 case from the literature. j rheumatol 1987; 14: 1139-1146. 28. klippel jh, grofford lj, stone jh, weyand cm. primer on the rheumatic diseases. in:adult still’s disease. 12th ed: arthritis foundation, 2001; 427-430. 29. adult-onset still’s disease. in: maddison pj id, woo p, glass dn, ed. oxford textbook of rheumatology. 2nd ed: oxford medical publication, 1998; 1127-1131. 30. larson e. adult onset still’s disease: evolution of a clinical syndrome and diagnosis, treatment and follow up of 17 patients. medicine 1984; 63: 82-91. 31. vukman r, rag gj. juvenile rheumatoid arthritis with pericardial tamponade in an adult. arch itern med 1981; 141: 1078-1079. submitted 14 sep 2022 1 revision req. 25 oct 22; revision recd. 23 nov 22 2 accepted 8 dec 22 3 online-first: february 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.008 5 6 identification of asymptomatic severe acute respiratory syndrome 7 coronavirus 2 infections among healthcare workers at sultan qaboos 8 university hospital, oman 9 *amal al shibli,1 mahmood al jufaili,1 awatif al alawi,1 abdullah 10 balkhair,2 ibrahim al zakwani,3 faisal al azri,4 khuloud al maamari,5 11 fatma ba alawi,5 azza al qayoudhi,5 hajar al ghafri5 12 departments of 1emergency medicine, 2internal medicine, 4radiology & molecular imaging 13 and 5microbiology & immunology, sultan qaboos university hospital, muscat, oman; 14 3department of pharmacology & clinical pharmacy, college of medicine and health 15 sciences, sultan qaboos university, muscat, oman. 16 *corresponding author’s e-mail: ashibli@squ.edu.om 17 18 abstract 19 objectives: this study aimed to describe the incidence and features of asymptomatic 20 covid-19 infections among hcws at a tertiary hospital in oman. methods: this cross-21 sectional study was conducted between august 2020 and february 2021 among hcws with 22 no history of covid-19 infection using an online questionnaire to collect sociodemographic 23 and clinical data. covid-19 infection was diagnosed using nasopharyngeal/throat swabs, 24 which were tested for severe acute respiratory syndrome coronavirus 2 (sars-cov-2). 25 analyses were performed using chi-squared test, fisher’s exact test, or univariate ordinary 26 least squares regression, as appropriate. results: a total of 583 hcws participated in the 27 study. most were female (56.6%) and the mean age was 35  8 years . only 9.6% (95% 28 confidence interval [ci]: 7.3–12.3%) of the hcws were at high exposure risk as they were 29 directly involved in the care of covid-19-infected patients. overall, 4.1% (95% ci: 2.7–30 6.1%) of the hcws screened positive for sars-cov-2; of these, five (20.8%) developed 31 symptoms within two weeks. the frequency of sars-cov-2 positivity among hcws 32 mailto:ashibli@squ.edu.om working in high, intermediate, low, and miscellaneous risk areas was 1.8% (95% ci: <0.1–33 9.6%), 2.6% (95% ci: <0.1–6.5%), 5.3% (95% ci: 0.3–9.3%), and 4.8% (95% ci: <0.1–34 69.3%), respectively. working in high-risk areas was associated with increased compliance 35 with various infection control strategies (p <0.001). conclusion: there was a greater 36 frequency of sars-cov-2 positivity among hcws working in lower-risk areas, whereas 37 hcws who worked in high-risk areas were significantly more likely to report increased 38 compliance with infection control strategies. 39 keywords: sars-cov-2; covid-19 nucleic acid testing; asymptomatic infections; 40 health personnel; occupational exposure; infection control; real-time polymerase chain 41 reaction; oman. 42 43 advances in knowledge 44 to the best of the authors’ knowledge, the incidence of asymptomatic coronavirus 45 disease 2019 (covid-19) infections among healthcare workers (hcws) in oman has 46 not previously been reported. 47 this study found that the prevalence of asymptomatic covid-19 infections among 48 hcws working at a tertiary hospital in muscat, oman, was 4.1% (95% confidence 49 interval [ci]: 2.7–6.1%), including 1.8% (95% ci: <0.1–9.6%), 2.6% (95% ci: <0.1–50 6.5%), 5.3% (95% ci: 0.3–9.3%), and 4.8% (95% ci: <0.1–69.3%) of hcws 51 working in high, intermediate, low, and miscellaneous risk areas, respectively. 52 overall, hcws in high-risk areas were significantly more likely to adhere to covid-53 19 infection control practices, including hand hygiene and wearing appropriate 54 personal protective equipment during interactions with infected patients. 55 56 application to patient care 57 the findings of this study indicate that asymptomatic covid-19-infected hcws may 58 constitute a significant transmission risk in hospital settings. 59 hospital authorities should consider implementing routine interval screening to detect 60 asymptomatic infections among hcws. in addition, there is a need to increase 61 adherence to infection prevention and control strategies among asymptomatic hcws 62 in lower-risk areas to reduce the possibility of unknowingly transmitting the disease to 63 others. 64 65 introduction 66 coronavirus disease 2019 (covid-19) is a respiratory illness caused by severe acute 67 respiratory syndrome coronavirus 2 (sars-cov-2). clinical manifestations of covid-19 68 infection range from a mild cough and sore throat to fulminant pneumonia and multi-organ 69 failure; however, a notable proportion of infected patients may be asymptomatic, especially 70 in the early stages of infection.1–3 in the absence of symptoms, covid-19 infections can be 71 identified using a positive sars-cov-2 rna test or based on chest x-ray or computed 72 tomography findings.2 since the initial outbreak of the disease in december 2019, covid-19 73 has proven to be highly transmissible, with more than 5.9 million confirmed cases worldwide 74 as of august 2022.4 75 76 according to back casting statistical estimates, the rate of covid-19 infection in the general 77 population is 6.08% (95% confidence interval [ci]: 4.24–10.68%).5 however, people who 78 reside or work in densely populated or confined environments such as cruise ships, homeless 79 shelters, and prisons can have even higher rates of infection.6–8 in addition, healthcare 80 workers (hcws) are at a generally increased risk of covid-19 infection due to their 81 exposure to, and their role in the care and management of, infected patients. in hubei, 82 china—the epicentre of the covid-19 outbreak—the number of infected hcws increased 83 from 1,502 to 3,062 in the span of 13 days.9 in the uk, a recent study reported that up to 84 24.4% of asymptomatic hcws may demonstrate sars-cov-2 seropositivity.10 85 86 asymptomatic covid-19 infections are defined by evidence of sars-cov-2 positivity in 87 the absence of self-reported or clinically discernible symptoms.3 the identification of 88 asymptomatic cases is an important factor in better understanding the epidemiology of 89 infectious diseases and may help inform appropriate measures to prevent transmission. 90 researchers have warned of the dangers posed by “invisible epidemics” or “silent spread”, 91 both because asymptomatic carriers are unlikely to seek timely treatment—which is 92 concerning as the absence of symptoms does not mean a lack of subclinical damage to the 93 lungs or other organs—as well as because of the risk they pose in unknowingly transmitting 94 the infection to others.11,12 a recent systematic review and meta-analysis by ma et al. found 95 the pooled percentage of asymptomatic sars-cov-2 infections to be 0.25% (95% ci: 0.23–96 0.27%) among 29,776,306 individuals reported in 95 studies, representing 40.5% of all 97 infections detected in the tested population.13 similarly, a narrative review by oran et al. 98 indicated that up to 40–45% of reported sars-cov-2 infections are asymptomatic in 99 nature.12 100 101 in the gulf cooperation council region, few studies have sought to assess the frequency of 102 asymptomatic infections among hcws. in the united arab emirates, researchers reported 103 that up to 43% of identified covid-19 cases were asymptomatic; however, only 3% of the 104 covid-19-infected patients being studied (i.e., both symptomatic and asymptomatic cases) 105 were employed in occupations with high exposure risk, including hcws.14 al-hakami et al. 106 identified the prevalence of asymptomatic infections to be 18.3% among 186 hcws working 107 in tertiary care centres in southwestern saudi arabia.15 another study found that the 108 seroprevalence of sars-cov-2 was 3.2% among asymptomatic hcws in a larger tertiary 109 hospital in riyadh, saudi arabia.16 however, to the best of the authors’ knowledge, the 110 incidence of asymptomatic covid-19-infected hcws in oman has not previously been 111 reported. furthermore, it is unclear whether specific clinical or sociodemographic factors 112 influence the risk of asymptomatic infection in this population. as such, this study aimed to 113 identify the prevalence of and sociodemographic and clinical characteristics associated with 114 covid-19 infections among asymptomatic hcws working at a tertiary university hospital in 115 muscat, oman. 116 117 methods 118 this cross-sectional study was conducted between august 2020 and february 2021 at the 119 sultan qaboos university hospital (squh), a large tertiary university hospital in muscat, 120 oman. the target population included all asymptomatic hcws from different squh 121 departments and of all job titles and responsibilities, including physicians, nurses, medical 122 orderlies and administrative and security personnel. only hcws without a previous diagnosis 123 of covid-19 disease were eligible for inclusion in the study. as such, the inclusion criteria 124 comprised hospital staff working in all clinical or administrative areas of the hospital. the 125 exclusion criteria consisted of staff who were symptomatic on the day of recruitment or those 126 who reported a history of positive sars-cov-2 swab results at any point beforehand. 127 however, staff who reported symptoms within 7 days of swab collection were included in the 128 study so long as they were asymptomatic upon the day of recruitment/collection. 129 130 an invitation to participate in the study was published on the hospital’s home page to recruit 131 participants. respondents were initially screened for inclusion in the study to identify those 132 who were asymptomatic and had no history of covid-19 infection. based on the initial 133 sample size calculation, a total of 992 subjects were needed (496 in each arm) to ensure 90% 134 power to detect a statistical difference of 10% (i.e., 30% versus 40% when detecting covid-135 19 in high-risk versus low-risk areas) at the 5% alpha level. however, only 583 hcws were 136 recruited and included in the final sample. participants were subsequently categorised into 137 four groups based on their level of risk of exposure to covid-19 infected patients, 138 including: (1) high-risk (i.e., hcws working in covid-19 wards or the covid intensive 139 care unit [icu]); (2) intermediate-risk (i.e., hcws working in the emergency medicine or 140 family medicine and public health departments and laboratories); (3) low-risk (i.e., hcws 141 working in all other wards, non-covid-19 icu, paediatric icu, and ambulatory clinics); 142 and (4) miscellaneous risk (i.e., all remaining hcws). 143 144 an online questionnaire was used to collect sociodemographic data from the participants, 145 including their gender, age, working area, place of residence, occupation and education level. 146 in addition, clinical information was elicited, including self-assessed symptomatology, 147 history of contact with covid-19-infected persons, personal protective equipment (ppe) use 148 and training, and other relevant epidemiological risk factors, including a recent history of 149 inter-city travel or attendance at large social gatherings. the questionnaire was adapted from 150 the world health organization’s data template; however, modifications were made to include 151 additional information, such as epidemiological risk factors, and the modified version of the 152 questionnaire was not validated.17 subsequently, combined nasopharyngeal/throat swabs 153 were collected from all participants by trained research assistants. rna was extracted from 154 the respiratory samples using fully automated nucleic acid extraction systems, including 155 either the magna pure lc 2.0 total nucleic acid isolation kit (roche diagnostics gmbh, 156 mannheim, germany) or liferiver ex3600 automated nucleic acid extraction system 157 (shanghai bio-tech co. ltd., shanghai, china). 158 159 the extracted rna was tested for sars-cov-2 using real-time polymerase chain reaction 160 (pcr) performed using either the lightmix® modular sars-cov-2 assay (roche 161 diagnostics gmbh), liferiver novel coronavirus real time multiplex rt-pcr (shanghai 162 bio-tech co. ltd.), or taqpath™ rt-pcr covid-19 kit (thermo fisher scientific inc., 163 waltham, massachusetts, usa). samples were considered positive when at least two targeted 164 genes were detected, negative when all targeted genes were negative, and inconclusive when 165 only one gene was detected. repeat sampling and testing was performed for all inconclusive 166 cases. participants with positive covid-19 results were informed of their diagnosis within 167 24–48 hours and quarantined as per local guidelines; in addition, they were assessed for 168 symptomatology for up to 2 weeks from the time of test positivity. 169 170 statistical analyses were conducted using the stata statistical software package, version 171 16.1 (stata corp., college station, texas, usa). descriptive results were presented as 172 frequencies and percentages (categorical variables) or means and standard deviations 173 (continuous variables), as appropriate. differences between exposure risk groups (i.e., hcws 174 working in high, intermediate, low, and miscellaneous risk areas) were analysed using either 175 pearson’s chi-squared test or fisher’s exact test (for cell frequencies of <5). differences 176 between continuous variables were assessed using univariate ordinary least squares 177 regression. the a priori two-tailed level of significance was set at the 0.05 level. 178 179 ethical approval for this study was obtained from the medical research and ethics 180 committee of sultan qaboos university, muscat, oman. all hcws provided written 181 informed consent prior to participation in the study. all study procedures were performed in 182 accordance with local and international ethical standards. data confidentiality was ensured at 183 all times in order to ensure privacy. 184 185 results 186 of the 583 hcws who participated in the study, over half were female (n = 330; 56.6%) and 187 approximately one-third (n = 212; 36.4%) were of omani nationality. the mean age was 35  188 8 years (range: 22–59 years). overall, 24 hcws (4.1%; 95% ci: 2.7–6.1%) tested positive 189 for sars-cov-2 based on the rna test; of these, five (20.8%; 95% ci: 7.1–42.2%) 190 developed covid-19 symptoms within two weeks of swab collection, including cough, 191 fever, sore throat, body aches, and pain. in addition, some of the participants reported a 192 history of symptoms within the week prior to the swab collection, although they were 193 asymptomatic upon enrolment into the study. the three most common of the pre-swab 194 symptoms were sore throat (n = 48; 8.2%;), muscle aches (n = 47; 8.1%), and fatigue (n = 42; 195 7.2%). 196 197 the distribution of sars-cov-2 positivity among asymptomatic hcws working in high, 198 intermediate, low, and miscellaneous risk areas was 1.8% (95% ci: <0.1–9.6%), 2.6% (95% 199 ci: <0.1–6.5%), 5.3% (95% ci: 0.3–9.3%), and 4.8% (95% ci: <0.1–69.3%), respectively 200 [table 1]. high-risk areas were more likely to be staffed by women than men in comparison 201 to intermediate, low, or miscellaneous risk areas (71.4% versus 64.3%, 65.2%, and 33.7%, 202 respectively; p <0.001). in addition, participants who reported having a sore throat in the 203 week prior to swab collection were less likely to work in high-risk areas compared to 204 intermediate, low, or miscellaneous risk areas (1.8% versus 10.4%, 11.1%, and 4.8%, 205 respectively; p = 0.026). no significant differences in age or other symptomatology were 206 noted according to differences in risk areas, including fever, fatigue, cough, sore throat, loss 207 of taste or smell, shortness of breath, chest pains, muscle aches, and 208 nausea/vomiting/diarrhoea. 209 210 participants working in high-risk areas were significantly more likely to adhere to anti-211 covid-19 protective measures compared to hcws working in intermediate, low, or 212 miscellaneous risk areas. specifically, they were significantly more likely to wear ppe as 213 recommended during interactions with covid-19-infected patients (94.6% versus 86.4%, 214 57.5%, and 54.8%, respectively; p <0.001) and perform hand hygiene before and after 215 interactions with covid-19-infected patients (94.6% versus 89.6%, 66.2%, and 63.3%, 216 respectively; p <0.001). in addition, when performing aerosol-generating procedures on 217 covid-19-infected patients, hcws working in high-risk areas were significantly more 218 likely to wear gloves (92.9% versus 85.7%, 61.8%, and 56.6%, respectively; p <0.001), wear 219 fit-tested n95 or equivalent respirators (69.6% versus 46.1%, 39.6%, and 44%, respectively; 220 p <0.001), wear face shields (92.9% versus 81.8%, 53.1%, and 47.6%, respectively; p 221 <0.001), and remove and replace their ppe according to hospital policy (92.9% versus 222 85.7%, 69.9%, and 53%, respectively; p <0.001) compared to those working in intermediate, 223 low, or miscellaneous risk areas. no significant differences were observed in terms of recent 224 epidemiological risk factors (e.g., recent history of travel, attendance at social gatherings, or 225 contact with an infected person) according to differences in exposure risk [table 2]. 226 227 discussion 228 in the current study, the overall prevalence of asymptomatic covid-19 infections among 229 hcws working at a large tertiary hospital in muscat was 4.1%; of these, 20.8% developed 230 mild symptoms within two weeks of swab collection. previous studies have shown 231 comparable prevalence rates of positive sars-cov-2 findings among asymptomatic hcws 232 elsewhere around the world (3.4–7.1%).18–20 overall, 9.6% of the asymptomatic hcws 233 enrolled in the present study were involved directly in the care of covid-19-infected 234 patients and therefore faced a high risk of exposure to infection, while 64% had either a low 235 or miscellaneous/unknown risk of exposure to covid-19-infected patients. 236 237 interestingly, adherence to various covid-19 infection control and protective measures was 238 significantly higher among hcws working in high-risk areas in the current study compared 239 to those working in lower-risk areas. this could be attributed to an increased awareness of 240 patient covid-19 status and clinical condition on the part of hcws working in high-risk 241 areas. nevertheless, it is important to acknowledge that pre-admission pcr testing for 242 covid-19 was not mandatory for asymptomatic patients; as a result, hcws working in low-243 risk areas may have been more frequently exposed to undiagnosed patients without being 244 aware. on the other hand, no significant differences were noted with regards to the frequency 245 of various epidemiological risk factors regardless of risk exposure level, including recent 246 inter-city travel, attendance at social gatherings, and visiting relatives. however, due to the 247 self-reported nature of these findings, the role of community transmission cannot be 248 dismissed entirely. 249 250 there is evidence to indicate that viral shedding and disease transmission can occur in the 251 absence of symptoms (asymptomatic cases), as well as before symptom onset 252 (presymptomatic cases).21–23 he et al. estimated that viral shedding in patients with 253 laboratory-confirmed covid-19 infections peaked at or before symptom onset, thus posing a 254 substantial risk of transmission before symptoms in the index case are clinically discernible.21 255 moreover, according to an analysis of seven epidemiological clusters, wei et al. found that 256 presymptomatic transmission of covid-19 occurred on an average of 1–3 days before 257 symptom onset.22 zou et al. reported that viral loads detected in asymptomatic patients were 258 similar to those found in symptomatic patients; in addition, the researchers confirmed that the 259 median duration of viral shedding among asymptomatic individuals was 16.4 days 260 (interquartile range: 7–28 days), comparable to symptomatic patients with mild-to-moderate 261 disease severity.23 such findings highlight the importance of preventing the spread of 262 infections by asymptomatic individuals. 263 264 chow et al. assessed the spectrum of initial symptoms among hcws working in a long-term 265 care facility in the usa; the researchers found that the median interval between disease onset 266 and the appearance of established covid-19 screening symptoms was 2 days (range: 1–7 267 days).24 treibel et al. also noted that 27% of hcws working in a uk-based hospital who 268 tested positive for sars-cov-2 reported no symptoms in the week before or after testing 269 positive.18 more inclusive contact tracing criteria are therefore needed to capture potential 270 transmission events before symptom onset.21,22 thus, a universal testing strategy, rather than 271 a symptom-triggered approach, is recommended to identify and mitigate the spread of 272 covid-19 by asymptomatic individuals.24 moreover, the use of combined nasal/throat swabs 273 is recommended due to conflicting findings as to differences in viral loads detected in swab 274 samples obtained from the nose compared to the throat.22,23 chow et al. also noted that the 275 inclusion of additional symptoms during covid-19 screening, such as myalgias and chills, 276 increased case detection by 6.3%.24 277 278 the findings of this study underscore the need for additional measures to prevent 279 asymptomatic infection spread by hcws. it is recommended that all hcws routinely wear 280 face masks and other appropriate ppe and conform to institutional hand hygiene and 281 infection control measures in order to prevent presymptomatic or asymptomatic transmission. 282 such measures are particularly crucial for hcws working in critical, chronic or long-term 283 patient care and in areas with a high frequency of community transmission.24 other 284 researchers have also recommended the implementation of a traffic control bundling 285 approach to protect hcws and to mitigate infection spread during epidemics in which 286 patients are triaged prior to entering the hospital and there is a clear segregation of different 287 risk zones, with strict disinfection protocol stations set up at inter-zone boundaries.25,26 288 289 nevertheless, it is important to note that such recommendations may not be helpful to prevent 290 the spread of covid-19 infections via community transmission. the difference between 291 nosocomial and community infections is contingent upon setting; nosocomial infections refer 292 to those that originate in hospital settings, so long as the infection was not present or 293 incubating upon admission, while community-acquired infections represent those which 294 develop elsewhere.27 developing effective infection prevention and control measures is only 295 possible by understanding differences between specific transmission settings and how these 296 contribute to the spread of a specific disease.28 however, distinguishing between hospital-297 acquired and community infections is often challenging due to uncertainty as to the onset of 298 the infection (i.e., prior to or within 48 hours of admission to hospital). moreover, in the 299 context of the present study, this determination would be made even more difficult in the 300 absence of clinically discernible symptomatology. as such, stringent surveillance measures 301 for all patients upon admission, and the routine screening of hcws, are recommended to 302 determine whether covid-19 infections can be classified as community or hospital-303 acquired. 304 305 this study was subject to several limitations, including the observational design, small 306 sample size, and absence of compulsory covid-19 screening for hcws. the present study 307 was also limited by the smaller sample size (n = 583) in relation to original requirements 308 based on sample size calculations with 90% power (n = 992). further studies are therefore 309 warranted to corroborate the findings. due to the voluntary nature of enrolment, there is a 310 high possibility of selection bias in the sample. furthermore, as a single-centre study 311 covering a known geographical area, the findings may not reflect the true incidence of 312 asymptomatic hcws in other institutions in muscat or elsewhere in oman. moreover, the 313 study period did not include the peak of the pandemic which could have resulted in a lower 314 prevalence. it is also important to note that the analysis did not distinguish between 315 asymptomatic and presymptomatic infections and did not consider vaccination status as the 316 vaccine roll-out in oman occurred after the recruitment and data collection process had 317 already begun. 318 319 in addition, the current study did not assess individual levels of occupational risk exposure 320 other than by designating risk levels to specific working areas. thus, future research should 321 be conducted to determine individual levels of occupational risk exposure, for instance using 322 the who risk assessment tool for hcws.29 in addition, other variables which could influence 323 risk of infection, such as demographic characteristics and ethnicity, were not considered in 324 the analysis. these factors should be considered in future studies. finally, findings related to 325 the participants’ recent epidemiological history were self-reported in nature and may 326 therefore have been subject to recall and social desirability bias; as such, community 327 transmission might have played a more significant role in the transmission of covid-19 328 among hcws than indicated. 329 330 conclusion 331 asymptomatic covid-19-infected hcws constitute a significant transmission risk in 332 hospital settings. overall, 4.1% of the studied asymptomatic hcws screened were positive 333 for sars-cov-2. moreover, there was greater frequency of sars-cov-2 positivity among 334 hcws working in lower-risk areas, whereas hcws who worked in high-risk areas were 335 significantly more likely to report increased compliance with infection control strategies. 336 hospital authorities should therefore implement interval screening for the detection of 337 asymptomatic infections among hcws, in addition to enforcing adherence to infection 338 control strategies. 339 340 acknowledgement 341 we thank the research council, oman for funding this project. we thank all colleagues from 342 sultan qaboos university hospital who provided insight and expertise that greatly assisted 343 the research. we also thank sn. karen manlangit and sn. amira al abri from emergency 344 medicine department for their help as research assistants. we thank all the participants who 345 helped in making this research successful. 346 347 conflicts of interest 348 the authors declare no conflict of interests. 349 350 funding 351 funding for this study was obtained from the research council, oman 352 353 authors’ contribution 354 aas, maj, aaa and ab conceptualized and designed the study. aas, aaa and iaz 355 drafted the proposal and maj revised it. aas, maj, aaa and ab prepared the 356 questionnaire. aas and aaa supervised the work and the data collection process. faa 357 provided equipment needed for sample analysis. kam, fba, aaq and hag contributed to 358 the processing of laboratory samples. aas and aaa analysed the data. iaz provided 359 statistical advice on study design and conducted the statistical analysis of the data. aas, 360 aaa, ab, iaz and kam contributed to drafting the manuscript. aas, maj, aaa, ab, 361 iaz and kam revised the manuscript. all authors approved the final version of the 362 manuscript. 363 364 references 365 1. da rosa mesquita r, francelino silva jr lc, santos santana fm, de oliveira tf, 366 campos alcântara r, monteiro arnozo g, et al. clinical manifestations of covid-19 367 in the general population: systematic review. wien klin wochenschr 2021; 133:377–368 82. https://doi.org/10.1007/s00508-020-01760-4. 369 2. lai cc, liu yh, wang cy, wang yh, hsueh sc, yen my, et al. asymptomatic 370 carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory 371 syndrome coronavirus 2 (sars-cov-2): facts and myths. j microbiol immunol 372 infect 2020; 53:404–12. https://doi.org/10.1016/j.jmii.2020.02.012. 373 3. you y, yang x, hung d, yang q, wu t, deng m. asymptomatic covid-19 374 infection: diagnosis, transmission, population characteristics. bmj support palliat 375 care 2021 [online ahead of print]. https://doi.org/10.1136/bmjspcare-2020-002813. 376 4. world health organization. coronavirus (covid-19) dashboard. from: 377 https://covid19.who.int/ accessed: may 2020. 378 5. phipps sj, grafton rq, kompas t. robust estimates of the true (population) infection 379 rate for covid-19: a backcasting approach. r soc open sci 2020; 7:200909. 380 https://doi.org/10.1098/rsos.200909. 381 6. mizumoto k, kagaya k, zarebski a, chowell g. estimating the asymptomatic 382 proportion of coronavirus disease 2019 (covid-19) cases on board the diamond 383 princess cruise ship, yokohama, japan, 2020. euro surveill 2020; 25:2000180. 384 https://doi.org/10.2807/1560-7917.es.2020.25.10.2000180. 385 7. baggett tp, keyes h, sporn n, gaeta jm. covid-19 outbreak at a large homeless 386 shelter in boston: implications for universal testing. medrxiv 2020; 04:20059618. 387 https://doi.org/10.1101/2020.04.12.20059618. 388 8. wallace d, eason jm, walker j, towers s, grubesic th, nelson jr. is there a 389 temporal relationship between covid-19 infections among prison staff, incarcerated 390 persons and the larger community in the united states? int j environ res public 391 health 2021; 18:6873. https://doi.org/10.3390/ijerph18136873. 392 9. xiang b, li p, yang x, zhong s, manyande a, feng m, et al. the impact of novel 393 coronavirus sars-cov-2 among healthcare workers in hospitals: an aerial overview. 394 am j infect control 2020; 48:915–17. https://doi.org/10.1016/j.ajic.2020.05.020. 395 10. shields a, faustini se, perez-toledo m, jossi s, aldera e, allen jd, et al. sars-396 cov-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a 397 cross-sectional study. thorax 2020; 75:1089–94. https://doi.org/10.1136/thoraxjnl-398 2020-215414. 399 11. jamrozik e, selgelid mj. invisible epidemics: ethics and asymptomatic infection. 400 monash bioeth rev 2020; 38:1–16. https://doi.org/10.1007/s40592-020-00123-z. 401 12. oran dp, topol ej. prevalence of asymptomatic sars-cov-2 infection: a narrative 402 review. ann intern med 2020; 173:362–7. https://doi.org/10.7326/m20-3012. 403 https://covid19.who.int/ 13. ma q, liu j, liu q, kang l, liu r, jing w, et al. global percentage of asymptomatic 404 sars-cov-2 infections among the tested population and individuals with confirmed 405 covid-19 diagnosis: a systematic review and meta-analysis. jama netw open 406 2021; 4:e2137257. https://doi.org/10.1001/jamanetworkopen.2021.37257. 407 14. al hosani f, aden b, al memari s, al mazrouei s, ajab s, abid m, et al. 408 epidemiology of asymptomatic and symptomatic coronavirus disease 2019 409 confirmed cases in the emirate of abu dhabi, united arab emirates: observational 410 study. medicine (baltimore) 2021; 100:e25219. 411 https://doi.org/10.1097/md.0000000000025219. 412 15. al-hakami am, al bshabshe a, alkahtani am, alsabaani aa, shehata sf, omar h, 413 et al. covid-19 among the asymptomatic healthcare workers in the tertiary care 414 centers of the southwestern region of saudi arabia: preventive and protective 415 insights. bahrain med bull 2022; 44:896–904. 416 16. almaghrabi rs, alsagheir oi, alquaiz rm, alhekail oz, abaalkhail am, alduaij 417 aa, et al. seroprevalence of sars-cov-2 antibodies in healthcare workers at a 418 tertiary care hospital in riyadh, saudi arabia. ijid reg 2022; 2:51–4. 419 https://doi.org/10.1016/j.ijregi.2021.11.009. 420 17. world health organization. risk assessment and management of exposure of health 421 care workers in the context of covid-19: data template. from: 422 https://www.who.int/publications/m/item/risk-assessment-and-management-of-423 exposure-of-health-care-workers-in-the-context-of-covid-19-data-template accessed: 424 apr 2020. 425 18. treibel ta, manisty c, burton m, mcknight á, lambourne j, augusto jb, et al. 426 covid-19: pcr screening of asymptomatic health-care workers at london hospital. 427 lancet 2020; 395:1608–10. https://doi.org/10.1016/s0140-6736(20)31100-4. 428 19. zhao d, wang m, wang m, zhao y, zheng z, li x, et al. asymptomatic infection by 429 sars-cov-2 in healthcare workers: a study in a large teaching hospital in wuhan, 430 china. int j infect dis 2020; 99:219–25. https://doi.org/10.1016/j.ijid.2020.07.082. 431 20. rivett l, sridhar s, sparkes d, routledge m, jones nk, forrest s, et al. screening of 432 healthcare workers for sars-cov-2 highlights the role of asymptomatic carriage in 433 covid-19 transmission. elife 2020; 9:e58728. https://doi.org/10.7554/elife.58728. 434 21. he x, lau ehy, wu p, deng x, wang j, hao x, et al. temporal dynamics in viral 435 shedding and transmissibility of covid-19. nat med 2020; 26:672–5. 436 https://doi.org/10.1038/s41591-020-0869-5. 437 https://www.who.int/publications/m/item/risk-assessment-and-management-of-exposure-of-health-care-workers-in-the-context-of-covid-19-data-template https://www.who.int/publications/m/item/risk-assessment-and-management-of-exposure-of-health-care-workers-in-the-context-of-covid-19-data-template 22. wei we, li z, chiew cj, yong se, toh mp, lee vj. presymptomatic transmission 438 of sars-cov-2: singapore, january 23–march 16, 2020. mmwr morb mortal 439 wkly rep 2020; 69:411–15. https://doi.org/10.15585/mmwr.mm6914e1. 440 23. zou l, ruan f, huang m, liang l, huang h, hong z, et al. sars-cov-2 viral load 441 in upper respiratory specimens of infected patients. n eng j med 2020; 382:1177–9. 442 https://doi.org/10.1056/nejmc2001737. 443 24. chow ej, schwartz ng, tobolowsky fa, zacks rlt, huntington-frazier m, reddy 444 sc, et al. symptom screening at illness onset of health care personnel with sars-445 cov-2 infection in king county, washington. jama 2020; 323:2087–9. 446 https://doi.org/10.1001/jama.2020.6637. 447 25. schwartz j, king cc, yen my. protecting health care workers during the coronavirus 448 disease 2019 (covid-19) outbreak: lessons from taiwan’s severe acute respiratory 449 syndrome response. clin infect dis 2020; 71:858–60. 450 https://doi.org/10.1093/cid/ciaa255. 451 26. yen my, schwartz j, hsueh pr, chiu awh, armstrong d. traffic control bundling 452 is essential for protecting healthcare workers and controlling the 2014 ebola 453 epidemic. clin infect dis 2015; 60:823–5. https://doi.org/10.1093/cid/ciu978. 454 27. ducel g, fabry j, nicolle l. prevention of hospital-acquired infections: a practical 455 guide, 2nd ed. geneva, switzerland: world health organization, 2002. 456 28. revelas a. healthcare-associated infections: a public health problem. niger med j 457 2012; 53:59–64. https://doi.org/10.4103/0300-1652.103543. 458 29. world health organization. risk assessment and management of exposure of health 459 care workers in the context of covid-19: interim guidance, 19 march 2020. from: 460 https://apps.who.int/iris/handle/10665/331496 accessed: nov 2022. 461 462 https://doi.org/10.1093/cid/ciu978 https://doi.org/10.4103/0300-1652.103543 https://apps.who.int/iris/handle/10665/331496 table 1: distribution of positive coronavirus disease 2019 cases among asymptomatic 463 healthcare workers at sultan qaboos university hospital, muscat, oman, according to in-464 hospital exposure risk status (n = 583) 465 risk* status n (%) total positive† covid-19 cases high 56 (9.6) 1 (1.8) intermediate 154 (26.4) 4 (2.6) low 207 (35.5) 11 (5.3) miscellaneous 166 (28.5) 8 (4.8) total 583 (100) 24 (4.1) covid-19 = coronavirus disease 2019. *participants were stratified according to level of 466 risk of exposure to covid-19 infected patients as either high-risk (those working in covid-467 19 wards or the covid intensive care unit [icu]), intermediate-risk (those working in the 468 emergency medicine or family medicine and public health departments and laboratories), 469 low-risk (those working in all other wards, the non-covid-19 icu, paediatric icu, and 470 ambulatory clinics), or miscellaneous risk (those working in all other hospital areas). 471 †positivity was based on real-time polymerase chain reaction of rna extracted from 472 combined nasopharyngeal/throat swab samples. 473 474 table 2: epidemiological history and adherence to anti-coronavirus disease 2019 protective measures among asymptomatic healthcare workers 475 at sultan qaboos university hospital, muscat, oman, stratified by in-hospital exposure risk (n = 583) 476 item risk* status, n (%) p value high (n = 56) intermediate (n = 154) low (n = 207) miscellaneous (n = 166) e p id e m io lo g ic a l h is to r y have you recently traveled between cities? 7 (12.5) 23 (14.9) 32 (15.5) 22 (13.3) 0.904 have you attended a gathering with a person who has had sars-cov-2 detected? 3 (5.4) 22 (14.3) 16 (7.7) 20 (12) 0.115 have you visited relatives within the last 14 days? 7 (12.5) 29 (18.8) 39 (18.8) 38 (22.9) 0.397 have many times have you gone shopping in the last 14 days? 0.437 1–2 44 (78.6) 111 (72.1) 157 (75.8) 134 (80.7) 3–5 10 (17.9) 35 (22.7) 44 (21.3) 24 (14.5) >5 2 (3.6) 8 (5.2) 6 (2.9) 8 (4.8) how often do you adhere to physical distancing requirements (i.e., keeping 1–2 m from others) during your daily activities? 0.448 always 12 (21.4) 29 (18.8) 32 (15.5) 17 (10.2) mostly 34 (60.7) 87 (56.5) 125 (60.4) 103 (62) sometimes 10 (17.9) 37 (24) 49 (23.7) 46 (27.7) never 0 (0) 1 (0.6) 1 (0.5) 0 (0) have you provided direct care to a confirmed covid-19 patient? 52 (92.9) 95 (61.7) 53 (25.6) 20 (12) <0.001 have you had unprotected contact with a confirmed covid-19 patient? 10 (17.9) 41 (26.6) 19 (9.2) 9 (5.4) <0.001 were you present during any aerosol-generating procedure performed on a patient? 39 (69.6) 65 (42.2) 27 (13) 10 (6) <0.001 were you recently in an environment in which a confirmed covid-19 patient was present? 47 (83.9) 102 (66.2) 66 (31.9) 30 (18.1) <0.001 c o m p li a n c e w it h i n fe c ti o n c o n tr o l m e a su r e s have you been wearing ppe as recommended during interactions with covid-19-infected patients? 53 (94.6) 133 (86.4) 119 (57.5) 91 (54.8) <0.001 do you remove ppe as recommended after interactions with covid-19-infected patients? 53 (94.6) 132 (85.7) 118 (57) 93 (56) <0.001 do you perform hand hygiene before and after interactions with covid-19-infected patients? 53 (94.6) 138 (89.6) 137 (66.2) 105 (63.3) <0.001 do you wear ppe during any aerosol-generating procedures performed on covid-19-infected patients? 51 (91.1) 132 (85.7) 119 (57.5) 88 (53) <0.001 do you wear gloves during aerosol-generating procedures performed on a covid-19 patient? 52 (92.9) 132 (85.7) 128 (61.8) 94 (56.6) <0.001 do you wear fit-tested n95 or equivalent respirators during aerosol-generating procedures performed on covid-19infected patients? 39 (69.6) 71 (46.1) 82 (39.6) 73 (44) 0.001 do you wear face-shields during aerosol-generating procedures performed on covid-19-infected patients? 52 (92.9) 126 (81.8) 110 (53.1) 79 (47.6) <0.001 do you wear disposable gowns during aerosol-generating procedures performed on covid-19-infected patients? 52 (92.9) 131 (85.1) 120 (58) 84 (50.6) <0.001 do you remove and replace ppe according to hospital regulations during aerosol-generating procedures performed on covid-19-infected patients? 52 (92.9) 132 (85.7) 124 (59.9) 88 (53) <0.001 sars-cov-2 = severe acute respiratory syndrome coronavirus 2; covid-19 = coronavirus disease 2019. *participants were stratified 477 according to level of risk of exposure to covid-19 infected patients as either high-risk (those working in covid-19 wards or the covid 478 intensive care unit [icu]), intermediate-risk (those working in the emergency medicine or family medicine and public health departments and 479 laboratories), low-risk (those working in all other wards, the non-covid-19 icu, paediatric icu, and ambulatory clinics), or miscellaneous 480 risk (those working in all other hospital areas). 481 1department of research section, royal hospital, muscat, oman; 2department of emergency, khoula hospital, muscat, oman; 3department of primary health care, ministry of health, muscat, oman *corresponding author’s e-mail: ammar.alkashmiri@moh.gov.om clinical profile of stroke patients presenting to the emergency department of a major stroke centre in oman hasina a. al harthi,1 *ammar al kashmiri,2 lubna m. zakaryia,2 jawad a. al-lawati,3 omar m. najem,1 isra al-lawati,1 ghulam r. memon,1 amr a. elfaham1 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 91–97, epub. 28 feb 22 submitted 14 aug 20 revisions req. 14 oct & 9 dec 20; revisions recd. 20 nov & 15 dec 20 accepted 29 dec 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.062 clinical & basic research abstract: objectives: stroke is a significant public health problem and one of the most important preventable non-communicable diseases. preventive stroke programmes with a better focus on increasing awareness among those who are currently at risk are yet to be properly established in oman. this study was conducted to describe the characteristics of stroke patients presenting to a tertiary care hospital in oman. methods: this crosssectional hospital-based study included 193 stroke cases which were prospectively recruited from the emergency department of khoula hospital, muscat, oman. data were collected from november 2017 to april 2018. results: the total number of patients was 193 with 82.9% of strokes being ischaemic strokes. of this, 58% were male. the mean age of stroke patients was 61.05 years. risk factors included hypertension (72.5%) and diabetes mellitus (54.4%). dyslipidaemia, atrial fibrillation and ischaemic heart diseases were not particularly prevalent in the studied population and 24.4% of ischaemic strokes had large artery atherosclerosis while 21.9% had small vessel occlusion. significantly more patients had lower glasgow coma scale scores, required intensive care unit admission and experienced in-hospital deaths due to haemorrhagic stroke compared to ischaemic stroke. conclusion: this study provides essential data regarding stroke characteristics specific to oman’s population. most of the information obtained appears to be in-line with what has been described internationally and, hence, preventive strategies similar to those indicated in extant literature can be implemented. this information can be utilised by health administrators in planning resource allocation. further research is needed to explore rehabilitation aspects and long-term outcomes. keywords: stroke; ischemic stroke; haemorrhagic stroke; risk factors; thrombolytic therapy; epidemiology; oman. advances in knowledge this study provides information on the characteristics of stroke patients specific to the local population of oman and compares them to benchmark international trends. information on the different risk factors associated with stroke in this population can help guide the development of specific preventive and possibly rehabilitative strategies for stroke. application to patient care this study highlights various stroke-related aspects among patients sustaining a stroke, one of the main causes of morbidity and mortality in oman. identifying the main risk factors is important in targeting the patient population at risk and providing them with the necessary means of prevention through better control of their disease. stroke is a prevalent illness worldwide withassociated morbidity, mortality and financial costs to health systems. it is the second most common cause of death and the third most common cause of disability-adjusted life-years (dalys) lost globally.1 stroke is more prevalent in the middle east compared to the western world with an annual incidence of 180 per 100,000 individuals, with ischaemic stroke being the most common subtype.2 one study revealed that it was the leading cause of death in several middle-income arab countries.3 although the overall percentage of the average stroke-related dalys lost is thought to have declined in some arab countries, the global burden of stroke continues to rise.4 the financial costs of strokes are multitudinous due to its effects on the health system as well as the economy from loss of labour, among other costs related to the survivors and their caregivers. strokes constitute a significant public health problem, being one of the important preventable non communicable diseases.5 the majority of risk factors for stroke are modifiable; therefore, preventive strategies would be effective in reducing the incidence of new and recurrent stroke. preventive stroke programmes with a better focus on increasing awareness among those who are currently at risk are yet to be properly https://creativecommons.org/licenses/by-nd/4.0/ clinical profile of stroke patients presenting to the emergency department of a major stroke centre in oman 92 | squ medical journal, februay 2022, volume 21, issue 1 established in many countries, including oman. patientsat risk of developing stroke have poor aware ness of their risks, according to one study from a primary healthcare setting in oman.6 furthermore, it appears that many other neighbouring countries of the gulf cooperation council (gcc) seem no different, with less than a third of the at-risk patients in these countries being barely familiar with the meaning of stroke.7 to the best of the authors’ knowledge, there has been only a single abstract of a study on ischaemic stroke patients in oman that has been published thus far.8 no detailed studies have been conducted in oman on stroke patients and hence, this study will be the first to provide the aforementioned information. this study aimed to describe the features of stroke presented by patients to a stroke centre in a tertiary care hospital in oman. the findings could aid health system planners in decisions for more efficient resource allocation, including necessary clinical services and development of preventive strategies. methods this cross-sectional hospital-based study included 193 stroke patients prospectively recruited from the emergency department (ed) of khoula hospital (kh) from november 2017 to april 2018. kh is one of the main governmental tertiary hospitals with a functioning stroke unit in the capital city of muscat in oman. in addition, it is the only tertiary stroke centre under the ministry of health with a stroke unit in muscat. this unit also receives referrals from private and remotely located hospitals. patients were included in the study if they had experienced an acute or a sub-acute stroke confirmed by computed tomography (ct) scans and/or magnetic resonance imaging (mri). they had to have also fulfilled the criteria of the american heart association/ american stroke association according to which an ischaemic stroke is defined as “an episode of neuro logical dysfunction caused by focal cerebral, spinal, or retinal infarction”, and a haemorrhagic stroke is defined as “rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma”.9 in the aforementioned regard, omani and non-omani patients aged 18 years or above with a confirmed diagnosis of either intra-cerebral haemorrhage or ischaemic stroke were included in the study. patients with stroke caused by complications arising from trauma were excluded. subarachnoid haemorrhage was not included in the analysis as there were no cases encountered during the study period. data was collected from the patients’ computerised records as well as from interviews with the patient or a close relative to obtain missing variables in the history. the data on functional assessment obtained by the neurology unit upon discharge was gathered from the patient’s medical record. the tools used for data collection purposes included standard, pretested forms extracting information regarding demographic characteristics, type of acute stroke, ischaemic stroke subtypes, severity, risk factors, acute management, medical comorbidities, duration of hospital admission, functional assessment and outcomes. information regarding the following parameters were evaluated as part of the risk factors for stroke (based on previous or current diagnosis): 1) hypertension, defined as systolic pressure ≥130 mmhg or diastolic pressure ≥80 mmhg or the use of antihypertensive medication; 2) diabetes mellitus (dm), defined as use of insulin or an oral hypoglycaemic agent or a fasting glucose value ≥126 mg/dl; 3) dyslipidaemia, defined as elevated total or low-density lipoprotein cholesterol levels or low levels of high-density lipoprotein cholesterol; and 4) cardiac diseases (atrial fibrillation [af] and myocardial infarction). additionally, information regarding a history of current or past tobacco and alcohol use was also obtained. furthermore, a history of previous stroke and transient ischaemic attacks was also considered. ischaemic stroke subtypes were defined according to the trial of org 10172 in acute stroke treatment (toast) criteria.10 this is a widely-used classification with good reliability and high sensitivity and specificity, based on its aetiology of large-artery atherosclerosis (laa), small-vessel disease or lacunar stroke, cardioembolic stroke, stroke of other defined aetiologies (od) or stroke of other undetermined aetiology. the severity of cases was assessed using the national institutes of health stroke scale (nihss).11 the total neurological impairment score was interpreted as being very severe (>25), severe (15–24), moderately severe (5–14) or mild (<5). the glasgow coma scale, in which cases are categorised as being mild (>12), moderate (8–12) and severe (<8), was also used.12 functional assessment was assessed using the modified rankin scale (mrs).13 the time taken for care provision at each stage of stroke management at the ed including triaging, doctor’s evaluation, imaging and time when management began were also recorded to evaluate and account for time delay as a potential reason for non-thrombolysis. hasina a. al harthi, ammar al kashmiri, lubna m. zakaryia, jawad a. al-lawati, omar m. najem, isra al-lawati, ghulam r. memon and amr a. elfaham clinical and basic research | 93 all the data were analysed using the statistical package for social science (spss), version 20 (ibm corp., chicago, illinois, usa). statistical inferences were drawn based on two-tailed tests and a p value <0.05 was considered statistically significant. for descriptive analysis, the means, medians, standard deviations and 95% confidence intervals were calculated. the prevalence and frequencies were expressed in terms of percentages and the appropriate tables were designed to describe the study population. further analysis of ischaemic stroke cases (n = 160) was also performed. the study was approved by the ethics and research committee under the administration unit of the directorate general of muscat. informed consent was obtained from each participant or his/her relative before any interview or neurologic examination was conducted. results a total of 193 confirmed cases of stroke with a mean age of 61.05 ± 13.81 years were included in this study. the majority of cases were categorised as ischaemic strokes (n = 160, 82.90%) and predominantly male (58%) among both omanis and non-omanis, with a male-female ratio of 1.38:1. there was no significant difference between the types of strokes in terms of gender distribution (p = 0.25) [table 1]. more than half (63%) of the total cases were below 65 years of age with haemorrhagic stroke found mostly among the younger patients. eight out of 10 stroke patients were omanis, which could be reflective of the free medical care offered to omani nationals compared to non-omanis. hypertension was the most prevalent risk factor (72.5%) followed by dm (54.4%), which was more common among ischaemic stroke cases. approximately a quarter of the ischaemic stroke patients reported hypertension, diabetes and dyslipidaemia and 51.3% of them were in the 40–60-year age group. among the ischaemic stroke cases, 16.9% (n = 27) and 6.9% table 1: characteristics of stroke patients presenting to the national stroke center in muscat, oman (n = 193) characteristics n (%) p value hs is total 33 (17.1) 160 (82.9) age 0.016 age range in years 27–100 27–96 mean age ± sd 55.79 ± 16.73 62.13 ± 12.93 nationality 0.14 omani 24 (72.7) 134 (83.8) non-omani 9 (27.3) 26 (16.3) gender 0.25 male 16 (48.5) 96 (60.0) female 17 (51.5) 64 (40.0) educational status 0.752 illiterate 9 (27.3) 38 (23.8) read/write 7 (21.2) 40 (25.0) elementary education 5 (15.2) 27 (16.9) secondary education 6 (18.2) 38 (23.8) higher education 6 (18.2) 17 (10.6) marital status 0.934 single 2 (6.1) 7 (4.4) married 24 (72.7) 121 (75.6) divorced 1 (3.0) 7 (4.4) widowed 6 (18.2) 25 (15.6) smoking status (current) 0.99 yes 2 (6.1) 13 (8.1) no 31 (93.9) 147 (91.2) alcohol consumption (current) 0.69 yes 1 (3.0) 11 (6.9) no 32 (97.0) 149 (93.1) hs = haemorrhagic stroke; is = ischaemic stroke; sd = standard deviation. table 2: stroke-related risk factors of stroke patients pre senting to the national stroke center in muscat, oman (n = 193) variable n (%) p value hs is total 33 (17.1) 160 (82.9) hypertension 21 (63.6) 119 (74.4) 0.21 diabetes mellitus 13 (39.4) 92 (57.5) 0.06 dyslipidaemia 7 (21.2) 51 (31.9) 0.29 ischemic heart disease 3 (9.1) 34 (21.3) 0.16 atrial fibrillation 4 (12.1) 11 (6.9) 0.30 hypertension + diabetes + dyslipidaemia 6 (18.2) 39 (24.4) 0.44 past history of stroke 4 (12.1) 27 (16.9) 0.40 family history of stroke 1 (3.0) 3 (1.9) 0.53 hs = haemorrhagic stroke; is = ischaemic stroke. clinical profile of stroke patients presenting to the emergency department of a major stroke centre in oman 94 | squ medical journal, februay 2022, volume 21, issue 1 (n = 11) reported history of previous stroke and transient ischaemic attack, respectively [table 2]. the distribution of cases according to severity are demonstrated in table 3. according to the nihss score ranking, haemo rrhagic stroke cases were more severe compared to ischaemic stroke cases (p = 0.005). the severity of stroke incidents correlated with the age group among the ischaemic stroke cases, with 69.2% of severe cases presenting among patients aged above 60 years (p = 0.004) but not among the haemorrhagic stroke cases (p = 0.816). the age group also correlated with outcomes among the haemorrhagic stroke cases (p = 0.002) with five deaths being reported among the haemorrhagic stroke cases; all of these patients were below 40 years of age and had an nihss score ranging from severe to very severe. there was no significant difference between the two genders in relation to the nihss score (p = 0.488) or outcome (p = 0.319). the average time (in minutes) spent on different steps of providing care in the ed for patients being attended to on the day of symptom presentation (n = 106) can be found in table 4. among these cases, 25.6% presented directly to the ed while the rest were escorted by ambulance. among those escorted by ambulance, 96.9% were diagnosed with a query stroke. around half of the cases (n = 82) were classified utilising the toast classification system, of which 45% were diagnosed with large artery atherosclerosis, 40% with small vessel occlusion, 9% with stroke of other undetermined aetiology and 6% were cardioembolic. the rest of the cases, however, did not receive any classification. the majority of the cases that were classified were diagnosed with laa followed by small vessel occlusion. around 53.7% of the ischaemic stroke cases presented on the day the symptoms of stroke developed. approximately 5.8% of early presenting cases had a contraindication for thrombolysis. only 19 (11.9%) of all ischaemic stroke cases (n = 160) had intravenous thrombolysis, five of whom died. discussion to the best of the authors’ knowledge, this is the first detailed account of the characteristics of stroke patients presenting to the main national stroke center in oman. in this study, several aspects related to stroke among patients presenting acutely to a tertiary care hospital were looked at. these included demographics, associated risk factors, clinical presentation and their sequelae. the mean age for stroke in the current table 3: severity of stroke and various other stroke-related outcomes of stroke patients presenting to the national stroke center in muscat, oman (n = 193) variable n (%) p value hs is total 33 (17.1) 160 (82.9) national institute of health scale score 0.005 mild 13 (39.4) 109 (68.1) moderate 11 (33.3) 38 (23.8) severe/very severe 9 (27.3) 13 (8.1) glasgow coma scale 0.001 mild 23 (69.7) 150 (93.8) moderate 4 (12.1) 7 (4.4) severe 6 (18.2) 3 (1.9) complications* 9 (28.1) 22 (14.2) 0.07 intensive care unit admission* 16 (50.0) 35 (22.6) 0.004 hospital stay ± sd 10.58 ± 11.89 7.94 ± 7.31 0.09 outcome 0.35 died 5 (15.2) 11 (6.9) survived 27 (81.8) 144 (90.0) signed lama 1 (3.0) 5 (3.1) modified ranking score upon discharge* 0.26 no symptoms 1 (3.1) 12 (7.7) no significant disability 3 (9.4) 30 (19.4) slight disability 4 (12.5) 32 (20.6) moderate disability 10 (31.3) 43 (27.7) moderately sever disability 6 (18.8) 21 (13.5) severe disability 3 (9.4) 5 (3.2) died 5 (15.6) 12 (7.7) hs = haemorrhagic stroke; is = ischaemic stroke; ci = confidence interval; sd = standard deviation; lama = left against medical advice. *patients who left against medical advice were excluded and percentages have been calculated based on the total number of remaining patients. table 4: average time spent during different stages of care provision at the emergency department for stroke patients presenting on the day of stroke symptom development to the national stroke center in muscat, oman (n = 106) variable mean in minutes ± sd time from arrival until triage 6.77 ± 4.5 time from arrival until doctor evaluation 7.58 ± 0.82 time from arrival until imaging 28.53 ± 3.08 sd = standard deviation. hasina a. al harthi, ammar al kashmiri, lubna m. zakaryia, jawad a. al-lawati, omar m. najem, isra al-lawati, ghulam r. memon and amr a. elfaham clinical and basic research | 95 population was similar to the mean age reported by many south asian countries. for example, the mean age was 59 years in pakistan and 63 years in india.14 in the western world, however, the mean age of incident stroke was higher, (68 years in the usa and 71 years in italy).15 this finding may be a source of concern considering the relatively young age of stroke onset for both its types in oman. however, it is known from experience that the documentation of age in oman has been inaccurate in the past, especially for generations born prior to the 1970s. during those times, oman had an underdeveloped system for civil registration of vital statistics, including recording birth dates. most of the current cohort afflicted by stroke were born at home with no birth certificates. furthermore, patients from this generation tended to underestimate their age when asked for the same as part of the medical records at admission. therefore, the average age of incident stroke cases at onset may actually be closer to that of the western world than it appears now. since stroke is potentially preventable through control of its risk factors, it is important to identify these risk factors and determine their relative prevalence in order to manage them through primary prevention. hypertension can lead to ischaemic stroke through acceleration of the development of atherosclerosis which results in atherothrombotic events. the relationship between hypertension and haemorrhagic stroke is also well documented with global consistency.16 uncontrolled hypertension is the main cause for primary intracerebral haemorrhage. this can be prevented through good blood pressure control and regular medical check-ups to diagnose hypertension early. patients are often diagnosed with hypertension only after the development of a target organ issue such as a haemorrhagic stroke.17 approximately half of the patient population in the present study had dm with a significantly higher prevalence in the ischaemic stroke group. ischaemic stroke is known to be independently associated with dm which increases its risk two to six times. however, with regards to haemorrhagic stroke, the link with diabetes has not been consistent. af is another risk factor associated with ischaemic stroke. af is also associated with a higher risk of stroke recurrence, whether it is diagnosed after or known before the stroke incident.18 it is interesting to note that the prevalence of af in the present ischaemic stroke group was approximately 8%, significantly lower than the internationally reported rate which can reach as high as one third of the stroke cases.19 whether this represents a generally lower incidence of af in the current sample or more efficient management of existing af with anticoagulation leading to a lower incidence of thrombotic complications remains unclear. however, it is important to note that af can get picked-up later during the patient’s hospital course or later during follow-up with a cardiologist using holter monitoring; hence, it is possible that some cases were not identified during the patients’ course of admission at the ed. other risk factors known to have an association with stroke were analysed. these included past history of transient ischaemic attacks, dyslipidaemia, ischaemic heart disease and a family history of stroke. these factors were more commonly absent than present in the current population. the majority of strokes were of the ischaemic type constituting more than 80% of cases with the rest being haemorrhagic. this is consistent with reports from western countries where ischaemic stroke is significantly more common than haemorrhagic stroke.20 studies from other arab countries, including the gcc, reported variable proportions for ischaemic stroke ranging from approximately 58% to 87%, with the highest being reported in saudi arabia and the lowest in bahrain and sudan, where haemorrhagic stroke comprised a larger percentage.21–23 the latter is more consistent with the pattern of strokes observed in the eastern part of the globe, where the incidence of haemorrhagic stroke is reported to be twice that seen in the west.24 this higher incidence is even seen in east asians who have immigrated to the west.25 these differences may partly be related to ethnicity, a factor which was not explored in this study.26 the fact that the current findings mirror the western patterns of this disease may be a reflection of the change in lifestyle in oman that has accompanied the rapid modernisation and development that the country has witnessed over the past four decades, including changes in the healthcare system. furthermore, the lower rate of haemorrhagic stroke is likely due to implementation of treatment screening programmes for the hypertension, a significant factor known to be related to haemorrhagic strokes.27,28 when comparing the severity of the two subtypes of stroke, haemorrhagic stroke had significantly worse outcomes compared to ischaemic stroke with a higher incidence of requiring admission to the intensive care unit and a longer hospital stay. the incidence of death was twice as common in haemorrhagic strokes. this is consistent with findings from many international studies.29 intracranial haemorrhage causes more severe strokes and is known to be an independent predictor of poor neurological outcomes with higher odds of long-term disability. this is a direct result of haemorrhage causing larger anatomic lesions when compared to ischaemia-induced strokes.30 the inclinical profile of stroke patients presenting to the emergency department of a major stroke centre in oman 96 | squ medical journal, februay 2022, volume 21, issue 1 hospital mortality rate of haemorrhagic stroke was relatively low compared to other reports.31 this study has certain strengths and limitations. this is the first study from oman to prospectively collect data from patients during their ed visits. it systematically reviewed the burden of stroke admitted to the national stroke center. the findings from this study can be utilised to inform future research in the country and to guide appropriate preventive strategies as well as resource allocation. one limitation of this study is that it is a singlecentre study; therefore, the findings may not be considered to be generalisable to the entire population. furthermore, the sample size was relatively small, which may affect the reliability of the obtained statistical results. another limitation is that patients were only interviewed during their ed visits, which limited the collection of other variables that may have been relevant and could have been collected if the study had included following the patients’ in-hospital course. in addition, patients were not followed-up with throughout their rehabilitation course, limiting the information obtained on their pattern of recovery. for future studies, it will be important to expand the research to include all stroke patients admitted to hospitals in oman. the adequacy of long-term and rehabilitation facilities for stroke patients is still to be assessed in oman. conclusion this study provides essential data on stroke charact eristics which is important in developing effective prevention, management and rehabilitation strategies specific to oman’s population. most of the information obtained conforms with that described internationally and, therefore, similar preventive strategies can be implemented. furthermore, the information can be utilised by health administrators in planning resource allocation. further research is needed to explore rehabilitation aspects and long-term outcomes. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n hh, ak, jl conceptualised and designed the study. lz, on, il, gm, ae ab collected the data. hh, ak, jl analysed and interpreted the results. hh, ak, jl drafted the manuscript. all authors reviewed the results and approved the final version of the manuscript. references 1. murray cj, vos t, lozano r, naghavi m, flaxman ad, michaud c, et al. disability-adjusted life years (dalys) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the global burden of disease study 2010. the lancet 2012; 380:2197–223. https://doi.org/10.1016/s0140-6736(12)61689-4. 2. feigin vl, forouzanfar mh, krishnamurthi r, mensah ga, connor m, bennett da, et al. global burden of diseases, injuries, and risk factors study 2010 (gbd 2010) and the gbd stroke experts group. global and regional burden of stroke during 1990–2010: findings from the global burden of disease study 2010. the lancet 2014; 383:245–54. https://doi. org/10.1016/s0140-6736(13)61953-4. 3. benamer ht, grosset d. stroke in arab countries: a systematic literature review. j neurol sci 2009; 284:18–23. https://doi. org/10.1016/j.jns.2009.04.029. 4. mokdad ah, jaber s, aziz mi, albuhairan f, alghaith aj, alhamad nm, et al. the state of health in the arab world, 1990–2010: an analysis of the burden of diseases, injuries, and risk factors. the lancet 2014; 383:309–20. https://doi.org/10.10 16/s0140-6736(13)62189-3. 5. world health organization. global burden of diseases. from: https://vizhub.healthdata.org/gbd-compare accessed: jun 2019. 6. al shafaee ma, ganguly ss, al asmi ar. perception of stroke and knowledge of potential risk factors among omani patients at increased risk for stroke. bmc neurol 2006; 6:38. https://doi. org/10.1186/1471-2377-6-38. 7. kamran s, bener ab, deleu d, khoja w, jumma m, al shubali a, et al. the level of awareness of stroke risk factors and symptoms in the gulf cooperation council countries: gulf cooperation council stroke awareness study. neuroepidemiol 2007; 29:235–42. https://doi.org/10.1159/000112856. 8. gujjar ar, ramachandiran n, jacob pc, al-azri f, ganguly ss, shoaib rh et al. ischemic stroke outcomes in oman: experience of a university-hospital based stroke registry. j neurol sci 2015; 357:e380. https://doi.org/10.1016/j.jns.2015.08.1353. 9. sacco rl, kasner se, broderick jp, caplan lr, connors jj, culebras a, et al. an updated definition of stroke for the 21st century: a statement for healthcare professionals from the american heart association/american stroke association. stroke 2013; 44:2064–89. https://doi.org/10.1161/str.0b013e318296aeca. 10. adams jr hp, bendixen bh, kappelle lj, biller j, love bb, gordon dl, et al. classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org 10172 in acute stroke treatment. stroke 1993; 24:35–41. https://doi.org/10.1161/01.str.24.1.35. 11. brott t, adams hp, olinger cp, marler jr, barsan wg, biller j, et al. measurements of acute cerebral infarction: a clinical exam ination scale. stroke 1989; 20: 864–70. https://doi.org/110.1161/0 1.str.20.7.864. 12. teasdale g, jennett b. assessment of coma and impaired consciousness: a practical scale. the lancet 1974; 304:81–4. https://doi.org/10.1016/s0140-6736(74)91639-0. 13. rankin j. cerebral vascular accidents in patients over the age of 60: ii. prognosis. scott med j 1957; 2:200–15. https://doi.org/1 0.1177/003693305700200504. 14. wasay m, khatri ia, kaul s. stroke in south asian countries. nat rev neurol 2014; 10:135–43. https://doi.org/10.1038/ nrneurol.2014.13. 15. grysiewicz ra, thomas k, pandey dk. epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. neurol clin 2008; 26:87195. https://doi.org/10.10 16/j.ncl.2008.07.003. https://doi.org/10.1016/s0140-6736(12)61689-4 https://doi.org/10.1016/s0140-6736(13)61953-4 https://doi.org/10.1016/s0140-6736(13)61953-4 https://doi.org/10.1016/j.jns.2009.04.029 https://doi.org/10.1016/j.jns.2009.04.029 https://doi.org/10.1016/s0140-6736(13)62189-3 https://doi.org/10.1016/s0140-6736(13)62189-3 https://doi.org/10.1186/1471-2377-6-38 https://doi.org/10.1186/1471-2377-6-38 https://doi.org/10.1159/000112856 https://doi.org/10.1016/j.jns.2015.08.1353 https://doi.org/10.1161/str.0b013e318296aeca https://doi.org/10.1161/01.str.24.1.35 https://doi.org/110.1161/01.str.20.7.864 https://doi.org/110.1161/01.str.20.7.864 https://doi.org/10.1016/s0140-6736(74)91639-0 https://doi.org/10.1177/003693305700200504 https://doi.org/10.1177/003693305700200504 https://doi.org/10.1038/nrneurol.2014.13 https://doi.org/10.1038/nrneurol.2014.13 http://v http://v hasina a. al harthi, ammar al kashmiri, lubna m. zakaryia, jawad a. al-lawati, omar m. najem, isra al-lawati, ghulam r. memon and amr a. elfaham clinical and basic research | 97 16. woo d, haverbusch m, sekar p, kissela b, khoury j, schneider a, kleindorfer d, et al. effect of untreated hypertension on hemorrhagic stroke. stroke 2004; 35:1703–8. https://doi.org/10.1161/01. str.0000130855.70683.c8. 17. zia e, hedblad b, pessah-rasmussen h, berglund g, janzon l, engström g. blood pressure in relation to the incidence of cerebral infarction and intracerebral hemorrhage. hypertensive hemorrhage: debated nomenclature is still relevant. stroke 2007; 38:2681–85. https://doi.org/10.1161/strokeaha.106.479725. 18. yang xm, rao zz, gu hq, zhao xq, wang cj, liu lp, et al. atrial fibrillation known before or detected after stroke share similar risk of ischemic stroke recurrence and death. stroke 2019; 50:1124–9. https://doi.org/10.1161/strokeaha.118.024176. 19. otite fo, khandelwal p, chaturvedi s, romano jg, sacco rl, malik am. increasing atrial fibrillation prevalence in acute ischemic stroke and tia. neurol 2016; 87:2034–42. https://doi. org/10.1212/wnl.0000000000003321. 20. koton s, schneider al, rosamond wd, shahar e, sang y, gottesman rf, et al. stroke incidence and mortality trends in us communities, 1987 to 2011. jama 2014; 312:259–68. https://doi.org/10.1001/jama.2014.7692. 21. yaqub ba, shamena ar, kolawole tm, patel pj. cerebrovascular disease in saudi arabia. stroke 1991; 22:1173–6. https://doi. org/10.1161/01.str.22.9.1173. 22. sokrab te, sid-ahmed fm, idris mn. acute stroke type, risk factors, and early outcome in a developing country: a view from sudan using a hospital-based sample. j stroke cerebrovasc dis 2002; 11:63–5. https://doi.org/10.1053/jscd.2002.126690. 23. al-jishi aa, mohan pk. profile of stroke in bahrain. neurosci 2000; 5:30–4 24. suzuki k, izumi m. the incidence of hemorrhagic stroke in japan is twice compared with western countries: the akita stroke registry. neurol sci 2015; 36:155–60. https://doi.org/10.1007/ s10072-014-1917-z. 25. khan fa, zia e, janzon l, engstrom g. incidence of stroke and stroke subtypes in malmo, sweden, 1990–2000: marked differences between groups defined by birth country. stroke 2004; 35:2054–8. https://doi.org/10.1161/01.str.0000135761.18954.0b. 26. sacco rl, boden-albala b, abel g, lin if, elkind m, hauser wa, et al. race-ethnic disparities in the impact of stroke risk factors: the northern manhattan stroke study. stroke 2001; 32:1725–31. https://doi.org/10.1161/01.str.32.8.1725. 27. liu xf, van melle g, bogousslavsky j. analysis of risk factors in 3901 patients with stroke. chin med sci 2005; 20:35–9. 28. song y-m, sung j, lawlor d, smith gd, shin y, ebrahim s. blood pressure, haemorrhagic stroke, and ischemic stroke: the korean national prospective occupational cohort study. bmj 2004; 328:324–5. https://doi.org/10.1136/bmj.328.7435.324. 29. andersen kk, olsen ts, dehlendorff c, kammersgaard lp. hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. stroke 2009; 40:2068–72. https://doi. org/10.1161/strokeaha.108.540112. 30. chiu d, peterson l, elkind ms, rosand j, gerber lm, silverstein md. comparison of outcomes after intracerebral hemorrhage and ischemic stroke. j stroke cerebrovasc dis 2010; 19:225–9. https://doi.org/10.1016/j.jstrokecerebrovasdis.2009.06.002. 31. gonzález-pérez a, gaist d, wallander ma, mcfeat g, garcía rodríguez la. mortality after hemorrhagic stroke: data from general practice (the health improvement network). neurol 2013; 81:559–65. https://doi.org/10.1212/wnl.0b013e31829e6eff. https://doi.org/10.1161/01.str.0000130855.70683.c8 https://doi.org/10.1161/01.str.0000130855.70683.c8 https://doi.org/10.1161/strokeaha.106.479725 https://doi.org/10.1161/strokeaha.118.024176 https://doi.org/10.1212/wnl.0000000000003321 https://doi.org/10.1212/wnl.0000000000003321 https://doi.org/10.1001/jama.2014.7692 https://doi.org/10.1161/01.str.22.9.1173 https://doi.org/10.1161/01.str.22.9.1173 https://doi.org/10.1053/jscd.2002.126690 https://doi.org/10.1007/s10072-014-1917-z https://doi.org/10.1007/s10072-014-1917-z https://doi.org/10.1161/01.str.0000135761.18954.0b https://doi.org/10.1161/01.str.32.8.1725 https://doi.org/10.1136/bmj.328.7435.324 https://doi.org/10.1161/strokeaha.108.540112 https://doi.org/10.1161/strokeaha.108.540112 https://doi.org/10.1016/j.jstrokecerebrovasdis.2009.06.002 https://doi.org/10.1212/wnl.0b013e31829e6eff august 2007 vol 7 copy.indd sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 75-81 sultan qaboos university© submitted 1st april 2007 ‘flying coffins’ and neglected neuropsychiatric syndromes in oman *aziz al-naamani, samir al-adawi improving health services to traumatic brain injury (tbi) patients and their families is paramount for the social and economical future of any country. the consequences of tbi are varied, but nevertheless devastating, both to the individual and to society in general. recently there has been tremendous improvement in emergency care, acute medical management and modern neurosurgical interventions in oman. one obvious omission from this development is neuropsychiatric intervention and rehabilitation using a multidisciplinary approach, including speech therapy and other outreach services, to integrate victims of brain injury back into the community. as in other countries, survivors of tbi are left with irreversible and debilitating neuropsychiatric complications. these complications are critical for the quality of life of both patients and their relatives.1 studies have shown that the most important factors predicting the post-rehabilitation adjustment, in addition to the severity of the brain damage, are psychosocial complications such as the nature of emotional and behavioural disturbances, the nature and responses of the family and the extent to which the patient has full insight into their functional impairment.2 in psychiatric parlance, these sequels of tbi amounts to the loss of of functions that are an integral part of one’s selfhood and, because of their isomorphic and protean signs and symptoms, they are generally neglected in algorithms of healthcare. utilizing the rehabilitation process is important for these patients since *department of behavioural medicine, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman *to whom correspondence should be addressed. email: aziz@squ.edu.om in addition to raising awareness, this article is a tribute to our colleagues who were killed or maimed in road accidents. in the recent past, we have lost dr. andzrjez krolikowski of our obstetrics & gynecology department and more recently mr. yusuf zahran al-waili, pharmacy department, sultan qaboos university hospital. “it began with three young friends taking what they thought was a life time ride on a night of fun the engine roared on speed, but slippery road waited lost control and crashed two out of three died as the one who drove remained alive in a vegetable state he wished he could bring his friends back in misery of this loss their families were wrecked as he remained in vegetable state agonized with memories” nasra al-adawi e d i t o r i a l عمان في العصبيه املهملة النفسية املتالزمات و الطائرة النعوش العدوي سمير النعماني، عزيز a z i z a l n a a m a n i a n d s a m i r a l a d aw i 76 minor gains in function can help alleviate the significant life alterations felt by their families. lower scores in indices of quality of life commonly found in such patients tend to increase the cost of their care. the aim of this paper is to highlight some of these subtle and yet debilitating impairments that have negative effects on a meaningful existence. the causative factors of tbi in oman will be considered, with particular attention to road traffic accidents (rtas). t h e m a g n i t u d e o f t h e p r o b l e m each year at least 10 million people worldwide sustain tbi and it is becoming increasingly clear that tbi is a leading cause of death and disability.3 most disheartening, tbi impacts individuals who are at their most productive in their respective society, namely, those who are under 45 years of age.4 if one considers that this age group is at risk, then the situation in oman is likely to be critical, as 88.6% of the omani population are within this age group.5 each year 300-400 per 100,000 people in oman incur tbi. this amounts to approximately 17 to 23 persons per day sustaining tbi.6 in a survey conducted by ministry of health,7 out of 17,791 individuals surveyed, 116 of them reported to have suffered ‘serious accidents’ in the preceding years. interestingly, 60.8% of the reported accidents were due to transport and traffic accidents. approximately 11% of those injured had been admitted in hospital “for long time” and at least 1.2% of them were living with varying degrees of disabling conditions that manifest as physical handicap. little has been reported on their emotional, cognitive and behavioural functioning. converging views strongly suggest that rtas are the main source of tbis, estimated to cause between 42.1% and 95% of tbi in oman.8 this statistic translates into a major cause of personal suffering for patients and their families and a loss of productivity for the nation. as the brain is one of the organs that is compromised with all the adverse consequences in term of personality change, reduced self-care and overall diminution of quality of life, the family members who are responsible for their injured relative’s care tend to be in an ‘emotional paradox’ when the life of a previously healthy individual is irrevocably altered.9 while the disabled person may not even realize anything has happened to him or her, the family may go through the burden and distress of ‘burying’ the person they previously knew and trying to develop a relationship with a new and less affable stranger.10 with the increasing rates of rtas and vehicle ownership, this situation is predicted to become worse in the coming years. each day 140,000 people are injured and 3,000 die from rtas world wide.11 rtas are the second leading cause of death among adults aged 15 to 44 years old. rtas was the eighth leading cause of disability-adjusted life years’ loss (dalys) in 2000 and will become the third leading cause of dalys by 20203 [table 1], obviously outstripping the current ‘enemies of health’ such as communicable diseases and malnutrition.12 studies have shown that there is no one strategy to reduce the rising tide of morbidity and mortality from rtas. it appears that a myriad of socio-cultural factors contribute to rtas 13, each one often having it own individual set of factors. there is cross-national disparity in the occurrence of rtas with developing countries suffering under the heaviest burden. in general, the majority of the accidents in developing countries affect non-drivers such as passengers and other road users. however, this view does not hold for oman and her neighbouring countries. previous studies have shown that the mortality from rtas in gulf countries is higher than that in developing countries with similar car ownership ratios [table 2].14 the effect of rtas appears to be evenly distributed for both drivers and 1998 disease or injury 2020 disease or injury 1. lower respiratory infections 1. ischaemic heart disease 2. hiv/aids 2. unipolar major depression 3. perinatal compromising conditions 3. road traffic injuries 4. diarrhoeal diseases 4. cerebrovascular disease 5. unipolar major depression 5. chronic obstructive pulmonary disease 6. ischaemic heart disease 6. lower respiratory infections 7. cerebrovascular disease 7. tuberculosis 8. malaria 8. war 9. road traffic injuries 9. diarrhoeal diseases 10. chronic obstructive pulmonary disease 10. hiv/aids table 1: causes of death and disability 1998-2020 adapted from: murray cjl, lopez ad, eds. the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. boston, ma, harvard school of public health, 1996. ‘ f ly i n g c o f f i n s ’ a n d n e g l e c t e d 77 non-drivers. the majority of non-drivers are children. if we compare the situation to industrialized countries, then the extent of the problem becomes even more obvious. the number of fatalities per hundred thousand vehicles in oman is nearly four times greater than that of uk. in real terms, oman’s mortality for road crashes was 28 per 100,000 of the population by the end of 2005, which far exceeds the global average of 19 per 100,000. mortality and morbidity from rtas in oman continue to increase annually. the situation is so serious that some commentators have dubbed motor vehicle ‘flying coffins’15 and resultant death as “vehicular manslaughter”.11 studies from the united arab emirates suggests that approximately 62% of rtas leading to fatalities are due to “carelessness” and “excessive speed”.14 in oman, a study has shown that children are generally either left unrestrained in a car without a seatbelt or incompliant to local traffic regulations.13 in addition to the huge human and social cost of these injuries, the related economic cost is also substantial. it has been estimated that just acute in-patient medical care costs the oman national coffers approximately 3.3 million omani riyals a years (c. us $8.5 million). if we add the cost of the services and support these patients need in the community, the figure would be much higher. furthermore, this cost is only for the moderate and severe cases of injury, which are brought to medical attention. there is also the yet to be calculated the cost of ‘doctor shopping’ where distressed family venture abroad in a bid to find a cure for their loved ones. there is a bright spot in this gloomy situation. in some countries, due to the improvement of road safety and emergency care, the mortality from rtas has actually decreased as shown in table 3. although some critics would point out that the decrease in mortality has paradoxically resulted in some victims surviving to live with more severe and debilitating, disability prevention is still infinitely superior to rehabilitation. oman has been instrumental in advocating road safety within the united nations which has culminated in a campaign for “global road safety a shared responsibility”.16 in 2006, there was also indication that the number of rta had reached asymptote.17 this resulted in a lower death rate, but still means that an unacceptably high number of people are surviving with more or less severe sequelae of rtas. it is possible that decrease in mortality may be partly due to recently improved critical care services as well as vigilant surveillance on the highways to curb speeding. n e u r o p s y c h i a t r i c s e q u e l a e o f t b i in addition to the various physical complications of tbi triggered by rtas, there are significant numbers of survivors of rtas who are marked with cognitive, behavioural and emotional impairment.18 despite being isomorphic complaints, these neuropsychiatric impairments have been estimated to affect 0.7% to 44% of the survivors of rtas depending on various factors including diagnostic criteria used, survey methodology and astuteness of the health-care provider. cognitive and emotional impairment from rtas tends to lead to poor impulse control whereby a premorbidly healthy individual may indulge into high risk taking. one imcountry and year united states 2000 uk 2000 united arab emirates 2000 oman 2000 qatar 2000 mortality from rta 41,471 3,409 673 492 85 registered vehicles 217,028,000 28,890,000 575,929 477,948 303,245 fatality per 100,000 vehicles 19.1 11.8 116.8 102.9 28 fatality rate per 100,000 population 15.1 5.7 21.6 20.5 14.7 population per vehicle 1.3 2.1 5.4 5 1.9 table 2: statistical comparison of fatalites due to road traffic accidents (rta) in united kingdom, united states, united arab emirates, oman and qatar adapted from: bener a, crundall d. road traffic accidents in the united arab emirates compared to western countries. advances in transportation studies an international journal section 2005; a 6: 5-12. a z i z a l n a a m a n i a n d s a m i r a l a d aw i 78 plication of this is that the adverse effect of rtas may beget cognitive impairment that compromise ones social and occupational competencies. it has been empirically demonstrated that some of these victims may succumb to drug and alcohol abuse in order to ‘medicate’ themselves against the effects of the unremitting afflictive emotions triggered by the injury.19 these substances interact with the culprit’s underlying brain damage to further undermine much needed neuroplasticity and functional recovery.20 in addition to ‘classical’ psychiatric disorders such as those shown in table 4, one of the commonest and least well-studied complications of tbi is apathy or sometime called abulia.21 apathy has been defined as lack of motivation that is not attributable to a diminished level of consciousness, cognitive impairment or emotional distress.22 motivation in tbi patients is essential for physical rehabilitation and for improving their quality of life. studies have shown that apathy is associated with several adverse outcomes including reduced functional level, decreased response to treatment, poor illness outcome, caregiver distress and chronicity.23 it has been estimated that approximately 18% to 90% of the survivors of tbi in oman are marked with poverty of action24 and other negative feature that are important indicators of a poor quality of life. world health organization statistics indicates that depression was the fifth leading cause of disability at the turn of this century. depression has been predicated to become the second leading cause of disability by 20203 [table 1]. it has been reported that up to 77% of tbi patients suffer from poor outputs and self-directedness after tbi. this may reflect the failure of the verbal regulation of behaviour and the spontaneous use of language to formulate strategic action plans; hence the survivor will become reactive rather than proactive, this suggesting the presence of a major depressive disorder.25 in a study in oman, 63% of omani tbi patients had such a temperament.26 the presence of depression is likely to have a negative effect on one’s cognitive functioning in addition to impaired motivation and afflictive emotions. early diagnosis and treatment of depression is important in order to improve the quality of life of these patients. as depressive syndromes have no universal phonotypical presentation, studies are needed to explore how depression in tbi is manifested in the omani population. conceptually related to impaired motivation, another widely neglected sequel of tbi is fatigue. fatigue is defined as the awareness of a decreased capacity for physical and/or mental activity due to an imbalance in the availability, utilization, and/or restoration of resources needed to perform activity.27 studies have found the incidence of fatigue in tbi patients to range from 32.4% to 73%.28 among omani patients with tbi, unreported data have found that 81% were marked with unremitting fatigue that results in in a poor quality of life. clinicians tend to perceived fatigue as poor compliance or outright laziness. most discouraging, fatigue in tbi is a chronic problem and not easily amenable to therapeutic interventions. in a sample of individuals with tbi living in the community, 68% were noted to be suffering from fatigue two years post-injury and 73% of patients with tbi had fatigue five years post-injury.29 the majority of these patients were inept in their social and daily living activities. the fourth neglected negative outcome of tbi is changes to individual cognition that are relevant to memory, attention, executive function and language. these deficits are so common that have been reported in up to 66.7% of tbi patients.28 impaired cognitive functioning is likely to have a significant impact on one’s social and occupational competency. these cognitive impairments sometime occur together with post-concussion symptoms that may manifest as irritability, inattention and impaired vegetative functioning. these functions are critically important in day-today life so the persistence of such deficits constitutes an obstacle for long-term functional independence and quality of life. in the instance of sleep/wake cycles, various types of reduced quality of sleep have been described in the literature, for example post-traumatic hypersomnia, post-traumatic narcolepsy and posttraumatic insomnia.30 these conditions and their varicountry or area change (%) canada -63% hong kong -62% sweden -58% france -42% new zealand -33% usa -27% japan -24% table 3: changes in road traffic fatality rates (deaths per 10,000 population), 1972-1998 source: modified from kopits e, cropper m. traffic fatalities and economic growth. washington, dc, the world bank, 2003 (policy research working paper no. 3035) ‘ f ly i n g c o f f i n s ’ a n d n e g l e c t e d 79 ants result in difficulty falling asleep, disturbed sleep, nocturnal awakenings, early morning awakenings, sleeping too much or too little, non-refreshing sleep, daytime fatigue and excessive daytime sleepiness. it is becoming increasingly evident that poor quality of sleep is an independent risk factor for heightened morbidity and mortality.30 to our knowledge, there are no studies in oman that have examined post-concussion symptoms in survivors of tbi. such data would essential for charting the most productive ways to rehabilitate such patients. the final neglected aftermath of tbi is a peculiar disorder where a poor quality of life is aggravated by a denial of disabilities. in psychiatric literature, this condition is known as anosognosia. damasio31 has stated that there are particular types of brain damaged patient who firmly believe that they are ‘fine’ despite severe neurological and cognitive incapacities. it has been reported that lack of insight reflects specific deficits resulting from brain damage.32 incidence of anosognosia, as should be expected, would be difficult to quantify, but it is well known that unawareness of loss of function is directly related to poor functional outcome. a similar generalization can be attributed to other neuropsychiatric complications following brain injury. in spite of their impact on the quality of life, neuropsychiatric complications are largely relegated to a category of ‘exotic’ conditions that bear little relevance to health care needs in developing countries. c o n c l u s i o n despite these very well documented behavioural, emotional and cognitive complications of tbi, most patients with tbi worldwide, including oman, do not receive any services helping them adjust to their newly acquired functional and cognitive limitation. when the past life of a productive member of the society is abruptly and irrevocably lost, the caregiver bears the brunt of such a predicament. emotional, behavioural and cognitive consequences of tbi are not well understood by family members and, for that matter, by many professionals either. it is not uncommon for clinicians to assume that these patients are exaggerating their symptoms or malingering.33 the family may find it very difficult to accommodate the erratic and less likeable survivor of the rta. as a result, emotional or behavioural problems are seen as psychological and not attributed directly to the head injury.34 unfortunately, this attitude can lead to delayed or wrong treatment of the problem. in oman, centres to provide such services are ostensibly absent. it is noteworthy that tbi patients need psychiatric consultation because emotional, cognitive distresses and behavioural problems are responsible for at least as much disability as physical symptoms.1 treatment of these complications should lead to decreased handicap, improved quality of life and minimized negative societal impact. in addition to various neuropsychiatric impairments, tbi patients also suffer from challenging social and economic consequences of their injuries. studies have found that, on average, 15 years post injury 75% of head injury patients are not working and 66% need assistance with their activities of daily living.35 studies examining the functional prognosis of victims of tbi would be essential in planning future healthcare provision in oman.36,37 disorder cases sustained tbi duration of follow-up in year cases with pd % with disorder relative risk depression 653 7.5 289 44% 7.5 panic disorder 282 7.5 26 9.2% 5.8 bipolar affective disorder 374 7.5 15 4.2% 5.3 obsessive compulsive disorder 282 7.5 18 6.4% 2.6 anxiety disorder 398 7.5 36 9.1% 2.3 post-traumatic stress disorder 441 7.5 52 14.1% 1.8 substance abuse 168 7.5 37 22% 1.3 schizophrenia 302 4.9 2 0.7% 0.5 table 4: traumatic brain injury (tbi) and psychiatric disorders (pd) source: van reekum, r, stuss dt, ostrander l. apathy: why care? j neuropsychiatry clin neurosci 2005; 17:7-19. while these victims are struggling with sequelae of rtas, flying coffins are speeding round the country. for the family or caregivers of these victims, the impact of these moving coffins has resulted in irrevocable loss or handicap of their loved ones. for victims, it does not matter any more since the coffin has either carried them to the next world or blighted their lives with neglected neuropsychiatric syndromes. in either case, the choices are stark. r e f e r e n c e s 1 lishman wa. the psychological consequences of cerebral disorder in organic psychiatry. oxford: blackwell science ltd, 1998. 2 chronister j, chan f. a stress process model of caregiving for individuals with traumatic brain injury. rehabil psychol 2006; 51:190-201. 3 murray cjl, lopez ad, eds. the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. cambridge, mass: harvard university press, 1996. 4 flaada jt, leibson cl, mandrekar jn, diehl n, perkins pk, brown aw, malec jf. relative risk of mortality after traumatic brain injury: a population-based study of the role of age and injury severity. j neurotrauma 2007; 24:435-45. 5 ministry of national economy: statistical yearbook 2004. (28th edition) muscat, oman, 2004. 6 ansari s, akhdar f, mandoorah m, moutaery k. causes and effects of road traffic accidents in saudi arabia. public health 2000; 114:37-39. 7 national health survey, 2000: study of life style risk factors. directorate of research and studies and directorate of general health planning, vol 1. muscat: ministry of health, 2000. 8 al-adawi s, burke dt. revamping neurorehabilitation in oman. sultan qaboos univ j sci res med sci 2001; 3:61-64. 9 chiambretto p, ferrario sr, zotti am. patients in a persistent vegetative state: caregiver attitudes and reactions. acta neurol scand 2001; 104:364-368. 10 niemeier jp, burnett dm. no such thing as ‘uncomplicated bereavement’ for patients in rehabilitation. disabil rehabil 2001; 23:645-653. 11 dahl r. vehicular manslaughter: the global epidemic of traffic deaths. environ health perspect 2004; 112:a62831. 12 al-adawi s. emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos univ med j 2006; 6:3-9. 13 mcilvenny s, al mahrouqi f, al busaidi t, al nabhani a, al hikmani f, al kharousi z, et al. rear seat belt use as an indicator of safe road behaviour in a rapidly developing country. j r soc health. 2004;124:280-3. 14 el-sadig mi, nelson nj, lloyd ol, romilly p, bener a. road traffic accidents in the united arab emirates: trends of morbidity and mortality during 1977-1998. accid anal prev 2002; 34:465-476. 15 nantulya vm, reich mr.the neglected epidemic: road traffic injuries in developing countries. bmj 2002; 324:1139-41. 16 peden m, scurfield r, sleet d, mohan d, jyder a, jarawan e, mathers c. eds. world report on road traffic injury prevention. geneva: world health organization, 2004. 17 road accidents. royal oman police. muscat, 2006. 18 deb s, burns j. neuropsychiatric consequences of traumatic brain injury: a comparison between two age groups. brain inj 2007; 21:301-7. 19 moser d, crespo-facorro b, robinson rg. alcohol misuse and mood disorders following traumatic brain injury. arch gen psychiatr 2005; 62:742-749. 20 goldstein lb. neurotransmitters and motor activity: effects on functional recovery after brain injury. neurorx 2006; 3:451-457. 21 al-adawi s, dawe gs, al-hussaini aa. aboulia: neurobehavioural dysfunction of dopaminergic system? med hypotheses 2000: 54:523-530. 22 marin r. differential diagnosis and classification of apathy. am j psychiatr 1990; 147:22-30. 23 van reekum, r, stuss dt, ostrander l. apathy: why care? j neuropsychiatry clin neurosci 2005; 17:7-19. 24 al-adawi s, dorvlo as, al-naamani a, glenn mb, karamouz n, chae h, zaidan za, burke dt. the ineffectiveness of the hospital anxiety and depression scale for diagnosis in an omani traumatic brain injured population. brain inj 2007; 21:385-393. 25 thombs bd, bresnick mg, magyar-russell g. depression in survivors of burn injury: a systematic review. gen hosp psychiatry 2006; 28:494-502. 26 al-adawi s, dorvlo ass, burke dt, huynh cc, jacob l, knight r, shah mk, al-hussaini a. apathy and depression in cross-cultural survivors of traumatic brain injury. j neuropsychiatry clin neurosci 2004; 16:435442. 27 aaronson ls, teel cs, cassmeyer v, neuberger gb, pallikkathayil l, pierce j, et al. defining and measuring fatigue. image j nurs sch 1999; 31:45-50. 28 masson f, maurette p, salmi lr, dartigues jf, vecsey j, destaillats jm, et al. prevalence of impairments 5 years after a head injury, and their relationship with disabilities and outcome. brain inj 1996; 10:487-497. a z i z a l n a a m a n i a n d s a m i r a l a d aw i 80 29 oliver jh, ponsford jl, curran, ca. outcome following traumatic brain injury: a comparison between 2 and 5 years after injury. brain inj 1996; 10:841-848. 30 al-adawi s, burke dt, dorvlo ass. the effect of methylphenidate on the sleep-wake cycle of brain-injured patients undergoing rehabilitation. sleep med 2006; 73: 287-291. 31 damasio ar. descartes’ error: emotion, reason and the human brain. london: picador, 1996. 32 vuilleumier p. anosognosia: the neurology of beliefs and uncertainties. cortex 2004; 40:9-17. 33 mcallister tw, arciniegas d. evaluation and treatment of postconcussive symptoms. neurorehabilitation 2002; 17:265-283 34 mayou ra, black j, bryant b. unconsciousness, amnesia and psychiatric symptoms following road traffic accident injury. br j psychiatry 2000; 177:540-545. 35 dawson dr, chipman m. the disablement experienced by traumatically brain-injured adults living in the community. brain inj 1995; 9:339-353. 36 shah mk, carayannopoulos ag, burke, dt, al-adawi s. a comparison of functional outcomes in hypoxis and traumatic brain injury: a pilot study. j neurol sci 2007; doi:10.1016/j.jns.2007.04.012. 37 shah mk, al-adawi s, dorvlo ass, burke dt. functional outcomes following anoxic brain injury: a comparison with traumatic brain injury. brain inj 2004;18:111 117. ‘ f ly i n g c o f f i n s ’ a n d t h e i r n e g l e c t e d 81 submitted 29 apr 22 1 revision req. 2 aug 22; revision recd. 14 aug 22 2 accepted 7 sep 22 3 online-first: september 2022 4 doi: https://doi.org/10.18295/squmj.9.2022.058 5 6 physiological intracranial calcifications in children 7 a computed tomography-based study 8 faiza al hajri,1 srinivasa rao sirasanagandla,2 ammar boudaka,3,4 9 humoud al dhuhli,5 *eiman al ajmi5 10 11 1radiology residency program, oman medical specialty board, muscat, oman; 12 departments of 2human & clinical anatomy, 4physiology and 5radiology & molecular 13 imaging, college of medicine & health sciences, sultan qaboos university, muscat, oman; 14 3department of basic medical sciences, college of medicine, qatar university, doha, qatar. 15 *corresponding author’s e-mail: ealajmi@squ.edu.om 16 17 abstract 18 objectives: physiological intracranial calcifications (pics) are benign in nature and related to 19 aging. we aimed to study the frequency of physiological intracranial calcifications (pics) in 20 pediatric population using computed tomography (ct). methods: the brain ct scans of 21 consecutive patients (age range, 0-15 years) who had visited sultan qaboos university 22 hospital from january 2017 to december 2020 were retrospectively assessed for the presence 23 of pics. the presence of calcifications was identified using 3 mm thick axial images, and 24 coronal and sagittal reformats. results: a total of 460 patients were examined and the mean 25 age was 6.54 ± 4.94 years. the frequency of pic in boys and girls was 35.1% and 35.4%, 26 respectively. pics were most common in choroid plexus with 35.21% (age range 0.4 -15 27 years; median, 12 years), followed by the pineal gland in 21.08% (age range 0.5 -15 years; 28 median, 12 years) and the habenular nucleus in 13.04% of subjects (2.9 -15 years; median, 12 29 years). pics were less common in falx cerebri with 5.86% (age range 2.8-15 years; median, 30 13 years) and tentorium cerebelli in 3.04% (age range 7-15 years; median, 14 years) of 31 subjects. pics increased significantly with increasing age (p<0.001). conclusion: choroid 32 plexus is the most frequent site of calcification. choroid plexus and pineal gland 33 mailto:ealajmi@squ.edu.om calcifications may be present at less than 1 year of age. recognizing pics is clinically 34 important for radiologists as they can be mistaken for hemorrhage or pathological entities like 35 neoplasms or metabolic diseases. 36 keywords: calcification; pineal gland; dura mater; brain; computed tomography 37 38 advances in knowledge 39  this is the first study to evaluate physiological intracranial calcifications in omani 40 children. 41  the choroid plexus is the most frequent site of physiological intracranial calcification. 42  choroid plexus and pineal gland calcifications may be present at less than 1 year of 43 age. 44 45 application to patient care 46  the baseline data of pics are clinically important for neuroradiologists and 47 neurosurgeons as they can be mistaken for hemorrhage or pathological entities 48 like neoplasms or metabolic diseases. 49 50 introduction 51 physiological intracranial calcifications (pics) are benign in nature and typically occur with 52 aging.1 pics are well known to occur in pineal gland, choroid plexus, habenula, dural folds: 53 falx cerebri, and tentorium cerebelli, sagittal sinus, and petroclinoid ligaments.2 structurally, 54 they are deposits of calcium and/or iron in the brain parenchyma or vasculature. pics are not 55 associated with any disease and/or underlying pathology.1,2 pics are incidental findings in 56 neuroimaging. pics occurrence at all ages of life has been reported. pics prevalence 57 increases with age, and its prevalence varies between 50% and 70% in subjects older than 30 58 years.1 however, their prevalence is low in preadolescents3 and children4. they can be 59 detected in both genders and any race or ethnic group.5 they can be detected by plain 60 radiography, sonography, computed tomography (ct), and magnetic resonance imaging. 61 however, ct is often preferred due to the hyperdense appearance of calcium deposits in this 62 imaging.6,7 63 64 in general, pics are smaller in size, and larger size (>1cm) calcifications should be suspected 65 of having an underlying pathological cause.2 intracranial calcifications may be pathological 66 due to a wide range of infectious, metabolic, neoplastic, and vascular etiologies or because of 67 prior brain insult.8 it has been reported that environmental factors such as altitude and 68 sunlight exposure influence the pineal gland calcification (pgc) process.9 till date, very few 69 studies exist on the prevalence of pics in the pediatric population, particularly choroid and 70 dural calcifications.4,10 in children pics are most commonly found in the choroid plexus and 71 less commonly found in dural folds.4 baseline data of pics are clinically important for 72 neuroradiologists and neurosurgeons as they can be mistaken for hemorrhage or pathological 73 entities like neoplasms or metabolic diseases. furthermore, the reported prevalence of pics in 74 children is varied among different studies. despite having tremendous clinical significance, 75 very few studies have been conducted on the prevalence of pics in children. hence, we 76 aimed to study the frequency of pics in omani children using ct. 77 78 materials and methods 79 study population 80 in this retrospective cross-sectional study, brain ct scans of consecutive omani children 81 aged ≤15 years who had visited sultan qaboos university hospital (squh) during the 82 period from january 2017 to december 2020 were assessed. each patient's demographic 83 information and diagnostic findings were obtained from the electronic medical records of 84 squh. after applying inclusion and exclusion criteria, we included a total of 460 patients. 85 relevant patients’ clinical information was obtained. the most common clinical indications 86 for ct examinations in our cohort were trauma, seizures, and headache. on the other hand, 87 the exclusion criteria considered patients with known neuronal diseases, which were 88 associated with calcifications, excessive motion artifacts, epithalamic masses, and cerebral 89 hemorrhages. patients with incomplete details and non-omanis were also excluded from the 90 study. 91 92 acquisition protocol and data acquisition 93 all brain ct examinations were performed using 64-slice multidetector ct scanner (siemens 94 sensation 64) with a slice collimation of 30 x 0.6 mm and a 512 x 512 matrix. the picture 95 archiving and communication system (pacs) (synapse pacs, fujifilm worldwide, 96 version 5.7.102) was used for screening the images. the studies were reviewed by a single 97 observer. in each case, presence of calcifications in the falx cerebri, tentorium cerebelli, 98 epithalamus, and choroid plexus were analyzed using 3 mm thick axial images and coronal 99 and sagittal reformats. based on their distinct locations, epithalamic calcifications were 100 identified separately as pineal or habenular calcifications. falcine and tentorial calcifications 101 were identified along the dural folds. the side of choroid plexus calcification was noted 102 whether unilateral or bilateral. positive intracranial calcification in any of the areas 103 mentioned above was defined by being of higher attenuation compared to the gray matter.4 104 the morphology of calcifications in the choroid plexus and the pineal gland was classified to 105 single or punctate versus large or multiple.4 the medical research ethics committee, sultan 106 qaboos university, muscat approved the study and waived the requirement for written 107 consent. 108 109 statistical analysis 110 statistical package for the social sciences (spss, version 23.0, ibm corporation, ny, usa) 111 for windows was used to present the data. the data was presented as mean and standard 112 deviation. chi-square test was used to determine the gender and age influence on frequency 113 of pics in different regions of the brain. the differences were considered significant at p 114 value <0.05. 115 116 results 117 in the present study, pics were examined in the ct scans of 460 children. the mean age of 118 the subjects was 6.54 ± 4.94 years. the study subjects were categorised into five age groups: 119 0-3 years (179); 3.1-6 years (71); 6.1–9 years (69); 9.1-12 years (48); >12 years (93). pics 120 increased significantly with increasing age (p<0.001; [figure 1]). among the study subjects, 121 265 (57.6%) were boys, and 195 (42.4%) were girls. the frequency of pics in boys and girls 122 was 35.1% (93/265) and 35.4% (69/195), respectively. the gender influence on pics 123 frequency was not significant (p = 0.311). in figure 2, the frequency of pics in different 124 regions of the brain (choroid plexus, pineal gland, habenular nucleus, falx cerebri, and 125 tentorium cerebelli) in each year, is presented. additionally, table 1 depicts the age range of 126 pic occurrence in different regions of the brain. the highest frequency of pics was observed 127 in the choroid plexus with 35.21% (162/460). the age range of choroid plexus calcification 128 was 0.4 -15 years (median, 12 years). majority of choroid calcification morphology was 129 either punctate or single, accounting for 90.7% (147/162) of the total, with large or multiple 130 accounting for 9.3% (15/162). choroid calcifications were found bilaterally in 84.57% 131 (137/162) of subjects and in 11.1% (18/162) on the right side of cerebrum and 4.32% (7/162) 132 on the left side. the overall epithalamic calcification frequency was 34.13% (157/460). 133 pineal gland calcification (pgc) was identified in 21.08% (97/460) of subjects with an age 134 range of 0.5 to 15 years (median, 12 years). majority of pgc morphology was punctate or 135 single with 83.51%, (81/97), followed by large or multiple with 16.49% (16/97). habenular 136 calcification was observed in 13.04% (60/470) of subjects with an age range of 2.9 -15 years 137 (median, 12 years). dural calcifications were observed most frequently in the falx cerebri 138 with 5.86% (27/460), followed by those in the tentorium cerebelli with 3.04% (14/460). the 139 age range of falx cerebri and tentorium cerebelli calcifications was 2.8-15 years (median, 13 140 years) and 7-15 years (median, 14 years), respectively. figure 3 and figure 4 are the 141 representative ct images showing pics in different regions of the brain. 142 143 discussion 144 knowing the detectable age of pics on imaging is crucial clinically, especially in the early 145 years of life. the current study demonstrated that pics are found in the pediatric population 146 across all age groups with varying frequency. 147 148 the pineal gland is a part of the epithalamus located in the midline at the quadrigeminal 149 cistern, close to the posterior end of the roof of the third ventricle. it secretes melatonin, 150 serotonin, and n, n-dimethyl-tryptamine hormones and plays an important role in circadian 151 rhythm regulation.11,12 light stimuli regulate its secretory activity and are highly active during 152 darkness.11,12 histologically, pgc or corpora arenacea consist of by-products of pineal 153 neuronal and glial polypeptide exocytosis, the exophytic membrane debris with surrounding 154 calcification.13 these calcified concentrations are mainly composed of calcium and 155 magnesium salts.14 pgc is known to appear early in life and increase gradually with 156 advancing age. a histopathology study has documented the presence of pgc even in fetal 157 life.15 although the prevalence rate of pgc is high in adults, it is less prevalent in children.9 158 in a study by helmke and winkler, the reported frequency of pgc was 3% in the first year of 159 life, and then it increased gradually to 7.1% in the first decade of life.16 in the same study, the 160 frequency of pgc increased to 33% in 10-18 year age group.16 in a study by doyle and 161 anderson, pgc was observed in 1% and 8% of subjects younger than 6 and 10 years old, 162 respectively, and 39% in 8-14 years old subjects.10 in this study, the youngest patient with 163 pgc was 3 years.10 similarly, in a study by whitehead et al., the youngest patient with pgc 164 was 3 years old.4 in this study pgc was observed only in 5% of children with an age range of 165 3.2 to 8.9 years.4 in a recent study by caliskan and ozturk, a high frequency of 35.8% pgc 166 was observed in the 7-12 year age group, and it increased to 67% in the 13-17 year age 167 group.3 in the present study, pgc was observed in 21.08% of subjects younger than 15 years. 168 169 similar to previous studies, in our study, pgc frequency increased gradually with increasing 170 age, with 7% in the 3-6 year age group and 51.6% in the 12-15 year age group, respectively. 171 in our study, the youngest patient with pgc was 5 months old. pgc was observed only in 172 four subjects younger than 3 years. to the best of our knowledge, this is the first time we 173 observed pgc at a very young age using contemporary ct technology. in the previous study, 174 in the majority of patients, pgc morphology was single or punctate (71%).4 similarly, in our 175 study, single or punctate pgc were the most common morphology pattern, with a frequency 176 of 83.51%. the habenula is a bilaterally paired epithalamic nuclear complex situated close to 177 the dorsomedial surface of the thalamus. it plays an important role in the limbic system and 178 acts as a relay and processing center between the midbrain and the limbic system.17 its 179 calcifications generally appear as a curvilinear pattern with a prevalence rate of 15% in 180 adults.1 the composition of these calcifications is found to be similar to that of the pineal 181 gland with salts of calcium and magnesium.14 in a previous study, habenular calcifications 182 were noted in 10% of subjects younger than 9 years old, and they were the most frequent site 183 of calcification in the epithalamus.4 in contrast, we observed habenular calcifications only in 184 4.1% of the patients younger than 9 years of age. however, it increased to 8.9% in subjects 185 aged 9-15 years. an association between habenular calcification and pathophysiology has 186 been postulated as habenular calcifications are observed in schizophrenia patients.18-20 hence, 187 baseline data of habenular calcifications are clinically important. 188 189 the choroid plexus produces cerebrospinal fluid and helps in the removal of brain metabolic 190 waste and xenobiotics.21 it is the major source of transferrin protein in the brain.22 the atria 191 of the lateral ventricles are the most commonly affected sites of calcification, followed by the 192 third or fourth ventricles.1 similar to previous studies,23,24 in our study, choroid plexus 193 calcification increased significantly with age. in a study by kendall and cavanagh, choroid 194 plexus calcification was found in only 2% of subjects younger than 8 years.24 modic et al. 195 have noted choroid calcification in 0.5% of subjects younger than 10 years old.25 in a study 196 by doyle and anderson, it was noted in 7% and 16% of subjects younger than 10 and 16 197 years, respectively.10 whitehead et al. have noted the calcification in 12% of children 198 younger than 9 years of age, and the youngest subject was less than 1 month old.4 in our 199 study, choroid plexus calcification was the most common intracranial calcification, with a 200 frequency of 35.21%. in subjects less than 9 years of age, it was noted in 35.1% of subjects. 201 the youngest patient with choroid calcification was 4 months old. in the previous study by 202 whitehead et al., the majority of choroid plexus calcifications were single or punctate 203 (93.1%).4 similarly, in our study, single or punctate choroid plexus calcifications were 204 observed in majority of the subjects (83.51%). furthermore, choroid calcifications were 205 found bilaterally in majority of the subjects. various pathological conditions such as 206 intraventricular infection, inflammation, hemorrhage, chronic calcium and phosphate 207 imbalance are known to be associated with premature choroid plexus mineralization. hence, 208 age thresholds of normally expected choroid plexus calcification are clinically important to 209 distinguish physiology from pathology.4 210 211 in children, pics in falx cerebri and tentorium cerebelli are rare, and is often identified as an 212 incidental finding during routine brain ct examination.26 in the skull radiographs of adults, 213 calcification of falx cerebri was observed in 7% of subjects.27,28 in two different ct studies of 214 adults, dural calcifications were observed in 7.3% and 12.5% of subjects,5,29 with a male 215 dominance.5 to the best of our knowledge, physiological calcifications in the dural folds in 216 children have been reported only in two studies. in a study by kendall and cavanagh, dural 217 calcifications were observed in 0.8% of subjects less than 15 years of age.24 in another study 218 by whitehead et al., it was observed in 1% of subjects less than 9 years of age.4 in this study, 219 dural calcifications were most prevalent in tentorium cerebelli followed by falx cerebri.4 220 221 in contrast, we observed 5.86% in falx cerebi and 3.04% in tentorium cerebelli. furthermore, 222 falx cerebri and tentorium cerebelli calcifications are not present in less than 2 and 7 years, 223 respectively. as falx cerebri is formed from pluripotent embryonic mesenchymal stem cells, 224 any external stimuli including, irritation, trauma, and haemorrhage would predispose these 225 mesenchymal cells to transform into osteogenic cells, resulting in falcine ossification.30,31 the 226 extensive dural calcifications are known to be associated with a few pathological conditions, 227 particularly basal cell nevus syndrome.32 there is inconsistency in the existing literature 228 regarding gender influence on the occurrence of pics in the paediatric population. in a study 229 by whitehead et al., no significant gender difference (p=0.41) was observed.4 two other 230 studies by doyle & anderson10 and caliskan and ozturk3, found no evidence of a gender 231 effect on pgc calcification. similarly, in the present study, gender influence on intracranial 232 calcification was not observed. in contrast, two studies have reported a significant gender 233 influence with male dominance.5,29 further research needs to be conducted to draw a 234 conclusive result in this regard. the prior knowledge of reference values of pics in children 235 is clinically important as this may frequently interfere with the differential diagnosis of 236 metabolic mineralization, intracranial hemorrhage, and tumours. the following are some of 237 the limitations of this study. the volume, or ct density of pic could not be performed. the 238 study sample may not be representative of the omani population because it is a single-239 centered study. a multi-centered study involving subjects from various parts of oman and 240 analysis of calcification quantification would be interesting. 241 242 conclusion 243 the study provides the reference values for pics in the omani paediatric population. pics 244 are detected in all age groups of the paediatric population. the choroid plexus is the most 245 frequent site of calcification, and it is bilateral. choroid plexus and pineal gland calcifications 246 may be present at less than one year of age. calcifications in dural folds are relatively less 247 common and are not present at less than 2 years of age. the baseline data of pics are 248 clinically important for neuroradiologists as they can be mistaken for hemorrhage or 249 pathological entities like neoplasms or metabolic diseases. 250 251 conflicts of interest 252 the authors declare that they have no conflict of interest 253 254 funding 255 no funding was received for this study. 256 257 author contributions 258 conceptualization and methodology was done by srs and ea. validation was done by ea 259 and ha. formal analysis was performed by srs and ab and investigation was done by fa. 260 fa and ea curated the data. the original manuscript draft preparation was done by srs and 261 the revision and editing were done by ea, ha and ab. visualization was done by fa, srs 262 and ea and supervised by ea. the project administration was handled by ea, srs and ha. 263 all authors approved the final version of the manuscript. 264 265 acknowledgment 266 we would like to thank dr sadhana roychoudhury for her assistance in english editing. the 267 present study has been presented at the 20th congress of the international federation of 268 associations of anatomists, held in istanbul, turkey. 269 270 references 271 1. kıroğlu y, callı c, karabulut n, oncel c. intracranial calcifications on ct. diagn 272 interv radiol 2010;16(4):263-9. doi:10.4261/1305-3825.dir.2626-09.1. 273 2. deepak s, jayakumar b, shanavas. extensive intracranial calcification. j assoc 274 physicians india 2005;53:948. 275 3. caliskan e, ozturk m. evaluation of physiologic pineal gland calcification via 276 computed tomography in the pediatric population. ann med res 2019;26:2391-2396. 277 doi:10.5455/annalsmedres.2019.06.338. 278 4. whitehead mt, oh c, raju a, choudhri af. physiologic pineal region, choroid plexus, 279 and dural calcifications in the first decade of life. ajnr am j neuroradiol 280 2015;36(3):575-80. doi:10.3174/ajnr.a4153. 281 5. yalcin a, ceylan m, bayraktutan of, sonkaya ar, yuce i. age and gender related 282 prevalence of intracranial calcifications in ct imaging; data from 12,000 healthy 283 subjects. j chem neuroanat 2016;78:20-24. doi:10.1016/j.jchemneu.2016.07.008. 284 6. gilman s. imaging the brain. second of two parts. n engl j med 1998;338(13):889-285 96. doi:10.1056/nejm199803263381307. 286 7. wu yw, hess cp, singhal ns, groden c, toro c. idiopathic basal ganglia 287 calcifications: an atypical presentation of pkan. pediatr neurol 2013;49(5):351-4. 288 doi:10.1016/j.pediatrneurol.2013.06.021. 289 8. deng h, zheng w, jankovic j. genetics and molecular biology of brain calcification. 290 ageing res rev 2015;22:20-38. doi:10.1016/j.arr.2015.04.004. 291 9. turgut at, karakaş hm, ozsunar y, altın l, ceken k, alıcıoğlu b, et al. age-related 292 changes in the incidence of pineal gland calcification in turkey: a prospective 293 multicenter ct study. pathophysiology. 2008;15(1):41-294 8. doi:10.1016/j.pathophys.2008.02.001. 295 10. doyle aj, anderson gd. physiologic calcification of the pineal gland in children on 296 computed tomography: prevalence, observer reliability and association with choroid 297 plexus calcification. acad radiol. 2006;13(7):822-6. doi:10.1016/j.acra.2006.04.004. 298 11. ostrin la. ocular and systemic melatonin and the influence of light exposure. clin exp 299 optom. 2019;102(2):99-108. doi:10.1111/cxo.12824. 300 12. barker sa, borjigin j, lomnicka i, strassman r. lc/ms/ms analysis of the endogenous 301 dimethyltryptamine hallucinogens, their precursors, and major metabolites in rat pineal 302 gland microdialysate. biomed chromatogr. 2013;27(12):1690-700. 303 doi:10.1002/bmc.2981. 304 13. lukaszyk a, reiter rj. histophysiological evidence for the secretion of polypeptides by 305 the pineal gland. am j anat. 1975;143(4):451-64. doi:10.1002/aja.1001430404. 306 14. vígh b, szél a, debreceni k, fejér z, manzano e silva mj, vígh-teichmann i. 307 comparative histology of pineal calcification. histol histopathol. 1998 jul;13(3):851-70. 308 doi:10.14670/hh-13.851. 309 15. maślińska d, laure-kamionowska m, deręgowski k, maśliński s. association of mast 310 cells with calcification in the human pineal gland. folia neuropathol. 2010;48(4):276-82. 311 16. winkler p, helmke k. age-related incidence of pineal gland calcification in children: a 312 roentgenological study of 1,044 skull films and a review of the literature. j pineal res. 313 1987;4(3):247-52. doi:10.1111/j.1600-079x.1987.tb00862.x. 314 17. bianco ih, wilson sw. the habenular nuclei: a conserved asymmetric relay station in 315 the vertebrate brain. philos trans r soc lond b biol sci. 2009 apr 12;364(1519):1005-316 20. doi:10.1098/rstb.2008.0213. 317 18. sandyk r. pineal and habenula calcification in schizophrenia. int j neurosci. 1992;67(1-318 4):19-30. doi:10.3109/00207459208994773. 319 19. caputo a, ghiringhelli l, dieci m, giobbio gm, tenconi f, ferrari l, et al. 320 epithalamus calcifications in schizophrenia. eur arch psychiatry clin neurosci 321 1998;248(6):272-6. doi:10.1007/s004060050049. 322 20. shepard pd, holcomb hh, gold jm. schizophrenia in translation: the presence of 323 absence: habenular regulation of dopamine neurons and the encoding of negative 324 outcomes. schizophr bull 2006;32(3):417-21. doi:10.1093/schbul/sbj083. 325 21. abbott nj, pizzo me, preston je, janigro d, thorne rg. the role of brain barriers in 326 fluid movement in the cns: is there a 'glymphatic' system? acta neuropathol. 327 2018;135(3):387-407. doi:10.1007/s00401-018-1812-4. 328 22. moos t, rosengren nielsen t, skjørringe t, morgan eh. iron trafficking inside the 329 brain. j neurochem 2007;103(5):1730-40. doi:10.1111/j.1471-4159.2007.04976.x. 330 23. admassie d, mekonnen a. incidence of normal pineal and chroids plexus calcification 331 on brain ct (computerized tomography) at tikur anbessa teaching hospital addis 332 ababa, ethiopia. ethiop med j 2009;47(1):55-60. 333 24. kendall b, cavanagh n. intracranial calcification in paediatric computed tomography. 334 neuroradiology 1986;28(4):324-30. doi:10.1007/bf00333438. 335 25. modic mt, weinstein ma, rothner ad, erenberg g, duchesneau pm, kaufman b. 336 calcification of the choroid plexus visualized by computed tomography. radiology 337 1980;135(2):369-72. doi:10.1148/radiology.135.2.7367628. 338 26. debnath j, satija l, george ra, vaidya a, sen d. computed tomographic 339 demonstration of unusual ossification of the falx cerebri: a case report. surg radiol anat 340 2009;31(3):211-3. doi:10.1007/s00276-008-0408-4. 341 27. kieffer sa, gold lh. intracranial physiologic calcifications. semin roentgenol. 342 1974;9(2):151-62. 343 28. saldino rm, di chiro g. tentorial calcification. radiology. 1974 apr;111(1):207-10. 344 doi:10.1148/111.1.207. 345 29. daghighi mh, rezaei v, zarrintan s, pourfathi h. intracranial physiological 346 calcifications in adults on computed tomography in tabriz, iran. folia morphol (warsz). 347 2007;66(2):115-9. 348 30. tubbs rs, kelly dr, lott r, salter eg, oakes wj. complete ossification of the human 349 falx cerebri. clin anat 2006;19(2):147-50. doi:10.1002/ca.20162. 350 31. rao sr, rao tr, ovchinnikov n, mcrae a, rao avc. unusual isolated ossification 351 of falx cerebri: a case report. neuroanatomy 2007;6:54-55. 352 32. makariou e, patsalides ad. intracranial calcifications. appl radiol 2009;38:48. 353 354 355 figure 1. the frequency of physiological intracranial calcification in different age groups. the 356 total number of patients analyzed was 460.note calcification increased with increasing age 357 (chi square test; p<00.1). 358 359 360 figure 2: the frequency of physiological intracranial calcifications among the 460 patients 361 across different ages. 362 363 364 a b 365 figure 3. examples of intracranial calcifications from the study. axial ct images of the brain 366 show (a) focal calcification in the falx (arrow), (b) bilateral calcifications of the choroid plexus 367 in the trigones of the lateral ventricles (arrows), (c) habenular calcification (small arrow), and 368 large pineal calcification (large arrow). (d) reformatted coronal ct image of the brain shows 369 right tentorial calcification (arrow). 370 371 372 figure 4: punctate calcifications versus large calcifications in the choroid plexus. (a) axial 373 ct image of the brain shows punctate calcifications in the choroid plexuses (arrows). (b) ct 374 image in another patient demonstrates large choroid plexus calcifications (arrows). 375 376 c d a b table 1. the age ranges of physiological intracranial calcifications at different regions of brain. 377 378 location of calcification no. of patients age range (years) falx cerebri 27/460 2.8-15 (median, 13) tentorium 14/460 7-15 (median, 14) choroid plexus 162/460 0.4 -15 (median, 12) pineal gland 97/460 0.5 -15 (median, 12) habenula 60/460 2.9 -15 (median, 12) 2008-issue1.indd haemoglobinopathies encountered at khoula hospital, oman a retrospective study *gihan adly, a rajappa sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 59-62 sultan qaboos university© submitted 23rd june 2007 accepted 6th february 2008 (عمان) مستشفى خولة في بالدم االعتالل اخلضابي حاالت استعادية دراسة رجابا أ. لطيف، عدلي جيهان النتائج ومقارنة ــان) (عم خولة ــفي ملستش احملولني في املرضي (الهيموجلوبني) ــي ــالل اخلضاب االعت حاالت ــار انتش مدي ــص: الهــدف: تقييم امللخ إليها احملولني من أو خولة مبستشفى الداخلني املرضى من سواء 27,403 حالة نتائج تقييم مت احلاالت. الطريقة: من كبير عدد بتقييم أخري بدراسات لديهم. اخلضابى اإلعتالل إنتشار مدى نسبة 2004 لتحديد ــمبر ديس 2001 و حتى يناير من بداية ــنوات س أربع فترة خالل متعددة صحية مراكز من املنجلي الدم فقر حاملي ــبة النتائج: نس . الدم خلضاب الكهربائي الرحالن و الذوبان طريق عن التمنجل اختبار هي ــتخدمة املس الفوحصات اتبرية واضح ترابط %.هناك فكانت0.102 بالدم اخلضابي االعتالل من االخري االنواع نسبة ,أما 0.46% هي املنجلي الدم بفقر املرضي %7.5 و نسبة هي بسلطنة بوزارة الصحة الدراسات و البحوث قسم بواسطة أجريت التي الوراثية الدم الضطرابات الوطني الترصد نتائج بني و الدراسة هذة نتائج بني إهتمام أكثر إعطاء فيجب لذا الدراسه موضوع املرضى عند اخلضابي االعتالل انتشار مدي بوضوح االستعادية الدراسة هذة .اخلالصة: أظهرت عمان . بالسلطنة العامة الصحية املشكلة لتجنب هذه الفحص اجلينى و للتثقيف الصحى عمان. ، الدم خضاب اعتالل ، لِيَّة ِنْجَ امل لَّةُ اخلليةِ خَ ، اخللية املنجلية ، الدم الكلمات: فقر مفتاح haematology section, khoula hospital laboratory, khoula hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: gihanadly@hotmail.com abstract objective: the objective of this study was to find out the frequency of abnormal haemoglobins (hb) in patients referred to khoula hospital, oman and compare the data from other studies by assessing a large number of patients. methods: the results of 27,403 patients, either admitted to khoula hospital or referred to it from different health centres during the 4 years of the study from january 200 till december 2004, were analysed for haemoglobinopathies. the laboratory methods used for detection of abnormal haemoglobins were sickle cell solubility test and haemoglobin electrophoresis. results: the frequency of sickle cell trait was 7.5%, sickle cell disease 0.46% and other hb variants were 0.02%. the results correlate well with that of the national genetic blood disorder survey carried out by the research and studies department, ministry of health, sultanate of oman, during a 4 year period from january 200 till december 2004. conclusion: this retrospective study demonstrates the high prevalence of haemoglobinopathies among the studied group of patients. more attention to the importance of health education and genetic counselling is required for the prevention of this public health problem in the country. keywords: anaemia, sickle cell; sickle cell trait; haemoglobinopathies; oman. advances in knowledge the study shows that haemoglobinopathies are prevalent at a significant rate among the patient group studied. the study stimulates the need to conduct regular surveys to monitor haemoglobinopathies as well as prevalent genetic blood disorders in oman. application to patient care knowledge gained by researchers and doctors that can be applied both to the early diagnosis of haemoglobinopathies and to the management of patients with these abnormalities including genetic counselling. c l i n i c a l a n d b a s i c r e s e a r c h g i h a n a d ly, a . r a j a p pa 60 the commonest genetic blood disorders that cause alterations in erythrocyte mor-phology and rheology are sickle cell anaemia, g6pd (glucose-6 phosphate dehydrogenase enzyme deficiency) and thalassemias.1 these inherited haemoglobinopathies are the commonest single-gene disorders; the world health organization estimates that about 7% of the world population are carriers.2 because of their worldwide distribution, the disorders resulting from abnormal haemoglobin structure (haemoglobinopathies) are of enormous clinical importance.3 these haemoglobin disorders occur in homozygous as well as heterozygous forms and involve the β-chain or the α-chain. in the homozygous state, hb a is totally lacking, and clinical manifestations are of variable severity. individuals so affected have anaemia, for example, sickle cell anaemia. in the heterozygotes, because they rarely have phenotypic expressions of clinical significance, they are said to have the trait for abnormality, for example, sickle cell trait.1 the thalassaemias are a heterogenous group of inherited conditions characterised by defects in the synthesis of one or more of the globin chains that form the haemoglobin tetramer. the clinical syndromes associated with thalassaemia arise from the combined consequences of inadequate haemoglobin production and of unbalanced accumulation of one type of globin chains.4 the main objective of this study was to estimate the prevalence of the most common haemoglobinopathies reported at khoula hospital and compare the data with other studies performed in oman. some studies were done before to estimate the prevalence of haemoglobinopathies in oman. khoula hospital is a tertiary hospital and is the national trauma centre. it therefore gets referrals from many other hospitals in oman, in addition to the referrals from the local health centres in muscat; so a large number of cases is assessed every year. this provided a good opportunity for further assessment and evaluation of haemoglobinopathies, especially those investigations that were already requested by the treating doctors in the hospital departments and health centres, as this meant no additional costs or patient disturbance. m e t h o d s in this study, we used the laboratory records to collect data on blood samples sent to the laboratory from khoula hospital and wattayah polyclinic and also those referred from health centres over a period of four years from january 2001 to december 2004. ours is a tertiary hospital and the national trauma centre of the sultanate of oman receiving referrals from different regions and different health centres. 27,403 patients had investigations done for them as in-patients in the hospital or outpatients from different health centres. the investigations were already requested by the treating doctors in different departments in the hospital and health centres so there were no additional costs or additional financial funds needed for the study and also no additional burden on the patients either physically or financially. all cases of haemoglobinopathies detected in the laboratory were tabulated noting the solubility sickle cell screening test results and their confirmation using the haemoglobin electrophoresis, hbl4, by helena method.4 for thalassemia confirmation, samples were sent to the laboratory at the royal hospital, muscat, where the high performance liquid chromatography (hplc) method is done.4 during the period of study, a total number of 27,403 cases were screened by the sickle cell solubility method and 3,158 cases were subjected to haemoglobin electrophoresis. r e s u l t s the results are charted in figures 1, 2 and table 1. the total number of patients assessed was 27,403 cases. of these 90.5% were omanis and expatriates 9.5% (indians 6.2%; egyptians 1.4%; bangladeshis 0.7%, sri lankans 0.3% and gulf cooperation council citizens 0.3%). out of these, according to our laboratory results, 2,057 cases (7.5%) had sickle cell trait with only a small numbers of patients having sickle cell disease itself: 128 cases (0.46%). other small groups of patients, 21 cases (0.102%), had a combination of sickle cell with abnormal haemoglobin. sickle thalassemias were encountered at a very low rate (0.01%). d i s c u s s i o n in a previous survey study done by the research and studies department of the oman ministry of health, 6,342 children under 5 years of age were taken by their parents to neighbourhood hospitals or health centres for blood collection. the study showed that the prevalence of sickle cell trait was 6%, b-thalassemia trait (heterozygous) was 2%, b-thalassaemia homozygous was 0.07% and sickle cell disease 0.2%. the combination of a b n o r m a l h a e m o g l o b i n s e n c o u n t e r e d at k h o u l a h o s p i ta l , o m a n : a r e t r o s p e c t i v e s t u d y 61 figure 1: values in numbers of the different haemoglobinopathies year no. % nor hb aa sc trait as sc disease ss total proc. fs se afs fsd ss-om s-dho ad ae dd hbl4 2001 no 179 465 18 1 1 2 1 1 668 % 26.8 69.6 2.69 0.15 0.15 0.3 0.15 0.15 2002 no 255 522 33 2 1 1 814 % 31.3 64.1 4.05 0.25 0.12 0.12 2003 no 141 461 31 1 2 1 637 % 22.1 72.3 4.87 0.16 0.31 0.16 2004 no 368 609 46 7 1 1 2 4 1 1039 % 35.4 58.6 4.43 0.67 0.1 0.1 0.19 0.38 0.1 totals no 943 2057 128 9 1 1 2 3 2 1 7 2 2 3158 % 29.8 65.1 4 0.03 0.03 0.03 0.06 0.01 0.007 0.003 0.025 0.007 0.007 aa-normal haemoglobin; as-sickle cell trait; ss sickle cell disease; fs-fetal and sickle haemoglobin ; se-sickle and haemoglobin d; afsadult, fetal and sickle haemoglobin ; fsd-fetal haemoglobin and sickle cell disease; s-th-sickle cell and β-thalassemia ; s-om-sickle cell-oman; s-dho-sickle cell-dhofar region oman; ad-adult and haemoglobin d; ae-adult and haemoglobin e; dd-haemoglobin d ; hbl4 -haemoglobin electrophoresis table 1: tables of values and percentages for the different haemoglobinopathies figure 2: percentage values of the different haemoglobinopathies g i h a n a d ly, a . r a j a p pa 62 sickle cell with other abnormal haemoglobins was also detected at a very low prevalence rate. among the studied children, three quarters (74.5%) were found to be free from haemoglobinopathies and g6pd normal, the other quarter of children, either had haemoglobin abnormalities (7.5%), g6pd (16%) or had a combination of g6pd with at least one abnormal haemoglobin (2%). the prevalence rate of the total haemoglobinopathies in oman is 9.5%.5 other abnormal haemoglobins detected in this survey were: hb d(0.6%), hb e(0.3%), hb c (0.02%).the combination of sickle cell with abnormal hb was also detected at low prevalence.5 in the study done by white et al, the frequencies of four major red cell genetic defects: sickle haemoglobin (hbs), glucose 6 phosphate dehydrogenase (g6pd), and α and βthalassemia, were determined in nearly 5,000 subjects from the three major peninsular arab states, namely yemen, the united arab emirates, and oman. the frequencies of these in oman were 0.389, 0.328, 0.024, and 0.038 respectively.6 in the khoula laboratory study, the prevalence rate of haemoglobinopathies was found to be 8.09%; sickle cell trait formed 7.5 %, while sickle cell disease formed 0.46 % of this total. the other variants encountered (hbd, e, s-oman, s-thalassemia, etc.) were 0.102%. our results are consistent with previous studies performed in oman. knowledge of the distribution of these genetic blood disorders is useful in health care planning and management of resources.7 in populations in which there is a significant incidence of severe forms of thalassemia or sickle cell anaemia, women should be screened early in pregnancy for thalassemia and the sickle cell trait. if both parents are carriers, prevention of severe disease is possible through genetic counselling and offering prenatal diagnosis through fetal blood analysis or amniocentesis and performing fetal dna analysis.8 also, the major objective of screening for genetic blood disorders is the identification of individuals who would benefit from genetic counselling. testing for haemoglobinopathies is best coordinated with comprehensive health screening programmes and integrated with meaningful education and ethical counselling.1 the technique chosen for screening should be genetically diagnostic and should clearly differentiate between sickle cell trait and those disorders of haemoglobin having implications for health.9 genetic blood disorder diseases can be prevented by establishing a proper preventive programme which includes health education, genetic counselling for heterozygotes, the improvement of curative and blood transfusion services, as well as newborn screening. the ministry of health in the sultanate of oman has recognised that genetic blood diseases are a public health problem in the country and need attention.5 many of the components of a genetic blood disorder prevention programme have already been successfully implemented in oman, for example, neonatal screening, premarital examination and genetic counselling. c o n c l u s i o n in conclusion, this retrospective study over 4 years demonstrated clearly the high prevalence of haemoglobinopathies among the studied group of patients. moreover, prompt and full implementation of the genetic blood disorder disease prevention programme is likely to reduce the numbers of homozygous patients and help early detection. r e f e r e n c e s 1. wintrobe’s clinical haematology, vol. 1. 9th ed. philadelphia: lea & febiger, 1993. 2 . hoffbrand av, catovsky d, tuddenham egd. postgraduate haematology, vol. 1. 5th ed. oxford: blackwell publications, 2005. 3. henry jb. md. clinical diagnosis and management by laboratory methods. 19th ed. philadelphia: wb saunders company, 1999. 4. dacie jv, lewis sm. practical haematology. 9th ed. edinburgh: churchill livingstone, 2001. 5. al riyami a, ebrahim gj. national genetic blood disorders survey ministry of health, sultanate of oman. j trop pediatr 2003; 49:1-20. 6. white jm, byrne m, richards r, buchanan t, katsoulis e,weerasingh k. red cell genetic abnormalities in peninsular arabs: sickle haemoglobin, g6pddeficiency, and alpha and beta thalassemia. j med genet 1986; 23:245251. 7. guidelines – the laboratory diagnosis of haemoglobinopathies. br j haematol 1998; 101:783–792. 8. weatherall dj, clegg jb. the molecular basis of blood disease, 2nd ed. philadelphia: wb saunders company, 1994. 9. serjeant gr. historical review – the emerging understanding of sickle cell disease. br j haematol 2001; 112: 3-18. insulinoma: a rare cause of a common metabolic disorder hypoglycaemia *omayma el shafie,1 dilip sankhla,2 nayil al-kindy,3 aisha al-hamadani,4 christopher grant,3 nicholas woodhouse1 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 63-67 sultan qaboos university© submitted 20sh june 2007 accepted 14th january 2008 c a s e r e p o r t األيضي لالضطراب نادر سبب : (انسولينوما) زيرِيّ اجلَ رَمٌ الوَ الدم سكر نقص االنتشار واسع (االستقالبي) وودهاوز جرانت، نيكوالس كريستوفر احلمداني، عائشة الكندي، نايل سانخال، ديليب الشافعي، أميمة املنظار. ــطة بواس البنكرياس غدة ذيل مع ــتئصاله اس والذي مت اجلزيري الورم من يعاني عماني ملريض عمان ــلطنة س في حاله أول عن تقرير امللخص: يعانون الذين الدم للمرضى في السكر نسبة فحص التقرير أهمية هذا يوضح كما . عائلته و/أو املريض تثبت أهمية اخذ تاريخ املرض من احلالة هذه االنسولني طليع ج – وبيبتايد ــولني األنس هرمون ــبة ونس املعمل في ــكر الس ــبة نس من للتأكد دم أخرى عينات ، وكذلك اخذ املتكرر الوعي من فقدان ، ميكن حينذاك الورم بالضبط موقع حتديد املغناطيسي الرنني ــتطاعة باس يكن لم واذا لذلك. ضرورة هناك كانت اذا ــلفونيل الس يوريا ــتويات ومس اذا البنكرياس في الورم ــكان م باالوكتيرويد لتحديد ــوم املوس الثالثي االنديوم ــتخدام باس رُّس بالتَفَ أو ، لِيّ اخِ الدَّ بالتَّنْظيرِ ى دَ طيطُ الصَّ بتَخْ ــص الفح باالوكتيرويد. للعالج الدم من انخفاض سكر الذي يعاني املريض استجاب البنكرياس. استئصال باملنظار ، اجلراحة ، الدم سكر انخفاض ، ج الكلمات: بيبتايد مفتاح departments of 1medicine, 2radiology and molecular imaging, 3surgery, 4pathology, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman. *to whom correspondence should be addressed. email: omayma0@hotmail.com hypoglycaemia is a common metabolic problem and may result from increased peripheral uptake of glucose, failure of glucose production or a combination of both. by far the commonest cause is increased peripheral glucose uptake resulting from stimulation of the insulin receptor (ins-r) by endogenous overproduction or exogenous administration of excess insulin. rarely, hypoglycaemia is caused by increased circulating levels of molecules resembling insulin such as insulin like growth factors (igfs) or antibodies directed against the ins-r. hypoglycaemia also occurs in patients with advanced liver disease resulting from a failure of gluconeogenesis. the role of the kidney is less certain; glucose uptake and synthesis is high normally and renal failure often results in hypoglycaemia. as insulin is degraded by the kidney, hypoglycaemia may in part be due to prolongation of its actions.1-5 hypoglycaemia has a potential for serious neuronal damage and death. the patient described here had recurrent symptoms for two years that were initially thought to result from epilepsy and later a conversion reaction. insulinoma is rare with an incidence of only 4 per 1 million persons per year, but it is the commonabstract we describe the first patient diagnosed with an insulinoma in oman and successfully managed with a distal laparoscopic pancreatectomy. the importance of obtaining a good history from the patient and/or his family is stressed. all patients with loss of consciousness must have a reflow check carried out and, if hypoglycaemic, this should be documented in the laboratory and a simultaneous serum sample stored for measurement of insulin, c-peptide proinsulin and sulphonylurea levels, if subsequently indicated. if magnetic resonance imaging fails to locate the tumour, endoscopic ultrasound of the pancreas, or indium  labelled octreotide scanning is indicated if the patient’s hypoglycaemia has previously responded to treatment with octreotide. key words: insulinoma; c-peptide; hypoglycaemia; laparoscopy; pancreatectomy. o m ay m a e l s h a f i e , d i l i p s a n k h l a , n ay i l a l k i n d y, a i s h a a l h a m a d a n i , c h r i s t o p h e r g r a n t, n i c h o l a s wo o d h o u s e 64 est cause of hypoglycaemia in otherwise healthy adults who are not taking antidiabetic drugs. the median age is 47 years with a slight female preponderance of 59%. 87% of insulinomas are single benign tumours, 6% are malignant and 7% are multiple benign tumours and associated with multiple endocrine neoplasia type 1 (men-1).1, 2 c a s e r e p o r t a 23 year old omani male had a 2 year history of recurrent loss of consciousness and convulsions. on the first day of ramadan (islamic month of fasting) in 2006, he presented to the accident and emergency department of sultan qaboos university hospital, oman, with loss of consciousness. his blood glucose was measured by reflocheck, a blood glucose monitor, and was found to be 1.5mmol/l. on receiving intravenous dextrose, he regained consciousness. he was then discharged with a referral letter to the endocrine clinic. this delayed his admission by two months. his attacks had started in ramadan 2005, when he was unable to fast for more than 10 days. a year later in ramadan 2006, fasting became impossible for more than a few hours hence his hospital visit. the family reported that frequent meals made him less liable to attacks. there was no family history of diabetes and he was not known to have diabetes. his parents and ten siblings were healthy. his physical examination was unremarkable. he was admitted and started on a 72 hour fast. after 8 hours, his blood glucose fell to 1.5 mmol. (reflocheck). blood samples were taken for laboratory confirmation of the plasma glucose, and levels of insulin, c-peptide, pro-insulin and sulphonylureas. the fast was terminated and he was given intravenous glucose. treatment glucose 1.5 (3.5 – 5.0) mm/l insulin 9.0 (1.9 – 23) miu/l c-peptide 2 (1.5 – 4.5) ug/l pro-insulin 21 (6.4 – 9.4) pm/l time (minutes) -15 0 30 60 120 glucose mmol/l 1.4 1.7 1.8 1.4 1.0 insulin miu/l 2.1 3.4 0.3 1.9 2.0 table 1: simultaneous blood sampling of patient when hypoglycaemic table 2: octreotide trial 100 micrograms s/c time 0 figure 1: a therapeutic trial of octreotide (sms) in 3 patienrs with insulinomas. insulin secretion can be inhibited, with normalisation of the blood sugar level, only in those patients whose tumours have receptors for octreotide (<50%). only patient 1 responded i n s u l i n o m a : a r a r e c au s e o f a c o m m o n m e ta b o l i c d i s o r d e r h y p o g ly c a e m i a 65 figure 3: patient’s pancreatic tumour figure 2: the patient’s ct scan was normal but an mri revealed a 1.5 x 2 cm tumour localized in the tail of the pancreas (arrows) figure 5: insulin staining. on left normal staining, on right patient’s tumour figure 4: microscopic view of tumour well differentiated endocrine tumours well differentiated (low grade maligant) carcinoma with gross local invasion or distant metastasis poorly differentiated endocrine carcinoma small cell neuroendocrine carcinoma table 3: who classification of pancreatic endocrine tumours o m ay m a e l s h a f i e , d i l i p s a n k h l a , n ay i l a l k i n d y, a i s h a a l h a m a d a n i , c h r i s t o p h e r g r a n t, n i c h o l a s wo o d h o u s e 66 was started with diazoxide 50 mg three times a day, and thereafter he remained asymptomatic. the results in table 1 show an inappropriately high insulin concentration for the level of blood glucose. the detectable c-peptide excludes the injection of exogenous insulin as commercial insulins contain no cpeptide.1, 2 sulphonylurea was not detected. these results confirm excessive and inappropriate endogenous insulin overproduction. normally, circulating proinsulin levels account for less than 22% of the serum insulin value, but the ratio of more than 24% is seen in 90% of all insulinomas when greater than 40% malignancy is usually indicated. our patient’s value was more than 50% and he has to be carefully followed up. an octreotide trial [table 2] produced no significant change in blood glucose or insulin levels and therefore an octreotide scan was not done. only 50% of insulinomas have octreotide receptors and in these cases the drug can be used therapeutically6 [fig 1] or to locate the tumour by scanning with indium iii labelled hormone. two weeks later, he was admitted for further assessment. there had been no attacks of hypoglycaemia since starting on diazoxide. he underwent laparoscopic distal pancreatectomy7 and the tumour was localized by intraoperative laparoscopic ultrasound during surgery.8 the surgery was uneventful and the histopathology confirmed an insulinoma [figs. 4-5] of “uncertain behaviour” by who classification [tables 3 & 4]. since surgery, the patient has been very well with no hypoglycaemic attacks and he is looking forward to the next ramadan moon to undertake his fast. d i s c u s s i o n this case illustrates the necessity of good history taking. the patient’s symptoms very clearly improved by taking food. the family gave a vivid description of how he was often too weak to walk to the table for his meals. he would sometimes sink to the ground and the family would restore him by bringing food to him. during ramadan, by midday, he would be weak and confused until breaking his fast. hypoglycaemia was not, however, suspected and he was referred to neurology and psychiatric clinics. in the mayo clinic series of 224 cases of insulinoma as many as 20% of patients had been misdiagnosed as having neurological or psychiatric disorders.2 in this article, we have outlined a systematic approach to the investigation and management of patients with spontaneous hypoglycaemia.9 the largest series in the literature is from the mayo clinic2 where, in an 80-year period, 224 cases were seen. 87% were benign tumours, 6% were malignant, and 7% were associated with men-1. their follow up shows a higher recurrence rate in patients with men-1 [figure 6]. patients with benign insulinomas had a survival rate which did not differ from that expected in the general population. this is not the case in those with malignant insulinomas [figure 7]. men-1 is excluded in our patient as the pituitary ct scan and bone profile were normal. he is now free of symptoms since surgery done in november 2006. in the mayo clinic series, a cure has been defined as being totally free of symptoms for 6 months after removal of the insulinoma.2 the next ramadan fast will be used to confirm the success or otherwise of his treatment. c o n c l u s i o n the symptoms of hypoglycaemia may include loss of consciousness, convulsions and personality changes. in such a patient, hypoglycaemia should be looked for and, if found by reflocheck, two venous samples must be taken immediately; one for laboratory confirmation of the glucose and insulin level and the other stored for cpeptide, pro-insulin and sulphonylurea measurement, if indicated. this must not delay the administration of intravenous glucose, which should be given without awaiting a result. if in such a patient hypoglycaemia is found by finger prick sampling, it is essential to take two venous samples immediately. one sample should benign no extrapancreatic spread no vascular invasion <2cm <2 mitoses/10hpf <2% ki-67 positive cells table 4: characteristics of well differentiated endocrine tumours uncertain behaviour no extrapancreatic extension but with one or more of these features: >2cm in size angioinvasion >2% ki-67 positive cells i n s u l i n o m a : a r a r e c au s e o f a c o m m o n m e ta b o l i c d i s o r d e r h y p o g ly c a e m i a 67 be taken for laboratory confirmation of the glucose and insulin levels. the other should be stored for other possible investigations (c-peptide, pro-insulin and sulphonylurea). you should then take a history from your recovering patient. r e f e r e n c e s 1. siperstein a, clark oh, rushakoff rj. tumor syndromes: insulinoma and other hypoglycemias. in: goldine id, rushakoff rj, eds. diabetes and carbohydrate metabolism. from http://www.endotext.org/diabetes/index. htm. accessed june 2007. 2. service fj. diagnostic approach to hypoglycemia in adults. from http://www.uptodate.com. accessed june 2007. 3. service, fj. hypoglycemic disorders. n engl j med 1995; 332:1144-1152. 4. vortmeyer ao, huang s, lubensky i, zhuang z. nonislet origin of pancreatic islet cell tumours. j clin endocrinol metab 2004; 89:1934-1938. 5. minn ah, kayton, m, lorang, d, et al. insulinomas and expression of insulin splice variant. lancet 2004; 363:363367. 6. romeo s, milione m, gatti a, fallarino m, corleto v, morano s, et al. complete clinical remission and disappearance of liver metastases after treatment with somatostatin analogue in a 40-year-old woman with a malignant insulinoma positive for somatostatin receptors type 2. horm res 2006; 65:120-125. 7. ayav a, bresler l, brunaud l, boissel p, sfcl (société française de chirurgie laparoscopique), afce (association francophone de chirurgie endocrinienne). laparoscopic approach for solitary insulinoma: a multicentre study. langenbecks arch surg 2005; 39:134-140. 8. mirallie e, pattou f, malvaux p, filoche b, godchaux jm, maunoury v, et al. value of endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localization of insulinomas and gastrinomas. experience of 54 cases. gastroenterol clin biol 2002; 26:360. 9. hirshberg b, livi a, bartlett dl, libutti sk, alexander hr, doppman jl, et al. forty-eight-hour fast: the diagnostic test for insulinoma. j clin endocrinol metab 2000; 85:3222-3226. submitted 7 nov 22 1 revisions req. 20 dec 22; revisions recd. 8 jan 23 2 accepted 5 feb 23 3 online-first: february 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.013 5 6 successful treatment of a case of crescentic glomerulonephritis in a patient 7 with primary peritoneal carcinoma 8 a case report 9 *aref zribi,1 amro nagy,2 marwa al riyami,3 ikram a burney1 10 11 1women health program and 2department of medicine, sultan qaboos comprehensive cancer 12 care and research centre, muscat, oman; 3department of pathology, sultan qaboos university 13 hospital, muscat, oman. 14 *corresponding author’s e-mail: arefdoc@gmail.com 15 16 abstract 17 crescentic glomerulonephritis (cgn) has been associated with several solid tumor malignancies. 18 only a few cases of nephropathy have been reported in association with tubo-ovarian/peritoneal 19 malignancies. we describe a case of 55 years old female who developed combined immune 20 complex-mediated glomerulonephritis and pauci-immune necrotizing crescentic vasculitis 21 simultaneously with the diagnosis of tubo-ovarian/peritoneal cancer. the baseline estimated 22 glomerular filtration rate (egfr) was 13 ml/min. the patient received two doses of rituximab and 23 three doses of pulse corticosteroids, leading to significant improvement in renal function and the 24 disappearance of her proteinuria. the egfr improved to >60ml/min, and her proteinuria gradually 25 resolved after 10 weeks of treatment. she was in a position to be given a combination 26 chemotherapy treatment for tubo-ovarian/peritoneal cancer because of normalization of her ca-27 125 after three months of therapy. 28 keywords: tubo-ovarian/peritoneal cancer, glomerulonephritis, vasculitis, chemotherapy. 29 30 introduction 31 glomerulopathy in the field of cancer was first described in 1922.1 glomerulonephritis has been 32 reported in patients with solid tumors, and only a few cases have been reported in patients with 33 tubo-ovarian/peritoneal cancer.2 the most common form of secondary glomerulonephritis is 34 membranous nephropathy (mn), which is most commonly presented as nephrotic syndrome. the 35 prevalence of malignancy with mn ranges from 1% to 22%.3 the glomerular lesions are 36 considered paraneoplastic; however, the exact pathogenesis remains unclear in most cases. renal 37 impairment is a limiting factor in the prescription of chemotherapy, especially nephrotoxic agents, 38 and thus can compromise the survival of patients. herein, we describe the case of a woman 39 diagnosed with metastatic tubo-ovarian/peritoneal cancer and severe acute kidney injury due to 40 crescentic glomerulonephritis. 41 42 case report 43 a 55-year-old woman was hospitalised for epigastric pain, weight loss, abdominal distension and 44 poor oral intake. she had a past medical history of hypertension (treated with amlodipine) and 45 hypothyroidism (treated with levothyroxine replacement). ten years prior to the current 46 presentation, the patient complained of abdominal pain and distention with abdominal mass in the 47 imaging; she had undergone a total abdominal hysterectomy with bilateral salpingo-oophorectomy 48 surgery. the postoperative histopathology report was consistent with serous cystadenoma with 49 borderline malignancy. the postoperative ca-125 was carefully followed up for one year after the 50 surgery, but the patient stopped her follow-up. during the current presentation, petct was done, 51 and the patient was found to have supraclavicular, mediastinal, paraaortic, iliac and inguinal lymph 52 nodes with moderate pleural effusion and ascites. she underwent a cervical lymph node biopsy 53 which was consistent with a new diagnosis of metastatic high-grade serous tubo-ovarian/peritoneal 54 carcinoma: ck7: positive (strong & diffuse), ca-125: positive (strong and diffuse), wt1: 55 positive, p16: positive (strong and diffuse.) er: positive (strong and diffuse) pr: negative. her 56 ca-125 was 1056 kiu/l (normal 0-35 kiu/l). during her hospitalization, she was found to have 57 acute kidney injury (aki), as she was found to have a serum creatinine of 217 umol/l (normal 45-58 84 umol/l) on presentation, and the serum urea was 10.9 mmol/l (normal 2.8-8.1 mmol/l). her 59 electrolytes were normal. the urine dipstick showed blood 3+, protein 1+, and positive leucocytes. 60 urine microscopy showed no casts or crystals. the urine culture showed significant growth of 61 extended-spectrum beta-lactamase-producing escherichia coli with (>100.000 cfu). she was 62 commenced on intravenous piperacillin/tazobactam antibiotic. however, she did not complete the 63 course of antibiotics as she only had mild symptoms, her inflammatory markers were not raised, 64 and the urine sample was taken. in contrast, the patient had a urinary catheter, but the renal 65 functions declined slowly. she also was found to have nephrotic range proteinuria with a urine 66 protein to creatinine ratio (upcr) of 436 mg/mmol (normal less 15 mg/mmol) and urine albumin 67 to creatinine ratio (uacr) of 312 mg/mmol (normal 0-3.5 mg/mmol). serum creatinine increased 68 to 257 umol/l despite hydration and appropriate urinary tract infection treatment. in light of her 69 metastatic disease, aki, and heavy proteinuria, a thorough workup was performed to seek possible 70 additional causes of the aki. she had normal complements, negative hepatitis b and c serology, 71 and negative hiv serology. the serum protein electrophoresis and urine protein electrophoresis 72 showed no abnormal serum protein bands or free light chains in the urine, respectively. the ana 73 was positive (titer 1:320) but negative anti-dsdna antibody. all extractable nuclear antigens 74 profile was negative. she had positive igg antibodies for cytomegalovirus and epstein-barr virus 75 but negative igm for both viruses. the cmv, adenovirus, and ebv tested negative on a 76 polymerase chain reaction. regarding her anti-neutrophil cytoplasmic antibodies (anca), the 77 cytoplasmic and perinuclear forms were both positive, the anti-proteinase 3 (pr3) was expected, 78 but mpo was borderline positive (titer was 24 u/ml, normal from 0.00 – 20.00 u/ml). a clinical 79 diagnosis of rapidly progressive glomerulonephritis was made, and a kidney biopsy was 80 performed. the light microscopy report was consistent with crescentic glomerulonephritis (gn) 81 with positive staining for igg, iga, c3, and c1q. later, further histopathologic examination of the 82 kidney tissue by electron microscopy revealed features consistent with immune complex-related 83 gn with mesangial and subendothelial deposits electron microscope (em) with extensive 84 effacement of podocyte foot processes. the patient received a diagnosis of aki secondary to 85 crescentic gn, likely due to pauci-immune gn with concomitant immune complex-mediated gn. 86 she received pulse intravenous (iv) methylprednisolone 500mg daily for three days with 87 appropriate calcium and vitamin d supplementations, then started on oral prednisone 30mg daily 88 with a gradual taper over 8 weeks and was finally maintained on prednisone 5mg daily. 89 additionally, she received iv rituximab 1gm once weekly for 2 weeks. rituximab infusions were 90 without any anaphylaxis and infusion-related reactions. two months later, the upcr was 43 91 mg/mmol, and uacr was 27.6 mg/mmol. serum creatinine decreased to 98 umol/l, and her 92 egfr was 50ml/min. the remission of her proteinuria and significant improvement in her renal 93 functions allowed for complete dose chemotherapy to be administered. she continued to show 94 significant improvement in her renal functions (serum creatinine was 78 umol/l, egfr: 95 66.5ml/min) and had a good response to chemotherapy (ca-125: 30.2 kiu/l). verbal and written 96 consent for publication purposes was taken from the patient. 97 discussion 98 historically, solid tumor malignancies, most commonly associated with nephropathy are 99 pulmonary and gastric carcinomas.3 membranoproliferative (mpgn) injury pattern has been 100 described in association with solid tumors of the lung, kidney and stomach. melanoma, breast 101 carcinoma, and thymoma have also been rarely reported in association with mpgn”3. crescentic 102 glomerulonephritis (cgn) has been associated with several solid tumor malignancies.3 only a 103 few cases of nephropathy have been reported in association with tubo-ovarian/peritoneal 104 malignancies.3 nephropathy seems to occur irrespective of the tubo-ovarian/peritoneal tumor 105 diagnosis, either during a relapse, two years after the first diagnosis or simultaneously. the 106 underlying glomerular lesions are reported to be membranous nephropathy, mpgn, aa 107 amyloidosis, minimal change nephropathy, and mesangial-proliferative glomerulonephritis.4 in 108 the case of nephropathy associated with tubo-ovarian/peritoneal tumors, the treatment includes the 109 administration of corticosteroids, surgery and chemotherapy.5 our patient was not fit for initial 110 debulking surgery as the disease was metastatic. corticosteroids and rituximab were prescribed, 111 resulting in complete nephropathy remission. chemotherapy paclitaxel and carboplatin could be 112 prescribed one month after her cancer diagnosis. the pathogenesis of secondary nephropathy has 113 not been clearly defined, but a cell-mediated immune response has been postulated; the secretion 114 of a tumoral factor and/or the appropriate production of lymphokines by t-cells to suppress tumor 115 growth could increase glomerular permeability.6 clinically, it is difficult to differentiate primary 116 mpgn from secondary mpgn associated with solid tumors. lefaucheur et al. 7 reported two risk 117 factors differentiating paraneoplastic mpgn from primary mpgn. these include an age of over 118 65 years and a history of smoking 20 pack-years. our patient was a no-smoker.beck et al. 8 119 identified circulating autoantibodies in most cases of adult primary mpgn. these autoantibodies 120 were not found in cases of secondary mpgn.4 .7 lefaucheur et al. reported an increased number 121 of inflammatory cells (more than eight cells per glomeruli) on the kidney biopsy of patients with 122 paraneoplastic mpgn as compared to patients with primary mpgn. in our case, biopsy showed 123 mixed inflammatory cell infiltrate consisting mainly of lymphocytes and a few neutrophils, which 124 is consistent with the paraneoplastic origin of glomerulonephritis. beck et al. 8 explain the possible 125 mechanisms, whereby solid tumors may be associated with mpgn. these include: (a) in-situ 126 immune-complex formation in which antibodies are formed against a tumor antigen that is 127 localized in the subepithelial location or to podocyte antigen that is identical or similar to the tumor 128 antigen, (b) tumor antigens may form circulating immune complexes that are subsequently trapped 129 in glomerular capillaries, and (c) external factors such as infections with oncogenic viruses or 130 altered immune function that can cause both the malignancy and mpgn. 131 132 the degree of proteinuria varies among patients with myeloperoxidase (mpo) vasculitis but is 133 usually subnephrotic. 9. 10 proteinuria of 1g per day or less in patients with anca-associated 134 vasculitis (aav) is most likely the consequence of fibrosed glomeruli or tubular fibrosis in an 135 individual who may or may not be in remission. higher amounts of proteinuria, including 136 proteinuria of more than 3g/day, may be more common in patients who present later in the course 137 of the disease and who have had previous necrotizing glomerulonephritis.11 in our patient, 138 although the biopsy had a limited number of glomeruli, all glomeruli were intact and showed a 139 mild increase in the mesangial matrix. all glomeruli showed cellular crescents with segmental 140 fibrinoid necrosis in the tuft. there were no signs of endocapillary hypercellularity or thrombosis 141 on light microscopy. capillary walls showed normal thickness with no spikes or double contours. 142 there was no tubular atrophy or interstitial fibrosis. further examination by em revealed 143 numerous small subendothelial deposits in the basement membrane with extensive effacement of 144 podocyte foot processes with mesangial expansion and mesangial deposits. in some patients with 145 aav with high amounts of proteinuria, there may be a second concurrent glomerular disease or 146 an atypical histologic pattern like a glomerular immune-complex deposition.12.13 the nephrotic 147 range proteinuria was most likely due to the extensive foot processes effacement found on 148 histopathologic analysis of the renal biopsy. 149 150 conclusion 151 we describe the case of a patient diagnosed with tubo-ovarian/peritoneal cancer and associated 152 with glomerulonephritis and vasculitis. clinical history, physical examination, laboratory data, and 153 kidney biopsy revealed the correct diagnosis. corticosteroids combined with rituximab resulted 154 in an improvement in renal functions, and the patient was able to receive a combination of 155 chemotherapy paclitaxel and carboplatin for tubo-ovarian/peritoneal cancer. the treatment of 156 paraneoplastic glomerulonephritis requires a multidisciplinary approach to monitor both cancer 157 and glomerular lesions. 158 159 authors’ contribution 160 az, an and iab managed the case. mr provided the details of histopathology. az, an and mr 161 drafted the manuscript. iab critically reviewed the manuscript. all authors approved the final 162 version of the manuscript. 163 164 acknowledgements 165 we would like to thank dr mohammad athar khan for kindly reviewing the manuscript, and 166 giving useful suggestions to improve its quality. 167 168 references 169 1. galloway j. remarks on hodgkin's disease. br med j. 1922 dec 23; 2(3234): 1201-1204 170 2. meyrier a, delahousse m, callard p, rainfray m. minimal change nephrotic syndrome 171 revealing solid tumors. nephron. 1992; 61(2):220-223. 172 3. bacchetta j, juillard l, cochat p et al. paraneoplastic glomerular diseases and 173 malignancies. crit rev oncol hematol. 2009; 70: 39–58. 174 4. jeroudi a, kadikoy h, gaber l, ramanathan v, frome a, anwar n, abdellatif a. 175 profound nephrotic syndrome in a patient with ovarian teratoma. saudi j kidney dis 176 transpl. 2013 jul;24(4):777-82. 177 5. salazar-exaire d, rodriguez a, galindo-rujana me, briones jc, arenas-osuna j, rocha 178 lm et al. membranoproliferative glomerulonephritis associated with a mixed-cell 179 germinal ovary tumor. am j nephrol. 2001 jan-feb;21(1):5154. 180 6. schnaper hw, robson am.: minimal change disease, focal glomerulosclerosis and 181 related disorders. disease of the kidney. 5th ed.1992; 1731-1784. 182 7. lefaucheur c, stengel b, nochy d et al. membranous nephropathy and cancer: 183 epidemiologic evidence and determinants of high-risk cancer association. kidney int 184 2006. volume 70, issue 8, pages 1510-1517 185 https://www.sciencedirect.com/journal/kidney-international/vol/70/issue/8 8. beck lh jr. membranous nephropathy and malignancy. semin nephrol 2010; 30: 635–186 644. 187 9. hoffman gs, kerr gs, leavitt ry, hallahan cw, lebovics rs, travis wd, rottem m, 188 fauci as. wegener granulomatosis: an analysis of 158 patients. ann intern med. 1992 189 mar 15;116(6):488-98. 190 10. savage co, winearls cg, evans dj, rees aj, lockwood cm. microscopic polyarteritis: 191 presentation, pathology and prognosis. q j med. 1985 aug;56(220):467-83 192 11. ronald j falk, peter a merkel, talmadge e king, (2022). granulomatosis with 193 polyangiitis and microscopic polyangiitis: clinical manifestations and 194 diagnosis. uptodate jun 09, 2022. 195 12. haas m, eustace ja. immune complex deposits in anca-associated crescentic 196 glomerulonephritis: a study of 126 cases. kidney int. 2004 jun;65(6):2145-52. 197 13. neumann i, regele h, kain r, birck r, meisl ft. glomerular immune deposits are 198 associated with increased proteinuria in patients with anca-associated crescentic 199 nephritis. nephrol dial transplant. 2003 mar;18(3):524-31. 200 201 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/abstract/13,19 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/abstract/13,19 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/abstract/13,19 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/contributors https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/contributors https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/contributors 202 figure1: a: shows two glomeruli, one with fibrinoid necrosis (arrow) and the other with a cellular 203 crescent (h&e stain). b: higher magnification of a glomerulus with a cellular crescent (jones 204 stain). c and d: electron micrograph highlighting mesangial and subendothelial deposits, 205 respectively (arrows). there is also extensive foot process effacement of podocytes. 206 magnifications: image a: 200x, image b: 400x, image c: 12,000x, image d: 10,000x. 207 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 1-4, epub 16th mar 2009 submitted 10th feb 2009, internally peer reviewed revision recd. 16th feb 09 plagiarism and other types of publication misconduct a case for teaching publication ethics in medical schools *lamk al-lamki the world association of medical editors (wame) in its publication, ethics policies for medical journals, defines plagiarism as “the use of others’ published and unpublished ideas or words (or other intellectual property) without attribution or permission, and presenting them as new and original rather than derived from an existing source. this applies whether the ideas or words are taken from abstracts, research grant applications, institutional review board applications, or unpublished or published manuscripts in any publication format (print or electronic)”1 the office of research integrity (ori) in the usa considers “plagiarism to include both the theft or misappropriation of intellectual property and the substantial unattributed textual copying of another’s work”. ori goes on to explain, “the theft or misappropriation of intellectual property includes the unauthorized use of ideas or unique methods obtained by a privileged communication, such as a grant or manuscript review.”2 plagiarism is the worst offence of all the various forms of publication misconduct. “in its worst form, it is as bad as any other scientific misconduct”. the recent increase in the amount of plagiarism is partly due to the pressure that university faculty is under to “publish or perish”. this mantra not only drives them to publish, but it also leads to an increased incidence of plagiarism and duplicate publications.3 the situation is further compounded by the proliferation of electronic publications which make ‘cut and paste’ an easy option. wame clearly states that plagiarism is scientific misconduct and should be addressed as such. they go further and define “self-plagiarism” as the practice of authors using portions of their previous writings or other publications without acknowledging the original source. best practice requires full disclosure of all original sources. therefore when one picks words, sentences or paragraphs from another’s writings, they must be put in “quotes” and referenced immediately at the end of that sentence. 1 at the recent 4th regional conference on medical journals in the eastern mediterranean region, 5-7th november 2008, in manama, kingdom of bahrain, the editors of medical journals in the emro (eastern mediterranean region of who) discussed publication misconduct extensively.4plagiarism, as well as other forms of publication misconduct, were discussed in the lectures as well as the workshops by speakers from various parts of the world, including the united kingdom, croatia, spain, austria, iran and pakistan. the consensus emerged that plagiarism and duplicate publication are the least acknowledged form of academic misconduct though they pervade many aspects of academic publication. editor-in-chief, squ medical journal, college of medicine, sultan qaboos university, muscat, sultanate of oman *email: mjournal@squ.edu.om e d i t o r i a l العلمي النشر في التصرف إساءات من وغيره االنتحال الطبية الكليات النشر في أخالقيات تدريس تستوجب قضية اللمكي ملك l a m k a l l a m k i 2 many attempts have been made to get to grips with this form of academic misconduct. in a project funded by the national institutes of health, mounir errami and harold garner used the déjà vu website,5 a database that aims to expose duplicate publication by finding passages that are ’extremely similar to medline citations’. the outcome of this quest was the staggering fact that there are an alarming number of duplicate papers.6 they reviewed 7 million biomedical abstracts and, with apologies to charles dickens, they published “a tale of two citations”. they point out, “it is the best of times, it is the worst of times” in the world of biomedical publications. the scholarly publication rate is at an all time high. however, there is also a high incidence of scientific misconduct, hence, this raises the question of “how much can we trust these publications”. these authors have unearthed duplicate publications from various quarters of the world. because of the sheer number of publications, the united states, japan, germany, china, uk and several western countries, ‘outshine’ developing countries in the league of misconduct. the usa was found to have the highest number of suspected duplicates, followed by japan, but these two countries also had the highest relative contribution to medline of all countries. how should we deal with plagiarism? there is no magic bullet against such misconduct. the rule of thumb is that editors should carry the responsibility of trying to detect misconduct and then report it to the culprit’s institution and to the authority who funded the author’s research. editors have a responsibility to the producers and publishers of good medical research, to the medical community, and to the public. they have to ensure that the manuscripts that are published are in accordance with the uniform requirements for manuscripts submitted to bio-medical journals published by the international committee of medical journal editors (icmje) and updated in 2008.7 these icmje requirements are further supported by wame in their publication on ethics policies.1 currently, some journals routinely run software that can detect plagiarism or duplication of part or whole of a manuscript.8the famous case of repeated plagiarism by an eminent croatian, clinician and academic, asim kurjak 9 has raised a lot of questions about how we deal with plagiarism and the responsibilities of both the editor and the institution. the icmje meets every year and updates their protocols periodically also updating the definition of plagiarism or other publication misconduct.7 in fact, there are several types of publication misconduct including “redundant or duplicate publications” which indicates publication of a paper that substantially overlaps with one already published.1 other publication misconduct includes “ghost authorship” whereby a name of an author appears on the manuscript but he/ she did not actually write the manuscript or contribute to it typically this is from a drug company; and then there is “photograph manipulation”.10 another form of scientific malpractice is “data forging” that is inventing data, for example by reporting results of experiments that were never conducted. “data cooking” entails discarding data that do not support a study’s hypothesis so that the study produces ‘better’ results. “data trimming” consists of changing data values so that they better fit the predictions made by the research hypothesis. most disheartening is the phenomon known as “data torturing” which is the improper exploitation of statistical tests, repeatedly analysing the same data in different ways until something anything emerges as statistically significant. upon discovering misconduct, editors have a responsibility to avoid publishing such manuscripts. however, they need the help of institutions and funding agencies that support research, in order to halt the apparent rise in this phenomenon. more importantly the authors have to be educated as to what constitutes plagiarism and also about publication ethics in general. this education has to be instilled during the early phase of the career, perhaps earlier than in medical school. medical schools must ensure that all graduating doctors are well versed in the basics of publication ethics and fully aware of what constitutes academic misconduct. it is quite common for medical students to prepare a project using extensive “cut and paste” without acknowledging the original source and therefore inadvertently misleading the reader as to the source of the text. thus this has been equated to “stealing and then lying about it”. we should also note that plagiarism includes paraphrasing without crediting the source.11 skandalakis and mirilas discussed the motivations for plagiarism and give two striking historical examples of plagiarism.11 as early as 1991, dr. berk, editor-in-chief of american journal of roentgenology (ajr), asked, “is plagiarism ever insignificant?”12 he pointed out that “plagiarism is plagiarism, just like theft is theft”. however, in a practical sense, the guilt can be mitigated by several factors, intentional or not, p l a g i a r i s m a n d o t h e r t y p e s o f p u b l i c at i o n m i s c o n d u c t 3 and there are degrees of guilt associated with plagiarism. dr. berk concluded that plagiarisn is a breach of professional ethics that must be exposed and unreservedly deplored.12 in a new england journal article,10 dr. laine et al. discuss the registration of clinical trials at the “clinicaltrials.gov” as a means of preventing or reducing publication misconduct. in this part of the world, more appropriate to us is the registration of clinical trials with the world health organization’s (who) international clinical trial registry platform (ictrp). this is particularly important as some authors or some investigators try not to publish negative results of their clinical trials another breach of publication ethics. registration of a clinical trial before starting it reduces the incidence of publication bias and its illegal counterpart, scientific misconduct. scientific and publication misconduct includes any form of bias, whether statistical bias, institutional bias, or other. according to rizk, “members of the medical profession and the public hence generally agree that there ought to be “zero tolerance” towards academic dishonesty, particularly publication misconduct”.13 he added that “medicine is a profession based on trust, integrity, philanthropy and altruism”,13 and therefore, the profession should maintain expected good practice. the public is becoming more acutely aware of the details of scientific inquiry and often quote the “internet and medical literature”; hence, extra vigilance is essential. this is consonant with the teaching of the father of modern medicine, claudius galen (a.d.193210), that “the true doctor will be found to be a friend of temperance and a companion of truth.” dealing with publication misconduct and scientific misconduct is a major dilemma to editors. help may be found in certain organisations such as the office of research integrity (ori) part of public health service in the usa, and the committee on publication ethics (cope) in the uk. these organisations define terms such as plagiarism and scientific misconduct and set guidelines for editors and institutes. the editor can be faced with the dilemma of plagiarism at two different stages and these need different approaches. they may detect plagiarism prior to publication, or after publication of the article. in the first case, the detection is usually a result of the efforts of the editorial team themselves or of reviewers, and the second often arises from a complaint by the victimised author or some other reader of the article. either way, editors are obliged to act. how exactly ‘to act’ in each of these cases is not yet well defined nor are specific guidelines yet provided by the medical community or by the professional organizations of medical editors. it is generally accepted, however, that the editor has to inform the guilty author as well as the institution with whom the author is affiliated and also, any funding agency that maybe involved in the research that was conducted. if the article is already published, the editor has to publish a retraction of the article as well as inform all the parties involved mentioned above as well as the editor of the journal where the victimised author originally published his or her work. further steps are not clearly defined although it is generally recommended that it is not the responsibility of the editors to go into detailed investigation of the case other than establishing that it is a case of plagiarism. several journals have spelled out the steps that they take to address plagiarism 8,14-19 . in the bmj article, fiona godlee also discusses the role of cope. cope has devised a series of flowcharts that outline what journals should do, but they repeat at the end, “we have to rely on the academic institutions to take the actions”. unfortunately, there is little evidence to suggest that institutions have mandated policies for dealing with academic misconduct. many medical journals have taken it upon themselves to carry out a sentence in case of proven guilt. some journals have elected to bar the guilty author from further publication in their journal for varying periods. the saudi medical journal has elected not to accept future submissions from that author for two years, as well as to send a notification to the head of the author’s institution and a warning to the author with prompt rejection of the submitted manuscript if discovered prior to publication.17 the annals of saudi medicine has elected to ‘blacklist’ guilty authors for 5 years.18 the problem of plagiarism and other forms of publication misconduct will not go away by punishment of the guilty. it needs education of authors. this education has to start as early as high school or perhaps even earlier. when students prepare a project, they should learn how to quote any cut-and-paste. they have to understand that just showing the references that were used, in the bibliography section, is not adequate to exonerate the authors. the reference has to be immediately at the end of the quoted sentence or paragraph. certainly, in medicine, we need to teach this in medical school. the medical ethics course should be expanded l a m k a l l a m k i 4 to include publication ethics. most medical schools have now started this by adding a short course of medical ethics even though, in some cases, it comprises only a very short series of lectures. nevertheless, any such course in medical school should include teaching on publication ethics and what constitutes scientific and research misconduct. medical undergraduate and postgraduate educators must be very vigilant in instilling in young medical minds the importance of exemplary publication ethics and scientific and research conduct. arab/islamic history probably presented the precursor of modern concerns about plagiarism. for instance, the hadith has been credited with requiring proper acknowledgement of the original source. one of the earliest accusations of plagiarism was in the 11th century when al-jahiz was accused of and prosecuted for allegedly plagiarising the greek philospher, aristotle, in writing kitāb al-hayawān.20,21 although the accusation was later recanted,22 it highlights the historical pervasiveness of this phenomenon. the solution to the current critical state of this problem will require a concerted effort from editors, institutions and, most importantly, educators at medical schools, in postgraduate medical teaching and, indeed, at all levels of education. r e f e r e n c e s 1. wame publication ethics policies for medical journals. from http://www.wame.org/resources/ethics-resources/publication-ethics-policies-for-medical-journals/ accessed february 2009. 2. office of research integrity. plagiarism. from http://ori. hhs.gov/policies/plagiarism.shtml accessed february 2009. 3. sarr mg, warshaw al. ethical misconduct in publishing: the editors’ perspective. world j surg 2006; 30:1374-6. doi: 10.1007/s00268-005-0646-0 4. the 4th regional conference on medical journals in the eastern mediterranean region, manama, bahrain, 5-7 november 2008. 5. déjà vu: a database of highly similar and duplicate citations http://spore.swmed.edu/dejavu 6. errami m., garner h. a tale of two citations. nature 2008; 451:397-9, published online 24 january 2008 at http://www.nature.com/nature/journal/v451/n7177/ edsumm/e080124-02.html doi: 10.1038/451397a 7. international committee of medical journal editors. uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication (updated october 2008). from http://www. icmje.org. accessed february 2009. 8. godlee f. editor’s choice plagiarism and punishment. bmj 2007; 335:1014. from http://www.bmj.com/cgi/ content/full/335/7627/maxtoshow=&hits=10&hits =10&resultformat=&fulltext=plagiarism&searc hid=1&firstindex=0&resourcetype=hwcit accessed february 2009. 9. chalmers i. role of systematic reviews in detecting plagiarism: case of asim kurjak. bmj 2006; 333:5946. published online: http://www.bmj.com/cgi/content/ full/333/7568/594?maxtoshow accessed february 2009. 10. laine c. horton r, deangelis cd. clinical trials registration looking back and moving ahead. nejm 2007; 356:2734-6. 11. skandalakis j, mirilas p. plagiarism. arch surg 2004; 139:1022-4. 12. berk r. is plagiarism ever insignificant? am j roentgenol (ajr) 1991; 157:614. 13. rizk dee. publication ethics: science at its best and always informative. int urogynecol j 2007; 18:7157. published online: www.springerlink.com/index/ m13754212402448r.pdf, doi 10.1007/s00192-0070363-3 accessed february 2009. 14. sriganesh v, parvati i. plagiarism and medical writing. ind j radiol & imaging 2007; 17:146-7. 15. katavic v. five-year report of croatian medical journal’s research integrity editor policy, policing, or policing policy. croat med j april 2006; 47:222-7. 16. peh wcg, arokiasamy j. plagiarism: a joint statement from the singapore medical journal and the medical journal of malaysia editorial. singapore med j 2008; 49:965-6. 17. al-deeb sm, alokaily f. saudi medical journal and the burden of ethic misconduct (editorial). saudi med j 2008; 28:5-6. 18. cathey jt, al-jurt m. duplicate and fragmented publication: the policy of the annals of saudi medicine. ann saudi med 2007; 27:1. 19. handa s. plagiarism and publication ethics: dos and don’ts. indian j derm, venrol & leprol (ijdvl) 2008; 74:301-3 20. syed aslam. muslim scientists and thinkers al-jahiz abu uthman ibn bahar. from http://muslimmedianetwork.com/mmn/?p=2356 accessed february 2009. 21. wikipedia. al-jahiz, muslim scholar medieval era. from http://en.wikipedia.org/wiki/al-jahiz accessed february 2009. 22. wikipedia. list of plagiarism controversies. from en.wikipedia.org/wiki/list_of_plagiarism_controversies accessed february 2009. submitted 13 aug 22 1 revision req. 21 sep 22; revision recd. 24 oct 22 2 accepted 9 nov 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.067 5 6 examination of behavioural patterns of psychological distress and 7 evaluation of related factors 8 a latent class regression 9 negar sangsefidi,1 *jamshid jamali,1 zahra rahimi,1 ana kazemi2 10 11 1department of biostatistics, school of health, mashhad university of medical sciences, 12 mashhad, iran; 2department of psychology, faculty of psychology and educational sciences, 13 kerman branch, islamic azad university, kerman, iran. 14 *corresponding author’s e-mail: jamalij@mums.ac.ir 15 16 abstract 17 objectives: psychological distress (pd) is a unique and suffering emotional state in response to 18 a stressor or specific need that leads to temporary or permanent impacts. due to its negative 19 effects on several features of life like the quality of life, health, performance, and productivity of 20 individuals, pd and its consequences are considered as a public health priority. in this study, we 21 aim to identify the behavioral pattern of pd in the population of 18 to 65 years old in mashhad 22 using latent class regression and evaluate the related factors. methods: a cross-sectional study 23 was performed on 425286 individuals aged 18 to 65, who were referred to health centers in 24 mashhad, northeastern iran in the first half of 2018. the information required for this study 25 including a checklist of demographic information and the six item kessler psychological 26 distress scale (k-6) was obtained from the sina system. results: latent class regression 27 identified three latent patterns of pd in answering the questions of the k-6 questionnaire, 28 including severe pd (14%), low pd distress (40%), and no pd (46%). statistical variables of this 29 study due to the results are considered as the following; women, illiterate people, unemployed 30 and divorced people, individuals aged between 50-59 years old, and people with low weight 31 were more likely to be in severe pd class than no pd class. conclusion: although a small 32 percentage of people were classified as severely disturbed, the findings showed a high rate of 33 symptoms of distress and sadness even in the no pd class. 34 keywords: cross-sectional studies, psychological distress, latent class analysis, iran 35 36 advances in knowledge 37  psychological distress (pd) is a unique and suffering emotional state in response to a 38 stressor or specific need that leads to temporary or permanent impacts. pd adverse effects 39 on health, performance, and productivity are proposed as a public health priority. 40 41 application to patient care 42  there is a high rate of symptoms of significant distress and sadness even in the no pd 43 class. 44  there is a need to develop appropriate strategies for prevention and treatment and 45 provide the necessary training and intervention for high-risk groups of pd, especially 46 women. 47  using the achieved results through careful planning, diagnosis, treatment, and prevention 48 of mental disease can lead to building a healthy and vibrant society away from mental 49 and psychosomatic illnesses. 50 51 introduction 52 tensions, stresses and life's problems are common phenomena of modern life, but ineffective 53 management of these challenges can lead to stress disorders, psychological distress (pd), and 54 physical ailments. according to numerous epidemiological studies in recent years, the 55 prevalence of mental disorders in different countries is increasing daily; the prevalence of these 56 disorders in different countries varies from 13 to 22 %.1 these disorders are one of the five 57 leading causes of disability and are known as an strong predictor of death from heart disease, 58 stroke, and cancer.1 it is estimated that 12% of the total burden of disease globally is due to 59 mental disorders and is expected to increase to 15% by 2020.2 the prevalence of these disorders 60 in iran is estimated between 11.9% to 23.8%.3, 4 61 62 pd as considered by mirowsky. j. is a state of emotional suffering consisting of symptoms 63 related to depression and anxiety,5 which lead to decline in quality of life at the individual level 64 and because of their adverse effects on health, performance, and productivity, are proposed as a 65 public health priority.1 it is noticeable to mention some symptoms of pd that include a wide 66 range of physical to mental states. sleep disturbance, anorexia, chronic pain, fatigue, loss of 67 menstruation for women and headaches are some of physical symptoms while some symptoms 68 like feeling of sadness, nervous, helplessness, hopelessness and worthlessness are known as 69 mental ones. the prevalence of mild mental disorders (depression, anxiety) in different countries 70 in general populations varies between 7.3 to 52.5%.6 according to dsm-5-tr high levels of pd 71 is considered as one of negative functional consequences of specific learning disorder.7 72 73 according to the results of the global burden of disease study (gbd) in 2016, depressive and 74 anxiety disorders from 2005 to 2016 were among the top ten causes of loss of iranians life due to 75 disability.8 the study estimated the number of people with mental illnesses and drug-related 76 disorders in 2016 at 1.1 billion worldwide.8 the term pd is a type of mental symptoms that is 77 used as an indicator of mental health issues in demographic and epidemiological studies.9 78 79 pd and its measurements strongly refer to the symptoms of depression and anxiety and mainly 80 refer to cognitive behaviors disorders, depressive disorders and anxiety disorders so reports 81 indicate that pd affected most of these disorders.10 as mentioned, pd is commonly referred to as 82 emotional suffering characterized by symptoms of depression (such as apathy, sadness, 83 hopelessness) and anxiety (such as restlessness, feeling tense).9 in other words, pd is used to 84 describe a short but acute period of a specific mental symptoms that first presents with features 85 of depression or anxiety and can be deemed as a type of abnormality that is responsible for 86 maladaptive cognitive behavior and thought, which requires specialized intervention.11 pd 87 encompasses a much wider range of experiences than mental illness, ranging from mild 88 symptoms to severe psychiatric disease.12 in these cases, it is noticeable that life enthusiasm 89 notably decreases, and also feeling of heartbreak and despair become dominant throughout an 90 individual's life.11 so severe pd is a predictor of serious mental illnesses like depression and 91 anxiety and other disorders.2 92 https://en.wikipedia.org/wiki/anorexia_(symptom) https://en.wikipedia.org/wiki/chronic_pain https://en.wikipedia.org/wiki/fatigue_(medical) https://en.wikipedia.org/wiki/headache https://apps.who.int/iris/bitstream/handle/10665/41864/0965546608_eng.pdf 93 based on the findings of previous studies, the prevalence of pd in india was estimated at 20.2%, 94 in japan at 6.7%, in the united states at 3.4%, in canada at 12%, and in australia at 11.1%.2, 13-95 15 96 97 the prevalence of pd in iran is reported to be very diverse, from 10.1% to 57.2%, depending on 98 the questionnaire used, the cut-off point considered, the demographic characteristics and the time 99 of the study.16-20 100 101 studies in different parts of iran also show that the prevalence of pd is not only less than the 102 recorded statistics of other countries but also not less than the reports of the world health 103 organization and the reported by noorbala study in mashhad and shafiei in isfahan.21, 22 104 105 three categories of factors include socio-demographic characteristics (e.g., gender, age, and 106 ethnicity), factors related to stress (e.g., living conditions and life events), and personal 107 resources (e.g., income, education, social network, and social support) are recognized as 108 influential factors in pd in the general population.2, 9, 23-25 109 110 recent studies conducted in different parts of the world showed a high prevalence of pd due to 111 increasing rate of mental disorders like anxiety and depression ones. such a trend has created the 112 need for appropriate health care and services to provide mental health services in health centers, 113 especially for high-risk groups of mental disorders. for this purpose, epidemiological studies of 114 pd play an important role in determining the general mental health status of the community, 115 identifying related demographic factors, and estimating the resources needed to provide better 116 health services in the country. health care centers can also play a critical role in different 117 processes such as diagnosis, care, and treatment of individuals grouped in high-risk mental 118 disorders. there are several fields of study such as the patterns of pd and the evaluation of 119 related factors simultaneously in a large-scale study, which has been less studied especially in 120 iran. therefore, this study intends to examine the pattern of pd of patients aged 18 to 65 years in 121 mashhad health centers based on the k-6 questionnaire. the research identifies related factors, 122 provides appropriate suggestions and programs in order to provide better mental health services 123 for people prone to psychological disorders, and also helps the relevant authorities. 124 125 methods 126 the present study is cross-sectional and descriptive-analytical research was performed in 127 mashhad. mashhad is the second-most-populous city in iran and the capital of razavi khorasan 128 province, which is located in the northeast of the country. the information used in this study was 129 extracted from the sina electronic health record system (sinaehr) database under the 130 supervision of mashhad university of medical sciences. sina system has been used since 2016 131 to electronically record the health records of patients who were referred to health centers in 132 khorasan razavi province and so far covers about 40% of the population of mashhad. this 133 system includes demographic information, health records of each individual, reports of 134 physicians and health care providers, laboratory results, screening forms and age group care, and 135 other details of clients' files. one of the screening forms used in this system is the k-6 136 questionnaire. in this study, information was received on people aged 18-65 who were referred to 137 mashhad health centers for the first time in the first half of 2018 and completed the k-6 138 questionnaire. the inclusion criterion in this study was the answer to at least 50% of questions 139 of the questionnaire (3 questions), and people who had a diagnosis of neurological problems in 140 the past were excluded from the study. data after correction and purification included 425286 141 people. 142 143 voluntary referral, the confidentiality of identity information, non-disclosure of individuals' 144 names, lack of prejudice, and involvement of inclinations in the research results, and mentioning 145 of all scientific sources have been among the ethical considerations considered in this research. 146 this study has been approved by the national committee of ethics in biomedical research with 147 the ethics id: ir.mums.rec.1398.058. 148 149 this survey comprised two instruments to gather data: standard demographic questions including 150 gender, age, marital status, level of education, job type, place of residence, body mass index, and 151 six-item kessler psychological distress scale (k-6) to measure the participants’ pd. the k6 scale 152 is a population-based screening measure for identifying pd and is widely used in general 153 populations.23, 26-28 this scale is a truncated version of 6 items from the k10 scale that was 154 introduced in 2002 by kessler et al. 8 responses were scored on a five-point likert scale 155 reflecting how much over the past month time respondents had experienced 6 symptoms, 156 including sadness, restless, nervous, helpless, hopeless, and worthless. the measure has five 157 response categories ranging from 0 (none of the time) to 4 (all of the time). the items were 158 summed to generate a total score ranging from 0 to 24, with higher scores indicating higher 159 levels of pd.10 the validity and reliability of its persian version have also been confirmed in 160 previous studies.10, 18, 29 161 162 latent class regression (lcr), a model-based clustering approach, was used to classify each 163 participant into a latent class whose members report similar patterns of responses k-6 164 questionnaire. determining the cut-off point for the pd questionnaire is challenging, and several 165 cut-off points have been proposed so far. 9, 15, 23 in lcr, there is no need for a cut-off point that 166 is a function of demographic characteristics of communities. 167 168 lcr can also assess the effect of covariates on the classification.30, 31 huang suggested a 169 generalization of lcr can evaluate the effect of covariates on latent variables as well as the 170 observed variables.32 interpretation of coefficients in lcr is similar to logistic regression based 171 on odds ratio. determining the optimal number of latent classes in lcr is challenging.33, 34 172 statistical criteria (such as akaike information criterion, bayesian information criterion, 173 likelihood-based tests, log-likelihood difference test, lo-mendell-rubin test, bootstrap 174 likelihood ratio test, and entropy) and interpretability are commonly used to determine the 175 number of classes.33 176 177 models with lower evaluation criteria (aic, bic, aic3, and caic) are preferred to those with 178 higher values for these criteria. other fit statistics such as likelihood tests (i.e., tests log-179 likelihood difference test, lo-mendell-rubin test, and the bootstrapped likelihood ratio test) 180 provide a p-value, which indicates if one model is statistically better than another.34 another set 181 of methods for evaluating lc cluster models is based on the uncertainty of classification or, 182 equivalently, the separation of the clusters. entropy as a diagnostic statistic, indicates how 183 accurately the model defines classes. in general, an entropy value close to 1 is ideal and above .8 184 is acceptable.35 185 186 in this study, k-6 questions are considered as indicator variables, the pd is known as a latent 187 variable, and gender, age, marital status, education level, job type, residence, body mass index 188 are covariates in lcr. all analyses were performed using latentgold 5. if the p-value was less 189 than 0.05 (typically ≤ 0.05), the result was considered significant. 190 191 results 192 out of 425286 participants, 72.7% were women, 90.6% were married, 72.5% had a diploma and 193 undergraduate education, and 54.2% were suburban residents. the mean age and body mass 194 index (bmi) of the participants were 36.02±9.58 years and 26.5±4.88, respectively. 195 demographic characteristics of the study population are presented in table 1. 196 197 the mean score of the k-6 questionnaire is 4.23±4.54. most people (over 75%) have 198 experienced little or no symptoms of anxiety. however, half of the people have always, 199 sometimes or most of the time been upset and sad. only 3% of people always or most often 200 suffered from feelings of emptiness and worthlessness. this rate was less than 5% for symptoms 201 of hopelessness and helplessness. it is worth mentioning that the rate of answering the questions 202 of the questionnaire is 98.5%. 203 204 to determine the optimal number of latent classes, goodness-of-fit criteria for the lcr model 205 with 2-6 latent classes fitted to the data, and the results are shown in table 2. as the number of 206 classes increased, the goodness-of-fit indices decreased, but for models with more than three 207 classes, no significant improvement in index values was observed. the value of entropy and r2 208 in the latent class model with three classes are 0.78 and 0.79, respectively, which is a statistically 209 significant value for a model and can well explain the latent pattern of the data. this model also 210 can interpret in practice. considering more than three classes makes it difficult to interpret the 211 data correctly. as a result, the latent class model with three classes is the optimal model for the 212 studying data. 213 214 the proportions of individuals in the classes that have been created based on the k-6 question 215 pattern are presented in table 3. 216 217 it can be seen that no pd class, which has the highest volume among the classes, people did not 218 report any pd symptoms during one month. in other words, more than 90% of these people have 219 never experienced symptoms of pd. in the low pd class, at least 80% of people have never or 220 minor experienced symptoms of nervous, helplessness, hopelessness, or worthlessness. 221 nevertheless, this rate was higher for the symptoms of sadness and restlessness; over a month, 222 more than 60% of people reported these symptoms slightly or occasionally. this class accounts 223 for 39% of the samples. it was estimated that 14% of people are suffered from severe pd. most 224 people in this class sometimes suffer from symptoms of pd. but, most of the time, they felt 225 sadness and restlessness. 226 227 the lcr model, in addition to determining the latent classes, also makes it possible to evaluate 228 the effect of independent variables on the placement of individuals in the formed latent classes. 229 in this study, the no pd class is considered as a reference category. the numerical value of the 230 coefficients (in terms of odds ratio) expresses the effect of increasing one unit in the independent 231 variable on the placement of individuals in classes of severe and low pd compared to no pd. 232 233 table 4 shows the effect of independent variables on the membership of individuals in pd 234 classes compared to the reference class in the form of regression coefficients. 235 236 the findings of huang's lcr model showed that most of the auxiliary variables have a 237 significant relationship with patterns of pd. 238 239 so that women, divorced, illiterate, unemployed, aged 50-59 years and underweight people have 240 a higher chance among other people to be in the class of severe pd. 241 242 in the lcr model, it is possible to evaluate the effect of independent variables that is influential 243 on the answers to each question of the questionnaire. in general, all independent variables had a 244 significant effect on answering the questions of the questionnaire. 245 246 discussion 247 as pd is known as predicator of some mental issues and disorders, epidemiological studies of 248 pd can play a constructive role in determining the general mental health status of society, 249 identifying demographic factors related to it in the country. having a significant sample size 250 available and using the lcr model, in this study, we were able to identify latent patterns of pd 251 among patients referred to mashhad health centers and evaluate the factors related to these 252 patterns. 253 254 using lcr, by entering the effect of auxiliary variables, the classification results were improved, 255 and three latent classes or different patterns in answering the questions of the k-6 questionnaire 256 were discovered. the first class consisted of 46% (no pd), the second class 40% (low pd), and 257 the third class 14% (severe pd). people in the severe pd class consistently reported most of the 258 symptoms, and in contrast, people in the no pd class never experienced these symptoms. a 259 similar study by barragan et al. had similar results and among the four latent identified classes, 260 2.8% were classified as severely disturbed and 13.6% as moderately disturbed.36 the structure of 261 the formed classes showed that the level of sadness and grief among people, even in the no pd 262 class, is higher than other symptoms, which is a matter for consideration and needs further 263 investigation to find the cause. 264 265 on the other hand, the feeling of emptiness and worthlessness in all classes, even among people 266 with severe pd, was the lowest compared to other symptoms. less of these symptoms may be 267 rooted in the culture and beliefs of the people, religious beliefs and values, relationships, and 268 solidarity between families, which despite the high mental pressures among individuals as a 269 protective factor, prevents people from the occurrence of such feelings. 270 271 women are more prone to pd than men. the barragan study in the united states found similar 272 results.36 compared to women, men were less likely to be in the moderate anxiety class, mild 273 distress, and restlessness than in the non-anxiety class. 26 factors influencing these results are 274 biological factors, environmental factors, gender roles, less social participation of women, and 275 their greater vulnerability in different life situations. in similar studies, mental distress had a 276 significant relationship with gender and it was more among women than men. 2, 23-25, 37 277 278 in addition, in parsaei 's study regarding the quality of life among employees, men were 279 classified better in the quality of life class and had less depression and anxiety than women.24 280 281 unlike barragan's study, in which the age variable was not significant,36 the results of the present 282 study indicate that by increasing age up to 59 years, the chances of being in the class of severe 283 pd increase compared to no pd. however, this rate is lower for the low anxiety class in the age 284 group of 60-65 years compared to the 50-59 age group. the lower prevalence in the elderly than 285 in the 50-59 age group is probably due to many factors like support and respect of family 286 members, reducing their role in education and family finances, in other words, reducing the 287 burden of responsibility. on the other hand, increasing the prevalence due to age can lead to 288 improving the burden of responsibility and raising children, biological changes related to 289 adulthood, and social responsibility. in another similar study, pd had a significant relationship 290 with age.2 also, a study in japan showed that until 2016, the highest questionnaire score was 291 among women aged 25-29 and then 30-34 years old.23 292 293 according to dsm-5-tr, psychological distress due to the different levels of life's traumatic 294 events and their contexts have diverse symptoms and forms.4 women who are single, widow, 295 and divorced compare to married people are more likely to be in the two low pd and serve pd 296 classes which divorced people have the highest chance of belonging to them. the results of 297 barragan's study also showed that married people are less likely to be in high, moderate, and 298 mild distress, restlessness, and restlessness classes.36 murugan's study also showed a significant 299 relationship between pd and marital statu.2 however, because in the present study, most of the 300 widows and divorced people are women, the reason for the above results can be a bitter 301 experience in their life, enduring the pressure and responsibility of living alone, economic 302 pressures, child care, and family management. on the other hand, for single individuals, some 303 concerns may increase the likelihood of pd such as their concerns about marriage and choosing 304 a spouse, and also their concerns about the confusion of future life. 305 306 findings showed that with increasing levels of education, the probability of severe and low pd 307 decreased. similar studies was also consistent with our results. 2, 36 probably the reason for the 308 high chance of illiterate people being in the class of severe and low pd can be attributed to the 309 inability and ignorance of these people to use appropriate methods of coping with stress, social 310 and cultural constraints. also, it is noticeable that the reason for the decrease this value in 311 educated people is their greater ability to access information, to communicate and understand 312 more correctly the existing situations, to observe the principles of mental health and timely 313 prevention and necessary treatment, and finally to use appropriate methods to deal with stress. 314 less chance of being in pd classes among people with a seminary education may indicate that 315 spirituality is involved in controlling emotions, and this can play a beneficial role in preventing 316 and treating mental illness and developing treatment plans for authorities. 317 318 employees were less likely than unemployed people to report severe pd. this rate was lower 319 among government employees than the unemployed compared to the self-employed. in the 320 barragan study, employees had a lower chance of getting into high and moderate pd than the 321 unemployed.36 lack of income, fewer social relationships, the monotony of daily life, and lack of 322 influential position in society are probably the reasons for the high chance of suffering from pd 323 among unemployed individuals. also, having a fixed income, insurance, pensions, and 324 employment facilities can be one of the reasons why governmental employees are less likely to 325 suffer from severe pd. 326 327 in our study, the higher prevalence of pd among urban residents than in the suburbs, similar to 328 the jaisoorya study,25 can be due to many reasons such as more stress in urban society, high cost 329 of living, environmental pollution, reduced cultural content of human communication in large 330 cities. 331 332 people with normal weight are less likely to be in the class of severe and low pd. while 333 underweight people are more likely to have severe and low pd. this result may be related to the 334 reported severe symptoms of hopelessness in these people compared to others. feelings of 335 hopelessness may also make them lose weight. however, the present study does not allow an 336 accurate assessment of the cause of this problem and needs further investigation in future studies. 337 338 examination of the coefficients of the effective variables on the symptoms of pd or the 339 questions of the k-6 questionnaire showed that some variables, as well as being effective on the 340 classification method, also had a significant effect on the observed variables. in this study, 341 women reported more pd than men. aging is also associated with increasing all symptoms 342 except hopelessness. by increasing age, disappointment will decrease and at younger ages, the 343 feeling of hopelessness is greater than in other ages. married people experienced less distressing 344 symptoms than singles. 345 346 as mentioned, among the structure of the formed classes, the amount of sadness and grief in all 347 classes is more than other symptoms. assessing the effect of auxiliary variables on the answer to 348 the question related to the feeling of sadness and grief also indicates that women, divorced 349 people, age-group of 40-49 years old and people with a diploma and undergraduate education are 350 more likely to experience the feeling of sadness and grief. after being exposed to a traumatic or 351 stressful event, pd is sometimes highlighted as anxiety or fear and in some cases as sadness. 7 352 353 increasing the level of sadness and grief among this group of people, especially in the age group 354 of 40-49 years, who are community actives and have the greatest role in the progress and 355 development, can hinder the progress and dynamism of a society. even if most of the people 356 studied in this age group are housewives, this is important because of the special role of women 357 in the home and family environment and their impact on spouses and the education of future 358 generations of society. 359 360 in this study, we tried to remove some of the limitations of previous studies, but this study also 361 had some limitations as well. in this study, we studied people who refer to health centers for 362 voluntary and optional action; some people with mental problems may not go to these centers 363 and so to this study. consequently, underestimates the prevalence for the general public in this 364 study. also, in health centers, health care workers complete the electronic file of individuals, 365 especially the k-6 questionnaire, and there is a possibility that individuals may not be honest in 366 answering the questions of the questionnaire; if the individuals themselves had completed the 367 questionnaire, they would have been more honest in answering the questions. on the other hand, 368 most of the women who went to the health centers were pregnant or mothers who came to 369 vaccinate their children, and we had a small percentage of single women in our database. 370 naturally, due to the high sample size, one of the limitations of this study is the significance of 371 all demographic variables in fitting the regression model, which tried to solve this problem by 372 reporting the effect size. 373 374 conclusion 375 according to the findings of this study, women than men, and divorced people than married ones 376 are more likely to experience severe symptoms of pd, considering that women are the 377 foundation of the family and the mother of the future generation of the country who they need 378 special attention and care. it is suggested that in addition to further research on the cause and its 379 clarification, the field of mental health in the family be provided through public education in the 380 mass media and schools. also, health centers can increase their effectiveness by continuing 381 existing activities, focusing on these high-risk groups, and designing targeted interventions for 382 them. given that cultural and social conditions can be effective in controlling and managing 383 emotions and stress, a similar plan can be implemented in other provinces and throughout iran. 384 in the present study, it was observed that people in all classes of pd reported feelings of sadness 385 and grief more than other symptoms; it is suggested that in close future studies, this issue be 386 seriously addressed, and also the causes of this issue would be investigated. 387 388 conflicts of interest 389 the authors declare no conflict of interests. 390 391 funding 392 this study was funded by the mashhad university of medical sciences (id: 971028). 393 394 authors’ contributions 395 jj conceptualized, designed, and supervised this study. ns and sr cleaned and analyzed the data 396 and interpreted the results. ak contributed to the interpretation of the results. all authors 397 contributed to the manuscript writing. all authors approved the final version of the manuscript. 398 399 acknowledgments 400 we thank dr. ehsan mussa farkhani for providing the data. the authors thank ms. zohreh 401 emamverdi for english editing. this study was financially supported by mashhad university of 402 medical sciences as a part of a msc thesis (third author). 403 404 reference: 405 1. alizade z, rejali m, feizi a, afshar h, hassanzade kashtali a, adibi p. investigation of 406 psychological disorders profile (anxiety, depression and psychological distress) in adult 407 population of isfahan province. j torbat heydariyeh uni med sci. 2016;3(4):42-8. 408 2. murugan n, mishra ak, chauhan rc, velavan a. psychological distress among adult urban 409 population of puducherry. int j community med public health. 2018;5(8):3265-9. 410 https://doi.org/10.18203/2394-6040.ijcmph20182984 411 3. noorbala aa, bagheri yazdi sa, yasamy mt, mohammad k. mental health survey of the 412 adult population in iran. br j psychiatry. 2004;184:70-3. https://doi.org/10.1192/bjp.184.1.70 413 4. pouretemad hr, naghavi hr, malekafzali h, noorbala aa, davidian h, ghanizadeh a, et al. 414 prevalence of mood disorders in iran. iran j psychiatry. 1970;1(2). 415 5. mirowsky j, ross ce. social causes of psychological distress. 2nd edition ed. new york: 416 routledge; 2017. 10.4324/9781315129464 417 6. roustaei n, ayatollahi smt, jamali j. relationship between minor psychiatric disorders and 418 job stability among southern iranian nurses: using latent class regression model. hayat. 419 2015;20(4):51-61. 420 7. american psychiatric association. diagnostic and statistical manual of mental disorders. 5th 421 edition ed. washington, dc: amer psychiatric pub inc; 2022. 422 8. gbd tuberculosis collaborators. global, regional, and national burden of tuberculosis, 1990-423 2016: results from the global burden of diseases, injuries, and risk factors 2016 study. 424 lancet infect dis. 2018;18(12):1329-49. https://doi.org/10.1016/s1473-3099(18)30625-x 425 9. firdaus g. increasing rate of psychological distress in urban households: how does income 426 matter? community mental health. 2017;54(5):641-8. https://doi.org/10.1007/s10597-017-427 0193-9 428 https://doi.org/10.18203/2394-6040.ijcmph20182984 https://doi.org/10.1192/bjp.184.1.70 https://doi.org/10.1016/s1473-3099(18)30625-x https://doi.org/10.1007/s10597-017-0193-9 https://doi.org/10.1007/s10597-017-0193-9 10. kessler rc, andrews g, colpe lj, hiripi e, mroczek dk, normand s-l, et al. short 429 screening scales to monitor population prevalences and trends in non-specific psychological 430 distress. psychol med. 2002;32(6):959-76. https://doi.org/10.1017/s0033291702006074 431 11. vaziri s, saydayi aghdam s, nobakht l, khalili m, vaziri y, masumi r, et al. comparison 432 of physical symptoms in people with low and high psychological distress patients disease. j 433 thought behav clin psychol. 2018;13(49):57-66. 434 12. rizvi ah, awaiz m, ghanghro z, jafferi ma, aziz s. pre-examination stress in second year 435 medical students in a government college. j ayub med coll abbottabad. 2010;22(2):152-5. 436 13. enticott jc, lin e, shawyer f, russell g, inder b, patten s, et al. prevalence of 437 psychological distress: how do australia and canada compare? aust n z j psychiatry. 438 2018;52(3):227-38. https://doi.org/10.1177/0004867417708612 439 14. weissman jf, pratt la, miller ea, parker jd. serious psychological distress among 440 adults: united states, 2009-2013. nchs data brief. 2015(203):1-8. 441 15. tanji f, tomata y, zhang s, otsuka t, tsuji i. psychological distress and completed suicide 442 in japan: a comparison of the impact of moderate and severe psychological distress. prev 443 med. 2018;116:99-103. https://doi.org/10.1016/j.ypmed.2018.09.007 444 16. moayed ms, vahedian-azimi a, mirmomeni g, rahimi-bashar f, goharimoghadam k, 445 pourhoseingholi ma, et al. coronavirus (covid-19)-associated psychological distress 446 among medical students in iran. adv exp med biol. 2021;1321:245-51. 447 https://doi.org/10.1007/978-3-030-59261-5_21 448 17. vahedian-azimi a, moayed ms, rahimibashar f, shojaei s, ashtari s, pourhoseingholi 449 ma. comparison of the severity of psychological distress among four groups of an iranian 450 population regarding covid-19 pandemic. bmc psychiatry. 2020;20(1):402. 451 https://doi.org/10.1186/s12888-020-02804-9 452 18. hajebi a, motevalian a, amin-esmaeili m, rahimi-movaghar a, sharifi v, hoseini l, et al. 453 adaptation and validation of short scales for assessment of psychological distress in iran: 454 the persian k10 and k6. int j methods psychiatr res. 2018;27(3):e1726. 455 https://doi.org/10.1002/mpr.1726 456 19. rahimi z, esmaily h, taghipour a, mosa farkhani e, jamali j. evaluation of the prevalence 457 of psychological distress and its related demographic factors in 18-65 year-old 458 https://doi.org/10.1017/s0033291702006074 https://doi.org/10.1177/0004867417708612 https://doi.org/10.1016/j.ypmed.2018.09.007 https://doi.org/10.1007/978-3-030-59261-5_21 https://doi.org/10.1186/s12888-020-02804-9 https://doi.org/10.1002/mpr.1726 population of khorasan razavi: a cross-sectional study. iran j epidemiol. 2021;16(4):316-459 24. 460 20. noorbala aa, bagheri yazdi sa, faghihzadeh s, kamali k, faghihzadeh e, hajebi a, et al. 461 a survey on mental health status of adult population aged 15 and above in the province of 462 isfahan, iran. arch iran med. 2017;20(11 suppl. 1):s51-s4. 463 21. noorbala aa, faghihzadeh s, kamali k, bagheri yazdi sa, hajebi a, mousavi mt, et al. 464 mental health survey of the iranian adult population in 2015. arch iran med. 465 2017;20(3):128-34. https://doi.org/0172003/aim.003 466 22. sharif f, joulaei h, kadivar m, rajaeefard a. mental health status and its related 467 demographic variables of families referring to shiraz health centers2002. armaghane 468 danesh. 2004;9(3):75-84. 469 23. nishi d, susukida r, usuda k, mojtabai r, yamanouchi y. trends in the prevalence of 470 psychological distress and the use of mental health services from 2007 to 2016 in japan. j 471 affect disord. 2018;239:208-13. https://doi.org/10.1016/j.jad.2018.07.016 472 24. parsaei r, roohafza h, feizi a, sarrafzadegan n. quality of life and common psychological 473 problems profile in a large sample of manufacturing employees in a developing country: an 474 association analysis using latent class regression. alexandria journal of medicine. 475 2019;55(1):37-43. https://doi.org/10.1080/20905068.2019.1592939 476 25. jaisoorya t, anjana r, priya gm, jeevan c, revamma m, vineetha j, et al. psychological 477 distress among college students in kerala, india—prevalence and correlates. asian journal of 478 psychiatry. 2017;28:28-31. https://doi.org/https://doi.org/10.1016/j.ajp.2017.03.026 479 26. goldstein sj, gaston sa, mcgrath ja, jackson cl. sleep health and serious psychological 480 distress: a nationally representative study of the united states among white, black, and 481 hispanic/latinx adults. nat sci sleep. 2020;12:1091-104. 482 https://doi.org/10.2147/nss.s268087 483 27. mewton l, kessler rc, slade t, hobbs mj, brownhill l, birrell l, et al. the psychometric 484 properties of the kessler psychological distress scale (k6) in a general population sample of 485 adolescents. psychol assess. 2016;28(10):1232-42. https://doi.org/10.1037/pas0000239 486 28. kilkkinen a, kao-philpot a, o'neil a, philpot b, reddy p, bunker s, et al. prevalence of 487 psychological distress, anxiety and depression in rural communities in australia. aust j rural 488 health. 2007;15(2):114-9. https://doi.org/10.1111/j.1440-1584.2007.00863.x 489 https://doi.org/0172003/aim.003 https://doi.org/10.1016/j.jad.2018.07.016 https://doi.org/10.1080/20905068.2019.1592939 https://doi.org/https:/doi.org/10.1016/j.ajp.2017.03.026 https://doi.org/10.2147/nss.s268087 https://doi.org/10.1037/pas0000239 https://doi.org/10.1111/j.1440-1584.2007.00863.x 29. dadfar m, atef vahid mk, lester d, bahrami f. kessler psychological distress scale (k6): 490 psychometric testing of the farsi form in psychiatric outpatients. adv biores. 2016;7(2):105-491 8. 492 30. jamali j, roustaei n, ayatollahi sm, sadeghi e. factors affecting minor psychiatric 493 disorder in southern iranian nurses: a latent class regression analysis. nurs midwifery 494 stud. 2015;4(2):e28017. https://doi.org/10.17795/nmsjournal28017 495 31. bandeen-roche k, miglioretti dl, zeger sl, rathouz pj. latent variable regression for 496 multiple discrete outcomes. j amer stat asso. 1997;92(440):1375-86. 497 https://doi.org/10.1080/01621459.1997.10473658 498 32. huang g-h, bandeen-roche k. building an identifiable latent class model with covariate 499 effects on underlying and measured variables. psychometrika. 2004;69(1):5-32. 500 https://doi.org/10.1007/bf02295837 501 33. kim sy. determining the number of latent classes in singleand multi-phase growth 502 mixture models. struct equ modeling. 2014;21(2):263-79. 503 https://doi.org/10.1080/10705511.2014.882690 504 34. nylund kl, asparouhov t, muthén bo. deciding on the number of classes in latent class 505 analysis and growth mixture modeling: a monte carlo simulation study. struct equ 506 modeling. 2007;14(4):535-69. https://doi.org/10.1080/10705510701575396 507 35. celeux g, soromenho g. an entropy criterion for assessing the number of clusters in a 508 mixture model. j classif. 1996;13(2):195-212. https://doi.org/10.1007/bf01246098 509 36. barragan a, yamada am, gilreath td. psychological distress behavioral patterns among 510 latinos: we don't see ourselves as worthless. community ment health j. 2018. 511 https://doi.org/10.1007/s10597-018-0273-5 512 37. shakeri mt, saleh moghaddam ar, tireh h, hadianfar a, yousefi r, navipour e. mental 513 health status of entrance students in mashhad university of medical sciences from the 514 national university entrance exam in the academic year 2014-2015. j fundam ment health. 515 2018;20(5):326-31. https://doi.org/10.22038/jfmh.2018.11400 516 517 https://doi.org/10.17795/nmsjournal28017 https://doi.org/10.1080/01621459.1997.10473658 https://doi.org/10.1007/bf02295837 https://doi.org/10.1080/10705511.2014.882690 https://doi.org/10.1080/10705510701575396 https://doi.org/10.1007/bf01246098 https://doi.org/10.1007/s10597-018-0273-5 https://doi.org/10.22038/jfmh.2018.11400 table 1: demographic characteristics of the subjects 518 variables n (%) gender male 116056 (27.3) female 309230 (72.7) age 18-29 113149 (26.6) 30-39 182226 (42.8) 40-49 82418 (19.4) 50-59 42261 (9.9) 60-65 5232 (1.2) marital status married 385424 (9.6) widow 5448 (1.3) absolute 4770 (1.1) single 14152 (3.3) education level illiterate 34129 (8.0) diploma and sub-diploma 308337 (72.5) university 81642 (19.2) seminary 1084 (3.3) job type unemployed 8737 (2.1) government employee 16261 (3.8) freelance 80230 (18.9) other 231884 (54.5) residence metropolis (non-marginal) 194859 (45.8) suburbs 230427 (54.2) body mass index weight loss 10735 (2.5) normal weight 146726 (34.5) overweight 141468 (33.3) obesity 83869 (19.7) total 425286 (100) 519 table 2: criteria for selecting the optimal number of latent classes 520 number of classes ll bic aic aic3 caic lmr blrt 𝑹𝟐 entropy 2 class -2368774 4737950 4737611 4737642 4737981 0.00 0.00 0.86 0.84 3 class -2283160 4566812 4566396 4566434 4566850 0.00 0.00 0.79 0.78 4 class -2262141 4524864 4524372 4524417 4524909 0.27 0.00 0.75 0.76 5 class -2249907 4500488 4499919 4499971 4500540 0.00 0.00 0.65 0.69 2 class -2368774 4737950 4737611 4737642 4737981 0.00 0.00 0.86 0.84 table 3. the percentage of people in each class by the percentage of answers to each question of 521 the pd questionnaire. 522 questions of questionnaire answers no pd class low pd class severe pd class question 1 sadness never / rarely 55.0 15.0 1.0 slightly 32.0 30.0 5.0 sometimes 12.0 38.0 28.0 most of the time 1.0 15.0 45.0 always 0.0 2.0 21.0 question 2 restless never / rarely 89.0 28.0 1.0 slightly 10.0 42.0 11.0 sometimes 1.0 25.0 37.0 most of the time 0.0 5.0 39.0 always 0.0 0.0 12.0 question 3 nervous never / rarely 93.0 41.0 1.0 slightly 7.0 39.0 12.0 sometimes 0.0 18.0 42.0 most of the time 0.0 2.0 35.0 always 0.0 0.0 1.0 question 4 helpless never / rarely 95.0 60.0 14.0 slightly 5.0 26.0 22.0 sometimes 0.0 12.0 37.0 most of the time 0.0 2.0 21.0 always 0.0 0.0 6.0 question 5 hopeless never / rarely 96.0 58.0 6.0 slightly 4.0 31.0 20.0 sometimes 0.0 10.0 39.0 most of the time 0.0 1.0 27.0 always 0.0 0.0 9.0 question 6 worthless never / rarely 99.0 77.0 23.0 slightly 1.0 18.0 26.0 sometimes 0.0 4.0 30.0 most of the time 0.0 1.0 15.0 always 0.0 0.0 5.0 class size 46.00 40.0 14.0 523 table 4: results of independent variables regression on pd classes using lcr 524 variables (reference) low pd severe pd or (95% ci) or (95% ci) age 18-29 reference 30-39 1.21 ** (1.19-1.24) 1.61 ** (1.57-1.67) 40-49 1.42 ** (1.38-1.45) 2.49 ** (2.40-2.58) 50-59 1.65 ** (1.60-1.71) 3.21 ** (3.08-3.36) 60-65 1.77 ** (1.64-1.92) 2.90 ** (2.62-3.20) gender male reference female 1.18 ** (1.14-1.21) 2.85 ** (2.70-3.00) marital status married reference widow 1.15 ** (1.07-1.24) 1.60 ** (1.43-1.74) divorced 1.40 ** (1.30-1.51) 2.18 ** (2.00-2.37) single 0.99 (0.95-1.04) 1.49 ** (1.40-1.58) education level illiterate reference diploma and subdiploma 0.99 (0.95-1.02) 1.00 (0.96-1.05) university 0.96 (0.93-1.00) 0.67 ** (0.64-0.71) seminary 0.85 * (0.73-0.99) 0.54 ** (0.40-0.73) job type unemployed reference government employee 0.98 (0.92-1.04) 0.59 ** (0.54-0.66) freelance 1.06 (1.00-1.11) 0.90 * (0.83-0.98) other 1.08 ** (1.02-1.14) 0.96 (0.88-1.04) residence suburbs reference metropolis 1.06 ** (1.05-1.08) 1.16 ** (1.14-1.91) body mass index obesity reference weight loss 1.09 ** (1.04-1.15) 1.38 ** (1.29-1.48) normal weight 1.00 (0.98-1.02) 0.88 ** (0.85-0.91) overweight 1.04 ** (1.02-1.06) 0.92 ** (0.89-0.95) *p < 0.05; **p < 0.01; reference category: no pd 525 526 527 figure 1: a pattern of answering the questions of the k-6 questionnaire based on the lcr 528 model 529 u n e a s y m o n th 0 -1 m e a n re s tl e s s m o n th 0 -1 m e a n d e p re s s io n m o n th 0 -1 m e a n h a rd w o rk m o n th 0 -1 m e a n h o p e le s s m o n th 0 -1 m e a n w o rt h le s s m o n th 0 -1 m e a n 1.0 0.8 0.6 0.4 0.2 0.0 2008-issue1.indd everyday memory sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 99-100 sultan qaboos university© submitted 28th september 2007 the statements such as ‘it is a memory when you think of it’ or ‘memory binds our mental life together’ highlight the mysterious nature of our ability to acquire, store and vividly recollect such diverse events as our first day in school. mankind has always been bewildered as to how we remember and forget information and fascinated by our ethereal experiences of déjà vu. initially, it was the philosophers’ role to speculate on such matters; later the baton was passed to great physiologists such karl lashley and ramón y cajal to excavate the ‘engram’, a supposedly neural repository for memory traces. the quest for the ‘engram’ did not bear fruit until it came to the attention of donald o hebb and erik kandel. the impetus they gave to the subject became a catalyst for the development of cognitive psychology as one of the main ways to decipher how we remember and recall, and, for that matter, forget. stemming from this background and written by a team of international authors not previously credited to be household names in the field, this volume synthesizes diverse research portfolios on memory. this new breed of authors from italy to norway was invited by the norwegian academy of science to tell the story of different aspects of everyday memory. they do this succinctly producing a volume that is basically a collection of detailed review chapters, which update the reader on the latest thinking as to how memory operates in everyday contexts. the topics are covered are diverse though the authors do not profess to have covered exhaustively all of the conflicting paradigms in the field. the approach is balanced with a wealth of novel information synthesized with clarity and exemplified with clinical and social vignettes. the volume is divided into 13 chapters, each chapter being followed by a comprehensive reference list and author index. the topics under scrutiny in everyday memory include a chapter on metaphors employed by researchers as well as the general public to fill gap between the process of encoding and retrieval. the other themes covered constitute what is what in the taxonomy of human memory systems from declarative to implicit memory types. each chapter tackles different themes with palatable headings including: visuospatial memory; recalling actions; odour memory; autobiographical memory; collaborative memory; illusion and false memories; expertise; memory impairment; meta-cognition; functional memory and retrieval processes. some of the topics are summarised with examples of public attitudes and knowledge towards different aspects of memory. it is commonly assumed that memory should be investigated in the laboratory rather via attitudinal self-rated questionnaires. the authors of this volume ostensibly show us the relevance of the latter approach despite the view that our cognition is often vulnerable to distortion. also, i should not forget to mention my favorite يوم كل ذاكرة هستروب تور ماجنسني و سفني احملررون: editors: svein magnussen and tore helstrup publisher:psychology press, taylor francis group. published 2007 isbn-978-1-84169-579-2 available at: http://www.psypress.co.uk b o o k r e v i e w b o o k r e v i e w : e v e r y d ay m e m o r y 100 chapter of this volume. it is the one that goes under the fancy banner, ‘memory illusions and false memories in the real world’. although this chapter repeats some concepts discussed elsewhere in the volume, its originality as well as the breath and depth of its scope is unquestionable. its coverage of controversial false memory and its review of the psychology of the eyewitness errors borders on surrealism, but it is narrated with reference to all the relevant literature in the field to the extent that a reader will not think that she or he is reading joseph conrad. the title of this volume, everyday memory, entices me to think that some people might think this book will feature in oprah winfrey’s chat shows. but we should not judge the book by its title. its content is too technical for the general public. the coverage may be too advanced even for undergraduate students. the volume can be a useful resource for those who teach the cognitive science of learning and memory. it carries a vast reservoir of information on the latest theories as to how memory works in every day situations. one of the assets of this volume is that it has decoded scientific jargon into language that could be easily grasped by any interested researcher. being unduly pessimistic of my own memory, i find it hard to remember a more readable and informative guide to the field than this volume but my memory could be wrong. r e v i w e r samir al-adawi department of behavioural medicine, college of medicine and health sciences, sultan qaboos university, muscat, sultanate of oman email: adawi@squ.edu.om submitted 6 feb 22 1 revision req. 6 apr 22; revision recd. 15 may 22 2 accepted 8 jun 22 3 online-first: june 2022 4 doi: https://doi.org/10.18295/squmj.6.2022.044 5 6 outcome of cochlear implantation in deaf children with co7 existing otitis media with effusion 8 a comparative study 9 sami al habsi,1 *khalid al zaabi,2 ammar al lawati1 10 1department of otolaryngology, head & neck surgery, al nahdha hospital, muscat, 11 oman; 2department of surgery, sultan qaboos university hospital, muscat, oman 12 *corresponding author’s e-mail: khaboore21.ka@gmail.com 13 14 abstract 15 objective: cochlear implantation (ci) is the definitive treatment for profound hearing 16 loss in children and adults. operating on an infected ear is considered a challenge; the 17 institution of cochlear implant the presence of otitis media with effusion (ome) prior 18 to ci surgery has created a debate among neuro-otologists: treat the ome first or go 19 ahead with surgical intervention. this study was conducted to determine whether 20 cochlear implantation in patients with ome at the time of surgery has any influence 21 on the procedure, post-operative complications and surgical outcome. methods: 22 retrospective descriptive analysis of data collected from records of patients who 23 underwent ci in a tertiary care hospital from 2000-2018 was done. the age targeted 24 was 6 months to 14 years old, excluding all adults, and those who had their operations 25 outside the chosen institution. results: out of 369 children, 175 had ome preceding 26 surgery compared to 194 who did not have ome. intra-operative oedematous 27 hypertrophied middle ear mucosa was observed only in ome patients (n=18, p 28 <0.050). moreover, among the ome patients, six cases developed mild intra29 operative bleeding compared to only one case from non-ome group (p <0.050). 30 overall, there was no significant difference in post-operative surgical complications 31 between the two groups (p >0.050). conclusion: the presence of ome is associated 32 with intra-operative technical difficulties, such as impaired visualization and bleeding. 33 mailto:khaboore21.ka@gmail.com however, ome is not determinative on performing cochlear implantation in terms of 34 post operative complications and outcome. therefore, there is no need to delay the 35 implantation until the ome resolves. 36 keywords: cochlear implantation, otitis media with effusion, children, and 37 sensorineural hearing loss 38 39 advances in knowledge 40 the study highlight that ci shouldn’t be delayed due to the existing ome as it 41 is not statistically influence the treatment of deaf children with ci. this 42 information is vital as early institution of ci is decisive in successful 43 rehabilitation of deaf children and the presence of ome should not delay 44 implantation which might affect the outcome. 45 46 applications to patient care 47 this study shows that the delay is not justified, so ci could be done as soon as 48 the patient is diagnosed with profound snhl regardless the finding of ome 49 50 introduction 51 otitis media with effusion (ome) is a common problem encountered in pediatric age 52 group. it is defined as presence of fluid (effusion) in the middle ear cavity without 53 infection.1 the nature of the fluid is either mucoid or serous. it is managed either by 54 watchful waiting, medical therapy or surgery. cochlear implantation (ci) is the 55 standard of care in management of children with profound sensorineural hearing loss 56 (snhl).2-15 in our health care system, children with a confirmed diagnosis of 57 profound snhl will be evaluated for potential ci. the indications of ci in our study 58 group were congenital, infection (e.g. meningitis) and or syndromic. the incidence of 59 complications among patients with ome who undergo ci ranges from 1.7 to 4.1%.3,16 60 61 management of ome in children who are the candidates for the ci is the subject of 62 debate on whether the ome should be treated prior to ci or not. the presence of 63 ome has been reported to increase the risk of post-operative surgical site infection, 64 meningitis and device extrusion4-11 as well as impaired visualization and bleeding in 65 the presence of inflamed middle ear mucosa, leading to a high risk of complications in 66 the post-operative period.5,6,7 some surgeons insert a ventilation tube (vt),7 while 67 others treat it medically, with some operating regardless.4-6,8-11 this study describes 68 our experience of ci in patients with ome prior to and at the time of surgery. the 69 effect of ome on the procedure, post-operative complications and surgical outcome 70 were evaluated and presented. 71 72 methods 73 this was a single-center retrospective case control study of consecutive pediatric 74 patients presenting with profound hearing loss and underwent cochlear implantation 75 from 2000 to 2018 in al nahdha hospital, muscat, oman. all data was collected from 76 electronic medical records. 77 78 we collected patient characteristics including age, gender, and demographic profiles. 79 the data related to assessment included clinical examination findings, complete 80 otological, head and neck examination in an outpatient setting. audiological test 81 results such as tympanometry, brainstem auditory evoked response audiometry 82 (baera) and the details of imaging (high resolution temporal bone computed 83 tomography (ct), magnetic resonance imaging (mri)) were also collected. the study 84 included all pediatric patients aged 6 months to 14 years. those who were above 14 85 years, those who presented after the first surgery done elsewhere then re-implanted in 86 our center and those with incomplete data were excluded. the surgery was performed 87 by our otology team in the department of ent including 3 senior otologists. 88 89 the total sample size was 369 patients who were divided into 2 groups: those with 90 ome and those without. patients who were suspected to have ome during the 91 clinical examination were subjected to acoustic immittance tympanometry. 92 radiological evidence of middle ear opacification on the ct scan was also considered 93 for further workup. b type flat curve on were considered positive of ome. the 94 treatment and follow up of these children were collected and analyzed. all children 95 who had ome prior to surgery underwent a period of watchful waiting or 96 symptomatic treatment in terms of nasal spray or antihistamine syrup. there was no 97 treatment given intra-operatively or post-operatively for these children. surgical steps 98 included post-auricular incision, followed by cortical mastoidectomy. surgeons 99 performed a posterior tympanotomy followed by a round window or cochleostomy 100 approach, based on the anatomical variations. device function was tested intra101 operatively using neural response telemetry (nrt) and stapedial reflex in most of the 102 patients. intra-operative findings and post-operative surgical outcomes were observed 103 in both groups. intraor post-operative portable x-ray was used to confirm the correct 104 placement of the electrode in all patients. the statistical package for social sciences 105 (spss), version 20 (ibm corp., armonk, ny) was used in data analyses. a p value 106 of <0.05 was considered statistically significant. ethical approval was obtained from 107 the research and ethical committee at the hospital. 108 109 results 110 the study included 369 patients. 195 (52.8%) were male and 174 (47.2%) female. 111 the ome group consisted of 175 (47.4%) children with 92 males (24.9%) and 83 112 females (22.5%). in the non-ome group, there were 194 (52.6%) patients in total, 113 103 (27.9%) were male and 91 (24.7%) were female. there was no statistically 114 significant difference between the two groups (p = 0.5). in the ome group, 42 (24%) 115 of patients were less than 2 years old at the time of evaluation and surgery whereas 116 133 (76%) children were 2 years old and older at the time of presentation. all the 117 children in both the age groups with ome had received treatment (medical or 118 surgical) prior to cochlear implantation, however, all of them scheduled for ci 119 regardless of treatments received. 120 121 the mean age at implantation was 3.2 years with no statistical significant difference 122 between the two groups. intra-operative findings and post-operative complications 123 with surgical outcomes were analyzed. the average operative time was 2.5 to 3 hrs. in 124 the ome group, middle ear inflammation was encountered in only 2 (1.1%) cases 125 compared to 1 (0.5%) case in the non-ome group (p = 0.46). granulation tissues 126 were seen in only 1 case (0.6%) in ome group compared to 2 (1%) cases in non127 ome group, with no statistically significant difference. hypertrophied mucosa was 128 observed in 18 cases (10.3%) in the ome group compared to no cases in the non129 ome group. this was statistically significant (p <0.001). intra-operative minimal 130 bleeding was encountered in 6 (3.4%) cases and 1 (0.5%) patient in the ome and 131 non-ome groups, respectively, with a significant p value of 0.046. perilymph leak 132 was observed in 5 cases from each group, intra-operatively, without statistical 133 significance. intra-/post-operative portable x-rays confirmed the correct placement of 134 the electrode in all patients. (table 1 summarizes the intra-operative findings in the 135 cases included in this study). post-operative complications were also analyzed for 136 both groups. immediate or early post-operative complications were recorded in 4 137 patients in both groups. early wound bleeding was observed in 1 (0.6%) patient in the 138 ome group and 2 (1%) in the non-ome group (p value = 0.53). only 1 patient was 139 taken to the operating room again on the same day for re-exploration from the non140 ome group due to a misplaced electrode. all other complications were delayed in 141 nature. one patient (0.5%) in the non-ome group developed a temporary facial nerve 142 palsy on the fifth post-operative day, compared to none of the patients in the ome 143 group (p value = 0.52). conservative management was successful in this child, with 144 full recovery. with regards to swelling at the wound site, 12 (6.9%) patients in the 145 ome group developed swelling compared to 22 (6%) in the non-ome group. 146 diagnosis ranged from simple induration at the wound site to seroma or hematoma. 147 these patients were managed accordingly using local antibiotic cream, needle 148 aspiration and pressure bandage or incision and drainage under general anesthesia. 149 device trauma was considered if there was a history of direct hit to the device with 150 external force either due to a fall, hit by an object or sport trauma; 8 patients (4.6%) in 151 the ome group had a trauma to the device, compared to only 6 (3.6%) in the non152 ome group. wound infection was reported in 3 (1.7%) patients in the ome group 153 and 7 (3.6%) in the non-ome group. wound dehiscence was only noted in one 154 patient in the ome group. ear discharge occurred in 5 patients from each group. six 155 patients were re-implanted in the ome group compared to 2 in the non-ome group. 156 in the ome group, the patients were re-implanted due to device failure. the reason of 157 this failure was not known in 4 of the cases. in one case, the reason was a kinked 158 electrode. the sixth patient had cracked the device after direct trauma. one patient in 159 the non-ome group was re-implanted due to device failure, while the other patient 160 had a misplaced electrode in the internal auditory meatus (iam). this child was re161 explored during the same admission and re-implanted. the difference in post162 operative complications between the two groups was not statistically significant. 163 (table 2 which illustrates the post-operative complications of the study groups). 164 165 discussion 166 our study showed that delaying the surgery in children with profound sensorineural 167 hearing loss to treat ome will not add any benefit during surgery. as literature 168 showed, management of ome in preparation for ci surgery is still an area of a 169 debate.4,11,17 does delaying the implant lead to easier middle ear access and electrode 170 insertion? additionally, the consequences of postponing the intervention on the 171 development of speech and language can be a major concern.8,14,17 the fear of post172 operative complications due to ome is justified.3 however, attributing complications 173 solely to ome has no solid ground. luntz et al. stated that ci surgery will not 174 increase the incidence or severity of otitis media, in fact, it does quite the 175 opposite.12,13 antihistamines and intra-nasal corticosteroids were noted to be the 176 treatment of ome.9 furthermore, vt insertion was recommended in patients with 177 ome who failed medical treatment.4,6,8,11 one study recommended vt insertion 178 around 6 weeks before ci.7 notably, vt-related problems, such as otorrhea and 179 residual tympanic membrane perforations do exist.18,19,20 we analyzed the 369 cases 180 included in this study, looking into the children who had ome before ci and 181 compared the findings intraoperatively with post-operative surgical outcome. acute 182 otitis media (aom) in these children was not included as a parameter in this analysis. 183 as aom is managed in primary care facilities, it is unusual to see patients with aom 184 in our institute, therefore we did not include these patients in this study, and it was not 185 noted if patients had aom previously. 186 187 inflammation, granulations and hypertrophied mucosa were some of the intra188 operative findings noted during ci, not during the clinical assessment. alzhrani et al. 189 considered children who were found to have granulations or effusion intra-operatively 190 with no findings pre-operatively to be aom patients.15 in this study, ome was a pre191 operative diagnosis. pre-operative diagnosis was not changed based on intra-operative 192 findings. the diagnosis of ome was based on clinical examination and audiological 193 evaluation by tympanometry. radiological investigations, such as ct scans, may 194 provide insight into ome as well. if the tympanic membrane cannot be visualized due 195 to wax impaction or a small/narrow canal, the canal will be cleaned and the diagnosis 196 of ome will be based on tympanometry flat curve. a b-curve without ome due to 197 small canals can be noted especially in children who are less than a year old. to 198 overcome this, this study only included those clearly diagnosed with ome clinically 199 and by tympanometry with direct visualization and flat b curve. dubious cases were 200 excluded. middle ear inflammation was noted in 2 cases in the ome group, compared 201 to one patient in the non-ome group. apart from minimal bleeding, no difficulties 202 were noted during ci surgery, either during drilling or in electrode insertion, and 203 finding the round window was not an issue as well. the method of checking electrode 204 placement changed over the period of study. previously, x-rays were used after 205 surgery to evaluate the position. one case of electrode misplacement led to a change 206 in practice. the current practice is to check the device function intra-operatively via 207 nrt and stapedial reflex test, with x-rays being obtained as well. one study, by 208 alzoubi et al., reported one case of excessive bleeding and middle ear inflammation 209 during ci in a patient with ome. despite this, they encouraged medical treatment 210 before ci surgery. this study also concluded that the decision for ci and the timing of 211 surgery should not be delayed to avoid the consequences of delaying the intervention. 212 a follow up did not show any long-term complications.10 the findings from this study 213 support this observation, that ci should not be delayed in fear of serious 214 complications. the patients in this study who had vts were delayed for at least 7 215 months. multiple factors played a role in this delay. firstly, the belief that operating 216 on a patient with ome has increased risk of intraand post-operative problems. 217 secondly, surgeons indicated that they wanted to wait until the vt was extruded to 218 avoid the risk of exposing the electrode to the exterior. furthermore, a limited 219 operating time created a long waiting list for surgery. all of these factors contributed 220 to surgery delay in the patients in this study, but particularly in patients with vts. 221 none of the vt patients developed any kind of vt-related complications. all of these 222 patients had an intact tympanic membrane before surgery. notably, we have observed 223 that some patients with ome on the operating table with no previous findings, 224 potentially indicating that spending time on a middle ear effusion issue could be a 225 waste of time. granulation tissues were encountered during the surgeries with or 226 without inflamed mucosa. sun et al. reported dealing with pathological granulation 227 tissues due to ome with bleeding in the surgical field, and this was managed using a 228 diamond burr.5 no post-operative complications were reported, even though the 229 patients in that study were below 2 years of age.5 in another study, published by 230 cevizci et al., 105 of a total of 890 had ome, with only 5 undergoing vt insertion. 231 all of the patients with ome were found to have granulation tissues, edematous 232 middle ear and mastoid mucosa.6 analysis revealed longer than average operating 233 times, but they did not report any complications attributed to ome after the surgery, 234 concluding that ome diagnosis should not delay the surgery.6 the findings from the 235 current study reflect the findings noted in other studies, such as those by alzoubi et al. 236 and cevizci et al. in this study, hypertrophied mucosa and minimal bleeding were 237 observed in 18 and 6 patients in the ome and non-ome groups, respectively. there 238 were no significant differences noted in the post-operative complication rates between 239 the two groups. five patients from each group developed a perilymph leak during ci, 240 due to inner ear anatomical malformations, similar to those noted by mondini. in the 241 current study, 3 patients with perilymph gusher had complications post-operatively. 242 two of these patients were from the non-ome group and one patient was from the 243 ome group. the patient from ome group had dysplastic cochlea with perilymph 244 gusher intra-operatively. this patient presented a few years later with device failure 245 and was re-implanted successfully. one child from the non-ome group presented 246 with a hematoma after a fall with direct trauma to the device. the second patient 247 presented a few months after the surgery with mild wound infection, treated 248 conservatively with local wound care. the presence of ome had no contribution to 249 either gusher or post-operative complications. 250 251 firstly, this was a retrospective study, limiting the planning and design. secondly, the 252 decision regarding the ome management pre-operatively was left up to the surgeon’s 253 preference, leading to variations in the standardization of treatment approach. it 254 should be noted, however, that all surgeons agreed on the same treatment duration. 255 another limitation is the duration of the surgery. as this was a retrospective study 256 retrieving the duration of surgery from old records was a challenge, however, the 257 average recorded surgical time of all cases was 2.5 to 3 hours. also, we did not 258 analyse the hearing and speech outcome specifically after the surgery as it was not an 259 objective of this paper. 260 261 conclusion 262 ome is a common pediatric problem that can be found in patients with profound 263 snhl undergoing ci surgery. difficulties during ci surgery, such as bleeding and 264 impaired visualization, should not prevent early intervention. the post-operative 265 compilations are not detrimental in patients with ome regardless of prior treatment as 266 revealed in our study and therefore, the presence of ome at the time of surgery 267 should not lead to its delay. we concluded that postponement or vigorous treatment of 268 ome prior to ci is no longer needed since ome does not affect the surgical outcome 269 afterwards. 270 271 conflicts of interest 272 the authors declare that they have no conflict of interest 273 274 funding 275 no funding was received for this study. 276 277 acknowledgement: 278 authors acknowledge that a preliminary version of the abstract was presented as a 279 poster at the oman medical specialty board research forum 2019/2020 in muscat, 280 oman on 7 december 2019 (oman medical specialty board research forum 281 2019/2020: abstracts. oman med j 2019; 34:1–20. 282 from: https://omjournal.org/pdf/supplement_abstracts%20%2802j%29_.pdf 283 authors would like to acknowledge mr. sathiya panchatcharm from department of 284 research and statistics in oman medical specialty board for his contribution in 285 statistical analysis of data. we would like also to acknowledge the senior cochlear 286 implantation team at al nahdha hospital, oman. 287 288 authors contribution: 289 al habsi s contributed via data collection, literature review and data analysis. al 290 zaabi k contributed to the work by supervising the first author, review of the data, 291 final literature review and write up of the manuscript. al lawati a is the senior author 292 who created the study question, designed and supervised the whole work scheme. 293 294 references: 295 1williamson i, benge s, barton s, petrou s, letley l, fasey n, et al. topical 296 intranasal corticosteroids in 4-11 year old children with persistent bilateral 297 otitis media with effusion in primary care: double blind randomised placebo 298 controlled trial. bmj 2009;339:b4984. https://doi.org/10.1136/bmj.b4984 299 2al zaabi k, al lawati a. delayed complications of cochlear implant 300 surgical site: al nahdha hospital 17 years’ experience. saudi j 301 otorhinolaryngol head neck surg 2018;20:29-34. https:// doi: 10.4103/1319302 8491.273916 303 3sugimoto h, hatano m, noda m, hasegawa h, yoshizaki t. cochlear 304 implantation in deaf patients with eosinophilic otitis media using subtotal 305 https://omjournal.org/pdf/supplement_abstracts%20%2802j%29_.pdf https://doi.org/10.1136/bmj.b4984 petrosectomy and mastoid obliteration. eur arch 306 otorhinolaryngol 2017;274, 1173–1177. https://doi.org/10.1007/s00405-016307 4091-5 308 4fayad jn, tabaee a, micheletto jn, parisier sc. cochlear implantation in 309 children with otitis media. the laryngoscope 2003;113(7):1224-7. 310 https://doi: 10.1097/00005537-200307000-00021 311 5sun j-q, sun j-w, hou x-y. cochlear implantation with round window 312 insertion in children with otitis media with effusion. orl j oto-rhino313 laryngol its relat spec 2014;76(1):13-8.https://doi.org/10.1159/000360007 314 6cevizci r, dilci a, celenk f, karamert r, bayazit y. surgical considerations 315 and safety of cochlear implantation in otitis media with effusion. auris nasus 316 larynx 2018;45(3):417-20. https://doi: 10.1016/j.anl.2017.07.012 317 7kim cs, chang so, lee hj, shim ws, oh sh, kim yh. cochlear 318 implantation in patients with a history of chronic otitis media. acta 319 otolaryngol 2004;124:1033-8. https://doi: 10.1080/00016480410017521-1. 320 8papsin bc, bailey cm, albert dm, bellman sc. otitis media with effusion in 321 paediatric cochlear implantees: the role of peri-implant grommet insertion. int 322 j pediatr otorhinolaryngol 1996;38(1):13-9. https://doi: 10.1016/s0165323 5876(96)01398-5 324 9lack g, caulfield h, penagos m. the link between otitis media with effusion 325 and allergy: a potential role for intranasal corticosteroids. pediatr allergy 326 immunol 2011;22:258-66. https://doi.org/10.1111/j.1399-3038.2010.01130.x 327 10alzoubi f, odat h, nuseir a, al omari a, al-zuraiqi b. effect of otitis media 328 with effusion on cochlear implant surgery: technical difficulties, post329 operative complications and outcome. j laryngol otol 2015; 129(8):762-6. 330 https://doi.org/10.1017/s0022215115001681 331 11kennedy rj, shelton c. ventilation tubes and cochlear implants: what do we 332 do? otol neurotol off publ am otol soc am neurotol soc eur acad otol 333 neurotol. 2005;26(3):438-41. 334 https://doi.org/10.1097/01.mao.0000169792.30330.18 335 12luntz m, hodges av, balkany t, dolan-ash s, schloffman j.otitis media in 336 children with cochlear implants. laryngoscope 1996;106:1403-5. 337 https://doi.org/10.1097/00005537-199611000-00018 338 https://doi.org/10.1007/s00405-016-4091-5 https://doi.org/10.1007/s00405-016-4091-5 https://doi.org/10.1097/00005537-200307000-00021 https://doi.org/10.1016/j.anl.2017.07.012 https://doi.org/10.1016/s0165-5876(96)01398-5 https://doi.org/10.1016/s0165-5876(96)01398-5 13luntz m, teszler cb, shpak t, feiglin h, farah-sima’an a. cochlear 339 implantation in healthy and otitis-prone children: a prospective study. 340 laryngoscope 2001;111:1614-18. https://doi.org/10.1097/00005537341 200109000-00023 342 14hehar ss, nikolopoulos tp, gibbin kp, o’donoghue gm. surgery and 343 functional outcomes in deaf children receiving cochlear implants before age 2 344 years. arch otolaryngol head neck surg 2002;128:11-4. 345 https://doi.org/10.1001/archotol.128.1.11 346 15alzhrani, f., alahmari, m.s., al jabr, i.k. garadat, soha n., hagr, 347 a. cochlear implantation in children with otitis media. indian j otolaryngol 348 head neck surg 2019;71, 1266–1271. https://doi.org/10.1007/s12070-018349 1301-z 350 16cunningham cd 3rd, slattery wh 3rd, luxford wm. postoperative infection 351 in cochlear implant patients. otolaryngol head neck surg 2004;131(1):109– 352 114. https://doi.org/10.1016/j.otohns.2004.02.011 353 17saad elzayat, ihab nada, hossam el sherif & ali mahrous. the safety of 354 posterior tympanotomy in otitis media with effusion during cochlear 355 implantation: clinical retrospective cohort study, acta oto356 laryngologica, 2021;141:1,1-4. https://doi: 10.1080/00016489.2020.1813905 357 18 vlastarakos pv, nikolopoulos tp, korres s, tavoulari e, tzagaroulakis a, 358 ferekidis e. grommets in otitis media with effusion: the most frequent 359 operation in children. but is it associated with significant complications? eur j 360 pediatr 2007; 166:385-91. https://doi: 10.1007/s00431-006-0367-x 361 19golz a, netzer a, joachims hz, westerman st, gilbert lm. ventilation 362 tubes and persisting tympanic membrane perforations. otolaryngol head neck 363 surg 1999;120:524-7. https://doi.org/10.1177/019459989912000401 364 20sokolov m, hilly o, ulanovski d, shkedy y, attias j, raveh e. is it 365 necessary to treat otitis media with effusion (ome) prior to cochlear 366 implantation? results over a long-term follow-up. otol neurotol 2016; 367 37:1529-34. https://doi.org/10.1097/mao.0000000000001221 368 369 370 371 372 https://doi.org/10.1016/j.otohns.2004.02.011 https://doi.org/10.1080/00016489.2020.1813905 https://doi.org/10.1007/s00431-006-0367-x https://doi.org/10.1177%2f019459989912000401 373 374 table 1: comparison of intra-operative findings among the study groups (n=369) 375 intra-operative finding ome (n = 175) non-ome (n = 194) statistical significance (p value) present absent present absent middle ear inflammation 2 (1.1%) 173 (98.9%) 1 (0.5%) 193 (99.5%) 0.601 glue ear 32 (18.3%) 143 (81.7%) 8 (4.1%) 186 (95.9) <0.001 granulation tissues 1 (0.6%) 174 (99.4%) 2 (1%) 192 (98%) 0.534 hypertrophied mucosa 18 (10.3%) 157 (89.7%) 0 194 (100%) <0.001 bleeding 6 (3.4%) 169 (96.6%) 1 (0.5%) 193 (99.5%) <0.046 perilymph leak 5 (2.9%) 170 (97.1%) 5 (2.6%) 189 (97.4%) 0.551 *% is within ome/non-ome, ome = otitis media with effusion 376 377 table 2: comparison of post-operative complications among the study groups (n = 378 369) 379 post-operative complications early vs delayed ome (n = 175) (%) non-ome (n = 194) (%) statistical significance (p value) present absent present absent facial nerve palsy delayed 0 175 (100%) 1 (0.5%) 193 (99.5%) 0.52 swelling at wound delayed 12 (6.9%) 163 (93.1%) 22 (6%) 172 (94%) 0.31 device trauma delayed 8 (4.6%) 167 (95.4%) 6 (3.1%) 188 (96.9%) 0.32 wound infection delayed 3 (1.7%) 172 (98.3%) 7 (3.6%) 187 (96.4%) 0.21 bleeding from wound early 1 (0.6%) 174 (99.4%) 2 (1%) 192 (99%) 0.53 wound dehiscence delayed 1 (0.6%) 174 (99.4%) 0 194 (100%) 0.47 ear discharge delayed 5 (2.9%) 170 (97.1%) 5 (2.6%) 189 (97.4%) 0.55 re-exploration early 0 175 (100%) 1 (0.5%) 193 (99.5%) 0.52 reimplantation delayed 6 (3.4%) 169 (96.6%) 2 (2.2%) 192 (99%) 0.111 *% is within ome/non-ome, ome = otitis media with effusion 380 pearson’s marrow-pancreas syndrome salem h al-tamemi squ med j, august 2009, vol. 9, iss. 2, pp. 196-197, epub 30th june 2009 submitted 20th dec 08 revision req. 29th apr 09, revision recd. 5th may 09 accepted 11th may 09 متالزمة نقي البنكرياس لبريسن سالم التميمي department of child health, sultan qaboos university hospital, muscat, sultanate of oman e-mail: tamemi@squ.edu.om a 12 month old female infant born at full term by spontaneous vaginal delivery presented at sultan qaboos university hospital, oman. her birth weight was 3.23kg, length 50cm and head circumference 34.5cm, all appropriate for her gestational age. the parents were first cousins and had lost three male children due to repeated severe infections. this infant developed chronic diarrhoea, recurrent chest and skin infections from the age of six months, and subsequently had failed to thrive with a weight, height and head circumference < 3rd centile for age. the physical examination revealed subtle facial dysmorphic features, partial bilateral ptosis, generalized hypotonia, mild hepatomegaly and developmental delay. investigations revealed hypochromic microcytic anaemia with a haemoglobin range 6-9 g/dl secondary to loss from the gastrointestinal tract. her liver enzymes were mildly elevated during the time of infectious interesting medical image figure 1: demonstrates the presence of vacuoles in the bone marrow precursor cells, a characteristic feature seen in the pearson’s marrow-pancreas syndrome salem h al-tamemi interesting medical image | 197 episodes. in the course of time, she developed intermittent severe neutropenia < 0.5/ cumm. bone marrow examination demonstrated hypercellular marrow with erythroid hyperplasia, the myeloid cell line showed normal maturation, but vacuolations were seen in keeping with a diagnosis of pearson’s marrow-pancreas syndrome. other investigations revealed normal serum creatinine kinase 17u/l (26140), and normal motor sensory nerve conduction studies for age. the evaluation of her chronic diarrhea included endoscopy that revealed nonspecific superficial inflammation. there was no evidence of coeliac disease or inflammatory bowel disease. examination of fat in the stool was not feasible. a trial dose of supplemental pancreatic enzymes improved the diarrhoea and the child started to gain weight, while her anaemia required blood transfusion. the neutropenia showed some response to granulocyte colony stimulating factor; however the patient experienced a fulminate sepsis and died of multi-organ dysfunction. pearson’s marrow-pancreas syndrome was first described by pearson et al. in 1979.1 this is a rare multi-system disorder with a poor prognosis. the defining features are marrow failure, anaemia, neutropenia, thrombocytopenia and characteristic vacuolation of haematopoietic precursors. an additonal defining feature of pearson’s syndrome is dysfunction of the exocrine pancreas due to fibrosis and acinar atrophy resulting in malabsorption and chronic diarrhoea with fatty stool. another cardinal feature of pearson’s syndrome is persistent or intermittent lactic acidaemia, which is caused by a defect in oxidative phosphorylation. variable hepatic, renal, and endocrine failure may also occur.2,3,4 the genetic defect in pearson’s marrowpancreas syndrome has been found to be a deletion in the mitochondrial dna. the most common deletion reported is a 4977 base pair deletion identified in > 80% of affected children. in the literature, there is a clear evidence of clinical phenotype heterogeneity which has been attributed to genetic variability in the proportion of mt dna deletions.5 references 1. pearson ha, lobel js, kocoshis sa, naiman jl, windmiller j, lammi at et al. a new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. j pediat 1979; 95:976-84. 2. rotig a, cormierv, blanche s, bonnefont jp, ledeist f, romero n, et al. pearson‘s marrow-pancreas syndrome: a multisystem mitochondrial disorder in infancy. j clin inves; 86:1601-18. 3. rotig a, cormier v, koll f, mize ce, saudubray jm, veerman a, et al. site-specific deletions of the mitochondrial genome in the pearson marrowpancreas syndrome. genomics 1991; 10:502-4. 4. seneca s, de meirleir l, de schepper j, balduck n, jochmans k, liebaers i, et al. pearson marrow pancreas syndrome: a molecular study and clinical management. clin genet 1997; 51:338-42. 5. jacobs lj, jongbloed rj, wijburg fa, de klerk jb, geraedts jp, nijland jg, et al. pearson syndrome and the role of deletion dimers and duplications in the mtdna. j inherit metab dis2004; 27:47-55. december 2007 vol 8 after meeting.indd effect of zinc supplementation on morbidity due to acute diarrhoea in infants and children in sanaa, yemen a randomized controlled double blind clinical trial *muna a m elnemr1 and ahmed k abdullah2 عند احلاد االسهال املراضة املصاحبة حلاالت على الزنك امداد تأثير (اليمن) صنعاء في �األطفال التعمية مزدوجة العشوائية مضبطة سريرية دراسة اهللا عبد قائد أحمد ، النمر محمد عبده منى دراسة الطريقة: هذه ــة. اخلامس ــن س األطفال دون لدى احلاد ــهال لإلس املصاحبة والوفيات املراضة على الزنك إعطاء تأثير ــة امللخص: الهدف: دراس لألمومة والطفولة السابني ــفى مستش 2006 في 2005 وأكتوبر ــبتمبر س الفترة بني أجريت في ، التعمية ــوائية مزدوجة العش مضبطة ــريرية س إلى ــوائيا عش احلاالت ــيم مت تقس ــهرا. 6-48ش بني أعمارهم تراوحت احلاد، ــهال باإلس أصيبوا ــة) اخلامس ــن س (دون 180طفال باليمن ل في صنعاء ملدة احلاالت متابعة ومتت كاذبا، عقارا الثانية مت إعطاء اموعة بينما ــبوعني أس ملدة بالفم الزنك ــيتيت اس محلول األولى اموعة أعطيت مجموعتني العينة 2:59 في مقابل الزنك أخذوا الذين األطفال 1.39 عند اإلسهال عدد نوبات متوسط من قلل الزنك إعطاء النتائج أن النتائج: أظهرت شهرين. كما هو الضابطة) العينة ــي 5.47 ف مقابل الزنك أخذت التي العينة (3.57 في ــهال كل نوبة إس في باليوم ــل مرات التغوط ــك قل كذل ــة. الضابط نوبات من حدوث قلل اإلسهال بنوبات اإلصابة ــبوعني أثناء أس ملدة الزنك اخلالصة: إعطاء املتابعة. مدة في ــهال نوبة إس في كل البراز حجم في احلال لسهولة وذلك كبيرة فائدة ذو يعتبر الزنك باستعمال احلاد ــهال لإلس املراضة املصاحبة معدالت تقليل إن هذه النوبات. ــدة وكذلك قلل ش ــهال اإلس األطفال. إسهال على للسيطرة يستعمل أن ميكن ولهذا ، ثمنه ولرخص استعماله ، اليمن. ، إسهال الكلمات: زنك مفتاح sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 219-225 sultan qaboos university© submitted 1st april 2007 accepted 29th july 2007 1department of pediatrics, faculty of medicine, university of science and technology, sana’a, yemen; 2department of physiology, faculty of medicine, thamar university, sana’a, yemen *to whom correspondence should be addressed. email: munaabdo@hotmail.com abstract objectives: to study the impact of zinc administration on the morbidity and mortality attributed to diarrhoea among children less than 5 years old. methods: the study design was a randomized double blinded controlled clinical trial, held at elsabeen hospital for maternity and childhood, sana’a, yemen. the study was conducted during the period september 2005 to october 2006 on 80 children less than 5 years old with acute diarrhoeal episodes. they were randomly allocated to two groups; one of them received a placebo and the other received zinc acetate syrup for 4 days. both groups were followed up for 2 months. results: zinc was able to decrease the mean number of diarrhoeal episodes: .39 in the intervention group versus 2.59 in the control group. it also reduced the mean frequency of stools per day in each attack (3.57 in the intervention group versus 5.47 in the control group) and the volume of stool in each attack during the follow-up period. moreover, zinc was significantly more palatable. conclusion: we can conclude from the study that administration of zinc for two weeks during acute diarrhoeal episodes could decrease the incidence of further diarrhoeal episodes as well as the severity of these episodes. the lower rates of child morbidity with zinc treatment represent substantial benefits from a simple and inexpensive intervention that can be incorporated in existing efforts to control diarrhoeal disease. key words: zinc; diarrhoea; children; yemen. c l i n i c a l a n d b a s i c r e s e a r c h m u n a a b d o m u h a m m e d e l n e m r a n d a h m e d k a i d a b d u l l a h 220 diarrhoea represents a leading cause of under 5 mortality in developing countries, includ-ing yemen and many other countries of the eastern mediterranean.1 overall under 5 mortality was estimated by world health report to be 113 per 100,000 live births of which diarrhoea accounted for 17%, while that of measles represented only 4% and that of malaria 3%. hence, reducing the burden of diarrhoea in these countries will significantly reduce overall mortality in such countries. zinc deficiency is highly prevalent among children in developing countries.2 diarrhoea causes loss of zinc in the stools, which exacerbates the zinc deficiency in children with acute diarrhoea. provision of zinc during diarrhoea is thus rationalized.3 therapeutic studies of giving zinc during diarrhoea proved that zinc administration during and for 14 days from the onset of acute attack will reduce the severity of diarrhoea.4 moreover, zinc therapy for diarrhoea has been shown to be beneficial in controlled trails, in reducing the need for antibiotic therapy and increasing the use of ort (oral rehydration therapy).5 in another study in 2004, baqui et al. found that zinc sulphate has an antimicrobial effect on the enteric pathogens in vitro.6 unlike other essential micronutrients such as iron and vitamin a, there are no conventional tissue reserves of zinc that can be released or sequestered quickly in response to variations in dietary supply. it is recognized that the equivalent of approximately one third (~450 mg) of total body zinc exchanges between the blood stream and other tissues.7 the major source of zinc intake is through diet, with the transcellular uptake occurring in the distal duodenum and proximal jejunum, potentially facilitated by specific transporters, such as zinc transporter protein-1 (zntp-1).8 the intestine also serves as the major conduit for zinc elimination from the body with almost 50% of the daily zinc losses occurring in the gut. however, much of the zinc that is secreted into the intestine is subsequently reabsorbed and this process serves as an important point of regulation of zinc balance. other routes of zinc excretion include the urine, which accounts for approximately 15% of total zinc losses, and epithelial cell desquamation, sweat, semen, hair, and menstrual blood, which together account for approximately 17% of total zinc losses.9 the mechanism by which zinc (zn) improves diarrhoea is not known but could result from the fact that zn inhibits camp-induced cl secretion by blocking basolateral membrane k channels. given the high prevalence of micronutrient deficiencies and infectious diseases in children of developing countries, interventions to reduce infant and pre-school morbidity are a public health priority.10 m e t h o d s this study was conducted in the oral rehydration therapy centre at elsabeen teaching hospital in sana’a,yemen. the following criteria were used to include subjects in the study: infants and children with acute diarrhoeal episodes aged 3 months to 2 years of both sexes either admitted to the medical ward or not. the following subjects were excluded from this study: infants with malnutrition (body weight <60% of the median for age and sex and/or stunting (low height for age ) or wasting (low weight for height) according to the 1995 who standard deviation classification (the use and interpretation of anthropometry , geneva,1995). infants with co-infections were also excluded as well as those with bloody diarrhoea. the study was a prospective randomized double blinded controlled clinical trial. sample size was calculated according to the suitable formula: employing the epiinfo package using an expected reduction of mortality and morbidity of 20%. the confidence interval was 95%; power of the test 90%; unexposed: exposed ratio: advances in knowledge in contrast to previous studies, this is the first study in yemen to utilise a special liquid preparation containing only zinc (dose = 20mg/ 5ml) with an acceptable taste. this study supports the efficacy of zinc in acute diarrhoea among children under five years. applications to patient care efficacy of zinc as an agent that could reduce the recurrence and duration of episodes of diarrhoea in children less than five years which, in turn, implies that zinc supplementation could be used routinely for every child with acute diarrhoea as a prophylactic measure. e f f e c t o f z i n c s u p p l e m e n tat i o n o n m o r b i d i t y d u e t o a c u t e d i a r r h o e a i n i n fa n t s a n d c h i l d r e n i n s a n a a , ye m e n 221 1:1. disease in unexposed: 30% (in yemen); risk ratio: .33. using the sample size collection of epiinfo 2000, the number of children was 100 per group. the total number of children was 200. the following sampling technique was used: the children were randomly allocated into two groups as soon as the enrolment was completed. the randomization was undertaken by blinded trained co-investigators in the study location and by the principal investigators. the control group received ort and advice to the mothers on feeding during diarrhoeal episodes. the intervention group received zinc acetate 20mg daily in the form of diazar syrup from indimedica pharmaceuticals, india, which was undistinguishable from the placebo bottles. treatment began as soon as the episode of diarrhoea started and continued for 14 days, in addition to ort and the advice to the parents. the data collectors taught the mothers how to use the zinc syrup, and visited or called on the mother or the care taker at day 7 and day 14 and then every 2 weeks for 2 months. children and infants eligible for the study were enrolled during the acute attack of diarrhoea. each infant and child in the first episode was submitted to the following: 1. a detailed and complete clinical history including previous diarrhoeal episodes and their duration; 2. an evaluation using a questionnaire designed to collect: personal data; regular follow up of the acute episodes and the subsequent attacks; adherence to the zinc therapy and occurrence of death and 3. complete clinical examination with special attention to nutritional status, dehydration status and chest examination. both groups were followed by observing and reporting the different outcomes mentioned in the record data form: name, age, sex, residency, weight, height, date of the first episode and its duration and frequency of stools, acceptability of the zinc medication, adherence to the treatment, as well as the number of episodes, amount and frequency in each episode, the duration of hospital stay, if any, and death and its cause, if any. it was very difficult to measure the amount of each motion so that we trained the data collectors and the parents to approximate the amount. training was given to the care givers and data collectors to approximate the amount of stools per motion according to accommodation of the diaper to each motion. st udy d e fi n i ti o n s an acute diarrhoeal episode was defined as three or more loose, liquid stools or at least one loose stool containing blood in a 24 hour period. an acute diarrhoeal episode, which led to inclusion of the patient, was defined as one that started during the 48 hours before the visit to the centre. resolution is defined as three consecutive days free from disease. the diagnosis of under nutrition was based on the who’s the use and interpretation of anthropometry, which uses using weight for age, weight for height and height for age. stunting was defined as height for age <2 standard deviations, while wasting was defined as weight for height < 2 standard deviations and under weight as weight for age < 2 standard deviations. figure 1: mean number of episodes, mean frequency of stool in these attacks, and mean duration of hospital stay during follow up. figure 2: average amount of stools per motion during follow up period m u n a a b d o m u h a m m e d e l n e m r a n d a h m e d k a i d a b d u l l a h 222 stati sti c a l a n a ly si s data were collected and analysed using the ssps programme for data analysis, and appropriate tests were used to test significant differences; p value of less than 0.05 was considered significant. e th i c s the ethical review committees of the hospital approved the study procedures. because this was a community based treatment trial, we obtained consent from parents that explained the purpose of the study and the potential risks and benefits of the new treatment. we obtained verbal or written informed consent for data collection (depending on education of the parent) from parents of both the intervention and comparison group children. verbal consent was taken from the few who were illiterate or where the data collectors did not take the written consent in the first visit. the majority provided written consent. r e sults in this double blind controlled randomized study, 180 children were enrolled with 92 in the control group and 88 in the intervention group. ten children were excluded from the study because of the discovery of underlying chronic diseases after enrolment and other ten children dropped out during the period of follow up due to difficult communication, 6 from the intervention group and the rest from the control group. the mean age of the children was14.10 months in the intervention group and 14.38 months in the control group. in the intervention group, 56 (63.6%) were males; 32 (36.4%) were females. in the control group, 51 (55.4%) were males and 41 (44.6%) were females. the two group were not statistical significant in term of gender. mean weight and height among the enrolled children are illustrated in table 1. it shows that there were no significant differences in the age, weight and height between the intervention and control groups. there were no significant differences in the mean duration of the initial attacks of diarrhoea (before starting intervention) between the two groups [table 2]. the mean durations of the initial attack (in days) in both groups were not significant; for the intervention group = 6.62 ±1.369; for the control group = 6.43 ±1.181. the mean number of diarrhoeal episodes during the follow up period was significantly lower in the intervention group compared to the control group (table 2 and figure 1]. the mean frequency of motions in each table 1: distribution of enrolled children, both groups, according to age, sex, and height table 2: mean number of episodes, mean frequency of stool in these attacks and mean duration of hospital stay during follow up p valuestd. error mean std. deviationmeantreatment group <0.051.0429.778months 14.10interventionage 1.187 11.383months 14.38control <0.050.24472.2953kg 8.167interventionweight 0.6162 5.9102kg 8.776control <0.051.06399.9799cm 71.856interventionheight 1.1639 11.1639cm 71.217control treatment group mean std. deviation std. error mean p value mean no. of episodes during follow up intervention 1.39 1.077 0.115 <0.05 control 2.59 1.224 0.128 mean frequency of motions in episodes during follow up intervention 3.57 2.116 0.226 <0.05 control 5.47 1.708 0.179 mean duration of hospital stay(day) intervention 2.00 0.000 0.000 <0.05 control 3.17 0.983 0.401 e f f e c t o f z i n c s u p p l e m e n tat i o n o n m o r b i d i t y d u e t o a c u t e d i a r r h o e a i n i n fa n t s a n d c h i l d r e n i n s a n a a , ye m e n 223 episode during the period of follow up was significantly lower in the intervention group. zinc was acceptable regarding palatability more than the control syrup, as shown in table 3. the data collectors had trained the mothers to assess approximately the amount of stools; the results showed that zinc was able to reduce the average amount of stools per motion during the follow up period as shown in table 4 and figure 2. on the whole, the present study suggests that zinc did not decrease the duration or the frequency of diarrhoea in the initial attack. no mortality was reported during the study or subsequent the follow up period in either group. d i s c u s s i o n in our study population, 88 children received zinc supplementation during and after diarrhoea, with ages ranging from 3 months to four years. there was a downward trend in the incidence of further episodes of diarrhoea and in the mean frequency of motions in each episode during the follow up period in the zinc treatment group, but not in the comparison group, suggested a benefit of zinc. the reductions in duration of diarrhoea, although not significant, also suggest a benefit of zinc. in a randomized controlled study in india in 2002, 11zinc supplementation substantially reduced the incidence and severity of diarrhoea, the two important determinants of diarrhoea-related mortality and malnutrition. this intervention also substantially reduced the proportion of children who experienced recurrent diarrhoea. the reduction in the duration of diarrhoeal episodes is consistent with earlier studies.12 a meta-analysis of five studies of zinc treatment for acute diarrhoea found a summary estimate for reduction in duration of 16%. possible mechanisms for the effect of zinc treatment on the duration of diarrhoea include improved absorption of water and electrolytes by the intestine, 13 faster regeneration of gut epithelium, increased levels of enterocyte brush border enzymes, 14 and enhanced immune response, leading to early clearance of diarrhoeal pathogens from the intestine. several controlled trials have shown a preventive effect of routine zinc supplementation on the incidence of diarrhoea15 and acute lower respiratory infection. however, these studies provided daily zinc supplementation for a period of 6-12 months, which is often not feasible in large scale programmes. three studies, in which zinc was given for two weeks during and after diarrhoea, found reductions in episodes of diarrhoea in the subsequent two to three months period without additional zinc.4, 11, 16 the same result were found in a previous study, in which the zinc-supplementation group showed a decrease of 39 percent (95 percent confidence interval, 6 percent to 70 percent) in the mean number of watery stools per day (p = 0.02).17 table 3: acceptability of zinc syrup and placebo to children in both groups table 4: average amount of stools per motion during follow up period treatment group yes no p value n % within group n % within group total acceptability intervention 80 90.9% 8 9.1% 88 <0.05 control 70 76.1% 22 23.9% 92 <0.05 average amount of stool per motion in attacks during follow up period mild moderate large p value no. % within group no. % within group no % within group intervention 64 73.6% 4 4.6% 0 o% < 0.05 control 56 61.5% 22 24.2% 9 9.9% total 120 67.4% 26 14.6% 9 5.1% m u n a a b d o m u h a m m e d e l n e m r a n d a h m e d k a i d a b d u l l a h 224 the lower rates of additional episodes of diarrhoea in this and other studies indicate that the reduction in incidence could be due to a systemic effect of zinc, probably through enhanced immune function. the reduction in hospital admissions for diarrhoea could have been due to effects of zinc on episode duration, or reduced incidence. an important aspect of our study is that it shows a reduction in the volume of each bowel motion in the subsequent episodes from the use of zinc as a treatment for diarrhoea, although in this study we depended on the care taker evaluation in determining the stool volume. three acute-diarrhoea trials with appropriate outcome measures all found reductions in diarrhoeal severity in zinc-supplemented children compared with control children. of the two trials conducted in india, one found 18% fewer diarrhoeal stools per day (p < 0.1) 11 and the other found 39% fewer watery stools per day (p < 0.02). 15 in the only hospital-based trial of acute diarrhoea, zinc-supplemented children had a 28% lower measured diarrhoeal stool output per day (p = 0.06) 18. the trial conducted in india reported a 21% lower diarrhoeal stool frequency (p = 0.08).11 two hospital-based trials in bangladesh and india found a 37% lower measured stool output (p < 0.02) in zinc-supplemented children.17, 19 in a study that investigated the effect of zinc on the duration of illness and the stool quantity in acute watery diarrhoea of infants aged less than 6 months in 2002, zinc supplementation did not affect diarrhoea duration or stool volume in young infants, although young infants tolerated zinc doses.20 a recently published randomised trial from india found a large reduction in overall mortality in infants who were small for gestational age and supplemented daily with zinc from 1 to 9 months of age.11 in our study, there were no differences in mortality between the two groups and this may be due to a relatively small sample. c o n c l u s i o n zinc supplementation in this study substantially reduced the subsequent incidence of severe diarrhoea and frequency of motions, the two important determinants of diarrhoea-related mortality and malnutrition. this intervention also substantially reduced the proportion of children who experienced recurrent diarrhoea. the effects are large enough to merit routine use of zinc during acute diarrhoea in developing countries. prompt measures to improve the zinc status of deficient populations are warranted. the potential approaches to achieve this goal include: food fortification; dietary diversification; cultivation of plants that are zinc dense or have a decreased concentration of zinc absorption inhibitors; zinc supplementation for selected groups of children. future studies should assess the impact of increased zinc intakes on childhood mortality in developing countries. for facilitating intervention, there is a need to obtain reliable estimates of zinc deficiency, particularly in developing countries. moreover, longer duration of zinc administration after the initial attack should be studied, for example a duration of 3-4 months of daily zinc supplementation. the intervention we evaluated is simple and inexpensive and can be incorporated into existing diarrhoeal disease control efforts. a c k n ow l e d ge me n ts this investigation received technical and financial support jointly from who eastern meditranean region (emro), division of communicable diseases (dcd), and the special programme for research and training in tropical diseases (tdr)). we also grateful to professor yeha raja, sanaa university, department of community medicine, for his help and support during statistical analysis. we would like also to thank with appreciation dr omar ali baashour, paediatric specialist, elsabeen paediatric teaching hospital, sanaa, and the rest of the paediatricians, general practitioners and nursing stuff in that hospital for their cooperation and support during the perod of data collection and follow up. r e f e r e n c e s 1. sazawal s, black re, menon vp, dinghra p, caulfield le, dinghra u, et al. zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. pediatrics 2001; 108:12801286. 2. sandest hh. zinc deficiency : a public health problem. am j child 1991; 145:853-859. 3. zinc investigators collaborative group.therapeutic effect of oral zinc in acute diarrhoea. am j clin nutr 2000; 72:1516-1522. 4. ruel mt, rivera ja, santizo mc, lonnerdal b, brown kh. impact of zinc supplementation on morbidity from diarrhoea and respiratory infections among rural guatemalan children. pediatrics 1997; 99:808-813. 5. baqui ah, black re, el-arifeen s, yunus m, zaman k, begum n, et al. zinc therapy for diarrhoea increased the use of oral rehydration therapy and reduced the use of e f f e c t o f z i n c s u p p l e m e n tat i o n o n m o r b i d i t y d u e t o a c u t e d i a r r h o e a i n i n fa n t s a n d c h i l d r e n i n s a n a a , ye m e n 225 antibiotics in bangladeshi children. j health popul nutr 2004; 22:440-442. 6. surjawidjaja, hidajat a, lesmana m. growth inhibition of enteric pathogens by zinc sulphate: an in vitro study. med princ pract 2004; 13:286-289. 7. juyal r, osmamy m, black re, dhingra u, sarkar a, dhingra p, et al. efficacy of micronutrient fortification of milk on morbidity in preschool children. am j clin nutr 2005; 82:1032-1039. 8. walker cf, black re. zinc and the risk for infectios disease. ann rev nutr 2004; 24:255-275. 9. fraker pj, king le, laakko t, vollmer tl. the dynamic link between the integrity of immune system and zinc status. nutr 2000; 130:1399-1406. 10. bhutta za. the role of zinc in health in developing countries. indian pediatr 2004; 41:429-433. 11. roy sk, tomkins am, akramuzzaman sm, behrens rh, mahalanabis d, fuchs g. randomised controlled trial of zinc supplementation in malnourished bangladeshi children with acute diarrhoea. arch dis child 1997; 77:196200. 12. golden be, golden, mhn. zinc, sodium and potassium losses in the diarrhoeas of malnutrition and zinc deficiency. in: mills cf, bremner i, chesters jk, eds. trace elements in man and animals tema 5. aberdeen: rowett research institute, 1985. p. 228-232. 13. bettger wj, o’dell bl. a critical physiological role of zinc in the structure and function of biomembranes. life sci 1981; 28:1425–1438. 14. ruel mt, rivera ja, santizo mc, lonnerdal b, brown kh. impact of zinc supplementation on morbidity from diarrhoea and respiratory infections among rural guatemalan children. pediatrics. 1997; 99:808-813. 15. sachdev hps, mittal nk, mittal sk, yadav hs. a controlled trial on utility of oral zinc supplementation in acute dehydrating diarrhea in infants. j pediatr gastroenterol nutr 1988; 7:877-781. 16. sazawal s, black re, bhan mk, jalla s, bhandari n, sinha a, et al. zinc supplementation in young children with acute diarrhea in india. n engl j med 1995; 333:839844. 17. sachdev hps, mittal nk, yadav hs. oral zinc supplementation in persistent diarrhoea in infants. ann trop paediatr 1990;10:63-69. 18. roy sk, tomkins am, akramuzzaman sm, behrens rh, haider r, mahalanabis d, et al. randomised controlled trial of zinc supplementation in malnourished bangladeshi children with acute diarrhoea. arch dis child 1997; 77:196-200. 19. bhandari n, bahl r, taneja s, strand t, molbak k, ulvik rj et al. substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north indian children. pediatrics 2002; 109:e86. department of radiology, st. john’s hospital, bengaluru, india *e-mail: ravikanthreddy06@gmail.com twin gestation with complete hydatidiform mole and demise of co-existing fetus ravikanth reddy sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 430–431, epub. 25 aug 22 submitted 5 jul 21 revision req. 26 aug 21; revision recd. 30 aug 21 accepted 16 sep 21 a 26-year-old primigravida at 20 weeks of gestation was admitted to the obstetrics and gynecology department, bengaluru, india, in 2021 with complaints of severe lower abdominal pain and bleeding per vaginum for one day. the patient had vaginal spotting one week prior to the date of presentation with the passage of grape like vesicles. at the time of presentation, the uterus was large for a date corresponding to 28 weeks of gestation (20 weeks on ultrasonography) with additional clinical features such as excessive retching suggesting hyperemesis gravidarum. the patient was hemodynamically stable with no clinical features to suggest distress. vitals such as pulse, blood pressure and respiratory rate were within normal limits. coagulation profile and thyroid function tests returned normal results. moreover, the patient tested negative for toxoplasmosis, rubella cytomegalovirus, herpes simplex and hiv (torch) screening profile. the ongoing bleeding characteristics included the passage of dark brown to bright red blood accompanied by clots and admixed with passage of grape-like cysts per vaginum. however, establishing a final diagnosis from the characteristics of the bleeding alone was difficult in this case, as the molar pregnancy characteristics such as bleeding and lower abdominal pain were indistinguishable from those of a miscarriage. on palpation, the uterine size corresponded to 20 weeks of gestational age. an urgent transabdominal (tas) obstetric ultrasonography scan was requested which revealed a twin pregnancy with a normal fetus and an echogenic mass with honeycomb like pattern and absent fetal parts. however, the normal fetus at the time of ultrasonography did not demonstrate spontaneous fetal movements and fetal heart rate [figure 1a]. the demised fetus was situated in the region of uterine fundus whereas the echogenic mass which was suggestive of a complete hydatidiform mole was situated adjacent to the region of cervical os in the lower uterine segment [figures 1b & c]. dimensions of the dead fetus were 9.3 × 6.9 × 10.2 cm with gestational age corresponding to 20 weeks. serum ß-hcg (beta human chorionic gonadotrophin) levels of the patient were found elevated at 217,341 miu/ml. chest radiograph did not reveal any focal abnormality. the patient along with her husband were counselled regarding the implications of molar pregnancy and the couple were informed regarding risks involved with the progression along the spectrum of gestational trophoblastic disease into more serious entities such as invasive mole and gestational choriocarcinoma, following which the couple had opted for a conservative management approach. on day one of admission, subsequent evacuation of the uterine cavity was performed via the vaginal route which revealed a this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.9.2021.132 interesting medical image figure 1: a: color doppler image showing fetus with absent fetal heart rate suggesting intrauterine fetal demise. b: high-resolution transverse ultrasonography image demonstrating intrauterine echogenic mass (asterisks) with honeycomb like pattern and absent fetal parts suggestive of a complete hydatidiform mole. c: high-resolution longitudinal ultrasonography image demonstrating fetal head (arrows) situated in the region of uterine fundus whereas the molar mass (yellow asterisk) is noted adjacent to the region of cervical os in the lower uterine segment. the anteriorly situated placenta (red asterisk) can be seen separately. https://creativecommons.org/licenses/by-nd/4.0/ ravikanth reddy interesting medical image | 431 dead fetus and vesicular tissue of the molar pregnancy. post-procedural recovery period was uneventful and weekly measurements of ß-hcg were performed during the post-evacuation follow-up. the presence of a dead fetus was histopathologically confirmed with a co-existing complete hydatidiform mole and a normal placental tissue [figure 2]. follow-up at 3 months revealed normal serum ß-hcg levels without requiring therapy with cytotoxic agents. at 12 months follow-up, serum ß-hcg levels remained normal without evidence of persistent trophoblastic disease. the authors certify that they have obtained all appropriate patient consent forms. in the form, the patients have given their consent for their images and other clinical information to be published. comment a normal fetus in a twin pregnancy with co-existing complete hydatidiform mole is an extremely rare entity, with a worldwide incidence ranging from one in 22,000 to one in 100,000 pregnancies.1 the condition poses major challenges during expectant management due to complications such as early fetal demise, bleeding per vaginum, pre-eclampsia, intrauterine fetal growth restriction, hyperthyroidism and torsion of theca lutein cysts. twin pregnancy with concomitant occurrence of live fetus and coexisting complete hydatidiform mole is also known as ‘sad fetus syndrome’, due to the coexisting fetus is potentially viable and usually has normal chromosomes.2 however, in the current case scenario, there was fetal demise at 20 weeks of gestation due to haemorrhage, which is a known and potentially fatal complication associated with this condition. zilberman et al. performed a systematic review and meta-analysis on 14 studies having 244 twin pregnancies with healthy co-twins and coexisting complete hydatidiform moles to ascertain the risk of continuing the pregnancy;3 it interpreted that there was an 80% incidence of maternal complications in ongoing pregnancies—including vaginal bleeding, hyperthyroidism and pre-eclampsia, a 50% chance of a live birth and a 34% chance of persistent gestational trophoblastic disease development—subsequently on continuation of pregnancy. however, termination of the pregnancy should only be considered if the patient has significant vaginal bleeding or develops severe pre-eclampsia or thyrotoxicosis or when embolisation of gestational trophoblastic tissue is suspected. nevertheless, close monitoring and timely surveillance regarding the patient’s well-being is recommended for identifying suspicious signs relating to maternal and fetal complications. a conservative approach may be deemed possible with the availability of resources and high standard of care.4 a literature review also recommended preoperative placement of bilateral uterine artery balloon catheters to minimise blood loss from the molar pregnancy during the process of delivering healthy and live coexisting twins as torrential hemorrhage is an expected complication of this rare entity.5 comprehensive counselling regarding the risks and management approach, long-term follow-up and timely intervention are imperative for the expectant management of this rare yet clinically relevant presentation of complete hydatidiform mole and coexisting twin gestation. a c k n o w l e d g e m e n t the author wishes to thank his assistants, ms. sweta and ms. babika, for help rendered in retrieving ultrasonography images. references 1. liu y, zheng x, wang y, li y, liu c. identification of a hydatidiform mole in twin pregnancy following assisted reproduction. j assist reprod genet 2020; 37:603–10. https:// doi.org/10.1007/s10815-019-01650-3. 2. rajasekaran k, dadhwal v, jassim m. incidental diagnosis of sad fetus syndrome in triplets. bmj case reports cp 2021; 14:e238977. https://doi.org/10.1136/bcr-2020-238977. 3. zilberman sharon n, maymon r, melcer y, jauniaux e. obstetric outcomes of twin pregnancies presenting with a complete hydatidiform mole and coexistent normal fetus: a systematic review and meta-analysis. bjog 2020; 127:1450–7. https://doi.org/10.1111/1471-0528.16283. 4. sheik s, al-riyami n, mathew nr, al-sukaiti r, qureshi a, mathew m. twin pregnancy with a complete hydatidiform mole and a coexisting live fetus: rare entity. sultan qaboos univ med j 2015; 15:e550–3. https://doi.org/10.18295/squmj.2 015.15.04.019. 5. johnson c, davitt c, harrison r, cruz m. expectant manage ment of a twin pregnancy with complete hydatidiform mole and coexistent normal fetus. case rep obstet gynecol 2019; 2019:8737080. https://doi.org/10.1155/2019/8737080. figure 2: histopathology image using haematoxylin and eosin staining at ×400 magnification of the evacuated specimen demonstrating trophoblastic proliferation and hydropic degeneration of villi consistent with features of a hydatidiform mole. https://doi.org/10.1007/s10815-019-01650-3. https://doi.org/10.1007/s10815-019-01650-3. https://doi.org/10.1136/bcr-2020-238977 https://doi.org/10.1111/1471-0528.16283 https://doi.org/10.18295/squmj.2015.15.04.019 https://doi.org/10.18295/squmj.2015.15.04.019 https://doi.org/10.1155/2019/8737080 march 2009.indd abstract objectives: evaluation of the intravesical instillation of doxorubicin for its effect on disease recurrence for patients with non-invasive bladder tumour. methods: the study was performed at al assad university hospital in lattakia, syria and included patients with non-invasive bladder tumours who were managed with transurethral resection and induction and maintenance therapy with intravesical doxorubicin. they were followed up by cystoscopy every 3 months for 2 years and every 6 months thereafter with special emphasis on recurrence rates. results: the study included 85 patients with non-invasive bladder tumours: 23 with non-invasive papillary carcinoma (stage ta), 62 with tumour invading subepithelial connective tissue (stage t). twelve patients had well differentiated tumours (grade ), 48 had moderately differentiated (grade 2), 25 had poorly differentiated (grade 3) tumours. the total recurrence rate was 23%. the rates of recurrence were 56% in grade 3 and 0% in grade . the recurrence rate was 4% in patients with large tumours versus 7% in those with small tumours; 44% in those with multiple tumours compared to 8% in those with solitary tumours; 30% of stage ta tumours recurred and 2% of stage t tumours. conclusion: in short term follow-up, our rate of recurrence was 23%. adjuvant intravesical doxorubicin was shown to reduce the recurrence of superficial bladder cancer. tumour grade, size and number were shown to be prognostic factors for recurrence. keywords: intravesical instillations; doxorubicin; non-invasive bladder cancer. the management of non-invasive bladder tumours with doxorubicin intravesical instillation after transurethral resection *musa i al-gallab, louai a naddaf, mohamad r kanan division of urology, department of surgery, al assad university hospital, faculty of medicine, tishreen university, lattakia, syria *to whom correspondence should be addressed. email: mjellap@hotmail.com املثانة داخل الدوكسوروبيسني بحقن الغازي غير املثانة عالج سرطان االحليل عبر الورم جتريف بعد اجلالب كنعان، موسى نداف، محمد لؤي . الغازية أورام املثانة غير عند مرضى ــة النكس ــبة نس تقليل في ــني بالدوكسوروبيس املثانة حقن ــطة بواس فعالية العالج امللخص: الهدف: تقييم عبر بتجريف الورم عوجلوا الذين الغازية غير املثانة أورام مرضى وشملت (سوريا) بالالذقية األسد اجلامعي مستشفى في الدراسة أجريت : الطريقة ــتنا على دراس وقد ركزنا في ذلك، بعد ــهر 6 أش كل ثم ــنتني س ــهر في أول 3 أش كل املرضى راقبنا املثانة. داخل ــني الدوكسوروبيس حقن االحليل ثم لدى و ( أ املرحلة ) غير غازية حليمية 23 مريضاً سرطانة لدى غازي، غير مثانة ورم لديهم 85 مريضاً الدراسة النتائج: شملت األورام. نكسة معدل ) التمايز متوسطة أورام 48 لديهم ، ( أولى درجة ) التمايز جيدة أورام لديهم 12 مريضاً األولى). املرحلة ) الظهارة حتت النسيج الضام يغزو 62 ورماً %0 في الثالثة و %56 في الدرجة النكسة كانت معدالت و .23% الكلي النكسة معدل بلغ .( ثالثة درجة ) التمايز سيئة 25 كانت ،( ثانية درجة الوحيدة األورام نكسة %44 بينما املتعددة األورام ــة نكس كانت و الصغيرة األورام %17 في %41 مقابل الكبيرة األورام ــة نكس األولى.كانت الدرجة 23% لدينا ــة النكس معدل كان األمد، قصيرة متابعة اخلالصة: بعد األولى. املرحلة أورام 21 % من %30 و أ أورام املرحلة ــة نكس كانت بينما .18% داخل املثانة بالدوكسوروبيسني املساعد العالج أن يبدو بالتالي و داخل املثانة مساعداً عالجاً تعط لم متعددة املراكز دراسة عاملية %54 في بـ مقارنة للنكسة. إنذاريه عوامل هي وعدد األورام درجة الورم وحجمه أن يبدو السطحي. املثانة سرطان نكسة يقلل الغازي. غير املثانة سرطان ، الدوكسوروبيسني املثانة ، الكلمات: حقن داخل مفتاح squ med j, april 2009, vol. 9, iss. 1, pp. 53-58, epub 16th mar 2009 submitted 6th may 08 revision req. 3rd sept 08, revision recd. 6th dec 08 accepted 14th dec 08 c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • intravesical chemotherapy with doxorubicin is effective in the treatment of non-invasive bladder tumours. • the grade, size, multifocality and stage of tumour are important prognostic indicators. l o ua i a n a d d a f, m o h a m a d r k a n a n a n d m u s a i a l g a l l a b 54 bladder cancer is the fourth most common cancer in men and the tenth most common cancer in women.¹ the most common type of bladder cancer in syria is urothelial carcinoma, also known as transitional cell carcinoma (tcc). bladder cancer has various causative factors. smoking leads to higher mortality from bladder cancer during long-term follow-up, even though in a multivariate analysis the prognostic effect of smoking was weaker than that of other factors, such as stage, grade, size and multifocality of the tumour.² bladder cancer is also associated with industrial exposure to aromatic amines in dyes, paints, solvents, leather dust, inks, combustion products, rubber, and textiles.³ approximately 80-90% of patients with bladder cancer present with painless gross haematuria, which is the classic presentation, but 20-30% of patients with bladder cancer experience irritative bladder symptoms.⁴ the diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue. small tumours can be resected in one chip where the chip contains the complete tumour plus a part of the underlying bladder wall. larger tumours have to be resected in fractions. approximately 75-85% of patients with bladder cancer present with the disease confined to the mucosa (non-invasive papillary carcinoma [stage ta], carcinoma in situ [cis]), or to the submucosa (tumour invading subepithelial connective tissue [stage t1]). the management of non-muscle invasive bladder cancer has become more complex with regard to initial investigation, treatment and follow-up.¹ although a state-of-the-art transurethral resection (tur) by itself could eradicate a ta or t1 tumour completely, these tumours recur in a high percentage of patients and progress to muscle-invasive bladder cancer in a significant number of cases. the choice between chemotherapy and immunotherapy largely depends on the risk that needs to be reduced: recurrence or progression. two meta-analyses demonstrated that bcg (bacille calmette-guérin) therapy prevents, or at least delays, tumour progression.⁵ a meta-analysis of european organization for research and treatment of cancer (eortc) and medical research council (mrc) data, comparing intravesical chemotherapy versus tur alone, demonstrated that chemotherapy does prevent recurrence but not progression.⁶ there is no one superior drug with regard to efficacy. mitomycin c, epirubicin and doxorubicin have all been shown to have a beneficial effect.⁷ a randomised trial documented that the concentration of the drug instilled was more important than the duration of the treatment.⁸ the treatment may be considered ineffective when a higher grade of t category or cis appears during therapy. if a recurrence (even of the same grade and t category) is detected after 3 months and 6 months, the therapy may be considered a failure, since few patients will respond to further intravesical therapy.⁹ severe complications have been reported in patients in whom extravasation of the drug occurred. thus, an immediate instillation should not be given in extensive tur procedures.¹⁰ the probability for recurrence and progression at 1 year vary from 15 to 61% and 0.2 to 17%, respectively. after 5 years of follow-up, recurrence and progression rates rang from 31% to 78% and 0.8-45% respectively.¹¹ the aim of the present study was to evaluate the intravesical instillation of doxorubicin for its effect on disease recurrence, patients’ tolerance, side effects and the complications of instillation, in patients with noninvasive bladder tumour. m e t h o d s the study included 85 patients with non-invasive bladder tumours who reported either to al assad university hospital or the center of nuclear medicine in tishreen university hospital, lattakia, syria between march 2005 and march 2008. this study was approved by the internal review board (no. 211) of tishreen university. the inclusion criteria were as follows: patients with non-invasive transitional cell carcinoma of the bladder who were managed with transurethral resection and induction and maintenance therapy with intravesical doxorubicin. from the original number of 96 patients, application to patient care • with minimal side effects, intravesical instillation of doxorubicin could be used as one of the interventions for non-invasive bladder tumours. th e m a n a g e m e n t o f n o n i n va s i v e b l a d d e r tu m o u r s w i t h d o xo r u b i c i n i n t r av e s i c a l i n s t i l l at i o n a f t e r tr a n s u r e t h r a l r e s e c t i o n 55 11 were excluded for the following reasons: one patient had adenocarcinoma, two patients underwent only 6 sessions of doxorubicin, 8 patients were treated with a radical cystectomy; one patient had tumours within a diverticulum and 7 patients had invasive bladder cancer on review of histopathology. after the diagnosis was determined by cystoscopy under local anaesthesia, the patients were admitted to the department of surgery and prepared for transurethral resection of bladder tumour (tur-bt). during the procedure, the tumour characteristics in terms of size (≤2.5cm, >2.5) and number (solitary, multiple) were recorded. intravesical chemotherapy was given routinely to patients with superficial (non-invasive) bladder tumours. we included only the patients with transitional cell carcinoma (tcc); we diagnosed one case with adenocarcinoma, but it was excluded. all patients consented to the adjuvant therapy. a week after the tur, the first session of doxorubicin was administrated. all sessions were conducted on an outpatient basis. each session began by emptying the bladder of any residual urine by a urethral catheter. then we instilled 50mg of doxorubicin diluted with 50ml normal saline, and removed the catheter. we asked the patient to rest in a bed for 105 minutes by taking right lateral, left lateral, prone and supine positions, and then walking in the hall for another 15 minutes before voiding out the drug. the session was repeated weekly 4 times then monthly 11 times. we further excluded any patient who was not given this regimen or was not given the maintenance therapy. two patients received only 6 sessions of doxorubicin, therefore they were excluded. the rationale for the selection of doxorubicin was its local availability. doxorubicin also represents an important drug for adjuvant intravesical chemotherapy. although bcg is considered the first choice as intravesical adjuvant therapy, it is not always available in the present setting. secondly, bcg is not relevant for most patients in our study since we had no cases of cis. mainly, we followed up the patients by using cystoscopy every 3 months in the first two years and every 6 months after that. we also performed a cystoscopy when patients had documented haematuria. r e s u l t s the study included 85 patients with non-invasive bladder tumours. table 1 shows the demographic characteristics of the study sample. the majority of the patients were males (97.6%). the mean age was 63 ± 9.6 years; the range was 34-85 years and the peak table 1: patients’ characteristics %n 85patients 97.683male 2.42female age / year 63mean 61 70peak 34 85range follow up / month 11mean 36 6range smoking habit 4.74l 24.721m 70.660h l: less than 1pack/day for10 years; m: less than 1 pack/ day for 20 years; h: more than 1 pack/day for 30 years %n primary or recurrent 85.973primary 14.112recurrent size 74.163≤2.5cm 25.922>2.5cm multifocality 78.867solitary 21.218multiple stage* 27.123stage ta 72.962stage t1 grade** 14.112grade 1 56.548grade 2 29.425grade 3 *ta: non-invasive papillary carcinoma t1: tumour invades subepithelial connective tissue **grade 1: well differentiated grade 2: moderately differentiated grade 3: poorly differentiated table 2: tumour characteristics l o ua i a n a d d a f, m o h a m a d r k a n a n a n d m u s a i a l g a l l a b 56 incidence was between 61 and 70 years. our patients were compliant to the treatment; usually attending for the cystoscopy on the specified date. the follow-up of the patients continued successfully for up to 36 months (average 11 months). smoking was the common risk factor for developing bladder cancer among our patients. most patients were heavy smokers (71%), defined as smoking more than 1 pack per day for 30 years or more. table 2 gives the full clinical and histopathologic characteristics of the tumours after tur-bt, of which 85.9% were primary and 14.1% recurrent. morphologically, most tumours were small, defined as less than 2.5cm. we considered the total volume when there was more than one tumour. the percentage of small tumours was 74%; 79% of tumours were solitary and the rest multiple. microscopically, cis was not diagnosed in any case and the tumours were staged as ta and t1 (27% and 73%), respectively. grade 2 (g 2) tumours (moderately differentiated) were the predominant type (56%) followed by grade 3 (g3) poorly differentiated tumours (30%). the rest were grade 1 (g1) tumours (well differentiated tumours). a total of 86% of our patients were diagnosed and treated for the first time, while 14% had been diagnosed and treated before, but had not been given intravesical adjuvant therapy. it is known that adjuvant intravesical chemotherapy mainly affects the recurrence rate; therefore, we studied its relation to the tumours’ characteristics [table 3]. the tumours recurred in 20 patients (23.5%). of these, tumours recurred in 35% of patients with ta and in 65% of patients with t1. no g1 tumours recurred, but 70% of g3 tumours recurred while only 30% of g2 tumours did. as to the link between size and recurrence, 45% of big tumours recurred, but only 55% of small tumours. multifocality affected the recurrence rate in the same way as size, with only 60% of solitary tumours recurring, while 40% of multiple tumours recurred. the maximum follow-up time was 36 months (average 11 months). in such a short-term study we therefore could not obtain a valid conclusion on progression rates and mortality [table 4]. we had 2 patients where the tumours progressed. in the first case, the tumour was a big multiple recurrent stage t1, g2 tumour. within 3 months, it became stage t2 and g2. this patient underwent radical cystectomy and is still in good health. the other case was that of a multiple small recurrent ta g2 tumour; in 6 months it became a t1, g2 tumour. the patient is under the intensive follow-up and the tur has been performed. two patients died, the first was an 85 year old heavy smoker, who worked in the cigarettes industry for 40 years. the other was 65 years old, and the cause of mortality is unclear. our patients tolerated the adjuvant chemotherapy well. table 5 shows the side effects seen during the session or during follow-up. to avoid the complications of extravasation, we waited for a week after tur for instillation of doxorubicin and avoided an instillation when there was significant haematuria. the catheter was placed by expert physicians without trauma of %n 23.520total recurrence stage* 357stage ta 6513stage t1 grade** 0.000grade 1 306grade 2 7014grade 3 size 5511≤2.5cm 459>2.5cm multifocality 6012solitary 408multiple *ta: non-invasive papillary carcinoma t1: tumour invades subepithelial connective tissue **grade 1: well differentiated grade 2: moderately differentiated grade 3: poorly differentiated table 3: factors of recurrence %n 2.32mortality 2.32progression 1.21stage* ta to stage t1 1.21stage t1 to stage t2 *ta: non-invasive papillary carcinoma t1: tumour invades subepithelial connective tissue **grade 1: well differentiated grade 2: moderately differentiated grade 3: poorly differentiated table 4: progression & mortality rates th e m a n a g e m e n t o f n o n i n va s i v e b l a d d e r tu m o u r s w i t h d o xo r u b i c i n i n t r av e s i c a l i n s t i l l at i o n a f t e r tr a n s u r e t h r a l r e s e c t i o n 57 the urethra. to avoid allergic reactions on the external genitalia, we withdrew the catheter slowly and then placed gauze on the meatus. one patient had severe urinary tract infection (uti) and did not tolerate the adjuvant therapy: in the urine culture there were colonies of e.coli (more than 1,000,000) and after that klebsiella was discovered. he was treated with appropriate antibiotics, but the irritative voiding symptoms continued and were very severe; therefore, he decided to stop the adjuvant therapy after 9 months, he remained recurrence free during the 18 months of follow-up. mild or moderately severe urinary tract infection (uti) occurred in 9.4% of patients and were effectively treated by antibiotics. haematuria occured in 12% without any tumour seen by cystoscopy. cold biopsy of bladder was performed in two cases and they showed chronic inflammation. the irritative voiding symptoms were the most common side effects; especially dysuria and frequency of urine (interval between micturition less than 2 hours) 14% and 16.4%, respectively. in summary, all patients, except one, tolerated the adjuvant intravesical chemotherapy. d i s c u s s i o n doxorubicin intravesical administration mainly affects the recurrence rate; therefore, we concentrated on evaluating the disease recurrence as well as side effects, complications and patients’ tolerance of the instillation. males were more dominant in this study compared to other studies.¹² this could be explained by the low incidence of smoking in women, and the fact that women rarely deal with the carcinogenic agents. we notice that our patients were younger than in other studies by 5-6 years. we reviewed the medical literature and noticed that the lower limit is always 40 years, indicating a worrying trend in bladder cancer occurrence in our region.¹² all patients were smokers and community awareness raising about the dangers of smoking is imperative since it is an important risk factor for non-invasive bladder tumours. a major limitation of our study was the pathological testing, because the pathologists did not use one system; some used the who 1973 classification, but others used the who 2004 classification. we therefore compared the corresponding grades between the two systems, and reclassified all patients according to who 1973 since this classification is better known. we compared our rate of recurrence with the published rate of recurrence without the intravesical adjuvant theraphy (54%),¹³ and found that the recurrence free survival in our study was 77%. as to the grade, we notice that the grade of tumour is an important indicator of recurrence: more than half of the patients with g3 (56%) had recurrence during follow-up, but none with g1. this accords with the opinion that g3 is a relative indication for radical cystectomy.¹⁴ the size and number of tumours also are shown; they are important indicators of recurrence, but less important than the grade. a total of 41% of patients with tumours greater than 2.5cm recurred and 44% of patients with multiple tumours recurred. saika et al. noted that only the adjuvant therapy (chemotherapy or immunotherapy) played an important role in the recurrence rate, when the non-invasive tumours were g3, while the size, multifocality and morphology did not play a role in terms of the recurrence rate.¹⁴ this difference to our results is perhaps unreal and could be occasioned by the fact that the tumours were high grade. cheng et al. showed in long term follow-up (17 years) that adjuvant intravesical doxorubicin did not improve the recurrence rate of superficial bladder cancer, compared with controls on long-term follow-up. tumour size and grade were shown to be prognostic factors for recurrence and progression respectively¹⁵, therefore we acknowledge the importance of long term follow-up in order to get valid conclusions. c o n c l u s i o n intravesical chemotherapy is safe and tolerable for non-invasive bladder tumours and has reduced tumour recurrence rates, especially when the grade is low, but it probably has no positive impact on disease progression or survival. hence we must continue following up these patients for a long time. also we sug%n 25.922side effects 16.514urinary frequency 14.112dysuria 14.112hematuria 9.48urinary tract infection 1.21intolerance of drug 0.000allergic reactions table 5: adverse drug reactions l o ua i a n a d d a f, m o h a m a d r k a n a n a n d m u s a i a l g a l l a b 58 gest the use of another drug such as mitomycin c in future trials for comparison with the current study’s results. the tumour grade, size and number are important prognostic factors in the recurrence. a c k n ow l e d g m e n t s the research was carried out at tishreen university, faculty of medicine, department of surgery, division of urology, al assad university hospital and the center of nuclear medicine at tishreen university hospital, lattakia, syria. s o u r c e o f f u n d i n g : tishreen university, syria c o n fl i c t o f i n t e r e st : none declared r e f e r e n c e s 1. oosterlinck w, lobel b, malnstrom pu, stockle m, sternberg c. european association of urology (eau) working group on oncological urology guidelines on bladder cancer. eur urol 2002; 24:105-12. 2. aveyard f, adab f, cheng k, wallace d, hey k, murphy m. does smoking status influence the prognosis of bladder cancer? a systematic review. bju int 2002; 90:22839. 3. mccahy pj, harris ca, neal f. the accuracy of recording of occupational history in patients with bladder cancer. br j urol 1997; 79:91-93. 4. grossfeld gd, litwin ms, wolf js. evaluation of asymptomatic microscopic hematuria in adults: the american urological association best practice policy part ii: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. urology 2001; 57:604-10 5. bohle a, bock p. intravesical bacillus calmette-guerin versus mitomycin c in superficial bladder cancer: formal meta-analysis of comparative studies on tumour progression. urology 2004; 63:682-7. 6. pawinski a. a combined analysis of european organization for research and treatment of cancer, and medical research council randomized clinical trials for the prophylactic treatment of tat1 bladder cancer european organization for research and treatment of cancer genitourinary tract cancer cooperative group and the medical research council working part on superficial bladder cancer. urol 1996; 156:1934-41. 7. sylvester a, oosterlinck w, van der meijden a. a single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage ta ti bladder cancer: a mete analysis of published results of randomized clinical trials. j urol 2004; 171:2186-90. 8. kuroda m, niijima t, kotake t, akaza h, hinotsu s. 6th trial of the japanese urological cancer research group. effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial hladder cancer the 6th trial of the japanese urological cancer research group (jucrg): a randomized trial of intravesical epirubicin at dose of 2omg/40m1, 30 mg/40 ml, 40 mg/40 ml. eur urol 2004; 45:600-5. 9. herr h, dalbagni o. defining bacillus calmette-guerin refractory superficial bladder tumors. j urol 2003; 168:1706-1708. 10. oddens jr. one immediate postoperative instillation of chemotherapy in low risk ta, ti bladder cancer patients. is it always safe? eur urol 2004; 46:336-8. 11. sylvester rj, vail der meijden ap, oosterlinck w, witjes a, bouflioux c, denis l, newling d, et al. predicting recurrence and progression in individual patients with stage tat1 bladder cancer using fortc risk tables: a combined analysis of 2596 patients from seven fortc trials. eur urol 2006; 48:466-77. 12. messin em. urothelial tumors of the bladder. in: wei aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. 9th ed. philadelphia: saunders-elsevier, 2007. pp.2407-46. 13. lamm d, riggs d, bugaj m. bcg vs chemotherapy in rapidly recurring papillary carcinoma and carcinoma in situ. j urol 1998; 160:63-72. 14. saika t, tsushima t. clinical study of g3 superficial bladder cancer without cis treated with conservative therapy. jpn j clin oncol 2002; 11:461-5. 15. cheng c, chan p, chan l, chan c, ng c, lai m. 17-year follow-up of a randomized prospective controlled trial of adjuvant intravesical doxorubicin in the treatment of superficial bladder cancer. int braz j urol 2005; 31:20413. radiology resident selection radiology resident selection objective restructured interview to assess five essential attributes *neela lamki, alfred b. watson, richard g. fisher squ journal for scientific research: medical sciences 2003 vol 5, no. –2, 27–30 ©sultan qaboos universit y r e v i e w dept of radiology, baylor college of medicine, 1 baylor plaza, houston, texas 77030, usa. *to whom correspondence should be addressed. email: nlamki@bcm.tmc.edu abstract. like in other medical fields, candidates seeking a career in radiology requires special skills and aptitudes. selecting candidates for radiology residency is made difficult by the fact that many of the essential qualities predictive of a good radiology consultant, such as interpersonal skills, recognition of limits, curiosity, conscientiousness, and confidence level, are “non-cognitive”, and thus difficult to assess. this paper describes the selection procedure developed by the department of radiology of baylor college of medicine to measure, as objectively as possible, both the cognitive and non-cognitive qualities of candidates, based on a combination of traditional screening and objective structured interviews. this paper highlights efficacy of this selection procedure that includes both cognitive and non-cognitive factors, that is relevant also to other medical specialities. key words: radiology, residency, cognitive, non-cognitive, objective structured interview selection of residents for training in any specialty of medicine is very difficult. the difficul-ties are compounded when it comes to selection of residents for specific specialties. radiology is one of the specialties that have special needs, with respect to the essential attributes that the future resident needs to have. in addition, the particular location, namely the university and the hospital where the resident will be working, also contributes to the specificity of the needs. it is generally accepted that criteria for selection of residents include, on one hand, indicators of their academic performance and on the other, such attributes that relate to attitude and behaviour. in the present paper, these two domains are termed cognitive and non-cognitive factors. in this sense, “cognitive” factors include a candidate’s medical school grades, national board examination scores, rank order, etc, while the “non-cognitive” factors refer to the personal characteristics such as conscientiousness and interpersonal skills. the cognitive factors are generally easier to assess than the non-cognitive ones. although both factors determine the quality and performance of the resident and of the future radiologist, it is generally accepted that the non-cognitive factors are better indicators than the cognitive factors.1–7 for example, medical school performance has been shown to be of little predictive value in the performance and quality of a resident.8,9,10 nevertheless, both are needed in the selection of ideal residents. this paper seeks to demonstrate a more objective method we have developed at baylor college of medicine in houston for the selection of radiology residents. it is based on structured interviews designed to enable the interviewers to select the best seven candidates every year out of the 70–90 interviewees. these interviewees are selected from about 350 candidates who apply annually for the 7 available positions. our radiology training programme has a total of 28 residents in a four-year programme, not counting the obligatory clinical year. neela lamki radiology selection ������������������������� ������������������������������������������ �������������������������������� ��������:����������������������������������������������������������������������������������� ������������������������������������������������������������������������������������� :���������� �����������������������������������������������������������������������.������������������������������� ������������������������������������������������������������������������������������������������������� ���������������������������������������������. 28 l a m k i e t a l because most candidates who apply to baylor college of medicine are la crème de la crème, it is particularly difficult to select from them the magnificent seven most suited for the positions. we select residents based on both cognitive and non-cognitive attributes. the cognitive attributes are generally extractible from the candidate’s application, while the non-cognitive attributes are elicited mainly at the interview. the question then arises as to what constitutes a good interview and how the interview can be made more objective.10–13 to elicit the non-cognitive attributes of the applicants, we have developed a specially structured interview. the interview was structured to assess the five attributes that we decided were essential for candidates of the residency programme at baylor and its hospitals. the selection committee of the radiology residency programme reviewed the literature, specifically the medical educational literature, and came to the conclusion that there is indeed a very good correlation between the candidates’ attributes and behaviours in post-graduate performance.5,14–16 in this paper we describe our experience with this structured interview and the attributes selected. m e t h o d initial screening of the applicants is performed by two members of the resident selection committee by screening the applications. typically, these members are the director and the assistant director of radiology education. the important factors considered in the screening process are the common cognitive ones such as () united states medical licensing examination (usmle ) scores, (2) medical school grades, including (a) basic science, and (b) more importantly, performance in clinical rotation, (3) the letter from the dean, (4) three letters of references, and (5) any other obvious factors. to evaluate the more non-cognitive factors, we chose the five attributes that were deemed most appropriate for training radiologists at our institution. baylor college of medicine uses a county hospital as a main base for the residents, with rotations in five other semi-private hospitals for the radiology training. hence the residency makes specific demands on the residents. the non-cognitive attributes that were thought to be essential to a radiology resident’s performance at baylor college of medicine radiology residency training programme were accordingly selected. these were: () interpersonal skills, (2) recognition of limits, (3) curiosity, (4) conscientiousness, and (5) confidence level. some of these attributes were derived from an extensive review of the literature and a combination of studies. one such study carried out structured interviews with experienced radiology faculty to find out what would constitute a good radiologist.16 some of these attributes have been found to be stable for over a decade by interviews with radiologists.14 the findings were similar in a study that involved three different institutions.15 our interviewers are given specific tasks, namely, to ask questions and present scenarios that can test the specific attributes of the applicants. sample questions are distributed to the interviewers as a guide. the resident selection committee of the department of radiology has developed these sample questions designed to explore each of the five attributes. the five essential attributes are distributed among three faculty interviewers. two of the interviewers are given the responsibility of exploring two attributes each, and the third interviewer is given only one attribute to explore. each faculty interviewer is instructed to note response to the questions related to the attribute he/she is responsible for. he/she is asked to rank the candidates individually from  to 5; a score of  being unacceptable, and 5 being well-above average. interviews are set for 30 minutes each, and all interviews are slated for the same afternoon. each candidate is thus interviewed by three faculty and one resident in the same afternoon. typically 6–8 candidates are interviewed in one day during the interview season. the committee members, who are not formally interviewing candidates on that day, assess candidates during the lunch gathering. the chief resident assesses them during the hospital tours that he/she conducts. definitions of the attributes selec ted . interpersonal skills • ability to interact effectively (orally and in writing) with patients • ability to interact effectively with faculty and clinicians • ability to react appropriately with the interviewer 2. recognition of limits • ability to identify a problem situation and its potential problems • recognition of lack of knowledge or skill • willingness to seek assistance when needed 3. curiosity • the ability to independently seek knowledge • an intrinsic interest in medicine or science beyond direct patient care • an interest in radiology and our programme 29 4. conscientiousness • thoroughness in work • willingness to go above and beyond the call of duty • ability to assertively put forth one’s own opinion 5. confidence • make decisions and implement choices appropriate to training level and education • ability to appropriately assess situations and prioritise tasks • aggressively seek opportunities for trying new skills sample questions asked at the interview . interpersonal skills • candidate’s relationship with friends; what they do together at leisure and other times, as well as their strengths and weaknesses • jobs held that interact with others and choice of coworkers • attitudes towards being yelled at mistakenly by an attending surgeon 2. recognition of limits • the candidate is asked to describe a situation in which the candidate felt like he/she was over his/her head. what got him/her into this situation and what did he/she did to get out of it? • the candidate is asked to express his/her limitations and weaknesses and what his/her efforts to work through them. • in a scenario that a patient is dying and the candidate is alone, would he/she do something for the patient that may exceed his/her limitations? 3. curiosity • how does a candidate arrive at a solution in a situation of a very puzzling patient’s ailment? • the elective courses the candidate chose at the university and whether they were enjoyable and why? to describe his/her research project if any. • why is the candidate interested in baylor radiology programme? 4. conscientiousness • an example of a deed that the candidate had done that might be considered “above and beyond” the call of duty • action taken after committing an error • how many times has he/she researched a disease process when not presenting the case at a conference? r a d i o l o g y r e s i d e n t s s e l e c t i o n 5. confidence • ability of the candidate to make decisions under difficult situations. • assessment of the candidate’s self worth, and selfconfidence. • ability of the candidate to facilitate appropriate diagnostic examination choices by the referring clinicians. d a t a a n a l y s i s a n d s e l e c t i o n p r o c e s s all interviewers, faculty and resident interviewers meet at the end of each interview day for about 90 minutes to discuss the 6–8 candidates interviewed that day. each interviewer discusses the ranking of the attributes he/ she is responsible for assessing. all the five attributes are evaluated and weighted accordingly. additional input from informal assessment by the chief resident, the noninterviewing faculty, and the resident interviewers are obtained and weighted accordingly. the cognitive and other standard hard data, e.g., grades, board scores, deans’ letters and letters of recommendations are revisited and reanalysed at this meeting. this group of individuals who have assessed the applicant then comes to a consensus as to the relative importance of each factor among the cognitive and the non-cognitive factors as they apply to each individual candidate. an overall score is assigned to the candidate on a scale of  to 0 by the radiology selection committee. at the end of the season, the scores of all candidates are reviewed and the best of the group are selected for the “national residency match programme.” d i s c u s s i o n preliminary results indicate that the use of the essential attributes-oriented interviews lead to a more standardised structure during the interview. interviewers who were initially uneasy about the standardised format, have now eventually accepted the idea. indeed, they find that it is easier to elicit important personality characteristics and with greater intensity and objectivity. experienced faculty interviewers find that these attribute-oriented interviews are more focused than the standard interviews, and they facilitate better comparison of candidates particularly with respect to the all-important non-cognitive factors. the interviews are found to be more equitable. however, the exact weighting of the factors to be considered has yet to be defined, and this will require a larger data base. after only the first two years of implementation, both the interviewers and the resident selection committee 30 found this method to be more objective. it has now been five years since we started implementing this, and so far, it appears that we did manage to select better residents, at least from personality point of view. cursory comparison with historic data to date indicates that there are less personality clashes and interpersonal problems arising from the residents—among themselves or with the staff. however, there is not enough data to analyse this more critically at this stage. likewise, for the other attributes, the impression of the teaching faculty at the baylor residency programme is that we now have a better group of residents—specifically with respect to the traits related to the 5 attributes. the residents tend to be more conscious of their limits, without losing confidence. they are more conscientious in their work and particularly when on night-duty call. they tend to research the literature in whatever they learn at conferences or from one-to-one teaching. they are more involved in research projects as evidenced by presentations at scientific meetings and publications in these last five years compared to before the implementation of the attribute-oriented interview. a larger pool of residents and a longer followup period will be required for a more accurate and statistically valid analysis of the relative contributions of each of the 5 attributes. there are several factors that play a role in the ideal performance of the resident during the residency, and also later as a consultant radiologist. the future performance of these residents as radiology consultants is the ultimate test of any resident selection criteria. criteria need to be established to assess not only the resident’s performance during the 4 years of radiology residency period but also the performance of the trainee later on as a consultant radiologist, and the position achieved. a further study will ascertain the success of this new attribute-oriented selection process that we are proposing. more time is needed to appropriately evaluate this concept in resident selection. r e f e r e n c e s . adusumilli s, cohan rh, marshall kw, fitzgerald jt, oh ms, gross bh, et al. how well does applicant rank order predict subsequent performance during radiology residency? acad radiol, 2000, 7, 635–40. 2. baker jd, bailey mk, brahen nh, conroy j m, dorman b h, haynes g r. selection of anesthesiology residents. acad med, 993, 68, 6–63. 3. smith wl, berbaum ks. improving resident selection: discrimination by perceptual abilities. invest radiol, 99, 26, 90–92. 4. johnson ek, edwards jc. current practices in admission interviews at u.s. medical schools. acad med, 99, 66, 408– 42. 5. wood ps, smith wl, altmaier em, tarico vs, franken ea jr. a prospective study of cognitive and noncognitive selection criteria as predictors of resident performance. invest radiol, 990, 25, 855–859. 6. garden fh, smith bs. criteria for selection of physical medicine and rehabilitation residents. am j phys med rehabil, 989, 68, 23–27. 7. komives e, weiss st, rosa rm. the applicant interview as a predictor of resident performance. j med educ, 984, 59, 425– 426. 8. wagoner ne, suriano jr, stoner ja. factors used by program directors to select residents. j med educ, 986, 6, 0–2. 9. sade rm, stroud mr, levine jh, fleming ga. criteria for selection of future physicians. ann surg, 985, 20, 225–230. 0. boyse td, patterson sk, cohan rh, korobkin m, fitzgerald jt, oh ms, et al. does medical school performance predict radiology resident performance? acad radiol, 2002, 9, 437–445. . mcdonald js, lingam rp, gupta b, jacoby j, gough hg, bradley p. psychologic testing as an aid to selection of residents in anesthesiology. anesth analg, 994, 78, 542–547. 2. gunderman rb, jackson vp. are nbme examination scores useful in selecting radiology residency candidates? acad radiol, 2000, 7, 603-606. 3. clarke jr, wigton rs. development of an objective rating system for residency applications. surgery, 984, 96, 302–307. 4. komives e, weiss st, rosa rm. the applicant interview as a predictor of resident performance. j med educ, 984, 59, 425– 426. 5. smith wl, wood ps, altmaier em, o’halloran c, franken ea jr. critical performance behaviors of radiology residents: evaluation of two category systems. am j roentgenol, 992, 59, 885–888. 6. altmaier e, smith wl, wood p, ross r, montgomery w, klatte e, et al. cross-institutional stability of behavioral criteria desirable for success in radiology residency. invest radiol, 989, 24, 249–25. l a m k i e t a l method definitions of the attributes selected 1. interpersonal skills 2. recognition of limits 3.  curiosity 4. conscientiousness 5. confidence sample questions asked at the interview 1. interpersonal skills 2. recognition of limits 3. curiosity 4. conscientiousness 5. confidence data analysis and selection process discussion references january 2007 vol 7 correct a.indd mucormycosis of the jaw after dental extractions: two case reports *abdulaziz a bakathir mucormycosis (phycomycosis, zygo-mycosis) is a rare invasive opportunistic infection caused by fungi of the order mucorales. the incidence of mucormycosis is very low.1-3 mucormycosis mainly attacks immunocompromised patients with a rapid fulminant course.1 the most commonly reported form of the disease is rhinocerebral mucormycosis, which is characterised by progressive fungal invasion of the hard palate, paranasal sinuses, orbit, and brain.2-4 successful management of this fulminant infection requires early recognition of the disease, aggressive medical and surgical interventions to prevent the high morbidity and mortality associated with the disease process.5,6 this paper presents two cases of mucormycosis diagnosed after dental extractions in a compromised host, which after comprehensive surgical and medical management led to favourable outcomes. c a s e r e p o r t 1 a 14 year old male patient with a two months diagnosis of acute myeloid leukaemia was referred to the oral health clinic, sultan qaboos university hospital, with a chief complaint of severe toothache in the upper right premolar region, which was not controlled by simple analgesics. the patient was under chemotherapy, antiviral, antifungal and anti-biotic agents. his blood investigations clearly demonstrated pancytopenia with low oral health department, sultan qaboos university hospital, sultan qaboos university, p.o box 35, al-khod-123, muscat, sultanate of oman. *email: abakathir@squ.edu.om abstract. mucormycosis is a rare opportunistic fungal infection, which is mainly reported to occur in patients with immunocompromised conditions such as uncontrolled diabetes mellitus and leukaemias. in this paper, two cases of mucormycosis are reported after dental extractions. the first case of mucormycosis occurred in the maxilla and mandible of a 4 year old male patient undergoing chemotherapy for acute myeloid leukaemia. the second case occurred in the mandible of a 49 year old male patient with a recently diagnosed type-2 diabetes mellitus, presenting with ketoacidosis and underlying undiagnosed acute lymphoblastic leukaemia. the outcome of these reported cases of mucormycosis was favourable after comprehensive surgical and medical management. keywords: mucormycosis, rhinocerebral mucormycosis, complication of dental extraction, case report, oman c a s e s t u d y خلع بعد الفكني عظم في ااطيه الفطرية داء حالتني عن تقرير االسنان مثل املناعة جهاز في املرضى املصابني عادة بها يصاب والتي ، ــدوث احل نادرة االنتهازية الفطرية االلتهابات من ااطية الفطرية ــر داء ــص: يعتب امللخ بعد الفكني في عظم تشخيصها ااطية مت الفطرية داء من حالتني نناقش هذا التقرير في وسرطان الدم. عليه املسيطر السكري غير داء مرضى عمره رجل فهو الثانية احلالة أما . الكيمياوي بالعالج وعولج النقياني احلاد الدم ــرطان بس مصاب 14 سنة عمره ــاب لش احلالة االولى . ــنان االس خلع بسرطان الدم ايضا مصاب أنه وتبني ، الكيتونِيّ احلُماضٌ عالمات عليه ظهرت أن بعد ، الثاني) (النوع السكر مصاب بداء انه اكتشف حديثا ، 49 سنة الشامل. والدوائي اجلراحي العالج اجراء بعد احلالتني كال في جيدة النتيجة كانت . احلاد فاوِيّ اللِمْ يَّ األَرومِ . عمان ، حالة تقرير ، االسنان خلع اختالطات ، الدماغية االنفية ااطية الفطريات ، ااطية املفردات املفتاحية: الفطريات sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© a b d u l a z i z a b a k at h i r 78 platelets (38x109). dental examination showed multiple carious teeth with a very tender and badly broken down upper right second premolar. after appropriate platelets transfusion, the upper right premolar was removed atraumatically under local anaesthesia by an oral & maxillofacial surgeon. two weeks post dental extractions, he developed a temperature of 38.1°c and complained of severe pain from the site of extraction with partial blockage of his right nostril. clinical examination showed a febrile, fully conscious patient with glasgow coma scale of 15, mild right infra-orbital swelling and paraesthesia of the right infra-orbital nerve. no abnormality was observed over the right eye and nasal examination showed blockage of the right nostril with no evidence of any necrosis or nasal discharge. intraoral examination demonstrated a tender swelling of the upper right buccal mucosa with black necrotic gingival tissue and area of necrotic bone extending from the extraction site to the adjacent teeth. in addition, the gingival necrosis had started to involve the palatal mucosal near the extraction site. gingival and bone biopsies were taken for histopathological diagnosis. a computed tomography (ct) scan was requested and this showed a soft tissue swelling of the right infra-orbital region and marked soft tissue obliteration of the right maxillary sinus, which had started to extend medially causing obstruction of the right medial conchae and invasion of the ethmoidal air cells [figures 1&2]. over the next few days, the patient’s condition remained much the same and the area of intraoral necrosis showed a marked increase in size. the histopathology diagnosis was positive for mucormycosis. upon confirmation of the diagnosis of mucormycosis, the patient was started on intravenous liposomal amphotericin-b (ambisome), after consultation with the infectious diseases team. he consented to surgical debridement under general anaesthesia and the haematology team prepared the patient for this procedure. the surgical debridement involved removal of the upper right canine, first premolar and molar, curettage of all necrotic tissues and partial maxillectomy. ear nose and throat colleagues joined us to assist with the debridement using functional endoscopic sinus surgery. the area was then packed with antiseptic bismuth iodine paraffin pack (bipp). over the course of the next few days, the patient condition was stabilised and the sinus was continuously irrigated with 0.2% chlorhexidine antiseptic mouth wash, 3% hydrogen peroxide solutions and the pack was regularly changed every ten days over a period of 8 weeks. the right infraorbital nerve paraesthesia had recovered well some 6 weeks post-surgical debridement. eight weeks post-surgical curettage, the ct scan was repeated and this showed an improvement in the appearance of the right paranasal sinuses. the residual small oro-antral fistula was temporarily sealed by an obturator and its surgical repair was deferred until the patient came off chemotherapy, when all the required dental treatment was to be carried out. unfortunately, the patient’s leukaemia relapsed and more aggressive chemotherapy was planned. during the chemotherapy course, the patient complained of pain and swelling related to the carious lower right first molar and this was subsequently removed under local anaesthesia. over the next few days the swelling and pain subsided. ten days post extraction, a small area of necrosis started to develop buccal to the site of extraction, which continued to enlarge over the next few days with evidence of necrotic bone. biopsy of the necrotic area was carried out and was again positive for mucormycosis. the patient was re-started on ambisome and as the patient leukaemic status showed improvement the plan was for debridement of the site of fungal infection, followed by multiple extractions and fillings under general anaesthesia. the mucormycosis site was widely debrided, the second premolar and molar were extracted and the area was packed with bipp. his post-operative period was uneventful, with the pack being replaced every ten days until the figure 1: axial ct of case 1 showing obliteration of the right maxillary sinus (black arrowhead) and soft tissue swelling over the right infraorbital region (white arrowhead) m u c o r m y c o s i s o f t h e j aw a f t e r d e n ta l e x t r a c t i o n s : tw o c a s e r e p o r t s 79 area had completely healed with healthy tissue, seven weeks post-surgical curettage. the patient’s condition continued to improve and he underwent a successful bone marrow transplant eight months following the initial diagnosis of leukaemia. c a s e r e p o r t 2 a 49-year old male patient was seen in the out-patient maxillofacial clinic at the oral health department, following referral from a family medicine clinic. his chief complaint was pain at the site of a recent extraction socket and paraesthesia of the right lower lip. the patient gave a history of extraction of the lower right second molar two weeks previously at a local private clinic. his medical history revealed a recent diagnosis of type-2 diabetes mellitus (dm) and the patient was taking metformin and glipizide tablets. clinical examination showed an afebrile, weak and pale patient with a sclera icterus. intraoral examination demonstrated an area of soft tissue necrosis posterior to the mobile lower right first molar. a panoramic radiograph showed a non-healing socket of the lower right second molar with evidence of a small area of bone destruction and generalised horizontal bone loss indicating adult periodontitis. the patient was admitted with a provisional diagnosis of mandibular osteomyelitis and was started on intravenous augmentin and metronidazole. on admission, his complete blood count showed low haemoglobin (hb 2.54 g/dl), marked neutropenia and pancytopenia (white cell count 1.52 x109/l, platelets 44.2 x109). his biochemical tests showed raised blood glucose (21 mmol/l), and his glycated haemoglobin was 19%. on the basis of these findings he was referred for an urgent opinion from the endocrine and the haematology teams. he was seen by an endocrinologist and the diagnosis of diabetic ketoacidosis was confirmed. the patient was started on insulin to control his diabetes. the haematology team collected a bone marrow sample, which later confirmed the diagnosis of acute lymphoblastic leukaemia and the patient was then planned for chemotherapy. the area of necrosis was debrided under local anaesthesia with appropriate platelet cover to raise the platelet count to > 50 x109. at the time of debridement, an area of black patches was seen over the bone in the right retro-molar region and a biopsy was accordingly taken for histopathology diagnosis. this was later to confirm the diagnosis of mucormycosis [figure 3]. following confirmation of mucormycosis, the patient was started empirically on amphotericin b (ambisome) and further debridement of the site was planned with removal of the mobile lower right first molar and packing the area with bipp. the debrided site was regularly packed and irrigated with antiseptic solutions (0.2% chlorhexidine and 3% hydrogen peroxide) every 10 days for a period of 9 weeks, until the wound healed with the formation of healthy granulation tissue. d i s c u s s i o n mucormycosis is an acute, opportunistic infection caused by a saprophytic fungus. in human beings there are three genera which are described as pathogens: rhizopus, absibia, and mucor. these are members of the family mucorales of the class phycomycetes.2 rhizopus is the predominant micro-organism, accounting for 90% of the cases of rhinocerebral mucormycosis.4,7 this pathogen can be found in fruits, soil, dust, and manure. in addition, it can be cultured from the oral cavity, nasal passages, throat and stools of healthy patients without a sign of disease.8 the infectious process usually results from inhalation of spores through the nose or mouth, or sometimes through a skin laceration.9 despite the fact that mucormycosis is ubiquitous and grows rapidly, it seldom causes infection in healthy patients. therefore, if an infection with mucormycosis does occur, it usually indicates a serious underlying medical condition as reported in our two cases. mucormycosis has been described in debilitated patients figure 2: coronal ct of case 1 showing obliteration of the right sinus causing blockage of the medial conchae and extension to the right ethmoid sinus (arrowhead) a b d u l a z i z a b a k at h i r 80 with medical conditions such as diabetes, leukaemia, lymphoma, renal failure, immunosuppressive therapy, malnutrition and severe burns.3,8-10 up to 40 – 50% of patients who present with mucormycosis have dm.1,8 studies have shown that dm alters the immunological capability to resist mucormycosis through a reduction of the phagocytic ability of granulocytes in the presence of acidosis and there is an inability of diabetic serum to inhibit rhizopus in vitro.11,12 in addition, rhizopus species thrive best in an acidic and glucose-rich environment. during the state of diabetic ketoacidosis (dka), the acidic environment and the increase in the levels of free iron ions favour fungal growth.13 neutrophils are also known to play an important role in the host protective response against fungal colonisation. as a result of this, patients with leukaemia have an increased susceptibility to develop fungal infections, such as mucormycosis, because of the dysfunctional neutrophils and myelosuppression resulting from chemotherapy which in turn causes a profound neutropenia.1,13 there are at least six clinical forms of mucormycosis: rhinocerebral, pulmonary, gastrointestinal, cutaneous, central nervous system, disseminated and miscellaneous, occurring at specific organ sites e.g. kidney and liver.1,2,8 the term rhinocerebral mucormycosis (rm) should be used when the paranasal sinuses, orbit and brain are involved.2-4 amongst the paranasal sinuses, the most frequently involved are the maxillary and ethmoid sinuses.1 rm is the most common form in patients with dka , accounting for 70% of reported cases.9 patients with rhinocerebral mucormycosis usually present with malaise, headache, facial pain, swelling and low grade fever.8 the disease usually begins in the nasal mucosa or palate and extends to the paranasal sinuses spreading through the surrounding vessels. in addition, mucormycosis can involve the retro-orbital region by direct extension.9,14 with orbital involvement cranial nerves iii, iv and vi functions may be impaired or lost resulting in proptosis, ptosis, pupillary dilatation, orbital cellulitis and loss of vision.8 as mucormycosis develops, the fungal hyphae start to invade local tissue. direct penetration and growth through the wall of blood vessels account for the propensity for thrombosis and tissue necrosis as occurred in our two cases [figure 3]. haematogenous spread to the cavernous sinus and fatal cavernous sinus thrombosis has been widely reported.4,8-9 beside haematogenous spread, rm can also spread by perineural invasion.15 an area of ulceration or an extraction socket in the mouth can be a port of entry for mucormycosis into the maxillofacial region, particularly when the patient is immunocompromised.16 kim et al. (2001) reported 4 cases of rm over a period of ten years, which were diagnosed post-dental extractions. in all these 4 cases, the patients had an uncontrolled dm with two of them in a dka state at the time of presentation. even though mucormycosis of the head and neck commonly occurs in the maxillofacial region, there are only few reported cases of rm in the mandible. 17-18 in our reported cases both patients developed mucormycosis in the mandible. radiographically, maxillary mucormycosis typically shows opacification of the paranasal sinuses without fluid level, thickening of the sinus mucosa and bone distraction of the sinus walls [figures 1 & 2]. as some of these radiographic features may resemble sinusitis, mcdonogh et al. warned that any diabetic patient in a ketoacidotic state presenting with clinical and radiographic features of rhinosinusitis should be suspected as having mucormycosis until proven otherwise.19 definitive diagnosis of rm is usually obtained by a tissue biopsy which identifies the characteristic hyphae.7 histologically, mucormycosis is characterised by extensive tissue necrosis and the presence of numerous, large (5-30 µm), thinned-wall fungal hyphae, which are non-septate, branched at right angles and have a ribbon-like appearance [figure 4]. figure 3: photomicrograph from retro-molar area showing area of bone necrosis with infestation of fungal hyphae (haematoxylin and eosin stain, original magnification _400) m u c o r m y c o s i s o f t h e j aw a f t e r d e n ta l e x t r a c t i o n s : tw o c a s e r e p o r t s 81 successful management of rhinocerebral mucormycosis includes both medical and surgical modalities. the initial medical approach to mucormycosis consists of aggressive treatment of the underlying predisposing medical condition and the use of systemic antifungal agents. the use of amphotericin b in patients with mucormycosis has been widely published and accepted as the best form of treatment with an overall survival rate of up to 72%.7-9 based on recent published data, spellberg et al. highlighted the recommended use of liposomal amphotericin b such as ambisome in the management of mucormycosis.20 surgical management is crucially important and should involve early debridement of all infected and necrotic tissues. this may have to be repeated based on progression of the disease. in some cases, radical resection may be required, which can include partial or total maxillectomy, mandibulectomy and orbital exenteration.3, 21 in our reported cases, the management was started early in the course of disease and involved aggressive local debridement with repeated antiseptic packing until the wound healed with healthy granulation tissue. in addition, the correction of the underlying medical condition, along with the use of liposomal amphotericin b therapy, resulted in good control of the disease with a favourable outcome. c o n c l u s i o n early recognition of mucormycosis is necessary to limit the spread of infection, which can lead to high morbidity and mortality. therefore, dental surgeons and medical practitioners should be familiar with signs and symptoms of the disease and should maintain a high index of suspicion in patients with dm, as it is estimated that 10% of the omani population have diabetes. finally, a multi-disciplinary team approach along with early diagnosis, reversal of the underlying medical condition accompanied by aggressive surgical intervention and the use of amphotericin b are the key to improving the outcome of patients with mucormycosis. a c k n ow l e d ge m e n t s the author would like to thank prof. k.f. moos from glasgow dental hospital, university of glasgow, uk, for proof-reading the script and dr. aisha al-hamdani from pathology department at college of medicine and health sciences, squ, oman for providing the histopathology illustrations. r e f e r e n c e s 1. mcnulty js. rhinocerebral mucormycosis: predisposing factors. laryngoscope 1982; 92:1140-1144. 2. deshazo rd, o’brien m, chapin k, soto-aguilar m, gardner l, swain r. a new classification and diagnostic criteria for invasive fungal sinusitis. arch otolaryngol head neck surg 1997; 123:1181-1188. 3. tryfon s, stanopoulos i, kakavelas e, nikolaidous a, kioumis i. rhinocerebral mucormycosis in a patient with latent diabetes mellitus: a case report. j oral maxillofac surg 2002; 60:328-330. 4. peterson kl, wang m, canalis rf. rhinocerebral mucormycosis: evaluation of the disease and treatment options. laryngoscope 1997; 107:855-861. 5. lehrer ri, howard dh, shepherd ps. mucormycosis. ann intern med 1980; 93;93-97. 6. shand jm, albrecht rm, burnett iii hf, miyake a. invasive fungal infection of the midface and orbital complex due to scedosporium apiospermum and mucormycosis. j oral maxillofac surg 2004; 62:231-234. 7. tugsel z, sezer b, akalin t. facial swelling and palatal ulceration in a diabetic patient. oral surg oral med oral pathol oral radilo endod 2004; 98:630-636. 8. kim j, fortson jk, cook he. a fatal outcome from rhinocerebral mucormycosis after dental extractions: a case report. j oral maxillofac surg 2001; 59:693697. figure 4: photomicrograph from retro-molar region showing elongated, broad, non-septate branching hyphae within the tissue and the bone marrow space (gomori methenamine silver nitrate stain, original magnification _400) a b d u l a z i z a b a k at h i r 82 9. sugar am. mucormycosis. clin infect dis 1992; 14:126129. 10. sykes lm, sukha a. potential risk of serious oral infections in the diabetes patient: a clinical report. j prosthetic dent 2001; 86:569-573. 11. gale gr, welch am. studies of opportunistic fungi. inhibition of rhizopus oryzae by human serum. am j med sci 1961; 241:604-608. 12. bauer h, flanagan jf, sheldon wh. experimental cerebral mucormycosis in rabbets with alloxan diabetes. yale j biol med 1955; 28:29-32. 13. damante jh, fleury rn. oral and rhinocerebral mucormycosis: case report. j oral maxillofac surg 1998; 56:267-271. 14. jones ac, bentsen ty, freedman pd. mucormycosis of the oral cavity. oral surg oral med oral pathol oral radilo endod 1993; 75:455-460. 15. mclean fm, ginsberg le, stanton ca. perineural spread of rhinocerebral mucormycosis. am j neuroradiol 1996; 17:114–116. 16. huang j-s, kok s-h, lee j-j, hsu w-y, chiang c-p, kuo y-s. extensive maxillary sequestration resulting from mucormycosis. br j oral maxillofac surg 2005; 43:532– 534 17. brown oe, finn r. mucormycosis of the mandible. j oral maxillofac surg 1986; 44:132-135. 18. salibsury pl, caloss r, cruz jm, powell bl, cole r, kohut ri. mucormycosis of the mandible after dental extraction in a patient with acute myelogenous leukaemia. oral surg oral med oral pathol oral radilo endod 1997; 83(3):340-344. 19. mcdonogh m, human p, odendaal w. mucorsinisitis in diabetes. s afr med j 1985; 67:78-81. 20. spellberg b, edwards j, ibrahim a. novel perspectives on mucormycosis: pathophysiology, presentation, and management. clin microbiol rev 2005; 18:556-569. 21. ribeiro nnf, cousin gcs, wilson ge, butterworth dm, woodwards rtm. lethal invasive mucormycosis: case report and recommendation for treatment. int j oral maxillofac surg 2001; 30:156-159. 1 submitted 4 jan 22 1 revision req. 16 feb 22; revisions recd. 17 mar 22 2 accepted 29 mar 22 3 online-first: april 2022 4 doi: https://doi.org/10.18295/squmj.4.2022.032 5 6 epidemiology of common ocular manifestations among patients on 7 haemodialysis in west bank, palestine 8 a cross-sectional study 9 yousef shanti1, hamza hamayel2, anas yasin1, abdul-raheem abu shanab1, 10 osama hroub2, zakaria hamdan3, *mujahed shraim4 11 12 departments of 1opthalmology and 3nephrology, an-najah national university hospital, nablus, palestine; 2college of medicine and health sciences, department of medicine, annajah national university, nablus, palestine; 4department of public health, college of health sciences, qatar university, qu health, doha, qatar. *correspondence author’s e-mail: mshraim@qu.edu.qa 13 14 abstract 15 objectives: to assess the prevalence of ocular manifestations and associated factors in patients 16 on haemodialysis. methods: a cross-sectional study of 191 patients on haemodialysis from a 17 haemodialysis unit in nablus, palestine. medical examination for ocular manifestations 18 (intraocular pressure, cataract, retinal changes, and optic neuropathy) was performed using tono-19 pen, portable slit-lamp, and indirect ophthalmoscope. predictor variables were age, gender, 20 smoking, medical comorbidities (diabetes, hypertension, ischemic heart disease (ihd), and 21 peripheral arterial disease (pad)), and use of antiplatelet or anti-coagulation medications. 22 results: the prevalence of any ocular manifestation in at least one eye was 68%. the most 23 common ocular manifestations were retinal changes (58%) and cataract (41%). the prevalence 24 of non-proliferative diabetic retinopathy (npdr), preoperative diabetic retinopathy (pdr), and 25 either npdr or pdr was 51%,16%, and 65%, respectively. increase in age by one year was 26 mailto:mshraim@qu.edu.qa 2 associated with increase in the odds of having cataract by 1.10 (95% confidence interval (ci), 27 1.06, 1.14). patients with diabetes had higher odds of having cataract (odds ratio (or) 7.43; 95% 28 ci, 3.26, 16.95) and any retinal changes (or 109.48, 95% ci, 33.85, 354.05) than patients 29 without diabetes. patients with diabetes and ihd or pad had higher odds of having npdr than 30 patients with diabetes and free from ihd or pad (or 7.62; 95% ci, 2.07, 28.03). conclusion: 31 retinal changes and cataract are very common ocular manifestations among patients on 32 haemodialysis. the findings emphasize the importance of periodic screening for ocular problems 33 this vulnerable population, especially older patients and those with diabetes, to prevent visual 34 impartment and associated disability. 35 keywords: kidney failure, chronic; renal dialysis; eye diseases; eye manifestations; cross-36 sectional studies. 37 38 advances in knowledge 39  the prevalence and factors associated with ocular manifestations among patients on 40 haemodialysis in west bank, palestine, is unknown. 41  the present study showed that 68% of patients on haemodialysis in west bank have at least one 42 ocular manifestation in at least one eye. the most common ocular manifestations were retinal 43 changes, cataract, and non-proliferative and proliferative diabetic retinopathy. 44  age and diabetes were associated with presence of cataract, and diabetes was associated with 45 retinal changes especially among patients with ischemic heart disease and peripheral arterial 46 disease. 47 application to patient care 48  ocular problems are highly prevalent among patients on haemodialysis. 49  periodic screening and early detection and management of ocular manifestations among 50 haemodialysis patients, especially older patients and those with diabetes, will help in prevention 51 of visual impartment and associated disability in this vulnerable population. 52 53 introduction 54 visual impairment and blindness represent a significant cause of disability. worldwide, about 55 2.2 billion people suffer from visual impairment, and 50% of these visual impairments are 56 3 preventable and treatable.1 chronic kidney disease (ckd) is very common, with a global 57 prevalence of 11% to 13%.2 ckd is often gradual and may lead to irreversible loss of kidney 58 function known as end-stage renal disease (esrd). dialysis, either haemodialysis or peritoneal 59 dialysis, and kidney transplantation are the only treatment options for patients with esrd.3, 4 60 patients with esrd are at increased risk of ocular problems due to uraemia, effects of 61 haemodialysis, and other co-morbid conditions, such as diabetes, hypertension, and 62 cardiovascular disease.5 common ocular problems among patients on haemodialysis include 63 cataract, retinal changes (retinopathy, retinal haemorrhage, vitreous haemorrhage, and retinal 64 detachment), and other conjunctival and corneal changes.5, 6 65 66 the prevalence of esrd in palestine reached 240.3 per million population in 2010,7 which is 67 relatively lower than that in other countries in the middle east and other regions in the world.8 68 however, the total number of patients with esrd on haemodialysis has increased from 666 69 cases in 2011 to 1014 cases in 2015.8, 9 therefore, early detection of ocular problems through 70 screening of patients with esrd may help in prevention of visual impairment and associated 71 disability in this population. research on epidemiology of ocular manifestations and associated 72 factors among esrd patients in palestine has been given little attention until now. the aim of 73 this study was to estimate the prevalence of ocular manifestations and associated factors in 74 sample of palestinian patients on haemodialysis. 75 76 methods 77 study design, population, and setting 78 this was a cross-sectional study of patients with esrd on haemodialysis from the 79 haemodialysis unit of an-najah national university hospital, nablus, west bank, palestine. all 80 patients were on four-hours haemodialysis three times per week. the number of haemodialysis 81 patients in this unit represents about 20% of all haemodialysis patients’ population in west 82 bank.9 during the study period (august and december 2016), there were 214 patients receiving 83 haemodialysis in the unit. all patients who agreed to participate in the study were included (n= 84 191). the study was approved by the institutional review board of an-najah national 85 university (ethical approval archive number 03/aug/2016). full verbal and written consent 86 have been obtained from all participants. 87 4 88 data collection 89 demographic and clinical information, previously associated with esrd and ocular problems10 90 were extracted from medical records (age, gender, duration on haemodialysis in years, diabetic 91 status (yes, no), hypertension status (yes, no), use of anti-platelet or anticoagulation medication 92 (yes, no), and diagnosis of ischemic heart disease (ihd) or peripheral arterial disease (pad) 93 (yes, no). patients were asked about their smoking history (yes, no). all patients underwent the 94 clinical ophthalmic examination in the haemodialysis unit after completing their dialysis sessions 95 by two registered ophthalmologists from an-najah national university hospital. for each 96 patient, the clinical ophthalmic examination started with intraocular pressure (iop) measurement 97 using a tono-pen xl tonometer11 after applying local anaesthetic drops (lidocaine 4%) in both 98 eyes. generally, normal iop ranges between 10 and 21 mmhg.12 iop more than 21 mmhg was 99 classified as raised iop. two iop measurements were taken on each eye and then were 100 averaged. after that, both pupils were dilated with tropicamide 1% (one drop per eye every 10 101 minutes for half an hour). presence of cataract was evaluated using a portable slit-lamp,13 and 102 presence of any vitreous or retinal changes was evaluated using indirect ophthalmoscope.14 any 103 vitreous or retinal changes in non-diabetic patients such as arteriovenous nipping or tortuous and 104 vitreous haemorrhage were classified as retinal changes. we used the international clinical 105 diabetic retinopathy disease severity scale to classify diabetic retinopathy among diabetic 106 patients into non-proliferative diabetic retinopathy (npdr) or proliferative diabetic retinopathy 107 (pdr).15 according to this classification, any microaneurysm or intraretinal macrovascular 108 abnormalities were classified as npdr, and neovascularization or vitreous/preretinal 109 haemorrhage were classified as pdr. presence of optic disc pallor or cupping were used as a 110 relative measure of optic neuropathy.16, 17 111 112 data analysis 113 descriptive statistics were used to summarize the data. categorical variables were summarized 114 with numbers and percentages. continuous variables were summarized with mean and standard 115 deviation (sd). we performed multivariable logistic regression analyses to obtain adjusted 116 associations between predictor variables (demographic and medical characteristics of patients) 117 and presence of ocular manifestations of interest (raised iop, cataract, retinal changes, optic 118 5 neuropathy) for all patients, and npdr, pdr, or either npdr or pdr for patients with diabetes. 119 in analysis, all ocular manifestations were categorized as binary variables (yes, no). associations 120 between the predictor variables and the ocular manifestations were summarised using odds ratios 121 (or) with 95% confidence intervals (ci). any association with a p-value of < 0.05 was 122 considered statistically significant. data analysis was performed using statistical package for 123 social sciences (spss) version 27.0. 124 125 results 126 table 1 presents the characteristics of participants. the mean age was 57.5 years, and 46.6% 127 were females. the mean duration on haemodialysis was 3.3 years. about 80.6% and 57.1% of 128 participants had hypertension and diabetes, respectively. around 19.4% had ihd or pad, and 129 52.4% were on antiplatelet or anticoagulant medications. the prevalence of smoking among 130 participants was 24.6%. 131 132 table 2 presents the prevalence of ocular manifestations in at least one eye among participants. 133 the overall prevalence of any ocular problem was 68.0%. about 40.8% of patients had cataract 134 in at least one eye, and 21.5% of patients had a history of cataract surgery. the prevalence of 135 retinal changes in at least one eye was 58.1%. about 9.9% of patients had optic neuropathy at 136 least in one eye. only 3 patients (1.6%) had raised iop at least in one eye. 137 138 around 51.4% and 15.6% of patients with diabetes had npdr and pdr in at least one eye, 139 respectively. the prevalence of either npdr or drp was 65.1% (table 2). 140 141 as shown in table 3, age and diabetes status were the only two variables associated with 142 presence of cataract. increase in age by one year was associated with higher odds of having 143 cataract in at least one eye by 1.10 (95% ci 1.06, 1.14). similarly, patients with diabetes had 144 higher odds of having cataract in at least one eye by 7.43 times (95% ci, 3.26, 16.95) than 145 patients without diabetes. 146 147 6 diabetes was the only variable associated with any retinal changes among participants (table 4). 148 patients with diabetes had significantly higher odds of having any retinal changes by 109.48 149 times (95% ci, 33.85, 354.05) as compared to patients without diabetes. 150 as shown in table 5, no statistically significant associations were found between characteristics 151 of participants and optic neuropathy including age (or 1.02, 95% ci 0.98, 1.05), gender (or 152 2.04, 95% ci 0.71, 5.86), duration on haemodialysis (or 1.04, 95% ci 0.87, 1.23), diabetes (or 153 0.83, 95% ci 0.28, 2.49), hypertension (or 0.98, 95% ci 0.17, 5.21), ihd or pad (or 0.63, 154 95% ci 0.16, 2.50), anti-platelet or anticoagulation therapy (or 1.98, 95% ci 0.70, 5.63), and 155 smoking (or 0.41, 95% ci 0.10, 1.63). 156 157 among patients with diabetes, there were no statistically significant associations between the 158 characteristics of participants and diabetic retinopathy (either npdr or pdr); see table 6. 159 patients with diabetes and ihd or pad had higher odds of having npdr than patients with 160 diabetes and without ihd or pad, but this was not statistically significant (or 2.09, 95% ci 161 0.78, 5.61) 162 163 discussion 164 the aim of current study was to estimate the prevalence of ocular manifestations among a 165 sample of palestinian patients on haemodialysis and identify associated factors. the study 166 showed that common ocular manifestations are highly prevalent among patients on 167 haemodialysis. about two thirds of patients had at least one ocular manifestation in at least one 168 eye. retinal changes and cataract were the most common ocular manifestations. about two 169 thirds of patients with diabetes had either npdr or pdr in at least on eye. about 10% of 170 patients had optic neuropathy at least in one eye. age was positively associated with cataract, 171 and diabetes was associated with presence of cataract and any retinal changes. among patients 172 with diabetes, the presence of ihd or pad was associated with npdr. 173 174 the study showed that 40.8% haemodialysis have cataract, and 21.5% of patients had cataract 175 surgery. this finding is consistent with prior studies that cataract is common among patients on 176 haemodialysis.18-20 for example, one study found that 61% of patients on haemodialysis have 177 cataract.20 in the current study, the prevalence of npdr (51%) and pdr (16%) are very similar 178 7 to those found in a previous study, which reported a prevalence of 57% and 14% for npdr and 179 pdr among patients on haemodialysis, respectively.20 similarly, the prevalence of optic 180 neuropathy (10%) in our study is consistent with the prevalence of optic neuropathy (7%) 181 reported in a previous study.21 this finding also agrees with previous reports on occurrence of 182 optic neuropathy among patients on haemodialysis.22 in the current study, the prevalence of 183 raised iop was very low (2%), which is identical to the findings of a prior study.20 our finding of 184 an independent positive associations between age and diabetes with cataract is consistent with 185 the findings of a 12-year prospective cohort study of patients on haemodialysis.23 we found that 186 diabetic patients had significantly higher odds of having any retinal changes, which is also 187 consistent with the literature.5, 6, 24 among patients with diabetes, we found no association 188 between any of the included patients’ characteristics and the prevalence of diabetic retinopathy. 189 this finding underscores the important independent associations between diabetes and retinal 190 changes, including npdr and pdr. diabetic retinopathy is the most common microvascular 191 complication of diabetes due to hyperglycaemia and related macro and microvascular 192 abnormalities.25-27 the independent association between ihd or pad and npdr observed in the 193 current study also agrees with the literature. prior studies have shown associations between 194 retinal microvascular abnormalities and coronary heart disease among patients with diabetes.28 195 the mechanisms underlying ocular manifestations and observed associations are likely explained 196 by multifactorial pathogenesis associated with aging, esrd and comorbid conditions (diabetes 197 and hypertension), uraemia and haemodialysis, chronic anaemia, and “polypharmacy”.10 the 198 main hypothesized multifactorial pathogenesis includes atherosclerosis, endothelial dysfunction, 199 oxidative stress, chronic inflammation, renin–angiotensin system dysfunction, genetic 200 polymorphisms, klotho, hypocalcaemia, the accumulation of toxic metabolites, and repeated 201 osmotic shift during dialysis.5, 6, 10, 23, 29 202 203 strengths and limitations 204 the main strength of this study is that patients in the haemodialysis unit in an-najah national 205 university hospital represent roughly 20% of patients on haemodialysis in west bank. 206 additionally, this study included the majority (89%) of patients undergoing haemodialysis in the 207 unit and covered a wide range of age groups. it is unlikely that the sociodemographic and clinical 208 characteristics of patients in an-najah national university hospital to differ from those in other 209 8 units in west bank because haemodialysis service and related costs is free and completely 210 covered by the palestinian ministry of health. additionally, ophthalmic examination of the 211 participants was performed independently by two resident ophthalmologists. very few 212 disagreements in classification of ocular manifestations were present. these were resolved by 213 discussion or by seeking the opinion of a third resident ophthalmologist. therefore, the potential 214 for diagnostic errors or misclassification of ocular manifestations is unlikely to have affected our 215 findings significantly. additionally, our findings were consistent with those of previous studies 216 on ocular manifestations among patients on haemodialysis. therefore, the findings from this 217 study are highly likely to be generalizable to other patients on haemodialysis in west bank. 218 219 the study has some limitations. this was a cross-sectional study design, and therefore, temporal 220 associations remain unclear. another limitation is that this study did not examine for other ocular 221 manifestations among patients on haemodialysis, such as dry eyes and corneal abnormalities. 222 however, our study covered most prevalent ocular manifestations among this population (e.g. 223 cataract, retinal changes, and optic neuropathy) which are associated with visual impairment and 224 disability globally.30 also, medical records had no clinical information on previous history of 225 ocular problems among patients, and many elderly patients said that they have a history of 226 ophthalmic problems but did not know what they were. so, we were not able to establish whether 227 the observed ophthalmic manifestations were new or old in majority of patients. however, our 228 aim was to estimate the prevalence of ocular manifestations rather than incidence of ophthalmic 229 manifestations which requires a different study design with long follow-up period. additionally, 230 although goldman applanation tonometer is considered the gold standard instrument for 231 measuring iop, we measured iop using a tono-pen instrument. prior research suggests that 232 tono-pen underestimates iop in persons with elevated iop.31 however, one study found no 233 statistically significant differences in iop values between goldman applanation tonometer and 234 tono-pen in non-glaucoma patients with systemic illness.32, 33 another limitation is that retinal 235 changes were examined using indirect ophthalmoscope. it would be more ideal to take fundus 236 photographs for evaluation by retina specialists. however, this was not feasible in the present 237 study. 238 9 239 conclusion 240 ocular problems are highly prevalent among patients on haemodialysis. most common ocular 241 manifestations were retinal changes and cataract. without early detection and treatment, such 242 conditions may lead to significant visual impairment and disability. the findings underscore the 243 importance of regular ophthalmic screening for patients on haemodialysis, especially older 244 patients and those with diabetes, to prevent visual impartment and associated disability in this 245 population. 246 247 authors’ contribution 248 ys and ms led study conception and design, supervision, data collection, statistical analysis, 249 interpreting data, and drafting of manuscript. oy, aas, zh, oh, and hh were involved in study 250 concept and design and data collection. all authors reviewed the manuscript critically for 251 important intellectual content. all authors read and approved the final version of the manuscript. 252 253 acknowledgement 254 we thank the participants and an-najah national university hospital for granting us the 255 privilege to conduct this study. 256 257 conflict of interest 258 the authors declare no conflicts of interest. 259 260 funding 261 no funding was received for this study. 262 263 references 264 1. world health organization. blindness and vision impairment. who; 2021 [30 december 265 2021]. available from: https://www.who.int/en/news-room/fact-sheets/detail/blindness-and-266 visual-impairment. 267 10 2. hill nr, fatoba st, oke jl, hirst ja, o'callaghan ca, lasserson ds, et al. global 268 prevalence of chronic kidney disease a systematic review and meta-analysis. plos 269 one. 2016;11(7):e0158765. 270 3. kidney disease international global outcomes. kdigo 2012 clinical practice guideline for 271 the evaluation and management of chronic kidney disease. kidney international 272 supplements. 2013;3(2). 273 4. grassmann a, gioberge s, moeller s, brown g. end-stage renal disease: global 274 demographics in 2005 and observed trends. artif organs. 2006;30(12):895-7. 275 5. mullaem g, rosner mh. ocular problems in the patient with end-stage renal disease. semin 276 dial. 2012;25(4):403-7. 277 6. okolo o, omoti a. ocular manifestations of chronic kidney diseaseamong adult patients 278 receiving hemodialysis. expert review of ophthalmology. 2014;7(6):517-28. 279 7. khader mi, snouber s, alkhatib a, nazzal z, dudin a. prevalence of patients with end-280 stage renal disease on dialysis in the west bank, palestine. saudi j kidney dis transpl. 281 2013;24(4):832-7. 282 8. younis m, jabr s, al-khatib a, forgione d, hartmann m, kisa a. a cost analysis of kidney 283 replacement therapy options in palestine. inquiry. 2015;52. 284 9. palestinian health information center. health annual report: palestine 2015. ramallah: 285 palestinian health information center, 2016. 286 10. wong cw, wong ty, cheng cy, sabanayagam c. kidney and eye diseases: common risk 287 factors, etiological mechanisms, and pathways. kidney int. 2014;85(6):1290-302. 288 11. tonopen xl tonometer. reichert, inc, new york, usa. 289 12. boyed k. what is glaucoma? symptoms, causes, diagnosis, treatment: american 290 academy of ophthalmology; 2021 [cited 30 december 2021]. available from: 291 https://www.aao.org/eye-health/diseases/what-is-glaucoma 292 13. portable slit lamp. keeler ltd. berkshire, uk. 293 14. binocular indirect ophthalmoscope. welch allyn, new york, usa. 294 15. wilkinson cp, ferris fl, klein re, lee pp, agardh cd, davis m, et al. proposed 295 international clinical diabetic retinopathy and diabetic macular edema disease severity scales. 296 ophthalmology. 2003;110(9):1677-82. 297 16. behbehani r. clinical approach to optic neuropathies. clin ophthalmol. 2007;1(3):233-46. 298 11 17. biousse v, newman nj. ischemic optic neuropathies. n engl j med. 2015;372(25):2428-299 36. 300 18. berlyne gm, ari jb, danovitch gm, blumenthal m. cataracts of chronic renal failure. 301 lancet. 1972;1(7749):509-11. 302 19. koch hr, siedek m, weikenmeier p, metzler u. [cataract during intermittent hemodialysis. 303 the influence of hypocalcemia on the development of opacities (author's transl)]. klin monbl 304 augenheilkd. 1976;168(3):346-53. 305 20. vrabec r, vatavuk z, pavlović d, sesar a, cala s, mandić k, et al. ocular findings in 306 patients with chronic renal failure undergoing haemodialysis. coll antropol. 2005;29 suppl 307 1:95-8. 308 21. haider s, astbury nj, hamilton dv. optic neuropathy in uraemic patients on dialysis. eye 309 (lond). 1993;7 ( pt 1):148-51. 310 22. nieto j, zapata ma. bilateral anterior ischemic optic neuropathy in patients on dialysis: a 311 report of two cases. indian j nephrol. 2010;20(1):48-50. 312 23. rim th, yoon cy, park hw, chung ej. association between starting hemodialysis for 313 end-stage renal disease and incident cataract surgery: a 12-year nationwide cohort 314 study. invest ophthalmol vis sci. 2016;57(3):1112-9. 315 24. williams r, airey m, baxter h, forrester j, kennedy-martin t, girach a. epidemiology of 316 diabetic retinopathy and macular oedema: a systematic review. eye (lond). 317 2004;18(10):963-83. 318 25. yau jw, rogers sl, kawasaki r, lamoureux el, kowalski jw, bek t, et al. global 319 prevalence and major risk factors of diabetic retinopathy. diabetes care. 2012;35(3):556-64. 320 26. ding j, wong ty. current epidemiology of diabetic retinopathy and diabetic macular edema. 321 curr diab rep. 2012;12(4):346-54. 322 27. lee r, wong ty, sabanayagam c. epidemiology of diabetic retinopathy, diabetic macular 323 edema and related vision loss. eye vis (lond). 2015;2:17. 324 28. mcclintic br, mcclintic ji, bisognano jd, block rc. the relationship between retinal 325 microvascular abnormalities and coronary heart disease: a review. am j med. 326 2010;123(4):374.e1-7. 327 29. evans rd, rosner m. ocular abnormalities associated with advanced kidney disease and 328 hemodialysis. semin dial. 2005;18(3):252-7. 329 12 30. world health organization. global data on visual impairments 2010. geneva: who, 2012. 330 31. horowitz gs, byles j, lee j, d'este c. comparison of the tono-pen and goldmann 331 tonometer for measuring intraocular pressure in patients with glaucoma. clin exp 332 ophthalmol. 2004;32(6):584-9. 333 32. hsu s, lin s, hsu a. measurements of intraocular pressure with tono-pen and goldmann 334 applanation tonometers in subjects with systemic illness. tzu chi medical journal. 335 2007;19(4):241-4. 336 33. yilmaz i, altan c, aygit ed, alagoz c, baz o, ahmet s, et al. comparison of three methods 337 of tonometry in normal subjects: goldmann applanation tonometer, non-contact airpuff 338 tonometer, and tono-pen xl. clin ophthalmol. 2014;8:1069-74. 339 340 table 1 characteristics of participants 341 variable mean (sd) or number (%) age (years) 57.5 (13.8) gender female male 89 (46.6) 102 (53.4) duration on haemodialysis (years) 3.3 (2.9) diabetes mellitus no yes 82 (42.9) 109 (57.1) hypertension no yes 37 (19.4) 154 (80.6) ihd or pad no yes 154 (80.6) 37 (19.4) anti-platelet or anticoagulation no yes 91(47.6) 100 (52.4) smoking no yes 144 (75.4) 74 (24.6) sd, standard deviation; ihd, ischemic heart disease; pda, peripheral arterial disease 342 13 table 2 prevalence of ocular manifestations in at least one eye among participants 343 ocular manifestation number (%) cataract no yes previous cataract surgery 87 (45.5) 78 (40.8) 41 (21.5) retinal changes no yes 80 (41.9) 111 (58.1) optic neuropathy no yes 172 (90.1) 19 (9.9) intraocular pressure normal raised 188 (98.4) 3 (1.6) npdr no yes 53 (48.6) 56 (51.4) pdr no yes 92 (84.4) 17 (15.6) npdr or pdr no yes 38 (34.9) 71 (65.1) npdr, non-proliferative diabetic retinopathy; pdr, proliferative diabetic retinopathy 344 14 table 3 association between characteristics of participants and cataract 345 variable patient has no cataract (n=87) patient has cataract (n=104) adjusted or (95 % ci) pvalue age (years) 50.1 (14.7) 63.6 (9.4) 1.10 (1.06, 1.14) <0.001 gender female male 41 (47.1) 46 (52.9) 48 (46.2) 56 (53.8) ref 0.80 (0.36, 1.81) 0.597 duration on haemodialysis (years) 3.4 (3.3) 3.2 (2.5) 1.13 (0.98, 1.30) 0.102 diabetes mellitus no yes 59 (67.8) 28 (32.2) 23 (22.1) 81 (77.9) ref 7.43 (3.26, 16.95) <0.001 hypertension no yes 22 (25.3) 65 (74.7) 15 (14.4) 89 (85.6) ref 0.65 (0.23, 1.85) 0.413 ihd or pad no yes 74 (85.1) 13 (14.9) 80 (76.9) 24 (23.1) ref 0.52 (0.20, 1.32) 0.165 anti-platelet or anticoagulation no yes 50 (57.5) 37 (42.5) 41 (39.4) 63 (60.6) ref 1.72 (0.78, 3.78) 0.178 smoking no yes 66 (75.9) 21 (24.1) 78 (75.0) 26 (25.0) ref 1.05 (0.39, 2.77) 0.930 ihd, ischemic heart disease; pad, peripheral arterial disease; or, odds ratio; ci, confidence 346 interval. note: percentages may not add up to 100 due to rounding 347 15 table 4 association between characteristics of participants and retinal changes 348 variable patient has no retinal changes (n=80) patient has retinal changes (n=111) adjusted or (95 % ci) pvalue age (years) 52.2 (16.4) 61.2 (10.1) 1.01 (0.97, 1.06) 0.561 gender female male 39 (48.8) 41 (51.2) 50 (45.0) 61 (55.0) ref 0.84 (0.25, 2.81) 0.771 duration on haemodialysis (years) 3.8 (3.5) 2.9 (2.2) 1.06 (0.88, 1.27) 0.558 diabetes mellitus no yes 73 (91.3) 7 (8.8) 9 (8.1) 102 (91.9) ref 109.48 (33.85, 354.05) <0.001 hypertension no yes 27 (33.8) 53 (66.3) 10 (9.0) 101 (91.0) ref 1.98 (0.51, 7.78) 0.326 ihd or pad no yes 75 (93.8) 5 (6.3) 79 (71.2) 32 (28.8) ref 2.44 (0.46, 13.02) 0.298 anti-platelet or anticoagulation no yes 47 (58.8) 33 (41.3) 44 (39.6) 67 (60.4) ref 1.33 (0.44, 4.03) 0.616 smoking no yes 61 (76.3) 19 (23.8) 83 (74.8) 28 (25.2) ref 0.42 (0.10, 1.74) 0.231 ihd, ischemic heart disease; pad, peripheral arterial disease; or odds ratio; ci, confidence 349 interval. note: percentages may not add up to 100 due to rounding 350 16 table 5 association between characteristics of participants and optic disc pallor/cupping 351 variable patient has no optic disc pallor (n=172) patient has optic disc pallor (n=19) adjusted or (95 % ci) pvalue age (years) 57.2 (14.0) 59.4 (12.3) 1.02 (0.98, 1.05) 0.411 gender female male 82 (47.7) 90 (52.3) 7 (36.8) 12 (63.2) ref 2.04 (0.71, 5.86) 0.188 duration on haemodialysis (years) 3.3 (2.8) 3.6 (3.6) 1.04 (0.87, 1.23) 0.678 diabetes mellitus no yes 73 (42.4) 99 (57.6) 9 (47.4) 10 (52.6) ref 0.83 (0.28, 2.49) 0.740 hypertension no yes 33 (18.6) 140 (81.4) 5 (26.3) 14 (73.7) ref 0.98 (0.17, 5.21) 0.984 ihd or pad no yes 138 (80.2) 34 (19.8) 16 (84.2) 3 (15.8) ref 0.63 (0.16, 2.50) 0.512 anti-platelet or anticoagulation no yes 84 (48.8) 88 (51.2) 7 (36.8) 12 (63.2) ref 1.98 (0.70, 5.63) 0.201 smoking no yes 128 (74.4) 44 (25.6) 16 (84.2) 3 (15.8) ref 0.41 (0.10, 1.63) 0.204 ihd, ischemic heart disease; pad, peripheral arterial disease; or odds ratio; ci, confidence 352 interval. note: percentages may not add up to 100 due to rounding 353 17 table 6 association between characteristics of participants and diabetic retinopathy 354 variable patient has no npdr or pdr (n=38) patient has npdr or pdr (n=71) adjusted or (95 % ci) pvalue age (years) 62.1 (7.2) 61.3 (10.7) 0.99 (0.95, 1.04) 0.710 gender female male 14 (36.8) 24 (63.2) 33 (46.5) 38 (53.5) ref 0.99 (0.39, 2.50) 0.981 duration on haemodialysis (years) 2.4 (2.4) 2.9 (2.0) 1.09 (0.89, 1.34) 0.423 hypertension no yes 4 (10.5) 34 (89.5) 5 (7.0) 66 (93.0) ref 1.88 (0.43, 8.24) 0.405 ihd or pad no yes 30 (78.9) 8 (21.1) 47 (66.2) 24 (33.8) ref 2.09 (0.78, 5.61) 0.142 anti-platelet or anticoagulation no yes 14 (36.8) 24 (63.2) 29 (40.8) 42 (59.2) ref 0.82 (0.32, 2.10) 0.667 smoking no yes 23 (60.5) 15 (39.5) 56 (78.9) 15 (21.1) ref 0.42 (0.15, 1.15) 0.091 npdr, non-proliferative diabetic retinopathy; pdr, proliferative diabetic retinopathy; ihd, 355 ischemic heart disease; pad, peripheral arterial disease; or odds ratio; ci, confidence interval. 356 note: percentages may not add up to 100 due to rounding 357 july 2008.indd assessment of the relationship of hepatic enzymes with obesity and insulin resistance in adults in saudi arabia ali ibrahim al-sultan department of internal medicine, college of medicine in al-ahssa, king faisal university, kingdom of saudi arabia email: dean-medicinehassa@kfu.edu.sa sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 185-192 sultan qaboos university© submitted 1st january 2008 accepted 15th april 2008 c l i n i c a l a n d b a s i c r e s e a r c h عند األنسولني ومقاومة والسمنة الكبدية األنزميات بني العالقة تقييم السعودية اململكة العربية في البالغني األفراد السلطان علي في البالغني األفراد عند األنسولني ومقاومة بالسمنة لأللبومني واملستوى املصلي الكبدية اإلنزميات عالقة ــة لتقييم الدراس أجريت امللخص: الهدف: األنثروبومترية املقاسات أخذ مت . بدين 68 غير و 68 بدينا من مكونه ، بالغ 136 سعودي ل دراسة مقارنة الطريقة: هذه السعودية. العربية اململكة النتائج: تقييم االستتباب. بنموذج األنسولني مقاومة وحتديد الدهون ــتوى ومس ــولني واألنس ، الدم وجلوكوز واأللبومني ، األنزميات الكبدية ــتوى ومس ، وحتديد ــولني واألنس إفطار) بدون – الصيام (بعد واجللوكوز ــة القلوي ــفاتيز الفوس إنزمي غلومتيل و غاما بيبتايد ناقالت ــتويات مس أن ــة الدراس ــرت أظه ارتبطت . (p<0.0001 و ,p<0.001, p<0.004, p<0.005, p<0.0001) ــني البدين ــد ــة عن عالي ــتتباب االس تقييم بنموذج ــولني مقاومة األنس مقاومة (حتديد ــولني األنس مقاومة وصمات مع الورك) اخلصر إلى محيط ــبة ونس ــم اجلس كتلة ــر (مؤش االنثروبومترية ــات باملقاس الكبدية األنزميات األقوى. هو غلومتيل غاما بيبتايد ناقالت ارتباط أن بينت فالدراسة ومع ذلك . الصيام) بعد ما جلوكوز واألنسولني و االستتباب تقييم بنموذج األنسولني تقييم مقاومة األنسولني بنموذج وحتديد اجلسم ومؤشر كتلة بني مستوى األلبومني اإلحصائية الناحية من معتدا ــيا عكس ارتباطا ــة الدراس أظهرت غاما بيبتايد ناقالت مستوى وخصوصا املعتلة الكبد وظائف اخلالصة: إن التوالي. على (p<0.01و ,p<0.01, p<0.05) واألنســــــولني االستتباب قد غلومتيل ناقالت بيبتايد غاما مستوى إن واألنســــــولني. االستتباب تقييم ومقاومة األنسولني بنموذج بالسمنة ارتباطه في هو األقوى غلومتيل هذه الكحول مقيد. استهالك حيث السعوديني البالغني عند األنسولني ومقاومة للسمنة املصاحبة املرضية الكبدية التغيرات على داللة أكثر يكون . في السمنة األلبومني أيض تغير احتمال تظهر النتائج العربية السعودية. اململكة املصل ، ألبومني ، األمني ناقالت أنزميات مقاومة األنسولني ، ، الكلمات: السمنة مفتاح abstract objectives: this study was conducted to assess the relationship of hepatic enzymes and serum albumin to obesity and insulin resistance in adults in saudi arabia. methods: a comparative study of 36 saudi adults, comprising of 68 obese and 68 nonobese was conducted. anthropometric measurements, hepatic enzymes, serum albumin, blood glucose, serum insulin, lipid profile, and homeostasis model assessment of insulin resistance (homa ir) were measured. results: the study showed significantly higher levels of gamma glutamyl transpeptidase (ggt), alkaline phosphatase, fasting glucose, serum insulin, and homa ir p < 0.00, <0.004 < 0.005, <0.000, <0.000, among obese subjects. hepatic enzymes correlated with both anthropometric measures (body mass index (bmi), and waist to hip ratio) and markers of insulin resistance (homa ir, insulin, and fasting glucose). however, the study found that ggt had the strongest associations. significant inverse correlation was found between serum albumin and bmi, homa ir, and serum insulin, p< 0.0, <0.05, <0.0, respectively. conclusion: deranged liver functions, especially ggt, had the strongest correlations with obesity and homa ir. ggt might be a better marker of hepatic pathology associated with obesity and insulin resistance in saudi adults with restricted alcohol intake. the results also propose that albumin metabolism might be altered in obesity. keywords: obesity; insulin resistance; transaminases; serum albumin; saudi arabia. advances in knowledge • gamma glutamyl transpeptidase might be a better marker of hepatic pathology associated with obesity and insulin resistance in saudi adults with restricted alcohol intake. a l i i b r a h i m a l -s u lta n 186 obesity is a major health problem. non-alcoholic fatty liver disease is a hepat-ic dysfunction frequently associated with obesity,1, 2 and the fatty liver changes correlate with the severity of obesity.3, 4 the literature is well documented for the association of the levels of hepatic enzymes and obesity,5-11 and for measured percentage body fat.12-14 this association with obesity had been shown for nonalcoholic fatty liver disease either diagnosed by ultrasound or liver biopsy.1, 4, 15, 16 the relationship of hepatic enzymes as markers of non-alcoholic fatty liver disease and insulin resistance was appreciated by the prediction of metabolic syndrome and type 2 diabetes mellitus. alanine aminotransferase (alt) predicts metabolic syndrome or correlates with its components,8, 17, 18 as well gamma glutamyl transpeptidase (ggt),6 or both.2 alt predicts diabetes mellitus,8, 9 and similar observations are attributed to ggt,19-23 or both. 10 alt and ggt correlates with surrogates of insulin resistance,2, 7, 10, 16, 24 and with directly measured insulin resistance.9, 12 ggt is a sensitive marker for liver damage, but less specific than other hepatic enzymes. alcohol intake is prohibited by religion and enforced by law in saudi arabia. the pattern of these enzymes in relation to obesity and insulin resistance is not well documented in such an environment. glycated albumin is associated negatively with obesity in non-diabetic children.25 it has been reported that serum albumin is low in obese individuals even with normal liver histology.3 the aim of the study was to assess the relationship of hepatic enzymes and serum albumin to obesity and insulin resistance in adult saudi individuals. m e t h o d s the study was conducted over a one year period (2004 2005) at the departments of internal medicine in the colleges of medicine in al-ahsa and dammam, at king faisal university, kingdom of saudi arabia. a total of 136 volunteer subjects were included. they were non-diabetic with normal blood urea nitrogen and serum creatinine, and had no microalbuminuria (urine albumin to creatinine ratio less than 0.03 mg/ mg in overnight early morning sample). they were stratified into obese and non-obese groups according to international criteria. serum liver chemistry, fasting glucose, insulin and lipid profile were measured. the scores for homeostasis model assessment of insulin resistance (homa ir) were calculated with the formula: fasting serum insulin (µu/ml) x fasting serum glucose (mmol/l) / 22.5 as described by matthews and his colleagues.26 there were 68 (34 males and 34 females) nonobese subjects with normal body mass index (bmi) less than 25, and 68 (34 males and 34 females) obese subjects with bmi equal or more than 30. non-obese subjects had normal blood pressure <18.66/11.99 kpa (<140 / 90 mmhg), normal oral glucose tolerance and within normal liver function tests. obese subjects had normal liver chemistry except 8 subjects (11.7%) with only alanine aminotransferase (alt) increased, which was less than 2 times the normal upper limit. there were nine subjects (13.2%) with blood pressure > 18.66/11.99 kpa (> 140 / 90 mmhg), eight subjects (11.7%) with impaired fasting glucose, two subjects (2.9%) with impaired glucose tolerance, and the rest had normal oral glucose tolerance. subjects were included with following criteria: age between 18 65 years, saudi nationals, normal blood urea nitrogen and serum creatinine, normal total bilirubin and no microalbuminuria (urine albumin to creatinine ratio less than 0.03 mg/mg in overnight early morning sample). subjects were excluded if they were diabetic, had abnormal hepatitis b or c serology, known liver disease, alcohol intake, medications, and current acute or chronic illness. the study was approved by the research and ethical committee of king faisal university and consent was taken from study subjects. height and weight was measured using detecto scale to the nearest 0.5 cm and 0.1 kg respectively. body mass index (bmi) was defined as the weight in kilograms divided by the square of the height in meters. waist circumference was measured at the highest point of the iliac crest and hip circumference measured at the maximum circumference of the buttocks. normal waist to hip ratio was < 0.9 for men and < 0.85 for women. a mean of two measurements of blood application to patient care • in patients with non-alcoholic fatty liver disease, gamma glutamyl transpeptidase has a stronger positive correlation to obesity than other hepatic enzymes in saudi adults. a s s e s s m e n t o f t h e r e l at i o n s h i p b e t w e e n h e pat i c e n z y m e s w i t h o b e s i t y a n d i n s u l i n r e s i s ta n c e i n a d u lt s i n s au d i a r a b i a 187 pressure at lying and sitting positions was calculated. serum glucose, total cholesterol, triglycerides, high-density lipoprotein (hdl)-cholesterol, blood urea nitrogen (bun), creatinine, serum albumin, total bilirubin, alanine aminotransferase (alt), aspartate aminotransferas (ast), gamma glutamyl transpeptidase (ggt), and alkaline phosphatase (alp) were measured by the dimension rxl analyzer (dade behring). serum insulin was measured by a microenzyme immunoassay using imx analyzer (abbott diagnostics). urine for micro-albumin was measured by a particle-enhanced turbidimetric inhibition immunoassay using the aca star analyzer by dade behring. a 75 g oral glucose tolerance test and early morning urine sample for microalbuminuria were carried out for all subjects. venous blood samples were obtained in the morning after 12 hours overnight fast. serum specimens were stored at 70c until analysis. normal ranges for liver chemistries in our hospital were total bilirubin 1.7 – 17.1 µmol/l, total protein 60 80 g/l, albumin 35 48 g/l, alt 20 65 u/l, ast 7 41 u/l, ggt 5 85 u/l, and alp 50 -140 u/l. a quality control program was carried out regularly in our laboratories including system check, quality controls, and calibrations/verifications according to system manufacturers’ instructions and recommendations. the sample size is based on assuming the worse acceptable probability of the adverse outcome: ‘elevated hepatic transaminases’ to be 20% in obese and 2% in non-obese adult individuals with a type ii error of 20% to achieve statistical significance at a confidence level of 95% and power of 80%. the least total number of obese and non-obese subjects would be 56 each. statistical analysis was performed using spss (statistical package for the social sciences) statistical software version 12.0. student t test, and mann-whitney test were carried out according to the results of levene’s test of homogeneity for equal variances as appropriate. pearson correlation coefficients were table 1: clinical and biochemical characteristics of all 136 study subjects. variable non-obese obese p value number of subjects 68 68 males (%) 34 (50%) 34 (50%) age (years) 24.6 + 3.7 28.8 + 6.9 <0.0001 body mass index 22.7 + 2.2 36.5 + 7.3 <0.0001 waist to hip ratio 0.796 + 0.094 0.885 + 0.083 <0.0001 systolic bp (kpa) 15.13 + 1.73 (113.5 +13.0 mmhg) 16.17 + 1.97 (121.3 + 14.8 mmhg) <0.007 diastolic bp (kpa) 9.53 + 1.12 (71.5 + 8.4 mmhg) 10.29 + 1.28 (77.2 + 9.6 mmhg) <0.002 albumin (g/l) 42.9 + 2.6 40.0 + 3.0 ns alt (u/l) 38.6 + 11.8 44.9 + 19.5 ns ast (u/l) 17.8 + 5.5 20.0 + 8.6 ns ggt (u/l) 24.3 + 8.9 33.6 + 16.4 <0.001 alp (u/l) 73.96 + 20.83 85.79 + 18.84 <0.004 homa-ir 2.09 + 1.4 3.86 + 1.9 <0.0001 insulin (pmol/l) 56 + 35 (9.35 + 5.85 µu/ml) 98 + 44 (16.36 + 7.32 µu/ml) <0.0001 fasting glucose (mmol/l) 4.9 + 0.3 (89.3 + 6.3 mg/dl) 5.2 + 0.6 (94.5 + 10.6 mg/dl) <0.005 total cholesterol (mmol/l) 4.40 + 0.73 (170.0 + 28.2 mg/dl) 4.76 + 0.84 (184.2 + 32.5 mg/dl) <0.023 triglyceride (mmol/l) 0.82 + 0.41 (72.9 + 36.2 mg/dl) 1.15 + 0.59 (101.6 + 52.6 mg/dl) <0.002 hdl-cholesterol (mmol/l) 1.47 + 0.40 (56.9 + 15.6 mg/dl) 1.29 + 0.33 (50.0 + 12.8 mg/dl) <0.02 values are means + sd; ns = not significant. legend: bp s= blood pressure; alt = alanine aminotransferase; ast = aspartate aminotransferase; ggt = gamma glutamyl transpeptidase; alp = alkaline phosphatase; homa ir = homeostasis model assessment of insulin resistance; hdl = high density lipoprotein a l i i b r a h i m a l -s u lta n 188 measured. results are presented as mean + standard deviation. r e s u l t s the clinical and biochemical characteristics of study subjects are shown in table 1. the obese subjects were significantly older than non-obese (p<0.0001). obese individuals had a mean age 28.8 + 6.9 years with a median 27.00 and a minimum and maximum age of 19 and 47 respectively. non-obese individuals had a mean age 24.6 + 3.7 years with a median 24.00 and a minimum and maximum age of 20 and 41 respectively. obese subjects had higher bmi, waist-to-hip ratio (whr), systolic and diastolic blood pressure ( p< 0.0001, <0.0001, < 0.007 and <0.002 respectively). the means of serum albumin levels were lower, and alt and ast levels were higher in obese individuals, but there was no significant statistical difference. the obese subjects had significantly higher ggt, and alp levels (p < 0.001 and 0.004 respectively). obese individuals had significantly higher fasting blood glucose, (p < 0.005). homa ir scores, and insulin were significantly higher in obese subjects (p <0.0001). total cholesterol, triglycerides, and hdlcholesterol were significantly higher in obese individuals (p <0.023, <0.002, and <0.02 respectively). table 2 shows correlations of liver function tests with clinical and biochemical variables. all hepatic enzymes (alt, ast, ggt, and alp) were associated with measures of obesity including bmi, and whr, but ggt had the strongest correlations with r 0.339, r 0.509 respectively, (p < 0.01). figure 1 shows the line graph of the correlation of alt, ast, and ggt with bmi. serum albumin was inversely associated with bmi r 0.426, (p < 0.01). systolic blood pressure correlated significantly with alt, ast, ggt, and alp, (p <0.01, <0.01, <0.01, and <0.01 respectively). diastolic blood pressure correlated significantly with alp, (p <0.05). alt, ast, and ggt correlated with measures of insulin resistance including homa ir, insulin, and fasting glucose. ggt had the strongest correlations with homa ir, and insulin r 0.481, r 0.476, respectively (p < 0.01). figure 2 shows the line graph of the serum albumin (g/dl) alt (u/l) ast (u/l) ggt (u/l) alp (u/l) body mass index 0.426 ** 0.263 ** 0.320 ** 0.339 ** 0.290** waist to hip ratio 0.041 0.302 ** 0.313 ** 0.509 ** 0.145 systolic blood pressure 0.117 0.263 ** 0.313 ** 0.369 ** 0.273** diastolic blood pressure 0.055 0.085 0.000 0.189 0.257* homa-ir 0.251 * 0.462 ** 0.354 ** 0.481 ** 0.143 insulin 0.279 ** 0.414 ** 0.318 ** 0.476 ** 0.146 fasting glucose 0.053 0.280 ** 0.278 ** 0.230 * 0.132 total cholesterol 0.039 0.204 * 0.150 0.295 ** 0.228* triglyceride 0.144 0.314 ** 0.206 * 0.493 ** 0.189 hdl-cholesterol 0.047 0.311 ** 0.285 ** 0.365 ** 0.118 * p < 0.05 and ** p value < 0.01 legend: alt = alanine aminotransferase; ast = aspartate aminotransferase; ggt = gamma glutamyl transpeptidase; alp = alkaline phosphatase; homa ir = homeostasis model assessment of insulin resistance; hdl = high density lipoprotein table 2: correlations of hepatic enzymes and serum albumin with the clinical and biochemical parameters of all 136 study subjects. a s s e s s m e n t o f t h e r e l at i o n s h i p b e t w e e n h e pat i c e n z y m e s w i t h o b e s i t y a n d i n s u l i n r e s i s ta n c e i n a d u lt s i n s au d i a r a b i a 189 correlation of alt, ast, and ggt with homa ir. alt, ggt, and alp correlated with total cholesterol. alt, ast, and ggt correlated with triglycerides, and inversely with hdl-cholesterol. serum albumin had significant negative correlation with homa ir, and insulin r 0.251, r 0.279 (p < 0.05 and <0.01 respectively). d i s c u s s i o n ggt and alp were significantly higher in obese than non-obese subjects, while alt and ast did not show a significant difference. alt, ast, and ggt correlated significantly with bmi. a similar significant correlation was found with whr and systolic blood pressure. homa-ir and serum insulin correlated significantly with alt, ast, and ggt. in various studies, aminotransferases, especially alt, have been shown to correlate with obesity,7-11, 27 and insulin resistance.7, 9, 12, 16, 27, 28 among hepatic enzymes, alt is the most specific indicator of hepatic pathology in non-alcoholic fatty liver disease. ggt is considered to be a sensitive marker of hepatic damage, but it is not specific especially in societies with abundance of alcohol intake. in this study, ggt had the strongest correlations for bmi r 0.339, whr r 0.509, systolic blood pressure r 0.369, insulin levels r 0.476, and homa ir r 0.481, compared to other liver enzymes. in addition, ggt correlated significantly with fasting glucose, total cholesterol, triglycerides, and inversely with hdl-cholesterol, r 0.230, r 0.295, r 0.493, r 0.365 (p <0.05, <0.01, <0.01, and <0.01 respectively). previous studies have shown positive correlation between ggt and measures of obesity and insulin resistance,2, 5, 6, 10, 13, 24, 30 and to predict diabetes mellitus.19-23 it is also reported to be increased in patients with ischaemic heart disease.5 the findings of this study and the literature suggest a major role of ggt in the manifestation of liver pathology associated with obesity and insulin resistance. in this study, alp correlated significantly with bmi, systolic and diastolic blood pressure, and tofigure 1: correlation of alanine aminotransferase (alt), aspartate aminotransferas (ast), and gamma glutamyl transpeptidase (ggt) with body mass index figure 2: correlation of alanine aminotransferase (alt), aspartate aminotransferase (ast), and gamma glutamyl transpeptidase (ggt) with homeostasis model assessment of insulin resistance (homa ir). a l i i b r a h i m a l -s u lta n 190 tal cholesterol. it had been reported to be higher in obese than non-obese subjects as has been observed in this study,3, 31, 32 without significant correlation with homa-ir. serum albumin showed significant inverse correlation with bmi, homa ir, and serum insulin. it has been reported that glycated albumin is associated negatively with obesity in non-diabetic children,25 and more recently in non-diabetic adults.33 glycated albumin is lower in obese diabetics,34 and correlates negatively with body mass index.35 the etiology of this observation is not yet known. in this study, a negative association between serum albumin and obesity was found. serum albumin level reflects the rate of synthesis, degradation, and volume of distribution. increase vasopermeability is suggested by literature reports of increase in albumin extravasation in skeletal muscles in the obese zucker rat model, 36 and as well by an increase in transcapillary escape rate of albumin in hypertensive patients with metabolic syndrome.37 endothelial dysfunction had been reported to be related to elevated alt levels among patients with diabetes mellitus.38 although microalbuminuria was not present in the study subjects as per inclusion criteria, it is another potential explanation and mechanism for the observed relationship of albumin and obesity. microalbuminuria is an established marker of cardiovascular disease and reflects vascular dysfunction as a manifestation of a proposed low grade inflammation associated with obesity and insulin resistance.39 obesity is an independent risk for microalbuminuria,40, 41 with the risk being parallel to changes in weight.42 c o n c l u s i o n in conclusion, alt, ast, and ggt correlated with measures of obesity, and homa-ir. ggt had the strongest correlations and might be a better marker of hepatic pathology associated with obesity, and insulin resistance in saudi and other subjects with no alcohol intake. serum albumin correlated inversely with bmi and homa-ir suggesting an altered metabolism or handling of albumin in obesity. a c k n ow l e d ge me n ts the research was performed at the colleges of medicine in al-ahsa and dammam, at king faisal university, saudi arabia. it was conducted during 2004-2005. it was funded by the deanship of research and the college of medicine in al-ahsa, at king faisal university. the author would like to thank dr. abdulmohsin al-elq, professor prem nath dogra, professor shahid baig, and professor amro heshmat rustem at the departments of internal medicine, surgery, and biomedical sciences at king faisal university, carmen lizardo, jacqueline manaois, purita cabinian, and issa jebreel from the laboratories of king fahd hospital of the university, for collection of data, review of manuscript and technical help. r e f e r e n c e s 1. hsiao tj, chen jc, wang jd. insulin resistance and ferritin as major determinants of nonalcoholic fatty liver disease in apparently healthy obese patients. int j obes relat metab disord. 2004; 28:167-172. 2. marchesini g, avagnina s, barantani eg, ciccarone am, corica f, dall’aglio e, et al. aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome. j endocrinol invest 2005; 28:333-339. 3. andersen t, christoffersen p, gluud c. the liver in consecutive patients with morbid obesity: a clinical, morphological, and biochemical study. int j obes 1984; 8:107-115. 4. luyckx fh, desaive c, thiry a, dewé w, scheen aj, gielen je, et al. liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. int j obes 1998; 22:222-226. 5. wannamethee g, ebrahim s, shaper ag. gammaglutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. am j epidemiol 1995; 142:699-708. 6. rantala ao, lilja m, kauma h, savolainen mj, reunanen a, kesäniemi ya. gamma-glutamyl transpeptidase and the metabolic syndrome. j intern med 2000; 248:230-238. 7. ruhl ce, everhart je. determinants of the association of overweight with elevated serum alanine aminotransferase activity in the united states. gastroenterology 2003; 124:71-79. 8. sattar n, scherbakova o, ford i, o’reilly ds, stanley a, forrest e, et al. elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and c-reactive protein in the west of scotland coronary prevention study. diabetes 2004; 53:2855-2860. 9. hanley aj, williams k, festa a, wagenknecht le, d’agostino rb jr, kempf j, et al. elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. diabetes 2004; 53:26232632. 10. wannamethee sg, shaper ag, lennon l, whincup ph. hepatic enzymes, the metabolic syndrome, and the a s s e s s m e n t o f t h e r e l at i o n s h i p b e t w e e n h e pat i c e n z y m e s w i t h o b e s i t y a n d i n s u l i n r e s i s ta n c e i n a d u lt s i n s au d i a r a b i a 191 risk of type 2 diabetes in older men. diabetes care 2005; 28:2913-2918. 11. west j, brousil j, gazis a, jackson l, mansell p, bennett a , et al. elevated serum alanine transaminase in patients with type 1 or type 2 diabetes mellitus. qjm 2006; 9:871-876. 12. vozarova b, stefan n, lindsay rs, saremi a, pratley re, bogardus c, et al. high alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. diabetes 2002; 51:1889-1895. 13. choi jw. association between elevated serum hepatic enzyme activity and total body fat in obese humans. ann clin lab sci 2003; 33:257-264. 14. kazumi t, kawaguchi a, hirano t, yoshino g. serum alanine aminotransferase is associated with serum adiponectin, c-reactive protein and apolipoprotein b in young healthy men. horm metab res 2006; 38:119124. 15. ardigo d, numeroso f, valtuena s, franzini l, piatti pm, monti l, et al. hyperinsulinemia predicts hepatic fat content in healthy individuals with normal transaminase concentrations. metabolism 2005; 54:1566-1570. 16oh sy, cho yk, kang ms, yoo tw, park jh, kim hj, et al. the association between increased alanine aminotransferase activity and metabolic factors in nonalcoholic fatty liver disease. metabolism 2006; 55:16041609. 17. hanley aj, williams k, festa a, wagenknecht le, d’agostino rb jr, haffner sm. liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. diabetes 2005; 54:31403147. 18. liangpunsakul s, chalasani n. unexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: results from the third national health and nutrition survey (nhanes iii). am j med sci 2005; 329:111-116. 19. perry ij, wannamethee sg, shaper ag. prospective study of serum gamma-glutamyltransferase and risk of niddm. diabetes care 1998; 21:732-737. 20. lee dh, jacobs dr, gross m, kiefe ci, roseman j, lewis ce, et al. gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the coronary artery risk development in young adults (cardia) study. clin chem 2003; 49:1358-1366. 21. lee dh, ha mh, kim jh, christiani dc, gross md, steffes m, et al. gamma-glutamyltransferase and diabetes a 4 year follow-up study. diabetologia 2003; 46:359-364. 22. nakanishi n, suzuki k, tatara k. serum gammaglutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged japanese men. diabetes care 2004; 27:1427-1432. 23. lee dh, silventoinen k, jacobs dr, jousilahti p, tuomileto j. gamma-glutamyltransferase, obesity, and the risk of type 2 diabetes: observational cohort study among 20,158 middle-aged men and women. j clin endocrinol metab 2004; 89:5410-5414. 24. ortega e, koska j, salbe ad, tataranni pa, bunt jc. serum gamma-glutamyl transpeptidase is a determinant of insulin resistance independently of adiposity in pima indian children. j clin endocrinol metab 2006; 91:14191422. 25. nishimura r, kanda a, sano h, matsudaira t, miyashita y, morimoto a, et al. glycated albumin is low in obese, non-diabetic children. diabetes res clin pract 2006; 71:334-338. 26. matthews dr, hosker jp, rudenski as, naylor ba, treacher df, turner rc. homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. diabetologia 1985; 28:412-419. 27. hanley aj, wagenknecht le, festa a, d’agostino rb jr, haffner sm.alanine aminotransferase (alt) and directly measured insulin sensitivity in a multi-ethnic cohort. the insulin resistance atherosclerosis study. diabetes care 2007; 30:1819-1827. 28. sung kc, ryan mc, kim bs, cho yk, kim bi, reaven gm. relationships between estimates of adiposity, insulin resistance and nonalcoholic fatty liver disease in a large group of nondiabetic korean adults. diabetes care 2007; 30:2113-2118. 29. wannamethee g, ebrahim s, shaper ag. gammaglutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. am j epidemiol 1995; 142:699-708. 30. yokoyama h, hirose h, moriya s, saito i. significant correlation between insulin resistance and serum gamma glutamyl transpeptidase (gamma-gtp) activity in non-drinkers. alcohol clin exp res 2002; 26:91s-94s. 31. ali at, paiker je, crowther nj. the relationship between anthropometry and serum concentrations of alkaline phosphatase isoenzymes, liver-enzymes, albumin, and bilirubin. am j clin pathol 2006; 126:437-442. 32. liu m, yan hm, gao x, gao j. association of abnormality of liver enzymes and metabolic syndrome in patients with nonalcoholic fatty liver disease. zhonghua yi xue za zhi 2007; 87:253-255. 33. koga m, otsuki m, matsumoto s, saito h, mukai m, kasayama s. negative association of obesity and its related chronic inflammation with serum glycated albumin but not glycated hemoglobin levels. clin chim acta 2007; 378:48-52. 34. miyashita y, nishimura r, morimoto a, matsudaira t, sano h, tajima n. glycated albumin is low in obese, type 2 diabetic patients. diabetes res clin pract 2007; 78:51-55. a l i i b r a h i m a l -s u lta n 192 35. koga m, matsumoto s, saito h, kasayama s. body mass index negatively influences glycated albumin, but not glycated hemoglobin, in diabetic patients. endocr j 2006; 53:387-391. 36. st-pierre p, bouffard l, papirakis me, maheux p. increased extravasation of macromolecules in skeletal muscles of the zucker rat model. obesity (silver spring) 2006; 14:787-793. 37. dell’omo g, penno g, pucci l, mariani m, del prato s, pedrinelli r.abnormal capillary permeability and endothelial dysfunction in hypertension with comorbid metabolic syndrome. atherosclerosis 2004; 172:383389. 38. schindhelm rk, diamant m, bakker sj, van dijk ra, scheffer pg, teerlink t, et al. liver alanine aminotransferase, insulin resistance and endothelial dysfunction in normotriglyceridaemic subjects with type 2 diabetes mellitus. eur j clin invest 2005; 35:369-374. 39. chugh a, bakris gl. microalbuminuria: what is it? why is it important? what should be done about it? an update. j clin hypertens 2007; 9:196-200. 40. chandie shaw pk, berger sp, mallat m, frolich m, dekker fw, rabelink tj. central obesity is an independent risk factor for albuminuria in “non-diabetic” south asian subjects. diabetes care 2007; 30:1840-1844. 41. hao z, konta t, takasaki s, abiko h, ishikawa m, takahashi t, et al. the association between microalbuminuria and metabolic syndrome in the general population in japan: the takahata study. intern med 2007; 46:341346. 42. bello ak, de zeeuw d, nahas me, brantsma ah, bakker sj, de jong pe, et al. impact of weight change on albuminuria in the general population. nephrol dial transplant 2007; 22:1619-1627. mjweb.indd  f-   ,  water, food and hands become contaminated with faecal material, and then come in contact with mouth, is the most common mode of gastrointestinal infections.1 studies indicate that parasitic infections aff ect the health of the population through malabsorption, diarrhoea, stunted growth in children and impaired work capacity.2–5 morbidity caused by enteric parasites has always been a public health problem, especially in the tropics. th e incidence and severity of intestinal parasitic infections may vary with place and time.6–9 estimates of prevalence usefulness of kato-katz and trichrome staining as diagnostic methods for parasitic infections in clinical laboratories *mohamed a idris, ayda m al-jabri department of microbiology and immunology, college of medicine, sultan qaboos university, p.o. box: , al-khod , muscat, sultanate of oman. *to whom correspondence should be addressed. midris@squ.edu.om. abstrac t. objectives: to assess the effi cacy of the kato-katz technique and to re-evaluate other routine procedures conducted in the microbiology clinical laboratory at sultan qaboos university hospital (squh) and to throw light on the prevalence of intestinal parasitic infections among a small group of food handlers in muscat. method: faecal samples collected from food handlers were examined using fi ve parasitological techniques. results: out of  faecal samples,  were positive for one or more of  intestinal parasites. the katokatz and trichrome stain methods were found superior to the other techniques in detecting helminthic and protozoan infections, respectively. the auramine stain was useful only in detecting cryptosporidium parvum oocysts. conclusion: a combination of trichrome stain and kato-katz techniques for stool examination is suffi cient and recommended for busy laboratories; auramine stain should be applied only to samples with suspected cryptosporidal infections. key words: kato-katz, wet preparation, concentration, trichrome and auramine stains, intestinal parasites, food handlers, oman. of intestinal parasitic diseases are at best extremely rough, especially in regions were these diseases are endemic, due to poor reporting.10 th e prevalence of intestinal parasites has been studied in many regions of oman, especially in dhofar.11,12 in a study conducted in  among adults and children in dhofar,  had parasites.13 studies of schoolchildren in muscat14 and in nizwa15 and of patients from musandam16 have shown percentage rates of , , and  respectively. recent studies from sur17 and ai-hamra wilayat18 also reported high prevalence. a survey among food handlers,     :   , : , : , – ©   :: . : .: . . .: .  mostly indians, revealed that . were infected with intestinal parasites.19 although numerous methods for diagnosing parasitic infections by stool examination are available, no single technique is satisfactory as none is equally applicable for trophozoites and cysts of protozoa, and eggs or larvae of helminths. for this reason, an optimum combination of two or more techniques of stool examination is desirable.6,10 accordingly, the objective of this study was to compare the sensitivity, reliability and practicability of the katokatz technique in detecting intestinal parasites, with the stool tests routinely performed at the clinical microbiology laboratory in squh, namely, the direct wet smear, concentration technique, trichrome stain and auramine-phenol staining, in order to recommend the most appropriate procedures. a subsidiary objective of this study was to throw light on the prevalence of enteric parasitic infections among a small group of food handlers in the capital city, muscat, because of the potential of transmitting these infections to the general population. m e t h o d s during january to march , stool samples of  food handlers, mostly indians, were collected in labelled plastic containers with covers at the communicable diseases centre in muscat. th e samples were investigated in the clinical microbiology laboratory, squh. each sample was subjected to the following fi ve diff erent techniques. . direct saline and iodine mount (wet preparation) an applicator stick was used to mix about  mg of faeces with one or two drops of normal saline or iodine placed on a clean slide. a uniform thin suspension was made and covered with a  mm square cover slip. th e entire fi lm was screened systematically for the presence of helminth ova and larvae or protozoan cysts and trophozoites. . formalin-ether concentration technique (fec) using an applicator stick, about  g of faeces was placed in a clean  ml conical centrifuge tube containing  ml formalin saline. th e sample was dissolved and mixed thoroughly with a vortex mixer. th e resulting suspension was fi ltered through a sieve into a beaker and the fi ltrate was poured back into the same tube. th e debris trapped on the sieve was discarded. aft er adding  ml of diethyl ether to the formalized solution, the contents were centrifuged at , rpm for  minutes. th e supernatant was poured away and the tube was replaced in its rack. iodine stain preparation was made. th e entire area under the cover slip was systematically examined using × and × objective lenses. . trichrome staining of faeces (gomori’s trichrome stain) about  g of faeces was placed into sodium acetate formalin (saf), mixed well and left overnight. th e contents were centrifuged at , rpm for  minutes. th e supernatant saf was poured off , the deposit re-suspended and replaced with normal saline, and then centrifuged for  minutes. a smear was prepared using an orange stick and a small drop of myer’s albumin to bind a drop of concentrated faeces to the slide. th e smear was dried for – minutes. th e prepared smear was then washed in  ethanol for  minutes and then in  ethanol for  minutes. th ereaft er the smear was stained with gomori’s trichrome for  minutes, diff erentiated in  ethanol for – seconds, and rinsed in  ethanol for  second. it was dehydrated in two changes of ethanol, each lasting  minutes. th e slide was cleaned twice in xylene, each time for  minutes, and mounted in dpx mounting medium with a large × mm cover slip. th e slide was left overnight before examining with the × oil immersion objective lens. . kato-katz technique, cellophane faecal thick smear a small amount of faecal material was placed on newspaper or scrap paper and a piece of nylon screen was pressed on top so that some of the faeces sieved through the screen and accumulated on top. a fl at-sided spatula was scraped across the upper surface of the screen to collect the sieved faeces. a template was placed on the slide and the sieved faeces was added with the spatula so that the hole in the template was completely fi lled. th e spatula was passed over the fi lled template to remove excess faeces from the edge of the hole. th e template was removed carefully so that a cylinder of faeces was left on the slide. th e faecal material was covered with a pre-soaked cellophane strip. th e slide was inverted and the faecal sample was pressed fi rmly against the hydrophilic cellophane strip to spread evenly. th e slide was placed on the bench with cellophane upwards to enable the evaporation of water while glycerol cleared the faeces. for all helminths, except hookworm eggs, the slide was kept for one or more hours at room temperature to clear the faecal material, prior to microscopic examination. . auramine-phenol staining th e air-dried faecal smear was fi xed for  minutes in absolute methanol and the slide was fl ooded with auramine for  minutes, washed in tap water and decolorized in  acid alcohol for a minimum of  minutes. th e slide was again              washed in tap water, stained with potassium permanganate solution for  minutes, washed and dried. th e slide was then examined under ultra/violet microscope to detect cryptosporidium oocysts that fl uoresce brightly against a dark red background. r e s u l t s out of the  stool samples,  were positive for one or more species of  intestinal parasites ( helminths and  protozoa). th e prevalence and percentages of parasites among food handlers obtained by using the fi ve procedures are shown in table . ascaris lumbricoides showed the highest overall prevalence (), followed by blastocystis hominis (), trichuris trichiura (), hookworm (), giardia lamblia and entamoeba coli ( each), endolimax nana (), cryptosporidium parvum, dientamoeba fragilis and iodamoeba butschlii () each and entamoeba histolytica (). single, double and multiple (– species of parasites) infections showed positive rates of , , and , respectively. out of the  cases of ascariasis recovered by kato-katz during this study, direct smear and fec recovered  and  cases, respectively. out of  cases of trichiurasis recovered by kato-katz,  and  cases were recovered by direct smear and fec, respectively. out of  hookworm cases recovered by each of kato-katz and fec, one case was recovered by direct smear. th e two cases of cryptosporidium were recovered only by auramine stain. th e kato-katz technique and auramine stain did not recover any other protozoan species, which were all partly recovered by trichrome stain, direct smear and fec methods. table  shows that the total number of helminthic infections was . all of them were detected by kato-katz followed by the fec () and direct smear (.). out of the  protozoan infections,  () were recovered by trichrome stain,  () by fec and  (.) by smear wet preparation. d i s c u s s i o n many pathogenic intestinal parasites are transmitted through the faecal-oral route. since unhygienic preparation, storage and handling of food by infected individuals are a major cause for food-borne diseases, food handlers need to be screened before they are allowed to work in food establishments such as restaurants, hotels, food stores, factories or as helpers and cooks in private houses. unfortunately, such screening is not simple, since no single technique of stool examination detects cysts and trophic forms of protozoa and helminth eggs or larvae equally well. as our results indicate, a combination of two or more techniques is more likely to be eff ective. our results indicate that the kato-katz technique is more sensitive for detecting helminthic parasites, followed by the fec technique and the smear wet preparation. th ese fi ndings agree with those of previous studies that showed the kato-katz technique to be an effi cient means of diagnosing intestinal schistosomiasis and intestinal helminths.20 auramine stain was useful only in the detection of cryptosporidium oocysts. th e trichrome stain was superior to all other procedures in the detection of cysts and trophozoites of protozoa. trichrome stain detected comparatively high numbers of seven diff erent species of protozoa while fec and direct smear could detect only small numbers of four protozoan species [table ]. trophozoites can be diffi cult to detect in faeces particularly when they are no longer motile and the cysts may be confused with pus cells or macrophages. th e use of gomori’s trichrome stain helps to overcome these problems and greatly assists in distinguishing between pathogenic and non-pathogenic entamoeba. furthermore, some parasites such as d. fragilis may only be seen using a staining procedure.20 th is study generally revealed low prevalence for all intestinal parasitic infections, especially for ascariasis, hook worm and trichiurasis which are considered to be the most prevalent in man, especially in developing countries.6,21-23 - table 1. number of parasites recovered from 100 faecal samples using five different techniques techniques used for parasite identification parasite total cases wp fec trich auram kato a. lumbricoides 24 9 15 24 t. trichuria 9 3 6 9 hookworm 7 1 7 7 g. lamblia 6 1 2 4 e. histolytica 1 0 0 1 e. coli 6 4 4 6 i. butschlii 2 0 0 2 b. hominis 17 1 0 17 d. fragilis 2 1 1 2 e. nana 6 0 1 6 c. parvum 2 2 wp: direct saline and iodine mount (wet preparation), fec: formalin-ether concentration technique, trich: trichrome staining of faeces, auram: auramine-phenol staining, kato: kato-katz technique  however, the small sample inspected in this study may not represent the whole community of food handlers in oman. it is also possible that some of our subjects had been inspected and treated in their home countries before travelling to oman, or in oman before they came for screening, which may account for the low infection rates. inspection and treatment of food handlers are necessary to reduce food borne infections and should be an integral part of public health education. we recommend that whenever possible more than one parasitological technique should be used in screening faecal samples before an individual can be considered free from intestinal infection. we also suggest that all food handlers should particularly be screened using multiple parasitological techniques and, if found infected, should be eff ectively treated before they are licensed, and re-examined annually. c o n c l u s i o n th e current fi ndings show that the kato-katz and trichrome stain are superior to other stool examination techniques for detecting helminthic and protozoan infections, respectively, and the authors recommend them for the clinical laboratory. th e auramine stain method should be used only when cryptosporidium is suspected. th e study also stresses the need to screen individuals, and particularly food handlers, using a combination of parasitological techniques before they can be considered free from enteric parasites. r e f e r e n c e s . arcari m, baxendine a, bennett ce. infections acquired through the gastrointestinal tract. http://www.soton.ac.uk/~ceb/ diagnosis/vol.htm. . tripathy k, dnque e, balanes o, lotero h, mayord, lg. malabsorption syndrome in ascariasis. am j clin nutr , , –. . arayat g, gignera g, espinosa j, montesinos n, spencer e, burnser g. acute diarrhoeal disease in children under  years of age in periurban slum of santiago, chile. j hyg , , –. . cooper es, bundy da, henry fj. chronic dysentery, stunting and whipworm infestation. lancet , , –. . world health orgn. prevention and control of intestinal parasitic infections. geneva: who, technical report no. , . . peters w. medical aspects—comments and discussion today. taylor aer & muller r (eds.) oxford: black well scientifi c publications, . . rawlins sc. changing patterns in the prevalence of intestinal parasites at the hospital of the west indies (–). west indies med j. , , –. . world health organization. manual of basic techniques for a health laboratory, a. . world health organization. prevention and control of intestinal parasitic infections. report of who expert commitee in geneva, – march b. . markell ek, voge m, john di. medical parasitology (th ed) philadelphia: wb saunders co, . . idris ma, shaban ma. changing patterns of intestinal parasitic infections among schoolchildren, outpatients and food handlers in salalah, dhofar. med newsletter oman. , , –. . idris ma, ruppel a, de carneri i, shaban ma, al wey sa, jayawardene cr et al. high prevalence and intensity of hook worm infection in the dhofar governorate, omanann trop med parasitol , , –. . idris ma, ruppel a, shaban ma, mehta f, al-aufy sam, badesab b, mohamed aj. study on intestinal parasitic infections in dhofar region, community health and disease surveillance newsletter , , –. . idris ma al-aufy sam. intestinal parasitic infection among schoolchildren in muscat, sultanate of oman. medl newsletter oman. , , –.  idris ma, al-aufy sam. intestinal parasitic infections among schoolchildren (– years old) in nizwa, sultanate of oman. med newsletter oman , , –. . florendo era. study of the prevalence of human intestinal parasites found in khasab, musandam province med newsletter oman , , –. . floredo er. pathogenic human intestinal parasites prevalent in sur, south sharqiya region: a six-year study. oman med j , , –. . al-shishtway mm, nanay am. intestinal parasitic infections, anaemia and underweight among -year-old schoolchildren in al hamra wilyat. oman med j , , –. . idris ma, al-awfy sam. parasitic infections in a pre-screening of food handlers in the sultanate. med newsletter oman , , –. . elkins db. a survey of intestinal helminths among children of diff erent social communities in madras, india. trans royal soc trop med hyg , , –. . belding, dl. text book of parasitology. (rd ed) meredith publishing co., new york . . bundy dap, th ompson de, golden mhn, copper es, anderson rm, harland pse. population distribution of trichuris trichiura in a community of saimacan children. trans roy soc trop med hyg , , –. . ilardi i, shurri cs, mohamed hh, hussein sa, mohamed sc, sebastia a, et al. prevalence and intensity of intestinal parasites in two somalian communities. trans roy soc trop med hyg , , –.             2008-issue1.indd re: our efforts are reflected in our health sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 103 sultan qaboos university© received 24th december 2007 to the editor, i write in response to your message from the editor-in-chief, ‘our efforts are reflected in our health’ which appeared in the august 2007 issue of squmj.1 i would like to make certain comments which are very much pertinent to the world in general and oman in particular. you have very rightly mentioned the fact that perhaps no other country in the world has achieved so much in so little a time in terms of health care. full credits to our achievement, but even more important now is the challenge to preserve and maintain this achievement and not allow other problems to take root. this can only happen if we are careful about our habits and lifestyle and do not accept everything without question from the west. the statistics of the oman national health survey 2000 show widespread health risks, all related to affluence and life style: high waist-hip ratio 49.1%; hyper-cholesterolemia 40.6%; overweight 28.9%; hypertension 21.5%; obesity-17.3%; diabetes 11.6%.2 the promise made by his majesty sultan qaboos bin said in his first address to the nation in 1970, that health would be one of his two top priorities, has been only partly translated into reality. it is now necessary for the people of this country to be aware of health issues and act responsibly so as to maintain this achievement and make it a full reality. you said that the who study of 2000 ranked oman eighth in the world for providing comprehensive health care. the word comprehensive entails three things, priority-wise they are: prevention, promotion and then cure. we need to look deeper into the first two aspects as our statistics say something else. our real goals and needs are to prevent and decrease diseases, but statistics show an increasing trend. our hopes and aspirations and our children who are our future citizens and workforce, and form 38% of our total population, are falling prey to many preventable risks, putting them in danger as parents, as adults and later in old age. can’t we do something urgently for this new, large and rapidly growing generation? you said that oman has largely achieved self-sufficiency with respect to health care. we should not take pride in this achievement because, if we do not control our lifestyle, our health statistics show that we are going to overburden our health services with increased demands and increased costs, making it necessary again for many omanis to go abroad for treatment. r e fe r e n c e 1. al lamki l. our efforts are reflected in our health message from editor-in-chief. squ medical journal 2007; 7:189190 2. oman national health survey 2000. muscat: ministry of health, 2001. mushtaq a khan department of family medicine and public health college of medicine & health sciences sultan qaboos university sultanate of oman l e t t e r t o t h e e d i t o r whole1.indd abstract objective: to analyse the pattern of patients attending the out patient department (opd) during the hajj season 423h with respect to their age, sex, nationality, services provided to them, and most importantly the disease trends and the medication given. method: a descriptive study was done at the opd department in al-noor specialist hospital, holy makkah for the 5 days period of the hajj, i.e., -5 /2/423 corresponding to 2-6/ 02/2003. all patients who arrived at the opd during that time whether on hajj or non-hajj and those who registered at opd service became part of our study. with the help of standard “blue form”(provided annually by ministry of health exclusively for the opd patients for every hajj season), their age, sex, nationality, clinics attended, diagnosis and medications were noted. results: the results revealed that 3876 patients arrived and 3856 got registration at opd. of the registered cases, 282 (33%) were hajj patients and of those 873 (22%) were males. the hajj patients were mostly non-saudi (30.8%). the majority of patients, 384 (26.%), were from the middle east. the largest category, 240 (6.2%), of hajj patients were in the age range 5-60 years. the medical clinic was the one attended by the maximum number of patients, 675 (43.4%), and respiratory disease cases, 582 (4%), were the commonest. single medication as monotherapy accounted for 3644 (94.5%) of patients. conclusion: non-hajj patients were in the majority at opd. respiratory diseases were the commonest complaints. this study highlights a precarious situation during the hajj where cross-infection proliferates in a dense population. effective services and preventative measures need to be contemplated in the light of the present finding. key words: hajj, hajj season, out patient department (opd), ministry of health (moh), antibiotics. outpatient services during (423h) hajj season *haani a s shakir, zohair j gazzaz, khalid o dhaffar and javeria shahbaz sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© hajj is a islamic pilgrimage of muslims, when around two million muslims gather for a period of about six weeks between the holy cities of makkah and medina in kingdom of saudi arabia (ksa).1 the hajj season is the time of maximum population in every sector of life in saudi arabia especially the holy makkah region. the medical services are one of the most affected sectors of the administration of the holy capital. as hajj has to be completed in a specified period of time, and many of the pilgrims use their lifetime savings for this purpose, they are often reluctant to seek early medical advice as health research centre, al-noor specialist hospital, p.o. box 6251, holy makkah, kingdom of saudi arabia *to whom correspondence should be addressed. email: hrd_alnoor@yahoo.com o r i g i n a l s t u d y (١٤٢٣ للهجرة) احلج موسم اخلارجية خالل العيادة خدمات باجلنس، يتعلق فيما للهجرة ١٤٢٣ لسنة احلج موسم خالل اخلارجية العيادة قسم راجعوا الذين املرضى نوع حتليل و دراسة الهدف: امللخص: اخلارجية العيادة قسم في الوصفية الدراسة هذه الطريقة: أجريت العالج. ونوع األمراض نزعة ذلك من أهمية املقدمة، واألكثر واخلدمات اجلنسية، كل .٢٠٠٣ /٢/ ٢-١٦ من املوافق /١٤٢٣ للهجرة ١٢/ ١-١٥ من أي ١٥ يوما، البالغة احلج فترة خالل مبكة املكرمة التخصصي مستشفى النور في سجلنا البحث. هذا مادة شكلوا العيادة تلك في سجلوا والذين غيرهم من أو احلجاج من كانوا سواء اخلارجية العيادة إلى قدموا الذين املرضى وزارة قبل من اهزة -القياسيةالزرقاء االستمارة في والعالج والتشخيص زيارتها مت التي والعيادة واجلنسية واجلنس بالعمر املتعلقة املتغيرات ٣٨٥٦ سجلوا وأن املستشفى زاروا ٣٨٧٦ مريضا أن النتائج النتائج: أظهرت احلج. مواسم في العيادة اخلارجية ألقسام فقط واصصة الصحة سنويا السعوديني غير من احلجاج املرضى معظم الذكور. من (٪٢٢) ٨٧٣ احلجاج، منهم من كانوا (٪٣٣) ١٢٨٢ هؤالء املسجلني، من اخلارجية. العيادة في العيادة حصلت ٥١-٦٠ سنة. بني (٪٢٢ مريضا ٢٤٠) انتشارا األكثر مدى العمر كان .(٪٢٦٫١) ٣٨٤األوسط دول الشرق من والغالبية .(٪٣٠٫٨) .(٪٤١ -١٥٨٢) انتشارا األكثر التنفسي اجلهاز حاالت كانت بينما ، (٪٤٣٫٤ (١٦٧٥مريضا املرضى من عدد أكبر على الباطنية لألمراض اخلارجية أن غريبا وليس احلجاج، غير من اخلارجية العيادة زاروا الذين املرضى غالبية كانت اخلالصة: .(٪٩٤٫٥ -٣٦٤٤) كان األكثر شيوعا بدواء واحد العالج ٪٥٫٥ فقط . املضادات احليوية هي وصفا األكثر األدوية غيرها. من األكثر انتشارا كانت األمراض التنفسية .١:٨ غيرهم إلى السعوديني املراجعني نسبة أو السعوديني غيرهم من أما فقط، للحجاج مخصصة احلج موسم في تكون اخلدمات أن السبب نوصي لهذا دواء. من أكثر استخدموا املرضى من كاهل املستشفيات التخفيف عن إلى وجهة نظرنا سيساعد من هذا اخلفيفة. احلاالت لعالج األولية الصحية املراكز مراجعة فاألفضل احلجاج غير الرعاية املطلوبة. تقدمي في كفاءتها على إيجابا ما سينعكس وهذا الساعة مدار على اخلدمات تقدم التي الكبيرة h a a n i a s s h a k i r , z o h a i r j g a z z a z , k h a l i d o d h a f fa r a n d j av e r i a s h a h b a z 48 this might affect their tight time schedule. when they do seek medical advice, they are always in a hurry to leave the hospital so as to avoid missing any of the hajj rituals.2 ,3 so the percentage of illnesses increases during the hajj season. even the ksa residents who are not performing the hajj also suffer perhaps due to the population increase and cross-infection. m e t h o d al-noor specialist hospital is one of the largest and most renowned tertiary care hospitals in the western region of the ksa. this study was conducted in the opd of al-noor hospital for a period of 15 days i.e., 1st of dhu al-hijjah 1423 hejre to 15th of dhu al-hijjah 1423 hejre (2-16 february 2003). all the cases either coming directly or referred from other primary or secondary health care units to opd were included. the data was collected from the standard “blue form” which was provided annually by ministry of health (moh) for every season. these forms were collected, the data was processed and then analyzed on a daily basis. the information includes the age, sex, nationality, diagnosis, referred clinic and the prescribed medications. r e s u l t s approximately 3876 patients arrived at opd for that period of hajj and 3856 patients got registrations. only 20 (1%) were not registered because these patients could not get the standard “blue form” or for some other reason. thus we interpreted the data of registered opd (n=3856) patients. table 1 shows that, of 3856 patients, 1282 (33%) were hajj patients and 2574 (67%) were non hajj patients. among the hajj patients 837 (22%) were males and 445 (11%) patients were females showing the ratio of 2:1 respectively. in non hajj patients, males dominate over females (1536 (40%) males, and 1038 (27%) females). the opd pacharacteristics hajj patients non-hajj patients total n=1282 % n=2574 % n=3856 % sex male 837 22 1536 40 2373 62 female 445 11 1038 27 1483 38 nationality saudi 38 1 2175 56.4 2213 57.4 non saudi 1191 30.8 281 7.3 1472 38.2 unknown 53 1.4 118 3.1 171 4.4 age in years <1 1 0.0 34 0.9 35 0.9 1-25 150 3.9 1020 26.5 1170 30.3 26-30 104 2.7 386 10.0 490 12.7 31-35 134 3.5 154 4.0 288 7.5 36-40 161 4.2 247 6.4 408 10.6 41-45 190 4.9 289 7.5 479 12.4 46-50 194 5.0 197 5.1 391 10.1 51-60 240 6.2 146 3.8 386 10 61-65 71 1.8 81 2.1 152 3.9 >65 37 1.0 20 0.5 57 1.5 * age groups confined to “blue form” officially table 1. demographic data of 3856 registered outpatients during hajj 1423h regions of the world hajj pts non-hajj pts total n % n % n % middle east 384 26.1 58 3.9 442 30.0 subcontinent 268 18.2 142 9.6 410 27.9 south east asia 147 10.0 49 3.3 196 13.3 arabian gulf 190 12.9 5 0.3 195 13.2 sub sahara 120 8.2 25 1.7 145 9.9 former soviet union 41 2.8 1 0.1 42 2.9 western countries 41 2.8 1 0.1 42 2.9 total 1191 80.9 281 19.1 1472 100 table 2. regional distribution of non saudi, hajj & non hajj outpatients during hajj season 1423h o u t pat i e n t s e r v i c e s d u r i n g ( 1 4 2 3 h ) h a j j s e a s o n 49 tients’ nationality question revealed that 2213 (57.4%) were saudi. among the saudia, 38 (1.0%) were hajj patients and 56.4% were non hajj patients, whereas in non-saudi patients 1191(30.8%) were hajj patients and 2819 (7.3%) were non hajj patients. the age of the patients was recorded according to the age groups in the “blue form”. among the hajj patients, the largest category, 240 (6.2%), was in the age group 51-60 and among the non-hajj patients the majority, 1020 (26.5%), were in the younger age group 1-25, as shown in table 1. the nationalities of non-saudi cases were classified into seven groups according to geographical zones: middle east, indo-pak subcontinent, south east asia, gulf and arabian peninsula, african countries, western countries and russian states. the majority, 442 (30%), were from the middle east as shown in table 2. table 3 presents the different clinics attended by hajj and non-hajj patients. the maximum load was on the medical clinic with 1675 (43.4%) patient visits and the least burden was on the psychiatry clinic. as to the diseases or diagnoses found, the largest number of patients came with respiratory diseases, 1582 patients (41%), and the smallest number with diseases of the ear and mastoid process, 67 patients (1.7%). there were 21 groups of diagnosis according to the cd 10 coding system. the ten diagnoses with more than 1% patients are shown in table 4. last but not least, the medications given by the opd doctors were also noted. the medicines recommended in the “blue form” provided by the ministry were dispensed. the data collected for medication revealed that 3644 (94.5%) patients used medicine as a single therapy. looking into individual medicines, the most commonly used were antibiotics and then analgesics in descending order as shown in table 5. the remaining 5.5% patients were using medicines in combination of two or more than two drugs. d i s c u s s i o n our study was of short duration and restricted to opd but it gives a reflection of the pattern of patients durclinics attended by pts hajj patients non-hajj patients total n % n % n % medical 636 16.5 1039 26.9 1675 43.4 ear, nose and throat 148 3.8 245 6.4 393 10.2 orthopedic 148 3.8 159 4.1 307 8.0 a.k.u 126 3.3 573 14.9 699 18.1 dermatology 78 2.0 108 2.8 186 4.8 general surgery 58 1.5 82 2.1 140 3.6 dental 39 1.0 81 2.1 120 3.1 obstetric 23 0.6 38 1.0 61 1.6 paediatric 17 0.4 229 5.9 246 6.4 psychiatric 9 0.2 20 0.5 29 0.8 total 1282 33.2 2574 66.8 3856 100 table 3. hajj & non-hajj outpatients in different clinics during hajj season 1423h sn icd-10 codes diagnosis hajj pts non-hajj pts total n % n % n % 1 j00-j99 diseases of respiratory system 570 14.8 1012 26.2 1582 41.0 2 n00-n99 diseases of genitourinary system 115 3.0 635 16.5 750 19.5 3 s00-t98 injury, poison & certain other consequences of extra cause of death 113 2.9 113 2.9 226 5.9 4 l00-l99 diseases of skin & soft tissue 99 2.6 174 4.5 273 7.1 5 k00-k93 diseases of gastro intestinal tract 92 2.4 169 4.4 261 6.8 6 m00-m99 diseases of musculoskeletal syst & connective tissue 83 2.2 93 2.4 176 4.6 7 r00-r99 symptoms, signs & clin/lab findings not elsewhere classified 60 1.6 92 2.4 152 3.9 8 i00-i99 disease of circulatory system 35 0.9 86 2.2 121 3.1 9 a00-b99 infectious & parasitic diseases 26 0.7 63 1.6 89 2.3 10 h60-h95 disease of ear & mastoid process 19 0.5 48 1.2 67 1.7 diagnosis with < 1% cases 70 1.8 89 2.3 159 4.1 total 1282 33.2 2574 66.8 3856 100 table 4. outpatients according to diagnosis during hajj season 1423h h a a n i a s s h a k i r , z o h a i r j g a z z a z , k h a l i d o d h a f fa r a n d j av e r i a s h a h b a z 50 ing the hajj season. it is based on a standard form provided officially. it highlights the personal as well as the hospital data of each patient. it displays the services of al-noor hospital for hajj pilgrims that could be compared with other hospitals in makkah. it also gives us a picture of different nationalities of hajj patients, male dominancy and also the dominancy of non-hajj patients over hajj patients especially on different clinics of opd. the age group 51-60 years of hajj patients correlates to the fact that muslims from most of the nationalities perform hajj after fulfilling their liabilities, such as marriages of their daughters etc. there were more patients from middle east, compared to other regions of the world, due to its close ness to holy makkah. our study highlights the percentage of various medical problems as compared to other studies.4,5,6 up to twenty years ago, cholera was the main cause of morbidity and mortality among pilgrims.7 even recently, gastroenteritis was responsible for 76% of hospital admission.8 now pneumonia infection in patients needs hospitalization.9 this time the hajj occurred during winter so our study shows a large number of respiratory illnesses. unfortunately, the data only shows the number of respiratory illnesses, not the specific diseases of the respiratory system. among medications most commonly used were the antibiotics that reflect the preponderance of respiratory cases. this finding should be taken into account for future hajj. acknowledgements we are eternally grateful for the services of female staff (umairah, fatima, nur insan, merly and jerinia) from the medical records department. r e f e r e n c e s 1. yousaf m, chaudry s. diabetic ketoacidosis in pilgrims visiting madina al-munawarah, saudi arabia. int diabetes digest 8: 14-16. 2. elhassan om, hameed mis. the pattern of general surgical problems among pilgrims admitted to king fahad hospital: madinah al-munawarah in 1987. saudi med j 1990; 4: 290-292. 3. yousaf m, zafar mo, maqbool m. medical problems of pakistan pilgrims in saudi arabia. pak j med res 1993; 32: 172-175. 4. fatani mi, al-afif ka, hussain h. pattern of skin diseases during hajj season in makkah, saudi arabia. int j dermatol 2000; 39: 493-496. 5. al-harthi as, al-harbi m. accidental injuries during muslim pilgrimage. saudi med j 2001; 22: 523-525. 6. khogali m. epidemiology of heat illness during the makkah pilgrimage in saudi arabia. int j epidemiol 1983; 12: 267-273. 7. rahim ma. pilgrimage and cholera epidemic in saudi arabia: a bibliographic survey from 1813-1979. hamdard medicus 1986; 29: 121-125. 8. ghaznawi o. health hazards and risk factors in the 1406h (1986) hajj season. saudi med j 1988; 9: 274282. 9. yousaf m, al-saudi daa, sheikh ra, lone ms. pattern of medical problem among hajj pilgrims admitted to king abdul aziz hospital, madinah al-munawarah. ann saudi med 1995; 15: 619-621. sn names of drug categories single therapy % 1 antibiotics 1669 43.3 2 analgesics and anti-pyretics 972 25.2 3 medication for *(ihd , crf, cns disorder) 610 15.8 4 miscellaneous drugs, medications other than for ihd, crf&cns disorders 393 10.2 total 3644 94.5 ihd ischemic heart disease crf chronic renal failure cns central nervous system disorder table 5. the most common medications dispensed during the hajj 2008-issue1.indd fundamentals of development the psychology of childhood sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 101-102 sultan qaboos university© submitted 2nd january 2007 as an introductory developmental psychology text, fundamentals of development achieves a passing grade. the authors adopt a topicbased approach which, though promoting the material’s accessibility to students, seems incomplete, disjointed and lacking in organisation. the text maintains a solidly cognitive approach, but it fails to assert the interactions among the biological, social and cultural influences present in each aspect of development. in terms of accessibility, the language used in this text is simple and presented conversationally. though this may appeal to introductory students, it often reduces the power of the theories being discussed, and allows the authors to pass judgements which may be considered inappropriate at this level of foundation. the simple and repetitive language may be an advantage to students who do not have english as their native language, but must be balanced with the fact that this often reduces the explanatory power of the presented theories. each chapter begins with chapter aims, and concludes with suggested further reading followed by a brief summary, which varies in depth and helpfulness depending on the chapter. key words are also provided, defined in the margins and in the glossary. conspicuously absent at the ends of the chapters are outlined reviews of the central themes, theories and terms. these are both conducive to a student’s initial learning of the concepts, and to his examination preparation. this text would also benefit from charts comparing theories and highlighting different theories’ strengths and weaknesses; a study aid frequently found to be useful for students. the organization of the book also leaves quite a lot to be desired. each chapter in this text is self-contained, but there is very little continuity between chapters or effort at linking ideas. it would appear that the chapters are meant to be used individually and perhaps not necessarily in the order in which they are presented in the book; this may be confusing to students. for example, the introductory chapter briefly presents, then quickly dismisses freud’s theory of development as “perverse,” and does not directly refer to it again until towards the end of the text, between chapters on parenting and moral development. there the authors return to freud’s stages of development and personality theory in التطور اساسيات نفس الطفولة علم زيجلر فينجا و ميتشل املؤلفون: بيتر authors: peter mitchell, fenja ziegler publisher: psychology press, taylor francis group. published 2007 . isbn: 978-1-84169-644-7 available at: www.psypress.com b o o k r e v i e w b o o k r e v i e w : f u n d a m e n ta l s o f d e v e l o p m e n t 102 greater detail, devoting an entire chapter to these topics and again refuting them. this fractured presentation makes it difficult for the authors to maintain a coherent narrative of the progression of developmental psychological research. the book ends with a chapter on aggression and provides no real conclusion chapter to wrap up the text or to incite the student to further study. there is no chapter addressing the implications of developmental research or new directions in contemporary work. the authors’ piecemeal presentation of the material in this book makes it seem more appropriate for supplementary use than as a core text in the classroom. although this book dabbles in several central areas of developmental psychology, covering the major theories albeit some quite briefly it often lacks the grounding and comparative substance necessary to tie the ideas together. the text provides a number of illustrated examples to demonstrate each of the groundbreaking experiments which advanced understanding of the discipline, but provides no introduction to the research methods of developmental psychology. there are a few elements of modern psychology that this book does not deeply consider. one of these is prenatal development: there is almost no consideration of the biological developments that accompany the cognitive developments addressed. another weakness of the text is the lack of recognition of recent findings surrounding the effects of cultural and racial factors beyond a mention of racial differences in iq and aggression due to environment. in addition, there is very little discussion about the range of developmental disorders beyond autism. a number of theoretical perspectives are also not mentioned: psychosocial theories, socio-historical theories and dynamic systems theories to name several. in conclusion, although this text does an excellent job of illustrating and explaining many of the major studies that brought advances in our understanding of psychological development, it lacks the cohesiveness and broad-spectrum approach that would make it a good introductory text for independent use. it is much better as a companion piece to a fuller text, so that its chapters can be used to flesh out concepts with examples and easy, conversational language. r e v i e w e r liyam eloul department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; stanford university, usa email: leloul@squ.edu.om oxygen therapy is a widely used treatment modality which, when administered correctly, can be life-saving. published data have demonstrated that a large proportion of doctors and nurses have been unable to accurately follow the proper methods for administration of oxygen.1,2 administration of oxygen through cold bubble humidifiers is part of the generic approach to acute respiratory failure due to a whole host of causes, especially in poorly resourced health systems.3,4 this article attempts to systematically challenge the age-old practice of cold bubble humidification by questioning the norm of prescribing ‘moist oxygen’ to all patients irrespective of oxygen flow rate. to establish our views, we have elucidated the concepts of low-flow and high-flow oxygen therapy, the physiology and physics of humidification and the risks of infections associated with cold bubble humidifiers. finally, we have concluded that cold bubble humidifiers are unable to meet the physiological needs of the upper airway, thereby rendering them far less effective when compared to heated humidifiers. low flow and high flow oxygen oxygen delivery systems have always remained a critical component of patient care both in hospitals or otherwise.3 devices for the delivery of medical oxygen can be broadly categorised on the basis of oxygen flow rates into high-flow and low-flow devices. the required flow rate is determined for individual patients on the basis of their peak inspiratory flow rate, which in turn is dependent on each patient’s pre-existing respiratory ailment.3 low-flow oxygen therapy devices are also known as variable performance devices.4 these devices deliver a variable fractional inspired concentration of oxygen (fio2) according to the variations in minute ventilation (variations in tidal volume, respiratory rate and inspiratory flow) of a patient. although the device delivers 100% oxygen to the upper airway, the final fio2 delivered is the result of mixing variable amounts of inhaled room air.5 severely breathless adult patients often generate inspiratory flows of greater than 40–60 l/min. as the low flow devices usually supply oxygen at flow rates (maximum 15 l/min in india) lower than the dyspnoeic patient’s inspiratory demand, a variable amount of room air is required to achieve the required flow.3,4 therefore, fio2 in inspired air varies substantially. examples of commonly used low-flow or variable performance oxygen therapy devices are nasal cannulae, simple face masks and partial rebreathing and non-rebreathing reservoir masks.5 high-flow or fixed performance devices such as air entrainment masks, large volume nebulisers and high-flow nasal cannulae (hfnc), provide oxygen at flow rates adequate enough to meet the inspiratory demands of the patient.5,6 these devices blend 100% oxygen with room air to produce a final inspired gas with the desired fio2. they also provide an inspiratory flow high enough to exceed any tidal volume, respiratory rate and inspiratory flow a breathless patient might usually generate, thereby preventing dilution of fio2 by entrained room air. therefore, highflow, fixed-performance devices deliver a predictable fio2. hfnc are always used with heated humidifiers. the delivered concentration and flow of oxygen affect the final fio2 and they can be controlled independently in some devices. however, direct caregivers should be cautious that even with these devices, the fio2 can be reduced if the inspiratory flow of an occasionally severe dyspnoeic patient exceeds the device’s total flow output. with the emergence of the covid-19 pandemic, the potential of hfnc as an alternative to standard oxygen therapy and non-invasive ventilation (niv) has been revisited with special interest across the globe. guy et al. in a monocentric study concluded that hfnc was effective in managing covid-19 patients in an intensive care unit setting.7 a study of moderate to severe covid-19 patients by geng et al. suggested that the administration of hfnc reduced the rate of intubation and improved the clinical outcome in type 1 acute respiratory failure.8 departments of 1critical care medicine and 2internal medicine, rg kar medical college and hospital, kolkata, india *corresponding author’s e-mail: chandraatanu123@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. cold bubble humidification of oxygen old habits die hard sugata dasgupta,1 shrestha ghosh,2 *atanu chandra2 editorial sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 309–313, epub. 25 aug 22 submitted 2 nov 21 revision req. 21 nov 21; revision recd. 30 nov 21 accepted 9 dec 21 https://doi.org/10.18295/squmj.1.2022.002 https://creativecommons.org/licenses/by-nd/4.0/ cold bubble humidification of oxygen old habits die hard 310 | squ medical journal, august 2022, volume 22, issue 3 p h y s i o l o g i c a l h u m i d i f i c a t i o n : absolute and relative humidity the importance of the upper airway is often understated. however, it holds special significance with regard to understanding the processes behind the physiological humidification of inspired air. besides the upper airway, the trachea provides a counter current mechanism for heat and moisture exchange during breathing and hence plays an important role in heating and humidifying inspired gas. understanding the concept of humidity and the ways to measure it is beneficial in a discussion pertaining to the physiology of humidification of inspired gas.4 humidity is quantified in two ways; absolute humidity (expressed in g/m3) defined as the mass of water vapour present per unit volume of gas at any given temperature and pressure.9 relative humidity (expressed as a percentage) is a comparative measurement describing the ratio between the mass of water vapour present in a given volume of air to the mass of water vapour required to completely saturate said volume of air at a particular temperature.4 the nose is the site of maximal heat and moisture exchange. a gradient of heat and absolute humidity is achieved down the upper airway.10 the normal temperature, relative humidity and absolute humidity of inspired gas at the airway opening are about 22°c, 50% and 10 g/m3, respectively. after normal heating and humidification mechanisms in the intact upper respiratory tract, these values reach 29–32°c, 95% and 28–34 g/m3 in the oropharynx and 32–36°c, 100% and 34–40 g/m3 in the trachea. on reaching the lungs, the inspired gas is fully saturated with water vapour at body temperature (37°c, 100% relative humidity, 44 g/m3 absolute humidity).11 the point at which this occurs is called the isothermic saturation boundary (isb) which is approximately 5 cm distal to the carina at the level of the third generation airways.4 nasal mucosa is kept warm and moist by secretions from goblet cells and mucous glands such that when inhaled air passes through the path created between the turbinates, incoming air is warmed by convection. liquid moisture from the epithelial lining evaporates by utilising latent heat of vaporisation to add to the humidity of inhaled air. heat and moisture exchange is crucial to maintaining mucociliary function as the ciliary motility is drastically reduced, airway irritation is increased and pulmonary secretions become viscid and inspissated when exposed to cold, dry air.12 respiratory heat loss occurs during exhalation as latent heat is released when water vapour from saturated exhaled air condenses in the upper airways. thus, the airways are prepared for another cycle of heating and humidification of inspired air. the physics of humidification humidifiers form an important part of oxygen delivery systems. a variety of devices are available to achieve ideal humidity levels that are as close to the physiological requirement as possible. based on their mechanism of action, humidifiers are divided into active and passive types.9 active humidifiers such as bubble and pass-over humidifiers add water or heat or both to the inspired gas. passive humidifiers such as heat and moister exchangers (hme) for example, use exhaled heat and moisture to humidify inspired gas. a nebulizer produces an aerosol (a suspension of water particles in gas) for humidification. bubble humidifiers are one of the most common humidifiers used in developing countries such as india.13 these are water containers in which gas is forced to escape through a tube placed at the bottom.14 the gas bubbles collect moisture as they move towards the water surface and pass through an outlet connected to an oxygen delivery device. a number of factors govern the amount of water vapour gained through this process. lower flow rates allow longer contact time between the gas and water thereby increasing humidity. the higher is the flow through a bubble humidifier, the lower the water vapour content and temperature of the gas leaving the device. flow rates of more than 10 l/min usually result in decreased contact time and inability to achieve required absolute humidity.13 the absence of a diffuser also lowers humidity. diffusers break larger gas bubbles into smaller ones, increasing the surface area thus enabling greater gas-liquid interaction. moreover, a heat source provides the latent heat of vaporisation required to maximize the humidification of gas. more often than not, especially in resourcelimited setups, there is an absence of a heat source. the resultant use of cold bubble humidification generates an absolute humidity of only 10–20 g/m3 at standard room temperature against the physiological requirements of at least 34 g/m3 in trachea and 44 g/ m3 below carina at the isb.13 a comparison of various humidifiers shows that while cold bubble humidifiers and hmes drastically fail to provide 100% saturation at 37°c and heated water baths just meet the requisite levels, heated nebulisers based on the bernoulli-effect and ultrasonic nebulisers more than surpass the mark.13 sugata dasgupta, shrestha ghosh and atanu chandra editorial | 311 infections associated with cold bubble humidifiers respiratory tract infections are the most common type of healthcare-associated infections (hai).15 elderly, immunocompromised or critically ill subjects are particularly susceptible to the nosocomial infections caused by several bacteria and fungi. equipment used for respiratory care such as nebulisers, ventilators and humidifiers may act as potential vehicles for transmission of those organisms, though their exact role in the causation of hai is still a matter of debate. humidifiers may serve as a reservoir of several microorganisms as the fluids inside them may be contaminated by different bacteria and fungi. some of the organisms may also multiply in the stagnant water. the organisms gain access to the host in two ways: either from the aerosolisation in the room or through direct delivery to the airways.16 moreover, many grampositive and gram-negative bacteria can form biofilms over medical devices; some of the important organisms among them are staphylococcus aureus, enterococcus faecalis, coagulase negative staphylococcus, klebsiella pneumonia and pseudomonas aeruginosa.17 la fauci et al. conducted a study by collecting water samples from disposable and reusable oxygen humidifiers from different wards and processed them for microbial analysis.18 they found a very high rate of microbial contamination in samples from reusable oxygen humidifiers in comparison to the disposable ones. the contamination rate in the reusable oxygen humidifiers in emergency areas was more than 50% and the most relevant pathogens were pseudomonas aeruginosa and staphylococcus aureus. another hospital-based study conducted by jadhav et al. showed that colonisation rates of the oxygen humidifier chambers of portable cylinders and pipelines by bacteria and fungi were 75% and 87% respectively.16 aspergillus spp. was the most common among the fungal isolates. among the gram negative bacteria, several multi-drug resistant organisms such as klebseilla pneumonia, pseudomonas spp., acinetobacter spp. and escherechia coli were isolated. recommendations jadhav et al. demonstrated the importance of disinfection, documenting reduced colonisation rates of 15% and 12% for fungi and bacteria, respectively, after maintenance of hand hygiene and disinfection of humidifier chambers with 70% ethanol.16 overall, it is recommended that sterile water be used instead of tap water along with regular and thorough cleaning and changing of humid ifiers to prevent microbial growth. however, with resources being stretched to a maximum, especially during the ongoing pandemic, meticulous implementation of such practices may prove to be difficult. hence, revisiting the rationale behind routine usage of humidified oxygen over ‘dry’ (without usual cold bubble humidification) oxygen is reasonable. non-humidified and non-heated air-oxygen mixtures can lead to increased airway resistance, dried up upper airway mucosa leading to reduced mucociliary clearance, airway mucosal inflammation and damage and an increase in the amount of energy expended by patients to warm and humidify the delivered gas.19 cold bubble humidifiers are unable to add the necessary amount of humidification and heat needed to prevent the above mentioned complications. over the years, several studies have validated that there is little difference in clinical outcomes and symptom severity between patient groups using humidified and non-humidified oxygen.20,21 the british thoracic society guidelines do not recommend routine humidification of oxygen when delivered under low flow (1–4 l/min) unless upper airways are bypassed, as in intubated or tracheotomised patients.22 higher flows of oxygen (>4 l/min) can cause upper airway discomfort due to dryness, although most patients may be able to tolerate it. the maintenance of adequate hydration of all patients receiving supple mental oxygen remains most essential. the guidelines also suggest administering normal saline nebulisation for liquefying viscid secretions, further negating the requirement of oxygen humidification.22 furthermore, high-flow oxygen therapy, if needed, should be provided with heated humidifiers as opposed to cold bubble humidifiers which are highly ineffective. studies by santana et al. and franchini et al. support that finding that cold bubble humidifiers fail to provide any additional humidity to nasal mucosa when compared to non-humidified oxygen therapy.23,24 humidification of inspired oxygen can only be considered in patients who complain of excessive nasal dryness associated discomfort. however, topical application of water-based lubricants can be a reasonable solution to this complaint.4 in published guidelines on oxygen therapy in paediatric patients, available evidence has not supported the use of heated or unheated humidification with low-flow oxygen delivery.25,26 conclusion warren buffet once said, ‘chains of habit are too light to be felt until they are too heavy to be broken;’ cold bubble humidification of oxygen old habits die hard 312 | squ medical journal, august 2022, volume 22, issue 3 in this context, it would be essential to consider the dangers of continuing the common practice of cold bubble humidification. with the growing need for oxygen administration due to covid-19 infection, the importance of heating and humidification with oxygen administration should be reaffirmed. however, the issue is universal and not associated only with the current pandemic. in light of better technology, cold water humidifiers have been rendered redundant as they are unable to provide the adequate humidification required by the respiratory tract. moreover, evidence suggests that humidification is not mandatory in patients on oxygen therapy with any of the low-flow delivery devices, as described earlier. furthermore, it is imperative that cold bubble humidifiers are acknowledged as a breeding ground of infections, especially in resource-stretched facilities due to difficulty in regular cleaning and maintenance. since cold bubble humidifiers are evidently unable to humidify to the levels required, it appears that its usage should be abandoned as it offers no significant added advantage over room air and also increases the potential for infection risk. a u t h o r s’ c o n t r i b u t i o n s sd and sg prepared the manuscript with adequate planning and execution. sd and ac contributed to the review of literature, critical revision of content and final approval of the manuscript. all authors agree to be accountable for all aspects of the work and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. a c k n o w l e d g e m e n t we are extremely grateful to dr farhad n. kapadia, consultant physician and intensivist at hinduja hospital, mumbai, india, for providing his valuable inputs on this topic. references 1. budinger grs, mutlu gm. balancing the risks and benefits of oxygen therapy in critically ill adults. chest 2013; 143:1151–1162. https://doi.org/10.1378/chest.12-1215. 2. cousins jl, wark pab, mcdonald vm. acute oxygen therapy: a review of prescribing and delivery practices. int j chron obstruct pulmon dis 2016;11:1067–75. https://doi.org/10.2147/copd. s103607. 3. hardavella g, karampinis i, frille a, sreter k, rousalova i. oxygen devices and delivery systems. breathe (sheff ) 2019;15:e108–16. https://doi.org/10.1183/20734735.0204-2019. 4. hess dr. humidity and aerosol therapy. in: hess dr, macintyre nr, mishoe sc, galvin wf, adams ab, eds. respiratory care: principles and practice, 2nd ed. boston: jones and bartlett learning, 2012. pp.303–36. 5. kallstrom tj. american association for respiratory care (aarc). aarc clinical practice guideline: oxygen therapy for adults in the acute care facility--2002 revision & update. respir care 2002;47:717–20. 6. renda t, corrado a, iskandar g, pelaia g, abdalla k, navalesi p. high-flow nasal oxygen therapy in intensive care and anaesthesia. br j anaesth 2018;120:18–27. https://doi.org/10.1016/j.bja.2017.11.010. 7. guy t, créac'hcadec a, ricordel c, salé a, arnouat b, bizec jl, et al. high-flow nasal oxygen: a safe, efficient treatment for covid-19 patients not in an icu. eur respir j 2020;56:2001154. https://doi.org/10.1183/13993003.01154-2020. 8. geng s, mei q, zhu c, yang t, yang y, fang x, et al. high flow nasal cannula is a good treatment option for covid-19. heart lung 2020; 49:444–5. https://doi.org/10.1016/j.hrtlng.20 20.03.018. 9. plotnikow ga, accoce m, navarro e, tiribelli n. humidification and heating ofinhaled gasin patients with artificial airway. a narrative review. revbras ter intensiva 2018; 30:86–97. https:// doi.org/10.5935/0103-507x.20180015. 10. shelly mp. the upper airway--the forgotten organ. crit care 2001; 5:1–2. https://doi.org/10.1186/cc971. 11. gross jl, park gr. humidification of inspired gases during mechanical ventilation. minerva anestesiol 2012; 78:496–502. 12. kilgour e, rankin n, ryan s, pack r. mucociliary function deteriorates in the clinical range of inspired air temperature and humidity. intensive care med 2004; 30:1491–4. https://doi. org/10.1007/s00134-004-2235-3. 13. davis pd, parbrook gd, kenny gnc. humidification. in: davis pd, parbrook gd, kenny gnceds. basic physics and measurement in anaesthesia, 4th ed. oxford: butterworthheinemann ltd, 1995. pp.146–57. 14. mcnulty g, eyre l. humidification in anaesthesia and critical care. bja educ 2015; 15:131–5. https://doi.org/10.1093/bjaceaccp/mku022. 15. haque m, sartelli m, mckimm j, abu bakar m. health careassociated infections an overview. infect drug resist 2018; 11:2321–33. https://doi.org/10.2147/idr.s177247. 16. jadhav s, sahasrabudhe t, kalley v, gandham n. the microbial colonization profile of respiratory devices and the significance of the role of disinfection: a blinded study. j clin diagn res 2013; 7:1021–6. https://doi.org/10.7860/jcdr/2013/5681.3086. 17. khatoon z, mctiernan cd, suuronen ej, mah tf, alarcon ei. bacterial biofilm formation on implantable devices and approaches to its treatment and prevention. heliyon 2018; 4:e01067. https://doi.org/10.1016/j.heliyon.2018.e01067. 18. la fauci v, costa gb, facciolà a, conti a, riso r, squeri r. humidifiers for oxygen therapy: what risk for reusable and disposable devices? j prev med hyg 2017; 58:e161–5. 19. fontanari p, burnet h, zattara-hartmann mc, jammes y. changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals. j appl physiol 1996; 81:1739–43. https://doi.org/10.1152/jappl.1996.81.4.1739. 20. wen z, wang w, zhang h, wu c, ding j, shen m. is humidified better than non-humidified low-flow oxygen therapy? a systematic review and meta-analysis. j adv nurs 2017; 73:2522–33. https://doi.org/10.1111/jan.13323. 21. poiroux l, piquilloud l, seegers v, le roy c, colonval k, agasse c, et al; reva network. effect on comfort of administering bubble humidified or dry oxygen: the oxyrea non-inferiority randomized study. ann intensive care 2018; 8:126. https://doi.org/10.1186/ s13613-018-0472-9. 22. o'driscoll br, howard ls, earis j, mak v. british thoracic society guideline for oxygen use in adults in healthcare and emergency settings. bmj open respir res 2017; 4:e000170. https://doi.org/10.1136/bmjresp-2016-000170. https://doi.org/10.1378/chest.12-1215 https://doi.org/10.2147/copd.s103607 https://doi.org/10.2147/copd.s103607 https://doi.org/10.1183/20734735.0204-2019 https://doi.org/10.1016/j.bja.2017.11.010 https://doi.org/10.1183/13993003.01154-2020 https://doi.org/10.1016/j.hrtlng.2020.03.018 https://doi.org/10.1016/j.hrtlng.2020.03.018 https://doi.org/10.5935/0103-507x.20180015 https://doi.org/10.5935/0103-507x.20180015 https://doi.org/10.1186/cc971 https://doi.org/10.1007/s00134-004-2235-3 https://doi.org/10.1007/s00134-004-2235-3 https://doi.org/10.1093/bjaceaccp/mku022 https://doi.org/10.2147/idr.s177247 https://doi.org/10.7860/jcdr/2013/5681.3086 https://doi.org/10.1016/j.heliyon.2018.e01067 https://doi.org/10.1152/jappl.1996.81.4.1739 https://doi.org/10.1111/jan.13323 https://doi.org/10.1186/s13613-018-0472-9 https://doi.org/10.1186/s13613-018-0472-9 https://doi.org/10.1136/bmjresp-2016-000170 sugata dasgupta, shrestha ghosh and atanu chandra editorial | 313 23. santana la, bezerra skm, saraiva-romanholo bm, yamaguti wp, de fátima lopes calvo tibério i, dos santos tm, et al. cold bubble humidification of low-flow oxygen does not prevent acute changes in inflammation and oxidative stress at nasal mucosa. sci rep 2021; 11:14352. https://doi.org/10.1038/s41598-021-93837-x. 24. franchini ml, athanazio r, amato-lourenço lf, carreirãoneto w, saldiva ph, lorenzi-filho g, et al. oxygen with cold bubble humidification is no better than dry oxygen in preventing mucus dehydration, decreased mucociliary clearance, and decline in pulmonary function. chest 2016; 150:407–14. https://doi.org/10.1016/j.chest.2016.03.035. 25. napolitano n, berlinski a, walsh bk, ginier e, strickland sl. aarc clinical practice guideline: management of pediatric patients with oxygen in the acute care setting. respir care 2021; 66:1214–23. https://doi.org/10.4187/respcare.09006. 26. world health organization. oxygen therapy for children: a manual for health workers. from: https://apps.who.int/iris/ handle/10665/204584 accessed: nov 2021. https://doi.org/10.1038/s41598-021-93837-x https://doi.org/10.1016/j.chest.2016.03.035 https://doi.org/10.4187/respcare.09006 departments of 1medical surgical nursing and 2biostatistics, iran university of medical science, tehran, iran; 3school of nursing and midwifery, sabzevar university of medical sciences, sabzevar, iran *corresponding author’s e-mail: 74ms13@gmail.com evaluating the effect of peer education on the hope of patients with thalassaemia major a quasi-experimental study mahnaz seyedoshohadaee,1 alice khachian,1 hamid haghani,2 *mohammad s. sargolzaei3 clinical & basic research sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 376–381, epub. 25 aug 22 submitted 8 feb 21 revision req. 4 apr 21; revision recd. 11 mar 21 accepted 10 jun 21 https://doi.org/10.18295/squmj.6.2021.087 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: thalassaemia major (tm) is one of the most common chronic genetic disorders in today’s world. the psychological impacts of this disease can affect patients’ hope. considering the positive role and importance of suitable educational methods, this study aimed to determine the effect of peer education on the hope of patients with tm. methods: this quasi-experimental single-group study included patients with tm undergoing treatment at the imam khomeini hospital, zabol, iran, between march and july 2020. a continuous sampling method was used and data collection tools included a demographic questionnaire and snyder’s hope scale. patients were educated in groups by eligible peers in two sessions for 60 minutes per session. hope was measured before (pre-test) and one month after (post-test) the educational sessions. descriptive statistics and a paired sample student t-test were used. results: a total of 50 participants were included in this study. the mean age of the participants was 24.5 ± 4.24 years. at the pre-test, the mean total hope score was 26.72 ± 5.82; this increased to 28.21 ± 5.11 at the post-test (p = 0.028). the mean hope score of patients in the pathway thinking dimension significantly increased after peer education (p = 0.01). despite an increase in the score of the agency thinking dimension, this was not statistically significant (p = 0.297). conclusion: the findings of this study indicate that peer education can improve hope in patients with tm. considering that this educational method is easy, cheap and experienced-based, it can be used in combination with other healthcare measures to improve tm patients’ hope. keywords: peer group; hope; beta-thalassemia major; patient education; iran. advances in knowledge according to the findings of this study, peer education may improve the level of hope in thalassaemia major (tm) patients. peers can help other patients because of their successful experiences in improving hope. application to patient care by recruiting peers in order to facilitate patient education, it is possible to increase the effectiveness of the educational process and improve hope in tm patients. using peer education as a cost-effective and easy method can increase the quality of patient care. thalassaemia is the most common hereditary haemoglobinopathy in the world.1 this chronic disease has been reported in more than 60 countries around the world.2 according to the statistics reported by the thalassaemia international federation, around 200,000 patients with thalassaemia major (tm) are currently under treatment worldwide.3 thalassaemia has a higher prevalence in south and southeast asia, the middle east and mediterranean and central african countries.4 so far, approximately 26,000 patients with tm have been reported in iran and approximately 1,500 new cases are annually diagnosed in the country.5 patients with tm depend on regular blood transfusions and continuous medical care to continue their lives.6 this lifelong and complex therapeutic protocol may affect the patient’s emotional status, daily activities, familial relationships and occupational opportunities.7 patients with β-tm, like all chronic diseases, are vulnerable to emotional and behavioural problems.8 while several factors can aggravate the psychological problems of these patients, various factors, including hope, also play a role in reducing these problems.9 hope is one of the basic concepts of optimistic psychology and a factor that enriches people’s lives.10 snyder et al. defines hope as “the capability to derive pathways to desired goals and motivate oneself via agency thinking to use those pathways”.11 hope as a healing, multidimensional, dynamic and powerful factor affects the capacity to adapt to problems and even to incurable diseases.12 hope improves individuals’ mental health and opens-up a way to increase knowledge and awareness and to rationally cope with a disease.13 for example, kao et al.’s study found that people who had higher levels of hope also had lower anxiety levels.14 https://creativecommons.org/licenses/by-nd/4.0/ mahnaz seyedoshohadaee, alice khachian, hamid haghani and mohammad s. sargolzaei clinical and basic research | 377 patient education can be seen as a way to improve the quality of life in patients with chronic diseases.15,16 recently, the educational methods that engage learners in this process have gained attention;17 one such method is peer education, which has been effective in promoting patient healthcare and learning activities.18 peer learning system is a novel and effective innovation in the field of educational methods that has shown positive effects on various aspects of education, especially in the field of healthcare.19 this type of education improves individuals’ knowledge, attitude and practice.20 peer groups can more effectively encourage their counterparts to adhere to appropriate health behaviours and share their strengths, weaknesses and experiences.21 the members of peer groups can also better communicate with their peers and help them behave better. studies show that peer education is a cost-effective approach to educate patients in different situations.22 meeting people with a similar disease experience provides patients with comfort and reassurance and can help them learn adaptive ways to overcome chronic illness and increase hope.23 many studies have asserted the usefulness of communication between patients and their peers. pasiar et al.’s study showed a positive effect of peer education on the hope of patients undergoing haemodialysis.24 furthermore, dant et al.’s study stated that peer education can improve the quality of life of diabetic patients.25 accordingly, the main hypothesis of the current study was that peer education is effective in improving the hope of tm patients. considering that thalassaemia patients suffer from psychological problems due to various reasons, only few studies have been conducted to evaluate the effects of educational intervention on the level of hope in these patients.24 in addition, due to the discrepancy in the results of studies such as the one conducted by molazem et al., which showed that peer group education had no effect on depression in patients undergoing coronary angiography, the table 1: thalassaemia major patients’ demographic and clinical characteristics (n = 50) characteristic n (%) age group in years 18–19 7 (14) 20–24 19 (38) 25–29 15 (30) 30–34 9 (18) mean ± sd (range) 24.5 ± 4.24 (18–34) gender female 28 (56) male 22 (44) education elementary 12 (24) middle school 16 (32) diploma 18 (36) higher than diploma 3 (6) no response 1 (2) economic status poor 20 (40) moderate 18 (36) good 8 (16) great 4 (8) residency urban 22 (44) suburban 5 (10) rural 23 (46) parents’ relationship consanguineous 30 (60) non-consanguineous 20 (40) transfusions per month once 6 (12) twice 44 (88) another affected child in the family yes 18 (36) no 31 (62) no response 1 (2) iron chelator type subcutaneous 12 (24) oral 3 (6) subcutaneous and oral 35 (70) regular drug consumption yes 39 (78) no 11 (22) sd = standard deviation. table 2: hope scores and its dimensions before and after peer education in patients with thalassaemia major (n = 50) hope dimension mean hope score ± sd p value* before peer education after peer education agency thinking 13.48 ± 3.24 14.30 ± 2.94 0.297 pathway thinking 12.88 ± 3.23 13.91 ± 3.09 0.01 total hope 26.72 ± 5.82 28.21 ± 5.11 0.028 sd = standard deviation. *using paired student t-test. evaluating the effect of peer education on the hope of patients with thalassaemia major a quasi-experimental study 378 | squ medical journal, august 2022, volume 22, issue 3 current study aimed to determine the effects of a peer education programme on the hope of tm patients.22 methods this quasi-experimental single-group study used a pre/post-test design. the studied population included patients with tm referred to the thalassaemia care centre of imam khomeini hospital, zabol, iran, between march and july 2020. patients were recruited using a continuous sampling method. those with a definite diagnosis of tm by a physician, a medical record, >18 years old, with no cognitive problems or physical disability, with the ability to read and write and who were willing to participate in the study were included. patients who did not attend one of the educational sessions or were unwilling to continue to participate in the study were excluded. considering the 95% confidence level, the power of 80% and a possible sample loss, the sample size was determined to be 50. data collection tools included a demographic and clinical information questionnaire and snyder’s hope scale.11 demographic and clinical information included age, gender, residency, level of education, economic status, parents’ familial relationship, the frequency of blood transfusions per month, the presence of other affected children in the family, the type of iron-chelating drug and adherence to regular drug consumption. snyder’s hope scale was originally developed for individuals over 15 years of age. the questionnaire has 12 items, of which four are related to the agency thinking dimension (2, 9, 10 and 12), four refer to the pathway thinking dimension (1, 4, 6 and 8) and four (3, 5, 7 and 11) are deviating items. this questionnaire assesses the two subscales of factors and strategies using a 5-point likert scale (1 = completely disagree, 2 = disagree, 3 = no opinion, 4 = agree and 5 = completely agree). no score is considered for the deviating items. scores could range from 8–40. snyder et al. assessed the reliability of the questionnaire in 1991 and reported a cronbach’s alpha coefficient of 80% following a 10-week retest interval.11 to evaluate the reliability of the questionnaire in the present study, the overall cronbach’s alpha obtained was 0.89 and the values were 0.84 and 0.78 for the agency thinking and pathway thinking subscales, respectively. after selecting and educating a peer group, the obtained knowledge was put into practice by the peers and data were collected before (pre-test) and one month after (post-test) the intervention. peers were selected among eligible individuals who fulfilled the inclusion criteria, volunteered to participate in the study, obtained a hope score >25 based on snyder’s hope scale, had the required communication skills and had at least a high school diploma or higher education. two of the participants who attained higher scores than others were selected as peers and were then trained by the researcher in three 60-minutelong educational sessions during one week. the educational content taught by the researcher included explanations about research objectives, the importance and benefits of peer education, educational concepts and communication skills including attention to verbal and non-verbal behaviours and how to be an active listener. the educational content for improving hope (such as purpose and meaning of life, increasing the sense of appreciation and gratitude, upholding faith, emphasising on accomplishments and successful past experiences and creating a positive attitude towards the disease and its treatment) was taught using audio-visual aids and through lectures and questionand-answer sessions. based on the training given by the researcher and the experiences expressed by the peers, they passed a final evaluation as a role-player. while the peers indicated their experiences, the researcher corrected and completed these statements based on scientific resources, so that the peers were able to transfer these concepts to patients during training sessions. finally, a booklet containing all the educational content was given to the peers. after providing a comfortable and calm place for the patients, the demographic and clinical information questionnaire was completed followed by snyder’s hope scale. then, the educational content of the provided booklet, with emphasis on the experiences of the peers, was provided to groups of 6–7 patients in two 60-minute-long sessions (with a gap of 60 minutes between the sessions) by each peer separately during one day. the first session included introducing the peers to the other patients, explaining the goals of the study and providing education on the concepts aimed at improving hope (i.e. the purpose and meaning of life, increasing the sense of appreciation and gratitude, upgrading faith, emphasising on accomplishments and successful past experiences and creating a positive attitude towards the disease and its treatment). the second session included a review of the topics of the previous session through asking questions and providing concluding remarks. at the end of the second session, a group discussion was held; the peers shared their successful experiences and the educational booklet was provided to all the patients. finally, one month after the intervention, hope was assessed again for all the patients. mahnaz seyedoshohadaee, alice khachian, hamid haghani and mohammad s. sargolzaei clinical and basic research | 379 for data analysis, statistical package for the social sciences (spss), version 20 (ibm spss inc., chicago, il, usa) was used. descriptive statistics were used to present the data and inferential statistics such as paired sample student t-test were used to determine statistically significant changes. hope scores are presented as mean ± standard deviation. statistical significance was set at p ≤0.05. the current study was approved by the ethics committee of iran university of medical sciences (ir. iums.rec.1398.910). written informed consent was obtained from all patients after explaining the goals of the study. results a total of 50 patients were included in this study. most participants were female (56%) and the mean age of the patients was 24.5 ± 4.24 years. in terms of education, most participants had a diploma (36%). also, the parents of most of the patients were related (60%) [table 1]. the mean of the tm patients’ total hope pretest score was 26.72 ± 5.82 while the post-test score increased to 28.21 ± 5.11. this increase was statistically significant (p = 0.028). the hope score in patients with tm after being trained by peers in the pathway thinking dimension increased from 12.88 ± 3.23 to 13.91 ± 3.09. this increase was also statistically significant (p = 0.01). however, in terms of the agency thinking dimension, despite the hope score increasing after the educational intervention from 13.48 ± 3.24 to 14.30 ± 2.94, it was not statistically significant (p = 0.297) [table 2]. discussion the present study’s results show that one month after peer-education, the total score of hope and pathway thinking significantly increased in tm patients compared to their pre-educational intervention hope scores. in other words, peer-education had a positive effect on the patients’ level of hope. the score of the agency thinking dimension also increased; however, this was not statistically significant. agency thinking refers to a sort of motivation driving people to start and continue moving towards their goals.26 the reason for the lack of a significant change in the agency thinking dimension score may be due to the chronicity of the disease and old age (the patients had little motivation to achieve their goals). thornton et al.’s study investigated the effects of a psychological intervention on the hope of women with cancer and reported positive effects for this intervention on the total level of hope and the score of the pathway thinking dimension, but no significant impact was observed on the agency thinking dimension, which is consistent with the findings of the present study.27 the positive effects of peer education have also been confirmed in patients with other chronic diseases. in a study by pasyar et al. on the effects of peer support on hope in haemodialysis patients, the results showed that peer education significantly increased the mean total score of hope in patients.24 in addition, safaei et al.’s study on the effects of a peer group educational programme in promoting self-care in tm patients indicated improvement in self-care behaviours in the intervention group compared to the control group up to four months after the intervention.21 also, giesedavis et al.’s study on the quality of life of patients with breast cancer showed that peer education improved the quality of life of these patients up to one year after diagnosis.28 in a study on diabetic patients, heisler et al. showed that a peer-support programme promoted self-care behaviours and proper use of drugs and decreased insulin requirements in the intervention group compared to the control group.29 the results of these studies are consistent with the current research. in light of this, it seems that peers can contribute to the success of educational programmes in patients suffering from chronic diseases. this is probably because patients are encouraged to share and discuss their concerns with their peers who have had similar experiences and obtain necessary information using a common and simplified language. hope is a powerful coping mechanism in patients with chronic diseases and people who are hopeful can endure disease-related damages more easily.30 thakre’s study showed that hopeful people, who are also satisfied with their lives, can tolerate challenges and be better prepared for the future.31 also, dezutter et al. noted that high levels of hope are related to more commitment to self-care activities and superior health status.32 a peer group can help patients choose a positive coping strategy and become compatible with disease-related challenges, raising the patient’s hope. it seems that group participation of people with tm in meetings and hope training through a hopeful peer who themself had had useful experiences in improving hope, helped patients with better exchange and understanding of the concepts of hope education such as having a goal, strengthening motivation to achieve the goal and have positive thinking to achieve a better level of hope. tm, as a chronic disease, affects aspects of quality of life from the earliest stages of diagnosis. most patients with tm need knowledge and useful evaluating the effect of peer education on the hope of patients with thalassaemia major a quasi-experimental study 380 | squ medical journal, august 2022, volume 22, issue 3 experiences to improve their quality of life. therefore, paying attention to peer education is very important. the results of the present study can be considered one way to use different types of peer education models and compare them with each other and choose a more effective method to enhance patients’ psychological variables. therefore, managers, policy-makers, planners, physicians, psychologists and nurses in this field can be encouraged to use peer education as a practical method to create a suitable educational and comfortable environment between patients to exchange useful information. and by designing and using this type of education properly, they can take an effective step towards meeting the educational needs of patients. this study was subject to certain limitations. there was limited space available in the special diseases care centre for conducting educational sessions; this was a single-centre study. additionally, this study was conducted among a single group of patients at one time as it was feared that information would be shared among groups if done with multiple sets of patients. in addition, continuous sampling, which is a non-probability method, limits the generalisability of the results. it is suggested to assess the effects of peer education on hope of patients with other chronic diseases in future studies. it is also suggested that in order to determine the effectiveness of the mentioned training method, studies with more samples and different intervals between the preand post-test should be done in different centres. conclusion thalassaemia is a chronic disease and the affected person deals with this condition from birth. health experts are always seeking for effective ways to reduce the direct and indirect complications and costs of chronic diseases. results of the present study showed that the mean score of hope in patients with tm after receiving peer-training in the pathway thinking dimension and overall score of hope increased significantly. however, in the agency thinking dimension, despite an increase in the hope score, there was no significant difference. therefore, it seems that peer education can increase the level of hope in tm patients. considering that this educational method is easy, cheap and experienced-based, healthcare personnel, as individuals who have important roles in educating and supporting patients, can use this type of intervention alongside other healthcare measures. a u t h o r s’ c o n t r i b u t i o n ms contributed to the study concept and design as well as the sampling process and manuscript writing. ak contributed to the writing and critical revision of the manuscript. hh contributed to the data analysis. mss contributed to the study concept and design as well as the process of sampling and manuscript writing. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this article is the result of a master’s thesis in iran university of medical sciences, who financially supported the project. references 1. ehsan h, wahab a, anwer f, iftikhar r, yousaf mn. prevalence of transfusion transmissible infections in beta-thalassemia major patients in pakistan: a systematic review. cureus 2020; 12:e10070. https://doi.org/10.7759/cureus.10070. 2. sargolzaei ms, jahantigh f, allahyari j. interventions to improve quality of life in patients with major thalassemia: a systematic review. payesh 2020; 19:723–33. https://doi.org/10.29252/paye sh.19.6.723. 3. naghibi f, ahadi h, tajeri b, seairafi mr. effectiveness of mindfulness-based stress reduction training on psychological symptoms, pain in patients with thalassemia major. adv cog nitive sci 2020; 22:45–53. https://doi.org/10.30699/icss.22.2.45. 4. origa r. β-thalassemia. genet med 2017; 19:609–19. https:// doi.org/10.1038/gim.2016.173. 5. pouraboli b, abedi ha, abbaszadeh a, kazemi m. self-care in patient with major thalassemia: a grounded theory. j caring sci 2017; 6:127–39. https://doi.org/10.15171/jcs.2017.013. 6. rivella s. β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. haemat ologica 2015; 100:418–30. https://doi.org/10.3324/haematol.20 14.114827. 7. yengil e, acipayam c, kokacya mh, kurhan f, oktay g, ozer c. anxiety, depression and quality of life in patients with beta thalassemia major and their caregivers. int j clin exp med 2014; 7:2165–72. 8. keşkek so, kırım s, turhan a, turhan fg. depression in subjects with beta-thalassemia minor. ann hematol 2013; 92:1611–15. https://doi.org/10.1007/s00277-013-1851-9. 9. movahedi m, movahedi y, farhadi a. effect of hope therapy training on life expectancy and general health in cancer patients. j holist nurs midwifery 2015; 25:84–92. 10. griffin b, hesketh b, loh v. the influence of subjective life expectancy on retirement transition and planning: a longitudinal study. j voc behavior 2012; 81:129–37. https://doi. org/10.1016/j.jvb.2012.05.005. 11. snyder cr, harris c, anderson jr, holleran sa, irving lm, sigmon st, et al. the will and the ways: development and validation of an individual-differences measure of hope. j pers soc psychol 1991; 60:570–85. https://doi.org/10.1037//00223514.60.4.570. https://doi.org/10.7759/cureus.10070 https://doi.org/10.29252/payesh.19.6.723 https://doi.org/10.29252/payesh.19.6.723 https://doi.org/10.30699/icss.22.2.45 https://doi.org/10.1038/gim.2016.173 https://doi.org/10.1038/gim.2016.173 https://doi.org/10.15171/jcs.2017.013 https://doi.org/10.3324/haematol.2014.114827 https://doi.org/10.3324/haematol.2014.114827 https://doi.org/10.1007/s00277-013-1851-9 https://doi.org/10.1016/j.jvb.2012.05.005 https://doi.org/10.1016/j.jvb.2012.05.005 https://doi.org/10.1037//0022-3514.60.4.570 https://doi.org/10.1037//0022-3514.60.4.570 mahnaz seyedoshohadaee, alice khachian, hamid haghani and mohammad s. sargolzaei clinical and basic research | 381 12. bodner e, bergman ys. loneliness and depressive symptoms among older adults: the moderating role of subjective life expectancy. psychiatry res 2016; 237:78–82. https://doi. org/10.1016/j.psychres.2016.01.074. 13. vadaei s, zamani ms, fatahmogham l. evaluation of mental health and hope in dialysis patients. iran j rehabil res nurs 2019; 6:132–9. 14. kao yc, liu yp, chou mk, cheng th. subjective quality of life in patients with chronic schizophrenia: relationships between psychosocial and clinical characteristics. compr psychiatry 2011; 52:171–80. https://doi.org/10.1016/j.compps ych.2010.05.008. 15. wang q, dong l, jian z, tang x. effectiveness of a precedebased education intervention on quality of life in elderly patients with chronic heart failure. bmc cardiovasc disord 2017; 17:262. https://doi.org/10.1186/s12872-017-0698-8. 16. mohammadi n, tizhoosh m, seyedoshohadaei m, haghani h. face-to-face education vs. group education on knowledge and anxiety of patients undergoing coronary angiography. hayat 2012; 18:44–53. 17. mohammadpour m, mohammadpour a, ajam zibad h, najafi s. comparison of the effect of peer-led education and education by the healthcare personnel on awareness, attitude and performance of lettered people toward organ donation. jbums 2019; 21:306–13. 18. edraki m, zarei a, soltanian m, moravej h. the effect of peer education on self-care behaviors and the mean of glycosylated hemoglobin in adolescents with type 1 diabetes: a randomized controlled clinical trial. int j community based nurs midwifery 2020; 8:209–19. https://doi.org/10.30476/ijcb nm.2020.82296.1051. 19. alizadeh m, gharibi f, asghari jafar abadi m, esmaeilinasab n, bostani z, zarghami f. the perspectives of medicine students and academic members in tabriz university of medical sciences about the required infrastructures for implementation of proposed peer assisted learning (pal) system. sdme 2012; 9:11–17. 20. biabanakigoortani a, namnabati m, abdeyazdan z, badii z. effect of peer education on the noise management in iranian neonatal intensive care unit. iran j nurs midwifery res 2016; 21:317–21. https://doi.org/10.4103/1735-9066.180392. 21. safaei s, abedi h, parand s, karimi m. evaluation of the effect of support-training system of peer group on promotion of self-care in β-thalassemia major patients in southern iran. hemoglobin 2019; 43:198–203. https://doi.org/10.1080/03630 269.2019.1651331. 22. molazem z, shahabfard z, askari a, kalyani mn. effects of a peerled group education on fear, anxiety and depression levels of patients undergoing coronary angiography. invest educ enferm 2018; 36:e13. https://doi.org/10.17533/udea.iee.v36n1e13. 23. wu cj, chang am, courtney m, shortridge-baggett lm, kostner k. development and pilot test of a peer-support based cardiac-diabetes self-management program: a study protocol. bmc health serv res 2011; 11:74. https://doi. org/10.1186/1472-6963-11-74. 24. pasyar n, rambod m, jowkar m. the effect of peer support on hope among patients under hemodialysis. int j nephrol renovasc dis 2020; 13:37–44. https://doi.org/10.2147/ijnrd. s240756. 25. danet a, prieto rodríguez má, gamboa moreno e, ochoa de retana garcia l, march cerdà jc. [peer training for patients with diabetes mellitus 2. a quantitative and qualitative evaluation in the basque country and andalusia]. aten primaria 2016; 48:507–17. https://doi.org/10.1016/j.aprim.2015.10.010. 26. snyder c, lehman ka, kluck b, monsson y. hope for rehabilitation and vice versa. rehabil psychol 2006; 51:89. https://doi.org/10.1037/0090-5550.51.2.89. 27. thornton lm, cheavens js, heitzmann ca, dorfman cs, wu sm, andersen bl. test of mindfulness and hope components in a psychological intervention for women with cancer recurrence. j consult clin psychol 2014; 82:1087–100. https://doi.org/10.1 037/a0036959. 28. giese-davis j, bliss-isberg c, carson k, star p, donaghy j, cordova mj, et al. the effect of peer counseling on quality of life following diagnosis of breast cancer: an observational study. psychooncology 2006; 15:1014–22. https://doi.org/10.1002/ pon.1037. 29. heisler m, vijan s, makki f, piette jd. diabetes control with reciprocal peer support versus nurse care management: a randomized trial. ann intern med 2010; 153:507–15. https:// doi.org/10.7326/0003-4819-153-8-201010190-00007. 30. rustøen t, cooper ba, miaskowski c. the importance of hope as a mediator of psychological distress and life satisfaction in a community sample of cancer patients. cancer nurs 2010; 33:258–67. https://doi.org/10.1097/ncc.0b013e3181d6fb61. 31. thakre n. satisfaction with life and hope in youth. ijpp 2013; 4:347. 32. dezutter j, casalin s, wachholtz a, luyckx k, hekking j, vandewiele w. meaning in life: an important factor for the psychological well-being of chronically ill patients? rehabil psychol 2013; 58:334–41. https://doi.org/10.1037/a0034393. https://doi.org/10.1016/j.psychres.2016.01.074 https://doi.org/10.1016/j.psychres.2016.01.074 https://doi.org/10.1016/j.comppsych.2010.05.008 https://doi.org/10.1016/j.comppsych.2010.05.008 https://doi.org/10.1186/s12872-017-0698-8 https://doi.org/10.30476/ijcbnm.2020.82296.1051 https://doi.org/10.30476/ijcbnm.2020.82296.1051 https://doi.org/10.4103/1735-9066.180392 https://doi.org/10.1080/03630269.2019.1651331 https://doi.org/10.1080/03630269.2019.1651331 https://doi.org/10.17533/udea.iee.v36n1e13 https://doi.org/10.1186/1472-6963-11-74 https://doi.org/10.1186/1472-6963-11-74 https://doi.org/10.2147/ijnrd.s240756 https://doi.org/10.2147/ijnrd.s240756 https://doi.org/10.1016/j.aprim.2015.10.010 https://doi.org/10.1037/0090-5550.51.2.89 https://doi.org/10.1037/a0036959 https://doi.org/10.1037/a0036959 https://doi.org/10.1002/pon.1037 https://doi.org/10.1002/pon.1037 https://doi.org/10.7326/0003-4819-153-8-201010190-00007 https://doi.org/10.7326/0003-4819-153-8-201010190-00007 https://doi.org/10.1097/ncc.0b013e3181d6fb61 https://doi.org/10.1037/a0034393 submitted 19 sep 21 1 revisions req. 25 nov 21 & 19 jan 22; revisions recd. 5 dec 21 & 24 jan 22 2 accepted 20 feb 22 3 online-first: march 2022 4 doi: https://doi.org/10.18295/squmj.3.2022.022 5 6 establishing trimester-specific hemoglobin a1c reference levels for 7 pregnant women 8 a retrospective study among healthy south asian women with normal 9 pregnancy outcomes 10 11 *john punnose,1 rajeev k. malhotra,5 komal sukhija,1 rashika m. 12 rijhwani,1 asha sharma,2 naimaa choudhary,2 prassan vij,3 renuka 13 joseph4 14 departments of 1endocrinology, 2obstetrics and gynecology, 3reproductive medicine and 15 4biochemistry, st. stephen’s hospital, new delhi, india; 5all india institute of medical 16 science, ansari nager, new delhi, india 17 *corresponding author’s e-mails: drpunnose@rediffmail.com; 18 drpunnose@ststephenshospital.org 19 20 abstract 21 objectives: this study aimed to define trimester-specific hemoglobin a1c (a1c) reference 22 intervals among healthy south asian pregnant women. methods: in this restrospective 23 study,1357 pregnant women without diabetes, gestational diabetes, gestational hypertension, 24 anemia, β-thalassemia, or systemic diseases were included. they had term delivery of babies 25 having weight appropriate for gestational age. a1c (using high performance liquid 26 chromatography, meeting the national glycohemoglobin standardization program and 27 international federation of clinical chemistry standards), hemoglobin, and rbc indices 28 were estimated at the first antenatal visit. the a1c levels were calculated in terms of non-29 parametric 2.5 and 97.5 percentiles for women in first (t1), second (t2), and third (t3) 30 trimester groups. the control group included 67 healthy non-pregnant women. statistical 31 tests were used to obtain the normal the normal reference values for the hba1c . and the tests 32 mailto:drpunnose@rediffmail.com mailto:drpunnose@ststephenshospital.org were considered significant when p value <0.05. results: the median hba1c (2.5 to 97.5 33 percentiles) was lower among the pregnant women; 4.8 (4-5.5) % or 32 (20-39) mmol/mol 34 than in the non pregnant women; 5.1 (4-5.7) % or 29 (20-37) mmol/mol ( p <0.001). these 35 were 4.9 (4.1-5.5) % or 30 (21-37) mmol/mol, 4.8 (4-5.3) % or 29 (20-34) mmol/mol, and 4.8 36 (3.9-5.6) % or 29 (19-38) mmol/mol for the t1, t2 and t3 groups, respectively; p-values:t1 37 vs t2=<0.001, t1 vs t3= 0.002, t2 vs t3= 0.111, t1 vs non pregnant group = <0.001. 38 conclusions: compared to normal non pregnant women, the a1c was lower in normal 39 pregnant women in south asian population. these a1c changes were observed despite 40 having significantly higher body max index among women in the t2 and t3 groups than in 41 the t1 and non pregnant groups. to understand the factors determining the a1c decrease in 42 pregnancy and to validate the findings of this study, we recommend further prospective 43 studies among south asian women 44 keywords: asian, gestational diabetes, hba1c , pregnancy trimesters, reference values. 45 46 advances in knowledge 47  earlier studies stressed the need to identify ethnicand trimester-specific hba1c 48 reference intervals in normal pregnant women. 49  compared to the non-pregnant state, there is significant decrease in hba1c levels in 50 pregnancy among south asian pregnant women; and this decrease is obvious in early 51 pregnancy. 52  among healthy south asian women, the suggested upper reference limits of hba1c in 53 first, second and third trimesters are 37,34, and 38mmol/mol, respectively 54 55 application to patient care 56  the proposed upper trimester-specific hba1c reference values may be used as threshold 57 values to identify women prone for gestational diabetes (gdm) and other adverse 58 pregnancy outcomes. 59  early identification of these high risk women will open up a window of opportunity to 60 introduce preventive strategies. 61  these hba1c reference values can guide in designing further prospective studies among 62 south asian pregnant women, and can develop alternate tests to ogtt for gdm 63 diagnosis and to establish glycemic targets in pregnancies complicated by diabetes. 64 65 introduction 66 glycated hemoglobin (a1c) is widely used as a standard biomarker for glycemic control 67 during management of diabetes mellitus in the general population,1 but, there is uncertainty 68 over the role of a1c for glycemic assessment during pregnancy. the accuracy of a1c 69 estimation in pregnancy is affected by several physiological changes in pregnancy like 70 increase in red cell production, younger red cell age distribution, and reduced red cell life 71 span.2 moreover, the high prevalence of iron deficiency and the common practice of iron 72 supplementation in pregnant women (especially in developing countries) can influence the 73 a1c estimation in pregnancy.3 despite these limitations, several prestigious organizations 74 have recommended a1c estimation in pregnancy for various reasons. the world health 75 organization advocates a1c estimation at the first ante natal visit to identify women with 76 ‘diabetes in pregnancy’(a1c > 6.5%, > 48 mmol/mol).4 77 78 many authors recommend a1c as a screening and even as a diagnostic test for gestational 79 diabetes mellitus (gdm).2,5 in 2011, the california state diabetes and pregnancy program 80 ‘sweet success’ adopted a new algorithm for the diagnosis and treatment of hyperglycemia 81 in pregnancy.6 accordingly, all women with a1c values of 5.7–6.4% (39–46 mmol/mol) in 82 early pregnancy are advised to undergo gdm treatment without further confirmatory ogtt. 83 the american diabetes association suggests periodic a1c estimations in pregnancy as a 84 secondary measure of glycemic control after self-monitoring of glucose.7 the national 85 institute for health and care excellence in the united kingdom proposes a1c in pregnancy 86 as a useful guide for risk stratification and prediction of pregnancy outcomes.8 this guideline 87 recommends hba1c testing at booking and in the second and third trimesters to ensure that 88 the targets are achieved. in many population groups, the first trimester a1c is recognized as a 89 predictor of gdm later in pregnancy,2,9 as well as of adverse pregnancy outcomes.2,10 second 90 and third trimester a1c levels are predictive of several obstetric complications: macrosomia, 91 gestational hypertension, preeclampsia, abnormal liquor volume, prematurity, and neonatal 92 deaths.2,11 93 94 however, many of these recommendations have not gained universal acceptance, due to the 95 lack of strong research evidence in obstetric population. the a1c cut off points for diagnosis 96 of ‘diabetes in pregnancy’ (> 6.5%, > 48 mmol/mol) and gdm in the ‘sweet 97 success’program (5.7to 6.4%, 39-48 mmol/mol) are guided by the a1c values for diagnosis 98 of diabetes and pre-diabetes in a non-obstetric population, respectively. however, a1c levels 99 in pregnancy are lower than in non obstetric population, and it shows physiological variations 100 between trimesters.12 there are significant racial and ethnic differences in glycation of 101 hemoglobin for a level of glycemia.13 clearly, there is a need to define ethnicand trimester-102 specific a1c reference levels in normal pregnant women, before it is recommended for gdm 103 screening and diagnosis, risk stratification and for measuring metabolic control. 104 there is an ongoing type 2 diabetes epidemic in the middle east and the south asian region 105 including the obstetric population. india has 5.7 million women with hyperglycemia during 106 pregnancy and ranks first in the world in this respect.14 however, to our knowledge, a1c 107 levels among normal pregnant south asian women are not yet defined. here, we identified, 108 trimester-specific a1c levels in healthy non-diabetic south asian pregnant women who 109 delivered babies with an age-appropriate weight. 110 111 methods 112 this retrospective study involved pregnant women who attended antenatal clinic at 113 st.stephen’s hospital, a tertiary care hospital in delhi, north india between january 2011 and 114 december 2016. our center follows a universal thalassemia screening strategy for pregnant 115 women at the first antenatal visit. the protocol includes estimation of hba, hba2, and hbf 116 through hemoglobin (hb) electrophoresis,with concurrent estimates of a1c. all women with 117 a1c >6.5% (48 mmol/mol) were diagnosed to have overt diabetes and those women having 118 a1c <6.5 % (48 mmol/mol) were screened for gdm through a universal one-step 75 g 119 ogtt between 24 and 28 gestational weeks or earlier if having high gdm risk factors. the 120 gdm diagnosis was made by the international association of diabetes and pregnancy study 121 group (iadpsg) recommendations.15 all pregnant women were on iron and folic acid 122 supplementation. 123 124 selection of the study population is shown in a flow diagram (fig.1). as part of universal 125 thalassemia screening, 9388 pregnant women had hb electrophoresis (a1c estimation) at the 126 first antenatal visit; all of them were evaluated for inclusion in this study. we excluded 8031 127 women due to unclear date of last menstrual period, delivery outside our hospital, diagnosis 128 of diabetes and gestational diabetes, gdm risk factors, anaemia,16 systemic diseases and 129 delivery of babies with smalland large-for gestational age babies.17 the remaining 1357 130 women in the study population were sub-categorized into three groups based on the 131 gestational age of a1c estimation: (a) first trimester <14 weeks (t1), n=513 women; (b) 132 second trimester-14-26 weeks (t2), n=550 women; and (c) third trimester 27-41 weeks (t3), 133 n=294 women. the body mass index (bmi) was calculated from the height and weight 134 recorded at first antenatal visit. the serum thyroid stimulating hormone (tsh ) was estimated 135 at first antenatal visit in all women and if elevated, was corrected with oral l-thyroxine 136 therapy (target serum tsh level below 2.5, 3 and 3 miu/l in the first, second and third 137 trimesters respectively) 138 139 a control group of 67 non–pregnant healthy women were recruited from 750 women, who 140 attended the pre-pregnancy counseling clinic of our hospital during the study period. the age 141 and bmi of the control group was comparable to those of whole and t1 pregnancy groups 142 respectively. (table 1&2) all had fpg < 5.5 mmol/l (< 100 mg/dl) or random plasma 143 glucose < 7 mmol/l (126 mg/dl), hb >11 g/dl, normal hba2 and hbf levels, no prior history 144 of gestational diabetes or abortion, no family history of diabetes in first degree relatives, and 145 had no systemic disease. the a1c levels of the study and the control groups were compared. 146 the reference intervals of a1c levels in each trimester were estimated and were compared for 147 any differences. this research protocol was approved by st.stephen’s hospital ethics 148 committee (no.sshec/r0136) with a waiver for patient consent form. 149 150 our laboratory is certified by the national accreditation board for testing and calibration 151 laboratories and uses bio-rad laboratories for proficiency testing. the complete blood count 152 was done on edta anticoagulated blood using beckman coulter lh 750/780 analyzer using 153 vcs technology. we used the standard protocol for the ogtt: ingestion of 75 g anhydrous 154 d-glucose dissolved in 250 ml distilled water.the sample for plasma glucose estimation was 155 collected in edta and sodium fluoride (grey top) vacuette. the glucose estimation was done 156 by hexokinase method on a beckman au680/480 analyzer. two levels of plasma glucose 157 controls (from bio rad) were run daily; level 1 4.53 mmol/l (81.50 mg/dl) and level 2-158 15.57 mmol/l (280.2 mg/dl). the monthly coefficient of variation (cv) % calculated for the 159 level -1 and level -2 controls were 1.7 % and 1.4% respectively. the blood for a1c 160 estimation was a non fasting sample collected in edta vial. estimation was done within two 161 hours of sampling by the ion exchange high performance liquid chromatography method 162 with a bio-rad d10tm machine (bio-rad laboratories, hercules ca). the estimation was 163 traceable to the reference methods of both the national glycohemoglobin standardization 164 program (ngsp) and the international federation of clinical chemistry and laboratory 165 medicine (ifcc). the inter-assay cv was 1.3% and 1.5% for low control (mean a1c 5.45%, 166 37 mmol/mol) and high control (mean 9.95%, 86 mmol/mol) respectively. our laboratory 167 participated in an external quality assurance scheme (eqas) for both glucose and a1c. the 168 z score for glucose was 0.60 and 0.65 for a1c. 169 170 all study groups had the minimum of 40 subjects mandated by ifcc for identification of 171 reference intervals.18 the data analysis was performed using spss version 16 (spss 172 inc.,chicago, usa) and r-software version 4.0.2. continuous variables were presented with 173 mean and standard deviation. an unpaired student’s ttest was used to compare the mean 174 between pregnant and non-pregnant women. the homogeneity of variances was checked 175 using leven’s test. one-way analysis of variance followed by post-hoc tukey’s test were 176 applied to compare the mean among groups t1,t2&t3. five normality statistical tests were 177 used to get the normal reference value of hba1c namely: anderson-darling, cramer-von 178 mises, kolmogorov-smirnov, shapiro-francia, and pearson chi-square. the mean + two 179 standard deviations were reported as reference values when the normality condition was 180 fulfilled or else a non-parametric method and median with percentiles (2.5th and 97.5th) were 181 reported as the normal range. the 95% confidence intervals of these percentiles were 182 determined with bootstrapping with 10000 replications using the boot package of r-software. 183 the mann-whitney u-test was applied to compare the distribution of a1c between pregnant 184 and non-pregnant women and between the trimesters and a p-value < 0.008 was considered 185 significant as per bonferroni correction (0.05/number of comparisons). a p-value < 0.05 was 186 considered as significant for other statistical tests. 187 188 results 189 table 1 shows reference intervals for a1c for the control group, study population, and t1, 190 t2, and t3 trimester groups expressed as median and percentiles. all five statistical tests to 191 assess normality of a1c values showed violation of normality. the median a1c value of 4.8 192 % (29mmol/mol) for the whole study population and 4.9 % (30 mmol/mol)for the t1 group 193 were lower than the median value of 5.1% (32 mmol/mol) in the control group ( p <0.001 for 194 both). the a1c median values for the t1,t2 and t3 groups were 4.9 %,4.8% and 4.8 % 195 (30,29 and 29 mmol/mol) respectively, with significant differences between t1 and t2 ( p 196 =0.001), t1 and t3 (p=0.001) and no difference between t2 and t3 ( p= 0.111). 197 fig. 2 presents the upper normal a1c level for the control,t1,t2 and t3 groups:5.7%(39 198 mmol/mol),5.5% (37mmol/mol),5.3% (34mmol/mol),and 5.6% (38 mmol/mol), 199 respectively.table 2 shows the clinical and laboratory parameters of the whole, trimester-200 specific pregnancy groups, and the control group. the women in all trimesters were age-201 matched, and the gestational age at delivery and the birth weight were comparable (p-values 202 > 0.05 for all parameters). the hb and rbc count were lower, and the mcv, mch, and 203 mchc were higher in pregnant women than in the control group; there was no difference of 204 hct and rdw between these groups. compared to the t1 group, there was a decrease in hb 205 and rbc count and an increase in mcv, mch and mchc in t2 group; the rdw and hct 206 remained static between groups. there was a significant rise of hemoglobin and rdw in t3 207 versus t2; hct, mcv, and mchc were constant. 208 209 discussion 210 the a1c is lower during pregnancy than when not pregnant in south asian women.the a1c 211 reference values for the first, second, and third trimesters were 4.15.5% (2137 mmol/mol), 212 4-5.3% (20-34 mmol/mol), and 3.9-5.6% (19-38 mmol/mol), respectively. earlier studies 213 revealed some racial differences in a1c reference intervals: (a) caucasian women in italy, 214 3.5-5.7% (15 39mmol/mol), 3.3-5.6 %(14-38 mmol/l), and 4.3-5.6 %(23-38 mmol/l) in 15-215 24, 25-27, and 28-36 gestational weeks, respectively;19 (b) mexican women, t1 4.5-5.6% 216 (26-38mmol/mol), t24.4-5.5% ( 26-37 mmol/mol), and t34.4-5.6% (25-38 mmol/mol);20 (c) 217 japanese women, t1 4.7-5.7% (28-39 mmol/mol), t2 4.4-5.4% (25-36mmol/mol), t3 4.6-218 5.8% (27-40mmol/mol).21 compared to these studies, the upper a1c reference values of our 219 south asian cohort were marginally lower. the stringent selection criteria (exclusion of 220 women having, gdm diagnosed by the most liberal iadpsg criteria and those with several 221 gdm risk factors and large or small for gestational age babies) as well as the racial 222 differences in the glycation of hemoglobin might have contributed to this modest a1c 223 difference. 224 225 compared to first trimester, a significant decrease in a1c level was noted in the second 226 trimester, but this remained constant in the third trimester [table 1]. the differences in a1c 227 levels between trimesters varied markedly between studies. in most populations, there was a 228 decrease in a1c level from the first to second trimester20-24 and this decrease was often 229 followed by a significant a1c rise in the third trimester (biphasic response ).19,20-24the a1c 230 rise in the third trimester was not seen in some studies,25,26 but a decrease was reported in one 231 study.12 in a japanese study, hashimoto et al reported that the a1c rise in late pregnancy is 232 mainly due to iron deficiencies in the third trimester.27 significant racial differences in 233 trimester-related a1c variations were reported in a multiethnic population in the united 234 kingdom by hartland et al; both caucasians and asians had a lower a1c in the second 235 trimester than in the first trimester, but thea1c rise in the third trimester was observed only in 236 causasian women (not in asians, as in our study).22 237 the metabolic changes leading to the significant decline in a1c levels in mid-pregnancy was 238 apparent in a longitudinal study by mills et al.28 this study demonstrated a significant drop in 239 plasma glucose values between 6 and 10 weeks of gestation which was followed by a 240 decrease in a1c levels in second trimester. the authors speculated that the maternal 241 metabolic and hormonal factors alter the plasma glucose concentration early in pregnancy, 242 independently of foetal glucose utilisation. another proposed mechanism for lowering 243 plasma glucose in late first trimester is the decrease in progesterone secretion during the 244 luteoplacental shift.28 the hba1c reduction in the second trimester is further exacerbated by 245 the physiological changes in pregnancy like high erythrocyte turnover and hemodilution. 246 subsequent compensatory mechanisms like maternal plasma reduction and increased atrial 247 natriuretic peptide, can again raise hb in the third trimester. 29 the high prevalence of iron 248 deficiency anemia and the common practice of universal iron supplementation in pregnancy 249 especially in developing countries, can modify a1c levels.3 we excluded women with anemia 250 and thalassemia and the changes in hb, mcv, mch, mchc,and rbc over trimesters is 251 attributable to the physiological changes in pregnancy and to iron supplementation.30 (table 252 2) 253 254 the proposed upper reference hba1c levels in early pregnancy in this study, can be clinically 255 relevant in the early identification of women prone for gdm and adverse pregnancy 256 outcomes. this approach can open up a window of opportunity for early initiation of gdm 257 preventive strategies. strikingly, the suggested upper reference values (5.5 % and 5.3 % in 258 first and second trimesters respectively) are lower than the generally recommended threshold 259 a1c value of 5.7 % (39 mmol/mol) for diagnosis of ‘pre-diabetes in pregnancy’.2 in an earlier 260 study, we observed that the first trimester a1c >5.5% (37 mmol/mol) was a strong predictor 261 (adjusted odds ratio 2.6, p < 0.001) of gdm later in pregnancy.12 similarly, rajput et al 262 studied the utility of a1c estimation between 24 and 28 weeks of gestation for gdm 263 diagnosis in 607 asian indian pregnant women.7 in that study, the a1c of 5.25% 264 (34mmol/mol) was a reliable cut off value for identification of gdm women when iadpsg 265 criteria was applied for gdm diagnosis. the a1c threshold values identified for gdm 266 diagnosis in first and second trimesters in these studies agree well with the corresponding 267 upper reference values of our study. further, maine et al also assessed the relationship of a1c 268 level in the first trimester with adverse pregnancy outcomes among a cohort of multiethnic 269 pregnant women residing in spain.17 270 271 the risk for eclampsia, lga and macrosomia increased at a1c threshold values of 5.3 %, 5.4 272 % and 5.7 % (34,36 and 39 mmol/mol) respectively for the south asian pregnant women in 273 this cohort. these cut off values are near (though not exact) to the first trimester a1c upper 274 reference value of 5.5% (37mmol/mol) in our study. the studies above suggest that the risks 275 for gdm and other adverse pregnancy events start in a1c levels lower than the ‘prediabetic’ 276 level of 5.7 % (39 mmols/mol).we recommend further prospective studies to validate the 277 proposed trimester specific a1c reference levels for prediction and identification of various 278 adverse events among south asian pregnant women. 279 280 our study has several limitations. the a1c reference values of this study are derived from a 281 cross-sectional analysis of different women who attended our antenatal clinic over three 282 trimesters. a longitudinal study on the sequential changes of hba1c levels of a cohort of 283 same women over different trimesters would have been ideal. the impact of this limitation is 284 alleviated significantly in this study: age, gravidity, family history of dm, history of gdm 285 and abortion, gestational age at delivery, birthweight, hb, hba2 and hbf of women in 286 different trimesters and the bmi between control and t1 groups were comparable (table 3). 287 the bmi rise in t2 and t3 groups are due to physiological gestational weight gain.the lack 288 of data on iron, folate and b12 status of women in different trimesters is a limitation, but the 289 rbc indices of these women do not suggest any major deficiencies of these factors. the 290 strengths of this study include the large study population, with identification and exclusion of 291 gdm by universal ogtt based screening as per iadpsg guidelines. all women with gdm 292 risk factors,anaemia and thalassemia (the common hemoglobinopathy of the region) were 293 excluded in this study. being a single center hospital based study, the blood samples were 294 sampled and processed under optimal conditions in one laboratory. 295 296 conclusion 297 the trimester specific hemoglobin a1c levels are not yet defined for healthy south asian 298 pregnant women. this study evaluated the upper reference limits for first, second and third 299 trimesters as 37, 34, and 38 mmol/mol, respectively. these trimester-specific a1c values can 300 be of clinical relevance for prediction and diagnosis of gdm and for risk stratification of 301 other adverse events among south asian pregnant women. further prospective studies to 302 validate the proposed a1c reference intervals are recommended. 303 304 conflicts of interest 305 the authors declare that they have no conflict of interest 306 307 funding 308 the present study is an unfunded project. 309 310 acknowledgements 311 we gratefully acknowledge the immense help received from sheeba samuel and sapna 312 robinson (diabetes nurses) as well as aashish kumar, nikita tyali, and deepali garg 313 (diabetes educators) at the dept of endocrinology, st. stephen’s hospital for the collection of 314 data for this study 315 316 author contributions 317 jp conceptualised the idea and prepared the manuscript. rm carried out statistical analysis 318 and contributed substantially in discussion and preparation of the manuscript. ks and rmr 319 contributed in discussion and provided constructive criticism regarding manuscript. as, pv, 320 nc assisted in clinical data collection, its analysis and contributed to manuscript preparation 321 and discussion rj assisted in analysis of laboratory data and contributed to the manuscript. 322 all authors approved the final version of the manuscript. 323 324 references 325 1. american diabetes association. glycemic targets: standards of medical care in 326 diabetes—2021 diabetes care 2021; 44 (supplement 1): s73-s84. 327 https://doi.org/10.2337/dc21-s006 328 2. hughes rce, rowan j, florkowski cm. is there a role for hba1c in pregnancy? 329 curr diab rep 2016; 6: 5-14. doi 10.1007/s11892-015-0698-y. 330 3. fogsi general clinical practice recommendations. management of iron deficiency 331 anemia in pregnancy available at the federation of obstetric & gynecological 332 societies of india. from: www.fogsi.org/wp-content/uploads/2017/07/gcpr-333 recommendation-ida.pdf. accessed; nov 2021. 334 4. world health organization. diagnostic criteria and classification of hyperglycaemia 335 first detected in pregnancy 2013. 336 https://care.diabetesjournals.org/content/44/supplement_1/s73 https://care.diabetesjournals.org/content/44/supplement_1/s73 https://doi.org/10.2337/dc21-s006 http://www.fogsi.org/wp-content/uploads/2017/07/gcpr-recommendation-ida.pdf http://www.fogsi.org/wp-content/uploads/2017/07/gcpr-recommendation-ida.pdf from:http://apps.who.int/iris/bitstream/10665/85975/1/who_nmh_mnd_13.2_eng337 .pdf. accessed; nov 2021. 338 5. rajput r, yogesh y, rajput m, nanda s. utility of hba1c for diagnosis of 339 gestational diabetes mellitus. diabetes res clin pract. 2012; 98:104-7. 340 6. california state diabetes and pregnancy program sweet success. from: 341 http://perinatology.com/reference/cdapp%20ss%20guidelines%202012.pdf. 342 accessed; nov 2021. 343 7. american diabetes association. management of diabetes in pregnancy: standards of 344 medical care in diabetes—2021 diabetes care 2021; 44 (supplement 1): s200-s210. 345 https://doi.org/10.2337/dc21-s014 346 8. nice guideline. national institute for health and care excellence (2015), diabetes in 347 pregnancy: management diabetes in pregnancy: management from preconception to 348 the postnatal from preconception to the postnatal period. from: 349 https://www.nice.org.uk/guidance/ng3. accessed; nov 2021. 350 9. punnose j, malhotra rk, sukhija k, mathew a, sharma a, choudhary n. glycated 351 haemoglobin in the first trimester: a predictor of gestational diabetes mellitus in 352 pregnant asian indian women. diabetes res clin pract. 2020 ;159: article107953 . 353 doi:10.1016/j.diabres.2019.107953. 354 10. hughes rc, moore mp, gullam je, joanna eg, muhammed k, rowan j. an early 355 pregnancy hba1c >5.9% (41 mmol/mol) is optimal for detecting diabetes and 356 identifies women at increased risk of adverse pregnancy outcomes. diabetes care. 357 2014; 37(11):2953–9. 358 11. mañé l, flores-le roux ja, gómez n, chillarón jj, llauradó g, gortazar l, et al. 359 association of first-trimester hba1c levels with adverse pregnancy outcomes in 360 different ethnic groups diabetes res clin pract. 2019;150:202-210. doi: 361 10.1016/j.diabres.2019.03.017.epub 2019 mar 15. 362 12. nielsen lr, ekbom p, damm p, glumer c, frandsen mm, jensen dm, et al. 363 hba1clevels are significantly lower in early and late pregnancy. diabetes care 2004; 364 5:1200–1. doi: 10.2337/diacare.27.5.1200 365 13. venkataraman k, kao sl, thai ac, salim a, lee jjm, heng d et al. ethnicity 366 modifies the relation between fasting plasma glucose and hba1c in indians, malays 367 and chinese. diabet med. 2012; 29 (7):911-917. 368 http://apps.who.int/iris/bitstream/10665/85975/1/who_nmh_mnd_13.2_eng.pdf http://apps.who.int/iris/bitstream/10665/85975/1/who_nmh_mnd_13.2_eng.pdf http://perinatology.com/reference/cdapp%20ss%20guidelines%202012.pdf https://care.diabetesjournals.org/content/44/supplement_1/s200 https://care.diabetesjournals.org/content/44/supplement_1/s200 https://doi.org/10.2337/dc21-s014 https://pubmed.ncbi.nlm.nih.gov/31794807/ https://pubmed.ncbi.nlm.nih.gov/31794807/ https://pubmed.ncbi.nlm.nih.gov/31794807/ https://pubmed.ncbi.nlm.nih.gov/?size=200&term=ma%c3%b1%c3%a9+l&cauthor_id=30880095 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=flores-le+roux+ja&cauthor_id=30880095 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=g%c3%b3mez+n&cauthor_id=30880095 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=chillar%c3%b3n+jj&cauthor_id=30880095 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=llaurad%c3%b3+g&cauthor_id=30880095 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=gortazar+l&cauthor_id=30880095 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=venkataraman+k&cauthor_id=22283416 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=kao+sl&cauthor_id=22283416 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=thai+ac&cauthor_id=22283416 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=salim+a&cauthor_id=22283416 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=lee+jj&cauthor_id=22283416 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=heng+d&cauthor_id=22283416 14. guariguata l, linnenkamp u, beagley j, whiting dr, cho nh. global estimates of 369 the prevalence of hyperglycemia in pregnancy. diabetes res clin pract 370 2014;103:176–185. 371 15. metzger be, gabbe sg, persson b, buchanan ta, catalano pa, damm p ,et al. 372 international association of diabetes and pregnancy study group. 373 consensus.international association of diabetes and pregnancy study groups 374 recommendations on the diagnosis and classification of hyperglycemia in pregnancy. 375 diabetes care 2010; 33:676–682. 376 16. world health organization, vitamin and mineral nutrition information system, 377 who, geneva, 2011 (who/nmh/nhd/mnm/11.1). from: 378 https://www.who.int/vmnis/indicators/haemoglobin/en/ accessed; sept 2020. 379 17. national neonatology forum. national neonatal-perinatal database (2002-03). 380 from: www.newbornwhocc.org/pdf/nnpd_report_2002-03.pdf. accessed; nov 2021 381 18. solberg he. the ifcc recommendation on estimation of reference intervals. the ref 382 val program. clin chem lab med.2004; 42 (7):710–4. 383 19. mosca a, paleari r, dalfrà mg, di cianni g, cuccuru i, pellegrini g, et al. 384 reference intervals for hemoglobin alc in pregnant women: data from an italian 385 multicenter study. clin chem. 2006; 52(6):1138–43. 386 20. sánchezgonzález cm, castillo-mora a, alvarado-maldonado in, ortega-gonzález 387 c, martínez cruz n, arce –sánchez l et al . reference intervals for hemoglobin a1c 388 (hba1c) in healthy mexican pregnant women: a cross-sectional study. bmc 389 pregnancy and childbirth. 2018; 18:424-429. doi: 10.1186/s12884-018-2057-x 390 21. hiramatsu y, shimizu i, omori y, nakabayashi m. determination of reference 391 intervals of glycated albumin and hemoglobin a1c in healthy pregnant japanese 392 women and analysis of their time courses and influencing factors during pregnancy. 393 endocr j. 2012;59 (2):145–51. 394 22. hartland aj, smith jm, clark pms, webber j, chowdhury t, dunne f. establishing 395 trimesterand ethnic group-related reference ranges for fructosamine and hba1c in 396 non-diabetic pregnant women. ann clin biochem 1999; 36:235–7. 397 23. phelps rl, honig gr, green d, metzger be, frederiksen mc, freinkel n. biphasic 398 changes in haemoglobin a1c concentrations during normal human pregnancy. am j 399 obstet gynecol 1983;147: 651-653. 400 https://www.who.int/vmnis/indicators/haemoglobin/en/ 24. worth r, potter jm, drury j, fraser rb, cullen dr. glycosylated haemoglobin in 401 normal pregnancy: a longitudinal study with two independent methods. diabetologia 402 1985; 28:76. 403 25. o’kane mj, lynch plm, moles kw, magee se. determination of a diabetes control 404 and complications trial-aligned hb a1c reference range in pregnancy. clin chim acta 405 2001; 311:157–9. 406 26. parentoni ls, de faria ec, bartelega mjlf, moda vms, facin acc, castilho ln. 407 glycated haemoglobin reference limits obtained by high performance liquid 408 chromatography in adults and pregnant women. clin chim acta 1998; 274:105–9. 409 27. hashimoto k , noguchi s, morimoto y, hamada s, wasada k, imai s, et al. a1c but 410 not serum glycated albumin is elevated in late pregnancy owing to iron deficiency 411 diabetes care 2008; 31(10):1945-8. doi: 10.2337/dc08-0352. epub 2008 jul 3. 412 28. mills jl, jovanovic l, knopp r, aarons j, conley m, park e , lee yj, et al : 413 physiological reduction in fasting plasma glucose concentration in the first trimester 414 of normal pregnancy: the diabetes in early pregnancy study. metabolism 1998; 415 47(9):1140–1144. doi: 10.1016/s0026-0495(98)90290-6 416 29. lurie s, mamet y. red blood cell survival and kinetics during pregnancy. eur j 417 obstet gynecol reprod biol.2000; 93:185–192. 418 30. milman n, byg ke, agger ao. hemoglobin and erythrocyte indices during normal 419 pregnancy and postpartum in 206 women with and without iron supplementation. 420 acta obstet gynecol scand. 2000; 79(2):89-98. doi: 10.1034/j.1600-421 0412.2000.079002089.x.pmid:10696955. 422 423 table 1: the median and percentiles of hba1c in non pregnant women, whole study 424 population, and in first (t1), second (t2) and third (t3) trimester groups. 425 study group n hba1c % median (0.95 ci) percentile (0.95 ci)a range (minmax) p value type of distributi on 2.5th (0.95 ci) 97.5th (0.95ci) non pregnant 67 5.1(4.9-5.2) 4.0 (3.94.6) 5.7 (5.56.0) 3.9-6.0 <0.001b nongaussian( 5)f pregnant (whole group) 135 7 4.8 (4.8-4.8) 4.0 (3.94.1) 5.5(5.4-5.5) 3.2-5.9 <0.001b nongaussian( 5) https://pubmed.ncbi.nlm.nih.gov/?size=200&term=hashimoto+k&cauthor_id=18599529 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=noguchi+s&cauthor_id=18599529 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=morimoto+y&cauthor_id=18599529 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=hamada+s&cauthor_id=18599529 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=wasada+k&cauthor_id=18599529 https://pubmed.ncbi.nlm.nih.gov/?size=200&term=imai+s&cauthor_id=18599529 https://pubmed.ncbi.nlm.nih.gov/10696955/ https://pubmed.ncbi.nlm.nih.gov/10696955/ t1 0-13weeks 513 4.9 (4.8-4.9) 4.1(4.04.2) 5.5(5.4-5.5) 3.7-5.8 <0.001c nongaussian( 5) t2 14-26 weeks 550 4.8 (4.7-4.8) 4.0 (3.94.1) 5.3 (5.25.4) 3.2-5.5 <0.001d nongaussian( 5) t3 27-41 weeks 294 4.8 (4.7-4.8) 3.9(3.84.1) 5.6(5.4-5.7) 3.6-5.9 0.002d 0.111e nongaussian( 5) n= number of women, a ci: confidence intervals , b p value for comparison of non-pregnant 426 with pregnant groups, c p value for comparison with non pregnant group , d p value for 427 comparison with t1 group , e p value for comparison of t2 and t3 groups, f values in 428 parentheses indicate number of tests for goodness of fit with p<0.05 429 430 table 2: comparison of clinical and laboratory parameters in mean + standard 431 deviation. (a) whole study population versus control group (b) between first (t1), 432 second (t2) and third (t3) trimesters. 433 parameter a whole study population b women in different trimesters women all trimest ers n=1357 non pregnant control group n= 67 p value 0-13 weeks n = 513 (t1) 14-26 weeks n = 550 (t2) 27-41 weeks n= 294 (t3) p valu e t1 vs t2 p value t1 vs t3 p value t2 vs t3 age (years) 26.67 3.51 26.662. 89 0.956 4 26.83  3.50 26.69  3.50 26.343. 57 0.790 0.135 0.351 ga at hba1c estimation (weeks) ---9.53 2.47 18.813. 62 31.23  3.02 -- hemoglobing/l 120.3 7.4 122.8 8.7 0.027 121.7  7.5 119 6.8 120.5 8.0 <0.0 01 0.081 0.016 mcvfl 88.36 5.61 84.097. 86 <0.00 1 87.735.8 4 88.705. 52 88.85 5.22 0.016 0.025 0.937 mch pg 29.38 2.41 28.182. 87 <0.00 1 29.06  2.38 29.61  2.23 29.532. 76 0.001 0.030 0.895 hct % 0.36  0.03 0.37 0.03 0.063 0.36  0.03 0.36  0.03 0.36 0.03 0.366 0.974 0.375 mchc g/l 332.5 10.2 328.5 8.9 0.003 330.9 9.7 333.61 0.1 333.1 11 <0.0 01 0.015 0.762 rdw% 14.75 2.16 14.761. 48 0.977 14.551.6 8 14.742. 19 15.182. 75 0.337 <0.00 1 0.021 rbc – 1012 l 4.100. 40 4.430.5 6 <000 1 4.140.41 4.070.3 9 4.100. 39 0.009 0.298 0.605 ga at delivery (weeks) ---38.53  1.02 38.56  1.02 38.531. 00 0.921 0.999 0.925 birth weight kg ---2.890.29 2.87 0.36 2.850.2 8 0.562 0.199 0.660 for (a) unpaired students t-test was applied to compare the mean value between the groups 434 and for (b) one-way analysis of variance followed by post-hoc turkey’s test. ga = 435 gestational age, mch = mean corpuscular hemoglobin, mcv = mean corpuscular volume, 436 mchc = mean corpuscular hemoglobin concentration, rdw = rbc diameter width. n= 437 number of women. 438 439 figure 1: flow diagram on selection of study population. ogtt= oral glucose tolerance 440 test, gdm= gestational diabetes mellitus; having fasting plasma glucose (pg) between 441 5.1-6.9 mmols/l, 1-hour pg > 10 mmol/l , 2-hour pg between 8.5 – 11.1 mmol/l in 442 ogtt , iadpsg = international association of diabetes and pregnancy study group, 443 pre-gestational diabetes = diabetes diagnosed before pregnancy , diabetes in pregnancy = 444 overt diabetes first diagnosed in pregnancy; hba1c > 48 mmol/mol or fpg > 7 mmol/l or 445 2-h pg > 11.1 mmol/l 446 447 448 figure 2: median and percentile (2.5 to 97.5) for hemoglobin a1c (%) for women in non-449 pregnant and different trimesters. 450 how a brain tumour took over my life diagnosis and removal of a benign meningioma *rosalind buckton-tucker patient’s viewpoint squ med j, august 2009, vol. 9, iss. 2, pp. 198-200, epub 30th june 2009 submitted 14th may 09 accepted 20th may 09 كيف سيطر ورم الدماغ على حياتي : تشخيص وازالة َوَرٌم ِسحائِّي محيد روزالني بكتون تكر department of english, college of arts, sultan qaboos university, muscat, sultanate of oman email: rjbuckton@yahoo.co.uk i have suffered from headaches, in particular migraine headaches, since i was a teenager, and there is a family history of the condition. while annoying and occasionally incapacitating, they did not affect my life in general. i have always otherwise enjoyed good health and fitness and taken part in a variety of active pursuits. it was, therefore, especially frustrating when from august 2008 onwards i experienced worsening headaches, sometimes migraine-type, sometimes a band of pain around the back of the head, which by the early part of 2009 were occurring on almost a daily basis. in addition to the headaches, i was experiencing intermittent vomiting, insomnia sometimes not sleeping until 5 or 6 a.m. weight gain, occasional dizziness, and general fatigue. i would return from work to spend much of the time resting (not a typical pattern for me) and found routine tasks an effort. since august 2008, i had been seeing a succession of doctors at the university health clinic, but no conclusion was reached about what was troubling me, although a variety of tests were carried out and medications tried. one doctor ordered a computed tomography (ct) scan and electroencephalogram in december, but the appointments were given for some months ahead. since the symptoms i had were similar to those for depression, i was evaluated for depression and given medication for the condition, and later started to see a psychiatrist at sultan qaboos university hospital (squh) on a regular basis. he prescribed medication for sleeping in addition to anti-depressant drugs, and carried out further tests. in march, with the headaches and insomnia continuing, the psychiatrist was concerned that i did not seem to be responding to any medication despite an increased dosage, and said he thought i should have an immediate ct scan, which he managed to arrange for the following morning. i had regarded this as in the nature of an exercise to eliminate possible conditions, and was therefore all the more stunned following the scan when he told me i had a brain tumour [figure 1]. specialists at the squh agreed that surgery was the only option, and arranged for me to be admitted to the neurosurgical unit, khoula hospital the same afternoon, with the operation scheduled to take place the following morning. the tumour i had was a benign meningioma, which is a tumour arising from the dura, one of the meninges or membranes surrounding the brain and spinal cord. the cells of the meninges multiply, leading to a tumour, but the cause is uncertain. a meningioma may occur wherever there is dura but the most common sites are over the cerebral hemispheres of the brain. it is the only brain tumour more common in women than men; it usually occurs between the ages of 40 and 60, but can occur at any age. it is rarely malignant.1 mine was 5cm x 5cm in size (about the size of a baseball, according to my american husband) with accompanying oedema. i was astounded to hear that it had probably been there for 15-20 years, as during this time i had taken part in several major mountaineering and adventure expeditions, and medical examinations prior to these had pronounced me not just fit but in excellent health. a doctor friend in england later rosalind buckton-tucker patient’s viewpoint | 199 commented on the difficulty of diagnosing such tumours; as mentioned, symptoms may be similar to those of depression, hence the likelihood of the latter diagnosis. a meningioma may remain small, causing no symptoms, and never require treatment. if it is diagnosed early and does not require immediate attention, the doctor may monitor the condition and discuss possible treatments.2 in my case, the meningioma had been growing gradually and had now reached the size where it was manifesting itself in clear physical symptoms, apparently displacing 20% of the brain matter, so i had no options to consider! fortunately, my tumour was in a frontal position (on the right side), where it was most accessible to surgery [figure 1]. because a meningioma is a vascular tumour, the operation carries risks of bleeding, and four units of blood were kept in reserve because of the size of the tumour, although none was needed during the operation. at khoula hospital, i went through the preliminary routines of examinations and talks with the surgeons, who were very reassuring and anticipated a straightforward operation. the reassurance was relative, and i did not sleep much prior to the surgery! at about 6.30 am, accompanied by my husband, who had come to the hospital to be nearby throughout the procedure, i was taken from the ward to the theatre and the anaesthetic administered. i woke up seemingly only a few minutes later, being wheeled along a corridor with my husband and two nurses in attendance, with a profusion of tubes surrounding me. in fact, the operation had taken six hours, longer than the original estimate of four, but the surgeons were able to report that they had removed the tumour in its entirety (initially, they had thought that a second operation might be needed) and that it was 100% benign. i spent the rest of that day and part of the next in the intensive care unit (icu), with vital signs being carefully monitored and my vision and movement of limbs tested. such an operation entails certain risks, which had been explained in advance. because the tumour was on the right side, there had been a chance that my vision might be affected or that there might be loss of motor skills on the left side. possible longer-term effects are difficulty in concentrating, memory loss, personality changes and seizures.2 immediately following the surgery, i was placed on a redivac drain, which sucks blood from the operation site so that it does not collect. this was kept in place for 24 hours and then removed. i received anti-convulsion medication (given after any brain operation), antibiotics and painkillers, some intravenously and some in tablet or liquid form. my blood sugar was high at first (although i have no history of diabetes), which necessitated additional medication. once i left the icu and returned to the neurosurgery ward, i was able to get up and move around, although on the day following the operation i was given one unit of blood as a precaution to counteract a low haemoglobin count. the surgeons advised me to walk frequently, and i became a familiar sight to the hospital personnel walking from the ward to the hospital exit and back, close to the hand rails just in case, a cap concealing my shaved head and scar. almost from the time the operation was over, i felt stronger and more energetic than i had done for months. i was also, naturally, in much better spirits now that the problem had been diagnosed and treated and i could foresee a return to my former state of health. just a week after the operation, instead of the expected ten days, the sutures were removed, the last cannula taken out, and i was free to go home. i did not need any further medication figure 1: computed tomography scan of patient’s meningioma how a brain tumour took over my life diagnosis and removal of a benign meningioma 200 | squ medical journal, august 2009, volume 9, issue 2 except an anti-epileptic prophylactic, which i would continue taking for the next three months in decreasing doses. thinking of the summer holidays, i asked when i could fly, and the surgeon said, “today, if you like.” two months after the operation, i have not had a single headache or bout of insomnia, and am feeling more energetic each day. however, i have tried to get plenty of rest and avoid strenuous exercise. i am now back at work and ready to face new challenges and adventures. i am awaiting my final check-up at khoula hospital in mid-june. the support and encouragement of friends were instrumental in my recovery. numerous visits to the ward, text messages and telephone calls were a wonderful tonic during the days following the operation. the highlight of my stay in hospital was the suprise visit of my 99-year-old mother and my brother, who had flown from england within two days of hearing the news of the impending surgery and who were a great source of positive energy as i recuperated. my husband set up a webpage on www. caringbridge.org, the website of an organisation designed to keep family and friends in touch in times of ill-health, and which i can strongly recommend to anyone in a similar situation. he wrote an initial account for the ‘story’ page explaining the operation and its background and updated the news assiduously during the following days. i was touched by the messages of good wishes posted by friends in oman and all around the world. in fact, i am still receiving messages as the latest progress in my recovery is reported. i cannot emphasise enough how indebted i am to the doctor who sensed the need for the immediate ct scan and to the excellent surgeons at khoula hospital for their skill, care and readiness to explain everything that was happening and to answer questions. the nursing teams in the icu and neurosurgery wards also deserve high praise for being so friendly, competent and professional at all times. following our expressions of thanks as my husband and i prepared to leave the hospital, we were asked if we would give a testimonial on video to convince others that there was no need to go abroad for such operations when the necessary expertise and facilities were right here in oman. we were only too delighted to do so. now all i need is a little more hair and i will be completely back to my old self! acknowledgement thanks are due to dr. g.p. mishra, neurosurgeon, khoula hospital, for his advice on medical issues with regard to this article. references 1. definition of meningioma. from http://www. medterms.com/script/main/hp.asp?articlekey=296. accessed 12 march 2009 2. meningioma. from http://www.mayoclinic.com/ health/meningioma/ds00901. accessed 9 may 2009. departments of 1paediatric infectious diseases and 2paediatric intensive care unit, royal hospital, muscat, oman *corresponding author’s e-mail: nawal.almaskari@gmail.com severe pneumonitis in omani infants during an in-hospital measles outbreak a report of three cases samiya al-hashmi,1 kholoud al-mukhaini,2 samiuddin shaikh,2 ahmad elkhamisy,2 nuha al tahir,1 *nawal al maskari1 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 129–133, epub. 28 feb 22 submitted 18 aug 20 revisions req. 9 dec 20 & 7 jan 21; revisions recd. 22 dec 20 & 18 jan 21 accepted 7 feb 21 measles-related pneumonia is a life-threatening complication that can lead to severe acute lung injury and acute respiratory distress syndrome. co-infection with other viruses and bacteria is not uncommon. the treatment for measles-related pneumonia primarily involves supportive care. in this article, we report three infants who developed measles-related pneu monia following exposure of the second and third patients to the index case during a hospitalisation. the early detection of measles, isolation of the affected individuals and performance of sensitive investigations in all contacts are needed to prevent the transmission of measles. case one a previously healthy six-month-old male infant was admitted to a tertiary care hospital in muscat, oman, in 2019 with febrile illness and a generalised rash of four days duration. on examination, he was lethargic, dehydrated, febrile and had a normal respiratory rate with bilateral normal breath sounds. he had a maculopapular rash on the face, trunk and extremities. he was admitted to the general ward initially upon suspicion of acute viral fever for hydration with intravenous (iv) fluids. on day three of admission, he became tachypnoeic, tachycardic, febrile with an oxygen saturation of 88–90% in room air; therefore, he was transferred to the high dependency unit for close monitoring and oxygen support via facial mask suspecting acute bronchiolitis. the patient’s complete blood count (cbc) test showed normal white blood cells at 4.0 × 109/l (normal measles is a highly contagious and potentially fatal viral illness that is especially dangerous for infants and malnourished and immunocompromised patients who can develop atypical and severe manifestations.1 the causative pathogen belongs to the paramyxoviridae family and is mainly transmitted by respiratory droplets. measles can be prevented by the available vaccine.2 the symptoms of measles are often mild; however, infants, malnourished and immunocompromised patients can develop atypical or severe manifestations including pneumonitis, acute disseminated encephalomyelitis and subacute sclerosing panencephalitis.3 measlesassociated mortality declined following the implem entation of vaccination programmes, although outbreaks of cases continue to occur when unvaccinated indiv iduals are exposed to the virus.2 the incidence of measles in oman is low (0.53 per 100,000 person-years) and the measles vaccine coverage has been consistently above 95% since 1990.4 in oman, the measles vaccine is administered to all children at 12 and 18 months of age, as recommended by the world health organization (who). however, the centers for disease control & prevention and who guidelines recommend the administration of the measles vaccine at nine months of age during measles outbreaks.5 gulf countries have implemented a vaccination schedule involving two doses of the measles, mumps, and rubella vaccine, with the first dose at 12 months of age. the measles vaccine coverage in bahrain has been more than 90% and has been sustained at >97% since 2001.6 vitamin a supplementation is recommended by the who for all children with measles.7 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.4.2021.063 case report abstract: measles is a highly contagious infectious disease. despite aggressive national initiatives to eradicate measles, outbreaks have occurred in recent years. we report three infants who presented to a tertiary care hospital in muscat, oman, in 2019 with measles and then developed pneumonitis, received intensive care treatment and made full recoveries. infants can have an atypical presentation and develop severe symptoms. pneumonitis is a serious complication and the management strategies are controversial. the early detection of measles and isolation of affected individuals play major roles in the elimination of measles outbreaks. keywords: measles; pneumonitis; infant; respiratory distress syndrome; vitamin; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ severe pneumonitis in omani infants during an in-hospital measles outbreak a report of three cases 130 | squ medical journal, february 2022, volume 22, issue 1 range: 1.4‒9.0 × 109/l) with normal neutrophils and lymphocyte count. he received dexamethasone, adrenaline nebulisation and oseltamivir. a nasopha ryngeal viral multiplex polymerase chain reaction (pcr) test was reported negative for respiratory viruses including respiratory syncytial virus, influenza a and b, rhino viruses, parainfluenza, coronaviruses, adenoviruses, bocavirus, enteroviruses, paraechoviruses, human metapneumovirus and mycoplasma pneumonia. his hospital stay was complicated with the development of respiratory distress and clinical sepsis requiring admission to the paediatric intensive care unit (picu) on day three and the use of non-invasive ventilation (niv). a chest x-ray (cxr) showed bilateral lung infiltration [figure 1]. his vital signs on admission to the picu showed persistent tachycardia (170 beats/min) with fever (38°c) and tachypnoea (70 breaths/min) with saturation above 93% on niv. on detailed clinical assessment, he was found to have koplik spots and bilateral conjunctivitis. a nasopharyngeal swab pcr test was reported positive for measles. measles immunoglobulin (ig)m antibody test was positive. he required niv support, which was weaned within one day and he was then transferred to an isolation room. he required oxygen for the subsequent three days and was discharged uneventfully to home on day eight of admission. a detailed examination of this case by infection control specialists did not reveal the source of the infection. case two a nine-month-old female infant was diagnosed with tracheoesophageal fistula for which she underwent an operation; previously, she had been diagnosed with hypotonia, developmental delay and hypothyroidism. additionally, she underwent investigations due to the suspicion of a glycogen storage disorder. she was admitted for endoscopic dilatation of the oesophageal stricture during which she was exposed to case one. ten days after exposure, she developed a high-grade fever with cough and irritability. a maculopapular rash appeared on day two of her illness. physical examination revealed a generalised maculopapular rash, a pulse rate of 170 beats/min and a blood pressure of 100/58 mmhg with tachypnoea; therefore, she was transferred to the picu. her cxr showed bilateral lung opacities. her cbc showed leukopenia at 2.9 × 109/l and lympho paenia 0.4 × 109/l (normal range: 4–10.5 × 109/l) with normal neutrophils. furthermore, her inflammatory marker levels were high with an erythrocyte sedimen tation rate of 72 mm/hr (normal range: 0–20 mm/hr) and c-reactive protein level of 89 mg/dl (normal range: <10 mg/dl). she was started on niv for respiratory distress. her pulmonary condition worsened clinically and radiologically with characteristics of acute respiratory distress syndrome (ards); therefore, the mode of respiratory support was changed to invasive ventilation. she also required inotropic support with an infusion of adrenaline. she had persistent fever despite antibacterial treatment and negative blood and tracheal cultures and was, therefore, treated for atypical kawasaki disease in view of features of prolonged fever, rash for 10-day duration and suspected coronary dilation on the echocardiography. however, a nasopharyngeal swab pcr test revealed a positive test for measles and her measles igm test was also positive. she received one day of high-dose methylprednisolone. she met the criteria for a diagnosis of ards with a partial pressure of oxygen to fraction of inspired oxygen ratio of 122, indicating severe acute lung injury. as part of the management strategy for ards, she was treated with a lung-protective ventilation strategy with the airway pressure release ventilation mode for seven days and 80% maintenance fluids. treatment for measlesrelated pneumonia included the administration of vitamin a for 48 hours and ribavirin for five days. over the course of five days in the picu, she gradually improved, and she was extubated on day seven after admission to the picu. she was transferred to the paediatric ward, where she stayed for three weeks. she continued to need supplemental oxygen, although that requirement was resolved before discharge. case three an 11-month-old female infant diagnosed with trisomy 21 who underwent surgery for ventricular septal defects was admitted with acute bronchiolitis figure 1: chest x-ray of a six-month-old infant (case one) with measles infection showing bilateral infiltrates. samiya al-hashmi, kholoud al-mukhaini, samiuddin shaikh, ahmad elkhamisy, nuha al tahir and nawal al maskari case report | 131 figure 2: chest x-ray of an 11-month-old infant (case three) with measles infection showing bilateral chest infiltration two days after paediatric intensive care unit admission. and needed niv support. she was discharged home but readmitted with febrile illness, respiratory distress, and maculopapular rash. her history revealed exposure to case one during hospitalisation 10 days before presentation. on examination, her temperature was 39.3°c, with a blood pressure of 102/62 mmhg, heart rate of 168 beats/minute and respiratory rate of 60 breaths/minute with oxygen saturation of 86% in room air, therefore, she required niv and picu care. she had a generalised maculopapular rash with a wheezy chest. investigations revealed normal cbc and negative blood culture. a cxr revealed bilateral infiltration, and she was, therefore, treated for suspected measles-related pneumonitis or acute viral bronchiolitis [figure 2]. nasopharyngeal swab for viral multiplex pcr test was positive for measles and negative for other viruses. measles igm antibody test showed a positive result. she required niv for one day in the picu due to respiratory distress. she was started on dexamethasone, vitamin a, ceftriaxone and oseltamivir. she gradually improved and showed complete recovery on the third day of admission and was transferred to the paediatric ward isolation room. she was observed in hospital for breathing difficulty and oxygen requirement and was discharged after three weeks stay breathing room air. overall, 10 patients were admitted with a diagnosis of measles to the current hospital over a period of seven years from 2013 to 2019. three required icu admission (cases one to three), four were discharged from the emergency room and the remaining three were admitted to the paediatric ward for fluid support. the average hospital stay was 2–3 days for those admitted to the general ward. none of the 10 patients had received the measles vaccine; nine were younger than one year old. there was a history of positive contact with a suspected or confirmed case for eight patients. the diagnosis of measles was made based on the finding of relevant clinical symptoms which was confirmed by positive serological tests, pcr from throat swab samples and the isolation of the virus from urine samples. this study was approved by the hospital’s scientific research committee (src#cr26/2020). discussion to the best of the authors’ knowledge, this is the first case report from oman to report three infants with severe respiratory manifestations related to measles [table 1]. measles is a highly contagious disease with a transmission rate of at least 90%.4 it can be prevented by the available vaccine, adherence to infection control measures and careful investigations of all reported measles cases.4 oman had measles outbreaks from 1992 to 1993 and 2016 to 2017.4 these outbreaks were attributed to imported cases leading to infections among the susceptible population, which is mainly composed of unvaccinated persons (unpublished data). to increase awareness, the ministry of health introduced many measures aimed table 1: characteristics of cases one to three characteristic case one case two case three age in months 6 9 11 gender male female female comorbidities none tracheoesophageal fistula, suspected glycosylated storage disease, hypotonia developmental delay trisomy 21, operated for vsd duration of positive pressure ventilation in days (type of ventilation) 1 (niv) 7 (invasive ventilation) 1 niv length of picu stay in days 1 10 1 complications none ards, secondary bacterial infection none vsd = ventricular septal defect; niv = non-invasive ventilation; picu = paediatric intensive care unit; ards = acute respiratory distress syndrome. severe pneumonitis in omani infants during an in-hospital measles outbreak a report of three cases 132 | squ medical journal, february 2022, volume 22, issue 1 at eliminating measles including introducing the fever and rash surveillance programme in 2004, developing national measles guidelines and conducting training workshops. widespread catch-up vaccine campaigns were conducted in march 1994 and 2017 that targeted the susceptible population.4 in their meta-analysis, nic lochlainn et al. showed that the measles vaccine is safe and effective for children less than nine months of age and that its early administration is an important step to reduce severe manifestations.8 however, it is challenging to sustain herd immunity in oman as not all of the population had received the measles vaccine.4 measles-related pneumonia is serious and is associated with high mortality, especially in children less than five years of age as well as malnourished and immune-compromised children.3 the described lung changes in patients with measles-related pneumonia include congestion, necrosis and exfoliation of bronchial and bronchiolar mucosa. these lung changes lead to increased susceptibility to other forms of viral and bacterial pneumonia, thus increasing the risk of acute lung injury and ards.9 coetzee et al. reported that the rate of mortality due to severe measles was higher than the rate of mortality due to other causes among a cohort of picu patients (the measles-related mortality rate was 31% and the non-measles-related mortality rate was 8.8%).10 the most common cause of measles-related mortality is ards with progressive respiratory failure (56%).10 in general, the majority of those admitted with severe pneumonia required ventilator support. ards and the presence of air leaks such as pneumothorax are associated with worse outcomes.11 the therapeutic strategies for ards include the initiation of lungprotective mechanical ventilation, lung recruitment manoeuvres, fluid management and the appropriate application of muscle relaxants.12 case two in this article was treated using lung-protective strategies, lung recruitment and fluid restriction in addition to supplementation with vitamin a and ribavirin. none of the current cases had received the measles vaccine as all were less than one year of age and the immunisation policy of the country is to vaccinate between 12 to 18 months of age. two of these cases had underlying chronic complex medical problems. case one was admitted with a history of fever, rash and conjunctivitis without a history of positive contact with a suspected or confirmed case. as the incidence of measles is low in oman, measles was not suspected in case one; therefore, he was admitted to the general ward rather than being isolated. as a result, case two and three were exposed to case one. this study emphasises the need to increase awareness of and adherence to infection control measures to prevent an in-hospital outbreak. all of the current cases had to be transferred to the picu due to hypoxaemia and the need for respiratory support. case two developed ards and required invasive mechanical ventilation while the other two cases had milder forms of respiratory distress and needed niv support; none of the other cases had air leak syndrome. all patients were treated supportively with vitamin a and appropriate antibiotics, as cxr showed pulmonary infiltration. case two was initially suspected to have atypical kawasaki disease based on her history of a prolonged fever lasting 10 days, high levels of inflammatory markers and suspected coronary dilation on echocardiography. however, upon reviewing the echocardiography findings, coronary dilatation was excluded. she showed clinical and radiological improvement one day after starting high-dose iv immunoglobulin (ivig) and methylprednisolone. however, her improvement could also be attributed to the change in ventilation and fluid restriction. despite recent advancements in medicine, the management of measles still relies primarily on supp ortive care and includes hydration, the administration of antibiotics for secondary bacterial infections and supplementation with vitamin a.13 a few studies have shown that the use of iv methylprednisolone is associated with improved patient outcomes.9 however, there have been no randomised controlled trials supporting the use of high-dose methylprednisolone in the treatment of measles-related pneumonia. meduri et al. demonstrated that early use of a low dose of methylprednisolone in patients with ards resulted in an improvement in oxygenation and reduction in duration of mechanical ventilation and icu length of stay.14 infection with measles can lower the immune function. ivig has been used successfully for measles post-exposure prophylaxis; however, it’s effectiveness in the treatment of measles pneumonia has not yet been identified. ivig may be used for measles pneumonia to boost the body's immune function, inhibit inflammatory reactions and thereby, accelerates the improvement of symptoms.15 conclusion healthcare providers need to increase their awareness of the criteria for the diagnosis of the measles, especially in countries where the incidence of measles is low. measles should be suspected in all unvaccinated infants and children presenting with fever and rash and diagnostic assessments should include surveillance samiya al-hashmi, kholoud al-mukhaini, samiuddin shaikh, ahmad elkhamisy, nuha al tahir and nawal al maskari case report | 133 for the pathognomonic signs of measles. adhering to the required infection control measures is essential to prevent in-hospital transmission. unvaccinated infants are prone to developing severe complications of measles; therefore, those with respiratory deter ioration need to be transferred to the picu at an early stage. a u t h o r s’ c o n t r i b u t i o n nam conceptualised the manuscript. sah and nat collected the clinical data. sah, ae and nat conducted the literature review. sah, kam, ss, ae and nam drafted the manuscript. kam, ss and nam critically reviewed the manuscript and provided intellectual input. all authors approved the final version of the manuscript. references 1. sindhu tg, geeta mg, krishnakumar p, sabitha s, ajina kk. clinical profile of measles in children with special reference to infants. trop doct 2019; 49:20–3. https://doi.org/10.1177 /0049475518804695. 2. uchendu o, ige o, adeyera o. knowledge and home treatment of measles infection by caregivers of children under five in a low-income urban community, nigeria. afr j prim health care fam med 2019; 11:e1–13. https://doi.org/10.4102/phcfm.v11i1.1744. 3. misin a, antonello rm, di bella s, campisciano g, zanotta n, giacobbe d, et al. measles: an overview of a re-emerging disease in children and immunocompromised patients. microorganisms 2020; 8:276. https://doi.org/10.3390/microorganisms8020276. 4. ministry of health, oman. public health bulletin: measles epidemiology and elimination status in oman. from: www.moh. gov.om/documents/236878/0/public+health+bulletin+%233/ db2a8256-b6a5-473d-a30b-b3a3b800ad8f accessed: jan 21. 5. soucheray s. reviews suggest first measles vaccination typically best after 9 months of age from: www.cidrap.umn.edu/news-per spective/2019/09/reviews-suggest-first-measles-vaccinationtypically-best-after-9-months-age accessed: jan 21. 6. jawad js, al-sayyad as, sataih f, naouri b, alexander jp jr. toward measles elimination in bahrain--a middle east country experience. j infect dis 2011; 204 suppl 1:s299–304. https:// doi.org/10.1093/infdis/jir105. 7. lindberg c, lanzi m, lindberg k. measles: still a significant health threat. mcn am j matern child nurs 2015; 40:298–305. https://doi.org/10.1097/nmc.0000000000000162. 8. nic lochlainn lm, de gier b, van der maas n, strebel pm, goodman t, van binnendijk rs, et al. immunogenicity, effective ness, and safety of measles vaccination in infants younger than 9 months: a systematic review and meta-analysis. lancet infect dis 2019; 19:1235–45. https://doi.org/10.1016/s1473-3099(19)30395-0. 9. suter c, buergi u, eigenmann k, franzen d. severe acute measles pneumonitis: virus isolation in bronchoalveolar lavage fluid. bmj case rep 2015; 2015:bcr2015210826. https://doi.org/10.11 36/bcr-2015-210826. 10. coetzee s, morrow bm, argent ac. measles in a south african paediatric intensive care unit: again! j paediatr child health 2014; 50:379–85. https://doi.org/10.1111/jpc.12486. 11. li j, zhao y, liu z, zhang t, liu c, liu x. clinical report of serious complications associated with measles pneumonia in children hospitalized at shengjing hospital, china. j infect dev ctries 2015; 9:1139–46. https://doi.org/10.3855/jidc.6534. 12. prodhan p, noviski n. pediatric acute hypoxemic respiratory failure: management of oxygenation. j intensive care med 2004; 19:140–53. https://doi.org/10.1177/0885066604263859. 13. huiming y, chaomin w, meng m. vitamin a for treating measles in children. cochrane database syst rev 2005; 2005:cd001479. https://doi.org/10.1002/14651858.cd001479.pub3. 14. meduri gu, golden e, freire ax, taylor e, zaman m, carson sj, et al. methylprednisolone infusion in early severe ards: results of a randomized controlled trial. chest 2007; 131:954–63. https://doi.org/10.1378/chest.06-2100. 15. chen l, qi x, li r, wang x, shi b, meng q. injection of immun oglobulin in the treatment process of children with severe pneu monia. pak j med sci 2019; 35:940–4. https://doi.org/10.12669/ pjms.35.4.83. https://doi.org/10.1177/0049475518804695 https://doi.org/10.1177/0049475518804695 https://doi.org/10.4102/phcfm.v11i1.1744 https://doi.org/10.3390/microorganisms8020276 https://doi.org/10.1093/infdis/jir105 https://doi.org/10.1093/infdis/jir105 https://doi.org/10.1097/nmc.0000000000000162 https://doi.org/10.1016/s1473-3099(19)30395-0 https://doi.org/10.1136/bcr-2015-210826 https://doi.org/10.1136/bcr-2015-210826 https://doi.org/10.1111/jpc.12486 https://doi.org/10.3855/jidc.6534 https://doi.org/10.1177/0885066604263859 https://doi.org/10.1002/14651858.cd001479.pub3 https://doi.org/10.1378/chest.06-2100 https://doi.org/10.12669/pjms.35.4.83 https://doi.org/10.12669/pjms.35.4.83 climate projections indicate catastrophic consequences in the middle east and north africa region why healthcare workers are conspicuously absent in climate change discourse samir al-adawi sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 441–442, epub. 7 nov 22 editor-in-chief, sultan qaboos university medical journal, muscat, oman author’s e-mail: adawi@squ.edu.om as the gregorian calendar reaches theend of 2022, the middle east and north africa (mena) or eastern mediterranean region has been lauded for hosting the 2022 united nations climate change conference (unfccc), widely dubbed as cop27 (conference of the parties of the unfccc). the meeting has been held at a critical junction for projected climate change: the mena region has been documented to be the region most vulnerable to experiencing the vagaries of the climate crisis, which means long-term changes in temperatures and weather patterns.1 historically, variations in the solar cycle contribute to natural changes in temperature and weather. more recently, however, the intergovern mental panel on climate change (ipcc) of the united nations has identified human activities as the "primary driver" for climate change.2 according to a recent article, the mena region will continue to experience climatic changes ‘two times faster than the global average’ in climatic changes.2 the region has already been dubbed as being part of the ‘global climate change hot spots’.2 due to these factors, vohra has suggested that the mena region will be “uninhabitable” before the end of the century.3 the situation is already more critical as the scorching sun in the summer dwells longer in the sky and the weather is becoming hotter and hotter. as a result of the lack of precipitation, rivers are dying, devastating wildfires are becoming common and the once-tranquil arabian sea is now more frequented by more devastating winds with rougher waves and clouds.4,5 the mena region has experienced increasing population growth, resulting in rapid urbanisation. studies have suggested that the growth of these cities has the potential to trigger the ‘urban heat island effect’ defined as the “phenomenon where roads and buildings in urban areas absorb and re-emit heat, resulting in warmer temperatures than surrounding nonurban areas by upward of 10° c”.6,7 for the mena region, possessing the ‘superpower’ of fossil fuels, climate projections are a cause for concern. although it is essential, if not paramount, for the mena region to kickstart decarbonisation strategies, in some of the countries in the mena region, fiscal policies strongly hinge on the exploitation of hydrocarbons. despite such a caveat, there is evidence to suggest that concerted efforts are underway in some of the oil producing countries to find alternative sources of energy. however, these efforts appear to have stalled due to geopolitical instability, the tribulations of covid-19 and the fact that the region itself is beset by many conflicts. but the issue of climate change should not only be gleaned from the ‘ism and schism' of global politics; healthcare workers (hcws) have a stake in the climate discourse. rising temperatures and meteorological condi tions should alert hcws to ‘think globally, act locally’. extensive empirical evidence suggests that the effect of climate change, directly and indirectly, affects the health and well-being of the world's population. extreme shifts in temperature and weather patterns have the potential to precipitate injuries and illnesses as well as disrupt the functioning of healthcare facilities.8 according to the centers for disease control and prevention of usa, adverse temperatures and weather conditions exacerbate the magnitude and pattern of ill-health and diseases.9 exposure to untimely floods, sandstorms, rising seas and wildfires has the potential to prompt poor coping, which, in turn, adversely impacts the integrity of the biopsychological system setting off cascades of pathological processes in the body and mind.10 depending on the organ of inferiority, the development of a spectrum of medical, psychological and neurological problems is likely to ensue. hence, such a scenario would increase the utilisation of healthcare services as well as spike morbidity and mortality.4 some of the evidence for the link between climate change and the pattern of diseases is becoming increasingly obvious. first, human activities burning fossil fuels such as coal, oil and gas tend to increase ground-level ozone and pollute the air, which, in turn, spikes the incidence of respiratory message from the editor-in-chief this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.10.2022.061 “this century is a special one, where we as humans destroy ourselves.” martin rees https://creativecommons.org/licenses/by-nd/4.0/ climate projections indicate catastrophic consequences in the middle east and north africa region why healthcare workers are conspicuously absent in climate change discourse 442 | squ medical journal, november 2021, volume 21, issue 4 disorders.4 related to this, living in a polluted setting has been documented to be critically associated with diminution of efficiency of higher human faculty, namely cognition with all the consequences this may entail.11 second, climate changes increase pollen concentrations in the atmosphere, which exacerbates the conditions that are associated with pollen and allergens. third, numerous vector-borne diseases and zoonotic phenomena are linked to climate change.4 the re-emergence of non-communicable diseases such as cholera and other killer diseases have recently been documented in lebanon and pakistan and climate change appears to be a strong suspect in this. this unfortunate occurrence is due to the fact that the mena region is still struggling with the ‘doubleedged sword’ of communicable diseases amid noncommunicable diseases. the prevalent poverty rate, food insecurity and inequality in the mena region imply that the region will have little recourse to mitigate the seismic effect of changes in temperatures and weather patterns. it is not clear whether the legal agreement reached at the cop27 at sharm el-sheikh, egypt, or for that matter, the previous meeting in the mena region (cop22 in 2016 held in bab ighli, marrakech, morocco) would recoup the tangible result to come to grips with the catastrophic consequences of projected and already prevailing climate change in the region. this implies that hcws in the region cannot stand on the sidelines when the world is experiencing these menacing temperatures and weather patterns. on the one hand, a study has examined awareness of the health implications of climate change among the general population and hcws. the data suggests that hcws tend to have suboptimal awareness of the health implications of climate change.12 according to kotcher et al., “health professionals have an extraordinary opportunity to become trusted voices in support of global efforts to reduce emissions and protect people from the threat of climate change”.13 such dormant power needs to be resuscitated and accompanied by the building of an evidence-based database of the health implications of climate change. according to the working group to advance action on climate change and health, all spheres of hcws should be able to “identify, prevent, and respond to the health impacts of climate change and environmental degradation”.14 part of this initiative is to incorporate the health implications of climate change into curriculum and research.13 intuitively, some healthy human activities (e.g. walking, less gluttony) reduce the carbon footprint. this means all cadres of the caring profession should not be bystanders of simply ‘treating the symptoms’ but be critically involved in thwarting the growing threat of a climate apocalypse. to echo a jamaican reggae singer, “how can you be sitting there, telling me that you care, that you care? when every time i look around, the people suffer in the suffering, in every way, in everywhere”. references 1. ipcc. summary for policymakers. in: masson-delmotte v, zhai p, pirani a, connors sl, péan c, berger s, et al, eds. climate change 2021: the physical science basis. contribution of working group i to the sixth assessment report of the intergovernmental panel on climate change. cambridge, uk: cambridge university press, 2021. pp. 3–32. 2. zittis g, almazroui m, alpert p, ciais p, cramer w, dahdal y, et al. climate change and weather extremes in the eastern mediterranean and middle east. rev geophys 2022; 60:e2021rg000762. 3. vohra a. the middle east is becoming literally uninhabitable. from: https://foreignpolicy.com/2021/08/24/the-middle-eastis-becoming-literally-uninhabitable/ accessed: oct 2022. 4. neira m, erguler k, ahmady-birgani h, daifallah al-hmoud n, fears r, gogos c, et al. climate change and human health in the eastern mediterranean and middle east: literature review, research priorities and policy suggestions. environ res 2022; 114537. https://doi.org/10.1016/j.envres.2022.114537. 5. evan at, kossin jp, chung ce, ramanathan v. arabian sea tropical cyclones intensified by emissions of black carbon and other aerosols. nature 2011; 479:94–7. https://doi.org/10.1038/ nature10552. 6. shandas v, voelkel j, williams j, hoffman j. integrating satellite and ground measurements for predicting locations of extreme urban heat. climate 2019; 7:5. 7. patel l, conlon kc, sorensen c, mceachin s, nadeau k, kakkad k, kizer kw. climate change and extreme heat events: how health systems should prepare. nejm catalyst innovations care delivery 2022; 3:cat–21. 8. arcaya m, raker ej, waters mc. the social consequences of disasters: individual and community change. ann rev sociol 2020; 46:671–91. https://doi.org/10.1146/annurevsoc-121919-054827. 9. centers for disease control and prevention. climate effects on health. cdc 24/7: saving lives, proteching people. from: http s ://w w w.cdc .gov/climate andhe alth/effe ct s/def ault . htm#:~:text=the%20health%20effects%20of%20these,and%20 threats%20to%20mental%20health accessed: oct 2022. 10. crews de, kawa nc, cohen jh, ulmer gl, edes an. climate change, uncertainty and allostatic load. ann hum biol 2019; 46:3–16. https://doi.org/10.1080/03014460.2019.1584243. 11. hu k, hale jm, kulu h, liu y, keenan k. a longitudinal analysis of the association between long-term exposure to air pollution and cognitive function among adults aged 45 and over in china. j gerontol b psychol sci soc sci 2022; gbac162. https://doi. org/10.1093/geronb/gbac162. 12. hathaway j, maibach ew. health implications of climate change: a review of the literature about the perception of the public and health professionals. curr environ health rep 2018; 5:197–204. https://doi.org/10.1007/s40572-018-0190-3. 13. kotcher j, maibach e, miller j, campbell e, alqodmani l, maiero m, et al. views of health professionals on climate change and health: a multinational survey study. lancet planet health 2021; 5:e316–23. https://doi.org/10.1016/s25425196(21)00053-x. 14. world heart federation. a call for strengthening climate change education for all health professionals. from: https:// world-heart-federation.org/news/a-call-for-strengtheningclimate-change-e ducation-for-all-healthprofessionals/ accessed: oct 2022. advances in knowledge 1. first report from oman describing the characteristics of patients with asthma and the management practices in a specialist centre. 2. allergic comorbidities and a strong family history are common in patients with asthma in oman. 3. concepts of short term and long term control in asthma introduced. application to patient care 1. goals of asthma treatment can be achieved if the international guidelines are followed properly. 2. more time needs to be spent on asthma education especially in the training of inhaler techniques and explanation of the need for regular use of controller medications. management and control of asthma in patients attending a specialist centre in oman omar a al-rawas,1 jayakrishnan b,2 fatma ben abid,2 jojy george,2 sawsan a baddar,2 bazdawi m al-riyami1 squ med j, august 2009, vol. 9, iss. 2, pp. 132-139, epub 30th june 2009 submitted 2nd february 09 revision req. 4th may 09, revision recd. 17th may 09 accepted 19th may 09 1department of medicine, college of medicine and health sciences, sultan qaboos university, muscat, sultanate of oman; 2department of medicine, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addresses. email: orawas@squ.edu.om clinical & basic research عالج الربو والسيطرة عليه مبركز ختصصي يف عمان عمر الرواس، جايا كريشنان، فاطمه بن عابد، جوجي جورج، سوسن بدار، بزدوي الريامي امللخص: الهدف: تكون الطريقة التي يستخدمها االختصاصيون لعالج الربو أكثر استنادا على األدلة عادة. في هذه الدراسة قمنا بتحليل خواص املرضى املراجعني لعيادتنا التخصصية من النواحي الدميغرافية ونوع األدوية املستعملة ومدى السيطرة على املرض. الطريقة: أجريت هذه الدراسة مابني ديسمبر 2005 ونوفمبر 2006 وشملت كل املرضى البالغني املصابني بالربو في مستشفى جامعة السلطان قابوس وذلك باستخدام بروتوكول مكتوب للتقييم. النتائج: شملت الدراسة 207 مرضى متوسط أعمارهم )40.64 ±14.8( سنة، وكان معظمهم من النساء )%72(، كما كان غالبية املرضى )%83.1( يعاني من الربو متوسط الشدة. بلغت نسبة حدوث حساسية األنف واجللد بني املرضى )%58.0( و )%11.1( على التوالي، فيما بلغت نسبة اإلصابة باحلساسية عند العائلة )%50.7(. كان مستوى الغلوبيولني املناعي الكلي نوع )e( في املصل مرتفعا )%66.7.( بينما كان فحص حساسية اجللد ايجابيا ألكثر من مستضدين عند )%52.3( من املرضى ، وكان مستضد غبار البيت فعاال في )%49( . بلغت نسبة العالج بالستيرويدات املستنشقة )%94.2( وموسعات الشعب الهوائية طويلة املفعول )ناهضات بيتا( )%85( ومضادات الهستامني )54.5%( ومضادات مستقبالت ليوكوترين)%11.6(. الغالبية )%40.1( استعملت الستيرويدات املنشقة بجرع متوسطة . وعلى الرغم من السيطرة على الربو في الشهر السابق بنسبة )%78.3(؛ فإن )%31.9( من املرضى راجعوا قسم الطوارئ و )%15( مت إدخالهم املستشفيات على األقل مرة واحدة بدقة الطبية النصائح فقط )25.6%( اتبع بينما صحيحة بطريقة البخاخ يستعملون فقط املرضى من )30.4%( السابق. ظهران العام في عائلي تأريخ وجود في احلال هو كما االنتشار واسعة االرجي بالطابع املتميزة املرافقة املراضة كانت الستيرويدية. اخلالصة: املنشقات باستخدام موجب للربو . على بالرغم من أن نسبة السيطرة على الربو في الشهر السابق كانت عالية ، إال أنها أقل بكثير على املدى الطويل ، وهذا يستدعي إعادة النظر في أساليب قياس معدل السيطرة على الربو على املدى القصير والطويل. مفتاح الكلمات: ربو، عمان، رعاية متخصصة، السيطرة على الربو. abstract: objectives: the management of asthma by specialists is likely to become more evidence-based. this study analysed the characteristics of patients reporting to a specialist clinic including demographics, dispensed medications and the level of asthma control. methods: all consecutive stable asthmatics seen in the adult pulmonary clinics of sultan qaboos university hospital, oman, between december 2005 and november 2006 were prospectively evaluated using a structured assessment protocol. results: of the 207 patients, )mean age 40.64 ±14.8(, 72% were females. the majority, 83.1%, had moderate persistent asthma. a positive history of allergic rhinitis, eczema and a family history of asthma were obtained in 58.0%, 11.1%, and 50.7% of patients respectively. total serum immunoglobulin e )ige( was elevated in 66.7%. skin testing was positive for more than 2 antigens in 52.3%, with the house dust antigen being reactive in 49%. inhaled steroids, long-acting beta agonists )laba(, antihistamines and leukotriene receptor antagonists were prescribed in 94.2%, 85%, 54.5% and 11.6% of cases respectively. the majority )40.1%( was receiving medium dose inhaled steroids. although asthma was controlled in 162 )78.3%(, during the previous month 66 )31.9%( patients had visited the emergency department and 31 )15.0%( patients were hospitalised at least once during the previous year. only 63 )30.4%( patients were using their inhalers correctly. good compliance with inhaled steroids was observed in only 53 )25.6%( patients. conclusion: allergic comorbidities and a strong family history of asthma were common. although the level of asthma control in the previous month was high, it was much lower in the long term. the concepts of short term, long term and total control of asthma need to be explored. keywords: asthma; oman; specialist care; asthma control. omar a al-rawas, jayakrishnan b, fatma ben abid, jojy george, sawsan a baddar and bazdawi m al-riyami clinical and basic research | 133 current asthma management is focused on asthma control.1 the management of asthma in a tertiary care centre by specialists is expected to be more scientific, following international or local guidelines more strictly. however, gaga et al. 2 reported that the goals of asthma treatment were not achieved, even under specialist care, as some patients were found not to follow prescriptions despite the distressing nature of their symptoms. in oman, no published data are available on the magnitude of asthma in adults, but the prevalence of allergic conditions in children, including asthma, was found to be higher than in neighbouring countries and that too with significant morbidity.3 a study among private practitioners in oman, undertaken a decade ago, showed that the treatment of both acute and stable asthma was sub-optimal.4 interestingly, a more recent survey among asthma specialists in the chicago area revealed that the care is consistent with national guidelines with certain differences and that the asthma care differed between the two subspecialty groups of allergists and pulmonologists.5 in this context of a higher prevalence of asthma and the reports of differences in the care rendered, it is important to study patients under the care of specialists in our area in order to plan optimal asthma control. the aim of this study was to document the characteristics of adult patients reporting to the specialists at sultan qaboos university hospital (squh) including demographics, dispensed anti-asthma medications and the level of asthma control. methods all consecutive patients referred to or followed up in the adult pulmonary clinics of squh between december 2005 and november 2006 with a diagnosis of asthma, were considered for enrolment in the study and were prospectively evaluated using a structured assessment protocol. squh is a teaching tertiary care hospital which receives referrals from all over oman. the diagnosis of asthma was made by the physician on the basis of typical history of wheezing, breathlessness, recurrent exacerbations, a previous response to asthma medications, spirometry results and peak expiratory flow rate (pefr) variability. a positive family history, elevated total serum immunoglobulin e (ige) and positive skin tests were also factors confirming the diagnosis. at the time of the evaluation, the patients were in their usual state of health, stable and with no evidence of asthma exacerbations. during assessment in the clinic, the following information was obtained: duration of asthma, smoking and family history, the degree of asthma control based on asthma symptoms, frequency of exacerbations, hospital admissions, emergency visits, and use of asthma medications. patients’ compliance with the medications and inhaler technique were also assessed and documented. current and ex-smokers were excluded from the study. patients with a history or evidence of co-existing chronic lung disease, heart disease or any other illness were not included. asthma severity was assessed by a composite score based on global initiative for asthma (gina) guidelines.6 plain chest radiographs were performed for all patients, and only those with normal or minor changes consistent with asthma like hyperinflation and increased lung markings were included. the forced vital capacity (fvc), the forced expiratory volume in the first second (fev1) and the response to bronchodilator administration were measured using a spirometer according to the european respiratory society guidelines.7 skin prick tests were performed using the bencard system with a panel of 25 allergens. positive skin reactions were assessed as wheal and flare reactions greater than 3mm. serum ige was measured using a microparticle enzyme immunoassay (abbot laboratories, il 60064, usa). atopy was defined as having an elevated serum level of total ige or having positive skin tests for more than two allergens. the body mass index (bmi) was calculated for each patient from their recorded height and weight. it was then classified as normal, overweight and obese as per the published criteria.8 a diagnosis of gastro-oesophageal reflux disease (gerd) was entertained by the presence of oesophageal symptoms such as heartburn and regurgitation and was confirmed after a gastroenterologist reviewed the patient. compliance for the study was categorised as good, partial or poor. good compliance was defined as self-reported meticulous adherence to the dose and frequency of the prescribed steroid inhalers. partial compliance was recorded when they reported management and control of asthma in patients attending a specialist centre in oman 134 | squ medical journal, august 2009, volume 9, issue 2 regular usage as per their prescription, but with occasional irregularity (mainly forgetting doses). all other patients who were not using the prescribed inhaled steroid, using them as and when needed or using them with frequent or regular omissions (e.g. using one puff instead of the prescribed 2 puffs daily or once instead of twice daily) were labelled as having poor compliance. the inhaler technique was assessed by a qualified respiratory therapist by a uniform protocol as outlined by hilton et al.9 each step of adequate preparation, adequate expiration, adequate inspiration and holding the breath was given one point. the above steps were clearly defined for different devices separately. though they used three categories, we defined only two groups: adequate and inadequate. only beclomethasone and salbutamol were available as metered dose inhalers (mdi). dry powder inhalers (dpi) were available as single dose dispensers for formoterol and multidose dispensers like turbohalers for budesonide and disk halers for fluticasone. for comparison, the doses of all inhaled steroids were converted to beclomethasone equivalent as given in the gina guidelines.6 the data were tabulated and analysed using the statistical package for the social sciences software (spss, pc version 11.0). the various variables were cross-tabulated and the chi square test or fischer’s exact test were used to see if any association existed or proportions were significantly different. the non-parametric mann-whitney test was used in analysing the age difference between male and female patients. results there were 207 patients with a diagnosis of asthma without any other illness or a smoking history during the study period. one hundred and fortynine (72.0%) were females and 58 (28.0%) were males. the mean age of the study population was 40.64 ±14.8 years. the baseline characteristics of the patients are given in table 1. a positive family history of asthma was obtained in 105 (50.7%). the mean fev1 was 2.0 ±0.72 liters and the fev1 percentage was 71.92 ±19.2. minor changes like hyperinflation, increased lung markings and some linear shadows were found in 46 (22.2%) patients. total serum ige was elevated in 138 patients (66.7%) and skin prick tests were positive for more than two antigens in 78 of the 148 patient who did this test (52.3%), indicating an atopic status. skin prick tests were positive for the house dust antigen in 76 (49%), grass antigen in 36 (23.2%), shrimp antigen in 41 (26.4%), cat fur antigen in 23 (14.8%) and feather antigens in 22 (14.2%). the details of asthma medications are given in table 1. one hundred and ninety-five patients table 1: baseline characteristics of patients with asthma n % asthma severity mild intermittant 12 5.8 mild persistant 23 11.1 moderate persistant 172 83.1 comorbidities allergic rhinitis 120 58.0 eczema 23 11.1 gerd 28 13.5 investigations abnormal chest radiograph n=207 46 22.2 spt with > 2 allergens n=148 78 52.3 high ige 138 66.7 medications inhaled steroids 195 94.2 laba 176 85.0 theophylline 42 20.3 montelukast 24 11.6 antihistamines 112 54.5 nasal steroids 79 38.2 bmi class normal 63 30.4 over weight 64 30.9 obese 79 38.2 gerd = gastro-oesophageal reflux disease; spt = skin prick test; ige = immunoglobulin e; laba = long-acting beta agonists; bmi = body mass index omar a al-rawas, jayakrishnan b, fatma ben abid, jojy george, sawsan a baddar and bazdawi m al-riyami clinical and basic research | 135 (94.2%) were prescribed inhaled corticosteroids (ics); 176 (85%) were receiving long acting beta agonists (laba), and 112 (54.5%) were receiving oral antihistamines. some of the patients were receiving ics and laba through the same device. in most of the patients, asthma was controlled as 162 (78.3%) were using salbutamol inhaler less than twice per week and only 26 (12.6%) were using it daily. the details of the steroid inhalers, the type of medication, the type of devices used and the dose converted to beclomethasone equivalent are given in table 2. most patients were on dry powder inhalers (dpi), and the majority was receiving medium dose inhaled steroids. only one patient was using ipratropium bromide inhaler. twenty eight (13.5%) were taking treatment for gerd. sixty-six (31.9%) patients reported an exacerbation requiring a visit to the emergency department at least once during the previous year. thirty-four (51.5%) had visited the emergency department three times or less, while 32 (48.5%) reported more than 3 visits. thirty-one (15.0%) patients were hospitalised at least once in the past year. the mean age of the females (41.32 ±13.6 years) was slightly higher when compared to the males, 38.91 ±17.7 (p = 0.164). patients with mild asthma were younger. the mean age of patients with mild intermittent, mild persistent and moderate persistent asthma were 31.92 ±11.5, 35.4 ±12.5 and 41.96 ±15.02 years respectively. only 63 (30.4%) patients were using their inhalers correctly: 22 (37.9%) males and 41 (27.5%) females (p = 0.178) [table 3]. in addition, only 53 (25.6%) were fully compliant with regular inhaler medications, whereas 82 (39.6%) were partially compliant and 72 (34.8%) showed poor compliance with no significant difference between the different types of inhalers (p = 0.906) [table 2]. the compliance was good in 9 (22.5%), partial in 17 (42.5%) and poor in 14 (35.5%) patients using mdi compared to good in 38 (24.5%), partial in 60 (38.7%) and poor in 57 (36.8%) of the patients using dpi. the distribution of patients with high ige was similar in patients with normal bmi, in overweight or in obese persons (p = 0.716). in the same way, the distribution of patients with different levels of asthma severity was also similar in the above groups discussion this report presents the characteristics of asthma patients receiving specialist care in our centre. the majority was female and had moderate persistent asthma. allergic comorbidities were common in our patients. the level of asthma control was relatively high, in spite of suboptimal compliance and inadequate inhaler technique. only a few patients had mild intermittent asthma, the majority had moderate persistent asthma. this was expected as the study was performed in a tertiary centre and the patients’ access to the services was only through referral. likewise mild intermittent asthma was seen in only 7.5% of patients reporting to large outpatient clinics of four teaching hospitals in greece.2 a positive family history of asthma was obtained in virtually half of the patients. asthma definitely has a heritable component the exact nature of which is table 2: details of prescribed inhalers and the compliance achieved n % generic beclomethasone 40 20.5 budesonide 67 34.4 fluticasone 88 45.1 devices metered dose inhaler 40 20.5 dry powder devices 155 74.9 dose low dose 47 22.7 medium dose 83 40.1 high dose 65 31.4 compliance good 53 25.6 partial 82 39.6 poor 72 34.8 inhaler technique adequate 63 30.4 management and control of asthma in patients attending a specialist centre in oman 136 | squ medical journal, august 2009, volume 9, issue 2 not clearly defined. bjerg et al.10 found that asthma in both parents conferred a multiplicative risk, whereas the effect of parental atopy was additive indicating that asthma and atopy, despite their causal relationship, may be separate entities and could be inherited differently. in a study from qatar, where consanguinity is as prevalent as in oman, it was found that 21.6% of asthmatic children had mothers with asthma and 18.2% had fathers with asthma.11 allergic rhinitis, but not eczema, was seen in a significant number of our patients. more than half had an atopic status with either a high total ige or positive skin prick tests. similar results were reported by cengizlier et al.12 where 57.6% of their patients had a history of atopy. farhoudi et al.13 noted that the most common risk factors were an elevated total ige and a positive family history of atopy. we also noted a strong family history of allergy. the total ige was elevated in more than 60% of our patients as well. like elsewhere, house dust was the main allergen in majority of our cases. minor non-specific chest radiographic abnormalities were recorded in 22.2%. similarly, hodson et al.14 reported that in nearly 81% of their patients with stable asthma the chest radiographs were normal. at the same time, in another study on acute asthma, only 50% of the chest radiographs were totally normal.15 most of our patients were overweight or obese which was more evident among females. this is of particular importance as obesity is known to be associated with increased asthma severity and a decreased response to inhaled corticosteroids.16,17 however, there was no significant correlation between bmi and asthma severity and control in our patients. the majority of the patients was prescribed inhaled steroids and laba. prescriptions of antihistamines were high which probably reflects the presence of allergic co-morbidities. additional controllers like montelukast or bronchodilators like theophylline were prescribed frequently which indirectly may suggest the severity of the disease. gerd was diagnosed in 13.5% and they were on regular treatment which is in keeping with previous reports.18,19 in the first multinational survey in western europe, the asthma insights and reality in europe (aire) study,20 only 5.3% of patients met all the gina criteria for asthma control. urgent care needs were reported by 27.9% and emergency visits by 11% of the adults. the most significant findings were the high levels of unscheduled emergency visits and hospitalisation by these patients and the major discrepancy between the patients’ perceived control and reported symptom severity. using the presence of symptoms and the frequency of salbutamol use during the previous month in our patients, asthma appeared to be controlled as the majority (78.3%) was using rescue doses of salbutamol less than twice a week. however, when we consider the hospital admissions (15%) or emergency visits (31.9%) over the previous one year this was not the case. this may be due to the fact that these patients referred to specialists had a moderate or severe spectrum of the table 3: gender differences in asthma severity, body mass index (bmi) class, steroid inhaler technique and the compliance characteristics males n=58 females n=149 p value asthma severity mild intermittant 6 (10.3) 6 (4.0) 0.142 mild persistant 8 (13.8) 15 (10.1) moderate persistant 44 (75.9) 128 (85.9) bmi class normal 28 (48.3) 35 (23.6) 0.001 over weight 17 (29.3) 47 (31.8) obese 13 (22.4) 66 (44.6) compliance good 17 (29.3) 36 (24.2) 0.746partial 22 (37.9) 60 (40.3) poor 19 (32.8) 53 (35.6) inhaler technique adequate 22 (37.9) 41 (27.5) 0.178 omar a al-rawas, jayakrishnan b, fatma ben abid, jojy george, sawsan a baddar and bazdawi m al-riyami clinical and basic research | 137 disease. it is also possible that there was reluctance on the part of the patients to use rescue doses of inhaled salbutamol frequently in spite of having symptoms. the difference between the measures of control using symptoms or rescue medication use in the past month and the emergency visits or admissions in the same year brings up a need for recording short term and long term control of asthma separately. adherence with controller therapy poses a major challenge to the effective management of persistent asthma. the data from the european community respiratory health survey documents that compliance to the treatment of asthma is poor worldwide and that there are large variations between countries.21 the compliance rates often are below 50%, the reasons for noncompliance being multiple and complex and not always clearly understood.22 only 25% of our patients were fully compliant with regular use of the prescribed steroid inhalers. nearly 40% were not using the steroid inhalers in the prescribed doses all the time. the rest of the patients (35%) were using them only when they had symptoms, or were not using them at all. this may reflect the lower perceived need for ics therapy in our patients or the patients own cultural beliefs preventing them from using medications, especially inhalers, regularly. non-adherence is usually associated with lower baseline rescue medication use, younger age, female sex, lack of symptoms, physical and psychological comorbidities or difficult social and economic circumstances.23-25 adding to this may be the fact that patients often underestimate the severity of their asthma.26 interestingly, a recent report from italy concludes that most people in the general population do not use drugs, in spite of reported respiratory disorders, though to a certain extent asthma was an exception.27 a more regional study documents that the most common fears hindering regular ics use were their potential to lead to addiction and the worry about steroid side effects.28 hilton et al.9 report that only 25% of their patients had inadequate technique, the turbohaler being the easiest inhaler to use and metered dose inhalers being the most difficult. the relatively low level of performance was unexpected in our patients as they were instructed in the proper technique more than once. it is also important that the prescriber is fully aware of the characteristics of the different types of dpi, so that the most appropriate one is suggested.29 this is often not the case as a review of 20 studies highlighted the lack of skill among healthcare professionals in using different inhalation devices.30 this was also documented from oman earlier where only 15% of the health care providers who participated in the study performed all the steps correctly.31 boys are consistently reported to have more prevalent wheeze, but after childhood it is more common and more severe in females.32-34 females also have significantly more asthma control problems and a lower asthma-related quality of life. the sex hormones are major determinants of these biological gender differences.35 however, despite their overall worse health outcomes, in another study, female subjects demonstrated better lung function, had similar treatment patterns, and showed no differences in physician approach.36 in our study, there were more females and they were older and heavier than the males. however, neither the asthma control nor the compliance were different between the sexes. though the inhaler techniques in females were inferior, the difference was not statistically significant. the limitations in our study are probably few, the first being the strict inclusion criteria. a large number of patients with other even minor associated illness were not included. asthmatics who smoke also were not included. the second limitation may be the fact that the some of the information, like compliance and the frequency of health care visits, were self-reported. in conclusion, most of the patients seen in our centre had moderately severe asthma with a high prevalence of atopy. although the majority appeared to be controlled on standard forms of treatment, we have identified areas where considerable improvement is needed. more effort is needed to teach the correct inhaler technique and more time needs be spent on educating the patients and ensuring proper compliance. we also would like to suggest that there should be separate indicators to assess long term and short term control of asthma which in turn would contribute to assessing total control. acknowledgement the authors would like to thank sultan qaboos university hospital for supporting this study. management and control of asthma in patients attending a specialist centre in oman 138 | squ medical journal, august 2009, volume 9, issue 2 conflict of interest the authors report no conflict of interest. references 1. bateman ed, hurd ss, barnes pj, bousquet j, drazen jm, fitzgerald m, et al. global strategy for asthma management and prevention: gina executive summary. eur respir j 2008; 31:143-78. 2. gaga m, papageorgiou n, zervas e, gioulekas d, konstantopoulos s. control of asthma under specialist care: is it achieved? chest 2005; 128:78-84. 3. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. a relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirology 2003; 8:69-76. 4 al riyami bm, dissanayake as. audit of asthma management in private general practice in oman. ann saudi med 1997; 17:555-7. 5. moy jn, grant en, turner-roan k, li t, weiss kb. asthma care practices, perceptions, and beliefs of chicago-area asthma specialists. chicago asthma surveillance initiative project team. chest 1999; 116:154s-62s. 6. global strategy for asthma management and prevention. global initiative for asthma gina, 2002. available from www.ginasthma.org date last updated, 2002. accessed december 2005. 7. miller mr, hankinson j, brusasco v, burgos f, casaburi r, coates a, et al. standardisation of spirometry. eur respir j 2005; 26:319-38. 8. world health organization. obesity: preventing and managing the global epidemic: report of a who consultation on obesity. pub. no. who/nut/ ncd/98.1. geneva: world health organization, 1997. 9. hilton s. an audit of inhaler technique among asthma patients of 34 general practitioners. br j gen pract 1990; 40:505-6. 10. bjerg a, hedman l, perzanowski ms, platts-mills t, lundback b, ronmark e. family history of asthma and atopy: in-depth analyses of the impact on asthma and wheeze in 7to 8-year-old children. pediatrics 2007; 120:741-8. 11. bener a, janahi i. association between childhood atopic disease and parental atopic disease in a population with high consanguinity. coll antropol 2005; 29:677-82. 12. cengizlier mr, misirlioglu ed. evaluation of risk factors in patients diagnosed with bronchial asthma. allergol immunopathol madr 2006; 34:4-9. 13. farhoudi a, razavi a, chavoshzadeh z, heidarzadeh m, bemanian mh, nabavi m. descriptive study of 226 patients with allergic rhinitis and asthma in karaj city. iran j allergy asthma immunol 2005; 4:99-101. 14. hodson me, simon g, batten jc. radiology of uncomplicated asthma. thorax 1974; 29:296-303. 15. zieverink se, harper ap, holden rw, klatte ec, brittain h. emergency room radiography of asthma: an efficacy study. radiology 1982; 145:27-9. 16. peters-golden m, swern a, bird ss, hustad cm, grant e, edelman jm. influence of body mass index on the response to asthma controller agents. eur respir j 2006; 27:495-503. 17. taylor b, mannino d, brown c, crocker d, twumbaah n, holguin f. body mass index and asthma severity in the national asthma survey. thorax 2008; 63:14-20. 18. gislason t, janson c, vermeire p, plaschke p, bjornsson e, gislason d, et al. respiratory symptoms and nocturnal gastroesophageal reflux: a populationbased study of young adults in three european countries. chest 2002; 121:158-63. 19. harding sm, richter je. the role of gastroesophageal reflux in chronic cough and asthma. chest 1997; 111:1389-402. 20. rabe kf, vermeire pa, soriano jb, maier wc. clinical management of asthma in 1999: the asthma insights and reality in europe aire study. eur respir j 2000; 16:802-7. 21. cerveri i, locatelli f, zoia mc, corsico a, accordini s, de mr. international variations in asthma treatment compliance: the results of the european community respiratory health survey ecrhs. eur respir j 1999; 14:288-94. 22. kaiser hb. compliance and noncompliance in asthma. allergy asthma proc 2007; 28:514-6. 23. smith jr, mildenhall s, noble m, mugford m, shepstone l, harrison bd. clinician-assessed poor compliance identifies adults with severe asthma who are at risk of adverse outcomes. j asthma 2005; 42:437-45. 24. ulrik cs, backer v, soes-petersen u, lange p, harving h, plaschke pp. the patient’s perspective: adherence or non-adherence to asthma controller therapy? j asthma 2006; 43:701-4. 25. williams lk, joseph cl, peterson el, wells k, wang m, chowdhry vk, et al. patients with asthma who do not fill their inhaled corticosteroids: a study of primary nonadherence. j allergy clin immunol 2007; 120:1153-9. 26. lurie a, marsala c, hartley s, bouchon-meunier b, dusser d. patients’ perception of asthma severity. respir med 2007; 101:2145-52. 27. simoni m, carrozzi l, baldacci s, borbotti m, pistelli f, di pf, et al. respiratory symptoms/diseases, impaired lung function, and drug use in two italian general population samples. respir med 2008; 102:82-91. omar a al-rawas, jayakrishnan b, fatma ben abid, jojy george, sawsan a baddar and bazdawi m al-riyami clinical and basic research | 139 28. al-jahdali hh, al-zahrani ai, al-otaibi st, hassan is, al-moamary ms, al-duhaim as, et al. perception of the role of inhaled corticosteroids and factors affecting compliance among asthmatic adult patients. saudi med j 2007; 28:569-73. 29. chrystyn h. do patients show the same level of adherence with all dry powder inhalers? int j clin pract suppl 2005; 149:19-25. 30. self th, arnold lb, czosnowski lm, swanson jm, swanson h. inadequate skill of healthcare professionals in using asthma inhalation devices. j asthma 2007; 44:593-8. 31. baddar s, al-rawas oa, al-riyami k, worthing e, hanssens y, taqi a, et al. metered-dose inhaler technique among healthcare providers practising in oman. squ j sci res: med sci 2001; 1:39-43. 32. almqvist c, worm m, leynaert b. impact of gender on asthma in childhood and adolescence: a ga2len review. allergy 2008; 63:47-57. 33. sinclair ah, tolsma dd. gender differences in asthma experience and disease care in a managed care organization. j asthma 2006; 43:363-7. 34. stallberg b, lisspers k, hasselgren m, johansson g, svardsudd k. factors related to the level of severity of asthma in primary care. respir med 2007; 101:207683. 35. melgert bn, ray a, hylkema mn, timens w, postma ds. are there reasons why adult asthma is more common in females? curr allergy asthma rep 2007 ; 7:143-50. 36. lee jh, haselkorn t, chipps be, miller dp, wenzel se, tenor study group. gender differences in igemediated allergic asthma in the epidemiology and natural history of asthma: outcomes and treatment regimens tenor) study. j asthma 2006; 43:17984. december 2008 no white pages.indd sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 266-274 sultan qaboos university© submitted 6th may 2008 accepted 13th september 2008 obstructive sleep apnoea/hypopnoea syndrome and hypertension *mohammed a al-abri, khamis m al-hashmi the obstructive sleep apnoea/hypop-noea syndrome (osahs) is a disorder char-acterised by repetitive upper airway collapse during sleep in association with daytime sleepiness that has an estimated prevalence of 2% among middleaged women and 4% among middle-aged men.1 it was recognised only quite recently, although it has been extensively researched in the last 30 years. 1department of clinical physiology, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: malabri@squ.edu.om r e v i e w بارتفاع وعالقتها الكامل/اجلزئي النومي النفس انقطاع متالزمة الدم ضغط محمد الهاشمي خميس بن عبداهللا العبري، بن محمد النفس انقطاع متالزمة بني ثيقة و عالقة توجد البالغني. 2-%4 من يصيب شائع اضطراب الكامل/اجلزئي النومي النفس انقطاع متالزمة امللخص: التدخلية. الدراسات الكبيرة وكذلك الوبائية ــات والدراس احليوانات على اجريت التي ــات للدراس وفقا وذلك الدم ضغط وارتفاع النومي الكامل/اجلزئي تؤدي أن ميكن عديدة هناك أسباب مستقبال. الدم ضغط ارتفاع من واخلطر النومي معدل انقطاع النفس بني طردية عالقة الوبائية الدراسات اظهرت وفي النوم اثناء يزيد هؤالء عند الودي ــي العصب اجلهاز ــاط فنش الكامل/اجلزئي. النومي انقطاع النفس مبتالزمة املصابني عند الدم ضغط ــاع ارتف ــى ال الكيمائية واملستقبالت مستقبالت الضغط تنشيط ناجتة عن تكون األشخاص رمبا هؤالء الودي عند العصبي اجلهاز في نشاط الزيادة هذه . اليقظة ضغط الهواء أن جهاز ــني تب النوم. أثناء الكامل/اجلزئي النفس انقطاع ــن الناجت ع الدم ــجني أكس ونقص املتكرر التيقظ نتيجة الدموية ــة األوعي ــي ف ذلك باإلضافة إلى الدم. وضغط ــودي ال ــاط اجلهاز من نش النفس النومي الكامل/اجلزئي يخفض كال متالزمة انقطاع لعالج ــتعمل الذي يس ــب املوج الكامل/اجلزئي. النومي النفس انقطاع مبتالزمة عند املصابني الدم ضغط ارتفاع في الدموية لألوعية البطانية ــية األغش وظائف في ــاعد اخللل يس قد نقص نتيجة ــخاص األش هؤالء عند ــع األوعية الدقيقة توس عن اختالل ــؤوال مس اجلذور احلرة وزيادة انتاج ــيد النيتريك اكس غاز نقص انتاج ــون ــد يك ق فعال. بشكل البطانية األغشية وظائف اعادة يساعد على املوجب الهواء العالج بجهاز ضغط أن الدراسات أظهرت االكسجني. الدم, ضغط ارتفاع ــة, البطاني ــية االغش وظائف ــية ، االنعكاس الكيميائية االفعال ، ضغط الدم ــية، االنعكاس الضغط الكلمــات: أفعال مفتــاح ودي. نشاط الكامل/اجلزئي, النومي النفس انقطاع متالزمة abstract the obstructive sleep apnoea/hypopnoea syndrome (osahs) is a common disorder, affecting around 2–4% of the middle-aged population. there is a strong association between osahs and hypertension, based on animal, large epidemiological and interventional studies. the epidemiological studies have shown a dose-response relationship between apnoea/hypopnoea index (ahi) and the risk of developing hypertension. different mechanisms may have a role in the process of elevated blood pressure in osahs. sympathetic activity is increased in osahs patients during sleep and wakefulness. this increase in sympathetic activity is probably due to activation of baroreflexes and chemoreflexes by frequent arousals and hypoxaemia a result of apnoea or hypopnoea events. continuous positive airway pressure (cpap) has been shown to reduce sympathetic stimulation and blood pressure in osahs patients. altered endothelial function may also have a role in the pathogenesis of hypertension in osahs subjects. reduction of nitric oxide (no) production and increase in the formation of free radicals may be responsible for the impairment of the vasodilatation of micro-vasculature in these subjects as a result of hypoxaemia. it has been shown that effective cpap therapy has a reversible effect on endothelial dysfunction. keywords: baroreflex; blood pressure; chemoreflexes; endothelial function; hypertension; osahs (sleep apnoea/hypopnoea syndrome); sympathetic activity. o b s t r u c t i v e s l e e p a p n o e a / h y p o p n o e a s y n d r o m e a n d h y p e r t e n s i o n 267 osahs-related features include excessive daytime sleepiness, 2, 3 neurocognitive impairment, 4 and increased motor vehicle accidents.5-7 it has also been associated with adverse cardiovascular consequences such as hypertension and impairment of cardiovascular variability. treating osahs is very rewarding, for the benefit to the patient is enormous in improving the quality of life as well as preventing long-term sequelae. there is strong evidence that patients with sleep apnoea might be at increased risk of cardiovascular disease. patients with sleep apnoea are often hypertensive8, 9 and up to one-third of hypertensive patients may have sleep apnoea.10 several cross-sectional studies have shown that the prevalence of hypertension increases progressively with the severity of osahs.11-13 how hypertension is associated with osahs is not fully understood. however, repetitive episodes of airway occlusion during sleep, with consequent hypoxia, hypercapnia, dramatic changes in intrathoracic pressure and repeated arousals, may provoke a number of autonomic, haemodynamic, humoral and neuroendocrine responses. this review focuses mainly on the epidemiological link between osahs and hypertension and the autonomic responses that might occur in osahs patients. other aspects of the possible vasculopathy in osahs will also be briefly reviewed. e p i d e m i o l o g y osahs and hypertension have common risk factors, such as obesity, alcohol intake, age, gender and lack of exercise, which makes causation impossible to prove, using epidemiology alone. however, several epidemiological studies have revealed a strong association between osahs and hypertension.11-17 o sa h s i n th e ge n e r a l p o p ul ati o n early studies of the association between hypertension and snoring came from norton et al. and koskenvuo et al., who found that snoring was a risk factor for hypertension.14, 15 subsequent studies found that sleep apnoea was an independent risk factor for the development of hypertension, similar to age and obesity.16 a large epidemiological study showed that sleep apnoea significantly contributed to hypertension, independent of other risk factors.11 each apnoeic event per hour of sleep added 1% to the risk of having hypertension. more evidence linking osahs with hypertension is provided by the wisconsin sleep cohort study, which showed a dose-response association between osahs and de novo hypertension after 4 years of follow-up independent of confounding factors although the number of new hypertensive subjects was small.13 in the original report, patients with an apnea-hypopnea index (ahi) > 25 had a fivefold risk of hypertension.17 the increase in risk of hypertension was greater in thinner patients who had abnormal breathing. after correction for confounding factors, those with an ahi >15 had a 2.9-fold greater chance of developing hypertension in the following four years. a similar relationship between osahs and hypertension was found in the sleep heart health study.12 in this study of 6,000 middle-aged and older adults, the prevalence of hypertension (defined as a resting bp ≥ 140/90 mmhg or the use of anti-hypertensive drugs) increased progressively with the severity of osahs. after adjusting for the confounding factors, including obesity, the odds ratio in the group with severe osahs (ahi >30) was 1.37 (95% confidence interval (ci), 1.03-1.83; p = .005) compared with those with lowest ahi (< 1.5). a crosssectional study in a normal population by bixler et al. also indicated an association between hypertension and sleep apnoea independent of other risk factors. the association was strongest in young subjects, and decreased with age.18 o sa h s i n th e h y pe rte n si v e p o p ul ati o n epidemiological studies of hypertensive patients have also suggested an association between sleep apnoea and hypertension. hypertensive patients had a greater prevalence of sleep apnoea than normotensive subjects.19 grote et al. found that osahs was a risk factor for poor blood pressure control in younger hypertensive patients.20 a greater prevalence of obstructive sleep apnoea is found in adults with drug-resistant hypertension (bp > 140/90 who require a combination of three or more antihypertensive drugs) 21 supporting the idea of an etiological role of osahs in the cause of hypertension. h y pe rte n si o n i n o sa h s sub je c ts animal models in dogs, obstructive sleep apnoea leads to the development of sustained hypertension.22 obstructive sleep apnoea (osa) was produced in four dogs using an occlusion valve attached to an endotracheal tube through which the dog could breathe. obstruction of the airway by the valve was controlled by telemetry of elecm o h a m m e d a a l a b r i a n d k h a m i s m a l h a s h m i 268 trocardiogram (ecg) and electromyography (emg) signals from the dog during a one to three month period. in the same dogs, sleep fragmentation was also induced. arterial blood pressure was monitored for 12 hours every night. obstructive sleep apnoea (osa) caused a progressive increase in night-time mean arterial bp in each of the four dogs. there was no difference between the change in night-time bp caused by sleep fragmentation and that caused by osa (p = 0.4). in contrast, the change in daytime bp caused by sleep fragmentation was significantly less than the change during osa (p = 0.001). there were no changes in night-time or daytime heart rates during either osa or sleep fragmentation. in another dog study of chronic osa by parker et al., acute airway occlusion during sleep increased left ventricular (lv) afterload and decreased fractional shortening. chronic osa caused a sustained decrease in lv systolic performance, caused by systemic hypertension and/or transient increases in lv afterload during episodes of airway obstruction.23 human studies a case-control study found that patients with osahs had higher blood pressure than matched control subjects. diastolic blood pressure in patients with osahs was significantly greater than controls during the daytime, night-time, and overall. osahs patients also had significantly greater night-time systolic bp (p = 0.01), although daytime and overall systolic blood pressure did not differ from control subjects.8 direct evidence that osahs causes hypertension is provided by intervention studies, in which continuous positive airway pressure (cpap) reduced bp.24, 25 nevertheless, in order to understand the pathophysiology of hypertension in osahs, the mechanism of blood pressure elevation is discussed below. o s a h s a n d b l o o d p r e s s u r e in healthy subjects, blood pressure normally decreases by 10% to 15% from its daytime value during sleep. this circadian drop in bp has been called dipping. however, some patients with osahs do not show nocturnal dipping of bp and are thus called non-dippers.26 this may relate to apnoeas and hypopnoeas, which cause repeated nocturnal increases in bp, which consequently increase the mean sleeping bp.27 the greatest pressure peaks occur after apnoea and may be 100 mmhg above the baseline value.28, 29 these acute nocturnal changes may lead to persistent daytime hypertension as a long-term consequence29 with an increased risk of target organ damage.30 in a case-control study, sleep apnoea patients had significantly increased mean diastolic bp during both the daytime and night-time, and systolic bp was higher among osahs patients at night compared with controls. the nocturnal dip in bp was smaller in patients with osahs than in matched control subjects.8 hypoxia may explain partly these variations in bp in sleep apnoea patients. in animals, repetitive episodic hypoxia causes diurnal elevation in bp in rats.31 similarly rises in daytime blood pressure follow induced apnoeas in dogs and are probably related to hypoxaemia rather than arousal, because noise-induced arousal did not cause daytime hypertension in the same dogs.22 increased sympathetic activation, perhaps induced by hypoxaemia, may be a key factor in causing long-term bp changes.32 however, other factors may be implicated in the development of hypertension in osahs patients, such as endothelial dysfunction, as discussed below. s y m p a t h e t i c a c t i v i t y i n o s a h s p a t i e n t s d ur i n g sl e e p normal sleep is physiologically divided into rapid eye movement (rem) and non-rapid eye movements (nrem) sleep. nrem is further divided into 4 stages from stage 1 to 4. in normal sleep, heart rate, blood pressure, and sympathetic nerve traffic usually decrease.33, 34 this reduction of sympathetic activity appears to increase progressively from stage 1 to stage 4 sleep.28 however, during rem sleep, sympathetic activity increases, to as much as double that of wakefulness.34 blood pressure and heart rate during rem are variable, but average about the same as during wakefulness.28 in contrast, sympathetic activity is increased during sleep in osahs patients and the sympathetic and the haemodynamic state during sleep is determined primarily by the duration and severity of apnoea rather than by the sleep stage itself.29 repetitive episodes of obstructive apnoea, hypoxia and hypercapnia probably act through chemoreceptor reflexes and other mechanisms to increase sympathetic drive. 35 furthermore, resumption of breathing results in increased venous return and increased cardiac output. this increased cardiac output is delivered into a severely constricted peripheral vasculature, with surges in bp.35 o b s t r u c t i v e s l e e p a p n o e a / h y p o p n o e a s y n d r o m e a n d h y p e r t e n s i o n 269 e ffe c ts o f a r o usa l fr om sl e e p o n bp normal spontaneous arousals from sleep are associated with transient increases in blood pressure, heart rate and ventilation.36 these increases are caused by changes in sympathetic activity caused by the arousal. in a study in dogs, 37 ventricular stroke volume (sv) remained constant when apnoea ended, if there was no arousal. however, with arousal from apnoeas, heart rate and cardiac output increased, although sv decreased. arousal increased the systemic, but not the pulmonary arterial pressure, in response to obstructive apnoea. the increase in systemic blood pressure was more marked during nrem sleep than in rem sleep.37 in a large population-based study, sleep fragmentation index (sfi), calculated as the total number of awakenings or shifts to stage 1 divided by the total sleep time per hour, was significantly associated with systolic, but not diastolic blood pressure, during wakefulness in individuals with ahi < 1. however, sleep fragmentation and blood pressure were not associated in those with ahi > 1 after controlling for the influence of the ahi. the authors concluded that sleep fragmentation was independently associated with a greater systolic blood pressure during wakefulness. 38 noda et al.39 found that end-apnoeic arousal and hypoxic asphyxia and the subsequent sleep fragmentation might contribute to nocturnal and diurnal elevation of bp. the rise in blood pressure with arousal might be caused by an increase in sympathetic activity. sympathetic outflow remained elevated for a substantial period even after a hypoxic stimulus was removed; 35 nevertheless, it is unwise to conclude that sleep arousal is the sole contributor to sustained hypertension in awake sleep apnoea patients. however, in patients with higher ahi, sleep disruption may modulate the bp along with other effects such as hypoxaemia and changes in intrathoracic pressure, which may overcome the effects of arousal. 38 d ur i n g wa k e f ul n e s s greater sympathetic activity in osahs patients may be present even during daytime wakefulness, when subjects are breathing normally and both arterial oxygen and carbon dioxide levels are normal.29, 40 circulating catecholamines41 and muscle sympathetic nerve activity42 were greater in patients with osahs compared with normal subjects, probably because of baroreflex dysfunction, chemoreflex excitation and endothelial dysfunction. greater sympathetic drive in these patients may contribute, to a certain extent, to chronic elevation of resting bp. the mechanism underlying the sustained increase in sympathetic drive is not clear. morgan et al. suggested that combined hypoxia and hypercapnia evoke long-lasting sympathetic activation.35 this may explain in part the increased daytime sympathetic drive in osahs patients. however, repeated bp increases, acting via the baroreceptors, may reset the baroreflex, permitting a higher level of sympathetic activity and bp even during wakefulness. to understand the role of the chemoreflexes and baroreflexes in bp control in osahs patients, these two aspects are explained in detail below. c h e m o r e f l e x e s the chemoreflexes are important and powerful modulators of sympathetic activation. hypoxia, which acts primarily on the peripheral chemoreceptors located in the carotid bodies, 43 and hypercapnia, acting on the central chemoreceptors located in the brain stem, trigger reflex increases in minute ventilation as well as sympathetic activity. patients with osahs have an enhanced vascular response to hypoxia.44 in a double-blind, randomised, controlled trial, it was found that muscle sympathetic nerve activity (msna) and mean arterial pressure were significantly reduced in osahs patients compared with control subjects during chemoreflex deactivation by 100% oxygen;44, 45 however, the enhancement of peripheral chemoreflexes is selective to autonomic, haemodynamic and ventilatory responses in normotensive osahs.44 furthermore, this enhancement of the reflex response to hypoxia is not explained by obesity, since obese subjects who are otherwise healthy with no osahs have chemoreflex responses similar to those seen in control subjects.44, 46 nevertheless, obese patients have a greater response to hypercapnia.46 48 both hypoxia and hypercapnia have local vascular effects, causing vasodilation, which lowers the blood pressure initially, which in turn increases sympathetic activity and catecholamine release.49 during apnoea, sympathetic activity rises gradually, reaching its peak at the end of the apnoea, when oxygen desaturation and carbon dioxide retention are most marked. 34, 45 on release of the airway obstruction and resumption of breathing, increased cardiac output, together with the constricted peripheral vasculature, result in a marked increase in blood pressure.34 there is also a carry-over effect to the tonic activation of the peripheral chemm o h a m m e d a a l a b r i a n d k h a m i s m a l h a s h m i 270 oreceptors, even during normoxia, which may partly explain the increased sympathetic activity during the daytime (see above). however a double-blind study suggested that hyperoxia can suppress peripheral chemoreceptors in osahs patients, shown by a decrease in blood pressure and slowing of heart rate.44 b a r o r e f l e x a n d h y p e r t e n s i o n there is evidence that the cardiac baroreflex is impaired if blood pressure is increased, in both humans 50, 51 and animals.52 floras et al. found that the arterial baroreflex could buffer acute changes in blood pressure in subjects with who stage 1 hypertension. however, this ability is weakened if the baroreflex sensitivity (brs) is reduced. with the development of clinically evident cardiac adaptation to hypertension (who stage 2), the contribution of the arterial baroreflex to the regulation of blood pressure is no longer detectable and the influence of cardiac and somatic afferents to reflex circulatory adjustment to activity may predominate.50 furthermore, lantelme et al. found that hypertensive rats have impaired cardiac baroreflex responses, characterised by a range-independent decreased gain, which is not caused by cardiac hypertrophy.52 the impaired baroreflex may even precede the development of hypertension. baroreflex inhibition of muscle sympathetic nerve activity is reduced in adolescents with a family history of hypertension, even when they are normotensive, which may lead to the development of hypertension by increasing sympathetic vasomotor tone.53 this could also be a factor for hypertension in osahs patients, although there is no evidence for this so far. b a r o r e f l e x i n s l e e p a p n o e a patients with osahs have baroreflex dysfunction. narkiewicz et al. used phenylephrine to activate baroreceptors and nitroprusside to deactivate them. normotensive patients with osahs had an impaired response to baroreceptor deactivation, but not to baroreceptor activation. they suggested that the reduced baroreflex sympathetic modulation in patients with sleep apnoea was not accompanied by any impairment of baroreflex control of heart rate.42 in addition, osah patients have impaired baroreflex responses to a hypotensive stimulus.54 using sequence method analysis, it has been noted that baroreflexes are impaired in osahs patients compared with healthy controls. 55, 56 e f f e c t o f t r e a t i n g s l e e p a p n o e a o n s y m p a t h e t i c a c t i v i t y a n d b p cpap is the treatment of choice for majority of osahs patients. in addition to improvement of symptoms, cpap treatment may also reduce sympathetic activity. nasal cpap was found to reduce catecholamines. 57 somers et al. found that cpap treatment caused an acute and marked reduction in nocturnal sympathetic nerve traffic.29 however, cpap does not reduce daytime blood pressure acutely, although it significantly reduces the large oscillations in blood pressure seen overnight in patients with untreated sleep apnoea.58 nevertheless, a small fall in night-time systolic bp was seen in osah patients after 2 weeks of treatment, 59 with some improvement in daytime mean arterial blood pressure in non-dippers after 3 weeks of cpap treatment compared with the placebo.60 however, when effective cpap treatment was given for a longer period (8 weeks) in a before-and-after non-placebo controlled design, there was a significant fall in both systolic and diastolic bp, independent of changes in body weight.61 thus, long-term treatment with cpap may be needed to attenuate sympathetic activation and consequently reduce bp. this idea is supported by the findings that cpap treatment reduced the muscle sympathetic nerve activity (msna) in otherwise healthy osahs patients, although the reduction was evident only after one and a half years of treatment.47 furthermore, in a randomized placebo-controlled crossover study, faccenda et al. found that cpap therapy reduced 24-hour diastolic blood pressure in comparison with the placebo, although the overall reduction was small, averaging 1.5mmhg over the 24 hours. the decrease was greater during the early morning period that is at 2:00 a.m. as predicted a priori, the decrease was greater in those with more nocturnal hypoxaemia (> 20% desaturations/hour).24 o s a h s a n d e n d o t h e l i a l d y s f u n c t i o n the endothelium is the cell layer lining the blood vessels. it is one cell thick and senses changes in haemodynamic states.62 the endothelium responds to physical and chemical stimuli by synthesis or release of substances such as nitric oxide (no), prostacyclin, endothelins, endothelial cell growth factors, intero b s t r u c t i v e s l e e p a p n o e a / h y p o p n o e a s y n d r o m e a n d h y p e r t e n s i o n 271 leukins, adhesion molecules, and fibrinolytic factors.63 therefore, the endothelium can greatly influence vascular tone and structure by releasing no. impaired endothelium dependent function and endothelium independent function in the forearm vascular bed is associated with an increased risk of acute cardiovascular events, including cardiac death.64, 65 the endothelium is a major target of oxidative stress, and this stress may play a role in the pathophysiology of vascular disease. in osahs, recurrent episodes of hypoxaemia followed by re-oxygenation may trigger endothelial damage, via oxidative stress, superoxide radical formation.66 the combination of superoxide radical with nitric oxide and reducing nitric oxide bioavailability in the vessel wall leads to vasoconstriction. more recent studies have shown that oxidative stress and lipid preoxidation do not appear to be the key mediator for the cardiovascular diseases in osahs.67, 68 this finding contradicts the results of other studies which showed that osahs patients have an increased status of oxidative stress such as thiobarbituric reactive substances and peroxides 69 and decreased antioxidant capacity which could be reversed by cpap treatment.70, 71 only a few studies have shown increased expression of adhesion molecules72 and production of reactive oxygen species in leukocytes of sleep apnoea patients.73, 74 proinflammatory factors such as interleukins, c-reactive protein and leukocyte adhesion molecules such as cd15 73 might also contribute to the pathogenesis of developing cardiovascular diseases and merit further evaluation. in addition, prothrombotic factors75 such as fibrinogen, plasminogen activator inhibitor, and reduced fibrinolytic activity with enhanced platelet activity, may play a role in the process.76 in a randomized double-blind placebo controlled crossover trial, it was shown that oshas is associated with endothelial dysfunction using venous occlusion plethysmography during intra-arterial infusion of endothelium-dependent (acetylcholine and substance p) and endothelium-independent (sodium nitroprusside) vasodilator. vasodilatation was significantly impaired in subjects with oxygen desaturations (20 dips of 4% desaturations/hr) compared to non-desaturators (p <0.05) in the same study, treatment with cpap for 6 weeks improved forearm blood flow to all vasodilators in comparison to results after sham cpap (p <0.05 for all vasodilators).77 c o n c l u s i o n obstructive sleep apnoea/hypopnoea syndrome is a common condition and its association with hypertension is very strong. clinically, it is essential to understand the relationship between osahs and hypertension for the benefit of patients in order to prevent long-term sequelae and optimise treatment. the mechanisms behind the elevation of blood pressure in osahs are mainly due to autonomic changes that occur as a result of recurrent arousal and hypoxia. impairment of baroreflex and chemoreflexes may lead to sustained activation of sympathetic activities. endothelial dysfunction may also have a role in the process of development of hypertension in sleep apnoea subjects. effective cpap therapy has been shown to reverse these changes and may prevent its occurrence. further studies are required to explore the role of osahs in the pathogenesis of atherosclerotic changes and subsequently developing arterial stiffness. randomised control trials are also needed to assess the effect of cpap therapy in reversing or preventing these changes. r e f e r e n c e s 1. young t, finn l. epidemiological insights into the public health burden of sleep disordered breathing: sex differences in survival among sleep clinic patients. thorax 1998; 53:s16-s19. 2. guilleminault c, tilkian a, dement wc. the sleep apnea syndromes. annual rev med 1976; 27:465-484. 3. stradling jr, barbour c, glennon j, langford ba, crosby jh. prevalence of sleepiness and its relation to autonomic evidence of arousals and increased inspiratory effort in a community based population of men and women. j sleep res 2000; 9:381-388. 4. engleman hm, kingshott rn, martin se, douglas nj. cognitive function in the sleep apnea/hypopnea syndrome (sahs). sleep 2000; 23:s102-s108. 5. young t, blustein j, finn l, palta m. sleep-disordered breathing and motor vehicle accidents in a populationbased sample of employed adults. sleep 1997; 20:608613. 6. engleman hm, hirst ws, douglas nj. under reporting of sleepiness and driving impairment in patients with sleep apnoea/hypopnoea syndrome. j sleep res 1997; 6:272-275. 7. george cf, boudreau ac, smiley a. simulated driving performance in patients with obstructive sleep apnea. am j respir crit care med 1996; 154:175-181. 8. davies cw, crosby jh, mullins rl, barbour c, davies rj, stradling jr. case-control study of 24 hour ambulam o h a m m e d a a l a b r i a n d k h a m i s m a l h a s h m i 272 tory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. thorax 2000; 55:736-740. 9. pankow w, nabe b, lies a, becker h, köhler u, kohl fv, lohmann fw. influence of sleep apnea on 24-hour blood pressure. chest 1997; 112:1253-1258. 10. berger ha, somers v, philips bg. sleep disordered breathing and hypertension. curr opin pulm med 2001; 7:386-390. 11. lavie p, herer p, hoffstein v. obstructive sleep apnoea syndrome as a risk factor for hypertension: population study bmj 2000; 320:479-482. 12. nieto fj, young tb, lind bk, shahar e, samet jm, redline s, et al. association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. sleep heart health study. jama 2000; 283:1829-1836. 13. peppard pe, young t, palta m, skatrud j. prospective study of the association between sleep-disordered breathing and hypertension. n engl j med 2000; 342:1378-1384. 14. koskenvuo m, kaprio j, telakivi i, partinen m, heikkila k, sarna s. snoring as a risk factor for ischemic heart disease and stroke in men. bmj 1987; 294:16-19. 15. norton pg, dunn ev. snoring as a risk factor for disease: an epidemiological survey. bmj 1985; 291:630632. 16. carlson j, hedner j, ejnell h, peterson le. high prevalence of hypertension in sleep apnea patients independent of obesity. am j respir crit care med 1994; 150:7277. 17. hla km, young t, bidwell t, palta m, skatrud j, dempsey j. sleep apnoea and hypertension. a populationbased study. ann intern med 1994; 120:382-388. 18. bixler eo, vgontzas an, lin hm, ten have t, leiby be, vela-bueno a, et al. association of hypertension and sleep-disordered breathing. arch intern med 2000; 160:2289-2295. 19. worsnop cj, naughton mt, barter ce, morgan to, anderson ai, pierce rj. the prevalence of obstructive sleep apnea in hypertension. am j respir crit care med 1998; 157:111-115. 20. grote l, hedner j, peter jh. sleep-related breathing disorder is an independent risk factor for uncontrolled hypertension. j hypertens 2000; 18:679-685. 21. logan ag, perlikowski sm, mente a, tisler a, tkacova r, niroumand m, et al. high prevalence of unrecognized sleep apnoea in drug-resistant hypertension. j hypertens 2001; 12:2271-2277. 22. brooks d, horner rl, kozar lf, render-teixeira cl, phillipson ea. obstructive sleep apnoea as a cause of systemic hypertension. evidence from canine model. j clin invest 1997; 99:106-109. 23. parker jd, brooks d, kozar lf, render-teixeira cl, horner rl, douglas bt, et al. acute and chronic effects of airway obstruction on canine left ventricular performance. am j respir crit care med 1999; 160:18881896. 24. faccenda jf, mackay tw, boon na, douglas nj. randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apneahypopnea syndrome. am j respir crit care med 2001; 163:344-348. 25. pepperell jc, ramdassingh-dow s, crosthwaite n, mullins r, jenkinson c, stradling jr, et al. ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. lancet 2002; 359:204-210. 26. pedulla m, silvestri r, lasco r, mento,g, lanuzza b, sofia l, et al. sleep structure in essential hypertensive patients: differences between dippers and non-dippers. blood press 1995; 4:232-237. 27. pinto jm, garpestad e, weiss jw, bergau dm, kirby da. hemodynamic changes associated with obstructive sleep apnea followed arousal in a porcine model. j appl physiol 1993; 75:1439-1443. 28. narkiewicz k, somers v. the sympathetic nervous system and obstructive sleep apnoea: implications for hypertension. j hypertens 1997; 15:1613-1619. 29. somers vk, dyken me, carly mp, abboud fm. sympathetic neural mechanisms in obstructive sleep apnoea. j clin invest 1995; 96:1897-1904. 30. palatini p, penzo m, racioppa a, zugno e, guzzardi g, anaclerio m, et al.clinical relevance of night time blood pressure and of daytime blood pressure variability. arch intern med 1992; 152:1855-1860. 31. fletcher e, lesske j, qian w, miller cc, unger t. repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. hypertension 1992; 19:555-561. 32. lesske j, fletcher ec, bao g, unger t. hypertension caused by chronic intermittent hypoxia-influence of chemoreceptors and sympathetic nervous system. j hypertens 1997; 15:1593-1603. 33. narkiewicz k, debrone pjh, cooley rl, dyken me, somers vk. sympathetic activity in obese subjects with and without obstructive sleep apnea. circulation 1998; 98:772–776. 34. somers v, dyken me, mark al, abboud fm. sympathetic nerve activity during sleep in normal humans. n engl j med 1993; 328:303-307. 35. morgan bj, crabtree dc, palta m, skatrud jb. combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. j appl physiol 1995; 79:205-213. o b s t r u c t i v e s l e e p a p n o e a / h y p o p n o e a s y n d r o m e a n d h y p e r t e n s i o n 273 36. horner rl. autonomic consequences of arousal from sleep: mechanisms and implications. sleep 1996; 19: s193-s195. 37. schneider h, schaub cd, chen ca, andreoni ka, schwartz ar, smith pl, et al. effects of arousal and sleep state on systemic and pulmonary hemodynamics in obstructive apnoea. j appl physiol 2000; 88:10841092. 38. morrell mj, finn l, kim h, peppard pe, badr ms, young t. sleep fragmentation, awake blood pressure, and sleep-disordered breathing in a population-based study. am j respir crit care med 2000; 162:2091-2096. 39. noda a, yasuma f, okada t, yokota m. influence of movement arousal on circulation rhythm of blood pressure in obstructive sleep apnoea syndrome. j hypertens 2000; 18:539-544. 40. hedner j, ejnell h, sellgren j, hedner t, wallin g. is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? j hypertens 1988; 6:s529-s531. 41. marrone o, riccobono l, salvaggio a, mirabella a, bonanno a, bonsignore mr. catecholamines and blood pressure in obstructive sleep apnea syndrome. chest 1993; 103:722-727. 42. narkiewicz k, pesek ca, kato m, philips bg, davison de, somers vk. baroreflex control of sympathetic nerve activity and heart rate in obstructive sleep apnea. hypertension 1998; 32:1039-1043. 43. daly md, angell-james je, elsner r. role of carotidbody chemoreceptors and their reflex interactions in bradycardia and cardiac arrest. lancet 1979; 1:764-767. 44. narkiewicz k, van de borne pj, montano n, dyken me, phillips bg, somers vk. contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. circulation 1998; 97:943-945. 45. narkiewicz k, van de borne pj, hausberg m, cooley rl, winniford md, davison de, et al. cigarette smoking increases sympathetic outflow in humans. circulation 1998; 98:528-534. 46. narkiewicz k, kato m, pesek ca, somers vk. human obesity is characterized by a selective potentiation of central chemoreflex sensitivity. hypertension 1999; 33:1153-1158. 47. narkiewicz k, kato m, phillips bg, pesek ca, davison de, somers vk. nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. circulation 1999; 100:2332-2335. 48. narkiewicz k, van de borne pj, pesek ca, dyken me, montano n, somers vk. selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. circulation 1999; 99:1183-1189. 49. shepard jw jr. cardiopulmonary consequences of obstructive sleep apnea. mayo clin proc 1990; 65:12501259. 50. floras js, hassan mo, jones jv, osikowska ba, sever ps, sleight p. consequences of impaired arterial baroreflexes in essential hypertension:effects on pressor responses, plasma noradrenaline and blood pressure variability. j hypertens 1988; 6:525-535. 51. siche jp, herpin d, asmar rg, poncelet p, chamontin b, comparat v, et al. non-invasive ambulatory blood pressure variability and cardiac baroreflex sensitivity. j hypertens 1995; 13:1654-1659. 52. lantelme p, lo m, sassard j. decreased cardiac baroreflex sensitivity is not due to cardiac hypertrophy in ngnitro-l-arginine methyl ester-induced hypertension. j hypertens 1994; 12:791-795. 53. yamada y, miyajima e, tochikubo o, matsukawa t, shionoiri h, ishii m, et al. impaired baroreflex changes in muscle sympathetic nerve activity in adolescents who have a family history of essential hypertension. j hypertens suppl 1988; 6:s525-s528. 54. carlson jt, hedner ja, sellgren j, elam m, wallin bg. depressed baroreflex sensitivity in patients with obstructive sleep apnea. am j respir crit care med 1996; 154:1490-1496. 55. bonsignore mr, parati g, insalaco g, marrone o, castiglioni p, romano s, et al. continuous positive airway pressure treatment improves baroreflex control of heart rate during sleep in severe obstructive sleep apnea syndrome. am j respir crit care med 2002; 166:279-286 56. tkacova r, dajani hr, rankin f, fitzgerald fs, floras js, bradley td. continuous positive airway pressure improves nocturnal baoreflex sensitivity of patients with heart failure and obstructive sleep apnea. j hypertens 2000; 18:1257-1262. 57. jennum p, wildschiodtz g, christensen nj, schwartz t. blood pressure, catecholamines, and pancreatic polypeptide in obstructive sleep apnea with and without nasal continuous positive airway pressure (ncpap) treatment. am j hypertens 1989; 2:847-852. 58. ali nj, davies rj, fleetham ja, stradling jr. the acute effects of continuous positive airway pressure and oxygen administration on blood pressure during obstructive sleep apnea. chest 1992; 101:1526-1532. 59. davies rj, crosby j, prothero a, stradling jr. ambulatory blood pressure and left ventricular hypertrophy in subjects with untreated obstructive sleep apnoea and snoring, compared with matched control subjects, and their response to treatment. clin sci (lond) 1994; 86:417-424. 60. engleman hm, asgari-jirhandeh n, mcleod al, ramsay cf, deary ij, douglas nj. self-reported use of cpap and benefits of cpap therapy: a patient survey. chest 1996; 109:1470-1476. m o h a m m e d a a l a b r i a n d k h a m i s m a l h a s h m i 274 61. wilcox i, grunstein rr, hedner ja, doyle j, collins, fl, fletcher pj, et al. effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. sleep 1993; 16:539-544. 62. raitakari o, celermajer d. testing of endothelial dysfunction. ann med 2000; 32:293-304. 63. jaffe ea. cell biology of endothelial cells. hum. pathol 1987; 18:234-239. 64. newby de, mcleod al, uren ng, flint l, ludlam ca, webb dj, et al. impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. circulation 2001; 103:1936-1941. 65. newby de, wright ra, labinjoh c, ludlam ca, fox ka, boon na, et al. endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. circulation 1999; 99:1411-1415. 66. row bw, liu r, xu w, kheirandish l, gozal d. intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. am j respir crit care med 2003; 167:1548-1553. 67. svatikova a, wolk r, lerman lo, juncos la, greene el, mcconnell jp, et al. oxidative stress in obstructive sleep apnoea. eur heart j 2005; 26:2435-2439. 68. svatikova a, wolk r, wang hh, otto me, bybee ka, singh rj, et al. circulating free nitrotyrosine in obstructive sleep apnea. am j physiol regul integr comp physiol 2004; 287:r284-r287. 69. lavie l. obstructive sleep apnoea syndrome-an oxidative stress disorder. sleep med rev 2003; 7:35-51. 70. lavie l, vishnevsky a, lavie p. evidence for lipid peroxidation in obstructive sleep apnea. sleep 2004; 27:123128. 71. barcelo a, barbe f, de la pena m, vila m, perez g, pierola j, et al. antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment. eur respir j 2006; 27:756-760. 72. lattimore jd, wilcox i, nakhla s, langenfeld m, jessup w, celermajer ds. repetitive hypoxia increases lipid loading in human macrophages-a potentially atherogenic effect. atherosclerosis 2005; 179:255-259. 73. dyugovskaya l, lavie p, lavie l. increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. am j respir crit care med. 2002; 165:934-939. 74. schulz r, mahmoudi s, hattar k, sibelius u, olschewski h, seeger w, et al. enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. impact of continuous positive airway pressure therapy. am j respir crit care med 2000; 162:566570. 75. robinson gv, pepperell jc, segal hc, davies rj, stradling jr. circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. thorax 2004; 59:777-782 76. parish jm, somers vk. obstructive sleep apnea and cardiovascular disease. mayo clin proc 2004; 79:10361046. 77. cross md, mills nl, al-abri m, riha rl, vennelle m, mackay tw, et al. continuous positive airway pressure improves vascular function in obstructive sleep apnea hypopnea syndrome: a randomized controlled trial. thorax 2008; 63:578-583. submitted 15 dec 2022 1 revision req. 2 jan 23; revision recd. 20 jan 23 2 accepted 5 feb 23 3 online-first: february 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.009 5 6 efficacy of granisetron versus sufentanil on reducing myoclonic 7 movements following etomidate 8 a double-blind, randomized clinical trial 9 mohammad alipour,1 naeem abdi,2 *parisa zaj,1 leila mashhadi1 10 11 1department of anesthesiology, faculty of medicine, mashhad university of medical 12 sciences, mashhad, iran; 2student research committee, school of nursing and midwifery, 13 shiraz university of medical sciences, shiraz, iran. 14 *corresponding author’s e-mail: parisazaj66@yahoo.com 15 16 abstract 17 objective: etomidate-induced myoclonus occurs in up to 85% of patients under general 18 anesthesia. this type of myoclonus can induce significant clinical and economic problems in 19 patients with special conditions. hence, to reduce the intensity of myoclonus movements, the 20 present study was conducted to compare the effectiveness of granisetron and sufentanil on 21 reducing the intensity of etomidate-induced myoclonic movements. methods: this double-22 blind randomized clinical trial study consisted of 96 adult patients. using block 23 randomization, subjects were divided into three groups of 32: the group receiving granisetron 24 40 μg / kg (group g), the group receiving sufentanil 0.2 μg / kg (group s), and the control 25 group who did not receive the pretreatment (group c). patients received these medications as 26 pretreatments 120 seconds before induction with etomidate. after injection of etomidate with 27 a dose of 0.3 mg/kg, the incidence of myoclonus was evaluated. after evaluating the 28 myoclonus, the full dose of narcotics (fentanyl 1 μg / kg) and muscle relaxants (atracurium 29 0.5 mg/kg) were administered to patients, and a suitable airway was established for them. 30 results: the findings indicated that granisetron reduced the intensity and incidence of 31 myoclonic movements more than sufentanil. in addition, myoclonic movements were 32 observed at a significantly higher intensity in the control group (p=0.001). conclusion: the 33 results obtained from the current study indicate that granisetron and sufentanil as 34 pretreatments are effective for reducing myoclonus in patients. 35 keywords: granisetron; sufentanil; etomidate; myoclonus; movement. 36 37 advances in knowledge: 38  clinical function: considering the effectiveness of granisetron in controlling and 39 reducing myoclonic movements during general anesthesia, it can be effective in 40 improving the quality of anesthesia when using in the hospital. 41  education: the results of this research can provide a new insight into the use of 42 granisetron in controlling and reducing myoclonic movements during general 43 anesthesia for professors, students, and educational planners. 44  research: the results of this research can set the ground for further quantitative 45 studies on the drug granisetron and comparing its effectiveness with other drugs in 46 controlling and reducing myoclonic movements during general anesthesia. 47 application to patient care: 48  regarding the use of granisetron and sufentanil in controlling and reducing myoclonic 49 movements during general anesthesia, it can be effective in improving the quality of 50 anesthesia in case of using in the hospital. 51 52 introduction 53 etomidate is an intravenous general anesthetic agent, whose clinical effects are developed 54 through enhancing the gaba inhibitory system by altering chloride conduction.1 due to its 55 rapid induction of anesthesia with minimal changes in cardiovascular function, it is one of the 56 most widely used intravenous anesthetics in patients with limited cardiorespiratory 57 function.1,2 it is derived from imidazole and may cause pain as well as myoclonus in patients 58 during and after injection.3 etomidate injection pain is minimized by applying fat emulsions 59 in etomidate compounds, but myoclonus caused by etomidate is still a clinical challenge. 4 60 myoclonus refers to sudden, brief twitching or jerking as well as shock-like involuntary 61 movements of a muscle or group of muscles5,6. myoclonus caused by etomidate occurs in up 62 to 85% of patients under anesthesia.5 it begins in a limited part of the body and spreads to 63 muscles in other areas. myoclonus can cause many significant problems in more severe 64 cases, such as ventilation disturbance.5,6 electrophysiological studies are useful in evaluating 65 myoclonus, not only for confirming the clinical diagnosis but also for understanding the 66 underlying physiological mechanisms. since the majority of myoclonic jerks are believed to 67 be caused by hyperexcitability of a group of neurons in certain cerebral structures, the 68 relationship of myoclonic jerks with eeg activity is of primary importance in the study of 69 myoclonus.7,8 70 71 different drugs (fentanyl,9 remifentanil,10 midazolam,11 etc.) have been used as pretreatment 72 for myoclonus caused by etomidate, each with exclusive side effects, while the best option 73 for clinical treatment of etomidate-induced myoclonus has not yet been determined.12 74 fentanyl is a single synthetic opiate used for analgesia. today, fentanyl is widely used for 75 anesthesia and pain relief. among the side effects of this drug are itching and impaired 76 breathing.5,9 as an opioid analgesic, sufentanil is an analog of fentanyl and is used to induce 77 as well as maintain anesthesia plus postoperative analgesia. in practice, it seems that the 78 hemodynamic stability of sufentanil anesthesia during surgery is better than that of other 79 opioids or inhaled anesthesia13,14. the side effects of sufentanil include hypotension and 80 impaired respiration.14,15the effect of sufentanil pretreatment on myoclonus caused by 81 etomidate has been studied by many researchers who have published different results. 82 according to a study in 2003, the incidence of etomidate-induced myoclonus in patients 83 receiving sufentanil as a pretreatment was zero.15 in another study in 2016, the incidence of 84 etomidate-induced myoclonus with sufentanil pretreatment was reported to be 28%. 16 85 86 granisetron is one of the serotonin receptor antagonists that is used as an anti-nausea and 87 vomiting drug in the operation room, chemotherapy, etc.,17 this drug has minor side effects 88 and may cause headaches, confusion in people who are allergic to the drug, and 89 constipation.17 the effect of granisetron on etomidate-induced myoclonus has not been 90 studied yet. however, the efficacy of granisetron was investigated as a pretreatment on 91 propofol-induced myoclonus in a study by alipour m (2013). it showed that the incidence of 92 propofol-induced myoclonus with granisetron was only 5.5% and most of the patients 93 (94.5%) experienced myoclonic movements with grade 0 (without myoclonus)18. since 94 myoclonus induced by etomidate injection in certain patients can have significant side 95 effects, this study was conducted for the first time to determine the effectiveness of 96 granisetron on intensity of myoclonus induced by intravenous administration of etomidate 97 and to compare with sufentanil. 98 99 materials and methods 100 this double-blind clinical trial study was performed on selected patients referring to 101 educational hospitals affiliated with mashhad university of medical sciences in 2021. after 102 obtaining the ethics approval from the medical ethics committee of mashhad university of 103 medical sciences (code: ir.mums.medical.rec.1399.509) and registration at the 104 iranian clinical trial center (#irct20210221050436n1), sampling and data collection 105 began. in this study, 96 patients were selected via convenience sampling and randomly based 106 on a table of random numbers created by a computer. then, based on random blocks and in 107 parallel, they were divided into two intervention groups (granisetron and sufentanil groups) 108 plus a control group with 32 subjects each. 109 110 inclusion criteria were patients undergoing general anesthesia with (1) american society of 111 anesthesiologists classification (asa) i, ii, (2) and age between 15-60 years. exclusion 112 criteria included (1) adrenal dysfunction, (2) history of allergy to opioid analgesics and 113 hypnotics drugs, (3) mental disorders, (4) neuromuscular diseases, (5) seizure, (6) electrolyte 114 imbalanced, (7) history of addiction, (8) long qt syndrome, as well as severe cardiovascular 115 diseases, (9) high intracranial pressure (icp) and intraocular pressure(iop), and (10) 116 increased intra-abdominal pressure. written consent was obtained from all subjects, and they 117 were assured that all their information would remain confidential. also, at any time, and even 118 after giving consent, they could withdraw from the study voluntarily (figure1). 119 120 patients underwent isotonic iv fluid therapy at 5ml/ kg for 10 minutes before induction. 121 further, standard monitoring, including pulse oximetry, electrocardiogram, non-invasive 122 blood pressure, and capnography, was performed on them. patients were randomly (block 123 randomization) assigned into three groups of granisetron (group g 40 μg / kg), sufentanil 124 (group s 0.2 μg / kg), and control group (group c). first, the studied drugs with a volume of 125 5 ml were administered within 30 seconds. then, after 120 seconds, etomidate was injected at 126 a dose of 0.3 mg/kg for 30 seconds. the incidence and intensity of myoclonus was evaluated 127 by a person who was not aware of the group allocations (anesthesia resident) 2 minutes after 128 administration of etomidate. the drugs were injected by an anesthetist who was unaware of 129 the type of drugs. 130 131 in this double-blind study, the intensity of myoclonus was measured with a score between 0 132 and 3, where 0 represents no myoclonus, 1 indicates mild as small movements of a part of the 133 body such as finger or wrist, 2 denotes moderate as gentle movements of two different 134 muscle groups such as face and legs, and 3 indicates severe as severe clonic movements in 135 two or more muscle groups or rapid limb adduction. thereafter, the three groups were 136 compared with each other.16,19 after evaluating the myoclonus, the patient was prescribed a 137 full dose of a narcotic drug (fentanyl 1 microgram/kg), muscle relaxant (atracurium 0.5 138 mg/kg), and a suitable airway was established for the patient. no pretreatment was injected 139 before etomidate administration in the control group. sixty seconds before and after injection 140 of each drug under study (sufentanil and granisetron), heart rate, systolic and diastolic blood 141 pressure, and arterial oxygen pressure were measured and recorded. according to the 142 patient's vital signs, fentanyl was injected as needed in all three groups. given that fentanyl 143 was administered after completion of the study, it did not affect the study process. all of the 144 administered drugs had been produced by abu reihan company in iran. 145 146 all patients were visited by an anesthesiologist for 24 hours after surgery, and their clinical 147 condition was assessed. confounding variables were controlled according to the control 148 group and random assignment of samples. using the formula of comparing a qualitative trait 149 in two communities and taking into account the findings of the study of alipour et al,16 who 150 reported the incidence of grade 0 myoclonus in sufentanil recipients as 72% and the clinical 151 estimate of this index as 35% in granisetron recipients, taking into account the 5% alpha error 152 and 80% power, the sample size in each group was equal to 29 people, which increased to 32 153 in each group after calculating a dropout of 10%. 154 155 in this study, descriptive statistical tests, and chi-square as a non-parametric test for 156 qualitative demographic variables and incidence of myoclonus was used. also, analysis of 157 variance (anova) was performed to compare the mean of quantitative variables between 158 groups using spss19 software. 159 160 results 161 in this study, from a total of 96 patients, the mean and standard deviation of the age variable 162 in the three groups of sufentanil (s), granisetron (g), and control (c) were 39.25±1.53, 163 39.25±12.03, and 38.63±10.61, respectively; according to the anova test, no significant 164 difference was observed among the three groups in terms of age variables (p = 0.96). the 165 results of this study revealed that the three groups were not significantly different in terms of 166 demographic characteristics such as gender, anesthesia class (asa), underlying diseases 167 (hypothyroidism and hyperthyroidism, hypertension, diabetes, and ischemia) based on the 168 chi-square test. also, other important demographic characteristics were height, weight, and 169 bmi (body mass index); according to the anova test, the mean and standard deviation of 170 these variables did not differ significantly between the three groups (table 1). in this study, 171 patients' hemodynamic status was monitored and recorded based on the variables of systolic 172 and diastolic blood pressure, heart rate, and arterial oxygen pressure 60 seconds before and 173 after injection of the studied drugs. the study results based on anova statistical test 174 indicated that there was no significant difference between the three groups (table 2). 175 according to the main objective of the present study, one of the most important variables was 176 the intensity of etomidate-induced myoclonic movements. patients in the granisetron group 177 showed less intensity of myoclonic movements relative to the sufentanil and control groups 178 based on chi-square test. however, in the control group, these movements were measured and 179 recorded with more intensity and created a statistically significant difference from the other 180 two groups (tables 3). 181 182 discussion 183 the major advantage of etomidate is its stable cardiovascular profile which aids in 184 counteracting the sympathetic stress response during laryngoscopy and intubation.20 despite 185 all benefits of this drug, myoclonus is still a significant side effect.16,21 the main mechanism 186 of myoclonus caused by etomidate is unknown. however, one hypothetical mechanism for 187 etomidate-induced myoclonus is that high concentrations of etomidate suppress cortical 188 activity earlier than subcortical function. for this reason, the extent and severity of 189 myoclonus can be reduced through pretreatments that inhibit the excitatory activity of the 190 subcortical region.16,19-21 the use of various drugs as pretreatment agents to reduce 191 myoclonus induced by etomidate injection has been investigated, such as dexmedetomidine,20 192 opioids,21 benzodiazepines,21 lidocaine,22 magnesium sulfate,20 muscle relaxants, 23,24 193 gabapentin.25 however, the drugs offered should be limited to specific and exact cases. it is 194 important to choose an optimal agent as a pretreatment in relation to the type and duration of 195 surgery as well as the patient's condition. accordingly, this double-blind study was 196 performed to evaluate the effect of granisetron and sufentanil on reducing the intensity of 197 myoclonic movements following etomidate injection as a pretreatment in comparison with 198 the control group. 199 200 one of the differences between this study compared to similar works was investigating the 201 effectiveness of granisetron that had not been studied before. the efficacy of granisetron was 202 investigated as a pretreatment in a study by alipour m (2013), showing that the incidence of 203 propofol-induced myoclonus with granisetron was only 5.5% and most of the patients 204 (94.5%) experienced myoclonic movements with grade 0 (without myoclonus)18. since the 205 results of the present study are in line with the previous study, and a significant reduction has 206 been observed in the intensity and incidence of myoclonus movements, although the 207 functional mechanism of granisetron in reducing myoclonus movements is not clear yet, it 208 can be introduced as a new and valuable pretreatment. the sufentanil group also experienced 209 less intensity and incidence of myoclonic movements compared to the control group, and the 210 results of this study confirm its effectiveness. numerous studies have shown that narcotics 211 effectively reduce the intensity of myoclonus movements, though they may come at the cost 212 of respiratory depression, apnea, nausea, and vomiting.26,27 nyman y et al. (2011) 213 demonstrated that pretreatment with 100 micrograms of fentanyl reduced the incidence of 214 myoclonus by up to 8%. 28 also, in a study by stockham rj et al., higher doses of fentanyl 215 (500 μg) significantly reduced myoclonic movements. however, the incidence of apnea 216 increased during induction.29a study by kelsaka e et al. (2006) demonstrated that 217 remifentanil injection (1μg/kg) 2 minutes before the etomidate injection reduced myoclonic 218 movements by up to 7% without any clinical changes.30 in many studies, it has been 219 demonstrated that sufentanil (0.3 μg/kg) is an effective pretreatment in reducing the intensity 220 of myoclonic movements induced by etomidate injection.15 in the study by alipour et al. 221 (2016), the effectiveness of sufentanil (0.2 μg/kg) in reducing the intensity and duration of 222 myoclonic movements was also confirmed, which was consistent with the present study. 16 a 223 study by feng et al (2022) clarified that etomidate increased the mean behavioral scores and 224 glutamate levels in the csf plus neocortex during anesthesia. more importantly, they 225 demonstrated a strong correlation between the myoclonus and neocortical glutamate 226 accumulation. in this study, they concluded etomidate-induced myoclonus is associated with 227 neocortical glutamate accumulation. suppression of the astrogliosis in neocortex and 228 promoting extracellular glutamate uptake by regulating glutamate transporters (eaats) in 229 the motor cortex may be the therapeutic target for preventing etomidate-induced 230 myoclonus.31 accordingly, it can be postulated that the action of granisetron in reducing 231 myoclonic movements is the above mechanism, though it needs more investigations 232 especially in terms of pharmaceutical, cellular, and molecular properties. in general, different 233 outcomes may depend on several factors and may be partly due to the dose as well as timing 234 of pretreatment agents along with the different conditions of patients. the findings of the 235 present study regarding reduction if the intensity of myoclonic movements due to the 236 pretreatment sufentanil are in line with the results of other studies. however, the pretreatment 237 effect of granisetron significantly reduced myoclonus induced by etomidate injection 238 compared to placebo, making it even superior to sufentanil. 239 240 in past studies, it has been stated that myoclonus can cause important clinical complications, 241 but whether these complications cause permanent damages or not has not been proven and is 242 debatable. 243 244 one of the most important limitations in this study was the lack of previous studies on the use 245 and effectiveness of granisetron as a pretreatment in reducing myoclonic movements. this 246 made the mechanism of action of granisetron for reducing myoclonic movements unclear. 247 thus, it is recommended to conduct larger studies with more samples and different doses of 248 granisetron. another limitation was that, although authors refer to it as a blinded study, 249 blinding was a nonformal "observer blinded" approach. 250 251 conclusion 252 overall, the study results suggest that granisetron is similar to sufentanil and even more 253 effective in reducing the intensity of myoclonic movements following etomidate's injection 254 and can be an important step in the development of further studies in this field. it is 255 recommended that further studies be performed to compare granisetron with other 256 pretreatment agents in the future. 257 258 authors’ contribution 259 ma, na, pz, lm conceptualised and designed the research. pz, ma and lm were 260 responsible for sampling and intervention. na was responsible for statistical analysis. pz, 261 ma drafted the manuscript. na and lm reviewed and edited the manuscript. all authors 262 approved the final version of the manuscript. 263 264 acknowledgments 265 we would like to thank all the patients and their families who made this research possible, 266 and we also thank the vice chancellor for research of mashhad university of medical 267 sciences for their good cooperation. 268 269 conflict of interest 270 the authors declare no conflicts of interest . 271 272 funding 273 no funding was received for this study. 274 275 references 276 1. tobias jd. etomidate in pediatric anesthesiology: where are we now? saudi j 277 anaesth. 2015;9(4):451-6. 278 2. shilpashri am, gayathri g, palakshappa kr. etomidate is rapid acting and has 279 good cardiovascular and respiratory stability than thiopentone sodium. indian 280 journal of public health research & development. 2015 jul 1;6(3). 281 3. bertram g. katzung, marieke kruidering-hall, anthony j. trevor. katzung & 282 trevor’s pharmacology examination& board review. 12th, editor. 592 p. 283 4. doenicke a, roizen mf, nebauer ae, kugler a, hoernecke r, beger-hintzen h. a 284 comparison of two formulations for etomidate, 2-hydroxypropyl-beta-cyclodextrin 285 (hpcd) and propylene glycol. anesth analg. 1994;79(5):933-9. 286 5. isitemiz i, uzman s, toptaş m, vahapoglu a, gül yg, inal fy, et al. prevention of 287 etomidate-induced myoclonus: which is superior: fentanyl, midazolam, or a 288 combination? a retrospective comparative study. med sci monit. 2014;20:262-7. 289 6. eberhardt o, topka h. myoclonic disorders. brain sciences. 2017;7(8):103. 290 7. halliday am. the electrophysiological study of myoclonus in man. brain 291 1967;90:241–284 292 8. shibasaki h, hallett m. electrophysiological studies of myoclonus. muscle & nerve: 293 official journal of the american association of electrodiagnostic medicine. 2005 294 feb;31(2):157-74. 295 9. prakash s, mullick p, virmani p, talwar v, singh r. effect of pre-treatment with a 296 combination of fentanyl and midazolam for prevention of etomidate-induced 297 myoclonus. turkish journal of anaesthesiology and reanimation. 2021 feb;49(1):11. 298 10. lang b, zhang l, li f, lin y, zhang w, yang c. comparison of the efficacy and 299 safety of remifentanil versus different pharmacological approaches on prevention of 300 etomidate-induced myoclonus: a meta-analysis of randomized controlled trials. drug 301 design, development and therapy. 2019;13:1593. 302 11. zhou c, zhu y, liu z, ruan l. effect of pretreatment with midazolam on etomidate-303 induced myoclonus: a meta-analysis. j int med res. 2017;45(2):399-406. 304 12. taher‐baneh n, ghadamie n, sarshivi f, sahraie r, nasseri k. comparação de 305 fentanil e dexmedetomidina como adjuvante à bupivacaína para raquianestesia 306 unilateral em cirurgia de membros inferiores: estudo randômico. brazilian journal of 307 anesthesiology. 2019;69(4):369-76. 308 13. monk jp, beresford r, ward a. sufentanil. drugs. 1988;36(3):286-313. 309 14. lv y, he h, xie j, jin w, shou c, pan y, et al. effects of transcutaneous acupoint 310 electrical stimulation combined with low-dose sufentanil pretreatment on the 311 incidence and severity of etomidate-induced myoclonus: a randomized controlled 312 trial. medicine (baltimore). 2018;97(23):e10969-e. 313 15. hueter l, schwarzkopf k, simon m, bredle d, fritz h. pretreatment with sufentanil 314 reduces myoclonus after etomidate. acta anaesthesiologica scandinavica. 315 2003;47(4):482-4. 316 16. alipour m, tabari m, azad am. comparative study evaluating efficacy of sufentanil 317 versus midazolam in preventing myoclonic movements following etomidate. j 318 anaesthesiol clin pharmacol. 2016;32(1):29-32. 319 17. spartinou a, nyktari v, papaioannou a. granisetron: a review of pharmacokinetics 320 and clinical experience in chemotherapy induced-nausea and vomiting. expert 321 opinion on drug metabolism & toxicology. 2017 dec 2;13(12):1289-97. 322 18. alipour m, tabari m, alipour m. comparison use of paracetamol, magnesium 323 sulfate, ondansetron, granisetron and lidocain on propofol injection pain in elective 324 surgeries, a thesis presented for the degree specialty of anesthesiology. mashhad 325 university of medical sciences, iran; 2013, 57-58. 326 19. doenicke aw, roizen mf, kugler j, kroll h, foss j, ostwald p. reducing 327 myoclonus after etomidate. the journal of the american society of anesthesiologists. 328 1999 jan 1;90(1):113-9. 329 20. ghodki ps, shetye nn. pretreatment with dexmedetomidine and magnesium sulphate 330 in prevention of etomidate induced myoclonus–a double blinded randomised 331 controlled trial. indian journal of anaesthesia. 2021 may;65(5):404. 332 21. sedighinejad, a., et al., comparison of the effects of low-dose midazolam, magnesium 333 sulfate, remifentanil and low-dose etomidate on prevention of etomidate-induced 334 myoclonus in orthopedic surgeries. anesthesiology and pain medicine, 2016. 6(2). 335 22. gultop, f., et al., lidocaine pretreatment reduces the frequency and severity of 336 myoclonus induced by etomidate. journal of anesthesia, 2010. 24(2): p. 300-302. 337 23. choi, j.m., et al., pretreatment of rocuronium reduces the frequency and severity of 338 etomidate-induced myoclonus. journal of clinical anesthesia, 2008. 20(8): p. 601-604. 339 24. nooraei, n., a. solhpour, and s.a. mohajerani, priming with atracurium efficiently 340 suppresses etomidate-induced myoclonus. acta anaesthesiologica taiwanica, 2013. 341 51(4): p. 145-148. 342 25. yılmaz çakirgöz, m., et al., efeito do pré-tratamento com gabapentina sobre a 343 mioclonia após etomidato: um estudo randômico, duplo-cego e controlado por 344 placebo. revista brasileira de anestesiologia, 2016. 66: p. 356-362. 345 26. he, l., et al., butorphanol pretreatment prevents myoclonus induced by etomidate: a 346 randomised, double-blind, controlled clinical trial. swiss medical weekly, 2014. 347 144(4142). 348 27. ko, b.j., et al., comparison of effects of fentanyl and remifentanil on hemodynamic 349 response to endotracheal intubation and myoclonus in elderly patients with etomidate 350 induction. korean journal of anesthesiology, 2013. 64(1): p. 12. 351 28. nyman, y., et al., effect of a small priming dose on myoclonic movements after 352 intravenous anaesthesia induction with etomidate-lipuro in children. british journal 353 of anaesthesia, 2011. 107(2): p. 225-228. 354 29. stockham, r., et al., fentanyl pretreatment modifies anaesthetic induction with 355 etomidate. anaesthesia and intensive care, 1988. 16(2): p. 171-176. 356 30. kelsaka, e., et al., remifentanil pretreatment reduces myoclonus after etomidate. 357 journal of clinical anesthesia, 2006. 18(2): p. 83-86. 358 31. feng y, liu j, zhang ws. etomidate-induced myoclonus correlates with the 359 dysfunction of astrocytes and glutamate transporters in the neocortex of sprague-360 dawley rats. european review for medical and pharmacological sciences. 2022 sep 361 1;26(17):6221-35. 362 363 364 365 366 367 enrollment 368 369 370 371 372 373 374 allocation 375 376 377 378 379 380 381 analysis 382 383 384 385 figure1: the consort flow diagram 386 387 assessed for eligibility (n=105) excluded (n=9) not meeting inclusion criteria (n=8) refused to participate (n=1) randomized (n=96) allocated to granisetron group (n=32) allocated to control group (n=32) analyzed (n=32) excluded from analysis (n=0) analyzed (n=32) excluded from analysis (n=0) allocated to sufentanil group (n=32) analyzed (n=32) excluded from analysis (n=0) table1. underlying diseases and demographic variables in the experimental and control 388 groups 389 variables group value p value granisetron sufentanil control gender male 15 46.9 12 37.5 15 46.9 3.28 0.19 female 17 53.1 20 62.5 17 53.1 asa class asai 21 65/50 26 81/3 22 68/8 2.16 0.33 asaii 11 34/50 6 18/2 10 31/2 htn yes 3 9.4 5 15.6 5 15.6 0.70 0.71 no 29 90.6 27 84.4 27 84.4 hypothyroidism yes 1 3.1 5 15.6 2 6.2 3.54 0.17 no 31 96.9 27 84.4 30 93.8 hyperthyroidism yes 1 3.1 0 00 0 00 2.02 0.36 no 31 96.9 32 100 32 100 diabetes yes 4 12.5 7 21.9 4 12.5 1.42 0.42 no 28 87.5 25 78.1 28 87.5 ihd yes 1 3.1 2 6.2 3 9.4 1.06 0.58 no 31 96.9 30 93.8 29 90.6 height(cm) ----172.50 4.62 171.62 5.67 172.69 5.16 5.87 0.82 weight(kg) -----73.68 3.84 72.50 4.13 72.40 3.89 6.45 0.89 bmi -----24.49 1.51 24.41 2.46 24.52 2.25 0.89 0.92 height, weight and bmi expressed as mean ± standard deviation. other variables expressed 390 as frequency and percent. 391 392 table 2: comparison of hemodynamic variables of patients in three groups 60 seconds 393 before and after injection of studied drugs. 394 variables group value p value granisetron sufentanil control mean sd mean sd mean sd 0.81 0.44 systolic i 135.00 20.85 133.84 23.18 128.25 23.86 diastolic i 92.81 16.22 90.13 17.18 87.78 14.16 0.80 0.45 systolic ii 133.75 20.81 125.41 16.54 124.50 22.61 6.63 0.48 diastolic ii 91.94 15.84 81.77 13.56 85.88 13.63 3.97 0.22 hr i 88.4 19.9 89.25 13.98 90.21 13.42 12.11 0.18 hr ii 86.19 13.96 87.63 11.02 88.66 11.62 11.31 0.20 spo2i 99.84 0.51 99.53 0.80 99.72 0.52 0.79 0.14 spo2ii 99.91 0.29 99.98 0.12 99.94 0.25 0.94 0.20 in the table above, hemodynamic variables recorded and measured 60 seconds before 395 injection are marked with roman numeral i, and variables recorded 60 seconds after injection 396 of the studied drugs are marked with roman numeral ii. 397 398 table 3: the intencity and incidence of myoclonus in the experimental and control groups 399 after injection of etomidate. 400 variables group p value granisetron sufentanil control frequent percent frequent percent frequent percent 0.001 0= without myoclonus 30 93.75 25 78.12 3 9.37 1= mild as small movements of a part of the body such as finger or wrist 2 6.25 5 15.62 20 62.50 2= moderate as gentle movements of 2 different muscle groups such as face and legs 0 0 2 6.26 7 21.88 3= severe as severe clonic movements in 2 or more muscle groups or rapid limb adduction 0 0 0 0 2 6.25 401 enhancing child development in oman applying global agenda into local context watfa al-mamari,1 *ahmed b. idris,1 kamila al-alawi,2 najma rashid,3 fannah al fannah al-araimi,4 khalid siddeeg5 1developmental pediatric unit, child health department, sultan qaboos university, muscat, oman; 2public health office, who country office for sultanate of oman, muscat, oman; 3independent early years’ consultant, kenya; 4imci expert, ministry of health, muscat, oman; 5department of healthier populations, who regional office for the eastern mediterranean, muscat, oman *corresponding author’s e-mail: ahmed30411@gmail.com the early years of life are considered the most critical time for neural and brain development, establishing the groundwork for long-term mental, social and educational achievements.1 during this time, the child's growth, sense of security and sense of well-being are substantially influenced by good nutrition and the thoughtful care of the family and other early caregivers. additionally, studies have shown that engaging, child-focused learning and promoting early childhood development (ecd) programmes showed their effectiveness in both formal and informal settings.2–7 the economic impact of investing in ecd care programmes was estimated to be approximately 13% per annum return on investment for every dollar spent.8 evidence basis of early developmental care the ability of the nervous system to adapt to experiences is one of the fundamental features of the human brain. epigenetic, immunological, physiological and psychological adaptations to the environment start before conception, according to studies on early human development, and impact brain development throughout a child's life.9 this is considered a direct function of the high degree of brain plasticity in early childhood.10 this insight necessitates a strategy that targets caregivers and children with efficient treatments at critical points throughout the child’s life; the 3–5-year window after conception is of particular significance. according to research on longterm effects from lowand middle-income countries, a programme in jamaica designed to improve the cognitive development of stunted children 25 years ago led to a considerable rise in average adult wages.11 on the other hand, growth failure in the first two years of life has negative repercussions on adult health and human capital, including chronic illness, reduced educational attainment and adult earnings.5,6 additionally, inadequacy and disadvantages continue into the next generation, creating a vicious intergenerational cycle that results in the loss of human capital and the continuation of poverty. these results highlight the ecd programmes' revolutionary potential.12 the global gap in reaching developmental potential in a global context, it was estimated that 43% of children under five years of age are not reaching their developmental potential; this gap was attributed to two main reasons: (1) the failure to apply evidencebased knowledge on ecd to shape young children's development and (2) the inability to integrate programmes utilising a multisectoral approach and scaling-up programmes during crucial stages in the early life course.10 the impact of early caregiving on children's learning outcomes, cognitive functions and social behaviours is undeniable in the modern scientific era. the lack of knowledge dissemination regarding the relationship between early caregiving experience and its underpinning neurobiological process hampers the expansion of ecd programmes. although these concepts originated in behavioural neuroscience, they have since found numerous applications and, as a result, have lost their connection to neurobiology. this is regrettable, but in many aspects, it illustrates how little is known about the brain’s mechanisms that develop, maintain and limit sensitive periods in human development.13 international experiences of early childhood development programmes the jamaica early childhood stimulation intervention project, which studied the effects of an early childhood home-visiting programme on education and labour market results at age 31, is one of the most renowned studies in early child development.11 the jamaica programme was a two-year home-based intervention meant to increase the quality of mother-child editorial this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.1.2023.014 sultan qaboos university med j, may 2023, vol. 23, iss. 2, pp. 143−147, epub. 31 may 23 submitted 28 nov 22 revision req. 8 jan 23; revision recd. 17 jan 23 accepted 9 feb 23 care for child development in oman paving the road for children to develop on track 144 | squ medical journal, may 2023, volume 23, issue 2 interactions in order to promote cognitive, linguistic and psychosocial abilities. the programme targeted children living in kingston's underprivileged districts who were stunted and disadvantaged; a randomised trial, including stunted children between 9–24 months, assessed the therapy. the researchers discovered substantial and statistically significant effects on income and education. in a long term follow-up, the treatment group earned 43% more in wages and 37% more in earnings than the control group.14 basic impact assessments comparing ecd to no ecd programmes have consistently demonstrated promising outcomes. children who participate in ecd programmes have better developmental results than those who do not, according to rigorous studies conducted in high-income countries such as the us and the united kingdom and in lowand middleincome countries such as argentina, bangladesh, indonesia, vietnam and mozambique.6,15 positive effects of preschool exposure on cognitive skills, including language, numeracy and psychomotor development, are the most constant finding.15 in order to help children around the globe benefit from those scientific results and reach their full potential, the lancet published a series titled “advancing early childhood development: from science to scale” that quantified the cost and demonstrated that children who are not adequately nurtured during their early years might lose a quarter of their adult earning potential. the series presents a road map for effective interventions in early life, as well as evidence that such programmes directly contribute to alleviating extreme poverty, improving shared prosperity, supporting healthy lives and learning, decreasing inequities and sustaining peaceful communities.16–19 early childhood development in international agenda ecd was included in united nations sustainable development goals (sdgs). in addition, the global strategy for women's, children's and adolescents' health (2016–2030) was issued by the world health organization (who) with a vision that women, children and adolescents in every setting achieve health and well-being and have social and economic opportunities and are able to participate fully in shaping prosperous societies. it aspires to keep women, children and adolescents at the centre of the sdg agenda. the vision of the global strategy is driven by the tremendous financial return on investment and the human rights of physical and mental health. a 60-indicator monitoring framework is included in the global strategy. the progress of ecd is measured by indicator 4.2.1: “the proportion of children under 5 years of age who are developmentally on track in health, learning, and psychosocial well-being, by sex”.20 subsequently, the who, united nations children's fund (unicef), the world bank group and other partners introduced the nurturing care framework (ncf) in 2018. the ncf provided a plan of action consisting of five tactical components to enable a whole-of-society and whole-of-government approach to ensuring that every child receives loving care. the ncf is a series of practices that promote children's health, nutrition, security and safety, responsive caring and early learning opportunities. nurturing children involves ensuring they are secure, healthy, wellnourished, paying attention to and reacting to their needs and interests, and encouraging them to explore their surroundings and engage with their caregivers and others. nurturing care is not just essential for the development of young children. in addition, it protects them from the most detrimental impacts of adversity by reducing their stress levels and fostering emotional and cognitive coping strategies. nurturing care is particularly crucial for children with developmental challenges and impairments, as well as for preventing child abuse.21,22 the ncf recommends multisectoral implementation policies and programmes that capitalise on the interdependencies across its components that extend from preconception through adolescence.22 an integral component of the ncf is responsive care which encompasses care for child development (ccd) programmes; these offer advice to assist caregivers in fostering closer bonds with young children and overcoming obstacles to delivering nurturing care.23 given the high social and economic return on investing in developmental care programmes, the development working group of the g-20 countries launched an initiative for ecd during their meeting in argentina in september 2018. the initiative supported the notion that early infancy is crucial for laying the groundwork for future health and well-being, which is advantageous for global society. the initiative calls for a closer examination of governmental investments in child development and increases in the resources that provide advantages to families in vulnerable situations. the working group expressed concern that investment in ecd remains insufficient despite considerably high-returns outcomes. a budget-based method was suggested to ascertain a minimum investment benchmark supporting this call. the cost of delivering the package in various situations is stated as a percentage of gross domestic product watfa al-mamari, ahmed b. idris, kamila al-alawi, najma rashid, fannah al fannah al-araimi and khalid siddeeg editorial | 145 (gdp). for upper-middle-income countries, the price of a minimal package to improve human capital has been estimated to be 0.8% of the gdp. this package requires a minimum average annual expenditure per child younger than six years of $390 in upper-middleincome countries.24 the situation in oman oman has made significant social and economic progress over the last few years. as a cascading effect, oman’s ranking in the human development category is improving tremendously on the global human development index. that improvement is coupled with political relationships and ties with different nations, culminating in oman's invitation to attend g-20 in new delhi in 2023 as a guest country.25 the world bank’s report on oman projected improvement in financial status driven by oil and gas production, robust energy prices and wide-ranging structural reforms; the country was classified as high-income, with its gdp growth forecasted to reach 3.2% in 2023– 24.26 there is however still room for improvement, especially in integrating ccd and scaling it up into existing multisectoral programmes. according to the oman multiple indicator cluster survey (mics), only 29.2% of children between the ages of 3–4 years have access to early childhood education. despite this, housing characteristics and personal assets revealed that the vast majority of the population lives in furnished houses with electricity and telecommunication facilities. three or more children's books are in the homes of 24.3% of children under five years old. although 74.7% of children under five years own at least two toys, 44.7 % were left with inadequate care during the week before the survey interview. interestingly, 68.3% of children between the ages of 3–6 years were found to be developing on-track.27 therefore, it could be argued that the situation of awareness about responsive caregiving in the country needs to be optimised. the ccd programme is wellpositioned to fill that gap in responsive care, given its authentication from the who and global partners and the availability of scientific evidence, efficacy and cost-effectiveness of its applicability. to scale-up the ccd package and ensure its sustainability, the programme needs to be integrated, institutionalised and supported by governmental policies. the health system can provide an excellent opportunity to integrate ccd into its services, as it spans from conception through pregnancy, childbirth and early childhood.28 the health system in oman is a governmentalbased service in which healthcare is provided for all nationals and governmental employees with almost negligible out-of-pockets charges. private enterprises are required to provide health insurance for their employees. the government's primary source of money is the oil market; hence health expenditures are financed by oil-related earnings. as a fast-expanding area, the omani health system is racing to incorporate new services to meet performance criteria. as a result of the country's rising urbanisation and industrialisation, the healthcare burden is moving from communicable to non-communicable diseases. lifestyle-related illnesses dominate the cost of healthcare; recent research anticipated that the percentage of oman's mortality attributable to non-communicable diseases would surpass 70% per cent.29,30 sultan qaboos university (squ) is a national leader in patient care, research and training related to developmental care and disorders and is wellequipped to train future medical leaders in this field. the squ hospital appeared as a potential entry point for the health system to scale-up the ccd in oman with the collaboration of the who-oman team. hence, squ signed a memorandum of understanding with the who-oman office on the 7th of july, 2022. the agreement aims to enhance ecd through capacity building, research and training utilising evidencebased integrative care regarding developmental care and neurodevelopmental disabilities. the collaboration between both entities was supported by the who regional office for the eastern mediterranean, culminating in the inauguration of the ccd programme in oman by conducting the first national training of healthcare workers from different regions of the country. the trainees were involved in a 5-day programme that utilised theoretical and practical training curricula to offer caregivers of young children age-appropriate direction for fostering cognitive, physical, communicative and socialemotional development via play and interaction. the training involved 22 candidates from different regions of oman who were carefuly chosen to carry out training of trainers and subsequent adaptation into omani culture. the trainees were first-line healthcare professionals, health administrators, speech & language therapists, social workers and teachers representing multiple sectors in preparation to upscale the programme in different sectors through an integrated model. the project is considered a milestone in oman's developmental care to promote young children's psychosocial development. enhancing child development in oman applying global agenda into local context 146 | squ medical journal, may 2023, volume 23, issue 2 future directions in the local context the who/unicef programme on care for child development has a unique monitoring and evaluation system. the approach presupposes that, prior to the execution of the intervention, a situational analysis will be conducted to recognise the need to enhance child development and family care practices. for instance, a situation analysis will identify children with low performance on developmental assessments, stunted growth or inadequate school readiness. mics conducted in oman can best represent the proposed situation analysis and monitoring framework because it includes proxy indicators of family practices and other conditions in the home that support learning and development, in addition to other indicators of child health, nutrition, protection and education.27 in addition, caregivers who are the focus of the care for child development intervention can be surveyed using the mics items that are most closely associated with the intervention. in general, the key performance indicators serve two functions: monitoring implementation and evaluating their impact.31 a future plan for the current programme was set to scale-up the ccd programme at the national level in oman, researching its feasibility and applicability and training more trainers. it is crucial to cross-culturally adapt ccd to be used on a large scale in oman, given the characteristics of the ccd programme and the dearth of validated, culturally appropriate, accessible and practicable programmes for promoting child development in the middle eastern population in general and oman in particular. this editorial aimed to document this vital step as a point of differentiation to monitor progress in united nations sdgs preand post-era. monitoring sdg indicators regarding developmental care will be followed to evaluate the programme's progress in oman and provide lessons for neighbouring countries. a u t h o r s’ c o n t r i b u t i o n editorial conception and design were done by wm and ai. the initial drafting of the manuscript was completed by ai, ks, ka, ff and nr. the manuscript was revised by all authors. all authors reviewed and approved the final version of the manuscript. references 1. shonkoff jp, garner as; committee on psychosocial aspects of child and family health; committee on early childhood, adoption, and dependent care; section on developmental and behavioral pediatrics. the lifelong effects of early childhood adversity and toxic stress. pediatrics 2012; 129:e232–46. https://doi.org/10.1542/peds.2011-2663. 2. rao n, sun j, chen ee, ip p. effectiveness of early childhood interventions in promoting cognitive development in developing countries: a systematic review and meta-analysis. hk j paediatr 2017; 22:14–25. 3. blewitt c, o’connor a, morris h, may t, mousa a, bergmeier h, et al. a systematic review of targeted social and emotional learning interventions in early childhood education and care settings. early child dev care 2019; 191:2159–87. https://doi.org/10.1080/03004430.2019.1702037. 4. emmers d, jiang q, xue h, zhang y, zhang y, zhao y, et al. early childhood development and parental training interventions in rural china: a systematic review and meta-analysis. bmj glob health 2021; 6:e005578. https://doi.org/10.1136/bmjgh-20 21-005578. 5. blewitt c, o’connor a, morris h, mousa a, bergmeier h, nolan a, et al. do curriculum-based social and emotional learning programs in early childhood education and care strengthen teacher outcomes? a systematic literature review. int j environ res public health 2020; 17:1049. https://doi. org/10.3390/ijerph17031049. 6. anderson lm, shinn c, fullilove mt, scrimshaw sc, fielding je, normand j, et al. the effectiveness of early childhood devel opment programs: a systematic review. am j prev med 2003; 24:32–46. https://doi.org/10.1016/s0749-3797(02)00655-4. 7. holmes m. do parents matter? curriculum inquiry. malden, massachusetts, usa: blackwell publishers, 1998. pp. 113–22. 8. heckman j. there’s more to gain by taking a comprehensive approach to early childhood development. the heckman equation. 2017. 9. kolb b, gibb r. searching for the principles of brain plasticity and behavior. cortex 2014; 58:251–60. https://doi. org/10.1016/j.cortex.2013.11.012. 10. britto pr, lye sj, proulx k, yousafzai ak, matthews sg, vaivada t, et al. nurturing care: promoting early childhood development. lancet 2017; 389:91–102. https://doi.org/10.10 16/s0140-6736(16)31390-3. 11. gertler p, heckman j, pinto r, zanolini a, vermeersch c, walker s, et al. labor market returns to early childhood stimulation: a 20-year followup to an experimental intervention in jamaica. from: https://www.nber.org/papers/w19185 accessed: jan 2023. 12. walker sp, chang sm, wright a, osmond c, granthammcgregor sm. early childhood stunting is associated with lower developmental levels in the subsequent generation of children. j nutr 2015; 145:823–8. https://doi.org/10.3945/ jn.114.200261. 13. hertzman c, wiens m. child development and long-term outcomes: a population health perspective and summary of successful interventions. soc sci med 1996; 43:1083–95. https://doi.org/10.1016/0277-9536(96)00028-7. 14. gertler pj, heckman jj, pinto r, chang sm, granthammcgregor s, vermeersch c, et al. effect of the jamaica early childhood stimulation intervention on labor market outcomes at age 31. nat bureau econ res 2021. https://doi. org/10.3386/w29292. 15. yoshikawa h, kabay s. education for all 2000-2015: achievements and challenges. from: https://unesdoc.unesco. org/ark:/48223/pf0000232456 accessed: jan 23. 16. richter lm, darmstadt gl, daelmans b, britto pr, black mm, lombardi j, et al. advancing early childhood development: from science to scale. an executive summary for the lancet’s series. from: https://www.thelancet.com/series/ecd2016 accessed: jan 23. 17. richter lm, daelmans b, lombardi j, heymann j, lopez boo f, behrman jr, et al. series advancing early childhood development: from science to scale 3 investing in the foundation of sustainable development: pathways to scale up for early childhood development. the lancet 2017; 389. watfa al-mamari, ahmed b. idris, kamila al-alawi, najma rashid, fannah al fannah al-araimi and khalid siddeeg editorial | 147 18. britto pr, lye sj, proulx k, yousafzai ak, matthews sg, vaivada t, et al. nurturing care: promoting early childhood development. lancet 2017; 389:91–102. https://doi.org/10.10 16/s0140-6736(16)31390-3. 19. black mm, walker sp, fernald lch, andersen ct, digirolamo am, lu c, et al. early childhood development coming of age: science through the life course. lancet 2017; 389:77–90. https://doi.org/10.1016/s0140-6736(16)31389-7. 20. world health organization. the global strategy for women’s, children’s and adolescents’ health (2016-2030). from: https:// w w w.who.int/data/maternal-ne wborn-child-adolescentageing/global-strategy-data accessed: jan 23. 21. who, unicef, the world bank. nurturing care for early childhood development: a framework for helping children survive and thrive to transform health and human potential. from: https://apps.who.int/iris/bitstream/handle/10665/27260 3/9789241514064-eng.pdf accessed: jan 23. 22. black mm, behrman jr, daelmans b, prado el, richter l, tomlinson m, et al. the principles of nurturing care promote human capital and mitigate adversities from preconception through adolescence. bmj global health 2021; 6:e004436. https://doi.org/10.1136/bmjgh-2020-004436. 23. wertlieb d. nurturing care framework for inclusive early childhood development: opportunities and challenges. dev med child neurol 2019; 61:1275–80. https://doi.org/10.1111/ dmcn.14234. 24. richter lm, desmond c, behrman j, britto p, daelmans b, devercelli ae, et al. g20’s initiative for early childhood development. lancet 2018; 392:2695–6. https://doi.org/10.1016/ s0140-6736(18)33058-7. 25. oman observer. invitation to the sultanate of oman to participate in the g-20 summit and meetings as a guest country. from: https://www.omanobserver.om/article/1125266/oman/ community/oman-invited-to-attend-g20-as-a-guest-country accessed: jan 23. 26. the world bank. gulf economic update green growth opportunities in the gcc. from: https://www.worldbank. org/en/countr y/gcc/publication/gulf-economicupdateoctober-2022 accessed: jan 23. 27. national center for statistics and information, unicef. sultanate of oman multiple indicator cluster survey 2014 final report. from: https://www.unicef.org/oman/media/391/ file/mics%202014%20report.pdf accessed: jan 23. 28. lake a, chan m. putting science into practice for early child development. lancet 2015; 385:1816–17. https://doi. org/10.1016/s0140-6736(14)61680-9. 29. al-mawali a. non-communicable diseases: shining a light on cardiovascular disease, oman’s biggest killer. oman med j 2015; 30:227–8. https://doi.org/10.5001/omj.2015.47. 30. al mawali ahn, al qasmi am, al sabahi sms, idikula j, elaty maa, morsi m, et al. oman vision 2050 for health research: a strategic plan for the future based on the past and present experience. oman med j 2017; 32:86–96. https://doi. org/10.5001/omj.2017.18. 31. unicef, world health organization, pan american health organization. a framework for monitoring and evaluating the who/unicef intervention. from: https://www.unicef. org/lac/media/8586/file/frame work%20for%20m&e%20 intervention.pdf accessed: jan 23. atopy in omani patients with asthma 5 atopy in omani patients with asthma *maha al-amri1, omar a al-rawas2, bazdawi ms al-riyami2, elizabeth r richens3 abstrac t. objectives: to determine the range of serum ige in healthy subjects and in asthmatic patients in oman and to assess the degree of atopy in the asthmatic patients. method: serum ige and in vivo (the skin prick test) and in vitro (the immunocap test) allergen-specific ige levels were measured in 44 patients with asthma. control groups were 19 healthy subjects and 27 asymptomatic allergic subjects. results: the normal range for serum ige in the omani population was established at ≥ 101 iu/ml. the geometric mean (and 95% confidence interval) for asthmatic patients was 468 iu/ml (323–676). positive results for allergen-specific ige, defined as responses to ≥ 1 allergen mix in the immunocap and to ≥ 3 allergens in the skin prick test, occurred in 26/35 (74%) and in 34/44(77%) asthmatic patients respectively. six out of 38 patients with serum ige ≥ 101 iu/ml and 2/6 with levels <101 iu/ml gave negative and positive results respectively in the skin prick test. overall, the degree of reactivity in the skin prick test correlated with the level of total serum ige (r= 0.54, p<0.001). a similar correlation could not be established with immunocap reactivity, but sige levels ≥ 101 iu/ml were supported by a high frequency of positive immunocap responses for the majority of allergen mixes. conclusions: total serum ige levels should be routinely monitored in asthmatic subjects as this may give an indication of atopy where skin prick testing is not indicated. since in a minority of patients serum ige levels and skin prick results do not predict in the same direction, all laboratory data should be interpreted in context of clinical history. keywords: atopy, asthma, oman 1department of ent, al-nahda hospital, ministry of health, po box 393, muscat 113, sultanate of oman. 2department of medicine, and 3department of microbiology and immunology, college of medicine and health sciences, sultan qaboos university, po box 35 al-khod, muscat 123, sultanate of oman. *to whom correspondence should be addressed. the clinical expression of asthma is characterised by chronic eosinophilic inflammation, airway hyperresponsiveness to a variety of specific and non-specific stimuli and reversible airway obstruction.3,4 whilst the pathogenesis of this inflammation has been shown to be increasingly complex, the interaction of immunoglobulin-e (ige) with high-affinity mast cell receptors and the consequent release of inflammatory factors, are still widely accepted as the initiating/triggering events.5 investigations of the role of the humoral immune system in the aetiology and presentation of asthma normally include the measurement both of total serum ige (sige) reactivity and levels of allergen-specific ige (asige). bronchial asthma is one of the most com-mon chronic disorders, both of children and of adults, worldwide. despite regional differences in its prevalence, asthma presents considerable socio-economic burden to all societies. in oman, studies are under way to determine the epidemiology and severity of asthma in children, through participation in the international study of asthma and allergies in childhood (isaac).1 as measured by the occurrence of wheezing, there is a prevalence of 9% in 3–4-year-olds.2 if these figures project through to the entire population, they suggest a high burden of disease from asthma in oman. squ journal for scientific research: medical sciences 2002, vol. 4, no. –2, 5–23 ©sultan qaboos universit y �richens atopy in asthma ������ ��������� ����� ���� ������)������ ���( ����� �������� � ������� ����� � ������ ��� � ������� ��� �������� :�����:��� ������� �������� ������ ����� ��� �����ige������� � ������ ������ ��� ���� ����� ���� � ������ �������� ���� ����� ��� ������� �����)������ ��� (����� ���� ��.�������:�� ����� ���� ��ige���� � ����� �� �� ������� ����ige������ �������� ������� ������ ������� �������"����� ��� "�� ������ � ������ ���“immunocap ”��� �� ��������������� ������� ������ �� � ����� ���� �������� ����� ����������� ����� ���� ��� ������ �� ������ ���� �����.�������:� �������� ������� ��� ���ige�� �������� ��� >�������� ����/������� �������� �� )������ %����� ��� ( ��� �������� ���������� ����/��)���-��� .( � �������� ������� ����� �� ���ige���� �� ������� ������ ������� ������� ������� >��� ������ �� ������� ������ ������ ����“immuno cap ”� >������� �� ������� ������ ������ "����� ��� "�� ����� ��/��)�� ( %�����/��)�� (%������� ��� ����� ��� �� .�� �������� ������ ����� ����� �������� › ige ����� ����/� �� ��������� ����� ����� ����ige<�������� ���� /������� � ����� ����� ����� ��)������� ��� (������ �� "����� ��� "��� ���� .��� ����� �������"����� ��� "� ����� ������� �� �����ige�� ������� ��� � ����� ��ige����� �� >�������� ����/�� ������� ������� �������� ������� ������ �������� ����.������:� ����� �������ige����� ���� �� ������ ���� ����� ��� ����� �� � ������� ����� ��� ��������� ������ ���)������ ��� (������ ������� ��� ��� �� ��� �"����� ��� "�� ����� �ige����� �� ������ ����� ������� �� ������� ��� ��� ����� ��� ���� � ������ �� ��� �� ����� �� ���� �. 6 asige has been measured by in vivo (skin prick test: spt) and in vitro (immunocap test) techniques. in the present study, we have investigated the following features of atopy in asthmatic patients in oman: () the relationship of total serum sige levels to reactivity in the skin prick test (spt) and to levels of asige, (2) the range of allergen reactivity in the omani patients and (3) the extent of concordance between the spt and the asige tests. p a t i e n t s a n d m e t h o d s subjec ts forty four patients with asthma [7, male; 27, female; 33.7 y±5.4 (mean±sd age)] seen routinely in the asthma clinic in sultan qaboos university hospital, muscat, were studied. the history of allergic asthma was established by full clinical history and examination. the standard bencard questionnaire was applied to all the patients included in the study, and skin tests were performed using the panel of bencard skin test allergens. in addition, sige and in vitro asige levels were also measured. control groups were: () 27 subjects [3, male; 4, female; 33.0 y±4.] with previous history of allergy, but currently asymptomatic, the asymptomatic allergic subjects (aas); (2) 9 [, male; 8, female; 29.3y±8.5] normal control subjects (ncs). m e t h o d s . serum ige this was measured using a micro particle enzyme immunoassay6 in the imx system (abbot laboratories, il 60064, usa). 2. allergen-specific ige in viv o test: the skin prick test (spt) this was measured using the bencard system, using a panel of 25 allergens. positive reactions in this test were assessed as wheal-and-flare reactions greater than 3 mm in patients who also gave positive reactions on provocation with histamine (positive control). 3. allergen-specific ige in vitro test: the immunocap test asige was measured using the automated immunocap system (pharmacia and upjohn diagnostics, uppsala, sweden). undiluted test sera and standards were incubated with allergens covalently coupled to a cnbractivated cellulose derivative (the immunocap) for 30 minutes. β-galactosidase conjugated anti-ige monoclonal antibodies against a range of allergens were added. the mixture was incubated for a further 50 minutes during which time a complex was formed. unbound enzyme anti-ige was washed away and the bound complex was incubated with a developing agent, 4-methylumbellifa l a m r i e t a l 24 10 100 1000 healthy (n=19) aas (n=8) asthma (n=44) si g e g eo m et ri c m ea n (iu /m l) bars represent geometric mean values sige, with 95% confidence limits figure 1. ranges of sige levels in normal control subjects, asymptomatic allergic subjects and patients with asthma. bars represent geometric mean values sige, with 95% confidence limits 7 lar frequency of response to the immunocap allergens euroglypus maynei and hollister-stier laboratories dust preparation [table a]. by contrast, the spt allergen house dust, (73% response) showed a similar frequency of response to each immunocap individual and mixed preparations of the dermataphagoides species allergens, and also to the euroglypus maynei and the hollisterstier laboratories dust preparations. skin prick tests . frequency of response the frequencies of positive responses to spt allergens are shown in table 2. the highest frequency was to house dust, where 73% of subjects responded, followed by cat fur (43%), house dust mite and lobster (each at 38%), mixed threshing (36%) and maize (34%). there was a less than 20% response rate for the majority of allergens. when spt allergens were examined on an individual basis, there was no significant difference in the frequency of responses for the majority of allergens between those patients with serum ige levels ≥ 0 and <0 iu/ ml respectively. the one exception to this was the allergen house dust mite, to which there was an increased response at sige levels ≥ 0 (χ2= 4.37, p<0.05). 2. association between sige level and positivity in spt the overall positive response in the spt was defined as reactivity to at least 3/25 of the spt allergens in the panel, and 34/44 patients (77%) were positive and 0/44 patients (23%) were negative in this test. of the 38 patients with sige ≥0 iu/ml, 32 (84%) gave a positive response in the spt, compared with 2/6 (33%) patients with sige <0 iu/ml—χ2=7.64, p<0.0. of the 0 patients with an overall negative response in the spt, 4 had sige <0 iu/ ml and 6 had sige ≥ 0 iu/ml. four patients gave zero responses in the spt; their sige levels were 467, 276, 224 and 57 iu/ml [figure 2]. there was an overall positive correlation between sige level and the number of allergens reactive in the spt (r=0.54, p<0.00) [figure 2]. allergen specific ige . frequency of response for these tests, data is available for both the aas group and the asthmatic patients. the frequency of responses to immunocap allergen mixes is shown in table 3. with regard to airborne allergens, 74% of asthmatic patients responded to the immunocap allergen, house dust mix, the same proportion as responded to house at o p y i n o m a n i pat i e n t s w i t h a s t h m a eryl-β-d-galactoside. after 0 minutes, the reaction was stopped and the fluorescence detected in a fluorimeter. the developed fluorescence was directly proportional to the concentration of allergen specific ige in the serum.7 for individual allergens, standardisation permits calculation of ige levels in allergen specific units. the system is calibrated over six ranges: <0.35 kua/l (not atopic) to >00 kua/l (strongly positive). for allergen mixes, only a positive/negative result is given. statistical analysis the frequency of responses to spt and immunocap allergens was compared by χ2 analysis. correlations between sige levels and allergen-specific ige data were made using pearson’s product-moment correlation coefficient and regression analysis. the significance of the differences in log sige levels between subject groups was compared by t-test. differences in quantitative reactions to immunocap allergens between different groups of subjects were made using the mann-whitney u test. ranges of sige levels are shown as the 95% confidence interval (ci) of the geometric mean. r e s u l t s total serum ige levels total sige levels for the three groups are illustrated in figure . the geometric mean and 95% ci for the asthmatic patients were 468 iu/ml and 323–676. this was significantly higher than for either the aas—30 iu/ml (3–68) (t=5.73, p<0.00)—or the ncs—68 iu/ml (4– 0) (t=5.79, p<0.00). there was no significant difference between these latter two groups. in this study therefore, the upper limit of the normal range has been set at <0 iu/ml. while 38 asthmatic patients had sige levels above this limit—632 iu/ml (45–887)—there were 6 patients in whom the sige levels were within the normal range— 67 iu/ml (54–83). comparison of allergens used in the in vivo and in the in vitro tests for atopy a similar frequency of positive responses was shown for the majority of allergen pairs analysed in the in vivo and in vitro systems (p value of χ2>0.05) [table a]. the only exception to this was the spt allergen house dust mite, to which there was a 38% response. this was significantly lower than the response frequency of greater than 70% for each of the three immunocap dermataphagoides species allergens and the immunocap house dust mix (p values of χ2<0.05) [table b], but it showed a simi8 dust in the spt. however, when the response to individual immunocap allergens was analysed, it became apparent that the highest proportion (73%), of subjects responded to dermatophagoides pteronyssinus and only 44% responded to the immunocap house dust preparation, (hollister-stier laboratories) i.e the reverse of the situation seen with spt allergens [table 2]. the response was greater than 50% for other airborne allergens. the numbers of asthmatic patients tested with the food allergen mixes was very low, so the results can only be interpreted with extreme caution. for all airborne allergens, and for nut mix, but not for cereal or for fish mixes, there was a significantly higher proportion of positive responses in asthmatic patients compared with the aas group [table 3]. 2. association between sige level and positivity to immunocap mixes due to the limited numbers there was no discrimination in the proportions of those patients with high and those with low sige levels reacting to allergen mixes in the immunocap test [table 4]. however, when those patients with sige ≥ 0 iu/ml were considered separately, it is apparent that positive results to immunocap allergen mixes occurred in the following proportions of patients: food 3/6 (8%) house dust 6/22 (72%) moulds 5/8 (63%) tree pollen 6/0 (60%) grass 8/2 (38%) thus, apart from grass allergen mix, levels of sige ≥ 0 iu/ml are supported by reactivity to immunocap allergen mixes in a diagnosis of atopy. coincidence of re ac tivit y to spt and to immunoc ap allergens in individual patients data was available from 3 asthmatic patients for both tests. positivity was again defined as reactivity to ≥ 3 spt allergens and to ≥ immunocap allergen. twenty three (74%), 2 (67%) and 9 (58%) patients were positive in the spt, in the immunocap and in both tests respectively. these data, together with the mean sige levels for each group, are shown in table 5. this illustrates very clearly that spt positivity is associated with high levels of sige, while negativity in the spt is associated with low levels of sige. a significantly higher proportion of the patients positive in spt had a positive response in the immunocap compared with those negative in the spt (χ2=9.04, p<0.0). that is, there is an overall tendency for the spt and the immunocap to predict in the same direction. the levels of sige were similar in immunocap positive and negative subjects, both in spt positive (t=0.28, df=2, p>0.05) and negative (t=0.23, df=6, p>0.05) patients. a l a m r i e t a l 25 figure 2 0 0.5 1 1.5 2 2.5 3 3.5 4 0 2 4 6 8 10 12 number of positive skin prick tests lo g s lg e r=0.54, p<0.001 horizontal line represents upper limit of normal range for ige horizontal line represents demarcation of overall negative and positive results in spt figure 2. correlation between sige levels and degree of positivity in the skin prick test. the horizontal line represents upper limit of normal range for ige. vertical line represents demarcation of overall negative and positive results in spt. 9 d i s c u s s i o n total sige levels and allergen-specific tests, both in vivo and in vitro, are commonly used to diagnose atopic diseases. at the present time, there is no established data on either sige levels or the immune status of asthmatic patients in this country. identification of triggering allergens in the gulf region is important for the informed clinical management of allergic diseases. this is particularly so where desensitisation therapy is considered. it is equally important to establish the clinical efficiency of in vivo and in vitro diagnostic tests for allergic diseases. the present study compares methodologies used in the diagnosis of asthma in adult omani patients attending the asthma clinic at sultan qaboos university hospital in oman; we report here the results of asige tests in the context of total sige levels in the study population. the mean sige level in healthy omani subjects was 68 iu/ml with a range of 4 to 0 iu/ml. these levels are comparable to those of other populations.8,9 the asige data in this study has been analysed in the context of a normal range for sige of <0 iu/ml. the mean level for the aas group, 30 iu/ml with a range 3 to 68 iu/ml, was lower than that of the healthy omani subjects; only one of the aas had an sige level above the normal range. it is perhaps of relevance here that the entire aas group were expatriates. hence the differences found may illustrate a real difference between the two control groups, since variations in sige may occur due to environmental factors such as diet and parasite burdens related to geographical location of origin. the level of sige in the healthy omani population can only be validated by increasing the size of the cohort studied. such studies are currently in progress. in agreement with previous findings,8 the geometric mean (469 iu/ml) and the range (323–676 iu/ml) of sige were increased in the omani asthmatic patients compared to healthy control subjects. since sige contributes significantly to the outcome of skin tests, the clinical significance of these sige levels and the interpretation of the results from the allergen-specific tests can only be assessed in context of the normal range for this population. however, in one study, skin reactivity was table i a. spt and immunocap allergens showing similar frequencies of responses on testing in asthmatic patients immunocap allergens spt allergens gx1: grass (mix) grass, hay dust, straw, mixed threshings t23: cupressus trees t72: queen palm trees tx7: tree (mix) trees m3: aspergillus a. niger, a. fumigata, hay dust, straw, mixed threshings m6: alternata a. alternata, hay dust, straw, mixed threshings mx2: mould (mix) a. alternata, hay dust, mixed threshings d74: e. maynei house dust, house dust mite h2: hollister-stier labs house dust, house dust mite dl: d. pteronyssinus house dust d2: d. farinae house dust d3: d. microcereus house dust hx2: house dust mix house dust el: cat cat fur e3: horse horse hair e4: cow cow hair e81: sheep sheep wool e85: chick feathers fi: egg egg f2: milk milk, chocolate f4: wheat wheat f8: maize maize f80: lobster lobster fx2: fish mix cod fx3: cereal (mix) wheat, maize for each immunocap allergen shown above there was no significant difference in frequency of response (p values of χ2>0.05) by comparison with related spt allergens. table 1 b. spt and immunocap allergens showing different frequencies of response in asthmatic patients immunocap allergens spt allergen dl: d. pteronyssinus 73% house dust mite 38% d2: d. farinae 73% d3: d.microcereus 77% hx2: house dust mix* 72% there was a significantly higher frequency of response (p values of χ2 <0.05) to each of these immunocap allergens than to the spt allergen “house dust mite.” *hx2 contains dl, d2, h2 and i6 (blatella germanica) allergens. at o p y i n o m a n i pat i e n t s w i t h a s t h m a 20 noted in 35% of asthmatic patients in the presence of low levels of sige.10 similarly, six patients in this study had sige levels <0 iu/ml, and two of them (33%) showed positivity in the spt. where there is the coincidence of a low level of sige and positivity in the spt in an individual patient, difficulties may occur in the classification of the asthma. positive spt responses and allergen-specific ige antibodies are both important markers of disorders in the upper respiratory tract. however, studies of their interactive functioning are seriously hampered by differences in the commercial antigen extracts available for use in the two tests. at the outset of this study, we established comparability of response between the two antigen systems used for a wide range of allergens. we employed the pharmacia immunocap system for in vitro asige measurements and the bencard system for in vivo spt testing. both systems are dependent on the quality of allergen extracts used in the tests. quality control is difficult and in practice it can only be achieved by correlation with clinical history data by an experienced allergologist. lack of standardisation between allergens of different manufacturers is also a major concern.11 the introduction of recombinant allergens, whilst encouraging in this respect12 brings further problems. due to the high specificity of band t-cell responses, the number of individual patients responding to a recombinant allergen will be restricted compared to the number responding to a heterogeneous allergen prepared from natural sources, because such allergens contain multiple epitopes and different isoforms.12 hence, the use of recombinant allergens may lead to underdiagnosis of allergic patients. studies in patients from the gulf region should ideally be performed using allergens prepared locally. these are not available at present. in their absence, it is difficult to draw definitive conclusions on the relative diagnostic efficiencies of assay modalities from studies using different commercial allergens. variations between them may reflect affinity and epitope recognition patterns within individual ige responses rather than imprecision in the test. a further complication is that in vivo and in vitro tests monitor different aspects of asige, tissuebound (i.e. stable over many months) in the spt, versus serum levels (with a half-life of only 2 days) in the immunocap. despite these factors, we found no statistical difference in response between the majority of comparable allergens in the immunocap and the spt, though other studies suggest a higher overall frequency of response in the spt.14,15 this is probably a reflection of the more persistent biological life of tissue bound ige. the only major discrepancy in this study between comparable allergens was between the house dust and house dust mite allergens. in agreement with another reported study, the immunocap was more sensitive for house dust mite allergens.16 by contrast, the spt was more sensitive for the house dust allergen. these data are suggestive of a crossover in specificities of these particular allergens a l a m r i e t a l table 2. skin prick test (spt ) response to allergens in asthmatic patients in relation to total sige level allergen positive response (n=44) positive response in patients with sige <101iu/ml (n=6) ≥101iu/ml (n=38) cat fur 19 (43%) 2 (33%) 17 (45%) cowhair 4 (9%) 0 (0%) 4 (11%) feathers 10 (23%) 0 (0%) 10 (26%) horse hair 7 (16%) 1 (17%) 6 (16%) human hair 6 (14%) 0 (0%) 6 (16%) sheep wool 13 (29%) 0 (0%) 13 (34%) house dust 32 (73%) 3 (50%) 29 (76%) hay dust 12 (27%) 1 (17%) 11 (29%) house dust mite* 17 (38%) 0 (0%) 17 (45%) cotton 6 (14%) 1 (17%) 5 (13%) a.alternata 6 (14%) 0 (0%) 6 (16%) a.fumigata 5 (11%) 0 (0%) 5 (13%) a.niger 3 (7%) 0 (0%) 3 (8%) grass 13 (30%) 1 (17%) 12 (32%) mixed threshings 16 (36%) 1 (17%) 15 (39%) trees 3 (7%) 0 (0%) 3 (8%) straw 9 (20%) 1 (17%) 8 (21%) cheese 4 (9%) 1 (17%) 3 (8%) chocolate 1 (2%) 1 (17%) 0 (0%) cod 0 (0%) egg 2 (4%) 0 (0%) 2 (5%) lobster 17 (38%) 3 (50%) 14 (37%) maize 15 (34%) 3 (50%) 12 (32%) milk 0 (0%) 0 (0%) wheat 1 (2%) 1 (3%) histamine 44 (100%) 6 (100%) 38 (100%) *using a cut off point of 101 iu/ml, sige levels do not differentiate frequency of spt response to individual allergens, except, in the case of “house dust mite”, which is only responsive in the spt at sige levels ≥101 iu/ml (χ2=4.37, p<0.05). 2 from the two different systems. there is as yet no agreement as to whether the spt and the immunocap tests are17 or are not18 complementary to each other. in this study, 34/44 (77%) of patients gave positive responses to the panel of allergens in the spt, and the association of these positive responses with raised levels of sige9 was confirmed. of the 0 (23%) patients negative in the spt, 6 had sige levels ≥ 0 iu/ml and 4 had sige levels <0 iu/ml. six out of 44 patients (4%) had sige levels <0 iu/ml, and 2 of these were positive in the spt. reactivity to individual allergens in the spt was associated with a large range of values of sige levels in different patients e.g., amongst those subjects with reactivity to 4 spt allergens, the range of sige levels was 99–5,52 iu/ ml [figure 2]. it has been suggested that where high levels of sige are found in atopic patients, they additionally reflect immune dysregulation. ige itself may be involved in allergen uptake via the cd23 receptor (fcer).5 such ige-mediated allergen presentation may lead to a continuous (over) activation of the immune system due to high levels of ige. this could explain the deterioration in the clinical condition of children with asthma, which is characterised both by increased severity of symptoms and sensitivity to an increased number of (non related) allergens.5 four patients in this study showed no reactivity to any spt allergens. three of them had sige levels above the normal range. this apparent anomaly may merely be a reflection of the lack of knowledge of the precise amount of the relevant allergen required to provoke an spt reaction in each individual patient, that is, inadequate technical understanding of the fundamental aspects of the tests. it has been shown that with similar levels of allergen-specific ige, the amount of allergen required for a positive spt may differ by as much as a factor of 00 between patients.19 thus, there may be a threshold amount of allergen required to provoke a response for each individual; this will be elucidated only when purified allergens become generally available. from this study, it is obvious that raised levels of serum ige and positivity in the spt both aid the diagnosis of atopy, but the absence of these factors does not exclude it. raised sige levels are thought to be predictive of the subsequent development of allergic disease in children,19,20 but in the adult, it does not appear that, alone, they invariably predict an allergic state. genetic and environmental factors also play an important role in the production of clinical symptoms. overall, the spt is considered to have a better diagnostic efficiency and sensitivity than in vitro methods,21,22 at o p y i n o m a n i pat i e n t s w i t h a s t h m a table 3. proportions of asthmatic and aas* subjects reacting to allergen mixes using the immunocap system allergens patient group aas (%) asthmatic (%) p value of χ2 grass pollen mix 2/19 (11%) 9/24 (37%) <0.05 tree pollen mix 3/20 (15%) 9/15 (60%) <0.05 mould mix 2/19 (11%) 5/12 (42%) <0.05 house dust mix 9/27 (33%) 26/35 (74%) <0.05 food (nut) mix 1/16 (6%) 3/3 (100%) <0.01 food (fish) mix 3/18 (17%) 3/8 (38%) >0.05 food (cereal) mix 3/17 (18%) 7/15 (47%) >0.05 *aas: asymptomatic allergic subjects table 4. numbers of asthmatic patients positive to immunocap mixes compared to their total serum ige allergen mix (n)* response to sige concentration of <101 iu/ml ≥101 iu/ml χ2 # p negative positive negative positive grass pollen (24) 2 1 13 8 0.23 >0.05 tree pollen (12) 2 0 4 6 0.60 >0.05 mould (12) 4 0 3 5 2.10 >0.05 house dust (25) 1 2 6 16 0.20 >0.05 food mixes combined (18) 1 1 3 13 0.00 >0.05 *number of cases tested #non-parametric χ2 for two independent samples table 5. coincidence of reactivity in spt and immunocap test result n geometric mean sige (iu/ml) and (95% ci) positive spt +ive immunocap –ive immunocap 23 19 4 776 (519–1161) 796 (512–1245) 684 (225–2080) positive spt +ive immunocap –ive immunocap 8 2 6 166 (67–302) 169 (30–1146) 156 (77–315) 22 and it has the advantage of providing immediate information for both patient and physician. the high degree of sensitivity offered by the spt is important when a patient is assessed for potentially life threatening allergies, for example, from penicillin or stinging insects. it is worth emphasising, however, that in a minority of patients the expected association of sige level with spt reactivity does not occur. as previously reported, some patients were found with sige levels in the normal range, but with multiple spt reactivity,10 and the converse, where some patients had raised sige levels but little or no spt reactivity. these findings are suggestive of false positive and false negative reactions in the spt, and they emphasise the care that must be taken in the categorisation of such patients. it is most important that a detailed clinical history is taken, as a third component of the diagnostic procedure. the subjects in the aas group had, as expected, low levels of sige and reduced immunocap reactivity compared with the asthmatic patients. c o n c l u s i o n we have described here a population of asthmatic patients in oman who have a sige profile comparable to that found in similar studies.9 estimation of sige may be helpful in the diagnosis of atopic asthma, but it has poor correlation with symptoms. in individual patients there is a good correlation between sige level and the degree of overall reactivity to the panel of allergens in the spt, irrespective of immunocap reactivity. sige levels, in combination with the spt, should therefore be used in the routine diagnosis of allergy in the majority of asthmatic patients who have no complications from skin conditions or medication or who are considered so sensitive by history that anaphylaxis is possible. in cases where these types of difficulties are found, use of the immunocap may be useful since its wide range of measurement permits a good discrimination of negative cases from those with atopic disease. due to nonspecific binding, high levels of sige may interfere with both in vivo and in vitro assays of asige. in view of the occasional occurences of false positive and false negative reactions in the skin prick test (spt), its results should always be interpreted in the context of a detailed clinical history. r e f e r e n c e s . isaac steering committee. worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema. lancet, 998, 35, 225–232. 2. al-riyami msb, al-rowas oas, al-riyami aa, jasim lg, mohamed aj. prevalence of asthma symptoms in omani schoolchildren. squ j sci res: med sci, 200, 3, 2–27. 3. kroegel c, virchow j-c, luttmann w, walker c, warner ja. pulmonary immune cells in health and disease: the eosinophil leucocyte. eur resp j, 994, 7, 59–543. 4. smith l, mcfadden er. bronchial hyperreactivity revisited. ann allergy, asthma and immunol, 995, 74, 454–469. 5. mudde gc, bheekha r, bruijnzeel-koomen cafm. consequences of ige/cd23 mediated allergen presentation in allergy. immunol today, 995, 6, 380–382. 6. yman l, roosdorp n, schroder h, andrae mi. methods for the determination of ige and allergen-specific antibodies. international allergy symposium, excerpta medica, 98, 67, 74–83. 7. paganelli, r. ansotegui j, sastre j, lang ce, roovers mh, de groot h, et al. specific ige antibodies in the diagnosis of atopic disease. clinical evaluation of a new in vitro test system, unicap tm, in six european allergy clinics. clin allergy, 988, 8, 58–587. 8. john ab, lee hs, lee fy, chug hh. allergen skin test and total ige in adults with rhinitis in singapore. asian pac j allergy immunol, 996, 4, 9–2. 9. janson df, rijeken b, schouten jp, kraan j, weiss st, timens w, et al. the relationship of skin test positivity, high serum total ige levels, and peripheral blood eosinophilia to symptomatic and asymptomatic airway hyperresponsiveness. am j respir crit care med, 999, 59, 924–93. 0. hoshina k, kawasaki a, mizushima y, yano s. positivities of skin test and ige rast to allergens in bronchial asthma with normal serum ige levels. arerugi, 99, 40, 6–20. . dolen wk. allergen extract standardization: reality. myth or dream. ann allergy asthma immunol, 996, 75, 8–82. 2. crameri r, lidholm j, gronlund h, stuber d, blaser k, menz g. automated specific ige assay with recombinant allergens: evaluation of the recombinant aspergillus fumigatus allergen i in the cap system. clin exp allergy, 996, 26, 4–49. 3. hayglass kt. allergy: who, why and what to do about it. immunol today, 995, 6, 505–507. 4. ewan pw, coote d. evaluation of a capsulated hydrophilic carrier polymer (the immunocap) for measurement of specific ige antibodies. allergy, 990, 45, 22–29. 5. gleeson m, cripps aw, hensley mj, wlodarczyk jh, henry rl, clancy rl. a clinical evaluation in children of the pharmacia immunocap system for inhalant allergens. clin exp allergy, 996, 6, 692–702. 6. plebani m, bourghesan f, faggian d. clinical efficiency of in vitro and in vivo tests for allergic diseases. ann allergy asthma immunol, 995, 74, 23–28. 7. droste jh kerhof m de monchy jg, schouten jp, rijken b. association of skin test reactivity, specific ige, total ige and eosinophils with nasal symptoms in a community-based population study. the dutch ecrhs group. j allergy clin immunol, 996, 97, 922–932. 8. witteman am, stapel so, perdok gj, sjamsoedin dh, jansen hm, aalberse rc, et al. the relationship between rast and skin tests in patients with asthma or rhinitis: a quantitative study with purified major allergens. j allergy clin immunol, a l a m r i e t a l 23 996, 97, 6–25. 9. kjellman ni. predictive value of high ige levels in children. acta paediatric scand, 976, 65, 465–47. 20. haahtela t, suoniemi i, jaakonmaki i, bjorksten f. relationship between sige and the occurrence of immediate skin test reactions and allergic disorders in young people. allergy, 982, 37, 597–602. 2. ownby dr. in vivo versus in vitro. pediatr clin north am at o p y i n o m a n i pat i e n t s w i t h a s t h m a 1988, 35, 995–009. 22. tschopp jm, sistek d, schindler c, leuenberger p, perruchoud ap, wuthrich b, et al. current allergic asthma and rhinitis: diagnostic efficiency of three commonly used atopic markers (ige, skin prick tests, and phadiatop). results from 8329 randomized adults from the sapaldia study. swiss study on air pollution and lung diseases in adults. allergy, 998, 53, 606–63. 2008-issue1.indd insulinoma: a rare cause of a common metabolic disorder hypoglycaemia *omayma el shafie,1 dilip sankhla,2 nayil al-kindy,3 aisha al-hamadani,4 christopher grant,3 nicholas woodhouse1 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 63-67 sultan qaboos university© submitted 20sh june 2007 accepted 14th january 2008 c a s e r e p o r t األيضي لالضطراب نادر سبب : (انسولينوما) زيرِيّ اجلَ رَمٌ الوَ الدم سكر نقص االنتشار واسع (االستقالبي) وودهاوز جرانت، نيكوالس كريستوفر احلمداني، عائشة الكندي، نايل سانخال، ديليب الشافعي، أميمة املنظار. ــطة بواس البنكرياس غدة ذيل مع ــتئصاله اس والذي مت اجلزيري الورم من يعاني عماني ملريض عمان ــلطنة س في حاله أول عن تقرير امللخص: يعانون الذين الدم للمرضى في السكر نسبة فحص التقرير أهمية هذا يوضح كما . عائلته و/أو املريض تثبت أهمية اخذ تاريخ املرض من احلالة هذه االنسولني طليع ج – وبيبتايد ــولني األنس هرمون ــبة ونس املعمل في ــكر الس ــبة نس من للتأكد دم أخرى عينات ، وكذلك اخذ املتكرر الوعي من فقدان ، ميكن حينذاك الورم بالضبط موقع حتديد املغناطيسي الرنني ــتطاعة باس يكن لم واذا لذلك. ضرورة هناك كانت اذا ــلفونيل الس يوريا ــتويات ومس اذا البنكرياس في الورم ــكان م باالوكتيرويد لتحديد ــوم املوس الثالثي االنديوم ــتخدام باس رُّس بالتَفَ أو ، لِيّ اخِ الدَّ بالتَّنْظيرِ ى دَ طيطُ الصَّ بتَخْ ــص الفح باالوكتيرويد. للعالج الدم من انخفاض سكر الذي يعاني املريض استجاب البنكرياس. استئصال باملنظار ، اجلراحة ، الدم سكر انخفاض ، ج الكلمات: بيبتايد مفتاح departments of 1medicine, 2radiology and molecular imaging, 3surgery, 4pathology, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman. *to whom correspondence should be addressed. email: omayma0@hotmail.com hypoglycaemia is a common metabolic problem and may result from increased peripheral uptake of glucose, failure of glucose production or a combination of both. by far the commonest cause is increased peripheral glucose uptake resulting from stimulation of the insulin receptor (ins-r) by endogenous overproduction or exogenous administration of excess insulin. rarely, hypoglycaemia is caused by increased circulating levels of molecules resembling insulin such as insulin like growth factors (igfs) or antibodies directed against the ins-r. hypoglycaemia also occurs in patients with advanced liver disease resulting from a failure of gluconeogenesis. the role of the kidney is less certain; glucose uptake and synthesis is high normally and renal failure often results in hypoglycaemia. as insulin is degraded by the kidney, hypoglycaemia may in part be due to prolongation of its actions.1-5 hypoglycaemia has a potential for serious neuronal damage and death. the patient described here had recurrent symptoms for two years that were initially thought to result from epilepsy and later a conversion reaction. insulinoma is rare with an incidence of only 4 per 1 million persons per year, but it is the commonabstract we describe the first patient diagnosed with an insulinoma in oman and successfully managed with a distal laparoscopic pancreatectomy. the importance of obtaining a good history from the patient and/or his family is stressed. all patients with loss of consciousness must have a reflow check carried out and, if hypoglycaemic, this should be documented in the laboratory and a simultaneous serum sample stored for measurement of insulin, c-peptide proinsulin and sulphonylurea levels, if subsequently indicated. if magnetic resonance imaging fails to locate the tumour, endoscopic ultrasound of the pancreas, or indium  labelled octreotide scanning is indicated if the patient’s hypoglycaemia has previously responded to treatment with octreotide. key words: insulinoma; c-peptide; hypoglycaemia; laparoscopy; pancreatectomy. o m ay m a e l s h a f i e , d i l i p s a n k h l a , n ay i l a l k i n d y, a i s h a a l h a m a d a n i , c h r i s t o p h e r g r a n t, n i c h o l a s wo o d h o u s e 64 est cause of hypoglycaemia in otherwise healthy adults who are not taking antidiabetic drugs. the median age is 47 years with a slight female preponderance of 59%. 87% of insulinomas are single benign tumours, 6% are malignant and 7% are multiple benign tumours and associated with multiple endocrine neoplasia type 1 (men-1).1, 2 c a s e r e p o r t a 23 year old omani male had a 2 year history of recurrent loss of consciousness and convulsions. on the first day of ramadan (islamic month of fasting) in 2006, he presented to the accident and emergency department of sultan qaboos university hospital, oman, with loss of consciousness. his blood glucose was measured by reflocheck, a blood glucose monitor, and was found to be 1.5mmol/l. on receiving intravenous dextrose, he regained consciousness. he was then discharged with a referral letter to the endocrine clinic. this delayed his admission by two months. his attacks had started in ramadan 2005, when he was unable to fast for more than 10 days. a year later in ramadan 2006, fasting became impossible for more than a few hours hence his hospital visit. the family reported that frequent meals made him less liable to attacks. there was no family history of diabetes and he was not known to have diabetes. his parents and ten siblings were healthy. his physical examination was unremarkable. he was admitted and started on a 72 hour fast. after 8 hours, his blood glucose fell to 1.5 mmol. (reflocheck). blood samples were taken for laboratory confirmation of the plasma glucose, and levels of insulin, c-peptide, pro-insulin and sulphonylureas. the fast was terminated and he was given intravenous glucose. treatment glucose 1.5 (3.5 – 5.0) mm/l insulin 9.0 (1.9 – 23) miu/l c-peptide 2 (1.5 – 4.5) ug/l pro-insulin 21 (6.4 – 9.4) pm/l time (minutes) -15 0 30 60 120 glucose mmol/l 1.4 1.7 1.8 1.4 1.0 insulin miu/l 2.1 3.4 0.3 1.9 2.0 table 1: simultaneous blood sampling of patient when hypoglycaemic table 2: octreotide trial 100 micrograms s/c time 0 figure 1: a therapeutic trial of octreotide (sms) in 3 patienrs with insulinomas. insulin secretion can be inhibited, with normalisation of the blood sugar level, only in those patients whose tumours have receptors for octreotide (<50%). only patient 1 responded i n s u l i n o m a : a r a r e c au s e o f a c o m m o n m e ta b o l i c d i s o r d e r h y p o g ly c a e m i a 65 figure 3: patient’s pancreatic tumour figure 2: the patient’s ct scan was normal but an mri revealed a 1.5 x 2 cm tumour localized in the tail of the pancreas (arrows) figure 5: insulin staining. on left normal staining, on right patient’s tumour figure 4: microscopic view of tumour well differentiated endocrine tumours well differentiated (low grade maligant) carcinoma with gross local invasion or distant metastasis poorly differentiated endocrine carcinoma small cell neuroendocrine carcinoma table 3: who classification of pancreatic endocrine tumours o m ay m a e l s h a f i e , d i l i p s a n k h l a , n ay i l a l k i n d y, a i s h a a l h a m a d a n i , c h r i s t o p h e r g r a n t, n i c h o l a s wo o d h o u s e 66 was started with diazoxide 50 mg three times a day, and thereafter he remained asymptomatic. the results in table 1 show an inappropriately high insulin concentration for the level of blood glucose. the detectable c-peptide excludes the injection of exogenous insulin as commercial insulins contain no cpeptide.1, 2 sulphonylurea was not detected. these results confirm excessive and inappropriate endogenous insulin overproduction. normally, circulating proinsulin levels account for less than 22% of the serum insulin value, but the ratio of more than 24% is seen in 90% of all insulinomas when greater than 40% malignancy is usually indicated. our patient’s value was more than 50% and he has to be carefully followed up. an octreotide trial [table 2] produced no significant change in blood glucose or insulin levels and therefore an octreotide scan was not done. only 50% of insulinomas have octreotide receptors and in these cases the drug can be used therapeutically6 [fig 1] or to locate the tumour by scanning with indium iii labelled hormone. two weeks later, he was admitted for further assessment. there had been no attacks of hypoglycaemia since starting on diazoxide. he underwent laparoscopic distal pancreatectomy7 and the tumour was localized by intraoperative laparoscopic ultrasound during surgery.8 the surgery was uneventful and the histopathology confirmed an insulinoma [figs. 4-5] of “uncertain behaviour” by who classification [tables 3 & 4]. since surgery, the patient has been very well with no hypoglycaemic attacks and he is looking forward to the next ramadan moon to undertake his fast. d i s c u s s i o n this case illustrates the necessity of good history taking. the patient’s symptoms very clearly improved by taking food. the family gave a vivid description of how he was often too weak to walk to the table for his meals. he would sometimes sink to the ground and the family would restore him by bringing food to him. during ramadan, by midday, he would be weak and confused until breaking his fast. hypoglycaemia was not, however, suspected and he was referred to neurology and psychiatric clinics. in the mayo clinic series of 224 cases of insulinoma as many as 20% of patients had been misdiagnosed as having neurological or psychiatric disorders.2 in this article, we have outlined a systematic approach to the investigation and management of patients with spontaneous hypoglycaemia.9 the largest series in the literature is from the mayo clinic2 where, in an 80-year period, 224 cases were seen. 87% were benign tumours, 6% were malignant, and 7% were associated with men-1. their follow up shows a higher recurrence rate in patients with men-1 [figure 6]. patients with benign insulinomas had a survival rate which did not differ from that expected in the general population. this is not the case in those with malignant insulinomas [figure 7]. men-1 is excluded in our patient as the pituitary ct scan and bone profile were normal. he is now free of symptoms since surgery done in november 2006. in the mayo clinic series, a cure has been defined as being totally free of symptoms for 6 months after removal of the insulinoma.2 the next ramadan fast will be used to confirm the success or otherwise of his treatment. c o n c l u s i o n the symptoms of hypoglycaemia may include loss of consciousness, convulsions and personality changes. in such a patient, hypoglycaemia should be looked for and, if found by reflocheck, two venous samples must be taken immediately; one for laboratory confirmation of the glucose and insulin level and the other stored for cpeptide, pro-insulin and sulphonylurea measurement, if indicated. this must not delay the administration of intravenous glucose, which should be given without awaiting a result. if in such a patient hypoglycaemia is found by finger prick sampling, it is essential to take two venous samples immediately. one sample should benign no extrapancreatic spread no vascular invasion <2cm <2 mitoses/10hpf <2% ki-67 positive cells table 4: characteristics of well differentiated endocrine tumours uncertain behaviour no extrapancreatic extension but with one or more of these features: >2cm in size angioinvasion >2% ki-67 positive cells i n s u l i n o m a : a r a r e c au s e o f a c o m m o n m e ta b o l i c d i s o r d e r h y p o g ly c a e m i a 67 be taken for laboratory confirmation of the glucose and insulin levels. the other should be stored for other possible investigations (c-peptide, pro-insulin and sulphonylurea). you should then take a history from your recovering patient. r e f e r e n c e s 1. siperstein a, clark oh, rushakoff rj. tumor syndromes: insulinoma and other hypoglycemias. in: goldine id, rushakoff rj, eds. diabetes and carbohydrate metabolism. from http://www.endotext.org/diabetes/index. htm. accessed june 2007. 2. service fj. diagnostic approach to hypoglycemia in adults. from http://www.uptodate.com. accessed june 2007. 3. service, fj. hypoglycemic disorders. n engl j med 1995; 332:1144-1152. 4. vortmeyer ao, huang s, lubensky i, zhuang z. nonislet origin of pancreatic islet cell tumours. j clin endocrinol metab 2004; 89:1934-1938. 5. minn ah, kayton, m, lorang, d, et al. insulinomas and expression of insulin splice variant. lancet 2004; 363:363367. 6. romeo s, milione m, gatti a, fallarino m, corleto v, morano s, et al. complete clinical remission and disappearance of liver metastases after treatment with somatostatin analogue in a 40-year-old woman with a malignant insulinoma positive for somatostatin receptors type 2. horm res 2006; 65:120-125. 7. ayav a, bresler l, brunaud l, boissel p, sfcl (société française de chirurgie laparoscopique), afce (association francophone de chirurgie endocrinienne). laparoscopic approach for solitary insulinoma: a multicentre study. langenbecks arch surg 2005; 39:134-140. 8. mirallie e, pattou f, malvaux p, filoche b, godchaux jm, maunoury v, et al. value of endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localization of insulinomas and gastrinomas. experience of 54 cases. gastroenterol clin biol 2002; 26:360. 9. hirshberg b, livi a, bartlett dl, libutti sk, alexander hr, doppman jl, et al. forty-eight-hour fast: the diagnostic test for insulinoma. j clin endocrinol metab 2000; 85:3222-3226. january 2007 vol 7 correct a.indd abstract a 75 years old lady from the dhaherah province, oman, presented at ibri hospital, complaining from abnormal vaginal bleeding. histopathological investigations of a cervical biopsy revealed no atypical features. a worm-like organism was removed from the vagina. histocytological investigations of the organism revealed typical structures of a leech. the case was identified as vaginal hirudiniasis, probably due to limnatis nilotica that necessitated a note on internal hirudiniasis. keywords: internal hirudiniasis, vagina, limnatis nilotica, case report, oman. vaginal hirudiniasis from dhaherah province, oman: with a note on internal hirudiniasis mohamed a idris sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© leeches of the class hirudinea may be aquatic, terrestrial, or amphibious in their hab-itat. they are characteristically bloodsuckers and, like ticks, are adapted to engorge large amounts of blood. they have a twofold medicinal importance: a) as an aid used for bloodletting and b) as injurious to man, painlessly inserting their jaws in the skin or mucus membrane of man and produce trickling blood. the medicinal leech (hirudo medicinalis) has been linked to the practice of medicine for years untold. its use for blood letting peaked in the mid 1800s. recently it was used by microvascular and plastic surgeons and by the public, who used it for the treatment of black eyes and varicose veins.1 internal hirudiniasis is due to aquatic leeches taken into the mouth or gaining entrance to the genitourinary tract (vulva, vagina and urethra), nostrils or conjunctiva from water.2 the presence of leeches in the throat and upper air passages is by far most common than vaginal hirudiniasis. medically important leeches mostly belong to the genus limnatis and were reported from various countries in africa, asia, southern europe and america.3,4 human infection with the most notorious species limnatis nilotica5,6 which lives in small streams, springs, wells, water-troughs, ponds, ditches and reservoirs7 has been recorded in most of the middle eastern countries,4 oman7 and yemen.8 t h e c a s e a slide containing two sections of a worm was received at the clinical microbiology laboratory, sultan qaboos university hospital, for identification from the department of histopathology and cytopathology, royal hospital, muscat, sultanate of oman, with the comment “worm from vagina, have you seen something like this before? the worm was removed from the vagina of a 75 years old lady”. the specimen was originally sent from ibri hospital, dhaherah province, sultanate of oman. the royal hospital, also received a white membranous fragment, 1 cm, of cervical biopsy. naked eye examination, considering the size, gave department of microbiology and immunology, college of medicine &health sciences, sultan qaboos university, p.o. box, 35, al khod 123, muscat, sultanate of oman email: midris@squ.edu.om c a s e s t u d y العلق الداخلي نبذه عن عمان: مع الظاهرة، من مهبلي علق عنق من (عينة) خزعة أخذ مت مهبلي. نزيف من تشكو وكانت الظاهرة من والسبعني اخلامسة سن سيده في عبري ملستشفى وصلت امللخص: يعزى قد مهبلي علق حالة تشخيص للكائن اتبرية الدراسة أكدت السيدة. مهبل من الدودة يشبه كائن أخرج طبيعيا. النسيج وكان الرحم العلق الداخلي. عن نبذه إضافة أستدعى مما النيلية بالبحيراء لإلصابة عمان. ، النيلية البحيراء ، حالة تقرير ، املهبل ، الداخلي املفردات املفتاحية: داء العلق 84 m o h a m m e d a i d r i s the impression that the sections might be of taenia segment/s that had incidentally entered the vagina. however, microscopic examination of the well-prepared sections and consultation of pearse et al.9 revealed typical sections of a leech. the case was identified as vaginal hirudiniasis, probably due to limnatis nilotica. d i s c u s s i o n small, young leeches can quickly enter the mouth or nostrils and attach to the wall of the respiratory passages, usually far back in the pharynx or larynx causing epistaxis and haemoptysis. they grow rapidly and reach a large size and often do much damage. normally the puncture is not painful, but the wounds remain open for a long time and heal slowly, even when not infected with pyogenic organisms. moreover, uncontrolled bleeding from the multiple abandoned sites has reportedly produced sufficient blood loss to cause anaemia and death.2 when a leech bites it excretes a local anaesthetic that allows it to bite and suck blood without causing pain to the host.10 it also secretes an anticoagulant (hirudin) from its salivary glands that inhibits table 1: summary of manifestations and management of internal hirudiniasis reported from the region country number and age of affected individuals site of infestation clinical presentation methods of removal treatment iraq3 9 (3-60) years nose, larynx, behind uvula bleeding, epistaxis, cough detachment by forceps iraq4 60 years male under vocal cord cough, hoarseness and hemoptysis lignocaine ethiopia13 50 years female posterior vaginal fornix bleeding and anaemia 1% lidocaine blood transfusion ethiopia14 larynx obstruction? local anaesthetic ethiopia15 vaginal wall bleeding detachment by forceps india16 16 years female uterine cavity bleeding dilatation & curettage india17 14 + (3-36) years nose and nasopharynx nasal blockage, bleeding, earache, epistaxis, headache, crawling sensation or pain weak solution of chloroform and turpentine oil zylocain drops, nasal packing in some cases india18 5 (3-12) years nostrils epistaxis, blockage of nostrils hypertonic saline symptomatic nasal packing india19 male urethra bleeding india20 male urethra bleeding turkey21 child eye ocular trauma, iris prolapse, subconjuntival haemorrhage extraction topical antibiotic and cycloplegic agent oman (personal communication) 18 years boy from dhofar nose nasal blockage fire 85 va g i n a l h i r u d i n i a s i s f r o m d h a h e r a h p r o v i n c e , o m a n : wi t h a n o t e o n i n t e r n a l h i r u d i n i a s i s thrombin in the clotting process11,12 and histaminelike substances to prevent closure of capillaries6,12, thus causing continuous bleeding even after the leech has dropped or been removed. in addition to the clinical symptoms presented in the table,3,4,13-21other leech bite complications include bullae, haemorrhage, pruritus, wheal formation, necrosis and ulceration.22 the table3,4,13-21 show that various methods were used to remove the leech, however, it is worthwhile mentioning that removal may be hastened by applying a few drops of brine, alcohol or vinegar to the site or a flame skillfully applied to the worm. the leech should not be pulled off forcibly, as the trauma resulting from the bite and from the leech jaws remaining in the lesion can predispose the lesion to malignancy.23 internal hirudinaisis is not uncommon in the middle east, india, and ethiopia3,4,13-20 and abnormal vaginal bleeding is common in internal hirudinasis.13,15,16,24 however, the presentation of this old lady with abnormal vaginal bleeding was suggestive of cervicitis/carcinoma and the histopathological examination of the cervical biopsy report reads “initial and deeper sections show strips of superficial, keratotic squamous epithelium. no submucosa included, no atypical features noted”. although abnormal vaginal bleeding is one of the commonest complications among women, vaginal hirudiniasis has to be included in the differential diagnosis of abnormal vaginal bleeding, particularly in post-menopausal cases13 and girls.15 also, attention should be given to leech infestation in the differential diagnosis of ocular trauma with iris prolapse in patients with a history of swimming in streams and lakes21 and so create awareness among professionals working in areas where aquatic leech infestation is prevalent.10,25 a c k n ow l e d ge me n ts i would like to thank dr. m m musa, previous head department of histopathology and cytopathology, royal hospital, ministry of health, sultanate of oman for sending the slide for identification. i am also grateful to dr. k al-haj, royal hospital and to dr. a alhakeem, ibri hospital for their help in retrieving the reports of this case. r e f e r e n c e s 1. adams la. the emergency management of a medicinal leech bite. ann emerg med 1989; 18:316–319. 2. cook gc. manson’s tropical diseases 20st ed, london: saunders, 1996. 3. almallah z. rare and interesting cases: internal hirudiniasis as an unusual cause of haemoptysis. brit j dis chest 1968; 62:215-218. 4. almallah z. internal hirudiniasis in man with limnatis nildica, in iraq. j parasitol 1968; 54:637-638. 5. hoeppil r, tang cc. leeches in old chinese and european medical literature. chinese med j 1941; 59:359378. 6. payton b. history of medicinal leech applying and medical references. in: muller kj, nicholls jg, stent gs, eds. neurobiology of the leech. new york: cold spring harbor publications, 1981. 7. nesemann h, forster r. first record of limnatis nilotica from oman (hirudinea : hirudinidae). miscnea zool hung 1997; 11:11-14. 8. al safadi mm, el-shimy na. freshwater leeches from yemen. hydrobiol 1993; 263:185-190. 9. pearse v, pearse j, buchsbaum m, buchsbaum r. living invertebrates. pacific grove, california: the boxwood press, blackwell scientific publications, 1992. 10. stammers fmg. observations on the behaviour of land leeches (haemadipsa). parasitol 1950; 40:237-240. 11. chin th. further note on leech infestation in man. j parasitol 1949; 35:215. 12. sawyer rt. leech biology and behavior. in: muller kj, nicholls jg, eds. neurobiology of the leech. new york: cold spring harbor publications, 1981. 13. hailemariam b. post-menopausal vaginal bleeding due to vaginal wall leech infestation. ethiop med j 1995; 33:183-185. 14. solomon e. leech unusual cause of laryngo-tracheal obstruction. ethiop med j 1991; 29:141-142. 15. mekasha a. correspondence. ethiop med j 1995; 33: 271. 16. parasad sb, sinha mr. vaginal bleeding due to leech. postgrad med j 1983; 59:272. 17. gupta sc. nasal hirudiniasis in kumaon hills, india. trop geogr med 1980; 32:303-305 18. rao kp, grover yk, mitra ak. nasal hirudiniasis. j indian med assoc 1986; 84:55-56. 19. mitra pn. a case of hirudiniasis of the male urethra. indian med gaz 1926; 1:22. 20. saha s, saha, i. unusual foreign body causing bleeding per urethra. j indian med assoc 1977; 69:286-287. 21. alcelik t, cekic o, totan y. ocular leech infestation in a child. am j ophthalmol 1997; 124:110-112. 22. nopadon n. hirudiniasis (leech bite). in demi jd et al. eds. clinical dermatology, 20th ed. philadelphia: jb lip86 m o h a m m e d a i d r i s pincott company 1993. 23. schamasaddini s, dabiri s. basal cell carcinoma on nickel dermatitis after leech applying. east mediterr health j 2000; 6:194-196. 24. brown wb, neva fa. basic clinical parasitology, fifth ed, north walk connecticut appleton century crofts 1983. 25. mekasha a. vaginal hirudiniasis. bull jimma inst health sci 1990; 1:35-38. march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 59-62, epub 16th mar 2009 submitted 23rd june 08 revision req. 18th nov 08, revision recd. 31st jan 09 accepted 2nd feb 09 a retrospective study of fungal corneal ulcers in the south sharqiyah region in oman *thara idiculla, george zachariah, br keshav, somansu basu department of ophthalmology, sur regional hospital, sultanate of oman *to whom correspondence should be addressed. email: gorgtara@omantel.net.om c l i n i c a l a n d b a s i c r e s e a r c h باملنطقة الفطريات عن الناجت القرنية لتقرحات استعادية دراسه عمان في (جنوب) الشرقية سومانسو باسو كيشاف ، آر بي ، زكريا جورج ايديكولال ، ثارا . الفطريات عن الناجتة القرنية التقرحات عالج وطرق السائدة اهرية األحياء وحتديد عوامل االختطار ومعرفة احلدوث معدل امللخص: الهدف: دراسة 2004 إلى للفترة من يناير (عمان) صور مبستشفى قسم العيون في عوجلت للحاالت التي القرنية للتقرحات حتليلية استعادية دراسة هذه الطريقة: عوامل ملعرفة الفطريات عن الناجتة القرنية بالتقرحات الزرع) طريق (عن إصابتها ثبت وثالثني حالة الثنني الطبية امللفات مراجعة 2007 . مت ديسمبر . ــبب الفطريات بس %13.22 منها القرنية كان قرحة من 242 حالة تعاني بني للعالج. النتائج: من ــتجابة واالس اتبرية ونتائج الفحوص االختطار اجلزء األكبر من على (34%) يَّة اشِ والرَشَّ (50%) زَالَوِيَّة ِغْ امل الفطريات حازت . منها (31.38% ) الفطريات شكلت بالزرع موجبة 102 حالة ومن بني (25% ) في العني وإصابات احلاالت %31.25 من في املوضعي الستيرويد كاآلتي: استخدام فكانت االختطار عوامل أما . الفطري الهياليني الطيف الناجت التقرح (%0.15) . اخلالصة: يبقى ــي ــني ب االمفوتيريس مع لوحده أو (2%) كيتوكينازول لعالج ــتجابت اس (60.62%) أكثرية احلاالت . ــا منه الفطريات . االختطار عوامل العني أهم وإصابات املوضعية الستيرويد ــتقات ملش العشوائي االستخدام . البصري للعجز رئيسيا ــببا س عن الفطريات . احلاالت معظم في فعاال جدا واالمفوتيريسني بالكيتوكينازول العالج املوضعي كان . هذه املنطقة في انتشارا األكثر املسببات من اخليطية . الزرع مستنبتات ، ،الفطريات القرنية ،التهاب القرنية قرحة الكلمات: مفتاح abstract objectives: to study the incidence, identify the risk factors and determine the predominant microorganisms and treatment regimen of fungal corneal ulcers. methods: this was a retrospective analysis of corneal ulcers treated in the ophthalmology department of sur hospital, oman, undertaken from january 2004 to december 2007. medical and microbiology records of thirty two culture proven cases of fungal keratitis were reviewed for risk factors, laboratory findings and response to treatment. results: out of the total 242 corneal ulcers, 3.22 % were fungal. among the 02 culture positive cases, 3.38 % were fungal isolates. fusarium spp (50%) and aspergillus spp (34.4%) predominated in the hyaline fungal spectrum. the important risk factors were topical steroid usage in 3.25 % of cases and ocular injury in 25 %. the majority of cases (90.62%) responded to 2% ketoconazole alone or in combination with 0.5% amphotericin b. conclusion: fungal ulcer remains one of the leading causes of visual disability. indiscriminate use of topical steroids and ocular trauma are the most important risk factors. filamentous fungi are common aetiological agents in this region. topical ketoconazole and amphotericin b were very effective for most of the cases. key words: corneal ulcer; keratitis; fungi; culture media. advances in knowledge • filamentous fungi are frequent causes of corneal ulcer in hot and dry climatic regions and it is imperative to keep a high level of suspicion. • direct wet mount potassium hydroxide (koh) preparation is an essential screening test in corneal ulcers. • therapies with reconstituted antifungal agents are highly effective. • treatment has to be continued for a minimum of three to four weeks. th a r a i d i c u l l a , g e o r g e z a c h a r i a h , k e s h av a n d s o m a n s u b a s u 60 fungal keratitis can pose diagnostic and therapeutic challenges for ophthalmolo-gists. although fungi cause only 5 to 10% of all corneal infections, devastating ocular damage can occur if they are not diagnosed promptly and treated effectively. through a defect in the epithelial barrier, fungi may gain access into the corneal stroma where they can cause tissue necrosis and a host inflammatory reaction. in addition, they may penetrate through an intact descemet’s membrane. once fungi reach the anterior chamber or spread to adjacent sclera, the infection becomes very difficult to control due to poor penetration of antimycotic agents. the pattern of mycotic keratitis varies with geographic region according to the local climate.1 corneal ulcers with an indolent course, stromal infiltrates with a dry texture and feathery borders, satellite lesions, immune ring infiltrates and unlevelled hypyon are highly suggestive of a fungal aetiology.2 in cases of a negative smear or culture and where there is a high suspicion for fungal keratitis, a corneal biopsy should be considered. in vivo confocal microscopy is a useful adjunct to slit lamp biomicroscopy for supplementing diagnosis in most cases and establishing early diagnosis in many cases of non-responding keratitis. this is a non-invasive, high resolution technique which allows rapid detection of fungal hyphae in the cornea long before laboratory cultures can give conclusive results.3 m e t h o d s case records of all corneal ulcers presented to ophthalmolgy department of sur hospital, oman, in the four year study period from january 2004 to december 2007, were analysed retrospectively. a proper history regarding the events leading to ulcers was recorded and all the patients were subjected to a thorough clinical and microbiological examination at the time of presentation. corneal scrapings, from the edge and base of the ulcers were subjected to complete microbiological examinations which included direct microscopic examination by 10% potassium hydroxide (koh) solution and inoculation into various culture media. the wet preparations of koh were examined under low magnification (x100) initially and then under high magnification (x400). corneal scrapings were transferred directly from spatula to agar media by a series of c-shaped cuts on the media. three different media were utilised: blood agar, chocolate agar and sabouraud’s dextrose agar with chloramphenicol (sda). the sda plates were incubated at 25°c for three weeks. most of the patients were admitted. visual acuity ranged from hand movement to 6/60. only culture proven cases of fungal ulcers were included in this study and they were reviewed for risk factors, laboratory findings and response to treatment. the data obtained from the study were analysed using 95% level of confidence at 5% significance level. r e s u l t s there were a total of 242 cases of corneal ulcers in our study period of 4 years, out of which 13.32% (95% ci: 8.95% to 17.49%) were fungal. among 102 culture positive cases, 32 (95% ci: 22.37% to 40.37%) were fungal and 70 were bacterial. the remaining 140 cases were culture negative. among the 32 fungal corneal ulcers, 19 (59.37%) were in male patients and 13 (40.63%) in female ones. the incidence was highest in the age group above 60 years (62.5%). analysis of risk factors for fungal ulcers showed a history of steroid use in 10 patients, most in the elderly age group of 50-70 years. five patients were on steroid treatment for unrelated eye problems and the remaining five were post operative cases on chronic steroid usage. the second commonest risk factor identified was ocular injury with plant debris in 8 patients. among this group, two were children in the age group 10-15 years; the remaining six patients were elderly in the age group 50-75 years. preexisting corneal patholapplication to patient care • there is a need to recognise the public heath risks of corneal ulcers and educate the community to prevent this avoidable cause of blindness. • the modifiable risk factors need to be understood to lessen the magnitude of fungal corneal ulcers. • any superficial corneal injury, especially with vegetable matter, has to be properly attended to. • the application of native medicines and eye drops containing steroids should be avoided. a r e t r o s p e c t i v e s t u d y o f f u n g a l c o r n e a l u l c e r s i n t h e s o u t h s h a r q i ya h r e g i o n i n o m a n 61 ogy like corneal degenerative keratopathy and trachoma sequelae were seen in 6 patients in the age group 50-80 years. the use of topical traditional medications for minor eye diseases was another risk factor in 5 patients, all in the age group 50-70 years. the remaining 3 patients had no predisposing factors. three were three diabetic patients, but all of them had additional predisposing factors [table 1]. in the laboratory investigations, the positive cultures obtained were corroborated with positive koh results. in direct microscopy, branching and septate hyphae were identified in 24 cases (75%). fusarium spp was the most common fungi isolated (50%) followed by aspergillus spp (34.4%). apart from filamentous fungi, 2 cases were yeast infection [table 2]. t r e a t m e n t a n d o u t c o m e the initial treatment given was ketoconazole 2% drops hourly with 14 (43.75%) cases responding well. the remaining 18 (56.25%) patients, who had unfavourable response after the third day, were given a combination of 2% ketoconazole and 0.15% amphotericin b. fresh preparations were reconstituted every third day. daily examination was done with clinical documentation of the size, extent and anterior chamber reaction. frequency of instillation was gradually tapered as the ulcers improved. treatment was continued for a minimum period of three weeks. six patients, who had lesions extending to the limbus and with thinning of cornea, were given oral ketoconazole 200mg twice daily for 7 days in addition to the combination drops. twenty nine patients (95% ci: 80.53% to 100.73%) responded well to this regimen. visual acuity improved in 15 patients, while it remained the same in 12 patients and deteriorated in 5 patients. the ulcers worsened in 3 patients and they were referred for further treatment to a tertiary centre. patients who were on native medication presented late with extensive ulcers. these patients needed a longer period of treatment and their outcome was dense scarring. d i s c u s s i o n even though fungal corneal ulcers are comparatively uncommon, they cause devastating ocular damage if not managed properly.2 our study shows an incidence of fungal keratitis (13.22%) comparable with other studies. in a similar study conducted in a tertiary referral centre in baghdad, an 18.7% incidence of fungal keratitis was reported.4 filamentous fungi like fusarium, aspergillus and pencillium were the predominant isolates in our study. world wide, aspergillus is the most common cause of mycotic keratitis. fusarium species are the most common cause of fungal corneal infection in the southern united states (45.76%), while aspegillus species followed by fusarium are the most common isolates in india.5,6,10 the baghdad study showed aspergillus in 56.8% and fusarium in 27%.4 our study shows a higher incidence of fusarium (50%) followed by aspergillus (34.4%).this may be due to the fact that the fusarium species is commonly found in soil and plants and most of our patients were from a rural background. when the risk factors were analysed, the highest risk factor noted was steroid usage (31.25%) followed by ocular trauma (25%). a similar study of fungal keratitis in melbourne showed chronic steroid usage in 31.4% and ocular trauma in 37%.7 corneal injury associated with outdoor activities with plant or soil material is a high risk factor for fungal keratitis. in a study of fungal keratitis in northern iran, trauma with plant debris and straws were noted in 28.6% of patients with fungal keratitis.8 other predisposing factors noted were ocular surface disorders in 18.75% and use of native medications in 15.62%. a study of fungal keratitis at wills eye hospital, pennsylvania, usa, reported chronic ocular surface disease in 41.7%.11 in a study from a rural area of india, usage of traditional meditable 1: predisposing risk factors in fungal corneal ulcers factors no. of cases age group percentage confidence interval steriod use 10 50-70 years 31.25 95% ci: 15.19% to 47.31% ocular injury 8 10-75 years 25.00 95% ci: 10% to 40% preexisting corneal pathology 6 50-80 years 18.75 95% ci: 5.23% to 32.27% topical traditional medications 5 50-70 years 15.62 95% ci: 3.05% to 28.21% th a r a i d i c u l l a , g e o r g e z a c h a r i a h , k e s h av a n d s o m a n s u b a s u 62 cations like human milk, leafy extracts and oil were reported in 47% of corneal ulcer patients.12,13 reconstituted topical 2% ketoconazole and 0.15% amphotericin b were very effective for most of the cases. fresh preparations were reconstituted on every third day and instilled hourly as ready made antifungal drops were not available.4,9 most cases of corneal ulcers presented in this study were already on topical antibiotics and this may explain the high percentage of culture negative cases. filamentous fungi are common aetiological agents for fungal keratitis in our region. hence this study is useful to institute appropriate empirical antifungal therapy based on this scenario. c o n c l u s i o n fungal keratitis presents both diagnostic and management challenges for the clinician. infection due to filamentous fungi is a frequent cause of corneal blindness and remains as a major ophthalmological problem. corneal injuries need to be treated and managed properly. indiscriminate use of steroid drops and the application of native medicines for unrelated eye problems may provide an environment for fungal growth. a wet smear of 10% koh preparation is an essential screening test for corneal ulcer.8 mycotic lesions are often recalcitrant and require many weeks of medical treatment. reconstituted antifungal drops are equally as effective as commercial antifungal drops which are not readily available in this region. it is imperative to maintain a high level of suspicion for fungal keratitis, so that appropriate therapy can be instituted immediately. c o n fl i c t o f i n t e r e st : none declared s o u r c e o f f u n d i n g : sur hospital, oman r e f e r e n c e s 1. khairallah sh, byrneka, tabbara kf. fungal keratitis in saudi arabia. doc ophthalmol 1992; 79:269-76. 2. kim mc, karp cl. managing fungal keratitis. amer acad ophthalmol, eye net magazine, march 2001. 3. gupta n, tandon r. investigative modalities in infectious keratitis. ind j ophthalmol 2008; 56:209-13. 4. al-shakarachi f. initial therapy for suppurative microbial keratitis. bjo 2007; 91:1583-87. 5. agarwal pk, roy p, das a, banerjee a. ind j ophthalmol 2001; 49:173-6. 6. gopinathan u, garg p, fernandes m, sharma s. the epidemiological features and laboratory results of fungal keratitis: a 10-year review at a referral eye care center in south india. cornea 2002; 21:555-9. 7. bhartiya p, daniell m, constantnou m. fungal keratitis in melbourne. clin experiment ophthalmol 2007; 35:124-30. 8. shokohi t, nowroozpoor-dailami k, moaddel-haghighi t. fungal keratitis in patients with corneal ulcer in sari, northern iran. arch iran med 2006; 9:222-7. 9. yavas gf, oztürk f, küsbeci t, cetinkaya z, ermis ss, kiraz n, et al. antifungal efficacy of voriconazole, itraconazole and amphotericin b in experimental fusarium solani keratitis. graefes arch clin exp ophthalmol 2008; 246:275-9. 10. chander j, singla n, agnihotri n, arya sk. keratomycosis in and around chandigarh: a five-year study from a north indian tertiary care hospital. ind j pathol microbiol 2008; 51:304-6. 11. tanure ma, cohen ej, sudesh s,rapuano cj,laibson pr, et al. spectrum of fungal keratitis at wills eye hospital, pennsylvania. cornea 2000; 19:307-12. 12. prajna v, pillai mr, manimegalai tk,srinivasan m, et al. use of traditional eye medicines by corneal ulcer patients. ind j ophthalmol 1999; 47:15-18. 13. bialasiewicz a, shenoy r, thakral a, al-muniri a, shenoy u, al-mughairi z. microbial keratitis: a 4 year study of risk factors and traditional/complimentary medicines in oman. ophthalmologe 2006; 103:682-87. species grown no of cases percentage confidence interval fusarium spp 16 50 % 95% ci: 32.68% to 67.32% aspergillus spp 11 34.4% 95% ci: 17.92% to 50.84% penicillium spp 3 09:4% 95% ci: -0.72 to 19.48% candida spp 2 06.2% 95% ci: -2.14 to 14.64% table 2: fungal culture: species grown january 2007 vol 7 correct a.indd the role of mathematics on human structure author: swapan k adhikari1 reviewers: *omar a habbal2, mohieddin al-baali3 sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© a u t h o r dr. swapan kumar adhikari msc (pure mathematics), phd, head of the institution & head of department of mathematics, ghusuri uchcha madhyamik vidyalaya (high), howrah, west bengal, india. b a c k g r o u n d t o t h e b o o k during 10 years research the author focused on the physiological and anatomical problems stemming from surgical anomalies. he came to the conclusion that it is surely the lack of mathematical precision in orthopaedic surgery that causes orthopaedic handicaps. the author firmly believes that if mathematical deductions were applied to orthopaedic knowledge many immediate complications and sequelae could be avoided and people could regain new life in the true sense of the term. c o n t e n t o f t h e b o o k the book has 156 pages. it consists of preface and index with 12 chapters as follows: 1. leonardo de vinci – the anatomist of great ability 2. physiological concepts from rené descartes 3. mathematical explanation of descartes’ concept of the pineal gland and the modern view 4. mechanism of the movements of the heart – mathematical concepts 5. cervical deformations – their causes and deductions on mathematical basis 6. mechanism of the skeletal shoulder joint – analyzed by mathematical process 7. vertebrae and their efficiencies – expressed in mathematical procedure 8. distribution of forces through the pelvis by mathematical deductions 9. human femur and mathematical examination 10. structure of the femoral condyles distributing weight to the lower part of the leg 11. structure of bone lamellae and distribution of forces on the hip joint 12. role of ligaments on the movements of the femur in comparison with the hip and its mathematical examination. th e r e a d e r sh i p mo st sui te d f o r th i s b o o k this book would be of value to professionals in the fields of human biomechanics and kinematics. these include physiologists, clinical anatomists, physicians, surgeons, radiologists and researchers. it will help them to calculate physiological movements on the basis of degrees of freedom and, in restorative procedures, to replace bones properly to avoid shortening and extension of limbs and other parts of the human structure and to b o o k r e v i e w االنسان تركيب في الرياضيات دور isbn 81-901643-0-9 price of the book including postage.$10.95. available at asian books pvt ltd (email: calasian@vsnl.com) 1head of the institution & head of department of mathematics, ghusuri uchcha madhyamik vidyalaya (high), howrah, west bengal, india email: swapu_adhi@rediffmail.com 2associate professor, department of human & clinical anatomy, college of medicine & health sciences, sultan qaboos university, sultanate of oman, 3associate professordepartment of mathematics & statistics, college of science, sultan qaboos university, sultanate of oman *to whom correspondence should be addressed. email: habbal@squ.edu.om s wa pa n k a d h i k a r t 94 restore the absolute normalcy of the original position. a ppr o pr i ate n e s s o f th e c o n te n t to ta r ge t r e a d e r sh i p the content, within the mentioned limitations below, seems to be appropriately suited for the intended readership. the interdisciplinary approach of the author to express some of the operations and distributions of weight in the human body through mathematics will help in the accurate management of physically handicapped or disabled patients. c ompr e h e n si v e n e s s o f th e c o n te n t the book covers a limited number of parts of the human body, such as movements of the heart, the pineal gland, cervical deformities, the vertebrae, pelvis, femur and hip joint. other areas of mathematical and dimensional importance are, unfortunately, inadequately covered or omitted. for example, it would have been appreciated if the synchronized movements of thoracic elements (respiratory elements), restoration of the cranial bones (neurosurgery) and facial bones (faciomaxillary and plastic surgery), dentistry (orthodontics), pelvi-foetal interrelationships (obstetrics) had also been covered by this book. indeed, the human body has many aspects relevant to this type of study. these areas are for the author to consider in future publications. o r g a n i sati o n o f th e c o n te n t from the title of the book, “the role of mathematics on human structure”, one expects human ‘structure’ to be the focus. yet, the author delves into wide areas of ‘function’ including blood chemistry, respiratory exchanges and thermodynamic concepts to explain some functional and biochemical reactions. this may well be unavoidable, but then the title should encompass such areas. this would in no way diminish the central interest of the book. m ath e m ati c a l a n a ly si s this book studies the useful role of applied mathematics for the human body by considering several mathematical expressions, which are illustrated for certain applications. the analyses are useful in most cases, but several statements require careful rewriting or corrections. in particular, pages 21-25 provide a lot of details, but some equations are not well described and are hard to follow. they should be written on similar lines to those in other chapters of the book. in the following list of examples, some comments and suggestions are to be considered: 1. the following mistakes should be corrected. • the equations for ρ and ∆f (see lines 7-10 from the bottom of page 22), • “ c/l2” (should be “1/l2”), (at the bottom of page 23) • the expressions for α and β (line 4 from the bottom of page 65) • the expression for log r on page 92. 2. details and explanations to clarify the methods of obtaining formulas are needed in many areas of the book where unclear mathematical statements are made. it would also be useful to provide some references for some known results. for example, the equations of motion on page 54 should be referred to a suitable book. g e n e r a l c o m m e n t s q ua l i t y o f c o n te n t to simplify a difficult biological process into an easy to understand mathematically applicable concept is not an easy task to achieve. however, the methodical and clear presentation and explanation of such difficult concepts makes this book, in my opinion, a unique publication. descriptive explanations of the laws of kinematics on body deformations, such as: compression forces on the nucleus pulposus and the tensile stresses on the annulus fibrosus of the intervertebral discs, are clear examples of how such forces can mathematically explain deformities and consequent ailments when the state of “perfect elasticity” of the body can be breached. it does this when it reaches the fatigue state beyond a certain value of the ‘elastic limit’. the spelling of a few medical terms needs to be revised. this mars, to some extent, the completeness of a polished work. q ua l i t y o f i l lustr ati o n s illustrations are in black & white and of moderate quality. at times this can hinder understanding of the message, especially when delicate structures are in question, such as cardiovascular and neural structures. good quality coloured illustrations would have been an asset to the content of the book. obviously, the publishing cost and consequently the book price would then have been increased. c ompl e te n e s s o f c o n te n t the author manages to cover adequately certain aspects of disease processes that result in deformations. examples are provided for the cervical spine, shoulder th e r o l e o f m at h e m at i c s o n h u m a n s t r u c t u r e 95 joint, femur and hip joint. detailed management of certain functional disorders can be ascertained mathematically and, therefore, mathematics can play a key role in solving those disorders. i reiterate that one of my main observations about this book is that it deals mainly with the role of mathematics in expressing body functions mainly, as described in the above examples, and not body structures as the book title indicates. o t h e r c o m m e n t s pa pe r a n d bi n d i n g q ua l i ti e s the paper and binding qualities are a disappointment. a work of this calibre should have been printed on good quality glossy paper. also, a hardback and better binding qualities would have added value to the book. this would indeed influence, to some degree, the net sale price of the book. december 2007 vol 8 after meeting.indd antiphosphatidyl serine autoantibodies and premature coronary events *hisham y m ali1 and zainalabideen a abdullah2 املبكرة القلبية واألزمات للفوسفاتيدل سيرين الذاتية املضادات اهللا عبد العزيز عبد العابدين زين ، علي محمد يوسف هشام الطريقة: من املرضى. مختارة مجموعة املبكرة لدى القلبية األزمات حدوث في سيرين ــفاتيدل الذاتية للفوس املضادات دور ــة امللخص: الهدف: دراس ودهوك/شمال اربيل, املوصل, من مدن جمعهم مت كمجموعة ضابطة ــخصا سليما 30 ش و قلبية بأزمات مصابا 50 مريضا ــة الدراس هذه ــملت ش تتكون ــنة) س (5.9 ± 39.6 ــنة ــني س اخلمس أعمارهم دون التي كانت املرضى مجموعة .2005 آذار/مارس 2004 إلى آذار/مارس من للفترة العراق الفحوصات .أجريت معروفة خطورة ــل عوام تكن لديهم ولم الصدرية ، بالذبحة مصابا 27 مريضا و القلب ــة عضل ــاء باحتش مصابا 23 مريضا ــن م املناعية األنزمية املقايسة ــتخدام فحص باس وذلك ،(igm) م نوع و (igg) ج نوع من ــيرين س ــفاتيدل للفوس الذاتية املضادات وجود ملعرفة الالزمة املضادات النتائج: شخصت الدراسة. في املشاركني لدى (igm) م نوع و (igg) ج نوع من ــيرين س ــفاتيديل للفوس املضادات الذاتية لقياس كمية معتد بفرق الضابطة ــة اموع لدى (3.3%) 1/30 ــت كان بينما املرضى من (20%) 10/50 ــي ف (iggج (نوع ــيرين س ــفاتيدل للفوس ــة الذاتي دون فقط املرضى من (6%) 3/50 لدى عنه ــف مت الكش igm فقد املضاد أما .(p < 0.05 ;9.1-odds ratio of 3.2 95%ci, 1.1) إحصائيا ــاف معدل اكتش يعني أن وهذا (igg ) ج للنوع ــبة بالنس موجبة احلاالت الثالثة تلك وكانت إحصائيا. معتد فرق بدون الضابطة اموعة وجوده لدى (66.7%) 12/8 في وجدت الواصمة املضادات هذه فان لذلك . إضافة igg لنوع املعدل نفس igm هو نوع سيرين للفوسفاتيدل الذاتية املضادات املرضى املصابني باجللطة لدى توجد ، ولم ــتقرة املس الذبحة الصدرية مرضى من (13.3%) 15/2 وفي ، ــتقرة املس غير الصدرية مرضى الذبحة من عند املبكرة خاصة القلبية األزمات حدوث في أهمية igg ذات الذاتية نوع سيرين الفوسفاتيدل مضادات بان الدراسة اخلالصة: تبني هذه القلبية. املستقرة. غير القلبية بالذبحة املصابني الشريان التاجي. ، احلوادث ، الذاتية املضادات سيرين الذاتية ، الفوسفاتيدل الكلمات: مضادات مفتاح 1college of medicine, university of dohuk, kurdistan region, iraq; 2college of medicine, university of mosul, iraq *to whom correspondence should be addressed. email: halsinde@yahoo.com sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 227-232 sultan qaboos university© submitted 9th april 2007 accepted 12th september 2007 c l i n i c a l a n d b a s i c r e s e a r c h abstract objectives: to determine whether antiphosphatidyl serine autoantibodies (aps) are associated with increased risk of occurrence of coronary events in selected patients. methods: this study compared 50 patients with coronary events with 30 controls, recruited from the cities of mosul, erbil, and dohuk cities, northern iraq, between march 2004 and march 2005. the patient group consisted of 23 individuals with myocardial infarction and 27 with angina. we evaluated the presence of aps antibodies (igg and igm isotypes) by an enzyme-linked immunosorbent assay. the studied cases were less than 50 years of age (mean ± sd, 39.6 ± 5.9) and had no recognizable risk factors. results: the frequency of detecting igg aps was 0/50 (20%) among patients and /30 (3.3%) among controls, with significant difference and with adjusted odds ratio (or) of 3.2 (95%ci, .-9.; p < 0.05). the igm aps frequency was 3/50 (6%) among patients and zero in the controls, with non-significant difference. the three cases were also igg positive (i.e. the frequency rate for detection of aps of igm was the same as for igg). moreover, this marker (aps) was detected in 8/2 (66.7%) of cases with unstable angina, in 2/5 (3.3%) with stable angina, and in none of the cases with myocardial infarction. conclusion: igg aps autoantibodies are associated with increased risk of coronary events especially angina of unstable subset. key words: antiphosphatidyl serine; autoantibodies; events, coronary. advances in knowledge recently, it was found that antiphosphatidyl serine (aps) antibodies detection correlated more specifically with aps than anti-cardiolipin (acl) antibodies in aps. since, cardiolipin is present in intracellular membranes and the dose not becomes exposed to coagulation proteins in vivo, it was hypothesized that tests for antibodies against antiphosphatidyl serine, which is normally present in the inner leaflet of the plasma membrane, may be more h i s h a m y m a l i a n d z a i n a l a b i d e e n a a b d u l l a h 228 the antiphospholipid syndrome (aps) is an autoimmune disease characterized by existence of antiphospholipid antibodies (aplas). this syndrome is characterized by susceptibility to vascular thromboembolism and fetal loss.1 the lupus anticoagulant (la) and acl antibodies are associated with clinical events related to aps with varying severities.2 antiβ 2glycoprotein i (aβ-2gpi) had been identified in patients with aps and found to play an important role in the pathogenesis of this syndrome.3 the aplas (la, acl, and aβ-2-gpi) have been studied frequently and reported to be associated with an increased risk of thromboembolic phenomena such as ischaemic stroke.2, 4-6 the aps antibodies have also been reported to be prevalent in adult stroke patients.7 there has been no study assessing the strength of their association with coronary events in the general population. the aim of this study was to determine the prevalence of aps in a highly selected group of patients with coronary events, who were below 50 years of age and without any conventional risk factors and had not been diagnosed as systemic lupus erythematosus (sle) cases. moreover, we compared the results of aps obtained in this study to those of acl autoantibodies from a previous study performed on the same group of patients. m e t h o d s individuals in this study were a subset of those who participated in a phd study disclosing the role of aplas in patients with cardio-cerebrovascular diseases in the region.8 this study was carried out on 50 patients suffering from different coronary events and 30 healthy individuals, recruited from the cities of mosul, erbil, and dohuk in northern iraq, during the period march 2004 and march 2005. the cases were selected to be under 50 years of age and having no recognizable risk factors including hypertension ( systolic blood pressure > 140 mm hg and/or diastolic of > 90 mm hg ), diabetes mellitus (fasting blood glucose of ≥ 126 mg/dl and/or 2-hours post-prandial glucose of ≥ 140 mg/dl ), dyslipidemia ( total cholesterol level of > 240 mg/dl and hdl of < 35 mg/dl ), non-smoking (current or previous), and lastly not overweight (body mass index of less than 25). the cases were not previously diagnosed as sle. the purpose of the study was discussed in detail with the participants of both groups and obligatory ethical agreement was obtained from the volunteer cases accepted for inclusion in this study. the age range of the studied cases was 29-49 years (mean ± sd, 39.6 ± 5.9) with premature coronary occlusive and ischaemia diseases. twenty-three patients had myocardial infarction (mi), 15 stable angina (sa) and 12 unstable angina (ua). these cases were diagrelevant pathophysiologically in this syndrome. the phosphatidyl serine is also exposed on syncytialized cells, on apoptotic cells and on activated platelets and their antibodies interfere more with anticoagulant cascade. the aps, the anionic non-cardiolipin phospholipid, have recently reported to be associated with an increased risk of stroke in young patients and positive association was reported among ischaemic stroke patients. therefore, the risk associated with aplas in aps may be underestimated if the testing of these autoantibodies is not included in the list of aplas used currently. consequently, the aps igg isotype showed to carry an independent risk factor associated with ischaemic events especially among cases with unstable angina. on the other hand, many clinical events related to aps were observed to be positive for this marker alone, in the absence of other markers. application to patient care it is generally assumed that an association does exist between aplas and ischaemic coronary events. this assumption is based mainly upon the results obtained from different studies. the evidence supporting this association needs to be strong enough since the presence of these autoantibodies influences the management approaches of such patients. furthermore, the clinicians who diagnose such cases should realize that these cases are prone to recurrences and long-term anticoagulants need to be prescribed. therefore, the recent trend of including aplas tests in cases with premature ischaemic events may totally change the therapeutic options from those used in traditional ischaemic cases. the diagnosis of aps attributed to detection of aps autoantibodies or other aplas may justify the need for more prolonged or even lifelong management to prevent recurrences. a n t i p h o s p h at i d y l s e r i n e a u t o a n t i b o d i e s a n d p r e m at u r e c o r o n a r y e v e n t s 229 nosed by a cardiac specialist depending on the acute clinical presentation, ecg changes, elevated serum cardiac marker such as creatine phosphokinase (cpk), exercise study, and echo study. the age range of the control group was 26-48 years (mean ± sd, 36 ± 6.5), with no history of any thromboembolic manifestations and without recognizable risk factors such as smoking, hypertension, diabetes mellitus, hyperlipidemia, or overweight. the individuals were recruited from the central blood bank, infertility unit, outpatient clinics, and volunteers. a blood sample of 10 ml was obtained from each participant and tested. a second blood sample taken after 6 weeks or more was collected from aplas positive cases. enzyme-immunoassay kits (orgentic diagnostika from mainz, germany) were used for the detection of igg or igm aps by indirect solid phase enzyme immunoassay (elisa) and the tests performed in the postgraduate study laboratory of dohuk medical college. the igg and igm isotype results were assessed in igg phospholipid (gpl) and igm phospholipid (mpl) units, with one unit equal to 1µg/ml of igg or igm. they were considered positive if the titer was > 10 gpl units and > 10 mpl units for both isotypes, as suggested by the elisa kit manufacturer. a significant relative risk factor was considered when the or was > 1. the proportions were compared using the chi-square test. the 95% ci of proportions were calculated according to the binomial distribution. r e s u l t s table 1 demonstrates the prevalence of igg and igm aps autoantibodies in the studied cases and controls. a persistence positive igg aps titer, in both samples, was present in 20% of patients (10/50) and 3.3% of controls (1/30), with significant difference and or of 3.2 (95%ci, 1.1 9.1; p > 0.05). moreover, a positive igm a ps titer was detected in 6% of patients (3/50) in initially tested samples and in 4% (2/50) in second tested samples and in none of the controls, with non-significant difference. these igm aps positive cases were also igg positive (i.e. the frequency rate for aps of any isotype were the same as for igg). eight out of the 10 igg aps positive cases had unstable angina, while, two igg aps positive cases had stable angina. however, none of the studied cases with a history of mi were revealed to be positive for any isotype of aps antibodies. the mean titers of igg isotype was 64.1µg/ml among patients with ua and 12.9µg/ml in patients with sa. however, the mean titer of igm aps in the 2 persistence positive cases was 29µg/ml with ua. in comparison, the frequency of persistent igg acl with a concentration of < 30 gpl units was detected in 14% of cases (7/50), with significant difference and or of 9.8 (95%ci, 7.8 76.4; p > 0.01), while none of the control showed such a concentration. the results of transthoracic echocardiographic findings of the 10 aps positive cases are summarized in table 2. normal results were reported in 40% of patients (4/10), two with sa and another two with ua. table 1: the frequencies of the different antiphospholipid autoantibodies in patients with coronary events. groups patients no. (%) control no. (%) or 95% ci p value* test aps (gpl units) < 10 40 (80) 29 (96.7) 3.2 1.1 – 9.1 p > 0.05 > 10 10 (20) 1 (3.3) aps (mpl units) < 10 47 (94) 30 (100) 3.8 1.7 – 24.6 ns > 10 3 (6) 0 (0.0) aps of igg and/or igm 10 (20) 1 (3.3) 3.2 1.1 – 9.1 p > 0.05 * chi-square test ns: not significant or: odds ratio 95% ci: confidence interval h i s h a m y m a l i a n d z a i n a l a b i d e e n a a b d u l l a h 230 abnormal findings were recorded in the remaining 60% (6/10), 4 in the form of hypokinetic ventricles (all were with ua) and three cases as heart valves abnormalities with ua. d i s c u s s i o n the association of aplas with coronary artery diseases has been shown in several studies but remains controversial.8, 9, 10 the mechanisms through which these aplas can induce pathological changes and tissue necrosis in mi or initiating atherosclerotic changes are debatable.9 the association between cardiac events especially mi and igg acl has been suggested in other studies.10, 11 billi et al.12 reported that in post-infarction patients elevated igg acl antibodies are an independent risk factor for recurrent cardiac events and patients with elevated igg acl and low igm acl antibodies have the highest risk. the aps antibodies, members of the non-cardiolipin aplas, have been shown to be associated with increased stroke risk in sle patients with a variety of aplas to non-cardiolipin antigens.13 another study by toschi et al.14 of stroke and/or transient ischaemic attack patients, but with unselected patients, demonstrated also a positive correlation. although these autoantibodies have been associated with stroke events related to aps, their prevalence in coronary events among patients without conventional risk factors is unknown. in this study, although the number of the studied cases were relatively small, a positive association was demonstrated between igg aps in patients with coronary events especially those with ua. on the other hand, three of our patients who were igg aps positive were negative for igg acl, i.e. 6% of the studied patients would have been characterized as aplas negative if only an acl assay were used. moreover, the estimated mean titer of igg aps was higher in patients with ua (64.1µg/ml) compared with cases with sa (12.9µg/ml). this finding could be attributed to the more intensified immune process going on in patients with ua than in sa events related to aps. the absence of aps autoantibodies in patients with mi may signal to the weak immune inducer effect of the tissue necrosis characterizing these events.9 an echocardiographic study of aps positive cases revealed that 60% (6/10) have abnormal cardiac findings in form of hypokinetic ventricles and valvular infection and all cases were sufferings from ua. one case was with mitral valve prolapse and one with aortic insufficiency. niaz and butany’s study in 199815 revealed that 35% of patients with primary aps had valvular abnormalities, while bouillanne et al., in 1996 16 reported that about 20% of cardiac patients with valvular heart disease had evidence for aplas compared with about 10% of matched control subjects. deposits of aplas such acl antibodies and of complement components are common in the affected valves of patients with primary or secondary aps.17 another study of patients with sle and primary aps did not find any relationship between increased acl antibodies and valvular abnormalities.18 a small number of studies investigated patients with cardiac events and their correlation with aps. some of them studied cases with mi and tested for acl antibodies only 10, 11, 19 while others studied the relationship between aplas and atherosclerosis in ischaemic heart disease using the aβ 2-gpi antibodies tests only.20, 21, 22 over the last decade, many studies have been performed and suggest that aβ 2-gpi plays a corner stone role in the pathological consequences 23, 24, but studies of aps and coronary events were lacking, the mechanisms by which these antibodies may influence thrombogenicity are incompletely understood, but these have recently been reviewed comprehensively.14, 25 these mechanisms may include the stimulation of platelet aggregation, the recognition of vascular endothelial cells and the disruption of the annexin-v shield that forms a carpet protecting anionic phospholipids on endothelial cell surfaces from participating in coagulation reactions.1, 14, 25 this last proposed mechanism may be applicable to the role of aps specifically because aps have been shown to remove annexin-v from and facilitate binding of prothrombin to cell surfaces.26 finding (s) no. (10) % normal 4 40 hypokinetic ventricles 4 40 valvular abnormality 2* 20 * one case with mitral valve prolapse and the other with aortic valve insufficiency. table 2: the echocardiographic findings in antiphosphatidyl serine autoantibodies positive patients with coronary events a n t i p h o s p h at i d y l s e r i n e a u t o a n t i b o d i e s a n d p r e m at u r e c o r o n a r y e v e n t s 231 c o n c l u s i o n the results of the current study demonstrate an increased risk and positive association between igg aps and coronary events of angina subsets among cases with ua. moreover, our results revealed that testing for this antibody, along with other aplas, may identify more cases related to aps. this, therefore, justifyies the routine use of aps as a serologic marker in the general population in suspected coronary events. r e f e r e n c e s 1. rand jh. antiphospholipid antibody syndrome: new insights on thrombogenetic mechanisms. am j med sci 1998; 316:142–151. 2. the antiphospholipid antibodies in stroke study (apass) group. anticardiolipin antibodies are an independent risk factor for first ischaemic stroke. neurology 1993; 43:2069-2073. 3. mcneil hp, simpson rj, chesterman cn, krilis sa. anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein i (apolipoprotein h). proc natl acad sci usa 1990; 87:4120-4124. 4. rauch j, tannenbaum m, janoff as. distinguishing plasma lupus anticoagulant from anti-factor antibodies using hexagonal (ii) phase phospholipids. thromb haemost 1999; 62:892-896. 5. lopez-soto a, cerver ar, font j, bove a, reverter jc, munoz fj, et al. isotype distribution and clinical significance of antibodies to cardiolipin, phosphatadic acid, phosphotidylinositol and phosphatidylserine in systemic lupus erthymatosus: prospective analysis of a series of 92 patients. clin exp rheumatol 1997; 15:143-149. 6. camerlingo m, casto l, censori b, drago g, frigeni a, ferraro b, et al. anticardiolipin antibodies in acute nonhemorrhagic stroke seen within six hours after onset. acta neurol scand 1995; 92:69-71. 7. toschi v, motta a, castelli c, paracchini ml, zerbi d, gibelli a. high prevalence of antiphosphatidylinositol antibodies in young patients with cerebral ischaemia of undetermined cause. stroke 1998; 29:1759–1764. 8. ali hisham ym. the role of antiphospholipid autoantibodies syndrome in patients with cardio-cerebro vascular diseases. phd thesis submitted to college of medicine, university of mosul, iraq 2006. 9. vaarala o. antiphospholipid antibodies and atherosclerosis. lupus 1996; 5:442-447. 10. zuckerman e, toubi e, shiran a, sabo e, shmuel z, golan td, et al. anticardiolipin antibodies and acute myocardial infarction in non-systemic lupus erythematosus patients: a controlled prospective study. am j med. 1996; 171:381-386. 11. wu r, nityanand s, berglund l, lithell h, holm g, lefvert ak. antibodies against cardiolipin and oxidatively modified ldl in 50 year old men predict myocardial infarction. arterioscler thromb vasc biol 1997; 17:3159-3163. 12. bili a, moss aj, francis cw, zareba w, watelet lf, sanz i. anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. thrombogenic factors and recurrent coronary events investigators. circulation 2000; 102:1258-1263. 13. tuhrim s, rand jh, wu x, horowitz dr, weinberger j, goldman me, godbold jh. antiphosphatidylserine antibodies are independently associated with ischaemic stroke. neurology 1999; 53:1523-1527. 14. toschi v, motta a, castelli c, gibelli s, cimminiello c, molaro gl, et al. prevalence and clinical significance of antiphospholipid antibodies to non-cardiolipin in systemic lupus erythematosus. haemostasis 1993; 23:275283. 15. niaz a, butany j. antiphospholipid antibody syndrome with involvement of a bioprosthetic heart valve. can j cardiol. 1998; 14:951-954. 16. bouillanne o, millaire a, de groote p, puisieux f, cesbron jy, jude b, et al. prevalence and clinical significance of antiphospholipid antibodies in heart valve disease: a case-control study. am heart j 1996; 132:790-795. 17. ziporen l, goldberg i, arad m, hojnik m, ordi-ros j, afek a, et al. libman-sacks endocarditis in the antiphospholipid syndrome: immunopathological findings in deformed heart valves. lupus 1996; 5:196-205. 18. gabrielli f, alcini e, prima ma, masala c. cardiac involvement in connective tissue diseases and primary antiphospholipid syndrome: echocardiographic assessment and correlation with antiphospholipid antibodies. acta cardiol 1996; 51:425-439. 19. raghavan c, ditchfield j, taylor rj, haeney mr, barnes pc. influence of anticardiolipin antibodies on immediate patient outcome after myocardial infarction. j clin pathol. 1993; 46:1113-1115. 20. vaarala o, manttari m, manninen v, tenkanen l, puurunen m, aho k et al. anticardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. circulation 1995; 91:23-27. 21. farsi a, domeneghetti mp, fedi s, capanni m, giusti b, marcucci r et al. high prevalence of anti-beta2 glycoprotein i antibodies in patients with ischaemic heart disease. autoimmunity 1999; 30:93-98. 22. brey rl, abbott rd, curb jd, sharp ds, ross gw, stallworth cl, et al. beta(2)-glycoprotein 1-dependent anticardiolipin antibodies and risk of ischaemic stroke and myocardial infarction: the honolulu heart program. stroke 2001; 32:1701-1706. 23. salemink i, blezer r, willems gm, galli m, bevers e, lindhout t. antibodies to β2-glycoprotein i associated h i s h a m y m a l i a n d z a i n a l a b i d e e n a a b d u l l a h 232 with antiphospholipid syndrome suppress the inhibitory activity to tissue factor pathway inhibitor. thromb haemost 2000; 84:653-656. 24. crowther ma, wisloff f. evidence based treatment of the antiphospholipid syndrome ii. optimal anticoagulant therapy for thrombosis. thromb res 2005; 115:3-8. 25. metz lm, edworthy s, mydlarski r, fritzler mj. the frequency of phospholipid antibodies in an unselected stroke population. can j neurol sci 1998; 325:64–69. 26. vogt e, ng a, rote ns. antiphosphatidyl serine antibody removes annexin v and facilitates the binding of prothrombin at the surface of a choriocarcinoma model of trophoblast differentiation. am j obstet gynecol 1997; 177:964–972. 1department of family medicine & public health, 2college of medicine & health sciences, sultan qaboos university, muscat, oman; 3research section, medical simulation and skills development centre, oman medical specialty board, muscat, oman *corresponding author’s e-mail: mhalazri@squ.edu.om abstract: objectives: many cancer patients experience social difficulties and feelings of isolation. this study aimed to evaluate patients’ and attendees’ attitudes towards cancer patients. methods: a cross-sectional study was conducted of patients and attendees attending sultan qaboos university hospital (squh), muscat, oman, from december 2018 to march 2019. results: a total of 1,190 people participated (response rate: 91.5%). the majority (90.7%) did not express reluctance to help cancer patients. most agreed that cancer patients were productive (76.2%) and are respected by the public (75.0%). however, many participants (63.1%) felt that cancer patients might face difficulties getting married. multivariate analysis showed that participants who had a family history of cancer or had previously been a caregiver for cancer patients were more likely to believe that cancer patients could be productive (odds ratio [or] = 1.92, 95% confidence interval [ci]: 1.31–2.82; p <0.05). less-educated participants were more likely to believe that cancer patients feared not being productive (or = 1.49, 95% ci: 1.01–2.19; p <0.05). male and single participants were more likely to perceive that cancer patients faced difficulties getting married (or = 1.56, 95% ci: 1.20–2.02 and or = 1.68, 95% ci: 1.22–2.32, respectively; p <0.05 each). conclusion: patients and attendees attending squh in oman appeared to have positive and supportive attitudes towards cancer patients, although some felt that cancer patients might encounter social obstacles. healthcare professionals should consider reassuring cancer patients of such positive sentiments. governmental and non-governmental organisations should act to promote a supportive environment for cancer patients in oman. keywords: cancer; attitudes; patients; surveys and questionnaires; oman. attitudes towards cancer patients a cross-sectional study of omani patients and attendees at a university teaching hospital *mohammed al-azri,1 fahad al-hattali,2 humaid al-ghafri,2 sathiya m. panchatcharam3 clinical & basic research sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e221–230, epub. 21 jun 21 submitted 22 apr 20 revisions req. 9 jun & 9 jul 20; revisions recd. 18 jun & 13 jul 20 accepted 11 aug 20 https://doi.org/10.18295/squmj.2021.21.02.010 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge patients and attendees to sultan qaboos university hospital (squh) in oman appeared to have positive attitudes towards cancer patients. in general, people who had previously been caregivers for cancer patients and whose family had a history of cancer had more positive views of cancer patients and were more supportive. some patients and attendees to squh perceived that cancer patients would face certain social obstacles, such as difficulties getting married. application to patient care healthcare professionals in oman should reassure cancer patients of the omani society’s positive views of cancer patients, particularly if patients raise concerns regarding this issue. government and non-governmental organisations might take advantage of the positive attitudes of society to help provide a more supportive environment for cancer survivors. for many patients, a cancer diagnosis is perceived as a death sentence and is associated with fear and social stigma.1 indeed, learning of a cancer diagnosis can be devastating and trigger adverse psychological symptoms in patients such as anxiety, depression, fatigue, difficulties in concentrating, fear of social isolation, concerns regarding sexuality and feelings of guilt and selfblame.2,3 imagining the emotional ramifications of this news on their families can also make some patients feel worse.2 these psychological phenomena can, in turn, lead to a lack of sleep, reduced quality of work and a tendency to stay away from the workplace, potentially resulting in job loss and even suicide.4,5 sociocultural perceptions and stigma play a crucial role in attitudes towards cancer patients.5 some societies regard cancer patients as victims, rendering such individuals prone to social isolation and feelings of exclusion from social circles, which can decrease emotional wellbeing and increase mortality risks.2,3,6 additionally, cancer survivors sometimes experience negative attitudes, stereotypes, discrimination and problems with coworkers following treatment.5 oman is an arab country with a population of 4.6 million and is located in the southeastern part of the arabian peninsula.7 in oman, cancer is one of the most frequent causes of death, with patients often presenting at a younger age and more advanced https://creativecommons.org/licenses/by-nd/4.0/ stage at the time of diagnosis.8,9 the burden of cancer in oman is expected to increase due to the country’s ageing population, rapid socioeconomic changes and the increase in popularity of more westernised lifestyles, with people smoking and eating diets high in saturated fats, engaging in less physical activity and experiencing increased obesity.10 previous studies in oman have shown that cancer patients often experience debilitating psychosocial problems, including mental stress and apprehension over how society might view and react to them as cancer patients.2,3 on the other hand, some patients perceive that members of the public view them in an overly sympathetic manner, thus constraining their social interactions.2 in reaction to these perceptions, patients may even move abroad to avoid meeting people who know that they have cancer.3 this study aimed to evaluate attitudes towards cancer patients among patients and attendees of a teaching hospital in oman. to the best of the authors’ knowledge, no previous study has sought to identify attitudes towards cancer patients among this specific group in the middle east. methods this cross-sectional study was carried out from december 2018 to march 2019 at sultan qaboos university hospital (squh), a tertiary care university hospital located in muscat, the capital city of oman. the hospital receives patients from primary healthcare centres and secondary care hospitals in all governorates of oman. all omani individuals >18 years old who were visiting outpatient clinics or various areas of squh during the study period were invited to participate. seriously ill patients or those who were in pain were excluded. the sample size was calculated at 1,067 subjects based on estimated moderate attitudes towards cancer patients (50%) and a precision of 3% and confidence interval (ci) of 95%. a total of 1,300 participants were targeted for inclusion in the study to adjust for missing responses. a 31-item questionnaire to evaluate attitudes towards cancer patients and willingness to disclose a cancer diagnosis was adapted from a validated englishlanguage tool used in south korea.5 two researchers were trained to distribute the questionnaires and collect data. the original questionnaire is divided into three domains, with the first domain assessing perceptions towards cancer patients including assessment of willingness to help cancer patients and perceptions of patients’ ability to be sociable. the second domain assesses perceptions of personal barriers for cancer patients including fears of negative side-effects of chemotherapy and radiotherapy, death due to cancer and pain associated with advanced stages of the disease. the third domain assesses perceptions of social barriers for cancer patients including difficulties getting married and relating to the community.5 for each item, participants could choose between strongly agree, agree, neither agree nor disagree, disagree or strongly disagree. during analysis, the agree and strongly agree options were combined, as were the disagree and strongly disagree options. participants were required to provide written informed consent before enrolling in the study. those who consented were given the questionnaire to complete. for illiterate participants, the questionnaire was administered by research assistants. the internal consistency of the items in the questionnaire was previously validated.5 in addition, a fourth section was included to collect socio demographic data relevant to oman. the final questionnaire was translated into arabic using forwardsbackwards translation methods. a pilot study of 50 participants was conducted to assess the clarity and reliability of the arabic version. based on a standardised item analysis, the cronbach’s alpha values of the arabic version were 0.75, 0.87 and 0.88 for the perceptions of cancer patients, personal barriers for cancer patients and social barriers for cancer patients domains, respectively. data were analysed using statistical package for the social sciences (spss), version 22 (ibm corp., armonk, new york, usa). for descriptive purposes, categorised variables were presented as numbers and percentages. a chi-square test (χ2) was used to find associations between sociodemographic variables and participants’ responses. a univariate analysis was conducted to determine differences between participants’ sociodemographic variables and their responses. a multivariate analysis was subsequently conducted for statistically significant variables. during both the univariate and multivariate analysis, the ‘agree’ responses were coded as ‘yes’, while the ‘neither agree nor disagree’ and ‘disagree’ responses were coded as ‘no’. a binary logistic regression model was used to adjust for various factors. a p value of <0.05 was considered statistically significant. this study was approved by the medical research and ethics committee of the college of medicine and health sciences at sultan qaboos university (mrec #1361). attitudes towards cancer patients a cross-sectional study of omani patients and attendees at a university teaching hospital e222 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e223 results a total of 1,190 individuals participated in the study (response rate: 91.5%). of this total, 704 (59.2%) were male and 486 (40.8%) were female. the mean age was 32.23 ± 10.18 years (range: 18–78 years). approximately one-third of the participants (34.2%) lived in muscat, while the remainder (65.8%) were from other regions of oman. most (67.5%) were married and 87.8% had completed school, college or a postgraduate degree. overall, 25.9% had a family history of cancer, and 33.3% had previously been caregivers for cancer patients [table 1]. most participants (n = 1,079; 90.7%) were willing to help cancer patients if needed and believed that cancer patients were able to participate in different occasions (n = 958; 80.5%) and be sociable (n = 946; 79.5%) and productive (n = 907; 76.2%). in addition, most declared that cancer patients were respected (n = 893; 75.0%) and given attention (n = 791; 66.5%) by the public. regarding the availability of medical facilities, 59.2% (n = 705) felt that cancer patients received good medical services, and 58.9% (n = 701) agreed that the government was attentive to the suffering of cancer patients. however, 55.5% (n = 660) stated that they would not reveal knowledge of a person’s cancer diagnosis to others. a minority felt that cancer patients were different from other people (n = 274; 23.0%) and that they should be isolated (n = 140; 11.8%) [table 2]. multivariate analysis showed that participants who had a family history of cancer were significantly more likely to believe that cancer patients can be table 1: sociodemographic characteristics of patients and attendees attending a teaching hospital in oman (n = 1,190) characteristic n (%) gender male 704 (59.2) female 486 (40.8) mean age in years 32.23 ± 10.18 origin muscat 407 (34.2) a’dhahira 89 (7.5) al batinah 314 (26.4) a’dakhilia 230 (19.3) al wusta 17 (1.4) a’sharqia 108 (9.1) dhofar 23 (1.9) musandam 2 (0.2) marital status single 368 (30.9) married 803 (67.5) divorced/widowed 19 (1.6) education level* none 145 (12.2) school 547 (46.2) college and above 492 (41.6) chronic diseases diabetes 86 (7.2) hypertension 141 (11.8) cancer 33 (2.8) obesity 43 (3.6) other 143 (12.0) none 744 (62.5) smoking status current smoker 39 (3.3) non-smoker 1,116 (93.8) ex-smoker 35 (2.9) alcohol intake yes 8 (0.7) no 1,182 (99.3) monthly income in omr <500 192 (16.1) 500–1,000 541 (45.5) 1,000–2,000 281 (23.6) >2,000 176 (14.8) family history of cancer† yes 308 (25.9) no 879 (74.1) knowledge of cancer screening facilities yes 149 (12.5) no 1,041 (87.5) plans to undertake cancer screening in future yes 745 (62.6) no 445 (37.4) previously been a caregiver for cancer patients yes 396 (33.3) no 794 (66.7) agreement with the statement that “cancer is common in oman” agree 276 (23.2) disagree 749 (62.9) don’t know 165 (13.9) omr = omani riyal. *the total is calculated out of 1,184 due to missing data from six participants. †the total is calculated out of 1,187 due to missing data from three participants. mohammed al-azri, fahad al-hattali, humaid al-ghafri and sathiya m. panchatcharam clinical and basic research | e223 table 2: attitudes towards cancer and cancer patients among patients and attendees attending a teaching hospital in oman (n = 1,190) item n (%) agree neither agree nor disagree disagree perceptions towards cancer patients i will help cancer patients if they need help 1,079 (90.7) 45 (3.8) 66 (5.5) i think cancer patients can participate on different occasions 958 (80.5) 109 (9.2) 123 (10.3) i think cancer patients can be sociable with other people 946 (79.5) 129 (10.8) 115 (9.7) i think cancer patients can be productive 907 (76.2) 171 (14.4) 112 (9.4) the public respects cancer patients 893 (75.0) 164 (13.8) 133 (11.2) the public pays attention to cancer patients 791 (66.5) 147 (12.4) 252 (21.2) cancer patients receive good medical services 705 (59.2) 292 (24.5) 193 (16.2) the government pays attention to cancer patients to reduce their suffering 701 (58.9) 293 (24.6) 196 (16.5) if i knew someone who had cancer, i would not tell other people about them 660 (55.5) 167 (14.0) 363 (30.5) cancer patients are different than other people 274 (23.0) 114 (9.6) 802 (67.4) i think cancer patients should be isolated 140 (11.8) 150 (12.6) 900 (75.6) personal barriers for cancer patients fear of the negative sideeffects of chemotherapy and radiotherapy 982 (82.5) 119 (10.0) 89 (7.5) fear of death due to cancer 970 (81.5) 122 (10.3) 98 (8.2) pain associated with advanced stages of the disease 786 (66.1) 297 (25.0) 107 (9.0) fear of not finding sufficient care 753 (63.3) 138 (11.6) 299 (25.1) fear of the views of society for having cancer 730 (61.3) 183 (15.4) 277 (23.3) fear of relying on family and the public 712 (59.8) 239 (20.1) 239 (20.1) fear of not being productive in the community 670 (56.3) 239 (20.1) 281 (23.6) difficulty in adapting to palliative care to control the pain 558 (46.9) 407 (34.2) 225 (18.9) cancer care services are often located far away 517 (43.4) 320 (26.9) 353 (29.7) often feeling introverted 489 (41.1) 346 (29.1) 355 (29.8) often feeling psychologically unwell 417 (35.0) 422 (35.5) 351 (29.5) social barriers for cancer patients lack of knowledge about cancer symptoms, screening, and treatment 763 (64.1) 199 (16.7) 228 (19.2) difficulties in getting married 751 (63.1) 209 (17.6) 230 (19.3) fear of discovering cancer as there is no treatment 530 (44.5) 109 (9.2) 551 (46.3) few community services for cancer patients 530 (44.5) 315 (26.5) 345 (29.0) i don’t trust primary healthcare providers 503 (42.3) 220 (18.5) 467 (39.2) fear of dealing with cancer patients due to the incorrect belief that cancer is contagious 471 (39.6) 164 (13.8) 555 (46.6) avoiding interacting with cancer patients 245 (20.6) 111 (9.3) 834 (70.1) i prefer to use herbs for any medical condition (even cancer), instead of radiation and chemicals 190 (16.0) 360 (30.3) 640 (53.8) self-care is not my top priority 160 (13.4) 237 (19.9) 793 (66.6) attitudes towards cancer patients a cross-sectional study of omani patients and attendees at a university teaching hospital e224 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e225 ta bl e 3: a ss oc ia tio ns b et w ee n so ci od em og ra ph ic v ar ia bl es a nd p er ce pt io ns to w ar ds c an ce r a nd c an ce r p at ie nt s a m on g pa tie nt s a nd a tt en de es a tt en di ng a te ac hi ng h os pi ta l i n o m an (n = 1 ,1 90 ) v ar ia bl e p er ce pt io n s to w ar ds c an ce r pa ti en ts , o r (9 5% c i) c an ce r pa ti en ts c an be s oc ia bl e w it h ot he r pe op le c an ce r pa ti en ts sh ou ld b e is ol at ed c an ce r pa ti en ts c an be p ro du ct iv e c an ce r pa ti en ts c an pa rt ic ip at e in d iff er en t oc ca si on s if i kn ew so m eo ne w ho ha d ca nc er , i w ou ld n ot te ll ot he r p eo pl e ab ou t t he m th e pu bl ic pa ys a tt en ti on to c an ce r pa ti en ts th e pu bl ic re sp ec ts ca nc er pa ti en ts c an ce r pa ti en ts a re di ffe re nt fr om ot he r p eo pl e i w ill h el p ca nc er pa ti en ts if th ey n ee d he lp c an ce r pa ti en ts re ce iv e go od m ed ic al se rv ic es th e go ve rn m en t pa ys a tt en ti on to c an ce r pa ti en ts to re du ce th ei r su ffe ri ng g en de r m al e 0. 50 * (0 .3 6– 0. 69 ) 1. 88 * (1 .2 4– 2. 85 ) 0. 64 * (0 .4 7– 0. 86 ) 0. 66 * (0 .4 8– 0. 91 ) 1. 04 (0 .8 1– 1. 34 ) 0. 68 * (0 .5 2– 0. 87 ) 1. 26 (0 .9 5– 1. 68 ) 1. 52 * (1 .1 2– 2. 06 ) 1. 03 (0 .6 8– 1. 57 ) 0. 51 * (0 .4 0– 0. 66 ) 0. 87 (0 .6 8– 1. 12 ) fe m al e 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 a ge in y ea rs <3 0 0. 72 (0 .4 6– 1. 12 ) 0. 75 (0 .4 1– 1. 35 ) 0. 75 (0 .4 8– 1. 18 ) 1. 48 (0 .9 4– 2. 35 ) 1. 38 (0 .9 6– 1. 98 ) 1. 37 (0 .9 5– 1. 97 ) 1. 12 (0 .7 6– 1. 66 ) 0. 72 (0 .4 8– 1. 07 ) 1. 82 * (1 .0 4– 3. 21 ) 0. 56 * (0 .3 9– 0. 80 ) 0. 83 (0 .5 9– 1. 18 ) 30 – 39 1. 08 (0 .7 1– 1. 65 ) 1. 33 (0 .8 2– 2. 16 ) 0. 51 * (0 .3 4– 0. 76 ) 0. 95 (0 .6 3– 1. 42 ) 0. 46 * (0 .3 3– 0. 65 ) 1. 38 (0 .9 8– 1. 94 ) 1. 02 (0 .7 0– 1. 47 ) 0. 50 (0 .3 4– 0. 73 ) 1. 82 * (1 .0 7– 3. 08 ) 0. 99 (0 .7 1– 1. 39 ) 1. 21 (0 .8 7– 1. 68 ) ≥4 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 m ar it al st at us si ng le 0. 80 (0 .5 5– 1. 17 ) 1. 65 (0 .9 7– 2. 80 ) 0. 64 * (0 .4 4– 0. 93 ) 0. 52 * (0 .3 5– 0. 78 ) 0. 54 * (0 .3 9– 0. 74 ) 0. 60 * (0 .4 3– 0. 83 ) 1. 08 (0 .7 6– 1. 55 ) 1. 05 (0 .7 3– 1. 51 ) 0. 79 (0 .4 6– 1. 35 ) 0. 33 (0 .6 9– 1. 27 ) 0. 97 (0 .7 2– 1. 32 ) m ar ri ed 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 ed uc at io n n on e 3. 06 * (2 .0 2– 4. 65 ) 0. 22 * (0 .1 3– 0. 35 ) 3. 27 * (2 .1 8– 4. 90 ) 2. 10 * (1 .3 6– 3. 26 ) 2. 90 * (1 .9 5– 4. 32 ) 1. 15 (0 .7 7– 1. 72 ) 0. 91 (0 .5 7– 1. 46 ) 0. 58 * (0 .3 8– 0. 87 ) 1. 62 (0 .9 0– 2. 90 ) 1. 18 (0 .8 0– 1. 73 ) 0. 97 (0 .6 6– 1. 42 ) sc ho ol 2. 99 * (1 .9 6– 4. 57 ) 0. 31 * (0 .1 9– 0. 50 ) 3. 63 * (2 .3 9– 5. 49 ) 1. 49 (0 .9 7– 2. 31 ) 2. 65 * (1 .7 7– 3. 95 ) 0. 87 (0 .5 8– 1. 30 ) 0. 54 * (0 .3 4– 0. 86 ) 0. 40 * (0 .2 6– 0. 61 ) 1. 57 (0 .8 7– 2. 82 ) 1. 60 * (1 .0 8– 2. 36 ) 0. 78 (0 .5 3– 1. 16 ) c ol le ge an d ab ov e 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 fa m ily h is to ry o f c an ce r ye s 1. 17 (0 .8 1– 1. 69 ) 0. 65 (0 .4 0– 1. 06 ) 1. 92 * (1 .3 1– 2. 82 ) 1. 57 * (1 .0 5– 2. 34 ) 1. 18 (0 .8 8– 1. 58 ) 1. 18 (0 .8 7– 1. 60 ) 0. 49 * (0 .3 6– 0. 66 ) 1. 21 (0 .8 6– 1. 69 ) 0. 94 (0 .5 9– 1. 49 ) 0. 59 * (0 .4 4– 0. 79 ) 0. 59 * (0 .4 5– 0. 79 ) n o 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 pr ev io us ly b ee n a ca re gi ve r f or c an ce r p at ie nt s ye s 0. 99 (0 .7 0– 1. 38 ) 1. 17 (0 .7 7– 1. 78 ) 1. 26 (0 .9 0– 1. 75 ) 1. 61 * (1 .1 3– 2. 31 ) 0. 73 * (0 .5 6– 0. 96 ) 0. 76 (0 .5 8– 1. 0) 1. 31 (0 .9 7– 1. 78 ) 0. 99 (0 .7 2– 1. 36 ) 0. 57 (0 .3 7– 0. 87 ) 1. 50 * (1 .1 3– 1. 98 ) 1. 58 * (1 .2 0– 2. 07 ) n o 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 o r = od ds ra tio ; c i = co nfi de nc e i nt er va l. *s ta tis tic al ly si gn ifi ca nt a t p < 0. 05 . mohammed al-azri, fahad al-hattali, humaid al-ghafri and sathiya m. panchatcharam clinical and basic research | e225 ta bl e 4: a ss oc ia tio ns b et w ee n so ci od em og ra ph ic v ar ia bl es a nd p er ce pt io ns o f c an ce rre la te d pe rs on al b ar ri er s am on g pa tie nt s an d at te nd ee s at te nd in g a te ac hi ng h os pi ta l i n o m an (n = 1 ,1 90 ) v ar ia bl e c an ce rre la te d pe rs on al b ar ri er s, o r (9 5% c i) o ft en fe el in g in tr ov er te d fe ar o f r el yi ng on fa m ily a nd th e pu bl ic fe ar o f no t b ei ng pr od uc ti ve in th e co m m un it y fe ar o f n ot fin di ng su ffi ci en t c ar e fe ar o f d ea th du e to c an ce r fe ar o f t he ne ga ti ve si de -e ffe ct s o f ch em ot he ra py an d ra di ot he ra py pa in as so ci at ed w it h ad va nc ed st ag es o f t he di se as e c an ce r c ar e se rv ic es a re of te n lo ca te d fa r a w ay d iffi cu lt y in ad ap ti ng to pa lli at iv e ca re to c on tr ol th e pa in o ft en fe el in g ps yc ho lo gi ca lly un w el l fe ar o f th e vi ew s of s oc ie ty fo r h av in g ca nc er g en de r m al e 1. 47 * (1 .1 4– 1. 89 ) 1. 35 * (1 .0 5– 1. 74 ) 1. 48 * (1 .1 5– 1. 90 ) 1. 04 (0 .8 1– 1. 35 ) 0. 75 (0 .5 4– 1. 04 ) 0. 51 * (0 .3 6– 0. 73 ) 0. 94 (0 .7 2– 1. 23 ) 1. 28 * (1 .0 0– 1. 65 ) 0. 82 (0 .6 4– 1. 05 ) 1. 55 * (1 .1 8– 2. 02 ) 0. 92 (0 .7 1– 1. 19 ) fe m al e 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 a ge in y ea rs <3 0 0. 72 (0 .5 1– 1. 02 ) 1. 07 (0 .7 5– 1. 52 ) 1. 31 (0 .9 3– 1. 85 ) 1. 79 * (1 .2 6– 2. 55 ) 2. 29 * (1 .4 7– 3. 58 ) 1. 33 (0 .8 4– 2. 12 ) 1. 26 (0 .8 7– 1. 85 ) 1. 55 (1 .0 9– 2. 19 ) 0. 97 (0 .6 9– 1. 37 ) 2. 50 * (1 .7 0– 3. 57 ) 2. 19 (1 .5 4– 3. 12 ) 30 – 39 0. 63 (0 .4 5– 0. 87 ) 1. 03 (0 .7 4– 1. 43 ) 0. 87 (0 .6 3– 1. 20 ) 1. 35 (0 .9 8– 1. 87 ) 1. 30 (0 .8 9– 1. 90 ) 1. 84 * (1 .1 9– 2. 83 ) 0. 77 (0 .5 5– 1. 09 ) 1. 49 (1 .0 7– 2. 07 ) 0. 62 (0 .4 5– 0. 87 ) 1. 11 (0 .7 9– 1. 58 ) 1. 46 (1 .0 6– 2. 03 ) ≥4 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 m ar it al st at us si ng le 2. 31 * (1 .7 0– 3. 15 ) 1. 75 * (1 .2 8– 2. 40 ) 1. 73 * (1 .2 7– 2. 36 ) 1. 42 * (1 .0 2– 1. 96 ) 1. 24 (0 .8 0– 1. 92 ) 0. 99 (0 .6 5– 1. 50 ) 0. 87 (0 .6 0– 1. 22 ) 1. 08 (0 .8 0– 1. 46 ) 1. 11 (0 .8 2– 1. 51 ) 0. 50 * (0 .3 6– 0. 69 ) 1. 00 (0 .7 3– 1. 38 ) m ar ri ed 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 ed uc at io n n on e 1. 30 (0 .8 7– 1. 92 ) 2. 20 * (1 .5 0– 3. 22 ) 1. 27 (0 .8 7– 1. 87 ) 1. 15 (0 .7 9– 1. 69 ) 1. 37 (0 .8 9– 2. 12 ) 1. 76 * (1 .1 4– 2. 71 ) 1. 32 (0 .9 0– 1. 94 ) 1. 47 (0 .9 9– 2. 16 ) 1. 37 (0 .9 3– 2. 02 ) 0. 73 (0 .4 9– 1. 09 ) 1. 82 * (1 .2 5– 2. 67 ) sc ho ol 1. 32 (0 .8 9– 1. 97 ) 2. 60 * (1 .7 6– 3. 84 ) 1. 49 * (1 .0 1– 2. 19 ) 1. 34 (0 .9 1– 1. 98 ) 2. 12 * (1 .3 5– 3. 34 ) 3. 36 * (2 .1 0– 5. 38 ) 1. 93 * (1 .3 0– 2. 87 ) 1. 30 (0 .8 8– 1. 93 ) 1. 17 (0 .7 9– 1. 73 ) 1. 0 (0 .6 8– 1. 50 ) 2. 36 * (1 .6 0– 3. 47 ) c ol le ge a nd ab ov e 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 fa m ily h is to ry o f c an ce r ye s 0. 99 (0 .7 4– 1. 32 ) 1. 32 (0 .9 9– 1. 78 ) 1. 34 * (1 .0 0– 1. 79 ) 0. 97 (0 .7 2– 1. 31 ) 0. 62 * (0 .4 3– 0. 88 ) 2. 07 * (1 .3 2– 3. 24 ) 1. 53 * (1 .1 1– 2. 11 ) 0. 96 (0 .7 2– 1. 28 ) 0. 71 (0 .5 3– 0. 95 ) 0. 77 (0 .5 7– 1. 04 ) 0. 85 (0 .6 4– 1. 14 ) n o 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 pr ev io us ly b ee n a ca re gi ve r f or c an ce r p at ie nt s ye s 1. 08 (0 .8 2– 1. 42 ) 1. 01 (0 .7 7– 1. 32 ) 0. 80 (0 .6 1– 1. 04 ) 1. 22 (0 .9 2– 1. 61 ) 1. 26 (0 .8 9– 1. 80 ) 1. 32 (0 .9 0– 1. 93 ) 2. 07 * (1 .5 3– 2. 79 ) 1. 32 * (1 .0 1– 1. 72 ) 2. 45 (1 .8 7– 3. 22 ) 1. 72 * (1 .3 0– 2. 27 ) 0. 96 (0 .7 0– 1. 26 ) n o 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 o r = od ds ra tio ; c i = co nfi de nc e i nt er va l. *s ta tis tic al ly si gn ifi ca nt a t p < 0. 05 . attitudes towards cancer patients a cross-sectional study of omani patients and attendees at a university teaching hospital e226 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e227 ta bl e 5: a ss oc ia tio ns b et w ee n so ci od em og ra ph ic v ar ia bl es a nd p er ce pt io ns o f c an ce rre la te d so ci al b ar ri er s am on g pa tie nt s an d at te nd ee s at te nd in g a te ac hi ng h os pi ta l i n o m an (n = 1 ,1 90 ) v ar ia bl e c an ce rre la te d so ci al b ar ri er s, o r (9 5% c i) fe ar o f d ea lin g w it h ca nc er p at ie nt s d ue to th e in co rr ec t b el ie f t ha t ca nc er is c on ta gi ou s fe ar o f di sc ov er in g ca nc er a s t he re is no tr ea tm en t d iffi cu lt ie s in g et ti ng m ar ri ed fe w c om m un it y se rv ic es fo r ca nc er p at ie nt s a vo id in g in te ra ct in g w it h ca nc er p at ie nt s la ck o f kn ow le dg e ab ou t ca nc er s ym pt om s, sc re en in g, a nd tr ea tm en t i d on ’t tr us t pr im ar y he al th ca re pr ov id er s i p re fe r t o us e he rb s f or an y m ed ic al c on di ti on (e ve n ca nc er ), in st ea d of ra di at io n an d ch em ic al s se lfca re is no t m y to p pr io ri ty g en de r m al e 1. 67 * (1 .2 9– 2. 16 ) 1. 16 (0 .4 9– 0. 90 ) 1. 56 * (1 .2 0– 2. 02 ) 1. 45 * (1 .1 3– 1. 86 ) 1. 13 (0 .8 4– 1. 54 ) 1. 07 (0 .8 2– 1. 38 ) 1. 56 * (1 .2 1– 2. 00 ) 0. 89 (0 .6 3– 1. 24 ) 1. 98 * (1 .3 4– 2. 93 ) fe m al e 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 a ge in y ea rs <3 0 1. 41 (0 .9 8– 2. 03 ) 1. 73 * 1. 20 – 2. 47 ) 0. 94 (0 .6 5– 1. 34 ) 1. 97 * (1 .3 9– 2. 79 ) 2. 54 * (1 .6 1– 4. 03 ) 1. 69 * (1 .1 8– 2. 44 ) 1. 31 (0 .9 2– 1. 86 ) 1. 05 (0 .6 4– 1. 72 ) 2. 38 * (1 .3 8– 4. 11 ) 30 – 39 1. 33 (0 .9 5– 1. 87 ) 2. 51 * (1 .7 9– 3. 52 ) 0. 76 (0 .5 5– 1. 07 ) 1. 18 (0 .8 5– 1. 64 ) 1. 56 (1 .0 0– 2. 42 ) 0. 93 (0 .6 7– 1. 30 ) 1. 11 (0 .5 4– 1. 54 ) 1. 25 (0 .8 0– 1. 95 ) 1. 58 (0 .9 6– 2. 61 ) ≥4 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 m ar it al st at us si ng le 1. 27 (0 .9 3– 1. 73 ) 1. 36 (1 .0 0– 1. 84 ) 1. 68 * (1 .2 2– 2. 32 ) 0. 82 (0 .6 1– 1. 12 ) 0. 84 (0 .5 8– 1. 21 ) 0. 92 (0 .6 7– 1. 28 ) 1. 49 * (1 .1 0– 2. 03 ) 1. 04 (0 .6 8– 1. 59 ) 0. 52 * (0 .3 3– 0. 82 ) m ar ri ed 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 ed uc at io n n on e 1. 27 (0 .8 6– 1. 88 ) 2. 17 * (1 .4 5– 3. 26 ) 1. 67 * (1 .1 4– 2. 45 ) 1. 23 (0 .8 4– 1. 80 ) 0. 86 (0 .5 4– 1. 38 ) 1. 98 * (1 .3 6– 2. 90 ) 0. 80 (0 .5 5– 1. 18 ) 0. 36 * (0 .2 3– 0. 55 ) 0. 51 * (0 .3 2– 0. 81 ) sc ho ol 0. 99 (0 .6 7– 1. 48 ) 1. 83 * (1 .2 1– 2. 76 ) 2. 40 * (1 .6 3– 3. 55 ) 1. 14 (0 .7 7– 1. 68 ) 0. 74 (0 .4 6– 1. 19 ) 3. 26 * (2 .2 1– 4. 82 ) 1. 21 (0 .8 2– 1. 78 ) 0. 27 * (0 .1 7– 0. 43 ) 0. 22 * (0 .1 3– 0. 38 ) c ol le ge a nd ab ov e 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 fa m ily h is to ry o f c an ce r ye s 0. 56 * (0 .4 1– 0. 76 ) 0. 80 (0 .6 0– 1. 07 ) 0. 95 (0 .7 1– 1. 27 ) 1. 32 (1 .0 0– 1. 76 ) 0. 49 * (0 .3 3– 0. 71 ) 0. 90 (0 .6 7– 1. 22 ) 1. 36 * (1 .0 2– 1. 81 ) 0. 84 (0 .5 6– 1. 27 ) 0. 41 * (0 .2 4– 0. 67 ) n o 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 pr ev io us ly b ee n a ca re gi ve r f or c an ce r p at ie nt s ye s 1. 01 (0 .7 6– 1. 32 ) 1. 32 * (1 .0 1– 1. 73 ) 0. 70 * (0 .5 3– 0. 92 ) 1. 19 (0 .9 1– 1. 55 ) 2. 30 * (1 .6 6– 3. 18 ) 0. 92 (0 .7 0– 1. 22 ) 0. 93 (0 .7 1– 1. 22 ) 0. 92 (0 .6 3– 1. 34 ) 1. 48 (0 .9 8– 2. 22 ) n o 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0 o r = od ds ra tio ; c i = co nfi de nc e i nt er va l. *s ta tis tic al ly si gn ifi ca nt a t p < 0. 05 . mohammed al-azri, fahad al-hattali, humaid al-ghafri and sathiya m. panchatcharam clinical and basic research | e227 productive (odds ratio [or] = 1.92, 95% ci: 1.31–2.82; p value <0.05) and participate in important occasions (or = 1.57, 95% ci: 1.05–2.34; p value <0.05). however, they were significantly less likely to believe that the public respects cancer patients (or = 0.49, 95% ci: 0.36–0.66; p <0.05), that cancer patients receive good medical services (or = 0.59, 95% ci: 0.44–0.79; p <0.05) or that the government pays attention to cancer patients to reduce their suffering (or = 0.59, 95% ci: 0.45–0.79; p <0.05). in addition, participants who had been a caregiver for cancer patients were significantly more likely to believe that cancer patients can participate in different occasions (or = 1.61, 95% ci: 1.13–2.31; p <0.05), that cancer patients receive good medical services (or = 1.50, 95% ci: 1.13–1.98; p <0.05) and that the government pays attention to cancer patients to reduce their suffering (or = 1.58, 95% ci 1.20–2.07; p <0.05) [table 3]. the majority of participants felt that cancer patients feared side-effects of cancer treatment (82.5%), death (81.5%), pain (66.1%), not finding adequate care (63.3%), society’s views (61.3%), having to depend on family and the public (59.8%) and not being productive in the community (56.3%). however, less than half agreed that cancer patients might have difficulties adapting to palliative care to control their pain (46.9%), that cancer care services are often located far away (43.4%) and that cancer patients often feel introverted (41.1%) and psychologically unwell (35.0%) [table 2]. multivariate analysis showed that less-educated participants were significantly more likely to believe that cancer patients feared relying on family and the public (or = 2.20, 95% ci: 1.50–3.22; p <0.05), not being productive (or = 1.49, 95% ci: 1.01–2.19; p <0.05), death (or = 2.12, 95% ci: 1.35–3.34; p <0.05), side effects of treatment (or = 1.76, 95% ci: 1.14–2.71; p <0.05) and societal views (or = 1.82, 95% ci: 1.25–2.67; p <0.05). in addition, those with a family history of cancer were significantly more likely to perceive fear of not being productive (or = 1.34, 95% ci: 1.00–1.79; p <0.05), fear of the negative side-effects of treatment (or = 2.07, 95% ci: 1.32–3.24; p <0.05) and pain (or = 1.53, 95% ci: 1.11–2.11; p <0.05) as cancer-related personal barriers. participants who had previously been a caregiver for cancer patients were significantly more likely to view pain (or = 2.07, 95% ci: 1.53–2.79; p <0.05), cancer care services being located far away (or = 1.32, 95% ci: 1.01–1.72; p <0.05) and cancer patients feeling psychologically unwell (or = 1.72, 95% ci: 1.30–2.27; p <0.05) as personal barriers [table 4]. more than half of the participants thought that a lack of knowledge of cancer symptoms, screening and treatment (64.1%) and difficulties getting married (63.1%) were social barriers faced by cancer patients. however, fewer participants were afraid of a cancer diagnosis due to a perceived lack of treatment (44.5%), feared dealing with cancer patients due to the incorrect belief that cancer is contagious (39.6%), avoided interacting with cancer patients (20.6%) and preferred herbal remedies for any medical condition, including cancer (16.0%) [table 2]. multivariate analysis showed that both male (or = 1.56, 95% ci: 1.20–2.02; p <0.05) and single (or = 1.68, 95% ci: 1.22–2.32; p <0.05) participants were significantly more likely to perceive that cancer patients face difficulties getting married. moreover, those with no formal education were significantly more likely to fear diagnosis due to lack of treatment (or = 2.17, 95% ci: 1.45–3.26; p <0.05), difficulties getting married (or = 1.67, 95% ci: 1.14–2.45; p <0.05) and a lack of cancer-related knowledge (or = 1.98, 95% ci: 1.36–2.90; p <0.05) as social barriers. however, they were also significantly less likely to prefer medicinal herbs (or = 0.36, 95% ci: 0.23–0.55; p <0.05). participants who had been caregivers of cancer patients were significantly more likely to fear diagnosis due to a perceived lack of treatment (or = 1.32, 95% ci: 1.01–1.73; p <0.05) and avoid interacting with cancer patients (or = 2.30, 95% ci: 1.66–3.18; p <0.05). however, they were significantly less likely to believe that cancer patients face difficulties getting married (or = 0.70, 95% ci: 0.53–0.92; p <0.05) [table 5]. discussion to the best of the authors’ knowledge, this study is the first conducted in the middle east to evaluate attitudes towards cancer patients among patients and attendees attending a teaching hospital. the majority of the participants in the current study held generally positive views of cancer patients including a willingness to help them if needed and the belief that such individuals were respected by society. this attitude is fortunate as individuals living in cultures that stigmatise cancer patients are less likely to adopt risk-reducing behaviours themselves or to seek support services when necessary.11 furthermore, cancer patients are more likely to develop adverse psychological sequelae if they live in a society where people hold negative prejudices and discriminating attitudes towards cancer patients.5,12 overall, while many of the participants in the present study demonstrated incorrect knowledge regarding cancer, they still held supportive attitudes towards cancer patients. this finding might reflect the predominantly islamic mindset of omani nationals, as religious beliefs contribute significantly to attitudes towards an individual’s health and wellbeing. in attitudes towards cancer patients a cross-sectional study of omani patients and attendees at a university teaching hospital e228 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e229 islam, support is considered integral to the healing process, and taking care of one’s health is viewed as a religious obligation.13 moreover, traditional cultural values in oman consider family to be of paramount importance, with the entire extended familial network obligated to care for and provide support to a sick relative.14 however, cancer is still viewed in many middle eastern countries as a death sentence; thus, initiatives are needed to educate individuals regarding recent advances in cancer treatment.2 more than half of the current study participants thought it would be better not to tell others of an individual’s cancer diagnosis, reflecting their wish to protect the patient’s privacy. however, in many arab countries, medical results and diagnoses are often disclosed first to family members rather than patients.13 these family members may then keep such information a secret from the patient and other members of the public due to the superstitious belief that disclosure would be bad luck, resulting in a loss of hope which in turn might increase the likelihood of the patient’s decline and death.2,14 in some western countries, one of the most important barriers for patients of ethnic minorities is the perceived social stigma of a cancer diagnosis.15 most of the participants in the present study believed that cancer patients might fear the negative side-effects of treatment, death due to cancer, pain in advanced stages of the disease, not finding sufficient care, the views of society with regards to cancer patients, having to depend on family and the public and not being productive community members. perceptions of personal barriers that cancer patients might encounter are likely to be fuelled by the actual concerns of such patients. indeed, women diagnosed with breast cancer reported being concerned about the side-effects of treatment and the possible impact on their body image.2 such concerns likely make it difficult for cancer patients to participate in social activities normally and may result in depression and anxiety.12 in the current study, men were significantly more likely than women to believe that cancer patients might face difficulties getting married. impaired fertility is a noted side-effect of cancer treatment and a particular source of concern for young male cancer survivors.16 in omani society, fertility is often valued as much as home-ownership or wealth. while many arabs believe that fertility is ultimately dependent on god’s will, the prospect of being infertile is nevertheless a source of shame, causing feelings of worthlessness and, potentially, for cancer patients who are married, resulting in divorce.17 in addition, treatment-induced infertility can lead to mental stress, depression and social and marital issues for cancer patients, particularly women.18 education was a significant factor affecting perceptions of cancer and cancer patients in the present study. in western countries, low educational levels along with low socioeconomic status and those in an ethnic group have similarly been associated with negative attitudes towards cancer.19 among cancer patients, a lack of education is associated with negative consequences such as inadequate access to cancer care, delays in diagnosis, suboptimal treatment, inadequate follow-up or monitoring, poor overall health status and failure to adopt a healthy lifestyle.19,20 both governmental and non-governmental organisations in oman should implement educational initiatives to encourage acceptance of cancer patients in the community and correct misconceptions regarding cancer diagnosis and treatment. in the current study, participants with a family history of cancer or those who had previously been caregivers for cancer patients were less apprehensive of interacting with cancer patients and were more aware of the physical and psychological consequences of having cancer. as the disease progresses, the family members or caregivers of a cancer patient begin to provide more psychological support and assume more responsibilities; such individuals are more likely to become distressed as their loved one becomes sicker and palliative care is initiated.21 many participants who had previously been caregivers for cancer patients reported often feeling psychologically unwell as a personal barrier; this finding might be attributed to the fact that middle eastern cultures often promote a strong sense of moral responsibility to one’s family.22 this study was subject to certain limitations. first, because the questionnaire tool was adapted from a previous south korean study, it may have resulted in significant cultural differences.5 however, a pilot study revealed that the tool was valid and had high internal consistency. second, the study was conducted among patients and attendees attending a teaching hospital in a single region of oman; moreover, some of them were patients, had cancer themselves or had a family history of cancer. these factors could affect the generalisability of the findings. indeed, a larger national study involving members of the general public recruited from community settings and other regions of oman is required for better representative sampling and generalisability of results. third, two approaches were used to administer the questionnaire to participants, with the survey being self-administered for literate participants and completed by the research assistants during face-toface interviews for illiterate participants. in order to mohammed al-azri, fahad al-hattali, humaid al-ghafri and sathiya m. panchatcharam clinical and basic research | e229 avoid bias, using a standardised method to administer the questionnaire should have been considered for all participants, irrespective of literacy status. fourth, responses from participants with a family history of cancer or those who had been caregivers for cancer patients might have resulted in reporting bias. finally, the results of this study are not generalisable outside of oman; however, the authors hypothesise that people in other middle eastern countries would demonstrate comparable attitudes towards cancer due to similar sociocultural and religious values. a larger multicentre study conducted in multiple countries is needed to verify this hypothesis. conclusion overcoming cancer-related stigma is necessary in order to normalise the experience of cancer. this study showed for the first time that patients and attendees of a teaching hospital in oman held relatively positive views regarding cancer patients. healthcare professionals should reassure cancer patients that the environment in oman is a supportive one. as education has been found to significantly influence perceptions of cancer patients, the government should implement educational initiatives to encourage acceptance of cancer patients in the community and correct misconceptions regarding cancer diagnoses and treatments. further collaborative research is recommended to explore public attitudes and perceptions towards cancer patients in other countries in the middle east. a c k n o w l e d g e m e n t s the authors would like to thank the participants for taking part in this study as well as the authorities at squh for allowing this study to be conducted. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. muzzin lj, anderson nj, figueredo at, gudelis so. the experience of cancer. soc sci med 1994; 38:1201–8. https://doi. org/10.1016/0277-9536(94)90185-6. 2. al-azri m, al-awisi h, al-rasbi s, el-shafie k, al-hinai m, al-habsi h, et al. psychosocial impact of breast cancer diagnosis among omani women. oman med j 2014; 29:437–44. https:// doi.org/10.5001/omj.2014.115. 3. al-azri mh, al-awisi h, al-rasbi s, al-moundhri m. coping with a diagnosis of breast cancer among omani women. j health psychol 2014; 19:836–46. https://doi.org/10.1177/1359105313479813. 4. ahn e, cho j, shin dw, park bw, ahn sh, noh dy, et al. impact of breast cancer diagnosis and treatment on workrelated life and factors affecting them. breast cancer res treat 2009; 116:609–16. https://doi.org/10.1007/s10549-008-0209-9. 5. cho j, smith k, choi ek, kim ir, chang yj, park hy, et al. public attitudes toward cancer and cancer patients: a national survey in korea. psychooncology 2013; 22:605–13. https://doi. org/10.1002/pon.3041. 6. kroenke ch, kubzansky ld, schernhammer es, holmes md, kawachi i. social networks, social support, and survival after breast cancer diagnosis. j clin oncol 2006; 24:1105–11. https:// doi.org/10.1200/jco.2005.04.2846. 7. national center for statistics and information. population clock. from: www.ncsi.gov.om/pages/ncsi.aspx accessed: jul 2020. 8. al-lawati ja, mabry r, mohammed aj. addressing the threat of chronic diseases in oman. prev chronic dis 2008; 5:a99. 9. kumar s, burney ia, al-ajmi a, al-moundhri ms. changing trends of breast cancer survival in sultanate of oman. j oncol 2011; 2011:316243. https://doi.org/10.1155/2011/316243. 10. al-lawati na, al-bahrani bj, al-raisi ss, al-lawati j. twentyyear trends of cancer incidence in omanis, 1996–2015. oman med j 2019; 34:361–87. https://doi.org/10.5001/omj.2019.74. 11. daher m. cultural beliefs and values in cancer patients. ann oncol 2012; 23:s66–9. https://doi.org/10.1093/annonc/mds091. 12. cho j, choi ek, kim sy, shin dw, cho bl, kim ch, et al. association between cancer stigma and depression among cancer survivors: a nationwide survey in korea. psychooncology 2013; 22:2372–8. https://doi.org/10.1002/pon.3302. 13. silbermann m, hassan ea. cultural perspectives in cancer care: impact of islamic traditions and practices in middle eastern countries. j pediatr hematol oncol 2011; 33:s81–6. https://doi.org/10.1097/mph.0b013e318230dab6. 14. aljubran ah. the attitude towards disclosure of bad news to cancer patients in saudi arabia. ann saudi med 2010; 30:141–4. https://doi.org/10.4103/0256-4947.60520. 15. the lancet oncology. perceptions of cancer in society must change. lancet oncol 2016; 17:257. https://doi.org/10.1016/ s1470-2045(16)00091-7. 16. schover lr, brey k, lichtin a, lipshultz li, jeha s. knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. j clin oncol 2002; 20:1880–9. https://doi.org/10.1200/jco.2002.07.175. 17. fido a, zahid ma. coping with infertility among kuwaiti women: cultural perspectives. int j soc psychiatry. 2004; 50:294-300. https://doi.org/10.1177/0020764004050334. 18. armuand gm, wettergren l, rodriguez-wallberg ka, lampic c. women more vulnerable than men when facing risk for treatment-induced infertility: a qualitative study of young adults newly diagnosed with cancer. acta oncol 2015; 54:243–52. https://doi.org/10.3109/0284186x.2014.948573. 19. aziz nm, rowland jh. cancer survivorship research among ethnic minority and medically underserved groups. oncol nurs forum 2002; 29:789–801. https://doi.org/10.1188/02.onf.789-801. 20. potter p, deshields t, kuhrik m, kuhrik n, o’neill j, rihanek a. an analysis of educational and learning needs of cancer patients and unrelated family caregivers. j cancer educ 2010; 25:538–42. https://doi.org/10.1007/s13187-010-0076-z. 21. pitceathly c, maguire p. the psychological impact of cancer on patients’ partners and other key relatives: a review. eur j cancer 2003; 39:1517–24. https://doi.org/10.1016/s0959-8049(03)00309-5. 22. gilbar r, miola j. one size fits all? on patient autonomy, medical decision-making, and the impact of culture. med law rev 2015; 23:375–99. https://doi.org/10.1093/medlaw/fwu032. attitudes towards cancer patients a cross-sectional study of omani patients and attendees at a university teaching hospital e230 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1016/0277-9536%2894%2990185-6 https://doi.org/10.1016/0277-9536%2894%2990185-6 https://doi.org/10.5001/omj.2014.115 https://doi.org/10.5001/omj.2014.115 https://doi.org/10.1177/1359105313479813 https://doi.org/10.1007/s10549-008-0209-9 https://doi.org/10.1002/pon.3041 https://doi.org/10.1002/pon.3041 https://doi.org/10.1200/jco.2005.04.2846 https://doi.org/10.1200/jco.2005.04.2846 https://doi.org/10.1155/2011/316243 https://doi.org/10.5001/omj.2019.74 https://doi.org/10.1093/annonc/mds091 https://doi.org/10.1002/pon.3302 https://doi.org/10.1097/mph.0b013e318230dab6 https://doi.org/10.4103/0256-4947.60520 https://doi.org/10.1016/s1470-2045%2816%2900091-7 https://doi.org/10.1016/s1470-2045%2816%2900091-7 https://doi.org/10.1200/jco.2002.07.175 https://doi.org/10.1177/0020764004050334 https://doi.org/10.3109/0284186x.2014.948573 https://doi.org/10.1188/02.onf.789-801 https://doi.org/10.1007/s13187-010-0076-z https://doi.org/10.1016/s0959-8049%2803%2900309-5 https://doi.org/10.1093/medlaw/fwu032 1departments of medicine and 4gastroenterology, royal hospital, muscat, oman; 2department of medicine, ibri hospital, ibri, oman; 3department of medicine, nhs trust, hull, united kingdom *corresponding author’s e-mail: npandak@gmail.com characteristics of pyogenic liver abscess experience of a single centre in oman *nenad pandak,1 asmaa s. mahdi,1 ali al majrafi,2 mariya molay,3 stepen s. deenadayalan,4 faryal khamis,1 zakariya al balushi1 sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 257–261, epub. 26 may 22 submitted 29 sep 20 revisions req. 23 dec 20 & 2 mar 21; revisions recd. 9 feb & 18 mar 21 accepted 13 apr 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.105 clinical & basic research abstract: objectives: this study aimed to analyse the epidemiological, aetiological and clinical characteristics of pyogenic liver abscess (pla) occurring in oman. the intention was to obtain the information needed for the adequate liver abscess (la) empirical treatment. la can develop as a complication of hepatobiliary disease or other intraabdominal infections, but more recently, it is associated with primary and secondary liver malignancies and their treatment. methods: this retrospective study took place in the royal hospital, muscat, oman. consecutive patients treated for la from january 2013 to december 2017 were enrolled. their demographic and clinical data were used to study the characteristics of pla occurring in oman. results: a total of 53 patients with pla were enrolled in the study. they were predominantly male and younger than 60 years. klebsiella pneumoniae was found to be the most common bacteria causing la. clinical presentation was non-specific, and abdominal pain and high fever were the most common symptoms. conclusion: the majority of plas are caused by k. pneumoniae, so the empirical treatment should begin with antibiotic directed against it. further studies are needed to establish the local role of anaerobic bacteria in pla and monitor the presence of hypervirulent k. pneumoniae in oman. keywords: pyogenic liver abscess; etiology; epidemiology; klebsiella pneumoniae; oman. advances in knowledge this study is the first to analyse the clinical, epidemiological and aetiological aspects of pyogenic liver abscess (pla) occurring in oman. klebsiella pneumoniae is the most common cause of pla in oman. the majority of patients have the cryptogenic form of liver abscess. application to patient care identifying the pla characteristics in the omani population will help the healthcare practitioners to plan the appropriate differential diagnosis workup and start the adequate empirical treatment. liver abscess (la) is defined as an encapsulated collection of pus within the liver parenchyma. las are predominantly caused by bacteria generating a pyogenic liver abscess (pla), while parasites and fungi are less common la causes.1 during the early years of the 20th century, pla was seen mostly as secondary to appendicitis, but later, biliary tract diseases usually preceded pla.2 more recently, plas can occur because of secondary infection of a primary liver tumour or metastatic liver lesions as well as their treatments, particularly as complications of trans-arterial chemoembolisation or radiofrequency ablation.3,4 in the situation where no obvious source of extra-hepatic infection is determined following a full investigation, pla is labelled as cryptogenic.5 the prevalence of cryptogenic plas varies throughout the world. it reached 17% in the uk and france, while in australia and asia, it was 34% and 65%, respectively.6 previous studies showed a significant difference in pla aetiology. in europe and north america, escherichia coli, staphylococcus spp., streptococcus spp. and enterococcus spp. are the most common causes of pla, while in asia, the predominant cause is klebsiella pneumoniae.7 moreover, several studies showed that k. pneumoniae is the main cause of cryptogenic pla regardless of geographical distribution.6,8 however, the characteristics of pla in gulf countries are not well known. to the best of the authors’ knowledge, only one study from qatar and a few case reports from oman and saudi arabia that describe pla have been published till date.9–11 this retrospective study aimed to establish the epidemiological, aetiological and clinical characteristics of pla in oman. methods the study was conducted at the royal hospital, muscat, oman, by collecting patients’ data from the royal hospital database. all patients >13 years old who were treated for la during the five-year period from january 2013 to december 2017 were enrolled in the study. the la aetiology was determined by abscess and/or blood culture. the blood for the aerobic and https://creativecommons.org/licenses/by-nd/4.0/ characteristics of pyogenic liver abscess experience of a single centre in oman 258 | squ medical journal, may 2022, volume 22, issue 2 anaerobic culture was taken at admission, and if the patient underwent the abscess percutaneous drainage procedure, the pus sample was sent for the aerobic culture. amoebic abscess was diagnosed using a commercial immunoglobulin g (igg) anti-amoebic assay (r-biopharm ag, darmstadt, germany). patients with confirmed amoebic la were excluded. to trace a possible but undetected underlying pla source during hospitalisation, after the discharge, the patients were followed-up through the hospital database system for one to six years. the approval for the study was obtained from the royal hospital scientific research committee (src#32/2018). results during the five-year study period, 76 patients were treated for la. of these, 53 had pla, while the remaining had amoebic la and, thus, were excluded from the analysis. out of the 53 selected, 40 (75.5%) patients were male and 13 (24.5%) were female. the mean age of the whole group was 46.8 years (range: 14–92 years). when comparing the average age of male and female patients, no statistical difference was observed, although the mean ages for the male and female patients were 51.3 and 44.7 years, respectively. the clinical presentation of pla was non-specific and upper abdominal pain was the most common symptom, being found in 42 (79.3%) patients. fever was present in 31 patients (58.5%) and 13 (24.5%) were observed to be icteric. at the time of admission to the hospital, 34 (64.2%) patients had leukocytosis above 10 × 109/l (reference range: 2.4–9.5 × 109/l). alanine aminotransferase (alt) above 40 iu/l (reference range: 0–40 iu/l) was found in 30 (56.6%) patients and bilirubin above 20 mmol/l (reference range: 0–20 mmol/l) in 18 (34.0%) patients. the definite pla diagnosis was established by a computed tomography (cat) scan, magnetic resonance imaging or abdominal ultrasound. a total of 35 (66.0%) patients had a single abscess. in 33 (62.3%) patients, pla was found in the right liver lobe. in 13 (24.5%) patients, it was in the left lobe, while in seven (13.2%) patients, both lobes were involved. the average pla size was 6.3 cm with median of 6 cm and the size ranged from 2 to 14 cm. the majority of the patients (n = 34; 64.2%) had cryptogenic pla [table 1]. of the 53 patients, blood and/or abscess culture were positive in 30 (62.3%) patients, while in the rest, pla aetiology was not determined since the cultures remained sterile. k. pneumoniae was the most common bacteria causing pla, and it was found in 22 patients, representing 41.5% of all patients treated for pla [table 2]. all except two of the isolated k. pneumoniae were susceptible to usual antibiotics. one of the resistant table 1: characteristics of patients with pyogenic liver abscess treated at the royal hospital, muscat, oman, between january 2013 and december 2017 (n = 53) characteristic n (%) gender female 13 (24.5) male 40 (75.5) age in years <60 36 (67.9) >60 17 (32.1) symptoms fever 31 (58.5) abdominal pain 42 (79.3) jaundice 13 (24.5) laboratory results wbc >10 34 (64.2) alt >40 29 (54.7) comorbidity hepatobiliary disease 17 (32.1) immunosuppression 3 (5.7) intraabdominal trauma 1 (1.9) diabetes mellitus 15 (28.3) none 12 (22.6) wbc = white blood cells; alt = alanine transaminase. table 2: aetiology of pyogenic liver abscess of patients treated at the royal hospital, muscat, oman, between january 2013 and december 2017 (n = 53) aetiology n (%) blood culture (n = 48) abscess culture (n = 37) klebsiella pneumoniae 5 (10.4) 17 (46.0) escherichia coli 1 (2.1) 3 (8.1) enterococcus spp. 1 (2.1) 1 (2.7) pseudomonas aeruginosa 0 (0) 1 (2.7) staphylococcus aureus 0 (0) 1 (2.7) streptococcus spp. 2 (4.2) 2 (5.4) sterile 39 (81.3) 12 (32.4) not done 5 16 nenad pandak, asmaa s. mahdi, ali al majrafi, mariya molay, stepen s. deenadayalan, faryal khamis and zakariya al balushi clinical and basic research | 259 k. pneumoniae was carbapenem-resistant enterobac teriaceae (cre) and the other extended-spectrum beta-lactamase (esbl). both were isolated in noncryptogenic patients. one of these patients had pancreatic cancer, while the other had non-hodgkin lymphoma and both of these patients died. the majority of pla patients (n = 46; 86.8%) were treated in the general ward, while the remaining seven (13.2%) were admitted directly to the intensive care unit due to sepsis. out of these seven patients, three had urgent abdominal surgery. in 40 (75.5%) patients, ultrasoundor cat-guided percutaneous abscess drainage was performed, after which the antibiotic treatment was continued. a total of 13 (24.5%) patients were treated only with antibiotics. the overall in-hospital pla mortality rate was 9.4% (n = 5). out of the five patients that died, two had pancreatic cancer, one had non-hodgkin lymphoma, one was a post-liver transplant patient and one had cryptogenic pla. discussion pla is an uncommon but potentially life-threatening disease with significant morbidity and mortality that varies around the globe. regarding its geographical distribution, pla is more often seen in asia than in europe or the usa.12 the annual incidence per 100,000 inhabitants ranged from 1.1 in denmark to 36.6 in taiwan over the last two decades.13 at the same time, in the usa, the annual hospitalisation incidence due to pla was 3.6 per 100,000 admissions.14 in this regard, as this study was based on a single-centre experience, it was not possible to estimate the pla incidence in oman. it is well-known that the pla incidence is higher in males than in females and the results of this study are concordant to this, as three quarters of the patients were male.15 likewise, pla is more often seen among the elderly population, where it might have an atypical clinical presentation; moreover, these patients do have more underlying diseases that can complicate the pla clinical course.16 nevertheless, the disease outcome in these patients is not significantly different when compared with younger pla patients.17 in the current study, the patients were younger than those in other published reports, where the average age was usually around 65 years.18–20 furthermore, in a few reports, the mean age as well as the majority of pla patients were in the fourth decade of life.21,22 pla symptoms are non-specific and, thus, it is difficult to diagnose the disease based only on the clinical presentation. the majority of patients in this study complained of abdominal pain, with fever presenting less frequently, in 42 (79.2%) and 31 (58.5%) patients, respectively. in other published reports, fever was usually the most common symptom followed by abdominal pain.5,22 however, mangukiya et al. reported that in their patients, abdominal pain was the most common clinical sign.23 the fact that the present study is retrospective in nature could explain why fever was not noted more frequently. the other reason could be that some of the patients were referred to the hospital under concern after the antibiotic treatment had already been started in their local hospital. previous studies indicated that comorbidities (diabetes mellitus, malignancies and liver cirrhosis), male gender, abscess size >5 cm and pla complications (i.e. sepsis with or without organ failure, abscess rupture and extrahepatic involvement) are the risk factors that increase the pla mortality rate.5 the mortality rate among the patients of the current study was 9.4%. one of the patients with a fatal disease outcome had cryptogenic pla and being male was the only risk factor he had. the other four patients that died had at least two risk factors (malignancies, male gender, abscess size and/or sepsis with multiorgan failure), which increased the possibility of a fatal outcome. in this study, k. pneumoniae was the most common cause of pla. no anaerobic bacteria were isolated, although several studies reported that these bacteria are detected in 9–46% of pla patients.24 this is probably because anaerobic pus cultures were not routinely tested nor specifically requested. the k. pneumoniae predomination was shown as the cause of pla, especially cryptogenic la, in other studies.6,25,26 the first reports about the community-acquired plas caused by hypervirulent k. pneumoniae (hvkp) in taiwan were published in 1986; now, the infection is recognised worldwide.27 the typical presentation of hvkp infection is a cryptogenic pla in a usually younger and previously healthy person. as hvkp has the tendency for metastatic spreading, these pla patients can present with extra-hepatic abscesses, pneumonia, necrotising fasciitis, endophthalmitis and meningitis.28 in the current study, two of the patients, both with cryptogenic pla, had pleural effusions and necrotising pneumonia with consequent cavitary lesions. these patients were diabetic without any other comorbidities; one was 21 and the other 49 years old. the clinical presentations of these two patients strongly suggested that k. pneumoniae causing the infections in both cases were most probably hvkp, although no phenotyping nor molecular analysis was done to confirm this. this study has various limitations. one of the limitations is that it was retrospective in nature, so the results should be interpreted with caution. moreover, characteristics of pyogenic liver abscess experience of a single centre in oman 260 | squ medical journal, may 2022, volume 22, issue 2 microbiological analysis was only partly done, thereby disregarding the proper anaerobic pus sample cultures. furthermore, as this study covered a single-centre experience, the results do not represent the overall pla situation in oman. conclusion this study provides important information about pla characteristics, at least with regard to the northern part of oman. presenting symptoms were nonspecific, indicating that in patients with abdominal pain and fever, the differential diagnosis process should include la. the majority of plas were caused by k. pneumoniae, therefore, the empirical treatment should be started with antibiotic directed against it. further studies are needed to establish the local role of anaerobic bacteria in pla and monitor the presence of hvkp in oman. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. a u t h o r s’ c o n t r i b u t i o n np conceived and designed the study, also drafted the manuscript. asm and am collected the data and performed the data analysis. mm and ssd performed the final data analysis. fk and zb supervised the data analysis. all the authors contributed to the revision of the manuscript. all authors approved the final version of the manuscript. references 1. akhondi h, sabih de. liver abscess. treasure island, usa: statpearls publishing, 2019. from: www.ncbi.nlm.nih.gov/book s/nbk538230/ accessed: mar 2021. 2. lardière-deguelte s, ragot e, armoun k, piardi t, dokmak s, bruno o, et al. hepatic abscess: diagnosis and management. j visc surg 2015; 152:231–43. https://doi.org/10.1016/j.jviscsur g.2015.01.013. 3. huang sf, ko cw, chang cs, chen gh. liver abscess formation after transarterial chemoembolization for malignant hepatic tumor. hepatogastroenterology 2003; 50:1115–8. 4. iida h, aihara t, ikuta s, yamanaka n. risk of abscess formation after liver tumor radiofrequency ablation: a review of 8 cases with a history of enterobiliary anastomosis. hepatogastroen terology 2014; 61:1867–70. 5. mavilia mg, molina m, wu gy. the evolving nature of hepatic abscess: a review. j clin transl hepatol 2016; 4:158–68. https:// doi.org/10.14218/jcth.2016.00004. 6. rossi b, gasperini ml, leflon-guibout v, gioanni a, de lastours v, rossi g, et al. hypervirulent klebsiella pneumoniae in cryptogenic liver abscesses, paris, france. emerg infect dis 2018; 24:221–29. https://doi.org/10.3201/eid2402.170957. 7. mücke mm, kessel j, mücke vt, schwarzkopf k, hogardt m, stephan c, et al. the role of enterococcus spp. and multidrugresistant bacteria causing pyogenic liver abscesses. bmc infect dis 2017; 17:450. https://doi.org/10.1186/s12879-017-2543-1. 8. mohan bp, meyyur aravamudan v, khan sr, chandan s, ponnada s, asokkumar r, et al. prevalence of colorectal cancer in cryptogenic pyogenic liver abscess patients. do they need screening colonoscopy? a systematic review and meta-analysis. dig liver dis 2019; 51:1641–45. https://doi.org/10.1016/j.dld.20 19.08.016. 9. abbas mt, khan fy, muhsin sa, al-dehwe b, abukamar m, elzouki an. epidemiology, clinical features and outcome of liver abscess: a single reference center experience in qatar. oman med j 2014; 29:260–3. https://doi.org/10.5001/omj.2014.69. 10. basu s. klebsiella pneumoniae: an emerging pathogen of pyogenic liver abscess. oman med j 2009; 24:131–3. https://doi.org/10.5 001/omj.2009.28. 11. enani ma, el-khizzi na. community acquired klebsiella pneu moniae, k1 serotype. invasive liver abscess with bacteremia and endophthalmitis. saudi med j 2012; 33:782–6. 12. jepsen p, vilstrup h, schønheyder hc, sørensen ht. a nation wide study of the incidence and 30-day mortality rate of pyogenic liver abscess in denmark, 1977–2002. aliment pharmacol ther 2005; 21:1185–8. 13. ko mc, lin wh, martini s, chang wh, chiu ct, li cy. a cohort study of age and sex specific risk of pyogenic liver abscess incidence in patients with type 2 diabetes mellitus. medicine (baltimore) 2019; 98:e15366. https://doi.org/10.1097/md.0000 000000015366. 14. meddings l, myers rp, hubbard j, shaheen aa, laupland kb, dixon e, et al. a population-based study of pyogenic liver abscesses in the united states: incidence, mortality, and temporal trends. am j gastroenterol 2010; 105:117–24. https://doi.org/10.1038/ ajg.2009.614. 15. chen yc, lin ch, chang sn, shi zy. epidemiology and clinical outcome of pyogenic liver abscess: an analysis from the national health insurance research database of taiwan, 2000–2011. j microbiol immunol infect 2016; 49:646–53. https://doi.org/10.1016/j.jmii.2014.08.028. 16. peris j, bellot p, roig p, reus s, carrascosa s, gonzález-alcaide g, et al. clinical and epidemiological characteristics of pyogenic liver abscess in people 65 years or older versus people under 65: a retrospective study. bmc geriatr 2017; 17:161. https://doi. org/10.1186/s12877-017-0545-x. 17. zhang j, du z, bi j, wu z, lv y, zhang x, et al. comparison of clinical characteristics and outcomes of pyogenic liver abscess patients < 65 years of age versus ≥ 65 years of age. bmc infect dis 2019; 19:233. https://doi.org/10.1186/s12879-019-3837-2. 18. czerwonko me, huespe p, bertone s, pellegrini p, mazza o, pekolj j, et al. pyogenic liver abscess: current status and predictive factors for recurrence and mortality of first episodes. hpb (oxford) 2016; 18:1023–30. https://doi.org/10.1016/j.hpb.2016.09.001. 19. pang tc, fung t, samra j, hugh tj, smith rc. pyogenic liver abscess: an audit of 10 years’ experience. world j gastroenterol 2011; 17:1622–30. https://doi.org/10.3748/wjg.v17.i12.1622. 20. serraino c, elia c, bracco c, rinaldi g, pomero f, silvestri a, et al. characteristics and management of pyogenic liver abscess: a european experience. medicine (baltimore) 2018; 97:e0628. https://doi.org/10.1097/md.0000000000010628. 21. kong h, yu f, zhang w, li x. clinical and microbiological characteristics of pyogenic liver abscess in a tertiary hospital in east china. medicine (baltimore) 2017; 96:e8050. https://doi. org/10.1097/md.0000000000008050. https://doi.org/10.1016/j.jviscsurg.2015.01.013 https://doi.org/10.1016/j.jviscsurg.2015.01.013 https://doi.org/10.14218/jcth.2016.00004 https://doi.org/10.14218/jcth.2016.00004 https://doi.org/10.3201/eid2402.170957 https://doi.org/10.1186/s12879-017-2543-1 https://doi.org/10.1016/j.dld.2019.08.016 https://doi.org/10.1016/j.dld.2019.08.016 https://doi.org/10.5001/omj.2014.69 https://doi.org/10.5 001/omj.2009.28 https://doi.org/10.5 001/omj.2009.28 https://doi.org/10.1097/md.0000000000015366 https://doi.org/10.1097/md.0000000000015366 https://doi.org/10.1038/ajg.2009.614 https://doi.org/10.1038/ajg.2009.614 https://doi.org/10.1016/j.jmii.2014.08.028 https://doi.org/10.1186/s12877-017-0545-x https://doi.org/10.1186/s12877-017-0545-x https://doi.org/10.1186/s12879-019-3837-2 https://doi.org/10.1016/j.hpb.2016.09.001 https://doi.org/10.3748/wjg.v17.i12. 1622 https://doi.org/10.1097/md.0000000000008050 https://doi.org/10.1097/md.0000000000008050 nenad pandak, asmaa s. mahdi, ali al majrafi, mariya molay, stepen s. deenadayalan, faryal khamis and zakariya al balushi clinical and basic research | 261 22. du zq, zhang ln, lu q, ren yf, lv y, liu xm, et al. clinical characteristics and outcome of pyogenic liver abscess with different size: 15-year experience from a single center. sci rep 2016; 6:35890. https://doi.org/10.1038/srep35890. 23. mangukiya do, darshan jr, kanani vk, gupta st. a prospective series case study of pyogenic liver abscess: recent trends in etiology and management. indian j surg 2012; 74:385–90. https:// doi.org/10.1007/s12262-011-0397-0d.0000000000008050. 24. kumar sk, perween n, omar bj, kothari a, satsangi at, jha mk, et al. pyogenic liver abscess: clinical features and microbiological profiles in tertiary care center. j family med prim care 2020; 9:4337–42. https://doi.org/10.4103/jfmpc.jfmpc_927_20. 25. chen j, zhang m, chen j, ning y, cai x, zhang l, et al. cryptogenic and non-cryptogenic liver abscess: a retrospective analysis of 178 cases revealed distinct characteristics. j int med res 2018; 46:3824–36. https://doi.org/10.1177/0300060518781256. 26. heo ny, hong ym, kim to, moon ys, yang sy, park sh, et al. the prevalence of colonic neoplasm in cryptogenic pyogenic liver abscess: a prospectively enrolled cross-sectional study. korean j gastroenterol 2016; 68:195–201. https://doi.org/10.4166/kjg.20 16.68.4.195. 27. oikonomou kg, aye m. klebsiella pneumoniae liver abscess: a case series of six asian patients. am j case rep 2017; 18:1028–33. https://doi.org/10.12659/ajcr.905191. 28. russo ta, marr cm. hypervirulent klebsiella pneumoniae. clin microbiol rev 2019; 32:e00001–19. https://doi.org/10.1128/ cmr.00001-19. https://doi.org/10.1038/srep35890 https://doi.org/10.1007/s12262-011-0397-0d.0000000000008050 https://doi.org/10.1007/s12262-011-0397-0d.0000000000008050 https://doi.org/10.4103/jfmpc.jfmpc_927_20 https://doi.org/10.1177/0300060518781256 https://doi.org/10.4166/kjg.2016.68.4.195 https://doi.org/10.4166/kjg.2016.68.4.195 https://doi.org/10.12659/ajcr.905191 https://doi.org/10.1128/cmr.00001-19 https://doi.org/10.1128/cmr.00001-19 division of respiratory medicine, mito medical center, university of tsukuba, mito-city, japan *corresponding author’s e-mail: hirosato@md.tsukuba.ac.jp disappearance of pulmonary cavity caused by fungal infection kengo nishino, yuika sasatani, *hiroaki satoh sultan qaboos university med j, may 2022, vol. 22, iss. 2, pp. 304–305, epub. 26 may 22 submitted 15 feb 21 revisions req. 29 apr 21;revisions recd. 17 may 21 accepted 2 jun 21 the disappearance of cavities associated with pulmonary fungal infections is rare.1 a 79-year-old male patient was admitted to a local hospital in mito-city, japan, in 2017 complaining of cough and fever for the previous two weeks. the patient had no history of diabetes or tuberculosis. at admission, a blood analysis showed a white blood cell count of 13,600/μl, c-reactive protein of 12.37 mg/dl, serum creatinine of 1.27 mg/dl and blood glucose of 206 mg/dl. chest computed tomography (ct) scan taken at admission showed consolidation in the left lung, but no cysts or cavities were observed [figure 1a]. cefepime was administered for three days but his symptoms worsened. considering the antibacterial spectrum, cefepime was changed to micafungin (100 mg/day). aspergillus antigen test was negative but plasma β-d-glucan was found to be 118 pg/ml (normal range: 0–20 pg/ml). although no pathogen grew in the culture of bronchial lavage fluid, septate hyphae with branching at 45-degree angles were observed, suggestive of aspergillus infection.2 micafungin was changed to oral voriconazole (300 mg/day) and intravenous liposomal amphotericin b (150 mg/day) was added and continued for three weeks. the cough and fever as well as inflammatory indices improved. however, the appearance of a cavity in the chest was found by ct taken two weeks after the initiation of antifungal treatment. in this scan, a spherical structure suspected to be a ‘fungus ball’ or blood clot was found in the cavity [figure 1b]. oral voriconazole was administered for 12 weeks but the cavity remained unchanged [figure 1c]. by 12 months, however, the cavity changed to linear shadow by ct [figure 1d], and at 18 months, it was not observed by ct [figure 1e]. the patient was well 37 months after this infection. this report conformed to the ethical guidelines for clinical studies issued by the ministry of health, labor and welfare in japan. written comprehensive consent was obtained from the patient. reporting of this case report was approved by the ethics committee in the presenting hospital (no16-66). comments pulmonary fungal infections are often refractory because they usually occur in compromised hosts.3,4 in patients with pulmonary mycosis, some develop this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.092 interesting medical image figure 1: chest computed tomography of a 79-year-old male patient showing changes until the disappearance of the cavity in left lower lobe of the lung. a: consolidation in left lung with no cysts or cavities in the left lung at admission. b: appearance of a cavity with a spherical structure suspected to be a 'fungus ball' or blood clot taken 2 weeks after the initiation of antifungal treatment. c: cavity that remained unchanged in shape and size after 12 weeks of administration of voriconazole. d: change from cavity to linear shadow 12 months after the diagnosis. e: disappearance of linear shadow 18 months after the diagnosis. https://creativecommons.org/licenses/by-nd/4.0/ kengo nishino, yuika sasatani and hiroaki satoh interesting medical image | 305 cavities.5 once formed, they often change to linear shadows or remain as cavities but rarely disappear.1 the current elderly patient had impaired glucose tolerance; in addition, the patient was diagnosed with left renal cancer one year after this infectious episode. it was unclear whether the impaired glucose tolerance and cancer-bearing status in this patient were associated with the fungal infection. to the best of the authors’ knowledge, there is one report of a patient with pulmonary fungal infection who followed a similar course until the disappearance of a lung cavity.1 this was a 26-year-old man with pulmonary aspergillosis, who had bronchial asthma as the underlying disease.1 since it was a pulmonary mycosis that developed in a compromised elderly patient, it was speculated that the cavity would remain after treatment. the patient could be followed-up for a long period of time, even after the inflammatory response had improved and the disappearance of the cavity was unexpectedly confirmed. the cavities formed by fungal infections usually remain and the residual cavities are often not followed for long periods of time after symptoms and the inflammatory response have improved. rare reports of cavity disappearance may be related to this. although the mechanism is unknown, cavities formed by fungal infection may disappear as observed in the current patient. a u t h o r s’ c o n t r i b u t i o n s kn, ys and hs collected the data. kn and hs prepared the manuscript. all authors approved the final version of the article. references 1. saitou m, suzuki t, niitsuma k. multiple pulmonary aspergillus fumigatus cysts and cavities that disappeared with anti-fungal agents. respirol case rep 2018; 6:e00327. https://doi.org/10.10 02/rcr2.327. 2. kradin rl, mark ej. the pathology of pulmonary disorders due to aspergillus spp. arch pathol lab med 2008; 132:606–14. https://doi.org/10.5858/2008-132-606-tpopdd. 3. giacobbe dr, riccardi n, vena a, bassetti m. mould infections of traumatic wounds: a brief narrative review. infect dis ther 2020; 9:1–15. https://doi.org/10.1007/s40121-020-00284-8. 4. azoulay e, russell l, van de louw a, metaxa v, bauer p, povoa p, et al. diagnosis of severe respiratory infections in immunocompromised patients. intensive care med 2020; 46:298–314. https://doi.org/10.1007/s00134-019-05736-5. 5. ketai l, currie bj, holt mr, chan ed. radiology of chronic cavitary infections. j thorac imaging 2018; 33:334–43. https:// doi.org/10.1097/rti.0000000000000346. https://doi.org/10.1002/rcr2.327 https://doi.org/10.1002/rcr2.327 https://doi.org/10.5858/2008-132-606-tpopdd https://doi.org/10.1007/s40121-020-00284-8 https://doi.org/10.1007/s00134-019-05736-5 https://doi.org/10.1097/rti.0000000000000346 https://doi.org/10.1097/rti.0000000000000346 1 submitted 21 feb 22 1 revisions req. 10 may & 1 jun 22; revisions recd. 12 may & 12 jun 22 2 accepted 15 jun 22 3 online-first: june 2022 4 doi: https://doi.org/10.18295/squmj.6.2022.043 5 6 cytotoxic and genotoxic effects of waterpipe on oral health status 7 a systematic review and meta-analysis 8 *ricardo grillo,1 mehdi khemiss,2 yuri slusarenko da silva3 9 10 1department of oral and maxillofacial surgery, faculdade são leopoldo mandic, 11 campinas, brazil; 2department of dental medicine, fattouma bourguiba university 12 hospital, university of monastir, monastir, tunisia; 3department of oral & 13 maxillofacial surgery, unifg university center, guanambi, brazil. 14 *corresponding author’s e-mail: doutorgrillo@uol.com.br 15 16 abstract 17 a worldwide increase in waterpipe consumption can be observed. the present 18 systematic review aims to assess cytotoxic and genotoxic impacts on oral health related 19 to waterpipe smoking. we searched medline, cochrane library, and dimensions 20 evaluating if waterpipe smokers (p) have any cytotoxic or genotoxic effects on oral cells 21 (i) compared to non-smokers (c) regarding mouth neoplasms (o). prisma guidelines 22 were adopted for the current systematic review. review manager was utilized for 23 statistical analysis (p < 0.05). a risk of bias and summary were performed to assess the 24 grade of the 20 included articles. with some of the articles included, a forest plot was 25 created in different levels. waterpipe smoking is harmful to oral health, causing 26 cytotoxic and genotoxic effects on oral cells with a risk difference of 0.16. it causes a 27 series of detrimental cellular and genetic modifications such as acanthosis, epithelial 28 dysplasia, and hyperparakeratosis. changes in dna methylation and p53 expression 29 were assessed among others. in addition, waterpipe has a bunch of carcinogenic 30 compounds. even with few publications on the subject, articles are very devastating in 31 confirming the carcinogenicity of waterpipe smoking. waterpipe smoke is cytotoxic and 32 2 genotoxic. due to the release of many organic compounds, it increases the incidence of 33 oral cancer. 34 keywords: mouth neoplasms; oral health; smoking water pipes; tobacco use; 35 toxicity measure. 36 37 introduction 38 tobacco may be smoked in different ways. waterpipe is one form of tobacco use that 39 has been gaining popularity during the last decades. a systematic review conducted in 40 2018 showed that waterpipe use prevalence was alarmingly high in the eastern 41 mediterranean and european regions, especially among youth.1 42 43 the waterpipe smoke contains a wide range of carcinogens such as naphthylamines, 44 tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, primary aromatic 45 amines, and carbon monoxide carbonyls like formaldehyde, acetaldehyde, or acrolein 2. 46 waterpipe use has been associated with dna damage and cell death, and these 47 genotoxicity and cytotoxicity are involved in oral carcinogenesis 3. laboratory-based 48 investigations have shown various genomic and transcriptomic alterations previously 49 categorized in various cancers 4. in fact, walters et al. 5 observed changes in dna 50 methylation at 727 locations in the genome. dna methylation may predispose the cells 51 to cancer by activating specific genes and repressing others 6. it also plays a significant 52 role in metastasis 7. in addition, nuclear changes in the oral mucosa cells of waterpipe 53 smokers (ws) were reported 8. these changes occur in the early stages of cancer and 54 may be used as biomarkers to screen oral dysplastic and malignant lesions 9. 55 56 however, the contribution of waterpipe use to the development of oral cancer is not 57 well-established 2. furthermore, the few available studies on this topic were not focused 58 explicitly on oral cancers 10. systematic reviews determine whether scientific evidence 59 is consistent and can be generalized across populations 11. therefore, this study aimed to 60 systematically review the scientific literature regarding the cytotoxic or genotoxic 61 effects of waterpipe smoking on oral mucosal cells. 62 63 3 materials and methods 64 a systematic review and meta-analysis were conducted according to the preferred 65 reporting items for systematic reviews and meta-analyses (prisma) guidelines 12. 66 this study protocol was registered in the prospero database. 67 68 cytotoxic and genotoxic original studies were considered in this systematic review. in 69 addition, inclusion criteria were considered: a) inclusion of waterpipe usual users; b) 70 any cytotoxic or genotoxic effects; c) comparison to group control. 71 72 the first hit was conducted online by two independent reviewers (rg and mk) in 73 medline (via pubmed), cochrane library, health virtual library (bvs) and 74 dimensions from inception until dec 12th of 2021. terms selected in the primary 75 articles selected to justify this review were combined with boolean operators (or / 76 and), answering the acronym pico (population, intervention, control, and outcome). 77 the following strategy was used: ((((hookah) or (shisha) or (waterpipe) or 78 (“waterpipe”) or (narghile)))) and (((oral) or (oral health) or (dental) or 79 (buccal))) not (systematic review). peco acronym to be answered was: do waterpipe 80 smokers (p) have any cytotoxic or genotoxic effects on oral cells (i) compared to non-81 smokers (c) regarding mouth neoplasms (o)? 82 83 exclusion criteria were: 1. clinical changes, and 2. radiographic modifications, 3. 84 studies performed out of head, face and neck region, and 4. animal studies. 85 comparative studies but with no conclusion specific to waterpipe toxicity were 86 excluded. studies that met the inclusion criteria or those with doubtful information 87 either in the title or abstract were selected for full-text assessment in this review’s 88 second round. 89 90 two different reviewers (rg and mk) independently extracted the following data from 91 the included studies for analysis: year of study, demographic data, cytotoxic and/or 92 genotoxic effect, waterpipe, and control group sizes. any discrepancies were resolved 93 by consensus. in the case of persistence, arbitration was performed by a third author 94 (y.s.s.). alteration such as micronuclei, pyknosis, karyorrhexis and karyolysis were 95 discussed. 96 4 to assess the studies’ quality, the risk of bias was assessed according to the quality 97 assessment tool for diagnosis accuracy studies (quadas-2) 13. the results were 98 used in review manager software 5.4 (review manager (revman) [computer 99 program]. version 5.4. copenhagen: the nordic cochrane centre, the cochrane 100 collaboration, 2014). results were considered statistically significant with a 95% 101 confidence interval. 102 103 the quadas-2 tool was assessed through risk of bias and risk of applicability across 104 studies to evaluate the following questions: (1) patient selection: description of patient 105 selection and inclusion; (2) index text: description of the index test, its conduction and 106 interpretation; (3) reference standard: description of the reference standard, its 107 conduction and interpretation; (4) flow and timing of ach included article: description 108 of the patient who did not receive the index test or reference standard and who were 109 excluded. 110 111 results 112 the first bibliographic search redeemed 346 records from databases. bvs have returned 113 no result. duplicates were removed, remaining 181 articles. after screen reading and 114 excluding paper unrelated to our search, 38 remained. reports from the same 115 authors/co-authors or same study center were excluded 14–19 as such reviews, comments, 116 letters, hypotheses, and expert opinions 3,20–26. two exclusive microbiological studies 117 were removed 27,28, same to animal studies 29,30. one study was not found 31. manual 118 search has retrieved no additional paper. the searched records distribution and the 119 number of studies finally selected are shown in the flow diagram (fig. 1). 120 121 the full text of all data sets viewed from the first round was independently checked for 122 the same reviewers’eligibility. a total of 20 articles were included in this review. 123 studies included authors, year of publication, demographic data, cytotoxic or genotoxic 124 evaluation, and the number of patients in waterpipe and control groups are in table 1. 125 126 three studies were in vitro 4,32,33, and biological samples were obtained from patients in 127 17 studies 8,31,33-37,39-48. in addition, the levels of pro-inflammatory cytokines, the 128 receptor activator of nuclear factor-κb (rankl), and osteoprotegerin were evaluated 129 34–36. 130 5 131 six studies investigated the genotoxic effect of waterpipe smoke 4,32,33,37–39. a comet 132 assay was performed in one study 33. cell line-based models were used to understand 133 the mechanisms of action of waterpipe smoke on oral cells 4,32. immortalized non-134 transformed normal human oral keratinocytes (okf6/tert1) chronically (eight 135 months) exposed to waterpipe smoke were developed by patil et al. 4. when phenotypic 136 alterations were studied, they revealed genomic anomalies in okf6/tert1-waterpipe 137 cells, with some overexpressed and some downregulated genes. in the other study that 138 developed a cell line-based model, two human normal oral epithelial were treated with 139 100g/l of waterpipe smoke solution for two days 32. when examined, both cells became 140 more elongated and showed decreased cell-cell contact compared to untreated ones. 141 this epithelial-mesenchymal transition was accompanied by the deregulation of a set of 142 genes related to oncogenesis 32. 143 144 on the other hand, eight studies evaluated nuclear changes in cytology samples from the 145 buccal mucosa of patients. some pathological assessments were performed, including 146 micronuclei (dna aggregates separate from the primary nucleus), karyorrhexis (nuclear 147 fragmentation), karyolysis (complete dissolution of nuclear components), pyknosis 148 (shrinkage or condensation of a cell), acanthosis (benign abnormal thickening of the 149 stratum spinosum), hyperparakeratosis (abnormal keratinization of the epidermal 150 stratum coreum), and epithelial dysplasia (architectural and cytological epithelial 151 changes). 152 153 the mean of micronuclei, cell nucleus perimeter, and area was contrasting in the ws 154 group compared to ns one 8,38–42. in addition, the mean percentages of karyorrhexis, 155 karyolysis, and pyknosis had substantial changes 43–45. other histopathologic changes 156 like acanthosis, hyperparakeratosis, and epithelial dysplasia were associated with 157 waterpipe use. an increased oral cancer incidence were related to different types of 158 tobacco use 46,47. 159 160 waterpipe smoke was associated with changes in dna methylation 37. in fact, about 161 64% of global dna methylation was detected in dna samples isolated from ws 162 compared to ns. in addition, promoter methylation of the mlh1 gene was observed in 163 the oral epithelium of the ws group 37. 164 6 the tumor suppressor protein p53 mutations were also associated with waterpipe use 165 48,49. this alteration could lead to apoptosis, suppression of the cell cycle, senescence, 166 differentiation, and dna repair 48. 167 168 a meta-analysis was carried out with revman 5.4. a forest plot created only with 169 revman was possible with different levels of variation. this happened because articles 170 use different cells to assess cytotoxicity and genotoxicity in different ways (fig.2). of 171 the 20 articles included, nine rated genotoxicity and 11 rated cytotoxicity. the evidence 172 on literature is that waterpipe smoke causes several cytotoxic and genotoxic effects on 173 oral cells with a risk difference (rd) of 0.16 (95% ci 0.09-0.23, p < 0.00001). 174 175 the graph for the risk of bias (fig. 3) was created with revman 5.4 using the 176 quadas-2 protocol. the high quality of the items can be seen in this picture. articles 177 come from all over the world, mainly from the middle east (13), three multicentre 178 studies, two from africa and one each from europe and south america. this can be 179 explained by the higher and more frequent consumption of waterpipe in the middle 180 east. 181 182 discussion 183 although waterpipe use is a world-spread epidemic, several included studies are 184 possible to note a colossal concern in middle east countries where waterpipe is smoke 185 is very usual 32,40,48. 186 187 waterpipe smoke condensate reveals many organic compounds like nicotine, tar, heavy 188 metals, polycyclic aromatic hydrocarbons (naphthalene, phenanthrene, fluoranthene), 189 aldehydes (5-hydroxymethyl-5-furancarboxaldehyde, 3-ethoxy-4-190 hydroxybenzaldehyde), moreover carbon monoxide, well-known substances for their 191 genotoxic and carcinogenic properties 33,40,43. formaldehyde was detected in waterpipe 192 five times higher than in one 2r4f cigarette 33. a 2r4f cigarette is a standard reference 193 cigarette. the tobacco industry and academic laboratories uses this reference to 194 standardize test items and inhalation toxicity research. 195 196 high values for all critical comet assay parameters (a sensitive technique for dna 197 damage detection) in buccal cells were found, suggesting waterpipe use is composed of 198 7 dna-damaging ingredients 32,33,37,38,44. for example, dna methylation could reach 199 increases of 64% 37; samples with 10% methylation are considered significantly 200 methylated. 201 202 one technique to evaluate the impact of environmental factors on genetic stability is the 203 investigation of micronucleus, products of early events in human carcinogenic 204 processes, especially on the oral cavity; it is considered a biomarker of genotoxicity 41. 205 total micronuclei (tmn) and cells with micronuclei (cmn) were significantly higher 206 among waterpipe users than never smokers and very similar to cigarette-smokers 8,41,49. 207 furthermore, there was no association between tmn and cmn with lifetime duration 208 of use, time to first waterpipe smoke of the day, and the number of hagars per day or 209 week 8. waterpipe use was also related to chromosomal aberrations 33 and enhanced 210 level of micronuclei 8,33,38–41. 211 212 in waterpipe smoke mixtures, mutagenic and genotoxic contaminants are present on low 213 levels, but they are challenging to be detected since a few components are in high 214 concentrations 33. in addition, genotoxicity is not related to a specific compound but a 215 set of properties and chemical interactions of the sample as a whole 33. waterpipe use is 216 related to genomic and gene expression alterations, both rna 4,32 and dna 33,37,44. 217 218 waterpipe use increased the risk of histopathologic changes, including acanthosis, 219 epithelial dysplasia, hyperparakeratosis, and the development of abnormal rete ridges 46. 220 acanthosis and epithelial dysplasia in ws were similar to cigarette-smokers (cs) 46. 221 cytomorphometric quantitative analysis showed higher values for waterpipe users than 222 in ns, including nuclear and cell perimeter, cytoplasm size, cell area, nuclear-223 cytoplasmic ratio, and relation big diameter of nucleus/small diameter of nucleus ratio 224 42,45 besides induction of heterochromatinization of cell nuclei, a situation caused by 225 different stress factors 42,44. there is an increase in many multinucleated cells, pyknosis, 226 karyorrhexis, karyolysis than in ns 38,39,43–45 and slightly higher than in cs 38,43. higher 227 incidence of vacuolization of cytoplasm concerning ns and even cs 45. malignant and 228 pre-malignant lesions have a nuclear-cytoplasmic ratio increase. 229 230 pro-inflammatory cytokine levels (interleukin-1β, interleukin-6, interleukin-3, and 231 tumor necrosis factor-α) were statistically higher among waterpipe-users when 232 8 compared to ns and similar to another kind of tobacco users 32,34–36. cell necrosis and 233 apoptosis have a higher relation to carcinomas. 234 235 protein p53 expression has a relation to regulation of apoptosis and genomic stability, a 236 crucial role in tumor suppression, named “guardian of the genome”. ws have a 237 significantly higher p53 mutation than non-smokers 48,49 in samples with malignant, pre-238 malignant, or even normal oral epithelium. this correlation is similar to cs group 49. in 239 addition, the repair index of oral mucosa cells of ws is significantly lower than in ns 240 39. it must be said that the cytotoxic effects of waterpipe are more correlated to time 241 exposure than cigarette smoking 50. 242 243 there is no peak incidence in oral cancer on ws regarding age or gender 43,47 although 244 few papers included female samples due to oral mucosa alterations concern hormonal 245 changes, and waterpipe use is much more common in male than female 45,46. 246 247 waterpipe and cigarette users had similar effects on oral mucosa 42,43,46, including a 248 substantial association increase with oral squamous cell carcinoma (oscc) 249 development 37,43,47–49. the combination between waterpipe and shammah (arabian 250 snuff) or waterpipe and cigarettes led to a higher incidence of oral cancer than just one 251 kind of tobacco use 47,49. the use of waterpipe has more unfavorable effects than 252 smoking cigarettes 38,42. waterpipe and shammah combined use increased the risk of 253 developing oscc by nearly 35 times 47. khat chewing did not show significant impact 254 on the development of oral cancer 47 . however, when associated with waterpipe use, 255 there was an increase of the risk 46. the cytotoxic effect of waterpipe smoke is more 256 correlated to time exposure than cigarette smoking 41,43,44. 257 258 in addition to more restrictive legislation and interventional policy aspects, tobacco 259 cessation programs must be a priority in some regions, consisting of education, 260 psychological therapy, and pharmacological aid 47 especially for young 40,44,48, who 261 believe waterpipe use is a safe addict. 262 263 9 conclusions 264 waterpipe use is genotoxic and cytotoxic with a risk difference of 0.16 (p< 0.05). it 265 seems to increase the incidence of oral cancer, contrary to popular belief. furthermore, 266 its carcinogenicity is similar to cigarette smoke. 267 268 conflict of interest 269 no conflict to disclose 270 271 funding 272 this research did not receive any specific grant from funding agencies in the public, 273 commercial, or not-for-profit sectors. 274 275 authors’ contribution 276 rg was involved in conceptualization, design, data collect and analysis and drafting the 277 manuscript. mk and yss contributed to the design, data collect and analysis and 278 drafting the manuscript. all authors approved the final version of the manuscript. 279 280 references 281 1. jawad m, charide r, waziry r, darzi a, ballout ra, akl ea. the prevalence and 282 trends of waterpipe tobacco smoking: a systematic review. plos one. 283 2018;13(2):e0192191. 284 2. bou fakhreddine hm, kanj an, kanj na. the growing epidemic of water pipe 285 smoking: health effects and future needs. respir med. 2014;108(9):1241–53. 286 3. souza acf, galvani mg, de souza dv, ribeiro da. cytogenetic biomonitoring on 287 oral mucosa cells of hookah users: is it possible? asian pacific j cancer prev. 288 2020 jul 1;21(7):1849–1849. 289 4. patil s, patel k, advani j, subbannayya t, rajagopalan p, babu n, et al. multiomic 290 analysis of oral keratinocytes chronically exposed to shisha. j oral pathol med. 291 2019;48(4):284–9. 292 5. walters ms, salit j, ju jh, staudt mr, kaner rj, rogalski am, et al. waterpipe 293 smoking induces epigenetic changes in the small airway epithelium. plos one. 294 2017;12(3):e0171112. 295 6. ringh m v., hagemann-jensen m, needhamsen m, kular l, breeze ce, sjöholm 296 lk, et al. tobacco smoking induces changes in true dna methylation, 297 10 hydroxymethylation and gene expression in bronchoalveolar lavage cells. 298 ebiomedicine. 2019;46:290–304. 299 7. szyf m, pakneshan p, rabbani sa. dna methylation and breast cancer. in: 300 biochemical pharmacology. 2004. p. 1187–97. 301 8. el-setouhy m, loffredo ca, radwan g, rahman ra, mahfouz e, israel e, et al. 302 genotoxic effects of waterpipe smoking on the buccal mucosa cells. mutat res 303 genet toxicol environ mutagen. 2008;695(1–2):36–40. 304 9. kamboj m, mahajan s. micronucleus an upcoming marker of genotoxic damage. 305 clin oral investig. 2007;11(2):121–6. 306 10. maziak w. the waterpipe: an emerging global risk for cancer. cancer epidemiol. 307 2013;37(1):1–4. 308 11. mulrow cd. rationale for systematic reviews. bmj. 1994;309(6954):597–9. 309 12. moher d, liberati a, tetzlaff j, altman dg, altman d, antes g, et al. preferred 310 reporting items for systematic reviews and meta-analyses: the prisma 311 statement. plos med. 2009;6(7):e10000097. 312 13. whiting pf, rutjes aws, westwood me, mallett s, deeks jj, reitsma jb, et al. 313 quadas-2: a revised tool for the quality assessment of diagnostic accuracy 314 studies. ann intern med. 2011;155(8):529–36. 315 14. patil s, babu n, subbannayya t, mohan s v., sathe g, solanki hs, et al. 316 secretome analysis of oral keratinocytes chronically exposed to shisha. cancer 317 biomarkers. 2019;25(1):29–41. 318 15. patil s, rajagopalan p, patel k, subbannayya t, babu n, mohan s v., et al. 319 chronic shisha exposure alters phosphoproteome of oral keratinocytes. j cell 320 commun signal. 2019;13(3):281–9. 321 16. patil s, subbannayya t, mohan s v., babu n, advani j, sathe g, et al. proteomic 322 changes in oral keratinocytes chronically exposed to shisha (water pipe). omi 323 a j integr biol. 2019;23(2):86–97. 324 17. dehghannezhad m, jalayer naderi n, semyari h, naderi nj, semyari h. 325 micronucleus assay of buccal mucosa cells in waterpipe (hookah) smokers: a 326 cytologic study. iran j pathol. 2020;15(2):75–80. 327 18. ibraheem wi, fageeh hi, preethanath rs, alzahrani fa, al-zawawi as, divakar 328 dd, et al. comparison of rankl and osteoprotegerin levels in the gingival 329 crevicular fluid of young cigaretteand waterpipe-smokers and individuals using 330 electronic nicotine delivery systems. arch oral biol. 2020;115:104714. 331 11 19. patil s, awan kh, arakeri g, aljabab a, ferrari m, gomes cc, et al. the 332 relationship of “shisha” (water pipe) smoking to the risk of head and neck cancer. 333 j oral pathol med. 2019 apr 1;48(4):278–83. 334 20. chaouachi k. micronuclei and shisha/goza smoking in egypt. mutat res genet 335 toxicol environ mutagen. 2009;675(1–2):81–2. 336 21. yakin m, gavidi ro, cox b ra. oral cancer risk factors in new zealand. n z med 337 j. 2017;130(1451):30–8. 338 22. dar na. narghile smoking is associated with the development of oral cancer at 339 early age. j evid based dent pract. 2015 sep 1;15(3):126–7. 340 23. warnakulasuriya s. waterpipe smoking, oral cancer and other oral health effects. 341 evid based dent. 2011;12(2):44–5. 342 24. albeitawi s, hamadneh j, al-shatanawi tn, al mehaisen l, al-zubi m. effect of 343 hookah (water pipe) smoking on semen parameters. andrologia. 2020 nov 344 1;52(10):e13723. 345 25. chaouachi k, sajid km. a critique of recent hypotheses on oral (and lung) cancer 346 induced by water pipe (hookah, shisha, narghile) tobacco smoking. med 347 hypotheses. 2010;74(5):843–6. 348 26. rastam s, li fm, fouad fm, kamal hma, akil n, moustafa ae al. water pipe 349 smoking and human oral cancers. med hypotheses. 2010;74(3):457–9. 350 27. shakhatreh mak, khabour of, alzoubi kh, masadeh mm, hussein ei, bshara 351 gn. alterations in oral microbial flora induced by waterpipe tobacco smoking. 352 int j gen med. 2018;11:47–54. 353 28. vallès y, inman ck, peters ba, ali r, wareth la, abdulle a, et al. types of 354 tobacco consumption and the oral microbiome in the united arab emirates 355 healthy future (uaehfs) pilot study. sci rep. 2018;8(1):11327. 356 29. nemmar a, al-salam s, beegam s, yuvaraju p, oulhaj a, ali bh. water-pipe 357 smoke exposure-induced circulatory disturbances in mice, and the influence of 358 betaine supplementation thereon. cell physiol biochem. 2017;41(3):1098–112. 359 30. imran s, shan m, muazam s. a comparative histological study of submucosal gland 360 hypertrophy in trachea of mice exposed to cigarette and shisha smoke. j coll 361 physicians surg pakistan. 2018 mar 1;28(3):192–5. 362 31. babu n, patil s, mohan s v., subbannayya t, advani j, datta kk, et al. signaling 363 alterations in oral keratinocytes in response to shisha and crude tobacco extract. j 364 oral pathol med. 2020; 50(5):459-469. 365 12 32. lópez-ozuna vm, gupta i, kiow rlc, matanes e, kheraldine h, yasmeen a, et 366 al. water-pipe smoking exposure deregulates a set of genes associated with 367 human head and neck cancer development and prognosis. toxics. 2020;8(3):73. 368 33. al-amrah hja, aboznada oa, alam mz, elassouli mzm, mujallid mi, elassouli 369 sm. genotoxicity of waterpipe smoke in buccal cells and peripheral blood 370 leukocytes as determined by comet assay. inhal toxicol. 2014 dec 1;26(14):891–371 6. 372 34. alqahtani ma, alayad as, alshihri a, correa fob, akram z. clinical peri-373 implant parameters and inflammatory cytokine profile among smokers of 374 cigarette, e-cigarette, and waterpipe. clin implant dent relat res. 2018 dec 375 1;20(6):1016–21. 376 35. abduljabbar t, akram z, vohra f, warnakulasuriya s, javed f. assessment of 377 interleukin-1β, interleukin-6, and tumor necrosis factor-α levels in the peri-378 implant sulcular fluid among waterpipe (narghile) smokers and never-smokers 379 with peri-implantitis. clin implant dent relat res. 2018;20(2):144–50. 380 36. mokeem sa, alasqah mn, michelogiannakis d, al-kheraif aa, romanos ge, 381 javed f. clinical and radiographic periodontal status and whole salivary cotinine, 382 il-1β and il-6 levels in cigaretteand waterpipe-smokers and e-cig users. 383 environ toxicol pharmacol. 2018 jul 1;61:38–43. 384 37. sabi sh, khabour of, alzoubi kh, cobb co, eissenberg t. changes at global and 385 site-specific dna methylation of mlh1 gene promoter induced by waterpipe 386 smoking in blood lymphocytes and oral epithelial cells. inhal toxicol. 2020 feb 387 23;32(3):124–30. 388 38. rajabi-moghaddam m, haji mirzamohammad m, yahyazadeh e, gholinia h, 389 abbaszadeh h. comparison of genotoxic effect in buccal exfoliated cells 390 between cigarette and waterpipe smokers. acta cytol. 2020;64(5):471–6. 391 39. taghibakhsh m, farhadi s, babaee a, sheikhi m. the effect of hookah use on 392 buccal mucosa: evaluation of repair index. asian pacific j cancer prev. 393 2019;20(4):1109–12. 394 40. eker ed, koyuncu h, şahin nö, yüksel a, berköz m, diler sb, et al. 395 determination of genotoxic effects of hookah smoking by micronucleus and 396 chromosome aberration methods. med sci monit. 2016;22:4490–4. 397 41. prasad p, hamed ms, nahar p. micronucleus assay in waterpipe tobacco and 398 cigarette smokers: a comparative study pubmed. j contem dent pr. 399 13 2019;20(1):101–7. 400 42. volkova o, ryabokon e, magda i, shckorbatov y. impact of smoking habits on the 401 state of chromatin and morphology of buccal epithelial cells among medical 402 students. georgian med news. 2017 jan 1;(262):111–5. 403 43. naderi nj, pasha mp. comparison of cytotoxic effect of cigarette and waterpipe 404 smoking on human buccal mucosa. int j prev med. 2017;8:98. 405 44. silveira mad, antonelli as, fiorelli bo, d’arce lpg. cytological multimarker 406 screening using bmcyt test in waterpipe smokers: an integrative study of cell 407 damage, toxicological and cancer risk. j genet. 2018 jun 1;97(2):399–404. 408 45. seifi s, feizi f, mehdizadeh m, khafri s, ahmadi b. evaluation of cytological 409 alterations of oral mucosa in smokers and waterpipe users. cell j. 410 2014;15(4):302–9. 411 46. ali aa. histopathologic changes in oral mucosa of yemenis addicted to water-pipe 412 and cigarette smoking in addition to takhzeen al-qat. oral surgery, oral med 413 oral pathol oral radiol endodontology. 2007;103(3):e55-9. 414 47. alharbi f, quadri mfa. individual and integrated effects of potential risk factors 415 for oral squamous cell carcinoma: a hospital-based casecontrol study in jazan, 416 saudi arabia. asian pacific j cancer prev. 2018 mar 1;19(3):791–6. 417 48. zaid k, azar-maalouf e, barakat c, chantiri m. p53 overexpression in oral 418 mucosa in relation to shisha smoking in syria and lebanon. asian pacific j 419 cancer prev. 2018 jul 1;19(7):1879–82. 420 49. amer hw, waguih hm, el-rouby dh. development of field cancerization in the 421 clinically normal oral mucosa of shisha smokers. int j dent hyg. 2019;17(1):39–422 45. 423 50. who study group on tobacco product regulation (tobreg). waterpipe tobacco 424 smoking: health effects, research needs and recommended actions for regulators. 425 geneva; 2015. 426 427 14 table 1: included studies in chronological order 428 author year locality (country) cytotoxic/ genotoxic waterpipe group control group ali 46 2007 (yemen) cytotoxic 11 11 el-setouhy et al. 8 2008 cairo (egypt) genotoxic 128 78 al-amrah et al. 33 2014 jeddah (saudi arabia) genotoxic 20 0 seifi et al. 45 2014 babol (iran) cytotoxic 40 40 eker et al. 40 2016 mersin (turkey) genotoxic 30 30 naderi, pasha 43 2017 tehran (iran) cytotoxic 25 25 volkova et al. 42 2017 krakiv (ukraine) cytotoxic 13 38 abduljabbar et al. 35 2018 riyadh (saudi arabia) cytotoxic 41 44 alharbi et al. 47 2018 jazan (saudi arabia) cytotoxic 70 140 alqahtani et al. 34 2018 multicenter cytotoxic 40 40 mokeem et al. 36 2018 riyadh (saudi arabia) cytotoxic 40 38 silveira et al. 44 2018 cascavel (brazil) genotoxic 40 40 zaid et al. 48 2018 syria (lebanon) cytotoxic 52 53 amer et al. 49 2019 cairo (egypt) cytotoxic 16 16 patil et al. 4 2019 multicenter genotoxic prasad et al. 41 2019 ajman (united arab emirates) genotoxic 100 100 taghibakhsh et al. 39 2019 tehran (iran) cytotoxic 36 36 lópez-ozuna et al. 32 2020 multicenter genotoxic rajabi-moghaddam et al. 38 2020 birjand (iran) genotoxic 30 30 sabi et al. 37 2020 irbid (jordan) genotoxic 150 150 429 15 430 figure 1: flow diagram of included articles. 431 432 16 433 figure 2: forest plot generated through revman 5.4 434 17 435 436 figure 3: risk of bias graph generated through revman 5.4 437 438 fundamentals of psychology author: michael w eysenck publisher: psychology press, taylor & francis group isbn: 978-1-84169-372-9 orders: www.psypress.com squ med j, august 2009, vol. 9, iss. 2, pp. 201-202, epub 30th june 2009 received 26th may 09 i sometimes wonder what the british poet, alexander pope, had in mind when he famously improvised “drink deep, or taste not the pierian spring: there shallow draughts intoxicate the brain, and drinking largely sobers us again”. in our original sin of ignorance, what would be the magic formula to sober us again? some would say that psychology is a field that is inherently endowed with this talent and that it is the only field of inquiry that leads us to introspective thinking which, in the present parlance, constitutes an important catalyst to sober us again from shallow draughts. by this do we mean the psycho-babble that often comes into our homes via oprah winfrey chat shows? no, i mean the volume entitled fundamental psychology. yes, there are many books on this topic; some would say every tom, dick and harry has churned out similar textbooks. check out amazon.com or any bookshop and you will find more psychobabble than books on any other topic. the shelves are filled with ‘self-help’ books or the success story of a businessman which, given today’s economic recession, will utterly fail to entice us. in contrast by all standards, this volume, fundamentals of psychology, has all the essential ingredients to sober us again. despite its huge size, multitude of images, and texts from self-quizzes to the eloquent summaries at the end of each of the 25 chapters, the book is easy to read and follow. the glossary and references as well as the author and subject indexes are meticulously arranged by the writer, michael w. eysenck, a renowned psychologist at the university of london, uk. the volume is divided into seven interesting themes. in sync with the modern focus on neurogenetic determinism, the first section deals with the biological basis of psychology which is preceded by a general introduction on the development of different scientific paradigms under the umbrella of psychology. as psychology is increasingly losing its central tenet of studying the ‘soul’, the second part of this volume focuses on cognitive psychology with an introduction and subsections on perception and human memory. in other words, the soul is alive and kicking but now it appears in scientific metaphor. if such cognitive psychology is too abstract for you, then please turn to the next section. here you will find vivid scientific descriptions of mundane issues such as intelligence and personality. in case you prefer the scientific counterpart of wordsworth’s euphemism that “the child is father to the man”, there is a section covering developmental psychology. this section features topics from cognitive development to the indispensible role of attachment. then if you are a sentimental type liking john donne’s notion that ‘no man is an island’, you will be enticed by the section covering social psychology. psychology cannot be complete unless there is a forum for pondering what constitutes the ‘normal’ and ‘abnormal’ repertoire of human behaviour. in favour of simplicity, yet without compromising the complexity of the issue, the topic of psychiatric nosology is therefore presented. the volume is completed by an introduction to research methods. as the title suggests, the volume is meant to be an introduction to the science of psychology. the book will be appropriate for undergraduate programmes, either for psychology majors or minors, from business to decision-making sciences. besides أساسيات علم النفس تأليف: مايكل أيسنيك book review fundamentals of psychology 202 | squ medical journal, august 2009, volume 9, issue 2 being a general introductory textbook, some of the chapters of this volume will fit well into the much heralded integrative curriculum in medical schools, for example the coverage of health psychology. the author has done an outstanding job in tackling complex issues derived from cutting-edge research and yet made them palatable and accessible to all. this has been done without compromising the central tenet of the new frontiers of psychological sciences. in the age of -ism and schism, paradigm and paradigm shift, the author has handled all the divergent conceptual frameworks evenhandedly from the most controversial to the most mundane. breaking away from the north american tradition, the book has laboriously attempted to bring out the cultural factors in human beings. this is an important inclusion since 80% of the world population lives outside the euro-american setting. from this perspective, students will find that this volume rings a bell with their own cultural issues. one may wonder why the author has not included more topics since everything has an element of psychology. however, he has careful chosen themes in psychology that have undergone full scientific scrutiny. many other topics are indeed interesting, but since their development is still in infancy, the author has carefully avoided producing chapters of psychobabble. if alexander pope were alive today, he might well judge that this textbook has some draughts to sober us again. had i had such a book when i was young, maybe my life would have taken another route. in the interim, i have a copy of this textbook on my bookshelf. whenever i look at it, i wonder why such treasure cannot be accessed by all. r e v i e w e r samir al-adawi department of behavioural medicine college of medicine & health sciences sultan qaboos university muscat, sultanate of oman. email: adawi@squ.edu.om submitted 25 nov 21 1 revision req. 26 jan 22; revision recd. 6 mar 22 2 accepted 15 mar 22 3 online-first: april 2022 4 doi: https://doi.org/10.18295/squmj.4.2022.033 5 6 first report of a derivative chromosome 13 with a duplicated 11p15 locus 7 associated with silver-russell syndrome 8 *nishath hamza, musallam al-araimi, kamla al salmani, salwa al 9 obeidani 10 11 national genetic centre, royal hospital, ministry of health, muscat, oman 12 *corresponding author’s e-mail: nishath.h@moh.gov.om 13 14 abstract 15 silver-russell syndrome (srs) is a disorder that is primarily characterized by intrauterine 16 growth restriction which may occur asymmetrically or in whole, leading to a fetus being small 17 relative to its gestational age. we present a female infant (proband), with severe congenital 18 anomalies. the proband carried a >25mb duplication of the chromosomal 11p15-11pter locus of 19 chromosome 13; creating a derivative chromosome 13 [der(13)] and was reported as 20 46,xx,der(13)add(11p15-11pter). a methylation-sensitive assay confirmed a diagnosis of 21 silver-russell syndrome (srs). although the prognosis for srs patients is generally good, our 22 proband presented with a clinically severe phenotype culminating in death at nine months. to the 23 best of our knowledge, this is the first report of a derivative chromosome 13 with a duplicated 24 11p15 locus being reported in a patient with srs. 25 keywords: silver-russell syndrome, growth retardation, imprinting, derivative chromosome. 26 27 mailto:nishath.h@moh.gov.om introduction 28 silver-russell syndrome (srs) is a disorder that is primarily characterized by intrauterine 29 growth restriction which may occur asymmetrically or in whole, leading to a fetus being small 30 relative to its gestational age. individuals are diagnosed with srs when they present with growth 31 restriction, relative macrocephaly at birth (head circumference ≥1.5 sd above birth weight 32 and/or length), prominent forehead usually with frontal bossing, triangular facies,micrognathia 33 and feeding difficulties.1,2 rarely, srs patients may also exhibit fifth-finger clinodactyly.1 34 35 srs is one of twelve imprinting disorders which are caused by epigenetic (methylation) or 36 genetic abnormalities. among srs patients, 35%-50% of cases are due to loss of paternal allele 37 methylation (lom) at the imprinted control region 1 (icr1) at 11p15.5 and 7%-10% are due to 38 maternal uniparental disomy (upd) of chromosome 7.3,4 in rare cases, somatic mosaicism for 39 maternal upd(11), duplication of the maternal 11p15.5, inversions and translocations affecting 40 chromosome 11, as well as maternal upd of chromosomes 14, 16 and 20 have also been 41 reported.5 in addition to epigenetic and copy number variants (cnvs), mutations in certain genes 42 have also been reported to cause srs. for example, maternal transmission of gain-of-function 43 mutations in the cdkn1c gene3 or paternal transmission of loss-of-function mutations in the 44 igf2 gene4 has been described in association with srs. also, genes which are upstream 45 regulators of igf2 such as hmga2 or plag1 are also associated with srs.4 46 47 case report 48 our proband was a female infant born in 2018 at a tertiary hospital in muscat, oman. she 49 presented with multiple anomalies such as intrauterine growth restriction, macrocephaly, broad 50 fontanelle, feeding difficulty, low set ears and failure to thrive without ventilator support (figure 51 1a). the proband was born to unrelated parents (family pedigree shown in figure 1b). a history 52 of miscarriage at six weeks of pregnancy in the proband’s mother prompted the special care 53 baby unit (scbu) physician at the referral hospital to request cytogenetic studies in the proband 54 and her parents. informed consent was obtained from the proband’s parents prior to the referral 55 for genetic studies. peripheral blood samples were obtained from the patient and her parents in 56 both heparin and edta tubes. the proband was referred to our genetic clinic a few days after 57 her birth. however, the infant was in a critical condition and remained in the scbu on ventilator 58 until her death at the age of nine months. as a result, a direct clinical assessment of the proband 59 could not be carried out by our genetic clinic. instead, a description of patient phenotype was 60 communicated to our clinical geneticist by the referring physician over phone. 61 62 chromosomal karyotyping of the proband yielded an abnormal karyotype with a large 63 heterozygous additional chromosomal region on the p-arm of chromosome 13. genomic dna 64 was extracted from the whole blood of the proband and used to perform array-based comparative 65 genomic hybridization (cgh) with the affymetrix cytoscan hd kit (thermo fisher scientific, 66 usa). array cgh data analysis using the chas software v.3.1.0.15 revealed a heterozygous 67 25,109kbp (~25 mb) duplication of the 11p15-11pter chromosomal locus (hg19:chr11:230,615-68 2,339,766). hence the karyotype (figure 2a) was reported as 46,xx,der(13)add(11p15-11pter). 69 to the best of our knowledge, this is the first report of a derivative chromosome 13 with a 70 duplicated 11p15 locus being reported in a patient with srs. 71 72 given the clinical feature of growth restriction in the proband, the involvement of the 11p locus 73 warranted further testing due to its association with srs. a methylation-sensitive multiplex 74 ligation-dependent probe amplification (ms-mlpa) assay6 was conducted on the dna from 75 the proband using the me030 (lot no:c3-0219) kit from mrc holland (the netherlands). this 76 kit is a multi-disease assay which tests the 11p15 locus for both bws and rss, as well as the 77 5q35.3 locus (nsd1 gene) for sotos syndrome. the assay samples were then run on the genome 78 analyzer abi 3700 and the data generated was analyzed using the coffalyser (v.210604.1451). 79 the ms-mlpa data (figure 2b) confirmed the duplication of the 11p15 locus, but also revealed 80 lom at the icr1. 81 82 meanwhile, karyotyping both parents of the proband revealed that the der(13) chromosome 83 observed in the patient was maternally inherited (figure 3). hence, the diagnosis of srs due to 84 maternal 11p duplication was established in the proband. 85 86 the 25 years old mother (figure 1, ii.3) of the proband was found to be a carrier of a 87 heterozygous balanced non-reciprocal translocation between chromosome 11 and 13: 88 46,xx,der(13)t(11;13)(p11;p12). this phenotypically normal, but genotypically abnormal 89 karyotype (figure 3) was characterized by one of the chromosomes 13 having an additional 90 translocated 11p15-11pter region on its p-arm creating the der(13) chromosome, and one of the 91 chromosomes 11 lacking the region from 11p15-11pter. the father of the proband was observed 92 to have a normal male karyotype. 93 94 the parents of the proband had not been amenable to an appointment at our clinic while their 95 child was in the scbu. after the death of the proband, the parents met with our genetic 96 counselor and the implications of the karyotype and ms-mlpa results were explained to them. 97 during genetic counseling of the proband’s parents, it transpired that there was a family history 98 of miscarriages reported in the 52 years old maternal grandmother (figure 1b, i.1) and a 30 years 99 old maternal aunt of the proband (figure 1b, ii.1). fertility problems were also reported in a 100 maternal 28 years old uncle (figure 1b, ii.2) of the patient who had a single offspring after 101 treatment for infertility. the maternal grandmother of our proband, i.1 was unable to recall the 102 number of miscarriages she underwent. these individuals were then invited for genetic 103 counseling and offered karyotyping after informed consent. all three tested family members 104 carried karyotypes identical to the proband’s mother (balanced non-reciprocal translocation; 105 figure 3). another 19 years old maternal uncle of the proband was reported to be diagnosed with 106 unilateral kidney disease (figure 1b, ii.). however, this individual was not willing to undergo 107 genetic counseling or testing. 108 109 informed consent for testing and publication of anonymized data was collected from all 110 patients/guardians involved in this study and appropriate ethical standards were employed in all 111 procedures. 112 113 discussion 114 this is the first report of a case where srs is associated with a derivative chromosome 13 115 carrying a duplicated 11p arm. in light of the fact that translocation events involving 116 chromosome 11p and chromosome 13 have never been reported before except in oncology 117 patients, this finding is quite novel. the der(13) chromosome in the proband, resulted in an extra 118 copy of the maternal 11p12 to 11pter region within the karyotype, with no apparent loss of 119 chromosome 13 regions according to array cgh analysis the der(13) chromosome was 120 transmitted through at least three generations of a family. 121 122 although rare, maternal duplications of 11p12-11pter which include the 11p15 locus, are 123 estimated to cause the associated srs phenotype in <1% of srs patients.7 the cases of maternal 124 11p15 duplications reported previously were mostly interstitial duplication events with or 125 without inversions, encompassing the 11p15 locus8 or rarely, due to unbalanced translocations 126 between chromosome 11 and chromosomes 4, 9, 10, 15, 16 and 17.9-13 while most of these 127 rearrangements involved icr1; duplications of the whole icr2 as well as partial duplication of 128 icr1 were also rarely reported in association with srs. however, in all of these cases, the 129 patients survived much longer than our patient, albeit with varying degrees of prognosis7-15. 130 131 srs patients generally have a good prognosis and can live well into adulthood with occasional 132 complications.14 however, the severity of clinical presentation in srs patients with copy number 133 variants (cnv) appears to be dependent on the extent of 11p locus involved in the cnv.7,14 this 134 is evident in our patient who was unable to survive independently outside of the scbu facility 135 because the ~25mb duplicated maternal allele in our proband covered almost the entire 11p15.5 136 band, which included both the icr1 and icr2 regions and was bigger than the majority of the 137 previously reported cnvs involving the 11p15 locus.7-15 this was accompanied by 138 hypomethylation of the h19 gene. hence, the classic srs phenotype of growth restriction in the 139 proband likely reflects an increased expression of the maternally expressed h19 gene and 140 consequent down-regulation of the igf2 gene expression.9-11 141 142 in the case of maternal inheritance, duplication of the 11p15 locus causes the srs phenotype, 143 whereas a paternally inherited similar duplication would cause the beckwith wiedemann 144 syndrome (bws) phenotype. no instances of bws were seen within our proband’s family, 145 especially since most of the carriers of the der(13) chromosome detected in this family were 146 females. the maximum likelihood of paternal transmission of the der(13) chromosome and risk 147 for bws is from the maternal uncle (figure 1, ii.2) of the proband, who has one normal 148 offspring. 149 150 a key point to be noted in this case is that patients suspected with srs are usually subjected to 151 molecular genetic tests which can characterize either methylation abnormalities or copy number 152 variants (cnvs) or both; but not chromosomal translocations. however, the clinically severe 153 presentation in our proband and the history of miscarriage in the proband’s mother had prompted 154 a referral for cytogenetic studies. this was key to the der(13) translocation-derivative 155 chromosome being detected in multiple members of the family and the provision of accurate 156 genetic counseling to other members of the family who had a history of miscarriages and 157 infertility. the affected couples in the proband’s extended family had not suspected a hereditary 158 component to their history of reproductive failures prior to our proband being tested. 159 160 the parents of the proband were counseled regarding future risk for affected offspring. however, 161 the mother refused to consider prenatal genetic testing combined with in-vitro fertilization as a 162 reproductive option, since abortion is generally prohibited in oman (with medical exceptions). 163 the mother decided to have future pregnancies monitored using first trimester ultrasonographic 164 diagnosis. 165 166 conclusions 167 although maternal duplications due to 11p15 translocation events are rare, they must be 168 suspected in patients with srs phenotype who also present with severe failure to thrive. offering 169 genetic testing to the parents of affected patients may help prevent further recurrences of affected 170 offspring. determining whether a duplication event is due to the transmission of translocated 171 chromosomes, or due to interstitial duplications or inversions, is also crucial as individuals who 172 carry translocations are at significantly higher risk for infertility, recurrent miscarriages and birth 173 of offspring with moderate to severe disease phenotypes. 174 175 data availability statement 176 data generated in this study is the sole property of the royal hospital, ministry of health, 177 oman. as such, any release of data from this study, outside of journal publications or scientific 178 abstracts, is subject to prior approval of the scientific research committee, royal hospital, 179 oman. 180 181 authors’ contribution 182 nh carried out molecular genetics analyses and wrote the manuscript; ma conducted clinical 183 sampling; patient counseling and manuscript review; ks carried out cytogenetic analyses and 184 manuscript review and so conducted patient counseling and manuscript review. all authors 185 approved the final version of the manuscript. 186 187 acknowledgements 188 the authors acknowledge the work of the cytogenetic and molecular genetics staff at the 189 national genetic center who carried out routine diagnostic processing of the patient samples 190 studied in this report. 191 192 references 193 1) netchine i, rossignol s, dufourg mn, azzi s, rousseau a, perin l, et al. 11p15 194 imprinting center region 1 loss of methylation is a common and specific cause of typical 195 russell-silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. 196 j clin endocrinol metab. 2007;92:3148-54. doi: 10.1210/jc.2007-0354. 197 2) patti g, giaccardi m, capra v, napoli f, cangemi g, notarnicola s, guzzetti s, russo 198 s, maghnie m, di iorgi n. clinical manifestations and metabolic outcomes of seven 199 adults with silver-russell syndrome. j clin endocrinol metab. 2018;103:2225-2233. 200 doi: 10.1210/jc.2017-02589. 201 3) brioude f, oliver-petit i, blaise a, praz f, rossignol s, le jule m, et al. cdkn1c 202 mutation affecting the pcna-binding domain as a cause of familial russell silver 203 syndrome. j med genet. 2013;50:823–30. doi: 10.1136/jmedgenet-2013-101691 204 4) abi habib w, brioude f, edouard t, bennett jt, lienhardt-roussie a, tixier f, et al. 205 genetic disruption of the oncogenic hmga2-plag1-igf2 pathway causes fetal growth 206 restriction. genet med. 2018;20:250–8. doi: 10.1038/gim.2017.105. 207 5) eggermann t, spengler s, bachmann n, baudis m, mau-holzmann ua & singer s et al. 208 chromosome 11p15 duplication in silver-russell syndrome due to a maternally inherited 209 translocation t(11;15). am j med genet. 2010; 152:1484–1487. 210 doi:10.1002/ajmg.a.33398. 211 6) jeuken jw, cornelissen sj, vriezen m, dekkers mm, errami a, sijben a, boots-212 sprenger sh, wesseling p. ms-mlpa: an attractive alternative laboratory assay for 213 robust, reliable, and semiquantitative detection of mgmt promoter hypermethylation in 214 gliomas. lab invest. 2007; 87:1055-65. doi: 10.1038/labinvest.3700664. 215 7) heide s, chantot-bastaraud s, keren b, harbison md, azzi s, rossignol s, et al. 216 chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 217 duplications with associated phenotypes and putative functional consequences. j med 218 genet. 2018;55:205-213. doi: 10.1136/jmedgenet-2017-104919. 219 8) vals ma, kahre t, mee p, muru k, kallas e, žilinao, et al. familial 1.3-mb 220 11p15.5p15.4 duplication in three generations causing silver-russell and beckwith-221 wiedemann syndromes. molsyndromol. 2015;6:147-151. doi:10.1159/000437061 222 9) south st, whitby h, maxwell t, aston e, brothman ar & carey jc. co–occurrence of 223 4p16.3 deletions with both paternal and maternal duplications of 11p15: modification of 224 the wolf–hirschhorn syndrome phenotype by genetic alterations predicted to result in 225 either a beckwith–wiedemann or russell–silver phenotype. am j med genet. 2008; 226 146:2691–2697.doi: 10.1002/ajmg.a.32516. 227 10) bliek j, snijder s, maas sm, polstra a, van der lip k & alders m et al. phenotypic 228 discordance upon paternal or maternal transmission of duplications of the 11p15 229 imprinted regions. eur j med genet. 2009;52:404–408.doi: 10.1016/j.ejmg.2009.08.006. 230 11) cardarelli l, sparago a, de crescenzo a, nalesso e, zavan b &cubellis mv et al. 231 silver-russell syndrome and beckwith–wiedemann syndrome phenotypes associated 232 with 11p duplication in a single family. pediatrdevpathol. 2010;13:326–330.doi: 233 10.2350/09-07-0686-cr.1. 234 12) bonaldi a, mazzeu jf, costa ss, honjo rs, bertola dr & albano lm et al. 235 microduplication of the icr2 domain at chromosome 11p15 and familial silver-russell 236 syndrome. am j med genet. 2011;155:2479–2483.doi: 10.1002/ajmg.a.34023. 237 13) cardarelli l, sparago a, de crescenzo a, nalesso e, zavan b, cubellis mv, selicorni 238 a, cavicchioli p, pozzan gb, petrella m, riccio a. silver-russell syndrome and 239 beckwith-wiedemann syndrome phenotypes associated with 11p duplication in a single 240 family. pediatr dev pathol. 2010;13:326-30. doi: 10.2350/09-07-0686-cr.1. 241 14) ballard lm, jenkinson e, byrne cd, child jc, davies jh, inskip h, lokulo-sodipe o, 242 mackay djg, wakeling el, temple ik, fenwick a. lived experience of silver-russell 243 syndrome: implications for management during childhood and into adulthood. arch dis 244 child. 2019;104:76-82. doi: 10.1136/archdischild-2018-314952. 245 15) tümer z, lópez-hernández ja, netchine i, elbracht m, grønskov k, gede lb, sachwitz 246 j, den dunnen jt, eggermann t. structural and sequence variants in patients with silver-247 russell syndrome or similar features-curation of a disease database. hum mutat. 248 2018;39:345-364.doi: 10.1002/humu.23382.249 250 figure 1: clinical details of the proband 251 (a)the female infant was born with macrocephaly, broad fontanelle, low set ears, intrauterine growth restriction and presented with 252 failure to thrive without ventilator support. (b) family pedigree of the proband 253 254 a. b. 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 figure 2: karyotype and ms-mlpa test results of the proband 273 (a) the derivative chromosome 13 with a duplicated 11p locus is indicated by a short black arrow in this karyotype of the proband 274 (b) ms-mlpa6 results: the upper panel shows the cnv analysis (c1) and methylation analysis (c1-d) in a normal control sample. 275 the bottom panel shows the cnv analysis (iii.1) and methylation analysis (iii.1-d) results for the proband. black probe signals 276 indicate normalized results in comparison to control samples within the ms-mlpa run. in the cnv panel iii.1, the blue signals 277 indicate the duplicated signals (3 copies) from all the probes targeting the 11p15 locus, at an average ratio of 1.5 on the y-axis; 278 whereas the red signal in the panel iii.1-d indicates the decrease in methylation of the h19 locus. the orange regions include the 279 probe signals from the 11p15 locus, the grey regions indicate signals from reference probes and the violet regions represent probe 280 signals from the nsd1 gene at the 5q35.3 locus. 281 282 283 figure 3: balanced, non-reciprocal translocation observed in the proband’s mother 284 the deletion at the 11p arm one of the chromosomes 11, and the addition of a 11p15-11pter region on the 13p arm of a chromosome 285 13 which created a der(13), are both indicated by black arrows. the abnormal chromosomes are compared against representative 286 ideograms. 287 submitted 21 jul 22 1 revisions req. 24 aug & 25 oct 22; revisions recd. 18 sep & 8 nov 22 2 accepted 16 nov 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.068 5 6 stigmatisation of obesity and its relation to the perception of 7 controllability in riyadh, saudi arabia 8 a cross-sectional study 9 *fatmah almoayad,1 nada felemban,1 shikhah a. alshlhoub,1 shatha h. 10 alqabbani,1 may n. al-muammar,2 nada benajiba3,4 11 12 1department of health sciences, college of health and rehabilitation sciences, princess 13 nourah bint abdulrahman university, riyadh, saudi arabia; 2department of community 14 health sciences, college of applied medical sciences, king saud university, riyadh, saudi 15 arabia; 3department of basic health sciences, deanship of preparatory year, princess 16 nourah bint abdulrahman university, riyadh, saudi arabia; 4joint research unit in 17 nutrition and food regional designated center of nutrition afra/iaea, ibn tofail 18 university, morocco. 19 *corresponding author’s e-mail: faalmoayad@pnu.edu.sa 20 21 abstract 22 objectives: this study assessed the stigmatisation of obesity among a sample of the general 23 population in riyadh and its association with the perception of controllability. methods: a 24 cross-sectional analytical study was carried out in riyadh, saudi arabia, during january–25 february 2021 and included 384 participants who were recruited through a convenience 26 sampling method. the data were collected using a self-administrated online questionnaire. 27 statistical analysis was performed using john’s macintosh project version 16.0.0. results: 28 most of the participants had a low level of stigma towards obesity (72.8%), and gender and 29 bmi were significantly associated with the level of stigma at (p = .0023) and (p = .0360) 30 respectively. the association between the perception of controllable factors and the level of 31 stigma was also significant (p = 0.0001). conclusions: the data supported the hypothesis 32 that there would be a significant association between stigmatisation on obesity and perception 33 of controllability among the general population in riyadh city. regarding recommendations, 34 the authors suggest that they should be based on joint international consensus statements for 35 ending the stigma of obesity in different settings and categories, and should include the 36 education of healthcare service providers and obese patients on the relationships shown in the 37 findings. 38 keywords: obesity, stigmatisation, perception 39 40 advances in knowledge 41  there is a low level of stigmatisation of obesity among the general population of 42 riyadh. 43  the characteristic of gender had a statistically significant association with the level of 44 stigma towards obesity. 45  the stigmatisation of obesity was significantly associated with a perception of 46 controllability. 47 48 application to patient care 49  policies are needed to prevent weight stigmatisation in different settings, including 50 healthcare. 51  promoting better healthcare services to obese patients should include educating 52 healthcare providers regarding stigmatisation in relation to controllability perceptions. 53  the healthcare service provided to obese patients should include educational sessions 54 on how to tackle stigmatisation incidents and the relation of stigmatisation to 55 controllability perceptions in the attitudes of those holding those views 56 57 introduction 58 obesity is one of the most common and preventable public health issues affecting individuals 59 of both genders and all ages worldwide.1 the global prevalence of obesity has increased 60 almost three times in the last four decades. in 2017, the world health organisation (who) 61 estimated that 39% of adults are overweight and 13% are obese, while 18% of children and 62 adolescents suffer from being either overweight or obese.2 being overweight or obese is 63 defined by who as “abnormal or excessive fat accumulation that presents a risk to health. it 64 is mainly measured by the body mass index (bmi) by dividing weight in kilograms by the 65 square of height in metres. bmi between 25–29 is considered overweight while bmi of 30 or 66 more is considered obese”. 2 67 68 in saudi arabia (sa), in particular, the shift away from a traditional way of living to a 69 westernised lifestyle and the reduction of the level of physical activity were recognisable risk 70 factors contributing to the growing numbers of individuals that are obese or overweight.3 in 71 2014, 3.6 million saudis who were 15 or above were obese, and the prevalence was 72 approximately 24.1% for men and 33.5% for women.1 . being overweight and obese are 73 associated with several health issues that lead to the development of other non-communicable 74 diseases, such as diabetes, heart diseases, and cancer 2 , that increase mortality rates.4 75 therefore, obesity management is essential for non-communicable disease prevention and the 76 promotion of quality of life.5 77 78 historically, those who were overweight or obese were positively perceived in saudi culture, 79 as this was a symbol of high income and wealth for men and good fertility in women.1 80 however, in recent years, obese people have been challenged by stigmatisation at a personal 81 level because of their excess weight and shape.6. a stigma can be defined as “the co-82 occurrence of labeling, stereotyping, separation status loss, and discrimination [in] a context 83 in which power is exercised".7 more than 60 years ago, racial and ethnic discrimination was 84 more prevalent in the world, while current statistics have demonstrated that obesity stigma is 85 becoming more prevalent compared to similar attitudes regarding race and ethnicity.8 this 86 shift has been attributed to westernisation and the idolisation of thinness9, which is 87 associated with recent social changes in saudi arabia.10 88 89 the stigmatisation of obesity has multiple negative effects on obese individuals, such as 90 further weight gain and a deteriorated health status. some medical ethicists believe that 91 applying a weight stigma and pressuring overweight and obese individuals socially might 92 discourage their attempts in weight management.8 overweight and obesity stigmatisation can 93 create obstacles to an individual’s daily activities, which can lead to depression, shame and 94 guilt, social isolation, and lower work achievement.5 a study was conducted in the united 95 states with 13,692 heavy adults; of this total, 5,079 demonstrated dangerous consequences of 96 weight stigma that can lead to increased mortality. people who reported experiencing weight 97 discrimination had a 60% increased risk of dying for several reasons, including poor health 98 care services or alcohol and substance abuse.8 99 100 weight stigma leads individuals to develop a distorted and dysfunctional image of 101 themselves, especially when they are unable to manage their weight. therefore, this 102 discrimination can create a variety of mental health issues, including affecting attitudes8 and 103 creating an increased risk of experiencing depression, low self-esteem, and low quality of 104 life.11 a study conducted in a university in the north-eastern united states found that people 105 had negative feelings, such as disgust, towards overweight and obese people.12 there is also 106 new scientific evidence that estimates increases in weight gain and reductions in metabolic 107 rate due to weight stigma.6 over the last 10 years, the united states has reported higher 108 numbers of weight discrimination in the past decade. unfairness because of weight 109 stigmatisation has been reported in employment, educational, and even health care settings. 110 employers have described multiple stereotypical attitudes against overweight and obese 111 workers, such as in hiring, salary levels, and receiving promotions. in 2006, a study 112 conducted in the united states of more than 2,000 participants reported that 25% of those of 113 heavy weight had faced job discrimination.6 furthermore, another study showed that more 114 than half (54%) of employees were subject to weight stigmatisation from their colleagues at 115 work, and 43% reported stigmatisation from their supervisors because of their weight. 116 117 in healthcare settings, patients who are obese or overweight can also be affected by situations 118 that involve a weight bias. in addition, negative attitudes from health care professionals, such 119 as physicians, nurses, psychologists, and medical students, towards their obese patients have 120 been registered. they have commonly stereotyped obese patients as lazy, uncommitted, and 121 lacking the power to control their weight.6 122 123 research on educational environments regarding this topic is less prominent than what has 124 been conducted in healthcare and employment environments. students who are overweight or 125 obese in educational settings are often stigmatised by their peers, teachers, or even their 126 parents.6 a nationwide study in saudi arabia that included 4,709 participants revealed that 127 the stigmatisation of obesity prevalence is 46.4%.13.another study including 1,459 128 participants found that obese people in saudi arabia face stigmatisation that is manifested in 129 different forms, including primarily negative behaviours (25.6%), bad comments (25.4%), 130 and physical barriers (25.2%).14 interestingly, khodari, et al. 15 recently explored weight self-131 stigma in jazan (in the southern region of saudi arabia) and demonstrated that it was 132 positively associated with bmi. 133 134 the attribution value model was developed by weiner 16 and may provide a plausible 135 explanation of stigmatisation towards a given person or group of people. weiner 17 suggested 136 that antipathy towards a specific group is the result of believing that this specific group can 137 control their own behaviours. in the context of those who are overweight and obese, evidence 138 has confirmed that weight stigma has increased rates of association with attributions of trying 139 to control a person’s weight.18 attribution theory tries to explain why people behave in a 140 certain way against a specific group based on their perceptions of the controllability of that 141 group.17 to manage the problem of the obesity epidemic, it is obligatory to address this other 142 aspect of the epidemic, which is weight stigma attitudes.8 indeed, when stigmatisation is 143 decreased, it will improve the overall quality of life and minimise mental health issues among 144 obese people by removing stereotypes, discrimination, and prejudices. 145 146 the existing literature regarding the stigmatisation of obesity in sa is scarce, mainly 147 focusing on body image and preferences and the effect of stigma. this is a limitation, even if 148 obesity as a public health problem is exhaustively investigated in sa. the present study’s 149 uniqueness comes from its attempt to understand the root cause of stigmatisation by using the 150 attribution-value model to assess obesity stigma and its relation to a perception of 151 controllability. our hypothesis is that there will be a significant association between 152 stigmatisation of obesity and perception of controllability among the general population in 153 riyadh city. 154 155 methods 156 this cross-sectional analytical study was carried out in riyadh city (sa) during january–157 february 2021. inclusion criteria included saudi and non-saudi individuals of both genders 158 who were residents of riyadh city and 18 years old and above. a non-probability, 159 convenient sampling technique was used. a brief introduction about the aim of the research 160 and the target population, along with a link to the first page of the electronic questionnaire, 161 was distributed through social media applications, such as whatsapp and telegram. the 162 sample size was calculated manually with a 95% confidence interval multiplied by a design 163 effect of one. the prevalence of stigma was estimated to be 50%, and the total population 164 under study was above 10,000. after adding 10% to account for any incomplete data, the 165 necessary sample size was calculated to be 422 participants. the actual collected sample was 166 533 participants; eight participants were excluded because they were under 18 years old. 167 168 the self-administrated online questionnaire was hosted by microsoft forms, which was used 169 for data collection. the questionnaire was distributed in both the arabic and english 170 languages. the questionnaire was developed and validated as described later, guided by the 171 obese stereotypes and causes of obesity scale14 and the anti-fat attitudes test 172 (afat).15the tool consisted of three sections. the first section included nine questions about 173 sociodemographic characteristics: gender, age, nationality, level of education, marital status, 174 monthly income, workplace, height (m), and body weight (kg). the last two were used for 175 body mass index (bmi) calculations. participants were then categorised based on the who 176 guidelines16: underweight, <18.50 kg/m2; normal, 18.50–24.99 kg/m2; overweight ≥25.00 177 kg/m2; and obese ≥30.00 kg/m2. the bmi could not be calculated for 14 of the participants, 178 as they did not provide the required information. 179 180 the second section assessed obesity stereotypes and social, character, physical and romantic, 181 and attractiveness aspects, along with weight control. it consisted of 20 questions, which 182 were assessed based on a five-point likert scale. the highest score of 5 was given to 183 “strongly agree”, and the lowest of 1 was given to “strongly disagree”. one question was 184 scored in reverse (“obese people are just as competent in their work as anyone else”). by 185 which a score of 1 was given to “strongly agree” and a score of 5 to “strongly disagree”. the 186 highest possible score was 100, and the lowest was 20. data were interpreted based on 187 percentages in which respondents with scores between 20.0 and 46.6 were categorised as 188 having low stigma. respondents who scored 46.7 to 73.3 were categorised as having 189 moderate stigma. finally, those who scored 73.4 or higher were categorised as having a high 190 level of stigma. 191 192 the last section assessed the controllability of obese individuals. it consisted of six questions, 193 which were assessed based on a five-point likert scale. the first three questions were scored 194 with 5 as “strongly agree”, and 5 as “strongly disagree”. the last three questions were 195 reversed: “strongly agree” was scored as 1, and “strongly disagree” was scored as 5. the 196 highest possible score for this section was 15. and the lowest was 3. the scores were divided 197 into high, moderate, and low levels of controllability. respondents with a score between 3 198 and 6 were categorised as having low levels of controllability. respondents who scored 7 to 199 10 were categorised as having moderate levels of controllability, and those with scores of 11 200 to 15 were categorised as having high levels of controllability. 201 202 a pilot study was planned to include 10% of the estimated sample size, which was 43 203 individuals; it was actually completed by a group of 45 residents of riyadh. the pilot took 204 place in january 2021 to test the clarity and feasibility of the questionnaire. three questions 205 were reported to be vague by the pilot participants, and they were modified for clarity. the 206 face validity was tested in terms of layout, feasibility, and the clarity of wording. moreover, 207 the questionnaire was validated by experts in the fields of nutrition and public health. 208 reliability was assessed using cronbach’s alpha. test section two showed high reliability 209 with a score of α = .8500. section three showed acceptable reliability with α = .6519 after 210 excluding three questions. 211 212 the data were coded and analysed using jmp, version 16.0.0 (sas institute inc., cary, nc, 213 1989-2021). descriptive data are presented in frequency tables as numbers and percentages. 214 the data were analysed according to the type of measure; categorical variables were 215 presented in frequency tables and graphs. associations between two categorical data 216 variables were tested using the chi-square test of two independent samples. a p-value <0.05 217 was considered as the cut-off point for significance. 218 219 ethical approval was obtained from the institutional review board (irb) at xxx (number 220 xxx). the research was performed in accordance with relevant guidelines/regulations. 221 informed consent was confirmed on the first page of the questionnaire before the respondents 222 answered any part of the questionnaire. participation in the research was voluntary, the data 223 were confidential, and there was no expected harm or risk to the participants. 224 225 results 226 table 1 summarises the characteristics of the study sample (n = 525). female participants 227 represented 62.7% of the study sample. participants aged 18–28 years constituted 41.9 % of 228 the sample. most of the participants were saudis (95.8%), and almost half were married 229 (53.0%). in terms of education and employment, 68.6 % reported that they had a bachelor’s 230 degree, and 37.3% were unemployed. as for monthly income, 47.6% reported earning less 231 than 8,000 sar. finally, based on the height and weight values provided by the respondents, 232 the bmi values were calculated for 510 individuals. more than half were either overweight or 233 obese (33.1% and 24.7 %, respectively). more than one-third had a normal bmi (36.9%), and 234 only 5.1% were underweight. 235 236 table 2 shows that most of the participants had a low level of stigma (72.8%) and only two 237 participants showed high level of stigma (.04%). slightly more than half (51.8%) and more 238 than one-third (35.4%) of the participants had moderate or high levels of perception of 239 controllable factors towards obesity, respectively. 240 241 table 3 displays the association between the level of stigma towards obesity and the 242 sociodemographic characteristics of the studied sample. as the category of high 243 stigmatisation was of only shown in 0.4% of the sample which does not provide good 244 implications about the study analysis capability. a category of moderate to high was created 245 and the associations were calculated for two categories. characteristics which are 246 significantly associated with stigma are gender (p = .0023) and bmi (p = .0360). 247 248 table 4 shows that more than half of the participants who had a high level of perception 249 regarding controllability also had a low level of stigma. there was a significant association 250 between the perception of controllable factors and the level of stigma (p = .0001). 251 252 table 5 displays a multivariate logistic regression to assess which factors successfully predict 253 intention. being a female was a negative predictor of stigma while being overweight and with 254 high perception of controllability positively predicted stigma. 255 256 discussion 257 this study assessed the stigmatisation of obesity and its relation to the perception of 258 controllability among a sample from the general population in riyadh city. the research 259 findings support the hypothesis, as there was a significant association (p = .0001) between 260 stigmatisation of obesity and perception of controllability. slightly less than one-third of the 261 participants had moderate stigma, and most of the participants demonstrated a low level of 262 stigma. this result is in concordance with previous findings showing that weight stigma of a 263 mild form was observed among the general public in riyadh.19 264 265 in the united states over the past decade, discrimination regarding obesity has increased by 266 approximately 66% compared to other forms of discrimination, such as those related to 267 race.20 this can be attributed to the fact that weight stigma is often considered normal 268 behaviour in society. also, some people think that it is humorous and acceptable to share 269 jokes about obese individuals. moreover, tv and other media often present negative 270 stereotypes about obese individuals, such as they are lazy and irresponsible.14 271 272 the present study confirms that gender had a significant relationship with stigma, in which 273 males showed more stigma towards obesity compared to females. in fact, the multiple logistic 274 regression model showed that being female is a negative predictor of stigma. in agreement 275 with the current study’s finding, flint, et al. 21 reported that males had significantly more 276 stigma towards obesity than females in the uk (p < 0.05). similarly, turkish male university 277 students had a higher stigma towards obese people compared to females.22 taken together, 278 this result might be attributed to societal pressures that females face regarding how a female 279 body shape should look, which affects their emotions; thus, females tend to be more caring of 280 others’ feelings when it comes to physical appearance.23 this study showed that 44.2% of 281 those with low stigma were in the age range of 18–28 years. this could be explained by the 282 fact that this young age group tends to be more knowledgeable about the negative effects of 283 the stigmatisation of obese people. however, these findings are different from those 284 demonstrated by jackson, et al. 24, which indicated that younger age groups have higher rates 285 of weight discrimination. 286 287 this study found that bmi was significantly associated with stigma (p=0.0360) in which 288 being overweight specifically positively predicted stigma. 38.6% of those with moderate to 289 high stigma were of normal weight and 39.3% of those with moderate stigma were 290 overweight; only 20.7% of those with moderate stigma were obese. a study conducted in the 291 united kingdom found that individuals who were underweight or overweight had higher 292 stigmatisation rates than other bmi groups.21 293 294 according to the results of the present study, 20.6% of the participants had a high perception 295 of controllability regarding obesity and a low obesity stigma. in addition, the level of stigma 296 was significantly associated with the perceptions of controllability regarding obesity. the 297 multiple logistic regression model found that being overweight was a positive predictor of 298 stigma. this could be explained by attribution theory, which discusses how weight stigma 299 increases when the factors are controllable and decreases when the factors are 300 uncontrollable.18 this result supports the study published by khan, et al. 25 these authors 301 revealed that when people know that the cause of obesity contains uncontrollable factors, 302 such as genetics, they express low stigma and are highly empathetic towards obese people. 303 however, when they know that the cause contains controllable factors, such as behaviour, 304 they highly express stigma and have low empathy towards obese people. 305 306 the strength of this study is that it is theoretically based. in terms of limitations, as the 307 sampling technique was based on a non-probability convenience technique, the results may 308 not be generalisable, although the study findings are of importance, as they provide an 309 explanation of one of the root causes of obesity stigmatisation. another limitation of the 310 study could be the self-reporting of anthropometric measurements by the participants, which 311 could affect the accuracy of bmi categorisation. however, allison, et al. 26 indicated that the 312 categorisation of bmi based on such values was more precise than using continuous values of 313 bmi when self-reported measures are used in health-related interventions. this was the case 314 in our study. 315 316 conclusion 317 in conclusion, this research supported the hypothesis stating that there was a significant 318 association between stigmatisation of obesity and a perception of controllability among the 319 general population in riyadh city, based on this particular sample. as for recommendations, 320 the authors suggest that they should be based on joint international consensus statements for 321 ending the stigma of obesity 27 in different settings and categories. at the research level, 322 conducting additional research in other cities in sa can provide a more holistic insight into 323 whether stigmatisation possibly influences obese people. at the community level, it is highly 324 recommended to establish strong policies that set a primary goal of filling the gap between 325 public health efforts and the general population regarding settings in which weight 326 discrimination occurs, such as healthcare, education, and workplaces. for example, in 327 healthcare settings, individuals who are trained to treat obese people should be concerned and 328 encourage them to seek medical help and also shift their attributions in messages from 329 focusing solely on diet and exercise (“calories in and calories out”) that can be controllable 330 factors for people to include other attributions that can be uncontrollable. it is important to 331 understand the etiology of obesity rather than just the traditional approach to obesity 332 management. 333 334 conflicts of interest 335 the authors declare no conflict of interests. 336 337 funding 338 no funding was received for this study. 339 340 author contributions 341 all authors substantially contributed to the design of the study. nf, saa and sha collected 342 the data, performed the statistical analysis and literature review. all authors participated in 343 the interpretation of the results and drafting the manuscript. fa, nb and ma revised the 344 manuscript and edited the english. all authors approved the final version of the manuscript. 345 346 references 347 1. memish, z. a., el bcheraoui, c., tuffaha, m., robinson, m., daoud, f., jaber, s., et al. 348 peer reviewed: obesity and associated factors—kingdom of saudi arabia, 2013. 349 preventing chronic disease; 2014; 11: 350 2. who. obesity. from: https://www.who.int/health-topics/obesity#tab=tab_1 accessed: 351 3-1-2022 352 3. al-shehri, f. s., moqbel, m. m., al-khaldi, y. m., al-shahrani, a. m., abu-melha, w. 353 s., alqahtani, a. r., et al. prevention and management of obesity: saudi guideline 354 update. saudi journal of obesity; 2016; 4: 25. 355 4. waxman, a. who global strategy on diet, physical activity and health. food and 356 nutrition bulletin; 2004; 25: 292-93. 357 5. obesity. from: https://www.mayoclinic.org/diseases-conditions/obesity/symptoms-358 causes/syc-20375742 accessed: 3-1-2022 359 6. puhl, r. m. and heuer, c. a. the stigma of obesity: a review and update. obesity; 2009; 360 17: 941. 361 7. hatzenbuehler, m. l., phelan, j. c. and link, b. g. stigma as a fundamental cause of 362 population health inequalities. american journal of public health; 2013; 103: 813-21. 363 8. tomiyama, a. j., carr, d., granberg, e. m., major, b., robinson, e., sutin, a. r., et al. 364 how and why weight stigma drives the obesity ‘epidemic’and harms health. bmc 365 medicine; 2018; 16: 1-6. 366 9. swami, v. cultural influences on body size ideals: unpacking the impact of 367 westernization and modernization. european psychologist; 2015; 20: 44-51. 368 10.1027/1016-9040/a000150 369 https://www.who.int/health-topics/obesity#tab=tab_1 https://www.mayoclinic.org/diseases-conditions/obesity/symptoms-causes/syc-20375742 https://www.mayoclinic.org/diseases-conditions/obesity/symptoms-causes/syc-20375742 10. alshebali, m., alhadi, a. and waller, g. the impact of ongoing westernization on eating 370 disorders and body image dissatisfaction in a sample of undergraduate saudi women. eat 371 weight disord; 2021; 26: 1835-44. 10.1007/s40519-020-01028-w 372 11. phelan, s. m., burgess, d. j., yeazel, m. w., hellerstedt, w. l., griffin, j. m. and van 373 ryn, m. impact of weight bias and stigma on quality of care and outcomes for patients 374 with obesity. obesity reviews; 2015; 16: 319-26. 375 12. vartanian, l. r. disgust and perceived control in attitudes toward obese people. 376 international journal of obesity; 2010; 34: 1302-07. 377 13. althumiri, n. a., basyouni, m. h., almousa, n., aljuwaysim, m. f., alhamdan, a. a., 378 al-qahtani, f. s., et al. exploring weight stigma in saudi arabia: a nationwide cross-379 sectional study. int j environ res public health; 2021; 18: 1-13. 380 10.3390/ijerph18179141 381 14. alenazy, f. r. and almutairi, a. the effect of obesity stigma on obese people, saudi 382 arabia, 2020. middle east journal of family medicine; 2021; 19: 65-74. 383 10.5742/mewfm.2021.93950 384 15. khodari, b. h., shami, m. o., shajry, r. m., shami, j. a., names, a. a., alamer, a. a., 385 et al. the relationship between weight self-stigma and quality of life among youth in 386 the jazan region, saudi arabia. cureus; 2021; 13: e18158. 10.7759/cureus.18158 387 16. weiner, b. an attribution theory of motivation and emotion. series in clinical & 388 community psychology: achievement, stress, & anxiety; 1982, 389 17. weiner, b. an attributional theory of motivation and emotion.springer science & 390 business media. 2012 391 18. o’brien, k. s., puhl, r. m., latner, j. d., lynott, d., reid, j. d., vakhitova, z., et al. the 392 effect of a food addiction explanation model for weight control and obesity on weight 393 stigma. nutrients; 2020; 12: 294. 394 19. turki, m. a., sudersanadas, k., wujd, s., tofail, a. a., marshad, y. a., sherbini, l. a., 395 et al. socio-demographic determinants of obesity stigma among the general public 396 from riyadh, ksa. international journal of current research; 2020; 12: 14885-90. 397 10.24941/ijcr.40185.11.2020 398 20. brandheim, s. a systemic stigmatization of fat people. karlstads universitet, 399 21. flint, s. w., hudson, j. and lavallee, d. uk adults’ implicit and explicit attitudes 400 towards obesity: a cross-sectional study. bmc obesity; 2015; 2: 1-8. 401 22. yildiz, m. and yalçinöz baysal, h. prejudice against obesity in university students 402 studying in health-related departments. perspectives in psychiatric care; 2019; 55: 170-74. 403 10.1111/ppc.12314 404 23. puhl, r. m., latner, j., o'brien, k., luedicke, j., daníelsdóttir, s. and forhan, m. a 405 multinational examination of weight bias: predictors of anti-fat attitudes across four 406 countries. international journal of obesity; 2015; 39: 1166-73. 407 24. jackson, s. e., steptoe, a., beeken, r. j., croker, h. and wardle, j. perceived weight 408 discrimination in england: a population-based study of adults aged⩾ 50 years. 409 international journal of obesity; 2015; 39: 858-64. 410 25. khan, s. s., tarrant, m., weston, d., shah, p. and farrow, c. can raising awareness 411 about the psychological causes of obesity reduce obesity stigma? health communication; 412 2018; 33: 585-92. 413 26. allison, c., colby, s., opoku-acheampong, a., kidd, t., kattelmann, k., olfert, m. d., 414 et al. accuracy of self-reported bmi using objective measurement in high school 415 students. j nutr sci; 2020; 9: e35. 10.1017/jns.2020.28 416 27. rubino, f., puhl, r. m., cummings, d. e., eckel, r. h., ryan, d. h., mechanick, j. i., et 417 al. joint international consensus statement for ending stigma of obesity. nature medicine; 418 2020; 26: 485-97. 10.1038/s41591-020-0803-x 419 table 1: sociodemographic characteristics of the studied sample (n = 525) 420 sociodemographic characteristics n (%) gender female male 329 (62.7) 196 (37.3) age (years) 18–28 29–39 40 and above 220 (41.9) 156 (29.7) 149 (28.4) nationality saudi non-saudi 503 (95.8) 22 (4.2) marital status married not married 278 (53.0) 247 (47.0) level of education less than high school high school or diploma bachelor's degree higher education 16 (3.0) 87 (16.6) 360 (68.6) 62 (11.8) workplace unemployed government sector private sector freelance retired 196 (37.3) 165 (31.4) 120 (22.9) 13 (2.5) 31 (5.9) monthly income (sar) < 8,000 8,000–16,000 > 16,000 250 (47.6) 180 (34.3) 95 (18.1) bmi categories (n = 510) underweight normal weight overweight obese 26 (5.1) 188 (36.9) 170 (33.3) 126 (24.7) sar = saudi riyals, 421 bmi categories: underweight, <18.50 kg/m2; normal, 18.50–24.99 kg/m2; overweight 422 ≥25.00 kg/m2; and obese ≥30.00 kg/m2 423 424 table 2: level of stigma and controllability toward obesity in the studied sample (n = 425 525) 426 n (%) level of stigma (score range) low (20.0–46.6) 382 (72.8) moderate (46.7–73.3) 141(26.9) high (73.4–100.0) 2 (0.4) level of controllability (score range) low (3–6) 67 (12.8) moderate (7–10) 272 (51.8) high (11–15) 186 (35.4) 427 table 3: association between level of stigma toward obesity and sociodemographic 428 characteristics of the studied sample (n = 525) 429 level of stigma low (n = 382) n (%) moderate to high (n = 143) n (% ) p-value gender male female 127 (33.3) 255 (66.8) 74 (51.8) 69 (48.3) 0.0023* age (years) 18–28 29–39 40 and above 169 (44.2) 106 (27.8) 107 (28.0) 51 (36.2) 50 (35.0) 42 (29.4) 0.1558 nationality saudi non-saudi 366 (95.8) 16 (4.2) 137 (95.8) 6 (4.2) 0.1487 marital status married not married 200 (52.4) 182 (47.6) 78 (54.6) 65 (45.5) 0.6948 level of education less than high school high school/diploma bachelor’s degree higher education 12 (3.1) 62 (16.2) 263 (68.8) 45 (11.8) 4 (2.8) 25 (17.5) 97 (67.8) 17 (11.9) 0.9844 workplace unemployed government sector private sector freelance retired 151 (39.5) 117 (30.6) 84 (22.0) 7 (1.8) 23 (6.0) 45 (31.5) 48 (33.6) 36 (25.2) 6 (4.2) 8 (5.6) 0.2938 monthly income (sar) < 8,000 8,000–16,000 > 16,000 185 (48.4) 129 (33.8) 68 (17.8) 65 (45.5) 51 (35.7) 27 (18.9) 0.3372 bmi cat. (n = 510) underweight normal weight overweight obese (n = 370) 24 (6.5) 134 (36.2) 115 (31.1) 97 (26.2) (n = 138) 2 (1.4) 54 (38.6) 52 (39.3) 28 (20.7) 0.0360* sar = saudi riyals 430 bmi categories: underweight, <18.50 kg/m2; normal, 18.50–24.99 kg/m2; overweight 431 ≥25.00 kg/m2; and obese ≥30.00 kg/m2 432 p-value is calculated using the chi2 test. 433 434 table 4: association between stigmatisation level and its relation to perception of 435 controllability (n = 525) 436 level of controllability level of stigmatisation of obesity p-value low moderate to high low 59 (15.5) 8 (5.6) 0.0001* moderate 215 (56.3) 57 (39.9) high 108 (20.6) 78 (54.6) total 382 (72.8) 143 (26.9) p-value is calculated using the chi2 test. 437 438 table 5: multiple logistic regression with gender, nationality, bmi, and controllability 439 parameter estimates term estimate std error chisquare prob>chisq intercept -1.5291252 0.3361126 20.07 <.0001* gender female -0.2397304 0.1066013 5.06 0.0245* nationality saudi 0.04284096 0.2654482 0.03 0.8718 bmi normal weight 0.42743278 0.2358471 3.28 0.0699 overweight 0.53475875 0.2387129 5.02 0.0251* obese 0.11420282 0.2561442 0.20 0.6557 controllability low -0.7423099 0.2635433 7.93 0.0049* high 0.85041049 0.1707867 24.79 <.0001* 440 1 submitted 1 sep 21 1 revision req. 27 oct 21; revision recd. 24 nov 21 2 accepted 28 dec 21 3 online-first: jan 2022 4 doi: https://doi.org/10.18295/squmj.1.2022.008 5 6 patterns of movement performance among japanese children and effects 7 of parenting practices 8 latent class analysis 9 zhu zhu,1,2 cunyoen kim,3 dandan jiao,1 xiang li,1 ammara ajmal,1 10 munenori matsumoto,1 yuko sawada,4 toshiyuki kasai,5 taeko 11 watanabe,6 etsuko tomisaki,7 emiko tanaka,8 sumio ito,9 12 rika okumura,9 *tokie anme10 13 14 1school of comprehensive human science, university of tsukuba, tsukuba, japan; 2faculty 15 of preschool and special education, xuzhou kindergarten teachers college, xuzhou, china; 16 3school of education science, leshan normal university, leshan, china; 4faculty of health 17 medicine, morinomiya university of medical sciences, osaka, japan; 5faculty of 18 foundational academics, miyagi university, miyagi, japan; 6faculty of nursing, shukutoku 19 university, chiba, japan; 7faculty of nursing and medical care, keio university, tokyo, 20 japan; 8faculty of nursing, musashino university, tokyo, japan; 9department of public 21 welfare, tobishima, aichi, japan; 10faculty of medicine, university of tsukuba, tsukuba, 22 japan. 23 *corresponding author’s e-mail: anmet@md.tsukuba.ac.jp 24 25 abstract 26 objectives: the study aimed to examine the long-term effects of parenting practice during 27 preschool years on children’s movement performance in primary school. methods: this 28 study involved a three-year longitudinal study including 225 children aged 3–6 years old. 29 parents reported baseline parenting practice and evaluated children’s movement performance 30 three years later. latent class analysis was used to explore latent classes of movement 31 performance. a post hoc test was used to identify the characteristics of different patterns. 32 mailto:anmet@md.tsukuba.ac.jp 2 finally, adjusted multinomial logistic regression models were used to test the influence of 33 parenting practice on identified patterns of movement performance. results: children in this 34 study were grouped into three movement performance pattens, labelled as ‘least difficulties’ 35 (58.2%, n = 131), ‘low back pain’ (30.2%, n = 68), and ‘most difficulties’ (11.6%, n = 26). 36 after controlling for age, gender, having siblings or not, family structure, bmi sds, sleep 37 condition and dietary habits, we found that if parents played games with children frequently, 38 the children would have a 0.287 times lower probability of being in the ‘low back pain’ class, 39 95%ci [0.105, 0.783], and if parents take children to meet peers of a similar age frequently, 40 the children would have a 0.339 times lower probability of being in ‘most difficulties’ class, 41 95%ci [0.139, 0.825]. conclusions: primary healthcare providers should pay careful 42 attention to children with movement difficulties. the study provides longitudinal evidence to 43 support the applicability of positive parenting practice in early childhood to prevent 44 children’s movement difficulties. 45 keywords: movement performance; parenting practice; latent class analysis; child; 46 longitudinal study; japan. 47 48 advances in knowledge 49  the study originally used person-centred method to explore three patterns of children’s 50 movement performance in a japanese community context. 51  this study confirmed the long-term effects of parenting practice during preschool years 52 on children’s movement performance when they enter primary school. we indicated that 53 playing games with children frequently contributed to preventing children from 54 developing low back pain, while taking children to meet peers of a similar age helped in 55 preventing children’s movement difficulties during their school age. 56 57 application to patient care 58  primary healthcare providers should pay special attention to children with movement 59 difficulties. the study provides longitudinal evidence to support the applicability of 60 positive parenting practice in early childhood to prevent children’s movement difficulties. 61 62 introduction 63 movement performance is defined as the competence or skills related to motor coordination, 64 muscle strength and balance, which are shown in self-care, sport, and other daily activities.1 65 3 school aged children need to possess motor skills, coordination, and body control in order to 66 complete daily activities.2 movement difficulties in childhood may reduce a child’s 67 participation in daily activities and even impact their quality of life in adulthood.3,4 the 68 prevalence of movement difficulties has been rising worldwide recently.5 in oman (n = 97; 69 mage = 12.9, sd = 1.6), 55% of the total sample developed low grip strength and around 45% 70 were scored low in flexibility and sit-up tests.6 national reports in japan also show a decline 71 in school-aged children’s movement performance, particularly among boys, which is at a 72 historically low level.7 however, there is no gold standard to measure children’s movement 73 performance in existing research.8 therefore, person-oriented cluster analysis might be a 74 possible method to identify the characteristics of movement performance of children in a 75 community. 76 77 movement performance is determined by complex interactions between biological 78 development and social environment.9 differences are always expected for the movement 79 performance of children in terms of age, gender, body size and lifestyles.10-13 home rearing 80 environment is one of the most important social environments, in which parenting practice 81 affects children directly.14 parenting practice refers to the observable behaviours that parents 82 use to socialise their children in daily activities.15 a cross-sectional study demonstrated that 83 maternal permissive parenting was gender-specifically associated with better pa performance 84 in children experiencing authoritative parenting.16 however, results were not consistent with 85 the findings of bradley et al. that indicated high parental monitoring was associated with 86 poorer pa performance for boys experiencing later puberty but increased pa performance in 87 boys experiencing early puberty using longitudinal data.17 furthermore, only sixteen of the 30 88 quantitative studies in an integrative review showed significant positive associations between 89 supportive pa parenting and children’s physical performance.18 the majority of studies to 90 date, have focused on the intensity and frequency of pa instead of using health conditions or 91 function status as the outcomes. limited studies have explored the relationships between 92 parenting practice and movement performance. 93 94 to fill gaps in existing research, the present three-year longitudinal study examined the 95 influence of specific parenting practices for preschool children on pattens of movement 96 performance while school aged. to avoid bias of variable-centred methods, we aimed to 97 investigate (1) the patterns of children’s movement performance based on person-oriented 98 4 cluster analysis and (2) the effects of daily parenting practice on children during the 99 preschool period. we hypothesised that (1) patterns of children’s movement performance 100 could be identified using different characteristics in a typical community and (2) more 101 positive stimulations in parenting contribute to preventing children from developing 102 movement difficulties. 103 104 methods 105 study design and participants 106 our three-year longitudinal research study was part of a cohort study named ‘community 107 empowerment and care for well-being and healthy longevity’ (cec), involving all residents 108 in t village, a typical suburban community of japan with a population of almost 5,000 from 109 1991. the inclusion criteria were as follows: (1) being aged 3–6 years old, (2) living in t 110 village, and (3) having at least one parent living together. the exclusion criteria were as 111 follows: (1) having a disability, serious disease, or developmental delay and (2) not living in 112 t village for the next three years. in the baseline survey, 289 parents with children aged 3–6 113 years provided the information on demographics and parenting practice. after 3 years, 114 children’s movement performance was evaluated by parents. as 27 families dropped out of 115 the project and 37 were excluded due to incomplete evaluation of movement performance, 116 the final sample size was 225. all research procedures were reviewed and approved by the 117 institutional review board and ethics committee of [blinded for review]. all participants 118 provided written consent before participation. 119 120 measures 121 parenting practice 122 parenting practice was measured using the index of child care environment (icce), which 123 has been used in japanese child cohort study for over 20. 19,20 icce is japanese questionnaire 124 edition of the globally-used scale called the home observation for measurement of the 125 environment (home) and shows high reliability (α = 0.891).21 126 127 the icce is a self-reported questionnaire for parents, consisting of 13 items regarding 128 parenting practice, which are used independently in the present study. questions for the 13 129 parenting practices are as follows: (1) how often do you play games with your child? (2) 130 how often do you go shopping with your child? (3) how often do you read to your child? (4) 131 5 how often do you sing songs with your child? (5) how often do you go to the park with your 132 child? (6) how often do you and your child meet with friends or relatives with children of a 133 similar age? (7) how often do you talk with your spouse about child care? (8) how often 134 does your spouse or other caregiver help you with the child? (9) how often do you and your 135 spouse eat meals together with the child? (10) what do you do if your child spills milk on 136 purpose? (11) how many times did you spank your child last week? (12) do you have 137 anyone else that helps you with daily home-rearing? (13) do you have anyone to consult with 138 about child care? items 1–9 were measured using five-point likert scale (1 = rarely, 2 = 1–3 139 times per month, 3 = 1–2 times per week, 4 = 3–4 times per week, 5 = almost every day). as 140 the responses were not normally distributed, binary-category classification was used in the 141 analysis based on icce manual (unfavourable group = the bottom 25% of the total sample, 142 favourable group = the rest). item 10 had five options (1= hit the child, 2 = scold the child, 3 143 = discipline in another way, 4 = determine how to prevent it in the future, 5 = in other ways). 144 item 11 had five different options (1 = never, 2 = 1-2 times, 3 = 3-4 times, 4 = 5-6 times, 5 = 145 almost every day). for items 10 and 11, responses were categorised into two groups 146 (unfavourable = spank children and favourable = no spank). for items 12 and 13, responses 147 were originally measured in a binary manner (i.e., yes or no), in which the answer ‘yes’ was 148 evaluated as favourable and ‘no’ was evaluated as unfavourable. 149 150 movement performance 151 movement performance of children in the present study was investigated using a nine-item 152 parent-reported movement performance questionnaire, which have been used by community 153 government in large scale population-based surveys of the general population in japan for 154 over 20 years.22 parents were required to compare their children’s coordination with other 155 children of the same age based on their daily observations after the community government 156 explained evaluation points in detail. the nine items included the following: (1) does your 157 child always appear energetic before and after school? (keep active) (2) are there any 158 difficulties for your child to keep running? (keep running) (3) does your child have 159 difficulties maintaining correct sitting posture? (good sitting posture) (4) does your child 160 have any arm pain? (arm strength) (5) does your child have any lower low back pains? (low 161 back strength) (6) does your child have any leg pain? (leg strength) (7) are there any 162 difficulties for your child in moving agilely to avoid obstacles? (agility) (8) dose your child 163 have any difficulties balancing? (balance) (9) does your child have any difficulties moving 164 6 their body flexibly? (flexibility). participants could respond to each item with ‘no’ (without 165 any difficulties) or ‘yes’ (having some difficulties). 166 167 covariates 168 demographics, children’s sleep condition, and their dietary habits were considered covariates 169 in the analysis models. demographics included children’s age, gender, bmi (standardised 170 bmi, bmi sds, was used in the analysis), having siblings or not, and family structure (e.g., 171 nuclear family type and extended family type). children’s sleep condition was reported by 172 parents as ‘sufficient’ or ‘not sufficient’. dietary habits were also reported by parents as ‘no 173 fussy eating’ or ‘having fussy eating behaviours’. 174 175 statistical analysis 176 first, we used descriptive statistics to confirm demographics, baseline condition of parenting 177 practice and follow-up year’s movement performance. second, latent class analysis (lca) 178 was used to explore patterns of movement performance.23 third, a post hoc test for the chi-179 square test (bonferroni) and anova analysis (lsd and s-n-k) was used to clarify 180 differences in demographics among the patterns of movement performance and identify the 181 characteristics of the patterns. finally, adjusted multinominal logistic regression analysis was 182 applied to confirm the associations between parenting practice and movement performance 183 patterns. 184 185 all statistical analyses were performed using spss (version 26.0; spss inc., chicago, il) 186 and mplus (version 8.0; muthén and muthén, los angeles, ca, usa). 187 results 188 table 1 shows descriptive statistic results of demographic background. a total of 225 children 189 (age: m = 4.13, sd = 0.87; bmi sds: m = 0.12, sd = 0.98) was even distributed in gender 190 and family structure (boys: n = 119, 52.9%; girls: n = 106, 47.1%; nuclear family: n = 107, 191 47.6%; extended family: n = 118, 52.4%), while 83.6% children (n = 188) had siblings. 192 85.8% children (n = 193) had sufficient sleep while 68.9% children (n = 155) had fussy 193 eating behaviours. 194 195 table 2 shows baseline parenting practice conditions and follow-up year’s movement 196 7 performance of children. in baseline year, the item with most negative evaluations was ‘how 197 many times did you spank your child last week?’, in which 37.8% parents (n = 85) reported 198 they had spanked their child in the last week. the item with least negative evaluations was 199 ‘do you have anyone else help you in daily home-rearing?’, in which only 2.2% parents (n = 200 5) reported they took care of children without any help from others. as for the movement 201 performance of children three years’ later, our study showed that more than half of the 202 children were reported to have some difficulties on (1) maintaining right sitting posture (n = 203 139, 61.8%), (2) arm strength (n = 127, 56.4%), (3) agility (n = 114, 50.7%), and (4) 204 flexibility (n = 163, 72.4%). 205 206 table 3 shows the model fit information for five lca models with two to six latent classes. 207 akaike information criterion (aic), bayesian information criterion (bic) and sample-208 adjusted bayesian information criterion (abic) in three-class model decreased sharply than 209 two-class model and the decline scope was the biggest among all the models (aic = -210 71.126, bic = -36.965, abic = -68.657). entropy in three-class model was the highest in 211 all the models (0.935). the smallest sample size of the latent class is just over 25 (n = 26). 212 and the three-class model was significantly better than two-class model (p＜0.01). based on 213 model selection recommendations for lca model, we considered three-class model as the 214 best identified class. 215 216 table 4 presents the results of the chi-square test and one-way anova analysis, showing 217 demographics and movement performance characteristics of the three latent patterns. there 218 was no significant difference between the demographics of the three movement performance 219 patterns (p＞0.1). all the nine items, except flexibility, showed significant differences among 220 three movement performance patterns (p＜0.05). the results of post hoc test indicated the 221 number of responses of movement with difficulties in class 3 was significantly greater than 222 that in class 1 among all the nine items, except flexibility (p＜0.05). no significant difference 223 between class 2 and class 1 was found in the following categories: keep active, keep running, 224 arm strength, agility, and flexibility. no significant difference between class 2 and class 3 was 225 shown in the following categories: good sitting posture, arm strength, leg strength, and 226 balanced (p＞0.05). the number of responses indicating having low back pain in class 2 was 227 significantly greater than that in class 1, but less than that in class 3 (p＜0.05). class 1 was 228 labelled as having the least difficulties (ld), class 2 was labelled as having low back pain 229 8 (lbp), and class 3 was labelled as having the most difficulties (md). figure 1 shows the item 230 probability of movement performance without difficulties in ld, lbp, and md classes. the 231 ld class contained 58.2% (n = 131) of the sample and had high probabilities of movement 232 performance without difficulties. the lbp class contained 11.6% (n = 26) of the sample, and 233 all samples showed low back pain in the group. the md class contained 30.2% (n =68) of the 234 sample and had low probabilities of movement performance without difficulties. 235 236 table 5 show the associations between parenting practice and children’s movement 237 performance. in the multinomial logistic regression models, each parenting practice was 238 considered as independent variable respectively, while age, gender, having siblings or not, 239 family structure, bmi sds, sleep condition and dietary habits were included in the models as 240 covariates. the ld class was used as the reference class to show the effect of positive 241 parenting practice on preventing movement difficulties. model 1 indicated that if parents 242 played games with children frequently, the children would have a 0.287 times lower 243 probability of being in the lbp class, 95%ci [0.105, 0.783]. model 2 indicated that if parents 244 take their children to meet peers of a similar age frequently, the children would have a 0.339 245 times lower probability of being in the md class, 95%ci [0.139, 0.825]. 246 247 discussion 248 to the best of the authors’ knowledge, this study is the first in japan to examine the long-term 249 effects of parenting practice in children’s preschool period on their movement performance 250 outcomes when they are school age. we originally explored three patterns of children’s 251 movement performance and identified their characteristics in a sample of children from a 252 suburban area in central japan. based on our longitudinal results, we indicated that more 253 positive stimulations in parenting practice, such as playing games with children frequently 254 and frequently taking children to meet peers of a similar age, contribute to preventing 255 children from developing movement difficulties three years later. 256 257 several studies have used person-oriented method to explore pattens of movement 258 performance, however, got inconsistent results. jaakkola et al. investigated pa, sedentary 259 time, perceived competence, motor competence, cardiorespiratory fitness, and muscular 260 fitness in a finnish elementary school student sample (n = 491; mage = 11.27, sd = 0.32) and 261 labelled three movement profiles as ‘at-risk’ (37.7%, n = 185), ‘intermediate’ (49.3%, n = 262 9 242), and ‘desirable’ (13.0%, n = 64).24 four movement profiles, which were ‘poor movers’ 263 (27.9%, n = 129), ‘average movers’ (38.4%, n = 177), ‘skilled movers’ (18.9%, n = 87), and 264 ‘expert movers’ (14.8%, n = 68), were identified when the performance of leap, throw-catch, 265 jump, push-up, sit-up tests were focused on.25 our study explored three patterns of children’s 266 movement performance and originally identified the characteristics associated with different 267 types of movement difficulties. the biggest cluster, ld (58.2%, n = 131), received 268 significantly higher probability of ‘no difficulties’ than the md cluster (30.2%, n = 68) for all 269 nine items except flexibility. all samples in the lbp cluster (11.6%, n = 26) reported having 270 pains in their low back, which was significantly different from the other two clusters. 271 previous studies highlighted the prevalence of low back pain in school-aged children was 272 24% in a british sample (n = 1376) while it was 22% in an american sample (n = 1241) and 273 51% in a danish sample (n = 1395. this suggests low back pain is an important and 274 relatively common problem in school children.26 our results are consistent with the existing 275 research and additionally suggested low back pains should also be given attention in japan. 276 277 many previous studies have indicated parent-related factors, such as parents’ attitude towards 278 children’s pa, parents’ exercise habits, and parenting practice, are associated with children’s 279 daily physical activities, and therefore, influence children’s motor competence and physical 280 performance.27 a systematic review indicated supporting children to do pa or enrol in pa 281 classes, doing pa together significantly contributed to improving children’s physical 282 performance.28 davison originally created the activity support scale (acts) to measure 283 parental support for children's pa and confirmed that providing children with the chance or 284 places to be active, and playing sports with children is beneficial for children to improve their 285 physical activity levels.29 in addition, previous studies also highlighted the important role of 286 peer interactions on children’s motor performance.30 one systematic review reported positive 287 influence of peers’ support on pa and health outcomes.31 our results are consistent with 288 previous studies and further clarified long-term effects of parenting practice during preschool 289 years on children’s movement performance when they entered primary school. we indicated 290 that playing games with preschool children frequently contributes to preventing children from 291 developing back pain three years later; while taking children to meet peers of a similar age is 292 beneficial to the prevention of children’s movement difficulties when reaching school age. 293 294 on the other hand, children’s age, gender, bmi, sleep condition, and dietary habits were not 295 10 significantly associated with children’s movement performance in the current study, which 296 are not consistent with existing research. boys performed better in ‘walking’, while girls 297 performed better in ‘ball control’, and no gender difference were observed in ‘running’ and 298 ‘kicking’ in a meta-analysis for japanese preschool children.32 cardio-respiratory fitness 299 (crf) and flexibility decreased with increasing age in a sample of 4,903 european children 300 aged 6–11 years.33 sleep duration did not have a consistent significant effect on physical 301 fitness while fruit and vegetable intake positively related to physical performance with small 302 effects.34 inconsistent results suggested influence factors and their effects of movement 303 performance are complex and different across culture. 304 305 several limitations should be considered when interpreting our results and designing future 306 studies. first, children’s movement performance was only measured by parent-reported 307 questionnaires in the present study. objective tests should be performed to verify the 308 consistency of the results in the future. second, although we have controlled several 309 covariates, more related factors, such as ses and baseline movement performance, should 310 also be included in the final analysis model. finally, the sample size was small because of the 311 loss of follow-up. 312 conclusions 313 in conclusion, children in this study were grouped into three movement performance pattens 314 labelled ‘least difficulties (ld)’, ‘low back pain (lbp)’, and ‘most difficulties (md)’, based 315 on a person-oriented perspective and cluster analysis. the ld group was characterised as 316 having highest probability of having no difficulties for all items, while the md group was 317 characterised as having lowest probability of having no difficulties. the lbp group was 318 characterised by having all samples in the group develop low back pain. more positive 319 stimulations in parenting practice during preschool years, such as frequently playing games 320 with children and taking children to meet peers of a similar age, contributed to preventing 321 children’s movement difficulties when they entered primary school. children with movement 322 difficulties should be carefully monitored by healthcare providers. parents’ support is 323 beneficial for children to prevent developing movement difficulties. nevertheless, there is 324 still a great need for more diverse samples and sufficient sample sizes to confirm the results 325 across cultures. 326 327 11 conflict of interest 328 the authors declare no conflicts of interest. 329 330 funding 331 japan society for the promotion of science under grants-in-aid for scientific research 332 17h02604. 333 334 acknowledgement 335 we express our deepest gratitude to all the participants and staff members of tobishima for 336 their voluntary participation in this study. the work was also supported by japan society for 337 the promotion of science (jsps) to provide the funding [grant nos. jp21h00790 and 338 jp21k18449]. 339 340 authors' contribution 341 conceptualization, zhu zhu and cunyoen kim; methodology, zhu zhu, dandan jiao, and 342 toshiyuki kasai; software, yantong zhu and xiang li; validation, zhu zhu, dandan jiao, 343 ammara ajmal, and munenori matsumoto; formal analysis, zhu zhu; investigation, dandan 344 jiao, xiang li, ammara ajmal, munenori matsumoto, yuko sawada, sumio ito, and rika 345 okumura; resources, tokie anme; data curation, dandan, jiao, yuko sawada, taeko 346 watanabe, etsuko tomisaki, emiko tanaka, and tokie anme; writing original draft 347 preparation, zhu zhu; writing—review and editing, cunyoen kim, dandan jiao, and xiang 348 li; visualization, tokie anme; supervision, tokie anme; project administration, tokie anme; 349 funding acquisition, tokie anme. all authors have read and agreed to the published version 350 of the manuscript. 351 352 references 353 1. missiuna c, moll s, king s, king g, law m. a trajectory of troubles: parents' 354 impressions of the impact of developmental coordination disorder. phys occup ther 355 pediatr. 2007; 27(1):81-101. 356 2. holm i, tveter at, aulie vs, stuge b. high intraand inter-rater chance variation of the 357 movement assessment battery for children 2, ageband 2. res dev disabil. 2013; 358 34(2):795-800. 359 12 3. kwan my, cairney j, hay ja, faught be. understanding physical activity and 360 motivations for children with developmental coordination disorder: an investigation using 361 the theory of planned behavior. res dev disabil. 2013; 34(11):3691-8. 362 4. canto eg, guillamon ar, lopez ln. relationship between overall physical condition, 363 211 motor coordination and perceived quality of life in spanish adolescents. acta colomb 364 de 212 psicol 2021; 24:96–106. https://doi.org/10.14718/acp.2021.24.1.9 365 5. world health organization. guidelines on physical activity, sedentary behaviour and 366 sleep for children under 5 years of age. from: 367 https://apps.who.int/iris/handle/10665/311664. accessed: aug 2021. 368 6. kilani h, alyaarubi s, zayed k, alzakwani i, bererhi h, shukri r, alrasadi k. physical 369 fitness attributes, vitamin d, depression, and bmd in omani's children. eur. sci. j. 370 2013; 9(30): 156-173. 371 7. japan sports agency. the national survey of children’s physical fitness, motor 221 372 competence, and physical activity. from: 222 373 https://www.mext.go.jp/sports/content/20191225-spt_sseisaku02-000003330_1.pdf. 374 accessed: 223 aug 2021. 375 8. cools w, martelaer kd, samaey c, andries c. movement skill assessment of typically 376 developing preschool children: a review of seven movement skill assessment tools. j 377 sports sci med. 2009; 8(2):154-68. 378 9. davids k, baker j. genes, environment, and sport performance: why the nature-nurture 379 dualism is no longer relevant. sports med. 2007; 37(11):961-80. 380 10. johnston lm, burns yr, brauer sg, richardson ca. differences in postural control and 381 movement performance during goal directed reaching in children with developmental 382 coordination disorder. hum mov sci. 2002; 21(5-6):583-601. 383 11. ikeda t, aoyagi o. relationships between gender difference in motor performance and 384 age, movement skills and physical fitness among 3to 6-year-old japanese children based 385 on effect size calculated by meta-analysis. school health 2009; 5:9-23. doi: 386 10.20812/jash.sh-2009_031 387 12. jaric s. role of body size in the relation between muscle strength and movement 388 performance. exerc. sport sci. rev. 2003; 31(1): 8-12. 389 13. tyler rpo. health, fitness, lifestyle and physical competency of school children in 390 wales. swansea university. 2018; https://doi.org/10.23889/suthesis.50798 391 13 14. newland la. family well‐being, parenting, and child well‐being: pathways to healthy 392 adjustment. clinical psychologist. 2020; 19(1):3-14. 393 15. kahraman h, yilmaz irmak t, basokcu to. parenting practices scale: its validity and 394 reliability for parents of school-aged children. educ. sci.: theory pract. 2017; 395 17:745–769. doi:10.12738/estp.2017.3.0312 396 16. jago r, davison kk, brockman r, page as, thompson jl, fox kr. parenting styles, 397 parenting practices, and physical activity in 10to 11-year olds. prev med. 2011; 398 52(1):44-7. 399 17. bradley rh, mcritchie s, houts rm, nader p, o'brien m. parenting and the decline of 400 physical activity from age 9 to 15. int. j. behav. nutr. phys. act. 2011; 8(1): 1-10. 401 18. hutchens a, lee re. parenting practices and children's physical activity: an integrative 402 review. j sch nurs. 2018;34(1):68-85. 403 19. anme t, tanaka e, watanabe t, tomisaki e, mochizuki y, tokutake k. validity and 404 reliability of the index of child care environment (icce). public health front 2013; 2: 405 141–5 https://doi.org/10.5963/phf0203003 406 20. chen w, tanaka e, watanabe k, tomisaki e, watanabe t, wu b, anme t. the influence 407 of home-rearing environment on children’s behavioral problems 3 years’ later. 408 psychiatry res. 2016; 244:185–193. 409 21. bradley rh, caldwell bm. the home inventory and family demographics. dev. 410 psychol. 1984; 20:315–320. 411 22. anme t. empowerment for healthy longevity–effective utilization as skills for care 412 prevention and health premotion (in japanese). tokyo, japan: ishiyaku publishers, inc., 413 2007. p. 42-55. 414 23. lanza st, cooper br. latent class analysis for developmental research. child dev 415 perspect 2016; 10: 59–64. https://doi.org/10.1111/cdep.12163 416 24. jaakkola t, yli‐piipari s, stodden df, huhtiniemi m, salin k, seppälä s, et al. 417 identifying childhood movement profiles and tracking physical activity and sedentary 418 time across 1 year. transl. sports med. 2020;3(5):480-7. 419 25. jaakkola t, hakkarainen a, grasten a, sipinen e, vanhala a, huhtiniemi m, et al. 420 identifying childhood movement profiles and comparing differences in mathematical 421 skills between clusters: a latent profile analysis. j sports sci. 2021;39(21): 2503-2508. 422 26. watson kd, papageorgiou ac, jones gt, taylor s, symmons dp, silman aj, 423 macfarlane, gj. low back pain in schoolchildren: occurrence and characteristics. pain 424 14 2002; 97(1-2): 87-92. 425 27. newland la. family well‐being, parenting, and child well‐being: pathways to healthy 426 adjustment. clinical psychologist. 2020;19(1):3-14. 427 28. sleddens ef, kremers sp, hughes so, cross mb, thijs c, de vries nk, et al. physical 428 activity parenting: a systematic review of questionnaires and their associations with 429 child activity levels. obes rev. 2012; 13(11):1015-33. 430 29. davison, k. activity-related support from parents, peers and siblings and adolescents' 431 physical activity: are there gender differences? j. phys. activ. health 2004; 1: 363–376. 432 30. herrmann c, bretz k, khnis j, seelig h, keller r, ferrari i. connection between social 433 265 relationships and basic motor competencies in early childhood. children 2021; 8:10. 434 266 https://doi.org/10.3390/children8010053 267 435 31. jenkinson ka, naughton g, benson ac. peer-assisted learning in school physical 268 436 education, sport and physical activity programmes: a systematic review. phys educ 437 sport 269 pedagogy 2014; 19: 253–77. https://doi.org/10.1080/17408989.2012.754004 438 32. ikeda t, aoyagi o. relationships between gender difference in motor performance and 439 age, movement skills and physical fitness among 3-to 6-year-old japanese children 440 based on effect size calculated by meta-analysis[j]. school health, 2009, 5: 9-23. 441 33. zaqout m, vyncke k, moreno la, de miguel-etayo p, lauria f, molnar d, et al. 442 determinant factors of physical fitness in european children. int j public health. 443 2016;61(5):573-82. 444 34. jaikaew r, satiansukpong n. movement performance and movement difficulties in 445 typical school-aged children. plos one. 2021; 16(4): e0249401. 446 15 table 1: demographic background in the baseline year n = 225 variables categories n % age of child (years) 4.13±0.87a gender of child boy 119 52.9 girl 106 47.1 siblings only child 37 16.4 having siblings 188 83.6 family structure nuclear family 107 47.6 extended family 118 52.4 bmi sds of child 0.12±0.98a sleep condition of child fussy eating behaviour of child sufficient not sufficient no yes 193 32 70 155 85.8 14.2 31.1 68.9 note: a mean and sd were shown for continuous variables. 16 table 2: parenting practice in baseline year and movement performance of children three years' later n = 225 items categories n % parenting practice play games with child few 44 19.6 frequently 181 80.4 shopping with child few 21 9.3 frequently 204 90.7 read books to child few 56 24.9 frequently 169 75.1 sing songs with child few 45 20.0 frequently 179 79.6 na 1 0.4 take child to play outside few 27 12.0 frequently 197 87.6 na 1 0.4 take child to meet peers of similar age few 46 20.5 frequently 178 79.1 na 1 0.4 eat meals together with child few 48 21.4 frequently 176 78.2 na 1 0.4 spank child for mistakes spank 14 6.3 not spank 210 93.3 na 1 0.4 spank child last week spank 85 37.8 not spank 138 61.3 na 2 0.9 take care of child with others few 18 8.0 frequently 204 90.7 na 3 1.3 talk with spouse about child few 50 22.3 frequently 174 77.3 na 1 0.4 have helpers no 5 2.2 yes 218 96.9 na 2 0.9 have someone to consult with no 7 3.1 yes 216 96.0 na 2 0.9 movement performance 17 keep active with difficulties 69 30.7 without difficulties 156 69.3 keep running with difficulties 62 27.6 without difficulties 163 72.4 good sitting posture with difficulties 139 61.8 without difficulties 86 38.2 arm strength with difficulties 127 56.4 without difficulties 98 43.6 low back strength with difficulties 59 26.2 without difficulties 166 73.8 leg strength with difficulties 54 24.0 without difficulties 171 76.0 agility with difficulties 114 50.7 without difficulties 111 49.3 balanced with difficulties 94 41.8 without difficulties 131 58.2 flexibility with difficulties 163 72.4 without difficulties 62 27.6 note: na = no answer 447 18 table 3: model fit information for the lca models log-likelihood df g-squared aic bic abic entropy blrt two-class model –1112.676 492 381.606 2263.352 2328.258 2268.043 0.827 <0.01 three-class model –1067.113 481 278.509 2192.226 2291.293 2199.386 0.935 <0.01 four-class model –1036.648 471 217.222 2151.296 2284.524 2160.925 0.903 <0.01 five-class model –1018.885 462 194.023 2135.769 2303.158 2147.867 0.921 <0.01 six-class model –1009.066 452 174.386 2136.133 2337.683 2150.700 0.935 0.122 note: df=degrees of freedom; aic=akaike information criteria; bic=bayesian information criteria; abic=adjusted bayesian information criterion; blrt= bootstrapped likelihood ratio test 448 19 table 4: demographics and movement performance characteristics of three patterns 449 variables categories movement performance f/c2 p class1 class 2 class 3 n % n % n % age 4.13±0.87 2.112 0.123 gender boy 65 54.6 14 11.8 40 33.6 1.533 0.465 girl 66 62.3 12 11.3 28 26.4 siblings single child 23 62.2 4 10.8 10 27.0 0.289 0.865 having siblings 108 57.4 22 11.7 58 30.9 family structure nuclear family 61 57.0 11 10.3 35 32.7 0.757 0.685 extended family 70 59.3 15 12.7 33 28.0 bmisds 0.12±0.98 0.389 0.678 sleep sufficient 19 59.4 3 9.4 10 31.3 0.175 0.916 not sufficient 112 58.0 23 11.9 58 30.1 fussy eating no 93 60.0 17 11.0 45 29.0 0.653 0.721 yes 38 54.3 9 12.9 23 32.9 keep active with difficulties 21a 30.4 5a 7.2 43b 62.3 48.721 0.000 without difficulties 110 70.5 21 13.5 25 16.0 keep running with difficulties 15a 24.2 4a 6.5 43b 69.4 62.315 0.000 without difficulties 116 71.2 22 13.5 25 15.3 good sitting posture with difficulties 66a 47.5 20b 14.4 53b 38.1 17.254 0.000 without difficulties 65 75.6 6 7.0 15 17.4 arm strength with difficulties 59a 46.5 16a, b 12.6 52b 40.9 18.300 0.000 without difficulties 72 73.5 10 10.2 16 16.3 low back strength with difficulties 12a 20.3 20b 33.9 27c 45.8 60.649 0.000 without difficulties 119 71.7 6 3.6 41 24.7 20 leg strength with difficulties 15a 27.8 14b 25.9 25b 46.3 30.083 0.000 without difficulties 116 67.8 12 7.0 43 25.1 agility with difficulties 47a 41.2 15a, b 13.2 52b 45.6 30.090 0.000 without difficulties 84 75.7 11 9.9 16 14.4 balanced with difficulties 42a 44.7 16b 17.0 36b 38.3 12.743 0.002 without difficulties 89 67.9 10 7.6 32 24.4 flexibility with difficulties 95a 58.3 18a 11.0 50a 30.7 0.175 0.916 without difficulties 36 58.1 8 12.9 18 29.0 note: a, b refers different groups based on the results of post hoc test using bonferroni method. 450 21 table 5: significant results of multinominal logistic regression model showing associations 451 between parenting practice and movement performance 452 variables lbp class vs. ld class md class vs. ld class or 95%ci p or 95%ci p model 1 play games with child 0.287 0.105 0.783 0.015 0.834 0.371 1.873 0.660 age 0.860 0.499 1.480 0.585 1.389 0.965 1.998 0.077 gender 1.101 0.453 2.674 0.833 1.491 0.804 2.764 0.205 having siblings or not 0.543 0.141 2.092 0.375 0.847 0.362 1.984 0.702 family structure 0.773 0.315 1.901 0.575 1.166 0.634 2.147 0.621 bmi sds 0.997 0.616 1.612 0.989 0.957 0.695 1.316 0.785 sleep condition 0.961 0.245 3.777 0.955 1.144 0.475 2.759 0.764 fussy eating 0.914 0.349 2.393 0.855 0.843 0.436 1.631 0.613 model 2 take child to meet peers of a similar age 1.175 0.443 3.115 0.746 0.339 0.139 0.825 0.017 age 0.936 0.552 1.586 0.806 1.401 0.973 2.019 0.070 gender 1.006 0.419 2.413 0.990 1.399 0.745 2.627 0.296 having siblings or not 0.634 0.169 2.378 0.499 0.837 0.357 1.964 0.682 family structure 0.880 0.367 2.110 0.774 1.155 0.626 2.134 0.645 bmi sds 1.085 0.681 1.728 0.732 0.941 0.685 1.294 0.710 sleep condition 0.853 0.220 3.300 0.818 1.117 0.459 2.718 0.807 fussy eating 0.921 0.356 2.385 0.865 0.878 0.450 1.712 0.703 note: 1. reference group: play games with child = few, encourage child to play with peers of 453 a similar age = few, gender = boy, having siblings or not = only child, family structure = 454 nuclear family, sleep = sufficient, fussy eating = no fussy eating behaviours, age, bmi sds = 455 continuous variables. 456 2. ld = least difficulties, lbp = low back pain, md = most difficulties 457 22 figure 1: item probability of movement performance without difficulties in three classes. 458 459 0.0 20.0 40.0 60.0 80.0 100.0 keep active keep running keep sitting posture arm strength low back strength leg strength agility balanced flexible p ro b a b il it y （%） class 1-least difficulties (n = 131, 58.2%) class 2-low back pain(n = 26, 11.6%) class 3-most difficulties (n = 68, 30.2%) july 2008.indd varied presentations of acute glomerulonephritis in children single centre experience from a developing country *kalpana malla, moinak s sarma, tejesh malla, anna thaplial sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 193-199 sultan qaboos university© submitted 11th spetember 2007 accepted 21th april 2008 c l i n i c a l a n d b a s i c r e s e a r c h عند األطفال لَى احلاد الكُ بَيباتِ كُ اللْتِهابُ العروض اتلفة في دولة نامية جتربة مركز منفرد ثاباليل أنا مال، تيجيش سارما، مويناك مال، كالبانا اتلفة ــريرية الس العروض التعليمي في بخارى لتوثيق مانيبال ــفى مستش في أجريت ــتباقية التي االس ــة الدراس الهدف: هدفت هذه امللخص: واتبرية ــريرية الس ُتَثابِتَات الطريقة: امل الغربية. نيبال في املتوفرة البيولوجية ُتَثابِتَات امل مع ومقارنة ذلك ، األطفال عند احلاد لَى الكُ بَيباتِ كُ اللْتِهابُ بالتهاب 92 طفال ــخيص مت تش (2007-2000) ــنوات ــبع س العيانية واهرية. النتائج: خالل س وِيَّة مَ الدَ والبِيلَةٌ الوذمة من يعانون الذين لألطفال اللْتِهابُ اتلفة العروض على الضوء ــلطت س احلالية ــة اخلالصة: الدراس باألحداث. زاخرة واتبرية كانت ــريرية الس التحليالت . احلاد لَى الكُ بَيباتِ كُ النيبال. من الغربية في املنطقة الكالسيكية العروض من انتشارا أكثر منطية الال واملضاعفات العروض أن وبينت ، احلاد لَى الكُ بَيباتِ كُ نيبال. ، البولية ااري التهاب ، حاد ، لَى الكُ بَيباتِ كُ الْتِهابُ ، الكلمات: مرض الكلية مفتاح department of pediatrics, manipal college of medical sciences, pokhara, nepal * to whom correspondence should be addressed. email: kalpana17@hotmail.coms abstract: objectives: the objective of this prospective study, carried out at manipal teaching hospital, pokhara, was to document the various clinical presentations of children with acute glomerulonephritis and compare them with the available biological parameters in western nepal. methods: clinical and laboratory parameters of children with oedema and microscopic/macroscopic haematuria. results: for seven years (2000-2007), 92 cases of children were clinically diagnosed with acute glomerulonephritis (agn). other clinical and laboratory anaylses were also eventful. conclusion: the present study highlights the varied presentations of agn, atypical presentations or complications of glomerulonephritis being more common than the classical presentation in the western region of nepal. key words: renal disease; glomerulonephritis, acute; urinary tract infection; nepal. glomerulonephritis (gn) is the term generally reserved for the variety of re-nal diseases in which inflammation of the glomerulus, manifested by proliferation of cellular elements, is secondary to an immunologic mechanism.1 most incidents of agn appear to be associated with a postinfectious state with known aetiological agents like bacteria, parasite, virus. amongst the gn secondary to bacterial infections, post-streptococcal gn is the most frequent and usually presents with typical clinical findings;2 however, the scenario in this study was different. out of 92 cases of acute glomerulonephritis, only 33 cases presented with typical clinical features of gn; the remaining 59 had atypical clinical presentations. atypical postinfectious glomerulonephritis (pign) may mimic a great variety of glomerular diseases.3, 4 m e t h o d s this prospective study was conducted between september 2000 and march 2007 at the department of pediatrics, manipal teaching hospital, pokhara, nepal. the case collection was from september 2000 to february 2005 and follow-up was continued until march 2007. ninety-two children of all age groups presenting either with oedema (facial puffiness and/or k a l pa n a m a l l a , m o i n a k s s a r m a , te j e s h m a l l a a n d a n n a th a p l i a l 194 pedal oedema) and haematuria (microscopic or frank and/or cola coloured urine) were considered for this study. borderline cases, those with urinary stones and with hypercholesterolemia suggestive of nephrotic syndrome, (4+ protenuria with high cholesterol level requiring treatment with prednisolone) were excluded from the study. both outpatients as well as hospitalized patients were enrolled for the study. consent of the patients was taken and the parents or guardians received information about the study and follow-ups. a detailed history was taken and a clinical examination performed, followed by relevant available investigations. the investigations included urine routine and microscopic examination, urine culture and sensitivity, renal function tests, antistreptolysin o (aso) titres and ultrasound of the abdomen. facilities for doing serum complement levels, electron microscopy and immunofluroscence studies for renal biopsy were not available in this centre. these cases were followed up for two years. r e s u l t s of the 92 children, 57 (61.95%) were male and 35 (38.05%) were female. all were diagnosed to have acute glomerulonephritis (agn). the male: female ratio was 1.6:1. eighty-eight children (95.7%) were above 5 years (school going age group); only four (4.3%) of the children were under 5 years (preschool age group) [table 1]. the classical presentation of agn was seen only in 33 (35.9%) cases, while 59 (64.1%) presented with atypical findings or complications [figure 1]. the pattern of atypical presentations/complications were hypertensive encephalopathy (n = 11, 18.6%); nephrotic onset (n = 10, 16.9%); urinary tract infection (uti) (n = 10, 16.9%); joint pains and rash (n = 2, 3.3%); heart failure (hf) (n = 6, 10.1%); combined hf and uti (n = 3, 5.1%); rapid deterioration or progression (n = 5, 8.5%); acute renal failure (n = 4, 6.7 %); combined cardiac and renal failure (n = 1, 1.69 %), associated with rheumatic fever (n = 3, 5.1%); epistaxis (n = 2, 3.3%); malena (n = 1, 1.69%); associated with enteric fever and uti (n = 1, 1.69 %) [table 2]. clinically, all (100%) children had facial puffiness and/or pedal oedema and macroscopic haematuria (frank and/or cola coloured urine). other main clinical features were hypertension (n = 80, 86.9%), fever (n = 60, 65.2%), headache (n = 58, 63.0%) and oliguria (n = 50, 54.3%) followed by pyodermas, vomiting, burning micturition, painful abdomen, sore throat, altered sensorium, convulsions and shortness of breath. some rare clinical features were also noted cough (n = 14, 15.2%), systolic murmur (n = 7, 7.6%), joint pains and rash (n = 2, 2.1 %), hepatomegaly (n = 3, 3.2 %), diarrhoea (n = 3, 3.2 %), epistaxis (n = 2, 2.1 %), malena (n = 1, 1.0 %) [table 3]. table 4 shows the results of the investigations into urea, creatinine and albumin levels in these patients. aso titres were found to be positive in only 50% of sex age <1yr >1-5yr >5-10yr >10yr male = 57 (61.95 %) female = 35 (38.04%) 0 0 3 1 21 12 33 22 acute glomerulonephritis (agn) (n = 92) total 0 4 33 55 92 table 1: age and sex distribution of patients at presentation figure 1: clinical presentation va r i e d p r e s e n tat i o n s o f a c u t e g l o m e r u l o n e p h r i t i s i n c h i l d r e n 195 the cases. an ultrasonography (usg) of the kidney, ureters and bladder revealed grade i renal parenchymal changes (rpc) in 48%; grade ii rpc, mild renal dysfunction (mrd) in 24%; grade iii rpc in 6.5% and normal in 22% cases [figure 2]. all the three renal biopsies showed cresentric glomerulonephritis. d i s c u s s i o n the global burden of severe group a streptococcal disease is concentrated largely in developing countries including nepal. group a streptococcal diseases are more common in children than in adults with diseases ranging from pharyngitis and impetigo to invasive infections and the post-streptococcal sequelae: acute rheumatic fever and acute post-streptococcal glomerulonephritis.3 acute post-streptococcal glomerulonephritis is the commonest cause of agn in this country which usually exhibits milder symptoms or signs like haematuria, mild oedema, oliguria and hypertension which has a simple clinical course and an excellent prognosis. on the other hand, atypical presentations may mimic a great variety of glomerular disease, have a worse prognosis and need better diagnosis and care. glomerular disease with atypical presentations will include mild mesangial and/or endocapillary glomerulonephritis (gn); focal segmental glomerulosclerosis (fsgs) with diffuse igm mesangial deposits; rapidly progressive or crescentic gn with c3 hump-like deposits or with microabscesses; focal mesangiocapillary gn superimposed on endocapillary pattern; membranous gn with diffuse exudative changes and postinfectious glomerulonephritis with anti–glomerular basement membrane (anti-gbm) linear deposits.4 some other study states that mesangial proliferative gn is the commonest histopathological lesion forming 66% of all primary gn. minimal lesion, focal global sclerosis and focal segmental glomerulosclerosis accounted for 7% each. membranous gn was uncommon (3%), while mesangiocapillary gn, diffuse endocapillary gn and crescentic gn were even rarer.5 in this study, we tried to ascertain age incidence, sex ratio, common clinical presentations and available biochemical parameters of primary glomerulonephritis. out of 92 children, there were 59 atypical findings of agn. those with positive aso titres were treated as poststreptococcal glomerulonephritis cases. the others were given the benefit of the doubt and treated for the same. lack of facilities for investigations and financial constraints in a developing country did not permit us to proceed with further workups. hence the confirmatory diagnosis could not be made in these cases. like other studies, this study also showed a preponderance of males (61.95%) as agn cases (n = 59) number percentage agn with hypertensive encephalopathy 11 18.6% agn with nephrotic picture 10 16.9 % agn with urinary tract infection (uti) 10 16.9 % agn with heart failure 6 10 .1% agn with rapid progressive gn 5 8.5% agn with acute renal failure 4 6.7 % agn with rheumatic fever 3 5 % agn with heart failure + uti 3 5 % agn with joint pains and rash 2 3.3 % agn with epistaxis 2 3.3 % agn with malena 1 1.69% agn with heart failure and acute renal failure 1 1.69 % agn with enteric fever and urinary tract infection 1 1.69 % total 59 100% table 2: pattern of atypical presentations/complications of acute glomerulonephritis (agn) table 3: signs and symptoms of patients at presentation signs and symptoms number (n=92) percentage hypertension 80 86.9% fever 60 65.2% headache 58 63% oliguria 50 54.3% pyoderma 42 45.6 % vomiting 33 35.8 % burning urine 32 34.7 % pain abdomen 31 33.6 % sore throat 28 30.4 % altered sensorium 21 22.8 % convulsions 21 22.8 % shortness of breath 18 19.5% cough 14 15.2 % systolic murmur 7 7.6 % hepatomegaly 3 3.2 % diarrhoea 3 3.2 % joint pain with rash 2 2.1 % epistaxis 2 2.1 % malena 1 1.0 % k a l pa n a m a l l a , m o i n a k s s a r m a , te j e s h m a l l a a n d a n n a th a p l i a l 196 compared to females (38.05%) with the ratio 1.6:1. the reasons for this male predominance are not known.1 as in other studies,6 most children were above 10 yrs (57.9%). hypertensive encephalopathy was found in 18.6%, a much higher percentage compared to 5% & 4.3 % in other studies. 7, 5 in these patients, hypertension is usually difficult to control and accompanied by signs of central nervous system dysfunction such as headaches, vomiting, depressed sensorium, confusion, visual disturbances, aphasia, memory loss, coma, and convulsions. all these features were also noted in our study. twelve of the cases, which presented as nephrotic onset, had anasarca with proteinuria >40 mg/ m2/hr. all of them (100%) had haematuria and hypertension; their features resolved with symptomatic treatment and did not require steroids. the incidence of nephrotic features was higher in other studies, 61.7%, 66%, 29% and 34.48% respectively as compared to ours which was only 13%. 5, 8-10 seventeen percent had associated uti which is quite frequently seen. agn complicated by uti was also observed in 20% cases in a study in nigeria.11 rapidly progressive glomerulonephritis (rpgn) is a disease of the kidney that results in a rapid decrease in the glomerular filtration rate of at least 50% over a short period, from a few days to 3 months and is irreversible.12 this was observed in 8.5 % in our study. the frequency is estimated at 1-2 cases per 100,000 persons internationally. the main pathologic finding is fibrinoid necrosis (>90% of biopsy specimens); extensive crescent formation is present in at least 50% of glomeruli.12 as biopsy was not done in our cases we could not confirm the cases by pathological findings, hence the observed frequency was higher. heart failure (hf) and acute renal failure (arf) were the sole systemic complications in 7/29 and 2/29 in agn patients respectively, noted by olowa wa in nigeria.10 heart failure was seen in 3% cases in another study, 13 whereas in our study 10% presented with shortness of breath, cough, hepatomegaly. acute renal failure is defined as abrupt or rapid decline in renal filtration function. the condition is often transient and usually completely reversible.14acute renal failure was present in 56 (76%) in one study and dialysis required in 14, but this presentation was much less in our study and only 4 required dialysis.9 we also observed some rare features like rheumatic fever (5%), epistaxis in 2 patients, melena in one. literature on these presentations was not available. a few double systemic complications were also noted: agn with enteric fever with uti (1.69%), agn with hf and arf (1.69%).three patients had double systemic complications in another study: one with hypertensive encephalopathy (hte) with hf, and two with acute renal failure (arf) with hf.10 the development of clinical nephritis (i.e. haematuria and/or oedema) either during or within 2-5 days after the onset of a respiratory tract infection is atypical and suggests the possibility of some other form of gn.15 in our study, nephritis developed following respiratory infection in 15% cases. hypertension was the commonest mode of presentation (87%) in a study by corpa, soares v. the prevalence of arterial hypertension was 62.7%16 and it was 50% and 86.7% respectively in another study. 17, 8 the pathogenesis of the hypertension is unknown; howevparameters number percentage urea : normal range 0.535-14.28mmol/l (15-40mg/dl) <14.28mmol/l (< 40mg/dl) 14.63-17.85mmol/l (41-50mg/dl) 18.20-35.70mmol/l (51-100mg/dl) >35.70mmol/l (>100mg/dl) 40 22 20 9 43.5% 24% 22% 10% creatinine: normal range 53.04-132.6µmol/l (0.6-1.5mg/dl) <132.6µmol/l (<1.5mg/dl) 141.44-142µmol/l (1.6-5mg/dl) >142µmol/l (5 mg/dl) 54 23 15 59% 25% 16% albumin: normal range 3.5-5gm/dl <25gm/l (2.5 g /dl) 26-30gm/l (2.6 -3.0g/dl) 31-35gm/l (3.1 3.5 g/dl) >35gm/l (3.5g/dl) 16 38 18 20 17.4% 41% 19.6% 22% table 4: biochemical parameters of the patients va r i e d p r e s e n tat i o n s o f a c u t e g l o m e r u l o n e p h r i t i s i n c h i l d r e n 197 er, it is probably multifactorial and related only in part to extracellular fluid (ecf) volume expansion. haematuria and protenuria was present in 41% in one study5 and in 48.8% in another study.8 according to some investigators, oedema is found in approximately 85% of patients.15 oedema usually appears abruptly and the degree of oedema varies markedly and depends on a number of factors, including the severity of glomerular involvement, the fluid intake, and the degree of hypoalbuminaemia. in our study also the degree of oedema was variable. gross haematuria occurs at onset in 30-50% of children with poststreptococcal glomerulonephritis (psgn) who require hospitalisation.18 the cardinal features are associated with various degrees of malaise, lethargy, anorexia, fever, abdominal pain and headache. observant parents may also note oliguria. all these features were observed in this study. almost characteristic by their absence are arthralgia, arthritis, carditis, hepatic involvement, and gastrointestinal bleeding, 19, 17 but in this study these findings were also noted. systolic murmur was observed in 7.6% of the cases, hepatomegaly in 3%, diarrhoea in 3% and joint pain with rash in 2%. in this study, pyoderma and sore throat were the preceding cause of gn in 46% and 30 % of cases respectively. this indicates the possibility of post streptococcal origin; however, in the remaining 24% cases there was no preceding pyoderma or sore throat. other postinfectious causes that have been reported are: streptococcus pneumoniae, staphylococcus aureus, staphylococcus epidermidis, rickettsia rickettsiae, mycoplasma species, meningococcus species, leptospira species. also, viral illnesses have preceded the onset of typical agn; among the most common are the varicella zoster virus, cytomegalovirus, and the epstein-barr virus.20 in the analysis of laboratory parameters, it was noted that impairment of urea was seen in 56% and impairment of creatinine in 41%. renal impairment observed in other studies was 33.3%8 and 5.5% respectively. 8, 21,19 low albumin levels of >35gm/l were observed in 78% of cases (25gm/l in 17.4%; 26-30gm/l in 41%; 31-35gm/ l in 19.6%) and normal levels of >35gm/l in 22%. in the majority (60.6%) of cases it was between 2.6 3.5 g/dl. the reason why many patients had albumin levels slightly on the low side can be explained by the fact that these children were malnourished, which is again a common problem of this country. a rise in the titer of aso is observed in only 50% of patients.22, 20 in our study too, aso was positive in 50% of cases. ultrasound of the kidney, ureters and bladder was normal in 22% cases. forty-eight percent of patients with rpc had rpc grade i (rpc), 24% had grade ii, and 6.5% had grade iii. rpc grade i is echogenicity of kidney the same as the liver, rpc grade ii is echogenicity of the kidney more than the liver. rpc grade iii means that renal fat sinus and renal parenchyma cannot be differentiated with accentuated/att corticomedullary differentiation.23, 21 the follow-up of this study was not good as just over half the patients (52.5%) did not return for followup. maybe the referral to a higher level centre was the reason for this. among those who came for follow-up, the ones with classical presentation agn had complete resolution of the disease. complete resolution was also observed in 42.85% cases that had atypical or complicated presentations. this means many may still have fallen into postinfectious forms, which are very common in our environment. of these, 32.14% classical presentation (n = 33) atypical or complicated presentation (n = 59) follow-up yes no 33 (100%) 0 (0%) n = 33 28 (30.4%) 31 (52.5%) n = 59 complete resolution with impaired renal function end stage renal disease on haemodialysis at higher centre mortality 33 (100%) 0 (0%) 0 (0%) 0 (0%) n = 33 12 (42.85%) 9 (32.14%) 5 (17.85%) 2 (7%) n = 28 table 5: follow-up of patients k a l pa n a m a l l a , m o i n a k s s a r m a , te j e s h m a l l a a n d a n n a th a p l i a l 198 had impaired renal function and 17.85% had gone into end stage renal disease and were on haemodialysis at a higher level centre. there was 7% mortality [table 5]. the enlisted cases were provisionally assumed to be of poststreptococcal origin and were treated likewise since psgn is the commonest cause in a developing country like ours. however, these cases, especially the ones which were aso negative, needed better diagnostic and confirmatory support such as complement c3, c4 levels and immunofluorescence for the biopsy specimens. these investigations were unfortunately unavailable at our setup and elsewhere in the city. many investigations were also limited due to financial constraints of the patients. as optimum workup was required, we referred many of the cases to higher level centres. some of these cases were subsequently lost to follow-up. c o n c l u s i o n we conclude that agn is common in children of the western region of nepal and that an unusual atypical presentation is frequent. better outcomes can be achieved with more detailed laboratory and diagnostic methods which are limited at present. renal biopsy in these cases is mandatory and helpful, especially in allowing rational use of corticosteroids and other immunosuppressive drugs. financial constraints are a major contributing factor in a developing country like nepal. nevertheless as psgn is the commonest cause of gn in our country, it is justified to give the benefit of treatment to these patients before considering other causes. symptomatic treatments and careful supportive care will allow the majority of children to recover from post streptococcal agn. a c k n ow l e d ge me n ts the authors wish to thank all the patients and their parents for their co-operation. r e f e r e n c e s 1. brouhard bh, travis lb. acute postinfectious glomerulonephritis. in: edelman cm (jnr), ed. pediatric kidney disease. boston: little, brown and co, 1992. p. 11691221. 2. barbiano di belgiojoso g, genderini a, ferrario f. post-infectious glomerulonephritis. g ital nefrol 2003; 20:184-99. 3. steer ac, danchin mh, carapetis jr. group a streptococcal infections in children. j paediatr child health 2007; 43:203-213. 4. sotsiou f, dimitriadis g, liapis h. diagnostic dilemmas in atypical postinfectious glomerulonephritis. semin diagn pathol 2002; 19:146-159. 5. woo kt, chiang gs, edmondson rp, wu ay, lee ej, pwee hs, lim ch. glomerulonephritis in singapore: an overview. ann acad med singapore 1986; 15:20-31. 6. ali ms, rahman s, siddiqui ni, talukder si, uddin mm, sofiullah m, et al. studies on clinical pattern of glomerulonephritis. mymensingh med j 2004; 13:3335. 7. hoyer jr, michael af, fish aj, good ra. acute poststreptococcal glomerulonephritis presenting as hypertensive encephalopathy with minimal urinary abnormalities. pediatrics 1967; 39:412-417. 8. mitwalli ah, al wakeel js, al mohaya ss, malik hg, abu-aisha h, hassan os, et al. pattern of glomerular disease in saudi arabia . am j kidney dis 1996; 27:797802. 9. montseny jj meyrier a, kleinknecht d, callard p. the current spectrum of infectious glomerulonephritis. experience with 76 patients and review of the literature. medicine (baltimore),1995; 74:63-73. 10. olowu wa. systemic complications of acute glomerulonephritis in nigerian children. niger postgrad med j 2002; 9:83-87. 11. michael io, gabriel oe pattern of renal diseases in children in midwestern zone of nigeria. saudi j kidney dis transpl 2003; 14:539-544. 12. andrassy k, kuster s, waldherr r, ritz e. rapidly progressive glomerulonephritis: analysis of prevalence and clinical course. nephron 1991; 59:206-212. 13 lagunju ia, omokhodion si childhood heart failure in ibadan. west afr j med 2003; 22:42-45. 14. agraharkar m, safirstein rl. pathophysiology of acute figure 2: results of ultrasonogram of kidney ureters and bladder region va r i e d p r e s e n tat i o n s o f a c u t e g l o m e r u l o n e p h r i t i s i n c h i l d r e n 199 renal failure. in: greenberg a, coffman t, eds. primer on kidney diseases. 3rd ed. san diego, calif: academic press, 2001. p. 243-286. 15. simckes am, spitzer a. poststreptococcal acute glomerulonephritis. pediatr rev 1995; 16:278-279. 16. corpa mv, soares v. systemic hypertension in patients with glomerulonephritis. ren fail 2002; 24:347-352. 17. vujić d, djukanović lj, petrović m, radmilović a. arterial hypertension in patients with primary glomerulonephritis. srp arh celok lek 1993; 121:130-132. 18. dodge wf, spargo bh, travis lb, srivastava rn, carvajal hf, debeukelaer mm, et al. poststreptococcal glomerulonephritis. a prospective study in children. n engl j med 1972; 286: 273-278. 19. hricik de, chung-park m, sedor jr. glomerulonephritis. n engl j med 1998; 339:888-899. 20. travis lb: acute postinfectious glomerulonephritis. in: rudolph am, hoffman ji, rudolph cd, eds. rudolph’s pediatrics. stamford, ct: appleton & lange, 1996. p. 1356-1358. 21. herthelius m, berg u. renal function during and after childhood acute poststreptococcal glomerulonephritis. pediatr nephrol 1999; 13:907-911. 22. roy s 3rd, stapleton fb: changing perspectives in children hospitalized with poststreptococcal acute glomerulonephritis. pediatr nephrol 1990; 4:585-588. 23. le quesne gw. assessment of glomerulonephritis in children by ultrasound. in: white d, lyons ea, eds. ultrasound in medicine, vol. l4. new york: plenum, 1978. p. 205-207. whole1.indd abstract objective: chronic pain is associated with increased incidence of hypertension. sleep deprivation, common in patients with chronic pain, is associated with increased blood pressure and heart rate. this study was designed to determine whether sleep deprivation induces increased cardiovascular responses to pain. in addition; we examined the role of melatonin and endorphins in mediating these responses. method: the study was conducted in sprague-dawely rats divided into a control group (n=8) and rapid eye moment sleep deprived (remsd) group (n=8). rem sleep deprivation was done for three days using the inverted flowerpot technique. systolic bp and hr were recorded at baseline as well as 5, 10 and 30 minutes after intra-plantar formalin injection. in addition, serum melatonin and endorphin levels were determined. results: under basal conditions, bp and hr and following acute pain (1st phase of formalin injection) were comparable with non-sleep deprived (non-sd) state. in contrast, the remsd rats showed significantly greater increases in hr and bp during the 2nd phase of formalin pain as compared to non-sd state. these changes were associated with significant reductions in serum melatonin and endorphin levels in remsd rats. conclusion: these data indicate that exaggerated blood pressure and hr responsiveness to pain in sleep deprivation could be mediated through reductions in melatonin and endorphin. keywords: rem sleep deprivation, blood pressure, heart rate, tonic pain, melatonin, endorphins. cardiovascular responses to tonic pain in rem sleep-deprived rats role of melatonin and beta endorphin *salah kassab1, usha sachdeva1, nagalla das2, tarik al-shaibani1 and usha nayar1 sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© an adequate amount of sleep is para-mount for a healthy and productive lifestyle. experimental short-term restriction of sleep results in a variety of adverse physiologic effects, including hypertension, activation of the sympathetic nervous system, impairment of glucose control, and increased inflammation.1 the interaction between sleep and pain is generating a considerable research interest as pain 1department of physiology, college of medicine and medical sc-iences, arabian gulf university, p.o. box 22979, manama, bahrain, 2department of clinical biochemistry, salmaniya medical complex, bahrain *to whom correspondence should be addressed. email: : skassab@agu.edu.bh o r i g i n a l s t u d y نوم من الفئران احملرومة في لأللم الدموية واألوعية القلب استجابة العني حركة واالندورفينات امليالتونني دور السريعة: من يعانون الذين املرضى عند واسع االنتشار يكون الذي النوم من واحلرمان الدم. ضغط ارتفاع حدوث بكثرة املزمن األلم يرتبط املقدمة: امللخص: قلب-وعائية استجابات يولد النوم احلرمان من كان اذا فيما الهدف:حتديد القلب ايضا. نبضات وسرعة الدم ضغط بأرتفاع يكون مرتبطا مزمن ألم تقسيمها حيث مت ، دولي – سبراج فئران في الدراسة اجريت ألطريقة: االستجابات. هذه في واالندورفينات امليالتونني دور اختبرنا اضافة لذلك، لأللم. بوت تقنية الفلور باستخدام أيام ثالثة لفترة دام النوم حرمان السريعة. العني حركة نوم من للحرمان تعرضت وأخرى (٨ (عدد ضابطة مجموعة إلى اسفل القدم. الفورمالني في بعد حقن ٣٠ دقيقة ١٠ و ٥ و وبعد بالبحث قبل البدء سجلت القلب نبضات االنقباضي وسرعة الدم ضغط املقلوب. حقن من األول (الدور احلاد األلم بعد القلب نبضات وسرعة الدم ضغط التجربة، قبل النتائج: اندورفني. والبيتا مستوى امليالتونني قياس مت لذلك إضافة يدرجة أظهرت النوم لفقدان املعرضة النقيض، الفئران على السريعة. العني حركة نوم لفقدان تتعرض لم التي للفئران مشابهة كانت الفورمالني) التغيرات هذه الضابطة. اموعة فئران مع باملقارنة الفورمالني ألم الثاني من الدور خالل القلب نبضات وسرعة الدم ضغط ارتفاع في زيادة ملحوظة االستجابة الى أن املعطيات تشير هذه اخلالصة: النوم. من احملرومة الفئران دم في اندورفني والبيتا امليالتونني مرتبطة بانخفاض ملحوظ في كانت وامليالتونني. االندورفني قلة الى تعزى ان ميكن النوم احملرومة من الفئران القلب لأللم في ونبضات الدم لضغط الزائدة s a l a h k a s s a b , u s h a s a c h d e va , n a g a l l a d a s a n d ta r i k a l -s h a i b a n i , u s h a n aya r 52 and sleep seems to have reciprocal relationships. patients who suffer from chronic pain experience difficulties in initiating and maintaining sleep and poor sleep can significantly decrease the pain threshold.2 chronic sleep deprivation has been suggested to be one of the factors which can trigger cardiovascular emergencies such as myocardial infarction.3 however, the mechanisms linking between sleep deprivation, pain and the cardiovascular system are unclear. sleep-deprived (sd) rats suffer from desynchronization of physiological and behavioural rhythms.4 the pineal gland, which controls and synchronizes the sleep-awake cycle, is affected by several stresses such as forced swimming and hypoglycemic shock.5 sleep deprivation also alters the pineal-melatonin system, which has an analgesic action and shares anti-stress activity.6,7 the endogenous opioid peptides have been postulated to have an interaction with melatonin secretion.8 sleep deprivation is also associated with changes in β-endorphin levels.9 despite these various studies, the role of melatonin and endorphins levels in altering the cardiovascular responses during stressful stimuli such as pain have not been tested. the aim of this study is to test the effect of rapid eye moment sleep deprivation (remsd) on blood pressure and heart rate responses to tonic pain in rats. furthermore, serum melatonin and β-endorphins levels were measured in sd and control rats during tonic pain. m e t h o d animals experiments were carried out on sprague-dawley male rats (n=16) approximately weighing 225-250sg. the animals were individually housed in a temperature (22-24oc), humidity (55%) and light-dark cycle (12 hours) controlled room. food and water were available ad libitum. the rats were randomly divided into 2 groups (n = 8 each). the control group remained in the home cages for the duration of the study, receiving only controlled handling (5-10 minutes/day). the experimental (remsd) group was subjected to rem sleep deprivation for 72 hours. rem sleep deprivation model rem sleep deprivation was induced by using the inverted flowerpot in water tank technique, as mentioned previously.10 briefly, animals were placed on a small inverted beaker (platform of 6.5cm diameter) surrounded by water reaching to a level of 1cm below the base of beaker. the covers of the cages were modified so as to enable the animal to reach for food and water easily. the water of the tank was changed daily in the morning. before the animals were subjected to sleep deprivation the rats were trained for 1-2 hours to reside on the platform and they learnt not to fall in the water. after training for 1-2 days, on the day of experiment they were taken from their home cage and placed individually in the sleep deprivation water tank cages. it has been shown that this method deprives the rat of almost 100% of rem sleep.11 blood pressure and he art r ate monitoring we used a computerized microprocessor based system for recording arterial blood pressure and heart rate. the measurement was performed non-invasively from the tail of the conscious rats with the aid of a pressure cuff (tail cuff method) and piezo-electric pulse transducer (technical and scientific equipment, gmbh). the rats were partially restrained during the period of recording. in order to achieve satisfactory results, rats were warmed for 10-15 minutes prior to recording by placing them in the pre-heated box (32oc). all the rats were trained for 3 consecutive days to adapt them to handling, heating, restraining, inflating and deflating the cuff pressure. we collected 3 recordings each at 1 minute interval; the average of 3 readings was calculated for each record of bp and hr. table1. effects of rem sleep deprivation on blood pressure and heart rate during acute and tonic pain in rats. basal formalin injection 5min 10min 30min non sd bp 148±3 183±2 162±4 149±4 hr 282±7 349±8 334±4 317±7 remsd bp 152±5 181±6 176±4* 180±3** hr 263±8 372±9 360±7ж 358±8 3 *p<0.02, **p<0.001, жp<0.034, 3p<0.006 non sd non sleep deprived remsed rem sleep deprived c a r d i o va s c u l a r r e s p o n s e s t o to n i c pa i n i n r e m s l e e p d e p r i v e d r at s 53 study design the experiments were conducted in the morning between 10:00-12:00 hours. in the experimental group, all the 8 rats served as their own control. they were subjected to the following protocol of recording bp and hr. 1. basal records: the basal records were taken immediately before injection of formalin. these values were used to calculate the respective changes in bp and hr. 2. formalin injection: after the basal record, rats were allowed 60 minutes of wash-out period in the home cage. subsequently, the rats receive a subcutaneous injection (50 µl) of dilute formalin (5%) into the plantar surface of their right hind paw. the pain usually starts within 5 minutes after injection.12 bp and hr were recorded at 5, 10 and 30 minutes after injection. after completing the entire recording, rats were given pentobarbital anesthesia (40 mg/kg ip) and blood samples were collected in heparinized syringes by cardiac puncture after performing thoracotomy. all samples were collected at 13:00 hours, taking into consideration the light dark cycle as the rate of melatonin production is low at this time. the blood was immediately centrifuged and serum was stored at 20oc for radioimmunoassay (ria). mel atonin and β-endorphin me asurements beta-endorphin was extracted by using seropack c18 cartridges. a competitive ria method using antibodies against β-endorphin was used to analyze the extracts. antibodies have specificity to n-terminal region of β-endorphin with low cross reactivity to β lipotropin. in order to increase the sensitivity of assay, sequential incubation was performed. polyethylene glycol was used to separate the bound fraction from unbound fraction. beta-endorphin has inter-assay coefficient of variance (cv) of 7.2% and intra-assay cv of 7.1%. the specificity of both the hormones was 100%. melatonin was assayed by enzymatic pretreatment and ria method (the melatonin assay has inter-assay cv of 4.5% and intra-assay cv of 3.8%, the reference range was < 0.078 nmol/ml). the antibodies to both β-endorphin and melatonin were supplied by immunobiological laboratories, hamburg. statistical asnalysis all the data in the study are expressed as mean ± sem. prior to formalin injection, records of bp and hr were obtained to serve as the baseline. the data of nonsleep deprived (non-sd) state were compared with remsd groups by using unpaired t-test. the level of significance was set at p <0.05. figure 1. line graphs ilustrating the changes in arterial pressure (left) and heart rate (bottom) in response to formalin induced pain in non sleep deprived (remsd) rats. data are presented as percentage changes in systolic pressure and heart rate. all data are presented as mean ± se, *=significance at p<0.05 s a l a h k a s s a b , u s h a s a c h d e va , n a g a l l a d a s a n d ta r i k a l -s h a i b a n i , u s h a n aya r 54 r e s u l t s the basal bp and hr recorded before sleep deprivation and after remsd were comparable and there was no significant difference, as shown in table 1. the effec t of formalin injec tion (tonic pain) on bp and hr response before and af ter remsd bp and hr responses to formalin injection were recorded at 5, 10 and 30 minutes. in the second tonic phase of pain i.e. after 10 minutes of formalin injection, the bp and hr were maintained at a level higher than basal values. the differences between the bp and hr responses to tonic pain, before and after sleep deprivation (10± 4% vs 17± 5%, respectively) were significant: p < 0.027, p <0.034 respectively. after 30 minutes of tonic pain the bp and hr in non-sd state tended to return towards the basal level. in sleep deprivation, the bp and hr remained elevated with no tendency to return towards the basal level. the differences between the bp and hr responses to 30 minutes of tonic pain in non-sd and after remsd (1± 0.5% vs 20± 5%) were significant (p=0.001). similarly, the hr responses before and after remsd (13% ± 5 vs + 37% ± 5) were also statistically significant (p= 0.006) respectively (figure 1). pl asma mel atonin and β-endorphin levels figure 2 shows the plasma levels of melatonin and βendorphin levels in rats with non-sd and after sleep deprivation. both these were significantly lower in remsd rats compared with controls. the melatonin levels in remsd were (0.07 ± 0.01 nmol/ml) compared with (0.22± .03 pmol/ml) in the controls (p < .001). beta-endorphin levels in remsd were (0.86 ± 0.17 pmol/ml) compared with (1.55 ± 0.43 pmol/ml) in the controls (p <0.002). d i s c u s s i o n we have demonstrated that rem sleep deprivation for 72 hours in rats significantly enhanced and prolonged the bp and hr response to formalin-induced tonic pain. in addition rem sleep deprivation significantly reduced serum melatonin and β-endorphins levels in rats. the mechanism by which rem sleep deprivation enhances the blood pressure and hr response to pain is probably fairly complex. possible explanations could be that rem sleep deprivation is associated with hyperalgesia in rats,13 due to lowered melatonin levels, which has a pain modulatory action.7 melatonin also acts as hypotensive hormone in rats14 and humans.15 it is therefore conceivable that the sleep deprivation that lowered the melatonin levels in sd rats could be responsible for the enhanced cardiovascular response to pain. examining previous studies the inhibitory role of melatonin on cardiovascular functions indicated that melatonin reduces peripheral norepirephrire release and increases central sympathetic activity.16 increased sympathetic nervous system activity has been proposed as one of the mechanisms for cardiovascular changes with pain in sleep deprivation.17 however, a study conducted to measure the sympathetic drive after sleep deprivation following stressful stimuli in human subjects failed to show an increased sympathetic activity.18 melatonin also increases vagal tone by direct action on the hypothalamus, decreases brain serotonin release and is an antioxidant with a vasodilator action directly on blood vessels.16 another possible explanation for enhanced cardiovascular response in our experiment is reduced β-enfigure 2. bar graphs illustrating the serum levels of melatonin and endorphins in non-sleep deprived (non-sd) and rem sleep-deprived (remsd) rats. ± se, * = significance at p<0.05. c a r d i o va s c u l a r r e s p o n s e s t o to n i c pa i n i n r e m s l e e p d e p r i v e d r at s 55 dorphin levels in rem sleep deprivation. these data support other findings that opioids play a tonic regulatory role on the cardiovascular control system.19,20 however, possible down regulation of opioid receptors in rem sleep deprivation could be involved. the locus ceruleus, the primary noradrenergic pathway for nociceptive cardiovascular response, has opioid receptors in large concentration.21 it is possible that remsd could have down regulated these receptors as well, resulting in exaggerated blood pressure and hr response in our study. however, there is a lack of available evidence to support this hypothesis. although our data indicate that exaggerated bp and heart rate changes with pain in remsd rats is associated with reduction in melatonin and β-endorphins, the cause and effect relationship is yet to be established. the associated reduction in levels of melatonin and β-endorphins in sd animals suggest possible involvement of these chemicals in regulating cardiovascular response to nociception. possible future research should be directed at examining whether this exaggerated cardiovascular response can be reversed by treating animals with melatonin or β-endorphins. extrapolation of these experiments to human studies is still to be determined. acknowledgements we are eternally grateful for the services of female staff (umairah, fatima, nur insan, merly and jerinia) from the medical records department. we also thank ibrahim biruar for typing the manuscript. r e f e r e n c e s . alvarez gg, ayas nt. the impact of daily sleep duration on health: a review of the literature. prog cardiovasc nurs 2004; 9: 56-59 2. drewes a. pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. rheumatology (oxford) 999; 38: 035-038. 3. tofler gh, stone ph, maclure m, edelman e, davis vg, robertson t, antman em, muller je. analysis of possible triggers of acute myocardial infarction (the milis study). am j cardiol 990; 66: 22-27. 4. rechtschaffen a, gilliand ma, bergmann bm, winter jb. physiological correlates of prolonged sleep deprivation in rats. science 983; 22: 8284. 5. champney th, steger r, christie d, reiter rj. alteration in components of pineal melatonin synthetic pathway by acute insulin stress in rat and syrian hamster. brain res 985; 338: 25-32. 6. poeggeler b rr, tan dx, chen ld, manchester lc. melatonin hypocotyl radical-mediated oxidative damage and aging: a hypothesis. j pineal res 993; 4: 5-68. 7. yu cx, zhu b, xu sf, cao xd, wu cc. the analgesic effects of peripheral and central administration of melatonin in rats. eur j pharmacol 2000; 403: 49-53. 8. lissoni p, esposti d, esposti g, mauri r, resentini m, morabito f, et al. a clinical study on the relationship between the pineal gland and the opioid system. j neural transm 986; 65: 63-73. 9. przewlocka b, mogilnicka e, lason w, van luijtelaar el, coenen am. deprivation of rem sleep in the rat and the opioid peptides beta-endorphin and dynorphin. neurosci lett 986; 70: 38-42. 0. jouvet d, vimont p, delorme f, jouvet m. study of selective deprivation of the paradoxical phase of sleep in the cat. j physiol (paris) 964; 56: 38. . kovalzon vm, tsibulsky vl. rem-sleep deprivation, stress and emotional behavior in rats. behav. brain res 984; 4: 235-245. 2. tjolsen a, berge og, hunskaar jh, rosland kh. the formalin test: an evaluation of the method. pain 992; 5: 5-7. 3. onen sh, abdelkrim a, didier j, alain e, claude d. effects of rapid eye movement (rem) sleep deprivation on pain sensitivity in the rat. brain res 200; 900: 26-267. 4. he w, zhu x, wang h, qiu y, qiu x. effect of melatonin on mean blood pressure and heart rate in morphine withdrawal rats. yao xue xue bao 998; 33: 727-730. 5. nishiyama k, yasue h, moriyama y, tsunoda r, ogawa h, yoshimura m, et al. acute effects of melatonin administration on cardiovascular regulation in healthy men. am heart j 200; 4: e9. 6. sewerynek e. melatonin and the cardiovascular system. neuroendocrinol lett 2002; : 79-83. 7. ogawa y, kanbayashi t, saito y, takahashi y, kitajima t, takahashi k, hishikawa y, shimizu t. total sleep deprivation elevates blood pressure through arterial baroreflex resetting: a study with microneurographic technique. sleep 2003; 26: 986-989. 8. kato m, phillips bg, sigurdsson g, narkiewicz k, pesek ca, somers vk. effect of sleep deprivation on neural circulatory control. hypertension 2000; 35: 73-8. 9. thurston cl, starnes a, randich a. changes in nociception, arterial blood pressure and heart rate by intravenous morphine in the conscious rat. brain res 993; 62: 70-77. 20. bhatnagar s, dallman mf, roderick re, basbaum ai, taylor bk. the effects of prior chronic stress on cardiovascular response to acute restraint and formalin injection. brain res 998; 797: 33– 320. 2. arvidsson u, riedle m, chakrabarti s, lee jh, nakano ah, dado rj, et al. distribution and targeting of a mu-opioid receptor (mor) in brain and spinal cord. j march 2007 vol 7 isuue 1 final without suicide .indd problem solving in diabetes authors: lee kennedy, iskandar idris, anastasios gazis reviewer: *masoud y al-maskari sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© a u t h o r s dr. lee kennedy, james cook university, queensland, australia; dr. iskandar idris, sherwood forest hospitals, sutton-in-ashfield, uk; and anastasios gazis, queen’s medical centre university hospital, nottingham, uk. b a c k g r o u n d t o t h e b o o k diabetes mellitus is considered an epidemic chronic disease, which may be prevented and/or controlled by intensive and effective available therapies, as well as better understanding of its pathophysiology. this book comes as an addition to the many publications available in the literature on understanding how to manage a complicated disease in a simple manner with support of evidence-based medical literature. o v e r v i e w o f c o n t e n t the book has 237 pages. it consists of preface, content, abbreviations and index with 8 sections as follows: 1. prevention and diagnosis: ways of diagnosing and preventing certain types of diabetes. 2. acute diabetes: types and means of management of acute complications of diabetes. 3. managing diabetes: means, methods and types of therapy available to mange difficult and various types of diabetes. 4. reproductive complications: how to mange fertility and reproductive problems in diabetes. 5. cardiovascular risk factors in diabetes: how to manage various habits, diseases associated with and/or risks factor for diabetes. 6. microvascular complications: how to manage chronic microvascular complications of diabetes. 7. macrovascular and other complications: how to manage chronic macrovascular complications of diabetes. 8. diabetes in special groups of patients: how to manage diabetes associated with certain diseases. th e r e a d e r sh i p mo st sui te d f o r th i s b o o k i recommend this book as a day-to-day reference guide for all professionals who are involved in providing care to diabetic patients. it will be valuable also to medical students during rotations in endocrinology. a ppr o pr i ate n e s s o f th e c o n te n t to ta r ge t r e a d e r sh i p the contents are presented in a simple, short and easy to read manner with brief literature references. this seems to be appropriate to the readership and easy to follow. b o o k r e v i e w السكري داء مشاكل حل جازيس اناستاسيوس ادريس، اسكندر كندي، �املؤلفون: لي املسكري مراجعة: مسعود isbn 1 90439261x price ₤35 sterling available at www.clinicalpublishing.co.uk *department of medicine, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman email: mmaskari@squ.edu.om l e e k e n n e d y, i s k a n d a r i d r i s , a n a s ta s i o s g a z i s 66 c ompr e h e n si v e n e s s o f th e c o n te n t this book covers most aspects of diabetic management in a simple and brief manner. some other aspects of diabetic management are omitted or little covered such as: the psychological and psychiatric aspects of diabetes; diabetes and education; diabetes and selfmanagement and finally diabetes and diets. o r g a n i sati o n o f th e c o n te n t each section of the book follows the title starting with a real case description with some stimulating questions followed by answers supported by recent literature with references for further reading. the first case in each section is presented in an evidence-based manner, but unfortunately the rest of cases do not follow the same style. g e n e r a l c o m m e n t s q ua l i t y o f c o n te n t this book contains up-to-date, rich and valuable literature about diabetes mellitus. the presentation of the literature made this book simple to read despite the complexity of this debilitating and complicated chronic disease. in the era of internet and fast paced work, a book of this quality is a valuable companion to diabetic health providers. q ua l i t y o f i l lustr ati o n s this book contains many good quality, coloured and easy to read illustrations, tables, figures and diagrammes. the inclusion of diabetic photographs would have been a strong asset to the book. s u g g e s t i o n s a n d c o r r e c t i o n s su g ge sti o n s the authors manage to cover most aspects of diabetes mellitus in a good quality text and illustrations with few exceptions. the following are suggestions for improvement for future editons: 1. presentation of all of the cases in an evidencebased manner would make the book more attractive and useful. 2. inclusion of some diabetic photographs would be most valuable. 3. addition of sections about diets, education and psychological aspects of diabetes would increase the quality of the book. c o r r e c ti o n s the following mistake should be corrected or amended: page 18: under prevention and diagnosis “screening and impaired glucose tolerance”; impaired fasting glucose (ifg): fasting plasma glucose not ≥6.1 mmol/l, but<7.0mmol/l to fasting plasma glucose not ≥ 5.6mmol/l but <7.0mmol/l. january 2007 vol 7 correct a.indd rhabdomyosarcoma of the nasal vestibule in a child george h tanyous about 5-8% of childhood tumours are rhab-domyosarcomas (rm).1 a sarcoma is a malig-nancy originating from primitive mesenchymal cells, which under normal circumstances develops in supportive tissues such as muscle and bone. t h e c a s e a two year old girl was brought in the ear nose throat (ent) department of squh by her parents with a mass blocking the right anterior nares completely, causing difficulty in breathing. the blockage had lasted already several weeks. there were no other symptoms like itching or bleeding. on examination, the child looked healthy, but had a spherical mass about 1cm x 1cm in diameter attached to the skin of the floor of the nasal vestibule. this was covered with intact skin, which although it looked pink had no ulceration or tenderness. the mass was not fixed to the surrounding tissue. there were no palpable cervical glands. the left nasal cavity and the oral cavity were normal. on admission and after a complete blood count and blood chemistry all results were found to be normal. it was obvious that an excision biopsy would provide the correct diagnosis. this was done under general anesthesia with an oro-tracheal intubation and a pharyngeal pack. the swelling was actually shaved out of the nasal vestibule taking care not to injure the cartilage of the vestibule. the bleeding was very mild and quickly stopped by application of pressure and a small anterior nasal pack. the specimen was sent to the histopathology department. postoperatively, the child made an uneventful recovery. the nasal pack was removed after 24 hours and the denuded area of the vestibule start to heal well without problems. the area was painted daily with antiseptic cream and the child was given prophylactic antibiotic for seven days (augmentin syrup). the specimen was sent to the histopathological department and the result came as rm of the alveolar type with positive monoclonal antibodies to desmin (tumour related antigen). the child was referred to the pediatric oncologist and was prescribed chemotherapy. it is well known that rm is chemosensitive, with the use of multiple drugs (5) normally required. the intensity of treatment depends on 3 cooliban st., merylands west, new south wales, 2160 australia email: scarface300@hotmail.com طفل أَنْف ليزُ دِهْ في ة طَ طَّ َ ُا لِيَّةُ ضَ العَ اركومةُ السَّ على حالتهاالسريرية تؤشر ال . حلصوله مسبق ب ؤَهِّ مُ عامل وجود بدون سنتني بعمر ة في طفلة طَ َطَّ ُلِيَّةُ ا ضَ العَ اركومةُ السَّ امللخص: نقدم حالة يّة. نْخِ السِ ة طَ َطَّ ُا لِيَّةُ ضَ العَ اركومةُ هو السَّ املرضي النسيجي الفحص تقرير كان . اتبر من كمفاجأة جاء الذي تشخيص املرض . عمان ، حالة تقرير ، الطفولة ، االنفية املفردات املفتاحية: الساركومة العضلية اططة abstract a case of rhabdomyosarcoma in a 2 year old girl without a pre-existing predisposing factor visited the ent department of sultan qaboos university hospital (squh). her clinical condition did not point to the diagnosis, which came as a histological surprise. the histopathology report was alveolar rhabdomyosarcoma. keywords: nasal rhabdomyosarcoma, pediatric age, case report, oman. sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© c a s e s t u d y g e o r g e h ta n y o u s 88 the stage of the sarcoma the site the histopathology the child initially recovered well, however she did not report one month later for the usual follow up. d i s c u s s i o n most sarcomas show some evidence of differentiation into a particular supportive tissue, but maturation is incomplete. the most common normal tissue counterpart for childhood sarcomas is skeletal muscle, and tumors having features of skeletal muscle differentiation are called rhabdomyosarcomas. a small subset of children with rhabdomyosarcomas, mostly genito-urinary rhabdomyosarcomas, belong to families in which multiple cancers such as breast lung and brain tumors occur. adrenocortical cancer and leukemia can also develop. constitutional mutation in the p53 can be found. the tumor suppressor gene located on the long arm of chromosome 17, characterizes this cancer predisposition syndrome (the li fraumeni syndrome). rm arise from mesenchymal tissue. the head and neck region is the most common site of origin in 40% of cases, the genito-urinary in 20% of cases, 20% in the extremities and 10% in the trunk.6 rm is the most common type of head and neck cancer in the first 2 years of life.1 50% of head and neck tumors arise in the orbit and the nasopharynx. subd i v i si o n 25% arise in the orbit, 50% in non-orbital parameningeal sites (the nasopharynx, middle ear, mastoid and pterygoid and infra temporal fossa) 25% are non-orbital non-parameningeal (the mouth, the neck, face, scalp, larynx).2 symptomatology it usually presents as a painless mass. in the larynx it results in upper airway obstruction. in a few cases there is persistent pain with sanguinous discharge and cranial nerve palsies. in the areas covered with mucous membrane it can have a botryoid (bunch of grapes) appearance. diagnosis this can be done by mri scan set at bone windows and/or biopsy. histopathology spindle shaped cells with eosinophlic cytoplasm or cross striation like striated muscles. however, the most common appearance is that of an undifferentiated small, round, blue cell tumour with the differential diagnosis of neuroblastoma, ewing’s sarcoma, primitive neuroectodermal tumour or non hodgkin’s lymphoma. monoclonal antibodies which are directed against the tumor-related antigens, such as desmin in rm or leucocytes common antigen (in case of lymphoma) or neuron specific enolase (in the case of neuroblastoma or primitive neuroectodermal tumors), can help in a differential diagnosis. pathological sub-types 1. embryonal (botryoid) variant with good prognosis, arising in a sub-mucosal location. 2. alveolar with poor prognosis, due to aggressive behaviour and tendency to metastasize early. 3. pleomorphic, the most common in adults, rare in children spread the tumor spreads to regional lymph nodes in 5% of cases and to lung, liver, bone and bone marrow, with 4 stages of tumor according to the degree of spread. treatment 1. surgical complete excision or biopsy. however, successful complete excision (biopsy) is normally achieved in only 4 out of 60 patients. 2. multiagent chemotherapy, judicious surgery and radiotherapy to selected patients 3. chemotherapy (chemo sensitive) with cyclophosphamide and ifosfamide. r h a b d o m y o s a r c o m a o f t h e n a s a l ve s t i b u l e i n a c h i l d 89 actinomycin d, vincristine, doxorubicin c, toposide, platinum analogues like cis and carboplatinum. at least 3 drugs should be given. prognosis 1. 5 years survival: 92% with in orbital rm. 2. 81% with non-parameningeal non-orbital. 3. 69% with parameningeal. r e f e r e n c e s 1. anderson, g j, tom l w c, womer r b, handler s d, wetmore r f, potsic w p. rhabdomyosarcoma of the head and neck in children. arc otolaryngol head neck surg 1990; 116:428-431. 2. kato m a d p, flamant f, terrier-lacombe m j, habrand j l, schwaab g, luboinski b, et al. rhabdomyosarcoma of the larynx in children: a series of five patients treated in the institut gustave roussy (villejuif, france). medical and pediatric oncology 1991; 19:110-114. 3. kilman j w, clatworthy h w, newton w a, grosfeld j w. reasonable surgery for rhabdomyosarcoma: a study of 67 cases. ann surgery 1993; 178:346-351. 4. maurer h m, gehan e a, beltangady m, et al. the intergroup rhabdomyosarcoma study ii. cancer 1992; 71:1904-1922. 5. stevens m, oberlin o, flamant f, rey a, praquin m t. siop mmt 89 protocol for non-metastatic rhabdomyosarcoma an update. medical and paediatric oncology 1993; 21:554. 6. corbett r, printh j, plowman pn. tumours of the head and neck. in: adams da, cinnamond mj, editors. paediatric otolaryngology. series: kerr ag ed. scott brown otolaryngology. 6th ed. oxford butterworth heinemann, 1977: 6/31/6-9. 7. herrmann b w, sotelo-avila c, eisenbeis j f. pediatric sinonasal rhabdomyosacrcoma: three cases and a review of the literature. am j otolaryngol 2003; 24:174-80 submitted 15 jan 2023 1 revision req. 20 feb 23; revision recd. 6 mar 23 2 accepted 21 mar 23 3 online-first: march 2023 4 doi: https://doi.org/10.18295/squmj.3.2023.015 5 6 recent increase in hiv cases in oman 7 *ali elgalib, samir shah, zeyana al-habsi, maha al-fouri, richard lau, 8 bader al-rawahi, seif al-abri 9 directorate general for disease surveillance and control, ministry of health, muscat, oman. 10 *corresponding author’s e-mail: elgalib@hotmail.com 11 12 the advent of antiretroviral therapy (art) has transformed the human immunodeficiency (hiv) 13 infection prognosis from a life-threatening disease to a manageable chronic condition with a 14 near-normal life expectancy.1 besides, people living with hiv/aids (plwha) on regular art 15 with a suppressed hiv viral load (vl) do not infect their sexual partners .2 despite these 16 remarkable developments in treatment and prevention, hiv/aids remains a major global public 17 health threat. the most recent joint united nations programme on hiv and aids (unaids) 18 global aids report shows that there were 38.4 million plwha in 2021; 1.5 million became 19 newly infected, far short of the 2025 target of 370,000 new infections.3 furthermore, 650,000 20 aids-related deaths occurred in 2021, more than 2 folds of 2025 target of 250,000 deaths.3 21 22 of concern, the 2022 unaids report warned that the global hiv/aids response was in danger. 23 in asia and the pacific region, new hiv infections increased in 2021 where they had been 24 decreasing over the last decade. in addition, the eastern europe and central asia, the middle 25 east and north africa (mena) and latin america have all seen surges in annual hiv infections 26 over the past 10 years.3 indeed, the new hiv infections in the mena region have increased by 27 33% over the last 10 years. of note, country-level data was only available for 11 out of 21 28 countries in the mena region; the annual new hiv cases, in the period from 2011 to 2021, had 29 increased in algeria (167%), yemen (77%), lebanon (41%), qatar (40%), oman (35%) and 30 bahrain (8%). in contrast, the annual new hiv infections, over the same period, had decreased 31 in djibouti (-63%), morocco (-48%), libya (-21%), sudan (-2%) and tunisia (-1%).4 32 33 oman is situated in the arabian peninsula, with a total population of 4,931,506; 2,064,778 34 (41.9%) are non-omanis.5 the first case of hiv/aids in oman was diagnosed in 1984, and the 35 national aids programme (nap) was formed in 1987. currently 14 public treatment centres 36 offer free hiv care, including antiretroviral therapy (art) and testing for hiv genotyping, hiv 37 vl, and cd4 count. the country adopted treatment for all, irrespective of cd4 cell count, in 38 december 2015.6 39 40 a total of 3580 omani citizens were diagnosed with hiv from 1984 to 2021, of whom 1996 41 (56%) were alive as of 31 december 2021.7 figure 1 shows the hiv cases among omani 42 nationals from 2010 to 2021, stratified by year of diagnosis and sex. males accounted for 62% 43 (88/143) and 84% (169/202) of hiv cases among omani citizens in 2010 and 2021, respectively; 44 however, the proportions of males among all hiv cases in the country, including the non-45 omanis, were 57% (154/272) and 67% (221/335) in 2010 and 2021, respectively. in addition, the 46 distribution of age at diagnosis has changed over time; the percentage of those aged 25-34 years 47 rose from 31 % (44/143) in 2010 to 46% (92/202) in 2021, while the proportion of persons aged 48 35-44 years decreased from 26% (37/143) to 19% (39/202) in the same periods; however, the 49 percentage of those aged ≥ 45 years had remained the same, at 18% (figure 1). sexual 50 transmission has been the main driver of the epidemic; the proportions of new infections 51 attributed to sexual contact accounted for 94% (134/143) of infections in 2010, compared to 97% 52 (195/202) in 2021. the cd4 count at diagnosis is often used as marker of late hiv diagnosis. 53 for omani plwha diagnosed between 2010-2021, about two-thirds (69.9%) had a baseline 54 cd4 count of < 350 cells/mm3 and 41.3% had a baseline cd4 count of <200 cells/mm3. out of 55 plwha who were alive as of 31 december 2021 (n=1996), 81% were on art; the proportion 56 of patients with viral suppression (hiv vl <1000 copies/ml) out of those on art was 90% 57 (1457/1617).7 58 59 the recent increase in the new diagnoses in oman may be explained, in part, by an increase in 60 hiv testing rather than an increase in the hiv incidence as suggested by the persisting high 61 levels of late hiv diagnosis. however, the rise in new cases in persons aged 25-34 years might 62 suggest high risk-taking behaviour in this cohort.8 indeed, the unaids 2021 report shows that 63 the overall hiv incidence (0.07 per 1000 population) and prevalence (0.2 per 1000 population) 64 in oman were stable in 2010-2021.3 future epidemiological and behavioural studies to determine 65 the precise dynamic of hiv incidence, and the key populations in oman are warranted. 66 67 the association between late hiv diagnosis and increased morbidity and mortality is well 68 established. late hiv diagnosis is associated with a ten-fold increased risk of death within 12 69 months of diagnosis.9 late-stage hiv diagnosis also increases the risk of onward transmission 70 and the cost of treatment and care.10, 11 the high proportion of late hiv diagnosis in oman could 71 be due to several reasons. a primary factor is the high level of hiv-related stigma and 72 discrimination that prevent access to hiv testing services.12, 13 in addition, hiv prevention 73 services targeting key populations and their partners are very limited. furthermore, social 74 disapproval of and punitive laws against high-risk behaviours such as sex work, injecting drug 75 use and homosexuality.13 to reduce the rates of late hiv diagnosis in oman, the nap has 76 recently published an hiv manual for primary health care (phc) intending to increase the hiv 77 testing levels in phc.14 evidence shows that primary and secondary care providers frequently 78 miss opportunities for earlier hiv diagnosis, through a combination of lack of awareness of 79 clinical syndromes, identifying possible risk factors and a general reluctance to discuss hiv 80 testing.15 81 82 in september 2022, the world health organization (who) certified that oman had eliminated 83 mother-to-child transmission of hiv and syphilis, becoming the first country in the who 84 eastern mediterranean region and only the sixteenth country in the world to achieve this.16, 17 85 this accomplishment is a testimony of oman’s potential to end the aids epidemic by 2030 86 realising the goal of the global health sector strategies on hiv, viral hepatitis and sexually 87 transmitted infections (ghss) for the period 2022-2030.18 to achieve this ambitious goal, the 88 nap in oman must focus on two key ghss targets, the reduction of the percentage of people 89 starting art with a cd4 count of < 200 cells/mm3 to <10% and the use of combination hiv 90 prevention by 95% of people at risk of hiv by 2025. 91 92 the rates of art coverage and viral suppression in oman are encouragingly high19, 20, with a 93 consequent decline in the community hiv viral load; however, this has not resulted in reducing 94 the hiv incidence in the country due to the high levels of late-stage hiv diagnosis. high 95 proportions of plwha in oman were diagnosed several years after acquiring the hiv infection 96 and would have infected many people prior to their hiv diagnosis and initiation of art. to 97 reduce the rate of late hiv diagnosis and maximize the public health benefit of treatment as 98 prevention, it is paramount to expand the hiv testing services in the country through 99 decentralized and differentiated hiv testing services, with timely linkage to treatment and care. 100 different hiv testing approaches, including clinical settings, community-based approaches or 101 self-testing might be used depending on epidemic dynamics and population needs; persons who 102 are at risk of hiv but who test hiv negative should also be linked to hiv prevention services. 103 while increasing the rates of hiv testing will, paradoxically, identify more cases in the short 104 term, the long term results will be improved morbidity and mortality in plwha and a decline in 105 onward transmission in the community. 106 107 establishing combination hiv prevention, including male and female condoms, treatment as 108 prevention, pre-exposure prophylaxis, post-exposure prophylaxis and harm reduction services for 109 persons who inject drugs, is challenging; only 8% of people at risk of hiv in the world used 110 combination hiv prevention in 2020. the lack of data about the size of and hiv prevalence 111 among people at risk of hiv and the cultural context in oman are compounding factors. 112 however, maintaining the status quo is not an option; establishing hiv prevention services that 113 respect oman’s religion, culture and traditions is warranted. to raise awareness of hiv among 114 the general population, culturally-sensitive information about hiv prevention, diagnosis and 115 prevention can be disseminated through mass media, including social platforms. in addition, 116 outreach awareness campaigns in colleges, universities and workplaces can target young people, 117 including those aged 25-34 years. these initiatives can be led by a national committee, with 118 members from all relevant stakeholders, including plwha, people at risk of hiv, community 119 and faith leaders, civil society organisations, the ministry of health, the ministry of education and 120 law-enforcing agencies. 121 122 to conclude, the annual new hiv cases in oman have exceeded 140 in the last four years. 123 however, despite this recent increase in hiv cases, the hiv epidemic in the sultanate has 124 remained a low-prevalence one over the past decade. sexual transmission has been the main 125 driver of the epidemic in the country, with males and those aged 25-34 years disproportionately 126 affected. future epidemiological studies to determine the characteristics of people at risk for hiv 127 in oman and inform targeted interventions are warranted. 128 129 authors’ contribution 130 ae and sa contributed to the idea conceptualization. ss, ma and ae contributed to data 131 curation and formal analysis. ae contributed to writing (original draft) the manuscript. ss, za, 132 ma, rl, ba and sa contributed to writing (review and editing) the manuscript. all authors 133 approved the final version of the manuscript. 134 135 references 136 1. gueler a, moser a, calmy a, günthard hf, bernasconi e, furrer h, et al. swiss hiv cohort 137 study,. swiss national cohort. life expectancy in hiv-positive persons in switzerland: 138 matched comparison with general population. aids 2017;31 (3):427–36. 139 2. prevention access campaign. undetectable=untransmittable. 140 https://www.preventionaccess.org/undetectable (accessed 16 august 2019). 141 3. joint united nations programme on hiv/aids. in danger: global aids update 2022. 142 geneva: unaids; 2022 https://www.unaids.org/en/resources/documents/2022/in-danger-143 global-aids-update. accessed 22 december 2022. 144 4. aids info. global data on hiv epidemiology and response https://aidsinfo.unaids.org. 145 accessed 26 december 2022. 146 5. national center for statistics and information. population clock. 2022, december. available 147 at: https://www.ncsi.gov.om/pages/ncsi.aspx. (accessed 27 december 2022). 148 6. hiv management in oman. a guide for health care workers, 3rd edition. 2015. available 149 from: www.moh.gov.om/en/web/directorate-general-of-disease-surveillance-150 control/resources. (accessed 20 december 2022). 151 7. annual health report. department of health information and statistics, moh (2021) 152 (https://www.moh.gov.om/en/web/statistics/annual-reports; accessed 26 february 2023). 153 https://www.unaids.org/en/resources/documents/2022/in-danger-global-aids-update https://www.unaids.org/en/resources/documents/2022/in-danger-global-aids-update https://aidsinfo.unaids.org/ http://www.moh.gov.om/en/web/directorate-general-of-disease-surveillance-control/resources http://www.moh.gov.om/en/web/directorate-general-of-disease-surveillance-control/resources https://www.moh.gov.om/en/web/statistics/annual-reports 8. kann l, mcmanus t, harris wa, shaanklin sl, flint kh, queen b, et al. youth risk 154 behavior surveillance—united states, 2017. mmwr surveill summ. 2018;67(8):1-114. 155 9. lucas sb, curtis h, and johnson ma. national review of deaths among hiv-infected adults. 156 clin med 2008; 8: 250–252. 157 10. marks g, crepaz n, and janssen rs. estimating sexual transmission of hiv from persons 158 aware and unaware that they are infected with the virus in the usa. aids 2006; 20: 1447–159 1450. 160 11. krentz h, auld m, and gill m. the high cost of medical care for patients who present late 161 (cd4 < 200 cells/ll) with hiv infection. hiv med 2004; 5: 93–98. 162 12. feyissa gt, lockwood c, woldie m, munn z. reducing hiv-related stigma and 163 discrimination in healthcare settings: a systematic review of quantitative evidence. plos 164 one. 2019;14(1):e0211298. 165 13. gökengin d, doroudi f, tohme j, collins b and madani n. hiv/aids: trends in the 166 middle east and north africa region. int j infect dis. 2016 mar;44:66-73. 167 14. hiv in primary health care manual, directorate general for disease surveillance and control, 168 ministry of health, oman, first edition, 2019. www.moh.gov.om/en/web/directorate-169 general-of-disease-surveillance-control/resources. 170 15. burns fm, johnson am, nazroo j, ainsworth j, anderson j, fakoya a, et al; sonhia 171 collaboration group. missed opportunities for earlier hiv diagnosis within primary and 172 secondary healthcare settings in the uk. aids 2008; 22: 115–122. 173 16. elgalib a, al-hinai f, al-abri j, shah s, al-habsi z, al-fouri m et al. elimination of 174 mother-to-child transmission of hiv in oman: a success story from the middle east. east 175 mediterr health j. 2021 apr 27;27(4):381-389. 176 17. world health organisation. press release: oman first country in the eastern mediterranean 177 region to eliminate mother-to-child transmission of hiv and syphilis. geneva: who; 2022 178 https://www.who.int/news/item/19-10-2022-oman-first-country-in-the-eastern-179 mediterranean-region-to-eliminate-mother-to-child-transmission-of-hiv-and-syphilis. 180 accessed 22 december 2022. 181 18. world health organisation. global health sector strategies on, respectively, hiv, viral 182 hepatitis and sexually transmitted infections for the period 2022-2030. geneva: who; 2022 183 https://cdn.who.int/media/docs/default-source/hq-hiv-hepatitis-and-stis-library/full-final-184 http://www.moh.gov.om/en/web/directorate-general-of-disease-surveillance-control/resources http://www.moh.gov.om/en/web/directorate-general-of-disease-surveillance-control/resources https://www.who.int/news/item/19-10-2022-oman-first-country-in-the-eastern-mediterranean-region-to-eliminate-mother-to-child-transmission-of-hiv-and-syphilis https://www.who.int/news/item/19-10-2022-oman-first-country-in-the-eastern-mediterranean-region-to-eliminate-mother-to-child-transmission-of-hiv-and-syphilis https://cdn.who.int/media/docs/default-source/hq-hiv-hepatitis-and-stis-library/full-final-who-ghss-hiv-vh-sti_1-june2022.pdf?sfvrsn=7c074b36_13 who-ghss-hiv-vh-sti_1-june2022.pdf?sfvrsn=7c074b36_13. accessed 22 december 2022. 185 19. elgalib a, shah s, al-habsi z, al-fouria m, al-sawafi h, al-noumani j, et al. hiv viral 186 suppression in oman: encouraging progress toward achieving the united nations ‘third 90’. 187 int j infect dis. 2018 jun; 71: 94-99. 188 20. elgalib a, shah s, al-habsi z, al-fouri m, lau r, al-kindi h, et al. the cascade of hiv care 189 in oman, 2015-2018: a population-based study from the middle east. int j infect dis. 2019 190 sep 27. doi: 10.1016/j.ijid.2019.09.017. 191 192 193 figure 1: new hiv cases among omani nationals stratified by sex, 2010-2021 194 https://cdn.who.int/media/docs/default-source/hq-hiv-hepatitis-and-stis-library/full-final-who-ghss-hiv-vh-sti_1-june2022.pdf?sfvrsn=7c074b36_13 1 submitted 9 nov 21 1 revisions req. 18 jan 22; revisions recd. 27 jan 22 2 accepted 27 feb 22 3 online-first: march 2022 4 doi: https://doi.org/10.18295/squmj.3.2022.023 5 6 radiologic assessment of orbital dimensions among omani subjects 7 computed tomography imaging-based study at a single tertiary center 8 eiman al ajmi,1 marwa al subhi,4 mallak al maamari,2 humoud al 9 dhuhli,1 *srinivasa r. sirasanagandla3 10 11 departments of 1radiology & molecular imaging and 3human & clinical anatomy, 2college 12 of medicine and health sciences, sultan qaboos university, muscat, oman; 4radiology 13 residency program, oman medical specialty board, muscat, oman. 14 *corresponding author’s e-mail: srinivasa@squ.edu.om 15 16 abstract 17 objectives: a sound knowledge of the normal orbital dimensions is clinically essential for 18 successful surgical outcomes. racial, ethnic, and regional variations in the orbital dimensions 19 have been reported. this study aimed to determine the orbital dimensions of omani subjects 20 who had been referred for computed tomography (ct) images at a tertiary care hospital. 21 methods: a total of 273 omani patients referred for a ct scan of the brain were evaluated 22 retrospectively, using electronic medical records database. the orbital dimensions were 23 recorded using both axial and sagittal planes of ct images. results: the mean orbital index 24 (oi) was found to be 83.25±4.83, and the prevalent orbital type was categorized as 25 mesoseme. the mean orbital index was 83.34±5.05 and 83.16±4.57 in males and females, 26 respectively, with their difference being statistically not significant (p=0.76). a statistically 27 significant association was observed between the right and left orbits regarding horizontal 28 distance (p<0.05) and vertical distance (p<0.01) of orbit and oi (p<0.05). no significant 29 difference between the oi and age groups was observed in males and females. the mean 30 interorbital distance and interzygomatic distance were found to be 19.45±1.52 mm and 31 95.59±4.08 mm, respectively. these parameters were significantly higher in males (p<0.05). 32 conclusions: results of the present study provide reference values of orbital dimensions in 33 mailto:srinivasa@squ.edu.om 2 omani subjects. the prevalent orbital type of omani subjects is mesoseme, which is a 34 hallmark of the white race. 35 keywords: computed tomography, ethnicity, orbit, oman, variation, hypertelorism. 36 37 advances in knowledge 38  this is the first study to evaluate the orbital dimensions of the omani population. 39  results of the present study provide reference values of orbital dimensions in omani 40  subjects. 41  the prevalent orbital type of omani subjects is mesoseme, a hallmark of the white race. 42 43 application to patient care 44 1.the reference values of orbital dimensions including orbital index, interorbital distance 45 and interzygomatic distance reported in this study are essential for diagnosing and treating 46 various orbital pathologies. 47 2.these values are also crucial for surgical corrections of craniofacial anomalies such as 48 orbital hypertelorism, hypotelorism, and orbital clefts. 49 50 introduction 51 the bony orbit or orbital cavity is a complex anatomical region of the facial skeleton. the 52 orbit and its contents are affected by various diseases1 and craniofacial anomalies such as 53 orbital hypertelorism, hypotelorism, and orbital clefts.2,3 the majority of orbital diseases and 54 craniofacial anomalies require a thorough knowledge of the normal orbital dimensions to 55 diagnose and treat them effectively. previously, many studies have enumerated the reference 56 values of orbital dimensions among different populations.1,4,5 these studies reported a 57 significant variation in orbital dimensions depending on the race and ethnicity of the 58 population. generally, the orbit shape differs according to ancestry: rectangular orbits are 59 present in africans, angular orbits in northern and southern europeans, and round orbits in 60 central asians and central europeans.6 in most circumstances, the breadth of the orbital 61 cavity is greater than the height, and the orbital index (oi) reflects this relationship. paul 62 broca has developed oi to quantitatively enumerate the orbit size and symmetry for the first 63 time.5 oi refers to the proportion of orbital height to the orbital width multiplied by 100%. 64 the shape of the face determines the oi of an individual.4 based on different values obtained 65 from previous research, oi is classified into three categories. the first category is megaseme, 66 3 which refers to a large index and is seen in yellow races. the second category is mesoseme, 67 which indicates intermediate value and is associated with the white races. and the small one, 68 microseme, is a characteristic of the black races.7 69 70 craniofacial indices are a reliable source to provide successful results for ethnicity 71 identification compared to appendicular skeletal remains indices.8 radiological investigations 72 are frequently used for craniofacial indices where the dry bone collection is impossible.9 73 factors such as gender, age and laterality influences on oi have been reported in the majority 74 of the studied populations.10-12 the interorbital distance (iod) is typically used as diagnostic 75 criteria in evaluating craniofacial anomalies such as hypertelorism, hypotelorism, and orbital 76 clefts.2,3,13 this parameter is also used to determine the severity of these anomalies and while 77 planning the surgical correction.14,15 in addition to the clinical importance, orbital dimensions 78 are frequently used in anthropology and forensic medicine.11 till date, there are no studies to 79 evaluate the orbital dimensions of the omani population. hence, in the present study, we 80 sought to provide the baseline data of oi and iod of omani subjects referred for ct scans at 81 a tertiary care hospital and classify them under one of the three predetermined categories. 82 83 materials and methods 84 in the present study, the adult omani patients (aged ≥18 years) who had visited tertiary care 85 referral center in the department of radiology and molecular imaging in oman were studied 86 retrospectively using an electronic medical records database (trakcare unified health 87 information system). the study was conducted after receiving ethical approval from the 88 medical research ethics committee. thank you for the comments. in the present study, we 89 included all the consecutive patients of either sex aged ≥18 years who had been referred for a 90 ct scan of the brain during the period from 1st january 2019 to 31st march 2019. after 91 applying the inclusion and exclusion criteria there were 273 omani patients. this statement 92 has been added in the methods section. the patients with orbital fractures and ocular or facial 93 surgery or deformity were excluded. in addition, scans with motion artifacts or incomplete 94 coverage of the orbits and those performed for non-omani patients were excluded as well 95 from the study sample. 96 97 all the ct scans were performed as per the routine standard protocol for non-enhanced ct of 98 the brain using 64 slice multidetector ct (siemens sensation 64) with kilovoltage peak of 99 120 kv and tube current modulation. the images and measurements were assessed using the 100 4 picture achieving and communication system (pacs) (synapse pacs, fujifilm 101 worldwide, version 5.7.102). 102 103 the measurements were performed using the reconstructed thin slices of 1.2 mm in the bone 104 window. a window width/window level of 2000/500 was used while screening the images. 105 the following measurements were performed for every subject: the inter-orbital distance, 106 inter-zygomatic distance, horizontal orbital diameter and vertical orbital diameter. first, the 107 orientation of the axial images was adjusted to frankfort horizontal plane which is defined as 108 the line from the highest point of the opening of the external auditory canal to the lower 109 margin of the orbital rim.16 after adjusting the axial plane, the iod was measured as the 110 minimal distance between the medial orbital walls (figure 1). the interzygomatic distance 111 (izd) was determined as the maximum distance between the anterior aspects of the 112 zygomatic arches (figure 1). the horizontal distance of orbit (hdo) for each orbit was 113 measured as the maximum distance from the anterior lacrimal crest to the lateral orbital wall 114 (figure 2a). the vertical distance of orbit (vdo) was performed in the sagittal plane after 115 adjusting the angulation of the sagittal image along the long axis of the orbit and measured as 116 the maximum distance between the frontal and the maxillary bones (figure 2b). finally, oi 117 was calculated using the following formula: oi = vdo/hdo*100. 118 119 statistical package for the social sciences (spss, version 23.0, ibm corporation, ny, usa) 120 for windows was used to analyze the data. the data were presented as mean and standard 121 deviation. independent sample t-test was used to determine the associations between the 122 orbital dimensions and gender, while paired t-test was used to determine the laterality 123 difference. the association between the orbital dimensions and age groups were determined 124 using one-way anova. the differences were considered significant at p-value <0.05. 125 126 results 127 in the present study, we evaluated 546 orbits from 273 patients. among these patients, males 128 were 136 (49.82%), and females were 137 (50.18%). the mean age of the study subjects was 129 58.81 years ± 19.41, with a range of 18 to 94 years. only one observer was involved in 130 screening all the 273 subjects’ ct scans to measure the orbital dimensions. the mean hdo 131 of the right and left orbits was 39.76±1.75 mm and 39.42±1.66 mm, respectively. the mean 132 vdo of the right and left orbits was 32.83±1.90 mm and 33.01±1.89 mm, respectively. 133 134 5 as described in the methods, the oi was calculated using the vdo and hdo. the mean oi 135 of the right side and left side orbits were found to be 82.67±5.36 mm and 83.83±4.93 mm, 136 respectively. a statistically significant association was observed between the right and left 137 orbits with regard to hdo (p<0.05) and vdo (p<0.01) and oi (p<0.05) (table 1). the 138 associations of orbital dimensions with respect to gender are presented in table 2. there was 139 no significant association between gender and oi of both sides of the orbit. the oi in 140 different age groups of female and male patients is presented in table 3 & 4, respectively. 141 there was no significant association between age groups and io among the study subjects. 142 the mean iod and the mean izd distance were found to be 19.45±1.52 mm and 95.59±4.08 143 mm, respectively. the mean iod (p<0.05) and the mean izd (p<0.05) were significantly 144 higher in males when compared to females. 145 146 discussion 147 in the past, several radiological and anatomical studies have been conducted to explore the 148 bony dimensions of the orbit. evidence from these studies reported a significant variation 149 among different races, ethnicities, and within the region. the reporting of reference values of 150 orbit dimensions is clinically important for a better diagnosis, surgical approach and outcome, 151 and follow-up of various orbital pathologies. the knowledge of orbit dimensions pertaining 152 to each race and ethnic group is also crucial in anthropology and forensic medicine, 153 particularly for identifying and classifying the skull. despite having tremendous importance, 154 the normative bony dimensions of the orbit were not studied in all populations world-wide. 155 to date, the oi has been documented only in three populations from the middle eastern 156 region, including egypt,17 turkish18 and iranian19 populations. to the best of our knowledge, 157 for the first time, we report the baseline data of orbit dimensions, including oi, iod, and izd 158 in the omani population. 159 160 the orbital cavity possesses greater height than width and is typically classified into three 161 categories: microseme, mesoseme, and megaseme. previously, studies from different asian 162 countries, including japan, china, india, sri lanka, turkey and iran, have documented the oi 163 of their respective populations and classified them under one of the categories.1,4,5 in the 164 present study, the mean oi of omani subjects was found to be 83.25±4.83, and the prevalent 165 orbital type was categorized as mesoseme. similar to the present study, the mesoseme orbital 166 class was found in the iranian population. in egyptian female subjects, it was mesoseme 167 6 while it was microseme in male subjects. in the turkish population from the middle-eastern 168 region, the megaseme orbital category was observed.18 169 170 in the literature, there are conflicting reports on the sexual dimorphism of oi. in omani 171 subjects, the observed oi of males was 83.34±5.05, while it was 83.16±4.57 in females. both 172 genders belonged to the mesoseme category. no significant gender difference in oi was 173 observed in the omani subjects. similar findings were reported in brazillian5 and south 174 indian subjects20, and in kalabaris and ikwerres of the rivers ethnic group of nigeria.21 in 175 contrast, a significant gender difference in oi was found in the igbo and urhobos ethnic 176 groups of nigeria and ghanaian subjects.4 in agreement with these studies, gender 177 differences in bony volume and dimensions were observed even in the iranian population.19 178 179 furthermore, in omani subjects, the laterality differences with hdo, vdo and oi were 180 statistically significant. these findings are similar to the study results from the iranian 181 population.19 however, contradictory findings of laterality differences were observed in 182 indian,20 nigerian22 and ghanaian4 populations. in the present study, there were no 183 significant differences in oi among different age groups in both males and females. similar 184 findings were observed in ghanaian subjects.4 however, in the malawian7 and igbo ethnic 185 groups of nigerian subjects,22 the oi was significantly different in different age groups. 186 these discrepancies observed between the studies with regard to orbital dimensions and their 187 associated factors are possibly due to genetic factors. 188 189 the iod is clinically used to diagnose both orbital hypotelorism and hypertelorism. orbital 190 hypertelorism is distinguished by a longer iod, most often associated with a variety of 191 craniofacial conditions, including crouzon syndrome, craniofacial dysplasias and clefts.23 on 192 the other hand, hypotelorism is also linked to several diseases, including holoprosencephaly 193 and craniosynostosis.24 reference values are also important while correcting the surgeries 194 involving the above-mentioned craniofacial anomalies. previously, authors have provided the 195 reference values of iod for different populations. an iod of 26.7 and 25.6 mm was 196 observed in american males and females, respectively.13 in the indian population, the 197 reported overall mean iod was 26.89 mm, while in males and females, the mean distance 198 was 27.46 mm and 25.93 mm, respectively.1 in the present study, the observed iod values 199 (males: 19.79±1.46; females: 19.12±1.52) were lower than those reported in indian and 200 american subjects. however, the mean iod of omani subjects was close to that of the 201 7 iranian population (males: 23 mm; females: 21.7 mm).25 in previous studies, the observed 202 normal izd was within the range of 90 mm and 109 mm.1,26,27 in line with these studies, the 203 interzygomatic distance in omani subjects is found to be within this range. 204 205 the variations in orbital dimensions among different populations world-wide could be 206 attributed to the evolutionary processes wherein inheritable mutations can generally occur by 207 natural selection. as a result, population-based differences reflect contemporary 208 environmental pressures, genetic drift, historical and present hybridization between 209 geographically disparate populations, and current selective adaptation of human varieties to 210 their surroundings.28 in forensic anthropology, human skeletal remains are considered strong 211 evidence for population origin identification and identification of other factors, including sex, 212 age, and stature. therefore, the reference values of orbital dimensions reported in the present 213 study are important in anthropological characterization. these values are also crucial for the 214 diagnosis as well as while planning the surgical treatments for various orbital pathologies. 215 the present study has the following limitation. as the present study is a single-centered 216 study, the study sample may not be a true representative of the omani population. a multi-217 centered study considering the ethic differences of omani subjects would be more interesting 218 to explore. 219 220 conclusion 221 results of the present study provide reference values of orbital dimensions in omani subjects. 222 the prevalent orbital type of omani subjects is mesoseme, which is a hallmark of the white 223 race. further, these findings may be helpful in the field of forensic medicine and 224 anthropology and also for ophthalmologists and neurosurgeons and maxillofacial surgeons. 225 226 conflicts of interest 227 the authors declare that they have no conflict of interest. 228 funding 229 the present study is an unfunded project. 230 231 authors contributions 232 study conception and design: ea, hd, srs; material preparation and investigation: ea, ms, 233 mm, srs; formal analysis: mm, srs, validation of the data collection and results analysis: 234 ea, srs, hd; visualization and/or presentation of data: ea, ms, srs, hd; original 235 8 manuscript preparation: ea, ms, mm, srs. all authors have read and approved the final 236 version of the manuscript. 237 238 references 239 1. gupta v, prabhakar a, yadav m, khandelwal n. computed tomography imaging-based 240 normative orbital measurement in indian population. indian j ophthalmol 2019; 241 67(5):659-663. doi: 10.4103/ijo.ijo_1187_18. 242 2. converse jm, mccarthy jg, wood-smith d. reconstructive plastic surgery for orbital 243 hypertelorism. in: converse jm, mc-carthy jg, wood-smith d. symposium on 244 diagnosis and treatment of craniofacial anomalies 1979; 20:207-221. 245 3. mafee mf, valvassori ge radiology of the craniofacial anomalies. otolaryngol clin 246 north am 1981; 14:939-988. 247 4. botwe bo, sule ds, ismael am. radiologic evaluation of orbital index among 248 ghanaians using ct scan. j physiol anthropol 2017; 36:29. doi: 10.1186/s40101-017-249 0145-7. 250 5. fernandes lc, rabello pm, santiago bm, carvalho mv, sena junior mr, soriano ep, 251 daruge junior e. craniometric study of the orbital index in brazilian skulls. rgo-252 revista gaucha de odontologia 2021; 19:69. https://doi.org/10.1590/1981-253 86372021001320190115. 254 6. husmann pr, samson dr. in the eye of the beholder: sex and race estimation using 255 the human orbital aperture. j forensic sci 2011; 56:1424-1429. doi: 10.1111/j.1556-256 4029.2011.01864.x. 257 7. igbigbi ps, ebite le. orbital index of adult malawians. anil aggrawal's internet journal 258 of forensic medicine and toxicology 2010; 11:1. 259 8. giles e, elliot o. race identification from cranial measurements. journal of forensic 260 sciences 1962; 2:147-57. 261 9. iscan m. forensic anthropology of sex and body size. forensic sci int 2005; 147:107–262 112. https://doi.org/10.1016/j.forsciint.2004.09.069. 263 10. mehta m, saini v, nath s, patel mn, menon sk. ct scan images to determine the 264 origin from craniofacial indices for gujarati population. journal of forensic radiology 265 and imaging 2014; 2:64-71. https://doi.org/10.1016/j.jofri.2014.02.001. 266 11. xing s, gibbon v, clarke r, liu w. geometric morphometric analyses of orbit shape in 267 asian, african, and european human populations. anthropological science 2012; 268 120803. https://doi.org/10.1537/ase.120803. 269 9 12. ebeye a, otikpo o. orbital index in urhobos of nigeria. iosr journal of dental and 270 medical sciences 2013; 2:51-53. doi:10.9790/0853-0825153 271 13. mafee mf, pruzansky s, corrales mm, phatak mg, valvassori ge, dobben gd, et al. 272 ct in the evaluation of the orbit and the bony interorbital distance. ajnr am j 273 neuroradiol 1986; 7:265-9. 274 14. sirimaharaj w, kanpuan w, angkurawaranon s. the relationship between external 275 bony defects and widened lateral interorbital distance in frontoethmoidal 276 encephalomeningocele. j craniomaxillofac surg 2019; 47:1563-1568. doi: 277 10.1016/j.jcms.2019.07.013. 278 15. chatdokmaiprai c, kiranantawat k, lertsithichai p, taeshineetanakul p. normative 279 data of the interorbital distance in thai population. j craniofac surg 2018; 29:1939-280 1944. doi: 10.1097/scs.0000000000005050. 281 16. jullabussapa n, khwanngern k, pateekhum c, angkurawaranon c, angkurawaranon s. 282 ct-based measurements of facial parameters of healthy children and adolescents in 283 thailand. ajnr am j neuroradiol 2020; 41:1937-1942. doi: 10.3174/ajnr.a6731. 284 17. fetouh fa, mandour d. morphometric analysis of the orbit in adult egyptian skulls and 285 its surgical relevance. eur j anat 2014; 4:303-15. 286 18. ozdikici m, bulut e, agca s. assessment of the orbital structures using computed 287 tomography in healthy adults. niger j clin pract 2021; 24:561-8. doi: 288 10.4103/njcp.njcp_77_20. 289 19. khademi z, bayat p. computed tomographic measurements of orbital entrance 290 dimensions in relation to age and gender in a sample of healthy iranian population. j 291 curr ophthalmol 2016; 28:81-4. doi: 10.1016/j.joco.2016.03.002. 292 20. mekala d, shubha r, rohini m. orbital dimensions and orbital index: a measurement 293 study on south indian dry skull. int j anatomy res 2015; 3:1387–1391. 294 21. leko bankole j, douglas p, ukoima hs, madugba c. radiological assessment of orbital 295 dimensions of the kalabaris and ikwerres of rivers state, nigeria. african journal of 296 biomedical research 2012; 15:197-200. 297 22. ezeuko v, om'iniabohs f. radiologic evaluation of orbital index among the igbo ethnic 298 group. eur j anatomy 2015; 1:9-14. 299 23. sharma rk. hypertelorism. indian j plast surg 2014; 47:284-92. doi: 10.4103/0970-300 0358.146572. 301 24. mirsky d, feygin t. imaging of fetal orbits. journal of pediatric neuroradiology 2015; 302 4:070-81. 303 10 25. bayani l. the bony interorbital distance and orbital measurements in the iranian 304 population: a ct study. iran j radiol 2006; 3:e79012. 305 26. ozgen a, ariyurek m. normative measurements of orbital structures using ct. ajr am 306 j roentgenol 1998; 170:1093-6. doi: 10.2214/ajr.170.4.9530066. 307 27. lee js, lim dw, lee sh, oum bs, kim hj, lee hj. normative measurements of 308 korean orbital structures revealed by computerized tomography. acta ophthalmol scand 309 2001; 79:197-200. doi: 10.1034/j.1600-0420.2001.079002197.x. 310 28. catalina-herrera cj. morphometric study of the orbit's base in male and female skulls of 311 spaniards. bull assoc anat (nancy) 1988; 72:5-7. 312 313 314 figure 1. axial ct image of the orbits in the bone window showing the interorbital distance 315 (short solid line) and inter-zygomatic distance (long dashed line). 316 317 318 figure 2. axial ct image at the level of the orbits shows (a) the horizontal orbital distance of 319 the right orbit and (b) a sagittal image shows the vertical orbital distance 320 321 table 1: comparison between left and right orbital dimensions. 322 parameters mean± sd p value oi% left orbit right orbit 83.83±4.93 82.67±5.36 0.05 11 vdo (mm) left orbit right orbit 33.01±1.89 32.83±1.90 0.003 hdo (mm) left orbit right orbit 39.42±1.66 39.76±1.75 0.05 oi: orbital index; vdo: vertical distance of orbit, hdo: horizontal distance of orbit 323 324 table 2: associations of orbital dimensions with respect to gender on right and left sides 325 of orbit. 326 parameters mean± sd p value roi (%) female male 82.49±4.93 82.85±5.77 0.59 loi (%) female male 83.82±4.71 83.83±5.16 0.99 rvdo (mm) female male 32.44±1.79 33.22± 1.95 0.001 lvdo (mm) female male 32.71± 1.76 33.31±1.98 0.01 rhdo (mm) female male 39.37±1.56 40.16±1.84 0.001 lhdo (mm) female male 39.07±1.57 39.77±1.68 0.001 roi: right orbital index, rvdo: right vertical distance of orbit, rhdo: right 327 horizontal distance of orbit, loi: left orbital index, lvdo: left vertical distance of 328 orbit, lhdo: left horizontal distance of orbit. 329 330 table 3: comparison between orbital indices of different age groups among females. 331 side age frequency mean (%) standard deviation p value right 18-25 5 82.78 5.49 0.93 26-35 7 82.66 3.6 36-45 19 82.49 3.9 46-55 20 81.63 5.17 56-65 24 81.76 4.36 66-75 38 82.85 5.77 ≥76 24 83.25 5.11 left 18-25 5 84.06 5.04 0.89 26-35 7 83.54 3.05 36-45 19 83.44 4.43 46-55 20 83.9 4.88 56-65 24 82.71 3.26 12 66-75 38 84.44 5.13 ≥76 24 84.17 5.82 332 table 4: comparison between orbital indices of different age groups among males. 333 side age frequency mean (%) standard deviation p value right 18-25 18 81.61 5.04 0.35 26-35 14 83.49 6.21 36-45 11 80.12 5.20 46-55 10 83.52 4.76 56-65 16 82.16 4.41 66-75 35 84.46 7.26 ≥76 32 82.55 4.99 left 18-25 18 83.40 4.79 0.34 26-35 14 84.07 5.12 36-45 11 80.96 5.07 46-55 10 79.44 5.33 56-65 16 83.64 3.02 66-75 35 85.34 5.61 ≥76 32 83.53 5.57 334 genotypes and allele frequencies of ace insertion/deletion polymorphism among omanis 25 genotypes and allele frequencies of angiotensin converting enzyme (ace) insertion/deletion polymorphism among omanis. *ali t. al-hinai1, mohammed o hassan2, mehmet simsek3, hameeda al-barwani3, riad bayoumi3 abstrac t. objective: to describe the angiotensin converting enzyme (ace) genotype frequencies among omani arabs. method: a polymerase chain reaction (pcr) test, based on separation of different size dna fragments, was developed to test the presence or absence (polymorphism) of a small dna deletion in the ace gene. the subjects were 124 omani arab students of sultan qaboos university, muscat. results: the frequency of the i allele was 0.29, while that of the d allele was 0.71. the gene frequency distribution did not deviate from hardy-weinberg equilibrium. conclusions: the frequency of d allele among omanis is similar to that among other arabs and africans, but differs significantly from that among the japanese and chinese. key words: allele, genotype, polymorphism, hypertension. departments of 1medicine, 2physiology and 3biochemistry, college of medicine & h sc, sultan qaboos university, p.o.box 35, al-khod-123, sultanate of oman. *to whom correspondence should be addressed. email: alihinai@squ.edu.om essential hypertension (htn) is a major risk factor for morbidity and mortality from car-diovascular diseases.1 the causes of htn have not yet been determined. it is considered as a multifactorial and polygenic disease,2 and occurs as a consequence of a complex interplay of genetic alterations and environmental factors.3 the angiotensin converting enzyme (ace) gene is one of the genes that control blood pressure and has been intensively investigated. the ace gene, first described by rigat et al in 990,4 has an insertion/deletion (i/d) polymorphism in intron 6. various published reports suggest an association or linkage of the d allele of the ace gene with myocardial infarction,5 essential hypertension,6 left ventricular hypertrophy,7 renal insufficiency8 and high fasting blood sugar levels.9 however, some other investigators have found no association between ace i/d polymorphism and htn.10,11 inter-ethnic variations in the frequency of allelic forms of certain genes, have been suggested as one of the reasons for such discrepancies.12 this is particularly true for the ace gene, since wide inter-ethnic allelic variations have been reported.13 the aim of our study was to find out ace allele and genotype frequencies among omani arabs and compare them with those among other ethnic groups. oman is one of the countries in arabian peninsula, and 85% of its population are arabs of bedouin descent; the remaining 5% originate from eastern africa and the indian subcontinent.14 s u b j e c t s one hundred and twenty four (24) unrelated omani arabs were randomly selected from among students of sultan qaboos university. after getting an informed consent, 5 ml of blood was collected from each into an edta-containing tube. squ journal for scientific research: medical sciences 2002, vol. 4, no. –2, 25–27 ©sultan qaboos universit y dr al hinai ����� ������� ������ ����������� ) ����� (����������� ������ ������ ��������� ��������� �� �������� ������� � ����� ������ ��� ����� ����� ������� ���� �������� ����� �������� ����� �������� :����� :���� ������� �������� ��������� �� ����������� ���� ����� ������� ����� ���� �����.������� :�� ��� ���� ��� ��� �� ���� � ������ ������ ��� ����� ��� ������� �������� ������� ���� ����� ������ �� ���� ����� ������� ���������� ������ ������ ������ �� ������� ���� �� ������ ������ �� ���� �� .��� ������������ ����� ��� �� ����� ���� �� ��������� ������.�������:���� ���� ���)���� (i���������� ���� ��� ����� �d������ . �� ������ ���� ������ �� ������ � ����� ����� �� ����������:���� ���� ��d�� ������ ����� ���� �������� ������ ����� �� ������ ������ ��� ��������� �� ��� �� �������������� ������� . 26 dna analysis dna was isolated from leukocytes by phenol/chloroform extraction. the insertion/deletion (i/d) polymorphism in intron 6 of the ace gene was detected by the polymerase chain reaction (pcr), following the method described previously by rigat et al,15 using a set of oligonucleotide primers which differentiate the three ace genotypes: ii, id and dd. using 2% agarose gel electrophoresis and ethidium bromide staining, the homozygote deletion (dd) alleles were visualised as 90 base pairs (bp) bands, homozygote insertion (ii) alleles as 490bp bands, and heterozygotes (id) alleles as two bands of 490 bp and 90 bp. since the d alleles in heterozygous samples (id) are preferentially amplified, some samples with id genotypes are liable to be mistyped as dd.16 therefore, each sample found to have the dd genotype was verified in an independent second pcr amplification. a 335 bp band was visualised only in the presence of an i allele and no bands were visualized in samples with dd. r e s u l t s the frequency distribution of genotypes and alleles of the ace (i/ d) polymorphism among omani arabs is summarised in table . the frequency of the i allele was 0.29 while that of the d allele was 0.7. ten heterozygotes were mistyped as dd, but proved to be heterozygotes on independent second pcr using insertion specific primers. the gene frequency distribution did not deviate from the hardy-weinberg equilibrium. d i s c u s s i o n the frequency of the d allele of the ace gene among omanis (0.7) is comparable to that in other arabs, such as the emiratis (0.66), somalis (0.73) and sudanese (0.64). compared to other ethnic groups (table 2) the frequency of the d allele seems to be among the highest reported. the frequency of the d allele seems to follow a clinal distribution, being highest among africans and arabs (0.70–0.60), followed by caucasians (0.46–0.58), then the japanese (0.33–0.35) and the chinese (0.29). the yanomami indians and samoans seem to have the lowest frequencies: 0.5 and 0.09, respectively. c o n c l u s i o n this study confirms the results obtained among other arabs and adds to the data indicating the wide variations observed in the frequency of the ace alleles among the peoples of the world. therefore, the interpretation of clinical data on the association of the ace alleles with cardiovascular disease must be approached with the greatest of care. table 2. prevalence of insertion/deletion polymorphisms of ace gene among different ethnic groups as per different studies. allele frequency ethnic group i d number of individuals tested i. arabs emirates17, 18 sudanese18 somalis18 omanis (present study) 0.34 0.39 0.36 0.27 0.29 0.66 0.61 0.64 0.73 0.71 159 111 121 53 124 ii. africans nigerians13 african-americans19 0.41 0.30 0.59 0.70 80 40 iii. caucasians5,20,21 0.42–0.54 0.46–0.58 1212 iv. asians japanese22,23,24 chinese25 0.65–0.67 0.71 0.33–0.35 0.29 354 189 v. others: yanomami indians13 samoans13 0.85 0.91 0.15 0.09 49 58 table 1. frequency of genotypes and alleles of ace (i/d) polymorphism in 124 omani arabs. genotypes allele fequency total number ii (n) o(e) id (n) o(e) dd (n) o(e) i d 124 8(10.1) 55(50.6) 61(63.2) 0.29 0.7 1 o: observed, (e): expected �2 : 0.896, for goodness of fit test. no deviation from the hardy-weinberg equilibrium was observed. a l h i n a i e t a l 27 r e f e r e n c e s . macmahon s, peto r, cutler j, collins r, sorlie p, neaton j, et al. blood pressure, stroke and coronary heart disease: part i, prolonged difference in blood pressure: prospective observational studies corrected for the regression dilution bias. lancet, 990, 335, 766–774. 2. lifton rp, jeunemaitre x. finding genes that cause human hypertension. j hypertens, 993, , 23–236. 3. hamet p, pausova z, adarichev v, adaricheva k, tremblay j. hypertension: genes and environment. j hyertens, 998, 6, 397–48. 4. rigat b, hubert c, alhenc-gelas f, cambien f, corvol p, soubrier f, et al. an insertion/deletion polymorphism in the angiotensin-converting enzyme gene accounting for half the variance of serum enzyme levels. j clin invest, 990, 86, 343– 346. 5. cambien f, poirier o, lecerf l, evans a, cambou jp, arveiler d, et al. deletion polymorphism in the gene for angiotensin converting enzyme is a potent risk factor for myocardial infarction. nature, 992, 359, 64–644. 6. zee ry, lou yk, griffiths lr, morris bj. association of a polymorphism of the angiotensin i-converting enzyme gene with essential hypertension. biochem biophys res comm, 992, 84, 9–5. 7. kimura m, yokota m, fujimura t, kato s, hirayama h, tsunekawa a, et al. association of a deletion polymorphism of the angiotensin-converting enzyme gene with left ventricular hypertrophy in japanese women with essential hypertension; multicentre study of 99 subjects. cardiology, 997, 88, 309–34. 8. yoshida h, mitarari t, kuriyama s. does the polymorphism of angiotensin-converting enzyme (ace) gene predict progression of diabetic nephropathy (dn) to chronic renal failure? am j hypertens, 995, 8, 30–3a. 9. zingone a, dominijanni a, mele e, marasco o, melina f, minchella p, et al. deletion polymorphism in the gene for angiotensin converting enzyme in association with elevated fasting blood glucose levels. hum genet, 994, 94, 207–209. 0. schmidt s, van hooft ims, grobbee de, ganten d, ritz e. polymorphism of the angiotensin i converting enzyme is apparently not related to high blood pressure: dutch hypertension and offspring study. j hypertens, 993, , 345–348. . jeunemaitre x, lifton rp, hunt sc, williams rr, lalouel jm. absence of linkage between the angiotensin converting enzyme locus and human essential hypertension. nature genet, 992, , 72–75. 2. altshuler d, kruglyak l, lander e. genetic polymorphism and disease. n eng j med, 998, 338, 626. 3. blackwood a, carter nd, crews de, barley j, cruickshank jk, jeffery s, et al. angiotensin converting enzyme insertion/deletion polymorphism: association with ethnic origin. j hypertens, 994, 2, 955-957. 4. al-shanfari am: oman in international enxyclopedia of national systems of education; 2nd edition, 995. editor t.n. postleth waite, pregamon, london. 5. rigat b, hubert c, corvol p and soubrier f: pcr detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (dcpi; dipeptidyl carboxypeptidase ). nucl acid res, 992, 20, 433. 6. shanmugam v, sell kw and saha kb: mistyping ace heterozygotes. pcr meth appl 993, 3, 20-2. 7. frossard pm, obineche en, elshahat yi, lestringant gg. deletion polymorphism in the angiotensin-converting enzyme gene is not associated with hypertension in a gulf arab population. clin genet, 997, 5, 2–23. 8. bayoumi ra, yehya tm, benedict s, al-hinai a, al-barwani h, simsek m and hassan mo. the insertion/deletion polymorphism in the angiotensin i – converting enzyme gene among the sudanese, somalis, emirates and omanis (submitted). 9. rutlidge dr, browe cs and ross ea. frequencies of the angiotensinogen gene and angiotensin  converting enzyme (ace) gene polymorphism in african americans. biochem mol biol int, 994, 34, 1271–1275. 20. raynolds mv, bristow mr, bush ew, abraham wt, lowes bd, zismann ls et al. angiotensin-converting enzyme dd genotype in patients with ischemic or idiopathic dilated cardiomyopathy. lancet, 1993, 342, 073–075. 2. tiret l, rigat b, visvikes s, breda c, corvol p, camien f, et al. evidence from combined segregation and linkage analysis, that a variant of the angiotensin-converting enzyme (ace) gene controls plasma ace levels. am j hum genet, 992, 5, 97–205. 22. nomura h, koni j, michishita y, morise t, takeda r. angiotensin-converting enzyme gene polymorphism in hemodialysis patients. lancet, 994, 343, 482–483. 23. doi y, yoshizumi h, yoshinari m, iino k, yamamoto m, ichikawa k, et al. association between a polymorphism in angiotensin-converting enzyme gene and microvascular complications in japanese patients with niddm. diabetologia, 996, 39, 97–02. 24. kario k, kanai n, nishiuma s, fujii t, saito k, matsuo t, et al. hypertensive nephropathy and the gene for angiotensinconverting enzyme. arterioscler thromb vasc biol, 997, 7, 252–256. 25. lee ejd. population genetics of the angiotensin-converting enzyme in chinese. br j clin pharmac, 994, 37, 22–24. a c e p o ly m o r p h i s m a m o n g o m a n i s 2008-issue1.indd intraorbital foreign body: clinical presentation, radiological appearance and management *abdullah al-mujaini,1 rana al-senawi,1 anuradha ganesh,1 sana al-zuhaibi,1 humoud al-dhuhli2 الشعاعي السريري، املظهر العرض العني: حجاج داخل غريب جسم العالجي والتدبير الذهلي حمود الزهيبي، سناء جانيش، انورادا السناوي، رنا ايني، اهللا عبد النادر ومن ، الصناعية احلوادث أو ــاص مثل طلقات الرص ــرعة الس عالية االصابات نتيجة عادة العني حجاج داخل ــام الغريبة األجس ــص: تدخل امللخ يلقي االستعادي التقرير هذا البصر. فقدان اسوأها األجسام الغريبة الى مضاعفات خطيرة هذه تؤدي ميكن أن بسيطة. اصابات بعد احلالة حدوث هذه من حيث ، عمان) (سلطنة قابوس السلطان جامعة ــفى مستش في ــافهما اكتش مت العني غريبة داخل ــام أجس مصابتني بدخول حالتني على الضوء وطرق اجلراحي واالجراء البصر حدة الدقيقة للحالتني مثل فحص التفاصيل ــجيل تس مت والتدخل اجلراحي. ــعاعي والتصوير الش ــريرية الس الصفات داخل العني الغريبة ــام االجس ــف عن وجود الكش مت وقد ، التوالي على ــنوات 9 س 10 و حادة هو بأدوات العني في اصيبا الذين املريضني عمر العالج. بعدها وتعافى ، فورا جراحية لعملية خضع حيث ، العني تتأثر األصابة ولم بعد مباشرة الينا املريض األول حضر للعني. املقطعية األشعة عن طريق وظائف جميع لذلك فقد املريض ، لَة ُقْ امل نِ اصابته بالتهاب بَاطِ وتبني االصابة بعد أيام بأربعة متاخرا حضر الينا فقد الثاني املريض أما بصورة كاملة. اجلسم ازالة ان سرعة كما ، مكانه وحتديد املقلة الغريب في اجلسم تقصي في مهما دورا تلعب بان األشعة املقطعية هنا االشارة يجدر املصابة. العني مضاعفات االصابة اخلطيرة. وتفادي العني على احملافظة على يساعد حيث ايجابية يؤثر بصورة جراحيا الغريب . عمان سلطنة ، حالة تقرير ، العني اختراق العني ، : اصابات الكلمات مفتاح departments of 1ophthalmology, 2radiology & molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: mujainisqu@hotmail.com sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 69-74 sultan qaboos university© submitted 3rd september 2007 accepted 14th january 2008 abstract intraorbital foreign bodies usually occur after a high velocity injury such as gunshot or industrial accidents; more rarely they occur following trivial trauma. a retained foreign body can give rise to serious complications, the most devastating of which is loss of the eye. this retrospective, interventional case report reviews the clinical features, radiological appearance and surgical management of two patients who presented at sultan qaboos university hospital, oman with intraorbital foreign bodies. details of ocular history, preoperative ocular examination findings including visual acuity, surgical procedure and subsequent management were noted. the two patients, aged 0 years and 9 years old respectively, sustained orbital trauma with sharp objects. both patients were found to have intraorbital foreign bodies that were documented clearly by computed tomography (ct) scans of the orbit. the first patient presented straight after injury, had no ocular involvement, underwent immediate surgical exploration and ended up with full recovery. the second patient presented to us after a delay of 4 days, and was found to have endophthalmitis. this patient ultimately lost all visual function in the affected eye. a ct scan is the modality of choice for orbital foreign body detection and localization. early surgical exploration and foreign body extraction greatly influence the visual prognosis and final outcome. key words: eye injuries, penetrating; case report; oman. an intraorbital foreign body is an important cause of ocular morbidity espe-cially in the peadiatric and adolescent age groups. the term refers to a foreign body that occurs within the orbit but outside the globe.1 it usually occurs after a high velocity injury such as a gunshot or an industrial accident, but even relatively trivial trauma can cause it.1 orbital foreign bodies are more commonly observed in males than in females and in younger than in older patients. they can be classified according to c a s e r e p o r t a b d u l l a h a l m u j a i n i , r a n a a l -s e n aw i , a n u r a d h a g a n e s h , s a n a a l z u h a i b i , h u m o u d a l d h u h l i 70 their composition into a) metallic such as steel; b) nonmetallic, which may be inorganic such as glass; c) organic such as wood or vegetable matter. in general, metal and glass are well tolerated, and if not causing any symptoms or signs, may be left in situ, while organic matter like wood and vegetable matters are poorly tolerated, elicits an intense inflammatory reaction, and need to be removed urgently.2 surgery is planned based on certain aspects that include the nature of the intraorbital foreign body (poorly tolerated organic objects such as wood and vegetable matter, or well tolerated objects such as stone, glass, plastic, iron, steel and aluminum); location of the foreign body (anterior or posterior orbit), and presence of other injuries or foreign body-related complications (such as optic nerve compression, infections, and extraocular muscle involvement).3 figure 1.1: pre-operative face photos show moderate lid ptosis, normal position of the globe in primary gaze, and conjunctival hyperemia in left eye (1.1b), with marked limitation in adduction and abduction (1.1 a and c) 1.1a 1.1b 1.1c a b figure 1.2: computed tomography (ct) images of the orbits axial ct images through the orbits show: a) high density linear foreign body (straight arrow) within the medial rectus muscle of the left orbit; b) the medial rectus muscle is enlarged due to a hematoma. the distal tip of the foreign body is seen against the medial wall of the orbit (arrow head) figure 1.3: foreign body ( fish bone), the larger piece is 2.5cm, the shorter is 2.0cm i n t r a o r b i ta l f o r e i g n b o d y : c l i n i c a l p r e s e n tat i o n , r a d i o l o g i c a l a p p e a r a n c e a n d m a n a g e m e n t 71 c a s e r e p o r t s the hospital charts of two patients who sustained orbital trauma, and who presented at the ophthalmology department of sultan qaboos university hospital (squh), oman, were retrospectively reviewed. c a se  a 10-year-old boy presented with orbital trauma sustained when he was struck in the left eye while swimming by what he described as a flying fish. ocular examintation showed a best corrected visual acuity of 20/20 in the right eye and 20/25 with -1.0 -0.75 x 75o in the left eye. ophthalmic examination of his right eye was unremarkable. examination of the left eye revealed ptosis and normal position of the globe in the primary gaze. there was lid oedema, conjunctival hyperemia, chemosis and a laceration over the insertion of the medial rectus muscle. limitation of movements in adduction and abduction was noted [fig1.1a-c]. the globe itself was intact and slit lamp biomicroscopy showed normal intraocular structures. computed tomography (ct) scan of the orbits revealed the presence of a hyper-dense foreign body dissecting the medial rectus, penetrating the periosteum and embedded in the left medial orbital wall [fig 1.2]. the child was admitted and commenced on intravenous ceftriaxone 1 gm daily and topical ofloxacin four times a day with a plan to intervene surgically. the foreign body was approached through transconjuctival medial orbitotomy. intraoperatively, the foreign body was found transecting all the way postero-medially towards the lacrimal bone. as it was very difficult to retrieve it in one piece, it was broken and extracted as two pieces (2.5 cm and 2.0cm in length) [fig 1.3]. the globe was intact and the wound sutured with 6/0 vicryl suture. post-operatively, topical tobradex® eye drops were administered four times a day. an uneventful recovery was observed; the patient maintained normal visual acuity and regained full ocular motility in all directions within 2 weeks following surgery [figs.1.4 and 1.5]. c a se 2 a 9-year-old boy, who sustained trauma in the right eye with a pencil, presented to squh four days after the trauma. initial management at a local hospital had included administration of topical antibiotics and steroids. over the following days, he experienced increasing redness and reduced vision in the affected eye. at presentation, his left eye showed a visual acuity of 20/20 and normal intraocular findings. the ocular examination of right eye revealed visual acuity of light perception with good projection, and lid oedema (lower lid more than upper) [fig. 2.1]. no wound of entry was detected. slit-lamp biomicroscopy revealed a hazy cornea, figure 1.4: face photo of same patient three days after intraorbital foreign body removal. lid edema and ptosis are reduced (1.4b). patient has mildy restricted adduction and abduction (1.4 a and c) 1.4a 1.4b 1.4c figure 1.5: two weeks post-operatively, the left eye looks normal in the primary position (1.5b). patient has recovered normal adduction and abduction (1.5 a and c) 1.5a 1.5b 1.5c a b d u l l a h a l m u j a i n i , r a n a a l -s e n aw i , a n u r a d h a g a n e s h , s a n a a l z u h a i b i , h u m o u d a l d h u h l i 72 anterior chamber filled with a fibrinous reaction and a indications large or sharp-edged foreign body signs of infection or inflammation proptosis restricted motility chemosis palpable orbital mass optic nerve compression abscess proved by imaging enhancing foreign body in imaging suspicion of a wood, vegetable matter or copper foreign body fistula formation table 1: indications for surgery in patients with intraorbital foreign bodies figure 2.1: photo of the right eye pre-operatively. it shows a swollen lower eyelid and an arrow pointing at possible location of foreign body in the lower lid a b figure 2.2: computed tomography (ct) images of the orbits axial ct images through the orbits show: a) high density linear foreign body (straight arrow) within the medial rectus muscle of the left orbit; b) the medial rectus muscle is enlarged due to a hematoma. the distal tip of the foreign body is seen against the medial wall of the orbit (arrow head) figure 2.3: foreign body: pencil tip, measuring 0.5 cm at its widest dimension figure 2.4: face photo after foreign body extraction. the swelling has subsided and the wound has healed completely, leaving no deformity i n t r a o r b i ta l f o r e i g n b o d y : c l i n i c a l p r e s e n tat i o n , r a d i o l o g i c a l a p p e a r a n c e a n d m a n a g e m e n t 73 1-mm hypopyon, cataractous lens, and 3+ cells in the vitreous. ophthalmoscopy revealed absent red reflex with no view of fundus details. b-mode ultrasound revealed medium amplitude echoes through out the vitreous with attached retina. a ct scan of the orbits showed a hyperdense foreign body embedded in the lateral 1/3 of the preseptal compartment of the right lower lid [fig 2.2]. the child was admitted and received intravenous ceftriaxone 500 mg twice per day besides topical ofloxacin, predforte ® eye drops and prednisolone tablet 10 mg (0.5mg/kg) per day with a plan to intervene surgically. intraoperatively, pars plana vitrectomy was performed to clear up the vitreous; endolaser photocoagulation was delivered to seal up the retinal hole and an intravitreal antibiotic injection was given. to remove the intraorbital foreign body the child underwent subciliary inferior orbitotomy, which revealed the presence of a pencil tip that had penetrated the orbital septum and was lying just in front of the inferior orbital wall [fig 2.3 and 2.4]. postoperatively, although the intraorbital foreign body was successfully removed, the eye went into secondary hypotony with a vision of no light perception as sequelae of endophthalmitis. d i s c u s s i o n two patients with orbital foreign bodies have been presented. both patients gave a history of trauma with a sharp object (case 1 while swimming and case 2 while playing with a pencil). both had foreign bodies located in their anterior orbit that were demarcated clearly by ct scans of the orbit. the first patient, who presented immediately, had no ocular involvement, underwent immediate surgical exploration and ended up with full recovery. the second patient presented to us after a delay of 4 days and was found to have endophthalmitis; extensive therapeutic (medical and surgical) measures could not save the sight in this eye. the presence of endophthalmitis in this patient is suggestive of globe penetration, but preoperative imaging as well as intraoperative exploration did not reveal evidence of ocular penetration. however, a possibility of partial scleral penetration and then subsequent migration of the foreign body and self-sealing of the scleral wound cannot be ruled out. the history of penetrating eyelid or orbital injury should always raise the suspicion of an embedded intraorbital foreign body, particularly if it is a high velocity injury. clinically, the presentation varies, with the patient being asymptomatic or having visual disturbances (decreased vision, double vision), pain, or swelling. the nature of injury and foreign object can be elicited by detailed history. however, it is well-known that the severity of injury in penetrating trauma of the orbit is often underestimated in physical examinations.3 therein lies the importance of a meticulous examination and radiological investigation. assessment through radiological images assists in the proper localization of the foreign body, estimation of its consistency and size, and evaluation of the response of surrounding orbital tissue. additionally, it is useful in determining the integrity of the globe. the choice of imaging modality chiefly depends on the nature of the suspected foreign body. plain film radiography is useful to localize radiopaque objects.4, 5 however, plain films lack the capacity to demonstrate the object details, their exact location in relation to surrounding structures and tissue response or damage. standardized ophthalmic ultrasonography (combination of standard a-mode and b-mode scanning) has been recommended as the imaging modality of choice during initial evaluation. nevertheless, this diagnostic method requires specific expertise and technology that may not be available in many institutions.3 ct scanning has therefore been recommended as the imaging modality of choice in this situation.1 ideally, a ct scan of the orbit must be ordered. thin axial and coronal views of 1.0-1.5 mm cuts of the orbit are extremely useful to delineate the shape and for determining the composition of the foreign body.6, 8 however, despite being highly sensitive and specific for detection of foreign bodies, ct scans may produce false negative results, particularly if the size of the foreign body is less than 0.5mm, and especially in the case of wooden objects. these are better seen with magnetic resonance imaging (mri). however, an mri is contraindicated if the suspected foreign body is ferromagnetic. once an intraorbital foreign body is diagnosed, appropriate management includes culture of the wound (or foreign body if removed) and administration of antibiotic(s). tetanus toxoid has to be administered according to the vaccination status. in general, surgery to remove the foreign body is planned based on certain aspects, which are summarized in table 1. in general, a posteriorly located foreign body may be observed if inert and not causing any complications, due to the risk of iatrogenic optic a b d u l l a h a l m u j a i n i , r a n a a l -s e n aw i , a n u r a d h a g a n e s h , s a n a a l z u h a i b i , h u m o u d a l d h u h l i 74 neuropathy or diplopia. similarly, small nonorganic foreign bodies may be left in the orbit. c o n c l u s i o n detection of intraorbital foreign bodies requires a high index of suspicion. obtaining an accurate and detailed history is absolutely essential. a ct scan of the orbit is the imaging modality of choice for detection and localization of the foreign body. early diagnosis, surgical exploration and extraction, when indicated, greatly influence the final outcome and at times the visual prognosis. r e f e r e n c e s 1. fulcher tp, mcnab aa, sullivan tj. clinical features and management of intraorbital foreign bodies. ophthalmology 2002; 109:494-500. 2. green bf, kraft sp, carter kd, buncic jr, nerad ja, armstrong d. intraorbital wood detection by magnetic resonance imaging. ophthalmology 1990; 97:608-611. 3. van thong ho, james f, mcguckin jr, smergel em. intraorbital wooden foreign body: ct and mr appearance. am j neuro surg 1996;17:134-136. 4. finkelstein m , legmann a, rubin pad. projectile metallic foreign bodies in the orbit. ophthalmology 1997; 104:96-103. 5. mcguckin jf jr, akhtar n, ho vt, smergel em, kubacki ej, villafana t. ct and mr evaluation of a wooden foreign body in an in vitro model of the orbit. am j neuroradiol 1996;17:129-133. 6. kunimoto dy, kanitkar kd, makar ms. intraorbital foreign body, in: the wills eye manual : office and emergency room diagnosis and treatment of eye diseases. fourth ed. philadelphia: lippincott williams & wilkins, 2004. p. 32-33. 7. lobue td, deutsch ta, lobick j, turner da. detection and localization of nonmetallic intraocular foreign bodies by magnetic resonance imaging. arch ophthalmol 1988; 106:260-261. 8. wilson wb, dreisbach jn, lattin de, stears jc. magnetic resonance imaging of nonmetallic orbital foreign bodies. am j ophthalmol 1988; 105:612-617. 9. simonton jt, arthurs bp. penetrating injuries to the orbit. adv ophthalmic plas reconstr surg 1987; 7:217227. 10. nasr am, haik bg, fleming jc, al-hussain hm, karcioglu za. penetrating orbital injury with organic foreign body. ophthalmology 1999; 106:523-532.   can pharmacists influence the health-related quality of life of patients with asthma? the new zealand pharmaceutical care experience *nadir kheir, lynne emmer ton, john shaw division of pharmacy, faculty of medical and health sciences, the university of auckland, private bag , auckland, new zealand *to whom correspondence should be addressed. e-mail: n.kheir@auckland.ac.nz a b s t r ac t. background: the newly emerging practice of pharmaceutical care requires that pharmacists take responsibility for the outcomes of drug therapy. improvement in quality of life (qol) represents the final outcome of the care process and indicates the success of interventions. objectives: to assess the impact of a pharmaceutical care specialist asthma service provided by community pharmacists to a sample of patients with asthma, the outcome indicators being changes in health status and qol. method: sixty-two adult asthma patients ( years and older) living in two rural regions of new zealand, were segregated into two groups for phased introduction to the service. the patients acted as their own controls before they received the pharmacists’ service. they had been diagnosed with asthma at least six months previously, and their asthma was symptomatic and not considered optimally controlled prior to the study. results: there was significant improvement in asthma-related qol (as measured by the asthma quality of life questionnaire) following introduction of the service, and pharmacists were able to identify, prevent or resolve over  drug-related problems. conclusion: the results suggest that with appropriate training and support, new zealand pharmacists can help asthma patients achieve greater quality of life. this research has implications for the introduction of pharmaceutical care services in other countries and for patients with other conditions who require ongoing management. key words: pharmaceutical care, quality of life, asthma, pharmacists, t      morbidity and mortality has increased worldwide, representing a challenge to healthcare providers.1,2 consequently, clinical services are sought to help patients manage their condition effectively. new zealand pharmacists have formally embraced the internationally recognised practice of pharmaceutical care, and new zealand has now probably the largest number of pharmaceutical care trained pharmacists per capita in the world.3,4 in a widely publicised article, hepler and strand defined the process of pharmaceutical care as ‘the responsible provision of drug therapy intended to achieve definite outcomes that will improve a patient’s quality of life.’5 is definition suggests that, as healthcare professionals, pharmacists take responsibility for the outcomes of drug therapy by adopting an active role in patient management. as the ultimate goal of drug therapy should be to improve the patient’s health-related quality of life (qol), it     :   , : , : , – ©   asthma new zealand ����� ���� ����� ������ ������� ��� ������� ������� ���� ��: ������ ������������� ���� ������ ���� ������ ��� ������:�����:����� ����� ������� �������� �������� ������� ������ ������ �������� ������� ����� ����������� �������. �������:����� ������������ ����� ���� �� ���� )������� ���� (������� �� ������� ������� ����� �������� �������� ��� ������� � �������� ������ .����� ����� �������� ������ ������������ ���� ��� ������ ��� ����� .��� ��� ������ ����� ����� �� ��� ��� ��� ������ ����� ����� ������� ��� �� ����� ������ ����� ���� ����� ����� �� ����.�������:�������� ��� �� ���� ���� � �� ���� ���� ����� �� �������� ���� ��� ������ ����� ��� ����� ���� ���� ����� ����������������� ���� ��� �����.������:��� � ���� ����� ��� ������ �� ����� ���� ������ �������� ������� ���� ������� ������� ����� ��� ���������� .��������� ����� ��� ������ ������ ����� ���� ����� ����� ���� ����� �� �������� ������� �����.   is imperative to assess the impact of medical interventions on qol. while considerable evidence exists demonstrating the worth of pharmaceutical care on a variety of patient outcomes, little has been provided on the impact of pharmaceutical care on qol as an end-point in the healthcare process. for example, fischer et al suggested that pharmaceutical care appears to increase the information given to patients about medications, promote more effective self-administration of medications by encouraging patients to use systematic reminders, and increase awareness of medication side effects.6 in another study, patients receiving pharmaceutical care reported receiving more information about asthma self-management, were more likely to monitor peak flow readings, and had increased satisfaction with care.7 munroe and colleagues reported that pharmacists’ interventions in a community pharmacy-based disease management model substantially reduced monthly healthcare costs in patients with hypertension, hypercholesterolaemia, diabetes, and asthma.7 more evidence is needed on the impact of pharmaceutical care on subjective outcomes, specifically qol. is paper outlines the findings of a pharmaceutical care specialist asthma service conducted as a demonstration project by the pharmacists in new zealand. although the paper does not provide data pertaining to the impact of the service on economical outcomes, the research has implications for other countries faced with rising secondary care costs due to asthma and other chronic conditions. m e t h o d s e aim of the study was to assess the health-related and qol outcomes in a group of asthma patients receiving a pharmacy-based asthma management service. is study was conducted in five community pharmacies in otago/southland regions of new zealand over a twoyear period. e school of pharmacy, university of otago, co-ordinated the study, which was funded by the health funding authority with support from glaxowellcome new zealand limited. e study was approved by the local ethics committee and patients gave informed written consent to participate. in consultation with the patients’ general practitioners, who were kept informed about the aims and progress of the study, pharmacists from the five pharmacies recruited  medically-diagnosed asthma patients each. inclusion criteria were that (i) the patients had been diagnosed with asthma at least six months previously, (ii) their asthma was symptomatic and not optimally controlled, and (iii) they did not suffer other co-morbidity. e latter criterion was based on the assumption that other chronic conditions could interfere with health outcomes measured, including the patient’s qol, and could make it difficult to identify the effect of the intervention on asthma. however, to simulate real-life situations, it was decided that if a concomitant condition were identified during the study, the patient continued participation. prior to the study, the status of the patients’ asthma was estimated by subjective self-assessment and by the frequency of visits to collect asthma medication. e patients were phased into the study in groups of  per pharmacy for stepwise introduction to the service. is avoided the pharmacies being overwhelmed by large numbers of patients at one time, and allowed variable baseline measurement periods for the preand post-intervention measures. based on a preliminary rating of asthma that used input from patients and their pharmacists, the patients were divided into two groups. while all patients recruited had what appeared to be poorly controlled asthma, group  included patients whom the research team felt were in need of immediate intervention. e study design dictated that group  receive the intervention first. it was considered unethical to deny these patients the opportunity for immediate care. at baseline (t), face-to-face interviews were conducted with all the patients. data collected included qol, specific symptoms, utilisation of health services, and beta-agonist (‘reliever’ medication) use. group  patients          ���������classification of medication-related problems ������ ��������������������� �������������������������� ���������������������������������������������������������������������������������������������������������������������������� ����������������������� ��������������������������������������������������������������������������������������������������������������� ������� �������������������������������������������������������������������������������������������������������������������� ����������� ������������������������������������������������������������������������������������������������������������������������������������ ������������������������������ �������������� ������������������������������������������������������������� �   then underwent a one-month run-in period during which standard pharmacy services were delivered (prescriptionrelated counselling, basic monitoring, advice on request). immediately aer the run-in period, the service was introduced to group . group  continued their run-in period for another four months, during which they received no intervention. only the data pertaining to adult patients (aged  years and over) in groups  and  (year  of the study) are covered in this review. patient training in both asthma management and the provision of the service was provided by the staff from the school of pharmacy, university of otago, in co-ordination with other specialists. specific material was provided on asthma presentation, aetiology, diagnosis, treatment protocols, therapies, devices, monitoring and features in special populations, such as children and pregnant women. an asthma educator attended the three training sessions. pharmacists initiated the service by arranging interviews with their patients at monthly intervals or as needed. e process was based on the guidelines of strand et al, given below.9 . patient consultation at this initial step, pharmacists elicit information on the patients’ asthma and other relevant history, including their concerns and understanding of their condition and their medication. e pharmacist also performs peak flow measurements, acquires the medication history, contacts other health professionals where necessary, checks compliance with asthma medication standards including inhaler technique, and documents the data using the soware ‘cognicare’, a window-based pharmaceutical care program designed for point-of-care cognitive services provision. . assessment at this stage, the pharmacist assesses the patient’s entire therapy, seeking potential or actual medication-related problems, such as overuse of bronchodilators (‘reliever’ medicines), under-use of inhaled corticosteroids (‘preventer’ medicines), and poor inhaler technique [table ]. . care plan based on the findings of steps  and  the pharmacist develops a plan to eliminate or minimise medication-related problems and maximise desired outcomes. is may involve written recommendations and an asthma action plan based on peak flow readings and symptom diaries. . patient education, recommendation and referral e pharmacist provides individualised education to the patient on drug therapy and usage of medication, and demonstrates inhaler technique and the ways to identify and avoid asthma ‘triggers’. if necessary, the pharmacist refers the patient to a general practitioner for specific assessment and management. . patient monitoring and follow-up monitoring enables the pharmacist and the patient to assess the progress towards therapeutic goals, and assures that new medication-related problems are avoided, and that the outcomes are evaluated and documented. both prevention and resolution of medication-related problems are a focus of the service. e medication-related problems were categorised for descriptive analysis. e classification system was based on a widely used united states system, with emphasis on asthma management.10        quality of life measures two questionnaires were used to quantify quality of life (qol): the short form- (sf-) and the asthma quality of life questionnaire (aqlq).11,12 e sf- is a general health questionnaire used internationally and previously validated for use in new zealand. it has eight domains of health that are generally summarised into physical and mental component summaries (pcs and mcs, respectively).13 e responses are transformed to a scale of –, where  denotes extreme impairment and  no impairment. e aqlq is an asthma-specific qol questionnaire, which has  items that address qol in four domains: activity limitation, symptoms, emotional function, and environmental stimuli. e response options are on a sevenpoint scale, where  indicates maximal impairment and  indicates no impairment. e participants are shown their previous answers before they give their new responses to the same questions (an ‘informed response’ strategy). responses to the aqlq were analysed as the mean for the overall aqlq and its separate domains. self-completed asthma symptoms diary e patients were asked to keep daily diaries documenting their asthma symptoms and peak flow monitoring record, based on the variables and scales used in existing asthma diaries.14 diaries were brought to the pharmacist at each subsequent appointment.                                    statistical analysis quantitative data for analysis included general and asthmaspecific qol data at baseline (t) and following four months of provision of the service (t). e significance of change in qol at t was expressed using analysis of variance, and p<. was considered statistically significant. e magnitude of the post-intervention change in scores was assessed by calculating the effect size of the overall and individual domain scores. effect size was calculated by dividing the change in the mean scores from baseline (t) to follow-up (t) by the standard deviation of the score at baseline.15 an effect size of  was considered small,  moderate and  large.16 e outcomes of medication-related problems and asthma symptoms were expressed qualitatively using the documentation system available, and detailed results have been published elsewhere.3 r e s u l t s of the  adult asthmatics ( males) recruited, one withdrew for personal reasons. demographics of the patients and their qol status at baseline (t) are shown in table . in summary, there were no significant differences between the two groups in their mean age, asthma duration, asthma severity, asthma-specific qol, and general qol as measured by the pcs and the mcs.           table  shows the change in qol of group  aer receiving the service for four months. with the exception of the environmental domain, all domains of the aqlq, including the overall aqlq, indicated different levels of statistically significant changes at t with a corresponding effect size. neither the pcs nor the mcs of the sf- indicated significant change at t (p=., and ., respectively). e aqlq scores of group  patients were also measured at t, at which time, this group were still receiving their baseline service [table ]. apart from the activity domain (p = .), all domains of the aqlq indicated small, non-significant improvements. again, general health, as measured by the pcs and the mcs, did not show significant difference at t in both the groups of patients.           while the current study design specifically addressed changes in qol in the two groups, other outcomes were collated and analysed in a more quasi-experimental and qualitative manner in the whole sample. individual case studies were used to provide evidence for the potential effectiveness of the service in different outcomes.3 a total of  medication-related problems were identified by the pharmacists, and all were documented using          �������� change in aqlq scores (group 1 patients, n=34) ������� ��������� ����� ����� �������� ���������� ����������� �� ��������� ���� ��������� ���������� ���������� ���������� ����� ���� ��������� ���������� ���������� ���������� ����� ���� ���������� ���������� ���������� ���������� ����� ���� �������������� ���������� ���������� ���������� ����� ���� ������������� ���������� ���������� ���������� ����� ���� �� ����������������������� ��� ������������������������������������������������������������������������������� �� ����������������������������������������������������������������������������� � � � ���������baseline (t1) characteristics of group 1 and group 2 patients (n=62) � ��������������� ��������������� ���������� ��������������� ���������� � ������������ ����� ������ ����� ������ ����� ������������������������ ����� ������ ����� ������ ����� ���������� ���� ������ ���� ����� ����� ������������� ���� ����� ���� ����� ����� ����������� ����� ������ ����� ������ ����� ����������� ����� ����� ����� ������ ����� �� ������������������������������������������������������������������ ������������������������������� � � ���������change in aqlq scores (group 2 patients, n=28) � ������� ��������� ���������� ������������� ����������� �� ��������� ����� ��������� ���������� ����������� ���������� ����� ���� ��������� ���������� ����������� ���������� ����� ���� ���������� ���������� ����������� ���������� ����� ���� �������������� ���������� ����������� ���������� ����� ���� ������������� ���������� ����������� ���������� ����� ���� ��� ����������������������� ����������������������������������������������������������������������������������� �� ����������������������������������������������������������������������������� � � �                                   ���������examples of problems faced by pharmacists providing pharmaceutical care � ����������������� ������������������� ���������������������������������������������� ����������������������� �������������������� ����������������������� ������������������������������ ������������������������������������������������������������� ������������������������������������������������������������� ������������������������������������������ ���������������������������������������������������������������������������������� ������������������������������������������� ������������������������������������������� �� ��������������������������������������������������������������� ��� �������������������������������������������������������������������������������������������������� � the designated computer soware. ere was no important difference between the groups, as these issues had been identified in the initial interview. on average, . medication-related problems were detected per patient, although the range was wide (between  and  per patient). about half of the patients recruited had approximately half of their medication-related problems resolved within the first six months of receiving the service. ten patients had at least  of their problems resolved. e pharmacists found out that while some problems were easy to resolve with simple interventions, others were more complex, some warranting referral to the general practitioner for more specific management. table  gives examples of the simple and complex problems faced by the pharmacists. e medication-related problems were classified as per the hepler and strand model, and about two-thirds were of ‘compliance/understanding’ type, such as overuse of bronchodilators and under-use of corticosteroids.10 e remaining problems were mostly related to choice of devices and adverse drug effects. choice of the drug did not feature highly, indicating that in most cases the choice of treatment was correct, but the patient did not know how to use the medication properly, or had chosen not to use it. all patients received some kind of intervention, including revision of action plan, referral to the gp, and/or further counselling or education. d i s c u s s i o n is study provided data that suggest that motivated and well-trained pharmacists can influence asthma-related outcomes in the community, with improvement in asthmarelated qol. e pharmacy services in new zealand are fully computerised, both at the community and the hospital levels. e consequent efficiency in in storage and access of medication histories enables quick identification of patients with medication-related problems, such as those failing to collect repeat prescriptions, and those who collect their bronchodilator therapy but not their inhaled corticosteroid therapy. in the current study, the pharmacists used their computer facilities to identify patients who were potentially suitable for inclusion in the study. asthma has been chosen in the current study because of its impact on qol. while it affects all age groups, older asthmatics have reportedly had significantly worse qol than ageand sexmatched controls, and had more frequent depressive symptoms.17 during an asthma attack, the patients’ functional capacity, and consequently their capability to lead normal daily life, becomes impaired. asthma sufferers report a wide range of restrictions due to their condition. ese include difficulties in performing housework, time off work, disruption of social life, avoidance of certain foods, and extra expenditure incurred in modifying their environment to suit their condition.18 emotional problems such as fear, helplessness, dependence and depression have also been identified as consequence of asthma in addition to physical one such as chronic lung diseases.19 erefore the most important goals in asthma management are improving patients’ everyday functioning, their emotional and social lives and subjective well-being. erefore, it would be logical to assume that should a demonstrable improvement in qol occur, the main objective of this specialist service could be considered achieved. pharmaceutical care services seek to add new dimensions to pharmacy practice, and to re-direct the focus of pharmacists from the product to the individual patient. structured and focussed processes have enabled the pharmacists participating in this study to realise improvements in daily performance of most patients. is has been demonstrated in the change observed at follow-up (aer four months of provision of the service), and evidenced by effect size, a statistical method that has been widely advocated in biomedical research to quantify magnitude of change.15 effect size has become popular in the social           and behavioural sciences, but not so much in medicine.16 while traditional clinical measures can estimate concrete phenomena related to change in biological functioning, they fall short of quantifying change in health status that have no direct biological meaning, such as anxiety, depression, and qol limitations. effect size measures the magnitude of change or ‘the clinically important change’ in health status, and not the statistical significance of the change.15 e larger the effect size, the greater the degree to which the phenomenon under study is manifested. e effect size therefore serves as an index of the degree of departure from the null hypothesis. in the current study, a moderate effect size was observed in the overall qol and in the symptoms domain of the patients who received the service. e majority reported significantly fewer asthma symptoms, fewer asthma-related emotional problems, and better performance of daily activities. at these changes occured within a short period, could be due in part to the erratic nature of asthma. however, simple interventions like correction of inhaler technique can lead to dramatic improvement in a short time.20 restrictions due to environmental triggers were found to be the most resistant to improvement. identification and avoidance of asthma triggers remains the best solution for these patients. e sf- physical and mental component summaries did not reflect significant changes in the patients’ general qol. however, the sf- taps areas of health that might have only been slightly affected by asthma, while the aqlq, being specific to asthma, demonstrated greater sensitivity in detecting change. e participating pharmacists acquired new communication and cognitive skills in their dealings with both patients and other health practitioners. indeed, the quality of interaction between the patients and their health professionals should determine to a large extent whether the desired outcomes are achieved. for example, the patient’s understanding of the importance of treatment influenced compliance more positively than the presence of perceived side effects, which again reflects the importance of communication with the patient.21 good communication, improved education, and tailoring therapy to the individual needs of the patient are all considered to improve asthma outcomes.22 in cases of mild asthma, rigid adherence to long-term daily peak flow measurement without taking into account the individual needs, does not appear to improve outcomes.23,24 as part of the intervention, medication-related problems were identified and acted upon. results related to medication-related problems were reported in a more qualitative manner, and a brief cross-section of these has been provided in the current article, where the emphasis is more towards the impact of the service on qol. e study also provided insight into the applicability of the pharmaceutical care service, and the difficulties faced by the pharmacists involved. ese have also been reported elsewhere.3 finally, while the sample size recruited might appear small, it is of the same order as in other qol studies and was based on calculations by guyatt et al using the responsiveness index approach.25–26,27 c o n c l u s i o n e pharmacist’s role and place in the healthcare structure has changed, and new opportunities have emerged. results from this study provide evidence that through providing structured, co-operative, patient-oriented pharmaceutical care, pharmacists can help asthma patients achieve desired health outcomes.              e authors thank the five pharmacists and the patients who took part in the study, and acknowledge the financial funding provided to the project by the health funding authority of new zealand and glaxowellcome (new zealand) limited. r e f e r e n c e s . lockey rf, dubuske lm, friedman b, petrocella v, cox f, rickard k. nocturnal asthma: effect of salmeterol on quality of life and clinical outcomes [in process citation]. chest , , –. . barnes pj, jonsson b, klim jb. e costs of asthma. eur respir j , , –. . shaw jp, emmerton l, kheir n, smith n, clareburt r, barron p, et al. otago/southland comprehensive pharmaceutical care asthma project [final report]. dunedin: school of pharmacy, university of otago, . . hepler cd. break on through, new zealand pharmacy conference. pharmacy today, , . . hepler cd, strand lm. opportunities and responsibilities in pharmaceutical care. am j hosp pharm , , –. . fischer lr, scott lm, boonstra dm, defor ta, cooper s, elkema ma, et al. pharmaceutical care for patients with chronic conditions. j am pharm assoc (wash) , , –. . knoell dl, pierson jf, marsh cb, allen jn, pathak ds. measurement of outcomes in adults receiving pharmaceutical care in a comprehensive asthma outpatient clinic. pharmacotherapy , , –. . munroe wp, kunz k, dalmady-israel c, potter l, schonfeld wh. economic evaluation of pharmacist involvement in disease management in a community pharmacy setting. clin er , , –.                                   . strand lm, cipolle rj, morley pc. documenting the clinical pharmacist’s activities: back to basics. drug intell clin pharm , , –. . strand lm, morley pc, cipolle rj, ramsey r, lamsam gd. drug-related problems: their structure and function. dicp , , –. . ware je jr, sherbourne cd. e mos -item short-form health survey (sf-). i. conceptual framework and item selection. med care , , –. . juniper ef, guyatt gh, epstein rs, ferrie pj, jaeschke r, hiller tk. evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. orax , , –. . ware je, konsiniski m, keller sd. sf- physical and mental health summary scales: a user’s manual. boston, ma, . . hyland me, crocker g. validation of an asthma quality of life diary in a clinical trial. orax , , –. . kazis le, anderson jj, meenan rf. effect sizes for interpreting changes in health status. med care , , s–. . cohen j. statistical power analysis for the behavioral sciences. new york: academic press, . . dyer ca, hill sl, stockley ra, sinclair aj. quality of life in elderly subjects with a diagnostic label of asthma from general practice registers. eur respir j , , –. . bowling a. measuring disease. review of disease specific quality of life measurement scales. nd ed. buckingham, open university press, . . maille ar, koning cj, zwinderman ah, willems ln, dijkman jh, kaptein aa. e development of the ‘quality-of-life for respiratory illness questionnaire (qol-riq)’: a disease-specific quality-of-life questionnaire for patients with mild to moderate chronic non-specific lung disease. respir med , , –. . muhlhauser i, richter b, kraut d, weske g, worth h, berger m. evaluation of a structured treatment and teaching programme on asthma. j intern med , , –. . van grunsven pm, van schayck cp, van deuveren m, van herwaarden cl, akkermans rp, van weel c. compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or chronic obstructive pulmonary disease (copd): results of the detection, intervention, and monitoring program of copd and asthma (dimca) study. j asthma , , –. . cochrane gm, horne r, chanez p. compliance in asthma. respir med , , –. . charlton i, charlton g, broomfield j, mullee ma. evaluation of peak flow and symptoms only self management plans for control of asthma in general practice. bmj , , –. . jones kp, mullee ma, middleton m, chapman e, holgate st. peak flow based asthma self-management: a randomised controlled study in general practice. british oracic society research committee. orax , , –. . juniper ef, buist as, cox fm, ferrie pj, king dr. validation of a standardised version of the asthma quality of life questionnaire. chest , , –. . row bh, oxman ad. performance of an asthma quality of life questionnaire in an outpatient setting. am rev respir dis , , –. . guyatt gh, kirshner b, jaeschke r. measuring health status: what are the necessary measurement properties? j clin epidemiol , , –. prevalence of depression, anxiety and stress as measured by the depression, anxiety, and stress scale (dass-42) among secondary school girls in abha, saudi arabia *khalid s. al-gelban,1 hasan s al-amri,2 ossama a mostafa1 squ med j, august 2009, vol. 9, iss. 2, pp. 140-147, epub 30th june 2009 submitted 6th november 08 revision req. 22nd april 09, revision recd. 11th may 09 accepted 12th may 09 departments of 1family and community medicine, 2internal medicine, college of medicine, king khalid university, abha, saudi arabia *to whom correspondence should be addressed. email: khalidgelban@hotmail.com clinical & basic research advances in knowledge 1. symptoms of negative emotional syndromes (depression, anxiety and stress) are highly prevalent among saudi female secondary school students. 2. these symptoms are higher among female than male secondary school students and do not differ significantly according to girls’ sociodemographic characteristics. application to patient care 1. it is important to screen adolescents for negative emotional syndromes and to refer those with morbid symptoms for psychiatric consultation. 2. school health unit staff and primary health care physicians can play a major role in the diagnosis and management of mental disorders. مدى انتشار االكتئاب والقلق والكرب النفسي )طبقا ملقياس داس-42( بني طالبات املرحلة الثانوية يف مدينة أبها باململكة العربية السعودية خالد سعد آل جلبان، حسن سعيد العمري، أسامة عبد الرحمن مصطفى امللخص: الهدف: قياس مدى انتشار أعراض االكتئاب والقلق والكرب النفسي بني طالبات املرحلة الثانوية. الطريقة: أجريت دراسة مقطعية على طالبات املرحلة الثانوية في مدينة أبها، مبنطقة عسير، باململكة العربية السعودية باستخدام النسخة العربية من مقياس داس-42 لقياس االكتئاب والقلق والكرب النفسي. النتائج :مت إدراج 545 طالبة في هذه الدراسة، التي أظهرت أن %73 من الطالبات لديهن أعراض أحد االعتالالت الثالثة حتت الدراسة على األقل، بينما %50.1 منهن لديهن أعراض العتاللني أو أكثر. كانت نسبة انتشار أعراض االكتئاب والقلق والكرب 41.5%، 66.2% والكرب والقلق االكتئاب أن الدراسة الشدة. أظهرت متوسط إلى بسيط من معظمها في االعتالالت هذه درجات التوالي. كانت %52.5 على و مترابطة مع بعضها إيجابيا بدرجة إحصائية ذات قيمة عالية. لم تظهر الدراسة ارتباطا بني اخلصائص االجتماعية للطالبات ومدى انتشار أعراض االعتالالت الثالثة التي متت دراستها. اخلالصة: أظهرت هذه الدراسة أن القدرة على تشخيص وعالج األمراض النفسية الشائعة بني طالبات املرحلة الثانوية يجب أن تكون من أولويات أطباء الرعاية الصحية األولية. مفتاح الكلمات: داس -42 ، اكتئاب ، قلق ، كرب نفسي، مراهقني ، بنات املدارس الثانوية ، اململكة العربية السعودية. abstract: objectives: to determine the prevalence of symptoms of depression, anxiety and stress among secondary school girls. methods: a crosssectional study was carried out on secondary school girls in abha city, aseer region, saudi arabia, using the arabic version of the depression, anxiety, and stress scale )dass-42(. results: of 545 female students recruited in this study, 73.4% had the symptoms of at least one of the three studied disorders; 50.1% had at least two disorders. the prevalence of symptoms of depression, anxiety and stress was 41.5 %, 66.2% and 52.5% respectively. the majority of symptoms were mild to moderate in severity. the scores for depression, anxiety, and stress were positively and significantly correlated. no significant association was found between the girls’ sociodemographic characteristics and the scores of the three studied disorders. conclusion: one of the most important aspects of a primary care physician’s care of females is to screen for and treat common mental disorders. keywords: dass-42; depression; anxiety; stress; adolescent; secondary school girls; saudi arabia. khalid s al-gelban, hasan s al-amri and ossama a mostafa clinical and basic research | 141 adolescence (11-21 years old) is a transitional stage from childhood to adulthood.1,2 during this stage, many psychological changes take place.1-3 psychiatric disorders in this period constitute a major public health concern and can result in serious consequences.1,2 research has shown that the majority of adult sufferers of mental disorders indicate that their symptoms began in childhood and adolescence.1-3 the appropriate identification and treatment of mental disorders in this period provide teenagers with immediate positive benefits, and serve to counteract consequences such as poor academic performance, substance abuse and suicidal behaviour.3-6 globally, roberts et al.7 reported that the prevalence rates of mental disorders among children and adolescents range from 1% to 51% with a mean rate of 15.8% for adolescents. in the usa and australia, one in five teenagers suffers from mental health problems.8, 9 in developing countries, the prevalence of mental disorders among adolescents attending primary health care facilities ranges between 12% and 29%.10 several studies indicate that prevalence rates of the individual disorders: depression, anxiety and stress are growing among adolescents.8, 9, 11 harrington and clark12 reported that 60% of adolescents experience depressive symptoms. an earlier study on saudi secondary school boys indicated that 38.2% had depression, while 48.9% experienced anxiety and 35.5% suffered from stress.13 the saudi community is undergoing great economic and social changes. it has a young population, with 60% under 30 years old, and 47% under 15 years;14 however, very little is known about the extent of psychiatric illnesses among saudi female adolescents. therefore, this study aimed to evaluate the extent of depression, anxiety, and stress among secondary school girls in abha city, saudi arabia. methods this cross-sectional study was conducted during the school year, in october 2007, in abha, the capital city of aseer region, in the southwest of saudi arabia with a total population of 300,000. through the school health unit for girls (shu-g), all secondary schools for girls located in abha city (n=10) were invited to participate in this study. principals and directors of these schools were provided with the important information about this study. all of them agreed to cooperate and to participate. in saudi arabia, general education of children starts at 7 years old. girls have separate schools from boys. each secondary school has three teaching levels, which represent the 10th, 11th, and 12th years of education. data were collected using the arabic version of the depression anxiety stress scale (dass),15 while demographic and environmental data, as well as the presence of associated psychological factors, were collected via a questionnaire devised for the study. the dass-42 is used for data collection to assess the negative emotional symptoms among students. it is a 42-item self-report inventory designed to measure the presence and severity of symptoms of depression, anxiety and stress among people as young as 12 years of age.15 this scale was psychometrically validated to the arabic culture by taouk et al.16 this screening and outcome measure reflects the experience of the person over the previous 7 days. gamma coefficients that represent the loading of each scale on the overall factor (total score) are 0.71 for depression, 0.86 for anxiety, and 0.88 for stress. one would expect anxiety and stress to load higher than depression on the common factors as they are more highly correlated and, therefore, dominate the definition of this common factor. the reliability of the test is considered adequate and test-retest reliability is likewise considered adequate with 0.71 table 1: scoring and grading of the depression, anxiety and stress scale (dass)15 category depression anxiety stress normal 0-9 0-7 0-14 mild 10-13 8-9 15-18 moderate 14-20 10-14 19-25 severe 21-27 15-19 26-33 extremely severe 28+ 20+ 34+ prevalence of depression, anxiety and stress as measured by the depression, anxiety, and stress scale (dass-42) among secondary school girls in abha, saudi arabia 142 | squ medical journal, august 2009, volume 9, issue 2 for depression and 0.79 for anxiety. exploratory and confirmatory factor analyses have sustained the proposition of its factors (p <0.05).15 table 1 shows the scoring and grading of the dass. at each school, one classroom from each year level was selected by simple random sampling. prior to administration of the questionnaire, the purpose of the study was briefly and clearly described to the students. they were informed that they could choose not to participate and were assured of the full confidentiality of their data. a total of 545 secondary school girls participated in this study, their age ranged from 14-20 years with an average of 17.13 ±1.12 years and a median of 17.0 years. data were collected by 4th year trained female medical students (n=20), under the supervision of their college professors (n=5). these medical students were trained on practical research methodology, as a part of their community medicine course. statistical analysis was conducted by the staff of the department of family and community medicine, college of medicine, king khalid university, using the statistical package for the social sciences (spss, version 15 for windows). the significance of differences was tested using the χ2 test at the 5% level of probability significance. students who obtained high dass scores (i.e. severe or extremely severe symptoms) were referred to the research psychiatrist to confirm the diagnosis and to provide proper psychiatric consultation and management. results table 2 shows the distribution of students’ age groups and scholastic years. about 60% of the students were enrolled in the 2nd and 3rd year, while 40.2% were enrolled in the first year. table 3 shows that the majority of girls lived with both their parents (89.0%). the most frequent level of education among fathers was university education (39.4%), while only 7.9% were illiterate. on the other hand, the most frequent mothers’ education level was primary education (29.9%) followed by illiterates (28.3%). the most frequent fathers’ occupations of the studied sample were retired or currently not working (34.5%) followed by governmental civil employee (29.7%), while most mothers were housewives (87.9%). table 4 shows that 73.4% of the girls had at least one of the three studied disorders (depression, anxiety or stress). moreover, 50.1% of subjects had at least two disorders, and more than one-third of the table 2: distribution of secondary school girls in abha, saudi arabia according to their age, scholastic year and type of study (n=545) student characteristics no. % age groups (in years) 14-15 1617 1820 22 333 190 4 61.1 34.9 school year first year 219 40.2 second year 163 29.9 third year 163 29.9 total 545 100 table 3: socio-demographic characteristics of secondary school girls, abha, saudi arabia (n=545) characteristics no. % parents’ status living within the family 485 89.0 divorced/separated 24 4.4 deceased father 28 5.1 deceased mother 5 0.9 both parents deceased 3 0.6 father’s education illiterate 43 7.9 primary 87 16.0 intermediate 93 17.1 secondary 107 19.6 university 149 27.3 postgraduate 66 12.1 father’s employment unemployed 25 4.6 military 89 16.3 governmental employee 162 29.7 private business 106 19.5 retired 163 29.9 mother education illiterate 154 28.3 primary 163 29.9 intermediate 88 16.1 secondary 69 12.7 university 54 9.90 post graduate 17 3.10 mother’s employment housewife 479 87.9 employed 66 12.1 khalid s al-gelban, hasan s al-amri and ossama a mostafa clinical and basic research | 143 students (35.5%) had all the three disorders under study. depression, anxiety, and stress were found in 41.5 %, 66.2% and 52.5% of the subjects respectively. table 5 reveals that depression, anxiety, and stress were positively and significantly correlated. table 6 shows that the prevalence of symptoms of depression, anxiety and stress among secondary school girls did not differ significantly according to their sociodemographic characteristics. discussion dass-42 was utilised in this research.15,16 it has the advantage that it can discriminate between the negative emotional symptoms of depression, anxiety, and stress; it is suitable for screening adolescents as young as 12 years of age; it is freely available in the public domain, and it is a short and easily answered questionnaire. the present study indicated high prevalence rates for symptoms of depression, anxiety and stress among saudi secondary school girls. about 10% of students showed severe or extremely severe symptoms of depression and stress while 25% of them showed severe or extremely severe symptoms of anxiety. moreover, results revealed that about 75% of the female saudi secondary school students reported the symptoms of at least one of the three studied disorders. this is higher than those reported by several national, regional and international studies7-10,12,13,17,18 a review of the literature reveals a considerable disparity in figures on the prevalence of psychiatric disorders in adolescents. this could be due to the diversity in methods, definitions used, or geographical locations.7 in 1998, robert et al.,7 reviewed 52 studies carried out in over 20 countries over the past four decades, and found that prevalence estimates of psychopathology ranged from 1 to 51%, (mean 15.8%), with a median rate of 15% among adolescents. in taif city, saudi arabia, abdel-fattah et al.17 reported that 8.3% of male pupils in primary and secondary schools (5.6% of the sample was adolescent) were emotionally disturbed as measured by the child behavior checklist “parent form”. using the “child behavior checklist”, eapen et al.18 conducted a study on schoolchildren aged 6 to 15 years in the united arab emirates, a neighbouring country which has a similar culture to saudi arabia, and found that 23.9% of children had a mental health problem. the prevalence estimate for behavioural disorders was 16.5%. of the individual disorders, anxiety was the most prevalent (66.2%), followed by stress (52.5 %), then depression (41.5%). this finding is in agreement with that of pelcovitz et al.,19 who found that anxiety disorders are the main psychiatric table 5: correlation matrix between severities of depression, anxiety, and stress among secondary school girls, abha, saudi arabia (n =545) depression anxiety stress r p-value r p-value r p-value depression --0.693 < 0.001 0.691 < 0.001 anxiety 0.691 < 0.001 --0.728 < 0.001 stress 0.694 < 0.001 0.728 < 0.001 --table 4: prevalence and intensity of depression, anxiety, and stress among secondary school girls, abha, saudi arabia. (n=545) psychological traits no. % depression 226 41.5 mild 92 16.9 moderate 77 14.1 severe 39 7.20 extremely severe 18 3.30 anxiety 361 66.2 mild 75 13.8 moderate 144 26.4 severe 81 14.8 extremely severe 61 11.2 stress 286 52.5 mild 108 19.8 moderate 114 20.9 severe 50 9.20 extremely severe 14 2.60 morbidity one symptom or more 400 73.4 more than one symptom 273 50.1 free of symptoms* 145 26.60 total 545 100 *depression, anxiety or stress prevalence of depression, anxiety and stress as measured by the depression, anxiety, and stress scale (dass-42) among secondary school girls in abha, saudi arabia 144 | squ medical journal, august 2009, volume 9, issue 2 table 6: prevalence of depression, anxiety and stress among secondary school girls according to their sociodemographic characteristics (n=545) depression anxiety stress normal depression p value normal anxiety p value normal stress p value no. % no. % no. % no. % no. % no. % age groups (in years) 14-15 15 68.2 7 31.8 7 33.3 14 66.7 12 54.5 10 45.5 16-17 195 59.3 134 40.7 106 32.2 223 67.8 153 46.8 174 53.2 18-19 109 58.9 76 41.1 0.697 71 38.6 113 61.4 0.345 94 50.3 93 49.7 0.627 school year first 126 58.3 90 41.7 71 32.9 145 67.1 103 48.1 111 51.9 second 93 57.4 69 42.6 55 34.6 104 65.4 70 42.9 93 57.1 third 100 63.3 58 36.7 0.507 58 36.5 101 63.5 0.767 86 54.1 73 45.9 0.135 parents’ status living within the family 288 60.4 189 39.6 163 34.3 312 65.7 234 49.1 243 50.9 divorced/separated 10 43.5 13 56.5 11 47.8 12 52.2 9 39.1 14 60.9 deceased father 15 53.6 13 46.4 7 25.0 21 75.0 13 46.4 15 53.6 deceased mother 4 80.0 1 20.0 1 20.0 4 80.0 1 20.0 4 80.0 both parents deceased 2 66.7 1 33.3 0.413 2 66.7 1 33.3 0.311 2 66.7 1 33.3 0.569 father’s education illiterate 26 60.5 17 39.5 19 44.2 24 55.8 24 57.1 18 42.9 primary 37 43.0 49 57.0 22 25.9 63 74.1 36 41.4 51 58.6 intermediate 53 58.2 38 41.8 19 20.7 73 79.3 40 43.5 52 56.5 secondary 68 65.4 36 34.6 43 41.7 60 58.3 54 52.4 49 47.6 university 94 63.9 53 36.1 58 39.5 89 60.5 73 49.7 74 50.3 postgraduate 41 63.1 24 36.9 0.125 23 35.9 41 64.1 0.106 32 49.2 33 50.8 0.457 mother’s education illiterate 56 36.6 97 63.4 76 49.7 77 50.3 11 45.8 13 54.2 primary 52 32.5 108 67.5 89 55.3 72 44.7 49 55.1 40 44.9 intermediate 25 29.1 61 70.9 37 42.5 50 57.5 88 55.3 71 44.7 secondary 25 36.2 44 63.8 26 38.2 42 61.8 65 61.9 40 38.1 university 20 40.0 30 60.0 22 43.1 29 56.9 106 66.7 53 33.3 postgraduate 6 37.5 10 62.5 0.772 9 56.3 7 43.8 0.150 319 59.5 217 40.5 0.118 father’s occupation unemployed 11 45.8 13 54.2 8 32.0 17 68.0 13 52.0 12 48.0 military 49 55.1 40 44.9 31 35.2 57 64.8 45 51.7 42 48.3 governmental employee 88 55.3 71 44.7 52 33.1 105 66.9 66 41.5 93 58.5 private business 65 61.9 40 38.1 39 37.1 66 62.9 54 51.4 51 48.6 retired 106 66.7 53 33.3 0.118 54 34.0 105 66.0 0.967 81 50.6 79 49.4 0.375 mother’s employment housewife 289 61.4 182 38.6 165 35.0 306 65.0 236 50.1 235 49.9 employed 30 46.2 35 53.8 0.119 19 30.2 44 69.8 0.483 23 35.4 42 64.6 0.126 diagnosis in adolescents. in a previous study on saudi male adolescents, symptoms of anxiety were the most prevalent (48.9%), followed by depression (38.2%), then symptoms of stress (35.5%).13 these high prevalence rates of symptoms of depression, anxiety and stress among saudi female students can be attributed to the increasing stresses on saudi females related to the social and cultural transformations in saudi society. in addition, choosing a career has grown more difficult as the job market for women has become more complex. furthermore, high psychological distress among students can be related to their study problems during the secondary school study period. in agreement with previous studies, where comorbidity among adolescents ranged from 25% khalid s al-gelban, hasan s al-amri and ossama a mostafa clinical and basic research | 145 to 68 %,20,21 the comorbidity in this study was 50.1%. psychiatric morbidity and comorbidity among girls in this study is higher than that reported in a study of 1,723 saudi secondary school boys in the same region using the same methodology where 59.4% had at least one of the three disorders, (38.2%) had depression, while 48.9% had anxiety and 35.5% had stress.13 in a study conducted at four primary care clinics affiliated to university hospitals throughout the eastern united states, women were more likely than men to have at least one mental disorder (43% versus 33%; p <0.05). psychiatric comorbidity was also more common in women (26% of women had two or more mental disorders versus 15% of men, p <0.05).22 unlike previous studies19,23,24 this research table 6: prevalence of depression, anxiety and stress among secondary school girls according to their sociodemographic characteristics (n=545) depression anxiety stress normal depression p value normal anxiety p value normal stress p value no. % no. % no. % no. % no. % no. % age groups (in years) 14-15 15 68.2 7 31.8 7 33.3 14 66.7 12 54.5 10 45.5 16-17 195 59.3 134 40.7 106 32.2 223 67.8 153 46.8 174 53.2 18-19 109 58.9 76 41.1 0.697 71 38.6 113 61.4 0.345 94 50.3 93 49.7 0.627 school year first 126 58.3 90 41.7 71 32.9 145 67.1 103 48.1 111 51.9 second 93 57.4 69 42.6 55 34.6 104 65.4 70 42.9 93 57.1 third 100 63.3 58 36.7 0.507 58 36.5 101 63.5 0.767 86 54.1 73 45.9 0.135 parents’ status living within the family 288 60.4 189 39.6 163 34.3 312 65.7 234 49.1 243 50.9 divorced/separated 10 43.5 13 56.5 11 47.8 12 52.2 9 39.1 14 60.9 deceased father 15 53.6 13 46.4 7 25.0 21 75.0 13 46.4 15 53.6 deceased mother 4 80.0 1 20.0 1 20.0 4 80.0 1 20.0 4 80.0 both parents deceased 2 66.7 1 33.3 0.413 2 66.7 1 33.3 0.311 2 66.7 1 33.3 0.569 father’s education illiterate 26 60.5 17 39.5 19 44.2 24 55.8 24 57.1 18 42.9 primary 37 43.0 49 57.0 22 25.9 63 74.1 36 41.4 51 58.6 intermediate 53 58.2 38 41.8 19 20.7 73 79.3 40 43.5 52 56.5 secondary 68 65.4 36 34.6 43 41.7 60 58.3 54 52.4 49 47.6 university 94 63.9 53 36.1 58 39.5 89 60.5 73 49.7 74 50.3 postgraduate 41 63.1 24 36.9 0.125 23 35.9 41 64.1 0.106 32 49.2 33 50.8 0.457 mother’s education illiterate 56 36.6 97 63.4 76 49.7 77 50.3 11 45.8 13 54.2 primary 52 32.5 108 67.5 89 55.3 72 44.7 49 55.1 40 44.9 intermediate 25 29.1 61 70.9 37 42.5 50 57.5 88 55.3 71 44.7 secondary 25 36.2 44 63.8 26 38.2 42 61.8 65 61.9 40 38.1 university 20 40.0 30 60.0 22 43.1 29 56.9 106 66.7 53 33.3 postgraduate 6 37.5 10 62.5 0.772 9 56.3 7 43.8 0.150 319 59.5 217 40.5 0.118 father’s occupation unemployed 11 45.8 13 54.2 8 32.0 17 68.0 13 52.0 12 48.0 military 49 55.1 40 44.9 31 35.2 57 64.8 45 51.7 42 48.3 governmental employee 88 55.3 71 44.7 52 33.1 105 66.9 66 41.5 93 58.5 private business 65 61.9 40 38.1 39 37.1 66 62.9 54 51.4 51 48.6 retired 106 66.7 53 33.3 0.118 54 34.0 105 66.0 0.967 81 50.6 79 49.4 0.375 mother’s employment housewife 289 61.4 182 38.6 165 35.0 306 65.0 236 50.1 235 49.9 employed 30 46.2 35 53.8 0.119 19 30.2 44 69.8 0.483 23 35.4 42 64.6 0.126 prevalence of depression, anxiety and stress as measured by the depression, anxiety, and stress scale (dass-42) among secondary school girls in abha, saudi arabia 146 | squ medical journal, august 2009, volume 9, issue 2 failed to find any association between psychiatric morbidity and the socio-demographic characteristics of the participants. in a study of 8,934 norwegian adolescents, those with a family history of divorce and parental distress were more vulnerable to symptoms of anxiety than those without such distress.24 vazsony looked at 6,935 adolescents from hungary, switzerland and the united states and found that increased anxiety occurred in the presence of extreme maternal and paternal closeness to the adolescents, possibly caused by parental over intrusiveness. the world health organization (who)25 noted that there are increasing numbers of people in the eastern mediterranean region, who are now entering the age of risk for development of mental disorders, i.e. adolescence/early adulthood and old age. existing conditions of social and physical strife provide fertile grounds for an upsurge in mental health problems and their consequences such as suicide and substance dependence. the school environment can offer an excellent opportunity to promote sound principles of mental health and healthy lifestyles. consequently, further national studies are needed to explore the ability of school health unit staff and primary health care physicians to diagnose and manage mental disorders. l i m i tat i o n s this study has the following limitations: it was performed exclusively in the city of abha, hence, its results exclusively reflect the psychiatric status of urban adolescents; it was restricted to female students only, which prevented the determination of sex-specific prevalence rates; it was a schoolbased study, which might therefore miss adolescents in the community who do not attend school. in addition, there is no built-in lie scale in dass, as it is just a self-reporting data collection tool (with triangulation). finally, no information on suicidal ideation can be picked up in dass. conclusion the present study confirms the high prevalence of depression, anxiety, and stress among saudi female adolescent students. the challenges ahead include the need to carry out extensive further research, and to develop national intervention programmes to promote mental health. acknowledgments the authors would like to thank 4th year female medical students for collecting the data and their professors at the department of family and community medicine, college of medicine, king khalid university, saudi arabia for their great help in supervising the data collection and conducting the statistical analysis. conflict of interest the authors report no conflit of interest. references 1. renouf ag, kovacs m, mukerji p. relationship of depressive, conduct, and co-morbid disorders and social functioning in childhood. j am acad child adolesc psychiatry 1997; 36:998-1004. 2. beautraise al. risk factors for suicide among young people. aust n z j psychiatry 2000; 34:420-36. 3. ringeisen h, oliver ka, menvielle e. recognition and treatment of mental disorders in children: considerations for pediatric health systems. paediatr drugs 2002; 4:697-703. 4. polloc r, rosenbaum j, marrs b, biederman j. anxiety disorders of childhood: implications for adult psychopathology. psychiatr clin north am 1995; 18:745-65. 5. brooks tl, harris sk, thrall js, woods er. association of adolescents risk behaviors with mental health symptoms in high school students. j adolesc health 2002; 31:240-6. 6. gregory am, caspi a, moffitt te, koenin k, eley tc, poulton r. juvenile mental health histories of adults with anxiety disorders. am j psychiatry, 2007; 164:301-8. 7. roberts re, attkisson cc, rosenblatt a. prevalence of psychopathology among children and adolescents. am j psychiatry 1998; 155:715-25. 8. kessler rc, mcgonagle ka, zhao s, et al. lifetime and 12-month prevalence of dsm-iii-r psychiatric disorders in the united states. results from the national comorbidity survey. arch gen psychiatry 1994; 51:8-519. 9. centre for epidemiology and research, nsw department of health. the health behaviors of secondary school students in new south wales 2002. n s w public health bulletin 2004; 15:s-2. 10. giel r, de arango mv, climent ce, harding tw, ibrahim hh, ladrido-ignacio l, et al. childhood mental disorders in primary health care: results of observations in four developing countries. a report from the who collaborative study on strategies for extending mental health care. pediatrics 1981; 68:677-83. khalid s al-gelban, hasan s al-amri and ossama a mostafa clinical and basic research | 147 11. newman dl, moffitt te, caspi a, magdol l, sliva pa, stanton wr. psychiatric disorder in a birth cohort of young adults: prevalence, comorbidity, clinical significance and new case incidence from ages 11-21. j consult clin psychol 1998; 64:552-62. 12. harrington r, clark a. prevention and early intervention for depression in adolescence and early adult life. eur arch psychiatry clin neurosci 1998; 248:32-45. 13. al-gelban ks. depression, anxiety and stress among saudi adolescent school boys. j r soc promot health 2007; 127:33-7. 14. khoja ta, farid sm. saudi arabia family health survey 1996: principal report. riyadh: ministry of health, 2000. 15. lovibond sh, lovibond pf. manual for the depression anxiety stress scales. 2nd ed. sydney: psychology foundation of australia, 1995. 16. taouk m, lovibond pf, laub r. psychometric properties of an arabic version of the depression anxiety stress scale (dass). from http://www.psy. unsw.edu.au/groups/dass/arabic/htm. accessed september 2008. 17. abdel-fattah mm, asal am, al-asmary sm, alhelali ns, al-jabban tm, arafa ma. emotional and behavioral problems among male saudi schoolchildren and adolescents prevalence and risk factors. ger j psychiatr 2004; 1:1-9. 18. eapen v, al-gazali l, bin-othman s, abou-saleh m. mental health problems among schoolchildren in united arab emirates. j am acad child adolesc psychiatry 1998; 37:880-6. 19. pelcovitz d, kaplan sj, derosa rr, mandel fs, salzinger s. psychiatric disorders in adolescents exposed to domestic violence and physical abuse. am j orthopsychiatry 2006; 47:75-84. 20. mcgee r, feehan m, williams s, anderson j. dsmiii from age 11 to 15 years. j am acad child adolesc psychiatry 1992; 31:50-51. 21. offord d, boyle mh, szatmari p, rae-grant ni, links ps, cadman dt, et al. ontario child health study ii. six-month prevalence of disorders and rates of service utilization. arch gen psychiatry 1987; 44:832-6. 22. aalto-setälä t, marttunen m, tuulio-henriksson a, poikolainen k, lönnqvist j. one-month prevalence of depression and other dsm-iv disorders among young adults. psychol med 2001; 31:791-801. 23. ghubash r, hamdi e, bebbington p. the dubai community psychiatric survey i. prevalence and socio-demographic correlates. soc psychiatry psychiatr epidemiol 1992; 27:53-61. 24. vazsony at, belliston lm, the cultural and developmental significance of parenting processes in adolescents anxiety and depression symptoms. j youth adolesc 2006; 35:491-505. 25. who. mental health in the eastern mediterranean region: reaching the unreached. who regional publications, eastern mediterranean series 29. cairo: world health organization regional office for the eastern mediterranean, 2006; pp. 10-60. august 2007 vol 7 copy.indd abstract since the discovery in the early eighties of the human immunodeficiency virus (hiv) that causes acquired immunodeficiency syndrome (aids), there have been reports of people who were completely resistant to infection with hiv and others who progressed at slower rates to aids. the present article summarises the mechanisms involved in resistance against hiv infection and progression to aids. the paper will specifically focus on the role of immunological mechanisms, genetics, ethnicity and cultural practices such as male circumcision in mitigating infection. the current understanding on host natural resistance against hiv infection and progression to aids would potentially contribute to better prevention strategies, delayed onset of aids in people living with hiv, the identification of more efficient types of therapy for aids patients and, possibly, appropriate vaccines against hiv/aids. this area of research has important implications for patient care through controlling factors that contribute to aids progression. key words: hiv; aids; resistance, natural; disease, progression. mechanisms of host resistance against hiv infection and progression to aids ali a al-jabri department of microbiology & immunology, college of medicine & health sciences, sultan qaboos university, p.o. box 35, pc 123, al-khod, muscat, sultanate of oman email: aaljabri@squ.edu.om نقص مبتالزمة واإلصابة فيروس نقص املناعة ضد املضيف مقاومة طرق (اإليدز) املكتسبة املناعة اجلابري علي تواجد إمكانية عن التقارير من العديد هنالك كان الثمانينيات بداية في اإليدز ملرض واملسبب ــبة املكتس املناعة نقص فيروس ــاف إكتش امللخص: منذ بل لديهم املرض يتطور ــخاص ال أش وجود إمكانية إلى ــير تش التي بعض التقارير أيضاً هنالك ذلك إلى باإلضافة للفيروس. مقاومة ذوي ــخاص أش ــبة املكتس املناعة نقص لفيروس املقاومة الطبيعية طرق الى نتطرق نحاول أن ــة املقال هذه في طويلة. ــنوات لس الفيروس مع التعايش ــم بإمكانه توصل وما املهم املوضوع على هذا الضوء بعض أن نلقي نحاول ذلك الى باالضافة الذكور. كاخلتان عند العادات وبعض واجلينية املناعية ــة الناحي ــن م فان باالضافة الى ذلك اإليدز. مرض ــد ض لقاح إلى والتوصل العالج الوقاية و في فعال ــكل بش ــاهم يس أن ميكن والذي احلاضر العلماء في الوقت ــه إلي العوامل التحكم في طريق عن وذلك االيدز مبرضى للعناية أهمية ذات تكون قد عديدة مزايا لها االيدز فيروس مقاومة طرق حول اجريت ــي الت ــوث البح التي تؤدي الى تطور املرض. االيدز، املقاومة الطبيعية، تطور املرض. املكتسبة، مرض املناعة الكلمات: نقص مفتاح sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 82-96 sultan qaboos university© submitted 8th january 2007 r e v i e w acquired immunodeficiency syndrome (aids) was first reported in the unitedstates of america in 1981 and has since become a major worldwide epidemic with over 40 million people infected. aids is caused by a retrovirus named the human immunodeficiency virus (hiv).1, 2, 3 by damaging or killing cells of the body’s immune system, hiv progressively destroys the body’s ability to fight infections and certain cancers. people diagnosed with aids may get life-threatening diseases and opportunistic infections (oi).4 hiv is spread most commonly by having unprotected sex with an infected partner.5, 6 hiv is also spread through contact with infected blood. the virus is frequently spread among injection drug users by the sharing of needles or syringes contaminated with very small quantities of blood from someone infected with the virus. women can transmit hiv to their babies during pregnancy or birth. approximately one-quarter to one-third of all untreated pregnant women infected with hiv will pass the infection to their babies.7, 8 hiv can also be spread to babies through the breast milk of a l i a a l j a b r i 84 mothers infected with the virus. if hiv-infected pregnant women are treated appropriately by antiretroviral drugs and deliver their babies by cesarean section, the chances of the baby being infected can be reduced to a rate of 1%. many people do not experience symptoms when first infected with hiv, however some have a flu-like illness within a month or two after exposure to the virus. even during the asymptomatic period, the virus is actively multiplying, infecting and killing cells of the immune system. the virus can also hide within infected cells and lie dormant. the most obvious effect of hiv infection is a decline in the number of cd4 positive t (cd4+) cells, the immune system’s key infection fighters. the virus slowly disables or destroys these cells without causing symptoms.9 as the function of the immune system deteriorates, a variety of complications start to take over. the term aids applies to the most advanced stages of hiv infection. the centre for disease control (cdc), in atlanta georgia (usa) has developed official criteria for the definition of aids.10, 11 the cdc’s definition of aids includes all hiv-infected people who have fewer than 200 cd4+ t cells per cubic millimeter of blood (healthy adults usually have cd4+ t-cell counts of ≥1,000 per mm3). in addition, the definition includes 26 clinical conditions that affect people with advanced hiv disease. most of these conditions are opportunistic infections that generally do not affect healthy people. during the course of hiv infection, most people experience a gradual decline in the number of cd4+ t cells, although some may have abrupt and dramatic drop in their cd4+ t-cell counts. a person with cd4+ t cells above 200 may experience some of the early symptoms of hiv disease. others may have no symptoms even though their cd4+ t-cell count is ≤200. recently and as a result of intensive research globally, two important breakthroughs in the aids epidemic have come to light. first, aids is now considered as a chronic medical condition, which is controllable by long-term therapy. advances in hiv/aids research have been able to change the fatal outlook of hiv infection into a more or less living condition. the second important breakthrough has been the discovery that there are certain individuals who may possess natural mechanisms to resist hiv infection and/or, if they do become infected, are able to control the infection so effectively that they remain asymptomatic for long periods of time.12 a small number of people first infected with hiv ≥ 15 years ago have not developed symptoms of aids.13 although these cases are still comparatively rare, studies of them have provided very important insights into natural mechanisms for resistance, or for overcoming hiv infection, which could be exploited for developing new antiretroviral drugs or hiv vaccines. scientists are trying to determine what factors may account for their lack of progression to aids, such as: whether their immune systems have particular characteristics, whether they were infected with a less aggressive strain of the virus, or whether their genes may protect them from the effects of hiv. it is known that many factors contribute to resisting infection with hiv; these include biological factors, host factors (e.g. immunologic such as cd8+ cell response), genetic factors (e.g. hlas, chemokine receptors etc.), viral factors (e.g. nef gene) and others including life style (see below). natural resistance to hiv/aids can be considered at different levels: 1) resistance to becoming infected with the virus; 2) resistance to progression of the disease after infection e.g. long-term non-progressors; 3) resistance after symptoms appear (cd4+<200) e.g. long-term aids survivors. in this review, we will discuss each of these issues in some detail with up to date knowledge on each issue. in addition, we will touch on the role of the immune response in the resistance to hiv infection. m e c h a n i s m s o f r e s i s t a n c e t o i n f e c t i o n b y h i v there are individuals who are repeatedly exposed to hiv infection but remain sero-negative.14 they are also referred to as highly exposed sero-negative individuals. they include persons who continue to indulge in high-risk activities, such as numerous unprotected sexual contacts with multiple partners, yet still remain antibody negative. in fact, the transmission of hiv is very inefficient in comparison to other human viruses. it is therefore difficult to establish how often exposures to hiv in nature, which fail to establish infection, are due to resistance or are merely part of the intrinsic inefficiency of hiv transmission. there are, however, a number of examples of defined instances of hiv exposure, which provide opportunities for the study of resistance to hiv infection. persons in “high risk” populations, who are repeatedly exposed to hiv infection yet remain sero-negative to hiv, include groups of female prostitutes in nairobi and the gambia and male homosexuals in los angem e c h a n i s m s o f h o s t r e s i s ta n c e a g a i n s t h i v i n f e c t i o n a n d p r o g r e s s i o n t o a i d s 85 les who have been subject to intense investigation.15 these individuals continue to engage in high risk, unprotected sexual activities yet remain antibody negative. there are also some long-term sexual-partners of hiv positive individuals who remain sero-negative, for example spouses of persons who have been infected by blood or blood products. finally, some seronegative infants are born to hiv positive mothers (see later section). two types of resistance to hiv infection have been recognized: 1) resistance due to mutations in co-receptors used by hiv to establish infection; 2) when hiv infection does become established, there are some individuals who appear to be able to mount a particularly vigorous and effective immune response which is able to overcome and clear the infection. mu tati o n i n th e h i v c o r e c e p to r cd4, the main receptor for hiv, is a membrane bound extracellular receptor used by some immune cells, such as t helpers, macrophages, dendritic cells and monocytes, to help detect foreign cells in the body.16 it helps to amplify the action of t cell receptors after stimulation with the major histocompatibility complex. upon finding a cell with a cd4 receptor, hiv (through its surface glycoprotein gp120) will bind to cd4 and another protein on the surface of the cell.17 this other protein is commonly a receptor which detects immune signals (a chemokine receptor, commonly ccr5 or cxcr4).18 once hiv has bound to either of these two proteins it will be able to infect the cell [figure 1a]. some people have a slightly differently shaped immune signal receptor, commonly due to a mutation, which leaves it slightly truncated. this means that hiv cannot bind to it and as such cannot infect the cell [figure 1b]. the role of the chemokine receptors, which serve as co-receptors for hiv infection, has been established.19 not surprisingly, therefore, individuals with mutations in the alleles coding for these receptors have been demonstrated to be resistant to hiv infection. chemokines are well known chemical messengers, which transmit activation signals to recipient cells. chemokines have been shown to be able effectively to inhibit hiv infection [figure 1b].17, 20, 21 the receptor for the cc chemokines is called ccr-5 and this has been demonstrated to be a crucial co-receptor for macrophage tropic (m-tropic) strains of hiv-1. the m-tropic strains of hiv-1 are the main strains, which are responsible for establishing infection and they predominate in the early stages of infection.22 these strains target macrophages and cd4+ lymphocytes. t-tropic strains predominate in the latter stages of infection and infect cd4+ lymphocytes, but not macrophages, and utilize another co-receptor called fusin. many chemokine co-receptors, including the figures 1a & 1b: a simplified diagram showing that hiv requires a chemokine co-receptor (ccr5 or cxcr4) in addition to the cd4, molecule the main receptor, to gain entry into the cell figure 1a virus entry due to availability of both cd4 receptor and a chemokine co-receptor figure 1b no virus entry due to availability of only cd4 receptor as the chemokine co-receptor (ccr5 or cxcr4) is engaged in the binding to its ligand a l i a a l j a b r i 86 ccr-5 and fusin, are known to act as secondary receptors for virus entry.17, 20, 21, 23, 24 based on the identification of its chemokine ligand, fusin was renamed cxcr-4. the discovery that cxcr-4 constitutes a functional co-receptor for t-tropic hiv-1 strains gave added significance to the earlier finding that the c-c chemokines (mip-1-alpha, mip-1-beta and rantes) are able to block infection of cd4+ human t-cells by m-tropic but not t-tropic hiv-1.25 ccr5 appears to be important for non-syncitium inducing (nsi) strains of hiv (the strains most common in early disease), while cxcr4 appears to be more important for syncytium inducing (si) strains (a more aggressive strain seen in some people with more aggressive disease).26 nsi strains of hiv are the most common sexually transmitted form of the virus. this type of hiv preferentially infects macrophages (often found in the skin and mucous membrane) rather than t-cells. therefore, it is m-tropic. when hiv is transmitted sexually, it first establishes itself as an m-tropic virus, later developing into t-cell-tropic viruses in some people. these t-tropic strains that prefer to infect t-cells are si viruses and may become more prevalent during later stages of the disease. it is unclear why the virus converts from an nsi to an si strain in some people. approximately 50% of people who die of aids still have a predominant nsi strain of virus. the si strain of hiv is more aggressive and its prevalence correlates with more rapid disease progression.27 additionally, anti-hiv drugs generally have less activity against si strains of hiv.26, 28 the ccr-5 receptor is responsible for the penetration and entry of hiv-1 into the cell after the virus has attached to the cd4+ cell surface antigen by its envelope glycoprotein gp120 [figure 1]. mutations in the ccr-5 receptor could therefore be expected to result in cells becoming resistant to hiv-1. a small number of individuals who are homozygous for the allele of ccr-5 have been found amongst the highly exposed group of sero-negative individuals. lymphocytes from these individuals have been shown to be highly resistant to infection with hiv-1. as yet no individuals with the homozygous mutant have been found to be hiv infected. approximately 1% of the caucasian population is homozygous and 20% are heterozygous. mutations in ccr-5 have not been found in african subjects. heterozygosity is thought to provide partial protection, i.e. individuals with one mutant copy of the ccr-5 gene appear to progress more slowly to aids than individuals without this mutation. mutations in the ccr-5 chemokine receptor have thus been shown to be a mechanism of hiv resistance in a small number of persons. many highly exposed seronegative individuals, however, do not have a ccr-5 mutation and the explanation for their resistance still needs to be elucidated. when the cd8+ cells effectively make a large quantity of the chemokines, they may fill up and block the ‘doorway’ for infection provided by the ccr5 protein.17, 20, 21, 29 conversely, when levels of the chemokines are low or absent for any reason, the virus is free to infect cells more easily because the ccr5 receptor protein is readily available to it. collectively, the backto-back discoveries of the role of the chemokines and the ccr5 receptor site shed important new light on how hiv infects cells and may explain why the disease process differs from person to person. certainly there are people with an inherited deletion who have progressed to aids and died. ccr5 deletion or not, monitoring health, making wise treatment choices and keeping the virus in check is critical to managing hiv disease. there are hundreds of people who have been categorized as long-term nonprogressors who have fully intact ccr5 genes. for example, there were a number of reports of identified individuals who had inherited the deletion in the ccr5 gene from both parents and were nonetheless infected with hiv. according to previous reports and identified cases, those who inherited the gene from both parents were assumed to have some natural immunity to hiv infection. to the contrary, rather than being infected with the most common strain of hiv, the individuals were infected with the type of virus typically only found in some people with advanced stages of hiv disease, that rely on the cxcr4 protein to support entry into the immune cell. this type of virus is associated with dramatic and rapid loss of cd4+ cells and more rapid progression of disease. in line with this, these reported individuals suffered a very rapid course of the disease.30 pr ote c ti o n a g a i n st h i v i n fe c ti o n r e l ate d to th e i mmun e s y ste m protection in infants approximately 25% of infants born to hiv-infected mothers are persistently infected with hiv and progress to aids. of the remaining 75%, many are uninfected because an inadequate dose of virus m e c h a n i s m s o f h o s t r e s i s ta n c e a g a i n s t h i v i n f e c t i o n a n d p r o g r e s s i o n t o a i d s 87 crosses the placenta. however, investigations of fetuses from hiv-positive mothers who were electively aborted in early pregnancy have shown that the majority have hiv-dna sequences in cells from various organs.31, 32, 33 from these studies, it would therefore appear that the majority of infected fetuses are able to overcome and clear the infection. the mechanism, however, is still unclear as the immune system of the fetus is immature and ineffective in clearing most transplacentally transmitted viruses. further evidence of protection related to the immune system in the infant are the manifestations of lymphocyte reactivity to hiv, which are found in seronegative infants. some 40% of uninfected infants demonstrated lymphocyte reactivity (by il-2 production) in their cord blood and peripheral blood lymphocytes in response to several hiv peptides including gp160 and nef proteins.34, 35 even more convincing is the finding of hiv-specific cytotoxic t-lymphocytes implying continuous antigenic stimulation and therefore viral replication in the host.34, 35 the most striking and widely publicized illustration of the ability of an infant to overcome hiv infection is that of a child in los angeles born to an hiv positive mother, who had negative hiv cultures of blood at birth, but then produced sub-sequent positive cultures at 19 days and 51 days.36, 37 however, numerous follow-up blood cultures were negative and the child has remained sero-negative and clinically well afterwards. several other cases of sero-reverting infants have also been described.34, 38 the exact mechanism for sero-reverting is not yet completely understood. protection in adults sero-negative adults who have been exposed to hiv also have demonstrated an immune response to the virus as shown by lymphocyte reactivity in response to hiv antigens. these individuals include those having unprotected sexual intercourse with multiple hiv infected partners, intravenous drug abusers, prostitutes, recipients of blood or blood products contaminated with hiv and healthcare workers who have been exposed to hiv through needle injuries with hiv infected blood.39, 40 some of the possible mechanisms could include exposure to virus-free antigens of hiv or defective strains of hiv. however, the finding of cd8+ cytotoxic t-lymphocytes, which were mhc class-i restricted, would indicate at least one round of viral replication and suggest that the immune system was able to overcome and clear the infection without seroconversion (the production of antibodies). m a l e c i r c umc i si o n circumcised males are less likely than their uncircumcised peers to acquire sexually transmitted infection and circumcision may reduce the risk of acquiring and spreading such infections by > 50%.41 adult male circumcision has been recognized to provide protection against hiv infection.42 adult male circumcision has been found to provide > 60% protective effect against infection with hiv in a randomized trial of >3,000 sexually active, heterosexual men in south africa.43 in this trial, subjects willing to be circumcised were randomized to receive immediate circumcision or to wait 20 months for the procedure. in the intervention group, medical physicians removed the penile foreskin after administering local anesthetic and using sterile surgical procedures. at 21 months, the researchers diagnosed 69 new hiv cases, 51 in the control group that had yet to be circumcised, and 18 in the group that had been circumcised. this translates into a 65% protective effect (with a 95% confidence interval of 40% to 80%). furthermore, other trials have been stopped due to dramatic preliminary results indicating that medical circumcision reduces the risk of men getting hiv during heterosexual intercourse by > 50%. results from these randomized controlled trials bolster previous evidence from more than 40 observational epidemiological studies and clinical trials that showed an association between male circumcision and a reduced risk of hiv infection. oth e r mo l e c ul e s other molecules have been implicated in the resistance and susceptibility to hiv infection. they include the human leukocyte antigens (hla) (see below), beta chemokines and defensins, polymorphism in the cytokine genes, configuration on chromosome-22, beta 2 microglobulin,44, 45 hiv-2,46 etc. m e c h a n i s m s o f r e s i s t a n c e t o w a r d s p r o g r e s s i o n t o a i d s i n d i v i d ua l s w h o se e m to mo un t a pa rti c ul a r ly v i g o r o us a n d e ffe c ti v e i mmun e r e sp o n se it has been reported that over a hundred people did not become infected with hiv despite hundreds of a l i a a l j a b r i 88 exposures through sexual contact or intravenous (iv) drug sharing. it has been hypothesised that they had a unique immunological ability to marshal the response of cd8+ lymphocytes.47 as in the general population, the cd4+ lymphocytes of these people were susceptible to hiv infection. it was only in the presence of the cd8+ cells that viral replication was stopped. the cd8+ cells of non-hiv exposed individuals studied did not mount this response. it is believed that this immunity results from exposure to low amounts of virus, which is enough to get the cellular immune antiviral response going. each subsequent exposure then acts as a kind of booster. researchers do not know why a strong cd8+ cell antiviral response occurs in some people and not in others. it was found that the antiviral action of cd8+ cells was amplified when exposed to macrophages expressing a cd86 molecule on their surface. macrophages play a role in increasing cd8+ cell function. researchers had previously suspected that the macrophages stimulate cd8+ cells through the cd80 molecule, rather than the cd86 molecule. the researchers demonstrated the role of the cd86 molecule by blocking the interaction of the cd28 molecule on cd8+ cells with the cd86 molecule found on macrophages, and showed that the macrophages’ enhancing effects were abrogated. when they exposed macrophages to anticd86 antibodies, the cd8+ cells were not stimulated. in contrast, anti-cd80 blocking antibodies had little effect on the ability of macrophages to enhance cd8+ cell antiviral response. moreover, the researchers were able to reverse the decreased antiviral response that followed treatment of macrophages with anti-cd86 neutralizing antibodies by exposing the cd8+ cells to anti-cd28 antibodies, which are able to carry out the same function as the cd86 molecule. these studies indicate that engagement of the cd28 molecule on cd8+ cells with the cd86 molecule on macrophages is critical for optimal suppression of hiv replication by the cd8+ cells.47 l o n g te r m n o n pr o gr e s s o r s ( ltn p) these hiv-positive individuals have not been on antiviral therapy yet have remained clinically well and have had a reasonable immune function with high and stable cd4+ lymphocyte counts for many years without showing signs of immune compromise or evidence of progression to aids.48 there is a wide range of clinical responses to hiv infection in humans. in about 80% of hiv infected individuals aids, develops within the median time of 12 years. individuals with this clinical course are referred to as typical progressors. in 10% of hiv infected subjects, aids develops within 3 years after infection; these individuals are referred to as rapid progressors. on the other side of the spectrum, about 10% of hiv infected persons remain asymptomatic for at least 15 years and often up to 20 years after hiv infection, despite not being on anti-retroviral therapy. their immune function is relatively well maintained with cd4+ lymphocyte counts above 600/mm3 and low plasma levels of hiv-1 rna. biopsies of their lymph nodes confirm the non-progressive nature of their infection with little evidence of the hyperplastic and involuted changes or lymphocyte depletion seen in lymph node tissue from subjects with progressive disease. these individuals are referred to as long-term non-progressors (ltnp) or long-term survivors. both viral as well as host factors play a role in long-term non-progression of hiv.49 factors related to the virus culture of hiv from the blood of ltnps is difficult and often unsuccessful because of the lower plasma viral load. molecular characterization of cultured isolates, have revealed the presence of a number of genetic defects which could be the basis for the attenuation of the virus.35, 50 occasionally, genetic defects such as in the nfkb or sp1 site within the long terminal repeats of the virus have been demonstrated. however, the best-documented and studied genetic lesions associated with virus attenuation in ltnps are the nef deletion mutants. the nef gene is a crucial regulatory gene of hiv-1. monkeys experimentally inoculated with simian immunodeficiency virus (siv) which have deletions in their nef gene, show no signs of disease and have low viral loads in the plasma and normal cd4+ lymphocyte counts.51 in humans, nef deleted mutants of hiv-1 have also been shown to play a role in the genesis of long-term non-progression. an hiv infected male homosexual donated blood and infected some 7 recipients over a period of 3 years (in the era before blood was routinely tested for hiv). surprisingly, neither the donor nor any of the recipients developed any symptoms and had remained healthy (with the exception of 2 who died from unrelated causes). molecular studies on isolates from 4 of the 8 subjects demonstrated defects in the nef gene. although nef deletion m e c h a n i s m s o f h o s t r e s i s ta n c e a g a i n s t h i v i n f e c t i o n a n d p r o g r e s s i o n t o a i d s 89 mutants still only account for a very small number of ltnps, they have aroused great scientific interest because of their potential usefulness in the development of an hiv vaccine. factors related to the host from studies of a number of cohorts of ltnps, a pattern appears to be emerging characterizing these individuals as having immune responses which are quantitatively and qualitatively more potent and more effective in controlling hiv infection.52 vigorous virusspecific humoral and cell mediated immune responses have been demonstrated in these subjects. high titres of potent neutralizing antibodies to a wide spectrum of hiv isolates have been shown to be present in the sera of ltnps. in addition, there are strong cd8+ cytotoxic lymphocyte responses in these individuals, reflecting long-standing stimulation of the immune system by continuing viral replication.53 the resulting immune response is able effectively to suppress viral replication and thus relatively low viral loads are found in their plasma and high cd4+ lymphocyte counts are maintained in the blood. the lymph node architecture remains intact and the degree of virus trapping in the follicular dendritic network in the lymph nodes is considerably lower. precisely why some individuals respond with a more favorable immune response than others is still not clear. it is also uncertain whether the more effective immune response is a cause of lower viral loads or whether the more effective immune response is the consequence of infection with more attenuated viral variants. h l a mo l e c ul e s a n d r e si sta n c e to h i v i n fe c ti o n a n d d i se a se pr o gr e s si o n evidence for acquired resistance to hiv infection54 reflects previous immunological priming with a low sub-infective dose of virus. individuals who appear to be naturally protected against hiv infection or from disease progression could be intrinsically resistant through genetic host factors such as genes coding for co-receptors e.g. ccr5, 17 discussed earlier, and their hla genotypes.55, 56, 57 aids pathogenesis would appear to involve multigene systems such as the hla complex and the derivative immune response genes of the t cell receptor (tcr). these and other cofactors (see table 1), such as psychosocial factors and nutrition, are believed to influence disease progression.55 there are two types of studies, in vitro and in vivo, on hla and susceptibility or resistance to hiv infection. 55 in vitro type studies we have shown that certain hla molecules correlate, with in vitro high or low hiv virus replication.55, 57-59 our own results showed clearly that certain hla specificities were significantly correlated in vitro with infectivity by both hiv-1 and hiv-2 isolates and that each isolate had its own correlation with hiv infection.55, 58 this may partly explain the differences in the in vivo results on the association of hla with certain features of aids and the difficulty in confirming such correlation. however, more studies in vitro on a large scale and on groups who are at high risk or low risk need to be addressed with the identification of the hiv isolate that is predominant in each individual patient. these studies will characterize better those hla specificities that are important for infectivity by hiv-1 and hiv-2. the existence of a significant hla association with all the known hiv-1 and all hiv-2 isolates infecting human populations may lead to the identification of important immunodominant epitopes that can be useful in vaccine development against the different clades (subtypes) of hivs. there is a possibility that hla are not the actual genes responsible for susceptibility or resistance to hiv infection, rather other, as yet unidentified genes closely linked to hla, or masked by the hla, could be the real genes determining susceptibility or resistance to hiv.60, 61 this can be revealed only by intensive future research work and by better knowledge appropriate drug treatment (eg. haart) non-adherence to drug therapy stress nutrition and malnutrition genetic make up of the individual age gender pregnancy environmental factors special habits effects of other diseases (sexual transmitted diseases, std) the degree and frequency of virus exposure co-infection with other viruses risk activity (behavior) additional immunosuppressive factors ethnic background drug addiction hemophiliacs autoimmune diseases exercise table 1: list of some of the factors that can affect aids progression a l i a a l j a b r i 90 and understanding of the genes that are linked to the hla molecules.55 many reports have already suggested the existence of an association between progression to full blown aids, or certain features of aids such as aids related kaposi’s sarcoma, with some hla haplotypes.56, 62-67 hla-b35 has been shown by many researchers to correlate with susceptibility to faster progression towards aids. however, the hla haplotypes associated either with progression, or with a defined aids related syndrome, are not identical in different studies. because of the nature of hiv-1 infection and the associated disease, it would have been surprising not to find some correlates with hla haplotypes in studies of an infected population. in order to understand a potentially complex disease, we have shown that the hla genotype of the individual may determine the rate of virus production, and possibly susceptibility to disease in hiv infected populations.58 not all of the known hla alleles are detected in the populations studied. relatively homogenous populations express a restricted range of hla alleles.56 in general, it is difficult to confirm an association between hla and disease, as frequencies of hla alleles between different populations can vary greatly, and more than one hla allele may be associated with susceptibility to infection or to disease progression.55 our own in vitro results showed clearly that hlab70 and also b58 alleles are indeed correlated with high viral replication to hiv-2 infection of peripheral blood mononuclear cells (pbmcs). the correlation was hiv-2 isolate dependent with the hla-b70 allele correlating with the growth of the hiv-2-rod strain and the b58 allele with the hiv-2-cbl-20 strain. in addition, hla-b44 seems to be important for resistance to hiv-1 infection.55, 58 previous hla-hiv correlations usually do not take into account the type of hiv isolate(s) within a particular cohort or a group of patients. this may partly explain the lack of agreement between studies on the involvement of a particular hla haplotype in the hiv-1 disease process.55 our results show that viral replication in different donor pbmcs depends both on the hiv strain, and also on the hla type of the pbmcs. the only two alleles, which were shown, to be significantly correlated with high viral replication, were both from the hla class i b locus and may indicate an important role for this locus in controlling hiv-2 replication.58 we have demonstrated that the rates of hiv-1 and 2 production in vitro vary greatly between individuals, even when other variables such as the degree of lymphocyte activation and culture conditions are carefully controlled.59 quantitative differences in virus production can differ by >3000 fold between the highest and the lowest virus producers. both host cellular factors and viral properties may influence the level of viral replication in any given virus-cell combination. high and low producers, in the case of hiv-1, can be predicted from the examination of how the hla-b locus, present in the individual, binds the gp120 peptide of hiv in comparison with the binding of hla-dr beta chain peptide fragment.68 although we do not know the exact mechanism accounting for our observed data at present, the mimicry of hla by hiv may theoretically provide the t-cell activation essential for virus replication.68 the amount of viral replication in culture, which depends upon the degree of t-cell activation, would depend on the degree of mimicry between the infecting hiv strain and the hla of the host. in vivo (cohort type) studies perhaps the most compelling evidence for the role of hla genes in susceptibility/resistance to hiv-1 infection comes from the investigation of cohorts of high-risk individuals with chronic or repetitive exposure.66, 67, 69-72 resistance to hiv infection in a cohort of highly exposed, persistently negative female sex workers in thailand was associated with an increased frequency of hla-b18.73 in a cohort of female sex workers in kenya, a decreased risk for hiv infection was associated with a cluster of related class i alleles-hla-a2/6802.65 moreover, resistance was consistently demonstrated to be independently linked with hla-drb1*01. increased susceptibility to hiv was linked with hla-a*2301 in the same cohort. the hla-a2/6802 cluster/supertype was also associated with a decreased risk of perinatal transmission in mothers of the same ethnic group. these sero-negative women have strong cytotoxic t cell responses to conserved hiv peptides presented by this hla-a2/6802 supertype. studies with several viral systems, including hiv, suggest that there are families of closely related hla alleles, like the cluster described above, that may present the same or highly similar peptide antigens. these have been termed hla super-types and the targeted viral epitopes, supertopes. super-types may be represented in as much as 50% of the general populam e c h a n i s m s o f h o s t r e s i s ta n c e a g a i n s t h i v i n f e c t i o n a n d p r o g r e s s i o n t o a i d s 91 tion and, therefore, may be desirable targets for broadly effective vaccines.74 combinations will certainly be necessary, and there are many potential limitations. population-based epitope/hla studies have often been conducted in cohorts from developed countries with caucasian majorities. recent emphasis has been on generating similar comprehensive databases for communities and ethnic groups that vaccine efforts will target. identification of hla alleles linked with natural resistance to hiv infectivity is critical for the design of peptide-based vaccines. l o n g t e r m a i d s s u r v i v o r s [ a f t e r s y m p t o m s a p p e a r s ( c d 4 < 2 0 0 c e l l s / m m 3 ) ] the main goal of antiretroviral therapy is to reduce viral load to below detectable levels and maintain patients free of symptoms. not all individuals undergoing highly active antiretroviral therapy (haart) respond positively to their treatment and not all aids patients with symptoms will progress to death at the same rate. this could be due to many factors [table 1] including non-adherence to the antiretroviral therapy and the genetic makeup of the individual.75 a group of aids patients exist who do not respond positively to antiretroviral treatment and therefore die much earlier than those who respond positively. the survival rate of other aids patients, who survive longer after their cd4+ counts are < 200 cells/mm3, is either due to good response to treatment or due to other factors. this group of patients can be considered as long-term aids survivors. in fact, not much research has been done on this group of patients and future studies may address this issue critically. f a c t o r s t h a t m a y a f f e c t a i d s p r o g r e s s i o n many factors are known to affect aids progression; these include life style, stress, nutrition and malnutrition, environmental factors and so on.55 table 1 shows some of these factors. it is beyond the scope of this review article to discuss these factors in depth. if some of these factors are adequately controlled, they have important implications for patient care and the onset of aids can be delayed. i m m u n e r e s p o n s e a n d n a t u r a l r e s i s t a n c e t o h i v i n f e c t i o n the natural resistance to hiv infection and its relation to the different elements of the immune response, although being mentioned in different sections above, will be briefly discussed below. i n n ate i mmun i t y a n d r e si sta n c e to h i v i n fe c ti o n innate immunity during hiv infection has been extensively studied, but mainly with the complement system, interferon, natural killer (nk) cells and gamma/delta t cells. many other areas of how innate immunity functions during hiv infection remain relatively unexplored. the complement system is highly activated during hiv infection, as determined by high levels of complement breakdown products in blood.76, 77,78 some of this activation is probably due to microorganisms associated with opportunistic infections. however, at least a portion of the complement activation during hiv infection is due to the interaction of hiv or hiv-infected cells with complement since the virus in infected individuals is coated with complement activation products, notably c3 fragments.79, 80, 81 primary isolates of hiv are much more resistant to destruction by complement, probably due to both the relatively low amount of antibody that binds to primary isolate virions82 and incorporation of different types of complement control proteins.83 interferons (ifn) have been known to play a role in the host defense against viral infections. ifn have been categorized as type-i (including ifn-α, ifn-β, ifn-ω)84 and type 2 (ifn-γ). type 1 ifn have been generally associated with natural host defenses, while type 2 ifn-γ is, among other sources, a principal product of activated t helper cell (th)-1 biased cd4+ t cells participating in the adaptive immune system and nk cells. ifn-γ has been known as an important macrophage activating cytokine, necessary for the final effector mechanisms of cellular immunity.85 ifn have been known to be involved in resistance to hiv; antibodies to ifn were incorporated into the initial culture systems utilized for the isolation of hiv (lymphadenopathy-associated virus).1 ifn-α, used to treat kaposi’s sarcoma, had an effect on hiv viremia, although notably only in patients having sufficiently high numbers of cd4+ t cells.86 their involvement in a l i a a l j a b r i 92 the pathogenesis of aids was recognized by the presence of ifn in serum during the latter stages of hiv infection.87,88 these ifn were considered acid-labile alpha-ifn because, despite their neutralization with anti-alpha antisera, they were destroyed by acidification, a characteristic of ifn-γ. notably, the long-term non-progressors had significantly higher numbers and functions of plasmacytoid dendritic cells (pdc) compared not only with patients with progressive hiv infection, but also with uninfected controls.89 the correlation noted between virus burden and pdc suggests that pdc function is, perhaps not surprisingly, involved in the suppression of hiv itself, either directly by ifn production acting on infected cells, or through a th-1 mechanism. soumelis, et al., (2001)89 showed that development of susceptibility to both oi and active kaposi’s sarcoma depends on the simultaneous depression of both cd4+ cell counts and pdc numbers below certain critical levels. 90 a c q ui r e d i mmun i t y humoral immunity some of the earliest studies evaluated the generation of humoral immunity in the form of broadly neutralizing circulating or mucosal antibody. its potential usefulness is based, in part, on vertical and horizontal transmission studies in which neutralizing antibody in the donor (positive partner or mother) was associated with reduced transmission. antibody responses observed to date in the natural setting or in laboratory or vaccine models have generally been strain-specific or non-protective. however, these responses may not be comparable or relevant to neutralizing antibody in the uninfected partner. in animal models, neutralizing antibody can prevent a simian virus-hiv chimeric infection, but the amount of neutralizing antibody required was far in excess of that found in humans.91 the primary role of neutralizing antibody in natural resistance to hiv is not clear. in addition, the passive administration of antibody is not feasible in the general, at-risk population. there have been surprisingly few studies on circulating neutralizing igg or iga antibody. cell mediated immunity studies on naturally resistant populations revealed that few studies analyzed more than one protective immune defense,92 although it is difficult to compare studies on natural resistance because most have measured only one or two defenses and techniques vary substantially. the most frequently studied natural defenses implicated in effective responses against hiv are: ctl effector response; cd4+ t lymphocyte helper responses; non-cytolytic cd8+ hiv suppression and cd8+ beta chemokine production. it is beyond the scope of this review article to discuss these in details, but interested readers may be directed to recent articles on these topics. c o n c l u s i o n the vast amount of evidence suggests that there is a natural resistance to hiv infection and to progression to aids. however, the exact mechanisms accounting for such resistance are not yet completely elucidated. future research may reveal the exact mechanisms by which this natural resistance operates, with the potential of developing appropriate therapeutic interventions and vaccines. long-term non-progression, as well as resistance to viral infections, is a relatively uncommon phenomenon. adequately controlling factors that contribute to fast progression to aids can delay the onset of the symptoms and provide a better life style for those patients. at the present time, however, and for the majority of hiv infected individuals, antiretroviral therapy remains the only effective way of controlling hiv infection. r e f e r e n c e s 1. barre-sinoussi f, chermann jc, rey f, nugeyre mt, chamaret s, gruest j, et al. isolation of a t-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (aids). science 1983; 220:868871. 2. popovic m, sarngadharan mg, read e, gallo rc. detection, isolation, and continuous production of cytopathic retroviruses (htlv-iii) from patients with aids and pre aids. science 1984; 244:497-500. 3. levy ja, hoffman ad, kramer sm, landis ja, shimabukuro jm, shiro ls. isolation of lymphocytopathic retroviruses from san francisco patients with aids. science 1984; 225:840-842. 4. levy ja. pathogenesis of hiv infection. microbiol rev 1993; 57:183-289. 5. cameron dw, simonsen jn, d’costa lj, ronald ar, maitha gm, gakinya mn, et al. female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men. lancet 1989; ii:403407. 6. padian ns, shiboski sc, jewell np. female to male transmission of human immunodeficiency virus. m e c h a n i s m s o f h o s t r e s i s ta n c e a g a i n s t h i v i n f e c t i o n a n d p r o g r e s s i o n t o a i d s 93 jama 1991; 266:1664-1667. 7. minkoff h, nanda d, menez r, fikrig s. pregnancies resulting in infants with acquired immunodeficiency syndrome or aids related complex. obst gynecol 1987; 69:285-287. 8. minkoff h, nanda d, menez r, fikrig s. pregnancies resulting in infants with acquired immunodeficiency syndrome or aids-related complex: follow up of mothers, children, and subsequently born siblings. obst gynecol 1987; 69:288-291. 9. cloyd mw, moore be. spectrum of biological properties of human immunodeficiency virus (hiv-1) isolates. virology 1990; 174:103-116. 10. cdc. classification system for human t-lymphotropic virus type iii/lymphadenopathy-associated virus infections. morbid mortal wkly rep 1986; 35:334-339. 11. cdc. revised classification system for hiv infection and expanded surveillance of definition for aids among adolescents and adults. morbid mortal wkly rep 1993; 41:17. 12. rutherford gw, lifson ar, hessol na, darrow ww, o’malley pm, buchbinder sp, et al. course of hiv-1 infection in a cohort of homosexual and bisexual men: an 11 year follow up study. bmj 1990; 301:1183-1188. 13. detels r, liu z, hennessy k, kan j, visscher br, taylor jm, et al. resistance to hiv-1 infection. multicenter aids cohort study. j aids 1994; 7:1263-1269. 14. paxton wa, martin sr, tse d, o’brien tr, skurnick j, vandevanter nl, et al. relative resistance to hiv-1 infection of cd4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. nature med 1996; 2:412-417. 15. rowland-jones s, sutton j, ariyoshi k, dong t, gotch f, mcadam s, et al. hiv-specific cytotoxic t-cells in hivexposed but uninfected gambian women. nature med 1995; 1:59-64. 16. dalgleish ag, beverley pc, clapham pr, crawford dh, greaves mf, weiss ra. the cd4 (t4) antigen is an essential component of the receptor for the aids retrovirus. nature 1984; 312:763-767. 17. dragic t, litwin v, allaway gp, martin sr, huang y, nagashima ka, et al., hiv-1 entry into cd4+ cells is mediated by the chemokine receptor cc-ckr-5. nature 1996; 381:667-673. 18. al-jabri aa. how does hiv-1 infect a susceptible human cell? current thinking! sultan qaboos univ j sci res med sci 2003; 5:31-44. 19. bowers m. chemokines and hiv. beta, 1997; 3:22-27. 20. feng y, border cc, kennedy pa, berger ea. hiv-1 entry cofactor: functional cdna cloning of a seven-transmembrane, g protein-coupled receptor. science 1996; 272:872-876. 21. deng h, liu r, ellmeier w, choe s, unutmaz d, burkhart m, et al. identification of a major co-receptor for primary isolates of hiv-1. nature 1996; 381:661-666. 22. chesebro b, wehrly k, nishio j, perryman s. macrophage-tropic human immunodeficiency virus isolates from different patients exhibit unusual v3 envelope sequence homogeneity in comparison with t-cell tropic isolates: definition of critical amino acids involved in cell tropism. j virol 1992; 66:6547-6554. 23. oberlin e, amara a, bachelerie f, bessia c, virelizier m, arenzana-seisdedos f, et al. the cxc chemokine sdf-1 is the ligand for lestr/fusin and prevents infection by t-cell-line-adapted hiv-1. nature 1996; 382:833-835. 24. bleul cc, farzan m, choe h, parolin c, clark-lewis i, sodroski j, et al. the lymphocyte chemoattractant sdf1 is a ligand for lestr/fusin and blocks hiv-1 entry. nature 1996; 82:829-833. 25. cocchi f, devico al, garzino-demo a, arya sk, gallo rc, lusso p. identification of rantes, mip-1 alpha, and mip-1 beta as the major hiv-suppressive factors produced by cd8+ t cells. science 1995; 270:18111815. 26. cornelissen m, mulder-kampinga g, veenstra j, zorgdrager f, kuiken c, hartman s, et al. syncytiuminducing (si) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/si phenotypically mixed human immunodeficiency virus population. j virol 1995; 69:1810-1818. 27. schuitemaker h, koot m, kootstra na, derksen m, de goede rey, van steenwijk p, et al. biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to t-celltropic virus populations. j virol 1992; 66:1354-1360. 28. koot m, keet ipm, vos ahv, degoede rey, roos mtl, coutinho ra, et al. prognostic value of hiv-1 syncytium-inducing phenotype for rate of cd4+ cell depletion and progression to aids. ann intern med 1993; 118:681-688. 29. arenzana-seisdedos f, virelizier jl, rousset d, clarklewis i, loetscher p, moser b, et al. hiv blocked by chemokine antagonist. nature 1996; 383:400. 30. moore jp. coreceptors: implications for hiv pathogenesis and therapy. science 1997; 276:51-52. 31. roques pa, gras g, parnet-mathieu f, mabondzo am, dollfus c, narwa r, et al. clearance of hiv infection in 12 perinatally infected children: clinical, virological and immunological data. aids 1995; 9:f19-f26. 32. joshi vv, oleske jm, minnefor ab, singh r, bokharit t, rapkin rh. pathology of suspected acquired immune deficiency syndrome in children: a study of eight cases. paediatr pathol 1984; 2:71-87. 33. just j, louie l, abramst e, nicholast sw, warat d, a l i a a l j a b r i 94 steins z, et al. genetic risk factors for perinatally acquired hiv-1 infection. paediatr perinat epidem 1992; 6:215-224. 34. baur a, schwharz n, ellinger s, ellinger s, korn k, harrer t, et al. continuous clearance of hiv in a vertically infected child. lancet 1989; ii:1045. 35. baur as, sawai et, dazin p, fantl wj, cheng mc, peterlin bm. hiv-1 nef leads to inhibition or activation of t cells depending on its intracellular localisation. immunity 1994; 1:373-384. 36. bryson y, chen isi. hiv clearance in an infant? nature 1995; 375:637-638. 37. bryson yj, pang s, wei ls, dickover r, diagne a, chen isi. clearance of hiv infection in a perinatally infected infant. n engl j med 1995; 332:833-838. 38. frenkel lm, nichols je, wagner le, haase at, roberts jr nj. loss of hiv-1 viremia with persistent specific immunity in a women and her child. j cellular biochem 1995; 21:234. 39. perrin lh, zubler r, hirschel b, martin jl, salomon d, saurat jh, et al. reversal of positive serology for human immunodeficiency virus (hiv). a propose of 2 case reports. schweiz med wochenschr 1988; 118:1641-1644. 40. taylor r. quiet clues to hiv-1 immunity: do some people resist infection? j nih res 1994; 6:29-31. 41. williams bg, lloyd-smith jo, gouws e, hankins c, getz wm, hargrove j, et al. the potential impact of male circumcision on hiv in sub-saharan africa. plos med 2006; 3:e262. 42. de vincenzi i, mertens t. male circumcision: a role in hiv prevention? aids 1994; 8:153-160. 43. auvert b, taljaard d, lagarde e, sobngwi-tambekou j, sitta r, puren a. randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs 1265 trial. plos med 2005; 2:e298. 44. lifson ar, hessol na, buchbinder sp, o’malley pm, barnhart l, segal m, et al. serum beta-2-microglobulin and prediction of progression to aids in hiv infection. lancet 1992; 339:1436-1440. 45. liu r, paxton wa, choe s, ceradini d, martin sr, horuk r, et al. homozygous defect in hiv-1 coreceptor accounts for resistance of some multiply-exposed individuals to hiv-1 infection cell 1996; 86:367-377. 46. travers k, mboup s, marlink r, gueye-ndiaye a, siby t, thior i, et al. natural protection against hiv-1 infection provided by hiv-2. science 1995; 268:1612-1615. 47. westby m, manca f, dalgleish ag. the role of host immune responses in determining the outcome of hiv infection. immunol today 1996; 17:120-126. 48. lemp gf, hirozawa am, cohen jb, derish pa, mckinney kc, hernandez sr. survival for women and men with aids. j infect dis 1992; 166;74-79. 49. dean m, carrington m, winkler c, huttley ga, smith mw, allikmets r, et al. “genetic restricion of hiv-1 infection and progression to aids by a deletion allele of the ckr-5 structural gene”. science 1996; 273:18561862. 50. ahmed n, venkatesan s. nef protein of hiv-1 is a transcriptional repressor of hiv-1 ltr. science 1988; 241:1481-1485. 51. kestler hw, ringler dj, mori k, panicali dl, sehgal pk, daniel md, et al. importance of the nef gene for maintenance of high virus loads and for development of aids. cell 1991; 65:651-662. 52. fernandez ce, desco m, montes mg, natividad l, gonzalez b, zabay jm. immunological and serological markers predictive of progression to aids in a cohort of hiv infected drug users. aids 1990; 4:987-994. 53. gao y, qing l, zhang lq, safrit jt, ho dd. virological and immunological characterization of long-term survivors of hiv-1 infection. n eng j med 1994; 332:201208. 54. steel cm, ludlam ca, beatson d, peutherer jf, cuthbert rjg, simmonds p, et al. hla haplotype a1, b8, dr3 as a risk factors for hiv related disease. lancet 1988; i:1185-1188 55. al-jabri aa. hla and in vitro susceptibility to hiv infection. mol immunol 2002; 38:959-967. 56. roe dl, lewis re, cruse jm. association of hla-dq and –dr alleles with protection from or infection with hiv-1. exp mol pathol 2000; 68:21-28. 57. al-jabri aa, bottazo gf, mccloskey d, oxford js. evidence for resistance among pbmcs from healthy bangladeshis to infection by certain isolates of hiv-1 & 2. abstr p5/1, first european meeting of virology, wurzburg, germany, september 1995; p. 10-13. 58. al-jabri aa, mccloskey d, addawee m, bottazzo fg, sachs j, oxford js. in vitro correlation between human leukocyte antigen class i and ii phenotype and hiv infectivity of activated peripheral blood mononuclear cell cultures. aids 1998, 12:217-8. 59. al-jabri aa, wigg md, oxford js. initial in vitro screening of drug candidates for their potential antiviral activities. in: kangro h. and mahy b, eds. virology methods manual. london: academic press, 1996; p. 293-308. 60. cameron pu, cobain tj, zhang wj, kay ph, dawkins rl. influence of c4 null genes on infection with human immunodeficiency virus. bmj 1988; 296:1627-1628. 61. cameron pu, mallal sa, french mah, dawkins rl. major histocompatibility complex genes influence the outcome of hiv infection, ancestral haplotypes with c4 null alleles explain diverse hla associations. hum immunol 1990; 29:282-295. 62. fabio g, scorza r, lazzarin a, marchini m, zarantonello m, d’arminio a, et al. hla associated susceptibility m e c h a n i s m s o f h o s t r e s i s ta n c e a g a i n s t h i v i n f e c t i o n a n d p r o g r e s s i o n t o a i d s 95 to hiv-1 infection. clin exp immunol 1992; 87:20-23. 63. carrington m, nelson gw, martin mp, kissner t, vlahov d, goedert jj, et al. hla and hiv-1: heterozygote advantage and b*35-cw*04 disadvantage. science 1999; 283:1748-1752. 64. de sorrentino ah, marinic k, motta p, sorrentino a, lopez r, and illiovich e. hla class i alleles associated with susceptibility or resistance to human immunodeficiency virus type 1 infection among a population in chac province, argentina. j infect dis 2000; 182:15231526. 65. macdonald ks, embree je, nagelkerke nj, castillo j, ramhadin s, njenga s, et al. the hla a2/6802 supertype is associated with reduced risk of perinatal human immunodeficiency virus type 1 transmission. j infect dis 2001; 183:503-506. 66. mann d, carrington m, kroner bl. the human major histocompatibility complex and hiv-1 pathogenesis. aids 1994; 8:s53-s60. 67. mcneil aj, yap pl, gore sm, brettle rp, mccoll m, wyld r, et al. association of hla types a1-b8-dr3 and b27 with rapid and slow progression of hiv disease. q j med 1996; 89:177-185. 68. habeshaw ja, wilson se, hounsell ef, oxford js. how hiv-1 lentivirus causes immune deficiency disease. med hypoth 1999; 52:59-67. 69. itescu s, mathur-wagh u, skovron ml, brancato lj, marmor m, zeleniuch-jacquotte a, et al. hla-b35 is associated with accelerated progression to aids. j ids 1991; 5:37-45. 70. sahmoud t, laurian y, gazengel c, sultan y, gautreau c, costagliola d. progression to aids in french haemophiliacs: association with hla-b35. aids 1993; 7:497-500. 71. scorza sr, fabio g, lazzarin a, eisera n, foppa ulberti c, moroni m, et al. hla associated susceptibility to aids: hla b35 is a major risk factor for italian hiv infected intravenous drug addicts. hum immunol 1988; 22:73-79. 72. scorza sr, fabio g, lazzarin a, eisera nb, moroni m, zanussi c. hla associated susceptibility to acquired immunodeficiency syndrome in italian patients with human immunodeficiency virus infection. lancet 1986; ii:1187-1189. 73. paul palumbo, joan skurnick, christine rohowsky-kochan, donald louria. natural resistance to hiv: is the evidence good enough to design an effective vaccine. aids science 2002; 2:11. 74. altfeld ma, livingston b, reshamwala n, nguyen pt, addo mm, shea a, et al. identification of novel hlaa2-restricted human immunodeficiency virus type 1-specific cytotoxic t-lymphocyte epitopes predicted by the hla-a2 supertype peptide-binding motif j virol 2001; 75:1301-1311. 75. louie lg, newman b, king m-c. influence of host genotype on progression to aids among hiv infected men aids 1991; 4:814-818. 76. spear gt. interaction of non-antibody factors with hiv in plasma. aids 1993; 7:1149-1157. 77. spear gt, sullivan bl, landay al, lint tf. neutralization of human immunodeficiency virus type 1 by complement occurs by viral lysis. j virol 1990; 64:58695873. 78. moir s, malaspina a, li y, et al. b cells of hiv-1-infected patients bind virions through cd21-complement interactions and transmit infectious virus to activated t cells. j exp med 2000; 192:637-646. 79. sullivan bl, knopoff ej, saifuddin m, et al. susceptibility of hiv-1 plasma virus to complement-mediated lysis. evidence for a role in clearance of virus in vivo. j immunol 1996; 157:1791-1798. 80. sullivan bl, takefman dm, spear gt. complement can neutralize hiv-1 plasma virus by a c5-independent mechanism. virology 1998; 248:173-181. 81. kacani l, prodinger wm, sprinzl gm, et al. detachment of human immunodeficiency virus type 1 from germinal centers by blocking complement receptor type 2. j virol 2000; 74:7997-8002. 82. takefman dm, sullivan bl, sha be, spear gt. mechanisms of resistance of hiv-1 primary isolates to complement-mediated lysis. virology 1998; 246:370-378. 83. spear gt, hart m, olinger gg, hashemi fb, saifuddin m. the role of the complement system in virus infections. curr top microbiol immunol 2001; 260:229-245. 84. bogdan c. the function of type i interferons in antimicrobial immunity. curr opin immunol 2000; 12:419424. 85. cousens lp, peterson r, hsu s, dorner a, altman jd, ahmed r, et al. two roads diverged: interferon alpha/ betaand interleukin 12-mediated pathways in promoting t cell interferon gamma responses during viral infection. j exp med 1999; 189:1315-1328. 86. krown se. interferon-alpha: evolving therapy for aidsassociated kaposi’s sarcoma. j interferon cytokine res 1998; 18:209-214. 87. destefano e, friedman rm, friedman-kien ae, et al. acid-labile human leukocyte interferon in homosexual men with kaposi’s sarcomaand lymphadenopathy. j infect dis 1982; 146:451-459. 88. ferbas j, navratil j, logar a, rinaldo c. selective decrease in human immunodeficiency virus type 1 (hiv1)-induced alpha interferon production by peripheral blood mononuclear cells during hiv infection. clin diagn lab immunol 1995; 2:138-142. 89. soumelis v, scott i, gheyas f, et al. depletion of circulating natural type 1 interferon-producing cells in hiva l i a a l j a b r i 96 infected aids patients. blood 2001; 98:906-912. 90. siegal fp, lopez c, fitzgerald pa, shah k, baron p, leiderman iz, et al. opportunistic infections in acquired immune deficiency syndrome result from synergistic defects of both the natural and adaptive components of cellular immunity. j clin invest 1986; 78:115-123. 91. smith sm. hiv vaccine development in the nonhuman primate model of aids. j biomed sci. 2002; 9:100-11. 92. haynes bf, pantaleo g, fauci as. toward an understanding of the correlates of protective immunity to hiv infection. science 1996; 271:324-328. 1department of radiology, rustaq hospital, ministry of health, rustaq, oman; 2department of radiology, royal hospital, muscat, oman *corresponding author’s e-mail: asdhahli@gmail.com a rare case of emphysematous endocarditis caused by escherichia coli *ahmed s. al-dhahli,1 rashid s. al-umairi,2 osama elkadi1 sultan qaboos university med j, february 2022, vol. 22, iss. 1, pp. 134–137, epub. 28 feb 22 submitted 29 sep 20 revision req. 23 dec 20; revision recd. 18 jan 21 accepted 7 apr 21 incidence of e.coli ie in oman.9 emphysematous type of ie is extremely rare with very limited reported cases in the literature.3,10–12 case report a 59-year-old female patient presented to the emergency department at a secondary care hospital in rustaq, oman, in 2017 with a five-day history of cough, shortness of breath, fever and chest discomfort. the patient had a medical history of uncontrolled diabetes, hypertension and ischaemic heart disease. her echocardiography 10 years prior to admission demonstrated left ventricular hypertrophy with a normal left ventricle ejection fraction. there was no mitral or tricuspid valve regurgitation. on physical examination, she was conscious, alert and oriented. her vital signs were as follows: blood pressure of 102/60 mmhg, body temperature of 38°c, heart rate of 109 beat per minute, o2 saturation of 90% and a random blood sugar of 19.3 mmol/l. chest auscultation revealed bilateral fine crepitation which was more prominent on the right. the remainder of the systemic examination was unremarkable. laboratory investigations showed high white blood cell counts at 17.8 × 103/ul (normal range: 2.4–9.5 × 103/ul) with 81% neutrophil predominance, high glycosylated haemoglobin at 9.6% (normal range: 4.8–6%) and high troponin t at 153.1 pg/ml (normal range: 0–14 pg/ml). platelet count, haemoglobin, infec tive endoc arditis (ie) is a life-threatening condition which is defined as an infection of the cardiac endocardium. the valves are the most common cardiac structure affected by the disease. ie is the most prevalent infection of the cardiovascular system.1 patients can present with constitutional symptoms including fever, chills and weight loss. other clinical presentations of the disease are related to cardiac involvement including heart failure, vasculitis and systemic embolic phenomena.2 ie is caused by gram positive organisms in the majority of patients; staphylococci, streptococci and enterococci are responsible for more than 80% of ie cases.3 rarely, ie can be caused by a group of gram-negative organisms other than haemophilus species, actinobacillus actinomycetemcomitans, card iobacterium hominis, eikenella corrodens or kingella kingae (hacek).4,5 in older publications, ie caused by non-hacek gram-negative organisms was predominantly seen among intravenous (iv) drug users.6 however, more recent studies have reported that the majority of non-hacek ie was among patients with implanted endovascular devices, including prosthetic valves, permanent pacemakers and implantable cardioverter-defibrillators.6 likewise, e. coli ie is rare with limited number of reported cases in the literature and it is usually associated with a higher mortality rate compared to hacek gram-negative ie.4–6 the reported inpatient mortality rate is 24% for non-hacek ie compared to 4% for hacek ie.7,8 al abri et al. has reported 4.1% this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.076 case report abstract: infective endocarditis (ie) is an infection of the heart endocardium with significant morbidity and mortality. gram negative infection, particularly emphysematous ie, is an extremely rare and life-threatening disease. we report a 59-year-old diabetic female patient who was admitted to a secondary care hospital in rustaq, oman, in 2017 with the diagnosis of pneumonia for which she was started on antibiotics. shortly afterwards, she developed facial and mouth deviation and became more tachypneic. computed tomography of the brain demonstrated bilateral multiple small infarcts. pulmonary angiography computed tomography was performed which ruled out pulmonary embolism. nonetheless, it revealed an air-containing lesion around the mitral valve. transthoracic echocardiography demonstrated a hyperechoic mobile lesion related to the mitral valve. blood culture grew escherichia coli and the diagnosis of e. coli emphysematous ie was made based on modified duke criteria. the patient’s clinical condition deteriorated and she suffered cardiac arrest leading to her death. the recommended treatment for non-hacek ie includes an extended antibiotic course and surgery for selected patients. keywords: endocarditis; escherichia coli; mitral valve; echocardiography; intracranial embolism; emphysema; case report; oman. https://creativecommons.org/licenses/by-nd/4.0/ ahmed s. al-dhahli, rashid s. al-umairi and osama elkadi case report | 135 procedure was performed craniocaudally with the following parameters: 0.625 mm detectors, automa (average of 224 ma), 120 kvp and a 512 × 512 matrix. the study was done with iv contrast material utilising pe protocol. coronal and sagittal reformats were reconstructed. the study ruled out pe, but it demonstrated an air-containing lesion around the mitral valve [figure 2]. there was mitral valve annulus calcification. transthoracic echocardiogram was performed which revealed mild mitral regurgitation with a mobile hyperechoic mass related to the anterior mitral valve leaflet associated with a posterior acoustic shadow [figure 3]. the left ventricle ejection fraction was 25%. blood culture from a single blood sample yielded growth of gram negative bacilli escherichia coli and consequently the antibiotic was changed, based on the sensitivity profile, to piperacillin/tazobactam (4.5 g three times/day) on the third day of admission. a diagnosis of ie was established based on modified duke clinical criteria.8 nevertheless, the patient’s clinical condition deteriorated on the fourth day of admission and eventually she suffered a cardiac arrest with ventricular arrhythmia then went into asystole leading to her death after a short period of restoration of normal sinus rhythm. discussion in this case report, we described a patient with uncontrolled diabetes who was admitted with an impression of pneumonia and who was later on found to have emphysematous ie which ultimately led to the patient’s death. although, it was not possible to obtain a tissue sample to confirm the diagnosis of ie, the diagnosis of possible ie was established based on the modified duke criteria which includes one major criterion (endocardial involvement as evident in echocardiogram as a lesion attached to the mitral leaflet) and two minor criteria (persistent fever and vascular phenomenon of multiple small creatinine and urea levels were normal. her chest radiograph showed a patchy opacity which was interpreted as pneumonic consolidation for which the patient was started on ceftriaxone. on the second day of admission, the patient’s glasgow coma scale score deteriorated as she was responsive only to pain stimuli. subsequently, she developed facial and mouth deviation, so a noncontrast enhanced computed tomography (ct) of the brain was performed using a 64-slice ct machine (philips, amsterdam, the netherlands) that demonstrated multiple small subtle hypodense foci in both the centrum semiovali and corpus callosum [figure 1]. the distribution and characteristics of the hypodensities were suggestive of acute ischaemic infarctions due to thromboembolic causes. on the third day of admission, the patient was persistently febrile despite antibiotic administration with a blood pressure drop to 87/50 mmhg. pulmonary embolism (pe) was suspected based on high d-dimer and worsening tachypnoea. subsequently, a pulmonary angiography computed tomography (ctpa) was performed on a 64-slice ct machine (philips). the figure 1: non-contrast enhanced computed tomogr aphy of the brain of a 59-year-old female patient showing bilateral ill-defined small hypodense foci in the bilateral centrum semiovale and corpus callosum (not shown) suggestive of acute ischaemic infarction (arrows). figure 2: a: axial pulmonary angiography computed tomography showing an air-containing lesion around the mitral valve (yellow arrow); note is made of mitral annual calcification (red arrow). b: coronal reformat demonstrating the air density lesion in the mitral valve (red arrow). ra = right atrium; rv = right ventricle; lv = left ventricle; la = left atrium. a rare case of emphysematous endocarditis caused by escherichia coli 136 | squ medical journal, february 2022, volume 22, issue 1 embolic infarcts in the brain).8 in the current case, the positive blood culture (from a single blood sample) revealed the growth of e. coli which is an atypical microorganism for ie. no significant bacterial growth could be obtained from urine culture and no other source of infection could be identified. e. coli is the most common non-hacek gramnegative organism that cause ie, accounting for approximately one third of the cases.10 ie secondary to e. coli is usually associated with higher mortality and morbidity compared to ie due to hacek gramnegative organisms. the source of ie secondary to e. coli is usually urinary tract infection.4,5 diabetes, malignancy, excessive alcohol consumption and haemodialysis are considered to be risk factors for developing ie secondary to e. coli.6 in the present case, an air-containing lesion was seen around the mitral valve on ctpa indicating emphysematous type of ie (ct is the radiological gold standard tool for the diagnosis of emphysema). literature review revealed two reported cases of e. coli related emphysematous ie.3,12 there are two additional emphysematous ie cases reported in the literature caused by finegoldia magna and citrobacter koseri.10,11 previous case reports share similar radiological findings with the present case of air density vegetation around the mitral valve. furthermore, all patients in these case reports had diabetes mellitus including the present patient.3,10–12 choosing the appropriate antibiotic treatment for non-hacek gram-negative-related ie is based on sensitivity profile of the responsible pathogen.13 treatment by a combination of antibiotics with β-lactams (penicillins, cephalosporins or carbapenems) and either an aminoglycoside or fluoroquinolone for six weeks is considered appropritate.8 an infectious disease expert opinion in ie should be obtained due to known antibiotic resistance in non-hacek organisms.8 some patients in this group may require surgical intervention especially for pseudomonasrelated left-sided ie.8,13 conclusion emphysematous infective endocarditis caused by e. coli is an extremely rare disease that is associated with increased mortality and morbidity. therefore, clinicians should be aware of this entity and pay close attention to the clinical course of patients with e. coli ie during hospitalisation in order to reduce mortality and morbidity related to the disease. a u t h o r s’ c o n t r i b u t i o n asa-d provided the diagnosis of the patient. asa-d, ra-u and oe drafted the manuscript. ra-u conducted the literature review. oe provided the echocardiography images. all authors approved the final version of the manuscript. references 1. yusuf sw, sharma j, durand jb, banchs j. endocarditis and myocarditis: a brief review. expert rev cardiovasc ther 2012; 10:1153–64. https://doi.org/10.1586/erc.12.107. 2. ferro jm, fonseca ac. infective endocarditis. handb clin neurol 2014; 119:75–91. https://doi.org/10.1016/b978-0-70204086-3.00007-2. 3. kim cj, yi je, kim y, choi hj. emphysematous endocarditis caused by ampc beta-lactamase-producing escherichia coli: a case report. medicine (baltimore) 2018; 97:e9620. https://doi. org/10.1097/md.0000000000009620. 4. chambers st, murdoch d, morris a, holland d, pappas p, almela m, et al. hacek infective endocarditis: characteristics and outcomes from a large, multi-national cohort. plos one 2013; 8:e63181. https://doi.org/10.1371/journal.pone.0063181. 5. morpeth s, murdoch d, cabell ch, karchmer aw, pappas p, levine d, et al. non-hacek gram-negative bacillus endocarditis. ann intern med 2007; 147:829–35 https://doi.org/10.7326/0 003-4819-147-12-200712180-00002. figure 3: a: four chamber view echocardiogram in the systole showing a hyperechoic lesion related to the anterior leaflet of the mitral valve (arrow). b: redemonstration of the mobile hyperechoic lesion related to the mitral valve in the diastole (arrow). https://doi.org/10.1586/erc.12.107. https://doi.org/10.1016/b978-0-7020-4086-3.00007-2 https://doi.org/10.1016/b978-0-7020-4086-3.00007-2 https://doi.org/10.1097/md.0000000000009620 https://doi.org/10.1097/md.0000000000009620 https://doi.org/10.1371/journal.pone.0063181 https://doi.org/10.7326/0003-4819-147-12-200712180-00002 https://doi.org/10.7326/0003-4819-147-12-200712180-00002 ahmed s. al-dhahli, rashid s. al-umairi and osama elkadi case report | 137 10. cohen m, stephens eh, garshick m, wang sh, frager sz, mautner l, et al. native valve emphysematous endocarditis caused by finegoldia magna in a novel pathogenic role. infect dis clin practice 2016; 24:57–9. https://doi.org/10.1097/ipc.0000000000000294. 11. kesler s, kim h, perlman d, dincer he, thenappan t, tomic r. air in the left ventricle. an unusual case of endocarditis. am j respir crit care med 2016; 193:1176–7. https://doi.org/10.1 164/rccm.201506-1156im. 12. law d, thomas m. escherichia coli emphysematous endocarditis. lancet infect dis 2020; 20:381. https://doi.org/10.1016/s14733099(19)30700-5. 13. sexton dj, chu vh. antimicrobial therapy of left-sided native valve endocarditis. from https://www.uptodate.com/contents/ antimicrobial-therapy-of-left-sided-native-valve-endocarditis accessed: jan 2021 6. akuzawa n, kurabayashi m. native valve endocarditis due to escherichia coli infection: a case report and review of the literature. bmc cardiovasc disord 2018; 18:195. https://doi. org/10.1186/s12872-018-0929-7. 7. chambers st, murdoch d, morris a, holland d, pappas p, almela m, et al. hacek infective endocarditis: characteristics and outcomes from a large, multi-national cohort. plos one 2013; 8:e63181. https://doi.org/10.1371/journal.pone.0063181. 8. baddour lm, wilson wr, bayer as, fowler vg jr, tleyjeh im, rybak mj, et al. infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the american heart association. circulation 2015; 132:1435–86. https://doi. org/10.1161/cir.0000000000000296. 9. al abri ss, zahedi fi, kurup pj, al-jardani ak, beeching nj. the epidemiology and outcomes of infective endocarditis in a tertiary care hospital in oman. j infect public health 2014; 7:400–6. https://doi.org/10.1016/j.jiph.2014.04.004. https://doi.org/10.1097/ipc.0000000000000294 https://doi.org/10.1164/rccm.201506-1156im https://doi.org/10.1164/rccm.201506-1156im https://doi.org/10.1016/s1473-3099(19)30700-5 https://doi.org/10.1016/s1473-3099(19)30700-5 https://doi.org/10.7326/0003-4819-147-12-200712180-00002 https://doi.org/10.7326/0003-4819-147-12-200712180-00002 https://doi.org/10.1371/journal.pone.0063181 https://doi.org/10.1161/cir.0000000000000296 https://doi.org/10.1161/cir.0000000000000296 https://doi.org/10.1016/j.jiph.2014.04.004 submitted 8 dec 21 1 revisions req. 21 feb 22; revisions recd. 5 apr 22 2 accepted 19 apr 22 3 online-first: april 2022 4 doi: https://doi.org/10.18295/squmj.4.2022.034 5 6 recurrent scrotal arteriovenous malformation as a slowly 7 increasing left testicular swelling 8 a case report 9 faisal m. alashaikh,1,2 *moustafa s. alhamadh,1,2 sulaiman i. 10 alsugair,1,2 abduallah alkhayal,1,2,3 saad abumelha,1,2,3 yousof al 11 zahrani,2,4 abdulrahman binswilim5 12 13 1college of medicine, king saud ben abdulaziz university for health sciences 14 (ksau-hs), ministry of the national guard-health affairs, riyadh, saudi arabia; 15 2king abdullah international medical research center, ministry of the national 16 guard-health affairs, riyadh, kingdom of saudi arabia; 3department of surgery, 17 division of urology and 4department of medical imaging, division of interventional 18 radiology, king abdulaziz medical city, ministry of the national guard-health 19 affairs, riyadh, kingdom of saudi arabia; 5department of medical imaging, king 20 khalid university hospital, riyadh, kingdom of saudi arabia. 21 *corresponding author’s e-mail: alhamadhmo@gmail.com 22 23 abstract 24 arteriovenous malformations (avms) are benign vascular lesions. although, the 25 majority of avms occur in the central nervous system, there are published reports of 26 avms involving all systems including the scrotum, kidney, and uterus. herein we 27 report a case of 37 years old male presented with recurrent gradual scrotal swelling 28 for 4 years attributed to scrotal avm. embolization was done but one year later his 29 symptoms reoccurred. as a result, left partial scrotal wall excision was carried out 30 without complications. 31 keywords: arteriovenous malformation, avm, scrotal swelling, scrotal malformation. 32 33 introduction 34 arteriovenous malformations (avms) are benign vascular lesions. they are described 35 as abnormal vessels fed by arteries and drained by veins without intervening 36 capillaries.1,2 although the majority of avms occur in the central nervous system, 37 there are published reports of avms involving the scrotum, kidney, and uterus.2,3,4 38 few cases of scrotal avms have been described in the literature. based on the 39 published reports, the clinical presentation of scrotal avms is highly variable, 40 ranging from an incidental finding on imaging for infertility to a bleeding mass.1,5 41 since scrotal avms have variable presentations and is rarely described in the 42 literature, we are reporting a case of a 37-year-old male presented with a slowly 43 increasing left testicular swelling attributed to scrotal avm. 44 45 case report 46 37 years old male smoker presented to the urology clinic with a gradual scrotal 47 swelling that started four years ago. he complained of on and off scrotal pain, 48 occasional feeling of scrotal warmth, and scrotal discomfort. the patient was 49 diagnosed in another hospital with a testicular artery aneurysm and left testicular 50 varicocele. the patient denied any history of trauma, urinary tract infection, voiding 51 symptoms, previous surgeries, and his past medical history was unremarkable. upon 52 physical examination, the testes were intra-scrotal. there were no signs of 53 inflammation, and the cremasteric reflex was intact bilaterally. both epididymides 54 were palpable and non-tender. however, pampiniform plexus at the neck of the 55 scrotum was very pulsatile (figure a). moreover, multiple skin varices over the left 56 scrotum were seen. urinalysis was normal and urine culture was negative. routine 57 laboratory tests were unremarkable. abdominal and pelvis computed tomography 58 (ct) showed left scrotal arteriovenous malformation with enlarged small and 59 medium-sized serpiginous structures with a feeder artery arising from the proximal 60 superficial artery. two months later, the patient was referred to interventional 61 radiology for embolization, which was successfully done utilizing onyx 18% (figure 62 b). after one year, on follow-up, the pampiniform plexus were pulsatile again which 63 necessitated a ct angiogram. ct angiogram confirmed the recurrence of 64 arteriovenous malformation. the patient was counselled about the available treatment 65 options and given time to decide. due to the risk of recurrence as well as the 66 possibility of technical failure with embolization, he decided to go with the surgical 67 treatment. the patient was booked for surgery, and partial scrotal wall excision was 68 done through an elliptical incision (figure c). three arteries that feed into the 69 arteriovenous malformation were identified and controlled with vicryl ties. the 70 malformation and the skin that covering it were removed and sent to the pathology 71 lab. dartos muscle was closed in a multi-fashion layer. the skin was closed by vicryl 72 rapide 4-0 in a vertical mattress. the histopathological study confirmed the diagnosis 73 by detecting vascular structures extending from fibrofatty tissues measuring 8x0.5 cm 74 grossly, and prominent subcutaneous large congested vascular spaces 75 microscopically. the patient was discharged one day after the surgery with no 76 complications. two months postoperatively, the patient was doing fine with no active 77 complaint, and the wound healed properly. 78 79 the consent was obtained orally as the images were taken from the patient in the 80 clinic. we explained to him the importance of reporting and publishing his case for 81 educational purposes, and he agreed. 82 83 discussion 84 avms are malformations in the circulatory system characterized by arteries and veins 85 that are not connected by capillaries leading to various degrees of ischemia and 86 pain.1,2 even though central nervous system cases represent the majority of avms, 87 there are published reports of avms involving the kidney, uterus, and scrotum.2,3,4 88 avms are rarely present in the urinary tract.6 we reviewed four previously published 89 scrotal avm cases (table 1). all revealed ages ranging from 19 to 31 years while our 90 patient was 37 years old. scrotal avm embraces wide-ranging presentations 91 including infertility, acute recurrent pain in the hemiscrotum, pain and swelling on the 92 testicle, and progressive diffused swelling in the scrotum with flashing skin and local 93 warmth. our case presented with gradually increasing left testicular swelling with on 94 and off scrotal pain, and occasional feeling of scrotal warmth and discomfort. of the 95 four cases we have reviewed, three denied any history of trauma, and one had a 96 positive trauma history which was a severe pelvic fracture, and the patient indicated 97 that there is difficulty in maintaining erection since. our patient denied any trauma 98 history. varicocele was found in two of the cases and was seen by sonography 99 whereas our patient had multiple skin varices above the left scrotum that was seen 100 during physical examination. each one of the four cases we reviewed diagnosed 101 scrotal avm with a different modality. some were challenging and required 102 orchiectomy for a diagnosis while others were simple and detected by pelvic 103 angiography. our patient was diagnosed by abdominal and pelvic ct. two studies 104 were able to find and embolize the feeding arteries. our patient underwent 105 embolization but had recurrence one-year later. similar to our case, surgical 106 intervention was eventually done in all four cases, and it varied from left scrotal avm 107 excision, orchiectomy, ileo-femoral bypass, and resection of the whole left side of the 108 scrotum. in our case, partial scrotal wall excision was done. after the surgical 109 intervention, all patients were symptom-free.5,6,7,8 we believe that the difference in 110 the presentation could be attributed to the location of the avm, onset, duration, and if 111 there is a history of trauma. a possible explanation for the differences in imaging 112 modalities used to diagnose scrotal avms is the availability of imaging techniques in 113 the hospitals that encountered those cases. the decision of surgical intervention is 114 mainly based on the symptoms and how symptoms negatively affect the patient's 115 quality of life. 116 117 conclusion 118 our case calls attention to a rare and challenging diagnosis that is scrotal avm. 119 recurrent scrotal pain, swelling, and warmth together with varicocele should raise 120 suspicion for scrotal avm. treatment varies depending on the symptoms present. we 121 believe that embolization of the feeding arteries is a possible option to start with, and 122 surgery should be preserved for recurrent cases. 123 124 authors’ contribution 125 fma, msa, and sia were responsible for conceiving the idea, literature search, data 126 acquisition, and manuscript writing and revision. aa, sa, ya, and ab were 127 primarily involved in the management of the case and critically reviewed the final 128 version of the manuscript. all the authors have read and approved the final version of 129 this manuscript. 130 131 references 132 1. capitano m, schieda n, robertson sj, et al. images: ruptured intratesticular 133 arteriovenous malformation. can urol assoc j. 2018;12(11):e489-e491. 134 doi:10.5489/cuaj.5049 135 2. lawton mt, rutledge wc, kim h, et al. brain arteriovenous malformations. nat 136 rev dis primers. 2015;1:15008. published 2015 may 28. doi:10.1038/nrdp.2015.8 137 3. wong c, leveillee rj, yrizarry jm, kirby k. arteriovenous malformation 138 mimicking a renal-cell carcinoma. j endourol. 2002;16(9):685-686. 139 doi:10.1089/089277902761403050 140 4. szpera-goździewicz a, gruca-stryjak k, bręborowicz gh, ropacka-lesiak m. 141 uterine arteriovenous malformation diagnosis and management. ginekol pol. 142 2018;89(5):276-279. doi:10.5603/gp.a2018.0047 143 5. monoski ma, gonzalez rr, thomas aj, goldstein m. arteriovenous 144 malformation of scrotum causing virtual azoospermia. urology. 2006;68(1):. 145 doi:10.1016/j.urology.2006.01.019 146 6. agrawal v, dangle p, minhas s, ralph d, christopher n. recurrent arteriovenous 147 malformation of the scrotum secondary to pelvic trauma. urol int. 2006;77(4):365-148 7. doi: 10.1159/000096343. pmid: 17135789. 149 7. sountoulides p, bantis a, asouhidou i, aggelonidou h. arteriovenous 150 malformation of the spermatic cord as the cause of acute scrotal pain: a case report. 151 j med case rep. 2007 oct 16;1:110. doi: 10.1186/1752-1947-1-110. pmid: 152 17939869; pmcid: pmc2194703. 153 8. mohammad a, sahyouni w, almeree t, alsaid b. angioembolization of scrotal 154 arteriovenous malformations: a case report and literature review. case rep 155 vasc med. 2020 feb 8;2020:8373816. doi: 10.1155/2020/8373816. pmid: 156 32089946; pmcid: pmc7031727. 157 158 figure 1: a picture of the left scrotal swelling with clear multiple skin varices. 159 160 161 figure 2: the left image (a) showing a feeder artery supplying scrotal avm. the right 162 image (b) angiogram following onyx embolization through the avm is almost 163 occluded. 164 165 166 figure 3: partial left scrotal wall with avm excision.167 a b author age trauma history presentation semen analysis varicocele diagnosis method embolization treatment follow-up monoski et al.5 31 no history of trauma infertility severe oligospermi a a left varicocele pelvic angiography performed surgical left scrotal avm excision 3 years postsurgery, successful spontaneous pregnancy agrawal et al.6 25 positive -severe pelvic fracture 4 years ago pain associated with a soft swelling on his right testicle not performed no evidence of varicocele histopathological examination not performed ileo-femoral bypass surgery not mentioned sountoulides et al.7 22 no history of trauma acute recurrent pain in the right hemiscrotum not performed no evidence of varicocele post-orchiectomy specimen not performed orchiectomy 2 years postsurgery, there was no complain mohammed et al.8 19 no history of trauma progressive diffused swelling in the scrotum with flashing skin and local warmth not performed varicocele with 1 cm dilated veins ct arteriography performed the whole left side of the scrotum was removed, and the left testicle was fixed to the right side 12 months postsurgery, there was no complain current case 37 no history of trauma gradually increasing scrotal mass with on and off scrotal pain and discomfort not performed multiple skin varices over the left scrotum were seen abdominal and pelvis ct performed partial scrotal wall excision two months postsurgery, there was no complain 168 submitted 12 oct 2022 1 revision req. 13 dec 22; revision recd. 15 jan 23 2 accepted 8 feb 23 3 online-first: february 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.010 5 6 effect of life-style modification intervention programme on bone mineral 7 density among postmenopausal women with osteoporosis 8 anupama d.s,1 *judith a. noronha,1 kiran k.v. acharya,2 mukhyaprana 9 prabhu,3 ravishankar n,4 baby s. nayak5 10 11 5department of child health nursing, 1manipal college of nursing, manipal academy of 12 higher education, manipal, india; departments of 3medicine and 2orthopedics, kasturba 13 medical college, manipal, india; 4department of biostatistics, vallabhai patel chest 14 institute, university of delhi, delhi, india. 15 *corresponding author’s e-mail: judith.n@manipal.edu 16 17 abstract 18 objectives: osteoporosis is one of the major public health problems worldwide among 19 postmenopausal osteoporotic women. lifestyle modification interventions along with 20 pharmacotherapy helps to revert the bone loss and prevent the complications. methods: a 21 randomized controlled trial was conducted at kasturba hospital, manipal from january 2019 22 to december 2021 among postmenopausal women with osteoporosis. the postmenopausal 23 women who attended the osteoporosis clinic and were within the age group of 45-65 years, 24 could speak and understand english or kannada, and whose bone mineral density (bmd) 25 score was between -1 and -3 were included for the study. the total sample size of the study 26 was 120 with 60 in each of the experimental and control group. after obtaining the informed 27 consent, stratified block randomization method was used to allocate the participants to 28 intervention and control group. the bmd was monitored by the portable ultrasound 29 densitometer by a technician at the outpatient departments. the baseline information was 30 collected by a structured demographic questionnaire. intervention group participants received 31 lifestyle modification intervention program (lmip) whereas control group received the 32 standard regular care by the physician. follow up was done at three and six months. results: 33 the results revealed that the increase in the bmd median score among the experimental 34 group was from -2.2 [(-2.5, -1.8)] to -1.5 [(-1.8, -0.65)] where as in the control group it was 35 from -2.3 [(-2.6, -1.9)] to -2.0 [(-2.4, -1.5)]. the increase in the median score of the 36 experimental group (0.7) was higher than in the control group (0.3). the results of mann 37 whitey u test showed a statistical significance between the intervention and control groups in 38 the post test after 6 months (u =.505.5, p<0.05). wilcoxon signed rank test showed the 39 significant change in both the intervention and control groups from pre-test to post-test i (3 40 months) and post-test ii (6 months) (p<0.001). conclusion: the lifestyle modification 41 intervention was found to be effective in improving the bone health status of postmenopausal 42 women. hence it is very important to integrate in regular therapy. 43 keywords: lmip, postmenopausal women, bone health status, bone mineral density 44 45 advances in knowledge 46  effective lifestyle modification intervention was efficient in improving the 47 bone mineral density of postmenopausal women with osteoporosis 48  the constant encouragement and motivation endure lifestyle modification 49  counselling and education are imperative to improve the bone health status of 50 the postmenopausal women 51 application to patient care 52  integrating lifestyle modification interventions with pharmacological 53 treatment would aid postmenopausal osteoporotic women in reversing bone 54 loss and speeding recovery. 55  the distribution of informational, educational, and communication materials, 56 as well as organized counselling services to postmenopausal osteoporotic 57 women, would be beneficial for the self-management of osteoporosis. 58 59 introduction 60 osteoporosis is a widespread illness that causes a systemic loss of bone mass and 61 microarchitecture, resulting in fragility fractures. 1 osteoporosis is more commonly seen in 62 older adults and women. 2 with an older population and an improvement in life expectancy, 63 osteoporosis is becoming a worldwide epidemic. according to estimates, more than 200 64 million individuals worldwide have osteoporosis3, and one in three women over 50 and one in 65 five men may experience osteoporotic fractures at some point in their lifetime4. these fractures, 66 which primarily occur at the hip, vertebrae, and distal forearm 5 are associated with significant 67 morbidity, mortality, and reduced quality of life, which can be attributed not only to the fracture 68 itself but also to the high prevalence of comorbidities.6 69 70 osteoporosis is diagnosed by measuring bmd of the hip and spine with dual energy x-ray 71 absorptiometry.7 bmd can be assessed using quantitative computed tomography, but it is 72 limited by radiation exposure and cost. quantitative calcaneal ultrasonography and peripheral 73 dexa, which measure bmd in the heel, finger, and forearm and can effectively predict 74 fracture risk, are much more portable and less expensive than central dexa. 8 the world 75 health organization defines osteoporosis as a bmd that is 2.5 standard deviations or more 76 below the average for young healthy women.6 77 78 since oestrogen is essential for maintaining bone health, postmenopausal women have a higher 79 prevalence of osteoporosis and associated fractures than older men. a 60-year-old woman has 80 an approximately 44% lifetime risk of fracture, which is nearly double the 25% risk for a man 81 of the same age.9. the prevention and treatment of postmenopausal osteoporosis may involve 82 a variety of non-pharmacologic approaches.10 certain osteoporosis risk factors in 83 postmenopausal women can be reversed by modifying one's lifestyle, for instance through 84 exercise, smoking cessation, and reducing consumption of caffeine and alcohol. regular 85 weight-bearing activity and a balanced diet with appropriate calcium and vitamin d 86 consumption are the main two lifestyle changes that can reduce the risk of fracture in 87 postmenopausal women. other modifiable lifestyle variables important for bone health and 88 lowering fracture risk include not smoking, weight management, reduced alcohol intake, and 89 precautions for potential falls at home.11,12 for people with osteoporosis who are at risk for 90 falls and fractures, improving lighting at home, removing obstacles from the home that can 91 cause falls, and using undergarments with hip protectors are advised. resistance training and 92 weight-bearing exercises are suggested for postmenopausal women because they help to 93 maintain bmd13 although lifestyle changes alone may not be sufficient to prevent bone loss 94 or reduce fracture risk, particularly in high-risk groups, they do provide an important 95 foundation along with pharmacologic approaches to prevent or treat osteoporosis.14 therefore, 96 it is very important to incorporate the lifestyle modification interventions in the mild stage of 97 osteoporosis and osteopenia so that further complications can be prevented. 15 98 99 health care providers play a crucial role in the management of osteoporosis with regard to the 100 exercise training and client education in maintaining the bone density. exercise programmes 101 have been found to be effective in improving the bone mineral density of postmenopausal 102 women. 16also, knowledge and belief changes in osteoporotic women can be facilitated by 103 brief written educational materials. 17a successful home rehabilitation programme typically 104 depends on maintaining a regular exercise schedule, which is strongly influenced by self-105 motivation and other extrinsic factors18 in addition, it is well known that non-adherence to 106 pharmacological treatment in osteoporosis is a concern19 and there is evidence that a group-107 based educational programme and multicomponent approach interventions 20would improve 108 patients' adherence with medical treatment. however, the studies that focus on comprehensive 109 lifestyle modification interventions along with patient education were not available in the 110 indian context. we therefore hypothesise that taking part in a lifestyle modification 111 intervention programme will increase the bone mineral density of postmenopausal women with 112 osteoporosis in light of the literature that is currently available. 113 114 methods 115 this randomized control trial was conducted at the osteoporosis clinic of the outpatient 116 department of the kasturba hospital, manipal from january 2019 to december 2021. 117 118 this trial was registered under the clinical trial registry of india (ctri) with trial no. 119 ctri/2019/05/019045 and ethical permission was obtained from institutional ethics 120 committee, kasturba hospital and kasturba medical college, manipal 121 122 inclusion criteria were postmenopausal women who attended the osteoporosis clinic and were 123 within the age group of 45-65 years, could speak and understand english or kannada, and 124 whose bmd score was between -1 and -3. postmenopausal osteoporotic patients who had a 125 history of fracture and were admitted to the hospital were excluded from the study. 126 127 sample size was calculated using the formula for two independent groups. 128 2[z1-α/2 + z1β/2] 2 σ2 129 n= ------------------------------------------130 d2 131 where 132 z1-α/2 is1.96 at a 95 % confidence interval. 133 z1β/2 is 0.84 at the power of 80% 134 σ is the standard deviation (56.78) 135 d is the clinically significant difference (40.68) 136 considering the 30% attrition rate, a total sample size of 120 was calculated, i.e. 60 each in of 137 the intervention and control group was included (standard deviation and clinically significant 138 difference were computed based on the pilot study findings). 139 140 data collection was done after obtaining written informed consent. a stratified block 141 randomization method was used to allocate the sample. strata were developed based on the age 142 groups, i.e., 45-55 years and 56-65 years, and there were 12 total blocks, with 10 samples in 143 each block. random numbers were created using a computer. the allocation concealment was 144 done by using sequentially numbered opaque sealed envelopes (snose), and it was 145 prepared by an external member who was not directly involved in the study. 146 147 bone mineral density was measured by portable ultrasound bone densitometer (sunlight mini 148 omni bone sonometer with frequency of 1.25mhz) at the wrist region by a technician at the 149 outpatient departments. the baseline information was collected by a structured demographic 150 questionnaire. intervention group participants received the lifestyle modification intervention 151 programme (lmip). the detailed process of rct is given in figure 1. 152 153 the lmip was based on three pillars: physical activity, health education (behavioural change 154 communication) on exercise, diet, and follow-up, and motivation for sustenance. it included 155 the components of exercise teaching, selflearning of exercises through videos, a brochure on 156 osteoporosis management, and motivational videos on management of osteoporosis, reminder 157 messages and regular phone calls as a follow up and motivation to adhere to the lifestyle 158 modification intervention. the lmip was developed by adopting a meticulous program 159 development approach including an extensive review of literature, designing of the program, 160 experts’ advice, validation of the program and piloting of the program. the exercises included 161 in lmip were stretching exercises, wall pushups, toe lifts, sitting on a chair and getting up, and 162 stepping up and down. the researcher taught these exercises to each participant individually in 163 the outpatient department. the same exercises video prepared by the researcher was sent to the 164 postmenopausal women's mobile phones. in addition, health education on osteoporosis and its 165 management was provided. the participants were also given a brochure on postmenopausal 166 osteoporosis management, which comprised a brief explanation of the disease condition, signs 167 and symptoms, diagnosis, follow-up, exercise, and dietary management. researchers used 168 mobile phones to deliver weekly texts and fortnightly calls, as well as motivational videos, to 169 emphasize the consistency of lmip. 170 follow ups for bmd were carried out at three and six months. however, there were dropouts 171 for follow ups due to covid-19 and lockdown. 172 173 the control group received the standard pharmacological treatment by the physician as per the 174 hospital protocol. they were allowed to perform their daily activities without any restriction 175 up to the end of the study (6 months). after which, the control group participants were provided 176 with the same lmip that was received by the experimental group. 177 178 statistical analysis 179 the data were coded and analysed using spss 22. descriptive and inferential statistical tests 180 were used for the analysis. homogeneity among the intervention and control groups at baseline 181 was tested using chi square test. if the frequency cells were less than five, then fisher's exact 182 test was considered. the shapiro-wilk test was used to determine normal distributions. as the 183 data was not normally distributed, non –parametric tests were used for statistical analysis. 184 differences between groups were analysed using the mann–whitney u test. the wilcoxon 185 signed-rank test was used to analyse the change in bmd at baseline and at 3 and 6 months. p 186 value of less than 0.05 was considered significant. 187 188 results 189 demographic characteristics 190 in this randomized control trial, 120 postmenopausal osteoporotic women were enrolled, with 191 60 in each of the intervention and control groups. during the follow up after six months, 18 192 sample from the intervention group and 15 from the control group were dropped out due to the 193 covid-19 pandemic and lockdown. the mean age of the intervention and control group were 194 56.8 (sd=2.5) and 55.7 (sd=1.8) respectively. higher proportions of the women were 195 housewives (70.83%). it was also found that 42.5% of the participants had two children and 196 58.33% had four or fewer family members (table 1). homogeneity test results showed that 197 both the intervention and control groups were homogenous (p>0.05) 198 199 effectiveness of lifestyle modification intervention on bone mineral density 200 as the data was not normally distributed, mann-whitney u test was used to compare the 201 differences in the median pre-test and post-test scores between the experimental and control 202 groups among postmenopausal osteoporotic women (table 2). the wilcoxon signed rank test 203 was used to compare the change in scores from pre-test to post-test ii (table 3). 204 the increase in the bmd median score among the experimental group was from -2.2 [(-2.5, -205 1.8)] to -1.5 [(-1.8, -0.65)] where as in the control group it was from -2.3 [(-2.6, -1.9)] to -2.0 206 [(-2.4, -1.5)]. the increase in the median score of the experimental group (0.7) was higher than 207 in the control group (0.3). the results of mann whitey u test showed a statistical significance 208 between the intervention and control groups in the post test ii (u =.505.5, p<0.05). 209 210 a wilcoxon signed rank test was computed to observe the change in bmd scores within 211 intervention and control groups from pre-test to post-test i and ii. the findings revealed 212 significant change in both the intervention and control groups from pre-test to post-test i and 213 post-test ii (p<0.001). hence, it can be concluded that lmip was very effective in increasing 214 the bone mineral density among the postmenopausal women with osteoporosis. 215 216 discussion 217 we aimed to investigate the effectiveness of lmip on the bmd of postmenopausal 218 osteoporotic women. in our study, lifestyle modification interventions were provided along 219 with the pharmacological treatment for the intervention group. our results demonstrated that 220 the lmip improved the bmd of the postmenopausal osteoporotic women in comparison to the 221 control group, which received only pharmacological treatment. this may be explained by the 222 fact that the integration of lifestyle modification components along with pharmacological 223 treatment, including exercise, regular physical activities, dietary management, reinforcement 224 of treatment, and follow-up, may have influenced the improvement of the bmd. it is significant 225 that the lmip was deemed safe because, over the course of the study, no injury incidences 226 were reported. additionally, regular phone calls for follow-up monitoring may have 227 encouraged participants to accomplish the activities. the health education provided by the 228 researcher motivated them to adhere to the therapy positively and have great enthusiasm for 229 performing the activities. 230 231 our study finding is consistent with a study that had 8-week physiotherapeutic education on 232 back extensor muscle (bem) strength, physical performance, balance, and qol in 233 postmenopausal women21. in addition, our findings are similar with a study where osteoporotic 234 women underwent a 6-month personalized drug therapy and focused mechanoacoustic 235 vibration which had a beneficial effect on bmd22. another study also reported a significant 236 increase in the bone mineral density of the participants after an intervention programme which 237 included physical activity and diet supplementation23. similarly, many other studies conducted 238 on the effect of different exercises on bone mineral density found them to be effective.24,25 239 there is evidence that increasing physical exercise improves bone mineral density.26 240 furthermore, there were independent studies and reviews on the impact of dietary management 241 on risk reduction and a better prognosis for osteoporosis.27 28 29 in addition, there was a study 242 which evaluated the impact of osteoporosis education on osteoporosis knowledge and calcium 243 intake.30 there were few systematic reviews conducted on the impact of exercises on bone 244 mineral density. as per the results of the systematic review, exercise could be a safe and 245 effective strategy to prevent bone loss in postmenopausal women. 31 246 247 there was a dearth of studies to compare the integration of lifestyle modification interventions 248 with pharmacological treatment, including exercise, dietary management, reinforcement of 249 treatment, and follow-up. furthermore, reinforcement and motivation were integrated into the 250 study through periodic phone calls and messages. individual counselling and educational 251 sessions were found to be essential to motivate the middle-aged women in their menopause. 252 this session helped participants by clarifying their doubts. thus, as the findings of this study 253 were encouraging, there is now a reason to undertake extensive research along similar lines. 254 255 osteoporotic fractures are the third-leading cause of disability; therefore, maintaining strong 256 bones is essential for extending a healthy lifespan. as various factors, including diet, exercise, 257 consumption of alcohol and tobacco products, and genetics, have an impact on bone mass, it is 258 very important to maintain bone health and prevent complications with a nutritious diet rich in 259 balanced nutrients, including calcium, vitamin d, and protein, as well as through regular 260 exercise and quitting smoking. our study results are supported by previous literature, showed 261 that lifestyle modification interventions along with the pharmacological treatments among the 262 postmenopausal osteoporotic women were effective in bringing the positive results. thus, it is 263 suggestive of the integration of lifestyle modifications in clinical practice while treating post-264 menopausal osteoporotic patients. 265 266 limitations 267 there are several limitations to this study. first, the participants in the experimental group 268 would have discussed the intervention with the control group. however, for the intervention 269 group, participants’ intervention was provided in a separate room. second, there was no 270 monitoring at home for compliance with lmip. however, the lmip developed for this study 271 was simple, low-cost, and convenient for the postmenopausal women to practice at home. 272 third, despite the fact that dexa is regarded as the gold standard for the diagnosis of 273 osteoporosis, bmd was measured using the ultrasound method in this study since it was 274 affordable and feasible for the study. finally, the data collection was carried out during the 275 covid-19 pandemic and lockdown, so we missed some of the postmenopausal women for the 276 follow up. however, the sample size was more than the estimated sample size and we could 277 manage the analysis. 278 279 conclusion 280 the study revealed that lifestyle modification along with pharmacotherapy for postmenopausal 281 osteoporotic women was found to be effective. regular implementation of this program for 282 women with primary osteoporosis who haven’t experienced the fracture yet will definitely help 283 to reverse the bone loss and bone health could be improved. clinicians and nurses should focus 284 on lifestyle modification interventions in addition to pharmacotherapy because it is cost-285 effective and affordable for patients to prevent the most severe complications such as fracture. 286 287 authors’ contribution 288 ads, jan, kkva conceptualized and designed the study. ads did the data collection and 289 involved in the manuscript writing. jan and kkva supervised the work and edited the 290 manuscript. bsn and mp contributed to manuscript writing. rn was involved in data analysis. 291 all authors approved the final version of the manuscript. 292 293 conflict of interest 294 the authors declare no conflicts of interest . 295 296 funding 297 no funding was received for this study. 298 299 references 300 1. rachner td, khosla s, hofbauer lc. osteoporosis: now and the future. lancet 301 2011;377:1276–87. https://doi.org/10.1016/s0140-6736(10)62349-5. 302 2. sozen t, ozisik l, calik basaran n. an overview and management of osteoporosis. 303 eur j rheumatol 2017;4:46–56. https://doi.org/10.5152/eurjrheum.2016.048. 304 3. ji m, yu q. primary osteoporosis in postmenopausal women. chronic dis transl med 305 2015;1:9–13. https://doi.org/10.1016/j.cdtm.2015.02.006. 306 4. aypak c, bircan ma, özdemir a. anti-osteoporotic drug utilization rates for 307 secondary prevention among patients with osteoporotic fractures. rambam 308 maimonides med j 2022;13. https://doi.org/10.5041/rmmj.10473. 309 5. minisola s, cipriani c, occhiuto m, pepe j. new anabolic therapies for osteoporosis. 310 intern emerg med 2017;12:915–21. https://doi.org/10.1007/s11739-017-1719-311 4/figures/2. 312 6. akkawi i, zmerly h. osteoporosis: current concepts. joints 2018;6:122–7. 313 https://doi.org/10.1055/s-0038-1660790. 314 7. park y-s. diagnosis and treatment of osteoporosis. journal of the korean medical 315 association 2012;55:1083–94. https://doi.org/10.5124/jkma.2012.55.11.1083. 316 8. pisani p, renna md, conversano f. casciaro e, muratore m, quarta e, et al. 317 screening and early diagnosis of osteoporosis through x-ray and ultrasound based 318 techniques. world j radiol 2013;5:398. https://doi.org/10.4329/wjr.v5.i11.398. 319 9. ji m, yu q. primary osteoporosis in postmenopausal women. chronic dis transl med 320 2015;1:9–13. https://doi.org/10.1016/j.cdtm.2015.02.006. 321 10. national osteoporosis guidelines group-uk. non-pharmacological management of 322 osteoporosis | nogg. available at: https://www.nogg.org.uk/full-guideline/section-5-323 non-pharmacological-management-osteoporosis. accessed january 5, 2023. 324 11. zhu k, prince rl. lifestyle and osteoporosis. curr osteoporos rep 2015;13:52–9. 325 https://doi.org/10.1007/s11914-014-0248-6. 326 12. ishimi y. osteoporosis and lifestyle. j nutr sci vitaminol (tokyo) 2015;61 327 suppl:s139–41. https://doi.org/10.3177/jnsv.61.s139. 328 13. benedetti mg, furlini g, zati a, letizia mauro g. the effectiveness of physical 329 exercise on bone density in osteoporotic patients. biomed res int 2018;2018. 330 https://doi.org/10.1155/2018/4840531. 331 14. christianson ms, shen w. osteoporosis prevention and management: 332 nonpharmacologic and lifestyle options. clin obstet gynecol 2013;56:703–10. 333 https://doi.org/10.1097/grf.0b013e3182a9d15a. 334 15. rajan r, paul j, kapoor n, cherian ke, paul tv. postmenopausal osteoporosis – an 335 indian perspective. current medical issues 2020;18:98. 336 https://doi.org/10.4103/cmi.cmi_5_20. 337 16. mohammad rahimi gr, smart na, liang mtc, bijeh n, albanaqi al, fathi m, et 338 al. the impact of different modes of exercise training on bone mineral density in 339 older postmenopausal women: a systematic review and meta-analysis research. 340 calcif tissue int 2020;106:577–90. https://doi.org/10.1007/s00223-020-00671-341 w/figures/4. 342 17. blalock sj, currey ss, devellis rf, devellis bm, giorgino kb, anderson jj, et al. 343 effects of educational materials concerning osteoporosis on women’s knowledge, 344 beliefs, and behavior. american journal of health promotion 2000;14:161–9. 345 https://doi.org/10.4278/0890-1171-14.3.161. 346 18. mcarthur d, dumas a, woodend k, beach s, stacey d. factors influencing 347 adherence to regular exercise in middle-aged women: a qualitative study to inform 348 clinical practice. bmc womens health 2014;14:1–8. https://doi.org/10.1186/1472-349 6874-14-49/tables/2. 350 19. garcía-sempere a, hurtado i, sanfélix-genovés j, rodríguez-bernal c, peiró s, 351 sanfélix-gimeno g. improving the accuracy of medication adherence measures using 352 linked prescription and dispensation data: findings from the esosval cohort of 353 patients treated with osteoporosis drugs. curr med res opin 2019;10. 354 https://www.tandfonline.com/doi/10.1080/03007995.2019.1601944 355 20. cornelissen d, de kunder s, si l, reginster j, evers s, boonen a, et al. interventions 356 to improve adherence to anti-osteoporosis medications: an updated systematic review. 357 osteoporosis international 2020;31:1645–69. https://doi.org/10.1007/s00198-020-358 05378-0/tables/6. 359 21. kuan cs, yian cy, kaur d, singh dk, mokhtar sa. effectiveness of 360 physiotherapeutic group education in improving quality of life, physical 361 performance and back extensor muscle strength among. medicupmedumy 362 2022;18:269–77. https://doi.org/10.47836/mjmhs18.s15.38. 363 22. saggini r, ancona e, carmignano sm, supplizi m, barassi g, bellomo rg. effect of 364 combined treatment with focused mechano-acoustic vibration and pharmacological 365 therapy on bone mineral density and muscle strength in post-menopausal women. clin 366 cases miner bone metab 2017;14:305–11. 367 https://doi.org/10.11138/ccmbm/2017.14.3.305. 368 23. sahaya rani g, swaminathan a. effectiveness of physical activity and diet 369 supplementation on body mass index and bone mineral density among 370 premenopausal women. j pharm negat results 2022;13:4403–11. 371 https://doi.org/10.47750/pnr.2022.13.s07.552. 372 24. razzak za, khan aa, farooqui si. effect of aerobic and anaerobic exercise on 373 estrogen level, fat mass, and muscle mass among postmenopausal osteoporotic 374 females. int j health sci (qassim) 2019;13:10. 375 25. watson sl., weeks bk, weis lj, harding at, horan sa, beck br. high-intensity 376 resistance and impact training improves bone mineral density and physical 377 function in postmenopausal women with osteopenia and osteoporosis: the 378 liftmor randomized controlled trial. j bone miner res 2018;33:211–20. 379 https://doi.org/10.1002/jbmr.3284. 380 26. muir jm., ye c, bhandari m, adachi jd, thabane l. the effect of regular physical 381 activity on bone mineral density in post-menopausal women aged 75 and over: a 382 retrospective analysis from the canadian multicentre osteoporosis study. bmc 383 musculoskelet disord 2013;14:1–9. https://doi.org/10.1186/1471-2474-14-384 253/tables/5. 385 27. rizzoli r, stevenson jc, bauer jm, van loon, l.j, walrand s, kanis, j.a, et al. the 386 role of dietary protein and vitamin d in maintaining musculoskeletal health in 387 postmenopausal women: a consensus statement from the european society for clinical 388 and economic aspects of osteoporosis and osteoarthritis (esceo). maturitas 389 2014;79:122–32. https://doi.org/10.1016/j.maturitas.2014.07.005. 390 28. muñoz-garach a, garcía-fontana b, muñoz-torres m. nutrients and dietary patterns 391 related to osteoporosis. nutrients 2020;12:1–15. 392 https://doi.org/10.3390/nu12071986. 393 29. guo d, zhao m, xu w, he h, li b, hou t. dietary interventions for better 394 management of osteoporosis: an overview. crit rev food sci nutr 2023;63. 395 https://doi.org/10.1080/10408398.2021.1944975. 396 30. laslett ll, lynch j, sullivan tr., mcneil jd. osteoporosis education improves 397 osteoporosis knowledge and dietary calcium: comparison of a 4 week and a one-398 session education course. int j rheum dis 2011;14:239–47. 399 https://doi.org/10.1111/j.1756-185x.2011.01628.x. 400 31. howe te., shea b, dawson lj, downie f, murray a, ross c, harbour rt, et al. 401 exercise for preventing and treating osteoporosis in postmenopausal women. cochrane 402 database syst rev 2011. https://doi.org/10.1002/14651858.cd000333.pub2. 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 assessed for eligibility -162 excluded (n=42)  not meeting inclusion criteria (n=25)  had history of fracture and other diseases like cardiovascular, cancer etc-10  joined for regular yoga classes-5  declined to take part in study (n=2) enrolment randomized-120 stratified block randomization 2 strata &12 blocks (1 block=10) allocation allocated to intervention group (n=60) received lmip (n=60) allocated to control group (n=60) received standard care (n=60) follow up follow up 1 lost to follow up due to covid-19 pandemic lockdown (n=15) follow up 1 lost to follow up due to covid-19 pandemic lockdown (n=8) follow up 2 lost to follow up due to covid-19 pandemic lockdown (n=18) follow up 2 lost to follow up (bmd) due to covid19 pandemic lockdown (n=15) 424 425 426 427 figure 1: consort flow diagram on process of randomized controlled trial 428 429 430 431 432 table 1: frequency and percentage distribution of demographic characteristics of 433 participants (n = 120) 434 variable experimental group (n=60) control group (n=60) overall p value mean (sd) freque ncy (f) percent age (%) frequenc y (f) percent age (%) mean (sd) freque ncy (f) percenta ge (%) age in years 56.8 (2.5) 55.7 (1.8) occupation daily labour housewife others (govt. and private jobs) 1 44 15 1.7 73.3 25.0 2 41 17 3.3 68.3 28.3 3 85 32 2.5 70.83 26.66 0.242 number of children 1 2 3 ≥4 9 24 17 10 15.0 40.0 28.3 16.7 6 27 20 7 10.0 45.0 33.3 11.7 15 51 37 17 12.5 42.5 30.83 14.17 0.332 number of members in the family 1-4 5 and above 34 26 56.7 43.3 36 24 60 40 70 50 58.33 41.66 0.561 435 table 2: mann whitney u value computed for pre-test, post-test 1 and post-test ii of 436 bmd scores among intervention and control group 437 bmd measurements group n median (q1, q3) p value analysis analyzed (n) =42 analyzed (n) =45 pre-test intervention 60 -2.2 (-2.5, -1.8) 0.431 control 60 -2.3 (-2.6, -1.9) post-test 1 intervention 45 -1.3 (-2.5, -1.0) 0.126 control 52 -1.8 (-2.4, -1.5) post-test ii intervention 42 -1.5 (-1.8, 0.65) <0.001 control 43 -2.0 (-2.4, -1.5) 438 439 440 table 3: wilcoxon signed rank test results to compare the change in bmd scores 441 within intervention and control groups from pre-test to post-test i and ii. 442 bmd groups z score p-value pre-test to post-test i intervention (n=60) -5.591 <0.001 control (n=60) -5.509 <0.001 pre-test to post-test ii intervention (n=45) -5.556 <0.001 control (n=52) -5.172 <0.001 post-test i to post-test ii intervention (n=42) -3.626 <0.001 control (n=45) -3.352 <0.001 *to adjust for multiple comparisons, p-value < 0.05/3 was considered as statistically 443 significant. 444 submitted 22 sep 21 1 revision req. 1 dec 21; revision recd. 21 dec 21 2 accepted 6 jan 22 3 online-first: jan 2022 4 doi: https://doi.org/10.18295/squmj.1.2022.009 5 6 urethral caruncle with associated renoureteric anomalies 7 sohail ahmad, *akash b. pati, santosh k. mahalik, kanishka das 8 9 department of pediatric surgery, all india institute of medical sciences, bhubaneswar, india 10 *corresponding author’s e-mail: patiakash.ap@gmail.com 11 12 abstract 13 a urethral caruncle is a rare differential diagnosis for a prolapsed mass at the urethral meatus in a 14 prepubertal girl. the aetiopathogenesis of this entity is unclear. we describe the presentation and 15 treatment of a patient with a urethral caruncle and associated renal anomalies that have not been 16 described earlier. the aetiology and treatment of the entity has also been discussed. 17 keywords: urethral caruncle, premature menarche, paediatric bleeding per vagina, crossed 18 fused ectopia 19 20 introduction 21 prepubertal bleeding at the introitus is infrequent and raises concern among parents and health 22 providers alike. a wide variety of differential diagnoses are considered from an innocuous 23 abrasion to malignancy. urethral etiologies include mucosal prolapse or polyps. a caruncle is a 24 rare cause that is commoner in middle aged or postmenopausal women. of 14 cases of urethral 25 caruncle in pediatric age group described in english literature, only 4 have been documented 1 in 26 detail, and none had an associated upper urinary tract anomaly. we describe a patient with a 27 urethral caruncle, bleeding per urethra and associated upper urinary tract anomaly. 28 29 case report 30 a 3–year female with normal perinatal and past medical history presented with intermittent 31 mailto:patiakash.ap@gmail.com bleeding from the introitus for a month. there was no history of sexual abuse, genital trauma or 32 recurrent urinary tract infections. in the interim, she was asymptomatic. general physical 33 examination and abdominal examination was unremarkable. the external genitalia were 34 phenotypically female; however, the urethral meatus was circumferentially large and exuberant. 35 the mucosa was relatively more everted along the inferior meatal margin. (figure 1a, b). 36 37 the results of routine hematological and biochemical examinations were normal. the urinalysis 38 showed plenty of red blood cells. an ultrasonogram revealed a small left kidney (45x20mm), a 39 larger right kidney (69x28mm) and crossed fused renal ectopia. renal cortical scintigraphy 40 (dimercapto succinic acid) showed a left to right crossed fused renal ectopia (figure -2). the left 41 renal unit was hydronephrotic and had mildly impaired cortical function and a mid-polar cortical 42 irregularity. the differential function was 43% in the left renal unit and 57% in the right renal 43 unit which was normal. a voiding cystourethrogram was normal. 44 45 examination under anesthesia and cystourethroscopy was performed. the urethral meatus was 46 wide (diameter 1.8cm) with its edges uniformly protuberant and firm. the mucosa was relatively 47 more everted at the inferior circumference. cystoscopy revealed anormal urethra with a mildly 48 trabeculated bladder. the right ureteric orifice was normal, whereas the left was 49 grossly superolateral and patulous. vaginoscopy was unremarkable. 50 51 the patient was discharged on sitz bath (advised to sit immersed in a warm water bath up to hip, 52 aids in reducing congestion) twice daily and advised to apply 0.1% betamethasone cream locally 53 once daily. by 6 weeks of therapy, there was a significant reduction in size of the everted mucosa 54 which appeared normal. at 2 years follow up, there has been no further gross hematuria and the 55 lesion has disappeared completely. the initial hydronephrosis is non progressive and renal 56 function is stable on scintigraphy. informed consent was obtained from the parents for publication 57 of this case report. 58 59 discussion 60 the urethral caruncle is a common benign tumor of the female urethra usually seen in 61 postmenopausal women. an occurrence in the premenarche period, as described here, is rare. the 62 caruncle appears like a raspberry protruding from a quadrant commonly posterior wall of the 63 urethral circumference. it is rarely observed at other locations.2 a circumferential caruncle 64 mimicking a urethral prolapse has been reported only twice since 1964. 1 65 66 the exact etiology of urethral caruncle is unknown; however, chronic inflammation and estrogen 67 deficiency have been implicated.1 according to jeffcott, a true caruncle is a vascular papilloma 68 that arises as a polyp from the posterior lip of the urethra, whereas a pseudo caruncle is a granuloma 69 arising as a diffuse, sessile red lesion. 3 urethral caruncles have been reported at birth; hence, a 70 congenital origin is possible. 4 71 72 symptoms include pain during micturition (51%), bleeding (49%), a mass at the meatus (41%) and 73 an increase in urinary frequency and urgency (36%)3 a ‘premature menarche’ without other 74 secondary sexual characters may point towards a bleeding urethral caruncle.5 the patient described 75 herein had gross intermittent hematuria and a prominent peri meatal mass. the clinical 76 differential diagnosis for a periurethral mass includes urethral prolapse, prolapsing ureterocele, 77 and a botryoid bladder or vaginal rhabdomyosarcoma. a urethral prolapse 78 79 protrudes circumferentially around the meatus like a soft rosette with a central dimple.6 also, 80 both urethral prolapse and polyp are mucosa covered. in contrast, a caruncle is covered with 81 granulation tissue and is liable to bleed. microscopically, the urethral caruncle is a bed of 82 granulation tissue that may feature squamous or transitional epithelium at places. besides, marked 83 inflammatory infiltrate and vascular engorgement of the stroma is common. 84 85 most authors consider them as acquired anomalies. 1,7 the present case features an ectopic left 86 kidney, ectopic termination of left ureter, and a urethral mega meatus. to the best of our 87 knowledge, such anomalies have not been previously reported. we suggest that patients with 88 urethral caruncle need to be evaluated for associated anomalies in the upper urinary tract. no 89 reports available regarding malignancy in urethral caruncle in children. however, in adults, 2.4% 90 of all patients with a preoperative diagnosis of urethral caruncle were found to have carcinoma.8 91 92 various treatment modalities are advocated ranging from conservative management with sitz bath, 93 estrogen creams, topical corticosteroids to surgery. 1,5,7 in unresponsive cases or those exhibiting 94 a progressive, irregular or suspicious growth, electrocoagulation of the base or excision are 95 surgical options. 1 surgical excision may cause urethral stenosis in a circumferential lesion. the 96 present case responded favorably to the initial conservative management. 97 98 conclusion 99 the patient had a granulated mass at the posterior margin of the circumference of the urethral 100 meatus that was diagnosed as a urethral caruncle. she presented with hematuria instead of the 101 typical blood spotting. it was associated with a crossed fused renal ectopia and a routine 102 ultrasonographic screening is suggested to detect associated reno ureteric anomaly. it was 103 managed conservatively with steroid creams and sitz baths. 104 105 authors’ contributions 106 all authors were involved in the conceptualization and preparing of the manuscript. all authors 107 approved the final version. 108 109 references 110 1. chiba m, toki a, sugiyanma a, suganuma r, osawa s, ishii r et al . urethral caruncle 111 in a 9-year-old girl: a case report and review of the literature. j med case reports, 2015: 112 28:9 https://doi.org/10.1186/s13256-015-0518-7 113 2. turkeri l, simsek f, akdas a. urethral caruncle in an unusual location occurring in 114 prepubertal girl.eur. urol. 1989;16:153-4 https://doi.org/10.1159/0004715553 115 3. becker le. urethral caruncle: a herald lesion for distal urethral stenosis? j natl med 116 assoc. 1975; 67: 228-30 117 4. jarvi oh, marin s, de boer wg. further studies in intestinal heterotopia in urethral 118 caruncle. acta pathol microbiol immunol scand.1984;92(6):469 119 https://doi.org/10.111/j4.tb04429.x 120 5. manori g, beneragama d. urethral caruncle presented as premature menarche in a 4121 year-old girl. case report in pediatrics. 2018, https://doi.org/10.1155/2018/34860326 122 6. murphy jp, gatti jm. abnormalities of the urethra, penis and scrotum. in : coran ag 123 editor pediatric surgery 7th ed philadelphia elseiver saunders; 2o12. p 1558 124 https://doi.org/10.1186/s13256-015-0518-7 https://doi.org/10.1159/0004715553 7. kim kk, sin dy, park hw. urethral caruncle occurring in a young girl: a case 125 report. j korean med sci. 1993;8:160-1 https://doi.org/10.3346/jkms.1993.8.2.160 126 8. marshall fc, uson ac, melicow mm. neoplasms and caruncles of the female urethra. 127 surg gynecol obstet. 1960 ;110:723-33. pmid: 14421527. 128 129 130 figure 1: a: hyperaemic exuberant mucosa at the urethral meatus. b: the exuberant mucosa 131 was more prononced inferiorly 132 133 figure 2: renal scintigraphy showing left to right crossed fused renal ectopia. 134 https://doi.org/10.3346/jkms.1993.8.2.160 august 2007 vol 7 copy.indd how to present at meetings second edition 2007 author: george m hall reviewer: *vaidyanathan gowri sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 165-168 sultan qaboos university© submitted 21st april 2007 a u t h o r the author of this book is a professor of anaesthesia, st george’s hospital, university of london, uk. b a c k g r o u n d t o t h e b o o k many trainees in medicine, while competent in their speciality, struggle to give a good presentation at a meeting. the aim of this book is to provide a basic framework around which a proficient talk can be built. the content covers the essential parts of presentation, preparation of visual aids and computer generated slides and provides advice on how to sell a message, how to appear on stage and how to deal with questions. o v e r v i e w o f c o n t e n t the book has 72 pages. it consists of preface and index with 11 chapters as follows: 1. principles of communication 2. preparation of the talk 3. the three talks 4. visual aids 5. computer generated slides: how to make a mess with power point 6. how to appear on stage 7. how to sell a message 8. how to present a talk 9. how to deal with questions 10. how not to give a presentation 11. how to chair a session t h e r e a d e r s h i p m o s t s u i t e d f o r t h i s the book is suited for all the training and trained health professionals starting from senior house officers to senior faculty in any speciality. it will be suitable for trainees preparing for a department preparation, interdisciplinary meetings and also faculty who are invited to speak as experts. this book is suitable for all teachers in medicine: there are also some valid points for a good lecture preparation. a p p r o p r i a t e n e s s o f t h e c o n t e n t t o t a r g e t r e a d e r s h i p the content is suitable for the intended readership. the fact that the editor included a variety of authors makes this book good reading for many categories of health b o o k r e v i e w 2007 الثانية الطبعة / االجتماعات في (تعرض) تقدم كيف هول جورج �تأليف: جوري فيديانثان مراجعة: blackwell publishing, bmj books isbn 13:978-1-4051-3985-4 price gbp 14.99 available at www.clinicalpublishing.co.uk *department of obstetrics and gynaecology, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman email: gowri@squ.edu.om g e o r g e m h a l l 166 professionals. c o m p r e h e n s i v e n e s s o f t h e c o n t e n t the book covers the principles of communication, how to prepare a talk well and the importance of rehearsal. there is very good advice on the various types of visual aids and how to use them well. there are also very good tips on the preparation of power point slides, how to appear on stage and how to get a message across. the importance of capturing the curiosity of the audience and aiming for brevity and clarity is underlined. there is also a chapter on how to deal with questions. o r g a n i z a t i o n o f t h e c o n t e n t the contents are well organized, but possibly the chapters on how to appear on stage and how to present a talk could have preceded the other chapters like “the three talks”. the chapter on how not to give a presentation is equally interesting and important. g e n e r a l c o m m e n t s o n q u a l i t y o f c o n t e n t a n d p r o d u c t i o n the book is small and easy to be carried around. it is a paperback edition and can easily be read during a short travel trip. it is worth possessing until you become a regular and popular speaker and even after that. march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 5-15, epub 16th mar 2009 submitted 24th jan 2009 revision req. 1st feb 09, revision recd. 7th feb 09, accepted 9th feb 09 silent epidemic of depression in women in the middle east and north africa region emerging tribulation or fallacy? liyam eloul,1 aamal ambusaidi,2 *samir al-adawi1 when, in 1948, the world health assembly conceived of health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”, it may not have been apparent to those attending the assembly that mental disorders would be conspicuously omitted in the algorithms of care for the rest of 20th century.1 as psychological concepts are protean and without central features, it was natural to think that health planners would not allocate resources to psychological disorders. the ‘enemy’ of health was poignantly perceived to be hiding in the realm of physical illness, most notably in communicable diseases. therefore, two-tier health systems emerged which further emphasised the irrelevancy of psychological disorders. the focus, on one hand, has been on 1department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; 2department of behavioural medicine, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: adawi@squ.edu.om r e v i e w شمال و الشرق األوسط منطقة في لدى املرأة الصامت وباء األكتئاب أفريقيا تضليل؟ أم مقبلة أزمة العدوي سمير أمبوسعيدي، آمال الول، ليام النفسي األكتئاب بأن البراهني لأليحاء النفسييني األحصاء علماء يكدس ، أجمع العالم على قبضته يحكم األقتصادي الكساد أن حني في امللخص: الهدف الهدف: أن أفريقيا. ــمال ش و ــط األوس ــرق منطقة الش في ذلك املرضي العاملي مبا تعاظم العبء في ــيا ــببا رئيس مس قد أصبحت ومتبايناته عرضة أكثر أفريقيا ــمال وش ــط األوس ــرق منطقة الش في ــاء النس تكون أنت في احتمالية تبحث نقدية ــة مناقش تقدمي هو ــي لهذه املقالة الرئيس الى الدراسة النتيجة: تشيرهذه املتاحة. العلمية األوراق استعراض خالل من العالم وذلك دول باقي مقارنة مبثيالتهن في النفسي باألكتئاب لألصابه أي تفلح لم أنه من اخلالصة: بالرغم أفريقيا. وشمال ــط األوس ــرق الش مبنطقه بالضرورة ظاهرة فردية مرتبطة ــيت لس املذكورة معدالت األكتئاب أن تراعي عاملية موحدة تصنيفات ــتخدام باس ــات احصائية تطويردراس الضروري من فأنه دورها، تفعيل وعدم املرأة تهميش جتاوز ظاهرة في اتمعات من للمرأة. النفسيه الوظيفة وتقييم املعقدة الظاهرة هذه استيعاب أجل من العاملي الثقافي التباين استعراض. ، األسالم ، أفريقيا شمال و األوسط الشرق ، اجلنس اختالف عند النساء، البحث: األكتئاب مفردات abstract background: as the world is being gripped by economic depression, international psychological epidemiologists have amassed evidence to suggest that psychological depression and its variants are becoming leading contributors to the global burden of disease with the middle east and north africa (mena) region being no exception. aim: the main aim of the present discourse, based on a review of the available literature, is to discuss critically whether women in the mena region have a higher rate of psychological depression than those in other parts of the globe. result: from the present synthesis, it emerges that the rate of depression may not be necessarily unique to the region. conclusion: although no society has totally overcome the marginalisation and lack of empowerment of women, in order to come to grips to this complex issue more vigorously designed epidemiological studies, using taxonomies that are standardised for cross-cultural populations, are needed to quantify the psychological functioning of women. keywords: depression in women; gender issue, middle east and north africa; islam; review l i ya m e l o u l , a a m a l a m b u s a i d i a n d s a m i r a l a d aw i 6 the control and eradication of communicable diseases and the improvement of reproductive, maternal, and child health, in particular in developing countries.2 on the other hand, in high income countries, resources have been mobilised to ‘fight’ against early death due to cancer, diabetes and heart disease.3 then came the new century and the pendulum began to swing towards the recognition of the impact of psychological disorders. among the many and varied types of psychological disorders, depression is one of the most intriguing.4 depression is something akin to feeling. it ranges from overreaction to normal sadness to pessimism and then utter despair. in severe depression, even bodily functions can slow down to such an extent that the quality of life, and sometimes life itself, can be threatened. one of the dark shadows accompanying depression is suicide often the result of a lack of treatment. once accepted as an integral part of human nature, recent surveys have converged on the view that depression is becoming a ‘silent epidemic’ which is contributing significantly to disability and mortality.4 depression is known to interact adversely with other health conditions and vice-versa.3,5 it is predicted that depression will become the leading cause of disability by the year 2020. 6 various factors have been attributed to the rising tide of depressive disorders. investigations into the cause of significantly higher depression rates in women as opposed to men in the middle east and north africa (mena) region have indicated a number of contributing factors; many are psychosocial in origin, but most controversial is the role of islam.7-9 this has been especially popular in western ideations regarding women from the mena region.10-13 one aim of the present discussion is to examine how the rate of psychological disorders in the mena region compares to global trends. wherever relevant, other regions or populations that bear resemblance to the mena region will also be considered. imbedded in this quest, is an examination of the hypothesis that islamic beliefs and practices exacerbate stress and distress in women. in order to discuss this issue, evidence from the mena region, including that on changing roles for women, issues related to reproductive health factors as well as inherent methodological problems of gauging subjective feelings like depression, is considered. d e p r e s s i o n i n w o m e n women across the globe have been found to be more susceptible to depression than men.14-16 there are a number of possible explanations. the cyclical fluctuation of female hormones intensifies the physical stress-response, which may amplify vulnerability to depression.17,18 social factors present the world over also result in certain features being more typical of women’s experience than men’s, thus predisposing them to have a higher rate of depression. these include the greater likelihood of experiencing sexual and physical abuse, a greater dependence and higher emotional reliance on social support, along with an increased willingness to report symptoms of current and past episodes of depression to physicians.7 in addition, poor education, including poor health education resulting in a lack of awareness, as well as orthodox customs, compound the situation of women all over the world.19 there has been a recent increase in interest and local research into depression and anxiety in the women of the mena region which offers insight into prevailing ideations of these women. it is pertinent here first to consider studies on depression in this region. ghubash, daradkeh and abou-saleh20 used a modified version of the world mental health composite international diagnostic interview in a systematic sample of 1,390 individuals from the general population in al ain, a principality of the united arab emirates (u.a.e.). they found that lifetime rates of depression were 2.5% for males and 9.5% for females (n = 1,390). this significant sex difference, though dramatic, actually reflects the average world female to male depression ratio of 4:1.21 the correlating factors included age under 55 (premenopausal), divorced women with four or more children, and those who reported a higher exposure to recent adverse life events. ghubash, daradkeh & abou-saleh20 concluded that the high correlation between the significant sex differences in depression rates and socio-demographic variables indicated that a significant cause of difference is likely to be based on social instead of biological factors. el-rufaie, albar and al-dabal22 used the hospital anxiety and depression scale to identify the presence of anxiety and depression among saudi primary care attendees. the prevalence rate of depression was 17%, with females showing the highest indices of depression. however, given that this sample was drawn from participants who were already patients in a clinic, and s i l e n t e p i d e m i c o f d e p r e s s i o n i n wo m e n i n t h e m i d d l e e a s t a n d n o r t h a f r i c a r e g i o n 7 the high rate of somatisation in the developing world, this may be a biased sample. alansari21 conducted an extensive study on depression and anxiety rates among undergraduates in seventeen islamic countries. his sample was wide-ranging, but it must be noted that this study only tapped a certain segment of the population. this produced marked bias since women in undergraduate institutions are likely, first, to be unmarried and without children, and, second, to come from families with a relatively higher socio-economic status and a more liberal view of women’s rights and freedoms. alansari 21 found that rates of depression among women were significantly higher than for men in nine of the seventeen countries. these countries were spread across the mena region: egypt, algeria and morocco in north africa, iraq and syria in the levant, oman, qatar and kuwait in the gulf, and pakistan in south asia. the countries where alansari found no significant difference in depression rates between men and women were equally wide-ranging: tunisia and sudan in north africa, lebanon, palestine and jordan in the levant, and u.a.e and yemen in the gulf. other reports from outside the mena region, but with islamic heritage, have reached similar conclusions. for example, mirza & jenkins23 in pakistan, found depression and anxiety rates to be 46% in women as compared to 15% in men, still reflecting the international ratio of 4:1, with correlates including unemployment, non-married status (widowed, separated or divorced), more than 4 children, loss of a child or father during childhood, housewife, absence of confiding relationship with husband, middle age, low level of education, and marked independent chronic difficulties (housing, finance, health). modabernia et al.24 have conducted a community survey on the prevalence of depression among women in iran using beck’s depression inventory. these authors found that less than 10% of the sample fulfilled the criteria for depression and the majority were marked with a less debilitating spectrum of depression rather than major depression. low socio-economic status was a strong predictor for depression in this population of women. on the whole, epidemiological surveys in the mena regions have shown that rates of depression range from 13 to 18% 25-28 with the highest rate occurring in lebanon in the aftermath of the civil war.29 it is important to note that none of the countries in the mena region appear to have a rate of depression exceeding the global ratio. therefore, although the reported rates of depression are significantly higher for women than for men in much of the mena region, they usually do not deviate greatly from the international average.14, 30 s h i f t i n g r o l e s f o r w o m e n since the introduction of universal free education, established in oman in the 1970’s, there has been a gradual increase in female literacy and a subsequently increased entrance of females into the labour market.31 in higher education, approximately 48% of all students are male, indicating that female enrolment has now surpassed that of males.31 as in many societies in transition from traditional ways to modern and urbanised lifestyles, a central issue currently facing women in the mena region is the increasing cultural struggle between women’s traditional, mainly home-based, role as wife and mother, and their modern role in higher education and the workforce, which brings them out into the public sphere.12,31,32 attempts to balance these conflicting roles, both valued by different elements of modern mena society, may be quite stressful for women who are trying to define their place in society. this stress may cause heightened anxiety and depression due to women feeling unfulfilled in one of their roles: either not living up to their responsibility to their family and community, or neglecting their own self-actualisation and autonomy.16 recent affluence and the resultant rapid socioeconomic change in parts of the mena region have significantly impacted the status of women in some countries33 and has provided new opportunities for women. however, some experts are suggesting that this new wind of change, by virtue of its novelty is, albeit indirectly, becoming an increasing source of stress for women. for example, al-lamky31 has indicated that the rapid modernisation, made possible by economic development, has not been paralleled by an equally dramatic change in the cultural values concerning the structure or roles of the family. many other researches, from different contexts, have reached similar conclusions.20,31,34 the gist of such thinking is that a large, hierarchical, and gender-segregated family is still the norm. in reference to women, this causes friction for all family members and all the stresses such a scenario may entail. the net source of anxiety in such a situation is that women see their roles rapidly l i ya m e l o u l , a a m a l a m b u s a i d i a n d s a m i r a l a d aw i 8 evolving outside the family, but see no corresponding changes within. according to the world bank,33 in the last three decades there has been a 47% percent increase in female labour participation in the mena region. this stems partly from increased literacy among women and partly from the demands of the rapidly shifting sands of modern economies, in which it is increasingly necessary for women to work outside the home to support their family. in such a scenario which is obviously still the exception rather than the norm, women often have to juggle what may appear to be polarised roles.35 as in many parts of the world, women are still often solely responsible for childcare and care for elderly and sick family members whatever their working situation.36 although there is cause for concern about the stress inherent to shifting roles for women, from a global perspective the situation is not unique to the mena region.16 hamid et al.37 investigated the psychosocial aggregate of depression in their sample in jordan. among many variables associated with depression, the contribution of marital status merits a brief comment. married women, in contrast to widowed or separated, scored highest in the indices of depression. this implies that divorced women did not fare worse compared to married or single women. the authors speculated that ‘widows would presumably receive more sympathy and social support from their extended family system” (p. 493). it is not clear why marriage is an important equation in psychological dysfunction in women and the question remains whether marriage becomes an added a source of stress against the background of recent affluence. an extremely important social factor that applies to the entire mena region is the period of socio-economic flux of the last 40 years, due both to the end of colonisation and to the discovery of oil in parts of the region.38 this flux has resulted in an increased exposure to elements considered to be risk factors for psychological distress in some part of the mena region including sociopolitical instability, socioeconomic insecurity, factional and international conflicts, and population displacement.36, 39,40 an additional outcome of this 40 year period has been a shift in social values, especially the erosion of traditional values and norms, which in sociological parlance could be deemed fertile ground for breeding maladjustment.41 however, such a social situation is not unique to the mena region.3,36 f e r t i l i t y , m o t h e r h o o d a n d p o s t p a r t u m r i s k one strong influence on the lives of women in the mena region is fertility and child-bearing.12,42 emerging empirical evidence suggests that women who have a high rate of childbirth are more valued and respected by the significant figures in their life, by their extended families, and the community.36 this may be partly due to the perception that children are ‘god’s greatest gift’.12 such an attitude has also been observed in other cultures.43 feminine identity is deeply tied to a woman’s role as mother and such importance is placed on child bearing in some areas of the mena region that this might contribute to higher rates of anxiety and depression in women of child bearing age.14,23,44 although oman’s birth spacing initiative, launched about a decade ago, has been internationally acknowledged as highly successful, contributing to a sharp fall in fertility rates, nevertheless the birthrate in oman is still high compared to many industrialised countries.45 high fertility rates not only endow many households with large concentrations of children, but, an often overlooked corollary, increase the risk of postpartum depression. green, broome and mirabella46 and ghubash and abou-saleh47 independently sampled parturients in the u.a.e and found that 17.8% at day 7 and 22% at 3 months were diagnosed as depressed. masmoudi et al.48 assessed parturients in tunisia with the edinburgh postnatal depression scale and reported a prevalence of postpartum depression of 19.2% in the initial phase and 13.2% at follow-up. chaaya et al.49 have examined rates of postpartum depression in two regions of lebanon, one rural and the other urban. the data indicated that the prevalence of depression was 21%, with rural women having a higher tendency towards postpartum depression. in contrast, a study from industrialised countries by cooper and murray50 reported that 10% of women sampled in britain in the weeks immediately following delivery and 12.5% at 6 months were diagnosed as depressed. however, the rate of postpartum depression, from the data that could be extrapolated from the global perspective, appears to fluctuate in complex ways. comparative studies on the rate of postpartum depression globally fail to suggest that women in mena are more necessarily prone to puerperium depression than elsewhere. the rate in the mena regions still falls within 5-25% 46 as reported in other populations.51 s i l e n t e p i d e m i c o f d e p r e s s i o n i n wo m e n i n t h e m i d d l e e a s t a n d n o r t h a f r i c a r e g i o n 9 the correlates of postpartum depression were based on a handful of themes that are psychosocial and ecological in origin. among women in the u.a.e, abou-saleh and ghubash52 reported that, among numerous correlates, a history of depression appears to be critically involved in the development of postpartum psychiatric disturbance. in other regions, which nonetheless have some features similar to mena countries, various reports have reached similar conclusions. for example, among turkish women, it was found that a bad relationship with the family-in-law was an important factor that significantly increased women’s vulnerability to post-partum depression.53 among middle eastern women living in australia, nahas and colleagues 54 found that loneliness attributed to a lack of felt social support, helplessness in facing the immense duty of the traditional wife-mother role, and intense apprehension about being thought to be a bad mother by in-laws were strong predictors of postpartum depression. as the samples from such studies are derived from immigrants populations, their generalisation to the mena region is limited as immigration alone constitutes a potential stress factor.55,56 on the whole, cultural factors, as well as a higher birthrate, may increase the risk of post-partum depression. this is despite the finding that traditional postpartum rituals, common in islamic mena cultures, usually reduce the risk of postpartum depression.47,57 it is intuitive to speculate that the high birthrate and early age of first conception common in mena countries increases the likelihood of postpartum depression in middle eastern women, and that this may contribute to the higher rate of depression. net incidence of postpartum depression appears to be critically associated with childbearing and possibly exacerbated by certain nonspecific psychosocial and ecological correlates. these correlates are ubiquitous but tend to vary from culture to culture.54 h e t e r o g e n e i t y o f t h e m e n a r e g i o n a n d r e p o r t i n g b i a s the mena area is a particularly complex and difficult study location given the region’s scepticism towards the field of psychology, and the acute stigma attached to mental health disorders.58 additionally, confounding factors such as the exact definition of the mena region, as well as inherent methodological limitations in gauging subjective events like depression, pose problems when highlighting psychological disorders in this vast mosaic of a region. these two issues are entertained in tandem in the ensuing paragraphs. first, as for the conception of mena, it is often difficult to disentangle features of the islamic religion from local tribal and arab culture, and to access data where a research culture is still developing. a distinction must be made between the terms ‘arab’ and ‘muslim’, which are often incorrectly used interchangeably although they are distinctly different terms.59 ‘arab’ is a descriptor for a majority of people living across the mena region, and also for significant minority populations living in east africa, europe, north america, and elsewhere who share a linguistic and cultural connection with a semitic people originating in the arabian peninsula.60 the ubiquity of arab identity throughout the mena region is the result of 1,400 years of growth of the islamic empires, the power vacuum left after the decline of greco-roman hegemony in the region, demographic differences among local populations, and more recent seismic political stirrings and historical revisionism.10 although most arabs are muslims, the mena is home to sizeable communities of arabs whose identify includes christianity and other creeds. 61 islam is the third-largest religion in the world, stretching across southeast, south and central asia, turkey, and the mena region, as well as encompassing a considerable segment of the immigrant populations in europe and the americas. it is important to remember this when making generalizations about ‘islam’ and ‘muslims’. there is incredible regional, national and tribal variation in the practice of islam. therefore, any statement citing islamic traditions as responsible for the psychological distress of a sub-population across the muslim world stands on delicate footing, and must be able to prove that the structures in islam that are responsible for the distress are present for the majority of the muslim sub-population. secondly, it is worthwhile noting that quantification of depression in cross-cultural populations presents a number of perhaps insurmountable problems.8 although the announcement of the ‘global silent epidemic’ should be welcomed as acknowledgment of the importance of psychological distress in health and wellbeing, the idea that psychological disorders exist outside non-western populations has an interesting and complex history. jean-jacques rousseau, a leading name among philosophers during the 18th century age of romanticism, idealised those who were on the l i ya m e l o u l , a a m a l a m b u s a i d i a n d s a m i r a l a d aw i margins of the european landscape, unencumbered by the exigencies and stresses of civilisation. accordingly, ‘noble savages’ by virtue of their intimate connection with simplicity and nature were shielded from the vagaries of psychological disorders.62 such a view also found expression among the ‘fathers’ of modern psychology. holliday63 expounded the view that mental disorders are rare among ‘savages’ while maudsley 64 thought that “the morbid mental phenomenon of an insane australian savage will of necessity be different from the morbid phenomenon of an insane european, just as the ruins of a palace must be vaster and more varied than the ruins of a log hut”.54 while jean-jacques rousseau and his followers would be turning in their graves on hearing that depression is alive and kicking even in far out regions of the world, there is still room for cautionary measures in the quantification of such a protean concept as depression in cross-cultural populations. it has well been established that applying the western model of, say depression, to other parts of the world may be an example of what kleinman 65 termed the ‘category of fallacy’ that is, the reification of a nosological category developed for a particular cultural group that is then applied to a member of another culture for whom it lacks coherence and whose validity has not been established. the implication of the ‘category of fallacy’ is therefore implicit in much of the debate on the alleged higher propensity towards depression among muslim women. the ‘category of fallacy’ appears to stem partly from inherent methodological limitations in gauging subjective events like depression. nasir and alqutob66 have reported a study conducted among primary health care physicians in jordan. this qualitative study pointed out that, although depression is common among clinic attendees, the health professionals working in such settings are often bewildered, having such barriers to identification, diagnosis and intervention of depression that low mental health service utilisation results. these authors pointed out that there is a need to train physicians to identify and treat depression. there is no reliable evidence to suggest how well non-psychiatric physicians at primary health care institutions are equipped to detect depression, which is, by definition, without central features and therefore protean67 and there is no evidence that current ‘checklists’ for the diagnosis of depression are suitable for cross-cultural populations.68 similarly, understanding of psychiatric illness in the mena region is likely to be hampered by the fact that sufferers may stay underground due to stigma until their illnesses have reached an advanced stage of irreversible pathology. indeed, the pathway for care seeking often starts within the realm of traditional healing.67 another contributing factor to the disparity in depression rates across different cultural groupings across the world is likely to be reporting bias.69 on the one hand, coker70 conducted a study on the social stigma of mental disorders in egypt, and found that, although for most mental illnesses there existed no gender difference in community acceptance of mentally ill individuals, when it came to depression, women were significantly more likely to be accepted within the family than depressed males. this finding supports the hypothesis that endorsing depressive symptoms on a diagnostic survey, admitting symptoms of depression to a primary care physician, or seeing a therapist to treat depression may be more acceptable behavior for women than for men in the mena region, and that this may compound the gender bias in depression rates. in addition, men, who are generally the public face of the family in arab society, may feel a greater responsibility to hide their emotion so as not to bring shame on the family.10 on the other hand, additional family pressures may affect women’s experience of depression.71 in the context that husbands may use an accusation of mental illness against a wife, in order to gain support for taking a second wife or for obtaining a divorce. it is therefore not surprising that some studies have shown that, contrary to established wisdom, men outnumbered women in mental health care seeking.72 some studies have suggested that women are likely to ‘mask’ their depression,66,73 further confounding the issue of diagnosis of depression in the mena region. it has been noted that mental illness is not endorsed and is often construed in other idioms of distress.74 in many traditional societies including those in the mena region, it is believed that disease or ill-health is caused by a disregard for some aspect of one’s spiritual life. the role of the belief system is also embodied in how people respond to adverse events, which, in turn, might shed light on how depression is handled outside the realm of biomedical care. in traditional communities around the world, misfortune, interpersonal problems and ill health, including something akin to depression, are often attributed to supernatural causes.74 sometimes depression is seen as a manifestation of s i l e n t e p i d e m i c o f d e p r e s s i o n i n wo m e n i n t h e m i d d l e e a s t a n d n o r t h a f r i c a r e g i o n possession by a spirit whereby a person’s behaviour is thought to be controlled by an anthropomorphic being that has entered his or her body.10 to strictly biomedically trained mental health professionals, such an appearance of distress would likely be equated with ‘magical belief ’, further contributing to misdiagnosis and, in the present context, to reporting bias. another important factor that may contribute to misconceptions about depression, therefore either deflecting or inflating the situation on the ground, is the tendency of some cultural groups to express psychological distress in physical symptoms.67 in oman, women often come into a mental health clinic because of a referral from a primary care physician due to physical discomfort that has no apparent organic cause.75 there is empirical support, although not widely accepted, that in western cultures there is a tendency to ‘psychologise’ distress which can be contrasted with the tendency in non-western cultures to ‘somatise’ it. among women in the developing world, and in much of the mena region, physical symptoms are often seen as a more legitimate and morally acceptable manifestation of distress76-78 since the expression of negative feelings, and conflict of any kind, are generally seen as not acceptable.34 according to al-issa,10 in reference to the mena region, “...mood disturbance are not at all verbalized” due to cultural teaching that “expression of emotion is shameful” (p. 234). this has resulted in primarily somatic presenting complaints.75 this adds another dimension to the likelihood of misdiagnosis and contributes to reporting bias. s y n t h e s i s f r o m t h e l i t e r a t u r e o n w o m e n a n d d e p r e s s i o n depression has been suggested to be a growing public health problem in different parts of the world and likely to remain so in the foreseeable future.79 there is no single causal factor for such an emerging trend. against the background of the ongoing debate that many arab/islamic societies are generally falling short of the much heralded ‘un millennium development goals’,62 the present discourse has aimed to address whether islam may be an important catalyst for the emerging trend of depressive disorders in the mena region. the present view, which does not pretend to be exhaustive in such a mosaic region, suggests that the depression rate in women in the mena region reflects the world average, and that the stressors on women are similar to those present in many developing societies across the globe.36 the problem of increased rates of depression in women is often systemic, not necessarily cultural or religious. this would suggest that accessibility to culturally-tailored mental health services should be part of the health agenda in the region. in answer to opinions that depression rates in women in the mena region are exceptional and due to some facet of islamic teaching, we found that this could not be proven from the present review. the role of religion hinges on the assumption that there is a monolithic view and practice of islam and that islam has a single effect as a determinant of depression. as demonstrated in various studies, religious practice is considerably modified by local traditions, social conventions, and socio-demographic characteristics.80,81 the fact that measured depression rates in women from the mena region vary greatly, sometimes exceeding rates reported by men, sometimes demonstrating no significant difference, but in no case found by this paper to exceed the world average, emphasises a pluralistic experience, and underscores the role of local norms and socio-cultural and political variables in women’s experience and expression of mental health. the variability in the rate of depression would certainly point to complex social and ecological factors. data from oman attest to the complexity of this issue. the country is a higher middle income group country with little gender gap.27 yet, oman is an islamic country, though with a distinctive history and subcultures further testifying to the view that the islamic part of the world is not homogenous. studies in oman have reported that there is gender discrepancy in the presentation of mental illness, but, contrary to ideation in the literature,9 female predominance was not marked in these domains, including those that are often attributed to ‘female disorders’ such as propensity toward spirit possession,74 somatisation,75 dissociative disorders,82 eating disorders83 and social phobia.84 contrary to what would be expected in such a patriarchal society as oman, males are more likely to seek psychiatric consultations and women are therefore underrepresented in mental health care seeking. it is intuitive that gender roles found in patriarchal societies with a strong public/private dichotomy would reinforce the under-presentation of females in mental health settings. however, community surveys in oman have reached the conclusion that being female, when considered with other confounding factors, was l i ya m e l o u l , a a m a l a m b u s a i d i a n d s a m i r a l a d aw i not a significant predictor of depression.82 most studies reviewed in this paper did not distinguish the religious views of their participants, so it is difficult to determine whether there exist any differences along religious lines. if the role of religion in female depression, as opposed to societal factors, is to be accurately investigated, it will be important to conduct comprehensive comparative studies between religious minority populations and a muslim majority sample. in addition, very little data on muslim women in southeast asia is currently available. this is another important point of comparison, as this region has a significant muslim population, but retains very different cultural and social behavior. c o n c l u s i o n this paper has found a few factors common to the region that may play a role in depression among women. it is far more likely that the higher rate of depression in women in some mena countries has to do with the higher exposure to postpartum depression, as well as the changing role of women in modernising arab culture, and the stress of their resultant conflicting dual roles as the centre of the family in the home and the modern necessity of participating in the workforce. however, these factors are also common to many areas of the developing world, and are likely to play a role outside the region as well. it is important to remember that, indeed, no culture has totally overcome the marginalisation and lack of empowerment of women, and that even in developed countries, women still report a rate of depression twice as high as men. the take-home message emanating from the present discussion is that a lowered view of women, not inherent to religion, but sometimes practised in the name of socio-cultural values, may reduce self-esteem in women and increase susceptibility to depression. however, it must be noted that the mena region is by no means the extent of the muslim world, and that distinctions must be made between religious, cultural and societal aspects. most important however, it appears that ideations regarding women in the region do not fare well when considered in terms of global epidemiological surveys of gender and depression. further research is imperative to understand why women appear to be more susceptible to depression than men. in order to come to grips with this complex issue, more vigorously designed epidemiological studies are needed to quantify the situation of women in the world. as the concept of depression has no universally accepted ‘phenotype’, studies using taxonomies that are standardised for the mena region are needed to quantify the psychological functioning of women. qualitative research with focus groups to procure in-depth information on women and men in the mena region related to depression would be essential groundwork for such a quest. a c k n ow l e d ge m e n t s we acknowledge our gratitude to dr sanjay jaju, professor amin gadit and ms sabah al-bahlani for their constructive comments and suggestions. r e f e r e n c e s 1. constitution of the world health organization. geneva: world health organization, 1948. 2. stonington s, holmes sm. social medicine in the twenty-first century. plos med 2006; 3:1661-2. 3. prince m, patel v, saxena s, maj m, maselko j, phillips mr, et al. no health without mental health. lancet 2007; 370:859-77. 4. ebmeier kp, donaghey c, steele jd. recent developments and current controversies in depression. lancet 2006; 367:153-67. 5. moussavi s, chatterji s, verdes e, tandon a, patel v, ustun b. depression, chronic diseases, and decrements in health: results from the world health surveys. lancet 2007; 370:851-8. 6. murray cj. rethinking dalys. in: murray cj, lopez ad, eds. the global burden of disease. geneva: world health organization, harvard school of public health, world bank, 1996. 7. douki s, zineb sb, nacef, f, halbreich u. women’s mental health in the muslim world: cultural, religious, and social issues. j affect disord 2007; 102:177-89. 8. nikelly ag. does dsm-iii-r diagnose depression in non-western patients? int j soc psychiatry 1988; 34:316-20. 9. chesler p. women and madness. new york: palgrave macmillan, 2005. 10. al-issa i. culture and mental illness in algeria. int j soc psychiatry 1990; 36:230-40. 11. winslow ww, honein g. bridges and barriers to health: her story--emirati women’s health needs. health care women int 2007; 28:285-308. 12. moghadam vm. patriarchy in transition: women and the changing family in the middle east. in: modernizing women: gender and social change in the middle east 2nd ed. boulder, co: lynne rienner publishers, 2003. pp.137-63. s i l e n t e p i d e m i c o f d e p r e s s i o n i n wo m e n i n t h e m i d d l e e a s t a n d n o r t h a f r i c a r e g i o n 13. laird ld, de marrais j, barnes ll. portraying islam and muslims in medline: a content analysis. soc sci med 2007; 65:2425-39. 14. trivedi jk, mishra m, kendurkar a. depression among women in the south-asian region: the underlying issues. j affect disord 2007; 102:219-25. 15. abumadini ms, rahim si. psychiatric admission in a general hospital. patients profile and patterns of service utilization over a decade. saudi med j 2002; 23:44-50. 16. schwartz s. women and depression: a durkheimian perspective. soc sci med 1991; 32:127-40. 17. seeman mv. psychopathology in women and men: focus on female hormones. am j psychiatry 1997;154:1641-7. 18. kaminsky z, wang sc, petronis a. complex disease, gender and epigenetics. ann med 2006; 38:530-44. 19. mabry r, al-riyami a, morsi m. the prevalence of and risk factors for reproductive morbidities among women in oman. stud fam plann 2007; 38:121-8. 20. daradkeh tk, ghubash r, abou-saleh mt. al ain community survey of psychiatric morbidity ii. sex differences in the prevalence of depressive disorders. j affect disord 2002; 72:167-76. 21. alansari bm. gender differences in depression among undergraduates from seventeen islamic countries. soc behav pers 2006; 34:729-38. 22 el-rufaie oe, albar aa, al-dabal bk. identifying anxiety and depressive disorders among primary care patients: a pilot study. acta psychiatr scand 1988; 77:2802. 23. fido a, zahid ma. coping with infertility among kuwaiti women: cultural perspectives. int j soc psychiatry 2004; 50:294-300. 24. modabernia mj, tehrani hs, fallahi m, shirazi m, modabbernia ah. prevalence of depressive disorders in rasht, iran: a community based study. clin pract epidemol ment health 2008, 4:20. 25. el-akabawi as, fekri i. anxiety and depressive disorder among users of general practice clinic in an industrial community in cairo. egypt j psychiatry 1983; 8:107-15. 26. ghubash r, hamdi e, bebbington p. the dubai community psychiatric survey iii. soc psychiatry psychiatr epidemiol 1994; 24121-31. 27. afifi m, al riyami a, morsi m, al kharusil h. depressive symptoms among high school adolescents in oman. east mediterr health j 2006; 12:s126-37. 28. okasha a, kamel m, sadek a, lotaif zb. psychiatric morbidity among university students in egypt. br j psychiatry 1977;131:149-54. 29. karam eg. the nosological status of bereavement-related depression. br j psychiatry 1994;165:48-52. 30. weissman mm, wickramaratne p, greenwald s, hsu h, ouellette r, robins ln, et al. the changing rate of major depression. cross-national comparisons. jama 1992; 268:3098-105. 31. al-lamky a. feminizing leadership in arab societies: the perspectives of omani female leaders. women in management review 2007; 22:49-67. 32. mazawi ae. besieging the king’s tower? en/gendering academic opportunities in the gulf arab states. in: brock c, levers lz, eds. aspects of education in the middle east and north africa. oxford: symposium books, 2007. pp. 77-97. 33. world bank. gender and development in the middle east and north africa: women in the public sphere. washington, dc: world bank, 2003. 34. mirza i, jenkins r. risk factors, prevalence, and treatment of anxiety and depressive disorders in pakistan: a systematic review. br med j 2004; 328:794-7. 35. khayata gm, rizk de, hasan my, ghazal-aswad s, asaad ma. factors influencing the quality of life of infertile women in united arab emirates. int j gynaecol obstet 2003; 80:183-8. 36. world health organization. women’s mental health: an evidence based-review, geneva: who, 2000. 37. hamid h, abu-hijleh ns, sharif sl, raqab mz, mas’ad d, abbas a. a primary care study of the correlates of depressive symptoms among jordanian women. transcult psychiatry 2004; 41:487-96. 38. yousef m. development, growth and policy reform in the middle east and north africa since 1950. j econ perspect 2004;18:91-116. 39. el-sendiony mf, abou-el-azaem mg, luza f. culture change and mental illness. int j soc psychiatry 1977; 23:20-5. 40. ibrahim as, alnafie a. perception of and concern about sociocultural change and general psychopathology in saudi arabian university students. j soc psychol 1991; 131:179-86. 41. ibn khaldūn. the muqaddimah: an introduction to history. rosenthal f,transl; dawood nj, ed. princeton and oxford: bollingen series, princeton university press, 2005. 42. al-ghanim ka. the increase of fertility and its influence on development procedures: analysis of the arab women case. j soc sci 2004; 32:297-325. 43. orji eo, kuti o, fasubaa ob. impact of infertility on marital life in nigeria. int j gynaecol obstet 2002; 79:61-2. 44. kadri n, moussaoui d. women’s mental health in the arab world. in: okasha a, maj m, eds. images in psychiatry: an arab perspective, cairo: wpa publications, 2001. pp. 189-206. l i ya m e l o u l , a a m a l a m b u s a i d i a n d s a m i r a l a d aw i 45. al-rawahi s. birth spacing initiative in oman. j cult divers 2002; 9:23-6. 46. green k, broome h. mirabella postnatal depression among mothers in the united arab emirates: socio-cultural and physical factors. j psychol health med 2006; 11:425-31. 47. ghubash r, abou-saleh mt. postpartum psychiatric illness in arab culture: prevalence and psychosocial correlates. br j psychiatry 1997;170:65-8. 48. masmoudi j, tabelsi s, charfeddine f, ben ayed b, guermazzi m, jaoua a. study of the prevalence of postpartum depression among 213 tunisian parturients. gynecol obstet fertil 2008; 36:782-7. 49. chaaya m, campbell om, el kak f, shaar d, harb h, kaddour a. postpartum depression: prevalence and determinants in lebanon. arch womens ment health 2002; 5:65-72. 50. cooper pj, murray l. postnatal depression. br med j 1998; 316:1884-6. 51. stuchbery m, matthey s, barnett b. postnatal depression and social supports in vietnamese, arabic and anglo-celtic mothers. soc psychiatry psychiatr epidemiol 1998; 33:483-90. 52. abou-saleh mt, ghubash r. the prevalence of early postpartum psychiatric morbidity in dubai: a transcultural perspective. acta psychiatr scand 1997; 95:42832. 53. danaci ae, dinç g, deveci a, sen fs, içelli, i. postnatal depression in turkey: epidemiological and cultural aspects. soc psychiatry psychiatr epidemiol 2002; 37:1259. 54. nahas v, amashen n. culture care meanings and experiences of postpartum depression among jordanian australian women: a transcultural study. j transcult nurs 1999; 10:37-45. 55. appleby l, luchins dj, freels s, smith me, wasmer d. the impact of immigration on psychiatric hospitalization in illinois from 1993 to 2003. psychiatr serv 2008; 59:648-54. 56. momartin s, steel z, coello m, aroche j, silove dm, brooks r. a comparison of the mental health of refugees with temporary versus permanent protection visas. med j aust 2006; 185:357-61. 57. good b. culture and psychopathology: directions for psychiatric anthropology. in: schwartz t, white g, lutz c, eds. new directions in psychological anthropology. cambridge: cambridge university press, 1992. pp. 181-205. 58. jumaian a, alhmoud n, al-shunnaq s, al-radwan s. comparing views of medical employees and lay people towards stigma in mental health issues. jordan med j 2004; 38: 80-3. 59. fonte j, horton-deutsch s. treating postpartum depression in immigrant muslim women. j am psychiatr nurses assoc 2005; 11:39-44. 60. padela ai, shanawani h, greenlaw j, hamid h, aktas m, chin n. the perceived role of islam in immigrant muslim medical practice within the usa: an exploratory qualitative study. j med ethics 2008; 34:365-9. 61. hourani a. a history of the arab peoples. london: faber and faber, 2005. 62. kleinman a, cohen a. psychiatry’s global challenge. sci am 1997; 276:74-7. 63. holliday a. a general view of the present state of lunatics and lunatic asylums in great britain, ireland and in some other kingdoms. london: thomas & george underworld, 1828. 64. maudsley h. the physiology and pathology of mind. new york: appleton, 1867. 65. kleinman a. depression, somatization and the new cross-cultural psychiatry. soc sci med 1977; 11:3-10. 66. nasir ls, al-qutob r. barriers to the diagnosis and treatment of depression in jordan. a nationwide qualitative study. j am board fam pract 2005; 18:125-3. 67. al-sinawi h, al-adawi s. psychiatry in the sultanate of oman. int psychiatry 2006; 3:14-16. 68. al-adawi s, dorvlo as, al-naamani a, glenn mb, karamouz n, chae h, et al. the ineffectiveness of the hospital anxiety and depression scale for diagnosis in an omani traumatic brain injured population. brain inj 2007; 21:385-93. 69. groenwold rh, van deursen am, hoes aw, hak e. poor quality of reporting confounding bias in observational intervention studies: a systematic review. ann epidemiol 2008; 18:746-51. 70. coker em. selfhood and social distance: toward a cultural understanding of psychiatric stigma in egypt. soc sci med 2005; 61:920-30. 71. maziak w, asfar t, mzayek f, fouad f, kilzieh n. sociodemographic correlates of psychiatric morbidity among low-income women in aleppo, syria. soc sci med 2002; 54:1419-27. 72. el-sayed sm, maghraby mm, hafeiz hb, buckley mm. psychiatric diagnostic categories in saudi arabia. acta psychiatr scand 1986; 74:553-4. 73. al-krenawi a. women of polygamous marriages in primary health care centers. contemp fam ther 1999; 21:417-30. 74. al-adawi s, martin r g, al-salmi a, ghassani h. ment health relig & cult 2001; 4: 47-61. 75. al lawati j, al lawati n, al siddiqui m, antony sx, al naamani a, martin rg, et al. psychological morbidity in primary healthcare in oman: a preliminary study. s i l e n t e p i d e m i c o f d e p r e s s i o n i n wo m e n i n t h e m i d d l e e a s t a n d n o r t h a f r i c a r e g i o n squ j sci res: med sci 2000; 2:105-10. 76. bazzoui w. affective disorders in iraq. br j psychiatry 1970; 117:195-203. 77. bensmail ab, bentorki h, touari m. depression in algeria: cultural aspects and epidemiological evolution. psychopathologie africaine 1981: 17:143-53. 78. hamdi e, amin y, abou-saleh mt. performance of the hamilton depression rating scale in depressed patients in the united arab emirates. acta psychiatr scand 1997; 96:416-23. 79. murray cjl, lopez ad. the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. global burden of disease and injury series, vol. 1. cambridge, ma: harvard school of public health on behalf of the world health organization and the world bank, 1996. 80. al-adawi s, burjorjee rn, al-issa i. mu ghayeb: a culture-specific response to bereavement in oman. int j soc psychiatry 1997; 43:144-51. 81. alansari bm, kazem am. optimism and pessimism in kuwaiti and omani undergraduates. soc behav pers 2008; 36:503-18. 82. chand sp, al hussaini aa, martin r, mustapha s, zaidan z, viernes n, et al. dissociative disorders in the sultanate of oman. acta psychiatr scand 2000; 102:1857. 83. al-adawi s, dorvlo ass, burke d, al-bahlani s, martin rg, al-ismaily s. presence and severity of anorexia and bulimia among male and female omani and non-omani adolescents. j am acad child adolesc psychiatry 2002; 41:1124-31. 84. al-hinai ss, al-saidy o, dorvlo ass, al-riyami bms, bhargava k, northway mg, et al. culture and prevalence of social phobia in a college population in oman. in: landow mv, ed. college students: mental health and coping strategies. hauppauge, newyork: nova science publishers, 2006. pp.2-19. squ med j, december 2009, vol. 9, iss. 3, pp. 219-223 , epub. 19th dec 2009 submitted 26th october 09 accepted 8th november 09 in the august 2009 issue of squmj 2009, professor c.b. hazlett wrote about the “prerequisite for enhancing student learning outcomes in medical education”.1 basically, he discussed the three requirements for good outcomes in medical education. these include active versus passive learning, and how active learning material needs to be constructed, contextualised and cooperatively acquired. he then went on to discuss the importance of the two types of assessment: summative and formative. summative assessments determine whether the individual should pass or be promoted, while formative assessments promote lifelong learning if accompanied by appropriate feedback. feedback is of paramount importance for this to happen, a point which professor hazlett underlined. professor hazlett then pointed out that the third requirement is the alignment of curriculum, course objectives, teaching and assessments: they must complement each other. kudos goes to the college of medicine and health sciences (com&hs) at sultan qaboos university (squ) for producing a set of “assessment policy & guidelines 2009”2 soon after the implementation of the new curriculum for the medical school. on the postgraduate front, congratulations are due to the oman medical specialty board (omsb) which is currently in the midst of changing its teaching to competency-based curricula and creating detailed guidelines for resident assessment. to stress the importance of residents’ training and assessment, the royal college of physicians & surgeons of canada recently devoted four days to resident education, at an international conference “innovations in residency education”, (icre) held in victoria, british columbia, 23-26 september 2009. it is thus appropriate that the com&hs of squ and the omsb both are now directing their energies towards ensuring the alignment of the curriculum, course objectives, training and assessment. this will help ensure that we produce quality assessment tools. only such efforts can assure the triple a doctors that we all would like to produce.1 we have to embrace the alignment of these four elements. the two levels of doctors’ training (undergraduate and postgraduate) have to work in concert to achieve that goal, and they have to involve the stakeholders such as the ministry of health, the health centres, the teaching and community hospitals, and the public in general. together, they need to decide what kind of doctors we need, thus establishing what the country needs. this, in turn, will dictate the type of core competencies that need to be established for future omani graduating doctors. in this era of quality assurance and accompanying accountability, it is imperative that we change the emphasis from structure and process to outcomebased education. we then have to develop or utilise 1editor-in-chief, squ medical journal, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; 2department of radiology & molecular imaging, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman, and oman medical specialty board, muscat, sultanate of oman *to whom correspondence should be addressed. email: mjournal@squ.edu.om أدوات التقييم للدراسة الطبية التخصصية هل حنتاج إىل أدوات “صنع يف ُعمان”؟ ملك اللمكي، نيلة اللمكي editorial evaluation tools in postgraduate medical education do we need “made in oman” tools? *lamk al-lamki1 and al-neela lamki2 evaluation tools in postgraduate medical education do we need “made in oman” tools? 220 | squ medical journal, december 2009, volume 9, issue 3 the existing assessment tools necessary to ensure that tomorrow’s young doctors achieve the required levels of core competencies. the examples of assessment tools recently cited in the “assessment policy, regulations and guidelines” of the com&hs at squ2 are mainly summative tools. while these constitute an excellent beginning, they need to be supplemented by some more formative assessment tools, e.g. those that can more comprehensively assess the 7 domains [figure 1] and their accompanying core competencies suggested by the institute for international medical education (iime) as the “global minimum essential requirements in medical education”.3,4 these are the expected competencies amongst medical school graduates, but unfortunately few medical schools have assessment tools specific for these 7 domains. using summative assessments alone is not adequate, especially for the more senior clinical students, as they alone cannot ensure fulfillment of the teaching mission of the medical school. to supplement medical school training and to achieve an expert doctor after postgraduate training, we need clearly defined core competencies and appropriate assessments to go with them. such an undertaking in the postgraduate arena belongs to omsb, which must step in to define the essential core competencies and the assessment tools they want trainers to employ. omsb is currently discussing whether to have “made in oman” core competencies and accompanying assessment tools or adopt what is available elsewhere, such as those from the royal college of physicians and surgeons of canada or those from the accreditation council for graduate medical education (acgme) of usa. the canadian royal college “7 core competencies” were established in 1996 as canmeds (canadian medical education directives for specialists)5 and then modified in 2005 [figure 2]. canmeds are well established and have been adopted by many countries including canada, australia and denmark and some far eastern medical schools. acgme modified the canmeds and came up with “6 core competencies” in 1999.6 the two are basically fairly similar [table 1]. it seems that the american acgme 6 competencies are not unlike the 7 canadian ones, but the acgme has dropped the scholar, perhaps believing that it is incorporated in medical knowledge (medical expert), and the names of the competencies are different. generally speaking, omsb postgraduate medical training is more aligned to canadian than american training largely because most new trainers have received their postgraduate training in canada. it will not be easy for oman to develop its own core competencies as it took the canadians four years (1993 to 1996) to develop canmeds. it thus stands to reason that we adopt the canmeds like many other countries have done.7 traditionally, “competency in a physician” critical �inking clinical skills scientific foundations population health professional values, attitudes information management communication skills figure 1: the 7 domains of the international institute for medical education to be achieved by medical school graduates figure 2: 7 core competencies of the canadian royal college to be achieved by the end of post-graduate residency training lamk al-lamki and neela al-lamki editorial | 221 revolved around being a medical expert; however, the patient-centered care that a physician with canmeds core competencies can provide will better meet the needs of omani patients and society. if we can assure ourselves that our residents are not only good medical experts, but are also competent communicators, managers, health advocates, scholars and are professional then we are winners. thus it is logical that oman adopts these 7 core competencies from canada. to ensure that our residents acquire the 7 competencies of canmeds, we need to have good set of assessment tools. the canadians have been developing guidelines on how to assess residents and came up with “preferred tools” for each of the canmed core competencies.8 however, this is an evolving process, the tools will continue to evolve and become more specific for each competency. the different universities that train residents in canada are still struggling to come up with more definitive tools.9,10 the acgme got together with american board of medical specialists (abms) and produced a “toolbox of assessment methods”11 which is also still evolving. they have so far come up with the following tools: 1. 360-degree evaluation (by faculty/supervisors peers, subordinates, patients families, nurses, allied health professionals, other residents) 2. chart simulated recall oral examination (30 minutes by each of two examiners) 3. checklist evaluation (for specific competency components and behaviours) 4. global rating of live or recorded performance (e.g. patient care skills, communication) 5. objective structured clinical examination (osce): standardised patient encounter stations and data interpretation 6. procedure/case logs (documentation of procedures performed) 7. patient surveys (include questions about physician competency and empathy) 8. portfolios (case logs with learning evidence and resident reflection) 9. record/chart review (review of patients’ medical records by the resident) 10. simulations and models (wide array of options resembling reality) 11. standardised patient examination (examiner uses checklist or rating form during observation) 12. written examinations: multiple choice questions (mcqs), modified essay questions (meqs) or short essay examination in some form or another, most of these 12 tools are used universally and the canadians have supplemented them with some more specific assessment tools, such as, the “in training evaluation report” (iter) done during and at the end of the monthly rotation. they have also added the cex (clinical evaluation exercise) and minicex (mini clinical evaluation exercise) which perhaps can be regarded as a complement to the chart stimulated oral examination. in the minicex, the faculty member observes and rates a trainee performing a focused clinical task (e.g. history taking or physical exam). perhaps now is a good time for oman to join the effort to create the ideal assessment tools by supplementing the currently accepted tools table 1: comparison of canadian medical education directives for specialists (canmeds) and (acgme) accreditation council for graduate medical education core competencies (adapted from ref. 5) canmeds acgme medical expert medical knowledge communicator communication and interpersonal skills collaborator patient care manager system-based practice health advocate practice-based learning and improvement scholar professionalism professionalism evaluation tools in postgraduate medical education do we need “made in oman” tools? 222 | squ medical journal, december 2009, volume 9, issue 3 described above. in the process, we can tailor them for the assessment of young omani doctors and so help in moulding future medical specialty care in oman. all the above assessment tools need criteria to indicate their reliability, reproducibility, validity and educational benefit. also, how labour intense will it be to implement any of these tools? also, do they give the residents an opportunity for feedback?12 this has to be an essential companion to all assessment tools. the next question is when to employ which tools, and at what stage of residency training? to approach this question more appropriately, one has to refer to miller’s pyramid for “the assessment of clinical skills, competence and performance”[figure 3].13 the lowest level “knows” refers to the basic knowledge needed by undergraduates and junior residents. hence, the assessment tools will be those that test knowledge, such as written examinations, mcqs, etc. this is followed by “knows how” which refers to competence; here the assessment tools have to test the competence of the skills and performance expected of mid-level residents. such tools include standardised patients, simulated direct observation and oral examinations. “shows how” refers to performance and is associated with senior residents. these assessment tools have to assess high-level competence and performance; tools such as the osce, log book, and the australian “structured assessment using multiple patient scenarios” (stamps)14 are all used at this level. “does” is at the highest level in post-graduate education. in clinical skills, it involves testing performance or action. it is applicable to the learned skills of senior residents and fellows and has also been applied to physicians in practice. the possible assessment tools at this level of miller’s pyramid are multiple, yet difficult to authenticate, and several parties are working on this.15 assessment tools that are commonly used include direct observation, minicex, multisource feedback (msf) and 360 degree evaluation. standardised patients, computer-based simulation, model-driven simulation and virtual reality/haptic devices can all be used to assess “does” and also some aspects of “shows how”. all these tools are available to us. what oman needs to do now is to select which of the above tools to adopt. overall, we suggest that omani postgraduate medical educators should adopt the assessment tools of canmeds core competencies for now, but, if necessary, these can be modified and further developed in the future to suit oman’s needs. for now, however, postgraduate medical education in oman has to adopt formally some core competencies before we can decide on specific tools. this will not only help us clarify what competencies we want our young omani doctors to develop, but it will also encourage us to develop assessment tools that are truly relevant to us for the adopted competencies. either way, it is imperative that we does (action) shows how (performance) knows how (competence) knows (basic knowledge) direct observation msf standardised patients osce oral examination simulations written examinations mcqs legend: msf= multi-source feedback; osce= objective structured clinical examination; mcqs= multiple choice questions figure 3: examples of assessment tools to be used for various levels of miller’s pyramid lamk al-lamki and neela al-lamki editorial | 223 give guidance to our trainers and medical educators on the competencies that we are targeting for our young doctors and on the assessment tools to be used. as indicated, adopting the canmeds core competencies will almost inevitably mean automatic adoption of all or some of the accepted and attested assessment tools. however, let us look into what it is like to create assessment tools for our specific needs i.e. “made in oman tools”. to do so, we have to find specific weaknesses amongst our residents or areas of necessary improvement if we want them to achieve canmeds core competencies like the residents in western countries like usa, canada countries that have adopted the core competencies and accepted the assessment tools. for example, omani residents need to enhance markedly their self-directed learning, their communication skills, their motivation to acquire knowledge, and their work ethics and also overcome other possible weaknesses. these four main weaknesses of many omani residents need to be addressed in training as well as in assessment. the “made in oman” assessment tools that will have to be created to improve these weaknesses need to be of a formative type so that the residents can learn through assessment. we need to appreciate that the four examples cited as weaknesses among our residents belong to different core competencies and thus their respective omani tools of evaluation, when developed, will have to be classified accordingly. for example, self learner belongs to “scholar” and work ethic belongs to “professionalism”. each core competency will need its own assessment tools and these will vary according to the level of the resident as per miller’s pyramid. it is now a most appropriate time for oman to assess the postgraduate assessment tools as the squ medical school has recently implemented its new curriculum and has also developed its assessment tools,2 while omsb is in the final stages of decision on core competencies and revision of its assessment tools. acknowledgments figures 1 and 2 are reproduced with permission. references 1. hazlett cb. prerequisite for enhancing student learning outcomes in medical education. squ med j 2009; 9:119-23. 2. college of medicine & health sciences, squ assessment policy, regulations, & guidelines. first edition 2009. from http://www.squ.edu.om/ medicine-health/tabid/1638/default.aspx accessed oct. 2009. 3. global minimum essential requirements in medical education. from http://www.iime.org/documents/ gmer.htm accessed oct. 2009. 4. the assessment of global minimum essential requirements in medical education. from http:// w w w. i n f o r m a w o r l d . c o m / s m p p / 2 1 3 1 0 3 3 6 9 74340499/content~db=all~content=a713626660 accessed oct. 2009. 5. canmeds. from http://rcpsc.medical.org/canmeds/ index.php accessed oct. 2009. 6. acgme outcome project. from http://www.acgme. org/outcome/comp/compmin.asp accessed oct. 2009. 7. are some of the challenging aspects of the canmeds roles valid outside canada? from http:// www3.interscience.wiley.com/journal/118729511/ abstract?cretry=1&sretry=0 accessed oct. 2009. 8. the canmeds assessment tools handbook. from http://www.rcpsc.edu/canmeds/resources/ handbook_e.php accessed oct. 2009 9. mickelson jj, macneily ae. tools for implementing the canmeds competencies in canadian urology residency training from http://www.ncbi.nlm.nih. gov:80/pmc/articles/pmc2532541/ accessed oct. 2009. 10. university of toronto, faculty of medicine, post graduate medical education. from http://www. p g m e . u t o r o nt o . c a / r e s o u r ce s / c a n m e d s . ht m accessed oct. 2009. 11. acgme outcome project toolbox of assessment methods. from http://www.acgme.org/outcome/ assess/toolbox.pdf. accessed oct. 2009. 12. mcaleer s. choosing assessment instruments. in: dent ja, harden rm, eds. a practical guide for medical teachers. new york: churchill livingstone, elsevier, 2009. section 6. 13. miller ge. the assessment of clinical skills/ competence/performance. acad med 1990; 65: s63-7. 14. rural and remote health australia. from http:// www.rrh.org.au/publishedarticles/article_print_805. pdf accessed oct. 2009. 15. association for medical education in europe (amee). from http://www.amee.org/index. asp?tm=22 accessed oct. 2009. december 2008 no white pages.indd quality of relationship with supervisor and work exhaustion among nurses *unnikammu moideenkutty,1 gary blau,2 ahmed al-mandhari3 املمرضات عند العمل وانهاك مع املشرف نوعية العالقة املندري أحمد ، بلو جاري ، مويدينكتي يونيكامو الطريقة: جمعت ــان. بعم ــفى في مستش العامالت املمرضات عند العمل انهاك في ــرفني املش مع نوعية العالقات ــة أثر لدراس ــص: الهدف: امللخ العمل، انهاك مباشرعلى عكسي تأثير لها واملمرضة املشرف االيجابية بني العالقة أن ــتبيان.النتائج: ظهر اس ــتخدام باس 229 ممرضة من املعطيات اخلالصة: ظهر العائلة. شؤون بالوظيفة وباملهنة والتداخل الوظيفي في والقناعة التعليم ــتوى ومس ــة والتجربة املهنية املؤسس جتربة على وكذلك املمرضات. عند العمل انهاك بتخفيف كبير تاثير لها مع املشرف املتميزة العالقة أن عمان. مهني، والعمليات، النفسية الكلمات: الظاهرة مفتاح sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 275-282 sultan qaboos university© submitted 27th february 2008 accepted 5th july 2008 1indian institute of management kozhikode, india and department of management and college of commerce & economics, sultan qaboos university, muscat, sultanate of oman; 2temple university, fsbm hospital, philadelphia, usa; 3department of family medicine & public health and directorate, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: umoideen@squ.edu.om abstract objectives: to study the impact of quality of relationships with supervisors, operationalised as leader-member exchange (lmx), on work exhaustion among nurses working for a hospital in oman. methods: data were collected from 229 nurses using a questionnaire. results: lmx was found to be a significant negative correlate of work exhaustion directly, as well as beyond the controlled-for correlates of gender, organisation experience, occupation experience, education level, job satisfaction, occupation satisfaction and work interfering with family. conclusion: a perceived higher quality work relationship with one’s supervisor appears to have a significant impact on reducing perceived work exhaustion among nurses. keywords: psychological phenomena and processes; burnout, professional; oman. c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • leader-member exchange (lmx) was found to impact work exhaustion after controlling for a powerful collective of control variables including: gender, organisation experience, occupation experience, education level, job satisfaction, occupation satisfaction and work interfering with family. • tested for the impact of lmx on work exhaustion in a non-western sample. applications to patient care • work exhaustion and burnout may have negative implications for employee and patient safety in health care organisations. • improving the quality of work relationship between supervisors and subordinates may help to prevent health care professional burnout. changes at work, including greater global competition, increased demand for services, increased use of technology, the corporate trend towards mergers, coupled with down-sizing, and greater micromanagement, have collec-tively helped to create a more demanding work enviu n n i k a m m u m o i d e e n k u t t y, g a r y b l au a n d a h m e d a l m a n d h a r i 276 ronment for many employees.1, 2 such changes have resulted in increased levels of employee burnout and exhaustion among various kinds of health care providers in developed westernised countries, including: doctors,3 nurses,4 radiology technologists,5 directcare professionals working with the mentally disabled,6 volunteer counsellors caring for the terminally ill and medical technologists.7 employee exhaustion has not been extensively studied in health care providers outside westernised countries, i.e., generally europe, the united states, canada, australia, and israel.8 the purpose of this study is to investigate correlates of work exhaustion for nurses working in a hospital in oman. d i sti n g ui sh i n g wo r k v e r sus e moti o n a l e x h austi o n two types of employee exhaustion have been examined in the burnout literature: emotional exhaustion 9 and, more recently, work exhaustion.10 emotional exhaustion is primarily due to extensive job-required interpersonal contact, while general work exhaustion has wider application to all types of jobs. moore has defined work exhaustion as: “the depletion of emotional and mental energy needed to meet job demands”. therefore, work exhaustion is meant to encompass emotional exhaustion.11 given the wide variety of the nurses sampled in this study, it will be argued that work exhaustion was the more appropriate measure to use. many researchers have argued that emotional or work exhaustion is the key component to experiencing burnout,12 as well as the first stage of the burnout process.13, 14 moore has argued that work exhaustion should be studied as a “stand alone” outcome. work exhaustion has been empirically linked to higher job turnover intention for information technology professionals.15 the meta-analysis of lee and ashforth showed that emotional exhaustion was significantly related to increased turnover intention. r o l e o f l e a d e r me mbe r e xc h a n ge i n r e d u c i n g wo r k e x h austi o n leader-member exchange (lmx) theory16 has argued that supervisors do not use the same style in dealing with all their subordinates, but instead develop different types of relationships or exchanges, including low lmx (based strictly on formalised employment contracts and job descriptions) to high lmx (characterised by mutual trust, emotional support, respect and reciprocal influence). lmx is typically measured from the subordinate perspective; while supervisor perceived exchange (slmx) can also be measured.17 prior research has found many positive outcomes for higher lmx levels, including greater job satisfaction and commitment, stronger performance appraisal ratings, and lower stress.18, 19, 20 work exhaustion is one kind of stress. most empirical lmx research, including studies already cited, also focus on westernised country samples from europe and the united states (for a recent exception, working with a chinese work sample, see aryee & chen).21 although less empirical research has directly tested the specific relationship of lmx to work exhaustion, a negative relationship would be expected. based on the conservation of resources theory of stress of hobfoll,22 lmx would be conceptualised as a resource condition, where a resource is defined as “any object, condition, personal characteristic or energy that is valued or serves as a means of obtaining resources that are valued”. this theory suggests that work exhaustion can occur when resources, such as lmx, are lost or perceived to be inadequate. related research has found consistent negative relationships between supervisor support and emotional exhaustion across different westernised country samples of teachers, police officers, social workers, nurses and other health care professionals.23 it seems logical that higher lmx subordinates would have less work exhaustion because potential stressors such as demands and task overload are mitigated by higher levels of support from one’s supervisor.24 using a large sample of dutch university employees, bakker, demenrouti and euwena25 found that the quality of the relationship of the subordinate with the supervisor was negatively related to exhaustion. this suggests the first hypothesis: h1 – lmx will be negatively related to work exhaustion. c o n tr o l l i n g f o r oth e r c o r r e l ate s o f wo r k e x h austi o n prior research on emotional exhaustion suggests that demographics can affect work exhaustion, including gender (females higher), and work experience (positive). prior research has not controlled for both organisational and professional (occupational) work experience. although they are related, employees changing organisations generally happens much more frequently than employees changing occupations. for example, bolles26 has pointed out that the average usa worker under 35 years of age will go job-hunting in a different organisation every one to three years, while over q ua l i t y o f r e l at i o n s h i p w i t h s u p e r v i s o r a n d wo r k e x h au s t i o n a m o n g n u r s e s 277 35 year olds will go look for a change of organisations every five to eight years. bolles also points out that many individuals will change occupations at least three times before exiting the work force. workload has been found to be positively related to emotional exhaustion. consistent with the idea of increased education credentials often leading to increased workload responsibilities for health care professionals,27 education level was also controlled for, as a proxy for workload responsibilities. thus, gender, organisational and professional (occupational) experience, and education level were controlled for in this study. most prior research on burnout is cross-sectional. therefore, job satisfaction can also be conceptualised as a negative antecedent or correlate of work exhaustion, i.e., lower job satisfaction leading to higher exhaustion. to the authors’ knowledge, prior studies have not controlled for both job satisfaction and occupational satisfaction. academic research on occupational satisfaction and leaving one’s occupation suggests that this is typically a much more difficult type of work transition (versus leaving one’s organisation) due to the greater costs of retraining and human capital investment, disrupted work relationships, and lost time and income, typically associated with occupational change.28, 29, 30 thus both job satisfaction and occupational satisfaction were controlled for in this study. role conflict is positively related to emotional exhaustion. one type of role conflict is work interfering with family,31 which is also a demand on the individual. cordes and dougherty have argued that individual and organisational demands placed on employees are the key determinants of their exhaustion. blau and colleagues found that work interfering with family was positively related to work exhaustion for medical technologists working in the usa. work interfering with family was therefore also controlled for. cumulatively, this suggests the following second hypothesis: h2 – lmx will have a significant impact on explaining work exhaustion beyond the controlled for correlates of gender, organisational experience, occupational experience, education level, job satisfaction, occupational satisfaction and work interfering with family. m e t h o d s the sample consisted of nurses working at sultan qaboos university hospital (squh), a large teaching hospital in the sultanate of oman. heads of various nursing departments in the hospital were asked to distribute surveys to the nurses in their departments. as a token of appreciation for completing the survey, a packet of candy was given to each department. a box was provided in the nursing superintendent’s office for submitting completed surveys. out of 448 surveys distributed, 275 completed surveys were returned, giving a response rate of 61.38%. however, due to missing values, the final sample used for analysis consisted of 229 nurses (51.12%). we were surprised to learn during survey pre-distribution and working with hospital administration that so many of the nurses were nonomani or expatriates. therefore, we decided to control also for expatriate status in the measures section. most of the expatriate nurses were from india and the philippines, with a smaller proportion of ethnic chinese malaysians. due to the international nature of the nursing and other hospital staff, english was the official language of the hospital and proficiency in english was a requirement of employment. work exhaustion was measured using a six-item measure based on previous research. copyright restrictions and cost associated with the maslach burnout inventory, as well as survey length constraints and the diversity of nursing grades across shifts sampled, made using this general exhaustion measure more appealing. subsequent reliability analyses, including item-total statistics (statistical package for the social sciences, spss-pc, version 14), indicated that one item from the work exhaustion measure, “i am often tired or fatigued”, had a lower squared multiple correlation with the other five items, and that deleting this item would improve the alpha or internal consistency of the scale. accordingly, this item was removed and five items were retained. sample retained items are: “my job demands too much from me”, and “at times i feel like giving up at my job”. these retained items are more consistent with the definition of work exhaustion suggested by moore, “the depletion of emotional and mental energy needed to meet one’s job demands”, while the deleted item focuses more on physical energy. unless otherwise noted, all multi-item scales used a 6-point response scale, where: 1 = strongly disagree; 2 = disagree; 3 = slightly disagree; 4 = slightly agree; 5 = agree and 6 = strongly agree. leader-member exchange was measured using version 6 of the lmx scale, which is a seven item measure and well accepted in the lmx literature. a sample item is: “my supervisor understands my probu n n i k a m m u m o i d e e n k u t t y, g a r y b l au a n d a h m e d a l m a n d h a r i 278 lems and needs”. the control variables were as follows: gender was measured by indicating 0 = male, 1 = female; organisational experience was measured by asking, “you have worked for squh for…” (which category): 1 = less than one year, 2 = 1-5 years, 3 = 6-10 years, 4 = 11-20 years, and 5 = more than 20 years; occupational experience was measured by asking, “you have been a nurse for…” and the above same 5 categories were used; expatriate status was measured by asking, “you are”: 0 = omani, 1 = expatriate; education level was measured by asking respondents to “check their level of professional qualification”, using the following choices: 1 = diploma; 2 = diploma plus post-basic specialisation certificate; 3 = bachelor’s degree, and 4 = masters’ degree. the diploma is the basic qualification for being a nurse. however, the education level attained is also affected by the expatriate status variable. for example, the qualification of omani nurses is a diploma, awarded by the omani institute for health services, while the indian nurses working at the hospital would have received a bachelor’s degree based on their training in india. due to survey constraints, job satisfaction was measured using a three-item measure based on cammann, fichman, jenkins & klesh.32 a sample item is: “in general, i like my job”. occupational satisfaction was measured by creating a parallel three-item measure, again due to survey constraints. a sample item is: “overall, i like working in the nursing profession”. work interfering with family was measured using the four-item measure developed by gutek and colleagues. a sample item is: “my work takes up time that i would like to spend with family/friends or just relaxing by myself ”. beyond these formal control variables, we need to comment on shifts. shift work research, on westernised country samples, has generally shown that nurses on rotating shifts have higher job stress than nurses on fixed shifts. 33, 34 however, in the omani hospital studied, all nurses were on “permanent rotation”, i.e., everyone worked a few days of night shift, then a morning shift, and then an evening shift and so on. thus, the current shift data we collected was very temporary. we did not control for shift as part of formally testing variable name m sd 1 2 3 4 5 6 7 8 9 10 gendera 0.92 0.27 (na)b organisation experiencec 2.31 0.95 0.01 (na) occupational experiencec 3.66 0.96 0.05 0.34 (na) expatriate statusd 0.93 0.26 0.05 0.07 0.46 (na) education levele 2.04 0.95 -0.16 -0.01 -0.05 0.21 (na) job satisfaction 4.95 0.84 -0.15 0.04 0.14 0.11 -0.26 (na) occupation satisfaction 5.21 0.71 0.16 0.01 0.19 0.19 -0.20 0.70 (na) work interfering with family 3.77 1.05 -0.12 -0.06 -0.13 -0.26 -0.04 -0.31 -0.31 (na) leader-member exchange 5.02 0.67 -0.05 -0.02 -0.02 0.06 -0.08 0.43 -0.47 -0.14 (na) work exhaustion 3.06 1.01 -0.10 -0.07 -0.04 -0.11 0.11 -0.51 -0.50 0.49 -0.36 (na) note. n = 229. r > .13 (p < .05); r > .18 (p < .01) both two-tailed a gender: 0 = male, 1 = female b coefficient alpha in parentheses, na = not applicable c categories are: 1 = less than one year; 2 = 1-5 years; 3 = 6-10 years; 4 = 11-20 years; 5 = more than 20 years d expatriate status: 0 = omani; 1 = expatriate e education level: 1 = diploma; 2 = diploma plus post-basic specialization certificate; 3 = bachelor’s degree; 4 = masters degree table 1: means, standard deviations, reliabilities and correlations for all study variables q ua l i t y o f r e l at i o n s h i p w i t h s u p e r v i s o r a n d wo r k e x h au s t i o n a m o n g n u r s e s 279 h2 because of additional missing data for this variable. however, to check for the potential impact of the current shift a separate series of t-tests was performed. these tests revealed that the current shift (morning versus evening versus night) did not affect work exhaustion. r e s u l t s ge n e r a l table 1 presents the means, standard deviations, scale reliabilities, and correlations for all study variables. inspection of the scale indicates that nurses were overwhelmingly female expatriates, with high levels of job satisfaction, occupation satisfaction and leader-member exchange. this sample had prior occupational experience to that with their present employer. all multi-item scale reliabilities were over .70.35 correlation results suggest that increased education level is associated with decreased job satisfaction and occupation satisfaction. job satisfaction and occupation satisfaction, while highly related, show less than 50% overlap (r = .70), and will be retained as distinct variables. consistent with the lmx literature, job satisfaction is positively related to lmx (r = .43). consistent with the exhaustion literature, job satisfaction is negatively related to work exhaustion (r = -.51) and work interfering with family is positively related to work exhaustion (r = .49). te sts f o r h y p oth e se s the results in table 1 support hypothesis 1(h1), lmx is negatively related to work exhaustion, r = -.36 (p < .01). hierarchical regression analysis was used to test h2, and the results are shown in table 2. controlled-for correlates were stepped into the regression equation as follow: step 1 gender, organisational experience, occupational experience, education level, and expatriate status; step 2 job satisfaction and occupational satisfaction; step 3 work interfering with family, and step 4 lmx. the results show that lmx results in a very modest but still significant increase. (b = -.18, change in r2 = 1%, p < .05) in explaining work exhaustion, beyond these controlled-for correlates. as such these results support h2. overall 41% (p < .01) of the variance in work exhaustion was accounted for. d i s c u s s i o n using a unique sample of nurses in oman and a powerful collective set of control variables, this study found that leader-member exchange (lmx) had a significant impact on reducing work exhaustion. as noted earlier, research testing lmx and work exhaustion variables in non-western samples is less prevalent. as described earlier, the expatriate nurses came from variable entered b adjusted r2 change r2 r2 significant f change gender organisation experience occupational experience expatriate status education level -0.07 -0.10 -0.01 0.03 0,02 2.00 job satisfaction occupation satisfaction -.27** -.26** 0.29 0.27 43.77** work interfering with family .34** 0.40 0.11 39.71** leader-member exchange -0.18* 0.41 0.01 4.04* note. n = 229, * p < .05; ** p < .01 (two-tailed) table 2: hierarchical regression for explaining work exhaustion u n n i k a m m u m o i d e e n k u t t y, g a r y b l au a n d a h m e d a l m a n d h a r i 280 india, the philippines and a smaller proportion from malaysia. to the authors’ knowledge, research has not tested for the impact of lmx on work exhaustion using a research design with as many relevant control variables. particularly in health care settings, where burnout and work exhaustion are too often found, 36 the importance of a perceived higher quality work relationship with one’s supervisor in reducing perceived exhaustion cannot be underestimated. there are some limitations to this study. from a measurement perspective, the high mean levels for the job and occupation satisfaction and lmx variables, while reassuring to the participating hospital, undoubtedly contributed to lower correlational findings through restriction of range. survey length constraints necessitated using proxy variables, such as education level for increasing task responsibilities. future research directly testing the relationship of task responsibilities to work exhaustion and burnout is needed. such constraints also necessitated using very short measures of job satisfaction and occupational satisfaction. although adequate reliabilities were found for both measures, testing the robustness of findings using more common job satisfaction measures, such as the job diagnostic survey37 is recommended. as noted earlier, work exhaustion was only partially measured, due to cost and survey length, and broader sample applicability issues. the measure of work exhaustion used demonstrated strong internal consistency (alpha = .81) and has been previously used.7 certainly testing for the impact of lmx on overall burnout and its specific components, emotional exhaustion, depersonalisation, and diminished personal accomplishment would be useful. while the maslach burnout inventory or mbi is still the most common measure of overall burnout, and its components, problems have been noted with the mbi and alternative measures do exist.38 studying the relationships of lmx to different types of burnout and its component measures is clearly needed in other health care organisation settings. a limitation of the research design is the focus on one demand, work interfering with family. given more survey space, it would have been desirable to have focused on other demands such as physical and emotional work demands. bakker and colleagues found some support for quality of relationship with one’s supervisor significantly interacting with work demands to decrease work exhaustion, which is consistent with the demand-control model of karasek.39 unfortunately, we did not find that lmx interacted with work interfering with family to affect work exhaustion. casting a ‘broader net’ of work demand variables, to test for such interactive effects would have been useful, and is highly recommended for future research. all data was collected at one point in time so that causal inference is limited. in addition, there is a common method variance problem since all data is selfreport. future research testing the impact of lmx on work exhaustion by assessing supervisor-perceived exchange or smlx40 is also needed. in order to test for the impact of common method variance on our results, we performed the harman one-factor test.41 if such a test shows that the majority of the covariance between independent and dependent variables loads on one factor, then method variance is a problem. we factor analysed all study variables and found seven factors with eigenvalues over one, including the first factor which only accounted for 28% of the cumulative covariance. given that our ratio of number of study respondents to total number of items in the scale of 229/27 (almost 9:1) was far over the minimum recommended of 5:1 for stable factor analysis,42 we are confident that method variance alone is not driving our results. future research designs working with lmx, work exhaustion, and burnout in health care organisation settings should include other antecedent and outcome variables. for example, lapierre, hackett and taggar recently found that the reverse of work interfering with family (wif) which is measured as family interfering with work (fiw), has a negative relationship to lmx. using a longitudinal research design and a sample of spanish teachers, carmona, buunk, peiro, rodriguez and bravo43 found that social comparison and coping style affected self-reported burnout over time. more specifically, the social comparison of downward identification, e.g., “when i see colleagues who are doing worse, i experience fear that my future will be similar”, was positively associated with burnout, while using a direct coping style, e.g., “planning ahead”, was negatively associated with burnout. in addition, the implication of work exhaustion and burnout for motivating health care professionals to change their occupations44 makes it important to continue to study in non-westernised countries. though the nurses were of different nationalities, we grouped them together as expatriates. perhaps future studies can examine if there q ua l i t y o f r e l at i o n s h i p w i t h s u p e r v i s o r a n d wo r k e x h au s t i o n a m o n g n u r s e s 281 are national differences in the relationship between the quality of relationship with a supervisor and work exhaustion. future studies could also use qualitative methods to uncover the nuances of the relationship between supervisors and employees and their effects on perceived work exhaustion. c o n c l u s i o n as already noted, from a practical implications perspective, this study shows the importance of a perceived higher quality work relationship with the supervisor in reducing perceived work exhaustion. prior research strongly suggests that work exhaustion is the key component to experiencing burnout, as well as the first stage of the burnout process.45 therefore a high quality work relationship with the supervisor may help to prevent burnout among health care professionals. we were surprised at the high ratio of expatriate to omani nurses who participated in the study. staffing requirements for many types of organisations, including health care, may necessitate the need to hire and retain expatriates.46 given the overwhelming percentage of expatriates comprising our sample (93%) we were not able to realistically test the impact of expatriate status on work exhaustion. to the extent that burnout may be more prevalent among expatriates, due to work and non-work factors (e.g., cultural differences in work settings, less family support), this is important for future research.47 finally, work exhaustion and burnout may have negative implications for employee and patient safety in health care organisations.48 we hope this paper stimulates follow-up research on such issues. r e f e r e n c e s 1. maslach c, leiter m. the truth about burnout. san francisco: jossey-bass, 1997. 2. uchitelle l. the disposable american: layoffs and their consequences. new york: knopf, 2006. 3. bakker a, van der zee k, lewig k, dollard m. the relationship between the big 5 personality factors and burnout: a study among volunteer counselors. j soc psychol 2006; 146:31-50. 4. aiken l, clarke s, sloane d, sochalski j, busse r, clarke, h, et al. nurses’ reports on hospital care in five countries. health affairs 2001; may/june:1-8. 5. akroyd d. survey reveals radiologic technologists affected by burnout. news across the profession 2001; december 18, 2001. from http://asahp.org. accessed sept 2006. 6. van dierendonck d, schaufeli w, buunk b. the evaluation of an individual burnout intervention program: the role of inequity and social support. j appl psychol 1998; 83:392-407. 7. blau g, surges tatum d, ward-cook k. correlates of work exhaustion for medical technologists. j allied health 2003; 32:148-157. 8. shirom a. reflections on the study of burnout. work & stress 2005; 19:263-270. 9. maslach c, jaskson s. the maslach burnout inventory. palo alto, ca: consulting psychologists press, 1986. 10. moore j. why is this happening? a causal attribution approach to work exhaustion consequences. acad management rev 2000; 25:335-349. 11. schaufeli w, leiter m, kalimo r. the general burnout inventory: a self-report questionnaire to assess burnout at the workplace. paper presented at work, stress and health: creating healthier workplaces, washington, dc, 1995. 12. bakker a, schaufel, w, sixma h, bosveld w, van dierendonck d. patient demands, lack of reciprocity and burnout: a five-year longitudinal study among general practitioners. j organis behav 2000; 21:425-441. 13. cordes c, dougherty t. a review and integration of research on job burnout. acad management rev 1993; 18:621-656. 14. lee r, ashforth b. a meta-analytic examination of the correlates of the three dimensions of job burnout. j appld psychol1996; 81:123-133. 15. moore j. one road to turnover: an examination of work exhaustion in technology professionals. mis quarterly 2000; 24:141-168. 16. liden r, maslyn j. multidimensionality of leader-member exchange: empirical assessment through scale development. j management 1998; 24:43-72. 17. schriesheim c, castro s. cogliser c. leader-member exchange (lmx) research: a comprehensive review of theory, measurement, and data-analytic practices. leadership quarterly 1999; 10:63-113. 18. gerstner c, day d. meta-analytic review of leadermember exchange theory: correlates and construct issues. j appl psychol 1997; 82:827-844. 19. schyns b, paul t, mohr g, blank h. comparing antecedents and consequences of leader-member exchange in a german working context to findings in the us. eur j work & organis psychol 2005; 14:1-22. 20. van bruekelen w, konst d, van der vlist r. effects of lmx and differential treatment on work unit commitment. psychol reports 2002; 91:220-230. 21. aryee s, chen z. leader-member exchange in a chinese context: antecedents, the mediating role of psychological empowerment and outcomes. j bus res u n n i k a m m u m o i d e e n k u t t y, g a r y b l au a n d a h m e d a l m a n d h a r i 282 2006; 59:793-801. 22. hobfoll s. conservation of resources: a new attempt at conceptualizing stress. amer psychologist 1989; 44:513524. 23. halbesleben j. sources of social support and burnout: a meta-analytic test of the conservation of resources model. j appl psychol 2006; 91:1134-1145. 24. harris k, kacmar k. too much of a good thing: the curvilinear effect of leadermember exchange on stress. j soc psychol 2006; 146:65-84. 25. bakker a, demerouti e, euwena, m. job resources buffer impact on job demands and burnout. j occup health psychol 2005; 10:170-180. 26. bolles r. what color is your parachute? berkeley, ca: ten speed press, 2006 27. american medical association. health professions: career and education directory. 30th ed. chicago: ama press, 2002-2003. 28. blau g. job, organizational, and professional context antecedents as predictors of intent for inter-role work transitions. j voc behav 2000; 56:330-345. 29. carson k, carson p, bedeian, a. development and validation of a career entrenchment measure. j occup organiz psychol 1995; 68:301-320. 30. neapolitan j. occupational change in mid-career: an exploratory investigation. j voc behav 1980; 16:212225. 31. gutek b, searle s, klepa l. rational versus gender role explanations for work-family conflict. j appl psychol 1991; 76:560-568. 32. cammann c, fichman m, jenkins d, klesh j. in: seashore s, lawler e, mirvis p, cammann c, eds. assessing organizational change: a guide to methods measures and practices. new york: john wiley, 1983. p. 71-138. 33. baba v, jamal m. routinization of job context and job content as related to employees’ quality of working life: a study of canadian nurses. j organiz behav 1991; 12:379-386. 34. jamal m, baba v. shiftwork and department-type related to job stress, work attitudes and behavioral intentions: a study of nurses. j organiz behav 1992; 13:449464. 35. nunnally j. psychometric theory. 2nd ed. new york: mcgraw hill, 1978. 36. lee j, akhtar s. influences of stressors and coping resources on job burnout among nurses. academy of management proceedings, health care management conference paper abstracts 2003; 8-9. 37. hackman r, oldham g. development of the job diagnostic survey. j appl psychol 1975; 60:159-170. 38. demerouti e, bakker a, nachreiner f, schaufeli w. the job demands-resources model of burnout. j appl psychol 2001; 86:499-512. 39. karasek r. in: j. stellman, ed. encyclopedia of occupational health and safety. geneva: international labour organisation, 1998. p. 34.6 – 34.14. 40. greguras g, ford j. an examination of the multidimensionality of supervisor and subordinate perceptions of leader-member exchange. j occup & organiz psychol 2006; 79:433-465. 41. podsakoff p, organ d. self-reports in organizational research: problems and prospects. j management 1986; 12:531-544. 42. gorsuch r. factor analysis. hillsdale, nj: erlbaum associates, 1983. 43. carmona c, buunk a, peiro j, rodriguez i, bravo m. do social comparison and coping styles play a role in the development of burnout? cross-sectional and longitudinal findings. j occup & organiz psychol 2006; 79:8599. 44. jackson s, schwab r, schuler r. toward an understanding of the burnout phenomenon. j appl psychol 1986; 71:630-640. 45. lee r, ashforth b. a longitudinal study of burnout among supervisors and managers: comparisons between the leiter and maslach (1988) and golembiewski et al. (1986) models. organiz behavior & hum decis processes 1993; 54:369-398. 46. mezias j, scandura t. a needs driven approach to expatriate adjustment and career development: a multiple mentoring perspective. j int business studies 2005; 36:519-538. 47. bhanugopan r, fish a. an empirical investigation of job burnout among expatriates. personnel rev 2006; 35:449-468. 48. naveh e, katz-navon t, stern z. the mediation and moderation effects of safety climate and structure on safety performance. academy of management proceedings, health care management conference paper abstracts, 2003. p.11. 1 submitted 27 jun 22 1 revision req. 20 jul 22; revision recd. 25 jul 22 2 accepted 3 aug 22 3 online-first: august 2022 4 doi: https://doi.org/10.18295/squmj.8.2022.046 5 6 monkeypox outbreak 7 more queries posed as cases globally soar 8 *salah t. al awaidy,1 faryal khamis,2 malik sallam,3 ramy m. ghazy,4 9 hassan zaraket5 10 11 1office of health affairs, ministry of health, muscat, oman; 2adult infectious diseases, 12 department of medicine, royal hospital, ministry of health, muscat, oman; 3department of 13 pathology, microbiology and forensic medicine, school of medicine, the university of 14 jordan, amman, jordan; 4high institute of public health, alexandria university, egypt; 15 5department of experimental pathology, immunology and microbiology, american 16 university of beirut, lebanon. 17 *corresponding author’s e-mail: salah.awaidy@gmail.com 18 19 introduction 20 emerging and re-emerging infectious diseases outbreaks are on the rise, with devastating 21 effects on people's health, society, and economy.1 an outbreak of human monkeypox (hmpx) 22 in multiple non-endemic countries has been announced by the world health organization 23 (who) in early may 2022 with the majority of cases having no confirmed travel to endemic 24 countries.2 the causative agent, monkeypox virus (mpxv), was isolated for the first time in 25 1958 by the staten’s serum institute in copenhagen, denmark.3 the virus is classified as a 26 species within the orthopoxvirus genus together with variola virus, the causative agent of 27 smallpox.4 the mpxv causes similar, albeit less severe clinical manifestations compared to 28 smallpox with lower case-fatality rate (cfr).4 29 30 monkeypox is considered a zoonotic disease, being transmitted from animals to humans with 31 limited chains of human-to-human transmission.5 the hmpx cases were frequently detected 32 near tropical rainforests, the habitat of a variety of animals known to harbour mpxv.5 33 2 examples of these animals include squirrels, gambian rats, dormice, monkeys of various 34 species, among other animals; however, the definitive animal reservoir of mpxv remains 35 unknown.4,5 prior to the current outbreak in non-endemic countries, hmpx has been endemic 36 in central and west africa.4 occasional outbreaks outside africa were linked to history of 37 travel or imported animals from endemic regions.4,5 38 39 the hmpx is a contagious infection that leaves a distinctive rash, following exposure via close 40 contact with an infected animal's bodily fluids or through a bite. it can also be acquired through 41 preparation of bush meat or with infectious sores, scabs, or body fluids (in human-to-human 42 transmission), or through respiratory secretions. the incubation period ranges from 5 to 21 43 days.6,7 the prodromal phase, which may not manifest in all cases, resembles influenza illness 44 and includes fever, headache, backache, lymphadenopathy and fatigue.8 following the 45 prodrome, the affected individuals develop a rash, initially macular that evolves to papules, 46 vesicles then pustules within 1-5 days.6 the skin lesions could be present on the hands, feet, 47 chest, face, genitalia or the anus.6,8 before healing, the pruritic skin lesions evolve through a 48 number of phases, eventually forming scabs.8 enanthems could occur as well, involving the 49 mouth, vagina or anus.8 complications such as sepsis, pneumonia, bacterial super-infection, 50 vision loss, skin scarring, encephalitis, dehydration, skin pigmentation, and death may occur.9 51 the smallpox vaccines used in the past are 85% effective in preventing hmpx, however, its 52 use has ceased since the eradication of smallpox.10 more recently, a novel two-dose vaccine 53 based on the modified attenuated vaccinia virus was approved. in addition, antivirals such as 54 tecovirimat, which was licensed by the european medicines agency (ema) in 2022, are 55 available, albeit with limited or no human safety and efficacy data.11 56 57 global burden of hmpx 58 before the ongoing 2022 hmpx outbreak, a majority of infections that were reported in the 59 endemic regions were caused by animal to human spillover, with rare cases of human-to-human 60 transmission that primarily involved household contacts.7 however, the present epidemic 61 serves as a reminder of how viruses capable of sustained human transmission can emerge 62 suddenly.12 63 64 until recently, hmpx was limited to west and central africa, where the virus can be found 65 in several animal species.5,13 and dominated by two separate clades, one of which is exclusive 66 to the congo basin and the other is prevalent in west africa.4 the congo basin lineage is 67 3 expected to be more contagious and has historically been associated with more severe illness 68 and a higher case fatality rate (cfr, 10.6% 95% ci 8.4-13.3%).4, 11 69 it has been confirmed that the west african clade is indeed the clade associated with the 70 current hmpx outbreak and is characterized by a lower cfr (3.6%, 95% ci 1.7 – 6.8%).14 71 an important and urgent call for modification of the mpxv clades’ nomenclature has been 72 advocated to make it non-discriminatory and non-stigmatizing with reliance on arabic 73 numerals for clade assignment rather than geographic location.15 74 75 the cumulative number of confirmed hmpx cases that have been reported to who exceeded 76 3500 and one fatality reported from 50 countries between april and till 27 june 2022.16 these 77 cases were reported in four different who regions namely the region of the americas, the 78 european, eastern mediterranean, and western pacific regions in countries where mpxv is 79 not endemic.16 the vast majority of confirmed hmpx cases were reported from the who 80 european region and the region of the americas [figure 1]. 81 82 the second meeting of who held on 23 june 2022, concurred with the international health 83 regulations (ihr) emergency committee that multi-country monkeypox outbreak does 84 presently constitute a public health emergency of international concern (pheic). the current 85 ongoing hmpx outbreak presents a moderate danger to global public health according to the 86 who.2 contrary to the previous hmpx cases in the endemic regions, no linkages to animals 87 have been traced amid the ongoing outbreak, and the initial cases were reported in europe, 88 which may hint that the virus could have been circulating between people for months 89 unnoticed.6,18 90 91 since the first recorded case in april 2022, no fatalities have been recorded so far amid the 92 ongoing outbreak in previously non-endemic countries as a result of the disease.2 males make 93 up the majority of confirmed cases of monkeypox, and the majority of these cases were among 94 males who have sex with males (msm) in densely populated metropolitan settings.2 in 95 addition, more cases of hmpx have been recorded in the who african region, where the 96 disease is endemic with 1536 suspected cases since the start of the year 2022, of which 59 cases 97 have been confirmed and 72 fatalities have been recorded.2 worth mentioning that contrary to 98 the relatively high case fatality rate in africa, the lack of fatalities in the current outbreak 99 outside africa could be linked to early detection of cases and quality of health care including 100 the use of antivirals and prophylactic vaccines. 101 4 102 the ongoing detection of the virus and the reported deaths in several african countries 103 underpin the urgent need to better understand the source and the transmission dynamics of the 104 diseases and to provide people with the knowledge and resources they need to safeguard 105 themselves and others in a variety of situations. 106 107 measures needed to mitigate and stop the spread. 108 the public health hazards of hmpx is on rise, with ongoing transmission of the virus and 109 potential spread to people at higher risk of development of severe illness, such as pregnant 110 women, young children and those with impaired immune systems (immune-compromised 111 individuals), as virus seizes the opportunity to establish itself as a resident human pathogen.19 112 113 in the context of the current multi-country hmpx outbreak, and at this stage, it is vital to 114 establish reliable and efficient surveillance at a national level, since failure to do so raises the 115 risk of undetected cases and uncontrolled spread of the outbreak to additional regions/countries. 116 117 another issue to be considered is that the majority of cases have been reported among msm 118 or in healthcare settings. therefore, the countries are recommended to seek out overlooked 119 cases while conducting contact tracing. testing and identification of suspected cases are 120 essential to monitor the progress of the outbreak and to direct the vaccination programs. 20 121 122 moreover, since a majority of emerging infectious disease incidents that afflicted humans in 123 the recent era were zoonotic in nature, the importance of proactive zoonotic and animal 124 surveillance activities should be highlighted.20 125 126 regarding the utility of smallpox vaccinations for the prevention of hmpx, the who released 127 interim recommendations, stating that vaccination should only be used when necessary and 128 does not advocate widespread hmpx immunization.21 to learn more about the effectiveness 129 of vaccines as they are used in the current situation, the countries are required to cooperate in 130 the adoption of standardized research protocols tackling this aim. 131 the who endorsed the use of vaccines in the fight against the outbreak. vaccination of 132 contacts cases, and post-exposure prophylaxis (pep) including health care workers, 133 researchers dealing with orthopoxviruses, and clinical lab technicians to be provided 134 5 preferably within four days of the initial exposure, in order to avoid the start of illness in 135 these contacts.21 136 in addition to the need of information on hmpx vaccinations and their usage 137 recommendations for exposed individuals, as well as antivirals and the necessity of deploying 138 these vaccines and antivirals where they are required. in january 2022, the european 139 medicines agency authorized tecovirimat, an antiviral originally designed to fight 140 monkeypox, for the treatment of monkeypox. in the context of a monkeypox epidemic, there 141 is a limited of experience with these therapies.21 additionally, it is crucial to improve 142 laboratory and diagnostic capabilities, clinical management, and measures to prevent and 143 control infection in health care and community settings. 144 145 conclusions and the way forward 146 the rapid transmission of hmpx and its widespread detection in various countries 147 worldwide can be viewed as an emergency of international concern.2 the current multi-148 country outbreak of the disease is evolving, with potential risk of further spread if swift 149 containment interventions are not promptly devised and followed. 150 151 the cfr observed in the african region in contrast to what we are seeing outside of africa 152 outbreak highlights the need for assistance involving all response components, including but 153 not limited to community awareness-raising, risk communication, human and animal 154 surveillance, diagnostic and laboratory assistance, and regional research and analysis of 155 antivirals and vaccines. this is critical to curb the current outbreak but also prevent future 156 ones at their source. countries that have recently been impacted by hmpx and those that 157 have experienced it for a long time need vigilant intervention measures. 158 159 to contain mpxv transmission, we call for an urgent action to interrupt the chains of virus 160 spread in non-endemic and endemic countries. a special attention should be focused on 161 ensuring effective surveillance in highly vulnerable groups in terms of exposure or disease 162 severity with cautious approach to avoid potential stigmatization of these groups.22 163 currently, global and regional public health authorities are recommended to: (1) amend the 164 law to enable it to list hmpx as a notifiable disease; (2) ensure robust surveillance with 165 emphasis of zoonotic disease surveillance in place by all countries, including appropriate 166 contact-tracing, isolation and care of patients; (3) call for immediate involvement by the 167 national advisory committees and panels of scientific experts and groups to formulate the 168 6 roadmap necessary to limit and contain the threat of hmpx. the who recommends that 169 potential cases should be reported immediately and investigated within 48 hours; and the 170 health professionals need to be aware and involved in the developing epidemic management 171 framework that has proven successful in other contexts for effective planning and response 172 owing to the nature of disease propagation in an outbreak environment.23 173 174 without increased and efficient efforts, we run the risk of the progress we have made toward 175 controlling this illness worldwide. collaborative efforts especially at the national levels are 176 urgently needed worldwide to provide accurate and reliable information about the disease to 177 the general population as well as to most-at-risk group which can help to halt the virus spread. 178 179 authors’ contribution 180 sa, fk generated the idea. sa, fk, ms, rg and hz designed and structured the manuscript. 181 sa, ms, hz, rg and fk drafted the manuscript. sa, ms, rg, hz and fk performed the 182 literature review and information extraction. sa, fk, ms, rg and hz revised and critically 183 reviewed the manuscript. all authors approved the final version of the manuscript. 184 185 references 186 1. baker re, mahmud as, miller if, rajeev m, rasambainarivo f, rice bl, et al. infectious 187 disease in an era of global change. nature reviews microbiology. 2022/04/01 188 2022;20(4):193-205, doi:10.1038/s41579-021-00639-z. 189 2. who | world health organization. multi-country monkeypox outbreak: situation update. 190 from: https://www.who.int/emergencies/disease-outbreak-news/item/2022-don390 191 accessed: june 2022. 192 3. magnus pv, andersen ek, petersen kb, birch-andersen a. a pox-like disease in 193 cynomolgus monkeys. acta pathologica microbiologica scandinavica. 194 1959;46(2):156-176, doi:https://doi.org/10.1111/j.1699-0463.1959.tb00328.x. 195 4. bunge em, hoet b, chen l, lienert f, weidenthaler h, baer lr, et al. the changing 196 epidemiology of human monkeypox—a potential threat? a systematic review. plos 197 neglected tropical diseases. 2022;16(2):e0010141, doi:10.1371/journal.pntd.0010141. 198 5. rimoin anne w, mulembakani prime m, johnston sara c, lloyd smith james o, kisalu 199 neville k, kinkela timothee l, et al. major increase in human monkeypox incidence 30 200 years after smallpox vaccination campaigns cease in the democratic republic of congo. 201 https://www.who.int/emergencies/disease-outbreak-news/item/2022-don390 7 proceedings of the national academy of sciences. 2010/09/14 2010;107(37):16262-16267, 202 doi:10.1073/pnas.1005769107. 203 6. vivancos r, anderson c, blomquist p, balasegaram s, bell a, bishop l, et al. 204 community transmission of monkeypox in the united kingdom, april to may 2022. 205 eurosurveillance. 2022;27(22):2200422, doi:doi:https://doi.org/10.2807/1560-206 7917.es.2022.27.22.2200422. 207 7. nolen ld, osadebe l, katomba j, likofata j, mukadi d, monroe b, et al. extended 208 human-to-human transmission during a monkeypox outbreak in the democratic republic 209 of the congo. emerg infect dis. 2016;22(6):1014-1021, doi:10.3201/eid2206.150579. 210 8. minhaj fs, ogale yp, whitehill f, et al. monkeypox outbreak — nine states. mmwr 211 morb mortal wkly rep. 2022;2022(71):764–769, doi:10.15585/mmwr.mm7123e1. 212 9. beer em, rao vb (2019) a systematic review of the epidemiology of human monkeypox 213 outbreaks and implications for outbreak strategy. plos neglected tropical diseases 13(10): 214 e0007791. https://doi.org/10.1371/journal.pntd.0007791 215 10. who | world health organization. monkeypox fact sheet. from: 216 https://www.who.int/news-room/fact-sheets/detail/monkeypox accessed: july 2022. 217 11. saxena sk, ansari s, maurya vk, kumar s, jain a, paweska jt, tripathi ak, abdel-218 moneim as. re-emerging human monkeypox: a major public-health debacle. j med virol. 219 2022 jun 1. doi: 10.1002/jmv.27902. epub ahead of print. pmid: 35652133. 220 12. sklenovská n, van ranst m. emergence of monkeypox as the most important 221 orthopoxvirus infection in humans. frontiers in public health. 2018-september-04 2018;6, 222 doi:10.3389/fpubh.2018.00241. 223 13. bunge em, hoet b, chen l, lienert f, weidenthaler h, et al. (2022) the changing 224 epidemiology of human monkeypox—a potential threat? a systematic review. plos 225 neglected tropical diseases 16(2): e0010141. from: 226 https://doi.org/10.1371/journal.pntd.0010141 227 14. selhorst p, rezende am, de block t, coppens s, smet h, mariën j, et al. belgian case of 228 monkeypox virus linked to outbreak in portugal. 2022; from: 229 https://virological.org/t/belgian-case-of-monkeypox-virus-linked-to-outbreak-in-230 portugal/801. accessed: june 2022. 231 15. happi c, adetifa i, mbala p, njouom r, nakoune e, happi a, et al. urgent need for a 232 non-discriminatory and non-stigmatizing nomenclature for monkeypox virus. from: 233 https://virological.org/t/urgent-need-for-a-non-discriminatory-and-non-stigmatizing-234 nomenclature-for-monkeypox-virus/853 accessed june 2022. 235 https://virological.org/t/urgent-need-for-a-non-discriminatory-and-non-stigmatizing-nomenclature-for-monkeypox-virus/853%20accessed%20june%202022 https://virological.org/t/urgent-need-for-a-non-discriminatory-and-non-stigmatizing-nomenclature-for-monkeypox-virus/853%20accessed%20june%202022 8 16. who | world health organization. multi-country monkeypox outbreak: situation 236 update. from: https://www.who.int/emergencies/disease-outbreak-news/item/2022-don396 237 accessed: june 2022 238 17. who | world health organization. the global distribution of human monkeypox. from: 239 https://www.who.int/emergencies/disease-outbreak-news/item/2022-don396. accessed july 240 2022. 241 18. adler h, gould s, hine p, snell lb, wong w, houlihan cf, et al. clinical features and 242 management of human monkeypox: a retrospective observational study in the uk. the 243 lancet infectious diseases. 2022, doi:10.1016/s1473-3099(22)00228-6. 244 19. reynolds mg, damon ik. outbreaks of human monkeypox after cessation of smallpox 245 vaccination. trends microbiol. 2012/02/01/ 2012;20(2):80-87, 246 doi:10.1016/j.tim.2011.12.001. 247 20. who | world health organization. questions and answers for monkeypox. from: 248 https://www.who.int/news-room/questions-and-249 answers/item/monkeypox?gclid=cjwkcajwrnmwbha4eiwahbjeqm3ca4rcohxbks5p250 d65waownh7yvkp4-s9sfmgdwqpbu0izuqqzkthociogqavd_bwe accessed: july 251 2022. 252 21. who | world health organization. vaccines and immunization for monkeypox: interim 253 guidance, 14 june 2022. from: https://www.who.int/publications/i/item/who-mpx-254 immunization-2022.1 accessed: june 2022. 255 22. bragazzi nl, khamisy-farah r, tsigalou c, mahroum n, converti m. attaching a 256 stigma to the lgbtqi+ community should be avoided during the monkeypox epidemic. 257 journal of medical virology. 2022/06/02 2022;n/a(n/a), 258 doi:https://doi.org/10.1002/jmv.27913. 259 https://www.who.int/emergencies/disease-outbreak-news/item/2022-don396 https://www.who.int/news-room/questions-and-answers/item/monkeypox?gclid=cjwkcajwrnmwbha4eiwahbjeqm3ca4rcohxbks5pd65waownh7yvkp4-s9sfmgdwqpbu0izuqqzkthociogqavd_bwe https://www.who.int/news-room/questions-and-answers/item/monkeypox?gclid=cjwkcajwrnmwbha4eiwahbjeqm3ca4rcohxbks5pd65waownh7yvkp4-s9sfmgdwqpbu0izuqqzkthociogqavd_bwe https://www.who.int/news-room/questions-and-answers/item/monkeypox?gclid=cjwkcajwrnmwbha4eiwahbjeqm3ca4rcohxbks5pd65waownh7yvkp4-s9sfmgdwqpbu0izuqqzkthociogqavd_bwe 9 260 figure 1: the global distribution of human monkeypox (hmpx) cases as of 27 june 2022.17 261 1department of psychiatry, oman medical specialty board, muscat, oman; departments of 2medicine and 3neurology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: mzadjali-89@hotmail.com post-covid-19 guillain-barré syndrome a case report from oman *mohammed m. al-zadjali,1 emaad al shibli,2 mohammed al maskari,2 arunodaya r. gujjar,3 abdullah al asmi3 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 409–412, epub. 25 aug 22 submitted 16 feb 21 revision req. 29 mar 21; revision recd. 22 apr 21 accepted 20 may 21 bilateral lower limb weakness and numbness. the symptoms evolved over few hours with numbness starting at his feet followed by heaviness in his legs and the inability to walk. the patient noted weakness and numbness in his upper limbs and also reported mild dysphagia starting a few days prior to the symptoms. he denied any difficulty in breathing, had normal bowel motions and showed no new urinary symptoms. there was no past medical history of any neurological symptoms. the patient also denied any history of smoking or alcohol consumption. on admission, the patient was alert, oriented and was in no pain or distress. he had a heart rate of 56 beats/minute, blood pressure of 162/96 mmhg, respiratory rate of 18 breaths/minute and oxygen saturation of 100% on room air. his random blood sugar was 6.3 mmol/l. the neurological examination showed normal cranial nerves. motor exam in the upper limbs was normal except for diminished reflexes. the tone in the lower limb was reduced and the patient’s strength, measured by medical research council scale, revealed hip flexion of 2/5, knee flexion of 3/5, knee extension of -4/5, plantar and dorsiflexion (of the ankles) of -4/5. the reflexes in his lower limbs were diminished and plantars were down-going. the sensory examination was normal apart from a decrease in the joint-position sense in the toes and coordination of the upper limbs was normal and not examined in lower limbs in view of the weakness. the laboratory investigations included normal complete blood count, urea and electrolyte, coagulation profile, liver function test, thyroid function test (tft) and serum folate. the c-reactive protein level was <1 mg/l (reference range: 0–5 mg/l), creatine kinase severe acute respiratory syndrome coronavirus 2 (covid-19) was announced as a pandemic in march 2020 by the world health organization (who).1 the neurological manifestations and compl ications of covid-19 have been reported since then.2 chinese and spanish studies reported the prevalence of neurological manifestations in admitted patients with covid-19 as 36.4% and 57.4%, respectively.3,4 guillain-barré syndrome (gbs) is an immunemediated inflammatory polyradiculoneuropathy with acute ascending symmetrical weakness along with areflexia.1,4,5 it is one of the demyelinating disorders affecting the peripheral nerves in the body.4 few case reports and series of post-covid-19 gbs cases have been published.1,4 these case reports have suggested a relationship between the occurrence of gbs and recent covid-19 infection that preceded the onset of gbs by a few weeks. thus, a post-infectious dysregulation of the immune system that is triggered by covid-19 appears to be the main cause.2,4 to the best of the authors’ knowledge, no case report of postcovid-19 gbs has been published in oman, at the time of writing. case report a 72-year-old male patient known to have hypertension and ischemic heart disease had mild covid-19 infection confirmed in august 2020. the patient did not require hospitalisation as he only suffered from mild fever, runny nose and myalgia for a few days after which the symptoms resolved. the patient presented to a tertiary care hospital in muscat, oman, in 2020 with a one-day history of this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.090 case report abstract: guillain-barré syndrome (gbs) has been reported as one of the neurological manifestations linked to covid-19, a severe acute respiratory syndrome caused by coronavirus 2. we present the case of a 72-year-old male patient attending a tertiary care hospital in muscat, oman, in 2020 with a history of progressive bilateral limb weakness and numbness. the current diagnosis was in line with a rare complication of covid-19. after exclusion of other possible causes, a diagnosis of gbs induced by covid-19 was made. the patient received 0.4g/kg of intravenous immunoglobulin (ivig) per day for five days. this case report highlights the characteristics and course of gbs following covid-19 infection. further studies are needed to characterize the manifestations and course of various neuromuscular disorders in relation to covid-19 infection. keywords: covid-19; guillain-barré syndrome; ivig; oman. https://creativecommons.org/licenses/by-nd/4.0/ post-covid-19 guillain-barré syndrome a case report from oman 410 | squ medical journal, august 2022, volume 22, issue 3 multiple nerves in the upper and lower limbs with prolonged distal motor latencies and mildly reduced velocities. f-waves were present in most of the nerves tested but were in the upper range. there was no conduction block or temporal dispersion. the sensory ncs revealed borderline reduced sensory nerve action potential amplitude from the upper limbs nerves with mildly reduced velocities. however, results from the sural nerve tests were normal [table 2]. these findings suggested diffuse motor and sensory neuropathy with a predominance of demyelinating changes. magnetic resonance imaging scans of the brain and spinal cord showed no acute changes. during admission, the patient’s upper limb weakness worsened with a shoulder abduction of 2/5 bilaterally, elbow extension of 3/5, elbow flexion of -4/5 and intrinsic hand muscle flexion and extension were 4/5. the patient was diagnosed with postcovid-19 gbs. therefore, he was given one course of intravenous immunoglobulin (ivig) at 0.4 g/kg/day for five days. additionally, the patient received a 10 mg hydrocortisone tablet (once, daily), 3 ml injection of vitamin b complex (daily, for four days) and extensive physiotherapy during admission. he showed slow but progressive improvement in his symptoms during admission. the patient’s neurological examination was normal apart from the minimal weakness of his limbs on the day of discharge. consent has been obtained from the patient for the publication of this case report. discussion the immune-mediated nature of gbs is mostly based on observational studies of campylobacter jejuniinduced gbs and the fact that immunotherapy has stood at 340 u/l (reference range: 39–308 u/l) and vitamin b12 at 128 pmol/l (reference range: 138–652 pmol/l). nasopharyngeal polymerase chain reaction (pcr) testing for covid-19, done during admission, confirmed covid-19. the results from the chronic hepatitis screen, hiv-1 and 2 antigen/antibody test, syphilis screen, blood culture and urine microscopy, culture and sensitivity were all negative. the patient’s cerebrospinal fluid analysis showed proteins of 2.7 g/l (reference range 0.15–0.45 g/l) with no leucocytes; however, pcr and autoantibodies were not tested again during admission. on the third day of admission, a detailed nerve conduction study (ncs) was performed [table 1]. the following motor nerves of the upper and lower limbs on both sides were stimulated: the median nerve on the wrist and elbow, the ulnar nerve on the wrist and below the elbow, the tibial nerve on the ankle and popliteal fossa and the peroneal nerve on the ankle and fibula head. the motor ncs showed a decrease in compound muscle action potential amplitude from table 1: motor nerve conduction study and f-wave values of a 72-year-old male patient with covid-19 admitted to a tertiary care centre in muscat, oman site nerve dml in ms amp* in mv cv in m/s duration† in ms tdr f wave latency in ms right median 5.8 5.5/6.8 46 8.6/8.1 1.060 35.9 ulnar 4.3 5.6/6.5 51 9.5/8.8 1.070 39.7 left median 5.7 5.5/6.0 41 9.9/9.8 1.125 34.8 ulnar 4.2 5.3/6.0 58 7.9/9.4 0.840 37.9 right tibial 7.6 1.7/3.5 32 16.2/11.2 1.450 53.3 peroneal 8.3 0.3/0.4 30 14.6/13.1 1.110 67.9 left tibial 8.2 0.6/0.9 32 20.4/15.5 1.300 nr peroneal 10.3 1.6/3.1 36 13.2/10.2 1.290 63.5 dml = distal motor latency; ms = milliseconds; amp = amplitude; mv = millivolt; m/s = metres/second; cv = conduction velocity; tdr = temporal dispersion ratio; nr = not recordable. *the amplitudes for each nerve are presented as proximal/distal amplitude. †the durations for each nerve are presented as proximal/distal compound muscle action potential duration. table 2: sensory nerve conduction values of a 72-yearold male patient with covid-19 admitted to a tertiary care centre in muscat, oman site nerve onset latency in ms peak latency in ms amp in µv cv in m/s right median 3.9 4.7 8 36 ulnar 3.0 4.4 8 37 left median 3.7 4.8 11 38 ulnar 3.2 4.1 8 35 right left sural 2.6 3.7 10 46 sural 2.3 3.3 15 52 ms = milliseconds; amp = amplitude; µv = microvolt; cv = conduction velocity; m/s = metres/second. mohammed m. al-zadjali, emaad al shibli, mohammed al maskari, arunodaya r. gujjar and abdullah al asmi case report | 411 a central role in the management of gbs.6–12 gbs is well-documented to be seen following a number of infections such as those caused by campylobacter jejuni, mycoplasma, epstein-barr virus, cytomega lovirus and recently the zika virus.7,13–15 the most common variant of gbs is acute inflammatory demyelinating polyneuropathy (aidp).6,16,17 the development of polyneuropathies due to any viral infection suggests molecular mimicry leading to a neural inflammatory reaction, even presenting as an inflammatory response syndrome.18,19 however, these mechanisms of covid-19 related neuropathy need to be studied more deeply. existing literature shows that the predominant clinical presentation of gbs induced by covid-19 is the classical sensorimotor gbs. in addition, a majority of the cases fulfilled the electrophysiological criteria for a diagnosis of aidp. there is a male predominance in the reported cases and it appears across a wide age range: patients from 11–94 years of age.19 however, the mean age of patients was approximately 55 years, with the majority of cases being reported among those above 40 years of age. while few cases reported para-infectious onset of gbs, most patients had a post-infectious onset of gbs. hence, gbs induced by covid-19 generally seems to follow similar trends to the classical post-infectious gbs that is induced by other infective organisms.19 the present case of gbs seems to be a postinfectious phenomenon as it manifested after the resolution of the initial covid-19 infection. his mild course of covid-19 is in keeping with some of the cases already reported in the literature.20 however, gbs has been reported to occur even after a severe form of covid-19.1,4 this might be interpreted to be an aidp variant.18 in comparison to the current patient’s significant improvement following the ivig course, a patient in the united kingdom with a case of para-infectious gbs due to covid-19 failed to respond to ivig with weakness progression, a drop in respiratory vital capacity and he required intubation with icu admission.1 worsening of such cases could be due to direct invasion of toxins from the covid-19 virus or related to the severity of pneumonia. however, there was no difference in response to ivig or plasma exchange between para-infectious and post-infectious gbs in covid-19 cases as per the few cases reported in the existing literature.4 although ribonucleic acid was detected in the nasopharyngeal swab, it is unclear evidence of an active infection as it only represents the shedding of viral rna.21,22 moreover, seroconversion to immunoglobulin g antibodies was detected in our patient. given that the current patient responded to the ivig course, it favours the conclusion that gbs, in this case, is a post-infectious immune-mediated phenomenon. conclusion as post-covid-19 gbs is becoming increasingly apparent, larger studies are needed to better characterise the illness, including its clinical presentation. in particular, the effectiveness of ivig or plasma exchange in para-infectious and post-infectious cases remains to be studies more extensively. therefore, it is important to report cases of gbs induced by covid-19 to help build the cumulative, worldwide evidence-base needed for the best approach to the management of similar cases. moreover, reports of gbs induced by covid-19 in the middle east are limited. such reports need to be published so any possible differences in the presentation or management of future cases between different populations can be detected. it is also vital to recognise that gbs could be an important comorbidity in critically ill covid-19 patients and should be considered in patients not improving despite improvement of other clinical parameters, especially when chest imaging is inconsistent with the poor respiratory status of the patient. a u t h o r s’ c o n t r i b u t i o n mmaz drafted the manuscript after extensive followup of patient records. eas and mam were involved in case report writing and extensive review of the manuscript before submission. arg was responsible for reviewing and re-writing the manuscript following the work that was done by the first three authors and answering all the reviewers’ questions that could not be answered by the first three authors. aaa was responsible for reviewing the entire manuscript before submission. all authors approved the final version of the manuscript. references 1. webb s, wallace vcj, martin-lopez d, yogarajah m. guillainbarré syndrome following covid-19: a newly emerging postinfectious complication. bmj case rep 2020; 13:1–4. https:// doi.org/10.1136/bcr-2020-236182. 2. paterson rw, brown rl, benjamin l, nortley r, wiethoff s, bharucha t, et al. the emerging spectrum of covid-19 neurology: clinical, radiological and laboratory findings. brain 2020; 143:3104–20. https://doi.org/10.1093/brain/awaa240. 3. romero-sánchez cm, díaz-maroto i, fernández-díaz e, sánchez-larsen á, layos-romero a, garcía-garcía j, et al. neurologic manifestations in hospitalized patients with covid-19: the albacovid registry. neurology 2020; 95:e1060–70. https://doi.org/10.1212/wnl.0000000000009937. https://doi.org/10.1136/bcr-2020-236182. https://doi.org/10.1136/bcr-2020-236182. https://doi.org/10.1093/brain/awaa240 https://doi.org/10.1212/wnl.0000000000009937 post-covid-19 guillain-barré syndrome a case report from oman 412 | squ medical journal, august 2022, volume 22, issue 3 14. orlikowski d, porcher r, sivadon-tardy v, quincampoix jc, raphaël jc, durand mc, et al. guillain-barré syndrome following primary cytomegalovirus infection: a prospective cohort study. clin infect dis 2011; 52:837–44. https://doi. org/10.1093/cid/cir074. 15. parra b, lizarazo j, jiménez-arango ja, zea-vera af, gonzález-manrique g, vargas j, et al. guillain-barré syndrome associated with zika virus infection in colombia. n engl j med 2016; 375:1513–23. https://doi.org/10.1056/nejmoa1605564. 16. doets ay, verboon c, van den berg b, harbo t, cornblath dr, willison hj, et al. regional variation of guillain-barré syndrome. brain 2018; 141:2866–77. https://doi.org/10.1093/brain/awy232. 17. ye y, wang k, deng f, xing y. electrophysiological subtypes and prognosis of guillain-barré syndrome in northeastern china. muscle nerve 2013; 47:68–71. https://doi.org/10.1002/ mus.23477. 18. sriwastava s, kataria s, tandon m, patel j, patel r, jowkar a, et al. guillain barré syndrome and its variants as a manifestation of covid-19: a systematic review of case reports and case series. j neurol sci 2021; 420:117263. https://doi.org/10.1016/j. jns.2020.117263. 19. abu-rumeileh s, abdelhak a, foschi m, tumani h, otto m. guillain-barré syndrome spectrum associated with covid-19: an up-to-date systematic review of 73 cases. j neuro 2021; 268:1133–70. https://doi.org/10.1007/s00415-020-10124-x. 20. metlay jp, waterer gw, long ac, anzueto a, brozek j, crothers k, et al. diagnosis and treatment of adults with community-acquired pneumonia: an official clinical practice guideline of the american thoracic society and infectious diseases society of america. am j respir crit care med 2019; 200:e45–67. https://doi.org/10.1164/rccm.201908-1581st. 21. bullard j, dust k, funk d, strong je, alexander d, garnett l, et al. predicting infectious sars-cov-2 from diagnostic samples. clin infect dis 2020; 71:2663–6. https://doi.org/10.1093/cid/ ciaa638. 22. liu wd, chang sy, wang jt, tsai mj, hung cc, hsu cl, et al. prolonged virus shedding even after seroconversion in a patient with covid-19. j infect 2020; 81:318–56. https://doi. org/10.1016/j.jinf.2020.03.063. 4. zito a, alfonsi e, franciotta d, todisco m, gastaldi m, cotta ramusino m, et al. covid-19 and guillain–barré syndrome: a case report and review of literature. front neurol 2020; 11:1–7. https://doi.org/10.3389/fneur.2020.00909. 5. aljaafari d, ishaque n. paraparetic variant of guillain-barré syndrome in first 24 hours of postpartum period: a case report. sultan qaboos univ med j 2020; 20:227–30. https://doi. org/10.18295/squmj.2020.20.02.015. 6. ogawara k, kuwabara s, mori m, hattori t, koga m, yuki n. axonal guillain-barré syndrome: relation to anti-ganglioside antibodies and campylobacter jejuni infection in japan. ann neurol 2000; 48:624–31. https://doi.org/10.1002/15318249(200010)48:4<624::aid-ana9>3.0.co;2-o. 7. rees jh, soudain se, gregson na, hughes ra. campylobacter jejuni infection and guillain-barré syndrome. n engl j med 1995; 333:1374–9. https://doi.org/10.1056/nejm199511233332102. 8. visser lh, van der meché fg, van doorn pa, meulstee j, jacobs bc, oomes pg, et al. guillain-barré syndrome without sensory loss (acute motor neuropathy): a subgroup with specific clinical, electrodiagnostic and laboratory features. brain 1995; 118:841–7. https://doi.org/10.1093/brain/118.4.841. 9. yuki n, yoshino h, sato s, miyatake t. acute axonal polyneuropathy associated with anti-gm1 antibodies following campylobacter enteritis. neurology 1990; 40:1900–2. https:// doi.org/10.1212/wnl.40.12.1900. 10. aspinall go, fujimoto s, mcdonald ag, pang h, kurjanczyk la, penner jl. lipopolysaccharides from campylobacter jejuni associated with guillainbarre syndrome patients mimic human gangliosides in structure. infection and immunity 1994; 62:2122–5. https://doi.org/10.1128/iai.62.5.2122-2125.1994. 11. osterman po, fagius j, lundemo g, pihlstedt p, pirskanen r, sidén a, et al. beneficial effects of plasma exchange in acute inflammatory polyradiculoneuropathy. lancet 1984; 2:1296-9. https://doi.org/10.1016/s0140-6736(84)90819-5. 12. hughes ra, swan av, van doorn pa. intravenous immunoglobulin for guillain-barré syndrome. cochrane database syst rev 2014; 2014:cd002063. https://doi.org/10.1002/14651858.cd002063. pub6. 13. winer jb, hughes ra, anderson mj, jones dm, kangro h, watkins rp. a prospective study of acute idiopathic neuropathy. ii. antecedent events. j neurol neurosurg psychiatry 1988; 51:613–8. https://doi.org/10.1136/jnnp.51.5.613. https://doi.org/10.1093/cid/cir074 https://doi.org/10.1093/cid/cir074 https://doi.org/10.1056/nejmoa1605564 https://doi.org/10.1093/brain/awy232 https://doi.org/10.1002/mus.23477 https://doi.org/10.1002/mus.23477 https://doi.org/10.1016/j.jns.2020.117263. https://doi.org/10.1016/j.jns.2020.117263. https://doi.org/10.1007/s00415-020-10124-x https://doi.org/10.1164/rccm.201908-1581st. https://doi.org/10.1093/cid/ciaa638. https://doi.org/10.1093/cid/ciaa638. https://doi.org/10.1016/j.jinf.2020.03.063. https://doi.org/10.1016/j.jinf.2020.03.063. https://doi.org/10.3389/fneur.2020.00909 https://doi.org/10.18295/squmj.2020.20.02.015 https://doi.org/10.18295/squmj.2020.20.02.015 https://doi.org/10.1002/1531-8249(200010)48:4<624::aid-ana9>3.0.co;2-o https://doi.org/10.1002/1531-8249(200010)48:4<624::aid-ana9>3.0.co;2-o https://doi.org/10.1056/nejm199511233332102 https://doi.org/10.1093/brain/118.4.841 https://doi.org/10.1212/wnl.40.12.1900 https://doi.org/10.1212/wnl.40.12.1900 https://doi.org/10.1128/iai.62.5.2122-2125.1994 https://doi.org/10.1016/s0140-6736(84)90819-5. https://doi.org/10.1002/14651858.cd002063.pub6 https://doi.org/10.1002/14651858.cd002063.pub6 https://doi.org/10.1136/jnnp.51.5.613 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 63-69, epub 16th mar 2009 submitted 13th aug 08 revision req. 7th dec 08, revision recd. 19th jan 09 accepted 28th jan 09 study of the effect of panax ginseng versus gliclazide on hyperglycaemia induced by dexamethasone in experimental animals doa’a a ibrahim في اجلليكالزيد بدواء ومقارنته جنسنج باناكس نبات تأثير دراسة في الديكساميثازون بواسطة احملفز الدم سكر مستوى تخفيض حيوانات التجارب ابراهيم انور دعاء اجلليكالزيد بدواء جنسنج ومقارنتها باناكس نبات باستعمال الديكساميثازون عن الناجت العالي الدم سكر مستوى تخفيض دراسة امللخص: الهدف: إلى 24 أرنبا ــيم مت تقس (اليمن). صنعاء في العلوم والتكنولوجيا بجامعة األدوية علم ــم قس في ــة الدراس التجارب.الطريقة: متت هذه حيوانات في بينما مجموعات في ثالث ــكر الس ارتفاع لتحفيز 14 يوما ملدة 10 ملجم/كجم مقدارها فموية بجرعة ــامثازون الديكس دواء أعطي مجموعات. أربع 80 بجرعة اجللبكالزيد ، ودواء 200 ملجم/كجم بجرعة ــنج اجلنس بنبات منها مجموعتني معاجلة متت ضابطة. اموعة الرابعة كمجموعة بقيت سكر مستوى في تخفيض معتدة إحصائية داللة ذات نتائج أعطى جنسنج باناكس نبات أن ــة ــبوعني. النتائج: أظهرت الدراس ملدة أس ملجم/كجم . 100 مل) / (154.17±21.18 ملجم إلى ( 100 مل / 215.33±27.67 ملجم (من /كجم 10 ملجم بجرعة ديكساميثازون إعطاء بعد الدم ودواء جنسنج باناكس نبات بني معتدة إحصائية داللة ذو إحصائيا.اخلالصة: هناك فرق معتد ــكل الوزن بش تخفيض ــنج على جنس نبات عمل كذلك يعانون الذين مرضى السكر قبل من يستخدم أن ميكن اجلنسنج نبات أن استخالص ميكن النتائج هذه من . والوزن الدم سكر تخفيض في اجلليكالزيد . األنسولني مستلمات في ويتحسن العمل الوزن يقل حيث ، األنسولني مقاومة من يعانون الذين أو السمنة من ديكساميثازون. ، سكر الدم جليكالزيد ، زيادة ، باناكس جنسنج الكلمات: نبات مفتاح department of pharmacology, university of science & technology, sana’a, yemen. *email: dr_d_anwar@hotmail.com abstract objectives: to study the effect of panax ginseng versus gliclazide on hyperglycaemia induced by dexamethasone in experimental animals. methods: the current study was conducted in the department of pharmacology, university of science & technology, sana’a, yemen. twenty-four rabbits were divided to 4 groups. three of them were administered oral doses of dexamethasone (0 mg/kg) for 4 days, one group was kept as a control. ginseng at dose (200 mg/kg) and gliclazide (80 mg/kg) were administered to rabbits with dexamethasone-induced hyperglycaemia. results: the effects of ginseng and gliclazide on fasting blood sugar (fbs) and body weight after continuous administration of dexamethasone (0 mg/kg) were measured. oral administration of ginseng (200mg/kg) for 2 weeks produced significant (p <0.05) reduction in fbs from 25.33±27.67 mg/dl in the dexamethasone group to 54.7±2.8mg/dl in the ginseng treated group. in addition, ginseng produced significant (p <0.05) reduction in body weight. conclusion: there was a significant difference between ginseng and gliclazide in reduction of fbs and body weight. from these results, it is suggested that ginseng could be used in obese diabetic patients or those suffering from insulin resistance as it reduces body weight. key words: panax ginseng; gliclazide; hyperglycaemia; dexamethasone. c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • unlike other studies, this study focused on the comparison between herbal and chemical medicines in regard to their efficacy and safety for treatment of chronic diseases like diabetes. • this study supports the efficacy of panax ginseng as a potent antidiabetic agent, which also produces reduction in body weight, in experimental animal subjects. d o a’a a i b r a h i m 64 plasma glucose is derived from three sources: intestinal absorption following diges-tion of dietary carbohydrates, glycogenolysis or the breakdown of glycogen (polymerised storage form of glucose) and gluconeogenesis.1 insulin is a hormone produced by the pancreas that helps unlock the body’s cells so that sugar (glucose) from the food can be used by the cells for energy.2 an increase in plasma glucose concentration is the most important physiologic regulator of insulin secretion. glucose metabolism, initiated by the enzyme glucokinase, which converts glucose to glucose-6-phosphate, is closely linked to insulin secretion. however, an increase of the adenosine trriphosphate/adenosine diphosphate (atp/adp) ratio results in inhibition of atp-sensitive k efflux channels. this causes depolarisation of beta cells and activation of voltage-sensitive ca channels. the ca influx results in insulin secretion.3 insulin binds to a receptor on the cell membrane, allowing the entry into muscle and fat cells of glucose to form glycogen, fatty acids to generate triglycerides, and amino acids for protein synthesis. it is a potent stimulator of growth factors, including insulin-growth factor 1 (igf-1). it also inhibits catabolic processes such as the breakdown of glycogen and fat, and decreases gluconeogenesis (the production of glucose from lactate and amino acids);4 however, if there are any disturbances to the binding of insulin to the receptors, or of the receptor response to insulin, there will be reduced insulin activity, or insulin resistance. if insulin is not functioning, there is reduced glucose entry into the cells, which is detected by the pancreas as raised blood sugar (hyperglycaemia). the pancreatic response is then to produce more insulin, (hyperinsulinaemia) to compensate for the lack of cellular response to the hyperglycaemia. 5 the most common species of ginseng is panax quinquefolius, commonly known as american or western ginseng. the most commonly sought part of the plant is its root. other characteristics of the wild or cultivated plant and different shapes of the root make it more valuable. traditionally, the best plants are at least 6 years old. panax ginseng is known as the asian, korean or japanese ginseng.6 ginseng is composed primarily of ginesosides, also known as panaxosides. other components of the plant, isolated for pharmacologic effects, include a volatile oil, beta-elemine, sterols, flavonoids, peptides, vitamins (b1, b2, b12, panthotenic acid, nicotinic acid, and biotin), fats, polyacetylenes, enzymes and choline. the elements phosphorus, potassium, calcium, thallium, manganese, iron, copper, zinc and strontium were detected by screening the components of ginseng.7 several pharmacologic effects have been noted that vary with dose and duration of treatment. the panaxosides found in the root, are thought to be the pharmacologically active agents. they have anticonvulsant, analgaesic, antipsychotic effects and stress-ulcer preventing action. in addition, they show antiarrhythmic activity similar to verapamil and amiodarone. oral ginseng was found to reduce cholesterol and triglycerides, decrease platelet adhesiveness, impair coagulation, and increase fibrinolysis in cholesterol-fed rats.8 moreover, ginseng decreased fasting blood glucose and haemoglobin a1c in both diabetic and nondiabetic patients such that some diabetics were free of insulin therapy for the duration of the study.9 some studies in animals have documented ginseng‘s anti-inflammatory and antiviral activities,10 hepatoprotective • panax ginseng may be used as a supportive therapy, but should not replace current diabetes medications like sulfonylurea. application to patient care • diabetes is a serious chronic metabolic disease and has significant impact on patient’s lives as well as making demands of health care systems. • panax ginseng possessed a significant antidiabetic effect as compared with well known sulfonylurea member gliclazide in experimental animals. • our data, suggest that panax ginseng as a dietary supplement or as medicine may have functional efficacy in obese diabetic patients or those suffering from insulin resistance as it is considered a potent antioxidant agent. s t u d y o f t h e e f f e c t o f pa n a x g i n s e n g v e r s u s g l i c l a z i d e o n h y p e r g ly c a e m i a i n d u c e d b y d e x a m e t h a s o n e i n e x p e r i m e n ta l a n i m a l s 65 and tumors suppressant effects 11 and its beneficial use in colon cancer.12,13 gilclazide is a hypoglycaemic agent of the sulfonylurea group. its hypoglycaemic action is related to an improvement in insulin secretion from the functioning beta-cells of the pancreas.14 gliclazide is rapidly absorbed from the gastrointestinal tract and the plasma peak of gliclazide occurs between 4 and 6 hours. it is highly bound to plasma proteins, about 94%. the mean elimination half-life approximates 10.4 hours.15 however, gliclazide controls diabetes mellitus of stable, mild, non-ketosis prone, maturity onset or adult types which can not be controlled by proper dietary management and exercise, or when insulin therapy is not appropriate.16 recently, it was found that gliclazide inhibits ischaemia-induced retinal neovascularisation.17 the side effects of this drug include hypoglycaemic reactions and, as with other sulfonylurea drugs, manifestations of hypoglycaemia including dizziness, lack of energy, drowsiness, headache and sweating as well as weakness, nervousness, shakiness and paresthaesia. sulfonylurea unfortunately has a tendency to promote weight gain. this effect is aggravated by insulin resistance.18 m e t h o d s this study was conducted in department of pharmacology, university of science and technology, sana’a, yemen between may and june 2008.the following criteria were used to include subjects in the study: adult male rabbits weighing 1-1.5 kg. the following subjects were excluded from this study: adult female rabbits in order to eliminate the influence of the oestrous cycle and pregnancy on our parameters. the rabbits were purchased from yemeni markets, habituated to the new environment at constant temperature, and fed with a standard chow diet ad libitum for 1 week for acclimatisation. a total of 24 rabbits were used in the experiment. after one week’s habituation period, the animals were divided into 4 groups (6 animals in each group), one group being kept as control. both control and experimental groups were maintained under the similar experimental conditions. the control group was given only normal saline, while the other three groups were given continuous oral administration of dexamethsone (10mg/kg) for two weeks for induction of hyperglycaemia (above the human dose). daily oral doses of panax ginseng (200 mg/kg) or gliclazide (80 mg/kg) were used to treat dexamethasone-induced hyperglycaemia in the third and fourth groups of animals respectively for two weeks. blood samples were collected after the end of the experiment early in the morning when the animals had been kept fasting over the night. the fasting blood sugar measurement was done according to the method of trinder.19 the body weight was measured regularly for 14 days. data were collected and analysed using the spss (statistical package for the social sciences) programme for data analysis, version 13. they are shown as mean ± standard error; ‘n’ indicates the number of animals used. statistical analysis was performed with student’s t test for unpaired observations. differences were considered to be statistically significant when p was less than 0.05. r e s u l t s administration of dexamethasone (10mg/kg) for 2 weeks produced significant (p <0.05) increase in fbs: figure 1: effect of oral administration of dexamethasone (10 mg/kg) on the mean (mean ± se) fasting blood sugar in adult male rabbits (n = 6) * 300 250 200 150 100 50 0 control dexamethasone eff ec t o f d ex am et h as o n e o n b lo o d s u g ar (m g /d l) fbs fbs *significant difference as compare with control group at p<0.05 fbs = fasting blood sugar figure 2: effect of oral administration of ginseng (200mg/kg) on the average mean (mean ± se) fasting blood sugar in dexamethasone induced hyperglycaemia in adult male rabbits (n=6) 300 250 200 150 100 50 0 dexamethasone ginseng eff ec t o f d ex am et h as o n e o n b lo o d s u g ar (m g /d l) fbs fbs ** **significant difference as compare with dexamethasone-induced hyperglycaemia group at p<0.05 fbs = fasting blood sugar d o a’a a i b r a h i m 66 142.83 ± 15.77mg/dl in the control group compared to 215.33 ± 27.67mg/dl in the dexamethasone group as shown in figure 1. oral administration of panax ginseng (200mg/kg) for 2 weeks produced a significant (p <0.05) decrease in fbs: from 215.33 ± 27.67mg/dl, in the dexamethasone group to 154.17 ± 21.18mg/dl, in the panax ginseng treated group as shown in figure 2. oral administration of gliclazide (80mg/kg) for 2 weeks produced significant (p <0.05) decrease in fbs: from 215.33 ± 27.67mg/dl in the dexamethasone group to 169.33 ± 16.51mg/dl in the gliclazide treated group as shown in figure 3. oral administration of panax ginseng (200mg/kg) produced significant (p <0.05) reduction in fbs (154.17 ± 21.18 mg/dl) in the panax ginseng treated group compared with the gliclazide treated group(169.33 ± 16.51mg/dl) as shown in figure 4. d i s c u s s i o n the present study showed that continuous oral administration of ginseng in doses of (200mg/kg) for 2 weeks produced significant reduction in fbs as compared with dexamethasone-induced hyperglycaemia in rabbits. our result was in agreement with luo and luo who found that ginseng attenuates hyperglycaemia in two ways: first, through enhancing pancreatic beta cell function and second, by reducing insulin resistance. this would make ginseng effective in both type i and type ii diabetes.20 other studies showed that ginseng affects pancreatic beta cells through altering cell metabolism, increasing insulin production and reducing apoptosis in a dosage dependent manner.21 in addition, ginseng extracts were able to enhance atp production and in turn increase insulin production, as insulin deficiency is often linked to a lack of atp.22, 23along with an increase in atp production, ginseng reduced mitochondrial protein uncoupling protein 2 (ucp-2), which negatively regulates insulin secretion.22 however, another study showed that the insulin secretionstimulating activity of ginseng was presumably associated with the atp sensitive k channel. this effect, however, was almost completely abolished in the presence of diazoxide (k channel opener) or nifedipine (ca channel blocker).24 in addition, compound k (ck), which is a final metabolite of ginsenosides, shifted glucose metabolism from hepatic glucose production to hepatic glucose utilisation in the liver and improved insulin sensitivity through enhancing plasma adiponectin levels, resulting in over expression of genes for adipogenesis and glucose transporters in adipose tissue. all these effects may suggest that ginseng could be developed as therapeutic tool in type 2 diabetic patients with insulin secretion disability and/or insulin resistance.25 another study suggests that ginseng may inhibit cytokine-induced apoptosis in beta cells and, thus, may contribute via this action to the antidiabetic influence in type 1 diabetes.26 continuous administration of gliclazide in an oral dose (80mg/kg) for 2 weeks produced significant reduction in fbs. our result is supported by wangnoo who found that glicalizide is one of the most frequently used sulfonylurea for the treatment of type 2 diabetes.27 its hypoglycaemic action is related to an improvement in insulin secretion from the functioning beta cells of the pancreas. it potentiates the insulin release and improves the dynamics of insulin. in addition, antidiabetic sulfonylureas are thought to stimulate insulin secretion solely by inhibiting their highfigure 3: effect of oral administration of glicalizide (80mg/kg) on the average mean (mean ± se) fasting blood sugar in dexamethasone induced hyperglycaemia in adult male rabbits (n = 6) 300 250 200 150 100 50 0 gliclazidedexamethasone eff ec t o f g lic la zi d e o n b lo o d s u g ar (m g /d l) fbs fbs **significant difference as compare with hyperglycaemic induced group at p<0.05 fbs = fasting blood sugar * * figure 4: effect of oral administration of panax ginseng (200mg/kg) or gliclazide (80 mg/kg) on the average mean (mean ± se) fasting blood sugar in dexamethasone induced hyperglycaemia in adult male rabbits (n = 6) * * * 300 250 200 150 100 50 0 gliclazide ginseng eff ec t o f g in se n g o n b lo o d s u g ar (m g /d l) fbs fbs **significant difference as compare with gliclazide treated group at p <0.05 fbs = fasting blood sugar s t u d y o f t h e e f f e c t o f pa n a x g i n s e n g v e r s u s g l i c l a z i d e o n h y p e r g ly c a e m i a i n d u c e d b y d e x a m e t h a s o n e i n e x p e r i m e n ta l a n i m a l s 67 affinity atp-sensitive potassium (k (atp)) channel receptors at the plasma membrane of beta-cells. this normally occurs during glucose stimulation, where atp inhibition of plasmalemmal k (atp) channels leads to voltage activation of l-type calcium channels for rapidly switching on and off calcium influx, governing the duration of insulin secretion.28 in contrast, another study showed that chronic sulfonylurea treatment in vivo causes loss of insulin secretory capacity due to beta-cell hyperexcitability, but also revealed rapid reversibility of this secretory failure, arguing against beta-cell apoptosis or other cell death induced by sulfonylureas. these in vivo studies may help to explain why patients with type 2 diabetes can show long term secondary failure to secrete insulin in response to sulfonylureas, but experience restoration of insulin secretion after a drug resting period, without permanent damage to beta-cells. 29 in addition, ginseng showed significant (p <0.05) reduction in total body weight compared with the dexamethasone and glicalizide groups [figure 5]. this effect is controversial owing to its mechanism of action. however, this effect may be due to the inhibition of pancreatic lipase activity.30 however, some studies showed that sulfonylurea may increase body weight due to an increase in leptin (an obesity gene product)31 or due to an insulin secretion effect.27 this is a single study with a small number of animals so these limitations have to be kept in mind when interpreting the results. further experimental and clinical investigations should be done to support the results of this work. c o n c l u s i o n it seems that ginseng is effective as an antidiabetic agent in experimental animal models. it is more than likely that ginseng affects not only the pancreas to increase insulin production, but also other tissue to utilise insulin as well as decrease insulin resistance through its various components. there was a significant difference between ginseng and gliclazide in reducing fasting blood sugar and body weight. from these results, it is suggested that ginseng might be used in obese diabetic patients or those patients suffering from insulin resistance as it reduces body weight so improving insulin receptors. r e c om m e n dat i o n s this study showed that panax ginseng may help to reduce blood glucose level and improve insulin sensitivity and hence may have potential use in management of diabetes mellitus patients with obesity. it was found that both agents are working by the same mechanism as they stimulate secretion of insulin from beta cell of pancreas. expected synergistic hypoglycaemic effect may be resulted if they are combined together. panax ginseng should be used cautiously in patients taking any hypoglycaemic medications. drug-drug interactions with digoxin and warfarin have also been reported. s o u r c e o f f u n d i n g : university of science & technology, sana’a, yemen c o n fl i c t o f i n t e r e st : none declared r e f e r e n c e s 1. mayes ap. gluconeogeogenesis & control of blood glucose. in: harper’s biochemistry. 25th edition. murray kr, granner kd, mayes ap, rodwell wv, eds. new york: mcgraw-hill, 2000. pp. 208-18. 2. samra g. hypoglycemia: a forgotten disease. the figure 5: effect of continuous oral administration of panax ginseng (200mg/kg) or gliclazide (80mg/kg) on average total body weight in adult male rabbits (n = 6) * ** 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 dexamethasone gliclazide control ginseng *significant as compared with control at p <0.05 **significant as compared with dexamethasone induced hyperglycaemia at p <0.05 a ve ra g e b o d y w ei g h t ch an g e (g /k g ) no. of days d o a’a a i b r a h i m 68 hypoglycemia association newsletter1998; 14:2. 3. granner dk. hormones of the pancreas and gastrointestinal tract. in: harper’s biochemistry. 25th edition. murray kr, granner kd, mayes ap, rodwell wv, eds. new york: mcgraw-hill, 2000. pp. 610-26. 4. reaven, gm. pathophysiology of insulin resistance in human diseases. physiol rev 1995; 75:473-85. 5. zavaroni i. hyperinsulinaemia, obesity and syndrome x. j int med 1994; 235:51-6. 6. d’angelo l. a double-blind, placebo-controlled study on the effect of standardized ginseng extract on psychomotor performance in healthy volunteers. j ethnopharmacol 1986; 16:15-22. 7. zucchi ol, moreira s, de jesus ef, neto hs, salvador mj. characterization of hypoglycaemiant plants by total reflection x-ray fluorescence spectrometry. boil trace elem res 2005; 103:277-90. 8. suzuki y, hikino h. mechanism of hypoglycemic activity of panaxans a and b, glycans of panax ginseng roots: effects on the key enzymes of glucose metabolism in the liver of mice. phytotherapy res 1989; 3:15-19. 9. sotaniemi e. ginseng therapy in non-insulin dependent diabetic patients. diabetes care 1995; 18:1373-5. 10. cho wc. application of proteomics in chinese medicine research. am j chin med. 2007; 35:91122. 11. wang cz, aung hh, ni m, wu ja, tong r, wicks s, et al. red american ginseng: ginsenoside constituents and antiproliferative activities of heatprocessed panax quinquefolius roots. planta med. 2007;73:669-74. 12. yun, tk, choi s. a case-control study of ginseng intake and cancer’. int j epidemol 1990; 19:871-6. 13. wargovich mj. colon cancer chemoprevention with ginseng and other botanicals. j korean med sci suppl 2001; 16: s81-6. 14. wangnoo sk. treatment of type 2 diabetes with gliclazide modified release 60 mg in the primary care setting of india. int j diab dev ctries 2005; 25:50-4. 15. carmer ja. a systemic review of adherence with medications for diabetes. diabetes care 2004; 27: 1218-24. 16. kimura t, takagi h, suzuma k, kita m, watanabe d, yoshimura n. comparisons between the beneficial effects of different sulphonylurea treatments on ischemia-induced retinal neovascularization. free radic biol med 2007; 43:454-61. 17. american diabetes association. standards of medical care for patients with diabetes mellitus. diabetes care 2002; 25:s33-s49. 18. bennett pm, brown mj. diabetes mellitus, insulin, oral antidiabetic agents, obesity. in: clinical pharmacology. 9th edition. new york: mcgraw-hill, 2004. pp. 679-98. 19. trinder p. enzymatic determination of glucose (single reagent). ann cli biochem1969; 6:24. 20. luo jz, luo l. ginseng on hyperglycaemia: effect and mechanisms. evid based complement alternat med. 2008 jan 3. [epub ahead of print] pp.111. 21. luo jz, luo l. american ginseng stimulates insulin production and prevents apoptosis through regulation of uncoupling protein-2 in cultured beta cells. evid based complement alternat med 2006; 3:365-72. 22. chan cb, macdonald pe, saleh mc, johns dc, marban e, wheeler mb . over expression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets. diabetes 1999; 48:1482-6. 23. zhang cy, baffy g, perret p, krauss s, peroni o, grujic d, et al. uncoupling protein 2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. cell 2001; 105:745-55. 24. park mw, ha j, chung sh. 20 (s)-ginsenoside rg3 enhances glucose-stimulated insulin secretion and activates ampk. biol pharm bull 2008; 31:748-51. 25. han gc, ko sk, sung jk, chung sh. compound s t u d y o f t h e e f f e c t o f pa n a x g i n s e n g v e r s u s g l i c l a z i d e o n h y p e r g ly c a e m i a i n d u c e d b y d e x a m e t h a s o n e i n e x p e r i m e n ta l a n i m a l s 69 k enhances insulin secretion with beneficial metabolic effects in db/db mice. j agric food chem 2007; 55:10641-8. 26. kim hy, kim k. protective effect of ginseng on cytokine-induced apoptosis i pancreatic beta-cells. j agric food chem 2007; 55:2816-23. 27. wangnoo sk. treatment of type 2 diabetes with gliclazide modified release 60mg in the primary care setting of india . int j diab dev ctries 2005; 25:50-4. 28. geng x, li l, bottino r, balamurugan an, bertera s, densmore e, su a, chang y, et al. antidiabetic sulfonylurea stimulates insulin secretion independently of plasma membrane katp channels. am j physiol endocrinol metab 2007; 293: e293-301. 29. remedi ms, nichols cg. chronic antidiabetic sulfonylurea in vivo: reversible effects in mouse pancreatic beta cells. plos med 2008; 5:e206 30. karu n, reifen r, kerem z. weight gain reduction in mice fed panax ginseng saponin, a pancreatic lipase inhibitor. j agric food chem 2007; 55:28248. 31. bhattacharya sk, madan m, mahajan p, paudel kr, rauniar gp, das bp, et al. relationship between plasma leptin and plasma insulin levels in type 2 diabetic patients before and after treatment with glibenclamide and glimepiride. indian j physiol pharmacol 2008; 52:43-52. submitted 21 nov 22 1 revisions req. 18 jan & 23 feb 23; revisions recd. 31 jan & 28 feb 23 2 accepted 1 mar 23 3 online-first: march 2023 4 doi: https://doi.org/10.18295/squmj.3.2023.016 5 6 pleural pseudo-tumor tuberculosis 7 mouaad amraoui,1 massine el hammoumi,1 mohamed oukabli,2 8 *el hassane kabiri1,3 9 10 1departments of thoracic surgery and 2pathology, mohamed v military teaching hospital, 11 rabat, morocco; 3faculty of medicine & pharmacy, mohamed v university, rabat, 12 morocco. 13 *corresponding author’s e-mail: hassankabiri@yahoo.com 14 15 the pseudotumoral form of bronchopulmonary tuberculosis is rare. it can manifestas a 16 bronchial, pulmonary, or pleural lesion, suggesting neoplasia, which makes the diagnosis 17 difficult. a 23-year-old female patient was referred to our department for management of a 18 right thoracic mass incidentally found on a chest computed tomography (ct). she reported 19 intermittent right-sided chest pain and fever. clinical examination was normal. chest ct 20 showed a well-defined, homogenous right low pleuro-parietal mass measured 50x50x24 mm 21 with a peripheral enhancement of contrast without bone invasion, pleural effusion, 22 parenchymal lesion, or mediastinal lymph nodes (figure 1 a, b, c). routine blood tests were 23 normal except for a high erythrocyte sedimentation rate (esr) at 32 mm/hr. bacteriological 24 testing for acid-fast bacilli and genexpert were negative in sputum. bronchoscopy and 25 percutaneous ct-guided needle-aspiration didn’t allow a pathological diagnosis. the patient 26 underwent an elective right posterolateral thoracotomy. pre-operative findings noted 27 capsulated fluids mass with the presence of caseous necrosis after the accidental opening of 28 the lesion (figure 2), the mass was resected completely. bacteriology revealed bacillus of 29 koch in caseous liquid culture and pathological exams revealed the presence of areas of 30 caseous necrosis with epithelioid granulomas, which were consistent with tuberculosis 31 infection. the patient received anti-tuberculous chemotherapy (2rhz + 4rh) with a good 32 clinical and radiological resolution (figure 3). patient consent was obtained for publication 33 purposes. 34 35 comment 36 the incidence of pulmonary pseudotumor tuberculosis varies from 2 to 4%.1-3 clinical and 37 radiological manifestations are not specific and may suggest malignancy, bronchoscopic 38 explorations can be negative. the differential diagnosis is lung cancer; metastasis, localized 39 mesothelioma, or benign disease like inflammatory myofibroblastic tumors. surgical removal 40 of the mass through thoracoscopic or conventional approach is the best approach when we fail 41 to establish a definite diagnosis and for management of complications like heamoptysis.4-5 42 43 authors’ contribution 44 ma conceptualized and drafted the manuscript. me interpreted the data in the manuscript. 45 mo interpreted the pathological data. ehk contributed to drafting and revising the 46 manuscript. all authors approved the final version of the manuscript. 47 48 references 49 1. arul p, varghese rg, ramdas a. pleural tuberculosis mimicking inflammatory 50 pseudotumour. j clin diagnres2013; 7(4):709-11. doi: 10.7860/jcdr/2013/4382.2888 51 2. le guillou f, hubscher p, cuvelier a, quieffin j, guyonnaud cd, el haite a et al. 52 bilateral pleural thickening pseudo-tumour due to tuberculosis. rev mal respir 2002; 53 19(4):515-7. pmid: 12417867 54 3. chaouch n, saad s, zarrouk m, racil h, cheikh rouhou s et al. diagnostic difficulty in 55 bronchopulmonary tuberculous pseudotumor. rev mal respir 2011; 28(1):9-13. doi: 56 10.1016/j.rmr.2010.05.014 57 4. schweigert m, dubecz a, beron m, ofner d, stein hj. pulmonary infections imitating 58 lung cancer: clinical presentation and therapeutical approach.ir j med sci. 2013; 182(1):73-59 80. doi: 10.1007/s11845-012-0831-8 60 5. ishida t, yokoyama h, kaneko s, sugio k, sugimachi k, hara n. pulmonary tuberculoma 61 and indications for surgery: radiographic and clinicopathological analysis. respir med 1992; 62 86:431-6. doi: 10.1016/s0954-6111(06)80011-9 63 64 65 https://pubmed.ncbi.nlm.nih.gov/23730653/ https://pubmed.ncbi.nlm.nih.gov/23730653/ https://doi.org/10.7860/jcdr/2013/4382.2888 https://pubmed.ncbi.nlm.nih.gov/12417867/ https://pubmed.ncbi.nlm.nih.gov/21277469/ https://pubmed.ncbi.nlm.nih.gov/21277469/ https://doi.org/10.1016/j.rmr.2010.05.014 https://pubmed.ncbi.nlm.nih.gov/22592566/ https://pubmed.ncbi.nlm.nih.gov/22592566/ https://doi.org/10.1007/s11845-012-0831-8 https://doi.org/10.1016/s0954-6111(06)80011-9 66 figure 1: ct scan of the thorax showing (a: axial b: frontal, c: coronal) pleural right 67 based mass lesion with calcification and irregular margins. 68 69 70 figure 2: operative view showing caseous necrosis after opening of the basal mass. 71 72 73 figure 3: ct scan of the thorax 2 years later showing (a: axial, b: frontal, c: coronal) no 74 signs of recurrence or remaining infection. 75 july 2008.indd abstract objectives: the world over, tonsillectomy is one of the operations most frequently performed by otolaryngologists, who are in search of a technique of tonsillectomy where the operation time and operative blood loss is reduced. this study was carried out to evaluate the effect of hydrogen peroxide 3% on tonsillectomy times, blood loss during the surgery and on the number of ties used. methods: a pilot study of 30 patients was carried out in the department of otolaryngology of basrah general hospital, iraq, in the period from february to july 2006. tonsillectomy was performed using hydrogen peroxide 3% as a haemostatic agent in group a (n = 5), while in group b (n = 5) no agent was used with the gauze pack. results: the application of hydrogen peroxide 3% in the tonsillar fossae reduced the operation time by 3%, the operative blood loss by 32.9% and also reduced the number of ties used by 50% in group a. all these results are statistically significant. conclusion: the local application of 3% hydrogen peroxide on the tonsillar bed after tonsillectomy is beneficial in regard to decreasing the procedure time, the volume of blood loss, and the number of ties used. keywords: tonsillectomy; hydrogen peroxide; haemostasis. hydrogen peroxide 3%: is it beneficial in tonsillectomy? *ahmed m al-abbasi,1 zahra k saeed2 1department of surgery, basrah medical college, basrah, iraq; 2basrah dentistry college, basrah, iraq *to whom correspondence should be addressed. email: mmalabbasi@yahoo.com اللوزتني؟ استئصال لعملية مفيد هو هل :3% الهيدروجني بيروكسيد زهره سعيد ، احمد العباسي أنحاء جميع ــي ف واحلنجرة ــاء األنف واألذن أطب قبل ــي تؤدى من الت العمليات أنواع ــر أكث إحدى هي اللوزتني ــتئصال ــة اس ــص: الهــدف: عملي امللخ 3% الهيدروجني ــيد بيروكس تأثير لتقييم ــة تهدف الدراس . فقدان الدم وكذلك وقت العملية تقلل ــة لطريق دائم بحث األطباء في ــؤالء ه ــم. العال عملية لهم أجريت مريضا ((30 ل ارتيادية ــة دراس هذه الطريقة: اللوزتني. ــتئصال اس لعملية الغرز املفقود وعدد الدم حجم ــتغرق، املس الوقت في .2006 لعام متوز إلى شهر ــباط ش ــهر ش من الفترة في ، العراق في البصرة العام ــفى مستش واألذن واحلنجرةاألنف ــعبة ش في اللوزتني ــتئصال اس شيء ــتخدم أي يس لم (15 مريضا)، بينما ــة الدراس مجموعة في للنزف موقف كعامل ــاش الش %3 مع حزمة الهيدروجني ــيد بيروكس ــتخدم اس %31 وتقليل بقدر تقليل وقت العملية إلى %3 أدى الهيدروجني ــيد بيروكس ــتخدام النتائج: اس (15 مريضا). اموعة الضابطة في ــاش الش مع معتدة. اخلالصة: إحصائية ذات داللة النتائج هذه كل . الضابطة اموعة مع %50 باملقارنة %32.9 وكذلك تقليل عدد الغرز إلى بقدر الدم فقدان الغرز وعدد املفقودة الدم وكمية العملية وقت اختزال إلى أدى استئصالها بعد اللوزة سرير %3 في الهيدروجني ــيد كس لبيرو املوضعي ــتخدام االس املستخدمة. . النزف ايقاف ، الهيدروجني بيروكسيد ، اللوزتني الكلمات: استئصال مفتاح sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 201-204 sultan qaboos university© submitted 30th october 2007 accepted 3rd march 2008 c l i n i c a l a n d b a s i c r e s e a r c h as far as we know, celsus was the first person to recognize tonsillar disease and its relationship to infection performing the first tonsillectomy in 40 a.d.1 the popularity of tonsillectomy peaked in the 1930s, but after the use of antibiotics became widespread, enthusiasm for the procedure waned and its use had decreased dramatically by the 1960s. concerned about the morbidity inherent in the surgical procedure, paediatricians began to question its value relative to medical management with antimicrobials. the tide turned again in the 1980s, when paradise et al demonstrated that surgery significantly improved patient outcomes compared with medical therapy.2 chronic tonsillitis is one of the most common and frequent illnesses within otolaryngology. tonsillectomy is also one of the most frequently performed surgical procedures. patients’ quality of life and general health becomes demonstrably reduced by chronic palate and pharyngeal infections.3 hitherto tonsillectomy outcome studies were mostly done on children.4, 5 hydrogen peroxide has been used as a disinfectant.6 delivering hydrogen peroxide into wounds kills fibroblasts and occludes local microvasculature.7, 8 it has been used for decades as an effervescent haemostatic agent in arthroplasty in orthopedics.9 s h ya m s g a n g u ly, m o h a m m e d a a l -s h a fa e e , a b d u l l a h a a l m a n i r i 202 the aims of this prospective study were to evaluate the effects of hydrogen peroxide 3% on tonsillectomy time, operative blood loss and the number of ties used to achieve complete haemostasis. m e t h o d s thirty randomly selected patients underwent tonsillectomy in the department of otolaryngology of basrah general hospital, iraq. as air embolism is occasionally known following h202 usage, the risk was mentioned to all patients. some then refused to take part in the study, but all those who were included accepted the possibility of risk and gave their permission. in group a (n = 15), a hydrogen peroxide 3% impregnated gauze pack was applied to one tonsillar fossa after the tonsil had been removed; in group b (n = 15), no agent was used with the pack. the tonsillectomy was performed by the conventional dissection and snare method. the stubborn bleeders were ligated with silk suture. tonsillectomy operation time was calculated as the time interval between the first incision to the time when all bleeding and oozing was secured completely. the operative blood loss was calculated by weighing the blood impregnated gauze packs against an equal number of unused packs as well by measuring the volume of blood for each group separately, subtracting the volume of hydrogen peroxide used. the volume of blood in the packs was calculated by dividing the weight of blood on the pack by the specific gravity of blood, i.e. 1.055.10 the results of the study were statistically analysed by using paired t -test for significance r e s u l t s the age range of the studied patients was 2-32 years: 17 were males and 13 were females. the average time for tonsillectomy in the non-hydrogen peroxide group was 12.9 minutes. with the use of hydrogen peroxide 3%, the average time was reduced to 8.9 minutes, which meant reduction in tonsillectomy time of 31%. this is statistically significant (p < 0.0001). the average operative blood loss in the non-hydrogen peroxide group was 45.5 ml while that in hydrogen peroxide group was 30.5 ml, which means a 32.9 % reduction in operative blood loss. these results are statistically significant (p < 0.0001). the maximum numbers of ties use were four. in the non-hydrogen peroxide group, the average number of ties was 1.5, while that in hydrogen peroxide group was 0.75. this mean a 50% reduction in the number of ligatures used in tonsillectomy after the use of hydrogen peroxide as a haemostatic agent, which is also statistically significant (p < 0.0001). all these results are shown in table 1. d i s c u s s i o n the first known tonsillectomy was performed by cornelius celsus about 2000 years ago. after enucleating the tonsil with his fingernail, he suggested the fossae should be washed with vinegar and painted with a medication to reduce bleeding.1 since that time techniques for faster tonsillectomy with less bleeding have been searched for and various haemostatic agents and technique been tried. sharp and rogers,11 used calcium alginate swabs to achieve haemostasis after tonsillectomy, but reduction in both tonsillectomy time and blood loss was not significant. in the past, many studies were done utilizing electro cauterization for haemostasis with papangelou12 demonstrated a 30% reduction. waston and murty, in their study of 1,036 cases, 13 achieved good haemostasis and a tonsillectomy time of 9.2 ± 40min, but the use of electro-cauterization results in increased postoperative pain and excessive slough formation in the tonsillar bed which results in infection and secondary haemorrhage.13 laser tonsillectomy under general anaesthesia is shown to reduce surgical blood loss and postoperative pain as well as increase the recovery rate.14-16 the use of hydrogen peroxide as a haemostatic agent in tonsillectomy was not found when reviewtable 1: comparison between non-h2o2 and h2o2 groups regarding time, blood loss and number of ties in tonsillectomy. groups average % decrease % time of tonsillectomy in minutes group b (n=15), non-h2o2 12.9 group a (n=15), h2o2 8.9 31 blood loss (ml) group b, non-h2o2 45.5 group a, h2o2 30.5 32.9 no. of ties used group b, non-h2o2 1.5 group a, h2o2 0.75 50 s o m e r i s k fa c t o r s f o r c o r o n a r y h e a r t d i s e a s e a m o n g o m a n i m a l e s 203 ing the available literature. hydrogen peroxide has been used for decades as a haemostatic agent in orthopaedics.9 chang et al, 17 carried out a study in 120 pediatric patients undergoing adenoidectomy with use of cold hydrogen peroxide. they found that the incidence of oozing and active bleeding decreased when cold hydrogen peroxide was applied. the present study confirms that the use of hydrogen peroxide in tonsillectomy achieved a reduction in tonsillectomy time and operative blood loss by 31% and 32.9%, respectively. all these results are statistically significant. no adverse effect was reported by the use of hydrogen peroxide in tonsillectomy in the present study despite some reports stating that dangerous sequelae can result from the use of such a preparation, especially when used in neurosurgical fields. dubey et al18 presented a case of suspected gas embolism following hydrogen peroxide irrigation of the surgical field during posterior fossa surgery in the prone position. severe cardiovascular collapse occurred when the wound was irrigated with a hydrogen peroxide solution. the interesting additional benefit of hydrogen peroxide is its action to clarify the exact localizations of bleeders which need to be ligated, especially in cases of difficult dissection in fibrotic tonsils with excessive bleeding. this advantage has been utilized by kalloo et al, who used hydrogen peroxide spray through an endoscope. this resulted in enhancement of clot dissolution and endoscopic visualization of the bleeding source.19 the limitations of this present study are the absence of testing the long term effect of hydrogen peroxide and no long term follow-up of the patients. the number of patients studied was also relatively small, indicating the need to perform a broader study with a longer period of follow up. c o n c l u s i o n local application of 3% hydrogen peroxide on the tonsillar bed after tonsillectomy is beneficial as it decreases the procedure time and the volume of blood loss as well as number of ties used. r e f e r e n c e s 1. curtin jm. the history of tonsil and adenoid surgery. otolaryngol clin north am 1987; 20:415-419. 2. paradise jl, bluestone cd, bachman rz, colborn dk, bernard bs, taylor fh, et al. efficacy of tonsillectomy for recurrent throat infection in severely affected children results of parallel randomized and nonrandomized clinical trials. n engl j med 1984; 310:674-683. 3. stewart mg, friedman em, sulek m, hulka gf, kuppersmith rb, harrill wc, et al. quality of life and health status in pediatric tonsil and adenoid disease. arch otolaryngol head neck surg 2000; 126:45–48. 4. goldstein na, fatima m, campbell tf, rosenfeld rm. child behaviour and quality of life before and after tonsillectomy and adenoidectomy. arch otolaryngol head neck surg 2002; 128:770–775. 5. stewart mg, friedman em, sulek m, dejong a, hulka gf, bautista mh, et al. validation of an outcomes instrument for tonsil and adenoid disease. arch otolaryngol head neck surg 2001; 127:29–35. 6. patai s, rapporport z, eds. the syntheses of sulphones, sulphoxides and cyclic sulphides. chichester, uk: john wiley and sons, 1994. p. 112-116. 7. branemark pi, ekholm r. tissue injury caused by wound disinfection. j bone joint surg 1967; 49:48-62. 8. lineweaver w, howard r, soucy d, mcmorris s, freeman j, crain c, et al. topical antimicrobial toxicity. arch surg 1985; 120:267-270. 9. guerin s, o’reilly p, kelly d. hydrogen peroxide as an irrigation solution: a comparative study of the effect of hydrogen peroxide versus normal saline on the strength of bone-cement interface in arthroplasty. j clin neurosci 2007; 14:488-490. 10. agrawal sr, jain ak, marathe d, agrawal r. the effect of bismuth subgallate as haemostatic agent in tonsillectomy. indian j otolaryngol 2005; 57:287-289. 11. sharp jf, rogers mj. combined study to assess the role of calcium alginate swabs and ligations of inferior tonsillar pole in the control of intra-operative blood loss during tonsillectomy. j laryngol otol 1991; 105:191194. 12. papangelou l. haemostasis in tonsillectomy a comparison of electrocoagulation and ligation. arch otolaryngol head neck surg 1970; 96:358-360. 13. murty ge, watson mg. diathermy haemostasis at tonsillectomy. j laryngol otol 1990; 104:549-52. 14. densert o, desai h, eliasson a, frederiksen l, andersson d, olaison j, et al. tonsillotomy in children with tonsillar hypertrophy. acta otolaryngol 2001; 121:854– 858. 15. hultcrantz e, linder a, markstrom a. tonsillectomy or tonsillotomy? a randomised study comparing postoperative pain and long-term effects. int j pediatr otorhinolaryngol 1999; 51:171–176. 16. linder a, markstrom a, hultcrantz e. using the carbon dioxide laser for tonsillotomy in children. int j pediatr otorhinolaryngol 1999; 50:31–36. 17. chang hj, baek sh, choi cy, kang sn, park jb, lee wy, et al. hemostatic efficacy of topical application of s h ya m s g a n g u ly, m o h a m m e d a a l -s h a fa e e , a b d u l l a h a a l m a n i r i 204 cold hydrogen peroxide in adenoidectomy. korean j otolaryngol head neck surg 2003; 46:946-949. 18. dubey, prakash k, singh, anuj k. venous oxygen embolism due to hydrogen peroxide irrigation during posterior fossa surgery. j neurosurg anesthesiol 2000; 12:54-56. 19. kalloo an, canto mi, wadwa ks, smith cl, gislason gt, okolo pi, et al. clinical usefulness of 3% hydrogen peroxide in acute upper gi bleeding: a pilot study. gastrointest endosc 1999; 49:518-21. departments of 1internal medicine and 4surgery, university of hail, hail, saudi arabia; 2family medicine post graduate center, ministry of health, hail, saudi arabia; 3department of psychiatry, jouf university, sakaka, saudi arabia *corresponding author’s e-mail: dr.a.aljadani@gmail.com abstract: objectives: burnout syndrome is a condition that is well-documented globally among medical students and affects their academic performance due to high levels of associated stress and psychiatric morbidities. this study aimed to assess burnout prevalence and predictors along with its association with academic performance among medical students at hail university, saudi arabia. methods: a questionnaire-based cross-sectional survey of medical students was conducted between may and june 2019 at the medical college at hail university. the english version of the maslach burnout inventory (mbi)-student survey was used to assess the three components of burnout syndrome— cynicism, emotional exhaustion and professional efficacy. a fixed-model multivariate logistic regression analysis was conducted for each of the three mbi components’ levels and for total burnout to identify factors significantly associated with burnout syndrome. results: a total of 218 students were included in this study (response rate: 53.8%). the majority of participants were female (n = 121; 55.5%) medical students ranging between 21–24 years of age. high emotional exhaustion, high cynicism and low professional efficacy was found among 79.4%, 61.0%, and 37.6%, respectively, of respondents. the overall prevalence of high burnout was 27.1% (n = 59). female students were at almost double the risk for high emotional exhaustion compared to male students (adjusted odds ratio [aor] = 2.14, 95% confidence interval [ci]: 1.06–4.34; p = 0.034). students with grade point averages (gpa; on a four-point scale) ranging between 3.51–4.0 were considerably less prone (83% less risk) to experience burnout as compared to students with a gpa ≤2.0 (aor = 0.17, 95% ci = 0.03–0.91, p = 0.039). conclusion: high levels of overall burnout were reported among hail university medical students. students with a higher gpa, however, were found to be less prone to burnout. keywords: burnout syndrome; medical students; fatigue; stress; saudi arabia. epidemiology of burnout and its association with academic performance among medical students at hail university, saudi arabia *ahmed h. aljadani,1 ahmed alsolami,1 samiah almehmadi,2 ahmed alhuwaydi,3 anas fathuldeen4 sultan qaboos university med j, may 2021, vol. 20, iss. 2, pp. e231–236, epub. 21 jun 21 submitted 16 mar 20 revisions req. 7 may, 14 jul & 19 aug 20; revisions recd. 11 jun, 23 jul & 20 aug 20 accepted 2 sep 20 advances in knowledge the current study found that undergraduate medical students studying at hail university in saudi arabia demonstrated high levels of burnout. the current study shows a higher risk of emotional exhaustion among female students compared to male students. application of patient care adoption of preventive measures and early detection of burnout syndrome are an important steps in mental health promotion for medical students especially those with low academic performance rate. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.011 clinical & basic research th e t e r m b u r n o u t s y n d r o m e wa s introduced in the late 1960s to describe the emotional or physiological stress and deper sonalisation experienced by health practitioners.1 over the years, it has been used more widely to acknowledge any job-related stress including depressive symptoms in medical practice.2 burnout syndrome is characterised by impaired personal accomplishments and is often induced by repeated workplace stressors.3 burnout syndrome affects medical students as well as experienced physicians and generally has three dimensions: cynicism, emotional exhaustion and low professional efficacy. cynicism refers to a student’s mental distance from lessons; exhaustion refers to severe fatigue and emotional depletion due to academic demands; and professional efficacy refers to a student’s self-perception as academically accomplished or incompetent.4 medical education is recognised for being long and emotionally exhausting. several studies have reported burnout rates among medical students ranging from 10.3–76.8%, with variable assessment methodologies.5–12 medical students often have a disproportionately work-focused work-life balance that affects their time for family, friends or leisure, leading to high levels of stress, anxiety and other psychiatric morbidities.13 a 2008 study from the usa demonstrated that approximately 50% of students had burnout syndrome and 10% experienced suicidal ideation during their study period.8 in a survey conducted in saudi arabia, severe depressive symptoms were reported in 11% and 71.9% of medical students at king saud university and jazan university, respectively.10 ibrahim et al. conducted a study about anxiety and depression https://creativecommons.org/licenses/by-nd/4.0/ epidemiology of burnout and its association with academic performance among medical students at hail university, saudi arabia e232 | squ medical journal, may 2021, volume 21, issue 2 among female medical students at king abdul aziz university, jeddah, saudi arabia, and found depression and morbid anxiety occurred in 34.9% and 14.7%, respectively.14 in a systematic review and metaanalysis, frajerman et al. uncovered a vast amount of literature on burnout syndrome among medical students.15 burnout syndrome has unfavourable effects on students’ performance; thus, preventive steps are required. although some medical schools have introduced mental health programmes to support students in their medical training period, most institutions have yet to address this issue. moreover, further studies are required to investigate burnout’s impact on academic performance for those students. therefore, this study aimed to measure the prevalence and predictors of burnout among medical students at hail university, saudi arabia, with a focus on its association with academic performance. the results of this study can help guide educational authorities to build more robust preventive strategies to enhance mental health among medical students during their training period. methods this cross-sectional study was conducted from may to june 2019 among medical students in hail medical college, hail university. medical students in saudi arabia spend two years in pre-clinical and three years in clinical training. hail university medical college enrolled 405 students in the year 2018/2019 of which most were male (n = 203). during the study period, male-to-female distribution was almost equal for all five levels at the college, with approximately 80 students per academic level. no specific exclusion criteria were used in this study. data were collected using an online form distributed to students via their official university e-mail addresses. individuals were contacted twice during the study in order to increase the number of responses. the english version of the maslach burnout inventory-student survey (mbi-ss), a modified version of the maslach burnout inventory-general survey, is a self-administered questionnaire and was used to assess burnout prevalence among the participants. it has been validated and has demonstrated adequate reliability among students from portugal, spain, the netherlands and china.16,17 however, this tool has yet to be validated in saudi arabia. the first section of the questionnaire captured students’ socio-demographic characteristics including age, gender, marital status, academic level and most recent grade point average (gpa). the second section consisted of 15 mbi-ss questions focusing on the triad of exhaustion (five items), cynicism (four items) and professional efficacy (six items). all items were assessed by a seven-point likert scale ranging from six (always) to zero (never). the total scores in each of the three domains were categorised into high, moderate or low scores. the scores for the mbi-ss survey were divided into three domains: professional efficacy (low ≤22; moderate = 23–27; high ≥28), emotional exhaustion (low = 0–9; moderate = 10–14; high >14) and cynicism (low = 0–1; moderate = 2–6; high >6). high scores for cynicism and emotional exhaustion with low scores for academic efficacy indicated a high level of burnout. data analysis was conducted using statistical package for the social sciences (spss), version 25 (ibm, corp., armonk, new york, usa). all categorical variables were presented as numbers and percentages. fisher's exact and chi-squared tests were used inter changeably; these tests helped determine significant associations between categorical variables. fisher`s exact test was used in cases with lower than expected frequencies (i.e. <5 in one or more cells). otherwise, the chi-squared test was used. a fixed model multivariate logistic regression analysis was conducted for each of the three mbi component levels and total burnout to identify factors significantly associated with burnout syndrome. using raosoft® (raosoft, inc., seattle, washington, usa), an online calculator, the minimum effective sample size was calculated to ensure the number of respondents required to justify the study’s findings were approached. the minimum required sample was 198 when calculated with a 95% confidence interval (ci), 5% margin of error, total number of students of 405 and prevalence of burnout of 50%. adjusted odds ratio (aor) and 95% ci were also calculated. a p value <0.05 was considered statistically significant. ethical approval from the institutional review board at hail university medical college was obtained (hrec 00061/cm-uoh.12/19). information about the study’s purpose appeared on the first page in the electronic survey indicating that students’ participation was voluntary. respondents’ identities were not collected so personal information could not be matched to individual responses. results a total of 218 medical students participated in this study (response rate: 53.8%) of which the majority were female (n = 121; 55.5%) and were 21–24 years old (n = 175; 80.3%). most respondents (n = 208; 95.4%) indicated that they were single. most students achieved a gpa of ≥3.01 (n = 154; 70.6%) of which ahmed h. aljadani, ahmed alsolami, samiah almehmadi, ahmed alhuwaydi and anas fathuldeen clinical and basic research | e233 96 students (44.0%) indicated maintaining a gpa between 3.51–4.00. the parameters of burnout syndrome such as high emotional exhaustion, high cynicism and low professional efficacy had a prevalence of 79.4% (n = 173), 61.0% (n = 133) and 37.6% (n = 82), respectively [figure 1]. the overall prevalence of high burnout was 27.1% (n = 59). high burnout was reported among 40% (n = 20) of students in their fourth year compared to 11.9% (n = 5) of students in their second year of medical school. the overall association between high burnout and academic level was significant (p = 0.050). the table 1: factors associated with high burnout and burnout components among medical students at hail university, saudi arabia, in 2019 (n = 218) characteristic n (%) high emotional exhaustion high cynicism low professional efficacy high burnout age in years 17–20 (n = 33) 25 (75.8) 19 (57.6) 7 (21.2) 4 (12.1) 21–24 (n = 175) 142 (81.1) 109 (62.3) 71 (40.6) 53 (30.3) >24 (n = 10) 6 (60.0) 5 (50.0) 4 (40.0) 2 (20.0) p value 0.240 0.853 0.171 0.086 gender male (n = 97) 71 (73.2) 58 (59.8) 36 (37.1) 27 (27.8) female (n = 121) 102 (84.3) 75 (62.0) 46 (38.0) 32 (26.5) p value 0.130 0.766 0.983 0.819 marital status single (n = 208) 165 (79.3) 128 (61.5) 78 (37.5) 56 (26.9) married (n = 10) 8 (80.0) 5 (50.0) 4 (40.0) 3 (30.0) p value 0.998 0.222 0.840 0.538 academic level second year (n = 42) 31 (73.8) 25 (59.5) 9 (21.4) 5 (11.9) third year (n = 43) 33 (76.7) 23 (53.5) 19 (44.2) 11 (25.6) fourth year (n = 50) 41 (82.0) 35 (70.0) 24 (48.0) 20 (40.0) fifth year (n = 43) 36 (83.7) 26 (60.5) 15 (34.9) 13 (30.2) sixth year (n = 40) 32 (80.0) 24 (60.0) 15 (37.5) 10 (25.0) p value 0.211 0.879 0.086 0.050 gpa ≤2.00 (n = 7) 6 (85.7) 5 (71.4) 4 (57.1) 3 (42.9) 2.01–2.50 (n = 15) 13 (86.7) 12 (80.0) 8 (53.3) 7 (46.7) 2.51–3.00 (n = 42) 33 (78.6) 30 (71.4) 21 (50.0) 18 (42.9) 3.01–3.50 (n = 58) 53 (91.4) 42 (72.4) 27 (46.6) 22 (37.9) 3.51–4.00 (n = 96) 68 (70.8) 44 (45.8) 22 (22.9) 9 (9.4) p value 0.134 0.009 0.001 <0.001 gpa = grade point average. figure 1: frequency of components of burnout among medical students at hail university, saudi arabia, in 2019. epidemiology of burnout and its association with academic performance among medical students at hail university, saudi arabia e234 | squ medical journal, may 2021, volume 21, issue 2 highest rate of cynicism was observed among students whose gpas ranged between 2.01–2.50, while the lowest rate was observed among those whose gpas ranged between 3.51–4.00 (80.0% versus 45.8%; p = 0.009). the highest rate of low professional efficacy was observed among students whose gpas were ≤2.0 while the lowest rate was observed among those whose gpas ranged between 3.51–4.00 (57.1% versus 22.9%; p = 0.001). regarding burnout, the highest rate was observed among students whose gpas ranged between 2.01–2.50, while the lowest rate was observed among those whose gpa ranged between 3.51–4.00 (46.7% versus 9.4%; p <0.001) [table 1]. the multivariate logistic regression analysis revealed that female students were at almost double the risk for high emotional exhaustion compared to male students (aor = 2.14, 95% ci = 1.06–4.34; p = 0.034). students with gpas ranging from 3.51–4.00 (44%) were considerably less prone to burnout compared to students with gpas ≤2.0 (aor = 0.17, 95% ci = 0.03–0.91; p = 0.039). other associations with high burnout and burnout components were not statistically significant. [table 2]. table 2: predictors of burnout among medical students based on results of multivariate logistic regression analysis (n = 218) high emotional exhaustion high cynicism low professional efficacy high burnout aor 95% ci p value aor 95% ci p value aor 95% ci p value aor 95% ci p value age in years 17–20* 1.0 1.0 1.0 1.0 21–24 0.74 0.21–2.63 0.644 0.90 0.30–2.63 0.840 1.38 0.42–4.58 0.596 1.05 0.23–4.79 0.945 >24 0.12 0.01–1.16 0.067 0.50 0.07–3.67 0.496 1.39 0.18–10.8 0.754 0.46 0.03–6.09 0.555 gender male* 1.0 1.0 1.0 1.0 female 2.14 1.06–4.34 0.034 1.21 0.67–2.17 0.525 1.15 0.64–2.07 0.649 1.10 0.57–2.13 0.781 marital status single* 1.0 1.0 1.0 1.0 married 2.38 0.28–20.31 0.428 0.65 0.14–2.99 0.578 0.90 0.19–4.26 0.891 1.37 0.24–7.78 0.724 academic level second year* 1.0 1.0 1.0 1.0 third year 1.30 0.38–4.51 0.677 0.65 0.22–1.87 0.424 2.09 0.67–6.51 0.204 1.83 0.44–7.61 0.408 fourth year 1.66 0.43–6.38 0.459 1.10 0.35–3.47 0.873 1.94 0.59–6.40 0.275 2.78 0.65–11.9 0.168 fifth year 1.90 0.48–7.59 0.363 0.75 0.23–2.37 0.618 1.15 0.34–3.93 0.821 1.86 0.42–8.29 0.415 sixth year 2.10 0.48–9.24 0.325 0.85 0.25–2.93 0.800 1.30 0.36–4.77 0.688 1.57 0.32–7.74 0.577 gpa ≤2* 1.0 1.0 1.0 1.0 2.01– 2.50 1.31 0.09–19.0 0.844 1.80 0.21–15.4 0.591 1.08 0.17–6.99 0.938 1.50 0.23–9.90 0.672 2.51– 3.00 0.67 0.07–6.45 0.730 1.02 0.17–6.12 0.985 0.85 0.16–4.38 0.846 1.02 0.20–5.27 0.981 3.01– 3.50 2.01 0.19–20.9 0.558 0.99 0.17–5.82 0.998 0.83 0.16–4.20 0.823 0.92 0.18–4.71 0.923 3.51– 4.00 0.43 0.05–3.88 0.453 0.31 0.06–1.73 0.183 0.29 0.06–1.45 0.132 0.17 0.03–0.91 0.039 aor = adjusted odds ratio; ci = confidence interval; gpa = grade point average. *reference category. ahmed h. aljadani, ahmed alsolami, samiah almehmadi, ahmed alhuwaydi and anas fathuldeen clinical and basic research | e235 discussion the present study discovered a high prevalence of burnout syndrome among medical students at hail university’s medical college. the results show alarming numbers that suggest that saudi medical students may experience high burnout levels. medical students are vulnerable to burnout as a result of high exposure to psychosocial stressors throughout their academic and training periods.18 different rates of burnout have been reported in different countries and even within the same country. the prevalence of high emotional exhaustion, high cynicism and low professional efficacy in the current study was found to occur in 79.4%, 61.0%, and 37.6% of respondents, respectively. the overall prevalence of high burnout was 27.1%. in a recent study carried out in riyadh, saudi arabia, a very high burnout prevalence of 67.1% was reported.4 in another study carried out in riyadh, the prevalence of high emotional exhaustion, high depersonalisation and low personal accomplishment was 17.4%, 56.9% and 14.9%, respectively, with an overall prevalence of burnout of 13.4%.19 the findings of the current study occur within the 13.4–67.1% range previously discovered in saudi arabian medical schools. the wide variation in reported rates of burnout in these studies, including the present one, could be attributed to the use of different instruments and scales in defining burnout. these instruments include the copenhagen burnout inventory, oldenburg burnout inventory, modified maslach burnout inventory, short perceived stress scale, emotional exhaustion subscale of the maslach burnout inventory and the english version of the mbi-ss. this variation could also be attributed to the cultural, social and environmental determinants of burnout in different situations. further studies are required to ascertain the cause for burnout’s wide-ranging prevalence among medical students. the high level of competition among medical students in saudi arabia to pursue desirable postgraduate residency programmes may also contribute to the high level of burnout reported in this study. during their training and in order to maximise their chances for securing positions at the desired residency programmes, medical students must build a strong curriculum vitae which includes published research, presentations at conferences and academic activities.4 this rigor contributes to burnout among medical students. careful analysis of other studies carried out inside and outside saudi arabia have revealed no association between students’ gender and burnout.4,20 in contrast, the current study shows a higher risk of high emotional exhaustion among female students when compared to their male peers. a recent chinese systematic review similarly reported gender as a significant determinant of burnout.21 the current study showed a higher rate of burnout in students in their clinical years compared to those in preclinical years. this same finding was observed in a study carried out in spain where the risk for burnout was significantly higher (p <0.0001) among sixth-year students (37.5%) compared to third-year students (14.8%).20 however, almalki et al. reported that academic year was not a predictor for burnout.4 the current study showed that high cynicism, low professional efficacy and overall high burnout were reported more among students with low gpas (≤2.00 out of 4.00). however, the number of study participants in the lowest gpa categories was relatively small, and the confidence intervals included one. the results of the multivariate logistic regression analysis revealed that students whose gpa ranged between 3.51–4.00 were less prone to burnout as opposed to those whose gpas were ≤2.00 out of 4.00. this finding was demonstrated in a saudi arabian study which reported that students with gpas <4.5 out of 5.0 had higher burnout rates (n = 73, 70.9%) compared to students with gpas ≥4.5 (n = 88, 62.9%).4 however, further studies are needed to investigate this issue. although the current study will add to the saudi arabian literature on burnout syndrome and may help in the early detection of burnout syndrome and the adoption of preventive measures, it has some important limitations. first, the cross-sectional design of this study determines statistical associations but not causal relationships. second, the utilisation of a self-administered questionnaire could be a source of information bias. finally, the study was carried out only in one location and thus was not representative of all saudi medical students’ burnout levels. furthermore, given the low response rate, some cases with higher levels of burnout were potentially missed thus impacting the generalisability of the results. numerous strategies are required to decrease the burden of burnout among medical students, including involving students in extracurricular activities, altering educational and clinical environments to reduce avoidable stressors, providing good social support and engaging students in community service.22,23 finally, longitudinal studies which follow medical students starting from college admission and ending at their graduation are warranted to explore potential burnout patterns. epidemiology of burnout and its association with academic performance among medical students at hail university, saudi arabia e236 | squ medical journal, may 2021, volume 21, issue 2 conclusion burnout was found to be prevalent among medical students at hail university, saudi arabia. students with high gpas were found to be less prone, however, to burnout syndrome. as burnout impacts the academic performance of medical students, further exploration of this problem and potential factors to reduce its burden should be of paramount importance to future researchers and medical educators. a c k n o w l e d g e m e n t the authors gratefully acknowledge mohammed altriefi, abdulrhman alluhaybi and talal banan who assisted in the data collection for this paper. ava i l a b i l i t y o f d ata a n d m at e r i a l s data used to support the findings of this study are available from the corresponding author upon request. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. s t r o b e g u i d e l i n e s this manuscript adheres to strobe guidelines. references 1. rotenstein ls, torre m, ramos ma, rosales rc, guille c, sen s, et al. prevalence of burnout among physicians: a systematic review. jama 2018; 320:1131–50. https://doi.org/10.1001/ jama.2018.12777. 2. kim mh, mazenga ac, simon k, yu x, ahmed s, nyasulu p, et al. burnout and self-reported suboptimal patient care amongst health care workers providing hiv care in malawi. plos one 2018; 13:e0192983. https://doi.org/10.1371/journal.pone.0192983. 3. mazurkiewicz r, korenstein d, fallar r, ripp j. the prevalence and correlations of medical student burnout in the pre-clinical years: a cross-sectional study. psychol health med 2012; 17:188–95. https://doi.org/10.1080/13548506.2011.597770. 4. almalki sa, almojali ai, alothman as, masuadi em, alaqeel mk. burnout and its association with extracurricular activities among medical students in saudi arabia. int j med educ 2017; 8:144–50. https://doi.org/10.5116/ijme.58e3.ca8a. 5. chang e, eddins-folensbee f, coverdale j. survey of the prev alence of burnout, stress, depression, and the use of supports by medical students at one school. acad psychiatry 2012; 36:177–82. https://doi.org/10.1176/appi.ap.11040079. 6. costa ef, santos sa, santos at, melo ev, andrade tm. burnout syndrome and associated factors among medical students: a cross-sectional study. clinics (sao paulo) 2012; 67:573–80. https://doi.org/10.6061/clinics/2012(06)05. 7. dahlin me, runeson b. burnout and psychiatric morbidity among medical students entering clinical training: a three year prospective questionnaire and interview-based study. bmc med educ 2007; 7:6. https://doi.org/10.1186/1472-6920-7-6. 8. dyrbye ln, thomas mr, massie fs, power dv, eacker a, harper w, et al. burnout and suicidal ideation among us medical students. j annal intern med 2008; 149:334–41. https://doi.org/10.7326/0003-4819-149-5-200809020-00008. 9. el-masry r, ghreiz sm, helal rm, audeh am, shams t. perceived stress and burnout among medical students during the clinical period of their education. ibnosina j med biomed sci 2013; 5:179–87. https://doi.org/10.4103/1947-489x.210543. 10. al-faris ea, irfan f, van der vleuten cp, naeem n, alsalem a, alamiri n, et al. the prevalence and correlates of depressive symp toms from an arabian setting: a wake up call. med teach 2012; 34:s32–6. https://doi.org/10.3109/0142159x.2012.656755. 11. muzafar y, khan hh, ashraf h, hussain w, sajid h, tahir m, et al. burnout and its associated factors in medical students of lahore, pakistan. cureus 2015; 7:e390. https://doi.org/10.7759/ cureus.390. 12. youssef ff. medical student stress, burnout and depression in trinidad and tobago. acad psychiatry 2016; 40:69–75. https:// doi.org/10.1007/s40596-015-0468-9. 13. campos ja, maroco j. [maslach burnout inventory-student survey: portugal-brazil cross-cultural adaptation]. rev saude publica 2012; 46:816–24. https://doi.org/10.1590/s0034-89102 012000500008. 14. ibrahim n, al-kharboush d, el-khatib l, al-habib a, asali d. prevalence and predictors of anxiety and depression among female medical students in king abdulaziz university, jeddah, saudi arabia. iran j public health 2013; 42:726–36. 15. frajerman a, morvan y, krebs mo, gorwood p, chaumette b. burnout in medical students before residency: a systematic review and meta-analysis. eur psychiatry 2019; 36–42. https:// doi.org/10.1016/j.eurpsy.2018.08.006. 16. schaufeli wb, martinez im, pinto am, salanova m, bakker ab. burnout and engagement in university students: a cross-national study. j cross-cult psychol 2002; 33:464–81. https://doi.org/10 .1177/0022022102033005003. 17. hu q, schaufeli wb. the factorial validity of the maslach burnout inventory-student survey in china. psychol rep 2009; 105:394–408. https://doi.org/10.2466/pr0.105.2.394-408. 18. tarnowski m, carlotto ms. burnout syndrome in students of psychology. temas psicol 2007; 15:173–80. 19. altannir y, alnajjar w, ahmad so, altannir m, yousuf f, obeidat a, et al. assessment of burnout in medical undergraduate students in riyadh, saudi arabia. bmc med educ 2019: 19;34. https:// doi.org/10.1186/s12909-019-1468-3. 20. galán f, sanmartín a, polo j, giner l. burnout risk in medical students in spain using the maslach burnout inventory-student survey. int arch occup environ health 2011; 84:453–9. https://doi.org/10.1007/s00420-011-0623-x. 21. chunming wm, harrison r, macintyre r, travaglia j, balasooriya c. burnout in medical students: a systematic review of experiences in chinese medical schools. bmc med educ 2017; 17:217. https://doi.org/10.1186/s12909-017-1064-3. 22. kim b, jee s, lee j, an s, lee sm. relationships between social support and student burnout: a meta-analytic approach. stress health 2018: 34;127–34. https://doi.org/10.1002/smi.2771. 23. fontana mcp, generoso ip, sizilio a, bivanco-lima d. burnout syndrome, extracurricular activities and social support among brazilian internship medical students: a cross-sectional analysis. bmc med educ 2020; 20:81. https://doi.org/10.1186/s12909020-01998-6. https://doi.org/10.1001/jama.2018.12777 https://doi.org/10.1001/jama.2018.12777 https://doi.org/10.1371/journal.pone.0192983 https://doi.org/10.1080/13548506.2011.597770 https://doi.org/10.5116/ijme.58e3.ca8a https://doi.org/10.1176/appi.ap.11040079 https://doi.org/10.6061/clinics/2012%2806%2905 v https://doi.org/10.7326/0003-4819-149-5-200809020-00008 https://doi.org/10.4103/1947-489x.210543 https://doi.org/10.3109/0142159x.2012.656755 https://doi.org/10.7759/cureus.390 https://doi.org/10.7759/cureus.390 https://doi.org/10.1007/s40596-015-0468-9 https://doi.org/10.1007/s40596-015-0468-9 https://doi.org/10.1590/s0034-89102012000500008 https://doi.org/10.1590/s0034-89102012000500008 https://doi.org/10.1016/j.eurpsy.2018.08.006 https://doi.org/10.1016/j.eurpsy.2018.08.006 https://doi.org/10.1177/0022022102033005003 https://doi.org/10.1177/0022022102033005003 https://doi.org/10.2466/pr0.105.2.394-408 https://doi.org/10.1186/s12909-019-1468-3 https://doi.org/10.1186/s12909-019-1468-3 https://doi.org/10.1007/s00420-011-0623-x https://doi.org/10.1186/s12909-017-1064-3 https://doi.org/10.1002/smi.2771 https://doi.org/10.1186/s12909-020-01998-6 https://doi.org/10.1186/s12909-020-01998-6 submitted 25 oct 21 1 revision req. 26 dec 21; revision recd. 24 jan 22 2 accepted 22 feb 22 3 online-first: march 2022 4 doi: https://doi.org/10.18295/squmj.3.2022.024 5 6 large intraosseous haemangioma of the sacral vertebra 7 the radiological imaging findings 8 nerbadyswari deep,1 *sudipta mohakud,1 mantu jain,2 suprava naik,1 9 manas baisakh3 10 11 departments of 1radiodiagnosis and 2orthopedics, all india institute of medical sciences, 12 bhubaneswar, india; 3department of pathology, prolife diagnostic, bhubaneswar, india 13 *corresponding author’s e-mail: drsudipta.m@gmail.com 14 15 a 28-year-old male technologist presented to the orthopedics department of the all india 16 institute of medical sciences, bhubaneswar, in 2020 with a complaint of dull aching low 17 back pain on prolonged sitting for six months. there was local tenderness in the sacral region 18 on deep palpation without local swelling or pain radiation to the limbs. the straight leg 19 raising test was negative. he was intact neurologically (asia e), and the pain score was low 20 (vas-2/10). an x-ray showed some suspicious lytic lesion in the sacral vertebra. he 21 underwent computed tomography (ct) scan and a contrast-enhanced magnetic resonance 22 imaging to characterize the lesion further. the ct highlighted a large expansile lucent lesion 23 associated with a soft tissue component involving the s2 s5 vertebrae producing a presacral 24 bulge and extension into bilateral sacral foramina (figure1a). the lesion had internal bony 25 septations with preserved vertebral height and bony outline. the mri showed an expansile 26 well-marginated t1 hypointense and t2 hyperintense lesion, which was hyperintense in the 27 short tau inversion recovery sequence (stir) (figure1b). post-gadolinium injection t1 fat-28 suppressed images showed avid homogeneous lesion enhancement (figure2a). the 29 imaging findings were suggestive of a benign lesion, most likely vertebral body 30 haemangioma (vbh). 31 32 mailto:drsudipta.m@gmail.com a biopsy was planned to exclude malignancy as there was a presacral soft-tissue bulge. the 33 histopathological study revealed readily recognizable vascular structures with red blood cells 34 or transudate, lined by a monolayer of endothelial cells characteristic of haemangioma 35 (figure2b). the patient was managed conservatively with yearly follow-up; there was no 36 interval change in the lesion's size on follow-up mri. 37 38 informed consent was obtained from the patient for using his medical data for publication 39 purposes. 40 41 comment 42 vbh occurs in more than 11% of the population, yet sacral involvement is uncommon. they 43 are seen in adults with a male to female ratio of 1:1.5.1 they are indolent except in < 1% 44 when they become symptomatic either by bone expansion with or without an associated 45 pathological fracture, extension into the neural foramen, or the spinal canal causing 46 radiculopathy or myelopathy and known as aggressive haemangiomas. 2,3 aggressive 47 haemangiomas present with pain, and they may have an extraosseous soft tissue component 48 contiguous with the osseous lesion. 49 50 the differential diagnoses are chordoma, giant cell tumors, enchondroma, chondrosarcoma, 51 aneurysmal bone cyst, metastases, and rarely hydatid cysts in endemic areas. 1,4,5 52 a haemangioma is well defined with a hyperintense signal on t1weighted imaging (t1wi) 53 and t2wi due to the fat content and avid homogeneous enhancement on post-contrast 54 imaging. the vascular elements make the signal high on fluid-sensitive sequences. the 55 thickened vertical trabeculae are more appreciated on the ct scans producing the "polka dot 56 sign." sometimes atypical presentation occurs due to variable amount of fat and vascular 57 components producing an atypical hypo to isointense signal on t1wi and heterogeneous 58 hyperintensity on t2wi and stir-sequences.2 59 60 sacral haemangiomas do not require any treatment until they become painful or encroach the 61 sacral nerves. 62 63 this case highlights the presence of a presacral soft tissue component in a haemangioma 64 mimicking a malignant lesion. accurate identification of imaging findings can reduce patient 65 anxiety and morbidity due to surgical intervention. 66 67 authors’ contribution 68 nd, sn and mb were involved in diagnosis, manuscript editing and reviewing the 69 manuscript. sm and mj were involved in data collection, drafting, editing and reviewing the 70 manuscript. all authors approved the final version of the manuscript. 71 72 references 73 1. vanheule e, huysse w, herregods n, verstraete k, jans l. sacral tumours on mri: 74 a pictorial essay. j belg soc radiol 2019 ;103(1):62. doi: 10.5334/jbsr.1887. 75 2. gaudino s, martucci m, colantonio r, lozupone e, visconti e, leone a, et al. a 76 systematic approach to vertebral hemangioma. skeletal radiol 2015;44(1):25-36. doi: 77 10.1007/s00256-014-2035-y. 78 3. wang b, zhang l, yang s, han s, jiang l, wei f, et al. atypical radiographic 79 features of aggressive vertebral hemangiomas. j bone joint surg am 80 2019;101(11):979-86. doi: 10.2106/jbjs.18.00746. 81 4. thornton e, krajewski km, o'regan kn, giardino aa, jagannathan jp, ramaiya n. 82 imaging features of primary and secondary malignant tumours of the sacrum. br j 83 radiol 2012 ;85(1011):279-86. doi: 10.1259/bjr/25247602. 84 5. mohakud s, ray b, naik s, deep n. isolated sacral vertebral hydatid cyst 85 presenting with pathological fracture. j neurosci rural pract 2019;10(3):565-6. doi: 86 10.1055/s-0039-1695700. 87 88 figure 1a: sagittal ct bone window image shows an expansile soft tissue density lytic 89 lesion involving the s2 to s5 sacral vertebrae with a presacral bulge and extension into sacral 90 foramina. 91 92 figure 1b: sagittal t1 weighted image shows a well-marginated expansile, predominantly 93 hypointense lesion involving the s2 to s5 vertebrae. 94 95 96 figure 2a: sagittal post intravenous gadolinium injection t1 fat-suppressed image showing 97 avid enhancement of the lesion with a presacral bulge, extension into the sacral foramen and 98 spinal canal. 99 100 figure 2b: the histopathology of the biopsy specimen of the sacral lesion (h& e stained, x 101 4 magnification) showing variable-sized blood-filled vascular spaces between mature bony 102 trabeculae, lined by a monolayer of endothelial cells. 103 female genital tuberculosis among infertile women and its contributions to primary and secondary infertility a systematic review and meta-analysis *musa a.e. ahmed,1,3 abdullah a.a. mohammed,1,4 abiodun o. ilesanmi,2 christopher o. aimakhu,2 amel o. bakhiet,5,6 suad b.m. hamad7 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 314–324, epub. 25 aug 22 submitted 24 jul 21 revision req. 31 oct 21; revision recd. 22 nov 21 accepted 6 jan 22 departments of 1reproductive health sciences, pan african university life and earth sciences institute (paulesi) and 2obstetrics & gynecology, college of medicine, university of ibadan, ibadan, nigeria; 3department of veterinary surgery, faculty of veterinary medicine, al-salam university, west kordofan, sudan; 4department of biomedical sciences, faculty of veterinary sciences, university of gadarif, gadarif, sudan; 5department of pathology, college of veterinary medicine and 6the scientific research deanship, college of veterinary medicine, sudan university of science & technology, khartoum, sudan; 7department of animal health & diseases control, ministry of animal recourses & fishers, south kordofan, sudan *corresponding author’s e-mail: musasergo@gmail.com tuberculosis (tb) is an infectious disease caused by mycobacterium tuberculosis which was recently listed among the top 10 diseases causing death around the world. according to the world health organization (who), 10.0 million people were infected with tb and there were 1.2 million tb deaths in 2019.1 two-thirds of this global burden was present in eight countries – india, indonesia, china, the philippines, pakistan, nigeria, bangladesh and south africa.1 female genital tuberculosis (fgtb) is commonly secondary to pulmonary tb (ptb) or extrapulmonary tb (eptb), with an incidence rate ranging between 9–20% and 5–13% among overall eptb and ptb cases worldwide according to many multitask studies, respectively.2–6 typically, fgtb is known as a disease of young women (20–40 years old);5,7 it is usually diagnosed during infertility evaluations.2,8 a previous study indicated that the infertility rates in women is higher compared to men.9 moreover, 76% of infertile women had a history of tb;10 infertility is the most frequent complaint of fgtb cases which occurs due to irreversible damage to the fallopian tube.4,11 in addition to infertility, other clinical presentations of fgtb include pelvic pain or menstrual irregularities, and it remains a major health problem in low-income countries.8,12 organs commonly affected by fgtb are the fallopian tube (90%), ovaries (10–30%), endometrium (50%), cervix and vagina.3,13 infertile fgtb patients have been reported to have a longer duration of infertility compared to infertility from other sources.14 this meta-analysis was conducted to investigate the prevalence of fgtb among infertile women of reproductive age and to evaluate the incidence of primary and secondary infertility among fgtb patients around the globe. methods e l i g i b i l i t y c r i t e r i a studies were eligible if they characterised the epidemiology of fgtb among women within reproductive age, if the study population was infertile women or at least indicated a proportion of infertility complaints with enough explanation of epidemiology of fgtb, were published in english, were published between 1971 to 17 july, 2021 and used the diagnostic methods of fgtb based on the particular infertility centres testing protocol. articles were excluded if they were characterised as only ptb or eptb regardless of fgtb and if the reported prevalence of fgtb was not that of infertile women. review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.1.2022.003 abstract: female genital tuberculosis (fgtb) is a widespread infectious disease among young women. this meta-analysis aimed to investigate the prevalence of fgtb among infertile women and its contribution to primary and secondary infertility. pubmed, medline®, worldcat, the lens, direct google search, google scholar and researchgate were searched from 1971 to july 17, 2021 using the following terms: “prevalence”, “epidemiology”, “urogenital tuberculosis”, “fgtb”, “infertile women”, “infertility complaints” and “fgtb testing methods”. data were extracted and a meta-analysis was performed. a total of 42 studies were selected with a total of 30,918 infertile women. of these, the pooled prevalence of fgtb was 20% (95% confidence interval: 15–25%, i2 = 99.94%) and the prevalence of overall infertility, primary infertility and secondary infertility among fgtb population were 88%, 66% and 34%, respectively. the proportion of fgtb is remarkable among infertile women globally. the biggest burden of the disease is present in low-income countries followed by lower-to-middleand upper-to-middle-income countries. keywords: female genital tuberculosis; female infertility; worldwide; prevalence of fgtb; mycobacterium tuberculosis; infertility. https://creativecommons.org/licenses/by-nd/4.0/ musa a.e. ahmed, abdullah a.a. mohammed, abiodun o. ilesanmi, christopher o. aimakhu, amel o. bakhiet and suad b.m. hamad review | 315 i n f o r m at i o n s o u r c e s this study was carried out in accordance with the guidelines of preferred reporting items for systematic reviews and meta-analyses (prisma). several electronic databases such as medline® (national library of medicine, bethesda, maryland, usa), worldcat (oclc, inc., dublin, ohio, usa), the lens (cambia, canberra, australia) and pubmed (national library of medicine) were used to retrieve published articles. in addition, other search engines were intensively combed through including direct google search (google llc, mountain view, california, usa), google scholar (google llc) and researchgate, in order to retrieve studies that were not indexed in pubmed. all mentioned databases were searched from their commencement for the period between 1971 to july 17, 2021, for human studies published in english. s e a r c h s t r at e g y the boolean search terms (and, or) were used to develop the research strategy to retrieve studies from pubmed and worldcat. the final search strategy included the use of title/abstract related to ([female genital tuberculosis] or [urogenital tuberculosis]) and ([prevalence] or [epidemiology]) and ([infertile women] or [infertility]). manual searches were applied in a direct google search, google scholar and researchgate for the same purpose. s t u d y s e l e c t i o n p r o c e s s all retrieved articles were first screened by title and abstract followed by a full-text screening. then, eligible articles were exported to the mendeley citation manager software (elsevier, amsterdam, the netherlands), version 1.19.8, to check for duplicates; all duplicated articles were removed. two authors (am and ma) screened and evaluated the remaining studies independently by a careful reading of the title and abstract followed by a full-text article screening if the particular records mentioned the outcomes of the review ‘prevalence of female genital tuberculosis among infertile women’ in their titles and abstract. however, the screened full-text articles were considered for further evaluation based on the objectives, methods, participants and key findings. the two authors (ma and am) independently evaluated the quality of the studies using the prisma checklist.15 any inconsistency for the included articles was resolved through discussion and by consulting an expert. the overall study selection process is presented using the prisma statement flow diagram [figure 1]. d ata c o l l e c t i o n p r o c e s s the relevant data from selected articles were extracted by three investigators independently (am, ma and sh) using a data extraction template by microsoft office word, version 2016 (microsoft corp., redmond, washington, usa). the extracted information included author name, year of publication, reference, study country, study design/setting, sample size, fgtb proportion among infertile women, the prevalence of overall infertility, primary infertility and secondary infertility among fgtb cases [table 1]. the data extraction accuracy was verified by comparing the data extraction results by a second group of investigators (ab, ai and ca), who independently extracted the data in a randomly-selected subset of papers (30% of the total). the extracted quantitative data were summarised in a microsoft excel sheet (microsoft corp.). based on the aim of this study, which is ‘to investigate the pooled prevalence of fgtb among infertile women globally’, the collected data was divided into four subgroups according to the world bank economical classification. the prevalence of fgtb among infertile women and prevalence of pooled infertility (primary and secondary) among fgtb cases were calculated using stata, version 16 (statacorp lp, college station, texas, usa). d ata i t e m s the main outcome of this study was the prevalence of fgtb among infertile women within reproductive age worldwide which is measured by the direct reports from individual studies. out of these, 26 studies from india, three studies from nigeria and two articles each from ethiopia, south africa and pakistan were retrieved. also, only one article each was retrieved from egypt, iraq, iran, usa, saudi arabia, sudan and yemen. to quantify the outcome, the investigators considered studies that reported the prevalence of fgtb among infertile women and the types of tb regarding fgtb among gynaecology-admitted/infertile women in their statistics. the result was interpreted by the proportions of the infertile population having any type of fgtb from the total population studied. s t u d y r i s k o f b i a s a s s e s s m e n t inclusion criteria were appraised for all retrieved articles by using the title and abstract; then, full-text articles were screened to check the quality of each study before final selection. the quality assessment criteria for the studies included in the current metaanalysis and systematic review is as follows: (1) the female genital tuberculosis among infertile women and its contributions to primary and secondary infertility a systematic review and meta-analysis 316 | squ medical journal, august 2022, volume 22, issue 3 diagnosis of the infertility cases were performed at an infertility centre with consideration that infertility is defined as one year without conception after unprotected intercourse; (2) the infertility was not due to the male factor; (3) the diagnosis included an infertile population who tested for fgtb willingly; (4) the diagnosis of fgtb was conducted after excluding the patients with confirmed fgtb; and (5) the sample size was representative of the population. a comprehensive search including electronic databases, grey literature and unpublished studies was done in order to manage and minimise the risk of bias. moreover, two groups of investigators (am, ma and sh) and (ab, ai and ca) used the joanna briggs institute quality assessment tool as a critical appraisal tool.16 the differences in the inclusion of the studies were resolved by consensus. the included studies were evaluated against each indicator of the tool and categorised as high-, moderateand lowquality. studies with a score ≥60% were included. the publication bias for the included studies was checked by both the visual inspection of the funnel plot and the statistical symmetry of the funnel plot using egger’s regression test. s u m m a r y m e a s u r e s the proportion of fgtb among infertile women and proportion of the type of infertility among fgtb patients were used to synthesise and present the results for the analysis. s y n t h e s i s m e t h o d s the collected data were synthesised and analysed in stata (statacorp lp). the recommendations of the i2 statistic described by higgins et al. (an i2 of 75/100% and above suggests considerable heterogeneity) were used to perform this meta-analysis.17 the effect size, with a 95% confidence interval (ci) and standard error (se), was used to calculate the results of this study. the effect size of this study was the prevalence of fgtb and the prevalence of the type of infertility subgroups; these were calculated using the binomial distribution. the se was calculated using the sample size (n) and the proportion of fgtb (p) using the following equation: any potential publication bias was checked using a funnel plot and egger’s regression test. subgroup analysis was applied to check the potential source of heterogeneity and possible source of bias. any study with missing data and/or a high risk of bias was excluded. p values were interpreted as statistically significant at a value of less than 0.10. the study results were reported according to the prisma guidelines and the findings were presented using a narrative synthesis followed by a meta-analysis chart. results s t u d y s e l e c t i o n a total of 1,203 articles/records were identified. of these, 961 articles/records were removed due to duplication and title screening resulting in 242 articles/records for further inspection. subsequently, another 180 articles were excluded after a very careful screening of abstracts. therefore, a total of 62 articles were eligible for full-text screening; 20 articles of these were excluded due to inconsistency with the study inclusion criteria. finally, 42 articles fulfilled √p(1–p) ÷ ɳ [equation 1] figure 1: flowchart showing the selection process for articles included in the current review. musa a.e. ahmed, abdullah a.a. mohammed, abiodun o. ilesanmi, christopher o. aimakhu, amel o. bakhiet and suad b.m. hamad review | 317 table 1: characteristics of studies included in the current meta-analysis4–7,10,12,19,20,23–28,38–64 author and year of publication study design/ setting world bank country income classification country infertile population fgtb testing method n (%) proportion of fgtb proportion of infertility among fgtb patient overall infertility pi si chattopadhyay et al.38 (1986) cs/ha high-income saudi arabia 945 na 40 (4.2) na na na tal et al.39 (2020) pc/hc high-income usa 323 quantiferontb 25 (7.7) na na na abdissa et al.4 (2018) cs/ha low-income ethiopia 152 pcr, cp, he 8 (5.3) 5 (62.5) 4 (50) 1 (12.5) abebe et al.13 (2004) cs/ha low-income ethiopia 25 afb, cp, he, pcr 16 (64) na na na ali and abdallah40 (2012) cs/ha low-income sudan 2,778 he 25 (0.9) na na na abdelrub and al harazi41 (2015) p/o/ha low-income yemen 151 afb, pcr, cp, he 47 (31.1) na na na nezar et al.42 (2009) p/o/ha lower-middle income egypt 420 laparoscopy, he, pcr 24 (5.7) 24 (100) na na kumar et al.6 (2008) cs/ha lower-middle income india 285 pcr 111 (39) 111 (100) na na mohakul et al.5 (2015) p/hc lower-middle income india 105 pcr, hysteroscopy 41 (39) 41 (100) 24 (58) 17 (42) jindal10 (2006) r/hc lower-middle income india 2,083 lap, afb, he, mt, elisa 10 (7.2) 146 (97.3) 105 (70) 41 (27.3) singh et al.43 (2008 r/hc lower-middle income india 140 mh, laparoscopy, hysteroscopy 34 (48.5) na na na sankar et al.44 (2013) r/ha lower-middle income india 620 afb, pcr, cp, he 158 (25.5) 151 (95.5) 119 (78.8) 32 (21.2) mahajan et al.45 (2016) cs/ha lower-middle income india 180 pcr, cp 74 (41) na na na sethi et al.46 (2016) cs/ha lower-middle income india 300 afb, pcr, cp, he 68 (22.7) na na na chatterjee et al.65 (2018) cs/ha lower-middle income india 120 pcr 2 (1.7) na na na chowdhury et al.47 (2010) co/ha lower-middle income india 517 pcr 230 (44.5) 114 (49.7) na na saraswat et al.48 (2010) cs/ha lower-middle income india 125 pcr, cp 26 (20.8) na na na malhotra et al.49 (2012) o/ha lower-middle income india 555 afb, pcr, cp 140 (25.22) na na na gajbhiye et al.50 (2019) cs/o/ha lower-middle income india 50 pcr 6 (12) 5 (83.3) 4 (80) 1 (20) bhanothu et al.51 (2014) p/cc/ha lower-middle income india 302 pcr 86 (28.47) na na na gurjar et al.20 (2018) o/ha lower-middle income india 100 pcr 52 (52) na na na fgtb = female genital tuberculosis; pi = primary infertility; si = secondary infertility; cs = cross-sectional study; ha = hospital admitted patients; na = not available; pc = prospective cohort study; hc = infertility centre admitted patient; pcr = polymerase chain reaction test; cp = culture proven; he = histopathological examination; afb = acid-fast bacilli test ; p = prospective study; o = observational study; r = retrospective study; lap = laparotomy; mt = mantoux test ; elisa = enzyme-linked immunosorbent assay; mh = menstrual history; cc = case control study; mtd= mycobacterium tuberculosis direct test ; cbnaat = cartridge based nucleic acid amplification test; zn = ziehl-neelsen (zn) smear microscopy. female genital tuberculosis among infertile women and its contributions to primary and secondary infertility a systematic review and meta-analysis 318 | squ medical journal, august 2022, volume 22, issue 3 table 1 (cont’d.): characteristics of studies included in the current meta-analysis4–7,10,12,19,20,23–28,38–64 author and year of publication study design/ setting world bank country income classification country infertile population fgtb testing method n (%) proportion of fgtb proportion of infertility among fgtb patient overall infertility pi si patil et al.52 (2015) cs/ha lower-middle income india 123 gen-probe mtd test 1 (0.8) na na na goel et al.53 (2013) r/ha lower-middle income india 546 pcr 20 (3.7) na na na kamal et al.54 (2020) p/ha lower-middle income india 100 pcr, he 27 (27) na 16 (59.4) 11 (40.6) kanti v et al.55 (2021) p/hc lower-middle income india 59 cbnaat, he 2 (3.4) na 2 (100) 0 meenu et al.56 (2020) cs/ha lower-middle income india 139 pcr 58 (41.7) na na na shende et al.57 (2017) p/ha lower-middle income india 120 pcr 32 (27) na na na shrivastava & patel7 (2014) p/hc lower-middle income india 218 afb, cp, he, pcr 86 (39.45) na na na ohri et al.58 (2016) p/ha lower-middle income india 50 pcr 9 (18) na 8 (88.9) 1 (11.1) parikh et al.59 (2014) p/ha lower-middle income india 50 pcr 6 (12) na 3 (50) 3 (50) gupta et al.60 (2007) r/ha lower-middle income india 150 afb, mt, pcr 40 (26.7) na 30 (75) 10 (25) rajaram et al.61 (2016) pc/ha lower-middle income india 50 he, pcr 14 (28) na na na ojo et al.19 (2008) r/ha lower-middle income nigeria 661 afb, he 3 (0.45) na 1 (33.3) 2 (66.7) ojo et al.23 (1971) cs/ha lower-middle income nigeria 11,896 he 82 (0.7) na na na emembolu28 (1989) r/ha lower-middle income nigeria 114 afb 19 (16.7) na 9 (47.4) 10 (52.6) gini and ikerionwu24 (1990) r/ha lower-middle income nigeria 4,700 he 10 (0.2) na na na shahzad62 (2012) r/ha lower-middle income pakistan 150 afb, pcr, cp 30 (20) na 25 (83.3) 5 (16.7) shaheen et al.63 (2009) cs/ha lower-middle income pakistan 534 cp, afb-zn, he 13 (2.43) 13 (100) na na khan25 (1985) r/ha upper-middle income iran 91 lap, he 21 (23.08) na 15 (71.4) 6 (28.6) shallal et al.64 (2021) pc/ha upper-middle income iraq 60 pcr, he 6 (10) na na na margolis et al.26 (1992) r/ha upper-middle income south africa 650 cp 40 (6.15) na 16 (40) 24 (60) oosthuizen et al.27 (1990) cs/ha upper-middle income south africa 109 cp 23 (21) na na na fgtb = female genital tuberculosis; pi = primary infertility; si = secondary infertility; cs = cross-sectional study; ha = hospital admitted patients; na = not available; pc = prospective cohort study; hc = infertility centre admitted patient; pcr = polymerase chain reaction test; cp = culture proven; he = histopathological examination; afb = acid-fast bacilli test; p = prospective study; o = observational study; r = retrospective study; lap = laparotomy; mt = mantoux test; elisa = enzyme-linked immunosorbent assay; mh = menstrual history; cc = case control study; mtd= mycobacterium tuberculosis direct test; cbnaat = cartridge based nucleic acid amplification test; zn = ziehlneelsen (zn) smear microscopy. musa a.e. ahmed, abdullah a.a. mohammed, abiodun o. ilesanmi, christopher o. aimakhu, amel o. bakhiet and suad b.m. hamad review | 319 the eligibility criteria (total of 30,846 participants with mainly infertility complaints) were included for the systematic review and meta-analysis [figure 1]. s t u d y c h a r a c t e r i s t i c s a total of 42 studies, including 30,846 participants were included in the quantitative analysis for this meta-analysis; 2 (4.8%) studies were from high-income countries, 4 (9.5%) from upper-middle-income countries, 32 (76.2%) from lower-middle-income countries and the remaining 4 (9.5%) were from lowincome countries. of the included studies, 17 were cross-sectional studies, 13 had a prospective study design and 12 were retrospective studies. the majority of studies were in hospital-admitted patient settings and most used diagnostic tests (only polymerase chain reaction [pcr] or pcr combined with other relevant test methods) [table 1]. s y n t h e s i s o f r e s u lt s out of the included study sample of 30,846 participants worldwide, there was a 20% (95% confidence interval [ci]: 15–25%) pooled prevalence of fgtb among infertile women. residual heterogeneity was high (i2 = 99.94, χ2 = 2553.37; p <0.001). for this analysis, the random effect model was employed [figure 2]. however, out of the 42 articles, only five, 15 and 14 articles were analysed to evaluate the pooled prevalence of overall infertility, primary and secondary infertility among fgtb patients, respectively; this resulted in a pooled prevalence rate of 88% (95% ci: 74–100%, i2 = 99.91), 66% (95% ci: 56–76%, i2 = 99.23) and 34% (95% ci: 24–43%, i2 = 98.04) and p <0.001 each [table 2]. in addition, the random effect model was applied because the heterogeneity was high with p <0.001. the publication bias was checked using the funnel plot of the forest plot and the plot was visually symmetric with egger’s test (p = 0.25). due to the very high heterogeneity level presented in fgtb among infertile women in this analysis, a two-subgroup analysis was performed to check the effect of the study’s publication year and the world bank economical country classification on the pooled prevalence of fgtb among the infertile population [table 3]. the included studies were divided as per the particular country’s classification (i.e. highincome, upper-middle-income, lower-middle-income and low-income groups). the analysed data showed that the lowest income countries have a higher pooled prevalence of fgtb; conversely, the highest income countries have a lower pooled prevalence of fgtb among infertile women. the results showed pooled proportions of 5.7% (i2 = 78.56%), 14% (i2 = 86.91%), 21% (i2 = 99.95%) and 24% (i2 = 99.48%) for highincome, upper-middle-income, lower-middle-income and low-income countries, respectively [table 2]. to evaluate the effect of the study’s publication year on the pooled prevalence of fgtb among infertile women, the included articles were divided into three groups. the results indicated a 10%, 23% and 22% pooled prevalence of fgtb among infertile women for the period before 2000, between 2001 to 2010 and between 2011 to 2021 of this study’s publication year subgroups, respectively [table 2]. discussion although men significantly have the bigger burden of tb compared to women, in 2018, the who estimated that 3.2 million women were infected with tb and the disease is accompanied with severe consequences, especially in women of reproductive age.18 although fgtb rarely occurs in developed countries,3 it represents an important cause of infertility in developing countries especially in countries with high tb-incidence rates.18 recently, many published studies have invest igated the prevalence of fgtb among infertile women of reproductive age which shows that the lowest prevalence was 0.45% in nigeria and the highest prevalence was 52% in india.19,20 worldwide, the prevalence was 24.2% in the first-published metaanalysis and systematic review in 2016.21 the current study’s finding shows this prevalence to be slightly less at 20%. this outcome is due to the relative progress in the availability of more sensitive tb diagnosis methods such as genexpert and pcr in developing countries. moreover, there is a relative increase in the number of tb healthcare services and many countries have adopted the who’s end tb strategy around the globe.22 in the current comprehensive research, the prevalence of fgtb among infertile women progr essively increased over time from 10%, 23% and 22% in the period before 2000, between 2001 to 2010 and between 2011 to 2021, respectively. this may be due to the differences in the diagnostic methods used for fgtb which have changed over time. surprisingly, the researchers noted that the pcr test was not used in studies published in the period before 2000 while the same diagnosis method was used by 70% and 80.8% studies for the period between 2001 to 2010 and 2011 to 2021, respectively. the utilised diagnostic methods in the analysed data were histopathological examination,23–25 culture,26,27 acid-fast bacilli test and laparotomy.25,28 according to the literature, there is female genital tuberculosis among infertile women and its contributions to primary and secondary infertility a systematic review and meta-analysis 320 | squ medical journal, august 2022, volume 22, issue 3 author and year of publication effect size (95% ci) weight in % ojo et al.23 (1971) 0.01 (0.01–0.01) 2.49 gini and ikerionwu24 (1990) 0.00 (0.00–0.00) 2.49 emembolu28 (1989) 0.17 (0.10–0.24) 2.37 khan25 (1985) 0.23 (0.14–0.32) 2.31 margolis et al.26 (1992) 0.05 (0.04–0.08) 2.48 oosthuizen et al.27 (1990) 0.21 (0.13–0.29) 2.36 chattopadhyay et al.38 (1986) 0.04 (0.03–0.05) 2.48 ali and abdallah40 (2012) 0.01 (0.01–0.01) 2.49 abebe et al.13 (2004) 0.54 (0.45–0.83) 1.82 jindal10 (2006) 0.07 (0.05–0.08) 2.49 shaheen et al.63 (2009) 0.02 (0.01–0.04) 2.48 ojo et al.19 (2008) 0.00 (-0.00–0.01) 2.49 gupta et al.60 (2007) 0.27 (0.20–0.34) 2.37 singh et al.43 (2008) 0.48 (0.40–0.57) 2.32 nezar et al.42 (2009) 0.05 (0.03–0.08) 2.48 kumar et al.6 (2008) 0.39 (0.33–0.45) 2.41 chowdhury et al.47 (2010) 0.45 (0.40–0.49) 2.44 saraswat et al.48 (2010) 0.21 (0.14–0.28) 2.36 abdissa et al.4 (2018) 0.05 (0.02–0.09) 2.46 abdelrub and al harazi41 (2015) 0.31 (0.24–0.38) 2.36 mohakul et al.5 (2015) 0.39 (0.30–0.48) 2.28 shahzad62 (2012) 0.20 (0.14–0.25) 2.39 sankar et al.44 (2013) 0.25 (0.22–0.29) 2.46 goel et al.53 (2013) 0.04 (0.02–0.05) 2.48 malhotra et al.49 (2012) 0.25 (0.22–0.29) 2.46 patil et al.52 (2015) 0.01 (-0.01–0.02) 2.48 shrivastava and patel7 (2014) 0.39 (0.33–0.45) 2.38 parikh kp et al.59 (2014) 0.12 (0.03–0.21) 2.30 bhanothu et al.51 (2014) 0.28 (0.23–0.34) 2.42 mahajan et al.45 (2016) 0.41 (0.34–0.48) 2.36 sethi et al.46 (2016) 0.23 (0.18–0.27) 2.43 gajbhiye et al.50 (2019) 0.12 (0.03–0.21) 2.30 kamal et al.54 (2020) 0.27 (0.18–0.36) 2.31 shende et al.57 (2017) 0.27 (0.19–0.35) 2.34 ohri et al.58 (2016) 0.18 (0.07–0.29) 2.23 chatterjee et al.65 (2018) 0.02 (-0.01–0.04) 2.48 gurjar et al.20 (2018) 0.52 (0.42–0.52) 2.26 kanti et al.55 (2021) 0.03 (-0.01–0.08) 2.43 meenu et al.56 (2020) 0.42 (0.34–0.50) 2.33 rajaramet al.61 (2016) 0.28 (0.15–0.40) 2.14 shallal et al.64 (2021) 0.10 (0.02–0.18) 2.36 tal et al.39 (2020) 0.08 (0.05–0.11) 2.47 overall 0.20 (0.15–0.25) heterogeneity: τ2 = 0.02, i2 = 99.94%, h2 = 1745.13 test of θ1 = θ1: q(41) = 2553.37; p = 0.00 test of θ = θ: z = 7.94; p = 0.00 figure 2: forest plot (random-effects model) showing the pooled prevalence of female genital tuberculosis among infertile women.4–7,10,13,19,20,23–28,38–65 ci = confidence interval. musa a.e. ahmed, abdullah a.a. mohammed, abiodun o. ilesanmi, christopher o. aimakhu, amel o. bakhiet and suad b.m. hamad review | 321 no gold-standard test for fgtb as this depends on the facilities’ test protocol. however, different fgtb testing methods have been providing various results of the disease rate among infertile women.20 the increase of the prevalence of fgtb among infertile women is due to the previously mentioned reasons, including utilisation of modern tb diagnosis methods and adopting the who’s end tb strategy.18 furthermore, the global funds on tb control have substantially increased in recent decades.29 the present study reveals that the prevalence of fgtb is inversely proportional to the economic situation of the country. the lowest prevalence was 5.7% in the high-income countries while the highest prevalence was 24% in the low-income countries. the upper-middle-income and lower-middle-income countries showed 14% and 22%, respectively. although, there was no published data to describe the rate of fgtb among infertile women in different countries based on their economic status, other studies have shown that fgtb is associated with ptb and eptb as secondary infections.2,3 this outcome may be due to the delay of tb diagnosis and other sociocultural reasons. in line with this, getnet et al. reported that 42% of ptb diagnoses were delayed for a varied period of time (a month to a year) in low-income and middleincome countries’ setting.30 furthermore, macpherson et al. indicated that 4–38% of tb-patients were lost to follow-up for treatment in the same setting.31 in the middle east and north africa, factors such as being female and having a low income per capita is relatively reflected in the delay of tb diagnosis;32 although, the proportions are 1.24% and 1.26%, respectively, it has considerable impact on fgtb incidence. in addition, the high incidence of fgtb in lowand middleincome settings is due to factors such as the higher rate of losses to follow-up with tb or eptb treatment and the relatively negative experiences of tb patients and their level of satisfaction with their healthcare system.33,34 moreover, poverty and the high cost of the accurate diagnosis of fgtb in developing countries have a largely negative effect on fgtb control and treatment.35,36 in accordance with this, cazabon et al. reported that 32% and 46% of tb patients had a negative experience and were dissatisfied with healthcare providers and tb services, respectively.34 the findings of the current study reveal that the pooled prevalence of infertility among overall fgtbpatients was very high (88%). of this, the pooled prevalence of primary infertility was higher than table 2: pooled prevalence of infertility among female genital tuberculosis (fgtb) patients, pooled proportion of fgtb among infertile women based on the world bank country economic classification and subgroup analysis of fgtb among infertile women based on year of publication* subgroup classification subgroup number of studies total number of patients fgtb proportion in % (95% ci) infertility proportion in % (95% ci) heterogeneity i2 in % p value type of infertility (among fgtb patients) pooled infertility 5 430 88 (74–100) 99.912 >0.001 primary infertility 15 560 66 (56–76) 99.226 >0.001 secondary infertility 14 558 34 (24–43) 98.039 >0.001 world bank country economic classification (among infertile patients) high income 2 1268 5.7 (2.3-9.1) 78.56 >.001 uppermiddle income 4 910 14 (6–23) 86.91 >0.001 lowermiddle income 32 25,562 21 (15–27) 99.95 >0.001 low income 4 3,106 24 (3–52) 99.48 0.084 year of publication (among infertile patients) <2000 7 18,530 10 (3–17) 99.96 <0.001 2001–2010 11 7,718 23 (10–36) 99.93 <0.001 2011–2021 24 4,623 22 (16–27) 97.98 <0.001 fgtb = female genital tuberculosis; ci = confidence interval. *out of 42 studies 34 were analysed for type of infertility (subgroup among fgtb patients) and the remaining studies were excluded as there was no mention of the prevalence of infertility, primary infertility or secondary infertility. female genital tuberculosis among infertile women and its contributions to primary and secondary infertility a systematic review and meta-analysis 322 | squ medical journal, august 2022, volume 22, issue 3 that of secondary infertility among fgtb patients. although these results are in agreement with other meta-analysis findings done by chaman-ara et al. (who reported 70.7%, 75.7% and 24.3% for infertility among fgtb patients, primary infertility and secondary infertility, respectively), the present study showed a slight increase in the pooled prevalence infertility and secondary infertility incidence among fgtb patients. on the other hand, the rate of primary infertility decreased over time.37 to achieve the who end tb strategy goal to eliminate catastrophic costs for tb-affected households by 2030 as sustainable development goal target, a more thorough clinical investigation should be admin istrated at the level of tb and infertility clinics, particularly in lowand lower-income settings.18 this review is subject to certain limitations. articles published in languages other than english were excluded and the study population included only infertile women of reproductive age. some grey literature may have also been missed. during the data collection process, no published studies investigating the incidence of fgtb among infertile women from the continents of australia, europe or south america were found. the likelihood for publication bias is high. conclusion the results of this meta-analysis found that the pooled prevalence of fgtb among infertile women is 20%, and the pooled prevalence of overall infertility, primary infertility and secondary infertility among fgtb patients globally is 88%, 66% and 34%, respectively. in the last two decades, the fgtb incidence rate was increasing gradually. the biggest burden of fgtb is reported in the lowand lower-middle-income countries with a pooled prevalence of 46% globally. a c k n o w l e d g e m e n t s the authors would like to thank the pan african university, institute life and earth sciences (including health and agriculture), the african union for financial support and university of ibadan for hosting this ph.d. programme. a u t h o r s’ c o n t r i b u t i o n s ma, am, ai, ca, ab and sh conceived and designed the review. ma, am and sh carried out the draft of the manuscript and ma is the guarantor of the review. ma, am, ai, ca, ab and sh developed the search strings. ma, am and sh screened, evaluated and selected the studies as well as extracted the data. ai, ca and ab evaluated the quality of the studies. ma and am carried out the statistical analysis and interpretation. ma, am, ai, ca, ab and sh rigorously reviewed the manuscript. all authors approved the final version of the manuscript. references 1. world health organization. global tuberculosis report 2020. from: https://www.who.int/publications/i/item/9789240013131 2. grace ga, devaleenal db, natrajan m. genital tuberculosis in females. indian j med res 2017; 145:425–36. https://doi. org/10.4103/ijmr.ijmr_1550_15. 3. parvez r, sugunan ap, vijayachari p, burma sp, mandal a, saha mk, et al. prevalence of female genital tuberculosis, its risk factors and associated clinical features among the women of andaman islands, india: a community-based study. public health 2017; 148:56–62. https://doi.org/10.1016/j.puhe.2017.03.001. 4. abdissa s, abebe t, ameni g, teklu s, bekuretsion y, abebe m, et al. endometrial tuberculosis among patients undergoing endometrial biopsy at tikur anbesa specialized hospital, addis ababa, ethiopia. bmc infect dis 2018; 18:1–8. https://doi. org/10.1186/s12879-018-3202-x. 5. mohakul sk, beela vrk, tiru p. hysteroscopy findings and its correlation with latent endometrial tuberculosis in infertility. gynecological surgery 2015; 12:31–9. https://doi.org/10.1007/ s10397-014-0865-1. 6. kumar p, shah np, singhal a, chauhan ds, katoch vm, mittal s, et al. association of tuberculous endometritis with infertility and other gynecological complaints of women in india. j clin microbiol 2008; 46:4068–70. https://doi.org/10.1128/jcm.01162-08. 7. shrivastava g, patel k. genital tuberculosis: evaluating microscopy, culture, histopathology and pcr for diagnosis all play their role. int j curr microbiol app sci 2014; 3:439–45. 8. fatima t, hasan r, malik fr, ahmed i, bartlett la, gravett mg, et al. female genital tuberculosis in pakistan – a retrospective review of 10-year laboratory data and analysis of 32 cases. int j mycobacteriol 2021; 10:66–70. https://doi.org/10.4103/ijmy. ijmy_6_21. 9. a aa, ahmed m, oladokun a. prevalence of infertility in sudan: a systematic review and meta-analysis. qatar med j 2021; 2021:47. https://doi.org/10.5339/qmj.2021.47. 10. jindal un. an algorithmic approach to female genital tuber culosis causing infertility. the int j tuberc lung dis 2006; 10:1045–50. 11. namavar jahromi b, parsanezhad me, ghane-shirazi r. female genital tuberculosis and infertility. int j gynaecol obstet 2001; 75:269–72. https://doi.org/10.1016/s0020-7292(01)00494-5. 12. bhanothu v, theophilus jp, reddy pk, rozati r. occurrence of female genital tuberculosis among infertile women: a study from a tertiary maternal health care research centre in south india. europ eur j clin microbiol infect dis 2014; 33:1937–49. https://doi.org/10.1007/s10096-014-2164-1. 13. abebe m, lakew m, kidane d, lakew z, kiros k, harboe, et al. female genital tuberculosis in ethiopia. int j gynaecol obstet 2004; 84:241–6. https://doi.org/10.1016/j.ijgo.2003.11.002. 14. dai w, ma l, cao y, wu d, yu t, zhai j. in vitro fertilization outcome in women with endometrial tuberculosis and tubal tuberculosis. gynecol endocrinol 2020; 36:819–823. https:// doi.org/10.1080/09513590.2019.1702639. 15. liberati a, altman dg, tetzlaff j, mulrow c, gøtzsche pc, ioannidis jp, et al. the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. j clin epidemiol 2009; 62:e1–34. https://doi.org/10.1016/j.jclinepi.2009.06.006. https://doi.org/10.4103/ijmr.ijmr_1550_15 https://doi.org/10.4103/ijmr.ijmr_1550_15 https://doi.org/10.1016/j.puhe.2017.03.001 https://doi.org/10.1186/s12879-018-3202-x https://doi.org/10.1186/s12879-018-3202-x https://doi.org/10.1007/s10397-014-0865-1 https://doi.org/10.1007/s10397-014-0865-1 https://doi.org/10.1128/jcm.01162-08 https://doi.org/10.4103/ijmy.ijmy_6_21 https://doi.org/10.4103/ijmy.ijmy_6_21 https://doi.org/10.5339/qmj.2021.47 https://doi.org/10.1016/s0020-7292(01)00494-5 https://doi.org/10.1007/s10096-014-2164-1 https://doi.org/10.1016/j.ijgo.2003.11.002 https://doi.org/10.1080/09513590.2019.1702639 https://doi.org/10.1080/09513590.2019.1702639 https://doi.org/10.1016/j.jclinepi.2009.06.006 musa a.e. ahmed, abdullah a.a. mohammed, abiodun o. ilesanmi, christopher o. aimakhu, amel o. bakhiet and suad b.m. hamad review | 323 16. porritt k, gomersall j, lockwood. study selection and critical appraisal: the steps following the literature search in a systematic review. cjajn 2014; 114:47–52. https://doi.org/10.1097/01. naj.0000450430.97383.64. 17. higgins jpt, thompson sg, deeks jj, altman dg. measuring inconsistency in knowledgebases. bmj 2003; 327:557–60. https://doi.org/10.1136/bmj.327.7414.557. 18. world health organization. global tuberculosis report 2018. from: https://www.who.int/publications/i/item/9789241565646 19. ojo ba, akanbi aa, odimayo ms, jimoh ak. endometrial tuberculosis in the nigerian middle belt: an eight-year review. trop doc 2008; 38:3–4. https://doi.org/10.1258/td.2007.052090. 20. gurjar k, meena kl, rajoria l, sharma n. comparison of diagnostic efficacy of usg, tuberculin test, nucleic acid amplification test (pcr) & histopathology for diagnosis of genital tuberculosis in infertile women, assuming culture as gold standard. imjh 2018; 4:138–43. 21. chaman-ara k, bahrami ma, bahrami e, bahrami s, bahrami mn, moosazadeh m, et al. prevalence of genital tuberculosis among infertile women: a systematic review and meta-analysis. int j med res health sci 2016; 5:208–15. 22. world health organization. framework for implementing the “end tb strategy” in the african region 2016 2020. from: https://www.afro.who.int/publications/framework-implem enting-end-tb-strategy-african-region-2016-2020 23. ojo oa, onifade a, akande eo, bannerman rh. the pattern of female genital tuberculosis in ibadan. isr j med sci 1971; 7:280–7. 24. gini pc, ikerionwu se. incidental tuberculous endometritis in premenstrual curettings from infertile women in eastern nigeria. int j gynaecol obstet 1990 ;31:141–4. https://doi. org/10.1016/0020-7292(90)90711-s. 25. khan sm. incidence of genital tuberculosis in infertile women. j pak med assoc 1985; 35:280–1. 26. margolis k, wranz pa, kruger tf, joubert jj, odendaal hj. genital tuberculosis at tygerberg hospital--prevalence, clinical presentation and diagnosis. s afr med j 1992; 81:12–15. 27. oosthuizen ap, wessels ph, hefer jn. tuberculosis of the female genital tract in patients attending an infertility clinic. s afr med j 1990; 77:562–4. 28. emembolu jo. endometrial flora of infertile women in zaria, northern nigeria. int j gynecol obstet 1989; 30:155–9. https:// doi.org/10.1016/0020-7292(89)90310-x. 29. floyd k, fitzpatrick c, pantoja a, raviglione m. domestic and donor financing for tuberculosis care and control in lowincome and middle-income countries: an analysis of trends, 2002–11, and requirements to meet 2015 targets. lancet glob health 2013; 1:e105–15. https://doi.org/10.1016/s2214109x(13)70032-9. 30. getnet f, demissie m, assefa n, mengistie b, worku a. delay in diagnosis of pulmonary tuberculosis in low-and middleincome settings: systematic review and meta-analysis. bmc pulm med 2017; 17:1–15. https://doi.org/10.1186/s12890-0170551-y. 31. macpherson p, houben rmgj, glynn jr, corbett el, kranzer k. pre-treatment loss to follow-up in tuberculosis patients in low and lower-middle-income countries and high-burden countries a systematic review and meta-analysis. bull world health organ 2013; 92:126–38. https://doi.org/10.2471/blt.13.124800. 32. eltayeb d, pietersen e, engel m, abdullahi l. factors associated with tuberculosis diagnosis and treatment delays in middle east and north africa: a systematic review. east mediterr health j 2020; 26:477–86. https://doi.org/10.26719/2020.26.4.477. 33. ade s, harries ad, trébucq a, ade g, agodokpessi g, adjonou c, et al. national profile and treatment outcomes of patients with extrapulmonary tuberculosis in bénin. plos one 2014; 9:e95603. https://doi.org/10.1371/journal.pone.0095603. 34. cazabon d, pande t, sen p, daftary a, arsenault c, bhatnagar h, et al. user experience and patient satisfaction with tuberculosis care in low-and middle-income countries: a systematic review. j clin tuberc other mycobact dis 2020; 19:100154. https://doi. org/10.1016/j.jctube.2020.100154. 35. lu c, liu q, sarma a, fitzpatrick c, falzon d, mitnick cd. a systematic review of reported cost for smear and culture tests during multidrug-resistant tuberculosis treatment. plos one 2013; 8:e56074. https://doi.org/10.1371/journal.pone.0056074. 36. lund c, de silva m, plagerson s, cooper s, chisholm d, das j, et al. poverty and mental disorders: breaking the cycle in lowincome and middle-income countries. lancet 2011; 378:1502–14. https://doi.org/10.1016/s0140-6736(11)60754-x. 37. chaman-ara k, bahrami ma, moosazadeh m, bahrami e. prevalence of infertility in women with genital tuberculosis: a systematic review and meta-analysis. ijbs 2017; 11:21–7. https://doi.org/10.15562/ijbs.v11i1.133. 38. chattopadhyay sk, sengupta bs, edrees yb, al-meshari aa. the pattern of female genital tuberculosis in riyadh, saudi arabia. br j obstet gynaecol 1986; 93:367–71. 39. tal r, lawal t, granger e, simoni m, hui p, buza n, et al. genital tuberculosis screening at an academic fertility center in the united states. am j obstet gynecol 2020; 223:737.e1-10. https://doi.org/10.1016/j.ajog.2020.05.045. 40. ali aa, abdallah tm. clinical presentation and epidemiology of female genital tuberculosis in eastern sudan. int j gynaecol obstet 2012; 118:236–8. https://doi.org/10.1016/j. ijgo.2012.04.005. 41. abdelrub as, al harazi ah. genital tuberculosis is common among females with tubal factor infertility: observational study. alexandria j med 2015; 51:321–4. https://doi.org/10.1016/j. ajme.2014.11.004. 42. nezar m, goda h, el-negery m, el-saied m, wahab aa, badawy am. genital tract tuberculosis among infertile women: an old problem revisited. arch gynecol obstet 2009; 280:787–91. https://doi.org/10.1007/s00404-009-1000-9. 43. singh n, sumana g, mittal s. genital tuberculosis: a leading cause for infertility in women seeking assisted conception in north india. arch gynecol obstet 2008; 278:325–7. https:// doi.org/10.1007/s00404-008-0590-y. 44. sankar mm, kumar p, munawwar a, kumar m, singh j, singh a, et al. usefulness of multiplex pcr in the diagnosis of genital tuberculosis in females with infertility. eur j clin microbiol infect dis 2013; 32:399–405. https://doi.org/10.1007/s10096012-1755-y. 45. mahajan n, naidu p, kaur sd. insight into the diagnosis and management of subclinical genital tuberculosis in women with infertility. j hum reprod sci 2016; 9:135–44. https://doi. org/10.4103/0974-1208.192043. 46. sethi s, dhaliwal l, dey p, kaur h, yadav r. loop-mediated isothermal amplification assay for detection of mycobacterium tuberculosis complex in infertile women. indian j med micro biol 2016; 34:322–7. https://doi.org/10.4103/0255-0857.188323. 47. chowdhury rg, paine sk, bhattacharjee b, chatterjee s. infestation of endometrium by mycobacterium tuberculosis bacilli-cause of reproductive failure. al ameen j med sci 2010; 3:322–31. 48. saraswat p, swarankar ml, bhandari a, soni rr. detection of active female genital tuberculosis by molecular method. int j pharma bio sci 2010; 1:328–34. 49. malhotra b, sinha p, hooja s, vyas l. rapid diagnosis of genital tuberculosis by real time polymerase chain reaction. j south asian feder obst gynae 2012; 4:39–42. https://doi. org/10.5005/jp-journals-10006-1170. 50. gajbhiye sb, bhakre jb, damle as. assessment of endometrial specimens for tubercular infection among infertile women using dna-pcr. j clin diagnostic res 2019; 13:dc01–5. https://doi.org/10.7860/jcdr/2019/42587.13208. https://doi.org/10.1097/01.naj.0000450430.97383.64 https://doi.org/10.1097/01.naj.0000450430.97383.64 https://doi.org/10.1136/bmj.327.7414.557 https://doi.org/10.1258/td.2007.052090 https://doi.org/10.1016/0020-7292(90)90711-s https://doi.org/10.1016/0020-7292(90)90711-s https://doi.org/10.1016/0020-7292(89)90310-x https://doi.org/10.1016/0020-7292(89)90310-x https://doi.org/10.1016/s2214-109x(13)70032-9 https://doi.org/10.1016/s2214-109x(13)70032-9 https://doi.org/10.1186/s12890-017-0551-y https://doi.org/10.1186/s12890-017-0551-y https://doi.org/10.2471/blt.13.124800 https://doi.org/10.26719/2020.26.4.477 https://doi.org/10.1371/journal.pone.0095603 https://doi.org/10.1016/j.jctube.2020.100154 https://doi.org/10.1016/j.jctube.2020.100154 https://doi.org/10.1371/journal.pone.0056074 https://doi.org/10.1016/s0140-6736(11)60754-x https://doi.org/10.15562/ijbs.v11i1.133 https://doi.org/10.1016/j.ajog.2020.05.045 https://doi.org/10.1016/j.ijgo.2012.04.005 https://doi.org/10.1016/j.ijgo.2012.04.005 https://doi.org/10.1016/j.ajme.2014.11.004 https://doi.org/10.1016/j.ajme.2014.11.004 https://doi.org/10.1007/s00404-009-1000-9 https://doi.org/10.1007/s00404-008-0590-y https://doi.org/10.1007/s00404-008-0590-y https://doi.org/10.1007/s10096-012-1755-y https://doi.org/10.1007/s10096-012-1755-y https://doi.org/10.4103/0974-1208.192043 https://doi.org/10.4103/0974-1208.192043 https://doi.org/10.4103/0255-0857.188323 https://doi.org/10.5005/jp-journals-10006-1170 https://doi.org/10.5005/jp-journals-10006-1170 https://doi.org/10.7860/jcdr/2019/42587.13208 female genital tuberculosis among infertile women and its contributions to primary and secondary infertility a systematic review and meta-analysis 324 | squ medical journal, august 2022, volume 22, issue 3 51. bhanothu v, theophilus jp, rozati r. use of endo-ovarian tissue biopsy and pelvic aspirated fluid for the diagnosis of female genital tuberculosis by conventional versus molecular methods. plos one 2014; 9:e98005. https://doi.org/10.1371/ journal.pone.0098005. 52. patil ad, shinde sk, sachdeva gm, pasi ar, chitlange sm, chandhiok n, et al. is testing of menstrual blood justifiable for diagfnosis of endometrial tuberoculosis among infertile women. ind j obstet gynecol res 2015; 2:103–7. 53. goel g, khatuja r, radhakrishnan g, agarwal r, agarwal s, kaur i. role of newer methods of diagnosing genital tuberculosis in infertile women. indian j pathol microbiol 2013; 56:155–7. https://doi.org/10.4103/0377-4929.118670. 54. kamal s, singh v, singh s. a clinical study of association of genital tuberculosis with infertility in a tertiary centre of jhark hand, india. int j reproduction, contraception, obstet gyne 2020; 9:120–6. https://doi.org/10.18203/2320-1770.ijrcog20196008. 55. kanti v, seth s, gupta s, verma v, singh a, maurya g, et al. comparison of the efficacy of the cartridge-based nucleic amplification (cbnaat)/xpert test and histology of genital tissues in diagnosing female genital tuberculosis. cureus 2021; 13:e15000. https://doi.org/10.7759/cureus.15000. 56. meenu s, ramalingam s, sairam t, appinabhavi a, panicker s, oommen s, et al. comparison of polymerase chain reaction (pcr), microbiological and histopathological observations in the diagnosis of endometrial tuberculosis. j obstet gynaecol india 2020; 70:510–15. https://doi.org/10.1007/s13224-020-01367-9. 57. shende p, valecha sm, gandhewar m, dhingra d. genital tuberculosis and infertility. int j reprod contracept obstet gynecol 2017; 6:3514–18. 58. ohri s, patil sk, patil a, patil y, kshirsagar ns. study of genital tuberculosis in infertile women. age 2016; 21:f1–3. 59. parikh kp, deshpande hg, madkar cs, jethani s. study to find out the incidence of genital tuberculosis as a cause for female infertility in semi-urban population. j evol med dent sci 2014; 3:3223–7. https://doi.org/10.14260/jemds/2014/2271. 60. gupta n, sharma jb, mittal s, singh n, misra r, kukreja m. genital tuberculosis in indian infertility patients. int j gynaecol obstet 2007; 97:135–8. https://doi.org/10.1016/j. ijgo.2006.12.018. 61. rajaram s, gupta p, gupta b, kaur ir, goel n. laparoscopy in the diagnosis of tuberculosis in chronic pelvic pain. int j mycobacteriol 2016; 5:318–23. https://doi.org/10.1016/j. ijmyco.2016.06.016. 62. shahzad s. investigation of the prevalence of female genital tract tuberculosis and its relation to female infertility: an observational analytical study. iran j reprod med 2012; 10:581–8. 63. shaheen r, subhan f, tahir f. epidemiology of genital tuberculosis in infertile population. j pak med assoc 2006; 56:306–9. 64. shallal mm, al-asadi fas, mizaal mi. detection of endometrial tb in patients with aub using pcr method of assessment of menstrual blood flow of iraqi females. indian j forensic med toxicol 2021; 15:1225. https://doi.org/10.37506/ ijfmt.v15i1.13584. 65. chatterjee t., basak ak. mycobacterium tuberculosis and non-tubercular mycobacterium infection in women with unexplained infertility from eastern india. int j reprod biomed 2018; 16:557–62. https://doi.org/10.1371/journal.pone.0098005 https://doi.org/10.1371/journal.pone.0098005 https://doi.org/10.4103/0377-4929.118670 https://doi.org/10.18203/2320-1770.ijrcog20196008 https://doi.org/10.7759/cureus.15000 https://doi.org/10.1007/s13224-020-01367-9 https://doi.org/10.14260/jemds/2014/2271 https://doi.org/10.1016/j.ijgo.2006.12.018 https://doi.org/10.1016/j.ijgo.2006.12.018 https://doi.org/10.1016/j.ijmyco.2016.06.016 https://doi.org/10.1016/j.ijmyco.2016.06.016 https://doi.org/10.37506/ijfmt.v15i1.13584 https://doi.org/10.37506/ijfmt.v15i1.13584 december 2007 vol 8 after meeting.indd sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 233-238 sultan qaboos university© submitted 9th april 2007 accepted 4th august 2007 department of physics, college of education, university of mosul, iraq *to whom correspondence should be addressed. email: faikaazooz@yahoo.com calculation of the inactivation cross section of v79 cells by protons in radiotherapy *faika a azooz and thamer j alkhalidy objective: for efficient applications of protons in radiotherapy, detailed knowledge of the corresponding radiobiological mechanism is necessary. the inactivation cross section is a useful tool to explore the interaction mechanism. hence, the inactivation cross section for proton irradiation on v79 cells has been calculated using published survival data. method: the linear quadratic equation was used to fit the survival curves and the parameter α was used to calculate the cross section. the cross section σ is plotted as a function of the mean free path λ and the linear energy transfer let. results: the cross section σ-versus-λ curve shows a saturation region between λ≥2 nm and λ≤5 nm. in this region, the inactivation cross section value is about the same as the geometrical area of the dna segment (≈4 µm2). such a saturation is also seen in the σ-let curve. conclusion: this implies that one dna segment is at a risk upon the traversal of a single proton. key words: radiotherapy; inactivation cross section; dna damage; mean free path; ionisation, specific primary; energy transfer, linear. البروتونات v79 بواسطة خاليا لتخميل العرضي حساب املقطع اخلالدي عزوز، ثامر فائقة للطريقة اآللية املطلوبة ــن ع تتوفر املعرفة التفصيلية أن ينبغي ــعة باألش العالج في ــتخدام الكفوء للبروتونات االس أجل ــص: الهــدف: من امللخ العرضي املقطع حساب مت ولهذا ، التفاعل وسيلة لكشف مفيدة ــيلة وس العرضي للتعطيل املقطع يعتبر العالقة. ذات ــعاعية اإلش – البيولوجية منحنيات ملطابقة التربيعية اخلطية املعادلة الطريقة: استخدمت . املنشورة البقاء معطيات v79 بواسطة خاليا على البروتون ألشعاع للتعطيل اخلطي. الطاقة وانتقال (λ) احلر ــار ملتوسط املس كدالة (σ) العرضي املقطع ــم ورس ــاب املقطع العرضي. حلس الف تَثابِتَة مُ ــتعملت اس بينما البقاء العرضي املقطع قيمة املنطقة هذه في λ ≤ 5 نانوميتر. λ ≥ 2 نانوميترو بني ــباع إش منطقة λ يظهر منحنى σ مقابل العرضي النتائج: املقطع اإلشباع هذا لوحظ كما .(µm2 4 (حوالي جني األوكسِ َنْزُوع النَّوَوِي امل الرِّيْبِيُّ ضُ احلَمْ لقطعة ــية الهندس للمساحة ــاوية تقريبا مس تكون للتخميل خطر تكون في ــجني األوكسِ َنْزُوع امل النَّوَوِي الرِّيْبِيُّ ضُ احلَمْ من قطعة أن يدل على اخلالصة: هذا اخلطي. الطاقة انتقال σlet منحنى ــي ف ــا أيض واحد. بروتون عبور عند الطاقة انتقال ، نوعي أولي ، التأين ، احلر املسار متوسط ، جني األوكسِ َنْزُوع امل الرِّيْبِيُّ النَّوَوِي ضُ احلَمْ ضرر ، للتخميل العرضي الكلمات: املقطع مفتاح خطي. ، c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge cell inactivation by ionising radiation has been studied in many ways such as survival curves shapes, dose rate survival dependence, and inactivation cross section etc. watt and his co-workers were the first to adopt the cross section trends in an attempt to find a universal manner of radiation action regardless of target and radiation type.14 they analysed published data for inactivation of enzymes, viruses and mammalian cells by accelerated ions and electrons, their analyses were based on the relationship between the inactivation cross section σ and the specific primary ionisation i, or the mean free path λ; in order to compare various kinds of cells; the inactivation cross section was normalized to the geometrical cross section. they observed discontinuities in the σ-i and σ-λ curves for double stranded mammalian cells, which were not seen in single stranded cells such as viruses and enzymes. the 234 fa i k a a a z o o z a n d th a m e r j a l k h a l i d y the increasing importance of protons in radiotherapy makes it essential to under-stand the damage mechanism of these particles. the interaction cross section has proved to be a good physical quantity to study the size of the effect and to give some idea about the physical mechanism in various fields of physics. theoretical investigations by physicists, radiobiologists and physicians have pointed out the superiority of charged particles in radiotherapy treatment. among these, protons have been found to provide the most clinical advantages for many reasons such as their ability to concentrate the dose in more discrete target volumes and the low scattering compared to electrons. also protons are considered to be a low-let radiation.7 this makes it essential to know the main physical processes involved in the interaction of proton beams with living cells, which are a manifestation of radiation quality and from which physical parameters descriptive of the quality may be extracted and used for other radiation types. whilst the biological processes initiated by the radiation action are thought to be immensely complex, there seems to be a general consensus that double strand breaks induced in the cellular dna constitute the predominantly important lesions; 2, 8 however, there are still considerable doubts about the most appropriate physical parameters to use for specification of radiation quality. empirical considerations suggest that energy deposition parameters such as let may be inappropriate.3 an approach predicted by watt and his co-workers suggests that the mean free path for primary ionisation plays a major role in the dna damage.3, 5 they found that a structure is observed at a mean free path for ionisation of between 1.5 and 2.0 nm and occurs only in those targets containing double stranded dna. this was explained as a matching between the dna strand separation (1.8-2.0 nm) in the double stranded dna and the mean free path for primary ionisation. in other words, maximum damage occurs when the mean free path for primary ionisation is of the same order of magnitude as the dna strand separation. as part of an investigation into a better method for specifying radiation quality for application to damage modelling, we have surveyed published survival curves data for proton irradiation on chinese hamster cells v79. the effective cross section was extracted from these data after fitting the survival curves to the linear quadratic equation; the initial slope α from the fitted equation was used to determine the cross section as this avoids any complications with cell recovery. cross section relation to the mean free path λ and the linear energy transfer let are given. our results show evidence supporting the predictions that the double strand breaks in the dna are the main cause of damage to mammalian cells. conclusion was that the dominant mechanism for reproductive death is determined by the matching of the mean free path between ionisations to the strand separation in double stranded dna. successive work was done on v79 cells inactivated by accelerated ions,5 the same conclusion was drawn in charged ions inactivation; however, the electrons showed a cross section approaching an order of magnitude smaller than that for heavy ions at the same λ. this work is concerned with the inactivation cross section of v79 cells by protons and its relation to the mean free path λ and the linear energy transfer (let). application to patient care systematic investigation of the biological effects caused by different radiation qualities are powerful tools for obtaining a better insight into the mechanism of radiation action in biological matter. there is now a substantial amount of theoretical work that addresses the relationship between radiation quality and the amount of energy deposited in the dna helix and the subsequent production of dna. it is commonly assumed that different particles having the same let have similar biological effectiveness. however, experimental data gathered in recent years provided evidence for z dependence of the biological effectiveness of radiation.6 moreover, experimental studies on the biological effects of low energy charged particles in v79 cells has shown that low energy (high let) protons are more effective in cell inactivation than other heavy charged particles as alpha particles. as accelerated protons have already proved their usefulness in clinical radiotherapy, the detailed understanding of the underlying radiobiological mechanism is necessary in order to take the advantage of their possible benefits and to optimize treatment procedures in individual cases. 235 c a l c u l at i o n o f t h e i n a c t i vat i o n c r o s s s e c t i o n o f v 7 9 c e l l s b y p r o t o n s m e t h o d survival curves data for proton irradiation of v79 cells were taken from literature, scanned and fed to the computer as image files readable by matlab (matrix laboratory a numerical computation programme) and transferred into figure files in pixel units. calibration curves relating the pixel units and the real coordinates units were used to extract the real data points. hence, a complete set of survival curves data points was obtained; the error bars were not taken into consideration. this was done for 15 survival curves ranging in energy between 0.04-3.6 mev. c r o s s se c ti o n c a l c ul ati o n the survival curves obtained were fitted to the linear quadratic equation 8, 9 using the matlab fitting tools: in s = exp(-αd-βd2) where s is the surviving fraction, d is the dose in gy and α and β represents the contribution to cell destruction. the goodness of fit was measured by the adjusted r-square value, which takes into account the number of degrees of freedom in the fitted equation (two in this case). r-square is defined as the ratio of the sum of squares of regression and the total sum of squares about the mean; it can take any value between 0 and 1, with a value closer to 1 indicating a better fit. r-square values obtained from the fit were very close to 1. table 1 shows the proton energies used, the values of α and β obtained from the fit and the adjusted r-square value for each fit. the α-values which represent the initial slope of the survival curve were used to calculate the inactivation cross section which is defined by the equation. 4, 5, 10 σ(µm2) = 0.16*lt(kev/µm)*α(gy) -1 ρ(g/cm)3 lt is the track average linear energy transfer and ρ is the tissue density taken as equal to 1. energy (mev) let (kev/µm) λ (nm) α (gy)-1 β (gy)-2 σ (µm)2 adjusted r=square references 0.04 72.3 1.13 0.171 0 1.98 0.9921 belli(12) 0.26 58.9 2.1 0.367 0 3.4586 0.9987 belli(12) 0.57 37.8 4.32 0.5952 0.0022 3.5998 0.9972 belli(13) 0.64 34.6 4.85 0.6157 0.0215 3.4085 0.997 belli(13) 0.73 34.5 5.3947 0.625 -0.065 3.45 0.9992 belli(9) 0.76 31.9 5.6579 0.6538 0.0945 3.337 0.9976 folkard(11) 0.84 30.4 6.0088 0.6938 -0.046 3.3746 0.9952 belli(9) 1 26.5 7.3246 0.733 0 3.1 0.993 schettino (14) 1.15 24.7 8.3772 0.6894 0.0809 2.7245 0.9987 folkard(11) 1.16 23.9 8.5526 0.6904 0.1363 2.7166 0.999 belli(9) 1.41 20 10.417 0.649 0.0441 2.0768 0.9994 belli(13) 1.7 17.8 12.588 0.5903 0.0493 1.6812 0.9973 belli(9) 1.9 16.72 14.079 0.3207 0.1061 0.8579 0.9968 folkard(11) 3.2 10.99 22.939 0.24 0.046 0.4219 1 schettino (14) 3.36 11.111 24.167 0.1851 0.1535 0.329 0.9992 belli(9) table 1: energy dependence of fitting parameters and cross section in the inactivation of v79 cells by protons 236 fa i k a a a z o o z a n d th a m e r j a l k h a l i d y r e s u l t s a n d d i s c u s s i o n the relation between the inactivation cross-section σ (µm2) and the mean free path for primary ionisation λ (nm) is shown in figure 1. a visual inspection of this curve can identify four regions: the first region, λ ≤ 2 nm, and the second nearly flat region for (2 ≤λ≤ 5) nm, followed by a decreasing cross section for λ≥5 nm up to λ≈15 nm, and finally the fourth region in which λ>15 nm, which shows the lowest cross section values. before we discuss each of these regions, we must refer to watt’s results, in which he applied his model to heavy charged particles of all kinds including α-particles, in addition to three points concerning the inactivation of v79 cells by protons.5 he obtained a nice grouping of data into two distinguished regions, one nearly flat region in which the data grouped around a horizontal straight line with a saturation cross section of about 38 µm2, and a clear point of inflection at λ≥2 nm to lower cross section values in which the data grouped around a straight line with a gradient of about -1.22. the three proton data points are randomly distributed below the saturation region with cross section values of about a factor of ten less than that for other charged particles in this region. returning to figure 1, we can say that regions 2 and 3 are similar in shape only to watt’s results for other charged particles, but with a lower cross section value in the saturation region which is about 3.5 µm2. this result is about the same as that obtained by watt 5 for protons i.e. about a factor of ten less than that for other charged particles; however, the inflection point occurs at λ≈5 nm instead of 2 nm. the observation of a saturation region between λ ≥ 2 and λ≤ 5 nm is certainly related to dna damage. the geometrical cross-sectional area of the intra-molecular dna is about (3.54) µm2. this cross-sectional area is consistent with the maximum observed value for protons that can penetrate one dna segment along a mean chord trajectory through the nucleus. a double strand break will occur and the chance of repair is very small. in the case of low energy protons (λ<2 nm), which are related to region 1 in figure 1, the particle tracks have a projected range less than the mean chord length through the cell nucleus, hencegiving lower cross section values, in other words fewer double stranded dna segments at risk and therefore an increased repair capability of the cell. in region 3, the mean free path is certainly larger than the mean chord length, but still there is a possibility of interaction occurring at least with one strand of the dna segment by one particle track and, if it happened that another particle track passed the dna and made a break to the opposite strand of the dna segment, then a double strand break will occur; of course, this possibility will decrease as λ increases. in region 4, λ becomes large and the probability of occurrence of double strand breaks is negligible compared to single strand breaks, which means an infigure 1: inactivation cross section σ of v79 cells by protons versus the mean free path for primary ionization λ 237 c a l c u l at i o n o f t h e i n a c t i vat i o n c r o s s s e c t i o n o f v 7 9 c e l l s b y p r o t o n s creased repair capability of the cell. the inactivation cross-section dependence on let is shown in figure 2. it is clear that there is a linear increase in cross section up to let = 30 kev/µm followed by a flat region between 30 and 60 kev/µm the lack of data points in this region makes it difficult to say if saturation occurs. the last point shows a decrease in cross section. at let values below 30 kev/µm, single strand breaks in the dna segment take place. the maximum cross section value at let ≈ 30 kev/µm is compatible with what has been found in the rbe-let relation by belli 9 and falkard 11 that the maximum damage for protons inactivation occurs at let ≈ 24-27 kev/µm. c o n c l u s i o n in the inactivation of v79 cells by protons, the maximum inactivation cross section occurs when the mean free path for the incident proton is between 2 and 5 nm. in this region the inactivation cross section is about the same as the geometrical cross sectional area of the dna in the cell. this means that one dna segment is at a risk upon the traversal of one charged particle. the inactivation cross section is found to be 3.5 µm2, this value is consistent with the geometrical cross sectional area of about 4.0 µm2 for the intra-molecular dna. in the cross section versus let curve, the maximum inactivation cross section occurs at let = 30 kev/µm. this value of let is very close to that found by belli9 and folkard11 at which maximum relative biological effectiveness (rbe) values were found in the rbe-let relationship. r e f e r e n c e s 1. watt de, al-affan iam, chen cz. identification of biological mechanism of damage by ionizing radiation. rad prot dos 1985; 13:285-294. 2. watt de, kadiri la. physical quantification of the biological effectiveness of ionizing radiation. j q chem 1990; 38:501-520. 3. watt de. on absolute biological effectiveness and unified dosimetry. radiat prot 1989; 9:33-49. 4. watt de, alkharam as. charged particle track structure parameters for application in radiation biology and radiation chemistry. int j q chem: quantum biology symposium 1994; 21:195-207. 5. alkharam as, watt de. risk scaling factors from inactivation to chromosome aberration. paper presented at the eighth symposium in neutron dosimetry, paris, france, 13-17 nov 1995. 6. goodhead dt, belli m, mill aj, bance da, allen la, hall sc et al. direct comparison between protons and alpha particles of the same let: i irradiation methods and inactivation of asynchronous v79, hela and c3h 10t½ cells. int j radiat biol 1992; 61:611-624. 7. eric j hall. why protons? int j radiat oncol biol phys 1995; 31:1005-1006. 8. alpen el. radiation biophysics. 2nd ed. new jersey: prentice-hall international, 1990. 9. belli m, cherubini r, finotto s, moschini g, sapors o, figure 2: inactivation cross section σ of v79 cells by protons versus the linear energy transfer let 238 fa i k a a a z o o z a n d th a m e r j a l k h a l i d y tabochini ma. rbe-let relationship for the survival of v79 cells irradiated with low energy protons. int j radiat biol 1989; 55:93-104. 10. belli m, goodhead dt, ianzini f, simone g, tabocchini ma. direct comparison of biological effectiveness of protons and alpha-particles of the same let. ii mutation induction at hprt locus in v79 cells. int j radiat biol 1992; 61:625-629. 11. folkard m, vojnovic b .the irradiation of v79 mammalian cells by protons with energy below 2 mev. int j biol 1989; 56:221-232. 12. belli m, cera f, cherubini r, haque ami, ianzini f, moschini g. inactivation and mutation induction in v79 cells by low energy protons: re-evaluation of the results of the lnl facility. int j radiat biol 1993; 63:331-337. 13. belli m, cera f, cherubini r, dalla vecchia m, haque ami, ianzini f, et al. rbelet relationship for cell inactivation and mutation induced by low energy protons inv79 cells: further results at lnl facility. int j radiat biol 1998; 74:501-509. 14. schettino g, folkard m, price km, vajnovic b, bowey ag, michael bd. low dose hypersensitivity in a chinese hamster v79 cells targeted with counted protons using charged particle micro beam. radiat res 2001; 156:526-534. submitted 8 aug 22 1 revision req. 13 sep 22; revision recd. 4 oct 22 2 accepted 1 nov 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.066 5 6 expression of dkk 1 in endometrial endometrioid carcinoma & its correlation 7 with wnt / β-catenin signaling pathway 8 abhijit das,1 *sandeep r. mathur,2 sunesh kumar,3 neerja bhatla3 9 10 1department of pathology, janakpuri super speciality hospital, new delhi, india; departments 11 of 2pathology and 3obstetrics and gynaecology, all india institute of medical sciences, new 12 delhi, india. 13 *corresponding author’s e-mail: mathuraiims@gmail.com 14 15 abstract 16 objective: endometrial cancer is the most common form of cancer affecting female reproductive 17 organs. most common histologic type endometrioid carcinoma constitutes 75 to 80% of all cases. 18 studies on dkk1 expression profiles and its inhibitory role in wnt signaling pathway in genesis 19 and development of endometrial carcinoma are very few. this study aims to investigate dkk1 20 expression in endometrial carcinoma and its correlation with wnt/β-catenin pathway. methods: 21 a total of 160 formalin fixed paraffin embedded samples including 50 cases each of endometrial 22 atypical hyperplasia and endometrioid endometrial carcinoma along with 30 cases each of 23 proliferative and secretory endometrium were included in this study. we investigated expression 24 pattern of dkk1, e-cadherin, β-catenin and c-myc in endometrial atypical hyperplasia and 25 carcinoma as well as compared with that of proliferative and secretory endometrium. 26 immunohistochemistry and analysis were performed from july, 2018 to june, 2020. results: we 27 showed decreasing pattern of immunopositivity for dkk1, e-cadherin and β-catenin from 28 proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid 29 carcinoma. increasing c-myc immunopositivity was noted from proliferative/secretory 30 endometrium to endometrial atypical hyperplasia and endometrioid carcinoma. moreover, 31 decreasing dkk1 immunopositivity was well correlated with both e-cadherin, β-catenin and c-32 myc immunopositivity. conclusion: decreasing dkk1 positivity from benign endometrium to 33 endometrioid carcinoma suggests a negative regulatory function of dkk1 in endometrioid 34 carcinoma. dkk1 is downregulated in wnt signaling pathway in endometrioid endometrial 35 carcinoma. thus, dkk1 can show promise as a biomarker for screening endometrioid carcinoma. 36 future researches can study the reactivation of the dkk1 gene that could be a valuable strategy 37 for antagonizing wnt signaling pathway. 38 keywords: endometrioid carcinoma, dkk1, wnt/β-catenin pathway, β-catenin, e-cadherin 39 40 advances in knowledge 41  dkk1 shows decreasing trend of immunoexpression from benign phase endometrium to 42 endometrioid endometrial carcinoma. 43  expression of dkk1 is well correlated with the markers (β-catenin, e-cadherin, c-myc) of 44 wnt signaling pathway. 45  dkk1 has an antagonistic role in wnt signaling pathway. 46 47 application to patient care 48  dkk1 can be a promising biomarker in screening progression of endometrioid 49 endometrial carcinoma. 50  reactivation of dkk1 gene could be a valuable strategy to antagonize wnt signaling 51 pathway in endometrioid endometrial carcinoma. 52 53 introduction 54 endometrial cancer is the most prevalent invasive gynecologic malignancy among american 55 women accounting for 7% of estimated new cancer cases in 2021.1 incidence and death rates of 56 endometrial cancer have been increasing by an average of 1.1% and 0.3% per year respectively.2 57 the most common histological type, endometrioid adenocarcinoma constitutes 75-80% of 58 endometrial cancers. the disease mostly affects postmenopausal women with an average age of 59 60 years at diagnosis, while in women younger than 40 years it constitutes only five percent.3 in 60 india it ranks third among female genital tract malignancies, after carcinoma cervix and 61 carcinoma ovary.4 most of the cases are diagnosed in early stages because of abnormal uterine 62 bleeding. the best diagnostic strategy in postmenopausal patient presenting with abnormal 63 uterine bleeding, still remains controversial. nowadays, endometrial biopsy and hysteroscopy 64 have almost replaced dilatation and curettage (d&c) for the diagnosis and management of 65 endometrioid carcinoma.5 recent studies showed that the first step in the diagnostic pathway 66 should be the measurement of endometrial thickness, followed by endometrial sampling.6 67 clinical assessment, radiological evaluation and histopathological examination have led the way 68 to study of molecular pathways like wnt signaling pathway. wnt signal transduction pathway is 69 activated by binding of a wnt protein to cell surface receptor. e-cadherin (a cell adhesion 70 molecule forming adherens junctions between cells), β-catenin (a subunit of cadherin protein 71 complex) and c-myc (a transcription factor protein regulating cell proliferation) are integral 72 components of wnt signaling pathway. abnormalities of wnt signaling transduction pathway 73 [figure 1] is responsible for genesis and development of some human malignant tumors.7 74 attempts have been made to investigate various regulators in the wnt signaling pathway as 75 targets for diagnosis and treatment of malignant tumors. several candidate markers, such as e-76 cadherin, β-catenin, c-myc and others have been proposed for use on cytologic or histologic 77 samples in endometrial carcinoma.8 as a negative regulator in wnt signaling pathway, dkk1 can 78 inhibit wnt activation in tumor progression.9,10 earlier studies in colorectum and placenta 79 showed that dkk1 was prominently expressed in normal cells but absent in cancer cells.11 at 80 present, studies on dkk1 expression profiles in endometrial carcinoma are very few.12 dkk1 81 expression pattern in endometrial carcinoma and its correlation with other components of wnt 82 pathway, especially β-catenin, e-cadherin and c-myc has not been studied so far in india. this 83 study will investigate the expression pattern of dkk1, e-cadherin, β-catenin and c-myc in 84 endometrial carcinoma. moreover, the expression pattern of these markers in endometrial 85 atypical hyperplasia and carcinoma will be compared with that of proliferative and secretory 86 endometrium. 87 88 methods 89 selection of cases 90 this retrospective study was conducted at the department of pathology where formalin fixed 91 paraffin embedded (ffpe) samples of endometrial lesions, age ranging from 21 to 77 years, 92 collected between january 2005 and march 2018, were selected including 50 cases each of 93 endometrial atypical hyperplasia and endometrioid endometrial carcinoma along with 30 cases 94 each of proliferative and secretory endometrium. endometrial samples in younger patients were 95 taken primarily to exclude the causes of infertility and abnormal uterine bleeding. standard 96 morphological criteria were used for diagnosis and selection of cases and control groups. the 97 study was approved by the institutional ethics committee. one section of each sample was 98 stained with hematoxylin and eosin (h&e) and four step sections on coated slides were used for 99 dkk1, e-cadherin, β-catenin and c-myc immunohistochemistry (ihc). immunohistochemistry 100 and analysis were performed over the next 2 years from july, 2018 to june, 2020. 101 102 immunohistochemistry 103 immunohistochemistry was performed using available monoclonal antibodies for dkk1, e-104 cadherin, β-catenin and c-myc (dkk1, abcam, 1:100; β-catenin, thermo scientific, 1:400; c-105 myc, thermo scientific, 1:100; and e-cadherin, thermo scientific, 1:200). 106 107 steps. serial 4-micron thick sections were cut from the selected representative paraffin 108 embedded tissue blocks and 3-aminopropyl triethoxysilane (aptes) coated slides were used for 109 ihc. slides were deparaffinized, followed by rehydration in decreasing concentration of alcohol. 110 for dkk1, e-cadherin and c-myc immunostains, antigen retrieval was done by heating the 111 sections in citrate buffer inside a 600 watt microwave oven at full power for 30 minutes. for β-112 catenin tris-edta buffer at ph 8 was used for heat mediated antigen retrieval. to diminish the 113 nonspecific immunostaining (i.e. endogenous peroxidase activity), each slide was treated with 114 methanol containing 4% hydrogen peroxide for 30 minutes. for all immunostains, sections were 115 then overlaid with adequate amount of appropriately diluted primary antibody followed by 116 overnight incubation at 40c in a humid chamber. after 3 changes of washing (5 minutes each) in 117 trishcl buffer peroxidase conjugated streptavidin was applied to cover the sections and 118 incubated at room temperature for 30 minutes. each section was then covered with substrate 119 chromogen solution freshly prepared by dissolving 50 µl of di-amino benzidine (dab) 120 chromogen to 1 ml of dab substrate buffer. the sections were counterstained with hematoxylin 121 for 10 seconds, followed by mounting with dpx. during staining of each bach, appropriate 122 positive and negative controls (by omitting primary antibody) were used. 123 124 analysis. ihc stains (dkk1, cytoplasmic; β-catenin, membranous; c-myc, cytoplasmic and 125 nuclear; e-caderin, membranous) were reviewed and analysed in conjunction with hematoxylin 126 and eosin (h&e) stained slides. immunoreactive score (irs) was obtained by multiplying 127 intensity score (0, no staining; 1, weak; 2, moderate and 3 strong staining) and percentage score 128 (0, nil; 1, <10%; 2, 10-50%; 3, 51-80% and 4, >80%). thus, the total irs score ranged from 0 to 129 12.13 two independent observers had analyzed the expression pattern of all four markers and 130 then an average was calculated for final analysis. appropriate statistical tests including 131 independent sample t test, chi-square test and pearson correlation test were applied to analyze 132 the significance of results between cases and control groups using the statistical package for the 133 social sciences (spss), version 21.0 (ibm inc., chicago, illinois, usa) software program. the 134 p<0.05 was considered statistically significant. 135 136 results 137 the retrospective study evaluated a total number of 160 samples including proliferative 138 endometrium, secretory endometrium, atypical hyperplasia and endometrioid carcinoma. 139 immunoprofiles using dkk1, e-cadherin, c-myc and β-catenin were compiled, compared and 140 analyzed for different expression pattern in various groups of endometrium. 141 142 age distribution. age pattern of proliferative group versus secretory group was statistically 143 insignificant (p value 1.000), while the age patterns between proliferative endometrium versus 144 endometrial atypical hyperplasia; proliferative endometrium versus endometrial carcinoma; 145 secretory endometrium versus endometrial atypical hyperplasia; secretory endometrium versus 146 endometrial carcinoma; as well as endometrial atypical hyperplasia versus endometrial 147 carcinoma were statistically significant (p value <0.001). 148 149 intergroup dkk1 immunopositivity. dkk1 showed mostly cytoplasmic expression in glandular 150 epithelium during proliferative phase, endometrial atypical hyperplasia and endometrioid 151 carcinoma. however, 2 cases of proliferative endometrium had nonspecific nuclear positivity 152 both in glandular epithelium and the stroma. secretory endometrium showed cytoplasmic 153 immunopositivity both in glandular as well as stromal cells. squamous morules associated with 154 endometrioid carcinoma also had similar cytoplasmic immunopositivity. we have studied 155 cytoplasmic expression among the groups. dkk1 immunopositivity of proliferative endometrium 156 versus secretory endometrium was statistically insignificant (p value 0.183). there was 157 increased dkk1 immunopositivity in proliferative endometrium as compared to endometrial 158 atypical hyperplasia and endometrioid carcinoma [figure 2], which was statistically significant 159 (p value <0.001). dkk1 immunopositivity of endometrial atypical hyperplasia versus 160 endometrioid carcinoma was statistically insignificant (p value 1.000). secretory endometrium 161 showed increased dkk1 immunopositivity as compared to endometrial atypical hyperplasia and 162 endometrioid carcinoma and the difference was statistically significant (p value <0.001). dkk1 163 showed decreasing trend of expression from endometrial atypical hyperplasia to grade i 164 endometrioid carcinoma to grade ii endometrioid carcinoma. when individual grades are 165 compared separately, the difference between endometrial atypical hyperplasia and grade i 166 endometrioid carcinoma was statistically insignificant (p value 1.000), but it was statistically 167 significant in between endometrial atypical hyperplasia and grade ii endometroid carcinoma (p 168 value 0.048). 169 170 intergroup e-cadherin immunopositivity. e-cadherin showed membranous immunopositivity. e-171 cadherin immunopositivity of proliferative endometrium versus secretory endometrium was 172 statistically insignificant (p value 1.000). immunopositivity of both proliferative endometrium 173 and secretory endometrium were higher than that of endometrial atypical hyperplasia and 174 endometrioid carcinoma [figure 3]; and the difference in immunopositivity among them were 175 statistically significant (p value <0.001). there was also statistically significant difference 176 between endometrial atypical hyperplasia and endometrioid carcinoma (p value <0.001). 177 178 intergroup β-catenin immunopositivity. membranous β-catenin expression was studied among 179 the groups. nuclear β-catenin was observed in 14% (7/50) of endometrioid carcinoma excluding 180 the areas of squamous morule formation that also showed nuclear positivity. β-catenin 181 immunopositivity of proliferative endometrium versus secretory endometrium was statistically 182 insignificant (p value 1.000). in this study, both proliferative endometrium and secretory 183 endometrium showed increased immunopositivity of β-catenin as compared to endometrial 184 atypical hyperplasia and endometrioid carcinoma [figure 4]; and the difference in β-catenin 185 immunopositivity among them were statistically significant (p value <0.001). immunopositivity 186 in endometrial atypical hyperplasia was statistically significant (p value <0.001) when compared 187 to that of endometrial carcinoma. 188 189 intergroup c-myc immunopositivity. we evaluated cytoplasmic c-myc immunopositivity among 190 the groups. additionally, nuclear expression was noted in 14 cases and 4 cases of proliferative 191 and secterory endometrium respectively. when c-myc immunopositivity of proliferative 192 endometrium versus secretory endometrium was compared, the difference was statistically 193 insignificant (p value 1.000). there was increased immunopositivity in endometrioid carcinoma 194 as compared to proliferative endometrium and endometrial atypical hyperplasia [figure 5]; the 195 difference in c-myc immunopositivity among them were statistically significant (p value 0.043 196 and <0.001 respectively). by contrast, c-myc immunopositivity of secretory endometrium versus 197 endometrial atypical hyperplasia was statistically insignificant (p value 0.384), while c-myc 198 immunopositivity of secretory endometrium versus endometrioid carcinoma was statistically 199 significant (p value <0.001). 200 201 intragroup correlation among immunohistochemistry markers. in endometrial atypical 202 hyperplasia group, we found statistically significant correlation between dkk1 and β-catenin 203 immunopositivity, as well as between e-cadherin and c-myc immunopositivity. rest three 204 groups didn’t show any significant correlation among the four ihc markers. comparison of 205 immunohistchemistry between two age groups in endometrial atypical hyperplasia and 206 endometrioid carcinoma as well as between grade i and grade ii endometrioid carcinomas didn’t 207 reveal any significant difference [table 1]. 208 209 discussion 210 endometrial cancer has surpassed cervical cancer as the most common gynecologic malignancy. 211 cervical cancer was much more prevalent in past few decades compared to endometrial cancer, 212 but earlier detection and eradication of cervical precursor lesions has reversed the ratio.14 213 endometrial carcinoma frequently occurs in peri-and post-menopausal women with 214 endometrioid carcinoma being the most common histological subtype.3,15 pten genetic 215 mutation is most frequent (39-83%) in endometrioid cancer, however β-catenin mutation 216 accounts for 31-47% of the cases.16 β-catenin is an integral component of wnt signaling 217 pathway [figure 1], that is dysregulated in many human cancers. on contrary, a negative 218 regulator of β-catenin pathway, dkk1 prevents tumor progression by inhibiting this signaling 219 pathway.9 some studies described role of dkk1 in non-endometrial tissues both in normal and 220 corresponding malignant cells, however studies on endometrial cancer are very less in english 221 literature.11,12 hence, we have tried to evaluate expression pattern of dkk1 in various groups of 222 benign, atypical and malignant endometrium as well as correlated with other markers like e-223 cadherin, β-catenin, c-myc of wnt pathway to show their relation among the groups. 224 225 dkk1. dkk1 is a glycoprotein and one of the members of dkk family (dkks), secreted by various 226 cells throughout the human body.17 the human dkk1 gene maps to chromosome 10q11.2, 227 which encodes a protein that acts as an antagonist in wnt signaling pathway [figure 1c] by 228 binding to and inhibiting lrp 5/6.18 yi n et al showed dkk1 positivity both in benign 229 endometrium and endometrial carcinoma, where dkk1 was mostly distributed in the cytoplasm 230 of glandular epithelium. they have documented ‘high expression’ of dkk1 predominantly in 231 benign endometrium, in contrast to “low expression” in endometrial cancer suggesting that this 232 reduction expression may be due to its negative regulatory function in wnt signaling pathway.12 233 we also found decreasing dkk1 immunopositivity from proliferative/secretory endometrium to 234 endometrial atypical hyperplasia and endometrioid carcinoma. in our study dkk1 positivity was 235 predominantly in the cytoplasm of glandular epithelium, however stromal cells also showed 236 weak cytoplasmic immunopositivity [figure 2]. we also found significant difference in dkk1 237 immunopositivity between endometrial atypical hyperplasia and proliferative/secretory 238 endometrium; as well as between endometrioid carcinoma and proliferative/secretory 239 endometrium. though there was increased dkk1 immunopositivity in endometrial atypical 240 hyperplasia as compared to endometrioid carcinoma, it did not achieve statistical significance. 241 interestingly some studies demonstrated reduced expression of β-catenin following treatment 242 with exogenous dkk1 probably indicating that increased dkk1 binding to lrp5/6 inhibits wnt 243 signaling leading to degradation of β-catenin.19 decreasing dkk1 positivity in our study from 244 benign endometrium to endometrioid carcinoma may suggest that negative regulatory function of 245 dkk1 is reduced from benign to malignant endometrium. thus at least in part, by inducing 246 abnormalities of wnt signaling pathway, dkk1 plays a role in the genesis and development of 247 endometrial carcinoma. similar patterns of dkk1 alterations have also been reported in some 248 other tumors including colorectal cancer, placental choriocarcinoma and non-small cell lung 249 cancers where dkk genes were frequently silenced.11,20 in our study decreasing positivity of 250 dkk1 from proliferative/secretory endometrium to endometrial atypical hyperplasia and 251 endometrioid carcinoma, suggests that dkk1 is involved in the early phase of endometrioid 252 carcinoma by suppressing wnt pathway. 253 254 e-cadherin. cell surface glycoprotein e-cadherin with a molecular weight of 120 kda is a major 255 cadherin molecule expressed by epithelial cells. it binds to catenin [figure 1a] to form a 256 cadherin-catenin complex that plays an important role in intercellular adhesion.21 shih et al 257 demonstrated that the cytoplasmic expression of e-cadherin in endometrial glandular cells 258 occurred mainly in the proliferative phase and decreased in the secretory phase.7 in contrast to 259 this study we found strong membranous immunopositivity both in proliferative and secretory 260 endometrium. although, similar to their study, we found decreased e-cadherin expression in 261 endometrioid carcinoma as compared to proliferative/secretory endometrium. the mechanism of 262 reduced of e-cadherin positivity has not been fully understood, however, saito et al showed that 263 loss of e-cadherin positivity was caused by promoter methylation of the e-cadherin gene.22 in 264 our study, we found significant difference in e-cadherin immunopositivity between endometrial 265 atypical hyperplasia and proliferative/secretory endometrium; as well as between endometrioid 266 carcinoma and proliferative/secretory endometrium. we also showed that e-cadherin 267 immunopositivity was significantly different between endometrial atypical hyperplasia and 268 endometrioid carcinoma. so far, none of the previous studies has mentioned difference in e-269 cadherin positivity between endometrial atypical hyperplasia and carcinoma. 270 271 β-catenin. β-catenin encoded by ctnnb1 gene is a subunit of the cadherin protein complex. it 272 takes part in the formation of adherens junctions [figure 1], that plays a pivotal role in 273 maintaining epithelial cell layers by regulating cellular adhesion and growth signals.23 several 274 studies showed that it has been implicated in the pathogenesis and progression of many human 275 malignancies involving wnt pathway. as a signal transducer in wnt pathway it induces targeted 276 gene expression and cytoplasmic β-catenin accumulation.24 previous studies demonstrated 277 greater positivity of cytoplasmic β-catenin in the glandular cells of proliferative endometrium as 278 compared to secretory phase. these studies also showed nuclear positivity of β-catenin in the 279 glandular cells of the proliferative and early secretory phase endometrium.7,24 however, we did 280 not find any difference in β-catenin immunopositivity between proliferative and secretory 281 endometrium as well as no nuclear β-catenin immunopositivity in proliferative/secretory 282 endometrium or in endometrial atypical hyperplasia. shih et al revealed that the nuclear β-283 catenin-positive cells lacked e-cadherin positivity which indicated an inverse correlation 284 between e-cadherin and nuclear β-catenin positivity.7,25 this result was concordant with our 285 study where 14% of endometrioid carcinoma showed nuclear β-catenin immunopositivity, and 286 most of them showed near total loss of membranous e-cadherin immunopositivity. exact 287 mechanisms behind this reduced positivity of e-cadherin at nuclear β-catenin positive sites are 288 still not elucidated, however it may be due to nuclear translocation of β-catenin that impairs the 289 β-catenin/e-cadherin adherent junction complex that finally leads to e-cadherin release from the 290 cell membrane. 291 292 the mechanisms of nuclear accumulation of β-catenin are reported to be responsible for the 293 mutation of β-catenin and related genes. studies on wnt pathway in colorectal cancers 294 demonstrated β-catenin stabilization and its significant accumulation in the cell which were 295 primarily attributed to the mutation of the adenomatosis polyposis coli (apc) or β-catenin gene 296 in the signaling pathway resulting in cell cycle progression in colorectal cancer.26 our study 297 showed decreasing membranous immunopositivity of β-catenin from proliferative/secretory 298 endometrium to endometrial atypical hyperplasia and endometrioid carcinoma. we also showed 299 that there was significant difference in β-catenin immunopositivity between endometrial atypical 300 hyperplasia and proliferative/secretory endometrium; between endometrioid carcinoma and 301 proliferative/secretory endometrium; as well as between endometrial atypical hyperplasia and 302 endometrioid carcinoma. in this study, nuclear β-catenin positive cases of endometrioid 303 carcinoma showed increased cytoplasmic c-myc immunopositivity. hence, both c-myc and β-304 catenin were found to be upregulated in these cases of endometrioid carcinomas. 305 306 c-myc. c-myc is a nuclear dna binding protein that is implicated in cell cycle regulation. c-myc 307 amplifications in many human cancers were found to be associated with tumor aggressiveness 308 and poor prognosis.27 a cyclic variation in the c-myc positivity was reported by odom et al with 309 higher expression in the proliferative than in the secretory phase.28 in contrast to this finding, we 310 observed increased c-myc immunopositivity in secretory endometrium as compared to 311 proliferative endometrium. bircan et al in their study showed that the anti c-myc monoclonal 312 antibody was detected both in the nucleus and the cytoplasm, which was concordant with our 313 study. actively dividing cells of proliferative phase endometrium displayed a nuclear 314 distribution, while in differentiated cells of the secretory phase the immunostaining was 315 primarily cytoplasmic.29 they showed cytoplasmic and perinuclear c-myc positivity in 15.3% of 316 endometrial cancers. another study by geisler et al demonstrated both cytoplasmic and nuclear 317 c-myc immunopositivity in 75.2% and 66.9% of cases of endometrial cancers respectively.30 by 318 contrast, we found only cytoplasmic c-myc immunopositivity in all cases of endometrioid 319 carcinomas along with few cases of proliferative and secretory endometrium showing nuclear c-320 myc immunopositivity. we also found increasing cytoplasmic immunopositivity of c-myc from 321 proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid 322 carcinoma. there was also significant difference in immunopositivity between endometrial 323 atypical hyperplasia and proliferative endometrium; between endometrioid carcinoma and 324 proliferative/secretory endometrium; as well as between endometrial atypical hyperplasia and 325 carcinoma. however, we did not find any significant difference in c-myc immunopositivity 326 between endometrial atypical hyperplasia and secretory endometrium. 327 328 conclusion 329 decreasing dkk1 immunopositivity from proliferative/secretory endometrium to endometrial 330 atypical hyperplasia to endometrioid carcinoma indicates that dkk1 is downregulated in 331 endometrioid endometrial carcinoma. immunoprofiles of dkk1 and the other markers associated 332 with wnt signaling pathway explain the antagonistic role of dkk1 in the wnt signaling pathway 333 in endometrial cancer. thus, dkk1 shows promise as a biomarker for screening progression of 334 endometrioid carcinoma. on the other hand, reactivation of the dkk1 gene could be a valuable 335 strategy for antagonizing wnt signaling pathway. 336 337 conflicts of interest 338 the authors declare no conflict of interests. 339 340 funding 341 no funding was received for this study. 342 343 author contributions 344 ad and sm conceptualised and designed the study. sm drafted the manuscript. sk and nb 345 performed critical review and contributed with suggestions. sm and ad were involved in data 346 collection, data entry, literature search, and data analysis. all the authors approved the final 347 version of the manuscript. 348 349 references 350 1. american cancer society. cancer facts and figures 2021. atlanta, ga: american cancer 351 society, 2021. available online last accessed november 23, 2021. 352 https://doi.org/10.1057/978-1-349-96042-2_16551. 353 2. lewis dr, chen hs, cockburn mg, wu xc, stroup am, midthune dn, zou z, krapcho 354 mf, miller dg, feuer ej. early estimates of seer cancer incidence, 2014. cancer 2017; 355 123:2524-2534. https://doi.org/10.1002/cncr.30630. 356 3. kushner dm, lurain jr, fu ts, fishman da. endometrial adenocarcinoma metastatic to the 357 scalp: case report and literature review. gynecol oncol 1997; 65:530-3. 358 https://doi.org/10.1006/gyno.1997.4718. 359 4. nath, a., & mathur, p. (2021). strengthening cancer surveillance in india: role of the 360 national cancer registry programme. indian journal of surgical oncology. 361 https://doi.org/10.1007/s13193-021-01473-8. 362 5. colombo n, preti e, landoni f, carinelli s, colombo a, marini c, sessa c; esmo 363 guidelines working group. endometrial cancer: esmo clinical practice guidelines for 364 diagnosis, treatment and follow-up. ann oncol 2011; 22 suppl 6:vi35-9. 365 https://doi.org/10.1093/annonc/mdr374. 366 6. vergote i, amant f, timmerman d. should we screen for endometrial cancer? lancet oncol 367 2011; 12:4-5. https://doi.org/10.1016/s1470-2045(10)70280-1. 368 http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf 7. bienz m, clevers h. linking colorectal cancer to wnt signaling. cell 2000; 103:311-20. 369 https://doi.org/10.1016/s0092-8674(00)00122-7. 370 8. shih hc, shiozawa t, miyamoto t, kashima h, feng yz, kurai m, konishi i. 371 immunohistochemical expression of e-cadherin and beta-catenin in the normal and 372 malignant human endometrium: an inverse correlation between e-cadherin and nuclear beta-373 catenin expression. anticancer res 2004; 24:3843-50. pmid: 15736420. 374 9. logan cy, nusse r. the wnt signaling pathway in development and disease. annu rev cell 375 dev biol 2004; 20:781-810. https://doi.org/10.1146/annurev.cellbio.20.010403.113126. 376 10. mao j, wang j, liu b, pan w, farr gh 3rd, flynn c, yuan h, takada s, kimelman d, li l, 377 wu d. low-density lipoprotein receptor-related protein-5 binds to axin and regulates the 378 canonical wnt signaling pathway. mol cell 2001; 7:801-9. https://doi.org/10.1016/s1097-379 2765(01)00224-6. 380 11. peng s, miao c, li j, fan x, cao y, duan e. dickkopf-1 induced apoptosis in human 381 placental choriocarcinoma is independent of canonical wnt signaling. biochem biophys res 382 commun 2006; 350:641-7. https://doi.org/10.1016/j.bbrc.2006.09.087. 383 12. yi n, liao qp, li t, xiong y. novel expression profiles and invasiveness-related biology 384 function of dkk1 in endometrial carcinoma. oncol rep 2009; 21:1421-7. 385 https://doi.org/10.3892/or_00000370. 386 13. pyo sw, hashimoto m, kim ys, kim ch, lee sh, johnson kr, wheelock mj, park ju. 387 expression of e-cadherin, p-cadherin and n-cadherin in oral squamous cell carcinoma: 388 correlation with the clinicopathologic features and patient outcome. j craniomaxillofac surg 389 2007; 35:1-9. https://doi.org/10.1016/j.jcms.2006.11.004. 390 14. kumar v, abbas ak, aster jc: robbins and cotran pathologic basis of disease. 9th ed. 391 elsevier saunders, philadelphia, 2015. p.1014. 392 15. bokhman jv. two pathogenetic types of endometrial carcinoma. gynecol oncol 1983; 393 15:10-7. https://doi.org/10.1016/0090-8258(83)90111-7. 394 https://doi.org/10.1016/s0092-8674(00)00122-7 16. bansal n, yendluri v, wenham rm. the molecular biology of endometrial cancers and the 395 implications for pathogenesis, classification, and targeted therapies. cancer control 2009; 396 16:8-13. https://doi.org/10.1177/107327480901600102. 397 17. bafico a, liu g, yaniv a, gazit a, aaronson sa. novel mechanism of wnt signalling 398 inhibition mediated by dickkopf-1 interaction with lrp6/arrow. nat cell biol 2001; 3:683-399 6. https://doi.org/10.1038/35083081. 400 18. mao b, wu w, li y, hoppe d, stannek p, glinka a, niehrs c. ldl-receptor-related protein 401 6 is a receptor for dickkopf proteins. nature 2001; 411:321-5. 402 https://doi.org/10.1038/35077108. 403 19. maniatis t. a ubiquitin ligase complex essential for the nf-kappab, wnt/wingless, and 404 hedgehog signaling pathways. genes dev 1999; 13:505-10. 405 https://doi.org/10.1101/gad.13.5.505. 406 20. licchesi jd, westra wh, hooker cm, machida eo, baylin sb, herman jg. epigenetic 407 alteration of wnt pathway antagonists in progressive glandular neoplasia of the lung. 408 carcinogenesis 2008; 29:895-904. https://doi.org/10.1093/carcin/bgn017. 409 21. fadare o, reddy h, wang j, hileeto d, schwartz pe, zheng w. e-cadherin and beta-410 catenin expression in early stage cervical carcinoma: a tissue microarray study of 147 cases. 411 world j surg oncol 2005; 3:38. https://doi.org/10.1186/1477-7819-3-38. 412 22. saito t, nishimura m, yamasaki h, kudo r. hypermethylation in promoter region of e-413 cadherin gene is associated with tumor dedifferention and myometrial invasion in 414 endometrial carcinoma. cancer 2003;97:1002-9. https://doi.org/10.1002/cncr.11157. 415 23. thompson md, monga sp. wnt/beta-catenin signaling in liver health and disease. 416 hepatology 2007; 45:1298-305. https://doi.org/10.1002/hep.21651. 417 24. gumbiner bm. signal transduction of beta-catenin. curr opin cell biol 1995; 7:634-40. 418 https://doi.org/10.1016/0955-0674(95)80104-9. 419 25. nei h, saito t, yamasaki h, mizumoto h, ito e, kudo r. nuclear localization of beta-420 catenin in normal and carcinogenic endometrium. mol carcinog 1999; 25:207-18. 421 https://doi.org/10.1002/(sici)1098-2744(199907)25:3<207::aid-mc7>3.0.co;2-4. 422 26. morin pj, sparks ab, korinek v, barker n, clevers h, vogelstein b, kinzler kw. 423 activation of beta-catenin-tcf signaling in colon cancer by mutations in beta-catenin or 424 apc. science 1997; 275:1787-90. https://doi.org/10.1126/science.275.5307.1787. 425 27. watson jv, curling om, munn cf, hudson cn. oncogene expression in ovarian cancer: a 426 pilot study of c-myc oncoprotein in serous papillary ovarian cancer. gynecol oncol 1987; 427 28:137-50. https://doi.org/10.1016/0090-8258(87)90207-1. 428 28. odom ld, barrett jm, pantazis cg, stoddard ld, mcdonough pg. immunocytochemical 429 study of ras and myc proto-oncogene polypeptide expression in the human menstrual cycle. 430 am j obstet gynecol 1989; 161:1663-8. https://doi.org/10.1016/0002-9378(89)90946-0. 431 29. bircan s, ensari a, ozturk s, erdogan n, dundar i, ortac f. immunohistochemical analysis 432 of c-myc, c-jun and estrogen receptor in normal, hyperplastic and neoplastic endometrium. 433 pathol oncol res 2005; 11:32-9. https://doi.org/10.1007/bf03032403. 434 30. geisler jp, geisler he, manahan kj, miller ga, wiemann mc, zhou z, crabtree w. 435 nuclear and cytoplasmic c-myc staining in endometrial carcinoma and their relationship to 436 survival. int j gynecol cancer 2004;14:133-7. https://doi.org/10.1136/ijgc-00009577-437 200401000-00018. 438 439 figure 1: a) absence of signaling molecule i.e., legend (wnt molecule) leads to formation of 440 ‘destruction complex’ that in turn creates a hyperphosphorylated β-catenin destined for 441 proteosomal degradation. also depicted is e-cadherin binding to β-catenin forming adherens 442 junction. b) wnt molecule binding to frizzled (fzd)/lrp 5/6 receptors inactivates ‘destruction 443 complex’ and stabilizes hypophosphorylatedβ-catenin that enter nucleus to interact with 444 tcf/lef family proteins to activate gene transcription. c) dkk1 binds to lrp5/6 co-receptor 445 and blocks wnt binding that ultimately results in β-catenin degradation and repression of gene 446 transcription. (illustration is created by the authors). 447 448 449 figure 2: dkk1 immunopositivity. proliferative endometrium (a, 400x magnification), 450 secretory endometrium (b, 400x magnification), endometrial atypical hyperplasia (c, 400x 451 magnification), and endometrioid carcinoma (d, 400x magnification). 452 453 figure 3: e-cadherin immunopositivity. proliferative endometrium (a, 400x magnification), 454 secretory endometrium (b, 400x magnification), endometrial atypical hyperplasia (c, 400x 455 magnification), and endometrioid carcinoma (d, 400x magnification). 456 457 458 figure 4: β-catenin immunopositivity. secretory endometrium (a, 400x magnification), 459 endometrial atypical hyperplasia (b, 100x magnification), endometrioid carcinoma (c, 400x 460 magnification), and nuclear positivity in endometrioid carcinoma (d, 400x magnification). 461 462 463 figure 5: c-myc immunopositivity. proliferative endometrium (a, 100x magnification), 464 secretory endometrium (b, 200x magnification), endometrial atypical hyperplasia (c, 200x 465 magnification), and endometrioid carcinoma (d, 400x magnification). 466 table 1: comparison of immunopositivity between grade i and grade ii endometrioid carcinoma 467 ihc grade (1 as grade i, 2 as grade ii) no. of cases mean irs±sd p value dkk1 1 2 39 11 4.10±2.222 3.18±1.601 0.207 e-cadherin 1 2 39 11 2.92±1.645 2.82±1.662 0.853 β-catenin 1 2 39 11 3.31±1.360 3.64±1.502 0.492 c-myc 1 2 39 11 8.67±3.198 8.27±2.970 0.716 468 caesarean sections at sultan qaboos university hospital 29 caesarean sections at sultan qaboos university hospital: a three year review *mariam mathew, radha kumari, vlasta vaclavinkova, andrzej krolikowski abstrac t. objective: to review the caesarean sections (c/s) performed at sultan qaboos university hospital (squh), muscat, oman, over a period of three years. method: the records of 727 patients who underwent c/s at squh during the three year period from 1st july 1998 to 30th june 2001 were analysed. results: the c/s rate during this period was 13%, 42.6% of which were repeat c/s. most were performed on women in the age group 26–30 years and of parity 2–3. the majority of the caesareans were at term and done under general anaesthesia. the most common indication was fetal distress and the most common complication was fever. conclusion: the rate, indications, nature and frequency of complications of c/s performed at squh are similar to those at obstetric departments in academic hospitals in developed countries. key words: caesarean section, cephalopelvic disproportion, prophylactic antibiotics, macrosomia, disseminated intravascular coagulation. department of obstetrics and gynaecology, sultan qaboos university hospital, p.o.box: 38, postal code: 123, al khod, muscat, sultanate of oman *to whom correspondence should be addressed. email: mathewz@omantel.net.om the rate of caesarean sections (c/s) has been continuously increasing around the world since 970, a major contributing factor being the fear of litigation.1 the average rate of c/s at most western obstetric units varies between 5 and 5%. data from the less developed countries are insufficient for comparison.2 oman is a country with extremely high parity. it is a common experience that the woman refuses caesarean section, fearing it might limit the number of her children. this different attitude was one of the reasons why we wanted to review the c/s performed at sultan qaboos university hospital (squh), muscat. m e t h o d the records of all patients who underwent c/s at squh between july , 998 and june 30, 200 were analysed. the age and parity of the women, gestational age, indications for the c/s, type of anaesthesia, abdominal incision-delivery interval, post operative complications, birth weights and apgar scores of the neonates were analysed. the decision to undertake each c/s was discussed with a consultant. r e s u l t s during the period of study, there were 5,57 deliveries at squh, of which 727 were by c/s, an incidence of 3 percent. all operations performed during the period of the study were lower segment caesareans except 3 cases of “inverted t” incisions. of these 727 patients, 502 (69.%) were multi-gravidae (gravida: 2–4). table  shows the number of deliveries by type and year during the period of the study. patients who had c/s were categorised according to age and parity [table 2]. the majority in the study group comprised of omanis, who numbered 576 (79.2%). most abdominal deliveries squ journal for scientific research: medical sciences 2002, vol. 4, no. –2, 29–32 ©sultan qaboos universit y caesarian mariam �������������������� �� ����� ���� �������� ����� ��� ��� ����� ������� ����� ����� ���� ������ ��������������� ������ ������������ ����� � �������� :�����:���������� ��� ��� ����� ������� ����� ������ �� ����� ���� �������� �������� � .������� :�� ������ ������ ������ ������������ �� ����� ��� ��� ����� ������� ����� ������ �� ������ ������� ��� ����� ����� �������������� �� ������� �����������.�������:����� �������� ������� ������� %�������� %���������� ����� ���� ����� ��� ����� ������� .���� ����������� ����� �� ������ �������� �������������-������������ �������-���������� � .������ ���� ����� ����� ������� ����� �������� ���� �������������� ����.������ : ��������� ������ �������� �������� ������ ���� ����� �������� ����� �� ��������� ���������� �� ������ ����� �� ���� ���� ��� ����� ������� ����� ������ �� ���� ������� . 30 were performed on women in the age group of 26–30, and those who were of parity 2–3. the indications for primary c/s are shown in table 3, which shows that fetal distress was the most common indication. there were 30 (42.6%) repeat c/s [table 4]. fetal macrosomia was present in only 3.4% of all caesareans. estimated blood loss during caesareans was less than 500 ml in 66.7%; only in 7.7% was it more than ,000 ml. most c/s were done under general anaesthesia—637 (87.6%). out of the 727 c/s, 629 (86.5%) were term pregnancies and 98 (3.5%) were pre-term. among the multiple pregnancies who had c/s, there were 5 sets of triplets and one set of sextuplets. the majority of c/s were emergencies—488 (67.%)—whereas 239 (32.9%) were elective. all the women except two (99.7%) patients had received antenatal care. most of our patients received antibiotics—623 (85.7%), of which 202 were prophylactic (single dose of .5 g cefuroxime). table 5 shows the maternal complications following c/s, the most common of which was fever (25%). there was one maternal death due to septicaemia followed by disseminated intravascular coagulation (dic). average incision-delivery interval was 8.4 minutes, and the average hospital stay, 6.4 days. 76 (98. 6%) of the neonates were born with the apgar score >7 at 5 minutes. among the singleton babies, the minimum birth weight was 575 g and the maximum was 5,00 g. four hundred and thirteen (56.8%) were male. d i s c u s s i o n no single factor can account for the dramatic increase in caesarean deliveries during the last 30 years around the world. the widespread introduction of electronic fetal monitoring coupled with the increase in litigation has undoubtedly played a major part.3 teaching hospitals tend to have lower caesarean delivery rates than do private institutions.4 when one considers that 30% of all table 3. indications for primary caesarean section indication no % fetal distress 134 32.1 breech 78 18.7 failure to progress 55 13.2 cephalo pelvic disproportion 31 7.4 antepartum haemorrhage 31 7.4 multiple pregnancy 23 5.5 abnormal lie 13 3.1 cord prolapse 10 2.4 failed induction 9 2.2 big baby (> 4 kg) 9 2.2 bad obstetric history 6 1.4 patient’s request 5 1.2 severe pre-eclampsia 4 1.0 previous myomectomy-opened cavity 4 1.0 previous pelvic floor repair 3 0.7 fibroid uterus-obstructing delivery 1 0.2 previous classical caesarean section 1 0.2 total 417 100.0 m at h e w at a l table 1. total number of deliveries by type and year type of delivery 1998 1999 2000 2001 no. % no. % no. % no. % vaginal delivery 658 82.3 1338 80.5 1740 84.3 864 82.8 caesarean 111 13.9 248 14.9 243 11.8 125 12.0 vacuum 25 3.1 72 4.3 74 3.6 47 4.5 forceps 6 0.8 5 0.3 7 0.3 8 0.8 total 800 100.0 1663 100.0 2064 100.0 1044 100.0 table 2. association between maternal age, parity and number of caesarean sections age(years) no. of c/s % parity no of c/s % < 20 46 6.3 primipara 225 30.9 21-25 204 28.1 2–3 362 49.8 26-30 225 30.9 4–6 85 11.7 31-35 164 22.6 >7 55 7.6 36-40 72 9.9 >40 16 2.2 total c/s 727 100.0 727 100.0 3 caesarean deliveries performed are repeat caesareans, it would be difficult to decrease the total c/s rate without reducing the repeat caesareans.5 in hospitals with appropriate facilities, services and staff, for a prompt emergency caesarean birth, a proper selection of cases should permit a safe trial of vaginal delivery for women who have had a previous lower segment transverse caesarean birth.5 in our hospital trial of vaginal delivery is the standard practice for such patients, provided the cause for the previous c/s does not recur. the indications for c/s can be maternal or fetal. in our study, the most common indication for primary c/ s was fetal distress. for repeat caesareans, two or more previous c/s was the most common indication. these findings agree with other recently published data.6,7 multiple pregnancy and breech presentation are additional factors contributing to the rise in c/s.7,8 each case should be thoroughly evaluated to determine the possibility for vaginal delivery. infection must never be underestimated as it continues to be an important cause of maternal mortality.9 the wound infection rate among the women in our study was 2.8% compared with other reports, which give figures as high as 0%.10 the infections in our group included a rare case of necrotising fascitis, successfully treated with wound debridement and antibiotics. confidential enquiries into maternal death in united kingdom during 994–96 shows an increase in the rate of maternal death from sepsis from 3.9 to 6.4 per million maternities compared to the last triennium.9 the onset of infection can be insidious and can rapidly progress to a fulminating septicaemia. the only mortality in our group was that of a 3-year-old primipara, who had an uncomplicated c/s under antibiotic cover, because of prolonged labour. few hours later she developed high fever and postpartum haemorrhage with a clinical diagnosis of dic. in spite of intensive treatment she could not be saved. according to murphy, the routine use of prophylactic antibiotics is associated with a statistically significant and clinically important reduction in postpartum febrile morbidity, wound infection and other serious infections.11 the average blood loss in our patients was 0.5–0.6 l, much less than the reported 0.7–.0 l.12 spontaneous expulsion of placenta at caesarean significantly reduces blood loss by about 300 ml.13 our patients with severe postpartum haemorrhage were successfully managed with uterotonics, replacement of blood/blood products and uterine artery ligation/embolisation, except for five patients who had hysterectomy for uncontrolled haemorrhage. though the average hospital stay was 6.4 days, many patients left earlier. literature shows that discharge as early as post operative day 2 has been safe.14 liberman et.al., in a recently published study, noticed an increase in the number of boys born by c/s, which is in agreement with our study, where 56% of the babies born were male.15 table 4. indications for repeat caesarean sections indication no % two or more caesarean sections previously 137 44.2 fetal distress 29 9.4 cephalo pelvic disproportion 28 9.0 failure to progress 24 7.7 patient request 17 5.5 big baby (> 4 kg) 16 5.2 breech 14 4.5 failed induction 10 3.2 antepartum haemorrhage 7 2.3 abnormal lie 7 2.3 multiple pregnancy 5 1.6 bad obstetric history 4 1.3 previous myomectomy -opened cavity 3 1.0 previous classical caesarean section 3 1.0 fibroid uterus -obstructing delivery 3 1.0 severe pre-eclampsia 2 0.6 cord prolapse 1 0.3 total 310 100 table 5. maternal complications maternal complication no. % fever 182 25.0 blood transfusion 62 8.5 wound infection 20 2.8 urinary tract infection 11 1.5 disseminated intravascular coagulation (dic) 3 0.4 respiratory tract infection 2 0.3 scar dehiscence 1 0.1 rupture of uterus 1 0.1 pulmonary embolism 1 0.1 postpartum blindness 1 0.1 maternal death 1 0.1 c a e s a e a n s e c t i o n s i n s q u h 32 c o n c l u s i o n in spite of high parity and the reluctance of our patients to undergo caesarean section, our rate of caesarean is similar to that of the rest of the world. the indications and the nature and frequency of complications of c/ s performed at squh are similar to other obstetric departments in academic hospitals in developed countries. our study also confirms that even though the caesarean is one of the most commonly performed surgical procedures today, it is not without risks. we agree with the other authors that the routine use of prophylactic antibiotics helps reduce the morbidity associated with caesarean sections. r e f e r e n c e s . akasheh hf, amarin v. caesarean sections at queen alia military hospital, jordan: a six year review. east mediterr health j, 2000, 6, 42–45. 2. dumont a, de bernis l, bouvier-colle mh, breart g. caesarean section rate for maternal indication in sub-saharan africa—a systematic review. lancet, 200, 358, 328–333. 3. sachs bp. vaginal birth after caesarean. a health policy perspective. clin obstet gynecol, 200, 44, 553–560. 4. sanchez-ramos l, moorhead rl, kaunitz am. cesarean section rates in teaching hospitals: a national survey. birth, 994, 2, 94–96. 5. zinberg s. vaginal delivery after previous caesarean delivery: a continuing controversy. clin obstet gynecol, 200, 44, 56– 570. 6. stembera z. vyvoj indikaci cisarskeho rezu v ceske republice a nekterych vyspelych zemich. development of indications for c/s in the czech republic and certain developed countries. cas lek cesk, 992, 3, 225–230. 7. tadesse e, adane m, abiyou m. caesarean section deliveries at tikur anbessa teaching hospital, ethiopia. east afr med j, 996, 73, 69–622. 8. diro m, puangsricharern a, royer l, sullivan mjo, burkett g. singleton breech deliveries in nulliparous and multiparous women—a five years experience at the university of miami/ jackson memorial hospital. am j obstet gynecol, 999, 8, 247–252. 9. crowhurst ja, platt f. why mothers die—report on confidential enquiries into maternal deaths in the united kingdom 994–96. anaesthesia, 999, 54, 207–209. 0. beattie pg, rings tr, hunter mf, lake y. risk factors for wound infection following caesarean section. aust nz obstet gynecol, 994, 34, 398–402. . murphy kw. reducing the complications of caesarean sections. in j bonnar, recent advances in obstetrics and gynecology. new york, elsevier, pp:4–52. 2. pritchard ja, baldwin rm, dickey jc, wiggins km. blood volume changes in pregnancy and the puerperium. red cell loss and changes in apparent blood volume during and following vaginal delivery, caesarean section, and caesarean section plus total hysterectomy. am j obstet gynecol, 962, 84, 27– 282 3. mc curdy cm, magann ef, mc curdy cj, saltzman ak. effect of placental management at caesarean delivery on operative blood loss. am j obstet gynecol, 992, 67, 363–367. 4. brooten d, roncoli m, finkler s, arnold l, cohen a, mennuti m. a randomized trial of early hospital discharge and home follow up of women having caesarean birth. obstet gynecol 1994, 84, 832–838. 5. lieberman e, lang jm, cohen ap, frigoletto fd jr, acker d, rao r. the association of fetal sex with the rate of caesarean section. am j obstet gynecol, 997, 76, 667–67. m at h e w at a l august 2007 vol 7 copy.indd essential endocrinology and diabetes fifth edition authors: richard ig holt, neil a hanley reviewer: *mohammed a al-lamki sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 97-98 sultan qaboos university© submitted 11th april 2007 b a c k g r o u n d t o t h e b o o k endocrinology and diabetes are a complex combination. this book has tried to encompass the factual complexities of updated knowledge and clinical experience. the history of endocrine diseases, enhances our understanding from clinical aspects through laboratory testing to diagnostic breakthroughs. o v e r v i e w o f c o n t e n t s the book has 272 pages with suggestions for further reading, a list of abbreviations and an index as well as some colour plates. the contents are in three sections as follows: part 1: principles of endocrinology (pages 3-52) 1. the endocrine system 2. the biological principles of endocrinology 3. the molecular basis of endocrinology 4. investigations in endocrinology, part 2: clinical endocrinology (pages 53-182) 5. the hypothalamus and pituitary gland, 6. the adrenal gland 7. reproductive endocrinology 8. the thyroid gland 9. calcium and metabolic bone disease 10. endocrine neoplasia part 3: clinical diabetes and obesity (pages 183-264) 11. overview of diabetes 12. type 1 diabetes 13. type 2 diabetes 14. complications of diabetes 15. obesity r e a d e r s h i p m o s t s u i t e d f o r t h i s b o o k students, interns and residents would benefit from reading this book, the latter during their initial introduction to clinical endocrinology. others doing their fellowship in endocrinology would find it an introductory factual revision to the subject. surgeons in endocrinology would find it useful and it would be a helpful reference book for practicing endocrine specialist nurses. b o o k r e v i e w الطبعة اخلامسة السكر/ وداء األساسي الهورمونات علم هانلي نيل هولت، ريتشارد �تأليف: اللمكي محمد مراجعة: blackwell publishing ltd. first published 1983. fifth edition 2007 isbn-13: 978-1-4051-3648-8 uk price 15.00 gbp available from: www.blackwellpublishing.com division of medicine royal hospital, muscat, sultanate of oman r i c h a r d i g h o lt a n d n e i l a h a n l e y 168 a p p r o p r i a t e n e s s o f t h e c o n t e n t t o t a r g e t r e a d e r s h i p the contents are well placed for understanding with a pre-amble outline of facts and associated clinical aspects. the use of objectives for each chapter and key points at the end is a perfect method to grasp knowledge. the reader is eager to follow the contents, which are easy to comprehend. this book is a prelude to further reading in a subject of this complexity. it is thus very appropriate for beginners, a sound solid foundation reading for the subject. c o m p r e h e n s i v e n e s s o f t h e c o n t e n t the content has covered most aspects within the scope of the book. the authors have managed to cover the basic facts as well as updates, especially in molecular biology, and have associated these to clinical practice. it would be more complete if it had a simplified methodology of growth charts and interpretations. o r g a n i s a t i o n o f t h e c o n t e n t the organization of the content is hard to fault. the facts are appropriately placed with targets, testing of knowledge by clinical cases and points of importance being emphasized at the end of each chapter. this is a very modern way of learning and knowledge stratification. g e n e r a l c o m m e n t s o n q u a l i t y o f c o n t e n t a n d p r o d u c t i o n again, this is a modern way of placing factual content, clinical aspects and emphasising important points. this is the basis of this book and with boxes and illustrations, for facts or molecular illustrations the reader is placed in an inviting aura of knowledge. the illustrations and the colour plates are well placed and of high quality. there is no doubt that the authors have been successful in reaching their targets. i congratulate them on a very useful book that is enjoyable to read. i read the history of endocrine disease with relish. very few books in the past have attempted this kind of history. the case histories and questions and answers are simple but testing. i would recommend the book for my residents and fellows as initial reading material. s u g g e s t i o n s in the future editions, the authors would do well to add: 1. growth charts and growth velocity charts with interpretations 2. insulin infusion sliding scale: digami and other subcutaneous sliding scales in brief 3. guide to csii (continuous subcutaneous insulin infusion). 4. references at the end of each chapter, for cross referencing. 5. practical aspects of carbohydrate-counting. submitted 7 oct 21 1 revision req. 17 nov 21; revision recd. 13 dec 21 2 accepted 6 jan 22 3 online-first: jan 2022 4 doi: https://doi.org/10.18295/squmj.1.2022.010 5 6 a cvc line misadventure 7 “doctor why do i have a humming sound in my ear?” 8 *edwin stephen,1 maitha al asmi,1 thekra al hadhrami,1 mohsin al 9 riyami,2 mohammed al badri,3 hanan al mawaali,1 khalifa al wahaibi1 10 11 1vascular surgery unit, 3division of surgery, sultan qaboos university hospital, muscat, 12 oman; 2general surgery, oman medical specialty board, muscat, oman 13 *corresponding author’s e-mail: edwinmay2013@gmail.com 14 15 abstract 16 we report a 32-year-old female patient who was referred to a tertiary care hospital in muscat, 17 oman, in 2021 with an iatrogenic arteriovenous fistula (avf) that presented as a neck swelling 18 which developed few weeks after an attempt of central venous catheterization through the right 19 internal jugular vein (ijv). the fistula was corrected surgically at our institute with a successful 20 outcome. avf is an abnormal communication between an artery and vein which can occur as a 21 congenital anomaly, after trauma or iatrogenic following central venous catheter (cvc) or 22 endovenous thermal ablation. 23 keywords: arteriovenous fistula, iatrogenic, central venous catheter, critically ill, icu 24 25 introduction 26 an arteriovenous fistula (avf) is an abnormal communication between an artery and vein. it can 27 occur as a congenital anomaly1 or iatrogenic during any arterial or venous instrumentation, trauma, 28 or endovenous thermal ablation2. one of the earliest cases of iatrogenic avf was published by 29 james and myers in 1973.3 the incidence of iatrogenic avfs has previously been described to be 30 mailto:edwinmay2013@gmail.com less than 0.6% of central line insertions.4 however, the introduction of ultrasound guidance causes 31 reduction in the incidence.5 our case report describes an iatrogenic avf that presented as a neck 32 swelling that developed several weeks after an attempt of central venous catheterization through 33 the internal jugular vein (ijv). the fistula was corrected surgically at our institute with a successful 34 outcome. 35 36 case report 37 we report a 32-year-old female patient who presented to a tertiary care hospital in muscat, oman, 38 in 2021. she was admitted earlier to the intensive care unit (icu) with an impression of sepsis; 39 hypotension with multiorgan failure and acute kidney injury (aki). the patient was 40 hemodynamically unstable at presentation to the center where she was managed, so a central 41 venous catheter (cvc) insertion was attempted through the right ijv for hemodialysis under 42 ultrasound guidance. as the dilator was not traversing freely, the procedure was abandoned, 43 pressure applied, and a femoral quinton line inserted. several days after discharge, the patient 44 developed a swelling on the right side of the neck associated with a humming sound in her right 45 ear and a thrill, she didn’t have coagulation abnormalities, so she was referred to us to rule out 46 iatrogenic avf and treat accordingly. 47 48 on examination, the patient had a pulsatile swelling that was 3 cm x 4 cm in size, with a thrill, and 49 a bruit on the right side of the neck between sternal head of sternocleidomastoid, clavicular head 50 of sternocleidomastoid and the clavicle. neurological examination was normal, and pulses were 51 intact. duplex ultrasound (us) was performed, a fistula was seen between the right ijv and the 52 right common carotid artery (cca), the ijv was pulsatile in the region of the fistula, and it showed 53 a focal dilation. a computed tomography angiography (cta) was performed (figure 1a & 1b), 54 and it showed an arteriovenous fistulous communication between the right cca and ijv. 55 56 the patient was taken for surgical closure of the iatrogenic avf. an incision along the lateral 57 border of the neck anterior to the sternocleidomastoid muscle was performed. a 4 mm mature neck 58 between the right ijv and cca was found, (figure 2). the fistula was divided between vascular 59 clamps (figure 3) and repaired directly on the venous and arterial side with 6-0 prolene sutures 60 (figures 4). cca was not clamped during surgery, she had normal left cca and intracranial 61 circulation, therefore cerebrovascular monitoring was not considered. 62 63 postoperatively, the patient was neurologically normal, the thrill and bruit on the neck disappeared. 64 at follow up, 4 weeks post-operatively, she remained well. 65 patient consent was obtained for publication. 66 67 discussion 68 catheterization of the ijv is commonly done for temporary hemodialysis, compared to subclavian 69 and femoral access, as it is considered a safer option.6 in the experience of the senior authors, an 70 ijv access is the preferred route for a cvc insertion, as a trendelenburg position is often used in 71 hemodynamically unstable patients. however, femoral access has been used when access to the 72 ijv is not possible usually when another team airway control of cases of maxilla-facial surgery / 73 trauma. 74 75 ijv catheterization can lead to several complications including venous perforation7, puncture of 76 the cca, pneumothorax8, cardiac tamponade9, and horner’s syndrome10. literature mentions that 77 valve incompetence in the ijv could impair cerebral venous drainage.11 another rare complication 78 of ijv catheterization is traumatic ccaijv fistula (cjf).2 traumatic cjf has an incidence of 4-79 7% of all traumatic avfs and it can be iatrogenic or due to penetrating injuries like gunshots or 80 stab injuries.2 although it is considered a rare entity there are several cases reported and published 81 where an iatrogenic avf was created by central venous catheterization of the ijv.2, 6, 12-13 if left 82 untreated, it can lead to further serious life-threatening complications such as embolization, 83 infection, and at later stages high-output cardiac failure.2 therefore, early detection and 84 intervention is crucial to prevent such consequences. 85 86 several techniques have been described to reduce the rate of complications during ijv cannulation 87 which include: cannulation under ultrasound guidance, locating the vein using a needle with a 88 smaller gauge, reducing head rotation to less than 40° as this reduces overlap between the vein and 89 artery, and using an alternative access if there’s difficulty during cannulation.5 & 10 90 91 there are various modalities that can be used to diagnose iatrogenic avf, including duplex, 92 magnetic resonance angiography (mra) and cta. duplex imaging in avf shows an 93 arterialized enlarged vein, high flow fistulous communication and a low resistance waveform of 94 the artery involved.11 it has an advantage of being fast. cta and mra provide a better anatomical 95 view of the vascular injury, like the size, type, and region, which will aid in choosing the best 96 treating modality.14 97 98 the options to consider while treating iatrogenic avfs are open surgery, endovascular stenting, 99 or embolization. a complex avf fistula has multiple draining vessels and a complex anatomy, 100 therefore it is better treated with endovascular embolization or stent grafting.11 embolization of 101 traumatic or iatrogenic avf’s can be offered if the communication is from side branches and not 102 for end arteries.16 furthermore, it can be done with coils, cyanoacrylate glue or onyx (covidien, 103 mansfield, ma).11 in our patient the cjf was not complex, and it was superficial, hence an open 104 surgical approach was preferred. 105 106 conclusion 107 iatrogenic avf is a rare complication of central venous catheterization, but it can have serious 108 outcomes. to prevent such outcomes, cvc insertion and other procedures should be carefully 109 performed i.e., under ultrasound-guidance, by experienced personnel and/or skilled supervision. it 110 is important to detect and treat iatrogenic avf early to prevent more severe complications such as 111 embolization, infection, atrial fibrillation and at later stages high-output cardiac failure. this case 112 report is to sensitize the medical fraternity about avoiding iatrogenic cvc misadventures and how 113 they can be managed. 114 115 authors’ contributions 116 maa, tah, mab, mar, ham – manuscript, literature review 117 es concept, manuscript, literature review, final approval 118 kaw manuscript, final approval 119 120 references 121 1. al mahruqi g, stephen e, abdelhedy i, al mawaali h, al musalhi b, al balushi z, al 122 sukeiti r, al wahaibi k. congenital vascular malformations – a quick recap. oman med 123 j. 2020 nov.  https://doi.org/10.5001/omj.2021.46. 124 2. sinha vk, yaduvanshi a, kataria v, nair m. traumatic common carotid–internal jugular 125 arteriovenous fistula manifesting as life-threatening epistaxis. jacc case rep. 2019 126 dec;1(4):576–8. http://doi.org/10.1016/j.jaccas.2019.08.023. 127 3. james pm jr, myers rt. central venous pressure monitoring: misinterpretation, abuses, 128 indications and a new technic. ann surg. 1972 may;175(5):693-701. 129 http://doi.org/10.1097/00000658-197205000-00009. 130 4. hansbrough jf, narrod ja, rutherford r. arteriovenous fistulas following central venous 131 catheterization. intensive care med. 1983 sep;9(5):287–9. 132 http://doi.org/10.1007/bf01691257. 133 5. salins s, stephen e, abdelhedy i, albusaidi m, alhashim a, alsukaiti r, et al. step-by-134 step guide to averting and managing a central line insertion misadventure. indian j vasc 135 endovasc surg. 2020;7(2):158. http://doi.org/10.4103/ijves.ijves_90_19. 136 6. el-shahawy ma, khilnani h. carotid-jugular arteriovenous fistula: a complication of 137 temporary hemodialysis catheter. am j nephrol. 1995;15(4):332–6. 138 http://doi.org/10.1159/000168859. 139 7. galbert mw, kay je. perforation of the right innominate vein by central venous 140 polyethylene catheter. br j anaesth. 1971 jul;43(7):713–4. 141 http://doi.org/10.1093/bja/43.7.713. 142 8. arnold s, feathers rs, gibbs e. bilateral pneumothoraces and subcutaneous emphysema: 143 a complication of internal jugular venepuncture. br med j. 1973 jan;1(5847):211–2. 144 http://doi.org/10.1136/bmj.1.5847.211 145 9. patel rb. dialysis catheter-induced pericardial tamponade. arch intern med. 1983 jan 146 1;143(1):181-182. http://doi.org/10.1001/archinte.1983.00350010193042. 147 10. cohen o, ayalon a, durst al. horner’s syndrome: a complication of internal jugular 148 vein cannulation. infusionsther klin ernahr. 1980 dec;7(6):317–8. 149 http://doi.org/10.1159/000221135. 150 11. patel r, nicholson a. arteriovenous fistulas: etiology and treatment. important 151 considerations from initial evaluation to treatment planning. from: 152 https://doi.org/10.18295/squmj.2017.17.03.007 http://dx.doi.org/10.1007/bf01691257 http://dx.doi.org/10.4103/ijves.ijves_90_19 https://evtoday.com/search?q=rafiuddin+patel https://evtoday.com/search?q=anthony+a+nicholson https://evtoday.com/articles/2012-apr/arteriovenous-fistulas-etiology-and-treatment. 153 accessed: oct 2021. 154 12. erkut b, becit n, kaygın ma, velioğlu y. iatrogenic arteriovenous fistula between the 155 common carotid artery and internal jugular vein: a case report. ejves extra. 2005 156 sep;10(3):74–6. http://doi.org/10.1016/j.ejvsextra.2005.07.001. 157 13. caldarelli c, biricotti m, materazzi g, spinelli c, spisni r. acquired carotid-jugular 158 fistula: its changing history and management. isrn vascular medicine. 2013 jul 159 8;2013:1–8. http://doi.org/10.1155/2013/320241. 160 14. mahajan a, luther a. acquired arteriovenous fistulae: a study of three cases and 161 review of literature. indian j vasc endovasc surg. 2016;3(4):125. 162 http://doi.org/10.4103/0972-0820.19149. 163 15. zivadinov r, chung cp. potential involvement of the extracranial venous system in central 164 nervous system disorders and aging. bmc med. 2013 dec 17;11:260. 165 http://doi.org/10.1186/1741-7015-11-260. 166 16. franz rw, jump ma. endovascular repair of post-traumatic, concomitant popliteal artery 167 pseudoaneurysm and arteriovenous fistula. int j angiol. 2009 spring;18(1):41-4. 168 http://doi.org/10.1055/s-0031-1278322. 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 https://evtoday.com/articles/2012-apr/arteriovenous-fistulas-etiology-and-treatment 184 185 figure 1a: computed tomography angiography (cta), coronal view, showing a right internal 186 jugular vein (ijv)-common carotid artery (cca) fistula 187 188 189 figure 1b: cta, axial view, showing a right ijv-cca fistula 190 191 figure 2: identification of the ijv-cca fistula intraoperatively 192 193 figure 3: division of the fistula 194 195 figure 4: post-repair of the fistula 196 january 2007 vol 7 correct a.indd 3 emergence of diseases of affluence in oman where do they feature in the health research agenda? samir al-adawi في عمان الغنى ظهور أمراض الصحة؟ مكانها في بحوث أين department of behavioral medicine, college of medicine & health sciences, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman email: adawi@squ.edu.om sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© the health status and living conditions in emerging economies, some-times called developing countries, have changed considerably because of the rapid growth of the biomedical healthcare infrastructure and acculturation and globalization. despite this, the previous emphasis that focuses on biological sciences alone in the prevention of and intervention in matters related to disease has not borne the expected results. “health for all by the year 2000”2 has proven to be an unattainable aspiration. whilst smallpox appeared to have been eradicated from all corners of the world, many communicable diseases remain endemic and multipleantibiotic resistance has become a major public health issue.3 in the midst of proliferating infectious diseases, there is also the ‘silent epidemic’ of non-communicable diseases, often precipitated and exacerbated by an individual’s behaviour and life style. there are a range of disorders that are often collectively referred to as “stress-induced” illnesses, which seem to stem from the way people respond to adverse environmental factors.4 there are also aspects of human behaviour such as smoking and reckless driving, which can result in serious distress and often fatal diseases. whilst models of health practice are presently undergoing a reassessment in both financial and political terms, the solution to emerging non-communicable disease would need to be addressed differently in developing countries, including oman. the present discussion, within the context of emerging non-communicable diseases and the interplay between socioeconomics, culture and health, will highlight some emerging themes from social medicine research in oman. social medicine, with its umbrella discipline behavioural sciences, is defined here as those field of inquiries using anthropological, psychological and biological techniques that lead to an appreciation of the social and cultural aspects of illness. the central objective of this discourse is to advance the view that stress and distress are experienced in a social and cultural context. the recognition of these effects will serve to emphasize the importance of maintaining biopsychosocial equilibrium in order to safeguard health. th e si t uati o n i n om a n oman has experienced rapid modernization and acculturation in the past few decades. once considered to be ‘the tibet of arabia’, according to smith,5 “money from oil has brought omanis progress through development in less than 20 years, development that took a “i went to the idol temple, to the ancient pagoda; no trace was visible there……. i gazed into my heart; there i saw him; he was nowhere else” jalalaldin rumi1 e d i t o r i a l s a m i r a l a d aw i 4 thousand years in europe”. one of the major benefits of recent modernization in oman is the improvement in living standards and the establishment of a modern health care delivery system. unicef 6 estimated that 96 percent of the population of oman has access to health care services. hospital bed space grew from 12 beds in 1970 to 5,200 beds and more than 120 health centres in 2000. with the improvements in health care, the country has experienced a significant decline in maternal and child mortality.7 the dramatic progress is testified in child survival rates that were 242 per 1,000 live births in 1970 compared to 13 in a more recent estimate. there is also a negligible gender gap in education and social empowerment. in a recent health system ranking, the world health organisation ranked oman as the most “efficient” health care system in the world in terms of outcomes.8 in demographic terms, the current population pattern in oman fits with a second phase ‘demographic transition’ characterised by declining death rates coupled with high birth rates.9 a recent census suggests a wide-based age pyramid, with 42 percent of the population under the age of 15.10 with this large, young population base, a 3.4 percent population growth and 38 births per 1,000 of the population, a ‘baby boom’ has been speculated.11 an unprecedented rise in the standard of living has shielded young omanis from many of the stresses of growing up that are typical for youth in some developing countries.12 there are also early indications of the social and economic consequences of a preponderantly youthful population. for example, the country has a far greater number of jobseekers pumped into a slow labour market than it can possibly absorb. the increase in the number of jobseekers coincides with the rise of intentional injury or suicidal behaviour in youths. deliberate self-harm, one important indication of the lack required of vicissitudes in life, increased among female adolescent omanis from 1.9 cases per 100,000 in 1993 to 12.8 per 100,000 in 1998.13 on the other hand, surveys conducted in oman suggest that the country is not immune to the ravage of infectious diseases,14-17 while unicef has estimated that 18 percent of children are moderately to severely malnourished.18 a previous notion known as ‘mckeown hypothesis’ posits the view that economic development is directly related to the health of the nation.19 more recently, it has become increasingly clear that economic development is not the only panacea for nation’s state of health as the situation in oman would suggest. economic development has resulted in the decline of infectious disease, but has probably ignited the emergence of ‘diseases of affluence’ in oman.20-24 diseases of affluence are those that are triggered by globalization and acculturation and all that it entails in terms of change of lifestyles. recent affluence is strongly associated with the fact that approximately 18 percent of urban dwellers have diabetes, while the country is also bracing itself for the sequelae of eating disorders, hypertension and lipidemia.25,26 with the advent of effective emergency care and good medical management of acute cases, the mortality rate, due to intentional and non-intentional injuries such as road traffic accidents, has decreased in oman.27 however, survivors of non-intentional injuries are left with an irreversible neurological impairment and debilitating loss of physical, cognitive, and psychosocial functions. the toll taken not only affects the person who sustained the injury, but also his or her entire social network.28 in this context, the only viable channel to curb the rising tide of non-intentional injury is to institute preventive measures, which would require an understanding of socio-cultural phenomena such as reckless driving. be h av i o ur a l r e se a r c h i n pe r spe c ti v e the recent affluence, the emergence of non-communicable diseases and diseases of affluence in oman seem to call for a conscious reassessment of this emerging situation. thus, the need to understand the behaviour of an individual in his or her social and cultural contexts should be crucial. thus research in social medicine in developing countries that will result in understanding the interplay between prevailing social conditions and diseases in those countries is essential. as will become apparent below, this has not been the case so far. instead, various factors hold back the development of culturally sensitive medical practice and research. the first is lack of understanding of the situation on the ground. the long period of training for medical personnel and the unique acculturation process of the training leave doctors alienated and cut off from the very societies and ethical values that they are assumed to understand and for which they eventually hope to provide their services. this leaves many healthcare providers in developing countries inadequate to communicate with their patients, whose views on health e m e r g e n c e o f d i s e a s e s o f a f f l u e n c e i n o m a n 5 and illness are incompatible or incongruent with the biomedical model. since healthcare practitioners tend to receive little training in cross-cultural clinical communication, this creates a communication disjunction in health care delivery with many ramifications on cost effectiveness, efficiency and compliance. the second factor holding back the development of culturally sensitive medical practice and research is the idea that people in developing countries are immune to non-physical illnesses. such ideas were probably promulgated by the conception that people who lived outside of industrialized countries are unencumbered by the exigencies of the ‘modern’ world.29 members of traditional societies, by virtue of their simple technology and mode of living, were considered as ‘uncorrupted children of nature’. this myth has largely been laid to rest as it is widely known that, in the global burden of diseases, diseases of affluence are becoming a global challenge, which transcend all borders and cultures. non-communicable diseases such as psychological disorders have become the leading cause of global mortality and account for a considerable proportion of disability and economic loss.30 the third issue that impedes an enlightened quest for the interplay between culture and diseases is the current preoccupation with ‘high tech’ research to understand the biological underpinning of diseases. such a focus brings prestige to the index of national development since it entails the employment of high profile techniques such as dna microarray technology. the highest funded research projects at the premier research centres in oman are those that aim to discover the genetic basis of diseases.31,32 it is natural to think that social medicines, with their focus on protean concepts that may be deemed to be unameable to scientific inquiry, are inadequate for modern needs. what is often overlooked is that the priority of medical sciences is to improve the quality of life. this requires not only molecular techniques but also the social correlation of diseases and potentially appropriate social interventions. in spite of the availability of sophisticated diagnostic tools and numerous other high profile technologies for medicine, global health inequalities are widening.33 one only has to consider the emerging view on the treatment of substance abuse to see how social concerns are becoming central both to the understanding of the origins of distress and to the treatment of the resulting condition. the world health organization measures the ‘global burden of disease” by creating a measure of disability, dalys (disability adjusted life years). it is made up of two components: years of life lost by premature death and years of life lived with a disability of known severity.34 using this yardstick, the leading disability risk factors in the world are alcohol and nicotine abuse and dependency. in the past years, the genetic codes for many mind altering drugs have been identified. for example, receptors for mind altering drugs have been cloned, receptor locations mapped and the neurotransmitter systems involved determined.35 despite these breakthroughs and the resultant pharmacological interventions to wean people off drugs by preventing withdrawal symptoms, no promising cure is currently available. it is possible that the relapsing nature of addiction may be more strongly related to re-exposure to environmental cues rather than to adverse withdrawal symptoms. in coming to grips with such exceedingly recalcitrant and chronic substance dependence, it has been suggested that drug associated cues play a major role in relapse. this suggests that “addiction represents a pathological usurpation of the neural mechanism of learning and memory that under normal circumstances serve to shape survival behaviours related to the pursuit of reward and cues that predict them” (p. 1414).36 this implies that environmental cues and not only genetic codes, play a crucial role in maintaining a compulsion to drug misuse. r e se a r c h i n s o c i a l me d i c i n e i n om a n as groundwork for the need to establish cultural variations as a key factor when delivering health services in oman, the following section examines the social determinants of disease in oman by highlighting research that has shown that non-communicable, nonphysical illnesses exist in oman and are invariably related to social and cultural factors. one approach to tease out whether social issues do impact on health is to examine whether the repertoire of human behaviour is a by-product of culture or of biology. one circuitous way to explore this issue is to examine whether isomorphous conditions such as psychiatric disorders have a universal, phenotypic presentation. one interpretation suggests that the ‘hardware’ or pathology of disease remains essentially constant throughout the world, irrespective of the cultural context in which they appear. on the other hand, reaction to illness (‘software’), like culture-spes a m i r a l a d aw i 6 cific signs and symptoms, are viewed to be shaped by one’s environment.37,38 on this basis, one could classify various reactions to stress as ‘culture-bound disorders’ within the diagnostic categories of western nosology. despite the eloquence of such a view, there is very little empirical evidence to show that diagnostic entities derived from another cultures are applicable to omani society.39-41 one conspicuous finding from such studies is that the central psychopathology of anorexia nervosa (morbid fear of fatness) is largely absent among adolescent omanis presenting with eating disorder.43 the lack of fat-phobia among adolescents in oman may have several reasons. primarily, the concept of body-image, as has been reported in western populations, may not be applicable to adolescents in oman. alternatively, there is culture-specific manifestation of eating disorder, which may not be parallel to that observed in western adolescent population. kleinman44 has cautioned that a view of human nature developed for one cultural group should not be uncritically applied to members of another group for whom its validity has not been established. to illustrate further that medicine is inescapably social, surveys in oman suggest that acute forms of unidentified medical illness are invariably present in all primary as well as tertiary care settings. as there is no evidence of ‘disease’ in these patients, it is assumed that their sickness occurs in response to psychological stresses. al-lawatia et al.45 have reported that approximately 77 percent of the patients seeking consultation in primary health care have non-physical illnesses. in tertiary care centres in oman, chand et al.21 reported that approximately 8.6 percent of those seeking consultation at sultan qaboos university hospital had various forms of non-physical illnesses. in a community survey, al-busaidi46 has reached similar conclusion. descriptive studies from sultan qaboos university have suggested that if the condition is refractory and not amenable to medical intervention, cultural beliefs about the causality and treatment of the distress are likely to be invoked.21,46 most of the complaints are expressed in “somatopsychic” rather than “psychological” ways, a communication style that has been often thought to reflect the communal nature of omani society.47,48 according to dwairy, “…in the absence of a distinct domain for the self, somatic complaints are sometimes the only expression of distress. in addition, complaints about fear or sadness are not encouraged in the arab/muslim culture” (p. 84)49 on the whole, emerging data suggest that many types of non-physical illness encountered in other countries are common in oman. some minor differences do exist, however, in the incidence of the types of reaction. other differences occur because of certain culturally determined aspects of symptomatology.24, 50, 51 more studies to substantiate this view are therefore required. it is worthwhile noting that high percentage of medical attendees in oman present with distress for which doctors tend to find no accompanying bodily disturbance. such patients account for a large number of consultations, ‘doctor shopping’, unnecessary tests, multiple surgeries and a variety of other procedures, which might ultimately lead to iatrogenic illnesses.45 globally, many young lives are blighted by the deterioration of public health services and worsening material and social conditions, in addition to road traffic accidents, war and violence, infectious diseases, stressinduced and self-inflicted death.52 inevitably, death is a universal phenomena, but does the reaction to it vary from culture to culture? this is a pertinent question as it may shed light on whether human emotions such as grief reactions are shaped by our socialization or by a biological predisposition. studies from oman suggest that there is a specific omani respond to death. following untimely death, omanis are likely to invoke the belief in revenants, known as ‘mu ghayeb’.53 this belief involves a complete denial of the loss for a long period, even after the rituals and mourning. the expectation is that the dead person will return. the belief assumes that the deceased are expected to leave the grave after burial and join their families when the spell placed on them by a sorcerer is broken. whatever the merit of this belief, it is clear that emotions even for losses as mundane as death appear to be culturally sanctioned and considerably modified by local, social and psychological characteristics.54 the fact that highly variable emotional reactions are found across very different populations suggests that sociocultural or ecological factors play a substantial role in emotional expression. it has long been established that emotional stress plays an important role in more than half of all medical problems.4 studies are needed to illuminate how emotions are expressed in oman and their impact on health and disease. studies coming from different parts of the world suggest that many problems, which were previously thought of as primarily medical, and hence demanding conventional medical intervention, are in fact e m e r g e n c e o f d i s e a s e s o f a f f l u e n c e i n o m a n 7 more appropriately disentangled by changing individual and social attitudes and behaviour.55 many health campaigns tend to have only modest success because traditional customs and health beliefs often override biomedical assumptions and considerations. as a result, communicable and non-communicable diseases are proliferating, not only because of poverty, but also because of prevailing traditional views on health and disease.56 it is also apparent that the extent to which any medical treatment is adhered to is often a function of a range of socio-cultural beliefs, such as the personality of the patient and the quality of interaction between doctor and patient. in this context, a person’s behaviour appears to impede an enlightened and costeffective delivery of health care. c o n c l u s i o n despite the much heralded rhetoric on the ‘human genome project’57 and the bombastic prediction that it “…could also spin off many other advantages for the future generation” (p. 15),58 mundane epidemiological surveys that would gather familiar aggregates of diseases have not been forthcoming in oman. according to finkler, skrzynia and evans, “… genetic prognostications apply to the aggregate rather than to the individual, whereas the patient desires information that is applicable to his or her specific condition” (p. 404).59 there is indication that diagnoses that are based on the genetic origins of illnesses are associated with unpredictability and stigma and these sufferers are likely to perceive their situation as ‘fate’ and, as a result, prefer not to modify their unhealthy lifestyle. most disheartening for developing countries, there is burgeoning research linking ethnicity and diseases.60, 61 in addition to being insensitive to heterogeneous communities in largely young countries, still on the verge consolidating their national identity, ‘geneticisation’ seems to hinge on the wrong assumption of ethnic homogeneity in terms of identity and functioning. this has the negative effect of stigmatizing vulnerable individuals and inadvertently their kindred also. in their quest to be associated with the fame of cutting edge research, medical researchers in developing countries are plundering much needed resources that could be fruitfully utilized for prevention of emerging disease and dispensing healthcare delivery consonant with the situation on the ground. at the dusk of last millennium, health planners predicted “health for all by the year 2000”. at the dawn of this century, some admirable achievements were accomplished including eradication, prevention and treatment of some diseases that were once thought to be impervious to intervention. the long cherished dream that one day biomedical sciences would decipher and cure all the diseases and suffering and that therefore human beings will become immortal is still a far fetched yearning. in the interim, new challenges have arisen on the horizon, including the proliferation of non-communicable diseases against the background of intransigent treatment resistant infectious diseases. the formidable challenge for this century is to come to grips with illnesses that stem from the way individuals respond to the external world. although our biology has been programmed to respond to environmental demands, this blueprint appears to be ill equipped to respond to 21 century reality. the challenge here will entail to explaining the interplay between socioeconomic, culture and biological aspects of human behaviour and resultant ill health. it appears that in the absence of coherent systems to embraced new challenges, the quality of health care may never rise above a certain ceiling and that this ceiling could be quite low. oman has marched to success in curbing familiar problems like malnutrition and infectious diseases, the next challenges are lifestyle diseases that stem from life itself and the results of recent affluence. a c k n ow l e d ge me n ts i would like to thank meriel carboni and lamk lamki for their guidance and am grateful to hiroko jimbo for invaluable discussions. c o n fl i c ts o f i n te r e st state me n t the author has no conflicts of interest concerning the work reported here in this paper. r e f e r e n c e s 1. arasteh ar. growth to selfhood. london: routledge kegan paul p, 1980 2. who/unicef. alma-ata declaraion primary health care. geneva: who, 1978. 3. ferber d. antibiotic resistance. superbugs on the hoof? science 2000; 288:792-794. 4. weinman j. an outline of psychology as applied to medicine. (2nd edition). cambridge: butterworth heinemann, 1987. 5. smith r . oman: leaping across the centuries. br med j 1988; 297:540-544. s a m i r a l a d aw i 8 6. unicef. the state of the world’s children 1997. oxford: university press, 1997. 7. sulaiman aj, al-riyami a, farid s, ebrahim gj. oman family health survey 1995. j trop pediatr 2001; 47 (suppl 1): 1-33. 8. jamison dt, sandbu me. global health. who ranking of health system performance. science 2001; 293: 15951596. 9. mohammed nsa. population and development of the arab gulf states: the case of bahrain, oman and kuwait. basingstoke: ashgate pub ltd, 2004. 10. sultanate of oman ministry of national economy: final results of the census 2003. muscat: ministry of national economy, 2003. 11. lambourne a. oman’s population profile 1970-2000. muscat, sultanate of oman: ministry of health, 1990. 12. parker dl. street children and child labour around the world. lancet 2002; 360:2067-2071. 13. zaidan za, burke dt, dorvlo as, al-naamani a, et al. deliberate self-poisoning in oman. trop med int health 2002; 7:549-556. 14. scrimgeour em, mehta fr, suleiman aj. infectious and tropical diseases in oman: a review. am j trop med hyg 1999; 61:920-925. 15. khandekar r, mohammed aj, al raisi a, kurup p, shah s, dirir mh, al harby s. prevalence and distribution of active trachoma in children of less than five years of age in trachoma endemic regions of oman in 2005. ophthalmic epidemiol 2006; 13:167-172. 16. idris ma, shaban ma, fatahallah m. effective control of hookworm infection in school children from dhofar, sultanate of oman: a four-year experience with albendazole mass chemotherapy. acta trop 2001; 80: 139143. 17. al-dhahry sh, koul rl, al-busaidy sm, al-awaidy st, al-khusaiby sm, suleman aj. poliomyelitis in oman. the last outbreak? acta trop 2001; 80: 125-130. 18. gohar a, ismaili i. child nutrition in oman. ministry of health, sultanate of oman: unicef oman, 2002. 19. harris b. public health, nutrition, and the decline of mortality: the mckeown thesis revisited. soc hist med 2004; 17:379-407. 20. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. a relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirology 2003; 8: 69-76. 21. chand sp, al hussaini aa, martin r, mustapha s, et al. dissociative disorders in the sultanate of oman. acta psychiatr scand 2000; 102:185-187 22. al-sharbati mm, al-lawatiya s, al-adawi s, martin r, al-hussaini a. urbanization, culture and hyperactivity: naturalistic observation in omani schoolgirls. women’s health & urban life 2003; 2:43-60. 23. al-sharbati mm, al-adawi s, al-lawatiya k, al-hussaini a. school failure: an exploratory observational study in omani school girls. j behav neurosci res 2005; 3:29-39. 24. al-sharbati mm, al-hussaini aa, antony sx. profile of child and adolescent psychiatry in oman. saudi med j 2003; 24:391-395. 25. al-moosa s, allin s, jemiai n, al-lawati j, mossialos e. diabetes and urbanization in the omani population: an analysis of national survey data. popul health metr 2006; 4:5 available: www.pophealthmetrics.com/ content/4/1/5. accessed 25 november 2006. 26. al riyami aa, afifi m. clustering of cardiovascular risk factors among omani adults. east mediterr health j 2003; 9:893-903. 27. al-adawi s, burke dt. revamping neurorehabilitation in oman. journal for scientific research: medical sciences 2001; 3:61-64. 28. simpson g, mohr r, redman a. cultural variations in the understanding of traumatic brain injury and brain injury rehabilitation. brain inj 2000; 14:125-140. 29. rousseau jj. discourse on the origin of inequality, translated by franklin philip and edited with an introduction and notes by patrick coleman. oxford: oxford university press, 1999. 30. boutayeb a. the double burden of communicable and non-communicable diseases in developing countries. trans r soc trop med hyg 2006;100:191-199. 31. rajab a, yoo sy, abdulgalil a, kathiri s, et al. an autosomal recessive form of spastic cerebral palsy (cp) with microcephaly and mental retardation. am j med genet 2006; 140:1504-1510. 32. bayoumi ra, simsek m, yahya tm, bendict s, et al. insertion-deletion polymorphism in the angiotensin-converting enzyme (ace) gene among sudanese, somalis, emiratis, and omanis. hum biol 2006; 78:103-108. 33. stonington s, holmes sm. social medicine in the twenty-first century. plos med 2006; 3:1661-1662. 34. murray cj, lopez ad. global mortality, disability, and the contribution of risk factors: global burden of disease study. lancet 1997; 349:1436-1442. 35. nestler ej, landsman d. learning about addiction from the genome. nature 2001; 409:834-835. 36. hyman se. addiction: a disease of learning and memory. am j psychiatry 2005; 162:1414-1422. 37. kiev a. transcultural psychiatry. new york: the free press, 1972. 38. al-adawi s, dorvlo ass, alexander pc, martin rg, e m e r g e n c e o f d i s e a s e s o f a f f l u e n c e i n o m a n 9 yoishiuchi k, kumano h, kuboki t. eating disorder and conception of fear of fatness among non-western adolescent population: experience from oman. psicologia conductual revista internacional de psicologia clinica de las salud 2004; 12:429-446 [spanish]. 39. al-adawi s, dorvlo as, burke dt, moosa s, al-bahlani s. a survey of anorexia nervosa using the arabic version of the eat-26 and “gold standard” interviews among omani adolescents. eat weight disord 2002; 7: 304-311. 40. al-hinai ss, al-saidy o, dorvlo ass, al-riyami bms, et al. culture and prevalence of social phobia in a college population in oman. in: college students: mental health and coping strategies. editor: mery v. landow, new york: nova science publishers inc, 2006: 115-132. 41. al-adawi s, dorvlo as, burke dt, huynh cc, et al. apathy and depression in cross-cultural survivors of traumatic brain injury. j neuropsychiatry clin neurosci 2004; 16:435-442. 42. al-adawi, s, dorvlo ass, martin rg, yoishiuchi k, kumano h, kuboki t. cultural differences in western, indian and omani adolescents to eating, weight and body image attitudes. swain, (editor). new developments in eating disorders research. new york, nova science publishers inc. 2006: 65-91 43. viernes n, zaidan zaj, dorvlo, ass, kayano m, yoishiuchi k, kumano h. et al. tendency toward deliberate food restriction, fear of fatness and somatic attribution in cross-cultural samples. eat behav (in-press). 44 kleinman a. social origin of distress and disease. new haven ct: yale university press, 1986. 45. al-lawati j, al-lawati n, al-siddiqui m, antony sx, et al. psychological morbidity in primary healthcare in oman: a preliminary study. journal for scientific research: medical sciences 2000; 2:105-110. 46. al-busaidi zq. rethinking somatisation: the attitudes and beliefs about mental health in omani women and their general practitioners. unpublished phd thesis, school for community health, division of psychiatry, university of nottingham, 2005. 47. al-adawi s, salmi a, martin rg, ghassani h. zar: group distress and healing. ment health, relig & cult 2001; 4:47-61. 48. al-adawi s, dorvlo ass, al-salmy h, martin rg et al. patient’s perspective on epilepsy: self-knowledge among omani. seizure 2003; 12:11-19. 49. dwairy m. counseling and psychotherapy with arabs and muslims: a cultural sensitive approach. new york: teachers college press, 2006. 50. al-adawi s, martin r, al-naamani a, obeid y, al hussaini a. body dysmorphic disorder in oman: cultural neuropsychological finding. east mediterr health j 2001; 7:562-567. 51. sakamoto n, martin rg, kumano h, kuboki t, aladawi s. hikikomori, is it a culture-reactive or culturebound syndrome? nidotherapy and a clinical vignette from oman. int j psychiatry med 2005; 35:191-198. 52. kleinman a, cohen a. psychiatry’s global challenge. sci am 1997; 276:86-89. 53. al-adawi s, burjorjee rn, al-issa i. mu ghayeb: a culture-specific response to bereavement in oman. int j soc psychiatry 1997; 43:144-151. 54. al-adawi s, tei s, tsujiuchi t, hayama r, kumano h, kuboki t. social origin of bereavement following traumatic loss: zombification as explanatory model in oman. jpn j psychosom med 2005; 45:933-941 [japanese]. 55. carolina ms, gustavo lf. epidemiological transition: model or illusion? a look at the problem of health in mexico. soc sci med 2003; 57:539-550. 56. unwin n, setel p, rashid s, mugusi f, mbanya jc, et al. noncommunicable diseases in sub-saharan africa: where do they feature in the health research agenda? bull world health organ 2000; 79:947-953. 57. daar as, thorsteinsdottir h, martin dk, smith ac, nast s, et al. top ten biotechnologies for improving health in developing countries. nat genet 2002; 32: 229-232. 58. bayumi r. it is in the genes! human genome project. mirat al-j’ama 2000; 50:11-15. 59. finkler k, skrzynia c, evans jp. the new genetics and its consequences for family, kinship, medicine and medical genetics. soc sci med 2003; 57:403-412. 60. pathare a, al kindi s, al haddabi h, dennison d, bayoumi r, muralitharan s. hereditary thrombophilia in ethnic omani patients. am j hematol 2006; 81:101106. 61. hassan mo, albarwani s, al yahyaee s, alhaddabi s, et al. a family study in oman: large, consanguineous, polygamous omani arab pedigree. community genet 2005; 8:56-60 how does hiv 1 infect a susceptible human cell? acquired immunodeficienc y syndrome (aids) was first described in 98 as a group of clinical signs and symptoms caused by the impairment of the immune system, mainly the cellular immune response.1,2 the conditions defining aids were recognised by the centre for disease control (cdc), in atlanta, georgia (usa), before the identification of the human immunodeficiency viruses (hivs) as the causative agents for the syndrome. the cdc classification for aids, list numerous opportunistic infections and neoplasms (cancers) which in the presence of hiv infection how does hiv-1 infect a susceptible human cell? current thinking ali a. al-jabri department of microbiology and immunology, college of medicine & health sciences, sultan qaboos university, p.o. box 35, al khod-123, muscat, sultanate of oman. email: aaljabri@squ.edu.om a b s t r ac t. to insure its survival, the human immunodeficiency virus (hiv), the causative agent of acquired immunodeficiency syndrome (aids), utilises more than one gate to enter a target cell. this strategy makes it more difficult for the immune system to defeat the virus. this has also made it difficult for scientists working in the hiv research to understand how exactly hiv infects a susceptible human cell. such understanding will no doubt open many gates for scientists to vanquish the virus by designing agents that can block hiv entry into target cells, thus rendering the virus vulnerable to immune destruction. this will also help in understanding the replication of the virus and the pathogenesis of the disease. the present article briefly describes the past and current thinking of how hiv-1 infects a susceptible human cell, and the dilemma scientists are facing when studying the infectivity of this virus and applying current knowledge to design agents that can block hivs entering target cells. in the context of our own experience with hiv infectivity in vitro, the present article will also address the behaviour of different hiv isolates, both laboratory-adopted and clinical (primary) isolates in culture and the difficulties in performing hiv infectivity testing. moreover, our experience of peripheral blood mononuclear cells’ (pbmcs) susceptibility to hivs infection in vitro is discussed. key words: hiv, aids, infection, immune, virus, susceptible cell constitute an aids diagnosis.3 in addition, a cd4+ tcell count below 200 per mm3 in the presence of hiv infection constitutes an aids diagnosis. people with aids often suffer infections of the lungs, brain, eyes and other organs, and frequently suffer debilitating weight loss, diarrhoea and are vulnerable to a type of cancer known as kaposi’s sarcoma. although there is no cure for aids at present, multiple drug therapy dramatically improves the quality of life for most people with aids.4 the hivs are well accepted as the causative agents of aids.5–8 formatted in medit hiv review �������� ������� ����� ���� ������ ������� ������ ���)����� (������ �������� ���� ���� ���������� ����� �� ��������:����� ���� ������������ ������� ����� ���� ������ ������� ���)����� (��� �� ���� ����������� ����� �� �� ������ ������ ��� �� ������� ���� ���� ������ ������� ������ ��� ����-� .���� ���� ������ ������� ���� ������� ������� ������� �� ������ �� ����� ������� .�������� ����� ���� ���� �� ����� ������ ������� ���� ������ ����� ���������� �������������� ��� ���� ���� ��� .���� ������ ���� ������ ����� �� ������� ������� �� �� ����� ����� ��� ������ ������� ������ �� ����� ��� �������� ������ ���� �� ������� ���� ���� �������� ������� ��� ���� �� ������� ���������� ���� ����� ����� ������.���� ��� ����� ���� ���� ������� ��� ���� ��� �� ����� ��� ������� ���� ���� ������ ����� ��� ��� �� ��� ������� ������ ����� ���.������������ ���������� ������ ������� ������������� ���� �� ������ ���� ������ �� ������� ���� ����� �������������� ��� ��� �������� �������� � .��� ��� ������������������������ ������� �� ��� ����� �� ������� �� ������ ������ �� ������ ������ ���� ���� �� ������ ������.�� ������ ����� ���� ���� �� �������� ������ ������ ��� ������ ���� ����� �� ������������ �� �� .��� �� ���� ������� ������ ������ �� ����� ���� ������� ���� ������ �� ������ �������� ��������� ����� ����� ��� ������ �� ������ �������. squ journal for scientific research: medical sciences 2003 vol 5, no. –2, 3–44 ©sultan qaboos universit y r e v i e w 32 al-jabri to be able to defeat the hivs and design the proper prevention tools, basic scientific knowledge on how exactly these viruses infect human susceptible cells is essential. although the literature is immense on this topic, in this short article i will briefly review our current understanding of how hivs infect human susceptible cells and the application of this knowledge in designing drugs that can inhibit hivs entering susceptible human cells. t h e h u m a n i m m u n o d e f i c i e n c y v i r u s e s ( h i v s ) the hivs are members of the lentivirus subgroup of the retroviridae family. they are rna viruses that posses the enzyme reverse transcriptase (rt). this enzyme allows the virus to reverse-transcribe its own rna, and the resultant complementary dna (cdna) is incorporated into the cellular dna of the host. two main types of hiv exist: hiv- and hiv-2, which differ in genomic structure and antigenicity as well as in their latent period as pathogenicity. hiv- was identified, as the causative agent of aids, by three different groups in the early eighties. these were montagnier’s at the pasteur institute in paris (france), gallo’s at the national institute of health (nih) usa, and levy’s at the university of california san francisco (ucsf), usa. the hivs were initially called lav (lymphadenopathy-associated virus), htlviii-human t lymphotropic virus and arv (aids associated retroviruses).5,6,8 in 986 a second virus (hiv-2) was identified,9 and the original was renamed hiv- to distinguish them. the diameter of the hiv virion is approximately 00 nm and electron microscopy studies have revealed a characteristic cylindrical core in hiv particles surrounded by an outer envelope [figure ]. hiv- the inner core of hiv- consists of p24 protein (capsid). inside this capsid are two copies of single stranded genomic rna and the enzymes required for the initial stages of hiv- replication. these include the reverse transcriptase (p5/66), integrase (p32) and protease (p22). the inner core also contains p7 nucleic acid binding protein and p9 gag binding protein. the inner core is surrounded by a p7 myristylated gag matrix protein, thought to be essential for maintaining the structure of the virus or stabilising the exterior and interior components of the virion. the p7 protein is bounded by a lipid bilayer membrane (the outer envelope). this outer envelope contains spikes made up of gp20 and gp4. the gp20 contains the receptor binding region involved in infectivity as well as in syncytia formation (a major cytopathic effect of hivs in vitro) and the gp4 is a transmembrane segment which is important for virus fusion.10,11,12 the hiv- lipid bilayer also contains various host cell proteins including hla class i and ii that are acquired during virus budding (figure ). hiv-2 although the general structure of hiv-2 is similar to that of hiv-, differences within the genomic structure exist and genetic regulation of hiv-2 also differs from that of hiv-.9,11,12 this article will be referring mainly to hiv-. figure 1 b. simple diagram illustrating the main components of the basic structure of hiv-1. figure 1. electron micrograph of hiv-1 and hiv-2 (mn and rod). hiv-1 (mn) virions are shown budding (arrow). hiv-2 (rod) virions are shown in (b) (above). magnification is 100,000 x. scale bar =100nm. this electron microscopy was kindly performed by dr. robert dourmashkin. 33h o w d o e s h i v i n f e c t h u m a n c e l l ? subt ypes of hivs now it is well established that there exist many subtypes of hivs. the hiv--m (main) group subtypes are phylogenetically associated groups or clades of hiv- sequences, and are labelled a, a2, b, c, d, f, f2, g, h, j and k. the sequences within any one subtype or subsubtype are more similar to each other than to sequences from other subtypes throughout their genomes. “o” is the “outlier” group, and group n is also a very distinctive form of the virus that is non-m, non-o (also sometimes referred to as the “new” group). for hiv-2, there exist a, b, c, f or g clades (formerly known as “subtypes”, now referred to as “groups”). the nomenclature of hivs is becoming even more difficult with the introduction of recombinants and circulating recombinant forms as a result of inter-subtype recombinant genomes of different hiv clades. the existence of many subtypes of hivs make it extremely difficult for vaccinologists to design the proper vaccine against hivs, since certain subtypes circulate more than others in different populations. for example subtype b of hiv- is more common in western countries than subtypes c and d. hivs are also named according to how they behave in culture producing cytopathic effects: sysncytium inducing isolates (si) and none syncytium inducing isolates (nsi). moreover, hivs can also be called macrophage tropic (m-trpic), t cell line tropic (t-tropic), or dual tropic, when they are able to infect macrophages, t cells and both macrophage and t cells, respectively. cell tropism in hivs hivs are termed retroviruses because they “reverse” the normal flow of the genetic information, i.e. rna is reverse-transcribed to dna. until the mid nineties, it was considered that hiv- enters its host cell through the attachment of the envelope glycoproteins (gp20) to the cd4 molecules (receptors), found on t-helper cells, monocytes and macrophages.10 hivs can also enter cells by other means, for example, through the fc receptors of antibodies and complement receptors cr2 and cr3.11,12 after gp20 binds to a cd4 molecule, a conformational change is induced in the gp20, leading to its dissociation from the viral membrane. this results in the exposure of the amino terminal hydrophobic domain of the gp4which initiates the fusion process. the hiv, then, enters its host cell via membrane fusion, a ph independent process.13,14,15 the virus sheds its protein coat after entry into the cell, exposing the rna core [figure 2]. the enzyme reverse transcriptase is activated and transcribes the rna into complementary dna. the rna is removed by ribonuclease h activity, and a second dna strand is synthesised complementary to the first. this double-stranded dna is integrated into the genome of the host cell by the viral integrase, with the potential for viral production at any time. the integrated dna is termed a provirus and this provirus dna can be transcribed into mrnas, which direct the synthesis of viral proteins.12 v3 loop of the glycoprotein (gp) 20 before hiv is able to gain entry into a target susceptible cell, the third hypervariable region (v3) loop of the surface glycoprotein gp20 molecule has been implicated as an important factor for cell tropism and for cell fusion. the determinants of hiv tropism can be mapped to the viral envelope gene,16–22 thus indicating that tropism is restricted at the level of virus entry. a significant finding was that a major determinant of hiv- tropism is the v3 region of the surface gp20.16–18 the hiv- envelope gene is approximately 2.5 kb in length and gp20 has a .6 kb nucleotide sequence. the gp20 is divided into six constant (c–c6) and five hyper-variable regions (v– v5).19,20 studies have already shown that mutations (substitutions) in the v3 loop are essential in cellular tropism and in the antigenicity of gp20.21 the v3 loop, known as the principal neutralising domain (pnd), is considered to be the major immunodominant region of the gp20 for both hiv-22,23 and hiv-2.24 this domain induces neutralising antibodies and is the target for cytotoxic t lymphocyte killing.25 neutralising antibodies are able to block infection in vitro by blocking fusion of the virus.23 the acquisition of the syncytium inducing (si) phenotype is linked to substitutions of acidic or neutral amino acids by more basic amino acids in the v3 loop.26 the v3 loop does not seem to play an important role in cd4 binding, since v3 specific antibodies do not affect the attachment of gp20 to cd4. however, the v3 loop is essential for virus infection, since v3 loop specific antibodies can block fusion and entry of hiv to susceptible cells.27 the v3 loop typically begins at amino acids number 300 and consists of between 33 to 35 amino acids bounded by disulphide linkage. at the tip of the loop is the sequence gly-pro-gly-arg (gpgr), known to be the most conserved region among hiv- clade b isolates.28 while the gpgr crown of the v3 loop of hiv- is conserved within all clade b isolates, the equivalent in hiv2, fshq, seem to be conserved among hiv-2 isolates. a single amino acid substitution in the hiv- v3 loop has already been shown to change an isolate from non syncytium inducing (nsi) to a syncytium inducing (si) phenotype.21 34 chemokines are the co-receptors for hivs entry nowadays it is well understood that the cd4 molecule alone is not sufficient to render a target cell permissive for fusion with virions (see below). although the main receptors for hiv- entry into target cells is the cd4 molecules, the seven trans-membrane spanning g protein chemokine receptor family are now accepted as important co-receptors for virus entry.14,29,30,31,32 many chemokine co-receptors were identified, including ccr-5 and fusin, and known to act as secondary receptors for virus entry.33,34,35 fusin is expressed on a wide range of human cell lines; those which do not express fusin are not infected by t cell-tropic hiv. importantly, cells expressing both cd4 and fusin remained refractory to macrophage (m)-tropic hiv envelope mediated fusion, consistent with the earlier prediction that fusion cofactors for tand m-tropic hiv- strains would be distinct moieties. furthermore, a cxc chemokine (sdf-), has subsequently been identified as a ligand which both binds fusin and specifically blocks infection by t-tropic but not m-tropic hiv- strains.36,37 based on the identification of its chemokine ligand, fusin was renamed cxcr-4. the discovery that cxcr-4—whose closest known homologous is the il-8 receptor (cxcr-2)—constitutes a functional co-receptor for t-tropic hiv- strains, added significance to the earlier finding that the c-c chemokines mip--alpha, mip--beta and rantes are able to block infection of cd4+ human t-cells by m-tropic but not t-tropic hiv-.38 thus, since certain chemokines are known to bind several of the seven transmembrane receptors, it became likely that the discovery of a chemokine receptor that is recognised by all three of these chemokines would also result in the identification of an m-tropic hiv- specific co-receptor. role of chemokine co-receptors the interaction of hivs with a target cell is initially with cd4, thereby inducing a conformational change in gp20, which facilitates subsequent binding of envelope to the co-receptor.33,34 it is likely that the virus binding site or sites on the co-receptor involve multiple extracellular domains, and that within each of these domains multiple amino acids contribute to co-receptor function. while this complexity has largely frustrated attempts to define precise virus binding sites, studies of chimeric and mutant co-receptors have, to some extent, illuminated our understanding of how hiv interacts with co-receptors and suggested that several, functionally redundant, interactions between co-receptor and virus envelope are likely to occur. this has implications for the feasibility of using co-receptor targeted inhibitors of virus entry as therapies.39 �������������������������������� figure 2. the life cycle of hivs al-jabri coursey of ms. lesley mclain, warwick university 35 co-receptor recognition culturing virus in the laboratory imposes different selective pressures on viral populations that are likely to impact on the nature of their interaction with receptors. in addition, there are examples of very minor envelope sequence changes drastically influencing co-receptor recognition,39,40,41,42 thus different results are likely to be obtained with cloned versus uncloned forms of the same virus isolate. the relative expression levels of co-receptors on transfected cells, as compared to the natural targets of virus infection, remain largely unexplored and clearly affect the efficiency of infection. it was noted that over-expression of some chemokine receptors render cells permissive for viral envelope induced cell fusion, while cells expressing lower levels of the same co-receptor remain resistant to infection by cell-free virus.43 it is clear that there is considerable plasticity in co-receptor usage, both in terms of the viruses ability to use one or more of a number of “optional” co-receptors and the ability of strains to use a given co-receptor in different ways.40,42 cell lines and in-vitro infec tion with hivs our experience with t cell lines, namely, c866, h9 and cem which we tested and compared in relation to infectivity by four different hivs, showed variation in both the time at which the hiv cytopathic effects (syncytia formation) were first observed, and the number of syncytia formed.44,45,46 moreover, the replication capacity of each virus in each of the cell lines differed widely. the cem cell line was shown to be the least infectable, whereas c866 was very susceptible to infection by the three laboratory-adopted hivs, mn, cbl-20, rod and one fresh clinical hiv- isolate (h995). although other factors may be involved in the susceptibility of the c866 cells to hiv infection, the characteristic tendency of these cells to clump in culture may facilitate the infectivity process. the c866 cell line was shown to be the most susceptible to infection by the laboratory adopted hiv strains mn, rod and cbl-20 with high rates of replication. the c866 cells showed large syncytia (balloon shaped) early in culture usually by day two post infection compared with other cell lines whilst the number of syncytia formed depended directly on the concentration of the virus [figure 3]. the h9 cell line was also infectable by all four mentioned hivs. however, it was not as susceptible as c866 in terms of the number of syncytia observed and the levels of viral replication. the cem cell line was the least infectable showing very few syncytia at the highest concentration of the mn strain (tcid50 of approximately 05/ml). all these experiments, performed on cell lines, were reproducible confirming that the syncytium inducing ability of each hiv strain was a stable property for that particular virus. this is important in studies when infectivity results are compared between different experiments. due to the differences in the behaviour of these cell lines to infection by each virus, and because these cell lines differ in their human leukocyte antigens (hla) type, it is possible that hla may have a role to play in hiv infectivity. the hla-a allele, expressed on the surface of the c866 cells, is believed to be associated with progression of aids from in vivo studies. in contrast, the cem cell line which expresses none (or very low levels) of hla class ii dr antigens when activated12 showed very small syncytia which took longer to develop compared to the other cell lines (c866 and h9). thus, figure 3b. cytopathic effects of hiv-1 infection in vitro, using h9 cells (syncytia formation) figure 3a. normal healthy h9 cells. h o w d o e s h i v i n f e c t h u m a n c e l l ? coursey of ms. lesley mclain, warwick university 36 these results on cell lines support the possibility of a role for the hla in the hiv infectivity process. furthermore, we have shown that hla do correlate, although weakly, with in vitro high or low hiv virus replication.44,45,46 our in vitro results showed clearly that certain hla specificities were significantly correlated in vitro with infectivity by both hiv-s and hiv-2s and that each isolate had its own correlation with hiv infection.44,45 this may partly explain the differences in the in vivo results on the association of hla with certain features of aids and the difficulty in confirming such correlation. however, more studies in vitro and in vivo on a large scale and on groups who are at high risk or low risk need to be addressed with the identification of the hiv isolate that is predominant in each individual patient. these studies will characterise better those hla specificities that are important for infectivity by hiv- and hiv-2. the existence of a significant hla association with all the known hiv- and all hiv-2 isolates infecting human populations may lead to the identification of important immunodominant epitopes that can be useful in vaccine development against the different clades (subtypes) of hivs. there is a possibility that hla are not the actual genes responsible for susceptibility or resistance to hiv infection, rather other, as yet unidentified genes closely linked to hla, or masked by the hla, could be the real genes determining susceptibility or resistance to hiv. this can be revealed only by intensive future research work and by better knowledge and understanding of the genes that are linked to the hla molecules.45 while many immortalised human t-cell lines can be infected by laboratory adapted hiv- and hiv-2 strains, other cd4 positive cell lines are sometimes selectively permissive only for specific virus types.32 from our laboratory experience, when dealing with hiv- and 2, laboratory-adopted strains compared to fresh clinical (primary) isolates, heterogeneity in tropism is evident within a given virus type. for hiv-, virtually all strains replicate efficiently in cd4+ peripheral blood mononuclear cells (pbmcs). however, many freshly isolated or primary strains are also able to propagate efficiently in primary macrophages but not in immortalised t-cell lines and are thus termed m-tropic. conversely, other strains, particularly those which have been adapted to growth in immortalised t-cell lines (ttropic), generally do not efficiently infect primary macrophages.47,48,49,50 other groups of hiv isolates (termed dual-tropic) are able to replicate well in both t-cell lines and primary macrophages in addition to pbmcs.51,52,53 dual-tropic and t-tropic strains induce cell fusion in primary and immortalised t-cells and are also referred to as syncytium-inducing (si). the v3 loop is an excellent candidate for being a component of a co-receptor binding site. the v3 loop is not the sole determinant of co-receptor recognition. in some cases, alternative tropisms can be mapped to non-v3 sequences.20,21,22 hivs affec t on receptor usage to speculate as to why hivs have evolved plasticity in their interactions with co-receptors is important. the ability to use multiple functionally redundant contacts with co-receptors could conceivably facilitate immunological escape.54-60 thus, in the face of a neutralising antibody response (which, in significant part, is directed against v3 sequences,61-65 a major modulator of co-receptor interaction), the selection of variants with altered envelope sequences would be permitted without compromising the ability of the virus to use a given coreceptor. 39 furthermore, changes in envelope sequence, that enable the virus to use additional co-receptors while retaining the ability to interact with ccr-5, could be tolerated. it appears that dual-tropic strains that use both ccr-5 and cxcr-4 are less tolerant of perturbations in ccr-5 sequence than are m-tropic strains,66,67 suggesting that acquisition of the ability to utilise cxcr4 might involve the sacrifice of a degree of functional redundancy and/or affinity in the envelope/ccr-5 interaction.39 during the early, asymptomatic phase of hiv- infection m-tropic strains predominate. it is quite possible that this is the simple consequence of a ‘founder effect’: it is likely that the major route of transmission of hiv- is via infection using ccr-5 as a co-receptor, given the observation that ccr5 delta32 homozygous individuals are much less likely to be hiv infected than those with other genotypes.39 however, why do strains that also use cxcr-4 tend to arise only late in the course of infection, when in many cases they retain the ability to use ccr-5? while it has often been noted that si viruses are associated with poor prognosis it is important to emphasise that the occurrence of si viruses that can use cxcr-4 (and usually ccr-5) is only a correlate of disease progression.64,65 although it is possible that a presumptive expansion in tropism might accelerate the course of hiv- disease, particularly since cxcr-4 is expressed on the naive t-cells subset from which ccr-5 is largely absent,68 it is equally possible that cxcr-4 utilising viruses arise as a consequence of, rather than being the cause of immunosuppression. viruses isolated from a laboratory worker who was accidentally infected with the exclusively t-tropic, iiib strain became m-tropic with time.69 it is known that the selective pressures on al-jabri 37 co-receptor utilisation are different in vivo as opposed to in vitro. at least two scenarios could be envisaged that provide ccr-5 utilising viruses with a selective advantage: firstly, it is conceivable that major selective influences are the result of envelope directed neutralising immune responses, which could impose a restriction on the nature of co-receptor utilisation. indeed, neutralisation phenotype and viral tropism (and therefore, presumably, co-receptor selection) are not independent properties of the viral envelope.70 a general observation is that primary hiv- isolates (which tend to use ccr-5 but not cxcr-4) are somewhat more resistant to neutralisation by naturally occurring hiv- antibodies than are laboratory adapted strains.71 thus, it is possible that immunological constraints are placed on envelope sequence and conformation that could negatively influence the ability of the virus to use cxcr-4 as a co-receptor.39 therefore, the occurrence of cxcr-4 utilising variants late in the course of disease might be a reflection of compromised ability of the infected individuals to mount immune responses to new variants capable of utilising cxcr-4 that would have been readily neutralised earlier during the infection. conversely, a selective advantage for hivs that use ccr-5 may be immune response-independence. an equally plausible hypothesis is that cxcr-4 utilising strains become prevalent only late in disease as a result of the selective depletion of cd4+ memory t-cells (the subset that preferentially expresses ccr-5). these are replaced at a high rate by naive counterparts which (at least in uninfected individuals), express higher levels of cxcr-4 than of ccr-5,68 thus providing tor dual-tropic strains with a selective advantage. regardless of the selective pressures on coreceptor usage, the occurrence of si viruses in only about 50% of patients with advanced disease indicates that the ability of the virus to use cxcr-4 is by no means necessary for the onset of immune suppression.72,73,74,75 glycoprotein-20 co-receptor inter ac tions it is known that gp20 cd4 interaction induces conformational changes in envelope, which expose previously concealed epitopes.76 these changes are not sufficient to induce membrane fusion; rather they are likely to facilitate co-receptor binding. presumably co-receptor binding results in additional conformational modification, ultimately resulting in exposure of the gp4 n-terminal fusion peptide. the physiological function of seven trans-membrane receptors is to transduce signals via coupling to g-proteins. in several cases where post signalling events have been studied (using predominantly the beta-2-adrenergic receptor as a prototype) signalling is rapidly followed by receptor phosphorylation (mediated by specific g-protein coupled receptor kinases). phosphorylation results in desensitisation of the receptor and recognition by arrestins that are necessary for the subsequent internalisation and recycling of the phosphorylated receptor.77 other scientists have investigated whether any of these processes are coupled to the function of ccr-5 as an hiv- co-receptor.39,78,79,80 it may be possible that gp20/ccr-5 interaction might result in signalling, even though this may not be a necessary event for hiv- entry to occur. clearly much remains to be learned about the nature of viral envelope–co-receptor interactions. the functional sequences of the first wave of co-receptors are only partially characterised, and more data relating to those of the newly identified co-receptors is awaited. moreover, the extent to which non-v3 sequences influence recognition of the expanding array of co-receptors is yet to be determined. it is also unclear to what extent co-receptors other that ccr-5 and cxcr-4 are truly utilised in vivo. for example, do viruses present in ccr-5 delta32 homozygotes utilise exclusively cxcr-4? is the frequency of viruses using alternative receptors more frequent in individuals who express low levels of ccr-5? virtually nothing is known about how the expression of co-receptor genes is regulated, and whether or not this might be a potential target for therapeutic intervention. given the many unanswered questions, there can be no doubt that the already substantial number of publications on the subject of hivs co-receptors will continue to grow for the foreseeable future.39 inhibition of hivs entry the entry of hivs is currently understood to be essentially a three-step process consisting of attachment, chemokine co-receptor interaction, and fusion. therefore, specific areas of interest to inhibit hivs entry include blocking gp20 binding to cd4 cell receptors (attachment inhibitors), blocking the binding sites of co-receptors such as ccr5 and cxcr4 (chemokine coreceptor inhibitors), and disrupting the fusion process (fusion inhibitors). the fusion inhibitor, enfuvirtide (formerly called t20), a 36-amino acid peptide being developed jointly by trimeris and roche, is in the most advanced stage of clinical development. hiv fusion with cd4 cells is a complex process, and not very well understood, and involves a conformational change in the hiv envelope gp20/gp4, leading to an interaction between gp4 that lead to intimate proximity between the hiv envelope h o w d o e s h i v i n f e c t h u m a n c e l l ? 38 and the cell membrane, allowing fusion to occur. enfuvirtide is active against both ccr-5and cxcr4using viruses and are synergistic with ccr5 and cxcr4 antagonists.60 many companies including glaxo smithkline are now investigating inhibitors of ccr5 and cxcr4. the lead pfizer compound, uk-427, 857, is a non-competitive inhibitor of ccr5 that has an ic50 of 0.7 nmol in pbmcs, making it a more potent inhibitor of the coreceptor than rantes, one of ccr-5’s natural ligands. the agent is active across a range of hiv- subtypes. another candidate, the takeda compound, tak-220, has a mean ic50 of 4.37–0.5 nmol in pbmcs with no toxic effects observed in cell cultures at concentrations up to 00 nmol. the ono compound, known as ak602, is active against hiv- with an ic50 of 0.2–0.6 nmol, and appears to bind non-competitively to the receptor.60 the identification of co-receptors that mediate hivs entry might well have major significance for attempts to treat hiv infection. the chemokines themselves are inhibitors of hiv entry,36,37,38 and modified forms of rantes, which bind ccr-5 yet fail to induce signal transduction, have similar properties.54,55 beta chemokine homologues encoded by kaposi’s sarcoma associated herpes virus have also been shown to block hiv- infection.56, 57 the lack of an overt phenotype associated with ccr-5 delta32, even among homozygotes,58,59 suggests that antagonists targeted specifically to this co-receptor should be relatively free of undesirable side effects. it might be possible to develop small molecule inhibitors that block viral interactions with cxcr-4 without compromising sdf- signal transduction, peptide and bicyclam compounds targeted to cxcr-4 that prevent t-tropic hiv infection have been described.61, 62, 63 however, all of these compounds also block signalling through cxcr-4. a potentially serious obstacle in the development of co-receptor targeted therapeutics is the plasticity of envelope co-receptor interactions.39 it is quite conceivable that co-receptor targeted compounds would simply select for strains that use an alternative co-receptor, or different regions of the same co-receptor. furthermore, since aids has been documented in ccr5 delta32 homozygotes, it is unlikely that even total ablation of the ccr-5 entry pathway will achieve much more than retardation of disease progression, once infection has been established. there is a possibility that ccr-5 targeted therapy might accelerate the course of disease by selection of viral strains that use alternative co-receptors (most notably cxcr-4, but also including ccr-2b and ccr-3) whose occurrence is associated with disease progression.64 it is possible that combinations of agents that ablate the co-receptor function of both ccr-5 and cxcr-4 would have a significant impact on the ability of hiv to propagate in vivo. cy topathic effec ts produced by in vitro infec tion with hivs the molecular mechanism by which hiv induces cytopathology in susceptible cells is not well understood. in vitro hiv infected cells formed multinucleated giant cells (syncytia) [figure 3] that can produce large amounts of virus before they die, within a period of a few days, normally within 48 hours.81 syncytia formation in culture results from fusion of infected cells with uninfected cd4+ cells82 and involves the cd4 molecule and hiv gp20 and gp4 proteins.83,84 although the precise mechanism is still not known, syncytia formation is linked to the v3 loop of gp20 envelope region.85,86 thus, the differences in the amino acids sequences of the v3 loop determine si versus nsi isolates and whether an hiv isolate will induce syncytia formation or not. t cell tropic (si) viruses generally have a basic amino acid at one or more of the positions , 24, 25 and 32 of the v3 loop, whereas macrophage tropic (nsi) viruses have either an acidic amino acid or alanine at position 25. generally syncytia formation is the most common event preceding cell death in vitro. there is some evidence that syncytia can occur in vivo and syncytia have been observed in the lymph nodes of homosexual men with lymphadenopathy, in lymph nodes and lungs of children with aids and in brain tissues of some adult patients who died with aids and is therefore possibly important in the pathogenesis of aids.87 although syncytia formation may be an indirect indication of how virulent an hiv isolate is, syncytia formation itself is a direct effect of viral replication. since the replication of hivs depends on cellular activation and because hla can cause activation of t cells through a mimicry mechanism,44,45,46 syncytia formation may indirectly depend on the hla type of the pbmcs, which will determine the degree of cellular activation and hence the degree of viral replication. as explained earlier, antigenic variation of the envelope protein of hiv is believed to be essential for the virus to escape specific humoral and cell-mediated immune responses that otherwise would suppress the replication of the virus. moreover genetic variation can also lead to the emergence of more virulent syncytium-inducing (si) isolates of hiv that may accelerate the progression of disease in infected individuals.88 millions of genetic variants of hivs can exist within one host and this diversity may be essential for the survival of the virus within its host. al-jabri 39 susceptibilit y of pbmcs to infec tion with hivs pbmcs include monocytes, lymphocytes and circulating dendritic cells. monocytes can be infected by hivs, and the susceptibility to infection can be observed at all stages of maturation.89 however, the kinetics of virus replication depends on the stage of cellular differentiation at the time of virus infection. cd4 (t helper) cells, the main target for hivs, express the cd4 receptors and their destruction is associated with the deterioration of the immune system. t-lymphocytes do not support a productive infection with hivs in vitro, unless they are first stimulated with agents such as mitogens or antigens.90 activated t lymphocytes are easier to infect than non-activated ones. our experience of the differences of hiv infection observed among pbmcs from different individuals was not due to the differences in cell types (t cells, b cells and monocytes). yamada et al,91 had found that differences between cultures still exist even if monocytes were removed and the remaining cells were only t cells. williams and cloyd92 also reported differences between cd4+ cell clones to infection by hiv indicating that the differences observed between different pbmcs to infection were most likely due to cellular factors. moreover, these differences were not related to differences in cd4 antigen positive lymphocytes or to differences in cell growth.91 in addition, our finding that cells from some individuals produced more virus than others may indicate that this was due to the differences in lymphocytes proliferating in culture.44,45,46 however, considering that the concentration of pha (and also il2) used for lymphocyte stimulation and activation was the same in all cultures used in our tests, and that the cell concentration was also the same, then cell proliferation due to the presence of pha may not be the answer for the differences observed among individual pbmcs. therefore, factors that can cause cellular activation (which are different between different batches of pbmcs—e.g. hla system)44,45,46 may provide an explanation for the differences in viral replication. knowing the factors that determine susceptibility of pbmcs of an individual may also be important for in vitro initial hiv drug screening using pbmcs.44,46 resistance to hiv infec tion the poorly understood phenomenon associated with the hiv- epidemic is the existence of individuals who have been repeatedly exposed to the virus but remain uninfected. it has been suggested that hiv- resistant individuals may have a non functioning co-receptor (such as ccr-5) preventing the virus from entering cells.59,93 the ccr-5 receptor was demonstrated as one of the main co-receptors for nsi (macrophage tropic) strains of hiv-.34 samson et al.,59 reported that a 32 bp deletion within the coding region for the ccr-5 generating a non-functional receptor that did not support infection by nsi strains of hiv-. moreover, white blood cells from individuals homozygous for the mutant ccr-5 were found to be highly resistant to infection by nsi viruses.59,93 population studies indicate that the homozygous defect is found in only % of caucasians of western european ancestry whereas the heterozygous defect is present in approximately 20% of this population.58 these results indicate that variants of the ccr-5 receptor could be responsible for the relative resistance to hiv- infection exhibited by some individuals and also for the variability of the course of the disease in infected patients. in vitro results reported by many studies and our own44–46,91,58,94 showed no single pbmc was completely resistant to infection by different hivs. the possibility that certain individuals are completely resistant to either, hiv-, hiv-2, or both, still exists. studies of larger groups may reveal whether certain individuals are completely resistant to hiv infection. in some of these cases, a substantial in vitro infection resistance (specifically to ccr-5 utilising, m-tropic strains) of pbmcs and macrophages is evident.95,96 in addition, it is well known that there are large variations in the rate of progress of the disease among individuals who do become infected. analysis of ccr-5 genes has revealed the existence of a defective ccr-5 allele that may contribute to each of these observations.58,59,97 moreover, individuals who are heterozygous for the two major ccr-5 alleles do not manifest a high degree of infection resistance.59, 97 however, once infected, the progression of disease in heterozygotes appears to be somewhat retarded. this phenotype is associated with a measurably reduced virus load post seroconversion, and a decrease in frequency of symptomatic primary infection.98 taken together, these observations strongly imply that the major route of hiv transmission both between individuals and between cells within an individual (at least during the early stages of infection) is mediated by the ccr-5 co-receptor. other receptors such as ccr-3 is only expressed in a restricted sub-population of t-cells99 and is, therefore, unlikely to play a major role in hiv infection of these cells. however, it is relatively abundant on microglial cells, the major targets of hiv- in the brain.100 eotaxin, the physiological ligand for ccr-3, and a ccr-3 reactive h o w d o e s h i v i n f e c t h u m a n c e l l ? 40 monoclonal antibody have both been reported to possess infection inhibiting properties in primary brain cultures. m-tropic strains that are unable to use ccr-3 can also infect brain cultures, suggesting that both ccr-3 and ccr-5 play a role in infection of these cells. an interesting, but as yet unexplained, observation is the association of a ccr-2b polymorphism with retarded disease progression.101 this is unexpected given that the great majority of hiv- strains are not able to use ccr-2b as a co-receptor. the mutant ccr-2b allele, which encodes a receptor with a single valine to isoleucine change, is invariably associated with an intact ccr-5 allele. since the two genes are very closely linked, it is quite likely that the mutant ccr-2b gene is associated with some, as yet unidentified, defect in ccr-5 expression, although this has not yet been thoroughly investigated. the wide variation of ccr-5 expression levels among individuals homozygous for intact reading frames has been documented, as has a measurably lower expression level in ccr-5 delta32 heterozygotes.102 it might well be that coreceptor expression levels contribute to the very large variation in rates of disease progression, particularly since the amount of ccr-5 expressed on pbmcs from different donors correlates with their ability to support the replication of m-tropic strains in vitro.102 c o n c l u s i o n this review has briefly described how hivs use different molecules, including cd4 receptors and chemokine co-receptors, to gain entry into a human susceptible cell causing infection. knowing exactly how hivs infect peripheral blood mononuclear cells, and the factors that control the susceptibility or resistance of these cells to infection, is of importance for the understanding of the hivs’ infectivity process. the chemokines are believed to be the most important molecules so far discovered which act as co-receptors for hiv entry. i believe that in the near future we will be seeing more details on the already discovered chemokine co-receptors, and more new co-receptors being discovered. this should aid in designing more potent weapons against the hivs. r e f e r e n c e s . gottlieb ms, schroff r, schanker hm, weisman jd, fan pt, wolf ra, et al. pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. n engl j med, 98, 305, 425–43. 2. masur h, michelis ma, greene jb, onorata i, vande stouwe ra, holzman rs, et al. an outbreak of communityacquired pneumocystis carinii pneumonia. n engl j med, 98 305, 43–438. 3. centers for disease control and prevention. revised classification system for hiv infection and expanded surveillance of definition for aids among adolescents and adults. mmwr, 993, 4, 7. 4. dybul m, fauci as, bartlett jg, kaplan je, pau ak. guidelines for using antiretroviral agents among hiv-infected adults and adolescents. ann intern med, 2002, 37, 38–433. 5. barre-sinoussi f, chermann jc, rey r, nugeyre mt, chamaret s, gruest j, et al. isolation of a t-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (aids). science, 983, 220, 868–87. 6. popovic m, sarngadharan mg, read e, gallo rc. detection, isolation, and continuous production of cytopathic retroviruses (htlv-iii) from patients with aids and pre aids. science, 984, 244, 497–500. 7. sarngadharan mg, popovic m, bruch l, schupbach j, gallo rc. antibodies reactive with human t lymphotropic retroviruses (htlv-iii) in the serum of patients with aids. science, 984, 224, 506–508. 8. levy ja, hoffman ad, kramer sm, landis ja, shimabukuro jm, shiro ls. isolation of lymphocytopathic retroviruses from san francisco patients with aids. science, 984, 225, 840–842. 9. clavel f, guetard d, brun-vezinet f, chamaret s, rey ma, santos-ferreira mo, et al., isolation of a new human retrovirus from west african patients with aids. science, 986, 233, 343–346. 0. dalgleish ag, beverley pc, clapham pr, crawford dh, greaves mf, weiss ra. the cd4 (t4) antigen is an essential component of the receptor for the aids retrovirus. nature, 984, 32, 763–767. . cullen br. human immunodeficiency virus as a prototypic retrovirus. j virol, 99, 65, 053–056. 2. levy ja. pathogenesis of hiv infection. microbiol rev, 993, 57, 83–289. 3. stein bs, gowda sd, lifson jd, penhallow rc, bensch kg, engleman eg. ph-independent hiv entry into cd4-positive t cells via virus envelope fusion to the plasma membrane. cell, 987, 49, 659–668. 4. berger ea, murphy pm, farber jm. chemokine receptors as hiv- coreceptors: roles in viral entry, tropism, and disease. annu rev immunol, 999, 7, 657–700. 5. murakami t, yamamoto n. roles of chemokines and chemokine receptors in hiv- infection. int j hematol 2000, 72, 42–47. 6. hwang ss, boyle tj, lyerly hk, cullen br. identification of the envelope v3 loop as the primary determinant of cell tropism in hiv-. science, 99, 253, 7–74. 7. shioda t, levy ja, cheng-mayer c. macrophage and t cellline tropisms of hiv- are determined by specific regions of the envelope gp20 gene. nature, 99, 349, 67–69. 8. o’brien wa, koyanagi y, namazie a, zhao j-q, diagne a, idler k, et al. hiv- tropism for mononuclear phagocytes can be determined by regions of gp20 outside the cd4-binding domain. nature, 990, 348, 69–73. 9. willey rl, rutledge ra, dias s, folks t, theodore t, buckler ce, et al. identification of conserved and divergent al-jabri 4 domains within the envelope gene of the acquired immunodeficiency syndrome retrovirus. proc natl acad sci usa, 986, 83, 5038–5042. 20. simmonds p, balfe p, peutherer jf, ludlam ca, bishop jo, brown ajl. human immunodeficiency virus-infected individuals contain provirus in small numbers of peripheral mononuclear cells and at low copy numbers. j virol, 990, 64, 864–872. 2. willey rl, theodore ts, martin ma. amino acid substitutions in the human immunodeficiency virus type  gp20 v3 loop that change viral tropism also alter physical and functional properties of the virion envelope. j virol, 994, 68, 4409–449. 22. goudsmit j, boucher ca, meloen rh, epstein lg, smit l, van der hoek l, et al. human antibody response to a strainspecific hiv- gp20 epitope associated with cell fusion inhibition. aids, 988, 2, 57–64. 23. kenealy wr, matthews tj, ganfield mc, langolis aj, waselefsky dm, petteway rj. antibodies from human immunodeficiency virus-infected individuals bind to a short amino acid sequence that elicits neutralising antibodies in animals. aids res hum retroviruses, 989, 5, 73–82. 24. de wolf f, meloen rh, bakker m, barin f, goudsmit j. characterisation of human antibody-binding sites on the external envelope of human immunodeficiency virus type 2. j gen virol, 99, 72, 26–267. 25. takahashi h, merli s, putney sd, houghten r, moss b, germain rn, et al. a single amino acid interchange yields reciprocal ctl specificities for hiv- gp60. science, 989, 246, 8–2. 26. fouchier ram, groenink m, koostra na, tersmette m, huisman g, miedema f, et al. phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type  gp20 molecule. j virol, 992, 66, 383–387. 27. ivanoff la, dubay jw, morris jf, roberts sj, gutshall l, sternberg ej et al. v3 loop region of the hiv- gp20 envelope protein is essential for virus infectivity. virology, 992, 87, 423–432. 28. foley b, korber b. global variation in the hiv- v3 region. in: human retroviruses and aids (eds) myers g, korber b, hahn bh, jeang k-t, mellors jw, mccutchan fe, henderson le, pavlakis gn. los alamos, national laboratory, los alamos, new mexico, usa 995, pp iii 77–08. 29. agrawal l, vanhom-ali z, alkhatib g. multiple determinants are involved in hiv coreceptor use as demonstrated by ccr4/ccl22 interaction in peripheral blood mononuclear cells (pbmcs). j leukoc biol, 2002, 72, 063–074. 30. planelles v, li q-x, chen isy. the biological and molecular basis for cell tropism in hiv. in cullen br (ed.), human retroviruses oxford university press, oxford, uk, 993, 7-48. 3. james w, weiss ra, simon jh. the receptor for hiv: dissection of cd4 and studies on putative accessory factors. curr top microbiol immunol, 996, 205, 37–58. 32. clapham pr, blanc d, weiss ra. specific cell surface requirements for the infection of cd4-positive cells by human immunodeficiency virus types  and 2 and by simian immunodeficiency virus. virology, 99, 8, 703–75. 33. feng y, border cc, kennedy pa, berger ea. hiv- entry cofactor: functional cdna cloning of a seven-transmembrane, g protein-coupled receptor. science, 996, 272, 872–876. 34. deng h, liu r, ellmeier w, choe s, unutmaz d, burkhart m, et al. identification of a major co-receptor for primary isolates of hiv-. nature, 996, 38, 66–666. 35. dragic t, litwin v, allaway gp, martin sr, huang y, nagashima ka, et al., hiv- entry into cd4+ cells is mediated by the chemokine receptor cc-ckr-5. nature, 996, 38, 667–673. 36. oberlin e, amara a, bachelerie f, bessia c, virelizier m, arenzana-seisdedos f, et al. the cxc chemokine sdf- is the ligand for lestr/fusin and prevents infection by t-cellline-adapted hiv-. nature, 996, 382, 833–835. 37. bleul cc, farzan m, choe h, parolin c, clark-lewis i, sodroski j, et al. the lymphocyte chemoattractant sdf- is a ligand for lestr/fusin and blocks hiv- entry. nature, 996, 382, 829–833. 38. cocchi f, devico al, garzino-demo a, arya sk, gallo rc, lusso p. identification of rantes, mip- alpha, and mip- beta as the major hiv-suppressive factors produced by cd8+ t cells. science, 995, 270, 8–85. 39. bieniasz pd, cullen br. chemokine receptors and human immunodeficiency virus infection. frontiers in bioscience 998, 3, d44–58. 40. atchison re, gosling j, monteclaro fs, franci c, digilio l, charo if, et al. multiple extracellular elements of ccr5 and hiv- entry: dissociation from response to chemokines. science, 996, 274, 924–926. 4. bieniasz pd, fridell ra, aramori i, ferguson ssg, caron mg, cullen br. hiv--induced cell fusion is mediated by multiple regions within both the viral envelope and the ccr-5 co-receptor. embo j, 997, 6, 2599–2609. 42. speck rf, wehrly k, platt ej, atchison re, charo, if, kabat d, et al. selective employment of chemokine receptors as human immunodeficiency virus type  co-receptors determined by individual amino acids within the envelope v3 loop. j virol, 997, 7, 736–739. 43. bron r, klasse pj, wilkinson d, clapham pr, pelchenmatthews a, power c, et al. promiscuous use of cc and cxc chemokine receptors in cell-to-cell fusion mediated by a human immunodeficiency virus type 2 envelope protein. j virol, 997, 7, 8405–845. 44. al-jabri aa, mccloskey d, addawee m, bottazzo fg, sachs j, oxford js. in vitro correlation between human leukocyte antigen class i and ii phenotype and hiv infectivity of activated peripheral blood mononuclear cell cultures. aids, 998, 2, 27–28. 45. al-jabri aa. hla and in vitro susceptibility to hiv infection. molecular immunology, 2002, 38, 959–967. 46. al-jabri aa, bottazo gf, mccloskey d, oxford js. evidence for resistance among pbmcs from healthy bangladeshis to infection by certain isolates of hiv- & 2. abstract p5/, the first european meeting of virology, wurzburg, germany, september, 995, 0–3. 47. gartner s, markovits p, markovitz d, kaplan m, gallo r, h o w d o e s h i v i n f e c t h u m a n c e l l ? 42 popovic m. the role of mononuclear phagocytes in htlviii/lav infection. science, 986, 233, 25–29. 48. cheng-mayer c, seto d, tateno m, levy ja. biological features of hiv that correlate with virulence in the host. science, 988, 240, 80–82. 49. fenyo e, morfeldt-mason l, chiodi f, lind b, vongegerfelt a, albert j, asjo b. distinctive replicative and cytopathic characteristics of human immunodeficiency virus isolates. j virol, 988, 62, 444–449. 50. schuitemaker h, kootstra n, de goede r, de wolf f, miedema f, tersmette m. monocytotropic human immunodeficiency virus type  (hiv-) variants detectable at all stages of hiv- infection lack t-cell line tropism and syncytium-inducing ability in primary t-cell culture. j virol, 99, 65, 356-363. 5. collman r, balliet jw, gregory sa, friedman h, kolson dl, nathanson n, srinivasan a. an infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type . j virol, 992, 66, 757–752. 52. simmons g, wilkinson d, reeves jd, dittmar mt, beddows s, weber j, et al. primary, syncytium-inducing human immunodeficiency virus type  isolates are dual-tropic and most can use either lestr or ccr5 as co-receptors for virus entry. j virol, 996, 70, 8355–8360. 53. zhang l, huang t, he y, cao y, ho dd. hiv- subtype and second-receptor use. nature, 996, 383, 768. 54. arenzanaseisdos f, virelizier jl, rousset d, clark-lewis i, loetscher p, moser b, baggiolini m. hiv blocked by a chemokine antagonist. nature, 996, 383, 400. 55. simmons g, clapham pr, picard l, offord re, rosenkilde mm, schwartz tw, et al. potent inhibition of hiv infectivity in macrophages and lymphocytes by a novel ccr-5 antagonist. science, 997, 276, 276–279. 56. kledal tn, rosenkilde mm, coulin f, simmons g, johnsen ah, alouani s, et al. a broad spectrum chemokine antagonist encoded by kaposi’s sarcoma-associated hepesvirus. science, 997, 277, 656–659. 57. boschoff c, endo y, collins pd, takeuchi y, reeves jd, schweickart vl, et al. angiogenic and hiv-inhibitory functions of kshv encoded chemokines. science, 997, 278, 290–294. 58. liu r, paxton wa, choe s, ceradini d, martin sr, horuk r., et al. homozygous defect in hiv- co-receptor accounts for resistance of some multiply-exposed individuals to hiv- infection. cell, 996, 86, 367–377. 59. samson m, libert f, doranz bj, rucker j, liesnard c, farber c-m, et al. resistance to hiv- infection in caucasian individuals bearing mutant alleles of the ccr-5 chemokine receptor gene. nature, 996, 382, 722–725. 60. cooley la, lewin sr. hiv- cell entry and advances in viral entry inhibitor therapy. j clin virol, 2003, 26, 2–32. 6. schols d, struyf s, van damme j, esté, ja, henson g, de clercq e. inhibition of t-tropic hiv strains by selective antagonization of the chemokine receptor cxcr4. j exp med, 997, 86, 383–388. 62. murakami t, nakajima t, koyanagi y, tachibana k, fujii n, tamamura h, et al. a small molecule cxcr4 inhibitor that blocks t cellline tropic hiv- infection. j exp med, 997, 86, 389–393. 63. doranz bj, grovit-ferbasi k, sharron mp, mao sh, goetz mb, daar es, et al. a small-molecule inhibitor directed against the chemokine receptor cxcr4 prevents its use as an hiv- co-receptor. j exp med, 997, 86, 395–400. 64. connor ri, sheridan ke, ceradini d, choe s, landau nr. change in co-receptor use correlates with disease progression in hiv--infected individuals. j exp med, 997, 85, 62–628. 65. connor ri, mohri h, cao y, ho dd. increased viral burden and cytopathicity correlate temporally with cd4+ t-lymphocyte decline and clinical progression in human immunodeficiency virus type -infected individuals. j virol, 993, 67, 772–777. 66. bieniasz pd, fridell ra, anthony k, cullen br. murine cxcr-4 is a functional co-receptor for t-cell-tropic and dualtropic strains of human immunodeficiency virus type . j virol 997, 7, 7097–700. 67. tachibana k, nakajima t, sato a, igarashi k, shida h, iizasa h, et al. cxcr4/fusin is not a species-specific barrier in murine cells for hiv- entry. j exp med, 997, 85, 865–870. 68. bleul cc, wu l, hoxie ja, springer ta, mackay cr. the hiv co-receptors cxcr4 and ccr5 are differentially expressed and regulated on human t lymphocytes. proc natl acad sci usa, 997, 94, 925–930. 69. malykh a, reitz ms, louie a, hall l, lori f. multiple determinants for growth of human immunodeficiency virus in monocyte-macrophages. virology, 994, 206, 646–650. 70. mcknight a, weiss ra, chotton c, takeuchi y, hoshino h, clapham pr. change in tropism upon immune escape by human immunodeficiency virus. j. virol, 995, 69, 367–370. 7. moore jp, cao y, qing l, sattentau qj, pyati j, koduri r, et al. primary isolates of human immunodeficiency virus type  are relatively resistant to neutralization by monoclonal antibodies to gp20, and their neutralization is not predicted by studies with monomeric gp20. j virol, 995, 69, 0–09. 72. biti r, french r, young j, bennetts b, stewart g. hiv- infection in an individual homozygous for the ccr-5 deletion mutant. nature med, 997, 3, 252–253. 73. o’brien tr, winkler c, dean m, nelson jae, carrington m, michael nl, white gc. hiv- infection in a man homozygous for ccr-5 delta32. lancet, 997, 349, 29. 74. theodorou i, meyer l, magierowska m, katlana c, rouzioux c. hiv infection in an individual homozygous for ccr-5 delta32. lancet, 997, 349, 29–220. 75. balotta c, bagnarelli p, violin m, ridolfo al, zho d, berlusconi a, et al. homozygous delta32 deletion of the ccr-5 chemokine receptor gene in an hiv--infected patient. aids, 997, , 67–7. 76. moore j, jameson b, weiss r, sattentau q. in viral fusion mechanisms. ed: j. bentz ed. crc press, boca raton, fl, 993, 233–289. 77. ferguson ssg, zhang j, barak ls, caron mg. g-proteincoupled receptor kinases and arrestins: regulators of g-protein-coupled receptor sequestration. biochem soc trans 996, 24, 953–959. 78. gosling j, monteclaro fs, atchison re, arai h, tsou c-l, goldsmith ma, et al. molecular uncoupling of c-c chemokal-jabri 43 ine receptor 5-induced chemotaxis and signal transd uction from hiv- co-receptor activity. proc natl acad sci, usa 997, 94, 506–5066. 79. farzan m, choe h, martin ka, sun y, sidelko m, mackay cr, et al. hiv- entry and macrophage inflammatory protein- beta-mediated signaling are independent functions of the chemokine receptor ccr5. j biol chem, 997, 272, 6854– 6857. 80. aramori i, zhang j, ferguson ssg, bieniasz pd, cullen br, caron m g. molecular mechanism of desensitization of the chemokine receptor ccr-5: receptor signalling and internalization are dissociable from its role as an hiv- co-receptor. embo j, 997, 6, 4606–466. 8. wigdahl b, guyton ra, sarin ps. human immunodeficiency virus infection of the developing human nervous system. virology, 987, 59, 440–445. 82. lifson jd, reyes gr, mcgrath ms, stein bs, engleman eg. aids retrovirus induced cytopathology: giant cell formation and involvement of cd4 antigen. science, 986, 232, 23– 27. 83. matthews tj, weinhold kj, lyerly hk, langlois aj, wigzell h, bolognesi dp. interaction between the human t-cell lymphotropic virus type iiib envelope glycoprotein gp20 and the surface antigen cd4: role of carbohydrate in binding and cell fusion. proc natl acad sci, usa 987, 84, 5424–5428. 84. andeweg ac, leeflang p, osterhaus adme, bosch ml. both the v2 and v3 regions of the human immunodeficiency virus type  surface glycoprotein functionally interact with other envelope regions in syncytium formation. j virol, 993, 67, 3232–3239. 85. travis bm, dykers ti, hewgill d, ledbetter j, tsu tt, hu sl, et al. functional roles of the v3 hypervariable region of hiv- gp60 in the processing of gp60 and in the formation of syncytia in cd4+ cells. virology, 992, 86, 33–37. 86. trujillo jr, goletiani nv, bosch i, kendrick c, rogers ra, trujillo eb, et al. t-tropic sequence of the v3 loop is critical for hiv- infection of cxcr4-positive colonic ht-29 epithelial cells. j acquir immune defic syndr, 2000, 25, –0. 87. sharer lr. pathology of hiv- infection of the central nervous system. j neuropathol exp neurol, 992, 5, 3–. 88. cornelissen m, mulder-kampinga g, veenstra j, zorgdrager f, kuiken c, hartman s, et al. syncytium-inducing (si) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/si phenotypically mixed human immunodeficiency virus population. j virol, 995, 69, 80–88 89. valentin a, matsuda s, asjo b. characterisation of the in vitro maturation of monocytes and the susceptibility to hiv infection. aids res hum retroviruses, 990, 6, 977–978. 90. wainberg ma, blain n, fitz-gibbon l. differential susceptibility of human lymphocyte cultures to infection by hiv. clin exp immunol, 987, 70, 36–42. 9. yamada o, matsumoto t, sasoaka r, kurimura t. variations in growth capacity of hiv in peripheral blood mononuclear cell preparations from different individuals. aids, 990, 4, 35–40. 92. williams lm, cloyd mw. polymorphic human gene(s) determines differential susceptibility of cd4 lymphocytes to infection by certain hiv- isolates. virology, 99, 84, 723–728. 93. philpott s, weiser b, tarwater p, vermund sh, kleeberger ca, gange sj et al. cc chemokine receptor 5 genotype and susceptibility to transmission of human immunodeficiency virus type  in women. j infect dis, 2003, 87, 569–575. 94. jennes w, sawadogo s, koblavi-deme s, vuylsteke b, maurice c, roels th et al. cellular human immunodeficiency virus (hiv)-protective factors: a comparison of hivexposed seronegative female sex workers and female blood donors in abidjan, cote d’ivoire. j infect dis, 2003, 87, 206– 4. 95. paxton wa, martin sr, tse d, o’brien tr, skurnick j, vandevanter nl, et al. relative resistance to hiv infection of cd4 lymphocytes from persons who remain uninfected despite multiple high risk sexual exposures. nature med, 996, 2, 42–47. 96. connor ri, paxton wa, sheridan ke, koup ra. macrophages and cd4+ t lymphocytes from two multiply exposed uninfected individuals resist infection with primary non-syncytium inducing isolates of human immunodeficiency virus type . j virol, 996, 70, 8757–8764. 97. dean m, carrington m, winkler c, huttley ga, smith mw, allikmets r, et al. genetic restriction of hiv- infection and progression to aids by a deletion allele of the ckr5 structural gene. science, 996, 273, 856–862. 98. meyer l, magierowska m, hubert j-b, rouzioux c, deveau c, sanson f, et al. early protective effect of ccr-5 delta32 heterozygosity on hiv- disease progression: relationship with viral load. aids, 997, , 73–78. 99. sallusto f, mackay cr, lanzavecchia a. selective expression of of the eotaxin receptor ccr-3 by human t helper 2 cells. science, 997, 277, 2005–2007. 00.he j, chen y, farzan m, choe h, ohagen a, gartner s, et al. ccr3 and ccr5 are co-receptors for hiv- infection of microglia. nature, 997, 385, 645–649. 0. smith mw, dean m, carrington m, winkler c, huttley ga, lomb da, et al. contrasting genetic influence of ccr2 and ccr5 variants on hiv- infection and disease progression. science, 997, 277, 959–965. 02. wu bl, paxton wa, kassam n, ruffing n, rottman jb, sullivan n, et al. ccr5 levels and expression pattern correlate with infectability by macrophage-tropic hiv- in vitro. j exp med, 997, 85, 68–69. h o w d o e s h i v i n f e c t h u m a n c e l l ? how does hiv-1 infect a susceptible human cell?current thinking ali a. al-jabri the human immunodeficiency viruses (hivs) hiv-1 hiv-2 subtypes of hivs cell tropism in hivs v3 loop of the glycoprotein (gp) 120 chemokines are the co-receptors for hivs entry role of chemokine co-receptors co-receptor recognition cell lines and in-vitro infection with hivs hivs affect on receptor usage glycoprotein-120 co-receptor interactions inhibition of hivs entry cytopathic effects produced by in vitro infection with hivs susceptibility of pbmcs to infection with hivs resistance to hiv infection conclusion references squ med j, december 2009, vol. 9, iss. 3, pp. 224-229, epub. 19th dec 2009 submitted 3rd oct 09 revision req. 21st oct 09, revision recd 24th oct 09 accepted 25th oct 09 beginning in march 2009, an outbreak of influenza in north america was found to be caused by a new strain of influenza virus, designated influenza a (h1n1) 2009, which is a reassortant of swine, avian and human influenza viruses.1 the world health organization (who) declared influenza a (h1n1) 2009 to be a pandemic predicting that a third of the world’s population would eventually be infected.2 in order to come to grips with such a dire situation, vaccines are being tried in various parts of the world. this article highlights the pros and cons of using vaccine for a disease that is akin to seasonal influenza. influenza virus is an enveloped virus, of the orthomyxoviridae family, which has a unique capacity for changing its genetic material continuously, based on genetic variation and molecular features that are inherited from the virus family.1 the surface proteins of the virus are highly variable due to genetic mutations which lead to changes in up to 50% of the amino acid with the continuous ability to cause infection. the viral genome is segmented, with eight segments of its rna molecules. when infection is caused by several different influenza genotypes, such segments can be randomly re-assorted resulting in hybrid genotypes with some segments derived from one virus strain, whereas, the others are derived from a second strain.3 over a thousand cases of influenza a (h1n1) were identified in the first month, mainly in the united states of america (usa) and mexico; thereafter thousands of cases were identified and reported all over the world. appropriate actions concerning influenza a (h1n1) 2009 need to be made based on facts discovered by scientists; however, these actions should not to be affected by political, legal, financial or any other interests.4 every influenza outbreak, or pandemic, is unique and therefore its features have to be carefully studied and evaluated before making any actions and/or recommendations. however, pandemic preparedness for some microorganisms may have to anticipate potential pandemic characteristics even before they develop in order to take pro-active actions and make pro-active recommendations. generally speaking, to protect individuals from a particular disease immunisation is essential. immunisation can be active (vaccination) or passive, natural or artificial. an unintentional (i.e. natural) immunisation can also happen when an individual is inadvertently exposed to an infectious agent. through vaccination, individuals receive a modified antigen that may consist of attenuated or killed organisms, subcellular components or detoxified toxins that trigger an immune response. the outcome of vaccination is that a subsequent exposure to the unmodified antigen will lead to rapid activation of the immune system to eliminate that pathogen before it can cause disease. unfortunately, no vaccination is without risk. this was certainly evident with the swine influenza epidemic which occurred in 1976, when there was a rush to protect division of immunology, department of microbiology and immunology, college of medicine and health sciences, sultan qaboos university, muscat, oman * to whom correspondence should be addressed. email aaljabri@squ.edu.om a )h1n1(2009 انفلونزا أخذ اللقاح من عدمه علي بن عبداهلل اجلابري، صدقي حسن editorial influenza a (h1n1) 2009 to vaccinate or not to vaccinate? *ali a al-jabri and sidgi s hasson ali a al-jabri and sidgi s hasson editorial | 225 individuals who were at risk (especially infants and the elderly). neurological complications such as guillain-barré syndrome and others were observed to arise from the vaccine.5 this has therefore caused an alert and raised a serious concerns about the safety and efficacy of receiving the h1n1 vaccine against the current influenza a (h1n1) 2009 virus. current issues and concerns of the influenza a (h1n1) 2009 vaccine media and broadcasts confirmed that many people worldwide expressed their concern about the safety and efficacy of the newly developed h1n1 vaccine. many questions were raised such as: 1) do we have enough knowledge about the side-effects of the newly developed vaccine, such as guillain-barré syndrome, which can lead to paralysis and even death? 2) are there any other side effects that we don’t yet know about? and 3) is it worth the risk to be vaccinated when the vaccine does becomes available? the influenza virus is known to be one of the most complex and confusing of all viruses due to its continuous genetic mutations. unlike other viruses such as measles, which stay the same year after year, every one to three years, influenza viruses mutate and therefore, people at risk have to get vaccinated yearly. early each year, health organisations worldwide routinely decide which influenza strains will be included in the subsequent seasonal influenza vaccine. however, one of the current dilemmas is the possibility that by the time the vaccine becomes available later on in the year, usually in september or october, the viruses may have undergone genetic mutation. therefore, the question then will be raised whether it is of practical use to expose human beings to the vaccine and its possible side effects. the concerns about the new vaccine are mainly due to what happened at fort dix in 1976, and was linked to a swine flu-like outbreak. in 1976, over 40 million people received the h1n1 vaccination over a period of a few months.5 the incidence of guillain-barré syndrome at that time was about one in 50,000. guillain-barré syndrome is a rare clinical disorder where the body’s immune system attacks the nerves, causing weakness and numbness to the arms and legs and sometimes even paralysis. the above figure compares to about one in a million people who normally develop the syndrome from a seasonal influenza vaccine. moreover, guillainbarré syndrome occurs naturally following upper respiratory illnesses, digestive illnesses and is also rarely associated with some drugs and vaccines. the new h1n1 vaccine is expected to be vigorously tested before it can be available to the public. in fact scientists cannot be sure that no incidence of guillain-barré syndrome will occur this time, but based upon the differences in the vaccine production in 1967 versus 2009 a similar incidence of vaccine related guillain-barré syndrome is not anticipated. however, if such rare side effects should occur, this would not be known until hundreds of thousands or even millions people had received the new vaccine. in addition to the above, it is important to know the contents of the newly developed vaccine, and what a regular influenza vaccine normally contains.6 there is also another concern as to whether the newly developed vaccine will be effective at all. it may be understandable that individuals who are in good health, and have no other risk factors, express reservations about receiving the vaccine because if they become infected with h1n1 they may develop natural immunity against the virus and in the worst scenario if they do develop any clinical complications they will still have access to the antiviral treatment that is currently available. however, it would be risky for individuals who have other health problems and for children not to receive the vaccine when it becomes available. the risk groups have already been identified by the who and included in the centre for disease control (cdc) recommendations (see below). advantages of the influenza a (h1n1) 2009 vaccine vaccines are the most powerful public health tool for the control of influenza infection. in the past 30 years, many hundreds of millions of doses of trivalent h1, h3 and b influenza vaccines have been administered without significant clinical complications, while saving countless lives. currently, the cdc in the usa has already isolated the new influenza a (h1n1) virus and modified the virus so that it can be used to make hundreds of millions of doses of the vaccine.7,8 influenza a (h1n1) 2009 to vaccinate or not to vaccinate? 226 | squ medical journal, december 2009, volume 9, issue 3 vaccine manufacturers have used the modified virus materials to produce vaccines.9,10,11 making a vaccine is a multi-step process which can take several months to complete. candidate vaccines must be tested through clinical trials over the few months following production. despite all the concerns stated earlier, many people who were around during the swine influenza outbreak in 1976 have been found to have some immunity to h1n1.11,12,13,14,15 also, people over the age of 50 who have received annual influenza vaccines for most of their adult lives (all influenza vaccines contain some form of the h1n1 virus) also appear to have partial immunity.11,13 people are strongly advised to receive the seasonal influenza vaccine because, during the h1n1 influenza virus pandemic, there may be other strains of influenza making their rounds, and people should not leave themselves susceptible to them. 11,13 the 1976 swine influenza virus and the influenza a (h1n1) 2009 virus are different enough so that its unlikely that a person vaccinated in 1976 will have full protection from the 2009 h1n1. people vaccinated in 1976 should still be given the h1n1 2009 vaccine.7 it is anticipated that both seasonal influenza and influenza a (h1n1) 2009 vaccines may be administered at the same time, despite the fact that seasonal vaccines are already available. the usual seasonal influenza viruses are still expected to cause illness this autumn and winter. so, at risk individuals are encouraged to get their seasonal influenza vaccine as soon as it is available.7 the cdc’s advisory committee on immunization practices (acip) has recommended that only certain at risk groups among the whole population are highly encouraged to receive the a (h1n1) 2009 vaccine immediately it becomes available. these target groups include pregnant women, people who live with or taking care for children younger than 6 months of age, health care and emergency medical services personnel, persons between the ages of 6 months and 24 years old, and people of 25 through 64 years of age who are at higher risk of a (h1n1) 2009 because of chronic health disorders or compromised immune systems.7,8 it is expected that the influenza a (h1n1) 2009 vaccine will have a similar safety profile to that of seasonal influenza vaccines, which have a very good safety track record. over the years, hundreds of millions of people have received seasonal influenza vaccines. the most common side effects following influenza vaccinations are mild, such as soreness, redness, tenderness or swelling where the shot was given. the cdc expects that any side effects following vaccination with the influenza a (h1n1) 2009 vaccine would be rare.7 however, if side effects occur, they will likely be similar to those experienced following seasonal influenza vaccines.7 if these problems occur, they usually begin soon after the vaccination is given and last 1 to 2 days. lifethreatening allergic reactions to vaccines are very rare.7,8 if they do occur, it is usually within a few minutes to a few hours after the vaccination is given. additionally, the cdc is planning to work with numerous partners, including other federal agencies, state and local health departments, professional organisations, and academic institutions to follow individuals actively after vaccination and to monitor for any potential adverse events.7,8 seasonal influenza vaccines are known to be highly effective in preventing the disease. the expectation is that a vaccine against influenza a (h1n1) 2009 would probably work in a similar fashion to the seasonal influenza vaccines. the cdc believes that the benefits to be gained from vaccination with the influenza a (h1n1) 2009 vaccine will far outweigh the risks.7,8 pregnant women, children and teens are the high risk groups who are susceptible to the clinical complications due to infection with h1n1. such complications include death so these groups should be vaccinated no matter what.7 other groups, however, may have some leeway to decide on vaccination or refuse it. individuals who had a documented case of h1n1 during the 20082009 influenza season have probably acquired partial immunity. but if the current strain changes between now and december, people could be highly susceptible to contracting the new virus without any immunity. despite the decline in the pandemic, those at risk should be vaccinated in case there is a second wave of infection. overall, development of antiviral vaccination has long been recognised as the most cost efficient use of public money in the entire health field, both in saving lives and for economic impact. ali a al-jabri and sidgi s hasson editorial | 227 references 1. outbreak of swine-origin influenza a (h1n1) virus infection mexico, march april 2009. mmwr morb mortal wkly rep 2009; 58:467-70. 2. who. influenza a (h1n1). from http://www.who. int/csr/disease/swineflu/en/index.html accessed oct. 2009. 3. kilbourne ed. influenza pandemics of the 20th century. emerg infect dis 2006; 12:9-14. 4. gallagher wr. towards a sane and rational approach to management of influenza h1n1 2009. virol j 2009 7; 6:51. 5. lessler j, cummings da, fishman s, vora a, burke ds. transmissibility of swine flu at fort dix, 1976. j r soc interface 2007; 4:755-62. 6. dimenna lj, ertl hc. pandemic influenza vaccines. curr top microbiol immunol 2009; 333:291-321. 7. centres for disease control. h1n1 flu (swine flu). from http://www.cdc.gov/swineflu. accessed oct. 2009. 8. centres for disease control. influenza: the disease. from http://www.cdc.gov/flu/about/disease/index. htm. accessed oct 2009. 9. clark tw, pareek m, hoschler k, dillon h, nicholson kg, groth n, et al. trial of influenza a (h1n1) 2009 monovalent mf59-adjuvanted vaccine preliminary report. n engl j med 2009; sep 10. [epub ahead of print]. 10. de groot as, ardito m, mcclaine e, moise l, martin b. immunoinformatic comparison of t-cell epitopes contained in novel swine-origin influenza a (h1n1) virus with epitopes in 2008-2009 conventional influenza vaccine. vaccine 2009; 4 aug. [epub ahead of print]. 11. cohen j. swine flu outbreak. past pandemics provide mixed clues to h1n1’s next moves. science 2009; 324: 996-7. 12. michaelis m, doerr hw, cinatl j jr. an influenza a h1n1 virus revival pandemic h1n1/09 virus. infection 2009 sep 18. [epub ahead of print]. 13. butler d. swine flu goes global. nature 2009; 458:1082-3. 14. sylte mj, suarez dl. influenza neuraminidase as a vaccine antigen. curr top microbiol immunol 2009; 333:227-4. 15. centres for disease control. serum cross-reactive antibody response to a novel influenza a (h1n1) virus after vaccination with seasonal influenza vaccine. mmwr morb mortal wkly rep 2009; 58:521-4. o n l i n e s u b m i s s i o n ! you can now submit your manuscript online on the squmj website www.squ.edu.om/squmj note: please make sure that you register only once for all your manuscripts submitted 6 apr 22 1 revision req. 8 jun 22; revision recd. 14 jun 22 2 accepted 20 jul 22 3 online-first: august 2022 4 doi: https://doi.org/ 10.18295/squmj.8.2022.047 5 6 simple arthroscopic technique to perform retrograde drilling for 7 osteonecrosis of the femoral condyles with the use of acl guide 8 nikolaos koukoulias,1 *angelo v. vasiliadis,2 theofilos dimitriadis1 9 10 1 orthopaedic department, saint luke’s hospital, thessaloniki, greece; 2 2nd orthopaedic 11 department, general hospital of thessaloniki “papageorgiou”, thessaloniki, greece. 12 *corresponding author’s e-mail: vasiliadis.av@gmail.com 13 14 abstract 15 a simple arthroscopic technique was introduced without the need for further staff 16 during the operation. a 2.4 mm pin is positioned through the sleeve of an acl tibial 17 guide and it is marked with a steri-strip at its body, aiming at 5-10 mm distance between 18 the tips of guide and the pin. the steri-strip serves as a mark and as a stop for 19 inadvertent violation of the cartilage. the tip of the acl is positioned just over the 20 bone lesion, while the marked 2.4 mm pin is inserted through the acl tibial guide from 21 anterior surface of the femur. a stab incision is made and without advancing the sleeve 22 to the bone, the pin is drilled to the marked position while cartilage integrity is 23 confirmed arthroscopically. our arthroscopic technique is simple, fast and effective and 24 it is performed without the need of a special equipment. 25 keywords: avascular necrosis; osteonecrosis; knee joint; arthroscopic; 26 decompression. 27 28 introduction 29 osteonecrosis of the femoral condyle is the second most common affected anatomic 30 location, following the femoral head and accounts for approximately 10% of all cases.1 31 it was first described by ahlback et al. in 1968 as a distinct clinical entity primarily 32 affecting older adulthood woman.2 following the classification of the osteonecrosis by 33 ficat3 and mont,4 the disease progresses through four stages and is based on a 34 combination of clinical and radiographic findings. although several risk factors for the 35 pathogenesis of osteonecrosis have been identified, three main theories of 36 pathophysiology have been advanced. the traumatic theory is based on a history of 37 repetitive trauma over time, causing interruption of blood flow, critical ischemia and 38 finally bone collapse.5,6 the ischemic theory in which ischemia can result from an 39 occlusion of the epiphyseal vessels, causing bone necrosis and collapse.5,6 another 40 theory is that there is an association with altered biomechanics of the knee joint 41 following meniscal root tear and meniscectomy, which often occur in younger and 42 active male.6 43 44 like the pathophysiology, there is still debate concerning the current treatment options 45 for this disease. in general, treatment include non-operative management with 46 pharmacologic agents, such as non-steroidal anti-inflammatory drugs (nsaids) and 47 bisphosphonates, as well as operative treatment with joint preserving and joint-replacing 48 surgeries.6 the operative treatment with core decompression is suggested for early and 49 pro-collapse stages of the disease.6-8 in this regard, there have been described various 50 techniques for performing femoral condyle core decompression with the majorities 51 aided by arthroscopy, fluoroscopy and navigation systems, in order to safe drill the 52 necrotic area.1-3 thus, the purpose of this technical note is to present a simple technique, 53 which enables retroarticular core decompression with an anterior cruciate ligament 54 (acl) tibial guide and a marked pin, without the need of fluoroscopic or/and navigation 55 assistance. 56 57 technique details 58 the arthroscopic procedure was performed by the senior author. two grams of 59 prophylactic cephalosporine was administered intravenously within 1 hour before the 60 surgery. the surgery was carried out with the patient in a supine position, while two 61 posts were attached to the surgical table to facilitate access by the surgeon and the 62 assistant. the first post lateral to the proximal thigh and the second as a foot rest to 63 maintain a 90 degrees of knee flexion. after the patient was positioned, cotton cast was 64 wrapped around the thigh in order to avoid wrinkles and a tourniquet was then applied 65 circumferentially at a pressure of 300 mmhg. 66 67 retrograde drilling is performed utilizing an acl tibial guide. the pin sleeve is placed 68 and secured into the guide leaving enough space for the extra articular course of the 69 acl guide. the 2.4 mm pin is positioned through the sleeve and is marked with a steri-70 strip at its body, aiming at 5-10 mm distance between the tips of guide and the pin, to 71 avoid articular cartilage blow-out [figure 1]. the steri-strip serves as a mark and as a 72 stop for inadvertent violation of the cartilage. 73 74 the integrity of the cartilage is confirmed arthroscopically. the acl tibial guide is 75 inserted through the antero-medial or antero-lateral portal for the medial and the lateral 76 femoral condyle lesions respectively. the tip of the tibial acl guide is positioned just 77 over the bone lesion, without touching the healthy cartilage [figure 2]. the pin is 78 inserted through the anterior surface of the femur. a stab incision is made and without 79 advancing the sleeve to the bone, the pin is drilled to the marked position while 80 cartilage integrity is confirmed arthroscopically. the procedure can be repeated several 81 times and at different knee angles, depended to the size and location of the lesion treated 82 [figure 3]. advantages and limitations of this technique are listed in table 1. 83 84 case study 85 a 47-year-old male visited our department with right knee pain and gradually 86 uncomfortable for 6 months. he had a history of a previous sports injury in the previous 87 year. symptoms rapidly worsened with limited activity in the last month. physical 88 examination showed focal tenderness over the medial femoral condyle and slight 89 limitation in the range of motion of the knee with positive mcmurray’s and thessaly 90 test. magnetic resonance imaging (mri) showed characteristic high intensity portions in 91 the subchondral area of medial femoral condyle, surrounded by diffuse high signal 92 intensity and a medial meniscal tear [figure 4]. the diagnosis was avascular necrosis of 93 the medial femoral condyle. due to the presence of a large lesion limited to the medial 94 femoral condyle, core decompression by retrograde drilling was recommended as an 95 effective treatment option in initial osteonecrosis of the knee (still radiographically 96 invisible). written informed consent was obtained from the patient in order to use his 97 images for publication purposes. the inclusion criteria for this study were the presence 98 of secondary osteonecrosis of stage i or stage ii disease according to ficat3 and mont4 99 as modified for the knee. exclusion criteria included a history of major trauma, the 100 presence of radiological collapse (stage iii and iv) and post-arthroscopic osteonecrosis. 101 102 post-operatively, patient was encouraged to do passive and active range of motion as 103 tolerated. partial weightbearing restriction for 6 weeks, in combination with pain killers 104 and muscle strengthening exercises were recommended, followed by a gradual return to 105 activities based on symptoms. six months post-operatively, the patient remains 106 asymptomatic with full participation in sport activities. 107 108 discussion 109 the pathophysiology of the osteonecrosis of the femoral condyles is not well 110 understood but there are a number of risk factors outlined in the literature which 111 indicate that the pathogenesis of avascular necrosis is likely multifactorial.5,6 common 112 risk factors include sickle cell disease, myeloproliferative disorders, alcohol 113 consumption, long-term corticosteroid use, tobacco smoking, prior trauma and 114 meniscectomy.5 115 116 over the past 2 decades, several treatment options for early stages of osteonecrosis have 117 been proposed, including core decompression, vascularized and non-vascularized bone 118 graft, cell-based therapies (bone marrow mesenchymal stem cells and/or platelet-rich 119 plasma) and osteotomies.5,8 the use of vascularized bone grafts has been associated 120 with possible disadvantages, including the extensive surgical time, prolonged 121 rehabilitation and possible donor site morbidity, such as numbness, weakness and ankle 122 pain (e.g. fibula bone graft).8 also, high tibial osteotomy requires careful pre-operative 123 planning and an experienced surgeon, with the potential risk of non-union, tibial plateau 124 fracture, lateral cartilage degeneration and a further operation for elective hardware 125 removal.9 therefore, retrograde core decompression remains an accepted treatment 126 option by most orthopaedic surgeons as the preferred option for the treatment of 127 avascular necrosis of the femoral condyles. 128 129 knee arthroscopy is currently the gold standard for diagnosing concomitant intra-130 articular knee pathology.6 mri, computed tomography and various adaptive 131 segmentation of knee radiographs have assisted for texture analysis of soft-tissue and 132 subchondral bone pathology, while can increase the diagnostic performance for 133 detecting the presence of knee osteonecrosis.10 although, knee arthroscopy is a common 134 and safe surgical procedure without associated major complications, the overall 135 complication rate was up to 2% varying with the age of the patient, the duration of the 136 tourniquet time and the complexity of the procedure.11,12 however, knee arthroscopy at 137 the time of core decompression of femoral condyles provides an accurate way to 138 confirm the presence or absence of osteochondral defects, collapsed lesions of the 139 femoral condyle, and combined disorders, such as cruciate ligament and meniscal 140 injuries.13 141 142 over the last years, many different procedures have been proposed for the treatment of 143 avascular necrosis of the femoral condyles.5,7,14 regarding retrograde core 144 decompression by precise drilling into ischemic lesions of the femoral condyle, while 145 remaining articular cartilage intact is always challenge. in conventional technique, the 146 exact locating of the drill was made by multiple checks of drilling course and depths 147 with the use of digital fluoroscopy.15 the advantage of using fluoroscopy is to detect the 148 exact position of the drill bit in which the drill has to be properly inserted in order to 149 avoid damage of articular cartilage and of extra-articular soft tissues.15 on the other 150 hand, the use of digital fluoroscopy exposes both the patient and operative staff to 151 enormous radiation, while it puts sterility at risk.5,15 in order to minimize this risk, 152 computer-assisted and navigation based techniques have been developed, regarding 153 retrograde core decompression of avascular necrosis of femoral condyle. these 154 techniques have been showed that improve intra-operative precision with the less 155 possible radiation.5,15 156 157 our surgical technique is a commonly performed arthroscopic surgical procedure in our 158 institution and makes it easy to perform retrograde core decompression of the femoral 159 condyles with the use of acl guide and a 2.4 mm pin marked with a steri-strip at its 160 body. this method reduces the overall surgical time of the procedure, eliminate the 161 expose in radiation and there is no need for further staff during the operation. 162 163 conclusion 164 we present a technical note of case with avascular necrosis of the medial femoral 165 condyle, which is treated with retrograde core decompression. fluoroscopyand 166 navigation-based techniques require extra space, have radiation exposure and they are 167 time consuming. our technique is simple, fast and effective, without the need of special 168 equipment. nevertheless, future studies should include more patients, in order to better 169 evaluate the results of this arthroscopic technique and to clarify possible complications 170 during this procedure. 171 172 conflict of interest 173 the authors declare no conflicts of interest. 174 175 funding 176 no funding was received for this research. 177 178 author contribution 179 nk, avv and td was involved in conceptualization, design, data collect and analysis 180 and drafting the manuscript. all authors approved the final version of the manuscript. 181 182 references 183 1. mankin hj. nontraumatic necrosis of bone (osteonecrosis). n eng j med 1992; 184 326:1473-9. doi: 10.1056/nejm1992055283262206 185 2. ahlback s, bauer g, bohne w. spotaneous osteonecrosis of the knee. arthritis 186 rheum 1968; 11:705-33. doi: 10.1002/art.1780110602. 187 3. ficat rp. idiopathic bone necrosis of the femoral head: early diagnosis and 188 treatment. j bone joint surg br 1985; 67:3-9. doi: 10.1302/0301-189 620x.67b1.3155745. 190 4. mont ma, baumgarten km, rifai a, bluemke da, jones lc, hungerford ds. 191 atraumatic osteonecrosis of the knee. j bone joint surg am 2000; 82:1279-90. 192 doi: 10.2106/00004623-200009000-00008. 193 5. beckmann l, goetz j, bathis h, kalteis t, grifka j, perlick l. precision of 194 computer-assisted core decompression drilling of the knee. knee 2006; 13:211-195 5. doi: 10.1016/j.knee.2006.02.005. 196 6. karim ar, cherian jj, jauregui jj, pierce t, mont ma. osteonecrosis of the 197 knee: a review. ann transl med 2015; 3:6. doi: 10.3978/j.issn.2305-198 5839.2014.11.13. 199 7. forst j, forst r, heller kd, adam g. spotaneous osteonecrosis of the femoral 200 condyle: causal treatment by early core decompression. arch orthop trauma 201 surg 1998; 117:18-22. doi: 10.1007/bf00703433. 202 8. moya-angeler j, gianakos al, villa jc, ni a, lane jm. current concepts on 203 osteonecrosis of the femoral head. world j orthop 2015; 6:590-601. doi: 204 10.5312/wjo.v6.i8.590. 205 9. liu x, chen z, gao y, zhang j, jin z. high tibial osteotomy: review of 206 techniques and biomechanics. j healthc eng 2019; 2019:8363128. doi: 207 10.1155/2019/8363128. 208 10. ciliberti fk, guerrini l, gunnarsson ae, recenti m, jacob d, cangiano v, et 209 al. ctand mri-based 3d reconstruction of knee joint to assess cartilage and 210 bone. diagnostics (basel) 2022; 12:279. doi: 10.3390/diagnostics12020279. 211 11. reigstad o, grimsgaard c. complications in knee arthroscopy. knee surg 212 sports traumatol arthrosc 2006; 14:473-7. doi: 10.1007/s00167-005-0694-x. 213 12. degen rm, lebedeva y, birmingham tb, marsh jd, getgood amj, giffin jr, 214 et al. trends in knee arthroscopy utilization: a gap in knowledge translation. 215 knee surg sports traumatol arthrosc 2020; 28:439-47. doi: 10.1007/s00167-216 019-05638-5. 217 13. ma j, ren y, wang b, yue d, sun w, wang w. autologous osteochondral 218 transplantation for young patients with postcollapse osteonecrosis of the knee: a 219 retrospective cohort study with an average 7-year follow-up. cartilage 2021; 220 13:1291s-7s. doi: 10.1177/19476035211023566. 221 14. hernigou p, gerber d, auregan jc. knee osteonecrosis: cell therapy with 222 computer-assisted navigation. surg technol int 2020; 36:281-7. 223 15. spadari a, forni g, del mango s, tagliavia c, canova m, grandis a, 224 rinnovati r. the comparison of latero-medial versus dorso-palmar/plantar 225 drilling for cartilage removal in the proximal interphalangeal joint. animals 226 2021; 11:1838. doi: 10.3390/ani11061838. 227 228 table 1: advantages and limitations of the surgical technique 229 advantages the procedure is minimally invasive the operation time is minimized due to the absence of intra-operative fluoroscopy use both the patient and the operative staff do not expose in extra radiation there is no need for extra staff to use the c-arm fluoroscopy machine minimize the sterility risk from the use of c-arm fluoroscopy machine limitations the procedure is not indicated in later stages of avascular necrosis (bone collapse) an additional assistance is needed during the surgery 230 231 232 233 234 235 236 237 238 239 240 241 242 243 figure 1: calibrated tibial guide. the pin was positioned through the transtibial acl 244 guide and was marked with the use of a steri-strip. 245 246 247 figure 2: retroarticular core decompression of the medial femoral condyle with 248 avascular necrosis. care is taken to prevent damage to the articular surface of the 249 femoral condyle with the tip of the transtibial acl guide. view from the anterolateral 250 portal showing the tip of the acl guide placed over different areas (a and b) of the 251 affected medial femoral condyle. 252 253 figure 3: illustration (a) and intraoperative pictures (b and c) of the surgical technique 254 with retroarticular core decompression for avascular necrosis (also known as 255 osteonecrosis) of the medial femoral condyle. 256 257 258 figure 4: magnetic resonance imaging of the right knee showing extensive avascular 259 necrosis in sagittal (a), coronal (b) and transverse (c) views. the bone marrow edema 260 was located in the medial femoral condyle. 261 262  assessment of aerobic fitness and its correlates in omani adolescents using the -metre shuttle run test a pilot study sulayma al bar wani1, mohammed al abri1, khamis al hashmi1, masoud al shukeir y1, khurram tahlilkar1, thuraya al zuheibi1, omar al rawas2, *mohammed o hassan1 departments of physiology1 and medicine2, college of medicine, sultan qaboos university, p o box  al khod muscat , sultanate of oman. *to whom correspondence should be addressed. e-mail: mhassan@squ.edu.om abstrac t. objective: to assess aerobic fitness in male and female adolescents using the multistage -metre shuttle run test and correlate it with selected fitness variables. method: the subjects comprised  girls and  boys aged – years, randomly selected from two segregated government schools in muscat. after the pupils filled in a short questionnaire on their personal leisure time activities of the preceding week, their heights and weights were measured. aerobic fitness was assessed by estimating each pupil’s minimal oxygen uptake levels (vo2max) using the multistage -metre shuttle running test (-mst). results: boys spent more time than girls on leisure physical activities, television, computer and video games and the internet. the estimated vo2max in both boys and girls showed high correlation with their weekly physical activities. the time spent on television and computer negatively correlated with vo2max in girls but not in boys. girls had higher body mass index (bmi) and less vomax compared to boys; bmi showed a negative correlation with vomax in girls but not in boys. conclusion: aerobic fitness in this sample was higher in boys than in girls and was strongly influenced by weekly physical activities in both genders. the -mst has proved a simple and inexpensive field test for aerobic fitness that could be implemented on a wide scale. key words: shuttle run test, aerobic fitness, leisure time activities, vo2max, adolescent, oman p      that comprises more than mere absence of disease. functional capacity, one aspect of which is aerobic capacity (the body’s ability to do heavy sustained work), is an important criterion of health. aerobic capacity, measured by determining the body’s maximal rate of oxygen consumption, is dependent on the ability of the cardiovascular system to deliver blood to working muscles and the cellular ability to take up and utilize this oxygen in energy production. maximal oxygen uptake (vo2max) is the most important indicator of physiological fitness, and is positively correlated with cardiovascular health.1,2 in developed nations the declining physical activity of children and adolescents has become a public health issue. programs such as the eurofit3–7 have been designed to combat the alarmingly low fitness and increased fatness in children and adolescents caused by a sedentary lifestyle primarily attributable to the time spent on television, video and computer games and the internet.8–14 very few similar studies have been carried out in developing countries.15 to     :   , : , : , – ©   shuttle run test ������� ����� �� ���������� ������� ������ �� ������� ������ �� ����������� �������� ����������� ���:������ ����� ���� ��������� ����� �������� ���� ������� ���� ������������� ��� ��� �� �������� ����� ����� ������ ��� ����� ������:�����:�� �� ������� ����� �� ������� ������ �� ���������� ������� ���������������� ��� �� ��� ������� ��� ����� ���� ���� .�������:����� ������ ���������� ������ �� �������� ������� �� ������� ������ ���� .���� ����� ����� ���� ����� �� ����� ���� �� ������� ������ ������� �������� ���� ������� ��������������� �� ������� �� ����� ��� ������ ���� ��� � ���� ������ ��� ����� �� ����������� ����� ������ ������� ��� .������� ����� ��� ���� ������ �� ��� ��� ������ �������� .�������:����� �������� ������ ������ �� �������� ������ �� ������������� ���� .������ ������� ��� ����� ��� ���� ������ ������ ����������������� ������ ��������������� ���� .����� �� ����� ���� ������ ����)����������� ���/�� (����� ��� ���� ���� �������� ��� ������)�����������/��� .(������:�� ���� ����� �� ���� ���������� ������� ���� ������� ������� ���� ������� �� ������ ������� .������ ��� �� ���� ������ �������� ����� ��� �� ����������� ���� � ���� ���� �������.   our knowledge no such study has been conducted in the arab countries, where physical fitness receives little attention from authorities and families. is has been compounded by the recent affluence with its sedentary lifestyle that has led to an alarming increase in obesity and associated diseases in both children and adults.16–18 e most vulnerable here is the female gender, who are targeted most by an ancient yet actively practised culture that promotes and values a sedentary way of life and obesity in women.19–21 m e t h o d two large segregated government secondary schools in a semi-urban area in the capital city of muscat were selected for their proximity to sultan qaboos university. each grade comprises  classes with – boys or – girls each. two classes of tenth graders (boys and girls aged –  years) were randomly selected from each school. eightythree girls and  boys participated in the study, indicating a response rate of . all tests were carried out between : and : hours. each pupil filled a short questionnaire on his or her personal leisure time activities during the preceding week. weights and heights were then taken, with sports clothing and without shoes, by an observer of the same gender. body mass index (bmi) was expressed as the weight in kilogram divided by the square of height in metres (kg.m–2).                   (     ) e -mst is an incremental maximal running test that has been validated by several studies as a suitable field test of aerobic fitness.22–25 e subject starts at a walking speed of . km.h–1 and proceeds by increments of . km.h–1 each minute (step) to reach a maximum speed of . km.h–1. e speed of each step is controlled by audio signals played from a tape recorder, announcing the step number. e maximal speed achieved corresponds to the last step. performing the test, one runs a -metre course back and forth endeavouring to touch the end of the track by her/his foot while maintaining synchrony with the audio signal for each step. e test ends for each participant when she/he can no longer reach the marker in time for the audio signal for that step. e last step number announced is used to predict the maximal oxygen uptake (vo2max, y, ml.kg–1.min–1) from the speed (x, km.h–1) corresponding to the step number (speed=. step number) and age using the equation vo2max, y=.+.x–.a+.ax, where x is speed and a is age.22 each pupil’s test was supervised by one trained observer of the same gender and  pupils were tested at a time.            statistical analysis was carried out using spss  statistical package for windows. e difference between the groups was ascertained using the independent sample t-test. correlates of personal variables were compared using pearson’s sample correlation coefficient, which was used for a two-tailed test of the hypothesis of no correlation. a p value of <. was considered significant. e z test was used to test the difference between means of the vo2max of this sample and the samples in other studies on similar age groups. r e s u l t s table  shows the main characteristics of the participants and results of the fitness variables measured. e girls had significantly higher bmi than the boys (p<.). e estimated vo2max was significantly higher in boys than in girls (p<.). e boys spent significantly more of their weekly leisure time on physical activities (p<.) as well as on television/computer games and the internet (p<.) than the girls did. table  shows the correlation between the estimated vomax and personal fitness variables. weekly physical activities showed the highest correlation with vo2max in � � � ��������������������������������������������������������� ��������������������������� � � ������������ ������������� � � �������� � �������� ������������� ������ ±����� ������ ±����� ������������� ������ ±���� ������ ±����� ����������������������� ������ ±���� ������ ±������ ������������������������ ������ ±���� ����� ±����� �������������������� �������� ������ ±���� ������ ±������ ���������������������������������� � � � � � �� �� � � ������������������������������������������������������������� ������������������������������������������� � �� ������������������� �������������������� � �� �� � �� �� ���������������� �� ����� ���� � � ������ ������� �������������� ����������� ������ �������� � ������ �������� ������������� ����� ����� ���� � � ������ ������ �������������������������������������������������� � � � � � � ��������������������������������������������������������� ��������������������������� � � ������������ ������������� � � �������� � �������� ������������� ������ ±����� ������ ±����� ������������� ������ ±���� ������ ±����� ����������������������� ������ ±���� ������ ±������ ������������������������ ������ ±���� ����� ±����� �������������������� �������� ������ ±���� ������ ±������ ���������������������������������� � � � � � �� �� � � ������������������������������������������������������������� ������������������������������������������� � �� ������������������� �������������������� � �� �� � �� �� ���������������� �� ����� ���� � � ������ ������� �������������� ����������� ������ �������� � ������ �������� ������������� ����� ����� ���� � � ������ ������ �������������������������������������������������� � � �              both genders (p<.). bmi showed a significant negative correlation with vomax in the girls (p<.) but not for the boys. weekly television and computer time showed a significant negative correlation in the girls (p<.) but not in the boys. d i s c u s s i o n to our knowledge this is the first study in the middle east that seeks to describe the level of physical fitness in adolescents and how it relates to personal variables. in this preliminary study, aerobic fitness is seen to be significantly higher in boys than in girls. similar gender differences in aerobic fitness were reported in other studies25,26 and were probably due to the higher bmi of girls who have relatively more body fat than boys.10,12,13 e higher bmi in girls may also explain the significant negative correlation between their bmi and vo2max. physical activities in personal leisure time, in our sample and in other studies, have the strongest influence on aerobic fitness in both genders and is believed to influence physical fitness through adulthood and across the lifespan.27–33 physical activity of the girls was apparently less than that of the boys probably because we did not include household activities in our questionnaire. in oman, girls of this age customarily participate in all aspects of household activities to help their mothers cope with the large family size. e boys spent more time watching television, playing video and computer games and on the internet. even in this semi-urban area of the middle east, the number of hours the boys spent on these activities was the same as their age-matched counterparts in urban north america.34,35 a recent study showed that television viewing and video/ computer games are the major causes of physical inactivity, and an emerging public health hazard.9 furthermore it has been shown that reducing television viewing leads to a reduction in obesity.14 in our study, the hours spent on television and virtual games had no effect on boys’ aerobic fitness, but did have a significant negative impact on that of girls, who spent less hours on these activities. while we do not have an explanation for this difference, it is possible that the boys’ recall of time was much higher than the girls (.±. versus .±. hours). using the -mst to estimate vo2max in girls and boys of same age in two separate studies, omani girls had significantly lower estimated vo2max values than tasmanian and irish girls (. versus . (p<.) and . ml/kg–1.min–1 (p<.) respectively). e boys also had significantly lower vo2max values than their tasmanian and irish counterparts—. vs ., (p<.) and . ml.kg1.min–1 (p<.) respectively. in both genders tasmanian adolescents had similar bmi as the omanis but their sample size in that national study was much larger.25 in the irish study both genders had higher bmi than the omanis but they were smaller groups selected to validate fitness tests.36 we postulate that the main reason for the reduced aerobic fitness in omani adolescents is probably due to the very small component that physical education occupies in omani schools curricula as well as the complete lack of extracurricular physical activities in all government schools. e strengths of this pilot study are derived from the fact that it was performed randomly and without prior notice on adolescents of the same age and gender, and from the high response rate of both genders. one potential weakness is the retrospective recall of weekly activities rather than having a record of daily leisure time activities during the study. e -mst will, however, need to be validated in the laboratory in both genders if a more accurate prediction of aerobic fitness is to be estimated in the national study. in conclusion, although our sample was small and was not representative of all oman, we have demonstrated that the -mst, if validated can be used to estimate aerobic fitness in both genders.             is project is funded by sultan qaboos university internal grant system, number ////. r e f e r e n c e s . pate rr, marsha dowda m, ross jg. associations between physical activity and physical fitness in american children. am j dis child, , , –. . shephard rj, allen c, davies ct, hedman r, kaneko m. e maximal oxygen intake: an international standard of cardiorespiratory fitness. bull world health orgn , , –. . council of europe. european tests of physical fitness. publishing and documentation service. strasbourg: nd edition , –. . sallis jf, mckenzie tl, alcaraz je, kolody b, faucette n, hovell mf. e effects of a -year physical education program (spark) on physical activity and fitness in elementary school students. sports, play and active recreation for kids. am j public health , , –. . heath gw, pratt m, warren cw, kann l. physical activity patterns in american high schools students. results from the  youth risk behavior survey. arch pediatr adolesc med , , –. . francis kt. status of the year  health goals for physical activity and fitness. phys er , , –. . gordon-larsen p, mcmurray rg, popkin bm. adolescent physical activity and inactivity vary by ethnicity: e national                                   longitudinal study of adolescent health. j pediatr , , –. . sleap m, warburton p. physical activity levels of –-year-old children in england: cumulative evidence from three direct observation studies. int j sports med , , –. . hernandez b, gortmaker sl, colditz ga, peterson ke, laird nm, parra-cabrera s. association of obesity with physical activity, television programs and other forms of video viewing among children in mexico city. int j obes relat metab disord , , –. . vilhjalmsson r, orlindsson t. factors related to physical activity: a study of adolescents. soc sci med , , –. . riddoch cj, boreham ca. e health-related physical activity of children. sports med ,, –. . sallis jf, alcaraz je, mckenzie tl, hovell mf. predictors of change in children’s physical activity over  months. variations by gender and level of adiposity. am j prev med , , –. . ward ds, trost sg, felton g, saunders r, parsons ma, dowda m, et al. physical activity and physical fitness in africanamerican girls with and without obesity. obes res , , –. . robinson tn. reducing children’s television viewing to prevent obesity. jama , , . . chu nf, rimm eb, wang dj, liou hs, shieh sm. clustering of cardiovascular disease risk factors among obese schoolchildren: the taipei children heart study. am j clin nutr , , –. . moussa ma, skaik mb, selwanes sb, yaghy oy, bin-othman sa. factors associated with obesity in school children. int j obes relat metab disord , , –. . moussa ma, skaik mb, selwanes sb, yaghy oy, bin-othman sa. contribution of body fat and fat pattern to blood pressure level in school children. eur j clin nutr , , –. . darwish oa. aetiological factors of obesity in children. hum nutr clin nutr , , –. . al-shammari sa, khoja ta, al-maatouq ma, al-nuaim la. high prevalence of clinical obesity among saudi females: a prospective, cross-sectional study in the riyadh region. j trop med hyg , , –. . musaiger ao, al-roomi ka. prevalence of risk factors for cardiovascular disease among men and women in an arab gulf community. nutr health , , –. . al nuaim aa, bamgboye ea, al rubeaan ka, al mazrou y. overweight and obesity in saudi arabian adult population: role of socio-demographic variables. j community health , , –. . leger la, mercier d, gadoury c, lambert j. e multistage -metre shuttle run test for aerobic fitness. j sports sci , , –. . liu ny, plowman sa, looney ma. e reliability and validity of the -metre shuttle test in american students  to  years old. res q exerc sport , , –. . naughton lm, cooley d, kearney v, smith s. a comparison of two different shuttle run tests for the estimation of vo2max. j sports med phys fitness , , –. . cooley d, mcnaughton l. aerobic fitness of tasmanian secondary school children using the -m shuttle run test. percept mot skills , , –. . nagle fj, hagberg j, kamei s. maximal o2 uptake of boys and girls ages –. eur j appl physiol , , –. . schmitz k, french sa, jeffery rw. correlates of changes in leisure time physical activity over  years: e healthy worker project. prev med , , –. . blair sn, kannel wb, kohl hw, goodyear n, wilson pw. surrogate measures of physical activity and physical fitness. evidence for sedentary traits of resting tachycardia, obesity and low vital capacity. am j epidemiol , , –. . stone ej, mckenzie tl, welk gj, booth ml. effects of physical activity interventions in youth. review and synthesis. am j prev med, , , –. . powell ke, dysinger w. childhood participation in organized school sports and physical education as precursors of adult physical activity. am j prev med , , –. . malina rm. tracking of physical activity and physical fitness across the lifespan. res q exerc sport , , s–. . penny gl, robert g, barry mp. adolescent physical activity and inactivity vary by ethnicity: e national longitudinal study of adolescent health. j pediatr , , –. . hassan mo, al kharusy w. physical fitness and fatness in  omani schoolboys aged – years. squ j sci res: med sci , , –. . armstrong ca, sallis jf, alcaraz je, kolody b, mckenzie tl, hovell mf. children’s television viewing, body fat and physical fitness. am j health promot , , –. . katzmarzyk pt, malina rm, song tm, bouchard c. television viewing, physical activity and health-related fitness of youth in the quebec family study. j adolesc health , , –. . boreham ca, paliczka vj, nichols ak. a comparison of the pwc and -mst tests of aerobic fitness in adolescent schoolchildren. j sports med phys fitness , , –.            august 2007 vol 7 copy.indd sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 109-115 sultan qaboos university© submitted 27nd january 2007 1pharmacy department, sultan qaboos university hospital p. o. box 35, al-khod 123, sultanate of oman; 2oman medical college, p. o. box 620, azaiba 130, muscat, sultanate of oman *to whom correspondence should be addressed. email: alsiyabi@dal.ca value and types of medicines returned by patients to sultan qaboos university hospital pharmacy, oman khalid al-siyabi,1 kassim al-riyami2 c l i n i c a l & b a s i c r e s e a r c h abstract objectives: frequent physician visits, improper therapeutic adherence and treatment modification after hospitalisation could result in unused medicine accumulating at home. this study aims to examine the value and types of medicines returned by patients at a tertiary care unit in oman. method: all medicines voluntarily returned to sultan qaboos university hospital main pharmacy between february and june 2003 were reviewed. the cost of these medicines and potential cost saving, if some were returned to the hospital distribution cycle, were computed. a method of determining by physical observation whether they can be recycled was developed based on institutional-based guidelines and criteria. results: three hundred and eighty one patients returned their medicines (69% female). the patients returned a total of 07 drugs (mean per patient 3. per month) corresponding to a total cost of omani rials (or) 20,40 (mean per patient or 0.6) ( or = 2.58 us dollar). potential cost saving was or 5,550 (mean per patient or 2.9). medicines of the cardiovascular group were returned in greatest number (24%) while anti-infective drugs had the highest share of the total cost (6%). conclusion: the study identified values and types of medicines returned by patients at tertiary care unit in oman. medications used for cardiovascular and infectious diseases appeared as the most frequent and the most expensive returned medicines. it suggests that health care providers in oman should devise health education programmes to improve proper utilization of medicine. keywords: drugs, supply and distribution; prescriptions, drug; health care economics; oman. مستشفى صيدلية إلى املرضى طريق عن املعادة قيمة وأنواع األدوية –عمان قابوس السلطان جامعة الريامي السيابي، قاسم خالد تراكم إلى باملستشفى الترقيد بعد العالج طرق وتعديل العالجية باخلطة وقلة االلتزام لألطباء الزيارات تكرار يؤدي أن املمكن امللخص: الهدف: من الطريقة: بعمان. الثالثية العناية إلى وحده املرضى طريق عن املعادة األدوية وأنواع قيمة معرفة إلى تهدف الدراسة البيوت.هذه في كميات من األدوية ومت 2003م ويونيو فبراير بني قابوس ــلطان الس جامعة ــفى مبستش ــية الرئيس الصيدلية إلى املرضى طريق عن طوعا املعادة األدوية كل مراجعة متت ــب حس ــر املباش الفحص طريقة مت إتباع . التوزيع حلقة إلى أعيدت األدوية هذه أن ــو ل توفيرها املفترض واملبالغ ــا بأنواعه األدوية هذه ــة قيم ــاء إحص بترجيع أدويتهم قاموا مريضا وثمانون النتيجة: ثالثمائة وواحد ال. أم ــتخدام لالس صاحلة األدوية هذه كانت إذا فيما ملعرفة املعروفة واألنظمة اللوائح مريض لكل (املتوسط 20140 رياال وقدرة إجماليا مبلغا يعادل والذي الشهر) 3.1 في مريض لكل (املتوسط 1071 دواءا استرجاع مت (%69 إناث). أكثر الدموية واألوعية القلب لعالج ــتخدمة األدوية املس كانت 2.9 رياال). املريض ــط (متوس 5550 رياال مبلغا قدره توفير ميكن وبهذا 10.6 رياال) اخلالصة: بينت هذه .(61% التكاليف مجموع من النسب بأعلى عالج العدوى املستخدمة في األدوية ساهمت بينما (24%) بلغت حيث إعادة األدوية واألمراض القلب لعالج ــتخدمة املس األدوية عمان.تعتبر الثالثية في العناية وحدات إحدى إلى بإعادتها يقوم املرضى التي األدوية وأنواع قيم ــة الدراس املثلى للطرق صحية توعية ــتحداث اس في الصحية بالرعاية واملهتمون القرار أصحاب يقوم بأن ــعرا.نقترح س وأغالها املعادة األدوية أكثر من املعدية األدوية. استعمال في عمان. اقتصاد الرعاية الصحية، األدوية، وصف وتوزيع، إمداد الكلمات: أدوية، مفتاح advances in knowledge this is the first study in oman to review the value and types of unused returned medicines. it has identified possible areas where there is a need to monitor drug therapy: cardiovascular and infectious diseases. the study stimulates the need to conduct a country-wide, sustained campaign for returning unused medicines to pharmacies. this may k h a l i d a l -s i ya b i a n d k a s s i m a l r i ya m i 110 a major health benefit to the general public in the sultanate of oman is the pro-vision of health services at all government hospitals and health centres free of charge including free medications. the health care services in oman are provided by the ministry of health (moh). they are divided into primary, secondary (regional), tertiary levels. the moh manages tertiary hospitals (4 hospitals), all located in the capital muscat.1 sultan qaboos university hospital (squh) is a tertiary teaching hospital independent of yet working closely with moh health care services. it accepts referred patients from and refers patients back to moh managed services. squh and all government owned health care institutions dispense the free prescribed medicines from the pharmacies located within the respective health care facilities. squh, a 350-bed tertiary teaching hospital, provides both general medical care and specialized treatment. in 2001, the hospital budget for the purchase of medicines was approximately three million or. the hospital pharmacy spent 40% and 60% of its medicines budget for inpatients and outpatients respectively.2 during that year, the pharmacy was dispensing an average of 300 prescriptions per day.2 the number of prescribed pharmaceutical items per prescription is continually rising and contributing to increase health care cost world wide. in england during 2001, there was 6.4% increase in prescription numbers and a total ingredient cost of £6.1 billion representing an expenditure rise of 6.9% from 2000.3 the proportion of unused prescribed medicines is also increasing. in the year ending march 2001, 584.6 tons of unwanted medicines were returned to community pharmacies in england for destruction under disposal of old pharmaceuticals (doop) scheme.4 this represented an increase in s of 65% over the preceding four years compared with a rise of only 14% in prescription numbers during the same periods.3 there have been a number of similar large and detailed studies undertaken in countries such as the usa, canada and sweden.5, 6, 7 for example, the us study conducted by morgan et al. found that the mean individual annual cost of wasted medication s was $30.47. waste represented 2.3% of total medication costs in their study. the study concluded that the individual costs were modest, but if $30 per person represents a low estimate of average annual waste, the us total national cost for adults older than 65 years would top $1 billion per year.7 the availability of unused medicines in the home may unfortunately constitute a source of material for intentional or accidental poisonings. in the united kingdom, in excess of 90,000 cases of poisoning associated with pharmaceutical products are treated in hospital each year.8 moreover, it is unclear how many medicines are disposed of through normal household refuse and the domestic sewerage system. the environmental impact of inappropriate medicine disposal by patients is a serious environmental issue.8, 9 one of the phenomena associated with the provision of free medications, in countries such as oman, is frequent switching by the patient from one hospital to another or multiple visits to one hospital.10 added to this is the medication dispensing policy of squh, by which most patients with chronic disease are prelead to better understanding of why medicines remain unused by patients. physio-chemical analysis of returned medicines should be looked into; this may help policy makers to review the issue of recycling of unused medicines. this study forms the basis for future research in this very important area of patient compliance with their prescribed medication. it also provides more data related to returned medication in oman in particular and the gulf region overall. application to patient care little was known about patients’ adherence to their therapy or about over prescribing by attending physicians in oman. this study indicated areas where increased interaction between physicians and their patients is needed. this study has identified that patients with cardiovascular disorders are more likely to require additional attention and monitoring of their therapy. if this were done, patient care could be improved. the study suggests the presence of large amount of unused medicines kept at patients’ homes. there is a potential risk of accidental dosing and/or unintentional overdosing which could adversely affect patient care. patient with chronic diseases should be encouraged to bring their medications every time they attend their clinics. this study has identified the need for policy makers to review the 3-months supply prescribing policy for outpatients. 111 va l u e a n d t y p e s o f m e d i c i n e s r e t u r n e d b y pat i e n t s t o s u lta n q a b o o s u n i v e r s i t y h o s p i ta l p h a r m a c y, o m a n scribed a three-month supply. in an attempt to tackle medicine waste, squh pharmacy has awareness campaigns. in an effort to improve compliance, notices were posted in strategic patient waiting areas requesting patients to return unused medicines to the pharmacy department for disposal. this is a passive ongoing campaign. the returned medicines are sorted and disposed by incineration at the squh facility. these returned medicines represent financial loss, possible treatment failure and/or over prescription. this study was initiated to address some of these issues. the goals of the study were to compute the types and values of unused medicines; assess the potential cost saving if medicines were returned to the distribution cycle and develop criteria aimed at recycling some of the returned medicines based only on a physical examination of them. m e t h o d the study was performed in the squh department of pharmacy between february and june 2003 when co-author, khaid al-siyabi, was a third year pharmacy student at dalhousie university, canada and doing experimental learning at squh pharmacy. returned medicines received by pharmacy staff, were used for the study. the patient name, drug name, strength, dosage form, date of dispensing and quantity returned were all documented. medicines were included if they had squh patients’ labels. this process was to insure that all items were squh items and were in the squh formulary. those items without squh patients’ labels were excluded. due to the lack of clear international definitions and guidelines on which medicines could be considered reusable and safe in an outpatient setting,11, 12, 13 the department developed its own guidelines and criteria taking patient safety into account. medicines were qualitatively assessed to determine if they could be theoretically recycled based on dosage form, physical and chemical features [table1]. two licensed pharmacists confirmed the selection process carried out by the investigator. the drugs were classified according to the classification index of the british national formulary.14 all data were entered into a microsoft excel programme for analysis and drug costs were computed using the acquisition cost in or, provided by the pharmacy department during the time of the study.15 figure 1: distribution of most returned medications by pharmacological class. cardio: cardiovascular system, cns: central nervous system, endo: endocrine, gi: gastrointestinal, immuno: immunosuppressant, resp: respiratory system, musclar: musculoskeletal k h a l i d a l -s i ya b i a n d k a s s i m a l r i ya m i 112 r e s u l t s three hundred and eighty one patients, of whom 263(69%) were female, voluntarily returned their medications. a total of 1,171 items were returned to the pharmacy, an average of 3.1 medications per patient. among these, 99 drugs were excluded. cardiovascular drugs were the most common pharmacological group of returned drugs representing 24% of the total returned medications. central nervous system drugs were the second most returned medications with 14% [figure1]. the remaining 1,072 drugs represented a total cost of or 20,140, an average of or 10.6 per patient per month during the time of the study. the anti-infective drugs represented the highest share of the total cost (61%), followed by cardiovascular (7%) and central nervous system (cns) drugs (7%) [figure 2]. the total cost of potentially reusable medications was or 5,550 (27.6% of the returned medicines cost), an average of or 2.9 per patient per month. d i s c u s s i o n this was an observational study, the first of its kind to be reported in oman. in arabian gulf countries, there have been similar studies addressing the economic impact of unused medicines and patients’ perception of safe medicine disposal.16, 17 hisham et al. found that families in saudi arabia and other gulf countries spent a total of us$ 150 million on medications that were never consumed. these results came from a predominantly saudi based questionnaire study.16 our study found that, on average, each of the 381 patients returned three medicines at an average total cost of or 10.6. this was a passive and voluntary exercise carried out in a tertiary teaching hospital. there are 15 government run hospitals available in oman and patients have access to all of them as well as access to all other health centres. patients may have been dispensed medicines whenever they had contacts with physicians. hence, we consider this study reveals only the tip of an iceberg. the study identified both possible therapeutic failure and/or over prescription. nearly one in five of the returned medicines were for cardiovascular therapy. it figure 2: percentage cost of most returned groups of medications (or) cardio: cardiovascular system, cns: central nervous system, endo: endocrine, gi: gastrointestinal, immuno: immunosuppressant, resp: respiratory system, musclar: musculoskeletal 113 va l u e a n d t y p e s o f m e d i c i n e s r e t u r n e d b y pat i e n t s t o s u lta n q a b o o s u n i v e r s i t y h o s p i ta l p h a r m a c y, o m a n is not clear if this result reflected a pure treatment failure, therapy modification or that this class of medication was prescribed more frequently than other classes hence the higher percentage of returns. cost wise, the anti-infective group of returned drugs was the highest (61%). one patient returned an anti-viral drug (valciclovir) costing or 800. this item increased the overall total cost of anti-infective drugs. from the clinical perspective, this study identifies the disease conditions to which health care providers need to pay more attention before repeat prescribing/ dispensing. large amounts of unused medicines in patients’ homes increase the risk of self-medication, the sharing of medications amongst those with similar symptoms, the use of expired medicines and the use of different brand of similar drugs leading to accidental over dosage.18, 19 the study emphasizes the need for a detailed dialogue prior to prescription so that patients and their physicians are in agreement and also the need to monitor the use of medicines, especially when modifying regimens. it is important to give clear and appropriate directions during patient counselling. the best way is to insist that patients bring all of their medicines with them whenever they visit a health care facility. equally, from the economic perspective, the study provided a quantitative estimate of wasted resources due to medicines voluntarily returned and unused. interestingly, while part of this waste was related to nonuse of medications for treating chronic diseases (e.g. cardiovascular drugs), an important proportion of this waste was related to non-use of highly expensive drugs especially of the anti-infective class [figure 3]. it could be very cost-effective to employ clinical pharmacists’ skills in specialized clinics, which are involved in prescribing these two pharmacological classes of drugs, in order to monitor the appropriate use of these medications. studies had proven the value of pharmacists in such specialized clinics.19-23 the current study also suggests that it could be economically viable to establish physico-chemical analyses for returned medicines. the availability of a biochemical analytical facility in the college of science on the sultan qaboos university campus would enable this development. in this way, it could be confirmed whether returned medicine could be returned to the distribution cycle or not. finally, from the health care perspective, the magnitude of the problem emphasizes the need for interfigure 3: percentage distribution of pharmacological groups, both quantity returned and cost cardio: cardiovascular system, cns: central nervous system, endo: endocrine, gi: gastrointestinal, immuno: immunosuppressant, resp: respiratory system, muscle: musculoskeletal k h a l i d a l -s i ya b i a n d k a s s i m a l r i ya m i 114 vention to avoid both health risks and waste of money. different kinds of policies can be explored,23, 18 such as patient counselling by pharmacists at the time of dispensing and drug utilization reviews applied to outpatient or inpatient healthcare settings,25 may decrease drug prescription and consumption, improve medication use and could save money.18 this study leads to some serious some important and serious recommendations for research and action: the need to explore similar exercises in other hospitals and health centres, carry out an active promotion of returning unused medicines to all pharmacy facilities, explore reasons for the return of medicines unused and the need to counsel patients before seeing a physician and during the dispensing process. l i m i t a t i o n s this study has some major limitations. first, all drugs returned were considered to be squh’s items if the returned medicine had an squh patient’s label. some of medications dispensed from other hospitals could have been mixed with squh items. this may have resulted in an overestimation, during the study, of the number of drugs returned to squh and their cost. we do not believe, however that the number was so high as to have a major effect on the overall estimate of the number and cost of items. this study did not investigate the reasons why patients were not using the medications. one study published by anders, 26 studied the reasons and the relative importance of why medicines were returned unused to swedish pharmacies. he concluded that the four main reasons for returning unused medicines to pharmacies were (1) the medicines were too old, (2) the user had died, (3) there was no need for the medicine any more and (4) the therapy had changed. these reasons made up 75% of all reported reasons.26 finally, the cost of returned valciclovir in the anti-infective group represented an extreme in this group and skewed the total cost of this group. c o n c l u s i o n the study identified a substantial waste of medicines posing a danger to the family and the environment. the study also identified both possible therapeutic failure and/or over prescription. patients with cardiovascular and anti-infective medications need to be targeted for the possible improvement in their medication use. pharmacist counselling and drug utilization reviews will improve patients’ compliance. other cost-saving measures may also be found. methods for analysing returned medicines should be adopted as this has the potential of making a substantial saving to this and other hospitals. further studies, such as survey of patients who have returned medications, should be carried out. this need for revision of the 3-months supply prescribing policy for outpatients is an important issue raised by this study. a k n ow l e d g me n ts we would like to thank all those who helped in the successful completion of this study. special thanks go to elizabeth worthing for her initial review of this article and also to, ahmed al-kindi, ali al-ma’awali and kamla al-rahbi who double checked the intial separation process. most importantly, all the thanks go to all squh pharmacy department staff for the provision of an appropriate and very friendly working environment. non-recyclable medications recyclable medications 1. compounded or reconstituted drugs 2. drugs that require refrigeration 3. drugs those are adulterated or misbranded 4. drugs which have had their integrity, packaging or labelling compromised (e.g., through environmental damage such as water damage, crushing, a broken seal, a torn or marked label and originally dispensed 5. expiry date of less than six months 6. ampoules for parenteral medication in single-dose sealed containers 7. suppositories and suspensions 1. intact, solid oral dosage forms 2. medications in multi-dose sealed containers that are dispensed pursuant to an order for an individual patient or resident and from which no doses have been withdrawn. 3. each item should have expiry date of more than six months 4. each package of the solid dosage form has to be sealed by the manufacturer. table 1: drug characteristics that allow or preclude reuse for outpatients 115 va l u e a n d t y p e s o f m e d i c i n e s r e t u r n e d b y pat i e n t s t o s u lta n q a b o o s u n i v e r s i t y h o s p i ta l p h a r m a c y, o m a n r e f e r e n c e s 1. statistics year book 2005, ministry of health, oman. 2. sultan qaboos university hospital annual financial statistics, 2002. 3. prescriptions dispensed in the community statistics for 1991 to 2001: england. london: department of health, hmso, 2002 4. community pharmacies in england and wales: department of health. london: hmso, 2001. 5. isacson d, olofsson c. drugs up in smoke: a study of caseated drugs in sweden. pharm world sci 1999; 21:96-99. 6. grainger-rousseau tj, fielding dw, smith ma, daws d, desrosiers d. what is left in the cabinet? the british columbia envir x project. pharmacotherapy 1999; 19:527. 7. morgan tm. the economic impact of wasted prescription medications in an outpatient population of older adults. j fam pract 2001; 50:779-781. 8. hospital episode statistics. london: department of health, 2000. from http:llwww.dh.gov.uk/assetroot/ 04/02/86/04028664.pdf. accessed november 2006. 9. kolpin dw, furlong et, meyer mt, thurman em, zaugg sd, barber lb et al. pharmaceutical, hormones, and other organic wastewater contaminants in u.s. streams, 1999-2000: a national reconnaissance. environ sci technol 2002; 36:1202-1211. 10. moorin re, holman cdaj. patient-initiated switching between private and public hospitalization in western australia 1980-2001; an analysis using linked data. aust new zealand health policy 2005;2:12. 11. return of unused medications from assisted living facilities. federal mandate review january 2003. office of performance evaluations. idaho state legislature: review 03-01hhw. 12. guidelines for responsible environmental practices for hospital pharmacy. canadian society of hospital pharmacists, 1994. 13. illinois general assembly: administrative code: automated dispensing and storage systems. titles 68, part 1330, chapter vii, section 1330.98. 14. british national formulary. edition 45. london: british medical association & royal pharmacological society of great britain, 2003. 15. drug price list. sultan qaboos university hospital, pharmacy department 2003. 16. abou-auda hs. an economic assessment of the extent of medication use and wastage among families in saudi arabia and arabian gulf countries. clin ther 2003; 25:1276-1292. 17. abahussain ea, ball de, matowe wc. practice and opinion towards disposal of unused medication in kuwait. med princ pract 2006; 15:352-357. 18. knight el, avorn j. quality indicators for appropriate medication use in vulnerable elders. ann intern med 2001; 135:307-310. 19. gurwitz jh, rochon p. considerations in designing an ideal medication use system: lessons from caring for the elderly. am j health syst pharm 2000; 57: 548-551. 20. schumock gt, butler mg, meek pd, et al. evidence of the economic benefits of the clinical services: 19962000. pharmacotherapy 2003; 23:113-132. 21. schumock gt, meek pd, ploetz pa, vermeulen lc. economic evaluations of clinical services: 1988-1995. pharmacotherapy 1996; 16:1188-208. 22. monson ra, bond ca, schuna a. role of clinical pharmacist in improving outpatient drug therapy. arch intern med 1981; 14:1441-1444. 23. gattis wa, hasselblad v, waellan sj, o’connor cm. reduction in heart failure events by the edition of clinical pharmacist to the heart failure team. arch intern med 1999; 159:1939-1945. 24. hammarlund er, ostrom jr, kethyley aj. the effect of drug counseling and other educational strategies on drug utilization of the elderly. med care 1985; 23:165170. 25. kidder sw. the cost-benefit of pharmacist-conducted drug-regimen reviews. consult pharm 1987; 2:394398. 26. anders be. reasons why medicines are returned to swedish pharmacies unused. pharm world sci 2006; 28:352-358. brief communication | 405 1department of fundamentals and administration, 2college of nursing, sultan qaboos university, muscat, oman *corresponding author’s e-mail: jannat@squ.edu.om student perceptions of and attitudes towards academic integrity policies at an omani university do healthcare students differ from others? mickael a. joseph1 and *jansirani natarajan2 sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 405–408, epub. 25 aug 22 submitted 23 feb 21 revisions req. 5 apr & 24 may 21; revisions recd. 4 may & 27 may 21 accepted 1 jun 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.6.2021.085 brief communication abstract: objectives: this study aimed to investigate omani university students’ perceptions of and attitudes towards academic integrity policies through a comparison between healthcare (nursing and medicine) and nonhealthcare students. methods: a cross-sectional study design was conducted during the 2018–2019 academic year wherein students were asked to complete an anonymous questionnaire. data were collected from nine colleges at sultan qaboos university and analysed. results: a total of 579 students completed the questionnaire (response rate: 90%). the results revealed that healthcare students have a significantly higher perception of and better attitudes towards academic integrity policies compared to their non-healthcare counterparts. conclusion: the results of this study should motivate faculty to foster better understanding and implementation of the honour code to encourage an environment of academic integrity for students. keywords: perception; attitude; ethics code; students; university; oman. academic integrity is defined as the adherence to five fundamental values: honesty, trust, fairness, respect and responsibility.1 most universities around the world are committed to academic integrity and ethical standards and invest in creating policies and codes of honour to direct student behaviour.2 yet, incidents of academic dishonesty are on the rise and becoming a matter of increasing concern.3 one of the greatest challenges many universities face is upholding academic integrity and limiting unethical behaviour, dishonesty and misconduct.4 studies have suggested that students who engage in academic dishonesty at the undergraduate level are likely to participate in dishonest behaviours in their subsequent work life.5 this is particularly troublesome among healthcare professionals who are expected to be sincere and trustworthy given that patients need to be able to trust their caregivers with their health and life.6 one of the most effective strategies to combat academic dishonesty is creating policies and codes of honour to nurture a culture of academic integrity.7 it has been shown that students who engage in cheating behaviours have little knowledge of these policies.8 on the other hand, students who are involved with, committed to and satisfied with honour codes tend to uphold academic integrity.9 therefore, there is a need to investigate the perceptions of academic integrity policies and the attitudes towards joining a university with an honour code for undergraduate students, especially those in healthcare programmes (nursing and medicine). there is a dearth of studies on academic integrity policies and students’ perceptions of and attitudes towards these policies based on their degree and fewer still about whether these differ among healthcare students relative to other majors. moreover, few studies have investigated academic integrity among undergraduate students in the gulf region as a whole and fewer still in oman. this study provides a comparison of the differences in perceptions and attitudes of academic integrity policies among healthcare and non-healthcare students. healthcare students should have a high level of integrity as they are expected to become healthcare professionals in the future who abide by a high standard of ethical principles. any dishonest behaviour can be detrimental, not only to the healthcare profession but also to patient safety. therefore, the results of this study may provide important insights to healthcare and non-healthcare educators to enhance the quality of education in order to reach the highest standards. methods this cross-sectional study was conducted during the 2018–2019 academic year at sultan qaboos university (squ), a public university in muscat, oman. the approximate student population of the university at the time of data collection was 18,000. a power analysis using the g-power computer programme indicated that a total sample of 580 students would be needed to detect moderate effects (d = 0.3) with 95% power using a t-test between means with alpha at 0.05. keeping the attrition rate of 10%, the required https://creativecommons.org/licenses/by-nd/4.0/ student perceptions of and attitudes towards academic integrity policies at an omani university do healthcare students differ from others? 406 | squ medical journal, august 2022, volume 22, issue 3 sample size was 638. university students enrolled in the nine colleges were made aware of the current research through emails accessed with the help of the deanship of student affairs. two research assistants approached the colleges with a list of randomised student names based on the number of students in each of those colleges and the inclusion criteria. after explaining the purpose of the study, the voluntary nature of participation, confidentiality and anonymity of the information, students were required to sign the informed consent form and complete the self-reported questionnaire. the data collection tool was a questionnaire developed by dr. donald mccabe of rutgers university, who administered his survey through the center for academic integrity.10 the questionnaire attempts to measure university students’ perceptions of and attitudes towards the academic integrity policies of the institution and their understanding and support of policies against cheating. perceived understanding/acceptance of the university’s academic integrity policies (six items) was measured using five-point likert scales with values ranging from one (very low) to five (very high). thus, the perceived understanding/acceptance variable ranged from six (low) to 30 (high). students’ attitudes were assessed with two questions on the awareness of the presence of an honour code at the university and whether the presence of an honour code affected their decision to enrol at squ. the cronbach’s alpha for this scale was 0.797 for the american population.10 in the current study population, cronbach’s alpha coefficient for the internal consistency of the scale was 0.644. statistical package for the social sciences (spss), version 22.0 (ibm corp., armonk, new york, usa) was used for data analysis after the investigators entered and audited the data. the data were analysed using descriptive (frequencies and percentages) and inferential statistics (chi-squared). the statistical significance was assessed at the p <0.05 level. the ethics committee of the college of nursing and the ethics committee of squ provided the authors with permission to conduct the study (rec/2018-2019/3). participants were informed that their participation was voluntary and that they could withdraw at any time. written informed consent was provided by participants before they began the survey questionnaire. to ensure participants’ anonymity, only code numbers were used for identification. results a total of 579 students responded to the survey on academic integrity (response rate: 90%). the results were analysed and the healthcare colleges (colleges of medicine and nursing) were compared with the non-healthcare colleges (colleges of engineering, agriculture, education, arts, science, law and economics) at the university. the majority of participants were from nonhealthcare colleges (395, 68.2%) compared to those from healthcare colleges (184, 31.8%). most respondents were in the third and fourth years of their programmes in the non-healthcare (n = 225; 57.0%) and healthcare colleges (n = 126; 68.5%). while a majority of participants in the non-healthcare colleges were male (n = 199; 50.4%), healthcare colleges had more female participants (n = 117; 64.0%). the mean age was 20.94 ± 1.36 years among non-healthcare students and 21.18 ± 2.34 years among healthcare students. there were six aspects analysed for the perception of the academic integrity environment at the university. students from the healthcare colleges had a higher level of understanding than those from non-healthcare colleges with the total mean scores of 18.87 ± 3.52 and 17.96 ± 3.44 respectively (t [569] = -2.873; p = 0.004) [table 1]. when asked about their awareness of the honour code at squ before applying, healthcare college students showed more awareness than their non-healthcare counterparts (91 [49.7%] versus 153 [39.0%]; p = 0.015). this awareness was more likely to affect the decision of healthcare college students to join the university than non-healthcare students (108 [59.6%] versus 190 [48.2%]; p = 0.012). moreover, students’ attitudes were analysed after dividing the study population based on gender. the results showed that female students from the healthcare colleges were more aware of the honour table 1: comparison between healthcare and non-healthcare students’ perceptions of the academic integrity environment at a public university (n = 579) variable college n* mean ± sd t df p value† perception of academic integrity environment‡ non-healthcare 393 17.96 ± 3.445 -2.873 569 0.004 healthcare 178 18.87 ± 3.528 sd = standard deviation. *there were missing data from eight students. †statistically significant at p <0.05; ‡questionnaire included questions regarding : 1) the severity of penalties for cheating at sultan qaboos university; 2) the average student’s understanding of campus policies concerning student cheating ; 3) the faculty’s understanding of these policies; 4) student support for these policies; 5) faculty support for these policies; 6) the effectiveness of these policies. mickael a. joseph and jansirani natarajan brief communication | 407 code than male students (65 [35.5%] versus 26 [14.2%]; p = 0.018). on the other hand, the fact that squ has an honour code had a greater effect on the decision of female as opposed to male students from nonhealthcare colleges to attend the university (105 [26.7%] versus 85 [21.6%]; p = 0.034) [table 2]. discussion the results from the current study indicate that healthcare students have a higher perception of and a better attitude towards academic integrity policies than non-healthcare students. a study by mccabe, treviño and butterfield found that students at universities with an honour code better understood and supported academic integrity policies, severity of academic dishonesty and effectiveness of penalties compared to universities without an honour code.11 considering that squ has an honour code, the discrepancy in students’ perceptions of the academic integrity policy between healthcare colleges and nonhealthcare colleges could result from the honour code being brought to the attention of students at the healthcare colleges more frequently. tatum and schwartz have suggested that for an honour code to work properly, universities need to not only create one but also discuss it with and emphasise its importance to students.12 the code of honour at squ is publicly available on the university’s website as a student academic misconduct policy in which the university pledges to ensure high standards of academic integrity.13 the college of nursing at squ, for instance, publishes the code of honour along with the consequences of dishonest behaviours in the student academic handbook which is distributed to students every semester. to the best of the authors’ knowledge, none of the non-healthcare colleges at squ appear to publish the code of honour in their student academic handbook at the time of this study. nursing and medical students also watch their peers pledge to uphold the honour code every year at a large graduation ceremony. when graduating, students take an oath as they receive their degrees. awareness that this will happen may enhance the perception of and attitudes towards academic honesty policies among these students. such understanding and approval of university policies have been found to correlate with higher academic integrity.14 indeed, vandehey et al. have found that students who endorse the honour code and do not cheat tend to act with significantly stronger integrity than those who cheat.15 reminding students of such policies is thought to contribute to lower rates of academic dishonesty.15 therefore, it is recommended that all colleges at squ include the honour code and academic integrity in their curricula and constantly remind students of its importance throughout the semester. gender differences could be another reason for this discrepancy in the perceptions and attitudes of squ students. it has been shown that women abide by the rules and are more sensitive to penalties than men.16 more importantly, instructions about ethics are more impactful on women than men.16 having a female majority among the participants from the healthcare colleges may have affected the results of this study, leading to the conclusion that healthcare students have higher perceptions of and better attitudes towards academic integrity policies. it is table 2: comparison between healthcare and non-healthcare students’ attitudes towards the academic integrity environment at a public university (n = 579) questions college response n (%) chi-squared value p value* female male total before you came to squ, were you aware that the school had an honour code? nonhealthcare† yes 82 (20.9) 71 (18.1) 153 (39.0) 1.488 0.255 no 113 (28.8) 126 (32.1) 239 (61.0) total 195 (49.7) 197 (50.3) 392 (100.0) healthcare‡ yes 65 (35.5) 26 (14.2) 91 (49.7) 5.043 0.018 no 51 (27.9) 41 (22.4) 92 (50.3) total 116 (63.4) 67 (36.6) 183 (100.0) did the fact that squ has an honour code impact your decision to attend? nonhealthcare‡ yes 105 (26.7) 85 (21.6) 190 (48.2) 4.889 0.034 no 90 (22.8) 114 (28.9) 204 (51.8) total 195 (49.5) 199 (50.5) 394 (100.0) healthcare† yes 75 (41.4) 33 (18.2) 108 (59.7) 3.338 0.083 no 41 (22.7) 32 (17.7) 73 (40.3) total 116 (64.1) 65 (35.9) 181 (100.0) squ = sultan qaboos university. *statistically significant at p <0.05. †there were missing data for three students. ‡there were missing data for one student. student perceptions of and attitudes towards academic integrity policies at an omani university do healthcare students differ from others? 408 | squ medical journal, august 2022, volume 22, issue 3 worth noting that researchers believe that teaching students about the importance of ethical behaviour at the undergraduate level has a greater effect on men who can improve their honest behaviour to reach a level equivalent to their female counterparts.17 the current study has some limitations: one is the relatively small size of the healthcare students group compared to non-healthcare students. the fact that statistically significant results were obtained with the current sample size suggests that it is adequate; however, the samples are from only one institution which makes it difficult to generalise the results. therefore, more studies need to be conducted among larger cohorts to discern whether the results are replicable. the cross-sectional research design is also a possible limitation that curtails the ability to establish causal associations. moreover, since it is difficult to obtain an objective measure of academic integrity, another limitation is the self-reported nature of this study. conclusion with the rise in incidents of academic dishonesty becoming a matter of increasing concern, many universities are facing the major challenge of upholding academic integrity and limiting unethical behaviour. the results from the current study indicate that healthcare students have higher perceptions of academic integrity and better attitudes towards having an honour code when compared to students from non-healthcare colleges. students should have a clear understanding of the policies, which will allow them to distinguish between what constitutes unethical behaviour and what does not. therefore, education is paramount to enhancing students’ knowledge of the honour code and academic integrity, which will, in turn, promote their perceptions and attitudes about academic integrity and ultimately decrease incidents of dishonest behaviour. a u t h o r s’ c o n t r i b u t i o n maj and jn contributed equally in the conception of the idea, proposal writing, data collection, screening and analysis as well as manuscript drafting. both authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this work was supported by the deanship of research at sultan qaboos university (grant number rec/2018-2019/3). references 1. fundamental values of academic integrity. international center for academic integrity. from: https://academicintegrity. org/resources/fundamental-values accessed: may 2021. 2. macleod pd, eaton se. the paradox of faculty attitudes toward student violations of academic integrity. j acad ethics 2020; 18:347–62. https://doi.org/10.1007/s10805-020-09363-4. 3. henning ma, ram s, malpas p, shulruf b, kelly f, hawken sj. academic dishonesty and ethical reasoning: pharmacy and medical school students in new zealand. med teach 2013; 35:e1211–7. https://doi.org/10.3109/0142159x.2012.737962. 4. gottardello d, karabag sf. ideal and actual roles of university professors in academic integrity management: a comparative study. stud higher educ 2022; 47:526–44. https://doi.org/10.10 80/03075079.2020.1767051. 5. brown t, bourke-taylor h, isbel s, gustafsson l, mckinstry c, logan a, et al. establishing similarities and differences among the self-reported academic integrity of australian occupational therapy undergraduate and graduate-entry master’s students. open j occup ther 2019; 7:1–16. https:// doi.org/10.15453/2168-6408.1558. 6. al gahtani hms, jahrami ha, silverman hj. perceptions of medical students towards the practice of professionalism at the arabian gulf university. bmc med educ 2021; 21:1–9. https:// doi.org/ 0.1186/s12909-020-02464-z. 7. raman v, ramlogan s. academic integrity and the implement ation of the honour code in the clinical training of undergraduate dental students. int j educ integrity 2020; 16:1–20. https://doi.org/10.1007/s40979-020-00058-2. 8. von dran gm, callahan es, taylor hv. can students’ academic integrity be improved? attitudes and behaviors before and after implementation of an academic integrity policy. teach bus ethics 2001; 5:35–58. https://doi.org/10.1023/a:1026551002367. 9. dix el, emery lf, le b. committed to the honor code: an investment model analysis of academic integrity. soc psychol educ 2014; 17:179–96. https://doi.org/10.1007/s11218-013-9246-2. 10. mccabe dl, feghali t, abdallah h. academic dishonesty in the middle east: individual and contextual factors. res higher educ 2008; 49:451–67. https://doi.org/10.1007/s11162-008-9092-9. 11. mccabe dl, treviño lk, butterfield kd. cheating in academic institutions: a decade of research. ethics behav 2001; 11:219–32. https://doi.org/10.1207/s15327019eb1103_2. 12. tatum h, schwartz bm. honor codes: evidence based strategies for improving academic integrity. theory pract 2017; 56:129–35. https://doi.org/10.1080/00405841.2017.1308175. 13. sultan qaboos university. student academic misconduct policy. from: https://www.squ.edu.om/portals/14/users/027 /27/27/students%20academic%20misconduct%20policy.pdf accessed: may 2021 14. mccabe dl, trevino lk. academic dishonesty: honor codes and other contextual influences. j higher educ 1993; 64:522–38. https://doi.org/10.1080/00221546.1993.11778446. 15. vandehey m, diekhoff g, labeff e. college cheating: a twentyyear follow-up and the addition of an honor code. j coll stud dev 2007; 48:468–80. https://doi.org/10.1353/csd.2007.0043. 16. zhang y, yin h, zheng l. investigating academic dishonesty among chinese undergraduate students: does gender matter? assess eval higher educ 2018; 43:812–26. https://doi.org/10.10 80/02602938.2017.1411467. 17. luthar hk, karri r. exposure to ethics education and the perception of linkage between organizational ethical behavior and business outcomes. j bus ethics 2005; 61:353–68. https:// doi.org/10.1007/s10551-005-1548-7. https://doi.org/10.1007/s10805-020-09363-4. https://doi.org/10.3109/0142159x.2012.737962. https://doi.org/10.1080/03075079.2020.1767051. https://doi.org/10.1080/03075079.2020.1767051. https://doi.org/10.15453/2168-6408.1558. https://doi.org/10.15453/2168-6408.1558. https://doi.org/ 0.1186/s12909-020-02464-z. https://doi.org/ 0.1186/s12909-020-02464-z. https://doi.org/10.1007/s40979-020-00058-2. https://doi.org/10.1023/a:1026551002367. https://doi.org/10.1007/s11218-013-9246-2. https://doi.org/10.1007/s11162-008-9092-9 https://doi.org/10.1207/s15327019eb1103_2. https://doi.org/10.1080/00405841.2017.1308175 https://doi.org/10.1080/00221546.1993.11778446. https://doi.org/10.1353/csd.2007.0043 https://doi.org/10.1080/02602938.2017.1411467. https://doi.org/10.1080/02602938.2017.1411467. https://doi.org/10.1007/s10551-005-1548-7. https://doi.org/10.1007/s10551-005-1548-7. march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 70-74, epub 16th mar 2009 submitted 10th june 08 revision req. 18th aug 08 & 20th jan 09, revision recd. 25th oct 08 & 28th jan 09 accepted 2nd feb 2009 objectives: this study investigates the in vitro effect of the antioxidant drug, n-acetyl-l-cysteine (nac), on cytokine production by peripheral blood mononuclear cells (pbmc). methods: pbmc were isolated by ficoll-hypaque, and stimulated with anti-cd3 antibodies, phytohaemagglutinin (pha), lipopolysaccharide (lps) for 24 hours in the presence or absence of 5 mm nac. the cytokines produced were measured by enzyme-linked immunosorbent assay (elisa). results: treatment with nac significantly up-regulates the secretion of il-β, il-5 (interleukin) and ifn-γ (interferon) and down regulates il-0 production, after anti-cd3 or pha (p<0.05), but not after lps stimulation. nac also significantly increased total il-2 secretion after anti-cd3 (but not pha or lps) stimulation and il-2p40 after anti-cd3, pha, and lps stimulation (p <0.05). conclusion: these results indicate that nac up-regulated the production of pro-inflammatory cytokines, and down regulated anti-inflammatory cytokine production by pbmc, in a process which may be associated with increased levels of glutathione (gsh). further work is required to determine whether this increase or decrease in cytokine production is due to direct effect of nac. key words: antioxidant; n-acetylcysteine; cytokines; peripheral blood mononuclear cells. effect of n-acetyl-l-cysteine on cytokine production by human peripheral blood mononuclear cells *ahmed al-shukaili,1 suad al-abri,2 alia al-ansari,2 michele a monteil1 1department of microbiology and immunology, college of medicine and health sciences, sultan qaboos university, muscat, sultanate of oman; 2department of biology, college of science, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: shukaily@squ.edu.om قبل اخلاليا من السايتوكني في إنتاج l سيستني n أسيتايل تأثير النواة في دم اإلنسان احمليطي وحيدة مونتيل ميشيل األنصاري، عالية العبري، سعاد الشكيلي، أحمد قبل اخلاليا من السايتوكني بإنتاج l سيستني) ــيتايل (n أس ــدة لألكس املضادة األدوية في تأثير تبحث اتبرية ــة الدراس هذه الهدف: امللخص: ،( cd3) نوع من األجسام فيكول هايبيك وحفزت مبضادات اخلاليا وحيدة النواة بواسطة على الطريقة: مت احلصول . احمليطي اإلنسان دم في �وحيدة النواة ــايتوكني الس قياس مت . ــتني l سيس ــيتايل n أس من 5 مل وبدون مع ــاعة 24 س ملدة يّ مِ ــحْ الشَّ ــكاريدِ السَّ ديدُ وعَ ، النَباتِيَّة وِيَّةٌ مَ الدَ ةٌ والراصَّ il-1β, il-5, ifn-γ)) من إنتاج l سيستني زاد n أسيتايل النتائج: إضافة ُرْتَبِط. امل لإلِنْزميِ يَّةُ َناعِ امل يَّةُ تِصاصِ االمْ ــةُ ُقايَسَ امل ــطة بواس املنتج ديدُ عَ بعد حتفيز ليس لكن إحصائيا ، النَباتِيَّة بشكل معتد وِيَّةٌ مَ الدَ ةٌ الراصَّ أو (cd3) األجسام مضادات إضافة بعد ، ( il-10) إنتاج قلل من بينما ( cd3) األجسام مضادات إضافة بعد (il-12) إفراز مجموع إحصائيا معتد l سيستني بشكل كذلك يزيدn أسيتايل . يّ مِ حْ كاريدِ الشَّ السَّ وِيَّةٌ النَباتِيَّة� مَ الدَ ةٌ والراصَّ ، ( cd3) مضادات حتفيز بعد (il-12p40) و يّ ، مِ حْ كاريدِ الشَّ السَّ ديدُ عَ أو النَباتِيَّة وِيَّةٌ مَ الدَ ةٌ الراصَّ بتحفيز ليس ولكن ويقلل إنتاج ، االلتهابي قبل ما السايتوكني إنتاج يزيد l سيستني n أسيتايل إلى أن تشير اخلالصة: هذه النتائج . يّ مِ ــحْ الشَّ ــكاريدِ السَّ ديدُ وعَ املطلوب . اجللوتاثايون مستويات بزيادة مرتبطة تكون رمبا ــيلة بوس ــان احمليطي ، اإلنس دم في النواة وحيدة اخلاليا قبل من املضاد لاللتهاب ــايتوكني الس . l سيستني n أسيتايل ل املباشر التأثير بسبب كانت السايتوكني انتاج قلة أو زيادة كانت لتبيان فيما إذا من البحث مزيدا احمليطي. اإلنسان دم في النواة وحيدة سايتوكني، خاليا l سيستني، n أسيتايل األكسدة، الكلمات: مضاد مفتاح b r i e f c o m m u n i c a t i o n n-acetyl-l-cysteine (nac) is a well-known medication which is common-ly used as a mucolytic agent in a variety of respiratory illnesses, in the treatment of paracetemol overdose, and in conditions characterised by decreased antioxidants or oxidative stress such as hiv infection, cancer, heart disease and cigarette smoking. this drug works as a free radical scavenger, as a glutathione (gsh) precursor, or as structural analogue of gsh, enriching the gsh pool in the cellular environment. the beneficial effects of nac are attributed either to its ability to reduce extracellular cysteine to cysteine, or as a source of sulfhydryl (sh) metabolites, which are important for gsh synthesis.1,2 e f f e c t o f n a c e t y l l c y s t e i n e o n c y t o k i n e p r o d u c t i o n b y h u m a n p e r i p h e r a l b l o o d m o n o n u c l e a r c e l l s 71 there are limited studies investigating the effects of nac on cytokine production by peripheral blood mononuclear cells (pbmc). a study by viora et al., using pbmc, demonstrated that nac up-regulated the secretion of interleukin, il-1β, il-2, il-12, and il-15 after phytohaemagglutinin (pha) stimulation.3 several reports have shown that nac treatment induced a significant up-regulation of il-12 production by isolated monocytes.4,5 in addition, pre-treatment with nac reduced lipopolysaccharide (lps)-mediated secretion of tnf-α (tumour necrosis factor) and il-6 by human alveolar macrophages6 and by rat epithelial cells.7 based on the hypothesis that antioxidant drugs such as nac can act as modulators of the immune response and can be used in antioxidant therapy in many human diseases with oxidative imbalance,1,2 we studied the in vitro effect of nac (as an active antioxidant agent) on the production of some of pro/anti-inflammatory cytokines by peripheral blood mononuclear cells isolated from normal healthy individuals. also, we examined whether nac can influence several cellactivation pathways using different stimuli. m e t h o d s peripheral blood (5ml) was collected in sodium heparin-containing tubes from 14 normal volunteers (10 males and 4 females, aged between 23-37 years) at the college of medicine and health sciences, sultan qaboos university (squ), muscat, oman. all the volunteers provided informed consent, and completed a questionnaire to assess their health status. the study was approved by the research committee of the college of science medicine at squ. pbmc were isolated by ficoll density gradient centrifugation (sigma diagnostics, usa) following the manufacturer’s instructions. buffy coats were harvested and cells were washed twice (centrifuged at 300g for 5 minutes) in hanks solution (gibco, paisley, uk) and resuspended in an rpmi-1640 medium (gibco) supplemented with 10% heat-inactivated fetal calf serum (fcs), (sigma diagnostics, usa), lglutamine and penicillin/streptomycin (gibco, usa, uk) (complete medium). the antioxidant compound nac (sigma diagnostics, usa) was dissolved in rpmi1640, the ph was adjusted to 7.4 by addition of sodium hydroxide (naoh), and used at final concentration of 5 mm, after addition to cell suspension. the trypan blue dye exclusion test was performed in order to exclude any drug toxicity. all the materials for this assay were purchased from sigma diagnostics (usa). total glutathione (reduced and oxidized gsh) was measured in pbmc lysates after 24 hour incubation with 5 mm nac. cells were lysed in 2ml of 0.05% v/v tritonx-100 in buffer (125 mm sodium phosphate, 6.3 mm sodium ethylenediamine tetra acetic acid (na-edta), adjusted to ph 7.5). the samples were assayed by enzymatic recycling procedure as described previously.8 pbmc were resuspended at concentration of 1 x 106 cell/ml (for il-1β, il-1ra, il-10, il-12p40, and ifn-γ) or 5 x 106 cell/ml (for il-5 and il-12) in complete medium, and cultured in 24-well plates (1ml/ well). cells were stimulated with mouse anti-human cd3 (serotec, uk, mca 463xz; 10µg/ml), pha, sigma diagnostics; 10µg/ml), or lipopolysaccharide (lps, escherichia coli serotype 055:b5, sigma diagnostics; 200ng/ml), in the presence or absence of 5 mm nac. cells were incubated for 24 hr at 37oc / 5% co2. supernatants were harvested and the cytokine content (except for il-1β) was measured using commercially available sandwich enzyme-linked immunosorbent assays (elisa) (r&d systems, usa), performed according to the manufacturer’s instructions. monocytes were isolated by an adherence method as previously described.9 the plastic-adherent cells were cultured for 24 hours in a complete medium containing 100 ng/ml lps in the presence or absence of 5 mm nac. a sandwich elisa was developed in our laboratory using a method previously described.10 elisa was performed to determine the production of il-1β in the supernatant of the cell cultures (pbmc and isolated monocytes). the spss (statistical package for the social sciences) software programme was used for data analysis. as all the data were normally distributed, pair-wise group (nac-treated cells and un-treated cells) comparison was carried out using student’s t-test. p values of less than 0.05 were considered statistically significant. r e s u l t s incubation of pbmc with 5mm nac for 24 hours resulted in a two-fold increase in total gsh levels in all treated samples. the range of gsh concentration was 0.56 0.85 and 1.2 1.5nmol/106 cells before and after treatment with 5mm nac respectively. as shown in figure 1, nac induced significant secretion of il-1β after anti-cd3 and pha stimulaa h m e d a l -s h u k a i l i , s ua d a l a b r i , a l i a a l a n s a r i a n d m i c h e l e a m o n t e i l 72 4000 3500 3000 2500 2000 1500 1000 500 0 il -1 β p g /m l * * 60 50 40 30 20 10 0 il -1 2 p g /m l * 40 35 30 25 20 15 10 5 0 il -5 p g /m l * * 2500 2000 1500 1000 1500 1000 500 0 il -1 2p 40 p g /m l * * * 1000 800 700 600 500 400 300 200 100 0 il -1 2p 40 p g /m l anti cd 3 anti cd3+nac pha pha+nac lps lps+nac nac pbmc only * * if -1 γ p g /m l anti cd 3 anti cd3+nac pha pha+nac lps lps+nac nac pbmc only 0 5 0 0 10 0 0 15 0 0 20 0 0 25 0 0 30 0 0 35 0 0 40 0 0 45 0 0 * * il = interleukin; nac = n-acetyl-l-cysteine ; pha = phytohaemagglutinin; lps = lipopolysaccharide ; pbmc = peripheral blood mononuclear cells figure 1: n-acetyl-l-cysteine (nac) modulates cytokine production. anti-cd3/pha/lps-stimulated peripheral blood mononuclear cells (pbmc) were treated with 5 mm nac for 24 hr. results are expressed aspg/ml. data presents the mean value ± s.d. of at least six experiments for six different blood volunteers. * = significant p value <0.05. e f f e c t o f n a c e t y l l c y s t e i n e o n c y t o k i n e p r o d u c t i o n b y h u m a n p e r i p h e r a l b l o o d m o n o n u c l e a r c e l l s 73 tion (p <0.05), and statistically insignificant secretion after lps stimulation. incubation of plastic-adhered monocytes with nac in the presence of lps resulted in increased il-1β production. although this increase is not statistically significant, it was a consistent in all five experiments (p value = 0.061). low concentrations of il-5 were detected after stimulation of pbmc with anti-cd3 (mean value of 15pg/ml), pha, (12pg/ml) and lps (5pg/ml) when compared to other cytokines. in the presence of nac, significant il-5 secretion was further increased after anti-cd3 or pha (but not with lps) stimulation, this achieved statistical significant (p <0.05) [figure 1]. nac had an inhibitory effect on il-10 secretion by pbmc. in the presence of nac, a significant decrease (p <0.05) in il-10 production was observed after anticd3, and pha stimulation, but not after lps stimulation. il-10 production, following lps stimulation in the absence or presence of nac, was twice the concentration achieved after anti-cd3 or pha stimulation [figure 1]. the levels of il-12 obtained after all three stimulants were low, similar to those of il-5. however, stimulation with anti-cd3 or pha induced better il-12 secretion than with lps. the addition of nac caused a significant increase in il-12 production after anticd3 (p <0.05); a slight increase was observed after pha stimulation, but this was not significant. there was no significant change in il-12 levels after lps stimulation [figure 1]. unlike total il-12, stimulation of pbmc with anticd3, pha, or lps induced substantial amounts of il12p40. the presence of nac with all three stimulants elicited higher levels (p <0.05) of il-12p40. this was highest after anti-cd3 stimulation [figure 1]. stimulation of pbmc with anti-cd3 or pha (but not lps), induced high levels of ifn-γ, compared to un-stimulated cells. lps (100 ng/ml) failed to induce a significant amount of ifn-γ. as shown in figure 1, exposure of pbmc to nac elicited a significant upregulation (p <0.05) of ifn-γ after anti-cd3 or pha stimulation and a slight increase after lps stimulation. d i s c u s s i o n nac significantly up-regulated ifn-γ, il-1β, il-5, il12, and il-12p40, and significantly down-regulated il10 production by pbmc after cellular stimulation. a number of studies investigated the effect of both nac on cytokine production by several cell types including alveolar epithelial cells,4 alveolar macrophages,11 and pbmc.3 some of our results (increase in il-1β and decrease in il-10 production) are in partial agreement with a study carried out viora et al. which demonstrated a significant up-regulation of il-1β, il-2, il-12 and il-15 production and an insignificant increase in il-10 and ifn-γ by pha-stimulated pbmc in presence of nac.3 this discrepancy in the production of il-10, may be related to the genetic variation among individuals, hence, immense differences in response to various stimulations and cytokine production was observed. t cells and monocytes are major sources of inflammatory mediators and can communicate with each other as well as with other cells12 this communication is mediated by soluble factors and by direct cell-cell contact.12 as traditionally known, potent cytokine polypeptides have pleiotropic activities and functional redundancy, acting in a complex intermingled network where one cytokine can influence the production of, and response to, many other cytokines.13 for example, th1 cells release ifn-γ, and to a lesser extent il-2 and il-12, promoting a proinflammatory response. th2 cells secrete il-4, and sometimes il-5, il-6, il-10 and il-13, and enhance anti-inflammatory responses.14 therefore, we were not able to prove that the decrease in il-10 or the increase of other inflammatory cytokines in our study is due to the direct effect of nac. moreover, our data showed that an increase in il1β production after anti-cd3 activation, is most likely due to the effect of t lymphocytes activation in this system. the effects of nac on cytokine production are still controversial. on the one hand, several studies (including this study), showed that, nac up-regulated proinflammatory cytokines.3 on the other hand, some studies reported that nac down regulated pro-inflammatory cytokines such il-6, tnf-α il-1β, and il8.7,15,16 in addition, stanislaus et al. reported that nac treatment blocked induction of tnf-α, il-1β, and ifn-γ.17 from the above discussion, it appears that, the effect of nac on cytokine production depends on cell types. c o n c l u s i o n nac up-regulates the production of pro-inflammatory cytokines and down regulates anti-inflammatory a h m e d a l -s h u k a i l i , s ua d a l a b r i , a l i a a l a n s a r i a n d m i c h e l e a m o n t e i l 74 cytokines by pbmc, in a process associated with increased levels of gsh. also this study indicated a side effect of nac when used as an anti-inflammatory drug. further studies are required to confirm whether this increase or decrease in cytokine production is due to a direct effect of nac. a c k n ow l e d g m e n t s we gratefully thank the medical research and ethics committee (mrec), college of medicine and health sciences, sultan qaboos university, for financially supporting this research. we appreciatively thank dr. abdullah al-maniri and dr. shyam s ganguly for their help in statistical analysis. c o n fl i c t o f i n t e r e st : none declared s o u r c e o f f u n d i n g : college of medicine and health sciences, sultan qaboos university, grant no. r e f e r e n c e s 1. zafarullah m, li wq, sylvester j, ahmad m. molecular mechanisms of n-acetylcysteine actions. cell mol life sci 2003; 60:6-20. 2. kelly gs. clinical applications of n-acetylcysteine. altern med rev 1998; 3:114-27. 3. viora m, quaranta m, straface e, vari r, masella r, malorni w. redox imbalance and immune functions: opposite effect of oxidized low-density lipoproteins and n-acetylcysteine. immunol 2001; 104:431-8. 4. dobashi k, aihara m, araki t, shimizu y, utsugi m, iizuka k, et al. regulation of lps induced il-12 production by ifn-γ and il-4 through intracellular glutathione status in human macrophages. clin exp immunol 2001; 124:290-6. 5. utsugi m, dobashi k, koga y, shimizu y, iizuka k, hamura j, et al. glutathione redox regulates lipopolysaccharide-induced il-12 production through p38 mitogen-activated protein kinase activation in human monocytes: role of glutathione redox in ifn-gamma priming of il-12 production. j leukoc biol 2002; 71:339-47. 6. gosset p, wallaert b, tonnel ab, fourneau c. thiol regulation of the production of tnf-alpha, il-6 and il8 by human alveolar macrophages. eur respir j 1999; 14:98-105. 7. haddad jj. the involvement of l-γ-glutamyl-l-cysteinylglycine (glutathione/gsh) in the mechanism of redox signalling mediating mapkp38-dependent regulation of pro-inflammatory cytokine production. biochem pharmacol 2002; 63:305-20. 8. griffith ow. determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. anal biochem 1980; 106:207-12. 9. sluyter r, shemon an, wiley js. glu496 to ala polymorphism in the p2x7 receptor impairs atp-induced il-1 beta release from human monocytes. j immunol 2004; 172:3399-405. 10. al-shukaili a, al-kaabi j, hassan b. a comparative study of interleukin-1beta production and p2x7 expression after atp stimulation by peripheral blood mononuclear cells isolated from rheumatoid arthritis patients and normal healthy controls. inflammation 2008; 31:8490. 11. coan c, hideg k, mehlhorn rj. protein sulfhdryls are protected from irreversible oxidation by conversion to mixed disulfides. arch biochem biophys 1992; 295:36978. 12. burger d, dayer jm. the role of human t-lymphocytemonocyte contact in inflammation and tissue destruction. arthritis res 2002; 4:s169-76. 13. haddad jj. cytokines and related receptor-mediated signaling pathways. biochem biophys res commun 2002; 297:700-13. 14. parris k. th1/th2 balance: the hypothesis. its limitations and implication for health and diseases. alt med rev 2003; 8:223-46. 15. peristeris p, clark bd, gatti s, faggioni r, mantovani a, mengozzi m, et al. n-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. cell immunol 1992; 140:390-9. 16. kim do y, jun jh, lee hl, woo km, ryoo hm, kim gs, et al. n-acetylcysteine prevents lps-induced proinflammatory cytokines and mmp2 production in gingival fibroblasts. arch pharm res 2007; 30:1283-92. 17. stanislaus r, gilg ag, singh ak, singh i. n-acetyl-lcysteine ameliorates the inflammatory disease process in experimental autoimmune encephalomyelitis in lewis rats. j autoimmune dis 2005; 2:4-15. august 2007 vol 7 copy.indd the endocrine system at glance authors: ben greenstein, diana f wood reviewer: *ali al-mamari sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 169-170 sultan qaboos university© submitted 30th april 2007 b a c k g r o u n d t o t h e b o o k this is the second edition of the book, which is one of a series of concise introductions to a subject intended mainly for undergraduate medical students. endocrinology refers to the study of endocrine glands. this book gives details on many aspects of endocrinology and advances that have occurred both in basic sciences and on clinical levels. for example, a major area of advance has resulted from the application of molecular biology to hormone synthesis and action and, in the foreseeable future, to aspects of treatment. o v e r v i e w o f c o n t e n t this book has 120 pages. it consists of preface, glossary and index with 11 parts divided into 54 sections as follows: part 1 fundamentals: basic endocrinology; illustrations of endocrine hormone secretion; chemical transmission; mechanisms of action; types of receptors and overall control of the hypothalamus and pituitary with explanation of feedback control. part 2 growth: cellular growth factors, normal growth facts and a short review of growth hormone pathophysiology as well as its clinical implications. part 3 thyroid: thyroid physiology, clinical presentations of thyroid diseases and methods of diagnosis. part 4 adrenal system: different hormones secreted by adrenals with features of associated clinical syndromes, in addition to a brief explanation of endocrine autoimmunity. parts 5, 6 & 7 sexual differentiation and development: illustrated information on this topic and the genetic background. the gonadal sex effects and the development of secondary sexual characteristics are covered with a short review of some of syndromes. emphasis is given to female reproduction and different aspects of menstrual irregularities. in addition, two sections discuss male reproduction, androgen secretions and spermatogenesis. part 8 posterior pituitary hormones: with a demonstration of the relationship between endocrinology and hypertension and the importance of the rennin-angiotensin-aldosterone system. part 9 pancreas and gastrointestinal system: its efb o o k r e v i e w الهورموني على اجلهاز حملة فورد ديانا جرينشتاين، تأليف: بن املعمري مراجعة: علي blackwell publishing ltd. second edition. first published in 2006. price £13 sterling isbn: 13: 978-1-4051-0930-7 available from: www.blackwellpublishing.com *department of medicine, college of medicine & health sciences, sultan qaboos university, al-khod -35, muscat, sultanate of oman r i c h a r d i g h o lt a n d n e i l a h a n l e y 170 fect on homeostasis and the development of the metabolic syndromes of diabetes with a short demonstration of its presentation, complications and treatment. part 10 energy homeostasis: as well as the discussion of different presentations of obesity, insulin resistance and complications. part 11 calcium metabolism and bone disease: pathophysiolgy of parathyroid hormone excess, the role of vitamin d and different presentations of bone diseases are discussed in the last section of this book. t h e r e a d e r s h i p m o s t s u i t e d f o r t h i s b o o k i recommend this book for undergraduate medical students. however, it would also be an additional source of medical information for junior doctors during their rotations in medicine and endocrinology. i suspect it might also prove valuable for many senior physicians as well. a p p r o p r i a t e n e s s o f t h e c o n t e n t t o t a r g e t r e a d e r s h i p the contents of this book are presented in an attractive, illustrative way that merges pathophysiology with clinical scenarios. this seems appropriate for individuals dealing with endocrionolgy as an understanding of normal physiology is important in order to interpret results and then proceed to good patient management. c o m p r e h e n s i v e n e s s o f t h e c o n t e n t this book fulfils its remit as it gives a concise, short and complete overview of clinical endocrinology. the clinical scenarios are usefully accompanied by appropriate diagrams, tables and photographs. they thus provide good material for readers to understand the sequence of events leading to different endocrinological problems. o r g a n i s a t i o n o f t h e c o n t e n t s each section of the book starts with an introduction, followed by a clinical scenario and then a demonstration of basic pathophysiology with attractive illustrations. the contents are presented in simple easy to follow format, giving readers the opportunity to come to grips with both physiology and clinical presentations. g e n e r a l c o m m e n t s q ua l i t y o f c o n te n t the authors of this book fulfil the objectives stated in their introduction, by presenting the data clearly and accurately. the information given is up-to-date and is presented in a simple and easy to understand manner. q ua l i t y o f i l lustr ati o n s this book contains very good illustrations and diagrams. they make it easy to understand and demonstrate, for example, the various steps in the actions of hormone mechanisms in different target tissues. c ompl e te n e s s o f c o n te n ts the authors mange to present concisely different aspects of the endocrine system. however, this book only gives an overview of the medical problems. it does not replace or substitute the information in text books on endocrinology. s u g g e s t i o n s the authors present data in a good, readable style with explanatory materials. however, the following suggestions are made: 1. the cover could be more attractive than its present darkish olive green format. 2. treatment plans should have been given more attention so as to complete the picture for the readers. july 2008.indd abstract this report presents the results of treatment of two adults, at the pain center of montreal general hospital, canada, with intravenous lidocaine for intractable orofacial pain. repeated lidocaine infusions (mg/kg in a bolus, followed by 4mg/kg infused over  hour) resulted in satisfactory pain relief in both patients, and the drug was well tolerated. intravenous lidocaine therapy may be considered for intractable orofacial pain; further research is warranted. keywords: facial pain; lidocaine; therapeutics; humans; review; literature; case reports; canada intravenous lidocaine for refractory chronic orofacial pain two case reports and a literature review abdulaziz almahrezi,1 louise lamb,2 mark a ware,2 yoram shir,2 *ibrahim al-zakwani3 1department of family medicine and public health, college of medicine & health sciences, sultan qaboos university, muscat, oman; 2mcgill university health centre, pain centre, montreal general hospital, montreal, quebec, canada; 3department of pharmacy, sultan qaboos university hospital, muscat, oman *to whom correspondence should be addressed. email: ial_zakwani@yahoo.com واملستعصي املزمن يّ هِ جْ الوَ ي وِ مَ الفَ األلم لعالج الوريدي الليدوكني لألدبيات ومراجعة حالتني تقرير الزكواني إبراهيم شير، يورام وير، مارك.أ. المب، لويز احملرزي، العزيز عبد عالج مركز في الليدوكني الوريدي حقن طريق عن مستعصية آالم فموية وجهية من يعانيان بالغني مريضني عالج نتائج التقرير امللخص: يستعرض على كحقنة جرام كيلو لكل 4 مليجرام ثم واحدة كدفعة جرام كيلو لكل (1 مليجرام املتكررة الليدوكني حقن مونتريال العام. مستشفى األلم في مفيدا يكون رمبا الوريدي الليدوكني جانبية. آثار أي من منهما أي ولم يعاني ، املريضني لكال مقبولة بدرجة إلى تخفيف األلم أدت واحدة) ساعة مدار هذا اال. في من البحوث ملزيد حاجة هناك املستعصية. الوجهية الفموية اآلالم عالج في ، كندا. حالة تقرير ، أدبيات ، مراجعة ، البشر ، العالج ، الليدوكني ، الكلمات: آالم الوجه مفتاح sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 205-209 sultan qaboos university© submitted 23rd february 2008 accepted 4th may 2008 chronic orofacial pain includes a group of disorders with diverse etiologies affecting approximately 10 % of the adult population and 50 % of the elderly1 of whom at least 50% seek medical treatment.2 diagnosis is difficult due to lack of a clear diagnostic classification3 and routine treatment modalities are often not effective.4 surgery may be considered in selected cases; however, current international guidelines recommend multi-modal approaches for the management of orofacial pain. these include pharmacological, nerve blocks, physiotherapy and psychological therapies. 5, 6 intravenous lidocaine has been used in a variety of neuropathic pain syndromes such as diabetic neuropathy7 and post herpetic neuralgia.8 to date, few published reports exist on the therapeutic role for intravenous lidocaine in chronic orofacial pain.9 here we describe two patients, who presented at the pain center, montreal general hospital, canada with features of a mixed nociceptive-neuropathic pain syndrome, but with a primarily nociceptive etiology. they both experienced long-term pain relief after repeated lidocaine infusions. c a s e 1 this 46-year old female presented with a long history of pain in the area of both temporomandibular joints (tmj). the pain was constant and sharp in nature and woke the patient up to 2-3 times per night. the average pain was 8 out of 10 on a visual analogue scale (vas), a measure of pain intensity expressed on a zero to ten score. in addition, the patient described severe c a s e r e p o r t a b d u l a z i z a l m a h r e z i , l o u i s e l a m b , m a r k a wa r e , yo r a m s h i r , a n d i b r a h i m a l z a k wa n i 206 attacks of intermittent ‘pulling-like’ pain, lasting for 30 to 60 minutes. the pain was provoked by chewing solid foods and exposure to humid weather. mild pain relief was obtained with local ice packs and rest. she had undertaken five surgical procedures on both tmjs, including a prosthesis on the right and an osteotomy on the left. apart from a small area of dysaesthesia in the distribution of the mandibular division of the right trigeminal nerve, the rest of the neurological examination yielded no pathologies. in particular, the patient had no evidence of facial muscles atrophy, weakness or allodynia. however, tenderness bilaterally over the tmjs was noted. the patient was diagnosed with a mixed nociceptive-neuropathic pain syndrome and she was treated with the following medications sequentially: amitriptyline, 25mg/day, gabapentin, up to 900mg/day and sustained release oxycodone up to 20mg/day. trials with each of these medications had to be abandoned prematurely due intolerable side effects experienced by the patient despite a very slow and careful titration. in view of the patient’s poor tolerance, further trials with other oral medications were not initiated. nerve blocks were not offered. furthermore, a trial of physiotherapy which included transcutaneous electrical nerve stimulation (tens) did not yield any significant result. as an alternative, the patient was given a trial of intravenous lidocaine, using 1 mg/kg in a bolus followed by an infusion of 4 mg/kg over 1 hour. response to treatment was recorded using both the vas and the neuropathic pain scale (nps)10: pre-infusion and at 1 hour, 4 days and 14 days post-infusion. during the infusion, and for 14 days thereafter, the patient’s pain decreased by more than 70% [figure 1]. she reported no pain while chewing, and was able to have a solid meal for the first time in years. the patient received four lidocaine infusions during a period of four months with ongoing pain relief. since beginning lidocaine treatment the patient has not been taking any other pain medications. c a s e 2 this 51 year old female presented with chronic pain over the right mandible. the patient had a history of a benign right mandibular cyst for which she had mandibular condyle and disc removal with graft reconstruction. the pain was refractory to botulinum toxin figure 1: (patient 1) pain intensity scores recorded over two weeks following the first intravenous lidocaine infusion (0-no pain; 10-the most intense pain sensation imaginable). i n t r av e n o u s l i d o c a i n e f o r r e f r a c t o r y c h r o n i c o r o fa c i a l pa i n 207 injections, sympathetic ganglion blocks, and various oral medications including opioids and anti-convulsants. the patient underwent replacement of the right tmj; however, despite significant improvement in function, the pain persisted. the pain was described as constant, deep, with numbness and tingling at the painful area and was triggered by eating and speaking. on examination, she had difficulty opening her mouth and moving her chin from side to side. the patient had no facial weakness or asymmetry. tactile and cold hyperalgaesia was detected over the lower part of the right face. the remainder of the neurological assessment including cranial nerves, motor, sensory, and cerebellar examination was normal. at the time of referral, she was taking amitriptyline 75mg/day, gabapentin 1800mg/day, lorazepam 1.5mg/day, and ketorolac 10 mg as necessary. further titration of the doses of both amitrpityline and gabapentin had previously failed due to the development of intolerable side effects. her average vas daily pain score was 8 out of 10. the patient was diagnosed with a mixed nociceptive-neuropathic chronic post-surgical pain. a trial of low dose methadone had to be stopped due to an allergic reaction. the patient was given a trial of intravenous lidocaine, 1 mg/kg in a bolus followed by an infusion of 4 mg/kg over 1 hour. one hour after the treatment the patient experienced total pain relief [figure 1]. pain levels increased during the ensuing two weeks, but remained low compared to the pre-infusion period. the patient subsequently received nine infusions in eight months, with ongoing pain relief and improved function, and has decreased her pain medications by 20-30%. d i s c u s s i o n lidocaine, an amide local anesthetic and an anti-arrhythmic agent, possesses analgesic properties when given systemically particularly in chronic neuropathic pain conditions,7, 8, 11, 12 cancer pain,13 fibromyalgia,14 and chronic daily headaches.15 findings from experimental models of neuropathic pain suggest that lidocaine acts by suppression of abnormal ectopic discharges which are generated by damaged primary afferents or dorsal root ganglion neurons.16 intravenous lidocaine was also shown to produce suppression of mechanical allodynia17, 18 and hyperalgaesia.16 the postulated mechanism of action was thought to be peripheral in origin; however, this view was later challenged with several lines of evidence suggesting that lidocaine may also have central effects. some of these observations include: suppression of polysynaptic c-fibre evoked flexor responses without evidence of conduction block at the periphery;19 suppression of the activity of dorsal horn neurons evoked by ionophoretically administered glutamate;20 and selective inhibition of a nociceptive response in the isolated rat spinal cord.21 clinical studies23, 24 and human experimental models25, 26 have reached similar conclusions as to the action of intravenous lidocaine on mechanical allodynia and hyperalgaesia. in one study on healthy volunteers using the heat/capsaicin sensitisation model, intravenous lidocaine (5 mg/kg) was shown to have a selective effect on secondary hyperalgaesia.25 several well-designed studies have documented the effectiveness of intravenous lidocaine. a randomised double-blind cross-over study showed that intravenous lidocaine (5mg/kg over 30 minutes), but not saline, reduced symptoms of pain, dysaesthesia, paraesthesia and nightly pain exacerbation as well as sleep disturbance in patients with chronic painful diabetic neuropathy for a period of 3-21 days.7 according to vas, 11 out of 15 patients had a significant reduction (a reduction of greater than 15 millimetres on the vas) in pain for a period of 3 days and no reported side effects.7 another similarly designed study investigated the effect of two different doses (1 mg/kg and 5 mg/kg over 2 hours) of intravenous lidocaine on 24 patients of postherpetic neuralgia.11 the investigators reported a significant reduction in vas for evoked pain and a decline in the area of allodynia for up to 120 minutes following treatment with intravenous lidocaine.11 circumoral paraesthesia was the only side effect reported by patients who received the higher dose.11 in a similar study investigating the effects of intravenous lidocaine (5 mg/kg over 30 minutes) on neuropathic central pain, a significant reduction (vas score decreased by 50% or more) in spontaneous pain was reported.12 this response was achieved by 10 out of 16 patients.12 the period of observation in this study was for 45 minutes after the infusion. investigators, using quantitative sensory testing, also reported a reduction in the intensity of mechanical allodynia and hyperalgaesia.12 side effects were reported as moderate and consisted mainly of lightheadedness, somnolence, nausea and dysarthia.12 sorenson et al studied a b d u l a z i z a l m a h r e z i , l o u i s e l a m b , m a r k a wa r e , yo r a m s h i r , a n d i b r a h i m a l z a k wa n i 208 11 fibromyalgia patients who were randomised to lidocaine (5 mg/kg over 30 minutes) and saline in a double-blind and crossed-over design trial.14 four patients were reported as responders (a reduction of 16 millimetres or greater on the vas). 14 three of the responders had a reduction in pain for 4-7 days. side effects were mild and included nausea, perioral numbness, drowsiness, dysarthia and tremor.14 in another study of postamputation pain, intravenous lidocaine (1 mg/kg bolus + 4 mg/kg over 40 minutes), but not the placebo (diphenhydramine) decreased stump pain until 30 minutes after the infusion.26 no side effects were reported. both of our patients had reported nausea and lightheadedness during the period of the infusion. this is consistent with previously mentioned studies which documented only mild and transient adverse effects; however, serious side effects such as arrhythmias and pulmonary edema can occur with high doses.27 close monitoring of the patient while receiving the infusion is therefore recommended. this is usually performed by means of a continuous electrocardiogram (ecg) and a regular check-up of blood pressure and heart rate. besides side effects, other problems associated with the use of intravenous lidocaine include: invasiveness and the inconvenience of the intravenous route. possible alternatives to intravenous lidocaine are transdermal lidocaine and oral congeners such as mexilitine. a lidocaine patch has been shown to be effective in a randomised controlled trial in postherpetic neuralgia;28 however, patients may find it inconvenient to apply a patch on the face. furthermore, it is not known if a good response to intravenous lidocaine would predict a similar response to transdermal lidocaine since the concentration of plasma lidocaine would be much lower with local administration. mexilitine has been suggested as an alternative particularly in patients who respond negatively to intravenous lidocaine;29 however, the use of this drug is associated with frequent side effects which limit its usefulness.23 in randomised controlled trials of chronic pain, the doses of intravenous lidocaine used ranged between 1 to 5 mg/kg. however, we elected to use a total dose of 5 mg/kg since this dose seems to be the best documented effective dose according to a systematic review of these trials.30 the significance of our case reports is twofold: first, they provide the first evidence of the usefulness of intravenous lidocaine as a therapeutic option in the management of chronic orofacial pain. second, these reports raise the likelihood that intravenous lidocaine is not only effective in pure neuropathic pain syndromes, as the current literature suggests, but may also be effective in mixed nociceptive and neuropathic pain conditions that are primarily nociceptive in origin. the observations that lidocaine is effective in non-neuropathic pain conditions such as burns31 and fibromyalgia,14 together with the variable effect of lidocaine in peripheral or central neuropathic pain conditions32 and its effect beyond the pharmacological half-life, are all supportive of this latter conclusion. c o n c l u s i o n in summary, based on this experience, intravenous lidocaine was a powerful and successful treatment option after several insufficient therapeutic attempts that included oral pharmacotherapy, nerve blocks and surgery. a trial of intravenous lidocaine should be considered much earlier, even if a multimodal management approach is used. moreover, intravenous lidocaine should also be tried in pain syndromes of nociceptive origin rather than reserving it only for patients with pure neuropathic pain conditions. however, further research is needed to determine the exact role of intravenous lidocaine in the treatment of orofacial pain. r e f e r e n c e s 1. shinal rm, fillingim rb. overview of orofacial pain: epidemiology and gender differences in orofacial pain. dent clin north am 2007; 51:1-18. 2. riley jl 3rd, gilbert gh, heft mw. health care utilization by older adults in response to painful orofacial symptoms. pain 1999; 81:67-75. 3. sarlani e, balciunas ba, grace eg. orofacial pain part i: assessment and management of musculoskeletal and neuropathic causes. aacn clin issues 2005; 16:333346. 4. wirz s, wartenberg hc, nadstawek j. pain management procedures used by dental and maxillofacial surgeons: an investigation with special regard to odontalgia. head face med 2005; 1:14. 5. türp jc, hugger a, nilges p, hugger s, siegert j, busche e et al. recommendations for the standardized evaluation and classification of painful temporomandibular disorders: an update. schmerz 2006; 20:481-489. 6. okeson jp. orofacial pain: guidelines for assessment, diagnosis, and management. 4th ed. chicago: quintessence publishing, 1996. 7. kastrup j, angelo h, petersen p, dejgard a, hilsted j. i n t r av e n o u s l i d o c a i n e f o r r e f r a c t o r y c h r o n i c o r o fa c i a l pa i n 209 treatment of chronic painful diabetic neuropathy with intravenous lidocaine infusion. br med j 1986; 292:173. 8. rowbotham mc, reisner-keller la, fields hl. both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. neurology 1991; 41:1024-1028. 9. scrivani sj, chaudry a, maciewicz rj, keith da. chronic neurogenic facial pain: lack of response to intravenous phentolamine. j orofac pain 1999; 13:89-96. 10. galer bs, jensen mp. development and preliminary validation of a pain measure specific to neuropathic pain: the neuropathic pain scale. neurology 1997; 48:332338. 11. baranowski, ap, de courcey j, bonello e. a trial of intravenous lidocaine on the pain and allodynia of postherpetic neuralgia. j pain symptom manage 1999; 17:429-433. 12. attal n, gaude v, brasseur l, dupuy m, guirimand f, parker f. intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. neurology 2000; 54:564-74. 13. brose wg, cousins mj. subcutaneous lidocaine for treatment of neuropathic cancer pain. pain 1991; 45:145-148. 14. sorensen j, bengtsson a, ahlner j, henriksson kg, ekselius l, bengtsson m. fibromyalgia are there different mechanisms in the processing of pain? a double blind crossover comparison of analgesic drugs. j rheumatol 1997; 24:1615-1621. 15. hand pj, stark rj. intravenous lignocaine infusions for severe chronic daily headache. med j aust 2000; 172:157-159. 16. abram se, yaksh tl. systemic lidocaine blocks nerve injury-induced hyperalgesia and nociceptor-driven spinal sensitization in the rat. anesthesiology 1994; 80:383-391. 17. abdi s, lee dh, chung jm. the anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. anesth analg 1998; 87:1360-1366. 18. chaplan sr, bach fw, shafer sl, yaksh tl. prolonged alleviation of tactile allodynia by intravenous lidocaine in neuropathic rats. anesthesiology 1995; 83:775-785. 19. woolf cj, wiesenfeld-hallin z. the systemic administration of local anaesthetics produces a selective depression of c-afferent fibre evoked activity in the spinal cord. pain 1985; 23:361-374. 20. biella g, sotgiu ml. central effects of systemic lidocaine mediated by glycine spinal receptors: an iontophoretic study in the rat spinal cord. brain res 1993; 603:201-206. 21. jaffe ra, rowe ma. subanesthetic concentrations of lidocaine selectively inhibit a nociceptive response in the isolated rat spinal cord. pain 1995; 60:167-174. 22. wallace ms, dyck jb, rossi ss, yaksh tl. computercontrolled lidocaine infusion for the evaluation of neuropathic pain after peripheral nerve injury. pain 1996; 66:69-77. 23. attal n, rouaud j, brasseur l, chauvin m, bouhassira d. systemic lidocaine in pain due to peripheral nerve injury and predictors of response. neurology 2004; 62:218-225. 24. wallace ms, laitin s, licht d, yaksh tl. concentration-effect relations for intravenous lidocaine infusions in human volunteers: effects on acute sensory thresholds and capsaicin-evoked hyperpathia. anesthesiology 1997; 86:1262-1272. 25. dirks j, fabricius p, petersen kl, rowbotham mc, dahl jb. the effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. anesth analg 2000; 91:967-972. 26. wu cl, tella p, staats ps, vaslav r, kazim da, wesselmann u et al. analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial. anesthesiology 2002; 96:841-8. 27. raphael jh, southall jl, treharne gj, kitas gd. efficacy and adverse effects of intravenous lignocaine therapy in fibromyalgia syndrome. bmc musculoskelet disord 2002; 3:21. 28. galer bs, rowbotham mc, perander j, friedman e. topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. pain 1999; 80:533-538. 29. galer bs, harle j, rowbotham mc. response to intravenous lidocaine infusion predicts subsequent response to oral mexiletine: a prospective study. j pain symptom manage 1996; 12:161-167. 30. kalso e, tramer mr, mcquay hj, moore ra. systemic local-anaesthetic-type drugs in chronic pain: a systematic review. eur j pain 1998; 2:3-14. 31. jonsson a, cassuto j, hanson b. inhibition of burn pain by intravenous lignocaine infusion. lancet 1991; 338:151-152. 32. galer bs, miller kv and rowbotham mc. response to intravenous lidocaine infusion differs based on clinical diagnosis and site of nervous system injury. neurology 1993; 43:1233-1235. hp submitted 21 apr 22 1 revisions req. 18 jul & 9 aug 22; revisions recd. 25 jul & 28 aug 22 2 accepted 20 sep 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.062 5 6 hematological and inflammatory biomarkers among stable copd and 7 acute exacerbations of copd patients 8 ramya priya a, *madhusmita m. mohapatra, vinod k. saka, rakhee 9 kar, sunitha v. chakkalakkoombil, mahesh b. vemuri 10 11 department of pulmonary medicine, jawaharlal institute of postgraduate medical education 12 and research, puducherry, india. 13 *corresponding author’s e-mail: drmadhusmita1@gmail.com 14 15 abstract 16 objectives: chronic obstructive pulmonary disease (copd) is heterogeneous in nature. 17 acute exacerbation of copd (aecopd) is diagnosed clinically which is subjective and 18 clinical judgment may vary from clinician to clinician. since chronic inflammation underlies 19 the pathogenesis of copd, markers of inflammation have generated lot of interest for their 20 potential to be used as biomarkers of copd. this study aimed to assess the variation in 21 levels of neutrophil lymphocyte ratio (nlr) and platelet indices in patients with stable 22 copd and acute exacerbation of copd patients and its association with gold stages. 23 methods: this prospective analytical study was carried out in our tertiary care hospital from 24 december 2018 to july 2020. about 64 subjects (32stable copd, 32aecopd) who 25 satisfied study criteria were included. blood sample was taken from stable and aecopd 26 patients and were compared. results: it was observed that neutrophil lymphocyte ratio, 27 platelet distribution width, erythrocyte sedimentation rate and c-reactive protein were 28 increased in aecopd patients when compared with stable copd patients which was 29 statistically significant with p value of <0.001. a positive correlation was observed between 30 neutrophil lymphocyte ratio, platelet distribution width and erythrocyte sedimentation 31 rate, c-reactive protein which was statistically significant with p value of <0.001. 32 conclusion: we found that neutrophil lymphocyte ratio and platelet distribution width values 33 increased significantly in aecopd patients when compared to stable copd patients. 34 keywords: aecopd; copd; neutrophil lymphocyte ratio; platelet distribution width. 35 36 advances in knowledge 37  this study was done to assess levels of neutrophil lymphocyte ratio, platelet indices 38 and inflammatory biomarkers among stable chronic obstructive pulmonary disease 39 (copd) patients and patients with acute exacerbation of chronic obstructive 40 pulmonary disease. 41  since chronic inflammation underlies the pathogenesis of copd, markers of 42 inflammation have generated lot of interest for their potential to be used as 43 biomarkers of copd. there are few studies done in india to study the role of these 44 biomarkers in copd patients. 45 46 application to patient care 47  the stable copd patients have low graded inflammation with increased 48 inflammatory protein levels and inflammatory cells. whereas in exacerbation, 49 systemic inflammation worsens and higher levels of inflammatory proteins and cells 50 and mediators have been demonstrated. 51  heightened inflammatory response is noted well before the clinical symptoms of 52 acute exacerbation period. 53  even though acute exacerbation of copd is a clinical diagnosis according to the 54 definitions provided in the literature, during routine follow up of copd patients, 55 when elevated nlr is detected, it aids in early detection of acute exacerbation and 56 appropriate intervention. 57 58 introduction 59 chronic obstructive pulmonary disease (copd) is one of the top three leading cause of 60 death worldwide. in 2012, about 3 million people died due to copd accounting to 6% death 61 all over the world. burden of copd is likely to rise in the coming years because of increased 62 prevalence of smoking and smokeless tobacco use, aging, environmental pollution and other 63 risk factors. copd is characterised by persistent respiratory symptoms and airflow limitation 64 that results secondary to airway and/or alveolar abnormalities caused mostly by significant 65 exposure to noxious particles or gases and can be influenced by host factors which include 66 abnormal lung development.1 67 68 from 1990 to 2016, prevalence of copd has increased by 29%. in 2016, out of the total 69 deaths, 8.7% of deaths was attributed to copd.2 it is a preventable and treatable disease with 70 considerable systemic and extra pulmonary effects. frequent exacerbations of copd not only 71 have serious impact on the severity and course of disease but also on the quality of life.3 72 therefore, strategy for prevention, early diagnosis and treatment of copd exacerbations is 73 essential to better address the disease. 74 75 since chronic inflammation underlies the pathogenesis of copd, markers of inflammation 76 have generated lot of interest for their potential to be used as biomarkers of copd. there are 77 few studies done in india to study the role of these biomarkers in copd patients.more 78 studies are needed to confirm their association with copd. it will help in assessing 79 individualized risk stratification, disease severity and better management of copd.4 under 80 this perspective, the study aimed to assess levels of neutrophil lymphocyte ratio, platelet 81 indices and inflammatory biomarkers among stable copd and acute exacerbation of chronic 82 obstructive pulmonary disease (aecopd) patients and association of haematological 83 markers with gold staging. 84 85 methods 86 this cross-sectional comparative study was conducted in department of pulmonary medicine 87 of a tertiary care centre for a period of 18 months from december 2018 to july 2020.patients 88 aged ≥ 18 years with clinical and spirometry based diagnosis of copd were recruited. stable 89 copd patients with or without inhaled medications and not on systemic steroid during the 90 last 3 months were recruited. aecopd patients having aggravation of symptoms reported to 91 emergency were also recruited. patients who were diagnosed and proven cases of asthma, 92 pneumonia, sepsis, pulmonary embolism and with obstructive sleep apnoea were excluded 93 from the study. patients with autoimmune diseases, haematological malignancies and solid 94 tumours were also excluded as they were potential confounders. demographic and clinical 95 details of the patients were noted in prerequisite data collection proforma. history of smoking 96 and biomass fuel exposure was obtained in a face-to-face interview. patients with smoking 97 history were categorized as never smoker/current smoker/ex-smokers. details of years of 98 biomass fuel exposure and details of the co-morbidities were also noted. patients underwent 99 spirometry by jaeger master screen pft machine in spirometry laboratory placed in 100 pulmonary medicine department. patients were given 400mcg of salbutamol by metered dose 101 inhaler and spirometry was repeated to get post bronchodilator value. patients with post-102 bronchodilator fev1/fvc ratio < 0.7 was included in the study and who were suspected to 103 have aecopd underwent spirometry after stabilization following a period of six weeks if 104 possible and were included if their post bronchodilator fev1/fvc < 0.7. eligible copd 105 patients meeting the inclusion criteria were subjected to chest x-ray pa view and high 106 resolution computed tomography (hrct) thorax in full inspiration at a later date when stable 107 to rule out alternative diagnosis and emphysema extent with philips 6 slice ct placed in 108 the department of radio diagnosis. blood sample of 5ml was taken from stable copd patients 109 during their outpatient visit. patients who presented with aecopd, blood sample of 5 ml 110 was taken within 1 hour of hospital admission or before administration of any treatment 111 whichever was the earliest. these blood samples were divided into two separate vials. a vial 112 with 2ml of blood was sent in ethylene diamine tetra acetate (edta) vials to department of 113 pathology for neutrophil-lymphocyte ratio, platelet indices and erythrocyte sedimentation rate 114 (esr). the remaining 3 ml sample was taken in plain vials and serum was separated and kept 115 at -70°c. this centrifuged blood sample was used for estimating creactive protein (crp) 116 values by elisa. neutrophil lymphocyte ratio (nlr), platelet indices including mean 117 platelet volume (mpv), platelet distribution width (pdw), esr, crp in both stable and 118 aecopd patients were noted down. 119 120 data was collected and spread in excel sheet. statistical analysis was done using spss 121 version 19.4 due to not normal distribution, nlr, mpv, pdw, esr, crp values were 122 presented as median and inter-quartile range. continuous variables were expressed as mean 123 and standard deviation. the dependent variables (haematological parameters and 124 inflammatory biomarkers) were compared between stable copd and aecopd by two-tailed 125 t test. karl pearson correlation analysis was used to compare the correlation between nlr, 126 mpv, pdw (haematological parameters) with esr and crp (inflammatory biomarkers). 127 confounders were analysed using multivariate regression analysis. 128 129 in a study done by sharma et al, mean nlr levels in stable copd group was 4.263±1.900 130 and in aecopd group was 6.389±3.071.5 nlr measurement demonstrated a sensitivity and 131 specificity of 40%and 77.14%. assuming a mean difference of 2.1, sample size was 132 calculated assuming a power of 80% as 32 patients in each group amounting to a total of 64 133 patients. 134 135 results 136 a total of 106 patients were screened during the study period from december 2018 to july 137 2020. eighteen stable copd patients and 7 aecopd patients were excluded from the study 138 as they did not fulfill the inclusion criteria. there was no statistically significant difference in 139 the age groups among stable copd and aecopd patients with a p value of 0.119. there 140 was male gender predilection in both stable aecopd patients group. majority of patients 141 belonging to both stable copd and aecopd groups were agricultural labourers. majority of 142 patients with aecopd were obese while majority of stable copd had normal body mass 143 index. baseline characteristics like gender, occupation, smoking index and biomass fuel 144 exposure were analysed with multivariate analysis and were found to have no significant 145 impact on the outcome of copd with exacerbation status. 146 mean fev1 value for stable copd patients was 44 ± 14.61 and for aecopd patients was 147 37.37 ± 14.72. mean fev1/fvc value for stable copd patients was 51.38 ± 11.04 and for 148 aecopd patients was 51.35 ± 9.69. in our study, majority of stable copd patients belonged 149 to ≤ 55years of age with mean age of 58.02 ± 8.07 and majority of aecopd patients were of 150 ≥ 65 years age group with a mean age of 62.56 ± 10.03.in our study, median ± interquartile 151 range for nlr in stable copd patients was (2.14 ± 0.97) and in aecopd patients was (11.2 152 ± 9.42). median ± interquartile range for mpv in stable copd patients was (9.40 ± 1.05) and 153 in aecopd patients was (13.657 ± 2.35). median ± interquartile range for pdw in stable 154 copd patients was (8.60 ± 1.33) and in aecopd patients was (8.35 ± 0.85). 155 156 statistically significant difference was noted for nlr and platelet distribution width (p < 157 0.001) between stable copd patients and aecopd patients.. statistically significant 158 difference for esr and crp (p < 0.001) was found between stable copd patients and 159 aecopd. 160 161 area under receiver operating characteristic analysis obtained for nlr was 0.986 (98%) 162 with 95% confidence interval. it was noted that sensitivity and specificity of nlr for 163 predicting aecopd were 94%and 94% respectively for the cut-off value of 3.79. the pdw 164 had an auc of is 0.99 (99%) with 95% confidence interval and the sensitivity and specificity 165 was 93.8% and 93.7 % respectively for the cut-off value of 11.55. area under receiver 166 operating characteristic analysis obtained for crp was 0.988 (98%). it was noted that 167 sensitivity and specificity of crp were 97% and 97%, respectively, for the cut-off value of 168 14.15. 169 170 there was a positive correlation between nlr and erythrocyte sedimentation rate with 171 correlation coefficient value of 0.489 (p< 0.001) and a positive correlation with c-reactive 172 protein with correlation coefficient value of 0.721 (p < 0.001). a positive correlation between 173 pdw and erythrocyte sedimentation rate with correlation coefficient value of 0.518 (p< 174 0.001) and c reactive protein with correlation coefficient value of 0.754 (p < 0.001) was 175 observed. pearson correlation analysis and scatter plot showed negative correlation 176 which was not statistically significant between mpv and esr (r 0.146, p value of 177 0.251), between mpv and crp (r -0.181 , p value of 0.151 ).9 178 the haematological markers like nlr, mean platelet volume and platelet distribution width 179 did not show any statistically significant difference in all the gold stages of copd and 180 regression coefficient was not significant. 181 182 discussion 183 during acute exacerbation of copd, systemic inflammation worsens and higher levels of 184 inflammatory proteins, cells and mediators are secreted. these forms the basis for 185 development of neutrophil lymphocyte ratio as a marker to predict increased systemic 186 inflammation during the period of acute exacerbation.6 a total of 64 patients were recruited 187 of which 32 were stable copd patients and 32 were aecopd patients. socio demographic 188 data, haematological and inflammatory biomarkers between the stable copd patients and 189 aecopd patients were compared and analyzed. in our study, it was observed that mean 190 neutrophil lymphocyte ratio among stable copd patients was 2.32 ± 8.4 and among 191 aecopd patients was 11.22 ± 5.88 which was statistically significant(p<0.001). ercan 192 kurtipek et al. did a cross sectional study on 94 male patients over 40 years.7 they observed 193 that nlr among stable copd patients was 2.75 ± 1.11 and among aecopd patients was 194 7.99±5.72. they proposed that mean nlr levels were higher in aecopd patients when 195 compared to patients with stable copd patients and the observation was statistically 196 significant. their findings were similar to our results. from the systematic review, in 197 aecopd, nlr cut-off value of 3.34 with a median auc of 0.86 would help in diagnosis 198 with sensitivity of 80% and specificity of 86%.8 in our study, it was found that auc obtained 199 for nlr was 0.986 (98%) with 95% confidence interval. it was noted that sensitivity of nlr 200 was 94%and specificity of 94% for the cut-off value of 3.79. it means that value of nlr ≥ 201 3.79 has 94% chance of predicting exacerbation in copd patients. 202 203 pearson correlation analysis and scatter plot showed positive correlation between nlr and 204 esr (r 0.714, p < 0.000), between nlr and crp (r 0.609, p < 0.000).9 205 206 observed elevated levels of willebrand factor, d-dimer, and prothrombin fragment1, 2 207 which are surrogate markers for inflammation, endothelial damage and clotting activation 208 respectively from various studies led to the concept that copd exacerbation is associated 209 with systemic inflammation and is a prothrombotic state.10 in our study, it was observed that 210 mean platelet volume among stable copd patients was 8.50± 0.84 and among aecopd was 211 8.27 ± 0.56 which was not statistically significant (p0.189). dentener et al. in 2001 212 proposed the idea that increased production of proinflammatory cytokines and acute phase 213 reactants during aecopd interfere with megakaryopoiesis thereby reducing the size of 214 platelets in the bone marrow which is then released into the blood circulation.10 thus explains 215 the fall in mpv in aecopd when compared to stable copd patients. 216 217 pearson correlation analysis and scatter plot showed negative correlation which was not 218 statistically significant between mpv and esr (r 0.146, p value of 0.251), between mpv 219 and crp (r -0.181 , p value of 0.151).9 220 221 the most widely used application of pdw is to provide information on the viability of 222 platelets which is to be transfused.12 increase in pdw indicate that abnormally large and 223 small platelets are in circulation. steiropoulos et al. reported no significance difference in 224 pdw amongst different stages of copd.13 in our study, we observed that mean pdw was 225 9.48 ± 0.94 for stable copd patients and 13.67 ± 1.43 for aecopd patients. statistically 226 significant difference was observed for pdw (p < 0.001) between stable copd patients and 227 aecopd patients. 228 229 günay e et al. did retrospective study on 319 subjects with 269 copd patients (178 stable 230 copd patients, 91 aecopd patients) and 50 were age and sex matched control group.14 231 they assessed the levels of nlr, mpv, pdw, rdw, crp among three groups (control, 232 stable copd and copd with acute exacerbation patients). they also assessed the levels of 233 these parameters among gold stages of copd. they observed that pdw levels were 234 similar in all 3 groups. so, further correlation of levels of pdw with crp was not done.our 235 study observed lower pdw values in stable and aecopd patients. variability could be due 236 to the presence or absence of underlying co-morbid conditions which was not noted in the 237 study by günay e et al.14 in the meta-analysis by ma et al., levels of mpv were compared 238 pair wise among control group, stable copd group, aecopd group.15 also, correlations 239 between mpv level and levels of systemic inflammatory biomarkers such as high sensitivity 240 c-reactive protein (hs-crp), c-reactive protein (crp), white blood cells (wbc), neutrophils 241 were also compared. they concluded that levels of mpv cannot be used to discriminate 242 between patients with stable copd group, aecopd group, and control group. the study 243 could not find significant correlation between mpv levels and other inflammatory 244 biomarkers. the proposed hypothesis for this was mpv can be affected by multiple risk 245 factors like diabetes, hypertension, dyslipidemia, smoking.15 it was observed from our results 246 that mean value for mpv for stable copd patients was 8.50 ± 0.84 and for aecopd 247 patients was 8.27 ± 0.56. the difference of mpv value between stable copd patients and 248 aecopd patients was not statistically significant (p= 0.189). ulasli et al. did a study on 47 249 patients with copd and on 40 healthy subjects.16 in their study they observed that the mean 250 mpv levels for control, stable and acute exacerbation group was 9.3 ±0.8 fl, 9.3 ±1.4 and 8.6 251 ±1.0 fl. they suggested that mpv can be used as a negative acute phase reactant in 252 aecopd.16 our study is also in agreement that mpv falls during acute exacerbation. 253 254 it was observed that there was a positive correlation between pdw and esr with correlation 255 coefficient value of 0.518 (p<0.001). also, positive correlation was observed between pdw 256 and crp with correlation coefficient value of 0.721 (p < 0.001). it was observed from the 257 current study that there was a positive correlation between nlr and esr with correlation 258 coefficient value of 0.489 (p<0.001). also, positive correlation was observed between nlr 259 and esr with correlation coefficient value of 0.754 (p < 0.001). to our knowledge, 260 correlation between mpv levels and esr has not been studied previously. we found that 261 mean platelet volume has negative correlation between esr which was not statistically 262 significant (p value0.251) and also negative correlation was observed between mpv and 263 crp which was not statistically significant (p value0.151).wang et al. did study on 70 264 patients with aecopd with age, sex matched controls.17 they compared levels of mpv, 265 crp, wbc and fibrinogen between stable copd patients and in patients with aecopd. 266 they shared their observation that during acute exacerbation, levels of mpv were lower and 267 crp values were higher. thus, a statistically significant negative correlation was found 268 between mpv and crp during the acute event (p<0.001).17 though negative correlation 269 between mpv and crp was observed in our results, it was not statistically significant. 270 estimated sample size could not be attained due to pandemic and trends of haematological 271 parameters could not be analysed. 272 273 conclusion 274 in our study, we assessed the utility of parameters like neutrophil lymphocyte ratio and 275 platelet indices (mean platelet volume, platelet distribution width) in stable copd and 276 aecopd patients. we found that neutrophil lymphocyte ratio and platelet distribution width 277 values increased significantly in copd patients with acute exacerbation when compared to 278 stable copd patients. thus, these biomarkers which could be obtained from routine 279 hemogram can be used for predicting acute exacerbation in copd patients. 280 281 authors’ contribution 282 rpa, mmm, vks, rk and svc conceptualized and designed the study. all authors 283 collected the data. rpa, vks, rk, svc and mbv analysed and interpreted the data. mmm 284 drafted the manuscript. all authors approved the final version of the manuscript. 285 286 conflict of interest 287 the authors declare no conflicts of interest. 288 289 funding 290 no funding was received for this study. 291 292 references 293 1. 2021 gold reports [internet]. global initiative for chronic obstructive lung disease 294 gold. [cited 2022 feb 15]. available from: https://goldcopd.org/2021-gold-reports/ 295 2. salvi s, kumar ga, dhaliwal rs, paulson k, agrawal a, koul pa, et al. the burden of 296 chronic respiratory diseases and their heterogeneity across the states of india: the global 297 burden of disease study 1990–2016. lancet glob health. 2018 dec;6(12):e1363–74. 298 3. stockley ra, halpin dm, celli br, singh d. chronic obstructive pulmonary disease 299 biomarkers and their interpretation. american journal of respiratory and critical care 300 medicine. 2019 may 15;199(10):1195-204. 301 4. ibm spss statistics 19 documentation [internet]. 2014 [cited 2022 feb 15]. available 302 from: https://www.ibm.com/support/pages/ibm-spss-statistics-19-documentation 303 5. kailash sharma, gajendra singh, ummed singh. to compare neutrophil lymphocyte 304 ratio with other parameters in acute exacerbation of copd and stable copd: a 305 hospital based study. asian j med res. 2020 may 3;9(1):pm20–3. 306 6. taylan m, demir m, kaya h, selimoglu sen h, abakay o, carkanat ai̇, et al. 307 alterations of the neutrophil-lymphocyte ratio during the period of stable and acute 308 exacerbation of chronic obstructive pulmonary disease patients. clin respir j. 2017 309 may;11(3):311–7. 310 7. kurtipek e, bekci tt, kesli r, sami ss, terzi y. the role of neutrophil-lymphocyte 311 ratio and platelet-lymphocyte ratio in exacerbation of chronic obstructive pulmonary 312 disease. jpma j pak med assoc. 2015 dec;65(12):1283–7. 313 8. pascual-gonzález y, lópez-sánchez m, dorca j, santos s. defining the role of 314 neutrophil-to-lymphocyte ratio in copd: a systematic literature review. int j chron 315 obstruct pulmon dis. 2018 nov 5;13:3651–62. 316 9. yousef am, alkhiary w. role of neutrophil to lymphocyte ratio in prediction of acute 317 exacerbation of chronic obstructive pulmonary disease. egypt j chest dis tuberc. 2017 318 jan 1;66(1):43–8. 319 10. agapakis di, massa ev, hantzis i, maraslis s, alexiou e, imprialos kp, et al. the role 320 of mean platelet volume in chronic obstructive pulmonary disease exacerbation. 321 respir care. 2016 jan;61(1):44–9. 322 11. dentener ma, creutzberg ec, schols am, mantovani a, van’t veer c, buurman wa, 323 et al. systemic anti-inflammatory mediators in copd: increase in soluble interleukin 1 324 receptor ii during treatment of exacerbations. thorax. 2001 sep;56(9):721–6. 325 12. vagdatli e, gounari e, lazaridou e, katsibourlia e, tsikopoulou f, labrianou i. 326 platelet distribution width: a simple, practical and specific marker of activation of 327 coagulation. hippokratia. 2010;14(1):28–32. 328 13. steiropoulos p, papanas n, nena e, xanthoudaki m, goula t, froudarakis m, et al. 329 mean platelet volume and platelet distribution width in patients with chronic obstructive 330 pulmonary disease: the role of comorbidities. angiology. 2013 oct;64(7):535–9. 331 14. günay e, sarınç ulaşlı s, akar o, ahsen a, günay s, koyuncu t, et al. neutrophil-to-332 lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study. 333 inflammation. 2014 apr;37(2):374–80. 334 15. ma y, zong d, zhan z, li h, dai z, cui y, et al. feasibility of mean platelet volume as 335 a biomarker for chronic obstructive pulmonary disease: a systematic review and meta-336 analysis. j int med res. 2019 dec;47(12):5937–49. 337 16. ulasli ss, ozyurek ba, yilmaz eb, ulubay g. mean platelet volume as an 338 inflammatory marker in acute exacerbation of chronic obstructive pulmonary disease. 339 pol arch med wewn. 2012;122(6):284–90. 340 17. wang r, li j-y, cao z, li y. mean platelet volume is decreased during an acute 341 exacerbation of chronic obstructive pulmonary disease. respirol carlton vic. 2013 342 nov;18(8):1244–8. 343 344 table 1: demographic details. 345 variables categories stable copd patients n = 32 aecopd patients n= 32 p value age ≤ 55 years 14(43.8) 8(25) 0.119 56-65 years 12(37.5) 11(34.4) ≥65 years 6(18.8) 13(40.6) gender male 31(96.9) 23(71.9) 0.006 female 1(3.1) 9(28.1) occupation laborer 31(96.9) 22(68.8) 0.012 house wife 1(3.1) 9(28.1) coal mine worker 0 1(3.1) systemic hypertension 5(15.6) 1(3.1) diabetes mellitus& systemic hypertension 1(3.1) 1(3.1) thyroid disorder 1(3.1) 1(3.1) systemic 0 1(3.1) hypertension and thyroid disorder none 22(68.8) 25(78.1) bmi underweight (<18.5) 3(9.4) 3(9.4) 3.841 overweight (25-29.9) 4(12.5) 6(18.8) obese (≥ 30) 12(37.5) 17(53.1) normal (18.5-24.9) 13(40.6) 6(18.8) 346 table 2: distribution of haematological and inflammatory biomarkers among stable copd 347 patients and copd with acute exacerbation patients. 348 s.no haematological parameter stable copd patients (median ± iqr) aecopd patients (median± iqr) p value 1. mean neutrophil lymphocyte ratio (2.14 ± 0.97) (11.24 ± 9.42) <0.001 2. mean platelet volume (fl) (8.60 ± 1.33) (8.35 ± 0.85) 0.189 3. mean platelet distribution width (9.40 ± 1.05) (13.65 ± 2.35) <0.001 1. erythrocyte sedimentation rate(mm/hr) (27 ± 23.25) (54 ± 10.25) <0.001 2. c-reactive protein(mg/dl) (5.95 ± 4.58) (22.3 ± 5.3) <0.001 349 table 3: correlation of haematological parameters (neutrophil lymphocyte ratio, mean 350 platelet volume, platelet distribution width) with gold stages of copd. 351 haematologic al parameter gold stage(i) (n=1) gold stage (ii) (n=15) range mean±sd gold stage (iii) (n=29) range mean±sd gold stage (iv) (n=19) range mean±sd f value p value neutrophil lymphocyte ratio 5.70 1.32-12.19 3.60 ± 3.42 1.02-23.65 7.36 ± 6.40 1.47-20.73 8.43 ± 6.80 1.996 0.124 mean platelet volume 8.30 7.20-10.60 8.53 ± 0.91 7.40-9.60 8.31 ± 0.62 7.10-9.40 8.37 ± 0.72 0.295 0.829 platelet distribution width 13.40 8.60-14.90 10.94± 1.96 8.20-15.90 11.58 ± 2.60 8.50-15.80 11.97 ± 2.52 0.692 0.561 352 353 area under the curve test result variable(s) area mpv .403 pdw .991 esr .878 crp .988 n_l_ratio .986 figure 1: receiver operating characteristic analysis to evaluate the performance of 354 haematological parameters (neutrophil lymphocyte ratio, mean platelet volume, platelet 355 distribution width) and inflammatory biomarkers (erythrocyte sedimentation rate, c-356 reactive protein). 357 december 2008 no white pages.indd contact lens induced corneal ulcer management in a tertiary eye unit in oman a descriptive study rikin shah,1 manali shah,1 *rajiv khandekar,2 abdulatif al-raisi1 sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 283-290 sultan qaboos university© submitted 23rdseptember 2008 accepted 2th june 2008 وحدة في عالجها مت والتي الالصقة العدسات عن الناجتة قرحة القرنية دراسة وصفية عمان في للعني املستوى الثالث الرئيسي اللطيف عبد راجيف خانديكار، شاه، مانالي شاه، ريكني ــات الالصقة، عن العدس الناجت القرنية بالتهاب أصيبوا مرضى حالة هنا ندرج عمان. في أولوية ذات ــكلة مش القرنية أمراض امللخص: الهدف: تعتبر بفحص العيون أطباء قام .2006 – 2005 في سنتي الدراسة عمان. ألطريقة: أجريت هذه في النهضة وحدة العيون مبستشفى والذين ادخلوا في اتبر إلى الالصقة والعدسات القرنية السحائج من أرسلت عينات سنيلني. طُ طَّ مبُخَ اإلبصار حدة فحص كما يّ احليوي. قِّ الشِّ بَاحِ ِصْ امل رُ هَ مبِجْ العني عند والبصر القرنية فحص مت عالجهم فيها. مت حيث ــفى املستش ــديد الش بالتهاب القرنية املصابني املرضى ادخل ــية. احلساس وفحص الزرع ألجراء و37 15 ذكرا (ل 52 عينا فحص النتائج: مت الثقة. فترات %95 من ال و والنسب األعداد مت حساب أسابيع. ستة املستشفى وبعد من املرضى اخراج حصول من 24 ساعة خالل (25%) فقط 13 مريضا الطبيب راجع 20 – 30 سنة. بني املرضى ثلثي أعمار كانت القرنية. بتقرحات املصابني من أنثى) وجدت ≥5 ملم. لديهم القرحة حجم كان (11.5%) ــى 6 مرض و مركزية بتقرحات مصابا (33%) 17 مريضا ــاك هن كان ــديد. الش القرنية ــاب الته 26 مريضا بعده. (9.6%) و5 عيون العالج قبل (23.1%) 12 عينا في قانوني) (عمى 60/6 اقل من كان البصر .(55.8%) 29 مريضا ــي ف ــة الزائِفَ بصرية. إعاقات الالصقة ــات عن العدس الناجتة ــديدة الش القرنية التهابات ــبب اخلالصة: تس بهم. وفقد االتصال ــفى املستش يراجعوا ــم ل (50%) . القرنية التقرحات عالج أهمية التأكيد على ولهذا يجب الرؤية يحسن أن العالج كما اجليد أساسيان. والتسجيل الوقاية االنكسار. خطأ من العمى، الوقاية القرنية، التهاب العمى القرني، الصقة، الكلمات: عدسات مفتاح 1department of ophthalmology, al nahdha hospital, ministry of health, muscat, oman; 2eye & ear health care, department of control of noncommunicable disease, directorate general health affairs, ministry of health, oman *to whom correspondence should be addressed. email: rajshpp@omantel.net.om abstract objectives: the corneal disease is a priority problem in oman. we present patients with contact lens (cl) induced severe keratitis, admitted in the corneal unit of al nahdha hospital in oman. methods: the study was conducted in 2005-2006. ophthalmologists examined the eyes using slit lamp bio-microscope. visual acuity was noted using snellen’s distance vision chart. specimens of corneal scraping and cls were sent for culture and sensitivity tests. patients with severe keratitis were admitted and treated with medicines. corneal and visual statuses were noted at the time of discharge from hospital and after six weeks. numbers, percentages and their 95% confidence intervals were calculated. preand post-treatment vision were compared using a scattergram. results: the 52 eyes of 5 males and 37 female patients with corneal ulcers were examined. thirty-two patients were between 20 to 30 years of age. only 3 (25%) patients had visited an ophthalmologist within 24 hours of developing severe keratitis. seventeen (33%) had central ulcers and six (.5%) had ulcer ≥5 mm in size. pseudomonas was found in 29 (55.8%) of cl and corneal material scraped from the eyes of 5 (28.8%) patients. vision was <6/60 (legally blind) in 2 (23.%) eyes before and in five (9.6%) eyes after treatment. twenty-six (50%) patients were lost to follow up. conclusion: cl related severe keratitis causes visual disabilities. prevention and proper records are essential. treatment improves vision and hence facilities for management should be strengthened. key words: contact lens; corneal blindness, keratitis; prevention of blindness; refractive error. c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • cl induced keratitis is not included in the world health organisation’s vision 2020 initiative to eliminate all causes of avoidable blindness by 2020. • the cl from an eye with keratitis should be sent to the laboratory in order to isolate the organisms. • proper and timely management can reduce long term visual disabilities in patients with corneal ulcer due to r i k i n s h a h , m a n a l i s h a h , r a j i v k h a n d e k a r , a b d u l at i f a l r a i s i 284 bacterial keratitis, although rare, is potentially the most devastating complication of contact lens (cl) wear. the occurrence is more common in soft lens wearers and extended wear of cls increases the incidence 10 to 15 fold.1 the causes of severe keratitis could be: 1. low knowledge and skills among cl providers; 2. poor quality of the product and/or 3. misuse of lenses by the user. whatever the cause, the sufferer is certainly the cornea and the patient. prompt treatment is essential and, even after proper treatment, sequelae may compromise the quality of vision. conflicting reports suggest trends both of rising and declining incidence of cl induced keratitis. 2, 3 the popularity of coloured cls has increased among younger generations in recent years. carelessness and abuse of cl wear could result in catastrophic blindness if proper steps are not taken; hence, the american academy of optometry has stressed the need to impart knowledge both about the advantages of cl system and about the risks if the care of cls is neglected. 4 in oman, cl practice is the domain of private sector opticians and ophthalmologists. the national eye health care committee recently introduced a programme approach to minimise adverse events related to cl wear. 5 we did not find any literature on cl related complications in middle eastern countries. in oman, like other gulf countries, the climate is not conducive to sustained and healthy tear film and, at the same time, the use of the cls is on the increase. hence, we reviewed the cases of cl induced severe keratitis that were admitted in the cornea unit of al nahdha hospital, a tertiary hospital in oman. the profile, clinical presentation, modalities of treatment and visual status are here presented. m e t h o d s this study was a retrospective descriptive study in which ophthalmological hospital records were reviewed. it was approved by the ethical and research committee of al-nahdha hospital. in this series, we included patients that were admitted in the cornea unit of the hospital between january 2005 and december 2006. three senior ophthalmologists of the cornea unit were our investigators. the computerised case records of these patients were used to generate relevant information. an agreed protocol is used by ophthalmologists of the cornea unit in all cases of corneal ulcer. the history included duration of using the present cls, initial symptoms, treatment before admission, sharing of cls and cl hygiene practices. eyes with acute onset of keratitis, involving the visual axis or with hypopyon, were considered to suffer from sight threatening condition and such patients were admitted into the hospital. the visual acuity of each eye of the patient was noted using snellen’s illiterate ‘e’ chart, held at a six metre distance from the patient. if the patient could not open the eye due to blepharospasm or photophobia, one drop of 0.4% oxybuprocaine hydrochloride (minims) was instilled. if the person could not identify the ‘e’ in the top line, the test was repeated at a three metre distance. the projection of light and perception of light rays were tested in all four quadrants for those who could not be tested for visual acuity even at 3 metre distance. the fluorescein minims were used and the corneal ulcer was observed using a slit lamp biomicroscope. the size of the ulcer was measured using a grid. the ulcer was graded as ‘less than 3 mm’, ‘3 to 5 mm’ and ‘more than 5 mm in size’. the location cl wear. • pseudomonas organisms were mainly responsible for corneal ulcer in our patients. corneal ulcer due to acanthomoeba was not found in our series. application to patient care • materials should be collected from corneal scraping and cls for culture and sensitivity tests before starting antibiotic treatment. • until the report of culture and sensitivity is available, one should assume that keratitis is due to pseudomonas and antibiotics should be given accordingly. • proper records of the extent of keratitis and visual acuity are useful to evaluate the response to treatment. c o n ta c t l e n s i n d u c e d c o r n e a l u l c e r m a n a g e d i n a te r t i a r y e y e u n i t i n o m a n a d e s c r i p t i v e s t u d y 285 of the ulcer was designated ‘central’ if it covered the pupil, ‘para-central’ if it partly covered the pupil or ‘peripheral’ if the central cornea that covers the pupil was not affected. the presence of hypopyon was grouped according to its level in the anterior chamber, the categories being: <1/3, between 1/3 and ½ and more than half of the anterior chamber. the cls were sent to the laboratory for culture and sensitivity tests. minims of oxybuprocaine hydrochloride 0.4% were used to anaesthetise the cornea. the culture specimen was obtained from the edge and the bed of the ulcer. the material was inoculated on culture media (blood agar, chocolate agar, sabraud’s agar, macconkey agar, brain-heartinfusion broth); gram and potassium hydroxide staining was carried out and subsequently culture and sensitivity tests were performed. the patients with severe keratitis were treated with wide spectrum antibiotics. in the presence of hypopyon, 1% atropine eye drop was instilled for cycloplegia and oral acetazolamide (250 mg four times a day) was given if the intraocular pressure was raised. the antibiotic was changed subsequently according to the culture and sensitivity report. when staining was negative and the ulcer was healed, the person was discharged. information on the status of vision and the cornea were noted before sending patients home and during the follow up at one and six weeks. the eye examination methods were similar on admission and follow up. the patient was advised not to use cls for the next 3 to 6 months depending upon size and severity of the ulcer. health education was given for the care of cls. all details were recorded in computerised case records. a pre-tested data collection form was used to gather information from the case records. personal logbooks of corneal specialists of the unit were also referred to. the data was then entered into a microsoft xl spreadsheet. it was converted to the statistical package for social studies (spss-12) and a univariate parametric type of analysis was carried out to calculate frequencies and percentage proportions. for statistical validation, we used 95% confidence intervals (95% ci) of percentage proportions. all patients with severe keratitis were treated free of cost. their identities were de-linked from the results at the time of analysis. the authors presented the outcomes of this study in a national ophthalmic meeting to increase the awareness and knowledge among the cl practitioners and ophthalmologists of oman. r e s u l t s fifty-two patients had corneal ulcers in their eyes (18 in the right eye, 27 in the left eye and 7 in both eyes). the profile of the patients with keratitis is shown in table 1. thirteen (25%) patients had approached a cornea clinic within 24 hours and 17 (32.7%) patients had used antibiotics before visiting our institution. twentable 1: profile of patients with contact lens induced severe keratitis patients with keratitis # % 95% confidence interval gender male female 15 37 28.8 71.2 6.632.0 69.2 73.2 age-group 10 to 20 years 21 to 30 years 31 to 40 years 41 years and more 10 32 6 4 19.2 61.5 11.5 7.7 8.822.6 2.263.8 8.015.0 4.111.3 reference pattern emergency in morning emergency in evening primary health centres regional hospitals private ophthalmologists 25 13 3 6 5 48.1 25.0 5.8 11.5 9.6 4.450.8 7.728.3 1.19.5 8.015.0 6.0 13.2 interval between keratitis and ophthalmic visit <24 hours 24 to 48 hours <1 week 1 to 2 week > 2 week 13 11 11 2 5 25.0 21.2 21.2 3.8 9.6 7.7 28.3 17.9 24.5 17.9 24.5 1.17.5 6.013.2 total 52 100 r i k i n s h a h , m a n a l i s h a h , r a j i v k h a n d e k a r , a b d u l at i f a l r a i s i 286 ty-six (50%) patients had not used antibiotics, while in nine (17.3%) patients, this information was not available. in our institute during the same period, 177 patients with corneal ulcers were admitted. the proportion of cl induced corneal ulcer to the total cases of corneal ulcer was 29.4%. daily wear is common and extended wear soft lenses and disposable cls are extensively used in oman compared to hard cls which are rarely used. therefore, we can safely assume that all the patients with keratitis in our series wear soft lenses. the salient features of the corneal ulcers in our series are given in table 2. one fourth of patients had peripheral ulcers. only 35 (67.3%) patients had brought their cls with them to be tested for bacterial growth and antibiotic sensitivity. thirty-seven (71.2%) patients were treated with fortified gentamycin (14mg/ml) and fortified cefuroxime (50mg /ml) eye drops, while in twelve (23%) patients ofloxacilline eye drops were used. three (6%) patients were treated with ofloxacilline and other fortified drugs (fortified gentamycin/ fortified amikacin). fourteen (30%) patients were admitted for three days, nineteen (36.5%) patients were admitted for one week and nine (17.3%) patients were in the hospital for two weeks. six (11.5%) patients left hospital against medical advice before completing the treatment. visual acuity was tested in the eye with keratitis on admission and at the time of discharge. twelve (23%) eyes of 52 patients with severe keratitis had visual acuity of <6/60 (legally blind) at the time of admission. in contrast, only five (9.6%) eyes of 52 patients had visual acuity of less than 6/60 following the management of severe keratitis. a percentage scattergram comparing preand post-treatment vision is given in table 3. in one eye only, the vision deteriorated following treatment. after leaving the hospital, 13 (25%) of patients did not return for follow up. only 16 (30.7%) patients had been followed up after 3 months. twenty-eight (53.8%) patients were advised to continue ofloxacillin eye drops even after leaving the hospital. another 18 (34.6%) patients were given the gentamycin eye drops in addition to the ofloxacillin eye drops. twenty-one (40.4%) patients were also given lubricant eye drops. topical steroids were used in treatment of only 8 (15.4%) patients. the status of the corneas following treatment is given in table 4. nearly half of the patients treated for severe keratitis were advised to use spectacles to correct their refractive error. corneal ulcer number of eyes percentage 95% confidence interval location central paracentral peripheral 17 21 14 32.7 40.4 26.9 29.6 35.8 37.5 -43.3 23.730.1 size <3 mm 3 to 5 mm 6 mm and more 39 6 6 75.0 11.5 11.5 73.176.9 8.0 -15.0 8.015.0 hypopyon absent 1/3 to ½ of anterior chamber >1/2 of anterior chamber 42 9 1 80.8 17.3 1.9 79.182.5 13.920.7 0.05.6 culture of corneal scrapping gram staining no growth gram +ve cocci gram – ve bacilli not done / missing culture no growth pseudomonas missing 35 1 4 12 28 15 9 67.3 1.9 7.7 23 53.8 28.8 17.3 65.169.5 -1.85.6 4.111.3 19.726.3 51.256.4 25.632.0 13.920.7 culture of contact lens pseudomonas other no growth not done 29 4 2 17 55.8 7.7 3.8 32.7 53.358.3 4.111.3 0.17.5 29.635.8 table 2: characteristics of ulcers in eyes of patients with contact lens induced severe keratitis c o n ta c t l e n s i n d u c e d c o r n e a l u l c e r m a n a g e d i n a te r t i a r y e y e u n i t i n o m a n a d e s c r i p t i v e s t u d y 287 d i s c u s s i o n our study highlights the importance of reviewing cl induced severe keratitis. eighty percent of our patients were less than 30 years of age. it is known that even after successful treatment of severe keratitis, corneal opacities will be unavoidable thus causing visual impairment, which could be a social and economic disaster at such a young age. fortunately, vision improved in all except in one case in our study. thus, prompt and standard treatment of severe keratitis is crucial to prevent visual disabilities. pseudomonas was the main organism found in cls used in the eyes of patients with corneal ulcer in our study. surprisingly, we did not come across keratitis due to acanthomoeba, but the fact that nearly 50% of the sample were ‘without growth’ after laboratory tests in our study is worthy to note. the ulcers were mainly in the visual axis and were of < 3 mm diameter. the main characteristics of the patients in our series were: a majority of female patients; age range from 20 to 30 years; coming for treatment in the early hours of the day 24 hours after symptoms appeared. unfortunately, a large number of cases were lost to followup and therefore we could not compare visual recovery in nearly 48% of cases. loss of data and patients in follow up visits are known limitations of a study based on data review.6 therefore, correlation of visual impairment to the categories like causative organisms or age group could not be attempted. further studies of a prospective nature with a larger sample are recommended. to the best of our knowledge, this study was the first of its kind in the gulf countries. since complication due to cl wear is a problem of the young generation, the loss of dalys (disability adjusted life years) will be high. in spite of treatment, it could cause unilateral blindness and/or low vision. in these circumstances, the outcomes of our study would be important not only to oman but also to many other countries having a similar cl delivery system. oman has prioritised corneal diseases within its vision 2020 initiative.7 corneal complications contributed to 14% of blindness in the population aged >40 years in 2005. the majority of them were due to corneal complications of trachoma. trachomatous trichaisis has declined in the last decade.8, 9 however, the cornea is now at a higher risk due to the increased use of cls in oman. the scope for using cls is large in oman since the prevalence of myopia in 16 to 17 years old school children is as high as 12% and the compliinitial visual acuity 6/6 (7) 6/9 (0) 6/12 (5) 6/18 (3) 6/24 (4) 6/36 (3) 6/60 (8) <6/60 to 3/60 (7) <6/60 plpr+ (5) missing (10) total (52) follow up visual acuity ‚ 6/6 1.9 3.8 5.8 3.8 5.8 11 6/9 1.9 1.9 1.9 1.9 1.9 5 6/12 1.9 1.9 1.9 3 6/18 1.9 1 6/24 3.8 2 6/36 1.9 1 6/60 1.9 1.9 2 <6/60 to 3/60 1.9 2 <3/60 to plpr + 1.9 1.9 1 not known 5.7 1.9 3.8 3.8 3.8 5.8 5.8 5.8 5.8 3.8 24 initial visual acuity ‡ <3/60 -plpr + <6/60 to 3/60 6/60 6/36 6/24 6/18 6/12 6/9 6/6 missing pl = perception of light; pr = projection of light table 3: percentage scatter gram: initial and final visual acuity in eyes treated for contact lens induced severe keratitis r i k i n s h a h , m a n a l i s h a h , r a j i v k h a n d e k a r , a b d u l at i f a l r a i s i 288 ance of spectacle wear is only 70%.10, 11 in industrialized countries, it has also been noted that the proportion of severe keratitis due to cl wear has increased the total number of cases of corneal ulcer needing admission by up to 50%.12 thus, awareness campaigns targeting these potential patients could use the information of our study to warn them of the consequences of abusing cls. cl induced keratitis was 30% of total admissions in our institute. this rate was close to the 33% reported by keay et al.13 pseudomonas was the main organism responsible for severe keratitis. many other researchers have also noted these organisms as the main culprit of keratitis.14, 15 we found bacteria both in the sample collected from the corneal ulcer and from the cl. mela et al., in their study, demonstrated the importance of sending both the material from corneal scraping and from the cls for culture.16 hence, it is important to inform the family physician or optician referring the case to ensure that the patient is sent with the cls when the case is referred for admission and care. we found four cases with gram negative bacilli and one case of gram positive cocci. but, we could not carry out culture and sensitivity tests for them as we could not culture them on artificial media and test for sensitivity. inoue et al. noted gram positive and gram negative bacteria and fungi and acanthamoeba in their specimen. 17 a study in belgium, reported pseudomonas as the main culprit of cl induced severe keratitis. 18 only 25% of our patients had consulted an ophthalmologist within 24 hours of development of symptoms showing that further strengthening of the reference system is therefore urgently needed. opticians and family physicians should be educated about the problems related to cl use and need for prompt treatment by experts to avoid sight-threatening complications. under the guidance of cornea specialists, a standard management protocol should be prepared to be followed by all ophthalmologists and cl practitioners. a large number of samples with ‘no growth’ after laboratory tests could be due to the use of antibiotics before the collection of the sample. the referring practitioners should be aware of the need to collect the sample both from the cornea and the lenses before commencing antibiotic treatment. central corneal ulcers and peripheral ulcers can be due to different causes and organisms.19 in our study also, we noted that central ulcers of more than 5 mm in size were due to pseudomonas organisms. however, gram negative organisms were noted in samples from both paracentral and peripheral keratitis. twenty eight (53.8%) of laboratory tests reported ‘no growth’, hence associating the site of ulcer to the type of organisms should be done with caution in our study. we could avoid perforation and its sequelae by good treatment; however, the vision remained < 6/60 due to corneal opacities in five (19%) patients. visual acuity following successful treatment of cl induced corneal ulcer in another study was < 20/200 in two out of nine cases in a group of myopic persons using soft cls. 20 adam et al. studied complications in persons using cosmetic cls and found that one out of six eyes were blind after treatment. 21 a study with a larger sample is recommended to confirm these observations. a limitation of our study is that patients presenting with mild corneal ulcers that were treated in clinics and not admitted into hospital were not included in number percentage location of opacity central paracentral peripheral no opacity missing 11 11 8 7 15 21.2 21.2 15.4 13.5 28.8 treatment of sequel keratoplasty no keratoplasty missing information 4 24 24 7.8 46.1 46.1 advice for correcting refractive error to continue contact lens use of spectacles undergone refractive surgery missing 4 12 1 1 7.7 25 1.9 1.9 table 4: corneal status and suggested correction following treatment of contact lens induced severe keratitis. c o n ta c t l e n s i n d u c e d c o r n e a l u l c e r m a n a g e d i n a te r t i a r y e y e u n i t i n o m a n a d e s c r i p t i v e s t u d y 289 our study. although computerised case records were useful, a switch from manual to computer records coincided with our study period. this could have affected our study as the learning curve of the ophthalmologists in using the computerised system may have resulted in incomplete data. our study was retrospective in nature; hence, the attrition of cases following discharge and loss of data were inherent limitations.6 thus, the results of our study are limited to cl induced severe keratitis that needed treatment under supervision. therefore, any attempt to extrapolate the result of our study should be undertaken with due caution. c o n c l u s i o n our study suggests that vision improves following prompt and standard treatment of cl induced severe keratitis. prompt referral, standard management, regular follow up and proper case records are essential. in view of the high rate of corneal ulcers in cl wearers, cl dispensing practice in oman should be monitored. ophthalmologists, cl providers and cl users should work jointly to solve this issue. a c k n ow l e d g me n ts we thank the staff of the ophthalmology department at al nahdha hospital for all their assistance and care of the patients. we also thank the staff of the health record section there. the hospital administrators gave their permission for this study and we appreciate their cooperation. we thank the patients and their relatives who in spite of their suffering gave their consent to use the information for improving eye care. we are grateful for their cooperation and support. the authors did not have any conflicts of interest (financial or other) in conducting this study. the subject was presented in international ophthalmology conference in february 2007 in muscat, oman. r e f e r e n c e s 1. albert dm, jakobiec fa. contact lens. in: principles and practice of ophthalmology, ch. 6, vol.6 2nd ed. philadelphia: wb saunders company, 2004. p. 5368. 2. verhelst d, koppen c, van looveren j, meheus a, tassignon mj; the belgian keratitis study group. contact lens-related corneal ulcers requiring hospitalization: a 7-year retrospective study in belgium. acta ophthalmol scand 2006; 84:522-526. 3. rattanatam t, heng wj, rapuano cj, laibson pr, cohen ej. trends in contact lens-related corneal ulcers. cornea 2001; 20:290-294. 4. sargie l. are your contact lenses uncomfortable? here’s what to do about it. from http://www.allaboutvision.com/contacts/contact-lens-discomfort.htm. accessed april 2007. 5. khandekar r, al fahdi m, mohammed aj, krishnan sg, talat a, al raisi a. evaluation of resources for contact lens practice in private contact lens clinics of muscat, oman. east med j ophthalmol. (in press) 6. hennekens ch, julie eb. epidemiology in medicine. in: evaluating the role of bias. boston: little brown and company, 1987. p. 272-286. 7. ministry of health, oman. corneal diseases in eye health care manual. 2nd edition. muscat: al zahra printing press, 2000. pp. 16-17. 8. khandekar r, mohammed aj, al-raisi a. prevalence and causes of blindness & low vision; before and five years after ‘vision 2020’ initiatives in oman: a review. ophthalmic epidemiol 2007; 14:9-15. 9. khandekar r, mohammed aj. the prevalence of trachomatous trichiasis in oman (oman eye study 2005). ophthalmic epidemiol 2007; 14:267-272. 10. khandekar rb, abdu-helmi s. magnitude and determinants of refractive error in omani school children. saudi med j 2004; 25:1388-1393. 11. khandekar r, mohammed aj, al raisi a. compliance of spectacle wear and its determinants among schoolchildren of dhakhiliya region of oman: a descriptive study. squ j sci res: med sci 2002; 4:39-43. 12. neumaier-ammerer b, stolba u, binder s, feichtinger h. corneal infiltrates and ulcers a retrospective study of 239 eyes. ophthalmologe 2004; 101:33-38. 13. keay l, edwards k, naduvilath t, taylor hr, snibson gr, forde k, et al. microbial keratitis predisposing factors and morbidity. ophthalmology 2006; 113:109-116. 14. derick rj, kelley cg, gersman m. contact lens related corneal ulcers at the ohio state university hospitals 1983-1987. clao j 1989; 15:268-270. 15. sharma s, gopalakrishnan s, aasuri mk, garg p, rao gn. trends in contact lens-associated microbial keratitis in southern india. ophthalmology 2003; 110:138143. 16. mela ek, giannelou ip, koliopoulos jx, gartaganis sp. ulcerative keratitis in contact lens wearers. eye contact lens 2003; 29:207-209. 17. inoue n, toshida h, mamada n, kogure n, murakami a. contact lens-induced infectious keratitis in japan. eye contact lens 2007; 33:65-69. 18. verhelst d, koppen c, van looveren j, meheus a, tassignon mj; the belgian keratitis study group. contact lens-related corneal ulcers requiring hospitalization: a 7-year retrospective study in belgium. acta ophthalmol scand 2006; 84:522-526. r i k i n s h a h , m a n a l i s h a h , r a j i v k h a n d e k a r , a b d u l at i f a l r a i s i 290 19. aasuri mk, venkata n, kumar vm. differential diagnosis of microbial keratitis and contact lens-induced peripheral ulcer. eye contact lens 2003; 29:s60-62. 20. weissman ba, mondino bj, pettit th, hofbauer jd. corneal ulcers associated with extended-wear soft contact lenses. am j ophthalmol 1984; 97:476-481. 21. adams cp jr, cohen ej, laibson pr, galentine p, arentsen jj. corneal ulcers in patients with cosmetic extended-wear contact lenses. am j ophthalmol 1983; 96:705-709. submitted 24 nov 21 1 revision req. 30 jan 22; revision recd. 6 feb 22 2 accepted 6 mar 22 3 online-first: march 2022 4 doi: https://doi.org/10.18295/squmj.3.2022.025 5 6 successful management of rhino-orbital-cerebral mucormycosis in a 7 child with acute-on-chronic kidney disease and malnutrition 8 case report and literature review 9 *mohammed al reesi,1 taleb al muqbali,2 ahmed al ajmi,3 varna menon4 10 11 departments of 1paediatrics, 2ears, nose & throat, 3oral maxillofacial surgery and 12 4laboratory, suhar hospital, suhar, oman. 13 *corresponding author’s e-mail: alreesimohammed@gmail.com 14 15 abstract 16 mucormycosis is a very rare fungal infection in children. it is caused by opportunistic fungi, and 17 mainly affects immunocompromised patients. early diagnosis is very important for a good 18 outcome. successful management requires the reversal of the underlying predisposing risk 19 factors, surgical debridement and prompt administration of active antifungal agents, with 20 liposomal amphotericin b being the first line therapy. this case, to the best of the authors’ 21 knowledge, is the first rhino-orbital-cerebral mucormycosis to be reported on among omani 22 children. we highlight the importance of early diagnosis and prompt surgical and medical 23 interventions in achieving a satisfactory outcome and we review the published literature in regard 24 to the management. 25 keywords: mucormycosis; sinusitis; proptosis; liposomal amphotericin b; rhizopus; 26 posaconazole; malnutrition. 27 28 introduction 29 mucormycosis is a very rare fungal infection in children. it is caused by opportunistic fungi, and 30 mainly affects immunocompromised patients.1 early diagnosis is very important for a good 31 outcome.2 successful management requires the reversal of the underlying predisposing risk 32 mailto:alreesimohammed@gmail.com factors, surgical debridement and prompt administration of active antifungal agents, with 33 liposomal amphotericin b being the first line therapy.3,4 this case, to the best of the authors’ 34 knowledge, is the first rhino-orbital-cerebral mucormycosis to be reported on among omani 35 children. we highlight the importance of early diagnosis and prompt surgical and medical 36 interventions in achieving a satisfactory outcome and we review the published literature in regard 37 to the management. 38 39 case report 40 we present a six-year-old omani girl who was referred to a tertiary care hospital in oman from 41 a local health centre in 2016 with sudden onset facial swelling, left periorbital skin rash and 42 reduced oral intake for one day. she had no history of fever, nasal congestion, ear pain or 43 toothache. there was no history of allergy, preceding trauma or insect bites. she was not a 44 diabetic and had no history of haematological malignancy or recurrent infections. she was 45 operated on for meningomyelocele in the neonatal period. that was complicated by reflux 46 nephropathy, chronic kidney disease and paraplegia. she had normal speech, vision and hearing. 47 48 the patient was very thin and weighed just 9 kilograms. she was tachypneic with acidotic 49 breathing and she had a respiratory rate of 40 per minute, a pulse rate of 120 beats per minutes, 50 and blood pressure (bp) of 100/80 mmhg, spo2 of 100% with 10 l of o2 via non-rebreathing 51 mask. she had mild proptosis of the left eye, left sided facial swelling of the left orbit with 52 multiple pustular lesions on the left eye brow, left side of forehead and nasal bridge (figure 1). 53 she was not able to see from her left eye, but she had a normal ocular motility and fundus. an 54 oral cavity examination showed multiple dental caries. her left palatal mucosa was coated by a 55 very thick white lesion opposite her upper first and second left molars, measuring 2x2 cm and 56 with central dark discoloration (figure 2-a). neurologically, she was conscious and oriented. 57 she was hypotonic in both upper and lower limbs with brisk reflexes (her baseline). other 58 systemic examinations were unremarkable. 59 60 an initial laboratory investigation showed a haemoglobin of 6.84 g/dl, a white blood cell count 61 of 38.8 x 103 with mainly neutrophils (35.35 x 103) and platelets count of 1078.00 x 103. her 62 c-reactive protein was very high (342 mg/l). her venous blood gas showed metabolic acidosis 63 with bicarbonate of 7.8 nmol/l and base excess of -22 mmol/l. she had acute-on-chronic kidney 64 disease. her urea was 22.6 mmol/l, her creatinine was 150.66 umol/l, while other electrolytes 65 were within normal limits. her random blood glucose was 6.27 mmol/l and glycosylated hb 66 (%hba1c) was 4.42%. her chest radiograph was normal. 67 68 she was initially admitted into the general paediatric ward and a diagnosis of periorbital cellulitis 69 was made. a few hours later, she was shifted to a paediatric intensive care unit after she 70 developed hypotension (bp: 48/40 mm hg), which was corrected by two boluses of normal 71 saline. a bicarbonate infusion was also given to correct her metabolic acidosis. she was given 72 cefotaxime, amikacin, metronidazole and cloxacillin intravenously. contrasted computed 73 topography (ct) of the orbits and brain revealed pan maxillary and ethmoid sinusitis (more on 74 the left side) with subtle rarefaction of the left lamina paprychea. there was an inflammatory 75 phelgmon of the medial and inferior wall of the left orbit measuring 28 x 7 mm. there was no 76 evidence of bone destruction or intracranial involvement. (figure 3). multidisciplinary teams 77 (mdts) were consulted urgently, including paediatric infectious diseases, ophthalmology, oral 78 maxillofacial surgery (omfs) and ear, nose and throat (ent) teams. the antimicrobial 79 regimen was changed to renal-adjusted doses of intravenous ceftazidime, clindamicin and 80 ciprofloxacin to cover the most likely causative organisms, including staphylococcus aureus, 81 anaerobes and pseudomonas aeruginosa. in addition, an invasive fungal infection, such as 82 mucormycosis was strongly suspected. therefore, a diagnostic nasal endoscopy was performed 83 within 24 hours of her being admitted, which showed necrosis of the left maxillary wall and 84 upper part of the left inferior turbinate. urgent koh staining of the biopsy specimen showed 85 aseptated cylindrical fungal hyphae. subsequently, liposomal amphotericin b was administered 86 empirically at a dose of 5 mg/kg/dose, once daily within 48 hours of admission. the 87 histopathology showed necrotic tissue containing aseptated, broad fungal hyphae, displaying 88 right angled branching with angio-invasion and thrombosis of the blood vessels, highly 89 suggestive of mucormycosis (figure 4). the culture of the initial swab confirmed the growth of 90 rhizopus spp. 91 92 the patient underwent a debridement of the left nasal cavity, an inferior turbinectomy, medial 93 maxillectomy and ethmoidotomy. unfortunately, she developed skin necrosis in the medial 94 aspect of the left eye two days after the operation. intraorally, the left palatal region had the 95 appearance of decreased vitality and bone necrosis was suspected. repeated ct demonstrated 96 that the left orbital phlegmon had extended up to the orbital apex, transformed into an abscess 97 and increased in size to 31 x 10 mm. the optic nerve had thickened. however, there was no 98 intracranial abnormal enhancement and dural sinuses were normal. a left orbital exenteration 99 was discussed, but the parents were reluctant to give consent. she underwent left palatectomy, 100 maxillectomy and debridement on the 10th day after her admission. there was no drainable pus 101 from the orbital abscess site. despite this, she still had left orbital proptosis and increasing 102 periorbital ecchymosis one week after the second operation. therefore, magnetic resonance 103 imaging (mri) with contrast was done to further delineate the anatomy and extension. that 104 showed left ethmoid opacification, abnormal enhancement of the left septal/preseptal area with 105 extension to retro-orbital space and a small abscess formation in the left orbit, measuring 1.9 x 106 0.8 cm with mass effect causing optic nerve deviation and proptosis. it also revealed abnormal 107 enhancement of the cavernous sinus, but no brain parenchyma extension. lumbar puncture could 108 not be done because she was not stable enough for the procedure. the addition of oral 109 posaconazole was planned but she was not able to tolerate it orally. instead, caspofungin was 110 added to ambisome on 17th day of admission due to an un-satisfactory response and ceftriaxone 111 was commenced to cover any secondary bacterial central nervous system infection. furthermore, 112 ethmoid sinus debridement was done and her left orbitotomy did not reveal any pus. 113 114 only after her third operation did the clinical signs start to gradually improve. she started to see 115 a little from her left eye and was able to count fingers with difficulty. but there was no further 116 improvement as the disease progressed. trans-orally, her inferior maxillectomy site was healing 117 well with good re-epithelialsation. she was able to take some medicine and food orally after 118 using a resin obturator to cover the post-operative palatal defect. eventually, the histopathology 119 from the third operation did not show any fungal elements and the culture was negative. twenty-120 four days after admission, her creatinine started to improve to 104 umol/l after a period of 121 fluctuation. subsequently, her ambisome dose was gradually increased to 9 mg/kg/day. she was 122 screened for immunodeficiency: she was not lymphopenic, her hiv serology was non-reactive, 123 immunoglobulin levels and lymphocyte subset were normal. an ultrasound of her abdomen did 124 not reveal any abscesses. after 8 weeks of ambisome and 4 weeks of caspofungin, she was 125 discharged home and her therapy was transitioned to oral posaconazole at a dose of 17mg/kg/day 126 in 3 divided doses. that was continued for 3 months whereupon a follow upmri showed a 127 complete resolution of the abscesses in the left orbital region and left maxillary sinus. she was 128 followed up regularly in the clinics by a multidisciplinary team. all her clinical signs improved 129 with no relapse of infection to date (figure 2-b). the mother has given written consent to publish 130 this case and its related images. 131 132 discussion 133 mucormycosis is a rare, aggressive, angio-invasive and highly destructive fungal infection with 134 very high morbidity and mortality.1,2,4 it is caused by ubiquitous fungi, predominantly belonging 135 to the order mucorales.5 the rhizopus species, the causative agent in our patient, is responsible 136 for about one third of mucormycosis cases overall and accounts for 85% of rhino-cerebral 137 cases.2,6,7 the most important predisposing factors for mucormycosis are malignancies and 138 poorly controlled diabetes mellitus.1-9 other predisposing factors include chronic kidney disease 139 and malnutrition,1 both of which were present in our patient. recently, increasing mucormycosis 140 cases were also identified worldwide in people with coronavirus disease 2019 (covid-19), 141 particularly more in those with pre-existing diabetes mellitus and corticosteroids use.8 142 143 rhino-cerebral mucormycosis has been associated with acute and chronic kidney disease with 144 fatal outcome. altered immune status, leucopenia and metabolic acidosis in those patients may 145 be a plausible mechanism of predisposition.10 as a risk factor, malnourishment in children is 146 mainly associated with gastrointestinal mucormycosis.1 there was no clinical or radiological 147 evidence of abdominal organ involvement in our patient. in addition, her investigations were 148 negative for diabetes mellitus and immunodeficiency. 149 150 the successful management of mucormycosis requires early diagnosis, reversal of underlying 151 predisposing risk factors, prompt administration of active antifungal agents and aggressive 152 surgical debridement.3,4 due to a lack of awareness of risk factors and nonspecific clinical and 153 radiologic findings, many cases are not diagnosed for many weeks after the time of 154 presentation.3,4 histopathology and fungal culture are considered the gold standard for the 155 diagnosis.4,7,11 mucorales are readily recognized morphologically on the basis of non-septate or 156 occasionally pauci-septate, broad, thin walled hyphae with wide angled branching and evidence 157 of angioinvasion.3,9,11 we believe that the early diagnosis achieved within 24 hours of patient’s 158 admission played a very important role in her satisfactory outcome. 159 160 mucorales are resistant to most antifungals, except amphotericin b(amb)–deoxycholate 161 (including lipid formulations of amb, ambisome) and the new triazole posaconazole.5 while 162 liposomal amphotericin b is the recommended first line therapy, posaconazole is mainly used as 163 a stepdown or salvage therapy.3,4,11,12 chamilos et al showed that delayed amphotericin b therapy 164 (>= 6 days after diagnosis) was associated with a two-fold increase in mortality in patients with 165 hematological malignancy and mucormycosis compared with early treatment (83% vs. 49%).5 166 ray et al reported a case of rhino-orbital mucormycosis in a child with acute kidney injury. 167 amphotericin b was started two weeks after admission. although some clinical response was 168 noticed, the child died of massive gastrointestinal hemorrhage.10 the response rate to liposomal 169 amphotericin b ranges between 23 to 58%.12 the optimal dose is not known, but most experts 170 recommend a daily dose of 5-7.5 mg/kg/day. although higher doses can lead to nephrotoxicity, 171 doses up to 10 mg/kg/day are recommended for disseminated diseases and are well-tolerated in 172 children.4,6,10,13 173 174 on the contrary, the use of amphotericin b-deoxycholate is limited by its substantial 175 nephrotoxicity, specifically in the doses and treatment duration needed for 176 mucormycosis.9 liposomal amphotericin b was commenced on our patient within 48 hours of 177 admission. she tolerated increasing the dose to 9 mg/kg/dose once daily without worsening her 178 renal parameters. posaconazole has an overall success rate of 60–70% when used as a salvage 179 agent.14 a dose between 17 and 24 mg/kg/day is suggested in order to achieve target plasma 180 concentration.15 the addition of oral posaconazole as a salvage therapy was postponed in our 181 case till the day of discharge because she was not able to tolerate it after the operation. despite 182 the late administration, our patient showed a good response to it on follow up. echinocandins 183 are not recommended because they have a modest effect against mucorales in vivo and virtually 184 no activity in vitro.10,16 however, some reports suggested its use based on the the theory that 185 rhizopus oryzae, expresses the target enzyme for echinocandins (1,3-b-glucan synthase). in a 186 small retrospective study, caitlin et al reported a superior success rate in patients with rhino-187 orbital-cerebral mucormycosis who received polyene-caspofungin therapy compared to patients 188 treated with polyene monotherapy.15 caspofungin was added to our case because of the 189 progressive disease whilst on liposomal amphotericin b therapy and an inability to tolerate oral 190 posaconazole initially. 191 192 interestingly, she started to improve after the third operation, which coincided with initiation of 193 caspofungin. stronger evidence is needed, however, before recommending this agent for the 194 treatment of mucormycosis.9 our patient received antifungal therapy for approximately 5 195 months. the reported length of treatment ranged between 3-36 months. this should be guided 196 by the clinical and radiological response.6,9 197 198 de-bulking the infection by early aggressive surgical debridement is very important and critical 199 component of therapy. multiple surgeries may be required in the case of extensive disease.11 200 pana et al has demonstrated less mortality in those patient given combined antifungals and 201 surgery compared to those given antifungals alone (18.5% versus 60%).17 our patient required 202 3 sessions of complex operations, without which, it was clear that pharmaceutical interventions 203 were not sufficient to control the infection. 204 205 conclusions 206 we described the successful management of severe rhino-orbital-cerebral mucormycosis in an 207 omani child. despite a very high mortality reported, early diagnosis and prompt medical and 208 surgical interventions were the key factors in achieving a good outcome in this case. keeping a 209 high index of suspicion and raising the awareness about this aggressive infection and its 210 predisposing factors among all clinicians dealing with immunocompromised paediatric patients, 211 is of paramount importance for early recognition and prompt management. 212 213 authors’ contribution 214 mar is the first author who prepared, wrote, and reviewed the manuscript. tam, aaa and vm 215 contributed to writing and reviewing the manuscript. all authors read and approved the final 216 manuscript. 217 218 references 219 1. binder u, maurer e and lass-florl c. mucormycosis – from the pathogens to the disease. 220 clin microbiol infect. 2014;20 (suppl. 6): 60–66. https://doi.org/10.1111/1469-221 0691.12566. 222 2. petrikkos g, skiada a, drogari-apiranthitou m. epidemiology of mucormycosis in 223 europe. clin microbiol infect. 2014 jun;20 suppl 6:67-73. https://doi: 10.1111/1469-224 0691.12563. 225 3. katragkou a, walsh tj, roilides e. why is mucormycosis more difficult to cure than 226 more common mycoses? clin microbiol infect. 2014 jun;20 suppl 6:74-81. https://doi: 227 10.1111/1469-0691.12466. 228 4. skiada a, lass-floerl c, klimko n, ibrahim a, roilides e, petrikkos g. challenges in 229 the diagnosis and treatment of mucormycosis. med mycol. 2018 apr 1;56(suppl_1):93-230 101. https://doi: 10.1093/mmy/myx101. 231 232 5. chamilos g, lewis re, kontoyiannis dp. delaying amphotericin b-based frontline 233 therapy significantly increases mortality among patients with hematologic malignancy 234 who have zygomycosis. clin infect dis. 2008 aug 15;47(4):503-9. https://doi: 235 10.1086/590004. 236 6. muggeo p, calore e, decembrino n, frenos s, de leonardis f, colombini a, et al. 237 invasive mucormycosis in children with cancer: a retrospective study from the infection 238 working group of italian pediatric hematology oncology association. mycoses. 2019 239 feb;62(2):165-170. https://doi: 10.1111/myc.12862. 240 7. jeong w, keighley c, wolfe r, lee wl, slavin ma, kong dcm, et al. the 241 epidemiology and clinical manifestations of mucormycosis: a systematic review and 242 meta-analysis of case reports. clin microbiol infect. 2019 jan;25(1):26-34. https://doi: 243 10.1016/j.cmi.2018.07.011. 244 8. singh ak, singh r, joshi sr, misra a. mucormycosis in covid-19: a systematic 245 review of cases reported worldwide and in india. diabetes metab syndr. 246 2021;15(4):102146. https://doi:10.1016/j.dsx.2021.05.019. 247 9. cornely oa, alastruey-izquierdo a, arenz d, chen sca, dannaoui e, hochhegger b, 248 et al; mucormycosis ecmm msg global guideline writing group. global guideline 249 for the diagnosis and management of mucormycosis: an initiative of the european 250 confederation of medical mycology in cooperation with the mycoses study group 251 education and research consortium. lancet infect dis. 2019 dec;19(12):e405-e421. 252 https://doi: 10.1016/s1473-3099(19)30312-3. 253 10. ray ms, kumar v, jain d, dubey nk. rhino-orbital mucormycosis in acute renal 254 failure. indian pediatr. 2002 apr;39(4):381-5. 255 11. srinivas r, jacob tjk, raj pm, korula s, mathew lg. paediatric mucormycosis: 256 tailoring surgical strategies to compliment antifungal chemotherapy. different strokes 257 for different folks. trop doct. 2020;50(1):87-90. 258 https://doi:10.1177/0049475519874270 259 12. lanternier f, dannaoui e, morizot g, elie c, garcia-hermoso d, huerre m, et al; french 260 mycosis study group. a global analysis of mucormycosis in france: the retrozygo 261 https://doi:10.1016/j.dsx.2021.05.019 https://doi.org/10.1177/0049475519874270 study (2005-2007). clin infect dis. 2012 feb;54 suppl 1: s35-43. https://doi: 262 10.1093/cid/cir880. 263 13. lewis re., lortholary o, spellberg b, roilides e, kontoyiannis dp, and walsh tj. how 264 does antifungal pharmacology differ for mucormycosis versus aspergillosis? clin 265 infect dis. 2012;54(s1): s67–72. https://doi: 10.1093/cid/cir884. 266 14. zaoutis te, roilides e, chiou cc, buchanan wl, knudsen ta, sarkisova ta, 267 schaufele rl, sein m, sein t, prasad pa, chu jh, walsh tj. zygomycosis in children: 268 a systematic review and analysis of reported cases. pediatr infect dis j. 2007 269 aug;26(8):723-7. https://doi: 10.1097/inf.0b013e318062115c. 270 15. ojeda-diezbarroso k, aguilar-rascón j, jiménez-juárez rn, moreno-espinosa s, 271 reséndiz-sánchez j and romero-zamora jl. successful posaconazole salvage therapy 272 for rhinocerebral mucormycosis in a child with leukemia. review of the literature. rev 273 iberoam micol. 2019;36(3):160–164. https://doi: 10.1016/j.riam.2018.07.008. 274 16. reed c, bryant r, ibrahim as, edwards j jr, filler sg, goldberg r, et al. combination 275 polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. clin infect dis. 276 2008 aug 1;47(3):364-71. https://doi: 10.1086/589857. 277 17. pana zd, seidel d, skiada a, groll ah, petrikkos g, cornely oa, et al; collaborators 278 of zygomyco.net and/or fungiscope™ registries*. invasive mucormycosis in children: 279 an epidemiologic study in european and non-european countries based on two registries. 280 bmc infect dis. 2016 nov 10;16(1):667. https://doi: 10.1186/s12879-016-2005-1. 281 282 figure 1: an image showing mild proptosis, swelling and redness of the left eye and multiple 283 pustular lesions on the left eyebrow, left side of the forehead and nasal bridge. 284 285 286 figure 2: (a) an image showing very thick white lesion coating the hard palate with central 287 dark discoloration, measuring 2x2 cm. (b) the oral cavity on follow up showing healthy and 288 clear margin of the lesion. 289 290 a b 291 figure 3: axial ct orbit showing left eye proptosis (star), maxillary and ethmoid sinusitis 292 (arrows) with subtle rarefaction of the left lamina paprychea. 293 294 295 figure 4: section of nasal biopsy showing blood vessel invasion by pas positive non-septate, 296 broad, ribbon-like fungal hyphae (arrow), (pas 200x). 297 the emergence of child protection capacities in oman lessons learned *shamsa s. al balushi,1,2 gillian morantz,2 geoffrey dougherty3 sultan qaboos university med j, november 2021, vol. 21, iss. 4, pp. 517–524, epub. 25 nov 21 submitted 25 aug 20 revisions req. 06 oct & 01 dec 20; revisions recd. 16 nov & 15 dec 20 accepted 23 dec 20 1department of pediatrics, ministry of health, muscat, oman; 2department of social pediatrics, mcgill university, montreal, canada; 3department of general pediatrics, montreal children’s hospital, montreal, canada *corresponding author’s e-mail: shamsalkone@yahoo.com child maltreatment (cm) is defined as the abuse and neglect of children under the age of 18 years. many forms of cm result in actual or potential harm to the child, including physical and/ or emotional ill-treatment, sexual abuse, neglect, negligence and commercial or other exploitation.1 cm is a widespread global phenomenon as summarised in a series of meta-analyses.2 although cm is ubiquitous, its parameters, recognition and management vary by region and country. compared to western countries, there is a paucity of medical literature related to cm within the gulf countries.3,4 according to al-mahroos, in the arab peninsula, medically reported cases most likely only represent the tip of the iceberg, while most of the less severe cases go unreported.4 nevertheless, several reports documenting cm in oman are now available in the medical literature. oman is a country in the gulf corporation countries (gcc), which is a group of countries with cultural similarities. oman has a fairly young population with half of the omani citizens being below the age of 25.5 in the past four decades, oman’s socioeconomic status has been characterised by rapid development, resulting in improved standards of living and significant gains in health and education. this rapid development has also led to a shift from a traditional society towards a more modernised one with potential implications for the safety and wellbeing of omani children.6 the united nations study on violence against children prohibits all forms of violence against children in all settings as required by international treaties, including the convention on the rights of the child, which was ratified by oman in 1996.7,8 oman child law was implemented in 2014 and is often considered the biggest turning point towards an effective child protection services (cps). it gave legal power to the cps and the law consists of 79 articles that specify childrens’ rights as well as protection measures and penalties for violating them.9 this review aimed to provide an overview of the state and patterns of cm in oman until the year 2020. this review also addresses the current cps in oman and the sociocultural constrains when dealing with cm in oman. this literature review should serve as a basic reference and as a background for further research in the field of child abuse and neglect in oman. methods this comprehensive literature review was conducted by reviewing all relevant medical literature about cm in oman that were published in english before january 2020. published reports were identified by searching the pubmed database and by using google scholar. the following terms were used during the search: child/physical/sexual/emotional/psychological/ münchhausen’s syndrome by proxy (msbp) + abuse/ maltreatment/neglect + oman. discharge against medical advice (dama) was also included as a search term. dama is a situation where a caregiver removes a paediatric patient from the hospital against the medical team’s recommendation.10 dama is considered a form of medical neglect, as it deprives review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.5.2021.073 abstract: child maltreatment (cm) is the abuse and neglect of children under the age of 18 years. many types of cm lead to actual or potential harm to the child’s health. it is a widespread phenomenon and is well reported in western countries in contrast with the gulf countries. reports documenting cm in oman are now available; therefore, this review aimed to provide an overview of the state and patterns of cm in oman. it also addresses the current child protection services (cps) in oman and the sociocultural constraints. all english-language relevant medical literature about cm in oman that were published before january 2020 were included. this review can serve as a basic reference in the field of cm in oman and should help to identify lacunas in the current cps as well as provide guidance in the establishment of a more effective one. keywords: child maltreatment; child protection services; child advocacy; oman. the emergence of child protection capacities in oman lessons learned 518 | squ medical journal, november 2021, volume 21, issue 4 a child of his/her medical rights. in addition, reports were obtained from references of articles and relevant conferences. the date of the last search was january 23, 2020. results a total of 19 medical articles and reports were included in this review.3,11–27,38 one of these articles described child abuse potential inventory translation to arabic, which is suitable to oman, and two were published to advocate and raise awareness in the field of cm.3,11,12 most articles were case reports or case series providing descriptions of different forms of cm [figure 1]. the following is a description of the remaining included studies. the first section includes the studies describing cm cases while the second section contains studies related to child protection capacities in oman. pat t e r n s o f c h i l d m a lt r e at m e n t r e p o r t e d i n o m a n the first report on child abuse and neglect in oman appeared in the year 2000. this report described five children with medical child abuse (formerly msbp) from 1996–1999. their ages were between 1–11 years. uncontrolled epilepsy was the history given by the mothers of all five children. the delay in the diagnosis of msbp was up to six years.13 in 2001, a case report of factitious hypoglycaemia, which described a child who first presented at the age of three years, was published. the child presented with multiple episodes of hypoglycaemia, sometimes with convulsion, up to the age of six years. he was lost to follow-up. a detailed psychosocial history of his mother (the alleged perpetrator) was provided and it included early childhood marriage twice with both marriages ending in divorce.14 in 2004, a survey was conducted on adolescent depression, which included questions on experiences of child abuse. the relationship with relatives, friends and teachers were assessed on a scale. it was found that 17% of the adolescents surveyed had depressive symptoms. approximately 25% of them reported being subjected to physical abuse during adolescence by their caregiver. the study showed that physical abuse during adolescence significantly predicted depressive symptoms and that social support could have a buffering effect on depressive symptoms.15 in 2004, al-lamky published an exploratory review of the available literature in oman (including arabic papers) to examine child neglect as a social phenomenon. she highlighted some alarming trends and she concluded that they had harmful implications for the country’s future development. some of those trends were as follows: increasing divorce rates; short maternity leave; increasing reliance on untrained, expatriate and overburdened housemaids for raising children; and fathers’ absence, often due to work and minimal involvement in their families.16 from 2006 until 2012, al-saadoon studied all cases suspected to be victims of medical child abuse registered at the sultan qaboos university hospital, muscat, oman. a total of four children were identified figure 1: flowchart summarising the results of the literature included in this review.3,11–27,38 sa = sexual abuse; dama = discharge against medical advice; cp = child protection; mca = medical child abuse (formerly known as munchausen syndrome by proxy [msp]). **reported cases in less details: 25 cases of neglect; dama (9 cases ); 4 cases of physical abuse; 2 cases of sexual abuse; 1 case of emotional abuse 7 cases with more than one type of abuse. shamsa s. al balushi, gillian morantz and geoffrey dougherty review | 519 who were aged between 4–12 years. the cases presented with multiple unexplained symptoms (vomiting, headache, chest discomfort, palpitations and breathing difficulty). all of the alleged perpetrators had major psychosocial issues. two out of the four cases reported using some type of physical abuse/punishment for the child, and in one case, there was a history of domestic violence among the couple. due to the lack of child protection regulations at that time, it was not possible to enforce some of the management plans. the patients were evaluated by the hospital child protection (cp) team with the active involvement of the ministry of social development. children and mothers were also referred for psychiatric evaluation and management, but for three cases, the service was not utilised due to transportation issues or lack of interest.17 in 2010, a case report was published that reviewed three children who suffered from heat stroke after being trapped in vehicles. the mechanism of heat stroke in two of the reported children was car doors being left unlocked and the children entering into them without their parents’ knowledge. all of the reported cases needed intensive care management and survived with residual brain damage. two of the children were left with attention-deficit/hyperactivity disorder, while the third had active epilepsy. the article concluded by advocating against leaving children unattended in or around vehicles and concluded that this was a serious problem and a form of neglect.18 in 2011, a case report was published that described an omani preschool child with cannabis exposure. she was brought by her parents to the emergency room four hours after the onset of symptoms (vomiting, abnormal eye movements, lethargy and inability to stand). the family had psychosocial and substance issues and loss of income. her father removed her from the hospital against medical advice. five days after discharge, tetracannabinoid substance was confirmed in the child’s vomit. the child was reported to have hyperactivity and developmental delay in gross motor skills and language skills; prenatal/chronic cannabis exposure may have been a contributing factor to these issues. it was not mentioned in the report whether this case was reported to a higher authority.19 between 2011 and 2013, al-saadoon et al. reported six cases of cm. the first case described was a newborn who was abandoned by his mother after delivery. since the criteria for placement in an orphanage states that only abandoned children of unknown parents are to be accommodated, the mother was forced to take the child into her care. the baby was brought back at the age of one month with bleeding from the nose and mouth and in cardiorespiratory arrest. unfortunately, the baby died. the second reported case was a previously healthy 12-year-old girl admitted to the paediatrics intensive care unit with fulminant hepatic and multi-organ failure. the girl, unfortunately, died of acute mercury poisoning. parents admitted that they had applied mercury as a traditional treatment for hair lice. the third case was a toddler who was playing unattended on a swing in her house. she was found hanging from the neck by the swing’s rope and was given initial resuscitation at home; fortunately, the child survived. the fourth case was a 12-year-old girl who was diagnosed with inflammatory bowel disease and started on therapy. at follow-up, the child had uncontrolled symptoms and a non-reduction in inflammatory indices. the mother admitted to not giving the child her medications. the fifth case was a three-year-old boy who presented with aggression, remarkable changes in his behaviour and sexualised behaviours noted by his mother. the parents were separated, and the child went to the father’s family home for weekly visits. the mother suspected recurrent sexual abuse of the child by three adolescent male relatives. the child was reported to have bruises around the anus. the boy’s mother and the cp team made significant efforts, which put an end to the abuse. the child and mother received psychotherapy. the sixth case was an infant with recurrent episodes of limb fractures, including a fracture of the distal humerus during the neonatal period, a second fracture of the left femur and a third fracture of the humerus at the age of four years and six months. investigations for bone diseases were negative at that stage. the parents denied any history of trauma and informed the cp team that they had sent an expatriate housemaid back to her country after the first event. both parents believed that there was a jinn (spirit of evil) that was hurting their child. the parents were extensively counselled. the child was placed under close followup and no further injuries were noted.20 in 2013, koul et al. reported a case of abusive head trauma (formally known as shaken baby syndrome; aht). a five-month-old, previously healthy child, presented with a 10-day history of repeated tonic seizures, which were controlled with antiepileptic medication during admission. after discharge, the parents did not continue medication and he was admitted several times with breakthrough seizures. a brain magnetic resonance imaging (mri) scan revealed a right-sided subdural haematoma. a metabolic workup (serum copper and urine organic acids) and a coagulation workup were carried out; the results were all normal. microscopic examination of the hair (to identify kinked hair) revealed normal results. the ophthalmic examination also revealed normal results. the parents refused further workup, the emergence of child protection capacities in oman lessons learned 520 | squ medical journal, november 2021, volume 21, issue 4 particularly a skeletal survey and left against medical advice. two months later, the child presented with status epilepticus and swelling of the right knee. the skeletal survey revealed a healing fracture in the right radius and an acute fracture of the right distal femur. a follow-up electroencephalography revealed features of epileptic encephalopathy, and over time, he developed refractory seizures. repeat brain mri scan showed brain atrophy and resolution of the previous subdural haematoma. the cp team became involved and the parents agreed to follow the treatment recommendations at that time. psychosocial evaluation of the family did not reveal any risk factors for inflicted injury. the authors concluded that there was no other cause found in this case except aht.21 two studies were conducted concerning dama. a significant number of the patients (57.9%) were discharged against medical advice despite having potentially life-threatening health conditions such as septicaemia, acute abdominal pain and inflammatory diseases of the central nervous system.22 in more than half of the cases, the reasons for dama were not reported. when reported, the reasons cited for dama included the following: maternal perception of improvement in the child's condition (40.4%) and social factors (e.g. arranging care for other children at home and the work commitments of the parents). in the prospective study, parents received a phone call two weeks later. the outcome of dama after two weeks indicated that 21.3% of the patients were still suffering from the same symptoms. in 4.3% of the cases, the interviewed mothers refused to reveal the condition of their child [table 1].22,23 in january 2020, a report was published on the characteristics and psychosocial effects of 34 children with a history of sexual abuse.24 this primarily consisted of case descriptions. many of the published reports aimed to increase the level of awareness about cm in oman and advocated for better child supervision and the establishment of an effective cps [table 2]. c h i l d m a lt r e at m e n t c a pa c i t y d e v e l o p m e n t i n o m a n in 2013, 136 participants (social workers, nurses, psychologists and health educators) were involved in a five-hour workshop on child protection and were asked to complete a questionnaire with 19 statements that described scenarios of child abuse. the participants filled-in the questionnaire before starting and at the end of the workshop. the results indicated that physical abuse, emotional abuse and neglect were less likely to be identified compared to sexual abuse. the post questionnaire results showed improved recognition of the scenarios of cm. the article concluded that training of health professionals can improve their knowledge about what constitutes abusive practices, thereby leading to better recognition of cm.25 a further study was conducted to determine the impact of the child law between 2013 and 2015 (one year before and after the implementation of the child law). the study reviewing all the cases reported and registered during this period. there was a modest increase in the number of reported cases from 20 to 28 cases per year. the reported cases of dama, for example, increased from one to eight cases. according to the author, this was possibly explained by the increased recognition of the legal responsibility by the doctors after the implementation of the law. it was also observed that the child law helped in the standardisation of the reporting of all cases to the child protection committee and in avoiding duplicated services being offered to the reported cases. the law also had a positive impact on the legal intervention process, follow-up and the services provided to the reported patients.26 in 2016, 49 key informants and decision-makers working in child protection were involved in a study on the readiness to implement the cm prevention programme using the world health organization’s 10 table 1: charactertistics of two studies concerning discharge against medical advice22,23 characteristic al-sadoon et al.22 2013 al-saadoon et al.23 study period 2004–2006 2013–2014 type of study retrospective prospective prevalence rate of dama in % 0.32 1 infants involved approximately two-thirds of the patients in both studies dama = discharge against medical advice. table 2: characteristics of 34 children with a history of sexual abuse24 characteristic n age <12 years 23 female 22 low family income 29 abused by a first-degree relative 10 abuse took place at the residence 28 full sexual penetration 15 a pre-disclosure period of more than 12 months 23 shamsa s. al balushi, gillian morantz and geoffrey dougherty review | 521 dimensional readiness tool. the dimensions with the highest scores were noted to be legislation, mandates and policies followed by knowledge. the dimensions with the lowest scores were noted to be human and technical resources and attitudes. the overall score of the 10 dimensions was 50.17 which reflected a modest readiness of the country to provide a cm prevention programme.27,28 these papers aimed at exploring the current resources for cm prevention in oman. the following section is a discussion of the current context and situation regarding cm in oman as revealed by this literature review. discussion in this section, the reported cm cases in the omani literature are discussed, contrasted and compared to the international data under four headings. the overall perception of cm data is presented first, followed by a discussion of the characteristics of the reported cases. risk factors associated with cm cases are presented. the final section concerns the reported child protection response to cm cases. c h i l d m a lt r e at m e n t d ata f r o m o m a n this review of the literature on cm in oman revealed that omani children are subjected to all known forms of cm. no national cross-sectional prevalence studies on cm were identified during this literature review, and due to the relative paucity of data from oman, it was difficult to estimate whether the magnitude of cm in oman is similar to what is seen in other parts of the world. it was noted that there has been an increase in publications from oman concerning cm in recent years, which might be due to the increase in the number of professionals with an interest in this field and an increase in awareness among professionals, particularly since the implementation of the child law in 2014. the first report on cm in oman appeared in the year 2000, which appears somewhat late compared to the first cases of cm worldwide which was reported in 1962.29 c h a r a c t e r i s t i c s o f c h i l d m a lt r e at m e n t i n o m a n most of the reports concerning cm were found to be hospital-based and usually represented very severe forms of cm, such as aht and neglect leading to death, or other forms of cm such as dama, medical child abuse and accidental injuries as a possible result of neglect. there were very few available reports in the omani medical literature on the more common forms of cm, such as inflicted bruises and fractures. this might reflect that physical abuse may be tolerated and often accepted as a form of physical discipline. another explanation for a lack of such data is that primary care physicians, who see such injuries first, fail to identify these cases. professionals, in general, may be unaware of the signs for cm as well as their legal responsibilities. this lack of recognition of cm seemed to have been particularly pervasive before the implementation of the child law, which was evidenced by the increase in reported cases as demonstrated in the study on the impact of the child law.26 similarly, any mention of psychological maltreatment including exposure to domestic violence, was conspicuously absent from the omani literature. medical child abuse was the first identified type of cm in the omani medical literature and it continued to be the only reported type until 2010. only one case of aht has been published in the omani literature thus far. it is known that aht is less often seen and reported in the gcc countries.21 however, aht can have a subtle clinical presentation and potential cases may have been going unrecognised and/or unreported. in the one case reported in the omani literature, there was a delay in obtaining head imaging as well as ancillary testing, which may have resulted in a delayed diagnosis. aiming to increase awareness about this type of cm, al-saadoon et al. published an advocacy paper in 2011.3 the authors opine that the prevalence of child sexual abuse is possibly lower in oman compared to worldwide averages because of its culture, but in order to reach such a conclusion extensive population-wide research would be required. only 37 cases of sexual abuse have been reported so far. this is not likely to be the actual number in the community and many sexual abuse victims may not be brought to medical or legal attention by caregivers, possibly due to a culture of ‘silence’ surrounding this issue. al shekaili et al. concluded that that the patterns of sexual abuse seemed to be similar to the trends worldwide given that the majority of the omani sexual abuse victims were female and aged below 12 years.30,31 however, it was a study with a small sample size and it included only cases referred for rehabilitation, which could have had biases due to the culture around female sexual abuse compared to male sexual abuse.24 dama is a significant issue in omani hospitals and it deprives a child of his/her right to necessary medical care. in some cases, children’s lives could have been placed at risk. the studied prevalence rate of dama in oman was 0.32–1%, which was comparable to a worldwide rate estimated to be approximately the emergence of child protection capacities in oman lessons learned 522 | squ medical journal, november 2021, volume 21, issue 4 1%.32–34 social problems are the major reasons cited for dama in oman. only one case report proved that a child was exposed to cannabis, and in this report, the child was discharged against medical advice. furthermore, there was no mention in the report about whether the cp team was engaged. neglect is reported indirectly as was seen in three cases of vehicular entrapment resulting in heat stroke and significant neurological sequelae and one case of lack of supervision resulting in a child being strangulated by a swing. omani adolescents with a history of physical abuse were found to be more likely to have depression. this finding was comparable to international studies that revealed that abused adolescents showed significantly higher prevalence rates of depression, conduct disorder, suicide and substance abuse.35,36 r i s k fa c t o r s f o r c h i l d m a lt r e at m e n t i n o m a n similar to the international medical literature, difficult socioeconomic conditions appeared to be major risk factors for child abuse in oman. these factors included divorced parents, early marriages and lack of social support. some mothers of abused children were themselves abused during their childhood and had psychological consequences that were likely left untreated. other socioeconomic issues that were mentioned included poverty, lack of parental medical literacy, beliefs in traditional medicine and loss of trust in health services. this suggests that primary and secondary cm prevention strategies might be effective in reducing cm as in other jurisdictions.37 in addition, it was found that a lack of child protection intervention in some cases allowed abuse to continue.19–21 certain social attitudes and traditional cultural practices were found to represent another challenge for the efforts to address cm prevention in oman. belief in evil spirits such as a jinn was a reason provided by some caregivers to explain abnormal behaviours of the abused child and for dama. the practice of remaining silent and fear of social taboo linked to sexual abuse resulted in fewer children being rehabilitated after abuse; these were found to be risk factors for continued child abuse. r e s p o n s e t o c h i l d m a lt r e at m e n t a n d t h e c u r r e n t c h i l d p r o t e c t i o n s e r v i c e s this review suggested that until recently, there had been a lack of child protection response to cm cases in oman, especially prior to the implementation of the child law in 2014. abused children were most often returned to their homes despite the certainty of abusive environments; many continued to suffer without psychological rehabilitation and some died without protection. monitoring of victims through hospital-based appointments or home visitation by child welfare services was rare and this led to a loss of the opportunity to monitor a maltreated child. in most cases, alleged perpetrators did not receive any educational interventions or face criminal punishment, nor were safety measures put into place. regarding mental health services, there are only two institutes in oman that provide child and adolescent mental health services. they offer services to the whole country and are both located in the capital.38 after the implementation of the child law, there was an increase in the number of reported cases and an improvement in the follow-up, legal intervention and services provided to the reported patients.26 in 2016, child protection delegates were appointed and they are considered judicial police. currently, there is a child helpline as well as child protection committees in all omani regions.26 l e s s o n s l e a r n e d a n d t h e way f o r wa r d the magnitude and the actual prevalence of cm in oman were found to be difficult to estimate from what has been published to date. this review highlighted the need to further understand the prevalence and patterns of cm in oman through population-based studies in order to inform omani child protection policy and programming. further research into the more common forms of cm (i.e. inflicted bruises and fractures) should be pursued. a review of the literature revealed that until recently, oman’s cps was significantly lacking in terms of effectiveness; in light of this, a detailed specific review for the current cps is recommended. this review also highlighted a lack of effective community-based services, such as family counselling programmes, to teach parenting skills. several such secondary prevention interventions have proven successful in other settings. it is important to continue to develop and implement culturally adapted community awareness cm prevention programmes. this review suggested that the role of cm awareness campaigns in the general community and among professionals caring for children, such as teachers and social workers, is important. in addition, social support services may help prevent dama occurrences and buffer depressive symptoms among abused children. there is a need to ensure access to rehabilitation and treatment for abused children as well as the provision of a larger number of mental health services that are shamsa s. al balushi, gillian morantz and geoffrey dougherty review | 523 more easily accessible. penal sanctions should be made more explicit so that they can act as a deterrent to potential perpetrators. there should be an opportunity for permanent placement in certain severe cases of abuse, such as kinship placement with relatives or even a foster care system. conclusion oman has made significant progress in the field of cm. social, medical and legal capacity to support the continuing promotion of cm systems can and should be further developed. a u t h o r s’ c o n t r i b u t i o n ssb and gd conceptualised and designed the review. ssb performed the literature review and collected the data. ssb and gm analysed and discussed the data. ssb drafted the manuscript, while gm and gd revised the manuscript. all authors approved the final version of the manuscript. references 1. world health organization. child maltreatment, 2016. from: https://www.who.int/news-room/fact-sheets/detail/childmaltreatment accessed: jan 2020. 2. stoltenborgh m, bakermns-kranenburg mj, alink lra, van ijzendoorn mh. the prevalence of child maltreatment across the globe: review of a series of meta-analyses. child abuse rev 2015; 24:37–50. https://doi.org/10.1002/car.2353. 3. al-saadoon m, elnour i, ganesh a. shaken baby syndrome as a form of abusive head trauma. sultan qaboos univ med j 2011; 11:322–7. 4. al-mahroos f. child abuse and neglect in the arab peninsula. saudi med j 2007; 28:241–8. 5. ministry of health, oman. annual health report 2018. table 1-1: population characteristics (omani population) page 4. from: https://www.moh.gov.om/en/web/statistics/-/20-59 accessed: dec 2020. 6. al-adawi s. tomorrow’s people matters: evidence for action in oman. oman med j 2014; 29:83–5. https://doi.org/10.5001/ omj.2014.21. 7. united nations. legal ban on violence against children. from: https://violenceagainstchildren.un.org/content/legal-banviolence-against-children accessed: dec 2020. 8. unicef oman. charting progress towards child protection in sultanate of oman – findings of a national consultative workshop. muscat, oman: unicef. p.6. 9. ministry of social development, oman. oman child law. from: https://www.mosd.gov.om/images/rules/childs%20law %20en.pdf accessed: dec 2020. 10. alfandre dj. “i’m going home”: discharges against medical advice. mayo clin proc 2009; 84:255–60. https://doi.org/10.1016/s00 25-6196(11)61143-9. 11. al abduwani j, sidebotham p, al saadoon m, al lawati m, barlow j. the child abuse potential inventory: development of an arabic version. child abuse negl 2017; 72:283–90. https:// doi.org/10.1016/j.chiabu.2017.08.012. 12. al-lamki l. child rights: what can we do in oman? sultan qaboos univ med j 2012; 12:1–4. https://doi.org/10.12816/0003081. 13. koul rl, chacko a, al-lamki z, al-amri am, al-khusaiby s. munchausen syndrome by proxy. saudi med j 2000; 21:482–6. 14. bappal b, george m, nair r, khusaiby sa, de silva v. factitious hypoglycemia: a tale from the arab world. pediatrics 2001; 107:180–181. 15. afifi m, al riyami a, morsi m, al kharusil h. depressive symptoms among high school adolescents in oman. east mediterr health j 2006; 12:s126–37. 16. al-lamky a. modernization and child neglect in oman: trends and implications. int j world peace 2004; 21:43–53. 17. al-saadoon m. munchausen syndrome by proxy (msbp): difficulties of applying diagnostic criteria. poster presented at: 13th ispcan european regional conference on child abuse and neglect; 2013 sep; dublin, ireland. 18. koul r, al-futaisi a, al-sadoon m, el-nour i, chacko a, hira m, et al. vehicular entrapment and heat stroke in three children: is it a form of child neglect? oman med j 2010; 25:222–4. https://doi.org/10.5001/omj.2010.61. 19. al-shidhani ta, arora v. cannabis exposure in an omani child: first case report from oman. sultan qaboos univ med j 2011; 1:511–14. 20. al-saadoon m, al-sharbati m, nour ie, al-said b. child maltreatment types and effects: series of six cases from a university hospital in oman. sultan qaboos univ med j 2012; 12:97–102. 21. koul r, poothrikovil r, al-azri f, al-sadoon m. evolution of epileptic encephalopathy in an infant with non-accidental head injury. neurosciences (riyadh) 2013; 18:264–8. 22. al-sadoon m, al-shamousi k. discharge against medical advice among children in oman: a university hospital experience. sultan qaboos univ med j 2013; 13:534–8. 23. al-saadoon m, al mahrouqi h, al jaafari n, al maawali h. reasons of discharge against medical advice among children in oman: squh experience. poster presented at:14th ispcan european regional conference on child abuse and neglect; 2015 sep; bucharest, romania. 24. alshekaili m, alkalbani y, hassan w, alsulimani f, alkasbi s, chan mf, et al. characteristic and psychosocial consequences of sexually abused children referred to a tertiary care facility in oman: sentinel study. heliyon 2020; 6:e03150. https://doi. org/10.1016/j.heliyon.2019.e03150. 25. al saadoon m, al hadifi f, al-said b. recognition of child abuse: are we using same definition. poster presented at: ispcan asia pacific regional conference on child abuse and neglect; 2015 oct; malaysia. 26. al saadoon m. impact of child law on hospital protection services: sultan qaboos university hospital (squh) experience. poster presented at: ispcan asia pacific regional conference on child abuse and neglect; 2015 oct; malaysia. 27. al saadoon m, al numani a, saleheen h, almuneef m, al eissa m. child maltreatment prevention readiness assessment in oman. poster presented at: the 2019 ispcan congress and the 6th arab international child abuse and neglect conference; 2019 sep 15–17; muscat, sultanate of oman. 28. al eissa m, saleheen h, almuneef m, al saadoon m, alkhawari m, almidfa a, et al. child maltreatment prevention readiness in gulf cooperation council (gcc) countries. int j pediatr adolesc med 2019; 6:92–100. https://doi.org/10.1016/j. ijpam.2019.07.009. 29. kempe ch, silverman fn, steele bf, droegemueller w, silver hk. the battered-child syndrome. jama 1962; 181:17–24. https:// doi.org/10.1001/jama.1962.03050270019004. the emergence of child protection capacities in oman lessons learned 524 | squ medical journal, november 2021, volume 21, issue 4 30. barth j, bermetz l, heim e, trelle s, tonia t. the current prevalence of child sexual abuse worldwide: a systematic review and meta-analysis. int j public health 2013; 58:469–83. https://doi.org/10.1007/s00038-012-0426-1. 31. kim h, drake b. cumulative prevalence of onset and recurrence of child maltreatment reports. j am acad child adolesc psy chiatry 2019; 58:1175–83. https://doi.org/10.1016/j.jaac.2019.02.015. 32. okoromah cn, egri-qkwaji mt. profile of and control measures for paediatric discharges against medical advice. niger postgrad med j 2004; 11:21–5. 33. aliyu zy. discharge against medical advice: sociodemographic, clinical and financial perspectives. int j clin pract 2002; 56:325–7. 34. gloyd s, koné a, victor ae. pediatric discharge against medical advice in bouaké cote d’ivoire, 1980–1992. health policy plan 1995; 10:89–93. https://doi.org/10.1093/heapol/10.1.89. 35. pelcovitz d, kaplan s, goldenberg b, mandel f, lehane j, guarrera j. post-traumatic stress disorder in physically abused adolescents. j am acad child adolesc psychiatry 1994; 33:305–12. https://doi.org/10.1097/00004583-199403000-00002. 36. kaplan sj, pelcovitz d, salzinger s, mandel f, weiner m. adolescent physical abuse and suicide attempts. j am acad child adolesc psychiatry 1997; 36:799–808. https://doi. org/10.1097/00004583-199706000-00017. 37. chaffin m, friedrich b. evidence-based treatments in child abuse and neglect. children and youth services review 2004; 26:1097–113. https://doi.org/10.1016/j.childyouth.2004.08.008. 38. mirza h. child and adolescent mental health services in oman. london j prim care (abingdon) 2018; 10:121–2. https://doi.or g/10.1080/17571472.2018.1482661. radiation exposure levels in family members of omani patients with thyrotoxicosis treated with radioiodine (131i) as outpatients *ibtisaam al-maskery and haddia bererhi squ med j, august 2009, vol. 9, iss. 2, pp. 148-152, epub 30th june 2009 submitted 22nd dec 08 revision req. 21st mar 09, revision recd. 10th may 09 accepted 18th may 09 department of radiology and molecular imaging, college of medicine & health sciences , sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: imaskery@squ.edu.om clinical & basic research advances in knowledge 1. this study show that, with good radiation safety instructions to patients and relatives, thyrotoxic patients may be treated as outpatients provided the patient is physically and mentally fit to comply with the given instructions and that factors such as travelling distance, socio-economic conditions and family life style are taken into account. application to patient care treating thyrotoxic patients, receiving radioiodine therapy, as outpatients will: 1. avoid the isolation of these patients with all of its complications. patients will be more comfortable in their own surroundings with their families. 2. outpatient treatment will reduce waiting lists allowing greater patient throughput this will lead to greater patient comfort and satisfaction. مستوى التعرض لالشعاع ألقرباء املرضى العمانيني املصابني بازدياد نشاط الغدة الدرقية بعد العالج باليود املشع كمرضى خارجيني ابتسام املسكري، هادية برارحي الغدة نشاط بازدياد املصابني العمانيني املرضى أقرباء عند لالشعاع التعرض مستوى كان اذا فيما ملعرفة الدراسة هذه اجريت الهدف: امللخص: الدرقية الذين عوجلوا باليود املشع كمرضى خارجيني ، ضمن احلدود املقبولة عامليا ومحليا ، وذلك للسماح لهم مبواصلة العالج كمرضى خارجيني. الطريقة: مت مراقبة اجلرعات االشعاعية ملدة عشرة ايام ل 86 من أقرباء 22 مريضا تلقوا العالج باليود املشع بدون ترقيد وذلك باستخدام جهاز قياس اجلرعة االشعاعية. اعطيت تعليمات الوقاية االشعاعية كتابيا وشفهيا للمرضى واقربائهم قبل مغادرتهم املستشفى. كان معدل األعمار لألقرباء )26.6( سنة واملدى يتراوح بني )17( شهرا و )75( سنة )29 طفال 16 ≥ سنة و57 بالغا منهم 11 زوج/زوجة و 8 والد/والدة (. كان معدل جرعة اليود املشع املعطاة للمرضى )mbq 610 ±79( )املدى بني mbq 520-862(. النتائج: اجلرعات االشعاعيه التي تلقاها افراد العائلة اقل من اشعاعيه جرعات تلقوا سنة ) 12و 13 و15 ( و شهرا )19( أعمارهم أطفال اربعة ماعدا ،)1msv( الناس لعامة بها املوصى السنوية اجلرعة مبعدل ) 1.2 1.2 ,2.9 و msv )1.2. اخلالصة: بناءا على اجلرعات االشعاعيه القليلة التي تلقاها أقرباء املرضى فاننا نوصي بعالج املرضى املصابني بازدياد نشاط الغدة الدرقية باليود املشع حتى جرعة )mbq 800( كمرضى خارجيني. مفتاح الكلمات: اليود املشع، اجلرعة االشعاعية، اقرباء املرضى، فرط نشاط الغدة الدرقية، مرضى خارجيني، جهاز قياس اجلرعة االشعاعية. abstract: objectives: this study was conducted to assess whether the radiation exposure levels of omani family members of thyrotoxic patients, if treated with radioiodine therapy as outpatients, are within the international and local radiation dose limits in order to allow them to be treated as outpatients. methods: the study included 86 family members of 22 self-dependent thyrotoxic patients )29 children ≤ 16 yrs and 57 adults including 11 spouses and 8 parents(. the mean age of the family members was 26.6 years )range 17 months 75 years(.they were treated with 131i as outpatients and monitored for 10 days in 2007-2008 for radiation exposure using thermoluminescent dosimeters )tlds(. the mean administered activity of 131i to patients )±sd( was 610 ±79mbq in the range 520-862 mbq. oral and written radiation safety instructions were given to patients and family members before leaving the hospital. results: the radiation doses received by family members were less than the annual recommended dose limit for general public of 1msv, except for four children aged 19 months, 12, 13 and 15 years, who received radiation doses of 2.9, 1.2, 1.2 and 1.2 msv respectively. conclusion: in view of the low radiation doses received by the family members, we recommend treating thyrotoxic patients undergoing radioiodine therapy with administered activities up to 800 mbq as outpatients. keywords: radioiodine; radiation dose; family members; thyrotoxicosis, outpatient; thermoluminescent dosimetry. ibtisaam al-maskery and haddia bererhi clinical and basic research | 149 radioiodine therapy, proven to be safe and relatively inexpensive, has been widely used over decades for the treatment of thyrotoxicosis.1,2 however, there are some radiation protection concerns associated with the treatment. in addition to beta particle emissions, 131i emits penetrating ionizing γ-radiation of 364kev. the therapeutic administration of 131i makes the patient a source of radiation exposure and a potential radiation hazard to individuals in their surroundings.1,2 radiation doses received by the public and family members are received through internal contamination as a result of excreted radioiodine or through external exposure which remains the main concern.3,4 to protect relatives from these radiation exposures, patients are admitted in radioiodine therapy wards for different lengths of time according to local regulations. nowadays, most countries treat thyrotoxic patients as outpatients. this is done provided they are given appropriate radiation safety instructions to limit the radiation exposures to their family members, particularly to children and pregnant women and the public, to 1.0msv per year as recommended by the international commission of radiological protection (icrp).5 however, higher radiation doses received by adult family members are acceptable as long as the average dose of five consecutive years does not exceed 5msv.5 these limits are also implemented in oman. the criteria for treating these patients as outpatients are based on the following conditions: a) administered activity should be less than 800mbq (±10%),6,7 and b) the dose rate should be less than 40μsv/h at a distance of one meter away from the patient.7 unless the above is achieved, to comply with the radiation limits to family members and the public, hospitalisation of patients is necessary. for social and cultural reasons in oman, thyrotoxic patients treated with 131i were hospitalised until their radiation level dropped to 2μsv/h at a distance of one meter corresponding to body retained activity of less than 30mbq as advised by uk guidance notes.8 using a similar body retention of 131i activity, a study performed by bererhi and constable9 in 2000, found that doses received by family members of treated thyrotoxic patients were within allowed limits. subsequently, a significant shortening of hospitalisation stays of these patients was implemented in oman. the advantage of treating these patients as outpatients is that it reduces the burden on the health care systems including treatment expense and waiting list length, with the added benefit of patient comfort and satisfaction. this study was conducted as a follow up study to that of bererhi and constable9 to test thyrotoxic patients as outpatients after radioiodine therapy. methods eighty-six family members of 22 self-dependent thyrotoxic patients, treated with 131i as outpatients, participated in this study which was conducted between february 2007 and march 2008. all patients agreed to participate in this study. patients and family members were monitored for radiation exposure for 10 days using thermoluminescent dosimeters (tlds). this period was selected as the highest radiation exposure falls within these days. the mean age of the family members was 26.6 years (range 17 months 75 years) and included 29 children ≤ 16 yrs and 57 adults (11 spouses and 8 parents). radiation dose rates at one meter from patients were measured following the administration of 131i using a portable calibrated dose rate meter (type pdr1). written and verbal local radiation safety instructions [table 1] were provided to all patients prior to discharge. patients and their accompanying relatives wore their dosimeters before leaving the hospital. on their journey back home, patients were advised to sit in the back of the car on the opposite side from the driver to keep the distance between them at a maximum. the selection criteria were based on the following: a) patient and family members had to consent to wearing the dosimeter at all times for 10 days starting from the day the patient returned home; b) patient and family members had to live together in the same house during the whole period the dosimeter was worn. some patients were called randomly to confirm that they were fulfilling the above criteria. thermoluminescent dosimeters (tld), tld 200 rods, (6mm x 1mm diameter) made of caf2:dy were used in this study. a harshow 5500 tld reader was used to read the tlds [figure 1]. the rods were carefully handled with a vacuum tweezer and stored on a numbered plate in order to keep radiation exposure levels in family members of omani patients with thyrotoxicosis treated with radioiodine (131i) as outpatients 150 | squ medical journal, august 2009, volume 9, issue 2 track of the individual dosimeters. the dosimeters were annealed at 320°c for 1 min. in a tld-oven to clear them from any residual absorbed doses. for individual tld calibration, all tlds were irradiated to a dose of 1.0mgy using a 90sr irridiator 2000. from the resultant tld readings, the mean reading was calculated. the ratio of the individual and mean reading was taken to represent a calibration factor known as element correction coefficient (ecc) to compensate for variations in geometry and sensitivity among dosimeters. the reader was calibrated to produce consistent and accurate readings in dosimetrically meaningful units (µgy) by applying a reader calibration factor (rcf).10 for every subject, three rods were inserted into a flexible black tube made of silicon rubber with one sealed end. the open end was sealed with a removable plug of black rubber. the tube was then put into a watertight painted capsule, with a screwin end piece, and a cord was threaded into two holes at the extremities of the capsule, designed in such a way that, once the cord was in place, the capsule could not be opened. the lengths of the cord were adjusted to bring the capsule to the level of the supra-sternal notch [figure 2]. the capsules were placed in individually labelled lead pots, which were then fitted into a wooden box [figure 3] together with a dosimeter for background measurement. the patients were asked to keep the background dosimeter in a place remote from general living activities. after the tlds were returned, they were preheated in the tld oven at 100°c for 20 minutes then read out in the tld reader using a timetemperature profile of 200oc for 100s, 400oc for 300s and 400oc for 200s for preheating, acquisition and annealing, respectively. the average doses from the three tld rods of each member were recorded after background subtraction. results in compliance with the european commission (ec) guidelines7 regarding radioiodine therapy patient discharge, our patients left the hospital with mean (±sd) administered doses of 609.8 ±79mbq in the range 520-862mbq and mean radiation exposure dose levels of 23.4 ±6.3µsv/h in the range 13 to 42µsv/h. at one meter from the patient. the cumulative radiation doses (µsv) over 10 days received by the family members are shown in table 2. all family members, including spouses, received less than the annual dose limit of 1msv except for four out of 29 children (14%), aged 19 months and 12, 13, 15 years, who received radiation doses of 2.9, 1.2, 1.2 and 1.2 msv, respectively [figure 4]. the 19 month-old infant’s mother was treated with 555mbq of 131i and her radiation level at one meter, when leaving the hospital, was 13µsv /h. the 12 and 15 year old children were the younger sisters of a patient who was treated with 585mbq of 131i and her radiation level at one meter, when leaving the hospital, was 26µsv/h. the 13 year old child’s mother was treated with 566mbq of 131i and her radiation level at one meter, when leaving the hospital, was 19µsv/h. discussion although the release criteria limit in this study were less stringent than the recommended limits in some developing countries, where literacy and socio-economical factors were taken into account, such as in india (patient retained activity at discharge ≤ 600 mbq, or dose rate level of 30 µsv/ figure 1: harshaw 5500 thermoluminescent dosimeter reader figure 2: dosimeter positioned at level of suprasternal notch figure 3: set of dosimeters in lead pots within wooden box for patients and family members ibtisaam al-maskery and haddia bererhi clinical and basic research | 151 hr at 1 meter from patient)11 and pakistan (patient retained activity at discharge < 370 mbq, or dose rate level of ~ 10 µsv/h. at 1 meter from patient),12 95% of family members in this study received radiation dose levels lower than the annual limit of 1msv [figure 4]. this proves that the radiation safety instructions given and explained to patients and family members were understood and taken seriously by both patients and family members. the remaining family members who received doses higher than the annual radiation dose limit were children. these doses were received due to socioeconomic conditions, i.e. children belonged to homes where they were no person other than the mother to take care of them. this is seen in the case of the 19 month old child who was looked after only by the mother and slept with her in the same bed, although clear radiation safety instructions were given to the mother strictly to avoid contact with her child. however, it is common practice in oman that mothers sleep with their infants in the same room and children are very much attached to their parents, making the situation difficult to avoid. living conditions of some families, i.e. number of rooms in the house, was a factor that caused high radiation exposure to the other three children. the 23 year old patient lived in a house with only two rooms and slept with four other family members in the same bedroom exposing her younger sisters aged 12 and 15 years-old to a radiation dose higher than the annual dose limit. the 13 year old girl lived in a house with three rooms and slept in the same bedroom with her mother who received the therapy. the mean cumulative radiation doses received by spouses of this study was lower than the mean cumulative radiation doses received by spouses in bererhi and constable’s9 study in 2000. these results were obtained taking into account that the retained mean body activity in our patients when leaving the hospital was about 20 times (609.8 versus 30mbq) more than that reported by bererhi and constable9, and the time the dosimeters were worn in our study was longer than in bererhi and constable’s study9 (10 days versus 7 days). our outpatients were also strictly advised to sleep separately from their spouses for a period of three weeks post-therapy whereas spouses in bererhi and constable’s study slept in the same bed. in the study by monsieurs et al.,13 recommendations for spouses of thyrotoxic patients treated with radioiodine was to sleep separately for a duration of 21 days in order to comply with the annual dose limit of 1msv. in our study, using the same instructions, the same results were achieved indicating good compliance with the radiation safety instructions given. conclusion in our institution, thyrotoxic patients treated with radioiodine are hospitalised for a few days. the results of this study show that with good radiation safety instructions to patients and relatives, thyrotoxic patients may be treated as outpatients provided the patient is physically and mentally fit enough to comply with the given instructions. however, the decision of releasing these patients from the hospital should be based on several factors including travelling distance, socio-economic conditions and family life style. we recommend that: 1) mothers with children below the age of 3 years should not be treated as outpatients unless arrangements can be made for their children to be looked after by someone else other than the mother for a few days as recommended elsewhere;14,15 2) patients sharing the same room with many other family members should be hospitalised for a few days to avoid unnecessary table 1: local radiation safety instructions for 131i therapy outpatients 1. avoid all close contact with children and pregnant women for three weeks 2. avoid prolonged personal contact with adults for two weeks 3. do not sleep with an adult/child on the same bed for three weeks 4. you may return to work after ……….days (depending on occupation) table 2: cumulative radiation doses over 10 days received by relatives of omani thyrotoxic out-patients treated with 131i with a mean of 609.8 ±79mbq relatives no. radiation dose (µsv) min max mean sd spouses 11 7 425 105 152 others 75 0 2921 (child) 206 440 radiation exposure levels in family members of omani patients with thyrotoxicosis treated with radioiodine (131i) as outpatients 152 | squ medical journal, august 2009, volume 9, issue 2 radiation exposure to others. acknowlegements the contents of this article were presented at the annual scientific meetingof the swiss society of radiobiology & medical physics in november 2008. the authors would like to thanks the college of medicince and health sciences and the hospital at sultan qaboos university for supporting this work conflict of interest the authors report with no conflit of interest. references 1. invited commentary. 131-i therapy: inpatient or outpatient? j nuclear med. 2000; 41:1876-8. 2. vetter rj. regulations for radioiodine therapy in the united states: current status and the process of change. thyroid 1997; 7:209-11. 3. athanasopoulou e, karaveli m, chatzigiannaki a, gotzamani-psarrakou a. unexpected dose to the daughter of a patient treated with iodine-131 for hyperthyroidism. hell j nucl med 2007; 10:175-6. 4. barrington s, doherty m, kettle a, thomson w, mountford p, burrell d, et al. radiation exposure of the families of outpatients treated with radioiodine (iodine-131) for hyperthyroidism. eur j nuclear med 1999; 26:686-92. 5. recommendations of the icrp. icrp publication 60. ann icrp 1991; 21:1-3. 6. cappelen t, unhjem j, amundsen a, kravdal g, folling i. radiation exposure to family members of patients with thyrotoxicosis treated with iodine-131. eur j nucl med mol imaging 2006; 33:81-6. 7. european commission. radiation protection 97: radiation protection following iodine-131 therapy (exposure due to out-patients or discharged in patients). brussels: directorate general for environment nuclear safety and civil protection, 1998. 8. hmso. guidance notes for the protection of persons against ionizing radiations arising from medical and dental uses. london: hmso, 1998. 9. bererhi h, constable ar. radiation exposure levels in relatives of patients after radioiodine therapy. squ j sci res: med sci 2000; 2:87-90. 10. bicron radiation measurement products. model 5500 automatic tld reader user’s manual. usa, 1993. 11. pant gs, sharma sk, bal cs, kumar r, rath gk. radiation dose to family members of hyperthyroidism and thyroid cancer patients treated with 131i. radiat prot dosimetry 2006; 118:22-7. 12. mohammad w, faaruq s, hussain ma, khan a. release criteria from hospitals of 131i thyrotoxicosis therapy patients in developing countries case study. radiat prot dosimetry 2006; 121:136-9. 13. monsieurs m, thierens h, dierckx r, casier k, baere e, ridder l, et al. real-life radiation burden to relatives of patients treated with iodine-131: a study in eight centers in flanders (belgium). eur j nucl med 1998; 25:1368-76. 14. reiners c, lassmann m. radioiodine (131i) treatment of hyperthyroidism: radiation protection and quality assurance. eur j nucl med 1999; 26:683-5. 15. barrington sf, kettle ag, mount ford pj, thomson wh, batchelor s, burrell dn, et al. radiation exposure of patient’s children at home post i-131 administration. eur j nucl med 1995; 22:798. 0 0.5 1 1.5 2 2.5 3 3.5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 age (years) ef fe ct iv e do se ( m sv ) 1 msv dose limit mean dose figure 4: dot-plot showing the radiation doses received by family members in reference to annual dose limit. the mean radiation dose is shown in dotted line the impact of chronic liver diseases on the level of heart-type fatty acid-binding protein (h-fabp) concentrations *hafidh a al-hadi,1 brent william,2 keith a fox3 squ med j, august 2009, vol. 9, iss. 2, pp. 153-156, epub 30th june 2009 submitted 3rd nov 08 revision req. 21st mar 09, revision recd. 29th mar 09 accepted 13th may 09 clinical & basic research تأثري أمراض الكبد املزمنة على تركيز بروتني محض القلب الدهين الرابط يف الدم حفيظ الهادي، برينت ويليام، كيث فوكس امللخص: الهدف: يعرف بروتني حمض القلب الدهني الرابط كأحد املؤشرات الكيميائية-احليوية اجلديدة التي ميكن استعمالها لتشخيص اجللطة القلبية مبكرا . ال يوجد حتى اآلن دليل على وجود بروتني حمض القلب الدهني الرابط في الكبد. الهدف من الدراسة هو مقارنة تأثير أمراض الكبد أمراض الكبد املزمنة مثل التهاب الكبد الوبائي ومرض التليف تأثير دراسة على مستوى بروتني حمض القلب الدهني الرابط في الدم. الطريقة: مت هو املعياري العمر± االنحراف ( متوسط األمراض هذه من يعانون أشخاص عشرة عند الرابط الدهني القلب حمض بروتني مستوى على الكبدي 58,33 ± 7,19 سنة). مت دراسة تركيز األنزميات و البروتينات التالية (بروتني حمض القلب الدهني الرابط، ناِقلَُة أَمنِي األاَلنني وبيليروبني) في املرضى و مقارنة تركيزها مع مجموعة ضابطة من األصحاء مكونة من عشرين متبرعا بالدم، متوسط العمر± االنحراف املعياري هو 63.8 ± 8.0 سنة) كان تركيز هذه املواد في اجملموعة الضابطة مقارنة مع اجملموعة املرضية كالتالي )املتوسط ± االنحراف املعياري(: بروتني حمض القلب النتائج: . الدهني الرابط 6,86 ± 2,21 ميكروجرام/ لتر مقابل 6,44 ± 3,06 ميكروجرام/ لتر، ناِقلَُة أَمنِي األاَلنني 29.8 14.7 ± وحدة / لتر مقابل 198,67 .)p > 0.0001 ( و البيليروبني 4.0 ± 9.6 ميكرومول / لتر مقابل 100,89 ± 87,85 ميكرومول / لتر ، )p> 0.0005 (122,89 وحدة / لتر ± اخلالصة: تبني هذه البيانات بوضوح انه ال يوجد هناك تأثير هام على مستوى تركيز بروتني حمض القلب الدهني الرابط نتيجة اإلصابة بأمراض الكبد ، على الرغم من االرتفاع الواضح في بروتينات و أنزميات الكبد في الدم. هذه الدراسة تدعم االستخدام النافع لبروتني حمض القلب الدهني الرابط في تشخيص إصابة عضلة القلب لدى املرضى املصابني بأمراض الكبد املزمنة. مفتاح الكلمات: أمراض الكبد املزمنة، بروتني حمض القلب الدهني الرابط، ناِقلَُة أَمنِي األاَلنني ، بيليروبني. abstract: objectives: heart-type fatty acid binding-protein )h-fabp( has been reported to be a potential novel biochemical marker for the early diagnosis of acute myocardial infarction )ami(. the presence of h-fabp in the liver has not been reported. the aim of this study was to compare the effect of chronic liver diseases on the level of h-fabp concentrations. methods: the effects of chronic liver diseases including infective hepatitis and cirrhosis on the concentration of h-fabp was studied in a small group of patients )n=10, mean age ±sd = 58.33 ± 7.19 years(. the serum concentrations of the following markers were measured: h-fabp, alanine aminotransferase )alt( and bilirubin and compared with a reference control group )20 healthy blood donors, mean age ±sd = 63.8 ±8.01(. results: the serum concentrations of these markers in the control group as compared to patients with chronic liver disease were as follows )mean ± sd(: h-fabp = 6.86 ±2.21 µg/l versus 6.44 ±3.06 µg/l )p = ns(; alt = 29.8 ±14.7 u/l versus alt = 198.67 ±122.89 u/l )p < 0.0005( and bilirubin = 9.6 ±4.0 µmol/l versus bilirubin = 100.89 ±87.85 µmol/l )p < 0.0001(. conclusion: these data illustrate clearly that there is no significant interference with the normal concentration of h-fabp in the presence of liver diseases, despite the significant elevation of liver enzymes and proteins. these data may support a useful role of h-fabp for the diagnosis of myocardial injury in patients with liver diseases. keywords: heart-type fatty acid-binding protein )h-fabp(; chronic liver diseases; bilirubin; alanine aminotransferase. 1department of medicine, sultan qaboos university hospital, muscat, sultanate of oman. 2department of medical sciences, faculty of medicine, university of edinburgh, uk. 3university of edinburgh, cardiovascular research unit, royal infirmary of edinburgh, uk. *to whom correspondence should be addressed. email: halhadi@hotmail.com advances in knowledge 1. heart-type fatty acid-binding protein is a useful early marker for the diagnosis of acute myocardial infarction. 2. the effect of chronic liver diseases on the diagnostic potential of this marker is not known. 3. this article illustrates the lack of interferences of the various types of chronic liver diseases on the ability to use heart-type fatty acid binding-protein as an early cardiac marker for the early diagnosis of acute myocardial infarction. application to patient care 1. the information provided in this article will help health institutions caring for patient’s with acute myocardial infarction on how best to use, interpret and apply the results obtained with heart-type fatty acid-binding protein in patients presenting with acute chest pain suggestive of evolving acute myocardial infarction who also have various co-existing types of chronic liver diseases. the impact of chronic liver diseases on the level of heart-type fatty acid-binding protein (h-fabp) concentrations 154 | squ medical journal, august 2009, volume 9, issue 2 heart-type fatty acid bindingprotein (h-fabp) is a small soluble non-enzyme protein composed of 132 amino acids.1 it is one of the most abundant proteins in the heart and comprises 5-15% of the total cytosolic protein pool. h-fabp exists in high concentrations in the heart; however, this protein is not totally cardiac specific and occurs in other tissues although in a much lesser concentrations.2,3 h-fabp was introduced by glatz et al. in 1988 as a potential novel biochemical marker for the early diagnosis of acute myocardial infarction (ami).4 this was soon confirmed in many other studies.5-9 some of the more recent studies have questioned the value of these early markers (h-fabp and myoglobin) when compared with specific markers like cardiac troponin i (ctni).10 h-fabp is released into plasma within 2 hours after symptom onset and is reported to peak at about 4-6 hours and return to normal base line value in 20 hours.7 within the period of 30-210 minutes after symptom onset, h-fabp has > 80% sensitivity for the diagnosis of ami.11 within the interval of 0-6 hours after symptom onset, the other cardiac markers such as creatine kinase (ck), ck-mb mass or activity, ctni and t (ctnt) will only be starting to accumulate in the plasma, and their sensitivity has been reported to be around 64%.12 the exact route(s) of excretion of h-fabp from the circulation is not fully understood. as suggested by previous studies, the kidney may be the major route of excretion of h-fabp from circulation. a rise in serum and urine h-fabp concentration above normal values is seen in patients who present with ami as early as 1.5 hours after symptom onset.13 studies in animals have also shown decreased myocardial tissue content and rising plasma and urine concentrations of h-fabp very early after coronary artery ligation.14-15 h-fabp circulates for a longer time (> 25 hours) after ami in the presence of renal failure.11 the presence of h-fabp in the liver has not been reported. however, an isoform specific to the liver called liver-type fabp exists.16 the interferences of this protein and chronic liver diseases on the concentration of h-fabp has not been studied before. also, the effect of chronic liver diseases on the release of h-fabp from other tissues has not yet been fully evaluated.17 therefore, the aim of the study was to compare the effect of chronic liver diseases on the serum levels of h-fabp. methods the effects of disease states in particular chronic liver diseases on the normal concentration of h-fabp was studied in 2003-2004 a small group of patients with a mixture of chronic liver disorders (n=10, mean age ±sd = 58.33 ±7.19 years, range 45-70 years, median = 59 years) these patients had a range of conditions including infective hepatitis and cirrhosis (chronic hepatitis b = 2, chronic hepatitis c = 2, chronic alcoholic hepatitis = 3, other cirrhosis = 3). they were recruited from the liver unit at the edinburgh royal infirmary, uk. ethical approval was obtained from the local ethical committee (lothian research ethics committee, edinburgh) and informed consent was obtained from each patient before beginning the study. the study complies with the declaration of helsinki. the serum concentrations of the following markers h-fabp, alt and bilirubin were measured in the study group and compared with the concentrations of these markers in a normal reference control group of healthy blood donor controls (n=20, mean age ±sd = 63.8 ±8.01, range 53-75 years, median = 65 years). peripheral blood samples for serum analysis were collected in white starstedt monovette vacutainer tubes by venepuncture. the blood samples (5mls) were taken through a peripheral line (intravascular access). the extracted samples were allowed to clot at room temperature for 1 hour and then centrifuged at 4°c, and the resulting serum was divided into small aliquots and frozen at -70°c until analysis. h-fabp was analysed by an enzyme linked immunosorbent assay method using commercially available assays (hycult, cambridge).17 bilirubin and alt were measured in the biochemistry department of the edinburgh royal infirmary on an automated analyser machine using commercial assays. statistical analyses were performed using the statistical package for social sciences (spsstm, pittsburgh, version 15). continuous variables were presented as mean ± standard deviation. comparisons between the study group and control group variables were conducted by the mannwhitney u test for continuous variables. significant results were indicated by probability values less than or equal to 0.05. hafidh a al-hadi, brent william and keith a fox clinical and basic research | 155 results the analytical sensitivity of h-fabp assay (mean ± 2sd) was 0.206 ±0.047 g/l.17 the normal concentrations of these markers in the normal reference control group of healthy blood donor controls were as follows: h-fabp = 6.86 ±2.21 µg/l; alt = 29.8 ±14.7 u/l and bilirubin = 9.6 ±4.0 µmol/l. the study group consisted of 10 patients. the concentration of these markers in patients with chronic liver diseases were as follows: h-fabp = 6.44 ±3.06 µg/l, (range 2-11 µg/l, median = 7 µg/l); alt = 198.67 ±122.89 u/l, (range 73-500 u/l, median = 114 u/l) and bilirubin = 100.89 ±87.85 µmol/l, (range 17 337 µmol/l, median = 66 µmol/l). there was no significant difference between the concentration of h-fabp in the study group and controls; however, the concentrations of liver enzymes and protein (alt and bilirubin) were significantly elevated in the study group [table 1]. discussion under normal conditions h-fabp is present in plasma in very low concentrations (< 5 µg/l), but it is significantly elevated upon cellular injury.18 this makes the plasma estimation of h-fabp suitable for the early detection and quantification of myocardial tissue injury. however, this protein is not totally cardiac specific as it occurs in skeletal muscle in concentrations varying between 0.05-0.2 mg/g wet weight of tissue, depending on muscle fibre type studied.5 it has also been reported in very low concentrations in tissues like the kidney, aorta, testes, mammary glands, placenta, brain, adrenal glands, adipose tissue, and stomach.2,3 the concentration of h-fabp in the study group was not statistically different from the control group. this finding leads to several assumptions. first, the liver-fabp (l-fabp) is a separate factor with no or negligible cross-reactivity with h-fabp assays. indeed, the cross-reactivity between these two proteins has been reported to be < 0.005.17 second, the release of h-fabp from other tissues containing this protein (see above) is at best minimal in patients who have chronic liver diseases. our study was the first of its kind to address the interference of chronic liver diseases on the normal concentrations of h-fabp. there are no data on this issue in the literature hence it is difficult to correlate our findings. in a previous study, we have shown major limitations for the use of h-fabp concentration for the diagnosis of myocardial injury in the presence of renal failure.19 the liver contains only l-fabp, but co-expression of h-fabp and l-fabp occurs in the kidney. similarly, intestinal-type fabp (i-fabp) and l-fabp are found in intestines, and brain-type fabp (b-fabp) and h-fabp occur in the brain. preliminary but promising applications of these proteins have been demonstrated for liver rejection, viability selection of kidneys from nonheart-beating donors (nhbd), inflammatory and ischaemic bowel disease, traumatic brain injury and in the prevention of muscle injury in trained athletes.20 measurement of h-fabp in the first 24 hours after onset of symptoms may be potentially useful for the diagnosis of ami; identification of patients who need reperfusion treatment early; identification of patients who reperfuse their infarct related artery; detection of re-infarction if it occurs early, and estimation of infarct size.21 conclusion these data illustrate clearly that there is no significant interference with the normal concentration of h-fabp in the presence of chronic liver diseases, despite the significant elevation of liver enzymes and proteins. this is consistent with the reduced cross-reactivity between h-fabp and other fabp table 1: age and concentrations of marker proteins in the control and study groups control group (blood donors) study group (liver disease patients) p value numbers n=20 n=10 age 63.8 ±8.0 58.33 ±7.2 (ns) alt 29.8 ±14.7 198.67 ±122.9 < 0.0005 bilirubin 9.6 ±4.0 100.89 ±87.9 < 0.0001 h-fabp 6.86 ±2.2 6.44 ±3.1 (ns) legend: ns = not significant; alt = alanine aminotransferase; h-fabp = heart-type fatty acid binding-protein the impact of chronic liver diseases on the level of heart-type fatty acid-binding protein (h-fabp) concentrations 156 | squ medical journal, august 2009, volume 9, issue 2 including l-fabp. these findings may support a useful role of h-fabp for the diagnosis of myocardial injury in patients with chronic liver diseases. source of funding: the research was funded by a grant from the cardiovascular research unit at the university of edinburgh. conflict of interest: the authors report no conflit of interest. references 1. offner gd, brecher p, sawlivich wb, costello ce, troxler rf. characterization and amino acid sequence of a fatty acid-binding protein from human heart. biochem j 1988; 252:191-8. 2. crisman ts, claffey kp, saouaf r, hanspal j, brecher p. measurement of rat heart fatty acid-binding protein by elisa. tissue distribution, developmental changes and subcellular distribution. j mol cell cardiol 1987; 19:423-31. 3. glatz gf, van der busse gl. cellular fatty acidbinding protein: their function and physiological significance. prog lipid res 1996; 35:243-82. 4. glatz jf, van bilsen m, paulussen rj, veerkamp jh, van der vusse gj, reneman rs, et al. release of fatty acidbinding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox. biochim biophys acta 1988; 961:148-52. 5. yoshimoto k, tanaka t, somiya k, tsuji r, okamoto f, kawamura k, et al. human heart-type cytoplasmic fatty acid-binding protein as an indicator of acute myocardial infarction. heart vessels 1995; 10:304-9. 6. abe s, okino h, lee s, toda h, miyata m, nomoto k et al. human heart fatty acid-binding protein. a sensitive and specific marker of coronary reperfusion. circulation 1991; 84:ii-291. 7. glatz jf, van der vusse gj, maessen jg, van dieijenvisser mp, hermens wt. fatty acid-binding protein as marker of muscle injury: experimental finding and clinical application. acta anaesthesiol scand suppl 1997; 111:292-4. 8. ishii j, wang jh, naruse h, taga s, kinoshita m, kurokawa h, et al. serum concentrations of myoglobin vs human heart-type cytoplasmic fatty acid-binding protein in early detection of acute myocardial infarction. clin chem 1997; 43:1372-8. 9. alhadi ha, fox ka. do we need additional markers of myocyte necrosis: the potential value of heart fatty acid-binding protein. qjm 2004; 97:187-98. 10. alansari se, croal bl. diagnostic value of heart fatty acid binding protein and myoglobin in patients admitted with chest pain. ann clin biochem 2004; 41:391-6. 11. kleine ah, glatz jf, van nieuwenhoven fa, van der vusse gj. release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. mol cell biochem 1992; 116:155-62. 12. bakkeraj, koelemay mj, gorgels jp, van vlies b, smits r, tijssen jg, et al. failure of new biochemical markers to exclude acute myocardial infarction at admission. lancet 1993; 342:1220-2. 13. tanaka t, hirota y, sohmiya k, nishimura s, kawamura k. serum and urinary human heart fatty acid-binding protein in acute myocardial infarction. clin biochem 1991; 24:195-201. 14. knowlton aa, apstein cs, saouf r, brecher p. leakage of heart fatty acid-binding protein with ischemia and reperfusion in the rat. j mol cell cardiol 1989; 21:577-83. 15. volders pg, vork mm, glatz jf, smits jf. fatty acidbinding proteinuria diagnoses myocardial infarction in the rat. mol cell biochem 1993; 123:185-90. 16. pelsers mm, morrovat a, alexandr gj, hermens wt, trull ak, glatz jf, et al. liver fatty acidbinding protein as a sensitive serum marker of acute hepatocellular damage in liver transplants. clin chem 2002; 48:2055-7. 17. hycult biotechnology b.v. hbt human h-fabp elisa test kit product information manual, 1999. insert sheet. 18. pelsers mm, chapelle jp, knapen m, vermeer c, glatz jf. influence of age, sex and day-today and withinday biological variation on plasma concentrations of fatty acid-binding protein and myoglobin in healthy subjects. clin chem 1999; 45:441-4. 19. alhadi ha, william b, kox ka. serum level of heart fatty acid binding protein in patients with chronic renal failure. squ med j (accepted for publication 10 may 2009). 20. pelsers mm, hermens wt, glatz jf. fatty acidbinding proteins as plasma markers of tissue injury. clin chim acta 2005; 352:15-35. 21. colli a, jossa m, pomar jl, mestres ca, gharli t. heart fatty acid binding proteins in diagnosis of myocardial infarction: where do we stand now? cardiology 2007; 108:4-10. 1 submitted 1 oct 21 1 revisions req. 8 dec 21 & 20 feb 22; revisions recd. 11 jan & 3 mar 22 2 accepted 27 apr 22 3 online-first: may 2022 4 doi: https://doi.org/10.18295/squmj.5.2022.035 5 6 social relationships and onset of functional limitation among older 7 adults with chronic conditions 8 does gender matter? 9 dandan jiao,1,9 kumi watanabe,3 yuko sawada,4 munenori matsumoto,1 10 ammara ajmal,1 emiko tanaka,5 taeko watanabe,6 yuka sugisawa,7 11 sumio ito,8 rika okumura,8 yuriko kawasaki,8 *tokie anme2* 12 1graduate school of comprehensive human sciences and 2faculty of medicine, university of 13 tsukuba, tsukuba, japan; 3riken center for advanced intelligence project, tokyo, japan; 14 4department of physical therapy, morinomiya university of medical sciences, osaka, 15 japan; 5department of community nursing, musashino university, tokyo, japan; 6college of 16 nursing and nutrition, shukutoku university, chiba, japan; 7department of nursing, 17 tsukuba international university, tsukuba, japan; 8department of public welfare, 18 tobishima, japan; 9department of nursing, the first affiliated hospital, and college of 19 clinical medicine of henan university of science and technology, luoyang, china. 20 *corresponding author’s e-mail: tokieanme@gmail.com 21 22 abstract 23 objective: this study aimed to examine the longitudinal association between social 24 relationships and physical functioning among community-dwelling older adults with chronic 25 conditions. methods: self-reported questionnaires were distributed and collected between 26 2014 and 2017 from participants aged 65 years and older. the index of social interaction was 27 used to evaluate social relationships, and the instrumental activities of daily living (iadl) 28 mailto:tokieanme@gmail.com 2 subscale of the tokyo metropolitan institute of gerontology index of competence was used 29 to examine functional status. data from 422 participants (190 men and 232 women) were 30 included in the final analysis. results: high social relationships demonstrated significant 31 adverse effects (or = 0.77, 95% ci = 0.64 – 0.93) on the decline of iadl in the overall 32 sample, particularly for women (or = 0.71, 95% ci = 0.55 – 0.93) but not for men ( p = 33 0.131). conclusion: the finding suggests that functional limitation was influenced by social 34 relationships among the disabled older adults, and the influence of social relationships on 35 functional limitation differed based on gender. 36 keywords: interpersonal relations; functional status; gender; aged; chronic disease; 37 longitudinal studies; health behaviour. 38 39 advances in knowledge 40 1. this study found that social relationships may prevent physical deterioration among 41 people with chronic conditions. 42 2. this positive association was observed among a female group, whereas no effect was 43 found among a male group. 44 3. taking measures to promote social relationships and being aware of gender differences 45 may improve the physical function of older adults with chronic conditions. 46 47 application to patient care 48 1. physicians, nurses, and other health professionals should encourage older people to 49 engage in social relations that will benefit disabled older people’s health outcomes. 50 2. social relationships should be a focus of chronic disease management. 51 52 introduction 53 aging is a global public issue, with at least one person out of eleven people being above 65 54 years of age in 2019. this number is expected to rise, with the older person being out of only 55 six people, by 2050.1 in japan, the aging rate is 28.8% (about one out of four people ) of the 56 total population as of 2020.2 most countries are experiencing not only a rapidly ageing 57 population but also the impact of related functional limitations. the latter refers to physical 58 3 restrictions in performing fundamental activities required in daily life (e.g., stooping, 59 climbing stairs and ambulating).3 functional decline begins earlier and manifests more 60 severely in older adults with chronic diseases.4 it has been argued that individuals with 61 functional limitations have higher risks of falling 5 and mortality.6 however, older adults with 62 chronic conditions are also willing to maintain their level of functioning,7 and therefore, 63 identifying factors that can be linked the maintenance of their physical function are needed. 64 65 social relationships are interactions between individuals and their social environment. 66 numerous studies have documented the effects of poor social relationships on health 67 outcomes (e.g., depressive symptoms8 and mortality9). additionally, social relationships have 68 an impact on functional limitations. for example, a prospective study indicated that baseline 69 social isolation predicted physical function decline after four years.10 another study suggested 70 that lack of social relationships is linked to poor activities of daily living (adl) and 71 instrumental activities of daily living (iadl).11 these studies have mainly focused on the 72 general older population. however, little is known about the beneficial effects of social 73 relationships and functional status on older adults with chronic health conditions. as 74 individuals with chronic conditions generally have restricted social participation,12 it is 75 necessary to investigate how social relationships affect them. a recent study suggested that 76 cancer survivors have higher chances of functional impairment when frequent contact with 77 others declines,13 and adults with type 2 diabetes with low levels of social support reported 78 higher functional disabilities.14 however, these studies only investigated the social relations of 79 individuals with specific chronic diseases (e.g., cancer, diabetes). as multiple chronic 80 diseases are increasing, studies investigating the comprehensive experiences of chronic 81 diseases are required. 82 83 regarding the gender differences in social relationships and health, it has been demonstrated 84 that women spend more time and resources building social relationships than men. 85 consequently, it is plausible that the negative impact of poor social relationships is greater for 86 women.15 for example, lee et al.16 found that social relations were significantly associated 87 with cognitive function in women only. however, hajek et al.17 found that decreased social 88 4 support impacts functional impairment in both genders. hence, consistent results regarding 89 the influence of gender on social relationships and health have not been established. further, 90 gender differences have not been thoroughly investigated in studies on individuals with 91 chronic diseases. 92 93 to address these gaps in the research, the current study examined the association between 94 social relationships and functional status among older adults with chronic diseases and 95 assessed the effects of gender on these associations. the results can be used to further the 96 understanding of social relationships and provide evidence for disease management to delay 97 deterioration and improve health-related quality of life for older adults with chronic diseases. 98 99 methods 100 design and participants 101 data for this three-year longitudinal study were extracted from a single-centre cohort project, 102 the community empowerment and care for well-being and health longevity (cec), which 103 was established in japan in 1991. the cec aims to explore the factors related to the well-104 being of residents in the context of the low birth rate, ageing population, and high medical 105 expenditure. this project was conducted in tobishima in aichi ken, central japan; the entire 106 population of around 4,800 participated in the survey. in 2020, the ageing rate was 107 approximately 28.0%. our research project was conducted in collaboration with the local 108 government municipality’s health policy evaluation, and our survey period was consistent 109 with that of the municipal survey. before 2011, the survey was conducted every one or two 110 years. since 2011, the survey has been conducted every three years. in each wave, the survey 111 is performed from april to may. to avoid selection bias, all the residents were invited to and 112 agreed to participate in the survey. questionnaires were mailed to all residents. the 113 questionnaire encompassed demographic characteristics, nutrition, lifestyle habits, long-term 114 care needs evaluation, evaluation of local services, social relationships, and medical 115 conditions. 116 117 unlike previous research related to this project, in the present study, we focused on older 118 5 adults living with chronic disease. we used data collected from individuals aged 65 years and 119 older with at least one chronic medical condition in 2014. the inclusion criteria were: (1) 120 people with at least one chronic disease (hypertension, stroke, heart disease, diabetes, 121 hyperlipidaemia, lung disease, arthritis, cancer, immune disease, depression, eye disease, and 122 ear disease), (2) physically independent at baseline, and (3) no missing information on iadl. 123 in 2014, 523 individuals who fit the inclusion criteria were enrolled. the chronic conditions 124 were determined using the question, ‘do you have an illness that is being treated, or do you 125 suffer from an illness sequela?’ in 2017, a follow-up study was conducted to assess the 126 participants for symptoms of physical functional decline. the data were collected from 1 127 april to 15 may in 2014 and 2017. between 2014 and 2017, 55 participants could not be 128 reached for the follow-up, and 46 participants were excluded owing to missing iadl 129 information (figure 1). we calculated the required sample size using the g*power. a 130 minimal sample size of 191 was required based on the expected 0.8 power and a 0.05 level of 131 significance. 132 133 measurements 134 functional competence was assessed by the iadl subscale of the tokyo metropolitan 135 institute of gerontology index of competence. the iadl subscale comprises five items: 136 using public transportation, shopping, preparing meals, paying bills, and individual banking 137 management. for each item, a positive response was coded as 1, and a negative response was 138 coded as 0. for example, regarding the use of public transportation, the response options to 139 the question ‘do you use public transportation (bus or train) to go out on your own?’ were ‘i 140 can and do’, ‘i can but do not’, and ‘i cannot’. a response of ‘i cannot’ received 0 point, 141 whereas the other two responses received 1 point. the total score ranged from 0 to 5, and a 142 score of 5 was considered a normal iadl, while a score of 0–4 indicated a low iadl.18 143 144 the index of social interaction (isi) was used to evaluate social relationships.19 the isi 145 includes five subscales and 18 items. the independence subscale has four items to assess 146 motivation to live, motivation to maintain a healthy life, taking an active approach towards 147 life, and having a regular lifestyle. the social curiosity subscale measures habits of reading 148 6 newspapers and books, using new equipment (e.g., a video system), hobbies, and a feeling of 149 importance in society. the interaction subscale measures communication with family 150 members and non-family members and interacting with non-family members. the 151 participation subscale measures participation in social groups, in neighbourhood groups, 152 watching television, and taking an active social role. the feelings of safety subscale tests if 153 participants have someone who can offer counselling and provide support during 154 emergencies. for all items, a positive response was coded as 1, and a negative response was 155 coded as 0. taking ‘do you have someone to counsel in a difficult situation?’ as an example, 156 the response options were ‘always’, ‘frequently’, ‘sometimes’, and ‘never’. a response of 157 ‘never’ received 0 point, while the other three received 1 point. the total score was 18, with a 158 higher score indicating good social interaction. the isi was taken as a continuous variable in 159 the analysis. 160 161 in accordance with previous studies,12,20 we considered age, sex, living status, exercise, 162 smoking, and drinking as covariates. age was measured as a continuous variable. exercise 163 was evaluated by the question ‘do you usually exercise?’ and was categorised as ‘yes’ if their 164 response were ‘always’ or ‘sometimes’ and ‘no’ if otherwise. living status was evaluated by 165 asking if the participants lived alone or with others. living with others included spouses, 166 sons, daughters, daughters-in-law, grandsons, brothers/sisters, and others. smoking was 167 evaluated by the question ‘do you smoke?’; those who responded ‘every day’ or ‘sometimes’ 168 were regarded as current smokers, ‘previously did but have stopped now’ as ex-smokers, and 169 ‘do not smoke’ as non-smokers. drinking was assessed by an item ‘do you drink?’ and was 170 dichotomised as yes if participants answered ‘every day’ or ‘sometimes’ and no if they 171 answered ‘do not drink’. 172 173 statistical analysis 174 baseline demographic information between gender groups was compared by chi-square (𝜒2) 175 tests or non-parametric tests. these tests were also implemented to examine demographic 176 information and the iadl for categorical and continuous variables, respectively. a multiple 177 logistic regression analysis was performed to examine the association between social 178 7 relationships and declining iadl after controlling for covariates that were statistically 179 significantly associated with iadl in the chi-square or non-parametric tests. we then fitted 180 additional models to examine gender differences in the association between the isi and iadl 181 using a gender stratified analysis. a sensitive analysis was also completed to compare the 182 demographic differences between included and excluded cases. all the analyses were 183 performed using ibm spss 26.0. 184 185 ethical consideration 186 this study was approved by the university of tsukuba ethics committee (no. 1331-1). the 187 survey data were anonymously provided by the local government. 188 189 results 190 data from 422 individuals were included in the analysis. of the 422 participants, most were 191 women, not living alone, doing exercise, non-drinkers, non-smokers, and diagnosed with one 192 chronic disease. while social relationships, age, living status, exercise, and disease status did 193 not differ between women and men, drinking and smoking differed significantly. specifically, 194 men reported higher percentages of smoking and drinking [table 1]. 195 196 the bivariate analysis demonstrated that age, exercise, and social relationships were 197 associated with the iadl after three years [tables 2 and 3]. after controlling for age and 198 exercise in the logistic regression models, the results demonstrated that higher social 199 relationship index was (or = 0.77, 95% ci =0.64–0.93) inversely associated with a low 200 iadl [table 4]. 201 202 the sex-stratified data revealed different results. in model 1, higher social relationship index 203 demonstrated a significant inverse association with a low iadl in men (or= 0.77, 95% ci = 204 0.61–0.98) and women (or= 0.69, 95% ci = 0.56–0.85). after adjusting for age (model 2) 205 and exercise (model 3), higher social relationship index was inversely related to low iadl in 206 women (or = 0.66, 95% ci = 0.51–0.86 and or = 0.71, 95% ci = 0.55–0.93, respectively). 207 however, social relationships index adjusted for age and exercise demonstrated no statistical 208 8 association with a low iadl in men, with p = 0.070 and p = 0.131 (table 4). 209 210 the sensitive analysis demonstrated the difference in age between the excluded case (72.9 ± 211 6.0) and included case (75.9 ± 6.6). the excluded group is older than the included cases (p < 212 0.05), and a gender difference was not observed. 213 214 discussion 215 this study examined the effects of social relationships on the functional status of older adults 216 with chronic conditions. the results demonstrated that higher social relationship index could 217 reduce older adults’ functional decline. however, the beneficial effects of social relationship 218 index are significantly evident only among women. 219 220 the stress-buffering model and main effect model are the two main theoretical models linking 221 social relationships to health outcomes.21 the stress-buffering model posits that social 222 resources, such as social companionship, may reduce stress by increasing positive moods. the 223 main effect model proposes that social support can reduce problematic behaviours (e.g., 224 smoking, drinking, and not seeking medical help) associated with poor health outcomes. 225 based on these theoretical models, chronic diseases and their consequences are stressors, 226 which may be reduced by their social resources. meanwhile, social relationships can directly 227 benefit functional status. 228 229 social relationships seem to have adverse effects on the functional decline among older adults 230 with chronic diseases. this result aligns with previous research22 conducted in six countries, 231 which demonstrated that social capital and well-being were positively associated, regardless 232 of chronic diseases. a systematic review indicated that social relationships play an important 233 role in improving well-being and mental health among people with disabilities.23 moreover, 234 another previous study also demonstrated that strong social relationships could decrease 235 functional decline even among individuals with multiple chronic diseases.20 social relations 236 affect health outcomes through a reciprocity exchange24— social relations might enhance 237 resources, including transportation support and caring, which can affect health-related 238 9 behaviours. for instance, social contacts may allow individuals with chronic diseases to 239 undergo medical check-ups, access important health-related information, and gain confidence 240 in health-promoting behaviours, which can delay the onset of physical decline. 241 242 chronic diseases are usually lifelong and cause earlier functional limitations; subsequently, 243 measures should be taken to prevent the deterioration of these conditions. this study 244 contributes to the existing literature through the identification of a cost-effective method to 245 gather evidence for chronic disease management. being aware of the benefits of social 246 relationships for health outcomes may provide evidence and directions for chronic disease 247 management and suggests that health promotion programmes should be expanded to include 248 social relationships and traditionally modified factors (e.g., physical activity and healthy 249 eating behaviour). 250 251 our findings further indicated that higher social relationship index could reduce the 252 probability of functional decline among women but not men. this finding aligns with a 253 previous 10-year longitudinal study25 that found that women with positive social support had 254 lower mortality risks than those with poor social support; however, this association was not 255 observed among men. additionally, another longitudinal study examining the effects of 256 participation in social activities and cognitive decline among older adults found that social 257 activities impacted cognitive decline only among women.26 the benefits women experience 258 due to strong social relationships are particularly relevant in potentially improving their 259 conditions as women with chronic diseases are more likely to experience functional 260 disabilities.27 one plausible reason is that women generally maintained stability in their social 261 activities, whereas men’s social activities declined over time.28 moreover, older women tend 262 to have larger social networks than older men.29 these findings support our results on the 263 gender-moderated effects of social relationships on functional status. 264 265 it is already known that behaviour change and improvements in the treatment of chronic 266 diseases may improve quality of life.30 our study demonstrated that social relationship index, 267 which encompass independence, social curiosity, interaction with others, participating in 268 10 social activities, and feeling safe in daily life, are effective in maintaining physical function. 269 regarding the practical implications of these findings, physicians, nurses, and social workers 270 need to consider the impact of social relationships on health and develop chronic disease 271 management interventions such as promoting interactions with family and non-family 272 members, using new equipment (e.g., video camera, internet), and reading newspapers. 273 moreover, team-based strategies should be developed; these must include various parties such 274 as medical staff, social workers, health policymakers, and other health stakeholders. further, 275 considering the gender differences in the effects of social relationships on health, more 276 integration measures should be included for men. additionally, longitudinal research could 277 facilitate the identification of other relevant aspects of men’s social relations. 278 279 this study has several limitations. first, disease severity and duration were not examined, 280 which may have affected the results. individuals with more severe and longer-lasting chronic 281 diseases may experience worse functional deterioration. subsequently, it is unclear if the 282 effects of social relationships differ among people with chronic diseases of different severity 283 and duration. further studies taking disease severity and duration into consideration are 284 therefore necessary. second, although some diseases can affect individuals’ social 285 interactions, we did not explore the effect of social relationships on functional limitation by 286 individual diseases. identifying the effects of specific diseases may facilitate the development 287 of targeted measures. third, the specific types and frequency of social relationships index 288 were not examined. knowing the specific source of social relationships would yield more 289 specific evidence for intervening to promote social engagement. fourth, only one indicator 290 was used to examine functional status; combining subjective and objective measurements for 291 functional indicators might strengthen the reliability of the results. fifth, even though we 292 highlighted the importance of social relationship index with regards to decreasing the odds of 293 functional decline, we did not examine interaction effects. thus, studies examining the 294 interaction effects (multiplicative or additive) of social relationship index and chronic 295 conditions, which might offer deeper insight into the target population, will be significant for 296 public health and psychosocial research. finally, this study was conducted in one area, which 297 may limit the generalisability of the results. considering that culture is crucial to social 298 11 relationships, studies using data from various countries to provide insight into the 299 comparative impacts of social relationships on health outcomes across cultures are necessary. 300 301 despite these gaps, this study addresses the association between social relationships and 302 functional status among community-dwelling older adults with chronic conditions and gender 303 differences. our results further imply that it may be beneficial to consider gender differences 304 when encouraging social relationships for disease management. a better understanding of 305 gender-based differences can help develop further interventional programmes and studies to 306 promote health outcomes linked to gender differences. 307 308 conclusion 309 social relationships influence physical functioning among older adults with chronic diseases. 310 based on the results of this study, among people with chronic disease, social relationships 311 were related to functional decline after three years; further, this association differed by 312 gender. professionals should assist older adults with developing, maintaining, and 313 strengthening their social relations in daily life through interventions such as using new 314 equipment, interacting with family and non-family members, participating in various 315 activities, receiving support from others, and taking an active approach to life, to increase the 316 sustainability of their functional independence. given their significance, social relationships 317 should form an important part of health policy decisions. further, being aware of the 318 moderating effects of gender differences may facilitate the development of more appropriate 319 measures to reduce functional decline among older adults, and encouraging older women to 320 maintain social relationships may be effective in reducing their vulnerability to functional 321 limitations. 322 323 conflict of interest 324 the authors declare no conflicts of interest. 325 326 funding 327 this work was supported by jsps kakenhi (grant number jp21k18449) and in part by 328 12 the jst spring (grant number jpmjsp2124). 329 330 authors’ contribution 331 dj and ta conceptualised and designed the study. et, tw and ys collected the data. dj and 332 kw analysed and interpreted the data. all authors were involved in the study investigation. 333 si, ro, yk and ta handled the project administration. dj drafted the manuscript. ys, mm 334 and aa reviewed and edited the manuscript. ta supervised the study and acquired the 335 funding. all authors approved the final version of the manuscript. 336 337 acknowledgement 338 we are grateful to all the participants and research members for their participation in this 339 study. the first author, dandan jiao would like to express her deep appreciation to receive the 340 fellowship from the sasagawa scholarship from the japan-china medical association. 341 342 references 343 1. world population ageing 2019: highlights new york city united nations, department of 344 economic and social affairs, population division; 2019. from: 345 https://www.un.org/en/development/desa/population/publications/pdf/ageing/worldpopul346 ationageing2019-highlights.pdf accessed: jul 2020. 347 2. statistic bureau of japan. statistic handbook of japan 2021. from: 348 https://www.stat.go.jp/english/data/handbook/c0117.html accessed: dec 2021. 349 3. verbrugge lm, jette am. the disablement process. soc sci med 1994; 38(1):1–14. 350 https://doi.org/10.1016/0277-9536(94)90294-1. 351 4. fong jh. disability incidence and functional decline among older adults with major 352 chronic diseases. bmc geriatr 2019; 19(1):323. https://doi.org/10.1186/s12877-019-353 1348-z. 354 5. deandrea s, bravi f, turati f, lucenteforte e, la vecchia c, negri e. risk factors for 355 falls in older people in nursing homes and hospitals. a systematic review and meta-356 analysis. arch gerontol geriatr 2013; 56(3):407–415. 357 https://doi.org/10.1016/j.archger.2012.12.006. 358 https://www.un.org/en/development/desa/population/publications/pdf/ageing/worldpopulationageing2019-highlights.pdf https://www.un.org/en/development/desa/population/publications/pdf/ageing/worldpopulationageing2019-highlights.pdf https://www.stat.go.jp/english/data/handbook/c0117.html 13 6. mutikainen s, rantanen t, alén m, kauppinen m, karjalainen j, kaprio j, et al. walking 359 ability and all-cause mortality in older women. int j sports med 2011; 32(3):216–222. 360 https://doi.org/10.1055/s-0030-1268506. 361 7. mcgilton ks, vellani s, yeung l, chishtie j, commisso e, ploeg j, et al. identifying 362 and understanding the health and social care needs of older adults with multiple chronic 363 conditions and their caregivers: a scoping review. bmc geriatr 2018; 18(1):231. 364 https://doi.org/10.1186/s12877-018-0925-x. 365 8. conde-sala jl, garre-olmo j, calvó-perxas l, turró-garriga o, vilalta-franch j. 366 course of depressive symptoms and associated factors in people aged 65+ in europe: a 367 two-year follow-up. j affect disord 2019; 245:440–450. 368 https://doi.org/10.1016/j.jad.2018.10.358. 369 9. takahashi s, ojima t, kondo k, shimizu s, fukuhara s, yamamoto y. social 370 participation and the combination of future needs for long-term care and mortality among 371 older japanese people: a prospective cohort study from the aichi gerontological 372 evaluation study (ages). bmj open 2019; 9:e030500. 373 https://doi.org/10.1136/bmjopen-2019-030500. 374 10. yu b, steptoe a, niu k, jia x. social isolation and loneliness as risk factors for grip 375 strength decline among older women and men in china. j am med dir assoc 2020; 376 21(12):1926-1930. https://doi.org/10.1016/j.jamda.2020.06.029. 377 11. cwirlej-sozanska a, wisniowska-szurlej a, wilmowska-pietruszynska a, sozanski b. 378 determinants of adl and iadl disability in older adults in southeastern poland. bmc 379 geriatr 2019; 19(1):297. https://doi.org/10.1186/s12877-019-1319-4. 380 12. griffith le, raina p, levasseur m, sohel n, payette h, tuokko h, et al. functional 381 disability and social participation restriction associated with chronic conditions in 382 middle-aged and older adults. j epidemiol community health 2017; 71(4):381–389. 383 https://doi.org/10.1136/jech-2016-207982. 384 13. guida jl, holt cl, dallal cm, he x, gold r, liu h. social relationships and functional 385 impairment in aging cancer survivors: a longitudinal social network study. gerontologist 386 2020; 60(4):607–616. https://doi.org/10.1093/geront/gnz051. 387 14. levy am, deschênes ss, burns rj, elgendy r, schmitz n. trajectories of social support 388 14 in adults with type 2 diabetes: associations with depressive symptoms and functional 389 disability. int j geriatr psychiatry 2019; 34(3):480–487. 390 https://doi.org/10.1002/gps.5042. 391 15. chemaitelly h, kanaan c, beydoun h, chaaya m, kanaan m, sibai am, et al. the role 392 of gender in the association of social capital, social support, and economic security with 393 self-rated health among older adults in deprived communities in beirut. qual life res 394 2013; 1371–1379. https://doi.org/10.1007/s11136-012-0273-9. 395 16. lee s, lee s, lee e, youm y, cho hs, kim wj. gender differences in social network of 396 cognitive function among community-dwelling older adults. geriatr gerontol intl 2020; 397 20(5):467–473. https://doi.org/10.1111/ggi.13906. 398 17. hajek a, brettschneider c, mallon t, van der leeden c, mamone s, wiese b, et al. how 399 does social support affect functional impairment in late life? findings of a multicenter 400 prospective cohort study in germany. age ageing 2017; 46(5):813–820. 401 https://doi.org/10.1093/ageing/afx012. 402 18. ishizaki t, kai i, kobayashi y, imanaka y. functional transitions and active life 403 expectancy for older japanese living in a community. arch gerontol geriatr 2002; 404 35(2):107–120. https://doi.org/10.1016/s0167-4943(02)00002-x. 405 19. anme t, shimada c. social interaction and mortality in a five-year longitudinal study of 406 the elderly. jpn j public health 2000; 47:127–133. [in japanese] 407 20. jiao d, watanabe k, sawada y, tanaka e, watanabe t, tomisaki e, et al. 408 multimorbidity and functional limitation: the role of social relationships. arch gerontol 409 geriatr 2020; 92:104249. https://doi.org/10.1016/j.archger.2020.104249. epub ahead of 410 print. 411 21. cohen s, wills ta. stress, social support, and the buffering hypothesis. psychol bull 412 1985; 98(2):310–357. 413 22. christian ak, sanuade oa, okyere ma, adjaye-gbewonyo k. social capital is 414 associated with improved subjective well-being of older adults with chronic non-415 communicable disease in six lowand middle-income countries. global health 2020; 416 16(1):2. https://doi.org/10.1186/s12992-019-0538-y. 417 23. tough h, siegrist j, fekete c. social relationships, mental health and well-being in 418 https://doi.org/10.1007/s11136-012-0273-9 15 physical disability: a systematic review. bmc pub health 2017; 17(1): 414. 419 https://doi.org/10.1186/s12889-017-4308-6. 420 24. cockerham wc, hamby bw, oates gr. the social determinants of chronic disease. am 421 j prev med 2017; 52(1s1):s5–s12. https://doi.org/10.1016/j.amepre.2016.09.010. 422 25. lyyra tm, heikkinen rl. perceived social support and mortality in older people. j 423 gerontol b psychol sci soc sci 2006; 61(3):s147–152. 424 https://doi.org/10.1093/geronb/61.3.s147. 425 26. hwang j, park s, kim s. effects of participation in social activities on cognitive function 426 among middle-aged and older adults in korea. int j environ res public health 2018; 427 15(10):2315. https://doi.org/10.3390/ijerph15102315. 428 27. calderón-larrañaga a, santoni g, wang hx, welmer ak, rizzuto d, vetrano dl, et al. 429 rapidly developing multimorbidity and disability in older adults: does social background 430 matter?. j intern med 2018; 283(5):489–499. https://doi.org/10.1111/joim.12739. 431 28. finkel d, andel r, pedersen nl. gender differences in longitudinal trajectories of 432 change in physical, social, and cognitive/sedentary leisure activities. j gerontol b 433 psychol sci soc sci 2018; 73(8):1491–1500. https://doi.org/10.1093/geronb/gbw116. 434 29. pillemer s, ayers e, holtzer r. gender-stratified analyses reveal longitudinal 435 associations between social support and cognitive decline in older men. aging ment 436 health. 2019;23(10):1326-1332. https://doi: 10.1080/13607863.2018.1495178. 437 30. preventing non-communicable diseases. [internet]. geneva: world health organization. 438 available from: https://www.who.int/activities/preventing-noncommunicable-diseases 439 accessed: jan 2020. 440 16 figure 1: flow chart of participants older adults aged ≥ 65 years n = 1004 provided valid questionnaire n = 976 excluding: people with no chronic disease (n = 267) poor iadl (n = 174) missing information on iadl (n = 12) target population at baseline (2014) n = 523 excluding: lost to follow-up (n = 34) dead (n = 21) participants included in the analysis n = 422 completed follow-up (2017) n = 468 excluding: missing information on iadl (n = 46) 17 table 1: baseline characteristics of the participants variables category total (n = 422) men (n = 190) women (n = 232) p n % n % n % age (mean ± sd) 72.8 ± 6.1 72.7 ± 6.1 72.9 ± 6.1 0.680 living status not alone 388 94.4 176 95.1 212 93.8 0.560 alone 23 5.6 9 4.9 14 6.2 missing 11 5 6 exercise yes 254 62.1 115 63.2 139 61.2 0.686 no 155 37.9 67 36.8 88 38.8 missing 13 8 5 drinking yes 142 35.1 106 41.1 36 16.1 < 0.001 no 262 64.9 74 58.9 188 83.9 missing 18 10 8 smoking current 32 8.2 30 17.0 2 0.9 < 0.001 ex-smoker 99 25.4 93 52.5 6 2.8 nonsmoker 259 66.4 54 30.5 205 96.3 missing 32 13 19 isi (mean ± sd) 16.5 ± 1.6 16.6 ± 1.5 16.4 ± 1.6 0.763 missing 45 15 30 number of diseases 1 235 55.7 103 54.2 132 56.9 0.581 2 187 44.3 87 45.8 100 43.1 sd: standard deviation; isi: index of social interaction. 18 table 2: baseline characteristics of participants per follow-up level of iadl variables category normal (n =359) low (n = 63) 2/z p n % n % age (mean ± sd) 71.9  5.4 78.5  6.8 -6.995 < 0.001 living status not alone 329 94.0 59 96.7 0.728 0.552 alone 21 6.0 2 3.3 missing 9 2 exercise activity 227 65.0 27 45.0 8.739 0.003 inactivity 122 35.0 33 55.0 missing 10 3 drinking yes 118 65.8 24 59.3 0.927 0.336 no 227 34.2 35 40.7 missing 14 4 smoking current 27 8.1 5 8.8 0.322 0.851 ex-smoker 83 24.9 16 28.1 non-smoker 223 67.0 36 63.1 missing 26 6 isi (mean ± sd) 16.6  1.4 15.7  1.9 -3.317 0.001 missing 41 4 number of diseases 1 198 55.2 37 58.7 0.278 0.598 2 161 44.8 26 41.3 iadl: instrumental activities of daily living; sd: standard deviation; isi: index of social interaction. 19 table 3: baseline characteristics and follow-up iadl by gender variables category men women normal (n = 161) low (n = 29) 2/z p normal (n = 198) low (n = 34) 2/z p n % n % n % n % age (mean  sd) 71.9  5.5 77.1  7.2 -3.686 < 0.001 71.85.3 79.66.3 -6.153 <0.001 living status not alone 147 94.2 29 100.0 1.759 0.359 182 93.8 30 93.8 0.000 1.000 alone 9 5.8 0 0.0 12 6.2 2 6.2 missing 5 0 4 2 exercise activity 102 65.4 13 50.0 2.268 0.132 125 64.8 14 41.2 6.777 0.009 inactivity 54 34.6 13 50.0 68 35.2 20 58.8 missing 5 3 5 0 drinking yes 87 56.5 19 73.1 2.527 0.112 31 16.2 5 15.2 0.024 0.876 no 67 43.5 7 26.9 160 83.8 28 84.8 missing 7 3 7 1 smoking current 25 16.5 5 19.2 1.834 0.400 2 1.1 0 0.0 1.416 0.493 ex-smoker 77 51.0 16 61.6 6 3.3 0 0.0 non-smoker 49 32.5 5 19.2 174 95.6 31 100.0 missing 10 3 16 3 isi (mean ± sd) 14.92.3 13.8  2.6 -2.080 0.038 14.72.6 13.12.4 -2.656 0.008 missing 15 0 26 4 number of diseases 1 88 54.6 15 51.7 0.085 0.770 110 55.6 22 64.7 0.991 0.320  73 45.4 14 48.3 88 44.4 12 35.3 iadl: instrumental activities of daily living; sd: standard deviation; isi: index of social interaction. table 4: logistic regression models of the association between baseline isi and follow-up low iadl variables model 1 model 2 model 3 or 95% ci p or 95% ci p or 95% ci p total isi 0.73 0.62 0.85 < 0.001 0.73 0.61 0.87 < 0.001 0.77 0.64 0.93 0.006 age 1.18 1.12 1.24 < 0.001 1.17 1.11 1.23 <0.001 exercise 1.67 0.86 3.26 0.130 men isi 0.77 0.61 0.98 0.035 0.79 0.61 1.02 0.070 0.80 0.60 1.07 0.131 age 1.13 1.06 1.21 < 0.001 1.11 1.04 1.19 0.003 exercise 1.21 0.44 3.28 0.714 women isi 0.69 0.56 0.85 0.001 0.66 0.51 0.86 0.002 0.71 0.55 0.93 0.011 age 1.24 1.14 1.35 < 0.001 1.25 1.45 1.36 < 0.001 exercise 2.56 0.98 6.65 0.054 iadl: instrumental activities of daily living; or: odds ratio; ci: confidence interval; isi: index of social interaction. 2008-issue1.indd 5th international obstetrics & gynecology conference, sultan qaboos university, sultanate of oman 0-3 december 2007 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 105-118 sultan qaboos university© submitted 8th december 2007 th r om b o e m b o l i c d i se a se i n o b st e t r i c s vidya kishore and majida al-irhayim, division of obstetrics and gynecology, royal hospital, muscat, oman. to study the incidence and etiology of thromboembolic disease in pregnancy and puerperium, a retrospective study of thromboembolic disease (vte) was done at the royal hospital for 9 years (1999-2007). thromboembolic disease is an important cause of direct maternal death; however, vte is 10 times more common in pregnant women than non-pregnant women of the same age and can occur at any stage of pregnancy, puerperium being the time of highest risk. the overall incidence of vte in the royal hospital in obstetrics was 0.08%. deep vein thrombosis (dvt) constituted 77.5%, pe 15% and cerebral vein thrombosis 7.5%. there were 13 maternal deaths in the last 9 years due to various causes. one was due to a massive pulmonary embolism in 2002. out of a total of 25 antenatal cases of dvt, two had dvt following a road traffic accident. there were 6 cases of dvt with a history of congenital thrombophilia and 4 with recurrent incidence. out of a total of 8 cases of postpartum dvt, six cases were following caesarean section, and two following vaginal delivery. amongst five cases of pulmonary embolism, three were after caesarean section, and two following vaginal delivery. there were three cases of cerebral vein thrombosis, two during the antenatal period and one in the postpartum period. dvt was more common in the second trimester, higher in para 1-5, higher in younger women 20-30yrs. of the six cases of thrombophilia, the commonest was protein s deficiency. recurrent dvt was also noted in patients with a family history of the disease and those with congenital thrombophilias. c h a n gi n g tr e n d s i n i n c i d e n c e a n d i n d i c at i o n s f o r c e sa r e a n se c t i o n at t h e r oya l h o spi ta l , o m a n : 9 9 9 – 2 0 0 6 seerat minocha and anita zutshi, division of obstetrics and gynecology, royal hospital, ministry of health, muscat, oman. syed guahar rizvi, sultan qaboos university hospital, muscat, oman. email: zutshi@omantel.net.om the rate of caesarean section, once performed as a maternal life saving procedure, has quadrupled since 1965. some of the reasons for increasing rates all over the world may be reduced parity, older women having children, electronic fetal monitoring, changing protocols for breech presentation management, the reduction in midpelvic vaginal deliveries, the rising incidence of hiv infection, prematurity and concerns about malpractice litigation. this study aims to review the changing trends of caesarean section at the royal hospital, which is the main tertiary care teaching hospital in oman. a retrospective analysis was performed on the obstetric data obtained from delivery suite and obstetric theatre computer records including indications and patient characteristics e.g. age, parity, previous scar on uterus, perinatal morbidity and mortality. a total of 6,950 caesarean sections were identified among 39,705 deliveries (17.5%). the caesarean rate increased over time from 11.07 % in 1999 to 13.8 % in 2001 and 18.6 % in 2006. in this group, total high risk pregnancies were 6,582 (94.5 %) and low risk 368 (5.5 %). indications arising during labour were the leading group (40%), followed by previous uterine scar (20%). the trend of the various indications was similar over 8 years. perinatal morbidity, identified through special care baby unit admissions and apgar score < 7, revealed a marginal decrease in 2006 (2.2%) as compared to 1999 (4.4%) but it was not statistically significant (p>.005). changes in the practice of obstetricians e.g. more elective caesarean deliveries for breech presentation, increasing expectations from prospective parents and women’s requests were the main causes of increasing rates. va gi n a l b i rt h a f t e r c a e sa r e a n s e c t i o n devyani narayan, department of obstetrics and gynecology, khoula hospital, muscat, oman. email: devnaryn@omantel.net.om caesarean section rates have risen worldwide to around 25%. approximately 10% of the obstetric population has had one caesarean section. obstetricians caring for these patients need to consider the implications for pregnancy, labour and delivery after previous caesarean section. the main consideration is the balance between risks and benefits of repeat elective caesarean sections versus trial for vaginal delivery. in time it has become apparent that a vaginal delivery could occur both successfully and safely after a previous lower segment caesarean section. various studies have noted a scar dehiscence rate of <1%, with no maternal mortality or significant morbidity. with the advent of better anaesthesia, surgical techniques and antibiotics, the maternal mortality and morbidity rates have decreased, but the maternal mortality with elective caesarian section is still higher than vaginal delivery. in addition to the inherent risks of any surgical procedure, there are several reports which discuss the negative impact on subsequent fertility and psychological status. the incidence of placenta praevia increases with increasing numbers of caesarean deliveries and is a recognized risk factor for placenta accreta. khoula hospital has an annual delivery rate of 4,000 and approximately 10% are with previous caesarean sections. an analysis of the various variables affecting vaginal birth after one previous caesarean section has been done. to analyse the variables affecting vaginal birth after one previous caesarean section, a prospective analysis of all cases of previous one caesarean section delivered at khoula hospital was carried out between december 2002 and october 2007. a b s t r a c t s 1 0 1 3 d e c e m b e r 2 0 0 7 106 o u t c om e o f a s si st e d va gi n a l b r e e c h d e l i v e ry v e r su s c a e sa r e a n se c t i o n f o r b r e e c h i n t e r m a n d pr e t e r m si n gl e t o n pr e gn a n c i e s at r oya l h o spi ta l : 9 9 7 2 0 0 6 anita zutshi and mary jacob, division of obstetrics and gynecology, royal hospital, muscat, oman; syed g rizvi, sultan qaboos university hospital, muscat, oman; priyanka zutshi, medical student, boston university, medical school, boston, usa. email: zutshi@omantel.net.om the management of preterm and term delivery of a fetus in breech presentation is a disputable issue. the randomized controlled study, term breech trial, results revealed that planned cesarean section reduces the risk of short term adverse perinatal outcomes, compared with the planned vaginal birth, with no significant differences in the long term outcome. to compare outcomes for fetuses at term and preterm singleton breech presentation delivered by assisted vaginal breech delivery or by caesarian section at royal hospital, oman, a retrospective study of computer records from 1997 to 2006 from the delivery suite and obstetrical operation theatre was performed. parameters such as maternal age, parity, gestational age at birth, birth weight, cesarean section rate, perinatal mortality rate, apgar scores and other complications occurring during delivery were statistically analysed. out of a total of 1,131 breech presentations at delivery in 10 years (1997–2006), 48 % had assisted breech vaginal delivery and 52 % were delivered by caesarian section. both groups of women had similar demographic details, periods of gestation and babies’ birth weight. the incidence of caesarian section amongst breech deliveries has increased in the past 10 years from 29 % in 1997 to 71 % in 2006 without significant change in the neonatal outcome in terms of special care baby unit admissions and apgar scores. at this moment, there is not enough evidence to support cesarean section as the method of choice for delivery of preterm and term breech. the decision to deliver babies presenting by breech vaginally or by cesarean section should be individual. pat i e n t s at i sfa c t i o n s u rv e y e x i t i n t e rv i e w f o l l ow i n g c a e sa r e a n s e c t i o n sarvasai seema and gazala khan, department of obstetrics and gynecology, khoula hospital, muscat, oman. this study was carried out with the view to gauging client satisfaction after caesarean section (cs) and discover the significance of antenatal counselling. a prospective study involving 100 women with a client exit interview on day 3 or 4 of caesarean delivery was done and included women’s knowledge, satisfaction and involvement in decision for current caesarean section, and their knowledge regarding its impact on future reproductive outcomes. the survey revealed 40% of these women were nulliparous. only 34 % of women said that the possibility of cs was discussed with them antenatally and most of them were multiparas with a previous cs. doctors informed 90% of the women about cs, while 84 % fully understood what was told them and 4% didn’t understand the indication of cs. all women who had elective cs were adequately counselled regarding the reason for cs and its implications for future pregnancy, but only 26% of the total number said they had been counselled about future reproductive implications. another startling finding was that 74% women revealed that birth spacing was not discussed. this interview was carried out on day 3 or 4 postpartum, and it is possible birth spacing was discussed later at the time of discharge. it appears from our study that most women were satisfied and understood the indication of caesarean section. detailed debriefing regarding indications for cs, and counselling regarding the effect on future fertility needs to be strengthened in our hospitals. training of doctors and staff nurses in the above topics and interpersonal communication skills is required in all hospitals. m a n a ge m e n t o f mu lt i pl e p r e gn a n c i e s : th e r oya l h o spi ta l e x pe r i e n c e rahma salim al-ghabshi and noor al-mandhari, division of obstetrics and gynecology, royal hospital, muscat, oman. there is increasing interest in the outcomes of multiple pregnancies as their numbers rise, mainly owing to advances in fertility-enhancing techniques. the objectives of this retrospective study were to asses the incidence of multiple pregnancies in consanguineous marriage and to analyse complications associated with multiple pregnancies at the royal hospital, muscat, oman, during a period of 31 months from january 2000 to september 2002. the total number of cases was 173, including eight sets of triplets and one set of quadruplets. the incidence of multiple pregnancies was found to be 12.25 per 1,000 deliveries. the commonest factor of spontaneous multiple conception was a positive family history of multiple pregnancy and consanguineous marriage. our study showed an increased incidence of complications, such as increased incidence of cesarean section rate at 47.98%, as compared with singleton pregnancy of 13-15 % in our hospital; increased mortality rate of 28.2 per 1000 live birth and increased prematurity of 30.9% (< 34 wks). in order to decrease its maternal and fetal complications, multiple pregnancies must be diagnosed early and all of them should have chorionicity determined at first scan, ideally in the first trimester. in order to meet the challenges, it is recommended that all multiple pregnancies in an individual hospital be cared for the same consultant-led team. in our community, as in similar communities in the gulf states, the incidence of spontaneous conception is higher due to consanguineous marriage, which is not seen in other countries where the commonest cause of multiple pregnancies is ovulation induction. a n t e n ata l a n d n e o n ata l o u t c om e s i n pr e gn a n t wom e n w i t h pe r si st e n t gly c o su r i a d e spi t e n o r m a l g t t aparna gumma and r ratnachalam, george eliot hospital, nuneaton,uk. email: adgumma@yahoo.co.uk in a retrospective audit at george eliot hospital, from may 2006 may 2007, 50 patients with persistent glycosuria were identified. the majority of the patients were in the age group 20-25 yrs (36%). 32% were primigravida and 74% had bmi < 35. 8% of the patients had a previous history of gestational diabetes and family history was positive for 38%. 52% of the patients had 3 or > episodes of glycosuria. repeat glucose tolerance test or random blood glucose was tested in 35 of the 50 patients and the result was normal. 22 % had urinary tract infections of > 2 episodes. growth scans were performed in 40% (large for dates) and polyhydramnios was noted in 14 %. 14 % of the patients developed pregnancy-induced hypertension. the mode of delivery was by caesarian section in 56% (elective = 32%, emergency = 24%). 18% had postpartum haemorrhage and post operative infection occurred in 26%. macrosomia was noted in 40% and neonates requiring special care baby unit admission occurred in 6 % of cases. renal glycosuria in pregnancy is a known entity and physiological phenomenon. it was thought to be benign with no adverse effects. in our study, we noted that the antenatal outcomes are similar to that of gestational or type 1 diabetes. neonatal outcomes were equal to that of the non-diabetic pregnant population. it is clear that from this small study, that ‘benign’ renal glycosuria of pregnancy is not so ‘benign’, but needs to be taken seriously and measures should be taken to optimise the outcomes. 5 t h i n t e r n at i o n a l o b s t e t r i c s & g y n e c o l o g y c o n f e r e n c e , s u lta n q a b o o s u n i v e r s i t y, s u lta n at e o f o m a n 107 e ffe c t i v e n e s s o f se l f pe r i n e a l c a r e ov e r a se p t i c pe r i n e a l c a r e o n e pi si ot om y wo u n d h e a l i n g savithri raman, department of nursing, sultan qaboos university, college of medicine and health sciences, muscat, oman. email: mmrssavithri@yahoo.com the main objective of the study was to compare the effectiveness of self perineal care (spc) versus aseptic perineal care (asp). further, the main factors such as birth weight of the baby and episiotomy length affecting episiotomy wound healing (ewh) were also analysed. a quasiexperimental, purposive sampling method was used to select 50 mothers to group i (asp) and group ii (spc) with total a sample size of 100 mothers. data were collected by a general postnatal observation rating scale and the reeda (redness, oedema, ecchymosis, drainage, approximation) check list on episiotomy wound assessment. they were analysed using descriptive and inferential statistics. major findings: group i and group ii were found to be comparable in terms of age, education, gestational age, parity, obstetrical problems, duration of rupture of membrane, baby weight, length of the episiotomy wound and general postnatal health status. a significant difference was found in ewh on second and third postnatal day between mothers of group i and group ii (p<0.05).the overall mean episiotomy wound score in group i was higher than the score of group ii (p<0.05). this indicates the inflammatory response in group ii was less evident compared to group i. therefore the ewh outcome in group ii was better than the group i. group i and group ii had delay in ewh as the episiotomy length increased (p<0.001) and as the birth weight of baby increased. the study showed that spc offers better ewh over asp, but increased birth weight and episiotomy length delays ewh. k n ow l e d ge a n d at t i t u d e s r e g a r d i n g hum a n m i l k d o n at i o n a m o n g h e a lt h c a r e p r ov i d e r s km girija, department of nursing, college of medicine and health sciences, sultan qaboos university, muscat, oman. email: km_girija@yahoo.com breast milk is a natural god-given gift of life. the american academy of pediatrics strongly emphasises that human milk is species specific and the optimal nutrition for infants. they recommend banked human milk (hmb) as a suitable alternative. breast milk is often disposed of without consideration of donation because the public and health care providers are unaware of hmb and its benefits. hmb is operated under strict guidelines established by the hmb association in western countries. donors are screened for safety precautions. it is imperative that healthcare providers become educated regarding hmb because it will provide human milk to preterm, sick or adopted infants who are in great need of breast milk. to assess the knowledge and attitudes towards hmb, this quantitative descriptive study was done on available healthcare providers in the maternity and pediatric departments of three baby friendly hospital initiative adopted hospitals in kerala, india. among 150 healthcare providers, a significant knowledge deficit regarding hmd was found (90%). nurses’ knowledge deficit related to hmb was highly significant (p<0.001). the overall attitude towards hmb was very good except for healthcare providers from an islamic background, due to the religious beliefs against sharing breast milk. healthcare providers use artificial formula in neonatal intensive care units. the breast milk from mothers who are unable to use their milk for varied reasons is not preserved although it is the most precious food for neonates and infants as hmb procedures are not established in kerala, india. a country like india where malnutrition and infections among infants are high can very well think of establishing hmb. o u t c om e o f m i d t r i m e st e r e m e r ge n c y c e r c l a ge o f i n c om pe t e n t c e rv i x w i t h o r w i t h o u t b u l gi n g fe ta l m e m b r a n e s . sushma dikhit, veena paliwal, selvamoni anderson, neesha sharma, department of obstetrics and gynecology, sultan qaboos hospital, salalah, oman. email: sushmadikhit@hotmail.com to evaluate the outcome of emergency mid trimester cerclage in a dilated and/or effaced cervix with or without bulging fetal membranes, a descriptive retrospective cohort study was carried out and charts of all patients with a diagnosis of incompetent cervix in second trimester, admitted from 2003 to 2007 in sqh salalah were reviewed. exclusion criteria were: twin pregnancy, premature rupture of membranes, clinical signs of chorioamnionitis and vaginal bleeding. the cervical dilatation and effacement, local infection, location of bulging membranes, subsequent pregnancy duration, maternal complications and neonatal outcomes were analysed. out of a total of 40 women included in the study, the first group of 25 women had membranes inside the cervical canal; in the other group, 15 women had bulging of membranes into the vagina as hourglass formation with dilated and effaced cervix. preoperative cervical assessment was done by visual, digital and ultrasonological examination. all women received broad spectrum antibiotics and tocolytics at the time of cervical cerclage (mcdonald technique). the emergency cerclage led to a mean 15.5 weeks (4-24) prolongation of pregnancy in group 1 and 6.23 weeks (0-18) in group 2. cerclage success was significantly lower when cervical effacement was > 50% and dilatation >3cm. overall neonatal survival was 75%, with 96% in group 1 and 40% in group 2. apgar scores and weight at birth were significantly good in group 1. other complications were one maternal morbidity, secondary postpartum haemorrhage, two cases of chorioamnionotis and prolonged hospital stay. favorable outcomes may be accomplished in patients with cervical incompetence in second trimester pregnancy following emergency suturing. p o ly h y d r a m n i o s r i sk fa c t o r s a n d o u t c om e s shabnam saquib, mariam mathew, syed g rizvi, sultan qaboos university hospital, muscat, oman. email: mathewz@omantel.net.om this was a prospective study of all deliveries complicated with polyhydramnios in sultan qaboos university hospital, sultanate of oman, during the period between 1 january 2005 and 30 april 2006. the objectives of the study were to determine the risk factors associated with polyhydramnios and assess the maternal and perinatal outcome in these patients. 208 women with singleton pregnancy, with amniotic fluid index (afi) >200mm were included in the study. 2,440 women with normal afi who delivered during this period formed the control group. polyhydramnios was divided into mild and moderate to severe based on afi values. patients’ demographic data, antenatal complications, gestational age at delivery, mode of delivery, postpartum complications and perinatal outcome were studied. a total of 2,648 deliveries occurred during the study period. among these, 208 (7.8 %) had polyhydramnios: of which 179 (86.1 %) were mild and 29 (13.9 %) moderate to severe. 1 0 1 3 d e c e m b e r 2 0 0 7 108 mean gestational age at delivery was 38.8±1.7 weeks. sixty-eight (32.7%) of these pregnancies were complicated with diabetes compared to 12.4% of the controls. preterm delivery occurred in 16 (7.7%) cases. caesarean section rate was 27.9%, compared to 17.3% in the control. major congenital anomalies were found in 2.8% of newborns compared to 1% among the control. eighteen babies were admitted to special care baby unit (scbu). diabetes in pregnancy and increasing maternal age were the main risk factors for polyhydramnios. we found a significant increase in birth weight with increasing afi scores. anaemia during pregnancy, fetal macrosomia, caesarean section rate and congenital anomalies were significantly higher in the study group. s a fe t y o f i n d u c t i o n o f l a b o u r w i t h va gi n a l pr o sta gl a n d i n s ( p ge 2 ) i n gr a n d mu lt i pa r a veena paliwal and sushama dikhit, department of obstetrics and gynecology sultan qaboos hospital, salalah, oman. email: paliwal@omantel.net.om the aim of this two year (jan 2004–dec 2005) prospective study was to determine the safety of labour induction in grand multi para with vaginal prostaglandins (pge2) and pregnancy outcomes. a total of 226 grand multi para (para>5) at 38 weeks gestational age and above, had induction of labor with pge2 for various indications. their outcome was compared with those of 400 women in spontaneous labour during same period with comparable variables like age and parity etc. maternal and fetal data included age, parity, and indication for induction, bishop score at induction, total dose of prostaglandin used and complications of the induction of labor. other information was: length of labour; need for syntocinon augmentation; blood loss during the third stage of labor; mode of delivery; birth weight; sex; apgar score at 1 and 5 minutes and admission to special care baby unit (sbcu) etc. statistical analysis was done using epi data 6. maximum inductions were for past dates (50%). the cesarean rate was higher in the induction group: 19 % as compared to 12% in the control group. this is due to a desire for tubal ligation with caesarean for religious beliefs and maternal request (p< .05). there were no significant differences in fetal outcomes in terms of meconium aspiration, apgar score and admission to scbu. there were no serious maternal complications like infection, uterine hypertonus or rupture. induction of labor with vaginal prostaglandins (e2) in grand multipara is a safe and acceptable method of induction. we recommend a large multicentric randomised coutrol trial to validate these observations. p e r i o d o n ta l d i se a se a n d g i n gi v i t i s a s a p o s si b l e r i sk fa c t o r f o r p r e t e r m l a b o u r a n d b i rt h neesha sharma and veena paliwal, department of obstetrics and gynecology, sultan qaboos hospital, salalah, oman. email: paliwal@omantel.net.om the objective of this study was to explore periodental disease as a risk factor for preterm labour and birth (ptb). a prospective observational study was undertaken over a period of six months from march to august 2007. cases of ptb and labour at sqh, salalah, were studied for oral hygiene, a pro-forma was made and data collection is going on. until now 50 cases of preterm labour and birth have been studied with promising results. there is good correlation between poor oral dental hygiene (odh) and preterm birth. as per various recent studies and meta-analysis there is good evidence of poor pregnancy outcome in patients with poor odh. our preliminary data also supports this hypothesis. preterm birth is a financial burden on health resources, family and community. therefore every effort should be made to prevent ptb by setting up dedicated clinics to identify the women at increased risk and intervene to reduce the incidence of ptb. ptb due to infection (c. 47%) is a preventable factor. good oral hygiene is certainly an inexpensive tool in preventing infective etiology of ptb. r a r e c au se o f i n t r au t e r i n e d e at h a b n o r m a l um b i l i c a l c o r d c o i l i n g sanjay s curpad and kab asaad, prince charles hospital, north glamorgan nhs trust, uk. email: scurpad@yahoo.com a 20 year primigravida was referred to the day assessment unit with a history of absent fetal movements. on examination, the uterus was corresponding to the period of gestation and non tender. fetal heart sounds were not located with doppler imaging and intrauterine death was confirmed by ultrasound examination. induction of labour with mifepristone and misopristol was uneventful and she delivered a macerated still born baby weighing 500 grams. post delivery recovery was uneventful. post delivery investigations were normal; the postmortem examination showed a 25 week fetus with borderline intrauterine growth restriction (iugr), birth weight being third centile, with no congenital anomalies identified. the umbilical cord showed increased cord coiling (0.5/cm) with narrowing at fetal end. umbilical cord coiling is a normal process of development of the umbilical cord. the origin is unknown; hypotheses include fetal movements, differential umbilical vascular growth rates, fetal haemodynamic forces and muscle fibres in the arterial wall. normal cord coiling index is 0.17(+/-0.009) spirals per centimeter. abnormal cord coiling is associated with adverse pregnancy outcomes. hypercoiling is associated with iugr, intrapartum fetal heart decelerations, thrombosis and cord stenosis. hypocoiling of the cord is associated with increased incidence of fetal demise, operative deliveries for fetal distress, anatomic and karyotypic abnormalities and proneness to chorioamnionitis. the coiling index is best identified in the second trimester and reflects true coiling of the cord as identified by pathological examination. the identification of the hyper/hypo coiling of the cord in the second trimester will identify high risk pregnancies which may benefit from increased surveillance in the antenatal and intrapartum periods. p r e gn a n c y i n wom e n w i t h c a r d i a c va lv e r e pl a c e m e n t a m a n a ge m e n t c h a l l e n ge chitra jha and majida al irhayim, division of obstetrics and gynecology, royal hospital, muscat, oman. email: amitabh@omantel.net.com pregnancies in patients with prosthetic cardiac valves carry a high risk associated with cardiac disease as well as the risk of medications and anticoagulants. a retrospective review of the pregnancies with cardiac valve replacement, managed at royal hospital during the past 10 years was carried out. the course of pregnancy, outcome, maternal, fetal morbidity and mortality were studied and followed up in detail in 40 patients through 111 pregnancies. the type and the site of valve replacement and choice of anticoagulant were noted. the protocol and guidelines of management of these pregnancies antenatally, intra and postpartum at our institution is presented. the incidence of cardiac valve replacement was about 10% of all cardiac disease in pregnancy. the incidence of congenital anomalies while continuing warfarin through out 5 t h i n t e r n at i o n a l o b s t e t r i c s & g y n e c o l o g y c o n f e r e n c e , s u lta n q a b o o s u n i v e r s i t y, s u lta n at e o f o m a n 109 pregnancy was not more than the background risk, though the incidence of miscarriages was higher. the risk of complications did not depend upon the dose of warfarin. r e t r o spe c t i v e a n a lysi s o f c e rv i c a l c e r c l a ge a n d o u t c om e o f pr e gn a n c y 2 0 0 0 2 0 05 : r oya l h o spi ta l , o m a n, e x pe r i e n c e kanchana rajan and chitra jha, division of obstetrics and gynecology, royal hospital, muscat, oman. the outcomes of pregnancy following cervical cerclage were studied. 308 cases of cervical cerclage performed over a period of 5 years from 2000 to 2005 in the division of obstetrics and gynecology of the royal hospital were analysed retrospectively by reviewing the case records, operation notes and delivery notes. the history, period of gestation, risk factors, digital examination and ultrasound examination were analysed. the operative findings of individual cases were reviewed and the delivery notes of each patient for outcome were analysed. the cerclages were categorized retrospectively into three groups namely: elective, urgent and emergency cerclage and the maternal morbidity and fetal outcomes were studied. over 21 cases of emergency cerclages performed during this period were analysed individually and the outcome discussed. a case of recurrent miscarriage due to uterus didelphys and successful pregnancy and delivery after abdominal cerclage is presented. an audit into record keeping, guidelines for future evaluation, classification, and counseling is discussed in detail. ju d i c i o u s p r om ot i o n o f va gi n a l b i rt h a f t e r c a e sa r e a n se c t i o n ( v b a c ) c a n c o u n t e r r i si n g c a e sa r e a n se c t i o n (c s) r at e s archna mohan, pooja vaswani, selvi anderson, indu jonathan, sultan qaboos hospital, salalah, oman. email: rayofhope254@yahoo.com to study the trend of mode of delivery and outcome in patients with previous one caesarian section (cs) and to plan a strategy for future reductions of cs rates, a retrospective study was done from january 2005 to september 2007 (33 months) in sqh, salalah. a total of 1,072 females with a history of previous one cs were analysed for mode of delivery in their current pregnancy; indication of first and repeat cs; gestation; induced or spontaneous labour; maternal bmi; previous vaginal birth; fetal weight; maternal complications and fetal outcome. a total of 90.33% of females attempted vaginal birth after caesarian section (vbac), and 54% had a vaginal birth. the most common indication for repeat elective cs was failed induction, followed by malpresentation and fetal macrosomia; in emergency cs, it was non progress of labour followed by fetal distress and scar tenderness. one patient had a ruptured uterus with a ruptured urinary bladder at 34 weeks of gestation and another patient had a subtotal abdominal hysterectomy for placenta previa increta. two patients had scar dehiscence after successful vaginal delivery and one had a haematoma at a previous uterine scar site. in scar tenderness only 0.02% had scar dehiscence/rupture. judicious promotion of vbac is a reasonable strategy to counter the rising cs rates as it has vast effect on cost saving and greater patient satisfaction with less maternal morbidity. with careful selection and monitoring, most of the cases can be delivered successfully vaginally. overdiagnosis of scar dehiscence needs to be re-evaluated and the involvement of a consultant for decision making can help in reducing cs rates. c o n se rvat i v e m a n a ge m e n t o f p l a c e n ta a c c r e ta – a c a se r e p o rt veena paliwal and selvamoni anderson, department of obstetrics and gynecology, sultan qaboos hospital, salalah, oman. email: veena_paliwal3@yahoo.com recent increase in the incidence of placenta accreta has led to widespread awareness of preoperative evaluation and planned management. a conservative approach can minimize complications and preserve fertility in selected cases. a 36 yrs old, gravida 6 para 4+1, visited sultan qaboos hospital for the first time in this pregnancy at 27 weeks of gestation. she was diagnosed to have central placenta previa and placenta accreta with previous four cesarean sections. emergency cs with bilateral tubal ligation was done at 33 wks of gestation for antepartum haemorrhage under general anesthetic. during the operation, the lower segment was highly vascular and had extensive pelvic adhesions. a female baby of 1.480 kg in good condition was delivered by high transverse incision in the uterus. the placenta was completely adherent to the uterine wall and bladder area with distorted anatomy; it was left in situ. intra-operative bleeding was controlled with bilateral uterine artery ligation and multiple haemostatic sutures in the uterus. the patient was kept under close observation in view of the risk of infection and haemorrhage. methotrexate 50 mg/m2 (85mg) imi on d15 with folinic acid next day (34mg ivi), second dose on d20. at 6 weeks postpartum, asymptomatic, she had a periuterine arteries embolisation followed by cervical dilatation and partial evacuation of placenta in the united arab emirates. the patient had multiple blood transfusions. at present she is having normal periods. in this patient, we were able to save the uterus as she was not willing to have a hysterectomy. a high index of suspicion in high risk cases with great vigilance and restricting primary caesarean rates will go a long way in protecting patients from these complications. e ffe c t o f m at e r n a l i n t r av e n o u s a m i n o a c i d i n f u si o n i n c a se s o f i n t r au t e r i n e gr ow t h r e ta r dat i o n meenakshi b chauhan and suman kohli, department of obstetrics and gynecology, postgraduate institute of medical sciences, rohtak, haryana, india. email: mbc51490@yahoo.co.in to assess the effect of amino acid infusion on fetal outcome, in cases of intrauterine growth restriction (iugr), 50 pregnant women with iugr were alternately assigned to one of two groups. group a received 200 cc each of a total of 7 intravenous amino acid infusions on alternate days for 14 days. group b was managed only with bed rest and a good diet. patients were followed up till delivery. parental outcome was noted and results were compared in the two group statistically applying the t-test. after amino acid infusion there was a mean increase in maternal weight, symphisiofundal height; estimated baby weight and amniotic fluid index and a decrease in the systolic/diastolic ratio on doppler study. the mean birth weight was higher and complication rate was less in neonates in the study group. the maternal amino acid infusion in the case of pregnancies complicated by mild iugr thus resulted in a significant improvement in overall parental outcomes. 1 0 1 3 d e c e m b e r 2 0 0 7 110 u se o f s u l pr o st o n e i n t h e t e r m i n at i o n o f se c o n d t r i m e st e r m i s c a r r i a ge a n d i n t r au t e r i n e fe ta l d e at h s q u h e x pe r i e n c e . anita k mohan and mariam mathew, department of obstetrics and gynecology, sultan qaboos university hospital, oman; sg rizvi, department of family medicine and public health, college of medicine and health sciences, sultan qaboos university, oman. email: mathewz@omantel.net.om to study the efficacy and safety of sulprostone (pge2 analogue) in the termination of second trimester miscarriages and intrauterine fetal death (iufd), a retrospective study was conducted in the department of obstetrics and gynecology, sultan qaboos university hospital, sultanate of oman, between january 2000 and december 2005. ninety seven women with 12 to 30 weeks gestation were included in this study. sulprostone was started as an intravenous infusion of 15µgm/hr and titrated to a maximum of 250µgm/hr to a total dose of 1500µgm/day. the patients’ demographic data; gestational age; induction-abortion interval; side effects; complications and the need for evacuation were studied. out of 97 women who received sulprostone, 90 aborted/delivered within 24 hours. the average induction-abortion interval was 11.9±8.0hours. sulprostone was associated with few side effects and was well tolerated by patients. although most of the patients required evacuation and curettage, the blood loss was minimal. only six out of 97 women required a blood transfusion and two needed a hysterotomy. we found sulprostone as an efficient drug for termination of second trimester miscarriage and iufd. h i st o c y t o si s x a n d p r e gn a n c y : a c a se r e p o rt khalsa al-hattali and majida al-irhayim, division of obstetrics and gynecology, royal hospital, muscat, oman. email: alirhayim@yahoo.com histocytosis is a rare disease which usually manifests in children and young adults. the origin of the disease is believed to be inflammatory rather than neoplastic. it is characterized by proliferation of reticuloendothelial cells in various organs. our case is a 28 year old female diagnosed with histocytosis x and diabetes insipidus at the age of 20. she had exophthalmos and sub-acute cerebellar syndrome. she was on desmopressin as a result of her condition. wheel chair bound, due to gait unsteadiness, the patient had bilateral nystagmus, bilateral pyramidal signs and mild trunkal ataxia. her mri report revealed demylinating-like lesions in the globus pallidus, thalami and cerebellar hemispheres. after diagnosis of this disease, the patient has conceived twice. she was followed up by a neurologist, an endocrinologist and an obstetrician. there were no major problems during pregnancy apart from fetal growth restriction. she had a normal vaginal delivery in both pregnancies, both with low birth weight 2.1kg and 2.2 kg. neither of the babies needed special care and they are currently alive and well. following the second delivery, the patient developed hypotension which was managed with desmopressin and intravenous fluids. the patient has since been discharged and is at home and doing well. to the best of our knowledge, there has only been one case reported with histocytosis x that has resulted in a successful pregnancy. d i a b e t i c pr e gn a n c y a n d m at e r n a l v i ta m i n d stat u s lisa campbell and kj erkine, homerton university hospital, london, uk. email: lisacampbell73@hotmail.co.uk diabetes is becoming more common in women of child bearing age and diabetic pregnancies are high risk. the role of vitamin d in the reproductive system is uncertain. increasing evidence suggests that pregnancy is associated with vitamin d hypovitaminosis and that this in turn can predispose a woman to diabetes. furthermore, vitamin d hypovitaminosis is itself associated with various poor pregnancy outcomes. we investigated the effect of diabetes during pregnancy on maternal vitamin d status. in a longitudinal study, two cohorts of pregnant women, 155 non-diabetic and 90 diabetic were followed up in a university teaching hospital in london, uk. serial vitamin d blood samples were taken at booking, 26 weeks and 34 weeks of gestation in non-diabetic women and at booking and at monthly intervals thereafter in diabetic women over a 15 month period (april 2006 to may 2007). at the same time glycosylated haemoglobin [hba1c] and fructosamine, measures of glycaemic control, were measured. ethnicity, age and type of diabetes of the women were characterized. birth weight was recorded. 46/90 (52%) of diabetic mothers were vitamin d deficient at some point during their pregnancy compared to 61/155 (39%) non diabetic mothers (p value < 0.05). diabetic women were twice as likely (95%, ci: 1.3 5.3) to have a vitamin d level below 24 nmol/l than non-diabetic women. compared to caucasian mothers, the odds of a vitamin d level below 24 nmol/l were far higher in black (or 2.2 95% ci: 1.1 4.4) and asian women (or 17.4 95%, ci: 6.2 48.7). au d i t o f th y r o i d d i s o r d e r s i n p r e gn a n c y anita nargund, u kiran, ls gokhale, royal gwent hospital, newport, uk. email: anitamn73@yahoo.co.uk this is a retrospective audit of 30 cases done at the royal gwent hospital, from june 2006 to may 2007. the aim of our audit was to confirm compliance with the management of thyroid disorders in pregnancy and their outcome. standards are: multi-disciplinary management, a booking plan to be written in detail about thyroid function tests (tft) done in each trimester/monthly if newly diagnosed; repeat tfts in 4-6 weeks after dose alteration and repeat tfts in 6-8 weeks postnatal. thyroid antibodies testing; in hyperthyroid propylthiouracil (ptu) should be used. maintain euthyroid levels and thyroid stimulating hormone at lower limit of normal, t3 at upper limit of normal. (handbook of obstetrics medicine by catherine nelson-piercy) we collected 27 hypothyroid cases and 3 hyperthyroid cases. our results are: multidisciplinary management 63%, booking plan written 8 cases, tfts in each trimester 97%, thyroid antibodies 33%; ptu used in all 3 hyperthyroid cases; repeat tfts in 4-6 weeks after dose alteration 100%; postnatal tfts 67%. our recommendations were to have a standard trust protocol, to write the plan in the booking clinic; antenatal thyroid antibodies testing; repeat tfts postnatal; and reaudit in 6 months. 5 t h i n t e r n at i o n a l o b s t e t r i c s & g y n e c o l o g y c o n f e r e n c e , s u lta n q a b o o s u n i v e r s i t y, s u lta n at e o f o m a n 111 h e a rt d i se a se i n p r e gn a n c y chitra jha and majida al irhayim, division of obstetrics and gynecology, royal hospital, muscat, oman. email: amitabh@omantel.net.om cardiac disease is an uncommon but potentially serious medical complication of pregnancy. the reported incidence is 0.3 to 3.5%. to review in detail the pregnancies in women with heart disease, attending the ‘cardiac disease in pregnancy’ clinic under the department of obstetrics and gynecology royal hospital, over the last 6 years, a retrospective study was done from jan 2001 to dec 2006. all patients were classified into low, medium and high risk groups depending upon the severity of their disease. 505 patients attended the clinic during this period. besides other congenital and acquired disorders, 35 of these had a prosthetic valve and were followed through 71 pregnancies. 17 patients were in the high risk group with cardiomyopathy and 3 women had been diagnosed to have a myocardial infarction in the past. the incidence, age, parity, outcome and maternal or fetal morbidity and mortality were studied in these patients. those patients with a prosthetic heart valve were studied in greater detail over a 10 year period. the incidence of cardiac disease in pregnant women in our population is just over 1%, which is comparable to world wide figures. the incidence of pregnancies in women with cardiac valve replacements and those with cardiomyopathies is higher, probably because of increase in multiparity and pregnancies in the older age group. there was no significant maternal mortality or morbidity. pregnancy outcome can be improved with proper counselling and assessment of risks. close obstetric and medical surveillance is required through out pregnancy. early identification and prompt correction of aggravating factors such as anaemia, infection, hypertension and arrhythmias is important. c a r d i om y o pat h y i n pr e gn a n c y khalsa al-hattali and majida al-irhyim, division of obstetrics and gynecology, royal hospital, muscat, oman. email: alirhayim@yahoo.com peripartum cardiomyopathy with high risk of morbidity and mortality is a subset of dilated cardiomyopathy with unknown etiology. the incidence highest is in haiti with 1:300 pregnancies and the lowest in the usa: 1:1300-1500. risk factors are increasing maternal age, multiparity, hypertension and multiple pregnancies. maternal complications include heart failure, arrhythmias and thromboembolic complications. reported maternal mortality is 4% 80%. fetal morbidity is due to iatrogenic prematurity and intrauterine growth restriction secondary to hypoxia. the objective of our study was to assess the maternal and fetal outcomes in a retrospective data analysis of all patients with cardiomyopathy between 2001-2007 at the cardiac disease with pregnancy clinic (wattayah polyclinic), the cardiac clinic (the royal hospital) and emergency admissions to the royal hospital. out of a total of 16 patients, 3 were under 30 years, 7 between 31-40 years and 6 between 41-45 years. most common, fifteen of the 16 patients had dilated cardiomyopathy with 7 peripartum cardiomyopathy. the severity of the condition was determined by the echocardiographic (echo) findings. there were 8 patients with severe left ventricular dysfunction (ejection fraction 15-20%), 4 patients with moderate impairment of left ventricular function and 4 with mild impairment. all patients with severe cardiomyopathy were delivered by caesarean section; out of these three were delivered at 32-33 weeks. in this series, 2 patients had pulmonary oedema and one patient died 3 days after delivery with left ventricular fibrillation. fetal morbidity was mainly due to prematurity, as 3 babies were delivered at 32-33 weeks, one of which with severe intrauterine growth restriction. pregnancy was well tolerated in the majority of the patients, showing no difference in parity. maternal mortality was 5%; however, the fetal outcome was good. early anticipation of complications through proper diagnoses and close maternal and fetal surveillance is essential to reduce maternal and fetal morbidity and mortality. c om pa r at i v e e va luat i o n o f s u b l i n g ua l m i s o pr o st o l wi t h i n t r av e n o u s m e t h e r gi n fo r p r e v e n t i o n o f p o st pa rt um h a e m o r r h a ge pushpa dahiya, oman medical college, sohar campus, oman; meenakshi chauhan postgraduate institute of medical sciences, rohtak, haryana, india. email: pushpadahiya@yahoo.com the aim of this study was to compare the efficacy of sublingual misoprostol with intravenous methergin for prevention of postpartum haemorrhage. one hundred and sixty women undergoing vaginal deliveries were randomly divided into 2 groups. group 1 (n = 80) received tablets of misoprostol 200ug sublingually and group 2 (n = 80) received an injection of methergin 0.2 mg intravenously at the time of delivery of the anterior shoulder of the baby. the duration of the third stage; the amount of blood loss; mean post delivery drop in haemoglobin; side effects and complications of drugs were compared in the two groups and statistically analysed. all the parameters were found comparable in the two groups and there was no statistical difference between them. misoprostol was found to have the advantage of easy storage, administration and was cheaper. sublingual misoprostol appears to be a promising drug in minimizing the blood loss during delivery, easy to store and simple to use and the low cost of the drug can be advantageous in developing countries where home deliveries are quite common. o b st e t r i c i a n ’s n i gh tm a r e ! p e r i pa rt um a c u t e a o rt i c d i s se c t i o n : a c a se r e p o rt a n d pr e v e n t i v e st r at e gi e s vidya kishore and meena kothari, department of obstetrics and gynaecology, royal hospital, muscat, oman. email: kkshetty@omantel.net.om we report a case of acute postpartum aortic dissection in a 32 yr old, para 2, requiring emergency vascular surgery. acute aortic dissection during pregnancy is a sudden catastrophic event with can be devastating for both mother and fetus with reported mortality of 1% per hour in untreated cases. we discuss the clinico-pathological features of acute aortic dissection and review the literature concerning the management of peripartum aortic dissection. the purpose of this report is to remind obstetricians and acute care physicians that, although rare, acute dissection can present in pregnancy as a life threatening emergency masquerading as a host of clinical conditions. the success in salvaging the patient depends on the prompt diagnosis and initiation of early treatment, for which a high degree of suspicion is needed, reinforcing the fact that ‘the eye cannot see what the mind does not know’. 1 0 1 3 d e c e m b e r 2 0 0 7 112 ve l a m e n t o u s i n se rt i o n o f c o r d c au si n g d i s c o r da n t gr ow t h i n m o n o c h o r i o n i c t w i n pr e gn a n c y devyani narayan, department of obstetrician and gynaecology, khoula hospital, muscat, oman. email: devnaryn@omantel.net.om discordant growth in twins contributes significantly to rates of perinatal morbidity and mortality. these rates vary according to chorionicity, timing of onset, and severity. abnormal umbilical cord insertion (uci) is a common finding in twins, more so in monochorionic twins and this is also associated with twin-to-twin transfusion syndrome (ttt). ultrasound identification of abnormal uci is reliable and should be undertaken during the evaluation of twins especially in cases where monochorionic diamniotic twins are suspected. in this group, the risk of birth weight discordancy in those with velamentous insertion is nearly 50%. although this is not amenable to intervention, its presence or absence warrants appropriate patient counselling and close surveillance of fetal growth. we present a case of monochorionic twin pregnancy with discordant growth due to velamentous insertion of cord which was not associated with ttt. the details of ultrasonography (usg) and monitoring of this high risk pregnancy and the outcome of both the fetuses are described in detail. h e a da c h e : a c om m o n sy m p t om b u t u n c om m o n pat h o l o g y i n p r e gn a n c y j kankanala, royal victoria infirmary, newcastle, uk. email: jyoti.kankanala@gmail.com neurological disorders are common in women of childbearing age and can lead to maternal death, as evident from previous reports of the confidential enquiry into maternal deaths in england and wales. idiopathic intracranial hypertension (pseudo tumour cerebri) is a condition that occurs predominantly in obese women. we report a case of a 32 year old caucasian primiparous woman who presented with visual complaints during her gestational period. following complete investigations, a diagnosis of benign intracranial hypertension was made. she was managed conservatively with serial lumbar punctures and cerebrospinal fluid drainage. the patient not only improved neurologically, but was able to continue her pregnancy till term until delivery by elective lower segment caesarean section under subarachnoid block. diagnosis, management, and pregnancy outcome of this active disease are discussed. pregnancy is not contraindicated in women with benign intracranial hypertension and termination of pregnancy is seldom required. m e ta stat i c m a l i gn a n t m e l a n om a d u r i n g pr e gn a n c y a c a se r e p o rt mariam mathew, shahila tazneem, kuntal rao, ikram a burney, azhar rizvi, sukpal sawhney, fatma ai ramadani, sultan qaboos university hospital, muscat, oman. email: mathewz@omantel.net.om we report a case of metastatic malignant melanoma diagnosed in the second trimester of pregnancy. a 28 yr old gravida 2 para 1 at 27 weeks gestation, diagnosed to have metastatic malignant melanoma, was referred to us for further management. she had initially presented with left inguinal lymphadenopathy at 16 weeks of gestation for which she was treated with antibiotics and referred to a surgeon as there was no relief. core biopsy from the inguinal lymph node and immunohistochemistry revealed a malignant melanoma showing positive staining with s-100 and hmb 45. after initial evaluation, labour was induced resulting in a male baby weighing 1.310 kg. the placenta was free of metastasis. there were no signs of the disease in the newborn. metastatic workup after delivery revealed extensive involvement of lungs, liver, spleen, and both breasts with melanoma. patient was started on combination chemotherapy with cisplatin, vinblastine and dacarbazine. malignant melanoma is the most dangerous form of skin cancer and the progression can be very rapid as in our case. our patient had a successful labour induction soon after attaining fetal viability and the chemotherapy was started without delay. treatment of early stage melanoma should be the same irrespective of whether or not the patient is pregnant. there is no conclusive evidence that pregnancy adversely affects overall survival in patients with melanoma. o va r i a n c yst i n p r e gn a n c y a r e v i e w o f c a se s meenakshi yelvantge and usha sharma, division of obstetrics and gynecology, royal hospital, muscat, oman. email: y_manoj@hotmail.com the routine use of ultrasound in pregnancy has been able to diagnose asymptomatic adnexal masses in pregnancy. the incidence of detection of ovarian cyst in pregnancy is about 4 % and 0.5 % during caesarean section. nearly all the ovarian masses detected in pregnancy are benign, but the overall incidence of ovarian cancer is 0.004-0.04 %. most of these malignant masses appear to be borderline with low malignant potential. these cysts pose diagnostic difficulties in differentiating between benign and malignancy. ca-125 levels can be helpful, but levels may be increased by pregnancy itself. suggestions are being made to take a cut off level of 112 u/ml instead of 35 u/ml as in non-pregnant patients. other tumour markers like alpha-fetoprotein (afp) and beta human chorionic gonadotropin (hcg) levels are of limited use, since these are synthesised by the placenta and are normally elevated in pregnancy. mri can be safely used, but is expensive. it has good sensitivity in diagnosing endometriotic, dermoid and malignant tumours. cost, claustrophobia and excessive fetal movements are the limiting factors for mri. a few interesting cases that were diagnosed either during pregnancy or intrapartum and were removed during caesarean section are discussed. p r e d i c t i o n / p r e v e n t i o n a n d tr e atm e n t o f p r e t e r m l a b o u r radha sharma and pamela issac, department of obstetrics and gynecology, sur hospital, oman. email: sksur@omantel.net.om in a prospective study from oman april 2004 to april 2005, 100 pregnant women at high risk of preterm birth (ptb) in the south sharqiya region, were followed with the objective to create awareness among the health care providers and clients about the problem of ptb and possible preventive measures available, to identify the high risk group for ptb and to take early precautionary measures and/or give specific treatment to improve the outcome. criteria for high-risk cases of ptb were identified and details were recorded in a pro forma. follow up included infection screening and 2 weekly cervical assessments from 14-24 weeks by transvaginal sonography (tvs). treatment for infection for positive 5 t h i n t e r n at i o n a l o b s t e t r i c s & g y n e c o l o g y c o n f e r e n c e , s u lta n q a b o o s u n i v e r s i t y, s u lta n at e o f o m a n 113 cases and cervical cerclage was done when indicated as per the criteria. the incidence of preterm delivery (ptd) was 16.8% with previous mid-trimester abortion in 33.3% of cases and previous ptb in 20.9%. 75% were 18-35 years old, and 25% were >35 years. infection screening was done (75% cases), but results were not conclusive. cervical assessment by transvaginal sonography (tvs) was done in 84.2% and cervical cerclage done in 21.3% cases; out of these 15.8% delivered preterm. among the previous cervical cerclage cases, repeat cerclage was not done in 78.9% out of these; only 8.5% delivered preterm. among the ptd cases, 40% received short term tocolysis, 46.6% received steroid for fetal lung maturity, 40% received antibiotics. 73.3% were of 32-36 weeks and 1% < 28 week. 26.6% required special care baby unit admission and all babies were discharged in good condition. there was one still birth due to an anomaly, but there were no intrapartum or neonatal deaths. cervical assessment by tvs in high risk cases and secondary cerclage, if indicated, is a good preventive measure. early reporting with warning signs and symptoms of preterm labour (ptl) will help in early detection of threatened ptl/early preterm labour so that specific therapy can be started to improve the neonatal outcome. p r e n ata l ly d i a gn o se d c o n ge n i ta l c a r d i a c m a l f o r m at i o n s – e x pe r i e n c e at wat taya h p o ly c l i n i c , o m a n megha venkatraman, khoula hospital, muscat, oman. the aim of this study was to review the diagnostic accuracy of fetal echocardiography, to review the association with extracardiac structural anomalies and evaluate the outcome of the pregnancy. this is a retrospective study reviewing all pregnancies complicated by fetal cardiac anomaly between january 2003 and june 2007 at khoula hospital, oman. congenital cardiac malformations comprised about 18% of the major anomalies seen during this period. these fetuses were classified into two groups – those with isolated congenital heart defects and those with associated extracardiac anomalies. the end points studied included chromosomal abnormality, correlation between the antenatal and postnatal findings and pregnancy outcome. the data confirm previous findings in a prenatal diagnosis series that the prognosis for fetal heart malformation depends on the type of lesion identified and the presence or absence of extracardiac anomalies. an associated extracardiac structural anomaly worsens the prognosis. results also suggest that a carefully performed detail fetal echocardiography can be highly accurate. da m a ge c o n t r o l su r ge ry i n o b st e t r i c s gy n a e c o l o g y a n d g e n e r a l s u r gi c a l p r a c t i c e : k h o u l a h o spi ta l o m a n ’s e x pe r i e n c e o f 50 c a se s . mohsin raza, yasser abbas, kameel rizk, department of general surgery, khoula hospital, muscat, oman. damage control surgery is defined as the termination of surgical procedures after rapid control of life-threatening haemorrhage and contamination, followed by correction of physiologic abnormalities and a definitive management later. this strategy comprises of a staged approach for severely exanguinating patients and is designed to prevent or correct the lethal triad of hypothermia, acidosis, and coagulopathy. during the first stage of damage control, the haemorrhage is stopped, and contamination is controlled using the simplest and most rapid means available. temporary wound closure methods are employed. the second stage is characterized by correction of physiologic abnormalities in the intensive care unit (icu). patients are warmed and resuscitated and coagulation defects are corrected. in the final phase of damage control, definitive operative management is completed in a stable patient. many problems are encountered in abdominal, pelvic and trauma surgery. the application of damage control techniques in this context, however, is contentious. possible indications for damage control in the general surgical setting include haemodynamic instability from massive haemorrhage, coagulopathy, abdominal compartment syndrome, acute mesenteric ischemia, necrotizing infections. patients with pelvic bleeding after gynaecologic surgery, abdominoperineal resection and pelvic fracture can be managed successfully by damage control surgery principles. we have reviewed our experience of 50 patients at khoula hospital with damage control surgery and will present our technique and results. a total mortality of 16% with zero mortality in obstetricsgynaecology patients was observed. c o l p o s c o p y, c y t o l o g y a n d h i st o pat h o l o g y i n t h e d i a gn o si s o f c e rv i c a l i n t r ae pi t h e l i a l n e o pl a si a s amal al fana and shahnaz wasti, division of obstetrics and gynecology, royal hospital, muscat, oman. email: aloud82@yahoo.com papanicolaou (pap) cervical cytology screening is one of the great success stories in modern medicine. since its implementation in the 1950s, routine pap screening has helped to reduce cervical cancer mortality by more than 70%. the very success of pap screening has fostered an unrealistic expectation that pap testing is perfect. in reality, the sensitivity of pap cytology for high-grade cervical intraepithelial neoplasia (cin) is only about 70-80 %. in defining the diagnostic accuracy of colposcopy, the histopathological diagnosis is the gold standard. eventually, the combined use of cytology, colposcopy, and histopathology was thought to secure the highest yield of detection of cervical neoplasia. the objective of this study was to assess the correlation between cervical cytology, colposcopy findings and histopathology diagnosis in women with abnormal cervical cytology. this was a prospective study of 100 women with abnormal cervical cytology who attended the colposcopy clinic at the royal hospital, oman. all these women had colposcopy and colposcopy directed biopsy. the histopathology was considered as the gold standard for comparison of cytology and colposcopy findings. out of the hundred cases with abnormal cervical cytology, 45 had cin i, 24 had cin ii and 5 had cin iii. colposcopy showed 63 cases of cin i, 27 cases of cin ii-iii and 1 case of squamous cell carcinoma. histopathology confirmed cin i in 52 women and cin ii-iii in 19 women. colposcopy has higher sensitivity, specificity and positive predictive value when compared to cytology in the diagnosis of precancerous lesions of cervix with histopathology as the gold standard. 1 0 1 3 d e c e m b e r 2 0 0 7 114 d o ppl e r d e t e r m i n a n t s i n o va r i a n tum o u r manjula dinakar, veena paliwal, neesha sharma, department of obstetrics and gynecology and radiology, sultan qaboos hospital, salalah, oman. email: arudhiman@yahoo.co.in the study was aimed at evaluating the efficacy of colour and spectral doppler imaging in diagnosing ovarian tumours. the study was performed in 100 patients with adnexal masses over a period of 2 years, out of which 60 patients with neoplastic ovarian tumours were retained as the study subjects. b-mode ultrasonography (usg) was done along with colour doppler which showed blood flow in 92.59 percent of malignant tumours in contrast to only 42.24 per cent of benign tumours. absent blood flow in a solid tumour almost always ruled out the possibility of malignancy. spectral doppler was also done. malignant tumors had a (pulsatility index) pi of less than 0.8. similarly, malignant tumors showed an pi of less than 0.6i. thus, colour doppler and spectral doppler tremendously increased the reliability in diagnosing malignant ovarian tumours. colour doppler serves as an important tool to rule out malignancy in solid tumours if they failed to show any intra tumoural vascularity. b-mode usg in combination with colour doppler and spectral doppler are proposed as the first and foremost diagnostic modality in patients with ovarian tumour, so as to establish the diagnosis of malignancy early in the course of the disease. d e fi n i t i o n , r o l e a n d c o r e va lu e s o f r e pr o d u c t i v e h e a lt h nu r se s jothi clara j, nursing program, sultan qaboos university, muscat, oman. email: jothiclara@yahoo.co.in the reproductive health status of individuals is the backbone of health of any country. ever since the concept of reproductive health was put forward at the international conference on population and development, the debate has remained as to where its boundary lies; however, the goals remains clear: preventing and treating reproductive diseases supporting normal functioning such as pregnancy and child birth, and aid in fertility, when the couple desires to have a child. for any country, investment in reproductive health brings benefit for young people and adults of today and the infants and children of tomorrow. reproductive health nurses are nurses with a specialised qualification who render specific reproductive care. these nurses are an essential member of the health team in all settings: hospital or health centre or community. they many times serve as the first hand health information provider and identifiers of health related problems and refer patients to appropriate health teams. this paper presents a definition of the reproductive health nurse; explains preventive, promotive, supportive, educative, rehabilitative and extended roles; and highlights the core values of the reproductive health nurse in relation specific to philosophy, education, ethics, theories, research, communication, counselling, the therapeutic environment, cultural diversity and the nursing process. va gi n a l e v i s c e r at i o n – a r a r e c om pl i c at i o n o f h yst e r e c t om y anita m nargund and mr el hamamy, royal gwent hospital, newport, uk email: anitamn73@yahoo.co.uk a 47 year woman presented to the gynaecology emergency department of royal gwent hospital, uk, with a history of vague lower abdominal pain and something coming out through the vagina. this was sudden in onset and occurred when she was straining to pass the urine. she had had a total abdominal hysterectomy for cervical fibroid and menorrhagia 10 weeks before. on examination, the patient was apyrexial, with normal vital signs. abdominal examination was normal, local genital examination revealed the sigmoid colon and omentum lying outside the introitus. this is a surgical emergency having a high morbidity with 15% of the patients having postoperative complications and 20% of the patients requiring bowel resection. this rare complication is more common following a vaginal hysterectomy rather than a abdominal hysterectomy. vaginal evisceration after vaginal hysterectomy followed mostly after a period of increased abdominal pressure such as coughing or straining; the next most common cause was following intercourse. the most common precipitating factor following abdominal hysterectomy is sexual intercourse followed by trauma, increased abdominal pressure or infection. vaginal evisceration is a rare complication of hysterectomy either abdominal or vaginal which is potentially life threatening and requires early identification and prompt management to avoid serious morbidity and mortality. this rare complication may occur in both preand postmenopausal women though the etiology in them is different. the ideal management is surgical, but is to be individualised to the patient depending on the presentation and the clinical picture. c a se r e p o rt o f vu lva l pa pi l l a ry h i d r a d e n om a i n t e e n a ge gi r l w i t h k l i ppe l -tr e n au n ay we b e r s y n d r om e atiqa al harthy and anita zutshi, division of obstetrics and gynecology, royal hospital, ministry of health, oman. email: zutshi@omantel.net.com we report a rare case of klippel-trenaunay-weber syndrome (ktws) with vulval papillary hidradenoma tumours in a 14 year old girl. she had painless left labial swelling of nine months which increased in size gradually. unfortunately, this young girl had to undergo below knee amputation of both legs due to lower limb gigantism in 2003 at ther age of 11 years. she had abdominal and chest wall lipomas measuring 6x6cm and 5x5 cm. the two left labial swellings were firm, non tender, measuring 4x3cm and 2x2 cm covered with labial skin which was mobile on the tumour. the left labial tumours were excised under general anaesthetic in july 2007 and the labia were reconstructed. histopathology report was vulval-papillary hidradenoma with no evidence of malignancy in the sections examined. most cases of ktws are sporadic. most patient demonstrate all three signs of the clinical syndrome: a distinctive port-wine stain with sharp borders; varicose veins; hypertrophy of bony and soft tissues that may lead to local gigantism or shrinking (occasionally) as in our case. ktws generally affects a single extremity, although cases of multiple affected limbs have been reported like in this case. the legs are the most common site. it is not believed to be genetic in nature, although testing is ongoing. debulking has been the most widely used treatment for the syndrome, and has been used for decades. a papillary hidradenoma is a benign, small, sharply circumscribed nodule arising from the apocrine sweat glands, covered by normal skin. it is often seen in the labia majora, or interlabial folds; it may ulcerate through the skin and simulate carcinoma. 5 t h i n t e r n at i o n a l o b s t e t r i c s & g y n e c o l o g y c o n f e r e n c e , s u lta n q a b o o s u n i v e r s i t y, s u lta n at e o f o m a n 115 e ffe c t o f e st r o ge n a n d t i b o l o n e o n se rum l i pi d pr o fi l e i n p o stm e n o pau sa l wom e n meenakshi b chauhan, smiti nanda, h mehta, department of obstetrics and gynecology, postgraduate institute of medical sciences, rohtak124001, haryana, india. email: mbc51490@yahoo.co.in the objective of the study was to evaluate the effects of estrogen and tibolone on serum lipid profile in postmenopausal women. sixty post menopausal women were randomised into two equal groups (conjugated equine estrogen, 0.625mg /daytibolone2.5mg/day). serum concentrations of total cholesterol, high density lipoproteins (hdl) cholesterol and triglycerides were determined at base line and after 3 and 6 months of therapy. a disturbed baseline lipid profile was observed in postmenopausal women. estrogen resulted in a significant increase in serum triglycerides whereas a significant decline was observed with tibolone. both drugs decreased serum cholesterol (total) and low density lipoproteins (ldl) cholesterol significantly. serum hdl cholesterol, however, increased with estrogen but decreased with tibolone. tibolone is found to be as effective or more than estrogen in improving the lipid profile in postmenopausal women; moreover, its side effects are less than those of estrogen. d i s c r i m i n at i o n o f o va r i a n t um o u r s : a l a se r s pe c t r o s c o p y a ppr oa c h rani akhil bhat, c murali krishna, k k mahato, pratap kumar n: department of obstetrics and gynaecology, oman medical college, sohar; center for laser spectroscopy, manipal academy of higher education, manipal 576104, india and department of obstetrics and gynaecology, kasturba medical college and hospital, manipal 576104, india. email: drraniakhil@hotmail.com detection of neoplastic changes using optical spectroscopy (raman, fluorescence and fourier transform infrared (ftir) spectroscopy) has been one of the active areas of research in recent times. these methods have the advantage of in vivo applicability without the need for a biopsy and hence have the potential of being an alternative to frozen section examination in the future. to explore the feasibility of discriminating normal, benign and malignant conditions in ovarian tissues by laser spectroscopy, a study of 50 patients undergoing oophrectomy (25 normal, 15 benign, 10 malignant) was undertaken; reflectance spectra of each sample were recorded with the raman and photoacoustic spectroscopy setup. this setup consisted of a diode laser (785 nm, 100mw) for excitation, and a high resonance (hr) 320 spectrograph and spectrum one liquid nitrogen cooled charge coupled device (ccd) for detection. a holographic filter was used to filter unwanted lines from the excitation source. a notch filter was used for removing the raleigh scattering. baseline corrected, smoothened, calibrated and normalized spectra were subjected to multivariate statistical analysis and principal components analysis (pca) for objective classification as normal and malignant tissue. randomly selected spectra from each category were used for pca. good classification between normal and malignant tissues was achieved using ‘scores of factors’ as the discriminating parameter. the great advantage of the optical method combined with statistical data analysis is that cases which show anomalous behaviour can be re-evaluated with a second scan with more sampling points. this is of great advantage especially for screening, surgical boundary demarcation and follow-up after therapy since there is no need for a repeat biopsy. the results of the study demonstrate that, the pca based k-nn classification achieves objective discrimination among normal, benign, and malignant ovarian tissues with high specificity and sensitivity. with possible in-situ application, this approach can be an effective clinical tool in diagnosing and differentiating normal ovary from pathological conditions. c o n se rvat i o n o f o va ry i n b i l at e r a l tw i st e d s p o n ta n e o u sly hy pe r st i mu l at e d o va r i e s i n s i n gl e t o n g e stat i o n houda al-yaqoubi, anita zutshi, noor al mandhari, division of obstetrics and gynecology, royal hospital, muscat, oman. email: zutshi@omantel.net.om spontaneous ovarian hyperstimulation syndrome (ohss) has been reported in twin and molar pregnancies with high endogenous human chorionic gonadotrophin (hcg) levels. however, the spontaneous form of this syndrome is extremely rare in the literature. this is a case report of spontaneous ohss in a singleton pregnancy with bilateral torsion of enlarged ovaries and one ovary conserved. a 27 years old lady was admitted with acute abdomen in her second pregnancy at 11 weeks of pregnancy. clinical examination and ultrasound examination revealed both ovaries with multi-loculated cysts, measuring 10 x 15 cm each, occupying the abdomen from the suprapubic to the hypochondrium area. on laparotomy both ovaries were enlarged and the left ovary was twisted on its pedicle 3 times with gangrenous tube and ovary. left salpingo-oophorectomy was done. the patient was discharged after an uneventful postoperative period. she was readmitted with similar acute abdomen picture at 15 weeks of gestation. relaparotomy revealed a triple twist on the right hyperstimulated ovarian pedicle involving the right tube. there was 500ml blood in the peritoneal cavity and the ovary was congested and purple in colour as the previous time. the pedicle was untwisted and a wedge resection of hyperstimulated ovary was done followed by reconstruction of the residual ovary. she had an uneventful postoperative period and her pregnancy continued till term. at term in labour she underwent emergency lower segment caesarean section for abnormal cardiotocograph with delivery of a healthy baby. a normal size right ovary and healthy right tube was seen. six months later she was pregnant again. this report concludes that after torsion even gangrenous looking ovaries when untwisted may recover their blood supply and be conserved. p e r si st e n t ge stat i o n a l t r o ph o b l a st i c t um o u r f o l l ow i n g a pa rt i a l m o l e mini benny poothavelil, ilham hamdi, geeta zunjurwad, department of obstetrics and gynaecology, nizwa hospital, oman. email: drminibenny@hotmail.com complete and partial moles may develop persistent gestational trophoblastic tumours, local uterine invasion and dissemination, although a partial mole has a risk of about only 0.5% requiring chemotherapy. we report a case of partial hydatidiform mole developing vaginal metastasis requiring a multidrug chemotherapy regimen. a 27 year old para 2 woman was diagnosed with a partial vesicular mole and underwent suction evacuation. she presented 2 weeks later with profused vaginal bleeding due to vaginal metastasis. she had rising beta human chorionic gonadotrophin (hcg) levels and was referred to a tertiary care centre for chemotherapy. she was later started on etoposide, methotrexate, actinomycin-cyclophosphamide, vincristine regimen due to plateauing beta hcg levels. a partial vesicular mole can have malignant sequelae although it is very unpredictable and can develop very soon after initial treatment. therefore initial assessment, treatment and postevacuation follow up are paramount. 1 0 1 3 d e c e m b e r 2 0 0 7 116 o c c lu si o n o f uppe r g e n i ta l tr a c t fo l l ow i n g l ow e r s e g m e n t c a e sa r e a n s e c t i o n f o r p l a c e n ta p r a e v i a mini benny poothavelil, ilham hamdi, geeta zunjurwad, department of obstetrics and gynaecology, nizwa hospital, oman. email: drminibenny@hotmail.com suterine cavity occlusion following caesarean section for central placenta praevia culminating in haematometra and thereby amenorrhoea is one of the rarest long term complications of lower segment caesarean section. we report a case of 28 year old primigravida with grade 4 placenta praevia who underwent an elective caesarean section at 35 weeks gestation. she presented after 7 months with cyclical lower abdominal pain and amenorrhoea. she was treated by hysteroscopic adhesiolysis and in utero foley’s catheter. she had complete resolution within 2 months and resumption of menstrual cycles. multiple haemostatic sutures at caesarean section for placenta praevia can be a causative factor for such a complication along with other risk factors like multiple caesarean sections, chorioamnionitis etc. recognition of these factors, meticulous surgical techniques and appropriate postoperative care can effectively prevent it. hyst e r o s c o p y – fi n d i n g s a n d d e c i si o n m a k i n g f o r t r e atm e n t o f a b n o r m a l u t e r i n e b l e e d i n g i n pr e a n d p o st m e n o pau sa l wom e n neesha sharma and veena paliwal, sultan qaboos hospital, salalah, oman. email: paliwal@omantel.net.om the objective of this study was to assess the feasibility of hysteroscopy (versascope) for identifying abnormal findings in uterine cavities of preand postmenopausal women presenting with abnormal uterine bleeding (aub) and to assess how this procedure can affect the decision for mode of treatment. this retrospective study was carried out at sultan qaboos hospital, salalah, oman, over the period december 2005 -august 2007. 42 patients of aub of different age groups had hysteroscopy by versascope as day care or inpatients. the procedure was done with/without anaesthesia as per need of patient. endometrial sampling was done at the end of procedure in all patients. all patients had a full workup and ultrasonography prior to hysteroscopy. the results were that 35 % of patients had normal uterine cavities. the most common funding was endometrial polyps (40%) and submucous fibroids (12%); other findings were atrophy, hyperplasia and cancer (2 cases). polypectomy was done in the same session. one patient had hysteroscopic myomectomy. seven patients had abdominal and vaginal hysterectomies. the rest could be managed with hormones/conservatively. the conclusion is that hysteroscopy is a feasible technique in identifying abnormal uterine findings in aub in preand postmenopausal women. based on hysteroscopic findings, the cause of aub can be accurately diagnosed and subsequently appropriate decisions regarding different treatment options can be made chosen. this is especially useful in cases of postmenopausal bleeding as most of them are high risk cases. this avoids the morbidity of surgery. if used as an office procedure it can further enhance efficiency and patient compliance; however, at present, due to limitations of logistics this is not used as office procedure at our hospital. c o n c om i ta n t c h e m o r a d i at i o n a n d h i gh d o se r at e b r a c h y t h e r a p y i n th e m a n a ge m e n t o f l o c a l ly a dva n c e d c e rv i c a l c a n c e r ashok kumar chauhan, harmeet singh, pushpa dahiya, departments of radiotherapy and obstetrics and gynaecology, postgraduate institute of medical sciences, rohtak, india. email: drchauhanashok@yahoo.co.in uterine cervical cancer is the commonest malignancy in women in developing countries. concomitant chemoradiation has become the standard of care and the introduction of high dose rate is a new radio therapeutic modality in developing countries. thirty local women with locally advanced uterine cervical cancer of squamous cell histopathology were entered into the study. they were administered chemotherapy carboplatin in dose of 450mg/m2 every three weeks along with external beam radiotherapy (ebrt) in a dose of 50 gy in 25 fractions over a period of 5 weeks. this was followed by intracavitary brachytherapy (icbt) with dose of 7 gy once a week for three weeks. the concomitant chemoradiation was tolerable with manageable acute chemoradiation side effects. the disease free survival (dfs) at 2 years is 52%. the concomitant carboplatin and radiotherapy was able to achieve better results in locally advanced cervical cancer. the administration of brachytherapy is must in case of management of cervical cancer to achieve good local control and high dose rate (hdr) is convenient as an outpatient procedure in this setting. r e v i e w o f wom e n w i t h e n d om e t r i o si s at t e n d i n g th e e n d o s c o pi c un i t, r oya l h o spi ta l , o m a n , 2 0 05 2 0 0 7 khalsa al hattali and noor al mandhari, division of obstetrics and gynecology, royal hospital, muscat, oman. email: nalmandhari@yahoo.com endometriosis is one of the commonest benign recurrent gynaecological conditions with 10-25% incidence in reproductive age. the objective of our study was to assess the severity of endometriosis, the recurrence rate after laparoscopic surgery and possible causes by retrospective analysis of computerised patient records from preendoscopy clinic and operative laparoscopic records. out of a total of 42 patients, almost half were unmarried (23/42) and the majority were below 31 years old (36/42=85%). out of 19 married patients, seven had primary infertility and seven secondary infertility. ultrasound was the main tool for the diagnosis of endometriosis. out of 23 estimated ca 125, nine (39%) had elevated levels. the majority of cases had grade iii or grade iv endometriosis on laparoscopy with no difference in the severity among the different age groups. after surgery, unmarried patients with severe endometriosis had gnrh analogues for 2-3 months followed by combined oral contraceptive pills (cocs) and patients with grade i-ii endometriosis had cocs till they got married. four infertility patients with grade iv endometriosis had gnrh analogues after surgery. two conceived spontaneously and two had an unsuccessful in vitro fertilisation (ivf) attempt. recurrence of endometriosis was found in 12 patients including 3 with ivf, 1 on clomid and 1 stopped contraceptive pills. four patients (35%) with infertility conceived after the surgery, 3 spontaneously, 1 on clomid and one on human gonadotrophins (hmg) with intrauterine insemination (iui). in our study endometriosis was more common in the younger age group, below 30 yrs. although the number in this study is small, the incidence of infertility was high after surgery as in other studies. ovulation induction is a known cause for recurrence of endome5 t h i n t e r n at i o n a l o b s t e t r i c s & g y n e c o l o g y c o n f e r e n c e , s u lta n q a b o o s u n i v e r s i t y, s u lta n at e o f o m a n 117 triosis as well as discontinuation of hormonal treatment. a n u n u sua l c a se o f b i l at e r a l t u b a l e c t o pi c pr e gn a n c y a ta l e o f c au t i o n archna mohan, pooja vaswani, bharthi balakrishna, sahar sheitty, sultan qaboos hospital, salalah, oman. email: rayofhope254@yahoo.com a 23 year old female, p0+2, treated for secondary infertility with gonadotrophins, presented in emergency with severe pelvic pain following amenorrhea of 7+ weeks. she was admitted with pain and bleeding per vaginal at 5 weeks amenorrhea with mild ovarian hyperstimulation and positive urine pregnancy test. she underwent evacuation under general anaesthetic with diagnosis of inevitable miscarriage. she remained well for two weeks and at 7 weeks had severe pelvic pain. on pelvic examination and ultrasonography the diagnosis of unruptured unilateral tubal ectopic pregnancy with 8 weeks size live fetus and hyperstimulated (7x8cm) ovarian cyst with minimal haemoperitoneum was made. emergency laproscopy revealed simultaneous bilateral tubal ectopic pregnancies. on one side, linear salpingotomy was performed, while on other side the tube was not salvageable so salpingectomy was done. histopathology confirmed a bilateral ectopic pregnancy. the postoperative period was uneventful with satisfactorily dropping serum beta human chorionic gonadotrophin (hcg) levels. the first report of an ectopic pregnancy following in vitro fertilisation was published in 1976, since then ectopic pregnancies have been reported at an increasing rate due to advanced management of subfertile females with ovulation induction and assisted reproductive techniques. still, a bilateral ectopic pregnancy remains a rare occurrence. until now > 200 cases have been reported in the literature with incidence between 1:725 and 1:1580 extrauterine pregnancies. diagnosis of ectopic pregnancy continues to be an important challenge faced by the emergency physician and obstetrician. if diagnosed in a timely manner, steps can be taken for conservative management to preserve future fertility and avoid complications. h i gh p r e va l e n c e o f o b e si t y i n su b fe rt i l e fe m a l e s st u dy i n d h o fa r r e gi o n o m a n archna mohan, selvi anderson, v paliwal, sultan qaboos hospital, salalah, oman. email: rayofhope254@yahoo.com to quantify the prevalence of obesity and its associated problems in the subfertile female population of the dhofar region of oman, a retrospective study was done from january 2001 to january 2003. a total of 235 patients at the infertility clinic were studied and analysed. out of 235 patients (average age = 26 yrs.), 17% were normal weight (bmi 19-24), 22% were overweight (bmi 25-29), 61% were obese (bmi>30) with 9% of bmi 45-50. 88% of obese cases had subovulation with or without polycystic ovarian syndrome (pcos). 30% of these cases responded to weight reduction and ovulation induction, 6% conceived with weight reduction alone, still 70% were awaiting conception and many of them were morbidly obese at a very young age of 25-26 yrs. it was found that with increasing bmi the percentage of menstrual disturbance also increased from 10% to 35%. obesity is associated with infertility and other long term diseases like menstrual disorders, pcos, ovarian and endometrial malignancies, cardiovascular diseases, diabetes mellitus, high surgical risks etc. dhofar region has an alarmingly high incidence of obesity due to lifestyle and genetic reasons. there is a great need to implement effective programmes to educate the population in terms of changing lifestyle, providing facilities for weight reduction and long term follow up. o b e si t y a gl o b a l e pi d e m i c ! vidya kishore, kanchana rajan, saadia amour sultan al riyami, royal hospital, muscat, oman. email: kkshetty@omantel.net.om obesity is a global epidemic. estimates suggest that 1.1 billion adults are overweight, 3.5 million of whom are obese. the prevalence of obesity has doubled or tripled in less than 2 decades while in children it is rising at a faster rate. the same problem is appearing in all developed and developing countries. the prevalence of obesity in women in the gulf countries is high. amidst a host of resulting complications, of particular concern to this paper presentation, is the effect of obesity and infertility in omani women. to find the prevalence of obesity and its associated problem in the subfertile omani female population, a retrospective study was done of 500 consecutive patients registered at the infertility clinic in wattayyah polyclinic, the tertiary referral health centre for the whole of oman. obesity is associated with infertility and many other complications. obesity is not simply the result of over-eating and not all types of obesity have the same significance. obesity is in part genetic and one particular type of obesity is the tendency to ‘truncal obesity’ that is, a raised waist to hip ratio. such obesity is associated with a tendency for diabetes and cardiovascular mortality (syndrome x). a weight reduction programme should be a major focus. there is a great need to educate the population regarding the risks of obesity and encourage the adoption of healthy life styles. s a l i n e i n f u si o n s o n o gr a ph y i n t h e e va luat i o n o f pat i e n t s w i t h a b n o r m a l u t e r i n e b l e e d i n g a n d i n t r au t e r i n e pat h o l o g y attuveppil raman vijayalakshmy, sultana khan, department of obstetrics and gynecology, khoula hospital, muscat, oman. eamil: drsaak@omantel.net.om purpose of this study was to determine whether hydrosonography improves the diagnostic accuracy in detecting intrauterine abnormalities and its correlation with direct visualization methods like hysteroscopy and hysterectomy. women presenting with abnormal uterine bleeding or suspected intrauterine pathology were subjected to saline infusion sonography from january 2004 to june 2007. the procedure was done using a transvaginal sonography (tvs) probe of 6mhz and no. 6 infant feeding tube. results guided further investigations. out of a total of 30 saline infusion sonography cases, 20 patients were diagnosed to have endometrial polyps, 6 to have submucous myoma, 3 to have fibroids elsewhere in the uterus and 1 patient a thickened endometrium. on hydrosonography, out of the 20 patients suspected to have polyps, 15 (75%) were confirmed to have polyps. no polyps were seen in 5 cases. submucous myoma, fibroid uterus and thickened endometrium were confirmed in the other above mentioned cases. hysteroscopy with or without polypectyomy/endometrial biopsy was done in 18 cases. total abdominal hysterectomy with or without bilateral salpingo-oophorectomy was done in 6 cases, laparo/hysteroscopy, cystectomy with polypectomy in 1 case. the findings of the hydrosonography and hysteroscopy in 18 cases were correlated. in 15 out of 18 cases (83%), the findings of hydrosonography were confirmed by hysteroscopy. in 2 cases of suspected polyps, there were no polyps, but the endometrium was polypoidal. in one case, which appeared as localized thickening on hydrosonography, it was found to be a polyp. saline infusion sonogrpahy is 1 0 1 3 d e c e m b e r 2 0 0 7 118 a noninvasive method of evaluating patients with abnormal uterine bleeding and those with intrauterine pathology for further management. the correlation between tvs and hydrosonography in this study was 75% and hydrosonography with hysteroscopy was 83 %, which is in agreement with other studies internationally. s p o n ta n e o u s ru p t u r e o f a gr av i d u t e ru s at 4 w k s i n a pat i e n t w i t h h i st o ry o f f u l l t e r m d e l i v e ry a f t e r my om e c t om y a c a se r e p o rt attuveppil raman vijayalakshmy and sultana khan, department of obstetrics and gynecology, khoula hospital, muscat, oman. email: yydas@hotmail.com a 35 yr old indian lady, gravida 2, para 1, with one live child, with a past history of myomectomy, was admitted at 14 weeks gestation with acute lower abdominal pain of a few hours duration. she had a myomectomy in past followed by one full term normal delivery. on admission, the patient was very pale with pulse of 120/mt and bp-110/70. her abdomen was distended with guarding and rigidity. the uterine size could not be made out. there was evidence of free fluid in the peritoneal cavity. an ultrasound scan revealed lot of fluid in the peritoneal cavity with suggestion of a ruptured left cornual ectopic of 14.3 wks gestation. on emergency laparotomy, the whole fundus of the uterus had ruptured transversely for about 5-6cm and a fetus with gestational sac was protruding through the rent with the haemoperitoneum. the fetus with sac and remaining placental tissue were removed, the ruptured edges were sutured and haemostasis was achieved. bilateral tubal ligation was done and the abdomen was closed. she had an uneventful post operative period and was discharged on day four. uterine rupture is a rare and often catastrophic complication associated with high incidence of fetal and maternal morbidity. the overall incidence of uterine rupture has been reported to be 0.07%. spontaneous rupture of unscarred uterus in developed countries has been variously reported ranging from 0.0033 to 0.13%. myomectomy by any route is associated with a risk ranging from 1.4-1.7%, though most ruptures have been reported to occur in labour or in the third trimester. our case is a rare incident where spontaneous rupture has occurred in early second trimester. a high index of suspicion of a ruptured uterus has to be maintained whenever a patient with myomectomy scar presents with acute abdominal pain and haemoperitoneum irrespective of the gestational age. march 2007 vol 7 isuue 1 final without suicide .indd domestic violence “what’s love got to do with it?” *samir al-adawi1, sabah al-bahlani2 sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© 1department of behavioral medicine, sultan qaboos university hospital, p. o. box 35, al-khod 123, sultanate of oman, 2director of health education and information, ministry of health, muscat, sultanate of oman *to whom correspondence should be addressed. email: adawi@squ.edu.om e d i t o r i a l العائلي العنف فيه؟ “ احلب دور ”ما البهالنية وصباح العدوي سمير surveys from different parts of the world have shown that a woman is more likely to be injured, raped or killed by an intimate partner than by any other person. there are a myriad of subtle but debilitating forms of violence directed towards women: dowry-related or son preference that leads to abortion of female fetuses, female infanticide and bride-burning homicides. the list also includes misdemeanours such as rape, sexual abuse, forced prostitution, female circumcision or genital mutilation.1, 2 although males are also abused by their female partners and intimate partner violence is not exclusively a male domain,3 for the present purpose, this paper will focus on violence directed at women; that is, women assaulted or harmed physically, psychologically or emotionally by their partner. the rationale for focusing on women is based on the widely established opinion that a female is more likely than the male to bear the adverse effect of intimate partner violence. the saying, ‘‘a hungry man is a hungry man, but a hungry women is a hungry world”, may be relevant a metaphor in coming to grips with the ill effects of abused women. despite its global occurrence, there is no standard classification for domestic violence in medical literature. the most widely used term for violence between husband and wife is ‘intimate partner violence’. the word ‘intimate’ is misleading since there is no intimacy in such tumultuous circumstances. other terms that encapsulate partner violence include domestic abuse, domestic violence, spouse abuse, courtship violence, battering, marital rape, and date rape or simply wife beating. for the present purposes, an abusive relationship between husband and wife occurs when a husband tries to harm his wife or to exert control that will harm her either immediately or eventually if repeated over the time. although data from elsewhere have suggested that women are more likely to experience lack of empowerment and be trapped on the margins of society than their male counterparts,4 in the past decades oman has begun to close this gender gap. in higher education, approximately 48 per cent of all students enrolled in tertiary education are males, suggesting that female enrollment rate in post secondary education has surpassed that of males.5 complementing their recent enrollment in education, one of major benefits of the recent literacy campaign is the entrance of women into the labour force. approximately 30% of the workforce in the omani civil service is female.6 an interrelated aim of the present discourse is to highlight the role of aggression in human nature with theoretical input from psychoanalytic, ethological, biological and social learning theories. the article will also synthesize the components of domestic violence s a m i r a l a d aw i a n d s a b a h a l b a h l a n i 6 such as the role of emotions like jealousy, the roles of hormones and substance abuse as well as consider the role of culture in the expression of domestic violence. awareness among health professionals of domestic violence is paramount as women experiencing intimate partner violence are at increased risk of various medical and psychosocial problems. it should be highlighted at the outset that, to our knowledge, there are no studies from oman in the public domain on domestic violence. therefore, the present discourse is inferential from evidence emerging from elsewhere that may not have direct bearing on the situation in oman. consistent with cultural teaching in oman that the only accepted intimate relationship is a conjugal one, the present focus will be on married couples but, in reviewing literature from other parts of the world, reference will be made to other types of intimate partner violence. i m p a c t a n d t y p e s o f d o m e s t i c v i o l e n c e in addition to overt physical harm, there are other enormous ill effects of domestic violence. the most common is emotional and psychological harm. women who have been the victims of persistent and unremitting domestic violence tend to experience somatic and psychological distress similar to those experienced by soldiers in war zones and victims of torture or natural disasters.7 these subjective feelings are accompanied by biological markers of distress such as elevated levels of cortisol.8 sequelae of domestic violence, whether manifest as psychological or as somatic distress, sometimes become chronic even after the abusive relationship has ended. while there are cases where even after separation the abusing husband may find ways to intimidate his ex-wife, some ‘pathological memory’ may persist as ‘flashbacks’ of traumatic experience to haunt and distress the victim. the form and content of intimate partner abuse is varied. the first and most common type is emotional abuse that includes using insulting names employing terms that are culturally devalued. an abusing husband may deprive his wife of social contact or can sometimes stalk her. domestic discord may include the husband withholding mundane things such as her money, jewellery or even her favorite perfumes or makeup. domestic violence may also be manifested in the husband preventing his wife from getting or keeping a job. domestic violence can also be seen in a wife being coerced into unwanted or forced sexual activity and/or other unremitting intimidations in matters related to marital intimacy. most dishearteningly, violence can lead to physical harm, disability or even death. however, there are rare cases in which the abused wife takes revenge and kills the husband. in some hallmark cases, the murder of the husband did not result in the prosecution of the wives. the act was considered as self-defense or ‘battered woman defense’.9 the magnitude of intimate partner violence hinges on which definition of violence is used and the context in which it is measured. as expected, domestic violence is likely to remain largely hidden and, despite its wide occurrence, violence towards wives has been seriously understudied. the studies that have been carried out in different parts of the world suggest that there are complex and interrelated reasons, which prevent battered women from seeking outside assistance.10 for the majority, there is the cultural proscription against breaking up the marriage as well as the strong stigma in many communities around the world attached to divorce. some women in an abusive relationship tend to be caught up with idea that they will not be able to survive outside the present household and therefore see their situation as unredeemable. others have pointed out that the wife tends to endure an abusive relationship for fear of the negative effects of a marriage breakup on the children.10 from earliest civilizations, it has been known that certain temperaments are prone to certain predispositions including the tendency for intimate partner violence. psychologists studying personality types have suggested that people with dissocial temperaments are more likely to be involved in intimate partner violence than the general population.11 in psychiatric literature and classification, dissocial individual tends to be callously unconcerned for the feelings of others and incapable of maintaining enduring relationships, although having no difficulty in establishing them. these individuals tend to be intolerant of frustration, get easily provoked and have a tendency to blame others. an interesting feature of these individuals is their communication style, characterized by a sense of grandiosity and highly persuasive statements of self-importance. there are a significant number of dissocial personality types, with a prevalence of 2-3% in the general population. this rate increases to 60% among males with poor impulse control and those with prison records.12 d o m e s t i c v i o l e n c e 7 the powerful nature of individuals with dissocial personalities means that their abused partners tend to perceive their situation as helpless, a hallmark of the condition known as the ‘battered wife syndrome’.13 the feeling of helplessness and the perceived futility of trying to change such a pathological relationship apparently leads to the abused person behaving as if the soul music lyric that ‘love hurts’ were an inescapable part of married life. walker14 has depicted the ‘cycle of violence’ as fluctuating in complex ways. according to her studies, there is period of ‘honeymoon’ where the couple cease to be caustic to each other and some element of expression of affection prevails. sometimes the couple vows not to dwell on the past turmoil and seeks to open a new chapter in their relationship. this is followed by a ‘tension building’ phase, characterized by poor communication and other interpersonal problems. the final phase in the circle is ‘acting-out’, where overt outbursts of violent and abusive incidents occur with all the consequences that this may entail. in addition to the physical, emotional or psychological harm to the female, there are also other ill effects of domestic violence. the most obvious victims of domestic violence are innocent children in the household, as violence is likely to have a detrimental effect on children’s cognitive and emotional development. studies have shown that infants as young as six months old can experience trauma symptoms as a result of hearing or witnessing intimate partner violence.15 there is also indication that domestic violence during pregnancy increases the risk factor for antepartum hospitalisation, obstetrical complications, low birth weight delivery and infant death. 16, 17 it was noted that even mature adolescents, who witnessed inter-parental violence, tend to suffer emotional and psychological distress as well as an increased rate of aggression, delinquency and poor academic performance.18 this echoes a famous african proverb that “when elephants fight, the reeds get hurt”. there is also indication of ‘triangulation’ whereby the simmering tension between the pair diverts the conflict on to a child, therefore stabilizing the relationship between the original pair. in the atmosphere of triangulation, the child may resort to attention seeking behaviour such as adopting a sick role to defuse conflict between the father and mother. the sick role as a result of triangulation has been shown to heighten the frequency of seeking medical help which, in turn, leads to a large number of consultations and iatrogenic illnesses in triangulated children.19 o v e r v i e w o f a g g r e s s i v e b e h a v i o u r i n h u m a n s by any definition, violence towards an intimate partner is a manifestation of aggressive behaviour. it is therefore pertinent to consider emerging views on aggression. aggression is defined as violence, the technical term being a behaviour that intends to injure physically and psychologically – another person using corporal or verbal means.20 for the present purpose, theories of aggression will be reviewed, though not exhaustively, from those that put forward the view that aggression is an instinct to those that posit aggression as learned behaviour. the first and foremost theory of aggression in humans suggests that our tendency for violence is innate or instinctive. one of the first persons to paint a pessimistic view of human nature and aggression was sigmund freud, 21 who famously said that ‘man is wolf to man’, ‘homo homini lupus’. aggression, violence and our propensity to harm others and ourselves is an inevitable predicament and at the heart of the human psyche, according to freud’s classic book, civilization and its discontents.21 as a basic part of human emotion, aggression can manifest itself inwardly as self-destructive behaviour. according to this view, reckless driving or puffing cigarettes encapsulates the internal channeling of aggression. according to freud,21 in order to harness such instincts, society should devise and encourage mechanisms to channel violence into more acceptable and less brutal activities. the natural extension of this view is to explore anthropological studies that have compared the rate of violence in human societies in order to test whether aggression is inevitable. the societies were classified as either ‘low conflict’ or with ‘high conflict’. it has been found that those societies that socialize to minimize interpersonal confrontation, in other words, operate to encourage ‘low-conflict’ paradoxically have higher rates of violent death. on the other hand, in societies that operate to have ‘high conflict’, whereby children are encouraged to be brave and bullying others is expected behaviour, the rate of violence is generally relative low.22 this seemingly counter-intuitive view appears to support the instinctual model of aggression. in this model, aggression is an instinct that cannot be ‘suppressed’ by any agent of socialization. it also implies that the atmosphere of violence paradoxically serves as cathars a m i r a l a d aw i a n d s a b a h a l b a h l a n i 8 sis for the aggressive instinct. otherwise, as has been observed in low conflict societies, attempts to harness aggressive behaviour are in fact counterproductive. while the view that human nature is inscribed in our genes has received some support, 23 there is also empirical evidence that aggression is a learned behaviour rather than an innate temperament. according to the seminal work of bandura,24 aggression is learned through observation. mass media have been known to instigate violence in real life, including the self-destructive type known as copycat suicide.25 preference for viewing violent programs among youngsters is disproportionally related to aggressive behaviour during adolescence. watching aggressive role models (either live or on film) significantly heightens the amount of aggressive behaviour displayed by children, compared to youngsters viewing a non-aggressive role model or not having access to violence scenes. interestingly, observation of live role models results in imitation of more specific aggressive acts, whereas observation of filmed (either real or cartoon) role models sets off more aggressive responses of all kinds.26, 27 in addition to longitudinal observation, there are psychological studies suggesting that those who commit violence have been themselves victim of violence, a phenomenon known as ‘identification with an aggressor”, where the victim takes the role of perpetrator. it is possible that an individual who sustains mistreatment in childhood is likely to internalize the view that violence is a means to conflict resolution. there is a strong link between currently experienced domestic violence and violence experienced as either a child or an adult.28 as the abused are likely to become abusers, then, by implication, violence begets violence and therefore it is a learnt behaviour.1 in support of this view, childhood experiences of abuse or witnessing family violence are independent predictors of that person becoming the abuser himself. this type of detrimental childhood experience has been shown to render its victims vulnerable to a multitude of longterm negative emotional, behavioral and academic outcomes, as well as poor physical health, in addition to perpetuating the circle of violence.2 if aggression is inevitable or otherwise, then it should be expressed more saliently in animals since animal are more driven by their instincts than humans are. ethological research notably by lorenz30 and goodall31 have shown that aggression is, in their term, ‘species-specific behaviour’ and therefore is a more complex phenomenon than that depicted by psychoanalysts such as sigmund freud. unlike humans, animals have evolved mechanisms to control aggression and, moreover, animals have not invented weapons, nor do they have the faculty for premeditated murder and violence. the incidence of intra-species violence and warfare is lower or largely nonexistent in animals compared to humans. interestingly, a study conducted on wild primates called bonobo (pan paniscus) suggests that there are few tendencies for intra-species aggression.32 it has been speculated that the largely peaceful life among bonobos might be related to strong bonds affinitive behaviors between males and females.33 bonobos’ social organization is based on the female lineage. the question here arises why apes have apparently succeeded while humans have pitifully failed. could it be that the gender imbalance that exists in human society that is to blame? countering such a view, there is indication that aggression is present on a wide scale even in human matrilineal societies where women are perceived to be endowed with some symbolic power.34 f a c t o r s i n d o m e s t i c v i o l e n c e while the debate lingers on as to whether aggression in humans is a learnt behaviour or neurogenetically determined, 35 it is relevant here to examine empirical data indicating the correlates of intimate partner violence. it should be said at the outset that there is no unitary profile of a violent husband or uniform socio-demographic background of the perpetrator of domestic violence.36 in the present context, the roles of emotions like jealousy, endogenous and exogenous substances that impact on mood and subsequently the tendency for domestic violence will be reviewed. finally, more consonant to oman, the role of cultural patterning in moderating or otherwise violence in the family will also be considered. th e r o l e o f je a l o us y i n d ome sti c v i o l e n c e among the repertoires of varied human emotional predispositions, jealousy has been largely ignored in the medical literature. jealousy is defined as an emotion experienced by one who perceives that another person is giving attention, love, or affection to a third party. as should be expected, jealousy is likely to play a significant role in intimate partner violence. it is difficult to demarcate between ‘healthy jealousy’, which d o m e s t i c v i o l e n c e 9 translates to a lay person as part of the concept of love, and ‘unhealthy’ jealousy. there is evidence that social customs define how jealousy should be perceived. according to mengali, mungai and rucci, 37 some societies embrace jealousy as acceptable social behaviour while other societies may view some expression of jealousy as abnormal, in particular when it exceeds a certain level of possessiveness. although genetic tests have shown that 20% of women had children by men other than their husbands,38, 39 jealousy, sometimes labeled obsessional jealousy, occurs without any shred of evidence of infidelity. such ideation appears to exist in 10% of the population.37 in the psychiatric fraternity, an extreme aberration or form of jealousy is known as ‘pathological jealousy’ or the ‘othello syndrome’.40 individuals afflicted with such an emotion tend to be preoccupied with unrelenting thoughts of the infidelity of their spouses. overt attempts to confirm these suspicions are common. for example, a husband may constantly check the whereabouts of his wife. one classical manifestation of pathological jealousy is when a husband seeks to discover all the phone calls his wife has made. in the extreme form, not only are the relationship and partner damaged, but the quality of life for the sufferers of pathological jealousy themselves is also severely compromised by the presence of obsessive and unremittingly distressing thoughts of their partner’s infidelity. the factors associated with pathological jealousy have not been widely documented though some single case reports have implicated the roles of coffee, hazardous and chronic abuse of alcohol and even overt brain injury.41, 42 there are some psychosocial correlates of pathological jealousy including perceived imbalance in the attributes of the couples. the perceived asymmetry that may threaten a partner can include education levels or, for that matter, even standards of beauty. it is suggested that spouses who perceive their partner as ‘attractive’ are vulnerable to fall pray to imagining that their partner is involved in marital infidelity. a woman who has attained higher educational achievement than her husband is likely to attract his jealousy. in polygamous societies, jealous tension may arise if a woman perceives neglect by her husband, usually in favour of a younger and more attractive wife.43 studies have found that the nature of jealousy is different between sexes.44 men become particularly jealous when they feel the potential loss of the partner, whereas women are more concerned about the effects of infidelity on the quality of the relationship.44 an in vivo neuro-imaging study supports the dichotomous processing of cues of sexual and emotional infidelity. for example, in a recent study, takahashi et al.45 have demonstrated that there is gender difference in cerebral perfusion in response to mock situations of infidelity. when exposed to a situation arousing jealousy, males showed greater activation in the amygdala and hypothalamus while women’s increased cerebral blood flow was significantly elevated in the posterior superior temporal sulcus. one of the consequences of an atmosphere of distrust in the household is discord leading to verbal threats and in extreme cases, to violence or even homicide. r o l e o f e n d o ge n o us a n d e xo ge n o us sub sta n c e s i n d ome sti c v i o l e n c e it has been long known that biological rhythms do play a part in behaviour and there is increasing evidence that certain phases of biological rhythms do coincide with family discords.46 hormonal changes have been suggested to lead to the distressing feelings accompanying menstruation on the part of the wife and lack of understanding on the part of the husband. such a scenario can fuel hostile communication that can heat up into verbal abuse or even trigger violence. on the male side, there is also an indication that the male’s predominant hormones, such as testosterone, may play a crucial role in the expression of violence. mazur & booth’s47 review study shows that men with higher levels of testosterone are more likely to divorce, be arrested for offenses other than traffic violations and use a weapon in fights. in animal experiments, castration has been shown to reduce aggression. in contrast, testosterone restores aggression in castrated mice. there is also evidence of the role of other neuromodulaters in violence. higley et al.48 studied free-ranging rhesus monkeys living on an island. they had the low serotonin metabolite and 5-hydroxyindole acetic acid levels, associated with high risktaking behaviour – such as aggression towards older, larger animals, and taking long leaps between trees. many died as a result of attacks from mature males. however, the direct link between aggression and violence is not clear. testosterone or other neuromodulators must be present for organisms to exhibit aggression, but injecting compounds with affinity to these neuromodulators has been shown to be insufficient to turn a previously non-aggressive mouse into an aggressive one or vice versa.48 as it takes ‘two to tango’, a simplistic association between biological rhythms, hormones and violence may not be adequate to capture the complexity of domestic violence although this link appears to be tantalizingly plausible. one plausible explanation is that rather than neurochemistry having a direct effect on aggression, there ought to be interplay between one’s temperament such as impulsivity, coupled with deranged biological rhythms and the exigent ecological or social milieu for expression of aggression to take place. among these factors, it appears that poor impulse control plays a critical role in the initiation of domestic violence.49 in addition to endogenous substances, such as the neuromodulators mentioned above, exogenous substances, such as some mind altering substances, have been shown to play significant roles in domestic violence. it has been repeatedly shown that alcohol abuse has a strong influence on the quality of marital life. in some parts of the world where there is a relaxed attitude to the availability of alcohol, the majority of patients attending emergency medical attention are victims of intimate partner violence.50 alcohol is prohibited in islam because it is believed to diminish one’s sense of responsibility, cloud the consciousness and challenge the precept of self-restraint accentuated in islamic teaching.51 more recently, emerging anecdotal reports and impressionistic observations suggest that there is a rise of alcohol-related illnesses and deaths and alcohol-related social problems in islamic societies, including oman.51 on the one hand, a husband who has been drinking may be perceived as ‘charming’ or even ‘cute’ when he loses his inhibition and starts to shower his wife with compliments. however, on the other hand, beyond such a convivial period, alcohol does impair judgment and often leads to erratic behaviour and different types of inhibition loss. there are speculations that alcohol intake tends to induce negative mood states as well as impulsiveness and aggression.52 individuals with a long-term history of hazardous and harmful alcohol abuse are prone to impaired processing of emotional stimuli and have been found to have ‘disturbed’ serotonin and testosterone activity.35 both serotonin and testosterone have been critically associated with aggression and impulsivity.35 there is also evidence that men with ‘verbal expressive deficits’ tend to get more frustrated and angry during tense verbal communication.53 this corroborates earlier findings suggesting males, in response to external threats, tend to rely more on ‘primitive’ brain regions to process emotion while females exposed to similar threats tend to show activation in brain areas involving the higher neurocognitive neural substrate controlling planning and rationality.54 the lack of neural apparatus to process emotion in males may explain that why even minor heated arguments may lead to violence in order for the man to ‘get his point across’ or ‘win’ the argument in particular when the situation is marked with social stress and intoxication. although the evidence appears to support the view that alcohol is an important indicator of domestic violence, it is worthwhile noting that approximately 76% of perpetrators of domestic violence have no apparent history of alcohol abuse. therefore, other factors should be considered. in a similar way to alcohol abuse, there is also a strong suggestion that the use of many mind altering substances tend to be a strong predictor of family violence, 11 either because they impair judgment or as part and parcel of the unpleasant emotions during withdrawal from the drug. despite the link between mind altering substances and domestic violence, there are myriad cases where domestic violence is independent of these substances – hence the importance of including other factors in the algorithms , including a history of being physically harmed by parental figures during childhood, certain personality profiles, and substance misuse. c u l t u r a l f a c t o r s a n d d o m e s t i c v i o l e n c e finally, although intimate partner violence is distributed throughout the world, there are cultural factors that contribute to its variations. douki et al. 55 have found that one in three women are likely to experience domestic violence in some countries in the middle east, but this may be ‘tip of the iceberg’ as the region has been described as being marked by a “culture of silence”.10, 56 therefore, it is not surprising that the majority of victims of violence studied were afraid, embarrassed or simply did not know where to seek help. within the constraints of the culture of silence, campaigns against domestic violence are yet to be held; in any case, the impact of such campaigns in other parts of the world leaves much to be desired.10, 57 it would be relevant to reflect on socio-cultural factors that might affect their impact in the arab/islamic part of the world. to paint a blanket picture, as if there were a unitary ‘arab character’, the collective identity 10 s a m i r a l a d aw i a n d s a b a h a l b a h l a n i of the family is arguably the central cultural patterning in the middle east. according to dwairy,58 individuals in the arab world live in a symbiotic relationship with their family that reinforces social behaviour reflecting group identity. in a traditional, collectivistic arab society, the intimate details of the household would not go beyond the family circle. indeed, reliance on the criminal justice system to confront the evil of family violence may be counterproductive.58 when a husband, the only deemed “protector’ for the welfare of the wife and children in these societies, becomes the abuser, outside encroachment into what is perceived as a private family matter may damage the whole family including the victim, as shame and honour have a strong role in the indices of social cohesion and family bonding.58 other family members may resist the ‘family secret’ being exposed to outsiders because the whole saga will sully the family’s honour. the need to preserve honour and social collectivity may override personal distress, even if it means submission to unremitting and lifelong abuse. although no formal study has been conducted in oman, there are two factors that may have moderated as well as perpetuated the incidence and magnitude of family violence. in the traditional setting, it has been commonly accepted that society is paternalistic and collectivistic.59 in such a setting, the norm is an extended family, with family members living in close proximity. marriage is a bond between the families, as the couple represents a small link in the chain of family ties. marriage is considered a sacred and unbreachable institution. the family plays a central role in the collectivistic society. if a misunderstanding happens between couples, violence is unlikely to occur as other family members will intervene to calm down the situation. in such a setting, couples are not alone in the household. however, wife beating may occur for two reasons. firstly, the cultural patterning discourages individuals to express their emotions and therefore, there is little room for dealing with marital stress in commonly accepted ways like reaching understanding by ‘talking it over’. without such an option, pent-up emotions are likely to be vented using physical channels. another factor that may lead to wife beating is the widely held folklore colloquialism that a man has the ‘right to slap’ his wife. while traditional omani society may have mechanisms to keep family violence in check, the situation may now be different compared to past decades. widespread education and the new social order have resulted in the vast majority of women aspiring to seek education and a global mode of lifestyle.59 with empowerment, it is likely that women will be less tolerant of abusive relationships. there are anecdotal reports suggesting that there is already a rising tide of divorces in some of the arabian gulf countries,60 which has been attributed to the physical and psychological effects of diabetes.61 similarly, social empowerment tends to shield one from becoming a victim of aggressive behaviour since positive self-image is an important moderator against violence.62 according to a recent report, omanis have entered the top echelons of ‘happiness’. oman was ranked as the second happiest country in the gulf region and the 30th happiest country in the world.63 another indicator of lower rates of domestic violence is education. studies from elsewhere have pointed out that education is an important factor in minimizing violence and victimization. since universal free education was instituted in oman in the 1970s, there has been a gradual increase of female participation and this has increased female entrance into the labour force.59 in real terms, in the recent history, oman has achieved significant social empowerment with little gender gap.64 however, there may be some downsides to the recent affluence that may be worthwhile speculating upon. with rapid urbanization and the supplanting of the traditional extended family by nuclear family forms, couples are left more on their own to handle marital stress. stresses triggered by the shifting sands of the modern economy may also contribute to domestic violence as men feel like failures at providing for their families and so, paradoxically, take this out on their families. elbedour et al.,63 in reference to the recently increased pace of westernization and globalization, have suggested that modernity tends to erode traditional cultural norms. as a result, “men are becoming more aggressive in order to restore their eroding sense of dominance and authority. thus, a total collapse of cultural values and the erosion of traditional collectivity have resulted in conflicting standards of behaviour that are confusing and unclear to parents, children and the society as a whole.”63 there is also a subtle challenge affecting women that reflects recent affluence in this part of the world. there are anecdotal reports suggesting that if a female is a breadwinner for the family, she may be coerced into not getting married as her departure from her parent house would end o m e s t i c v i o l e n c e 11 tail lost of income for the family. there is also indication that some of these career women, when they are married, are enticed to give up their salaries to their husband. these subtle economic abuses have given rise to an unprecedented social phenomenon: parents of these career women tend to demand an exorbitant bride service, mahr, from the prospective husband. the mahr is likely to be high if a career woman fetches good salary and if her workplace is socially construed to parallel the traditional domestic sphere suitable for women. there is also indication that in some rare cases wives are literally ‘abandoned’ by their husbands, but without due recourse for divorce. these ‘run way husbands’ usually do not give financial support to their wife or children. beside impressionistic and anecdotal observation, there is no study to elucidate the magnitude of these phenomenona and little is known of their impact on the wellbeing of those who are affected by them. studies are therefore indicated to shed light on our ignorance on these issues. it remains to be seen whether the pressures of modern life are heightening tensions in the family. in such a scenario, it can be speculated that family discord will proliferate, but the magnitude of domestic violence will likely remain hidden under the mantle of family secrecy as any discussion on domestic violence is likely to be perceived as culturally taboo. c o n c l u s i o n it is becoming increasingly clear that there is gender symmetry in domestic violence though this article has focused on violence towards women.3 the global nature of domestic violence attests to the view that it transcends age, sex, race, culture, religion, education, employment and marital status.3 in some countries, between 12% to 80% of those who are married or have an intimate partner tend to endure beating or humiliation from their partners 65, 66 to the extent that some in the medical profession are suggesting that all women should be screened for domestic violence.67 some studies have suggested that abused women tend to use more primary care, emergency hospital services than non-abused women.28 to paraphrase an arabic poem, domestic violence is closer to many households than our jugular vein and this opens up an immediate pandora’s box of complex ethical, legal and medical issues and concerns. the victims of domestic violence are often at their prime age, between 19 and 30 years old.68 for them it is all the more harrowing if the abuse sometimes persists, ironically as in the marriage vow, “until death us do part”. although previously considered a private family matter, violence in the domestic sphere should be more discussed in the public domain as it appears to be a catalyst for many social ills. the psychological, emotional and social burdens of violence on the victims and perpetrators and others in the household are enormous. with repeated incidents of violence, the quality of life is likely to be compromised in the whole household. children who are exposed to such a situation are likely to enter in to a cycle of perpetuating abuse themselves, in addition to having to live with such traumas and thus being prone to psychological disorders. the partners who fight each other are in danger of exposing themselves to grievous bodily harm not to mention both incurring debilitating emotional and mental scars. society as a whole feels the effect of domestic violence through having to provide social and economic support to dysfunctional individuals. if the phenomenon of domestic violence is so common in all segments of society and throughout the world, to use tina turner’s famous lyric, “what’s love got to do with it?” a c k n ow l e d ge me n ts our gratitude goes to dr. cashmera bhaya for her insight on the local sociology of domestic violence. we thank meriel carboni and hiroko jimbo for constructive criticism on the various versions of this manuscript and last, but not least, we thank lamk lamki for opening this journal for such discourse. r e f e r e n c e 1. widom, cs. the cycle of violence. science 1989; 244:160–166. 2. nelson t. violence against women. world watch 1996; 9:33-38. 3. straus ma. future research on gender symmetry in physical assaults on partners. violence against women 2006; 12:1086-1097. 4. mousavi, sm, eshagian a. wife abuse in esfahan, islamic republic of iran, 2002. east mediterr health j 2005; 11:860-869. 5. ministry of development. sixth five year development plan: 2001–2005. muscat: volume ii, sultanate of oman, 2002. 6. rassekch s. education as a motor for development: recent education reforms in oman with particular reference to the status of women and girls. international s a m i r a l a d aw i a n d s a b a h a l b a h l a n i 12 bureau of education, geneva, unesco, 2004. 7. vieweg wv, julius da, fernandez a, beatty-brooks m, hettema jm, pandurangi ak post-traumatic stress disorder: clinical features, pathophysiology, and treatment. am j med 2006; 119:383-390. 8. inslicht ss, marmar cr, neylan tc, et al. increased cortisol in women with intimate partner violence-related posttraumatic stress disorder. psychoneuroendocrinology 2006; 31:825-38. 9. stuart gl, moore tm, gordon kc, hellmuth jc, ramsey se, kahler cw. reasons for intimate partner violence perpetration among arrested women. violence against women. 2006;12:609-621. 10. diop-sidibe n, campbell jc, becker s. domestic violence against women in egypt-wife beating and health outcomes. soc sci med 2006; 62:1260-1277. 11. fals-stewart w, leonard ke, birchler gr. the occurrence of male-to-female intimate partner violence on days of men’s drinking: the moderating effects of antisocial personality disorder. j consult clin psychol 2005; 73:239-248. 12. moran p. the epidemiology of antisocial personality disorder. social psychiatry psychiatr epidemiol 1999; 34:231-242. 13. parker b, schumacher dn. the battered wife syndrome and violence in the nuclear family of origin: a controlled pilot study. am j public health 1977; 67:760-761. 14. walker, le. assessment of abusive spousal relationships. in: kaslow a, florence w, eds. handbook of relational diagnosis and dysfunctional family patterns. oxford: john wiley & sons, 1996. p. 338-356. 15. rivett m, howarth e, harold g. ‘watching from the stairs’: towards an evidence-based practice in work with child witnesses of domestic violence. clin child psychol psychiatry 2006; 11:103-125. 16. kaye dk, mirembe fm, bantebya g, johansson a, ekstrom am. domestic violence during pregnancy and risk of low birthweight and maternal complications: a prospective cohort study at mulago hospital, uganda. trop med int health 2006; 11:1576-1584. 17. jejeebhoy sj. associations between wife-beating and fetal and infant death: impressions from a survey in rural india. stud fam plann 1998; 29:300-8. 18. haj-yahia mmi, ben-arieh a. the incidence of arab adolescents’ exposure to violence in their families of origin and its sociodemographic correlates. child abuse negl 2000; 24:1299-315. 19. waters hr. hyder aa. rajkotia y. basu s. butchart a. the costs of interpersonal violence an international review. health policy 2005; 73:303-315. 20. dula cs, geller es. risky, aggressive, or emotional driving: addressing the need for consistent communication in research. j safety res 2003; 34:559-66. 21. freud s. civilization and its discontents. strachan j, trans & ed. reissue ed. w. w. norton & company, 1989. 22. wilson eo. on human nature. boston: harvard university press, 1978. 23. zalcman ss, siegel a. the neurobiology of aggression and rage: role of cytokines. brain behav immun 2006; 20:507-514. 24. bandura a. aggression: a social learning analysis. englewood cliffs: prentice-hall, 1973. 25. stack s. media coverage as a risk factor in suicide. j epidemiol community health 2003; 57:238-240. 26. singer mi, slovak k, frierson t, york p. viewing preferences, symptoms of psychological trauma, and violent behaviors among children who watch television. j am acad child adolesc psychiatry 1998; 37:1041-1048. 27. huesmann lr, taylor ld. the role of media violence in violent behaviour. annu rev public health 2006; 27:393-415. 28. mccauley j, kern de, kolodner k, et al. the “battering syndrome”: prevalence and clinical characteristics of domestic violence in primary care internal medicine practices. ann intern med 1995; 123:737-746. 29. bensley l, van eenwyk j, wynkoop simmons k. childhood family violence history and women’s risk for intimate partner violence and poor health. am j prev med 2003; 25:38-44. 30. lorenz k. on aggression. new york: harvest books, 1974 31. goodall j. my life with the chimpanzees. london: aladdin, 1996. 32. sannen a, van elsacker l, heistermann m, eens m. urinary testosterone-metabolite levels and dominance rank in male and female bonobos (pan paniscus). primates 2004; 45:89-96. 33. idani g. social relationships between immigrant and resident bonobo (pan paniscus) females at wamba. folia primatol 1991; 57:83-95. 34. moane, g. gender and colonialism: a psychological analysis of oppression and liberation. new york: st. martin’s press, 1966. 35. george dt, phillips mj, doty l, umhau jc, rawlings rr. a model linking biology, behaviour and psychiatric diagnoses in perpetrators of domestic violence. med hypotheses 2006; 67:345-353 36. bitler da, linnoila m, george dt. psychosocial and diagnostic characteristics of individuals initiating domestic violence, j nerv ment dis 1994; 182:583–585. 37. mengali f, mungai f, rucci p. normal and obsessional d o m e s t i c v i o l e n c e 13 jealousy: a study of a population of young adults. european psychiatry 2003; 18:106-111. 38. cherkas lf, oelsner ec, mak yt, valdes a, spector td. genetic influences on female infidelity and number of sexual partners in humans: a linkage and association study of the role of the vasopressin receptor gene (avpr1a). twin res 2004; 7:649-582. 39. kirn w. curing casanova: a pharmacological infidelity inhibitor just may be on its way. should we welcome it? n y times mag 2004:13, 14. 40. mullen pe. jealousy: the pathology of passion. br j psychiatry 1991;158:593-601. 41. michael a, mirza s, mirza ka, babu vs, vithayathil e. morbid jealousy in alcoholism. br j psychiatry 1995; 167:668-672. 42. westlake rj, weeks sm. pathological jealousy appearing after cerebrovascular infarction in a 25-year-old woman. aust n z j psychiatry 1999; 33:105-107. 43. el islam mf. cultural aspects of morbid fears in qatari women. soc psychiatry psychiatr epidemiol 1994; 29:137-140. 44. de steno d, bartlett my, braverman j, salovey p. sex differences in jealousy: evolutionary mechanism or artifact of measurement? j pers soc psychol 2002; 83:11031116. 45. takahashi h, matsuura m, yahata n, koeda m, suhara t, okubo y. men and women show distinct brain activations during imagery of sexual and emotional infidelity. neuroimage 2006; 32:1299-1307. 46. soler h, vinayak p, quadagno d. biosocial aspects of domestic violence. psychoneuroendocrinology 2000; 25: 721-739. 47. mazur a, booth a. testosterone and dominance in men. behav brain sci 1998; 21:353-363; 48. higley jd, mehlman pt, poland re, et al. csf testosterone and 5-hiaa correlate with different types of aggressive behaviors. biol psychiatry. 1996; 40:1067-1082. 49. schafer j, caetano r, cunradi cb. a path model of risk factors for intimate partner violence among couples in the united states. j interpers violence 2004; 19:127142. 50. collins j jnr, messerschmidt pm. epidemiology of alcohol-related violence. alcohol health res world 1993; 17:93-100. 51. zaidan, zaj, dorvlo aas, viernes n, al-suleimani a, al-adawi s. social-demographic correlate of hazardous and harmful alcohol consumption in oman. int j ment health addiction 2007; 5:3-15 52. van erp am, miczek ka. increased aggression after ethanol self-administration in male resident rats. psychopharmacology 1997; 131:287-295. 53. cohen ra, brumm v, zawacki tm, paul r, sweet l, rosenbaum a. impulsivity and verbal deficits associated with domestic violence. j int neuropsychol soc 2003; 9:760-770. 54. kaiser a, kuenzli e, zappatore d, nitsch c. on females’ lateral and males’ bilateral activation during language production: an fmri study. int j psychophysiol 2007; 63:192-198. 55. douki s, nacef f, belhadj a, bouasker a, ghachem r. violence against women in arab and islamic countries. arch womens ment health 2003; 6:165-171. 56. ashy ma. saudi arabia. in: malley-morrison k, ed. (2004). international perspectives on family violence and abuse: a cognitive ecological approach. new jersey: lawrence erlbaum associates publishers, 2004. p. 167-186. 57. ahmed am, elmardi ae. a study of domestic violence among women attending a medical centre in sudan. east mediterr health j 2005; 11:164-174. 58. khawla abu baker k, dwairy m. cultural norms versus state law in treating incest: a suggested model for arab families. child abuse negl 2003; 27:109-123. 59. albelushi a. gender issues in teacher development: career choice and commitment in oman. engl lang teac educat develop 2004; 8:1-25. 60. el-haddad y. major trends affecting families in the gulf countries 2003. http://www.un.org/esa/socdev/ family/publications/mtelhaddad.pdf, accessed february 10, 2007. 61. one in four marriages ends up in divorce. arab news. sunday 24 december, 2006. 62. elbedour s, abu-bader s, onwuegbuzie aj, abu-rabia a, el-aassam s. the scope of sexual, physical, and psychological abuse in a bedouin-arab community of female adolescents: the interplay of racism, urbanization, polygamy, family honor, and the social marginalization of women. child abuse negl 2006; 30:215-229. 63. marks n, abdallah s, simms a, thompson s. the happy planet index. london: new economics foundation, 2006:318 64. al-adawi s. (2006). emergence of diseases of affluence in oman: where do they feature in the health research agenda? sultan qaboos university medical journal 2006 6:3-9. 65. faramarzi m, esmailzadeh s, mosavi s. prevalence and determinants of intimate partner violence in babol city, islamic republic of iran. east mediterr health j 2005; 11:870-879. 66. parish wl, wang t, laumann eo, pan s, luo y. intimate partner violence in china: national prevalence, risk factors and associated health problems int fam plan perspect 2004; 30:174-181 67. ramsay j, richardson j, carter y, feder g. appraisal of evidence about screening women for domestic violence. (report to national screening committee, 2001.) www. nelh.nhs.uk/screening/adult_pps/domestic_violence. html (accessed 11 february 2007). 68. vos t, astbury j, piers ls, magnus a, heenan m, stanley l, walker l, webster k. measuring the impact of intimate partner violence on the health of women in victoria, australia. bull world health organ 2006; 84:739-744. s a m i r a l a d aw i a n d s a b a h a l b a h l a n i 14 submitted 30 mar 22 1 revision req. 14 jun 22; revision recd. 16 jun 22 2 accepted 21 jul 22 3 online-first: august 2022 4 doi: https://doi.org/ 10.18295/squmj.8.2022.048 5 6 long-standing lymphocutaneous sporotrichosis 7 israel perez-lópez and *ricardo ruiz-villaverde 8 9 department of dermatology, hospital universitario san cecilio, inst invest 10 biosanitaria ibs, granada, spain 11 *corresponding author’s e-mail: ismenios@hotmail.com 12 13 introduction 14 a 36-year-old male, farmer, with no relevant personal or family medical history , 15 attended our dermatology outpatient clinic, complaining of a warty plaque on the back 16 of his right hand that involved the entire dorsal aspect of the third finger and that 17 presented two satellites lesions on the arm with a linear arrangement (fig.1.). 18 locoregional adenopathies were not noted. he recalled a previous traumatic history 19 performing his work 10 months earlier. two weeks later the lesions began to develop 20 until they reached their current state. 21 22 laboratory examinations included blood sample test (haemogram and basical 23 coagulation), general biochemistry (lipid profile, hepatic and renal function), 24 autoimmunity (autoantibodies, immunoglobulins, complements), thyrotropin and 25 thoracoabdominal ct was requested to evaluate systemic dissemination with normality 26 of all the tests mentioned. no skin biopsy was performed. regarding the initial clinical 27 suspicion of sporotrichosis, we started treatment with itraconazole 200mg/12h, which 28 had to be discontinued due to gastrointestinal discomfort 10 days later. the study by 29 pcr assay of m. tuberculosis complex and non tuberculous mycobacterium spp was 30 negative. however, culture showed positive results for sporothrix schenckii in five days 31 (being reported two days later). one week later the patient began treatment with 32 liposomal amphotericin b at a dose of 5 mg/kg/day for 3 days as an induction regimen 33 and then once monthly as maintenance treatment until resolution of the clinical course, 34 four months later with no skin lesions. there have been no recurrences of the lesion six 35 months after the end of treatment. written informed consent of the patient for 36 publication purposes has been obtained. 37 38 comment 39 sporotrichosis is a subcutaneous mycosis caused by a dimorphic fungus of the genus 40 sporothrix. sporotrichosis can be observed in any part of the world, with some areas of 41 "hyperendemicity", being particularly frequent in tropical and subtropical countries (in 42 peru the reported incidence is 1/1,000 cases/year, while in the united states it is 12 43 cases per million) due to more occupational exposure.1 44 45 without predilection for age, sex or race, the occurence of the disease depends on the 46 fungus being in the environment and traumatic inoculation into the skin . the male 47 predominance is believed to be due to greater exposure rather than greater 48 predisposition. traumatic inoculation is the reason why the extremities (particularly 49 upper extremities) and bare parts are affected most often. single or multiloculated 50 cutaneous forms, lymphocutaneous, as in the case at hand, and systemic (may 51 compromise lung, breasts, liver, kidney, eyes, heart, and genitalia) have been 52 described.2 culture in sabouraud dextrose agar continues to be the gold standard, since 53 histological study may be less profitable and require histochemical techniques such as 54 pas, groccot or gomori to identify fungal structures. in some reference centers, pcr 55 assay is used for its diagnosis, although the kits are not commercially available. the 56 differential diagnosis following a sporotrichoid eruption pattern is wide, encompassing 57 cutaneous tuberculosis, leishmaniasis, nocardiosis, chromoblastomycosis, 58 blastomycosis, paracoccidioidomycosis, and atypical mycobacteriosis. 59 60 the first line of treatment in the lymphocutaneous variety is oral itraconazole 61 100mg/day.3 oral terbinafine has been used with moderate success and in more 62 resistant cases the use of oral saturated solution of potassium iodide (sski) has been 63 reported. this last modality lacks a standardized commercial formulation and its 64 metallic taste and uncertain mechanism of action have relegated it to a second or third 65 line choice. liposomal amphotericin b may be a more effective option in 66 immunosuppressed patients or those with low therapeutic adherence.4 among its side 67 effects are fever, headache, malaise, hypokaliemia, hypomagnesemia, cardio and 68 nephrotoxicity. the use of other less conventional treatments such as photodynamic 69 therapy has only been carried out in case series and with uneven results.5 70 71 author contributions 72 ipl and rrv were both involved in conceptualization, collection of data, writing and 73 final approval of the manuscript. 74 75 references 76 1. sharma b, sharma ak, sharma u. sporotrichosis: a comprehensive review on 77 recent drug-based therapeutics and management. curr dermatol rep. 2022 78 mar 17:1-10. doi: 10.1007/s13671-022-00358-5. 79 2. martínez-herrera e, arenas r, hernández-castro r, frías-de-león mg, 80 rodríguez-cerdeira c. uncommon clinical presentations of sporotrichosis: a 81 two-case report. pathogens. 2021 sep 27;10(10):1249. doi: 82 10.3390/pathogens10101249. 83 3. poester vr, basso rp, stevens da, munhoz ls, de souza rabello vb, 84 almeida-paes r, zancopé-oliveira rm, zanchi m, benelli jl, xavier mo. 85 treatment of human sporotrichosis caused by sporothrix brasiliensis. j fungi 86 (basel). 2022 jan 10;8(1):70. doi: 10.3390/jof8010070. 87 4. belda w jr, domingues passero lf, stradioto casolato at. lymphocutaneous 88 sporotrichosis refractory to first-line treatment. case rep dermatol med. 89 2021 oct 6;2021:9453701. doi: 10.1155/2021/9453701. 90 5. legabão bc, fernandes ja, de oliveira barbosa gf, bonfim-mendonça ps, 91 svidzinski tie. the zoonosis sporotrichosis can be successfully treated by 92 photodynamic therapy: a scoping review. acta trop. 2022 apr;228:106341. 93 doi: 10.1016/j.actatropica.2022.106341. 94 95 96 fig. 1: verrucous plaque on the back of the right hand that involved the entire dorsal 97 aspect of the third finger with two satellites lesions on the arm with a linear 98 arrangement. 99 a strange type of pica a strange type of pica *marwan m. al-sharbati1, ziad a. j. zaidan1, ala’adin al-hussaini1, khalid al-khalili2 abstrac t. pica, where the patient eats non-food items such as mud, clay, varnish etc., is a common behavioural problem seen in children, pregnant women and the mentally retarded. however sponge pica is a very rare variation. we report a case of a 5-year-old omani girl, who presented with sponge pica since the age of two years, with recent abdominal pain. investigations showed anaemia, elevated liver enzymes and normal intelligence. there was no evidence of obsessive-compulsive disorder. both clinical and laboratory findings showed complete recovery after a few weeks of oral iron therapy. her appetite improved, and she started to gain weight. no recurrence was observed when followed up after two years. awareness is necessary to detect and treat pica as early as possible to prevent its complications. keywords: pica, anemia, sponge pica, abdominal pain, oman. 1department of behavioural medicine, college of medicine & health sciences, sultan qaboos university, p o box 35, 2department of behavioural medicine, sultan qaboos university hospital, p o box 38, al khod 123, sultanate of oman. *to whom correspondence should be addressed. email: marwan@squ.edu.om pica is the persistent, culturally and developmentally inappropriate ingestion of non-nutritive substances,1 which is common in small children, the mentally retarded, and in pregnant women.2 in spite of being common, pica is infrequently diagnosed.2,3 the risk for accidental poisoning is significant.2,4 pica can also cause abdominal pain, intestinal obstruction, perforation, worm infestations and secondary anaemia. the commonly ingested non-food material constitute soil, clay, paper, paint, coins, strings, rags, hair, faeces, vomitus, leaves, worms and cloth.2,5 children are rarely brought for psychiatric treatment for the isolated problem of pica. ten to twenty per cent of children in the usa are reported to exhibit pica at some point in their lives, while up to 50–70% of children living in inner cities, particularly those of low socio-economic classes, display pica-like behaviour between the ages of –6 years. different causes are claimed to predispose one to pica, such as iron deficiency anaemia6 and obsessive-compulsive disorder.7 t h e c a s e a 5-year-old omani girl from a middle-class family presented with eating sponge since the age of two years. she started to suffer from abdominal pain and nausea, without vomiting. she extracted and ate sponge from furniture when others were sleeping or busy, and washed down large chunks of sponge by drinking water. nothing in her history suggested compulsive behaviour, anxiety or depression. her weight was5.6 kg (<0th percentile). this child had been born of non-consanguineous parents, as the fourth among five children. she had been the product of normal gestation and delivery, weighed 3 kg at birth and had been breastfed for two years. the postnatal period had been uneventful, and her development was within normal limits. she used to sleep late and wake up early, without having day naps. she was a sociable child, mixing and playing with other children without difficulty, and tended to prefer children older than herself. there was no history of pica or other psychiatric disorders among her family or relatives. a strange type of pica ����� ��� ���� ��� ���� ���� ����������������� ��� ������������ ���� � ������� ����� ��� ��������:����� � ����� � ����� ��� ����� ��� ���� ��� �� ����� �����...�������� ������ ��� ���� ����� ������� ������� ������ ������� �������� .����� ����� ������� ��� ����� ���� �� .������ ���)����� ���� ��� ��� (����� ���� ����� .��� ���� ����� ����� ��� ��� ������ ��� �� ����� ���� ����� ��� ����� ��� ��� ���� ���� .����� ����� �� ��� �� ���� ����� . �������� ����� ������ � ������ ���� ���� ��� �� ����� ����� � ����� ������ ���� �� ������ � .������� ������ ����� ��� ���� ���� � ������ ������� .���� ���� �� ������� ����� �� ������ ���� ��� ������� ��� ����� ���� ����� ��������� � �������� ����������� ������ ��� � ������ ���� .����� �� ���� ������� ������ ��� ������� ���� �� .����� ����� ��� � ����� ��� �� ����� ����� �������� �������� ����� �����. c a s e r e p o r tsqu journal for scientific research: medical sciences 2003 vol 5, no. –2, 49–50 ©sultan qaboos universit y 50 during the consultation, she came across as smiling, yet shy and not very communicative, and calm. the clinical examination yielded normal results. investigations showed high liver enzymes – alanine amino transferase (alat) at 49 u/l, aspartate amino transferase (asat) at 44 u/l, leucocyte count 2.×03 (lymphocytes 67%), low haemoglobin at 0.8 g/dl, low mean corpuscular haemoglobin (mch) 22.3 pg/cell, low mean corpuscular volume (mcv) 67.4 fl, and thrombocytosis 596×09/l. she scored average on raven’s intelligence test.8 the child was prescribed ferrous fumarate syrup at 45 mg thrice daily after food for six weeks. the mother observed substantial improvement; the child nearly stopped eating sponge and showed a remarkable improvement in her appetite. her blood tests showed a return to normal levels, and the liver enzymes decreased. she was given additional iron syrup for another four weeks. follow up during two years thereafter showed a stable condition without recurrence. d i s c u s s i o n a n d c o n c l u s i o n this is an unusual case of pica. a survey of the internet only yielded one paper describing sponge pica.9 although some attribute pica to obsessive compulsive disorder (ocd),7 we did not find any evidence of ocd in this case. the drastic improvement in the patient’s state after anaemia correction is of interest, simulating other studies,10 and raises the question of whether the pica was caused by malnutrition. on the other hand, sponge, a hydrocarbon, might have affected bone marrow activity causing secondary anaemia. indeed pica can have serious medical implications3,4 such as lead poisoning, helminthic infestations and iron-deficiency anaemia. the last could be due to competition of the ingested material with iron absorption, or its effect on bone marrow.6,11,12 it is important for the parents and physicians to be aware of this often overlooked condition. r e f e r e n c e s . american psychiatric association. diagnostic and statistical manual of mental disorders (4th edition). washington dc, 994. 2. popper ch, west sa. disorders usually first diagnosed in infancy, childhood or adolescence. in: essential of clinical psychiatry based on the american psychiatric press textbook of psychiatry, 3rd ed. hales re, yudofsky sc (eds). american psychiatric press. inc. washington dc, 999, 539–645. 3. rose ea, porcerelli jh, neale av. pica: common but commonly missed. j am board fam prac, 2000,3, 353–358. 4. roberts jw, dickey p. exposure of children to pollutants in house dust and indoor air. rev environ contam toxicol, 995, 43, 59–78. 5. solyom c, solyom l, freeman r. an unusual case of pica. can j psychiatry 99, 36, 50–53. 6. ivascu ns, sarnaik s, mccrae j, whitten-shurney w, thomas r, bond s. characterization of pica prevalence among patients with sickle cell disease. arch pediatr adolesc med, 200, 55, 243–247. 7. stein dj, bouwer c, van heerden b. pica and the obsessivecompulsive spectrum disorders. s afr med j, 996, 86 (suppl), 59–592. 8. raven j. the raven’s progressive matrices: change and stability over culture and time. cogni psychol, 2000, 4, –48. 9. mcalinden mg, potts sr. sponge bezoar: a rare cause of abdominal pain. ulster med j 999, 68, 36–37. 0. geissler pw, mwaniki dl, thiong’o f, michaelsen kf, friis h. geophagy, iron status and anaemia among primary school children in western kenya. trop med int health, 998, 3, 529– 534. . menge h, lang a, cuntze h. pica in germany--amylophagia as the etiology of iron deficiency anemia. z gastroenterol 998, 36, 635–640. 2. federman dg, kirsner rs, federman gs. pica: are you hungry for the facts? conn med 997, 6, 207–209. a l s h a r b at i e t a l a strange type of pica *marwan m. al-sharbati1, ziad a. j. zaidan1, ala’adin al-hussaini1, khalid al-khalili2 the case discussion and conclusion references abstract: objectives: this study aimed to report the clinicopathological features, management and long-term outcomes of patients with gastrointestinal stromal tumours (gists) in oman. methods: this retrospective study was conducted on patients treated for gist between january 2003 and december 2017 at three tertiary referral centres in muscat, oman. all patients with confirmed histopathological diagnoses of gist and followed-up at the centres during this period were included. relevant information was retrieved from hospital records until april 2019. results: a total of 44 patients were included in the study. the median age was 55.5 years and 56.8% were female. the most common primary site of disease was the stomach (63.6%) followed by the jejunum/ileum (18.2%). two patients (4.5%) had c-kit-negative, discovered on gist-1-positive disease. a total of 24 patients (54.5%) presented with localised disease and eight (33.3%) were classified as being at high risk of relapse. patients with metastatic disease received imatinib in a palliative setting, whereas those with completely resected disease in the intermediate and high-risk groups were treated with adjuvant imatinib. of the six patients (13.6%) with progressive metastatic disease, of which four had mutations on exon 11 and one on exon 9, while one had wild-type disease. overall, rates of progression-free survival and overall survival (os) at 100 months were 77.4% and 80.4%, respectively. rates of os for patients with localised and metastatic disease were 89.9% and 80.2%, respectively. conclusion: the presenting features and outcomes of patients with gists in oman were comparable to those reported in the regional and international literature. keywords: gastrointestinal stromal tumors; proto-oncogene proteins c-kit; protein kinase inhibitors; imatinib; adjuvant chemotherapy; survival rate; oman. clinicopathological features and outcomes of gastrointestinal stromal tumours in oman a multi-centre study *zainab al-maqrashi,1 ikram a. burney,2 kadhim m. taqi,3 yaqoob al-sawafi,4 asim qureshi,5,6 ritu lakhtakia,7 itrat mehdi,8 bassim al-bahrani,8 shiyam kumar,9 mansour al-moundhri2 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e237–243, epub. 21 jun 21 submitted 11 may 20 revision req. 16 jul 20; revision recd. 13 aug 20 accepted 9 sep 20 1department of medicine, mcmaster university, hamilton, canada; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman; 3division of general surgery, department of surgery, faculty of medicine, university of british columbia, vancouver, canada; 4department of general surgery, armed forces hospital, muscat, oman; 5department of pathology, king’s mill hospital, sherwood forest hospitals national health service foundation trust, mansfield, nottinghamshire, uk; 6department of pathology, sultan qaboos university hospital, muscat, oman; 7department of pathology, mohammed bin rashid university of medicine & health sciences, dubai, united arab emirates; 8national oncology centre, royal hospital, muscat, oman; 9department of medical oncology, yeovil district hospital nhs foundation trust, somerset, uk *corresponding author’s e-mail: zmaqrashi@gmail.com this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.012 clinical & basic research advances in knowledge survival data from the current study were comparable with previous findings published in regional and international literature. to the best of the authors’ knowledge, this is the first study to report the long-term outcomes of patients with gastrointestinal stromal tumours (gists) in the middle east and may serve as a benchmark for future studies. application to patient care results from this study support the use of international gist treatment protocols in the local setting of oman. gastrointestinal stromal tumours (gists) are the most common mesenchymal tumours of the gastrointestinal tract (git), yet account for only 2% of all git cancers.1 while gists can arise from any part of the git, the most commonly affected sites are the stomach (60%) and small intestine (30%); however, gists can also arise from other intra-abdominal sites including the mesentery and omentum.2,3 although a diagnosis of a gist can be indicated based on histological features, it is established via the immunohistochemical expression of either the cluster of differentiation (cd)117 protein coding for the c-kit gene or the discovered on gist1 (dog-1) protein.4,5 overall, cd117 is expressed in approximately 90–95% of cases, although such patients may harbour mutations on different exons.4 patients with gists without cd117 expression may harbour mutations in the platelet-derived growth factor receptor-α (pdgfr-α) gene or may have wildtype tumours with substantial reductions in the expression of succinate dehydrogenase.6 complete surgical resection is the mainstay of treatment for gist cases with localised disease.4 more recently, it has become possible to stratify patients based on risk of recurrence into various categories using either the national institutes of health (nih), armed forces institute of pathology (afip) or modified jonessu criteria.4,7,8 in general, the risk of relapse depends on the site and size of the tumour and its mitotic rate.8–10 in particular, metastatic gists are resistant to standard chemotherapy.11 the introduction of tyrosine kinase inhibitors (tkis) https://creativecommons.org/licenses/by-nd/4.0/ clinicopathological features and outcomes of gastrointestinal tumours in oman a 15-year multi-centre study e238 | squ medical journal, may 2021, volume 21, issue 2 has not only dramatically improved the prognosis of patients with unresectable, recurrent or metastatic gists, but also reduced the risk of recurrence and improved progression-free survival (pfs) and overall survival (os) rates in patients considered to have a high risk of relapse after complete resection.12 nevertheless, while several studies have sought to report the presentation and outcomes of gist cases across the world, there remains a scarcity of literature from oman and the gulf region.13–16 as such, this study aimed to report the clinicopathological features and outcomes of gist cases in oman. methods this retrospective multicentre study was conducted between january 2003 and december 2017 at the sultan qaboos university hospital, armed forces hospital and royal hospital in muscat, oman. these three major tertiary hospitals receive referrals from all over the country for the evaluation and management of cancer cases. all patients diagnosed with histopathologically-confirmed gists during the study period at these hospitals and with complete followup data were included. patients with incomplete data, including patients who were lost to follow-up, those diagnosed elsewhere and those for whom a major part of treatment was carried out at other hospitals were excluded. the patients’ clinical and sociodemographic data were collected from paper and electronic hospital records. in addition, other information was recorded, including primary tumour site, metastatic sites, histopathological subtype and immunohistochemical patterns of expression of relevant diagnostic markers, as well as type of surgery employed, use of tkis and indications for treatment with imatinib (i.e. in an adjuvant, neoadjuvant or palliative setting). for cases in which the tumour was completely resected, risk of relapse was determined using the afip-miettinen criteria incorporating tumour size, mitotic rate and site as prognostic factors.7 subsequently, the nih criteria was utilised for the purposes of comparative stratification with regional data, with patients subcategorised into four risk groups based on tumour size and mitotic activity.4 kaplan-meier curves were used to estimate survival rates, with os calculated from the date of diagnosis to the date of death or last follow-up. the data cut-off point was the end of april 2019. a logrank test was used for the purposes of comparative analysis. this study was approved by the individual institutional ethical committees of all three hospitals. results over the 15-year study period, a total of 44 patients were diagnosed with gists and treated at the three referral centres. of these, 19 (43.2%) were male and 25 (56.8%) were female. the median age at diagnosis was 55.5 years (range: 26–83 years). the majority of patients presented with abdominal pain (81.8%; n = 36), git bleeding (47.7%; n = 21) or constitutional symptoms (29.5%; n = 13) such as fever, weakness and weight loss. the most common primary site of the tumour was the stomach (63.6%) followed by the jejunum/ileum table 1: clinicopathological characteristics of patients diagnosed with gastrointestinal stromal tumours over a 15-year period at three tertiary referral centres in muscat, oman (n = 44) characteristic n (%) gender male 19 (43.2) female 25 (56.8) age in years mean ± sd 55.5 ± 13.1 range 26–83 site of primary tumour stomach 28 (63.6) jejunum/ileum 8 (18.2) duodenum 4 (9.1) rectum 3 (6.8) extraintestinal 1 (2.3) histological subtype spindle cell 26 (59.1) epithelioid 2 (4.5) mixed 16 (36.4) disease extension localised 24 (54.5) metastatic 20 (45.5) risk category* none 2 (8.3) very low 4 (16.7) low 5 (20.8) moderate (intermediate) 4 (16.7) high 8 (33.3) unknown 1 (4.2) sd = standard deviation. *including only those patients with localised disease. risk stratification was performed using the armed forces institute of pathology-miettinen criteria.7 zainab al-maqrashi, ikram burney, kadhim m. taqi, yaqoob al-sawafi, asim qureshi, ritu lakhtakia, itrat mehdi, bassim al-bahrani, shiyam kumar and mansour al-moundhri clinical and basic research | e239 (18.2%). one patient (2.3%) had an extraintestinal gist. in addition, one patient had underlying neurofibromatosis type i, while another had concomitant colon cancer. overall, 24 (54.5%) and 20 (45.5%) patients presented with localised and metastatic disease, respectively [table 1]. the majority of tumours were of the spindle cell type (59.1%; n = 26). tumours ranged in size from 2–29 cm, with 29 patients (65.9%) having tumours of >5 cm in its greatest dimension. a total of 42 patients (95.5%) had cd117-immunoreactive disease. the remaining two cases (4.5%) were negative for cd117 but positive for dog-1. the most common sites of metastases were the liver (n = 18; 90%), peritoneum (n = 7; 35%), lungs (n = 4; 20%) and skeleton (n = 2; 10%). out of the 20 patients diagnosed with metastatic disease, six (30%) had progressive disease; of these, four had mutations on exon 11 and one on exon 9. the remaining patients had underlying neurofibromatosis and was diagnosed with wild-type disease. of the patients who presented with localised disease, two (8.3%) received neoadjuvant imatinib and both responded to the treatment, subsequently allowing for wedge resection of the stomach. a total of 14 patients (58.3%) received adjuvant imatinib according to the guidelines, whereas eight (33.3%) were diagnosed before 2009 and treated using an expectant approach. among the patients presenting with metastatic disease, all but one (95%) received palliative treatment using imatinib. the only patient who did not receive imatinib presented with a score of 4 on the eastern cooperative oncology group/world health organization performance status scale and died within a week of diagnosis.17 table 2: management of patients diagnosed with gastro intestinal stromal tumours and treated surgically over a 15-year period at three tertiary referral centres in muscat, oman (n = 34) primary site of tumour/ type of surgery disease extension, n (%) localised* (n = 24) metastatic† (n = 10) upper git wedge resection/excision 11 (45.8) 2 (20) partial gastrectomy 3 (12.5) 0 (0) subtotal/total gastrectomy 3 (12.5) 2 (20) small intestine resection and anastomosis 5 (20.8) 3 (30) rectum hartman’s procedure 0 (0) 2 (20) abdominoperineal resection 0 (0) 1 (10) multivisceral resection (gastric: distal gastrectomy with cholecystectomy and gastrojejunostomy; duodenal: whipple’s procedure) 2 (8.3) 0 (0) *treated using curative resection. †only those treated with palliative surgery. figure 1: kaplan-meier curves showing (a) progression-free survival and (b) overall survival among patients diagnosed with gastrointestinal stromal tumours over a 15-year period at three tertiary referral centres in muscat, oman (n = 44). figure 2: kaplan-meier curves showing (a) progression-free survival and (b) overall survival according to disease extension among patients diagnosed with gastrointestinal stromal tumours over a 15-year period at three tertiary referral centres in muscat, oman (n = 44). clinicopathological features and outcomes of gastrointestinal tumours in oman a 15-year multi-centre study e240 | squ medical journal, may 2021, volume 21, issue 2 out of the 19 patients treated with imatinib, 11 (57.9%) were still being treated at the time of the data cut-off point and eight (42.1%) relapsed after a mean of 55 months and were switched to second-line treatment with either high doses of imatinib (n = 4; 50%) or sunitinib (n = 4; 50%). in addition to palliative systemic treatment, 10 metastatic patients (50%) underwent palliative surgical resection of the primary tumour site due to either bleeding or obstruction [table 2]. overall, the 100-month pfs and os rates were 77.4% and 80.4%, respectively [figure 1]. for patients with localised and metastatic disease, os rates were 89.9% and 80.2%, respectively [figure 2]. among patients with localised disease, the os rate for those with very low or low risk of relapse was 100%, dropping to 81% for those at intermediate or high risk [figure 3]. discussion to the best of the authors’ knowledge, this is the first study to report the long-term outcomes of gist cases in oman. in total, 44 patients were diagnosed with gists and followed-up over a 15-year period at the three main tertiary referral centres in oman. this likely constitutes the vast majority of national gist cases during this period, given that these centres receive cancer referrals from all over the country. overall, 24 patients presented with localised disease and underwent complete resection, followed by adjuvant treatment according to institutional guidelines, while 19 patients who presented with metastatic disease table 3: studies assessing overall survival and risk of relapse among patients with gastrointestinal stromal tumours13–16,18–22 author and year of publication country sample size metastatic at presentation, n (%) mean age in years ± sd (range) risk of relapse*, n (%) os rate in % (period)very low low intermediate high makar et al.13 (2002) kuwait 26† 54.0 ± 12.2 (25–80) 2 (9.5)‡ 6 (28.6)‡ 2 (9.5)‡ 11 (52.4)‡ barakat et al.14 (2010) jordan 42 3 (7.1) 53 2 (5.1) 6 (15.4) 4 (10.3) 27 (69.2) al hussaini15 (2012) saudi arabia 75 56.5 ± 16.95 (8–90) 12 (16) 25 (33.3) 17 (22.7) 21 (28) al-thani et al.16 (2014) qatar 48 48.4 ± 13.7 0 (0) 0 (0) 18 (37.5) 9 (18.8) 43.8 yacob et al.18 (2015) india 150 (19–79) 73 (48.6)§ 35 (23.3) 42 (28) 86.6% (three-year rate) ud din et al.19 (2015) pakistan 255¶ 51 (16–83) 3 (1.4)// 24 (10.9)// 39 (17.7)// 154 (70)// salem et al.20 (2016) egypt 36 14 (28.9) 52.8 ± 14.4 (17–76) 1 (2.8)** 4 (11.1)** 11 (30.6)** 18 (50.6)** 51 (fiveyear rate) mcdonnell et al.21 (2017) uk 42 68 (43–91) 2 (8) 7 (28) 4 (16) 12 (48) cavaliere et al.22 (2005) italy 22 2 (9.1) 67 ± 10 (47–86) 1 (5) 9 (45) 3 (15) 7 (35) 78.9 (fiveyear rate) present study (2021) oman 44 20 (45.5) 54.2 ± 13.1 (26–83) 2 (8.4) 5 (20.8) 6 (25) 11 (45.8) 80.4 (100 month rate) sd = standard deviation; os = overall survival. *including only those patients with localised disease. risk stratification was performed using the national institutes of health criteria.4 †including five cases (19.2%) diag nosed by core biopsy. ‡percentages were calculated out of 21 cases. §very lowand low-risk categories were combined. ¶including 35 cases (13.7%) diagnosed by core biopsy. //percentages were calculated out of 220 cases. **percentages were calculated out of all cases, not just those with localised disease. figure 3: kaplan-meier curve showing overall survival according to risk category* among patients diagnosed with gastrointestinal stromal tumours over a 15-year period at three tertiary referral centres in muscat, oman (n = 44). *risk stratification was performed using the armed forces institute of pathology-miettinen criteria.7 zainab al-maqrashi, ikram burney, kadhim m. taqi, yaqoob al-sawafi, asim qureshi, ritu lakhtakia, itrat mehdi, bassim al-bahrani, shiyam kumar and mansour al-moundhri clinical and basic research | e241 received imatinib. a comparative analysis of regional and international research concerning gist cases is presented in table 3.13–16,18–22 in the current study, the median age at presentation was 55.5 years. while this finding is consistent with other studies published from countries in south east asia and the middle east, it varies compared to studies from the uk and italy.13–16,18–22 this could be explained by either methodological differences in patient selection or may be reflective of the average age of the local population; however, this remains speculative. the stomach was the primary site of involvement in almost two-thirds of patients in the present study. similarly, miettinen et al. reported the stomach to be the most common primary site (60%) followed by the jejunum and ileum (30%), duodenum (5%) and colorectum (5%), while dematteo et al. reported involvement of the stomach, small intestine and rectum in 50%, 42% and 1% of gist cases, respectively.2,9 the biological behaviour of resected gists are a particular focus of interest worldwide. moreover, with the emergence of risk stratification systems, predictions regarding a patient’s prognosis have become more reliable. initially, tumour size and mitotic figures were used to categorise gist patients into subgroups in terms of risk of relapse; the nih consensus criteria, also known as fletcher’s criteria, uses both parameters to stratify patients into very low, low, intermediate and high-risk groups.4 dematteo et al. suggested that location of the primary tumour be added as an independent factor; however, this has not yet been included in the nih criteria.9 in contrast, the afip criteria, also known as miettinen’s criteria, incorporates this as a prognostic factor.7 patients are categorised into four groups based on tumour size and two groups with regards to mitotic count, while primary tumours are classified into either stomach, duodenum, ileum/jejunum or rectum tumours.10 in 2008, joensuu revised the nih criteria and proposed the inclusion of both tumour site and rupture as high-risk factors.8 several other modifications have been suggested—such as peritoneal dissemination, metastasis and invasion and the mutation status of the c-kit and pdgfr-α genes—as risk stratification criteria continue to evolve.23 in addition, two nomograms have been proposed for the purposes of risk assessment.24,25 in the current study, as data regarding tumour rupture were not available for all patients, the afip-miettinen criteria were used to categorise patients into risk categories.7 nonetheless, according to nih scoring system, among patients with localised disease, seven (29.2%) were at very low to low risk, six (25%) were at intermediate risk and 11 (45.8%) were at high risk of relapse [table 3]. these observations compare favourably with reports from the uk, qatar, kuwait, jordan, egypt and pakistan, but are at variance with reports from saudi arabia and india.13–16,18–21 this discrepancy could be attributed to variations in patient populations, referral patterns or the risk criteria being used. imatinib was approved for use in cd117expressing metastatic gists in 2002; however, the drug was only approved in intermediate-to-high-risk cases in an adjuvant setting in 2008.26 subsequently, in 2012, a confirmatory phase iii trial suggested that patients taking imatinib for 36 months in an adjuvant setting had better five-year os rates compared to those who took the drug for one year (92% versus 82%); furthermore, three-year treatment resulted in a 54% reduction in recurrence and a 55% reduction in risk of death compared to one-year treatment.27 almost all patients with metastatic disease in the present cohort were treated with imatinib; however, patients with completely resected gists did not receive imatinib in an adjuvant setting until 2008. one patient received treatment for 12 months according to available data at the time, with the rest treated for three years according to more recent clinical practice guidelines.28 in the current study, all patients initially received 400 mg of imatinib. according to previous research, there is no difference in survival between patients treated with 400 mg of imatinib compared to 800 mg, except in a subset of patients with exon 9 mutations on the c-kit gene.29 according to recent clinical practice guidelines, 800 mg of imatinib is recommended for patients with metastatic and inoperable disease including those with exon 9 mutations.28 in the present cohort, exon 9 mutations were only identified in a single case. this patient was subsequently treated with 800 mg of imatinib, tolerated the escalated dose and has been in stable remission for the last five years as of the time of writing. following mutational analysis, all four patients with exon 11 mutations were treated with sunitinib and regorafenib as secondand thirdline treatments, respectively. in the current study, the 100-month pfs rate was 77.4%, whereas the os rate was 80.4%, signifying that >80% of patients were alive and free of disease after eight years. overall, 89.9% of those with localised disease survived, as did 80.2% of those who presented with metastatic disease. in terms of risk of relapse, 100-month os rates were 100% for very low to low risk of relapse patients’ group and 81% for those at intermediate to high risk, 100% and 80% for patients in low, intermediate or high-risk categories, respectively. in a cohort of 124 gist patients, of which 47% were high-risk cases, mucciarini et al. reported five-year disease-free survival rates of 94%, 92%, 100% and 40% clinicopathological features and outcomes of gastrointestinal tumours in oman a 15-year multi-centre study e242 | squ medical journal, may 2021, volume 21, issue 2 for patients at very low, low, intermediate and high risk, respectively.30 according to findings from a large intergroup trial, casali et al. reported a median pfs and os duration of 1.7 and 3.9 years, respectively, among 472 patients treated with 400 mg of imatinib daily for metastatic or locally advanced disease.12 although the current study had multiple strengths—such as the involvement of multiple tertiary cancer referral centres, a lengthy follow-up duration of 15 years and the inclusion of almost all gist patients in oman—it was also subject to several limitations. due to the retrospective nature of the study, certain information was not available including the incidence of tumour rupture or bleeding. however, international risk stratification criteria were used, incorporating recognised prognostic factors such as tumour site, size and mitotic count. furthermore, mutational analysis was only performed for those in whom the disease progressed in order to guide subsequent treatment; nevertheless, this is not currently indicated for patients receiving adjuvant imatinib, as it does not affect survival.31 conclusion this study reported the outcomes of localised and metastatic gist cases presenting to three tertiary referral centres in oman over a 15-year period, as well as clinical presentations, risk categories for relapse and pfs and os rates. the presenting features and outcomes of patients with gists in oman were comparable to those reported in the regional and international literature. to the best of the authors’ knowledge, this is the first study to report the longterm outcomes of patients with gists from the middle east and may serve as a benchmark for future studies. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. miettinen m, sarlomo-rikala m, lasota j. gastrointestinal stromal tumors: recent advances in understanding of their biology. hum pathol 1999; 30:1213–20. https://doi.org/10.1016/ s0046-8177(99)90040-0. 2. miettinen m, lasota j. gastrointestinal stromal tumors: pathology and prognosis at different sites. semin diagn pathol 2006; 23:70–83. https://doi.org/10.1053/j.semdp.2006.09.001. 3. miettinen m, lasota j. gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. arch pathol lab med 2006; 130:1466–78. https:// doi.org/10.5858/2006-130-1466-gstrom. 4. fletcher cd, berman jj, corless c, gorstein f, lasota j, longley bj, et al. diagnosis of gastrointestinal stromal tumors: a consensus approach. hum pathol 2002; 33:459–65. https:// doi.org/10.1053/hupa.2002.123545. 5. west rb, corless cl, chen x, rubin bp, subramanian s, montgomery k, et al. the novel marker, dog1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of kit or pdgfra mutation status. am j pathol 2004; 165:107–13. https://doi.org/10.1016/s0002-9440(10)63279-8. 6. janeway ka, kim sy, lodish m, nosé v, rustin p, gaal j, et al. defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking kit and pdgfra mutations. proc natl acad sci u s a 2011; 108:314–18. https://doi.org/10.1073/pnas.10 09199108. 7. miettinen m, sobin lh, lasota j. gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohisto chemical, and molecular genetic study of 1765 cases with longterm follow-up. am j surg pathol 2005; 29:52–68. https://doi. org/10.1097/01.pas.0000146010.92933.de. 8. joensuu h. risk stratification of patients diagnosed with gastrointestinal stromal tumor. hum pathol 2008; 39:1411–19. https://doi.org/10.1016/j.humpath.2008.06.025. 9. dematteo rp, gold js, saran l, gönen m, liau kh, maki rg, et al. tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (gist). cancer 2008; 112:608–15. https://doi. org/10.1002/cncr.23199. 10. rutkowski p, nowecki zi, michej w, debiec-rychter m, woźniak a, limon j, et al. risk criteria and prognostic factors for predicting recurrences after resection of primary gastrointestinal stromal tumor. ann surg oncol 2007; 14:2018–27. https://doi.org/10.1 245/s10434-007-9377-9. 11. joensuu h, fletcher c, dimitrijevic s, silberman s, roberts p, demetri g. management of malignant gastrointestinal stromal tumours. lancet oncol 2002; 3:655–64. https://doi.org/https:// doi.org/10.1016/s1470-2045(02)00899-9. 12. casali pg, zalcberg j, le cesne a, reichardt p, blay jy, lindner lh, et al. ten-year progression-free and overall survival in patients with unresectable or metastatic gi stromal tumors: long-term analysis of the european organisation for research and treatment of cancer, italian sarcoma group, and australasian gastrointestinal trials group intergroup phase iii randomized trial on imatinib at two dose levels. j clin oncol 2017; 35:1713–20. https://doi.org/10.1200/jco.2016.71.0228. 13. makar rr, al-waheeb s, john b, junaid ta. gastrointestinal stromal tumors: clinicopathological and immunohistochemical features. med princ pract 2002; 11:93–9. https://doi.org/10.11 59/000058014. 14. barakat fh, haddad ha, matalka ii, al-orjani ms, al-masri mm, sughayer ma. characteristics of gastrointestinal stromal tumors in a middle eastern population. saudi med j 2010; 31:797–802. 15. al hussaini hf. gist in saudi arabia: multicentric histopath ological genetic study of 75 surgically excised cases. gulf j oncolog 2012; 11:31–7. 16. al-thani h, el-menyar a, rasul ki, al-sulaiti m, el-mabrok j, hajaji k, et al. clinical presentation, management and outcomes of gastrointestinal stromal tumors. int j surg 2014; 12:1127–33. https://doi.org/10.1016/j.ijsu.2014.08.351. 17. oken mm, creech rh, tormey dc, horton j, davis te, mcfadden et, et al. toxicity and response criteria of the eastern cooperative oncology group. am j clin oncol 1982; 5:649–55. https://doi.org/10.1097/00000421-198212000-00014. https://doi.org/10.1016/s0046-8177%2899%2990040-0 https://doi.org/10.1016/s0046-8177%2899%2990040-0 https://doi.org/10.1053/j.semdp.2006.09.001 https://doi.org/10.5858/2006-130-1466-gstrom https://doi.org/10.5858/2006-130-1466-gstrom https://doi.org/10.1053/hupa.2002.123545 https://doi.org/10.1053/hupa.2002.123545 https://doi.org/10.1016/s0002-9440%2810%2963279-8 https://doi.org/10.1073/pnas.1009199108 https://doi.org/10.1073/pnas.1009199108 https://doi.org/10.1097/01.pas.0000146010.92933.de https://doi.org/10.1097/01.pas.0000146010.92933.de https://doi.org/10.1016/j.humpath.2008.06.025 https://doi.org/10.1002/cncr.23199 https://doi.org/10.1002/cncr.23199 https://doi.org/10.1245/s10434-007-9377-9 https://doi.org/10.1245/s10434-007-9377-9 https://doi.org/https://doi.org/10.1016/s1470-2045%2802%2900899-9 https://doi.org/https://doi.org/10.1016/s1470-2045%2802%2900899-9 https://doi.org/10.1200/jco.2016.71.0228 https://doi.org/10.1159/000058014 https://doi.org/10.1159/000058014 https://doi.org/10.1016/j.ijsu.2014.08.351 https://doi.org/10.1097/00000421-198212000-00014 zainab al-maqrashi, ikram burney, kadhim m. taqi, yaqoob al-sawafi, asim qureshi, ritu lakhtakia, itrat mehdi, bassim al-bahrani, shiyam kumar and mansour al-moundhri clinical and basic research | e243 18. yacob m, inian s, sudhakar cb. gastrointestinal stromal tumours: review of 150 cases from a single centre. indian j surg 2015; 77:505–10. https://doi.org/10.1007/s12262-013-0899-z. 19. ud din n, ahmad z, arshad h, idrees r, kayani n. gastrointestinal stromal tumors: a clinicopathologic and risk stratification study of 255 cases from pakistan and review of literature. asian pac j cancer prev 2015; 16:4873–80. https:// doi.org/10.7314/apjcp.2015.16.12.4873. 20. salem aas, elshoieby mh, maximos dw, el-saba tm. gastrointestinal stromal tumors (gists), surgical management and clinical outcome. j cancer ther 2016; 7:319–28. https:// doi.org/10.4236/jct.2016.74034. 21. mcdonnell mj, punnoose s, viswanath yks, wadd nj, dhar a. gastrointestinal stromal tumours (gists): an insight into clinical practice with review of literature. frontline gastroenterol 2017; 8:19–25. https://doi.org/10.1136/flgastro-2015-100670. 22. cavaliere d, griseri g, venturino e, schirru a, cosce u, caristo i, et al. management of patients with gastrointestinal stromal tumors: experience from an italian hospital. tumori 2005; 91:467–71. https://doi.org/10.1177/030089160509100604. 23. takahashi t, nakajima k, nishitani a, souma y, hirota s, sawa y, et al. an enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. int j clin oncol 2007; 12:369–74. https://doi. org/10.1007/s10147-007-0705-7. 24. gold js, gönen m, gutiérrez a, broto jm, garcía-del-muro x, smyrk tc, et al. development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. lancet oncol 2009; 10:1045–52. https://doi.org/10.1016/s1470-2045(09)70242-6. 25. rossi s, miceli r, messerini l, bearzi i, mazzoleni g, capella c, et al. natural history of imatinib-naive gists: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables. am j surg pathol 2011; 35:1646–56. https://doi.org/10.1097/pas.0b013e31822d63a7. 26. demetri gd, von mehren m, blanke cd, van den abbeele ad, eisenberg b, roberts pj, et al. efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. n engl j med 2002; 347:472–80. https://doi.org/10.1056/nejmoa020461. 27. joensuu h, eriksson m, sundby hall k, hartmann jt, pink d, schütte j, et al. one vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. jama 2012; 307:1265–72. https://doi.org/10.1001/jama.2012.347. 28. judson i, bulusu r, seddon b, dangoor a, wong n, mudan s. uk clinical practice guidelines for the management of gastrointestinal stromal tumours (gist). clin sarcoma res 2017; 7:6. https://doi.org/10.1186/s13569-017-0072-8. 29. gastrointestinal stromal tumor meta-analysis group (metagist). comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. j clin oncol 2010; 28:1247–53. https://doi.org/10.1200/jco.2009.24.2099. 30. mucciarini c, rossi g, bertolini f, valli r, cirilli c, rashid i, et al. incidence and clinicopathologic features of gastrointestinal stromal tumors: a population-based study. bmc cancer 2007; 7:230. https://doi.org/10.1186/1471-2407-7-230. 31. corless cl, ballman kv, antonescu cr, kolesnikova v, maki rg, pisters pw, et al. pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary gi stromal tumor: the acosog z9001 trial. j clin oncol 2014; 32:1563–70. https://doi.org/10.1200/ jco.2013.51.2046. https://doi.org/10.1007/s12262-013-0899-z https://doi.org/10.7314/apjcp.2015.16.12.4873 https://doi.org/10.7314/apjcp.2015.16.12.4873 https://doi.org/10.4236/jct.2016.74034 https://doi.org/10.4236/jct.2016.74034 https://doi.org/10.1136/flgastro-2015-100670 https://doi.org/10.1177/030089160509100604 https://doi.org/10.1007/s10147-007-0705-7 https://doi.org/10.1007/s10147-007-0705-7 https://doi.org/10.1016/s1470-2045%2809%2970242-6 https://doi.org/10.1097/pas.0b013e31822d63a7 https://doi.org/10.1056/nejmoa020461 https://doi.org/10.1001/jama.2012.347 https://doi.org/10.1186/s13569-017-0072-8 https://doi.org/10.1200/jco.2009.24.2099 https://doi.org/10.1186/1471-2407-7-230 https://doi.org/10.1200/jco.2013.51.2046 https://doi.org/10.1200/jco.2013.51.2046 submitted 10 jun 21 1 revision req. 16 aug 21; revision recd. 16 sep 21 2 accepted 21 oct 21 3 online-first: jan 2022 4 doi: https://doi.org/10.18295/squmj.1.2022.011 5 6 leukocytoclastic vasculitis 7 a peculiar presentation of scrub typhus 8 anila vasireddy, 1 kanthilatha pai, 2 varsha m. shetty, 3 raviraja v. acharya, 4 9 ramamoorthi k., 4 akhila doddamani, 5 *sharath madhyastha p. 4 10 11 departments of 2 pathology, 3 dermatology, 4 medicine and 5 community medicine, 1 kasturba 12 medical college, manipal academy of higher education, manipal, india 13 *corresponding author’s e-mail: dr.sharathymc@gmail.com 14 15 abstract 16 scrub typhus is a disease endemic to the indian subcontinent caused by the obligate intracellular 17 pleomorphic organism, orientia tsutsugamushi. scrub typhus among other acute febrile illnesses 18 present with prodromal symptoms of fever, malaise, myalgia, anorexia followed by a distinct 19 maculopapular rash, hepatosplenomegaly, and lymphadenopathy. in this case report, we present 20 a patient who developed a rare cutaneous vasculitis secondary to infection with orientia 21 tsutsugamushi. after performing the weil felix test, a diagnostic titer of 1:640 against ox-k 22 was obtained. furthermore, a skin biopsy was carried out which confirmed the diagnosis of 23 leukocytoclastic vasculitis. the patient was treated with doxycycline and showed a drastic 24 improvement in his symptoms. 25 keywords: scrub typhus, rickettsia; vasculitis; doxycycline. 26 27 introduction 28 scrub typhus is a disease endemic to the indian subcontinent caused by the obligate intracellular 29 pleomorphic organism, orientia tsutsugamushi. this organism is transmitted naturally through 30 mailto:dr.sharathymc@gmail.com the leptotrombidium mite population and is accidentally acquired in humans via the bite of a 31 mite as a dead-end host. scrub typhus among other acute febrile illnesses present with prodromal 32 symptoms of fever, malaise, myalgia, anorexia followed by a distinct maculopapular rash, 33 hepatosplenomegaly, and lymphadenopathy. rarely, it can even progress to septic shock/multi-34 organ failure. as in every disease, scrub typhus can have some peculiar manifestations. there 35 have been previous case studies reporting features of hemophagocytic syndrome, 1 epididymo-36 orchitis, 2 acute severe monoarthritis, 3 and guillain barre syndrome. 4 in this case report, we 37 present a patient who developed a rare cutaneous vasculitis in setting of orientia tsutsugamushi 38 infection with good response to doxycycline. 39 40 case report 41 a 28-year-old man farmer presented with high grade, intermittent fever (102°f), vomiting and 42 generalized muscle pain to a local primary center and was treated with antipyretics. four days 43 later, the patient developed multiple palpable purpuric eruptions predominantly affecting the 44 lower limbs. thereafter, the patient was subsequently transferred to our tertiary care hospital in 45 2021. 46 47 on examination, the patient’s vital signs were stable and he was afebrile when he presented to 48 our hospital. skin examination revealed multiple palpable purpuric eruptions arranged in a 49 retiform pattern with a dusky necrotic center and peripheral rim of erythema distributed 50 symmetrically over bilateral lower limbs [figure 1a-1c]. the mucosa, palms and soles were 51 spared. the rest of the systemic examination was deemed to be normal. 52 a panel of laboratory investigations were carried out to determine the etiology [table 1]. a 53 routine urinalysis was unremarkable, confirming no renal involvement. antinuclear antibody 54 (ana) and antineutrophil cytoplasmic antibodies (anca), serum c3 and c4 complement levels 55 were negative, making vasculitis due to autoimmune inflammatory disorders less likely. 56 57 this constellation of findings is unique to acute febrile illnesses. therefore, a panel of serum 58 studies were performed to determine the organism. subsequently, leptospirosis, dengue (ns1 ag 59 & anti-dengue igm), malaria, and hepatitis b & c were ruled out. 60 61 however, a weil felix test (wft: tube agglutination) was performed and a diagnostic titer of > 62 1:640 against ox-k was obtained. the skin biopsy done from the lesion revealed necrotizing 63 vasculitis [figure 2]. in most cases, a skin biopsy is not routinely performed if clinical and 64 serological criteria for scrub typhus are met. however, due to the rare manifestation of this 65 disease, a skin biopsy was done in order to rule out other etiologies of vasculitis in the patient. 66 hence, the patient was treated with doxycycline 100 mg twice daily. on day 3, improvement of 67 the vasculitis and other symptoms were noticeable [figure 1b] and the patient was discharged on 68 day 7 with an additional week of doxycycline 100 mg twice daily. the patient followed up three 69 weeks later with a significant improvement in his lesions [figure 1d]. the patient provided 70 informed consent to the publication of this case. 71 72 discussion 73 scrub typhus is a common cause of pyrexia of unknown origin in india due to its nonspecific 74 clinical features. it is caused by the organism o. tsutsugamushi which was previously classified 75 under the genus rickettsia. however, due to different phenotypic and genotypic features, the 76 organism has its own separate genus. in fact, it is a component of the tsutsugamushi triangle 77 formed by northern japan/east russia (north), afghanistan/pakistan (west), and northern 78 australia (south). 5 there are three strains of orientia tsutsugamushi namely karp, gilliam, and 79 kato strains. infection with one particular strain does not confer immunity to infection with 80 another strain. 5 81 82 the organism enters the human body via the bite of a chigger (trombuculid mite) where it 83 multiplies and then disseminates through the blood and lymph. at the site of inoculation, 84 necrosis of the skin occurs forming a black eschar, which is typical of scrub typhus. however, in 85 the indian subcontinent, a necrotic eschar can only be detected 10% of the time due to darker 86 skin complexions of the majority of the population and bites located in hidden areas. hence, 87 serology or a high degree of clinical suspicion based on epidemiological data must be used to 88 guide the diagnosis. 5 89 90 scrub typhus usually targets a specific population encompassing rural populations predominantly 91 involved in agriculture and those who engage in poor protective personal habits. moreover, 92 overcrowding plays a huge role in dissemination of the disease as rodents often act as amplifiers 93 of infection. 94 95 o. tsutsugamushi breaches the endothelial cell barrier creating vascular and perivascular lesions 96 that ultimately cause vascular leakage and end-organ damage to multiple organs in the body. 6 97 once the organism successfully evades the innate human host defenses, various cytokines such 98 as tnf-α, ifn-γ, and m-csf are produced that results in the multitude of symptoms 99 experienced by the patient. both humoral and cellular immunity play a role in combating this 100 organism. it involves the production of antibodies against o. tsutsugamushi which can be 101 detected by the wft and activation of macrophages and helper t cells (th1) which secrete ifn-102 γ. 6 103 104 the pathophysiology of o. tsutsugamushi causing widespread endothelial damage involves 105 disruption of the adherens junction of the endothelial cells. this results in increased vascular 106 permeability, formation of inter-endothelial gaps, development of actin stress fibers, and change 107 in the shape of the endothelial cells from polygonal to a spindle form. 7 furthermore, there is also 108 increased vascular expression of nitric oxide and cox-2 expression by the endothelial cells, 109 resulting in the production of prostaglandins. 8 in addition, o. tsutsugamushi multiplies within the 110 endothelial cells and via oxidative stress, destroys the integrity of the blood vessels. 13 this can 111 be established by immunohistochemical staining of endothelial cells which demonstrates rich 112 deposits of the o. tsutsugamushi antigens. 14 113 114 scrub typhus can present with a few dermatological manifestations that can overlap with other 115 acute febrile diseases. the typical erythematous maculopapular rash and necrotic eschar can 116 point to a diagnosis of scrub typhus, especially in an area of high endemicity. moreover, the site 117 of the rash can help differentiate between rickettsial diseases. a maculopapular rash distributed 118 across the trunk, sparing the face, palms and soles makes rickettsial spotted fevers an unlikely 119 diagnosis. 12 other tropical diseases with a similar dermatological presentation include dengue, 120 leptospirosis, enteric fever, malaria, and melioidosis. 9 121 122 infectious causes of leukocytoclastic vasculitis are most commonly viral in origin such as 123 hepatitis b (polyarteritis nodosa), hepatitis c (mixed cryoglobulinemia), cytomegalovirus, or 124 parvovirus b19. 13 parasites, bacteria, rickettsia are lesser known culprits of systemic vasculitis. it 125 is paramount to determine the underlying cause of the vasculitis, as this governs the treatment 126 regimen. 13 127 128 the organism is mainly confined to the reticuloendothelial system resulting in 129 hepatosplenomegaly and generalized lymphadenopathy along with other features like fever, 130 myalgia, and a centripetally-distributed maculopapular rash. complications include acute 131 respiratory distress syndrome, acute renal failure, disseminated intravascular coagulation, 132 meningoencephalitis, myocarditis, pericarditis, and acute hearing loss. it is imperative that 133 serology be done in order to ascertain proper treatment. 9 134 135 wft is a heterophile agglutination test that can be used to diagnose scrub typhus infection. this 136 test relies on the principle that an antibody triggered by a particular antigen can cross-react with 137 antigens of other species. in this test, antibodies produced by o. tsutsugamushi cross-react with 138 the antigen ox-k of proteus mirabilis. in our patient, we received a titer of 1:640 which is 139 above the diagnostic titer of 1:320. 15 wft only tests positive during the 2nd week of illness and 140 has a low sensitivity and specificity as compared to the indirect fluorescent antibody (ifa) test 141 and indirect immunoperoxidase (iip) test. even though ifa/iip are more accurate and precise, 142 wft is used because of its cost-effective and swift results. 10 a recent case report was published 143 linking a case of henoch-schönlein purpura to scrub typhus which used indirect 144 immunofluorescence to confirm the diagnosis (igm antibody: 1:1024). this is an accurate and 145 precise tool to corroborate the etiology. 16 146 147 the current guidelines for the treatment of scrub typhus include doxycycline 100 mg twice daily. 148 alternatives such as chloramphenicol, azithromycin, tetracycline, and rifampicin can be used as 149 second-line options. treatment with doxycycline renders the patient afebrile within 48 hours. 150 due to the rarity of the necrotic eschar in the indian population and nonspecific clinical features, 151 a delay in the start of treatment increases the risk of developing complications and causing 152 irreversible damage. as a result, empirical therapy with doxycycline should be started without 153 delay if there is a high degree of clinical suspicion. 11 154 155 conclusion 156 scrub typhus remains to be a common zoonotic disease in the indian subcontinent which is often 157 misdiagnosed or underdiagnosed. this may be due to overlapping clinical features of other 158 tropical diseases, lack of highly sensitive and specific equipment for diagnosis in endemic areas, 159 or delay in presentation. cutaneous vasculitis secondary to o. tsutsugamushi is an unusual 160 manifestation of this disease and should be considered in endemic areas to avoid delay in 161 treatment. 162 163 authors’ contribution 164 av, rva and smp conceptualized the report. kp provided the pathology report of the skin 165 biopsy. vms analysed the skin findings and performed the skin biopsy. av drafted the 166 manuscript writing. rva, rk, ad and smp reviewed the manuscript and provided intellectual 167 input. all authors approved the final version of the manuscript. 168 169 references 170 1. lin m, huang a, zheng x, ge l, he s. misdiagnosis of scrub typhus complicated by 171 hemophagocytic syndrome. bmc pediatr. 2019 apr 10;19(1):102. doi: 10.1186/s12887-019-172 1475-x. pmid: 30971222; pmcid: pmc6458710. 173 2. shanmugapriya v, sangeetha da, sampath s, kasthuri rk. epididymo-orchitis: a rare 174 manifestation of scrub typhus in a child. j vector borne dis. 2014 mar;51(1):69-70. pmid: 175 24717207. 176 3. handattu k, bhat yellanthoor r, konda kc, kini s. acute severe monarthritis: a rare 177 manifestation of scrub typhus. bmj case rep. 2018 dec 3;11(1):bcr2018227002. doi: 178 10.1136/bcr-2018-227002. pmid: 30567173; pmcid: pmc6301600. 179 4. sawale vm, upreti s, singh ts, singh nb, singh tb. a rare case of guillain-barre 180 syndrome following scrub typhus. neurol india. 2014 jan-feb;62(1):82-3. doi: 181 10.4103/0028-3886.128340. pmid: 24608469. 182 5. chogle ar. diagnosis and treatment of scrub typhus--the indian scenario. j assoc 183 physicians india. 2010 jan;58:11-2. pmid: 20649092. 184 6. chakraborty s, sarma n. scrub typhus: an emerging threat. indian j dermatol. 2017 sep-185 oct;62(5):478-485. doi: 10.4103/ijd.ijd_388_17. pmid: 28979009; pmcid: pmc5618834. 186 7. valbuena g, walker dh. infection of the endothelium by members of the order 187 rickettsiales. thromb haemost. 2009 dec;102(6):1071-1079. doi: 10.1160/th09-03-0186. 188 pmid: 19967137; pmcid: pmc2913309. 189 8. praveen kumar as, prasad am, gumpeny l, siddappa r. leukocytoclastic vasculitis and 190 polyarthralgia in scrub typhus: an unusual presentation. int j med public health 2013;3:352-191 4. 192 9. wang cc, liu sf, liu jw, chung yh, su mc, lin mc. acute respiratory distress 193 syndrome in scrub typhus. am j trop med hyg. 2007 jun;76(6):1148-52. pmid: 17556627. 194 10. janardhanan j, trowbridge p, varghese gm. diagnosis of scrub typhus. expert rev anti 195 infect ther. 2014 dec;12(12):1533-40. doi: 10.1586/14787210.2014.974559. epub 2014 oct 196 31. pmid: 25359599. 197 11. mahajan sk. scrub typhus. j assoc physicians india. 2005 nov;53:954-8. pmid: 16515236. 198 12. rajagopal r, khati c, vasdev v, trehan a. scrub typhus: a case report. indian j dermatol 199 venereol leprol 2003:69:413-415 200 13. suja l, krishnamoorthy s, sathiyan s, siyanandam s, koushik ak. scrub typhus vasculitis 201 causing pan digital gangrene int j case rep images 2015;6(7):416-421. 202 14. kim dm, park cj, lim sc, park kh, jang wj, lee sh. diagnosis of scrub typhus by 203 immunohistochemical staining of orientia tsutsugamushi in cutaneous lesions. am j clin 204 pathol. 2008 oct;130(4):543-51. doi: 10.1309/x17hnnjkmyght4hp. pmid: 18794046. 205 15. cox al, tadi p. weil felix test. [updated 2021 may 9]. in: statpearls [internet]. treasure 206 island (fl): statpearls publishing; 2021 jan-. available from: 207 https://www.ncbi.nlm.nih.gov/books/nbk559225/ 208 16. im, j.h., choi, s.j., chung, mh. et al. a case of henoch-schönlein purpura associated with 209 scrub typhus. bmc infect dis 20, 286 (2020). https://doi.org/10.1186/s12879-020-05001-x 210 211 212 213 https://www.ncbi.nlm.nih.gov/books/nbk559225/ table 1: laboratory investigations. 214 lab investigation value normal range haemoglobin (g/dl) 13.1 13–17 platelet count (cells/µl) 2,00,000 1,50,000–4,00,000 white blood cell count (cells/µl) 15,300 4,000–11,000 aspartate transaminase (iu/l) 69 5–40 alanine transaminase (iu/l) 274 5–40 alkaline phosphatase (u/l) 78 40 – 130 erythrocyte sedimentation rate (mm/hr) 2 0–22 c-reactive protein (mg/l) 40.92 0–5 215 216 217 figure 1: clinical image showing multiple, palpable purpuric lesions arranged in a retiform 218 pattern with a dusky necrotic center and peripheral rim of erythema distributed symmetrically 219 over bilateral lower limbs on day 1 (a) and day 3 (b). a close-up view of skin lesion over the 220 left leg on day 1 (c) and a significant improvement in his lesions on day 21 (d) 221 222 223 figure 2: photomicrograph (h&e), (a: x 100) shows dermis with prominent vasculo-centric 224 infiltrate. (b: x 200) shows vessels showing fibrinoid necrosis of vessel walls, dense infiltration 225 of vessel walls by neutrophils with leukocytoclasis. 226 fluctuating antibody response in a cohort of hepatitis patients 33 fluctuating antibody response in a cohort of hepatitis c patients *said h s al dhahry1, shahina daar2, jameel c nograles1, situsekara m w w b rajapakse1 fadhila s s al toqi1, geraldine z kaminski1 abstrac t. objective: this project was designed to longitudinally study persons who had antibodies to hepatitis c virus (hcv) to characterise the serologic course of infection. methods: the subjects were 149 multitransfused patients (141 with thalassaemia major, 3 with thalassaemia intermedia, and 5 with sickle cell anaemia) who had been regularly followed up for 3 to 7 years. sequential serum samples obtained semi-annually between january 1994 and january 2001 were tested, prospectively, by second or third generation hcv enzymelinked immunosorbent assay (elisa), followed by confirmatory recombinant immunoblot assay (riba-2 or riba-3). results: of the 149 patients, 90 did not seroconvert to hcv, whereas 59 had detectable antibodies. on the basis of riba results in these 59 patients, 24 (41%) had persistent high antibody levels to structural and non structural hcv antigens, 11 (19%) had persistent low antibody levels, 17 (29%) showed fluctuating antibody levels, and in 5 patients (8%) there was a total or a partial disappearance of specific antibodies (seroreversion), mainly anti-core antibodies. two patients (3%) had antibody responses that did not fit into any of these four categories. in patients with fluctuating antibody levels, there were periods ranging from 6 months to 2 years when anti-hcv antibodies could not be detected. conclusion: this study shows that the antibody response to hcv in patients who receive frequent blood transfusions is very variable. individuals who exhibit intermittent seropositivity are a challenge to diagnosis. key words: thalassaemia, antibody response, hepatitis c virus departments of 1microbiology and immunology, and 2haematology, sultan qaboos university hospital, p o box 38 , al khodh, muscat 123, sultanate of oman. *to whom correspondence should be addressed. email: dhahrys@omantel.net.om hepatitis c virus (hcv), the major cause of parenterally-transmitted and community-acquired non-a, non-b hepatitis, was cloned in 989.1 the medical importance of hcv resides in its propensity to persist. in the general population, persistent infection leads to chronic hepatitis in 50–80% of patients, often accompanied by an increase in serum transaminase levels.2–4 chronic hcv infection affects an estimated 70 million individuals worldwide with the majority of countries reporting a prevalence of .0– 5.5%.5,6 however, in patients with haemoglobinopathies such as thalassaemia major, the prevalence of hepatitis c is high. before the introduction of routine screening of donated blood for hcv antibody, these patients were at high risk of exposure to the virus as a result of frequent transfusions with packed red blood cells. the reported prevalence in thalassaemics varied geographically from 23% to 72%.7 following the discovery of hcv genome, a variety of diagnostic tests based on detection of anti-hcv antibodies have been developed and refined. three generations of enzyme-linked immunosorbent assay (elisa) have been developed using recombinant and peptide antigens derived from different regions of hcv genome squ journal for scientific research: medical sciences 2002, vol. 4, no. –2, 33–38 ©sultan qaboos universit y arabic abstract said al dhahry hepatitis c (new �� �� ����) ������� ����� ������ ������ ������� �������� ��������)�( ������ �� ���� ��� ������ ������� �������� �������� ����� ����������� ,���������� ,���������� ,����������������� ,����������� ,�������� �������� �������� :��� ������� ����� ������ ������ ����� ����� ����� ������� �������� �������� �����)� .(�������:���� ������������� ���������� ������ ����������� �������� �������� ����������� ������������ ���� ���� ���� .���� ������ �� ��� ��� ������ ����� �������–������ .�� ������ ����� ������� �������� �������� ���� ���� ��� �� ����� ��� ������� ��� �� ������ ������������������ ��� �������� ����� ����� �� ��� ������ ��� �������� �.�������:��� ����������������� ������� ����������� ����������� �������������� ����� ������ .����� ����� ������ ����������)�� (%������� ������ �������� ������� ������ �� ����� ������� ����� .����������)�� (%������� ����������� ���� �������������������������)�� (% ������ ����� ��� ���� ����� ������ ������� .���������)� (%������ ����� ��������������� ������� �������� �������� . ������)�(%�� ����������������� �������� ������ �� �� ������ � ���� ����� ������.������:������������ �������� �� ����� ��� ������� ����� ������ ������ �������)� (������ �� ���� ��� ����� ��� ���� �������. 34 (figure ). each new generation provided incremental improvements in sensitivity to anti-hcv. in high prevalence populations, such as patients with chronic liver disease, third generation elisas have high sensitivity and specificity. unfortunately, they have suboptimal sensitivity and specificity in low prevalence populations, such as blood donors.8 thus, to confirm the presence of hcv antibodies, immunoblot assays were developed in parallel with elisas. the current (third) generation of recombinant immunoblot assay (riba) detects antibodies to four hcv antigens (figure ). although elisa and riba are useful in the diagnosis of hcv infection, the presence of antibodies which they detect does not necessarily mean that the virus is present. detection of hcv rna by polymerase chain reaction (pcr) can differentiate between ongoing and resolved infection. further, pcr is useful in assessing the antiviral response to therapy, and can help resolve weakly positive or negative antibody test results when clinical signs and/or risk factors are compatible with hcv infection. the table compares two generations of elisa and riba with hcv pcr in subjects at lowand high-risk for hcv infection since hcv has been identified only recently, little is known either about the natural history of infection, or about the mechanisms associated with the immunologic responses to it. the number of long-term sequential evaluations of viraemia and of anti-hcv immune response has been limited. thus we undertook a prospective, seven-year study of serological markers of hcv infection in multitransfused patients treated at sultan qaboos university hospital (squh) to establish antibody patterns in these subjects. p a t i e n t s a n d m e t h o d s patients. from january 994 to january 200, a total of 236 patients (27m, 09f) with haemoglobinopathies were treated in the department of haematology of sultan qaboos university hospital. their ages at entry into the study ranged from 6 months to 40 years (median 6.5). among these patients, 29 had thalassaemia major, 9 had thalassaemia intermedia, and 8 had sickle cell disease. the diagnosis of haemoglobinopathy had been made on the basis of family histories, cell counts, and haemoglobin electrophoresis. all the patients were routinely transfused with packed red blood cells (generally every 4 weeks in patients with thalassaemia major) and were followed up at the day care centre of squh. at approximately 6-month intervals, blood samples were collected at the time of routine visit before transfusion. serum samples were separated from whole blood within 3 hours after venipuncture, and were kept at +4º c if testing was carried out within 24 hours of collection, or at –20º c if they were to be tested at a later date. detection of serum hcv antibodies. serum samples structural non-structural core envelope helicase & protease rna polymerase 5’— c e1 e2 ns2 ns3 ns4 ns5 — 3’ 5-5-1 c22 c33 c100 ns5 figure 1. organization of hepatitis c virus genome and location of antigens licensed for diagnostic use. — a l d h a h r y e t a l table 1. riba and pcr testing in anti-hcv (elisa) positive blood donors and patients with suspected viral hepatitis c population study population generation elisa /riba number elisa positive riba %pcr positive in riba % posα %indβ %negδ pos ind neg blood donors9 2/2 340 23 38 39 84 6 0 blood donors10 2/2 1105 17 38 45 75 2 ndφ blood donors11 2/3 750 37 29 35 80 1 0 patients10 2/2 283 79 11 10 90 68 nd patients12 3/3 114 46 34 20 100 46 0 patients13 3/3 54 94 6 0 94 0 0 αpositive, βindeterminate, δnegative, φno data 35 were screened by an enzyme-linked immunosorbent assay (elisa). to assess the specificity of the elisa, a confirmation recombinant immunoblot assay (riba) was performed on positive sera. between 994 and 996, second generation elisas (abbott hcv eia, abbott imx hcv, or abbott axsym hcv, abbott diagnostics division, germany) and riba (chiron corp. emeryville, california) were used. these assays contain antigens figure 3. persistent low levels of antibodies to hepatitis c virus antigens in a patient who was followed over a six-year period figure 2. six and half years’ follow-up in a thalassaemic patient, showing persistently high levels of antibodies to hepatitis c virus antigens a n t i b o d y r e s p o n s e i n h e pat i t i s c pat i e n t s 36 coded by the structural gene (core) and non-structural genes (ns3 and ns4) of hcv (figure ). third generation elisa (abbott axysm hcv 3.0, abbott diagnostics division, germany) and riba (chiron corp., emeryville or genelabs diagnostics, singapore) contain an extra antigen from the ns5 region of hcv genome (figure ); they were used from 997 to 200. as instructed by the manufacturer, the intensity of each band in the riba was rated from 0 to 4+. results were interpreted as positive, indeterminate or negative based on the intensity and distribution of the bands. the riba score of each band was a measure of the level of antigen-specific antibody in the sample. detection of human immunodeficiency virus (hiv): testing for hiv antibodies was performed by elisa (abbott diagnostics, germany) with confirmatory western blot assays (novopath hiv- from biorad, or new lavblot i from diagnostics pasteur, for hiv- and new lavblot ii, from diagnostics pasteur for hiv-2). r e s u l t s when tested by second or third generation elisa, 39 (59%) patients had no detectable anti-hcv antibodies at any time during the study period, whereas 97 (4%) patients were seropositive. of this total of 236 patients, 49 had been followed up for 3 to 7 years (mean 6.5), and had serum samples collected and tested every six months. data of these patients were analysed further to establish antibody responses to hcv. of the 49 patients, 90 (89 with thalassaemia major,  with thalassaemia intermedia) did not seroconvert to anti-hcv during the study period. fifty nine patients (52 thalassaemia major, 2 thalassaemia intermedia, 5 sickle cell disease) had detectable anti-hcv antibodies when tested by second or third generation elisa and riba. on the basis of riba results, four serological patterns were observed. twenty four out of 59 patients (4%) had persistently elevated antibody levels, with riba scores of 3+ or 4+ to structural and non structural hcv antigens. figure 2 shows data of one such patient. eleven patients (9%) had low antibody levels, with riba scores of 2+ for nearly all hcv antigens throughout the study period. samples from these patients were weakly positive or indeterminate (figure 3). in 7 patients (29%), there were wide fluctuations in antibody levels (figure 4). they showed transitions between riba-indeterminate and –positive status interspersed with riba-negative status. some of figure 4. fluctuating levels of antibodies to hepatitis c virus antigens in a atient over a six-year period of follow-up a l d h a h r y e t a l 37 the patients had no detectable antibodies for periods of 6 months to 2 years. there was progressive loss of hcv antibodies (seroreversion) in 5 patients (8%), one of whom lost all hcv antibodies (figure 5). none of these patients was on antiviral therapy for hcv, and none was hiv-infected. serological response in 2 patients did not fit into any of these 4 categories. one patient had low antibody levels for 5 consecutive years followed by a strong antibody response. the second patient, who had been riba-negative for 2 consecutive years, seroconverted in 999, lost all antibodies in 2000, and seroconverted again in 200. d i s c u s s i o n approximately two thirds of our multitransfused patients who were regularly tested for a mean period of 6.5 years did not seroconvert to anti-hcv, strongly suggesting that they did not acquire hcv infection during the study period. in the one third that were seropositive, our data indicate that the antibody response to hcv infection is variable. four serological patterns were observed. most patients (4%) had high antibody levels that were sustained throughout the study period, and 9% had persistent, but low antibody levels. in a similar study in homosexual men, persistent anti-hcv seropositivity was reported in 6 of 26 subjects.14 intermittent seropositivity which we observed relatively frequently could be attributed to reinfection. the possibility of reinfection with hcv arises because of at least two reasons. first, chimpanzee studies have shown that recovery from hcv infection does not confer immunity to the individual.15 second, although screening of blood donations for hcv antibodies has drastically reduced the risk of post-transfusion hepatitis c, a residual risk, mainly linked to viraemic bloods donated by seronegative individuals, persists.5,16 fluctuating hcv serology may be common in the general population.14 it poses a challenge to diagnosis and contributes to the continuing problem of transfusion-associated hepatitis. partial or full seroreversion may be observed in three circumstances: spontaneously, induced by therapy, and in conjunction with hiv infection. in our patients, seroreversion was spontaneous and was probably associated with clearence of infection.17, 18 our findings indicate that spontaneous seroreversion is relatively rare and are in agreement with observations by others. in a longitudinal study lasting 8 years, only 2 of 30 patients with thalassaemia major seroreverted.17.an assessment of 03 transfusion-associated hcv cases 20 years after disease onset revealed that 0% had lost hcv serologic markers18. a n t i b o d y r e s p o n s e i n h e pat i t i s c pat i e n t s figure 5. seroreversion in a patient infected by hepatitis c virus 38 the presence of detectable anti-hcv antibody may reflect a past resolved infection or chronic persistent infection. usually, the majority (≥80%) of riba positives are viraemic.9–13 samples from persons with persistent and intermittent hcv elisa seropositivity are positive by polymerase chain reaction 76% and 50% of the time respectively.14 based on these data, we infer that the antibody responses we observed reflect different dynamics of hcv infection. we have recently started prospective evaluations of viraemia by pcr in parallel with antibody studies to have a better understanding of the natural history of hcv infection and the antibody response to it. c o n c l u s i o n this study clearly shows that the antibody response to hcv infection in patients who receive frequent blood transfusions, such as those with thalassaemia major, is very variable. hcv infection in these patients is not always characterised by a persistent antibody response. a significant proportion may either show intermittent seropositivity, or they may progressively lose antihcv antibodies. this variability in antibody levels poses difficulties in the serological diagnosis of viral hepatitis c. r e f e r e n c e s . choo q-l, kuo g, weiner a, overby l, bradley d, houghton m. isolation of a cdna clone derived from a blood-borne viral hepatitis genome. science, 989, 244, 359–362. 2. van der poel cl, cuypers h t, reesink hw. hepatitis c virus six years on. lancet, 994, 344, 475–479. 3 tong mj, el-farra ns, reikes ar, co rl. clinical outcomes after transfusion-associated hepatitis. n eng j med, 995, 332, 463–466. 4. alter hj, seef lb. recovery, persistence, and sequelae in hepatitis c infection: a perspective on long-term outcome. sem liver disease, 2000, 20, 7–35. 5. herrine sk, weinberg ds. epidemiology of hepatitis c viral infection. infect med, 999, 6, –7. 6. world health organization. hepatitis c global prevalence (update). weekly epidemiol rec, 999, 75, 425–427. 7. de montalembert m, girot r, mattlinger b, lefrere jj. transfusiondependent thalassaemia: viral complications (epidemiology and follow-up). sem haematology, 995, 32, 280–287. 8. schiff er, de medina m, kahn r. new perspectives in the diagnosis of hepatitis c. sem liver disease, 999, 9, 3–5. 9. dow bc, coote i, munro h, mcomish f, yap pl, simmonds p, et al. confirmation of hepatitis c virus antibody in blood donors. j med virol, 993, 4, 25–220. 0. bresters d, zaaijer hl, cuypers htm, reesink hw, winkel in, van exel-oehlers pj, et al. recombinant imunoblot assay reaction patterns and hepatitis c virus rna in blood donors and non-a, non-b hepatitis patients. transfusion, 993, 33, 634–638. . damen m, zaaijer hl, cuypers htm, vrielink h, van der poel cl, reesink hw, et al. reliability of the third-generation recombinant immunoblot assay for hepatitis c. transfusion, 995, 35, 745–749. 2. soffredini r, rumi m, lampertico p, aroldi a,ttarantino a, ponticelli c, et al. increased detection of antibody to hepatitis c virus in renal transplant patients by third generation assays. am j kidney dis, 996, 28, 437–440. 3. courouce am, bouchardeau f, chauveau p, le marrec n, girault a, zins b, et al. hepatitis c virus (hcv) infection in haemodialysed patients: hcv-rna and anti-hcv antibodies (third generation assays). nephrol dial transplant, 995, 0, 234–239. 4. ndimbie ok, nedjar s, kingsley l, riddle p, rinaldo c. longterm serologic follow-up of hepatitis c virus-seropositive homosexual men. clin diag lab immunol, 995, 2, 29–224. 5. farci p, alter hj, govindarajan s, wong dc, engle r, lesniewski rr, et al. lack of protective immunity against reinfection with hepatitis c virus. science, 992, 258, 35–40. 6. sugitani m, inchauspe, shindo m, prince am. sensitivity of serological assays to identify blood donors with hepatitis c viraemia. lancet, 992, 339, 08–09. 7. lefrère jj, guiramand s, lefrère f, mariotti m, aumont p, lerable j, et al. full or partial seroreversion in patients infected by hepatitis c virus. j infect dis, 997, 75, 36–322. 8. seeff lb, hollinger fb, alter hj, wright ec, bales zb, the nhlbi study group. long-term morbidity of transfusionassociated hepatitis (tah) c. hepatology, 998, 28, 407a. a l d h a h r y e t a l december 2007 vol 8 after meeting.indd from hiv abandonment to adoption case study of new life home for abandoned babies, kenya *abdul majid wangai jr, maryam wangai, mary beckenham, clive beckenham sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 239-246 sultan qaboos university© submitted 23th may 2007 accepted 12th september 2007 c l i n i c a l a n d b a s i c r e s e a r c h التبني إلى البشري املناعة نقص فيروس إهمال عالج من املهملني الرضع لألطفال جديد بيت في حياة حالة دراسة بيكنهام كليف واجنبي، ميري بيكنهمام، مرمي آر، جي وجني ايد عبد الرضع اجلديد لرعاية األطفال البيت مهام من . البشري اجلائِحَ املناعة نقص فيروس نتيجة وباء في العالم واملعرضون اليتامى األطفال عدد زاد امللخص: هذا البحث يتحرى عن . للتبني ــة بحاج مما يجعلهم املذكور، للفيروس تعرضهم ــبب بس الغالب في كذلك أصبحوا الذين أو املهملني ، ــى ــن اليتام م رضيعا 490 طفال عن منط التحري في االستعادي التحليل بني . املذكور البيت من إنشاء ونصف سنوات ــع تس ألول ــتنبطة املس الدروس بتوثيق ويقوم ، املنظمة/ للفيروس التعرض ، ــوزن ال البيولوجية ، ، وحتليل املعطيات ــال األطف هؤالء إقامة ونتائج صفات مراجعة حيث متت ــت، البي ــي هذا ف ــوا ادخل الذين ، أو البيت ذلك خارج يتم تبنيه رضيع/رضيعة أي تتابع ال ــة الدراس هذه البيت. في التداخل ونتيجة الطفل ومصير ، احلالة حولت الوكالة التي من (15%) الصحية ، املراكز طريق عن األطفال من (58%) حتويل مت . األصلية باألسر إحلاقهم اعيد الذين أكبر عمرا أو ألطفال بيت إلى نقلوا أو ماتوا يزالون ال رضيعا (92%) 425 هناك كان ــة الدراس في نهاية األخرى. األطفال بيوت من و(25%) ، اليهودية من اجلمعيات (2%) ، احمللية ــلطات الس 45%)) وكان ، <0.003) (احتمالية واضح إحصائي فرق مع ــهر أش ــتة الس ــن س ((%80 منهم دون هناك فكان ماتوا الذين .أما احلياة قيد على والوزن ،<000) (احتمالية للفيروس التعرض إليه: أدت العوامل التي ومن ،1000-/77.6 األطفال وفيات معدل كان للفيروس. بالنسبة موجبا منهم 6 عمر 1.6 – 2في ــبة املعرضني بنس غير أكبر من للفيروس املعرضني األطفال وفيات كان معدل . =0.002) (احتمالية البيت في ــجيل التس عند 12 عمر 1000/94.7 في ، 6 أشهر عمر 1000/71 في املعرضني للفيروس وفيات األطفال معدل كان 18شهرا. و التوالي على ــهرا 12ش و ــهر أش شهرا. عشر اثنا عمر و1000/46.7 في ــهر أش ــتة س 1000/43.3 في عمر املعرضني بينما كان لغير ، ــهرا 18 ش عمر 1000/100.6 في و ــهرا ش تبنيهم مت الرضع األطفال معظم . (22%) وِيّ مَ واإلِنْتانٌ الدَ (56%) االلتهاب الرئوي هو العرضني للفيروس األطفال عند ــي الرئيس الوفاة ــبب س كان حياة . سنا أطفاال أكبر ترعى اخرى بيوت الى حولوا (1.4%) 7 الباقي والقليل األصلية عوائلهم الى 32 منهم أعيد(6.3%) بينما ،(67%) 323 جديدة والبدء بحياة التبني احلصول على ميكنهم املعرضني األطفال ألن غالبية ، األطفال اليتامى واملعرضني لرعاية محتمال مثاال توضح اجلديد البيت نقص فيروس ــار انتش التي يكون األفريقية الصحراء جنوب في دول األطفال مثل هؤالء معضلة لتخفيف وتطبيقها ــتها دراس ميكن الطريقة هذه . . كبيرا املكتسب املناعة ، كينيا. اليتامى املناعة البشري ، نقص : فيروس الكلمات مفتاح new life home, p. o. box 62610, city square, nairobi 00200, kenya, east africa * to whom correspondence should be addressed. email: drmajidwangai@yahoo.co.uk objective: the number of orphaned and vulnerable children (ovc) worldwide has increased as a result of the human immunodeficiency virus (hiv) pandemic. new life home (nlh) specialises in the care of infants who have been orphaned or abandoned, often because of their exposure to hiv and places them for adoption. this paper documents the lessons learnt from the home’s first 8.5 years of existence. methods: this retrospective study analyses the pattern of the 490 infants admitted at nlh. the characteristics of the infants’ stay are analysed: bio-data, weight, hiv exposure, referring organisation/agent and outcome. this study ceased to follow infants after adoption, death, transferral to other homes, or reunion with own family. the infants came via health facilities (58%), local authorities (5%), good samaritans (2%), and other children’s homes (25%). results: at the end of the study period, 425 (92%) of babies were still alive. of those who died, 80% were less than 6 months old (p<0.003) and 45% were hiv positive. a child mortality rate of 77.6/000 was demonstrated with the key associated factors being hiv exposure (p <000), and weight at admission (p=0.002). the mortality rate for the hiv exposed was 7/000 at 6 months, 94.7/000 at 2 months and 00.6/000 at 8 months, while for those not exposed to the virus it was 43.3/000 at 6 months and 46.7/000 at 2 months. the major cause of death in the hiv exposed was pneumonia (56%) and septicaemia (22%). the majority of infants, 323 (67%) were adopted, some were reabsorbed into their biological families 3(6.3%) and a minority 7(.4%) transferred to other children’s homes which cater for older children. conclusion: nlh demonstrates a possible model of care for ovc as majority of vulnerable child can have the opportunity to be adopted and thereby a ‘second lease’ of life. this strategy is worth studying and duplicating in the mitigation of the ovc dilemma in hiv high prevalence countries in sub-saharan africa. keywords: hiv; aids; care, orphans, kenya. a b d u l m a j i d wa n g a i j r , m a r ya m wa n g a i , m a r y b e c k e n h a m a n d c l i v e b e c k e n h a m 240 in the last two decades, kenya has seen an unprecedented increase in the number of orphans. in 2001, it was estimated that there were about 1 million orphans countrywide. this number was projected to rise to 1.8 million by 2005 and 2.2 million by 2010. the majority (90%) of these orphans are as a result of the hiv/aids epidemic.1, 2, 3 this problem is not unique to kenya. worldwide, 13.2 million children are orphaned as a result of aids.4 by the year 2010, this number is expected to rise to more than 25 million.4 in 12 african countries, projections show that orphans, who constituted 12% of all children under 15 years of age in 2001, will increase to 15% by 2010.5, 6 to compound this scenario further, orphaned children living in areas with a high hiv prevalence are especially vulnerable to a myriad of problems, including hiv infection, malnutrition, high morbidity and mortality, physical and social abuse, exploitation, illiteracy, fear, isolation and loss of inheritance.7, 8, 9 households headed by orphans are also becoming increasingly common in these areas.10 the hiv/aids epidemic is having a devastating impact on children in sub-saharan africa. regardless of whether a baby is infected or not, the mortality in children born to hiv positive mothers is higher than those born into non-hiv affected households.7, 10, 11 the past decade alone has seen an increasing disparity in infant mortality rates between the least developed countries (lcd) and other developing countries. the difference in the rates between these countries is widening from 2.1 to 2.3 fold.12 this disparity has been attributed to three key factors: hiv/aids epidemic, underinvestment in children, instability and conflict. secondly, there has been a steady increase in the under-5 child mortality rate. in kenya, under-5 mortality has risen from 87 per 1000 live births in 1986 to 115 per 1000 live births in 2003.13 this denotes a reversal of health gains made over the previous three decades.14 however, there are some valiant efforts being made on behalf of young children. individuals, communities and governments as a whole are responding in various ways to stem the negative effects of the epidemic.3 orphanages and other formal institutions have proved to be an inadequate part of the response to orphaned and vulnerable children. the financial costs to maintain each child outstrips that of other forms of care. furthermore, the children are left without the psychological, social and cultural skills which they need to function successfully as adults. orphanages are therefore seen as a last or temporary resort.14 the government of kenya has shown commitment to mitigating the effect of the hiv/aids pandemic on children by developing policies and guidelines to give strategic direction in the care of orphaned and vulnerable children, for example: national programme guidelines on orphans and other children made vulnerable by hiv/aids.1 this has been done as part of the wider multisectoral approach to controlling hiv/aids in the country. this has resulted in close collaboration between government and various organisations in order to implement effective programmes which meet the needs of vulnerable children. to be part of the mitigation efforts, while recognising the importance of the first months and years of a child’s life, new life home (nlh) in nairobi, has sought to provide a home for orphaned, abandoned and hiv positive babies. the children receive food, shelter, clothing, free medical care, love and caring support within the environment of an actual home, and are eventually put up for adoption. the purpose of this study is to examine the characteristics of the children admitted into this home and their exposure to hiv and the lessons learned therein. m e t h o d s a n d m a t e r i a l s st udy si te this is a case study based on data compiled from records of all infant admissions into the nlh for abandoned and hiv babies in nairobi, kenya. the home is advances in knowledge this article highlights one of the social impacts of the hiv/aids pandemic with reference to orphaned and vulnerable children. application to patient care the article demonstrate a pioneering model and concerted effort to rehabilitate orphaned and vulnerable children in a region gripped by the hiv/aids pandemic and hampered by limited resources. f r o m h i v a b a n d o n m e n t t o a d o p t i o n 241 situated in a residential area within the city’s environs. the building in which the home is located was renovated to incorporate an acute medical care unit and a well-baby residential portion. the administrators are a live-in couple. the home is registered with the ministry of home affairs and national heritage as a children’s home, while the medical care unit is registered by the ministry of health as a private medical centre and nursing home. in a bid to sensitise the public about the home and encourage adoptions, targeted promotions were held in collaboration with opinion leaders at religious meetings, and in the print and electronic media. the procedures used for adoption were adapted from laws of england by the home’s board of management with the support of the children’s department in the ministry of home affairs. this was necessary because at the time the national guidelines were still under development. the adoption procedure used involved assessments of interested families for the stability of their homes and their socioeconomic base. this was done by a social worker in collaboration with the directors of the home. when the interested families met the criteria a lawyer was contracted to process the adoption through the high court of kenya for expatriate families or through the local magistrates courts for kenyan citizens. the adoption process took four to six months to complete. st udy p o p ul ati o n a n d pe r i o d the study examines data from 490 infants’ records over a period of 8.5 years from june 1994 to december 2002. within this period, the home admitted 490 infants from various sources: hospitals, police, good samaritans, other children’s homes, including an infant rescue centre and the kenya red cross. the infant rescue centre is located in kisumu, a high hiv prevalence region, 350 km from nairobi. infants were admitted from all over the country within the age group of 0 to 6 months. upon admission, the infants underwent a medical examination and a rapid hiv test. for the initial two years of the home, elisa tests were used to determine possible exposure to the virus. subsequently, rapid test kits were used: determine® and unigold®. the testing algorithm involved the use of the two different rapid test kits simultaneously (parallel testing). due to the high costs, polymerase chain reaction (pcr), using roche rna amplification assay, was only conducted for the babies who demonstrated that they had been exposed to hiv and were candidates for adoption. the data extracted from the children records include the infant’s bio-data, weight, hiv exposure, referring organisation/agent, and outcome. the infants were referred for admission from private and public hospitals, local government administration (e.g. police and chiefs), other children’s homes, a nlh rescue centre based in kisumu (350 km away) and the kenya red cross. figure 1: organisations that refer infants to new life home in nairobi a b d u l m a j i d wa n g a i j r , m a r ya m wa n g a i , m a r y b e c k e n h a m a n d c l i v e b e c k e n h a m 242 this study ceased to follow each infant once he/she was adoption out, died, transferred to other homes for older children or reunited with the biological family. a future study in progress traces adopted babies after they leave nlh. data m a n a ge me n t the data tabulation and cleaning was done using statistical package for social sciences (spss) version 12. analysis and mining was done using frequency distribution and cross tabulation. frequency distribution was used for data cleaning. analysis began by examining frequency distribution of each variable. also statistical analysis was done using frequency and cross tabulation to characterize the hiv exposure and referring organisations/agencies, gender and infant mortality. the predictive value for statistical significance was 0.05 (p < 0.05). r e s u l t s between june 1994 and december 2004, 490 infants were admitted into nlh. the female infants (245) were equal in number to the male babies. the infants were admitted from various organisations: 129 (26.3%) from kenyatta national hospital, 59 (12%) non-governmental health facilities, 96 (19.6%) other public health facilities and 107 (2.8%) from the new life home rescue centre in kisumu. the local police were also involved in bringing in 73 (15%) of the abandoned infants to the home. these babies were entrusted to nlh by the relevant government agencies with legal mandates to take care of them for life, until adoption or upon their unfortunate demise. nlh is therefore the custodian of all infants brought under its care. the home is not an orphanage. it is a home. the live-in couple are the parents of all babies, who mix with the couple’s own children, eat with them, play with them and are basically taken care of as the couple’s own children. all children get the same treatment. extra hands by many staff assist the couple to provide the extra help needed to take care of all these babies. in essence, it is an enlarged home environment, rather than an impersonal orphanage. the age of the infants at admission ranged from one day to 320 days (11 months) with a mean of 53 days (7.5 months). however, of those admitted 186 (38%) were neonates and 476 (97%) were below 6 months. once admitted the average length of stay was 150 days (5 months; interquartile range (iqr) 1.5-6 months) and a maximum of 3 years. the longest staying children were those infected with the hiv virus (x2 = 381; p<000). the age at which the children are discharged ranged from 2 days to 785 days (2.2 yrs) with a mean of 203 days (6 months) and iqr of 3-9months. c h i l d mo rta l i t y a n d h i v e x p o sur e at the close of the study period, a total of 452 (92%) out of 490 infants were still alive denoting a child mortality figure 2: comparison of adoption between kenyan and expatriate parents over time f r o m h i v a b a n d o n m e n t t o a d o p t i o n 243 rate of 77.6 per 1000 live births. of the infants who died 22 (58%) were female and 16 (42%) were male. eighteen (47%) of the infants who died had been exposed to hiv. of all the children who died, 32(84%) were 198 days old (6.5 months) and below. twenty two (58%) of the infants who died were referred from the various health facilities, 7 (18%) from police and 8 (21%) from children’s homes. the factors associated with infant mortality weight at admission (p=0.002), hiv exposure (p<0001) and length of stay (p=0.16). on admission, 177 (36%) infants tested positive for antibodies to the hiv virus. of all the children, eighteen (3.7%) were hiv exposed children who died. one hundred and thirteen (35%) of the children adopted demonstrated evidence of having been exposed to hiv before their admission into the home. the mortality rate of children exposed to hiv was 1.6 and 2 times higher at 6 and 12 months respectively than that of non-exposed children. the mortality rate for the hiv exposed was 71/1000 at 6 months, 94.7/ 1000 at 12 months and 100.6/1000 at 18 months while for those not exposed to the virus it was 43.3/1000 at 6 months and 46.7/1000 at 12 months. in the age bracket 6 to 12 months, the mortality rate was 23.7/1000 in hiv exposed infants and 3.3/1000 in the non-exposed infants, while in the age bracket 12-18 months mortality in the hiv exposed children was 100.6/1000 live births. there were no deaths recorded in the home in children older than 18 months. c h a r a c te r i sti c s o f th e a d o p ti o n s the majority of infants, 323 (67%), left the home to join adoptive parents/families. at the end of the study period, 160 (32.7%) of the children had been adopted by expatriate families, 166 (34%) adopted by kenyan citizens, while only 87 (18%) were still resident in the home. over the years, adoption by kenyan citizens has increased nine-fold. in 1996 only 6% of adoptions were to kenyan families while in 1999 this had changed to 56%. the average age at which the infants were adopted was 181 days (6 months) (iqr 4 to 7.7 months). these infants had an average weight of 6.2kg (iqr 4.8-7.6kg). over the latter two years the rate of adoption declined from 85% in 2001 to 30% in 2003. this denotes nearly a three-fold decline. the expatriate families were three times less likely to adopt than kenyan families. seven (1.4%) of the transfers to other children’s homes have been of hiv positive children. a few children 31 (6.3%) were reabsorbed back into their biological families. d i s c u s s i o n this study of nlh seeks to demonstrate that irrespective of the referring agent or hiv exposure the outcome of a well managed abandoned or orphaned baby can be figure 3: profile of infants’ discharge destinations a b d u l m a j i d wa n g a i j r , m a r ya m wa n g a i , m a r y b e c k e n h a m a n d c l i v e b e c k e n h a m 244 good. nearly 40% of admitted infants demonstrated exposure to the hiv virus. this is in contrast to the general kenyan hiv prevalence at antenatal surveillance clinics, which ranged between 9 and 13% over the study period.2 this implies that abandoned children are possibly more likely to have been exposed to hiv from their mothers. accommodating the hiv exposed infants at the home where they are fed on breast milk reduces the risk of transmission of the virus. meta-analytical studies have shown that frequency of breast milk transmission is 14% for women with established infection and 29% during acute maternal illness.15 it has also been demonstrated that the use of breast milk substitutes prevents 44% of infections.16 the home’s infant mortality rate was estimated at 78 per 1000 live births. mortality was noted to be substantially higher in the children previously exposed to hiv. this was especially evident in the age group between 6 to 12 months where a seven-fold difference was seen. the fact that hiv exposure and infection is a contributing factor to mortality has been demonstrated in various studies.11, 17, 18 however, the mortality rate of infants at 12 months for both hiv exposed and nonexposed infants is considerably lower at the home than is documented in a study conducted in urban malawi on the effect of hiv on birth weight, infant and child mortality.18 the malawi study reported a mortality rate that was 2.3 times higher for hiv exposed children at 223/1000 and 1.5 times higher in the non-exposed at 68/1000. however, further study into the home’s model of care, support and treatment is needed for it to demonstrate fully its successes. the commonest causes of death, regardless of the exposure to hiv, were septicaemia (39%) pneumonia (26%) and cardiac conditions (10.5%) in all the children; however, in the hiv exposed children, pneumonia was the commonest cause of death followed by septicaemia(56% and 22%, respectively). the cause of death in the hiv exposed children seen in this study is in line with other studies done in malawi, where one of the frequent causes of death was pneumonia.19 the majority of surviving infants (67%) were adopted into both expatriate families and indigenous kenyan families. adoptive parents seemed to prefer to adopt younger children aged about 6 months and weighing about 6kg. initially, in the early years of the home, the adoptions were by expatriate families; kenyan families were slow to adopt. this may be a result of cultural perceptions on adoptions among other reasons. however, once opinion leaders adopted children there was a notable increase in young kenyan couples adopting. the trend noted in this study represents a twelve fold table 1: characteristics of infants admitted into new life home hiv not exposed hiv exposed not tested total gender no. (% within gender) no.(% within gender) no. female 155 (63.3) 83 (33.9) 7(2.9) 245 male 145 (59.2) 94 (38.4) 6(2.4) 245 referring agent no. (% within the referring agent) no.(% within the referring agent) not tested no. kenyatta national hosp. 73 (56.6) 65 (42.6) 1(0.8) 139 other public health facilities 41 (42.7) 55 (57.3) 0 96 good samaritans 9(75) 3(25) 0 12 ngo health facilities 38 (64.4) 20 (33.9) 1(1.7) 59 police/local administration 50 (68.5) 13 (17.8) 10(13.7) 73 other children homes 1 (7.1) 12 (85.7) 1(7.1) 14 nlh rescue centrekisumu 53 (21.6) 54 (22) 0 107 infant mortality no. (% within hiv exposure) no. (% within hiv exposure) not tested no. alive 286 (95.3) 159 (89.8) 7 452 dead 14 (4.7) 18 (10.2) 6 38 fate of children no. (% within hiv exposure) no. (% within hiv exposure) not tested no. kenyan adoptions 115 (38.3) 51 (28.8) 0 166 expatriate adoptions 97 (32.3) 62 (35) 1(7.7) 160 transfers to children homes 3 (1) 4 (4.3) 0 7 transfer to biological family 14 (4.7) 12 (6.8) 5 (38.5) 32 resident at new life home 57 (19) 29 (6.4) 1(7.7) 87 f r o m h i v a b a n d o n m e n t t o a d o p t i o n 245 increase over a 9 year period. expatriate families who were equally willing to participate in adoption supplemented this trend. in countries hardest hit by hiv/aids, care for orphans and children affected by hiv/aids lies primarily with their families and communities. this places a heavy burden on the extended family system, which is the backbone of african societies. in response to this, the malawian and namibian governments in conjunction with unicef provide equipment, supplies and materials to day-care centres that provide free services to orphans.6 other countries such as botswana provide support to ngos, extended and foster families. the support ranges from family counselling to meeting physical basic needs such as food, clothing and education.20 experience shows that successful programmes are those that are child-centred, family and community focused, and where the rights of the child are respected and protected.21 nlh participates actively in facilitating adoption procedures of the infants into kenyan or expatriate families. adoption is encouraged because it allows the infants to transit into homes where there is greater personalised attention. child socialization can thus be effected while also seeking to secure their future. within the country, this strategy is deemed one of the avenues for effectively caring for orphans and children affected by hiv/aids (ovc’s). in the absence of adoption, aids orphans contribute substantially to the number of street children. the study had various limitations as it was dependent on extracting previously recorded data from children’s records and gaps in the records existed. first, the completeness of the records was dependent on the thoroughness of the nursing and managerial staff who had previously attended the children. for example, large number of records did not contain the birth weight and heights of the infants therefore analysis was not possible. second, the retrospective nature of the study (as opposed to prospective) precluded the collection and analysis of other important variables and associations that would affect outcomes such as the nutritional status of the infants, and the hiv/aids and health status of birth mothers. third, being in a resource constrained setting the home can only provide for minimal laboratory and radiologic tests. the cost of pcr (rna) was us$114-157 for each specimen; hence it was not be possible to determine rates of hiv infection in admitted infants at less than 18 months of age, as pcr (ribonucleic acid rna) was not universally done. pcr (dna), being the better diagnostic test for infant diagnosis, was not done because it was not readily available in the country during the study period. c o n c l u s i o n the strategy used by the nlh for addressing the vacs’ situation, with particular reference to abandoned infants, is reproducible. its strength lies in the rescuing of abandoned infants, who are vulnerable to hiv infection, morbidity, mortality or dysfunctional livelihood. these infants are cared for, while community members are encouraged to participate in their adoption. in effect, the home serves as a transition for ovcs in their infancy. all in all, the mitigation of the hiv impact on children of all ages is a challenge that demands a multisectoral response and needs to be dealt with as priority for hiv positive no. (% in group) hiv negative no. (% within group) total (%) pneumonia 10 (56) 2 (10) 12 (26) heart defects and congestive cardiac failure 2 (11) 2 (10) 4 (10.5) strangulated hernia 2 (10) 2 (5) meningitis 1 (13) 1 (5) 2 (5) septicaemia 4 (22) 11 (52) 15 (38) cot death 1(13) 0 1 (3) malnutrition 2 (10) 2 (5) aspiration pneumonia 1 (5) 1 (3) total 18 (46) 21 (54) 39 (100) table 2: cause of infant deaths a b d u l m a j i d wa n g a i j r , m a r ya m wa n g a i , m a r y b e c k e n h a m a n d c l i v e b e c k e n h a m 246 the sake of securing our next generation, our future. r e f e r e n c e s 1. republic of kenya, department of children’s services, ministry of home affairs (moha) and national aids control council. national programme guidelines on orphans and other children made vulnerable by hiv/ aids. nairobi, 2003. 2. republic of kenya, ministry of health, national aids and std control programme. aids in kenya: background projections, impact, interventions and policy. 6th ed. nairobi: nascop, 2001. 3. joint united nations programme on hiv/aids. report on the global hiv/aids epidemic: 4th report. unaids, 2004. p. 65 4. joint united nations programme on hiv/aids and united nations children’s fund (unicef) us agency for international development (usaid). children on the brink 2002: a joint report on orphan estimates and program strategies. geneva: unaids, 2002. 5. unaids. report on the global hiv/aids epidemic. unaids, july 2002. 6. bellamy c. state of the world’s children 2001: early childhood. unicef, 2000. 7. abrams ej, matheson pb, thomas pa, thea dm, krasinski k, lambert g, et al. neonatal predictors of infection status and early death among 332 infants at risk of hiv-1 infection monitored prospectively from birth. new york city perinatal hiv transmission collaborative study group. pediatrics 1995; 96:451-458. 8. barnett t and blake p. aids in africa. it’s present and future impact. london: the bellhaven press, 1992 9. world bank, aids and development: moving beyond the partial paradigm. new york: oxford press, 1995. 10. mukoyogo m c, williams g. aids orphans: a community perspective from tanzania strategies for hope. london: action aid, 1992. 11. newell ml, coovadia h, cortina-borja m, rollins nc, gaillard p, dabis f. mortality of infected and uninfected infants born to hiv-infected mothers in africa: a pooled analysis. lancet 2004; 364:1236-1243. 12. united nations children’s fund. poverty and children: lessons of the 90’s for least developed countries. unicef, 2002. p. 9. 13. republic of kenya, central bureau of statistics, ministry of health. kenya demographic health survey 2003. calverton, maryland: dhs, moh and orc macro, 2004. 14. unaids. report on the global hiv/aids epidemic. unaids, 2000. 15. dunn dt. newell ml, ades ae, peckham cs. risk of human immunodeficiency virus type and transmission through breastfeeding. lancet 1992; 340:585 -588. 16. nduati r, john g, mbori-ngacha d, richardson b, overbaugh j, mwatha a, et al. effect of breastfeeding and formula feeding on transmission of hiv-1: a randomised clinical trial. jama 2000; 283:1167-1174. 17. zijenah l, mbizvo mt, kasule j, nathoo k, munjoma m, mahomed k, maldonado y, et al. mortality in the first 2 years among infants born to human immunodeficiency virus-infected women in harare, zimbabwe. j infect dis 1998; 178:109-113. 18. taha te, dallabetta ga, canner jk, chiphangwi jd, liomba ng, hoover dr, et al. the effect of human immunodeficiency virus infection on birthweight, and infant and child mortality in urban malawi. int j epidemiol 1995; 24:1022-1029. 19. sherry b, embree je, mei z, ndinya-achola jo, njenga s, muchunga er, et al. sociodemographic characteristics, care, feeding practices, and growth of cohorts of children born to hiv-1 seropositive and seronegative mothers in nairobi, kenya. trop med int health 2000; 5:678-686. 20. unaids/unicef. children orphaned by aids: frontline responses from easter and southern africa. unaids/unicef, 1999. 21. unicef. poverty reduction begins with children. unicef, 2000. 1 submitted 23 jun 22 1 revisions req. 18 sept & 14 nov 22; revisions recd. 23 oct & 24 nov 22 2 accepted 8 dec 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.069 5 6 machine learning approach for predicting systemic lupus erythematosus 7 in oman-based cohort 8 *alhassan alshareedah,1 hamza zidoum,1 sumaya al-sawafi,1 batool al-9 lawati,2 aliya al-ansari3 10 11 departments of 1computer science and 3biology, college of science and 2department of 12 medicine, college of medicine, sultan qaboos university, muscat, oman. 13 *corresponding author’s e-mail: al.hassan.satii@gmail.com 14 15 abstract 16 objectives: design a machine learning-based prediction framework to predict the presence or 17 absence of systemic lupus erythematosus (sle) in a cohort of omani patients. methods: records 18 of 219 patients from 2006 to 2019 were extracted from squ hospital electronic records, 138 19 patients have sle, and the remaining 81 have other rheumatologic diseases. clinical and 20 demographic features were analyzed to focus on the early stages of the disease. our design 21 implements recursive feature selection (rfe) to select only the most informative features. in 22 addition, the catboost classification algorithm is utilized to predict sle and an explainer algorithm 23 (shap) is applied on top of the catboost model to provide individual prediction reasoning which is 24 then validated by rheumatologists. results: catboost achieved an area under the roc curve 25 (auc) score of 0.95 and a sensitivity of 92%. four clinical features (alopecia, renal disorders, 26 acute cutaneous lupus, and hemolytic anemia) along with the patient’s age were shown to have 27 the greatest contribution to the prediction by the shap algorithm. conclusion: we have designed 28 and validated an explainable framework to predict sle patients and provide reasoning for its 29 prediction. our framework enables early intervention for clinicians which leads to positive 30 healthcare outcomes. 31 2 keywords: systemic lupus erythematosus; interpretation; machine learning; supervised; 32 clinical decision support system; statistical data; data analysis. 33 34 advances in knowledge 35  the first self-explainable prediction framework for sle disease specific to the omani 36 population is developed. 37  achieved an auc score of 0.956 and sensitivity of 92%. 38  identifies patterns in clinical manifestation which are unique to the omani population. 39  the patient’s age and four clinical features (renal disorders, alopecia, cutaneous lupus, and 40 hemolytic anemia) had the highest contribution to the model’s prediction. 41  compared to other arab ethnicities, renal disorders frequency in oman was the highest 42 while alopecia frequency was the lowest. 43  44 application to patient care 45  the model can potentially be used as a clinical decision support system that alerts clinicians 46 to the presence of sle which prompts further investigation until an official diagnosis is 47 made. 48  enabling clinicians to contrast the information reported by the model with their knowledge 49 through an interpretation algorithm. thereby increasing the probability of correct diagnosis 50 and encouraging the adoption of machine learning (ml) in healthcare. 51  a practical introduction of machine learning and interpretation tools to the medical 52 diagnosing process that improves early detection of sle; a crucial factor in lowering flare 53 rate and reducing mortality. 54 55 introduction 56 systemic lupus erythematosus (sle) is a chronic multisystem autoimmune disease. sle is 57 caused by genetic and environmental factors that potentiate the creation of high-titer 58 autoantibodies aimed at native dna and other cellular elements.1 the creation of these 59 autoantibodies leads to a pathological process that manifests into different medical conditions 60 in different organ systems, from skin arthralgia to cardiovascular and renal morbidity.2 the 61 clinical phenotype of sle varies with race, gender, and age which makes the disease difficult 62 3 to diagnose.3 in oman, it is estimated that the mortality rate is at 5% and the mean prevalence 63 is 38 per 100,000 individuals,4 this is higher than in saudi arabia and lower than in uae. 64 initial sle symptoms are often nonspecific and mimic other medical conditions, increasing 65 the risks of diagnostic delay. additionally, the heterogeneity of manifestations makes early 66 diagnosis even more difficult and subsequently delays the start of effective treatment before 67 the occurrence of organ damage. 68 69 in recent years, great improvements in treatment strategies for sle have been made. however, 70 despite the improved prognosis, various challenges remain for the diagnosis and therapeutic 71 management of sle.5 one of those challenges is early diagnosis. sle onset is gradual and 72 clinically-evident manifestation develops over the years. moreover, a variety of conditions 73 may mimic sle conditions, including infectious and hematologic diseases.6 it has been proven 74 from database analysis that patients with a diagnosis window below 6 months (between 75 probable sle onset and diagnosis) had low flare rates and hospitalizations compared with 76 patients with late diagnosis.7 late diagnosis is also associated with the risk of developing 77 progressive organ damage and subsequently increases the mortality rate.8 78 79 this study focuses on effective sle prediction as well as finding the associated clinical 80 features. with the aid of interpretation tools, clinicians can understand the decision-making 81 process of machine learning (ml) models. this, in turn, enables clinicians to be alerted to 82 different manifestations and symptoms at early stages and provide better healthcare outcomes. 83 the model is trained on a local cohort of 219 omani patients with sle as well as other control 84 diseases. additionally, we identified the minimum set of clinical and demographic features 85 required for an accurate prediction. finally, an explainable approach based on shapley 86 additive explanations (shap) method was applied to generate individual explanations of the 87 model's decisions as well as ranking clinical features by contribution. 88 89 methods 90 the dataset used in this study was collected from structured and unstructured sources. this 91 includes the electronic medical records (emr) in sultan qaboos university hospital’s 92 rheumatology clinic named trakcare. trakcare stores the patients’ information, medical 93 4 state, and medical history. patients' demographic data were obtained directly from trakcare 94 meanwhile clinical data was unstructured as it was stored in the patient's medical history as 95 clinical notes from each visit to the hospital. entry criteria for rheumatology patients is a 96 positive antinuclear antibodies test (ana test) while the exclusion criteria included all non-97 omani patients as well as patients with non-sufficient data. to separate patients with sle and 98 control diseases, the most recent sle classification criteria set by eular/acr were used.9 99 when applied, patients with a score of 10 or above are diagnosed with sle. a total of 219 100 patient records match the entry criteria, 138 are diagnosed with sle, and 81 have other control 101 diseases, this was also validated by a rheumatologist on case-by-case bases. 102 103 our framework contains three main stages, starting with feature selection that reduces noisy 104 data and utilizes only the most informative features followed by the classifier, which trains and 105 tests the model to predict the presence of sle. after the model is trained, the explainer 106 algorithm proceeds to provide individual prediction breakdown through informative visual 107 plots. 108 109 in the first stage [figure 1], the recursive feature elimination (rfe) algorithm with ten-fold 110 cross-validation (cv) was used. rfe works by building a model, selecting the best feature, 111 picking out the selected feature, and then repeating this process for the remaining features until 112 all the features are traversed. for the second stage of this framework, we have implemented 113 categorical boosting or catboost, an ensemble learning algorithm that is based on gradient 114 boosting.10 115 116 for the final stage, the shap library is implemented.11 shap calculates ‘shapley values’ for 117 each feature to determine the contribution of a feature to the final prediction represented by the 118 magnitude and sign of the shapley value. specifically, the importance of the feature relative to 119 the prediction is represented by the magnitude of the shapley value. shap tool can also 120 perform local and global interpretability simultaneously. with the help of shap algorithm, we 121 can break down each prediction individually. as a demonstration, we took two individuals 122 from the testing set, one that was predicted to have the disease and one that was not. three 123 types of figures were used to show the prediction breakdown, force plot, waterfall plot, and 124 5 summary plot. the force plot demonstrates how the features contributed to the model’s 125 prediction for a specific observation. the colors in the force plot correspond to the feature 126 pushing the prediction probability higher or lower. the target in our model has two classes, 127 class 1 for a positive diagnosis of sle and class 0 for a negative diagnosis of sle. to obtain a 128 full list of features ranked by their contribution we use a waterfall plot. the summary plot 129 displays the feature's effects and their importance. each point on the summary plot represents a 130 shapley value for a feature and an instance. 131 132 to train and validate the performance of catboost, the dataset was divided into training and 133 testing sets. the former is used to train the model and the latter is used to test the performance 134 of the model. additionally, a subset of the training data set was used for cross-validation to 135 protect the models from overfitting and optimize the model's parameters. each of the models 136 undergoes a hyper-parameter optimization through grid search with five-fold cross-validation. 137 to avoid reporting biased results and limit overfitting, we calculated the measurement’s 138 average of 10 repetitions for each model. finally, three other classifiers were evaluated 139 similarly, which are multi-layer perceptron (mlp), support vector machine (svm), and 140 random forest. their performance evaluations were compared to catboost to observe the 141 effectiveness of catboost. the classifiers were selected based on related studies that employed 142 ml for disease prediction.12 13 143 144 due to the imbalanced nature of the problem, the auc (area under roc curve) and sensitivity 145 parameters are used to evaluate the classification performance. 146 147 the study was approved by the ethics committee of the college of medicine and health 148 science at sultan qaboos university (squ) in protocol number merc #1418 and #1650. no 149 participant consent is required for this study as per the regulation of sultan qaboos 150 university’s hospital. 151 152 results 153 the extracted data covers patient records from january 2006 to december 2019. female 154 patients represent the majority of our records with 92%. patients between 25 years old and late 155 6 30’s represent the largest age group with a mean age of 38. al batinah governorate had the 156 highest number of patients (37.9%) followed by muscat (23.7%). 157 158 initial data contained 28 clinical, demographic, laboratory variables (so-called “features” in 159 ml), and no missing values were found in the data [table 1]. laboratory features include 160 immunological test results such as anti-dsdna test, anti-smith antibody, and more. these 161 features however, are highly sensitive to sle and can introduce bias to the prediction model 162 therefore it was dropped. the remaining data consist of 20 clinical and demographic features. 163 the majority of the features are represented by non-numerical (categorical) values. this entails 164 a transformation (encoding) to numerical values as this is a prerequisite for all statistical 165 models. thus, ordinal encoding was applied, moreover, because of the variance in range for 166 different features, min-max normalization was also applied.14 167 168 applying the rfe feature selection algorithm, the optimal number of features selected was 13. 169 from the rfe selected features, three demographic features, as well as 10 clinical features, 170 were selected. catboost had an auc score of 0.956, with the random forest classifier and 171 svm scoring 0.935 and 0.916 auc respectively. for sensitivity, catboost had 92%, random 172 forest achieved 89% and svm score is 86%. 173 174 two samples from the testing set were used to generate the different shap plots. the first 175 sample (patient 1) is predicted to have sle, the force plot attributes this to renal disorders, and 176 the patient’s age [figure 2.a]. since the values are normalized we cross-referenced them with 177 test data and found that the patient’s age is 40 which falls within the age group sle that is 178 most active. additionally, the patient has been diagnosed with lupus nephritis a disease that 179 is commonly caused by an auto-immune disorder. on the other hand, the second sample 180 (patient 2) displays a lack of any autoimmune manifestation [figure 2.b], a long disease 181 duration, and the age of 56 makes him outside the age group that sle is most active. 182 183 looking at the waterfall plot for patient 1[figure 3.a], the feature with the highest shap value 184 is renal by a large margin. due to its high shap value, the presence of renal disorder in 185 patient 1 had the greatest contribution to the positive prediction of sle. this was followed by 186 7 the age and province features. overall, four blue features were pushing the prediction 187 probability lower toward class 0. the non-existence of alopecia, hemolytic anemia, and acute 188 cutaneous lupus (acl) in the patient 1 profile resulted in negative shap values. the 189 remaining features had minimal impact on the prediction probability evidenced by their low 190 shap values. in contrast, the waterfall plot for patient 2[figure 3.b] indicates that age is the 191 largest contribution toward class 0, followed by the absence of any renal disorders. 192 193 in [figure 4], similar to what was deduced, the older the patient is the less likely it is to have 194 sle, which is evident by the red dots on the negative scale of shap values. the same can be 195 said for disease duration, we find that long disease durations without autoimmune 196 manifestation correlated with the absence of sle. our result indicates that the higher the 197 patient’s age and disease duration the less likely that sle is the cause. renal disorders are 198 ranked the highest in contribution followed by alopecia, acl, and hemolytic anemia. the 199 lowest contributing features are serositis, proteinuria, and leukopenia. 200 201 discussion 202 in clinical applications, the ability to justify the prediction is equally as important as the 203 prediction score itself. this is because of the high sensitivity of the medical environment 204 where misclassification could lead to devastating results. it is therefore challenging to trust 205 complex ml models for several reasons. first, the models are often designed and rigorously 206 trained on specific diseases in a narrow environment. second, it depends on the user’s 207 technical knowledge of statistics and ml. third, how the data is labeled affects the results 208 produced by the model.15 for these reasons and more, interpretable ml has thus emerged as 209 an area of research that aims to design transparent and explainable models by developing 210 means to transform a black-box ml model into white-box ml models. by providing 211 transparent prediction, domain experts can accurately interpret the results meaningfully. 212 213 through the use of shap algorithm, clinicians can understand the model’s reasoning, thus 214 resembling clinical reasoning. our model is situated between early to mid-screening 215 suggesting that physicians have minimum visible clinical symptoms and subsequently no 216 immunological test data.16 the model can reasonably make predictions that can alert clinicians 217 8 to investigate the presence of sle by requesting immunological tests once suspicion of sle is 218 predicted. specifically, the ana test and the anti-double stranded dna (anti-dsdna) are 219 highly sensitive and decisive if found positive.17 additionally, an immunologist has compared 220 multiple individual prediction breakdown plots and validated the results and the model 221 justification. 222 223 one of the features that were used to profile patients are age, age-onset, and disease duration 224 features. it was deduced from the shap algorithm that older patients were the least affected 225 by the disease. similarly, patients with long disease duration without adverse manifestations 226 such as anemia or lupus nephritis are shown statistically to be less likely diagnosed with sle. 227 experts point out, however, that sle intensity increases and decreases at intervals differently 228 from patient to patient, thus in rare occasions clinical symptoms might not manifest until the 229 late phases of the disease.18 research suggests that late-onset sle occurs at a rate of 3-18% in 230 the exposed population.19 231 232 renal disorders were the highest feature in contribution according to shap [figure 4]. this 233 was in concordance with beckwith and lightstone (2014) who states that about 40-70% of 234 sle patients develop clinically diagnosed renal involvement which is known as lupus 235 nephritis.20 lupus nephritis (ln) is commonly diagnosed through kidney biopsy, previous 236 research identified proteinuria, urine protein-to-creatinine ratio, anti-dsdna, and complement 237 levels as laboratory markers of ln. however, these ln laboratory markers lack specificity 238 and sensitivity for identifying renal activity and damage.21 in oman, ln is the most frequent 239 glomerular disease occurring in about 30%-36% of all patients who had a renal biopsy. this is 240 supported by al adhoubi (2020),4 where 52% of sle patients have developed ln. despite the 241 majority of our data lacking kidney biopsy information, ln is also present in 11% of patients 242 with renal disorders. 243 244 moreover, we found other clinical features that had about the same influence on the prediction. 245 these are alopecia, cutaneous lupus, and anemia. alopecia is a hair loss that also varies in 246 damage activity from non-scarring to scarring. currently, it is estimated that more than half of 247 sle patients develop alopecia, although most of the research that estimates alopecia 248 9 prevalence is limited by the small population size. cutaneous lupus which includes a butterfly 249 rash across the face between the eyes and nose. acl is a sign of vgll-3 & anti-ssa 250 antibodies which indicate skin damage activity caused by lupus.22 anemia is the most 251 common blood disorder, affecting about half of all people with active lupus.23 anemia is 252 caused by a shortage of healthy red blood cells needed by the body to carry oxygen to the 253 body's tissues. hemolytic anemia, however, is not exclusive to sle. 254 255 the prevalence of these influential clinical features across other arab ethnicities was also 256 investigated. while no study examined the differences between ethnicities within the arab 257 region, there have been few studies that have collected data on the sle population locally. we 258 looked at three cohorts from saudi arabia,24 uae,25 and egypt [figure 5].26 acl or skin rash 259 was found more prevalent in all other arab cohorts reaching as high as 62% in uae. 260 hemolytic anemia was the most varying feature, in egypt and uae, it is less prevalent than in 261 oman while in saudi arabia it is more prevalent than in oman.27 renal disorders remained 262 high at around 50% of all cohorts having some renal damage except for a slight decrease to 263 33% in egypt. studies also indicate that out of all renal biopsies, approximately 10%–36% are 264 diagnosed with ln in the gulf region. ln also tends to run a severe course in gulf populations 265 with a high incidence of class iv ln.28 266 267 overall, with three critical features out of four found more prevalent in other arab ethnicities, 268 our model can be extended to include not only omanis but also other arab cohorts. it is 269 important to note that all of these clinical features are not exclusive to sle, but to autoimmune 270 diseases in general. however, classification models can be trained to detect patterns specific to 271 the omani population, these patterns are the bases of the model’s prediction for sle presence. 272 273 these findings help to identify patterns in clinical manifestation which are unique to the 274 omani population and the arab region by employing explainable prediction. moreover, our 275 research also highlights catboost algorithm, which had widespread attention in recent years 276 for its fast calculation speed, powerful generalization ability, and strong predictive 277 performance.29 30 31 we achieved a margin of improvement of 0.21 auc over the other 278 classifiers, this may be attributed to its novel implementation of ordered boosting, and 279 10 permutation-driven alternative to the classic algorithm. this study also acknowledges the 280 problem with imbalanced classification evaluation where the research is biased toward the 281 performance of cases that are poorly represented in the data samples.32 standard evaluation 282 criteria tend to focus the evaluation of the models on the most frequent cases, thus if applied, 283 could lead to sub-optimal classification models. thus, auc and sensitivity were selected as 284 evaluation criteria. 285 286 finally, by combining the framework’s prediction with the interpretation algorithm we are 287 promoting self-explainable frameworks that enable physicians to make meaningful decisions 288 based on ml-based information combined with their knowledge. thereby improving the 289 probability of correct diagnosis and encouraging the adoption of ml in healthcare. these goals 290 however are hindered by the retrospective nature of the data. an ideal framework is much 291 more effective with longitudinal data of sle patients that include pre-diagnosis profiles before 292 the appearance of adverse symptoms. moreover, our framework may not scale properly with 293 large datasets. specifically, large data will significantly increase the computational time for 294 shap, and categorical data with high cardinality is inefficient with the ordinal encoder 295 algorithm.33 different tools can also be applied to increase the accessibility and presentation of 296 our model such as presenting the outcome as a prediction probability instead of a binary value. 297 298 conclusion 299 this study proposes a three-stage interpretable framework for predicting the presence or 300 absence of sle in an omani cohort of 219 patients. catboost classifier and shap 301 interpretation tool were implemented to predict and justify individual predictions and eliminate 302 any risk of misclassification. four clinical features were identified to have the highest 303 influence on the prediction in addition to the patient’s age. alopecia, renal, acute cutaneous 304 lupus, and hemolytic anemia are all indicators of lupus activity at varying rates, combined 305 with the patient’s age and age-onset the model was able to establish a profile of the disease 306 relative to omanis. overall, our findings aid in providing a practical introduction of machine 307 learning and interpretation tools to medical diagnosis, thereby increasing the efficiency of 308 medical testing and subsequently enabling early intervention which leads to better treatment 309 and a positive healthcare outcome. 310 11 311 authors’ contribution 312 hz and aa conceived the idea. h.z. and a.a. designed the study. sa collected the data. ba 313 and aa-a have validated the data and results. research experiments, implementation, and 314 results were performed by aa with input from ha. aa drafted the manuscript with edits from 315 hz, aa-a and ba. all authors approved the final version of the manuscript. 316 317 acknowledgment 318 we would like to thank the oman research council for supporting this research. we also 319 gratefully acknowledge the support from the sultan qaboos university hospital for their 320 cooperation. 321 322 conflict of interest 323 the authors declare no conflicts of interest. 324 325 funding 326 this work was supported in part by an internal grant. 327 328 references 329 1. gaipl u, munoz l, grossmayer g, lauber k, franz s, sarter k et al. clearance 330 deficiency and systemic lupus erythematosus (sle). j autoimmun 2007;28(2-3):114-331 121. doi: 10.1016/j.jaut.2007.02.005 332 2. nisengard r. diagnosis of systemic lupus erythematosus. importance of antinuclear 333 antibody titers and peripheral staining patterns. arch dermatol 1975;111(10):1298-1300. 334 doi: 10.1001/archderm.111.10.1298 335 3. lewis m, jawad a. the effect of ethnicity and genetic ancestry on the epidemiology, 336 clinical features and outcome of systemic lupus erythematosus. rheumatology (oxford) 337 2016; kew399. doi: 10.1093/rheumatology/kew399 338 4. al‐adhoubi n, al‐balushi f, al salmi i, ali m, al lawati t, al lawati b et al. a 339 multicenter longitudinal study of the prevalence and mortality rate of systemic lupus 340 erythematosus patients in oman: oman lupus study. int j rheum dis 2021;24(6):847-341 854. doi: 10.1111/1756-185 x.14130 342 12 5. felten r, lipsker d, sibilia j, chasset f, arnaud l. the history of lupus throughout the 343 ages. j am acad dermatol 2020; doi: 10.1016/j.jaad.2020.04.150 344 6. piga m, arnaud l. the main challenges in systemic lupus erythematosus: where do 345 we stand?. j clin med 2021;10(2):243. doi: 10.3390/jcm10020243 346 7. oglesby a, korves c, laliberté f, dennis g, rao s, suthoff e et al. impact of early 347 versus late systemic lupus erythematosus diagnosis on clinical and economic 348 outcomes. appl health econ health policy 2014;12(2):179-190. doi: 10.1007/s40258-349 014-0085-x 350 8. murimi-worstell i, lin d, nab h, kan h, onasanya o, tierce j et al. association 351 between organ damage and mortality in systemic lupus erythematosus: a systematic 352 review and meta-analysis. bmj open 2020;10(5):e031850. doi: 10.1136/bmjopen-2019-353 031850 354 9. aringer m, brinks r, dörner t, daikh d, mosca m, ramsey-goldman r et al. european 355 league against rheumatism (eular)/american college of rheumatology (acr) sle 356 classification criteria item performance. ann rheum dis 2021;80(6):775-781. doi: 357 10.1136/annrheumdis-2020-219373 358 10. dorogush a, ershov v, gulin a. catboost: gradient boosting with categorical features 359 support. arxiv [pre-print] 2018. doi: https://doi.org/10.48550/arxiv.1810.11363 360 11. lundberg sm, lee si. a unified approach to interpreting model predictions. adv neural 361 inf process syst 2017;30. doi: https://dl.acm.org/doi/10.5555/3295222.3295230 362 12. adamichou c, genitsaridi i, nikolopoulos d, nikoloudaki m, repa a, bortoluzzi a et 363 al. lupus or not? sle risk probability index (slerpi): a simple, clinician-friendly 364 machine learning-based model to assist the diagnosis of systemic lupus erythematosus. 365 ann rheum dis 2021; 80(6): 758-766. https://doi.org/10.1136/annrheumdis-2020-366 219069 367 13. nalband s, sundar a, prince a, agarwal a. feature selection and classification 368 methodology for the detection of knee-joint disorders. comput methods programs 369 biomed 2016;127:94-104. https://doi.org/10.1016/j.cmpb.2016.01.020 370 14. patro sgk, sahu kk. normalization: a preprocessing stage. arxiv [pre-print] 2015. 371 doi: 10.48550/arxiv.1503.06462 372 https://doi.org/10.48550/arxiv.1810.11363 https://dl.acm.org/doi/10.5555/3295222.3295230 https://doi.org/10.1016/j.cmpb.2016.01.020 13 15. stiglic g, kocbek p, fijacko n, zitnik m, verbert k, cilar l. interpretability of machine 373 learning‐based prediction models in healthcare. wiley interdiscip rev data min knowl 374 discov 2020;10(5). doi: https://doi.org/10.1002/widm.1379 375 16. binder a, ellis s. when to order an antinuclear antibody test. bmj 2013; 347 :f5060 376 doi:10.1136/bmj.f5060 377 17. wichainun r. sensitivity and specificity of ana and anti-dsdna in the diagnosis of 378 systemic lupus erythematosus: a comparison using control sera obtained from healthy 379 individuals and patients with multiple medical problems. asian pac j allergy immunol 380 immunology 2013;31(4). doi: 10.12932/ap0272.31.4.2013 381 18. arnaud l, mathian a, boddaert j, amoura z. late-onset systemic lupus 382 erythematosus. drugs aging 2012;29(3):181-189. doi: 10.3899/jrheum.080957 383 19. lalani s, pope j, de leon f, peschken c. clinical features and prognosis of 384 late-onset systemic lupus erythematosus: results from the 1000 faces of lupus study. 385 j rheumatol 2009;37(1):38-44. doi: 10.3899/jrheum.080957 386 20. beckwith h, lightstone l. rituximab in systemic lupus erythematosus and lupus 387 nephritis. nephron clin pract 2014;128(3-4):250-254. doi: 10.1159/000368585 388 21. mahajan a, amelio j, gairy k, kaur g, levy r, roth d, et al. systemic lupus 389 erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping 390 disease severity and progression. lupus 2020;29(9):1011-1020. doi: 391 10.1177/0961203320932219 392 22. yu h, nagafuchi y, fujio k. clinical and immunological biomarkers for systemic 393 lupus erythematosus. biomolecules 2021;11(7):928. doi: 10.3390/biom11070928 394 23. giannouli s. anaemia in systemic lupus erythematosus: from pathophysiology to clinical 395 assessment. ann rheum dis 2006;65(2):144-148. doi: 10.1136/ard.2005.041673 396 24. al arfaj a, khalil n. clinical and immunological manifestations in 624 sle patients in 397 saudi arabia. lupus (2009); 18(5):465–473. https://doi.org/10.1177/0961203308100660 398 25. alsaleh j, jassim v, elsayed m, saleh n, harb d. clinical and immunological 399 manifestations in 151 sle patients living in dubai. lupus 2008; 17(1):62-66. 400 doi:10.1177/0961203307084297 401 26. el hadidi k, medhat b, abdel baki n, abdel kafy h, abdelrahaman w, yousri a, et al. 402 characteristics of systemic lupus erythematosus in a sample of the egyptian population: a 403 14 retrospective cohort of 1109 patients from a single center. lupus. 2018;27(6):1030-1038. 404 doi:10.1177/0961203317751856 405 27. al rasbi a, abdalla e, sultan r, abdullah n, al kaabi j, al-zakwani i, et al. spectrum 406 of systemic lupus erythematosus in oman: from childhood to adulthood. rheumatology 407 international 2018; 38(9):1691–1698. https://doi.org/10.1007/s00296-018-4032-2 408 28. al-shujairi a, elbadawi f, al-saleh j, hamouda m, vasylyev a, khamashta m. 409 literature review of lupus nephritis from the arabian gulf region. lupus 2022; 0(0). 410 doi:10.1177/09612033221137248 411 29. hancock j, khoshgoftaar t. catboost for big data: an interdisciplinary review. j big 412 data 2020;7(1). doi: 10.1186/s40537-020-00369-8 413 30. prokhorenkova l, gusev g, vorobev a, dorogush a, gulin a. catboost: unbiased 414 boosting with categorical features. arxiv [pre-print] 2017 version 5 doi: 415 https://doi.org/10.48550/arxiv.1706.09516 416 31. anghel a, papandreou n, parnell t, de palma a, pozidis h. benchmarking and 417 optimization of gradient boosting decision tree algorithms. arxiv preprint 2018. version 418 3 doi: https://doi.org/10.48550/arxiv.1809.04559 419 32. branco p, torgo l, ribeiro r. a survey of predictive modeling on imbalanced 420 domains. acm comput surv 2016;49(2):1-50. doi: 421 https://dl.acm.org/doi/10.1145/2907070 422 33. pargent, f., pfisterer, f., thomas, j., bischl, b. regularized target encoding outperforms 423 traditional methods in supervised machine learning with high cardinality features. 424 comput stat 2022. https://doi.org/10.1007/s00180-022-01207-6 425 426 table 1: dataset’s features and its occurrence 427 feature name categories occurrence in sle population (no. %, n=138) occurrence in control population (no. %, n=81) fever yes no 41 (29.7%) 97 (70.2%) 7 (8.6%) 74 (91.3%) acute cutaneous lupus (acl) yes (rash) no 63 (45.6%) 75 (54.3%) 7 (8.6%) 74 (91.3%) chronic cutaneous lupus yes no 5 (3.6%) 133 (96.3%) 0 81 (100%) oral ulcers yes 29 (20%) 0 https://doi.org/10.1007/s00296-018-4032-2 https://doi.org/10.48550/arxiv.1809.04559 https://dl.acm.org/doi/10.1145/2907070 https://doi.org/10.1007/s00180-022-01207-6 15 no 109 (79%) 81 (100%) alopecia yes no 57 (41.3%) 81 (58.7%) 4 (4.9%) 77 (95%) joint involvement yes no 121 (87.7%) 17 (12.3%) 0 81 (100%) serositis yes no 9 (6.5%) 129 (93.5%) 0 81 (100%) renal disorders yes no 62 (44.9%) 76 (55%) 0 81 (100%) lupus nephritis class none (no kidney biopsy) class ii class iii class iv class v 35 (25.3 %) 1 (0.4%) 4 (1.8%) 16 (7.3%) 5 (2 %) 0 0 0 0 0 proteinuria yes no 51 (37%) 87 (63%) 0 81 (100%) vasculitis yes no 12 (8.7%) 126 (91.3%) 0 81 (100%) neurologic disorder none psychosis seizure 121 (87.7%) 5 (3.6 %) 12 (8.7%) 81 (100%) 0 0 hemolytic anemia yes no 47 (34%) 91 (66%) 6 (7.4%) 75 (92.6%) leukopenia yes no 18 (13%) 120 (86.9%) 1 (1.2%) 80 (98.7%) thrombocytopenia yes no 11 (8%) 127 (92%) 0 81 (100%) anti-dsdna positive negative 102 (73.9%) 36 (26%) 2 (2.4%) 79 (97.5%) anti-smith (sm) antibody positive negative 17 (12.3%) 121 (87.7%) 0 81 (100%) antiphospholipid antibodies positive negative 46 (33.3%) 92 (66.6%) 2 (2.5%) 79 (97.5%) c3 complement positive negative 95 (68.8%) 43 (31.1%) 2 (2.5%) 79 (97.5%) c4 complement positive negative 95 (68.8%) 43 (31.1%) 2 (2.5%) 79 (97.5%) rheumatoid factor positive negative 18 (13%) 120 (86.9%) 0 81 (100%) gender male 5 (3.6%) 12 (14.8) female 133 (96.4%) 69 (85.2%) 20 years or less 16 (11.6%) 1 (1.2%) 21 – 25 year 15 (10.8%) 5 (6.2%) 26 – 30 year 25 (18.1%) 9 (11.1%) 16 age period 31 – 35 year 29 (21%) 11 (13.6%) 36 – 40 year 16 (11.6%) 8 (9.9%) 41 – 45 year 23 (16.6%) 7 (8.6%) 46 – 50 year 5 (3.6%) 7 (8.6%) more than 50 year 6 (4.3%) 33 (40.7%) 428 429 430 figure 1: flowchart of the three-stage interpretable framework. 431 432 17 433 figure 2: force plot of catboost model prediction (values are normalized). f(x) is the 434 predicted probability. the arrows in each plot show the direction of influence each predictor 435 has over the payout i.e. the prediction. the colors are used to indicate the influence of the 436 predictors, whether it increases (red) or reduces (blue) the probability of having sle. 437 438 439 figure 3: waterfall plot of catboost model. the waterfall plot displays shap values 440 representing feature contribution toward a positive prediction. it reflects the magnitude of 441 influence each predictor had. the colors represent negative shap values for blue, and 442 positive shap values for red. 443 444 18 445 figure 4: summary plot of catboost model. the summary plot combines feature importance 446 with feature effects. each point on the summary plot is a shapley value for a feature and an 447 instance. the position on the y-axis is determined by the feature’s importance and on the x-448 axis by the shapley value. the summary plot is similar to the waterfall plot in ranking the 449 contribution of all features based on shap values. the major difference between the two is 450 that it is applied to the entire testing set rather than one single data observation. each dot 451 represents an observation from the testing set, and the color of the dot reflects the value of the 452 associated feature. for example, in the feature ‘age’ red dots correspond to patients with high 453 value i.e. old patients and blue corresponds to young patients. 454 455 19 456 figure 5: the frequency of the most influential features as shown by shap in cohorts across 457 the arab region. 458 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 75-78, epub 16th mar 2009 submitted 7th may 08 revision req. 25th oct 08, revision recd. 17th nov 08 accepted 28th jan 09 departments of 1medicine, 3radiology & molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman; 2department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: mansours@omantel.net.om gastric adenocarcinoma in association with tuberous sclerosis case report saeed ahmed,1 ikram burney,1 sukhpal sawhney,3 *mansour s al-moundhri2 abstract we report the first case of gastric cancer in association with tuberous sclerosis. tuberous sclerosis is an autosomal dominant disorder which presents with a constellation of signs including benign tumours in the brain and in other vital organs such as the kidneys, heart, eyes, lungs, and skin. a combination of symptoms may include seizures, developmental delay, behavioural problems, skin abnormalities, and lung and kidney disease. it is caused by mutations on either of two genes, tuberous sclerosis genes, tsc or tsc2, which encode for the proteins hamartin and tuberin respectively. these proteins act as tumour growth suppressor agents that regulate cell proliferation and differentiation. tuberous sclerosis has been associated with hamartomatous growths and angiomyolipomas, an association with gastric cancer has not been reported; however, this could be a co-incidental finding and further cases need to be reported. keywords: mucinous adenocarcinoma; tuberous sclerosis; hamartoma; lymphangiomyomatosis; gastric cancer; case report; oman. بِيّ دَ احلَ لُّبٌ للتَصَ املصاحبة املعدية الغدية السرطانة حالة تقرير سوهني سخبال برني، اكرام أحمد سعيد، منصور املندري، خالل يتجلى من أن ميكن سائد يَّ دِ سَ جَ اضطراب وِراثيٌ احلدبي هو والتصلب . احلدبي للتصلب املصاحب املعدة لسرطان حالة أول امللخص: ندرج هنا الصرع األعراض فقد تشمل أما . والرئتني واجللد والعيون والقلب كالكليتني احليوية األجهزة بقية وفي الدماغ في احلميدة األورام مثل معقدة عالمات 1 (رقم املورثات اثنني من في طفرات نتيجة احلدبي التصلب يحصل . الكلية والرئتني وأمراض اجللد ــوهات تش ، ــلوكية الس ــاكل املش ، النمائي ، التأخر يصاحب . ومتايزها اخلاليا عملية تكاثر ــم تنظ يتم األورام وبذا منو جماح كبح على اللذان يعمالن ، والتيوبرين الهامارتني ــي بروتين ــفران يش ــن اللذي و2) نحتاج إلى هذه مجرد صدفة ولهذا تكون ميكن أن . ــرطان املعدة س وكذلك ، الوِعائِيّة لِيةٌّ ضَ العَ يةٌّ مِ ــحْ واألورام الشَ العابِيّة األوَراَمِ منو احلدبي التصلب . أخرى حلاالت تقارير . عمان ، حالة تقرير ، املعدة ،سرطان وِعائِيّ يٌّ ْفِ ملِ لِيٌّ ضَ عَ وُرامٌ ، احلدبي التصلب ، العابِيّة األوَراَمِ ، يَّة خاطِ مُ يَّةٌ دِّ غُ رَطانَةٌ سَ الكلمات: مفتاح we report the case of a lady diagnosed to have gastric adenocar-cinoma, who was also known to have tuberous sclerosis. although, tuberous sclerosis is known to be associated with hamartomatous growths and angiomyolipomas and fibromas, an association with gastric cancer has not been reported previously. c a s e r e p o r t a 45 years old omani lady presented at sultan qaboos university hospital, muscat, oman, with a one-week history of marked decrease in appetite and excessive vomiting. clinical examination showed epigastric fullness, an enlarged palpable hard liver and a sister mary joseph’s nodule. these are described as metastatic lesions to the umbilicus from many primary sources (e.g. stomach, pancreas, endometrium, ovary, cervix, c a s e r e p o r t 76 a h m e d s a e e d , m a n s o u r s a l m o u n d h r i , i k r a m b u r n e y a n d s u k h pa l s aw h n e y colon, small bowel, gallbladder, prostate, lung, and breast). in addition, the left kidney was noted to be enlarged and easily palpable. examination of her face revealed multiple adenoma sebaceum consistent with tuberous sclerosis [figure 1]. she also had an incidental finding of bilateral corneal opacities, which have not been reported before in association with tuberous sclerosis. her past medical history was significant for diagnosis of tuberous sclerosis and a right nephrectomy. initial investigations showed normal haemogram and biochemistry, while a high resolution computed tomography (ct) scan of her lungs showed numerous thin walled cystic air spaces of varying sizes distributed diffusely throughout the lungs with intervening normal lung parenchyma suggestive of lymphangiomyomatosis [figure 2]. a contrast enhanced ct scan of the abdomen showed the left kidney replaced by a large vascular mass with fat content (arrows) representing an angiomyolipoma [figure 3]. a non-contrast ct brain scan showed a calcified subependymal and left frontal lobe hamartomas (arrows) ( fig 4). in view of obstructive symptoms, she underwent distal palliative gastrectomy. intra-operative findings showed an antral mass invading into the head of the pancreas. metastatic disease was also noted in pre-pyloric and portal lymph nodes as well as the peritoneum. the histopathology of postoperative samples showed a moderately differentiated mucin secreting adenocarfigure 3: a contrast enhanced computed tomography scan of the abdomen shows the left kidney replaced by a large vascular mass with fat content (arrows) representing an angiomyolipoma figure 4: non contrast computed tomography scan of brain shows calcified left subependymal hamartomas (arrows) along left lateral ventricle and another one in left frontal lobe with surrounding hypodense white matter suggestive of demyelination figure 1: image of part of face showing adenoma sebaceum figure 2: high resolution computed tomography scan of lungs shows bilateral, scattered, thin walled cysts, with intervening normal lung parenchyma 77 g a s t r i c a d e n o c a r c i n o m a i n a s s o c i at i o n w i t h tu b e r o u s s c l e r o s i s cinoma of the stomach with metastatic deposits in the pre-pyloric and portal lymph nodes as well as the peritoneum. in summary, this 45 years old lady was found to have stage iv adenocarcinoma of the stomach, against a background of tuberous sclerosis, and had undergone palliative gastrectomy, with gross macroscopic residual disease. she was subsequently treated with palliative chemotherapy. following four cycles of palliative 5-flourouracil by continuous intravenous infusion, she had a partial response. more recently she has developed obstructive jaundice, but still enjoys a world health organisation/european clinical oncology group (who/ecog) performance status of 1 [table 1]. d i s c u s s i o n tuberous sclerosis is a genetic disorder with autosomal dominant inheritance.1 the incidence of tuberous sclerosis is 1 in 6,000 births. mutations in one of two tumour suppressor genes, tuberous sclerosis complex gene type 1 (tsc1) and tuberous sclerosis gene type 2 (tsc2), cause tuberous sclerosis. 1,2 it is characterised by a tendency to develop tumourous growths in widespread locations throughout the body.1,3 characteristic skin lesions often suggest the diagnosis. often there is no family history since as many as 60% of cases are due to a new germ line mutation. usual presentations are either with epilepsy or due to abnormal hamartomatous growths noted incidentally.4 the most important hamartomas are cerebral, cortical tubers, which are regions of abnormal cortical architecture with distinctive large neuronal cells. cortical tubers cause some of the most important clinical manifestations of tuberous sclerosis namely epilepsy, mental retardation, and abnormal behaviour including autism.5 other hamartomatous lesions in tuberous sclerosis include sub-ependymal nodules, facial angiofibromas, sub-ungual fibromas, forehead plaques, shagreen patches, cardiac rhabdomyomas, and renal angiomyolipomas and cysts.6 pulmonary lymphangiomyomatosis is a rare disease which results from benign proliferation of smooth muscle in lung and other organs.7 cystic lung changes associated with tuberous sclerosis are exceedingly rare occurring in less than 1% of patients.8 genetic predisposition to neoplasia often involves mutations in the tumour suppressors (tuberous sclerosis complex) tsc1 and tsc2. inactivation of tsc1 and tsc2 genes contributes to the development of a wide range of hamartomatous lesions. tsc genes play a role in the phosphoinositide 3-kinase pathway, dysregulation of which is implicated in a wide range of human malignancies, raising the possibility that their activation or suppression could contribute to the development of some sporadic cancers such as transitional cell bladder cancer, renal cell cancer and sporadic astrocytomas. due to improved identification of the variable phenotypic expression, the reported incidence of tuberous sclerosis has increased. variations in tsc1 and tsc2 mutations are related to different phenotypic manifestations and risks of malignancy, such as an increased incidence of the tsc 2 mutation are reported in patients with renal cell carcinoma. tuberous sclerosis is well known to be associated with gastric hamartomas; however, association with gastric adenocarcinomas has not yet been reported. hamartomas are not considered to be a predisposing factor for adenocarcinoma and our case did not show signs of hamartomatous polyps. c o n c l u s i o n in conclusion, we report the case of a patient who was diagnosed to have a mucin-secreting adenocarcinoma. table 1: eastern cooperative oncology group (ecog, zubrod) performance scale performance status description 0 fully active; no performance restrictions 1 strenuous physical activity restricted; fully ambulatory and able to carry out light work 2 capable of all self care, but unable to carry out any work activities. up and about >50 percent of waking hours 3 capable of only limited self care; confined to bed or chair >50 percent of waking hours 4 completely disabled; cannot carry out any self care; totally confined to bed or chair oken mm, et al. am j clin oncol 1982; 5:649. 78 a h m e d s a e e d , m a n s o u r s a l m o u n d h r i , i k r a m b u r n e y a n d s u k h pa l s aw h n e y although hamartomatous polyps have been reported in the stomach in association with familial polyposis coli, a definite association of tuberous sclerosis with stomach cancer is lacking. however, this may be a coincidental finding and needs further reports to establish the association. r e f e r e n c e s 1. knowles ma, hornigold n, pitt e. tuberous sclerosis complex (tsc) gene involvement in sporadic tumours. biochemical soc trans 2003; 31:597-602. 2. carsillo t, astrinidis a, henske ep. mutations in the tuberous sclerosis complex gene tsc2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. proc natl acad sci usa 2000; 91:11413-16. 3. parry l, maynard jh, patel a, clifford sc, morrissey c, maher er, et al. analysis of the tsc1 and tsc2 genes in sporadic renal cell carcinomas. br j cancer 2001; 85:1226-30. 4. parry l, maynard jh, patel a, hodges ak, von deimling a, sampson jr, et al. molecular analysis of the tsc1 and tsc2 tumour suppressor genes in sporadic glial and glioneuronal tumours. hum genet 2000; 107:3506. 5. lendvay ts, marshall ff. the tuberous sclerosis complex and its highly variable manifestations. j urol 2003; 169:1635-42. 6. kim bk, kim yi, kim wh. hamartomatous gastric polyposis in a patient with tuberous sclerosis: j korean med sci 2000; 15:467-70. 7. luna c, gene r. pulmonary lymphangiomyomatosis associated with tuberous sclerosis. chest 1985; 88:47375. 8. gold a. tuberous sclerosis. in: rowland m, ed. meritt’s textbook of neurology. 8th edition. philadelphia, usa: lea and farber. p. 590. 1 submitted 20 jun 22 1 revision req. 1 aug 22; revision recd. 16 aug 22 2 accepted 7 sep 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.063 5 6 unilateral retroorbital pain secondary to isolated sphenoid sinus 7 aspergillosis 8 *toshimasa yamaguchi, rie oyama, katsushu shimizu 9 10 primary care and advanced triage section, osaka city general hospital, osaka, japan. 11 *corresponding author’s e-mail: dtoryamaguchi@gmail.com 12 13 a 75-year-old man with type 2 diabetes mellitus presented with a one-day history of general 14 fatigue, vomiting, and headache. he noted severe pain in the left retroorbital region, not 15 increasing on eye movement. he was awake and alert, and febrile (38.6 °c). no meningeal 16 signs, diplopia, or visual disturbance were noted. laboratory examination revealed a white 17 blood cell count of 7.23 × 103 cells/μl (normal range, 3.58 × 103 to 8.15 × 103 cells/μl) with 18 90.1% neutrophils (normal range, 39.6% to 67.0%) and c-reactive protein level of 27.1 mg/l 19 (normal value < 2.6 mg/l). his nasal endoscopic examination findings were unremarkable. 20 plain cranial computed tomography revealed a soft tissue density with high-density 21 calcifications on the left sphenoid sinus (figures 1a and b; blue arrowheads), suggestive of 22 fungal sinusitis. bone destruction and other sinus lesions were not noted. 23 24 the patient underwent trans-nasal endoscopic sphenoidotomy. examination of the resected 25 tissue revealed mycetoma with longitudinal septate hyphae. these branched at acute angles 26 and stained black on grocott’s methenamine silver stain under bright-field microscopy 27 (figure 2). these findings were indicative of aspergillosis. the resected tissue culture was 28 positive for aspergillus fumigatus. the patient was prescribed 400 mg oral voriconazole twice 29 daily on the first day, followed by 200 mg twice daily for eight weeks. his headache 30 eventually subsided, and the postoperative course was uneventful. he was discharged three 31 weeks after admission. no recurrence was found on computed tomography performed at the 32 12-week follow-up visit. 33 34 2 patient consent for publication has been obtained. 35 36 comment 37 isolated sphenoid sinus aspergillosis is rare due to the preferential seeding of fungal spores in 38 the ethmoid and maxillary sinuses.1,2 the incidence of sphenoid sinus aspergillosis is low, 39 between 0.5 and 1.2% per year.1 the most common symptom is retroorbital and occipital 40 headaches, followed by nasal blockage or discharge and recurrent mild epistaxis.1 however, 41 the diagnosis of aspergillosis in an isolated sphenoid sinus is challenging because of its non-42 specific symptoms. therefore, this condition is often diagnosed at the time of operation or 43 postoperatively and perhaps is even underdiagnosed. 44 45 fortunately, chronic non-invasive sphenoid sinus aspergillosis is a benign disease. however, 46 the sphenoid sinus is adjacent to vital structures, such as the cranial nerves, including the 47 optic nerve, internal carotid artery, and cavernous sinus. therefore, a prompt diagnosis is 48 essential for patients with sphenoid sinus aspergillosis because its delayed diagnosis may lead 49 to serious complications such as cerebral nerve involvement and cavernous sinus thrombosis 50 due to bone destruction and invasion to adjacent organs. 51 52 imaging modalities are essential in the diagnosis of sphenoid sinus aspergillosis. with the 53 prevalent use of computed tomography for the evaluation of headaches, the identification rate 54 of sphenoid sinus aspergillosis has increased considerably. the central high density in 55 sphenoid sinus lesions on computed tomography, caused by the accumulation of calcium salts 56 towards the necrotic area of central mycetoma, is considered characteristic of aspergillosis 57 and is useful in the diagnosis of this condition.3 it has been reported that the sensitivity of 58 computed tomography for the diagnosis of this disease is 53%1 based on the presence of 59 calcification in the sphenoid sinus, as seen in this case. moreover, magnetic resonance 60 imaging is useful due to its high sensitivity and specificity, especially in differentiating 61 sphenoid sinus tumours.1 therefore, if computed tomography findings are suggestive of a 62 tumour, magnetic resonance imaging may be useful to more clearly delineate the lesion.4 63 histological examination using grocott's methenamine silver stain is sufficient to confirm the 64 diagnosis of sinus aspergillosis. however, because the fungal ball is composed of dead spores, 65 it is estimated that culture identifies the pathogen in only 30% of the cases.1 moreover, 66 invasive aspergillosis requires prompt diagnosis and treatment, and the presence of invasion 67 of the mucosa by the pathogen should be confirmed. 68 3 69 the sphenoid sinus aspergillosis in this case was of a non-invasive type and was considered to 70 be aspergilloma of the sphenoid sinus.5 since this condition has a chronic course, an acute 71 course of fever and elevated c-reactive protein, an inflammatory marker, as observed in this 72 case were findings suggestive of a bacterial infection. therefore, although culture of the 73 resected tissue and pus were negative for bacteria, it cannot to be ruled out that complications 74 from an acute bacterial sinusitis with aspergilloma increased the pressure in the sphenoid 75 sinus, leading to retroorbital pain. although no antibiotics were prescribed in this case, 76 drainage, a basic surgical principle for abscesses, may have been sufficiently effective for 77 bacterial sinusitis. medical therapy alone is insufficient for aspergilloma, and a surgical 78 intervention is always recommended. 79 80 isolated sphenoid sinus aspergillosis is a rare but crucial disease that should be considered as 81 a cause of sphenoid sinusitis. moreover, surgical resection of the aspergilloma may prevent 82 further complications, such as acute bacterial sinusitis, and more invasive sinus involvement, , 83 especially in patients with diabetes and other immunocompromised conditions. 84 85 authors’ contribution 86 all authors had access to the patient's data and played a role in writing the manuscript. all 87 authors approved the final version of the manuscript. 88 89 acknowledgements 90 we would like to thank dr. keiji konishi for the useful discussion. we are grateful to editage 91 (www.editage.com) for english language editing. 92 93 4 references 94 1. thery a, espitalier f, cassagnau e, durand n, malard o. clinical features and outcome of 95 sphenoid sinus aspergillosis: a retrospective series of 15 cases. eur ann otorhinolaryngol 96 head neck dis 2012;129:179-184. https://doi.org/10.1016/j.anorl.2011.06.005. 97 2. deutsch pg, whittaker j, prasad s. invasive and non-invasive fungal rhinosinusitis-a 98 review and update of the evidence. medicina (kaunas) 2019;55:319. 99 https://doi.org/10.3390/medicina55070319. 100 3. lee dh, yoon tm, lee jk, joo ye, park kh, lim sc. invasive fungal sinusitis of the 101 sphenoid sinus. clin exp otorhinolaryngol 2014;7:181-187. 102 https://doi.org/10.3342/ceo.2014.7.3.181. 103 4. kumar d, nepal p, singh s, ramanathan s, khanna m, sheoran r, et al. cns 104 aspergilloma mimicking tumors: review of cns aspergillus infection imaging 105 characteristics in the immunocompetent population. j neuroradiol 2018;45:169-176. 106 https://doi.org/10.1016/j.neurad.2017.11.001. 107 5. charakorn n, snidvongs k. chronic sphenoid rhinosinusitis: management challenge. j 108 asthma allergy 2016;9:199-205. https://doi.org/10.2147/jaa.s93023. 109 110 https://doi.org/10.3390/medicina55070319 5 111 figure 1: axial (a) and coronal (b) planes of plain cranial computed tomography 112 demonstrating a soft tissue mass with abnormal high-density calcifications in the left 113 sphenoid sinus (blue arrowheads). 114 6 115 figure 2: bright-field microscopy of the resected tissue showing septate hyphae branching at 116 acute angles and producing the characteristic black stain on grocott’s methenamine silver 117 staining, indicative of aspergillosis. 118 july 2008.indd cushing’s disease pituitary surgery versus adrenalectomy omayma el-shafie,1 fatma b abid,1 nayal al-kindy,1 dilip sankhla,2 nicholas j woodhouse3 sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 211-214 sultan qaboos university© submitted 31st october 2007 accepted 31st march 2008 c a s e r e p o r t كوشينغ مرض الكظرية الغدة استئصال مقابل النخامية الغدة جراحة وودهاوز نيكوالس شنكال، ديليب الكندي، نايل عبد، بن اميمة الشفيع، فاطمة املرض سبب كان عمان. ــلطنة س في قابوس ــلطان الس جامعة ــفى الطب الباطني مبستش ــم قس ــينغ من ملرض كوش حالتني امللخص: هذا وصف األول املريض ــافه. اكتش من ــي املغناطيس الرنني صور ــتطع تس النخامية لم بالغدة حجم الورم لصغر ونظرا بالغدة النخامية. جدا ورم صغير وجود الدم ارتفاع ضغط العظام، في أدى إلى هشاشة وكسور مما مبكرا يكتشف ولم سنوات لعدة هذا املرض من يعاني وكان عاما ((14 العمر من يبلغ إزالة بواسطة عالجها 40 عاما ومت العمر من فتبلغ الثانية املريضة أما املنظار. بواسطة الكظرية الغدة استئصال بواسطة عالجه مت قامته. وقصر لعالج املثلى والطريقة كلتا العمليتني ــاوئ ومس لفوائد كامل وصف املقال هذا في متاما. املريضني ــفاء ش مت األنف. فتحة خالل من النخامية الغدة األمراض. النوع من هذا عمان. حالة، تقرير الكظر، استئصال الداخلي، التنظير النخامية، الغدة اجلراحة، الكلمات: مرض كوشينغ، مفتاح department of 1medicine, 2radiology & molecular imaging, sultan qaboos university hospital, muscat, oman; 3department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, oman *to whom correspondence should be addressed. email: omayma0@hotmail.com cushing’s disease is an uncommon and complex disorder.1 only six cases have been seen at sultan qaboos university hospital, (oman) since 1986 (personal observation by nicholas j woodhouse). cushing’s disease is caused by excessive adrenocorticotropic hormone (acth) production by a pituitary tumour2 and must be distinguished from cushing’s syndrome, due to ectopic acth overproduction by endocrine tumours of the lung, pancreas and other rarer sites.3 in this article, we describe two patients with cushing’s disease whose pituitary magnetic resonance imaging (mri) scans were negative. additional studies were then required to document the presence of a pituitary lesion and exclude an ectopic acth source. our adult female patient was cured by transphenoidal surgery (tss) and the young boy with growth retardation by bilateral endoscopic adrenalectomy. the reasons for these different therapeutic approaches are discussed below. c a s e 1 a 40-year-old english woman was referred for further investigation of recent onset hypertension. on examination, central obesity was observed. she also had ulcerated mosquito bites on both shins that had not healed for four months. cushing’s syndrome was suspected clinically and acth dependant disease confirmed by finding raised cortisol and acth levels. cortisol levels were suppressed by more than 50% by high dose dexamethasone which suggested pituitary abstract we describe two patients of the department of medicine at sultan qaboos university hospital, muscat, oman, with cushing’s disease. their magnetic resonance imaging scans of the pituitary were negative. one patient was treated by transsphenoidal surgery and the other by bilateral endoscopic adrenalectomy. both procedures were successful and the patients cured. the advantages and disadvantages of these two approaches are discussed. key words: cushing’s disease; surgery, pituitary; endoscopy; adrenalectomy; case report; oman. o m ay m a e l -s h a f i e , fat m a b a b i d , n aya l a l k i n d y, d i l i p k u m a r a n d n i c h o l a s j wo o d h o u s e 212 disease. as there was no evidence of a pituitary or ectopic tumour on the mri or computed tomography (ct) scans, her disorder was initially controlled using oral ketaconazole and metyrapone. she was then referred to the endocrine unit at the hammersmith hospital in london where she underwent selective inferior petrosal sinus sampling with acth measurement following the intravenous administration of cortisol releasing hormone. this confirmed the presence of a left-sided pituitary lesion, and subsequently the left side of the pituitary gland was blindly removed by tss sugery. histology revealed a basophilic tumour positive for acth on immunofluroscence. she remains well four years later, only taking replacement thyroxine. c a s e 2 a 14-year-old boy was referred with a five-year history of growth retardation, hypertension, obesity, delayed sexual development (testosterone 1.8 (n = 627nmol/l)) and severe low back pain. earlier studies had shown acth levels repeatedly within the ‘normal’ (4.2, 4.0, 3.5 [n=2.2-10.0pmol/l]) range at a time when his cortisol levels were elevated (923, 918, 812 [n = 240-620nmol/l]). upon examination, he was clinically short with a height of 128 cm, and cushingoid features. his bp was 140/80 on lisinopril. an x-ray of the lumbar spine revealed severe loss of bone mineral density and multiple wedge compression fractures [figure 1]. the bone densitometry was very low at 0.542 g/cm2. cortisol levels were suppressed by 95% after high dose dexamethasone suppression [table 1] indicative of pituitary acth production, but as in case 1, there was no evidence of a pituitary tumour on his initial mri scan. ectopic acth production was deemed unlikely in the absence of any obvious source on the ct or mri scans of the lungs or abdomen; furthermore, the administration of octreotide (100 mcg 8 hourly subcutaneously for 3 days), failed to lower his cortisol levels. the patient then underwent bilateral laparoscopic adrenalectomy rather than pituitary surgery, as there were concerns that his subsequent growth and sexual development might be adversely affected. the histology revealed bilateral adrenal hyperplasia. within twenty-six months of taking replacement hydrocortisone and fludrocortisone his table 1: cortisol levels both patients after dexamethasone given 2 mg 6 hourly for 48 hours cortisol nmol/l cortisol nmol/l before dexametasone after dexametasone patient 1 861 344 patient 2 812 40 figure 1: patient 2. x-ray of the lumbar spine showing severe loss of bone mineral density with multiple wedge compression fractures in the lower dorsal and upper lumbar vertebral body (d12 & 4) c u s h i n g ’ s d i s e a s e 213 height had increased from 123 to 140 cm and testosterone from 1.8 to 10.1 nmol/l. unfortunately, there was only minimal improvement of his bone mineral density 0.554 g/cm2, but his total skeletal calcium must have increased considerably having grown 17cm. we expect his bone mineral density to increase when his growth spurt is completed. twenty six months later, however, he had become more pigmented, the acth level having increased from 4 to 22.6pmol/l and he developed an obvious microadenoma in the anterior lobe of the pituitary [figure 2]. he was then referred for tss abroad. d i s c u s s i o n both of these patients had cushing’s disease but their pituitary tumours were not visible on mri at presentation. this is reportedly the case in up to 40 % of newly diagnosed patients.3 in these circumstances, therapeutic decision-making becomes more difficult as invasive measures are required to document the pituitary origin of the excess circulatory acth levels before referral for surgery. the first patient underwent canulation with sampling of the petrosal sinus veins, and later removal of the left half of her pituitary gland. the disease was cured, but five years later she still requires thyroxine replacement therapy. varying degrees of postoperative hypopituitarism are seen in 30-40 % of all cases particularly those whose surgery is carried out blindly as in this case.4 recently the european cushing’s disease survey group reviewed 668 patients: major non-hormonal complications of transseptosphenoidal occurred in 14.5% of the patients; hypogonadism in 14-53%; hypothyroidism in 14-40%, and severe growth hormone deficiency in 13%.5 we concluded that the second patient also had pituitary dependant disease evidenced by his response to high dose dexamethasone6 and an absence of any obvious ectopic acth source on ct or mri scanning of the lungs and abdomen. furthermore, there was no response to octreotide; cortisol levels are usually unchanged in cushing’s disease whereas a fall is observed in patients with ectopic acth production as such tumours express somatostatin receptors.7 in the 14 year-old boy whose complaints were short stature and back ache, we were faced with two options: either to refer him abroad for petrosal sinus sampling and pituitary surgery, or to remove his adrenals. the former procedure would involve the risk of developing growth or sex hormone deficiencies5 whereas adrenalectomy by laparoscopy is safe and immediately curative.8 moreover, the patient’s sphenoid sinus had failed to pneumatise making a transsphenoidal approach more difficult. we therefore proceeded with laparoscopic bilateral adrenalectomy. nelson’s syndrome, characterized by accelerated growth of the pituitary tumour in the face of postoperatively reduced cortisol levels, occurs in between 8 and 38%9, 10 of patients with cushing’s disease after adrenalectomy, usually 7 to 24 years after surgery.11, 12 after 26 months, he became more pigmented, his acth level increased and an mri scan showed an 8 mm anterior lobe tumour [figure 2]. the rapid growth of our patient’s tumour is unusual and might have been related to the dramatic response to dexamethasone evidenced by a 95% reduction of his cortisol level during testing. this observation prompted us to speculate that patients with cushing’s disease who have the most dexamethasone sensitive pituitary tumours are more likely to develop nelson’s syndrome following adrenalectomy than those whose tumours are more resistant. however, in two other reports, the degree of susceptibility to the dexamethasone suppression test did not provide evidence for prediction of nelson’s syndrome.9-12 age itself appears to be important; nelson’s syndrome being more common in young patients figure 2: (patient 2) magnetic resonance imaging of the pituitary (t1w sagittal image, 2007) shows an 8 mm hypointense lesion in anterior lobe (microadenoma) after adrenalectomy. and rare after the age of 40.9 the patient has now been referred for tss abroad. r e f e r e n c e s 1. brown rl, weiss re. an approach to the evaluation and treatment of cushing’s disease. expert rev anticancer ther 2006; 6:s37-s46. 2. labeur m, theodoropoulou m, sievers c, paez-pereda m, castillo v, arzt e, et al. new aspects in diagnosis and treatment of cushing’s disease. front horm res 2006; 35:169-178. 3. kaye tb, crapo l. the cushing syndrome: an update on diagnostic tests. ann intern med 1990; 112:434-444. 4. de herder ww, uitterlinden p, pieterman h, tanghe hl, kwekkeboom dj, pols ha, et al. pituitary localization in patients with cushing’s disease by magnetic resonance imaging. is there a place for petrosal sinus sampling? clin endocrinol 1994; 40:87-92. 5. bochicchio d, losa m, buchfelder m. factors influencing the immediate and late outcome of cushing’s disease treated by transsphenoidal surgery: a retrospective study by the european cushing’s disease survey group. j clin endocrinol metab 1995; 80:3114-3120. 6. damian g, morris, grossman b. cushing’s syndrome. endotext.com, chapter 7, 6 dec 2002. from www.endotext.com. accessed october 2007. 7. woodhouse nsy, dagogo-jack s, ahmed m, judzewitsh r. acute and long term effects of octreotide in patients with acth dependant cushing’s syndrome. am j med 1993; 95:305-308. 8. mccance e, russell cf, kennedy tl, hadden dr, kennedy l, atkinson ab. bilateral adrenalectomy: low mortality and morbidity in cushing’s disease. clin endocrinol 1993; 39:315-321. 9. kemink l, pieters g, hermus a, smals a, kloppenborg p. patient’s age is a simple predictive factor for the development of nelson’s syndrome after total adrenalectomy for cushing’s disease. j clin endocrinol metab 1994; 79:887-889. 10. assie g, bahurel h, coste j, silvera s, kujas m, dugue ma, et al. corticotroph progression after adrenalectomy in cushing’s disease: a reappraisal of nelson’s syndrome. j clin endocrinol metab 2007; 92:172-179. 11. assié g, bahurel h, bertherat j, kujas m, legmann p, bertagna x. the nelson syndrome revisited. pituitary. 2004; 7:209-215. 12. nagesser sk, van seters ap, kievit j, hermans j, krans hm, van de velde cj. long-term results of total adrenalectomy for cushing’s disease. world j surg 2000; 24:108-113. o m ay m a e l -s h a f i e , fat m a b a b i d , n aya l a l k i n d y, d i l i p k u m a r a n d n i c h o l a s j wo o d h o u s e 214 august 2007 vol 7 copy.indd keyhole surgery of the kidney at sultan qaboos university hospital, oman *mohammed s al-marhoon, josephkunju mathew, hawraa al-lawati عمان ، قابوس جامعة السلطان مستشفى جراحة الكلى باملنظار في اللواتي حوراء ماثيو، كوجنو جوسيف املرهون، سالم محمد 31 مريضا في أول جتربتنااملبكره ــرض نع .1998 عام في قابوس ــلطان الس ــفى جامعة مستش في باملنظار الكلى جراحة الهدف: أدخلت ــص: امللخ الكلية حصى لتكسير خضعوا الذين املرضى 25 من استعراض مت ــتعادية اس بطريقة الطريقة: . ــنوات س ثماني مدى على العملية هذه لهم أجريت باملنظار احلالبي احلويضي االتصال منطقة لتوسيع خضعوا 6 مرضي و كبيرة كلوية حصى لوجود اجللد) خالل من الكلية حصاة (استخراج باملنظار 28% املرضى وكان معدل املضاعفات من (25/17) 68% ــي ف احلصى إزالة حتقق الكلية ــير حصى تكس في مجموعة النتائج: . احلويض ــالل خ ــن م ومقارنة ناجحة املنظار عمليات نتائج كانت اخلالصة: .(6/5) 83% احلالب ضيق إزالة في النجاح نسبة كانت مجموعة توسيع احلالب في .(25/7) للنتائج العاملية. ؛ فتح احلويض. الكلى حصى الكلية باملنظار، حصى الكلمات: تكسير مفتاح department of surgery, sultan qaboos university hospital, p. o. box 35, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: mmarhoon@squ.edu.om sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 117-122 sultan qaboos university© submitted 6th march 2007 c l i n i c a l a n d b a s i c r e s e a r c h abstract objectives: percutaneous access surgery of the kidneys was introduced in sultan qaboos university hospital (squh) in 998. we are presenting our early experience in the first 3 patients operated on over an eight year period using the percutaneous approach. methods: a retrospective review of 25 patients, who underwent percutaneous nephrolithotomy (pcnl) for the treatment of large renal stones and 6 patients who underwent endopyelotomy for the treatment of pelviureteric junction (puj) obstruction. results: in the pcnl group complete stone clearance was achieved in 68% (7/25) patients and the complication rate was 28% (7/25). in the endopyelotomy group the success rate of relief of obstruction of puj measured by renogram and relief of symptoms was 83% (5/6 patients). conclusion: our early results of pcnl are promising and comparable to international results. keywords: percutaneous nephrolithotomy; kidney calculi; endopyelotomy. advances in knowledge this article describes the technique of pcnl and how to deal with large renal stones and the different ways of managing residual stones. application to patient care the article educates the treating doctor that large renal stones (> 3 cm) are likely to be associated with decreased stone clearance. it is therefore advisable to discuss different treatment options to deal with residual stones with the patient before surgery. the prevalence of renal stones in oman is unknown, however a study in the gulf area has shown a clear stone season corresponding to the hot summer months.1 data from developing countries have shown that calcium oxalate was the commonest constituent of both kidney and bladder stones.2 the percutaneous approach to the kidney for the management of large kidney stones and puj obstruction has revolutionised their management by avoiding large surgical incisions to access the kidm o h a m m e d s a l m a r h o o n , j o s e p h k u n j u m at h e w a n d h aw r a a a l l awat i 118 neys. pcnl and extracorporeal shock wave lithotripsy (eswl) have largely replaced open surgical intervention for the management of upper urinary tract calculi. eswl is the preferred treatment modality for calculi less than 3 cm in diameter as morbidity is lower than pcnl and success rates are comparable, however in stones 3 cm or larger (staghorn calculi) the morbidity of eswl rises substantially while the stone-free rate is less when compared to pcnl. pcnl is preferred for stones which are hard in consistency, in a dependent position or associated with distal obstruction. fernstrom and johansson reported the first percutaneous stone removal through mature nephrostomy tract in 1976, subsequently kurth and colleagues used an ultrasonic lithotrite to fragment and retrieve a staghorn calculus successfully.3 endopyelotomy, albeit seemingly new, is a contemporary of pyeloplasty. smith popularized the endourologic incisional approach in the united states and named it endopyelotomy.3 at sultan qaboos university hospital (squh), keyhole surgery of the kidney for removal of renal stones and repair of puj obstruction was introduced in 1998. the aim of this paper is to present our series of cases including 25 cases of pcnl and 6 cases of endopyelotomy. m e t h o d s the study included a review of 31 patients who were in two groups. the first group comprised 25 patients, who had pcnl for large kidney stones, and the second group comprised 6 patients who had endopyelotomy for puj obstruction. the study included all patients who underwent these two procedures over an 8 year period from may 1998 to october 2005 at squh. the patient files in both the groups were reviewed retrospectively and the following data were collected: clinical presentation, age of the patient, preoperative investigations, indications for surgery, complications and the outcome. preoperative assessment included: urine culture, renal function, coagulation, abdominal ultrasound and computed tomography (ct) scan. a ct scan of the abdomen (noncontrast and contrast) is obtained to identify the number and position of the stones, as well as to demonstrate the renal anatomic detail necessary for planning the percutaneous approach. a prophylactic parenteral antibiotic (gentamicin or ceftriaxone) was given at induction of anesthesia. a ureteric catheter was passed on the affected side using cystoscope and the patient was put in a prone position on the operative table. in both groups, a percutaneous nephrostomy tract was created to gain access to the renal pelvicaliceal system. this was done by a 1cm skin incision and puncture with 18-gauge needle into the desired calyx under x-ray control. in pcnl, the selection of the appropriate calyx used for percutaneous puncture was chosen to achieve the shortest tract to the stone. by taking a posterolateral transparenchymal path, damage to major blood vessels was avoided. the calyx was inspected for three factors: the relation to the 12th rib, the degree of hydronephrosis, and any malrotation. in endopyelotomy, generally, a midposterior or superolateral calyx was chosen, although, occasionally, an inferolateral calyx might be utilized. a guide wire was placed into the pelvicaliceal system and the needle was removed. the tract was then dilated by a set of dilators over a guide wire. finally, a rigid nephroscope was passed through a 30 french amplatz sheath into the collecting system [figure 1]. in pcnl the stone was broken by a pneumatic lithotripsy probe (lithoclast) whereas in endopyelotomy the stricture was cut by a cold urethrotome knife. postoperatively, in the pcnl group, the nephrostomy tube was removed within 48 hours after a check x-ray of kub (kidney, ureter, bladder) had ruled out residual fragments. if residual stones were present a second-look pcnl was done through the same track immediately on removing the nephrostomy tube in the operation theater, or if the residual stones were inaccessible, eswl was done at a later date. in the endopyelotomy group, a special nephrostomy tube with ureteral stent was left in place for 2-6 weeks and the patient was followed up by diuretic renogram after nephrostomy tube removal. r e s u l t s in the pcnl group of 25 patients, the mean age was 33 years (age range 2-60 years), of which 2 (8%) were children, including 16 males (64%) and 9 females (36%) the most common presentation was flank pain, 28% of patients had left flank pain and 24% had right flank pain [figure 2]. the indications for percutanous surgery were the removal of staghorn calculi in 36% (9/25) of patients, partial staghorn calculi in 28% (7/25) and lower caliceal calculi in 16% (4/25). the complication rate was 28% (7/25). the complications included urine leaking from the nephrostomy site 16% (4/25), urinary tract infection 8% (2/25), and one pak e y h o l e s u r g e r y o f t h e k i d n e y at s u lta n q a b o o s u n i v e r s i t y h o s p i ta l , o m a n 119 tient was converted to open surgery (pyelolithotomy) for failure to place the guidewire due to nondilatation of the lower calyx which was filled with the stone. complete stone clearance by pcnl was achieved in 68% (17/25) and 32% (8/25) of patients had residual stones that were cleared by eswl in 4% (1/25), second-look pcnl in 20% (5/25) and second-look pcnl followed by eswl in 4% (1/25) of patients [figure 3]. the size of stones treated were 1-2 cm (20%), 2-3 cm (32%) and more than 3 cm (48%). in the patients with residual stones, 87.5% (7/8) had stones larger than 3 cm. clinically insignificant residual fragments of less than 4 mm were kept under observation. the mean operative time for pcnl was 3.5 hours (range 2-6 hours). no blood transfusion intra or postoperative was required. the time between first and second look pcnl ranged from 5 to 7 days. the mean duration of follow up was 6 months. in the endopyelotomy group (6 patients), 66.6% (4/6) presented with left flank pain; one was found incidentally and one presented with abdominal mass (palpable kidney). the age ranged from 4-67 years. fifty percent (3/6) had endopyelotomy for secondary puj obstruction following failed pyeloplasty. all patients in this group had a preoperative renogram to establish the functional obstruction of puj and a postoperative renogram to assess relief of obstruction in combination with the clinical assessment of relief of symptoms. the success rate after endopyelotomy was 83% (5 patients out of 6 had relieve of obstruction documented by renogram and improvement in their symptoms). one patient had perinephric fluid collection and fever postoperatively for 1 week, which was resolved with antibiotics. the endopyelotomy stent was kept in for an average of 4 weeks. d i s c u s s i o n a n d c o n c l u s i o n pcnl and endopyelotomy are considered minimal access surgery for the kidney. they have several advantages over open surgery including small incision, minimal postoperative pain, rapid recovery and early return to work. pcnl has an additional advantage over open surgery in that the stone bearing calyx is directly entered, ensuring stone clearance under direct vision. pcnl is safe during pregnancy and is ideal for large, multiple, hard stones. co-existing distal obstruction such as infundibular stenosis and puj stenosis can be corrected during pcnl. the pcnl is the treatment figure 1: the operative settings with c-arm fluroscopy monitoring for the percutaneous approach m o h a m m e d s a l m a r h o o n , j o s e p h k u n j u m at h e w a n d h aw r a a a l l awat i 120 of choice for partial and complete staghorn stones and eswl can be used as ancillary treatment for residual fragments. endopyelotomy is especially advantageous when dealing with restenosis following pyeloplasty where open surgery is difficult due to adhesions. the stone free rate in our study is 68%. review of the literature shows that the overall stone-free rate for pcnl monotherapy for staghorn calculi ranges between 60% and 92%, whereas the stone-free rate for lower pole calculi treated with pcnl is 91%.3 in our study, all patients with lower caliceal stones, 16% (4/25), had complete stone clearance. chibber,4 in his study of 878 patients with staghorn calculi treated by pcnl showed that the overall complete clearance rate is 93%. in our study, the patients with residual stones, 87.5% (7/8), had stones larger than 3 cm emphasizing that the presence of staghorn calculus is a factor that leads to an increased risk of residual calculi. in our study of the pcnl group, there were 2 children (the 9 year old male presented with left pyelonephritis and the 2 year old male presented with left pyonephrosis), both of them had complete stone clearance by pcnl. shokeir et al.,5 in their study of 166 children for treatment of 1 to 2 cm stones, have shown that pcnl is better than eswl, yielding higher stone-free and lower re-treatment rates. in the present study we have used pneumatic lithotripsy in the fragmentation of the stones. it can effectively fragment stones of varying composition with a wide range of safety, however one of the disadvantages is that it is necessary to keep the probe as straight as possible. the holmium:yag laser has been found to be an effective and safe lithotriptor for most percutaneous stone surgery, however in patients with a very large stone burden the combination of laser with another more powerful intracorporeal lithotriptor may be necessary.6 the percutaneous approach to the kidney is not free of complications; the reported complications in the literature for pcnl are bleeding, urosepsis, retained stone fragments, ureteral injury, risk of injury to the bowel, duodenum, liver or spleen, and perforation of the collecting system of the kidney, which can result in extravasation of irrigant fluid into the peritoneal cavity, retroperitoneum or intravascular space. rare complications of pcnl include arteriovenous fistula and aneurysm of renal artery branches. the periooperative complications of pcnl reported in 128 patients figure 2: clinical presentation of the 25 patients who had pcnl k e y h o l e s u r g e r y o f t h e k i d n e y at s u lta n q a b o o s u n i v e r s i t y h o s p i ta l , o m a n 121 studied by vorrakitpokatorn et al.7 were hypothermia 56%, cardiovascular changes (57%) related to volume of irrigation fluid (normal saline), electrolyte changes, pleural tear, infection and bleeding. traditionally, a nephrostomy tube is placed in the tract at the end of pcnl to assure proper renal drainage, facilitate a second-look if necessary and ensure haemostasis. however, serial reports about tubeless percutaneous surgery for selected patients have recentely been published.8, 9 gelatine matrix haemostasis sealant has been used to seal nephrostomy tracts to reduce bleeding and extravasation after tubeless mini-percutaneous pcnl.10 however, aghamir et al.11 found that sealing the nephrostomy tract with surgicel (oxidized cellulose) after totally tubeless pcnl did not decrease bleeding or extravasation from the tract. the ‘mini-percutaneous’ technique was first developed for use in children. an 11to 15-f peel-away vascular access sheath was used instead of the commonly used 24to 30-f amplatz sheaths. pcnl was performed using pediatric instruments.12 the mini-percutaneous technique was adapted to adult patients with stones smaller than 2 cm. the mini-percutaneous technique requires a longer operative time and fragmentation of relatively small, otherwise extractable, stones. the advantages of this technique over standard pcnl remain to be established. in our study, 16% had second-look pcnl. davol et al.13 have reported that aggressive stone clearance obviates the need for routine second-look pcnl. endopyelotomy is a widely accepted alternative in the treatment of puj obstruction with a success rate between 63% and 88%.14 the success rate of our endopyelotomy group was 83%, which is based on the patients being symptom free as well as the postoperative diuretic renogram showing evidence of relief of obstruction. endopyelotomy related complications reported in the literature include stent-related problems, infection, urinoma and unrecognized incision of renal pelvis and, rarely, necrosis of the entire ureter.15 the serious complication of endopyelotomy is bleeding, which constitutes a 15% risk according to the series of gallucci, in their study of 976 patients.16 in our endopyelotomy group, the average time for leaving the stent in place was 4 weeks, however in an experimental study in an animal model (minipigs), kerbl and his co-workers,17 showed no statistical significance in the healing of ureters of animals with stents removed at 1 week or 4 weeks, but this finding has to be supported by clinical studies on humans. one of the limitations of this study, in addition to being retrospective, is the short follow-up period that makes comparisons to other data difficult. our results of stone free-rate after pcnl and the improvement of puj obstruction after endopyelotomy are comparable to international results. r e f e r e n c e s 1. al hadramy ms. seasonal variations of urinary stone colic in arabia. j pak med assoc 1997; 47:281-284. 2. hodgkinson a. composition of urinary tract calculi from some developing countries. urol int 1979; 34:2635. 3. clayman rv, mcdougall em, nakada sy. endourology figure 3: outcome of the 25 patients who had pcnl. 68% had complete stone clearance. m o h a m m e d s a l m a r h o o n , j o s e p h k u n j u m at h e w a n d h aw r a a a l l awat i 122 of the upper urinary tract, percutaneous renal and ureteral procedures. in: patrick cw, alan br, e. darracott v, alan jw, eds. campbell’s urology. philadelphia: w b saunders, 1998. p. 2809-2852. 4. chibber pj. percutaneous nephrolithotomy for large and staghorn calculi. j endourol 1993; 7:293-295. 5. shokeir aa, sheir kz, el-nahas ar, el-assmy am, eassa w, el-kappany ha treatment of renal stones in children: a comparison between percutaneous nephrolithotomy and shock wave lithotripsy. j urol 2006; 176:706-710. 6. jou yc, shen jh, cheng mc, lin ct, chen pc. percutaneous nephrolithotomy with holmium: yttriumaluminum-garnet laser and fiber guider-report of 349 cases. urology 2005; 65:454-458. 7. vorrakitpokatorn p, permtongchuchai k, raksamani eo, phettongkam a. perioperative complications and risk factors of percutaneous nephrolithotomy. j med assoc thai 2006; 89:826-833. 8 . yu ds. gelatin packing of intracortical tract after percutaneous nephrostomy lithotripsy for decreasing bleeding and urine leakage. j chin med assoc 2006; 69:162165. 9. limb j, bellman gc. tubeless percutaneous renal surgery: review of first 112 patients. urology 2002; 59:527531. 10 . nagele u, schilling d, anastasiadis ag, corvin s, seibold j, kuczyk m et al. closing the tract of mini-percutaneous nephrolithotomy with gelatine matrix hemostatic sealant can replace nephrostomy tube placement. urology 2006; 68:489-93. 11. aghamir sm, khazaeli mh, meisami a. use of surgicel for sealing nephrostomy tract after totally tubeless percutaneous nephrolithotomy. j endourol 2006; 20:293295 12. jackman sv, docimo sg, cadeddu ja, bishoff jt, kavoussi lr, jarrett tw the “mini-perc” technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol 1998; 16:371-374. 13. davol pe, wood c, fulmer b. success in treating renal calculi with single-access, single-event percutaneous nephrolithotomy: is a routine “second look” necessary? j endourol 2006; 20:289-292. 14. niemczyk p, krisch eb, zeiger l, marmar jl. use of diuretic renogram in evaluation of patients before and after endopyelotomy. urology 1999; 53:271-275. 15. sutherland rs, pfister rr, koyle ma. endopyelotomy associated ureteral necrosis: complete ureteral replacement using the boari flap. j urol 1992; 148:1490-1492. 16. gallucci m, fortunato p, schettini m, vincenzoni a. management of hemorrhage after percutaneous renal surgery. j endourol 1998; 12:509-12. 17. kerbl k, chandhoke ps, figenshau rs, stone am, clayman rv. effect of stent duration on ureteral healing following endoureterotomy in an animal model. j urol 1993; 150:1302-1305. july 2008.indd physicians, climate change and human health the theme of the world health organisation (who) initiated 2008 world health day, held on 7 april 2008, was protecting health from climate change.1 communities and organisations around the world hosted activities to establish greater public awareness of the health consequences of the climate changes that we are experiencing. who has specifically put a great effort into increasing awareness of the effects of global warming and other climate related factors that impact on human health. we, as physicians, also have an important and potentially major role to play in this exercise. in her world health day 2008 address, “the impact of climate change on human health”, 2 who director-general, dr. margaret chan, said, “the core concern is succinctly stated: climate change endangers health in fundamental ways. the warming of the planet will be gradual, but the effects of extreme weather events – more storms, floods, droughts and heatwaves will be abrupt and acutely felt……. affecting some of the most fundamental determinants of health: air, water, food, shelter, and freedom from disease”. she also pointed out that while climate change is a global phenomenon, its consequences will not be evenly distributed. certain populations are more susceptible than others e.g. children, the elderly and the infirm, and more so in developing countries. she drew attention to the fact that, “last year marked the turning point in the debate of climate change. the scientific evidence continues to mount that the climate is changing and human activities are the principal cause”. 2,3 the secretary-general of the united nations, ban ki-moon, in his world health day 2008 address,3 stated that “we need to give voice to this often overlooked reality, ensuring that protecting human health is anchored at the heart of the global climate change agenda.” he also pointed out that the impact will be most severe in poor countries e.g. by the year 2020, up to a quarter of a billion africans will experience increased water stress and up to 50% drop in crop yields. climate-related infectious diseases take their heaviest tolls on the most vulnerable, the children, the elderly and the infirm. we must do more to prepare for these challenges because climate change is real. it is accelerating and threatens all of us. climate change will erode the foundations of health. who has identified five major health consequences of climate changes:3, 4 (i) the agricultural sector is extremely sensitive to climate variability. rising temperatures and more frequent droughts and floods can compromise food security. 5 (ii) more frequent extreme weather events mean more potential deaths and injuries caused by storms and floods. the most recent cyclone nargis in myanmar, 5, 6 with over a hundred thousand deaths, is a typical example for this. our own experience in oman with cyclone gonu 7 last year was evidence enough with scores of deaths from flooding wadis and thousands of citizens suffering from a lack of clean fresh water, albeit only temporarily because of prompt government action.8 (iii) water is essential for hygiene, but in excess it will increase the burden of diarrhoeal diseases which are spread through contaminated water and food. these diseases are responsible for 1.8 million deaths each year and are the second leading infectious cause of childhood mortality. 2 (iv) heatwaves increase morbidity and mortality mainly in the elderly with cardiovascular or respiratory disease. (v) changing temperatures and patterns of rainfall are expected to alter the geographic distribution of insect vectors that spread infectious diseases such as malaria and dengue fever. in short, climate change can exacerbate problems that are already huge, largely concentrated in the developing world and already difficult to combat. what can we, as physicians, do and what role can we play? as clinicians, we owe it to our patients to explain to them the dangers of extremes of temperatures and exposure. estimates suggest that in 2003, during the european summer heat wave, approximately 70,000 more people died than would have been otherwise expected. it has been demonstrated that weather is associated with changes in birth rates and sperm counts, and with outbreaks m e s s a g e f r o m t h e e d i t o r i n c h i e f 125 126 m e s s a g e f r o m t h e e d i t o r i n c h i e f of pneumonia, influenza and bronchitis.9 decreased humidity in some countries in winter leads to drying of nasal mucosa and respiratory passages with increased respiratory infections. as family and community physicians, we owe it to the community and the public, to explain the dangers of climate change and to explain that most of the climate change is the result of human activities. 3, 10-12 global warming is not only made worse by greenhouse gases from industry, but all of us contribute to it by our daily habits. we also contribute to the change in climate by indiscriminate industrial logging and by cutting trees for fuel as in some communities. as educator physicians, we owe it to our students to explain the impact of changing climate on human health. climate change brings new challenges to the control of infectious diseases. seasonal changes in the availability of fresh water, regional drops in food production, and rising sea levels have the potential to force population displacement and increase the risks of civil conflict. as physician administrators, we owe to our community to ensure proper disposal of all wastes that may impact on the environment. we have to point out the need for clean air and unpolluted water. we also have to point out dangers of epidemics related to climate change such as the cholera outbreak in bangladesh closely linked to flooding and unsafe water. changing air and water temperatures and precipitation can also lead to increased infectious diseases among plants and animals through vector-borne and rodents, as well as to outbreaks of disease in coral reefs and trees overgrown with fungus.13 as physician researchers, the possibilities of contributing are only limited by our imagination. physician researchers can contribute effectively to understanding the root causes as well as the effects of global warming and changing climate on individual patients and on the community. as travellers in this space ship called earth, we need to be very prudent as to how we use the resources vital to our health such as air, clean water and our atmosphere. we as physicians can play a relatively major role in reducing the negative impact of climate on human health and also have an impact on root causes. physicians and researchers in oman and beyond need to review their resources and evaluate the possible ways that we can contribute. let us all join in the spirit of this year’s world health day and make a difference in human health. squmj will help by publishing news of the efforts and results. lamk al-lamki md, frcpc, facr, facnm editor-in-chief email: mjournal@squ.edu.om tel. number: (+968) 2414 3457 r e f e r e n c e s 1. world health organisation “world health day 2008: protecting health from climate change” from www.who.int/ world-health-day/en/. accessed may 2008. 2. statement by who director-general dr margaret chan on world health day, 7 april 2008. from http://un.by/en/who/ news/world/08-04-08-st.html. accessed may 2008. 3. un secretary-general, in message for world health day, april 7th 2008. from http://www.un.org/news/press/docs/2008/ sgsm11491.doc.htm. accessed may 2008. 4. “climate change and health: preparing for unprecedented challenges” by dr. margaret chan, director-general of world health organisation. the 2007 david e. barmes global health lecture, bethesda, maryland, usa, 10 december 127 p h y s i c i a n s , c l i m at e c h a n g e a n d h u m a n h e a lt h 2007: from www.who.int/mediacenter/news/statements/208/s05/en/index.html accessed may 2008. 5. myanmar – cyclone nargis. from http://www.ifrc.org/what/disasters/response/myanmar-nargis/index.asp?gclid=cmfv mp3mr5mcfqhklaodoxr8ng accessed may 2008. 6. death toll from myanmar cyclone nearly doubles, associated press 17 may 2008, from http://ap.google.com/article/ aleqm5iy-mfhln9q7mwtq1vlrvexljr2dad90n4s302. accessed may 2008. 7. thousands evacuated as cyclone gonu hits oman; international herald tribune 06 june 2007 from http://www.iht. com/articles/2007/06/06/africa/storm.4-70547.php accessed may 2008. 8. cyclone gonu aftermath: from http://fonzation.com/blog/2007/06/10/cyclone-gonu-aftermath accessed may 2008. 9. kalkstein ls, valimont km. 1987. climate effects on human health. in potential effects of future climate changes on forests and vegetation, agriculture, water resources, and human health. epa science and advisory committee monograph no. 25389, 122-52. washington, d.c.: u.s. environmental protection agency. 10. climate, ecology, and human health. from http://www.gcrio.org/consequences/vol3no2/climhealth.html accessed may 2008. 11. climate and health. from www.who.int/mediacentre/factsheets/fs266/en accessed may 2008. 12. impact of climate change on human health. from http://www.climate.org/2002/topics/health/index.shtml accessed may 2008. 13. “climate future health threat”. from http://news.bbc.co.uk/1/hi/sci/tech/2055890.stm accessed may 2008. a swallowed fishbone penetrating the oesophagus into the sternomastoid muscle a swallowed fishbone penetrating the oesophagus into the sternomastoid muscle sabah m al-shukry squ journal for scientific research: medical sciences 2003 vol 5, no. –2, 5–52 ©sultan qaboos universit y c a s e r e p o r t department of surgery, rustaq hospital, po box 2, rustaq-239, sultanate of oman. email: sabah45@omantel.net.om. abstract. a 40-year-old woman presented with the history of swallowing a fishbone one hour earlier. since the patient was swallowing normally and the x-ray results were negative, she was reassured and sent home. twenty days later, when the patient again presented with pain and tenderness in her neck, the fishbone was detected in the left sternomastoid muscle, and removed under local anaesthesia. accidental swallowing of fishbone is very common in fish eating communities and usually the swallowed bone is small or soft and will pass down the gut without consequences. still the medical literature contains many reports of fishbone or similar foreign bodies stuck in the throat or penetrating the pharynx, oesophagus or stomach1 causing retropharyngeal abscesses,2,3,4 mediastinal abscesses,5 or even penetrating the pericardium causing cardiac tamponade.6 this report documents an unusual case where a fishbone penetrated the oesophagus and settled in the left sternomastoid muscle. t h e c a s e a 40-year-old woman presented to the casualty department of rustaq hospital, rustaq, sultanate of oman, with a history of swallowing a fishbone one hour earlier with the bone stuck in the upper oesophagus at the level of suprasternal notch. examination of the throat did not show any abnormality and no foreign body could be detected. as the patient was swallowing fluids and solids normally and x-ray of the neck did not show a shadow in the neck, the patient was reassured and sent home .two days later she came back with persisting pain in the anterior aspect of the left lower neck but she reported that she was taking food normally. on examination there was diffused tenderness over the left side of the lower neck but no palpable lymph nodes or mass. examination of hypopharynx was negative. ten days later she was reviewed at the ent clinic and only tenderness over the lower part of the left sternomastoid muscle was noticed. the patient presented on the 20th day after the incident with a painful swelling in the left lower neck and was referred to the surgical clinic as cervical lymph node enlargement. the patient was in good general condition and vital signs were normal. local examination of the neck revealed tender induration of the lower part of the left sternomastoid muscle [figure 1]. aspiration was non productive but during examination, the presence of a sharp point was felt in the subcutaneous plane. exploration under local anaesthesia showed localised inflammatory indurations in the muscle just above its attachment to the clavicle. a 3 cm long thin fishbone with one sharp end was located and removed from the indurated area in the muscle. post operatively the patient developed a serosanguinous fluid collection of 3 ml in the wound. this was aspirated, and the culture yielded negative results. on further follow up, the area of tender indurations resolved completely. d i s c u s s i o n a n d c o n c l u s i o n in this case the patient was fortunate in that the fishbone did not penetrate into more vital tissue or structure and no deep infection developed. the forces driving a foreign body through the wall of swallowed fiash bone ���������������������������������������� �������������� ��������:� ������������������������������������������ ������ ��� ������ ��������������������� ������������������������������������������������������������������������������������������������� ��������������������������������������������������������. 52 al-shukri the oesophagus and the forces directing its passage to the ultimate site need some consideration. () the intraluminal pressure in the oesophagus may force a transverse or oblique positioned sharp foreign body through the wall of the gut. (2) the site of penetration in the oesophagus may play a role in the track of movement and site of settlement. (3) a foreign body under the forces of gravity and pressure in the surrounding tissues tends to move towards planes of least resistance, and like pus, will find its way out. x ray, especially routine exposures, does not always help detect a relatively delicate object such as a fishbone. an ultrasound study of the neck and intraoesophageal probe may yield better results. when patients present with persistent complaint of a foreign body sticking in the throat or oesophagus, the physician should conduct a direct examination of the pharynx and oesophagus and even the stomach, to trace the foreign body and check for the site of penetration, and take all possible measures to retrieve the object. r e f e r e n c e s . polcrova a, wiedermann j, vomacka j. foreign bodies in the deglutition tract and their complications. cas lek cesk, 990, 29, 467–468. 2. swoniski h, gracz j. foreign bodies in the retro pharyngeal space. otolaryngol pol, 983, 37, 59–6. 3. bizakisjg, sega j, skoulakis h, voludakis a, velegrakis g, christodoulou p, helidonis e. retropharyngoesophageal abscess associated with a swallowed bone. am j otolaryngology, 993, 4, 354–357. 4. janecka v. voluminous retropharyngo-esophageal abscesses resulting from neglected foreign bodies (fish bones) in the hypopharyngo-esophageal region. cesk otolaryngol, 973, 22, 49–52. 5. mateo s, blazquezc, ortega j, cabajo m, hernandez m, torre w. mediastinal abscess secondary to esophageal perforation caused by foreign body. med cli (barc), 984, 82, 779– 780. 6. sharland mg, mccaughan bc. perforation of the esophagus by fish bone leading to cardiac temponade. ann thorac surg, 993, 56, 969–97. figure 1. induration visible as on the 20th day of fishbone impaction a swallowed fishbone penetrating the oesophagus into the sternomastoid muscle sabah m al-shukry the case discussion and conclusion references august 2007 vol 7 copy.indd 8th advanced medicine symposium sultan qaboos university, sultanate of oman 5th 8th march 2007 sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 179-184 sultan qaboos university© submitted 15th april 2007 a b s t r a c t s املتقدم الثامن الطبي ملؤمتر عمان سلطنة قابوس، السلطان جامعة 2007 5-8 مارس va s c u l a r d i s o r d e r s i n vo lv i n g t h e l i v e r elwyn elias, liver & hepatobiliary unit, birmingham university hospital, uk. email: elwyn.elias@uhb.nhs.uk in the budd chiari syndrome hepatic venous outflow typically presents with ascites, sometimes accompanied by pain over the liver. interventional radiology produces excellent results from treatment by hepatic vein angioplasty and transjugular intrahepatic portosystemic shunt (tips). haematological investigations have a high yield revealing a prothrombotic condition such as factor v leidenn (circa 25%) and myeloproliferative disease. hepatic venoocclusive disease is typically due to an inflammatory and fibrotic reaction which occludes the hepatic sinusoids. historically, it was associated with a variety of toxic injuries (e.g. bush tea disease), but now almost exclusively in the context of bone marrow transplantation. typically portal vein thrombosis presented with bleeding varices, but increasingly it is recognized as a cause of cholestatic jaundice with choledocholithiasis from portal biliopathy. the hepatopulmonary syndrome is characterized by dilatation of pulmonary capillaries to such an extent that oxygen is unable to diffuse adequately to prevent hypoxemia. the diagnosis of portopulmonary hypertension requires a demonstration of increased pulmonary vascular resistance. congential and hereditary vascular anomalies include persistent patency of the ductus venosus. liver involvement by hereditary haemorrhagic telangiectasia may produce symptoms from high output cardiac failure, portal hypertension or biliary disease. both benign and malignant primary vascular lesions also occur. a n updat e o n na s h ( n o n a l c o h o l i c st e at o h e pat i t i s) elwyn elias, liver & hepatobiliary unit, birmingham university hospital, uk. email: elwyn.elias@uhb.nhs.uk fatty liver is most commonly associated with obesity, type ii diabetes mellitus and hyperlipidemia. it is known that free fatty acids (ffa) are mobilized far more readily from visceral than subcutaneous adipocytes, and visceral fat also drains directly to the liver via the portal blood supply. insulin resistance is a key feature in its causation, even in the non-diabetic and non-obese. lipid peroxidation due to oxidatie stress may arise from induced and highly active polymorphic forms of cyp 2e1, peroxisomal β-oxidation of ffa or coexistent liver disease such as iron overload or viral hepatitis c infection. splanchnic adipocytes have long been known to be several-fold more resistant to insulin than their peripheral counterparts. one of the new understandings to emerge is that these splanchnic fat storage cells constitute a major endocrine influence on the liver and that imbalance of their hormonal products, “adipokines” (adipocyte cytokines) influences hepatic fat deposition, insulin resistance and pros u lta n q a b o o s u n i v e r s i t y 180 gression to nash. the role of insulin resistance in promotion of nash provided the rationale for treatment with metformin, rosiglitazone and pioglitazone. stomach stapling (laparoscopic adjustable gastric binding) has been shown to be beneficial since weight loss was sustained and accompanied by complete resolution of the histological changes of nash in a majority of patients. c y t o k i n e st o r m i n a p h a se  tr i a l o f t h e a n t i c d 2 8 m o n o c l o n a l a n t i b o dy tg n 4 2 gordon duff, molecular medicine department, university of sheffield, uk. email: g.w.duff@sheff.ac.uk six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of tgn1412, a novel supragonist anti-cd28 monoclonal antibody that directly stimulates t cells. within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation and hypotension. within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure and disseminated intravascular coagulation. sever and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. all six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an antileukin-2 receptor antagonist antibody. prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. despite evidence of the multiple cytokine-release syndrome, all patients survived. documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease. i n fe c t i o n s i n t h e i m mum o c om pr om i se d nicholas j beeching, tropical and infectious disease unit, royal liverpool university hospital, liverpool l7 8xp, uk. email: nicholas.beeching@rlbuht.nhs.uk the number of people who are immunocompromised continues to rise, as more patients undergo invasive support with indwelling lines and tubes, radiotherapy, chemotherapy and immunotherapy, and with increased survival of those with malignancies and other inherently immunosuppressive conditions. this creates challenges in the diagnosis, treatment and prevention of a variety of infections, and offers fascinating insights into the pathophysiology and significance of different forms of immunosuppression. for example, cmv (cytomegalovirus) infection in patients with solid organ transplants typically causes pneumonitis and transplant rejection, while in those with advanced hiv the predominant syndromes are in the eye, central nervous system and gastrointestinal tract.diagnostic techniques need critical revaluation in different groups of patients and settings, using as much rigour as that applied to multicentre therapeutic trials. tests may be overly sensitive e.g. molecular diagnostics, or perform less well in immunocompromised groups e.g. tests based on host antibody response. examples include the measurement of cmv viraemia levels in hiv, the new gamma-interferon release assays for past exposure to tuberculosis, and galactomannin assays for invasive aspergillosis. supportive therapies such as the use of cell growth factors and the true benefit of protective isolation of patients with neutropenia need further evaluation. in the hiv setting, endpoints for starting primary and/or secondary prophylaxis have been determined (or discarded as unnecessary) for many opportunistic infections, but endpoints for stopping such prophylaxis are more difficult to define, especially in the presence of immune reconstitution syndromes. in some cases, e.g. oropharyngeal candidiasis in hiv, preemptive therapy is preferable to prophylaxis, and more such comparisons are needed for other opportunistic infections and hosts. the care of immunosuppressed patients requires coordinated multidisciplinary teams, which should critically evaluate the clinical approaches most appropriate for their own geographical setting. 8 t h a d va n c e d m e d i c i n e s y m p o s i u m 181 fe v e r i n r e t u r n e d t r av e l l e r s nicholas j beeching, tropical and infectious disease unit, royal liverpool university hospital, liverpool l7 8xp, uk. email: nicholas.beeching@rlbuht.nhs.uk febrile illnesses account for about 40% of acute hospital admissions for tropical illness in british referral units. a sensible working diagnosis can usually be formulated on the basis of a good history and examination and initial simple investigations. history should include details of exactly where the patient has been, what conditions they were living in, and the exact dates of arrival and departure. the quality of pre-travel advice and vaccinations, adherence to chemoprophylaxis against malaria, avoidance of insect bites and general behaviour abroad (including sexual history) are also important. other localizing features of the illness should be sought, particularly rashes, chest signs, hepato-splenomegaly, lymphadenopathy etc. maintain a high index of suspicion for underlying hiv especially in expatriates or immigrants from africa but increasingly sex tourists from thailand, india etc. (nb. oral candida, past or present herpes zoster are 2 common physical signs missed by general physicians). the most important illness to consider and to exclude is malaria (approximately 40% of cases), and the majority of the remainder will have cosmopolitan viral infections or imported infections such as arboviruses (dengue fever), enteric fever or viral hepatitis. rarer causes will usually be evident from the history and examination, which presupposes a good knowledge of geographical medicine. the possibility of a viral haemorrhagic fever should always be considered. late presentations of imported infection, including tuberculosis and vivax malaria, should always be borne in mind and recent immigrants or those going from the uk to visit family abroad are a particularly high risk group for such infections. initial investigations should include adequate malaria films (supplemented by quick antigen detection tests in many labs) and blood count, repeated as necessary, blood, urine and faecal cultures, serum biochemistry, chest x-ray and other imaging e.g. liver ultrasound as indicated, and storing serum for virus serology. for patients in whom malaria is still suspected despite negative films, the combination of thrombocytopenia and hyperbilirubinaemia is supportive but not diagnostic of malaria. eosinophilia suggests worm or fluke (e.g. schistosomiasis) infections, serology for which may be negative during early invasive stages. au t o i m mu n e p ota s si um c h a n n e l o pat h i e s ian hart, university of liverpool and walton centre for neurology and neurosurgery, uk ion channels are fundamental to the function of every cell in the nervous system. pioneering work on acetylcholine receptor antibodies in myasthenia gravis and calcium channel antibodies in the lambert-eaton myasthenic syndrome established, the concept of the channelopathy and laid down the principles for the study of both autoantibodies and ion channels in the pathogenesis of peripheral neurological disorders. the large extracellular domains shared by many types of ion channel, including potassium channels, seem to be favoured targets for humoral and cellular immune attack in the central as well as the peripheral nervous system. autoimmunity especially the autoantibody-mediated pathways is now recognized as the crucial pathogenetic process in a diverse range of acquired conditions caused by channel dysfunction including peripheral nerve hyperexcitability, paraneopiastic and autonomic syndromes, and some forms of limbic encephalitis, epilepsy, and narcolepsy, as well as in diseases of neuromuscular transmission. further advances in the characterization of ion channels and autoimmune mechanisms combined with improvements in the clinical understanding of the phenotypes of hereditary as well as acquired channelopathies have the potential to transform the diagnosis of these disorders, shed light on the pathogenesis of many common neurological diseases and open the gates for novel treatments based on modulation of channel and immune function. s u lta n q a b o o s u n i v e r s i t y 182 th e n e u r o l o g y, o n c o l o g y a n d i m mu n o l o g y o f pa r a n e o pl a st i c s y n d r om e s ian hart, university of liverpool and walton centre for neurology and neurosurgery, uk paraneoplastic neurological syndromes (pns) occur in 1 2% of people with cancer. they are usually caused by autoimmune responses triggered by and directed against a tumour that cross-react with proteins expressed by neural tissue. any part of the nervous system can be affected and patients often develop severe and permanent disability. diagnosis can be difficult as two-thirds of patients develop their neurological problems up to 5 years before the tumour manifests. however, the discovery that many pns are associated with serum autoantibodies against neural antigens expressed by the tumour-onconeural antibodies has greatly improved our ability to identify neurological disorders as paraneoplastic. in addition, the finding of a particular onconeural antibody can help focus the search for an underlying tumour thus allowing earlier identification and treatment of the cancer. the first antibodies to be isolated, and their associations with clinical syndromes and tumours defined, were hu, yo, and ri the classic onconeural antibodies. others characterized over the past 10 years, including cv2, ma, amphiphysin and tr, are proving to be equally useful tumour markers and have been crucial to the identification of novel pathogenic mechanisms for several pns such as stiff person syndromes and some types of encephalitis. th e r o l e o f c h r o n i c i n fl a m m at i o n i n c a n c e r emad m el-omar, department of medicine and therapeutics, university of aberdeen, uk. email: e.el-omar@abdn.ac.uk chronic inflammation has long been known to increase the risk of cancer in the affected tissues. this complication is particularly notable in the gastrointestinal tract. helicobacter pylori (h. pylori -associated gastric cancer represents a classic example of this paradigm, and the unravelling of this model will enhance our understanding of many other cancers of unknown aetiology. gastric cancer occurs in a milieu characterized by severe inflammation, hypochlorhydria and atrophy, all of which precede malignant transformation by decades. h. pylori infection is now recognized as the initiating factor for this cascade of pathophysiological abnormalities that culminates in cancer. there is ample epidemiological evidence to support this link, but increasingly the basic molecular pathways of this association are being uncovered. inflammatory cells produce a wide range of mediators including pro-inflammatory cytokines, chemokines, reactive oxygen species, growth factors and eicosanoids. cox-2 may be a linchpin in orchestrating many of the mutagenic effects of these products and this is supported by the studies showing the chemo-preventative benefits of cox inhibitors. cytokine gene polymorphisms undoubtedly contribute to individual risk of malignancy, but their importance lies in their contribution to the understanding of inflammation-mediated carcinogenesis. the fact that chronic inflammation impacts on crucial cellular processes, such as proliferation, adhesion, apoptosis, angiogenesis and transformation, highlights its pivotal role in the pathogenesis of gastrointestinal malignancy. h e l i c o b a c t e r p y l o r i : c u r r e n t c o n c e p t s a n d m a n a ge m e n t emad m el-omar, department of medicine and therapeutics, university of aberdeen, uk. email: e.el-omar@abdn.ac.uk helicobacter pylori infection affects half the world’s population and is responsible for significant gastroduodenal diseases including peptic ulcers and gastric cancer. the european helicobacter study group (ehsg) convened the third maastricht consensus conference in 2005, to update guidelines on the management of helicobacter pylori. the guidelines cover indications for therapy, management strategies and potential for gastric cancer prevention. the eradication of h. pylori infection is recommended in patients with (i) gastro-duodenal pathologies such as peptic ulcer disease and low-grade gastric mucosa-associated lymphoid tissue lymphoma (malt lymphoma), (ii) atrophic gastritis, (iii) first-degree relatives of gastric cancer patients, (iv) unexplained iron deficiency anaemia (v) chronic idiopathic thrombocytopenic purpura. recurrent abdominal pain in children is an indication for a test and treat strategy if other causes are excluded. the eradication of h. pylori infection (i) does not cause gastrooesophageal reflux disease (gord) or exacerbate gord, and (ii) may prevent peptic ulcer in patients who are naive non-steroidal anti inflammatory drugs (nsaids) users. h. pylori eradication is less effective than proton pump inhibitor treatment in preventing ulcer recurrence in long term nsaid users. in primary care a ‘test and 8 t h a d va n c e d m e d i c i n e s y m p o s i u m 183 treat’ strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. the non-invasive tests that should be used for the diagnosis of h. pylori infection are the urea breath test, stool antigen tests and serological kits with a high accuracy. triple therapy using a ppi (??) with amoxiciliin and clarithromycin or metronidazole given twice daily remains the recommended first choice therapy. bismuth containing quadruple therapy, if available, is also a first choice treatment option. rescue therapy should be based on antimicrobial susceptibility. eradication of h. pylori infection has the potential to reduce the risk of gastric cancer development. th e r a pe u t i c st r at e gi e s i n h a e m at o l o gi c m a l i gn a n c i e s john m goldman, haematology department, imperial college, london, uk. email: goldmanj2@nhlbi.nih.gov (.uk?) in the 1960s all haematologic malignancies were regarded as incurable and treatment was directed only at palliation. the suggestion that any form of leukemia might be curable was regarded as highly unlikely and indeed heretical. it became clear, however, in the 1970s that children with acute lymphoblastic leukemia (all) who achieved remission and then continued maintenance therapy might not relapse; this benefit was enhanced when neuroprophylaxis was added to the systemic regimen and a cure became a reality. in the 1980s, it began to be gradually accepted that younger patents with acute myeloid leukemia (aml) who received intensive chemotherapy or post-remission therapy followed by allogeneic stem cell transplantation (sct) might similarly survive without relapse for many years. the more recent introduction of all-trans retinoic acid (atra) in conjunction with anthracyclines seems to be a way to cure aml-m3 (acute promyelocytic leukemia) without the need for sct. while progress was made in treating and sometimes curing the acute leukemias, the chronic leukemias continued until recently to be regarded as incurable. for chronic myeloid leukemia (cml), however, the introduction of allogeneic sct in chronic phase did indeed result in cures in eligible patients; in the last 7 years the possibility that selected patients may cured by administration of the tyrosine kinase inhibitor imatinib has become a reality. by contrast, relatively few patients with chronic lymphocytic (cll) leukemia have been treated by sct, but there is a real possibility that some of these may be cured. monitoring of minimal residual disease (mrd) after chemotherapy or allogeneic sct has become extremely important for assessing benefit, predicting clinical relapse and adjusting therapy when appropriate. the principal techniques are immunophenotyping and monitoring expression of leukemia-specific or leukemia-associated genes. for the present, cml and aml lend themselves most obviously to molecular monitoring, but it is likely that within a few years all haematologic malignancies will be followed routinely either by immunophenotypic or molecular studies for mrd. lung cancer remains the biggest killing cancer in the world for men and is rapidly becoming the biggest killer for women. 80% of lung cancer are caused by smoking and smoking trends in young women are increasing. there are no good prognostic symptoms to detect the disease early and presentation is almost always too advanced for surgery, only 10% of patients with non-small cell lung cancer (nsclc) go to resection.. considerable efforts are being made to improve staging with the use of pet scanning and mediastinal assessment using transbronchial and transoesophagel ultrasound guided cytology and biopsy sampling. advances in treatment have been poor in small cell lung cancer with very little new emerging in the last 15 years. in nsclc, there is emerging a clear role for adjuvant chemotherapy following successful surgery. there is no role for neo-adjuvant chemotherapy or peri-operative radiotherapy. chemotherapy in advanced nsclc offers some advantages both in terms of median survival and quality of life. targetted therapy is another potential treatment in some patients relapsing after initial chemotherapy. screening for lung cancer is currently being assessed by ct and endobronchial surveillance in randomised controlled trials. these subjects will be discussed and summarised. s u lta n q a b o o s u n i v e r s i t y 184 th e tr e atm e n t o f o b st ru c t i v e s l e e p a pn o e a ( o s a ) john m goldman, haematology department, imperial college, london, uk. email: goldmanj2@nhlbi.nih.gov (.uk?) sleepy people are dangerous. in doctors, there is a 50% higher serious error rate to patients and a fivefold serious diagnostic error rate as well as a 2.3 hazard ratio of the risk of car crashing. 1-2% of western middle aged men have osa. osa and snoring is the commenest outpatient respiratory referral to most uk hospitals, but around 90% remain undiagnosed. the main causes are obesity in 70%, retrognathia and oropharyngeal abnormalities in a small numbers. the condition is familial. its association with road accidents is increased three to sixfold. osa is. associated with increased systolic blood pressure, arterial wall stiffness and imparied glucose tolerance in diabetes. the condition is underprovided for, particularly in the uk, with 1.4 sleep laboratories per million of the population. treatment with cpap is extremely effective for severe osa, but compliance is poor for mild or moderate severity individuals. mandibular advancement splints are extremely effective provided the individual is motivated to wear the splint. although common and dangerous, osa has not yet achieved the level of importance in funding for treatment and multidisciplinary care in the uk. 1 submitted 13 oct 20 1 revisions req. 9 dec 20 & 8 feb 21; revisions recd. 18 jan & 21 feb 21 2 accepted 23 feb 20 3 online-first: may 2022 4 doi: https://doi.org/10.18295/squmj.5.2022.036 5 6 loeffler's syndrome and multifocal cutaneous larva migrans 7 case report of an uncommon occurrence and review of the literature 8 *abheek sil,1 dibyendu b. bhanja,2 atanu chandra,3 surajit k. biswas1 9 10 1department of dermatology, venereology, and leprosy, rg kar medical college and 11 hospital, kolkata, india; 2department of dermatology, venereology, and leprosy; 12 midnapore medical college and hospital, west bengal, india; 3department of internal 13 medicine, rg kar medical college and hospital, kolkata, india. 14 *corresponding author’s e-mail: abheek.sil@gmail.com 15 16 abstract 17 cutaneous larva migrans (clm) is a zoonotic skin disease that is frequently diagnosed in 18 tropical and subtropical countries. loeffler’s syndrome (ls) is a transient respiratory ailment 19 characterized by pulmonary infiltration along with peripheral eosinophilia and commonly 20 follows parasitic infestation. we report here an interesting case of a patient presenting with 21 ls that was attributed secondary to multifocal clm. treatment with seven-day course of oral 22 albendazole (400mg daily) coupled with nebulization (levosalbutamol and budesonide) led to 23 complete resolution of cutaneous lesions and respiratory complaints in two weeks. there was 24 complete resolution of pulmonary pathology at 4 weeks follow-up. as there are only a few 25 reported cases of ls associated with clm, we also reviewed the literature on this rare 26 association. 27 keywords: loeffler's syndrome; peripheral eosinophilia; cutaneous larva migrans; multifocal; 28 disseminated; helminths, albendazole. 29 30 introduction 31 cutaneous larva migrans (clm) is a distinct cutaneous entity that is relatively common in the 32 warmer tropical and sub-tropical regions. it is characterized by tortuous skin lesions attributed 33 2 to epidermal burrowing by certain helminthic larvae.1 apart from the cutaneous affliction, this 34 condition is rarely uneventful. on rare occasions, clm can culminate into loeffler's syndrome 35 (ls), which is characterized by migratory pulmonary infiltrates and peripheral eosinophilia.2 36 here we describe an interesting case of ls associated with multifocal cutaneous larva migrans 37 and review the literature on this uncommon association. 38 39 case report 40 an otherwise healthy 33-year-old gentleman presented with intense, non-productive cough for 41 the last 7 days with occasional breathlessness on exertion. the pulmonary symptoms were 42 accompanied by abrupt onset pruritic skin eruptions over chest and abdomen for the same 43 duration. recently he had returned from a vacation to a nearby coastal town where he had spent 44 a significant time on the sandy beaches. there was no history of fever, hemoptysis, wheeze, 45 chest pain, allergic rhinitis or relevant drug intake (prescription, over the counter or illicit). his 46 primary care physician had initiated a 5-day course of oral azithromycin (500mg daily) without 47 any significant improvement. his medical and family history was non-contributory. on general 48 examination, he was afebrile, normotensive (126/78 mm hg) with a saturation of 97% on room 49 air. bi-basilar crackles was appreciated on chest auscultation. cutaneous examination revealed 50 multiple discrete thread-like skin-coloured to erythematous serpiginous tract of various sizes 51 (4 to 12 cm in length) distributed over the chest and abdomen. (figure 1) focal excoriation 52 and pustules were noted over few lesions. other mucocutaneous sites were uninvolved. 53 evaluation of other organ systems was uneventful. 54 55 laboratory examination was notable for peripheral eosinophilia (absolute eosinophil count 56 2200 cells/μl). stool examination for ova, parasite, and cyst was negative. chest radiography 57 showed ill-defined bilateral pulmonary infiltrates. a high-resolution computed tomography 58 (hrct) thorax revealed the presence of ground-glass opacities mainly in mid and lower zone 59 of both lungs with predominant peripheral distribution. (figure 2a) based on suggestive 60 history, characteristic clinical presentation, laboratory and radiological findings, the final 61 diagnosis of loeffler's syndrome secondary to multifocal cutaneous larva migrans was 62 established. he was treated with oral albendazole (400mg) once daily for 7 consecutive days 63 along with nebulization with levosalbutamol and budesonide as required. his respiratory 64 symptoms and cutaneous lesions completely subsided in 2 weeks. there was complete 65 radiological resolution at 4 weeks follow-up. (figure 2b) 66 3 an informed written consent was obtained from the patient after full explanation regarding his 67 images being published for academic interest. the patient did not have any objection regarding 68 use of his images which may reveal his identity and gave due permission to use them. 69 70 discussion 71 ls is a transient respiratory illness associated with peripheral eosinophilia as a response to 72 parasitic infestation or medications.3 ascaris lumbricoides is most commonly implicated with 73 the condition followed by trichuris, strongyloides, taenia saginata, entamoeba histolytica, 74 and as a complication of chronic asthmatic states. however, it has rarely been reported with 75 clm. in 1946, wright and gold first described 26 patients with cutaneous larva migrans who 76 developed loeffler’s syndrome.4 subsequently this rare complication of clm has been 77 reported only in handful of cases.3, 5-16 table 1 summarizes the previous published case report 78 of clm with ls. 79 80 clm, also termed as “creeping eruption,” is a parasitic infestation caused by the invasion and 81 migration of parasitic larvae in the skin. the burrowing of the larva of ancylostoma braziliense, 82 ancylostoma caninum, necator americanus, uncinaria stenocephala and strongyloides 83 stenocephala have been implicated in such creeping eruptions.17 adult hookworms infest the 84 intestines of cats and dogs and their ova in excreta hatch under favourable conditions. these 85 larvae then penetrate intact or abraded skin following exposure with soil contaminated with 86 faeces. humans act as an accidental dead-end host as the travelling parasite perishes, and the 87 cutaneous manifestations usually resolve uneventfully within months. warm, sandy, humid 88 and shady fields, sandpits or sea shores are particularly favoured areas. this makes barefoot 89 walkers, farmers, gardeners, hunters, hod carrier or beach visitors particularly susceptible to 90 acquire the infestation. exposed anatomical sites like hands and feet are usually affected. 91 however, involvement of atypical locations like the buttocks, genitalia, scalp, and multifocal 92 or disseminated lesions have also been rarely reported in the literature. clinically an initial 93 small reddish papule progresses to a serpiginous pruritic rash with a slow rate of progression 94 from less than 1–2 cm/day.1, 17-20 clm may be complicated by secondary bacterial infection, 95 allergic reaction, eczematisation, or very rarely ls. concurrently or subsequently patient may 96 develop non-productive cough, exertional breathlessness, exacerbation of pre-existing asthma 97 which should raise the clinical suspicion of ls. interestingly, a unique case of asymptomatic 98 ls in clm has been reported recently.12 99 4 the exact pathogenesis of pulmonary infiltrates in clm remains poorly understood. the 100 current understanding encompasses a systemic immunologic process in which hookworm in 101 the skin leads to generalized sensitization. the lung reacts with the soluble larval antigen and 102 produces the eosinophilic pulmonary infiltration. the complete resolution of pulmonary 103 infiltrates and skin eruptions with oral anti-helminths supports this proposed mechanism.21 104 associated eosinophilia is teleologically related to the role of eosinophils in parasitic 105 destruction. in parasitic infestation like clm, eosinophilic chemotaxis may result from ige-106 mediated reactivity against the infestant, direct chemotactic property of certain parasites, t-107 cell dependent mechanism, and immune-complex related.13 108 109 the differential diagnoses we considered for the cutaneous lesions included larva currens, 110 migratory myasis, gnathostomiasis, cercarial dermatitis, allergic contact dermatitis, 111 inflammatory tinea, and scabies. all the above mentioned conditions were ruled out based on 112 history, and clinical examination. loeffler’s syndrome should be considered early in the 113 differential diagnosis for community acquired pneumonia and asthma unresponsive to classic 114 antibiotic therapy in individuals with associated cutaneous pruritic eruption. pulmonary 115 fibrosis and respiratory failure may rarely complicate ls.3, 6, 7, 22 116 117 the condition is primarily self-limiting but appropriate pharmacological intervention leads to 118 faster resolution. veraldi et al23 reported a new therapeutic regimen of oral albendazole 119 (400/day for 7 days) to be highly effective. single dose therapy of oral ivermectin (200ug/kg) 120 is equally effective with near 100% cure rates. topical 10% thiabendazole may be used as an 121 alternative. opting for surgery or cryotherapy rarely proves to be effective. sometimes 122 supportive therapy like oxygen inhalation, systemic, or inhalational corticosteroids may be 123 required to alleviate the respiratory symptoms.4, 8, 9, 24 124 125 conclusion 126 in conclusion, we report this case to add to the existing literature on this rare association. ls 127 secondary to multifocal clm has rarely been documented previously. ls should be considered 128 early in the differential diagnosis for respiratory complaints in association with pruritic 129 cutaneous eruption especially in an individual having recently returned from a vacation at a 130 tropical destination. in this era of global migration, physicians should be aware of the 131 uncommon systemic manifestation of this uncommon tropical infestation and provide prompt 132 treatment to avoid long-term complication. 133 5 authors’ contribution 134 as, dbb and ac drafted the manuscript. as and skb contributed to patient management, 135 review of literature and critical revision of the manuscript. all authors approved the final 136 version of the manuscript. 137 138 references 139 1. brenner ma, patel mb. cutaneous larva migrans: the creeping eruption. cutis 140 2003;72:111-5. 141 2. ekin s, sertogullarindan b, gunbatar h, arisoy a, yildiz h. loeffler's syndrome: an 142 interesting case report. clin respir j 2016;10:112-4. 143 3. podder i, chandra s, gharami rc. loeffler's syndrome following cutaneous larva 144 migrans: an uncommon sequel. indian j dermatol 2016;61:190-2. 145 4. wright do, gold em. loeffler's syndrome associated with creeping eruption 146 (cutaneous helminthiasis). arch int med 1946;78:303. 147 5. tebooij m, de jong e, bovenschen hj. löffler syndrome caused by extensive 148 cutaneous larva migrans: a case report and review of the literature. dermatol online j 149 2010; 16:2. 150 6. del giudice p, desalvador f, bernard e et al. loeffler's syndrome and cutaneous larva 151 migrans: a rare association. br j dermatol 2002;147:386-8. 152 7. tan sk, liu tt. cutaneous larva migrans complicated by löffler syndrome. arch 153 dermatol 2010;146:210-2. 154 8. gao yl, liu zh. cutaneous larva migrans with löeffler's syndrome. am j trop med 155 hyg 2019;100:487-8. 156 9. guill ma, odom rb. larva migrans complicated by loeffler's syndrome. arch 157 dermatol 1978;114:1525–6. 158 10. schaub n, perruchoud ap, buechner s. cutaneous larva migrans associated with 159 löffler's syndrome. dermatology 2002;205:207-9. 160 11. butland rj, coulson ih. pulmonary eosinophilia associated with cutaneous larva 161 migrans. thorax 1985;40:76-7. 162 12. ng j, lee d, kryzstofiak m. a unique case of cutaneous larva migrans and 163 asymptomatic löeffler's syndrome. cureus 2021;13(6):e15960. 164 13. wong-waldamez a, silva-lizama e. bullous larva migrans accompanied by loeffler's 165 syndrome. int j dermatol 1995;34:570-1. 166 6 14. guill ma, odom rb. larva migrans complicated by loeffler's syndrome. arch 167 dermatol 1978;114:1525-6. 168 15. wang s, xu w, li lf. cutaneous larva migrans associated with löffler's syndrome 169 in a 6-year-old boy. pediatr infect dis j 2017;36:912-4. 170 16. darocha s, wawrzyńska l, oniszh k, dziewulska b. eosinophilic pneumonia in 171 response to cutaneous larva migrans syndrome--a case report. pneumonolalergol pol 172 2011;79:365-70. 173 17. sil a, mukherjee gs, bhanja db, panigrahi a. multiple curvilinear lesions on a 174 patient's back. neth j med2020;78:92. 175 18. das a, panigrahi a, bhanja db, sil a, biswas sk. pruritic genital rash. j paediatr 176 child health 2021;57:302. 177 19. sil a, panigrahi a, pramanik j. isolated cutaneous larva migrans over the scalp in a 178 hod carrier. br j dermatol 2021. doi: 10.1111/bjd.20589. epub ahead of print. pmid: 179 34346073. 180 20. sil a, panigrahi a, bhanja db, chakraborty s. cutaneous larva migrans over penis. 181 urology 2020;140:e6-e7. 182 21. gandullia e, lignana e, rabagliati am, penna r. visceral larva migrans caused by 183 ancylostoma caninum. minerva pediatr 1981;33:917-23. 184 22. panigrahi a, sil a, bhanja db. pruritic curvilinear track over penis. paediatr child 185 health 2020;26:268-9. 186 23. veraldi s, bottini s, rizzitelli g, persico mc. one-week therapy with oral albendazole 187 in hookworm-related cutaneous larva migrans: a retrospective study on 78 patients. j 188 dermatolog treat 2012;23:189-91. 189 24. caumes e. treatment of cutaneous larva migrans. clin infect dis 2000;30:811–4. 190 7 table 1: comparison of clinical characteristics of previous case reports of loeffler’s syndrome 191 in association with cutaneous larva migrans 192 case report (year) country age, sex travel / exposure history location of clm pulmonary symptoms absolute eosinophil count(mm3) imaging finding (chest x-ray and/or ct scan) treatment outcome guill ma et al (1978) usa 40,m and his spouse 36,f vacation in gulf of mexico feet nonproductive cough, tightness in chest, exertional dyspnoea 7598 (male) and 2528 (female)* multiple patchy consolidations in lung fields (cxr) thiabendazole oral suspension, 0.1% triamcinolone acetonide cream (four times daily), symptomatic management for respiratory symptoms resolution after 8 weeks of onset of symptoms butland rj et al (1985) uk 58,f holiday trip to barbados buttocks, legs and abdomen cough 3000 ill-defined patchy shadowing in the left upper and middle zones (cxr) topical thiabendazole complete resolution within 2 months wongwaldamez a et al (1995) guatemala 21,m none disseminated bullous lesions over trunk and extremities (especially lower) none 710 diffuse miliary infiltrate in both lung fields (cxr) single dose albendazole (400 mg) resolution in one week del giudice p et al (2002) france 41,m holiday trip to thailand left foot intense nonproductive cough 1100 ill-defined reticulonodular infiltrates in both lungs (ct scan) oral thiabendazole (25 mg/kg) twice daily for 10 days; oral corticosteroids 1 mg/kg daily complete resolution within 5 days schaub n et al (2002) switzerlan d 39, m holiday trip to thailand on the buttocks dyspnoea 1616 bilateral diffuse ground-glass opacities (cxr; further confirmed on ct scan) oral albendazole 400 mg on 5 consecutive days and a single dose of oral praziquantel (3600 mg) complete resolution tebooij m et al(2010) netherland s 27, m holiday trip to thailand both feet exacerbation of pre-existing asthma 2700 small nodular granular infiltrates and linear paracardial opacities in both lungs (cxr) ivermectin, inhalation medication (budesonide/formoterol) andtopical potent steroid complete resolution tan sk et al (2010) singapore 47,m trip to beach holiday in bali, indonesia both feet and his right thigh and buttock dyspnea, wheezing and chest discomfort 2903 reticulonodular infiltrates in the right middle and lingular lobes (cxr and ct scan) oral mebendazole (3 days) followed by albendazole and intravenous hydrocortisone (5 days) with oxygen supplementation complete remission in 2 weeks darocha s et al (2011) poland 28,m trip to sri lanka both feet cough and dyspnoea at rest with exacerbation of asthma 3400 multiple poorly defined consolidations and ground-glass attenuation areas, some of them peripherally involving bilateral upper and lower lobes (ct scan) salbutamol, nebulisation with budesonide, prednisolone, topical albendazole complete resolution on scheduled follow-up after 3 months podder i et al(2016) india 30,m agriculturi st both hands nonproductive cough 5200 fleeting opacities (cxr) oral albendazole (400 mg/day) for 5 days complete resolution 8 *the maximum absolute eosinophil count recorded during hospital stay 193 abbreviations: m=male, f=female, cxr=chest x-ray, ct=computed tomography scan 194 occasional exertional breathlessness wang s et al (2017) china 6,m vacation in malaysia left pretibial and tarsal skin eruptions severe cough 1870 bilateral small nodular infiltrates in lower lungs (cxr) oral albendazole (400mg/day) for 7 days complete resolution in 2 weeks gao yl et al (2019) china 26, f a trip to sabah, malaysia right upper and lower extremity nonproductive cough and occasional breathlessness mild eosinophilia showed ill-defined reticulonodular infiltrates in both lungs (ct scan) oral albendazole 400 mg for seven consecutive days complete resolution within 7 days ng j et al (2021) usa 52, m working outside barefoot in an area where feral cats frequently defecate right foot, chest and abdomen asymptomatic 2100 nodular opacities bilaterally (cxr) oral albendazole 400 mg single dose complete resolution present case (2021) india 33, m farmer chest and abdomen intense, nonproductive cough with occasional exertional breathlessness 2200 ill-defined pulmonary infiltrates (cxr); nodular opacities bilaterally (ct scan) oral albendazole (400mg) once daily for 7 consecutive days along with nebulization with levosalbutamol and budesonide respiratory and cutaneous lesions resolved within 7 days; complete radiological resolution on 4 weeks follow-up 9 195 figure 1: multiple discrete thread-like skin coloured to erythematous serpiginous tract of 196 various sizes (4 to 12 cm in length) distributed over the abdomen (a) and chest (b) 197 198 199 figure 2: (a) computed tomography of chest showed the presence of ill-defined 200 reticulonodular infiltrates in both lungs; (b) complete resolution after 4 weeks 201   exaggerated blood pressure reactivity in the offspring of first-cousin hypertensive parents *amal m ziada, waheed al kharusi, mohammed o hassan department of physiology, college of medicine, sultan qaboos university, p o box , al khod-, muscat, sultanate of oman. *to whom correspondence should be addressed. e-mail: ziada@squ.edu.om abstract. objective: to study blood pressure and blood pressure reactivity in young offspring of normotensive or hypertensive parents who are consanguineous (first cousins) or are not blood-related. method: blood pressure, heart rate and body mass index (bmi) were measured in – year-old male offspring of  pairs of first-cousins normotensive,  pairs of first-cousin hypertensive and  pairs of nonblood-related hypertensive parents. results: the offspring of first-cousin hypertensive parents exhibited the greatest systolic and diastolic blood pressure reactivity to their first casual blood pressure measurement, while the offspring of first-cousin normotensive parents showed the least reactivity. the offspring of the hypertensive parents who were not blood-related showed an intermediate reactivity. basal systolic blood pressure (sbp) was also highest in the offspring of first-cousin hypertensive parents, and their basal diastolic blood pressure (dbp) was higher than that in offspring of first-cousin normotensive parents. conclusion: the augmented blood pressure response in the offspring of hypertensive parents may have prognostic implications and serve as an important and significant indicator of predisposition to hypertension later in life. key words: consanguineous marriage, offspring, blood pressure reactivity, oman. g       blood pressure (bp) in populations has been well established.1–3 is effect has been repeatedly demonstrated by strong evidence of familial aggregation of bp.3–9 significant correlations exist between offspring’s and parent’s blood pressure, and more so between twins.10–12 is familial influence on bp can be detected from early childhood and tends to track over the years increasing in magnitude as the child progresses towards adolescence.4,5,13 children of hypertensive parents have higher average systolic and diastolic bp than children of normotensive parents, and are about . times more likely to have high bp before the age of .1,14 research indicates that essential hypertension has origins in childhood.15 tracking studies have shown that children and adolescents with elevated bp, though not necessarily in the hypertensive range, may be at     :   , : , : , – ©     increased risk for developing hypertension later in life.16–19 it is therefore useful to identify such familial predisposition in the offspring of parents with high blood pressure. cardiovascular reactivity is defined as the change in bp, heart rate, or other haemodynamic parameters in response to physical or mental stimuli.20 exaggerated bp reactivity has been observed in patients with hypertension compared to normotensive subjects and has also been described in young people, usually in connection with risk factors of hypertension.20–24 such studies demonstrate that bp reactivity to laboratory stressors tends to aggregate in families.25–27 hypertensive and pre-hypertensive subjects with positive family histories of hypertension show greater bp reactivity to mental and physical stressors than do subjects with no family history and a matching basal bp.1 such excessive responses of bp to stress may be a risk factor for the development of hypertension and other cardiovascular morbidities.24,28,29 among the various methods to measure bp reactivity is a simple one that takes advantage of the ‘white coat effect’, the exaggerated bp response that many people exhibit when examined in a clinical setting. e difference between an individual’s ‘clinic bp’ and the his ‘daytime average -hour bp’ can be used to quantify his bp reactivity due to the white coat effect.30,31 in our study, we investigated whether familial similarity could be detected via casual bp estimations in the offspring of consanguineous marriage of hypertensive parents—a unique sample from the population that runs the highest risk of developing hypertension, and therefore in our opinion may provide a better approximation of the extent to which familial aggregation of bp can be expressed than all models studied before. is excellent opportunity was rendered possible by a strong cultural disposition in the arab gulf region towards consanguineous marriages. in oman, a  survey estimated that first-cousin marriages under the age of  years formed  of the total marriages.32 m e t h o d e participants were  schoolboys aged – years who were taking part in a summer sports camp in the city of muscat. aer obtaining parental consent to the study, a screening examination was conducted within the offices of the sports complex by a qualified cardiovascular technician who did not wear a white coat. e sbp, dbp, and heart rate were recorded from the le arm, for the first time ever in those children, using an automated device (propaq, : protocol systems inc, or, usa). one measurement was taken aer  minutes of supine rest, and another aer  minutes. for each measurement the mean of two readings were calculated, however, if the first two readings differed by  mm hg or more, a third reading was taken and the mean of the three was used. bp reactivity was taken as the difference between the first ( min) and the second ( min) readings. body mass index (bmi; kg.m–2) was calculated. aer all examinations were completed, each participant carried home a short simplified questionnaire on his parents’ blood relationships, and whether one or both were on antihypertensive treatment. pairs were then divided into first-cousin parents and parents who were not bloodrelated. forty one pairs were first-cousin parents,  pairs of whom did not report for bp measurement, and were excluded from the study. irteen first-cousin parents were already on antihypertensive medication, and  were newly diagnosed with a sbp≥ and/or a dbp≥ mmhg on two separate visits each, as confirmed later by an independent physician at sultan qaboos university hospital. e occurrence of hypertension varied among the  first-cousin hypertensive parents: in  pairs both parents, in  pairs the mothers only, and in  pairs the fathers only were hypertensive. e normotensive group among the first-cousin parents comprised  pairs, and both parents had a sbp≤ and dbp≤ mm hg. e incidence of hypertension also varied in the parent pairs who were not consanguineous: in  pairs both parents were hypertensive; in  pairs only the father and in , only the mother were hypertensive. in the non-consanguineous cohort all hypertensives were already on antihypertensive medication.               e children were divided into three groups. e low risk (lr) group consisted of the offspring of first-cousin normotensive parents, the medium risk (mr) group comprised the offspring of one or two non-consanguineous hypertensive parents, and in the high risk (hr) group were the offspring of one or two first-cousin-related hypertensive parents. mean first and second sbp and dbp and heart rate values of hr children were compared to the corresponding values of the mr and lr children. statistical analysis was performed using spss version . for windows. to determine significance of the difference between the three groups, the independent sample t-test with  confidence interval was used. a p value <. was considered significant. r e s u lt s one hundred and sixteen parent pairs () responded to the questionnaire. e mean age of the fathers was             years (range –) which was significantly higher than that of the mothers (, range –), p<.. e main findings in the offspring are shown in table . ere was no significant difference between the the bmi of the three groups of children. e hr children exhibited the highest first sbp compared to the mr and lr children (p<. and p<. respectively). e second sbp reading was also significantly higher in the hr children than in the mr and the lr groups (p<. for both). similarly the first dbp readings were significantly higher in the hr and mr than the lr groups (p<. and p<. respectively) with no significant difference between the hr and mr groups. e second dbp reading was also significantly higher in the hr and mr groups compared to the lr group (p <. for both) with no significant difference between the readings in the hr and mr groups. ere were no significant differences between the groups in the first and second heart rate estimations. figure  summarizes the sbp and dbp reactivity in the three groups. e hr group exhibited the highest sbp and dbp reactivity (p<. and p<. respectively) the mr group an intermediate reactivity (p<. and p . respectively) while the lr group showed the least response with a slight but significant sbp reactivity (p<.) and non-significant dbp reactivity. d i s c u s s i o n all the subjects were of the same sex, similar bmi and age group, thereby eliminating the possible interaction of such factors. our results show that a family history of hypertension did predict both the differential bp and bp reactivity in these children in accordance with the three group designations. hr children showed the greatest systolic and diastolic bp reactivity, mr children occupied an intermediate position, and the lr showed the least reactivity. ese results are in agreement with other studies in which even milder levels of hypertensive heredity have revealed inclinations towards higher systolic and/or diastolic bp as well as higher bp reactivity to mental stress.26,34–38 we can only speculate on the mechanism responsible for this variation between groups. some studies have proposed that the exaggerated cardiovascular responses to stress are provoked by a differential sensitivity of adrenergic receptors and sympathetic overactivity.39,40 enhanced sympathetic activity may occur because of increased sympathetic stimulation and/or attenuated sympathoinhibition.41 overactivity starts in childhood and is easily evident in  of patients with incipient hypertension.40 it is possible that there is a genetic component in sympathetic overactivity expressed with more vigour in high risk individuals. although environmental factors do have a role in the development of high bp in humans, – of bp variations are attributed to genetic factors, and even this would probably be an underestimation in our and other similar populations.2,3,12 e prevalence of consanguineous marriages in oman places many of its children in the high risk group. attention should therefore be drawn towards a probable high level of hypertension in this population. one potential weakness of this study is that it is a ��������������������������������������������������������������� ������������������� � �������� ������������� �������������� ��������������� ����������������� ������������� �������������� ����������� ���� ������� ����� �� ��� ��� ��� ���������������� �������� ��������� ����������� ����������� �������������������������������� ���������������� �������� �������������� �������������� ���������������� ��������� ����������� �������������� ��������������������������������� ���������������� ��������� ���������� ���������� ���������������� ��������� ���������� ���������� ����������������������������� ���������������� ��������� ��������� ��������� ���������������� ��������� ��������� ��������� ��������������������������������������������������������������������������������������� ��������������������������������������������������������������������������������� ��������������������������� � � � ������� ����������������������������� ������������ ������������� ���������������� ������������������������� � � �� �������� � �� �������� � �������� �� ���������� �� ��������� � � � �� �� ����������� ������������ �� �� �� �� �� �� �� ��� �� ��� ��� ��� � �� �� �������� ����������� ���������                          deductive one that compares the bp of the offspring of hypertensive and normotensive parents and not to the parents’ actual bp values. although most studies on the heritability of bp were based on estimations of casual bp readings, it is now accepted that -hour ambulatory bp monitoring is a superior clinical tool in predicting the basal bp since it may be less affected by artefacts such as the white coat effect.30,34,42 even though our technician did not wear a white coat, the children in our study were going through the experience for the first time in their lives, that too in a formal (office) setting, which could have elicited stress comparable to the white coat effect.43 with this assumption we recorded the first round of bp measurement, aer giving each child  minutes of rest. e -minute gap before the second bp measurement was to allow the child’s bp to settle to its basal level. we acknowledge that this setting was suboptimal for estimating basal bp, and cannot confirm that the casual reading aer  minutes is a ‘true’ representative of basal levels: it still might have been confounded with the white coat effect. however, the setting was consistent for both the measurements and in all groups of children. moreover it has been shown that the artefact inherent in both casual bp and basal readings is heritable and appears to aggregate in first-degree relatives.42 c o n c l u s i o n e augmented bp reactivity found in the offspring of hypertensive parents might have prognostic implications and serve as an important early sign of familial predisposition to hypertension. our findings emphasise the need for special follow up of children with family histories of hypertension, and for a national educational programme on the genetic risks of consanguineous marriages.              is project was funded by sultan qaboos university internal grant system  ////. r e f e r e n c e s . hamet p, pausova z, adarichev v, adarichev k, tremblay j. hypertension: genes and environment. j hypertens , , –. . bouchard tj, lykken dt, mcgue m, segal nl, tellegen a. sources of human physiological difference: e minnesota study of twins reared apart. science , , –. . hong y, de faire u, heller da, mcclearn ge, pederson n. genetic and environmental influences on blood pressure in elderly twins. hypertension , , –. . wilson dk, klesges lm, klesges rc, eck lh, hackett-renner ca, alpert bs, dalton et. a prospective study of familial aggregation of blood pressure in young children. j clin epidemiol , , –. . van hoo im, hofman a, grobbee de, valkenburg ha. change in blood pressure in offspring of parents with high or low blood pressure: the dutch hypertension and offspring study. j hypertens suppl , , s–. . fossali e, ruzza ml, codega c, di francesco c, iurato m, migliaccio mc, et al. familial aggregation of blood pressure in a paediatric population. acta paediatr scand , , –. . brandao ap, brandao aa, araujo em, oliveira rc. familial aggregation of arterial blood pressure and possible genetic influence. hypertension , , –. . fuentes rm, notkola il, shemeikka s, tuomilehto j, nissinen a. familial aggregation of blood pressure: a population-based family study in eastern finland. j hum hypertens , , –. . wang x, wang b, chen c, yang j, fang z, zuckerman b et al. familial aggregation of blood pressure in rural chinese community. amm j epidemiol , , –. . stamler r, stamler j, reidlinger w, algera g, roberts r. familial parental history and prevalence of hypertension. jama , , –. . havlik rj, garrison rj, feinleib m, kannel wb, castelli wp, mcnamara pm. blood pressure aggregation in families. am j epidemiol , , –. . hunt sc, hasstedt sj, kuida h, stults bm, hopkins pn, william rr. genetic heritability and common environmental components of resting and stressed blood pressure, lipids, and body mass index in utah pedigrees and twins. am j epidemiol , , –. . michels vv, bergstralh ej, hoverman vr, o’fallon wm, weidman wh. tracking and prediction of blood pressure in children. mayo clin proc , , –. . curro v, de luca f, guisti d, bracaglia g, buffetti a, pelargonio s et al. correlations between blood pressure values, familial hypertension and anthropometric parameters in a sample of -year-old children. pediatr med chir , , –. . bao w, reefoot sa, srinivasan sr, berenson gs. essential hypertension predicted by tracking of elevated blood pressure from childhood to adulthood: the bogalusa heart study. am j hypertens , , –. . lauer rm, clarke wr, mahoney lt, witt j. childhood predictors for high adult blood pressure: the muscatine study. pediatr clin north am , , –. . kotchen jm, kotchen ta, guthrie gp jr, cottrill c, kean he. correlates of adolescent blood pressure at five–year follow-up. hypertension , , –. . clarke wr, woolson rf, lauer rm. changes in ponderosity and blood pressure in childhood: the muscatine study. am j epidemiol , , –. . lauer rm, clarke wr. childhood risk factors for high adult blood pressure: the muscatine study. paediatrics , , –. . falkner b. e role of cardiovascular reactivity as a mediator of hypertension in african americans. semin nephrol ,, –. . schulte w, neus h, von eiff aw. blood pressure reactivity to emotional stress in uncomplicated forms of hypertension. klin wochenschr , , –. . saab pg, llabre mm, ma m, dilillo v, mccalla jr, fernanderscott a et al. cardiovascular reactivity to stress in adolescents            with and without persistently elevated blood pressure. j hypertens , , –. . matthews ka, woodall kl, allen mt. cardiovascular reactivity to stress predicts future blood pressure status. hypertension , , –. . falkner b. blood pressure response to mental stress. am j hypertens , , –. . matthews ka, manuck sb, stoney cm, rakaczky cj, mccann bs, saab pg et al. familial aggregation of blood pressure and heart rate responses during behavioral stress. psychosom med , , –. . cavalcante jw, cavalcante lp, pacheco ws, de menezes mg, gama filho cg. blood pressure responses in children of normotensive and of hypertensive parents treated with pressor stimulus. arq bras cardiol , , –. . al’ absi m, everson sa, lovallo wr. hypertension risk factors and cardiovascular reactivity to mental stress in young men. int j psychophysiol , , –. . krantz ds, manuk sb. acute psychophysiologic reactivity and risk of cardiovascular disease: a review and methodological critique. psychol bull , , –. . matthews ka, weiss sm, detre t, dembroski tm, falkner b, manuk sb et al. handbook of stress, reactivity, and cardiovascular disease. new york, john wiley & sons , . . pickering tg, james gd. some implications of the differences between home, clinic and ambulatory blood pressure in normotensive and hypertensive patients. j hypertens suppl , , –s. . verdecchia p, schillaci g, boldrini f, guerrieri m, gatteschi c,benemio g et al. risk stratification of le ventricular hypertrophy in systemic hypertension using non-invasive ambulatory blood pressure monitoring. am j cardiol , , –. . sulaiman a j, al riyami a, farid s. oman family health survey; ministry of health, muscat. , –. . koch vh, colli a, saito mi, furusawa ea, ignes e, okay y et al. comparison between casual blood pressure and ambulatory blood pressure monitoring parameters in healthy and hypertensive adolescents. blood press monit , , –. . lemne ce. increased blood pressure reactivity in children of borderline hypertensive fathers. j hypertens , , –. . marrero af, al’absi m, pincomb ga, lovallo wr. men at risk for hypertension show elevated vascular resistance at rest and during mental stress. int j psychophysiol , , –. . al’absi m, everson sa, lovallo wr. hypertension risk factors and cardiovascular reactivity to mental stress in young men. int j psychophysiol , , –. . manuk sb, prolefrone jm, terrell df, muldoon mf, kasprowicz al, waldstein sr et al. absence of enhanced sympathoadrenal activity and behaviorally evoked cardiovascular reactivity among offspring of hypertensives. am j hypertens , , –. . nystrom f, aardal e, ohman kp. a population-based study of the white-coat blood pressure effect: positive correlation with plasma cortisol. clin exp hypertens , , –. . de champlin j, petrovich m, gonzalez m, lebeau r, nadeau r. abnormal cardiac reactivity in borderline and mild essential hypertension. hypertension , , –. . mills pj, dimsdale je, nelesen ra, jasiewicz j, zeigler mg, kennedy b. patterns of adrenergic receptors and adrenergic agonists underlying cardiovascular responses to a psychological challenge. psychosom med , , –. . julius s. e evidence for a pathophysiologic significance of the sympathetic overactivity in hypertension. cin exp hypertens , , –. . jamerson ka, schork n, julius s. effect of home blood pressure and gender on estimates of the familial aggregation of blood pressure. e tecumseh blood pressure study. hypertension , , –. . lantelme p, milton h, buttard p, fortrat jo, gayet c, gharib c. reactivity of “white coat” type is associated with reactivity to mental stress. arch mal coeur vaiss , , –.                        submitted 30 jan 23 1 revision req. 19 mar 23; revisions recd. 23 mar 23 2 accepted 4 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.023 5 6 longitudinal extensive transverse myelitis (letm) in a four-year-old 7 boy liver transplant recipient 8 *roshan koul,1 shalini thapar,2 rajeev khanna,3 seema alam3 9 10 departments of 1neurology, 2radiology and 3pediatric hepatology, institute of liver and 11 biliary sciences, new delhi, india 12 *corresponding author’s e-mail: koulroshan@gmail.com 13 14 acute transverse myelitis (atm) is defined as acute onset quadriplegia or paraplegia with 15 sensory and autonomic involvement progressing in three to four days’ time. 1 if the myelitis 16 involves more than three consecutive vertebral segments on magnetic resonance imaging 17 (mri), it is called longitudinal extensive transverse myelitis (letm). 1 on google and 18 pubmed search only, one adult case of transverse myelitis was seen in a liver transplant (lt) 19 recipient.2 this is the first case of letm to be reported in a child who had lt. 20 21 introduction 22 four years eight months old boy diagnosed with biliary atresia at neonatal period, underwent 23 living liver donor transplantation at the age of one year and five months. he was third child in 24 the family with no family history of liver disease. he had tubercular lymphadenitis soon after 25 transplant which was treated appropriately. he also had prolonged unprovoked seizure in 26 november 2020, which was treated with levetiracetam. he developed epstein-barr virus 27 (ebv) infection and was treated with ganciclovir. he had graft dysfunction due to hepatitis e 28 infection which settled of its own. two years and ten months after transplant (june 2022) he 29 developed right mandibular mass. positron emission tomography (pet) computerized 30 tomography (ct) scan showed fluoro-deoxy glucose (fdg) avid irregular mass involving 31 right maxillary sinus, retro-orbital region, and ethmoid sinus with lytic destruction of maxilla. 32 histopathology revealed burkett’s lymphoma stage iv. bone marrow and cerebro spinal fluid 33 (csf) were normal. he was started on rituximab, cyclophosphamide, hydroxydaunorubicin, 34 vincristine, prednisolone (r-chop) chemotherapy along with intrathecal methotrexate. by 35 end of august 23, 2022 he had received 3 cycles of chop with intrathecal methotrexate and 36 5th pulse of rituximab. on september 5th 2022 he was admitted with progressive weakness of 37 all four limbs which started in the left arm first and completely paralyzed him below neck in 38 three days’ time. his cranial nerves and sensorium were normal. mri brain was normal and 39 mri spine revealed almost whole length spinal cord myelitis [figure 1]. csf examination 40 was normal. no malignant cells were seen. viral studies were negative. aquaporin antibody 41 test was not done as the facility to test this, was not available in the hospital. he was treated 42 with pulse methylprednisolone 30mg/kg/day for five days followed by oral steroids for four 43 weeks and ivig 400mg/kg/day for five days. he started improvement in his weakness after 44 ten days of treatment. currently he has grade three power (medical research council grading) 45 in right upper limb, grade 2 to 3 in lower limbs and grade 1 in left upper limb. sensory 46 examination was normal all over. he received repeat chemotherapy on 29th november 2022, 47 including intrathecal methotrexate. there was no worsening of his weakness after intrathecal 48 methotrexate. during the hospital stay he had recurrence of seizures which evolved into 49 status epilepticus requiring four anti-epileptic drugs (midazolam, levetiracetam, phenytoin 50 sodium, lacosamide and phenobarbital) to control. 51 52 comment 53 there are many neurological complications seen in liver transplant recipients. 3 these may 54 be related to the transplant or immunosuppressants used in the treatment. 3 atm is the rarest 55 of all complications. only few reports are in the literature. 2 most of the atm in children 56 are of unknown etiology, believed to be some form of nervous system demyelinating illness 57 in response to varied etiology. 1,4 a thorough workup is required in atm to rule out 58 infectious, autoimmune disorders or infiltrations. 1,4 in a single case of atm reported in an 59 adult liver transplant recipient, it was correlated to the high levels of tacrolimus.2 this patient 60 was a 39 years old male, with chronic liver disease due to budd-chiari syndrome. he 61 underwent deceased liver transplant and was put on tacrolimus. he developed weakness of all 62 four limbs on day five post operation. blood tacrolimus level was normal. mri brain was 63 normal and mri spine revealed whole length spinal cord demyelination. no underlying 64 etiology was found on investigation. immunoglobulins did not improve the weakness. 65 cyclosporine was added in the treatment and tacrolimus was stopped. this change of 66 immunosuppressant resulted in improvement of his weakness. 2 our patient had not received 67 tacrolimus, and csf study was normal. intrathecal methotrexate is widely used and there are 68 few reports in literature about association of atm and intrathecal methotrexate. 5 however 69 our patient had received three doses previously and the weakness developed after thirteen 70 days of the third dose. further he was given fourth dose on 29th november 2022, without 71 worsening of his neuro status. this observation rules out methotrexate induced atm. our 72 patient is the first case of letm seen in a liver transplant recipient. atm is uncommon in 73 children.1,6 letm presentation in our patient is possible due to his medical condition, 74 making him more prone to various autoimmune conditions or coincidental. several 75 cofounders in setting of lt, it is difficult to pinpoint what predisposed this boy to letm. a 76 repeat follow up mri spine and clinical monitoring will determine his long-term therapy for 77 the letm. 78 79 authors’ contribution 80 rok, sa and rak managed the patient. rok provided the diagnosis. st provided the 81 radiological images. rok drafted the manuscript and sa edited the manuscript. all authors 82 approved the final version of the manuscript. 83 84 references 85 1. wolf vl, lupo pj, lotze te. pediatric acute transverse myelitis. overview and 86 differential diagnosis. j child neurol 2012;27:1426-87 1436.doi:10.1177/0883073812452916 88 2. aksoy f, dundar hz, demir ab, kiyici m, kaya e. .myelitis after liver 89 transplant: a case report. experimental and clinical transplantation. 2021; 1-3. 90 doi:10.6002/ect.2020.0278 91 3. weiss n, thabut d. neurological complications occurring after liver 92 transplantation: role of risk factors, hepatic encephalopathy and acute (on 93 chronic) brain injury. liver transplantation.2019;25:469-487 94 https://doi.org/10.1002/lt.25420 95 4. scott te, frohman em, de seze j, gronseth gs, weinshenker bg. evidence based 96 guidline: clinical evaluation and treatment of transverse myelitis: report of the 97 therapeutics and technology assessment subcommittee of the american academy 98 of neurology. neurology 2011; 77:2128-2134. 99 5. castillo-torres sa, soto-rincón ca, villarreal-montemayor hj, chávez-luévanos 100 b. case of neuromyelitis optica: bilateral sensorineural hearing loss 101 https://pubmed.ncbi.nlm.nih.gov/32300035/ and transverse myelopathy following intrathecal chemotherapy. bmj case rep. 2020 102 apr 15; 13(4):e234076. doi: 10.1136/bcr-2019-234076 103 6. koul r, alfutaisi a, mani r, abdelrahim r, sankhla dk, alazri fm. longitudinal 104 extensive transverse myelitis in children from oman. neurosciences (riyadh) 105 2017;22:127-130, doi.10.17712/nsj.2017.2.20160352 106 107 108 figure 1:mri short tau inversion recovery (stir) sagittal image of spine, a shows cervical 109 1to dorsal 7 vertebra hyper-intense lesion, b shows dorsal 8 to conus medullaris lumbar 1 110 vertebra hyper-intense lesion (whole spine could not come in single image due to mild 111 scoliosis). c. stir sagittal image spine as control shows normal appearance of the spinal 112 cord. 113 https://pubmed.ncbi.nlm.nih.gov/32300035/ january 2007 vol 7 correct a.indd the role of caregivers in the management of alzheimer’s disease examples from asian countries *joydeep d chaudhuri1, srijit das2 the demographic profile in many asian countries is in the process of a major shift due to an increasing ageing population that has been arbitrarily defined as one where seven percent of the people are aged over 60 years [table 1]. the aged population in asia was conservatively estimated at 8.2 % in 1995 1 and has been predicted to increase to about 10% by year 2010.1 a similar distribution has also been noted in the eastern mediterranean region 2 that also includes the gulf cooperation council (gcc) [table 2]. while the percentage increase over these years is not very remarkable, in absolute numbers it translates to an enormous increase in aged population and related health care issues. the increase in the aged population has been attributed to an overall improvement in lifestyle standards and consequent longevity.3 a l z h e i me r’ s d i se a se it is paradoxical that improvement in healthcare facilities has resulted in an increased lifespan and a related increase of age-related diseases, significant among which is alzheimer’s disease (ad). ad is a chronic neurodegenerative disorder, the most dominant feature of which is cognitive decline. it is characterised by progressive memory loss, personality changes and in its final stages hamper the activities of daily living. the incidence of ad has been directly linked to a high percentage of individuals over 65 years of age, with up to 55% of people over 65 years of age being affected by the 1department of anatomy, midwestern university, 19555 n, 59th avenue, glendale, az 85306, usa, 2department of anatomy, maulana azad medical college, new delhi-110002, india *to whom correspondence should be addressed. email: jchaud@midwestern.edu الزهامير مرض مع التعامل في الرعاية مسئولي دور (لتحسن األعمار زيادة معدالت ــبب بس الناس من املعمرة خاص الفئة ــكل بش وتزداد ، ــرعة بس ــيا آس ــعوب ــكانية لش الس امللخص: تتغير الطبيعة ــكلة مش اصبح الذي الزهامير, مبرض االصابة معدالت ازدياد الى أدى ذلك كل . اخرى جهة من الوالدة معدالت ــان ولنقص جهة من ــة) الطبي ــات اخلدم . احلاالت مع هذه التعامل ــي األهم ف باملريض اجلزء العناية أصبحت ، املذكور ــرض للم ناجع عالج ولعدم وجود . ــيوية اس بلدان عدة في ــرة ــة كبي صحي رعاية شؤون املقالة تعالج هذه بطيئة. كانت اال هذا في ــيوية االس الدول مبادرة ما ، لكن حد الى ــكلة املش هذه ــتطاعت حل اس البلدان الصناعية . وخصوصيتها االسيوية البيئة يالئم مبا الزهامير مبرض املصابني الكلمات مفتاح . األهل رعاية ، املعمرون مرض الزهامير ، املفردات املفتاحية: abstract the demographic profile of the asian population is rapidly changing, with a fast increasing ageing population, owing to an increase in longevity and a decreasing birth rate. moreover, due to improved medical facilities and the increased aged population, alzheimer’s disease (ad) is fast emerging as a major health problem in many asian countries. as curative treatment for ad is still elusive, care giving is an important component of the management of ad. while western countries have recognised this issue, besides highly industrialized japan, the asian initiative has been relatively slow. this article aims to address issues involved in caregiving in ad in some asian countries. keywords: alzheimer’s disease, ageing population, caregivers sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© r e v i e w j o y d e e p d c h au d h u r i a n d s r i j i t d a s 12 disease.3 this has obvious implications for the already over stretched health care system in many asian counties. it is noteworthy that although females are more represented in caregiving in asia, their presence does not have a significant impact on the overall caregiving in ad.3 although ad was identified almost a century ago, a definitive treatment has still eluded mankind. at this juncture, symptomatic palliative treatment along with effective caregiving appears to be the only therapeutic option, with most of the affected persons being cared for at home by informal caregivers, who are usually family members or relatives.4 ad has been identified as the single largest cause of dementia in the western world5 and its prevalence in some asian countries is also high [table 3] and references therein). thus, as the ageing population continues to grow, society is faced with the dilemma of an increasing prevalence of ad patients and the responsibilities of caring for them. though the importance of caregiving in ad management has been recognised by many western countries,6,7 the effort in many asian counties. the development of caregiver resources has not been significant, except for a few isolated programs.8,9 in many asian counties., it is generally believed that caregiving is not just a duty, but also an expression of love and devotion, and there is a great reliance on the family system for support. however, as many asian caregivers lack adequate medical knowledge, social and emotional skills, the task of care giving becomes even more challenging. this article aims to discuss the issues involved in caregiving in ad in general and specifically in relation to the asian context. c a r e gi v e r i s sue s caregiving broadly includes the assistance and monitoring of activities of people affected by disease or disability. assistance may be in the form of medical, financial, emotional or legal support. on a daily basis, it includes personal care, housekeeping, administration of medication and execution of financial transactions and other responsible activities. thus, in severely affected persons, such as those with ad, the caregiver becomes an important, albeit essential, factor for their well-being and often existence. in fact, it has been shown that the single predictor of placement of an affected person in a nursing home is the absence of caregivers.10 in the broader context, the important issues involved in the caring of ad patients include: recognition of the needs of ad patients. the recognition of the needs and problems of persons affected by ad appears fundamental to caregiving. however, it has been seen that a significant number of caregivers tend to overestimate the physical and mental capabilities of ad patients under their care. they at times fail to realize that even simple directions and instructions maybe be difficult for ad patients to follow due to their dementia. consequently, failure of their patients to comply with directions often leads to frustration, anger and depression for both the patient and the caregiver.11 further, dying people have certain rights that broadly include relief from pain, affirmation of the whole person and the right to die with dignity.12 caregivers need to learn the specific issues in the promotion and protection of these rights in order to provide a positive death experience for a person with ad. country 1991 2001 bangladesh 6 million 11.4 million china 42 million 97 million hong kong 772,400 i million indonesia 53 million 113 million table 1: total population over 60 years of age in selected asian countries (based on ref : 1) country 60 years and older % bahrain 5.2 iraq 4.8 jordan 3.8 kuwait 3.9 lebanon 10.4 oman 4.5 palestine 4.9 qatar 6.0 saudi arabia 4.0 syrian arab republic 4.8 table 2: proportion of population 60 years and older for selected countries of the world health organization eastern mediterranean region (based on ref : 2) th e r o l e o f c a r e g i v e r s i n t h e m a n a g e m e n t o f a l z h e i m e r ’ s d i s e a s e 13 th e c a r e gi v e r bur d e n caregiving is a complex task that is often underplayed. it is physically, mentally and financially stressful for the caregiver, due to complex emotions such as resentment about time and effort expended, sympathy and the anticipated loss of a loved one and often loss of income.13 the resultant changes in lifestyles and goals of a caregiver, often involve a major reorganization of priorities. this results in the loss of free time, neglect of friends and hobbies, often manifesting as social isolation and a consequent decrease in the quality of life of caregivers.13, 14 analyses have shown that the levels of anxiety and depression in caregivers are directly related to the hours of care required and the physical and psychological illness scores of the ad patients under their care.15 investigations have been carried out into the reasons for distress of ad caregivers. at the forefront are the low levels of knowledge of caregivers about the prevalence, causes, symptoms and management of ad.16 for example, caregivers often complain of a loss of functional communication with ad patients, who are unable to follow verbal commands. the knowledge that simple sentences, instead of slow speech, while communicating with ad patients is more effective, has been shown to significantly reduce caregiver stress.17 further, the knowledge of other communication strategies such as direct questioning in contrast to parallel questioning has also been shown to lower the caregiver’s burden.18 parallel questioning refers to addressing issues in an indirect manner that require a more complicated reply, as compared to direct questioning which usually require a “yes” or “no” response.18 another significant problem outlined by caregivers is difficulty in finding adequate resources such as effective and convenient medical support and community resources for management of ad patients.19 the importance of this point is emphasized by two studies that have reported that caregivers who attended counselling, where information on care giving in ad was given, had lesser depressive symptoms and anxiety.20,21 however, it is encouraging that in contrast to their counterparts in the western world, though some asian caregivers report a general reduction in vitality, many do not experience a decreased level of social functioning.14 be n e fi ts o f g o o d c a r e gi v i n g an efficient system of caregiving in ad is advantageous to all. it is of benefit to affected patients and their caregivers and also the formal health care system. proper training of caregivers resulted in a general improvement of the physical and psychological health of ad patients, with significantly beneficial effects on their sleeping habits and increased daytime activity.22, 23 further, training of caregivers that included sessions on good nutritional practices helped in preventing weight loss in ad patients.24 moreover, affected persons gained significantly from the advantage of being cared for in their familiar surroundings. caregivers are particularly vulnerable to physical and mental strain, especially if they are female. training of caregivers enhances their management ability and enables them to handle disruptive behaviour of their wards and obtain an overall mastery of their situation.21, 22, 24 this training will have to be carried out by health care professionals and will results in less leave of absence from duty and consequently less loss of income. further, as ad patients decline in their mental state, they become increasingly dependent on their caregivers for important decisions. at this juncture caregivers have an important role in deciding various issues concerning ad patients. effective care giving in ad also benefits the formal health care system by reducing the costs of institutionalisation of patients. current health care practices aim at providing acute care and the convalescent period has shifted from hospitals to the community and home.25 further, caregivers are able to provide valuable prognostic and therapeutic information to health care professionals regarding the patient’s progress and response to treatment. moreover, the caregiver is also able to help with memory aids, behavioural interventions, exercise and nutrition and the overall effectiveness of various palliative measures in ad that would otherwise have to be managed by the formal health care system.26 th e r o l e o f d o c to r s a n d h e a lth c a r e pr o fe s si o n a l s i n th e tr a i n i n g o f c a r country prevalence rate (%) india34 4.7 sri lanka36 4.0 china37 4.4 south korea38 4.2 japan39 4.8 table 3: prevalence of ad in some asian countries j o y d e e p d c h au d h u r i a n d s r i j i t d a s 14 e gi v e r s o f a d pati e n ts while it is obvious that the training of caregivers has important beneficial effects, a study conducted on 200 clinicians in california, usa showed that though a vast majority of them routinely carried out neurological interventions for patients, only a small number of them actively implemented caregiver support practices.27 an australian study has also reported that caregivers of ad patients complained of insufficient support from the health care system regarding adequate information about the disease, methods to deal with problem behaviour of their patients and how to access support services from health care agencies.28 while similar studies have not been carried out in asian countries it can be anticipated that asian clinicians would demonstrate the same disregard for caregiver support practices. a study carried out in the uk highlighted three important areas where interventions by doctors or health care professionals can be instrumental in improving caregiving in ad.29 these areas include (i) the caregiver education component, in which the knowledge of the caregiver regarding ad is assessed and the caregiver’s personal model of ad is discussed, (ii) stress management of caregivers, wherein techniques for personal stress management, self monitoring and relaxation are taught and (iii) advice on how to respond to problematic behaviour of ad patients. hebert et al., 2002, have emphasised that the focus of training of caregivers should be more on methods of coping with the stressful demands of demented patients and task oriented aspects of caregiving, rather than with information on the disease process.30, 31 a more recent report by greenberger and litwin 2003, 32 has shown that the most important resources identified by caregivers include a sense of competence and adequate support from professional healthcare providers.31 further, doctors need to be particularly concerned when the female spouse is the caregiver as a study has shown that as caregivers, wives generally fare worse than husbands due to a possible role reversal.32, 33 this is especially important in the asian context where men traditionally have more responsible roles than females. while these specific interventions have largely have been described in the european context, they can be modified to suit the asian context. thus, doctors and health care workers need to be aware of the need for adequate training and counselling of caregivers, so they can be effectively incorporated into the treatment plans of ad patients. it is significant to note that, in many cases, most of the physicians find it difficult to explain the diagnosis and treatment to a patient and in such cases the role of caregivers is important regarding the disclosure and figure 1: effect of changing demographic profile and increased prevalence of alzheimer’s disease on the asian population. th e r o l e o f c a r e g i v e r s i n t h e m a n a g e m e n t o f a l z h e i m e r ’ s d i s e a s e 15 treatment of the disease.31-33 c a r e gi v i n g i n a l z h e i me r’ s d i se a se : in many asian counties with the growing number of aged people and a decreasing household size, many asian countries are faced with the spectre of an increasing incidence and prevalence of ad and less people to care for the patients.34-39 care giving in many asian socieies is at present carried out by family members, with support from family members and friends. it is largely because of tradition inculcated at an early age, that caregiving is perceived as an integral part of life to be carried out with love and sympathy, and as a sign of family and kinship support, though this cultural teaching cannot enhance care for the elderly.40 moreover, the lack of adequate formal health care support facilities for older people has forced families and other informal caregivers to form the mainstay of support for those affected by ad.41 however, there are certain constraints. one is the need for involvement of caregivers in early detection, diagnosis and treatment of patients who demonstrate early symptoms of ad.42 further, with the growth of technology, caregivers are using more technology when caring for ad patients. however, adequate skill is lacking in many asian caregivers.43 moreover, there is a lack of adequate communication between caregivers and doctors responsible for the management of the patients.44 however, this practice is being forced to undergo transformations, largely due to the pressures of socio-economic changes. the dissolution of extended families because of space constraints and job obligations and an increasing number of women working outside their homes has increased the challenge of caring for older people with ad. further, effective birth control measures and the resultant reduction in household size and number of siblings to assist parental care has increased the load of caregiving for elders, including those affected by ad4. it is also significant to note that the negligible financial support available to affected people and their caregivers has added to the burden of caregiving in ad, highlighting the importance of monetary resources in the management of ad [table 4]. 44 thus the changing socioeconomic scenario in asian countries underscores the need for training of caregivers of ad patients and the development of an effective support system. this is further emphasized by the identification of stress levels being specifically linked to caregiving of ad patients.12-15, 45 it has been shown that relevant information regarding ad was the most important factor in reducing caregiver burden and ensuring effective caregiving for ad patients.46 further, since caregivers are responsible for many of the decisions regarding ad patients, it strongly suggests the need to provide caregivers with more information in order to promote good decision making.17 thus, the foremost step in the management of caregiving in ad in many asian countries is the need for education and an assessment of the perceptions of ad among the lay public and particularly of caregivers of ad patients.47 a study in hong kong showed that the vast majority asian caregivers in many asian counties. welcomed training workshops for caregivers.41 while this is a laudable approach, it is limited in most asian countries due to monetary constraints. a more feasible approach, as suggested by shaji et al., 2003, would be the training of domiciliary outreach services and community-based multipurpose health workers to impart knowledge regarding ad and provide the necessary support to caregivers, which have been highlighted in the previous paragraph, the most salient feature being the identification of the stress levels of caregivers.43 this could be carried out during normal hours as a part of training of the public regarding other health issues. however, it must be emphasised that health workers in developing countries can underreport or overreport services rendered due to inefficient data collection systems or recall bias in the population.47 thus, appraisal methods for evaluation of caregiver services need to be developed as caregiver support is one of the most important predictors of the well being of an ad patien, and health workers should be utilized for such evaluations. further, inadequate caregiver support leads to an early discontinuation of home treatment of ad patients and a consequent increase in health management costs when they are institutionalised. another useful approach to reducing caregiver burden in ad is by the creation of support groups country 1991 2001 bangladesh 6.7 5.5 china 4.4 3.9 hong kong 5.3 4.5 table 4: average household size in some asian countries (based on ref : 44) j o y d e e p d c h au d h u r i a n d s r i j i t d a s 16 for caregivers. a study carried out in hong kong41 showed that the creation of a mutual support group programme for caregivers of ad had a significant role in improving the quality of life and could be incorporated into health care practices in many asian countries.48 however, it needs to be noted that that such a support system will be maximally effective only when an adequate care giving system has been developed. another study has also highlighted that professional contact between caregivers was significant in developing the home skills of caregivers thereby reducing their behavioural symptoms.49, 50 another significant development that has transcended continental boundaries is the development of internet-based groups that offer caregivers the opportunity to interact with other caregivers for guidance, information and encouragement [table 5]. the overall development of such resources in the different asian countries in native languages will significantly improve the quality of life of ad patients and reduce the caregiver’s burden, as caregivers in contact with each other are consistently more knowledgeable. educating the general public about ad and its care through electronic media would remove much of the social stigma associated with the disease. a significant development in this respect is the development of the alzheimer’s caregiver support online (http://www.alzonline.net/), a web-based support network for caregivers. a similar online service is offered by the eastern michigan university for the health care professionals and caregivers (http://www.emuonline.edu). c o n c l u s i o n scientific advances in diagnosis and management of disease has resulted in greater longevity and a consequent increase in the aged population. as definitive treatment for ad is still unavailable, caregiving needs to be recognised as an important component of the management of ad. caregiving in ad requires a variety of skills that include education about ad, assessment of the physical and mental condition of an ad patient and an effective support system for the caregiver. disseminating knowledge about the disease, its treatment and the role of caregivers should be the prime aim of ad management. according to a report, the united nations estimated that the total number of individuals over 65 years of age, living in the countries of the eastern mediterranean region of the world health organization (who) is approximately 3.5%, and is expected to approach 3.6% by 2005.47 however, there are differences in the size of the elderly population among the member countries of the gcc, with values ranging from a low 1.1% in qatar and the united arab emirates to a high of 11% in cyprus.48 a number of factors like reductions in infant and child mortality over several decades, together with a reduction in birth rates, have contributed to a high proportion of elderly people in cyprus, while a large influx of young immigrant workers has resulted in a low proportion elderly people in the member countries of the gcc.47, 48 it has been noticed that a national policy means a national committee for care of the elderly, usually administered by the ministry of social affairs (or the ministry of health in one country and the directorate of elderly care and gerontology in another).49,50 a decree on social benefits for the elderly exists in one country, while another member country is changing the structure of its national committee to conform to the policy on the elderly adopted by the league of arab states. most of these national committees were established between 1996 and 1997, almost immediately after the release in 1995 of the strategy paper on the health care of the elderly by the who regional office for the eastern mediterranean.51,52, 53 currently there is no significant support program for patients with ad and also for their caregivers in most asian countries. the majority of this function is table 4: websites related to the information regarding care giving in alzheimer’s disease. name website alzheimer’s caregiver support online http://www.alzonline.net the combined health information database http://chid.nih.gov alzheimer’s disease education & referral centre http://www.alzheimers.org national family caregivers association http://www.nfcacares.org alzheimer’s association safe return http://www.alz.org/services/safereturn.asp elder care locator http://www.eldercare.gov th e r o l e o f c a r e g i v e r s i n t h e m a n a g e m e n t o f a l z h e i m e r ’ s d i s e a s e 17 being carried out by non-governmental organizations, which have tried to highlight the role of caregivers in the management of ad patients. thus, closer collaboration and flexibility is necessary between researchers, clinicians, health care support staff and health policy makers in the different asian countries to support and strengthen the role of caregivers in ad. r e f e r e n c e s 1. achir y. indonesian family planner warns of 400 million population by 2053. asia-pacific popin bulletin 2003: 15. 2. hafez g, bagchi k, mahaini r. caring for the elderly: a report on the status of care for the elderly in the eastern mediterranean region. east mediterr health j 2000; 6:636-643. 3. lopes ma, bottino cm. prevalence of dementia in several regions of the world: analysis of epidemiologic studies from 1994 to 2000. arq neuropsiquiatr 2002; 60:61-69. 4. alzheimer’s association. (2001). statistics/prevalence (on line). available: http://www.alz.org/facts/rstats. htm. accessed october 13, 2005. 5. foley dj, brock db, lanska dj. trends in dementia mortality from two national mortality followback surveys. neurology 2003; 60:709-711. 6. monsch au, ermini-funfschilling d, mulligan r, et al. memory clinics in switzerland. collaborative group of swiss memory clinics. ann med interne 1998; 149:221227. 7. tanner rc. providers issue brief: family caregiving: year end report-2003. issue brief health policy track serv 2003; 1-12. 8. olson p. caregiving and long-term health care in the people’s republic of china. j aging soc policy 1993; 5: 91-110. 9. washio m, arai y. the new public long-term care insurance system and feeling of burden among caregivers of the frail elderly in rural japan. fukuoka igaku zasshi 2001; 92;292-298. 10. finch j, mason j. negotiating family responsibilities. london: routledge 1993; 23-56. 11. arguelles s, loewenstein da, eisdorfer c, arguelles t. caregivers’ judgments of the functional abilities of the alzheimer’s disease patient: impact of caregivers’ depression and perceived burden. j geriatr psychiatry neurol 2001; 14:91-98. 12. bosek ms, lowry e, lindeman da, burck jr, gwyther lp. promoting a good death for persons with dementia in nursing facilities: family caregivers’ perspectives. jonas health law ethics regul 2003; 5:34-41. 13. biegel de, sales e, schultz r. family caregiving in chronic illness. newbury park, ca: sage publications, 1991: 465-470. 14. rodriguez g, de leo c, girtler n, vitali p, grossi e, nobili f. psychological and social aspects in management of alzheimer’s patients: an inquiry among caregivers. neurol sci 2003; 24:329-335. 15. morimoto t, schreiner as, asano h. caregiver burden and health-related quality of life among japanese stroke caregivers. age ageing 2003, 32:218-223. 16. sansoni j, vellone e, piras g. anxiety and depression in community-dwelling, italian alzheimer’s disease caregivers. int j nurs pract 2004; 10:93-100. 17. werner p. correlates of family caregivers’ knowledge about alzheimer’s disease. int j geriatr psychiatry 2001;16:32-38. 18. small ja, gutman g, makela s, hillhouse b. effectiveness of communication strategies used by caregivers of persons with alzheimer’s disease during activities of daily living. j speech lang hear res 2003; 46:353-367. 19. roberto ka, richter jm, bottenberg dj, campbell s. communication patterns between caregivers and their spouses with alzheimer’s disease: a case study. arch psychiatr nurs 1998; 12:202-208. 20. farran cj, loukissa d, perraud s, paun o. alzheimer’s disease caregiving information and skills. part ii: family caregiver issues and concerns. res nurs health 2004; 27:40-51. 21. mittelman ms, roth dl, coon dw, haley we. sustained benefit of supportive intervention for depressive symptoms in caregivers of patients with alzheimer’s disease. am j psychiatry 2004; 161:850-856. 22. akkerman rl, ostwald sk. reducing anxiety in alzheimer’s disease family caregivers: the effectiveness of a nine-week cognitive-behavioral intervention. am j alzheimers dis other demen 2004; 19:117-123. 23. mccurry sm, gibbons le, logsdon rg, vitiello m, teri l. training caregivers to change the sleep hygiene practices of patients with dementia: the nite-ad project. j am geriatr soc 2003; 51:1455-1460. 24. riviere s, gillette-guyonnet s, voisin t, et al. a nutritional education program could prevent weight loss and slow cognitive decline in alzheimer’s disease. j nutr health aging 2001; 5:295-299. 25. gitlin ln, winter l, corcoran m, dennis mp, schinfeld s, hauck ww. effects of the home environmental skillbuilding program on the caregiver-care recipient dyad: 6-month outcomes from the philadelphia reach initiative. gerontologist 2003; 43:532-546. 26. clark m, steinberg m, bischoff n. patient readiness for return home: discord between expectations and reality. aust occup ther j 1997; 44:132-141. 27. ham rj. evolving standards in patient and caregiver j o y d e e p d c h au d h u r i a n d s r i j i t d a s 18 support. alzheimer dis assoc disord 1999; 13:27-35. 28. rosen cs, chow hc, greenbaum ma, finney jf, moos rh, sheikh ji, yesavage ja. how well are clinicians following dementia practice guidelines? alzheimer dis assoc disord 2002; 16:15-23. 29. bruce dg, paterson a. barriers to community support for the dementia carer: a qualitative study. int j geriatr psychiatry 2000; 15:451-457. 30. marriott a, donaldson c, tarrier n, burns a. effectiveness of cognitive-behavioural family intervention in reducing the burden of care in carers of patients with alzheimer’s disease. br j psychiatry 2000; 176:557-562. 31. hebert r, levesque l, vezina j, et al. efficacy of a psychoeducative group program for caregivers of demented persons living at home: a randomized controlled trial. j gerontol b psychol sci soc sci 2003; 58:58-67. 32. greenberger h, litwin h. can burdened caregivers be effective facilitators of elder care-recipient health care? j adv nurs 2003; 41:332-341. 33. hooker k, manoogian-o’dell m, monahan dj, frazier ld, shifren k. does type of disease matter? gender differences among alzheimer’s and parkinson’s disease spouse caregivers. gerontologist 2000; 40:568-573. 34. chandra v, pandav r, dodge hh, et al. incidence of alzheimer’s disease in a rural community in india: the indous study. neurology 2001; 57:985-989. 35. cantegteil-kallen, turbelin c, olaya e, et al. disclosure of diagnosis of alzheimer’s disease in french general practice. am j alzheimers dis other demen 2005; 20:228-232. 36. de silva ha, gunatilake sb, smith ad. prevalence of dementia in a semi-urban population in sri lanka: report from a regional survey. int j geriatr psychiatry 2003; 18:711-715. 37. yan f, li s, liu j, zhang w, chen c, liu m et al. incidence of senile dementia and depression in elderly population in xicheng district, beijing, an epidemiologic study. zhonghua yi xue za zhi 2002; 82:1025-1028. 38. suh gh, kim jk, cho mj. community study of dementia in the older korean rural population. aust n z j psychiatry 2003; 37:606-612. 39. ikeda m, fukuhara r, shigenobu k, et al. dementia associated mental and behavioural disturbances in elderly people in the community: findings from the first nakayama study. j neurol neurosurg psychiatry 2004; 75:146-148. 40. subgranon r, lund da. maintaining caregiving at home: a culturally sensitive grounded theory of providing care in thailand. j transcult nurs 2000; 11:166173. 41. prince m. 10/66 dementia research group. care arrangements for people with dementia in developing countries. int j geriatr psychiatry 2004; 19:170-177. 42. lai ck, wong fl, liu kh. a training workshop on latestage dementia care for family caregivers. am j alzheimers dis other demen 2001, 16:361-368. 43. shaji ks, smitha k, lal kp, prince mj. caregivers of people with alzheimer’s disease: a qualitative study from the indian 10/66 dementia research network. int j geriatr psychiatry 2003; 18:1-6. 44. carter re, rose da, palesch yy, mintzer je. alzheimer’s disease in the family practice setting: assessment of a screening tool. prim care companion j lin psychiatry 2004; 6:234-238 45. lehoux p. patients’ perspectives on high-tech home care: a qualitative inquiry into the user-friendliness of four technologies. bmc health serv res 2004; 4:28-36. 46. bruce dg, paley ga, underwood pj, roberts d, steed d. communication problems between dementia carers and general practitioners: effect on access to community support services. med j aus 2002; 177:186-188. 47. sullivan k, o’conor f. providing education about alzheimer’s disease. aging ment health 2001; 5:5-13. 48. nair v, thankappan k, sarma p, vasan r. changing roles of grass-root level health workers in kerala, india. health policy plan 2001; 16:171-179. 49. fung wy, chien wt. the effectiveness of a mutual support group for family caregivers of a relative with dementia. arch psychiatr nurs 2002; 16:134-144. 50. gitlin l n, hauck w w, dennis m p, winter l. maintenance of effects of the home environmental skill-building program for family caregivers and individuals with alzheimer’s disease and related disorders.j geontol a biol sci med sci 2005; 60:368-374. 51. economic and social commission for asia and the pacific, asian population studies series no 145: available at: http://www.unescap.org/pop/publicat/apss145/ apss145tc.htm. accessed october 13, 2005. 52. the elderly in the eastern mediterranean region: an overview in ageing. exploding the myths. international year of older persons. alexandria, world health organization, regional office for the eastern mediterranean 1999. 53. regional strategy for health care of the elderly in the eastern mediterranean reg ion:1992-2001.reg ional advisory panel on health care for the elderly. alexandria: world health organization, regional office for the eastern mediterranean, 1994. december 2008 no white pages.indd serum copper, zinc and copper/zinc ratio and their relationship to age and growth status in yemeni adolescent girls *raba’a m jumaan sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 291-299 sultan qaboos university© submitted 29th march 2008 accepted 12th august 2008 c l i n i c a l a n d b a s i c r e s e a r c h مصل في إلى الزنك النحاس ونسبة والزنك مستويات النحاس تقييم في هذه األمالح مستويات بني العالقة ودراسة اليمنيات املراهقات النمو ومقاييس املصل رابعه محمد جمعان العالقة إلى تقييم وتهدف اليمنيات املراهقات مصل في والزنك النحاس ــتويات مس تعني بقياس اليمن في ــة دراس أول هذه امللخص: الهدف: تعتبر مت 2007 حيث أبريل ــي ف العمل بدأ الطريقة: البنات. عند ــدية اجلس واملقاييس اتلفة العمرية الفئات ــني وب في املصل األمالح هذه ــتويات مس ــني ب اختيرت ــه في مدرس املنهجية الطبقية العينة ــتخدام باس 114 مراهقة اختيار مت العاصمة صنعاء. في مديريه الوحدة في ــل ابرية ــراء التحالي إج وأوزان أطوال قياس مت كما الالزمة، ــه ابري الفحوصات دم إلجراء عينات اخذ مت ــك املديرية. تل في املوجودة احلكومية البنات ــن بني مدارس م ــوائيا عش كاآلتي: هو البنات كل عند املصل في الزنك / النحاس والزنك ونسبة النحاس معياري مستوى انحراف ± متوسط إن النتائج النتائج: أظهرت البنات. %4.4 بينما كان معدل النحاس نقص ــار انتش معدل كان التوالي. 1.44±0.31 على ، 12.24±1.04 مكرومول/لتر 17.47±3.31مكرومول/لتر، مستويات كانت .3.5% الزنك انخفاض انتشار ومعدل ، البنات %96.5 من في هامشية كانت مستويات الزنك أخرى جهة من .2.6% النحاس نقص من العمرية الفئة في (p=0.003) إحصائيا معتدة بصورة منخفضة الزنك ــتويات مس بينما (p=0.007) إحصائيا معتدة بصورة عالية النحاس الزنك ومستويات الطول بني والعالقة (p=0.01) سلبية النحاس الطول ومستويات كانت العالقة بني العمرية. الفئات من غيرها عن 10-12 سنة أدنى 10 – 12 سنة من العمرية الفئة وأن لدى اليمنيات ، البنات لدى مستوى الزنك منخفض أن الدراسة اخلالصة: أظهرت .(p=0.008) إيجابية فترة خالل للزنك ــم اجلس في حاجة زيادة هناك أن علمنا ما إذا خاصة الصحة ــلبية على الس بالتأثيرات ينذر هذا العمرية. الفئات بقية من ــتوى مس . املراهقة املراهقات ، اليمن. البنات ، النمو ، الزنك النحاس/ زنك ، نسبه ، الكلمات: نحاس مفتاح department of biochemistry, faculty of medicine and health sciences, sana’a university, yemen *email: rjumaan@hotmail.com abstract objectives: as no previous study has evaluated copper and zinc status in adolescent yemeni girls, the purpose of this study was to measure their serum levels of zinc and copper and to examine the relationship between the serum levels of these two trace minerals with age, and anthropometric parameters. methods: the study was conducted in april 2007 in alwehda district in the municipality of sana’a, yemen. one hundred and fourteen adolescent girls were selected using systematic stratified sampling from a representative school which was randomly selected. anthropometric indices were measured and blood samples were collected for biochemical analysis. results: the mean ±sd for copper, zinc, and copper/zinc ratio for the entire cohort were 7.47±3.3 µmol/l, 2.24±.04 µmol/l, and .44±0.3, respectively. the prevalence of hypocuprimea was 4.4% and hypercuprimea was 2.6%. the levels of zinc were marginal in 96.5% of the girls and the prevalence of hypozincimea was 3.5%. the levels of copper were significantly higher (p = 0.007) and the levels of zinc were significantly lower (p = 0.003) in the 0-2 yrs girls than in other age groups. height showed significant negative correlation with the levels of copper (p = 0.0) and significant positive correlation with the levels of zinc (p = 0.008). conclusion: the results revealed that the yemeni girls had marginal serum zinc levels, and 0-2 yrs girls had significantly lower zinc levels than other age groups. this provides a warning of consequent negative health effects since the physiological requirements for zinc are high in adolescence. key words: copper; zinc; copper/zinc ratio; growth; adolescent girls; yemen. r a b a’a m j u m a a n 292 adolescence is a period of intense physical growth and evidence from sup-plementation trials suggests that marginal zinc status may be common in adolescents and limit skeletal growth.1 zinc and copper are essential trace elements involved in adolescent growth and development. 2 both copper and zinc have diverse physiological roles and the interaction between them was considered to be mutually antagonistic. zinc is required for the optimum function of as many as 300 enzymes.3 these metalloenzymes are involved in the metabolism of proteins, nucleic acids carbohydrates and lipids. they also influence gene transcription.4 therefore, zinc is vital for growth and development,5 sexual maturation and reproduction,6 dark vision adaptation, olfactory and gustatory activity,7 insulin storage and release,8, 9 and for a variety of host immune defense,10 among other things. zinc deficiency can result in growth retardation, immune dysfunction, increased incidence of infections, hypogonadism, oligospermia, anorexia, diarrhoea, weight loss, delayed wound healing, fetal neural tube defects, increased risk of abortion, alopecia, decreased ethanol clearance, mental lethargy and skin changes.1113 zinc deficiency is usually nutritional, but can also be associated with malabsorption, acrodermatitis enteropathica, chronic liver disease, chronic renal disease, sickle cell disease, diabetes, malignancy, and other chronic illnesses copper is necessary for growth development and maintenance of bone, connective tissue, the brain, the heart, and many other body organs. it is involved in the formation of red blood cells, the absorption and utilisation of iron, and the synthesis and release of lifesustaining protein and enzymes. copper stimulates the immune system to fight infections, 14-17repairs tissues and promotes healing. copper also helps to neutralize ‘free-radicals’ which can cause severe damage to cells.18 deficiency in humans is rare, but it does occur under certain circumstances such as high intake of zinc or iron, increased requirement induced by rapid growth, and increased copper losses or decreased copper intake.19 in recent years, nutritionists have been more concerned about copper toxicity than copper deficiency. some experts believe that elevated copper levels, especially when zinc levels are also low, may be a contributing factor in many medical conditions including schizophrenia, hypertension, stuttering, autism, fatigue, muscle and joint pain, headaches, childhood hyperactivity, depression, insomnia, senility, and premenstrual syndrome.20, 21 studies have shown that zinc-induced alteration in other essential metals, especially copper, 22-25 is responsible for the production of biological effects. a decreased plasma zinc level and increased plasma copper level have been reported in pregnancy, acute infections, malignancy, cardiovascular disease, renal disease, schizophrenia, and certain endocrine diseases such as acromegaly and addison’s disease. therefore, the copper/zinc ratio is clinically more important than the concentration of each metal separately. as shown above, it is important to assess the serum levels of copper and zinc, particularly in adolescents. the enhanced growth during adolescence makes the advances in knowledge • this is the first study in yemen assessing the serum levels of zinc and copper in adolescent yemeni girls. • the yemeni girls had adequate serum levels of copper, but marginal serum levels of zinc. • a significant correlation was found between the levels of the two trace minerals in relation to height and age categories. applications to patient care • the reported results call for more attention to the girls' dietary zinc intakes because inadequate diet during adolescence can substantially delay sexual maturation and growth. • special care should be given to girls aged 10-12 years because the results show a significant increase in the levels of copper and a significant decrease in the levels of zinc compared to other age categories. this is critical in this stage of life during which a growth spurt begins. • routine screening for these trace minerals should be undertaken by paediatricians in yemen. s e r u m c o p p e r , z i n c , a n d c o p p e r / z i n c r at i o a n d t h e i r r e l at i o n s h i p t o a g e a n d g r o w t h s tat u s i n ye m e n i a d o l e s c e n t g i r l s 293 table 1: descriptive data of the general characteristics of the yemeni adolescent girls in the alwehda district sample number of girls (n) percent (%) age (years) 10-12 34 30.4 13-15 38 33.9 16-19 40 35.7 total 112a 100.0 stature-for-age percentile < 3rd 21 19.3 3rd 10 9.1 5th10th 44 40.4 25th75th٭ 33 30.3 > 75th 1 0.9 total 110b 100.0 bmi-for-age percentile <5th 16 14.8 5th<85th ٭ 85 78.8 85th<95th 4 3.7 >= 95th 3 2.8 total 109c 100.0 copper (µmol/l) entire cohort <12.56 5 4.4 12.56-29.83** 106 93.0 >24.34 3 2.6 total 114 100.0 10-12yrs <12.56 0 0 ٭12.56-29.8 34 100.0 >29.83 0 0 total 34 100.0 13-19yrs <12.56 5 6.4 ٭12.56-24.34 72 92.3 >24.34 1 1.3 total 78a 100.0 zinc (µmol/l) <10.7 4 3.5 ٭10.7-22.9 110 96.5 >22.9 0 0 total 114 100.0 *international reference range **extended normal reference range to include pre-adolescence reference range atwo girls did not know their exact date of birth bfive girls did not respond when they were called for weight measurement. cfour girls were absent during height measurement r a b a’a m j u m a a n 294 requirement of these minerals of paramount importance. the present study was designed to determine the serum levels of copper and zinc in a randomly selected sample of yemeni adolescent girls and to study associations between these minerals and some anthropometric indices. m e t h o d s the study area was the alwehda district, one of ten districts that exist in the capital city of the republic of yemen, sana’a. the study subjects consisted of 114 apparently healthy girls aged 10-19 years. they were students in grades 4th-12th in a representative public school, randomly selected from a total of 5 public schools for girls that exist in that area. twenty girls were chosen from each class using the school records by systematic sampling technique. from the 180 students selected, girls who were not in the age range of 10-19 years old were excluded. girls with normal blood chemistry and haematology were included. girls using vitamins and minerals supplementations and girls suffering from chronic diseases were excluded. the purpose of the study was explained to the school administration and the parents of the students, and girls who did not obtain parental written consent were also excluded. finally, 114 apparently healthy adolescent school girls were enrolled in this study. the study was approved by the research and ethics committee at the sana’a university and the ethical clearance was obtained before the study was started. a face to face interview was conducted to record information regarding age, class level, health problems, any supplements or medications used, and menarcheal status. anthropometric measurements were taken in school. the students were asked to remove heavy clothing and shoes. weight was taking in kilograms using and electronic scale and height was measured using a standiometer. height and weight measurements were compared to the international reference values of the national center for health statistics/center for disease control and prevention (nchs/cdc). body mass index (bmi) was calculated by dividing the weight (kg) by square of height (m2). under weight was defined as the cdc bmi-for-age percentile <5. overweight was defined as bmi-for-age percentile ≥95 and those which fell between 85th and <95th percentiles were considered to be at risk of overweight. stunting was defined as the cdc stature-forage <3rd percentile, short stature <5th percentile, and long stature >75th percentile.26 in april 2007, the girls were taken to althawra general hospital by bus in the early morning in groups of 15-30 girls each day for 5 days. fasting blood samples (approx. 5ml) were collected in the morning between 9 and 11am at the laboratory department. blood samples were drawn by venipuncture into vacutainer tubes and the samples were immediately centrifuged, after clotting, in patches of five clotted blood samples. the serum obtained was kept in freeze at -20 c until it was analysed 4 months later for serum copper and zinc. the metals zinc and copper were analysed by the direct colorimetric method using kits from quimica clinica aplicada s.a. and analysed by the hitachi 912 analyser. the colour reagent for copper was 3,5-dibrpaesa stain in acid solution. copper is released from the ceruloplasmin protein and reduced; the cuprous ion forms a coloured complex with the stain and is measured photometrically at 582nm. the zinc ions of the sample produce a red coloured complex with 2-(5brom-2-pridylazo)-5-[-n-propyle-n-(3-sulfopropyl) amino]-phenol in alkaline solution, and the colour intensity was measured at 560nm. the normal reference values for the instruments for women were 80-155 µg/dl for copper and 68-115 µg/dl for zinc. the values obtained in µg/dl were converted to the international unit (µmol/l) using conversion factors (x 0.157 and x 0.153 for copper and zinc respectively). mean std. deviation minimum maximum copper (µmol/l) 17.47 3.31 9.02 29.96 zinc (µmol/l) 12.24 1.04 10.26 16.44 copper/zinc 1.44 0.31 0.65 2.67 zinc/copper 0.73 0.15 0.37 1.53 table 2: the mean values and ranges of copper, zinc, and copper/zinc and zinc/copper ratios for the entire cohort (n = 114) of yemeni adolescent girls in alwehda district s e r u m c o p p e r , z i n c , a n d c o p p e r / z i n c r at i o a n d t h e i r r e l at i o n s h i p t o a g e a n d g r o w t h s tat u s i n ye m e n i a d o l e s c e n t g i r l s 295 data were analysed using the statistical package for the social science (spss), version 15. a kolmogorovsmirov test for normality was performed and the means and standard deviations and prevalence were obtained by descriptive statistics. data were analysed using the one way analysis of variance (anova) followed by tukey’s test to assess differences of continuous variable between two or more groups. pearson’s r coefficient was used to assess the correlation between two continuous variables. statistical significance was assigned for p values less than 0.05. r e s u l t s the study subjects consist of 114 apparently healthy yemeni adolescent girls. the mean age was 14.42yrs ± 2.71 and ranged from 10-19 years. the general characteristics of the girls according to age, anthropometric measurements, copper, and zinc concentrations are presented in table 1. table 1 shows the percentage of girls with abnormal characteristics as compared to the international reference values. the results revealed that 96.5% of the girls had marginal serum levels of zinc and 68.8% of the girls were below the normal stature-for-age percentiles, of which 19.3% were stunted. because the copper international normal reference range for preadolescent girls aged 10-12yrs was different from that for the older adolescent girls, separate descriptive data for copper were added in table 1, and the normal reference value for the entire cohort was extended to cover both ranges. the mean levels and the ranges for copper, zinc, copper/zinc ratio, and zinc/copper ratio for the girls residing in alwehda district are shown in table 2. for the entire cohort, the mean value for serum copper was normal (17.47 ± 3.31 µmol/l; 111.32µg/ dl), and the mean value for serum zinc was at the lower edge of the normal value (12.24 ± 1.04µmol/l; 80.01 µg/dl), while the mean value for serum copper/zinc ratio was 1.44 ± 0.31 ranging from 0.65 to 2.67. c o ppe r , z i n c , a n d c o ppe r / z i n c r ati o age (years) n mean sd minimum maximum p-value a copper (µmol/l) 10-12 34 18.66 3.51 14.16 29.96 13-15 38 17.65 3.30 9.02 26.48 16-19 40 16.34 2.87 11.71 23.83 total 112b 17.49 3.33 9.02 29.96 0.002 zinc (µmol/l) 10-12 34 11.80 0.78 10.26 13.85 13-15 38 12.61 1.19 11.06 16.44 16-19 40 12.25 0.96 10.54 15.07 total 112b 12.24 1.05 10.26 16.44 0.094 copper/zinc ratio 10-12 34 1.59 0.34 1.10 2.67 13-15 38 1.41 0.29 0.65 2.22 16-19 40 1.34 0.24 0.97 1.81 total 112b 1.44 0.30 0.65 2.67 <0.001 zinc/copper ratio 10-12 34 0.65 .12 .37 .91 13-15 38 0.74 .17 .45 1.53 16-19 40 0.77 .13 .55 1.04 total 112b 0.72 .15 .37 1.53 0.001 abased on pearson’s correlation analysis test btwo girls were not included because they did not know their exact date of birth table 3: the copper, zinc and cu/zn ratio of the yemeni adolescent girls in alwehda district according to the age category r a b a’a m j u m a a n 296 l e v e l s i n a s s o c i ati o n w i th a ge c ate g o r i e s when the girls were divided into three age categories, there was a statistically significant negative correlation between the age and the levels of copper (r = –0.284, p = 0.002), and the levels of copper tended to decrease with increasing age. further analysis showed that copper levels were significantly lower in the 16-19 year old girls than the 10-12 year olds (p = 0.007) and there were no significant differences in the levels of copper between the 13-15 year olds as compared to the 1012 year olds (p = 0.383) and the 16-19 year olds (p = 0.179). bivariate correlation analysis showed no significant correlation between the levels of zinc and the age of the girls (r = 0.159, p = 0.094). further investigations with one-way analysis of variance (anova) revealed statistically significant differences in the levels of zinc between the 10-12 year old girls and the 13-15 year olds (0.003), but no significant differences were found among the other age groups. analysis with one-way anova also indicated statistically significant differences in the levels of copper/zinc between 10-12 year olds and the 13-15 year old girl ( p = 0.024) and between the 10-12 year olds and the 16-19 year old girls (0.001). copper/zinc ratios tended to decrease with increasing age. the mean values for copper, zinc, copper/zinc, and zinc/copper ratio according to the age category are shown in table 3. c o ppe r , z i n c , a n d c o ppe r / z i n c l e v e l s i n a s s o c i ati o n w i th a n th r o p ome tr i c va r i a bl e s a statistically significant negative correlation was found between the levels of copper and the height of the girls (r = -0.245, p = 0.010), and there was a statistically significant positive correlation between the serum levels of zinc and the height of the girls (r = 0.250, p = 0.008). no significant correlation was found between the levels of zinc or copper and the other anthropometric variables [table 4]. despite the findings that copper and zinc levels did not correlate significantly with stature-for-age percentiles, the results revealed a decreasing trend in the levels of copper and an increasing trend in the levels of zinc with increasing stature-for-age percentiles [table 5]. short girls had the lowest levels of zinc and the highest levels of copper compared to normal and tall anthropometric indices copper zinc copper/zinc ratio r p-value r p-value r p-value height -0.245(*) 0.010 0.250(**) 0.008 -0.325(**) <0.001 weight -0.072 ns 0.167 ns -0.143 ns bmi-for-age percentile 0.001 ns 0.093 ns -0.050 ns stature-for-age percentile -0.032 ns 0.030 ns -0.038 ns *correlation is significant at the 0.01 level (2-tailed). **correlation is significant at the 0.05 level (2-tailed). table 4: correlation (pearson’s r) between copper, zinc, cu/zn and anthropometric indices in the yemeni adolescent girls. stature-for-age percentile category mean copper (µmol/l) zinc (µmol/l) copper/zinc ratio <25th (short) 17.61 12.22 1.45 25th-75th (normal) 17.47 12.26 1.43 >75th (tall) 16.33 12.53 1.30 total 17.56 12.24 1.44 table 5: mean values for serum copper, zinc and copper/zinc ratio of the yemeni adolescent girls in alwehda district according to stature-for-age category s e r u m c o p p e r , z i n c , a n d c o p p e r / z i n c r at i o a n d t h e i r r e l at i o n s h i p t o a g e a n d g r o w t h s tat u s i n ye m e n i a d o l e s c e n t g i r l s 297 girls. furthermore, girls who were above the normal bmi-for-age percentile reference range had higher serum levels of both copper and zinc compared to girls who were below the normal reference range [table 6], although, this trend was not statistically significant. c o ppe r z i n c i n te r a c ti o n there was a negative association between the levels of the copper and zinc, however, this was not statistically significant (r = – 0.018, p = 0.849). d i s c u s s i o n copper and zinc are essential trace elements involved in adolescent growth and development. they have diverse physiological roles and both are particularly related to linear physical growth. nevertheless, copper and zinc status have not been assessed in yemeni adolescents. the first purpose of this study was to measure the levels of zinc and copper in the serum of randomly selected yemeni adolescent girls, and the second purpose was to study the association between the levels of copper and zinc in relation to age and anthropometric indices. the results revealed that yemeni adolescent girls had normal serum levels of copper (17.48µmol/l; 111.32µg/dl), but marginal serum levels of zinc (12.24µmol/l; 80.01µg/dl), as compared to the international reference ranges. comparisons with other populations showed that the obtained mean values for copper and zinc were lower than those reported for the kuwaiti population (24.9µmol/l; 158.6µg/dl, and 15.5µmol/l; 101.31µg/dl for copper and zinc respectively) 27 and were close to those reported for the greek population (18.13µmol/l, 115.46 µg/dl; and 11.79µmol/l, 77.11 µg/dl for copper and zinc respectively).28 the results also revealed that 96.5% of the girls had marginal serum levels of zinc, which is critical at this stage of life, when the requirements for zinc are high to meet the demands for increased physical growth. these results demanded nutritional assessments because common causes of low zinc levels are usually nutritional due to inadequate dietary zinc intakes or a diet high in fibre and phytate which reduces zinc absorption. a high percentage (68.8%) of the girls was found to be below the normal stature-for-age percentile of which approximately 20% were stunted. these findings call for studying the effect of low serum zinc levels on some anthropometric indices, since zinc was particularly related to physical growth impairment. when relationships between the levels of zinc and the height and stature-for-age percentiles were investigated, this study revealed a statistically significant effect of zinc on the height of the girls. in fact, girls who were short had the lowest zinc levels and the highest copper levels and the levels of zinc were increasing with increased stature-for-age percentiles. however, this trend was not significant probably because the study sample size was not large enough to show any existing significance. the relationship between the levels of copper and zinc and the age of the girls was also investigated and results showed a statistically significant correlation between them. the levels of zinc were significantly lower and the levels of copper were significantly higher in girls aged 10-12 years than the other age categories. this might cause some concerns since the adolescent growth spurt begins in girls at age 10 or 11 and reaches its peak at age 12. this intensive growth period (between 10-12 years) is characterised by a dramatic increase in height and an immense demand for zinc bm-for-age percentile category mean copper (µmol/l) zinc (µmol/l) copper/zinc ratio <5th (underweight) 17.92 12.27 1.47 5th-<85th (normal) 17.39 12.22 1.43 85th-<95th (at risk of overweight) 18.62 12.38 1.51 >=95th (overweight) 18.50 12.39 1.48 total 17.55 12.24 1.44 table 6: mean values for serum copper, zinc and copper/zinc ratio of the yemeni adolescent girls in alwehda district according to bmi-for-age category r a b a’a m j u m a a n 298 which can exhaust body zinc. the low zinc levels can substantially delay sexual maturation and growth and, therefore, more care should be given to the yemeni girls in this age group. the mean value for the copper/zinc ratio was 1.44, ranging from 0.65 to 2.67 and the results revealed that copper/zinc ratio tended to be significantly higher in girls at the pre-menarcheal age (10-12 years), than in the older post-menarcheal girls (13-19 years). these findings were in accordance with what was previously reported.27, 29 the mean age for the first onset of menarche in the studied girls was found to be 13 years, and puberty could affect the cu/zn imbalance. copper levels are sensitive to estrogen levels which increase during puberty while zinc is depleted by the rapid cell divisions during growth at puberty.29 c o n c l u s i o n a high percentage of marginal zinc levels is considered alarming in adolescence age, especially for girls aged 10-12 years, a period where the growth spurt demands high levels of zinc. there are some concerns, at the present time, about the consequences of marginal zinc status on the health and the linear physical growth of the studied girls. in the near future, there should be some concerns about the health of these girls as pregnant women and the health of their offspring since, traditionally, a high percentage of girls get married after they finish high school, if not before. a c k n ow l e d g me n ts the author is particularly grateful for the financial support provided by the national trade company natco to conduct this study. the author also expresses sincere thanks to the general director of the al-thawra general hospital, members of the laboratory department for their technical assistance, the principal of the alqods public school, and all the students who participated in this study. r e f e r e n c e s 1. walravens, pa, hambidge, km. growth of infants fed a zinc supplemented formula. am j clin nutr 1976; 29:1114–1121. 2. bianculli cn. physical growth and development in adolescents. in: the health of adolescents and youths in americas. paho scientific publication no. 489, oms, 1985. p. 45-50. 3. vallee bl, auld ds. zinc coordination, function, and structure of zinc enzymes and other proteins. biochemistry 1990; 29:5647-5659. 4 vallee bl, falchuck kh. the biochemical basis of zinc physiology. physiol rev 1993; 73:79-118. 5 cunningham bc, bass s, fuh g, wells ja. zinc mediation of the binding of human growth hormone to the human prolactin receptor. science 1990; 250:1709-1712. 6. prasad as, halsted ja, nadimi m. syndrome of iron deficiency anemia, hepatosplenomegally, hypogonadism, dwarfism andgeophagia. am j med 1961; 31:532. 7. henkin ri, schechter ph, friedewald wvt, demets dl, raff m. a. double blind study of the effects of zinc sulfate on taste and small bowel dysfunction. am j med sci 1976; 272:285-299. 8. jhala us, baly dl. zinc deficiency results in a post transcriptional impairment in insulin synthesis. faseb j 1991; 5:a941. 9. huber am, gershoff sn. effect of zinc deficiency in rats on insulin release from the pancreas. j nutr 1973; 103:1739-1744. 10. fraker pj, gershwin me, good ra, prasad a. interrelationships between zinc and immune function. fed proc 1986; 45:1474-1479. 11. prasad as. clinical spectrum and diagnostic aspects of human zinc deficiency. in: prasad as, ed. essential and toxic trace elements in human health and disease. new york: alan r liss inc., 1988. p. 3-53. 12. penland jg. cognitive performance effects of low zinc (zn) intakes in healthy adult men. faseb j 1991; 5: a938 (abs.) 13. milne db, johnson pe, gallagher sk. effect of shortterm dietary zinc intake on ethanol metabolism in adult men. am j clin nutr 1991; 53:25. 14. failla ml, hopkins rg. is low copper status immunosuppressive? nutr rev 1998; 56:s59-64. 15. percival ss. copper and immunity. am j clin nutr 1998; 67:1064s-1068s. 16. heresi g, castillo-duran c, munoz c, arevalo m, schlesinger l. phagocytosis and immunoglobulin levels in hypocupremic children. nutr res 1985; 5:1327-1334. 17. kelley ds, daudu pa, taylor pc, mackey be, turnlund jr. effects of low-copper diets on human immune response. am j clin nutr 1995; 62:412-416. 18. johnson ma, fischer jg, kays se. is copper an antioxidant nutrient? crit rev food sci nutr 1992; 32:1-31. 19. olivares m, uauy r. copper as an essential nutrient. am j clin nutr 1996; 63:791s–796s. 20. turnlund jr, jacob ra, keen cl, strain jj, kelley ds, domek jm, et al. long-term high copper intake: effects on indexes of copper status, antioxidant status, and immune function in young men. am j clin nutr 2004; 79:1037-1044. s e r u m c o p p e r , z i n c , a n d c o p p e r / z i n c r at i o a n d t h e i r r e l at i o n s h i p t o a g e a n d g r o w t h s tat u s i n ye m e n i a d o l e s c e n t g i r l s 299 21. turnlund jr, keyes wr, kim sk, domek jm. longterm high copper intake: effects on copper absorption, retention, and homeostasis in men. am j clin nutr 2005; 81:822-828. 22. moses ha, parker he. influence of dietary zinc and age on the mineral content of rat tissues. fed proc 1964; 23:132. 23. prasad as, oberleas d, wolf p, horwitz jp, miller er, luecke rw. changes in trace elements and enzyme activities in tissues of zinc deficient pigs. am j clin nutr 1969; 22:628-637. 24. petering hg, johnson ma, horwitz jp. studies of zinc metabolism in the rat. arch environ health 1971; 23:93101. 25. burch re, williams rv, hahn hkj, jetton mm, sullivan jf. serum and tissue enzyme activity and trace element content in response to zinc deficiency in the pig. clin chem 1975; 2:568-577. 26. national center for health and statistics. cdc growth charts: united states 2000 (revised). hyattsville, md: national center for health and statistics, 2000: 1-28 (vital and health statistics no. 314). 27. abiaka c, olusi s, al-awadhi a. reference ranges of copper and zinc and the prevalence of their deficiencies in the arab population aged 15-80 years. biol trace elem res 2003; 91:33-43. 28. kouremenou-dona e, dona a,papoutsis j, spiliopoulou c. copper and zinc concentrations in the serum of healthy greek adults. sci total environ 2006; 359:7681. 29. arvanitidou v, voskaki i, tripsianis g, flippidis s, schulpis k, androulakis i. serum copper and zinc concentrations in healthy children aged 3-14 years in greece. biol trace elem res 2007; 115:1-12. december 2007 vol 8 after meeting.indd abstract nodular lymphocyte predominant hodgkin’s lymphoma (nlphl) is a recently described type of hodgkin’s lymphoma (hl) and accounts for 5-6% of all the cases of hl. here we report the case of an elderly man who presented to sultan qaboos university hospital, oman, with severe hypercalcemia, and was diagnosed to have stage iv nlphl. although the incidence of hypercalcemia is estimated to be between -5% in classical hl, to our knowledge this is the first report of nlphl presenting with severe hypercalcemia. the patient responded to the anti-cd20 monoclonal antibody, rituximab, and has been in clinical remission for more than 3 years. keywords: hodgkin’s lymphoma; hypercalcemia; thrombocytopenia; monoclonal antibody; rituximab; case report; oman n0dular lymphocyte predominant hodgkin’s lymphoma presenting as severe hypercalcaemia: a case report *ikram a burney,1 v nirmala,2 mansour s al-moundhri,1 nicholas j woodhouse1 1department of medicine, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman; 2department of pathalogy, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: ikram@squ.edu.om شديد كفرط املعروض السائدة اللمفاوية العقد ذي هودجكن ملفومة حالة تقرير الدم: كالسيوم في وودهاوز ، نيكوالس ، منصور املندري ،في نرماال برني اكرام ملفومة كل حاالت وتشكل5-%6 من ، وصفت حديثا التي هودجكن ملفومة أنواع احدى هي السائدة العقد اللمفاوية ذي امللخص: ملفومة هودجكن ، وكان بالدم مستوى الكالسيوم في شديد ولديه فرط (عمان) قابوس جامعة السلطان ــفى مستش راجع ــن الس رجل كبير حالة نورد هنا هودجكن. بالدم ــيوم الكالس ــتوى مس فرط حصول معدل ولو أن ، ــائدة العقد اللمفاوية الس ذي هودجكن من ملفومة الرابعة املرحلة في مرضه انه ــخيص تش يعرض الذي السائدة اللمفاوية ذي العقد هودجكن للمفومة تقرير أول هذا يكون وحسب علمنا ، الكالسيكية ملفومة هودجكن 1-%5 في بني يتراوح من خاليا وكان ، (ريتوكسيماب) النسيلة احادية املضادة االجسام cd20 من املريض ملضاد استجاب في الدم. الكالسيوم مستوى في طبيا كفرط سنوات. ملدة ثالث سريرية) أَة دْ (هَ االعراض عمان. حالة، تقرير ريتوكسيماب، ، النسيلة احادية مضادة أجسام عالج ، ، يحات فَ الصُّ قِلَّةُ ، الدم في الكالسيوم فرط هودجكن ، الكلمات: ملفومة مفتاح sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 247-251 sultan qaboos university© submitted 15th april 2007 accepted 1st september 2007 c a s e r e p o r t a 75 year old omani gentleman, presented with a 6 month history of weak-ness, weight loss of 20 kg, loss of appetite and a two month history of low grade fever, cough and difficulty in walking. the past medical history was significant for hypertension for 20 years (treated with atenolol), type ii diabetes mellitus (treated with oral hypoglycemics), chronic renal failure for 8 years; hypertrophic cardiomyopathy diagnosed 2 years previously; and osteoarthritis with a right knee joint replacement. general physical examination was unremarkable except for generalized body weakness and an ejection systolic murmur suggestive of aortic sclerosis. laboratory investigations revealed: hb 13g/dl, wbc 6.5 x 109/l, platelets 66 x 109/l; creatinine 313 µmol/l; na+ 132 mmol/l; k+ 3.8 mmol/l; cl 100 mmol/l; co2 19 mmol/l; corrected serum calcium 4.08 mmol/l; po4 1.88 mmol/l; alkaline phophatase 94 u/l. serum para-thyroid hormone (pth) levels were appropriately reduces to 0.7 pmol/l (1.3-7.6 pmol/l), whereas, serum para-thyroid hormone related peptide (pth-rp) < 1.0 pmol/l (<1.3 pmol/l); was within the normal limits; however, 1,25 dihydroxyvitamin d3 [1,25 (oh) d3] was elevated at 411 pmol/l (43-148 pmol/l). an assessment of thyrombocytopenia, renal failure and severe hypercalcemia secondary to elevated 1,25 (oh) d3 was made. an upper gi endoscopy revealed severe hemori k r a m a b u r n e y, v n i r m a l a , m a n s o u r s a l m o u n d h r i a n d n i c h o l a s j wo o d h o u s e 248 rhagic gastritis and reflux esophagitis. the parathyroid scan was reported normal. a ct (computed tomography) scan of the chest and abdomen revealed a left axillary lymph node measuring 4x2 cm, which was not palpable on clinical examination. a core biopsy of the lymph node was done which revealed an infiltrate consisting of occasional atypical large cells (positive for cd20, cd79a, and cd45, weakly positive in a few cells for cd30, and negative for cd5, cd10, cd15, bcl-1, and epithelial membrane antigen). these large atypical cells were interspersed within a background of small lymphocytes (positive for cd3 and cd5), some of which were arranged in a rosette fashion (positive for cd57) around the cd20 positive large atypical lymphocytes. overall, the histopathological picture was suggestive of either a lymphocyte predominant hodgkin’s lymphoma (nlphl) or a t-cell/histiocyte rich b-cell lymphoma (t/hrbcl). the bone marrow biopsy showed increased cellularity and scattered large atypical lymphocytes, staining positively for the cd20 antigen. the patient was diagnosed to have nlphl/ t/hrbcl, stage iv. although the histopathology was more in favor of nlphl, the clinical presentation (age and stage iv disease) was more in keeping with t/hrbcl. a second opinion, sought from a reference pathology centre (armed forces institute of pathology, washington, usa), was consistent with the original impression of nlphl. however, in view of the cd57 positive small lymphocytes arranged in a rosetting manner around the large malignant cells, a diagnosis of nlphl was favoured. the patient was treated with zolendronic acid resulting in normalization of elevated calcium levels in the next 48 hours. subsequently, the patient was treated with anti-cd20 antibody (rituximab) weekly for 4 weeks. platelet count improved and reached normal limits during the course of treatment with rituximab. the 1,25 (oh) d3 returned to 45 pmol/l in 2 weeks. re-evaluation ct scans at 2 months revealed a partial remission (pr) and at 6 months revealed complete remission (cr). a bone marrow biopsy 2 months later was reported to be within the normal limits. d i s c u s s i o n nlphl is a rare type of b-cell lymphoma with unique pathologic and clinical features that distinguish it from classical hodgkin’s lymphoma.1-3 patients with nlphl tend to be younger males who present with indolent and asymptomatic lymphadenopathy limited to peripheral lymph nodes. the immunophenotype of the malignant lymphocytic and/or histiocytic cells forms the basis of the pathologic distinction from the subtypes of classical hodgkin’s disease.1 despite an excellent response to an initial combined-modality treatment, patients with nlphl tend to relapse.2 the benign nature of these relapses and the incidence of late treatment-related toxicity have raised questions about the need for an aggressive upfront approach. however, recent insights into the molecular pathogenesis of nlphl and the development of novel targeted therapies promise to improve future treatment.3 although, in our case, a diagnosis of nlphl was entertained, t/hrbcl was a close differential. nlphl and t/hrbcl are distinct tumors and are treated differently. they are linked by a morphologic and figures 1: photomicrographs of section from the lymph node. (1a) h&e stain. arrows indicate the atypical cells. (1b) staining with cd20 antibody. arrow indicates the membrane staining of the large atypical cell. (1c) staining with cd57 antibody. arrows indicate the small lymphocytes arranged in a rosette fashion around the large atypical cells n 0 d u l a r ly m p h o c y t e p r e d o m i n a n t h o d g k i n ’ s ly m p h o m a p r e s e n t i n g a s s e v e r e h y p e r c a l c e m i a 249 probably a biologic continuum, which renders the differential diagnosis difficult.4, 5 the nlphl is characterized by atypical lymphocytic and histiocytic (l&h) or ‘popcorn’ cells, embedded in the background of progressively transformed follicles. the atypical cells are cd45+, express the b-cell associated antigens cd19, cd20, cd22, cd79a, and epithelial membrane antigen (ema), but lack the expression of cd15 and cd30.6 while tumor cells in nlphl and t/hrbcl are immunophenotypically similar, the background composition differs. in nlphl, small b cells are cd3+ cd4+ cd57+ t cells, whereas in t/hrbcl, cd8+ t cells and histiocytes dominate. while cd57+ t cells surrounding the ‘popcorn cells’ are typically seen in nlphl, the absence of these cells in the rosettes form does not argue against the diagnosis.3 tumor cells either are loosely scattered or formed clusters, thus resembling areas of either t/hrbcl or inflammatory diffuse large bcl (dlbcl) within the nodules.5 on the other hand, diffuse large b cell lymphoma (dlbcl) can arise in patients previously known to have, or have been treated for nlphl. for example, the nebraska group has reported 21 patients in whom dlbcl was diagnosed either concurrently or subsequent to a diagnosis of nlphl.7 of the ten patients who presented with nodal dlbcl only, six patients presented with both nodal and extra-nodal involvement, and five presented with only extra-nodal dlbcl. the median overall survival and failure-free survival of the entire group was 35 months and 11 months. importantly, there were no significant differences in the survival outcomes between patients with dlbcl arising in nlphl and age-and sex-matched patients with de novo dlbcl. our patient remained progression-free after 6 months of treatment, and is on regular follow up. the vast majority of patients with nlphl present with stage i/ii disease and bone marrow involvement is rare.2, 3 however, a small subset of patients in whom lymph node biopsy shows nlphl with a nodular pattern also may have lymphoma in the bone marrow. khoury et al. reported the incidence of bone marrow involvement to be 2.5% in a series of 275 patients with classical hl.8 bone marrow involvement is associated with laboratory, radiological, or morphologic evidence of aggressive disease, and our patient did present with severe hypercalcemia. hypercalcemia is not a common feature of hodgkin’s lymphoma.9, 10 the incidence has been reported to be 0.9%, 1.6%, and 5.4% in different series of patients with classical hl.11 however, little information exists on hypercalcemia in patients with nlphl. hodgkin’s lymphoma associated hypercalcemia, although uncommon, has been variously ascribed to be mediated through the secretion of pth-rp, osteoclast activating factors (oafs), overproduction of 1,25 (oh) d3 (calcitriol), or due to prostaglandin synthesis.12-15 in our case, serum pth and pth-rp levels were either suppressed or within the normal limits. however, serum 1,25 (oh) d3 levels were found to be elevated. calcitriol has been most consistently implicated as the mediator of hypercalcemia in hl.16 monocytes and macrophages seem to play a pivotal role in the production of calcitriol in hl and nhl, as is the case in tuberculosis and sarcoidosis. calcitriol synthesis by macrophages is enhanced by interferon-γ, the expression of which in turn is dependent upon stimulation by interleukin-1 and tumor necrosis factor secreted by the t lymphocytes.17 calcitriol binds to a specific intracellular receptor present in many tissues, particularly the bone and intestine. ligand-receptor interaction results in increased intestinal absorption of calcium and phosphate from the intestine, and enhanced osteoclastic activity leading to osteolysis and hypercalcemia. nlphl is characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. the malignant cells of nlphl are cd20+ and therefore rituximab may have activity with fewer late effects than standard therapy. recently, two phase ii studies and a few case reports have been reported on the use and efficacy of rituximab in patients with nlphl. in a phase ii study reported by ekstrand et al.,18 22 patients with cd20+ nlphl received 4 weekly doses of rituximab at 375 mg/m2. ten patients had previously been treated for hodgkin’s disease, while 12 patients had untreated disease. all 22 patients responded to rituximab (overall response rate, 100%) with complete response in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). acute treatment-related adverse events were minimal. with a median follow-up of 13 months, 9 patients had relapsed, and the estimated median freedom from progression was 10.2 months. progressive disease was biopsied in 5 patients: 3 had recurrent nlphl, while 2 patients had transformed to nhl. all 3 patients with recurrent nlphl were retreated with rituximab again. in a second study rei k r a m a b u r n e y, v n i r m a l a , m a n s o u r s a l m o u n d h r i a n d n i c h o l a s j wo o d h o u s e 250 ported by rehwald et al., 19 14 patients were treated in a manner similar to the one described earlier. however, in this series, all patients had received at least one prior chemotherapy regimen. the overall response was 86%, with 8 complete remissions and 4 partial remissions, and 2 patients with progressive disease. at a median follow-up of 12 months, 9 of 12 responders were in remission. our patient was treated with single agent rituximab, because of poor performance status at presentation, multiple co-morbids including acute renal failure and diabetec neuropathy, and cardiomyopathy, and perceived poor tolerance to combination chemotherapy. in conclusion, we report the case of an elderly gentleman, with multiple co-morbids, who presented with severe hypercalcemia secondary to nlphl, which to our knowledge has not been reported before, and was successfully treated with anti-cd20 antibody, and is in complete remission more than 3 years after completion of treatment. a c k n ow l e d ge me n ts we acknowledge with gratitude the help of medical, nursing and the technical staff involved in the care of this patient at sultan qaboos university hospital, oman. our special thanks are due to dr. omayma elshafie and dr. azhar rizvi for the help in the medical management. r e f e r e n c e s 1. ekstrand bc, horning sj. lymphocyte predominant hodgkin’s disease. curr oncol rep 2002; 4:424-433. 2. diehl v, sextro m, franklin j hansmann ml, harris n, jaffe e et al. clinical presentation, course, and prognostic factors in lymphocyte predominat hodgkin’s disease and lymphocyte rich classic hodgkin’s disease: report from european task force on lymphoma project on lymphocyte predominant hodgkin’s disease. j clin oncol 1999; 17:776-783. 3. nogova l, rudiger t, engert a. biology, clinical course and management of noular lymphocyte predominant hodgkin’s disease. american society of hematology education program book, 2006. p. 266-272. 4. rudiger t, gascoyne rd, jaffe es, de jong d, delabie j, de wolf-peeters c, et al. workshop on the relationship between nodular lymphocyte predominant hodgkin‘s lymphoma and t cell/histiocyte-rich b cell lymphoma. ann oncol 2002; 13:44-51. 5. boudova l, torlakovic e, delabie j, reimer p, pfistner b, wiedenmann s, et al. nodular lymphocyte-predominant hodgkin lymphoma with nodules resembling t-cell/histiocyte-rich b-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant hodgkin lymphoma and t-cell/histiocyte-rich b-cell lymphoma. blood 2003; 102:3753-3758. 6. anagnostopoulus i, hansmann ml, franssila k, harris m, harris nl, jaffe es et al. european task force on lymphoma project on lymphocyte predominat hodgkin’s disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of hodgkin’s disease with a nodular growth pattern and abundant lymphocytes. blood 2000; 96:1889-1899. 7. huang jz, weisenburger dd, vose jm, greiner tc, aoun p, chan wc, et al. nebraska lymphoma study group. diffuse large b-cell lymphoma arising in nodular lymphocyte predominant hodgkin lymphoma. a report of 21 cases from the nebraska lymphoma study group. leuk lymphoma 2003; 44:1903-1910. 8. khoury jd, jones d, yared ma, manning jt jr, abruzzo lv, hagemeister fb, et al. bone marrow involvement in patients with nodular lymphocyte predominant hodgkin lymphoma. am j surg pathol 2004; 28:489-495. 9. utkan g, buyukcelik a, yalcin b, tek i, doruk h, dincol d, et al. extranodal hodgkin’s disease presenting with gluteal mass and hypercalcemia. south med j 2006; 99:1149-1150. 10. roca b, simon e. hodgkin’s disease presenting with hypercalcaemia of unknown origin. ir med j 1998; 91:102. 11. linde r, basso l. hodgkin’s disease with hypercalcemia detected by thallium-201 scintigraphy. j nucl med1987; 28:112-115. 12. karmali r, barker s, hewison m, fraher l, katz dr, o’riordan jl. intermittent hypercalcaemia and vitamin d sensitivity in hodgkin’s disease. postgrad med j 1990; 66:757-760. 13. jacobson jo, bringhurst fr, harris nl, weitzman sa, aisenberg ac. humoral hypercalcemia in hodgkin’s disease. clinical and laboratory evaluation. cancer 1989; 63:917-923. 14. bolo-deoku j, basu s, lakhani s, dunne f, ratcliffe wa, clarke m, et al. parathyroid hormone related protein in hypercalcaemia of hodgkin’s disease. j clin pathol 1992; 45:541-542. 15. laforga jb, vierna j, aranda fi. hypercalcemia in hodgkin’s disease related to prostaglandin synthesis. j clin pathol 1994; 47:567-568. 16. seymour jf, gagel rf. calcitriol: the major humoral mediator of hypercalcemia in hodgkin’s disease and non-hodgkin’s lymphomas. blood 1993; 82:1383-1394. 17. rieke jw, donaldson ss, horning sj. hypercalcemia and vitamin d metabolism in hodgkin’s disease. is there an underlying immunoregulatory relationship? cancer 1989; 63:1700-1707. 18. ekstrand bc, lucas jb, horwitz sm, fan z, breslin s, n 0 d u l a r ly m p h o c y t e p r e d o m i n a n t h o d g k i n ’ s ly m p h o m a p r e s e n t i n g a s s e v e r e h y p e r c a l c e m i a 251 hoppe rt, et al. rituximab in lymphocyte-predominant hodgkin disease: results of a phase 2 trial. blood 2003; 101:4285-4289. 19. rehwald u, schulz h, reiser m, sieber m, staak jo, morschhauser f, et al. german hodgkin lymphoma study group (ghsg). treatment of relapsed cd20+ hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the german hodgkin lymphoma study december 2007 vol 8 after meeting.indd jawetz, melnick & adelberg’s medical microbiology 24th edition sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 273-275 sultan qaboos university© submitted 25th august 2007 the authors of this book are professors from various prominent american universities and institutions: 1. geo f brooks, md, professor of laboratory medicine, university of california, san francisco. 2. karen c carroll, md, professor of pathology, the johns hopkins university school of medicine, baltimore. 3. janet s butel, phd, distinguished professor, baylor college of medicine, houston. 4. stephen a morse, phd, associate director for science, cdc, atlanta. the book’s purpose is to introduce basic clinical microbiology through the fields of bacteriology, virology, mycology, and parasitology to provide a brief, accurate, and up to date presentation of these aspects of medical microbiology that are of particular significance in the fields of clinical infections and chemotherapy. the current edition reflects the remarkable advances that have been made in our knowledge of microbes, their dna sequence and the molecular mechanism of microbial disease. the changes to the new edition are based on the understanding of these aspects that have developed as a consequence from those studies. the contents of the book are in seven sections distributed over 832 pages. it consists of a preface, an index and 48 chapters. se c ti o n  : f un da me n ta l s o f mi c r o bi o l o g y. ( 7 c h a p te r s) this section covers an introduction to the science of microbiology, the structure and function of the components of prokaryotic and eukaryotic cells, the classification of bacteria and cultivation of microorganisms. the last chapters discuss the growth, survival and death of microorganisms, microbial metabolism and, finally, microbial genetics. se c ti o n 2 : i mmun o l o g y (  c h a p te r) an introduction to immunology, which also contains a glossary of important immunology definitions. b o o k r e v i e w واديلبيرج ميلنيك جاويتز, الطبية الدقيقة �األحياء ستيفن موريس بيوتيل, بروك,كارين كارول,جانيت �تأليف: جيو الكبيسي مراجعة: مهند *department of microbiology and immunology, college of medicine and health sciences, sultan qaboos university, p.o. box 35, al-khod 123, sultanate of oman email: kobaisi@squ.edu.om authors: geo f brooks, karen c carroll, janet s butel, stephen a morse publisher: mcgraw-hill; first published 1954, 24th edition 2007 isbn-13: 978-0 -07-1287357 us price: $49.95 available at: http://www.mcgraw-hill.co.uk/html/0071476660.html reviewer: *muhannad f al-kobaisi b o o k r e v i e w : j aw e t z , m e l n i c k & a d e l b e r g ’ s m e d i c a l m i c r o b i o l o g y 274 se c ti o n 3 : b a c te r i o l o g y ( 2 0 c h a p te r s) this section starts with the pathogenesis of bacterial infection and antimicrobial chemotherapy, then proceeds with normal microbial flora of the human body and continues with the different bacterial families to end up with mycoplasmas and cell wall-defective bacteria, rickettsia, ehrlichia and chlamydiae. se c ti o n 4 : v i r o l o g y ( 6 c h a p te r s) these chapters discuss first the general properties of viruses then the pathogenesis and control of viral diseases, followed by the important human virus families and a chapter on the viruses which cause human cancer, aids and lentiviruses. se c ti o n 5 : myc o l o g y (  c h a p te r) this chapter deals with all the medical mycology information starting with the properties and ending with different types of mycoses. se c ti o n 6 : pa r a si to l o g y (  c h a p te r) the chapter involves a wide spectrum of medical parasitology information. se c ti o n 7 : d i a gn o sti c mi c r o bi o l o g y a n d c l i n i c a l c o r r e l ati o n ( 2 c h a p te r s) the first chapter deals with the principles of diagnostic medical microbiology while the last discusses different cases and clinical correlations. a wide spectrum of readers may benefit from this book: medical students, life sciences undergraduate, postgraduate students, all medical laboratory technologist and senior microbiology professionals, also academics and microbiology teachers. this print of the book is the 24th edition, therefore, we should realize one important issue that is, this text book has survived for 53 years and if the information or the way it was presented fell short during any of these past years it would have for sure been discontinued. i myself have used this book a long time ago and i still use it as a source of significant microbiology information. that is why, in my opinion, the information compiled in this text book and the long-established continuous updates should make it a very vital review text book for most readers. this book offers a very broad look at bacteriology and virology (with some immunology and parasitology). the chapters are full of information: brief descriptions of organisms, vital perspectives on pathogenesis, diagnostic laboratory tests, clinical findings, treatment and epidemiology, the role microorganisms play in human health and illnesses and other detailed information that will be of interest to those who make a living in the field of microbiology. there might be books with far less information and easier to use; however, as mentioned earlier, this book is comprehensive and has been extensively revised and updated. the main structure and organization of this book is done to link fundamental microbiology concepts with the diagnosis and treatment of clinical infections. the authors have tried to integrate extensive updates throughout the text, including the use of current nomenclature as well as coverage of some newly viruses such as west nile virus, coronaviruses, metapneumoviruses, hendra and other detailed information associated with them and the agents of bioterrorism. the chapters are rich in such information and structured in a coherent approach to reflect the overall consistency of the growing information in this field of medical science. also, at the end of each chapter a group of review questions and case studies that really are a bonus for students, trainees and readers in general. as we look back at the early editions of this book, we find that a lot of effort has been applied to generate and develop this new edition in order to fulfill the user’s requirements. however, there are a few points which need to be raised: 1. there are around 300 informative illustrations and tables, each designed to clarify and drive some important chapter concepts. although i do not doubt the standards and professionalism of this book, i still think that it would have been more fascinating if colours were introduced to at least some of the illustrations to brighten up the text. 2. when we flip through different chapters we find that references have been added at the end, but there is no indication as to whether the information is a suggested source for extra study or if it is already incorporated into the chapters. 3. it is quite clear that the authors have realized the need to add further issues, as in the case of the last two chapters that involves diagnostic medical microbiology and clinical correlations. for that purpose, a new author was employed, since microbiology diagnostics have been evolving very fast b o o k r e v i e w : j aw e t z , m e l n i c k & a d e l b e r g ’ s m e d i c a l m i c r o b i o l o g y 275 during the past two decades. nevertheless, i still believe that part of these two chapters should have been incorporated into the counterpart chapters (i.e. the clinical cases could have merged with the appropriate chapters), while the diagnostic part could have been combined or added to the first section, or as an individual section that follows the immunology section. this would further strengthen and enhance the arrangement and structure of the text book. finally, i am sure that this new edition will add significantly to our knowledge and understanding of microbiology as past editions have always done. whole1.indd world health day is celebrated by the world health organization each year on 7th april and the theme of this year was ‘road safety’. road safety is no accident and coincides with the release of a world bank and who report (world report on road traffic injury prevention).1 road traffic injuries kill 1.2 million people each year and injure or disable as many as 50 million, which represents a 60% increase in the last five years.2 road crashes are the second leading cause of death globally among young people and affect the most economically active members of the population. it has been reported that 86% of deaths from road traffic injuries occur in low and middle income countries even though these account for only 40% of all motor vehicles.3 in these countries, reasons cited for the high burden include the growth in motor vehicles, higher number of people killed per crash, poor public health structure and poor enforcement of traffic regulations. the sultanate of oman has seen very rapid development in the last thirty years and in 2000 who ranked number one in improving the level of health of its population. oman has an extensive road building program with road calming measures in operation and road safety programs run by the royal oman police (rop). however, deaths from road traffic accidents are (rtas) a major concern. in 2001, there were an estimated 117 cars per thousand population in the country with 13,101 rtas (5.45 per thousand population)4 499 deaths and 9625 people were injured. forty percent of fatalities were vehicle passengers and 44% of incidents was due to speeding as reported by the traffic authority. generally, car crashes represent the conjunction of multiple factors involving road infrastructure, vehicles and people. safe human behaviour is a major risk factor in accounting for road traffic injuries (rtis) especially in developing countries where it is estimated that 64% to 95% of casualties are due to improper human activity as either a driver, passenger or pedestrian. safe behaviour includes pre-crash elements of road user activity (e.g. speeding, attitudes, behaviour and pedestrian habits), crash elements (e.g. use of restraints) and post-crash elements (e.g. first aid skills and access to medical treatment). wearing a seat belt can be a good indicator of safe road behaviour especially when comparing rear and front seat passengers. although wearing a seat belt in the front seat is compulsory in oman and the rop makes spot checks on vehicles, many drivers and passengers do not comply with the regulations. furthermore, there are no regulations regarding wearing a seat belt in the rear and few people bother to ‘belt up’ in the back. a study carried out by family and community health residents in the oman medical specialty board training program examined seat belt wearing in cars entering sultan qaboos university complex on a single day.5 the results indicated that 90.1% of drivers and 80.9% of front seat passengers wore their seat belt. only 1.4% of rear seat passengers wore a seat belt. surprisingly, front seat passengers were not as compliant as drivers despite the fact that police staff all the gates into the campus and spot checks on the highways often result in fines (seat belt fines constitute 9% of traffic offences nationwide). researchers also reported that they could see front seat occupants putting on their seat belts as they approached the gates. studies in other middle east countries have shown that seat belt use is infrequent.6 however, it can increase with a general understanding of road safety rules.7 bener et al have shown that there is awareness of the benefits of wearing seat belts in middle east countries and strong sup sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© callander cottage, lochgoilhead argyll, pa 24 8aq, scotland, united kingdom . email: minibarrs@hotmail.com e d i t o r i a l road traffic accidents a challenging epidemic shirley mcilvenny الوبائي التحدي حوادث الطرقماكليفني شيرلي shirley mcllvenny 4 port for its enforcement.8 poor enforcement of traffic regulations is one reason why low income countries have such a high burden of death and disability from rtas.9 although there appears to be good compliance with the law, evidence suggests that compliance in front seat occupants would not be as good in areas where they are unlikely to be observed. wearing a seat belt is not compulsory in the back and very few back seat passengers were strapped in. this indicates that complying with regulations is more important than wearing a seat belt for protection and there is probably little knowledge of the dangers to other passengers and the driver. however, legislation is only part of the answer. since compulsory rear seat belt wearing was introduced in uk in 1989, recent research (1998) reveals that even now, only 48% of adult passengers wear seat belts in the back compared with 92% in the front.10 back seat passengers who do not wear seat belts are three times more likely to suffer death or serious injury than those who do. furthermore, the uk department of transport estimates that some 40 front seat passengers die each year in britain because of un-belted back seat passengers crashing into them. there is evidence that safety education can improve knowledge and behaviour but that improvement declines with time so must be repeated at regular intervals.11 a further study by the residents has investigated attitudes and knowledge to seat belt wearing in the omani population and also attitudes to safety education but the results are not yet available. regarding children, only 3.7% of ‘under fives’ were in a child restraint and this was probably due to lack of knowledge of the parents. jan et al also showed infrequent use of child restraints in saudi arabia (8% of families), where seat belt use in general was linked to higher income families.12 even though child restraints may be employed, their use may be incorrect and this has been recognized in western countries.13 the fact that so many parents in the front were restrained, while the children in the back were not, also indicates a willingness to comply with local laws rather than an understanding of the risks. perhaps more worrying is the fact that so many ‘under fives’ sat in the front seat (34.6%). there is a perception among the population that it is cruel to keep a child alone in the back of the car and there is probably little awareness of the dangers to children of sitting in the front seat. a frequent occurrence is a child sitting in the front on the mother’s knee, close to the windscreen. an education program needs to be instituted to increase knowledge and awareness and to ensure that parents understand the importance of using child restraint equipment properly. according to haddons’ matrix [figure 1],14 most pre-crash prevention can be attributed to the vehicle driver in attitudes and actions, and in maintaining road worthiness of the vehicle. since most injuries can be attributed to improper human behaviour, driver responsibility seems to be a good place to start. ensuring all occupants are wearing a seat belt would be a simple activity, which would have an impact on mortality and morbidity from rtis and put the responsibility onto the driver of the vehicle. health education agencies, for example local community clinics, could be involved in increasing the awareness of the population and promoting new regulations. other areas for development involving the health services include the provision of emergency services, especially at the roadside. it is an auspicious development that an ambulance service for rtas has been introduced by the rop this year. many local primary health care clinics are also involved in managing rtis people vehicle environment pre-crash crash prevention education/training impairment/attitudes/behaviour road-worthiness system (lights, brakes etc) road design signs, markings maintenance crash injury prevention use of restraints impairment restraints crash worthines maintenance protection (barrier) pedestrian crossings post-crash life sustaining first aid skill/access to medics ease of access/fire risk rescue facilities/congestion figure 1. haddon’s matrix: basic road safety elements 5 r o a d tr a f f i c a c c i d e n t s a c h a l l e n g i n g e p i d e m i c especially in remote areas. these facilities would benefit from first aid and emergency management training. health care workers are very aware of the burden to the health service and the community of rtas particularly in emergency care, rehabilitation and care following permanent injuries and the consequences of the loss of the bread winner or main carer in a family. road traffic injuries are responsible for the majority of disability and occupation handicap from major traumatic injury.15 on top of that, road crashes absorb a huge amount of financial resources particularly in developing countries. this can be as much as 1% of the gross national product and represents more than the total development aid they receive. by 2020, road traffic injuries are forecast to become the second leading cause of disability-adjusted life years lost in developing countries and decreasing the burden of injuries is one of the main challenges for public health in the next century.16 the who recommends that raising the awareness of all interested parties is the first step in injury prevention. partnerships with other interested agencies, for example police and town planners, would allow health agencies to be involved in developing safety strategies to reduce rtis and deaths from rtas. the new ambulance service is a good example of co-operation in action. health workers could also show these groups the cost to the health service of accident black spots, for example by producing figures comparing the cost of road improvements versus the financial burden on health services and the community. who challenged nations to manage this epidemic of disability and financial burden in this year. health care agencies can be involved at the forefront of the race to confront the challenge and control the latest man-made epidemic to spread across the globe. r e f e r e n c e s 1. world health day 2004: road safety. www.who.int/ world-health-day/2004/en/. 2. peden m sr, sleet d, mohan d, hyder aa, jarawan e. world report on road traffic injury prevention. world health organization 2004. 3. road safety at a glance. world bank health nutrition population, march 2002. 4. traffic accidents in oman 2001. facts and figures. royal oman police 2002. 5. mcilvenny s amf, al-busaidi t, al-nabhani a. rear seat-belt use as an indicator of safe road behaviour in a rapidly developing country. j r soc health 2004; 124: 280-283. 6. shanks nj am, al-kalai d. road traffic accidents in saudi arabia. publichealth 1994; 108:7-34. 7. al-madhani h. influence of drivers’ comprehension of posted signs on their safety related characteristics. accid anal prev 2000; 32: 575-581. 8. bener a an, sankaran kutty m, ware j, cheema my, al-shamsi ma. casualty risk reduction from safety seat belts in a desert country. j r soc health 1994; 114: 297-299. 9. vinand m nantulya mrr. the neglected epidemic: road traffic injuries in developing countries. brit med j 2002; 324: 1139-1141. 10. think! seatbelts. fact about rear seat belts. uk department for transport. www.thinkroadsafety.gov.uk/campaigns/seatbelts/seatbelts.htm. 11. duperrex o, roberts i, bunn f. safety education of pedestrians for injury prevention. cochrane databas syst rev 2002; 2: cd001531. 12. jan mm, hasanain fh, al-dabbagh aa. infant and child safety practice of parents. saudi med j 2000; 21: 1142-1146. 13. campbell h, macdonald s, richardson p. high levels of incorrect use of car seat belts and child restraints in fife–an important and under-recognised road safety issue. inj prev 1997; 3: 17-22. 14. haddon w. advances in the epidemiology of injuries as a basis for public policy. public health rep 1980; 95: 411-421. 15. airey cm, chell sm, rigby as, tennant a, connelly jb. the epidemiology of disability and occupation handicap resulting from major traumatic injury. disabil rehabil 2001; 23: 509-515. 16. krug eg, sharma gk, lozano r. the global burden of injuries. am j public health 2000; 90: 523-526. submitted 2 dec 21 1 revision req. 23 jan 22; revision recd. 26 jan 22 2 accepted 15 feb 22 3 online-first: may 2022 4 doi: https://doi.org/10.18295/squmj.5.2022.037 5 6 bullous allergic contact dermatitis caused by potassium dichromate 7 *francisco j. navarro-triviño,1 álvaro prados-carmona,2 juan pablo 8 velasco-amador,2 ricardo ruiz-villaverde,2 9 10 1department of contact eczema and immunoallergic diseases, dermatology and 11 2department of dermatology, hospital universitario san cecilio, granada, spain. 12 *corresponding author’s e-mail: fntmed@gmail.com 13 14 introduction 15 contact dermatitis comprises eczematous and non-eczematous reactions. certain 16 allergens can trigger very intense reactions, which can be confused with other dermatoses. 17 18 a 66-year-old man presented with rapidly progressive pruritic erythematous-oedematous 19 eruption with blistering on his abdomen (fig. 1). the patient was attended in the 20 emergency department. a diagnosis of second-degree burn was made, indicating 21 treatment with silver sulfadiazine cream. the evolution was unfavourable, with the 22 formation of new blisters and more intense itching. the patient returned to the emergency 23 department. he was assessed by a dermatologist. the directed anamnesis detected contact 24 with cement sacks 48 hours before the onset of the cutaneous blistering eruption. bullous 25 allergic contact dermatitis to potassium dichromate was suspected. he worked as an 26 aeronautical engineer. contact with multiple metals, including chromium, was confirmed. 27 he also reported dermatitis on wrists with leather bracelets, as well as eczematous lesions 28 on the back of the feet with leather shoes. treatment with oral corticosteroids was 29 prescribed for 10 days, with complete improvement of the rash. the patch test showed 30 positivity to potassium dichromate +++ at 48 and 96 hours. bullous allergic contact 31 dermatitis to potassium dichromate was confirmed. patient consent was obtained for 32 publication purposes. 33 34 comment 35 the most frequent source of contact to potassium dichromate in men is through cement1. 36 other sources2 are stainless steel objects, orthopaedic prostheses, dental implants, 37 orthodontic appliances, green dyes from textiles and tattoos, matches, paints and 38 varnishes, anti-corrosion agents, cutting oils, degreasing solvents, electrolysis baths, 39 electric batteries, waterproof fabrics, tv manufacturing, photocopy paper, solder, floor 40 waxes, shoe polish, paints, glues, eye shadow and eye mask pigments, detergents, 41 analytical reagents, chrome catgut. 42 43 the application of barrier creams with glutathione and iron sulphate could inhibit the 44 elicitation phase of patients predisposed to develop allergic contact dermatitis to 45 hexavalent chromium3. hand dermatitis is the most frequent location when the source of 46 contact is cement. other locations such as the feet are related to leather footwear4. 47 eczematous and blistering rash on the back of the foot is suggestive of allergic contact 48 dermatitis caused by potassium dichromate5. the anamnesis is crucial to correctly 49 approach the diagnosis of the patient. other allergens associated with the development of 50 bullous allergic contact dermatitis include diethylthiourea6, and colophonium7, among 51 others. 52 53 contact dermatitis can manifest itself in various clinical forms. bullous lesions can be 54 observed in both irritant and allergic forms. anamnesis is crucial in order to correctly 55 approach the diagnosis as well as the scheduling of the patch test. 56 57 authors’ contribution 58 all authors contributed equally to conception and design, data collection, data analysis 59 and interpretation, drafting and editing the manuscript. all authors approved the final 60 version of this manuscript. 61 62 references 63 1. mowitz m, zimerson e, hauksson i, pontén a. chromate and amine contact 64 allergies in workers manufacturing precast concrete elements. contact dermatitis. 65 2016;75(6):363-369. 66 2. bregnbak d, johansen jd, jellesen ms, zachariae c, menné t, thyssen jp. 67 chromium allergy and dermatitis: prevalence and main findings. contact 68 dermatitis. 2015;73(5):261-80. 69 3. lejding t, engfeldt m, bruze m, isaksson m, svedman c, zimerson e, verma 70 k, mowitz m. skin application of glutathione and iron sulfate can inhibit 71 elicitation of allergic contact dermatitis from hexavalent chromium. contact 72 dermatitis. 2020;82(1):45-53. 73 4. adams dw, marshall-battle mr. shoe contact dermatitis: a case report of an 74 acute severe reaction to potassium dichromate. foot (edinb). 2012;22(3):141-5. 75 5. thyssen jp, strandesen m, poulsen pb, menné t, johansen jd. chromium in 76 leather footwear risk assessment of chromium allergy and dermatitis. contact 77 dermatitis. 2012;66(5):279-85. 78 6. bregnhøj a, sommerlund m. severe bullous allergic contact dermatitis caused by 79 diethylthiourea 20 years after sensitization to neoprene. contact dermatitis. 80 2017;76(4):236-237. 81 7. christoffers wa, coenraads pj, schuttelaar ml. bullous allergic reaction caused 82 by colophonium in medical adhesives. contact dermatitis. 2014;70(4):256-7. 83 84 85 figure 1. eczematous and bullous rash on the abdomen. 86 college of nursing, sultan qaboos university, muscat, oman *corresponding author’s e-mails: reemal-sharqia@hotmail.com and eiman@squ.edu.om nursing students’ perception and attitude towards objective structured clinical examination in oman shaikha alamri, *iman al hashmi, kholah shruba, suad jamaan, zaina alrahbi, thuraiya al kaabi sultan qaboos university med j, august 2022, vol. 22, iss. 3, pp. 343–350, epub. 25 aug 22 submitted 23 jan 21 revision req. 1 apr 21; revision recd. 22 apr 21 accepted 24 may 21 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2.2022.012 clinical & basic research the objective structured clinical examination (osce) is a universal format used by healthcare professionals to measure students’ clinical competence.1 in nursing programmes, clinical education forms the core of a nurse’s professional practice. therefore, assessing nursing students’ clinical competence is crucial to their education.2 the osce has gained acceptance since its development in the 1970s as a method to evaluate the clinical performance of nursing students.3 it uses standardised scenarios that mimic real-life clinical situations and is administered in a highly controlled environment.4 unlike traditional clinical exams, which have been criticised for lacking objectivity and uniformity,5 the osce is one of the most reliable assessment tools; it enhances students’ learning, allowing students to demonstrate the full extent of their knowledge and skills, all the while providing a more objective method of assessment.5,6 additionally, the simulation of patients in osces provides a safe environment for students to practice a wide range of practical skills without feeling discomposed about causing harm to the patient. it further creates a culture relatively similar to the hospital environment.7 osce helps in enhancing the safety and quality of nursing care and ultimately prepares students for their future professional role. besides the summative assessment, osce can also be used as a formative assessment through which the abstract: objectives: this study aimed to explore undergraduate nursing students’ perception and attitude towards the objective structured clinical examination (osce). methods: this cross-sectional descriptive study was conducted between april–may 2020 among undergraduate nursing students at the college of nursing at sultan qaboos university, muscat, oman. two self-administered questionnaires were utilised to obtain data on students’ perception and attitude towards osce. students’ feedback on osce was collected using open-ended questions about osce strengths, weaknesses and recommendations for improvement. survey responses were based on a fivepoint ordinal scale, ranging from strongly disagree to strongly agree. students’ feedback on osce was analysed as descriptive data by identifying the common themes and categorising them in groups. results: a total of 160 students completed the study questionnaires. most did not find the atmosphere of osce to be pleasant (66.3%) and preferred more modes of practical examination (40.6%). moreover, 64.4% believed the time limitation to be inadequate. the data depict that 33.1% of the examinees deemed the osce more stressful than the full practical examination. in addition, a few students confirmed that the osce improved their communication skills and confidence in nursing skills. conclusion: the findings of this study appear alarming in regard to students’ perception regarding the overall process and validity of osce as an assessment method. nursing educators must consider further evaluation and improvement of the osce in order to improve students’ acceptance and appreciation of osce as an important form of clinical learning and assessment. keywords: clinical competence; nursing education; baccalaureate; evaluation; attitude; nursing students; practical nursing; oman. advances in knowledge the study indicates that further improvement of the objective structured clinical examination (osce) is necessary to ensure better assessment of students’ clinical skills and knowledge. adequate preparation of students prior to the osce, determination of the appropriate time-frame for each station and encouragement of examiner’s positive attitudes during the exam are recommended strategies for reducing osce-related stress and improving students’ overall performance. technical preparation, adequate orientation of examinee and examiners and redesigning of the skill laboratories for enhanced legitimacy are required for more efficient and effective conduction of the osce. application to patient care the objective structured clinical exam is an effective assessment strategy for measuring the clinical competence of nursing students to ensure patient safety and quality of care. https://creativecommons.org/licenses/by-nd/4.0/ nursing students’ perception and attitude towards objective structured clinical examination in oman 344 | squ medical journal, august 2022, volume 22, issue 3 nursing educator provides feedback to students as part of the teaching process.1 while the osce has been found to be an effective method in clinical education and assessment,2,4 it may also induce high levels of anxiety in students due to its interactive nature.8,9 several studies have documented that nursing students found the osce to be quite stressful, such that they were unable to perform well compared to their relative performance in the actual clinical environment. this is due to the pressure of observation by examiners as well as the time limit allocated for each skill.9 furthermore, several students perceive the osce as a noncomprehensive examination that does not reflect reality since simulated patients or mannequins are utilised instead of real patients. these responses might not be conclusive, yet it is imperative to look into the osce as an effective tool to support student learning needs.8,10 to the best of the authors’ knowledge, the perception and attitude of omani nursing students about the osce as an assessment approach has not been comprehensively documented. the published studies are limited as they either evaluate the impact of test anxiety on the students’ academic performance or compare their self-assessment to the examiners’ assessment in the osce.11,12 none of the abovementioned studies have addressed the perception of omani nursing students regarding the osce. this study aimed to fill this gap in the literature and lay a foundation for succeeding studies that seek to understand omani nursing students’ perceptions of the osce. it seeks to do this by investigating the perception and the attitude of omani nursing students towards the osce. methods this cross-sectional descriptive study was conducted at the college of nursing (con), sultan qaboos university (squ), muscat, oman from april–may 2020. the con is one of the leading nursing colleges for both baccalaureate and master degrees across the country. it is internationally recognised and accredited by the accreditation commission for education in nursing. students enrolled at squ predominately comprise omani citizens from various regions; thus, it is the ideal setting for the study as the students represent the omani nursing student population. the osce is a scenario-based assessment method in which the student is required to demonstrate safe and high-quality skills related to nursing care in a simulated environment on standardised patients or mannequins. in the osce, students’ clinical competence is assessed at a series of stations, which are developed according to the course objectives. at squ, the osce is considered a standard method of assessment for undergraduate nursing students and is implemented across all clinical courses. the entire nursing faculty in the con are well prepared to conduct osce and receive frequent training in osce development. the con’s laboratories maintain state-of-the-art equipment that can easily replicate the environment of healthcare facilities. standardised patients and low-fidelity and high-fidelity mannequins are utilised in the osce stations as deemed convenient by the clinical course coordinator. the osce scenarios are developed by phd nursing faculty by replicating real clinical cases. the examination may include two to three manned stations, each requiring about 15–20 minutes depending on the skill being tested. at least two examiners are responsible for assessing students’ performance on the required clinical competence and rate them on a standardised assessment tool with a predetermined safety criterion. students rotate through the osce stations in order to complete the exam. this means that all students complete the same stations, and hence, are assessed using the same assessment tool. the sample for this study comprised active omani undergraduate nursing students attending the con at squ during the study timeframe. the sample was required to be able to speak, read and write in arabic, with a previous experience with osce as an assessment method. undergraduate nursing students with known anxiety disorders or those without previous experience with the osce were excluded from the study. during the study timeframe, 250 nursing students were identified with a previous experience of osce and met the inclusion criteria. the sample size was calculated using the yamane formula. considering that the accessible population was equal to 250 subjects, the formula indicated that a sample size of 109 participants at a confidence level of 95% and an error of 5% was adequate to achieve a minimum power of 80%. incorporating a 10% attrition rate, the final required sample size was set at 119 subjects. convenient sampling was used to recruit the required study sample. four instruments were forwarded to the potential participants, including the demographic information sheet, the nursing students’ perception of the osce tool, the students’ attitude towards the osce and the students’ feedback on the osce. all the instruments provided to the participants were in arabic. approval to use these instruments was obtained from the tools’ developer prior to use. shaikha alamri, iman al hashmi, kholah shruba, suad jamaan, zaina alrahbi and thuraiya al kaabi clinical and basic research | 345 the demographic information sheet was developed by the study investigators and included data on participants’ gender, academic year, osce course name and type of study track. the perception of osce tool was used to assess the nursing students’ perception before, during and after osce.13 this 11-item, selfadministered structured questionnaire was scored on a five-point ordinal scale ranging from ‘strongly disagree’ to ‘strongly agree’. responses were grouped as positive responses (including agree and strongly agree) or negative responses (including disagree and strongly disagree), with positive responses suggestive of students’ good perception of the osce. the internal reliability of the original tool was deemed to be good (cronbach’s alpha value: 0.9).13 the 12-item attitude towards osce scale was used to measure the attitude of nursing students towards osce.14 students’ responses were scored on a five-point ordinal scale ranging from ‘strongly disagree’ to ‘strongly agree’, with positive scores indicating students’ good attitude towards osce. the internal reliability of the original tool was established to be good.14 students’ feedback regarding the osce was assessed through three open-ended questions concerning the strengths and the weaknesses of the examination from the students’ perspective and their recommendations to improve osce.14 the data were analysed using the statistical package for social sciences (spss) software, version 24.0 (ibm corporation, armonk, new york, usa) and double-checked for accuracy. the results were checked for outliers or missing data to determine the need for transformation or use of non-parametric methods. descriptive statistics and graphical summaries were run for all the key outcomes. categorical variables were presented as frequencies and percentages. an anova test was employed to test the difference between students’ academic year and their perception and attitude towards the osce. students’ feedback on the osce was analysed as descriptive data by identifying similar themes and subsequently categorising them into groups. prior to the beginning of the study procedures, ethical approval was obtained from the scientific ethics committee at the con (con/gp/2020/01). the participant recruitment process was coordinated with the help of the assistant dean of undergraduate study as well as the course coordinators of the clinical nursing courses, who had been informed of the study purpose and eligibility criteria. a list of all clinical nursing courses that had used osce in the previous semester was generated along with the students’ email list. the study investigators manually checked students’ emails against courses to prevent duplication of participants. all the students in the list were invited to participate in the study via email, which included the study information sheet (e.g. purpose, study title, researchers, eligibility criteria, participants’ role and study expectations) and an electronic link to the study questionnaires and the consent form. to prevent measurement-related errors, the investigators standardised the procedure by providing uniform information and instruction to all potential participants. results a total of 160 nursing undergraduate students completed the study questionnaire with a 0% attrition rate. of these, 127 (79.4%) were female and 31(19.4%) were male. most of the students were in their third (n = 42; 26.3%) and fourth year (n = 57; 35.6%) [table 1]. the extent and the quality of information with respect to osce was determined. most of the students rated the osce negatively, as they disagreed with the view that osce equipment and scenarios are realistic, relevant and logistic (n = 83; 51.9%). they also disagreed with the notion that the time allowed to read osce instructions (n = 96; 60%) and the time allocated to complete the skill (n = 103; 64.4%) was sufficient. more than the half of the students (n = 94; 58.8%) perceived table 1: sample demographic and academic characteristics (n = 160) characteristic n (%) gender female 127 (79.4) male 31 (19.4) missing 2 (1.3) academic year first year 8 (5) second year 8 (5) third year 42 (26.3) fourth year 57 (35.6) missing 53 (33.1) academic track regular track 131 (81.9) bridging 28 (17.5) missing 1 (0.6) previous osce experience yes 153 (95.6) no 1 (0.6) nursing students’ perception and attitude towards objective structured clinical examination in oman 346 | squ medical journal, august 2022, volume 22, issue 3 osce examiners as being uncorteous, unfriendly and non-cooperative. however, half the students (n = 84; 52.5%) declared a positive view that the procedures given in osce were applicable during clinical posting, and 78 (48.8%) possessed a high level of confidence to demonstrate the same procedure on a real patient. only 70 (43.8%) students believed that osce helped them identify their deficiencies in clinical skills, while the remaining 90 (56.3%) disagreed with this statement. furthermore, 91 (56.9%) did not support the statement ‘to continue the way the osce was conducted as a practical examination in the future’ [table 2]. regarding students’ attitude towards the osce, 57 (35.6%) believed that the osce encourages students to be more attentive in practical classes, table 2: nursing students’ perception towards objective structured clinical examination (n = 160) item n (%) positive negative missing osce atmosphere is good 51 (31.9) 106 (66.3) 3 (1.9) extent and quality of information received about osce 70 (43.8) 87 (54.4) 3 (1.9) enough time allowed for reading the instruction 62 (38.8) 96 (60) 2 (1.3) time allotted for the completion of the procedure is enough 54 (33.8) 103 (64.4) 3 (1.9) equipment and scenarios are realistic, relevant and logistic 77 (48.1) 83 (51.9) 0 (0.0) examiners are courteous, friendly and cooperative 62 (38.8) 94 (58.8) 4 (2.5) procedures given in osce are applicable during clinical posting 84 (52.5) 76 (47.5) 0 (0.0) confidence to conduct a similar procedure on a real patient is high 78 (48.8) 80 (50) 2 (1.3) student perceptions on osce results 78 (48.8) 80 (50) 2 (1.3) continue the way osce was conducted as a practical examination in the future 64 (40) 91 (56.9) 5 (3.1) helped students to identify their deficiencies in clinical skills 70 (43.8) 90 (56.3) 0 (0.0) osce = objective structured clinical examination. table 3: students’ attitude towards objective structured clinical examination (n = 160) item n (%) positive negative neutral missing osce encourages students to be more attentive in practical class. 57 (35.6) 60 (37.5) 42 (26.3) 1 (0.6) there is ample time at all the stations. 47 (29.4) 73 (45.6) 36 (22.5) 4 (2.5) osce tests details of the steps of a procedure. 62 (38.8) 50 (31.3) 47 (29.4) 1 (0.6) osce is a more challenging form of examin ation. 57 (35.6) 33 (20.6) 68 (42.5) 2 (1.3) osce tests recall of knowledge. 58 (36.3) 57 (35.6) 46 (28.1) 0 (0.0) osce is quite an easy examin ation. 51 (31.9) 58 (36.3) 51 (31.9) 0 (0.0) time is sufficient at procedural stations. 52 (32.5) 66 (41.3) 38 (23.8) 4 (2.5) osce should be the only mode of practical examin ation. 62 (38.8) 65 (40.6) 32 (20.0) 1 (0.6) cannot pass in osce without attending class regularly. 56 (35.0) 59 (36.9) 45 (28.1) 0 (0.0) osce is more stressful than a full practical examin ation. 53 (33.1) 42 (26.3) 63 (39.4) 3 (1.3) easier to pass in osce than in full practical examin ations 58 (36.3) 61 (38.1) 40 (25.0) 1 (0.6) not much difference between osce and other practical examin ations. 54 (33.8) 68 (42.5) 37 (23.1) 1 (0.6) osce = objective structured clinical examination. shaikha alamri, iman al hashmi, kholah shruba, suad jamaan, zaina alrahbi and thuraiya al kaabi clinical and basic research | 347 while the remaining either disagreed (n = 60; 37.5%) or remained neutral (n = 42; 26.3%) regarding this notion. the majority (n = 57; 35.6%) of the responses indicated positively that the osce is a more challenging form of examination and 53 (33.1%) students believed the osce to be more stressful than clinical examination. furthermore, 54 (33.8%) students argued that there was not much difference between the osce and other clinical examinations and 56 (35.0%) declared that they could not pass the osce without attending their classes regularly. moreover, the majority of students (n = 65; 40.6%) disagreed that the osce should be the only mode of practical examination [table 3]. table 6: osce-related weaknesses as percieved by nursing students attending the college of nursing at sultan qaboos university, muscat, oman (n = 160) weakness total sample n (%) osce is a stressful examination 22 (35.0) there is time limit to perform procedures 15 (24.0) unfriendly examiners 5 (8.0) nature of the examination is not good 3 (5.0) table 4: effect of students’ academic year on students’ perception and attitude towards objective structured clinical examination predictor sum of squares df mean square f p value osce atmosphere is good 2.73 3 0.91 1.06 0.37 extent and quality of information received about osce 0.58 3 0.19 0.29 0.84 enough time allowed for reading the instructions 3.23 3 1.08 1.31 0.27 equipment and scenarios are realistic, relevant and logistic 2.99 3 0.99 1.25 0.29 examiners are courteous, friendly and cooperative 3.29 3 1.09 1.29 0.28 procedures given in osce are applicable during clinical posting 3.22 3 1.07 1.23 0.30 confidence to conduct a similar procedure on a real patient is high 6.25 3 2.08 2.68 0.05 student perceptions on osce results 2.17 3 0.72 1.07 0.36 continue the way osce was conducted as a practical examination in the future 3.77 3 1.25 1.56 0.20 helped students to identify their deficiencies in clinical skills 5.06 3 1.69 2.16 0.09 osce encourages students to be more attentive in practical class 8.62 3 2.87 2.43 0.07 there is ample time at all the stations 9.75 3 3.25 2.56 0.05 osce tests details of the steps of a procedure 5.18 3 1.73 1.448 0.22 osce is a more challenging form of examination 9.09 3 3.03 2.42 0.07 osce tests recall of knowledge 4.83 3 1.61 1.24 0.29 osce is quite an easy examination. 1.44 3 0.48 0.34 0.79 osce should be the only mode of practical examination 0.35 3 0.12 0.20 0.89 cannot pass in osce without attending class regularly. 6.68 3 2.22 1.57 0.19 osce is more stressful than a full practical examination 8.29 3 2.77 1.80 0.15 easier to pass in osce than in full practical examinations 0.74 3 0.25 0.19 0.89 not much difference between osce and other practical examinations. 9.08 3 3.03 2.79 0.04 osce = objective structured clinical examination. table 5: osce-related strengths as percieved by nursing students attending the college of nursing at sultan qaboos university, muscat, oman (n = 160) strength n (%) osce improves students’ skills and communication 13 (21.0) osce increases students’ confidence level 7 (11.0) osce helps students to learn time management 3 (5.0) osce gives students the chance to work in a hospital-like environment 3 (5.0) osce improves students’ critical thinking 3 (5.0) osce = objective structured clinical examination. nursing students’ perception and attitude towards objective structured clinical examination in oman 348 | squ medical journal, august 2022, volume 22, issue 3 the analysis of variance indicated that the effect of the students’ academic year was significant on their perception of ‘not much difference between osce and other practical examinations’ (f [3,155] = 2.79, p = 0.04) and ‘there is ample time at all the stations’ (f [3,155] = 2.56, p = 0.05) [table 4]. the osce’s strengths frequently reported by students are that it improves students’ skills and communication (n = 13; 21%) and increases students’ confidence level (n = 7; 11%) [table 5]. the top osce-related weaknesses declared by the participants include the osce being a stressful examination (n = 22; 35%) and the time limit (n = 15; 24%). other reported weaknesses include unfriendly examiners (n = 5; 8%) [table 6]. the recommendations provided by the students to improve their experiences during the osce included providing at least 30 minutes of time to perform the skill (n = 26; 42%) as well as enough lab practice prior to the examination (n = 10; 16%). discussion osce is considered the gold standard for assessing the clinical proficiency of health professionals in various health-related institutions worldwide.15,16 in nursing programmes, clinical assessment competence is one of the core components that the students must master to be able to provide safe and quality nursing care.17 the sample of the current study revealed unfavourable and negative responses for the osce in the context of practical examination, which varies from other evidence that reported overall favourable perception and attitude towards the osce.18–20 students’ view of the osce might have been influenced by stress and lack of confidence and preparation associated with this assessment method. in this study, more than onethird of the participants declared the osce to be a stress-inducing and difficult examination. this finding is consistent with observations from other studies; however, it contradicts the study conducted by shitu and girma (2018).9,21 more than half the students indicated that they had not received adequate orientation to the osce, believing osce’s simulations to be unrealistic, irrelevant and illogical. this finding is consistent with other similar studies.22 lack of awareness of, preparation for and orientation to the exam format may negatively impact students’ stress level and performance in the osce.23 therefore, it is recommended to brief students and provide them with adequate information regarding the nature, format, objectives and content of each station to decrease their stress level during the examination, thereby improving their performance.18 additionally, 60% of the study participants believed that the time allocated to read osce instructions was insufficient. similarly, 64.4% of them stated that the time allocated to complete the procedure was inadequate and suggested increasing the time up to thirty minutes. these findings are consistent with other studies, in which more than half the study participants mentioned the need for more time to complete each station in the osce.15,18 unrealistic time limits for each station may be one of the reasons for students’ anxiety.24 usually, during the development stage of the osce, nursing educators estimate the time allocated to each station considering several factors, such as learning outcomes, students’ level, objectives and the skill being assessed. this study suggests that the instructors perform osce trials to determine the time required for each station. this could decrease students’ stress and improve their scores for the osce.25 additionally, training the students in time management prior to the adminsteration of the osce is important. the results of this study indicate that more than half the students found the examiners at manned stations to be uncourteous, unfriendly and noncooperative. concerns regarding unsympathetic characteristics of the examiners have also been reported in previous studies.21 this provides another potential explanation for the students’ stress perceived during the osce. this finding has an important implication for osce developers who need to orient and prepare examiners adequately for the examination to positively influence students’ performance. a high percentage (56.9%) of the study participants suggested the osce be reconstructed for practical examinations in the future. moreover, almost a similar percentage of the students (40.6%) implied that the osce should not be the only method for practical examination. this contradicts chongloi et al., who found that their study participants preferred the osce to be the only method for practical examination as they believed it requires less preparation and efforts and values high scores.18 in the current study, almost half the students indicated that the osce did not help them identify their deficiencies in clinical skills or improve their confidence level for similar procedures on real patients. in contrast, aung et al. observed that the osce provided the majority of the participants the opportunity to practice rare or advanced nursing procedures.26 consequently, the osce practice improved students’ confidence level to demonstrate similar procedures on a real patient. in the current study, the students suggested having adequate practice shaikha alamri, iman al hashmi, kholah shruba, suad jamaan, zaina alrahbi and thuraiya al kaabi clinical and basic research | 349 prior to the osce. this was possibly due to the students’ inexperience with this method of evaluation. practice trials may help in the improvement of students’ confidence level to perform clinical skills and their acceptance and appreciation of osce as a significant way of clinical learning. furthermore, students in this study recommended the organisation of all osce stations in a single area. this finding exemplifies the importance of focusing not only on the osce process and preparation, but also on the environment and setting of the exam. the skill laboratories in the facility lack space and are not well-designed to conduct osce. therefore, their structure must be reconsidered to conduct the osce more effectively. to the best of the authors’ knowledge, this is the first study of its kind in oman among nursing students. it provides an insight regarding osce from the perspective of omani nursing students. the major strengths of this study include the study design, adequate sample size and the use of validated questionnaires. altogether, these aspects provide greater confidence regarding the study results. in addition to the above-mentioned strengths, a few limitations must be acknowledged while interpreting the results of this study. first, this study was conducted after one semester had passed following the osce, as the teaching in the institution was suspended due to the covid-19 pandemic. therefore, students’ recollection of the osce might have been impacted during that time period. second, this study cannot be generalised among nursing students as it was conducted in a single institution and on a relatively smaller sample of students by employing convenience sampling. conclusion the authors’ findings of nursing students’ perception of the osce were consistent with a few previous studies. the majority of the participants provided unfavourable and negative responses for osce, including stressful examination, lack of confidence to perform, unrealistic timing to complete tasks, unfriendly examiners and poor organisation of osce stations. therefore, providing students with practice trials before the osce, determining the appropriate time frame for each station, training the students in time management and encouraging positive examiner attitudes during the exam are recommended for reducing exam-related stress and improving students’ performance. in addition, technical preparation and orientation of students as well as examiners to the exam process may aid in promoting its efficacy. redesigning the skill laboratories for enhanced legitimacy would also allow for more efficient and effective conducting of the osce. a u t h o r s’ c o n t r i b u t i o n sa, ks, sj, za and tak: conceived the project, collected the data and drafted the manuscript. iah is the project lead, made conceptual contributions to the study design, analysed and intrepreted the statistical data and critically read the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. elbilgahy aa, eltaib fa, mohamed rk. implementation of objective structured clinical examination (osce): perceiving nursing students and teachers attitude & satisfaction. am j nurs 2020; 8:220–6. https://doi.org/10.12691/ajnr-8-2-11. 2. smrekar m, ledinski fičko s, hošnjak am, ilić b. use of the objective structured clinical examination in undergraduate nursing education. croatian nurs j 2017; 1:91–102. https://doi. org/10.24141/2/1/1/8. 3. miller ge. the assessment of clinical skills competence perfor mance. acad med 1990; 65:s63–7. https://doi.org/10.1097/000 01888-199009000-00045. 4. aronowitz t, aronowitz s, mardin-small j, kim b. using objective structured clinical examination (osce) as education in advanced practice registered nursing education. j prof nurs 2017; 33:119–25. https://doi.org/10.1016/j.profnurs.2016.06.003. 5. frantz jm, rowe m, hess da, rhoda aj, sauls bl, wegner i. student and staff perceptions and experiences of the introduction of objective structured practical examinations: a pilot study. afr j health prof educ 2013; 5:72–4. https://doi.org/10.7196/ ajhpe.218. 6. kowlowitz v, hoole aj, sloane pd. implementing the objective structured clinical examination in a traditional medical school: academic medicine. j assoc am med coll 1991; 66:345–7. https://doi.org/10.1097/00001888-199106000-00008. 7. zayyan m. objective structured clinical examination: the assessment of choice. oman med j 2011; 26:219. https://doi. org/10.5001/omj.2011.55. 8. al-ghareeb a, mckenna l, cooper s. the influence of anxiety on student nurse performance in a simulated clinical setting: a mixed methods design. int j nurs stud 2019; 98:57–66. https:// doi.org/10.1016/j.ijnurstu.2019.06.006. 9. nasir aa, yusuf as, abdur-rahman lo, babalola om, adeyeye aa, popoola aa, et al. medical students’ perception of objective structured clinical examination: a feedback for process improve ment. jo surg educ 2014; 71:701–6. https://doi.org/10.1016/j. jsurg.2014.02.010. 10. robinson p, morton l, haran h, manton r. mock osces improve medical students’ confidence and reduce anxiety related to summative examinations. educ med j 2017; 9:41–5. https://doi.org/10.21315/eimj2017.9.2.4. https://doi.org/10.12691/ajnr-8-2-11 https://doi.org/10.24141/2/1/1/8 https://doi.org/10.24141/2/1/1/8 https://doi.org/10.1097/000 01888-199009000-00045 https://doi.org/10.1097/000 01888-199009000-00045 https://doi.org/10.1016/j.profnurs.2016.06.003 https://doi.org/10.7196/ajhpe.218 https://doi.org/10.7196/ajhpe.218 https://doi.org/10.1097/00001888-199106000-00008 https://doi.org/10.5001/omj.2011.55 https://doi.org/10.5001/omj.2011.55 https://doi.org/10.1016/j.ijnurstu.2019.06.006 https://doi.org/10.1016/j.ijnurstu.2019.06.006 https://doi.org/10.1016/j.jsurg.2014.02.010 https://doi.org/10.1016/j.jsurg.2014.02.010 https://doi.org/10.21315/eimj2017.9.2.4 nursing students’ perception and attitude towards objective structured clinical examination in oman 350 | squ medical journal, august 2022, volume 22, issue 3 11. qutishat mg, leocadio m, cayaban a. extent of test anxiety among nursing students in oman and impact on academic performance. j health sci nurs 2018; 3:11–25. 12. jahan f, shaikh n, norrish m, siddqi n, qasim r. comparison of student’s self-assessment to examiners assessment in a formative observed structured clinical examination: a pilot study. jpmi 2012; 27: 94–9. 13. small lf, pretorius l, walters a, ackerman m, tshifugula p. students’ perceptions regarding the objective, structured, clinical evaluation as an assessment approach. health sa 2013; 18:629–636. https://doi.org/10.4102/hsag.v18i1.629. 14. malik sl, manchanda sk, deepak kk, sunderam kr. the attitudes of medical students to the objective structured practical examination. med educ 1988; 22:40–6. https://doi.org/10.11 11/j.1365-2923.1988.tb00407.x. 15. al-zeftawy am, khaton se. student evaluation of an osce in community health nursing clinical course at faculty of nursing. tanta university. iosr j nurs health sci 2016; 5:68–76. https:// doi.org/10.9790/1959-0504036876. 16. al nazzawi aa. dental students’ perception of the objective structured clinical examination (osce): the taibah university experience, almadinah almunawwarah, ksa. j taibah univ med sci 2018; 13:64–9. https://doi.org/10.1016/j.jtumed.2017.09.002. 17. association of colleges of nursing. the essentials of baccal aureate education for professional nursing practice. from: http://www.aacnnursing.org/nursing-education-programs/ baccalaureate-education accessed: apr 2021. 18. chongloi n, thomas p, ara m, deepak kk. attitudes of under graduate nursing students toward objective structure practical examination: an exploratory study. int j nurs sci 2017; 4:68–72. https://doi.org/10.1016/j.ijnss.2016.12.003. 19. furlong e, fox p, lavin m, collins r. oncology nursing students’ views of a modified osce. eur j oncol nurs 2005; 9:351–9. https://doi.org/10.1016/j.ejon.2005.03.001. 20. saeed a, al suwayh wm, alomri as. students’ perceptions and attitudes towards objective structured clinical examination (osce) in the college of medicine, ksau-hs, king fahad medical city, riyadh, saudi arabia. j med sci clin res 2016; 4:9741–7. https://doi.org/10.18535/jmscr/v4i3.29. 21. shitu b, girma t. objective structured clinical examination (osce): examinee’s perception at department of pediatrics and child health, jimma university. ethiop j health sci 2008; 18:47–52. 22. khan a, ayub m, shah z. an audit of the medical students’ perceptions regarding objective structured clinical examination. educ res int 2016; 2016:4806398. https://doi.org/10.1155/2016/ 4806398. 23. massey d, byrne j, higgins n, weeks b, shuker ma, coyne e, et al. enhancing osce preparedness with video exemplars in undergraduate nursing students. a mixed method study. nurse educ today 2017; 54:56–61. https://doi.org/10.1016/j.nedt.20 17.02.024. 24. jay a. students’ perceptions of the osce: a valid assessment tool? br j midwifery 2007; 15:32–7. https://doi.org/10.12968/ bjom.2007.15.1.22677. 25. bani-issa w, al tamimi m, fakhry r, al tawil h. experiences of nursing students and examiners with the objective structured clinical examination method in physical assessment education: a mixed methods study. nurse educ pract 2019; 35:83–9. https://doi.org/10.1016/j.nepr.2019.01.006. 26. aung kt, binti zakaria an. nursing students’ perceptions on objective structured clinical examination (osce). perception 2016; 4:220–3. https://doi.org/10.4103/2321-7006.306243. https://doi.org/10.4102/hsag.v18i1.629 https://doi.org/10.11 11/j.1365-2923.1988.tb00407.x https://doi.org/10.11 11/j.1365-2923.1988.tb00407.x https://doi.org/10.9790/1959-0504036876 https://doi.org/10.9790/1959-0504036876 https://doi.org/10.1016/j.jtumed.2017.09.002 https://doi.org/10.1016/j.ijnss.2016.12.003 https://doi.org/10.1016/j.ejon.2005.03.001 https://doi.org/10.18535/jmscr/v4i3.29 https://doi.org/10.1155/2016/4806398 https://doi.org/10.1155/2016/4806398 https://doi.org/10.1016/j.nedt.20 17.02.024 https://doi.org/10.1016/j.nedt.20 17.02.024 https://doi.org/10.12968/bjom.2007.15.1.22677 https://doi.org/10.12968/bjom.2007.15.1.22677 https://doi.org/10.12968/bjom.2007.15.1.22677 https://doi.org/10.4103/2321-7006.306243 compliance of spectacle wear 39 compliance of spectacle wear and its determinants among schoolchildren of dhakhiliya region of oman: a descriptive study *rajiv khandekar1, ali jaffer mohammed2, abdulatif al raisi3 abstrac t. objective: to determine the degree of compliance of spectacle wear and some of its determinants among school children of dhakhiliya region of oman. methods: this was a cross-sectional descriptive study of a sample of 663 students who had been prescribed spectacles for constant wear. after one year, experienced field staff conducted a follow-up visit where 571 of these students were examined. information on age, gender, type and severity of refractive error was collected from the school health records and refractionist’s report and analyzed to associate them to the compliance of spectacle wear. results: the majority (71.6%) of students were using spectacles at the time of follow up. the compliance rate was 65.1% in boys and 78.3% in girls. agewise, it was 66.7% in 6–7-year-olds, 66.7% in 12–13-year-olds and 79.1% in 16–17-year olds. the rate was 72.5% among students with myopia and 67.9% among those with hypermetropia. the compliance of spectacle wear was significantly higher among students with myopic refractive error of 2.5 d or more compared to those with less than 2.5 d. the difference in the compliance rates among students with hypermetropia of different grades was not significant. conclusions: the study identifies the factors of high-risk of non compliance as (a) male gender, (b) younger age, and (c) low myopic refractory error. the eye health care program of oman should focus on these high risk groups to further improve the compliance for visual aids. key words: compliance, spectacle wear, schoolchildren, oman 1ophthalmologist-in-charge, eye & ear health care program, 2director general of health affairs, 3head of ophthalmic services, ministry of health, p o box: 393, postal code: 113, muscat, sultanate of oman *to whom correspondence should be addressed. email: rajshpp@omantel.net.om the world health organisation recom-mends monitoring the outcome of refractive services, using appropriate indicators for it and conducting operational research on the issue to achieve the goal of eliminating avoidable visual disability due to refractive error.1 sultanate of oman, one of the member countries of who, has about 40% of its population aged 6–8 years.2 refractive error in this age affects development of the children. hence, health initiatives for school children in oman include detection and management of this easily rectifiable problem. the eye health care program in oman provides refractive services to the students of first primary, first preparatory and first secondary grades on annual basis since 993.3 the students of these three grades are 6–7, 2–3 and 6–7 years old respectively. the refractionists visit schools once a year. and follow the guidelines for prescribing spectacles as recommended by who and adopted in oman. students with defective vision detected during screening are subjected to retinoscopy and subjective refraction testing using trial lenses. in case of students having hypermetropia, the refraction spectacle wear moh �������� ������� ���� ��� ������� � ������ �������� ������� ������� ��� ����� ������ ��������–����� ����� ��� � ���� ���� ��� ��������� ������������ ������ �������� :�����:������� �� ������� ���� ��� ������� ��� � ������ ������� ������� ������� ��� ����� ��� ������� ���� ����� ����� �� ��������.������� :�� ���� ��� ������ ������ ������ ����� �������� ��� ���� ����� ��� �� ��� ���� ������������ ��������� ����� ��� .��� �� ��� ������ ���� ������� ������ ��� �� ��� ���� ��� ����� ��� ������������� ��� � ������ �������� ��� ������ ������� ���� ���� � ��� ������ �������� ��� .������ � ������ ����� �������� ����� ���� ��� �� ��� � ����������� ����� .������ ������� ������� �������� ������� ��� ������ ��� ��� ������ �������� ����� ��.�������:������ ������ ��� ) ���� (%�������� ��� ������� ������ .������ ��� ������� ������� ������� ���� ��� �� �)���� (%����� � )���� .(%������ ���� ������� � ��� ������� %�� ���–�� ��������� %�� ����–��� ������� %�� ����–����� .������ ��� ������� %������ ��� � ����� ��� �� ������ ��������� %����� ��� �� ������ ����� ������ ���.���� ����� ������ ��� ������ ������� ������� ������� ��� ����� �� ����� ������d�� ��� ����� ��� �� ������ ����� ������ ���� ��� ���� �����d . ������ ��� ������� ���� ����� ������� ���� ���� �� ������ ������ ����� ��� �� ������ �����.������:������� ������� ���� ���� ���� ������ ������� ����� ������� ���������� ������� ����� ���� �������� ������� ���� �� ������ ����� ����� ���� ������� ���.������� ����� ������ ����� ��� ������ ��� ��� ������ �������� ������� ������� ������ ���� ������ ���� ������� . squ journal for scientific research: medical sciences 2002, vol 4, no –2, 39–43 ©sultan qaboos universit y 40 is performed under cycloplagia at an eye clinic. a child with myopia of more than –0.5 dioptre (d) or hypermetropia of more than +d are prescribed spectacles. all students with myopia of more than –5.0 d are also referred to ophthalmologist for retinal evaluation. a child with strabismus or amblyopia is also referred to ophthalmologist for further care. the dhakhiliya region of oman had 6,83 students in the first primary grade, 7,496 students in first preparatory grade and 5,492 students in first secondary grade with the prevalence of refractive error of 0.8%, 4.4% and 0.3% respectively during the academic year 2000–0. the rate of myopia was 0.3%, 3.7% and 8.7% respectively. the rate of hypermetropia was 0.4% at all three levels. although comprehensive eye care for children with refractive error is practised in oman, only limited information is available on the magnitude of the compliance for spectacle wear and their determinants. this information is crucial for the program to strengthen its efforts for eye care of children with refractive error. therefore, the eye health care programme established the system of follow up of students with refractive error to evaluate their compliance of spectacle wear. the school health nurse ensures that students who have been advised spectacles are counselled, and those referred to ophthalmologists are sent by the school transport. this study was carried out between january and april 200. it aimed to review the rate of the spectacle wear one year after advice to the school children of dhakhiliya region and identify the determinants of the non-compliance to visual aids. based on the outcomes, strategies to improve the compliance could be recommended. m e t h o d this was a cross sectional descriptive study. the school students of dhakhiliya region who were prescribed the spectacles during school year 999-2000 were the study population. a refractionist and the regional eye healthcare supervisor were the field investigators. they visited the schools and examined the students with refractive error. to minimise dropout, the school health staff was informed in advance regarding the dates and purpose of the follow up visit. revisit to cover absentees was not possible due to logistic problems. the students’ identity, age, gender, school level, type and severity of refractive error were noted. on the basis of reported age at three levels of school, the sample was divided into age groups of 6–7, 2–3 and 6–7 years. the field staff listed all students who had been advised spectacles and noted whether each student was wearing spectacles in the class or not. if a student had spectacles but was not wearing it, the student was considered as “not using visual aid”. the criteria of compliance used in this study were decided for its feasibility and as per the protocol of follow up.2 the data was computed and analysed using microsoft excel 2000. frequencies of students using spectacles and crude percentage proportions were calculated. univariate statistical model was used in this study. for each sub unit of school level, gender and wilayat (district), the number of compliant students were projected to the study population and adjusted rates were calculated for different variants by using direct standardisation method. the proportion of both male and female population in different regions that were documented in the demographic projections for the mid 20002 were taken as reference for direct method of standardisation. for the statistical validation, 95% cis were calculated. the width of the ci and the overlapping of the values, χ2 and p values were noted to determine the statistical significance. verbal consent of the school authorities was obtained on behalf of minor children, to undertake this non-invasive operational research. (in oman, school authorities can give consent on behalf of parents for including a child into a non-invasive operational research undertaken by health and school authorities.) permission to undertake this study was obtained from the ministry of health, both at regional and national levels. the students not wearing spectacles at the time of survey were again counselled and the school authorities were requested to discuss the issue with the parents so that the spectacles could be procured and used by the students. the study noted the compliance rate on the basis of one visit to school. the compliance of spectacle wear in relation to time can be assessed through frequent observation, which was not done in the present study. therefore, the reported compliance rate does not give picture of constant use of spectacles. r e s u l t s participation r ate six hundred and sixty three students who had been prescribed spectacles were the enumerated sample of the study. of them, 57 were examined. the participation rate was 86.%. the remaining 92 students (5 boys and 4 girls) (seven 6–7 year-old, forty five 2–3 yearold and forty 6–7-year-old) were absent on follow up visit or their family had migrated elsewhere. no student refused to participate. k h a n d e k a r e t a l 4 representativeness the profile of study sample by age group and gender is given in table . the participation rate was lower in 6–7year-old boys than girls. in other two age groups, boys had lower rates of participation than girls. direct agesex standardisation of the compliance rates was carried out. compliance r ate of we aring spec tacles the frequency, crude and adjusted rates of the compliance for spectacle wear along with 95% confidence interval (ci) are given in table 2. more than two thirds of the students who had been advised spectacles seemed to be using them after one year. girls had significantly higher compliance rates than boys. secondary students showed significantly higher compliance than preparatory students. compliance by t ype and severit y of refr ac tive error the frequency, crude and adjusted rates of the compliance for spectacle wear among myopics both of mild (<2.5 d) and severe (≥ 2.5d) grades and hypermetropics both of mild (<d) and severe (≥ d) grades are given in table 3. for comparison, χ2 and p values are also given. the compliance rate significantly differed by severity of myopia. d i s c u s s i o n evaluation of the impact of the ongoing refractive activities as recommended by who1 would not only help the program to determine the magnitude of the compliance of spectacle wear but also understand its determinants like age, gender, type and severity of refractive error. based on the outcome of this study, to strengthen the uptake of spectacle wear among students, recommendations could improve eye care of children with refractive error. the study had more than 85% coverage. the non table 1. profile of the study sample by gender and age age group (years) b oys girls enumerated examined (%) enumerated examined 6–7 15 13 (86.7%) 21 16 (76.2%) 12–13 100 74 (74.0%) 153 134 (87.6%) 16–17 160 137 (85.6%) 214 197 (92.1%) total 275 224 (81.5%) 388 347 (89.4%) table 2. compliance rates of spectacle-wear sub-group (examined sample) number of students wearing spectacles compliance rate (%) confidence interval (ci) 95% ci p crude adjusted male (n=224) 146 65.2 64.1 57.82 70.38 0.2072 female (n=388) 272 78.4 78.1 73.98 82.22 1st primary (n=29) 19 65.5 65.5 48.20 82.80 0.0004 1st preparatory (n=208) 134 64.4 64.4 57.89 70.91 1st secondary (n=334) 265 79.3 79.3 74.95 83.65 myopia (n=540) 397 73.5 72.5 68.73 76.27 0.4801 hypermetropia (n=31) 21 67.7 67.9 51.47 84.33 total (n=571) 418 73.2 72.3 68.63 75.97 c o m p l i a n c e o f s p e c ta c l e w e a r 42 participation was at random. with low rate of non participation and lack of evidence of systematic differential loss in the present study, the results are likely to be representative of the students with refractive error in dhakhiliya region during the study period. if all absentees are considered to be non-compliant, the rate of compliance could be considered as underestimation by 4%. this, however, is unlikely. the representation of different subgroups in the enumerated and examined sample differed. adjustments of the rates by gender and age group minimised the influence of these and other unknown confounders. involvement of only one team of field investigators minimised the inter-observer variation. the use of qualified personnel speaking the local language and working in the field since ten years minimised measurement error and also ensured cooperation of the students and school staff. the refractionist was a graduate optician. the sanitary inspector held a diploma in public health. both had fifteen years of field experience of eye care and conducting operational research. thus, the learning curve of the field staff is less likely to affect the study results. the use of school health booklets for information on students’ previous records, and the well-defined observation methodology reduced the chances of information bias in the study. standard data collection method and instrument, and matching it with the computer format prior to the study, minimised the loss of data and in data entry. the measurement criteria for the compliance of spectacle wear was stringent in this study. the assessment of dropouts of medical care attending a health institution is also evaluated strictly using the parameter of those attended on the day or not. similar measures were used in this study to determine the compliance of the spectacle wear. the compliance rate was above 70% among students with refractive error. in a uk study, the compliance to first-time spectacle wear by children aged less than eight years was 79.5%.4 another study in uk found that only two-thirds of 0-year-old children were using spectacles on follow up.6 a study in fiji had compliance rate of full-time spectacle wear of only 28% and occasional use of 35%.5 thus the compliance rate for using visual aids in the present study matched those observed in other studies except the one in fiji.. poor compliance of spectacle wear was more prevalent among boys than among girls. this is paradoxical, since girls, who are cosmetically more conscious, would be expected to avoid wearing spectacles. their head scarves that cover the ears should further discourage spectacle wear. as such, the higher compliance in girls is needs further investigation. poor compliance was more in younger children. the ability of older children to better understand the desirability of compliance, and the more precise visual needs for higher studies, could be the reasons. the attitude of the parents to delay or ignore advice for spectacles for their younger children might also cause differential compliance rate by age group. students in preparatory and secondary classes are provided health education by the health staff at the time of prescribing spectacles. they are also guided to procure their spectacles at subsidised rate from specified optical shops of the area. for primary school children, the health staff forwards prescriptions to the school authorities, who forward them to the parents. the different modes for younger and older children might have resulted in high compliance in secondary students compared to younger ones. for the younger children who do not procure their spectacles within reasonable time, parent-teacher meetings should be organised to discuss the table 3. compliance of spectacle wear by severity and type of refractive error sub-group (examined sample) number of students wearing spectacles compliance rate (%) confidence interval (ci) 95% ci p crude adjusted myopia of <2.5 d spectacles (n= 417) 292 70.0 68.9 64.8 73.1 0.0007 myopia of ≥2.5 d spectacles (n= 123) 105 85.4 85.1 81.7 88.5 hypermetropia of < +1 d (n=8) 6 75.0 74.1 45.4 99.9 0.6905 hypermetropia of ≥ +1 d (n=23) 15 65.2 64.0 47.1 80.9 k h a n d e k a r e t a l 43 issue of procurement and use of spectacles. due to small sample of primary school children with refractive error in the present study, the determinants of compliance with statistical significance in the younger age group could not be deduced. however, the study in uk revealed that fit of the spectacles and peer pressure/ response were the main factors affecting the compliance of spectacles wear in young children.4 myopia was more prevalent in the study group than other conditions. the compliance of spectacle wear was only marginally higher in students with myopia than those with hypermetropia, and the element of chance in this observation cannot be ruled out. comparison between these two groups is further detracted due to the much smaller sample size of students with hypermetropia. compliance rate was significantly higher among students afflicted with myopia of higher refractive error compared to those with lower error. age and gender could be confounders, but by direct age sex standardisation, their effect was minimised. since this condition is asymptomatic in many cases, students with myopia of less than 2.5 d could continue their daily activities with less difficulty. the students with severe grade of myopia might be more likely to be wearing spectacles, as it could affect their studies. c o n c l u s i o n the compliance of spectacle wear was high among students of dhakhiliya region. in spite of being advised and prescribed spectacles, male, younger students and those with myopia of less than 2.5d seem to be at higher risk of not using spectacles after one year. the programme aiming at reducing eye strain due to refractive error should further focus on these groups. the determinants for compliance of visual aid found in this study could be compared with other regions of oman and then polices for improving the refractive services could be revised accordingly. acknowledgement we acknowledge the support of the director general of health services of dhakhiliya region and the eye health care staff especially mr. n sarvanan and mr. khalfan al hadrami, for their sincere efforts. the cooperation of school authorities and students was crucial for the success of the study. we thank the ministry of health for permitting and encouraging the distribution of our findings to the scientific fraternity. r e f e r e n c e s . world health organization. elimination of avoidable visual disability due to refractive errors report on informal planning meeting who/pbl/00.79 pp2, 2000, 4, 46. 2. ministry of health. sultanate of oman annual health report for year 2000. 2001. 3. ministry of health. sultanate of oman eye health care manual 2nd edition, 2000. 4. horwood am. compliance with first time spectacle wear in children under eight years of age. eye, 998, 2, 73–78. 5. johnson b, yolton rl effectiveness of optometric aid to fiji, south pacific. j am optom assoc, 986, 57, 436–439. 6. stewart-brown s. spectacles prescribing among 10 year old children br j ophthalmol, 1985, 69, 874–880. 7. vitale s, schein od, meinert cl, et al. refractive status and vision profile: a questionnaire to measure vision related quality of life in persons with refractive error. ophthalmology, 2000, 07, 529–530. c o m p l i a n c e o f s p e c ta c l e w e a r departments of 1obstetrics & gynecology and 5medicine, 3college of medicine and health sciences, sultan qaboos university, muscat, oman; 2pharmacy department and 4department of obstetrics & gynecology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drriyami@hotmail.com abstract: objectives: this study was conducted to assess pregnancy outcomes in women with systemic lupus erythematosus (sle) in oman. methods: a retrospective cohort study of 149 pregnancies in 98 women with sle was conducted over 10 years to evaluate the impact of clinical and laboratory parameters in predicting adverse pregnancy outcomes. results: mean maternal age was 30.6 ± 5 years ranging from 20–44 years, and the mean disease duration was 10 ± 5 years, ranging from 2–27 years. the most common maternal manifestations were joint pain in 36 (24.2%), lupus nephritis (ln) in 18 (12.08%), preeclampsia in 11 (7.4%), eclampsia in three (2%) and lupus flare in one pregnancy. the live birth rate was 139 (93.3%) with a mean gestational age of 36 ± 2 weeks ranging from 26–40 weeks. in total, 55 (39.6%) were preterm deliveries, six (4%) pregnancies ended in miscarriage, and four (2.7%) resulted in intrauterine fetal death. intrauterine growth restriction was observed in 49 babies (35%). a significant association was found between hypertension (htn) and miscarriage (p = 0.024) and preterm birth (p = 0.019). in addition, htn was positively associated with preeclampsia (p = 0.004) and ln (p = 0.048). antiphospholipid syndrome impacted preterm birth (p = 0.013) and postpartem haemorrhage (pph) (p = 0.027) and was found to be a significant predictor for women developing deep vein thrombosis and pulmonary embolism (p <0.001 for both). conclusion: despite potential complications, most pregnancies complicated by sle in oman result in good outcomes. adverse pregnancy outcomes, however, may still occur in women with sle. in women with sle, pregnancy planning, careful antenatal monitoring and efficient sle treatment need to be undertaken for successful pregnancy outcomes. keywords: systemic lupus erythematosus; pregnancy outcomes; lupus nephritis; antiphospholipid antibodies; neonatal lupus. pregnancy outcomes in systemic lupus erythematosus women a single tertiary centre experience *nihal al-riyami,1 bushra salman,2 amani al-rashdi,3 tamima al-dughaishi,4 rahma al-haddabi,4 batool hassan5 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e244–252, epub. 21 jun 21 submitted 28 mar 20 revision req. 7 jun 20; revision recd. 8 jul 20 accepted 13 aug 20 https://doi.org/10.18295/squmj.2021.21.02.013 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. advances in knowledge the live birth rate of sle women was high and attributable to good disease control and patient care during pregnancy. pregnancy complications were low and were mainly associated with chronic hypertension and antiphospholipid syndrome. application to patient care the findings of this study will increase obstetricians’ awareness of sle and help them improve counselling and care in patients with sle. controlling sle activity and remission will help improve the outcomes for both mothers and neonates. systemic lupus erythematosus (sle) is a chronic, multi-system, connective tissue autoimmune disease which predominantly affects females of reproductive age. sle is characterised by a pattern of remission and relapse and occurs in approximately one per 1,000 women.1,2 the prevalence of sle has increased in the last few years due to improvements in disease diagnosis. according to a retrospective cohort study conducted in the uk using clinical practice research data (cprd) from between 1999 and 2012, the prevalence of sle increased from 64.99/100,000 in 1999 to 97.04/100,000 in 2012.3 because more than 90% of cases of sle occur in females of reproductive age, pregnancy is an important consideration in the progression of the disease.4 sle’s presentation varies from simple polyarth ralgia with a rash to a multi-organ life-threatening affliction.5,6 fertility rates in women with sle are not affected, but pregnancy in some circumstances can be associated with poor outcomes for both mother and fetus.7,8 pregnancy outcomes are usually affected by several factors in women with sle, including the presence of previous lupus nephritis (ln), antiphospholipid (apl) antibodies and maternal hypertension (htn), and the exacerbation of lupus activity during pregnancy.7 improvements in healthcare and medical discoveries in recent decades have improved sle patients’ quality of life (qol) including pregnancy outcomes.9 a systematic review and meta-analysis of pregnancy outcomes in patients with sle and ln conducted by the american society of nephrology in 2010 included 37 studies with 1,842 patients and 2,751 pregnancies. the results showed that the most common maternal https://creativecommons.org/licenses/by-nd/4.0/ clinical and basic research | e245 complications in pregnant women with sle were lupus flare (26%), htn (16%), nephritis (16%), preeclampsia (8%) and eclampsia (1%).10 fetal outcomes reported by the same study were spontaneous abortion (16%), neonatal death (3%), stillbirth (4%), intrauterine growth restriction (iugr; 13%) and premature birth (39%). finally, premature birth rate, active nephritis and increased htn rates in patients with active nephritis or a history of nephritis were found to increase the risk of adverse fetal and maternal outcomes. a positive and significant correlation was found between nephritis history and preeclampsia as well as apl antibodies and premature birth, and htn and an increased rate of induced abortions. both ln and anti-apl antibodies exacerbated both maternal htn and premature birth.10 understanding the association between sle and pregnancy is critical for healthcare providers in order to improve women’s care and pregnancy outcomes.7 the recommendations, therefore, are that pregnancies should be planned, sle should be in remission for a minimum of six months and medications should be adjusted prior to pregnancy.1 sultan qaboos university hospital (squh) is a tertiary hospital in oman with multiple specialties, including a rheumatology unit and an obstetrics and gynaecology department with a maternal medicine team. the hospital receives patients from all over oman, including far reaching areas, through the emergency department. since pregnant women with sle are mainly managed at two tertiary centres in oman, the aim of this study was to share experiences in managing those patients at squh. this study was conducted by evaluating maternal and fetal outcomes and complications in pregnant women with sle who were followed up and delivered at squh. this study aimed to determine risk factors that predict adverse outcomes for women with sle and their babies. methods a retrospective cohort study was conducted at squh from august 2006 to january 2016 and included 149 pregnancies in 98 women with sle which met the american college of rheumatology (acr) 1997 classification criteria.11 delivery and neonatal ward registries were reviewed after obtaining ethical approval from the ethics committee of the college of medicine and health sciences at sultan qaboos university (squ). pregnant women diagnosed with sle who were in remission were included in the study. all patients were on prednisolone, hydroxychloroquine and aspirin as a standard of care. they were closely monitored during pregnancy with close follow-ups by maternal medicine specialists and rheumatologists who looked for symptoms and signs of lupus flare and adverse pregnancy outcomes. patients with missing data, who delivered elsewhere, with disease activity just prior to pregnancy or who had been diagnosed with sle during pregnancy were excluded from the study. collected maternal demographics included age, gravidity, parity, duration of disease, history of deep vein thrombosis (dvt), pulmonary embolism (pe), diabetes mellitus (dm), htn, previous miscarriages, caesarean section (cs) and intrauterine fetal death (iufd). laboratory characteristics collected included anti-sjögren syndrome-a (ssa)/anti-ro, anti sjögren syndrome-b (ssb)/anti-la, lupus anticoagulant (lac), anti-cardiolipin antibody (acl), anti-beta-2 glycoprotein 1 antibodies (anti-b2gp1), anti-double stranded deoxyribonucleic acid (anti-dsdna), antinuclear antibody (ana), c-reactive protein (crp), complement 3 (c3), complement 4 (c4) and vitamin d3 levels. maternal outcomes reviewed included mode of delivery, gestational age at delivery and obstetrical complications. complications included preeclampsia (i.e. gestational htn with proteinuria), eclampsia (i.e. gestational htn followed by one or more convulsions or coma as a consequence of convulsion), antepartum haemorrhage (aph) (i.e. prepartum bleeding starting from 22 gestational weeks) and postpartum haemorrhage (pph) (i.e. 500–1000 ml or more of blood lost within 24 hours following delivery).12–15 disease manifestations reviewed included sle flare, ln, the presence of antiphospholipid syndrome (aps), joint pain and involvement of other organs such as the heart. fetal outcomes included miscarriage before 20 gestational weeks, iufd or iugr with an estimated fetal weight less than the tenth centile, birth weight, apgar scores, admission to the neonatal intensive care unit (nicu), congenital heart block, prematurity and neonatal lupus. descriptive statistics were used to summarise data. mean and standard deviation (sd) were used for continuous variables. for categorical variables, frequencies and percentages were reported. continuous variables were analysed using student’s t-test where the distribution was normal. a chi-squared test was used to evaluate the impact of clinical and laboratory characteristics on maternal and fetal outcomes. for cell frequencies ≤5, fisher's exact test was used. significant predictors of adverse pregnancy outcomes (i.e. miscarriage, cs, prematurity, iufd, sle flare, ln, joint pain, dvt, pe, preeclampsia, eclampsia, aph and pph) were further analysed using multivariable logistic nihal al riyami, bushra salman, amani al rashdi, tamima al dughaishi, rahma al haddabi and batool hassan regression and odds ratios (or) with 95% confidence intervals (ci). each pregnancy was considered a separate observation. in all cases, a p-value of <0.05 was considered statistically significant. all statistical analyses were performed using stata, version 13 (statacorp, college station, texas, usa). results in total, 149 pregnancies in 98 women with sle were studied. mean maternal age was 30.6 ± 5 years (range: 20–44), and the mean disease duration was 10 ± 5 years (range: 2–27). according to the sledai index, all patients were in clinical remission. previous pregnancy complications included miscarriages (n = 50; 33.56%), iufd (n = 24; 16.22%), cs (n = 38; 25.50%), dvt (n = 19; 12.75%), pe (n = 9; 6.04%), preeclampsia (n = 8; 5.41%) and eclampsia (n = 2; 1.35%) [table 1]. clinical manifestations of sle across the current pregnancies included arthritic joint pain (n = 36; 24.2%), ln (n = 18; 8%), preeclampsia (n = 11; 7.4%) and eclampsia (n = 3; 2%). aph and pph were seen in two (1.3%) and eight (5.4%) pregnancies, respectively. only one patient had lupus flare. this patient presented with joint pain at 23 gestational weeks and was managed with high-dose prednisolone. the patient was a 21-year-old primigravida with known sle for two years. her disease was in remission. unfortunately, she experienced iufd at 26 gestational weeks [table 2]. laboratory investigations were also considered. positive ana was found in 83 (56%) and positive anti-dsdna antibodies in 80 (54%) pregnancies. crp was elevated in 53 (36%) pregnancies. antissa and anti-ssb were positive in 68 (48.57%) and 15 (10.87%) pregnancies, respectively. in total, 25 patients (16.78%) had documented secondary aps prior to the current pregnancy. positive anti-beta-2 glycoprotein1 antibodies were seen in 17 (11%) pregnancies as igm antibodies while igg was found in two (1.34%) pregnancies. eight (5.37%) women were acl igg positive while nine (6.04%) pregnancies were acl igm positive. in addition, seven (4.70%) pregnancies had positive lac. furthermore, c3 and c4 were below the normal level in about 21 (14.09%) and seven (5%) pregnancies, respectively, but these patients were asymptomatic for lupus flare. regarding table 1: maternal demographics of patients diagnosed with systemic lupus erythematosus who presented at sultan qaboos university hospital from august 2006 to january 2016 (n = 149) variable number of pregnancies percentage range (mean; sd) age 20–44 (30.6; 5) gravidity 1–12 (3.8; 2.4) parity 0–8 (2; 1.7) history of miscarriages 50 33.56 history of dvt 19 12.75 history of pe 9 6.04 history of dm 51 34.46 history of htn 18 12.16 history of cs 38 25.50 history of preeclampsia 8 5.41 history of eclampsia 2 1.35 history of iufd 24 16.22 ln 18 12.08 sd = standard deviation; dvt = deep vein thrombosis; pe = pulmonary embolism; dm = diabetes mellitus; htn = hypertension; cs = caesar ean section; iufd = intrauterine fetal death; ln = lupus nephritis. table 2: current pregnancy outcomes of patients diagnosed with systemic lupus erythematosus who presented at sultan qaboos university hospital from august 2006 to january 2016 (n = 149) variable number of pregnancies percentage neonatal outomes live delivery 139 93.3 miscarriage 6 4.0 iufd 4 2.7 mode of delivery cs 47 33.8 svd 89 64 assisted 3 2.2 preterm delivery (<37 weeks) 55 39.6 eclampsia 3 2.0 preeclampsia 11 7.4 aph 2 1.3 pph 8 5.4 joint pain 36 24.2 dvt 26 17.0 pe 11 7.4 worsening ln 18 8.0 iufd = intrauterine fetal death; cs = caesarean section; svd = spontaneous vaginal delivery; aph = antepartum haemorrhage; pph = post-partum haemorrhage; dvt = deep vein thrombosis; pe = pulmonary embolism; ln = lupus nephritis. pregnancy outcomes in systemic lupus erythematosus women a single tertiary centre experience e246 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e247 table 3: association of laboratory parameters and maternal lupus disease activity with adverse pregnancy outcomes (n = 149) clinical and lab findings adverse pregnancy outcomes mc fetal loss iufd ptb cs ln joint pain aph pph e pre-e dvt pe htn yes (n = 18) 3 3 0 12 9 5 1 0 3 0 5 4 0 no (n = 130) 3 7 4 47 42 13 35 18 5 3 6 21 14 p value 0.024 0.105 1.0 0.019 0.139 0.048 0.074 1.0 0.058 1.0 0.004 0.509 0.219 dm yes (n = 51) 4 5 1 16 18 9 9 1 3 0 2 14 8 no (n = 97) 2 5 3 43 33 9 27 1 5 3 9 11 6 p value 0.182 0.314 1.0 0.074 1.0 0.185 0.227 1.0 1.0 0.551 0.331 0.013 0.061 aps yes (n = 25) 3 4 1 16 10 2 6 0 4 0 1 8 5 no (n = 124) 3 6 3 44 41 16 30 2 4 3 10 18 9 p value 0.059 0.064 0.524 0.013 0.505 0.739 0.984 1.0 0.027 1.0 0.691 <0.001 <0.001 ssa/ anti-ro positive (n = 68) 1 2 1 33 18 7 18 0 4 3 7 9 3 negative (n = 72) 5 7 2 25 32 10 18 2 4 0 2 15 9 missing (n = 9) p value 0.108 0.09 1.0 0.106 0.027 0.609 0.842 0.497 1.0 0.112 0.09 0.233 0.130 ssb/ anti-la positive (n = 15) 0 0 0 7 2 1 6 0 1 0 0 1 2 negative (n = 123) 6 9 3 49 46 16 30 2 7 3 9 23 10 missing (n = 11) p value 1.0 0.597 0.612 0.704 0.085 0.694 0.194 1.0 1.0 1.0 0.597 0.469 0.620 low c3 yes (n = 21) 0 0 0 11 13 3 9 0 1 2 5 2 1 no (n = 122) 6 9 3 48 36 15 25 2 7 1 5 24 12 missing (n = 6) p value 0.592 0.357 1.0 0.22 0.004 0.730 0.026 1.0 1.0 0.056 0.007 0.265 0.692 dsdna positive (n = 80) 1 3 2 14 33 9 23 1 3 3 9 9 9 negative (n = 43) 4 4 0 36 7 5 7 1 4 0 1 7 3 missing (n = 26) p value 0.05 0.238 0.542 0.156 0.005 1.0 0.125 1.0 0.238 0.551 0.163 0.429 0.539 lac positive (n = 7) 1 2 1 1 4 0 0 0 1 0 0 2 1 negative (n = 126) 4 7 3 50 40 13 31 2 7 3 10 22 13 missing (n = 16) p value 0.240 0.072 0.197 0.245 0.219 1.0 0.134 1.0 0.359 1.0 1.0 0.609 0.550 b2gp1 igg positive (n = 2) 0 0 0 1 0 0 1 0 1 0 0 1 0 negative (n = 106) 5 7 2 43 34 10 21 1 6 3 11 19 11 missing (n = 41) p value 1.0 1.0 1.0 1.0 1.0 1.0 0.367 1.0 0.126 1.0 1.0 0.337 1.0 igm positive (n = 17) 1 2 1 11 6 1 2 0 3 0 1 5 3 mc = miscarriage; iufd = intrauterine fetal death; ptb = preterm birth; cs= caesarean section; ln = lupus nephritis; aph = antepartum haemorrhage; pph = postpartum haemorrhage; e = eclampsia; pre-e = preeclampsia; dvt = deep vein thrombosis; pe = pulmonary embolism; htn = hypertension; dm = diabetes mellitus; aps = antiphospholipid syndrome; ssa = sjögren syndrome-a; ssb = sjögren syndrome-b; c3 = complement 3; dsdna = double stranded dna; lac = lupus anticoagulant ; b2gp1 = beta-2 glycoprotein 1 antibodies; aca = anti-cardiolipin antibody; igg = immunoglobulin g; igm = immunoglobulin m. nihal al riyami, bushra salman, amani al rashdi, tamima al dughaishi, rahma al haddabi and batool hassan vitamin d3 level, 80 (53.69%) women were deficient (vitamin d [25-oh] <50 nmol/l) while 52 (34.9%) were insufficient (vitamin d [25-oh] 50–75 nmol/l). out of 149 pregnancies, 139 (93.3%) were live births, six (4.02%) ended in a miscarriage and four (2.7%) were complicated by iufd between 26–28 gestational weeks. of the live births, 92 (66.1%) were vaginal deliveries and 47 (33.8%) were through cs mainly for obstetrical reasons, including previous css, severe preeclampsia or eclampsia. the mean gestational age at delivery was 36 ± 2 (range: 26–40) weeks. a total of 55 (39.6%) deliveries were preterm (i.e. <37 gestational weeks). of those pregnancies, 35 (63.6%) occurred late preterm (i.e. >34 gestational weeks). out of the 92 vaginal deliveries, 89 (96.7%) were spontaneous while the other three (2.2%) were assisted vaginal deliveries via forceps or a vacuum device due to either non-reassuring fetal heart rate patterns on cardiotocogram or maternal exhaustion [table 2]. the association between clinical and laboratory markers of disease in pregnant women with sle and certain adverse pregnancy outcomes was analysed [table 3]. age was not a predictor for any of the adverse pregnancy outcomes. the association between preexisting htn during the current pregnancy and several pregnancy outcomes was assessed. significant associations were found between htn and miscarriage (p = 0.024) and preterm birth (p = 0.019). in addition, htn was positively associated with preeclampsia (p = 0.004) and ln (p = 0.048). dm was found to significantly affect the risk of dvt (p = 0.013) and increase pe risk, but this finding was not statistically significant (p = 0.061). women who had three or more previous miscarriages had a higher risk of miscarriage in the current pregnancy (4/13 with recurrent miscarriage versus 2/129 without recurrent miscarriage) (or = 19.8, 95% ci = 2.5–228.9; p = 0.0016). aps impacted preterm birth (p = 0.013) and pph (p = 0.027) and was found to be a significant predictor for developing dvt and pe (p <0.001 for both). all patients with aps received low dose aspirin and prophylactic doses of low molecular weight heparin (enoxaparin). on studying the impact of anti sjögren’s syndrome antibodies on adverse maternal outcomes, no clear influence was found for either anti-ssa or anti-ssb on any adverse pregnancy outcomes except table 3 (cont’d): association of laboratory parameters and maternal lupus disease activity with adverse pregnancy outcomes clinical and lab findings adverse pregnancy outcomes mc fetal loss iufd ptb cs ln joint pain aph pph e pre-e dvt pe b2gp1 negative (n = 96) 4 5 1 34 33 11 21 1 4 3 10 15 8 missing (n = 33) p value 0.565 0.283 0.279 0.03 0.941 0.690 0.517 1.0 0.068 1.0 1.0 0.179 0.367 aca igg positive (n = 8) 0 1 1 5 0 0 1 0 3 0 0 3 2 negative (n = 106) 5 7 2 40 37 10 26 1 4 3 9 18 11 missing (n = 35) p value 1.0 0.452 0.198 0.266 0.052 1.0 0.678 1.0 0.007 1.0 1.0 0.163 0.226 igm positive (n = 9) 0 1 1 7 4 0 1 0 2 0 1 2 2 negative (n = 111) 5 7 2 40 39 12 27 1 5 3 8 19 11 missing (n = 29) p value 1.0 0.475 0.210 0.029 0.720 0.596 0.683 1.0 0.087 1.0 0.517 0.656 0.252 vitamin d3 deficient (n = 80) 3 4 1 33 22 5 22 1 5 2 8 15 7 sufficient (n = 52) 5 5 2 21 24 9 11 0 1 1 2 8 6 missing (n = 17) p value 0.680 0.316 0.561 0.850 0.039 0.079 0.411 1.0 0.402 1.0 0.314 0.618 0.599 mc = miscarriage; iufd = intrauterine fetal death; ptb = preterm birth; cs= caesarean section; ln = lupus nephritis; aph = antepartum haemorrhage; pph = postpartum haemorrhage; e = eclampsia; pre-e = preeclampsia; dvt = deep vein thrombosis; pe = pulmonary embolism; htn = hypertension; dm = diabetes mellitus; aps = antiphospholipid syndrome; ssa = sjögren syndrome-a; ssb = sjögren syndrome-b; c3 = complement 3; dsdna = double stranded dna; lac = lupus anticoagulant ; b2gp1 = beta-2 glycoprotein 1 antibodies; aca = anti-cardiolipin antibody; igg = immunoglobulin g; igm = immunoglobulin m. pregnancy outcomes in systemic lupus erythematosus women a single tertiary centre experience e248 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e249 for an association between anti-ssa/anti-ro and a lower risk of cs (p = 0.027). the study showed a significant association between low c3 levels and preeclampsia (p = 0.007) and a trend towards an increased risk of eclampsia which was just below the level of significance (p = 0.056). in addition, low c3 levels were associated with increased risk of cs (p = 0.004) and joint pain (p = 0.026). while studying the impact of high anti-dsdna level on adverse maternal outcomes, a significant association with miscarriage (p = 0.05) and cs (p = 0.005) was reported. positive lac anti-b2gp1-igg was not associated with adverse outcomes. on the contrary, anti-b2gp1-igm was significantly associated with preterm birth (p = 0.03) and caused a higher risk of pph, but the association was not statistically significant (p = 0.068). the only significant associations between adverse outcomes and acl antibodies were between acl-igg and pph (p = 0.007) and between acl-igm and pre-term birth (p = 0.029). vitamin d levels did not influence pregnancy outcomes except for an unexpected association of higher vitamin d levels (>50 nmol/l) with a higher risk of cs (p = 0.039). using multivariable regression of the main adverse outcomes of pregnancy, miscarriage was found to be significantly predicted by htn (or = 25.8, 95% ci = 2.8–231.3; p = 0.004) and dsdna (or = 0.07, 95% ci = 0.005–0.81; p = 0.034). prematurity was determined by htn (or = 4.2, 95% ci = 1.2–14.9; p = 0.026), aps (or = 3.8, 95% ci = 1.2–11.9; p = 0.022) and acl-igm (or = 4.1, 95% ci = 0.8–26.7; p = 0.091) but not by anti-b2gp1-igm (or = 0.8, 95% ci = 0.2–3.4; p = 0.789). multivariable analysis showed that cs risk was only influenced by positive anti-dsdna (or = 4.7, 95% ci = 1.4–15.4; p = 0.048) and higher vitamin d levels (or = 2.8, 95% ci = 1.2–6.8; p = 0.02). pph had a significant association only with acl-igg (or = 10.7, 95% ci = 1.7–67.6; p = 0.012). preeclampsia was almost equally determined by both htn and low c3, with ors of 14.4 and 15.3, respectively (95% ci = 2.4–86.3 and 2.8–85.2, respectively) and p-values of 0.003 and 0.002, respectively. dvt was found to correlate with dm (or = 8.9, 95% ci = 1.9–42.8; p = 0.006) and aps (or = 87.2, 95% ci = 17.8–427.7; p <0.001). as discussed above, prematurity was seen in 50 babies, and four suffered an iufd. mean birth weight in the study sample was 2.72 ± 0.673 kg; range: 0.525–4.25 kg). iugr was observed in 49 babies (35%) mainly due to preterm birth (n = 34). in total, 11 newborns had an apgar score of less than seven at one minute, and only three had a score of less than seven at five minutes. about one-third of the neonates (n = 45; 33%) were admitted to the neonatal intensive care unit (nicu) due to respiratory distress, neonatal sepsis or prematurity and one neonate suffered from intraventricular haemorrhage. no neonatal lupus or congenital heart block was seen in the study sample. aps significantly predicted prematurity (p = 0.013). fetal loss was also found to be higher in patients with aps and among those who were lac positive, but the associations did not reach statistical significance (p = 0.064 and 0.072, respectively). discussion this study looked into various pregnancy outcomes and predictors that resulted in complications. in this study, most pregnancies (93.3%) resulted in live births. the incidence of live births in pregnancies complicated by sle was reported as ranging from 72–89% in larger studies done in argentina and north america.16,17 in contrast, an egyptian study reported a much lower incidence (45–50%).9 the higher live birth rate in this study could be attributed to good disease control but could also be due to the fact that the current patients were in clinical remission before conception except for one case who was in flare during pregnancy, and that case resulted in iufd. most pregnancies ended with a normal vaginal delivery (64%), while 33.8% were delivered by cs and 4% resulted in miscarriage. preterm delivery occurred in 39.6% of the pregnancies and mostly in late preterm after 34 gestational weeks. in a previous prospective study in california that included 91 sle pregnancies, a higher rate of cs deliveries (53%) was seen, while only 32% had a normal vaginal delivery.9 a similar rate of preterm birth was reported in previous studies, with the rate reaching up to 54%.7,9,18 the current results showed six cases of miscarriage (4%). a miscarriage incidence of 11–24% was reported in sle pregnancies in a prospective study in france.19 on the other hand, a range of fetal loss rates were reported in rheumatic disease clinics in north america, with cases occurring in 10% of mild ln cases and in up to 60% of severe cases.16,20 in contrast, this study found four (2.7%) women with fetal loss and only one of the women had ln. in general, the fetal loss rate is comparable to healthy women (8–12%) for women with inactive sle at conception.21 despite improvements in pregnancy management in patients with sle, adverse pregnancy outcomes and higher perinatal morbidity and mortality risk are still noticed in comparison with pregnant women without sle, even among those who are in clinical remission.16,18,22 in this retrospective cohort study, preeclampsia was observed in 7.4% of the patients while ranges from 3–26% were reported in similar studies in argentina.19 nevertheless, only 2% of the current patients progressed to eclampsia. the current nihal al riyami, bushra salman, amani al rashdi, tamima al dughaishi, rahma al haddabi and batool hassan study reported 12.08% of patients with ln during pregnancy while another similar study reported higher rates (21%).9 this variation might be explained by good disease and htn control in the current patient cohort. autoantibodies and ana serve as key diagnostic and classification criteria for sle, with the latter being recently used as entry criteria for diagnosing sle.23,24 ana was detected in only 56% of the current cohort, which is lower than expected. this finding could be explained by low numbers in the cases studied, variability in testing protocols, type of assay used or not repeating the testing. a recent study concluded that ana is not always found in sle patients.25 the researchers reported negative and fluctuating ana results in 36.9% and 33.3% of patients, respectively. another study found ana positivity in only 23.7% of patients.26 this study examined various predictors that resulted in adverse pregnancy outcomes. a significant association was found between htn and miscarriage, preterm birth, pre-eclampsia and ln. similarly, a study done at the university of california davis school of medicine reported a significant association between htn and miscarriage as well as preterm birth (p = 0.001 and 0.017, respectively).8 an increased risk of developing preeclampsia and ln was also found in previous studies.9,27 aps is frequently seen in patients with sle and may result in various pregnancy-related complications. aps was found in 16.78% of the pregnancies in the current cohort. similarly, a meta-analysis reported its presence in approximately one-quarter of the pregnancies in which the mother had been diagnosed with lupus.10 the presence of aps is strongly associated with the development of dvt, pe and fetal loss but, in the current study, the latter did not reach statistical significance. previous studies have reported similar outcomes.5,9,28 an italian study correlated aps with prematurity and this correlation was also observed in the current study.1 in addition, aps was associated with pph in the current cohort which could be attributed to antithrombotic treatment; such a correlation, however, was not reported in previous studies.29,30 a study conducted in mexico of 1,334 pregnant women with sle reported low c3 levels in almost 50% of the patients.31 this finding is considered a very high incidence in comparison with the current finding as only 14.09% of the current cohort had low c3 levels. patients with low c3 levels were more likely to deliver via cs, but this observation could be related to obstetrical indications. more research is needed in order to establish the possibility of a causal relationship. preeclampsia in the current study was exacerbated by low c3 level. patients with low c3 level were 15 times more likely to develop preeclampsia than those with normal c3 levels (or = 15.3). in contrast, other studies have shown positive associations between preexisting renal disease and htn.7 this finding was not present in the current study probably because of a limited sample size. in comparison, eclampsia was only present with a decreased level of c3 (p = 0.035). the presence of anti ro/ssa and anti la/ssb antibodies has been associated with neonatal lupus and congenital heart block (chb) in previous studies.32,33 none of the current neonates, however, had neonatal lupus or chb, perhaps due to the finding that maternal antibodies were low in this cohort. in addition, the current patients were on hydroxychloroquine, which is usually associated with a lower risk of chb.34,35 this study successfully detected factors that can be used as indicators to determine women with sle who might be at risk of adverse pregnancy outcomes. a significant relationship was found between htn and preterm birth, preeclampsia, ln and miscarriage. these findings along with those of other practitioners can be used to establish guidelines to help doctors treat and manage pregnant women with sle, thus resulting in successful outcomes. this study has multiple limitations including a small sample size which is due to the small population in oman compared to other countries and the fact that it was conducted in a single tertiary centre. however, the study was sufficiently powered (85%) to detect a rate of preeclampsia of up to 22.5% and predict the effect of htn on preeclampsia. in total, 45% of hypertensive women in the current study developed preeclampsia. a significant drawback was that this study did not look at sle pharmacological management and its relation to various pregnancy outcomes. finally, a comparative study with healthy pregnant women is recommended to solidify knowledge and guideline development. conclusion although most pregnancies complicated by sle have good outcomes, adverse outcomes may still occur in women with sle. planning pregnancies and careful pregnancy monitoring coupled with efficient treatment need to be enhanced for successful outcomes. further studies which include larger sample sizes and multiple centres caring for women with sle are recommended. a c k n o w l e d g e m e n t the abstract was submitted and presented at the 22nd figo conference, rio de janeiro, brazil, 14–19 october 2018. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. pregnancy outcomes in systemic lupus erythematosus women a single tertiary centre experience e250 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e251 f u n d i n g no funding was received for this study. references 1. andreoli l, fredi, m, nalli c, reggia r, lojacono a, motta m et.al. pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome. j autoimmun. 2012; 38:j197–j208. https://doi.org/10.1016/j.jaut.2011.11.010. 2. mecacci f, pieralli a, bianchi b, paidas m. the impact of auto immune disorders and adverse pregnancy outcome. semin perinatol 2007; 31:223–6. https://doi.org/10.1053/j.semperi.2007.05.005. 3. rees f, doherty m, grainge m, davenport g, lanyon p, zhang w. the incidence and prevalence of systemic lupus erythematosus in the uk, 1999-2012. ann rheum dis 2016; 75:136–41. https://doi.org/10.1136/annrheumdis-2014-206334. 4. clowse me, jamison m, myers e, james ah. a national study of the complications of lupus in pregnancy. am j obstet gynecol 2008; 199:127:e1–6. https://doi.org/10.1016/j.ajog.2008.03.012. 5. porth, c, gaspard k. essentials of pathophysiology, 1st ed. philadelphia: wolters kluwer, 2015. 6. gómez-puerta j, cervera r. diagnosis and classification of the antiphospholipid syndrome. j autoimmun 2014; 48–49:20–25. https://doi.org/10.1016/j.jaut.2014.01.006. 7. chakravarty e, colón i, langen es, nix da, el-sayed yy, genovese mc, et al. factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. am j obstet gynecol 2005; 192:1897–1904. https://doi.org/10.1016/j.ajog.2005.02.063. 8. borchers a, naguwa s, keen c, gershwin m. the implications of autoimmunity and pregnancy. j autoimmun 2010; 34:j287–99. https://doi.org/10.1016/j.jaut.2009.11.015. 9. aly eah, riyad mr, mokbel an. pregnancy outcome in patients with systemic lupus erythematosus: a single center study in the high risk pregnancy unit. middle east fertil soc j 2016; 21:168–74. https://doi.org/10.1016/j.mefs.2015.12.003. 10. smyth a, oliveira g, lahr b, bailey k, norby s, garovic v. a systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. clin j amer soc nephrol 2010; 5:2060–8. https://doi. org/10.2215/cjn.00240110. 11. hochberg m.c. updating the american college of rheumatology revised criteria for the classification of systemic lupus erythe matosus. arthritis rheum 1997; 40:1725. https://doi.org/10.1002/ art.1780400928. 12. nhs.uk. pre-eclampsia—nhs choices. from: www.nhs.uk/ conditions/pre-eclampsia/pages/introduction.aspx accessed: jul 2020. 13. healthline. eclampsia. from: www.healthline.com/health/ecla mpsia. accessed: mar 2017. 14. rosalba giordano m. antepartum haemorrhage. from: www. ncbi.nlm.nih.gov/pmc/articles/pmc3263934/ accessed: jul 2020. 15. emedicine medscape. postpartum hemorrhage: background, problem, epidemiology. from: emedicine.medscape.com/articl e/275038-overview accessed: jul 2020. 16. lateef a, petri m. systemic lupus erythematosus and pregnancy. rheumatic dis clin north amer 2017; 43: 215–26. 17. cavallasca j, laborde h, ruda-vega h, nasswetter g. maternal and fetal outcomes of 72 pregnancies in argentine patients with systemic lupus erythematosus (sle). clinical rheumatol 2007; 27:41–6. https://doi.org/10.1007/s10067-007-0649-3. 18. pastore dea, costa ml, surita fg. systemic lupus erythe matosus and pregnancy: the challenge of improving antenatal care and outcomes. lupus 2019; 28:1417–26. https://doi. org/10.1177/0961203319877247. 19. huong d, wechsler b, vauthier-brouzes d, beaufils h, lefebvre g, piette j. pregnancy in past or present lupus nephritis: a study of 32 pregnancies from a single centre. ann rheum dis 2001; 60:599–604. https://doi.org/10.1136/ard.60.6.599. 20. dhar j, essenmacher l, ager j, sokol r. pregnancy outcomes before and after a diagnosis of systemic lupus erythematosus. am j obstet gynecol 2005; 193:1444–55. 21. yan yuen s, krizova a, ouimet jm, pope je. pregnancy outcome in systemic lupus erythematosus (sle) is improving: results from a case control study and literature review. open rheumatol j 2008; 2:89–98. https://doi.org/10.2174/187431290 0802010089. 22. phansenee s, sekararithi r, jatavan p, tongsong t. pregnancy outcomes among women with systemic lupus erythematosus: a retrospective cohort study from thailand. lupus 2018; 27:158–64. https://doi.org/10.1177/0961203317721353. 23. aringer m, costenbader k, daikh d, brinks r, mosca m, ramsey-goldman r, et al. 2019 european league against rheumatism/american college of rheumatology classification criteria for systemic lupus erythematosus. arthritis rheumatol 2019; 71:1400–12. https://doi.org/10.1002/art.40930. 24. fritzler mj, choi my. autoantibodies in sle: prediction and the p value matrix. lupus 2019; 28:1285–93. https://doi. org/10.1177/0961203319868531. 25. tarazi m, gaffney rg, kushner cj, chakka s, werth vp. cutaneous lupus erythematosus patients with a negative antinuclear antibody meeting the american college of rheum atology and/or systemic lupus international collaborating clinics criteria for systemic lupus erythematosus. arthritis care res (hoboken) 2019; 71:1404–9. https://doi.org/10.1002/ acr.23916. 26. yavuz go, yavuz ih, bayram i, aktar r, bilgili sg. clinic experience in discoid lupus erythematosus: a retrospective study of 132 cases. adv dermatol allergol 2019; xxxvi:739–43. https://doi.org/10.5114/ada.2018.77726. 27. maynard s, guerrier g, duffy m. pregnancy in women with systemic lupus and lupus nephritis. adv chronic kidney dis 2019; 26:330–7. https://doi.org/10.1053/j.ackd.2019.08.013. 28. do prado ad, piovesan dm, staub hl, horta bl. association of anticardiolipin antibodies with preeclampsia: a systematic review and meta-analysis. obstet gynecol 2010; 116:1433–43. https://doi.org/10.1097/aog.0b013e3181fe02ec. 29. yelnik cm, lambert m, drumez e, le guern v, bacri j-l, laskin ca, et al. bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome. lupus 2018; 27:1679–86. https://doi.org/10.1177/0961203318787032. 30. rezk m, dawood r, badr h. maternal and fetal outcome in women with antiphospholipid syndrome: a three-year observ ational study. j matern fetal neonatal med 2016; 29:4015–9. https://doi.org/10.3109/14767058.2016.1152254. 31. de jesus gr, mendoza-pinto c, de jesus nr, dos santos fc, klumb em, carrasco mg, et al. understanding and managing pregnancy in patients with lupus. autoimmune dis 2015; 2015:943490:1–18. https://doi.org/10.1155/2015/943490. 32. jaeggi e, laskin c, hamilton r, kingdom j, silverman e. the importance of the level of maternal anti-ro/ssa antibodies as a prognostic marker of the development of cardiac neonatal lupus erythematosus: a prospective study of 186 antibody-exposed fetuses and infants. j amer col cardiol 2010; 55:2778–84. https://doi.org/10.1016/j.jacc.2010.02.042. nihal al riyami, bushra salman, amani al rashdi, tamima al dughaishi, rahma al haddabi and batool hassan https://doi.org/10.1016/j.jaut.2011.11.010 https://doi.org/10.1053/j.semperi.2007.05.005 https://doi.org/10.1136/annrheumdis-2014-206334 https://doi.org/10.1016/j.ajog.2008.03.012 https://doi.org/10.1016/j.jaut.2014.01.006 https://doi.org/10.1016/j.ajog.2005.02.063 https://doi.org/10.1016/j.jaut.2009.11.015 https://doi.org/10.1016/j.mefs.2015.12.003 https://doi.org/10.2215/cjn.00240110 https://doi.org/10.2215/cjn.00240110 https://doi.org/10.1002/art.1780400928 https://doi.org/10.1002/art.1780400928 https://doi.org/10.1007/s10067-007-0649-3 https://doi.org/10.1177/0961203319877247 https://doi.org/10.1177/0961203319877247 https://doi.org/10.1136/ard.60.6.599 https://doi.org/10.2174/1874312900802010089 https://doi.org/10.2174/1874312900802010089 https://doi.org/10.1177/0961203317721353 https://doi.org/10.1002/art.40930 https://doi.org/10.1177/0961203319868531 https://doi.org/10.1177/0961203319868531 https://doi.org/10.1002/acr.23916 https://doi.org/10.1002/acr.23916 https://doi.org/10.5114/ada.2018.77726 https://doi.org/10.1053/j.ackd.2019.08.013 https://doi.org/10.1097/aog.0b013e3181fe02ec https://doi.org/10.1177/0961203318787032 https://doi.org/10.3109/14767058.2016.1152254 https://doi.org/10.1155/2015/943490 https://doi.org/10.1016/j.jacc.2010.02.042 33. martínez-sánchez n, pérez-pinto s, robles-marhuenda a, arnalich-fernández f, martín cameán m, hueso zalvide e, et al. obstetric and perinatal outcome in anti-ro/ssa-positive pregnant women: a prospective cohort study. immunol res 2017; 65:487–94. https://doi.org/10.1007/s12026-016-8888-5. 34. barsalou j, costedoat-chalumeau n, berhanu a, fors-nieves c, shah u, brown p, et al. effect of in utero hydroxychloroquine exposure on the development of neonatal lupus erythematosus. ann rheum dis 2018; 77:1742–9. https://doi.org/10.1136/ annrheumdis-2018-213718. 35. do sc, druzin ml. systemic lupus erythematosus in pregnancy: high risk, high reward. curr opin obstet gynecol 2019; 31:120–6. https://doi.org/10.1097/gco.0000000000000528. pregnancy outcomes in systemic lupus erythematosus women a single tertiary centre experience e252 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.1007/s12026-016-8888-5 https://doi.org/10.1136/annrheumdis-2018-213718 https://doi.org/10.1136/annrheumdis-2018-213718 https://doi.org/10.1097/gco.0000000000000528 the impact of chronic liver diseases on the level of heart-type fatty acid-binding protein (h-fabp) concentrations *hafidh a al-hadi,1 brent william,2 keith a fox3 squ med j, august 2009, vol. 9, iss. 2, pp. 153-156, epub 30th june 2009 submitted 3rd nov 08 revision req. 21st mar 09, revision recd. 29th mar 09 accepted 13th may 09 clinical & basic research تأثري أمراض الكبد املزمنة على تركيز بروتني محض القلب الدهين الرابط يف الدم حفيظ الهادي، برينت ويليام، كيث فوكس امللخص: الهدف: يعرف بروتني حمض القلب الدهني الرابط كأحد املؤشرات الكيميائية-احليوية اجلديدة التي ميكن استعمالها لتشخيص اجللطة القلبية مبكرا . ال يوجد حتى اآلن دليل على وجود بروتني حمض القلب الدهني الرابط في الكبد. الهدف من الدراسة هو مقارنة تأثير أمراض الكبد أمراض الكبد املزمنة مثل التهاب الكبد الوبائي ومرض التليف تأثير دراسة على مستوى بروتني حمض القلب الدهني الرابط في الدم. الطريقة: مت هو املعياري العمر± االنحراف ( متوسط األمراض هذه من يعانون أشخاص عشرة عند الرابط الدهني القلب حمض بروتني مستوى على الكبدي 58,33 ± 7,19 سنة). مت دراسة تركيز األنزميات و البروتينات التالية (بروتني حمض القلب الدهني الرابط، ناِقلَُة أَمنِي األاَلنني وبيليروبني) في املرضى و مقارنة تركيزها مع مجموعة ضابطة من األصحاء مكونة من عشرين متبرعا بالدم، متوسط العمر± االنحراف املعياري هو 63.8 ± 8.0 سنة) كان تركيز هذه املواد في اجملموعة الضابطة مقارنة مع اجملموعة املرضية كالتالي )املتوسط ± االنحراف املعياري(: بروتني حمض القلب النتائج: . الدهني الرابط 6,86 ± 2,21 ميكروجرام/ لتر مقابل 6,44 ± 3,06 ميكروجرام/ لتر، ناِقلَُة أَمنِي األاَلنني 29.8 14.7 ± وحدة / لتر مقابل 198,67 .)p > 0.0001 ( و البيليروبني 4.0 ± 9.6 ميكرومول / لتر مقابل 100,89 ± 87,85 ميكرومول / لتر ، )p> 0.0005 (122,89 وحدة / لتر ± اخلالصة: تبني هذه البيانات بوضوح انه ال يوجد هناك تأثير هام على مستوى تركيز بروتني حمض القلب الدهني الرابط نتيجة اإلصابة بأمراض الكبد ، على الرغم من االرتفاع الواضح في بروتينات و أنزميات الكبد في الدم. هذه الدراسة تدعم االستخدام النافع لبروتني حمض القلب الدهني الرابط في تشخيص إصابة عضلة القلب لدى املرضى املصابني بأمراض الكبد املزمنة. مفتاح الكلمات: أمراض الكبد املزمنة، بروتني حمض القلب الدهني الرابط، ناِقلَُة أَمنِي األاَلنني ، بيليروبني. abstract: objectives: heart-type fatty acid binding-protein )h-fabp( has been reported to be a potential novel biochemical marker for the early diagnosis of acute myocardial infarction )ami(. the presence of h-fabp in the liver has not been reported. the aim of this study was to compare the effect of chronic liver diseases on the level of h-fabp concentrations. methods: the effects of chronic liver diseases including infective hepatitis and cirrhosis on the concentration of h-fabp was studied in a small group of patients )n=10, mean age ±sd = 58.33 ± 7.19 years(. the serum concentrations of the following markers were measured: h-fabp, alanine aminotransferase )alt( and bilirubin and compared with a reference control group )20 healthy blood donors, mean age ±sd = 63.8 ±8.01(. results: the serum concentrations of these markers in the control group as compared to patients with chronic liver disease were as follows )mean ± sd(: h-fabp = 6.86 ±2.21 µg/l versus 6.44 ±3.06 µg/l )p = ns(; alt = 29.8 ±14.7 u/l versus alt = 198.67 ±122.89 u/l )p < 0.0005( and bilirubin = 9.6 ±4.0 µmol/l versus bilirubin = 100.89 ±87.85 µmol/l )p < 0.0001(. conclusion: these data illustrate clearly that there is no significant interference with the normal concentration of h-fabp in the presence of liver diseases, despite the significant elevation of liver enzymes and proteins. these data may support a useful role of h-fabp for the diagnosis of myocardial injury in patients with liver diseases. keywords: heart-type fatty acid-binding protein )h-fabp(; chronic liver diseases; bilirubin; alanine aminotransferase. 1department of medicine, sultan qaboos university hospital, muscat, sultanate of oman. 2department of medical sciences, faculty of medicine, university of edinburgh, uk. 3university of edinburgh, cardiovascular research unit, royal infirmary of edinburgh, uk. *to whom correspondence should be addressed. email: halhadi@hotmail.com advances in knowledge 1. heart-type fatty acid-binding protein is a useful early marker for the diagnosis of acute myocardial infarction. 2. the effect of chronic liver diseases on the diagnostic potential of this marker is not known. 3. this article illustrates the lack of interferences of the various types of chronic liver diseases on the ability to use heart-type fatty acid binding-protein as an early cardiac marker for the early diagnosis of acute myocardial infarction. application to patient care 1. the information provided in this article will help health institutions caring for patient’s with acute myocardial infarction on how best to use, interpret and apply the results obtained with heart-type fatty acid-binding protein in patients presenting with acute chest pain suggestive of evolving acute myocardial infarction who also have various co-existing types of chronic liver diseases. the impact of chronic liver diseases on the level of heart-type fatty acid-binding protein (h-fabp) concentrations 154 | squ medical journal, august 2009, volume 9, issue 2 heart-type fatty acid bindingprotein (h-fabp) is a small soluble non-enzyme protein composed of 132 amino acids.1 it is one of the most abundant proteins in the heart and comprises 5-15% of the total cytosolic protein pool. h-fabp exists in high concentrations in the heart; however, this protein is not totally cardiac specific and occurs in other tissues although in a much lesser concentrations.2,3 h-fabp was introduced by glatz et al. in 1988 as a potential novel biochemical marker for the early diagnosis of acute myocardial infarction (ami).4 this was soon confirmed in many other studies.5-9 some of the more recent studies have questioned the value of these early markers (h-fabp and myoglobin) when compared with specific markers like cardiac troponin i (ctni).10 h-fabp is released into plasma within 2 hours after symptom onset and is reported to peak at about 4-6 hours and return to normal base line value in 20 hours.7 within the period of 30-210 minutes after symptom onset, h-fabp has > 80% sensitivity for the diagnosis of ami.11 within the interval of 0-6 hours after symptom onset, the other cardiac markers such as creatine kinase (ck), ck-mb mass or activity, ctni and t (ctnt) will only be starting to accumulate in the plasma, and their sensitivity has been reported to be around 64%.12 the exact route(s) of excretion of h-fabp from the circulation is not fully understood. as suggested by previous studies, the kidney may be the major route of excretion of h-fabp from circulation. a rise in serum and urine h-fabp concentration above normal values is seen in patients who present with ami as early as 1.5 hours after symptom onset.13 studies in animals have also shown decreased myocardial tissue content and rising plasma and urine concentrations of h-fabp very early after coronary artery ligation.14-15 h-fabp circulates for a longer time (> 25 hours) after ami in the presence of renal failure.11 the presence of h-fabp in the liver has not been reported. however, an isoform specific to the liver called liver-type fabp exists.16 the interferences of this protein and chronic liver diseases on the concentration of h-fabp has not been studied before. also, the effect of chronic liver diseases on the release of h-fabp from other tissues has not yet been fully evaluated.17 therefore, the aim of the study was to compare the effect of chronic liver diseases on the serum levels of h-fabp. methods the effects of disease states in particular chronic liver diseases on the normal concentration of h-fabp was studied in 2003-2004 a small group of patients with a mixture of chronic liver disorders (n=10, mean age ±sd = 58.33 ±7.19 years, range 45-70 years, median = 59 years) these patients had a range of conditions including infective hepatitis and cirrhosis (chronic hepatitis b = 2, chronic hepatitis c = 2, chronic alcoholic hepatitis = 3, other cirrhosis = 3). they were recruited from the liver unit at the edinburgh royal infirmary, uk. ethical approval was obtained from the local ethical committee (lothian research ethics committee, edinburgh) and informed consent was obtained from each patient before beginning the study. the study complies with the declaration of helsinki. the serum concentrations of the following markers h-fabp, alt and bilirubin were measured in the study group and compared with the concentrations of these markers in a normal reference control group of healthy blood donor controls (n=20, mean age ±sd = 63.8 ±8.01, range 53-75 years, median = 65 years). peripheral blood samples for serum analysis were collected in white starstedt monovette vacutainer tubes by venepuncture. the blood samples (5mls) were taken through a peripheral line (intravascular access). the extracted samples were allowed to clot at room temperature for 1 hour and then centrifuged at 4°c, and the resulting serum was divided into small aliquots and frozen at -70°c until analysis. h-fabp was analysed by an enzyme linked immunosorbent assay method using commercially available assays (hycult, cambridge).17 bilirubin and alt were measured in the biochemistry department of the edinburgh royal infirmary on an automated analyser machine using commercial assays. statistical analyses were performed using the statistical package for social sciences (spsstm, pittsburgh, version 15). continuous variables were presented as mean ± standard deviation. comparisons between the study group and control group variables were conducted by the mannwhitney u test for continuous variables. significant results were indicated by probability values less than or equal to 0.05. hafidh a al-hadi, brent william and keith a fox clinical and basic research | 155 results the analytical sensitivity of h-fabp assay (mean ± 2sd) was 0.206 ±0.047 g/l.17 the normal concentrations of these markers in the normal reference control group of healthy blood donor controls were as follows: h-fabp = 6.86 ±2.21 µg/l; alt = 29.8 ±14.7 u/l and bilirubin = 9.6 ±4.0 µmol/l. the study group consisted of 10 patients. the concentration of these markers in patients with chronic liver diseases were as follows: h-fabp = 6.44 ±3.06 µg/l, (range 2-11 µg/l, median = 7 µg/l); alt = 198.67 ±122.89 u/l, (range 73-500 u/l, median = 114 u/l) and bilirubin = 100.89 ±87.85 µmol/l, (range 17 337 µmol/l, median = 66 µmol/l). there was no significant difference between the concentration of h-fabp in the study group and controls; however, the concentrations of liver enzymes and protein (alt and bilirubin) were significantly elevated in the study group [table 1]. discussion under normal conditions h-fabp is present in plasma in very low concentrations (< 5 µg/l), but it is significantly elevated upon cellular injury.18 this makes the plasma estimation of h-fabp suitable for the early detection and quantification of myocardial tissue injury. however, this protein is not totally cardiac specific as it occurs in skeletal muscle in concentrations varying between 0.05-0.2 mg/g wet weight of tissue, depending on muscle fibre type studied.5 it has also been reported in very low concentrations in tissues like the kidney, aorta, testes, mammary glands, placenta, brain, adrenal glands, adipose tissue, and stomach.2,3 the concentration of h-fabp in the study group was not statistically different from the control group. this finding leads to several assumptions. first, the liver-fabp (l-fabp) is a separate factor with no or negligible cross-reactivity with h-fabp assays. indeed, the cross-reactivity between these two proteins has been reported to be < 0.005.17 second, the release of h-fabp from other tissues containing this protein (see above) is at best minimal in patients who have chronic liver diseases. our study was the first of its kind to address the interference of chronic liver diseases on the normal concentrations of h-fabp. there are no data on this issue in the literature hence it is difficult to correlate our findings. in a previous study, we have shown major limitations for the use of h-fabp concentration for the diagnosis of myocardial injury in the presence of renal failure.19 the liver contains only l-fabp, but co-expression of h-fabp and l-fabp occurs in the kidney. similarly, intestinal-type fabp (i-fabp) and l-fabp are found in intestines, and brain-type fabp (b-fabp) and h-fabp occur in the brain. preliminary but promising applications of these proteins have been demonstrated for liver rejection, viability selection of kidneys from nonheart-beating donors (nhbd), inflammatory and ischaemic bowel disease, traumatic brain injury and in the prevention of muscle injury in trained athletes.20 measurement of h-fabp in the first 24 hours after onset of symptoms may be potentially useful for the diagnosis of ami; identification of patients who need reperfusion treatment early; identification of patients who reperfuse their infarct related artery; detection of re-infarction if it occurs early, and estimation of infarct size.21 conclusion these data illustrate clearly that there is no significant interference with the normal concentration of h-fabp in the presence of chronic liver diseases, despite the significant elevation of liver enzymes and proteins. this is consistent with the reduced cross-reactivity between h-fabp and other fabp table 1: age and concentrations of marker proteins in the control and study groups control group (blood donors) study group (liver disease patients) p value numbers n=20 n=10 age 63.8 ±8.0 58.33 ±7.2 (ns) alt 29.8 ±14.7 198.67 ±122.9 < 0.0005 bilirubin 9.6 ±4.0 100.89 ±87.9 < 0.0001 h-fabp 6.86 ±2.2 6.44 ±3.1 (ns) legend: ns = not significant; alt = alanine aminotransferase; h-fabp = heart-type fatty acid binding-protein the impact of chronic liver diseases on the level of heart-type fatty acid-binding protein (h-fabp) concentrations 156 | squ medical journal, august 2009, volume 9, issue 2 including l-fabp. these findings may support a useful role of h-fabp for the diagnosis of myocardial injury in patients with chronic liver diseases. source of funding: the research was funded by a grant from the cardiovascular research unit at the university of edinburgh. conflict of interest: the authors report no conflit of interest. references 1. offner gd, brecher p, sawlivich wb, costello ce, troxler rf. characterization and amino acid sequence of a fatty acid-binding protein from human heart. biochem j 1988; 252:191-8. 2. crisman ts, claffey kp, saouaf r, hanspal j, brecher p. measurement of rat heart fatty acid-binding protein by elisa. tissue distribution, developmental changes and subcellular distribution. j mol cell cardiol 1987; 19:423-31. 3. glatz gf, van der busse gl. cellular fatty acidbinding protein: their function and physiological significance. prog lipid res 1996; 35:243-82. 4. glatz jf, van bilsen m, paulussen rj, veerkamp jh, van der vusse gj, reneman rs, et al. release of fatty acidbinding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox. biochim biophys acta 1988; 961:148-52. 5. yoshimoto k, tanaka t, somiya k, tsuji r, okamoto f, kawamura k, et al. human heart-type cytoplasmic fatty acid-binding protein as an indicator of acute myocardial infarction. heart vessels 1995; 10:304-9. 6. abe s, okino h, lee s, toda h, miyata m, nomoto k et al. human heart fatty acid-binding protein. a sensitive and specific marker of coronary reperfusion. circulation 1991; 84:ii-291. 7. glatz jf, van der vusse gj, maessen jg, van dieijenvisser mp, hermens wt. fatty acid-binding protein as marker of muscle injury: experimental finding and clinical application. acta anaesthesiol scand suppl 1997; 111:292-4. 8. ishii j, wang jh, naruse h, taga s, kinoshita m, kurokawa h, et al. serum concentrations of myoglobin vs human heart-type cytoplasmic fatty acid-binding protein in early detection of acute myocardial infarction. clin chem 1997; 43:1372-8. 9. alhadi ha, fox ka. do we need additional markers of myocyte necrosis: the potential value of heart fatty acid-binding protein. qjm 2004; 97:187-98. 10. alansari se, croal bl. diagnostic value of heart fatty acid binding protein and myoglobin in patients admitted with chest pain. ann clin biochem 2004; 41:391-6. 11. kleine ah, glatz jf, van nieuwenhoven fa, van der vusse gj. release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. mol cell biochem 1992; 116:155-62. 12. bakkeraj, koelemay mj, gorgels jp, van vlies b, smits r, tijssen jg, et al. failure of new biochemical markers to exclude acute myocardial infarction at admission. lancet 1993; 342:1220-2. 13. tanaka t, hirota y, sohmiya k, nishimura s, kawamura k. serum and urinary human heart fatty acid-binding protein in acute myocardial infarction. clin biochem 1991; 24:195-201. 14. knowlton aa, apstein cs, saouf r, brecher p. leakage of heart fatty acid-binding protein with ischemia and reperfusion in the rat. j mol cell cardiol 1989; 21:577-83. 15. volders pg, vork mm, glatz jf, smits jf. fatty acidbinding proteinuria diagnoses myocardial infarction in the rat. mol cell biochem 1993; 123:185-90. 16. pelsers mm, morrovat a, alexandr gj, hermens wt, trull ak, glatz jf, et al. liver fatty acidbinding protein as a sensitive serum marker of acute hepatocellular damage in liver transplants. clin chem 2002; 48:2055-7. 17. hycult biotechnology b.v. hbt human h-fabp elisa test kit product information manual, 1999. insert sheet. 18. pelsers mm, chapelle jp, knapen m, vermeer c, glatz jf. influence of age, sex and day-today and withinday biological variation on plasma concentrations of fatty acid-binding protein and myoglobin in healthy subjects. clin chem 1999; 45:441-4. 19. alhadi ha, william b, kox ka. serum level of heart fatty acid binding protein in patients with chronic renal failure. squ med j (accepted for publication 10 may 2009). 20. pelsers mm, hermens wt, glatz jf. fatty acidbinding proteins as plasma markers of tissue injury. clin chim acta 2005; 352:15-35. 21. colli a, jossa m, pomar jl, mestres ca, gharli t. heart fatty acid binding proteins in diagnosis of myocardial infarction: where do we stand now? cardiology 2007; 108:4-10. a female child with skin lesions and seizures case report of incontinentia pigmenti sana al-zuhaibi,¹ anuradha ganesh,1 ahmed al-waili,³ faisal al-azri,4 hashim javad,² *amna al-futaisi ² case report squ med j, august 2009, vol. 9, iss. 2, pp. 157-161, epub 30th june 2009 submitted 10th feb 2008 revision req. 30th nov 08, revisions recd. 21st jan 09 & 22nd feb 09 accepted 1st april 09 طفلة مع آفات جلدية وحالة صرع باغ تقرير عن حالة َسلَُس الصِّ سناء الزهيبي، أنورادها غانيش، أحمد الوائلي ، فيصل العزري، هاشم جواد، آمنة الفطيسي اِهرِ الَعَصِبّي تشمل اجللد باغ مرض وراثي نادر مرتبط باجلنس وذو وراثة سائدة. املرض يصيب أجهزة متعددة متعلقة باألَدميِ الظَّ امللخص: َسلَُس الصِّ والعني والشعر واألظافر واألسنان واجلهاز العصبي املركزي. عادة ما يكون املرض قاتال عند الذكور ، بينما يكون ذا أشكال متغيرة سريريا عند اإلناث. ننشر هنا تقريرا عن حالة طفلة عمرها ستة أشهر أدخلت إلى مستشفى جامعة السلطان قابوس )سلطنة عمان( بحالة صرع حديثي الوالدة مصحوبة بآفات جلدية ناقصة الصباغ أو مفرطته و لديها مظاهر عينية وعصبية متعددة غير طبيعية نوقشت في هذا التقرير. مفتاح الكلمات: سلس الصباغ، صرع، عينية، نقص امليالنني اليتو، مرض عصبي، تقرير حالة،عمان abstract: incontinentia pigmenti )ip(, )omim # 308300(, is a rare x-linked dominant condition. it is a multisystemic disease with neuroectodermal findings involving the skin, eyes, hair, nails, teeth, and central nervous system. it is usually lethal in males; the disease has variable expression in an affected female. we report the case of a 6 month old girl who presented at sultan qaboos university hospital, oman, with neonatal seizures and hypopigemented/hyperpigmented skin lesions. she had multiple ophthalmic abnormalities and neurological manifestations which are discussed in this report. keywords: incontinentia pigmenti (ip); seizures; ophthalmic; hypomelanosis of ito; neurologic diseases; case report; oman. departments of 1ophthalmology, ²child health, ³family and community health, and 4radiology & molecular imaging, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: amnaf@squ.edu.om incontinentia pigmenti (ip) type 2, also known as bloch-sulzberger syndrome, is an inherited multisystem neurocutaneous disorder with a low incidence (1% of all neurocutaneous disorders).1 it is an x-linked dominant condition dominant inheritance. the disease is lethal in males, except in rare cases of somatic mosaicism, or mutations in ikbkg, and when the condition occurs in patients with klinefelter syndrome.2,3 typical skin lesions are seen in 100% of (ip) patients.2 other manifestations include dental (90%), skeletal (40%), central nervous system (cns) (40-50%) and ocular (35%) conditions.4,5 patients with ip frequently have systemic involvement, similar to the involvement in patients with hypomelanosis of ito, including cns manifestations. in patients with ip, cutaneous lesions undergo three stages, which may overlap.6 in this report, we discuss the dermatologic, neurological and ophthalmologic findings of a 6 month old female who presented with early onset neonatal seizures and displayed hypopigmented/ hyperpigmented skin lesions. in addition, this child had characteristic ophthalmologic findings. case report this 6 month old girl was born by spontaneous vaginal delivery to healthy non-consanguineous parents with two normal sons. she was referred to sultan qaboos university hospital (squh), oman, from a peripheral hospital for evaluation of abnormal skin lesions and seizures. she was reported to have had hyper/ hypopigmented skin lesions all over her body except the face since she was 6 days old. the skin lesions were noted to be of linear pattern over the upper and lower limbs and of a whorled pattern over the anterior and posterior chest wall. the mother denied the presence of any skin lesion at birth. her examination showed evidence of hypotonia and a female child with skin lesions and seizures case report of incontinentia pigmenti 158 | squ medical journal, august 2009, volume 9, issue 2 mild developmental delay with microcephaly where her head circumference was significantly below the third percentile for age. her weight was below the third percentile, but her height was normal for age. her tone was mildly decreased with normal reflexes and positive babinski reflex. she had a normal visual following, but was not able to respond to sound clinically. other systemic examinations were normal. the child developed clonic seizures at the age of 3.5 months and was commenced on oral phenobarbitone with good seizure control. the computed tomography (ct) scan of the brain (performed at a peripheral hospital) showed atrophy of the frontal horns with corpus callosum agenesis. a chromosomal study showed a normal female karyotype. at squh, a magnetic resonance imaging (mri) of the brain showed hypoplasia of the corpus callosum and hypomyelination with perivetricular white matter hyperintense signal abnormalities [figures 1a and 1b]. electrophysiological testing showed positive visual evoked potential (vep) responses using a flash stimulation, but negative responses for brain stem auditory evoked potentials (baep). an ophthalmologic evaluation was performed at the age of 5 months. the child was able to follow and fixate with both eyes. there was no obvious nystagmus, ocular deviation or ptosis. further examination under anaesthesia revealed bilateral inferior superficial epithelial corneal erosions; there were no stromal infiltrates or any increase in corneal thickness. the corneal size was normal for age in both eyes. she had a bilateral mild form of persistent pupillary membrane. she had a normal red reflex and normal reacting pupils with no evidence of any relative afferent defect. the intraocular pressure was 24mmhg in both eyes. no major refractive error was noted. a dilated fundus examination showed a large optic disc cup (disc cup ratio of 0.8 in both eyes). there were diffuse non-specific retinal pigment epithelial changes. the peripheral retinal examination revealed areas of fibrovascular proliferation with no evidence of retinal traction or detachment [figures 2a and 2b]. the child was started on latanoprost 0.05% eye drops q.h.s. in both eyes with regular follow-ups at the eye clinic. histological studies of the skin lesions and genetic studies were scheduled; unfortunately, the child died from status epilepticus at a peripheral hospital before these studies could be undertaken. discussion ip is characterized by abnormalities of the tissues and organs embryologically derived from ectoderm and neuroectoderm.4 the diagnosis of ip is made on figure 1a: magnetic resonance imaging scan: sag t1w se, midline. there is hypoplasia of the corpus callosum. optic chiasm, pituitary gland and midbrain are grossly normal. figure 1b: magnetic resonance imaging scan: axial t2w se at level of basal ganglia. there is bilateral hyperintense signal abnormality in the periventricular white matter associated with brain atrophy. no imaging findings of acute ischemia or cortical necrosis sana al-zuhaibi, anuradha ganesh, ahmed al-waili, faisal al-azri, hashim javad and amna al-futaisi case report | 159 clinical grounds aided by histological confirmation. the skin lesions may follow the blaschko lines and the initial appearance of skin lesions can be seen immediately after birth or early during the neonatal period. timely recognition of ip by pediatricians and dermatologists is therefore crucial. ip overlaps with hypomelanosis of ito, which is a syndrome with hypopigmented whorls of the skin along the blaschko lines, especially when it presents at the stage of skin hypopigmentaion. chromosomal mosaicism is believed to be the reason that hypomelanosis of ito is so varied in phenotype. certain genes, namely, those on 9q33-qter, 15q11-q13, and xp11, have been implicated in hypomelanosis of ito; however, no consensus exists about the identity of the hypomelanosis of ito gene.5, 6 in around 40-50% of ip cases, there may be neurological problems such as seizures, spasticity, or mental retardation.1 seizure can be the first manifestation of the disease.2 abnormal tooth eruption, malformed tooth crowns, and patchy alopecia are commonly seen. retinal dysplasia can sometimes lead to visual problems. the diagnosis of ip is also aided by family history and a history of miscarriages of the male gender as the disease is prenatally lethal in males. the disease is caused by a genomic rearrangement of the gene for nemo, or nuclear factor kappa b essential modulator (ikbkg-ikk gamma). the defect in the x chromosome is proximal to the gene for factor viii at xq28. 7, 8 although this child was the first affected in her family with two normal male siblings and no previous miscarriages in the family, she had hypopigmented/hyperpigmented lesions suggestive of the disease. initially, the diagnosis was not entertained, despite the skin manifestations, until her presentation with partial seizures. the possibility of hypomelanosis of ito diagnosis was also kept in mind though further evidence of neurological involvement and the eye manifestations were suggestive of ip. the skin lesions in ip manifest in stages that evolve sequentially.7 the onset and duration of each stage vary among individuals; not all individuals experience all four stages.1 typically four dermatological stages are seen: 1) the bullous stage; early blistering with eosinophilia; 2) the verrucous stage: eruption of hyperkeratotic lesions; 3) the hyperpigmentation stage: hyperpigmentation along the lines of blaschko and, finally, 4) the atretic stage: dermal scarring. in the vast majority of cases, the onset of skin changes is before 6 weeks of age.1 our patient had the third stage which was not preceded by the first or second stages. the differential diagnosis of patients presenting with stage 3 and 4 skin lesions includes: hypomelanosis of ito; ip achromians; focal dermal hypoplasia syndrome (goltz syndrome) and x-linked dominant chondrodysplasia punctata. in ip, variable clinical expressions of cns involvement are seen. they include epilepsy, mental retardation, hemiparesis, spasticity, microcephaly, and cerebellar ataxia.5 the pathogenesis of the cns lesion in ip remains unclear.9,10,11 recent brainimaging techniques, such as mri and magnetic resonance angiogram (mra), have provided a better understanding of the nature of the cns pathology. these imaging studies have demonstrated scattered cortical neuronal and white-matter necrosis, figure 2a: retcam fundus photo of the right eye showing large disc cupping and epiretinal pseudoglial tissue superior to the fovea (arrow) figure 2b: retcam fundus photo of the right eye showing large disc cupping and epiretinal pseudoglial tissue superior to the fovea (arrow) a female child with skin lesions and seizures case report of incontinentia pigmenti 160 | squ medical journal, august 2009, volume 9, issue 2 hypoplasia of the corpus callosum, periventricular white-matter cystic lesions, neuronal heterotopia, and cerebral atrophy.12, 13 our patient had evidence of hypoplasia of the corpus callosum and decreased myelination of the white matter and, clinically, both seizures and developmental delay. the presence of cns involvement, such as seizures, in the neonatal period is a poor prognostic sign.4, 6, 7 ocular abnormalities occur in 35% or more of patients and 19% are at risk of severe visual loss in one or both eyes.14,15 a wide range of ophthalmologic findings are seen in patients with ip.7 the commonest reported are strabismus in 18.2% and a retrolental mass or retinal pseudoglioma in 15.4%. there are previous reported cases in literature of multiple corneal abnormalities including megalocornea, corneal oedema, band keratopathy, bullus keratopathy, variable corneal epithelial and stromal changes and iridocorneal attachments.10 the corneal findings in this child were superficial punctuate epithelial erosion and features suggestive of an inflammatory noninfectious process. the posterior segment findings may include multiple retinovascular abnormalities (such as retinal vascular tortuosity, macular capillary dropout, peripheral arteriovenous shunts, retinal neovascularisation, and vitreous haemorrhage). subsequently, preretinal fibrosis, pseudoglioma and traction retinal detachment can result.14 this child had findings suggestive of what looked like pseudogliomas in both eyes [figures 2a and 2b] and peripheral fibrovascular lesions ou with no evidence of retinal traction. holstrom proposed a scheme for following patients with ip and eye manifestations. they recommended that eyes should be examined soon after birth, and then at least monthly for three to four months, at three-month intervals for one year, and twice yearly up to three years. they also recommended that the frequency of examinations should be increased in children with retinal disease. if, at three years of age, no abnormalities, refractive errors or strabismus are found, they state that the follow-up can cease.16 during the ophthalmic follow-up, visual functions should be assessed by both clinical and electrophysiological measures including vep and electroretinography (erg).16,17 any significant refractive errors should be corrected and amblyopia therapy as well as strabismus treatment should be provided.18,19 cryotherapy or laser photocoagulation should be applied for active peripheral retinal abnormalities and tractional retinal detachment should be treated surgically. conclusion in summary, ip or bloch-sulzberger syndrome is a rare x-linked dominant syndrome. it has multisystemic involvement that includes the skin, central nervous system and eyes. in neurocutaneous syndromes, multidisciplinary care with periodic consultations with a paediatric ophthalmologist, neurologist and other specialists depending on the associated anomalies are essential. the differentiation between hypomelanosis of ito and ip can be difficult as the two disorders overlap considerably. clinicians need to be aware of the variable manifestations of this disease for a timely and multidisciplinary management of such patients. acknowledgments thanks are due to the parents of this child who consented to publication of this report and the photos in a medical journal. references 1. landy sj, donnai d. incontinentia pigmenti (blochsulzberger syndrome). j med genet 1993; 30:53-9. 2. traupe h. functional x-chromosomal mosaicism of the skin: rudolf happle and the lines of alfred blaschko. am j med genet 1999; 85324-9. 3. scheuerle ae. male cases of incontinentia pigmenti: case report and review. am j med genet 1998; 77:201-18. 4. türkmen m, eliaçik k, temoçin k, savk e, tosun a, dikicioğlu e. a rare cause of neonatal seizure: incontinentia pigmenti. turk j pediatr 2007; 49:32730. 5. fritz b, kuster w, orstavik kh, naumova a, spranger j, rehder h. pigmentary mosaicism in hypomelanosis of ito. further evidence for functional disomy of xp. hum genet 1998; 103:441-9. 6. glover mt, brett em, atherton dj. hypomelanosis of ito: spectrum of the disease. j pediatr 1989; 115:7580. 7. berlin al, paller as, chan ls. incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. j am acad dermatol 2002; sana al-zuhaibi, anuradha ganesh, ahmed al-waili, faisal al-azri, hashim javad and amna al-futaisi case report | 161 47:169-87. 8. fusco f, bardaro t, fimiani g. molecular analysis of the genetic defect in a large cohort of ip patients and identification of novel nemo mutations interfering with nf-kappab activation. hum mol genet 2004; 13:1763-73. 9. nenci a, huth m, funteh a, schmidt-supprian w, bloch d, metzger p, et al. skin lesion development in a mouse model of incontinentia pigmenti is triggered by nemo deficiency in epidermal keratinocytes and requires tnf signaling. hum mol gene 2006; 15:531-42. 10. nehal ks, pebenito r, orlow sj. analysis of 54 cases of hypopigmentation and hyperpigmentation along the lines of blaschko. arch dermatol 1996; 132:116770. 11. cohen ba. incontinentia pigmenti. neurol clin 1987; 5:361-77. 12. pascual-castroviejo i, roche mc, martinez fernández v, perez-romero m, escudero rm, garcia-peñas jj, et al. incontinentia pigmenti: mr demonstration of brain changes. ajnr am j neuroradiol 1994; 15:1521-7. 13. lee ag, goldberg mf, gillard jh, barker pb, bryan rn. intracranial assessment of incontinentia pigmenti using magnetic resonance imaging, angiography, and spectroscopic imaging. arch pediatr adolesc med 1995; 149:573-80. 14. carney rg. incontinentia pigmenti: a world statistical analysis. arch dermatol 1976; 112:535-42. 15. kasmann-kellner b, jurin-bunte b, ruprecht kw. incontinentia pigmenti (bloch-sulzbergersyndrome): case report and differential diagnosis to related dermato-ocular syndromes. ophthalmologica 1999; 213:63-9. 16. holmstrom, g, thoren k .ocular manifestations of incontinentia pigmenti. acta ophthalmol scand 2000; 78:348-53. 17. o’brien je, feingold m. incontinentia pigmenti a longitudinal study. am j child 1985; 139:711-2. 18. mayer ej, shuttleworth gn, greenhalgh kl. novel corneal features in two males with incontinentia pigmenti. br j ophthalmol 2003; 87:554-6. 19. taylor d, hoyt cs, eds. pediatric ophthalmology and strabismus, 3rd ed. philadelphia: wb saunders, 2004. august 2007 vol 7 copy.indd omenn’s syndrome a rare primary immunodeficiency disorder *ibtisam b elnour,1 shakeel ahmed,2 kamal halim,3 v nirmala4 sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 133-138 sultan qaboos university© submitted 25th april 2007 omenn’s syndrome is a rare autosomal recessive form of severe combined immun-odeficiency. omenn gs first described it in 1965. he described an extended american-irish family with clinical features of recurrent infections, skin eruptions, eosinophilia, lymphadenopathy and hepatosplenomegaly with accompanied respiratory, gastrointestinal symptoms and failure to thrive. t lymphocyte numbers may be normal or high, but eosinophils are virtually increased. there is marked lymphocyte depletion in the thymus and lymphoid tissue. a given subset of t lymphocytes represents the majority of the blood t cells in each patient. elevated numbers of t cells are found in the skin and gut, some of which have the phenotype of activated t cells. omenn’s syndrome is fatal if untreated. patients have life-threatening bacterial, viral and fungal infections as in other forms of severe combined immunodeficiency. allogenic haematopoitic stem cell transplant has treated the condition successfully. omenn’s syndrome is a genetically heterogeneous condition. patients with similar immunophenotypes may have as yet unidentified gene defects. the majority of mutations are missense mutations in recombinase activating genes rag-1 and rag-2, which have been mapped to chromosome band 11p13. mutation in rag-1 and rag2 results in partial v(d)j recombination activity and dysregulation of t and b cell functions. recent publications have described omenn’s syndrome in the absence of rag mutations. omenn’s syndrome has been reported in patients from north america, europe and asia. el-arabi reported an infant with omenn’s syndrome from qatar. to our knowledge, there is no other report from the arabian area.1 c a s e r e p o r t اومني متالزمة االولي املناعة لنقص نادر اضطراب نرماال في حليم، شاكيل احمد، كمال النور، ابتسام مسقط قابوس ، السلطان جامعة مستشفى في الشديد نقص املناعة املركب من عديدة انواع تشخيص مت 17 املاضية ال السنوات : في امللخص أسابيع كان ــتة س عمره رضيع عماني هنا نعرض . ــديد الش ملركب املناعة لنقص املتنحية ــدية الوراثة الصبغية اجلس من نادرة اومني حالة متالزمة . . النادرة لهذه املتالزمة ملناعية اجلوانب خاللها من ناقشنا . املتالزمة لتلك واملناعية السريرية الصفات عليه باديا عمان. حالة، تقرير أولى، الشديد، املركب املناعة نقص املناعة، نقص اومني، الكلمات: متالزمة مفتاح 1department of child health, college of medcine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman; 2college of medicine, agha khan university, karachi, pakisthan; 3department of immunology, military hospital, riyadh, kingdom of saudi arabia; 4department of pathology, psg institute of medical sciences and research, coimbatore, tamil nadu, india. *to whom correspondence should be addressed. email: ibtisamb@squ.edu.om abstract: over the last 7 years different forms of severe combined immunodeficiency have been diagnosed at sultan qaboos university hospital, muscat. omenn’s syndrome is a rare autosomal recessive form of severe combined immunodeficiency. we report a 6 weeks old omani infant who presented with the characteristic clinical and immunological phenotype of omenn’s syndrome. we take the opportunity to discuss and review the immunological aspect of this rare syndrome. keywords: omenn’s syndrome; immunodeficiency, severe, combined; immunodeficiency, primary; case report; oman. i b t i s a m b e l n o u r , s h a k e e l a h m e d , k a m a l h a l i m a n d v n i r m a l a 134 c a s e r e p o r t a 6 weeks old omani male infant was referred to sultan qaboos university hospital with generalized lymphadenopathy and gross hepatomegaly. he was the second child of consanguineous parents, delivered normally with a birth weight of 3.5 kg. he received the bcg and the first dose of oral polio vaccine (opv), together with hepatitis b vaccines immediately after birth according to the routine schedule of immunization in oman. the first child in the family was normal. symptoms were first noticed at the age of 3 weeks with progressive diffuse erythrodermic scaly skin rashes, which spread over the whole body including the scalp. this was diagnosed and treated as extensive seborrheic dermatitis. two weeks later, the mother noticed swelling of the face, neck and at the subaxillary areas. physical examination revealed a febrile and sick baby who had generalized lymphadenopathy with huge cervical lymph nodes, oedema of the face and the extremities, diffuse erythrodermic scaly icthyotic skin rashes over the entire body and hepatosplenomegaly of 4cm each. cardiovascular, respiratory and neurological examinations were normal. a complete range of hematological, immunological and biochemical tests was performed. blood test showed haemoglobin of 9.3g/dl, leukocyte count of 40.3x109/l, of which the neutrophil count was 7.92x109/l and lymphocyte count was 11.8x109/l. the eosinophils count was very high (17.4x 109/l). the platelet count was normal. flow cytometry analysis of peripheral blood cells revealed lymphocytosis with virtually absent b cells as marked by anti cd20. all lymphocytes were cd3+. there was oligoclonal predominance of activated memory cells cd4+/cd29, [table 1]. bone marrow aspiration confirmed the absence of b cells and t cells were present. human leukocyte antigen typing revealed that the child was not identical to his mother. serum immunoglobulin levels were low except for extremely high serum ige levels. in the absence of b cells, igg level was certainly of maternal origin. ige level was 19188.0 kiu/l and later rose to 25200 kiu/l [table 2]. evaluation of cytokines revealed normal interleukin 4 < 5pg/ml and high interleukine 5 level 25 pg/ml (normal <l3 & < 3 pg/ml respectively). torch screening for congenital infections gave similar results in the mother and child, with positive igg and negative igm immunoglobulins for epstein barr virus, cytomegalovirus virus, rubella and toxoplasmosis infections suggestive of vertical transmission. hiv 1 and 2 were negative as well as screening for mycobacterium infections. post vaccination hepatitis b surface antibody titer was 10-100 iu/l. radiological assessment revealed bronchopneumonia on the chest x-ray. computed tomography of the chest showed normal sized thymus and no hilar lymphadenopathy. histopathological examination of lymph node showed loss of follicular architecture with preserved hilar structure and sinusoids. polymorphous population of small lymphocytes, large activated lymphoid cells and numerous eosinophils replaced the lymph figures 1: omenn’s syndrome lymph node biopsy immunohistochemistry staining showing t lymphocyte (cd3+) proliferation. majority of the cells are cd30. immunoperoxidase x 200 figures 2: omenn’s syndrom skin biopsy skin with parakeratosis (á) and lymphohistocytic infiltrate. the lymphocytes expressed cd3+ (‡) and were mostly cd8+. the histocytes in the skin were s-100 non reactive. hematoxylin and eosin x 200. o m e n n ’ s s y n d r o m e 135 node architecture. the lymphoid cells are predominantly t lymphocytes (cd3 positive) with occasional b cells (cd20 positive). considerable proportions of cd30 positive t cells were present. large dendritic cells of the node were shown which immunoreact for marker s-100 [figures 1]. the epidermis in the skin biopsy showed parakeratosis. the dermis contained a moderately heavy lymphohistocytic infiltrate. marked exocystosis was present associated with basal cell vaculation and focal keratinocyte necrosis [figure 2]. the lymphocytes cells were immunoreactive for marker cd8 and did not express cd4 (cd3+/cd8+). the histocytes expressed marker cd68 and were negative for s-100, ruling out the possibility of a langerhans’ cell infiltrate in the skin. although the child was treated with broad-spectrum antibiotics and immunoglobulin infusions, he continued to have recurrent bronchopneumonia and died at the age of 4 months of coagulase negative staphylococcus septicaemia and septic shock. d i s c u s s i o n omenn’s syndrome is a genetic disorder with recessive autosomal inheritance, characterized by lymphocytic infiltration of the skin, gut, liver and spleen, leading to erythroderma and protracted diarrhoea with failure to thrive.2-6 in 1965, omenn presented a kinder with 12 children suffering from skin eruptions followed by hepatosplenomegaly, generalized lymphadenopathy, eosinophilia, poor growth and recurrent infections.2 skin lesions are very similar to those observed in graftversus-host disease. all children had fatal outcomes within two to six months of life. other features include extremely elevated serum immunoglobulin e levels and hypogammaglobulinaemia. a series of case reports expanded the clinical picture.3-6 t lymphocyte number may be normal or high, but eosinophils are virtually increased. a given subset of t lymphocytes represents the majority of the blood t cells in each patient.7 there is undue susceptibility to serious infections of the skin, lungs, joints and septicemia. pneumonia and septic shock are the usual cause of death in this syndrome. unless treated with allogenic haematopoitic stem cell transplantation, the prognosis of omenn’s syndrome will prove fatal within the first two to six months of life.8-20 poor clinical status before stem cell transplantation results in high transplantation related mortality. omenn’s syndrome is genetically a heterogeneous condition. the majority of mutations are missense mutations in recombinase activating genes rag1 and rag2, which have been mapped to chromosome band 11p13.11-12 the remainder of the mutations are nonsense, deletion, frameshift, duplication and splice mutations. recent reports described omenn’s syndrome in the absence of rag mutations. ege et al. described a patient with omenn’s syndrome due to artemis mutation.13 giliani et al. described an infant with the phenotype picture of omenn’s syndrome and il7ra lymphocyte type numbers percentage (%) reference range 0-3 months total 19.5 2.9-8.8 x109 /l cd3+ 18.779 96.3 2.1-6.5 x109 /l cd20+ 0.0 0.0 0.4-1.0 x109 /l cd3+/cd4+ cd4+/cd29+ cd4+/cd45ra 14.430 74.0 73.4 0.7 1.5-5.1 x109 /l cd3+/cd8+ cd8+/cd11a+ cd8+/cd11a4.349 22.35 2.7 19.4 0.7-2.5 x109 /l cd4:cd8 ratio 3.3:1 1.3-3.5 x109 /l nk cells 0.644 3.3 0.3-0.7 x109 /l table 1: result of lymphocyte subsets i b t i s a m b e l n o u r , s h a k e e l a h m e d , k a m a l h a l i m a n d v n i r m a l a 136 gene mutation.14 patients with similar immunophenotypes may have as yet unidentified gene defects.15 the recombination activating enzymes rag1 and rag2 are essential in the assembly of v(d)j segments, which form the variable portions of immunoglobulin and t cell receptors (tcr) proteins.16 mutations in either the rag1 or rag2 genes were identified to cause severe combined immunodeficiency with markedly reduced numbers of t and b cells (t-b-nk+ phenotype).17 missense mutations of rag1 or rag2 in omenn’s syndrome lead to partial activities of rag1 or rag2,18 and impair variable diversity joining v (d) j recombination, which is required for the development of mature t and b cells. there is marked lymphocyte depletion in the thymus and lymphoid tissue. rudimentary thymus tissue shows poorly formed and decreased hassall corpuscles with few lymphocytes.19 predominance of few t cell receptors clonotype is detectable in the thymus and is further selected in the periphery, with a different distribution of clonotype in different tissues. the gut lacks lymphocytes in peyer’s patches and in the lamina propria. elevated numbers of t cells are found in skin and gut, some of which has the phenotype of activated t cells. skin biopsy shows an activated autologous t cell infiltrate and psoriasiform hyperplasia of the epidermis, parakeratosis, cellular dyskeratosis and necrosis.20 reactive lymph nodes show infilterating eosinophils and histocytes, but they lack germinal centers and cortical lymphocytes.21 immunological abnormalities in this syndrome may include normal to high t lymphocytes count with variable distribution ratio of cd4+:cd8+ subsets. b cells are absent and nk cells are present. (t-b+nk+ phenotype).21 an oligoclonal th2 population is expanded, possibly as a result of increased exposure to inadequately cleared antigen, or to an aberrant response to infection by non-antigen specific t cells receptors, leading to massive release of inflammatory cytokines. those autoreactive cells have a highly restricted receptor repertoire.19-21 oligoclonicity of t cell repertoire in omenn’s syndrome is due both to intrathymic restriction and to the peripheral expansion.19, 20, 22 lymphocyte stimulation with mitogens, phytohaemagglutinin (pha), concavalin a (con a) and pokeweed mitogen (pwa) are absent or profoundly reduced. in contrast, response to anti-cd3, phorbol myristate acetate (pma) may be detectable.15 immunoglobulin levels show absent immunoglobulin a and m levels and increased immunoglobulin e level. immunoglobulin g level is of maternal origin. interleukin-4 (il-4) and interleukin (il-5) levels are typically increased.22 the increased level of il-5 suggests th2 cells activation and favor eosinophils differentiation. t helper 2 cells usual function is to promote ige production, but they it also have and inhibitory effects on macrophages. therefore, it is accepted that elevated ige production also goes along with t cell dysfunction. our patient had the typical clinical features of omenn’s syndrome. he presented with progressive diffuse erythrodermic scaly icthyotic skin eruptions started at the age of 3 weeks. then he developed generalized lymphadenopathy, hepatosplenomegaly, pneumonitis and loss of weight. although treated with broad-spectrum antibiotics and immunoglobulin infusions, he continued to be sick with persistent pneumonitis and died of staphylococcal septic shock at the age of 4 months. investigation showed leucocytosis, lymphocytosis and severe eosinophilia. lymphocyte subsets’ analysis of immunoglobulin level normal range igg 3.6 2.1 7.7 g/l iga <0.07 0.05 0.4 g/l igm 0.16 0.08 0.4 g/l ige 19188.0 10 29.2 kiu/l anti staphylolysin antibodies < 1.0 <2 iu anti-corps anti staphylolysin gamma 10 160 iu table 2: immunoglobulin levels o m e n n ’ s s y n d r o m e 137 our patient showed a virtual absence of b cells on both peripheral blood and bone marrow. cd4+ and cd8+ numbers were increased with oligoclonal expansion of th2 cells (cd4+/cd29) typical of omenn’s syndrome. with virtually absent b cells, the igg level is certainly of maternal origin. immunoglobulin studies showed very high serum ige and il-5 levels. the increased level of il5 suggests th2 cells activation and favours eosinophil differentiation. lymphocyte transformation tests were not available in our laboratory, but there was poor response to hepatitis b vaccination with low anti hepatitis b surface antibody level. pathological lymph node examination was diagnostic of omenn’s syndrome. there was loss of follicular architecture. the lymphoid cells were predominantly t lymphocytes (cd3 positive). considerable proportions of cd30 positive t cells were present. the epidermis in the skin biopsy showed parakeratosis and marked exocystosis. the lymphocytes cells were immunoreactive for marker cd8 and did not express cd4 (cd3+/cd8+). early presentation, icthyotic scaly skin lesion, absence of b cells, low immunoglobulin levels and negativity of antistaphylococcal antibodies signal towards omenn’s syndrome and not towards hyper ige syndrome. although the skin biopsy mimicked graft-versus host disease, heavy lymphohistocytic infiltrate and parakeratosis exclude graft-versus host disease.23 the child’s and mother’s human leukocyte antigens were not identical, excluding materno-foetal engraftment. the histocytes in the skin biopsy expressed marker cd68 and were negative for s-100, ruling out the possibility of a langerhans’ cell infiltrate in the skin. c o n c l u s i o n in summary, the clinical picture of omenn’s syndrome resembles infantile histiocytosis. our patient presented with a clinical and immunological picture consistent with previous reviews of this syndrome. at the time of presentation, neither lymphocyte stimulation tests nor bone marrow transplantation were available for children with primary immunodeficiency. recognition of different forms of severe combined immunodeficiency in our hospital has led to improvement of the clinical immunological services for our patient, as well as availability of haematopoitic stem cell transplant for patients with primary immunodeficiency. genetic evaluation for all types of severe combined immunodeficiency is in process. we should shortly be able to confirm whether this child had a rag 1 or rag 2 mutation. there was no family history suggestive of immunodeficiency in this child. physicians at the secondary care and primary health care levels should withhold all life-attenuated vaccines whenever there is family history suggestive of primary immunodeficiency. bcg vaccination at birth as well as live poliovirus vaccine could be fatal in these patients. r e f e r e n c e s 1. el araby i, abulaban m, abdul wahab a, salem mm, al-saad i, morsi n. omenn’s syndrome the first case in qatar. qatar med j 1998; 7:53-54. 2. omenn gs. familial reticuloendotheliosis with eosinophilia. n engl j med 1965; 273:427-432. 3. businco l, di fazio a, ziruolo mg, boner al, valletta ea, ruco lp et al. clinical immunological findings in four infants with omenn’s syndrome: a form of severe combined immunodeficiency with phenotypically normal t cells, elevated ige and eosinophilia. clin immunol immunopath 1987; 44:123-33. 4. cederbaum sd, niwayama g, stiehm er, neerhout rc, ammann aj, berman w jr. combined immunodeficiency presenting as a letterer-sewi syndrome. j pediatr 1974; 4: 466-471. 5. velders aj, et al. omenn’s syndrome: familial reticuloendotheliosis with eosinophilia and combined immunodeficiency. br j dermatol 1983; 108:118-20 6. rosen f, geha r. omenn’s syndrome. in: case studies in immunology, a clinical companion. new york: garland publishing, 2001. p. 59-63. 7. de saint-basile g, le deist f, de villartay jp, cerf-bensussan n, journet o, brousse n et al. restricted heterogeneity of t lymphocytes in combined immunodeficiency with hypereosinophilia (omenn’s syndrome). j clin invest 1991; 87:1352-1359. 8. gomez l, l deist f, blanche s, cavazzana-calvo m, griscelli c, fischer a. treatment of omenn’s syndrome by bone marrow transplantation. j pediatr 1995; 127:7681. 9. junker ak, chan wk, massing bg. clinical and immune recovery from omenn’s syndrome after bone marrow transplantation. j pediatr 1989;114:596-600. 10. benito a, diaz ma, alonso f, fontan g, madero l. successful unrelated umbilical cord blood transplantation in a child with omenns syndrome. pediatr hematol oncol 1999; 16:361-366. 11. villa a, santagata s, bozzi f, imberti l, notarangelo ld. omenn’s syndrome: a disorder of rag1 and rag2 genes. j clin immunol 1999;19:87-97. 12. oettinger ma, stanger b, schatz dg, glaser t, call k, i b t i s a m b e l n o u r , s h a k e e l a h m e d , k a m a l h a l i m a n d v n i r m a l a 138 housman d et al. the recombination activating genes, rag1 and rag2, are on chromosome 11p in humans and chromosome 2p in mice. immunogenetics 1992; 35:97-91. 13. m. ege, ma y, manfras b, kalwak k, lu h, lieber mr et al. omenn’s syndrome due to artemis mutation. blood 2005; 105: 4179-4186. 14. giliani s, bonfim c, de sainte-basile g, lanzi g, brousse n, koliski a et al. omenn’s syndrome in an infant with phenotype picture of omenn’s syndrome and il7ra gene mutation. j pediatr 148:272-274. 15. andrew r, gennery. omenn’s syndrome occurring in patients without mutation in recombinase activating genes. clin immunology 2005; 116: 246-256. 16. roman ca, baltimore d. genetic evidence that the rag1 protein directly participates in v(d)j recombination through substrate recognition. proc natl acad sci usa 1996; 93:2333-2338. 17. schwarz k, gauss gh, ludwig l, pannicke u, li z, lindner d et al. rag mutation in human b cell negative scid. science 1996; 274:97-99. 18. villa a, santagata f, bozzi s, giliani a, frattini l, imberti lb et al. partial v(d)j recombination activity leads to omenn’s syndrome. cell 93 1998; 93:885-896. 19. signorini s, imberti l, zambello r, sottini a, raimondi r, facco m et al. intrathymic restriction and peripheral expansion of the t cells repertoire in omenn’s syndrome. blood 1999; 94:3468-78. 20. rieux-laucat f, bahadoran p, brousse n, selz f, fischer a, le deist f et al. highly restricted human t cell repertoire in peripheral blood and tissueinfiltrating lymphocytes in omenn’s syndrome. j clin inves 1998; 102:312-321. 21. martin jv, willoughby pb, giusti v, price g, cerezo l. the lymph node pathology of omenn syndrome. am j surg pathol 1995; 19:1082/087. 22. harville to, adams dm, howard ta, ware re. oligoclonal expansion of cd45ro+ t lymphocytes in omenn’s syndrome. j clin immunol 1997; 17:322-32. 23. scheimberg i, hoeger ph, harper ji, lake b, malone m. omenn’s syndrome: differential diagnosis in infants with erythroderma and immunodeficiency. pediatr dev pathol 2001; 4:237-245. submitted 11 feb 23 1 revision req. 2 apr 23; revision recd. 8 apr 23 2 accepted 19 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.024 5 6 absent septum pellucidum 7 search for other anomalies 8 khadija saleh,1 eiman al-ajmi,2 *amna al futaisi3 9 10 1pediatrics program, oman medical specialty board, muscat, oman; 2department of 11 radiology and molecular imaging, sultan qaboos university hospital, sultan qaboos 12 university, muscat, oman; 3department of paediatrics, college of medicine and health 13 sciences, sultan qaboos university, muscat, oman 14 *corresponding author’s e-mail: amnaf@squ.edu.om 15 16 introduction 17 a 6-week-old infant was referred to the paediatric neurology unit of a tertiary care hospital, 18 in 2019 from a peripheral hospital for further evaluation. this referral was prompted by an 19 antenatal scan that revealed an absent cavum septum pellucidum and a postnatal head 20 ultrasound that suggested septo-optic dysplasia. despite these findings, the infant appeared to 21 be developing normally with normal muscle tone, strength and sucking reflex. the infant was 22 born at full term via spontaneous vaginal delivery with a birth weight of 3 kg, head 23 circumference of 34 cm, length of 52 cm and a good apgar score; he had also received all the 24 vaccinations recommended at birth. there was no history of maternal infection during 25 pregnancy, medication intake, smoking or substance abuse. his parents were 26 consanguineous, but there was no family history of genetic or neurological disorders. 27 28 an ophthalmologist examined the patient and found no optic nerve atrophy or other ocular 29 abnormalities. magnetic resonance imaging (mri) of the brain at the age of thirty-three 30 months revealed an isolated absence of the septum pellucidum (asp) but no signs of septo-31 optic dysplasia, optic nerve hypoplasia or visible pituitary abnormalities (figure 1). 32 furthermore, an endocrinological evaluation revealed no endocrine abnormalities. the 33 mailto:amnaf@squ.edu.om patient, who is currently 3 years old, is healthy with no obvious physical abnormalities and 34 shows age-appropriate development; thus, was diagnosed with isolated asp. 35 36 informed consent was obtained from the parents for the publication of the images. 37 38 comment 39 asp is a rare developmental brain anomaly that can be partial or complete. it is often 40 associated with congenital brain defects, such as holoprosencephaly, septo-optic dysplasia, 41 schizencephaly and corpus callosum agenesis. isolated asp should be suspected in infants 42 with normal findings on neurological examination but with an absent cavum septum 43 pellucidum on antenatal scans.1 it is challenging to differentiate between isolated asp and 44 septo-optic dysplasia in utero using current imaging techniques because it can be difficult to 45 rule out the possibility of optic nerve hypoplasia and endocrine abnormalities.2 prenatal 46 ultrasonography can detect cavum septum pellucidum between 18 and 37 weeks of gestation, 47 or with a biparietal diameter of 44-88mm.the mean width of the cavum septum pellucidum is 48 5.3 +/1.7 mm with a range of 2 to 9 mm.3 if the cavum septum pellucidum is not detected on 49 antenatal scanning during this period, it may indicate abnormal brain development and 50 necessitate further examination.4 51 52 isolated asp is uncommon, occurring in approximately 0.2–0.3 of every 10,000 people. 53 however, the true incidence might be higher due to limitations in sonography such as skills 54 of the operator, restricted field of view and visualization.5 the prognosis of this condition is 55 presently unknown, but it has been associated with undetectable pathological changes on 56 ultrasound or mri.4 57 few cases of isolated septal agenesis have been associated with schizophrenia as it is 58 considered part of the limbic system.4 other cases have been associated with speech delays or 59 behavioural problems.4 in a retrospective cohort study, antenatal genetic tests were performed 60 in 30 foetuses with suspected isolated asp, 2 of which had an abnormal result.6 the majority 61 of cases with a prenatal isolated asp diagnosis have a favourable prognosis.6 however, if 62 other anomalies are detected, the clinical outcome is worse.6 screening for associated 63 anomalies is mandatory for new-borns who are identified with asp on antenatal ultrasound. 64 an early understanding of whether asp is an isolated anomaly or part of a syndrome enables 65 the clinicians to provide appropriate counselling for families and to establish early 66 rehabilitation and guidance for future management of such patients. 67 68 authors’ contribution 69 ks did the initial writing of the manuscript. ea prepared the images and description and 70 revised and edited the manuscript. af was responsible for the idea of the manuscript as well 71 as the revision and editing at all stages. all authors approved the final version of the 72 manuscript. 73 74 references 75 1. ben m'barek i, tassin m, guët a, simon i, mairovitz v, mandelbrot l, et al. 76 antenatal diagnosis of absence of septum pellucidum. clin case rep. 2020 feb 77 5;8(3):498-503. https://doi.org/10.1002/ccr3.2666 78 2. garcía-arreza a, garcía-díaz l, fajardo m, carreto p, antiñolo g. isolated absence 79 of septum pellucidum: prenatal diagnosis and outcome. fetal diagn ther. 80 2013;33(2):130-132. https://doi.org/10.1159/000338009 81 3. falco p, gabrielli s, visentin a, perolo a, pilu g, bovicelli l. transabdominal 82 sonography of the cavum septum pellucidum in normal fetuses in the second and third 83 trimesters of pregnancy. ultrasound obstet gynecol. 2000;16(6):549-553. 84 https://doi.org/10.1046/j.1469-0705.2000.00244.x 85 4. pilu g, tani g, carletti a, malaigia s, ghi t, rizzo n. difficult early sonographic 86 diagnosis of absence of the fetal septum pellucidum. ultrasound obstet gynecol. 87 2005;25(1):70-72. https://doi.org/10.1002/uog.1786 88 5. hosseinzadeh k, luo j, borhani a, hill l. non-visualisation of cavum septi 89 pellucidi: implication in prenatal diagnosis?. insights imaging. 2013;4(3):357-367. 90 https://doi.org/10.1007/s13244-013-0244-x 91 6. di pasquo, e., kuleva, m., arthuis, c., morganelli, g., ormitti, f., millischer, a. e., 92 et al. prenatal diagnosis and outcome of fetuses with isolated agenesis of septum 93 pellucidum: cohort study and meta-analysis. ultrasound obstet gynecol. 94 2022;59(2):153-161. https://doi.org/10.1002/uog.23759 95 96 97 https://doi.org/10.1002/ccr3.2666 https://doi.org/10.1159/000338009 https://doi.org/10.1046/j.1469-0705.2000.00244.x https://doi.org/10.1002/uog.1786 https://doi.org/10.1007/s13244-013-0244-x https://doi.org/10.1002/uog.23759 98 figure 1. magnetic resonance imaging of the brain done for the patient at age of thirty-three 99 months shows absence of the septum pellucidum in an axial t2-weighted image (a). (b) 100 coronal t2-weighted image showing squaring of the frontal horns with inferior pointing 101 (dashed arrows). the pre-chiasmatic segments of the optic nerves are bilaterally visible with 102 normal size (arrows). (c) an axial t2-weighted image from another patient shows normal 103 septum pellucidum (black arrow). 104 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 79-83, epub 16th mar 2009 submitted 9th june 08 revision req. 26th aug 08, revision recd. 6th sept 08 accepted 14th sept 08 metastatic malignant melanoma during pregnancy case report and a review of the literature *mariam mathew,1 shahila sheik,1 kuntal rao,1 ikram a burney,2 sukhpal sawhney,3 aisha al-hamdani4 تقرير حالة احلمل خالل منتشر خبيث �ورم ميالنيني ادبيات مراجعة مع احلمداني عائشة سوهني، سخبال برني، اكرام راو، كانتال شيك، شاهيال ماثيو، مرمي أشارت السابقة التقارير إلى املشيمة واجلنني. ينتقل أن احلمل ميكن أثناء يحصل وعندما ، كبير بشكل اخلبيث امليالنيني الورم انتشار يزداد امللخص: احلوامل عند يختلف ال اخلبيث امليالنني ورم أن وجدت احلديثة املضبطة ــات الدراس أن غير ، سيئا مآله ويكون ــريعا س يكون احلوامل عند ــاره انتش أن إلى املرض. مآل كفيالن بتحسني الفوري والعالج املبكر التشخيص املرض. مرحلة احلسبان في اخذ ما إذا غيرهم عن عمان. حالة، تقرير احلمل، انتشار، بيث، خَ ميالنينيٌّ الكلمات: وَرَمٌ مفتاح departments of 1obstetrics & gynaecology, 2medicine, 3radiology & molecular imaging and 4pathology, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: mathewz@omantel.net.om abstract malignant melanoma is one of the most rapidly increasing cancers and, when it occurs during pregnancy, it can frequently metastasise to the placenta and the foetus. earlier reports suggested a rapid progress of the disease during pregnancy with a poor prognosis; however, recent controlled studies found that stage for stage, the prognosis of melanoma during pregnancy is similar to that in a non-pregnant state. early diagnosis and prompt treatment can avoid a tragic outcome. key words: malignant melanoma; pregnancy; metastasis; case report; oman. c a s e r e p o r t melanomas are relatively common in white-skinned women of childbear-ing age and many may have the diagnosis made during pregnancy;1 in dark-skinned races the incidence is reported to be much less. the general incidence of melanoma has been increasing over the last few decades at a rate greater than any other malignancy;2 melanoma is now a major cause of cancer death in women of childbearing age. the incidence in pregnancy has been estimated to range from 0.14 to 2.8 per 1,000 live births and melanoma accounts for about 8% of all malignant tumors arising during pregnancy. 3 as there are now an increasing numbers of pregnancies in older women, it is expected that more melanomas will be seen. for several years, it was assumed that hormonal changes during pregnancy might cause a rapid progress of melanoma with poor maternal and fetal outcomes. however most of the recent studies found no difference in overall survival between pregnant and non-pregnant women with melanoma.4, 5 additionally, melanoma is known to metastasise to the placenta and the foetus. metastasis to the products of conception portends a poor prognosis for the mother.6 we report a case of metastatic malignant melanoma diagnosed in the second trimester of pregnancy in a light skinned asian-arab lady. the consequences of a delay in diagnosis are discussed. c a s e r e p o r t a 28 year old light-skinned lady, gravida 2 and para 1, was referred at 27 weeks gestation to the department of obstetrics and gynaecology, sultan qaboos university hospital for management of a locally advanced malignant melanoma. the history dated back to 12 weeks of gestation when the patient presented with left groin pain. she was found to have left inguinal lymphadenopathy and was treated with antibiotics m a r i a m m at h e w, s h a h i l a s h e i k , k u n ta l r a o , i k r a m a b u r n e y, s u k h pa l s aw h n e y a n d a i s h a a l h a m d a n i 80 and subsequently referred to surgeons with no relief. a needle core biopsy from the node at 16 weeks of gestation revealed a metastatic malignant tumor. subsequently, the slide review and immuno-histochemistry studies done at a tertiary centre showed positive staining for s-100, melanin-a, vimentin and focal positivity for human melanoma black (hmb)-45 confirming the diagnosis of a metastatic malignant melanoma. the patient did not arrive at our institution until 11 weeks after the initial biopsy, where the examination revealed a left inguinal dark mass measuring 10 x 7cm size and extending from the left anterior superior iliac spine to the pubic symphysis. the mass was mostly solid and lobulated with some cystic component and was very tender [figure 1]. a complete physical examination revealed a raised nevus 8 x 7mm size with figure 1: pregnant uterus with mass in the left groin figure 2: t2w coronal oblique magnetic resonance imaging scan of pelvis shows lobulated mass in left inguinal region with infiltration of skin and sub-cutaneous tissues. dilated lymphatics seen extending up to vulva (arrows) figure 3: chest x-ray pa view: shows multiple, scattered, nodular, metastatic lesions in both lungs m e ta s tat i c m a l i g n a n t m e l a n o m a d u r i n g p r e g n a n c y 81 satellite lesions in the upper lateral part of left thigh. both breasts had mobile non-tender firm masses: 3 x 3cm in the right breast and 2 x 1cm in the left breast. an ultrasound scan of the foetus revealed a well grown foetus of 27 weeks gestation with normal placenta and amniotic fluid volume. after a multidisciplinary evaluation by the oncologist, the pain management team and the neonatologist, it was decided to deliver the foetus. a magnetic resonance imaging (mri) of the left groin [figure 2] was done to ascertain the extent of the tumour in the anterior abdominal wall and the labour was induced at 28 weeks of gestation, resulting in a male baby weighing 1,310gm with an apgar score of 8 at 1 minute and 9 at 5 minutes. gross as well as histological examination of placenta did not show any metastasis. a complete physical examination, including an examination of the optic fundi, did not reveal any sign of disease in the newborn. the patient received cabergoline for suppression of lactation. a metastatic workup soon after delivery revealed extensive involvement of the lungs [figure 3], liver, spleen [figure 4], and both breasts [figure 5]. a needle core biopsy from the breast lesion confirmed the presence of metastatic melanoma [figure 6]. a magfigure 4: contrast enhanced ct scan shows hypodense, metastatic lesions in right lobe of liver and spleen (arrows) figure 5: ultrasound scan of both breasts showing thick walled necrotic masses figure 6: (a) needle core breast biopsy showing malignant cells with mitotic figures (single arrow) and nuclear inclusions (double arrow), hematoxylin and eosin stain x 60. (b) immunohistochemistry studies showing strong s-100 positivity m a r i a m m at h e w, s h a h i l a s h e i k , k u n ta l r a o , i k r a m a b u r n e y, s u k h pa l s aw h n e y a n d a i s h a a l h a m d a n i 82 netic resonance imaging (mri) scan of the brain did not show any metastasis. the patient was started on combination chemotherapy with cisplatin, vinblastine and dacarbazine with subjective improvement following the first cycle. the treatment was complicated and delayed by the refusal of the patient to continue with intravenous chemotherapy. a chest x-ray following 2 cycles of chemotherapy showed a stable disease state. however, once the intravenous chemotherapy was discontinued, the disease progressed and the patient died 4 months after the delivery. the baby was well for two weeks, then developed a bowel perforation due to necrotising enterocolitis and was transferred to another tertiary care centre with paediatric surgery facilities. laparotomy revealed multiple bowel perforations; unfortunately, the baby died of septicaemia at 3 months of age. d i s c u s s i o n malignant melanoma is the most aggressive form of skin cancer with an increasing incidence over the past decade. although it used to be more common in men, it now affects equal numbers in both sexes. the mean age for diagnosis is 52 years, some 10 years earlier than the more common tumors such as breast, lung and prostate. about 30-35% of women with melanoma are at the childbearing age at the time of diagnosis. the most likely aetiology is reported as intermittent, blistering sun exposure among susceptible individuals.7 common sites of metastasis of malignant melanoma include the lymph nodes, lungs, liver, spleen and the brain. breast metastasis has been reported in cases of cutaneous melanoma, mainly from the upper limb and trunk. our patient had bilateral breast metastasis from a primary tumour in the left lower limb which is extremely rare.8 for several years, it was widely held that the prognosis of melanoma was worse during pregnancy and that subsequent pregnancies increased the risk of recurrence.9,10 also, the use of estrogen containing hormonal preparations was thought to be associated with a worse prognosis. the myths have arisen as a result of the misconception that because skin darkens in pregnancy, melanomas are hormonally sensitive;2 however, recent studies have not found estrogen receptors in melanoma cells.1, 11 these myths about melanoma were strengthened by a report in 1951 from pack and scharnagel9 who reviewed 1,050 patients with malignant melanoma. out of the ten pregnant women in this study, five died within 3 years of diagnosis due to progressive disease. the authors concluded that the women diagnosed with localised melanoma during pregnancy had a worse prognosis, but in this study, only ten pregnant women were included without any comparison group or staging of the disease. multiple controlled series and investigations have found, however, that stage for stage melanoma is not adversely affected by pregnancy. the prognosis, recurrence and incidence of melanoma seem to be unaffected by pregnancy.4, 5, 12 melanoma is one of several tumors which metastasise to the placenta, including lymphomas, leukaemias, breast and lung cancer.13 although melanoma is the most common maternal malignant tumour to metastasise to the placenta, the occurrence is very rare. a review of literature showed 87 cases of placental/foetal involvement with maternal malignancies. of these 72 (83%) reported placental involvement only, 10 (11%) reported foetal metastasis without placental examination, and 5 (6%) reported both placental and foetal metastasis.6 during the period from 1918 to 2002, melanoma was the cancer most commonly found to involve the placenta and foetus, accounting for 27 of 87 (31%) cases. microscopic evaluation of the placenta was performed in 24 of 27 patients, and placental involvement was documented in all 24 patients. six of the 27 reports indicated foetal metastasis, but 3 reports did not document corresponding placental involvement. 6 male infants seemed to be at a higher risk than females for developing metastasis of any maternal cancer. males comprised 80% of all infants with metastasis of melanoma and 75% with metastasis of all cancers.6 previously published reviews have calculated an approximate 25% mortality risk to babies born to mothers with placental involvement. infants developing clinical evidence of maternally derived metastasis have an exceptionally poor prognosis, with death typically occurring within 3 months of diagnosis. the neonates delivered with concomitant placental involvement, but without clinical evidence of the disease, should be considered a high risk population. they should be periodically evaluated for development of melanoma for at least 24 months postpartum. adjuvant treatment of infants born to women with placental metastasis of melanoma has not been reported.14 the management of melanoma during pregnancy requires several difficult decisions as the disease inm e ta s tat i c m a l i g n a n t m e l a n o m a d u r i n g p r e g n a n c y 83 volves both the mother and the foetus. decision making should be based on: 1) the impact of pregnancy on the outcome of the metastatic melanoma; 2) the gestational age and the risk of metastasis to the placenta and foetus; 3) the safety of radio diagnostic tests and chemotherapy during pregnancy, and 4) the treatment options for metastatic melanoma during pregnancy. although surgery is the definitive therapy for early stage disease, rapidly progressive metastatic disease during pregnancy is difficult to treat. chemotherapeutic regimens for metastatic disease administered during pregnancy have not demonstrated significant efficacy.15 the decision to deliver our patient at 28 weeks of gestation was to give the mother the best chance of survival. the neonatal survival in our institution at 28 weeks is more than 90%. the dilemma was the mode of delivery; induction of vaginal delivery versus cesarean section. at 28 weeks, the failure of labour induction is very high, but cesarean section was also risky as the tumor was infiltrating into the incision site. hence we decided to try induction of labour first; fortunately the patient responded. the delay in the diagnosis of our case may be because of the low index of suspicion; considering that this was a young, asian-arab woman, where the risk of melanoma was perceived to be less. the rapid progression of the disease as mentioned may have been due to the natural history of the disease, although it is impossible to know whether hormonal changes during pregnancy had an impact. whereas most of the data regarding malignant melanoma comes from white-skinned races, its natural history and progression during pregnancy in coloured races, although light-skinned as in our case, may be different. c o n c l u s i o n malignant melanoma is not uncommon during pregnancy, although this is the first case reported from our institution in the past eighteen years. as early diagnosis may lead to cure, it is essential that all clinicians who care for pregnant women understand this disease. obstetricians and midwives should do a full skin examination of all parts of the body during evaluation of the pregnant women and any suspicious nevi should be biopsied. treatment of early stage melanoma is the same irrespective of whether or not the patient is pregnant. delay in the diagnosis and treatment may result in a tragic outcome as in our case. r e f e r e n c e s 1. mackie rm: pregnancy and exogenous hormones in patients with cutaneous malignant melanoma. curr opin oncol 1999; 11:129-31. 2. katz vl, farmer rm, dotters d: focus on primary care: from nevus to neoplasm: myths of melanoma in pregnancy. obstet gynecol surv 2002; 57:112-19. 3. ernstoff ms, christopher pg, tretter md, titus-ernstoff l. update: medical therapy for cutaneous melanoma. am soc clin oncol 2003; 198-207. 4. wiggins cl, berwick m, bishop ja. malignant melanoma in pregnancy. obstet gynecol clin north am 2005; 32:559-68. 5. silipo v, paola ds, giustino m, pierluigi b, angela f, caterina c. malignant melanoma and pregnancy: melanoma res 2006; 16:497-500. 6. nikolin bl, sveljo o. metastatic melanoma and pregnancy. arch oncol 2005; 13:31-4. 7. berwick m, wiggins c. the current epidemiology of malignant melanoma. front biosci 2006; 11:1244-54. 8. bassi f, gatti g, mauri e, ballardini b, de pas t, luini a. breast metastasis from cutaneous malignant melanoma. breast 2004; 13:533-5. 9. pack gt, scharnagel im: prognosis of malignant melanoma in pregnant women. cancer 1951; 4:324-34. 10. sutherland cm, loutfi a, mather fj, carter rd, krementz et: effect of pregnancy upon malignant melanoma. surg gynecol obstet 1983; 157:443-6. 11. schwartz jl, mozurkewich el, johnson tm. current management of patients with melanoma who are pregnant, want to get pregnant, or do not want to get pregnant. cancer 2003; 97:2130-3. 12. o’meara at, cress r, xing g, danielsen b, smith lh. malignant melanoma in pregnancy a population based evaluation. cancer 2005; 103:1217-26. 13. alexander a, samlowski we, grossman d, bruggers cs, harris rm, zone jj, et al. metastatic melanoma in pregnancy: risk of transplacental metastsis in the infant. j clin oncol 2003; 21:2179-86. 14. borden ec. melanoma and pregnancy. semin oncol 2000; 27:654-5. 15. leachman sa, jackson r, eliason m, larson aa, bolognia jl. management of melanoma during pregnancy. dermatol nurs 2007; 19:145-52. submitted 14 sept 22 1 revisions req. 31 oct 22; revision recd. 20 nov 22 2 accepted 15 dec 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.070 5 6 the yield of cardiac investigations in patients presenting with an acute 7 ischemic stroke 8 a single tertiary centre experience 9 azhaar alshukri,1 *sunil k. nadar,2 arunodaya r. gujjar,2 hatim al 10 lawati,2 mohammed al-rawahi,2 isra al-kindi,3 maathar alfarsi3 11 1department of medicine, oman medical specialty board, muscat, oman; 2department of 12 medicine, sultan qaboos university hospital, muscat, oman; 3department of medicine, college 13 of medicine, sultan qaboos university, muscat, oman. 14 *corresponding author’s e-mail: sunilnadar@gmail.com 15 16 abstract 17 objectives: strokes are a major source of morbidity and mortality. the aim of this study was to 18 evaluate the effectiveness of routine cardiac investigations in identifying a cardioembolic aetiology 19 for ischemic strokes. methods: this was a retrospective study of patients who had presented with 20 a stroke to our institution between january and december 2019. results: a total 183 patients 21 (mean age 66.2+13.5 years, 109 or 59.6% male) were included in the final analysis. the common 22 risk factors were hypertension (74.9%) diabetes (61.7%), and hyperlipidaemia (54.6%). the 23 middle cerebral artery (mca) was the commonest artery affected (44 or 24%). on admission, 24 14(7.6%) patients were in atrial fibrillation with the rest being in sinus rhythm. on 24-hour ecg 25 holter monitoring, no abnormalities were noted in 135 patients. atrial fibrillation was seen in 26 15(8.1%) patients (inclusive of the 14 who had af on resting ecg). 32 (17.4%) patients had 27 evidence of non-sustained atrial arrhythmia and 9(4.9%) had non sustained ventricular tachycardia. 28 thirty patients(16.3%) were also noted to have frequent supraventricular ectopics (>30/hour) 29 while 5(2.7%) patients had a high ventricular ectopic burden (>10% burden). no significant 30 abnormalities were noted in the echocardiograms of the patients, but 10 out of 132 (7.5%) patients 31 had a positive bubble echo. twenty-four (13.1%) patients had enlarged left atria. conclusion: the 32 overall diagnostic yield of abnormalities from routine cardiac testing for patients with stroke 33 appears to be low. targeted screening of patients with crytogenic stroke as suggested by newer 34 guidelines is recommended. 35 keywords: cerebrovascular accidents; echocardiography; atrial fibrillation; oman. 36 37 advances in knowledge 38  routine cardiac testing in patients with stroke has a low yield rate in terms of identifying 39 cardiac source of embolism 40  however, these tests help identify patients at high risk for future atrial fibrillation 41 application to patient care 42  although 24 hour monitoring does not identify all patients with atrial fibrillation, it helps 43 identify those at risk of atrial fibrillation 44  careful evaluation of these patients must be made to assess suitability for anticoagulation. 45 46 introduction 47 strokes are a leading cause of morbidity and mortality worldwide. according to figures from 2019, 48 the reported prevalence was 101 million cases worldwide with around 12.2 million incident cases 49 of stroke.1 they are the second leading cause of death and the third leading cause of death and 50 disability combined.1 this is associated with increased costs and loss of productivity and in the 51 united states alone, it is projected that the medical costs related to stroke will increase from around 52 75 billion dollars annually in 2010 to around 180 billion dollars by 2030, in addition to indirect 53 costs due to loss of productivity from around 30 billion dollars annually in 2010 to around 55 54 billion dollars annually during the same period.2 according to the latest data published by the 55 who, stroke related deaths accounted for 11.1% of the total deaths, with the age adjusted death 56 rate at 94.98 per 100,000 population in oman. it is the third leading cause of mortality in oman 57 after coronary heart disease and diabetes mellitus.3 additionally, the prevalence of risk factors for 58 stroke is high among the omani population, adding to the potential economic burden of the 59 disease.4 60 61 the aetiology of ischemic strokes can be divided into five categories based on the toast (trial 62 of org 10172 in acute stroke treatment) criteria, large artery atherosclerosis, cardioembolism, 63 small vessel occlusion, stroke of other determined aetiology, and stroke of undetermined 64 (“cryptogenic”) aetiology.5 cardioembolic stroke accounts for about 20–25% of all ischemic 65 strokes and is associated with a worse prognosis with respect to disability, mortality and both early 66 and long -term recurrences compared to other aetiologies.6;7 67 68 sources for cardioembolism are further classified into majoror minor-risk sources according to 69 their (thrombo-) embolic potential.8 the most common major-risk source of cardioembolism is 70 atrial fibrillation (af).9 less frequent major-risk sources are cardiomyopathies with left 71 ventricular (lv) dysfunction, intracardiac thrombi, cardiac tumours, prosthetic valves, and 72 endocarditis. minor-risk sources include patent foramen ovale (pfo), atrial septum aneurysm 73 (asa), and calcification of aortic and mitral valves.8 74 75 the overall purpose of such classification of strokes using toast system (or any other similar 76 ones) is that it has major implications for preventive management.6 strokes have a high incidence 77 of recurrence with a five-year recurrence rates of around 30%.10 identifying the aetiology of the 78 stroke is therefore important in preventing future strokes. while the large majority of larger or 79 small artery strokes are treated with antiplatelet agents and statin, their long term relative risk 80 reduction in the recurrence of stroke is about 20-25%,11 in contrast, using anticoagulants for 81 prevention of definitively recognized cardio-embolic stroke results in a long term relative risk 82 reduction of 60-65%.11 further, cardio-embolic strokes are associated with a much higher 83 morbidity and mortality as compared to other forms of stroke by virtue of their tendency to cause 84 large infarcts with poor cardiovascular support for re-establishment of cerebral circulation. thus 85 diagnosis and prevention of cardioembolic strokes is relatively more effective (with 86 anticoagulationas compared to non-cardioembolic strokes) as well as more cost-effective (in that 87 it prevents higher morbidity and mortality). 88 89 in the above context, the american heart association/american stroke association (aha/asa) 90 and the european stroke organisation (eso) had recommended routine cardiac testing such as a 91 minimum of 24 hours of cardiac ecg monitoring and a transthoracic echocardiogram for all 92 patients who have suffered a stroke.11;12 the diagnostic yield from these sets of investigations is 93 variable with many studies recommending longer durations of cardiac monitoring to improve the 94 diagnosis and identification of atrial fibrillation.9;13 similarly, there are studies suggesting the 95 routine use of transoesophageal echo over transthoracic echo to improve the identification of 96 cardiac abnormalities that can predispose to strokes.14 while the older guidelines recommended 97 cardiac investigations in all patients presenting with a stroke, newer guidelines however 98 recommend these investigations in patients with cryptogenic strokes.15 99 100 in our institution, it is standard practice to perform 24-hour ecg holter monitoring and a 101 transthoracic echocardiogram (with a bubble study) for all patients presenting with an ischemic 102 stroke. the aim of this study was to assess the rate of identification of abnormalities with these 103 tests in our institution. 104 105 methods 106 all patients aged 18 and above, who were admitted with a final diagnosis of stroke between 107 january and december 2019 at the sultan qaboos university hospital (squh) were identified. 108 their electronic case records were reviewed and only those who had full cardiac evaluation were 109 included in the final analysis. we excluded those whose scans had demonstrated an intracranial 110 bleed or who died before any cardiac investigations were performed or those on whom 111 investigations were not done due to presumed very poor prognosis or for other clinical reasons. 112 we also excluded those in whom the case records were incomplete. patients were diagnosed to 113 have a stroke based on clinical findings and from a ct scan of the brain. carotid artery imaging 114 and mri scans of the brain were not routinely performed. ethical approval was obtained from the 115 medical research ethical committee of the sultan qaboos university hospital, muscat, oman 116 (mrec number 1365). 117 118 all eligible patients had undergone 24-hour holter ecg monitoring and a standard transthoracic 119 echocardiogram with an agitated saline contrast study. the holter data were analysed by seer 120 1000 (ge medical systems technologies ltd., boston ma, usa). the abnormalities were 121 classified as in other major studies. atrial fibrillation was considered if the episode lasted more 122 than 30 seconds. anything less was classified as atrial tachyarrhythmia. 16;17 the frequency of 123 premature ventricular contractions (pvc) was reported as high if the burden was greater than 10% 124 of the total qrs complexes in a 24-hour period. 18 we classified those from 1-10% as medium 125 and anything less was considered low. the frequency of premature atrial contractions (pac) was 126 considered to be high if it exceeded 30 pacs/hour (720 pacs in 24 hours), medium if it was 127 between 10-30 pacs per hour (240-720 pacs per 24 hours) and low if less than 10 pacs per 128 hour.19 129 130 echocardiograms were performed using a ge vivid 7 machine as per standard protocol.(20) the 131 abnormalities that were examined for included valvular abnormalities such as mitral stenosis, 132 intracardiac masses such as vegetations, tumors or thrombi and evidence of intracardiac shunts. 133 an agitated saline study was also performed according to standard protocol with normal respiration 134 and post-valsalva manoeuvre where possible.(20) the study was positive if agitated saline was 135 noted at the left sided cardiac chambers in less than 4 cardiac cycles. this could then identify 136 patients with a patent foramen ovale (pfo) or other causes of an intracardiac shunt. the left atrium 137 was considered to be enlarged if it measured more than 4cm in men and 3.9cm in women. 138 pulmonary hypertension was defined as mild if the mean pressure was calculated to be 25-139 35mmhg, moderate if between 35-45 mmhg and severe greater than 45 mmhg. 16 140 141 the rope (risk of paradoxical embolism) score has been developed and validated as an 142 assessment tool to determine the probability that a pfo is responsible for a cryptogenic stroke.21 143 it can be used when assessing patients with a pfo preceding closure. a high score correlates with 144 increased likelihood that a pfo is responsible for the index stroke. the pfo‐attributable fraction 145 of stroke for a score of 7, 8, and 9 is 72%, 84%, and 88%, respectively, and defines a subset of 146 patients who may benefit from pfo closure. we calculated the rope score for our patients as 147 described before. 21 148 149 the collected data were analysed using statistical software spss statistics (spss inc., chicago, 150 us) version 22. a descriptive analysis of the categorized variables was presented as proportions, 151 and continuous variables were presented as the mean and standard deviation. chi-square test was 152 used to check for differences among groups for categorical variables. 153 154 results 155 a total of 215 patients were identified who were admitted with a diagnosis of stroke during the 156 specified time period. of these 32 patients did not fulfil our inclusion criteria and 183 patients 157 (mean age 66.2+13.5 years, 109 (59.6%) male and 74 (40.4%) female) were included in the final 158 analysis of the study. the risk factors of the patients are summarized in table 1. hypertension was 159 the commonest risk factor (74.9%) followed by diabetes (61.7%), and hyperlipidiemia (54.6%). 160 79 (43.2%) of patients had three cardiovascular risk factors followed by 36 (19.7%) who had two 161 risk factors. forty patients (21.9%) had one risk factor, while 28(15.3%) did not have any 162 cardiovascular risk factor. data on smoking habits was incomplete. 26.2% of patients had a 163 previous myocardial infarction and in 52 patients (28.4%), this was a recurrent stroke. one patient 164 had a prosthetic cardiac valve, and one was already known to have atrial fibrillation and both 165 patients were on anticoagulation. at the time of admission with a stroke both these patients had 166 inr values that were in the therapeutic range. all the patients with previous myocardial infarction 167 were on a single antiplatelet agent. there were no differences between the demographics of the 168 patients who presented with a first stroke or a recurrent stroke. 169 170 as per the toast classification types, small vessel disease was the commonest mechanism of 171 stroke in this cohort accounting for 112 (61.2%) patients. large artery stroke was the mechanism 172 in 56 (30.6%) patients, while in 15 (8.2%) it was of undetermined aetiology. cardioembolism, on 173 its own, was not identified as a mechanism of stroke in any of these patients. the patients with 174 atrial fibrillation had multiple atherosclerotic risk factors and therefore classified as stroke of 175 undetermined aetiology. the middle cerebral artery (mca) was the commonest artery to be 176 affected (44 or 24%), followed by the posterior cerebral artery in 13 (7.1%) patients. almost a 177 third of the patients (67 of 183 or 36.6%) had involvement of the left sided limbs, while 45 of 183 178 (24.6%) had involvement of right sided limbs and in another 71 patients (38.8%), the side of 179 hemiplegia was not documented or there was no focal hemiplegia as it was either symptoms of 180 posterior circulation (such as dizziness, cerebellar signs etc.) or a lacunar infarct or the patient was 181 comatose. 182 183 all the patients had undergone a resting 12-lead-ecg on arrival. this identified 14 patients to be 184 in atrial fibrillation on presentation with the rest being in sinus rhythm. all patients underwent a 185 24hour holter ecg monitoring. the findings are summarized in table 2. the 24hour recording 186 did not show any abnormality in 135 patients. atrial fibrillation was seen in 15 patients (one newly 187 diagnosed in addition to the 14 who had af on their resting ecg). 32 patients had evidence of 188 non-sustained atrial arrhythmia and 9 had non sustained ventricular tachycardia. thirty patients 189 were also noted to have frequent supraventricular ectopics (defined as more than 30/hour) while 5 190 patients had a high ventricular ectopic burden (more than 10% burden). there were no differences 191 between the findings in patients with a first or recurrent stroke. 192 193 a total of 165 patients had an echocardiogram performed during their stay in the hospital [table 194 3]. there is no documented reason why the remaining 18 did not have an echocardiogram. none 195 of the patients had any mass or vegetation or thrombus noted in the scan. severe aortic stenosis 196 was identified in 3 patients, severe mitral stenosis in one patient and severe mitral regurgitation in 197 three patients. two were found to have severe pulmonary hypertension. 132 patients had an 198 agitated saline contrast scan done of which 10 were reported as positive for a left to right shunt 199 (positivity rate of 7.7%). the rope score of these patients were a median of 5 with a range from 200 2 to 8. three patients had a score of 6 and one of 8. twenty-four patients had a left atrial size that 201 was above the upper limits of normal (4cm in males and 3.9 cm in females). there were no 202 differences between patients presenting with a first or recurrent stroke. 203 204 the relationship between left atrial size and atrial arrhythmias is shown in table 4. there was a 205 higher proportion of patients having af and atrial tachyarrhythmias in the group with enlarged left 206 atria. although numerically different, there was no statistical difference between the pac burden 207 in the two groups. 208 209 discussion 210 the primary aim of cardiac investigations after a stroke is to identify any potential source of 211 cardioembolism with the intention to treat and prevent recurrence of strokes. these could be 212 obvious thrombi or masses within the cardiac chambers, cardiac valve abnormalities or 213 arrhythmias such as atrial fibrillation. though the old stroke guidelines recommended routine 214 testing in all patients with strokes, the current guidelines recommend routine imaging in the form 215 of transthoracic echocardiography and monitoring for rhythm disturbances especially atrial 216 fibrillation for patients with cryptogenic strokes. similarly, whilst earlier guidelines recommended 217 a minimum of 24 hours of ecg monitoring, subsequent studies have demonstrated that longer 218 monitoring increases the detection rate of atrial fibrillation17;22;23 the latest guidelines have 219 embraced this and recommend prolonged ecg monitoring of at least 48 to 72 hours or longer if 220 possible.24 none of the patients in our study had undergone prolonged monitoring. besides the 14 221 patients who had af on their resting ecg, 24-hour monitoring identified only one further patient. 222 223 besides episodes of atrial fibrillation, there has been interest in atrial ectopics or premature atrial 224 contractions (pac) as a precursor to af. studies have demonstrated conclusively that patients 225 with a high burden of pacs have a higher risk of developing af.19;25 binici et al have shown that 226 patients with a pac rate of more than 30 per hour had a 2.7-fold increase in the risk of developing 227 af and also had a greater than 60% increased risk of death or stroke.(19) they found that for each 228 increase of 10 pac per hour, the risk of the primary end point of death or stroke increased by 27% 229 and the risk of atrial fibrillation by 50%. while the american guidelines on stroke prevention do 230 not specifically mention these patients, it has been previously recommended that patients with a 231 high pac burden would benefit from anticoagulation especially if their chads2vasc score is 232 greater than 2. however, there are no studies to back this recommendation. in our study, 36 patients 233 had some form of atrial arrhythmia with a similar number having a high burden of pacs. given 234 the propensity of these patients to develop af in the future and in the absence of facilities to 235 perform long term ecg monitoring, careful consideration should be given regarding 236 anticoagulation of these patients. 237 238 the other abnormality that is commonly identified on holter monitoring is frequent ventricular 239 ectopics. these can predispose to impaired lv systolic function and formation of lv thrombus 240 which can embolise.(26) in our study, almost a fifth of the patients had at least moderate to high 241 burden of ves. although this can represent a high adrenergic stage in the immediate post stroke 242 state, these patients should be monitored for development of tachycardia related cardiomyopathy 243 or other abnormalities.(26) conduction abnormalities are a commonly reported findings on holter 244 monitoring, but in our study, we did not detect any patients with significant conduction 245 abnormalities. 246 247 echocardiography can detect many potential cardiac sources of embolism such as left atrial 248 thrombus, patent foramen ovale, atrial septum aneurysm, valvular or myocardial disease, 249 vegetations or cardiac tumors amongst others.(27) furthermore, it can reveal other cardiac 250 pathologies of potential therapeutic consequences such as wall motion abnormalities or a reduced 251 left ventricular function. the mode of echocardiography could be either transthoracic (tte), 252 which is widely available, non-invasive, less personnel-intensive and cheap or transoesophageal 253 echocardiography (toe) which is otherwise superior for evaluation of the aortic arch, left atrium 254 and its appendage, and atrial septum.(14) 255 256 agitated saline contrast study is often considered to be part of the protocol for echocardiography 257 in patients who have a stroke with the aim of identifying any left to right shunts notably pfos. 258 the role of closing a pfo post stroke is still not clear with conflicting data. earlier randomized 259 controlled trials failed to show a statistically significant benefit for a pfo closure;(28;29) thus, many 260 investigators believed that a pfo, being a not uncommon occurrence, was an incidental bystander 261 in patients with stroke. however, meta-analyses and more recent specific trials have eliminated 262 several confounding factors and possible biases and have demonstrated a benefit of the use of a 263 shunt closure over medical therapy in patients with cryptogenic stroke, particularly among those 264 below the age of 60 years with no obvious risk factors explaining the incident stroke.(30-32) 265 266 in our study 10 out of the 132 patients who had undergone an agitated saline contrast study were 267 positive for a pfo. this is lower than the reported incidence of pfos in the general population 268 (20-30%) and the stroke population (around 50%).(33;34) we are unable to explain this discrepancy. 269 except for one patient, all had a rope score of less than 7. the reason for the patient with a high 270 rope score not being referred for further tee assessment was not documented. it could be argued 271 therefore that to be cost effective, the agitated saline study should be performed only in those with 272 a high rope score. 273 274 the tte may also identify other surrogate markers of potential af such as increased left atrial 275 volume and left atrial strain. besides this, other anatomical variations that can favour the 276 promotion of thrombi can also be diagnosed. these include aneurysm of the interatrial septum 277 (defined as a septal protrusion of greater than 11 to 15 mm and which is often associated with 278 pfos),(35) the persistence of eustachian valve (which directs fetal blood flow towards the pfo) (36) 279 and a prominent chiari network (persistence of a remnant of the fetal atrial development).(37) in 280 our study, the echo reports did not comment on the presence of any of these abnormalities in any 281 of the patients. the other abnormalities that were diagnosed on tte in our study were minor valve 282 abnormalities. however, it is unlikely that this contributed to the stroke. 283 284 the overall yield of positive tests from routine cardiac investigations for all patients presenting 285 with a stroke appears low from our study. 14 patients had newly diagnosed af on their presenting 286 ecg with only one extra patient identified on 24-hour holter monitoring. echocardiography 287 identified 4 cases with significant valve disease and a doubtful link to the presenting stroke this 288 is similar to other reported studies, where the diagnostic yield of routine testing was low and where 289 the cost effectiveness of such routine tests was questioned.(38) however, if we include all the cases 290 with surrogate markers of potential atrial fibrillation such as high pac burden and dilated left atria 291 on echocardiography, the diagnostic yield for all directly and indirectly linked pathologies is 292 higher. additional studies are needed to systematically ascertain whether anticoagulation in such 293 patients carries any long-term benefits, especially as it relates to stroke prevention. furthermore, 294 we observed that the results of the cardiac investigations (apart from those with af) did not 295 appreciably alter the final management, thereby questioning the usefulness of these investigations 296 in all patients with a stroke. indeed, the newer guidelines, recommend these tests only in patients 297 with cryptogenic strokes in contrast to the older guidelines where these tests were recommended 298 in all patients with a stroke and would suggest that we change the policy in our hospital. 299 300 there were a few limitations in our study. this was a retrospective study that involved examining 301 past electronic case records of the enrolled patients. the comprehensiveness of the case records 302 therefore was a limiting factor as some patients had incomplete data and these were not included 303 in the final diagnosis. we did not follow up the prognosis of these patients to see whether they had 304 a recurrent stroke. another limitation was the fact that the left atrium size was measured in two-305 dimension, but newer guidelines suggest that the la area is to be calculated and adjusted to body 306 surface area. this could have given us a more accurate account of the state of the la. 307 308 conclusion 309 the overall yield from cardiac investigations in patients presenting with a stroke is relatively low. 310 they are, however, useful in identifying surrogate markers that increase the future risk of atrial 311 fibrillation, though studies are required to investigate the effectiveness of long-term 312 anticoagulation in these patients. further studies are also required to ascertain the cost 313 effectiveness of routine cardiovascular testing in all patients with a stroke and whether they 314 influence management and outcome beyond identifying patients with af. 315 316 author contribution 317 aa, ia and ma collected the data. skn, arg, ha and mar analysed the data and drafted the 318 manuscript. all authors approved the final version of the manuscript. 319 320 conflict of interest 321 the authors declare no conflicts of interest. 322 323 funding 324 no funding was received for this study. 325 326 references 327 1. global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic 328 analysis for the global burden of disease study 2019. lancet neurol 2021 oct;20(10):795-329 820. doi: 10.1016/s1474-4422(21)00252-0 330 2. ovbiagele b, goldstein lb, higashida rt, howard vj, johnston sc, khavjou oa, et al. 331 forecasting the future of stroke in the united states: a policy statement from the american 332 heart association and american stroke association. stroke 2013 aug;44(8):2361-75. doi: 333 10.1161/str.0b013e31829734f2 334 3. incidence of non communicable diseases in oman. 2022. available at 335 https://www.worldlifeexpectancy.com/oman-stroke accessed on 8 november 2022 336 4. ganguly ss, gujjar ar, al hh, al ha, jaju s, al-mahrezi a, et al. risk factors for 337 ischaemic stroke in an omani community: a case-control study. sultan qaboos univ med j 338 2021 nov;21(4):585-90. doi: 10.18295/squmj.4.2021.043 339 https://doi.org/10.18295%2fsqumj.4.2021.043 5. adams hp, jr., bendixen bh, kappelle lj, biller j, love bb, gordon dl, et al. 340 classification of subtype of acute ischemic stroke. definitions for use in a multicenter 341 clinical trial. toast. trial of org 10172 in acute stroke treatment. stroke 1993 342 jan;24(1):35-41. doi: 10.1161/01.str.24.1.35 343 6. kolominsky-rabas pl, weber m, gefeller o, neundoerfer b, heuschmann pu. 344 epidemiology of ischemic stroke subtypes according to toast criteria: incidence, 345 recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. 346 stroke 2001 dec 1;32(12):2735-40. doi: 10.1161/hs1201.100209 347 7. perera ks, swaminathan b, veltkamp r, arauz a, ameriso s, marti-fabregas j, et al. 348 frequency and features of embolic stroke of undetermined source in young adults. eur stroke 349 j 2018 jun;3(2):110-6. doi: 10.1177/2396987318755585 350 8. cohen a, donal e, delgado v, pepi m, tsang t, gerber b, et al. eacvi recommendations 351 on cardiovascular imaging for the detection of embolic sources: endorsed by the canadian 352 society of echocardiography. eur heart j cardiovasc imaging 2021 may 10;22(6):e24-e57. 353 doi: 10.1093/ehjci/jeab008 354 9. haeusler kg, tutuncu s, schnabel rb. detection of atrial fibrillation in cryptogenic stroke. 355 curr neurol neurosci rep 2018 aug 8;18(10):66. doi: 10.1007/s11910-018-0871-1 356 10. kolmos m, christoffersen l, kruuse c. recurrent ischemic stroke a systematic review 357 and meta-analysis. j stroke cerebrovasc dis 2021 aug;30(8):105935. doi: 358 10.1016/j.jstrokecerebrovasdis.2021.105935 359 11. jauch ec, saver jl, adams hp, jr., bruno a, connors jj, demaerschalk bm, et al. 360 guidelines for the early management of patients with acute ischemic stroke: a guideline for 361 healthcare professionals from the american heart association/american stroke association. 362 stroke 2013 mar;44(3):870-947. doi: 10.1161/str.0b013e318284056a 363 12. european stroke organisation executive committee: guidelines for management of 364 ischaemic stroke and transient ischaemic attack 2008. cerebrovasc dis 2008;25(5):457-507. 365 doi: 10.1159/000131083 366 13. wachter r, groschel k, gelbrich g, hamann gf, kermer p, liman j, et al. holter-367 electrocardiogram-monitoring in patients with acute ischaemic stroke (find-368 afrandomised): an open-label randomised controlled trial. lancet neurol 2017 369 apr;16(4):282-90. doi: 10.1016/s1474-4422(17)30002-9 370 https://doi.org/10.1177%2f2396987318755585 14. de bruijn sf, agema wr, lammers gj, van der wall ee, wolterbeek r, holman er, et al. 371 transesophageal echocardiography is superior to transthoracic echocardiography in 372 management of patients of any age with transient ischemic attack or stroke. stroke 2006 373 oct;37(10):2531-4.v 374 15. kleindorfer do, towfighi a, chaturvedi s, cockroft km, gutierrez j, lombardi-hill d, et 375 al. 2021 guideline for the prevention of stroke in patients with stroke and transient 376 ischemic attack: a guideline from the american heart association/american stroke 377 association. stroke 2021 jul;52(7):e364-e467. 378 16. stahrenberg r, weber-kruger m, seegers j, edelmann f, lahno r, haase b, et al. enhanced 379 detection of paroxysmal atrial fibrillation by early and prolonged continuous holter 380 monitoring in patients with cerebral ischemia presenting in sinus rhythm. stroke 2010 381 dec;41(12):2884-8. 382 17. wasser k, weber-kruger m, jurries f, liman j, hamann gf, kermer p, et al. the cardiac 383 diagnostic work-up in stroke patients-a subanalysis of the find-afrandomised trial. 384 plos one 2019;14(5):e0216530. 385 18. baman ts, lange dc, ilg kj, gupta sk, liu ty, alguire c, et al. relationship between 386 burden of premature ventricular complexes and left ventricular function. heart rhythm 2010 387 jul;7(7):865-9. 388 19. binici z, intzilakis t, nielsen ow, kober l, sajadieh a. excessive supraventricular ectopic 389 activity and increased risk of atrial fibrillation and stroke. circulation 2010 may 390 4;121(17):1904-11. 391 20. mitchell c, rahko ps, blauwet la, canaday b, finstuen ja, foster mc, et al. guidelines 392 for performing a comprehensive transthoracic echocardiographic examination in adults: 393 recommendations from the american society of echocardiography. j am soc echocardiogr 394 2019 jan;32(1):1-64. 395 21. collado fms, poulin mf, murphy jj, jneid h, kavinsky cj. patent foramen ovale closure 396 for stroke prevention and other disorders. j am heart assoc 2018 jun 17;7(12). 397 22. sanna t, diener hc, passman rs, di l, v, bernstein ra, morillo ca, et al. cryptogenic 398 stroke and underlying atrial fibrillation. n engl j med 2014 jun 26;370(26):2478-86. 399 23. sposato la, cipriano le, saposnik g, ruiz ve, riccio pm, hachinski v. diagnosis of 400 atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-401 analysis. lancet neurol 2015 apr;14(4):377-87. 402 24. prefasi d, martinez-sanchez p, fuentes b, diez-tejedor e. the utility of the rope score in 403 cryptogenic stroke patients </=50 years in predicting a stroke-related patent foramen ovale. 404 int j stroke 2016 jan;11(1):np7-np8. 405 25. wallmann d, tuller d, wustmann k, meier p, isenegger j, arnold m, et al. frequent atrial 406 premature beats predict paroxysmal atrial fibrillation in stroke patients: an opportunity for a 407 new diagnostic strategy. stroke 2007 aug;38(8):2292-4. 408 26. panizo jg, barra s, mellor g, heck p, agarwal s. premature ventricular complex-induced 409 cardiomyopathy. arrhythm electrophysiol rev 2018 jun;7(2):128-34. 410 27. pepi m, evangelista a, nihoyannopoulos p, flachskampf fa, athanassopoulos g, colonna 411 p, et al. recommendations for echocardiography use in the diagnosis and management of 412 cardiac sources of embolism: european association of echocardiography (eae) (a registered 413 branch of the esc). eur j echocardiogr 2010 jul;11(6):461-76. 414 28. furlan aj, reisman m, massaro j, mauri l, adams h, albers gw, et al. closure or medical 415 therapy for cryptogenic stroke with patent foramen ovale. n engl j med 2012 mar 416 15;366(11):991-9. 417 29. meier b, kalesan b, mattle hp, khattab aa, hildick-smith d, dudek d, et al. percutaneous 418 closure of patent foramen ovale in cryptogenic embolism. n engl j med 2013 mar 419 21;368(12):1083-91. 420 30. saver jl, carroll jd, thaler de, smalling rw, macdonald la, marks ds, et al. long-421 term outcomes of patent foramen ovale closure or medical therapy after stroke. n engl j 422 med 2017 sep 14;377(11):1022-32. 423 31. sondergaard l, kasner se, rhodes jf, andersen g, iversen hk, nielsen-kudsk je, et al. 424 patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. n engl j med 425 2017 sep 14;377(11):1033-42. 426 32. lee ph, song jk, kim js, heo r, lee s, kim dh, et al. cryptogenic stroke and high-risk 427 patent foramen ovale: the defense-pfo trial. j am coll cardiol 2018 may 428 22;71(20):2335-42. 429 33. hara h, virmani r, ladich e, mackey-bojack s, titus j, reisman m, et al. patent foramen 430 ovale: current pathology, pathophysiology, and clinical status. j am coll cardiol 2005 nov 431 1;46(9):1768-76. 432 34. mazzucco s, li l, binney l, rothwell pm. prevalence of patent foramen ovale in 433 cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-434 based study, systematic review, and meta-analysis. lancet neurol 2018 jul;17(7):609-17. 435 35. mas jl, arquizan c, lamy c, zuber m, cabanes l, derumeaux g, et al. recurrent 436 cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. 437 n engl j med 2001 dec 13;345(24):1740-6. 438 36. onorato em. large eustachian valve fostering paradoxical thromboembolism: passive 439 bystander or serial partner in crime? world j cardiol 2021 jul 26;13(7):204-10. 440 37. edwards p, wozniak m, corretti m, price tr. cardiac chiari network as an etiology for 441 embolic stroke. j stroke cerebrovasc dis 1994;4(4):238-41. 442 38. douen a, pageau n, medic s. usefulness of cardiovascular investigations in stroke 443 management: clinical relevance and economic implications. stroke 2007 jun;38(6):1956-8. 444 445 table 1: demographics of the patients 446 overall group (percentage) first stroke (n=131) recurrent stroke (n=52) p value age 66.2+ 13.5 65.6+13.7 67.9+12.8 0.2 gender male female 109(59.6%) 74(40.4%) 79 (60.3%) 52 (39.7%) 30 (57.6%) 22 (42.4%) 0.7 diabetes 113 (61.7%) 82 (62.5%) 31 (59.6%) 0.7 hypertension 137 (74.9%) 95(72.5%) 42 (80.7%) 0.2 dyslipidemia 100(54.6%) 66 (50.3%) 34 (65.3%) 0.06 previous mi 48 (26.2%) 29 (22.1%) 19 (36.5%) 0.04 artery involved mca pca basilolateral aca pica ica no clear artery identified 44(24%) 13(7.1%) 5(2.7%) 5(2.7%) 2 (1.1%) 2(1.1%) 112(61.2%) 25 (19.1%) 10 (7.6%) 5 (3.8%) 3 (2.3%) 1 (0.7%) 2 (1.4%) 85 (64.8%) 19 (36.5%) 3 (5.7%) 0 2 (3.8%) 1 (1.9%) 0 27(51.9%) 0.14 site of hemiplegia right 45(24.6%) 35 (26.7%) 10 (19.1%) left indeterminate* 67(36.6%) 71(38.8%) 45 (34.3%) 51 (38.9%) 22 (42.3%) 20 (38.4%) 0.59 mimyocardial infarction, mcamiddle cerebral artery, pcaposterior cerebral artery, aca447 anterior cerebral artery, picaposterior inferior cerebellar artery, icainternal carotid artery 448 *“indeterminate” includes patients without hemiplegia such as lacunar infarcts, posterior 449 circulation strokes, or where patient was comatose and it was difficult to ascertain the site of 450 infarct or where site of hemiplegia was not documented. 451 analysis by chi-square test or students t-test as appropriate 452 453 table 2: ecg and holter monitoring 454 test overall group number(percentage) first stroke (n=131) recurrent stroke (n52) p value rhythm on resting ecg normal sinus rhythm atrial fibrillation 169(92.3%) 14(7.7%) 122 (93.1%) 9 (6.9%) 47 (90.3%) 5 (9.7%) 0.5 holter findings normal atrial fibrillation atrial tachycardia svt vt conduction abnormalities 135 (73%) 15(8.2%) 32 (17.5%) 4(2%) 9(4.9%) 2(1.1%) 98 (74.8%) 9 (6.8%) 21 (16%) 4 (3%) 5 (3.8%) 2 (1.5%) 37 (71.1%) 6(11.5%) 11 (21.1%) 0 0 4 (7.6%) 0.38 pvc burden <1% 1-10% >10% 148(80.9%) 30(16.4%) 5(2.7%) 109 (83.2%) 20 (15.2%) 2 (1.5%) 39(75%) 10 (19.2%) 3(5.7%) 0.21 pac burden <10/hr 10-30/hr >30/hr 143(78.1%) 10(5.5%) 30(16.4%) 102 (77.8%) 7 (5.3%) 21(16%) 41(78.8%) 2 (3.8%) 9(17.3%) 0.9 svtsupraventricular tachycardia, vtventricular tachycardia, pvcpremature ventricular 455 contraction, pacpremature atrial contraction 456 analysis by chi-square test 457 458 table 3: echo findings 459 findings overall group (n=165) first stroke (n-120) recurrent stroke (n=45) p value ejection fraction (%) 54.2 +11.1 54.8+11.2 52.6+10.7 0.23 la size (mm) 25.7 (23.8-33.7) 26.86(24-34) 25.0(22.8-29.9) 0.07 lvidd (mm) 4.2+0.73 4.19+0.72 4.13+0.69 0.66 aortic regurgition no/mild moderate severe 157 (85.7%) 8 (4.4%) 0 114 (95%) 6(5%) 0 43 (95.5%) 2(4.4%) 0 0.64 aortic stenosis no/mild moderate severe 161 (97.6%) 1(0.6%) 3(1.8%) 117(97.5%) 1(0.8%) 2 (1.7%) 44(97.7%) 0 1(2.3%) 0.68 mitral stenosis no/mild moderate severe 164(99.4) 0 1(0.6) 120 (100%) 0 0 44 (97.7%) 0 1(2.3%) 0.21 mitral regurgitation no/mild moderate severe 150(90.9%) 12(7.3%) 3(1.8%) 108(90%) 9(7.5%) 3(2.5%) 42(93.3%) 3(6.7%) 0 0.26 pulmonary hypertension no mild moderate severe 144(87.3%) 12(7.3%) 7(4.2%) 2(1.2%) 101(84.1%) 10(8.3%) 7(5.8%) 2(11.7%) 43(95.5%) 2(4.4%) 0 0 0.20 agitated saline echo (n=132) positive 10 (7.6%) 6(5%) 4(8.9%) 0.38 enlarged la 24 (13.1%) 21(17.5%) 3(6.7%) 0.08 laleft atrium, lviddleft ventricular internal diameter in diastole, left atrium was 460 considered to be enlarged if it measured more than 4cm in men and 3.9cm in women. 461 analysis by chi-square test, students t-test or mann-whitney u test as appropriate 462 463 table 4: left atrial size and atrial arrhythmias 464 normal la size (n=139) enlarged la (n=24) p value pac burden low medium high 113 (81.2%) 7 (5.1%) 19 (13.7%) 15 (62.5%) 2 (8.3%) 7 (29.2%) 0.11 atrial fibrillation 8 (5.7%) 5 (20.8%) 0.01 atrial tachyarrhythmias 24 (17.2%) 5 (20.8%) 0.1 pac count 6(0-58) 33 (80-2402) 0.06* values are number (percentage) or median(interquartile range) analysis by chi-square test, 465 *analysis by mann-whitney test; pacpremature atrial contraction 466 1 submitted 18 apr 22 1 revision req. 8 jun 22; revision recd. 13 jul 22 2 accepted 3 aug 22 3 online-first: august 2022 4 doi: https://doi.org/ 10.18295/squmj.8.2022.049 5 6 parental attitude towards the prescription of psychotropic medications for 7 mental disorders in children in a tertiary care university hospital in oman 8 hiba al-harthi1, salim al-huseini1, mohammed al-shukaili1, moon fai 9 chan2, tamadhir al-mahrouqi1, mohammed al-breiki3, amira al-hosni4, 10 *hassan mirza4 11 12 1psychiatry residency training program, oman medical specialty board, muscat, oman; 13 departments of 2family medicine & public health and 4behavioural medicine, sultan qaboos 14 university, muscat, oman; 3saham polyclinic, ministry of health, saham, oman. 15 *corresponding author’s e-mail: mirza@squ.edu.om 16 17 abstract 18 objectives: this study investigated parental attitudes towards psychotropic drugs for children's 19 mental disorders. methods: a questionnaire was distributed to parents of children attending a 20 child psychiatry clinic at a tertiary hospital in muscat, oman. similarly, in a small proportion, 21 other caregivers filled out the questionnaire in case the child attended with them. the 22 questionnaire comprised questions regarding parents' opinions, and attitudes about psychotropic 23 medications use. the logistic regression model was used to identify the risk factors associated 24 with parents who prefer to consult a folk healer (fh) for children with mental disorders. results: 25 a total of 299 parents agreed to participate in the study. the majority of them (81.6%, n=244) 26 agreed that they would give their child psychotropic medications if necessary, but 25.4% of them 27 (n=76) would consult a fh before consulting a psychiatrist if their child experienced psychiatric 28 symptoms. married parents were 14 times (or=14.5, p=0.011) more likely to consult a fh than 29 were separated or divorced parents. caregivers with a monthly income below 500 omr and 30 mailto:mirza@squ.edu.om 2 between 500-1,000 omr were two times (or=2.5, p=0.016) and three times (or=3.2, p<.001), 31 respectively, more likely to consult a fh than those with a monthly income of more than 1,000 32 omr. parents who disagreed with giving psychotropic medications to their children were three 33 times (or=3.7, p<.001) more likely to consult a fh than were parents who agreed to give 34 psychotropic medications to their children if necessary. conclusion: most parents agreed to give 35 their children psychotropic medications if it were deemed necessary. however, a sizeable 36 proportion of parents and caregivers preferred to consult a fh before accessing mental health 37 services. 38 keywords: parents; children; attitudes; psychotropic drugs; oman. 39 40 advances in knowledge 41 -as a flagship institute, the sultan qaboos university hospital aims to provide all our service 42 users with the best care. 43 -therefore, this study helped us identify the parents’ and caregivers' opinions, concerns, and 44 perceptions on the use of psychotropic medications in children. 45 46 application to patient care 47 -the results of this study and its implications will help us better understand parents' and 48 caregivers’ attitudes towards using psychotropic medications in children. 49 -in addition, the feedback will help us develop parent support groups to discuss the concerns 50 further and improve our services, which translates into better concordance and compliance with 51 the formulated management plan. 52 53 introduction 54 the number of evidence-based treatments for child psychiatry is growing.1,2 there has been a 55 dramatic rise in the use of psychiatric drugs in children over the past four decades.3-5 56 unfortunately, studies have shown a sceptical view and stigma among parents and caregivers of 57 psychiatric patients on using psychotropic medications for their children. 6,7 therefore, most 58 families prefer psychotherapy over drugs, even when psychopharmacological agents are deemed 59 crucial. 8,9 previous studies suggest that parents are reluctant to commence their children on 60 psychotropic medications. this attitude is due to concerns about severe and harmful side effects, 61 3 leading to reducing or stopping the medication earlier than recommended. 10 in addition, studies 62 identified existing racial/ethnic disparities among parents agreeing to prescribe psychotropic 63 medications for their children. for example in the usa, white children are more likely to 64 receive psychotropic drugs than black and latino children. 11,12 however, the view of and 65 attitude toward the use of psychotropic medications in children in oman have never been 66 explored. therefore, understanding the cultural context and establishing relationships between 67 mental health care providers and parents may offer the best strategies for reducing the negative 68 parental perceptions relating to prescribing psychotropic medications for their children. 69 70 the current study aims to explore and understand the opinion and attitudes of omani parents 71 towards prescribing psychotropic medications to their children with mental disorders. it is hoped 72 that child psychiatrists will alleviate parental concerns regarding psychotropic medications use in 73 their children and effectively reduce parental stigma regarding mental health. 74 75 methods 76 study design, settings and participants 77 this cross-sectional study was conducted at the department of behavioural medicine, sultan 78 qaboos university hospital (squh) in oman, between december 2020 and march 2021. in this 79 study, all patients aged younger than 18 years who were attending their regular appointment at 80 the child and adolescent clinic during the study period were eligible to be included in the study 81 which was a total of approximately 450. however, parents or caregivers of patients older than 18 82 years of age and those of children below 18 who did not consent were excluded from the study. 83 84 data collection and handling 85 the data collection took place in the child psychiatry outpatient clinic at squh while patients 86 were waiting for their appointment. the study was carried out between december 2020 and 87 march 2021. all parents of attendees of the child psychiatry outpatient services at squh during 88 the study period were included in the study. information on the nature and goals of the research, 89 the right to anonymity, and the right to withdraw at any stage with no effect on the clinical care 90 was disseminated to the participants. the questionnaire was offered in arabic, the first language 91 of most participants, and an english version was an option for the participants who preferred 92 4 filling it in english. it consisted of two parts, namely, socio-demographic and clinical factors, 93 and the data collected included the age, gender, and the diagnosis of the child (neurodevelopment 94 disorder, mood disorder, psychotic disorder, others (epilepsy, genetic syndromes, metabolic 95 syndromes), place of residence (urban, rural), age of parents, marital status (married, divorced, 96 and separated), and educational level of parents; data regarding socioeconomic status (family 97 monthly income) and occupation were also collected. the second part of the questionnaire 98 looked into parents' opinions, knowledge, and attitudes about children's psychotropic 99 medications. anonymised data were saved on a password-protected electronic database and 100 securely destroyed following the code of conduct for handling research data (ukrio, 2009). 101 signed consent forms were stored separately in a locked compartment. 102 103 sample size calculation and sampling method 104 the required sample size was calculated using medcal software, allowing for a 95% confidence 105 interval, a 5% type i error, and 80% power. the minimum sample size was calculated to be 260. 106 107 a simple random sampling method was used to recruit the study participants from the list of 108 patients expected to attend the child and adolescent clinic during the study period. randomiser 109 software generated a list of participants. those selected randomly and who did not meet the 110 inclusion criteria or opted not to participate were substituted with the next randomly selected 111 participant chosen to fulfil the required sample size. considering a 20% attrition rate, including 112 non-completed questionnaires and unsigned consent forms, 299 participants were recruited. 113 114 data analysis: 115 descriptive statistics, including mean, standard deviation (sd), median, range, frequency, and 116 percentage, were used to report participants' demographic and clinical data and response to the 117 use of children's psychotropic medications. the dependent variable is from one attitude question: 118 "if your child experienced psychiatric symptoms, would you first consult a fh before consulting 119 a psychiatrist? yes/no'. those parents who replied 'yes' were categorised as the 'prefer fh' 120 group, and otherwise as the 'non-fh' group. univariate comparison between the two groups 121 (yes vs no) was evaluated using chi-square / fisher's exact test to explore demographic, 122 clinical, and other attitudes variables. those variables with p < 0.05 in the univariate analysis 123 5 were included in the multivariate logistic (wald) regression for further analysis to identify the 124 risk factors associated with the ‘prefer fh’ group. all statistics, including the odds ratio (or) 125 with 95% confidence intervals (ci), were obtained by the statistical package for the social 126 sciences (spss), version 27.0 (ibm spss inc. chicago, il, usa), set at a 5% level of 127 significance. 128 129 ethical approval 130 ethical approval was granted by the college of medicine and health sciences at sultan qaboos 131 university, muscat, oman. the study was conducted as per the declaration of helsinki and the 132 american psychological association regarding human ethical research, including confidentiality, 133 privacy, and data management. written informed consent was obtained from the participants. 134 135 results 136 profile of the participants 137 details of the profiles of the respondents are shown in table 1. a total of 299 parents and 138 caregivers agreed to participate in the study, with a response rate of 95% (299/314). the basic 139 demographic breakdown of the respondents was 117 (39.1%) fathers, 156 (52.1%) mothers, and 140 26 (8.7%) other caregivers. the majority of the fathers (75%, n=223) had a high school 141 certificate or higher, almost 40% (n=119) ranged between 30 to 40 years old, and most (77.3% 142 n=231) were employed. the majority of the mothers (76%, n=228) had a high school certificate 143 or higher, more than half (52.8%, n=158) were between 30 to 40 years old, and more than half 144 were unemployed (59.2%, n=177). the majority of the parents were living in an urban area 145 (81.3%, n=243), were married (91.6%, n=274), and more than half of them had a monthly 146 income of up to omr 1,000 (56%, n=170). for the children, there were more male patients 147 (68.2%, n=204) than females (31.8%, n=95). the majority had an age range of below 10 years 148 old (44.9%, n=134), and more than (74%, n=224) had a diagnosis of neurodevelopmental 149 disorders, followed by psychotic disorder (13.7%), mood disorder (8.7%), and other conditions 150 like epilepsy (3.6%). tables 2 shows the response to questions on attitudes towards psychotropic 151 medications, the majority of them replied that they did not suffer from a psychiatric disorder 152 (86.3%, n=258), had never taken any psychiatric medications (88.3%, n=264), had no family 153 member with a psychiatric illness (66.2%, n=198), and had no family member who had taken 154 6 any psychiatric medications (67.9%, n=203). regarding the beliefs the respondents had about the 155 use of psychotropic medicines in children, 44% (n=132) believed that these medications lead to 156 addiction in children, 27% (n=82) thought that they cause brain damage, and 28% (n=85) had 157 concerns about the serious side effects of these medications. the majority of the respondents 158 (92%, n=274) preferred psychotherapy as the first step of treatment for their children. however, 159 82% (n=244) agreed to give their child psychotropic medications if necessary, whereas 25.4% of 160 them (n=76) would consult a fh before consulting a psychiatrist if their child experienced 161 psychiatric symptoms. 162 163 risk factors associated with parents preferred folk healer 164 table 3 shows the univariate and multivariate (logistic) analysis of the demographic and attitudes 165 towards psychotropic medications variables associated with a preference to consult a fh. in the 166 univariate analysis, the results showed that marital status (p=0.010), monthly income (p<.001), 167 education level (p=0.026), and employment status (p=0.026) of the mother were linked to a 168 negative attitude towards the use of psychotropic medications in children (p<.001) and were 169 significantly associated with parents who would prefer to consult a fh. 170 171 in the multivariate analysis shown in table 4, the logistic (wald) regression showed that marital 172 status, monthly income, and attitudes towards giving psychotropic medications to their children 173 if necessary were significant risk factors for parents to prefer to consult a fh. according to the 174 hosmer-lemeshow goodness-of-fit test (χ2=0.567, p=0.967), the model had a good fit with a 175 predicting power of 65.9%. married parents were 14 times (or=14.5, p=0.011) more likely to 176 consult a fh than were separated/divorced parents. those parents with a monthly income below 177 500 omr and between 500-1,000 omr were two times (or=2.5, p=0.016) and three times 178 (or=3.2, p<.001), respectively, more likely to prefer to consult a fh than were those with a 179 monthly income of more than 1,000 omr. regarding the attitude question, parents who 180 disagreed with giving psychotropic medications to their children were three times (or=3.7, 181 p<.001) more likely to consult a fh than were parents who agreed to give psychotropic 182 medications to their children if necessary. 183 184 discussion 185 7 over the past decades, there has been a rise in the prescription of psychotropic medications for 186 mental health difficulties in children and adolescents. 13oman is a country with a predominantly 187 youthful population, and its economic growth and rapid demographic shift are witnessing a surge 188 in young people with mental health problems. 14yet, many do not seek care from qualified mental 189 health professionals. 15however, since the development of child and adolescent mental health 190 services (camhs) in oman in the late 1990s, several challenges have emerged, specifically, the 191 maldistribution and scarcity of services for young people and the lack of a mental health act. 116,17 192 this study identified parents’ and caregivers' attitudes and concerns about using psychiatric 193 medications for children attending the camhs in squh. in this study, one of the caregivers' 194 central beliefs regarding psychotropic medicines was that they lead to addiction, which was present 195 in 44% (n=132) of the respondents, which echoes the findings of other studies. 8,9 similarly, close 196 to 28% (n=85) of the respondents believed that the medications may lead to toxic and severe side 197 effects, which is in line with a plethora of studies in the literature with similar findings. 18,19 198 regarding treatment modalities, the majority of the respondents preferred psychotherapy as a 199 treatment for their children, and this is consistent with the results of international studies in which 200 parents chose counselling as the first line of treatment and believed it to be beneficial and to have 201 fewer risks compared to medications. 20 202 203 furthermore, although the vast majority of parents agreed they would give medications to their 204 children if necessary, 25.4% (n=76) of them would first consult an fh, probably due to the socio-205 cultural beliefs and social stigma associated with mental disorders. 21in our study, parents who 206 disagreed with giving psychotropic medications to their children were three times (or=3.7, 207 p<.001) more likely to consult an fh than were parents who agreed to prescribe psychotropic 208 medications to their children if necessary. therefore, consulting an fh before accessing mental 209 health services causes a treatment delay and probably may result in negative mental health 210 consequences. 21 on analysing the sociodemographic factors associated with consulting an fh 211 prior to a psychiatrist, we found that marital status, unemployment, lower income, and lower 212 education level had significant associations. in addition, the existing literature suggests that being 213 single was associated with a higher tendency to visit an fh. 22still, in our study, the finding was 214 the opposite, as married couples were more likely to consult fhs; however, this is not necessarily 215 8 accurate, as more than 90% of the parents in this study were married, and the overall prevalence 216 of single-parent families in oman is low. 217 218 moreover, the results of our research showed that respondents with the education of grade 12 or 219 lower were more likely to consult fhs, and the same applied to those with lower income and 220 unemployment; this concurs with studies done elsewhere. 23furthermore, it is common for those 221 living in low and middle-income countries to access fhs; 24however, oman is a high-income 222 country, yet, based on the findings of our study, it remains influenced by such practices. 223 therefore, even in wealthier countries, the relative popularity of fhs and alternative medicine 224 should be scrutinised in the context of broader social, cultural, and religious perspectives, as 225 local values and beliefs influence people in making such decisions, 25 which confers with a 226 crucial national-level study conducted in oman suggesting underutilization of health care 227 services in people with mental health difficulties 26 finally, in oman and the wider arab region, 228 there is a need for culturally-specific psychoeducation to address the contextual and socio-229 religious factors and the stigma to improve access to mental health services. 27,28 230 231 despite sharing emerging information from oman, the study has some limitations. because of the 232 social stigma, some responses given by parents, particularly in relation to personal or family 233 history with regard to psychiatric problems, might be unreliable and should be treated with caution. 234 conducting the study in a city like muscat, although people from other parts of oman were 235 included, may have missed a large proportion of the wider omani community. moreover, it is 236 essential to acknowledge that the study is subjective and quite a bit of the finding depend on the 237 parents' opinions which different factors could influence. 238 239 conclusion 240 most parents agreed they would give their children psychotropic medications if deemed 241 necessary. however, a sizeable proportion of parents and caregivers preferred to consult an fh 242 before accessing mental health services. parents' opinions and beliefs on psychotropic 243 medications are not in line with the scientific facts. concerted efforts and increased awareness 244 are needed to address parents' concerns regarding the safety and effectiveness of psychotropic 245 medications in children to improve treatment outcomes. moreover, incorporating psychosocial 246 9 and behavioural interventions, parent training, and psychiatric rehabilitation must be an integral 247 part of the holistic approach to managing the mental health difficulties of children and young 248 people. overall, mental health professionals play a significant role in promoting the best 249 practices in the middle east region and offering psychoeducation to parents and caregivers on 250 the safe use and side effects of psychiatric medications in children, and them in shared decision-251 making about medication regimens. 252 253 authors’ contribution 254 hm designed the study, drafted and critically reviewed the manuscript. sah, mas, tam, and 255 mab collected the data, while mfc analysed the data and interpreted the results. aah revised 256 the manuscript. all authors approved the final version of the manuscript. 257 258 conflicts of interest 259 the authors declare that there are no conflicts of / or competing interests. 260 261 funding 262 this research received no specific grant from any funding agency in the public, commercial, or 263 not-for-profit sectors. 264 265 references 266 1. unwin gl, deb s. efficacy of atypical antipsychotic medication in the management of 267 behaviour problems in children with intellectual disabilities and borderline intelligence: a 268 systematic review. res dev disabil. 2011 nov-dec;32(6):2121-33. doi: 269 10.1016/j.ridd.2011.07.031. 270 2. cortese s, adamo n, del giovane c, mohr-jensen c, hayes aj, et al. comparative 271 efficacy and tolerability of medications for attention-deficit hyperactivity disorder in 272 children, adolescents, and adults: a systematic review and network meta-analysis. lancet 273 psychiatry. 2018 sep;5(9):727-738. doi: 10.1016/s2215-0366(18)30269-4. 274 3. zito jm, safer dj, dosreis s, gardner jf, boles m, lynch f. trends in the prescribing of 275 psychotropic medications to preschoolers. jama. 2000 feb 23;283(8):1025-30. doi: 276 10.1001/jama.283.8.1025. 277 10 4. girand hl, litkowiec s, sohn m. attention-deficit/hyperactivity disorder and 278 psychotropic polypharmacy prescribing trends. pediatrics. 2020 jul;146(1):e20192832. 279 doi: 10.1542/peds.2019-2832. epub 2020 jun 2. 280 5. wong ic, murray ml, camilleri-novak d, stephens p. increased prescribing trends of 281 paediatric psychotropic medications. arch dis child. 2004 dec;89(12):1131-2. doi: 282 10.1136/adc.2004.050468. erratum in: arch dis child. 2005 feb;90(2):219. 283 6. hamrin v, mccarthy em, tyson v. pediatric psychotropic medication initiation and 284 adherence: a literature review based on social exchange theory. j child adolesc psychiatr 285 nurs. 2010 aug;23(3):151-72. doi: 10.1111/j.1744-6171.2010.00237.x. 286 7. gronholm pc, ford t, roberts re, thornicroft g, laurens kr, evans-lacko s. mental 287 health service use by young people: the role of caregiver characteristics. plos one. 2015 288 mar 26;10(3):e0120004. doi: 10.1371/journal.pone.0120004. 289 8. al-haidar fa. parental attitudes toward the prescription of psychotropic medications for 290 their children. j family community med. 2008 jan;15(1):35-42. 291 9. lazaratou h, anagnostopoulos dc, alevizos ev, haviara f, ploumpidis dn. parental 292 attitudes and opinions on the use of psychotropic medication in mental disorders of 293 childhood. ann gen psychiatry. 2007 nov 15;6:32. doi: 10.1186/1744-859x-6-32. 294 10. mclaren jl, barnett er, acquilano sc, concepcion zayas mt, drake re, et al. 295 psychotropic polypharmacy and antipsychotics in children: a survey of caregiver's 296 perspectives. community ment health j. 2022 apr;58(3):512-516. doi: 10.1007/s10597-297 021-00845-2. epub 2021 may 31. 298 11. cook bl, carson nj, kafali en, valentine a, rueda jd, et al. examining psychotropic 299 medication use among youth in the u.s. by race/ethnicity and psychological impairment. 300 gen hosp psychiatry. 2017 mar-apr;45:32-39. doi: 10.1016/j.genhosppsych.2016.12.004. 301 epub 2016 dec 15. 302 12. cummings jr, ji x, lally c, druss bg. racial and ethnic differences in minimally 303 adequate depression care among medicaid-enrolled youth. j am acad child adolesc 304 psychiatry. 2019 jan;58(1):128-138. doi: 10.1016/j.jaac.2018.04.025. epub 2018 oct 17. 305 13. pescosolido ba, perry bl, martin jk, mcleod jd, jensen ps. stigmatizing attitudes and 306 beliefs about treatment and psychiatric medications for children with mental illness. 307 psychiatr serv. 2007 may;58(5):613-8. doi: 10.1176/ps.2007.58.5.613.14. al-sharbati 308 11 mm, al-farsi ym, al-sharbati zm, al-sulaimani f, ouhtit a, al-adawi s. profile of 309 mental and behavioral disorders among preschoolers in a tertiary care hospital in 310 oman: a retrospective study. oman med j. 2016 sep;31(5):357-64. doi: 311 10.5001/omj.2016.71. 312 15. al-adawi s. tomorrow's people matters: evidence for action in oman. oman med j. 2014 313 mar;29(2):83-5. doi: 10.5001/omj.2014.21. 314 16. mirza h. child and adolescent mental health services in oman. london j prim care 315 (abingdon). 2018 jun 8;10(4):121-122. doi: 10.1080/17571472.2018.1482661.17. al-316 maamari a, al-kindi q, mirza h. ethical dilemmas in child and adolescent mental 317 health services in oman. ethics soc welf. 2021;15(2):219-223. 318 doi:10.1080/17496535.2021.1897641. 6535.2021.1897641 319 18. dodangi n, vameghi r, habibi n. evaluation of knowledge and attitude of parents of 320 attention deficit/hyperactivity disorder children towards attention deficit/hyperactivity 321 disorder in clinical samples. iran j psychiatry. 2017 jan;12(1):42-48. 322 19. stevens j, wang w, fan l, edwards mc, campo jv, gardner w. parental attitudes 323 toward children's use of antidepressants and psychotherapy. j child adolesc 324 psychopharmacol. 2009 jun;19(3):289-96. doi: 10.1089/cap.2008.0129. 325 20. kaur d, verma r, ghildiyal r. attitudes and perceptions of parents towards child and 326 adolescent psychiatric consultation, diagnosis and treatment. bjpsych open. 2021 jun 327 18;7(suppl 1):s262–3. doi: 10.1192/bjo.2021.700.21. al-alawi m, al-sinawi h, 328 al-adawi s, jeyaseelan l, murthi s. public perception of mental illness in oman: a cross 329 sectional study. int j cult ment health. 2017;10(4):389-399. 330 doi:10.1080/17542863.2017.1325916. 331 22. younis ms, lafta rk, dhiaa s. faith healers are taking over the role of psychiatrists in 332 iraq. qatar med j. 2019 nov 29;2019(3):13. doi: 10.5339/qmj.2019.13. 333 23. zingela z, van wyk s, pietersen j. use of traditional and alternative healers by psychiatric 334 patients: a descriptive study in urban south africa. transcult psychiatry. 2019 335 feb;56(1):146-166. doi: 10.1177/1363461518794516. epub 2018 oct 3. 336 24. gureje o, nortje g, makanjuola v, oladeji b, seedat s, jenkins r. the role of global 337 traditional and complementary systems of medicine in treating mental health problems. 338 lancet psychiatry. 2015 feb;2(2):168-177. doi: 10.1016/s2215-0366(15)00013-9. 339 12 25. mcgregor kj, peay er. the choice of alternative therapy for health care: testing some 340 propositions. soc sci med. 1996 nov;43(9):1317-27. doi: 10.1016/0277-9536(95)00405-341 x. erratum in: soc sci med 1996 apr;42(7):iii. 342 343 26. al riyami aa, al adawi sh, al kharusi ha, morsi mm, jaju ss. health services 344 utilization by school going omani adolescents and youths with dsm iv mental disorders 345 and barriers to service use. int j ment health syst. 2009 sep 25;3(1):22. doi: 346 10.1186/1752-4458-3-22. 347 348 27. elhusein b, eltorki y, abdallah o, el tahir m. antipsychotic prescribing for patients with 349 intellectual disabilities and challenging behaviours. adv ment health intellect disabil. 350 2021;15(2/3):79-88. doi:10.1108/amhid-11-2020-0030. 351 28. al-huseini s, al-barhoumi a, al-balushi m, al-hosni a, al-mahrouqi t, et al. 352 effectiveness and adverse effects of risperidone in children with autism spectrum 353 disorder in a naturalistic clinical setting at a university hospital in oman. autism res 354 treat. 2022 jan 31;2022:2313851. doi: 10.1155/2022/2313851. 355 356 table 1. basic demographic profile of the parents/caregivers/child (n=299) demographic n (%) demographic n (%) child’s gender place of residence boy 204 (68.2) urban 243 (81.3) girl 95 (31.8) rural 56 (18.7) age (years) of the child marital status of the parents <= 10 134 (44.9) married 274 (91.6) 11-15 94 (31.4) separated 13 (4.3) > 15 71 (23.7) divorced 12 (4.0) diagnosis of the child income per month (omr) neurodevelopmental disorder 224 (74.9) < 500 69 (23.1) mood disorder 26 (8.7) 500-1,000 101 (33.8) 13 psychotic disorder 41 (13.7) 1,001-2,000 74 (24.8) other (e.g., epilepsy) 8 (2.7) > 2,000 55 (18.4) age (years) of father age (years) of mother < 30 7 (2.3) < 30 20 (6.7) 30-40 119 (39.8) 30-40 158 (52.8) 41-50 119 (39.8) 41-50 113 (37.8) > 50 54 (18.1) > 50 8 (2.7) education level of father education level of mother illiterate to grade 11 76 (25.4) illiterate to grade 11 71 (23.7) grade 12 98 (32.8) grade 12 105 (35.1) diploma and above 125 (41.8) diploma and above 123 (41.1) employment status – father employment status mother employed 231 (77.3) employed 102 (34.1) unemployed 13 (4.3) unemployed 177 (59.2) retired 55 (18.4) retired 20 (6.7) respondents father 117 (39.1) mother 156 (52.2) other caregiver 26 (8.7) 357 table 2. frequency of responses to the questionnaire on attitudes towards the prescription of psychotropic medications in children q1. would you agree to give your child psychotropic medications if necessary? q2. do you suffer or have you suffered from a psychiatric disorder? yes 244 (81.6) yes 41 (13.7) no 55 (18.4) no 258 (86.3) 14 q3. have you ever taken psychiatric medication? q4. has any member of your family experienced a psychiatric disorder? yes 35 (11.7) yes 101 (33.8) no 264 (88.3) no 198 (66.2) q5. has any member of your family taken psychiatric medication? q6. what is your concern regarding the use of psychotropic medication in children? yes 96 (32.1) it causes addiction 132 (44.1) no 203 (67.9) it causes brain damage when used for long periods. 82 (27.4) it has serious side effects. 85 (28.4) q7. if your child were diagnosed with a psychiatric disorder, would you prefer your child to receive psychotherapy before being started on medication? q8. if your child experienced psychiatric symptoms, would you first consult a folk healer before consulting a psychiatrist? yes 274 (91.6) yes 76 (25.4) no 25(8.4) no 223 (74.6) 358 table 3. univariate and multivariate (logistic) analysis showing the association between respondents’ attitude towards consulting a folk healer and demographic factors q8. preferred to consult a folk healer univariate# multivariate~ yes (n=76, 25.4%) no (n=223, 74.6%) factor n (%) n (%) p-value or p-value 15 demographic respondents father 33 (43.4) 84 (37.7) 0.794 mother 35 (46.1) 121 (54.3) 0.354 other caregiver (ref) 8 (10.5) 18 (8.1) child’s gender boy 54 (71.1) 150 (67.3) 0.540 girl (ref) 22 (28.9) 73 (32.7) age (years) of the child <= 10 30 (39.5) 104 (46.7) 0.485 11-15 27 (35.5) 67 (30.0) 0.781 > 15 (ref) 19 (25.0) 52 (23.3) diagnosis of the child neurodevelopmental disorder 53 (69.7) 171 (76.7) 0.404^ mood disorder 8 (10.5) 18 (8.1) 0.997^ psychotic disorder 12 (15.8) 29 (13.0) 0.687^ other (e.g., epilepsy) (ref) 3 (3.9) 5 (2.2) place of residence urban 57 (75.0) 186 (83.4) 0.105 rural (ref) 19 (25.0) 37 (16.6) marital status of the parents married 75 (98.7) 199 (89.2) 0.010 14.512 0.011* separated/divorced (ref) 1 (1.3) 24 (10.8) income per month (omr) <500 18 (23.7) 51 (22.9) 0.098 2.519 0.016* 500-1,000 37 (48.7) 64 (28.7) <.001 3.185 <.001* >1,000 (ref) 21 (27.7) 108 (48.4) age (years) of father <=40 37 (48.7) 89 (39.9) 0.211 41-50 28 (36.8) 91 (40.8) 0.645 16 > 50 (ref) 11 (14.5) 43 (19.3) education level of father illiterate to grade 11 23 (30.3) 53 (23.8) 0.227 grade 12 26 (34.2) 72 (32.3) 0.484 diploma and above (ref) 27 (35.5) 98 (43.9) employment status – father unemployed/retired 20 (26.3) 48 (21.5) 0.389 employed (ref) 56 (73.7) 175 (78.5) age (years) of mother <=40 45 (59.2) 133 (59.7) 0.967^ 41-50 29 (38.2) 84 (37.7) 0.986^ > 50 (ref) 2 (2.6) 6 (2.7) education level of mother illiterate to grade 11 19 (25.0) 52 (23.3) 0.258 grade 12 34 (44.7) 71 (31.8) 0.026 diploma and above (ref) 23 (30.3) 100 (44.8) employment status – mother unemployed/retired 58 (76.3) 139 (62.3) 0.026 employed (ref) 18 (23.7) 84 (37.7) 359 table 4. univariate and multivariate (logistic) analysis on respondents’ attitude towards consulting a folk healer in association with using psychotropic medications in children univariate# multivariate~ p-value or p-value q1. would you agree to give your child psychotropic medications if necessary? no 25 (32.9) 30 (13.5) <.001 3.754 <.001* yes (ref) 51 (67.1) 193 (86.5) q2. do you suffer or have you suffered from a psychiatric disorder? yes 8 (10.5) 33 (14.8) 0.350 17 no (ref) 68 (89.5) 190 (85.2) q3. have you ever taken psychiatric medication? yes 8 (10.5) 27 (12.1) 0.711 no (ref) 68 (89.5) 196 (87.9) q4. has any member of your family experienced a psychiatric disorder? yes 26 (34.2) 75 (33.6) 0.927 no (ref) 50 (65.8) 148 (66.4) q5. has any member of your family taken psychiatric medication? yes 24 (31.6) 72 (32.3) 0.909 no (ref) 52 (68.4) 151 (67.7) q6. what is your concern towards the use of psychotropic medication in children? it causes addiction. 39 (51.3) 93 (41.7) 0.076 it causes brain damage when used for long periods. 21 (27.6) 61 (27.4) 0.291 it has serious side effects (ref). 16 (21.1) 69 (30.9) q7. if your child were diagnosed with a psychiatric disorder, would you prefer your child to receive psychotherapy before being started on medication? yes 68(89.5) 206(92.4) 0.287 no (ref) 8(10.5) 17(7.6) #, 2 test; ^, fisher's exact test; *, sig., p<0.05; ref: reference point; or, odds ratio; , logistic (wald) regression: hosmer & lemeshow test ( 2=0.567, p=0.967); nagelkerke r square=0.176; sensitivity=60.5%, specificity=65.8%, overall=65.9% 360 march 2007 vol 7 isuue 1 final without suicide .indd abstract acute epibulbar infections in humans are one of the most frequently diagnosed eye diseases. the majority of these are thought to be caused by the adenovirus. this review focuses on the features of the human adenovirus eye diseases, mode of transmission, signs and symptoms, available interventions, and preventive measures. it is concluded that infection control is still widely accepted to be the key to the management of human adenovirus infection in order to prevent the spread, individual suffering and economic damage. key words: adenovirus, keratoconjunctivitis, eye, infection control adenoviral keratoconjunctivitis *alexander bialasiewicz انيَّة دَّ الغُ بالرواشح ة مَ واملُلْتَحِ رْنِيَّةِ الْتِهابُ القَ اليكساندر بياالسويكز ــببها يس التي العني أمراض صفات على تركز املراجعة هذه الغداني. ــح الراش ــببها يس القرنية وامللتحمة التهاب حاالت معظم أن يعتقد امللخص: تعتبر يَة دِ ُعْ امل رَاضِ األَمْ ةُ افَحَ كَ مُ بأن ــتنتج نس أن ميكن الوقاية. وطرق املتاح، التدخل والعالمات، وكذلك واألعراض االنتقال، وطريقة الغداني، ــح الراش االقتصادي. املعاناة والهدر وتقليل الغداني، الراشح انتقال على السيطرة في األساس احلجر واسع بشكل العدوى. على السيطرة وامللتحمة، العني، القرنية التهاب الغدانية، الكلمات: الرواشح مفتاح *department of ophthalmology, sultan qaboos university, p.o. box 35, al khod 123, muscat, sultanate of oman email: alexander@squ.edu.om sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© r e v i e w acute epibulbar infections in humans are one of the most frequently diagnosed eye diseases, comprising 2.3-10% of all ophthalmological diagnoses, with a prevalence of 0.6-3.5 new cases per 1,000 patients in oman. although almost any microbe can elicit an inflammation in the outer eye, about 92% of these are thought on clinical grounds to be caused by adenovirus-associated epidemic keratoconjunctivitis. in healthy eyes, most of these infections are self-limited and without late sequelae, but in compromised surface conditions visionthreatening sequelae may result.1, 2, 3 the identification and notification of patients harbouring conditions and infections with a high morbidity (e.g. loss of workdays, high disability adjusted life years) and with nosocomial relevance is very important for the economy of a country.3, 4, 5 this overview will focus on the clinical ophthalmology of adenovirus infections, which plays a key role in this scenario. the ophthalmologist can make a focused differential diagnosis taking a detailed history (contacts, course), asking for symptoms and observing signs by biomicroscopy (localization, type and access of the inflammation). a clinical diagnosis can be established by a morphological examination and complemented by laboratory evidence of the infectious agent to identify the suspected organism.6, 7 close cooperation with infection control specialists may prevent potential harm to the healthy population as well as limit costly laboratory work-ups. a l e x a n d e r b i a l a s i e w i c z 16 e pi d e mi o l o g y follicular epidemic keratoconjunctivitis (ekc): adenoviruses are the most important and most frequent cause of follicular epidemic keratoconjunctivitis (classification according to international classification of dieases 10: b 30.0: keratoconjunctivitis by adenovirus, b 30.1: conjunctivitis by adenovirus, b 30.2.: pharyngoconjunctival fever by adenovirus [table 1].3 adenovirus infections are responsible for 92% of all keratoconjunctivitis cases, and appear mostly in late winter, spring and early summer.8, 9, 3 the viruses implicated are adenovirus hadv1-11, 14-17, 19-22, 26, 29 and 37. the most frequent types in europe are hadv 8>3>7>19/37, in japan hadv 8>81>4>19/37>3, and in usa 8, 19, and 37.10, 9, 11, 12 nosocomial infections have been reported to be associated more often with hadv8, while hadv 7, 19, 37 are more often associated with infections from the environment such as lakes and swimming pools.9, 13, 14, 15 adenovirus types responsible for nosocomial infections are defined by molecular epidemiologic methods such as genome and subgenome typing.14 virus shift, appearance of new virus types and simultaneous infections by several virus types can circumvent the type-specific acquired immunity in a population and may result in a new symptomatic outbreak.16, 14, 12, 17, 18 acute hemorrhagic conjunctivitis: acute hemorrhagic conjunctivitis can be caused by hadv8 and (rarely) hadv11 in addition to enterovirus 70, 71 and coxsackievirus a24, b2.3, 19 this adenoviral inflammation is also self-limited, as symptoms disappear after 6 days, faster than the non-hemorrhagic variant. ard-associated keratoconjunctitivis: adenovirus-associated acute respiratory disease (ard) with conjunctivitis was first reported in military recruits during world war ii. epidemics of febrile disease with conjunctivitis can be due to waterborne transmission of hadv4 and hadv7 from inadequately chlorinated swimming pools and small lakes.20 ard is most often associated with adenovirus types hadv4 and hadv7. tr a n smi s si o n direct inoculation by fingers is to be considered a major mode of transmission when taking into account that the eyelids and tarsal conjunctiva are touched around 14 times per day involuntarily, and additionally voluntarily during make-up or application of facial cosmetics. person-to-person transmission of adenovirus 8 is established to primarily occur through the hands of personnel and/or other persons in contact with patients. outbreaks originating in health units can often be traced down to one or a few health care providers.10, 21, 22, 23, 24 in nosocomial infections inadequate hand washing by health-care personnel between patient contacts and inadequate disinfection of equipment is the main risk factor for an outbreak or an epidemic. in larger teaching hospitals (>500 beds), the attack rate of patients with ekc has been estimated at 4.7 per 1000 treatment cases. transmission may also occur as smear droplet infection in crowded health institutions or in overpopulated areas with low personal hygiene and behaviour (hadv 8, 19). medical and paramedical staff mainly in ophthalmic units and hospitals are the most frequent sources of infections.15, 6 in addition, the improper use of dropper bottles and vials with contaminated tips, tonometer tips and other inadequately disinfected contact instruments, inappropriate patching or multiple use of contact lenses are other important risk factors. c o n ta gi o si t y adenoviruses are exceptionally stable to chemical or physical agents and adverse ph conditions, allowing for prolonged survival outside of the body. thus the high rate of transmission in an ophthalmic unit, e.g. the contagiosity of adenovirus-associated ekc, can be best understood when considering data of hadv19 being viable up to 8 days on paper, 9 days on tonometer tips, 10 days on textiles and metal and up to 35 days on plastics.25, 26 these results emphasize the need for proper selection and application of germicides for use in disinfecting non-critical surfaces and semi-critical medical devices, such as applanation tonometers, in order to prevent outbreaks of epidemic keratoconjunctivitis. the necessity for the implementation of infection control measures also seems to result from these data and the lack of effective medical treatment.27, 28 c l i n i c a l pi c t ur e a d ults symptoms: patients diseased with the complex of “epidemic keratoconjunctivitis” complain about unilateral (right or left depending on handedness) itching, tearing, burning and foreign body sensation as well as photoa d e n o v i r a l k e r at o c o n j u n c t i v i t i s 17 phobia. in case of acute hemorrhagic conjunctivitis (ahc), extensive epibulbar and tarsal hemorrhages and precervical lymph node enlargement may manifest as early as 48 hours after the first symptoms in >90% of patients. signs: biomicroscopy reveals a serofibrinous, sometimes mucopurulent exudate, accompanied by chemosis, hyperemia and swelling of the plica [fig.1]. tarsal and epibulbar follicles (and petechial hemorrhages in case of hadv3, 4) [fig.2] appear. corneal sensitivity is not affected. after a few days, multifocal non-vascularized, centrally located, nummular corneal infiltrates follow in 95% of cases. they consist of dendritic cells, lymphocytes, histiocytes and fibroblasts [fig.3].29 rarely, a superficial punctate keratitis may present, particularly with hadv8. an esthesiometry should be done in all cases of corneal signs, in order to differentiate potentially blinding herpetic disease from adenovirus infections. tarsal pseudomembranes, which consist of necrotic tissue and fibrin on an intact epithelial surface (caveat: no hemorrhage when being removed), can be seen in acute fulminant disease [fig. 4], and in association with immunodeficiency syndromes [fig.5]. they tend to form conjunctival scars and mild symblephara. preauricular, submandibular and cervical lymph node swelling are typically associated with all adenovirus infections and can be seen and palpated in acute hemorrhagic conjunctivitis [fig.6] 48 hours after onset of symptoms. lid edema, secondary inflammatory ptosis, and an upper respiratory tract infection as well as severe malaise may accompany some cases. ard is particularly pronounced in hadv3 and hadv4 infections of adults and in hadv7 and hadv8 infections in children. sequelae [figs.7-8]: the clinical symptoms of ekc and ahc are generally self-limiting after 2-3 weeks respectively 4-6 days, however, even after 2 years nummular corneal lesions (and a decrease in vision from 1.0 to 0.5) can be biomicroscopically documented for hadv8 infections in 47% of patients.30 adenovirus can be isolated from the conjunctiva of a cohort of patients in a decreasing time pattern about 50% of patients after 10 days are still infective, some remain infective for more than 2 years. in case of ahc, hadv2, hadv3, hadv4, hadv5, hadv19 can also be isolated even several months after onset. any cytopathogenic agents infecting the ocular surface, including the adenovirus, result in a post infectious dry eye syndrome due to the loss of goblet cells. this event is clinically relevant in about one third of patients. this may sometimes be difficult to differentiate from an ongoing infection. the differential diagnosis can be made utilizing tests such as schirmer’s, bengal rose stain, break-up time, tear film interference, and impression cytology. rarely, (sub)epithelial conjunctival scars can develop particularly in patients that had experienced fulminant and pseudomembraneous disease and lead to persisting corneal irritation and pain sensation [fig. 9]. also, as a sequel to the more serious dry eye syndromes with persistent infection and ongoing inflammation, mild symblephara can result. risk factors: the adenovirus reservoir responsible for nosocomial ocular infections is the infected human. the mechanisms of transmission include contaminated skin, inorganic devices, secretions, aerosols, and droplets. the environmental ard-associated adenovirus has a reservoir in pools and lakes. humans infect themselves while bathing. c l i n i c a l pi c t ur e – n e o n ate s neonatal adenovirus infections involving the eye are rare compared to the frequent bacterial inflammations. conjunctivitis has been reported in neonates surviving systemic disease.31 symptoms: simultaneously bilateral “red eyes“ and tearing can be easily differentiated from the mucopurulent exudate in bacterial infections. signs: lacrimal gland swelling, lid edema, conjunctival hyperemia, and conjunctival papillary reaction can be observed. table 1: ophthalmologically relevant adenovirus types in europe follicular conjunctivitis ad3, 4, 7 epidemic keratoconjunctivitis ekc ad8,19, 37 acute respiratory disease ard ad1–3, 4, 6, 7, 14, 21 pharyngoconjunctival fever ad3, 7, 14 a l e x a n d e r b i a l a s i e w i c z 18 sequelae the clinical symptoms are self-limited after less than 10 days, and compromising corneal disease and vision impairment have not been reported yet. risk factors it has been documented in heidelberg recently that the prior examination of neonates by ophthalmologists for screening of retinopathy of prematurity was the only significant risk factor for subsequent adenovirus conjunctivitis in the newborn.15 l a b o r ato ry d i a gn o si s i n o ph th a l mo l o g y in the differential diagnosis of microbial conjunctivitis, particularly in immunocompromised patients, a laboratory diagnosis supporting and detailing the clinical impression is desirable. since sometimes multiple types of adenovirus can contribute to an outbreak or epidemic, typing is of considerable epidemiologic relevance. a dacronor wood-tipped applicator for conjunctival swab should be inserted deep enough (caveat: use topical anesthetics and nacl moisterization for applicators) to scrape epithelial cells. the material can be forwarded in commercially available virus transport media, e.g. vt8 for culture, which is still the reference method, however slow (5-33 days) and troublesome. the more practical method is the quantitative real-time polymerase chain reaction (pcr) to prove nucleic acid of hadv3, 4, 6, 7, 8, 14, 19, 37, which are particularly important in europe.6, 7 enzyme immunoassays are a cheaper and faster option with a high sensitivity of 91%; however, they bear a variable specificity depending on contaminations and false positive results. even cheaper are direct immunofluorescence tests, which have a very variable sensitivity and specificity and are therefore currently not recommendable for a molecular epidemiologic investigation. for immune dot-blot tests, the sensitivity is 67-84%32 compared to culture, and for the bedside immunochromatographic test it is 95%.33 tr e atme n t prerequisites in all self-limiting diseases the evaluation of treatment trials is difficult. success concerning the disappearance of the infection is often measured by less organisms to be found at the site of infection, less subjective symptoms, amelioration of inflammatory signs (e.g. conjunctival hyperemia, exudate, corneal involvement) and decrease of morbidity (e.g. office presentations). medical curative experimental and clinical success has been reported for topical alpha-interferon, 34 cidofovir, 35 pvp-iodine 5%.36 however, none of these agents could withstand the test of cost-effectiveness or freedom of limiting side-effects. as well, the most promising substance in vitro, cidofovir, has been doubted to be effective at all in clinical trials.37 currently, n-chlorotaurin, which has been proven to be effective against adenovirus and adenovirus infection in vivo and in vitro and has been reported tolerable is entering a phase iii clinical trial. however, data regarding the actual shortening of the disease, the duration of symptoms, and the effect on shedding of the virus in humans have not yet been reported and are difficult to obtain in a self-limiting disease figure 1: epidemic keratoconjunctivitis: 20 year old patient featuring conjunctival hyperemia, chemosis, plica swelling and accompanying reactive tearing splenic rupture figure 2: epidemic keratoconjunctivitis: 16 year old patient with petechial hemorrhages on the subtarsal conjunctiva of the ectropionated upper eyelid ( frequent cytopathogenic effect) a d e n o v i r a l k e r at o c o n j u n c t i v i t i s 19 anyway.38, 39, 40 the use of antiherpetic medications such as arabinoside, 41 iodine-desoxyuridine, 42 or trifluorothymidine43 has not been successful. medical symptomatic topical corticosteroids may mitigate the subjective symptoms and may delay or prevent the development of corneal infiltrates. after tapering the corticosteroids off, a recurrence rate of 30% has been reported.30 it has been documented in animal experiments that the adenoviral replication may increase under the influence of corticosteroids.44 therefore, the application of corticosteroids may only be legitimate in massive fulminant infections with the intention to prevent symblephara, corneal scarring and permanent vision impairment. a consensus for the use or the dosing intervals for corticosteroids does not exist. in only one study topical cyclosporin a has been reported beneficial with regard to the removal or disappearance of corneal infiltrates.37 topical antihistaminics and physical supportive measures such as ice-cold bandages have also been advised.18 topical combinations of tetracyclines and corticosteroids are frequently prescribed; however, there is no evidence to support a beneficial symptomatic or curative effect. medical prophylactic vaccines were developed for hadv4 and hadv7 infections (ard associated conjunctivitis), but they were conceived only for preventing ard among military recruits and were never relevant for ophthalmologists.20 surgical late sequelae such as persisting scars, irregular shaping and irregular astigmatism after ekc may result in a compromised image quality or impairment of vision. in these cases a topographyor wavefront-guided phototherapeutic keratectomy may restore vision.45 i n fe c ti o n c o n tr o l general although the beneficial effect of infection control measures has recently been controversially discussed, the mainstream consensus is to pay strict attention to good infection-control practices that may be effective to stop nosocomial outbreaks of adenovirus-associated disease.24, 6, 5 disinfecting agents proven to be active in vitro against the virus have been listed in the environmental protection agency46 and rki/berlin 4 lists of disinfectants. however, the in vitro conditions and interaction between test strains and germicides may not simulate in vivo conditions. for example, hadv2 and hadv7, is susceptible to alcohols after 10 minutes of contact time, 47 but adenovirus 8 is resistant to the action of 70% isopropyl alcohol.48 thus, research results concerning hygiene issues in adenovirus infections have often been confusing for the practicing clinician. maintaining adequate levels of chlorination is necessary and effective to prevent swimming pool-associated outbreaks of adenovirus conjunctivitis.24, 20 ophthalmology – medical staff the main task of medical staff during an outbreak is strictly to adhere to hand disinfection to prevent figure 3: epidemic keratoconjunctivitis: 26 year old patient with one paracentral subepithelial irregularly demarcated “dendritic” corneal infiltrate figure 4: epidemic keratoconjunctivitis: 28 year old immunocompetent patient with subconjunctival hemorrhages and tarsal pseudomembranes (no hemorrhage at removal) a l e x a n d e r b i a l a s i e w i c z 20 person-to-person spread of infection using the recommended germicides and gloves for the handling of infectious patients or (potentially) contaminated materials. of the germicides suitable for use as an antiseptic, 70% ethanol achieved a 3 log 10 reduction under four of the five test conditions.49 these measures may limit the spread of ekc acutely and may achieve a long-term reduction of incidence rates.50, 32, 9 in a convincing comparative 6-year study employing enforced infection control measures in an ophthalmic unit, 0.54 outbreaks involving 5.66 infected patients per 10,000 patient examinations have been documented in contrast to 3.89 outbreaks involving 54.09 infected patients per 10,000 patient examinations without those measures (p<0.005 und p<0.0005).13 physicians suffering from adenovirus conjunctivitis should in any case be restricted from working with patients. this results from a study in canada when an outbreak of ekc could be traced back to 4 of 20 doctors of a health centre being responsible for 61% of the infections.51 hand disinfection after glove removal should be performed using 80% ethanol for at least 5 minutes. or using tosylchloramide sodium 1% or 2% for at least 1 minute.4 hand washing with a detergent is not sufficient. hand towels must be single use paper and not reusable cotton towels. ophthalmology – equipment etc: dropping bottles and eye ointment should only be used by one patient, and single-use units should be preferred.52 patient-relevant areas, equipment, instruments, and other devices undergoing patient contact like slit lamp accessories must be disinfected with recommended germicides.46, 4, 49 tonometry: contact tonometry with the schitz tonometer or the applanation tonometer is a risk factor for ekc, and the pneumotonometer has also has been associated with nosocomial ekc outbreaks.24, 53 problems regarding disinfection or sterilization of the tonometers particularly the disassemblement have been elucidated.54, 55 tonometers vary in design and material composition; therefore, disinfection or sterilization procedures that are appropriate for one type of tonometer may not be suitable for another.55, 56, 57 adequate disinfection or sterilization cannot be achieved if the instruments are not initially cleaned thoroughly of any organic material that can impede contact between the disinfectant and the microorganism during the disinfection process. in the absence of controlled studies, specifically on disinfection or sterilization of the pneumotonometer and other tonometers, the tips of such tonometers must be cleaned, then disinfected or sterilized after each patient use. the irradiation of tonometer tips with ultraviolet light (maximal antiviral effectiveness: 253.7nm) has been proven effective in studies using hadv2, but it has not been generally recommended due to the variable dosages in various adenovirus types (id90 20.0 to 50.0 mws/cm2) and undefined exposure times.58, 54 figure 5: epidemic keratoconjunctivitis: 35 year old aids patient with severe pain and pseudomembranes on the lower tarsal conjunctiva figure 6: acute hemorrhagic conjunctivitis: 81 year old patient 2 days after intraocular pressure profile for glaucoma, featuring bilateral massive (sub)conjunctival hemorrhages, lid edema and nonbacterial mucopurulent exudate a d e n o v i r a l k e r at o c o n j u n c t i v i t i s 21 other contact instruments: thermal disinfection is preferred at 93°c 5 minutes in disinfection and cleansing machines, otherwise a virucidal 3% formaldehyde solution may be used for soaking (4 hours recommended contact), or a more practical 5% tosylchloramide sodium solution (10 minutes. recommended contact) can be applied, for example for three mirror lenses. chlorhexidine has been tested on contact instruments (eye lid spatula) for screening of rop patients and thermal disinfection was found to be superior to chlorhexidine, but chlorhexidine was found to be preferable with regard to 70% isopropyl alcohol. however, chlorhexidine is a weak disinfectant and highly irritating for the eye.59 areas: patient contact areas such as slit lamp accessories must be treated with virucidal preparations or by meticulous cleansing with 70% ethanol for at least 5 minutes.46, 5 textiles: contaminated textiles must be treated with a thermal (90°c, 10 min.) or chemothermal disinfection.47 other: ancillary procedures are necessary to control nosocomial ekc outbreaks including, 1) cohorting of ekcinfected health-care personnel only with patients known to have ekc, 2) preventing infected personnel from having direct patient contact for up to 14 days following onset in affected personnel, and 3) using unit-dose eye solutions. control of large epidemics or those that occur in association with a community outbreak require more stringent measures, such as triaging patients and assigning those suspected of being infected to waiting and examining rooms that are separate from those for uninfected patients and admitting into the clinic only emergency cases, while postponing examination and treatment of elective patients until after the outbreak. n oti fi c ati o n notification of suspects and/or diagnosed cases of nosocomial adenovirus infections is requested by law in most western countries. in germany, the outbreak must be notified anonymously according to the impfschutzgesetz (ifsg) § 6 (3.5). if laboratory evidence has been found, the notification must be by name according to ifsg § 7.5 in the usa, patients must be reported through state health departments to the epidemiology branch, center for infectious diseases, atlanta.20 r e f e r e n c e s 1. krumpaszky hg, klauss v. epidemiology of blindness and eye diseases. ophthalmologica 1996; 210:1-84. 2. bialasiewicz aa. nosocomial keratitis. hyg med, 2000; 11:458-463. 3. klauss v, schaller uc, bialasiewicz aa. importance and epidemiology of infectious eye diseases. in: kramer a, behrens-baumann w, ed. antiseptic prophylaxis and therapy in ocular infections. dev ophthalmol 2002; 33:145-190. figure 7: epidemic keratoconjunctivitis – sequelae: 46 year old patient 7 days after start of clinical symptoms with persistent pronounced central subepithelial corneal infiltrates with a free zone towards the limbus. photophobia, visual impairment figure 8: epidemic keratoconjunctivitis – sequelae: 49 year old patient 5 months after start of clinical symptoms with pronounced central nonvascularized subepithelial corneal scars and a degenerative iron line. vision os cc 0.2, highly irregular astigmatism. a phototherapeutic keratectomy was successful, vision increased to 0.8 a l e x a n d e r b i a l a s i e w i c z 22 4. rki-ratgeber infektionskrankheiten keratoconjunctivitis epidemica und andere konjunktivitiden durch adenoviren. merkblätter für ärzte. robert koch institut, 2004. 5. bales s, baumann hg, schnitzler n. infektionsschutzgesetz: kommentar und vorschriftensammlung. 2. auflage. stuttgart-berlin: kohlhammer verlag, 2003. 6. cheung d, bremner j, chan jt. epidemic keratoconjunctivitis do outbreaks have to be epidemic? eye 2003; 17:356-363. 7. wolfel r, pfeffer m, essbauer s, nerkelun s, dobler g. evaluation of sampling technique and transport media for the diagnostics of adenoviral eye infections/adenovirus sampling and transport. graefes arch clin exp ophthalmol 2006; 244:1497-1504. epub 21 march 2006 8. mueller aj, klauss v. main sources of infection in 145 cases of epidemic keratoconjunctivitis ger j ophthalmol 1993; 2:224-227. 9. aoki a, isobe k, ohno s. nationwide surveillance program of epidemic conjunctivitis in japan. in: bialasiewicz aa, schaal kp, ed. infectious diseases of the eye. philadelphia: butterworth-heinemann, 1994. p. 309316. 10. d’angelo lj, hierholzer jc, holman rc, smith jd. epidemic keratoconjunctivitis caused by adenovirus type 8: epidemiologic and laboratory aspects of a large outbreak. am j epidemiol 1981; 113:44-49. 11. bialasiewicz aa, jahn gj. augenbefunde bei virusinfektionen. dtsch arztebl 1994; 91b:685-694. 12. chang ch, lin kh, sheu mm, huang wl, wang hz, chen cw. the change of etiological agents and clinical signs of epidemic viral conjunctivitis over an 18-year period in southern taiwan. graefes arch clin exp ophthalmol 2003; 241:554-60. 13. gottsch jd, froggatt jw 3rd, smith dm, et al. prevention and control of epidemic keratoconjunctivitis in a teaching eye institute. ophthalmic epidemiol 1999; 6:29-39. 14. takeuchi s, itoh n, uchio e, et al. adenovirus strains of subgenus d associated with nosocomial infection as new etiological agents of epidemic keratoconjunctivitis. j clin microbiol 1999; 37:3392-3394. 15. chaberny ie, schnitzler p, geiss hk, wendt c. an outbreak of epidemic keratoconjunctivtis in a pediatric unit due to adenovirus type 8. infect control hosp epidemiol 2003; 24:514-519. 16. kemp mc, hierholzer jc, cabradilla cp, obijeski jf. the changing etiology of epidemic keratoconjunctivitis: antigenic and restriction enzyme analyses of adenovirus types 19 and 37 isolated over a 10 year period. j infect dis 1983; 148:24-33. 17. adhikary ak, inada t, banik u, et al. serological and genetic characterization of a unique strain of adenovirus involved in an outbreak of epidemic keratoconjunctivitis. j clin pathol 2004; 57:411-416. 18. majeed a, naeem z, khan da, ayaz a. epidemic adenoviral conjunctivitis report of an outbreak in a military garrison and recommendations for its management and prevention. j pak med assoc 2005; 55:273-275. 19. bialasiewicz aa. infektionskrankheiten des auges. g fischer verlag,1995. 20. cdc. respiratory and enteric viruses branch: adenovirus. national center for infectious diseases. www. cdc.gov/ncidod/ accessed 20 june 2006. 21. ford e, nelson ke, warren d. epidemiology of epidemic keratoconjunctivitis. epidemiol 1987; 9:244-261 22. garner js, simmons bp. guideline for isolation precautions in hospitals. atlanta: us department of health and human services, public health service, cdc. dhhs publication no. 83, 1985. p. 8314. 23. reilly s, dhillon bj, nkanza km. adenovirus type 8 keratoconjunctivitis an outbreak and its treatment with topical human fibroblast interferon. j hygiene 1986; 96:557-575. 24. anonymous. epidemiologic notes and reports: epidemic keratoconjunctivitis in an ophthalmology clinic – california. morbid mortal wkly rep 1990; 39:598601. 25. wegman dh, guinee ve, millian sj. epidemic keratoconjunctivitis. am j pub health 1970; 60:1230-1237. 26. gordon yj, gordon ry, romanowski e, araullo-cruz tp. prolonged recovery of desiccated adenoviral serotypes 5, 8, 19 from plastic and metal surfaces in vitro. ophthalmology 1993; 100:1835-1839. 27. wu e, trauger sa, pache l, et al. membrane cofactor protein is a receptor for adenoviruses associated with epidemic keratoconjunctivitis. j virol 2004; 78:38973905. 28. bialasiewicz aa, richard g. nosokomiale infektionen am auge und krankenhaushygienische massnahmen in der augenheilkunde. in: beck eg, eikmann t, tilkes f, ed. hygiene in krankenhaus und praxis. landshut: ecomed verlag, 1997. bd. 8, iii/3.19, p. 1-16. 29. knappe s, stave j, guthoff rf. epidemic keratoconjunctivitis. in vivo images of corneal structures with the confocal rostocker laser scanning microscope (rlsm)]. ophthalmologe 2005; 102:798-801. 30. freyler h, sehorst w. the fate of corneal infiltrations in cases of epidemic keratoconjunctvitis. wien klin wochenschr 1976; 28:341-343. 31. elnifro em, cooper rj, dady i, hany s, mughal zm, klapper pe. three non-fatal cases of neonatal adenovirus infection. j clin microbiol 2005; 43:5814-5815. 32. ankers he klapper pe, cleator gm, bailey as, tulo ab. the role of a rapid diagnostic test (adenovirus ima d e n o v i r a l k e r at o c o n j u n c t i v i t i s 23 mune dot-blot) in the control of an outbreak of adenovirus type 8 keratoconjunctivitis. eye 1993; 7:15-17. 33. fujimoto t, okafuji t, okafuji t, et al. evaluation of a bedside immunochromatographic test for detection of adenovirus in respiratory samples, by comparison to virus isolation and real-time pcr. j clin microbiol 2004; 42:5489-5492. 34. sundmacher r, wigand r, cantell k. the value of exogenous interferon in adenovirus keratoconjunctivitis. graefes arch clin exp ophthalmol 1982; 218:139-145 35. gordon yj, romanowski eg, araullo-cruz t. topical hpmpc inhibits adenovirus type 5 in the new zealand rabbit ocular replication model. invest ophthalmol vis sci 1994; 35:4135-4143. 36. abel r, abel ad. use of pvp iodine in the treatment of presumptive adenoviral conjunctivitis. ann ophthalmol glaucom 1998; 30:341-343. 37. hillenkamp j, reinhard t, ross rs, et al. topical treatment of adenoviral keratoconjunctivitis with 0.2% cidofovir and 1% cyclosporine: a controlled clinical pilot study. arch ophthalmol 2001; 119:1487-1491 38. nagel m, teuchner b, pottinger e, ulmer h, gottardi w. tolerance of n-chlorotaurine, a new antimicrobial agent, in infectious conjunctivitis – a phase ii pilot study. ophthalmologica 2000; 214:111-114. 39. romanowski eg, yates ka, teuchner b, nagl m, irschick eu, gordon yj. n-chlorotaurine is an effective antiviral agent against adenovirus in vitro and in the ad5/nzw rabbit ocular model. invest ophthalmol vis sci 2006; 47:2021-2026. 40. teuchner b, nagl m, schidlbauer a, et al. tolerability and efficacy of n-chlorotaurine in epidemic keratoconjunctivitis a double-blind, randomized, phase-2 clinical trial. j ocul pharmacol ther 2005; 21:157-165. 41. dudgeon j. treatment of adenovirus infection of the eye with 5-iodo2’-deoxyuridine. br j ophthalmol 1969; 53:530-533. 42. hecht sd, hanna l, sery tw, jawetz e. treatment of epidemic keratoconjunctivitis with idouxirine. arch ophthalmol 1965; 73:49-64 43. ward jb, siojo lg, waller sg. a prospective masked clinical trial of trifluridine, dexamethasone and artificial tears in the treatment of epidemic keratoconjunctivitis. cornea 1993; 12:216-221. 44. romanowski eg, zates ka, gordon yj. topical corticosteroids of limited potency promote adenovirus replication in the ad5/nzw rabbit ocular model. cornea 2002; 21:289-291. 45. quentin cd, tondrow m, vogel m. phototherapeutische keratektomie nach keratokonjunktivitis epidemica. ophthalmologe 1999; 96:92-96. 46. epa. antimicrobial pesticide products. www.epa.gov, accessed on 20 june 2006. 47. klein m, deforest a. principles of viral inactivation. in: sm block, ed. disinfection, sterilization and preservation. philadelphia: lea and febiger, 1983. p. 422-434. 48. nagington j, stehall gm, whipp p. tonometer disinfection and viruses. br j ophthalmol 1983; 67:674-676. 49. rutala wa, peacock je, gergen mf, sobsey md, weber dj. efficacy of hospital germicides against adenovirus 8, a common cause of epidemic keratoconjunctivitis in health care facilities. antimicrob agents chemother 2006; 50:1419-1424. 50. buehler jw, finton rj, goodman ra. epidemic keratoconjunctivitis: report of an outbreak in an ophthalmology practice and recommendations for prevention. infect control 1984; 5:390-394. 51. montessori v, scharf s, holland s, werker dh, roberts fj, bryce e. epidemic keratoconjunctivitis outbreak at a tertiary referral eye care clinic. am j infect control 1998; 26:399-405. 52. draeger j, prueter jw. importance of diagnosis and preoperative care of the conjunctiva. klin monatsbl augenheilkd 1990; 197:210-213. 53. warren d, nelson ke, farrar ja. a large outbreak of epidemic keratoconjunctivitis: problems in controlling nosocomial spread. j infect dis 1989; 160:938-943. 54. draeger j, hinzpeter t, mai k. tonometer sterilization. doc ophthalmol 1969; 26:648-663. 55. clarke skr, hart jcd, barnard dl. the disinfection of instruments and hands during outbreaks of epidemic keratoconjunctivitis. trans ophthalmol soc u k 1972; 92:613-618. 56. wood rm. prevention of infection during tonometry. arch ophthalmol 1962; 68:202-218. 57. corboy jm, goucher cr, parnes ca. mechanical sterilization of the applanation tonometer. pt 2. viral study. am j ophthalmol 1971; 71:891-893. 58. schmitz h, draeger j, emmerich p. tonometer sterilization. the inactivation of hsv 1 and ad 2 by ultraviolet irradiation. klin mbl augenheilkd 1990; 196:225-227 59. hutchinson ak, coats dk, langdale lm, steed ll, demmler g, saunders ra. disinfection of eyelid specula with chlorhexidine gluconate (hibiclens) after examinations for retinopathy of prematurity. arch ophjuly 2008.indd sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 129-135 sultan qaboos university© submitted 27th april 2008 accepted 20th may 2008 genetic services in the sultanate of oman and other gulf countries progress is needed now! sandy raeburn during the past decade there has been an explosion of new genetic information, with a greater understanding of gene functions and more powerful dna-based technologies.1 the challenge is to apply such knowledge to the greatest benefit of patients and their families.2 in oman and neighbouring countries, genetic services have been developed, both within the health care system and in universities. 3, 4 such genetic services have been prompted by local needs as well as by prevention agendas, often initiated internationally. 4 – 9 given the different origins of these services, they may have been established piecemeal, without a unifying vision of the community objectives. dependent on whether a service originates from a research laboratory setting or from clinical needs, there may be a laboratory or clinical focus. this editorial emphasises that, in oman and in neighbouring gulf states, high quality integrated genetic services are needed now. genetic consultations and tests must be professionally designed, as well as made accessible, cost-effective and equitable. simple low-cost strategies, applied in the community health services could improve access to genetic resources, facilitating the effective use of laboratory services. patient and family needs are the priority. a g l o b a l v i e w in most developed countries, genetic counselling services have been in place for many years.10-11 clinical services were usually established first, often within departments of paediatrics, but some cytogenetic services date from the early 1960s. the organisation of such services, in each country, reflects the common genetic diseases, the type of health care provision and the culture.10-12 thus european community genetic services address disorders such as cystic fibrosis, duchenne muscular dystrophy, huntington’s disease and the fragile x syndrome.11. countries with citizens of mediterranean, bedouin, african or asian origins will focus first on haemoglobinopathies such as thalassaemias or sickle cell disease. 3, 13, 14 rare genetic disorders are seen in all countries and are always difficult to diagnose and to manage. investigation of such disorders often involves international cooperation and sharing of clinical information, of blood and dna samples and of specialised technology, to the benefit of the patient, the family and the global community. but differences must be acknowledged; they will influence the design of any nationally planned genetic service. in europe and north america, rare disorders usually occur in small families with a single affected person. there may be doubts about the mode of indepartment of genetics, college of medicine & health sciences, sultan qaboos university, muscat, oman email: sandy.raeburn@nottingham.ac.uk e d i t o r i a l اخلليج دول وبقية عمان سلطنة في (الوراثية) اخلدمات اجلينية اآلن! مطلوب التقدم ريبورن ساندي s a n d y r a e b u r n 130 heritance; therefore, investigations (to clarify both the diagnosis and the mode of inheritance) will focus more on affected persons and less on the family tree.12 the emphasis is on the rare disorders of that community. in contrast, affected arab families in the middle east region often have disorders causing several people to be affected, either in a sibship or in the wider family,3,14 usually the mode of inheritance is mendelian and is not in doubt. informative family trees here can confirm the single gene inheritance and focus investigation using tests which should have high predictive values. for example, whole genome genetic marker studies (e.g. using single nucleotide polymorphisms (snps) or microsatellite markers) in affected and unaffected people in the family may now be more logical as a first step in a multiplex omani family than the protocols used in the west. even if a country like oman can call on much collaboration from international genetic centres (and will frequently need this for specialised techniques in some families), their primary and secondary genetic services must reflect what is common in the omani community. strategies in ‘old world’ countries are necessarily different and should not be applied ‘off the shelf ’. g e n e t i c d i s o r d e r s i n t h e g u l f c o o p e r a t i o n c o u n c i l c o u n t r i e s lihadh al gazali has pointed out the high proportion of unique disorders in the uae; 7 similar data come from other arab countries3, 5, 14-16 including oman. in summary, there are regions with a high prevalence of sickle cell disease and β thalassaemia, as well as moderate numbers of worldwide disorders. rajab and her colleagues have reported the approximate birth incidences of some key conditions in oman.5 some approximate incidence figures from that report are summarized in table 1.5 in most of these countries there are also many families with other progressive single gene disorders which lead to early death in affected people. here, in addition to the health effects, severe social and financial difficulties can occur in sibships with several affected people. also, discrimination against healthy members of the family can happen, for example when they consider marriage. individually, such disorders may be uncommon but their cumulative effect in the population can be major. s e r v i c e s a v a i l a b l e n o w i n g c c c o u n t r i e s most gulf countries have established genetic services, but there are urgent calls for greater integrated service provision.3, 4 genetic departments comprising clinical, molecular and cytogenetic sections (and often biochemical genetics, immunogenetics and/or hla and tissue typing too), work best as an integrated team. 3,17 health services in kuwait, the united arab emirates (uae), the kingdom of saudi arabia, qatar, oman and kingdom of bahrain all have genetic centres and departments that meet some of the needs of families with genetic disorders. in addition, there have been excellent pan-arab initiatives to pool important genetic information, backed up by international conferences (e.g. the centre for arabic genomic studies based in the uae). these existing services can delineate the clinical features of a disease in affected individuals, exclude or confirm chromosomal abnormalities and initiate molecular investigation towards identifying causative gene mutations. sometimes they also access centres abroad for specialised molecular studies, but access to fully integrated services may be patchy; other affected people in an identified family may not receive the support they need and genetic counselling facilities for the ‘cascade’ of genetic information to relevant family members may be limited. we note that simple feedback to a family after successful gene mapping may empower the family,17 by clarifying future genetic risks. for example, even if the causative mutation is unknown, carrier testing in an undiagnosed autosomal recessive disorder could be based on linkage if the gene has been mapped. the predictive value in such families would be less than 100%, but is better than no information at all. genetic centres need to establish family counselling urgently, with follow-up to record the natural history of the disorder and to offer further counselling as the family extends and ages. these elements would be essential in future genetic services. beyond the genetic investigation and counselling needs, there may also be requirements for financial support or for aids towards normalisation of the affected people. genetic centres should therefore interact with the support services of the ministries of social affairs as well as with charitable organisations. g e n e t i c s e r v i c e s i n t h e s u lta n at e o f o m a n a n d o t h e r g u l f c o u n t r i e s 131 m i n i s t r y o f h e a l t h : h e a l t h c a r e i n o m a n healthcare services in oman are administered centrally in muscat by the ministry of health (moh) which coordinates healthcare provision in semi-autonomous regions. each region has resources to provide health care through purpose-built family clinics and regional hospitals. nationally, there are also tertiary referral centres for specialised services, mostly located in or near to the capital. the main moh genetic centre is in the royal hospital, backed up by a cytogenetics laboratory and a molecular laboratory in another part of the city. plans are well advanced for there to be a national genetic centre, funded by the moh, which would draw together these elements of the genetic service. however, there may not yet be provision for university input, which would coordinate the teaching of the new generation of medical undergraduates as well as assimilating new research findings into future services of the moh centre. the college of medicine and health sciences of sultan qaboos university (squ) has a genetics department with 4 sections: clinical genetics, cytogenetics, immunogenetics and molecular genetics. the mission of this team is: ‘to seek greater understanding of serious genetic disorders in the sultanate of oman, to apply new knowledge to the investigation, diagnosis and genetic counselling of affected families and to teach present and future doctors and scientists how to use genetic principles in their work’. this means that the traditional academic roles of a university department, teaching and research, are intended to be augmented by some service provision. currently, five doctors are training to be consultant clinical geneticists, there are three holders of phds leading cytogenetic, immunogenetic and molecular genetic sections respectively, a scientist is abroad for phd training and several others are planning to study, or already taking part in, relevant master’s programmes. all sections of the department perform service work for patients attending the sultan qaboos university hospital (squh), usually as tertiary referrals. space both for genetic clinics and laboratories is very limited. s e r v i c e s t h a t c o u l d b e a v a i l a b l e s o o n i n g c c c o u n t r i e s the genetic literature is awash with studies of disorders in which causative gene mutations have been identified by the new methodologies.18,19 often these have included arab families with informative structures. in particular, whole genome scanning in single arab families has sometimes provided opportunities for rapid mapping of new disease genes.19 a caveat to this optimism is that the complex nature of some families, including consanguineous marriage, may on the one hand simplify a whole genome search whilst making fine mapping more difficult. the urgent need in oman and other gcc countries now is to design services which utilise arabian family structures (and genetic disease patterns), as well as available global genetic expertise. these services must address the questions asked by arab families, within the context of their culture and existing health service provision. condition total affected birth incidence bardet-biedl syndrome 14 1/30,000 congenital adrenal hyperplasia 55 1/10,000 cystic fibrosis 32 1/10,000 ellis van creveld syndrome 18 1/25,000 meckel-gruber syndrome 9 1/50,000 metachromatic leukodystrophy 18 1/25,000 microcephaly (primary) 31 1/15,000 spinal muscular atrophy 56 1/10,000 taken from rajab et al5 table 1: incidence of some autosomal recessive genetic disorders in oman (based on a total of 420,000 live births in the period 1993-2002) s a n d y r a e b u r n 132 facilitation of this pro-active approach needs three simple elements: (i) strong collaboration between the moh and the universities; (ii) access points in the community for the primary recognition of genetic disease in families and (iii) a positive role for diseasecentred parent and patient organisations. patient organisations could play a part in the identification of needs and also in the coordination with agencies outside health which are required. the model of the genetic interest group (gig) in the uk could be applied in the gcc countries, but with a special focus on autosomal recessive disorders. a v i s i o n f o r g e n e t i c s e r v i c e s i n t h e a r a b i a n p e n i n s u l a in all gcc countries, collaboration between the ministries of health and the universities could now be strengthened and built into robust partnerships. coordinating committees and conferences are valuable, but must be seen as steps towards improving genetic health, not the final outcome. some pilot initiatives from the genetics department of sultan qaboos university are relevant here. these have shown the acceptability of university-led outreach genetic clinics in regional moh hospitals (sultan qaboos hospital in salalah and nizwa and sohar hospitals). the enthusiasm and support from families, who have much shorter distances to travel with their affected offspring could have been expected. but there has been support too from the specialists and medical directors in those regional hospitals.20 the paradigm is to work together to provide holistic genetic health care for the many, not to make research forays into the community to gain publications for the few. a spin-off of the specialised genetic outreach clinics has been experiences gained when visiting omani families at their home, usually when there are several affected people. a glance at one family tree shows why it is better for the genetic team to visit the home [figure 1]. after a home visit the team was able to confirm that the proband in generation 5 (arrow) had the same disorder as the 3 living affected people in generation 4, who were siblings of the proband’s mother. a valuable outcome of home visiting in village communities has been the opportunity to meet nonmedical professionals in the health centres. these professionals take great pride in their work but often feel isolated; they are willing to contribute to genetic health care if they are taught how to do so.20 this raises the issue of the degree of genetic competence figure 1: a typical family tree of an autosomal recessive disorder in an omani family g e n e t i c s e r v i c e s i n t h e s u lta n at e o f o m a n a n d o t h e r g u l f c o u n t r i e s 133 needed in such health centres. a provocative answer might be that the genetic package may be extremely simple, involving just the ability to answer 3 questions [table 2]. g e n e t i c k n o w l e d g e i n t h e o m a n i c o m m u n i t i e s a substantial proportion of omani families touched by a genetic disease are aware that the disorder in their family is inherited and can lead to increased risk of the disease in relatives. as in any country, they may deny the diagnosis, or shop around for second opinions. also unrelated families may be (excessively) concerned about future risks if they marry into an affected family. they may choose to avoid such marriages, often based on inaccurate information. omani families also know that marriages between close relatives may increase the risk of having affected children. they face the dilemma of choosing whether to abandon traditional practices or to consider procedures which are ethically sensitive (such as prenatal diagnosis) or expensive and less likely to result in much-wanted pregnancies (such as pre-implantation genetic diagnosis).21, 22 these families may wish to consider other ways to utilise genetic tests. for example, carrier tests might assist family decisions if several cousins were tested before engagement or marriage; genetic counselling approaches might then be used to identify the low and high risk partnerships.20 omani families at the squ genetic clinics have welcomed simple biological information about the mode of inheritance of the disease in their family. as in the uk, this information-giving element of counselling can ease psychological traumas, probably by reducing uncertainty.22-23 in any case, such information is required by families before they decide to embark on carrier testing, prenatal diagnosis, pre-implantation genetic diagnosis or presymptomatic detection. they also need to understand why genetic testing is only required or helpful in certain family members. this preparatory work has shown us that a greater attention to the family tree and less emphasis initially on laboratory tests is more appropriate for genetic counselling in the gulf setting [table 3]. w h a t a r e t h e c o n s t r a i n t s i n o m a n ? i n a d e q uate f un d i n g oman, the united arab emirates and the kingdom of saudi arabia face greater numbers of autosomal recessive conditions5, 7 than europe and double the european prevalence of genetic malformations and handicaps.4 logically, they should need higher staffing levels than recommended in, for example, the uk;12 however, this wish is unrealistic in oman, both at present and in the near future. we recommend measures to tackle the major needs of families with genetic disadvantages which are realistic, in terms of resources.20 w i d e ge o gr a ph i c a l d i str i bu ti o n o f fa mi l i e s w i th spe c i a l i se d ge n e ti c se rv i c e n e e d s the distance travelled to attend specialist genetic centres creates problems for many families, especially for those with limited resources. i n a d e q uate ge n e ti c un d e r sta n d i n g by c l i n i c a l sta ff a n d fa mi l i e s this may be exacerbated by an excessive enthusiasm of doctors to initiate dna-based genetic investigations without first assessing the family tree and the prior risks of the family or their psychosocial, informational or financial needs. a r e s t u d i e s o f o t h e r g e n e t i c s e r v i c e s r e l e v a n t ? there are extensive publications on genetic counselling and other genetic services published from well-established genetic institutes in the west.10,12, 21 caution should be exercised before planning genetic services 1. do all ‘affected’ people have the same condition? 2. are ‘unaffected’ people in the family definitely free from the disorder? 3. does the family tree suggest a need for specialist referral? table 2: three questions which non-medical health centre staff could answer accessible clinics with trained staff, nationally and in the regions genetic service laboratories with trained staff: * cytogenetics covering both constitutional chromosome disorders and cancer cytogenetics * molecular genetic staff trained in service provision in preference to research training * immunogenetic staff experienced in general tissue typing and in transplant donor matching table 3: elements of an integrated genetic service s a n d y r a e b u r n 134 in oman, based on such models. the options available might not be acceptable in omani communities; more importantly, the spectrum of genetic diseases differs considerably from the west. health care providers and practitioners in oman may need to adopt a more pragmatic and family-focused approach. e v o l v i n g s o l u t i o n s there must be universal support for the moh initiatives towards offering genetic counselling for all families with people affected by genetic disorders. however, families with multiply affected members need to be ascertained too and prioritised. in such families, with several affected people already, there should be opportunities for pre-marital counselling and relevant carrier testing. an accurate family tree, as well as considerable practical molecular genetic expertise is crucial to success here. simple genetic counselling needs to be provided regionally and should be organised in consultations separate from clinical management of affected patients. this is because either the impact of the genetic risks or concerns about progression disease will limit understanding. the patient needs time to absorb information on genetic risks and separate allocations of time. the progress and treatment of disease is a clinical issue which needs to be distinct from genetic counselling. in the long term, each region requires a consultant, trained in clinical genetics, to lead and coordinate the local programme. the consultant fulfilling this role regionally may have joint accreditation, e.g. as a clinical geneticist and a paediatrician (or physician). each regional team requires a genetic nurse specialist, who can prepare family trees, collect blood samples and give counselling support. this nurse will see high risk couples with the geneticist and provide follow-up. each team also requires a part-time coordinator, who will organise genetic clinics. later, regional teams will include trained genetic counsellors. regional genetic teams do not need laboratory facilities locally except those for dna separation; specialist genetic laboratory services will be provided by laboratories in the new moh genetic centre, complemented by the genetic laboratories at squ. the model for genetic service development described here may be of interest to neighbouring arab nations; services designed for the middle east region could be piloted jointly by oman and by neighbours with larger populations. the ‘action list’ (table 4) summarises what could be completed with some speed. 1. more integrated departments of genetics are needed, so that clinical needs set the agenda in the laboratories as well as for management. 2. closer collaboration between the moh and university departments dealing with genetic disorders is essential. 3. outreach clinics are needed in main regional hospitals: consultants with a genetic interest in each region, backed by a genetic counsellor or specialist nurse and a part-time coordinator. resources to facilitate the interaction between staff in the genetic centre in muscat and in regions. travel expenses and short term accommodation costs for staff from the national genetic centre and the reverse for regional teams. 4. facilitation of home visits to families in which multiple affected individuals are identified. transport availability, occasional overnight accommodation etc. 5. genetic database resources in the genetic centre, compatible with local computing facilities and laptops for outreach work and home visiting. 6. adequate resources for other specialties that see genetic disorders frequently, e.g. electroretinogram equipment may be needed for the tertiary referral departments of ophthalmology. 7. development of a simple community teaching package for health centre staff. the aim will be to have one or two staff members in each health centre with skills in family tree preparation and simple interpretation. table 4: action points g e n e t i c s e r v i c e s i n t h e s u lta n at e o f o m a n a n d o t h e r g u l f c o u n t r i e s 135 c o n c l u s i o n this editorial is based on real experience and figures from oman, backed up with data from neighbouring countries. the action points are therefore not hypothetical, nor are they based on a blind willingness to copy genetic services of the western developed countries. it is hoped that the issues raised will stimulate actions as well as discussions, along with the confidence to go in a different direction from established (western) genetic services. solutions for genetic services in the middle east need to be designed for their purpose, not translocated from other less relevant structures in the ‘first world’! a c k n ow l e d ge me n ts it is a pleasure to acknowledge the many discussions with my colleagues in the genetics department of the college of medicine and health sciences at the sultan qaboos university, particularly dr. aisha al shehi, rayhanah al-mjeni, dr almundher al-maawali and my wife, arlene raeburn. rahma al-jashmi kindly prepared the family tree. r e f e r e n c e s 1. brand a, brand h, schulte in den baumen t. the impact of genetics and genomics on public health. eur j hum genet 2008; 16:5-13. 2. pagon r. genetests: integrating genetic services into patient care. am j hum genet 2007; 81:658-661. 3. rajab a, el-hazmi m. the gulf cooperation countries genetics services. saudi med j 2007; 28:1321-1323. 4. modell b. possibilities for the control of congenital and genetic disorders in oman. who consultant’s report. muscat: ministry of health, 2003. 5. rajab a, bappal b, al-shaikh h, al-khusaibi s, mohammed aj. common autosomal recessive diseases in oman derived from a hospital-based registry. community genet 2005; 8:27-30. 6. international centre for birth defects. world atlas of birth defects. 2nd edition. geneva: world health organisation, 2003. 7. al gazali li. genetic disorders in the united arab emirates. in: teebi as, farag ti eds. genetic disorders among arab populations. oxford: oxford university press, 1997. p. 341-372. 8. rajab a, patton ma. major factors determining the frequencies of hemoglobinopathies in oman. am j med genet 1997; 71:240 –242. 9. goud mt, al-harassi sm, al-khalili sa, al-salmani kk, al-busaidy sm, rajab a. incidence of chromosome abnormalities in the sultanate of oman. saudi med j 2005; 26:951-7. 10. raeburn j a, kent a, gillott j. genetic services in the uk. in: harris r, ed. concerted action on genetics services in europe: a comparative study of 31 countries. eur j hum genet 1997; 5:188-195. 11. harris r, ed. concerted action on genetics services in europe: a comparative study of 31 countries. eur j hum genet 1997; 5:1-220. 12. harper ps, hughes he, raeburn ja. clinical genetics services into the 21st century. a report from the clinical genetics committee of the royal college of physicians. london: royal college of physicians, 1996. 13. alwan aa, modell b. community control of genetic and congenital disorders. emro technical publications series 24. cairo: world health organisation regional office for the eastern mediterranean, 1997. 14. rajab a, patton ma. analysis of the population structure in oman. community genet 1999; 2:23-25. 15. christianson a, howson cp, modell b. global report on birth defects: the hidden toll of dying and disabled children. white plains, ny: march of dimes birth defects foundation, 2006. 16. der kaloustian vm, naffah j, loiselet j, pitz jm. genetic diseases in lebanon. am j med genet 1980; 7:187203. 17. al-maawali a, al-mjeni r, al shehi a, raeburn s. informative families in oman. article in preparation, may 2008. 18. frossard p, john a, dawson k. cystic fibrosis in the uae ii – molecular genetic analysis. emirates med j 1994; 12:249-254. 19. white dra, ganesh a, nishimura d, rattenberry e, ahmed s, smith um, et al. autozygosity mapping of bardet–biedl syndrome to 12q21.2 and confirmation of flj23560 as bbs10. 2007. eur j hum genet 15:173178. 20. raeburn ar, john b, nyall a, raeburn s. experience with genetic clinics & home visits in dhofar: meeting the family halfway. article in preparation, may 2008. 21. modell b, harris r, lane b, khan m, darlison m, petrou m, et al. informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential enquiry. bmj 2000; 320: 325-390. 22. raeburn ja. genetic counselling and prenatal diagnosis. in: mason jk, ed. paediatric forensic medicine and pathology. london: chapman & hall ltd, 1990. p. 2136. 23. modell b, darr a. genetic counselling and customary consanguineous marriage. nat rev genet 2002; 3:225229. december 2007 vol 8 after meeting.indd harrison’s neurology in clinical medicine sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 277-278 sultan qaboos university© submitted 31st july 2007 different chapters of this book have different authors who are experts in their fields. the book is edited by; stephen l hauser, md; robert a fishman distinguished professor and chairman, department of neurology, university of california, san francisco, usa. associate editors, all from the same department as the editor, are: scott andrew josephson, md, neurovascular and behavioral neurology fellow; joey d english, md, phd, assistant professor; john w engstrom, md, professor and vice-chairman patients with neurological disorders are common in day to day clinical practice. most of these patients initially present to non-neurologists. mastering clinical skills and examination is essential in order to localise the most probable neuroanatomical site of the patient’s problem. this will enable the physician to order a focused investigation and request appropriate consultations. however, exposure to patients with neurological disorders is limited during training due to various reasons. this book is therefore written to serve non-neurologist who are expected to encounter patients with neurological problems on a day to day basis. this paperback book has 368 pages. it is divided into seven sections, which contain a total of 43 chapters. in addition, there is an appendix, review and selfassessment section, and an index. the seven sections are as follows: 1. introduction to neurology this section deals with pathogenesis and approaches to patients with various neurological diseases. in addition, it gives a brief introduction to neuroimaging in neurological disorders. 2. clinical manifestations of neurological diseases this section presents in detail 10 common neurological presentations. examples include pain, headache, vertigo, change in mental state, imbalance and sleep disorders. 3. diseases of the central nervous system this section contains 19 chapters which cover various central nervous system disorders in detail with up to date information. examples of chapters include: seizures and epilepsy, cerebrovascular diseases, neurodegenerative disorders like alzheimer’s disease, parkinson’s disease, amyotrophic lateral sclerosis, ataxic disorders and multiple sclerob o o k r e v i e w في الطب السريري األعصاب هاريسن لعلم كتاب هوسر ال. احملرر: ستيفن جون اجنستروم ، اجنليش د. جويي ، جوزيفسن اندرو �احملررون املشاركون: سكوت العاصمي اهللا مراجعة: عبد editor: stephen l hauser associate editors: scott a josephson, joey d english, john w engstrom publisher: mcgraw hill, 2006. isbn: 0-07-145745-3 available at: http://www.mcgraw-hill.co.uk/html/0071457453.html stockist in oman: al-manahil educational consultancy, po box 552, pc 116, muscat tel: 00968 24487707/ fax: 00968 24485757 reviewer: *abdullah al-asmi *department of medicine, college of medicine & health sciences, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman email: alasm@squ.edu.om b o o k r e v i e w : h a r r i s o n ’ s n e u r o l o g y i n c l i n i c a l m e d i c i n e 278 sis. in addition, central nervous system infections have also been covered like meningitis, encephalitis, brain abscesses, and empyema, hiv in relation to neurology, and prion diseases. 4. diseases of nerve and muscle there are seven chapters covering most common diseases of the neuromuscular disorders. the section starts with an approach to patients with peripheral neuropathy. inherited neuropathies, guillain-barré syndrome, and myasthenia gravis are discussed in detail. one chapter is devoted to an approach to the patient with muscle disease followed by a discussion on common inherited and acquired muscular disorders. 5. chronic fatigue syndrome this section is devoted to discussing fibromyalgia and chronic fatigue syndrome. this syndrome is at times challenging to diagnose and manage, usually requiring a multidisciplinary approach. 6. psychiatric disorders this sections, which contains a single chapter, discusses common mental disorders. 7. alcoholism and drug dependence this section has two chapters, one on alcohol and alcoholism and the other on cocaine, opioids and other commonly abused drugs. this book is intended for students, residents, primary care physicians and internists. the content of this book is presented in a very simple and concise way. it has many colourful illustrations. detailed neuroanatomical pathways are nicely illustrated. in addition, some chapters contain flowcharts to assist readers in taking medical decisions. this book, as mentioned earlier, is intended for non-neurologists who encounter patients with neurological disorders. it is nicely written and fulfills this requirement being well organized and easy to read with many illustrations. the book starts by describing the common manifestations and presentations of neurological diseases based on different symptoms and syndromes. thereafter, detailed manifestations and the management of various neurological diseases are presented, divided into central nervous system diseases and those of the peripheral nervous system, as well as common neurological manifestation of psychiatry and drug abuse. the text is supplemented by excellent illustrations and diagrams. section one in the book gives an overview of the pathogenesis of neurological disorders with an excellent concise review of basic neuroscience, relevant to clinical practice. the second chapter details the approach to the patient with neurological disease and highlights the importance of neuroanatomical localisation. the chapters on specific diseases cover the disorders under discussion in detail including causes, basic mechanism, evaluation, differential diagnosis, laboratory studies and management. the chapter on mental illnesses presents common psychiatric disorders and their management. this chapter is enriched with many tables listing common drugs used to manage these disorders and their potential side effects. at the end of every chapter, references are provided for further reading. the book covers the most common neurological manifestations as well as specific diseases in an up to date manner, which is required by the intended readers of the book. the book has more than 100 full colour drawings as well as clinical and laboratory images, which enhance the readability and understanding of the subject under discussion. the availability of an electronic version of the book would be useful for readers for quick access and making use of the contents, especially the illustrations, in various presentations. december 2007 vol 8 after meeting.indd abstract hemophagocytic lymphohistiocytosis (hlh) implies a benign generalized histiocytic proliferate with erythrophagocytosis and it includes familial hemophagocytic lymphohistiocytosis and secondary hemophgocytosis. spinal fluid changes like mild to moderate pleocytosis (most of the cells are lymphocytes and macrophages) and sometimes hemophagocytosis are seen in primary hlh but are not reported in secondary hlh. here we report a case of a previously healthy 0 months old male infant who was diagnosed as familial hlh with evidence of csf hemophagocytosis. he was started on the hlh 2004 treatment protocol with no improvement. a second bone marrow aspiration revealed leshmania donovani antibodies and he was started on anti-leishmania treatment with dramatic response.to the best of our knowledge, this is the first case of secondary hlh with evidence of hemophagocytosis in cerebrospinal fluid. key words: lymphohistiocytosis, hemophagocytic; leishmaniasis; cerebrospinal fluid; case report; oman. cerebrospinal fluid involvement in a case of visceral leishmaniasis associated with hemophagocytic lymphohistiocytosis mahmoud fathalla, javad hashim, hussein alkindy, *yasser wali sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 253-256 sultan qaboos university© submitted 17th march 2007 accepted 19th september 2007 department of child health, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman *to whom correspondence should be addressed. email: yawali@squ.edu.om c a s e r e p o r t خلاليا املرافقة الليشمانيا االحشائية في حالة النخاعي السائل تأثر رَيَّات الكُ ةُ مَ بَلْعَ مرض والي الكندي، ياسر جافاد هاشم، حسني اهللا، فتح محمود هذه اخلاليا وتقوم باألنسجة املناعية ة جَ ُنْسِ للخاليا امل حميد بتكاثر مرض يتميز البالزماوي هو يٌّ جِ ُنْسِ امل فاوِيٌّ اللِمْ رَيَّات الكُ ةُ مَ بَلْعَ مرض امللخص: إن اخلاليا الليمفاوية في ــر تكاث مثل النخاعي ــائل الس في تغيرات حتدث . ثانوي واألخر وراثي أحدهما نوعني املرض هذا ــمل ويش . ر ــاتِ احلُمْ رَيَّ الكُ ــام بالته مصاب أشهر ذكر عمره عشرة طفل التقرير نشرح حاله هذا وفي فقط. الوراثي النوع في املناعية اخلاليا في تكاثر وأيضا البلعمة عملية وأحيانا حتصل هناك أن تبني الثاني العظم نقي فحص في . حتسن 2004 دون عولج سنة . الشوكي رَيَّات في السائل الكُ ةُ مَ بَلْعَ عنده وكان ، املرض من الوراثي بالنوع من حالة أول أن هذه علمنا حد وعلى . كبير ــكل حتسن بش وقد األساس هذا على عولج ــائية). (الليشمانيا االحش ونُوفانِيَّة الدُّ ــمانِيَّةُ اللِّيشْ ــام أجس . الشوكي في السائل رَيَّات الكُ ةُ مَ بَلْعَ وجود مع البالزماوي يٌّ جِ ُنْسِ امل فاوِيٌّ اللِمْ رَيَّات الكُ ةُ مَ بَلْعَ مرض عمان. ، حالة تقرير سائل شوكي، بالزماوي، ثانوي، يٌّ جِ نْسِ مُ ْفاوِيٌّ ملِ رَيَّات، الكُ ةُ مَ الكلمات: بَلْعَ مفتاح haemophagocytic lymphohistiocytosis (hlh) includes familial haemophagocytosis (fhlh) and secondary haemophagocytic syndrome. primary (familial) hlh is an autosomal recessive disease. by homozygosity mapping, two loci for fhlh have been identified, one each at 9q213-22 fhli and 10q21-22 (fhl2). the incidence of fhlh is approximately one case per 50,000 live births. males and females are affected at equal frequencies and 80% of cases present in the first year of life.1 in oman, 27 cases have been diagnosed so far, most of them (24) familial; genetic study was done in 8 families.2, 3 the typical hlh is diagnosed on the basis of hentel et al’s guidelines.1 secondary hlh may occur at any age, commonly in association with immunosuppressive therapy, infection (usually viruses) and or malignancy. the central nervous system (cns) symptoms are usually linked to familial hlh. this is a rare case of secondary hlh that m a h m o u d fat h a l l a , j ava d h a s h i m , h u s s e i n a l k i n d y a n d ya s s e r wa l i 254 presented with cns symptoms as well as evidence of csf haemophagocytosis. c a s e r e p o r t a 10 month old omani male infant, was referred to sultan qaboos university hospital, (squh) oman, from a peripheral omani hospital as a suspected case of hlh. he was admitted to squh with a history of high grade fever associated with diarrhoea and vomiting for the previous two weeks. he was a product of a consanguineous marriage, with no past history of diseases or previous admissions to hospitals; however, there was the unexplained early infant death of one of his siblings in his family history. on examination, he was sick looking, febrile, pale and had tachycardia. there was splenomegaly of 10 cm below the left costal margin and a large liver of 7 cm. after his admission, he developed generalized convulsions that responded to iv phenytonin treatment (loading followed by maintenance). his complete blood count showed evidence of pancytopenia with wbc 2.37x109/l; absolute neutrophil count was 0.36x109/l and platelets were14.1x109/l. other laboratory investigations revealed: lactate dehydrogenase 829; erythrocyte sedimentation rate 47; c-reactive protein 65; albumin 24; serum ferritin 4687 ng/ml that increased to 25973 µ/ml within few days. serum triglycerides were 3.0 mmol/l and fibrinogen was 1.9 g/l. prothrombin time was 14 seconds and activated partial thromboplastin time was 55 seconds. renal and liver function tests were within normal limits and hepatitis and hiv serology tests were negative. the bone marrow aspiration (bma) was completely normal. the cerebrospinal fluid showed evidence of haemophagocytosis, genetic study for perforin, munc and syntaxin ii genes were done in the squh genetic laboratory and found to be negative. the results of these tests usually come after one month. a provisional diagnosis of primary (familial) hlh was established on the basis of the young age of presentation, the unexplained death of a 6 months old sibling and the severe clinical course. subsequently, treatment with hlh 2004 protocol was started for 2 weeks. the child’s fever continued to spike with no improvement. as per protocol, after 2 weeks, a second bma was done and revealed leishmania donovani antibodies. the hlh 2004 protocol was stopped and iv ambisome was started with no clinical improvement. treatment was changed to na-stiblogluconate (20mg/kg/day). he received a full course of 21 days and improved significantly with disappearance of the fever and organomegaly. the bma showed no evidence of leishmania or haemophagocytosis. the patient was subsequently discharged home. at a follow up visit after 6 months, he maintained his general well being and was completely normal. d i s c u s s i o n hlh implies a benign, generalized histiocytic proliferation with erythrophagocytosis and it includes fhlh and secondary haemophagocytic syndrome1, 2, 4 associated with viral infections, protozoal infections and malignancy. these disorders are indistinguishable pathologically and are characterized as ‘reactive’ disorders of antigen-presenting and antigen-processing histiocytes. the hallmark of these disorders is marked haemophagocytosis in the lymphoreticular system.5, 6 the symptoms are supposed to be due to hyperactivity of macrophages.1 the cause of the inappropriate immune activation in fhlh has been shown in some families to be due to the genetic encoding of perforin, munc and syntoxin ii.7, 8 the figure 1: there was a family history of unexplained death of one of his siblings c e r e b r o s p i n a l f l u i d i n v o lv e m e n t i n a c a s e o f vi s c e r a l l e i s h m a n i a s i s a s s o c i at e d w i t h h e m o p h a g o c y t i c ly m p h o h i s t i o c y t o s i s 255 typical hlh is diagnosed on the basis of henter et al’s guidelines9: (a) clinical criteria: fever and splenomegaly (both to be present); (b) laboratory criteria: cytopenias (affecting 2 of 3 lineages in the peripheral blood); haemoglobin (<9 g/l); platelets (<100 x 109/l); neutrophils (<1.0x109); hypertriglyceridemia and/or hypofibrinogenemia fasting triglycerides ≥2.0 mmol/l or ≥3 sd of the normal value for age; fibrinogen (≥1.5 g/l or ≥3 sd); (c) histopathological criteria: haemophagocytosis in the bone marrow or spleen or lymph nodes, cerebrospinal fluid (csf) and no evidence of malignancy. neurological symptoms may complicate and sometimes dominate the clinical course of the familial cases. hepatic abnormalities, including elevated serum transaminases or hyperbilirubinemia, appear to be related to the degree of liver involvement. elevated ferritin, lactate and coagulation derangement are also common during active disease. 10 the haemophagocytosis mostly affects erythrocytes, but occasionally also platelets and leukocytes.11, 12 infection by the protozoan pathogen leishmania is a public health problem in certain regions of oman such as north batinah.13 although, there are a number of different species, all of which are transmitted by phlebotomine sand flies,12 there are only two primary types of clinical disease: cutaneous and visceral leishmania (vl).14 visceral leishmaniasis revealed by haemophagocytic syndrome (hs) is an extremely rare event that can cause considerable diagnostic difficulty. the first case of leishmaniasis revealed by a reactive hs was reported by matzner et al and concerned a 22 year old adult.15 cns involvement has been almost totally linked to primary fhlh. in a retrospective study on visceral leishmaniasis carried out on 33 omani children from 1993 to 1999 at sultan qaboos university hospital, oman,16 there was no haemophagocytosis. two children had cns involvement in the form of encephalopathy, but there was no haemophagocytosis in the csf. in another study regarding the current status of hlh in infants and children from the division of pediatrics, children’s research hospital, kyoto, japan,17 82 cases of pediatric hlh without familial inheritance were studied. there were cns symptoms in 32.3 cases, but none of them had spinal fluid haemophagocytosis. all of the cases revealed lymphohistiocytosis with the presence of haemophagocytosis in bone marrow and reticuloendothelial cells.18 from the indian subcontinent, there are reports of secondary hlh following malaria and leishmaniasis (also called ‘kala-azar’).19 in 14 cases of secondary hlh following malaria and kala-azar there were no features of csf haemophagocytosis. this is probably the first case of secondary hlh that presented with cns symptoms with evidence of csf haemophagocytosis. r e f e r e n c e s 1. henter ji. biology and treatment of familial hemophagocytic lymphohistioctytosis. importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis. med pediatr oncol. 2002; 38:305-309. 2. al lamki z, wali ya, pathare a, ericson k, henter ij. clinical and genetic study of hemophagocytic lymphohistiocytosis (hlh) in oman: need for early treatment. pediatr hematol oncol 2003; 20:603-609. 3. muralitahran s, al-lamki z, dennison d, christie bs, wali ya, zachariah m, et al. an inframe perforin gene deletion in familial hemophgocytic lymphocytosis is asfigure 1: cerebrospinal fluid showing histiocytes with evidence of hemophagocytosis. m a h m o u d fat h a l l a , j ava d h a s h i m , h u s s e i n a l k i n d y a n d ya s s e r wa l i 256 sociated with perforin expression. am j hematol 2005; 78:59-63. 4. henter ji, tondini c, pritchard j. histiocyte disorders. crit rev oncol hematol. 2004; 50:157-174. 5. imashuku s, hibi s, todo s. hemophagocytic lymphohistiocytosis in infancy and childhood. j pediatr 1997; 130:352-358. 6. ladisch s, ho w. immunologic and clinical effects of repeated blood exchange in familial erythrophagocytic lymphohistiocytosis. blood 1982; 60:814-820. 7. stepp se, lagelouse rd, le deist f, bhawan s, certain s, mathew pa, et al. perforin gene defects in familial hemophagocytic lymphohistiocytosis. science 1999; 286:1957-1959. 8. zur stadt u, beutel k, kolberg s, schneppenheim r, kabisch h, janka g, et al. mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of prf1, unc13d, stx11 and rab27a. hum mutat 2006; 27:62-68. 9. henter ji, elinder g, ost a. diagnostic guidelines for hemophagocytic lymphohistiocytosis. the fhl study group of the histiocyte society. semin oncol 1991; 18:29-33. 10. favara b. hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. semin diagn pathol 1992; 9:63-74. 11. stephan jl. histiocytoses. eur j pediatr 1995; 154:600609. 12. sulivan jl, woda ba. lymphohistiocytic disorders. in: nathan dg, oski fa, eds.: hematology of infancy and childhood. 5th ed. philadelphia: wb saunders, 1998. p.1359-1380. 13. elnour b, akinbami fo, shakeel a, venugopalan p. visceral leishmaniasis in omani children: a review. ann trop pediatr 2001; 21:159-163. 14. pearson rd, sousa aq. clinical spectrum of leishmaniasis. clin infect dis 1996; 2:11-13. 15. kinmond s, galea p, simpson em. kala-azar in a scottish child. lancet 1989; 2:325. 16. matzner y, behar a, beeri e, herskko c. systemic leishmaniasis mimicking malignant histiocytosis. cancer 1979; 43:398-402. 17. ib elnour, fo akinbami, shakeel a. visceral leishmaniasis in omani children. areview. ann trop paediatr 2001; 21:159-163. 18 imashuku s, hibi s, todo s. hemophagocytic lymphohistiocytosis in infancy and childhood. j pediatr 1997; 130:352-356. 19. phawa r, singh t, khurana n. hemophagocytic syndrome in malaria and kala-azar. indian j pathol microbiol 2004; 47:348-350. 1department of pharmacy, 3breast cancer program, 4women health program and 7gastroenterology oncology program, sultan qaboos comprehensive cancer care and research centre, muscat, oman; 2department of pharmacy, sultan qaboos university hospital, sultan qaboos university, muscat, oman; 5general medicine department, king’s mill hospital, nottinghamshire, united kingdom; 6department of pharmacology and clinical pharmacy, college of medicine and health sciences, sultan qaboos university, muscat, oman *corresponding author’s e-mail: bsalman1213@gmail.com predictors of hypersensitivity reactions to platinum-based chemotherapy in a tertiary care hospital in oman a case control study *bushra salman,1 fatma al-rasbi,2 nameer al-ward,1 khalid al-baimani,3 ikram a. burney,4 eman abdullah,5 buthaina al-azizi,1 khulood al-mishaikhi,1 ibrahim al-zakwani,6 mansour al-moundhri7 sultan qaboos university med j, may 2023, vol. 23, iss. 2, pp. 233–238, epub. 31 may 23 submitted 18 apr 22 revision req. 15 aug 22; revision recd. 21 aug 22 accepted 19 sep 22 https://doi.org/10.18295/squmj.1.2023.001 clinical & basic research this work is licensed under a creative commons attribution-noderivatives 4.0 international license. pl atinum-based compounds (pb cs;e.g. cisplatin, carboplatin, oxaliplatin) play a very important role in cancer therapy. they act by inhibiting dna replication through the formation of dna adducts leading to apoptosis and thus prevent replication of cancer cells.1 these compounds have been approved for treatment of several cancers of different origins. for several cancers, pbcs form the backbone of treatment.2 however, one of the drawbacks of pbcs is the occasional occurrence of hypersensitivity reaction (hsr), which can be potentially fatal. the incidence of hsrs to pbcs is rising due to the growing use of these agents in cancer management.2 the symptoms of hsrs range from a mild skin rash to severe anaphylaxis, and multiple types of hypersensitivity pathways seem to be implicated.2,3 the reported incidence of hsrs to pbcs differs according to the specific agent used, ranging from 5–20% for cisplatin, depending on the concomitant therapy.4 for carboplatin, hsr occurs at a rate <1% during the first five cycles, with a sharp increase to 44% in the third-line treatment setting, after more than eight cycles have been administered.5 oxaliplatinrelated hsr has been reported to be less common, but with the growing use of this drug, the frequency ranges from 3.6–18.9% in clinical practice.2,3 the risk of hsrs to both cisplatin and carboplatin increases with the increase in the number of infusions abstract: objectives: this study aimed to estimate the prevalence and evaluate risk factors of hypersensitivity reactions (hsrs) to platinum-based compounds (pbcs) in cancer patients. pbcs play an important role in cancer therapy. however, one of the drawbacks of pbcs is the occasional occurrence of hsrs, which can lead to serious consequences. methods: this retrospective case control study was conducted from january 2013 to december 2020 at sultan qaboos university hospital, muscat, oman and included patients who received any pbc for the management of non-haematological cancers. data regarding demographic characteristics and diseases and treatment details were collected from the hospital’s electronic database. the data were quantitatively described and student’s t-test and wilcoxon mann-whitney tests were used to detect significant differences. results: a total of 38 cases and 148 matched controls were studied. the prevalence of hsrs to pbcs in the cohort of this study was 4.7% (95% confidence interval: 3.33–6.37%), higher with carboplatin compared with cisplatin and oxaliplatin. the female gender (p = 0.032), concomitant taxanes (p = 0.002) and concurrent radiation (p <0.001) were significant predictors of hsrs to pbcs. the majority of the reactions were of mild to moderate severity, and the rechallenge rate after hsr development was 13%. conclusion: hsrs to pbcs impact therapy decisions and understanding the risk factors is important to improve treatment outcomes in cancer patients. keywords: anti-neoplastic agent; hypersensitivity; medical oncology; platinum; oman. advances in knowledge this is the first report from a middle eastern country reporting on the incidence, presentation, outcomes and predictive factors of hypersensitivity reactions (hsrs) to platinum-based compounds (pbcs). applications to patient care this study showed that approximately 5% of patients can develop hsrs to pbcs, and the combination of platinum–taxane in addition to concurrent chemo-radiation significantly predicted higher hsr rates, this should be taken into consideration during treatment planning. as most hsrs were of a lower grade, further studies should be conducted on challenge criteria and protocols, so as to not compromise treatment outcomes caused by the elimination of platinum use in patients showing mild signs of hsr. predictors of hypersensitivity reactions to platinum-based chemotherapy in a tertiary care hospital in oman a case control study 234 | squ medical journal, may 2023, volume 23, issue 2 and the cumulative dose delivered, as well as the type of concomitantly administered antineoplastic drugs.2 hsrs to cisplatin also increase with concurrent radiation therapy.4 patients who receive first-line platinum-based chemotherapy and are then treated again with a platinum agent at the time of relapse are at the greatest risk of experiencing hsrs after a long platinum-free interval.6 other factors such as higher lymphocyte and neutrophil count and lower monocyte count are also considered potential risk factors.7,8 the occurrence of hsrs raises important issues when it comes to subsequent therapy decisions, because changing the chemotherapy could affect the tumour’s evolution. though the characteristics of platinum-based hsrs are widely reported, limited data are available regarding such reactions in different types of patients. additionally, to the best of the authors’ knowledge, hsrs to pbcs have not been previously studied in the omani population and ethnic variations could play an important role in determining such outcomes. therefore, this study aimed to estimate the prevalence of hsrs and evaluate the predictive factors for the occurrence of allergic reactions to pbcs in cancer patients treated at a tertiary care hospital in oman. methods this retrospective case control study included patients who had received any platinum-based chemotherapy regimen for the treatment of non-haematological tumours at the sultan qaboos university hospital (squh), a tertiary care and cancer centre in muscat, oman, between january 2013 and december 2020. adult cancer patients, who had received at least one dose of a platinum agent during this period were included. details of chemotherapy were retrieved from the cytosoft© software (guava technologies, inc., hayward, california, usa) used for chemotherapy order management. chemotherapy protocols at the authors’ institution are based on british columbia cancer agency protocols. all patients had received dexamethasone and an antihistamine prior to every dose of platinum chemotherapy as part of the routine supportive care protocol. data on hsrs were collected from either the adverse drug reaction form or the electronic patient’s record (epr). this reporting system can be activated by the physician, the pharmacist or the nurse involved in the patient care and sent to a central pharmacovigilance centre. only patients with acute infusion-related hsrs were included in the study. the hsr severity was defined according to the common terminology criteria for adverse events version 4. for each case, four controls were selected. controls were randomly selected patients who received platinum-based chemotherapy and did not develop symptoms of hsrs; they were stratified according to age, gender and the year of treatment. approximately 18–20 random patients, with males and females in equal numbers, were selected from each treatment year within the study period. the controls for disease site or chemotherapeutic regimens were not matched. patient data were collected from the epr, including demographic characteristics (age, gender, height, weight, diagnosis and stage of the disease), history of allergy to other medications, baseline laboratory parameters (complete blood count including haemoglobin, white blood cell with differentials, platelet count) and treatment details (type of platinum agent used, treatment setting, number of cycles received prior to the development of hsr, cumulative dose received prior to hsr, grade of hsr, platinum-free interval, concomitant chemotherapy, concomitant radiotherapy and subsequent therapy after occurrence of hsr). descriptive statistics were used to describe the data. for categorical variables, frequencies and percentages were reported. differences between the groups were analysed using pearson’s χ2 tests (or fisher’s exact tests for expected cells <5). for continuous variables, mean and standard deviations were used and differences between the groups stratified by platinumbased hsrs were analysed using student’s t-test. variables that were not normally distributed (e.g. number of cycles, cumulative dose) were summarised using median and interquartile range and the analysis was performed using the wilcoxon-mann-whitney test. the kolmogorov–smirnov test was used to determine normal distribution. odds ratios (or) with their respective 95% confidence intervals (cis) were derived using the univariate logistic regression model. an a priori two-tailed level of significance was set at 0.05. statistical analyses were conducted using stata, version 13.1 (stata corporation, college station, texas, usa). ethical approval of the study was granted by the medical research ethics committee at squ college of medicine and health sciences (mrec # 2478). results a total of 812 patients received pbcs of which there were 38 cases of hsrs (20 for carboplatin, 13 for oxaliplatin and five for cisplatin). the incidence of hsrs in patients receiving pbcs was 4.7%. all cases developed an immediate allergic reaction to a platinumbased drug during infusion and up to one hour later. bushra salman, fatma al-rasbi, nameer al-ward, khalid al-baimani, ikram burney, eman abdullah, buthaina al-azizi, khulood al-mishaikhi, ibrahim al-zakwani and mansour al-moundhri clinical and basic research | 235 clinical features of allergy ranged from a mild skin rash to more severe bronchospasm and tachycardia. a total of 186 patients including cases (n = 38) and casematched controls (n = 148) were studied for predictive factors. of the cohort, 88 (47.3%), 89 (47.8%) and 37 (19.9%) patients received carboplatin, oxaliplatin and cisplatin, respectively, whereas four patients (2.2%) received all three types of platinum compounds, and 21 patients (11.3%) received at least two platinum compounds before the occurrence of hsr. the mean age of the cohort was 52.6 ± 15.7 years, and 53.2% of the cohort were female. no significant difference in age was noted between the cases and the controls (51.6 versus 52.8 years; p = 0.704); however, females were significantly more likely than males to be associated with hsr reactions (68.4% versus 49.3%; p = 0.032). in addition, a trend of a higher hsr rate with a lower body surface area was observed between the controls and cases (1.67 versus 1.59 m2; p = 0.064). no significant differences were observed in other demographic features, clinical stage, blood counts and prior exposure to platinum compounds between the cases and controls [table 1]. the majority of the patients were treated for stage iv disease (67.7%). consequently, 67.7% of the patients received palliative chemotherapy, whereas 15.1% and 17.2% of the patients received neoadjuvant and adjuvant chemotherapy, respectively. the most frequently used concomitant chemotherapeutic agents were paclitaxel, gemcitabine and 5-fluorouracil. concurrent radiation was used in 28 (15.1%) patients [table 2]. patients who developed a reaction to carboplatin had a median number of five (range: 2–8) cycles prior to the hsrs, compared with a median of three cycles (range: 1–6) for cisplatin and eight (range: 7–10) cycles for oxaliplatin. only three out of 38 patients developed an hsr with the first dose of a platinum agent. the cumulative number of cycles of any platinum received by the patient was not a significant predictor for an hsr, with an average of nine cycles in each group (p = 0.431). the average cumulative total dose of carboplatin, cisplatin and oxaliplatin prior to an hsr was 3,362 mg, 3,449 mg and 1,699 mg, respectively. a higher rate of hsr was observed with the concomitant use of taxane chemotherapy and concurrent chemoradiation. a taxane was administered concomitantly with a platinum in 42 patients in the entire cohort. out of the 38 cases, 16 developed hsr (42.1%, 95% ci: 26–59%), compared to 26 out of 148 controls (17.6%, 95% ci: 12–25%; p = 0.002). the use of a taxane was significantly associated with the development of hsr to platinum-based table 1: characteristics of included patients on platinumbased chemotherapy (n = 186) characteristic n (%) p value all (n = 186) controls (n = 148) cases (n = 38) mean age in years ± sd 52.6 ± 15.7 52.8 ± 15.7 51.6 ± 15.9 0.704 gender female 99 (53.2) 73 (49.3) 26 (68.4) 0.032 male 87 (46.8) 75 (50.7) 12 (31.6) mean bsa in m2 ± sd 1.65 ± 0.24 1.67 ± 0.24 1.59 ± 0.26 0.064 mean bmi in kg/m2 ± sd 25.07 ± 8.64 23.53 ± 6.57 25.46 ± 9.07 0.218 diagnosis lower git 70 (37.6) 58 (39.2) 12 (31.6) gynaecol ogical 24 (12.9) 16 (10.8) 8 (21.1) breast 24 (12.9) 18 (12.2) 6 (15.8) upper git 22 (11.8) 16 (10.8) 6 (15.8) lung 18 (9.7) 17 (11.5) 1 (2.6) urological 15 (8.1) 14 (9.5) 1 (2.6) head and neck 8 (4.3) 5 (3.4) 3 (7.9) skin 3 (1.6) 2 (1.4) 1 (2.6) bone 2 (1.1) 2 (1.4) 0 (0.0) concurrent chemotherapy type 5-fu-based 77 (41.4) 65 (43.9) 12 (31.6) 0.168 paclitaxel 42 (22.6) 26 (17.6) 16 (42.1) 0.001 gemci tabine 39 (21.0) 30 (20.3) 9 (23.7) 0.645 etoposide 17 (9.1) 17 (11.5) 0 (0.0) 0.026 pemetrexed 6 (3.2) 5 (3.4) 1 (2.6) 1.000 capeci tabine 3 (1.6) 3 (2.0) 0 (0.0) 1.000 doxorubicin/ epirubicin 2 (1.1) 2 (1.4) 0 (0.0) 1.000 mean baseline blood count ± sd hb in g/dl 11.1 ± 1.7 12.0 ± 1.8 10.9 ± 1.7 0.487 wbc × 103/l 6.6 ± 2.9 6.6 ± 3.0 6.5 ± 2.5 0.912 anc × 103/l 4.3 ± 4.8 4.1 ± 4.3 4.9 ± 6.4 0.372 eosinophils × 103/l 0.29 ± 0.70 0.32 ± 0.77 0.19 ± 0.20 0.291 monocytes × 103/l 0.64 ± 0.55 0.67 ± 0.6 0.53 ± 0.26 0.204 alc × 103/l 2.07 ± 1.6 1.99 ± 1.01 2.3 ± 2.8 0.21 plt × 103/l 339 ± 144 336 ± 151 350 ± 118 0.594 allergy to other medications 10 (5.4) 7 (4.7) 3 (7.9) 0.427 sd = standard deviation; bsa = body surface area; bmi = body mass index; git = gastrointestinal tract; 5-fu = 5-fluorouracil; hb = haemoglobin; wbc = white blood cell; anc = absolute neutrophil count; alc = absolute lymphocytes count; plt = platelets. predictors of hypersensitivity reactions to platinum-based chemotherapy in a tertiary care hospital in oman a case control study 236 | squ medical journal, may 2023, volume 23, issue 2 agents (or = 3.4, 95% ci: 1.6–7.4; p = 0.002). likewise, of the 28 patients who received concurrent radiation, 13 out of 38 cases (34.2%) and 15 out of 148 controls (10.1%) developed hsr (or = 4.8, 95% ci: 2.1–11.4; p <0.001). eight patients developed grade iii hsr and no patient developed a grade iv reaction. after the onset of an allergic episode, the platinum agent was permanently discontinued in 33 (86.8%) patients. two patients received the same agent successfully at a slower rate and three patients with an hsr to carboplatin were shifted to cisplatin. out of the three, only one showed cross-reactivity. all patients who received a platinum agent after a documented hsr had grade i–ii hsrs initially, mainly manifesting as itching, urticaria and erythema within a few minutes of administration [table 3]. discussion to the best of the authors’ knowledge, this is the first report from a middle eastern country on the incidence, presentation, outcomes and predictive factors of hsrs to pbcs. over a period of eight years, the incidence of hsr was 4.7%; it was higher with carboplatin compared with either cisplatin or oxaliplatin. patients receiving a taxane or radiotherapy concomitantly were at a significantly higher risk of developing an hsr. although the majority of the patients developed either grade i or ii hsr, a platinum compound of any kind was omitted from the chemotherapy combination for the subsequent cycles. the widespread use of pbcs in the last decade has contributed significantly to hsr development in the treatment of cancer patients. in the literature, varying hsr rates between different platinumbased agents have been reported.2 the results of the current study are consistent with the published data, suggesting that hsrs are characteristically uncommon in the first few cycles of treatment with pbcs.2,3 for carboplatin, the incidence was reported to be as low as 1% in the first five cycles with an exponential surge up to 6.5% during the sixth cycle and up to 27% in patients who received seven or more cycles.2,9,10 at the authors’ institution, patients taking carboplatin had a cumulative rate of hsr of 22.7%, higher than the rate of hsrs with cisplatin or oxaliplatin. carboplatin hypersensitivity occurred after a median of five cycles, which is considered borderline in other reports.2 the rate of cisplatin hypersensitivity was 14.6%, and the occurrence of hsrs was evident between the first and the sixth cycles (median = 3), which is earlier than the 4–8th cycle mark.2 on the other hand, oxaliplatin hsr was found to manifest after a median of eight cycles, which is significantly later than a median of three cycles.11 these discrepancies in the characteristics of hsr between different populations warrant further investigations. hsrs may happen in association with multiple factors such as gender, concomitant chemotherapy and radiation therapy. only a few studies have investigated the association between hsrs occurring in different table 2: predictors associated with hypersensitivity reaction characteristic n (%) p value all (n = 186) controls (n = 148) cases (n = 38) disease stage i 5 (2.7) 3 (2.0) 2 (5.3) 0.557 ii 18 (9.7) 15 (10.1) 3 (7.9) iii 37 (19.9) 31 (20.9) 6 (15.8) iv 126 (67.7) 99 (66.9) 27 (71.1) previous lines of therapy neoadjuvant 28 (15.1) 21 (14.2) 7 (18.4) 0.441 adjuvant 32 (17.2) 28 (18.9) 4 (10.5) palliative 126 (67.7) 99 (66.9) 27 (71.1) previous exposure to platinum 20 (10.8) 16 (10.8) 4 (10.5) 1.000 median number of cycles (iqr) 9 (6–12) 9 (6–12) 8 (5–12) 0.431 median cumulative dose in mg (iqr) 1,890 (1,200– 3,684) 1,800 (1,174– 3,615) 2,075 (1,352– 3,795) 0.446 concomitant taxane therapy 42 (22.6) 26 (17.6) 16 (42.1) 0.002 concomitant radiotherapy 28 (15.1) 15 (10.1) 13 (34.2) <0.001 iqr = interquartile range. table 3: hypersensitivity reaction grade according to national cancer institute-common terminology criteria for adverse events version 4 (n = 38) grade of hsr n (%) i 15 (39.5) ii 15 (39.5) iii 8 (21.1) iv 0 (0.0) hsr = hypersensitivity reaction. bushra salman, fatma al-rasbi, nameer al-ward, khalid al-baimani, ikram burney, eman abdullah, buthaina al-azizi, khulood al-mishaikhi, ibrahim al-zakwani and mansour al-moundhri clinical and basic research | 237 genders. shibata et al. reported that there was no interrelation between hsrs and gender;12 while seki et al. suggested that young female patients were more prone to experiencing hsrs when compared with males of the same age.8 the analysis in this study showed that females were significantly more likely to develop hsrs than males (68.4% versus 49.3%; p = 0.032); the reason for this prevalence is unknown. however, some investigators proposed that hormonal influences play a significant role in developing hsrs, as well as the presence of pre-existing allergies to food, drugs and allergens.13 patients who were treated at the authors’ hospital were asked about any known allergies to food, drugs as well as other allergens. however, the low level of awareness of patients regarding their preexisting allergies cannot be ruled out. the concomitant use of other antineoplastic drugs has been reported to increase the rate of hsrs in cancer patients, especially when carboplatin is used concomitantly with paclitaxel.2 the data in this study showed that the incidence of hsrs when using concurrent paclitaxel was significantly higher when compared with other antineoplastics, such as gemcitabine and 5-fluorouracil-based chemotherapies. studies suggest that other chemotherapeutic agents should be used to avoid this interaction. for example, pegylated liposomal doxorubicin (pld) was studied, which demonstrated a lower incidence of hsr when compared with paclitaxel, where the combination of carboplatin–paclitaxel versus carboplatin–pld was associated with a risk of 18.8% and 5.6% of hsr occurrence, respectively.14 as studies have reported, the patho-physiology of hsrs to pbcs is not limited to type i hsr,2,3 and this might overlap with the mechanism of hsr to taxanes, which is probably not immunoglobulin e mediated.15 however, in clinical practice the features of hsrs to pbcs and taxanes are distinct, and clinicians are less likely to misclassify the cause of hsrs.15 concomitant use of radiation therapy might also be considered a predictor for hsrs. in this study, a significant association was found (34.2%; p <0.001). this observation is consistent with multiple reports that have suggested the occurrence of hsrs when using pbcs followed by radiation therapy.4 this might be related to the antigen release of cytokine release caused by irradiation and caution is warranted in this group of patients.4,16 approximately 80% of the hsrs seen in this study were grades i and ii. however, platinum chemotherapy was permanently discontinued in 90% of the cases. out of the five patients who were rechallenged, four were able to successfully receive the same or a different platinum agent without untoward reactions; one patient showed cross-reactivity with another platinum agent. this rate of rechallenge was very low. tate et al. demonstrated the safety of changing the platinum compound with a low risk of hsr recurrence.17 in addition, slowing the infusion rate was found to allow successful delivery of the platinum agents in 97% of 174 patients with platinum hsr.18 furthermore, skin testing, despite its limited use, was shown to have a high level of accuracy of detecting an hsr (81–88%);19,20 these management lines should be considered to allow those patients at high risk to receive a safe course of treatment without compromising in efficacy. this study was subject to certain limitations, such as the case-control design with inherent selection bias risk and the long period of time taken to accumulate the data. however, this is due to the rarity of hsr events. in addition, the fact that physicians, pharmacists and nurses can enter information in either hard or soft copy reduces the chances of underreporting. conclusion hsrs to platinum agents are common but fortunately, most patients experience mild reactions. predicting the risk depends on multiple factors, and that can be used to monitor future patients to prevent unwanted hsrs. further studies may help elucidate the interactions and dynamics of hsrs with other chemotherapeutic agents and radiation therapy. a u t h o r s’ c o n t r i b u t i o n mm conceptualised the idea of the study and bs managed the project. kb designed the study. fr, ba and km collected the data. ea conducted the literature review and structured the study background. bs, fr and nw analysed and interpreted the data. iz conducted the statistical analysis. bs and nw drafted the manuscript. kb, ib and km reviewed and edited the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interests. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors would like to thank dr. murtadha alkhabori for his kind advice on the study design. in addition, they would like to thank dr. anjum hassan and dr. rami abu omar for independently validating predictors of hypersensitivity reactions to platinum-based chemotherapy in a tertiary care hospital in oman a case control study 238 | squ medical journal, may 2023, volume 23, issue 2 the status and labelling of the patients who developed hsrs. references 1. bardal sk, waechter je, martin ds. neoplasia. applied pharmacology. philadelphia, usa: w.b. saunders, 2011. pp. 305–24. 2. makrilia n, syrigou e, kaklamanos i, manolopoulos l, saif mw. hypersensitivity reactions associated with platinum antineo plastic agents: a systematic review. met based drugs 2010; 2010:207084. https://doi.org/10.1155/2010/207084. 3. otani im, wong j, banerji a. platinum chemotherapy hyper sensitivity: prevalence and management. immunol allergy clin north am 2017; 37:663–77. https://doi.org/10.1016/j. iac.2017.06.003. 4. koren c, yerushalmi r, katz a, malik h, sulkes a, fenig e. hypersensitivity reaction to cisplatin during chemoradiation therapy for gynecologic malignancy. am j clin oncol 2002; 25:625–6. https://doi.org/10.1097/00000421-200212000-00020. 5. markman m, kennedy a, webster k, elson p, peterson g, kulp b, et al. clinical features of hypersensitivity reactions to carboplatin. j clin oncol 1999; 17:1141. https://doi. org/10.1200/jco.1999.17.4.1141. 6. miyamoto s, okada r, ando k. platinum hypersensitivity and desensitization. jpn j clin oncol 2015; 45:795–804. https://doi. org/10.1093/jjco/hyv081. 7. cetean s, ciuleanu t, leucuta dc, cainap c, constantin am, cazacu i, et al. hypersensitivity reactions to platinum derivatives: findings of new predictive markers. j buon 2015; 20:1617–23. 8. seki k, senzaki k, tsuduki y, ioroi t, fujii m, yamauchi h, et al. risk factors for oxaliplatin-induced hypersensitivity reactions in japanese patients with advanced colorectal cancer. int j med sci 2011; 8:210–15. https://doi.org/10.7150/ijms.8.210. 9. sliesoraitis s, chikhale pj. carboplatin hypersensitivity. int j gynecol cancer 2005; 15:13–18. https://doi.org/10.1136/ijgc00009577-200501000-00003. 10. sugimoto h, iwamoto t, murashima y, tabata t, sagawa n, okuda m. risk factors contributing to the development of carboplatin-related delayed hypersensitivity reactions in japanese patients with gynecologic cancers. cancer chemother pharmacol 2011; 67:415–19. https://doi.org/10.1007/s00280010-1338-5. 11. parel m, ranchon f, nosbaum a, you b, vantard n, schwiertz v, et al. hypersensitivity to oxaliplatin: clinical features and risk factors. bmc pharmacol toxicol 2014;15:1. https://doi. org/10.1186/2050-6511-15-1. 12. shibata y, ariyama h, baba e, takii y, esaki t, mitsugi k, et al. oxaliplatin-induced allergic reaction in patients with colorectal cancer in japan. int j clin oncol 2009; 14:397–401. https://doi. org/10.1007/s10147-009-0883-6. 13. kim bh, bradley t, tai j, budman dr. hypersensitivity to oxaliplatin: an investigation of incidence and risk factors, and literature review. oncology 2009; 76:231–8. https://doi. org/10.1159/000205263. 14. pujade-lauraine e, wagner u, aavall-lundqvist e, gebski v, heywood m, vasey pa, et al. pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. j clin oncol 2010; 28:3323–9. https://doi.org/10.1200/ jco.2009.25.7519. 15. joerger m. prevention and handling of acute allergic and infusion reactions in oncology. ann oncol 2012; 23:x313–19. https://doi.org/10.1093/annonc/mds314. 16. randall jm, bharne aa, bazhenova la. hypersensitivity reactions to carboplatin and cisplatin in non-small cell lung cancer. j thorac dis 2013; 5:e53–7. https://doi.org/10.3978/j. issn.2072-1439.2012.06.12. 17. tate s, nishikimi k, matsuoka a, otsuka s, kato k, takahashi y, et al. tailored-dose chemotherapy with gemcitabine and irinotecan in patients with platinum-refractory/resistant ovarian or primary peritoneal cancer: a phase ii trial. j gynecol oncol 2021; 32:e8. https://doi.org/10.3802/jgo.2021.32.e8. 18. o'cearbhaill r, zhou q, iasonos a, hensley ml, tew wp, aghajanian c, et al. the prophylactic conversion to an extended infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian cancer patients during carboplatin retreatment. gynecol oncol 2010; 116:326–31. https://doi.org/10.1016/j.ygyno.2009.10.070. 19. lee cw, matulonis ua, castells mc. rapid inpatient/ outpatient desensitization for chemotherapy hypersensitivity: standard protocol effective in 57 patients for 255 courses. gynecol oncol 2005; 99:393–9. https://doi.org/10.1016/j. ygyno.2005.06.028. 20. castells mc, tennant nm, sloane de, hsu fi, barrett na, hong di, et al. hypersensitivity reactions to chemotherapy: out comes and safety of rapid desensitization in 413 cases. j allergy clin immunol 2008; 122:574–80. https://doi.org/10.1016/j. jaci.2008.02.044.  abstrac t. objectives: to assess the effects of vipassana meditation on the physical and psychological health in a multi-ethnic population in the city of muscat. method: the subjects were participants of a vipassana meditation course taught in a ten-day residential retreat. self-assessments of health-related parameters and physical and psychological symptomatology were collected from them before and immediately after the course. a control group was tested for a similar time interval. results: immediately after their -day training, the vipassana participants assessed themselves significantly higher compared to their levels prior to the course, suggesting that the  days’ practice had significantly improved their physical and psychological well-being. the control group did not exhibit such changes. conclusion: the present preliminary findings, juxtaposed with the results of studies from other parts of the world, suggest that the practice of vipassana meditation may help mitigate psychological and psychosomatic distress. key words: vipassana, meditation, stress, physiological, psychological, oman. 1department of behavioural medicine, college of medicine, sultan qaboos university, p.o. box: , al-khod , muscat, sultanate of oman. 2department of mathematics and statistics, college of science, sultan qaboos university, p.o.box: , al-khod , muscat, sultanate of oman. 3vipassana research institute, igatpuri- , dist. nashik, maharashtra, india. *to whom correspondence should be addressed. e-mail: adawi@squ.edu.om v,        really are, is an ancient technique to improve concen-tration and self-awareness through meditation. e theory and philosophy of vipassana have been extensively reviewed elsewhere.1–3 vipassana seeks self transformation through self observation, where the meditator pays disciplined attention to the physical sensations that continuously interact with and condition the mind.3,4 being an ancient technique, many schools of vipassana—both sectarian and non-sectarian—have evolved. prominent among the non-sectarian approaches is the one adopted by s. n. goenka and assistant teachers in their ten-day residential courses conducted in many countries including uae and oman.3–6 one of their courses conducted in oman provided data for this study. vipassana’s observation-based journey to the common root of mind and body is expected to reduce the tendency of the mind to dwell on the past (thereby reducing regrets), or to delve into the future (thus lowering expectations and anxieties), helping the participant to remain in the ‘here and now’ and achieve relative mental tranquillity.1,3,4,7,8 both traditional and clinical literature suggest that vipassana practice increases awareness, promotes integration of subjective experience and facilitates acceptance and tolerance to sufficiently reduce physical and psychological distress.2,3 with the advent of invasive measurement tools, there is also evidence that changes reported from noninvasive assessment measures are accompanied by altered physiological parameters.9 if a technique has universal application, then it ought vipassana meditation: a naturalistic, preliminary observation in muscat ala’aldin al-hussaini1, atsu s.s. dor vlo2, sajjeev x. antony1 dhananjay chavan3, jitu dave3, vimal purecha3, samia al-rahbi1, *samir al-adawi1     :   , : , : , – ©     to transcend cultural barriers and show its efficacy in all populations. studies in the west on meditative techniques akin to vipassana have demonstrated enhancement in functional status, and physical and mental well-being in practitioners.10 studies in asia have also reported similarly.2,6,7 among the most intriguing of these cross-cultural studies have been the ones conducted among prisoners where vipassana meditation reportedly improved the inmates’ mood and behaviour. 2, 6, 11 ere is a need for the quantification of the relevance of these health-promoting techniques in other regions of the world, especially in the middle east.12 lack of reports from the arab world prompted the need for testing the effect of vipassana meditation on the health-related quality of life and physical and psychological symptomatology in the residents of this region. e present study was therefore designed to test the hypothesis that vipassana training could improve the health-related quality and impact on physical and psychological symptomatology in a multiethnic population like that in oman. m e t h o d     e study constituted a naturalistic experiment with  vipassana participants who were voluntarily attending a ten-day residential meditation course in muscat, oman, during july . e participants were tested twice, once at the beginning of the -day course and thereaer upon completion of the course. e control group consisted of  students of sultan qaboos university. ese students did not take part in the meditation sessions but were given the same assessment instruments both at the beginning and at the end of the -day period. being a naturalistic experiment, the groups were not initially matched for specific factors that could arise by chance. vipassana meditation course requires the novice to maintain strict silence for  days except to clear doubts with the teacher or to solve material problems with volunteers. e meditators are permitted to break their silence on the morning of the th day, to facilitate their transition back to the outside world. e course ends the th day morning. prior to start of the course, a brief explanation of the study was given to the participants and they were assured that the data and results would be treated confidentially. eir oral consent was then taken. e control group students were also similarly assured and their oral consent obtained. both the groups were assessed twice. e first assessment () was administered just before the start of the day meditation training session. e second assessment () was done immediately aer the conclusion of the training. even though the group of students did not take part in the training, their assessment was done at the same time as that of the training group. both the groups were asked during the assessment not to discuss the questionnaire between themselves so as to avoid peer pressure.             all the participants were assessed with non-invasive measures, via self-report questionnaires. in this study, it was not viable to collect biochemical markers or conduct clinical interviews to verify self-report data. since the participants could elect not to fill the questionnaire, there was no obvious reason for them to give inaccurate information. e subjective functioning data using likert type self-report are described in the result. conventional assessment measures were also used and included ghq-, a -item scaled version of the original �������������������������������������������������������������� ���������������������������������������������������� � � ���� ��� ������ �� ���������� ��� �� ��� �������� ��� �� ��� � ������ ������ ��� ��� ��� ������ � � � � ���������������������������������������������������������������� ��������������������������������� � � ���� ��� ������ �� ���������� ��� �� ��� �������� ��� �� ��� � ������ ������ ��� �� ��� ������ � � � � ������������������������������������������������������������ ������������������ � � ����������� ������������� � �� ���������� �� �� ��� �������� �� ��� ��� � ������ ������ ��� ��� ��� ������ �                 general health questionnaire (ghq), with four subscales derived by factor analysis.13 ese include somatic symptoms, anxiety and insomnia, social dysfunction, and severe depression. e validity of the subscales is discussed in goldberg & williams.14 e four subscales in ghq- represent dimensions of symptomatology; thus more symptoms result in a higher score but high scores do not necessarily correspond to any psychiatric diagnosis. e present analysis was derived from the composite score of ghq-. e other conventional assessment measure used, the hospital anxiety and depression scale (hads),15 is a -item questionnaire with two -item sub-scales, one for depression and the other for anxiety. symptoms are listed and subjects rate the frequency or severity of these during the preceding week on a -point scale (–), making a maximum possible score of  on each sub-scale. e original validation study for the hads suggested that on either sub-scale, non-cases scored  or less, doubtful cases –, and definite cases  or more. separate indices of anxiety and depression were recorded for the present analysis.            e statistical soware spss version  for windows was used to analyse the data. e summary statistics were computed for some of the demographic variables by group. independent-sample t-test and paired t-test were used to compare group means. cross-tabulation was used on the categorical variables and the chi-square (χ2) statistic and corresponding p-values computed were applicable. for × tables, fisher-exact p-values were computed. r e s u l t s (i) demographic information fourteen subjects ( male and  female; mean age .±. years) participated in the vipassana training session. irty-one subjects ( male and  female; mean age .±.) formed the control group. e two groups differed significantly in age (p<.). being a naturalistic experiment, it was logistically not possible to balance ages between the groups. in terms of marital status, in vipassana group,  were married and  were single. among the controls, only  were married and the rest were single. (ii)  : subjective functioning on health-related quality of life e subjective functioning pertaining to health parameters are summarized below. most participants believed in their own abilities to overcome difficult situations [table ], with no significant difference between the two groups (p=.). over  (/) of the participants agreed that faith or spiritual values helped them cope with pressures of life [table ]. ere was no significant differences between the two groups, p=.. e control group perceived they had insufficient or poor financial resources [table ], as is typical of students. e perceived fitness levels of the two groups were similar [table ]. irteen percent felt they were in excellent physical condition while  felt the opposite. (iii) performance across  and  e subjective functioning of the participants is summarized in table . in the first assessment, the majority (/ ) felt undecided whether they were happy or unhappy. however, the majority of the vipassana group (/) felt happy about life in the first assessment itself. at the second assessment, four more participants from the vipassana group indicated that they felt happy about life. all vipassana meditators showed a pronounced improvement in hospital anxiety and depression scale and modified general health questionnaire. scores for  and  are presented in table . affective functioning e summary statistics of the hospital anxiety and depression scale are provided in table . all the participants of vipassana showed a pronounced improvement in anxiety and depression. e drop in the anxiety level in this group was particularly significant: an average drop from  to . (p=.). on the other hand, the average                 � ������� ��� ���� ������� ��� ���������� ��������� ��� �������� ���� ���������� � � � � � � � �� �� �������������������� ����� ������������������ ����� ������������� ��������������� ��������������������� ����� �� �� �� ��� ��� �� �� �� �� � ������ ������   anxiety level of the control group increased marginally. e vipassana group also showed a marked drop on the depression score (p=.). before meditation, they scored , but aer the course the score dropped significantly to .. general health ere were significant changes (p<.) between the  and  assessment using the modified general health questionnaire (ghq-). as can be seen from table  and figure , the control group’s total score remained relatively stable. in contrast, the vipassana group showed steep reduction in the indices of psychiatric symptomatology, suggesting the retreat was effective in ameliorating their psychiatric symptomatology. d i s c u s s i o n in this age when many people seek alternative therapeutic methods, there is a dearth of research of the efficacy on such interventions in the population in the middle east, and particularly in oman. is pilot study has attempted to address this lack by examining the effects of vipassana training on health-related quality of life and physical and psychological symptomatology in a heterogeneous group of subjects from among the resident population of muscat. studies from elsewhere provide evidence that such an undertaking can enhance one’s functional status and wellbeing as well as reduce physical symptoms and psychological distress.4,16,17 in the present study, prior to vipassana training, the performance of those subjects who voluntarily elected to enrol in the -day course of vipassana meditation had not differed from that of the control group. specifically, on subjective functioning (apart from the issue pertaining to income and whether they were happy or not) the two groups did not differ. ese results support the observation by gillani18 and smith19 that prospective meditators do not differ from the general population in their level of stress or distress. when tested immediately aer the -day training, their performance on several parameters changed, suggesting alleviation of physical symptoms and decreased psychological distress. in contrast, such fluctuations were not seen in the control subjects who were tested at the same interval. is finding is compatible with emerging evidence suggesting that meditative techniques can have a great effect on physical and psychological functioning.2,19,20 � ��������������������������������������������������������������� ���������� � � ���������� ����� ����� ������ �� ���������� �� �� �� ��� �������� �� ��� ��� ��� ������ ������ �� ��� ��� ��� ������ � � � � ������������������������������������������������������������� ������������������� � � � ������ ���������� �������� �� ���������� �� �� �� ������ �������� �� ��� �� ������� ���������� ��� �� �� ������ �������� �� ��� �� ������� � � � � ��������������������������������������������������� � � � ������ ������ � � ����� ���� ����� ���� �� ���������� ������ ����� � ����� ����� �������� �������� ����� ����� � ������ ����� ������ ���������� ����� ����� � ����� ����� ����������� �������� ������ ����� � ������ ����� ������ �� � � � ������������������������������� � � ������ ������ � ����� ���� ����� ���� �� ���������� ������ ������ ������ ������ �������� ������ ������ ������ ������ ������ � �               � ������������������������������ � � � �� �� �� �� �� �� �� ��������������� ������������� �� �� �� ��� ��� �� �� �� �� � ������ ������   e present study is, however, not conclusive and had several possible limitations. e scope of generalizing its findings could be limited due to various factors. first, the sample size was small. second, the vipassana subjects were a self-selective group of different ages and it was not clear how many participants had previous experience with meditation. ird, being naturalistic, the study relied entirely on subjective reports. to overcome these limitations, it would be necessary to replicate the study in different and larger populations and to use stronger experimental methodology with random allocation between conditions. future studies could also employ objective physiological measures to confirm the subjects’ perceived improvement. in the emerging functional in-vivo neuro-imagining techniques, misreporting by subjects can be independently verified.21,22 fourth, it was not clear how long the observed improvement would persist, since the post assessment was conducted right at the end of the retreat. on the other hand, some studies have reported that one-year follow-up revealed maintenance of initial improvements on several outcome parameters.2 data collection by questionnaire is also not without problems.23 although some structured questionnaires are easy to apply, studies have found that different cultures attach different meanings to life and thus conceive reality differently.24although all the items of the screening instrument have been validated in cross-cultural settings,,25–26 its usefulness could still be hampered by subtle linguistic and conceptual misunderstandings. erefore, specificity and sensitivity of these assessment tools need to be examined. a factor that could have enhanced the positive subjective states of the vipassana participants is the retreat environment itself rather than the exercise per se: the subjects were residing in a tension-free, cloistered environment for  days. ey were completely sheltered from outside happenings, since tv, newspapers, telephones and visitors were forbidden. e simple food served could also have had a positive effect. breakfast was served at : am, lunch at : am, and tea and fruit at  pm, aer which no food was served. e meditators went to sleep at : pm to awake the next day at : am. no physical exertion apart from walking in a confined area was permitted. ten days of such an uncomplicated routine could have contributed positively to the mood and behaviour of the novice. again, since the meditators spent ten valuable days on this process, they might have liked to think that their efforts were successful.18 is might have caused them to rate themselves higher in the second assessment. similarly, the researcher’s expectations could have influenced the results. however, the authors are of the view that these limitations do not obscure the fact that vipassana meditation, with its simple technique and tightly controlled variables, offers a fertile field for future studies, which should comprise precise invasive and non-invasive methods. e evidence from this study, however partial, combined with those from other studies around the world, suggests that vipassana meditation may have the potential to enhance the health-related quality of life and physical and psychological symptomatology, irrespective of ethnic or cultural backgrounds. in oman, the population has been growing since the late s at an annual rate of .,27 one of the fastest in the world, which would increase competition for social and occupational roles, and leave many failed individuals behind.28 such a demographic trend would place more and more individuals at risk for developing various adjustment problems.29 e trend so far has been to embrace ‘hi-tech’ therapeutic methods including psychotropic medications which are expensive and oen have side effects.30-32 with the rising cost of running health care systems33 and in an age where many physical and psychological disorders arise because of what people do to themselves rather than solely from external sources,34 a non-sectarian technique such as vipassana may help in prevention and therapy. e next challenge to the healthcare planners in developing countries like oman would be how to respond to the rising tide of the ‘diseases of affluence.’ 23,35 serious contemplation of these considerations should make clear the need to develop and allocate low-cost therapeutic interventions such as meditation that have potential to alleviate suffering and improve people’s functionality. c o n c l u s i o n e results from this pilot study on participants of vipassana meditation in muscat, oman, when juxtaposed with the results of studies in other parts of the world, suggest that this meditation technique may help mitigate psychological and psychosomatic distress. e study also implies that vipassana meditation, with its simple method and controllable variables, offers a fertile field for future research, which should comprise invasive and non-invasive methods. r e f e r e n c e s . kahn m. vipassana meditation and the psychobiology of reich, wilhelm. j humanist psychol , , –. . chandiramani k, verma sk, dhar pl. psychological effects of vipassana on tihar jail inmates. maharashtra, vipassana research institute, . . fleischman pr. e experience of impermanence. maharashtra: vipassana research institute, .                   . srinivasan s. understanding the process of vipassana meditation. int j psychol , ,. . emavardhana t, tori cd. changes in self-concept, ego defence mechanisms, and religiosity following seven-day vipassana meditation retreats. j sci study relig , ,–. . khurana a, dhar pl. effects of vipassana meditation on quality of life, subjective wellbeing, and criminal propensity among inmates of tihar jail, delhi. monograph submitted to indian institute of technology, . . hirai t. zen meditation and psychotherapy. tokyo, japan publication inco, . . morris js, ohman a, dolan rj. conscious and unconscious emotional learning in the human amygdale. nature , , –. . aanas li, golocheikine sa. human anterior and frontal midline theta and lower alpha reflect emotionally positive state and internalized attention: high-resolution eeg investigation of meditation. neurosci lett , , –. . reibel dk, greeson jm, brainard gc, rosenzweig s. mindfulness-based stress reduction and health-related quality of life in a heterogeneous patient population. gen hosp psychiatry , , –. . studer um. vipassana, professional erapy and science. taipei: torch of wisdom, . . sinnott jd. “a time for the condor and the eagle to fly together”: relations between spirit and adult development in healing techniques in several cultures. j adult dev , , –. . goldberg dp, hillier vfa. scaled version of the general health questionnaire. psychol med , , –. . goldberg dp, gater r, sartorius n, ustun tb, piccinelli m, gureje o, rutter c. e validity of two versions of the ghq in the who study of mental illness in general health care. psychol med , , –. . zigmond as, snaith rp. e hospital anxiety and depression scale. acta psychiatr scand , , –. . kabat-zinn j, wheeler e, light t, skillings a, scharf mj, cropley tg, et al. influence of a mindfulness meditation-based stress reduction intervention on rates of skin clearing in patients with moderate to severe psoriasis undergoing phototherapy (uvb) and photochemotherapy (puva). psychosom med , , –. . mason o, hargreaves l. a qualitative study of mindfulness-based cognitive therapy for depression. bri j med psychol , , –.               . gillani nb, smith jc. zen meditation and abc relaxation theory: an exploration of relaxation states, beliefs, dispositions, and motivations. j clin psychol , , –. . smith r. oman: leaping across the centuries. bmj , ,–. . coleman, d. e psychology of meditation. in, psychotherapy, meditation and health, m.g.t. kwee, editor. e hague: east-west publications, . . williams ka, kolar mm, reger be, pearson jc. evaluation of a wellness-based mindfulness stress reduction intervention: a controlled trial. am j health promot , , –. . baerentsen kb, hartvig nv, stokilde-jorgensen h, mammen j. onset of meditation explored with fmri. neuroimage , , s. . al-adawi s, salmi a, martin rg, ghassani h. zar: group distress and healing. ment health rel cult , , –. . al-adawi s. a glimpse into traditional outlook towards health: a literature review. j med humanit , , –. . malasi th, mirza ia, el-islam mf. validation of the hospital anxiety and depression scale in arab patients. acta psychiatr scand , , –. . el-rufaie of, daradkeh tk. validation of the arabic versions of the thirtyand twelve-item general health questionnaires in primary care patients. br j psychiatry , , –. . ministry of national economy. e statistical yearbook, sultanate of oman: ( edition). muscat: information and publication centre, . . easterlin ra. birth and fortune: the impact of numbers on personal welfare. new york: basic books easter, . . kleinman a, cohen a. psychiatry’s global challenge. sci am , , –. . smith r. oman: leaping across the centuries. bmj , , –. . ernst e.complementary medicine for disease and illness prevention? a research perspective. forsch komplementarmed , ,–. . calderon r jr, schneider rh, alexander cn, myers hf, nidich si, haney c. stress, stress reduction and hypercholesterolemia in african americans: a review. ethn dis , , –. . world health organization. world health report . geneva, . . weinman j. an outline of psychology as applied to medicine ( edition). oxford: butterworth heinemann. . martin r, al-adawi s. psychiatric treatments: an exciting new century. hosp med , , –. squ med j, december 2009, vol. 9, iss. 3, pp. 231-246, epub. 19th dec 2009 submitted 2nd nov 08. reformat recd. 4th april 09. revision req. 19th aug 09 revision recd. 9th sept 09 accepted 12th oct 09 acute myocardial infarction (ami) is the leading cause of death in developed countries;1 however, in-hospital mortality from this cause has been declining over the last three decades.2 this reduction in mortality coincides with the improvement in health and living standards and with new treatments like thrombolysis and new interventions like percutaneous coronary intervention (pci) and coronary artery bypass grafting (cabg). secondary and primary prevention strategies have contributed significantly and the age-adjusted mortality is expected to continue to decline with further improvements in treatments, better uptake of primary and secondary prevention strategies and also with further improvement in our ability to recognise this challenging disease very early in its course. the success of treatment rests on: 1) identification of patients in the very early stages of ami; 2) implementation of treatment to recanalise the occluded artery; 3) access to early defibrillation and 4) admission to properly monitored coronary care or intensive care units (ccu or icu) for the 1cardiology unit, department of medicine, sultan qaboos university hospital, muscat, sultanate of oman; 2the university of edinburgh, cardiovascular research unit. the royal infirmary of edinburgh, scotland *to whom correspondence should be addressed: halhadi@hotmail.com استخدام العالمات القلبية الواصمة يف التشخيص والعالج املبكر للمرضى الذين يعانون من املتالزمة القلبية احلادة حفيظ الهادي، كيث فوكس الطبية. الرعاية طلب على املريض يجبر الذي حدوثا األكثر السبب يكون ما غالبا أنه من الرغم على نوعية غير شكوى الصدر ألم يعد امللخص: مجموعة صغيرة من هؤالء املرضى يعانون من املتالزمة القلبية احلادة. نظام التشخيص املتبع حاليا واملبني على التاريخ السريري وتخطيط القلب غير كافي، وقد يؤدي في بعض األحيان إلى التشخيص اخلاطئ وإدخال املرضى إلى األقسام غير املناسبة، أو أن يتلقوا رعاية أو أدوية أو فحوًصا غير مناسبة. وفي بعض املرضى يتأخر التشخيص وهذا يؤدي إلى تأخير إعطاء األدوية الضرورية أو حتى عدم إعطائها. قليل من املرضى الذين يعانون من املتالزمة القلبية احلادة قد يتم إخراجهم من الطوارئ خطأ، مما قد يترتب عليه أخطار صحية وقانونية. كما أن نظام التشخيص هذا قد يؤدي أيضا إلى إدخال عدد كبير من املرضى الذين ال يعانون من أمراض قلبية إلى املستشفى بدون داع. ميكن تطوير النظام احلالي لتشخيص وعالج املرضى الذين يعانون من آالم الصدر بشكل العالمات يتناول املقال احلادة. هذا القلبية اجللطة عن جدا املبكر للكشف املتسلسلة الواصمة القلبية العالمات فحص نظام إدخال طريق عن كبير كاينيز كرياتني فاعلية)، و (كتلة والدماغ العضلة كاينيز كرياتني كاينيز، كرياتني مثل القلب عضلة تلف لتشخيص حاليا املتوفرة الواصمة القلبية العضلة والدماغ (مثلي)، البروتني الرابط حلمض القلب الدهني، مايوجلوبني، تروبنني القلب (ت) وتروبنني القلب ( أ). مفتاح الكلمات: العالمات القلبية الواصمة، املتالزمة القلبية احلادة، جلطة قلبية حادة، ألم الصدر. abstract: chest pain is a non-specific complaint and is the most frequent reason for patients seeking urgent medical attention. a small group of these patients will have acute coronary syndromes (acs). the current diagnostic and triage systems based on clinical history and electrocardiograms are insufficient. they may result in some of these patients being misdiagnosed and being admitted to the wrong units or receiving inappropriate care, treatment and investigations. in some patients, the diagnosis is delayed resulting in the late administration (or no administration) of essential early treatment. a few patients with acs may be inadvertently discharged from the emergency department leading to serious health and legal implications. these systems also result in the unnecessary admission of a substantial number of patients without acs. the triage and management of patients with chest pain can be considerably improved by implementation of serial cardiac markers testing that can identify acs in the very early stages of presentation. this review article will discuss the currently available markers of myocardial damage such as creatine kinase (ck), creatine kinase muscle and brain (ck-mb) (mass and activity), ck-mb isoforms, heart-type fatty acid-binding protein, myoglobin, cardiac troponin t, and cardiac troponin i. keywords: cardiac markers; acute coronary syndromes; acs; acute myocardial infarction; ami; non-st elevation myocardial infarction; nstemi; chest pain. review cardiac markers in the early diagnosis and management of patients with acute coronary syndrome *hafidh a al-hadi,1 keith a fox2 cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 232 | squ medical journal, december 2009, volume 9, issue 3 detection and treatment of complications. the diagnosis of ami was previously based on the criteria set by the world health organization (who) and had to include two of the following: 1) typical history of prolonged ischaemic chest pain; 2) presence of typical acute ischaemic changes on the admission electrocardiograms (ecg); 3) typical rise and fall of cardiac enzymes in blood.3 this old definition has recently been changed with the publication of a new definition of myocardial infarction by the joint european society of cardiology/american college of cardiology (esc/ acc) committee, which redefines myocardial infarction (mi) according to cardiac markers as follows: 1) an increase in cardiac troponin ctni, ctnt exceeding the decision limit (99th percentile of the value for a reference control group) on at least one occasion; 2) an increase in creatine kinase muscle and brain (ck-mb), preferably ck-mb mass exceeding the decision limit (99th percentile of the value for a reference control group) on at least two occasions with a rise and fall pattern, or greater than twice the upper limit of the reference range on one occasion. within this definition, acute coronary syndromes (acs) are classified into st and non-st elevation. st elevation acs is further classified into q-wave and non q-wave mi. non-st elevation mi (with cardiac marker elevation) is also classified into q-wave and non q-wave mi. non-st elevation acs without cardiac markers elevations is called unstable angina.4 the very early diagnosis of ami can be a challenging task for many physicians in an emergency department. when a typical history is present, it helps to orient the clinician to the right diagnosis, but its absence by no means rules it out. this is often the case in a significant proportion of patients in whom the history is either atypical or absent. diabetic, hypertensive, and elderly patients often have silent ami. in these cases ami may go unnoticed or may produce atypical symptoms such as hypotension, breathlessness, syncope, or arrhythmias.5 the ecg is an important tool for detecting ami, but it lacks sensitivity and as many as 30-50% of patients may initially present with normal or non-diagnostic ecg.6 the ecg has an overall diagnostic sensitivity for ami of 70-81%;7 however, when changes typical of ami are present on the admission ecg (st elevation and new q-wave) they are highly specific and have a very high positive predictive value for the diagnosis of ami. cardiac markers are formidable tools for the diagnosis of ami.8 characteristic features of biochemical markers of myocardial injury the ideal characteristics of a marker of myocardial injury are: 1) it should be abundant in the myocardium and not present in other tissues. this gives it a high specificity for the myocardium and reduces the rate of false positive results; 2) it should have a high concentration in the myocardium and a low or undetectable concentration in the blood in the absence of disease. this gives it a high sensitivity so that the release of only a small amount can be readily detected thereby reducing the rate of false negatives; 3) it should be released completely and quickly when myocardial damage occurs. this will allow its utilisation for the early detection and quantification of injury; 4) it should persist in the circulation to give a convenient diagnostic window, but not so long as to prevent the detection of complications such as early re-infarction, and 5) the assay must have a high analytical sensitivity and specificity and a short turn around time, so that results could be obtained fast enough to influence the decision-making process regarding patients’ triage and management. biochemical markers and early detection of acute myocardial infarction cardiac markers play an important role in the detection of ami when the patient’s history and ecg are non-diagnostic or equivocal.9 diagnosing ami early (i.e. within 6 hours after symptom onset) is difficult, because some time must elapse after symptom onset for markers to exceed values above the reference range. the diagnosis of ami based only on one single value at presentation or soon after admission is unreliable, and serial sampling is the most effective method. the sensitivity and specificity of cardiac markers for the early diagnosis of ami is influenced by several factors such as: 1. time of presentation: early presentation after symptom onset is likely to show a relatively hafidh a al-hadi and keith a fox review | 233 increased sensitivity for markers like myoglobin, which is released very early in the course of ami, and less sensitivity for markers like ck-mb or ctni, which are released slightly later. a delayed presentation is likely to have the opposite effect. therefore, the onset of symptoms should be used as the reference point when commenting on the sensitivity and specificity of the markers for the early diagnosis of ami rather than criteria such as time of presentation, and time of admission.10 2. size of infarct: cardiac markers are released in proportion to the volume of myocardium in jeopardy, the bigger the infarct the greater the quantity of cardiac markers released. this will lead to improved sensitivity compared to small infarcts where a limited release of markers may be close to the threshold for detection.11 3. selection criteria and prior probability of acute myocardial infarction: selecting certain group(s) of patients for the study with a high possibility of ami, such as those admitted to the ccu, can also influence sensitivity of a marker. 4. treatment: treatment can have an influence on the sensitivity of the marker. for example, patients who have been successfully thrombolysed show a greater and earlier peak of some of the markers compared to those who were not successfully reperfused.12 5. diagnostic threshold: the selection of an appropriate diagnostic threshold requires careful consideration of concentrations seen in the normal and disease free population and those seen in diseased populations. there is always a continuous balance between the sensitivity and specificity of any marker. if the cut-off concentration used is low, the sensitivity is improved at the expense of specificity unless the marker is 100% cardiac specific, and only present in diseased populations.13 6. kinetic factors: kinetic factors like the molecular size of the marker, the biological compartment of the marker (i.e. whether it exchanges freely in the cytoplasm or is attached to structural elements within the cell), the volume of distribution, and whether the marker is released directly into the blood or cleared by the lymphatic system can all influence plasma concentration. markers that have a low molecular weight, lie free in the cytoplasm, and are released directly into the circulation show better early sensitivity compared with larger molecules that are attached to structural elements and/or cleared slowly by the lymphatic system.14 it is not surprising therefore that different studies report differing results for sensitivity and specificity for the various cardiac markers for the early diagnosis of ami. the variations in the reported results will predominantly be influenced by the above factors. this review article will discuss the currently available markers of myocardial damage like creatine kinase (ck), ck muscle and brain (mb) (mass and activity), ck-mb isoforms, heart-type fatty acid-binding protein (h-fabp), myoglobin, cardiac troponin t (ctnt) and ctni. the discussion will focus in particular on the suitability of these markers as tools for: 1) the early diagnosis of mi within 6 hours; 2) their ability to detect myocardial damage during ischaemic episodes in patients with non-st elevation mi or undergoing cardiac intervention like pci or surgery; 3) their ability to guide further treatments i.e. antiplatelets, antithrombotics, coronary interventions, etc; 4) their ability to detect reperfusion and re-infarction; 5) their specificity and limitations and 6) future directions with these markers. for the sake of clarity, unstable angina with elevated cardiac markers quoted in various references in the literature will be used synonymously with non-st elevation mi using the recent new definition of acute coronary syndromes referred to above.4 creatine kinase creatine kinase is an enzyme composed of two subunits, m and/or b. three different pairs of these units combine to give rise to three different isoenzymes, ck-bb, ck-mb and ck-mm. ckbb is the brain isoenzyme and is present in large quantity in the brain and many internal organs. ckmb is the heart specific isoenzyme and has been the gold standard method for the diagnosis of ami in many laboratories. it exists in large quantity in heart muscle, but is not totally cardiac specific and exists also in skeletal muscles and other tissues. cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 234 | squ medical journal, december 2009, volume 9, issue 3 about 15-40% of the total ck activity of heart muscle is due to ck-mb, the rest is largely due to the ck-mm isoenzyme. ck-mm is the skeletal muscle isoenzyme. it has the highest distribution in skeletal muscles. the three isoenzymes are present in varying concentrations in the smooth muscle of the colon, ileum, stomach, and urinary bladder.15 the reference range for ck is approximately 80-200 iu/l for men and 60-140 iu/l for women. this is the result of the normal turnover of this enzyme in skeletal muscles, and it is influenced by factors like muscle mass and physical work. c r e at i n e k i n a s e a n d a c u t e m y o c a r d i a l i n fa r c t i o n creatine kinase was introduced in 1965 as a biochemical marker for myocardial damage and it is one of the oldest markers in this field.16 it has a clinical sensitivity for the diagnosis of ami of 90%. unfortunately, this is not matched by high specificity. it is released within 12 hours after symptom onset of ami, peaks in serum at 24-36 hours, and returns to normal in 48-72 hours. as a result of these release kinetics, measurement of total ck is not suitable for the early diagnosis (within 6 hours) of ami. ck as a marker is also unsuitable for the detection of myocardial damage that may occur in patients presenting with non-st elevation mi, or in patients undergoing pci or surgery. as mentioned earlier, a marker that is suitable for the early diagnosis of ami, and the detection of small injuries to the heart should have: a high cytoplasmic (cell) to vascular (plasma) ratio, very low or undetectable normal plasma concentration and total cardiac specificity. ck does not fulfil these criteria since it has a moderate cytoplasmic to vascular ratio of 60,000:1; a high reference range up to 200 iu/l, and is widely distributed in the body. to improve on the cardiac specificity of ck for the diagnosis of ami, it was recommended to measure both total ck and ck-mb (the cardiac specific isoenzyme of ck). a ck-mb to ck ratio of > 6% is reported to be specific for myocardial injury, whereas a ratio of < 6% is consistent with skeletal muscle damage or non-cardiac causes. in some clinical settings, a ck-mb test is not requested unless the total ck activity is elevated. the use of total ck as a screening test before ordering ck-mb could miss some patients with ami and should be used with caution. there are cases of ami without elevation of total ck concentration, but the total ck-mb fraction and the ck-mb to ck ratio in these patients is diagnostic for ami. this is likely to happen in situations when there is a small mi in a small sized person with a low muscle bulk, and a low baseline value of total ck. the normal reference range of ck is very broad and these patients could release small amounts of the enzyme, insufficient to raise the concentration above the reference range. if this possibility is not borne in mind, the diagnosis could be missed when ck is used. unless the baseline total ck is known in a patient presenting with highly suspicious diagnosis of ischaemia, a low total ck should not exclude the diagnosis nor should it preclude requests for ck-mb.10 l i m i tat i o n s a n d f u t u r e d i r e c t i o n o f c r e at i n e k i n a s e m e a s u r e m e n t the ck enzyme is widely distributed and there are various causes of elevated total ck in the absence of myocardial injury.17 haemolysis leads to the release of the adenylate kinase enzyme, which interferes with the assay and causes false elevation of total ck activity. various forms of skeletal muscle injury can lead to increased ck activity including strenuous exercise, intramuscular injection, rhabdomyolysis, burns, and trauma. chronic muscle diseases like polymyositis, dermatomyositis, and myopathy can all lead to increased concentrations of ck. total ck activity is a very sensitive indicator of injury to skeletal muscles. drugs like cocaine and alcohol can also raise ck concentrations to abnormal values, presumably due to the associated myopathy that can occur with the use of these drugs. neurological conditions like myasthenia gravis also elevate total ck activity. other miscellaneous conditions including pregnancy, hypothermia, and sepsis can increase total ck concentrations.18 in many of these situations, the activity of ck-mb is also increased, giving a ratio of ck-mb to ck that remains below the 6% cut-off point required to differentiate between skeletal muscle injury and cardiac muscle injury.19 measurement of ck is a relatively cheap assay that is widely available. for this reason, total ck measurement will probably continue to be used as a marker for myocardial injury especially in situations such as: 1) absence of ctni, ctnt, and ck-mb assays; 2) patients with unequivocal ecg diagnosis of mi where a non-specific marker such as ck can be used to confirm the diagnosis, monitor hafidh a al-hadi and keith a fox review | 235 the progress of the patient in hospital and to gauge infarct size. creatine kinase muscle brain isoenzyme the ck-mb isoenzyme has been considered as the gold standard for the diagnosis of ami. it is the isoenzyme of ck specific for heart muscle. it is measured in serum or plasma by one of two methods: 1) ck-mb activity: this measures the total activity of the enzyme in serum/plasma by methods like electrophoresis, column chromatography, immunoinhibition or immunoprecipitation. the results are reported as iu/l. these methods are non-specific, measure only active enzymes, and have a low analytical sensitivity (5 iu/l); 2) ckmb mass: this measures the protein mass in serum/ plasma using specific antibodies against the m, b or mb subunits. the results are reported in ng/ml or µg/l. these assays are highly specific and have a high analytical sensitivity (0.3ng/ml) and can measure both active and inactive enzymes. the reference ranges using various methods have been reported to be 8-16 iu/l for ck-mb activity, and 5-10 ng/ml (µg/l) for ck-mb mass.10 c r e at i n e k i n a s e-m b a c t i v i t y v e r s u s c r e at i n e k i n a s e-m b m a s s different groups have reported that measurement of ck-mb using mass is better than that measuring ck-mb activity.20 the recent guidelines for the redefinition of ami recommend the use of ck-mb mass as opposed to ck-mb activity.4 the problems inherent in measuring activity are: 1. the enzyme may become deactivated by experimental manipulations leading to a low value or underestimation. this is likely to happen in the low range of ck-mb activity such as in patients with small ami or with minor myocardial damage. in an extreme situation, a false negative result could result in the missed diagnosis of ami. unlike ck-mb activity assays, ck-mb mass assays measure both active and inactive enzyme. 2. in haemolysed blood samples, interference from adenylate kinase, an enzyme released from red blood cells which catalyses the same reaction as ck-mb, could result in false positive results. this problem is irrelevant with mass assays because the antibodies are specific for the ck-mb and the presence of adenylate kinase has no effect on the assay.17 3. creatine kinase-mb measurement using mass has better early sensitivity for the diagnosis of st elevation ami. it has also been reported to be more sensitive in detecting small injuries to the myocardium that occur in patients with non-st elevation acs.21 4. the presence of ck-bb, macro ck type 1, or macro ck type 2 in high concentrations could interfere with the result and lead to false elevation of ck-mb when activity measurement is used. these interferences have no such effects when mass assays are used because the antibodies are specific for ck-mb and do not cross-react with these compounds.22 c r e at i n e k i n a s e-m b a n d s t e l e vat i o n m y o c a r d i a l i n fa r c t i o n creatine kinase mb follows the same release kinetics as ck and has a sensitivity and specificity for the diagnosis of ami of more than 90%. this sensitivity and specificity changes with the time of presentation after symptom onset. measurement of ck-mb activity is most reliable in the 12-24 hours period after symptom onset.23 a negative result earlier than 12 hours from the start of symptoms is too early to rule out ami, and a negative result after 24 hours may be too late. studies comparing the utilisation of these assays for the early diagnosis of ami have shown that ck-mb mass reaches the cut-off point in serum several hours before ck-mb activity and have claimed its superiority within 4-8 hours after symptom onset.21 the ckmb mass assay has been shown to be sensitive for the diagnosis of ami even in situations where the ecg is equivocal and can increase the number of diagnoses made within the time scale required for the administration of reperfusion treatment.24 c r e at i n e k i n a s e-m b a n d n o n-s t e l e vat i o n m i creatine kinase mb activity tends to be normal in patients with non-st elevation mi, whereas ck-mb mass is increased in a proportion of these patients. this observation has been substantiated by different groups.25 a study by seo et al. in 1993 cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 236 | squ medical journal, december 2009, volume 9, issue 3 compared ck-mb mass versus ck-mb activity and concluded that ck-mb mass is more sensitive when ck-mb concentration is in the low range.26 this is important especially in cases of myocardial injury in non-st elevation mi, following complicated pci, and in radiofrequency ablation of arrhythmias when the amount of ck-mb released can be small. sensitive ck-mb mass assays can detect prolonged ischaemia in non-st elevation mi and have been used for risk stratification in these patients. one small study has shown a very high death rate (64%) during four years follow-up in patients who were admitted to the ccu with chest pain, positive ckmb mass, and non-diagnostic ecg changes of st elevation mi.27 several investigators have also studied the release of ck-mb mass following pci.28 they demonstrated that ck-mb mass is a sensitive indicator of myocardial injury following pci. one study reported that 40% of patients showed evidence of myocardial damage following pci using both ck-mb mass and ctnt.29 l i m i tat i o n s a n d f u t u r e d i r e c t i o n o f c r e at i n e k i n a s e-m b a s s ay s creatine kinase mb measurement is not totally specific for mi and there are various causes for elevated ck-mb concentrations other than ami.17 cardiac pathologies like congestive cardiac failure and arrhythmia lead to elevated ck-mb concentration. severe skeletal muscle damage e.g. acute muscle trauma, skeletal muscle disorders like myositis, polymyositis, chronic inflammatory and degenerative muscle disorders can lead to ck-mb elevation. in these situations, the ck-mb to ck ratio or cardiac troponins can be used to differentiate cardiac and non-cardiac pathologies.30 measurement of ck-mb is a widely accepted assay that is both sensitive and relatively specific for the detection of ami. however, ck-mb (activity or mass) is not sufficiently sensitive in the first 6 hours after symptom onset for the early diagnosis of ami.4 c r e at i n e k i n a s e m u s c l e b r a i n i s o f o r m s (s u b f o r m s) creatine kinase mb isoforms are variants of the ckmb isoenzyme, which result from post-synthetic modification of the m subunit. they were discovered by weavers in 1972.31 after ischaemic damage to the heart, the ck-mb isoenzyme is released from the damaged heart muscle into the blood. this isoenzyme is converted into other forms by the action of the plasma enzyme carboxypeptidase n (cpn) according to the following reaction: 32 ck-mb2 (tissue form)  cpn (-lysine)  ckmb1 (plasma form) in this reaction, the cpn enzyme removes one lysine amino acid from the m subunit of the released ck-mb2 to produce ck-mb1. ck-mb2 and ckmb1 exist in equilibrium (1:1 ratio) in the serum of normal healthy people. therefore, measurement of total ck-mb at any point in time is equivalent to 50% ck-mb2 and 50% ck-mb1. most assays that measure ck-mb use a relatively high upper limit of reference range (10ng/ml, 14 iu/l). humans differ in their background level of ck-mb and some people may express normal concentrations as low as 1-2 iu/l (or ng/ml). therefore, in the event of myocardial injury, it will require a several-fold increase in the marker before it exceeds the upper limit of the reference range. ck-mb, being a relatively large molecule, may take even longer to reach the circulation and become important diagnostically. when myocardial injury occurs, there is a sudden release and rise of the tissue isoforms, i.e. ck-mb2 compared to the plasma form ck-mb1, leading to a rise in the ratio of ck-mb2 to ck-mb1. by using ck-mb isoforms effectively each patient acts as his own control, and a release of only a small amount of the marker is required to raise the ratio much earlier to a significant level. the requirement for the diagnosis of ami is two-fold: 1) increase of ck-mb2 > 2.6 iu/l and 2) increase of ck-mb2 to ck-mb1 ratio > 1.7. c r e at i n e k i n a s e-m b i s o f o r m s a n d a c u t e m y o c a r d i a l i n fa r c t i o n creatine kinase mb isoforms are reported to be released within 1 hour after symptom onset and peak at 4 hours. evidence of ami can be detected as early as 1-2 hours post-infarction, several hours before total ck-mb reaches diagnostic level.33 these release kinetics make ck-mb isoforms potential markers for the early diagnosis of ami. the sensitivity and specificity of ck-mb2 to ckmb1 ratio for the diagnosis of ami was reported to be 92% and 95% respectively within 6 hours of infarction.34 during this time interval, total ck-mb hafidh a al-hadi and keith a fox review | 237 mass or activity would just be approaching the upper limit of the reference range. one study reported a sensitivity and specificity of 95.7% and 93.9% respectively with a high positive predictive value and a high negative predictive value within 6 hours of infarction. a total of 114 out of 118 patients with ami were identified using ck-mb isoforms within 6 hours. the sensitivity and specificity of conventional ck-mb during this time interval was 48% and 94% respectively.35 seventeen patients who were discharged from the emergency department fulfilled the criteria for the diagnosis of ami using ck-mb isoforms (missed diagnosis). the test was also positive in patients with hypothyroidism and rhabdomyolysis.35 these findings were also substantiated by other studies.36 some investigators however, have questioned the value of ck-mb isoforms for the early diagnosis of ami. a study by laurino et al. in 1996 showed no difference between ck-mb isoforms and conventional ck-mb isoenzyme at 6 hours after symptom onset.37 another study by bhayana et al., using comparison between ck-mb mass, ckmm3 to ck-mm1 ratio, and ck-mb2 to ck-mb1 ratio found no significant advantage of isoforms over ck-mb mass for the diagnosis of ami within 6 hours.38 l i m i tat i o n s o f c r e at i n e k i n a s em b i s o f o r m s a s s ay s there are still unresolved issues surrounding the use of ck-mb isoforms for the early diagnosis of mi. there is still some concern regarding the stability of these isoforms in serum/plasma after their release from damaged tissues.39 there are also some reports of possible variations in the activity of the cpn enzyme among humans.40 this may have a profound effect on the use of the isoforms as markers for the early diagnosis of ami and could lead to false positive or false negative results.39 the other drawback is that the use of isoforms does not obviate the need to analyse total ck and the relative index of ck-mb to total ck to exclude false positive results.41 myoglobin myoglobin is a small heme protein (17 k da) that functions in oxygen binding and transport. it stores oxygen in red muscles (skeletal and cardiac) and, under conditions of severe oxygen deprivation, it releases the oxygen to be used by muscle mitochondria for synthesis of adenosine triphosphate (atp). the myoglobin content of heart muscle is reported to be 2.5mg/g wet weight of tissue and the skeletal muscle content is 4.0mg/g wet weight of tissue.42 myoglobin constitutes 2% of the total cytosolic protein content of cardiac muscle. the reference range of serum myoglobin is about 20-80ng/ml. males have higher levels than females because they have bigger body size and muscle bulk. m y o g l o b i n a n d a c u t e m y o c a r d i a l i n fa r c t i o n myoglobin is one of the best available early markers of ami within 3 hours after symptom onset. the relationship between ami and high myoglobin levels was first reported in 1975.43 myoglobin starts to increase in blood within 2 hours after symptom onset of ami, peaks at 6-9 hours, and returns to normal within 24 hours. in a study by bhayana in 1994, myoglobin was found to be superior to ckmb mass and tnt for ruling out ami within the period of 3-6 hours after symptom onset.44 this early release feature of myoglobin is attributed to its small size and localisation within the cytosol of the cell. several investigators have confirmed a significant role for myoglobin in the early diagnosis of ami, the most promising role being in the early exclusion of ami in patients presenting within 6 hours after symptoms onset.45 within this period, the overall diagnostic sensitivity and specificity ranged from 77-97% and 90-97.9% respectively. the variation in sensitivity depends mostly on the time of presentation after symptom onset and drops considerably with very early (< 2 hours) or late presentation (> 15 hours) to the hospital.11 a consistently negative result within this time interval has such a high negative predictive value for ruling out ami that confident decisions regarding patients’ management can be based on it. however, a positive result should be used with caution, as there are many situations that could give rise to myoglobin elevation in the absence of ami.46 l i m i tat i o n s o f m y o g l o b i n m e a s u r e m e n t myoglobin is a non-specific marker protein for myocardial injury. serum myoglobin is raised in cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 238 | squ medical journal, december 2009, volume 9, issue 3 skeletal muscle damage including intramuscular injection, exhaustive exercise, muscle trauma, direct current shock cardioversion, and also in patients and carriers of genetic muscle disease. severe renal disease leads to failure of clearance of myoglobin from the circulation. the concentration tends to rise and the circulation time is prolonged in these patients. although these factors interfere with the specificity of the test, in clinical practice most of them could be ruled out by careful attention to history taking and simple blood tests. the specificity is increased when myoglobin measurement is combined with other diagnostic methods like ecg or more specific cardiac markers like ck-mb, ctnt, or ctni.47 m y o g l o b i n a n d t h e d e t e c t i o n o f r e p e r f u s i o n ideally, all ami patients should be treated with intravenous thrombolytic treatment or pci. the success of thrombolytic treatment in establishing reperfusion is reported to be 50-80% depending on the thrombolytic agent.48 establishment of reperfusion after the initiation of thrombolytic treatment is important to clinicians in terms of treatment and prognostic implications. coronary angiography is the most definitive method to assess the success of thrombolytic treatment, but this procedure is invasive, carries morbidity and mortality risks, requires a catheterisation laboratory team, and is not widely available. biochemical markers like myoglobin (among others) offer an alternative non-invasive, safe and potentially sensitive method for the detection of reperfusion. this can be done by monitoring the changes in serum concentration immediately before and 60 or 90 minutes after initiation of thrombolysis. patients who successfully reperfuse their occluded artery show a higher and early concentration peak of the biochemical marker compared to those who fail to reperfuse.49 patients with uncomplicated mi who reperfuse achieve a peak value of myoglobin at 1 hour, whereas those who fail to reperfuse reach peak value about 5 hours later.50 a two-fold increase in myoglobin concentrations within 60 minutes compared to the base line pre-thrombolysis value is associated with 95% predictive accuracy for the detection of reperfusion.51 the existence of “no-reflow” is an important indicator of impaired reperfusion and functional recovery. thus a patent artery does not invariably indicate tissue reperfusion. accurate markers of tissue reperfusion are required. the combination of serial 12-lead ecg, clinical features, and serial cardiac markers testing offer a practical alternative to coronary angiography for assessment of reperfusion status. heart-type (h-fabp) fatty acid-binding protein heart-type fatty acid binding protein (h-fabp) is a small (15 kda) soluble non-enzyme protein. it is composed of 132 amino acids. it is one of the most abundant proteins in the heart and comprises 5-15% of the total cytosolic protein pool in the aqueous cytoplasm. it was introduced by glatz et al. in 1988 as a potential novel biochemical marker for the early diagnosis of ami;52 this was soon confirmed in other studies.53-54 under normal conditions, h-fabp is not present in plasma or interstitial fluid, but is released into the blood upon cardiac cellular injury. the cytoplasmic to vascular concentration of h-fabp is of the order of 200,000:1.55 the plasma or serum concentration of h-fabp under normal conditions is < 5µg/l. this makes the plasma estimation of h-fabp a suitable indicator for the early detection and quantification of myocardial tissue injury. h-fa b p a n d a c u t e m y o c a r d i a l i n fa r c t i o n heart-type fabp is released into plasma within 2 hours after symptom onset and is reported to peak at about 4-6 hours and to return to normal base line level in 20 hours.55 within the period of 30210 minutes after symptom onset, h-fabp has > 80% sensitivity for the diagnosis of ami.56 within the interval of 0-6 hours after symptom onset, the other cardiac markers such as ck, ck-mb (mass or activity), i ctni and ctnt will only be starting to accumulate in the plasma, and their sensitivity has been reported to be around 64%.57 a rise in serum and urine h-fabp concentration above reference values is seen in patients presenting with ami as early as 1.5 hours after symptom onset. serial measurements of h-fabp in the first 24 hours after onset of symptoms may be potentially useful for: the diagnosis of ami; to identify patients who need early reperfusion treatment; to identify patients who reperfuse their infarct related artery; to detect hafidh a al-hadi and keith a fox review | 239 re-infarction if it occurs early and for estimation of infarct size.58 however, some of the more recent studies have questioned the value of these early markers (h-fabp and myoglobin) when compared with specific markers like ctni.59-60 l i m i tat i o n s a n d f u t u r e d i r e c t i o n s o f h-fa b p m e a s u r e m e n t s heart-type fabp exists in high concentrations in the heart only. however, this protein is not totally cardiac specific and occurs in other tissues although in much lower concentrations.57 it is present in skeletal muscles in concentrations varying between 0.05-0.2 mg/g wet weight of tissue, depending on the muscle fibre type studied.61 it has also been reported in very low concentrations in tissues like the kidney, aorta, testes, mammary glands, placenta, brain, adrenal glands, adipose tissue, and stomach.57 heart-type fabp is secreted by the kidney and circulates for a longer time (> 25 hours) after ami in the presence of renal failure. gorski et al. reported that h-fabp and myoglobin concentrations were both significantly elevated in patients with renal failure. the concentrations of these markers were not affected by dialysis.62 we have also shown that the efficiency of h-fabp for the diagnosis of ami is severely limited in patients with renal failure.63 skeletal muscle damage during the course of ami, e.g. intramuscular injections, electric cardioversion and traumatic cardiopulmonary resuscitation, may result in the leakage of h-fabp and this could interfere with the results of the assays.64 diagnosis of ami in these groups of patients using h-fabp alone can be difficult. h-fabp is increased in the plasma of healthy volunteers after strenuous exercise.65 surgery (both cardiac and non-cardiac) causes elevation of h-fabp concentration. h-fa b p a n d m y o g l o b i n myoglobin and h-fabp share many key features: 1) low molecular weight proteins (17 and 15kda, respectively); 2) abundant concentrations in the cytosol of myocardial cells; 3) substrate for mitochondrial oxidation (oxygen and fatty acids, respectively and 4) both are released within 2 hours after symptom onset, peak early (6 hours) and return to normal baseline concentration within 24 hours. both proteins are present in the heart and skeletal muscle in different concentrations. the concentration of myoglobin in heart and skeletal muscle is 2.5 and 4.0mg/g wet weight of tissue, respectively. the h-fabp concentration in heart and skeletal muscle is 0.5 and 0.05-0.2 mg/g wet weight of tissue, respectively. the myoglobin content of skeletal muscle is twice that of the heart. the h-fabp content of skeletal muscle is only 10-50% of that of the heart. the normal plasma concentration of h-fabp (< 5µg/l) is 10 to 15-fold lower than that of myoglobin (30-80µg/l). h-fabp is therefore more cardio-specific than myoglobin. the normal ratio of myoglobin: h-fabp in the myocardium is about 1:5, whereas the ratio in skeletal muscle is in the order of 21:70 (depending on muscle type).66 the main disadvantage of myoglobin and h-fabp as early markers of myocardial injury is their lack of total specificity due to their presence in skeletal muscle. because both proteins are released into plasma after injury at about the same time and in a ratio similar to the protein’s concentration in the tissue of origin, the measurement of the myoglobin: h-fabp ratio could be a useful index for discrimination between cardiac and skeletal muscle damage. a myoglobin: h-fabp ratio that is around 1:5 is considered to be specific for the heart and a ratio that is between 21:70 is more specific to skeletal muscle damage.64 the ratio has been reported by some investigators to increase the diagnostic specificity for the diagnosis of ami more than relying on either marker alone. however, the use of this ratio should not be a rigid criterion as overlaps do occur. some investigators did not support additional value over the measurement of h-fabp alone.64,67 cardiac troponins the troponin complex is found on the thin filament (actin) of all types of striated muscle (fast, slow, and cardiac). its function is to regulate calcium dependent contraction of muscles. there are three types of troponins: tnt, tni and tnc. they are designated with a letter that refers to the function of the troponin protein; tnc binds calcium; tni inhibits the action of the enzyme actomyosin adenosine triphosphatase; tnt binds to tropomyosin.68 they are called isoforms and have a pre-fix to indicate the muscle type they are in e.g. ctnt, stnt, ftnt stand for cardiac muscle, slow twitch skeletal muscle, and fast twitch skeletal muscle tnt respectively. cardiac tnt has more tissue distribution and more free cytoplasmic cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 240 | squ medical journal, december 2009, volume 9, issue 3 concentration and is released as a complex with the other cardiac troponin t-i-c. cardiac tni is released more in the binary form (troponin i-c complex).69 each troponin protein within these muscles has a different molecular weight, different amino acids, and an amino acid sequence unique to that muscle type. the different isoforms of tnt and tni share between 40-55% of amino acid sequence homology.70 c a r d i a c t r o p o n i n t a n d a c u t e m y o c a r d i a l i n fa r c t i o n cardiac-tnt (34 kda) was first introduced in 1989 as a marker for ami.71 the upper limit for ctnt has been reported as < 0.1µg/l, but concentrations between 0.03-0.1µg/l may also have significance as markers of an adverse outcome.72 cardiac-tnt appears in the serum within 12 hours after symptom onset in patients with ami. it shows similar release kinetics to ck-mb and ctni, and thus does not provide an earlier detection for ami than ckmb or ctni within the first 6 hours after symptom onset.73 once in the circulation, it persists for a long time (2-3 weeks) after symptom onset. the halflife of ctnt in circulation is 120 minutes and this long diagnostic window is thought to be due to the continuous release of the marker from myocardial cells after necrosis, and not due to slow clearance from the circulation.74 the clinical sensitivity of ctnt for the diagnosis of ami approaches 100% at about 12 hours after symptom onset and remains elevated at 100% for at least 4 days.74 u n s ta b l e a n g i n a a n d i n c r e a s e d c a r d i a c t r o p o n i n t (n o n-s t e l e vat i o n m i) unstable angina/non-st elevation mi carries significant morbidity and mortality risks and early detection and treatment are essential to minimise complications.75 cardiac-tnt has been shown to be elevated in patients with non-st elevation mi and the magnitude of elevation can be used for diagnostic purposes, risk stratification, and for selection of appropriate patient groups for treatment. elevated ctnt in patients with non-st elevation mi is associated with poor prognosis.76 the increase correlates well with the severity of coronary artery lesions determined by angiography.77 in one important study, the prognostic value of ctnt was assessed in 967 patients with unstable angina. it was found that the group that had elevated concentrations of ctnt had an increased risk of cardiac events and the higher the ctnt the more frequent the complications. patients were followedup for 6 months for cardiac complications. the risk of further ami and death was 4.3% in patients with ctnt less than 0.06µg/l and 16.1% for those with ctnt equal or greater than 0.18µg/l.78 in another study by stubbs et al., 62 non-st elevation mi patients were followed-up for about three years after their admission with ctnt concentration greater or equal to 0.2 ng/ml. the incidence of complications in this group was very high: cardiac death (12 patients), coronary revascularisation (22 patients), death and non-fatal ami (18 patients).79 cardiac-tnt measurement can help select the appropriate patients for treatment with antithrombotics. treatment of non-st elevation mi patients with thrombolytic therapy had not been found to be useful.80 however, treatment of non-st elevation mi with antiplatelet and antithrombotic drugs like aspirin, clopidogrel, low molecular weight heparin (lmwh) and glycoprotein iib/iiia (gp iib/iiia) receptor antagonist was associated with 30% reduction in the incidence of mortality and ami.81 those patients with ctnt < 0.1 ng/ ml fared equally well whether they were treated by lmwh, deltaparin or a placebo (4.7 versus 5.7% x 40 day mortality respectively). however, patients with ctnt greater than or equal to 0.1ng/ ml had reduced ami and mortality if they received deltaparin rather than a placebo (7.4 versus 14.2% respectively).82s p e c i f i c i t y o f c a r d i a c t r o p o n i n t a s s ay s elevated ctnt concentration has been reported in a significant numbers of patients with chronic renal failure. these levels do not seem to be affected by haemodialysis, with elevations persisting after treatment.83 in chronic kidney disease patients on haemodialysis without acute coronary syndrome, ctni was reported to have better sensitivity and specificity for the diagnosis of ami compared with ctnt, but positive ctnt was associated with increased all cause mortality during follow up.84-85 vigorous exercise, e.g. marathon runners; rhabdomyolysis; inflammatory muscle disease, e.g. polymyositis and dermatomyositis, and degenerative muscle disease, e.g. duchenne/becker hafidh a al-hadi and keith a fox review | 241 muscular dystrophy, have been reported to show elevated concentrations of ctnt.86 high ctnt and ctni concentrations have been reported in critically ill patients who had not been diagnosed with comorbid ami.87 blunt trauma to the chest, closed heart massage, external defibrillation is also reported to result in elevation of ctnt.88 elevations have also been reported in cases of myocarditis and drug induced cardiac toxicity.89,90 elevated troponin levels (i and t) occur in some patients with acute pulmonary embolism and this elevation has been associated with a high risk of short-term death and an adverse outcome events.91 the advantage of the ctnt immunoassay is that currently it is marketed by one source only hence there are well-established standards in terms of reference range, detection limits, and clinical cut-off concentrations. there is however, a slightly higher rate of positive results with ctnt assays in some patients with chronic renal failure and acute or chronic muscle disease.86,92 c a r d i a c t r o p o n i n i a n d a c u t e m y o c a r d i a l i n fa r c t i o n cardiac-tni (24 kda) is reported to have a unique segment containing 31 amino acids that makes it different to either stni or ftni (19 kda). during foetal development both stni and ctni are expressed in the myocardium; however, at birth, the ctni remains as the only isoform present in the human myocardium.93 cardiac-tni has not been shown to be expressed in any type of skeletal muscle during either development or disease stimuli.94 this makes ctni 100% specific for the myocardial tissue and an excellent marker for the detection of myocardial injury in serum. cardiactni was first reported as a biochemical marker of myocardial injury in 1992 and has since been shown to be a very sensitive and specific marker for the diagnosis of ami. it has similar release kinetics to ck-mb and to ctnt and does not provide an earlier detection for ami within the first 6 hours after symptom onset.95 cardiac-tni peaks between 1236 hours after onset of ami and remains elevated for 3-7 days after ami. the half-life of ctni is < 2 hours and the prolonged diagnostic window is due to the continuous release of this marker from the myofibril. c a r d i a c t r o p o n i n i a n d n o n-s t e l e vat i o n m i cardiac-tni is cardiac specific and its concentration in normal and disease free populations is undetectable or very low. this makes it a suitable marker for the detection of myocardial injury in patients with non-st elevation mi as well as other situations where myocardial injury is expected, but the amount released could be small, e.g. following pci.96 many studies have also shown ctni to have prognostic value in patients with non-st elevation mi similar to that of ctnt. those patients showing higher levels at admission have more complications increased mortality and ami on subsequent follow-up.97 the prognostic risk in these patients is significantly altered if early intervention (pharmacological and invasive) is undertaken in these patients compared to conservative treatment. s p e c i f i c i t y o f c a r d i a c t r o p o n i n i a s s ay s cardiac-tni was not found in patients who underwent uncomplicated angioplasty.98 in patients with chest trauma, cocaine associated chest pain, and hypothyroidism where ck and ck-mb were elevated, ctni was able to distinguish true myocardial injury from cases with false elevation. in marathon runners, more than 80% of samples were positive for ck-mb and in all of these samples ctni was negative. cardiac-tni was found to be significantly elevated (43%) in patients with bacteraemia.99 the main problem with ctni is that there are several commercial assays available, and each assay differs with respect to reference range, detection limit, and medical decision cut-off limits. thus, there is a lack of standardisation of methodology for ctni assays. however, ctni has been reported to show slightly better specificity in situations where there is severe skeletal muscle injury and renal failure.84,85 s p e c i f i c i t y o f c a r d i a c t r o p o n i n s f o l l o w i n g s u r g e r y cardiac-tni was not elevated in patients who underwent non-cardiac surgery, but was raised in patients undergoing cabg due to surgical injury of the myocardium. cardiac-tni or ctnt may be the preferred markers of choice to detect myocardial injury in patients who undergo non-cardiac surgery. in the situation of non-cardiac surgery, ctni (or ctnt), being specific to the myocardium, will also cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 242 | squ medical journal, december 2009, volume 9, issue 3 help to distinguish elevation of ck-mb due to skeletal muscle damage alone from elevation due to myocardial injury.100 conclusion the markers that are well suited for the early diagnosis of ami within the time interval 0-6 hours after symptom onset are myoglobin, h-fabp and ck-mb isoforms. although all have been shown to be excellent sensitive early markers, there are still significant issues concerning its specificity. h-fabp is more cardio-specific than myoglobin and the use of h-fabp as a marker for the early diagnosis of ami seems preferable. ck-mb mass measurement is suitable in the 6-24 hours interval; ck-mb based on activity measurement is more sensitive in the 12-24 hours interval, and the other cardiac markers like total ck, ctnt, and ctni are most reliable after 12 hours from symptom onset. the prolonged diagnostic window of cardiac troponins of several days that is highly sensitive and specific obviates the needs for less specific markers with long diagnostic window like aspertate aminotransferase (alt) and ck. decision-making regarding triage and treatment of patients should not be based on a single measurement of cardiac markers alone because of the time delay required for the marker to exceed the upper limit of reference range. based on the recent recommendations by the esc/ acc, ctni and ctnt are the best markers for the confirmation of ami. ck-mb (preferably mass) is the second best marker in the absence of troponins assays. patients who present with acute chest pain suspicious of acs are best managed within specifically designated units that have rapid access to specific equipment (ecg, echocardiogram) and facilities (point of care instruments to measure cardiac markers), and with appropriate staffing. acute chest pain units attached to emergency departments can accommodate patients for 12 hours, so that appropriate investigations can be carried out quickly after presentation in order to identify patients with evolving infarction who are at increased risk. a serial combination testing of a sensitive early marker (e.g. h-fabp, myoglobin or ck-mb isoforms) and one of the cardiac specific troponins (ctnt or ctni) offers the best approach. two serial testings within a minimum of 12 hours (e.g. at 0 hour, 4-6 hours, or at 12 hours) after symptom onset provide reliable sensitivity and specificity for detecting ischaemia and evolving infarction within the time interval required for the implementation of reperfusion therapy. this 12 hour strategy also identifies patients at low-risk for acute ischaemic events. references 1. sans s, kesteloot h, kromhout d. the burden of cardiovascular disease mortality in europe. task force of the european society of cardiology on cardiovascular mortality and morbidity statistics in europe. eur heart j 1997; 18:1231-48. 2. ericsson cg, lindvall b, olsson g. trends in coronary care. a retrospective study of patients with myocardial infarction treated in coronary care units. acta med scand 1988; 224:507-13. 3. nomenclature and criteria for diagnosis of ischemic heart disease. report of the joint international society and federation of cardiology/world health organization task force on standardization of clinical nomenclature. circulation 1979; 59:607-9. 4. alpert js, thygesen k. myocardial infarction redefined a consensus document of the joint european society of cardiology/american college of cardiology committee for the redefinition of myocardial infarction. eur heart j 2000; 21:1502-13. 5. cohn pf. silent myocardial ischemia. ann intern med 1989; 109:312-17. 6. gibler wb, lewis lm, erb re, makens pk, kaplan bc, vaughan rh, et al. early detection of acute myocardial infarction in patients presenting with chest pain and nondiagnostic ecg’s: serial ck-mb sampling in the emergency department. ann emerg med 1990; 19:1359-66. 7. stark me, vacek jl. the initial electrocardiogram during admission for myocardial infarction. use as a predictor of clinical course and facility utilization. arch intern med 1987; 147:843-6. 8. adams je 3rd, abendschein dr, jaffe as. biochemical markers of myocardial injury. is mb creatine kinase the choice for the 1990s? circulation 1993; 88:75063. 9. hedges jr, rouan gw, toltzis r, goldstein-wayne b, stein ea. use of cardiac enzymes identifies patients with acute myocardial infarction otherwise unrecognized in the emergency department. ann emerg med 1987; 16:248-52. 10. van blerk m, maes v, huyghens l, derde mp, meert r, gorus fk. analytical and clinical evaluation of creatine kinase mb mass assay by imx: comparison with mb isoenzyme activity and serum myoglobin for early diagnosis of myocardial infarction. clin chem 1992; 38:2380-6. hafidh a al-hadi and keith a fox review | 243 11. de winter rj, koster rw, sturk a, sanders gt. value of myoglobin, troponin t, and ck-mb mass in ruling out an acute myocardial infarction in the emergency room. circulation 1995; 92:3401-7. 12. apple fs, henry td, berger cr, landt ya. early monitoring of serum cardiac troponin i for assessment of coronary reperfusion following thrombolytic therapy. am j clin pathol 1996; 105:6-10. 13. henderson ar, bhayana v. a modest proposal for the consistent presentations of roc plots in clinical chemistry. clin chem 1995; 41:1205-6. 14. wu ahb. introduction to coronary artery disease (cad) and biochemical markers. in: wu ahb, ed. cardiac markers. totowa, nj: human press inc 1998. pp. 3-20. 15. perryman mb, strauss aw, buettner tl, roberts r. molecular heterogeneity of creatine kinase isoenzymes. biochim biophys acta 1983; 747:28490. 16. duma rj, seigel al. serum creatine phosphokinase in acute myocardial infarction. arch intern med 1965; 115:443-51. 17. pierce gf, jaffe as. increased creatine kinase mb in the absence of acute myocardial infarction. clin chem 1986; 32:2044-51. 18. wu ahb. creatine kinase, isoenzymes, and variants in: wu ahb, ed. cardiac markers. totowa, nj: humana press inc, 1998. pp.113-20. 19. sasse ea, madiedo g, kopenski w. evaluation of abbott imx: ck-mb immunoassay. clin chem 1990; 36:1858-9. 20. delanghe jr, de mol am, de buyzere ml, de scheerder ik, weime rj. mass concentration and activity concentration of creatine kinase isoenzyme mb compared in serum after acute myocardial infarction. clin chem 1990; 36:149-53. 21. bakker aj, gorgels jp, van vlies b, haagen fd, smits r. the mass concentrations of serum troponin t and creatine kinase-mb are elevated before creatine kinase and creatine kinase-mb activities in acute myocardial infarction. eur j clin chem 1993; 31:71524. 22. venta r, geijo sa, sanchez ac, bao cg, bartolome la, casares g, et al. iga-ck-bb complex with ckmb electrophoretic mobility can lead to erroneous diagnosis of acute myocardial infarction. clin chem 1989; 35:2003-8. 23. irvin rg, cobb fr, roe cr. acute myocardial infarction and mb creatine phosphokinase. relationship between onset of symptoms of infarction and appearance and disappearance of enzyme. arch intern med 1980; 140:329-34. 24. gibler wb, young gp, hedges jr, lewis lm, smith ms, carleton sc, et al. acute myocardial infarction in chest pain patients with nondiagnostic ecgs: serial ck-mb sampling in the emergency department. the emergency medicine cardiac research group. ann emerg med 1992; 21:504-12. 25. ravkilde j, hansen ab, horder m, jorgensen pj, thygesen k. risk stratification in suspected acute myocardial infarction based on a sensitive immunoassay for serum creatine kinase isoenzyme mb. a 2.5 year follow-up study in 156 consecutive patients. cardiology 1992; 80:143-51. 26. seo h, miyazaki s, furuno t. creatine kinase-mb protein mass is a better indicator for the assessment of acute myocardial infarction in the lower range of creatine kinase level. jpn heart j 1993; 34:717-27. 27. pettersson t, ohlsson o, tryding n. increased ck-mb (mass concentration) in patients without traditional evidence of acute myocardial infarction. a risk indicator of coronary death. eur heart j 1992; 13:1387-92. 28. ravkilde j, nissen h, mickley h, andersen pe, thayssen p, horder m. cardiac troponin-t and ck-mb mass release after visually successful percutaneous transluminal coronary angioplasty in stable angina pectoris. am heart j 1994; 127:13-20. 29. abbas sa, glazier jj, wu ah, dupont c, green sf, pearsall la, et al. factors associated with the release of cardiac troponin t following percutaneous transluminal coronary angioplasty. clin cardiol 1996; 19:782-86. 30. sasse ea, madiedo g, kopenski w. evaluation of abbott imx: ck-mb immunoassay. clin chem 1990; 36:1858-9. 31. wevers ra, delsing m, klein gebbink ja, soons jb. post-synthetic changes in creatine kinase isoenzymes (ec 2.7.3.2). clin chim acta 1978; 86:323-7. 32. hendriks d, soons j, scharpe s, wevers r, van sande m, holmquist b. identification of the carboxypeptidase responsible for the post-synthetic modification of creatine kinase in human serum. clin chim acta 1988; 172:253-60. 33. hossein-nia m, kallis p, brown pa, chester mr, kaski jc, murday aj, et al. creatine kinase mb isoforms: sensitive markers of ischemic myocardial disease. clin chem 1994; 40:1265-71. 34. puleo pr, guadagno pa, roberts r, scheel mv, marian aj, churchill d, et al. early diagnosis of acute myocardial infarction based on assay for subforms of creatine kinase-mb. circulation 1990; 82:759-64. 35. puleo pr, meyer d, wathen c, tawa cb, wheeler s, hamburg rj, et al. use of a rapid assay of subforms of creatine kinase-mb to diagnose or rule out acute myocardial infarction. n engl j med 1994; 331:561-6. 36. zimmerman j, fromm r, meyer d, boudreaux a, wun cc, smalling r, et al. diagnostic marker cooperative study for the diagnosis of myocardial infarction. circulation 1999; 99:1671-7. 37. laurino jp, bender ew, kessimian n, chang j, pelletier t, usategui m. comparative sensitivities and specificities of mass measurements of ck-mb2, ckcardiac markers in the early diagnosis and management of patients with acute coronary syndrome 244 | squ medical journal, december 2009, volume 9, issue 3 mb, and myoglobin for diagnosing acute myocardial infarction. clin chem 1996; 42:1454-9. 38. bhayana v, cohoe s, leung fy, jablonsky g, henderson ar. diagnostic evaluation of creatine kinase-2 mass and creatine kinase-3 and -2 isoform ratios in early diagnosis of acute myocardial infarction. clin chem 1993; 39:488-95. 39. davies j, reynolds t, penney md. creatine kinase isoforms: investigation of inhibitors of in vitro degradation and establishment of a reference range. ann clin biochem 1992; 29:202-5. 40. schweisfurth h, pickert e, gramer e, reiners c. alterations of carboxypeptidases n activities in patients with thyroid dysfunction. clin biochem 1987; 20:43-6. 41. wu ah, wang xm, gornet tg, ordonez-llanos j. creatine kinase mb isoforms in patients with skeletal muscle injury: ramifications for early detection of acute myocardial infarction. clin chem 1992; 38:2396-400. 42. van nieuwenhoven fa, kleine ah, wodzig kw, hermens wt, kragten ha, maessen jg, et al. discrimination between myocardium and skeletal muscle injury by assessment of the plasma ratio of myoglobin over fatty acid-binding protein. circulation 1995; 92:2848-54. 43. kagen l, scheidt s, roberts l, porter a, paul h. myoglobinemia following acute myocardial infarction. am j med 1975; 58:177-82. 44. bhayana v, cohoe s, pellar tg, jablonsky g, henderson ar. combination (multiple) testing for myocardial infarction using myoglobin, creatine kinase-2 (mass), and troponin t. clin biochem 1994; 27:395-406. 45. vaidya hc. myoglobin: an early biochemical marker for the diagnosis of acute myocardial infarction. j clin immunoassay 1994; 17:35-9. 46. varki ap, roby ds, watts h, zatuchni. serum myoglobin in acute myocardial infarction: a clinical study and review of the literature. am heart j 1978; 96:680-8. 47. collins r, tucker j. myoglobin and ck-mb for the diagnosis of acute myocardial infarction in emergency room patients. clin chem 1991; 37:978. 48. anderson hv, willerson jt. thrombolysis in acute myocardial infarction. n engl j med 1993; 329:703-9. 49. ishii j, nomura m, ando t, hasegawa h, kimura m, kurokawa h, et al. early detection of successful coronary reperfusion based on serum myoglobin concentration; comparison with serum creatine kinase isoenzyme mb activity. am heart j 1994; 128:641-8. 50. zabel m, honloser sh, koster w, prinz m, kasper w, just h. analysis of creatine kinase, ck-mb, myoglobin and troponin t time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. circulation 1993; 87:1542-50. 51. miyata m, abe s, arima s, nomoto k, kawataki m, ueno m, et al. rapid diagnosis of coronary reperfusion by measurement of myoglobin level every 15 min in acute myocardial infarction. j am coll cardiol 1994; 23:1009-15. 52. glatz jf, van bilsen m, paulussen rj, veerkamp jh, van der vusse gj, reneman rs, et al. release of fatty acid-binding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox. biochim biophys acta 1988; 961:148-52. 53. ishii j, wang jh, naruse h, taga s, kinoshita m, kurokawa h, et al. serum concentrations of myoglobin vs human heart-type cytoplasmic fatty acid-binding protein in early detection of acute myocardial infarction. clin chem 1997; 43:1372-8. 54. alhadi ha, fox ka. do we need additional markers of myocyte necrosis: the potential value of heart fatty acid-binding protein. qjm 2004; 97:187-98. 55. glatz jf, van der vusse gj, maessen jg, van dieijenvisser mp, hermens wt. fatty acid-binding protein as marker of muscle injury: experimental finding and clinical application. acta anaesthesiol scand suppl 1997; 111:292-4. 56. kleine ah, glatz jf, van nieuwenhoven fa, van der vusse gj. release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. mol cell biochem 1992; 116:155-62. 57. bakker aj, koelemay mj, gorgels jp, van vlies b, smits r, tijssen jg, et al. failure of new biochemical markers to exclude acute myocardial infarction at admission. lancet 1993; 342:1220-2. 58. colli a, jossa m, pomar jl, mestres ca, gharli t. heart fatty acid binding proteins in diagnosis of myocardial infarction: where do we stand now? cardiology 2007; 108:4-10. 59. alansari se, croal bl. diagnostic value of heart fatty acid binding protein and myoglobin in patients admitted with chest pain. ann clin biochem 2004; 41:391-6. 60. iiva t, lund j, poreta p, mustonen h, voipio-pulkki lm, eriksson s, et al. early markers of myocardial injury: ctni is enough. clinica chimica acta 2009; 400:82-5. 61. crisman ts, claffey kp, saouaf r, hanspal j, brecher p. measurement of rat heart fatty acid-binding protein by elisa. tissue distribution, developmental changes and subcellular distribution. j mol cell cardiol 1987; 19:23-31. 62. gorski j, hermens wt, borawski j, mysliwiec m, glatz jf. increased fatty acid-binding protein concentration in plasma of patients with chronic renal failure. clin chem 1997; 43:193-5. 63. alhadi ha, william b, fox ka. serum level of heart fatty acid binding protein in patients with chronic renal failure. squ med j 2009; 9:311-13. hafidh a al-hadi and keith a fox review | 245 64. van nieuwenhoven fa, kleine ah, wodzig kw, hermens wt, kragten ha, maessenn jg et al. discrimination between myocardium and skeletal muscle injury by assessment of the plasma ratio of myoglobin over fatty acid-binding protein. circulation 1995; 92:2848-54. 65. sorichter s, mair j, kollar a, pelsers mm, puschendorf b, glatz jf. early assessment of exercise induced skeletal muscle injury using plasma fatty acid binding protein. br j sports med 1998; 32:121-4. 66. glatz jf, van der vusse gj, maessen jg, van dieijenvisser mp, hermens wt. fatty acid-binding protein as marker of muscle injury: experimental finding and clinical application. acta anaesthesiol scand suppl 1997; 111:292-4. 67. ishii j, wang jh, naruse h, taga s, kinoshita m, kurokawa h et al. serum concentrations of myoglobin vs human heart-type cytoplasmic fatty acid-binding protein in early detection of acute myocardial infarction. clin chem 1997; 43:1372-8. 68. greaser ml, gergely j. purification and properties of the components from troponin. j biol chem 1973; 248:2125-33. 69. wu ah, feng yj. biochemical differences between ctnt and ctni and their significance for diagnosis of acute coronary syndromes. eur heart j 1999; 19 suppl: n25-n29. 70. dhoot gk, frearson n, perry sv. polymorphic forms of troponin t and troponin c and their localization in striated muscle cell types. exp cell res 1979; 122:339-50. 71. katus ha, remppis a, looser s, hallermeier k, scheffold t, kubler w. enzyme linked immuno assay of cardiac troponin t for the detection of acute myocardial infarction in patients. j mol cell cardiol 1989; 21:1349-53. 72. muller-bardorff m, hallermayer k, schroder a, ebert c, borgya a, gerhardt w, et al. improved troponin t elisa specific for cardiac troponin t isoform: assay development and analytical and clinical validation. clin chem 1997; 43:458-66. 73. gerhardt w, ljungdahl l, herbert a. troponin t and ck-mb (mass) in early diagnosis of ischemic myocardial injury. the helsingborg study, 1992. clin biochem 1993; 26:231-40. 74. wu ah, valdes r jr, apple fs, gornet t, stone ma, mayfield-stokes s, et al. cardiac troponin-t immunoassay for diagnosis of acute myocardial infarction. clin chem 1994; 40:900-7. 75. hugenholtz pg. unstable angina revisited once more. eur heart j 1986; 7:1010-15. 76. ohman em, armstrong pw, christenson rh, granger cb, katus ha, hamm cw et al. cardiac troponin t levels for risk stratification in acute myocardial ischemia. gusto iia investigators. n engl j med 1996; 335:1333-41. 77. jurlander b, farhi er, banas jj jr, keany cm, balu d, grande p, et al. coronary angiographic findings and troponin t in patients with unstable angina pectoris. am j cardiol 2000; 85:810-14. 78. lindahl b, venge p, wallentin l. relation between troponin t and the risk of subsequent cardiac events in unstable coronary artery disease. the frisc study group. circulation 1996; 93:1651-7. 79. stubbs p, collinson p, moseley d, greenwood t, noble m. prospective study of the role of cardiac troponin t in patients admitted with unstable angina. bmj 1996; 13:262-4. 80. schreiber tl, rizik d, white c, sharma gv, cowlev m, macina g, et al. randomized trials of thrombolysis versus heparin in unstable angina. circulation 1992; 86:1407-14. 81. fox ka. acute coronary syndromes: presentationclinical spectrum and management. heart 2000; 84:93-100. 82. lindahl b, venge p, wallentin l. troponin t identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic treatment. fragmin in unstable coronary artery disease (frisc) study group. j am coll cardiol 1997; 29:43-8. 83. li d, jialal i, keffer j. greater frequency of increased cardiac troponin t than increased cardiac troponin i in patients with chronic renal failure. clin chem 1996; 42:114-15. 84. needham dm, shufelt ka, tomlinson g, scholey jw, newton ge. troponin i and t levels in renal failure patients without acute coronary syndrome: a systematic review of the literature. can j cardiol 2004; 20:1212-18. 85. khan na, hemmelgarn br, tonell m, thompson cr, levin a. prognostic value of troponin t and i among asymptomatic patients with end-stage renal disease: a meta-analysis. circulation 2005; 112:308896. 86. kobayashi s, tanaka m, tamura n, hashimoto h, hirose s. serum cardiac troponin t in polymyositis/ dermatomyositis. lancet 1992; 340:726. 87. guest tm, ramanathan av, tuteur pg, schechtman kb, ladenson jh, jaffe as. myocardial injury in critically ill patients: a frequently unrecognized complication. jama 1995; 273:1945-9. 88. grubb nr, fox ka, cawood p. resuscitation from out-of-hospital cardiac arrest: implications for cardiac enzyme estimation. resuscitation 1996; 33:35-41. 89. lauer b, niederau c, kuhl u, schannwell m, pauschinger m, strauer be, et al. cardiac troponin t in patients with clinically suspected myocarditis. j am coll cardiol 1997; 30:1354-9. 90. herman eh, lipshultz se, rifai n, zhang j, papoian t, yu zx, et al. use of cardiac troponin t levels as an indicator of doxorubicin-induced cardiotoxicity. cancer res 1998; 58:195-7. cardiac markers in the early diagnosis and management of patients with acute coronary syndrome 246 | squ medical journal, december 2009, volume 9, issue 3 91. becattini c, vedovati mc, agnelli g. prognostic value of troponin in acute pulmonary embolism: a meta-analysis. circulation 2007; 116:427-33. 92. agezew y. elevated serum cardiac troponin in nonacute coronary syndrome. clin cardiol 2009; 32:1520. 93. sasse s, brand nj, kyprianou p, dhoot gk, wade r, arai m, et al. troponin i gene expression during human cardiac development and in end-stage heart failure. circ res 1993; 72:932-8. 94. bodor gs, porterfield d, voss em, smith s, apple fs. cardiac troponin-i is not expressed in adult human skeletal muscle tissue. clin chem 1995; 41:1710-15. 95. adams je 3rd, schechtman kb, landt y, ladenson jh, jaffe as. comparable detection of acute myocardial infarction by creatine kinase mb isoenzyme and cardiac troponin i. clin chem 1994; 40:1291-5. 96. genser n, mair j, talasz h, puschendorf b, puschendorf b, calzolari c, et al. cardiac troponin i to diagnose percutaneous transluminal coronary angioplasty-related myocardial injury. clin chim acta 1997; 265:207-17. 97. galvani m, ottani f, ferrini d, ladenson jh, destro a, baccos d, et al. prognostic influence of elevated values of cardiac troponin i in patients with unstable angina. circulation 1997; 95:2053-9. 98. hunt ac, chow sl, shiu mf, chilton dc, cummins b, cummins p. release of creatine kinase-mb and cardiac specific troponin-i following percutaneous transluminal coronary angioplasty. eur heart j 1991; 12:690-4. 99. kalla c, raveh d, algur n, rudensky b, yinnon am, ballan j. incidence and significance of a positive troponin test in bacteremic patients without acute coronary syndrome. am j med 2008; 121:909-15. 100. adams je 3rd, sicard ga, allen bt, bridwell kh, lenke lg, davilla-roman vg, et al. diagnosis of perioperative myocardial infarction with measurement of cardiac troponin i. n engl j med 1994; 330:670-4. january 2007 vol 7 correct a.indd abstract objective: to evaluate the impact of the national cholesterol educational program adult treatment panel iii (atp iii) and the framingham offspring study on omani diabetic subjects. methods: 22 subjects with type 2 diabetes (86 females and 35 males) and 56 non-diabetic subjects (70 females and 86 males) aged 30-70 years attending sultan qaboos university hospital between 999-2002 were recruited. lipid profile, glucose, %hbac, apoproteina- and apoproteinb were measured. low density lipoprotein was calculated using the friedwald formula. atp-iii and framingham offspring study guidelines were used to classify lipid parameters into coronary heart disease-risk categories. results: diabetic compared to non-diabetic subjects had significantly higher triglycerides of >.7 mmol/l (p=0.0) and lower low density lipoprotein cholesterol of >4.2 mmol/l (p=0.02 ) and, in female subjects only, lower high density lipoprotein cholesterol of <.5 mmo/l for ( p<0.000). in addition, 57% of diabetic subjects had abnormal aplipoproteinb of >.2 g/l compared to 49% of non-diabetic subjects. combined raised levels of triglycerides, apolipoproteinb and low levels of high density lipoprotein were found in 42% of diabetic compared to 26% of the non-diabetic subjects (p=0.05). diabetic subjects had significantly higher (p=0.008) ncep risk-score for coronary artery disease, however, only 34% conformed to a ncep 0-year-risk score of >0%. conclusion: a substantial proportion of the omani diabetic subjects were dyslipidaemic according to the atp iii guidelines. this study recommends the implementation of a lower cut-off threshold for starting lipid-modifying agents for omani diabetics when using the 0-year framingham risk scoring equation. key words: lipids, lipoproteins, diabetes mellitus, oman, and ncep risk score. abbreviations: tc, total cholesterol; ldl-c, low density lipoprotein cholesterol; hdl-c, high density lipoprotein cholesterol; lipids-risk categories in omani type 2 diabetics impact of the national cholesterol educational program ali i al-bahrani, riad bayoumi, *said a al-yahyaee sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© department of biochemistry, college of medicine and health sciences sultan qaboos university. p.o. box 35, al-khoud 123, sultanate of oman *to whom correspondence should be addressed. email: syahyaee@squ.edu.om o r i g i n a l s t u d y الثاني النوع السكر العمانيني املصابني بداء عند الشحوم خطورة تصنيف الكوليستيرول حول التربوي البرنامج أهمية ــل ــة فرمنجهام لنس (ncep atp iii) و دراس للبالغني العالجي التوعوي الوطني ــترول الكوليس تطبيق برنامج ــر تأثي ــص: الهــدف: تقييم امللخ و135 رجال 86 امرأة بينهم الثاني) – من (النوع السكر بداء مصابا 221 شخصا هذه الدراسة ــملت الطريقة: ش . ــكر الس بداء املصابني العمانيني السطان جامعة ــفى مبستش ، 30-70 عاما بني أعمارهم تتراوح 86 رجال) ، و (70 امرأة ــكري الس بداء مصاب غير ــخصا 156 ش من ضابطة وعينة ، (أ1-) نوع البروتيني ميمٌ والصَ الدم خلضاب املئوية والنسبة واجللوكوز ، الدم في ــحوم الش لَة شاكِ ــتوى مس مت قياس .2002-1999 بني عامي قابوس مقادير الشحوم لتصنيف لألنسال فرامنجهام دراسة وارشادات فرايدوالد طريقة حسب الكثافة قليل الشحمي البروتني ــتوى ــاب مس مت حس و(ب). الغليسيريد ثالثي 0.01) من (احصائياأعلى مستوى السكر بداء املصابني ألنتائج: كان لدى القلبية. الشرايني في االصابة بأمراض خطورتها حسب 1.15 ملي مول/ل) ( من (أكثر الكثافة قليل ــحمي الش البروتني من ــتوى مس ــكر، وأقل بداء الس بغير املصابني ل) مقارنة 1.7 ملي مول/ من (أكثر .(p=0.0001) (1.15 ملي مول/ل (أقل من منخفضا عالي الكثافة ــحمى الش البروتني ــترول كوليس ــتوى مس كان فقط ــاء p=0.012) . وعند النس العينة %49 من ب ــة 1.2 جرام/ل) مقارن من (أكثر ب ــوع ن ميمٌ البروتيني الصَ ــن طبيعية م ــتويات غير مس ــكر الس بداء %57 من املصابني ــدى ل 42% في منخفضا الكثافة عالي ــحمي البروتني الش ــتوى ومس ، ب عالية البروتيني نوع ميمٌ والصَ ــريد الغليس ثُالَثِيُّ ــتويات مس كانت . الضابطة (p=0.008) خلطورة احصائيا عالية مستويات السكر بداء املصابني (p=0.05) . لدى الضابطة العينة %26 من مقارنة ب السكر بداء املصابني من ألكثر سنوات عشر مدى على االصابة خطر حرز مطابقني %34 من هؤالء atp iii ncep . ولكن مقياسحسب الوعائية القلب بأمراض االصابة االدوية باستعمال atp iii . نوصي تعليمات ــب حس الدم ــحوم ش في اضطراب ــكر الس بداء املصابني العمانيني من لدى الكثير اخلالصة: .10% من حسب ــنوات س ــر مدى عش على اخلطورة مقياس ــتعمل عندما نس عليه املتعارف من أقل ــتويات مس في االخيرة تكون عندما الدم ــحوم افضة لش فرامنجهام. الشحمي البروتني صميم الشحميات، عمان، ، السكري املفردات املفتاحية: مرض a l i i a l b a h r a n i , r i a d b ay o u m i a n d s a i d a a l -ya h ya e e 20 diabetes mellitus is a growing health problem in oman. according to the national omani survey carried out in 1991, the prevalence was 10% for type 2 diabetes and 13% for impaired glucose tolerance (igt).1 this study also showed that the prevalence of diabetes in oman rose with age and may exceed 50% in the seventh and eighth decade of life, in females and males respectively. recently, it was reported that the prevalence of diabetes in oman had increased over the past decade reaching 16.1% of the population aged 30-64 years old.2 furthermore, a cross-sectional random sample survey reported that approximately 20% of the population had high fasting plasma glucose.3 type 2 diabetes is associated with an increased risk for cardiovascular disease.4 this risk in part is due to diabetic dyslipidaemia.4,5 the report from national cholesterol educational program adult treatment panel iii (ncep atp iii) recognized the importance of early detection of diabetic dyslipidaemia. according to the atp-iii report, the presence of diabetes or of multiple risk factors with a 20% high 10-year risk for coronary artery disease (cad) events are now considered to be cad equivalents, requiring aggressive treatment as for established cad and other types of atherosclerotic diseases.5 atp iii had further endorsed the importance of including high density lipoprotein cholesterol (hdl-c) as part of their guidelines for assessing the risk of cad and had re-categorized some of the cut-off values of atherogenic lipoproteins. furthermore, ncep atp iii had recommended a scoring system based on the framingham risk equation using clinical and lipid data. thus, it helps to calculate the 10-year absolute cad risk i.e. the percentage probability of having a cad event in 10 years and to identify certain subjects with multiple (2+) risk factors for intensive treatment therefore, this study was aimed to determine the impact of the ncep atp-iii on omani subjects with type 2 diabetes in comparison with nondiabetic subjects r e s e a r c h d e s i g n a n d m e t h o d s pati e n t se l e c ti o n the study recruited 221 patients (86 females and 135 males) with type 2 diabetes and compared them with bmi and age matched 156 (70 females and 86 males) non-diabetic patients from patients attending diabetic and lipid clinics at the sultan qaboos university hospital, between 1999-2002. all the subjects diagnosed as type 2 diabetics fulfilled the world health organization criteria for diagnosis of type 2 diabetes mellitus either by an abnormal oral glucose tolerance test (ogtt), or two abnormal fasting blood glucose tests (>7.0 mmol/l). none of the diabetic subjects were on insulin or thiazolidinediones (tzds) therapy. 40% of the diabetic subjects were on dietary control and the rest on oral hypoglycaemic agents, as follows: glibenclamide (39%), glipizide (24%), gliclazide (6%), biguanides (13%, metformin) and combined therapy (10%). patients were excluded from the study if they had a myocardial infarction in the three months prior to entry to the study, or uncontrolled thyroid disease (hypo or hyperthyroidism), macro-proteinuria (positive urine protein dip-stick x2), severe hepatic impairment (known subject with chronic active liver disease or those individuals with obstructive liver pattern) or renal impairment (creatinine level >114 ųmol/l) and those on lipid modifying agents. this study was approved by the medical ethics and research committee at college of medicine and health sciences, sultan qaboos university and patients gave informed consent prior to the study. c l i n i c a l a n d l a b o r ato ry a s se s sme n t all subjects underwent a clinical physical examination and any abnormality was documented. the subjects’ blood pressure was measured to the nearest even digit using a sphygmomanometer, with the subject in the sitting position after a 5-10 minutes rest. subjects were labeled hypertensive if blood pressure was equal or greater than 140/90 mmhg on two repeated occasions or by 24 bp monitoring and those on anti-hypertensive therapy. bmi was calculated as weight (kg) divided by height (m2) and used as an index of adiposity. subjects were labeled cad if they had had a previous myocardial infarction or had a stable angina pectoris with positive thallium stress test or coronary angiogram or percutaneous coronary angioplasty (ptca). following a 10-hour overnight fast, blood samples were taken for measurement of hba1c, tc, tg, tg, triglycerides; apob, apolipoprotien b; apoa-, apolipoprotein a-; cad, coronary artery disease; ogtt; oral glucose tolerance test, ncep; national educational cholesterol program; atp iii, adult treatment panel iii; bmi, body mass index. l i p i d s r i s k c at e g o r i e s i n o m a n i t y p e 2 d i a b e t i c s 21 hdl-c, apoa-1, and apob. cholesterol, tg and glucose measurements were performed using timed endpoint enzymatic methods on the synchron cx system (beckman, brea, usa). the within-run and betweenrun precisions for cholesterol (4.3 mmol/l) were 3% and 4.5%, respectively; for tg (2.0 mmol/l) 3% and 4%, respectively; for glucose (5.5 mmol/l) 2 and 3%, respectively. hdl-c was determined using a timed-endpoint direct homogenous assay on the same system, with-run of 2.5% and between-run of 3% precisions for hdlc of 1.2 mmol/l. apoa-1 and apob were determined using rate nephelometric immunochemistry assay by the immage system (beckman). the within-run and between-run precision profiles for apob (1.2 g/l) were 2.5% and 2.9%, respectively; for apoa-1 (1.05 g/l) they were 3.4% and 3.9%, respectively. both the apob and apoa-1 methods used have been standardized according to the international federation of clinical chemistry.6 ldl-c was calculated using the friedtable 1 :the clinical and metabolic characteristics of subjects with type 2 diabetes compared to nondiabetic subjects non-diabetic subjects subjects with type 2 diabetes p value diabetic vs. non-diabetic women men both women men both number 70 86 156 86 135 221 age 48.3 (1.8) 45.7 (1.5) 46.6 (1.3) 47.8 (1.1) 49.5 (1.0) 47.9 (0.91) 0.30 bmi 31.2 (0.76) 31.3 (0.61) 31.2 (0.5) 30.2 (0.98) 30.9 (0.8) 30.2 (0.61) 0.45 tg (mmol/l) 1.29 (1.03-1.6) 1.41 (1.23-1.61) 1.36 (1.21-1.57) 1.77 (1.65-2.01) 1.86 (1.75-2.09) 1.82 (1.69-1.98) <0.0001 tc (mmol/l) 6.2 (0.21) 5.8 (0.15) 5.93 (0.11) 5.92 (0.18) 5.75 (0.14) 5.85 (0.11) 0.79 ldl-c (mmol/l) 4.10 (0.19) 4.2 (0.13) 4.2 (0.10) 3.8 (0.11) 3.6(0.12) 3.7 (0.09) 0.04 hdl-c (mmol/l) 1.47 (1.27-1.58) 1.19 (1.05-1.24) 1.24 (1.13-1.37) 1.17 (1.15-1.26) 1.10 (1.05-1.14) 1.12 (1.10-1.18) 0.10 apo b (g/l) 1.33 (0.05) 1.29 (0.04) 1.30 (0.03) 1.31(0.04) 1.23 (0.03) 1.25 (0.02) 0.53 apoa1 (g/l) 1.3 (0.04) 1.13 (0.02) 1.18 (0.02) 1.24 (0.04) 1.15 (0.02) 1.18 (0.02) 0.89 hypertension (%) 35 36 35 61 60 60 <0.0001 cad % 15 25 20 22 40.8 34 <0.0001 fasting glucose (mmol/l) 5.4 (0.12) 5.2 (0.11) 5.3 (01) 5.8 (0.22) 6.0 (0.21) 5.9 (0.2) 0.006 hba1c (%) 5.5 (0.05) 5.4 (0.06) 5.4 (0.05) 8.09 (0.3) 7.6 (0.22) 7.7 (0.16) <0.0001 ncep risk-score 9.8 (0.8) 8.1 (0.9) 8.7 (0.8) 11.2 (0.8) 10.8 (0.5) 10.98 (0.4) 0.008 data are number, means +/sem, 95% ci for log transformed variables and %. tg and hdl-c a l i i a l b a h r a n i , r i a d b ay o u m i a n d s a i d a a l -ya h ya e e 22 wald formula and was not calculated when tg level was >4.0 mmol/l. the department of biochemistry at the sultan qaboos university hospital is engaged in an external quality control scheme of the royal college of pathologists, association of clinical biochemistry, australia. the ncep atp iii (2001) guidelines were used to classify lipoproteins concentration into cad risk categories.5 the ldl-c levels were defined as low (<3.4 mmol/l), borderline (3.4-4.19 mmol/l), borderline-high (4.2-5.0 mmol/l), and high (>5.0 mmol/l) risk categories. the risk categories of hdl-c levels were defined as high (<1.05mmol/l), borderline (1.051.15 mmol/l), and low (>1.15 mmol/l). however, no gender cut-off value was used. as far triglycerides, the cut-off value of >1.7 mmol/l was used as borderlinehigh risk level. the borderline high risk categories for cut-off values were <1.2 g/l for apoa-1 and >1.2 g/l for apob. these cut-off values were selected from the framingham offspring study and the international federation of clinical chemistry guidelines.7 the 10year-risk for cad was determined using the framingham risk scoring system as recommended by the ncep atp iii descriptive analysis including the estimation of mean values and the sem for continuous variables were documented. prevalence and frequencies were expressed as percentages. skewed parameters were logarithmically transformed when a parametric test was used. categorical variables were compared by the χ2 statistic with the yates correction or the exact fisher test when appropriate. binary regression analysis was carried out to study the influences of diabetes and gender on the probability of having high-risk categories for cad for the different lipid and lipoprotein parameters, after adjustment of the other observational variables. anova was used to determine differences in subject characteristics. ρ value (two-tailed) <0.05 was considered as statistically significant. all data was analyzed with the spss. r e s u l t s a comparison of clinical parameters and the means of fasting lipid profile between diabetic and non-diabetic subjects showed that diabetics had significantly higher mean levels of tg (p<0.0001) and lower of hdl-c (for female gender only, p<0.0001) and ldl-c (p=0.04) [table 1]. using ncep-atpii cut-off values for high borderline and high risk categories [figure 1] indicated that 29% of diabetic subjects had significantly lower probability ldl -c> 4.2 mmol/l p value tg >1.7 mmol/l p value hdl-c <1.15 mmol/l p value apo b >1.2 g/l p value apo a-1 <1.2 g/l p value diabetic subjects vs. nondiabetic subjects 0.572 (0.357-0.918) 0.02 2.183 (1.344 -3.548) 0.002 1.334 (0.836 -2.181) 0.25 1.334 (0.776 -2.205) 0.31 1.205 (0.170 -2.023) 0.48 diabetic women vs. nondiabetic women 0.581 (0.259 -1.256) 0.15 2.520 (1.129 -5.627) 0.024 3.724 (1.458 -9.522) 0.006 1.529 (0.662 -3.760) 0.35 1.846 (0.752 -4.536) 0.18 diabetic women vs. diabetic men 2.472 (1.485 4.115) <0.0001 0.660 (0.357 -1.221) 0.18 1.052 (0.589 -1.945) 0.87 1.508 (0.780 -2.910) 0.22 0.718 (0.379 -1.377) 0.30 diabetic men vs. nondiabetic men 0.495 (0.265-0.926) 0.03 2.021 (1.096 -3.725) 0.024 0.860 (0.466 -1.586) 0.63 1.200 (0.631 -2.282) 0.57 0.978 (0.509 -1.879) 0.95 women vs. men 2.320 (1.440-3.745) 0.001 1.275 (0.819 -1.984) 0.28 0.468 (0.296 -0.742) 0.001 1.170 (0.746 -1.834) 0.49 0.658 (0.4170.989) 0.04 data are odd ratio (95% ci). adjusted for age, hba1c, and bmi table 2: logistic regression analysis examining the influence of diabetes and gender on the probability of having ldl-c, hdl –c, tg, apo b, and apo a-1 outside the recommended target l i p i d s r i s k c at e g o r i e s i n o m a n i t y p e 2 d i a b e t i c s 23 ldl-c level of (>4.2 mmol/l), compared to 43% of non-diabetic subjects ((p=0.012) ). on the other hand, 57% of diabetic subjects had abnormal apob of >1.2 g/l compared to 49% non-diabetic subjects. a significantly higher level (p=0.01) of tg (>1.7 mmol/l), was found in diabetic subjects (63%) compared to nondiabetic subjects (43%), irrespective of gender. the percentage of diabetic (56%) and non-diabetic (48%) subjects showed no significant difference on abnormal level of <1.15 mmol/l hdl-c when the same cut-off value was used for both genders as recommended by ncep atp iii guidelines. however, despite a significantly larger percentage of male subjects, compared to female subjects, who had an hdl-c levels of <1.15 mmol/l, (p=0.001), there was a significantly higher (p=0.05) percentage of female diabetic subjects with abnormally low hdl-c levels compared to nondiabetic subjects. borderline high-risk of apoa-1 1.0-1.2 g/l and high-risk of apoa-1 <0.9 g/l were detected in 60% of males compared to 48% of females subjects; such a difference was statistically significant (p=0.01). logistic regression analysis of the influence of type 2 diabetes and gender on the probability of having serum lipids that were outside the recommended targets adjusted for age, bmi and hba1c , showed that diabetic compared to non-diabetics subjects had a significantly higher likelihood ratio of having tg of >1.7 mmol/l and a lower likelihood ratio of having an abnormal, ldl-c of >4.2 mmol/l, irrespective of gender [table 2]. female diabetics had a significantly higher likelihood ratio of having an abnormal hdl-c level of <1.15 mmo/l compared to female non-diabetic subjects. furthermore, female subjects had a significantly higher likelihood ratio of having an ldl-c of combined dyslipidaemia non-diabetic(%) diabetic (%) ldl-c (>3.4 mmol/l) and tg (>1.7 mmol/l)* 24 34 tg (>1.7 mmol/l) and hdl-c (<1.15 mmol/l)* 23* 37* ldl-c (>3.4 mmol/l) and hdl-c (<1.15 mmol/l) 30 30 all the three 15 19 tg (>1.7 mmol/l) and apo b (>1.2 g/l) 27* 43* tg (>1.7 mmol/l), apo b (>1.2 g/l) and hdl-c (<1.15 mmol/l) 18 25 * statistically significant, p value = 0.04 table 3 :proportion of subjects having combined dyslipidemia, borderline-high risk categories for c ad, according to the ncep atp iii and the framingham offspring study figure 1: percentage of diabetic subjects with abnormal lipids and lipoproteins levels compared to non-diabetic subjects a l i i a l b a h r a n i , r i a d b ay o u m i a n d s a i d a a l -ya h ya e e 24 >4.2 mmol/l and a lower likelihood ratio of having an hdl-c of <1.15mmol/l and apoa-1 of <1.2 g/l compared to males. combined dyslipidaemia of two or more lipid abnormalities was observed in 89% of diabetic and 76% of non-diabetic subjects. combined raised levels of tg and apob and raised tg and low level of hdl-c was highly prevalent (p=0.05) among diabetic compared to non-diabetic subjects, [table 3]. omani subjects with type 2 diabetes had significantly higher (p=0.008) ncep risk-score compared to non-diabetics [table 1]. the framingham scoring divides subjects with multiple risk factors into those with 10-year-risk for cad of >20%, 10%-20%, and <10%. the percentage of diabetic subjects (34%) with a 10-year risk for cad of >10%-20% was significantly higher (p=0.05), compared to non-diabetics (24 %,). d i s c u s s i o n detection and treatment of dyslipidaemia are means of reducing the risk of cad associated with type 2 diabetes.4,8 when applying the recent guidelines released by ncep atp iii and the framingham offspring study to classify lipoprotein concentrations, a large proportion of studied omani diabetic subjects turned out to be dyslipidaemic. combined raised levels of apob, triglycerides and low levels of hdl-c were highly prevalent among omani diabetic subjects compared to non-diabetic subjects, despite the fact that the proportion of omani diabetic subjects with borderline-high and high-risk categories of ldl-c for cad was significantly lower compared to non-diabetic subjects. the ncep recommends an optimal goal of ldl cholesterol to be <2.6 mmol/l for diabetics.4 when using this clinical end point, a substantial percentage of the diabetics would require intervention and ongoing monitoring to ensure that the recommended ldl-c goal is reached and maintained. although the gender comparisons for hdl-c risk categories were statistically significant, female subjects with type 2 diabetes had a six to seven-fold increased likelihood of having high-risk category levels of hdl-c for cad compared to non-diabetics. this may explain why the protective effect of gender against cad is not evident in diabetic women. however, a similar proportion of males with borderline-high and high-risk categories was noticed in both diabetic and non-diabetic subjects. the latter finding could in part explain the high risk of cad among the males compared to the females. given the recent findings of the beneficial effect of increasing hdl-c levels, these data indicate that increasing this lipoprotein, along with lowering ldl-c levels, should be an important target for intervention among omani subjects irrespective of the diabetic status.9, 10 the 10-year absolute risk-score for cad was calculated for all subjects studied using the framingham risk-scoring equation. this study indicated that omani subjects with type 2 diabetes had significantly higher risk-score for cad compared to non-diabetics and were more significant among those diabetic subjects with established cad. however, only a small proportion of omani diabetic subjects showed a risk-score for cad of >20%. a similar finding was reported by durrington in 2001, who highlighted the above point and suggested an cad risk score of >15% over 10-year as a threshold for starting statin therapy.11 recognizing that diabetes confers a cardiovascular risk equivalent to that of established atherosclerotic disease, the atp iii set the same ldl-c target (<2.6 mmol/l) for diabetic patients and, therefore, recommended aggressive treatment with lipid lowering drugs to achieve this target. clinical trials have confirmed the benefits of ldl-c lowering as an effective primary prevention strategy for diabetic patients8,12 and recommended the use of statin without a particular threshold level of ldl-c as the sole arbiter of which patients with type 2 diabetes should receive statins. however, in many patients with diabetes and cardiovascular disease, it will be difficult to attain an ldl-c goal of <1.8 mmol/l since approximately 25% of patients will require more than two lipid-lowering drugs at maximal doses to attain this goal, assuming 100% tolerance of lipid-lowering medications.13 there remains an important opportunity to improve the quality of care for these high-risk patients if the management of dyslipidemia is set optimally to achieve guideline-recommended lipid targets14 , which may be achieved by the combination of drugs15 and/or rosuvastatin.16 indeed, an economic simulation model suggested that increasing the use of rosuvastatin can result in cardiovascular event reduction and cost savings.17 this implies that our diabetic patients who have high prevalence of dyslipidemia, but low calculated cad risk, may benefit substantially from earlier intervention and therefore be prevented from having cardiovascular events. l i p i d s r i s k c at e g o r i e s i n o m a n i t y p e 2 d i a b e t i c s 25 a c k n ow l e d ge me n t we would like to thank dr. ali al-hinai, consultant cardiologist, for his support in patients recruitment and the finncial support by sultan qaboos university grant; ig/med/bioc/00/0 r e f e r e n c e s 1. asfour mg, lambourne a, soliman a, et al. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman: results of the 1991 national survey. diabet med 1995; 12:1122-1125. 2. al-lawati a, riyami a, mohammed a, jousihati p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954-957 3. al-lawati ja, mohammed aj, al-hinai hq, jousilahti p. prevalence of the metabolic syndrome among omani adults. diabetes care 2003; 26:1781-1785 4. american diabetic association. standards of medical care for patients with diabetes mellitus. diabetes care 2003; 26:s33-s50 5. third report of the expert panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel iii). jama 2001; 285:24862497 6. jungner i, marcovina sm, walldius g, holme i, kolar w, steiner e l. apolipoprotein b and a-1 values in 127,576 swedish males and females, standardized according to the world organization–international federation of clinical chemistry first international reference materials. clin chem 1998; 44:1641-1649 7. contois jh, mcnamara jr, lammi-keefe cj, wilson pw, massov t, schaefer ej. reference intervals for plasma apolipoprotein b determined with a standardized commercial immunoturbidimetric assay: results from the framingham offspring study. clin chem 1996; 42:515-523. 8. collins r, armitage j, parish s, sleigh p, peto r. heart protection study collaborative group. mrc/bhf heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. lancet 2003; 361:2005-2016. . 9. haim m, benderly m, brunner d, behar s, graff e, reicher-reiss h, et al. elevated serum triglyceride levels and long-term mortality in patients with coronary heart disease: the bezafibrate infarction prevention (bip) registry. circulation 1999; 100:475-482. 10. rubins hb, robins sj, collins d, fye cl, anderson jw, elam mb et al. gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol interventional trial study group. n engl j med 1999; 341:410-18. 11. durrington p. calculation of coronary risk in type ii diabetes. clinical science 2001; 101:681-682. 12. colhoun hm, betteridge dj, durrington pn, et al. primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (cards): multicentre randomised placebo-controlled trial. lancet 2004; 364:685-696. 13. kennedy ag, maclean cd, littenberg b, ades pa, pinckney rg. the challenge of achieving national cholesterol goals in patients with diabetes. diabetes care 2005; 28:1029-1034. 14. yan at, yan rt, tan m, hackam dg, leblanc kl, kertland h, et al. vascular protection (vp) and guidelines oriented approach to lipid lowering (goall) registries investigators. contemporary management of dyslipidemia in high-risk patients: targets still not met. am j med 2006; 119:676-683. 15. carmena r. type 2 diabetes, dyslipidemia, and vascular risk: rationale and evidence for correcting the lipid imbalance. am heart j 2005; 150:859-870. 16. guthrie rm. rising to the challenge of treating highrisk patients. am j manag care 2006; 12:s318-s324. 17. huse dm, song x, ozminkowski rj, et al. impact of rosuvastatin use on costs and outcomes in patients at high risk for cardiovascular disease in us managed care and medicare populations: a data analysis. clin ther 2006; 28:1425-1442. 1 submitted 28 feb 23 1 accepted 28 mar 23 2 online-first: march 2023 3 doi: https://doi.org/10.18295/squmj.3.2023.017 4 5 re: leukocytoclastic vasculitis 6 a peculiar presentation of scrub typhus 7 8 dear editor, 9 we read with interest the recent report of vasireddy a et al. about 10 leukocytoclastic vasculitis (lv) associated with a scrub typhus infection affecting a 28-11 year-old male, who presented with multiple, palpable purpuric eruptions mainly on the 12 lower extremities.1 the routine laboratory determinations were unremarkable, and blood 13 specific tests for autoimmune disorders, as well as malaria and bacterial and viral 14 infections were negative; except for the weil felix test that was positive with a titer over 15 than 1:640 against oxk. biopsy study of skin lesion showed the dermis with vasculo-16 centric infiltrate, and vessel walls with fibrinoid necrosis and dense infiltration by 17 neutrophils, and leukocytoclasis. the final confirmed diagnosis was of lv, an 18 uncommon manifestation of the orientia tsutsugamushi infection, which is a zoonosis 19 naturally transmitted by mite bites. undergoing antimicrobial schedule of doxycycline, 20 the patient improved in three weeks.1 in fact, the authors emphasized the major 21 infectious causes of leukocytoclastic vasculitis; but in the current global scenario one 22 could include covid-19 among the etiologies.2-5 23 24 capoferri g et al.2 described a 93-year-old man who had covid-19 infection 25 and 8 days later presented lv evolving with extensive skin necrosis in the lower 26 extremities. the lesions were erythematous and purpuric macules, hemorrhagic papules, 27 and blisters. skin biopsy study revealed the classic features of lv that was treated with 28 corticosteroids. he evolved with dry gangrene of both legs and feet and declined the 29 amputations; being discharged one month later, he died seven weeks after the initial 30 diagnosis of covid-19. the unfavorable evolution at least in part was due risk factors 31 including older age, arterial hypertension, peripheral artery disease, and a heterozygous 32 factor v leiden mutation2 corrà a et al.3 reviewed 19 cases with histological 33 2 confirmation of lv, 68.4% males, median age of 48.4 (13-93) years; 3 patients had 34 diagnosis of iga vasculitis, 5 had diagnosis of urticarial vasculitis, and the 11 others 35 were considered as lv. palpable purpura (with or without necrosis and hemorrhagic 36 blistering) was the predominant manifestation; and the commonest affected areas were 37 the lower limbs and the trunk.3 the span of time from the covid-19 infection to the 38 appearance of the skin rash ranged from concomitant until more than 30 days after the 39 first positive nasopharyngeal swab. worthy of note, the sars-cov-2 was found in the 40 vessel wall in 3 cases by pcr technique, supporting the direct virus role in the 41 pathogenesis of cutaneous vasculitis.3 after vaccination, 39 cases had vasculitis, 61.5% 42 women, mean age of 53.2 (22-94) years; the predominant manifestation was purpuric 43 papules or maculae in the lower extremities. direct immunofluorescence was not cited 44 in 21 cases, and in 5 was negative; among the remaining 13 cases, 5 cases were of iga 45 vasculitis and 3 of vasculitis with c3 deposition.3 kutlu ö et al.4 compared 198 people 46 (111 patients with covid-19 and 87 age and sex-matched patients with other diseases) 47 regarding the common dermatologic comorbidities. in covid-19 group, the most 48 common entities were pruritus (8.1%), eczema (6.3%), infections (3.6%), lv (1.8%), 49 and urticaria (0.9%); while in control group were infections (9.2%), eczema (3.4%), 50 pruritus (2.3%), urticaria (1.1%), and none of patients had lv; the findings showed that 51 pruritus and lv are more common in severe covid-19 cases.4 the authors also 52 emphasized the pathogenic mechanism of th1 cells hyperactivation to produce il 6, il 53 2, and tnf‐α is a major cause of death in severe covid‐19 cases.4 wong k et al.5 54 reviewed 9 cases of vasculitis secondary to covid-19, with mean age of 29.17 ± 28.2 55 years, age range from 6 months to 83 years, and male to female ratio of 4:5. most 56 common lesions were maculopapular, violaceous, popular, and erythematous rash. the 57 patients utilized heparin (n = 2), methylprednisolone (n = 6), and intravenous 58 immunoglobulin (n = 4); and significant improvement was obtained in 89% of patients. 59 a 7-year-old patient who died due to hypoxia was the unique death in the studied group. 60 61 the high-quality report of vasireddy a et al. is really very useful, including for 62 physicians out of the “tsutsugamushi triangle” who can have diagnostic challenges to 63 care of infected travelers. nevertheless, the current pandemic may be also included in 64 the roll of the lv differential diagnosis, because an earliest diagnosis will allow better 65 outcomes. we strongly believe that descriptions of case studies may enhance the 66 3 suspicion index about uncommon conditions, which favors prompt diagnosis and 67 adequate management. 68 69 authors’ contribution 70 vms and tams drafted the manuscript. vms and tams reviewed the literature and 71 performed the critical revision of the manuscript. all authors approved the final version 72 of the manuscript. 73 74 *vitorino m. dos santos1 and taciana a.m. sugai2 75 1department of internal medicine, armed forces hospital, and catholic university of 76 brasília, brasília, brazil; 2department of neurophysiology, american society of 77 neurophysiology, brasília, brazil 78 *corresponding author’s e-mail: vitorinomodesto@gmail.com 79 80 references 81 1. vasireddy a, pai k, shetty vm, acharya rv, kusugodlu r, doddamani a, et al. 82 leukocytoclastic vasculitis: a peculiar presentation of scrub typhus. sultan qaboos 83 univ med j. 2023; 23(1):109-12. doi: 10.18295/squmj.1.2022.011. 84 2. capoferri g, daikeler t, mühleisen b, trendelenburg m, müller s. cutaneous 85 leukocytoclastic vasculitis secondary to covid-19 infection leading to extensive skin 86 necrosis. clin dermatol. 2022; 40(4):397-401. doi: 10.1016/j.clindermatol.2022.02.013. 87 3. corrà a, verdelli a, mariotti eb, ruffo di calabria v, quintarelli l, aimo c, et al. 88 cutaneous vasculitis: lessons from covid-19 and covid-19 vaccination. front med 89 (lausanne). 2022 dec 9;9:1013846. doi: 10.3389/fmed.2022.1013846. 90 4. kutlu ö, öğüt nd, erbağcı e, metin a. dermatologic comorbidities of the patients 91 with severe covid-19: a case-control study. dermatol ther. 2021; 34(1):e14731. doi: 92 10.1111/dth.14731. 93 5. wong k, farooq alam shah mu, khurshid m, ullah i, tahir mj, yousaf z. covid-94 19 associated vasculitis: a systematic review of case reports and case series. ann med 95 surg (lon 96 mailto:vitorinomodesto@gmail.com january 2007 vol 7 correct a.indd behçet’s disease bilateral pulmonary arterial aneurysms presenting as pulmonary embolism rajeev jain1, samir s hussein1, *sukhpal sawhney1 بهجت مرض رئوي انصمام شكل على الظاهر الرئويني الشريانني في ام الدم sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© m e d i c a l i m a g e 1department of department of radiology and molecular imaging, sultan qaboos university hospital, p. o. box 35, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: sukh@squ.edu.om figure 1: perfusion lung scintigraphy with 99mtc-maa.multiple segmental defects in both lungs. high probability of pulmonary embolism) r a j e e v j a i n , s a m i r s h u s s e i n , s u k h pa l s aw h n e y 92 figure 2: maximum intensity projection (mip) of contrast-enhanced magnetic resonance angiogram of the pulmonary arteries shows multiple aneurysms (open arrows) of the right pulmonary arterial branches and a branch of the left inferior pulmonary artery a 30 years old soldier presented with a three-year history of recurrent oral ulcers and stomatitis, recurrent lobar pneumonias with hemoptysis, intermittent fever and weight loss. c o m m e n t pulmonary artery aneurysms associated with pulmonary artery thromboses are characteristic features of behçet’s disease.1,2 pulmonary artery aneurysm formation has a very poor prognosis,3 and death typically results from the rupture of aneurysms and massive hemoptysis.4 r e f e r e n c e s 1. ahn jm, im jg, ryoo jw, et al. thoracic manifestations of bechet syndrome: radiographic and ct findings in nine patients. radiology 1995; 194:199-203. 2. winer-muram ht, headley as, menke p, eltorky m. radiologic manifestations of thoracic vascular bechet’s disease in african-american men. j thorac imaging 1994; 9:176-179. 3. erkan f, gul a, tasali e. pulmonary manifestations of bechet’s disease. thorax 2001; 56:572-578. 4. durieux p, bletry o, huchon g, wechsler b, chretien j, godeau p. multiple pulmonary arterial aneurysms in bechet’s disease and hughes-stovin syndrome. am j med 1981; 71:736-741. december 2007 vol 8 after meeting.indd evidence-based pediatric oncology author: ross pinkerton, ag shankar and katherine matthay reviewer: *yasser wali sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 279-280 sultan qaboos university© submitted 12th august 2007 this is the second edition of the book. pediatric oncology refers to the study of childhood cancer. this book gives details on many aspects of pediatric oncology and the recent advances that have occurred on clinical levels. the aim of this book is to summarise the information that is available from randomised clinical trials in childhood cancer. this book has 565 pages. it consists of an introduction, main contents and an index. it has three major parts divided into 28 chapters as follows: part 1 solid tumours: this part has 10 chapters and is edited by dr. ross pinkerton. it deals with the most common solid tumours in childhood namely, rhabdomyosarcoma, osteosarcoma, ewing’s sarcoma, wilm’s tumour, neuroblastoma, hepatoblastoma, medulloblastoma, glioma, non-hodgkin’s lymphoma and hodgkin’s disease. in each of these chapters there is a review of the background of the disease, most popular clinical trials and studies, lessons from these trials, their outcome and a conclusion. part 2 leukemia: this part has 6 chapters: three on acute myeloid leukemia, its different stages of treatment and the best available evidence; the other three chapters deal with acute lymphoblastic leukemia, induction treatment, central nervous system prophylaxis and continuation therapy. part 3 supportive care in pediatric oncology: the authors focus in this part on the use of hematopoietic colony stimulating factors, g-csf (granulocyte colony stimulating factor); gm-csf (granulocyte monocyte colony stimulating factor) and erythropietin to avoid the severe effects of bone marrow suppression secondary to chemotherapy. they discuss 14 different randomized studies on g-csf, four on gm-csf and another four on the use of erythropoietin. these studies emphasise the importance of these agents in improving quality of life during intensive chemotherapy; however, most of them do not show any evidence of improving survival. the other chapter of this part describes the most recent cardio-protective agent against cardiotoxic chemotherapeutic drugs (e.g. anthracyclins). it focuses mainly on a new drug called dexrazoxane (dxn). they conclude from two large randomized studies that dxn is cardio-protective and does not adversely affect chemotherapy response or chemotherapy tolerability. i recommend this book for postgraduate pediatricians dealing with oncology patients and suspect it might also prove valuable for many more senior doctors. the book is very appropriate for both junior and b o o k r e v i e w الدليل على املبني األطفال سرطان علم ماثاي كاثرين أ.ج، شانكار بينكرتون، �احملررون: روس مراجعة: ياسر والي blackwell publishing ltd., bmj books, second edition 2007 first published 2002 isbn: 978-1-4051-42687 available from www.blackwellpublishing.com *department of child health, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman email: yawali@squ.edu.om b o o k r e v i e w : e v i d e n c e b a s e d p e d i at r i c o n c o l o g y 280 senior pediatricians specialised in the field of oncology. the contents are presented in an attractive way with evidence from the latest clinical trials. the book provides good material for readers to get up-to-date with the latest clinical trials in the field of pediatric oncology. it covers topics of solid tumours, leukemia and supportive care. the contents of this book are presented in an interesting way starting with comments from an authority in the field about the issue under discussion, followed by the results of the most up-to-date large randomized clinical trails in this subject. the conclusions of these studies are stated very clearly at the end of each study. q ua l i t y o f c o n te n t the information given is up-to-date and is presented in a simple and easy to understand manner. su g ge sti o n s this book reviews only the latest clinical trials in the filed of pediatric oncology. the details of these diseases were beyond the scope of this book. the authors commented briefly and generally on the diseases and the latest clinical trials for their treatment protocols only at the beginning of each main part of the book. however, there were no specific comments or authors’ views on the different conclusions of these clinical trials. these comments would have been very valuable to the reader, particularly in the diseases or areas where more than 20 clinical studies were presented with different opinions, outcomes and conclusions. whole1.indd abstract a revolution in thinking and redefinition of traditional scholarship by prioritising teaching skills and achievements has led to the birth of the teaching portfolio, designed to carry a comprehensive and dynamic record of the teaching activities of the faculty. a teaching portfolio documents the faculty’s teaching scholarship and effectiveness. it is a record of selected information on one’s teaching achievements, skills and strategies and dynamically represents the faculty’s growth, progress and teaching record. the author suggests a template for the teaching portfolio of a medical educator, which consists of four parts: () evaluation, (2) personal professional development, (3) learning processes and (4) an appendix. the medical educator teaching portfolio its compilation and potential utility *neela lamki1, mark marchand2 sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© in recent years, the three pillars of aca-demic medicine, patient care, research and teach-ing, have undergone a revolution resulting in many changes, chief among these being a potential equalisation between the three. there is now new weighting for the educational component in faculty promotion. until recently, research carried a disproportionately higher credit than teaching or patient care. a corollary product of this revolution has been the emergence of new faculty positions such as clinician-educators in various medical schools. these new positions were created to retain valuable clinical teachers, thereby propagating medical education.1 in 1997, the association of american medical colleges (aamc) conducted a survey that showed nearly 75% of medical schools in the us have separate promotion tracks for faculty whose primary responsibilities lie in teaching and in patient care.2 these new tracks have aided medical education resulting in better recognition of the value of medical education, more faculty dedicating their lives to careers in academia, and increased numbers of innovations in medical education.3 evaluation of the performance of these faculty has become an area of much debate. in consideration for faculty appointment and promotion, the classic criteria of scholarship in original research and discovery is now significantly modified. schools are now relying more on an expanded definition of scholarship defined by boyer, namely the scholarship of integration, application, and teaching in addition to the classical scholarship of discovery.4 through this expanded view of scholarship, medical schools have developed new criteria for evaluating faculty that serve as clinician-educators.3,5 medical schools have realized that a typical curriculum vitae (cv) as based on classical guidelines is heavily weighted towards the traditional definition of 1department of radiology, college of medicine and health sciences, p.o box 35, al-khod, muscat 123, sultanate of oman. 2formerly medical student, baylor college of medicine; currently radiology resident at university of new mexico, usa. *to whom correspondence should be addressed. email: : neela@squ.edu.om r e v i e w الطبي املعلم ملف استعماله وإمكانيات وتصنيفه جمعه امللف والدة إلى قادت التعليمية، واألهداف للمهارات األولويات بوضع وذلك التقليدي، التعليم تعريف وإعادة التفكير في ثورة هناك امللخص: ونشاطات الطبي يوثق فعاليات املعلم ملف التدريسية. الهيئة عضو بها يقوم التي الفعاليات لكل وحركيا كامال يكون لكي صمم التعليمي الذي وهو واستراتيجيته إجنازات تعليمية، وكذلك مهاراته من به ذلك العضو ملا يقوم ملعلومات مختارة تسجيل عن عبارة وهو التدريسية، الهيئة عضو أقسام: (١) من أربعة يتكون التدريس، والذي هيئة لعضو التعليمي معني للملف منط يقترح املقال كاتب علمية. وإجنازات من تطور به يقوم ميثل ما امللحق. (٤) و التعليمية الطرق (٣) الشخصي، املهني التطور (٢) التقييم، scholarship. most of the space in a typical cv is devoted to the faculty’s accomplishment in research and service to the institution with minimal devotion to teaching efforts and achievement. therefore, the revolution, incorporating the concept of a teaching portfolios, was born. this has now become synonymous with the evaluation of clinician-educators. the small section on education in the traditional cv has now matured to a separate teaching portfolio. when harvard medical school created their clinician-educator track in the late 1980s, they required the faculty to develop a teaching portfolio before they could be considered for promotion.3 mchugh, a former chairman of the professional promotion committee at john’s hopkins medical school, writes, “the major hindrance to promotion is vagueness about the career achievement of the candidate”.6 he continues to state that “the most problematic” faculty on the clinician-educator track are those who have not created a document that can show their accomplishments. a teaching portfolio is such a document, a collection meant to convey the quality and quantity of a faculty’s teaching effort, effectiveness and achievements. it is an example of what the 1997 acme-tri report meant, when it called for “administrative mechanisms to document teaching accomplishments”.7 there is no consensus as to what such a portfolio should contain. there are several diverse ideas in the literature. we set forth in this paper suggestions to create a holistic medical educator teaching portfolio (metp) that includes not only materials necessary for evaluation for faculty promotion, but also those to aid the educator in improving his/her own teaching skills through reflection and continued learning. further, we discuss the potential uses of a metp in appointment and promotion as well as concerns related to such portfolios. c o n t e n t s o f a t e a c h i n g p o r t f o l i o we are proposing a template for a teaching portfolio for medical educators based on components of several models created at various medical schools and institutions of higher learning. the contents of this metp are based on an extensive review of the literature, including a 1996 survey conducted by beasley and colleagues regarding what criteria medical schools and their faculty promotions and tenure committees use in the evaluation of clinician-educators for promotion.1,3,5–11 we also address the concerns of the critics of such portfolios as voiced in the literature or at national forums. we propose that an metp be divided into four parts: (1) evaluation, (2) personal professional development, (3) learning processes and (4) appendix [table 1]. part 1. evaluation the evaluation part of the metp is suggested to be divided into four major categories in accordance with the responsibilities of clinician-educators: (i) teaching, (ii) clinical, (iii) administrative, and (iv) educational development. these form the main body of the metp. this portion should contain cv-like entries, summaries of data, and brief narrative accounts.12 this should include teaching responsibilities and experience, evaluations by one’s students, mentees, audience and peers, and details of preceptorship and directorship of a thesis or dissertation and service to student/faculty committees. where applicable, these entries should be succinct, yet supported by reference to the appendix section that should contain concrete examples of the individual’s achievement, such as curriculum/syllabus development, lecture notes, tests prepared, and evaluations7 described above. for instance, a summary of student evaluations of the faculty can be included within the body of the metp, and then referenced to copies of the actual evaluations in the appendix. the body of the metp therefore provides a succinct review of the objective data found in the appendix, allowing reviewers fast access to a variety of information. together, these components can be used to evaluate clinician-educators for new jobs, promotion, merit pay, teaching awards, and funding for projects/grants.10 they also have a variety of other potential uses due to their much greater detail and clarity than obtainable from a cv. part 2. personal professional development in this second part of the metp, the faculty member gets the opportunity to document the complete circle of his or her education, philosophy, goals/objectives, lectures/conferences, tests/examinations and results/ outcome. for example, this part should include a personal statement prepared by the faculty regarding his/ her philosophy on medical education, goals/objectives, and strengths and weaknesses7— an overview of his/her interest in medical education and the goals for future involvement in medical education and its 8 n e e l a l a m k i , m a r k m a r c h a n d importance in his/her career plans. here the faculty can expand reflection on how his or her philosophy of teaching correlates with the objective contents available in the metp. the faculty can show relationship of lectures and talks delivered to results of tests and examinations and to final outcome. if the faculty is a member of thesis or advisory committees for ms or phd, the outcome and successes of the candidate are recorded here. preceptorship outcomes are another good example part ii records. table 1. contents of a medical educator’s teaching portfolio part i evaluation 1. teaching awards received list of courses taught (hours, # and types of students, # of years taught) formal presentations (lectures, cme, reviews, grand rounds) invited lectures/seminars & type of audience objective criteria (e.g. student scores) evaluation summaries (e.g. by peers, students) 2. clinical awards received objective measures (# of hours, # of students, # of patients,) clinical service with house staff (# months in attending/consulting-duty) clinical leadership roles preceptorship and a list of students certification/re-certification examination results cme credits accumulated activities that develop the doctors’ clinical skills letters of recommendation from colleagues evaluation summaries (by patients, nurses, students, residents, referring doctors, peers) evaluation by department chairperson 3. administrative national / international peer-reviewed awards education committee involvement/position (& comments by the committee) office held in academic societies (regional, national & international) study groups membership (e.g. nih & other granting agencies) director of a thesis or dissertation member of thesis or advisory committee for ms or phd student directorship of courses (for medical students, residents, fellows) chairmen duties (task forces, societies) association with student organization or student-faculty committee visiting professorships peer reviewed committee letter recruitment of talent (by schools) assistant/associate dean of education position held role model/mentor responsibilities (students, residents, fellows, junior faculty) evaluations from mentees, junior faculty, etc. 4. educational development curriculum and syllabus number developed publications related to a curriculum/syllabus curriculum innovations presentation of a curriculum at a national meeting number of learners exposed to the curriculum/usage statistics evaluation of a curriculum (by students, peers, editorial review) course syllabi evaluations (by learners) journal publications grant support teaching materials published (and reference) number of peer reviewed publications (and reference) publication impact (determined via: citation index) enduring educational material book chapters review articles teaching aids for students and residents patient education materials videotapes cd roms computer software web-based teaching materials lecture handouts examinations / tests evaluations and reviews of materials produced other service to or position on editorial boards presentation of an abstract/poster/exhibit at a national meeting development of a workshop for a national meeting reviewer of medical education grants/papers/exhibits examiner for peers (e.g. american board of radiology, royal colleges) medical education journal club oral presentations part ii personal professional development philosophy of education long-term goals/objectives to attain them results/outcome of examination/tests of mentees & students positions achieved by students, mentees & trainees self-assessment (strengths/weaknesses) part iii learning process areas of needed professional growth record of queries & answers; problems & solutions methods of attaining growth record of past growth 9 th e m e d i c a l e d u c at o r te a c h i n g p o r t f o l i o record of achievements cme classes/activities part iv the appendix (attachments) tests/examinations curriculum lecture notes/handouts examples of students’ work evaluations from various sources journal articles enduring educational material by striving for consistency across all components of the metp (philosophy-goals-objectives-lecturestests-outcomes), clinician-educators can help ensure the entire spectrum of their teaching is congruent. the metp needs to be objective and concise, with ample evidence that the philosophy is matched by the outcomes. pa rt 3 . th e l e a r n i n g pr o c e s s this part should include components pertaining to areas of professional growth specifically needed by the faculty; methods of attaining growth and a record of past growth.13 by documenting queries and their answers, problems and their solutions, etc., the faculty can add structure to the account of their journey of continuing education. this section can serve as an assessment tool for what needs to be learned by the faculty, a planning tool for how to go about this learning and a historical record of what has been learned13 as well as the path to this achievement. such a process forces physicians to become active participants in their continuing education, rather than passive lecture-goers. mathers and colleagues found that portfolios are an effective and efficient means of pursuing continuing medical education.14 in future, computer and telecommunication technology might allow physicians to fulfil cme requirements through self-directed learning documented in online learning portfolios.15 metp is an effective way of documenting and continuously updating all this. c o l l e c t i n g d a t a the process of creating an metp is one that is best undertaken with the assistance of a mentor.10 this is particularly true for junior faculty, but helpful for all. such a relationship can help ensure that the resulting metp is as objective as possible. furthermore, such a partnership would help foster standardization across the institution. as an alternative to mentorship, workshops could be conducted to introduce faculty to the process of creating an metp.3 the very process of assembling an metp fosters improved teaching through reflection on the contents.10 seldin writes that the very act of creating a portfolio causes faculty to reevaluate their teaching activities and change them to increase their teaching effectiveness.16 it acts as a tool of self-improvement for the medical educator. beecher and colleagues determined that 100% of faculty in their study “reflected” on education as a result of composing a portfolio.17 ideally, educators would improve their teaching efficacy by developing their metp via critical writing on a regular basis. meticulous care should be taken in acquisition of data for all the three parts of metp. there needs to be an accurate record of lectures/conferences given, workshops delivered or attended and also evaluations by students and audience. evidence of quality of teaching is extremely important. in addition, it should contain a record of role as preceptor. this includes evaluations by students, mentees, peers, course director, department heads etc., as well as test scores, national and local. evidence of quality of teaching is also provided by the progress of the medical students, residents and other students that the faculty taught or was a preceptor to, as well as any junior faculty mentored. in addition, the positions achieved by mentees and trainees of the faculty should be recorded. innovation in teaching is often reflected by international, national and local recognitions and awards received. d i s c u s s i o n despite the merits of an metp, there are many detractors of such an assessment tool. a recurring theme highlights the subjective, rather than objective, nature of portfolios filled with “selected details” as opposed to hard data.5,10,18 there is obvious truth in this statement; however, there are several ways to increase the objectivity of an metp. first, the aforementioned mentor would serve to oversee the process and help ensure that the resulting metp reflects the clinicianeducator’s entire teaching efforts.10 secondly, the appendix should be filled with hard evidence in the form of evaluations, examples of teaching material created, and the students’ accomplishment of stated objectives (e.g.. scores on national board examinations, achievements of physicians/scientists mentored by the n e e l a l a m k i , m a r k m a r c h a n d 10 faculty,7 results of public education, etc. the evidence in the appendix should support the individuals stated philosophy on education, from the goals to the outcome with inclusion of all the intermediary steps. in 1999, pitts and colleagues conducted a smallscale study to determine the reliability of the assessment of portfolios by general practitioners.19 they found the assessors to have moderate consistency within their own assessments, but the reliability between assessors to be less than adequate. the most commonly expressed hindrance to their assessment was the “individuality” of the portfolios rendering them hard to compare. others have reported concern over the assessment of “non-standardised” material and the labour-intensive nature of such an endeavour.18 we believe these factors can be solved in part by standardisation of the metp across an institution and eventually across the country. each institution must create their own metp template. harvard medical school reports that “standardization of criteria [for teaching portfolios] did much to objectify and enhance confidence in the [clinician-educator] track”.3 furthermore, as the numbers of faculty evaluated via portfolios increase, the promotion committees’ ability to assess them accurately, reliably, and expeditiously assess them will improve. further, beasley and colleagues voice concerns over the use of an “indirect measure” (i.e. metp) replacing the more first-hand method of direct observation.8 we agree with such a concern and we do not believe that the metp can take the place of direct observation of classroom teaching or video review, but rather that it should be used as an adjunct in a complete assessment of all of the clinician-educator’s activities. some educators have voiced concerns over the criteria for promotion of clinician-educators. the concern refers to the traditional requirement of “research experience” and discovery, peer-reviewed articles and national or international reputation.8,9,20 in spending time developing original articles and cultivating a national reputation, clinician-educators are liable to neglect their primary responsibilities, namely, patient care and teaching.20 despite the development of clinician-educator tracks and discussion of the need to use an expanded definition of scholarship in their evaluation, many schools continue to require peer reviewed original publications in reputable journals.2,3,8,20 we wish to raise awareness of this concern and ask the promotion committees to revisit, reevaluate and reconsider the activities that are most important for this faculty. it is indeed already happening in a few centres in the usa and canada. in canada, the teaching portfolio is referred to as “educators dossier”.21 c o n c l u s i o n the portfolio described is meant to be a complete account of a teacher’s thoughts, activities, and successes —a dynamic collection that is never finished, but rather actively supplemented. in its fullest capacity, a metp can be used for evaluation, reflection, continued learning and, of paramount importance, improved teaching. compiled with the aid of a mentor and with a well-referenced appendix, the metp becomes a more objective measure of an educator’s value. such an assessment tool is not meant to be used alone, but rather in conjunction with other established methods including the standard cv and direct observation where possible. as portfolios become standardized, their value and ease of use increases. each institution must create its own template that the faculty can use in the creation of his/her metp. we offer in this article an example that can be used as a step toward developing a standardized template for medical institutions. potentially it could be a stimulant or a future model for an improved universally acceptable medical educator’s teaching portfolio. acknowledgements many thanks go to becky baxter and lori burlin for their secretarial assistance in the preparation of this manuscript. also many thanks go to dr. lamk lamki (dr. neela’s husband) for his inspiration, guidance and untiring support in the preparation and editing of this paper. r e f e r e n c e s . bickel j. the changing faces of promotion and tenure at u.s medical schools. acad med 99; 66:249–256. 2. jones rf, gold js. faculty appointment and tenure policies in medical schools: a 997 status report. acad med 998; 73: 22–29. 3. lovejoy f. a promotion ladder for teachers at harvard medical school: experience and challenges. acad med 995; 70: 079–086. 4. boyer e. scholarships reconsidered: priorities of the professoriate. san francisco, ca: carnegie foundation for the advancement of teaching, 990. 5. carey rm, wheby ms, reynolds re. evaluating faculty clinical experience in the academic health th e m e d i c a l e d u c at o r te a c h i n g p o r t f o l i o 11 sciences center. acad med 993; 68: 83–87. 6. mchugh pa. “letter of experience” about faculty promotion in medical schools. acad med 994; 69: 877–88. 7. simpson d, morzinski j, beecher a, lindemann. meeting the challenge to document teaching accomplishments: the educator’s portfolio teach and learn in med 994; 6: 203–206. 8. beasley bw ws, cofrancesco j, babbott sf, thomas pa, bass eb. promotion criteria from clinician-educators in the united states and canada: a survey of promotion committee chairpersons. jama 997; 278: 723–728. 9. lubitz r. guidelines for promotion of clinicianeducators. j gen intern med 997; 2:57–577. 0. zubizarreta j. teaching portfolios: an effective strategy for faculty development in occupational therapy. am j ot 998; 53: 5–55. . collins j, smith wl. promotion based on teaching efforts requires ongoing documentation of scholarly teaching activities. acad radiol 200; 8: 77–776. 2. lindemann jc ba, morzinski, ja, simpson, de. translating family medicine’s educational expertise into academic success. fam med 995; 27: 306– 309. 3. crist p, wilcox bl, mccarron k. transitional portfolios: orchestrating our professional competence. am j ot 998; 52: 729–736. 4. mathers nj cm, howe ac, field nj. portfolios in continuing medical education – effective and efficient? med educ 999; 33:52–530. 5. parboosingh j. learning portfolios: potential to assist health professionals with self-directed learning. j cont educ in health prof 996; 6: 75–8. 6. seldin p. successful use of teaching portfolios. boston: anker publ co, 993. 7. beecher a, lindemann jc, morzinski ja, simpson de. use of the educator’s portfolio to stimulate reflective practice among medical educators. teach and learn in med 997; 9: 56–59. 8. snadden d. portfolios – attempting to measure the unmeasurable? med educ 999; 33: 478–479. 9. pitts j, coles c, thomas p. educational portfolios in the assessment of general practice trainers: reliability of assessors. med educ 999; 33: 55–520. 20. levinson w, rubenstein a. mission critical – integrating clinician-educators into academic medical centers. n engl j med 999; 34: 840–843. 2. university of toronto – “the department of medicine education dossier”. (internal correspondence). n e e l a l a m k i , m a r k m a r c h a n d 12 march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 84-88, epub 16th mar 2009 submitted 28st june 08 revision req. 19th aug 08, revision recd. 26th aug 08, accepted 13th sept 08 abstract sigmoid volvulus is an extremely rare cause of intestinal obstruction in pregnancy. the rarity of the condition and the fact that pregnancy itself clouds the clinical picture invariably leads to a delay in diagnosis with an increased risk of gangrene of the gut. the majority of these patients would then require resection and colostomy. however, an early diagnosis and intervention as in our patient, which would require a high index of clinical suspicion, could significantly improve the outcome of the foetus and the mother. a case of sigmoid volvulus in pregnancy is reported which was managed by resection and primary anastomosis. a review of literature revealed no previous reports of sigmoid volvulus in pregnancy managed by primary anastomosis following resection of the sigmoid volvulus. the literature is also reviewed regarding predisposing factors, management options and the outcome of sigmoid volvulus complicating pregnancy. key words: sigmoid volvulus; pregancy; resection; case report; oman; sigmoid volvulus complicating pregnancy managed by resection and primary anastomosis case report with literature review *norman o machado,1 lovina s m machado2 intestinal obstruction, which is rare in pregnancy, has a reported prevalence of 1 in 1,500 to 1 in 66,431 pregnancies.1-3 sigmoid volvulus contributes to 12% of these cases.3 the essential problems of sigmoid volvulus in pregnancy are those of delay in presentation and diagnosis. delay in diagnosis invariably leads to ischaemia of the colon, which warrants resection and colostomy as noted in most of the reported cases.1-5 prompt surgical intervention is necessary to minimise maternal and foetal morbidity and mortality. the reported maternal mortality is 6% with a foetal mortality of 26%.3 c a s e r e p o r t a 24 year old lady, gravida 2, para 1 presented at 18 weeks gestation with complaints of intermittent abdominal pain and recent onset of worsening lower abdominal distension over 12 hours. her pregnancy had been otherwise uneventful. she had no previous medical problems or prior abdominal surgery. on exdepartment of 1surgery, 2obstetrics and gynaecology, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: norman@omantel.net.om ومعاجلته باالستئصال احلمل خالل ينِيّ تالٌ السِّ االِنْفِ مضاعفات األولي والتفاغر أدبيات مع مراجعة حالة تقرير ماتشادو لوفينا ماتشادو، نورمان يؤخر التشخيص السريري للوضع احلمل تشويش إضافة إلى احلالة هذه ندرة . الوالدة أثناء األمعاء جدا النسداد حالة نادرة ينِيّ السِّ تال االِنْفِ امللخص: رُ فَغْ و من األمعاء املصاب استئصال اجلزء يحتاج غالبية املرضى إلى السبب لهذا . األمعاء بغنغرينة باإلصابة االختطار إلى زيادة مما يؤدي على األغلب عالية من درجة إلى يحتاج وهذا ، مبكرا والتدخل ــخيص التش إذا مت واجلنني فيما لألم ــبة بالنس النتيجة ــني حتس ، ميكن أخرى جهة من لكن . ولون القَ التي حلالتنا حالة مشابهة جند لم الطبية مراجعة األدبيات بعد . األولي باالستئصال والتفاغر عوجلت ــينِيّ تالٌ سِّ اِنْفِ حالة هنا ندرج . ــك والش احلذر مع أثناء احلمل ــينِيّ السِّ تال لالِنْفِ املؤهبة العوامل حول األدبيات الطبية مراجعة متت كذلك ــة. املصاب ــتئصال املنطقة اس بعد األولي التفاغر ــا مت فيه . والنتائج العالج طرق عمان. حمل ، استئصال ، تقرير حالة ، الكلمات: انفتال سيني ، مفتاح c a s e r e p o r t s i g m o i d vo lv u l u s c o m p l i c at i n g p r e g n a n c y m a n a g e d b y r e s e c t i o n a n d p r i m a r y a n a s t o m o s i s 85 amination, she was afebrile and had mild generalised abdominal tenderness. her abdomen was distended with the gravid uterus corresponding to 18 weeks size and a gas-filled gut. routine laboratory studies were significant only for an elevated white blood cell count of 13,500 x 109/l, which could have been due to normal physiological response in pregnancy. in view of her pregnancy, no radiological examinations were performed. she was admitted for close observation and given a fleet enema with no result and no effect on her abdominal pain or distension. over the next 6 hours the abdominal pain continued to worsen, relieved partially by narcotic analgesics. the abdomen was distended, soft, hyperesonant and hyperperistalitic. a diagnosis of sigmoid volvulus was then entertained as the abdominal distension was predominantly in the lower abdomen and progressed along with colicky abdominal pain. obstetric assessment revealed an active foetus and there were no signs of threatened abortion. after informed consent, and 8 hours after admission, the patient was prepared for an attempt at sigmoidoscopic detorsion, with a possibility of laparotomy in the event of failure. sigmoidoscopy confirmed the obstruction due to a twist in the sigmoid colon; however, the attempt to negotiate the obstruction failed, necessitating laparotomy through a lower midline incision. the sigmoid colon was grossly distended table 1: reported cases of sigmoid volvulus in pregnancy author between year number of cases reviewed gestational age in weeks duration initial symptoms & management (in hours) present study 2006 1 18 18 alshawi12 2005 1 28 & 35 (recurrent) <24 de u et.al.8 2005 1 24 >72 joshi et.al.9 1999 1 28 >48 lurie et.al.13 1997 1 ectopic pregnancy 36 lord et.al.6 1996 1 36 >24 allen.14 1990 1 28 >12 keating et al.5 1985 1 34 12 hofmeyr et al.10 1985 2 33 >48 26 >48 fraser et al.11 1983 1 32 >12 lazaro et al.2 1958-1969 13 harer & harer.4 before 1958 52 figure 1: sigmoid volvulus showing grossly dilated, viable sigmoid colon n o r m a n o m a c h a d o a n d l o v i n a s m m a c h a d o 86 but viable. a 180 degree anticlockwise twist was noticed [figure 1]. in view of the proximal colon being relatively empty and the sigmoid colon viable [figure 2], a resection of the sigmoid colon was performed [figure 3] with primary anastamosis in 2 layers with vicryl. the patient had an uneventful postoperative recovery and was discharged on the fifth postoperative day. she has been symptom free since then and had a spontaneous vaginal delivery of a normal healthy male baby at 38 weeks of gestation. d i s c u s s i o n a review of medical literature in english revealed 75 cases of sigmoid volvulus in pregnancy [table 1] since the first case was reported in 1885.2-14 rare as the condition is, it is the second commonest cause of intestinal obstruction in pregnancy and a high index of clinical suspicion needs to be maintained to achieve an early diagnosis.1, 3 several previously described cases of volvulus in pregnancy were found at laparotomy to have predisposing causes including adhesions, previous salpauthor sigmoid colon treatment outcome foetus patient present study viable sigmoid colectomy & primary anastomosis healthy good alshawi12 viable sigmoidoscopic detorsion in pregnancy elective sigmoid colectomy post delivery healthy good de u8 gangrenous hartman’s procedure iufd good joshi m9 gangrenous hartman’s procedure iufd good lurie13 viable laparotomy & detorsion ectopic good lord6 gangrenous hartman’s procedure healthy good allen14 viable sigmoidoscopic decompression healthy good keating5 viable sigmoid colectomy & double barrel colostomy healthy good hofmeyr10 gangrenous hartman’s procedure iufd good gangrenous hartman’s procedure iufd dead fraser11 viable laparotomy & detorsion healthy good legend: iufd = intrauterine foetal death table 2: management and outcome of sigmoid volvulus in pregnancy (series since 1983) figure 2: sigmoid volvulus partly decompressed and the gravid uterus (arrow) figure 3: resected sigmoid colon s i g m o i d vo lv u l u s c o m p l i c at i n g p r e g n a n c y m a n a g e d b y r e s e c t i o n a n d p r i m a r y a n a s t o m o s i s 87 ingitis and abnormalities in gastrointestinal tract development.2-5 the patient described here showed none of these features other than a redundant sigmoid loop and a narrow base of the mesocolon. the mechanism of sigmoid volvulus in pregnancy has been suggested to be due to displacement, compression and partial obstruction of an abnormally mobile sigmoid colon by the enlarging uterus.4 this could probably explain the increased incidence of sigmoid volvulus in the third trimester.3, 7 eight of the 11 recent cases since 1983 were in the third trimester. diagnosis of the condition is often delayed. the average length of time from the onset of obstructive symptoms until presentation is reported to be 48 hours.3 this is mainly because pregnancy itself clouds the clinical picture since abdominal pain, nausea, and leukocytosis can occur in an otherwise normal pregnancy.5 in addition, the reluctance to obtain radiological evaluation in pregnancy may contribute to diagnostic delay. among the 11 recent cases, the average duration between the start of symptoms and definitive treatment was 32 hours. of these 11 patients, 4 (36%) were managed after 48 hours of obstructive symptoms.8-11 all these four patients delivered a dead foetus and there was one maternal mortality among them. it was also noted that these four patients had a gangrenous sigmoid colon and underwent hartman’s procedure and colostomy.8-10 in contrast, the 6 patients, including the present case, who were managed within 24 hours of initial symptoms had good foetal and maternal outcomes.5,6,11,12,14 moreover, they were amenable to lesser invasive procedures like sigmoidoscopic detorsion.12, 14 or surgical interventions without colostomy like laparotomy and sigmoidopexy11 or, as in our case, resection and primary anastomosis. a literature review revealed no previous reported case of primary anastomosis following resection [table 2]. the management of sigmoid volvulus in the pregnant patient involves aggressive fluid resuscitation, decompression of the proximal bowel and recognition of this entity as an acute surgical emergency.3,5,6 in the absence of peritoneal signs or mucosal ischaemia, it would seem reasonable to attempt detorsion and decompression via sigmoidoscopic placement of a soft rectal tube.12, 14 alshawi12 proposed the following management options based on the stage of pregnancy: in the absence of signs of peritonitis in the first trimester of pregnancy, a nonoperative procedure with colonoscopic detorsion and rectal tube decompression is recommended. this can be repeated in recurrent cases until the second trimester when sigmoid colectomy is recommended. since continuing with the nonoperative approach until foetal maturity is reached is associated with a high recurrence rate, and surgery in the second trimester reduces the miscarriage rate, elective sigmoid colectomy is recommended in the second trimester. it is technically difficult to operate in the pelvis in the third trimester. hence it is acceptable to do colonoscopic detorsion and tube decompression until foetal maturity, when elective labour followed by sigmoid colectomy would provide a definitive treatment. although colonoscopic detorsion is often successful in non-pregnant patients, successful use of this approach in late pregnancy is rarely reported.12,14 this could probably be due to the large gravid uterus acting as a mechanical impediment to detorsion. when surgical intervention is required in these patients, a standard midline incision allows maximal exposure with minimal uterine manipulation. the non-viable bowel is resected with a diverting colostomy performed, the stomata being sited away from an elective area of a possible caeserean section.5 primary anastomosis of an unprepared distended paretic and oedematous large bowel is generally avoided as it could be hazardous to both mother and foetus.5 this is particularly so when there has been a significant delay in establishing a diagnosis. early diagnosis, however, would make resection and primary anastomosis a safe approach, as in our patient, with the distinct advantage of reduced hospital stay and avoidance of further surgery c o n c l u s i o n sigmoid volvulus complicating pregnancy is an uncommon and potentially devastating development. early diagnosis mandates a high index of clinical suspicion in a patient who presents with complaints of abdominal pain of increasing severity associated with lower abdominal distension. delay in diagnosis and treatment beyond 48 hours results in increased foetal and maternal morbidity and mortality. prompt intervention is necessary to minimise these complications and achieve a definitive cure. r e f e r e n c e s 1. coughlan bm, o’herlihy co. acute intestinal obstruction during pregnancy. j r coll surg edinb 1978; 23:1757. n o r m a n o m a c h a d o a n d l o v i n a s m m a c h a d o 88 2. lazaro ej, das pb, abraham pv. volvulus of the sigmoid colon complicating pregnancy. obstet gynecol 1969; 33:553-7. 3. perdue pw, johnson hw jr, stafford pw. intestinal obstruction complicating pregnancy. am j surg 1992; 164:384-8. 4. harer wb jr, harer wb sr. volvulus complicating pregnancy and puerperium. obstet gynecol 1958; 12:399406. 5. keating jp, jackson ds. sigmoid volvulus in late pregnancy. j r army med corps 1985; 131:72-4. 6. lord sa, boswell wc, hungerpiller jc. sigmoid volvulus in pregnancy. am surg 1996; 62:380-2. 7. kohn sg, henry ab, douglass lh. volvulus complicating pregnancy. am j obstet gynecol 1944; 48:398-404. 8. de u, de kk. sigmoid volvulus complicating pregnancy. indian j med sci 2005; 59:317-9. 9. joshi ma, balsarkar d, avasare n, pradhan c, pereira g, subramanyan p, et al. gangrenous sigmoid colon in a pregnant woman. trop gastroenterol 1999; 20:141-2. 10. hofmeyr gj, sonnendecker ew. sigmoid volvulus in advanced pregnancy. report of 2 cases. s afr med j 985; 67:63-4. 11. fraser jl, eckert la. volvulus complicating pregnancy. can med assoc j 1983; 128:1045 12. alshawi js. recurrent sigmoid volvulus in pregnancy. report of a case and review of the literature. dis colon rectum 2005; 48:1811-3. 13. lurie s, katz z, rabinerson d, simon d. sigmoid volvulus after medical management with subsequent operative laparoscopy of unruptured ectopic pregnancy. gynecol obstet invest 1997; 43:204-5. 14. allen jc. sigmoid volvulus in pregnancy. j r army med corps 1990; 136:55-6. visceral leishmaniasis and haemophagocytic syndrome in an omani child 45 visceral leishmaniasis and haemophagocytic syndrome in an omani child khalfan al sineidi1, *yasser a. wali1, anil v. pathare2, zakia al lamki1 abstrac t. the paper reports the case of a previously healthy 4-year-old-girl who presented with pallor, fever and hepatosplenomegaly. laboratory findings included pancytopenia, hypertriglyceridemia and hyperferritinemia. initial diagnosis of kala-azar could not be confirmed because of the absence of clinical evidence, negativity of bone marrow aspiration or specific serology for visceral leishmaniasis. repeated marrow aspiration, performed due lack of clinical response, revealed histiocytes showing haemophagocytosis consistent with haemophagocytic lymphohistocytosis (hlh) and appropriate treatment was started. she continued to have high-grade fever, and a third bone marrow aspiration ultimately revealed presence of leishmania amastigotes with evidence of active haemophagocytosis. the girl was treated with liposomal amphotericin (ambisome) for 5 days, following which she recovered rapidly with definitive remission. key words: haemophagocytic syndrome, visceral leishmaniasis, oman. department of child health (haematology/oncology unit), college of medicine & health sciences, sultan qaboos university, p.o.box: 35, al khod-123, sultanate of oman. department of haematology, sultan qaboos university hospital, p.o.box: 38, al khod-123, sultanate of oman *to whom correspondence should be addressed. email: yawali@squ.edu.om a 4-year-old omani girl, not known to have any previous medical illness, presented with a one-month history of high grade fever associated with rigors 2–3 times a day, as well as body ache. she was admitted for 8 days in one of the peripheral hospitals where she was found to have hepatosplenomegaly and pancytopenia. on physical examination she was pale and febrile (40°c). her spleen was 3 cm and liver 3 cm below the costal margin. laboratory tests showed: hb 7.2 g/dl, absolute neutrophil count (anc) .46×09/l, total leukocyte count (tlc) 4.0×09/l, platelets 7×09/l and reticulocytes 2.6%. peripheral blood smear showed no blasts and also was negative for malarial parasite. liver function tests showed aspartate amino transferase (asat) of 230 u/l, alanine amino transferase (alat) of 36 u/l and albumin of 26 g/l. coagulation profile showed prothrombin time (pt) of 2.5 sec (normal range –4), activated partial thromboplastin time (aptt) of 35. sec (26–37), fibrinogen of 5. g/l (.5–4.5) and d-dimers of >2.0<4.0 mg/l (<0.5). esr was 9 in 2 hours and c-r-eactive protein (crp) was 84 mg/l. rheumatoid factor, ana, anti dna antibody and direct coombs test all yielded negative results. her serum triglycerides were 3.2 mmol/l (0.5–.7) and immunoglobulin g (igg) was 32 g/l. chest x ray was normal and ultrasound abdomen showed hepatosplenomegaly. a provisional diagnosis of visceral leishmaniasis was made with the possibility of malignancy to be ruled out. bone marrow aspiration (bma) was negative for any malignant cells and despite extensive search no leishmania amastigotes (ld bodies) were found. the child underwent a battery of investigations for pyrexia of unknown origin (puo), and several blood, urine and stool cultures were negative. hepatitis profile, brucella, hiv  and 2, ebv, and widal screening also yielded negative results. serologic test results for leishmaniasis were also negative. the child continued to have high-grade fever (>40°c) despite antibiotic coverage with ceftriaxone and azithromycin. bma was repeated afer one week, which showed hypercellular squ journal for scientific research: medical sciences 2002, vol. 4, no. –2, 45–48 ©sultan qaboos universit y final version ��/�/���� yasser wali lieshmaniasis ����� ��� �� ����������������� ������� �������� ���������� ������� ���������� ���� ����������� ����������� ���� �������� :����� ������ ����� ����� ���� ������ ��� ���������� ����� ��� ��� �������� �� ����� �� ���� ������ � ������� ����� �� ����� .������ ������ ������ ���� �� ������� ���� ������ �� �� ���� ��� ��� �������� �������� ����� ������ .������ ������ ����� ������� �������� ������ ����� ���� ���������� ���� ��� ���� �� ������� �� ���� ����������� ��.��� �������� �������� ����� ���� ����������������� ������ ���� ����� ���� ��� ���� �������hlh.���� ��� ����� ������� ���� ����� ����� ������ ������� ��� ��� ��� ������ �� ���������� ����� ���� ������ ����� ��� ���� ��� ������ ��� ��� .�������� ����� ����� ������ ���� ������� ���� �������� ����� ��. 46 marrow with erythroid hyperplasia showing histiocytes [figure ] with haemophagocytosis consistent with haemophagocytic lymphohistocytosis syndrome (hlh). the hepatosplenomegaly, together with signs of haemophagocytosis on the marrow smear, and seronegativity for leishmania, led to tentative diagnosis of familial lymphohistocytosis. the child was put on chemotherapy as per hlh 94 protocol. she received etoposide intravenously (50 mg/ m2 twice weekly) and oral dexamethasone daily (0 mg/ m2) for 2 weeks. during this period the child improved clinically as the fever settled. genetic study and hla typing of the family was done preparing for bone marrow transplantation. as per the protocol, a third bone marrow examination revealed presence of ld bodies together with haemophagocytosis [figure 2]. etoposide and dexamethasone were stopped and the child was put on sodium stilbogluconate (20 mg/kg/day) but she continued to have high spikes of fever and pancytopenia, also she started to have very severe myalgia. taking all the above into consideration, sodium stilbogluconate was stopped after receiving five doses and she was started on liposomal amphotericin intravenously (ambisome), in a dose of 3 mg/kg for 5 days. the child’s general condition dramatically improved and she became afebrile. liver size reduced to  cm and spleen was not palpable. repeat bma two weeks after starting ambisome showed haemophagocytosis but no ld bodies. her full blood count on discharge was as follows: tlc of 7.84×09/l, hb of .2 g/dl and platelets of 88×09/l. two weeks after the discharge, on her followup visit, she was doing well and her cbc showed: tlc 6.69×09/l, platelets 270×09/l, hb .8 g/dl and anc of .4×09/l.the fourth bma was done at this time and it showed no ld bodies nor haemophagocytes. she was seen in the outpatient department after 4 month of the second discharge and was in good normal health. d i s c u s s i o n it is important for any physician to be able to identify early potentially life-threatening disorders in diseases that may lead to severe permanent disabilities, in particular if they are treatable. haemophagocytic lymphohistocytosis (hlh) is such a disorder. it usually affects infants who develop the disease very early in life with around 70% being less than one year of age at onset. a crude annual incidence of .2 cases of familial haemophagocytic lymphohistocytosis (fhl) per million children has been reported in sweden.2 large series of hlh cases have been reported in hong kong3,4 and taiwan.5 a seasonal pattern has been suggested; cases may occur more often in summer.6 the disorder occurs in primary and secondary forms. the more common primary form, fhl, typically seen during infancy and early childhood, is inherited as an autosomal recessive trait. possible loci for s i n e i d i e t a l figure 1. photomicrograph of bone marrow aspiration, showing hypercellular marrow with erthroid hyperplasia showing histiocytes figure 2. photomicrograph of aspirated bone marrow, showing macrophage with intracellular ld bodies with haemophagocytosis. 47 a responsible gene or genes have recently been mapped to the long arms of chromosomes 9 and 0, andis invariably fatal with a median survival without therapy of two months after onset.7,8 secondary hlh can affect all ages and is also associated with high mortality. it has been linked to viral, bacterial, fungal and parasitic infections (the so called infection-associated hs) and to a broad spectrum of malignant and genetic disorders, such as chediak-higashi disease, griscelli disease and xlp syndrome.9,10 hlh is now diagnosed on the basis of henter et al’s guidelines:10 (a) clinical criteria: fever and splenomegaly (both to be present); (b) laboratory criteria: cytopenias (affecting 2 of 3 lineages in the peripheral blood), haemoglobin (<9 g/l), platelets (<00×09/l), neutrophils (<.0×09), hypertriglyceridemia and/or hypofibrinogenemia (fasting triglycerides ≥2.0 mmol/l or ≥3 sd of the normal value for age, fibrinogen ≥.5g/l or ≥3 sd) (c) histopathological criteria: haemophagocytosis in bone marrow or spleen or lymph nodes, no evidence of malignancy. neurological symptoms may complicate and sometimes dominate the clinical course. hypertriglyceridemia is common in systemic disease with fever. hepatic abnormalities including elevated serum transaminases or hyperbilirubinemia appear to be related to degree of liver involvement. elevated ferritin and lactate coagulation derangement is also common during active disease.12 pathophysiology of hlh is believed to be due to uncontrolled non-malignant proliferation of t lymphocytes and macrophages, leading to increased cytokine production. the haemophagocytosis mostly affects erythrocytes but occasionally also platelets and leukocytes.9,10 the organs most frequently involved are the spleen, liver, lymph nodes bone marrow and central nervous system.13 infection by the protozoan pathogen leishmania is a public health problem in certain regions of oman as north batinah.14 although there are a number of different species, all of which are transmitted by phlebotomine sand flies,15 there are only two primary types of clinical disease, cutaneous and visceral leishmania (vl).16 visceral leishmaniasis revealed by haemophagocytic syndrome (hs) is an extremely rare event that can cause considerable diagnostic difficulty. the first case of leishmaniasis revealed by a reactive hs was reported by matzner et al and concerned a 22-year-old adult.17 our patient had an abnormal coagulation profile, elevated liver enzyme activities, very high triglyceride level, low plasma fibrinogen levels and bone marrow haemophagocytosis, keeping with all the diagnostic criteria of hs as defined by the hlh study group of the histiocyte society in 99.10 no other cause of hs was found despite extensive microbiologic and serologic investigation. the other signs presented by her were common to hs and vl (hepatosplenomegaly, fever and pancytopenia). leishmania was considered in the differential diagnosis, but leishmania amastigotes were not present on the first marrow smear. neurological involvement is very common in fhl with histiocytes in csf. this should distinguish fhl from the secondary hlh.18 the recent description of mutation in the perforin gene in patients with fhl linked to 9 q22 may also facilitate the diagnosis.6 in our case, etoposide was wrongly prescribed. this drug, cytotoxic for the monocyte-macrophage lineage, is the effective treatment of fhl but can have catastrophic consequences by increasing the risk of aplasia and aggravating the vl. bone marrow transplantation was planned in our case, but fortunately the correct diagnosis was made during the pre-transplant workup. another important issue is the lack of response to pentavalent antimonials and the immediate and definite response to ambisome. ambisome was recently shown to be optimal for the treatment of vl in immunocompetent children.19 in this case of secondary hlh, it seems to be particularly suitable as lipid formulation amphotericin b is taken up by macrophages and targets the drug to the site of infection leading to very high concentration in the liver, spleen and bone marrow.20 whatever treatment regimen is used, long-term follow up is essential to ensure complete cure. c o n c l u s i o n this is the first reported case of visceral leishmania associated with hlh in arabian gulf region. it is also among the very few such reported cases in the literature. this diagnosis of hlh matched the diagnostic criteria by henter et al in 99,10 but later on, the bma on second week of therapy as per hlh protocol 94 proved the case to be secondary to leishmaniasis. previous reports of association between erythroid hyperplasia, histocytosis with haemophagocytic changes and leishmaniasis have been reported by al-jurayyah et al.21 ld antibodies should be sought stubbornly on bm smears, with repeated sampling and use of modern diagnostic methods. leishmania can now be identified in tissues by means of pcr with species-specific probes and this should simplify the diagnosis of these very rare cases. this case also shows that it is not always easy to know v i s c e r a l l e i s h m a n i a s i s a n d h a e m o p h a g o c y t i c s y n d r o m e 48 which occurs first, visceral leishmaniasis or haemophagocytosis. r e f e r e n c e s . henter ji, elinder g, soder o, ost a. incidence in sweden and clinical features of familial hemophagocytic lymphohistiocytosis. acta paediatr scand, 99, 80, 428–435. 2. wong k, chan j. reactive hemophagocytic syndrome: a clinicopathologic study of 40 patients in an oriental population. am j med, 992, 93, 77–80. 3. wong kf, chan jk, lo es, wong cs. a study of possible etiologic association of epstein-barr virus with reactive hemophagocytic syndrome in hong kong chinese. hum pathol, 996, 27, 239–242. 4henter ji, arico m, elinder g, imashuku s, janka g. familial hemophagocytic lymphohistocytosis (primary hlh). hematol oncol clin north am, 998, 2, 47–433. 5. chen rl, su ij, lin kh, lee sh, lin dt, chuu wm, et al. fulminant childhood hemophagocytic syndrome mimicking histiocytic medullary reticulosis. an atypical form of epsteinbarr virus infection. am j clin pathol, 99, 96, 7–76. 6. ohadi m, lalloz mr, sham p, zhao j, dearlove am, shiach c, et al. localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q2.3-22 by homozygosity mapping. am j hum genet, 999, 64, 65–7. 7. dofourcq-lagelouse r, jabado n, le diest f, stephan j, souillet g, bruin m, et al. linkage of familial hemophagocytic lymphohistiocytosis to 0q2-22 and evidence for heterogeneity. am j hum genet, 999, 64, 72–79. 8. favara be, feller ac, pauli m, jaffe es, weiss lm, arico m, et al. contemporary classification of histiocytic disorders. the who committee on histiocytic/reticulum cell proliferations. reclassification working group of the histiocyte society. med pediatr oncol, 997, 29, 57–66. 9. stephan jl. histiocytoses. eur j pediatr 1995, 54, 600–609. 0. henter ji, elinder g, ost a.diagnostic guidelines for hemophagocytic lymphohistiocytosis. the fhl study group of the histiocyte society. semin oncol, 99, 8, 29–33. . koduri pr, carandang g, demarais p, patel ar. hyperferritinemia in reactive hemophagcytic syndrome: report of four adults cases. am j hematol, 995, 49, 247–249. 2. favara b. hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. semin diagn pathol, 1992, 9, 63–74. 3. ost a, nilsson-ardnor s, henter j. autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. histopathology, 998, 32, 30–36. 4. elnour b, akinbami fo, shakeel a, venugopalan p. visceral leishmaniasis in omani children: a review. ann trop pediatr, 200, 2, 59–63. 5. pearson rd, sousa aq. clinical spectrum of leishmaniasis. clin infect dis, 996, 2, 11–13. 16. kinmond s, galea p, simpson em. kala-azar in a scottish child. lancet, 989, 2, 325. 7. matzner y, behar a, beeri e, herskko c. systemic leishmaniasis mimicking malignant histiocytosis. cancer, 979, 43, 398–402. 8. hadad e, sulis ml, jabado n, tardieu m. ferquency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. blood, 997, 89, 794–800. 9. di martino l, davidson rn, giacchino r. treatment of visceral leishmaniasis in children with liposomal amphotericin b. j pediatr, 997, 3, 27–277. 20. coukell aj, brogden rn. liposomal amphotericin b: therapeutic use in fungal infections and visceral leishmaniasis. drugs, 998, 55, 585–62. 2. al-jurayyah na, al-nasser mn, al-ayed ih, al-herbish as, al-mazrc am, al-sohaibani mo.the hematological manifestation of visceral leishmaniasis in infancy and childhood. j trop pediatr, 995, 4, 43–48. s i n e i d i e t a l december 2008 no white pages.indd abstract objective: pseudoexfoliation (pex) syndrome is one of the leading causes of secondary open angle glaucoma and blindness. this study explored whether in pex eyes, preoperative changes in corneal endothelial cell morphology might be a risk factor for postoperative corneal decompensation. methods: one hundred twenty six eyes of 69 preoperative cataract patients (43 males, 26 females) were enrolled in this cross-sectional study from the ophthalmology department at sultan qaboos university hospital between 2003-2005. all patients were subjected to confocal biomicroscopy. results: the mean age of patients with pex eyes was 63.2 years. one hundred and eight (85.7%) eyes with pex had endothelial cell counts within the normal range (650-3500/mm²). the qualitative morphology of the endothelium of pex corneas was highly abnormal in term of polymegathism and pleomorphism. twelve eyes had endothelial cell counts higher than normal for that age group. only 6 eyes had endothelial cell counts lower than normal. the mean value for the pleomorphism was found to be significantly lower than normal and for polymegathism significantly more than normal. the relationship between pleomorphism and polymegathism was stronger for males than for females and stronger for patients under 60 years than patients over 60 years. the same relationship between pleomorphism and polymegathism showed a stronger relationship for the glaucoma group as compared to the non-glaucoma group. conclusion: this study revealed that corneal decompensation in pex eyes can occur in presence of abnormalities in polymegathism and pleomorphism, even when the endothelial cell counts may be normal. key words: pseudoexfoliation; pleomorphism; polymegathism; confoscan. quantitative and qualitative corneal endothelial morphology of omani patients with pseudoexfoliation syndrome *upender k wali,1 abdullah s al-mujaini,1 nadia s al-kharusi,1 alexander a bialasiewicz,1 syed g rizvi2 departments of 1ophthalmology, 2family medicine and public health, sultan qaboos university, college of medicine and health sciences, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: wali@squ.edu.om مبتالزمة املصابني العمانيني املرضى لدى قرنية العني بطانة خاليا وضع الكاذب لعدسة العني التقشر ريزفي سيد بيالسويتز، أليكاسندر نادية اخلروصي، ايني، والي، عبداهللا أوبندار املصابة العني أن حيث ، والعمى الثانوي األزرق باملاء اإلصابة إلى املؤدي الرئيسي العني السبب لعدسة الكاذب التقشر متالزمة امللخص: الهدف: تعتبر ــة الدراس الطريقة: في هذه العملية. بعد القرنية تدهور تؤدي إلى قد قبل العملية القرنية ــا بطانة خالي في تغيرات يرافقها من وما ــة املتالزم ــك بتل جامعة ــفى العيون مبستش أمراض ــم قس في األبيض املاء عملية نزول إجراء قبل 26 أنثى) و (43 ذكرا 69 حالة ل 126 عينا ــة مت دراس املقطعية عمر متوسط النتائج: بلغ الدقيق. العني احليوي مجهر بواسطة فحصهم مت كل املرضى 2005 ميالدية. 2003 إلى بني الفترة قابوس في السلطان -1650) العني بطانة في خاليا ــا تعدادا طبيعي (85.7%) 108 عينا أظهرت 63.2 عاما. ــني الع ــة الكاذب لعدس ــر املصابني مبتالزمة التقش املرضى خاليا تعداد كان فقد ــكالها. أش وتعدد اخلاليا حجم اختالف ناحية من كبيرة بصورة طبيعي غير كان اخلاليا فقد لنوع ــبة بالنس 3500/ملم² ). أما متوسط كان كما ل6 عيون. املستوى الطبيعي من أقل ، بينما كان التعداد في تلك الفئة العمرية الطبيعي املستوى من أعلى 12 عينا ل البطانة وتعدد حجم بني كانت العالقة الطبيعي. ــتوى املس من اخلاليا أقل حجم ، بينما كان عن الوضع الطبيعي ملحوظ ــكل أعلى بش اخلاليا ــكال أش تعدد أيضا كبيرة العالقة هذه كانت كما 60 عاما. أعمارهم تتعدى الذين للمرضى كبيرا كان كما باإلناث ، الذكور مقارنة املرضى في كبيرا اخلاليا أشكال الكاذب ميكن التقشر املصابة مبتالزمة للعني القرنية تدهور أن الدراسة هذه اخلالصة: تبني املصابني. غير األزرق مقارنة باملرضى باملاء املصابة الفئة بني طبيعيا. اخلاليا كان تعداد وان حتى أشكالها تعدد وفي اخلاليا في حجم طبيعية غير عالمات يظهر أن الدقيق. العني مجهر ، العني بطانة خاليا حجم العني ، بطانة خاليا أشكال تعدد ، العني لعدسة الكاذب التقشر الكلمات: متالزمة مفتاح sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 300-305 sultan qaboos university© submitted 29th march 2008 accepted 21st july 2008 c l i n i c a l a n d b a s i c r e s e a r c h q ua n t i tat i v e a n d q ua l i tat i v e c o r n e a l e n d o t h e l i a l m o r p h o l o g y o f o m a n i pat i e n t s w i t h p s e u d o e x f o l i at i o n s y n d r o m e 301 since 1917 when the finnish ophthalmologist lindberg first described thepseudoexfoliation (pex) syndrome, the main intraocular production sites of pex material have been identified as the epithelial cells of the lens capsule, the iris, the non-pigmented ciliary epithelium, and the trabecular meshwork, as well as the corneal endothelial cells.1 since pex is also associated with hypoxia of the anterior segment, it seems pertinent to acquire more knowledge of the in vivo morphology of corneal endothelial cells in addition to the existing histopathological features in order to predict problems for intraocular surgery in these eyes. the pex syndrome is a systemic disease with mainly ocular manifestations.1 its most common systemic manifestations include ischaemia, infarctions and strokes involving the myocardium, bowels and intracranial structures. epidemiologically, pex has a wide geographical distribution with the highest incidence in countries prone to ultra-violet light, in northern latitudes and at high altitudes.2, 3 the prevalence of pex is variable: usa (1.6%), germany (4.0%), england (4.7%), france (5.5%), norway (6.3%), saudi arabia (13%), finland (20%), and iceland (25% in more than 60 years of age). the risk of developing glaucoma in pex is 20-77%.1, 4 aasved found a nine fold increase in prevalence of pex in first degree relatives over age of 40 years compared to the general population, suggesting an autosomal dominant inheritance.5 this study was commenced with the aim of highlighting the importance and need for preoperative evaluation of corneal endothelial cells in pex eyes in the omani population undergoing cataract, or other intraocular anterior segment surgery. m e t h o d s a total of 69 adult patients (43 males and 26 females) and 126 eyes (78 male eyes and 48 female eyes), who met the inclusion and exclusion criteria, were enrolled in this study. the inclusion criterium was patients aged 40 years and above. eyes with any other corneal pathology or prior surgery that would prevent reliable confocal microscopy were excluded. all patients were subjected to refraction, applanation tonometry, slit-lamp biomicroscopy, gonioscopy and fundus examination. eyes confirmed to have pex on the anterior lens capsule, iris and/or endothelium before or during mydriasis were subjected to a confocal microscopic examination (confoscan 2, nidek japan). patients diagnosed with glaucoma were examined by frequency-doubled perimetry (matrixr, zeisshumphrey), humphrey automated perimetry and oct 2 papillometry (oct 2 nidek). confocal biomicroscopy was done under topical anesthesia (benoxinate 0.4%) using sterile transparent gel as a coupling medium. the confocal microscopy outcome of corneal endothelium was assessed in terms of endothelial cell count, polymegathism and pleomorphism. the endothelial cell count was calculated on the basis of a sample size which was different for different eyes and compared with age-matched mean values for other studies in the normal population. the pleomorphism and polymegathism values were defined against normal values of >59.0 for pleomorphism and <30.0% for polymegathism, which means that a normal healthy cornea should have at advances in knowledge • ocular pseudoxfoliation syndrome induces structural changes in the morphology of the cornea that directly reflects the high risk of postoperative corneal decompensation. • confocal scans can help the surgeon predict this possibility and so properly counsel the patient prior to the surgery. • this can make postoperative management more specific and result oriented. application to patient care • the study shows the importance of confocal biomicroscopy in ocular pseudoexfoliation syndrome. • patient care can be more predictive and specific if the corneal status is known preoperatively. • this can make postoperative management more specific and result oriented. u p e n d e r k wa l i , a b d u l l a h s a l m u j a i n i , n a d i a s a l k h a r u s i , b i a l a s i e w i c z a a a n d s y e d g r i z v i 302 least 60% endothelial cells with regular shape or hexagonality and should not have abnormal endothelial cell sizes or areas (normal 312-320 micron square) in more than 30% of cells. the statistical package for the social scienes (spss software, version 10) was used for the analysis of the data and to make the figures. the student’s t-test was applied to test the significance difference between the means of the groups for the variables under study and the chi-square test was used to compare the categorical variables. a p-value of .05 or less was taken as significant. selection of the type of regression curve is based on the r2-values for different types of regression [table 4]. a higher degree curve was preferred only when the difference in r2 -values was significant. r e s u l t s sixty nine patients (43 males, 26 females), with 126 eyes diagnosed to exhibit ocular pex on slit-lamp biomicroscopy, were selected for morphometric analysis of corneal endothelium by confoscan 2 (nidek). all the patients were of omani origin. the patient characteristics were as follows, [table 1]: the mean age of the patients was 63.45 ± 7.40 years for males and 62.77 ± 7.85 years for females. of 126 pex eyes the majority of patients (42.9%) belonged to age group 61-70 years, followed by 38.1% in 51-60 years age group, 15.9% in >70 years age group and 3.2% aged <50 years. the mean age for patients with pex glaucoma was 60.81 years as compared to 64.65 years in patients with pex without glaucoma, suggesting a younger age group for pex glaucoma. the endothelial cell count [tables 1 & 2] was as follows: seventy eight male pex corneas had a mean endothelial cell counts of 2463.18 ± 485.28 cells/mm² compared to 2470.21 ± 544.93 cells/mm² for 48 female pex corneas; this difference was not found to be statistically significant (p = 0.942). the overall mean endothelial cell count for all 69 patients with 126 pex eyes was 2465.86 ± 506.68 cells/mm². the endothelial cell count of pex eyes in this study was found to be within the normal range in 86.5%. only 3.2% of pex eyes had endothelial cell counts less than agematched normal eyes. a total of 10.3% pex eyes had endothelial cell counts that ranged even higher than that of age-matched control eyes. most frequently (62 pex eyes) the endothelial cell counts ranged between 2000-2500 cells/mm², and six eyes even had endothelial cell counts of more than 3500 cells/mm². the mean endothelial cell count for the pex eyes with glaucoma (48) was 2438 ± 503.4 (1579-3974) compared to 2483 ± 511.2 (1595-4239) in pex eyes without glaucoma (78); this difference was also not found to be statistically significant (p = 0.629). as far as pleomorphism and polymegathism [table 1 & 2] were concerned the following results were found. the pleomorphism (loss of hexagonality) data were abnormal in 122 pex eyes (96.8%). only four pex eyes had pleomorphism of 60 and above (normal > 59.0%). similar changes in cell density and hexagonality have been reported by hatorri.6 forty three pex eyes had pleomorphism values in the range of 20-30. the mean pleomorphism for 126 eyes was 34.63% ± 11.92 (normal >59.0%). in spite of having slightly and statistically non-significant lower endothelial cell counts compared to females, the males showed better, though statistically non-significant, pleomorphism values (34.70% ± 11.90) compared to females (34.52% ± 12.12). males (78) females (48) total (126) pex with glaucoma (48) pex with no glaucoma (78) age 63.45 ± 7.40 (49 84) 62.77 ± 7.85 (41 76) 63.19 ± 7.55 60.81± 8.33 (41 84) 64.65 ± 6.67 (49 76) endothelium 2463.18 ± 485.28 (1579 3974) 2470.2± 544.9 (1595 4239) 2465.9 ± 506.7 2438.0 ± 503.4 (1579 3974) 2483.0 ± 511.2 (1595 4239) pleomorphism 34.70 ± 11.90 (7.70 69.80) 34.52 ± 12.12 (16.2 59.8) 34.63 ± 11.92 37.09 ± 12.43 (16.2 65.4) 33.12 ± 11.44 (7.7 69.8) polymegathism 57.89 ± 15.66 (28.3 103.5) 60.10 ± 18.14 (30.7 105.1) 58.73 ± 16.61 59.69 ± 16.79 (30.0 105.1) 58.14 ± 16.58 (28.3 -105.1) each cell display; mean ± sd and (minimum value, maximum) table 1: characteristics of 126 pex eyes q ua n t i tat i v e a n d q ua l i tat i v e c o r n e a l e n d o t h e l i a l m o r p h o l o g y o f o m a n i pat i e n t s w i t h p s e u d o e x f o l i at i o n s y n d r o m e 303 the eyes with pex glaucoma had more pleomorphism (37.09 ± 12.43) than eyes with pex without glaucoma (33.12 ± 11.44) [table 1]. polymegathism was very frequent in 124 pex eyes (98.4%) exhibiting abnormal size and area of endothelial cells (average area of a normal endothelial cell is 312-320µ²). the normal value for polymegathism is <30.0%. in this study, only two eyes had normal cell size/area, or had polymegathism <30.0%. the mean value for polymegathism in 126 eyes was 58.73% ± 16.61 (normal <30.0%). females showed more abnormal values for polymegathism (60.10% ± 18.14) than males 57.89 ± 15.66), although it was not a statistically significant result. eyes with pex glaucoma had more polymegathism (59.69 ± 16.79) than pex eyes without glaucoma (58.14 ± 16.58) [table 1]; however, this difference was not significant. the quadratic relationship of pleomorphism on polymegathism displayed a strong inverse relationship. classifying this relationship into different categories, it was observed that this relationship is stronger for males (r2 = 0.638) than females (r2 = 0.602). the same association was found stronger in the under 60 years old age group (r2 = 0.727) as compared to above 60 years old age group (r2 = 0.581). classifying the same relationship according to glaucoma versus non-glaucoma groups, it was observed that eyes with pex glaucoma exhibit a stronger relationship (r2 = 0.766) than pex eyes without glaucoma (r2 = 0.604), [table 4]. however, the relationship between endothelium and polymegathism was not as strong as the relationship between pleomorphism and polymegathism. even the cubic regression of endothelium on polymegathism did not exhibit a strong relationship for the same categories: gender groups: males (r2=0.121) versus females (r2 = 0.167); age groups: <60 years (r2 = 0.129) versus > 60 years (r2 = 0.129), and glaucomas: (r2 = 0.142) versus non-glaucomas (r2 = 0.121) [table 4]. pex-glaucoma eyes were then compared with nonglaucomatous eyes. the mean age of pex patients with glaucoma (60.81 years ± 8.33) was found to be significantly lower than the mean age of the pex patients without glaucoma (64.65 years ± 6.67, p = 0.005); also, among the ≤60 years old age group (52 eyes), 55.8% were glaucoma cases, compared to only 25.7% glaucoma cases among > 60 year old age group (74 eyes). this difference was also found to be statistically significant (p = .001), evidencing a trend for the predominance of pex glaucoma in the younger age group, maybe due to earlier and better means of diagnosis. pex glaucoma seems more common among males (41%) than in females (33.3%), however, this difference was not found to be statistically significant. the mean endothelial cell count for pex glaucoma eyes (2438.0 ± 503.43 cells/mm²) was less than for nonglaucomatous pex eyes (2483 ± 511.46 cells/mm²). higher values for pleomorphism were found in eyes with pex glaucoma (37.09 ± 12.43) compared to pex eyes without glaucoma (33.12 ± 11.44). polymegathism was slightly more prevalent (59.69 ± 16.79) in pex factor normal high low endothelium 108 (85.7%) 12 (9.5%) 06 (3.2%) pleomorphism 04 (3.2%) not applicable 122 (96.8%) polymegathism 02 (1.6%) 124 (98.4%) not applicable table 2: abnormal values/cells of different factors in 126 pex eyes factors/variables pearson correlation significance endothelium versus pleomorphism 0.246 p = .005 endothelium versus polymegathism 0.072 not significant pleomorphism versus polymegathism 0.683 p < .000001 table 3: correlations and their significance u p e n d e r k wa l i , a b d u l l a h s a l m u j a i n i , n a d i a s a l k h a r u s i , b i a l a s i e w i c z a a a n d s y e d g r i z v i 304 glaucoma compared to pex eyes without glaucoma (58.14 ± 16.58); the above mentioned differences were not found to be statistically significant [table 1]. the statistical evaluation is shown in table 2. according to pearson’s 2-tailed correlation significance, the following parameters revealed statistically significant values (p = .005 or p <.005): 1. pleomorphism and polymegathism for age groups <60 years versus >60 years in pex eyes 2. pleomorphism and polymegathism for male and female pex eyes versus non-pex eyes. 3. pleomorphism and polymegathism for glaucomatous versus non-glaucomatous pex eyes. a significant inverse relationship was found between endothelium and pleomorphism (p = .005) and a very strong inverse relationship was observed between endothelium and polymegathism (p < .00001) [table 3]. d i s c u s s i o n this study has shown in vivo that the corneal endothelium is significantly affected quantitatively and qualitatively by cells producing pseudoexfoliation material. similar changes have been reported by miyake et al.7 pex eyes with glaucoma have more polymegathism than pex eyes without glaucoma. the qualitative changes of the corneal endothelium by pex, in the form of degenerating, irregular, loosely adherent cells have also been reported by schlotzer et al.8 seitz and naumann have reported 85% polymegathism in pex endothelial cells compared to 98.4% in our study.9 in another series, the same authors have reported 77% pleomorphism compared to our data of 96.8%. the difference could be due to more severe pex in our patients. this study, however, revealed more pleomorphic values for pex eyes with glaucoma than pex eyes without glaucoma. in contrast to their data, this study shows normal age-matched cell counts in most of the pex eyes. most of the recent series from different countries show a female preponderance of pex; however, reports from ethiopia,10 greece11 and oman4 show that males are affected more than females. notwithstanding, these data may be biased since the diagnoses have mainly been done on clinical grounds. our study has revealed pex glaucoma in a younger age group which means that these patients should be followed up early in life. the present study shows less endothelial cell counts in the pex eyes with glaucoma as compared to pex eyes without glaucoma. the difference, however, is not significant. this observation is supported by knorr et al.12 thus, even though endothelial cell counts may be normal in age-matched pex eyes, the latter may exhibit significant morphological changes with respect to their size/area (polymegathism) and shape/hexagonality (pleomorphism). this could be the reason for pex keratopathy with subsequent early and rapid corneal decompensation.13 since cataract is the most common anterior segment intraocular surgery performed world wide, the implications of pex on corneal endothelial cells are quite demanding.14,15 the overall incidence of intra-operative complications in pex eyes has been reported to be 4-7% depending on the preexisting pathology. the general clinical opinion is that in pex eyes a prolonged corneal recovery after intraocular surgery is frequent. this study has shown that corneal endothelial cell anomalies may provide a morphological basis for this event. the data clearly emphasises the importance of preoperative confocal analysis of pex corneas. table 4: r2 values for different type of regression curves type of regression regression curve of: linear quadratic cubic pleomorphism on polymegathism males and females age ≤ 60 yrs. and age > 60 yrs, glaucoma and no glaucoma 0.467 0.461 & 0.484 0.586 & 0.406 0.643 & 0.402 0.619 0.638 & 0.604 0.725 & 0.573 0.765 & 0.604 0.625 0.648 & 0.603 0.727 & 0.581 0.765 & 0.623 endothelium on polymegathism males and females age ≤ 60 yrs. and age > 60 yrs. glaucoma and no glaucoma 0.017 0.070 & 0.001 0.010 & 0.038 0.002 & 0.036 0.060 0.077 & 0.099 0.039 & 0.075 0.068 & 0.065 0.124 0.121 & 0.167 0.129 & 0.129 0.142 & 0.121 q ua n t i tat i v e a n d q ua l i tat i v e c o r n e a l e n d o t h e l i a l m o r p h o l o g y o f o m a n i pat i e n t s w i t h p s e u d o e x f o l i at i o n s y n d r o m e 305 c o n c l u s i o n pseudoexfoliation in omani population is associated with increased corneal endothelial pleomorphism and polymegathism predisposing to early corneal decompensation after intraocular, mainly cataract, surgeries, even when the endothelial cell counts may be within normal limits. a c k n ow l e d g me n ts the authors have no commercial or proprietary interest in any of the equipment mentioned in the study. no financial support has been received from any source during this study. r e f e r e n c e s 1. schlotzer-schrehardt um, koca mr, naumann go, volkholz h. pseudoexfoliation syndrome. ocular manifestations of a systemic disorder? arch ophthalmol 1992; 110: 1752-1756. 2. forsius h. exfoliation sybdrome in various ethnic populations. acta ophthalmol 1988; 66:71-85. 3. allingham rr, loftsdottir m, gottfredsdottir ms, thorgeirsson e, jonasson f, sverisson t. pseudoexfoliation syndrome in icelandic families. br j ophthalmol 2001; 85:702-707. 4. bialasiewicz aa, wali u, shenoy r, al-saeidi r. patients with secondary open angle glaucoma in pseudoexfoliation (pex) syndrome among a population with high prevalence of pex: clinical findings, morphological and surgical characteristics. ophthalmologe 2005; 102:10641068. 5. aasved h. study of relatives of persons with fibrillopathia epithelio capsularis (psedoexfoliation of the lens capsule). acta ophthalmol 1975; 53:879-886. 6. hattori y. corneal endothelial examination of pseudoexfoliation syndrome. nippon ganka gakkai zasshi 1990; 94:957-963. 7. miyake k, matsuda m, inaba m. corneal endothelial changes in pseudoexfoliation syndrome. am j ophthalmol 1989; 108:49-52. 8. schlotzer-schrehardt um, dorfler s, naumann go. corneal endothelial involvement in pseudoexfoliation syndrome. arch ophthalmol 1993; 111:666-674. 9. seitz b, muller ee, langenbucher a, kus mm, naumann go. endothelial keratopathy in pseudoexfoliation syndrome: quantitative and qualitative morphometry using automated video image analysis. klin monatsbl augenheilkd. 1995; 207:167-175. 10. pseudoexfoliation syndrome in ethopian glaucoma patients. east afr med j 1999; 76:278-280. 11. correlation between age-related macular degeneration and pseudoexfoliation syndrome in the population of crete (greece). arch ophthalmol 1999; 117:664-669. 12. knorr l, junemann a, handel a, naumann go. morphometric and qualitative changes in corneal endothelium in pseudoexfoliation syndrome. fortschr ophthalmol; 1991; 88:786-789. 13. gottfried oh, naumann go, ursula schlotzer-schrehardt. keratopathy in pseudoexfoliation syndrome as a cause of corneal endothelial decompensation. ophthalmology 2000; 107:1111-1124. 14. wirbelauer c, anders v, pham dt, wollensak j . corneal endothelial cell changes in pseudoexfoliation syndrome after cataract surgery. arch ophthalmol 1998; 116:145-149. 15. brooks am, grant g, robertson if, gillies we. progressive corneal endothelial cell changes in anterior segment disease. aust nz j ophthalmol 1987; 15:7178. women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review *amal al hadi,1,2 michelle paliwoda,2 jennifer dawson,3 karen walker,4,5 karen new2,6 sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 455–471, epub. 7 nov 22 submitted 8 dec 21 revision req. 19 jan 22; revision recd. 28 jan 22 accepted 2 mar 22 1midwifery program, higher institute of health specialities, muscat, oman; 2school of nursing, midwifery and social work, the university of queensland, brisbane, australia; 3newborn research centre, the royal women’s hospital, melbourne, australia; 4newborn care, royal prince alfred hospital, sydney, australia; 5faculty of medicine and health, the university of sydney, sydney, australia; 6school of health and behavioural science, university of the sunshine coast, queensland, australia *corresponding author’s e-mail: a.alhadi@uq.net.au the maternity continuum includes postpartum care, which is delivered following childbirth, most commonly over a six-week period and comprises three stages: the immediate stage (0–24 hours after birth), the early stage (days 2–7) and the late stage (days 8–42).1 care during the immediate stage is mostly administered in birth facilities, whereas earlyand late-stage care is community-based. care during the postnatal period is as important as antenatal and intrapartum care as complications can arise, resulting in adverse outcomes and leading to increased morbidity and mortality for the mother and/or newborn.1 moreover, determining women’s satisfaction with postnatal care is essential as it has a direct influence on the utilisation of the postnatal follow-up care.2 utilisation of healthcare services is crucial for not only women’s physical health but also their mental health. early detection and management of postnatal mental health conditions such as anxiety and depression are vital, as such conditions have a significant impact not only on the woman but also upon the well-being of the newborn and the entire family.3 the world health organization (who) recom mends that mothers and newborns receive postnatal care at the birthing facility for at least 24 hours.4 however, birthing facilities (e.g. hospitals) in many countries discharge women and their newborns before that time.5 a systematic review by campbell et al. reported that the length of stay in birthing facilities has decreased, with women staying less than 24 hours following vaginal birth and less than 72 hours following a caesarean section.6 kumar and dhillon reported that early discharge underpins the lack of early detection and management of complications for both the mother and the newborn, which increases the risk of morbidity and mortality.7 early discharge is also associated with increased neonatal readmission within 28 days of birth and increased risks of maternal postpartum depression.5,8 immediate postnatal care is focused on the immediate general well-being of the mother and newborn following childbirth and involves treating complications, such as infections, perineal pain, vaginal discharge and excessive bleeding and supporting breastfeeding.7,9 early and late postnatal care tends to focus on maximising maternal and newborn health and well-being through health monitoring and health promotion during postnatal follow-up care.10 this may include screening for maternal postpartum depression, checking and treating childbirth-related complications and having discussions on parenting and family planning.4,11 for the newborn, this covers breastfeeding support, monitoring of the newborn’s growth, development and overall health and referrals for specialised care, if required.1 additionally, while becoming a new parent is exciting, it can also be a stressful time, particularly for first-time parents and those without strong social support and role models.12 thus, early and late postnatal periods are review this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.10.2022.059 abstract: postnatal follow-up care is reported to be the ‘underutilised’ aspect of the maternity care continuum. this review explores women’s utilisation of early and late postnatal follow-up and their experiences and satisfaction with it. five online databases were searched for english or arabic articles published between 2011 and 2021. methodological quality of included studies was assessed using the mixed methods appraisal tool; the andersen healthcare utilisation model was the framework for data analysis. a total of 19 articles met all inclusion criteria. utilisation facilitators included complications, travel distance, knowledge of the importance for attending and being offered a telephone call and home visit or clinic visit as options for follow-up. impediments included lack of perceived need and not being provided with information about postnatal care. comprehensive discussions with and examination by health providers were reported as positive experiences and influenced repeat utilisation. dissatisfaction was associated with inconsistent information provided by health providers. keywords: postpartum period; postnatal care; women; literature review. https://creativecommons.org/licenses/by-nd/4.0/ women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 456 | squ medical journal, november 2022, volume 22, issue 4 important periods during which education from health professionals has the potential to influence positive parenting experiences and healthy child development.12 forster et al. found that the majority of mothers (90%) viewed their experiences of a flexible model of care, which included early hospital discharge (within 12 hours) and four planned home visits, as positive; the majority (88%) of mothers indicated their willingness to participate in this model of care again.13 additionally, yonemoto et al.’s cochrane systematic review found that home visits were associated with reduced newborn re-admissions in the weeks following birth, continued and exclusive breastfeeding and increased maternal satisfaction with postnatal care.14 the importance of postnatal contacts by healthcare professionals has been further emphasised by the who via the recommendation of three contacts following discharge from a health facility or home birth, in line with target three of the sustainable development goals (sdgs).4,15 thus, scheduled contacts and home visits during the postnatal period are essential to ensuring the ongoing monitoring of maternal and newborn health and wellbeing. national and international guidelines and recomm endations for immediate, early and late postnatal care following birth at a health facility or at home have been developed by many countries, professional organisations and professional groups.4,11,16–19 postnatal follow-up is provided in the early and late stages and it appears to vary from two postnatal visits around two and six weeks after birth to three visits starting at day three (47–72 hours), between days seven and 14 and at 42 days after birth.4,16 additionally, there are reports in the literature that postnatal follow-up care is the “neglected”, under offered and/or underutilised aspect of the maternity care continuum.3,4,20 this may result in lost opportunities for health promotion and monitoring of mothers and their newborns. promoting postnatal follow-up care is important to the whole family unit as mothers often have the role and responsibility of overseeing the family’s health in both health promotion and illness prevention and of managing ill health.21 although there are many studies reporting on satisfaction and experiences of immediate postnatal care, less is known about the factors that influence women’s decisions with regard to utilising early and late postnatal follow-up and their experiences and satisfaction with care received. thus, this review aimed to explore women’s utilisation of early and late postnatal follow-up and their experiences and satisfaction with it. methods this systematic review used the population, exposure and outcome framework to guide the search strategy instead of the population, intervention, comparison and outcome, as the purpose of this review was not to investigate or compare exclusive interventions. several preliminary searches were performed to identify commonly used keywords and the final search strategy was developed in collaboration with a senior librarian. wildcard symbols were used in line with database requirements and medical subject headings (mesh; us national library of medicine, bethesda, maryland, usa) for pubmed (us national library of medicine) and cumulative index to nursing and allied health literature (cinahl; ebsco information services, ipswich, massachusetts, usa) databases, where appropriate. for example, the question mark symbol “?” was used when searching for words that can be spelt with both an ‘s’ or a ‘z’ (utilisation/utilization) or for words with singular and plural forms (woman/ women). between march and april 2021, pubmed (us national library of medicine), cinahl (ebsco information services), scopus (elsevier, amsterdam, the netherlands), web of science (clarivate analytics, philadelphia, pennsylvania, usa) and google scholar (google llc, mountain view, california, usa) electronic databases were systematically searched using the english search terms “wom?n”, “maternal”, “post-partum period”, “post-partum care”, “postnatal care”, “postnatal follow-up”, “home-based”, “utili?ation”, “experience” and “satisfaction”. the language filter was not applied. primary studies of any study design that reported one or more of the outcomes of women’s utilisation of or experience or satisfaction with early (2–7 days) or late (8–42 days) postnatal care, irrespective of birth setting (e.g. hospital, health centre, home), were eligible for inclusion. full text publications in english or arabic were eligible for inclusion; however, no studies published in arabic were retrieved. publications in which data collection occurred within the last 10 years (between january 2011 and july 2021) and within one year of childbirth were eligible. the search parameter was limited to articles published with data collected within the last 10 years to capture recent perspectives from women on postnatal service utilisation, experiences and satisfaction and to limit potential variation in practice change that may have occurred along with changes that have occurred around antenatal and intrapartum care. studies were excluded if the data included immediate postnatal care and if the data specifically for early and/or late amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 457 follow-up could not be extracted. likewise, studies in which the views and experiences of women and their support network (partners or other family members) were presented collaboratively and wherein women’s responses could not be extracted were excluded. abstracts, thesis, conference proceedings and secondary studies were also excluded. search results were uploaded into zotero reference management software, version 5.0.96.2. following the removal of duplicates, title and abstract screening was undertaken independently by three reviewers (ah, jd and mp) and arbitrated by a fourth reviewer (kn), if needed. review of full texts was undertaken independently by three reviewers (ah, jd and mp) and the opinion of a fourth reviewer (kn) was sought to reach a final decision regarding eligibility when needed. a data extraction spreadsheet was developed by the review team. data were extracted by one reviewer (ah) and verified by two others (mp and kn). any disagreements were discussed to reach consensus. the review team continuously discussed and validated decisions made during all stages of the review process. the mixed methods appraisal tool (mmat) 2018 was used to appraise the included studies as this tool permits the appraisal of qualitative, quantitative descriptive, mixed methods and non-randomised studies and randomised controlled trials.22 quality assessment is undertaken by answering ‘yes’, ‘no’ or ‘can’t tell’ for five methodological quality criteria specific to each study design. for this review, a quality rating was assigned using a star (*) rating system from one star (20% of quality criteria met = one criterion received yes) to five stars (100% of quality criteria met = five criteria received yes).23 two reviewers (ah and mp) independently assessed the quality of the included studies and discrepancies were resolved via discussions or the involvement of a third reviewer.24 the data analysis framework was based on the andersen healthcare utilisation model of predisposing factors, enabling (and impeding) factors and need factors.25 as the review contained quantitative and qualitative studies, numerical data on utilisation and factors reported qualitatively that facilitated or impeded utilisation, influenced experiences positively or negatively and resulted in satisfaction or dissatisfaction with care received were summarised. results a total of 172 articles were identified as potentially eligible. following the removal of duplicates and the screening and data extraction processes, a total of 19 studies met the eligibility criteria for inclusion in this review [figure 1]. figure 1: flowchart showing the article selection process. cinahl = cumulative index to nursing and allied health literature. women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 458 | squ medical journal, november 2022, volume 22, issue 4 t ab le 1 : c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g u til is at io n ex pe ri en ce s sa tis fa ct io n a bu ka a be bo a nd je m be r te sf ay e2 6 (2 01 8) et hi op ia n = 4 01 w om en a ge d 15 – 49 y ea rs w ho h ad a li ve bi rt h w ith in on e ye ar p ri or to th e su rv ey st ud y de si gn : c om m un ity -b as ed c ro ss se ct io na l s tu dy d at a co lle ct io n: s tr uc tu re d, c lo se den de d, in te rv ie w er -a dm in is te re d, p re -t es te d qu es tio nn ai re c on du ct ed in 2 01 6 sa m pl in g: s tr at ifi ed r an do m pn c w as u til is ed b y 19 1 (4 7. 6% ) w om en b et w ee n on e an d 42 d ay s af te r bi rt h. fa ct or s t ha t f ac ili ta te d ut ili sa ti on : m at er na l e du ca tio n, o cc up at io n, h ou se ho ld m on th ly in co m e an d jo in t d ec is io nm ak in g (h us ba nd /w ife d ya d) th e gr ea te r nu m be r of a n c v is it s w as a ss oc ia te d w ith in cr ea se d po st na ta l u til is at io n. a w ar en es s of a t l ea st o ne p os tp ar tu m d an ge r si gn w as a ls o as so ci at ed w ith in cr ea se d ut ili sa tio n. fa ct or s t ha t i m pe de d ut ili sa ti on : bi rt hi ng a t h om e w as a ss oc ia te d w ith d ec re as ed ut ili sa tio n. n ot r ep or te d n ot r ep or te d ** ** * a lm al ik 44 (2 01 7) jo rd an n = 1 50 w om en , a ge d 17 – 46 y ea rs , re cr ui te d on th e da y of h os pi ta l di sc ha rg e w ith a fo llo w -u p at 6 – 8 w ee ks po st na ta lly st ud y de si gn : p ro sp ec tiv e co ho rt s tu dy d at a co lle ct io n: s el fad m in is tr at ed po st pa rt um le ar ni ng n ee ds o n a 50 -i te m s ca le co m pl et ed o n th e da y of d is ch ar ge ; a t 6 – 8 w ee ks a ft er g iv in g bi rt h, w om en w er e as ke d to c om pl et e th e po st pa rt um p er ce iv ed m et le ar ni ng n ee ds s ca le fo llo w in g a po st pa rt um ch ec kup a t a h ea lth c en tr e. d at a co lle ct io n oc cu rr ed in 2 01 5. sa m pl in g: c on ve ni en ce s am pl in g 11 7 (7 8% ) w om en a tt en de d th e he al th c en tr e fo r a po st pa rt um c he ck -u p be tw ee n 6 an d 8 w ee ks . w om en w ho w er e ol de r, w er e em pl oy ed , ha d a hi gh er le ve l o f ed uc at io n, h ad r eg ul ar at te nd an ce a t a n c vi si ts , h ad a c ae sa re an se ct io n an d w an te d m or e in fo rm at io n, “h ad hi gh er le ar ni ng n ee ds ”. pr im ar y un m et le ar ni ng n ee ds w er e da ng er s ig ns p os tca es ar ea n se ct io n, ph ys ic al c ha ng es , br ea st fe ed in g an d ne w bo rn c ar e. n ot r ep or te d ** ** b el ih u an d d er es sa 27 (2 02 0) et hi op ia n = 3 32 w om en w ith a m ea n ag e of 2 7. 8 ye ar s w ho h ad g iv en bi rt h w ith in si x w ee ks a nd at te nd ed o ne of fo ur h ea lth ce nt re s fo r ea rl y po st na ta l fo llo w -u p ca re (w ith in o ne w ee k) st ud y de si gn : i ns tit ut io nba se d cr os sse ct io na l s tu dy d at a co lle ct io n: s tr uc tu re d in te rv ie w er ad m in is te re d qu es tio nn ai re d es ig ne d fo r th e st ud y ba se d on ‘d iff er en t l ite ra tu re s an d m od ifi ed fo r th e ob je ct iv e of th e st ud y’ to as se ss p n c u til is at io n at o ne w ee k af te r de liv er y. d at a co lle ct io n oc cu rr ed in 2 01 8. sa m pl in g: s ys te m at ic s am pl in g pn c w as u til is ed b y on ly 8 4 (2 5. 3% ) w om en w ith in th e fir st w ee k. fa ct or s th at fa ci lit at ed e ar ly u til is at io n: c om pl ic at io ns d ur in g la bo ur a nd d el iv er y, li vi ng w ith in 3 0 m in ut es o f a h ea lth c en tr e, b ei ng a w ar e th at th ey s ho ul d at te nd fo r pn c w ith in o ne w ee k. fa ct or s th at im pe de d ea rl y ut ili sa tio n: b ei ng u ni nf or m ed a nd /o r no t g iv en a n ap po in tm en t f or a tt en di ng c ar e in o ne w ee k, b ut fo r si x w ee ks , l iv in g m or e th an a 3 0m in ut e w al k aw ay fr om th e he al th c en tr e, p ar tn er s el fem pl oy ed (e .g ., fa rm er ) a nd c ul tu ra l r ea so ns (n ot s pe ci fie d) -th e m aj or ity o f w om en re po rt ed th e ne ed fo r ad vi ce o n m at er na l a nd ne on at al p os tp ar tu m co m pl ic at io ns . n ot r ep or te d * m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 459 t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g br od ri bb e t al .40 (2 01 3) a us tr al ia n = 8 8 w om en , in cl ud in g 18 w om en a ge d 21 – 41 y ea rs , in vo lv ed in th e pi lo t s tu dy , re cr ui te d in ho sp ita l a ft er ch ild bi rt h an d fo llo w ed -u p ap pr ox im at el y 10 w ee ks af te r bi rt h; 70 w om en , ag ed 2 1– 39 ye ar s, w ho h ad gi ve n bi rt h le ss th an tw o ye ar s pr io r an d pa rt ic ip at ed in an e va lu at io n st ud y st ud y de si gn : q ua lit at iv e st ud ie s. -th e pi lo t s tu dy in ve st ig at ed p ri m ar y ca re se rv ic es w om en a cc es se d du ri ng th e ei gh tw ee k po st pa rt um p er io d. -th e se co nd s tu dy e va lu at ed a u ni ve rs al po st na ta l c on ta ct s er vi ce (i nc lu di ng p ho ne co nt ac t o r a ho m e vi si t w ith in 1 0 da ys o f di sc ha rg e po st -b ir th ). -d at a w er e an al ys ed to ge th er b ec au se b ot h st ud ie s as ke d si m ila r qu es tio ns r eg ar di ng po st pa rt um c ar e in th e co m m un ity . d at a co lle ct io n: d at a w er e co lle ct ed u si ng se m ist ru ct ur ed , f ac eto -f ac e in te rv ie w s co nd uc te d be tw ee n 20 10 a nd 2 01 2 (s tu dy 1 ) an d in 2 01 1 (s tu dy 2 ). sa m pl in g: n ot r ep or te d -w om en d id n ot a pp ea r to b e gi ve n co ns is te nt in fo rm at io n ab ou t w he n th ey s ho ul d vi si t t he ir g p fo r m at er na l a nd n ew bo rn p os tp ar tu m c he ck -u ps . -f ir st p os tp ar tu m v is it ra ng ed fr om fi ve d ay s to 2. 5 m on th s, w ith m os t v is it s ar ou nd s ix w ee ks , co m m on ly fo r th e ne w bo rn im m un is at io ns . -s om e w om en fo llo w ed in st ru ct io ns g iv en in th e ne w bo rn p er so na l h ea lth r ec or d bo ok (r ec om m en da tio n: a tt en d g p w ith in th e fir st fo ur w ee ks ). fa ct or s th at fa ci lit at ed u til is at io n: e xp lic it in fo rm at io n/ in st ru ct io ns (w om en w ho b ir th ed in th e pu bl ic s ec to r co m pa re d to th e pr iv at e se ct or re po rt ed h av in g re ce iv ed e xp lic it in st ru ct io ns fr om a m id w ife to a tt en d th ei r g p in th e fir st tw o w ee ks af te r ch ild bi rt h, e sp ec ia lly if th ey w er e di sc ha rg ed w ith in 4 8 ho ur s of b ir th .)f ac to rs th at im pe de d ut ili sa tio n: l ac k of k no w le dg e re ga rd in g th e re as on s fo r fo llo w -u p po st -b ir th , n o pr ob le m s w er e ev id en t, w er e m ul tip ar ou s, e xp er ie nc ed a s en se o f ab an do nm en t b y th e ho sp ita l a nd th ei r sp ec ia lis ts w om en r ep or te d th at g ps w er e se en fo r an y m at er na l o r in fa nt h ea lth is su es , w he re as k no w le dg e on in fa nt b eh av io ur pr ob le m s an d pa re nt in g ad vi ce w as so ug ht fr om c hi ld a nd fa m ily h ea lth c en tr es , te le ph on e ad vi ce li ne s or m ot he rs ’ g ro up s. po si tiv e ex pe ri en ce fa ct or s: c om pr eh en si ve di sc us si on o f t he ir so ci al s itu at io n, ho w th e fa m ily w as m an ag in g, s pe ci fic qu es tio ns a bo ut pr ob le m a re as e ith er ph ys ic al o r m en ta l an d a co m pr eh en si ve ex am in at io n of th em se lv es a nd th ei r ne w bo rn n eg at iv e ex pe ri en ce fa ct or s: c ur so ry e xa m in at io n w ith li tt le d is cu ss io n d is sa tis fa ct io n w as as so ci at ed w ith th e di ve rg en ce o f in fo rm at io n gi ve n ar ou nd c he ck up s: s ix w ee ks fo r m ot he r/ ne w bo rn ; fo ur w ee ks fo r ba by an d si x w ee ks fo r m ot he r; a ro un d fiv e w ee ks fo r ne w bo rn , m ot he r di d no t ne ed a ny c he ck -u ps ; fir st 5 – 10 d ay s fo r m ot he r/ ne w bo rn an d ag ai n at s ix w ee ks fo r m ot he r an d ei gh t w ee ks fo r ne w bo rn o r ad vi se d at o ne , t w o an d th en fo ur m on th s. ** ** * c re an ga e t al .34 (2 01 7) m al aw i n = 1 ,3 01 w om en a ge d 15 – 49 y ea rs w ho h ad a li ve bi rt h w ith in th e la st 1 2 m on th s st ud y de si gn : b as el in e, tw ost ag e cl us te r sa m pl in g ho us eh ol d su rv ey d at a co lle ct io n: -s el fre po rt ed s ur ve y w ith d at a co lle ct ed in 2 01 2, p ri or to im pl em en ta tio n of a n in te rv en tio n to im pr ov e ut ili sa tio n an d qu al ity o f p er in at al h ea lth s er vi ce s. th e qu es tio ns to a ss es s qu al ity o f c ar e w er e de ve lo pe d se pa ra te ly fo r ea ch ty pe o f p n c us in g th e h ul to n fr am ew or k on q ua lit y of m at er ni ty c ar e as g ui de . s am pl in g: t w ost ag e cl us te r sa m pl in g 1, 00 9 (7 7. 5% ) p os tp ar tu m w om en h ad a t l ea st o ne po st na ta l c he ck . t im in g of th e fir st p os tn at al v is it fo r m at er na l a nd /o r ne w bo rn w as o n av er ag e 3. 1 w ee ks a nd a ve ra ge n um be r of p os tn at al c he ck s w ith in e ig ht -w ee k po st pa rt um p er io d w as 3 .1 . fa ct or s th at fa ci lit at ed u til is at io n: l iv ed c lo se to a he al th fa ci lit y (< 30 m in ut es ) a nd h is to ry o f f am ily pl an ni ng fa ct or s th at im pe de d ut ili sa tio n: l iv ed > 1 ho ur fr om a h ea lth fa ci lit y o f t he w om en w ho an sw er ed q ua lit y of pn c q ue st io ns , 9 0. 4% re po rt ed th ey w er e ad vi se d on d an ge r si gn s to w at ch fo r in bo th th em se lv es a nd th ei r ne w bo rn , 9 5. 4% re ce iv ed b re as tf ee di ng su pp or t a nd c ou ns el lin g an d 97 .9 % r ec ei ve d co un se lli ng o n m et ho ds to a vo id o r de la y an ot he r pr eg na nc y. n ot r ep or te d ** ** d ar eg a et al .28 (2 01 6) et hi op ia n = 7 03 w om en , a ge d ≥1 8 ye ar s, w ho g av e bi rt h w ith in p as t 1 2 m on th s st ud y de si gn : c om m un ity -b as ed c ro ss se ct io na l s tu dy d at a co lle ct io n: in te rv ie w er ad m in is te re d, s tr uc tu re d qu es tio nn ai re s de si gn ed fo r th e st ud y, a da pt ed fr om pe rt in en t l ite ra tu re a nd p re -t es te d on 5 % o f ta rg et p op ul at io n no t i nc lu de d in th e st ud y. d at a w er e co lle ct ed in 2 01 3. s am pl in g: r an do m o f t he to ta l r es po nd en ts , 5 56 (7 9. 1% ) h ad h ea rd ab ou t p n c s er vi ce s bu t o nl y 22 3 (3 1. 7 % ) u til is ed pn c s er vi ce s ov er a p er io d of u p to s ix w ee ks . th e m aj or ity u se d he al th e xt en si on w or ke rs a t h ea lth ai d po st s (9 1. 5% ) a nd h ad h om e bi rt he d (n = 2 12 , 30 .2 % ). fa ct or s th at fa ci lit at ed u til is at io n: u til is ed a n c s er vi ce s, a bl e to d ec id e fo r th em se lv es , l iv ed le ss th an 5 k m fr om a h ea lth fa ci lit y n ot r ep or te d n ot r ep or te d ** ** * m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 460 | squ medical journal, november 2022, volume 22, issue 4 t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g g eb re hi w ot et a l.2 9 (2 01 8) et hi op ia n = 3 67 w om en , a ge d >1 5 ye ar s, w ho ha d a ch ild ag ed 4 5 da ys u p to s ix m on th s st ud y de si gn : f ac ili ty -b as ed , c ro ss se ct io na l s tu dy d at a co lle ct io n: s tr uc tu re d qu es tio nn ai re a da pt ed b y re vi ew in g re le va nt lit er at ur e an d qu es tio nn ai re s uc h as e d h s 20 11 a nd w h o g ui de lin e fo r po st na ta l c ar e; p re -t es te d am on g 5% o f t ot al s am pl e po pu la tio n no t s el ec te d fo r th e st ud y. d at a co lle ct io n pe ri od o cc ur re d in 2 01 4. s am pl in g: r an do m 17 0 (4 6. 3% ) k ne w a bo ut th e av ai la bi lit y of p n c at h ea lth fa ci lit ie s; o f t he se , 7 3 (4 2. 9% ) k ne w th e fr eq ue nc y of v is it s. o nl y 11 8 (3 2. 2% ) h ad u til is ed po st na ta l f ol lo w -u p at le as t o nc e w ith in 4 2 da ys of d el iv er y. th e m aj or ity (5 1. 7% ) h ad fi rs t v is it be tw ee n da ys 1 5 an d 42 , 2 8. 8% b et w ee n da ys s ev en an d 14 a nd 1 9. 4% w ith in th re e da ys . o f t ho se w ho ut ili se d fo llo w -u p, 3 8. 1% a tt en de d fo r pn c v is it , 28 % fo r ca re o f s ic k m ot he r, 20 .3 % c ar e of s ic k ba by an d 13 .6 % fo r ba by im m un is at io n. f ac to rs th at fa ci lit at ed u til is at io n: h ad a tt en de d a n c a t l ea st on ce , k ne w a bo ut p n c a nd ti m in g of v is it s, h ad at te nd ed p n c a ft er p re vi ou s pr eg na nc y an d ha d co m pl ic at io ns d ur in g de liv er y, li ve d w ith in w al ki ng di st an ce to th e he al th c en tr e. w om en ’s oc cu pa tio n (p ri va te e m pl oy ee s an d bu si ne ss w om en ) a nd ed uc at io n le ve l, hu sb an d’ s oc cu pa tio n an d ed uc at io n le ve l i nfl ue nc ed a tt en da nc e. fa ct or s th at im pe de d ut ili sa tio n: n o kn ow le dg e ab ou t th e av ai la bi lit y of p n c s er vi ce s (n = 1 84 , 7 3. 9% ), fo ur o r m or e pr ev io us c hi ld re n, h ea lth y an d hi gh w or kl oa d in th ei r ho us e o f t he w om en w ho h ad vi si te d a pn c c lin ic (n = 11 8) , m os t ( n = 10 3, 87 .3 % ) h ad e xp er ie nc ed re ce iv in g le ss th an s ix el em en ts o f p os tn at al fo llo w -u p ca re , t he lo w es t e le m en ts w er e on p er so na l h yg ie ne , m ea su ri ng b od y te m pe ra tu re o f t he ba by , c ou ns el lin g on h iv tr an sm is si on , ba by c ar e an d ex cl us iv e br ea st fe ed in g. n ot r ep or te d ** ** iz ud i e t a l.3 2 (2 01 7) su da n n = 3 85 w om en w ith a m ea n ag e of 2 7. 9 ye ar s w ho a tt en de d a po st na ta l fo llo w -u p vi si t w ith in 2 – 7 da ys a ft er b ir th st ud y de si gn : a na ly tic al c ro ss -s ec tio na l s tu dy d at a co lle ct io n: d at a w er e co lle ct ed in 2 01 6 vi a in te rv ie w s us in g st ru ct ur ed q ue st io nn ai re s at 1 3 lo ca tio ns (o ne r eg io na l r ef er ra l h os pi ta l, tw o co un ty h os pi ta ls a nd 1 0 pr im ar y he al th ca re c en tr es ). sa m pl in g: s ys te m at ic ra nd om a nd c on ve ni en ce o nl y 44 (1 1. 4% ) w om en u til is ed e ar ly p n c (w ith in 2 – 7 da ys )f ac to rs th at fa ci lit at ed e ar ly ut ili sa tio n: s ec on da ry le ve l o f e du ca tio n or b ey on d, at te nd ed a n c v is it s, b ir th ed in h ea lth fa ci lit y, h ad he al th e du ca tio n on p n c v is it s, in fo rm ed a bo ut pn c c he ck -u ps a ft er b ir th , k ne w p os tp ar tu m co m pl ic at io ns , h ad fr ie nd ly h ea lth w or ke rs a nd w itn es se d pr es en ce o f h ea lth w or ke rs a t h ea lth fa ci lit ie sf ac to rs th at im pe de d ea rl y ut ili sa tio n: h ad ho m e bi rt h, a cc es se d he al th s er vi ce s at g ov er nm en t he al th fa ci lit ie s, r ep or te d m or e th an 1 h ou r to re ac h th e ne ar es t h ea lth fa ci lit y, li ve d m or e th an 5 km fr om th e ne ar es t h ea lth fa ci lit y n ot r ep or te d n ot r ep or te d ** ** iz ud i a nd a m on gi n3 1 (2 01 5) u ga nd a n = 3 57 w om en a ge d 15 – 49 y ea rs w ho h ad g iv en bi rt h be tw ee n on e w ee k an d on e ye ar st ud y de si gn : c ro ss -s ec tio na l s tu dy d at a co lle ct io n: s tr uc tu re d qu es tio nn ai re co ns is tin g of b ot h op en an d cl os ed -e nd ed qu es tio ns , p re te st ed to a ss es s it s ac ce pt ab ili ty , va lid ity , r el ia bi lit y an d ap pr op ri at en es s. d at a w er e co lle ct ed in 2 01 4. s am pl in g: s ys te m at ic ra nd om a nd c on ve ni en ce . a to ta l o f 2 88 (8 0. 7% ) w om en h ad fu ll kn ow le dg e of th e av ai la bl e pn c s er vi ce s at th e ne ar es t h ea lth fa ci lit y. e ar ly p n c (b et w ee n 2– 7 da ys p os tbi rt h) w as o nl y ut ili se d by 5 5 (1 5. 4% ) w om en ; 1 91 w om en (5 3. 5% ) u til is ed p n c w ith in 4 2 da ys p os tde liv er y. fa ct or s th at fa ci lit at ed e ar ly u til is at io n: f or m al em pl oy m en t, ed uc at io n ab ou t p n c s ch ed ul es an d co m pl ic at io ns , a tt en da nc e at p ri va te h ea lth fa ci lit y. fa ct or s th at im pe de d ea rl y ut ili sa tio n: p n c at p ub lic h ea lth fa ci lit y, n ot g iv en e du ca tio n on po st pa rt um c om pl ic at io ns b ef or e di sc ha rg e, s el fem pl oy ed m ot he rs , a lo ng o r ve ry lo ng q ue ui ng tim e at th e he al th fa ci lit y, e nc ou nt er ed r ud e he al th w or ke rs . n ot r ep or te d n ot r ep or te d ** ** m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 461 t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g jo ha ns so n et a l.4 2 (2 01 9) sw ed en n = 1 80 he al th y w om en , m os tly ag ed 2 5 ye ar s, of s w ed is h or ig in , w ho ha d a hi gh le ve l of e du ca tio n, liv ed w ith th ei r pa rt ne r, ha d an un co m pl ic at ed pr eg na nc y an d bi rt h an d w er e on e w ee k po st pa rt um st ud y de si gn : c ro ss -s ec tio na l s tu dy u si ng qu an tit at iv e an d qu al ita tiv e da ta w ith a co nc ur re nt m ix ed m et ho ds d es ig n d at a co lle ct io n: v ia a n on lin e qu es tio nn ai re ad m in is te re d on e w ee k po st -b ir th . th e qu es tio nn ai re c on si st ed o f 2 2 cl os ed en de d an d fo ur o pe nen de d qu es tio ns . th e qu es tio nn ai re w as p ilo t t es te d by fo ur p ar en ts (b ot h m ot he rs a nd th ei r pa rt ne rs ) w ho h ad re ce iv ed s im ila r pn c ju st b ef or e th e st ar t o f da ta c ol le ct io n, w hi ch to ok p la ce b et w ee n 20 17 a nd 2 01 8. s am pl in g: p ur po si ve (a ll w om en w ho p ar tic ip at ed in a h om eba se d m od el o f m id w ife ry c ar e ov er 1 2 m on th s w er e in vi te d to p ar tic ip at e [n = 2 47 ].) -e ar ly d is ch ar ge a nd u til is at io n of o pt io na l po st na ta l f ol lo w -u ps b y te le ph on e, h om e vi si ts a nd ho sp ita l v is it s. -1 00 % u til is ed te le ph on e co nt ac t ( m ea n: 2 .0 6 ± 1. 08 7) , 9 3. 9% (n = 1 69 ) h om e vi si t( s) a nd 9 8. 3% (n = 17 7) h os pi ta l v is it( s) 15 2 (8 4. 4% ) r ep or te d po si tiv e pn c ex pe ri en ce s. h av in g th e op po rt un ity to r ec ei ve br ea st fe ed in g su pp or t an d to a sk m id w iv es qu es tio ns c on tr ib ut ed to th is e xp er ie nc e. po si tiv e ex pe ri en ce fa ct or s: e ar ly d is ch ar ge fo llo w ed b y ho m e vi si ts (w as e xp er ie nc ed as p er so na l, ca lm in g, co m fo rt ab le a nd ha rm on io us ), te le ph on e co nt ac ts , o rg an is ed an d eff ec tiv e ho sp ita l vi si ts a s w el l a s ha vi ng en ou gh ti m e fo r ch ec kup .n eg at iv e ex pe ri en ce fa ct or s: -s om e m ot he rs w an te d a lo ng er h os pi ta l s ta y w he n ne ed in g m or e br ea st fe ed in g or in fo rm at io na l s up po rt be fo re d is ch ar ge , la ck o f c oor di na tio n of c ar e w he n ex tr a ch ec k u ps w er e ne ed ed fo r th e in fa nt , b ei ng un ab le to c ho os e th e da y fo r th e ho sp ita l vi si t o r ch os e ei th er ho sp ita l o r ho m e vi si ts , st re ss ed p ro fe ss io na ls , pr of es si on al s w ho ga ve c on tr ad ic tin g ad vi ce a nd th e fa th er or th e fa m ily n ot b ei ng in vo lv ed in th e vi si t. -a ls o, fe w m ot he rs ha d a le ss p os iti ve ex pe ri en ce o f t he h om e vi si t, as th ey p er ce iv ed th at th e m id w ife w as un sk ill ed . te le ph on e co nt ac t fo llo w -u p: 1 72 (9 7. 2% ) w om en re po rt ed b ei ng ve ry s at is fie d or sa tis fie dh om e vi si t fo llo w -u p: 1 63 (9 6. 5% ) w om en re po rt ed b ei ng ve ry s at is fie d or sa tis fie dh os pi ta l vi si t f ol lo w -u p: 1 57 (9 1. 3% ) w om en re po rt ed b ei ng v er y sa tis fie d or s at is fie d ** ** m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 462 | squ medical journal, november 2022, volume 22, issue 4 t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g la lib er té e t al .43 (2 01 6) c an ad a n = 4 72 w om en a ge d 18 y ea rs a nd ol de r w ho h ad de liv er ed a he al th y te rm si ng le to n in fa nt st ud y de si gn : r an do m is ed c on tr ol le d tr ia l us in g a 1: 2 ra tio to r an do m is e m ot he rs to ei th er s ta nd ar d ca re (c on tr ol g ro up , n = 1 57 ) or m an da to ry a tt en da nc e of o ne v is it to a ne w ly e st ab lis he d in te gr at iv e po st pa rt um co m m un ity -b as ed c lin ic (i nt er ve nt io n gr ou p, n = 31 5) d at a co lle ct io n: u nd er ta ke n in 2 01 4; fo llo w -u p da ta w er e co lle ct ed fr om m ot he rs at tw o, fo ur , 1 2 an d 24 w ee ks p os tn at al ly v ia a se lfre po rt w eb -b as ed s ur ve y (r ed c ap ) or a te le ph on e in te rv ie w sa m pl in g: s tr at ifi ed ra nd om in te rv en tio n gr ou p: c ou ld a tt en d th e cl in ic a s m an y tim es a s th ey d es ir ed u p to s ix w ee ks a ft er bi rt h. a to ta l o f 3 4 (1 0. 8% ) d id n ot a tt en d th e cl in ic at a ll, 5 6 (1 7. 8% ) v is ite d on ce , 6 2 (1 9. 7% ) v is ite d tw ic e, 6 4 (2 0. 3% ) h ad th re e vi si ts a nd 9 9 (3 1. 4% ) vi si te d fo ur o r m or e tim es .c on tr ol g ro up : f ou r w om en w ith dr ew fr om th e st ud y. d at a on c lin ic at te nd an ce w er e no t r ep or te d. th e ex pe ri en ce s of w om en a tt en di ng a n in te gr at ed c om m un ity ba se d cl in ic d id n ot re su lt in s ig ni fic an t di ffe re nc es in br ea st fe ed in g ou tc om es (e xc lu si ve ly , p ar tia lly o r an y) a t t w o, fo ur o r 12 w ee ks . s im ila rl y, th er e w er e no s ig ni fic an t di ffe re nc es b et w ee n th e gr ou ps fo r de pr es si on sc or es a t t hr ee w ee ks , m ea n se lfeffi ca cy sc or es a t t w o, fo ur a nd 12 w ee ks . th e in te rv en tio n gr ou p w as si gn ifi ca nt ly m or e sa tis fie d w ith th e br ea st fe ed in g su pp or t t he y re ce iv ed c om pa re d to th e co nt ro l gr ou p. th ey w er e al so s at is fie d w ith th e br ea st fe ed in g cl in ic in te rm s of lo ca tio n, p hy si ca l en vi ro nm en t, op en in g ho ur s an d ea si ne ss to g et a n ap po in tm en t a t a co nv en ie nt ti m e. ** ** o ng e t a l.3 5 (2 01 4) si ng ap or e n = 1 3 fir st tim e m ot he rs ag ed 2 1– 39 ye ar s w er e in te rv ie w ed be tw ee n 7– 11 d ay s po st h os pi ta l di sc ha rg e st ud y de si gn : d es cr ip tiv e qu al ita tiv e st ud y d at a co lle ct io n: o ne s em ist ru ct ur ed in te rv ie w w as c on du ct ed w ith e ac h m ot he r at he r ho m e/ or a t t he h os pi ta l a ft er e ar ly (fi rs t) po st na ta l c on su lta tio n. a n in te rv ie w g ui de w as d ev el op ed w ith th e co ns ul ta tio n of tw o ex pe rt s in q ua lit at iv e re se ar ch . d at a w er e co lle ct ed in 2 01 1– 20 12 . s am pl in g: p ur po si ve n ot r ep or te d -i nf or m at io n gi ve n pr io r to d is ch ar ge d id no t p re pa re m ot he rs fo r th e po st na ta l p er io d at h om e re su lti ng in a pe rc ei ve d la ck o f kn ow le dg e in v ar io us as pe ct s of in fa nt an d m at er na l c ar e, in cl ud in g ba th in g an d sw ad dl in g, a s w el l a s fa ct ua l i nf or m at io n on co m m on n or m al a nd ab no rm al s ym pt om s. -p ar tic ip an t’s ex pe ri en ce w as th at m or e gu id an ce a nd su pp or t i s ne ed ed in th e ea rl y po st na ta l pe ri od a nd th at h om e vi si ts w er e ne ed ed . -n ot a ll of th e w om en re ce iv ed in fo rm at io n of c on ta ct d et ai ls fo r a ‘h ot lin e’ p ho ne nu m be r to c on ta ct a he al th p ro fe ss io na l w he n ad vi ce is n ee de d po st d is ch ar ge (a st an da rd p ra ct ic e w he re in a ll w om en sh ou ld b e pr ov id ed th is in fo rm at io n) . d is sa tis fa ct io n w as e xp re ss ed ar ou nd a dv ic e gi ve n by la ct at io n co ns ul ta nt s ov er th e ph on e re ga rd in g br ea st fe ed in g (‘i m pr ac tic al a dv ic e’ ) ** ** * m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 463 t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g sa ck s et a l.3 3 (2 01 7) u ga nd a an d z am bi a n = 3 93 w om en w ith a m ea n ag e of 2 6. 3 ye ar s w ho h ad g iv en bi rt h w ith in o ne ye ar o f t he d at a co lle ct io n pe ri od st ud y de si gn : d es cr ip tiv e qu al ita tiv e ne st ed st ud y (w ith in a la rg er e va lu at io n st ud y) d at a co lle ct io n: fo cu s gr ou ps (n = 4 8) w er e he ld a cr os s fo ur ru ra l c on tig uo us d is tr ic ts in u ga nd a an d fo ur ru ra l n on -c on tig uo us d is tr ic ts in z am bi a. -s em ist ru ct ur ed in te rv ie w g ui de s w er e tr an sl at ed a nd b ac k tr an sl at ed fo r ac cu ra cy . d at a co lle ct io n to ok p la ce in 2 01 2– 20 13 . sa m pl in g: n ot r ep or te dth e m aj or ity o f p ar tic ip an ts r ep or te d no t s ee ki ng pn c . f ac to rs th at fa ci lit at ed u til is at io n: b ot h co un tr ie s’ co m m un ity h ea lth w or ke rs a nd n ur se s ta ug ht w om en th e im po rt an ce o f p n c f ac to rs th at im pe de d ut ili sa tio n: l ac k of im po rt an ce in b ot h co un tr ie s, a h ea lth y m ot he r an d ba by m ea ns n o ne ed to s ee k pn c , c os t ( fo r tr an sp or t a nd u nd er fiv e ca rd ) a nd d is ta nc e (r ep or te d m or e in z am bi a) , fe ar o f m is tr ea tm en t a t h ea lth fa ci lit ie s an d pr ev io us ne ga tiv e ex pe ri en ce (b ei ng m ad e to w ai t, ye lle d at , c ri tic is ed , p hy si ca lly a bu se d; r ep or te d m or e in u ga nd a) in a pp ro xi m at el y ha lf of th e fo cu s gr ou ps in bo th c ou nt ri es , w om en ex pe ri en ce d di re ct d en ia l of c ar e, d is co ur ag em en t fr om s ee ki ng c ar e or fe ar of b ei ng tu rn ed a w ay (p re do m in an tly r el at ed to h av in g gi ve n bi rt h at ho m e) . z am bi a: m os t fo cu s gr ou ps r ep or te d po si tiv e ex pe ri en ce s w ith pn c . m ot he rs s ta te d th at th ey w er e ‘re ce iv ed w el l’ an d ex am in ed fo r po ss ib le c om pl ic at io ns an d th at th e nu rs es ’ at tit ud es w er e ge ne ra lly po si tiv e an d ‘w el co m in g’ . u ga nd a: m os t f oc us gr ou ps r ep or te d ne ga tiv e ex pe ri en ce s w ith p n c (m os tly r el at ed to g iv in g bi rt h at h om e) . in b ot h co un tr ie s: w om en r ep or te d be in g sa tis fie d w ith pn c g iv en to th ei r ne w bo rn w he n ex am in ed , t re at ed fo r co m pl ic at io ns , im m un is ed a nd g iv en an u nd er fi ve c ar d. z am bi a: m an y w om en w er e pl ea se d w ith th e m an ne r in w hi ch th e nu rs es a tt en de d to th em a nd th ei r ne w bo rn s. th ey w er e al so s at is fie d w ith th e ca re th ey r ec ei ve d w he n th ey d ev el op ed co m pl ic at io ns , s uc h as ex ce ss iv e bl ee di ng . ** * se lv ar aj e t al .36 (2 02 1) in di a n = 2 27 po st na ta l m ot he rs a ge d 19 – 42 y ea rs , be tw ee n 6– 10 w ee ks p os tbi rt h st ud y de si gn : c om m un ity -b as ed c ro ss se ct io na l s tu dy d at a co lle ct io n: d at a w er e co lle ct ed u si ng p re te st ed s em ist ru ct ur ed pr of or m a w as d ev el op ed b as ed o n th e pn c as se ss m en t a s pe r ip h s gu id el in es . d at a w er e co lle ct ed u p to fo ur w ee ks a ft er th e co m pl et io n of th e po st pa rt um p er io d (s ix w ee ks ) i n 20 15 – 20 16 .s am pl in g: s im pl e ra nd om h om e vi si ts : o nl y 47 (2 0. 7% ) h ad r ec ei ve d at le as t on e ho m e vi si t b y an y he al th w or ke r, w ith 3 6 (7 6. 6% ) oc cu rr in g be tw ee n da ys 2 9– 42 . s ev en (1 4. 9% ) oc cu rr ed w ith in fi rs t s ev en d ay s an d th e re m ai ni ng fo ur (8 .5 % ) b et w ee n da ys 1 4– 28 . d ur in g th es e vi si ts , ne ith er th e m ot he r no r ne w bo rn w er e as se ss ed fo r an y he al th p ro bl em s. n on e of th e m ot he rs h ad re ce iv ed ‘a de qu at e’ v is it s (a t l ea st th re e pe r th e ip h s gu id el in es ). h ea lth fa ci lit y vi si ts : 9 8 (4 3. 2% ) w om en vi si te d th e ho sp ita l f or th em se lv es (n = 2 0, 9 % ) o r th ei r ne w bo rn (n = 7 8, 3 4. 4% ) d ur in g th e po st na ta l pe ri od (m os t f re qu en tly fo r m ot he r: lo w er b ac k ac he , p ro lo ng ed b le ed in g, in ad eq ua te m ilk s ec re tio n; fo r ne w bo rn : u pp er r es pi ra to ry in fe ct io n, ja un di ce , ph ys io lo gi ca l i ss ue s) . n ot r ep or te d n ot r ep or te d ** * sh ah ja ha n et al .38 (2 01 7) b an gl ad es h n = 3 60 po st na ta l m ot he rs , a ge d >1 6 ye ar s w ho at te nd ed fo r pn c w ith in 4 2 da ys o f d el iv er y. st ud y de si gn : c om m un ity -b as ed c ro ss se ct io na l s tu dy d at a co lle ct io n: f ac eto -f ac e in te rv ie w u si ng a s tr uc tu re d qu es tio nn ai re , w hi ch w as d ev el op ed in a s im pl e, a cc es si bl e la ng ua ge a nd c om pi le d by a da pt in g qu es tio ns fr om p ub lis he d st ud ie s w ith a pp ro pr ia te m od ifi ca tio ns a nd /o r im pr ov em en t. th e qu es tio nn ai re w as p ilo te d w ith 2 0 w om en pr io r to u se in th is s tu dy . d at a w er e co lle ct ed in 2 01 2. s am pl in g: r ec ru itm en t u ni ts (f am ily w el fa re a ss is ta nt h ea lth w or ke rs ) w er e ra nd om ly s el ec te d (n = 1 2) a nd th en 3 0 w om en fr om e ac h he al th w or ke r ca tc hm en t a re a w er e ‘sy st em at ic al ly id en tifi ed ’ f or in cl us io n as th e sa m pl e. 64 (1 7. 8% ) w om en u til is ed p n c s er vi ce s w ith in th e fir st 4 2 da ys p os tn at al ly (8 0% o f b ir th s w er e ho m e bi rt hs ). 13 5 (3 7. 5% ) w om en r ep or te d th ey kn ew th at r eg ul ar p n c w as n ec es sa ry . f ac to rs th at fa ci lit at ed u til is at io n: h ig h in co m e, h ig he r m at er na l ed uc at io n (m or e th an n in e ye ar s sc ho ol in g) , r ea di ng ne w sp ap er /m ag az in es , w at ch in g t v , h av in g m ob ile p ho ne a nd th os e w ho c ou ld w al k to th e he al th fa ci lit y fa ct or s th at im pe de d ut ili sa tio n: n o ed uc at io n or h av in g 1– 5 ye ar s of s ch oo lin g, h ig h tr an sp or ta tio n co st to th e ne ar es t h ea lth fa ci lit y an d m at er na l a ge n ot r ep or te d n ot r ep or te d ** ** m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 464 | squ medical journal, november 2022, volume 22, issue 4 t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g te sf ah un e t al .30 (2 01 4) et hi op ia n = 8 20 m ot he rs a ge d >1 5 ye ar s w ho ha d gi ve n bi rt h w ith in th e pa st ye ar c om pl et ed th e su rv ey . n = 16 m ot he rs pa rt ic ip at ed in o ne o f t hr ee fo cu s gr ou ps st ud y de si gn : m ix ed m et ho ds s tu dy d at a co lle ct io n: q ua nt ita tiv e da ta w er e co lle ct ed b y in te rv ie w u si ng a s tr uc tu re d pr ete st ed q ue st io nn ai re . i t w as d ev el op ed th ro ug h re vi ew o f r el at ed e th io pi an a nd in te rn at io na l l ite ra tu re . f or th e qu al ita tiv e da ta , g ui di ng q ue st io ns fo r th e fo cu s gr ou ps w er e de ve lo pe d in e ng lis h an d tr an sl at ed to a m ha ri c an d th en c he ck ed fo r va lid ity . d at a w er e co lle ct ed in 2 01 1. sa m pl in g: m ul tis ta ge sa m pl in g te ch ni qu e w as u nd er ta ke n fo r th e qu es tio nn ai re , f ol lo w ed b y st ra tifi ed r an do m sa m pl in g of w ar ds p ro po rt io ne d fo r ru ra l a nd ur ba n, th en r an do m s am pl in g of h ou se ho ld s. if o ne h ou se ho ld h ol d ha d m or e th an o ne el ig ib le m ot he r, th en r an do m lo tt er y m et ho d un de rt ak en to s el ec t t he m ot he r. f oc us gr ou ps : p ur po si ve q ue st io nn ai re : -6 92 (8 4. 4% ) w om en w er e aw ar e th ey s ho ul d at te nd , a nd 6 09 (7 4. 3% ) s ta te d it w as n ec es sa ry fo r w om en a nd n ew bo rn s, b ut o nl y 54 8 (6 6. 8 % ) ut ili se d pn c s er vi ce s. 3 71 (6 7. 7% ) w om en a tt en de d on ce , 1 53 (2 7. 9% ) t w ic e an d ju st 2 4 (4 .4 % ) v is ite d th re e or m or e tim es w ith in s ix w ee ks a ft er d el iv er y. h al f ( 52 .2 % ) u til is e se rv ic es fr om h ea lth e xt en si on w or ke rs a nd c om m un ity h ea lth o ut re ac h se rv ic es , 49 .9 % a tt en de d a he al th in st itu tio n an d 0. 9% u se d tr ai ne d bi rt h at te nd an ts . -r ea so ns fo r ut ili si ng in cl ud ed : n ew bo rn im m un is at io n (n = 4 96 , 6 0. 5% ), fa m ily p la nn in g (n = 1 75 , 2 1. 3% ), co un se lli ng o n pn c (n = 1 29 , 15 .7 % ), co un se lli ng o n br ea st fe ed in g (n = 2 9, 3 .5 % ) an d ph ys ic al e xa m in at io n (n = 1 5, 1 .8 % ) f ac to rs th at fa ci lit at ed u til is at io n: k no w in g ab ou t t he pn c s er vi ce (9 0. 7% w ho a tt en de d kn ew a bo ut th e se rv ic e) , b ei ng p ro vi de d w ith in fo rm at io n po st -b ir th a bo ut p n c b y he al th e xt en si on w or ke rs (8 5. 5% ), nu rs es (1 7. 8% ), fa m ily (8 .2 % ) a nd d oc to rs (1 .1 % ), m at er na l a ge (o ve r 25 y ea rs ), m ar ri ed , l iv ed in u rb an a re a, li ve d le ss th an tw o ho ur s fr om a he al th fa ci lit y, h ad a tt en de d a n c , s up po rt o f a he al th e xt en si on w or ke r f ac to rs th at im pe de d ut ili sa tio n: l ac k of ti m e (3 0. 5% ), lo ng d is ta nc e to pr ov id er (1 9. 3% ), la ck o f g ua rd ia ns fo r ch ild re n ca re (1 6. 1% ), la ck o f a w ar en es s (1 2. 7% ), cu ltu ra l ba rr ie rs (8 .6 % ), la ck o f s er vi ce (8 .6 % ) a nd c os tly tr an sp or ta tio n (3 .4 % ). a to ta l o f 3 52 (6 4. 2% ) w om en w ho d id n ot u til is e pn c r ep or te d no t ha vi ng th e ab ili ty to m ak e de ci si on s fo r ut ili sa tio n. q ue st io nn ai re : 4 20 (7 6. 6% ) w om en w ho ut ili se d pn c h ad a po si tiv e pe rc ep tio n to w ar ds p n c . fo cu s g ro up s: m os t m ot he rs as su m ed th at p n c se rv ic es w er e on ly av ai la bl e 45 d ay s af te r bi rt h (o nl y fo r ne w bo rn va cc in at io ns ). m os t m ot he rs e xp er ie nc ed a po si tiv e pe rc ep tio n to w ar ds p n c , a nd th ey en co ur ag e ot he rs to u se pn c . n ot r ep or te d ** * u pa dh ya i an d g up ta 39 (2 01 9) in di a n = 4 88 w om en , < 20 to > 35 y ea rs , w ho d el iv er ed w ith in th e pa st th re e m on th s st ud y de si gn : c ro ss -s ec tio na l c om m un ity ba se d st ud y d at a co lle ct io n: in te rv ie w s of m ot he rs w er e co nd uc te d in th ei r ho us e us in g a pr et es te d an d pr ed es ig ne d qu es tio nn ai re . d at a w er e co lle ct ed fo r a pe ri od fr om 2 01 4 to 2 01 5. s am pl in g: u nc le ar (t w ost ag e sy st em at ic r an do m s am pl in g. f ir st s ta ge : sl um s w er e id en tifi ed r an do m ly , a nd 3 0 sl um s w er e id en tifi ed . s ec on d st ag e: p ro po rt io na te to s iz e, s am pl in g w as d on e in th e se le ct ed sl um s to c ov er th e de si re d sa m pl e si ze o f 4 88 by h ou se -t oho us e vi si ts . 15 9 (3 2. 6% ) w om en r ec ei ve d no p n c p os tbi rt h an d 25 6 (5 2. 5% ) h ad a p os tn at al v is it w ith in 4 8 ho ur s of d el iv er y an d on ly 7 6 (1 5. 6% ) r ec ei ve d al l re co m m en de d th re e or m or e vi si ts f ac to rs th at fa ci lit at ed u til is at io n: a ge (2 0– 35 y ea rs ), hi gh er so ci oec on om ic c la ss , e du ca tio n le ve l ( w om en a nd hu sb an d) , r ec ei ve d fo ur o r m or e an te na ta l c he ck up s, b el on gs to jo in t f am ily , h ad c ae sa re an d el iv er y, ha d in st itu tio na l b ir th a nd h ad c om pl ic at io ns o r pe rc ei ve d he al th p ro bl em s af te r de liv er y fa ct or s th at im pe de d ut ili sa tio n: a ge (< 20 o r >3 5 ye ar s) , lit er ac y, n uc le ar fa m ily a nd h ad a h om e bi rt h n ot r ep or te d n ot r ep or te d * m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 465 t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g *w oo dw ar d et a l.4 1 (2 01 6) a us tr al ia n = 1 5 m ot he rs , a ge d 25 – 43 y ea rs w ho h ad a n in fa nt a ge d un de r 12 m on th s st ud y de si gn : q ua lit at iv e de sc ri pt iv e d at a co lle ct io n: s em ist ru ct ur ed , f ac eto -f ac e in te rv ie w . d at a w er e co lle ct ed in 2 01 2. sa m pl in g: p ur po si ve -th e m aj or ity o f w om en w ho r ec ei ve d pr iv at e ob st et ri ci an c ar e (n = 8 ) w er e di sc ha rg ed w ith a si xw ee k ch ec kup a pp oi nt m en t. -w om en w ho b ir th ed in p ub lic in st itu tio ns (n = 4 ) al l r ec ei ve d a ho m e vi si t o r a ph on e ca ll w ith in 1 0 da ys o f g oi ng h om e. -c om m un ity p os tbi rt h ca re u til is ed in cl ud ed ph ar m ac y nu rs e (n = 1 0) , c hi ld a nd fa m ily h ea lth cl in ic (n = 1 0) a nd g p (n = 9 ). a p ri va te m id w ife w as u til is ed b y th re e w om en fo r al l p os tp ar tu m ca re . -th e w om en w ho re ce iv ed a h om e vi si t o r ph on e ca ll ex pe ri en ce d re as su ra nc e an d su pp or t t hr ou gh th e co m m un ic at io n as th ey co ul d se ek a nd o bt ai n re lia bl e in fo rm at io n; th is e as ed th ei r tr an si tio n to p ar en tin g an d ga ve th em co nfi de nc e. -th e w om en w ho re ce iv ed p ri va te ob st et ri ci an c ar e ex pe ri en ce d re ce iv in g a la ck o f i nf or m at io n ab ou t w he re o r ho w to ac ce ss p n c . -w om en e xp er ie nc ed ps yc ho so ci al s up po rt by th e ph ar m ac y nu rs es w ith a fo cu s of p os iti ve pa re nt in g va lid at io n. -w om en d id n ot re po rt e xp er ie nc in g ps yc ho so ci al s up po rt an d re as su ra nc e fr om g ps o r th e ch ild a nd fa m ily h ea lth c lin ic s. th ei r ex pe ri en ce w ith g ps w as li m ite d to m ed ia l i ss ue s, h ea lth pr ob le m s or r ou tin e va cc in at io ns . sa tis fa ct io n: th e hi gh es t l ev el s of sa tis fa ct io n w er e re po rt ed b y w om en w ho h ad a h om e bi rt h (n = 3 ) a s th ey re ce iv ed c on tin uo us ho m e ca re b y a pr iv at el y pa id fo r m id w ife . w om en w er e ge ne ra lly sa tis fie d w ith p n c pr ov id ed b y th e ph ar m ac y nu rs es as it w as a cc es si bl e an d pr ov id ed co nt in ui ty o f c ar e. d is sa tis fa ct io n: -w om en e xp re ss ed di ss at is fa ct io n at ch ild a nd fa m ily he al th c lin ic s ar ou nd a la ck o f a ‘w om en ce nt re d’ a pp ro ac h, co nt in ui ty o f c ar er an d to fo cu se d on su rv ei lla nc e ra th er th an s up po rt , w ith th e in fo rm at io n ab ou t w he re a nd ho w to a cc es s po st bi rt h ca re in th e co m m un ity , w ith pn c a t l ar ge a s th ey d es cr ib ed it a s ‘re gi m en te d ca re ’ a s it fo cu se d on in fa nt su rv ei lla nc e ra th er th an s up po rt fo r m ot he rs . -a t p ha rm ac ie s, w om en w er e di ss at is fie d w ith th e ph ys ic al en vi ro nm en t ( pn c w as p ro vi de d in a n op en a re a of th e ph ar m ac y, a nd it w as av ai la bl e fo r lim ite d ho ur s) . ** ** m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 466 | squ medical journal, november 2022, volume 22, issue 4 c h a r a c t e r i s t i c s o f i n c l u d e d s t u d i e s included studies were conducted in low-, middle and high-income countries, with the majority from africa (n = 9), followed by asia (n = 5) and australia (n = 2).26–41 there was one study each from europe, north america and the middle east.42–44 the majority of included studies were quantitative and descriptive (n = 11), with participant response rates ranging from 11.4–80.7%.26–29,31,32,34,36,38,39,44 five studies were qualitative, two were mixed methods and one was an experimental study.30,33,35,37,40–43 based on the quality assessment of the studies using the mmat tool, two studies were rated one star because of concerns regarding the clarity on sampling strategies, sample representative of the target population, measurements used, the risk of nonresponse bias and the appropriateness of the statistical analyses.27,39 most studies (n = 17) were assigned a rating of three or more stars [table 1]. u t i l i s at i o n overall utilisation rates of 11.4–100% were reported in 15 studies.26–34,36,38,39,42–44 the remaining four studies did not report utilisation rates. several studies reported that while women were aware of the need for regular postnatal visits or the importance of attending, they did not utilise postnatal follow-up care.30,38 factors that influenced greater utilisation during early and/or late postnatal periods were complications during labour, birth and after birth, distance from a health centre and knowledge on the importance of postnatal review.27–32,34,38,39 additionally, women who had completed advanced education (secondary and above), and thus who had higher monthly incomes, were reported as having higher utilisation of postnatal care services.26,29,32,38,39 several studies reported increased use of postnatal care if women’s husbands had completed advanced education from college and above.29,30,39 women who were 18–48 years and had attended an antenatal review during pregnancy were more likely to utilise postnatal care.26,28–30,32,39 women who identified that they were able to decide for themselves or were involved in joint decision-making (husband–wife dyad) were more likely to attend postnatal visits.26,28 other factors that were reported to increase utilisation of postnatal follow-up care included awareness of at least one postpartum danger sign, attendance at family planning services and use of postnatal care after a previous pregnancy.26,29,34 major factors reported by women that impeded the utilisation of postnatal services included a lack of knowledge about postnatal services, beliefs that there t ab le 1 (c on t’d .): c ha ra ct er is ti cs o f i nc lu de d st ud ie s an d th e m ix ed m et ho ds a pp ra is al t oo l 2 01 8 qu al it y ra ti ng a ut ho r an d ye ar o f pu bl ic at io n c ou nt ry pa rt ic ip an ts m et ho do lo gi ca l c ha ra ct er ist ic s p os tn at al fo ll ow -u p fi n di n gs m m a t qu al ity ra tin g x ia o et a l.3 7 (2 02 0) c hi na n = 2 2 w om en ag ed b et w ee n 22 – 43 y ea rs w ho ha d gi ve n bi rt h to a h ea lth y te rm ba by w ith in s ix w ee ks , w ith ou t co m pl ic at io ns , re tu rn ed to th e he al th c en tr e fo r a ch ec kup o n th e 30 th o r 42 nd d ay af te r bi rt h st ud y de si gn : q ua lit at iv e ex pl or at or y st ud y d at a co lle ct io n: -i nde pt h, s em ist ru ct ur ed , f ac eto -f ac e in te rv ie w s -th e de m og ra ph ic in fo rm at io n sh ee t a nd th e in te rv ie w g ui de w er e de ve lo pe d ba se d on th e re se ar ch er ’s ex pe ri en ce in w or ki ng w ith p os tp ar tu m w om en , a nd d is cu ss ed w ith tw o ac ad em ic s in ob st et ri c nu rs in g an d fa m ily n ur si ng . d at a w er e co lle ct ed in 2 01 8. s am pl in g: p ur po si ve a ll w om en h ad r ec ei ve d a ho m e vi si t b y a nu rs e w ith in tw o da ys o f d is ch ar ge (s ta nd ar d pr ac tic e at s tu dy s ite h os pi ta l) an d ad di tio na l h om e vi si ts (n ot s ta te d/ re po rt ed fo r ea ch pa rt ic ip an t) . a ls o th ey a tt en de d ei th er 3 0 o r 42 -d ay p n c ch ec kup a t t he h os pi ta l. h om e vi si t n ur se s w er e w ar m a nd p ro vi de d co nt in uo us c ar e in st ea d of ‘ta sk -o ri en te d’ fr ag m en te d ca re . sa tis fa ct io n: m os t w om en w er e sa tis fie d w ith th e po st pa rt um h om e vi si t bu t s ug ge st ed th e ne ed fo r a m or e co m pr eh en si ve po st pa rt um c ar e pr og ra m th at c at er ed to th ei r ne ed s. d is sa tis fa ct io n: n ot r ec ei vi ng ti m el y in fo rm at io n fr om h ea lth pr of es si on al s, s ug ge st ed ne ed fo r in te rn et -b as ed or h ot lin e ph on e su pp or t; ne ed in g to ta ke th ei r ba by to a c lin ic fo r ex am in at io n w ith in th e fir st m on th (d ue to c ul tu ra l b el ie fs th at m ot he rs n ee d to re st a nd s ta y at h om e fo r a m on th to r eg ai n st re ng th ); br ea st fe ed in g co ns ul ta tio ns n ot p ar t o f po st pa rt um h om e vi si ts ** * m m at = m ix ed m et ho ds a pp ra is al t oo l; pn c = p os tn at al c ar e; a n c = a nt en at al c ar e; g p = ge ne ra l p ra ct iti on er ; e d h s = et hi op ia n d em og ra ph ic a nd h ea lth s ur ve ys ; w h o = w or ld h ea lth o rg an iz at io n; ip h s = in di an p ub lic h ea lth st an da rd s. amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 467 was no need for postnatal review if one was feeling well, not being given information regarding postnatal complications before discharge, long distance to health facilities, high transportation costs, home birth, cultural barriers and lack of education, long queues at health facilities, experiences of abandonment by healthcare providers and fears of mistreatment by health professionals.26,27,29–34,38–40 there were also additional impediments [table 1]. e x p e r i e n c e s a total of 12 studies reported women’s experiences, with most reporting positive and negative factors that influenced their experiences.27,29,30,33–35,37,40–44 several studies reported that women felt they were not provided with enough information on maternal and newborn postpartum complications or ‘danger signs’, physical changes, breastfeeding and general maternal and newborn care [table 1].27,35,44 gebrehiwot et al. found that women had experienced receiving advice or information on fewer than six elements of postnatal care at postnatal followup visits.29 the least discussed elements included exclusive breastfeeding, baby care and personal hygiene. ong et al. reported that women felt that more guidance and support was needed during the early postnatal period, particularly with regard to breastfeeding and also expressed the need for more home visits due to expectations around cultural postnatal confinement practices.35 women’s positive experiences were predominantly related to quality time with and comprehensive inform ation provided by the healthcare provider.34,37,40 three women who received early contact after discharge (home visit, telephone contact) reported feeling reassured and supported.41,42 postnatal follow-up care that was organised and effective and allowed sufficient time for check-up of both the mother and infant was viewed positively. negative experiences were more commonly reported by women and were related to cursory examinations or unfulfilling discussions with health professionals, conflicting information given by health professionals and not receiving adequate or enough information from health professionals.29,30,35,40–42 in some countries, women reported experiencing a direct denial of care, discouragement from seeking care or fear of being turned away, particularly if they had given birth at home [table 1].33 s at i s fa c t i o n the majority of studies (n = 12) did not report on women’s satisfaction with postnatal follow-up care. satisfaction or dissatisfaction when reported was mostly associated with consistency of advice received and continuity of care.33,37,40–43 johansson et al. reported that women were satisfied with telephone follow-up (97.2%), home visit (96.5%) and hospital follow-up (91.3%).42 woodward et al. found that women who had home births were satisfied with follow-up when they received continuity of care.41 women who attended an integrated community-based clinic providing comprehensive support for postpartum women reported that they were satisfied with the breastfeeding support they received.43 women reported dissatisfaction with divergent information and impractical advice as well as with a lack of timely advice and a ‘women-centred’ approach and continuity of care [table 1].35,37,40,41 discussion this review aimed to explore women’s utilisation of early and late postnatal follow-up and their experiences and satisfaction with it. overall, the majority of the included studies when appraised using the mmat tool were assessed as meeting three or more of the five quality criteria.26,28–38,40–44 low utilisation was mostly reported from lowand middle-income countries (lmics).26–29,31–33 this finding could be attributed to limited postnatal follow-up care options offered to women and newborns in lmics, such as lack of home visits and telephone contact, compared to high-income countries. a number of studies reported the use of mobile technology such as short message service as being a cost-effective method in enhancing maternal and newborn outcomes in early postnatal period in both lowand high-income settings.45,46 furthermore, perrenoud et al. reported that immediate messaging application from ‘whatsapping’ contributes to women-centred care and enhances continuity of care.47 this aligns with the recommendations of the american college of obstetrics and gynecologists on optimising women’s and newborns’ health through offering various services to meet individualised needs.17 the limited services reflect the distinctive distribution of maternal and newborn deaths globally. international organisations reported that approximately 295,000 maternal deaths occurred globally in 2017, and 86% of these occurred in subsaharan africa and south asia.48 in addition, it is estimated that 2.4 million neonatal deaths occurred globally in 2019.49 as such, improving maternal health and putting an end to preventable maternal deaths women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 468 | squ medical journal, november 2022, volume 22, issue 4 have been the focus of various organisations, such as the who through its launch of the sdgs. an examination of utilisation is needed to identify potential target areas to improve the quality and use of healthcare services provided during the postnatal period. many of the included studies undertaken in lmics focused on the utilisation of postnatal care and reported low overall rates, which appeared to be associated with transport costs, distances to health centres and the importance of postnatal follow-up care not being conveyed by healthcare professionals around the time of discharge from hospitals.26–32,34,36,38,39,43,44 comparatively, the studies conducted in high-income countries reported high rates of utilisation, and the focus was on experiences and satisfaction with postnatal services.35,37,40–43 while some women reported a lack of awareness of the need or availability of services, others who were aware still did not use these services or were likely to use them only once.26,27,29,30,34,36,38–41,44 it appears that women were most likely to utilise postnatal care services during the late postnatal period, despite the fact that the who recommends at least three contacts following childbirth: on day three, between days seven and 14 and at six weeks.26,29,31,32,34,36,40,41,44 women seem to have fewer than the recommended number of contacts during the postnatal period. a lack of knowledge regarding the accessibility and importance of postnatal care services was reported in a number of studies.27,29,33,40 while the study by angore et al. could not be included in this review as it reported on women using postnatal follow-up care over one year, it is crucial to note that the authors found that women who were informed about the importance of attending postnatal care services after birth had high utilisation rates.50 cultural practices surrounding non-utilisation did not feature strongly in the studies undertaken in africa or india. in contrast, the study by ong et al. with singaporean mothers in asian countries revealed that traditional practices, such as ‘seclusion’, may account for the lack of use of care services within the first two weeks postpartum.35 a study conducted by almalik in jordan reported that 78% of women attended postnatal follow-up between six and eight weeks, with a focus on whether attendance met their perceived requirements.44 to the best of the authors’ knowledge, no data has been published on either the early postnatal period or the influence of cultural practices such as seclusion, which is practiced in the middle east. the practice of seclusion is well known in middle eastern countries, such as oman, where women are expected to be confined to their homes for 40 days, to rest and eat traditional foods (e.g. honey) to regain strength and be healthy to take care of their newborn.51 during this period, the mother and newborn are viewed as vulnerable and at high risk for illness and death as well as the ‘evil eye’.52 the women in ong et al.’s study reported the need for more home visits during this early period when they cannot leave the house.35 access to detailed information about the postnatal period was reported to have a positive influence on maternal experience.34,37,40,42 in contrast, the scarcity of information was associated with maternal dissatisfaction and increased breastfeeding problems, especially at 3–6 weeks after birth.30,35,41 women’s satisfaction with the care provided during the postnatal period was explored in a number of studies.33,37,40–43 women appeared to be dissatisfied when there was a lack of consistent information provided and satisfied when there was continuity of care provided.40,41 interestingly, two australian studies reported a lack, or inconsistency, of information.40,41 this may be due to the lack of clarity in the royal australian college of general practice guidelines, which do not make any recommendations regarding the timing and number of postnatal contacts.19 women reported that information provided by health providers was not practical or helpful and that there was a need for more targeted education, especially related to breastfeeding, physical changes and newborn care.27,35,44 interestingly, however, laliberté et al. found that the provision of a community-based clinic with a focus on providing breastfeeding support did not result in significant differences in breastfeeding outcomes or depression scores up to 12 weeks postnatally when comparing women who visited the clinic and those who did not.43 that study concluded that the reason for the lack of significant differences between the two groups could be that the majority of the women were over 29 years old and had a high educational level, hypothesising that this group of well-educated women sought advice from other sources. health providers’ provision of information and the way in which information is provided are important to women. almalik stated that women reported unmet needs at 6–8 weeks and emphasised the need to change policymakers’ focus from reducing maternal mortality rates to providing more womencentred approaches that address their needs and concerns.44 similarly, in woodward et al.’s australian study, women attending a community-based child and family health clinic felt that the nurses/midwives were more interested in collecting data and undertaking surveillance than providing support and positive parenting advice.41 women in that study found nurses/ amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 469 midwives located in pharmacies to be much more supportive. thus, the attitudes of health professionals play an important role in whether women seek followup care.30,53 this was evident in low-income country settings where women reported they were reluctant to attend postnatal follow-up care because of health workers’ attitudes and fear of mistreatment.31,33 the findings of this review should be considered in light of its strengths and potential limitations. a strength of this review was that the systematic search was developed in conjunction with a senior librarian and was not limited by study design, country context or postnatal follow-up setting. the english language filter was not applied; however, searching with mesh terms and keywords was undertaken in english only. therefore, it was unlikely for articles published in arabic but without an english-translated abstract and keywords to have appeared in the search results. the selection of studies was restricted to data collection taken place within the last 10 years and from women who had given birth within 12 months of the study period, to ensure that the information was contemporary and to limit potential variation in practice change that may have occurred along with changes in and around antenatal and intrapartum care. additionally, while women’s recall has been shown to be consistent around antenatal and childbirth events, this is not the case for the postnatal period, with sensitivity of reporting lower at six weeks and six months than at one week postnatally.54 only studies that collected data up to 12 months following childbirth were included in this review; therefore, future reviews should consider studies in which participants are interviewed or surveyed within a shorter time frame following the six-week follow-up appointment. this may provide additional insights due to increased clarity of recall. conclusion this systematic review highlights the need for increasing women’s awareness of the importance of postnatal follow-up care. this includes discussing postnatal anxiety and depression, providing more individualised options for receiving postnatal followup care such as telephone call, home visit or health facility visit and improving conformity of information provided to women by healthcare providers. these could be facilitated by providing written/electronic resources to women around the time of discharge after childbirth, mandating annual training for healthcare providers and ensuring that local policies are aligned with national policies and guidelines. future research should explore the influence of social and cultural practices on the utilisation of postnatal follow-up care and alignment of postnatal follow-up services and policies such that they are women-centred and culturally acceptable. a u t h o r s’ c o n t r i b u t i o n s ah, mp, jd, kw and kn conceptualised and designed the study. ah administered the study, while mp, jd, kw and kn supervised the work. ah, mp and kn analysed the data. all authors drafted, reviewed and edited the manuscript. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t the authors would like to thank mr michael fagg, the expert senior librarian at the university of queensland, for his support during the systematic search for relevant studies. references 1. world health organization. who technical consultation on postpartum and postnatal care. geneva: world health organization. who/mps/10.03. p. 12. 2. odetola td, fakorede eo. assessment of perinatal care satisfaction amongst mothers attending postnatal care in ibadan, nigeria. ann glob health 2018; 84:36–46. https://doi.org/10.29024/aogh.10. 3. mclellan j, laidlaw a. perceptions of postnatal care: factors associated with primiparous mothers perceptions of postnatal communication and care. bmc pregnancy childbirth 2013; 13:227. https://doi.org/10.1186/1471-2393-13-227. 4. world health organization. who recommendations on post natal care of the mother and newborn. from: https://www.n c b i . n l m . n i h . g o v / b o o k s / n b k 1 9 0 0 8 6 / p d f / b o o k s h e l f _ nbk190086.pdf accessed: jan 2022. 5. jones e, stewart f, taylor b, davis pg, brown sj. early postnatal discharge from hospital for healthy mothers and term infants. cochrance database of syst rev 2021; 6:cd002958. https://doi. org/10.1002/14651858.cd002958.pub2. 6. campbell om, cegolon l, macleod d, benova l. length of stay after childbirth in 92 countries and associated factors in 30 low and middle-income countries: compilation of reported data and a cross-sectional analysis from nationally representative surveys. plos med 2016; 13:e1001972. https://doi.org/10.1371/ journal.pmed.1001972. 7. kumar p, dhillon p. length of stay after childbirth in india: a comparative study of public and private health institutions. bmc pregnancy childbirth 2020; 20:181. https://doi.org/10.11 86/s12884-020-2839-9. 8. bravo p, uribe c, contreras a. early postnatal hospital discharge: the consequences of reducing length of stay for women and newborns. rev esc enferm usp 2011; 45:758–63. https://doi. org/10.1590/s0080-62342011000300030. 9. world health organization. improving early childhood develop ment: who guideline. geneva: world health organization. p. 29. 10. finlayson k, crossland n, bonet m, downe s. what matters to women in the postnatal period: a meta-synthesis of qualitative studies. plos one 2020; 15:e0231415. https://doi.org/10.1371/ journal.pone.0231415. 11. national institute for health and care excellence. postnatal care up to 8 weeks after birth. london: national institute for health and care excellence. from: https://www.nice.org.uk/guidance/ n g 1 9 4 / re s o u rce s / p o s t n at a l c a re p d f 6 6 1 4 2 0 8 2 1 4 8 0 3 7 accessed: jan 2022. https://doi.org/10.29024/aogh.10 https://doi.org/10.1186/1471-2393-13-227 https://doi.org/10.1002/14651858.cd002958.pub2 https://doi.org/10.1002/14651858.cd002958.pub2 https://doi.org/10.1371/journal.pmed.1001972 https://doi.org/10.1371/journal.pmed.1001972 https://doi.org/10.1186/s12884-020-2839-9 https://doi.org/10.1186/s12884-020-2839-9 https://doi.org/10.1590/s0080-62342011000300030 https://doi.org/10.1590/s0080-62342011000300030 https://doi.org/10.1371/journal.pone.0231415 https://doi.org/10.1371/journal.pone.0231415 women’s utilisation, experiences and satisfaction with postnatal follow-up care systematic literature review 470 | squ medical journal, november 2022, volume 22, issue 4 12. bryanton j, beck ct, montelpare w. postnatal parental education for optimizing infant general health and parent-infant relationships. cochrane database syst rev 2013; cd004068. https://doi.org/10. 1002/14651858.cd004068.pub4. 13. forster da, savage tl, mclachlan hl, gold l, farrell t, rayner j, et al. individualised, flexible postnatal care: a feasibility study for a randomised controlled trial. bmc health serv res 2014; 14:569. https://doi.org/10.1186/s12913-014-0569-2. 14. yonemoto n, dowswell t, nagai s, mori r. schedules for home visits in the early postpartum period. cochrane database syst rev 2017; 8:cd009326. https://doi.org/10.1002/14651858.cd0 09326.pub3. 15. united nations. transforming our world: the 2030 agenda for sustainable development. from: https://sustainabledevelo pment.un.org/content/documents/21252030%20agenda%20 for%20sustainable%20development%20web.pdf accessed: jan 2022. 16. sultanate of oman ministry of health. pregnancy and childbirth management guidelines. muscat: sultanate of oman ministry of health. 2016. ml-60. pp. 105–8. 17. mckinney j, keyser l, clinton s, pagliano c. acog committee opinion no. 736: optimizing postpartum care. obstet gynecol 2018; 132:784–5. https://doi.org/10.1097/aog.0000000000002849. 18. international confederation of midwives. essential competen cies for midwifery practice. london: international confederation of midwives. pp. 19–21. 19. royal australian college of general practitioners. guidelines for preventive activities in general practice. victoria: royal australian college of general practitioners. pp. 127–38. 20. langlois év, miszkurka m, zunzunegui mv, ghaffar a, ziegler d, karp i. inequities in postnatal care in low-and middleincome countries: a systematic review and meta-analysis. bull world health organ 2015; 93:259–70. https://doi.org/10.2471/ blt.14.140996. 21. mcguigan k. the role of mothers in family health: a thesis presented in partial fulfilment of the requirements for the degree of masters of science in psychology at massey university, albany, new zealand. master’s thesis, 2012, massey university, albany, new zealand. 22. pluye p, robert e, cargo m, bartlett g, o’cathain a, griffiths f, et al. mixed methods appraisal tool (mmat) – version 2011. from: http://mixedmethodsappraisaltoolpublic.pbworks.com accessed: jul 2021. 23. reporting the results of the mmat (version 2018). from: http://mixedmethodsappraisaltoolpublic.pbworks.com/w/ file/fetch/140056890/reporting%20the%20results%20of%20 the%20mmat.pdf accessed: jul 2021. 24. elshafay a, omran es, abdelkhalek m, el-badry mo, eisa hg, fala sy, et al. reporting quality in systematic reviews of in vitro studies: a systematic review. curr med res opin 2019; 35:1631–41. https://doi.org/10.1080/03007995.2019.1607270. 25. andersen rm. revisiting the behavioral model and access to medical care: does it matter? j health soc behav 1995; 36:1–10. https://doi.org/10.2307/2137284. 26. abuka abebo t, jember tesfaye d. postnatal care utilization and associated factors among women of reproductive age group in halaba kulito town, southern ethiopia. arch public health 2018; 76:9. https://doi.org/10.1186/s13690-018-0256-6. 27. belihu tm, deressa at. postnatal care within one week and assoc iated factors among women who gave birth in ameya district, oromia regional state, ethiopia, 2018: cross sectional study. ethiop j health sci 2020; 30:329–36. https://doi.org/10.4314/ ejhs.v30i3.3. 28. darega b, dida n, tafese f, ololo s. institutional delivery and postnatal care services utilizations in abuna gindeberet district, west shewa, oromiya region, central ethiopia: a communitybased cross sectional study. bmc pregnancy childbirth 2016; 16:149. https://doi.org/10.1186/s12884-016-0940-x. 29. gebrehiwot g, medhanyie aa, gidey g, abrha k. postnatal care utilization among urban women in northern ethiopia: cross-sectional survey. bmc womens health 2018; 18:78. https://doi.org/10.1186/s12905-018-0557-5. 30. tesfahun f, worku w, mazengiya f, kifle m. knowledge, perception and utilization of postnatal care of mothers in gondar zuria district, ethiopia: a cross-sectional study. matern child health j 2014; 18:2341–51. https://doi.org/10.1007/s10995-014-1474-3. 31. izudi j, amongin d. use of early postnatal care among post partum women in eastern uganda. int j gynaecol obstet 2015; 129:161–4. https://doi.org/10.1016/j.ijgo.2014.11.017. 32. izudi j, akwang gd, amongin d. early postnatal care use by post partum mothers in mundri east county, south sudan. bmc health serv res 2017; 17:442. https://doi.org/10.1186/s12913-017-2402-1. 33. sacks e, masvawure tb, atuyambe lm, neema s, macwan’gi m, simbaya j, et al. postnatal care experiences and barriers to care utilization for homeand facility-delivered newborns in uganda and zambia. matern child health j 2017; 21:599–606. https://doi.org/10.1007/s10995-016-2144-4. 34. creanga aa, gullo s, kuhlmann aks, msiska tw, galavotti c. is quality of care a key predictor of perinatal health care utilization and patient satisfaction in malawi? bmc pregnancy childbirth 2017; 17:150. https://doi.org/10.1186/s12884-017-1331-7. 35. ong sf, chan wc, shorey s, chong ys, klainin-yobas p, he hg. postnatal experiences and support needs of first-time mothers in singapore: a descriptive qualitative study. midwifery 2014; 30:772–8. https://doi.org/10.1016/j.midw.2013.09.004. 36. selvaraj r, ramakrishnan j, sahu sk, kar ss, roy g. communitybased assessment of postnatal care in puducherry—a crosssectional study. j family med prim care 2021; 10:798–803. https://doi.org/10.4103/jfmpc.jfmpc_1083_20. 37. xiao x, ngai fw, zhu sn, loke ay. the experiences of early postpartum shenzhen mothers and their need for home visit services: a qualitative exploratory study. bmc pregnancy child birth 2019; 20:5. https://doi.org/10.1186/s12884-019-2686-8. 38. shahjahan m, chowdhury ha, al-hadhrami ay, harun gd. antenatal and postnatal care practices among mothers in rural bangladesh: a community based cross-sectional study. midwifery 2017; 52:42–8. https://doi.org/10.1016/j.midw.2017.05.011. 39. upadhyai n, gupta sk. utilization of postnatal care services and factors affecting it among women of urban slums in dehradun, uttarakhand. indian j community health 2019; 31:470–6. https://doi.org/10.47203/ijch.2019.v31i04.009. 40. brodribb w, zadoroznyj m, dane a. the views of mothers and gps about postpartum care in australian general practice. bmc fam pract 2013; 14:139. https://doi.org/10.1186/14712296-14-139. 41. woodward bm, zadoroznyj m, benoit c. beyond birth: women’s concerns about post-birth care in an australian urban comm unity. women birth 2016; 29:153–9. https://doi.org/10.1016/j. wombi.2015.09.006. 42. johansson m, thies-lagergren l, wells mb. mothers’ experiences in relation to a new swedish postnatal home-based model of midwifery care–a cross-sectional study. midwifery 2019; 78:140–9. https://doi.org/10.1016/j.midw.2019.07.010. 43. laliberté c, dunn s, pound c, sourial n, yasseen as 3rd, millar d, et al. a randomized controlled trial of innovative postpartum care model for mother-baby dyads. plos one 2016; 11:e0148520. https://doi.org/10.1371/journal.pone.0148520. 44. almalik mm. understanding maternal postpartum needs: a descriptive survey of current maternal health services. j clin nurs 2017; 26:4654–63. https://doi.org/10.1111/jocn.13812. 45. jones rm, kimenju g, subbiah s, styles a, pearson n, rajasekharan s. a short message service (sms) increases postpartum careseeking behavior and uptake of family planning of mothers in peri-urban public facilities in kenya. plos one 2020; 15:0239213. https://doi.org/10.1371/journal.pone.0239213. https://doi.org/10.1002/14651858.cd004068.pub4 https://doi.org/10.1002/14651858.cd004068.pub4 https://doi.org/10.1186/s12913-014-0569-2 https://doi.org/10.1002/14651858.cd009326.pub3 https://doi.org/10.1002/14651858.cd009326.pub3 https://doi.org/10.1097/aog.0000000000002849 https://doi.org/10.2471/blt.14.140996 https://doi.org/10.2471/blt.14.140996 https://doi.org/10.1080/03007995.2019.1607270 https://doi.org/10.2307/2137284 https://doi.org/10.1186/s13690-018-0256-6 https://doi.org/10.4314/ejhs.v30i3.3 https://doi.org/10.4314/ejhs.v30i3.3 https://doi.org/10.1186/s12884-016-0940-x https://doi.org/10.1186/s12905-018-0557-5 https://doi.org/10.1007/s10995-014-1474-3 https://doi.org/10.1016/j.ijgo.2014.11.017 https://doi.org/10.1186/s12913-017-2402-1 https://doi.org/10.1007/s10995-016-2144-4 https://doi.org/10.1186/s12884-017-1331-7 https://doi.org/10.1016/j.midw.2013.09.004 https://doi.org/10.4103/jfmpc.jfmpc_1083_20 https://doi.org/10.1186/s12884-019-2686-8 https://doi.org/10.1016/j.midw.2017.05.011 https://doi.org/10.47203/ijch.2019.v31i04.009 https://doi.org/10.1186/1471-2296-14-139 https://doi.org/10.1186/1471-2296-14-139 https://doi.org/10.1016/j.wombi.2015.09.006 https://doi.org/10.1016/j.wombi.2015.09.006 https://doi.org/10.1016/j.midw.2019.07.010 https://doi.org/10.1371/journal.pone.0148520 https://doi.org/10.1111/jocn.13812 https://doi.org/10.1371/journal.pone.0239213 amal al hadi, michelle paliwoda, jennifer dawson, karen walker and karen new review | 471 46. patel a, kuhite p, puranik a, khan ss, borkar j, dhande l. effectiveness of weekly cell phone counselling calls and daily text messages to improve breastfeeding indicators. bmc pediatr 2018; 18:337. https://doi.org/10.1186/s12887-018-1308-3. 47. perrenoud p, chautems c, kaech c. “whatsapping” the continuity of postpartum care in switzerland: a socio-anthropological study. women birth 2022; 35:e263–74. https://doi.org/10.1016/j.wom bi.2021.06.009. 48. world health organization, united nations population fund, world bank group and the united nations population division. trends in maternal mortality 2000 to 2017. from: https://www. unfpa.org/sites/default/files/pub-pdf/maternal_mortality_ report.pdf accessed: jan 2022. 49. world health organization. newborns: improving survival and well-being. from: https://www.who.int/news-room/fact-sheets /detail/newborns-reducing-mortality accessed: jan 2022. 50. angore bn, tufa eg, bisetegen fs. determinants of postnatal care utilization in urban community among women in debre birhan town, northern shewa, ethiopia. j health popul nutr 2018; 37:10. https://doi.org/10.1186/s41043-018-0140-6. 51. missal b. gulf arab women’s transition to motherhood. j cult divers 2013; 20:170–6. 52. hundt gl, beckerleg s, kassem f, abu jafar am, belmaker i, abu saad k, et al. women’s health custom made: building on the 40 days postpartum for arab women. health care women int 2000; 21:529–42. https://doi.org/10.1080/07399330050130313. 53. adams y. use of postpartum care services in rural central malaw. phd thesis, 2016, michigan state university, michigan, usa. pp. 55–63. 54. zimmerman la, shiferaw s, seme a, yi y, grove j, mershon ch, et al. evaluating consistency of recall of maternal and newborn care complications and intervention coverage using pma panel data in snnpr, ethiopia. plos one 2019; 14:e0216612. https:// doi.org/10.1371/journal.pone.0216612. https://doi.org/10.1186/s12887-018-1308-3 https://doi.org/10.1016/j.wom bi.2021.06.009 https://doi.org/10.1016/j.wom bi.2021.06.009 https://doi.org/10.1186/s41043-018-0140-6 https://doi.org/10.1080/07399330050130313 https://doi.org/10.1371/journal.pone.0216612 https://doi.org/10.1371/journal.pone.0216612 august 2007 vol 7 copy.indd abstract to our knowledge, there is no report of dermis-fat graft (dfg) implant for orbital reconstruction from oman. we hereby presented a case report of a 0-year-old boy with a blind and painful left eye secondary to penetrating eye injury presented with implant extrusion following evisceration with a polymethyl methacrylate implant. the evisceration procedure was converted to enucleation and a dfg orbital implant was then performed. postoperatively, the graft was observed to be well integrated with the host orbital tissues and had good cosmetic and functional outcomes. keywords: anophthalmos; eye enucleation; orbital implants; case report; oman. autogenous dermis-fat orbital impant for anophthalmic socket *abdullah al-mujaini, anuradha ganesh, sana al-zuhaibi department of ophthalmology, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: mujainisqu@hotmail.com املقلة لعدمي احلجاج لشحمة ادمة الذاتية الزراعة سناء الزهيبي جانيش، أنورادا ايني، عبد هللا كفيف صبي حالة عن تقرير هنا ــتعرض نس ، احلجاج أدمة ــحمة ش ترقيع ــلطنة عن الس من تقرير أي هناك يوجد لدينا ال معلوم : كما هو امللخص وبعد ميثيل بولي امليثاكريليك بغرس غاز العني فقء مت حيث بالعني نافذة إصابة نتيجة ــرى اليس بالعني ألم من ويعاني ــنوات س ــر عش العمر من يبلغ نتيجة وهي ، احلجاج ــجة أنس مع جيدا الترقيع التئام العملية بعد لوحظ . العني حجاج ــة أدم ــحمة لش ذاتي ترقيع وعمل قلع العني مت ــراء اإلج ــذا ه . واجلمالية العملية الناحية من جيدة عمان تقرير حالة، العني، محجر استئصال العني، ترقيع العني، مقلة الكلمات: فقدان مفتاح sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 145-148 sultan qaboos university© submitted 23 december 2006 c a s e r e p o r t the autogenous dermis-fat graft (dfg) orbital implant, composed of dermis and ap-pended subcutaneous fat, is one of the many alternatives available for orbital volume augmentation in an anophthalmic socket.1 in adults, unpredictable fat reabsorption poses a serious drawback to this technique; however in children the composite dfg demonstrates continued growth along with the surrounding orbital tissue, thereby stimulating orbital development and maintenance of lost orbital volume after enucleation.2 to the best of our knowledge this is the first case of a dfg implant for orbital reconstruction performed in oman. c a s e r e p o r t a 10-year-old boy presented with an exposed orbital implant in an anophthalmic socket. he had undergone evisceration of the left eye three weeks prior to presentation. the patient had sustained a penetrating cornea-lens-retina injury with a knife at the age of 9 years and was left with a blind and painful left eye. examination revealed an unaided snellen visual acuity of 20/20 at distance and near in the right eye and no light perception in the left eye. anterior segment and fundus examination of the right eye were unremarkable. additionally, visual field examination of the right eye was within normal limits. examination of the left eye showed complete exposure of a spherical polymethylmethacrylate implant with conjunctival and scleral wound dehiscence [figure 1]. after obtaining informed consent, the child underwent socket reconstruction with dfg. the scleral shell was removed by transection of the optic nerve after imbricating the four recti muscles with 6-0 vicryl sutures, thus converting the evisceration into an a b d u l l a h a l m u j a i n i , a n u r a d h a g a n e s h , s a n a a l z u h a i b i 146 enucleation. hemostasis was obtained with pressure and mild wet-field cautery. orbital soft-tissue reconstruction was then done with dfg obtained from the left gluteal region. after raising the epidermis with a subcutaneous injection of xylocaine with epinephrine, an elliptical skin incision was made. the epidermis was dissected away from the underlying dermis by a combination of sharp and blunt dissection [figure 2a]. subsequently, a 20x20mm area of dermis with underlying fat was harvested [figure 2b]. the gluteal wound was closed with interrupted 4-0 vicryl sutures. the dermis-fat graft was then inserted into the orbital socket cavity with the dermis layer anteriorly and the fatty side posteriorly oriented [figure 3a]. the extraocular muscles and conjunctiva were sutured into the border of the dermis-fat graft using 6-0 vicryl sutures for the former and 5-0 interrupted vicryl sutures for the latter [figure 3b]. a plastic conformer was inserted and after instillation of ointment, the eye was patched with a light pressure pad. on the first post-operative day, examination showed the graft tissue well apposed with the host tissue [figure 4], thus the patient was discharged with instructions to use antibiotic eye ointment. when seen in the clinic a month later, the dfg was well integrated with the orbital tissue. the graft-host junction was healthy, with epithelialization of the surface of the graft. there was no evidence of necrosis or infection [figure 5]. d i s c u s s i o n since their first use in orbital surgery by smith and petrelli in 1978, 3 dfgs have been widely used in the reconstruction of the anophthalmic socket, both primarily after enucleation and secondarily after extrusion or migration of an existing alloplastic implant. dfg orbital implant is an effective means of replacing orbital volume and affording motility of the ocular prosthesis. it is associated with low morbidity and a satisfactory cosmetic result.1 the dfg is composed of dermis and appended subcutaneous fat, after removal of the epidermis. the dermis is believed to enhance vascularization and decrease the incidence of fat atrophy. it also acts as a barrier against fatty augmentation. the site most frequently used to harvest the graft is the gluteal area, but other areas such as the abdomen and the periumbilical can also be used to harvest such a graft.4 indications contraindications primary implantation post enucleation post evisceration secondary implantation post irradiation spherical (alloplastic implant related complications) severely contracted socket compromised orbital vascular supply severe chemical injury post irradiation multiple orbital surgery table 1: dermis-fat graft indications and contraindications hematoma infection graft-wound dehiscence conjunctival cysts granulomas graft ulcers pyogenic granuloma socket keratinization cilia retention at the recipient site fat atrophy and volume loss excessive dermis-fat growth graft failure table 2: complications of orbital dermis-fat graft figure 1: complete exposure of the polymethylmethacrylate spherical orbital implant after the first surgery figure 2a: an elliptical skin incision has been marked. the epidermis is being dissected away from the underlying dermis a u t o g e n o u s d e r m i s fat o r b i ta l i m pa n t f o r a n o p h t h a l m i c s o c k e t 147 in the orbit, special attention should be given when performing this procedure, the most important being to respect the vascular supply of the recipient bed. thus, it should not be used in any orbit with compromised vascular supply, such as after severe trauma (in particular chemical burns), irradiation, or in patients with systemic vascular disease because the risk of graft atrophy and loss is significantly increased [table 1]. the dfg should be in contact with orbital fat to enhance graft viability. thus, tenon’s fascia, sclera, or pseudocapsule left after implant extrusion should be incised or excised to facilitate this. other important aspects to prevent or minimize the complications are to avoid the following: excessive cautery of the graft bed, use of oversized grafts, excessive handling of the graft and excessive pressure on the graft following implantation. a meticulous suturing technique is mandatory. it has been seen that a fat pad thickness of 20mm significantly lowers the incidence of enophthalmos and superior sulcus deformity with no compromise to implant motility.5 although mainly performed following enucleation, dfg orbital implants have been performed following evisceration whereby the edge of the graft was sutured to the anterior scleral ring.6 conjunctival re-epithelialization of the dermal surface and enhancement of figure 2b: the dermis fat graft (20x20mm) figure 3a: the dfg is being inserted into the orbital socket cavity with the dermis layer anteriorly and the fatty side posteriorly oriented figure 3b: the extraocular muscles and conjunctiva are being sutured into theborder of the dermis fat graft using 6-0 vicryl sutures for the former and 5-0 interrupted vicryl sutures for the latter figure 4: first post-operative day: graft tissue is wellapposed with the host tissue figure 5: one month postoperative period: the dfg is well integrated with the orbital tissue. the surface of the graft has epithelialized. there is no evidence of necrosis or infection a b d u l l a h a l m u j a i n i , a n u r a d h a g a n e s h , s a n a a l z u h a i b i 148 orbital volume after dermis-fat grafting in eviscerated sockets have been reported.6 it is advisable to make relaxing incisions into the base of the existing scleral bed to provide an adequate vascular bed for the composite dfg.7 dfg offers the advantages of replacing the lost orbital volume as well as preserving conjunctival surface area. this is achieved by partially covering the implanted dermis with conjunctiva and leaving an exposed area of dermis similar to the diameter of the cornea. normal fornix depth is also maintained. there is no risk of infection transmission, implant extrusion or exposure. additionally, this procedure carries no extra cost and offers excellent cosmetic and functional results. disadvantages include a certain lack of predictability such as underestimation of the adequate volume required of the harvested graft. further, dfgs also produces a scar at the donor site. complications are usually minor [table 2]. most complications can be avoided by employing the careful surgical techniques mentioned earlier. fat atrophy and volume loss are variable and may require further dermis-fat grafting. this complication is commonly seen in cases of secondary implantation, particularly following chemical injuries.1 graft atrophy is usually seen in older patients. in contrast, fatty augmentation causing increase in the size of the graft is usually seen in young children, representing the normal proliferation of fat cells seen in the young. this complication is managed by surgical debulking of the graft.8 graft failure is usually associated with a compromised orbital vascular supply. c o n c l u s i o n in summary, a dfg orbital implant is a relatively extensive surgery with minor complications. the excellent functional and cosmetic results and safety of this method make it an excellent alternative procedure for orbital volume augmentation in anophthalmic sockets. r e f e r e n c e s 1. smith b, bosniak s, nesi f, lisman r. dermis-fat orbital implantation: 118 cases. ophthalmic surg 1983; 14:941943. 2. the autogenous dermis-fat orbital implant in children. mitchell kt, hollsten da, white wl, o’hara ma. j aapos 2001; 5:367-369. 3. smith b, petrelli r. dermis-fat graft as a movable implant within the muscle cone. am j ophthalmol 1978; 85:62-66. 4. bonavolonta g, tranfa f, salicone a, strianese d. orbital dermis-fat graft using periumbilical tissue. plast reconstr surg 200; 105:23-26. 5. sihota r, sujatha y, betharia sm. the fat pad in dermis fat grafts. ophthalmology 1994; 101:231-234. 6. borodic ge, townsend dj, beyer-machule ck. dermis fat graft in eviscerated sockets. ophthal plast reconstr surg 1989; 5:144-149. 7. lasudry j, jonckheere p, robert p-v, adenis j-p. dermis-fat graft in orbital surgery. oper tech in oculoplast orbit and reconstr surg 2001; 4:15-24. 8. smith em jr, dryden rm, tabin gc, thomas d, to kw, hofmann rj. comparison of the effects of enucleation and orbital reconstruction using free-fat grafts, dermis grafts, and porous polyethylene implants in infant rabbits. ophthal plast reconstr surg 1998; 14:415-424. march 2007 vol 7 isuue 1 final without suicide .indd double inferior vena cava *anupam k kakaria االجوف املزدوج الوريد كاكاريا كومار انوبام sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© i n t e r e s t i n g m e d i c a l i m a g e *department of radiology,armed forces hospital, p.o. box 726, pc 111, cpo seeb, muscat, sultanate of oman email: bittanupam@yahoo.om figure 1: the right (black arrowhead) and the left common iliac veins (white arrowhead) fail to unite at the level of the aortic bifurcation figure 2: the two inferior venae cavae (white arrowheads) ascend on both sides of the aorta the patient is a 42 year old female. she is a chronic carrier of hepatitis b virus and is on regular follow up for the same. the computed tomography was done to look for a suspicious area in the liver, detected on a routine ultrasound of the abdomen. the liver examination was normal. incidentally, a congenital anomaly of the inferior vena cava was detected. the two common iliac veins failed to unite at the level of the aortic bifurcation. the two venae cavae ascend on both sides of the aorta. the left inferior vena cava drains into the left renal vein. the left renal vein crosses anterior to the aorta to form the normal right prerenal inferior vena cava. the prevalence of this anomaly is 0.2%-3%.1 this arrangement of the left renal a n u pa m k k a k a r i a 64 figure 3: the left ivc (white arrowhead) drains into the left renal vein (white arrow) figure 4: coronal oblique reformat shows the right ivc (white arrowhead) and left ivc (black arrow) ascending on both sides of the aorta. the left ivc crosses over to the right ivc through the left renal vein (white arrow) vein crossing anterior to the inferior vena cava to form normal right prerenal inferior vena cava is the commonest arrangement in the duplication of inferior vena cava.1 r e f e r e n c e s 1. bass je, redwine md, kramer la, huynh pt, harris jh. spectrum of congenital anomalies of the inferior vena cava: cross sectional imaging findings. radiographics 2000; 20:639-652 1 submitted 17 nov 22 1 revisions req. 13 feb & 4 apr 23; revisions recd. 6 mar & 8 apr 23 2 accepted 11 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.025 5 6 interim use of hyrax screw assembly for single-step closure of small 7 alveolar cleft prior to anterior maxillary distraction osteogenesis 8 a technical note 9 sonal mishra,1 *harpreet singh,2 dhirendra srivastava,1 poonam sharma2 10 11 departments of 1oral & maxillofacial surgery and 2orthodontics & dentofacial 12 orthopedics, esic dental college and hospital, new delhi, india 13 *corresponding author’s e-mail: drhpreet_mamc04@yahoo.co.in 14 15 abstract 16 anterior maxillary distraction osteogenesis (amdo) is often used for correction of maxillary 17 retrognathia in select cleft lip and palate cases. restoration of alveolar arch continuity is 18 desirable prior to initiation of amdo in these cleft maxillary deformities. however, amdo 19 is technically difficult in a patient with coexisting alveolar cleft where there is a discontinuity 20 of the defect that presents a challenge in terms of adequate vector control of movement of 21 anterior segment and potential risk of tipping of teeth which already have compromised 22 anchorage/bone support on the cleft side. treatment process becomes further challenging 23 when ongoing management is compounded by failed previous alveolar cleft grafting 24 procedures along with the patient’s reluctance to undergo further grafting of alveolar clefts. 25 herein, we report a technical note demonstrating a novel application of the modification of 26 the hyrax screw wherein an initially fully opened hyrax screw was utilized as an interim 27 assembly for accomplishing single-step closure of small alveolar cleft prior to 28 commencement of anterior maxillary distraction osteogenesis. this technique may prove to 29 be feasible for patients presenting with alveolar cleft defects of smaller widths of up to 5 mm 30 and relatively well-aligned upper arches. 31 keywords: alveolar cleft; amdo; hyrax screw; single-step closure. 32 33 2 introduction 34 maxillary hypoplasia and retrusion represent a significant component of class iii deformity 35 in most patients with cleft lip and palate. inspite of being widely adopted technique for one-36 stage correction of maxillary retrusion in cleft patients,1 le fort i osteotomy technique is 37 associated with higher relapse rates and may lead to emergence of velopharyngeal 38 insufficiency and hypernasality of voice, especially with advancements greater than 10 39 mm.2,3 on the other hand, by virtue of offering sufficient time for overcoming the tension on 40 the palatal scar and for regeneration of the membranous bone along with coverage of 41 adequate soft tissue, distraction osteogenesis (do) results in better skeletal stability when 42 compared to conventional le fort i orthognathic surgery.4,5 however, when extraoral or 43 intraoral distraction is performed at a le fort i level, the risk of velopharyngeal insufficiency 44 and speech impairment has been shown to be similar to the risk observed in conventional le 45 fort i advancement surgery.6 46 47 to overcome this potential disadvantage, tooth borne distraction of the anterior maxilla using 48 anterior maxillary distraction osteogenesis (amdo) has proven to be a feasible and stable 49 modality,6 while also offering alveolar bone space for correction of tooth malalignment and 50 without hampering speech.1 rao janardhan et al7 reported successful utilization of tooth-51 borne distraction device for advancement of the anterior maxilla with no worsening of 52 speech. promising results with the use of hyrax distractor (for anteroposterior maxillary 53 advancement) in terms of its efficacy, patient's satisfaction, and stability have also been 54 demonstrated in literature.8 however, amdo is difficult in a patient with alveolar cleft 55 where there is a discontinuity of the defect that presents difficulty in terms of vector control 56 of movement of anterior segment and the probable risk of tipping of teeth which already have 57 compromised anchorage/bone support on the cleft side. the present manuscript describes the 58 novel application of the modification of the hyrax screw wherein a conventional hyrax screw 59 after being fully opened was utilized as an interim assembly for accomplishing single-step 60 closure of small alveolar cleft of up to 5 mm prior to commencement of anterior maxillary 61 distraction osteogenesis. 62 63 methods 64 case description 65 an 18-year-old female patient with an operated left cleft lip and palate presented seeking 66 treatment for correction of mid face retrusion. case history was indicative of two previous 67 3 alveolar cleft grafting surgeries at ages of 11 years and 15 years, respectively, at another 68 institution. the cleft was present between maxillary right central incisor (11) and left canine 69 (23) and was 5 mm wide at the level of the cementoenamel junction/ cervical margin of the 70 adjoining teeth. reverse overjet of 11 mm was noticed (fig. 1a, b, c & d). the upper 71 dentition was relatively well-aligned. there was scarring at the sites of surgery in the palate, 72 alveolus and lip. 73 74 the patient as well as her parents declined for any further grafting of the alveolar cleft. in 75 order to correct the alveolar discontinuity prior to maxillary advancement, closure of this 76 small alveolar cleft as well as osteotomy cuts for amdo were planned in a single step. the 77 treatment protocol was approved by the institutional ethical committee and patient gave 78 informed consent and acceptance about the treatment protocol. 79 80 description of technique 81 following preparation of the models in die-stone, proposed vertical osteotomy cuts were 82 made on both sides between the premolar and molar on the cast. a 9 mm hyrax expansion 83 screw (leonne, italy) (pitch = 1 mm) was fully opened, and its arms were adapted at the 84 labial aspect of the anterior teeth with its body positioned between 11 and 23. the appliance 85 was acrylized in self-cure polymerizing resin at the labial, occlusal, and lingual aspects, and 86 subsequently finished, polished and tried-in for passive fit (fig 2a, b). 87 88 intraoperatively, the osteotomy was performed as follows: under general anesthesia with oral 89 endotracheal intubation, a maxillary vestibular incision was made from first molar to first 90 molar. a mucoperiosteal flap was reflected to expose the maxilla. a horizonal osteotomy cut 91 parallel to the occlusal plane was made on both sides 5mm above the level of the root apices 92 from the lateral nasal rim to the distraction site between the premolars and molars. lateral 93 nasal osteotomies were performed whilst protecting the nasal mucosa. the nasal septum was 94 detached by using a guarded septal osteotome. vertical osteotomy/interdental cuts were made 95 in the buccal cortex between the second premolar and first molar (fig. 3a). the palatal 96 osteotomy was executed gently under tactile guidance with curved osteotome while taking 97 care not to damage the palatal mucoperiosteum. 98 99 after confirming the completion of osteotomy, the acrylized hyrax assembly was seated 100 passively over the segment anterior to the osteotomy cuts, and the screw was closed with the 101 4 key till approximation was achieved by mesial movement and docking of two bony segments 102 towards the cleft between teeth 11 and 23 (fig.3b). as the bony segments from both sides 103 closely approximated towards each other in an evenly controlled vector (without over-riding 104 of segments), the closure of the cleft was visualized. bone chips produced during osteotomy 105 were placed in the region of the residual cleft site. a 1.5 mm titanium straight plate was 106 adapted on both bony segments across the cleft and fixed with monocortical screws ensuring 107 that the anterior maxilla remained as one single unit (fig. 3c), in preparation for facilitating 108 amdo for correction of cleft maxillary retrognathia. the interim hyrax assembly was 109 removed following closure using a 3-0 vicryl suture. thereafter, a three-part tooth-borne 110 bonded hyrax distractor assembly (with 90° orientation for anteroposterior movement) 111 oriented parallel to mid palatine plane was cemented. gap created at the area of the two 112 vertical osteotomies was utilized for anterior maxillary distraction at a rate of 1 mm per day 113 as follows (fig. 3d): after a latency period of 5 days, amdo was initiated by turning the 114 screw of the distractor assembly by half a turn (0.5 mm) every 12 hours, resulting to a total of 115 one full turn every day i.e. 1mm/day. the screw was activated for 13 days, thereby 116 amounting to a total correction of 13 mm. after completion of distraction, the central portion 117 of the distractor assembly was sealed with composite resin and retained through a 118 consolidation period of 4 months to allow for the mineralization and corticalization of the 119 newly formed bone tissue prior to removal of distractor assembly. postoperatively, the 120 recovery period was uneventful with no detection of any relapse and complications. 121 122 favourable results of the technique showing postoperative approximation of the bone in the 123 cleft site and satisfactory improvement in esthetics along with good bone regeneration at the 124 area of distraction are demonstrated through figure 4a-4c. alveolar space with good, 125 regenerated bone quality and implants placed bilaterally in the distracted bone are evident by 126 iopa radiographs (fig. 4d). 127 128 ethical approval to report this case was obtained from the institutional research ethics 129 committee. written informed consent was obtained from the patient for her information and 130 images to be published in this article. 131 132 https://www.sciencedirect.com/topics/medicine-and-dentistry/informed-consent 5 discussion 133 premaxillary/ anterior maxillary and alveolar distraction osteogenesis (do) have been widely 134 used for management of severe midfacial retrusion including anterior crossbite in cleft lip and 135 palate patients.9-11 136 137 restoration of alveolar arch continuity is desirable prior to initiation of amdo in cleft 138 maxillary deformities. restoration of large alveolar cleft defects by alveolar distraction 139 osteogenesis utilizing intraoral tooth-borne distractor has been successfully reported in 140 literature.1,9 the tooth-borne trifocal distraction appliance involving the use of two hyrax-141 screws has also been described for the controlled closure of a large alveolar cleft.12 in cases 142 of small alveolar clefts with enhanced chances of graft survival, bone grafting is an ideal 143 option for the closure of cleft defects in order to achieve arch continuity, stabilise the 144 maxillary segments, eliminate oronasal fistulae, optimise nasal morphology through nasal 145 alar cartilage support, and finalize implant placement.13 however, before commencement of 146 amdo, waiting time of at least 3-6 months is recommended for stabilization of graft. 147 challenge is usually encountered when some patients with history of previously failed 148 alveolar bone grafting surgeries refuse to undergo another grafting procedure. 149 150 the conventional application of the hyrax screw for closure of large alveolar clefts 151 (activation of the appliance by opening the screw) has been widely documented in 152 literature.9,12 the majority of these applications involving hyrax screw and fan-shaped screw 153 entail opening of the screws to facilitate approximation of the alveolar segments towards each 154 other.8,12,14 on the other hand, the current technical note describes the novel application of the 155 modification of the hyrax screw wherein a conventional hyrax screw after being fully opened 156 was utilized as an interim assembly for accomplishing single-step closure of small alveolar 157 cleft of up to 5 mm prior to commencement of anterior maxillary distraction osteogenesis. 158 the present interim tooth-borne hyrax screw assembly facilitated controlled mobilization, 159 docking and evenly close approximation of the bony segments (without over-riding of 160 segments) towards the defect. this assembly enabled more precise bony movements while 161 simultaneously maintaining bone to bone contact and stabilization of the osseous segments in 162 the intended position during fixation, thereby aiding in accomplishing the anatomic objective 163 in a single step. 164 165 6 thus, based on the principle of patient-centred outcome and in accordance with patient’s 166 wishes, this technique involving the use of interim tooth-borne hyrax screw assembly is 167 suitable for clinical application in patients who are potential candidates for amdo and also 168 presenting with small alveolar interdental clefts (of up to 5 mm) that persist even after 169 previous alveolar bone grafting surgeries. the advantages of this technique are the possibility 170 of achieving arch continuity in the same operation by evenly controlled mesial movements of 171 the bony segments towards each other, thus obviating the need for additional alveolar bone 172 grafting surgery and preventing creation of any extraoral wound, making such therapy 173 feasible especially for patients with small alveolar cleft defects of up to 5 mm. simplicity of 174 the design, ease of fabrication and exclusive tooth-borne usage minimizes the invasiveness of 175 the procedure. 176 177 limitations in generalizing the innovation: this technique cannot not be employed in large 178 alveolar cleft defects wherein significant bone segment movements may be associated with 179 significant relapse. compromised periodontal support and advanced interdental bone loss are 180 contraindications to the use of this approach. 181 182 conclusion 183 in view of the promising results of this approach, this procedure may prove to be feasible for 184 patients presenting with alveolar cleft defects of smaller widths and relatively well-aligned 185 upper arches. large sample size studies involving different populations with long-term 186 follow-up are necessary to validate the current approach for routine use. 187 188 conflict of interest 189 the authors declare no conflicts of interest. 190 191 funding 192 no funding was received for this research. 193 194 authors’ contribution 195 sm, hs and ds were responsible for the study conception and design and treatment of the 196 patient. hs and sm contributed to the literature search and drafting the article. sm, hs, ds 197 and ps contributed to the final editing and critical revision of the article. all authors have 198 7 made substantive contribution to this manuscript, and all have reviewed the final paper prior 199 to its submission. 200 201 references 202 1. terbish m, choi hy, park yc, yi ck, cha jy. premaxillary distraction osteogenesis using 203 an intraoral appliance for unilateral cleft lip and palate: case report. cleft palate craniofac 204 j 2015;52:e95-e102. https://doi.org/10.1597/14-105. 205 2. cheung lk, chua hd. a meta-analysis of cleft maxillary osteotomy and distraction 206 osteogenesis. int j oral maxillofac surg 2006;35:14-24. 207 https://doi.org/10.1016/j.ijom.2005.06.008. 208 3. janulewicz j, costello bj, buckley mj, ford md, close j, gassner r. the effects of le fort 209 i osteotomies on velopharyngeal and speech functions in cleft patients. j oral maxillofac surg 210 2004;62:308-14. https://doi.org/10.1016/j.joms.2003.08.014. 211 4. kim jh, lee ih, lee sm, yang be, park iy. distraction osteogenesis and orthognathic 212 surgery for a patient with unilateral cleft lip and palate. am j orthod dentofacial orthop 213 2015;147:381-93. https://doi.org/10.1016/j.ajodo.2014.03.026. 214 5. binger t, katsaros c, ru¨cker m, spitzer wj. segment distraction to reduce a wide alveolar 215 cleft before alveolar bone grafting. cleft palate craniofac j 2003;40:561-5. 216 https://doi.org/10.1597/1545-1569_2003_040_0561_sdtraw_2.0.co_2. 217 6. richardson s, agni na, selvaraj d. anterior maxillary distraction using a tooth-borne 218 device for hypoplastic cleft maxillas-a pilot study. j oral maxillofac surg 2011;69:e542-e548. 219 https://doi.org/10.1016/j.joms.2011.08.013. 220 7. rao janardhan s, kotrashetti sm, lingaraj jb, pinto px, keluskar km, jain s, sone p, rao 221 s. anterior segmental distraction osteogenesis in the hypoplastic cleft maxilla: report of 222 five cases. sultan qaboos univ med j. 2013;13:454-9. epub 2013 jun 25. 223 8. upadhyay n, singh ak, prashad v, upadhyaya dn. use of hyrax distractor in maxillary 224 hypoplasia associated with cleft lip and palate patients. j cleft lip palate craniofac anomal. 225 2019;6:17-22. doi: 10.4103/jclpca.jclpca_33_18. 226 9. dolanmaz d, karaman ai, durmus e, malkoc s: management of alveolar clefts using dento-227 osseous transport distraction osteogenesis. angle orthod 2003;73:723-9. 228 https://doi.org/10.1043/0003-3219(2003)073<0723:moacud>2.0.co;2. 229 10. tong ac, yan bs, chan tc. use of interdental distraction osteogenesis for orthodontic 230 tooth alignment and correction of maxillary hypoplasia: a case report. br j oral maxillofac 231 surg 2003;41:185–7. https://doi.org/10.1016/s0266-4356(03)00080-9. 232 https://doi.org/10.1016/j.joms.2003.08.014 https://doi.org/10.1016/j.joms.2011.08.013 8 11. choi sh, park jh, cha jy, jung hd. intraoral premaxillary distraction in a patient with 233 maxillary retrognathic cleft lip and palate: a case report. cleft palate craniofac j 234 2019;56:827-30. https://doi.org/10.1177/1055665618813084. 235 12. neha, tripathi t, mohanty s, rai p: a novel minimally invasive technique of using 236 tooth-borne hyrax expansion screw for distraction osteogenesis of large alveolar cleft 237 defects (hydis-tb). cleft palate craniofac j. 2018;55:895-902. https://doi.org/10.1597/15-238 335. 239 13. peamkaroonrath c, godfrey k, chatrchaiwiwatana s. new clinical method for alveolar 240 bone graft evaluation in cleft patients: a pilot study. cleft p craniof j. 2011;48:286–92. 241 https://doi.org/10.1597/09-222. 242 14. aravindaksha sp, batra p, sadhu p. bilateral alveolar distraction for large alveolar 243 defects: case report. cleft palate craniofac j. 2015;52:614-7. https://doi.org/10.1597/13-058. 244 245 246 figure 1: pretreatment extraoral and intraoral photographs showing a cleft palate on the left 247 side and alveolar cleft between 11 and 23: (a) frontal photograph (b) profile photograph (c) 248 intraoral occlusal view (d) axial view. 249 250 251 https://doi.org/10.1597/15-335 https://doi.org/10.1597/15-335 9 252 figure 2: marking of osteotomy cuts site and acrylized appliance with hyrax screw in fully 253 opened position: (a) palatal view of the appliance (b) front view of the appliance 254 255 256 figure 3: (a) intraoperative photograph showing placement of osteotomy cuts, (b) 257 intraoperative photograph showing appliance in seated position and closure of screw assembly 258 with key, (c) approximation accomplished by mesial movement and docking of bony segments 259 towards the interdental alveolar cleft between teeth 11 and 23, (d) occlusal radiograph taken 260 intraoperatively before commencement of amdo 261 262 10 263 figure 4: treatment results: (a) favourable frontal esthetics after completion of amdo, (b) 264 improved profile esthetics after completion of amdo, (c) immediate post-distraction occlusal 265 view after removal of distractor appliance, (d) iopa x-rays showing good bone regeneration 266 and implants placed bilaterally in the distracted bone between second premolar and first molar 267 march 2007 vol 7 isuue 1 final without suicide .indd abstract objective: from a recently instituted web-based pituitary tumour registry at sultan qaboos university hospital, oman, this study explores the results of comprehensive clinical evaluation, hormonal levels, radiological evidence of pituitary mass lesion using magnetic resonance (mri) and the different treatment modalities. methods: all patients who were diagnosed with pituitary mass tumours in our tertiary care endocrinology clinic between january 998 and february 2006 were registered in the oman pituitary tumour registry. two physicians performed hospital chart review and data entry. results: a total of 60 entries were made into the pituitary tumour registry. the overall mean age of the cohort was 32 ±2 years (age range 8-73 years). the majority of registrations were female (n=4; 7%). there were 8 patients with non-functioning adenomas (50.6%), 59 with prolactinoma (36.9%) eight with acromegaly (5%), seven with craniopharyngioma (4.4%), four with cushing’s disease (2.5%) and one with sarcoidosis (0.6%). sub-group analyses were done only for the subjects with the 3 most prevalent pituitary tumours (non-functioning adenomas, prolactinomas, and acromegaly). the most prevalent symptoms are amenorrhea-galactorrhea (n=55; 37%), headache (n=3; 2%) and fatigue (n=23; 6%). the most common treatment modality was medical (n=58; 39%), followed by observation (n=56; 38%), surgery (n=3; 2%) and surgery plus medical (n=3; 2%). none of the patients in this registry are recorded to have died. conclusion: to our knowledge, this is the first pituitary tumour registry in the arabian gulf countries using a web-based programme. this tumour registry will enable us to clinical and epidemiological characteristics of pituitary tumours using a web-based pituitary tumour registry in oman *abdullah al-futaisi 1, al-yaarubi saif1, ibrahim al-zakwani 2, salim al-qassabi 3, shaden al-riyami 4, yasser wali 4 1department of medicine, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman, 2department of pharmacy, sultan qaboos university hospital, p. o. box 35, al-khod 123, sultanate of oman, 3department of medicine, royal hospital, muscat, oman, 4child health department, college of medicine & health sciences, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman. *to whom correspondence should be addressed. email: alfutaisi@squ.edu.om الشبكة باستعمال الغدة النخامية ألورام الصفات السريرية والوبائية عمان في سلطنة العاملية والي وياسر الريامي شادن القصابي، سالم الزكواني، إبراهيم اليعربي، سيف الفطيسي، عبداهللا السلطان مستشفى جامعة في النخامية في الغدة بأورام املصابني املرضى املعلومات عن جميع بتجميع قمنا الدراسة هذه امللخص: الهدف: في العاملية. ــبكة الش في النخامية الغدة ــأورام اخلاص ب ماني العُ ــجل الس في وإدخالها بتحليلها ــابقة وقمنا الس ــنوات الس الثماني خالل ــوس في قاب 2006 فبراير 1998 إلى يناير من للفترة قابوس السلطان جامعة ــفى مستش في النخامية الغدة بأورام املصابني املرضى ــجيل كل تس الطريقة: مت تتعلق من معلومات السجل يتكون املرضى. عن هؤالء املعلومات كل بتجميع طبيبني قام العاملية. بالشبكة النخامية الغدة بأورام خاص سجل في 160 حالة تسجيل طرق العالج. النتائج: مت ومختلف األورام تُبني التي املغناطيسي الرنني وصور الدم في الهرمونات مستوى ، املريض الصحية بحالة .(71% 114) اإلناث من املرضى معظم (8 الى73 سنة). من واملدى ، ــنة) املرضى(12±32 س أعمار ــط متوس بلغ النخامية. الغدة بتورم مصابة ، (36.9%) البروالكتني بورم يفرز هرمون مصابا 59 مريضا و ، (50.6%) ــبة بنس هرمون أي ال يفرز النخامية بورم الغدة مصابا 81 مريضا ــجيل مت تس يفرز بورم 4 مرضى مصابني و ،(4.4%) النخامية الغدة في يّ يٌّ بُلْعومِ فِ قِحْ بوَرَمٌ مصابني 7 مرضى و ،(5%) النمو هرمون يفرز بورم مصابني 8 مرضى و األورام من 3 أنواع انتشار تبني الفرعية وقد اموعات حتليل يتم أيضاً .(0.6%) بساركويدوسيس مصاب ومريض واحد ر ظْ الكُ رِ شْ هُ لقِ ُوَجِّ ونُ امل رْمُ الهُ الشهرية الدورة انقطاع من تعاني كانت احلاالت أكثر النمو). هرمون تفرز التي واألورام البروالكتني هرمون تفرز التي واألورام هرمونات تفرز ال التي (األورام األدوية بواسطة العالج كان الدراسة هذه في شيوعاُ العالج طرق أكثر .(16% (23 حالة واالرهاق (21% (31 حالة الصداع و (37% (55 حالة يتوفى لم .(2% (3 مرضى مع األدوية اجلراحي والتدخل (21% (31 حالة والتدخل اجلراحي (38% (56 مريضا واملالحظة (39% (58 مريضا ــجالت في الس أوائل من ــبكة العاملية الش في النخامية الغدة ألورام ماني العُ ــجل الس اخلالصة: يعد هذا ــة. الدراس فترة املرضى خالل هؤالء من أي البحوث إجراء على يساعد مما املرضى، هؤالء عن جتميع املعلومات سهولة على والباحثني يساعد األطباء سوف السجل هذا تكوين أن اخلليج العربي. ماني. العُ اتمع في الصحية الكفاءة ورفع عالجهم طرق تسهيل إلى وهذاسيؤدي األورام، هذه عن علم االوبئة. سريري، مان، عُ تسجيل، ، يّ نُخامِ يٌّ دِّ غُ الكلمات: وَرَمٌ مفتاح sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© c l i n i c a l & b a s i c r e s e a r c h a b d u l l a h a l f u ta i s i , a l -ya a r u b i s a i f, i b r a h i m a l z a k wa n i , s a l i m a l q a s s a b i , s h a d e n a l r i ya m i , ya s s e r wa l i 26 pituitary adenomas are tumours of the anterior pituitary that are relatively common neoplasms representing 10% to 15% of all intracranial tumours.1, 2 pituitary adenomas are the most common cause of a mass in the sella constituting over 90% of pituitary lesions.3, 4 the prevalence of silent pituitary microadenomas detected by high-resolution computer-tomography (hrct) or magnetic-resonance imaging (mri) is approximately 20%.5, 6, 7, 8, 9 at autopsy, careful histological assessment identifies pituitary adenomas in 10% to 20% of unselected series.10 the incidence peaks in the third and fourth decades of life; children and adolescents account for about 10% of total patients.10,11 for clinical purposes, pituitary adenomas are arbitrarily divided by size into microadenomas (<1.0 cm in diameter) or macroadenomas (≥1.0 cm in diameter). when tumours erode the dura or bone, they are considered invasive and may infiltrate surrounding structures, such as the cavernous sinus, cranial nerves, blood vessels, sphenoid bone and sinus or brain. locally invasive pituitary adenomas are nearly always histologicaly benign.12 they can also be classified on the basis of excessive hormonal secretion into secreting and non-secreting types.2 pituitary tumours with no enhanced biological activity of the anterior pituitary hormones are called non-functioning pituitary adenomas (nfpa). however, approximately 90% of these tumours will produce or secrete low amounts of follicle-stimulating hormone (fsh) and luteinizing hormone (lh) and or their α and β subunits 2,13 using immunoassay and in-situ hybridization, a minority of the nfpas shows no evidence of hormone production. these tumours are called null cell adenomas. the true incidence of pituitary tumours is still not known and accurate tumour type-specific epidemiological information is unreliable.14 this is probably due to the lack of an international pituitary tumour registry, the long natural history of tumours and the low annual incidence of pituitary adenoma diagnosis. in an effort to register these patients in oman, we created a retrospective and prospective pituitary tumour registry in the year 2004 using an access 2000 microsoft web-based programme. this programme was used to collect demographic data, biochemical results, therapeutic options and clinical outcomes from patients with different pituitary mass lesions referred to our endocrinology clinic at sultan qaboos university hospital (squh), the main referral hospital for these patients, or submitted by other tertiary institutions since january 1998. the web-address for the registry (http://www.omands.org:2082/frontend/rvblue/files/ showfile.html?dir=/home/omands&file=list.htm) is password-protected to prevent any unauthorized access and preserve the privacy and confidentiality of the patients. the purpose of this study is to use this pituitary tumour registry to characterize the clinical and epidemiological features of pituitary tumours in the sultanate of oman. m e t h o d s all patients who were suspected to have a pituitary mass tumour and were referred to our tertiary care endocrinology clinic at squh, between january 1998 characteristic nfpa (n=81) prolactinomas (n=59) acromegaly (n=8) total (n=148) p-value age, mean±sd 33±14 32 ±8 42 ±15 33 ±12 0.058 male gender, n (%) 23 (28%) 14 (24%) 5 (63%) 42 (28%) 0.087 microadenoma, n (%) 54 (67%) 51 (86%) 2 (25%) 107 (72%) <0.001 macroadenoma, n (%) 27 (33%) 8 (14%) 6 (75%) 41 (28%) with extension, n (%) 24 (30%) 4 (7%) 4 (50%) 32 (22%) <0.001 without extension, n (%) 57 (70%) 55 (93%) 4 (50%) 116 (78%) non-functioning adenomas; sd=standard deviation; percents are total percents; p-values were generated using univariate statistics; the 0.058 represents the p-value for the overall f-statistic, derived from univariate regression analysis. however, group-wise differences for age did exist, especially between the cohorts, acromegaly and nfpa (42 vs. 33 years; p=0.045) and acromegaly and prolactinomas (42 vs. 32 years; p=0.018). table 1 : demographic and tumour characteristics of the three most prevalent pituitary tumours characterize clinical and the epidemiological features of pituitary tumours in the sultanate of oman. keywords: pituitary adenomas, registry, oman, clinical, epidemiology. c l i n i c a l a n d e p i d e m i o l o g i c a l c h a r a c t e r i s t i c s o f p i t u i ta r y tu m o u r s u s i n g a we b b a s e d p i t u i ta r y tu m o u r r e g i s t r y i n o m a n 27 and february 2006, were included in the newly developed oman pituitary tumour registry. other tertiary hospitals in the country were invited to submit their data. the analysis performed was retrospective and did not in anyway interfere with the management of the patients. futhermore, those involved in the data analysis did not have access to patient details. therefore, present study was not deemed to contravene ethical dimensions or patient confidentiality. after confirming the diagnosis for each new patient, his/her data were entered in the software programme, a web-based pituitary tumour registry computer programme, access 2000 from microsoft corporation, 2000. up to february 2006, the study had enrolled 160 patients. the data include demographic information (age, gender, area of residence), a comprehensive clinical evaluation, hormonal levels, medications and radiological evidence of pituitary mass lesion using mri. pituitary tumour type was confirmed by the clinical presentation of patients, hormones levels, radiographic presentations, and immuno-histochemical detection of hormone content whenever available. the standard protocol for the evaluation of pituitary gland with mri was used to visualize intrasellar pituitary mass lesion. it consists of obtaining t1-weighted images and then repeating the t-1 images after administration of an intravenous contrast agent containing gadolinium-based media.12 not all of the mri’s were done at squh. others were performed elsewhere and brought in by patients themselves. the size of the adenomas was classified by radiographic analysis. pituitary adenomas were divided by size into microadenomas (<1.0 cm in diameter) or macroadenomas (≥1.0 cm in diameter).12 the hormonal samples were analyzed using beckman-coulter immunochemistry system analyzer for prolactin, fsh, lh, growth hormone (gh), thyroid-stimulatory hormone (tsh), cortisol and insulin-like growth factor (igf-i). all variables were updated and tracked on each visit. patient confidentiality was maintained by entering a pre-assigned arbitrary identification number known only to the investigators. clinical and mortality outcomes were also collected and tracked on flow worksheets. stati sti c a l a n a ly si s descriptive statistics were used to describe the data. for categorical variables, frequencies and percentages were reported. differences between groups were analyzed using pearson’s x2 tests (or fisher’s exact tests for cells less than 5). for continuous variables, means and standard deviations (±sd) were presented. mean differences between groups were analyzed using student’s t-tests. an a priori two-tailed level of significance was set at the 0.05 level. r e s u l t s d e mo gr a ph i c a n d t umo ur c h a r a c te r i s ti c s over an 8-year period (1998-2006), a total of 160 entries representing a heterogeneous mixture of the omani population were made into the pituitary tumour registry. the overall mean age of the cohort was 32±12 years with an age range from 8 to 73 years. the majority of the registrations were females (n=114; 71%). just over half of the pituitary tumours were non-functioning adenomas (n=81; 50.6%), followed by prolactinomas (n=59; 36.9%), acromegaly (n=8; 5.0%), craniopharyngiomas (n=7; 4.4%), cushing’s disease (n=4; 2.5%), and sarcoids (n=1; 0.6%). sub-group analyses feature column percentages non-functioning adenomas (n=81) prolactinomas (n=59) acromegaly (n=8) =148 amenorrhea-galactorrhea 4 (4.9%) 50 (84.7%) 1 (12.5%) headache 29 (35.8%) 2 (3.4%) 0 visual field defects 4 (4.9%) 0 0 diabetes insipidus 3 (3.7%) 0 0 hypogonadal symptoms 11 (13.6%) 4 (6.8%) 0 delayed growth 2 (2.5%) 0 0 hypopituitary symptoms 7 (8.6%) 1 (1.7%) 1 (12.5%) fatigue 21 (25.9%) 2 (3.4%) 0 acral enlargement 0 0 6 (75.0%) table 2: clinical features of the three most prevalent pituitary tumours a b d u l l a h a l f u ta i s i , a l -ya a r u b i s a i f, i b r a h i m a l z a k wa n i , s a l i m a l q a s s a b i , s h a d e n a l r i ya m i , ya s s e r wa l i 28 were performed only for those subjects with the three most prevalent pituitary tumours (non-functioning adenomas, prolactinomas and acromegaly). there were significant age differences in patients with the three most prevalent pituitary tumours [table 1]. the subjects with acromegaly were significantly older compared to those with non-functioning adenomas (42 versus 33 years; p=0.045) or prolactinomas (42 versus 32 years; p=0.018). those with acromegaly were more likely to be males than females (63% versus 37%; p=0.042). furthermore, subjects with acromegaly were significantly more likely to have macroadenomas than those with either non-functioning adenomas or prolactinomas (75% versus 33% versus 14%; p<0.001). additionally, those with acromegaly were also more likely to have tumours with extension than those with either non-functioning adenomas or prolactinomas (50% versus 30% versus 7%; p<0.001). those with extension were significantly more likely to be males than females (38% versus 15%; p=0.002). in addition, males were also significantly more likely to have macroadenomas as compared to females (45% versus 21%; p=0.003). tumour-specific presenting clinical features are presented in table 2. the most prevalent symptoms were amenorrhea-galactohorrhea (n=55; 37.2%), headache (n=31; 21%) and fatigue (n=23; 16%). the symptom, amenorrhea-galactohorrhea, was mostly associated with those patients with prolactinomas rather than those with non-functioning adenomas or acromegaly (84.7% versus 4.9% versus 12.5%; p<0.001). headache was most associated with those with nonfunctioning adenomas rather than those with either prolactinomas or acromegaly (35.8% versus 3.4% versus 0%; p<0.001). furthermore, fatigue was also mostly associated with non-functioning adenomas rather than prolactinomas or acromegaly (25.9% versus 3.4% versus 0%; p=0.001). th e r a p y a n d c l i n i c a l o u tc ome several therapeutic modalities were employed for the treatment of the different pituitary tumours including observation, medical, surgery, and medical plus surgery [table 3]. out of the three most prevalent pituitary tumour types, the most common treatment modality was medical (n=58; 39%) followed by observation (n=56; 38%), surgery (n=31; 21%) and surgery plus medical (n=3; 2%). those with prolactinomas were all medically treated compared with those with either non-functioning adenomas or acromegaly (98% versus 0% versus 0%; p<0.001). observation was the main treatment modality for those with non-functioning adenomas, compared with those with either prolactinomas or acromegaly (69% versus 0% versus 0%; p<0.001). surgical intervention was mostly associated with those that have acromegaly than those with either non-functioning adenomas or prolactinomas (75% versus 31% versus 0%; p<0.001). up to february 2006 none of the patients were recorded to have died. d i s c u s s i o n during the past 3 decades, the sultanate of oman has undergone a remarkable transformation and modernization in all fields, including education and health care. it has progressively established a nationwide network of modern health services that are accessible even at the village level and have ranked oman with the developed world.15 world wide, tumour registries have become one of the strongest tools used to help health workers in the clinical and epidemiological studies of cancer. the true incidence of pituitary tumours is still not known and accurate tumour typespecific epidemiological information is lacking, due to the non-existence of any web-based international pituitary tumour registry. in addition, accurate records of outcomes and mortality are not available. for all these reasons, we developed a web-based programme in which all patients in oman with pituitary tumours are registered and followed. to our knowledge, this is non-functioning adenomas (n=81) prolactinomas (n=59) acromegaly (n=8) medical 0 98% 0 observation 69% 0 0 surgery 31% 0 75% surgery+medical 0 2% 25% total 100% 100% 100% table 3: therapeutic modalities of the three most prevalent pituitary tumours c l i n i c a l a n d e p i d e m i o l o g i c a l c h a r a c t e r i s t i c s o f p i t u i ta r y tu m o u r s u s i n g a we b b a s e d p i t u i ta r y tu m o u r r e g i s t r y i n o m a n 29 the first pituitary tumour registry in the arabian gulf countries and the middle east. of maximum interest is the unexpectedly large number of new patients (160) registered in a country with a population of a 2.3 million15 over the past 8-year period, giving one case per 14,375 of the population. the majority of patients were symptomatic and almost half of them had functioning adenomas. in a recent article by drange et al., who reviewed the hospital charts of patients with pituitary tumours between 1982 to 1999 in california state (with a population of more than 35 million), usa, they found 404 patients,14 an incidence of 1 per 86,634 of the population. there are many factors that might explain the higher numbers in the omani population. genetic, ethnic and environmental differences and the extended use of traditional medicine may contribute. these hypotheses need further studies. the mean age of acromegalic patients at diagnosis (42 years) did not differ from those reported in previous series.14,16 there was a significant male predominance 63% versus 37% (p=0.042). beauregard et al. reported a similar male predominance, however several other studies reported female predominance.17 the female predominance may be due to the fact that females usually present earlier with amenorrhea.2, 3, 11, 12, 13, 15 additionally, those with acromegaly were also more likely to have tumours with extension than those with either non-functioning adenomas or prolactinomas (50% versus 30% versus 7%; p<0.001). those with extension were significantly more likely to be males than females (38% versus 15%; p=0.002). in addition, males were also significantly more likely to have macroadenomas as compared to females (45% versus 21%; p=0.003). this gender difference could be due to the fact that more men feel shy to complain about their sexual problems (decreased libido and impotence). in our study, these patients appeared to be less symptomatic in comparison to patients with other tumour types. this can be explained by the fact that growth harmone gh secreting tumours grow slowly and result in subtle changes in body features. all of them were treated surgically and 25% of them received medical treatment as well gh receptor antagonist. fifty-nine patients in the database were confirmed as having prolactinomas; females (44) constituted 76% of them. they were predominantly microadenomas (86%). these results are consistent with the results of previously published figures.18 in our patients, the most frequent clinical presentations were amenorrhea and galactorrhea followed by hypogonadal symptoms and headache. the tumour showed evidence of extension in 2 males (14.3%) and 2 females (4.6%). males were more likely to have tumour extensions due to their late presentation. non-functioning pituitary tumours were the most frequent tumour (n=81) and most commonly affected the females (72%). they were mostly microadenoma with no extension (70%). the most common presenting symptoms were headache (35.8%) followed by fatigue (25.9%), hypogonadal symptoms (13.6%) and amenorrhea (4.9%). in our study we found that 8.7% of patients with non-functioning adenomas had hypopituitary symptoms. pituitary insufficiency can be encountered in patients with any size or type of intrasellar mass and, thus, serves as an important diagnostic indicator of a pituitary lesion.19 c o n c l u s i o n a tumour registry systematically collects information about the occurrence of cancer, the types of cancer that occur (site, morphology and behaviour), extent of disease at the time of diagnosis (stage), the kinds of treatment received by cancer patients and the outcomes of treatment (survival). the ultimate goal of the analysis of cancer data is to prevent and control cancer. data is also used to respond to local questions about referral patterns and trends by disease site, by treatment modality and even by clinician. the registry’s role of evaluating clinical outcomes and quality of medical care includes assessing treatment patterns, complications, cancer recurrence and survival. the goal of the pituitary tumour registry is improvement in early identification of these patients, tumour management strategies, and long-term outcomes. in conclusion, we have developed a novel computerized pituitary tumour registry programme in the sultanate of oman designed to collect comprehensive demographic, therapeutic, pathologic, and outcome information on patients harbouring these rare tumours and who are referred for tertiary consultation. this registry can be used to improve surveillance protocols and long-term therapeutic outcomes. a c k n ow l e d ge me n ts the authors would like to acknowledge the work of all the healthcare professionals who were involved in the management of the patients. a b d u l l a h a l f u ta i s i , a l -ya a r u b i s a i f, i b r a h i m a l z a k wa n i , s a l i m a l q a s s a b i , s h a d e n a l r i ya m i , ya s s e r wa l i 30 r e f e r e n c e s 1. gsponer j, de tribolet n, deruaz jp, et al. diagnosis, treatment, and outcome of pituitary tumours and other abnormal intrasellar masses. retrospective analysis of 353 patients. medicine 1999; 78:236-269. 2. freda pu, post kd. differential diagnosis of sellar masses. endocrinol metab clin north am 1999; 28:81-117. 3. molitch me. pituitary incidentalomas. endocrinol metab clin north am 1997; 26:725-740. 4. kovacs k, scheithauer bw, horvath g, lloyd rv. the world health organization classification of adenohypophysial neoplasms. cancer 1996; 78:502-510. 5. auer rn, alakija p, sutherland gr. asymptomatic large pituitary adenomas discovered at autopsy. surg neurol 1996; 46:28-31. 6. burrow gn, wortzman g, rowcastle nb, holgate rc, kovacs k. microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. n engl j med 1981; 304:156-158. 7. hall wa, luciano mg, doppman jl, patronas nj, oldfield eh. pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. ann intern med 1994; 112:817-820. 8. freda pu, wardlaw sl, post kd. unusual causes of sellar/parasellarmasses in a large transsphenoidal surgical series. j clin endocrinol metab 1996; 81:3455-3459. 9. molitch me, russell ej. the pituitary incidentaloma. ann intern med 1990; 112:925-931. 10. annegers jf, coulam cb, abboud cf, laws er, kurland lt. pituitary adenoma in olmstead county, minnesota, 1935–1977. a report of an increasing incidence of diagnosis in women of childbearing age. mayo clinic proc 1978; 53:641-643. 11. kurland lt, schoenber bs, annegers jf, okazaki h, molgaard ca. the incidence of primary intracranial neoplasms in rochester, minnesota, 1935–1977. ann ny acad sci 1982; 381:6-16. 12. pressman, bd. pituitary imaging. in: melmed s. ed. the pituitary. 2nd ed. , cambridge: blackwell scientific publications, 2002. p. 690-730 13. katnelson l, alexander jm, klibanski a. clinically nonfunctioning pituitary adenomas. j clin endocrinol metab 1993; 76:1089-1094. 14. drange mr, fram nr, herman-bonert v, melmed s. pituitary tumour registry: a novel clinical resource.j clin endocrinol metab. 2000; 85:168-174. 1department of medical education, college of medicine, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia; 2king abdullah international medical research center, riyadh, saudi arabia; 3department of family medicine, king fahd medical city, riyadh, saudi arabia; 4department of medicine, king abdulaziz medical city, ministry of national guard health affairs, riyadh, saudi arabia *corresponding author’s e-mail: saeedalshahrani158@gmail.com abstract: objectives: this study aimed to explore saudi arabian medical students’ perceptions of patient safety. methods: a cross-sectional descriptive study was conducted in the college of medicine, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia, in september 2019. the attitudes to patient safety questionnaire (apsq iii) was used to explore undergraduate medical students’ attitudes towards and knowledge of ps. the main outcomes measured were the apsq iii’s nine domains. data were analysed using statistical package for the social sciences and students’ attitudes were communicated as mean scores ± standard deviations. results: a total of 301 participants were included in this study (response rate: 85.75%). six domains reflected a positive attitude while three domains showed a neutral attitude. the domain of ‘team functioning’ had the highest mean score (5.8) followed by ‘working hours as a cause of error’ (5.6) and ‘error inevitability’ (5.4). there was a significant difference between gender in the domain ‘patient involvement in reducing error’ (p = 0.012) and ‘importance of patient safety (ps) in the curriculum’ (p = 0.001). in addition, the ‘importance of ps in the curriculum’ domain was significantly different across different age groups (p = 0.039). conclusion: medical students were highly interested in ps and recommended implementing a comprehensive undergraduate ps programme to fulfil their educational needs. keywords: undergraduate medical education; patient safety; medical errors; attitude; medical students; medical ethics; patient care; saudi arabia. medical students’ insights towards patient safety *saeed alshahrani,1,2 ahmad alswaidan,1,2 ala alkharaan,1,2 abdulrahman alfawzan,1,2 aysha alshahrani,2,3 emad masuadi,1,2 awad alshahrani1,2,4 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e253–259, epub. 21 jun 21 submitted 26 mar 20 revision req. 31 may 20; revision recd. 16 jun 20 accepted 16 jul 20 https://doi.org/10.18295/squmj.2021.21.02.014 clinical & basic research advances in knowledge the presence of receptive learning environment is one of the most important determinants to establish a patient safety programme of the best outcomes. the confidence of medical students to report an error is negatively implicated by the unprofessional role modeling within a dominant clinical hierarchy. male physicians prefer to follow a paternalistic relationship with patients compared to their female encounters. application to patient care undergraduate education serves an important role in maintaining patient safety and the introduction of an undergraduate patient safety programmes in saudi universities would highly benefit the quality of future healthcare. pateint safety curriculam should provide practical guidance for healthcare providers to achieve better doctor-patient relationships and outstanding problem solving skills and minimise unwanted complications if adverse events occur. medical students’ educational needs, course timing and differences in exposure to hospital environments should be considered when designing an undergraduate medical curriculum in patient safety. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. with developments in science and technology, the modern healthcare system has hugely improved the quality of medical care. however, medical errors have become a serious issue globally over the past decades.1,2 in 1999, the usa’s institute of medicine committee on quality of health care in america reported that 98,000 hospitalised patients die annually due to medical error, exceeding the number of deaths caused by motor vehicle accidents, breast cancer or aids.1 in response to the striking number of deaths caused by medical error, an institute of medicine report aimed to raise attention around patient safety and the need for such an important discipline as a part of medical education.1 between 1999–2013, preventable deaths caused by adverse medical events exceeded 250,000 in the usa and medical error now ranks as the third most common cause of death in the usa.2 medical errors are becoming a major consumer of healthcare system resources, causing burdens associated with both economics and death. in 2008, medical errors cost the usa $19.5 billion and $1.4 billion were ascribed to increased mortality rate and the resulting loss of productivity, which is estimated to equate to 10 million work days lost due to missed work caused by disability claims.3 in saudi arabia, the rate of medical errors has been escalating. the total number of medical error claims in saudi arabia in 1999 were 440 and increased to 1,356 cases in 2008.4 in 2016, a local study reported that financial compensation due https://creativecommons.org/licenses/by-nd/4.0/ to medical errors claims was rising in saudi arabia, with 45.78% of death cases compensated with between usd $26,000–130,000 and 53.65% of disability cases compensated with between usd $260–13,000.5 one of the most-known solutions to reduce medical error and improve patient care is implementing a patient safety system in hospitals through a critical incident reporting system. these systems provide clear guidelines on how and what to report and enhances the availability of valuable feedback through local meetings, paper contributions or email alerts.6 patient safety systems encourage education and training on patient safety topics by providing useful tools such as checklists, structured language, or set of phrases the team has agreed to use in operating rooms.7 in 2009, the world health organization (who) stated the importance of incorporating patient safety into medical curricula in order to orient medical students to the need for patient safety.8 the who’s patient safety curriculum guide for medical schools contains 11 evidencebased chapters on patient safety and demonstrates that traditional medical schools teach and assess student performance in three main areas: medical knowledge, technical skills and clinical decision-making.8 newer medical education teaches and evaluates these three traditional technical skills in addition to non-technical skills: communication, risk awareness and management, teamwork and leadership.8 several measurements have recently been used to assess medical errors and many actions have been taken to enhance patient safety globally. the widespread culture among physicians and their attitudes towards patient safety, remain important determinant factors; however, these attitudes may present an obstacle.9 therefore, many studies have recommended instituting patient safety educational programmes in hospitals for physicians and other healthcare providers.10 previous questionnaires, such as the madigosky et al. questionnaire and the attitudes to patient safety questionnaire iii (apsq-iii), have been used to determine medical students’ awareness and knowledge of and attitudes towards patient safety.9,11 these tools can potentially help medical educators plan and implement classroom experiences to fulfil students’ needs around patient safety.9,11 because healthcare systems worldwide are under going transformational development in the quality of patient care, it is essential to ensure satisfactory education in patient safety for future doctors. it is also important to provide baseline characteristics of students’ perceptions and needs regarding patient safety to serve as useful data when designing an appropriate curriculum for undergraduate medical students. there is a shortage of studies on this topic in saudi arabia. therefore, this study aimed to explore the perceptions and attitudes of undergraduate medical students towards patient safety education. methods this cross-sectional descriptive study was conducted in september 2019 at the college of medicine, king saud bin abdelaziz university for health sciences (ksauhs), which is located in riyadh, the capital of saudi arabia. participants were undergraduate medical students from first to fourth year programmes. the academic programme at ksauhs’s college of medicine is a total of four years. the first and second years are the pre-clinical phase while the third and fourth years are devoted to clinical rounds. students from other colleges were excluded. based on an estimated total population of 4,000 medical students in riyadh, the necessary sample size was calculated using a raosoft calculator (raosoft inc., seattle, washington, usa) at a 95% confidence level and a 5% margin of error. assuming a 50% response rate, 351 participants were recruited with non-probability convenience sampling. at ksauhs, all students must attend a problembased learning (pbl) session twice weekly. in this pbl session, students are usually divided into groups of 10 table 1: characteristics of saudi arabian undergraduate medical students included in this study (n = 301) characteristic n (%) gender male 249 (82.72) female 52 (17.28) academic year first 70 (23.26) second 80 (26.58) third 95 (31.56) fourth 56 (18.60) age in years 20 24 (7.97) 21 75 (24.92) 22 77 (25.58) 23 64 (21.26) 24 23 (7.64) ≥25 38 (12.62) mean age in years ± sd 22 ± 1.94 sd = standard deviation. medical students’ insights towards patient safety e254 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e255 to discuss a medical case for 90 minutes. after this pbl session ended, a self-administered questionnaire was given to all groups. only students who agreed to participate stayed after the pbl session to complete the questionnaire. data were collected between 17–31 september 2019 by research team members who were also medical students. this study provided baseline characteristics of students’ perceptions of and attitudes towards patient safety education using the apsq-iii. the questionnaire was adapted and validated by carruthers et al., and permission to utilise the apsq-iii was obtained from the original author via email.9 demographic data collected included age, gender, academic year or batch group and respondent’s college. measured outcomes were student perceptions and attitudes; these were assessed through 26 questions in nine domains: ‘ps training received’ (items 1–3); ‘error reporting confidence’ (items 4–6); ‘working hours as a cause of error’ (items 7–9); ‘error inevitability’ (items 10–12); table 2: attitude of saudi arabian undergraduate medical students towards patient safety using the attitudes to patient safety questionnaire items* mean score ± sd 1. my training is preparing me to understand the causes of medical errors. 4.57 ± 1.54 2. i have a good understanding of patient safety issues as a result of my undergraduate medical training. 4.45 ± 1.53 3. my training is preparing me to prevent medical errors. 4.62 ± 1.63 4. i would feel comfortable reporting any errors i had made, no matter how serious the outcome had been for the patient. 4.75 ± 1.77 5. i would feel comfortable reporting any errors other people had made, no matter how serious the outcome had been for the patient. 4.29 ± 1.81 6. i am confident i could talk openly to my supervisor about an error i had made if it had resulted in potential or actual harm to my patient. 4.99 ± 1.76 7. shorter shifts for doctors will reduce medical errors. 5.54 ± 1.63 8. by not taking regular breaks during shifts, doctors are at an increased risk of making errors. 5.63 ± 1.46 9. the number of hours doctors work increases the likelihood of making medical errors. 5.75 ± 1.41 10. even the most experienced and competent doctors make errors. 5.79 ± 1.41 11. a true professional does not make mistakes or errors.† 2.43 ± 1.66 12. human error is inevitable. 4.97 ± 1.80 13. most medical errors result from careless nurses.† 3.04 ± 1.69 14. if people paid more attention at work, medical errors would be avoided.† 4.87 ± 1.68 15. most medical errors result from careless doctors.† 3.63 ± 1.71 16. medical errors are a sign of incompetence.† 3.52 ± 1.56 17. it is not necessary to report errors which do not result in adverse outcomes for the patient.† 2.71 ± 1.78 18. doctors have a responsibility to disclose errors to patients only if they result in patient harm.† 3.70 ± 2.04 19. all medical errors should be reported. 5.66 ± 1.64 20. better multi-disciplinary teamwork will reduce medical errors. 5.88 ± 1.51 21. teaching teamwork skills will reduce medical errors. 5.79 ± 1.49 22. patients have an important role in preventing medical errors. 4.88 ± 1.61 23. encouraging patients to be more involved in their care can help to reduce the risk of medical errors occurring. 5.25 ± 1.53 24. teaching students about patient safety should be an important priority in medical students training. 5.67 ± 1.57 25. patient safety issues cannot be taught and can only be learned by clinical experience when qualified.† 3.47 ± 1.79 26. learning about patient safety issues before i qualify will enable me to become a more effective doctor. 5.41 ± 1.60 *graded according to a 7-point likert scale (7 = strongly agree to 1 = strongly disagree). a score of >4 indicates a positive attitude, a negative attitude is indicated by a score <4 and a neutral attitude by a score of 4. †reverse coded items. saeed alshahrani, ahmad alswaidan, ala alkharaan, abdulrahman alfawzan, aysha alshahrani, emad masuadi and awad alshahrani ‘professional incompetence as a cause of error’ (items 13–16); ‘disclosure responsibility’ (items 17–19); ‘team functioning’ (items 20 and 21); ‘patient involvement in reducing error’ (items 22 and 23); and ‘importance of ps in the curriculum’ (items 24–26).15 a 7-point likert scale (1 = strongly disagree, 2 = disagree, 3 = somewhat disagree, 4 = neutral, 5 = somewhat agree, 6 = agree and 7 = strongly agree) was used to measure students’ perceptions and attitudes. the instrument’s creator reversed the coding on items 11, 13, 14, 15, 16, 17, 18 and 25, where the highest score is one and seven is the lowest because those items indicate negative beliefs. reverse coding was used for those items to obtain the mean score of each domain. an excel (microsoft, corp., redmond, washington, usa) sheet was used for data entry, and statistical package for the social sciences (spss), version 21 (ibm, corp., armonk, new york, usa) was used for data analysis. students were grouped based on gender, academic year and age. descriptive statistics were used to present demographic data in frequency and percentages. students’ perceptions of each statement in the apsq-iii were displayed in mean ± standard deviation. the perception score was considered positive if the response range was from 5–7 or negative if the score was from 1–3. in the case of reverse coded questions, responses were considered positive if the response range was from 1–3. a mean score of 4 in both cases was considered neutral. students’ perceptions and attitudes were also analysed according to the corresponding nine domains of the apsq-iii. one-way analysis of variance was used to compare the mean scores of the students’ perceptions between the five age categories. to note differences by gender, a student’s t-test was used to compare the mean scores of students’ perceptions and attitudes. the level of statistical significance was set at p <0.05. informed written consent was given by all participants and questionnaire completion was voluntary and anonymous. the study was approved by king abdullah international medical research center, and the data were collected after gaining approval from the university’s institutional review board (rc19/065/r). confidentiality and anonymity were maintained during and after data collection. results a total of 301 participants were included in this study (response rate: 85.75%). there was a male predominance (n = 249; 82.72%) and most participants were in their third year (n = 95; 31.56%) and 22 years old (n = 77; 25.58%) [table 1]. interestingly, no items were perceived with a negative attitude and 12 items revealed a positive attitude while 14 items showed a neutral attitude [table 2]. most participants (82.40%) agreed that ‘better multi-disciplinary teamwork will reduce medical errors’ (mean = 5.88). most participants supported the perception that ‘teaching teamwork table 3: saudi arabian undergraduate medical students’ attitudes towards patient safety according to the nine domains of the attitudes to patient safety questionnaire domain mean overall score ± sd gender age in years male female p value* 20 21 22 23 24 ≥25 p value† 1. ps training received 4.6 ± 1.33 4.55 4.55 0.989 4.18 4.72 4.49 4.51 4.93 4.43 0.360 2. error reporting confidence 4.7 ± 1.56 4.65 4.67 0.939 4.97 4.86 4.81 4.43 4.39 4.38 0.278 3. working hours as a cause of error 5.6 ± 1.27 5.60 5.65 0.763 5.71 5.79 5.76 5.40 5.39 5.65 0.423 4. error inevitability 5.4 ± 1.22 5.49 5.43 0.746 5.14 5.44 5.66 5.22 5.45 5.54 0.276 5. professional incompetence as a cause of error 4.2 ± 1.18 4.42 4.19 0.207 4.31 4.26 4.08 4.04 4.34 4.70 0.092 6. disclosure responsibility 5.1 ± 1.22 5.12 5.07 0.780 5.00 5.27 4.87 4.96 4.88 5.48 0.090 7. team functioning 5.8 ± 1.36 6.13 5.77 0.088 5.33 5.77 5.91 5.70 6.24 6.11 0.162 8. patient involvement in reducing error 5.1 ± 1.32 5.48 4.98 0.012 4.94 5.07 4.86 4.98 5.24 5.61 0.101 9. importance of ps in the curriculum 5.2 ± 1.20 5.09 5.69 0.001 5.31 5.07 5.11 4.99 5.52 5.70 0.039 sd = standard deviation; ps = patient safety. *calculated using student’s t-test. †calculated using anova. medical students’ insights towards patient safety e256 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e257 skills will reduce medical errors’ and ‘even the most experienced and competent doctors make errors’ (mean = 5.79 each). in regard to the nine domains, ‘team functioning’ had the highest score (mean = 5.8) followed by ‘working hours as a cause of error’ (mean = 5.6) and ‘error inevitability’ (mean = 5.4) [table 3]. there was a statistical difference between gender in two key domains: ‘patient involvement in reducing error’ (p = 0.012) and ‘importance of ps in the curriculum’ (p = 0.001). in addition, the perception of ‘importance of ps in the curriculum’ showed a significant difference (p = 0.039) in terms of participants’ ages. discussion in order to encourage quality patient care in saudi arabia, the present study explored medical students’ perceptions of and attitudes towards ps. medical students’ interests in ps are highlighted and common misconceptions that need to be addressed when building an undergraduate curriculum in such a field are discussed below. in the present study, ‘team functioning’ had the highest score among all domains. similarly, a study conducted in pakistan also showed team functioning to be the highest scored item.12 this similarity reflects the importance of team-based teaching in medical curricula and healthcare institutions. communication and collaboration skills as well as establishing a teamwork-focused culture are essential factors in ps and, hence, the quality of healthcare.13 interestingly, the positive attitudes of medical students towards team functioning showed a nearly escalating pattern according to participants’ ages. heavy workloads of more than 40 hours a week and long overtime shifts of more than 12.5 hours per shift among healthcare providers were significantly associated with an increased risk of medical error (p value = 0.0001 and 0.005, respectively).14 similar to previous findings reported in the literature, medical students who participated in the current study strongly agreed that human error is inevitable and working hours are potential causes of medical errors.12,13,15 traditional educational institutions assume that ps education is gained through clinical experience rather than educational knowledge-based courses.16 nevertheless, the inclusion of ps education in under graduate medical curricula would further strengthen practitioners’ abilities to identify and deal with situations threatening ps.2,3 undergraduate students in different countries have supported such a suggestion.12,13,15 in the present study, the attitudes of students positively (5.2 ± 1.20) supported implementing a knowledgebased programme designed for undergraduate medical students. the reported need of medical students to receive ps education could be explained by the absence of comprehensive undergraduate educational courses in medical schools. in saudi arabia, various academic institutions, that target all healthcare providers, provide selective courses, short lectures and annual meetings concerning topics related to ps. however, an undergraduate curriculum in ps is not mandatory for completing undergraduate medical education in saudi universities and has been developed informally through bedside teaching in the clinical years with minimal exposure to ps-related terminology. bedside teaching, where trainees interact with patients under the supervision of a clinician, remains an essential educational tool especially for junior doctors to promote and accelerate clinical maturity.17 however, reliance only on bedside teaching model, which is often provided in a heterogeneous manner, is challenging to reach a standardised consistent ps education. standardisation of the required knowledge and skills would result in achieving a satisfactory level of knowledge related to ps. a lack of available faculty, time and funding, accreditation requirements and differing hospital environments diversifies students’ exposure to bedside teaching across various medical colleges.16,17 undergraduate students in the current study showed a uniquely positive attitude towards teaching ps. a receptive learning environment is key in establishing a curriculum that supports best outcomes.18 nursing students, who are thought to be more familiar with ps topics, think that there is insufficient time spent learning about ps and quality of patient care.19 this finding is relative to undergraduate courses that extensively discuss pathophysiology, management and prognosis of medical diseases.19 although the average score of the domain ‘importance of ps in the curriculum’ was high for both males and females, there was a significant difference between the genders (p = 0.001); a significant difference was also noted in terms of students’ ages (p = 0.039). the average score of this domain increased gradually with the increase in academic years. this finding might indicate a higher need for ps education, particularly for senior students. in the current study, most participants over 25 years old had previous healthcare experience and had joined medical school after completing a bachelor's degree in other healthcare specialties. the factor of receiving ps training had the second lowest score in the current study, which may indicate a knowledge gap in understanding ps issues and the ability to prevent medical error. madigosky et al. investigated the effects of introducing a ps and medical saeed alshahrani, ahmad alswaidan, ala alkharaan, abdulrahman alfawzan, aysha alshahrani, emad masuadi and awad alshahrani fallibility course for undergraduate medical students by evaluating students’ responses to a knowledge, skills and attitudes questionnaire before and after course completion.11 a total of 72% of students responded that the course fulfilled their medical objectives, including recognising human inevitability, addressing factors related to medical errors, learning and improving skills for error disclosure and providing a guide for ideal communication within healthcare environments. the introduction of a ps course has been identified as beneficial and has been highly recommended for undergraduate medical education.9,11–13,15,19 in the asser region of saudi arabia, the apsq-iii was given to primary care physicians; one-fifth were unsatisfied with their training and 70% had not received any training, although most participants demonstrated a positive attitude towards ps education.20 these results show the necessity of prioritising ps education to undergraduate medical students. in the current study, students showed positive attitudes towards disclosure responsibility. the level of error reporting confidence was shown to be good, to a limited extent, among the current participants. the willingness to report error declines in students as they achieve higher academic levels. this decline in error reporting confidence might be caused by a fear of speaking-up within a dominant clinical hierarchy. in germany, first-year students have been found to have higher willpower to disclose medical errors.13 the exposure of medical students to negative role modeling or toxic bedside teaching during their clinical experience might promote the development of unprofessional behaviours such as neglecting important ethical concepts related to patient autonomy and avoiding disclosing adverse medical events.13 the effect of the ‘hidden curriculum’, which dominates medical education, affects medical students as they develop ethical and professional identities as junior doctors. educators and clinicians must take into consideration the harmful influence of the ‘hidden curriculum’ and instead promote open discussion among team members to convey any concerns related to ps.21 to support the practice of error disclosure, healthcare providers should avoid blaming each other and instead encourage an interdisciplinary clinical culture that understands limited human capability and prioritises outstanding patient care through proper communication between team members.13,22–24 in fact, the practice of error disclosure is subjected to cultural considerations because unnecessary disclosure, if no clear adverse events were encountered, might result in patient distress.22 hammami et al. surveyed patients visiting outpatient clinic in riyadh and found that 95% of participants prefer to be informed if major, minor or near-miss medical errors had occurred.23 from an islamic point of view, error must be disclosed and forgiveness should be sought.23 ‘professional incompetence as a cause of error’ scored the lowest among all domains. although most of students had positive perceptions regarding error inevitability, the misconception that medical errors are due to underlying individual failures should be addressed when implementing patient safety curricula in the future. the attitude towards patient involvement in reducing medical errors significantly differs between genders (p = 0.012). in terms of communication, roter et al. reported that female physicians were more likely to spend greater time in patient-centred talk than their male colleagues, with an average of two minutes or 10% of the time per visit.25 löffler-stastka et al. stated that female students were more likely to express empathy, address psychosocial concerns while taking medical history and spend greater time communicating with patients.26 on the other hand, löffler-stastka et al. estimated that one-third of male physicians preferred to follow a paternalistic relationship with patients, whereas female physicians were more interested in patient-centred communication.26 using a validated and reliable tool to assess students’ thinking, including students from four academic years and recruiting a larger number of participants relative to previous studies, are strong features of the present study. however, this study has some limitations. first, it could not investigate the effectiveness of introducing an educational programme in patient safety for medical students. rather, this study provides baseline data to help design a proper undergraduate curriculum in the future. second, the response rate in the current study was lower than expected, especially from female students; this low response rate was in part due to the study’s convenience sampling, which was a result of students’ absence during the data collection and a higher percentage of male students than female students in the college of medicine. in order to determine the effectiveness of ps education on the quality of patient care, a longitudinal evaluation should be done during and after introducing a ps education programme. conclusion the apsq-iii tool revealed a positive attitude among saudi undergraduate medical students towards ps. a knowledge gap still exists in major aspects of ps such as the role of professional incompetence in causing errors and the confidence to report medical errors. the current status of undergraduate education on ps has also been reported as inadequate. clinical-year medical students’ insights towards patient safety e258 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e259 students are likely to benefit more from introducing undergraduate courses in ps. educational institutions should consider implementing a comprehensive under graduate educational programme on ps to meet the needs of future doctors. further longitudinal studies are required to evaluate the effectiveness of such an intervention. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. institute of medicine (us) committee on quality of health care in america, kohn lt, corrigan jm, donaldson ms, eds. to err is human: building a safer health system. washington, dc, usa: national academies press, 2000. 2. makary ma, daniel m. medical error-the third leading cause of death in the us. bmj 2016; 353:i2139. https://doi. org/10.1136/bmj.i2139. 3. andel c, davidow sl, hollander m, moreno da. the economics of health care quality and medical errors. j health care finance 2012; 39:39–50. 4. al-saeed ah. medical liability litigation in saudi arabia. saudi j anaesth 2010; 4:122–6. https://doi.org/10.4103/1658354x.71133. 5. alshammari mh, mital dp. medical errors in saudi arabia: understanding the pattern and associated financial cost. int j med engin inform 2016; 8:41–8. https://doi.org/10.1504/ ijmei.2016.073652. 6. health quality ontario. patient safety learning systems: a systematic review and qualitative synthesis. ont health technol assess ser 2017; 17:1–23. 7. oppikofer c, schwappach d. the role of checklists and human factors for improved patient safety in plastic surgery. plast reconstr surg 2017; 140:812e–17e. https://doi.org/10.1097/ prs.0000000000003892. 8. world health organization. who patient safety curriculum guide for medical schools. from: https://who.int/iris/ handle/10665/44091 accessed: jun 2020. 9. carruthers s, lawton r, sandars j, howe a, perry m. attitudes to patient safety amongst medical students and tutors: devel oping a reliable and valid measure. med teach 2009; 31:e370–6. https://doi.org/10.1080/01421590802650142. 10. hindle d, braithwaite j, iedema r. the centre for clinical governance research, patient safety research: a review of the technical literature. sydney, australia: university of new south wales; 2005. 11. madigosky ws, headrick la, nelson k, cox kr, anderson t. changing and sustaining medical students’ knowledge, skills, and attitudes about patient safety and medical fallibility. acad med 2006; 81:94–101. https://doi.org/10.1097/00001888-20060 1000-00022. 12. kamran r, bari a, khan ra, al-eraky m. patient safety awareness among undergraduate medical students in pakistani medical school. pak j med sci 2018; 34:305–9. https://doi. org/10.12669/pjms.342.14563. 13. kiesewetter j, kager m, lux r, zwissler b, fischer mr, dietz i. german undergraduate medical students' attitudes and needs regarding medical errors and patient safety--a national survey in germany. med teach 2014; 36:505–10. https://doi.org/10.31 09/0142159x.2014.891008. 14. rogers ae, hwang wt, scott ld, aiken lh, dinges df. the working hours of hospital staff nurses and patient safety. health aff (millwood) 2004; 23:202–12. https://doi.org/10.1377/hlt haff.23.4.202. 15. leung gk, ang sb, lau tc, neo hj, patil ng, ti lk. patient safety culture among medical students in singapore and hong kong. singapore med j 2013; 54:501–5. https://doi.org/10.1162 2/smedj.2013172. 16. wu aw, busch im. patient safety: a new basic science for professional education. gms j med educ 2019; 36:doc21. https://doi.org/10.3205/zma001229. 17. peters m, ten cate o. bedside teaching in medical education: a literature review. perspect med educ 2014; 3:76–88. https:// doi.org/10.1007/s40037-013-0083-y. 18. bowman c, neeman n, sehgal nl. enculturation of unsafe attitudes and behaviors: student perceptions of safety culture. acad med 2013; 88:802–10. https://doi.org/10.1097/acm.0b 013e31828fd4f4. 19. vaismoradi m, salsali m, marck p. patient safety: nursing students' perspectives and the role of nursing education to provide safe care. int nurs rev 2011; 58:434–42. https://doi. org/10.1111/j.1466-7657.2011.00882.x. 20. al-khaldi ym. attitude of primary care physicians toward patient safety in aseer region, saudi arabia. j family community med 2013; 20:153–8. https://doi.org/10.4103/2230-8229.121976. 21. lehmann ls, sulmasy ls, desai s; acp ethics, professionalism and human rights committee. hidden curricula, ethics, and professionalism: optimizing clinical learning environments in becoming and being a physician: a position paper of the american college of physicians. ann intern med 2018; 168:506–8. https://doi.org/10.7326/m17-2058. 22. ethics committee of the american society for reproductive medicine. disclosure of medical errors involving gametes and embryos. fertil steril 2006; 86:513–15. https://doi.org/10.10 16/j.fertnstert.2006.07.1448. 23. hammami mm, attalah s, al qadire m. which medical error to disclose to patients and by whom? public preference and perceptions of norm and current practice. bmc med ethics 2010; 11:17. https://doi.org/10.1186/1472-6939-11-17. 24. almaramhy h, al-shobaili h, el-hadary k, dandash k. knowledge and attitude towards patient safety among a group of undergraduate medical students in saudi arabia. int j health sci (qassim) 2011; 5:59–67. 25. roter dl, hall ja, aoki y. physician gender effects in medical communication: a meta-analytic review. jama 2002; 288:756–64. https://doi.org/10.1001/jama.288.6.756. 26. löffler-stastka h, seitz t, billeth s, pastner b, preusche i, seidman c. significance of gender in the attitude towards doctor patient communication in medical students and physicians. wien klin wochenschr 2016; 128:663–8. https://doi.org/10.1007/ s00508-016-1054-1. saeed alshahrani, ahmad alswaidan, ala alkharaan, abdulrahman alfawzan, aysha alshahrani, emad masuadi and awad alshahrani https://doi.org/10.1136/bmj.i2139 https://doi.org/10.1136/bmj.i2139 https://doi.org/10.4103/1658-354x.71133 https://doi.org/10.4103/1658-354x.71133 https://doi.org/10.1504/ijmei.2016.073652 https://doi.org/10.1504/ijmei.2016.073652 https://doi.org/10.1097/prs.0000000000003892 https://doi.org/10.1097/prs.0000000000003892 https://doi.org/10.1080/01421590802650142 https://doi.org/10.1097/00001888-200601000-00022 https://doi.org/10.1097/00001888-200601000-00022 https://doi.org/10.12669/pjms.342.14563 https://doi.org/10.12669/pjms.342.14563 https://doi.org/10.3109/0142159x.2014.891008 https://doi.org/10.3109/0142159x.2014.891008 https://doi.org/10.1377/hlthaff.23.4.202 https://doi.org/10.1377/hlthaff.23.4.202 https://doi.org/10.11622/smedj.2013172 https://doi.org/10.11622/smedj.2013172 https://doi.org/10.3205/zma001229 https://doi.org/10.1007/s40037-013-0083-y https://doi.org/10.1007/s40037-013-0083-y https://doi.org/10.1097/acm.0b013e31828fd4f4 https://doi.org/10.1097/acm.0b013e31828fd4f4 https://doi.org/10.1111/j.1466-7657.2011.00882.x https://doi.org/10.1111/j.1466-7657.2011.00882.x https://doi.org/10.4103/2230-8229.121976 https://doi.org/10.7326/m17-2058 https://doi.org/10.1016/j.fertnstert.2006.07.1448 https://doi.org/10.1016/j.fertnstert.2006.07.1448 https://doi.org/10.1186/1472-6939-11-17 https://doi.org/10.1001/jama.288.6.756 https://doi.org/10.1007/s00508-016-1054-1 https://doi.org/10.1007/s00508-016-1054-1 1department of family medicine and public health, sultan qaboos university hospital, muscat, oman; 2department of dermatology, jewish general hospital, mcgill university, montreal, canada *corresponding author’s e-mail: a.alkhalili@hotmail.com re: elevated peripheral blood eosinophils during acute exacerbation of chronic obstructive pulmonary disease prevalence and clinical significance sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 595–596, epub. 7 nov 22 submitted 24 aug 22 accepted 15 sep 22 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.10.2022.060 letter to the editor dear editor, we read with interest, the article by al sibani et al. published in the august 2022 issue of squmj.1 on elevated peripheral blood eosinophils (pbe) during acute exacerbation of chronic obstructive pulmonary disease (aecopd). patients who have been treated for copd may develop acute exacerbations and respond to corticosteroids.2 pulmonary function tests in these patients show that fev1.0 can be markedly improved in stable conditions after corticosteroid administration.2 in the last several years, we also encountered three copd patients with increased peripheral eosinophils during acute exacerbations. two of them were severe copd patients who required home oxygen therapy. intravenous corticosteroids resulted in marked improvement in the patient's symptoms and fev1.0. therefore, we speculate that some patients who seem to have only copd might have factors of bronchial asthma. we agree with the authors' view that peripheral eosinophil counts during acute exacerbations should be noted. however, there are some aspects where questions remain. it would be beneficial to know whether it was considered that increased eosinophils suggested that the patients had bronchial asthma. it was unclear if the patients had a history of paroxysmal dyspnoea at night or early in the morning or if there were any changes in eev1.0 before and after beta-agonist inhalation in pulmonary function tests. for patients who had exacerbation eosinophilia, it was not clear if the peripheral eosinophil counts remained normal in the resting state when steroids were restored to pre-exacerbation levels. finally, it would be helpful to know whether patients with eosinophilia were considered those with so-called ‘asthma-chronic pulmonary obstructive disease overlap’.3 shinichiro okauchi and *hiroaki satoh division of respiratory medicine, mito medical center, university of tsukuba-mito kyodo general hospital, mito, japan *corresponding author’s e-mail: hirosato@md.tsukuba.ac.jp references 1. al sibani m, al alawi am, al aghbari j. elevated peripheral blood eosinophils during acute exacerbation of chronic obstructive pulmonary disease: prevalence and clinical significance. sultan qaboos univ med j 2022: 22;339–42. https://doi.org/10.18295/squmj.8.2021.099. 2. hizawa n. pharmacogenetics of chronic obstructive pulmonary disease. pharmacogenomics 2013; 14:1215–25. https://doi.org/10.2217/ pgs.13.107. 3. cazzola m, rogliani p, matera mg. unmet needs and the future of asthma-chronic pulmonary obstructive disease overlap. immunol allergy clin north am 2022; 42:691–700. https://doi.org/10.1016/j.iac.2022.04.006. response from the authors dear reader, eosinophilic airway inflammation has been an increasingly recognised subtype of copd and is unrelated to bronchial asthma.1,2 in addition, the strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease proposed by the global initiative for chronic obstructive lung disease (gold) has recommended initiating inhaled steroids of patients with stable copd based on the eosinophils count.3 in regards to our sample, we excluded all patients with a history of bronchial asthma or symptoms suggestive of bronchial asthma;4 also, we have used the gold criteria to ascertain copd diagnosis for all patients in our study.5 https://creativecommons.org/licenses/by-nd/4.0/ https://doi.org/10.18295/squmj.8.2021.099. https://doi.org/10.2217/pgs.13.107. https://doi.org/10.2217/pgs.13.107. https://doi.org/10.1016/j.iac.2022.04.006. re: elevated peripheral blood eosinophils during acute exacerbation of chronic obstructive pulmonary disease prevalence and clinical significance 596 | squ medical journal, november 2022, volume 22, issue 4 with steroid therapy, a remarkable reduction in eosinophils count was noted from 0.6 cells × 109/l on admission to 0.2 cells × 109/l on discharge; however, there are no follow-up data on eosinophils counts when patients returned to the pre-exacerbation state. in our study, patients with elevated eosinophilic count had a shorter length of hospital stay but a higher one-year readmission rate. our findings support the possibility that elevated eosinophils count is a unique entity related to a subtype of copd rather than a manifestation of overlap between copd and bronchial asthma, hence eosinophilic count should be used as a surrogate marker to guide steroid use in acute exacerbation of copd and to guide long-term steroid treatment. *abdullah m. al alawi, maitha al sibani, jamal al aghbari department of medicine, sultan qaboos university hospital, muscat, oman; oman medical specialty board, muscat, oman *corresponding author’s e-mail: dr.abdullahalalawi@gmail.com references 1. saha s and brightling ce. eosinophilic airway inflammation in copd. int j chron obstruct pulmon dis 2006; 1:39–47. https://doi. org/10.2147/copd.2006.1.1.39. 2. ashdown hf, smith m, mcfadden e, pavord id, butler cc, bafadhel m. blood eosinophils to guide inhaled maintenance therapy in a primary care copd population. erj open res 2022; 8:00606-2021. https://doi.org/10.1183/23120541.00606-2021. 3. oliver b, tonga k, darley d, rutting s, zhang x, chen h, et al. copd treatment choices based on blood eosinophils: are we there yet? breathe (sheff ) 2019; 15:318–23. https://doi.org/10.1183/20734735.0254-2019. 4. al sibani m, al alawi a and al aghbari j. elevated peripheral blood eosinophils during acute exacerbation of chronic obstructive pulmonary disease: prevalence and clinical significance. sultan qaboos univ med j 2022; 22:339–42. https://doi.org/10.18295/ squmj.8.2021.099. 5. global initiative for chronic obstructive lung disease. 2020 global strategy for prevention, diagnosis and management of copd. from: https://goldcopd.org/gold-reports/ accessed: sep 2021. https://doi.org/10.2147/copd.2006.1.1.39. https://doi.org/10.2147/copd.2006.1.1.39. https://doi.org/10.1183/23120541.00606-2021. https://doi.org/10.1183/20734735.0254-2019. https://doi.org/10.18295/squmj.8.2021.099. https://doi.org/10.18295/squmj.8.2021.099. january 2007 vol 7 correct a.indd abstract objective: to ascertain the relationship between serum leptin levels and related variables (weight, body mass index (bmi) and fat percentage) in a group of omani obese and non-obese healthy subjects. methods: leptin levels were assessed in serum samples from 35 obese omanis and 20 non-obese healthy subjects. results: there was a significant difference (p< 0.00) in serum leptin between the obese group (34.78 + 3.96 ng/ml) and the control non-obese subjects (0.6 ± 4.2 ng/ml). leptin levels were higher in females compared to males. there was a significantly positive correlation between leptin levels in obese subjects with weight (p=0.002), body fat percentage (p=0.000) and bmi (p=0.00). conclusions: we concluded that serum leptin levels are higher in the omani obese group and correlate positively with body fatness and obesity. keywords: leptin, obesity, body weight, oman, body mass index correlation between serum leptin levels, body mass index and obesity in omanis *masoud y al maskari1, adel a alnaqdy2 sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© the name leptin is derived from the leptose, meaning thin.1,3,5 it is secreted by the adipose tissue in proportion to adipose mass and therefore its circulating levels increase with weight gain and decrease with weight loss.1,2 a large amount of research has been conducted on leptin since its discovery in 1994 and it is now possible to evaluate the physiological significance of leptin.1,2,3,4 leptin is considered to play a wide range of functions in humans such as decreasing appetite and thereby food intake, stimulating and maintaining energy expenditure and acting as a metabolic hormone in a wide range of processes by binding to receptors in the brain.5 leptin functions primarily as an anti-obesity hormone. its serum concentrations in healthy individuals positively correlate with body fat content,3 but it correlates negatively when energy intake is reduced and energy stores in fat are declining.6 in most obese subjects, leptin levels are high and correlate with the body mass index (bmi) and the percentage of body fat,3 leptin levels are found to be correlated with a number of endocrine substances such as insulin, glucocorticoids, thyroid hormones and testosterone.7 similar studies also indicate that it may be involved in mediating some endocrine-related processes, like the onset of puberty.8 impaired or modified receptor functions may be associated with certain medical conditions other than obesity, such as cardiovas1department of medicine, college of medicine and health sciences, sultan qaboos university, p.o. 35 al-khod 123, sultanate of oman 2department of microbiology & immunology, college of medicine and health sciences, sultan qaboos university, p.o. 35 al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: mmaskari@squ.edu.om o r i g i n a l s t u d y و والسمنة كتلة الوزن، ومؤشر الليبيتني هرمون مستويات بني الترابط البدينني مانيني العُ عند اجلسم في الدهون نسبة ــبة ونس ــم اجلس كتلة معامل (الوزن، العالقة ذات املتغيرات بعض مع الدم الليبيتني في هرمون ــتويات بني مس من العالقة امللخص: الهدف: التحقق 35 عمانيا دم عيناتِ في الليبيتني هرمون ــتويات مس فحص الطريقة: مت غير البدينني. من البدينني وأخرى العمانيني من موعة ــم) الدهون في اجلس ng/± 34.78) البدينة ــة اموع بني (p<0.001) الليبتني هرمون ــتوى تَدّ في مس عْ مُ إحصائي فرق ــر النتائج: ظه . بدينَ ــرَ غي ــا 20 عماني و ِ ــا ، بدين الذكورِ في ــه من اإلناثِ في أعلىَ ــت كان الليبيتني هرمون ــتويات مس ــد أن وج . (4.2±ng/ml10.6 ) ــة البدين ــر غي ــة الضابط ــة ml13.96 ) واموع في الدهون ــبة ، نس (p=0.002) ــمِ اجلس وزنِ مع البدينني الليبيتني في ــتويات هرمون مس بني قوي ارتباط إيجابي وجد أيضا أن هناك كما .(p<0.05) اموعةِ في كانت أعلى الدم في الليبيتني هرمون مستويات أن ذلك من اخلالصة: يستنتج .(p=0.001) ومؤشر كتلة اجلسم (p= 0.0001) اجلسم والسمنة. اجلسم الدهون في نسبة الوزن، مع وتقترن إيجابيا البدينةِ بدين ، اجلسم كتلة ، مؤشر ، السمنة مان عُ املفردات املفتاحية: هرمون الليبيتني، m a s o u d y a l m a s k a r i a n d a d e l a a l n a q d y 28 cular disease9 and certain types of cancer.10 research findings also indicate that leptin can act as a growth factor in the foetus and in the neonate.7 it has been reported that obesity is a major risk factor for the development of diabetes mellitus11, therefore, leptin might play a role in this disease. many studies have documented a high prevalence of diabetes and metabolic syndrome among the omani population.12,13,14 no data are available in the literature for levels of serum leptin among the omani population. studying leptin levels in omanis may be relevant in the light of reported associations of leptin serum status with obesity and diabetes. certain social economic and environmental factors may be unique in the omani population. the objective of this study was to report leptin profiles in omanis and to ascertain the relationship between serum leptin levels and related variables (weight, bmi and fat percentage) between two groups of omanis, obese and non-obese healthy subjects. m e t h o d s this study was approved by the sultan qaboos university medical research and ethics committee (project no. mrec 155). sub je c ts a group of 35 omani subjects, who were attending our obesity clinic (25 female and 10 males, age range 22-49 years) and were considered to be obese on the basis of bmi. bmi was defined as weight in kilogrames divided by height in meters (kg/m2). a bmi value of > or equal to 30 was used as an indicator of obesity. fat percentage was measured by a tanita fat analyser (usa) using the bioelectrical impedance method. twenty healthy non-obese subjects of similar age range (2050 years) served as a control group. none of the subjects studied had any clinical or laboratory (e.g: fasting blood glucose, urea & electrolytes, liver and thyroid function tests) signs of disease associated with obesity and were taking no drugs. se rum l e p ti n a s say an in vitro sandwich enzyme-linked immunosorbent assay (elisa) (drg instrument gmbh, germany) was employed for the quantitative measurement of human leptin in serum. the microtiter wells were coated with a monoclonal anti-leptin antibody. test and control samples were incubated in the coated wells with a specific rabbit anti-leptin antibody. after incubation the unbound material was washed off and anti-rabbit peroxidase conjugate was added for detection of the bound leptin. the intensity of colour developed was proportional to the concentration of leptin table 1: comparison between charateristics of obese subjects (25 female: 10 male; mean ± se) character female(n=25) male(n=10) age (years) 29.2 ± 1.6 30.0 ± 3.1 leptin(ng/ml) 38.2 ± 2.5 27.0 ± 4.9 weight (kg) 97.9 ± 3.9 108.4 ± 7.6 bmi (kg/m2) 39.6 ± 1.5 39.0 ± 2.9 %fat 44.1 ± 1.0 38.3 ± 3.9 figure 1: leptin levels (mean + se) in obese (bmi>30kg/m2) and non-obese omani subjects c o r r e l at i o n b e t w e e n s e r u m l e p t i n l e v e l s , b o d y m a s s i n d e x a n d o b e s i t y i n o m a n i s 29 in the sample. stati sti c a l a n a ly si s we used a statistical product and service solutions (spss) software program for statistical analysis of data. a p value of < 0.05 was considered statistically significant. r e s u l t s as seen in figure 1, there was a significant difference (p=0.001) in serum leptin levels (mean + s.e.) between the obese group (34.78 + 13.96 ng/ml) and levels in the control (non-obese) subjects (10.6 + 4.2 ng/ml). a strongly significant positive correlation was observed between leptin levels with weight (r=0.5, p =0.002), bmi (r= 0.51, p =0.001) and body fat percentage (r=0.7, p =0.0001) [figure 2]. leptin concentrations and body fat percentages were higher in women than in men within the obese group table 1. a strong positive correlation (r=0.528, p <0.007) was present when leptin concentration and bmi of the female obese group was compared. d i s c u s s i o n in this study, we have described significantly high serum leptin levels among obese omani subjects compared to the non-obese group, though the number studied here is small. to our knowledge, this has not been reported previously in the omani population. normal ranges of leptin (in caucasian and arab residents of kuwait),15,26 which have been reported in previous studies, are comparable to the range observed in the non-obese group in the current study. in a study carried out by concidine et al.,3 it was found that obese humans had (on average) leptin levels four times higher than non-obese individuals. the present study confirms results of previous reports16,17 regarding a gender difference in leptin levels between males and females. females have higher serum leptin concentrations than males, which confirms the previously reported range in female kuwaitis.26 the reason for this is unclear; the larger amounts of body fat mass, predominantly subcutaneous fat, in women and the effect of sex steroid hormones which increase leptin production have been suggested.18 since leptin reflects mainly the amount of body fat, this seemes to be a logical explanation for the observed gender differences. gender differences and their relationship to body composition were examined in several studies and leptin levels were still found to be significantly higher in women, even after correction was made for bmi or fat mass.19 the current study shows that serum leptin concentrations were increased in relation to increased body fat content. the positive correlation between body fat and serum leptin is probably explained primarily by the increased release of leptin from large fat cells.19 in fact, some studies have proposed that leptin can serve as an indicator of fat content and that its levels increase exponentially with increasing body fat percentage.3 leptin levels decrease by reduction of body fat even though bmi values remain unchanged.20 in our study, we found a significant relationship between circulating leptin and bmi, an observation that is associated with the relationship of leptin to tofigure 2: correlation between leptin levels (ng/ml) with (a) fatness (kg) and (b) bmi (kg/m2) in obese omani patients m a s o u d y a l m a s k a r i a n d a d e l a a l n a q d y 30 tal body weight as bmi and fatness.2 in all previous investigations, leptin levels have been shown to be high and correlated to bmi.2,3 in agreement with our findings, regarding the existence of a positive correlation between the circulating leptin levels and the body weight, other studies have reported the relation of spontaneous or enforced weight changes and serum leptin levels.3 whatever the initial concentration, weight loss due to food restriction was found to be associated with a decrease in serum leptin in both obese and normal weight humans.2 based on the above findings, leptin concentrations can be considered as a marker of the extent of obesity in human(s). the one relatively common clinical condition, in which a significantly elevated serum leptin concentration occurs without an increase in body mass, is chronic renal failure, probably as a result of decreased renal clearance.21 a number of researchers however, have claimed subtle leptin abnormalities in conditions such as diabetes22 and thyroid disease.23 in addition, leptin seems to be involved in the pathogenesis of some obesity-associated conditions such as anovulatory infertility24 and type 2 diabetes mellitus.25 although the number of individuals in this study was relatively small, it was found that circulating leptin levels were high and positively correlated to body weight, the percentage fat and bmi among obese omani subjects. the pattern of this increase may reflect the differences in lifestyle, diet, physical activity and other cultural and economic factors that are specific for people in this part of the world. the significance of this study in relation to high and increased prevalence of diabetes in oman requires further evaluation. r e f e r e n c e s 1. zhang y, proenca r, maffei m, barone m, leopald l, friedman j.m. positional cloning of mouse ob gene and its human homologue. nature 1994; 737:425-432. 2. maffei m, halaas j, ravussin e, pratly r e, lee g h, zhang y, fei h, kim s, lallone r, ranganathan s. leptin levels in human and rodent; measurement of plasma leptin and ob rna in obese and weight-reduced subjects. nat med 1995; 1:1155-1161. 3. considine r v, sinha m k, heiman m, kriauciunas a, stephens t, nyce m, ohannesian j p, marco c c, mckee j, bauer l. serum immunoreactive-leptin concentrations in normal-weight and obese humans. n engl j med 1996; 334:292-295. 4. chow vt, phoon mc. measurement of serum leptin concentrations in university undergraduates by competitive elisa reveals correlations with body mass index and sex. adv physiol educ 2003; 27:70-77. 5. trayhurn p, hoggard n, mercer j d, rayner d.v. leptin: fundamental aspects. int. j. obes. relat metab disord 1999; 23:22-28. 6. boden g, chen x, mozzoli m, ryan i. effect of fasting on serum leptin in normal human subjects. j clin endocrinol metab 1996; 81:3419-3443. 7. janeckova r(a). the role of leptin in human physiology and pathophysiology. physiol res 2001; 50:443-459. 8. janeckova r(b). new findings on the role of leptons in regulation of the reproductive system in humans. cesk fysiol 2002; 50:25-30. 9. chu n, spiegelman d, hotamisligil g, rifai n, stampfer m, rimm e. plasma insulin, leptin and soluble tnf receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men. atherosclerosis 2001; 157:495-503. 10. larmore k, o’connor d, sherman t, funanage v, hassink s, oerter klein k. leptin and estradiol as relate to changes in pubertal status and body weight. med sci monit 2002; 8:206-210. 11. lahlou n, issa t, leboue y, carel j, camoin l, roger m. leptin might play a role in diabetes. diabetes 2002; 51: 1980-1985. 12. asfour m, lambourne a, al-bahlani s, al-asfoor d, bold a, mahtab h, king h. high prevalence of diabetes mellitus and impaired glucose tolerance in the sultanate of oman. results of the 1991 national survey. diabet med 1995; 12:1122-1125. 13. al-lawati ja, al riyami am, mohammed aj, jousilahti p. increasing prevalence of diabetes mellitus in oman. diabet med 2002; 19:954-957. 14. al-asfoor dh, al-lawati ja, mohammed aj. body fat distribution and the risk of non-insulin-dependant diabetes mellitus in the omani population. east mediterr health j 1999; 5:14-20. 15. haluzik m, kabrt j, nedvidkora j, svobodova j, kotrlikora e, papezova h. relationship of serum leptin levels and selected nutritional parameters in patients with protein-caloric malnutrition. nutrition 1999; 15:829833. 16. rosenbaum m, nicolson m, hirsch j, heymsfield s b, gallagher d, chew f, leibel r. effects of gender, body composition, and menopause on plasma concentrations of leptin. j clin endocrinol metab 1996; 81:34243427. 17. licinio j, negrao a b, mantzoros c, kaklamani v, et al. sex differences in circulating human leptin pulse amplitude: clinical implications. j clin c endocrinol metab 1998; 83:4140-4147. 18. cassabiell x, pineiro v, peino r, et al. gender differences in both spontaneous and stimulated leptin secretion c o r r e l at i o n b e t w e e n s e r u m l e p t i n l e v e l s , b o d y m a s s i n d e x a n d o b e s i t y i n o m a n i s 31 by human omental adipose tissue in vitro: dexamethasone and estradiol stimulate leptin release in women, but not in men. j clin endocrinol metab 1998; 83:21492155. 19. lonnqvist f, nordfors l, jasson m, thorne a, shalling m, arner p. leptin secretion from adipose tissue in women. relationship to plasma levels and gene expression. j clin investig 1997; 99:2398-2404. 20. stejskal d, jedelsky l, ruzicka v, bartek j. leptin, insulin a proinsulin vzajemne vztahy. vnitrini lekarstvi 1998; 44:361-365. 21. nordfors l, lonnqvist f, heimburger o, danielsson a, schalling m, stenvinkel p. low leptin gene expression and hyperleptinemia in chronic renal failure. kidney int 1998; 54:1267-1275. 22. rudberg s, persson b. serum leptin levels in young females with insulin-dependent diabetes and the relationship to hyperandrogenicity and microalbuminuria. horm res 1998; 50:297-302. 23. valcavi r, zini m, peino r, casaneuva f.f., dieguez c. influence of thyroid status on serum immunoreactive leptin levels. j clin endocrinol metab 1997; 82:16321634. 24. karlsson c, lindell k, svensson e, bergh c, lind p, billig h, carlsson lm, carlsson b. expression of functional leptin receptors in the human ovary. j clin endocrinol metab 1997; 82:4144-4148. 25. morton n, emilsson v, de groot p, pallett a l, cawthorne m. leptin signalling in pancreatic and clonal insulin-secreting cells. j mol endocrinol 1999; 22:173184. 26. kamal a.s. al-shoumer, bagavathy a.k. vasanthy, hanan a. makhlouf, mona m. al-zaid. leptin levels in arabs with primary hyperthyroidism. ann of saudi med 2000; 20:113-118. 1 1 submitted 22 mar 22 1 revision req. 9 jun 22; revision recd. 3 jul 22 2 accepted 3 aug 22 3 online-first: august 2022 4 doi: https://doi.org/ 10.18295/squmj.8.2022.050 5 6 determinants of physicians’ job satisfaction 7 a national multi-centre study from the sultanate of oman 8 ikram a. burney,1 *sulaiman d. al sabei,2 omar al-rawajfah,2,3 leodoro j. 9 labrague,2 raeda abualrub4 10 11 1the sultan qaboos comprehensive cancer care and research center, muscat, oman; 12 2college of nursing, sultan qaboos university, muscat, oman; 3college of nursing, al albayt 13 university, mafraq, jordan; 4faculty of nursing, jordan university of science and technology, 14 irbid, jordan 15 *corresponding author’s e-mail: alsabei@squ.edu.om 16 17 abstract 18 objectives: physician satisfaction with their job can lead to a better quality of care, fewer 19 chances of making errors, and better patient outcomes. the purpose of the study was to examine 20 physician satisfaction; and to assess job satisfaction across several factors, such as quality of 21 care, ease of practice, relationship with leadership, and inter-professional collaboration. method: 22 a descriptive cross-sectional design was used. data were collected between july 2019 and 23 january 2020. participants provided demographic information and completed surveys related to 24 physician satisfaction (13-item likert type items on a scale from 1 to 5), and inter-professional 25 collaboration (15-item, 4-point likert scale, ranging from 1 for “strongly disagree” to 4 for 26 “strongly agree”). multiple linear regressions were used to determine the relationship between 27 overall job satisfaction and demographic features and inter-professional collaboration. results: 28 out of 396 physicians who were contacted, 354 responded (response rate = 89.4%). the median 29 age was 40 years, and there were 208 male and 124 female physicians. the vast majority 30 mailto:alsabei@squ.edu.om 2 2 (238/354 = 62%) were expatriates. seventy percent had a post-graduate degree. the vast 31 majority (308 = 87%) worked in government hospitals. results showed that 15 (5%) of the 32 physicians were not satisfied with their job (<3.00), 179 (40%) expressed a moderate level of 33 satisfaction (3.00 – 3.75), and 129 (55%) were highly satisfied (>3.76). there was no difference 34 in mean job satisfaction score among different groups of study participants, except for gender, 35 and the working grade (p < 0.05). the overall job satisfaction rates were higher for the quality of 36 care (m = 3.93, sd = 0.61), and for ease of practice (m = 3.89, sd = 0.55) and lower for the 37 relationship with leadership (m = 3.67, sd = 0.86). having a clinical postgraduate degree 38 together with a phd, a senior level of responsibility and good inter-professional relationship 39 were associated with higher job satisfaction rates (p = 0.003 and 0.007, respectively). 40 conclusion: overall, the job satisfaction rate was high. there was no difference among different 41 groups of study participants, except for the working grade. having a clinical postgraduate 42 degree, a senior level of responsibility, and good inter-professional relationship were associated 43 with higher job satisfaction rates. the overall job satisfaction rates were higher for the quality of 44 care, and for ease of practice, and lower for relationship with the leadership. relationship with 45 the leadership is a modifiable factor and efforts at enhancing the physician-leadership 46 relationship may lead to even higher satisfaction rates. 47 keywords: interprofessional relations; job satisfaction; leadership; oman; physician; quality of 48 health care 49 50 advances in knowledge 51  this is the first multi-center study to report job satisfaction of physicians from the 52 sultanate of oman. 53  working in an environment that facilitates interprofessional collaboration has a positive 54 impact on physicians’ job satisfaction. 55 56 application to patient care 57  the current study findings inform policy-makers of modifiable work-related factors that 58 can enhance physicians' satisfaction. 59  health care providers' job satisfaction is positively correlated with the quality of care they 60 provide. 61 3 3 62 introduction 63 job satisfaction is defined as ‘a pleasurable or positive emotional state, resulting from the 64 appraisal of one’s job or job experiences’.1 interaction between work experience and 65 organizational environment determine satisfaction with the job. physician satisfaction with their 66 job can lead to better patient outcomes and satisfied patients which can lead to better outcomes 67 and fewer litigations.2 furthermore, satisfied physicians are known to provide a better quality of 68 care, are more conscientious with their attitude towards prescribing treatment, and have less 69 chances of making errors.3,4 on the other hand, a lack of job satisfaction is related to higher 70 attrition rates, work-related stress, burnout, and work-family conflict.3,5-7 71 72 several personal, workplace-specific and other modifiable factors contribute to physician 73 satisfaction, and these can be measured using different scales. for example, domagala et al. used 74 a 17-item questionnaire to measure the level of physicians' satisfaction working in polish 75 hospitals in four domains; personal, professional, performance, and inherent factors.8 warr-76 cook-wall scale is a 10-item scale consisting of one item for overall job satisfaction and 9 other 77 items for different aspects of satisfaction, such as variety in job, opportunity to use abilities, 78 freedom of working method.9 factors which have been well studied include professional 79 autonomy, doctor-patient relationship, academic involvement, and work-life balance.5,10,11 other 80 factors include quality of care, ease of practice, relationship with leadership and management, 81 and inter-professional relationship.8 a systematic review from 12 european countries consisting 82 of 24 studies on more than 20,000 physicians identified several scales and classified the factors 83 into three groups: personal, intrinsic, and contextual.12 the majority of contextual or 84 professional-related factors are modifiable, such as, the quality of care, the ease of practice, the 85 opportunity for professional development, inter-professional collaboration, and relationship with 86 the leadership. healthcare organizations can study these factors to modify the work environment, 87 in turn facilitating and improving physician satisfaction. 88 89 oman is one of the rapidly developing arab countries, located in southeast of the arabian 90 peninsula, with a population of around 5 million, of which 60% are omani nationals, and their 91 treatment expenses are fully covered by the government.13 as a result of effective planning, the 92 4 4 health care system in oman has seen significant advances in the last 4 decades,.14 oman spends 93 3.8% of its gross domestic product (gdp) on health and is placed at number 60 on the human 94 development index (hdi), with an average life expectancy of 77.9 years at birth.15 the world 95 health organization (who) ranked oman’s healthcare system as number 8 among all the 96 member states based on population health indicators, such as, the overall level of population 97 health, health inequalities within the population, responsiveness of the health system, and the 98 distribution of responsiveness and health system’s financial resources within the population.16 99 harvard university and other joint commissioned organizations appreciated oman’s healthcare 100 achievements and consider it as a model for other countries.17 there are more than 6,500 101 physicians, including 2400 specialists and consultants in oman, with a density of 2.0 physicians 102 per 1,000 population. however, there are only a few reports assessing physician satisfaction with 103 their job in oman.18,19 almost all these studies assessed various determinants of physician 104 satisfaction in the capital area, muscat, and the last study was published more than 10 years 105 back. over the last few years, healthcare system in oman has expanded, and it is important to 106 study the factors and determinants of physician satisfaction, especially the modifiable factors. 107 108 the aims of the current study were twofold: to examine physician job satisfaction rate; and to 109 assess job satisfaction across several factors including demographic features, quality of care, ease 110 of practice, relationship with leadership, and inter-professional collaboration. 111 112 methods 113 study design 114 a descriptive study using a cross-sectional design, and a convenience-sampling method was 115 carried out. 116 117 participants 118 registered omani and non-omani physicians were eligible to participate in the study. the 119 sample represented all geographical areas of oman including 11 governorates. the sample was 120 proportional to the healthcare facility (ministry of health (moh), non-moh and private 121 hospitals). the study approval was obtained from the medical research ethics committee of the 122 moh, the relevant participating hospitals not related to moh, and the selected private hospitals. 123 5 5 data were collected between july 2019 and january 2020. informed consent was obtained from 124 study participants. the participants were assured of anonymity and confidentiality. 125 the purpose and significance of the study was discussed with hospital administrators. 126 consenting participants were contacted by one of the research officers and invited to participate 127 voluntarily. the data was collected via a self-filling questionnaire. a survey packet containing a 128 letter explaining the purpose of study and its significance, and the instruments were handed to 129 the physicians, together with a return envelope. participants were asked to drop the completed 130 surveys in a locked box in their unit. 131 132 instruments 133 date were collected using three paper-based self-reported surveys to collect information related 134 to participant’s demographics, satisfaction, and their perception of interprofessional 135 collaboration. 136 137 demographic information. information was collected using a demographic sheet developed by 138 the authors. the validity of the instrument was assessed by three investigators from both 139 academia and the clinical setting. information about participants’ age, gender, educational level, 140 nationality, years of work experience, marital status, place of work, and position was obtained. 141 142 job satisfaction. the physician satisfaction survey, developed by wolosin et al. 21 was used to 143 assess physician’s satisfaction. the survey consists of 13 likert-type items, on a scale from 1 to 144 5. the scale is divided into three subscales, with adequate degree of reliability: quality of patient 145 care; ease of practice; and relationship with leadership. the construct validity of the survey is 146 well established and the tool demonstrated acceptable level of reliability. (cronbach α = 0.76 to 147 0.92 for the three scales).21 148 149 inter-professional collaboration is defined as the ability of every health care provider to effectively 150 complement each other roles, share the responsibility and work collaboratively to make decisions about 151 patients’ care. the assessment for collaborative environment tool, developed by tilden et al.,22 152 was used to measure physician’s perceptions of the quality of inter-professional collaboration. 153 the tool consists of 15 items rated on a four-point likert scale, ranging from 1 for “strongly 154 6 6 disagree” to 4 for “strongly agree”. the validity and reliability has been well-established.22,23 155 the range of possible total scores is 15 (lowest possible score) to 60 (highest possible score). 156 the higher the score; the higher is the perception of interprofessional collaboration. the 157 reliability has been well-established (cronbach’s alpha of 0.80). the tool demonstrated 158 acceptable convergent validity (r = 0.81).22 159 160 sample size 161 using the standardized formula for calculating sample size from the defined population, the 162 estimated sample size was calculated to be 396 physicians with a 95% ci and a p-value of 0.05.20 163 164 statistical methods 165 the statistical package for social sciences software (spss) version 22 was used for analysis. 166 participant’s background variables were analyzed using descriptive statistics. overall job 167 satisfaction was assessed by looking at the mean scores across all domains. reliability was 168 assessed using cronbach α. job satisfaction was plotted as, ‘low’ (score ≤ 3, ‘moderate’ (score 169 3.01 – 3.76), or ‘high’ (score ≥ 3.76) level of satisfaction using bar charts. the relationship between 170 job satisfaction and interprofessional collaboration was assessed using multiple linear regression. 171 the regression model was adjusted for participants’ demographic data including age, gender, 172 educational level, nationality, years of work experience, marital status, and place of work. the 173 four assumptions of linear regression including normality, linearity, homoscedasticity, and 174 independence, were assessed and found to be satisfactory. 175 176 results 177 over the study period, a total of 396 physicians were contacted, and 354 responded (response rate 178 89.4%). characteristics of study participants are shown in table 1. the median age of study 179 participants was 40 years; the vast majority of participants were between the ages 30 and 40 years. 180 there were more males than female physicians. the majority of physicians were non-omani, 181 married, had 1-3 children, had a postgraduate clinical degree, and worked as full-time physicians. 182 a significant number of physicians had more than 5 years of overall work experience, and 183 experience in the place of work at the time of interview. the vast majority of participants were 184 working as specialist or senior house officer. 185 7 7 186 the mean satisfaction rate was 3.85 ± 0.55 on the job satisfaction scale. overall, 5% of the 187 physicians were not satisfied with their job (mean satisfaction score <3.00), 40 % had moderate 188 level of satisfaction (mean satisfaction score, 3.00-3.75), and 55% were highly satisfied with their 189 job (mean satisfaction score >3.76). there was no difference in mean job satisfaction score among 190 different groups of study participants, except for gender, and the working grade. the means score 191 amongst the 208 male physicians was 3.76 ± 0.54 compared to 124 female physicians (3.90 ± 0.52; 192 p-value 0.026 using anova). figure 1 shows job satisfaction rates according to the working 193 grade. almost equal number of senior house officers, specialists and senior specialists expressed 194 ‘moderate’ or ‘high’ level of satisfaction, whereas, the vast majority of consultants and senior 195 consultants had a ‘high’ level of satisfaction with their job. 196 197 mean satisfactions scores across the three domains and the 13 items are shown in table 2. the 198 overall job satisfaction rate was 3.82 ± 0.55; for quality of care the rate was 3.93 ± 0.61; for ease 199 of practice 3.89 ± 0.55, and for relationship with leadership, the score was 3.67 ± 0.55. overall 200 satisfaction score, as well as across the 3 domains showed a high level of internal consistency. 201 please see the table for cronbach α levels. 202 203 whereas, the vast majority of physicians were ‘moderately’ or ‘highly’ satisfied with ease of 204 practice, and quality of care, 14.5% expressed a low level of satisfaction with their relationship 205 with leadership [figure 2]. table 3 shows the results of physician’s perceptions of the quality of 206 inter-professional collaboration. the overall mean satisfaction rate was 3.045 ± 0.39, and the 207 results showed a high degree of internal consistency (cronbach’s α = 0.89). the results were 208 consistent across the various items of the scale. the relationship between demographic variables 209 and physician’s perception of inter-professional collaboration and overall job satisfaction was 210 assessed using linear regression. overall, the results indicate that physicians were satisfied or 211 highly-satisfied with different dimensions of their job, especially, if they had a clinical 212 postgraduate degree together with a phd (p = 0.003), were on a senior level of responsibility (p = 213 0.007), and had good inter-professional relationship (p <0.001) [table 4]. 214 215 discussion 216 8 8 this study describes the level and determinants of job satisfaction of physicians from various 217 parts from the sultanate of oman. out of the 354 physicians who responded, 95% were satisfied 218 with their job. the majority of satisfied physicians were women, and senior consultants. 219 satisfaction was observed in different modifiable domains of patient care, was higher in quality 220 of care and ease of practice, but was marginally lower in relationship with the leadership. 221 physicians were also perceived to be satisfied with inter-professional collaboration. majority of 222 satisfied physicians had a postgraduate clinical degree, and had been working for more than five 223 years in the current job, and were working at a rank of consultant or above. 224 225 a validated, 13-item physician satisfaction survey measuring physician satisfaction across the 226 three domains of professional practice was employed.21 the domains included quality of patient 227 care, ease of practice, and relationship with leadership. the scale has a high degree of internal 228 consistency, and our results are not only reliable, but match the internal consistency mark 229 reported in the literature. although the vast majority of physicians were satisfied or highly 230 satisfied, with the quality of care and the ease of practice, relationship with leadership was 231 identified as an area of opportunity for further improvement. the important determinates which 232 could potentially enhance satisfaction were confidence of the leadership in the staff, and 233 responsiveness of the hospital administration to the ideas and needs of the medical staff 234 members. 235 236 in the highly complex working environment, health organizations depend on collaborative work 237 within teams and across different teams. teamwork not only provides specialist care, but also 238 enhances quality of care. team member satisfaction is one of the important determinants of job 239 satisfaction. in fact, team climate has been shown to be a better predictor of team satisfaction 240 than team leadership.24 the results demonstrate that the majority of physicians had the 241 perception of being satisfied with the quality of inter-professional collaboration. our results are 242 consistent with the results of studies from an academic hospital in brazil, family physicians in 243 canada, and primary care physicians in germany, where an important determinant of overall job 244 satisfaction was having a good inter-professional relationship.9,25-26 245 in terms of degree of satisfaction with the job, the current study findings showed that physicians 246 working in oman reported higher levels of satisfaction compared with physicians working at 247 9 9 saudi arabia, iraq, and pakistan. the study from a tertiary hospital in saudi arabia reported that 248 as many as 30% of the 344 participants were dissatisfied with their job, mainly either due to the 249 nature of job (intensive care physicians), or low income.27 another study from saudi from a 250 tertiary medical center demonstrated more than 30% of the 217 respondents to be dissatisfied 251 with their job, mainly because of low income, health coverage and the overall benefit package.26 252 a study on 237 family physicians from two different areas of saudi arabia revealed an overall 253 job satisfaction rate of 62%. factors significantly associated with professional dissatisfaction 254 included the physicians having an opinion that they were not respected by community members 255 and their own perception of being inferior to other specialties.28 a study from pakistan 256 conducted on hospital doctors revealed that only 35% had well-above-average or outstanding job 257 satisfaction. factors associated with lack of satisfaction with job included younger age, lower 258 income, fewer number of years in service, and a lack of postgraduate qualification. 29 another 259 study from pakistan assessed job satisfaction using 35 questions about sources of work-related 260 stress and satisfaction, and concluded that overall satisfaction rate was low at 2.69±0.37. job 261 dissatisfaction was more amongst government sector doctors; whereas, increasing age, duration 262 of current posting and work experience positively correlated with satisfaction level.30 263 264 there are at least two other studies from oman assessing job satisfaction of physicians. al 265 shafaee18 used qualitative and quantitative tools to assess job satisfaction amongst physicians 266 working in the capital area, muscat governorate, and explored several organizational and job-267 related factors which influence satisfaction rate. amongst the 371 physicians, the job satisfaction 268 rate was 68.4%. physicians were satisfied with their professional status and teamwork, however, 269 they were less satisfied with administration, pay and workload. al touby19 reported job 270 satisfaction amongst 50 physicians working in two tertiary care hospitals in the capital area, and 271 identified younger age and fewer years of experience to be inversely related with job satisfaction. 272 the current study was different in several respects. the survey included physicians from all 273 geographical areas of oman, used a validated job satisfaction tool with high degree of internal 274 validity, assessed modifiable factors in relation to job satisfaction, and reported an overall 275 satisfaction rate of 95%. the results should be reassuring for the health managers, as the level of 276 job satisfaction amongst physicians in the sultanate of oman is higher compared to many centers 277 in the region. furthermore, as the health care system in oman continues to evolve and improve,14 278 10 10 it should be satisfying to note that that the average job satisfaction rate has increased 279 considerably compared to the two earlier studies18, 19. while there are ongoing efforts and 280 initiatives to assess and improve satisfaction of healthcare professionals14, this study provides 281 areas and avenues for specific targets for improvement, including the modifiable factors, such as, 282 relationship with leadership. 283 284 study limitations 285 there are several limitations of the study. physician’s income was not assessed in relationship 286 with job satisfaction. this has been shown to be inversely related to job satisfaction in several 287 studies. however, over the last few years, the salary structure for physicians in the government 288 sector in oman has been revised and unified, and is dependent on the grade. grade of work was 289 assessed, and inherent in the grade is the salary. secondly, very few physicians working in 290 private hospitals were invited to participate, or agreed to be surveyed. however, it may be of 291 interest to note that healthcare in private sector is only beginning to emerge in oman, and at the 292 moment, the vast majority of hospitals are government-managed facilities. the proportion of 293 physicians surveyed in this study reflect the overall proportion of private hospitals in healthcare 294 sector. thirdly, a higher level of job satisfactions was observed amongst female doctors. this 295 was an important observation from this study, however, reasons were not explored further and 296 remain speculative. it may be argued that in a cross-sectional study design, only an association 297 can be described and not causality. longitudinal studies are needed to establish causal 298 relationship between dependent and independent variables. in addition, this study used a self-299 reported method, which may be associated with a response bias. to minimize the possibility of 300 this bias, all data were collected anonymously, without collecting any identification information. 301 furthermore, extra-ordinary circumstances, such as, covid-19 pandemic may affect job 302 satisfaction levels, due to factors such as, risk perception, psychological stress and burnout, and 303 other factors, not studied here31, 32. however, data for the current study were acquired before the 304 onset of the pandemic. finally, organizational factors, such as, human resource management, 305 details of ancillary facilities and leadership factors were not analyzed separately. the primary 306 aim of the study remained to assess job satisfaction across several factors, such as, quality of 307 care, ease of practice, relationship with leadership, and inter-professional collaboration in the 308 11 11 area / place or work. therefore, the current study results and conclusions need to be interpreted 309 with caution, as the management and leadership details specific to the site were not studied. 310 311 conclusion 312 in conclusion, satisfaction of physicians with their job from the sultanate of oman was high, and 313 the majority of physicians were highly satisfied. there was no difference in the level of 314 satisfaction among different groups of study participants, except for the working grade. having a 315 clinical postgraduate degree, a senior level of responsibility, and the perception of a good inter-316 professional relationship were associated with higher job satisfaction rates. the overall job 317 satisfaction rates were higher for the quality of care, and for ease of practice, and lower for 318 relationship with the leadership. relationship with the leadership is a modifiable factor and 319 healthcare policymakers should target interventional programs to improve satisfaction of junior 320 physicians. these results highlight areas of strength, as well as the area of opportunity, in which 321 efforts could be made to enhance job satisfaction. 322 323 conflict of interest 324 the authors declare no conflicts of interest. 325 326 funding 327 this work was supported by the research council, oman, (rc/rg-con/facn/18/01) and 328 sultan qaboos university (rf/com/facn/19/01). 329 330 authors contribution 331 ib prepared the article. sas conducted the analysis, interpreted the data and provided critical 332 revisions for the article. oa-r contributed substantially to the conception and design of the 333 study. ljl and ra provided critical revisions for the article. all authors approved the final 334 version for submission. 335 336 acknowledgements 337 the authors would like to acknowledge sultan qaboos university and the research council for 338 their support and thank all physicians who contributed to this study. 339 12 12 340 references 341 1. locke ea. the nature and causes of job satisfaction. in: dunnette md, editor. handbook 342 of industrial and organizational psychology. chicago: rand mcnally; 1976. 1297–1343 343 p. 344 2. kravitz rl. physician job satisfaction as a public health issue. isr j health policy res. 345 2012;1:51. doi:10.1186/2045-4015-1-51. 346 3. cooper cl, rout u, faragher b. mental health, job satisfaction, and job stress among 347 general practitioners. bmj. 1989; 298:366–370. 348 4. devoe j, fryer ge, hargraves jl, phillips rl, green la. does career dissatisfaction 349 affect the ability of family physicians to deliver high-quality patient care? j fam pract. 350 2002; 51:223–228. 351 5. friedberg m, chen p, busum k van. factors affecting physician professional satisfaction 352 and their implications for patient care. health systems, and health policy; 2013. 353 http://www.rand.org/pubs/research_reports/rr439.html. 354 6. osborn, m., satrom, j., schlenker, a., hazel, m., mason, m., & hartwig, k. physician 355 assistant burnout, job satisfaction, and career flexibility in minnesota. journal of the 356 american academy of pas, 2019; 32(7):41-47. 357 7. lu y, hu x-m, huang x-l, zhuang x-d, guo p, feng l-f, et al. the relationship 358 between job satisfaction, work stress, work–family conflict, and turnover intention 359 among physicians in guangdong, china: a cross-sectional study. bmj open, 2017; 7(5), 360 e014894. 361 8. domagała a, peña-sánchez jn, dubas-jakóbczyk k. satisfaction of physicians working 362 in polish hospitals—a cross-sectional study. int j environ res public health. 2018 363 dec; 15(12): 2640. doi: 10.3390/ijerph15122640 364 9. goetz k, mahnkopf j, kornitzky a, steinhäuser j. difficult medical encounters and job 365 satisfaction results of a cross sectional study with general practitioners in germany. 366 bmc fam pract. 2018; 19: 57. doi: 10.1186/s12875-018-0747-0 367 10. bovier pa, perneger tv. predictors of work satisfaction among physicians. eur j pub 368 health. 2003;13(4):299–305. 369 http://www.rand.org/pubs/research_reports/rr439.html 13 13 11. leigh jp, kravitz rl, schembri m, samuels sj, mobley s. physician career satisfaction 370 across specialties. arch intern med. 2002;162(14):1577–84. 371 12. domagala a, bala mm, storman d, et al. factors associated with satisfaction of hospital 372 physicians: a systematic review of literature on european data. int j environ res public 373 health. 2018; 15: 2546 doi:10.3390/ijerph15112546 374 13. regional health systems observatoryemro. health system profile oman. cairo, 375 egypt: regional office for the eastern mediterranean, world health organization; 2006 376 available from: http://apps.who.int/medicinedocs/documents/s17304e/s17304e.pdf. 377 14. al shishtawy mm. four decades of progress: evolution of the heath system in oman. 378 sultan qaboos univ med j. 2010; 10(1): 12-22 379 15. united nations development program: human development reports. 380 http://hdr.undp.org/en/countries/profiles/omn. accessed on march 12, 2021 381 16. world health organization. world health report 2000: health systems: improving 382 performance geneva: who 2000. 383 17. hill gh, muyed az, al-lawati ja. the mortality and health transition in oman: 384 patterns and processes: a study commissioned by the government of oman, unicef 385 oman office, and the who regional office for the easter mediterranean, 386 december 2000. 387 18. al shafaee mim. determinants of job satisfaction of doctors and nurses in organized 388 settings (hospitals and health centers) in muscat governate, sultanate of oman. doctoral 389 thesis. 2001. available at https://hydra.hull.ac.uk/resources/hull:5405. accessed on 390 march 24, 2021. 391 19. al touby ss. a study to assess the job satisfaction of omani physicians and nurses 392 working in ministry of health hospitals in muscat, oman. global journal for research 393 analysis. 2014; 3(5): 1-4 394 20. yamane, taro. (1967). statistics: an introductory analysis, 2nd edition, new york: 395 harper and row. 396 21. wolosin rj, gesell sb, taber b, epting gj. construct validation of a physician 397 satisfaction survey. j healthcare qual, 2006; 28(4), 10-21. 398 http://apps.who.int/medicinedocs/documents/s17304e/s17304e.pdf http://hdr.undp.org/en/countries/profiles/omn https://hydra.hull.ac.uk/resources/hull:5405 14 14 22. tilden vp, eckstrom e, dieckmann nf. development of the assessment for collaborative 399 environments (ace-15): a tool to measure perceptions of interprofessional “teamness.” j 400 interprofessional care, 2016; 30(3), 288–294.doi: 10.3109/13561820.2015.1137891 401 23. al sabei, sd, et al. the impact of perceived nurses' work environment, teamness, and 402 staffing levels on nurse‐reported adverse patient events in oman. nurs forum 2021; 403 56(4):897-904. 404 24. espinoza p, peduzzi m, agreli hf, sutherland ma. interprofessional team member’s 405 satisfaction: a mixed methods study of a chilean hospital. hum resour health 2018; 406 16:30 https://doi.org/10.1186/s12960-018-0290-z 407 25. filho pov, de souza mr, elias pem, viana ald. physicians’ job satisfaction and 408 motivation in a public academic hospital. hum resour health. 2016; 14: 75. 409 doi: 10.1186/s12960-016-0169-9 410 26. bahnassy aa, saeed aa, al kadhi y, al-harbi j. physicians’ job satisfaction and its 411 correlates in a tertiary medical care center, riyadh, saudi arabia. saudi j med med 412 sci. 2016 may-aug; 4(2): 112–117. doi: 10.4103/1658-631x.178343 413 27. aldrees t, al-eissa s, badri m, aljuhayman a, zamakhshary m. physician job 414 satisfaction in saudi arabia: insights from a tertiary hospital survey. ann saudi med. 415 2015 may-jun; 35(3): 210–213. doi: 10.5144/0256-4947.2015.210 416 28. bawakid k, rashid oa, mandoura n, shah hbu, mugharbel k. professional 417 satisfaction of family physicians working in primary healthcare centers: a comparison of 418 two saudi regions. j family med prim care. 2018 sep-oct;7(5):1019-1025. doi: 419 10.4103/jfmpc.jfmpc_6_18. 420 29. atif k, khan hu, maqbool s. job satisfaction among doctors, a multi-faceted subject 421 studied at a tertiary care hospital in lahore. pak j med sci. 2015 may-jun; 31(3): 610–422 614. doi: 10.12669/pjms.313.7402 423 30. ali fs, zuberi bf, rasheed t, shaikh ma. why doctors are not satisfied with their job-424 current status in tertiary care hospitals. pak j med sci. 2019 jan-feb; 35(1): 205–210. 425 doi: 10.12669/pjms.35.1.72 426 31. risk perception and psychological impact of covid-19 pandemic among healthcare 427 workers in primary and secondary healthcare settings in qatar: a national study. j 428 https://doi.org/10.1186/s12960-018-0290-z 15 15 primary care comm health, 12, 429 21501327211039714. https://doi.org/10.1177/21501327211039714 430 32. al sabei sd, al rawajfah o, abualrub r, labrague lj, burney ia. nurses’ job burnout and its 431 association with work environment, empowerment and psychological stress during covid-19 432 pandemic. int j nurs practice. 2022: 1-10. doi: 10.1111/ijn.1307. 433 434 table 1: demographic characteristics and work environment 435 demographic features working environment age (years) experience as a physician (years) less than 30 26 (7.4%) less than 5 19 (5.3%) 30 – 40 123 (34.8%) 5-15 150 (42.4%) 41 – 50 80 (22.7%) 16 and more 149 (42.2%) 36 (10.2%) 51 – 66 n/r 49 (13.9%) 76 (21.4%) experience in current working place (years) gender less than 5 90 (25.4%) male 208 (58.7%%) 5-15 164 (46.3%) female n/r 124 (35%) 22 (6.6%) 16 and more 54 (15.2%) 46 (13%) nationality duration working with the team (years) omani 91 (25.7%) 5 or less 150 (42.4%) non-omani n/r 238 (67.2%) 25 (7%) more than 5 181 (51.1%) 23 (6.5%) marital status current grade single 34 (10%) medical intern 15 (4.2%) married 298 (89.2 senior house officer 63 (17.7%) divorced n/r 2 (.05%) 20 (5.6%) specialist 139 (39.2%) number of children senior specialist 41 (11.6%) none 48 (13.5%) consultant 27 (7.6%) 1-3 182 (51.4%) senior consultant 23 (6.4%) 4 and more 40 (11.2%) 84 (23.7%) others 24 (6.7%) 22 (6.1%) highest educational level specialty md 99 (27.9%) obstetrics & gynecology 55 (17%) post-graduate degree 199 (56.2%) general medicine 44 (13.6%) clinical + phd 26 (7.3%) general surgery 39 (12%) phd 4 (<1%) 26 7%) accident & emergency 30 (9.2%) employment status icu and anesthesia 26 (8%) https://doi.org/10.1177/21501327211039714 16 16 full time 335 (94.6%) child health 25 (7.7%) part time 10 (2.8%) 9 (2.5%) others 104 (32.2%) place of work public hospitals 308 (87%) private hospitals 46 (13%) note. n/r: no response 436 **include internal medicine, cardiology, otorhinolaryngology, orthopedics, behavioral 437 medicine, radiology, urology, dermatology, ophthalmology, and oral health 438 439 440 figure 1: job satisfaction rate according to responsibility 441 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% medical intern senior house officer specialist senior specialist consultanat senior consultant low moderate high 17 17 table 2: job satisfaction using the physician satisfaction survey 442 mean cronbach alpha quality of care 3.932 ±0.61 .83 quality of nursing staff 3.96 ±0.76 staff’s concern and interest in your patient 3.95 ±0.79 timeliness of follow-through on written orders 3.85 ±0.76 staff’s reliability in recognizing and reporting changes in patients’ conditions 3.95 ±0.70 ease of practice 3.889 ±0.55 .75 turnaround for lab results 3.92 ±0.70 ease of scheduling inpatient test/therapy 4.01 ±0.69 ease of admitting patients 3.97 ±0.77 medical technology and equipment available in icu/ccu 3.91 ±0.84 overall rating of the emergency department 3.65 ±0.89 relationship with leadership 3.670 ±0.86 .89 communication between yourself and the hospital administration 3.79 ±0.86 responsiveness of the hospital administration to ideas and needs of medical staff members 3.57 ±0.99 your confidence in the hospital administration to ideas and needs of medical staff members 3.65 ±0.96 overall job satisfaction scale 3.846 ±0.55 .90 443 444 445 figure 2: job satisfaction rate according to physician satisfaction survey 446 0 50 100 150 200 250 relationship with leadership ease of practice quality of care low moderate high 18 18 table 3: inter-professional collaboration 447 n mean ± sd 1. team members contribute to setting and evaluating goals for improving the practice. 346 3.29 ±0.59 2. the team has a culture of mutual continuous learning. 344 3.15 ±0.59 3. the team fosters a culture of continuously improving communication. 338 3.19 ±0.60 4. the team is well supported by the overall organization (e.g., practice improvement is encouraged; team training is supported). 342 3.06 ±0.67 5. team members fail to appreciate each other’s values and diversity. 339 2.85 ±0.77 6. team members appreciate each other’s roles and expertise. 346 3.11 ±0.62 7. team members have the autonomy to implement their part of the plan once the patient’s needs and goals are clear. 343 3.13 ±0.56 8. the team is effective in assigning and implementing administrative tasks (e.g., leadership, record keeping, meeting facilitation, etc.) 348 3.08 ±0.63 9. team members do not feel safe bringing up concerns about roles and responsibilities for discussion, proactive improvement, and prevention. 339 2.83 ±0.73 10. all voices on the team are heard and valued. 342 2.96 ±0.69 11. the team encourages trust by paying attention to important personal or professional connections (e.g., celebrating achievements, milestones, etc.). 347 3.09 ±0.54 19 19 12. members of the team are active listeners and pay close attention to the contributions of others, including the patient and family. 345 3.17 ±0.57 13. the team engages in routine, frequent, meaningful evaluation to improve its performance. 344 3.05 ±0.58 14. team members tend not to recognize their own limitations in knowledge and skills. 342 2.78 ±0.79 15. the team constructively manages disagreements among team members. 336 2.95 ±0.60 note: item numbers 5, 9, and 14 were reversed coded. 448 449 table 4. predictors of overall job satisfaction 450 predictor unstandardized β s.e standardized β t p-value 95% ci lower upper inter-professional collaboration .864 .071 .603 12.155 <0.001 .724 1.004 education md .100 .059 .086 1.716 .087 -.015 .216 clinical + phd .293 .097 .152 3.017 .003 .102 .484 phd .406 .320 .065 1.271 .205 -.223 1.036 grade as physician medical intern -.034 .127 -.014 -.267 .789 -.284 .216 medical officer -.103 .077 -.069 -1.336 .183 -.256 .049 specialist -.136 .081 -.085 -1.672 .096 -.295 .024 senior specialist -.094 .100 -.048 -.936 .350 -.291 .103 consultant -.107 .126 -.045 -.844 .400 -.355 .142 senior consultant .297 .109 .138 2.720 .007 .082 .511 note. r2= 0.453; adjusted r2 = 0.404 451 whole1.indd abstract objective: our two main objectives are to assess the incidence and the outcome of severe hyponatremia in young hospitalized patients. method: we retrospectively reviewed the incidence and outcome of severe hyponatremiac (na <25 mmol/l) inpatients less than 8 years of age, admitted as consecutive admissions during one calender year. psuedohyponatremia and artifactual hyponatremia were excluded. patients’ demographics, clinical features, laboratory, treatment and outcomes were recorded. results: of 356 admissions of patients less than 8 years of age, 20 developed severe hyponatremia. nausea, vomiting, irritability, clouded sensorium and seizures were the most common symptoms and signs. underlying central nervous system disease, pneumonia and malignancy were major co-morbid conditions. the initial volume status was determined as hypervolemia (n=7), hypovolemia (n=7) and euvolemia (n=6). iatrogenic (diuretics 5 and hypotonic fluids 7) hyponatremia accounted for 60% of all cases. mortality was 20%. conclusion: patients receiving intravenous hypotonic fluids should be closely monitored for the development of hyponatremia. the common etiology of hyponatremia in our studied cohort of patients is iatrogenic. keywords: iatrogenic hyponatremia, high morbidity incidence and outcome of severe hyponatremia in children and young adults a single institution experience *zakia al-lamki, mahfooz a farooqui and saeed ahmed sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© hyponatremia (serum sodium <135 mmol/l) has an incidence ranging from 15-20% in hospitalized patients.1 severe hyponatremia is less common and studies addressing this particular issue in pediatric inpatients are few.2-13 although the incidence of severe hyponatremia is not very high, this particular patient population is clinically significant due to associated predisposing conditions and adverse outcomes.2 severe hyponatremia is also known to be a marker of serious illness in sick children.3 department of child health, sultan qaboos university, college of medicine and health sciences, p.o.box 35, al-khod, muscat 123, sultanate of oman *to whom correspondence should be addressed. email: zakiya@squ.edu.om o r g i n a l s t u d y ونتائجه الشديد الصوديوم انخفاض انتشار مدى معهد جتربة والشباب األطفال عند املرضى هذا االنخفاض عند نتائج ومعرفة الشديد الصوديوم انخفاض انتشار مدى تقييم وهما رئيسيني للدراسة هدفني امللخص: الهدف: هناك ١٢٥ ملي مول/ (أقل من الشديد الصوديوم انخفاض انتشار مدى حسبنا استعادية الطريقة: بصورة والشباب. األطفال من املستشفى في الراقدين نقص حاالت استبعاد مت واحدة. تقوميية سنة خالل متتابعة ملرات أدخلوا والذين ١٨ سنة، سن حتت املستشفى في الراقدين املرضى عند ونتائجه ليتر) النتائج: والعالج والنتائج. اتبرية واملعطيات الدميوغرافية والعالمات السريرية املعلومات تسجيل مت الفنية. عن األمور الناجتة احلقيقي غير الصوديوم والعالمات األكثر األعراض بني كان من الشديد. الصوديوم بانخفاض مصابا ٢٠ مريضا هناك كان ال١٨ سنة، حتت سن مرقدا ٣٥٦١ مريضا مجموع من اجلهاز أمراض فكانت لذلك املصاحبة األعراض أما والنوبات الصرعية. اخلارجي باحمليط اإلحساس وضعف االستقرار وعدم والتقيؤ انتشارا: الغثيان (٦ حاالت). وطبيعي (٧ حاالت) الطبيعي من وأقل (٧ حاالت) الطبيعي من حالة احلجم كانت أكثر تقدير الرئة واألورام اخلبيثة. املركزي وذات العصبي ٧ حاالت. في القليل) التركيز ذي (والسوائل ٥ حاالت، في للبول) املدرة األدوية (استخدام احلاالت من ٪ ٦٠ في احلجم ألسباب طبية نقص لوحظ انخفاض حالة لكشف دقيقة بصورة الوريد طريق عن التركيز قليل سوائل يعطون الذين املرضى مراقبة ٢٠٪. اخلالصة: يجب الوفاة حاالت بلغت طبي املنشأ. هو في هذه الدراسة حلاالت نقص الصوديوم الرئيسي السبب الصوديوم. 14 z a k i a a l l a m k i , m a h f o o z a fa r o o q u i a n d s a e e d a h m e d no. age sex prefluids lowest na volume status treatment co morbidities symptoms outcome 1 8 m none 110  d dcm sob died 2 5 m hypo 123  ns dm n, v, i discharged 3 3 m hypo 107  ns scd n, v discharged 4 9 m none 124  fr bmt n, v discharged 5 9 m none 122  none surg, cns i discharged 6 8 m hypo 124  ns, abx scd n, v, sz discharged 7 7 m none 122  ns cld ac, hem discharged 8 6 f hypo 120  ns scd pain discharged 9 2 m hypo 111  d, hs pneumonia n, v, i discharged 10 1 m hypo 123  abx down synd, a-v shunt, sepsis n, v, sz discharged 11 2 m none 123  ns pneumonia n discharged 12 2 m hypo 122  d fanconi synd, rickets none discharged 13 <1 m hypo 117  abx preterm, sepsis none discharged 14 <1 f none 117  ns asphyxia, sah sz died 15 <1 m ns 107  d cah v, i discharged 16 <1 f none 120  hs inborn error of metabolism sz died 17 <1 m hypo 123  d cns v discharged 18 <1 m hypo 117  none preterm sz discharged 19 <1 f hypo 123  abx cns,sepsis sz discharged 20 <1 m none 120  none heart block, renal failure, dm none died m= male; f= female; pre-fluids= fluids administered before the development of hyponatremia; hypo= hypotonic fluids; =hypervolemic; = hypovolemic; = euvolemic; d= diuretics; ns= normal saline; fr=fluid restriction; abx=antibiotics; d=diuretics; dcm= dilated cardiomyopathy; dm=diabetes mellitus; bmt= bone marrow transplant; surg= surgical procedure performed; cns= central nervous system disease; scd= sickle cell disease; cld= chronic liver disease; sah= subarachnoid hemorrhage; cah= congenital adrenal hyperplasia; sob=shortness of breath; n=nausea; v=vomiting, i=irritability; ac=altered level of consciousness; hem=hematemesis; sz=seizure table 1. patients’ demographics, clinical features, laboratory, treatment and outcome 15 incidence and outcome of severe hyponatremia in children and young adults m e t h o d we retrospectively studied hospitalized patients <18 years old with severe hyponatremia (arbitrarily defined as serum sodium less than 125 mmol/l) admitted to sultan qaboos university hospital from 1st january 1998 to 31st december 1998. these patients were identified through the computerized hospital information system (his). patients where hyponatremia was considered to be artifactual (single serum sodium measurement of <125 mmol/l, which on repeat assessment within 6 hours, was normal >135 mmol/l without any therapeutic intervention) were excluded. serum sodium was measured by indirect ion-selective electrode method (beckman) and quality control values were set within 2%. demographic data, physical signs and symptoms, laboratory data, treatment before and after the diagnosis of severe hyponatremia, associated comorbid conditions and outcome were collected. total number of pediatric admissions and deaths were also obtained for comparison. r e s u l t s there were 3561 admissions of patients less than 18 years of age in 1998. twenty one patients had serum sodium of <125 mmol/l but one patient was excluded due to artifactual hyponatremia. the remaining 20 patients were considered having true severe hyponatremia. out of the 20 patients studied, 16 were male and 4 were females. all patients developed severe hyponatremia during hospitalization. major co-morbid conditions included central nervous system disease 3, malignancy 2, pneumonia 2, diabetes mellitus 2, hypertension 2, and post-surgery 1. nausea, vomiting, irritability and seizures were the most common clinical features. seven patients were considered as hypervolemic (hypertensive, elevated central venous pressure, edema and/ or use of diuretics). seven patients were dehydrated (judged on the basis of clinical findings of dry mucus membranes, sunken eyes, hypotension and intravenous fluid requirement). six patients were classified as euvolemic (not falling into either hypovolemic or hypervolemic categories). use of hypotonic fluids was observed in 11 patients (35%) and diuretics in 5 (25%) prior to development of severe hyponatremia. none of the patients received antidiuretic hormone (adh) analogs. two patients were treated with hypertonic fluids; four were treated with isotonic fluids while the rest were managed with discontinuation of inciting agent (hypotonic fluids or diuretics). of 3561 patients, thirty-one deaths were recorded for non-hyponatremic pediatric and young adult inpatients during the same period and four deaths in twenty patients with severe hyponatremia. hence the mortality in general pediatric inpatients was 0.87% compared to 20% in patients with severe hyponatremia. although we did not compare our patients with a cohort of similar co-morbid conditions without hyponatremia, but comparison with unselected non-hyponatremic patients showed mortality rate of 20 times high for hyponatremic patients. one patient was discharged with residual neurological deficits and four patients (2 male and 2 female) died. d i s c u s s i o n hyponatremia has been described with variable frequencies in children and young adults. the described frequency varies according to the level of hyponatremia and age range under study. iatrogenic factors are known to account for 40-66% of cases of hyponatremia.1 common causes of iatrogenic hyponatremia include excessive water intake5 or intravenous administration of hypotonic fluids,6 use of antidiuretic hormone or its analogs,7 carbamazepine,8 diuretics and postoperative hyponatremia.9 administration of hypotonic fluids and diuretics were common causes in our series. postoperative hyponatremia was seen in only one patient. neurological symptoms such as irritability and seizures are dependant on the rate of development of hyponatremia. chronic hyponatremia tends to be less symptomatic because of adaptation of cells in response to slowly developing hypoosmolality.10 patients who developed seizures have a higher mortality. routine anticonvulsants may be ineffective in seizures due to hyponatremia.11 use of hypertonic saline to correct hyponatremia, if used judiciously, is known to be safe and effective. however, because of the risk of development of osmotic demyelination syndrome (ods), hypertonic saline should preferably be reserved for patients with acutely developing hyponatremia who become symptomatic. acute hyponatremia should be corrected slowly and during the infusion of hypertonic saline serum levels should be monitored closely. in our series only two patients who had seizures were treated with hypertonic fluids and one of the two died. as these patients did not have autopsies, ods was not diagnosed. imaging studies such as ct and 16 z a k i a a l l a m k i , m a h f o o z a fa r o o q u i a n d s a e e d a h m e d mri of brain may not show lesions typical of ods for as long as a month. it may take 10 months for typical ct and mri changes of ods to appear.2 mortality associated with hyponatremia is often high. it is difficult to determine the direct effect of hyponatremia to mortality rates due to the usual coexistence of the other high risk co-morbid conditions. dunn and butt reported a mortality of 19% in their study of severe hyponatremia in pediatric inpatients,13 which is comparable to our observation. c o n c l u s i o n we confirm that severe hyponatremia in pediatric inpatients is associated with 20-times higher mortality when compared to unselected patients of the same age range. caution should be exercised in administration of hypotonic feeds or fluids. patients, who for some reason receive hypotonic fluids, should be monitored for development of hyponatremia. hypotonic fluids need to be discontinued if hyponatremia develops. for symptomatic hyponatremia, hypertonic fluids should be considered and used judiciously. serum sodium should be monitored closely during therapy with hypertonic saline. in the presence of significant comorbid conditions, it is difficult to assess direct contribution of hyponatremia to death. prospective studies are therefore required to assess accurately the etiology, iatrogenic component, adverse neurological and fatal outcomes, and the cost of care. r e f e r e n c e s 1. verbalis j. hyponatremia epidemiology, pathophysiology, and therapy. urr opin nephrol hypertens 1993; 2: 636-652. 2. arieff ai, ayus jc, fraser cl. hyponatremia and death or permanent brain damage in healthy children. brit med j 1992; 304: 1218-1222. 3. singhi s, prasad sv, chugh ks. hyponatremia in sick children: a marker of serious illness. indian pediatr 1994; 31: 19-25. 4. wattad a, chiang ml, hill ll. hyponatremia in hospitalized children. clin pediatr 1992; 31: 153-157. 5. bhalla p, eaton fe, coulter jbs, amegavie fl, sills ja, abernethy lj. hyponatraemic seizures and excessive intake of hypotonic fluids in young children, lesson of the week. brit med j 1999; 319: 1554-1557. 6. jackson j, bolte rg. risks of intravenous administration of hypotonic fluids for pediatric patients in ed and outpatient settings: let’s remove the handle from the pump. am j emerg med 2000; 18: 269-270. 7. anderson rj, chung hm, kluge r, schrier rw. hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. ann intern med 1985; 102: 164-168. 8. kastner t, friedman dl, pond ws. carbamazepineinduced hyponatremia in patients with mental retardation. am j ment retard 1992; 96: 536-540. 9. bohn d. children are another group at risk of hyponatremia perioperatively. brit med j 1999; 319: 1269. 10. verbalis jg, drutarosky md. adaptation to chronic hypoosmolality in rats. kidney int 1988; 34: 351-360. 11. sarnaik ap, meert k, hackbarth r, fleischmannl. management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy. crit care med 1991; 19: 758-762. 12. clifford db, gado mh, levy bk. osmotic demyelination syndrome: lack of pathologic and radiologic imaging correlation. arch neurol 1989; 46: 343-347. 13. dunn k, butt w. extreme sodium derangement in a paediatric inpatient population. j paediatric child health 1997; 33: 26-30. 1 submitted 21 aug 22 1 revision req. 25 sept 22; revision recd. 24 nov 22 2 accepted 15 dec 22 3 online-first: january 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.002 5 6 long-term survival in patients with cancers 7 a seer-based analysis 8 rokia a. sakr,1 abdelrahman a. nasr,2 *eman i. zineldin,3 mohamed a. 9 gouda4 10 departments of 1pathology and 2hepatobiliary surgery, national liver institute and 3student 11 research unit and 4department of clinical oncology, faculty of medicine, menoufia 12 university, menoufia, egypt. 13 *corresponding author’s e-mail: eman.ibrahiem43@med.menofia.edu.eg 14 15 abstract 16 objectives: long-term survival is an important endpoint in management of different 17 malignancies which is rarely assessed due to unfeasibility of follow-up for long duration of 18 time. in this study, we explored real-world data on cancer’s long-term survival using 19 historical records from the surveillance, epidemiology, and end results (seer) program. 20 besides reporting the 5-year relative survival, we analyzed the 10and 20year survival rates 21 for different types of cancers. additionally, survival trends as a function of time, age, and 22 tumor type were reviewed and reported. methods: we used seer*stat (version 8.3.6.1) for 23 data acquisition from the seer 9 regs (nov 2019 submission) database. data of patients 24 diagnosed with cancer between 1975 and 2014 were retrieved and included in the analysis. 25 results: for patients diagnosed with any malignant disease (n = 4,412,024), there was a 26 significant increase in median overall survival over time (p<0.001). the 20-, 10-, and 5-year 27 survival rates were higher in solid tumors compared to hematological malignancies (50.8% 28 vs. 38%, 57% vs. 47.4%, and 62.2% vs. 57.4%, respectively). the highest 20-year relative 29 survival rates were observed in thyroid cancer (95.2%), germ cell and trophoblastic 30 neoplasms (90.3%), melanoma (86.8%), wilms’ tumor (86.2%), and prostate cancer (83.5%). 31 conclusions: long-term follow-up data were suggestive of high 20-year relative survival 32 2 rates for most tumor types. relative survival showed an improving trend over time especially 33 in solid tumors. 34 keywords: survival; neoplasms; seer program; prognosis; united states. 35 36 advances in knowledge 37 • there was a significant increase in long-term survival rates in cancer patients over 38 the period between 1975 and 2014. 39 • the highest 20-year relative survival rate is seen in thyroid cancer, germ cell and 40 trophoblastic neoplasms, melanoma, wilms’ tumor, and prostate cancer. 41 • twenty-year relative survival rate is higher in solid cancers compared to 42 hematological malignancies. 43 44 application to patient care 45 • improved cancer diagnostics and therapeutic options have led to a substantial 46 increase in survival rates over time. this necessitates the development of long-47 term follow-up programs to accommodate the growing number of cancer 48 survivors. 49 • twenty-year survival rates for some malignancies are high. patients diagnosed 50 with those types of tumors should be aware of their probability of survival and 51 counseled about cancer survivorship. 52 53 introduction 54 in the united states (us), nearly 609,360 persons are projected to die from cancer in the year 55 2022. in fact, cancer is currently considered the second most common cause of death in both 56 men and women in the us.1 this domination over other causes of death is a daunting fact for 57 cancer patients and their families that remains consistent among different races and variable 58 age groups.2 59 60 although many researchers have studied cancer-related mortality, cancer survivorship usually 61 remains an underrepresented topic in literature despite growing interest in the concept in the 62 past decade. in 2019, more than 16.9 million americans have survived cancer—a number that 63 is projected to reach more than 22.1 million by 2030.3 with recent advances in cancer 64 diagnostics and therapeutics, survival is expected to become even much better with a further 65 increase in the number of cancer survivors among the overall population.4,5 66 3 67 cancer survival rates can vary according to tumor type and patients’ clinicodemographics.4,5 68 exploring survival rates can not only provide insights into the natural history of different 69 cancers but also enlighten us about the changes that happened across time because of the 70 introduction of novel treatment options or incorporation of new preventive strategies including 71 screening programs. most studies reporting on cancer survival, including clinical trials, have 72 addressed either 5-year or 10-year survival rates.6–9 however, looking into survival rates from 73 a more holistic approach that goes beyond 10 years is imperative; though this is usually 74 impractical to address in short-term studies or even in the context of prospective clinical trials. 75 76 in this study, we aimed to investigate long-term survival, including 20-year survival rates, of 77 different cancers in the us. we also tried to explore possible differences in survival rates across 78 tumor types, their association with different sociodemographic parameters, and their trends as 79 a function of time. 80 81 methods 82 data were obtained from the surveillance, epidemiology, and end results (seer) program.10 83 seer is a program that was initiated in the early 1970s by the us national cancer institute to 84 collect data from nationwide cancer registries. its current databases cover 47.9% of the us 85 population and are presumably generalizable to patients with cancer all over the us. the seer 86 9 database (nov 2019 submission), which covers 9.4% of the population and includes historic 87 data that go back to 1973, was used as the data source in this study. the study was exempted 88 from institutional review board approval being a seer-based study according to national 89 bureau of economic research`s guidance.11 90 91 the case-listing function in seer*stat 8.3.6.1 was used to export data on cancer cases 92 diagnosed between 1975 and 2014. we included patients with known ages who had cancers 93 with malignant behavior at the time of initial data entry. the relative survival was calculated 94 in seer*stat using the ederer ii method. the probability of relative survival compares 95 survival in the patients included in the analysis with the expected survival of the general 96 population obtained from the us 1970–2017 expected survival life tables.12 for relative 97 survival, cases with a missing cause of death and/or survival time were excluded from the 98 analysis. 99 100 4 according to the third edition of the international classification of diseases for oncology, we 101 classified tumors into either solid tumors (8000/3-9581/3) or hematological malignancies 102 (9590/3+). age at diagnosis was categorized into five main categories (0–14, 15–24, 25–54, 103 55–64, and 65+ years). for comparing trends over time, we stratified years of diagnosis into 104 four groups with a 10-year interval for each group. 105 106 statistical analysis was performed using ibm spss statistics for windows, version 26.0. 107 (armonk, ny: ibm corp). frequencies and percentages were used to describe categorical 108 variables. survival analysis was performed using the kaplan–meier analysis method, where 109 the log-rank test was used to test for statistical difference. cox regression analysis was 110 performed to adjust for potentially confounding factors. the p-value of 0.05 was used to 111 determine statistical significance. 112 113 results 114 in this analysis, we included 4,412,024 cases diagnosed with cancer between 1975 and 2014. 115 elderly population (65 years and over) was the largest age group in our study (55.6%; n = 116 2,452,512). the majority of the study cohort were male (51.3%; n=2,262,378) and white (84%; 117 n=3,705,309). the most commonly encountered diagnosis was breast cancer (14.9%; n = 118 657,211); with solid tumors constituting 91.1% (n = 4,019,427) of the included cohort (table 119 1). 120 121 the median overall survival for all patients included in the study was 66 months (95% 122 confidence interval (ci): 65.8–66.2 months) and showed a significant increase over time (35 123 months, 51 months, 77 months, and 101 months for cases diagnosed between 1975 and 1984, 124 1985 and 1994, 1995 and 2004, and 2005 and 2014, respectively; p<0.001) (figure 1). the 125 highest 20-year relative survival was observed in thyroid cancer (95.2%), germ cell and 126 trophoblastic neoplasms (90.3%), melanoma (86.8%), wilms’ tumor (86.2%), and prostate 127 cancer (83.5%) (table 3). 128 129 survival was compared across different prognostic factors including age, gender, stage, grade, 130 and cancer type. results revealed that the 15-24 age group had better median overall survival 131 compared to 25-54, 55-64 and 65+ age groups (363.3 months vs 261 months, 112 months, and 132 37 months ; p<0.001) (figure 1). female patients had longer overall survival compared to male 133 patients (83 months vs 54 months, p<0.001) (figure 1). patients of black races had lower 134 5 survival rates compared to (american indian/ak natives, asian/pacific islanders) and white 135 races (115.2 months vs 152.2 months, and 134.9 months, p<0.001). in cox regression analysis, 136 improvement in survival across time remained significant (hazard ratio (hr)= 0.899) and the 137 significance was also maintained across different age groups (hr=1.865), genders (hr: 138 1.008), races (hr: 0.939), and tumor types (hr: 0.781) (table 2). 139 140 despite consistent increase in survival rates in both tumor types, the 20-, 10-, and 5-year 141 survival rates were higher in solid tumors compared to hematological malignancies (50.8% vs. 142 38%, 57% vs. 47.4%, and 62.2% vs. 57.4%, respectively). table 4 shows survival rates for 143 commonly diagnosed cancers.1 144 145 discussion 146 the progress made in the oncology field has substantially improved cancer outcomes 13 but 147 little is known about how this was translated into a long-term survival benefit in patients with 148 cancer. to the best of our knowledge, this is the widest-scale analysis of long-term survival for 149 cancer patients that explored follow up data for up to 20 years after diagnosis using a tumor 150 agnostic approach. data presented in this study are crucial to inform treating physicians about 151 the probability of long-term survival in different malignancies. this information is commonly 152 addressed during doctor–patient conversations, particularly in patients with advanced disease. 153 current evidence suggests that the accuracy of oncologists’ expectations for survival in end-154 stage cancer patients was as low as 25%. this inaccuracy can not only lead to a lack of 155 credibility in physicians’ disclosed information but also mislead treatment-related decisions, 156 such as the need to refer patients for hospice care or the necessity of continuation of active 157 treatment.14–16 158 159 we have demonstrated, based on data from us cancer registries, that several malignancies have 160 a considerable long-term survival. the highest 20-year relative survival was observed in 161 thyroid cancer (95.2%), followed by germ cell and trophoblastic neoplasms, melanoma, and 162 wilms’ tumor (90.3%, 86.8%, and 86.2%, respectively). a potential explanation for high 163 survival rates in these tumors is the early disease-related manifestations, the availability of 164 easy-access diagnostic approaches, and the advances in treatment options with curative intent 165 in those tumor types. similar data were reported in the united kingdom (uk) by quaresma et 166 al., who have reported the highest 10-year survival in patients with testicular cancer (98.2%).19 167 168 6 although some data support the notion that the highest rates of cancer survival are reported in 169 the us and canada,18 trends in our survival analysis were consistent with findings from other 170 studies in other parts of the world. most publications addressing shorter survival intervals have 171 reported improved survival over time; which is usually attributed to the introduction of new 172 treatment options for various tumors.18–20 this has been consistent with data reported in our 173 study, which showed a steady increase in 5-, 10-, and 20-year survival across almost all tumor 174 types. interestingly, the survival probability showed an incremental decrease after 5 years as 175 compared to anticipated linear increase in the probability of death. for example, breast cancer 176 survival probability fell from 86.4% at the 5-year follow-up to only 70.1% at 20 years. in 177 colorectal cancer, the 20-year survival rate of 50.5% actually compares to that of 61.4% at 5 178 years. this highlights the fact that most death events would occur early in the course of disease. 179 therefore, informing patients about the long-term prognosis of their illness should not rely 180 only on short-term survival data, which can sometimes be misleading. our findings are 181 concordant with data from a similar study that was done twenty years ago and reported on long-182 term survival of patients diagnosed between 1974-1991. in the study by wingo et al, an 183 incremental decrease in survival rates happened after 5 years in patients with colorectal cancer 184 with 15-years survival rate reported as 50% compared to 57% survival rate at 5 years.17 185 186 our findings suggest that solid malignancies have a higher 20-year relative survival than 187 hematological malignancies. this difference in survival was consistent among all age groups 188 and was more prominent in older patients versus patients less than 14 years old who had better 189 survival with hematological malignancies. improvements in the survival rate in hematological 190 malignancies seem more prominent (73.6% increment increase) than solid malignancies 191 (51.2% increment increase). these data conform to the data reported in previous studies from 192 different geographic areas.7,21,22 the survival difference between different age groups was also 193 reported in a population-based study in the uk where the net survival in the elderly population 194 was lower than that in younger patients over a 40-year period (1971–2011).19 thus, observing 195 such a discrepancy is not surprising as both solid and hematological malignancies are a 196 heterogeneous group of different diseases with different natural histories and treatment options. 197 elderly patients commonly show late manifestations and have multiple comorbidities that can 198 affect both treatment decisions and liability to treatment-induced toxicity. 199 200 improvements in survival, however, do not come without a cost. long-term cancer survivors 201 are more likely to experience treatment-induced long-term side effects, including organ failure 202 7 and secondary malignancies. long-term nonmedical effects, including financial toxicity and 203 lifestyle changes, can also add a burden to long-term survivors. thus, addressing cancer 204 survivorship issues, particularly in patients with potentially high survival rates, and 205 establishing follow-up guidelines that not only go beyond the normal follow-up periods but 206 also address medical and non-medical needs of cancer survivors are imperative. an effort to 207 address the cancer survivorship issue was made by the european society for medical oncology 208 (esmo) which provided expert consensus guidelines for management of cancer survivorship. 209 the guidelines identified core components that need to be addressed in cancer survivors 210 including physical and psychological effects, social and financial impact, active surveillance 211 for recurring cancers and second primaries, and promotion of well-being including 212 improvement of cancer prevention approaches and overall health. 23 213 214 this study addressed a huge number of patients with a long follow-up duration. 215 notwithstanding the resulting comprehensiveness of analysis, our study has several limitations. 216 first, the seer database does not provide detailed data on treatment options that patients 217 received. the included cohort was diagnosed over a long period of time which might have 218 resulted in heterogenous availability of treatment options and subsequent differences in clinical 219 outcomes. second, the 20-year survival data could only be calculated for the seer 9 database, 220 which includes cancer registries present since the inception of the seer program. major 221 updates in seer were performed, which currently include 22 cancer registries covering 47.9% 222 of the total cancer population in the us. however, the use of long-term data from newly 223 incorporated cancer registries will not be feasible until a couple of years later when the follow-224 up duration can allow for long-term survival analysis. third, methods to evaluate survival rates 225 can vary and lead to differences in outcome interpretation 24. for example, there has been a 226 reported slightly higher relative survival rates with ederer ii method compared to hakulinen 227 or ederer i method when follow up duration exceeds ten years. in some cases, as in 228 malignancies that are diagnosed over a wide range of ages (e.g. thyroid), long term relative 229 survival for all ages combined may vary depending on the method used to estimate expected 230 survival; since ederer i and hakulinen methods will provide similar and higher relative survival 231 compared to that calculated by ederer ii 25. finally, in general and as with data originating 232 from cancer registries, seer extracted data must be interpreted with caution given the 233 challenges of unrecorded variables, underreported and incomplete adjuvant treatment data, 234 disparity in coding and reporting, and migration of patients between seer registry regions .26 235 236 8 conclusions 237 long-term follow-up data suggests that 20-year relative survival rates are high for many 238 tumor types. the relative survival rates have significantly improved over time. long-term 239 follow up programs for cancer survivors should be incorporated into clinical management of 240 patients with cancer. 241 242 acknowledgments 243 we would like to thank enago for their consult and help in the language editing of our 244 manuscript. 245 246 authors’ contribution 247 mag conceptualised the study. ras, eiz and mag designed the methodology. ras, aan, 248 eiz and mag drafted the original manuscript. aan reviewed and edited the manuscript and 249 supervised the work. all authors approved the final version of the manuscript. 250 251 references 252 1. siegel rl, miller kd, fuchs he, jemal a. cancer statistics, 2022. ca cancer j clin. 253 2022;72(1):7-33. doi:10.3322/caac.21708 254 2. heron m. national vital statistics reports volume 67, number 5 july 26, 2018.; 2018. 255 3. miller kd, nogueira l, mariotto ab, et al. cancer treatment and survivorship 256 statistics , 2019. 2019;69(5):363-385. doi:10.3322/caac.21565 257 4. zeng c, wen w, morgans ak, pao w, shu x-o, zheng w. disparities by race, age, 258 and sex in the improvement of survival for major cancers. jama oncol. 259 2015;1(1):88. doi:10.1001/jamaoncol.2014.161 260 5. dal maso l, panato c, guzzinati s, et al. prognosis and cure of long-term cancer 261 survivors: a population-based estimation. cancer med. 2019;8(9):4497-4507. 262 doi:10.1002/cam4.2276 263 6. abbema d van, vissers p, vos-geelen j de, lemmens v, janssen-heijnen m, tjan-264 heijnen v. trends in overall survival and treatment patterns in two large 265 population-based cohorts of patients with breast and colorectal cancer. 266 7. monnereau a, troussard x, belot a, et al. unbiased estimates of long‐term net 267 survival of hematological malignancy patients detailed by major subtypes in france. 268 int j cancer. 2013;132(10):2378-2387. doi:10.1002/ijc.27889 269 8. gatta g, botta l, rossi s, et al. childhood cancer survival in europe 1999–2007: 270 9 results of eurocare-5—a population-based study. lancet oncol. 2014;15(1):35-47. 271 doi:10.1016/s1470-2045(13)70548-5 272 9. de angelis r, sant m, coleman mp, et al. cancer survival in europe 1999–2007 by 273 country and age: results of eurocare-5—a population-based study. lancet oncol. 274 2014;15(1):23-34. doi:10.1016/s1470-2045(13)70546-1 275 10. surveillance, epidemiology, and end results (seer) program (www.seer.cancer.gov) 276 seer*stat database: incidence seer research data, 9 registries, nov 2019 sub 277 (1975-2017) linked to county attributes time dependent (1990-2017) 278 income/rurality, 1969-2018 counties, national cancer institute, dccps, surveillance 279 research program, released april 2020, based on the november 2019 submission. 280 11. guidance: data sets not requiring irb review. from:shorturl.at/owek. 281 accessed:22nd nov 2022. 282 12. arias e, xu j. united states life tables, 2017.; 2019. 283 13. hajdu si, vadmal m, tang p. a note from history: landmarks in history of cancer, 284 part 7. cancer. 2015;121(15):2480-2513. doi:10.1002/cncr.29365 285 14. chow e, harth t, hruby g, finkelstein j, wu j, danjoux c. how accurate are 286 physicians’ clinical predictions of survival and the available prognostic tools in 287 estimating survival times in terminally iii cancer patients? a systematic review. 288 clin oncol. 2001;13(3):209-218. doi:10.1053/clon.2001.9256 289 15. vasista a, stockler m, martin a, et al. accuracy and prognostic significance of 290 oncologists’ estimates and scenarios for survival time in advanced gastric cancer. 291 oncologist. 2019;24(11). doi:10.1634/theoncologist.2018-0613 292 16. glare p. a systematic review of physicians’ survival predictions in terminally ill 293 cancer patients. bmj. 2003;327(7408):195-0. doi:10.1136/bmj.327.7408.195 294 17. wingo a, parker l, gloeckler la, heath w. long-term cancer patient survival in 295 the united states. 1998;7(april). 296 18. allemani c, matsuda t, di carlo v, et al. global surveillance of trends in cancer 297 survival 2000–14 (concord-3): analysis of individual records for 37 513 025 298 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 299 countries. lancet. 2018;391(10125):1023-1075. doi:10.1016/s0140-6736(17)33326-3 300 19. quaresma m, coleman mp, rachet b. 40-year trends in an index of survival for all 301 cancers combined and survival adjusted for age and sex for each cancer in england and 302 wales, 1971–2011: a population-based study. lancet. 2015;385(9974):1206-1218. 303 doi:10.1016/s0140-6736(14)61396-9 304 10 20. allemani c, weir hk, carreira h, et al. global surveillance of cancer survival 1995–305 2009: analysis of individual data for 25 676 887 patients from 279 population-based 306 registries in 67 countries (concord-2). lancet. 2015;385(9972):977-1010. 307 doi:10.1016/s0140-6736(14)62038-9 308 21. cowppli-bony a, uhry z, remontet l, et al. survival of solid cancer patients in 309 france, 1989–2013. eur j cancer prev. 2017;26(6):461-468. 310 doi:10.1097/cej.0000000000000372 311 22. sant m, minicozzi p, mounier m, et al. survival for haematological malignancies in 312 europe between 1997 and 2008 by region and age: results of eurocare-5, a 313 population-based study. lancet oncol. 2014;15(9):931-942. doi:10.1016/s1470-314 2045(14)70282-7 315 23. vaz-luis i, masiero m, cavaletti g, et al. esmo expert consensus statements on 316 cancer survivorship: promoting high-quality survivorship care and research in europe. 317 ann oncol. 2022;33(11):1119-1133. doi:10.1016/j.annonc.2022.07.1941 318 24. makkar n, ostrom qt, kruchko c, barnholtz-sloan js. a comparison of relative 319 survival and cause-specific survival methods to measure net survival in cancer 320 populations. cancer med. 2018;7(9):4773-4780. 321 doi:https://doi.org/10.1002/cam4.1706 322 25. cho h, howlader n, mariotto ab, cronin ka. estimating relative survival for cancer 323 patients from the seer program using expected rates based on ederer i versus ederer 324 ii method. 2011. 325 26. park hs, lloyd s, decker rh, wilson ld, yu jb. limitations and biases of the 326 surveillance, epidemiology, and end results database. curr probl cancer. 327 2012;36(4):216-224. doi:https://doi.org/10.1016/j.currproblcancer.2012.03.011 328 11 329 figure 1: kaplan–meier curve for cases diagnosed with cancer between 1975 and 2014 330 stratified by age group, race, gender, stage, grade, and year of initial diagnosis. 331 332 12 333 figure 2: twenty-year survival for different age groups stratified according to tumor type. the 334 highest survival rates are observed in the 15-24 age group. age groups are plotted on the x axis 335 and survival probability is plotted on the y axis. 336 337 table 1: patients’ characteristics in the included cohort. 338 n % age group 0–14 years 31,594 0.7% 15–24 years 41,614 0.9% 25–54 years 917,720 20.8% 55–64 years 968,584 22% 65+ years 2,452,512 55.6% gender male 2,262,378 51.3% female 2,149,646 48.7% race white 3,705,309 84% black 407,066 9.2% other (american indian/ak native, asian/pacific islander) 281,266 6.4% unknown 18,383 0.4% year of diagnosis 1975–1984 758,808 17.2% 1985–1994 1,025,529 23.2% 1995–2004 1,220,374 27.7% 2005–2014 1,407,313 31.9% tumor type solid 4,019,427 91.1% hematology 392,597 8.9% 0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00% 0-14 years 15-24 years 20-54 years 55-64 years *65 years 20 year relative suvival solid hematological all 13 diagnosis breast 657,211 14.9% prostate 610,247 13.8% lung and bronchus 592,921 13.4% urinary bladder 196,378 4.5% melanoma of the skin 168,236 3.8% corpus uteri 136,199 3.1% nhl nodal 120,148 2.7% kidney and renal pelvis 114,658 2.6% pancreas 112,114 2.5% other tumors 1,703,912 39% 339 table 2: cox regression analysis for different prognostic factors affecting survival time. p-340 value < 0.001 341 regression coefficient hr 95.0% ci for hr lower upper age 0.623 1.865 1.862 1.867 year of diagnosis -0.106 0.899 0.898 0.900 stage 0.163 1.177 1.176 1.178 grade 0.071 1.073 1.073 1.074 cancer type (solid and hematological) -0.242 0.785 0.781 0.788 sex 0.008 1.008 1.006 1.011 race -0.063 0.939 0.938 0.940 342 14 table 3: survival data of cancers having highest 20-year relative survival. 5 year survival 10 year survival 20 year survival 19751984 19851994 19952004 20052014 all years 19751984 19851994 19952004 20052014 all years 19751984 19851994 19952004 20052014 all years thyroid carcinoma 92.90% 94.60% 96.60% 98.50% 96.80% 91.40% 93.50% 95.90% 98.50% 96.10% 90.10% 92.40% 95.10% n/a 95.10% germ cell and trophoblastic neoplasms 85.10% 92.50% 94.40% 95.50% 92.60% 83.80% 91.50% 94.20% 95.20% 92.00% 80.40% 90.30% 93.30% n/a 90.30% melanoma 82.00% 87.50% 91.00% 93.10% 89.90% 77.10% 84.40% 89.10% 92.10% 87.40% 75.00% 83.40% 88.90% n/a 86.70% wilms tumor 79.30% 91.10% 90.70% 94.10% 89.00% 77.70% 90.50% 89.10% 93.00% 87.80% 76.60% 89.00% 86.10% n/a 86.20% n/a: 20 years survival rates cannot be calculated for this patient population due to short follow up to date. table 4: survival data for commonly diagnosed tumors. cancers listed are those shown to have highest incidence rates according to siegel et al 2022. 5 year survival 10 year survival 20 year survival 19751984 19851994 19952004 20052014 all years 19751984 19851994 19952004 20052014 all years 19751984 19851994 1995-2004 20052014 all years breast 75.50% 84.00% 89.00% 91.10% 86.10% 63.60% 76.10% 83.50% 86.30% 78.80% 53.20% 67.50% 75.70% n/a 69.80% prostate 70.50% 89.10% 98.60% 99.10% 93.40% 55.70% 81.90% 97.90% 99.10% 89.70% 39.60% 72.40% 94.40% n/a 81.70% lung and bronchus 12.70% 13.40% 15.30% 19.60% 15.40% 8.70% 9.00% 10.20% 13.10% 10.40% 4.80% 4.80% 5.50% n/a 5.60% colon and rectum 52.10% 60.00% 64.00% 66.40% 60.80% 46.50% 53.90% 58.40% 60.10% 54.90% 42.60% 49.50% 52.60% n/a 50.00% corpus and uterus, nos 83.50% 82.80% 83.60% 83.20% 83.30% 81.60% 80.40% 80.70% 80.30% 80.80% 79.50% 76.80% 76.40% n/a 77.70% urinary bladder 74.60% 78.80% 79.80% 78.70% 78.20% 66.50% 71.50% 73.10% 72.30% 71.00% 55.20% 60.10% 61.50% n/a 59.70% melanoma of the skin 82.90% 88.60% 92.00% 94.00% 90.90% 78.40% 86.00% 90.50% 93.40% 88.90% 76.60% 85.20% 90.40% n/a 88.40% kidney and renal pelvis 51.50% 58.40% 65.50% 75.10% 65.80% 44.50% 50.80% 57.70% 68.80% 58.40% 36.80% 40.90% 47.00% n/a 47.60% non-hodgkin lymphoma 49.00% 51.30% 63.20% 73.40% 61.70% 37.20% 41.10% 55.70% 66.50% 52.60% 26.80% 31.70% 46.60% n/a 41.80% oral cavity and pharynx 52.50% 55.00% 60.50% 67.40% 59.30% 42.30% 44.40% 51.30% 59.30% 49.40% 29.80% 32.40% 38.40% n/a 36.10% leukemia 36.20% 44.20% 52.30% 64.50% 50.90% 25.40% 33.90% 44.70% 57.60% 41.60% 17.90% 26.70% 37.00% n/a 32.90% pancreas 2.70% 3.80% 4.90% 9.10% 5.60% 1.80% 2.60% 3.60% 6.50% 3.90% 1.30% 1.80% 2.10% n/a 2.60% thyroid 92.70% 94.40% 96.50% 98.40% 96.60% 91.30% 93.30% 95.80% 98.40% 96.00% 89.90% 92.10% 94.90% n/a 95.00% n/a: 20 years survival rates cannot be calculated for this patient population due to short follow up to date. august 2007 vol 7 copy.indd abstract a sickle cell crisis can occur during cardiopulmonary bypass for cardiac surgical procedures in patients with sickle cell hemoglobin, which could lead to hemolysis. there is a dearth of such reports from the arab world. we hereby present two cases from oman with subclinical sickle cell crisis during cardiopulmonary bypass. the timely detection and early management resulted in good outcome. the good clinical practice for management of such patients is also discussed. key words: sickle cell trait; cardiopulmonary bypass; hemolysis; case report; oman. subclinical sickle cell crisis during cardiopulmonary bypass timely detection and early management raj gopal menon,1 *madan m maddali,2 adil al-lawati,1 hilal al-sabti3 sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 79-81 sultan qaboos university© submitted 28th february 2007 1department of surgery, royal hospital, muscat, sultanate of oman; 2department of anesthesia, royal hospital, muscat, sultanate of oman; 3department of surgery, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, muscat, sultanate of oman *to whom correspondence should be addressed. email: madan@omantel.net.om c a s e r e p o r t وِيَّة الرِئَ بِيَّةٌ لْ ازَةٌ القَ َالسريرية أثناء ا دون املنجلية اخللية أزمة مبكرا وعالجها املناسب في الوقت اكتشافها السبتي علي هالل اللواتي، ايد مادالي، عادل عبد م مادان مانون، راج جوبال اخللية هيموجلوبني ــن م يعانون الذين للمرضى اجلراحية ــب القل لعمليات لْبِيَّةٌ الرِئَوِيَّة القَ ــازَةٌ َا املنجلية أثناء ــة أزمة اخللي حتدث أن ــن ميك ــص: امللخ اخللية أزمة من يعانيان مان عُ من حالتني هنا نقدم العربي. العالم في التقارير هذه من القليل هناك احلمراء. الدم خاليا قد يؤدي إلى حتلل املنجلية مما أيضاً متت . جيدة نتائج إلى مبكر يؤديان ــكل بش الالزم وإجراء ــب املناس الوقت ــاف احلالة في اكتش . لْبِيَّةٌ الرِئَوِيَّة القَ ازَةٌ َا أثناء ــريرية الس دون املنجلية املرضى. هؤالء مثل لعالج اجليدة السريرية املمارسة مناقشة مان عُ حالة، احلمراء، تقرير الدم خاليا الرِئَوِيَّة، حتلل لْبِيَّةٌ ازَةٌ القَ َاملنجلية، ا اخللية الكلمات: سمة مفتاح a sickle cell crisis can occur in patients with sickle cell trait (sct) under extremely stressfully conditions albeit the incidence is much less than in patients with sickle cell disease (scd). 1, 2 we report two consecutive cases of sct who developed subclinical sickle cell crisis during cardiopulmonary bypass (cpb) resulting in haemolysis without overt haematuria. observation of an alteration in the color of the ultrafiltrate and a simultaneous fall in haematocrit, as noticed in the intraoperative arterial blood gas analysis report, led to the detection and eventual mitigation of the problem. c a s e r e p o r t s c a se  a 50-year lady underwent a coronary artery bypass graft (cabg) on cpb under a narcotic based general anesthesia and appropriate life support monitoring. the preoperative haematological results revealed sickle cell trait due to presence of heterozygous haemoglobin s (hbs) of 29.7%. the intraoperative arterial blood gas (abg), inclusive of those on cpb, showed: ph ranging from 7.37 to 7.4, pao2: 108 to 154, paco2: 34 to 38 and mixed venous saturations were more than 70%; all were suggestive of adequate perfusion. in addition, the temperature of the perfusate was maintained above 34oc and nitroglycerine infusion was administered to prer a j g o pa l m e n o n , m a d a n m m a d d a l i , a d i l a l l awat i , h i l a l a l -s a b t i 80 vent vasoconstriction. a centrifugal pump was used to minimize blood trauma. myocardial protection was achieved using cold antegrade blood cardioplegia. however, as soon as the cardioplegia was given, the ultrafiltrate from the hemofilter became bloodstained without obvious haematuria. an abg analysis was immediately repeated and showed a haematocrit of 16%. blood samples for surrogate markers of haemolysis were sent [table 1]. even though the urine appeared clear, urinalysis showed presence of haemoglobin. immediately, 2 units of cross-matched blood were added to the pump to increase the haematocrit to 24%. shortly afterwards, the ultrafiltrate became clear. following this, the surgery was completed uneventfully. the patient did well postoperatively. the preoperative hematology status, values of markers for haemolysis during haemolysis and after transfusion have been tabulated [table 1]. c a se 2 a 70 years old gentleman underwent cabg on cpb. preoperative haematological tests revealed sct (hbs 30%). like in case 1, all precautions were taken to avoid a sickling episode. however, soon after cardioplegia administration, the haematocrit dropped to 18% and the ultrafiltrate changed its colour without any change in the urine color. after sending blood specimens for identifying markers for haemolysis, two units of cross-matched blood were infused immediately. soon after, the haematocrit improved to 22% and the ultrafiltrate cleared. the blood investigations are shown in table 1. d i s c u s s i o n in oman, the prevalence of sct is 6% and scd is 0.9%.3 patients with sickle cell abnormalities undergoing surgery are generally at a greater risk of perioperative complications such as precipitation of a sickle cell crisis, microvascular occlusion, red cell membrane case 1 case 2 parameters preoperative during the hemolytic event post transfusion post operative (immediately on reaching the icu) pre operative during the hemolytic event post transfusion post operative (immediately on reaching the icu) hemoglobin [hb] (g/dl) 11 5.4 8.4 9 11.2 5.8 7.8 9.2 hematocrit (%) 33 16 24 24 34 18 22 28 urinalysis clear free hb trace of rbc clear clear free hb clear clear total bilirubin [µmol/l] 9.5 12.5 12.1 1 3.5 10.4 13.5 13.9 13.2 serum haptoglobin (mg/l) not done 690 900 380 not done 520 513 360 serum ldh (iu/l) not done 298 108 100 not done 304 104 102 absolute reticulocyte count 109/l not done 5 5 5 not done 3.9 5.9 4.0 table 1: hematological values and markers of hemolysis wnl: within normal limits normal ranges: hb: 10.9 – 16.1 g/dl, hematocrit: 33-46%, total bilirubin: 3-17 µmol/l, serum haptoglobin: 360-1950 mg/l, serum ldh: 95-190 iu/l, absolute reticulocyte count: 5-200 x 109/ l s u b c l i n i c a l s i c k l e c e l l c r i s i s d u r i n g c a r d i o p u l m o n a r y b y pa s s 81 fragility and haemolysis.1, 2 in addition, cpb can cause a sickling crisis due to aortic cross clamping, hypothermia, cold crystalloid cardioplegia, haemodilution and low perfusion pressures. as both patients mentioned above were diagnosed to have sct by routine sickle cell screen and subsequent haematological investigations, all steps were taken to prevent a haemolytic episode during surgery. however, immediately after cross clamping and cardioplegia administration, the ultra filtrate appeared bloodstained in both patients, which indicated haemolysis. the urine remained clear. we suggest that this event was triggered by haemodilution following cardioplegia administration with a precipitous fall in haematocrit. intraoperatively, it becomes difficult to make an immediate diagnosis of a sub-clinical sickling crisis and one has to depend on surrogate markers of haemolysis i.e. total bilirubin, serum lactate dehydrogenase (ldh) serum haptoglobin and absolute reticulocyte counts. the ldh levels were elevated in both patients (normal range: 95-190 iu/l) concurrent with a low haematocrit. haptoglobin, an acute phase protein, was mildly elevated from the lower range of normalcy and absolute reticulocyte counts remained unchanged probably indicating that the haemolytic process had just begun. as soon as the ultrafiltrate became bloodstained, we suspected subclinical haemolysis, despite the fact that there was no obvious haematuria and transfused cross-matched blood to elevate the haematocrit to above 20%. the colour of the ultrafiltrate cleared and serum haptoglobin that was slightly elevated and serum ldh levels normalized rapidly indicating a short duration of a sickling related haemolysis. following a haemolytic episode, surrogate markers (total bilirubin, serum haptoglobin, serum ldh and reticulocyte counts) are usually elevated. the elevation of these markers depends to a large extent on the duration and severity of the episode. total bilirubin, serums ldh and serum haptoglobin are sensitive indicators and are elevated earlier than absolute reticulocyte counts. when the surrogate markers are considered individually in both the patients, the total bilirubin was slightly elevated from its preoperative values. serum haptoglobin levels, though within the normal range, were elevated during the episode compared to postoperative values. serum ldh was elevated, but once again normalized postoperatively. it is true that the institution of a cardiopulmonary bypass could derange several biochemical values. at the same time, macroscopic haemolysis and a drop in haematocrit per se are not markers for haemolysis. however, based on an overt change in ultrafiltrate colour that rapidly corrected after elevation of the haematocrit, presence of free haemoglobin in urine and mild elevation in some of the haemolytic markers, a working diagnosis of a short-lived subclinical haemolysis was made. the shortcoming in this case report is that we did not measure the surrogate markers for haemolysis prior to surgery. this would have provided base line values for confirming the diagnosis and would have aided in identifying any pre-existing problems. other than total bilirubin, as all the other markers were measured for the first time only intraoperatively, an elevation from their respective normal ranges was taken as diagnostic criteria. in patients with sickle cell haemoglobin, preoperative partial exchange transfusion to achieve a haematocrit of 30% with hbs < 30% has been recommended for major surgery.1 this is done to reduce the overall burden of hbs mass to less than 30% thereby avoiding a sickling episode. as both our patients had base line haemoglobin (hb) levels above 10gms, no blood transfusions were administered preoperatively. in conclusion, in the absence of other triggering factors, a drop in haematocrit during cardiopulmonary bypass in patients with sickle cell alone could lead to a subclinical sickle cell crisis and haemolysis. this might not necessarily be associated with haematuria. in the event of such a crisis being precipitated on cpb and if the cause is deemed to be haemodilution, rapid restoration of the haematocrit to above 20% would avoid further progress of the crisis. lastly, a preoperative estimation of all the surrogate markers of haemolysis would aid in identifying any pre-existing problems as well as serve as base line values for identifying perioperative sickle cell related issues. r e f e r e n c e s 1. maddali mm, rajakumar mc, fahr j, albahrani mj, amna ma. cardiopulmonary bypass without preoperative exchange transfusion in sicklers. asian cardiovasc thorac ann 2006; 14:51-56. 2. singh j, mehta s, sharma r, rana ss, thingnam sk, dhaliwal rs. cardiopulmonary bypass in sickle cell disease. asian cardiovasc thorac ann 2006; 14:445-46. 3. al riyami a, ebrahim gj. genetic blood disorders survey in the sultanate of oman. j tropical pediatrics 2003; 49:11-20. december 2008 no white pages.indd use of intravenous sulprostone for the termination of pregnancy with fetal death in second and early third trimester of pregnancy *anita k mohan,1 mariam mathew,1 syed g rizvi2 وفاة حالة في احلمل إلنهاء الوريدي حقن السلبروستون استخدام احلمل من الثالث الثلث وبداية الثاني الثلث في اجلنني رزفي جواهار سيد ، ماثيو مريام ، موهان كريشنا أنيتا من الثالث ــوث االثل وبداية الثاني االثلوث ــي ف اجلنني موت حالة ــي احلمل ف إلنهاء (ناالدور) ــتون السلبروس حقن فعالية ــة دراس ــص: الهــدف: امللخ مضاهية مبادة الوريدي بالزرق عوجلن احلمل 12-30 من ــبوع األس بني اجلنني لوفاة حامل تعرضن 97 امرأة ل ــتعادية اس ــة الطريقة: هذه دراس احلمل. في قابوس السلطان جامعة ــفى مبستش والتوليد النسائية قسم في ــة الدراس أجريت اجلنني. ــقاط إس أجل من ، ــتون سلبروس ، ــتاجالندين للبروس 15 مايكروجرام/ بجرعة بالوريد السلبروستون بحقن البدء مت .2005 سنة ديسمبر بداية 2000 إلى سنة يناير من جمعت املعطيات عمان. سلطنة كذلك القسم. في به معمول هو كما 1500 مايكروجرام/يوم القصوى إلى اجلرعة ووصلت ، 240 مايكروجرام/ساعة اجلرعة إلى وصلت أن إلى ساعة مجموع واملضاعفات. النتائج: من واألعراض اجلانبية التفريغ إلى واحلاجة بني التحريض واإلجهاض والفترة احلمل الدميغرافية وعمر املعطيات دراسة مت 11.9 ± 8.0 ساعة. واإلجهاض بني التحريض الفترة متوسط كان 24 ساعة. 90 منهن خالل أجهضت (97) بالسلبروستون عوجلن اللواتي احلوامل كان الدم فقدان لكن ــط تفريغ وكش احتجن إلى املريضات معظم أن ولو ــكل جيد. بش حتمله املريضات ــتطاعت واس قليلة جانبية أعراض هناك كان احلمل حني يكون إنهاء في فعال دواء ــتون السلبروس اخلالصة: وجدنا أن م. الرَّحِ عُ بَضْ إلى ومريضتني الدم نقل إلى ــت مريضات احتجن س فقط قليال. احلمل. الثالث م االثلوث وبداية الثاني االثلوث ميتا في اجلنني عمان. ، اجلنني ، موت احلمل إنهاء ، سلبروستون ، الكلمات: بروستاجالندين مفتاح 1department of obstetrics and gynecology, sultan qaboos university hospital, muscat, sultanate of oman; 2department of family medicine & public health, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman *to whom correspondence should be addressed. email: dr_anita_mohan@hotmail.com sultan qaboos university medical journal november 2008, volume 8, issue 3, p. 306-309 sultan qaboos university© submitted 27th february 2008 accepted 2nd september 2008 abstract objective: to study the efficacy of intravenous sulprostone (nalador) for the termination of pregnancy with fetal death in second and early third trimester of pregnancy. methods: this is a retrospective collection and analysis of data from a cohort of 97 women with fetal death between 2-30 weeks gestation treated with intravenous infusion of a prostaglandin analogue, sulprostone, to achieve expulsion of the products of conception. it was conducted in the department of obstetrics and gynaecology, sultan qaboos university hospital, oman. the data collected was from january 2000 to december 2005. sulprostone was started as an intravenous infusion of 5µgm/hr and titrated to a maximum of 240µgm/hr to a total dose of 500µgm/day, as per the departmental protocol. the patients’ demographic data, gestational age, induction-expulsion interval, the need for evacuation, side effects and complications were studied. results: out of the 97 women who received sulprostone, 90 aborted within 24 hours. the average induction-expulsion interval was .9 ± 8.0 hours. sulprostone use was associated with few side effects and was well tolerated by patients. although most of the patients required evacuation and curettage, the blood loss was minimal. only six out of 97 women required blood transfusions and two patients needed hysterotomy. conclusion: we found sulprostone an efficient drug for termination of pregnancy with fetal death in second and early third trimester of pregnancy. keywords: sulprostone; prostaglandin; intrauterine fetal death. c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • this is the first study from oman that analyses use and effect of sulprostone for the termination of pregnancy with fetal death in second and early third trimester of pregnancy. • the findings of this study confirm the safety of sulprostone for the above mentioned indication. u s e o f i n t r av e n o u s s u l p r o s t o n e f o r t h e te r m i n at i o n o f p r e g n a n c y w i t h f e ta l d e at h i n s e c o n d a n d e a r ly th i r d tr i m e s t e r o f p r e g n a n c y 307 termination of pregnancy with intrauterine fetal death in the second and third trimester has always posed a challenge to the obstetrician. various surgical and medical methods have been used for this purpose. sulprostone (pge2 analogue) and misoprostol (pge1 analogue) are the most widely used prostaglandins for termination of pregnancy. sulprostone has been the only drug used for termination of pregnancy in our institute since the year 1995. most studies used intramuscular sulprostone with or without intravenous sulprostone.1 a review of the literature shows only a few studies using intravenous sulprostone alone. we undertook this study to find out the safety and efficacy of intravenous sulprostone in cases of termination of pregnancies with second and early third trimester fetal deaths m e t h o d s this was an observational cohort study with retrospective data collection and analysis conducted in the department of obstetrics and gynaecology, sultan qaboos university hospital, muscat, oman. the data collected was between january 2000 and december 2005. all ninety seven (97) women with a gestational age ranging from 12 to 30 weeks and fetal death, confirmed by ultrasound, were included in this study. six women with medical complications like hypertension, cardiovascular disease and bronchial asthma were excluded. all 97 women who received sulprostone were included in the analysis. these patients were admitted to the gynaecology ward and intravenous sulprostone was started as per the departmental protocol, after confirming normal full blood count and serum electrolytes. written consent was obtained from all women. none of the patients received cervical priming prior to sulprostone infusion. sulprostone is a 16-phenoxy derivative of methylsulphonylamid prostaglandin e2. one ampoule contains 500µgm of active sulprostone in 7.45 mg dried form. the known side effects are nausea, vomiting and diarrhoea. the departmental protocol for use of sulprostone was as follows: the infusion is prepared by adding 500µgm sulprostone to 50 ml of normal saline and the infusion is started via a syringe pump at 1.5 ml/hr (15µgm/hr). the rate is doubled every hour to a maximum of 240µgm/hr and a total dose of 1500 µgm over 24 hours. medical records were reviewed regarding each patient’s age, parity, any previous cesarean section, gestational age, induction-expulsion interval, blood loss, need for analgesia, evacuation, side effects and complications. the induction-expulsion time interval was taken as the primary end point and the others as secondary end points. statistical analysis was performed using spss (statistical package for the social sciences), version 10 computer software. a p value <0.05 was considered to be statistically significant. the chi square test was used to test the association of categorised variables; the t-test and anova (analysis of variance between groups) test were used to test the significance of the difference in induction abortion interval between different groups. r e s u l t s during the six-year period from january 2000 to december 2005, 97 women had induction with sulprostone for fetal death in the second and early third trimester of pregnany. figure 1 shows the age distribution of the study group. the age ranged from 18 to 42 years with a mean of 28.6 ± 6.0 years. eighty-five women were between 12 to 22 weeks of gestation and 12 were at more than 22 weeks. most of our patients were omani nationals (86.7%) and the rest were from various other countries. the primary end point induction-expulsion time interval, was calculated from the start of the sulprostone until the expulsion of the fetus. the average time required for patients of less than 22 weeks gestation was 10.9 ± 8.6 hours and those at more than 22 weeks was 12.0 ± 8.0 hours. this difference was also not found to be statistically significant (p = 0.649). a total of 90 patients expelled the fetus within 24 hours. the longest time taken was 62 hours 25 minutes and the shortest was 1 hour 25 minutes with a mean of 11.9 ± 8.0 hours. two (2.1%) patients needed repeat doses application to patient care • this data can be compared with other prostaglandins in recent use, like misoprostol. • sulprostone can be safely used for termination of pregnancy in patients with a previous caesarean section. a n i ta k m o h a n , m a r i a m m at h e w a n d s y e d g r i z v i 308 after the initial dose of 1500 µgm. twenty-seven women (27.8 %) were nulliparous and five (5.2%) were of parity 8 or more. the highest parity in this study group was 12. figure 2 shows the relationship between parity and the time taken for expulsion. although nullipara showed the shortest induction-expulsion time and para 8 and above showed the maximum time, this difference was not found to be significant (p = 0.821) the rate of complete expulsion, defined as the simultaneous passage of the fetus and placenta was 22.7%. seventy-three women (75.3%) needed evacuation. no relationship was found between complete expulsion rate and age (p = 0.372) or parity (p = 0.643) of the women. there were 11 (11.3%) patients with previous caesarean sections, including two patients with two previous and one with three previous caesareans. sixtyseven percent of patients with previous caesarean sections needed evacuation whereas 78% of the group without a previous caesarean needed evacuation; this difference was not found to be statistically significant (p = 0.447). none of the patients with a previous caesarean section had a scar rupture or blood transfusion, whereas five patients without a previous caesarean required a blood transfusion. the requirement of analgesia in the study group was as follows: 47% of patients required analgesia with pethidine, 42% received no analgesia and the others received diclofenac or midazolam. the incidence of gastrointestinal side effects was limited and clinically acceptable. systemic side effects requiring discontinuation of therapy with sulprostone were not observed in this study. only 3 patients (3.06%) had itching and redness at the intravenous cannula site. two women in this group had a hysterotomy. the first patient was a gravida 2 para 1 with a previous caesarean section at 14 + weeks gestation and confirmed fetal death. she had a large cervical fibroid (10 cm diameter). she received 2 courses of sulprostone without any response hence a hysterotomy was done. the second patient was a gravida 4 para 2 at 16 weeks gestation, confirmed fetal death, with two previous caesarean sections. after 8 hours of sulprostone infusion the patient complained of severe abdominal pain. a laparotomy and hysterotomy was done. the previous scar was found to be intact. d i s c u s s i o n various medical methods have been described for the expulsion of the fetus in pregnancies with intrauterine fetal deaths: prostaglandin (pg) analogues (misoprostol, gemeprost or sulprostone) 2 with or without antiprogesterone priming (mifepristone). in our institution the pge2 analogue, sulprostone, is used as a continuous infusion for management of second and early third trimester fetal deaths. intravenous, intramuscular and extra amniotic use of sulprostone has been described in the literature. intramuscular sulprostone has been effectively used for preoperative cervical dilatation in the first trimester with minor side effects, mainly abdominal pain. antiprogestin mifepristone given orally prior to intramuscular sulprostone facilitates termination of second trimester pregnancies by sulprostone alone without added side effects.1 our study did not use mifepristone. intramuscular sulprostone is no longer recommended for medical abortion due to its association with myocardial infarction.1 kunz et al. in his study of 160 women on second trimester pregnancy termination with intravenous (iv) sulprostone found a mean induction-expulsion interval of 16h 56min. our primary end point, i.e. induction-expulsion time interval, was 11.9 ± 8.0 hours. haemorrhage occurred in 6% of our patients compared to 7.5% in kunz’s study.3 jain and mishell defined ‘complete expulsion’ as expulsion of both the fetus and the placenta without operative assistance.4 the rate of complete expulsion in our study was 22.7 % compared to 32% in jain and mishell’s study. the risk of haemorrhage is 4 in 1,000 at more than 20 weeks.5 we had five patients who required blood transfusion as a result of excessive bleedfigure 1: age distribution u s e o f i n t r av e n o u s s u l p r o s t o n e f o r t h e te r m i n at i o n o f p r e g n a n c y w i t h f e ta l d e at h i n s e c o n d a n d e a r ly th i r d tr i m e s t e r o f p r e g n a n c y 309 ing with prolonged retention of the placenta. caring for pregnancy with a previous uterine scar is always a challenge. no matter what method is used for termination, there is a greater risk of uterine rupture in these patients than in those women without a scar. prostaglandins are still a reasonably safe and predictable method of termination of pregnancy even in cases of previous caesarean section. women should be appropriately counselled about the risks and consequences and supervised closely in labour.6 shapira et al., in their study of second trimester abortion by extra-amniotic prostaglandin infusion in 282 women including 35 cases with previous caesarean section, did not observe any case of uterine rupture.7 there are few case reports of uterine rupture after use of sulprostone with fetal deaths in second and third trimester in a scarred uterus.6, 8 out of the 12 women with previous caesarean sections in our study, there was no case of uterine rupture. side effects including nausea, vomiting and diarrhea are characteristics of prostaglandin administration and are due to prostaglandin’s stimulatory effect on the gastrointestinal tract. gastrointestinal side effects were minimal in our study. only 3% patients had itching and redness at the cannula site, which, however, did not warrant a discontinuation of the therapy. cardiovascular disease, liver/kidney disease and bronchial asthma are contraindications for the use of sulprostone as suggested by the manufacturer. cardiac arrests have been reported with bolus dose of iv sulprostone of 30µgm.9 gemund et al. have reported the use of continuous low-dose sulprostone intravenous for pregnancy termination in 30 women with severe preeclampsia and eclampsia.10 this study, including two patients with a severe deterioration of pulmonary function and one maternal death after induction, does not permit definitive conclusions regarding safety in such patients. patients with hypertension, heart disease and bronchial asthma were not included in our study. c o n c l u s i o n our study showed that intravenous use of sulprostone was both safe and effective in the termination of pregnancy with fetal death in second and early third trimester of pregnancy; however it requires continuous intravenous access and close monitoring of maternal vital signs. r e f e r e n c e s 1. ho pc, ma hk. termination of second trimester pregnancy with sulprostone and mefipristone: a randomized double-blind placebo-controlled trial. contraception 1993; 47:123-129. 2. ngai sw, tang os, ho pc. prostaglandins for induction of second trimester termination and intrauterine death. best pract res clin obstet gynaecol 2003; 17:765-775. 3. kunz j. experiences with pregnancy termination in the second trimester in a peripheral hospital. practice 2004; 93:27-28. 4. jain jk, mishell dr. a comparison of intravaginal misoprostol with prostaglandin e2 for termination of second trimester pregnancy. new eng j med 1994; 5:290293. 5. national evidence based clinical guideline no: 7. the care of women requesting induced abortion. summary of recommendations. london: rcog press, 2004. p. 18. 6. prasad rn, ratnam ss. uterine rupture after induction of labour for intrauterine death using the prostaglandin e2 analogue sulprostone. aust n z j obstet gynecol 1992; 32:282-283. 7. shapira s, goldberger s, beyth y, fejgin m. induced second trimester abortion by extra-amniotic prostaglandin infusion in patients with a cesarean scar: is it safe? acta obstet gynecol scand 1999; 78:511-514. 8. corrado f, d’anna r, cannata ml. rupture of the cervix in a sulprostone induced abortion in the second trimester. arch obstet gynecol 2000; 264:162-163. 9. chen fg, koh kf, chong ys. cardiac arrest associated with sulprostone use during caesarean section. anaesth intensive care 1998; 26:298-301. 10. van gemund n, deboer ma, van selm m, scherjon sa, kanhai hh. sulprostone for pregnancy termination in women with severe preeclampsia. hypertens pregnancy 2002; 21:115-122. figure 2: induction-abortion/delivery interval in different parity group march 2009.indd squ med j, april 2009, vol. 9, iss. 1, pp. 89-94, epub 16th mar 2009 submitted 31st aug 08 revision req. 18th nov 08, revision recd. 6th dec 08, accepted 7th dec 08 post-traumatic abdominal aortic aneurysms are relatively uncommon. we re-port a patient with post-traumatic pseudo-aneurysm of the abdominal aorta, which presented with life-threatening complications due to its communication with the portal venous system. this patient is important to report because of the unusual problems encountered during his management, especially during attempts at percutaneous embolisation of the fistula. c a s e r e p o r t a 35-year-old man was stabbed in the right upper quadrant of the abdomen. an exploratory laparotomy revealed a tear in the left lobe of the liver that was sutured, and a retroperitoneal haematoma in the upper abdomen which was left undisturbed. his postoperative course was uneventful and he was discharged on the tenth postoperative day. five days later, he had a small amount of haematemesis which stopped spontaneously. after that, he had recurrent episodes of haematemesis once or twice a week. none of these was associated with hypotension, nor did he require hospitalisation or blood transfusions. two months after the initial injury, he presented at the department of gastrointestinal surgery and liver transplantation of the all india institute of medical sciences with a history traumatic aorto-mesenteric-portal fistula: percutaneous management case report *rajeev jain,1 girish k pande,2 peush sahni,2 dev n dwivedi2 c a s e r e p o r t اجللد طريق عن العالج : يّ حِ الرَضْ ٌّ البَابِيّ يّ املَساريقِ رِي بْهَ الناسور األَ حالة تقرير دويفدي ديف ، ساهني باند ، بوش جيريش ، راجيف جني مع دموي وصدمة يعاني من تقيؤ ــنة 35 س عمره للعلوم الطبية رجل الهند كل معهد الى جاء البطن في جرح قاطع ــهرين من ش امللخص: بعد البطني األبهر في دَمٍ كاذِبَة مُّ أَ بني يربط ناسورا كبيرا ــفت كش البطنية األوعية وتصوير للبطن ــب َوسَ احملُ يٌّ عِ طَ َقْ ويرٌ امل التَصْ . البابِيّ مِ الدَّ طِ غْ ضَ فَرْطُ الناسور الستئصال عملية نهائية إجراء ثم ومن الدموي ، مت تثبيت الضغط اجللد حيث طريق ــور عن الناس اغلق . لْوِيّ العُ يُّ ــاريقِ َس امل الوَريدُ من فرع و واصالح العيب األبهري. الهند. ، حالة ، تقرير التدخل عمليات ، األبهر تصوير ، أم الدم الكلمات: األبهر ، مفتاح 1department of radiology, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; 2department of gastrointestinal surgery and liver transplantation all india institute of medical sciences, ansari nagar, new delhi, india *to whom correspondence should be addressed. email: rajeev.squ.edu.om abstract two months after a stab injury to the abdomen, a 35-year-old male presented at the all india institute of medical sciences with haematemesis, shock and portal hypertension. computed tomography of the abdomen and abdominal angiography revealed a large fistulous communication between an abdominal aortic pseudoaneurysm and a branch of the superior mesenteric vein. the fistula was occluded percutaneously, which allowed the patient to stabilise haemodynamically and, finally, to undergo a definitive surgical excision of the pseudoaneurysm and repair of the aortic defect. keywords: aorta; trauma; aneurysm; aortography; interventional procedures; case report; india. 90 r a j e e v j a i n , g i r i s h k pa n d e , p e u s h s a h n i a n d d e v n d w i v e d i 2 of progressively increasing abdominal distension for one week, decreased urine output for three days and a large bout of haematemesis just prior to admission. at the time of examination he was anxious and anaemic. he was tachycardiac (140/minute), hypotensive (systolic 70mmhg), and tachypnoeic (36/minute). there were tense ascites and an upper abdominal bruit. all his peripheral pulses were palpable and equal in volume. a diagnostic paracentesis revealed straw-coloured fluid, and the nasogastric aspirate showed fresh blood. his haemoglobin was 7 g/dl, blood urea 241 mg/dl, serum creatinine 3.5 mg/dl, serum sodium 129 meq/ dl and serum potassium 6.6 meq/dl. the serum bilirubin was 0.7 mg/dl, alkaline phosphatase 313 u/l, serum aspartate aminotransferase/serum alanine aminotransferase (ast/alt) 97/108 u/l [table 1], and the prothrombin time was markedly prolonged (more than 60 seconds; control of 12 seconds). blood gas analysis showed metabolic acidosis. he was resuscitated with intravenous crystalloids and blood transfusions. endoscopy showed congested and oozing gastric mucosa, but no gastro-oesophageal varices. a large volume paracentesis was done to improve the patient’s respiratory status. despite this, he remained oliguric, acidotic, tachypnoeic and haemodynamically unstable. the ascites re-accumulated rapidly (within hours). administration of fresh frozen plasma improved his prothromin time to within 5 seconds of the control value. a contrast enhanced computed tomography scan showed massive ascites. there was a dilated, tortuous vascular channel anterior to the aorta at the level of the origin of the renal arteries. this structure (pseudoaneurysm) was in direct communication with a branch of the superior mesenteric vein (smv). the draining superior mesenteric and portal veins were dilated (2.5cms diameter) and showed marked enhancement with contrast [figure 1]. the liver was markedly hyperdense compared to the spleen, which showed little enhancement. the kidneys showed poor enhancement and the aorta below the site of abnormality had a smaller lumen, indicating a shunt from the aorta into the portal venous system, resulting in ‘functional’ portal hypertension. an abdominal angiogram confirmed the presence figure 1: contrast enhanced scan of the abdomen at the level of the renal vessels shows the following structures. [1] aorta, [2] a large, vascular channel (pseudoaneurysm) just anterior to the aorta, [3] the draining branch of the smv, [4] dilated smv, and [5] retrograde flow into splenic vein. note the presence of gross ascites and the differential enhancement of the liver and spleen. the punctate high-density structures in the head of the pancreas represent dilated venules secondary to high-pressure retrograde flow in the mesenteric-portal venous system days after embolisation 0 1 2 5 12 15 urea (mg/dl) 212 209 201 117 12 12 serum creatinine (mg/dl) 2.3 3.2 3.4 1.7 0.6 0.6 serum bilirubin (mg/dl) 0.8 0.8 0.7 0.7 0.7 0.7 serum alkaline phosphatase (u/l) 332 330 412 504 653 290 aspartate aminotransferase (u/l) 481 5730 2090 147 52 36 alanine aminotransferase (u/l) 436 2080 1295 365 106 23 table 1: liver and renal function tests after embolisation 91 tr au m at i c a o r t o m e s e n t e r i c p o r ta l f i s t u l a : p e r c u ta n e o u s m a n a g e m e n t of an 8mm wide communication between the aorta (at the level of the origins of the renal arteries) and a large pseudoaneurysm. the latter, in turn, was draining through a 1cm wide defect into a dilated (1.5cm) branch of the smv [figures 2a and 2b]. as an emergency measure, it was decided to attempt an occlusion of the aortic opening of the pseudoaneurysm, with the possibility of encouraging thrombosis of the abnormal vascular channel. an 8mm diameter balloon catheter was placed across the aortic end of the pseudoaneurysm, and the balloon gently inflated until a waist was identified, to block the aortic opening temporarily [figure 3], and with the hope of inducing thrombosis of the pseudoaneurysm. over the next 6-8 hours the patient became normotensive, his urine output increased, he did not require further paracentesis and his respiratory parameters improved. a follow-up angiogram after 12 hours revealed a patent fistulous tract. an embolisation of the fistula was attempted using large diameter coils. two 12mm diameter 3.5-turn platinum coils were placed at the junction of the branch vein and the smv. this was followed by release of multiple steel coils into the pseudoaneurysm [figure 4a]. this resulted in cessation of the blood flow through the fistula into the smv [figure 4b]. the abdominal bruit disappeared and the patient had a rapid clinical recovery with resolution of the ascites. the serum biochemistry also showed a gradual but sustained improvement [table 1]. as the ascites disappeared, a small, ill-defined, non-expansile lump became palpable in the epigastric region. ten days later, the abdominal bruit reappeared. figure 2: abdominal aortogram, catheter tip at l1 vertebral level (a) lateral, and (b) anteroposterior projections. angiogram demonstrates a large fistulous communication between the aorta and a branch of the smv, at the l2 vertebral level. most of the injected contrast is diverted into the portal venous system, with hardly any flow into the renal arteries. the superior mesenteric and portal veins are grossly dilated. numeric labelling in the figures indicates the same structures as in fig. 1. ([6] portal vein) 92 r a j e e v j a i n , g i r i s h k pa n d e , p e u s h s a h n i a n d d e v n d w i v e d i 2 angiography demonstrated recurrence of a small amount of flow across the fistula and into the smv. release of more steel coils into the pseudoaneurysm resulted in cessation of flow into the smv, but a small amount of flow persisted through the aortic opening into the pseudoaneurysm. therefore, the patient was offered a surgical repair. he, however, refused surgery at that time due to social reasons. he was discharged from the hospital with normal renal and liver function tests. he was readmitted 3 weeks later and had remained well during this period. the abdominal lump and bruit were still present but there was no ascites. the haemogram, renal and liver function tests were within normal limits. an ultrasound doppler study confirmed the persistence of blood flow across the aortic opening into the pseudoaneurysm. however, the superior mesenteric and portal venous blood flow was normal with no evidence of arterial pulsations. the patient underwent surgical exploration through a midline laparotomy. a 4 x 5cm size retroperitoneal mass was palpated. the mass was densely adherent to the smv. the abnormal communication was successfully excised with repair of the aorta and the smv. postoperatively, the patient had an uneventful recovery. at follow-up clinical examinations 2 and 4 months after the surgical procedure, his renal and liver functions were normal, and doppler studies on both occasions did not demonstrate any recurrence of the fistula. d i s c u s s i o n a number of patients with aortic injury exsanguinate prior to reaching a hospital. the mortality has been reported to be up to 70% even among those who survive long enough to undergo surgery. these injuries are often associated with other visceral and vascular injuries of the abdomen that may obscure the diagnosis. in some patients, a fistulous communication may occur between the aorta and a major vein, either as a result of trauma or spontaneous rupture of a pseudoaneurysm. this may control the aortic bleeding and might lead to the diagnosis being missed at the initial laparotomy.1 such patients usually survive the initial injury and may present weeks to months later, with manifestations of portal hypertension or congestive heart failure depending on the site of communication the portal system or the vena cava.2 we came across only four previous reports in the literature of traumatic aorto-portal fistulae. in one patient, a preoperative angiogram demonstrated the abnormality, which was corrected surgically.3 two patients presented with signs of portal hypertension, 14 and 18 months after the initial laparotomy. the aorto-portal fistulae in these patients were managed surgically,4 and with angiographic embolisation,5 respectively. the fourth patient had presented one year after the initial laparotomy, with a two months’ history of melaena, intermittent haematemesis and signs of right heart failure, and was treated surgically.6 in our patient, the aortic injury was overlooked at the initial laparotomy. the recurrent gastrointestinal bleeding and the gradually progressive abdominal distension preceding his presentation at our institution suggested a progressive increase in the blood flow across the fistula leading to severe ‘functional portal figure 3: angiographic balloon dilatation catheter inflated across the aortic opening. the site and size of the opening are identified by the waist of the balloon (arrow). the distal part of the balloon, tip and coiled guidewire are across the aortic opening within the pseudoaneurysm 93 tr au m at i c a o r t o m e s e n t e r i c p o r ta l f i s t u l a : p e r c u ta n e o u s m a n a g e m e n t hypertension’, and prerenal azotaemia compounded by hypovolaemia due to multiple episodes of haematemesis. the gastrointestinal bleeding was the result of marked congestion of the gastric mucosa a picture akin to severe portal hypertensive gastropathy. however, the absence of varices suggests that there was a rapid increase in the blood flow across the fistula over a few days prior to his presentation to us. angiographic management of the aorto-mesenteric-portal fistula presented an interesting challenge. the ideal technique for occlusion of a similar fistula in a more peripheral location would have been placement of a covered metallic stent graft. however, in this case, the site of the fistula at the level of renal arteries, and in close proximity to the origin of the superior mesenteric artery, precluded the use of a covered stent graft. the next option could have been a detachable balloon, but a balloon large enough to occlude the 4cm diameter pseudoaneurysm was not available. the presence of rapidly accumulating large volume ascites prevented pre-embolisation percutaneous transhepatic occlusion of the junction of the branch vein with the smv. therefore, to tide over the immediate crisis, we inflated a balloon catheter across the aortic opening of the fistula. this was successful in occluding the opening, and the patient’s condition stabilised. subsequently, the pseudoaneurysm was successfully embolised with multiple metallic coils and the patient improved rapidly. however, the aortic end of the pseudoaneurysm could not be fully obliterated due to the rapid flow and its large size. this resulted in persistent blood flow into the pseudoaneurysm (but not into the mesenteric vein) with reappearance of a figure 4a: lateral projection shows large diameter platinum coils occluding the junction of the branch vein with the smv (arrow), and multiple steel coils within the pseudoaneurysms (arrowheads) figure 4b: abdominal aortogram performed after embolisation of the fistula with steel coils, showed good flow in the distal aorta, with filling up of the major branches. the pseudoaneurysm (arrows) showed minimal filling from the aortic opening. there was no flow of contrast into the portal venous system. good flow of contrast is now shown in both renal arteries (arrowheads) 94 r a j e e v j a i n , g i r i s h k pa n d e , p e u s h s a h n i a n d d e v n d w i v e d i 2 bruit necessitating surgical repair. though we did not attempt this, an injection of thrombin solution has been used successfully to effect complete thrombosis of pseudoaneurysms.7 in retrospect, two alternative techniques could have been employed for occlusion of the fistula. the first was the placement of an atrial septal defect occluder across the aortic opening; the potential drawbacks of this technique would have been the possibility of occluding the renal artery origins, and prevention of any subsequent surgical repair of the aortic defect. theoretically, it should also have been possible to perform a transjugular transhepatic approach into the smv (similar to a transjugular intrahepatic portasystemic stent shunt [tipss]) followed by placement of a large diameter covered stent across the opening of the branch vein into the smv, prior to transaortic embolisation of the pseudoaneurysm; however, we did not have the expertise for performing tipss at our institution. also, this approach would have resulted in a permanently dilated (2.5cm diameter) segment of the smv (due to the implanted metallic stent), with the potential for thrombosis and infection. after successful embolisation, the serum transaminases increased [table 1] and then gradually normalised. this probably happened due to a relative ischaemia secondary to the disruption of arterial blood flow through the portal vein. the subsequent normalisation suggested that the hepatic arterial flow had returned to normal volume. unlike the previous case of aorto-portal fistula treated successfully by embolisation,5 in our patient angiographic embolisation did occlude the fistula, but could not block the large aortic opening of the pseudoaneurysm. however, it helped to stabilize the patient, restore normal liver function and allowed a delayed elective surgical procedure. to conclude, post-traumatic aorto-portal fistula is a rare complication. this patient presented with secondary functional portal hypertension, and shock due to the steal phenomenon because of the large diameter, high-flow aorto-mesenteric-portal fistula. unconventional percutaneous techniques had to be employed to occlude the fistula, which subsequently permitted elective surgery. c o n c l u s i o n this report describes the rare condition of post-traumatic aorto-mesenteric-portal fistula with functional portal hypertension and its emergent radiological management as a bridge to definitive surgical therapy. the techniques involved in the successful radiological management were dictated by the location of the large fistulous communication in proximity to origins of important vascular structures, which could not be occluded, hence the difficulty encountered in using standard occlusion devices. this in turn prompted the use of unconventional equipment and procedures in an emergent setting. a c k n ow l e d g m e n t s this work was performed at the departments of radiodiagnosis and gastrointestinal surgery and liver transplantation at the all india institute of medical sciences, ansari nagar, new delhi, india. r e f e r e n c e s 1. robertson g. combined stab wounds of the aorta and vena cava of the abdomen. arch surg 1967; 95:12-15. 2. saunders ms, riberi a, massullo ea. delayed traumatic superior mesenteric arteriovenous fistula after a stab wound: case report. j trauma 1992; 32:1016. 3. buscalgia lc, blaisdell fw, lim rc jr. penetrating abdominal vascular injuries. arch surg 1969; 99:764-9. 4. little jm, sheldon dm, mills fh. traumatic aorto-portal vein fistula: repair using intraperitoneal hypothermia. am surg 1968; 34:350-3. 5. raabe r, lawrence pf, luers pr, miller fj. radiographic and clinical findings in unusual abdominal aortic aneurysms. cardiovasc intervent radiol 1986; 9:176-81. 6. epstein bm, bocchiola fc, andrews jc, bester l. case report: traumatic arterio-venous fistula involving the portal system. clin radiol 1987; 38:91-3. 7. krüger k, zähringer m, söhngen f-d, gossmann a, schulte o, feldmann c, et al. femoral pseudoaneurysms: management with percutaneous thrombin injections—success rates and effects on systemic coagulation. radiology 2003; 226:452 epidemic infections and their relevance to the gulf -and other arabian peninsula countries epidemic infections and their relevance to the gulf and other arabian peninsula countries euan m. scrimgeour squ journal for scientific research: medical sciences 2003 vol 5, no. –2, –4 ©sultan qaboos universit y e d i t o r i a l department of medicine, college of medicine and health sciences, sultan qaboos university, po box 35, al-khod-123, sultanate of oman. email: scrim@squ.edu.om the strategic location of the arabian peninsula between africa, asia and europe, has since early historical times drawn travellers, seafarers, and merchants to this part of the middle east. it is inevitable that importation of communicable diseases should be a feature of such population movements. in saudi arabia, this has been demonstrated repeatedly over past decades, with epidemics occurring during the annual hajj, when over a million pilgrims from more than 80 countries congregate together with a similar number of local worshippers for a week in mecca and medina. plague used to break out almost every year until 98,1 and other frequent outbreaks have included smallpox,2 cholera,3 and meningococcal infection.3,4 the latter has continued to pose a problem despite the use of bivalent (a,c) vaccination for intending pilgrims, and two recent meningococcal outbreaks in 2000 and 200 caused by new serogroups required planning to introduce quadrivalent (a,c,y, w35) vaccination in the future.5 all arabian peninsula countries have been subject to outbreaks of introduced communicable diseases caused by various micro-organisms, although these have not always been so well documented as the saudi epidemics. parasitic infections have not posed a significant threat in recent decades except perhaps, falciparum malaria. it likely that malaria was introduced to the western region of saudi arabia and the united arab emirates in the very remote past since a large proportion of inhabitants of oases have one or more red cell markers which confer resistance, e.g., thalassaemia or the sickle cell trait.3 suitable anopheles mosquito vectors are present in all countries in the region. although effective malaria-control programmes have been implemented in most countries in the region, the emergence of chloroquine-resistant falciparum malaria contracted overseas has created a new concern, and this has been noted in saudi arabia,3 kuwait,6 oman,7 and the united arab emirates.8 leishmaniasis occurs widely in the middle east. the cutaneous form causes minor morbidity in a relatively immune population, but the occasional complication of systemic infection, especially in the non-immune, became significant during operation desert storm when eight american servicemen stationed in the eastern province of saudi arabia developed visceral leishmaniasis after leishmania tropica infection.9 the usual species causing visceral leishmaniasis or kala azar in the middle east is l. infantum. (this is the probable cause of kala azar in oman.10) as a result of exposure of overseas troops to sandfly vectors of leishmaniasis during the recent war in iraq, thousands of potential blood donors among the american troops were excluded as future donors. it is probable that schistosomiasis mansoni and haematobium which are widely prevalent in the middle east, were introduced from the nile valley of egypt in prehistoric times to saudi arabia, yemen and probably oman.11 snail vector control programmes in most countries have limited transmission, but the need to implement vector control indefinitely was demonstrated recently in dhofar province in oman, when suspension of regular mollusciciding resulted in a new epidemic of schistosomiasis mansoni.12 bacterial infections of potential epidemic significance to the arabian peninsula other than meningococcus infection, are few. small outbreaks of typhoid fever are not infrequent, but do not pose a major community threat. cholera has been introduced sporadically, e.g. by illegal immigrants from pakistan and afghanistan in oman in 2000, and occasionally in other countries. in scrimgeour editorial ������� ������� ���� ������ ���� �������� �������� ��������� ������� ����� mailto:scrim@squ.edu.om 2 s c r i m g e o u r the iraqi war, the breakdown in communicable disease control programmes led to epidemic cholera affecting 94 patients.13 there has been one documented outbreak of plague which spread from affected rodents on the saudi arabian-yemen border in 969 with 0 deaths.14 anthrax is rare in the region,3 but its use as a possible biological weapon has lately received notorious publicity. a second agent with potential as a biological weapon is the rickettsial infection q fever, caused by coxiella burnetii. this would have limited impact in the middle east where it is widely endemic, and there is widespread immunity, such as in saudi arabia3 and in oman.15 viruses are currently the most likely source of significant epidemic infections in the arabian peninsula. the era of air travel has increased the opportunities for introduction of viral infections with short incubation periods from distant locations. among these, viral haemorrhagic fevers (vhf) are regarded as one of the most serious risks. many of these are arbovirus infections (spread by arthropod vectors). there is always the possibility of importing ebola and marburg disease (caused by filoviridae viruses) from africa, lassa virus (an arenavirus) from west africa, or kyasanur forest disease (caused by a flavivirus) from india, but fortunately, these have never been reported. sources of infection of vhfs include rodent urine (lassa fever), hantaan virus disease (caused by a hantavirus, a genus of the bunyaviridae which is widely prevalent in neighbouring regions), vector ticks (kyasanur forest disease and crimean-congo haemorrhagic fever (which is caused by a nairovirus), possibly monkeys, (ebola) or aerosol spread (ebola, marburg disease, lassa fever, crimean congo haemorrhagic fever). accordingly all major hospitals in the region should have an admission policy for suspected vhf.16 crimean congo haemorrhagic fever is widely prevalent in the middle east wherever suitable vector idoxid (hard) ticks (especially hyalomma spp.) are present. the disease can also be spread from contact with blood or meat from an infected animal, or by aerosol. it was almost certainly already indigenous to the western province of saudi arabia,17 when over a decade ago, there was evidence of new introduction through jeddah seaport by imported small sudanese ruminants.18 similarly, because the vector ticks for cchf were already indigenous to oman,19 and no doubt also present in the united arab emirates, the first diagnoses of disease in a man in buraimi, northern oman, and at the same time in a patient in muscat, merely confirmed that the disease was present.20 luckily epidemiological studies elsewhere have shown that even when this zoonosis is prevalent in a country, human cases are infrequent and sporadic. alkhurma virus (family flaviviridae, genus flavivirus) is another emerging vhf in the middle east. it was reported to have caused haemorrhagic fever in saudi patients in 995,21 infection being contracted from viraemic vertebrates by tick bite, parenteral exposure to their blood, or drinking unpasteurised milk. other vhfs include the arbovirus infections yellow fever and dengue fever which cannot be spread directly from person to person but require a mosquito vector. arbovirus infections occupy a special category of communicable disease epidemiology. the majority are zoonoses which immediately poses a problem in control. when suitable vectors such as mosquitoes or ticks are already present in a region, there is always the risk of importation of a new virus infection. although dengue fever (which is strictly anthroponotic) had never occurred in saudi arabia, the presence of indigenous aedes aegypti mosquitoes in jeddah allowed dengue type 2 to become established in 994. (the first patient, a saudi, who died from dengue haemorrhagic fever, was under the care of the author). it was suspected that a viraemic indonesian visitor to jeddah had infected local mosquitoes which then infected the saudi population. it proved to be impossible to eliminate the vector mosquitoes, and surveillance thereafter showed that two other serotypes,  and 3 had become established in the community.22 fortunately, oman has so far escaped an epidemic of dengue fever despite its diagnosis in several patients who had visited india, possibly because the aedes spp. in northern oman is not a suitable vector. it is only in dhofar that a. aegypti is present (d. roberts, personal communication). rift valley fever, another arbovirus infection, has become of concern to the arabian peninsula. the responsible virus is a member of the phlebovirus genus, one of the five genera of bunyaviridae. its first detection on the arabian peninsula was southern saudi arabia and yemen in september, 2000. genetic analysis supported the belief that this zoonosis originated in east africa and was probably imported to saudi arabia and/ or yemen in livestock.23 the natural hosts include birds and animals including cattle, sheep, goats and camels, and the vectors include a. aegypti and other mosquitoes including anopheles and culex, as well as ticks. transovarian virus infection results in the new generation of infected arthopods, perpetuating infection in the community. infected mosquito eggs may survive several years in dry conditions. the disease causes haemorrhagic fever and necrotising retinitis with blindness, in a small percentage of patients. in livestock, it causes 3 abortions and mortality among young animals. in saudi arabia, a total of 884 hospitalized cases occurred with 24 deaths, whereas in yemen, it was estimated that ,087 cases occurred with 2 deaths.23 a major control programme in saudi arabia and yemen, was implemented with advice from international experts from who, the united states naval medical research unit (namru2) based in egypt, experts form oman, and the food and agriculture organisation. measures included limiting population movements in affected areas, wholesale slaughtering of potentially infected livestock, and control of arthropod vectors, and a limited vaccination programme. (an animal vaccine is routinely used to protect susceptible livestock, but supplies of an experimental inactivated vaccine for man are not commercially available.) the measures.appear to have been successful in localising the infection and preventing its spread elsewhere in the peninsula. at the time of writing (october 2003), cases have not been reported in oman. west nile virus a flavivirus spread from birds by culex mosquitoes to man, horses, and other mammals, occurs in the nile valley and around the mediterranean basin. it may well have been indigenous to the arabian peninsula as well, although it had never been detected here the virus has shown an ability to spread and become established wherever suitable mosquito vectors are present e.g. it became widespread in the usa following its accidental introduction to new york in 999. it was first reported in israel several years ago, and appeared to have been spread from geese and migrating storks.24 it has also been of concern in lebanon and jordan25,26 and poses a definite risk to gulf countries including oman. the virus has become more neuropathic in recent years with a higher rate of encephalitis. viruses other than arboviruses pose a threat of epidemic infection in the arabian peninsula. outbreaks of human-strain influenza a in jeddah regularly follow the hajj, presumably having been introduced by pilgrims.3 avian influenza is an important source of epidemic influenza in man. it is believed that the 98 pandemic of spanish influenza,27 and certain that the last three pandemic strains of influenza a virus-asian/57, hong kong/68, and russian/77, which originated in china, arose from interspecies transmission of viruses, from avian and other sources.28 reassortment of human and avian virus genes in a permissive host e.g. the pig has been proposed as an amplifying source of virus.29 genetic analysis of avian influenza viruses allows tracking of subtypes which may be associated with human infection. severe acute respiratory syndrome (sars), a newly identified epidemic disease, appeared for the first time in february, 2003 in hanoi, vietnam. the causal virus was later identified as a previously unrecognized species from the coronavirus family.30 (coronaviruses cause about one third of common colds.) the new virus spread locally and cases were confirmed in canada, china, hong kong, singapore and taiwan. the source of the virus was unknown, but later, it was reported to be similar to a coronavirus in civet cats (popular as food in south china). it became apparent that person-to-person spread was responsible for its rapid dissemination and a number of health workers contracted the disease, with fatalities in some cases. in oman, as in other arabian peninsula countries, the ministry of health implemented a comprehensive, extensive (and expensive) public health project to prevent introduction of sars. similar preventative measures were in force in other gulf countries. a large team of health personnel was at hand with 24 hour airport surveillance of visitors who may have been in contact with the infection, to evaluate and treat suspected cases. after many weeks of surveillance, the epidemic waned in the far east, and as no cases were encountered in oman, the project was concluded. there are other conditions apart from those mentioned, which could cause epidemic disease in the arabian peninsula. the bovine spongiform encephalopathy (bse) epidemic in the united kingdom, caused by a variant prion (an infectious amyloid protein) derived from the scrapie prion (which causes spongiform encephalopathy in sheep), and its passage into the food chain, resulted in the emergence of variant creutzfeldtjakob disease (v-cjd). in 990s bse was identified in oman in two cattle imported from the uk.31 the report that sporadic, endemic cjd occurred in oman32 gave further impetus to the decision to ban the importation of british beef into oman. similar bans were imposed in other gulf counries. surveillance for possible cases of v-cjd in omanis continues, but until now, no case has been diagnosed. nevertheless, prior to the ban, beef imports both fresh, frozen, and canned, may have been infected in some cases, and v-cjd may yet appear in oman and perhaps other gulf countries. this disease has an incubation period of several years, possibly decades. the evidence to date indicates that a major epidemic is unlikely, but the median incubation period has not yet been ascertained. the evidence suggests all countries of the arabian peninsula will have to remain constantly vigilant to the importation of recognised as well as new epidemic infectious diseases in the future. most of these countries have a well-established public health programme e p i d e m i c i n f e c t i o n s 4 of surveillance of diseases, and an effective system of preventing introduction of infections. the ministries of health and veterinary services within the gulf and neighbouring countries can collaborate to mutual advantage, sharing expertise in this field where many infections are zoonotic. r e f e r e n c e s . ghaznawi hi, khalil mh. health hazards and risk factors in the 406 (986) hajj season. saudi med j, 988, 9, 274–282. 2. corkhill nl. epidemic smallpox in jeddah: treatment with antibiotics. br med j, 95, 2, 663–667. 3. scrimgeour em. communicable diseases in saudi arabia: an epidemiological review. trop dis bull, 995, 92, r75–95. 4. memish za, ventkatesh s, ahmed qa. travel epidemiology: the saudi perspective. int j antimicrob agents, 2003, 2, 96–0. 5. memish za, alrajhi aa. meningococcal disease. saudi med j, 2002, 23, 259–264. 6. iqbal j, hira pr, al-ali f, sher a. imported malaria in kuwait (985–2000). travel med, 2003, 6, 324–329. 7. scrimgeour em, mehta fr, suleiman a.j.m. infectious and tropical diseases in oman: a review. am j trop med hyg, 999, 6, 920–925. 8. dar fk, bayoumi r, al karmi t, shalabi a, beidas f, hussein mm. status of imported malaria in a control zone of the united arab emirates bordering an area of unstable malaria. trans r soc trop med hyg, 993, 87, 67–69. 9. magill aj, grogl m gasser ra jr, sun w, ister cn. visceral infection caused by leishmania tropica in veterans of operation desert storm. n engl j med, 993, 328, 383–387. 0. scrimgeour em, barker dc, al-waily a, idris m, lambson b, nirmala v, et al. first identification of a leishmania species causing visceral leishmaniasis in the sultanate of oman, in a patient with aids. trans r soc trop med hyg, 998, 92, 356–357. . nozais jp. hypothesis sur le role du sahara prehistorique dans la reparatition de certaines affections parasitaires et hematologiques. bull soc pathol exot fil, 987, 80, 2–3. 2. scrimgeour em, koul r, sallam j, idris ma. resurgence of schistosomiasis mansoni in oman. tropical doctor, 200, 3, 85–86. 3. valenciano m, coulombier d, lopes cardozo b, colombo a, alla mj, samson s, et al. challenges for communicable disease surveillance and control in southern iraq april–june 2003. jama, 2003, 290, 654–658. 4. bahmanyar m. human plague episode in the district of khawlan, yemen. am j trop med hyg, 97, 20, 23–28. 5. scrimgeour em, al-ismaily sin, rolain jm, al-dhahry shs, el-khatim hs, raoult d. q fever in human and livestock (goat and sheep) populations in oman. ann n y acad sci, 2003, 990, –5. 6. scrimgeour em, el-azazy ome. viral haemorrhagic fever: admission policy for hospitals in the arabian peninsula. ann saudi med, 998, 8, 273–274. 7. el-azazy ome, scrimgeour em. crimean-congo haemorrhagic fever virus in the western province of saudi arabia. trans r s trop med hyg, 997, 9, 275–278. 8. hassanein km, el-azazy om, yousef hm. detection of crimean-congo haemorrhagic fever virus antibodies in humans and imported livestock in saudi arabia. trans r soc trop med hyg, 997, 9, 536–537. 9. scrimgeour em. crimean-congo haemorrhagic fever in oman. lancet, 996, 347, 692. 20. scrimgeour em, zaki a, mehta fr, abraham ak, albusaidy s, el-khatim h, et al. crimean-congo haemorrhagic fever in oman. trans r soc trop med hyg, 996, 90, 290–29. 2. charrel rn, de lamballierie x. the alkhurma virus (family flaviviridae, genus flavivirus): an emerging pathogen responsible for haemorrhagic fever in the middle east (in french). med trop (mars), 2003, 63, 296–299. 22. fakeeh m, zaki am. virologic and serologic surveillance for dengue fever in jeddah, saudi arabia 994–999. am j trop med hyg, 200, 65, 764–767. 23. shoemaker t, boulianne c, vincent mj, pezzanite l, alqahtani mm, al-mazrou y, et al. genetic analysis of viruses associated with emergence of rift valley fever in saudi arabia and yemen. emerg infect dis, 2002, 2, 45–420. 24. malkinson m, banet c, weisman y, pokamunski s, king r, drouet mt, et al. introduction of west nile virus in the middle east by migrating white storks. emerg infect dis, 2002, 4, 392–397. 25. batieha a, saliba ek, graham r, mohareb e, hijazi y, wijeyaratne p. seroprevalence of west nile, rift valley, and sand-fly arboviruses in hashimiah, jordan. emerg infect dis, 2000, 6, 358–362. 26. mushaarrafieh u, brizr ar. west nile virus: reasons for concern in lebabon. j med liban, 200, 49, 6–64. 27. webster rg, sharp gb, claes ec. interspecies transmission of influenza viruses. am j resp crit care med, 995, 52, s25– 30. 28. capua i, alexander dj. avian influenza and human health. acta trop, 2002, 83, –6. 29. zhou n, he s, zhang t, zou w, shu l, sharp gb, webster r. influenza infection in humans and pigs in southeastern china. arch virol, 996, 4, 649–66. 30. abdullah as, tomlinson b, cockram cs, thomas gn. lessons from the severe acute respiratory syndrome outbreak in hong kong. emerg infect dis, 2003, 9, 042–045. 3. scrimgeour em, chand pr, kimber k, brown p. creutzfeldt-jacob disease in oman, report of two cases. j neurol sci, 996, 42, 48–50. 32. carolan dj, wells ga, wilesmith jw. bse in oman (letter). vet rec, 990, 26, 92. s c r i m g e o u r references march 2007 vol 7 isuue 1 final without suicide .indd abstract objective: in view of the large number of pregnancies complicated by neural tube defect (ntd) in khuzestan, south west iran, this study assesses the prevalence of ntd and its ecological and social factors. methods: this is a retrospective study, based on medical documents using an analytic assessment of ntds in pregnant women attending the jundi shapur university hospitals in ahvaz from 2 march 2002 to 20 march 2004. results: the total number of pregnant women was 3,262 and 56 pregnancies were complicated with ntd. a large number of the infants with ntds were female (70%) and the most common anomaly was anencephaly. the prevalence was 4.2 in ,000 births. the percentage in primigravida was 42.6% and in multigravida 57.4%. the main risk factor for ntd was age of the mother, those between 2 and 30 being the most affected. consanguinity is the second risk factor with 3% of couples who were close relatives. other socio-demographic factors were also significant. conclusion: this retrospective study confirms clinical observation that pregnancies complicated by ntd in khuzestan are common. there are various ecological and social factors that correlate with the prevalence of ntd. keywords: neural tube defect, social and ecological factors, retrospective study, khuzestan, iran, prevalence and correlates of neural tube defect in south west iran retrospective analysis *ahmad behrooz, mohammad h gorjizadeh sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© neural tube defects (ntds) are among the most common defect of human con-genital malformations, affecting 0.6 per 1,000 live births in the united states, where there are approximately 4,000 ntd complicated pregnancies annually.1 spina bifida and anencephaly are the most commonly reported ntds, which affect 4,000 pregnancies resulting in 2,500 to 3,000 births in the united states each year.2, 3 although its etiology remains a mystery, remarkable advances have been made in the understanding and prevention of ntds over the past few decades. department of obstetrics and gynecology, jondishapur university of medical sciences, 54 west 1st street kianpars, ahvaz, iran 6155815111 *to whom correspondence should be addressed. email: ahmadbehrooz@yahoo.com c l i n i c a l & b a s i c r e s e a r c h إيران غرب جنوب في به املرتبطة والعوامل األنبوب العصبي عيوب انتشار استعادي حتليل جورجيزادة ومحمد بهروز أحمد (جنوب غرب ــتان خوزس في العالقة ذات والبيئية االجتماعية والعوامل ، أثناء احلمل العصبي ــوب األنبوب عي ــار انتش مدى الهدف: تقييم ــص: امللخ عند العصبي عيوب األنبوب وتقييم حتليل في الطبية على الوثائق اعتمدت ــتعادية اس ــة دراس الطريقة: هذه ــارها. انتش لكثرة بالنظر إيران)، وذلك للحوامل الكلي العدد النتائج: كان .2004 20 مارس 2002 إلى 21 مارس من للفترة األهواز في شابور جندي جامعة املراجعات ملستشفى احلوامل ــارا انتش األكثر احلالة وكانت ،(70%) احلاالت أكثرية الرضع البنات ــكل ش العصبي. األنبوب في عيوبا لديهم أطفاال ولدن 56 حامال منهن ،13262 عمر هو خطورة األكثر 42.6 % . كان العامل (البكر) األولى للمرة احلوامل ــبة نس كانت .1000 4.2 لكل ــار االنتش وكان الدماغ، ــخ) (مس انعدام هي العوامل أن كما %31 منهم. في ظهر حيث زواج األقارب، الثاني اخلطورة عامل كان بينما ــنة، 30 س 21 و بني تقع تأثرا األكثر األعمار كانت أالم، حيث في العصبي عيوب األنبوب انتشار كثرة املالحظات السريرية حول االستعادية الدراسة هذه أيضا. اخلالصة: أثبتت مهمة والدميوغرافية االجتماعية العيوب. تلك بانتشار عالقة لها التي والبيئية االجتماعية العوامل مختلف خوزستان، وهناك االجتماعية والدميغرافية العوامل الفوليك، حامض العصبي، األنبوب الكلمات: عيب مفتاح a h m a d b e h r o o z a n d m o h a m m a d h g o r j i z a d e h 32 a number of risk factors are associated with ntds. a previous pregnancy with an ntd has the strongest association, with a relative risk of 10. there are strong ethnic and geographical associations with ntds.4 the most commonly cited causes for ntds include a deficiency in folate concentrations.5, 6 genetic susceptibility, environmental factors, in utero drug exposure, and/or abnormal metabolic pathways that lead to a failure of neural tube closure during fetal development has also been linked with ntds.7, 8 in view of the large number of pregnancies complicated by ntds in khuzestan and because of the many risk factors, such as socioeconomic status, nutritional deficiency, ethnicity, consanguinity, multiparity, geography and mutagens like chemical bombing in this region, this study aims to explore retrospectively the rate and associate factors for ntds in this particular region of iran. m e t h o d s the medical records of all pregnant women, including those with documented ntds, who attended the jundishapur university hospitals, in ahvaz, from 21 march 2002 till 20 march 2004, were reviewed. data regarding ntd variations, the gender of affected fetuses, maternal age, parity, any family relationship of the couple, previous affected pregnancies or wastage, and mother’s blood group and rhesus factor (rh) were looked for and recorded. moreover, the results were also analytically assessed. data were compared using chi square test: ρ-values < 0.05 were considered statistically significant. all analyses were performed using the statistical package for social science /pc+ software (version 7). the study was approved by the internal review board of the obstetrics & gynecology department at jundishapur university of medical sciences. r e s u l t s among 13,262 medical records of live births, 56 women had fetuses or newborns with ntds (4.2 per 1,000 births): anencephaly (n=30, 53.6%), spina bifida (n=15, 26.8%), meningocele (n=5, 8.9%), encephalocele (n=3, 5.4%), anencephaly plus meningo-myelocele (n=3, 5.4%). as for the gender factor, among 56 pregnancies affected with ntd, 39 (70%) were female and 17 (30%) were male. this difference is statistically significant (p<0.05). among the 56 women whose pregnancies were affected by ntds, 7 (12.5%) were 10-20 years old, 39 (69.7%) 21-30 years, while 10 (17.8%) were 3140 years old. as far as the parity factor was concerned, among the mothers whose pregnancies were affected by ntds, 24 (42.8%) women were primiparous and 32 (57.1%) were multiparous. there was no significant difference between the two groups (p=0.07). as for the family relationship of the couple, 31% of women with pregnancies affected by ntds were related to their husbands. fifty three (94.6%) of women had ntds for the first time in pregnancy, whereas only 3 (5.4%) women had a history of ntds in previous pregnancies. among 56 women with pregnancies affected by ntds, 10 (17.8%) had a history of one previous abortion and 6 (10.7%) had had more than one abortion. in terms of blood group and rh compatibility, the blood group b was the most represented and the blood group ab was the least in women with ntd affected pregnancies. most of the women were rh positive. a final correlate of ntds that was explored in this study is climatic condition. the data suggest that there is a temporal relationship between the frequency of ntd and prevailing hot weather. the present study unequivocally suggests that ntd is highest during the two seasons of spring and autumn and thus among births in late winter and early spring. d i s c u s s i o n ntds are thought to have multifactor etiology with environmental and genetic susceptibility, maternal age, nutritional intake, exposure to drugs and harmful material, geographic region and socioeconomic status.9 in this study, we reviewed medical records of all pregnant women with documented ntds, who attended our university hospitals between 21 march 2002 and 20 march 2004. among 13,262 women, 56 fetuses had ntds (4.2 per 1000 birth). this incidence is markedly higher (2 to 4 fold) than the prevalence reported elsewhere. worldwide, prevalence of ntds ranges from 1.4-2 per 1,000 live births.8-10 it is important to speculate on factors contributing to the high incidence of ntd in this population. it is possible that eight years of war (1980-1987) that affected this region may have led to the area being contaminated with mutagen substances. this issue would require more systematic study. p r e va l e n c e a n d c o r r e l at e s o f n e u r a l tu b e d e f e c t i n s o u t h we s t o f i r a n 33 in our study, the defect with highest frequency was anencephaly with 22.6 per 10,000 births, followed by myelomeningocele (11.3 per 10,000 births), meningocele (3.8 per 10,000 births) and encephaloceles (2.3 per 10,000 births). the rate is significantly higher than previously published studies. for example, hendricks11 in his study of a western population found a rate of anencephaly of 6.4 per per 10,000 births, spina bifida: 7.1 per 10,000 births, encephalocele: 1.1 per 10,000 births in 1999, leach et al12 reported 2.6 per 1,000 births, the prevalence of anencephaly in poland. a study from rosch et al. in 1999 reported 1.64 per 1000 births, the incidence of neural tube defects in magdeburg, germany.13 the incidence of ntds in oman is 1.25 per 1,000 births, according to study of rajab et al.14 there is some evidence to suggest that the female gender may be associated with a higher risk for ntds.15 two-thirds of newborns affected with ntds are female.16 in our study, 70% of new borns affected with ntds were female. the effect of maternal age on risk of ntds is generally considered to be small. when an association can be found, risk tends to be elevated in older or very young mothers.17 in our study, most women with pregnancies affected by ntds were 21 to 30 years old. although women aged 21-30 had more pregnancies affected by ntds, this seems to be due to a bias in our study, because the vast majority of the cases studied were in that age group. the effect of maternal parity on the risk of ntd is probably stronger than maternal age. studies have shown both a modest risk in mothers of parity three or more and an increased risk in primiparous mothers.18 we found no difference in occurrence rate of ntds between primiparous and multiparous mothers (p=0.02). most cases are the first affected child in their families, although inheritance of this trait is influenced by familial predisposition, which is due to its threshold hereditary patterns.16 in our study, most of the malformed fetuses were the first affected individuals in their big families. in about 30% of cases, parents of the child affected by ntds had first cousin relationships, so predisposition to these defects is increased. indeed, there is no clear inheritance pattern in a single family and the presence of more affected cases in a family shows a higher susceptibility in that particular family. women with a previous history of ntd birth have a 10 times increased risk for another ntd birth. however, the majority (95%) of ntd pregnancies occur in women without a previous history of ntd births.19 thus the prevention of the first occurrence is of real public health importance.20 the frequency of ntd is the highest during the two seasons of spring and autumn,15 so the defects are mostly seen in individuals born late in winter and early in the spring.6 in our study, the season in which ntds prevalence is highest was spring. with respect to neural tube development in the first trimester, in our analysis most affected fetuses born occurred with mothers who became pregnant early in the summer. obviously, the environmental temperature during summer in khuzestan is 50 degrees centigrade, which could affect the prevalence of ntds. as in the study made by rajab and colleagues in the royal hospital of oman in 1999, an environmental temperature of more than 48 degree centigrade was suggested to be risk factor in development of neural tube defects.14 this corroborates an animal study experiment, where pregnant mice, when exposed to high temperatures, had a high rate of ntds.21 c o n c l u s i o n because of the high incidence of ntds and especially anencephaly in khuzestan, it is recommended to institute a nationwide educational programme and to establish public health guidelines for the prevention of neural tube defects. over the last few decades, there has clearly been a substantial body of literature that supports the association of maternal use of multivitamins containing folic acid in early pregnancy and a reduced risk for offspring with neural tube defects. the rationale for the folate deficiency hypothesis is that prenatal supplementation with antioxidant vitamins containing folic acid decreases the incidence of birth defects, especially neural tube defects. other preventative measures ought to be systematically explored. a c k n ow l e d g me n t we express our appreciation to mrs. raana ghomi maibodi for her assistance in data collection. r e f e r e n c e s 1. nakano kk. anencephaly: a review. dev med child neurol 1973; 15:383-400. 2. mulinare j, erickson d. prevention of neural tube defects. teratology 1997; 56:17-18. 3. honein ma, paulozzi lj, mathews tj, erickson jd, a h m a d b e h r o o z a n d m o h a m m a d h g o r j i z a d e h 34 wong ly. impact of folic acid fortification of the us food supply on the occurrence of neural tube defects. jama 2001; 285:2981-2986. 4. harris ja, shaw gm. neural tube defects—why are rates high among population of mexican descent? environ health perspect 1995; 103:163-164. 5. maclone tg. central nervous system. in: sadler tw, editor. langman’s medical embryology. philadelphia: lippincot williams & wilkins, 1996. p. 385-390. 6. thomas ma. some malformations and diseases determined by multifactorial inheritance. in: nora jj, fraser fc, ed. medical genetics principles and practice. 4th ed. philadelphia: lea and febiger, 1989. p. 240-243. 7. lorber j. malformation of neural tube closure. in: larsen wj, human embryology. churchill livingstone, 1997. p. 22-95. 8. haslem ma. congenital anomalies of the central nervous system; in: behrman re, ed. nelson textbook of pediatrics. wb saunders, 2000. p. 1803-1806. 9. duncan s, merco s, lopez cendes i. repeated neural tube defects and valperate monotherapy suggest a pharmacogenetic abnormality. epilepsia 2001; 42:750-753. 10. thompson mw, mcinnes rr, huntington wf. prenatal diagnosis and fetal therapy. in: cunningham fg, gunt nf, leveno kj, gill strup lc, hauth jc, wenstrom kd, ed. williams obstetrics. 21st ed. mcgraw-hill, 2001. p. 956-960. 11. hendricks ka. neural tube defects along the texas mexico border; 1993-1995; am j epidemiology 1999; 149:1119-1127. 12. lech m. prevention using folic acid, a good method for reduction of neural tube defects in poland. przegl-lek 1999; 55:334-336. 13. rosch c. incidence of neural tube defects in the magdeburg administrative district. gesundheitswesen 1998; 60:563-566. 14. rajab a. neural tube defects and congenital hydrocephalus in the sultanate of oman. j trop pediatr 1998; 44: 300-303. 15. haslam rh. prenatal diagnosis. in: singer sam, ed. human genetics. wh freeman, 1985: 122-124. 16. gilman s. genetics disorders with multifactorial inheritance. in: thompson mh, mcinnes r, willard h, eds. genetics in medicine. philadelphia: wb saunders co, 1991. p. 349-357. 17. frey l, allen hauser w. epidemiology of neural tube defects. epilepsia 2003; 44(supp 3): 4-13. 18. elwood jm, little j, elwood jh. fetal loss. in: elwood jm, little j, elwood jh, eds. epidemiology and control of neural tube defects. vol 20 monographs in epidemiology and biostatistics. oxford: oxford university press, 1992. p. 324-334. 19. geisel j. folic acid and neural tube defects in pregnancy. j perinat & neonat nurs 2003; 17:268-279. 20. birnbacher r, messerschmidt am, pollak ap. diagnosis and prevention of neural tube defects. curr opin urol 2002; 12:461-464. 21. shin jh, shiota k. folic acid supplementation of pregnant mice suppresses heat-induced neural tube defects in the offspring. j nutr 1999; 129:2070-2073. 1 submitted 3 jan 23 1 revision req. 27 feb 23; revision recd. 5 mar 23 2 accepted 14 mar 23 3 online-first: march 2023 4 doi: https://doi.org/10.18295/squmj.3.2023.018 5 6 molecular and clinical features of heterogeneous vancomycin 7 intermediate staphylococcus aureus in tertiary care hospitals of south 8 india 9 sreejisha m,1 shalini shenoy m,1 suchitra shenoy m,1 dhanashree b,1 10 chakrapani m,2 *gopalakrishna bhat k1 11 12 departments of 1microbiology and 2medicine, kasturba medical college, mangalore, 13 manipal academy of higher education, manipal, karnataka, india 14 *corresponding author’s e-mail: gkbhat999@gmail.com 15 16 abstract 17 objectives: this study aimed to detect heterogeneous vancomycin-intermediate 18 staphylococcus aureus (hvisa) among methicillin resistant s. aureus (mrsa) isolated from 19 healthcare-associated infections and identify staphylococcal cassette chromosome mec 20 (sccmec) types. methods: isolation and identification of mrsa were done using standard 21 bacteriological methods. antimicrobial susceptibility testing was done using kirby-bauer disc 22 diffusion and macrolide-lincosamide-streptogramin b (mlsb) phenotypes identified using d 23 test. the minimum inhibitory concentration (mic) of vancomycin was determined using agar 24 dilution. hvisa were confirmed by modified population analysis profile-area under the curve 25 (pap-auc) test. sccmec types and panton-valentine leukocidin (pvl) were detected using 26 multiplex pcr. results: out of 220 mrsa stains, 14 (6.4%) were hvisa. none of the 27 mrsa isolate was vancomycin intermediate or resistant. all hvisa were susceptible to 28 linezolid and teicoplanin. macrolide-streptogramin b (msb) phenotype was present in 42.9% 29 hvisa. 92.9% hvisa strains had vancomycin mic in the range 1-2 µg/ml. majority of 30 hvisa and vancomycin susceptible mrsa were isolated from skin and soft tissue infections. 31 sccmec iii and iv were present in 50% and 35.7% hvisa respectively. 14.3% hvisa 32 harboured sccmec v. conclusion: the rate of hvisa among mrsa was 6.4%. mrsa 33 mailto:gkbhat999@gmail.com 2 strains should be tested for hvisa before starting vancomycin treatment. none of the isolates 34 was vancomycin intermediate or resistant. all the hvisa strains were susceptible to linezolid 35 and teicoplanin. the majority of hvisa were isolated from skin and soft tissue infections. 36 the majority hvisa harboured sccmec iii and iv. 37 keywords: mrsa; hospital infection; molecular typing; vancomycin 38 39 advances in knowledge 40 • to the best of our knowledge, this is the first report of heterogeneous vancomycin 41 intermediate staphylococcus aureus (hvisa) infections in tertiary care hospitals of 42 coastal karnataka, south india. 43 • this study showed high frequency of staphylococcal cassette chromosome mec 44 (sccmec) types iii and iv among hvisa. 45 application to patient care 46 • methicillin resistant staphylococcus aureus (mrsa) isolated from clinical specimens 47 should be tested for the presence of hvisa before starting vancomycin treatment. 48 • susceptibility of all hvisa strains to linezolid and teicoplanin. 49 50 introduction 51 methicillin resistant staphylococcus aureus (mrsa) continues to be an important pathogen 52 that can cause a variety of healthcare-associated and community-associated infections.1 53 although, vancomycin was the drug of choice for severe mrsa infections after its 54 introduction, the emergence of organisms with reduced susceptibility and complete resistance 55 has been a challenge in the treatment of such cases.2 mrsa with reduced susceptibility to 56 vancomycin includes heterogeneous vancomycin intermediate s. aureus (hvisa) and 57 vancomycin intermediate s. aureus (visa), both first reported in japan in 1997.3 the clinical 58 and laboratory standards institute (clsi) defines visa as s. aureus with vancomycin 59 minimum inhibitory concentration (mic) 4-8 µg/ml.4 hvisa shows mic of vancomycin in 60 the susceptible range (≤ 2 µg/ml) but, contains a subpopulation at the rate 10-5 to 10-6 with 61 vancomycin mic in the intermediate range (4-8 µg/ml).5 the prevalence of hvisa and 62 visa has increased worldwide from 4.68% and 2.05% in 2006 to 7.01% and 7.93% in 2014.6 63 a recent study from south india showed the prevalence of hvisa at 12.4%.7 64 65 3 mutations of genes associated with the cell wall, thickened cell wall, slow growth, and 66 reduced autolysis are believed to be responsible for reduced susceptibility of hvisa/visa 67 phenotypes to vancomycin.8 mutations in the walkr (sensor protein kinase/regulator), grasr 68 (glycopeptide resistance–associated sensor/regulator), and vrasr (vancomycin resistance 69 associated sensor/regulator) and genes are considered important.2,9,10 prolonged exposure to 70 vancomycin could induce these mutations.11 71 72 vancomycin therapy has been shown to be ineffective for infections caused by hvisa.2 73 therefore, detection of hvisa in the clinical specimens is essential before starting 74 vancomycin treatment. detection of hvisa among mrsa is a challenge for clinical 75 microbiologists, because it exhibits vancomycin mic in the susceptible range.2,5 the 76 antimicrobial susceptibility tests such as kirby-bauer disk diffusion, broth dilution, agar 77 dilution, and automated methods fail to detect hvisa.5 screening tests such as macro e-test 78 (met), vancomycin screen agar, and glycopeptide resistance detection (grd) e-test vary in 79 their sensitivity and specificity.10,12 population analysis profile-area under the curve (pap-80 auc), which is considered a reference method is labour intensive, expensive and 81 inappropriate for the routine clinical microbiology laboratories.12 82 83 staphylococcal cassette chromosome mec (sccmec) typing is being used for understanding 84 the epidemiology of mrsa infections. healthcare-associated mrsa (ha-mrsa) normally 85 harbours sccmec i, ii and iii. whereas, community-associated mrsa (ca-mrsa) harbours 86 sccmec iv, v and panton-valentine leukocidin gene (pvl).1,13 pantonvalentine leukocidin 87 is an important virulence factor in ca-mrsa.13 several recent studies have reported 88 overlapping of sccmec types between ha-mrsa and ca-mrsa.14,15 studies conducted in 89 europe, usa, australia and japan have shown presence of sccmec ii, iii, and iv among 90 hvisa.6 however, reports from india have shown predominance of sccmec v in hvisa.10,16 91 therefore, there are differences in the sccmec types harboured by mrsa in different parts 92 of the world. the objectives of the present study were to determine the rate of hvisa among 93 mrsa isolated from healthcare-associated infections (hais) and to identify the sccmec 94 types present in these strains. 95 96 methods 97 4 the present cross-sectional study was conducted on nonrepetitive mrsa strains isolated from 98 patients admitted in four tertiary care hospitals attached to a private medical college in 99 coastal karnataka south india during the period from february 2019 to march 2020. hais 100 were identified using centers for disease control and prevention (cdc) guidelines.17 101 102 isolation and identification of s. aureus was done using standard bacteriological methods.18 103 methicillin resistance was detected using cefoxitin (30 µg) disk diffusion method4 and 104 confirmed by detecting meca gene using pcr.19 s. aureus atcc 43300 and s. aureus atcc 105 25923 were used as positive and negative controls respectively. antimicrobial susceptibility 106 testing was done using the kirby-bauer disk diffusion. the following antibiotics (bd bbl™ 107 sensi-disc™ antimicrobial susceptibility test disks) were used: ciprofloxacin (5 µg), 108 clindamycin (2 µg), erythromycin (15 µg), gentamicin (10 µg), linezolid (30 µg), rifampicin 109 (5 µg), teicoplanin (30 µg) tetracycline (30 µg) and trimethoprim-sulphamethoxazole 110 (1.25µg/ 23.75 µg). results were interpreted as per clsi guidelines.4 s. aureus atcc 25923 111 was used as the control. 112 113 identification of macrolide lincosamide streptogramin b (mlsb) was done using d test. 4 114 mueller-hinton agar (mha) (himedia laboratories, mumbai, india) plates were lawn 115 cultured with test bacterial inoculum with turbidity matching mcfarland 0.5 standard 116 (bacterial count 1.5 x 108 cfu/ml). clindamycin (2 µg) and erythromycin (15 µg) disks 117 placed at a distance of 15 mm edge to edge on the inoculated plate. the plates were incubated 118 at 35°c for 16-18 h and the results were interpreted according to clsi guidelines.4 119 120 the mic of vancomycin to mrsa was determined using agar dilution method.4 mha agar 121 plates with range of vancomycin (sigma-aldrich corporation, st. louis, us) concentrations 122 (32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125 µg/ml) were prepared. two to three colonies of the test 123 organism grown on blood agar plate were inoculated into mueller-hinton broth (himedia 124 laboratories, mumbai, india) and incubated at 37°c for 4 to 6 h until the turbidity was 125 matched with mcfarland 0.5 standard. the broth culture was diluted 10-1 to prepare the 126 working inoculum (1.5 x 107 cfu/ml). 2 µl was spot inoculated on each plate. the plates 127 were incubated at 35°c for 24 h and observed for growth. the minimum concentration of 128 vancomycin inhibiting the bacterial growth was considered as mic and the results were 129 interpreted as per clsi guidelines.4 mrsa isolates with mic of vancomycin ≤ 2 µg/ml, 4-8 130 5 µg/ml and ≥ 16 µg/ml were considered vssa, visa and vrsa respectively.4 131 enterococcus faecalis atcc 29212, and s. aureus atcc 29213 were used as vancomycin 132 susceptible controls. e. faecalis atcc 51299 was vancomycin resistant control. 133 134 screening of mrsa for hvisa was done using brain heart infusion agar (bhia) (himedia 135 laboratories, mumbai, india) containing 16 g/l pancreatic digestion of casein and 4 µg/ml 136 vancomycin.12 the test organisms were grown in brain heart infusion broth till the turbidity 137 matched with mcfarland 0.5 and 2.0 standard. four 10 µl drops from each suspension were 138 spot inoculated on bhi screen agar plates and allowed to dry for 10 minutes. the plates were 139 incubated at 35°c for 48 h and observed for bacterial growth. an isolate was considered 140 hvisa if at least one drop had 2 or more colonies.12 s. aureus atcc 700698 (mu3 strain of 141 hvisa) and s. aureus atcc 29213 were used as a positive and negative controls 142 respectively. 143 144 confirmation of hvisa was done using the modified population analysis profilearea under 145 the curve (pap-auc) method.20 in brief, the test and control (mu3) were grown at 35°c for 146 4-6 hours in brain heart infusion broth, and the turbidity was matched with mcfarland 0.5 147 standard. (1.5 x 108 cfu/ml). the broth culture was further diluted 10-4 to achieve viable 148 bacterial count of 104 cfu/ml and used for inoculation.5 a 10 µl bacterial inoculum 149 was spread on bhi agar plates with a range of vancomycin concentrations (16, 8, 4, 2, 1, 0.5, 150 0.25, and 0.125 µg/ml). the inoculated plates were incubated at 35°c for 48 h and colonies 151 were counted. the log10 number of colonies was plotted against the concentrations of 152 vancomycin and the area under the curve (auc) was determined using graphpad prism 153 software version 9.0 (graphpad software usa).20 auctest /aucmu3 ratio was calculated and 154 used for the confirmation of hvisa. mrsa strains with auctest/aucmu3 ratio 0.9-1.3 were 155 considered hvisa [figure 1] and strains with auc ratio > 1.3 were considered visa.5 mu3 156 strain of hvisa (s. aureus atcc 700698) and s. aureus atcc 292l3 (vssa) were used as 157 positive and negative controls respectively. 158 159 sccmec types i-v and pvl in the test organisms were identified using multiplex pcr with 160 specific primers and controls.19,21 dna was extracted using qiagen dna extraction kit as per 161 manufacturer’s instructions. the principle of present multiplex pcr performed was based on 162 a previous study by zhang et al.19 multiplex pcr kit was purchased from qiagen, hilden, 163 6 germany. the list of primers used for the molecular detection and characterization of ha-164 mrsa isolates are listed in table 1. 165 166 a 50 μl pcr mixture containing 25 μl multiplex master mix (containing taq dna 167 polymerase, dntps and 1x qiagen multiplex pcr buffer with 6 mm mgcl2), 5 μl 10x 168 primer mix, 15 μl water and 5 μl dna extract was prepared in 0.2 ml pcr tubes. multiplex 169 pcr reaction was performed for 1 cycle of initial denaturation at 97°c for 5 minutes, 170 followed by 30 cycles of 30 seconds at 94°c, 30 seconds at 54°c and 90 seconds at 72°c, 171 with a final extension for 10 minutes at 72°c. the amplicons were analysed using 2% agarose 172 gel electrophoresis in 1x tris-acetate edta (tae) buffer. the electrophoresis was carried 173 out at 120 v for 90 minutes, and the gel was stained with ethidium bromide staining solution 174 for 30 minutes. the gel was then visualized under an ultraviolet (uv) illuminator, and the 175 size of the bands was compared with the 100 base pair ladder (bangalore genei private 176 limited, bengaluru, india). 177 178 sensitivity and specificity analyses were done to evaluate the performance of vancomycin 179 agar screen. the data were analysed using the statistical package for the social sciences 180 (spss) version 29.0 (ibm corp., chicago, illinois, usa). the rate of hvisa among mrsa 181 was expressed in percentage. the results were analysed using fisher’s exact test. p value of ≤ 182 0.05 was considered statistically significant. 183 184 this study had the approval of the institutional ethics committee, kasturba medical college, 185 mangalore. the isolates for the present study were collected from the clinical specimens 186 received at the laboratory for investigation. the samples were anonymized and the patient 187 details were not disclosed. therefore, informed consent was not obtained in the present 188 investigation. 189 190 results 191 out of 220 nonrepetitive strains of mrsa isolated form healthcare associated infections, 14 192 (6.4%) were confirmed hvisa by pap-auc and the remaining 206 (93.6%) were 193 vancomycin susceptible. vancomycin screen agar using both mcfarland 0.5 and 2.0 standard 194 inoculum density detected hvisa in 21(9.5%) mrsa isolates. this included 14 isolates 195 confirmed by pap-auc. the sensitivity and specificity of the screening method were 100% 196 7 and 96.6% respectively. however, the end point (minimum 2 colonies) was clear in the 197 screening method using mcfarland 2.0 standard inoculum. none of the isolates was visa or 198 vrsa. out of 14 hvisa, 10 (71.4%) and 4 (28.6%) were isolated from male and female 199 patient respectively. in case of 206 vancomycin susceptible mrsa, 133 (64.6%) and 73 200 (35.4%) were isolated from male and female patients respectively. the majority of hvisa 201 (6/14; 42.9%) were isolated from patients belonging to age group 61-70 years whereas 202 majority of vancomycin susceptible mrsa (48/206; 23.3%) were isolated from patients 203 belong to age group 41-50 years. 204 205 out of 14 patients infected with hvisa, 11 (78.6%) were diabetic, 13 (92.9%) were 206 previously hospitalized, 8 (57.1%) received previous vancomycin treatment and 8 (57.1%) 207 underwent surgery previously. the majority of hvisa and vancomycin susceptible mrsa 208 were isolated from skin and soft tissue infection. 21.4% of hvisa and 10.7% of vancomycin 209 susceptible mrsa were isolated from cases of bacteremia [table 2]. 210 211 table 3 shows the antimicrobial resistance profile of the test organisms. compared with 212 vancomycin susceptible mrsa more number of hvisa were resistant to antimicrobial agents 213 except trimethoprim-sulphamethoxazole. all the test organisms were susceptible to linezolid 214 and teicoplanin. more than 80.0% of the isolates were resistant to ciprofloxacin and 215 erythromycin. msb phenotype was more common in both hvisa (6/14; 42.9%) and 216 vancomycin susceptible mrsa (82/206; 39.8%). 92.9 % hvisa had vancomycin mic 217 ranging from 1 to 2 µg/ml [table 4]. for both hvisa and vancomycin susceptible mrsa 218 mic50 and mic90 were 1 µg/ml and 2 µg/ml, respectively. 219 220 results of sccmec typing are presented in table 5 and figure 2. the majority of hvisa and 221 vancomycin susceptible mrsa carried sccmec iii and iv. there was no significant 222 difference between hvisa and vancomycin susceptible mrsa with regards to sccmec type. 223 6.8% of vancomycin susceptible mrsa were nontypeable. pvl gene was detected in 2/14 224 (14.3%) hvisa and 57/206 (27.7%) of vancomycin susceptible mrsa isolates. 225 226 discussion 227 in this study we present the prevalence and molecular features of hvisa in four tertiary care 228 hospitals of coastal karnataka, south india. the hvisa phenotype was detected among 6.4% 229 8 of mrsa strains isolated from healthcare-associated infections. a recent systematic review 230 and meta-analysis has reported the rate of hvisa around the world.22 the hvisa phenotype 231 was reported in 82 studies on a total of 47,721 strains with an average prevalence of 4.6%. 232 this study showed that the prevalence of hvisa has increased over the last few years in 233 different parts of the world.22 three previous studies from india have reported the prevalence 234 of hvisa ranging from 2 to 12.4%.7,23,24 the differences in the prevalence of hvisa could be 235 due to geographical area of the study, sample size, patient population and testing methods. 236 increase in the rate of hvisa is a matter of concern. further, since hvisa is considered as 237 the precursor stage of visa,2,3 we may expect an increase in the rate of visa in the future. 238 239 in this study there was no association between hvisa and type of infections. factors such as 240 age, extended hospital stay, previous vancomycin treatment, diabetes mellitus, 241 instrumentation and surgery may increase in the risk of hvisa infections.2 in the present 242 study, more than 50 per cent of the patients infected with hvisa had risk factors such as 243 diabetes mellitus, previous hospitalization and vancomycin treatment. the clinical profile of 244 pvl positive cases was not different from the negative ones. 245 246 vancomycin treatment of hvisa infections may result in persistence of infection, greater risk 247 of complications and treatment failure.2,25 some researchers believe that hvisa arises as a 248 consequence of prolonged vancomycin treatment.25 studies have demonstrated that area under 249 curve/mic of vancomycin > 400 can bring about effective treatment.26 this can be achieved 250 if vancomycin mic is ≤ 1 µg/ml. the european committee on antimicrobial susceptibility 251 testing (eucast) classifies s. aureus with vancomycin mic >2 µg/ml as vancomycin 252 resistant.27 a previous study reported higher mortality among patients with hvisa infection 253 admitted in intensive care unit.28 in the present study, patients with hvisa deep infections 254 responded for vancomycin treatment. however, in cases where vancomycin toxicity 255 developed, vancomycin was replaced with teicoplanin. 256 257 identification of hvisa phenotype among mrsa is difficult.2,12 the screening methods vary 258 in sensitivity, specificity and validity. vancomycin screen agar method used in the present 259 study had sensitivity and specificity of 100% and 96.6% respectively. the pap-auc, which 260 is the reference method for the confirmation of hvisa is laborious.12 it may be difficult to 261 test all mrsa strains for hvisa. in this study, 92.9% of hvisa had vancomycin mic 262 9 ranging from 1 to 2 µg/ml. similar observations were made by other researchers too.10,29 263 therefore, we suggest mrsa strains with mic range 1-2 µg/ml could be chosen for 264 detection of hvisa phenotype. in critically ill patients with mrsa infection, hvisa 265 identification may have to be done upfront. in non-critical conditions, hvisa identification 266 may be carried out if clinical response is sub-optimal. 267 268 in this study, none of the mrsa was vancomycin intermediate or resistant. all hvisa and 269 vancomycin susceptible mrsa were susceptible to linezolid and teicoplanin. msb phenotype 270 was most common followed by imlsb (inducible clindamycin resistance). in routine disk 271 diffusion test, mrsa exhibiting inducible clindamycin appears resistant to erythromycin but 272 susceptible to clindamycin. if clindamycin is wrongly used for the treatment of infections 273 caused by such organisms, treatment failure occurs. therefore, hvisa strains resistant to 274 erythromycin and susceptible to clindamycin should be subjected to d test to detect the 275 possibility of inducible clindamycin resistance. 276 277 in this study, the majority of hvisa harboured sccmec iii and iv. this in contrast to the 278 previous indian studies which reported high frequency of sccmec v among hvisa.7,10,16 279 presence of hvisa harbouring sccmec iv, v and pvl in the present study is suggestive of 280 entry of ca-mrsa into hospitals. this also shows that molecular differences between ha-281 mrsa and ca-mrsa is blurring. although all hvisa strains in the present study could be 282 typeable, 6.8% vancomycin susceptible mrsa were nontypeable. it is possible that these 283 strains could harbour sccmec types not included in the present study. a recent study from 284 south india also reported nontypeable strains among clinical isolates of mrsa.30 285 286 the present study had some limitations. it is difficult to draw general conclusions based on 287 investigations conducted on small number of hvisa. a larger sample size would have given 288 better understanding of hvisa infections. multiplex pcr was designed for the detection of 289 sccmec types i-v only. additional genetic and molecular tests could have helped in better 290 understanding of the epidemiology hvisa. 291 292 conclusion 293 the rate of hvisa among mrsa was 6.4%. mrsa strains should be tested for hvisa 294 phenotype before starting vancomycin treatment. vancomycin agar screen with 4 µg/ml 295 10 vancomycin and mcfarland 2.0 inoculum could be used for screening of mrsa for hvisa. 296 however, confirmation needs pap-auc. none of the isolates was vancomycin intermediate 297 or resistant. all hvisa strains were susceptible to linezolid and teicoplanin. the majority of 298 hvisa were isolated from skin and soft tissue infections. sccmec iii and iv were 299 predominant among hvisa and vancomycin susceptible mrsa. 300 301 conflicts of interest 302 the authors declare no conflict of interests. 303 304 funding 305 this project was funded by the department of science and technology, inspire fellowship, 306 government of india, ministry of science and technology (order no. dst/inspire 307 fellowship/2018/1f180903, dated december 11, 2019) and manipal academy of higher 308 education (mahe), manipal, india 309 310 authors’ contribution 311 sm collected and organized data, performed the experiments, carried out the statistical 312 analysis of the results, and wrote the initial draft of the article. gbk conceived and designed 313 the study, reviewed the results, analysed and interpreted the data, wrote the initial and final 314 draft of the article, and supervised the study. sm and gbk acquired financial support for the 315 project and participated in the literature review, methods, and discussion. ssm (second 316 author), ssm, and gbk planning and execution of the research activity. ssm provided 317 logistic support and provided research materials. ssm (second author), ssm, db, and cm 318 designed the study, analysed and interpreted the data, participated in the literature review, 319 methods, and discussion, participated in the final writing, and provided supervision. all 320 authors approved the final version of the manuscript. 321 322 acknowledgments 323 the authors gratefully acknowledge the department of science and technology (dst), 324 ministry of science and technology, government of india for sanctioning inspire 325 fellowship to sreejisha m. the authors are thankful to the head of the institution and 326 manipal academy of higher education (mahe), manipal, india for providing the financial 327 assistance, materials and infrastructure to conduct the study. 328 11 329 references 330 1. lakhundi s, zhang k. methicillin-resistant staphylococcus aureus: molecular 331 characterization, evolution, and epidemiology. clin microbiol rev 2018;31(4): e00020-332 18. https://doi.org/10.1128/cmr.00020-18. 333 2. howden bp, davies jk, johnson pdr, stinear tp, grayson ml. reduced vancomycin 334 susceptibility in staphylococcus aureus, including vancomycin-intermediate and 335 heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory 336 detection, and clinical implications. clin microbiol rev 2010:23(1): 99–139. 337 https://doi.org/10.1128/cmr.00042-09. 338 3. hiramatsu k, aritaka n, hanaki h, kawasaki s, hosoda y, hori s, et al. dissemination 339 in japanese hospitals of strains of staphylococcus aureus heterogeneously resistant to 340 vancomycin. lancet 1997;350 (9092):1670-73. https://doi.org/10.1016/s0140-341 6736(97)07324-8. 342 4. clinical and laboratory standards institute (clsi). performance standards for 343 antimicrobial susceptibility testing, 32nd ed. clsi standard m02, m07, and m11, wayne, 344 pa. 2022. 345 5. charlton cl. detection of vrsa, visa, and vancomycin-heteroresistant staphylococcus 346 aureus (hvisa). clinical microbiology procedure handbook, 4th ed. washington, dc: 347 asm press, 2016. pp.5.7.1-5.7.9. doi:10.1128/9781555818814.ch5.7. 348 6. zhang s, sun x, chang w, dai y, ma x. systematic review and meta-analysis of the 349 epidemiology of vancomycin-intermediate and heterogeneous vancomycin-intermediate 350 staphylococcus aureus isolates. plos one 2015; 10(8): e0136082. 351 https://doi.org/10.1371/journal.pone.0136082. 352 7. amberpet r, sistla s, sugumar m, nagasundaram n, manoharan m, parija s. detection 353 of heterogeneous vancomycin-intermediate staphylococcus aureus: a preliminary report 354 from south india. indian j med res 2019;150(2):194-8. 355 https://doi.org/10.4103/ijmr.ijmr_1976_17. 356 8. deresinski s. the multiple paths to heteroresistance and intermediate resistance to 357 vancomycin in staphylococcus aureus. j infect dis 2013;208(1):7-9. 358 https://doi.org/10.1093/infdis/jit136. 359 9. kang yr, kim sh, chung dr, ko jh, huh k, cho sy, et al. impact of 360 vancomycin use trend change due to the availability of alternative antibiotics on the 361 https://doi.org/10.1128/cmr.00020-18 12 prevalence of staphylococcus aureus with reduced vancomycin susceptibility: a 14-year 362 retrospective study. antimicrob resist infect control 2022;11(1):1–10. 363 https://doi.org/10.1186/s13756-022-01140-9. 364 10. bakthavatchalam yd, babu p, munusamy e, dwarakanathan ht, rupali p, zervos m, et 365 al. genomic insights on heterogeneous resistance to vancomycin and teicoplanin in 366 methicillin resistant staphylococcus aureus: a first report from south india. plos one 367 2019;14(12):e0227009. https://doi.org/10.1371/journal.pone.0227009. 368 11. hu q, peng h, rao x. molecular events for promotion of vancomycin resistance in 369 vancomycin intermediate staphylococcus aureus. front microbiol 2016:1601. 370 https://doi.org/10.3389/fmicb.2016.01601. 371 12. satola sw, farley mm, anderson kf, patel jb. comparison of detection methods for 372 heteroresistant vancomycin intermediate staphylococcus aureus, with the population 373 analysis profile method as the reference method. j clin microbiol 2011;49(1):177–83. 374 https://doi.org/10.1128/jcm.01128-10. 375 13. appelbaum pc. microbiology of antibiotic resistance in staphylococcus aureus. clin 376 infect dis 2007;45 suppl 3:s165-70. doi:10.1086/519474. 377 14. moghaddam ts, namaei mh, afshar d, yousefi m. high frequency of sccmec type iv 378 and multidrug-resistant sccmec type i among hospital acquired methicillin resistant 379 staphylococcus aureus isolates in birjand imam reza hospital, iran. iran j microbiol 380 2022;14(1):67-75. https://doi.org/10.18502/ijm.v14i1.8803. 381 15. archana g, sinha a, annamanedi m, asrith, k, kale s, kurkure n, et al. molecular 382 characterisation of methicillin-resistant staphylococcus aureus isolated from patients at a 383 tertiary care hospital in hyderabad, south india. indian j med microbiol 2020;38(2):183-384 91. doi:10.4103/ijmm.ijmm_20_151. 385 16. singh a, prasad kn, rahman m, rai rp, singh sk, srivastava jk. high frequency of 386 sccmec type v and agr type i among heterogeneous vancomycin-intermediate 387 staphylococcus aureus (hvisa) in north india. j glob antimicrob resist 2017;8:110-14. 388 doi:10.1016/j.jgar.2016.11.006. 389 17. centers for disease control and prevention. cdc/nhsn surveillance definition for 390 specific types of infection. from: www.cdc.gov/nhsn/pdfs/ manual/ 17pscnosinfdef_ 391 current.pdf. accessed: sep 2022. 392 18. baird d. staphylococcus. cluster-forming gram-positive cocci. in: collee jg, fraser ag, 393 marmion bp, simmons a, eds. mackie & mccartney practical medical microbiology. 394 https://doi.org/10.1186/s13756-022-01140-9 13 14th ed. churchill livingstone: 2014. pp. 245-61. 395 19. zhang k, mcclure ja, elsayed s, louie t, conly jm. novel multiplex pcr assay for 396 characterization and concomitant subtyping of staphylococcal cassette chromosome mec 397 types i to v in methicillin-resistant staphylococcus aureus. j clin microbiol 398 2005;43(10):5026-33. doi:10.1128/jcm.43.10.5026-5033.2005. 399 20. wootton m, howe ra, hillman r, walsh tr, bennett pm, macgowan ap. a modified 400 population analysis profile (pap) method to detect hetero-resistance to vancomycin in 401 staphylococcus aureus in a uk hospital. j antimicrob chemother 2001;47(4):399-403. 402 doi: 10.1093/jac/47.4.399. 403 21. lina g, piemont y, godail-gamot f, bes m, peter mo, gauduchon v, et al. involvement 404 of panton-valentine leukocidin-producing staphylococcus aureus in primary skin 405 infections and pneumonia. clin infect dis 1999; 29(5):1128-32. doi: 10.1086/313461. 406 22. shariati a, dadashi m, moghadam mt, van belkum a, yaslianifard s, darban-407 sarokhalil d. global prevalence and distribution of vancomycin resistant, vancomycin 408 intermediate and heterogeneously vancomycin intermediate staphylococcus aureus 409 clinical isolates: a systematic review and meta-analysis. sci rep 2020;10(12689). 410 doi:10.1038/s41598-020-69058-z. 411 23. iyer rn, hittinahalli v. modified pap method to detect heteroresistance to vancomycin 412 among methicillin resistant staphylococcus aureus isolates at a tertiary care hospital. 413 indian j med microbiol 2008;26(2):176-79. doi:10.4103/0255-0857.40537. 414 24. chaudhari cn, tandel mk, grover n, et al. heterogeneous vancomycin-intermediate 415 among methicillin resistant staphylococcus aureus. med j armed forces india 2015;71 416 (1):15-18. doi:10.1016/j.mjafi.2014.03.008. 417 25. holmes ne, johnson pdr, howden bp. relationship between vancomycin-resistant 418 staphylococcus aureus, vancomycin-intermediate s. aureus, high vancomycin mic, and 419 outcome in serious s. aureus infections. j clin microbiol 2012;50(8):2548-52. 420 doi:10.1128/jcm.00775-12. 421 26. tsutsuura m, moriyama h, kojima n, mizukami y, tashiro s, osa s, et al. the 422 monitoring of vancomycin: a systematic review and meta-analyses of area under the 423 concentration-time curve-guided dosing and trough-guided dosing. bmc infect dis 424 2021;21(1):1–15. doi: 10.1186/s12879-021-05858-6. 425 14 27. the european committee on antimicrobial susceptibility testing (eucast). breakpoint 426 tables for interpretation of mics and zone diameters. version 12.0, valid from 2022-01-427 01. from: http://www.eucast.org accessed: oct 2022. 428 28. hu hc, kao kc, chiu lc, chang ch, hung cy, li1 lf, et al. clinical outcomes and 429 molecular typing of heterogenous vancomycin-intermediate staphylococcus aureus 430 bacteremia in patients in intensive care units. bmc infect dis 2015;15 (444):1-7. 431 doi:10.1186/s12879-015-1215-2. 432 29. sancak b, yagci s, gur d, gulay z, ogunc d, soyletir g et al. vancomycin and 433 daptomycin minimum inhibitory concentration distribution and occurrence of 434 heteroresistance among methicillin-resistant staphylococcus aureus blood isolates in 435 turkey. bmc infect dis 2013;13(1):1-6. doi:10.1186/1471-2334-13-583. 436 30. nagasundaram n, sistla s. existence of multiple sccmec elements in clinical isolates of 437 methicillin-resistant staphylococcus aureus. j med microbiol 2019;68(5):720-27. 438 doi:10.1099/jmm.0.000977. 439 440 table 1: primer sequence, control strains with their respective genes used for multiplex pcr 441 and size of amplicon (base pair) post amplification 442 genes sequence control strain amplicon size (bp) meca fgtg aag ata tac caa gtg att ratg cgc tat aga ttg aaa gga mrsa atcc 43300 147 sccmec i fgct tta aag agt gtc gtt aca gg rgtt ctc tca tag tat gac gtc c mrsa nctc 10442 613 sccmec ii f-cgttgaagatgatgaagcg r-cgaaatcaatggttaatggacc mrsa n315 398 sccmec iii f-ccatattgtgtacgatgcg r-ccttagttgtcgtaacag atcg mrsa 85/2082 280 sccmec iva f-gccttattcgaagaaaccg r-ctactcttctgaaaagcgtcg mrsa jcsc 4744 776 sccmec ivb f-tctggaattacttcagctgc r-aaacaatattgctctccctc mrsa jcsc 2172 493 f-acaatatttgtattatcggagagc 200 http://www.eucast.org/ 15 sccmec ivc r-ttggtatgaggtattgctgg mrsa mr 108 sccmec ivd f-ctcaaaatacggaccccaataca r-tgctccagtaattgctaaag mrsa jcsc 4469 881 sccmec v f-gaacattgttacttaaatgagcg r-tgaaagttgtacccttgacacc mrsa jcsc 4469 325 pvl f-atcattaggtaaaatgtctggacatgatcca r-gcatcaagtgtattggatagcaaaagc mrsa mr108 433 mrsa= methicillin resistant staphylococcus aureus; sccmec= staphylococcal cassette 443 chromosome mec; 444 445 table 2: isolation of heterogeneous vancomycin intermediate staphylococcus aureus and 446 vancomycin susceptible methicillin resistant staphylococcus aureus 447 type of infections (number) hvisa (n=14) number (%) vancomycin susceptible mrsa (n=206) number (%) p value surgical site infection (87) 4 (28.6) 83 (40.3) 0.385 wound infection (63) 3 (21.4) 60 (29.1) 0.762 bacteremia (25) 3 (21.4) 22 (10.7) 0.220 abscess (18) 1 (7.1) 17 (8.3) 0.883 cellulitis (6) 1 (7.1) 5 (2.4) 0.295 osteomyelitis (6) 0 (0.0) 6 (2.9) 0.517 carbuncle (5) 0 (0.0) 5 (2.4) 0.555 gangrene (3) 1 (7.1) 2 (1.0) 0.054 septic arthritis (2) 0 (0.0) 2 (1.0) 0.711 umbilical site infection (2) 0 (0.0) 2 (1.0) 0.711 necrotising fascitis (2) 0 (0.0) 2 (1.0) 0.711 sepsis (1) 1 (7.1) 0 (0.0) 0.064 hvisa= heterogeneous vancomycin intermediate staphylococcus aureus; 448 mrsa= methicillin resistant staphylococcus aureus 449 450 table 3: antimicrobial resistance profile of heterogeneous vancomycin intermediate 451 staphylococcus aureus and vancomycin susceptible methicillin resistant 452 staphylococcus aureus 453 antimicrobial agents hvisa (n=14) number (%) resistant vancomycin susceptible mrsa (n=206) number (%) resistant p value ciprofloxacin 14 (100.0) 179 (86.9) 0.227 16 clindamycin 3 (21.4) 32 (15.5) 0.472 erythromycin 13 (92.9) 173 (84.0) 0.701 gentamicin 8 (57.1) 102 (49.5) 0.784 linezolid 0 (0.0) 0 (0.0) rifampicin 6 (42.9) 11 (5.3) <0.001* teicoplanin 0 (0.0) 0 (0.0) tetracycline 5 (35.7) 63 (30.6) 0.767 trimethoprimsulphamethoxazole 4 (28.6) 101 (49.0) 0.172 mlsb phenotypes imlsb 4 (28.6%) 59 (28.6%) 1.000 cmlsb 3 (21.4%) 32 (15.5%) 0.472 msb 6 (42.9%) 82 (39.8%) 1.000 *p value ≤ 0.05 statistically significant 454 cmlsb= constitutive clindamycin resistance; hvisa= heterogeneous vancomycin 455 intermediate staphylococcus aureus; imlsb= inducible clindamycin resistance; mlsb= 456 macrolide lincosamide streptogramins b; msb= macrolide streptogramins b; mrsa= 457 methicillin resistant staphylococcus aureus 458 459 table 4: minimum inhibitory concentration of vancomycin to heterogeneous vancomycin 460 intermediate staphylococcus aureus and vancomycin susceptible methicillin resistant 461 staphylococcus aureus 462 vancomycin mic (µg/ml) hvisa (n=14) number (%) vancomycin susceptible mrsa (n=206) number (%) 0.125 0 (0.0) 0 (0.0) 0.25 0 (0.0) 5 (2.4) 0.5 1 (7.1) 55 (26.7) 1 8 (57.1) 93 (45.1) 2 5 (35.7) 53 (25.7) 4 0 (0.0) 0 (0.0) 8 0 (0.0) 0 (0.0) 16 0 (0.0) 0 (0.0) 32 0 (0.0) 0 (0.0) mic50 a 1 µg/ml 1 µg/ml mic90 b 2 µg/ml 2 µg/ml 17 hvisa= heterogeneous vancomycin intermediate staphylococcus aureus; mic= minimum 463 inhibitory concentration; mrsa= methicillin resistant staphylococcus aureus 464 amic50 = mic value at which growth was inhibited in 50% of isolates; bmic90 = mic values 465 at which growth was inhibited in 90% of isolates 466 467 table 5: staphylococcal cassette chromosome mec types of vancomycin to heterogeneous 468 vancomycin intermediate staphylococcus aureus and vancomycin susceptible methicillin 469 resistant staphylococcus aureus 470 sccmec types hvisa (n=14) number (%) vancomycin susceptible mrsa (n=206) number (%) p value sccmec i 0 (0.0) 0 (0.0) sccmec ii 0 (0.0) 3 (1.5) 0.649 sccmec iii 7 (50.0) 73 (35.4) 0.389 sccmec iva 4 (28.6) 47 (22.8) 0.621 sccmec ivb 0 (0.0) 0 (0.0) sccmec ivc 0 (0.0) 12 (5.8) 0.353 sccmec ivd 1 (7.1) 20 (9.7) 0.752 sccmec v 2 (14.3) 37 (18.0) 0.727 hvisa= heterogeneous vancomycin intermediate staphylococcus aureus; sccmec= 471 staphylococcal cassette chromosome mec; mrsa= methicillin resistant staphylococcus 472 aureus 473 474 475 476 18 477 figure 1: confirmation of hvisa using modified pap-auc 478 mu3hvisa reference strain (s. aureus atcc 700698) 479 auctest = 9.750; aucmu3 =10.50; auctest/aucmu3 ratio = 0.93 (hvisa) 480 auc= area under the curve; cfu= colony forming unit; mrsa= methicillin resistant 481 staphylococcus aureus; hvisa= heterogeneous vancomycin intermediate staphylococcus 482 aureus; pap-auc= population analysis profile-area under the curve 483 484 0 1 2 3 4 5 6 7 8 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 lo g 1 0 c f u /m l vancomycin concentration (µg/ml) mu3 (s.aureus 700698) hvisa 19 485 figure 2: gel electrophoresis of multiplex pcr for the detection of meca, sccmec types 1-v 486 and pvl gene 487 lane 1: 100 bp dna ladder; lane 2: positive controls; lane 3: negative control (master mix 488 and nuclease-free water); lane 4-8, 14, 15 and 18: vancomycin susceptible mrsa isolates 489 positive for meca, and sccmec iii; lane 9, 10, 17, 19: vancomycin susceptible mrsa 490 isolates positive for meca, and sccmec iva; lane 16: hvisa isolate positive for meca, and 491 sccmec iva, lane 11 and 12: vancomycin susceptible mrsa isolates positive for meca, 492 sccmec v, and pvl; lane 13: vancomycin susceptible mrsa isolate positive for meca, and 493 sccmec v; lane 20: vancomycin susceptible mrsa isolate positive for meca, sccmec 494 ivc, and pvl 495 sccmec= staphylococcal cassette chromosome mec; hvisa= heterogeneous vancomycin 496 intermediate staphylococcus aureus; pvl= panton-valentine leukocidin gene 497 498 sccmec ivd (881bp) sccmec iva (776bp) sccmec i (613bp) sccmec ivb (493bp) pvl (433bp) sccmec ii (398bp) sccmec v (325bp) sccmec iii (280bp) sccmec ivc (200bp) meca (147bp) 1 2 3 4 5 6 7 8 9 10 1 13 16 18 19 20 11 12 14 15 17 august 2007 vol 7 copy.indd the preclinical-clinical divide: building bridges *omar a habbal, abdul m el-mardi, ibrahim inuwa medical education is evolving. it has become a real challenge as it tries to keep pace with the ever-accelerating developments in communications and digital innovations. within the last few decades, medical education has witnessed radical changes in both content and methodology. the discipline-based traditional teaching of medicine was replaced by the system-based curriculum, which questioned the total autonomy of departments to control the content and methods of instruction. a greater challenge is now, almost universally, posed by the problem-based curriculum, which radically dismantled the preclinical-clinical divide, and takes advantage of advances in digital and virtual media. it is believed that such innovations render curricula more interactive.1, 2 the outcome of good clinical practice and professional competency depends largely upon curricular design and evaluation.3 this basically revolves around three axes: content, methodology and environment.4 content is driven by many factors, among which are expert opinion, social expectations, scientific development and educational standards as defined by various accreditation bodies. ever since the flexner report5 introducing basic medical sciences as an educational necessity, medical curricula have gone through changes manifested first in the sequential two-phase model. this is a discipline-based model, which was subsequently modified by integrating basic sciences within the pre-clinical first phase. this, until recently, has been practiced and used to be referred to as the ‘system-based’ or the ‘organ-based’ model. however, evolving societal expectations of the modern day physician are expressed in newly articulated competencies. traditional methods were supplanted by didactic methods (lectures and practical laboratory classes). the start of the new millennium sees a mixed economy of curriculum models with some medical schools retaining the traditional structures, but many turning to hybrid approaches with varying amounts of problembased learning and systems-based integrated courses. the impact of problem-based learning (pbl) has been witnessed during the last two decades with important implications for the content of educational blueprints. environmental factors affecting curricular design are numerous and may be categorized broadly as health care delivery systems, economy, politics and technological advances. ongoing key issues that face curriculum designers include the continued integration of basic and clinical sciences and the adoption of the appropriate strategies to meet the demands of the new and expected competencies. with this in mind, some educational centres half moved to an integrated developmental student-centred curriculum that emphasizes bedside teaching and role modelling and promotes fundamental clinical skills using a competency-based college approach.6 this is achieved by assigning each student a core mentoring clinical faculty member for the duration of his or her medical school career, who provides an ongoing personal faculty contact and spends substantial time continuously teaching and reflecting with the student on clinical skills development and professionalism and working intensively with him/her at the bedside. department of human and clinical anatomy, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: habbal@squ.edu.om sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 97-103 sultan qaboos university© submitted 7th november 2006 s p e c i a l c o n t r i b u t i o n اجلسور بناء املرحلتني السريريّة وما قبلها: بني الشرخ إنوّا إبراهيم املرضي، املنعم عبد ل، احلبا عمر o m a r h a b b a l , a b d u l l a h m e l m a r d i a n d i b r a h i m i n u wa 98 e v o l v i n g c u r r i c u l u m a t s q u at the college of medicine and health sciences (cm&hs), sultan qaboos university (squ), sultanate of oman, the current medical curriculum is twophased. the 4-year first phase is pre-clinical where students are exposed to integrated, system-based basic medical sciences, after which they attain the bsc degree in health sciences. the second phase is clinically-based and lasts for a further 3 years after which they attain the professional md degree. until recently, and we believe that this is the experience of many other medical schools, students went through adjustment difficulties when progressing from one phase to another.7 this was mainly due to the preclinical-clinical divide, each phase having different modalities, approaches and content. although most medical schools are increasingly adopting ‘problem-based’ learning, cognitive and psychomotor skills would somewhat still be lacking. consequently, students would still lack self-confidence when suddenly find themselves in the clinical ward. the curriculum is evolving to consolidate the educational ideology of practice-based learning. such learning experiences are believed to address competency expectations3 and are approached integratively revolving around three pre-clinical courses: a ppl i e d b a si c me d i c a l s c i e n c e s this is based on a case and problem solving approach. the course provides the students with a chance to acquire problem-solving skills that will help them during the clinical years and even after they graduate. the students are expected to use a problem-based approach to integrate the knowledge of basic medical sciences as it applies to some examples of common clinical problems and be able to interpret clinical and laboratory data and relate them to the pathophysiology of disease. during the course, groups of students are given a clinical case scenario and are required to prepare a figure 1: clinical skills resource centre (college of medicine and health sciences, sultan qaboos univeristy) th e p r e c l i n i c a l c l i n i c a l d i v i d e 99 presentation in which they discuss the pathophysiology of the disease condition presented in the scenario. resources are mainly web-based; however, in addition to that, tutors are specifically allocated to each case to act as resource persons. c ommun i c ati o n sk i l l s this course focuses on the cognitive approach to patient management. it aims at developing the ability to communicate with patients during clinical encounters. it emphasises the need to be able to pass on accurate information to patients and/or relations using simple language (‘bridge the communication gap’). it uses real and/or simulated patients in the teaching of doctorpatient communication c l i n i c a l me th o d s this course has hands-on experience, based on a series of modular themes, which focus on psychomotor skills. each of these core themes revolves around basic clinical examination techniques in a system-based approach, which prepares students for bedside physical examination during the clinical phase of the curriculum. by bridging the preclinical-clinical gap, these three courses together aim to enhance clinical competence and to provide basic academic and professional skills to equip students for lifelong medical practice on behalf of the patients, the community and the health service.3 in this paper, we elucidate and focus on the early introduction of ‘clinical methods’ with e-learning support and how students react to such learning practices. c l i n i c a l m e t h o d s the three bridging courses mentioned above provide students with opportunities to learn and practice skills in history taking, good communication practices, physical examination, basic data interpretation and practical procedures, identifying radiological figure 2: clinical skills resource centre (college of medicine and health sciences, sultan qaboos univeristy) o m a r h a b b a l , a b d u l l a h m e l m a r d i a n d i b r a h i m i n u wa clinical methods spring semester (8) 2:00 pm 4:00 pm venue: skill lab (annex building, ground floor) sun mon tue skill topics leading department contributing department(s) week 1 jan 30 31 feb 1 introduction human & clinical anatomy biochemistry clinical physiology week 2 6 7 8 general physical examination & vital signs medicine famcoh* nursing week 3 13 14 15 examination of ear, nose & throat oral cavity surgery (ent) oral health famcoh* week 4 20 21 22 cardiovascular examinationi medicine clinical physiology human & clinical anatomy week 5 27 28 mar 1 cardiovascular examinationii clinical physiology medicine week 6 6 7 8 examination of he respiratory system medicine clinical physiology child health week 7 13 14 15 chest wall & abdominal examination surgery medicine week 8 20 21 22 self study self study self study week 9 27 28 29 in-course assessment in-course assessment in-course assessment week 10 april 3 4 5 examination of the genitourinary system obstetrics & gynaecology surgery week 11 10 11 12 examination of the musculoskeletal system medicine (rheumatology) human & clinical anatomy accident & emergency physiotheraphy week 12 17 18 19 examination of the nervous system 1 medicine clinical physiology opthalmology child health week 13 24 25 26 examination of the nervous system 2 medicine nursing radiology human & clinical anatomy week 14 may 1 2 3 side room tests & imaging biochemistry nursing radiology human & clinical anatomy week 15 8 9 10 self study self study self study table 1: time table for clinical methods course *family medicine & community health department th e p r e c l i n i c a l c l i n i c a l d i v i d e anatomy, undertaking basic function tests and demonstrating the use of a variety of instruments. clinical methods is a ‘hands-on’ course based on series of modular themes. each of these core themes revolves around basic techniques in system-based practices, which prepare students for the clinical phase of their curriculum. this should make them feel at ease as they move on to clinical training.6 this foundation provides students with confidence and competence to interact with patients during the latter part of their preclinical studies.7 furthermore, the skills may be practiced iteratively in a non-threatening environment, without fear of embarrassment or of harming a patient. in the semester-based curriculum, the 15 week period allows preclinical students, prior to their commencement of the clinical component of the md programme, to have weekly contact with clinical tutors when they can practice what are considered to be basic and fundamental techniques, which they will require for their every day clinical training and practice in the management of patients. the course is divided into two parts, a compulsory practical part where students attend in small groups to examine and/or practice certain skills on surrogate models performing as patients. activities are pre-arranged each week and clinical departments take a leading role in organising, coordinating and standardising techniques with other participating departments. each student will have to perform each of the practical activities in a manner that is based on sound and standardised techniques before leaving the weekly session. this is then recorded on the student’s log-book to certify that such a skill has been performed properly. this will be counted as part of the student’s continuous assessment and is part of the final total mark of the course. these activities take place in a purpose-built skills resource centre/laboratory [figure. 2], which is well equipped and staffed. clinical tutors are provided by the clinical departments from the near-by university teaching hospital. students have full access to the laboratory to practice, train and use equipment while it is otherwise not in use. e l e a r n i n g s u p p o r t the door to the digital future is just ajar. opportunities for medical curricula to make use of digital support media are vast and are not beyond reach. e-learning, when it is available, offers important advantages to medical education, 8-13 and an opportunity for implementing flexible patterns of teaching. in this era of growing health consumer awareness, patients are also perceived as the target audience for medical digital libraries that are accessible to everybody to view and be enlightened. the cm&hs at squ has adopted e-learning as a useful and important enhancement to more traditional forms of learning. to accustom the students to using electronic formats for accessing information, course descriptions, objectives, schedule details and faculty information are posted on course-management software (web course tools or web-ct) that is accessible by the students and staff alike, both on the intranet and the world-wide web. in addition to these mandatory weekly practical sessions, online resources are used for cognitive learning of these clinical skills. when we planned the layout of the course on webct, we had to consider the pace of change that will inevitably occur and, therefore, allow for maximum flexibility and accessibility by our students. the digital layout was designed to reflect the theoretical background of the course modules. these modules follow a particular theme and are built on the basic sciences content of the bsc health sciences curriculum. these modular themes were laid down [table 1] to consolidate the relationship between them and their practical application in clinical skills sessions. synchronisation with other bridging course modules is accommodated as much as practically possible. groups of students who are not engaged in the practical classes can attend the computer laboratory and access the skills’ website and prepare or revise the skills demonstrated to them in text and various digital media formats (sound, animations, videos, etc). included on the website, are course information, timetables, text-based learning aids and links to interactive material. other site facilities include chat and email tools that provide students with an effective means of communication between themselves and faculty members. they are able to email each other, sign up for attachments and special subject modules and provide feedback to faculty on the teaching and management of the course. later on in their course (years 5-7), students return to the clinical skills resource centre (csrc), where the course is conducted, to consolidate skills learned including advanced resuscitation and other practical procedures [figure 1]. the most significant difficulties encountered were o m a r h a b b a l , a b d u l l a h m e l m a r d i a n d i b r a h i m i n u wa student motivation to participate in electronic discussions and feed-back from the tutors. it is difficult to find equilibrium between the time spent at the clinical skills resource centre and the web-based cognitive learning. further experience by both staff and students and careful planning, together with the use of present and future technologies that improve interaction and discussion, will increase the quality of this new mode of learning. a s s e s s m e n t in today’s culture of clinical governance and litigation, it is imperative that some form of assessment is developed to consolidate standards and protect patients, staff and hospital trusts. consequently, in addition to the log-book records as a form of continuous assessment (15%), other formal assessment of the course is done on two occasions. a halfway in-course assessment counts for at least 35% of the total mark and a final assessment carries a minimum of 50% of the total mark. both are objectively structured clinical examinations (osce). clinical tutors assess students on those clinical competencies they have already practiced, taking into account their preclinical background. s t u d e n t f e e d b a c k student feedback is very positive, as indicated by formally and informally conducted surveys. we look forward to monitoring their performance and competencies as they progress in their training. it is envisaged that feedback will also be provided by our clinical colleagues, who are mentoring these cohorts of students. we also would like to enhance our e-learning facilities in basic medical sciences, 14 to include a virtual hospital/clinic and interact with other medical centres. this can prove to be of value even in developing countries with limited facilities where educational resources can be enhanced by the introduction of such e-learning modules in the medical curriculum15 and even in the clinical services.16 c o n c l u s i o n despite their difficulties, students do eventually adjust to ‘cultural differences’ between the classroom and clinical settings. however, as educators, we believe that we should shoulder our responsibility and acknowledge the unsatisfactory situations that can stifle students’ progress. the building of bridges to close the gap between the preclinical and clinical arenas is a worthwhile undertaking. this may start by careful consideration of students’ recommendations, such as the gradual transition and better integration of the preclinical and clinical phases, all of which are consistent with recommendations in the literature.17, 18 with e-learning we are experiencing how a more effective modular structure creates a form of knowledge architecture in a learning module so that skills, knowledge and learning, both cognitive and psychomotor, can be integrated for enhanced professional development. r e f e r e n c e s 1. prufert mk. efficient e-learning with a well-founded media-didactic concept. int j comput dent 2005; 8:2739. 2. whitson ba, hoang cd, jiet t, maddaus ma. technology-enhanced interactive surgical education. j surg res 2006; 136:13-18. 3. frey k, edwards f, altman k, spahr n, gorman rs. the ‘collaborative care’ curriculum: an educational model addressing key acgme core competencies in primary care residency training. med educ 2003; 37:786-789. 4. muller s. “physicians for the twenty first-century: report of the project panel on the professional education of the physician and college preparation for medicine. j med educ 1984; 59:1-208. 5. flexner a. medical education in the united states and canada: a report to the carnegie foundation for the advancement of teaching. bulletin no. 4. new york: carnegie foundation for the advancement of teaching, 1910. 6. goldstein ea, maclaren cf, smith s, mengert tj, maestas rr, foy hm, et al. promoting fundamental clinical skills: a competency-based college approach at the university of washington. academic medicine 2005; 80:423-433. 7. prince kja, boshhuizen hpa, van der vleuten cpm, scherpbier ajja. students’ opinions about their preparation for clinical practice. med educ 2005; 39:704-712. 8. ryan m, mulholland cw, gilmore ws. applications of computer-aided learning in biomedical sciences: considerations in design and evaluation. br j biomed sci 2000; 57:28-34. 9. mas fg, plass j, kane wm, papenfuss rl. health education and multimedia learning: connecting theory and practice (part 2). health promot pract 2003; 4:464-469. 10. vincent ds, berg bw, hudson da. interactive nursing skills training using advanced network technology. j telemed telecare 2003; 2:s68-70. 11. huang c. virtual labs: e-learning for tomorrow. plos biology 2004; 2:157-159. th e p r e c l i n i c a l c l i n i c a l d i v i d e 12. schultz-mosqua s, thorwarth wm, grabenbaur gg, amann k, zielinski t, lochner j, et al. the concept of a clinical round as a virtual, interactive web-based, e-learning model for interdisciplinary teaching. int j comput dent 2004; 7:253-262. 13. welk a, splieth ch, wierinck e, gilpatrick ro, meyer g. computer-assisted learning and simulation systems in dentistry a challenge to society. int j comput dent 2006; 9:253-265. 14. habbal oa and harris pf. teaching of human anatomy: a role for computer animation. j audiov media med 1995; 18:69-73. 15. riveros re, espinosa a, jimenez p martinez l. e-learning experience: a teaching model with undergraduate surgery students in a developing country. stud health technol inform 2005; 111:404-406. 16. cherian mn, noel l, buyanjargal y, salik g. essential emergency surgical procedures in resource-limited facilities: a who workshop in mongolia. world hosp health serv 2004; 40:24-29. 17. general medical council. tomorrow’s doctors. london: general medical council, 1993. 18. general medical council. tomorrow’s doctors: recommendations on undergraduate medical education, london: general medical council, 2003. this work is licensed under a creative commons attribution-noderivatives 4.0 international license. erratum notice erratum notice of figure legend correction pulmonary aspergillus and mucor co-infection a report of two cases the editors of sultan qaboos university medical journal (squmj) have been informed of an error in an article by ravindra et al. in the august 2021 issue of squmj.1 a reader of squmj contacted the editorial office in september 2022 to inform the editors of an error in the descriptive arrows in the figure 2 legend: “histopathology of lung biopsy showing aspergillus and mucor in a 65-year-old male patient. this is a periodic acid-schiff staining at ×40 magnification showing multiple branching septated hyphae (black arrow) consistent with aspergillus along with broad-based, ribbon-like, non-septate hyphae (red arrow) suggestive of mucor.” however, this correction could not be made as the article had already been published a year prior.1 the editors of squmj wish to notify readers that the correct figure legend is as follows: “histopathology of lung biopsy showing aspergillus and mucor in a 65-year-old male patient. this is a periodic acid-schiff staining at ×40 magnification showing multiple branching septated hyphae (red arrow) consistent with aspergillus along with broad-based, ribbon-like, non-septate hyphae (black arrow) suggestive of mucor.” the corresponding author takes sole responsibility for this notice and would like to apologise to the readers, reviewers and editors of squmj for this correction made after publication. references 1. ravindra cm, rajaram m, mm, chtoi p, ls. pulmonary aspergillus and mucor co-infection: a report of two cases. sultan qaboos universition med j 2021; 21:495–8. https://doi.org/10.18295/squmj.8.2021.126. notice of erratum for: ravindra et al. pulmonary aspergillus and mucor coinfection: a report of two cases sultan qaboos univ med j 2021; 21:495–8. https://doi. org/10.18295/squmj.8.2021.126. sultan qaboos university med j, november 2022, vol. 22, iss. 4, p. 597, epub. 7 nov 22 https://doi.org/10.18295/squmj.9.2022.054 erratum notice | 597 https://creativecommons.org/licenses/by-nd/4.0/ https://doi.org/10.18295/squmj.8.2021.126. whole1.indd abstract background: plastibell circumcision complications can be life-threatening. objective: the aim of this paper is to review the complications of plastibell circumcision reported in the literature and in our own patients to determine the safety of the procedure. method: a retrospective study of 7 neonates circumcised in sultan qaboos university hospital over a 4-year period from 997 to 2000. results: minor complications occurred in 4 (2.3 %) of circumcisions. two cases were converted to formal circumcision due to bleeding and failure to introduce the bell respectively. one had delayed passage of urine for 24 hours and in one neonate, the parents were concerned about inadequate removal of foreskin. conclusion: plastibell circumcision is a safe technique in experienced hands. the risk of complications with this procedure is increased eight-fold when performed by nurses compared to surgeons. keywords: plastibell, circumcision, neonates. pla stib ell ci rc u mci sion: how s afe i s it? experience at sultan qaboos university hospital *mohammed s al-marhoon1, said m jaboub2 sultan qaboos university medical journal june 2006 vol 6, no. 1 sultan qaboos university© circumcision is probably the most com-mon surgical procedure in children world-wide. the practice of circumcision is thought to be at least 15,000 years old.1 cave drawings dated to paleolithic age show illustrations of circumcised men. there are reports of royal mummies who were circumcised. the role of circumcision owes its origin from the circumcision of abraham when he was circumcised at age of 99 years as a covenant with god. muslim tradition dates the ritual to the circumcision of ishmael, abraham’s eldest son who was circumcised at age of 13 years with his father.2 during world war ii tropical diseases of foreskin in american servicemen led to an increase in the trend towards routine neonatal circumcision. neonatal circumcision as a routine procedure underwent a phase of controversy in non-islamic countries. a report issued in 1975 by the committee on the fetus and newborn of the american academy of pediatrics stated that there was no absolute medical indication for routine circumcision of the newborn.3 in islamic countries circumcision is a must for all males for religious reasons, but the issue here is whether to do neonatal circumcision or operate at older age. the natural history of the foreskin was described in 1949. in newborn males the foreskin is fully retractable in 4%, the glans can be retracted to the urethral meatus in 54% and the tip of the glans cannot be seen in the remaining 42%. the foreskin is retractable in 25% of children at 6 months of age, 50% at one year, 80% at two years and 90% by four years.2 1 school of biomedical sciences, university of leeds, uk & department of surgery, sultan qaboos university hospital, muscat, sultanate of oman, 2 department of surgery, army force hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: almarhoon@hotmail.com o r i g i n a l s t u d y سالمتها؟ مدى :(plastibell ) بواسطة الذكور ختان السلطان قابوس جامعة جتربة مستشفى (plastibell) بواسطة اخلتان مضاعفات استعراض إلى الدراسة هذه .تهدف احلياة تهدد عملية اخلتان قد تترتب على التي الهدف: املضاعفات امللخص: ثم ١٧١ وليدا االستعادية الدراسة هذه الطريقة: ضمت هذه العملية. مثل خطورة مدى للتعرف على هنا التي حصلت وتلك في األدبيات املسجلة في بسيطة مضاعفات النتائج: ظهرت .٢٠٠٠ ١٩٩٧ إلى من للفترة سنوات أربع خالل قابوس السلطان جامعة مستشفى في الطريقة بتلك ختانهم وكانت هناك حالة واحدة تأخر فيها خروج . اجلرس إدخال في والفشل النزيف بسب وذلك إصالحي ختان إلى حتويلها مت اثنتان ، اخلتان حاالت من (٪٢٫٣) ٤ املذكورة الطريقة بواسطة الذكور اخلالصة: ختان كاملة. بصورة اجللد إزالة عدم قلقني بسب الطفل والدا كان حالة أخرى وفي ، ٢٤ ساعة ملدة البول باجلراح. مقارنة قبل املمرضات من أجريت إذا ٨ مرات الطريقة هذه مضاعفات تزداد وقد كفوءة أيدي بواسطة أجريت إذا سليمة تقنية m o h a m m e d s a l m a r h o o n , s a i d m j a b o u b 18 the indications for circumcision in oman are mainly for religious reasons, besides the medical indications of phimosis, paraphimosis, recurrent balanoposthitis and recurrent urinary tract infections. a variety of clamp methods were developed including the gomco clamp in the 1930’s and the plastibell in the 1960’s. they are the most commonly used devices in newborn circumcisions. the aim of this paper is to review the complications of plastibell circumcision reported in the literature and to review our own complications in sultan qaboos university hospital (squh) and to emphasis the need for skilled surgeons to perform the procedure to make it free of the serious complications. m e t h o d this study included 171 neonates who underwent plastibell circumcision. they were operated on by one surgeon over 4 years period from 1997 to 2000 at squh. the data, including complications of the technique, were collected retrospectively by going through the patients’ files including emergency visits. a policy of preoperative genital examination, consent-taking and full explanation to the parents is used. all neonates with jaundice, hypospadias and small size penis were not circumcised. the procedure was performed as follows: the baby is identified and restrained. the penis is prepared with an antiseptic solution and local anesthesia provided by 1% lignocaine as penile block. the preputial ring is dilated with a hemostat and the urethral meatus definitely identified. the foreskin is grasped with hemostats at 10 and 2 o’clock positions. a dorsal slit is made after crushing the skin for 5 seconds. the foreskin is freed off the entire glans and completely retracted to expose the whole glans, then the correct size plastibell is selected by testing it directly on the glans. the foreskin is pulled over the plastibell which is stabilized by a hemostat clamping the skin to the handle of the plastibell. the tie is applied on the plastibell groove using a surgeon’s knot for the first throw. the foreskin is excised just past the outermost edge of the plastibell taking care not to damage the glans. final checking for bleeding, meatal opening and correct position of the tie was performed at the end of the procedure. the parents are advised to watch for complications and strongly encouraged to come back to the hospital in case of any problems and they were given contact numbers for any queries. figure 1. plastibell sizes (cm) used in the circumcision of 171 babies. table 1. complications observed in 4 cases out of 171 cases. complication number of cases (%) not passing urine for 24 hours 1 (0.58) inadequate removal of foreskin 1 (0.58) conversion to formal circumcision 2 (1.17) p l a s t i b e l l c i r c u m c i s i o n : h o w s a f e i s i t ? 19 r e s u l t s the commonest plastibell ring size used was 1.3 cm with sizes ranging from 1.1 to 1.7 cm [figure 1]. most circumcisions were performed in the neonatal age group (158 cases (92 %)). the majority of circumcised babies (93.6 %) had birth weights ranging from 2.5 to 4 kg. preoperative examination of the infants revealed 2 babies with congenital hydroceles, one with left undescended testis, one with umbilical hernia, and one with glandular hypospadias. the complications observed, shown in table 1, included one child who was unable to pass urine for 24 hours. he was brought to the emergency department where he passed urine with no intervention. one child who was brought by his father to the outpatient clinic because he was concerned about inadequate removal of foreskin, but the circumcision was deemed adequate. two cases were converted to formal circumcision. the first was converted in the same sitting due to excess dorsal slit which made no room for the bell to fit in. the second was converted due to bleeding within 24 hours. this child had a very adherent prepuce with difficulty in releasing it, which had created raw oozing areas. d i s c u s s i o n plastibell circumcision is a simple technique for neonatal circumcision. however, the complications of this technique can sometimes be life-threatening. the reported complications of plastibell circumcisions range from very minor ones to serious ones as shown in table 2. complications of concern that have been reported in the literature include proximal migration of the bell on to the distal penile shaft causing circumferential compression; denution of penile skin or persistent disfigurement of the glans penis;4 two cases of necrotizing fasciitis;5 one case of rupture of bladder due to urinary obstruction by the plastibell.6 the complication rate of plastibell circumcision performed by trained nurses in bradford hospital in uk7 [table 3] was 18.5 % (31 out of 168 cases) compared to, only 2.3 % (4 out of 171 cases) in this study and 2.4 % (5 out of 205 cases) in the jamaican study.8 the low complication rate in the present study and the jamaican study may be attributed to the procedures being performed by experienced surgeons. therefore we strongly support that this procedure is performed by surgeons or trained doctors rather than nurses. although plastibell circumcision is a simple technique and can be easily learnt, it is not to be taken lightly as serious complications like necrotizimg fasciitis and rupture of bladder have been reported. r e f e r e n c e s 1. darby r. “where doctors differ”: the debate on circumcision as a protection against syphilis. soc hist med, 2003; 16: 57-78. 2. anderson g. circumcision. in: tm h, ed. ashcraft kw. 2 ed. wb saunders company: paediatric surgery, 1993; 715-719. 3. rose v. aap updates its recommendations on circumcision: american academy of pediatrics, 1999; 59: 2918-2923. 4. cilento bg, holmes nm, canning da. plastibell complications revisited. clin pediatr 1999; 38: 239-242. 5. bliss dp, healey pj, waldhausen ht. necrotizing fasciitis after plastibell circumcision. j pediatr 1997; 131: 459-461. 6. jee ld, millar aj. ruptured bladder following circumcision using the plastobell device. br j urol 1990; 65: 216-217. table 3. summary of the 31 children out of 168 with complications after plastibell circumcision5 complications number of cases (%) bleeding 7 (4.2) ring tracking back in penile shaft after separation 6 (3.5) early separation of ring 12 (7) wound infection 4 (2.3) post-op pyrexia 1 (0.6) inadequate removal of foreskin 1 (0.6) table 2. complications of plastibell circumcision some of the reported complications of plastibell circumcision wound infection bleeding inadequate removal of foreskin penile adhesions phimosis excess removal of foreskin necrotizing fasciitis sepsis urinary retention meatal ulceration/meatal stenosis/meatitis bladder rupture penile hematoma(due to local anaesthesia) failure of plastibell to separate plastibell ring too tight migration of plastibell to midshaft m o h a m m e d s a l m a r h o o n , s a i d m j a b o u b 20 7. shah t, raistrick j, taylor i, young m, menebhi d, stevens r. a circumcision service for religious reasons. br j urol 1999; 83: 807-809. 8. duncan nd, dundas se, brown b, pinnock-ramsaran c, badal g. newborn circumcision using the plastibell device: an audit of practice. west indian med j 2004; 53: 23-26. august 2007 vol 7 copy.indd abstract bilateral absence of the arcuate artery was observed during routine dissection of the lower limbs of a 60-year-old male cadaver. running distally on the dorsal aspect of both feet and opposite the tarso-metatarsal joint, the dorsalis pedis artery diverged 2cm lateral to the tendon of the extensor hallucis longus. the 2nd dorsal metatarsal artery was found originating from the dorsalis pedis artery opposite the intermediate cuneiform bone. the 3rd and 4th dorsal metatarsal arteries originated from the lateral tarsal artery. although absence of the arcuate artery has been previously described, the arterial variant described here is thought to be distinct from those previously reported. the variant 2nd dorsal metatarsal artery was found to originate from the dorsalis pedis artery. knowledge of anatomical variations of arteries supplying the feet and toes has important clinical significance in reconstructive surgery and in determining associated pathology. keywords: anatomy, tarsal; dorsal; metatarsal; arcuate; pedis; arteries; case report; oman. bilateral absence of the arcuate artery on the dorsum of the foot with anomalous origin of dorsal metatarsal arteries nilesh k mitra, *omar a habbal, abdulghaffar h el-hag, nasser a al-hashmi sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 153-155 sultan qaboos university© submitted 6th march 2007 numerous variations of the arterial anatomy of the foot and toes have been described.1, 2, 3, 4 awareness of the anatomical variations in arteries of the foot and toes is important for angiographers, vascular surgeons and reconstructive surgeons to deal with diagnosis and treatment of arterial occlusive diseases. the dorsal artery of the foot, arteria dorsalis pedis, dorsalis pedis artery, is the continuation of the anterior tibial artery distal to the ankle. it courses distally along the dorsum of the foot to the proximal end of the 1st intermetatarsal space, where it turns into the sole to complete the plantar arch. the branches of the dorsalis pedis include the lateral and medial tarsal, 1st dorsal metatarsal, deep plantar and arcuate arteries. the arcuate artery arises near the medial cuneiform, passes laterally over the metatarsal bases deep to the digital extensor tendons and gives rise to the 2nd to 4th dorsal metatarsal arteries (dmas) before anastomising with the lateral tarsal artery.5 the dmas are important as they are responsible for the blood supdepartment of human and clinical anatomy, college of medicine and health sciences, sultan qaboos university, p. o. box 35, al-khod 123, sultanate of oman *to whom correspondence should be addressed. email: habbal@squ.edu.om c a s e r e p o r t منابت في تغيرات وجود مع كال القدمني ظهر من املقوَس الشريان غياب الظهرية (العرشية) املشطيِِة الشرايني الهاشمي عايش ناصر احلاج، حسني الغفار عبد احلبال، الرحمن عبد عمر مترا، نيليش كومار ، القدمني ظهركال من املقوس ــريان الش غياب لوحظ عاماً، ــتون س العمر من يبلغ ذكر جلثة ــفلية الروتيني لألطراف الس ــريح التش امللخص: خالل 2 سنتيمتر متنحياً الشريان القدمي الظهري شوهد كما الرسغي-املشطي. املفصل مقابل للقدمني الظهرية الناحية يجتازان كالهما حيث وجد املقوس الظهري ــريان من الش ــطي الظهري الثاني كان ــريان املش الش وأن منبت الطويلة. ــطة الباس القدم إبهام عضلة وتد من ــي الوحش للجانب ــغي الرس ــريان الش كانت منابتهما من فلقد والرابع الظهريني الثالث ــطيني املش ــريانني أما الش ــطة. املتوس (الوتدية) ــفينية الس العظمة قبالة عن ومتميزة قبل توصف من لم الشريانية من املتغيرات نصفه هنا ما املقوس فإن الشريان لغياب ــبق املس الوصف وجود الرغم من وعلى ــي. الوحش معرفة املتغيرات وإن الظهري. القدمي الشريان من مبتدئاً وجد الثاني الظهري املشطي الشريان منبت بديل أن حيث ، التشريحية املتغيرات من غيرها املتغيرات. لهذه املرضية املتالزمات عن والبحث الترميم جراحة مجاالت في خاص وبشكل سريرية لها أهمية واألصابع األقدام لشرايني التشريحية عمان. حالة، تقرير قدمي، مشطي، ظهري، شرايني، الكلمات: تشريح، مفتاح m i t r a n k , h a b b a l o, e l h a g a h a n d a l h a s h m i n a 154 ply to the toes through their digital branches. also, free transfer of flaps from the web spaces of toes containing dmas are used for micro-vascular anastomosis in reconstruction of the hand.6 the following is a report of bilateral absence of the arcuate artery with variations in origin of the 2nd, 3rd, and 4th dorsal metatarsal arteries found during routine gross anatomy dissection at the college of medicine and health sciences, sultan qaboos university, sultanate of oman c a s e r e p o r t during routine dissection of the lower limbs of a 60year-old male cadaver, it was observed that the arcuate artery on the dorsum of the foot was absent bilaterally [figs. 1 & 2]. after reflection of the tendons of the extensor digitorum longus (edl) and extensor digitorum brevis (edb) muscles, the dorsalis pedis artery was cleaned, along with accompanying veins and traced distally. it entered the 1st intermetatarsal space where it gave rise to the 1st dma. in both lower limbs, the artery was also found to give rise to the 2nd dorsal metatarsal artery (dma) opposite the intermediate cuneiform bone (the usual point of origin of the arcuate artery) [figure 1]. the 2nd dma passed forward between the 2nd and 3rd metatarsal bones resting on the belly of the 2nd dorsal interosseous muscle. the 3rd and 4th dma were found to arise from the lateral tarsal artery opposite the lateral cuneiform and cuboid bones [figure 1]. the 2nd through 4th dmas originated much more proximally than their usual textbook description of origin at the bases of the metatarsals. similarly, the lateral tarsal artery also arose much more proximally and laterally over the dorsal aspect of the calcaneus. in the absence of the arcuate artery, it ended anteriorly by dividing into the 3rd and 4th dmas. a muscular branch from the lateral tarsal artery was found, as usual, joining to the edb, and a lateral branch joined the lateral malleolar network. d i s c u s s i o n anomalies of the dorsalis pedis artery and its branches on the dorsum of the foot have been mostly reported in cadaveric dissections1,2,3,4,7,8,9 out of these studies, yamada et al.2 and dilandro et al.4 reported variations in the arcuate artery. dissection, arteriographic and corrosion cast studies by yamada et al.2 involving 30 limbs from 17 cadavers revealed that the arcuate artery was absent in 33% of feet and the dorsalis pedis artery was absent in 6.7% of feet. in our case, we report bilateral absence of the arcuate artery in a male cadaver. yamada et al. (1993) found no strong association between the right and left feet of the same person for the presence of the arcuate artery. dilandro et al.4 reported the absence of the arcuate artery in 83.3% of cases variations in dorsal metatarsal arteries have been reported in several studies.1, 4, 8, 9 the 1st dorsal metatarsal artery was found to originate from its usual origin, the dorsalis pedis artery, in 90.6%1, 4, 8, 9 and 86% of cases.9 lee and dauber8 reported anomalous origin of the 1st dorsal metatarsal artery from the lateral tarsal artery in only 9.4% cases and it was also found to arise from the plantar network in 10% of cases.9 our study found no variation in origin of the 1st dorsal metatarsal artery. the arcuate artery is classically described as giving rise to the 2nd to 4th dorsal metatarsal arteries.5 in the study by gabrielli and olave9 the 2nd dma originated from the arcuate artery exclusively in 10% of cases, the 3rd dma in 6% of cases and the 4th dma in 10% of cases. in its absence (48%), the lateral tarsal arteries and the proximal perforating branches were responfigure 1: photograph of the dissected right foot showing the dorsalis pedis artery giving origin to the 1st and 2nd dorsal metatarsal artery (dma) and absence of arcuate artery. the 3rd and 4th dma are seen to be arising from the lateral tarsal artery. arrow shows lateral diversion of the dorsalis pedis artery 2 cm away from the tendon of ehl. 1. dorsalis pedis artery; 2. 1st dma; 3. 2nd dma; 4. 3rd dma; 5. 4th dma; 6. lateral tarsal artery; 7. medial division of the deep peroneal nerve. extensor hallucis longus (ehl); extensor digitorum brevis (edb); extensor digitorum longus (edl) b i l at e r a l a b s e n c e o f t h e a r c uat e a r t e r y o n t h e d o r s u m o f t h e f o o t w i t h a n o m a l o u s o r i g i n o f d o r s a l m e tata r s a l a r t e r i e s 155 sible for the formation of the second dma in 52%, of the third dma in 54%, and of the fourth dma in 72% of cases. the proximal perforating branches made an important contribution to the formation of such arteries, contributing partially or totally to the second dma in 90%, to the third dma in 92%, and to the fourth dma in 86%.4, 9 in 72 cadaveric dissections, found that the lateral tarsal artery supplied the 2nd, 3rd, and 4th dma more frequently (47.2%) than the arcuate artery. the proximal perforating arteries as well as various combinations of all three sources were also found to contribute complete blood supply to dorsal metatarsal arteries 2 through 4. in our study the 3rd and 4th dma arose from the lateral tarsal artery. c o n c l u s i o n the anatomical variation in this report describes the 2nd dma as originating from the dorsalis pedis artery when the arcuate artery was found to be absent. to the best of our knowledge, this variation is distinct and has not yet been reported. even studies by gabrielli and olave9 found that in the absence of the arcuate artery, the lateral tarsal arteries (52% of cases) and proximal perforating arteries (90% of cases) were responsible for the origin of the 2nd dma. documentation of anomalous origins of the 2nd, 3rd, and 4th dorsal metatarsal arteries, such as reported in this case study, is important to clinicians doing reconstructive surgeries of the foot. a c k n ow l e d g me n ts we thank all dissection room staff of the department of human and clinical anatomy at sultan qaboos university, oman, for their assistance and support in this study. r e f e r e n c e s 1. hamada n, ikuta y, ikeda a. arteries to the great and second toes based on three-dimensional analysis of 100 cadaveric foot. surg radiol anat 1993;15:187-192. 2. yamada t, gloviczki p, bower tc, naessens jm, carmichael sw. variations of the arterial anatomy of the foot. am j surg 1993;166:130-135. 3. tuncel m, maral t, celik h, tascioglu b. a case of bilateral anomalous origin for dorsalis pedis arteries (anomalous dorsalis pedis arteries). surg radiol anat 1994;16:319-323. 4. dilandro ac, lilja ec, lepore fl, viscovich jb, campion n, datta uk, signorile j. the prevalence of the arcuate artery: a cadaveric study of 72. j am podiatr med assoc 2001; 91:300-305. 5. standring s, ellis h, healy j, johnson d, williams a. pelvic girdle and lower limb. in sandring s, ed. gray’s anatomy: the anatomical basic for clinical practice. 39th ed. edinburgh: elsvier, churchill livingstone, 2005. p. 1600. 6. rose eh, buncke hj. free transfer of a large sensory flap from the first web space and dorsum of the foot including the second toe for reconstruction of a mutilated hand. j hand surg 1981; 6:196-201. 7. chiba s. two cases of the superficial dorsalis pedis artery observed in man. anat anz 1996; 178:183-189. 8. lee jh, dauber w. anatomical study of the dorsalis pedis-first dorsal metatarsal artery. ann plast surg 1997; 38:50-55. 9. gabrielli c, olave e. origins of the dorsal metatarsal arteries in humans. scand j plast reconstr surg hand surg 2002; 36:221-225. figure 2: schematic representation showing comparison between normal and anomalous origin of the dmas (1-4). the left-sided figure shows the normal description of the 1st dma arising from the dorsalis pedis artery and the 2nd, 3rd, and 4th dmas arising from the arcuate artery. the rightsided figure shows the variations found in this study; normal origin of the 1st dma arising from the dorsalis pedis artery and anomalous origins of the 2nd dma from the dorsalis pedis artery, and the 3rd and 4th dmas from the lateral tarsal artery. ddorsalis pedis artery; aarcuate artery; llateral tarsal artery 1 submitted 13 feb 23 1 revisions req. 26 mar 23; revisions recd. 1 apr 23 2 accepted 3 may 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.026 5 6 is forced coughing effective in reducing pain during cervical biopsy? 7 a systematic review and meta-analysis 8 yassamine ouerdane,1 aya abd elmegeed,2 mohammed tarek,3 imane 9 bakhtaoui,4 ahmed k. awad,5 *nihal al riyami,6 ahmed samy7 10 11 departments of 1medicine and 4pediatric surgery, saad dahlab university, blida, algeria; 12 2department of zoology, menofia university, menofia, egypt; 3department of medicine, al-13 azhar university, cairo, egypt; 5department of medicine, ain-shams university, cairo, egypt; 14 6department of obstetrics and gynecology, sultan qaboos university, muscat, oman; 15 7department of obstetrics and gynecology, cairo university, cairo, egypt. 16 *corresponding author’s e-mail: drriyami@hotmail.com 17 18 abstract 19 our objective was to compare potential analgesic effect of forced coughing (fc) technique 20 versus local anesthetics (la) or placebo during cervical biopsy. we systematically searched five 21 electronic databases from inception till march 2021; scopus, pubmed, web of science, 22 cochrane library, google scholar. the data was extracted from six rcts and analyzed them 23 using review manager software. during cervical biopsy, the overall effect estimate favored la 24 over fc group (md =1.06; 95% ci [0.58 to 1.54]; p < 0.0001). on the other hand, when 25 compared to no pain management pooled data were comparable between the two groups (md = -26 1.2; 95% ci [-3.35 to 0.94]; p = 0.27). procedure duration was significantly longer in la than 27 fc group (md = -1.94; 95% ci [-2.47 to 1.41]; p < 0.00001). fc and la seemed to useful 28 pain-lowering modalities during the cervical biopsy according to settings and availability. 29 further studies are recommended. 30 2 keywords: cervical biopsy; colposcopy; forced coughing; pain. 31 32 introduction 33 colposcopic-guided biopsy (cgb) is an easily performed outpatient procedure and is generally 34 done without anesthesia to diagnose and follow up precancerous and cancerous cervical 35 diseases.1 nevertheless, procedural discomfort and pain could exacerbate patients' anxiety and 36 fear during the procedure, the speculum insertion, or solution application.2 furthermore, women 37 with known with pre-invasive cervical disease or human papillomavirus (hpv) infection have a 38 higher risk for experiencing pain during the procedures thus needing additional analgesia.3 39 40 in the past two decades, various pharmacological and nonpharmacological methods have been 41 evaluated to reduce pain with cgb. these include benzocaine gel and its spray forms, lidocaine 42 injections, ibuprofen, topical lignocaine gel, and prilocaine anesthesia; however, their results 43 were mixed and non-conclusive.4-6 injection of 1% lidocaine decreased pain during procedures 44 compared with no anesthetics.7,8 however, it has several disadvantages, such as painful 45 injections, difficulty accessing the injection site, the possibility of tissue damage by needles, thus 46 interfering with the pathological diagnosis, risk of accidental intravascular injection, and allergic 47 reactions.9 in addition, the use of benzocaine spray or topical xylocaine before cervical biopsy 48 showed no benefit in reducing procedural pain.10,11 oral delivery of pain medication, e.g., 49 ibuprofen, also did not provide an advantage over a placebo in decreasing pain associated with 50 colposcopic-guided cervical biopsy.4 51 52 similarly, trials of nonpharmacological methods such as coughing, simple visual distraction, 53 hypnosis, and music reported non-conclusive results.12,13 among all nonpharmacological 54 approaches, forced coughing (fc) has the most significant contribution to pain relief during 55 cgbs, while among pharmacological approaches, local anesthetic agents such as prilocaine and 56 lidocaine have the most significant potential as pain-relieving medication. however, local 57 anesthetic agents have adverse effects that do not exist with forced coughing.9 58 consequently, this systematic review and meta-analysis was performed to synthesize evidence 59 from published rcts and compare the efficacy and safety of forced coughing versus local 60 3 anesthetics compared with no analgesia in reducing pain associated with colposcopic-guided 61 biopsy. 62 63 methods 64 all phases of this study was performed according to the cochrane handbook for systematic 65 reviews of treatments.14 we also followed the prisma statement requirements during reporting 66 of this systematic review and meta-analysis.14 because this study was a systematic review and 67 meta-analysis, formal ethical approval was not required. 68 69 literature search strategy 70 a comprehensive search was conducted including the following electronic databases: pubmed, 71 cochrane central, scopus, and web of science from inception till march 2021. the combination 72 of the following terms were used in our search strategy; (forced and cough or coughing and 73 cervical or cone or cervix and biopsy or colposcopic). no restrictions by language or publication 74 period were employed. we manually screened the references of included studies to retrieve those 75 not identified by database searching. 76 77 eligibility criteria and study selection 78 all clinical trials that met the following criteria were included in the study:(1) population: 79 patients undergoing colposcopic guided cervical biopsy; (2) intervention: forced coughing; (3) 80 comparator: local anesthetics or control (without any intervention); (4) outcomes: our primary 81 outcome was vas pain score during cervical biopsy while secondary outcomes were vas pain 82 score during speculum insertion, immediately and five minutes after the procedure, and duration 83 of the cervical biopsy for both the groups; (5) study design: randomized controlled trials. there 84 was no restriction regarding age, ethnicity, location, and publication date. 85 86 we excluded in vitro and animal studies; studies whose data were unreliable for extraction and 87 analysis overlapped datasets; non-english studies; and conferences, books, review articles, 88 posters, thesis, editorial, notes, letters, case series, and case reports. two authors independently 89 screened the titles and abstracts of retrieved records for eligibility. in case of disagreement, the 90 full text was retrieved and reviewed independently by a senior author for a final decision. 91 4 92 data extraction 93 two authors extracted the studies data independently using an offline data extraction form. the 94 extracted data were study design, population characteristics; risk of bias domains; and study 95 outcomes. two investigators scored the studies and collected the information independently. in 96 case of discrepancies in scoring, a consensus was reached after discussion. the primary outcome 97 was pain score during cervical biopsy measured by visual analog scale (vas), while secondary 98 outcomes were vas pain score during speculum insertion, immediately after the procedure, five 99 minutes after the procedure, and duration of the cervical biopsy. 100 101 risk of bias assessment 102 two independent reviewers used the cochrane risk of bias (rob) assessment tool to assess the 103 quality of retrieved rcts, as described in chap. 8.5 of the cochrane handbook of systematic 104 reviews of interventions 5.1.0.14 the cochrane collaboration risk of bias tool includes six 105 domains, namely random sequence generation (selection bias), allocation sequence concealment 106 (selection bias), blinding of participants and personnel (performance bias), blinding of outcome 107 assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting 108 (reporting bias), and other potential sources of bias. the authors classified studies in each 109 domain as low, high, or unclear risk of bias. 110 111 data synthesis 112 changes in vas scores were calculated as mean difference (md) and 95% confidence interval 113 (ci) in a fixed-effect model using the mantel–haenszel (m–h) method. the fixed-effect model 114 was used, assuming that the included studies were homogeneous and comparable in terms of 115 study design, quality, and measures of treatment effect. review manager 5.3 was used for 116 windows during data synthesis and a sensitivity analysis was performed to ensure that none of 117 the included studies affected the results and whether the overall effect size was statistically 118 robust. this resulted in excluding two studies. 119 120 assessment of heterogeneity 121 5 heterogeneity was assessed by visual inspection of the forest plots and measured statistically by 122 i2 statistics and chi-square tests. the chi-square test measures significant heterogeneity, while 123 the i2 statistics quantify the magnitude of heterogeneity in the effect size. we assessed and 124 interpreted heterogeneity according to the cochrane handbook of systematic reviews and meta-125 analysis (chapter 9).14 in this handbook, an alpha level (for chi-square test) below 0.1 is 126 indicative of significant heterogeneity, and the i2 statistic is interpreted as follows: (0–40 %: 127 might not be important; 30–60 %: may represent moderate heterogeneity; 50–90 %: may 128 represent substantial heterogeneity). in the case of significant heterogeneity, the random-effects 129 model was used. otherwise, the fixed-effect model was employed. 130 131 publication bias 132 the number of included studies in the analysis was less than 10. therefore, we cannot assess the 133 publication bias using the egger test.15 134 135 results 136 search results 137 we searched databases for randomized controlled trials matching our eligibility criteria and 138 found a total of 501 records. only 12 articles were eligible for full-text screening after the title 139 and abstract screening. of them, only six articles (n=532 patients) were included in our meta-140 analysis, as shown in the prisma flow diagram (supplementary fig.1); three studies compared 141 fc with la (1.0–2.0 ml of 1% lidocaine), two studies compared fc with no pain management, 142 and only one study reported the results of fc compared with la and no pain treatment. the 143 baseline characteristics of patients and a summary of included studies are shown in table 1 and 144 supplementary table 1. 145 146 risk of bias assessment 147 using the cochrane risk-of-bias tool (version 2) for randomized trials (rob 2), we found that 148 the quality of included studies was low in most criteria except for bias due to missing outcome 149 data and bias in the selection of reported results. the summary of quality bias assessment 150 domains of included studies is shown in (supplementary fig.2). 151 152 6 pain during cervical biopsy 153 pooled data from four studies2,5,16,17 with 378 patients showed a lower pain score in la group 154 than fc group (md =1.06; 95% ci [0.58to 1.54]; p ˂ 0. 0001; supplementary fig.3). pooled 155 studies were homogenous (p =0.27). 156 157 the effect size of a subgroup analysis that compared fc and no pain management showed no 158 statistically significant difference between the two groups (md = -1.2; 95% ci [-3.35 to 0.94]; p 159 = 0.27; fig.1). significant heterogeneity was observed in subgroup analysis that compared fc 160 versus no pain management (p =0.05, i2 = 67%), best resolved by excluding goldesteinakavia et 161 al. study,18 as shown in fig.1. 162 163 pain during speculum insertion 164 pooled data from four studies2,5,16,17 showed a statistically significant difference between the fc 165 and la groups with a reduction in the pain score in the fc group (md = -0.33; 95% ci [-0.64 to 166 -0.01]; p =0.04; fig.2). pooled studies were homogenous (p =0.2). 167 168 on the other hand, the overall effect from kuhn et al.19 and nakiet al.5 showed no statistically 169 significant difference in pain score during speculum insertion between fc and no pain 170 management group (md = -0.06; 95% ci [-0.25 to 0.13]; p = 0.53; fig.2). pooled studies were 171 homogenous (p =0.91). 172 173 overall pain score immediately post-procedure 174 the overall effect size showed no significant difference between fc and la (md = 075; 95% ci 175 [-0.27 to 1.78]; p = 0.15). pooled data were homogenous (p=0.45). 176 177 there was no significant difference in overall pain score immediately post-procedure between 178 fc and no pain management group (md = -2.10; 95% ci [-5.81 to 1.61]; p = 0.27) (fig.3). 179 pooled studies were heterogeneous (p ˂ 0. 0001; i2 = 90%). heterogeneity was best resolved by 180 excluding goldesteinakavia et al. study,18 as shown in fig.3. 181 182 overall score 5 minutes post procedure 183 7 the overall effect size showed no significant difference between fc and la (md = 0.20; 95% 184 ci [-0.89 to -0.58]; p = 0.62; supplementary fig.4). the results were heterogeneous under a 185 random effect model (p ˂ 0. 00001; i2 = 96%). 186 187 duration of procedure 188 pooled data from four studies2,5,16,17 showed a statistically significant difference between fc and 189 la with longer procedure duration in la group than fc group (md=-1.94; 95% ci [-2.47 to -190 1.41]; p ˂ 0. 00001; supplementary fig.5). pooled studies were heterogeneous under a random-191 effect model (p =0.0003; i2 =84 %; supplementary fig.5). heterogeneity was best resolved by 192 excluding naki et al. study,5 as shown in supplementary fig.5. 193 194 discussion 195 to the best of our knowledge and based on a literature search, this is the first systematic review 196 and meta-analysis to investigate the efficacy of fc in relieving pain during the colposcopic-197 guided biopsy. our systematic review and meta-analysis showed that fc was better than local 198 anesthesia in reducing pain during speculum insertion; however, no significant differences were 199 found compared to the non-pain management. on the other hand, our analysis favored the la 200 group with more reduction in pain scores during cervical biopsy compared to the fc group; 201 however, pain scores were comparable in the la group compared with the non-pain 202 management group. there was no significant difference in the overall pain score postprocedure 203 in the fc group compared to the la and no pain management. moreover, the duration of the 204 procedure was shorter in the fc group than in the la group due to time spent to inject the drug, 205 however this did not affect the amount of tissue obtained. 206 207 colposcopic-guided biopsy (cgb) has great value in modern gynecology; it is used to examine 208 patients with abnormal cytology and can be used to diagnose changes in cervical or vaginal 209 epithelium. however, many patients remain reluctant to undergo a cgb due to procedure-related 210 pain, anxiety, and discomfort. the fear of pain seems to be the main obstacle to proper 211 gynecological examination.20 the la injection, such as lidocaine, was painful, and many women 212 were afraid of needles and refused to have those injections. an alternative nonpharmacological 213 pain management technique is fc which can replace la injections.18 the published literature 214 8 reported no adverse effects or other reactions or costs in the fc group.2,5,16-19 conversely, 215 injecting a local anesthetic might cause tissue damage that interferes with the pathological 216 diagnosis.16 217 218 pain is a highly subjective, complex phenomenon, and its perception can be influenced by 219 several factors such as race/ethnicity, gender, previous experience, number of vaginal births, and 220 psychological state.21,22 several pharmacological and nonpharmacological interventions could 221 help minimize pain sensation,23 and fc is one of the effective pain-relieving measures.16 forced 222 coughing proved effective during speculum insertion and post-procedure.24 based on our 223 analysis, the procedure duration in the fc group was shorter than the la group; the latter might 224 be considered time-consuming due to the inclusion of injection as an additional step in the entire 225 surgical procedure. 226 227 in numerous cases, fc and other methods such as cognitive tasks, music cartoons in children, 228 humor, and imagining pleasant scenes work as distraction methods and could reduce procedural 229 pain.25-27 however, the mechanisms are not fully understood. the gate control theory of pain 230 may explain it.28,29 moreover, fc results in a sudden rise in blood pressure, which could be a 231 source of pain relief.30,31 232 233 in terms of cervical biopsies, la was more effective in reducing pain than fc. this was also 234 demonstrated in a recent study by naki et al.,5 in which they conducted a randomized study 235 comparing local lidocaine injection vs. fc as a distracting method. they found that the fc 236 method may not be a potent distractor, and la provided significant pain relief during the 237 cervical biopsy. on the other hand, another study by schmid et al.16 reported that fc during 238 cervical biopsies reduced patients' discomfort to a comparable extent to local anesthesia. so, 239 these conflicting results were evaluated in our analysis, and we also found no differences 240 between the two methods in the overall pain score post-procedure. pain associated with the 241 injection is missing during forced coughing; however, this advantage did not reduce pain 242 sensation during cgb. 243 244 9 the colposcopic procedure is performed as an outpatient clinical practice, and physicians give 245 attention to doing this procedure at an appropriate time. fc cuts down the costs associated with 246 the biopsy, and we show here that fc is time-saving compared with la, in which its use would 247 be an important issue for clinics with low resources and a high volume of patients when choosing 248 their pain relief methods. 249 250 however, the use of la is encouraged due to its significant effect in reducing pain sensation 251 during cervical biopsy compared with the nonpharmacological forced coughing method. 252 253 strengths and weaknesses 254 we included six rcts in the quantitative analysis constituting a strong evidence level. the 255 included studies range from moderate to high quality. the main limitation of our study is related 256 to the evaluation of pain with a vas score which is not an objective method and can be 257 influenced by several factors, such as social and cultural status. 258 259 conclusion 260 the forced coughing technique and local anesthetics are useful as pain-lowering modalities 261 during the colposcopy-guided biopsy, however local anesthetics seemed to be more beneficial 262 but this was not statistically significantaccording to settings and availability.we advise using 263 local anesthetics as potentially effective pain lowering modality during colposcopy and cervical 264 biopsy. if not available, forced coughing technique would be an appropriate, simple and practical 265 alternative to lower pain during colposcopy. further studies with larger sample size are 266 recommended to support this recommendation. 267 268 conflict of interest 269 the authors have no conflicts of interest. 270 271 authors’ contribution 272 as conceptualized the idea. yo validated the idea and formulated the search strategy. yo, aae, 273 ib, mt and aka collected the data. aae, ib, mt and aka assessed the quality of the data and 274 prepared the graphs. ib prepared the summary and baseline tables. yo and aae analyzed the 275 10 data. yo, aae, mt and aka drafted the manuscript. nar and as reviewed and edited the 276 manuscript. all authors approved the final version of the manuscript. 277 278 references 279 1. escobar pf, rojas-espaillat l, tisci s, enerson c, brainard j, smith j, et al. optical 280 coherence tomography as a diagnostic aid to visual inspection and colposcopy for preinvasive 281 and invasive cancer of the uterine cervix. int j gynecol cancer [internet]. 2006 sep;16(5):1815–282 22. available from: https://ijgc.bmj.com/lookup/doi/10.1111/j.1525-1438.2006.00665.x. doi: 283 10.1111/j.1525-1438.2006.00665.x 284 2. bogani g, serati m, cromi a, di naro e, casarin j, pinelli c, et al. local anesthetic 285 versus forced coughing at colposcopic-guided biopsy: a prospective study. eur j obstet gynecol 286 reprod biol [internet]. 2014 oct;181:15–9. available from: 287 https://linkinghub.elsevier.com/retrieve/pii/s0301211514003947. doi: 288 10.1016/j.ejogrb.2014.07.022 289 3. mercier rj, zerden ml. intrauterine anesthesia for gynecologic procedures. obstet 290 gynecol [internet]. 2012 sep;120(3):669–77. available from: 291 http://journals.lww.com/00006250-201209000-00027. doi: 10.1097/aog.0b013e3182639ab5 292 4. church l. analgesia for colposcopy: double-masked, randomized comparison of 293 ibuprofen and benzocaine gel. obstet gynecol [internet]. 2001 jan;97(1):5–10. available from: 294 http://linkinghub.elsevier.com/retrieve/pii/s002978440001084x. doi: 10.1016/s0029-295 7844(00)01084-x 296 5. naki mm, api o, acioglu hc, uzun mg, kars b, unal o. analgesic efficacy of forced 297 coughing versus local anesthesia during cervical punch biopsy. gynecol obstet invest 298 [internet]. 2011;72(1):5–9. available from: https://www.karger.com/article/fulltext/320842. 299 doi: 10.1159/000320842 300 6. wong g, li r, wong t, fan s. the effect of topical lignocaine gel in pain relief for 301 colposcopic assessment and biopsy: is it useful? bjog an int j obstet gynaecol [internet]. 2008 302 jul;115(8):1057–60. available from: http://doi.wiley.com/10.1111/j.1471-303 0528.2008.01780.xdoi: 10.1111/j.1471-0528.2008.01780.x 304 7. oyama ia, wakabayashi mt, frattarelli lc, kessel b. local anesthetic reduces the pain 305 of colposcopic biopsies: a randomized trial. am j obstet gynecol [internet]. 2003 306 https://ijgc.bmj.com/lookup/doi/10.1111/j.1525-1438.2006.00665.x https://linkinghub.elsevier.com/retrieve/pii/s0301211514003947 http://journals.lww.com/00006250-201209000-00027 http://linkinghub.elsevier.com/retrieve/pii/s002978440001084x https://www.karger.com/article/fulltext/320842 11 may;188(5):1164–5. available from: 307 https://linkinghub.elsevier.com/retrieve/pii/s0002937803001200. doi: 10.1067/mob.2003.290. 308 8. duncan id, mckinley ca, pinion sb, wilson sm. a double-blind, randomized, 309 placebo-controlled trial of prilocaine and felypressin (citanest and octapressin) for the relief 310 of pain associated with cervical biopsy and treatment with the semm coagulator. j low genit 311 tract dis [internet]. 2005 jul;9(3):171–5. available from: https://journals.lww.com/00128360-312 200507000-00008. doi:10.1097/01.lgt.0000171663.86847.45 313 9. speca sj, boynes sg, cuddy ma. allergic reactions to local anesthetic formulations. 314 dent clin north am [internet]. 2010 oct;54(4):655–64. available from: 315 https://linkinghub.elsevier.com/retrieve/pii/s0011853210000649. doi: 316 10.1016/j.cden.2010.06.006 317 10. clifton pa, shaughnessy af, andrews s. ineffectiveness of topical benzocaine spray 318 during colposcopy. j fam pract [internet]. 1998 mar;46(3):242–6. available from: 319 http://www.ncbi.nlm.nih.gov/pubmed/9519022 320 11. prefontaine m, fung-kee-fung m, moher d. comparison of topical xylocaine with 321 placebo as a local anesthetic in colposcopic biopsies. can j surg [internet]. 1991 apr;34(2):163–322 5. available from: http://www.ncbi.nlm.nih.gov/pubmed/2025805 323 12. carwile jl, feldman s, johnson nr. use of a simple visual distraction to reduce pain 324 and anxiety in patients undergoing colposcopy. j low genit tract dis 325 [internet]. 2014 oct;18(4):317–21. available from: https://journals.lww.com/00128360-326 201410000-00008. doi:10.1097/lgt.0000000000000024 327 13. chan y., lee pw., ng t., ngan hy., wong l. the use of music to reduce anxiety for 328 patients undergoing colposcopy: a randomized trial. gynecol oncol [internet]. 2003 329 oct;91(1):213–7. available from: 330 https://linkinghub.elsevier.com/retrieve/pii/s0090825803004128. doi: 10.1016/s0090-331 8258(03)00412-8 332 14. higgins jp, green s, editors. cochrane handbook for systematic reviews of 333 interventions. chichester, uk: john wiley & sons, ltd; 2008. 334 15. stuck ae, rubenstein lz, wieland d, vandenbroucke jp, irwig l, macaskill p, et al. 335 bias in meta-analysis detected by a simple, graphical. bmj. 1998 feb;316(7129):469–469. 336 https://linkinghub.elsevier.com/retrieve/pii/s0002937803001200 https://journals.lww.com/00128360-200507000-00008 https://journals.lww.com/00128360-200507000-00008 https://linkinghub.elsevier.com/retrieve/pii/s0011853210000649 https://journals.lww.com/00128360-201410000-00008 https://journals.lww.com/00128360-201410000-00008 https://linkinghub.elsevier.com/retrieve/pii/s0090825803004128 12 16. schmid bc, pils s, heinze g, hefler l, reinthaller a, speiser p. forced coughing versus 337 local anesthesia and pain associated with cervical biopsy: a randomized trial. am j obstet 338 gynecol [internet]. 2008 dec;199(6):641.e1-641.e3. available from: 339 https://linkinghub.elsevier.com/retrieve/pii/s0002937808008016. doi: 340 10.1016/j.ajog.2008.07.017 341 17. karaman e, kolusarı a, alkış i̇, çetin o. comparison of topical lidocaine spray with 342 forced coughing in pain relief during colposcopic biopsy procedure: a randomised trial. j obstet 343 gynaecol (lahore) [internet]. 2019 may 19;39(4):534–8. available from: 344 https://www.tandfonline.com/doi/full/10.1080/01443615.2018.1538329 doi: 345 10.1080/01443615.2018.1538329 346 18. goldstein akavia t, segev y, balan e, siegler e. the analgesic efficacy of forced 347 coughing during cervical punch biopsy: a prospective randomised controlled study. aust new 348 zeal j obstet gynaecol [internet]. 2018 dec 7;58(6):681–5. available from: 349 https://onlinelibrary.wiley.com/doi/abs/10.1111/ajo.12784. doi: 10.1111/ajo.12784 350 19. kuhn t, ukazu a, strickland po, roche n, taveras y, kovalenko o, et al. 351 the effect of forced cough to minimize pain and discomfort at the time of colposcopy-352 guided cervical biopsy. j low genit tract dis [internet]. 2020 apr;24(2):211–4. available 353 from: http://journals.lww.com/10.1097/lgt.0000000000000517. doi: 354 10.1097/lgt.0000000000000517 355 20. stafl a. colposcopy. cancer [internet]. 1976 jul;38(1):432–5. available from: 356 https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(197607)38:1%3c432::aid357 cncr2820380167%3e3.0.co;2-q 358 21. linton sj, shaw ws. impact of psychological factors in the experience of pain. phys 359 ther [internet]. 2011 may 1;91(5):700–11. available from: https://academic.oup.com/ptj/article-360 lookup/doi/10.2522/ptj.20100330. doi: 10.2522/ptj.20100330 361 22. wandner ld, scipio cd, hirsh at, torres ca, robinson me. the perception of pain in 362 others: how gender, race, and age influence pain expectations. j pain [internet]. 2012 363 mar;13(3):220–7. available from: 364 https://linkinghub.elsevier.com/retrieve/pii/s152659001100873x. doi: 365 10.1016/j.jpain.2011.10.014 366 https://linkinghub.elsevier.com/retrieve/pii/s0002937808008016 https://onlinelibrary.wiley.com/doi/abs/10.1111/ajo.12784 http://journals.lww.com/10.1097/lgt.0000000000000517 https://academic.oup.com/ptj/article-lookup/doi/10.2522/ptj.20100330 https://academic.oup.com/ptj/article-lookup/doi/10.2522/ptj.20100330 https://linkinghub.elsevier.com/retrieve/pii/s152659001100873x 13 23. bukola im, paula d. the effectiveness of distraction as procedural pain management 367 technique in pediatric oncology patients: a meta-analysis and systematic review. j pain 368 symptom manage [internet]. 2017 oct;54(4):589-600.e1. available from: 369 https://linkinghub.elsevier.com/retrieve/pii/s0885392417302695. doi: 370 10.1016/j.jpainsymman.2017.07.006 371 24. kiviharju m, kalliala i, nieminen p, dyba t, riska a, jakobsson m. pain sensation 372 during colposcopy and cervical biopsy, with or without local anesthesia: a randomized 373 trial. j low genit tract dis [internet]. 2017 apr;21(2):102–7. available from: 374 https://journals.lww.com/00128360-20170400000004. doi: 10.1097/lgt.0000000000000292 375 25. tsao jci, fanurik d, zeltzer lk. long-term effects of a brief distraction intervention 376 on children’s laboratory pain reactivity. behav modif [internet]. 2003 apr 26;27(2):217–32. 377 available from: http://journals.sagepub.com/doi/10.1177/0145445503251583. 378 doi.org/10.1177/0145445503251583 379 26. fowler-kerry s, lander jr. management of injection pain in children. pain [internet]. 380 1987 aug;30(2):169–75. available from: https://journals.lww.com/00006396-198708000-00003. 381 doi: 10.1016/0304-3959(87)91072-4. 382 27. weisenberg m, tepper i, schwarzwald j. humor as a cognitive technique for increasing 383 pain tolerance. pain [internet]. 1995 nov;63(2):207–12. available from: 384 https://journals.lww.com/00006396-199511000-00009. doi: 10.1016/0304-3959(95)00046-u 385 28. melzack r, wall pd. pain mechanisms: a new theory. science (80) [internet]. 1965 386 nov 19;150(3699):971–8. available from: 387 https://www.sciencemag.org/lookup/doi/10.1126/science.150.3699.971. doi: 388 10.1126/science.150.3699.971 389 29. bruehl s, chung oy, ward p, johnson b, mccubbin ja. the relationship between 390 resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain 391 sufferers: the effects of opioid blockade. pain [internet]. 2002 nov;100(1):191–201. available 392 from: https://journals.lww.com/00006396200211000-00020. doi: 10.1016/s0304-393 3959(02)00295-6 394 30. kern mj, gudipati c, tatineni s, aguirre f, serota h, deligonul u. effect of abruptly 395 increased intrathoracic pressure on coronary blood flow velocity in patients. am heart j 396 [internet]. 1990 apr;119(4):863–70. available from: 397 https://linkinghub.elsevier.com/retrieve/pii/s0885392417302695 http://journals.sagepub.com/doi/10.1177/0145445503251583 https://journals.lww.com/00006396-198708000-00003 https://journals.lww.com/00006396-199511000-00009 https://www.sciencemag.org/lookup/doi/10.1126/science.150.3699.971 14 https://linkinghub.elsevier.com/retrieve/pii/s0002870305803242. doi: 10.1016/s0002-398 8703(05)80324-2 399 400 https://linkinghub.elsevier.com/retrieve/pii/s0002870305803242 15 table 1: baseline characteristics of included studies 401 study id arms total number age m±sd bmi m±s d obstetric history indication for biopsy vagina l birth numbe r (%) cesarean birth number (%) curettage number (%) h-sil number (%) l-sil number (%) bogani 2014 (2) forced coughing 49 34±11.25 7 (14%) 2 (4%) 11 (22%) 32(66%) local anesthetic 51 38±11.5 14 (27%) 1(2%) 8 (16%) 40 (78%) goldstein akavia 2018 (17) forced coughing 45 33.02±3.7 8 1 (2.2%) 11 (24.4%) no pain management 45 31.23±3.4 1 4 (8.8%) 11 (24.4%) karaman 2019 (20) forced coughing 42 41.6± 10.9 26.9 ± 4.2 30 (71.4%) 5 (12.5%) 6 (14.2%) 20 (47.6%) lidocaine spray 44 42.1 ± 11.4 27.62 ± 3.2 32 (72.7%) 6 (14.2%) 6 (13.6%) 20(45.4%) kuhn 2020 (18) forced coughing 56 36.8± 11.1 29.1 (6.5) 14 (25) 46 (82.1) no pain management 54 37.9±10.3 28.5 (4.9) 22 (40.7) 40 (74.1) naki 2011 (5) forced coughing 39 37.3±9.9 local anesthetic 39 40.4±9.1 no pain management 36 38.9±7.6 schmid 2008 (21) forced coughing 34 local anesthetic 34 * sd: standard deviation; bmi: body mass index, h-sil: high grade squamous intraepithelial 402 lesion; l-sil: low grade squamous intraepithelial lesion; ascus: atypical squamous cell of 403 undetermined significance. 404 16 405 figure 1: vas pain score during cervical biopsy in the forced coughing group compared with 406 la and no pain management group respectively after resolving heterogeneity. 407 408 409 figure 2: vas pain score during speculum insertion in forced coughing group compared with 410 la and no pain management group respectively 411 412 413 17 414 figure 3: overall vas pain score immediately after the procedure in the forced coughing group 415 compared with la and no pain management group respectively, after removing heterogeneity. 416 417 418 july 2008.indd sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 137-148 sultan qaboos university© submitted 20th january 2008 accepted 4th february 2008 department of medicine, sultan qaboos university, muscat, oman *to whom correspondence should be addressed. email: ikramburney@hotmail.com major advances in the treatment of cancer what does a non-oncologist need to know? *ikram a burney and mansour s al-moundhri r e v i e w abstract the last few years have seen major advances in the management of cancers. since it is not possible for the non-oncologist to keep abreast with the latest developments in the field of oncology, this review summarises the most significant advances in the area of treatment of various cancers over the past four years. in some areas, a paradigm shift has occurred setting new standards of care, for example, the use of targeted therapy (trastuzumab) in adjuvant treatment of breast cancer; the use of monoclonal antibodies (rituximab), with or without chemotherapy, in the treatment and maintenance of indolent lymphoma; the use of the tyrosine kinase inhibitor, imatinib, in the adjuvant setting in resected gastrointestinal stromal tumours. in other areas, new treatments have emerged, such as, the use of targeted therapies in hepatocellular carcinoma (sorafenib) and renal cell carcinoma (sunitinib, sorafenib, temsirolimus, bevacizumab). in some other cancers, the addition of targeted therapies has improved survival rates, for example, in colon cancer (bevacizumab, cetuximb, panitumumab), head and neck cancers (cetuximab), and pancreatic adenocarcinoma (erlotinib). in yet another group, new targeted therapies have emerged where resistance was previously observed with the existing targeted therapies, for example, breast cancer (lapatinib), chronic myeloid leukemia (dasatinib). finally, the addition of chemotherapeutic agents has improved survival in some forms of cancer, for example, oxaliplatin in adjuvant treatment of colon cancer, temozolamide in glioblastoma multiforme, and adjuvant chemotherapy in non-small cell lung cancer. the information summarized here may provide useful for the busy physician needing an update in the field of oncology. keywords: medical oncology; trastuzumab; rituximab; imatinib; sorafenib; sunitinib; bevacizumab. عالج السرطان في الرئيسية التطورات األورام علم في املتخصص غير معرفته يحتاج ما املندري منصور برني، إكرام األورام في مجال التطورات مواكبة آخر عدم إمكانية إلى ونظرا السرطان. أنواع مختلف عالج في كبيرة تطورات املاضية القليلة ــنوات الس ــهدت ش ــنوات األربع الس على مدى ــرطان الس أنواع مختلف عالج في أهم التطورات احلاصلة التقرير في هذا خلصنا ، العلم في ذلك املتخصصني ــل قب ــن م إال كعالج (trastuzumab) ــتهدف املس العالج ــتخدام اس املثال، ــبيل س على للرعاية، جديدة معايير وضع في حتوال حصل ااالت بعض في املاضية. عالج ومداومة معاجلة في الكيميائي بدون العالج مع أو (rituximab) ــيلة النس أحادية املضادة ــام األجس ــتخدام ــرطان الثدي، واس ــاعد لس مس ااالت وفي املستأصلة. وِيةّ ــدَ السَ املعوية املعدية األورام حتديد ــاعد في (imatinib ) كمس كيناز التيروزين مانع أنزمي ــتخدام واس املهاودة ، اللمفوما sunitinib,) و ، الكلية خاليا ــرطان (torafenib)، س ــرطان الكبد س في ــتهدفة املس ــتعمال العالجات اس مثل العالج، من أخرى أنواع ظهر األخرى البقاء، ــني معدل حتس في دور ــتهدفة املس العالجات ــرطان كان إلضافة الس أنواع بعض وفي . (sorafenib, temsirolimus, bevacizumab البنكرياس ــرطانة ، س (cetuximab) والرقبة الرأس ــرطان ، س (bevacizumab, cetuximb, panitumumab) ــرطان القولون س ذلك مثال مثال ، ــتهدفة املوجودة املس للعالجات مقاومة أن هناك عندما لوحظ أخرى ــتهدفة عالجات مس ظهرت أخرى مجموعة (erlotinib ). وفي الغدية في حسنت البقاء عالجية كيميائية عوامل أن إضافة وجد وأخيرا .(dasatinib) املزمن النخاعي الدم ــرطان س , (lapatinib) الثدي ــرطان س ذلك كال دُ األَشْ دِ تَعَ مُ يٌّ يٌّ دِبْقِ رومِ أَ وَرَمٌ (temozolamide ) في ، القولون سرطان في ــاعد مس كعالج (oxaliplatin) ذلك ، مثال ــرطان الس أنواع بعض والذين في لديهم وقت ال الذين األطباء تفيد املعلومات امللخصة قد هذه الصغيرة. اخلاليا ال يصيب الذي الرئة ــرطان س في ــاعد مس كيماوي وعالج األورام. مجال علم في اجلديد يريدون معرفة الوقت نفسه بيفاسيزوماب. سونيتينيب، سورافينيب، اميايتيناب، ، ريتوكسيماب تراستوزوماب، األورام، الكلمات: علم مفتاح the last few years have seen major advances in the management of cancers, which have changed the way these cancers are now managed. some of the advances can easily be regarded as having changed the paradigm of cancer management, while others represent continued ini k r a m a b u r n e y a n d m a n s o u r s a l m o u n d h r i 138 cremental gains. the management of cancers includes prevention, surveillance and early detection, treatment of early and advanced disease, and the issues related to long-term survival after the cure. for the purposes of this review, only advances related to treatment of the disease, both in adjuvant and palliative settings are described. besides obtaining information from a review of the literature over the past four years, information was obtained from the series ‘clinical cancer advances’ published in the journal of clinical oncology for the past three years.1-3 the cancer sites/organs are arranged in alphabetical order and the setting of treatment (adjuvant or palliative) are described where appropriate, as follows: 1. breast cancer 2. chronic myeloid leukemia (cml) 3. colon cancer 4. gastric cancer 5. gastrointestinal stromal tumour (gist) 6. glioblastoma multiforme (gbm) 7. head and neck cancer 8. hepatocellular carcinoma (hcc) 9. lung cancer 10. multiple myeloma 11. non-hodgkin’s lymphoma (nhl) 12. ovarian cancer 13. pancreatic cancer 14. prostate cancer 15. renal cell carcinoma (rcc) b r e a s t c a n c e r a d j u va n t tr e atme n t adjuvant trastuzumab improves survival when added to standard adjuvant chemotherapy since the publication of the meta-analysis establishing the role of adjuvant chemotherapy and hormonetherapy in early stage breast cancer, several important strides have been made. the addition of either anthracyclines (doxorubicin or epirubicin), and/or taxanes (paclitaxel or docetaxel) to cyclophosphamide with or without 5-flurouracil has been shown to improve disease free survival (dfs) and the overall survival (os). the improvement in survival rates were of the order of 4-7% (absolute difference) at the end of 5 years.4 more recently, the addition of trastuzumab to the chemotherapy has been shown to improve further the survival in patients with breast cancer expressing the her-2/neu oncogene (also called c-erbb2). around 25-30% women with breast cancer have the oncogene, causing expression of the protein on the cell surface, which is detected by either immunohistochemistry (ihc) or fluorescent in-situ hybridization (fish). the protein is associated with an increased risk of cancer recurrence and a decreased sensitivity to some forms of chemotherapy. trastuzumab is a monoclonal antibody that blocks the protein her-2/neu and had been in clinical use since at least 1998 for metastatic breast cancer, where together with palliative chemotherapy, the survival was shown to be prolonged in women treated with trastuzumab. four randomised trials involving more than 13,000 women have been reported within the past 3 years, all leading to the same conclusion.5-8 the analysis showed for the first time that adding trastuzumab to standard chemotherapy for early-stage breast cancer that expresses her-2 reduced the risk of recurrence in women by almost half after three years compared with chemotherapy alone. the four trials varied in design to some extent, and the details are shown in table 1.5-8 the national surgical adjuvant breast and bowel project (nsabp) trial compared 4 cycles of doxorubicin and cyclophosphamide followed by four cycles of paclitaxel followed by observation or one calendar year of trastuzumab therapy. the intergroup trial compared, in a three arm study, 4 cycles of doxorubicin and cylophosphamide followed by weekly paclitaxel for 12 weeks with either observation, concomitant trastuzumab with paclitaxel or sequential trastuzumab for one year. the breast cancer international research group (bcirg), also in a three arm study, compared 4 cycles of doxorubicin and cylophosphamide followed by 4 cycles of docetaxel with either observation or trastuzumab for a year. the third arm consisted of 6 cycles of docetaxel and carboplatin followed by one year of trastuzumab. the fourth and the largest trial, the european herceptin adjuvant trial (hera), in addition to randomising patients between the observation and the trastuzumab arm after completion of the chemotherapy according to the institutional guidelines, also studied the relationship between duration of trastuzumab use (one year versus two years) and breast cancer recurrence in more than 5,000 women in 39 countries. taken together, the four trials demonstrated that addition of adjuvant trastuzumab for one calendar year improves the dfs from 67% to 85% at 4 years. this degree of improvement 139 m a j o r a d va n c e s i n t h e tr e at m e n t o f c a n c e r represents the most significant gain in survival in the history of adjuvant treatment of breast cancer. however, the addition of trastuzumab was not free of side effects. all trials showed an increased risk of congestive heart failure associated with the drug.8 the incidence of severe congestive heart failure or death from heart problems ranged from 2.9% and 4.1% in the women taking trastuzumab, versus up to 0.8% in the observation group group. in an attempt to reduce the cardiotoxicity, without compromising the survival gain, yet another trial called the finher trial, studied the possibility of using attenuated trastuzumab therapy for 9 weeks compared to the observation group.9 the trial was small including only 232 women. women in the trastuzumab group were significantly less likely to experience a recurrence with fewer cardiac side effects. with a longer follow-up, this trial might suggest that patients would be able to safely take a shorter course of the therapy, limiting the cost of the drug and the risk of serious side effects, without reducing efficacy. however, currently, the individual and the pooled results of the four large clinical trials, represent a very significant advance in breast cancer treatment, and have already changed the standard of care for the women who express her-2 protein. aromatase inhibitors improve the overall survival compared to tamoxifen in an adjuvant setting over the past 30 years, tamoxifen has been the standard of care for the adjuvant hormone treatment in hormone receptor positive early breast cancer.4 in the last few years alone, three third-generation aromatase inhibitors (letrozole, anastrazole, and exemestane) have been shown to improve the dfs and the os in the adjuvant setting. previously these agents had been shown to be effective in metastatic breast cancer. more recently, the three agents have been investigated as adjuvant therapy of early breast cancer employing various treatment strategies: replacement of tamoxifen as adjuvant therapy for 5 years, sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years, or following 5 years of tamoxifen. in the first adjuvant trial (arimidex, tamoxifen alone or in combination [atac]), anastrozole was significantly superior to tamoxifen in reducing risk of disease recurrence.10 the breast international group (big) trial big 1-98 demonstrated the significant superiority of letrozole over tamoxifen in improving disease-free survival.11 a large trial (international collaborative cancer group [iccg] trial 96) investigated the sequencing of 2 to 3 years of exemestane after 2 to 3 years of tamoxifen and found that switching to exemestane was significantly superior in disease-free survival compared with continuing on tamoxifen.12 trial ma17 evaluated extended adjuvant therapy with letrozole versus a placebo following 5 years of tamoxifen. dfs was significantly improved with letrozole versus a placebo, irrespective of whether patients had lymph node-positive or nodenegative tumours13. all three aromatase inhibitors are generally well tolerated. however, the long-term side effects remain to be studied. results of these trials indicate that aromatase inhibitors provide important benefits relative to tamoxifen in each of these adjuvant treatment settings. trial no of patients treatment scheme nsabp-31 1960 ac x 4 > pac 3 weekly x 12 wks ac x 4 > pac 3 weekly x 12 wks + tras weekly x 52 wks intergroup n-9831 3046 ac x 4 > pac weekly x 12 wks ac x 4 > pac weekly x 12 wks + tras weekly x 52 wks ac x 4 > pac weekly x 12 wks > tras weekly x 52 wks bcirg 006 3222 ac x 4 > doc 3 weekly x 4 ac x 4 > doc 3 weekly x 4 + tras weekly > 3 wkly x 52 wks carboplatin + doc 3 weekly x 6 + tras 3 weekly x 52 wks hera 5090 any ct±rt > observation any ct±rt > tras 3 weekly for 12 months any ct±rt > tras 3 weekly for 24 months nsabp = national surgical adjuvant breast and bowel project; bcirg = breast cancer international research group; hera = health, empowerment, research, and awareness foundation; ac = doxorubicin + cyclophosphamide; pac = paclitaxel; doc = docetaxel; tras = trastuzumab; ct = chemotherapy; rt = radiotherapy; table 1: different treatment strategies employing trastuzumab in an adjuvant setting for breast cancer i k r a m a b u r n e y a n d m a n s o u r s a l m o u n d h r i 140 tr e atme n t o f me ta stati c d i se a se patients with her-2/neu positive disease, who fail first line treatment with anthracycline, taxane and trastuzumab are usually treated with the prodrug of 5-fluorouracil, capecitabine. recently two trials have been reported, in which a combination of either a tyrosine kinase inhibitor, or a chemotherapeutic agent of a novel class, epothilone, were found to be superior than capecitabine alone in terms of dfs. lapatinib, a tyrosine kinase inhibitor of her2/neu and epidermal growth factor receptor (egfr),was used in combination with capecitabine in a phase iii international multicentre trial in patients expressing her-2/neu protein.14 time to progression was almost twice as long in the lapatinib/capecitabine group: (36.9 weeks) compared with the capecitabine only group (19.7 weeks). the combination was well tolerated. in another phase iii trial, ixabepilone and capecitabine prolonged progression-free survival (pfs) (5.8 months) relative to capecitabine (4.2 months).15 for the first time the pfs has been shown to be prolonged in this difficult-totreat group of patients. c h r o n i c m y e l o i d l e u k e m i a since the approval of imatinib by the us food and drug administration (fda), the treatment of chronic myeloid leukaemia (cml) has been revolutionised so that very few patients now receive the toxic treatment of allogeneic bone marrow transplant. imatinib is an inhibitor of the tyrosine kinase produced by a mutation in the bcr-abl gene. however, some patients develop additional mutations in this gene, causing their cancers to become resistant to the drug. dasatinib targets these secondary mutations. in a phase i clinical trial to determine the optimal dose of dasatinib for those who could not tolerate or had become resistant to imatinib, 92.5% of the patients had no evidence of disease after receiving dasatinib.16 additionally, 70% of patients in the accelerated phase experienced a significant decrease in the number of blast cells after receiving dasatinib. the duration of benefit was dependent on the phase of the disease when the patient was treated. dasatinib represents a significant improvement in the overall treatment of cml in general, and imatinib resistant cases in particular. c o l o n c a n c e r a d j u va n t tr e atme n t over the years, modulated 5-fu has remained the standard of care for fully resected stage ii and iii colon cancer in the adjuvant setting. several different regimens incorporating leucovorin with 5-fu given for 6 months, had been shown to reduce the recurrence rates by 40% in stage iii colon cancer, and a lesser degree in stage ii disease. more recently, one large study (the mosaic trial) found that adding oxaliplatin to standard chemotherapy after surgery for early-stage colorectal cancer reduced the risk of recurrence by 24%.17 a separate study from the national surgical adjuvant breast and bowel project (nsabp) showed that adding oxaliplatin to standard chemotherapy reduced the risk of recurrence by 21% in early-stage colorectal cancer patients.18 coupled with similar data from other smaller studies, these findings have changed the treatment approach for patients with early-stage colorectal cancer who need chemotherapy after surgery. tr e atme n t o f me ta stati c d i se a se three signal transduction inhibitors, bevacizumab, cetuximab, and pannitumab have been approved in the past three years for treatment of metastatic colorectal cancers in the first and the second line. bevacizumab is a recombinant, humanised monoclonal antibody against vascular endothelial growth factor (vegf) that is used to inhibit vegf function in vascular endothelial cells and thereby inhibit tumour angiogenesis. the addition of bevacizumab to 5-fu, with or without irinotecan or oxaliplatin, in both the firstand second-line treatment of metastatic colorectal cancer, has been shown to significantly increase pfs in several randomised trials. the overall survival advantage attributable to bevacizumab is 4.7 months with first-line therapy and 2.1 months with second-line therapy.19 bevacizumab has acceptable tolerability, with the majority of adverse events being generally mild and clinically manageable; however, cost effectiveness remains a concern in this setting. another monoclonal antibody cetuximab, an inhibitor of the epidermal growth factor receptor (egfr) has been shown, together with chemotherapy, to improve survival in metastatic colon cancer. a phase iii clinical trial involving patients with advanced colorectal cancer showed that the addition of cetuximab to a standard first-line chemotherapy combination called folfiri (folinic acid, 5-fu, and irinotecan) reduced 141 m a j o r a d va n c e s i n t h e tr e at m e n t o f c a n c e r the risk of progression by 15%.20 significantly more patients were able to undergo surgeryfor the complete removal of their tumours. in addition, more than twice as many patients with liver metastases were able to have their tumours completely removed in the cetuximab plus folfiri group. the study was the first to evaluate this combination, providing a new treatment option and enabling more patients to have their tumours surgically removed. g a s t r i c c a n c e r n e o -a d j u va n t a n d a d j u va n t tr e atme n t stomach cancer is conventionally regarded as a difficult tumour to treat and most of the patients diagnosed with it die of the cancer despite adequate surgery. over the past 7 years, two significant advances have occurred, which have set new standards in the management of completely resected gastric cancer. a large u.s. intergroup study (int-0116) demonstrated that combined chemoradiation following complete gastric resection improves median time to relapse (30 versus 19 months, p <.0001) and overall survival (35 months versus 28 months, p =.01).21 subsequently, the results of the medical research council adjuvant gastric infusional chemotherapy (magic) trial, conducted in the uk, provided another significant advance. neo-adjuvant chemotherapy, employing three cycles of a combination of epirubicin, cisplatin and 5-fu (ecf), was not only able to downsize several tumours, rendering them resectable , but was also associated with improvement in os.22 three further cycles of the same regimen were administered after the resection in an adjuvant setting. the updated results of the magic trial showed that 36% of patients who received chemotherapy were still alive five years after diagnosis, compared with 23% of those who received surgery alone. taken together, the results of the two trials have changed the standard of care of gastric cancer. g a s t r o i n t e s t i n a l s t r o m a l t u m o u r gastrointestinal stromal tumours (gist) are characterised by the presence of c-kit receptor, which in turn can be blocked by imatinib. imatinib has been in clinical use for the treatment of metastatic gist for several years, and has response rates of up to 70%. imatinib has also been used to downsize the large tumours, and make them amenable to surgery. more, recently, imatinib has been found to have improved the recurrence free survival (rfs) in patient with resected gist when used in the adjuvant setting. a national cancer institute sponsored study randomised patients to receive either 1 year of imatinib, or a placebo after completely resecting the gist.23 at the end of the first year of treatment, 97% of patients in the imatinib group had not experienced a recurrence, compared with 83% in the placebo group. the differences were most notable in patients with tumours larger than 10 cm. no differences in the overall survival rates were noted with this short follow-up. based on the findings, the study was stopped early and the patients on the placebo arm were allowed to cross over to use imatinib. this study would have major implications in the management of this rather rare tumour. g l i o b l a s t o m a m u l t i f o r m e glioblastoma multiforme (gbm) is one of the commonest brain tumours in adults and is associated with poor survival rates. the conventional treatment has been resection followed by radiotherapy. recently, two studies have shown for the first time that additional use of temozolamide, an alkylating agent, together with radiotherapy and subsequently for another 6 months after resection of gbm, can prolong the os. the first study showed that patients with previously untreated gbm who received temozolamide with radiotherapy had a median survival of 14.6 months compared to 12.1 months for patients who received radiotherapy alone.24 the difference was more apparent after two years, when more than twice as many patients in the temozolamide group were still alive. a separate study of these patients found that those who benefited from temozolamide were more likely to have a particular genetic marker in their tumour cells. patients with this marker (an alteration of the mgmt gene) who received temozolamide plus radiation lived 21.7 months, compared with 15.3 months among those who received radiation alone25 h e a d a n d n e c k c a n c e r until recently, the standard of care for the squamous cell cancers of the head and neck region has been either curative resection, or radiotherapy, or resection followed by adjuvant radiotherapy; however, most of the patients still relapse loco-regionally. the addition of chemotherapy has little or no benefit. more recently, the addition of cetuximab to radiotherapy i k r a m a b u r n e y a n d m a n s o u r s a l m o u n d h r i 142 was shown to improve os for patients with head and neck cancers. cetuximab, a monoclonal antibody that targets the egfr in cancer cells, had previously been approved for use in colorectal cancers. the pfs was significantly longer in the cetuximab group: 24.4 versus 14.9 months.26 the os in the cetuximab group was also significantly longer: 49 versus 29.3 months. also, patients with locally advanced hypopharyngeal or laryngeal cancer who received cetuximab with radiation therapy were more likely to have their larynxes preserved compared with patients who received radiation therapy alone.27 the addition of cetuximab produced relatively mild side effects, including an acne-like rash and local reactions to the drug infusion also recently, data demonstrated that adding cetuximab to standard chemotherapy for head and neck cancers increases survival. data from four clinical trials confirmed that cetuximab also may prolong os in patients with recurrent head and neck cancers; the difference was statistically significant: the os was 5.9 months for those who received cetuximab compared with 3.4 months for patients who did not.28 following publication of these studies, the fda this year approved the drug for use in combination with radiation therapy to treat squamous cell cancer of the head and neck, making it the first drug to be approved for this disease in 45 years. h e p a t o c e l l u l a r c a r c i n o m a hepatocellular carcinoma (hcc) is the third leading cause of cancer death globally, often resulting in death within a year of diagnosis, and is one of the most difficult cancers to treat. more than 90% of the patients present at a stage where curative treatment with either resection or transplantation is not feasible. for the past 30 years and more, several agents, including chemotherapeutic agents, have been tried, tested, and found to be ineffective. at the american society of clinical oncology (asco) meeting in 2008, results of a phase iii trial were presented. patients who were treated with a multi-kinase inhibitor, sorafenib, had a median survival of 10.7 months, compared to 7.9 months for those who received a placebo.29 time to cancer progression was also significantly longer in the treatment group: 5.5 versus 2.8 months. sorafenib is also approved for treating advanced kidney cancer. the study was terminated early due to the positive results, and represents a one of a kind study where a survival benefit led to rapid approval by the fda. l u n g c a n c e r chemotherapy has been shown to improve survival in a select group of patients with non-small cell lung cancer (nsclc), and is currently considered the standard of care for patients with stage iiib and iv disease with a good performance status; however, until now, questions persisted about the benefit of adjuvant chemotherapy. the national cancer institute of canada clinistudy no of patients treatment orr pfs p-value motzer 375 ifn-α 6% 5 375 sunitinib 31% 11 <0.001 escudier* 451 placebo 37% 2.8 452 sorafenib 62%** 5.5 <0.001 hudes 207 ifn-α 4.8% 3.1 209 temsiroimus 8.6% 5.5 <0.008 210 ifn+temsirolimus 8.1% 4.7 escudier 324 ifn-α 12.4% 5.4 325 bevacizumab+ifn-α 10.2 10.2 <0.0001 orr = overall reponse rates; ttp = time to progression; ifn-α = interferon –α. * second line treatment, ** disease control rate (complete response + partial response + stable disease) table 3: randomised trials in metastatic renal cell carcinoma 143 m a j o r a d va n c e s i n t h e tr e at m e n t o f c a n c e r cal trials group and the u.s. national cancer institute intergroup trial found that os among those patients with early-stage nsclc who received adjuvant chemotherapy with vinorelbine and cisplatin after surgery was 94 months, compared to 73 months for patients who did not.30 five-year survival was also higher in the chemotherapy group (69% versus 54%), and the risk of recurrence was 40% lower in the chemotherapy group. these findings, together with those reported recently by the adjuvant navelbine international trialist association (anita) and the cancer and leukemia group b (calgb), confirm that adjuvant chemotherapy has a significant role in the treatment of patients with operable nsclc.31, 32 these studies resolve a long-standing debate about the benefit of adjuvant chemotherapy, definitively demonstrating that such treatment has a beneficial role in the care of patients with operable nsclc. m u l t i p l e m y e l o m a multiple myeloma (mm) was considered to be an incurable b-cell neoplasm. for the first time in several years, use of two new classes of drugs, immunomodulatory (thalidomide and lenalidomide) and proteosome inhibitors (bortezomib) have been considered as major therapeutic advances in the treatment of mm. previously, thalidomide had been shown to improve the response rate and survival when used in combination with melphalan and prednisolone, and had become an integral part in the management of mm; however, the drug is not free of side-effects. more recently, the effectiveness of lenalidomide has been demonstrated in phase iii clinical trials.33, 34 patients with relapsed/refractory mm were randomised to lenalidomide plus dexamethasone or dexamethasone alone. patients in the lenalidomide group had superior response rates and duration of response. lenalidomide is an analogue of thalidomide, and works by inhibiting angiogenesis and immune modulation, and increasing apoptosis. lenalidomide is generally better tolerated than thalidomide. the proteosome inhibitor bortezomib is another recent addition to the mm treatment armamentarium. the target of bortezomib is the 26s proteasome. the benefit of bortezomib was shown in the phase iii apex trial. patients with relapsed/refractory mm were randomised to receive bortezomib or dexamethasone35. the response rate, median time to progression, and 1-year survival were significantly increased in the bortezomib group. in addition, clinical trials have further established the role of stem cell transplantation and the benefits of post-transplant maintenance therapy. these advances have resulted not only in expanded treatment options, but seem to have changed the natural history of mm which was once considered to be an incurable neoplasm. n o n h o d g k i n ’ s l y m p h o m a follicular lymphoma (fl) is an indolent form of nonhodgkin’s lymphoma (nhl), the outcomes of which had not improved over the past 3 decades.36 in the last 3 years, four large scale randomized trials have shown that adding the anti-cd20 monoclonal antibody, rituximab, to conventional combination chemotherapies improves the pfs and the os.37-40 rituximab added to a combination of cyclophosphamide, vincristine, prednisolone (cvp); cyclophosphamide, doxorubicin, vincristine, prednisolone (chop); mitoxantrone, cyclophosphamide, prednisolone (mcp) or chlorambucil, vincristine, prednisolone with interferon maintenance (chvp-ifn-α), brought clear survival advantage (see table 2 for details). a combination of rituximab and chemotherapy has now become the standard of care in the treatment of the commonest form of indolent lymphoma, the fl.41, 42 furthermore, another series of studies have established the successful role of rituximab for maintenance after completion of chemotherapy.43-45 used in this way, pfs and os rates are prolonged. for example, in one study, 56% of patients who received maintenance rituximab showed no progression, compared with 33% of patients who were observed following chemotherapy. moreover, 88% of the rituximab group was still alive after 4 years, compared with 72% of the observation group in a different setting, radioactivity conjugated with the anti-cd antibody has shown to induce higher remission rate, prolong the pfs and the os. two agents, 90y and 131i have been extensively studied and the results have been reported. increasingly, the radioimmuno-labelled antibodies are being incorporated in the management of indolent lymphomas not only after relapsed fl, but also in first line therapy.46, 47 as a result of recent developments, not only rituximab and radiolabelled antibodies have become the standard of care in the management of fl, but also, for the first time in the last three decades, the natural history of the disease seems to be changing, with the hope of a cure. i k r a m a b u r n e y a n d m a n s o u r s a l m o u n d h r i 144 o v a r i a n c a n c e r the vast majority of patients with epithelial ovarian cancer present with advanced stage disease, and the standard of care is debulking surgery followed by adjuvant systemic chemotherapy. despite the treatment, more than 80-90% of the patients relapse and die of their disease within few years of diagnosis. continued attempts to improve the survival rates have been unsuccessful in the past 10 years, since adjuvant chemotherapy with a combination of platinum with paclitaxel emerged as the standard of care.48 however, recently, the results of a phase iii trial including 415 patients with advanced ovarian cancer revealed that intra-peritoneal administration of chemotherapy extended the median survival by more than 1 year (49.7 months versus 65.6 months) compared with intravenous chemotherapy.49 patients with stage iii ovarian cancer were randomly assigned to either intravenous paclitaxel plus cisplatin or intravenous paclitaxel plus intra-peritoneal cisplatin and paclitaxel. however, patients who received intra-peritoneal therapy experienced more toxic side effects, and were more likely to report poorer quality of life, compared with women who received intravenous therapy. only 42% of women in the intra-peritoneal chemotherapy group were able to complete all six cycles of therapy, compared with 83% of those who received intravenous chemotherapy.50 such toxicity has limited the widespread use of intra-peritoneal therapy. p a n c r e a t i c c a n c e r patients with advanced pancreatic cancer have a poor prognosis and the standard of care for the past 12 years has been the use of single agent gemcitabine. several attempts to use combinations, such as with cisplatin, oxaliplatin, capecitabine and 5-fu have not yielded encouraging results. pancreatic cancers are known to over-express egfr and recently a tyrosine kinase inhibitor of the egfr, erlotinib, was used in combination with gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.51 a total of 569 patients were randomly assigned to receive either gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus a placebo in a double-blind, international phase iii trial. one-year survival was also greater with erlotinib plus gemcitabine (23% versus 17%). pfs was significantly longer with erlotinib plus gemcitabine. for the first time, a combination has been found to be superior than the single agent chemotherapy; however, given the modest gain in survival, pending complementary studies, the addition of erlotinib can not still be considered the standard of care. nonetheless, this study paves the way for further trials employing signal transduction inhibitors in the management of unresectable pancreatic cancer. p r o s t a t e c a n c e r prostate cancer is one of the most common cancers in men in the western world. effective screening using digital rectal examination (dre), and serum estimatable 2: randomised trials comparing standard chemotherapy with standard chemotherapy and rituximab for non-hodgkins lymphoma study no. of patients treatment ttp p-value os p-value solal-celingy 159 cvp 14 81%* 162 r-cvp 34 <0.0001 89% =0.053 hiddeman 205 chop 29 90%** 223 r-chop nr <0.001 95% =0.016 herold 96 mcp 25 74% 105 r-mcp 54 <0.0001 88% =0.014 salles 175 chvp-ifn 62%*** n/a 184 r-chvp-ifn 78% <0.03 n/a ttp = time to progression; os = overall survival; cvp = cyclophosphamide, vincristine, prednisolone; r-cvp = rituximab, cyclophosphamide, vincristine, prednisolone, chop = cyclophosphamide, doxorubicin, vincristine, prednisolone; r-chop = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; mcp = mitoxantrone, cyclophosphamide, prednisolone; rmcp = rituximab, mitoxantrone, cyclophosphamide, prednisolone; chvp-ifn = chlorambucil, vincristine, prednisolone, interferon α; rchvp-ifn = rituximab, chlorambucil, vincristine, prednisolone, .interferon α; *3 year survival; **2 year survival; ***event-free survival 145 m a j o r a d va n c e s i n t h e tr e at m e n t o f c a n c e r tion of the prostate specific antigen (psa) means that more patients are being diagnosed at an early stage. however, since the majority of patients is diagnosed at an old age and has a higher chance of dying because of the cancer-unrelated causes, an expectant approach or ‘watchful waiting’ has been employed as a method of early treatment. as yet there is no clear understanding as to which patients require aggressive treatment. a total of 695 men with early prostate cancer were randomly assigned to radical prostatectomy (347 men) or ‘watchful waiting’ (348 men).52 during a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died. radical prostatectomy was found to have reduced the diseasespecific mortality, overall mortality, and the risks of metastasis and local progression. the absolute reduction in the risk of death after 10 years was small, but the reductions in the risks of metastasis and local tumour progression were substantial. when analysed by age, the benefits of surgery were greatest among younger men: among men under age 65, 19.2% in the ‘watchful waiting’ group had died after 10 years compared with 8.5% of those who had surgery, while among men age 65 and older, 11.5% in the ‘watchful waiting’ group died versus 8.5% of those in the surgery group. based on these data, men under age 65 who have early-stage prostate cancer should undergo surgery to remove the prostate, while older men may choose ‘watchful waiting’. r e n a l c e l l c a r c i n o m a nearly one-half of patients with renal cell carcinoma (rcc) have metastatic disease at the time of initial presentation. the tumour is not sensitive to chemotherapy, and the options included treatment with interferon-α (ifn-α) or interleukin-2 (il-2) or surgical resection of metastases. however, response rates to the cytokine treatment do not exceed 10-20%, and the long-term prognosis remains dismal. high-dose il-2, approved for treatment of advanced rcc, has significant limitations. the treatment must usually be administered in an intensive care unit, is associated with significant toxicity, and has not demonstrated a survival benefit. over the past two years, four different agents have been proved to be effective in inducing responses, with the possibility of some longer remissions. sunitinib, sorafenib, temsirolimus, and bevacizumab have demonstrated significant efficacy in clinical trials and have been approved by the fda for the treatment of advanced rcc [table 3].53-56 ever since the recognition that the tumour-suppressor von hippel-lindau (vhl) gene is mutated in most clear-cell carcinomas, resulting in angiogenesis and cell growth, a number of targeted therapies that block the downstream effects of the mutated gene have been developed. sunitinib and sorafenib, for example, inhibit multiple receptor tyrosine kinases. temsirolimus inhibits mtor, which functions as an intermediary in a variety of cell signalling events to regulate cell growth and proliferation as well as angiogenesis and cell survival. bevacizumab binds to vegf and inhibits angiogenesis. in the first study, a total of 750 patients with a good performance status and goodand intermediate-risk clear cell rcc were randomized to receive either sunitinib or ifn α. the median pfs was 11 months for study no of patients treatment orr pfs p-value motzer 375 ifn-α 6% 5 375 sunitinib 31% 11 <0.001 escudier* 451 placebo 37% 2.8 452 sorafenib 62%** 5.5 <0.001 hudes 207 ifn-α 4.8% 3.1 209 temsiroimus 8.6% 5.5 <0.008 210 ifn+temsirolimus 8.1% 4.7 escudier 324 ifn-α 12.4% 5.4 325 bevacizumab+ifn-α 10.2 10.2 <0.0001 orr = overall reponse rates; ttp = time to progression; ifn-α = interferon –α. * second line treatment, ** disease control rate (complete response + partial response + stable disease) table 3: randomised trials in metastatic renal cell carcinoma i k r a m a b u r n e y a n d m a n s o u r s a l m o u n d h r i 146 the sunitinib arm and 5 months for the ifn α arm (p < 0.000001).53 in an another study, 905 patients who had failed one prior systemic therapy in the last 8 months and had measurable disease, clear cell histology, a good or intermediate prognosis, and an eastern cooperative oncology group (ecog) performance status of 0 to 1 were randomised to receive either sorafenib or placebo. sorafenib significantly prolonged median pfs compared with placebo (24 vs 12 weeks, p < 0.000001).54 in a different study, 626 patients with several poor-risk features were randomised to receive either ifn α, temsirolimus or a combination of temsirolimus plus ifn α. the median survival of patients was superior in the temsirolimus-alone arm compared with ifn α (10.9 versus 7.3 months, p < 0.007), while the combination arm was not superior to ifn α (8.4 months, p = 0.69). the median pfs was statistically superior for both temsirolimus arms (3.7 months) compared with ifn α (1.9 months).55 in the fourth study, patients with metastatic kidney cancer who had undergone nephrectomy were randomly assigned to receive either bevacizumab or a placebo in addition to interferon. adding bevacizumab nearly doubled pfs, from 5.4 months to 10.2 months. the tumour response rate was 31% for the bevacizumab group versus 13% for the placebo group.56 over the past 2 years, the use of these agents has essentially replaced the standard cytokine treatment, which had been the standard of care for more than two decades. c o n c l u s i o n oncology treatment has begun to progress by quantum leaps. a glance at this review would suggest that whereas, in some areas, a paradigm of management has shifted, for example, the use of targeted therapy in the adjuvant treatment of breast cancer, and the use of monoclonal antibody together with chemotherapy in indolent lymphoma, resulting in the cure of many more patients than were seen in the very recent past, in other areas, new treatments have emerged, in hardto-treat cancers, such as, hcc and rcc, offering hope of a meaningful prolongation of life to thousands of patients annually. the improved survival seen with the addition of targeted therapies as well as chemotherapeutic agents in cancers of the colon, head and neck, nsclc, and the pancreas represents the continual improvement seen using the phase iii randomised trials. r e f e r e n c e s 1. herbst rs, bajorin df, bleiberg h, blum d, hao d, johnson be, et al. american society of clinical oncology. clinical cancer advances 2005: major research advances in cancer treatment, prevention, and screening a report from the american society of clinical oncology. j clin oncol 2006; 24:190-205. 2. ozols rf, herbst rs, colson yl, gralow j, bonner j, curran wj jr, et al. american society of clinical oncology. clinical cancer advances 2006: major research advances in cancer treatment, prevention, and screening a report from the american society of clinical oncology. j clin oncol 2007; 25:146-162. 3. gralow j, ozols rf, bajorin df, cheson bd, sandler hm, winer ep, et al. american society of clinical oncology. clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening a report from the american society of clinical oncology. j clin oncol 2008; 26:313-325. 4. clark m. meta-analyses of adjuvant therapies for women with early breast cancer: the early breast cancer trialists’ collaborative group overview. ann oncol 2006; s10:59-62. 5. romond eh, perez ea, bryant j, suman vj, geyer ce jr, davidson ne, et al. trastuzumab plus adjuvant chemotherapy for operable her2-positive breast cancer. n engl j med 2005; 353:1673-1684. 6. robert n, leyland-jones b, asmar l, belt r, ilegbodu d, loesch d, et al. randomized phase iii study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with her-2 overexpressing metastatic breast cancer. j clin oncol 2006; 24:2786-2792. 7. piccart-gebhart mj, procter m, leyland-jones b, goldhirsch a, untch m, smith i, et al herceptin adjuvant (hera) trial study team. trastuzumab after adjuvant chemotherapy in her2-positive breast cancer. n engl j med 2005; 353:1659-1672. 8. viani ga, afonso sl, stefano ej, de fendi li, soares fv. adjuvant trastuzumab in the treatment of her-2positive early breast cancer: a meta-analysis of published randomized trials. bmc cancer 2007; 7:153. 9. joensuu h, kellokumpu-lehtinen p, bono p, alanko t, kataja v, asola r, et al. adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. n engl j med 2006; 354:809-820. 10. forbes jf, cuzick j, buzdar a, howell a, tobias js, baum m. arimidex, tamoxifen, alone or in combination (atac) trialists’ group. effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the atac trial. lancet oncol 2008; 9:45-53. 11. thürlimann b, keshaviah a, coates as, mouridsen h, mauriac l, forbes jf, et al. breast international group (big) 1-98 collaborative group. a comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. n engl j med 2005 29; 353:27472757. 147 m a j o r a d va n c e s i n t h e tr e at m e n t o f c a n c e r 12. coombes rc, hall e, gibson lj, paridaens r, jassem j, delozier t et al. a randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. n engl j med 2004; 350:1081-1092. 13. efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: national cancer institute of canada clinical trials group ma.17. j clin oncol 2007; 25:2006-2011. 14. geyer ce, forster j, lindquist d, chan s, romieu cg, pienkowski t, et al. lapatinib plus capecitabine for her2-positive advanced breast cancer. n engl j med 2006; 355:2733-2743. 15. thomas es, gomez hl, li rk, chung hc, fein le, chan vf, et al. ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. j clin oncol 2007; 25:5210-5217. 16. talpaz m, shah np, kantarjian h, donato n, nicoll j, paquette r, et al. dasatinib in imatinib-resistant philadelphia chromosome-positive leukemias. n engl j med 2006; 354:2531-2541. 17. anmdre t, boni c, mounedji-boudiaf l, navarro m, tabernero j, hickish t, et al. oxaliplatin, fluorouracil and leucovorin as adjuvant treatment of colon cancer. n eng j med 2004; 350:2343-2351. 18. kuebler jp, wieand hs, o’connell mj, smith re, colangelo lh, yothers g et al. oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage ii and iii colon cancer: results from nsabp c-07. j clin oncol 2007; 25:21982204. 19. golfinopoulos v, salanti g, pavlidis n, ioannidis jp. survival and disease progression benefits with treatment regimens for advanced colorectal cancer: a metaanalysis. lancet oncol 2007; 8:898-911. 20. tol j, koopman m, rodenburg cj, cats a, creemers gj, schrama jg, et al. a randomized phase iii standy of capecitabine, oxaliplatin, and bevacizumaab with or without cetuximab in first-line advanced colorectal cancer, the cairo 2 study of the dutch colorectal cancer study group (dccg). an interim analysis of the toxicity. ann oncol 2008; 19:734-738. 21. macdonald js. treatment of localized gastric cancer. semin oncol 2004; 31:566-573. 22. cunningham d, allum wh, stenning sp, weeden s. for the ncri upper gi cancer clinical studies group. perioperative chemotherapy in operable gastric and lower oesophageal cancer: final results of a randomised, controlled trial (the magic trial, isrctn 93793971). j clin oncol 2005; 23:4001. 23. dematteo r, owzar k, maki r,pisters m, blackstein c, antonescu c, et al. adjuvant imatinib mesylate increases recurrence free survival in patients with completely resected localized primary gi stromal tumor: north american intergroup phase iii trial acosog z9001. j clin oncol 2007; 25:abs 10079. 24. stupp r, mason wp, van den bent mj, weller m, fisher b, taphoorn mj, et al. radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. n engl j med 2005; 352:987-996. 25. hegi me, diserens ac, gorlia t, hamou mf, de tribolet n, weller m, et al. mgmt gene silencing and benefit from temozolomide in glioblastoma. n engl j med 2005; 352:997-1003. 26. bonner ja, harari pm, giralt j. radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. n engl j med 2006; 354:567-578. 27. vermorken j, bourhis j, trigo j, kies x, leon m, mueser n, et al. cetuximab (erbitux) in recurrent/metastatic (r&m) squamous cell carcinoma of the head and neck (scchn) refractory to first-line platinum-based therapies. j clin oncol 2005 asco annual meeting proceedings 2005; 23:5505. 28. bonner ja, harari pm, giralt j, baselga d, shin r, cohen j, et al. improved preservation of larynx with the addition of cetuximab to radiation for cancers of the larynx and hypopharynx. j clin oncol 2005 asco annual meeting proceedings 2005; 23:5533. 29. llovet j, ricci s, mazzaferro v, hilgard j, raoul s, zeuzem m, et al. sorafenib improves survival in advanced hepatocellular carcinoma (hcc): results of a phase iii randomized placebo-controlled trial (sharp trial). j clin oncol 2007 asco annual meeting proceedings 2007; 25:lba1. 30. winton t, livingston r, johnson d, rigas j, johnston m, butts c, et al. vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. n engl j med 2005; 352:2589-2597. 31. douillard j, rosell r, delena m,carpagnano f, ramlau r, gonzales-larriba jl, et al. adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage ib-iiia non-small-cell lung cancer (adjuvant navelbine international trialist association [anita]): a randomised controlled trial. lancet oncol 2006; 7:719-27. 32. strauss gm, herndon j, maddaus ms, johnstone dw, johnson ea, watson dm, et al. randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage ib non-small cell lung cancer (nsclc): report of cancer and leukemia group b (calgb) protocol 9633. j clin oncol 2004 asco annual meeting proceedings 2004; 22:7019. 33. dimopoulos m, spencer a, attal m, prince hm, harousseau jl, dmoszynska a, et al. lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. n eng j med 2007; 357:2123-2132. 34. weber dm, chen c, niesvizky r, wang m, belch a, stadtmauer ea, et al. lenalidomide plus dexamethasone for relapsed multiple myeloma in north america. n engl j med 2007; 357:2133-2142. 35. richardson pg, sonneveld p, schuster mw, irwin d, stadtmauer ea, facon t, et al. bortezomib or high-dose dexamethasone for relapsed multiple myeloma. n engl i k r a m a b u r n e y a n d m a n s o u r s a l m o u n d h r i 148 j med 2005; 352:2487-2498. 36. liu q, fayad l, cabanillas f, hagemeister fb, ayers gd, hess m, et al. improvement of overall and failure-free survival in stage iv follicular lymphoma: 25 years of treatment experience at the university of texas m.d. anderson cancer center. j clin oncol 2006; 24:15821589. 37. marcus r, imrie k, belch a, cunningham d, flores e, catalano j, et al. cvp chemotherapy plus rituximab compared with cvp as first-line treatment for advanced follicular lymphoma. blood 2005; 105:417-423. 38. hiddemann w, kneba m, dreyling m, schmitz n, lengfelder e, schmits r, et al. frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (chop) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with chop alone: results of a prospective randomized study of the german. low-grade lymphoma study group. blood 2005; 106:3725-3732. 39. forstpointner r, unterhalt m, dreyling m, böck hp, repp r, wandt h, et al. german low grade lymphoma study group (glsg). maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (r-fcm) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the german low grade lymphoma study group (glsg). blood 2006; 108:4003-4008. 40. herold m, haas a, srock s, neser s, al-ali kh, neubauer a, et al. east german study group hematology and oncology study. rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an east german study group hematology and oncology study. j clin oncol 2007; 25:1986-1992. 41. marcus r. use of rituximab in patients with follicular lymphoma. clin oncol 2007; 19:38-49. 42. fisher ri, leblanc m, press ow, maloney dg, unger jm, miller tp. new treatment options have changed the survival of patients with follicular lymphoma. j clin oncol. 2005; 23:8447-8452. 43. forstpointner r, unterhalt m, dreyling m, bock hp, repp r, wandt h, et al. maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (r-fcm) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the german low grade lymphoma study group (glsg). blood 2006; 108:4003-4008. 44. van oers mh, klasa r, marcus re, wolf m, kimby e, gascoyne rd, et al. rituximab maintenance improves clinical outcome of relapsed/resistant follicular nonhodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. blood 2006; 108:3295-3301. 45. van oers mh. rituximab maintenance therapy: a step forward in follicular lymphoma. haematologica 2007; 92:826-833. 46. kaminski ms, tuck m, estes j, kolstad a, ross cw, zasadny k, et al. 131i-tositumomab therapy as initial treatment for follicular lymphoma. n engl j med 2005; 352:441-449. 47. zinzani pl, d’amore f, bombardieri e, brammer c, codina jg, illidge t, et al. consensus conference: implementing treatment recommendations on yttrium-90 immunotherapy in clinical practice report of a european workshop. eur j cancer 2008; 44:366-373. 48. mcguire wp, hoskins wj, brady mf, kucera pr, partridge ee, look ky, et al. cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage iii and stage iv ovarian cancer. n engl j med 1996; 334:1-6. 49. armstrong dk, bundy b, wenzel l, huang hq, baergen r, lele s, et al. intraperitoneal chemotherapy and paclitaxel in ovarian cancer. n engl j med 2006; 354:3443. 50. swart amc, burdett s, ledermann j, mook p, parmar mkb. why i.p. therapy cannot yet be considered as a standard of care for the first-line treatment of ovarian cancer: a systematic review. ann oncol 2008; 19:688695. 51. moore mj, goldstein d, ham j, figer a, hecht jr, gallinger s, et al. erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer: a phase iii trial of the national cancer institute of canada clinical trials group. j clin oncol 2007; 20:1960-1966. 52. bill-axelson a, holmberg l, ruutu m, haggman m, andersson so, bratell s, et al. radical prostatectomy versus watchful waiting in early prostate cancer. n engl j med 2005; 352:1977-1984. 53. motzer rj, hutson te, tomczak p, michaelson md, bukowski rm, rixe o, et al. sunitinib versus interferon alfa in metastatic renal-cell carcinoma. n engl j med 2007; 356:115-124. 54. escudier b, eisen t, stadler wm, szczylik c, oudard s, siebels m, et al. target study group. sorafenib in advanced clear-cell renal-cell carcinoma. n engl j med 2007; 356:125-134. 55. hudes g, carducci m, tomczak p, dutcher j, figlin r, kapoor a, et al. temsirolimus, interferon alpha, or both for advanced renal cell carcinoma. n eng j med 2007; 356:2271-2281. 56. escudier b, pluzanska a, koralewski p, ravaud a, bracarda s, szczylik c, et al. avoren trial investigators. bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, doubleblind phase iii trial. lancet 2007; 370:2103-2111. departments of 1obstetrics & gynaecology and 3family medicine & public health, 2college of medicine & health sciences, sultan qaboos university; 4department of obstetrics & gynaecology, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: drriyami@hotmail.com abstract: objectives: this study aimed to generate baseline evidence regarding the effectiveness of atosiban in delaying delivery by ≥48 hours among pregnant women presenting with threatened preterm labour (tpl). the secondary objective was to assess the relationship between atosiban success and various perinatal factors and neonatal outcomes. methods: this retrospective study was conducted between june 2008 and may 2018 at the sultan qaboos university hospital, muscat, oman. the medical records of all pregnant women who received atosiban between 24–34 gestational weeks for tpl during this period were reviewed. results: a total of 159 women were included in the study. atosiban was successful in delaying delivery by ≥48 hours in 130 cases (81.8%). approximately half of the women (50.9%) achieved uterine quiescence in <12 hours. failure to delay delivery by ≥48 hours was significantly lower among women with normal versus abnormal cervical findings (11.1% versus 25.6%; p = 0.023). only 9.4% of women experienced minor side-effects. mean birth weight (2,724.55 versus 1,707.59 g; p <0.001) and apgar scores at 5 minutes (9.66 versus 8.28; p <0.001) were significantly higher among neonates delivered at ≥48 versus <48 hours post-atosiban, whereas the rate of neonatal respiratory distress syndrome was significantly lower (18.4% versus 81.6%; p <0.001). conclusion: atosiban was highly effective in delaying delivery by ≥48 hours and resulted in few adverse maternal side-effects and neonatal outcomes. to the best of the authors’ knowledge, this is the first study conducted in oman to evaluate the effectiveness of atosiban in preventing preterm labour. keywords: preterm labor; atosiban; tocolytic agents; treatment outcome; patient outcome assessment; oman. short-term outcomes of atosiban in the treatment of preterm labour at the sultan qaboos university hospital, muscat, oman a tertiary care experience *nihal al-riyami,1 hanin al-badri,2 sanjay jaju,3 silja pillai4 sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e260–265, epub. 21 jun 21 submitted 8 apr 20 revisions req. 3 jun & 21 jul 20; revisions recd. 27 jun & 21 jul 20 accepted 3 aug 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.015 clinical & basic research advances in knowledge the results of this study will inform future research comparing the effectiveness and safety profile of atosiban to other tocolytic agents such as nifedipine. to the best of the authors’ knowledge, this is the first study conducted in oman to evaluate the use of atosiban as a tocolytic drug for managing threatened preterm labour (tpl). application to patient care the findings of this study indicate that atosiban is highly effective in delaying delivery by ≥48 hours among selected patients presenting with tpl. in addition, the successful administration of this agent resulted in few maternal side-effects or adverse neonatal outcomes. preterm birth (ptb) is a leading causeof perinatal morbidity and mortality worldwide.1 threatened preterm labour (tpl) is defined as regular uterine contractions leading to cervical changes before 37 gestational weeks that may result in ptb.2 globally, the incidence of preterm labour has increased dramatically in recent years, mainly due to a rise in multiple pregnancies, use of assisted reproductive techniques and increase in birth rate among women over 34 years of age.3 in 2014, approximately 10.6% of live births were preterm, of which 84.7% occurred in the late preterm period (i.e. at 34–37 gestational weeks).4 the highest rate of ptb worldwide was reported in asia and sub-saharan africa (81.1%).4 although the exact mechanisms behind preterm labour are still unclear, various risk factors have been identified such as multiple pregnancies, cervical disease, decidual haemorrhage, placental ischaemia, fetal endocrine activation, intrauterine infections and various immunological or allergic phenomena and inflammatory processes.2 maternal ethnicity and a previous history of preterm delivery, undernutrition, smoking and stress may also contribute to preterm labour.5 in 30% of ptbs, preterm rupture of the membranes occurs at least one hour prior to the onset of uterine contractions, whereas 15–20% result from iatrogenic causes such as pre-eclampsia and fetal growth restriction which necessitate medically indicated or elective preterm deliveries due to maternal or fetal indications.1,5 late ptb occurs more often than early ptb and has significantly greater risks of adverse complications and outcomes compared to full-term births.4 https://creativecommons.org/licenses/by-nd/4.0/ clinical and basic research | e261 tocolytic drugs are the primary form of pharmacological management for tpl and are used to inhibit uterine contractions in a current episode of preterm labour as a first-line therapy or to maintain uterine relaxation after an acute episode as maintenance therapy.6,7 tocolytic agents aim to prolong pregnancy by at least 48 hours so that pregnant women with tpl can be transferred to a tertiary care centre and fetal lung maturation can be induced with glucocorticoids. tocolytic drugs include β-adrenergic receptor agonists, oxytocin receptor antagonists, calcium channel blockers, nitric oxide, prostaglandin synthase inhibitors and magnesium sulphate.8 atosiban is a synthesised cyclic nonapeptide that behaves as a competitive oxytocin receptor antagonist to inhibit the oxytocin-mediated increase of intracellular calcium concentration that induces uterine muscle contractions.9,10 in the late 1980s, the first pilot study of atosiban analysed its effect on 13 patients and demonstrated its dose-dependent tocolytic effect.11 it is administered as an initial bolus of 6.75 mg over the first minute followed by an infusion of 18 mg/hour for three hours, before being reduced to 6 mg/hour for up to 45 hours.5 a recent meta-analysis found that atosiban was as effective as betamimetics in prolonging pregnancy and neonatal development.12 maternal side-effects are rare (<1%) and may include nausea, headaches and vomiting.12,13 a follow-up study showed that the drug had no adverse effects on neonatal motor and psychosocial development up to the age of two years.8 however, a more recent study showed some behavioural effects between 2.5 and 5.5 years.14 in oman, atosiban is the most common tocolytic agent administered to pregnant women presenting with tpl. however, there is a lack of data regarding the effectiveness of atosiban for this purpose and its impact on maternal and perinatal outcomes. this study was therefore conducted to generate baseline evidence regarding the effectiveness of atosiban in preventing preterm labour and to establish the proportion of women who achieved complete uterine quiescence at 48 hours. in addition, the study aimed to examine the relationship between atosiban success and neonatal outcomes and degree of cervical dilatation at admission, as well as to document the occurrence of maternal side-effects. methods this retrospective study was conducted from june 2008 to may 2018 at the sultan qaboos university hospital (squh), a tertiary care institution in muscat, oman. all pregnant women between 24–34 gestational weeks who presented with tpl and received atosiban during this period were included in the study. a diagnosis of tpl was based on the presence of regular uterine contractions—defined as 2–3 contractions of ≥30 seconds’ duration every 30 minutes—confirmed by external tocography, alongside evidence of cervical dilatation of 0–3 cm in nulliparous women or 1–3 cm in primior multiparous women with ≥50% effacement. women with multiple pregnancies, ruptured membranes, chorioamnionitis, severe preeclampsia, antepartum haemorrhage or allergy to atosiban were excluded from the study, as were those with less frequent contractions or no cervical changes. data were collected from the patients’ electronic medical records on the hospital information system including maternal clinical and demographic charact eristics (i.e. maternal age, gravidity, parity, gestational age at both admission and delivery, time to achieve uterine quiescence and cervical length and dilatation at admission). in addition, any adverse maternal effects from atosiban use were recorded such as headaches, vertigo, hypotension or tachycardia. subsequently, information regarding neonatal outcomes was also gathered included birth weight, apgar score, admission to the neonatal intensive care unit (nicu) and compl ications such as respiratory distress syndrome (rds), necrotising enterocolitis and hyperbilirubinaemia. following delivery, all neonates received at least one dose of 12 mg of dexamethasone. for the purposes of the study, atosiban success was defined as delivery delaying by ≥48 hours. in order to assess the relationship between degree of cervical dilatation at admission and atosiban success, patients were divided into two groups. the first group consisted of women with normal cervical findings in whom the cervix was dilated to 0–10 mm in nulliparous or 10–15 mm in primior multiparous women; the second group was composed of women with abnormal cervical findings in whom the cervix was dilated to >10 mm in nulliparous or >15 mm in primior multiparous women. data were analysed using the statistical package for the social sciences (spss), version 23.0 (ibm corp., armonk, new york, usa). continuous variables were tested for normality of distribution and presented as either means and standard deviations or medians, ranges and interquartile ranges (iqrs). categorical variables were presented as frequencies and proportions. a pearson’s chi-squared test was used to examine differences between expected and observed frequencies for categorical variables. neonatal outcomes such as birth weight and apgar scores at 5 minutes were compared with regards to atosiban failure (i.e. delivery in <48 hours) or success (i.e. nihal al-riyami, hanin al-badri, sanjay jaju and silja pillai delivery in ≥48 hours). differences were analysed using an independent-samples t-test or mann-whitney u test, as appropriate. a p value of <0.050 was considered statistically significant. ethical approval for this study was obtained from the medical research & ethics committee of the college of medicine & health sciences at sultan qaboos university (mrec#1711). results a total of 159 pregnant women received atosiban for tpl during the study period, of which 132 (83%) subsequently delivered at squh. the median maternal age was 27 years (iqr: 9 years; range: 16–40 years) and median gravidity, parity and abortions was 2 (iqr: 3; range: 1–10), 1 (iqr: 2; range: 0–7) and 0 (iqr: 1; range: 0–6), respectively. the median gestational age at admission was 31.4 weeks (iqr: 3.5 weeks; range: 24–33.6 weeks). mean cervical dilatation at admission was 9.9 mm (95% confidence interval: 7.35–10.82 mm) [table 1]. based on degree of cervical dilatation, normal and abnormal cervical findings were reported in 81 (50.9%) and 78 (49.1%) women, respectively. atosiban was successful in delaying delivery by ≥48 hours in 130 cases (81.8%). uterine quiescence was achieved in <12 hours in 81 women (50.9%) and 12–36 hours in 47 women (29.6%). however, uterine quiescence was only achieved in >36 hours for two women (1.3%) and failed entirely in 29 women (18.2%) [table 2]. in terms of gestational age, atosiban was successful in 16 out of 23 women (69.6%) at 24–27.6 gestational weeks compared to 56 out of 69 women (81.2%) at 28–31.6 weeks and 58 out of 67 women (86.6%) at 32–33.6 weeks (p = 0.187). the rate of atosiban failure was significantly lower among women with normal cervical findings at admission compared to those with abnormal findings (11.1% versus 25.6%; p = 0.023) [table 3]. no maternal side-effects were reported in 144 women (90.6%). the remaining 15 patients experienced minor side-effects, including hypotension (4.4%), headaches (3.8%), dizziness (0.6%) or tachycardia (0.6%). perinatal outcomes were analysed only for the 132 women who delivered at squh. the median gestational age at delivery was 37 weeks (iqr: 5.7 table 1: maternal characteristics of pregnant women pre senting with threatened preterm labour to the sultan qaboos university hospital, muscat, oman (n = 159) characteristic median (iqr; range) age in years 27 (9; 16–40) gravidity 2 (3; 1–10) parity 1 (2; 0–7) abortions 0 (1; 0–6) gestational age at admission in weeks 31.4 (3.5; 24–33.6) mean cervical dilatation at admission in mm (95% ci) 9.9 (7.35–10.82) iqr = interquartile range; ci = confidence interval. table 2: time taken to achieve uterine quiescence among pregnant women presenting with threatened preterm labour to the sultan qaboos university hospital, muscat, oman (n = 159) time in hours n (%) not achieved 29 (18.2) <12 81 (50.9) 12–35.9 47 (29.6) 36–48 1 (0.6) >48 1 (0.6) table 3: perinatal factors associated with atosiban success among pregnant women presenting with threatened pre term labour to the sultan qaboos university hospital, muscat, oman (n = 159) factor n (%) p value† atosiban success* (n = 130) atosiban failure (n = 29) gestational age in weeks 0.187 24–27.6 16 (12.3) 7 (24.1) 28–31.6 56 (43.1) 13 (44.8) 32–33.6 58 (44.6) 9 (31) cervical findings at admission 0.023 normal‡ 72 (55.4) 9 (31) abnormal 58 (44.6) 20 (69) *defined as prolonging delivery by ≥48 hours. †calculated using a chisquared test. ‡defined as cervical dilation of 0–10 mm in nulliparous or 10–15 mm in primior multiparous women. table 4: perinatal outcomes associated with atosiban succ ess among pregnant women presenting with threatened preterm labour to and delivering at the sultan qaboos university hospital, muscat, oman (n = 132) outcome mean ± sd p value† atosiban success* (n = 103) atosiban failure (n = 29) birth weight in grams 2,724.55 ± 607.93 1,707.59 ± 734.15 <0.001 apgar score at 5 minutes 9.66 ± 0.75 8.28 ± 2.09 <0.001 sd = standard deviation. *defined as prolonging delivery by ≥48 hours. †calculated using a student’s t-test. short-term outcomes of atosiban in the treatment of preterm labour at the sultan qaboos university hospital, muscat, oman a tertiary care experience e262 | squ medical journal, may 2021, volume 21, issue 2 clinical and basic research | e263 weeks; range: 24–41.3 weeks). mean birth weight was significantly higher in cases in which atosiban was successful in delaying delivery by ≥48 hours compared to those in which delivery occurred at <48 hours (2,724.55 ± 607.93 g versus 1,707.59 ± 734.15 g; p <0.001). in addition, the mean apgar score at 5 minutes was significantly higher among neonates who were delivered ≥48 hours after receiving atosiban compared to those delivered at <48 hours (9.66 ± 0.75 versus 8.28 ± 2.09; p <0.001) [table 4]. the frequency of neonatal rds was significantly lower in neonates in whom atosiban was successful in delaying delivery by ≥48 hours compared to those delivered at <48 hours (18.4% versus 81.6%; p <0.001). atosiban success also resulted in a significant reduction in the rates of neonatal hyperbilirubinaemia (13.6% versus 48.3%; p <0.001) and nicu admission (27.2% versus 93.1%; p <0.001) compared to neonates in whom atosiban failed to prolong delivery by ≥48 hours. finally, there was a significant reduction in neonatal deaths among those in whom atosiban successfully delayed delivery by ≥48 hours compared to those delivered at <48 hours (1% versus 20.7%; p <0.001) [table 5]. discussion in the current study, atosiban was found to be highly effective (81.8%) in delaying delivery by ≥48 hours among pregnant women presenting with tpl to a tertiary hospital in oman. this finding agrees with previous studies showing a significant increase in the proportion of women in whom delivery was delayed by ≥48 hours among those receiving atosiban compared to a placebo.15–18 further analysis in the present study also showed that the success rate of atosiban increased alongside gestational age. the majority of women in the present study achieved uterine quiescence in <12 hours following the administration of atosiban. a similar study conducted in india showed that atosiban resulted in a statistically significant reduction in the frequency of uterine contractions.19 a large randomised trial of 531 women by romero et al. concluded that the use of atosiban in patients with tpl in comparison to a placebo was effective in prolonging pregnancy by up to seven days for those at ≥28 gestational weeks, with a low rate of maternal or fetal adverse effects.20 similarly, the current study found that atosiban resulted in no serious adverse effects in terms of maternal safety profile, with only 9.4% of women reporting minor side-effects such as hypotension, headache, dizziness and tachycardia. other studies have also reported fewer adverse effects with atosiban, with this agent appearing to be better tolerated by pregnant women compared to other tocolytic drugs.21–23 with regards to neonatal outcomes, the current study found that atosiban success was associated with a significant reduction in the frequency of rds. this can be attributed to the fact that the administration of atosiban was successful in delaying delivery, thus allowing for the prolonged administration of corticosteroids to enhance fetal lung development. this is in agreement with the results of the present study, that showed statistical significance (p <0.001). however, previous randomised trials comparing atosiban with other tocolytic drugs have shown that the former results in a higher rate of nicu admission.20,24 in contrast, the present study found that atosiban success was associated with a significant reduction in nicu admissions. this could be attributed to several factors including the careful selection of patients presenting with tpl and early intervention with atosiban, resulting in a high success rate in terms of delaying delivery by ≥48 hours. in addition, most patients included in such trials are <28 gestational weeks, whereas the median gestational age in the current study was 31.4 weeks.25,26 according to previous research, the administration of atosiban has been found to result in a higher frequency of neonatal deaths compared to those who received a placebo.5,27 however, the present study observed a statistically significant reduction in neonatal deaths nihal al-riyami, hanin al-badri, sanjay jaju and silja pillai table 5: neonatal outcomes associated with atosiban succ ess among pregnant women presenting with threatened preterm labour to and delivering at the sultan qaboos university hospital, muscat, oman (n = 132) outcome n (%) p value† atosiban success* (n = 103) atosiban failure (n = 29) rds <0.001 present 19 (18.4) 22 (75.9) absent 84 (81.6) 7 (24.1) hyperbilirubinaemia <0.001 present 14 (13.6) 14 (48.3) absent 89 (86.4) 15 (51.7) nicu admission <0.001 yes 28 (27.2) 27 (93.1) no 75 (72.8) 2 (6.9) neonatal death <0.001 yes 1 (1) 6 (20.7) no 102 (99) 23 (79.3) rds = respiratory distress syndrome; nicu = neonatal intensive care unit. *defined as prolonging deliver y by ≥48 hours. †calculated using a chi-squared test. in cases in which atosiban was successful in delaying delivery by ≥48 hours compared to neonates in whom delivery occurred at <48 hours. this could be attributed to the fact that other studies include a greater number of women at <26 gestational weeks randomised to the atosiban group, whereas most women in the present study were admitted at a more advanced gestational age.5,27 to the best of the authors’ knowledge, this is the first study from oman to evaluate the effectiveness of atosiban in prolonging pregnancy and preventing ptb among women with tpl. however, there were several limitations. in addition to the retrospective nature of the study design, the low sample size and inclusion of pregnant women from a single tertiary hospital could have affected the generalisation of the results. moreover, neonatal outcome information was not available for those women who did not deliver at squh. finally, it was not possible to compare outcomes among women receiving other tocolytic drugs, as atosiban has been the most commonly tocolytic agent used for the management of tpl in oman over the past decade. additional multicentre studies are therefore recommended to compare the effectiveness and safety profile of atosiban with other tocolytic agents. conclusion the current study found atosiban to be highly effective in delaying delivery by ≥48 hours in pregnant women with tpl, with very few adverse maternal side-effects or neonatal outcomes. however, further research is recommended to compare the safety and efficacy of atosiban with other cost-effective tocolytic drugs such as nifedipine. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. beck s, wojdyla d, say l, betran ap, merialdi m, requejo jh, et al. the worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. bull world health organ 2010; 88:31–8. https://doi.org/10.2471/blt.08.062554. 2. hubinont c, debieve f. prevention of preterm labour: 2011 update on tocolysis. j pregnancy 2011; 2011:941057. https:// doi.org/10.1155/2011/941057. 3. kinney mv, lawn je, howson cp, belizan j. 15 million preterm births annually: what has changed this year? reprod health 2012; 9:28. https://doi.org/10.1186/1742-4755-9-28. 4. chawanpaiboon s, vogel jp, moller ab, lumbiganon p, petzold m, hogan d, et al. global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. lancet glob health 2019; 7:e37–46. https://doi. org/10.1016/s2214-109x(18)30451-0. 5. hamilton sa, tower cl. management of preterm labour. obstet gynaecol reprod med 2013; 23:114–20. https://doi. org/10.1016/j.ogrm.2013.02.009. 6. national institute for health and care excellence. preterm labour and birth: nice guideline [ng25]. from: www.nice. org.uk/guidance/ng25/documents/preterm-labour-and-birthdraft-guideline-nice2 accessed: jul 2020. 7. berkman nd, thorp jm jr, lohr kn, carey ts, hartmann ke, gavin ni, et al. tocolytic treatment for the management of preterm labor: a review of the evidence. am j obstet gynecol 2003; 188:1648–59. https://doi.org/10.1067/mob.2003.356. 8. schleußner e. the prevention, diagnosis and treatment of premature labor. dtsch arztebl int 2013; 110:227–35. https:// doi.org/10.3238/arztebl.2013.0227. 9. kim sh, riaposova l, ahmed h, pohl o, chollet a, gotteland jp, et al. oxytocin receptor antagonists, atosiban and nolasiban, inhibit prostaglandin f2α-induced contractions and inflamm atory responses in human myometrium. sci rep 2019; 9:5792. https://doi.org/10.1038/s41598-019-42181-2. 10. papatsonis dn, flenady v, liley hg. maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. cochrane database syst rev 2013; 10:cd005938. https://doi.org/10.1002/14651858.cd005938.pub3. 11. papatsonis d, flenady v, cole s, liley h. oxytocin receptor antagonists for inhibiting preterm labour. cochrane database syst rev 2005; 3:cd004452. https://doi.org/10.1002/14651858. cd004452.pub2. 12. flenady v, reinebrant he, liley hg, tambimuttu eg, papatsonis dn. oxytocin receptor antagonists for inhibiting preterm labour. cochrane database syst rev 2014; 6:cd004452. https://doi.org/10.1002/14651858.cd004452.pub3. 13. lamont rf, jørgensen js. safety and efficacy of tocolytics for the treatment of spontaneous preterm labour. curr pharm des 2019; 25:577–92. https://doi.org/10.2174/13816128256661903 29124214. 14. van winden tm, klumper j, kleinrouweler ce, tichelaar ma, naaktgeboren ca, nijman ta, et al. effects of tocolysis with nifedipine or atosiban on child outcome: follow-up of the apos tel iii trial. bjog 2020; 127:1129–37. https://doi.org/10.111 1/1471-0528.16186. 15. de heus r, mulder ej, visser gh. management of preterm labor: atosiban or nifedipine? int j womens health 2010; 2:137–42. https://doi.org/10.2147/ijwh.s7219. 16. rundell k, panchal b. preterm labor: prevention and manage ment. am fam physician 2017; 95:366–72. 17. wathes dc, borwick sc, timmons pm, leung st, thornton s. oxytocin receptor expression in human term and preterm gestational tissues prior to and following the onset of labour. j endocrinol 1999; 161:143–51. https://doi.org/10.1677/joe.0.16 10143. 18. arrowsmith s, kendrick a, wray s. drugs acting on the pregnant uterus. obstet gynaecol reprod med 2010; 20:241–7. https://doi.org/10.1016/j.ogrm.2010.05.001. 19. dewan b, shah d. the clinical experience of atosiban in preterm labour. j adv med med res 2016; 13:1–9. https://doi. org/10.9734/bjmmr/2016/23823. 20. romero r, sibai bm, sanchez-ramos l, valenzuela gj, veille jc, tabor b, et al. an oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo controlled trial with tocolytic rescue. am j obstet gynecol 2000; 182:1173–83. https://doi.org/10.1067/mob.2000.95834. short-term outcomes of atosiban in the treatment of preterm labour at the sultan qaboos university hospital, muscat, oman a tertiary care experience e264 | squ medical journal, may 2021, volume 21, issue 2 https://doi.org/10.2471/blt.08.062554 https://doi.org/10.1155/2011/941057 https://doi.org/10.1155/2011/941057 https://doi.org/10.1186/1742-4755-9-28 https://doi.org/10.1016/s2214-109x%2818%2930451-0 https://doi.org/10.1016/s2214-109x%2818%2930451-0 https://doi.org/10.1016/j.ogrm.2013.02.009 https://doi.org/10.1016/j.ogrm.2013.02.009 https://doi.org/10.1067/mob.2003.356 https://doi.org/10.3238/arztebl.2013.0227 https://doi.org/10.3238/arztebl.2013.0227 https://doi.org/10.1038/s41598-019-42181-2 https://doi.org/10.1002/14651858.cd005938.pub3 https://doi.org/10.1002/14651858.cd004452.pub2 https://doi.org/10.1002/14651858.cd004452.pub2 https://doi.org/10.1002/14651858.cd004452.pub3 https://doi.org/10.2174/1381612825666190329124214 https://doi.org/10.2174/1381612825666190329124214 v v https://doi.org/10.2147/ijwh.s7219 https://doi.org/10.1677/joe.0.1610143 https://doi.org/10.1677/joe.0.1610143 https://doi.org/10.1016/j.ogrm.2010.05.001 https://doi.org/10.9734/bjmmr/2016/23823 https://doi.org/10.9734/bjmmr/2016/23823 https://doi.org/10.1067/mob.2000.95834 clinical and basic research | e265 21. fullerton gm, black m, shetty a, bhattacharya s. atosiban in the management of preterm labour. clin med insights womens health 2011; 4:9–16. https://doi.org/10.4137/cmwh.s5125. 22. coomarasamy a, knox em, gee h, song f, khan ks. effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with an indirect comparison of randomised trials. bjog 2003; 110:1045–9. https://doi.org/10.1111/j.14710528.2003.03071.x. 23. sanu o, lamont rf. critical appraisal and clinical utility of atosiban in the management of preterm labor. ther clin risk manag 2010; 6:191–9. https://doi.org/10.2147/tcrm.s9378. 24. salim r, garmi g, nachum z, zafran n, baram s, shalev e. nifedipine compared with atosiban for treating preterm labor: a randomized control trial. obstet gynecol 2012; 120:1323–31. https://doi.org/10.1097/aog.0b013e3182755dff. 25. tsatsaris v, carbonne b, cabrol d. atosiban for preterm labour. drugs 2004; 64:375–82. https://doi.org/10.2165/00003495200464040-00003. 26. denny jm, culhane jf, goldenberg rl. prevention of preterm birth. womens health (lond) 2008; 4:625–38. https://doi. org/10.2217/17455057.4.6.625. 27. meher s, alfirevic z. choice of primary outcomes in randomized trials and systematic reviews evaluating interventions for preterm birth prevention: a systematic review. bjog 2014; 121:1188–94. https://doi.org/10.1111/1471-0528.12593. nihal al-riyami, hanin al-badri, sanjay jaju and silja pillai https://doi.org/10.4137/cmwh.s5125 https://doi.org/10.1111/j.1471-0528.2003.03071.x https://doi.org/10.1111/j.1471-0528.2003.03071.x https://doi.org/10.2147/tcrm.s9378 https://doi.org/10.1097/aog.0b013e3182755dff https://doi.org/10.2165/00003495-200464040-00003 https://doi.org/10.2165/00003495-200464040-00003 https://doi.org/10.2217/17455057.4.6.625 https://doi.org/10.2217/17455057.4.6.625 https://doi.org/10.1111/1471-0528.12593 january 2007 vol 7 correct a.indd oman is an islamic country on the arabian peninsula in the middle east. the popula-tion of oman is about 2.5 million with the bulk concentrated in the north and the south of the country. prior to 1970 there were only one small missionary hospital and a few clinics scattered over the country. oman has witnessed great strides in development during the last thirty years. the hospital bed space grew from only 12 beds in 1970 to 5,200 beds and about 120 health centers in 2000. with the improvements in health care, infant mortality has decreased from 110 per 1000 in 1970 to 17 per 1000 in 2000.1 the 1993 census of oman suggests a wide-based age pyramid, with the majority of the population under the age of 20. this large young population base is likely to herald a ‘baby boom’, and a doubling of the population in 14 years is expected.2,3,4,5 as a response the ministry of health started to institute a number of birth spacing initiatives in the early 1990s.1 comprehensive studies are needed to appraise the effect of such programmes. at the turn of this century, the population of the world surpassed 6.1 billion. this means that the number of people has more than doubled in the past 50 years. however, population growth has leveled off in most industrialized countries and in some countries has even begun to decline.6,7 although debilitating diseases such as malaria and acquired immune deficiency sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© 1 department of mathematics and statistics, sultan qaboos university, sultanate of oman, 2 department of studies and research, ministry of health, sultanate of oman, 3 department of behavioral medicine, sultan qaboos university, sultanate of oman *to whom correspondence should be addressed. email: atsu@squ.edu.om a study of fertility patterns of ever married women in oman *atsu s s dorvlo1, charles s bakheit1, asya al-riyami2, magdi morsi2, samir al-adawi3 abstract objective: to examine the relation between age, education, residence and fertility rate and change in fertility rate between 994/95 and 999/2000. methods: the data for the study was extracted from the oman national health survey, 2000. the birth histories data was used to extract data on woman years and births in the periods 990 to 994 and 995 to 2000. results: the marital fertility rate in 999/2000 was 7.2 births. the rates for rural and urban dwellers were 8.07 and 6.75 respectively in 999/2000. corresponding rates in 994/95 (8.65, 8.30 and 9.69 respectively) were significantly higher than those in 999/2000 for all categories, indicating a reduction in rates. in both periods the higher the education level of the mother the lower her fertility. conclusion: education was a strong determinant of fertility. this study confirms that the higher the education of the woman the lower her fertility and that fertility is on the decline in oman. keywords: fertility rate, marital fertility, reproductive history, woman years العمانيات النساء اخلصوبة عند مناذج دراسة فيما ومعرفة ، أخرى جهة من (التحضر) والتمدين والعمر التعليمِ جهة، ومستوى معدالت اخلصوبة الزوجية من امللخص: الهدف: إيجاد العالقة بني مان عُ صحة مسح من الدراسة معطيات الطريقة: أخذت .2000/1999 وسنة (املرجع) 95/ 1994 سنة بني تغيّرتْ قد الزوجية اخلصوبة كانت إذا .2000 1995 إلى ومن ،1994 1990 إلى من الفترات في ــاء النس ووالدات أعمار ملعرفة ــتعمل تس كانت تأريخ الوالدة بيانات .2000 ــنة لس الوطني /1999 6.75 على التوالي في (8.07 و ــة واملدين ــكان الريف س معدالت كانت 7.12 والدة. 2000/1999 كان في الزوجي اخلصوبة ــدل مع النتائــج: 2000/1999 ــنة س معدالت من أعلى وهي التوالي) 8.30 و9.69 على ,8.65) 95/1994 فكانت منهما في لكل اخلصوبة ــدالت ــا مع أم . (2000 تعليمَ ــةِ أن الدراس هذه د اخلالصة: تُؤكّ اخلصوبة. في احملددة العوامل القوية من التعليم كان املعدالت. تلك انخفاض في إلى ــير يش مما األصناف، لكلّ انخفاض. في وان اخلصوبة أقل ، اخلصوبة كانت كلما عاليا كان املرأةِ كلما املرأة. عمر ، التناسل تأريخ ، الزوجية اخلصوبة ، اخلصوبة املفردات املفتاحية: معدل o r i g i n a l s t u d y at s u s s d o r v l o , c h a r l e s s b a k h e i t, a s ya a l r i ya m i , m a g d i m o r s i a n d s a m i r a l a d aw i 34 disease are likely to mitigate the current estimate of population growth,8 the trend in developing countries, including arab countries, suggests the existence of various factors favoring rapid population growth. various studies have given conflicting reports on population growth in the islamic world.1,2,3,4,5,11,12,13,14 to our knowledge, no such studies have come out of oman. in a paternalistic society such as oman, women have traditionally played domestic and gender roles that are strongly associated with women’s biological imperatives.14,15 however, the recent acculturation and the spread of education in the country have ushered in new roles and opportunities for women.16 despite cultural constraints, women in oman have infiltrated positions that were once considered male domains.17 in education, females appear to be performing better than their male counterparts.18 it is apparent that such newly found social status has impacted on fertility rates. studies from developing countries suggest that education appears to be an antidote to high birth rates, since fertility is highly influenced by the level of education of women.19,20 the relationship between education and fertility has yet to be clearly established in oman. previous studies have also suggested that there are significant differences between fertility in urban and rural areas in many developing countries.21 similar studies are needed to examine the fertility rate between rural and urban populations in oman so that effective family planning strategies can be contemplated. the aim of this paper is three-fold: (i) to examine the marital fertility rate, which is the general fertility rate for ever married women in oman; (ii) to assess the impact of education and dwelling on fertility; and (iii) to examine whether the rate of fertility has changed over time. data the data for this study were derived from the oman national health survey-2000 (nhs-2000), which alriyami22 conducted nationally from september 1999 to march 2000. the oman national health survey was a comprehensive survey that generated information on, among other things, patterns and determinants of morbidity and mortality, reproductive health and the prevalence of some common diseases. a multi-stage stratified probability-sampling plan was used to select respondents that covered the 10 regions of oman. suleiman et al.1 reported the details of the design. the ministry of health of oman conducted the nhs-2000 with support from unicef and unfpa. a questionnaire administered by trained personnel was used in collecting the various pieces of information. some parts of the questionnaire were filled from documents provided by respondents. the reproductive health questionnaire consisted of six modules – a woman’s background, reproductive history, maternal health, family planning knowledge, social status and aids awareness. the reproduction module on which the current article was based obtained information on the number of children and the dates of birth of all children ever born. for the present analysis the relevant variables from that survey included the date of birth, age, dwelling and level of education. this study focused on only ever-married omani women and hence the rates discussed in this article are called marital fertility rates, which are in effect the general fertility rates for ever-married women. in oman 37% of all women are single, 52% are married and about 3% are divorced (nhs-2000). over 84% of all women in the age group 25 to 49 are married, while 8% of women between 15 and 19 are married. since the database contained the birth dates of all children ever born to the women, two secondary data sets were generated; the first, called 1999/2000 data, used the actual interview date as the reference date in computing the number of children and woman years. the second data set, called 1994/95 data, assumed a hypothetical survey date that was five years earlier than the actual interview as the reference date. women who were 15 to 49 in 1999/2000 were 10 to 44 in 1994/95. therefore to compare the same set of cohorts in 1994/95 with similar cohorts in 1999/2000, only women who were 20 – 49 during the interview in 1999/2000 were included in that part of the computations [tables 5 and 6]. besides, women who had died between 1994/95 and 1999/2000 were not included in the 1994/95 data, though they would have been included if the interview had actually taken place then. excluded also from the 1994/95 computations were all women who were married between 1994/95 and 1999/ 2000 as they were not married before the hypothetical interview in 1994/95. that is, data on 15-49 year olds in 1999/2000 were used in computing the estimates reported in tables 3 and 4, while 15 to 44-year olds in 1999/2000 were used for estimates reported in tables 5 and 6. the data were analyzed using the statistical package statxact. nonparametric anova was used to 35 a s t u d y o f f e r t i l i t y pat t e r n s o f e v e r m a r r i e d wo m e n i n o m a n compare the rates. m e t h o d o f e s t i m a t i n g f e r t i l i t y r a t e s the marital fertility rate, mfr, is computed using the method described in the next section. readers are referred to schmertmann and caetano23 for more details. since there may be only one data set for the estimations the degree of accuracy of the estimate is usually not possible to determine. bootstrap24 methods were used to compute the 95% confidence bounds for the estimates of the fertility rates. note that these bounds are not symmetric about the mean as normality was not assumed. 3.1 estimation of fertility by last t woman-years method suppose x is the number of years between the time of marriage and the interview date for a particular woman, that is, x = interview date – marriage date. this woman will be deemed to be susceptible to having a child in these x+1 years. in this conservative society, sexual activity usually starts at marriage. assuming a truncation time of t years, this woman would contribute z equal to minimum (x+1, t) woman years of susceptibility to child bearing. if this woman was y years old at the time of the survey then these z woman years of susceptibility are distributed one woman year each for the years y, y-1, y-2,-y-z. in addition, if this woman had provided k births during the z years, these births would be counted against the particular years. for example, consider a woman 25 years old at the time of the survey that was married at age 19 and had births at ages 22 and 24. she would provide one woman-year of susceptibility to each of ages 19, 20, 21, 23 and 25 and provide a birth and a woman year to each of the ages 22 and 24 (w1, tables 1 and 2). another woman (w2) who was married at 20 and had no children by age 22, when she was interviewed, would contribute only 3 woman years. see tables 1 and 2 for more illustrations. the estimator of the fertility rate for a particular year is the number or sum of births in that year divided by the number or sum of all woman years for that age [table 2]. in this formulation a decision needs table 1: sample data from birth histories of 5 women years from interview date 0-1 1-2 2-3 3-4 4-5 5-6 6-7 woman 1 25 (24) 23 (22) 21 20 [19] woman 2 22 21 [20] woman 3 23 22 21 20 19 [18] woman 4 (24) 23 22 (21) [20] woman 5 24 (23) [22] nb: (23) indicates birth at age 23, [20] indicates marriage at 20 table 2: distribution of woman years by age at risk for 5 women, t=5 age at risk w1 w2 w3 w4 w5 total births at age woman years rate 18 [1]* 0 0 0 19 [1]* 1 [1]* 0 1 0/1 20 1* [1] 1 1 0 3 0/3 21 1 1 1 (1) 1 4 1/4 22 (1) 1 1 1 [1] 1 5 1/5 23 1 1 1 (1) 1 4 1/4 24 (1) (1) 1 2 3 2/3 25 1 0 1 0/1 1.37 nb: (1) indicates a woman year and a birth. 1 indicates one woman year. [1] indicates marriage year and a woman year; * indicates the year is not contributed because of truncation at s u s s d o r v l o , c h a r l e s s b a k h e i t, a s ya a l r i ya m i , m a g d i m o r s i a n d s a m i r a l a d aw i 36 to be made on how far back (t years) from the interview date to truncate the data. if t=1 is used then the method is equivalent to the “birth last year” method.23 the truncation time, t, equal to 5 years, is usually taken since it is not too far from the interview date to make the results outdated. the fertility rate of any group is obtained as the sum of the ratio of number of births to number of woman years over the individual years/ages. for example the fertility rate of these five women will be 1.37. r e s u l t s the women in this data set were between 14 and 49 years old. their average age was 31 years with a standard deviation of 7.8 years. seventy-three percent lived in the urban areas while 23% lived in the rural areas. on average the women in this sample were married by age 17 years and the average number of children born was 5. m a r i ta l fe rti l i t y r ate s i n om a n , 9 9 9 / 2 0 0 0 i n te rv i e w date data table 3 shows the estimates of the marital fertility rates of omani women aged 15 to 49 years by categories. the marital fertility rate (mfr) based on the 1999/2000 survey date was 7.12. the 95% confidence interval was (6.90, 7.37). obermeryer14 reported that between 1950 and 1990 oman had a constant total fertility rate of 7.2. according to a recent report the total fertility rate has declined to 4.8 in 2000 (nhs-2000). note that the marital fertility rate is the total fertility rate for only married women as the base group. hence it is expected that the marital fertility rate will be higher than the total fertility rate. there was a marked difference between the mfr for the rural dwellers and the urban dwellers (p-value<0.01). the rate for the rural dwellers was 1.3 births more than that of the urban dwellers. education also had a marked effect on the fertility rates (p-value<0.01). the more educatation omani women achieved the lower the rates. the college or university educated had a rate of 4.75 births while the lowest educated achieved a rate of almost 8 births. m a r i ta l fe rti l i t y r ate s i n om a n , a s sumi n g 9 94 / 95 i n te rv i e w date assuming a 1994/95-interview date the marital fertility rate for oman was 8.65 with 95% confidence limits (8.36, 8.95) [table 4]. the fertility rate was higher in the rural areas than in the urban areas. the rates were 9.69 in the rural areas compared to 8.30 in the urban areas. as in 1999/2000 results, education had an inverse relationship with fertility. the difference between the rates for the no-education group of women and the college or university educated women was 4.3 births. the rates in 1994/95 were higher than the corresponding rates in 1999/2000. c ompa r i s o n o f fe rti l i t y r ate s f o r 9 94 / 95 a n d 9 9 9 / 2 0 0 0 table 5 gives the fertility rates in 1994/95 compared with those in 1999/2000. it should be noted that only women who were between 20 and 49 during the 1999/ 2000 interviews were used for the computations for the 1994/95 estimates while the estimates for 1999/ 2000 were restricted to women who were between 15 and 44 years old, in order that the same groups could be compared. for oman as a whole, the fertility rate reduced by about 1.8 births, from 8.65 in 1994/95 to 6.86 in 1999/2000. there was a reduction for all age cohorts. there was a drop of almost two births in the urban areas and 1.6 in the rural areas in this time interval. the standardized fertility ratios in the table 3: bootstrap estimates of marital fertility using data on 15-49 year olds in 1999/2000 sample size no. of births up to t=5 no. of woman years estimate of fertility 95% lower confidence limit 95% upper confidence limit oman 2037 2338 9482 7.12 6.90 7.37 urban 1492 1612 6934 6.75 6.47 7.01 rural 545 726 2548 8.07 7.60 8.48 no education 747 817 3703 7.70 7.22 8.22 up to primary 680 843 3221 7.03 6.65 7.45 prep-secondary 488 547 2037 6.17 5.68 6.82 college-university 122 131 521 4.75 4.06 5.49 37 a s t u d y o f f e r t i l i t y pat t e r n s o f e v e r m a r r i e d wo m e n i n o m a n last column of the table, quantified the general reductions in the rates from 1994/95 to 1999/2000.25 all the education categories showed big drops in rates. the education classification in 1999/2000 was retained for their status in 1994/95 since this classification was not available for the 1994/95 data. table 6 shows the rates by age cohorts. again all categories experienced decreases in the fertility rates. the biggest drops were in the 35-44 cohorts. d i s c u s s i o n studies of fertility from different parts of the arab world suggest that since the late 1970s there has been a steady decline in fertility.26 however, such decline is not uniform.26,27,28,29,30,31 in yemen, where women begin childbearing at a relatively early age and a large proportion of ever-married women reach high parity at a relatively fast pace, the fertility rate exceeds seven children per woman of reproductive age.23 in contrast, in north africa women are characterized by delays in the onset of and a slow pace of childbearing; and a smaller proportion of ever-married women reach high parity with a fertility rate of less than 5 births per woman.23 while a woman’s fertility has been suggested to be inversely related to her level of education,20 this issue has so far not been sufficiently investigated in the arab world32. the present data suggest that in oman the higher the education of a woman, the lower the fertility rate, which tend to agree with similar studies cited earlier. this largely supports previous studies that empowerment of women with education is a strong catalyst for a successful campaign for health related matters.26 the high fertility rates in developing countries place heavy financial burdens on families with the resultant negative effect on economic growth and quality of life. table 4: bootstrap estimates of marital fertility using data on 15-44 year olds in 1994/95 sample size no. of births up to t=5 no. of woman years estimate of fertility 95% lower confidence limit 95% upper confidence limit oman 1675 2499 7598 8.65 8.36 8.95 urban 1224 1778 5579 8.30 7.97 8.64 rural 451 721 2019 9.69 9.07 10.26 no education 729 1205 3558 9.54 9.10 10.01 up to primary 594 920 2689 9.25 8.11 10.24 prep-secondary 280 304 1084 5.71 5.17 6.26 college-university 72 70 267 5.25 4.32 6.37 table 5: estimates of age specific fertility rates for oman for 1994/95 and 1999/2000 and the corresponding standardized fertility ratios 1994/95 1999/2000 standardized fertility ratio with 1994/95 as base year no. of births woman years marital fertility no. of births woman years marital fertility oman 2499 7598 8.65 2288 8882 6.86 0.80 urban 1778 5579 8.30 1574 6469 6.44 0.79 rural 721 2019 9.69 714 2413 8.13 0.84 no education 1205 3558 9.54 773 3193 7.42 0.78 up to primary 920 2689 9.25 838 3161 6.76 0.81 prep-secondary 304 1084 5.71 546 2017 6.21 0.94 college-university 70 267 5.25 131 511 4.75 0.91 nb: educational status as at 1999/2000 used for 1994/95 classification at s u s s d o r v l o , c h a r l e s s b a k h e i t, a s ya a l r i ya m i , m a g d i m o r s i a n d s a m i r a l a d aw i 38 like elsewhere, oman has traditionally had high fertility rates under the impression that some children may not survive into adulthood.2,33 with very limited or almost non-existent medical services prior to 1970, mortality rates, both for mother and child, were very high in oman. however with improved medical facilities after 1970 and the resultant increase in life expectancy, coupled with high fertility, population growth increased rapidly.3 children are also perceived as gifts from god, and this perception might also encourage high fertility. this could entail difficulties in employment provision, infrastructure development and service delivery, particularly in education and health.34,35 the above explains to some extent the high fertility rates reported in this study. however there are indications that the rates are decreasing. the standardized fertility ratios indicated a general decrease from 1994/95 to 1999/2000 within all cohorts. the older women had higher decreases. although this should be a welcome beginning, more concerted effort is needed to target women who are not yet benefiting from modern education. as family planning is sometimes viewed with suspicion in many traditional societies,36 its implementation needs to be handled with cultural sensitivity and skill for it to be acceptable. the current emphasis of family planning programs should be on educating families to increase the intervals between births rather than focus on reducing the number of children. this apparently is more compatible with socio-cultural teaching especially in the middle east. for such programs to work, less educated women will have to be especially targeted, as these are the groups with the highest fertility rates. l i m i t a t i o n s o f t h e s t u d y some limitations associated with the data analyzed in this paper have potential implications on the interpretation of the findings. a common problem with retrospective studies is the reliability of recall.37 the older women may not be able to remember accurately information related to the birth of older children. secondly, this study hinges on the idea that there is a clear dichotomy between urban and rural areas, both socially and geographically. in oman the urban-rural divide is not very clear. most urban dwellers have very strong ties with the rural areas, which they visit almost on a weekly basis. also many urban residents tend to marry from the rural areas. this notwithstanding, the present data show that there are discernible differences in fertility rates between rural and urban areas in oman. thirdly, the term education tends to pose difficulties in the arab/islamic world where many individuals do receive a traditional education known as ‘madrasa’, leading to a literacy or at least cursory knowledge of the koran.38 however, information about whether the present cohort acquired a madrasa education was not elicited. in addition, the level of education as elicited from the present sample is likely to have missed other important variables such as quality and skills acquisition. future studies ought to explore the contribution of traditional education and other skills to fertility. this study has explored the relationship between marital fertility rates and the level of education, age and urbanization, and assessed whether the rate of fertility has changed over time. in general the fertility rates were high but a decline was noted since the rates in 1994/95 were significantly higher than the rates in 1999/2000. despite these caveats, the impact of educatable 6: estimates of age specific fertility rates for oman for 1994/95 and 1999/2000 and the corresponding standardized fertility ratios by cohorts cohorts 1994/95 1999/2000 standardized fertility ratio with 1994/95 as base yearno. of births woman years marital fertility no. of births woman years marital fertility 15-19 362 1125 1.47 198 739 1.17 0.78 20-24 686 1874 1.83 655 1991 1.64 0.90 25-29 660 1855 1.78 624 2123 1.47 0.83 30-34 511 1582 1.60 471 1881 1.25 0.78 35-39 226 881 1.26 280 1586 0.87 0.69 40-44 54 281 0.71 60 562 0.46 0.57 39 a s t u d y o f f e r t i l i t y pat t e r n s o f e v e r m a r r i e d wo m e n i n o m a n tion, age and urbanization on fertility rates were found to be significant. a c k n ow l e d ge me n ts this study was supported by internal grant ig/sci/ doms/01/05 from sultan qaboos university. we are grateful to the ministry of health, sultanate of oman for providing us with the data. r e f e r e n c e s 1. sulaiman aj, al-riyami a, farid s, ebrahim, gj oman family health survey 1995. j trop pediatr 2001; 1:33. 2. al-rawahi s, sharts-hopko nc. birth spacing initiative in oman. j cult divers 2002 9:23-26. 3. eickelman c. fertility and social change in oman women’s perspective. middle east j 1993; 47:652-666. 4. lambourne a. oman’s population profile 1970-2000. muscat, sultanate of oman: ministry of health, 1990. 5. unicef . the state of the world’s children. oxford. oxford university press 1997 6. bongaarts j. fertility decline in the developed world: where will it end? the am econ rev 1999; 89:256-260. 7. o’neill, b. & balk, d. (2001). popul bul. population bulletin 56: 3-38. 8. stover j. modeling the demographic impact of aids. j health popul nutr 2001; 20:102-103. 9. birks js. some aspects of demography related to development in the middle east with special reference to the sultanate of oman. bulletin bull br soc middle east stud 1976; 3:79-88. 10. courbage y. economic and political issues of fertility transition in the arab world answers and open questions. popul environ 1999; 20:353-380. 11. eickelman c. oil, fertility, and women’s status in oman in, everyday life in the muslim middle east. in. d.a. bowen and e.a. early ed. bloomington, indiana: indiana university press, 2002: 128-135. 12. ladier-fouladi m. the fertility transition in iran. population and development review 1997; 9:191-213. 13. lambourne a. oman’s population profile 1970-2000. muscat, sultanate of oman: ministry of health, 1990. 14. obermeyer cm. islam, women, and politics the demography of arab countries. population and development review 1992; 18:33-60. 15. riphenburg cj. changing gender relations and the development process in oman. islam, gender, and social change 1998, oxford: oxford university press, 1998, 144-168. 16. al-riyami, warren rl, gerald mcelwee. opportunities and challenges for omani women entrepreneurs. inte j entrepren innova 2002; 3:133-144. 17. al-lamki, sm. women in the labor force: the case of the sultanate of oman. international journal of management. int j manag 2000; 17:166-174. 18. sulaiman sm, elmneizel f. adjustment level among sultan qaboos university students and its relation to sex, class level, grade point average, and residency. dirasat 1999; 26:1-18. 19. appiah en, mcmahon ww. the social outcomes of education and feedbacks on. growth in africa. j dev stud 2002; 38:27-68. 20. gupta n, mahy m. adolescent child bearing in sub-saharan africa: can increased schooling alone raise ages at first birth? demogr res 2003; 8:93-105. 21. potter je, schmertmann cp, cavenaghi sm. fertility and development: evidence from brazil demography 2002; 39:739-761. 22. al-riyami a, afifi mm, al-kharusi h, morsi m. oman national health survey 2000. ministry of health, sultanate of oman 2001; 9:893-903. 23. schmertmann cp, caetano aj. estimating parametric fertility models with open birth interval data. demogr res 1999; 1-5:28. 24. efron b. bootstrap methods: another look at the jackknife. annals of statistics 1979; 7:126. 25. hinde a. demographic methods. in. london: edward arnold publishers, 1998: 305. 26. amin s, lloyd cb. women’s lives and rapid fertility decline: some lessons from bangladesh and egypt. popul res policy rev 2002; 21:275-317. 27. courbage y. declining fertility in the arab peninsula. 1995; 50:415-445. 28. o’neill b, balk d. world population futures. popul bull 2001; 56:3-38. 29. misch a. purdah and overpopulation in the middle east. world watch 1990; 3:10-11. 30. nijim bk. spatial aspects of demographic change in the arab world. j asian afr stud 1984; 19: 150-173. 31. roudi n. population policies vary in the middle east. popul bul 1993; 21:3-10. 32. murthi m. fertility change in asia and africa. world development 2002; 30:1769-1778. 33. kridli s. health beliefs and practices among arab women. mcn am j matern child 2002; 27:178-182. 34. the world bank. world development report oxford: oxford university press 1998. 35. zaidan za, burke dt, dorvlo ass, et al. deliberate self-poisoning in oman. trop med int health 2002; at s u s s d o r v l o , c h a r l e s s b a k h e i t, a s ya a l r i ya m i , m a g d i m o r s i a n d s a m i r a l a d aw i 40 7:549-556. 36. naamane-guessous s. traditional methods still widely used. plan parent chal 1993; 1:14-16. 37. vitzthum vj. suckling patterns lack of concordance between maternal recall and observational data. am j hum biol 1994; 6:551-562. 38. kemper m. madrasa. the transmission of learning in the muslim world. islam 2000; 77:189-190.   neuropharmacology of dopamine receptors: implications in neuropsychiatric diseases frank i. tarazi abstrac t. there has been an extraordinary recent accumulation of information concerning the neurobiology and neuropharmacology of dopamine (da) receptors in the mammalian central nervous system. many new da molecular entities have been cloned, their gene, peptide sequences and structures have been identified, their anatomical distributions in the mammalian brain described, and their pharmacology characterized. progress has been made toward developing selective ligands and drug-candidates for different da receptors. the new discoveries have greatly stimulated preclinical and clinical studies to explore the neuropharmacology of da receptors and their implications in the neuropathophysiology of different neuropsychiatric diseases including schizophrenia, parkinson’s disease and attention-deficit hyperactivity disorder. accordingly, it seems timely to review the salient aspects of this specialized area of preclinical neuropharmacology and its relevance to clinical neuropsychiatry. key words: antipsychotics, adhd, basal ganglia, dopamine receptors, parkinson’s disease, schizophrenia consolidated department of psychiatry and neuroscience program, harvard medical school; boston, ma; mailman research center, mclean division of massachusetts general hospital, belmont, ma , usa. e-mail: ftarazi@hms.harvard.edu d ()     within the mammalian central nervous system (cns). da-containing neurons arise mainly from da cell bodies in the substantia nigra and ventral tegmental area in mid-brain region, and are organized into four major subsystems [figure ]:1–6 (i) the nigrostriatal system involving neurons projecting from the substantia nigra pars compacta to the caudate-putamen of the basal ganglia. is is the major da system in the brain as it accounts for about  of the total da in the brain, and its degeneration makes a major contribution to the pathophysiology of parkinson’s disease; (ii) the mesolimbic system that originates in the midbrain tegmentum and projects to the nucleus accumbens septi and lateral septal nuclei of the basal forebrain as well as the amygdala, hippocampus, and the entorhinal cortex, all of which are considered components of the limbic system and so are of particular interest for the pathophysiology of idiopathic psychiatric disorders; (iii) the mesocortical system, which also arises from neuronal cell bodies in the tegmentum which project their axons to the cerebral cortex, particularly the medial prefrontal regions; (iv) the tuberinfundibular pathway, which is a neuroendocrinological pathway arising from the arcuate and other nuclei of the hypothalamus and ending     :   , : , : , – ©   dopamine (tarazi( �� �������������������� ��������� �����: �� ���������������� ����-����� ���� ����� ������:������ �� ������������ �� ����������� ��������� ������ ������ ����� ���� ������� ������ ��� ����� ������� ����� �������� ������� ������.����� �������� �� ���� ��������������� ����� ��� ���������������� ������� ����� .������� ����� �� ������� ������� ���� � �������� �� �� ��� �������� .������� ������ ������ ������ � ����� ������ ����� ��� ���� ���� ��������� .��� ������������� �������� ����� ������ ������� �������������� ��������� �������� ������� ��������� ���� ������� �����-������������ ����� ��������� ��� ���� �������� ��� .���� ������ ����� ������ �� ����� ������� �� ��� ���� ����� ����� ������� ������� �������� ��� ������� �������� �� �������-�����.       in the median eminence of the inferior hypothalamus. da released in this system exerts regulatory effects in the anterior pituitary and inhibits the release of prolactin. da mediates its neurocheantimical and physiological actions via membrane receptor proteins. da receptors are found on postsynaptic neurons in brain regions that are da-enriched. in addition, they reside presynaptically on da neuronal cell bodies and dendrites in the midbrain as well as on their terminals in the forebrain. stimulation of these ‘autoreceptors’ inhibits da synthesis by blocking the activity of tyrosine hydroxylase, the rate-limiting enzymatic step in catecholamine synthesis. in addition, da autoreceptor activation blocks da release from presynaptic membrane-enclosed storage vesicles, and significantly attenuate the firing rate of the da neurons.7,8 all da receptor proteins belong to a superfamily of large peptides that are coupled to g-proteins and modified by attached carbohydrate, lipid-ester or phosphate groups. ey are characterized by having seven hydrophobic transmembrane-spanning regions, as well as a functionally critical third intracytoplasmic loop that interacts with g-proteins and other effector molecules to mediate the physiological and neurochemical effects of the receptors.2–5 e da receptors were originally differentiated into two major types.9 is was mainly based on the presence or absence of ability of da to stimulate adenylyl cyclase and produce the second-messenger molecule cyclic-amp (camp) to distinguish receptor types d1 and d2. d1 receptors were characterized initially as mediating the stimulation of camp production. d2 receptors, which inhibit the production of camp, were pharmacologically characterized based on the ability of only some da agents to block adenylyl cyclase activity, and on the ability of catecholamines including da to inhibit the release of prolactin in vivo and in vitro in a camp-independent fashion.10 applications of recent technical advances in molecular genetics have greatly facilitated the isolation and characterization of novel da receptors, d3, d4 and d5, with different anatomical localization from traditional d1 or d2 receptors. based upon their pharmacological profiles, including their effects on different signal transduction cascades, these receptors are currently divided into two families: the d1-like family, which includes d1 and d5 receptors, and the d2-like family which includes d2, d3 and d4 receptors.11–13 m o l e c u l a r b i o l o g y o f d o p a m i n e r e c e p t o r s        1        d1 receptors e da d1 receptor is the most abundant da receptor in the central nervous system. e d1 receptor gene, which lacks any introns, encodes a protein that extends for  amino acids.14 e human gene has been localized to chromosome  [table ].15 d1 receptors show characteristic ability to stimulate adenylyl cyclase and generate inositol ,,-trisphosphate (ip3) and diacylglycerol via the activation of phospholipase c.16,17 d1 receptors are highly expressed in basal ganglia followed by cerebral cortex, hypothalamus and thalamus. in striatal neurons of the basal ganglia, the mrna for d1 receptors has been colocalized with mrna for darpp- (a daand cyclicamp-regulated phosphoprotein of molecular mass , daltons, or  kd), suggesting that darpp- may contribute to the actions of d1 receptors.18–19 d5 receptors e intronless d5 receptor gene encodes a protein that extends for  amino acids [table ].20 e protein has an overall  homology with the d1 receptor and  if only the seven transmembrane segments are considered. e gene encoding the human d5 protein is located at figure 1. schematic organisation of the four major dopamine systems in the brain.2                                            the short arm of chromosome , the same region where the huntington disease gene has been located.21 it is unknown, however, if there is any functional interaction between the two genes. molecular studies identified two d5-like pseudogenes that extend for  amino acids and show  homology to the d5 receptor genomic sequence. ese pseudogenes, however, contain stop codons in their coding regions that prevent them from expressing functional receptors. e functions of these pseudogenes, which appear so far to be specific to humans, are not yet known.22 expression of d5 mrna is unique and limited to the hippocampus and parafascicular nucleus of the thalamus,23 a thalamic nucleus involved in pain perception, suggesting that d5 receptors may be involved in the thalamic processing of painful stimuli.24 d5 receptors, like d1 receptors, appear to interact with g-proteins and can stimulate adenylyl cyclase, with relatively high affinity for da and d1-selective agonists [table ].20        2        d2 receptors e da d2 receptor was the first da receptor to be cloned.25 e d2 receptor gene encodes a protein that extends for  amino acids [table ]. similar to other g-protein coupled receptors, the d2 gene product has seven transmembrane segments, but in contrast to d1-like receptors, the third cytoplasmic domain is long and the carboxyl terminus is short. unlike the d1-like receptor genes, the d2 receptor gene contains seven introns that are spliced out during mrna transcription.26 e gene encoding this receptor was found to reside on q-q of human chromosome .27 d2 receptors are involved in several signal transduction cascades, including inhibition of camp production,28 inhibition of phosphoinositide turnover,29 activation of potassium channels, and potentiation of arachidonic acid release [table ].30 d2 receptors are highly expressed in basal ganglia, nucleus accumbens septi, and ventral tegmental area.31 � � ������������������������������������������� � ����� ������������� ����������� �������� ��������������� ������ ����������� ��������� ����������� ������������ ���������� ������������������ � � � � � � ��� �������� �������� �� ��������������� ������������������ ���������������� �������������������� �������� ����������� �������������� ����������������� ������������� �������������� ������ ������� ��� �������� �������� �� ������������ ��������� �������������������� ����������������� ������ ������������������ � � � � � � ��� �������� ��� �������������������� �������������� ���������� ����������������� ��������������� ����������� ��������������� ��������������� ������ �������������� �������������� ������������������ ��� �������� �������� �� �������������������� ������������������� ����������� ������������� �������������� ������������ �������� ���������� ��� �������� ������������� ������� ��� ���������������� ������������� ��������� ����������� ����������� ���������� ���������� �������� ��������� ������ ������ � ���������������������������������������������������������������������������������������� �������������������������������������������������������������������������������������������������������������������������������������������������������������������� ��������������������������������������� ������������������������������������������������������������ �       molecularly, d2 receptor protein exists in two isoforms derived from the same gene by alternative rna splicing which occurs during the maturation of the d2 receptor pre-mrna.32 both isoforms (known as d2l and d2s) vary within each species by the presence or less frequent absence of a -amino acid sequence in the third cytoplasmic domain of the d2 receptor peptide chain. pharmacologically, both isoforms exhibit nearly similar profiles in terms of their affinities to different d2-selective agents, and both inhibit adenylyl cyclase activity. however, they display an opposite regulatory response to da treatment: da induces up-regulation of d2l isoform and downregulation of d2s isoform.33 d3 receptors e d3 receptor gene contains five introns and encodes a  amino acid protein.34 e gene encoding this receptor resides on chromosome  [table ].35 e d3 receptors bear close structural and pharmacological similarities to the d2r and, like the genes for d2 receptor variants, d3 mrna also occurs in longer and shorter spliced forms generated from the same gene.36 distribution of d3 mrna indicated that these receptors are mainly expressed in subcortical limbic regions including islands of calleja, nucleus accumbens septi and olfactory tubercle, with low levels of expression in the basal ganglia [table ].31 surprisingly, d3r mrna has also been found in neurons of the cerebellum, which may regulate eye-movements.37 e status of the d3 molecular entity as a functional receptor remains uncertain since it neither couples to g-proteins nor consistently transduces an effector mechanism.34,38 however, the structural similarity with d2 receptor raises the possibility that d3 receptor may also inhibit adenylyl cyclase activity in its normal cellular setting. more recent studies reported that d3 receptors might mediate positive regulatory influences of da on production of the peptide neurotensin.39 d4 receptors e human d4 receptor gene contains four introns and encodes a  amino acid protein.40 e overall homology of the d4 receptor to the d2 and d3 receptors is about  and  respectively, but this homology increases to  for both receptors when only the transmembrane spanning segments are considered. e gene encoding the human d4 protein is located at the tip of the short arm of chromosome .41 histoprobes for its mrna localized this gene product in non-extrapyramidal regions of human brain including hippocampus and frontal cerebral cortex.42 like the d2 receptors, stimulation of the d4 receptors can inhibit adenylyl cyclase activity and activate release of arachidonic acid in brain neurons [table ].43 human, but not primate or rodent, d4 receptors are known to occur in several genomic polymorphic variants that contain from two to eleven repeats of a  base-pair segment expressed in the third cytoplasmic domain.44 two, four and seven repeats (designated as d4.2, d4.4 and d4.7) are the most common d4 alleles. ese variants may contribute to the pathophysiology of certain neuropsychiatric disorders or their improved treatment.4                                e basal ganglia consist of five interconnected subcortical nuclei including the striatum (caudate nucleus and putamen), globus pallidus, subthalamic nucleus, and substantia nigra pars compacta and pars reticulata.45–47 e medium spiny neurons, which constitute – of the neurons in the striatum, receive the bulk of the incoming excitatory input from the cerebral cortex. ese neurons send their projections through two major striatal output pathways. e direct or striatonigral pathway, where striatal neurons project to the internal segment of the globus pallidus and the substantia nigra pars reticulata and the indirect or striatopallidal pathway where striatal neurons project to the external segment of the globus pallidus, then to the subthalamic nucleus and terminate in the substantia nigra pars reticulata. e later region sends projections to the ventral anterior, ventral lateral and mediodorsal thalamic nuclei, which in turn provide an excitatory input to the cerebral cortex.45–47 in the striatum, the majority of d1 receptors are expressed on striatonigral neurons, whereas d2 receptors are predominately localized to striatopallidal neurons.46,47 some d4 receptors are co-expressed with the excitatory glutamate nmda receptors, on terminals of glutamatergic corticostriatal projections innervating striatum, as well as on medium spiny neurons in striatum.48 both d2 and d3 subtypes are found on terminals of dopaminergic nigrostriatal neurons projecting from substantia nigra pars compacta to striatum.49 e basal ganglia are involved in programming and initiation of movement, particularly slow movements, and in motor memory and retrieval. abnormalities in da neurotransmission in the basal ganglia nuclei and/or their projecting targets have been linked to attention-deficit hyperactivity disorder (adhd) and schizophrenia.1,2,50 in addition, disorders of the basal ganglia may produce restricted and rigid movements as in parkinson’s disease or uncontrollable and involuntary movements as in huntington’s disease.51                                            d o p a m i n e r e c e p t o r s a n d n e u r o p s y c h i a t r i c d i s e a s e s da receptors have been implicated in a variety of neuropsychiatric disorders, most notably in schizophrenia, parkinson’s disease and attention-deficit hyperactivity disorder (adhd). other brain disorders in which da receptors are involved or dopaminergic drugs have a therapeutic role are huntington’s chorea, tourette’s syndrome, and hyperprolactanemia.          schizophrenia is one of the most common neuropsychiatric diseases affecting  of the general population. is rate is fairly uniform throughout the world, even though the environmental and socio-economical factors vary among different countries. additional – of the general population has schizotypal personality disorder, which is a milder form of the disease.52–55 e symptoms of schizophrenia start to develop in late adolescence or early adulthood. e ‘positive’ symptoms include thought disorder, perceptual disturbances, visual and auditory hallucinations and delusions while the ‘negative’ symptoms include loss of executive functions such as planning and working memory, neglect of hygiene, social isolation and withdrawal from interaction with other people.52–55 genetic studies suggested that genetic factors play an important role in the pathophysiology of schizophrenia. monozygotic twins, who have identical genome, show a concordance rate of about –, but in dizygotic twins, the rate drops to only .55–57 ese rates, however, indicate that genetic predisposition alone is insufficient to produce the disease, and that other neurochemical and environmental factors also contribute to the development of the disease. injuries in the normal development of human brain including maldevelopment of the anatomical organization and connectivity of cortical afferents innervating the limbic regions may contribute to neurobiological substrates for schizophrenia.58 disturbances in the concentrations and subsequent alterations in the neurotransmission of different neurotransmitters, including da, serotonin and glutamate, in different cortical and limbic and extrapyramidal pathways have been also proposed to underlie the pathophysiology of schizophrenia.59–61 treatment of schizophrenia treatment of schizophrenia and other idiopathic psychotic disorders was revolutionized by the serendipitous discovery of chlorpromazine (phenothiazine derivative) and haloperidol (butyrophenone derivative) in the s. is was followed by introduction of other effective antipsychotic compounds including thioxanthenes (clopentixol, flupentixol, and thiothixene), benzepines (loxapine, clothiapine and zotepine), diphenylbutylpiperidines (spiperones), indolones (molindone and oxypertine) and other heterocyclic compounds.1,2 virtually, all of these drugs, which collectively are known as typical antipsychotic drugs, reduce da neuronal activity, reverse the psychotic symptoms induced by psychostimulants such as amphetamine and cocaine, and block da d2 receptors in a direct correlation with their antipsychotic efficacy.1,2,62,63 typical antipsychotics are effective in alleviating the positive symptoms of schizophrenia. however, their effectiveness is limited and non-specific as they fail to significantly improve the cognitive deficits and negative symptoms of schizophrenia. moreover, treatment with these medications is commonly associated with neurological extrapyramidal and endocrinological side effects, of both acute and delayed nature.1,2 parkinsonism, a syndrome with similar symptoms to parkinson’s disease, is the most frequent acute side effect. other acute side effects include dystonia (sustained contraction of orofacial muscles), akathisia (motor restlessness with anxiety and agitation), and galactorrhea (excessive lactation). ese side effects are the result of d2 receptor blockade in either the striatum or pituitary gland.1,2 a potentially life-threatening adverse effect of antipsychotic drug treatment is known as neuroleptic malignant syndrome.64,65 it is characterized by muscle rigidity, dystonia, unstable pulse, blood pressure, fever, and elevated serum concentrations of muscle proteins (creatine kinase, myoglobin). e syndrome has been attributed to d2 receptor blockade by typical antipsychotic agents, but its pathophysiology remains obscure, and may involve hypothalamic and brainstem dysfunction as well as extrapyramidal motor effects mediated by the basal ganglia. long-term treatment of schizophrenic patients with typical antipsychotic agents has been also associated with tardive dyskinesia, a delayed-onset hyperkinetic movement disorder that is oen irreversible even aer drug discontinuation.1,2 e most characteristic features of this syndrome are abnormal movements of the mouth, face, extremities, and trunk. da receptor supersensitivity that results from antipsychotic-induced blockade and upregulation of d2 receptors,66,67 an imbalance in d1/d2 receptor densities in striata of medicated schizophrenic patients,10 or a disruption in γ-amino butyric acid (gaba) neurotransmission in the basal ganglia may contribute to the development of tardive dyskinesia.68,69 all these side effects prompted the search for novel drugs with less risk of the adverse effects of typical       antipsychotics, but similar or even superior antipsychotic effects. is led to the introduction of several new drugs, classified as atypical antipsychotic drugs. e current prototype ‘atypical’ antipsychotic agent is clozapine (clozaril®), a dibenzodiazepine derivative. several basic and clinical studies have provided substantial evidences that clozapine exhibit superior antipsychotic effectiveness over standard antipsychotics, especially in improving negative symptoms and cognitive deficits in schizophrenia. clozapine is also effective in treatment-resistant schizophrenia, and other poorly responsive primary psychotic disorders, along with its very limited profile of extrapyramidal side effects or hyperprolactinemia.1,2,70,71 e pharmacological basis of the unusual clinical properties of this unique agent remains unclear. clozapine interacts high or moderate potency at a wide range of neurotransmitter receptors including serotonergic (-ht1a, -ht2a, -ht2c, -ht6, -ht7), acetylcholinergic (muscarinic m1–m4), adrenergic (α1, α2, β2), and histaminic (h1) receptors. in contrast, it has only moderate affinity for both da d1 and d2 da receptors.1,2,70–72 clozapine has greater affinity for serotonin -ht2a than da d2 receptors and this receptor-interaction pattern may contribute to its low risk of extrapyramidal side effects.73 clozapine also displays somewhat greater affinity for d4 than other da receptors, suggesting that these receptors may represent potential sites of action of clozapine and perhaps other antipsychotic agents.,74–76 post mortem brain tissue studies reported that d4 receptors are increased in the striata of medicated schizophrenic patients.77,78 in addition, laboratory studies found that repeated administration of clozapine, as well as other typical and atypical antipsychotics increased the abundance of d4 receptors in rat striatum and nucleus accumbens septi.79–82 ese agents also up-regulated d2 receptors in rodent and primate prefrontal cortex but had little or no effect on d1 or d3 receptors.79–83 ese findings support the view that d4 receptors in striatum and nucleus accumbens, as well as d2 receptors in prefrontal cortex are common sites where both typical and atypical antipsychotics mediate their beneficial therapeutic effects.1,2 in contrast, typical neuroleptics, but not clozapine, also increased d2 receptor binding and expression in rat and monkey striatum.79–83 is selective increase in d2 receptor labelling in the striatum may contribute to the development of neurological side effects typical of standard antipsychotics.1,2 lack of effect of typical and atypical antipsychotic agents on d1 and d3 receptors suggest that these receptors are less likely to be involved in the mechanisms of antipsychotic drug actions.1,2 despite its favourable characteristics, clinical use of clozapine is complicated by its high risk of potentially fatal bone marrow toxicity, agranulocytosis.1,70,84,85 patients on clozapine are required to undergo regular monitoring of their complete blood count to ensure that the development of agranulocytosis is detected early. in addition, clozapine has other adverse effects, including dose-dependent risk of epileptic seizures, excessive sedation, significant weightgain, and a higher incidence of hypertension and type ii diabetes mellitus.1,70,84,85 ese side effects collectively le the door opened for developing novel antipsychotic medications with less adverse risk than clozapine, but comparable antipsychotic effects. several newer agents have emerged. among them are clozapine analogues olanzapine (zyprexa) and quetiapine (seroquel), the benzisoxazole derivative risperidone (risperidal) and its analogue ziprasidone (geodon).1,2,84,86 like clozapine, these compounds have multiple sites of molecular interaction, and greater affinity for serotonin -ht2a than da d2 receptors, which again may contribute to their benign extrapyramidal profile.1,2,84,86 ese newer agents have undergone extensive pharmacological and behavioural characterization in animals, 86–88 and their therapeutic effects were assessed in many clinical trials.1,85 despite the favourable clinical profile of most of the second generation of antipsychotic drugs, and their effectiveness in treating psychotic symptoms of schizophrenia, they are also associated with different adverse side effects. with the remarkable exception of clozapine, and perhaps quetiapine, other atypical antipsychotic agents have brought only relative avoidance of side effects on central neural control of posture and movement, urging continued searches for novel principles of developing novel antipsychotic drugs.1,85       ’     parkinson’s disease (pd) develops later in life with the average age of onset of  years. pd patients suffer from disturbances of movements (akinesia), increased muscle tone (rigidity), tremor (– per second at rest), and postural defects, along with speech and writing problems. ese symptoms progress with a gradual exacerbation along with the progress of the disease.89 cognitive deficits and psychiatric disturbances are also common in patients with pd. e main cognitive deficits include disturbances in memory, fluency, visuospatial and construction abilities accompanied by dementia.90 e most common psychiatric disturbances include depression, anxiety, mania and psychosis. pd is observed in more than  of individuals over the age of .91 genetics may also play a role in the aetiology of pd, but perhaps less prominent than that of                                            schizophrenia. recent studies have found that mutations in three different proteins (alpha-synuclein, parkin and uchl) can lead to autosomal dominant form of the disease.92,93 e pathological hallmark of pd is the specific degeneration of more than  of the nigrostriatal dopaminergic neurons and the appearance of intracellular inclusions known as lewy bodies.94,95 is results in a profound depletion of da in the substantia nigra pars compacta, caudate nucleus, putamen, and causes an increase in striatal d2 receptor levels. e loss of striatal da will decrease the inhibitory activity of nigrothalamic projections, which in turn will increase the activity of the thalamocortical neurons leading to the excitation of motor cortex and spinal motor neurons. e end results will be increased contraction of both flexors and extensors at the same time causing cogwheel rigidity and movement disorder.51,89 e discovery that -methyl--phenyl-,,,-tetrahydropyridine (mptp) can reduce the da levels in the brain by selectively degenerating the nigrostriatal dopaminergic pathway, and producing a clinical syndrome similar to pd, helped to develop a useful animal model for pd and stimulated new approaches to investigating its pathophysiology and therapy.96,97 mptp is converted by monoamine oxidase b to mpp+ (-methyl--phenyl pyridinium) which is taken up by the da neurons via presynaptic da transporters. mpp+ is then accumulated in the mitochondria where it inhibits complex i of the mitochondrial electron transport chain. is blocks the process of oxidative phosphorylation and generates toxic free radicals, which in turn attacks the integrity of cell cytoskeleton and eventually leads to cell death.96–98 treatment of parkinson’s disease e simplest way to replace depleted da would be to administer da itself. however, da does not cross the blood brain barrier and therefore its direct administration is ineffective. levodopa (l–,-dihydroxyphenyl alanine; l-dopa) is the immediate precursor of da which readily crosses blood brain barrier and is converted to da by decarboxylation within the remaining few intact dopaminergic neurons.99 administration of levodopa, at least early in the course of the disease, significantly improved tremor, rigidity and motor-impairment in pd patients.89,99 it should be noted, however, that the peripheral tissue conversion of levodopa to da by aromatic amino acid decarboxylase permits only a small percentage of levodopa to reach the brain. erefore, it is necessary to co-administer with levodopa, selective inhibitors of peripheral decarboxylase enzyme activity that do not cross the blood brain barrier, such as carbidopa (sinemet) or benserazide (madopar) to profoundly increase the availability of levodopa in the brain.100,101 long-term therapy of levodopa is complicated by the fact that the beneficial effects of levodopa start to wear off and patients start to experience response fluctuations with each dose of levodopa despite maintaining the same treatment regimen.102,103 later, patients starts to show the ‘on/off phenomenon’ in which sudden periods of tremors and rigidity alternate with periods of mobility. increasing the dose and frequency administration of levodopa can improve this situation, but this increases the risk of dyskinesias and excessive and involuntary movements.102,103 in addition, patients may experience dopaminergic psychosis. e novel atypical antipsychotic agents, such as clozapine or quetiapine, have been shown to be effective in improving levodopa-induced psychosis.104 inhibitors of the enzyme monoamine oxidase (mao) represent another class of drugs for the treatment of pd. two isoenzymes of mao (mao-a and mao-b) oxidize monoamines. mao-b is the predominant form in the striatum and is responsible for the oxidative metabolism of striatal da.105 deprenyl (eldepryl), also known as selegiline, is a selective mao-b inhibitor that irreversibly inhibits mao and slows the breakdown of da in the striatum. a combination of deprenyl and levodopa is useful in prolonging the effects of levodopa and in reducing the ‘on/off ’ effects.106 currently, deprenyl is considered as one of the drugs of choice for treatment of early or mild pd.107 however, in more advanced pd patients, deprenyl may accelerate the motor and cognitive side effects of levodopa therapy. metabolites of deprenyl include amphetamine and methamphetamine, which can cause insomnia, anxiety and mood elevation in treated pd patients.89 an alternative to levodopa or deprenyl therapy is the use of direct da receptor agonists. ese drugs are more specific in their actions and can selectively target one or more da receptor subtype, in contrast to the non-selective effects of levodopa or deprenyl. in addition, these agonists are well absorbed orally, have longer duration of actions than levodopa and are more effective in the management of fluctuations in motor activity.108 four da receptor agonists are available for treatment of pd: the standard agents, bromocriptine (parlodel) and pergolide (permax), and the more recently introduced agonists, ropinirole (requip) and pramipexole (mirapex).89,108 bromocriptine is strong d2 receptor agonist with partial antagonistic activity at d1 receptors, while pergolide is an active agonist on both da receptor subtypes. ropinirole and pramipexole are active agonists at d2/d3 sites with negligible activity at d1 sites.89,108   despite the progress in pd pharmacotherapy, many medications tend to loss their beneficial effects aer longterm administration. alternative therapies try to restore da function by means of intracerebral tissue gras. one approach focuses on transplanting adrenal medulla tissue either into a lateral ventricle or into the striatum itself.109 another approach is to implant fetal substantia nigra tissue with the anticipation that new da neurons will grow, sprout and restore the lost nigrostriatal dopaminergic connectivity. is approach, however, remains controversial due to its ethical implications.110 a third approach involves the use of xenogras, that is tissue gras obtained from other species like pigs or monkeys, although the clinical outcome of these gras have not been well established.111 neurosurgical intervention to selectively lesion the inner segment of globus pallidus (also known as pallidotomy) has been also utilised in treatment of pd. however, because of the risk of permanent damage to the brain, this treatment remains as the last resort.112                             adhd is a neuropsychiatric condition characterized by inattention, impulsivity and inappropriate behavioural hyperactivity, typically associated with impaired academic and social functioning in school-aged children.50 several studies have implicated environmental and psychosocial factors, such as pregnancy and delivery complications, marital distress, family dysfunction and low social class as predisposing risk factors for adhd.50,113 e neuroanatomical networks involving frontal cortex and basal ganglia are proposed to be critically involved in the pathophysiology of adhd.114,115 neuroimaging studies found that frontal cortex, caudate and globus pallidus were smaller in children diagnosed with adhd compared to normal controls.116,117 in addition, a functional deficit was detected in the putamen of children with adhd relative to normal peers.118 ese findings provide a compelling support for the suggested dysfunction in fronto-subcortical pathways in patients diagnosed with adhd.119 molecular genetic studies have identified a genetic linkage between adhd and an allele of da transporter using a family based association study.120,121 is association has been supported by the development of genetically altered mice that lack functional da transporters. such mice displayed a hyperdopaminergic state that included spontaneous hyperactivity similar to adhd.122 in addition, an association of d4 receptor polymorphism and clinical adhd has been also reported.75,76,123,124 is association involves increased incidence of a -repeat allele (receptor type d4.7) coding for a -amino acid sequence in the functionally critical third intracytoplasmic loop of the d4 receptor in patients diagnosed with adhd compared to normal controls. additional support for possible involvement of d4 receptors in adhd is provided by recent findings that transgenic mice lacking d4 receptors show increased sensitivity to psychostimulants and increased metabolic turnover of striatal da compared to wild type mice.125           psychostimulants are considered the first line of treatment for adhd, since the pathophysiology of adhd involves deficiency in da neurotransmission. e most widely used compounds in this class include methylphenidate (ritalin), amphetamines (adderall and dexedrine) and pemoline (cylert).126,127 ese compounds, which enhance da neurotransmission, increase synaptic da by inhibiting the reuptake of da into presynaptic vesicles (methylphenidate, amphetamines and pemoline) or by releasing presynaptic da into synaptic cle.126–128 although these compounds are quite effective in alleviating the symptoms of adhd and in improving attention and academic performance adhd patients, they are associated with different side effects. most notable, all these medications are considered controlled substances of potential abuse. in addition, they cause insomnia, anorexia, jitteriness, and headaches. moreover, pemoline can cause hepatitis and liver toxicity, and so monitoring liver functions is essential for patients on pemoline.126–128 antidepressants follow psychostimulants as the second line of choice for treatment of adhd. e tricyclic antidepressants (tcas), such as imipramine, desipramine, venlafaxine and atomoxetine, block the reuptake of monoamine neurotransmitters, especially norepinephrine.126–129 tcas are effective in controlling abnormal behaviours and reducing cognitive impairment in adhd patients. ey are also useful if depression or anxiety symptoms co-exit with adhd.126–129 antihypertensive drugs such as clonidine and guanfacine are also used for treatment of adhd in young patients. ey are particularly effective against aggressiveness and sleep disturbances. however, cardiovascular monitoring of patients on these medications is recommended.126–128 finally, recent reports have suggested that selective da d4 receptor antagonists may provide much-needed innovative treatments for adhd. motor hyperactivity observed in juvenile rats with neonatal -hydroxydopamine lesions, a laboratory model for adhd, was reversed in dosedependent manner by highly selective d4 antagonists, and worsened by selective d4 agonists.130 a direct correlation        was also observed between motor hyperactivity in lesioned rats and increases in d4 receptor levels in rat caudate-putamen.130 ese findings provided behavioural and pharmacological evidences for the suggested genetic association between d4 receptor alleles and adhd.75,76,123,124 it is still premature to judge the effectiveness of d4-antagonists in treatment of adhd. post-mortem studies on brain tissue from patients diagnosed with adhd are still needed to clarify the role of d4 receptors in its neuropathology or pathophysiology. in addition, selective d4-antagonists should be tested in clinical trials to determine their safety and effectiveness for treatment of adhd.75,76 c o n c l u s i o n s e new neuropharmacology of da receptors and their effectors stimulates renewed interest in many aspects relevant to da neurotransmission, including the molecular control of the da synthesis and release, as well as the rational development of novel cns drugs. e advances in molecular biology have revealed the presence of two classical da receptors (d1 and d2) as well as novel gene products that present novel da receptors (d3, d4, d5). clarification of the sites of expression of classical and novel da receptor mrnas and proteins in mammalian brain, characterization of their effector systems, and the identification of novel chemical or drug molecules selective for each receptor subtype have rapidly advanced the understanding of these novel da receptors. such understanding is relevant to the pathophysiology of major neuropsychiatric diseases, including schizophrenia, parkinson’s disease and adhd, as well as to understanding the mechanisms of action and side effects of many drugs currently used in treatment of these disorders. e exciting neuropharmacological leads reviewed here should open new avenues of research on the preclinical aspects of different da receptor subtypes, and should lead to innovative principles guiding discovery of novel drugs for improved treatment of neuropsychiatric diseases.             supported, in part, by national alliance on research on schizophrenia and depression (narsad) and eodore and vada stanley research foundation. r e f e r e n c e s . baldessarini rj, tarazi fi. drugs and the treatment of psychiatric disorders. in: hardman jg, limbird le, eds. goodman and gilman’s e pharmacologic basis of erapeutics, mcgraw-hill, new york , –. . baldessarini rj, tarazi fi. brain dopamine receptors: a primer on their current status, basic and clinical. harvard rev psychiatry , , –. . florijn wj, tarazi fi, creese, i. dopamine receptors. in: bittar ee, bittar n, eds, principles of medical biology, jai press, new york , –. . cooper j, bloom f, roth r. dopamine. in: cooper, bloom, roth, eds, e biochemical basis of neuropharmacology, oxford university press, new york , –. . carlsson a. irty years of dopamine research. adv neurology , ,–. . moore k, lookingland k. dopaminergic neuronal systems in the hypothalamus. in: bloom f, kupfer d, eds. psychopharmacology: fourth generation of progress, raven press, new york , –. . chiodo l, freeman a, bunney b. dopamine autoreceptor signal transduction and regulation. in: bloom f, kupfer d, eds. psychopharmacology: fourth generation of progress, raven press, new york , –. . roth r, elsworth j. biochemical pharmacology of midbrain dopamine neurons. in: bloom f, kupfer d, eds. psychopharmacology: fourth generation of progress, raven press, new york , –. . kebabian j, calne d. multiple receptors for dopamine. nature, , –. . seeman p. brain dopamine receptors. pharmacol rev , , –. . civelli o, bunzow j, grandy d. molecular diversity of the dopamine receptors. ann rev pharmacol toxicol , , –. . sibley d, monsma f, shen y. molecular neurobiology of dopaminergic receptors. intl rev neurobiol , , –. . sokoloff p, schwartz j. novel dopamine receptors half a decade later. trends pharmacol sci , , –. . dearry a, gingrich j, falardeau p, fremeau r, bates m, caron mg. molecular cloning and expression of the gene for a human d1 dopamine receptor. nature , , –. . sunahara r, niznik h, weiner d, sturmann t, brann m, kennedy j, et al. human dopamine d1 receptor encoded by an intronless gene on chromosome . nature , , –. . mahan l, burch r, monsma f, sibley d. expression of striatal d1 dopamine receptors coupled to inositol phosphate production and ca2+ mobilization in xenopus oöcytes. proc natl acad sci usa , , –. . monsma f, mahan l, mcvittie l, gerfen c, sibley d. molecular cloning and expression of a d1 dopamine receptor linked to adenylyl cyclase activation. proc natl acad sci usa , , –. . hemmings h, greengard p. darpp-, a dopamine and ’-’ monophosphate-regulated phosphoprotein: regional, tissue and phylogenetic distribution. j neurosci , ,–. . hemmings h, walaas s, ouiment c, greengard p. dopaminergic regulation of protein phosphorylation in the striatum: darpp-. trends neurosci , , –. . sunahara rk, guan h-c, o’dowd bf, seeman p, laurier lg, george s, et al. cloning of the gene for a human dopamine d5 receptor with higher affinity for dopamine than d1. nature , , –. . gusella jf. location cloning strategy for characterizing genetic                                             defects in huntington’s disease and alzheimer’s disease. faseb , , –. . grandy d, zhoung y, bouvier c, zhou q, johnson r, allen l, et al. multiple human d5 dopamine receptor genes: a functional receptor and two pseudogenes. proc natl acad sci usa , , –. . meador-woodruff jh, mansour a, grandy dk, damask sp, civelli o, watson sj jr. distribution of d5 dopamine receptor mrna in rat brain. neurosci lett , , –. . giesler gj, menetrey d, basbaum ai. differential origins of spinothlamic tract projections to medial and lateral thalamus in the rat. j comp neurol , , –. . bunzow jr, van tol hm, grandy dk, albert p, salon j, chisre m, et al. cloning and expression of a rat d2 dopamine receptor cdna. nature , , –. . grandy dk, marchionni ma, makam h, stoo re, alfano m, fischer jb, et al. cloning of the cdna and gene for a human d2 dopamine receptor. proc natl acad sci usa , , –. . grandy dk, litt m, allen l, bunzow jr, marchionni m, makam h, et al. e human dopamine d2 receptor gene is located on chromosome  at q-q and identifies a taqi rflp. am j hum genet , , –. . vallar l, meldolesi j. mechanisms of signal transduction at the dopamine d2 receptor. trends pharmacol sci , , -. . enjalbert a, sladeczek f, guillon g, bertrand p, shu c, epelbaum j, et al. angiotensin ii and dopamine modulate both camp and inositol phosphate productions in anterior pituitary cells. j biol chem , , –. . kanterman ry, mahan lc, briley em, monsma fj jr, sibley dr, axelrod j, et al. transfected d2 dopamine receptors mediate the potentiation of arachidonic acid release in chinese hamster ovary cells. mol pharmacol , , –. . bouthenent m-l, souil e, martres m-p, sokoloff p, giros b, schwartz j-c. localization of dopamine d3 receptor mrna in the rat brain using in situ hybridization histochemistry: comparison with dopamine d2 receptor mrna. brain res, , –. . giros b, sokoloff p, martres m-p, riou j-f, emorine lj, schwartz j-c. alternative splicing directs the expression of two d2 dopamine receptor isoforms. nature , , –. . zhang l, lachowicz j, sibley d. e d2s and d2l dopamine receptor isoforms are differentially regulated in chinese hamster ovary cells. mol pharmacol , , –. . sokoloff p, giros b, martres m, bouthenet m, schwartz j-c. molecular cloning and characterization of a novel dopamine receptor (d3) as a target for neuroleptics. nature , , –. . giros b, sokoloff p, martres mp, riou jf, emorine lj, schwartz j-c. cloning of the human d3 dopaminergic receptor and chromosome identification. c r acad sci, paris, serie iii , , –. . giros b, martres m, pilon c, sokoloff p, schwartz j-c. shorter variants of the d3 dopamine receptor produced through various patterns of alternative splicing. biochem biophys res commun , , –. . lévesque d, diaz j, pilon c, martres m, giros b, souil e, et al. identification, characterization and localization of the dopamine d3 receptor in rat brain using -[3h]hydroxy-n,n-di-n-propyl-aminotetralin. proc natl acad sci usa , , –. . sokoloff p, andrieux m, besancon r, pilon c, martres mp, giros b, et al. pharmacology of human dopamine d3 receptor in a mammalian cell line: comparison with d2 receptor. eur j pharmacol , , –. . lévesque d, martres m, diaz j, griffon n, lammers c, sokoloff p, et al. a paradoxical regulation of the dopamine d3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons. proc natl acad sci usa , , –. . van tol hhm, bunzow jr, guan h-c, sunahara rk, seeman p, niznik hb, et al. cloning of a human dopamine d4 receptor gene with high affinity for the antipsychotic clozapine. nature , , –. . gelernter j, kennedy jl, van tol hhm, civelli o, kidd kk. e d4 dopamine receptor (drd) maps to distal p close to hras. genomics , , –. . meador-woodruff j, grandy d, van tol h, damask s. little k, civelli o et al. dopamine receptor gene expression in the human medial temporal lobe. neuropsychopharmacology , , –. . chio c, drong r, riley d, gill g, slightom j, huff r. d4 dopamine receptor-mediated signaling events determined in transfected chinese hamster ovary cells. j biol chem , , –. . van tol h, wu c, guan h, ohara k, bunzow j, civelli o, et al. multiple dopamine d4 receptor variants in the human population. nature , , –. . graybiel a. neurotransmitters and neuromodulators in the basal ganglia. trends neurosci , , –. . alexander g, crutcher m. functional architecture of basal ganglia circuits: neuronal substrates of parallel processing. trends neurosci , , –. . gerfen c. e neostriatal mosaic: multiple levels of compartmental organization. trends neurosci , , –. . tarazi fi, baldessarini rj. regional localization of dopamine and glutamate receptor subtypes in striatolimbic brain regions. j neurosci res , , –. . tepper jm, sun b-c, martin lp, creese i. functional roles of dopamine d2 and d3 autoreceptors on nigrostriatal neurons analyzed by antisense knockdown in vivo. j neurosci , , –. . barkley ra. attention deficit hyperactivity disorder: a handbook for diagnosis and treatment. guilford press, new york . . albin rl, young ab, penney jb. e functional anatomy of basal ganglia disorders. trends neurosci , , –. . baldessarini rj. schizophrenia. n engl j med , , –. . nasrallah ha, weinberger dr. e neurology of schizophrenia. elsevier science publishers, amsterdam, . . tamminga ca, schulz sc. advances in neuropsychiatry and psychopharmacology: schizophrenia research. raven press, new york, . . kandel er. disorders of thought and volition: schizophrenia. in: kandel er, schwartz jh, jessell tm, eds. principles of neural science, elsevier, new york , –. . kety ss, rosenthal d, wender pm, schulsinger f, jacobsen b. mental illness in the biological and adoptive families of adopted individuals who become schizophrenic who have become schizophrenic: a preliminary study. in: fieve rr, rosenthal d, brill h, eds. genetic research in psychiatry, johns hopkins university press, baltimore , –.        . kendler ks. e genetics of schizophrenia and related disorders: a review. in: dunner dl, gershon es, barrett je, eds. relative at risk for mental disorder, raven press, new york , –. . weinberger dr. implications of normal brain development for the pathogenesis of schizophrenia. arch gen psychiatry , , –. . davis k, kahn r, ko g, davidson m. dopamine in schizophrenia: a review and reconceptualization. am j psychiatry , , –. . meltzer hy. clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. psychopharmacology , , s–. . goff dc, coyle jt. e emerging role of glutamate in the pathophysiology and treatment of schizophrenia. am j psychiatry , , –. . creese i, burt dr, snyder sh. dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. science , , –. . seeman p, lee t, chau-wong m, wong k. antipsychotic drug doses and neuroleptic/dopamine receptors. nature , , –. . pearlman ca. neuroleptic malignant syndrome: a review of the literature. j clin psychopharmacology , , –. . addonizio g, susman vl, roth sd. neuroleptic malignant syndrome: review and analysis of  cases. biol psychiatry , , –. . baldessarini rj, tarsy d. dopamine and the pathophysiology of dyskinesia induced by antipsychotic drugs. ann rev neurosci , , –. . tarsy d, baldessarini rj. movement disorders induced by psychotherapeutic drugs. in: shah n, donzid a, eds. movement disorders. plenum press, new york , –. . aker gk, tamminga ca, alphs ld, lafferman j, ferraro tn, hare ta. brain gamma-aminobutyric acid abnormality in tardive dyskinesia. reduction in cerebrospinal fluid gaba levels and therapeutic response to gaba agonist treatment. arch gen psychiatry , , –. . aker gk, nguyen ja, tamminga ca. increased saccadic distractibility in tardive dyskinesia: functional evidence for subcortical gaba dysfunction. biol psychiatry , , –. . baldessarini rj, frankenburg fr. clozapine–a novel antipsychotic agent. n engl j med , , –. . brunello n, masotto c, steardo l, marstein r, racagni g. new insights into the biology of schizophrenia through the action mechanism of clozapine. neuropsychopharmacology , , –. . meltzer hy. effects of antipsychotic drugs on serotonin receptors. pharmacol rev , , –. . meltzer hy, matsubara s, lee j-c. classification of typical and atypical antipsychotic drugs on the basis of dopamine d, d and -ht pki vales. j pharmacol exp er , , –. . tarazi fi, baldessarini rj. dopamine d receptors: neuropsychiatric implications. e economics of neuroscience , , –. . tarazi fi, baldessarini rj. brain dopamine d4 receptors: current basic and clinical status. int j neuropsychopharmacol , , –. . tarazi fi, baldessarini rj. dopamine d4 receptors: significance for molecular psychiatry at the millennium. molecular psychiatry , , –. . seeman p, guan h-c, van tol hhm. dopamine d4 receptors elevated in schizophrenia. nature , , –. . murray am, hyde tm, knable mb, herman mm, bigelow lb, carter jm, et al. distribution of putative d4 dopamine receptors in postmortem striatum from patients with schizophrenia. j neurosci , , –. . florijn wj, tarazi fi, creese i. dopamine receptor subtypes: differential regulation following  months treatment with antipsychotic drugs. j pharmacol exp er , , –. . tarazi fi, florijn wj, creese i. differential regulation of dopamine receptors following chronic typical and atypical antipsychotic drug treatment. neuroscience , , –. . tarazi fi, yeghiayan sk, baldessarini rj, kula ns, neumeyer jl. long-term effects of s(+)n-n-propylnorapomorphine compared with typical and atypical antipsychotics: differential increases of cerebrocortical d2-like and striatolimbic d4-like dopamine receptors. neuropsychopharmacology , , –. . tarazi fi, yeghiayan sk, neumeyer jl, baldessarini rj. medial prefrontal cortical d2-like and striatolimbic d4-like dopamine receptors: common targets for typical, atypical and experimental antipsychotics. prog neuropsychopharmacol biol psychiatry , , –. . lidow ms, goldman-rakic ps. differential regulation of d2 and d4 dopamine receptor mrnas in the primate cerebral cortex vs. neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs. j pharmacol exp er , , –. . jibson md, tandon r. new atypical antipsychotic medications. j psychiatr res , , –. . tarsy d, baldessarini rj, tarazi fi. atypical antipsychotic agents: effects on extrapyramidal function. cns drugs , , –. . waddington jl, casey d. comparative pharmacology of classical and novel (second-generation) antipsychotics. in: waddington jl, buckley pf, eds. schizophrenia and mood disorders. butterworth-heinemann, oxford , –. . arnt j, skarsfeldt t. do novel antipsychotics have similar pharmacological characteristics? a review of the evidence. neuropsychopharmacology , , –. . tarazi fi, zhang k, baldessarini rj. long-term effects of olanzapine, risperidone, and quetiapine on dopamine receptor types in regions of rat brain: implications for antipsychotic drug treatment. j pharmacol exp er , , –. . standaert dg, young ab. treatment of central nervous system degenerative disorders. in: hardman jg, limbird le, eds. goodman and gilman’s e pharmacologic basis of erapeutics, mcgraw-hill, new york , –. . sano m, marder k, dooneief g. basal ganglia diseases. in: fogel bs, schiffer rb, rao sm, eds. neuropsychiatry, williams & wilkins, baltimore , –. . tanner cm. epidemiology of parkinson’s disease. neurol clin , , –. . duvoisin rc. role of genetics in the cause of parkinson’s disease. mov disord , (suppl. ), –. . golbe li. alpha-synuclein and parkinson’s disease. mov disord , , –. . hornykiewicz o, kish sj. biochemical pathology of parkinson’s disease. adv neurol , , –. . gibb wr. neuropathology of parkinson’s disease and related syndromes. neurol clin , , –. . burns rs, lewitt pa, ebert mh, pakkenberg h, kopin ij.                                             e clinical syndrome of striatal dopamine deficiency. parkinsonism induced by -methyl--phenyl-,,,-tetrahydropyridine (mptp). n engl j med , , –. . langston jw, irwin i. mptp: current concepts and controversies. clin neuropharmacol , , –. . tipton kf, singer tp. advances in our understanding of the mechanisms of the neurotoxicity of mptp and related compounds. j neurochem , , –. . mouradian mm, heuser ij, baronti f, chase tn. modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced parkinson’s disease. ann neurol , , –. . papavasiliou ps, cotzias gc, duby se, steck aj, fehling c, bell ma. levodopa in parkinsonism: potentiation of central effects with a peripheral inhibitor. n engl j med , , –. . pletscher a. levodopa treatment of parkinson’s syndrome: past and future. adv neurol , , –. . rinne uk. problems associated with long-term levodopa treatment of parkinson’s disease. acta neurol scand , , –. . chase tn, fabbrini g, juncos jl, mouradian mm. motor response complications with chronic levodopa therapy. adv neurol , , –. . friedman jh, factor sa. atypical antipsychotics in the treatment of drug-induced psychosis in parkinson’s disease. mov disord , , –. . olanow cw. oxidation reactions in parkinson’s disease. neurology , , –. . olanow cw. mao-b inhibitors in parkinson’s disease. adv neurol , , –. . myllyla vv, sotaniemi ka, vuorinen ja, heinonen eh. selegiline as initial treatment in de novo parkinsonian patients. neurology , , –. . goetz cg. dopaminergic agonists in the treatment of parkinson’s disease. neurology , , –. .freed wj, poltorak m, becker jb. intracerebral adrenal medulla gras: a review. exp neurol , , –. . lindvall o, rehncrona s, brundin p, gustavii b, astedt b, widner h, et al. human fetal dopamine neurons graed into the striatum in two patients with severe parkinson’s disease. a detailed account of methodology and a -month follow-up. arch neurol , , –. . subramanian t. cell transplantation for the treatment of parkinson’s disease. semin neurol , , –. . bronstein jm, desalles a, delong mr. stereotactic pallidotomy in the treatment of parkinson disease: an expert opinion. arch neurol , , –. . biederman j, milberger s, faraone sv, kiely k, guite j, mick e, et al. impact of adversity on functioning and comorbidity in children with attention-deficit hyperactivity disorder. j am acad child adolesc psychiatry , , –. . barkley ra. behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of adhd. psychol bull , , –. . niedermeyer e, naidu sb. attention-deficit hyperactivity disorder (adhd) and frontal-motor cortex disconnection. clin electroencephalography , , –. . castellanos fx. toward a pathophysiology of attention-deficit/ hyperactivity disorder. clin pediatrics , , –. . castellanos fx, giedd jn, march wl, hamburger sd, vaituzis ac, dickstein dp, et al. quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. arch gen psychiatry , , –. . teicher mh, anderseon cm, polcari a, glod ca, maas lc, renshaw pf. functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry. nature medicine , , –. . faraone sv, biederman j. neurobiology of attention-deficit hyperactivity disorder. biol psychiatry , , –. . cook eh jr, stein ma, krasowski md, cox nj, olkon dm, kieffer je, et al. association of attention-deficit disorder and the dopamine transporter gene. am j hum genet , , –. . gill m, daly g, heron s, hawi z, fitzgerald m. confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. mol psychiatry , , –. . giros b, jaber m, jones sr, wightman rm, caron mg. hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. nature, , , –. . la hoste gj, swanson jm, wigal sb, glabe c, wigal t, king n, et al. dopamine d4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. mol psychiatry , , –. . faraone sv, biederman j, weiffenbach b, keith t, chu mp, weaver a, et al. dopamine d4 gene -repeat allele and attention deficit hyperactivity disorder. am j psychiatry , , –. . rubinstein m, philips tj, bunzow jr, falzone tl, dziewczapolski g, larson jl, et al. mice lacking dopamine d4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. cell , , – . . goldman l, genel m, bezman r, slanetz p. diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. jama , , –. . vitiello b. long-term effects of stimulant medications on the brain: possible relevance to the treatment of attention deficit hyperactivity disorder. j child adolesc psychopharmacol , , –. . spencer t, biederman j, wilens t, harding m, o’donnell d, griffin s. pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. j am acad child adolesc psychiatry , , –. . biederman j, spencer t. attention-deficit/hyperactivity disorder (adhd) as a noradrenergic disorder. biol psychiatry , , –. . zhang k, tarazi fi, baldessarini rj. role of dopamine d receptors in motor hyperactivity induced by neonatal -hydroxydopamine lesions in rats. neuropsychopharmacol , , –.      2008-issue1.indd abstract we describe the first case of graves’ disease occurring at sultan qaboos university hospital, oman, in a patient who was under treatment with interferon alfa for hcv infection. inf-α is now being widely used to treat patients with a variety of disorders including infection with hepatitis c virus. clinical thyroid disease, hypo and hyperthyroidism can occur in up to 5% of patients. we emphasize the need for thyroid function screening before and during therapy to identify patients early in the course of their disease.. key words: interferon; thyroid function test; thyrotoxicosis; antibodies, thyroid; case report, oman. graves’ disease following interferon therapy for chronic hepatitis c infection *omayma el shafie,1 samir hussein,2 waheed el awady,3 nicholas woodhouse1 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 75-77 sultan qaboos university© submitted 20th june 2007 accepted 14th january 2007 interferon α ifn-α is a major therapeutic modality for patients with severe malignant and non-malignant disease including hepatitis c, the latter being fairly common in oman.1-4 prospective studies have shown that up to 15% of those treated with interferon for hepatitis c virus (hcv) will develop clinical thyroid disease and 40% thyroid antibodies. ifn-α induced thyroiditis is of 2 types, autoimmune or nonautoimmune. the former is characterised by the development of thyroid antibodies, with or without clinical disease. these can either block the thyroid stimulating hormone receptor (tsh-r) causing hypothyroidism or stimulate it causing graves’ disease. non-autoimmune disease can present as destructive thyroiditis and sometimes transient thyrotoxicosis followed by hypothyroidism with negative thyroid antibodies.1 in this paper, we report the first case of ifn-α induced graves’ disease in oman. with increasing use of infα in patients with hcv infections we should screen every patient for thyroid disease before and during therapy. c a s e r e p o r t a 60-year old indian female was diagnosed as having had chronic hepatitis c infection for many years. she had undergone a hysterectomy for carcinoma of the uterus 17 years previously and received a blood transfusion. the patient had no history of thyroid disease and no relevant family history. the genotype of the virus being type iv, the patient was treated with peginterferon alfa-2a (ifn-α) (180 µg once weekly by subcutaneous administration) from september 2006 through february 2007. before treatment was started her thyroid function tests: free thyroxine, triiodothyronine and thyroid stimulating hormone (ft4, ft3 and 1department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; departments of 2radiology and molecular imaging, and 3medicine, sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: omayma0@hotmail.com باالنترفيرون (ج) نوع الكبد املزمن التهاب عالج عن الناجت جريفيز مرض وودهاوز العوضي، نيكوالس وحيد حسني، سامر اميمة الشافعي، االنترفيرون بعقار عالجها نتيجة عمان) (سلطنة قابوس ــلطان الس جامعة ــفى مستش في جريفز اصيبت مبرض ملريضة حالة عن أول تقرير امللخص: قد . (ج) نوع ــي الفيروس الكبد التهاب منها عديدة اضطرابات في عالج ــتخدم يس هذا العقار .) (ج الكبد نوع من التهاب ــت تعاني ــا كان ألنه ، ــا ألف ننصح ولذا . املرضى %15 من ــبة الدرقية بنس الغدة هرمون افراز انخفاض ارتفاع أو ــبب في يتس مما الدرقية الغدة عمل اضطراب إلى العقار هذا يؤدي . املذكور االضطراب حصول املبكر على للتعرف العقار هذا استعمال وأثناء قبل الدرقية الغدة هرمون بفحص . عمان ، حالة تقرير ، الدرقية ، املضادة األجسام ، الدرقي التسمم ، الدرقية الغدة فحص ، انترفيرون الكلمات: مفتاح c a s e r e p o r t o m ay m a e l s h a f i e , s a m i r h u s s e i n , wa h e e d e l awa d y, n i c h o l a s wo o d h o u s e 76 tsh) and thyroid antibody studies (antimicrosomal and antithyroglobulin negative) were normal. twelve weeks after initiation of ifn-α therapy, she complained of palpitations and fatigue and was admitted to the hospital. physical examination revealed tachycardia, finger tremor, eyelid oedema and a soft thyroid gland with diffuse enlargement: ft4 was 30 (7.9-14.4 pmol/l), tsh <0.005 (0.34-5.6 miu/l). ifn-α therapy was discontinued and the patient was started on carbimazole (cb) 45 mg and propanolol 40 mg twice daily. after three months treatment she was euthyroid and was referred to sultan qaboos university hospital for radio-active iodine therapy [table 1]. her tc99m thyroid scan showed a diffuse uptake consistent with graves’ disease [figure 1], having been on carbimazole for 3 months, with ft4: 8.3 (7.9-14), tsh: 0.34 (0.34-5.6). the tsh receptor antibodies were raised 4.5 (-ve < 1 u/l) as were her thyroid antibodies at 420 iu/ml (n 0 100). she received i-131 therapy 653 mbq on 22 april 2007 and it was planned to have a repeat thyroid function tests after 2 months. d i s c u s s i o n this patient developed thyrotoxicosis while taking ifn-α therapy. a diagnosis of graves’ disease was made as the patient showed: 1) clinical signs of thyrotoxicosis with a diffuse goiter and periorbital oedema; 2) elevated levels of thyroid hormones and undetectable levels of tsh; 3) diffuse high uptake on tc99m scan and 4) a raised tsh receptor antibody titer. it has been well documented that treatment of chronic hepatitis b and c infections with ifn-α can lead to induction of thyroid antibodies with hypothyroidism or thyrotoxicosis.1 8 the mechanism by which ifn-α induces thyroid dysfunction remains unclear, but the autoimmune mechanism is thought to play an important role. ifnα enhances the surface expression of major histocompatibility complex (mhc) class i antigens, which activate cytotoxic t cell function. ifn-α also induces mhc class ii antigens on thyroid cells in patients with autoimmune thyroid diseases. the aberrant expression of mhc antigens on the cell surface, in association with cellular antigens, may be sufficient to interrupt the tolerance and induce autoantibody production. cytokines (tnfα, il-1β) that are induced by ifn-α may directly or indirectly disturb the thyroid function by their immunomodulatory effects.2 interferon-associated thyroid disease was first reported in 1985 when three cases of hypothyroidism were seen following ifn-α treatment of breast cancer.2 since then, many more cases of thyroid disease induced by ifn-α have been published.1–8 ifn-α may provoke two different forms of thyrotoxicosis: a graves’ disease picture or thyroiditis. the two forms of thyrotoxicosis should be differentiated as they have different implications for therapy.3 the two forms can readily be distinguished by tsh serology and thyroid scintigraphy. the bi-phasic thyroiditis would not require specific anti-thyroid medications, and the thyrotoxicosis would resolve spontaneously. if the clinical picture is severe, the use of corticosteroids may be appropriate for an antiinflammatory effect. more important, the risk of subsequent hypothyroidism is high and this requires close monitoring. by contrast, graves’ disease requires standard and prolonged anti-thyroid drugs. long term follow up of this group of patients will be interesting as their risk of recurrent thyrotoxicosis or subsequent hypothyroidism is unknown. radioactive iodine therapy may be necessary for some patients. early detection and therapy of these conditions is table1: thyroid hormones and thyroid antibodies before, during, after discontinuation of ifn treatment ft4 tsh thyroid antibodies before ifn 12 2.4 ve on ifn (3/12) 30 <0.005 + ve on cb (1/12) 18 0.005 + ve on cb (3/12) 12 0.005 + ve after i-131 (1/12) 8.3 0.34 + ve normal values: ft4 (7.9-14.4) pmol/l, tsh (0.34 – 5.6) mlu/l ifn: interferon; cb: carbimazole; ft4: free thyroxine; tsh: thyroid stimulating hormone g r av e s ’ d i s e a s e f o l l o w i n g i n t e r f e r o n th e r a p y f o r c h r o n i c h e pat i t i s c i n f e c t i o n 77 important in order to avoid the complications of thyroid disease such as life threatening cardiac arrhythmias. while it is not clear which factors contribute to susceptibility to interferon induced thyroiditis (iit), recent evidence suggests that genetic factors, gender and hepatitis c infection may play a role. viral genotype and therapeutic regimen do not influence susceptibility to iit. the etiology of iit is unknown and may be secondary to immune modulation by ifn-α and/or direct effects of interferon on the thyroid.1 our patient, in view of old age, was treated with i131 therapy, and our plan is to repeat thyroid function tests after two months. if she becomes hypothyroid, she will require lifelong thyroxine. c o n c l u s i o n clinical thyroid disease occurs in up to 15% of patients with interferon-α therapy. we therefore recommend measuring the thyroid function tests and thyroid antibodies before, during, and after interferon therapy to avoid any associated complications such as life threatening cardiac arrhythmias. r e f e r e n c e s 1. mandac jc, chaudhry s, sherman ke, tomer y. the clinical and physiological spectrum of interferon-alpha induced thyroiditis: toward a new classification. hepatology, 2006; 43:661-672. 2. koizumi s, mashio y, mizuo h, matsuda a, matsuay k, mizumoto h, et al. grave’s hyperthyroidism following transient thyrotoxicosis during interferon therapy for chronic hepatitis type c. intern med 1995; 34:58-60. 3. wong v, xi-li fu a, george j, wah cheung n. thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis. clin endocrinol 2002; 56:793-798. 4. tran ha, jones tl, batey rg. the spectrum of thyroid dysfunction in an australian hepatitis c population treated with combination interferon-alpha2beta and ribavirin. bmc endocr disord 2005; 5:8. 5. wong v, fu ax, george j, cheung nw. thyrotoxicosis induced by alpha-interferon in chronic viral hepatitis. clin endocrinol 2002; 56:793-798. 6. bohbot nl, young j, orgiazzi j, buffet c, francois m, bernard-chabert bg, et al. interferon-alpha-induced hyperthyroidism: a three-stage evolution from silent thyroiditis toward grave’s diseases. eur j endocrinol 2006; 154:367-372. 7. labbadia g, martocchia a, mammarella a, paoletti v, rocco a, benvenuto r, et al. association between human leukocyte antigen (hla) and interferon-induced thyroid diseases in four patients with hcv-related chronic hepatitis. neuro endocinol lett 2005; 26:109112. 8. lin yq, want x, murthy ms, agarwala s. life-threatening thyrotoxicosis induced combination therapy with peg-interferon and ribavirin in chronic hepatitis c. endocr pract 2005; 11:135-139. figure 1: tc-99m thyroid scan with diffuse uptake 3.5% (n 1.0 – 4.0) copy of case report today.docx 1 submitted 16 nov 22 1 revision req. 16 jan 23; revision recd. 13 feb 23 2 accepted 7 mar 23 3 online-first: march 2023 4 doi: https://doi.org/10.18295/squmj.3.2023.019 5 6 protracted chemical peritonitis following laparoscopy for dermoid cyst 7 a management dilemma 8 miriam g. fenn,1 sreedharan v. koliyadan,2 lovina machado,1 shahila sheik,2 9 *nihal al riyami3 10 11 departments of 1obstetrics & gynecology and 2surgery, sultan qaboos university hospital, muscat, 12 oman; 3department of obstetrics & gynecology, college of medicine and health sciences, sultan 13 qaboos university, muscat, oman 14 *corresponding author’s e-mail: drriyami@hotmail.com 15 16 abstract 17 dermoid cysts are common benign ovarian tumors arising from totipotent germ cells. we report a 18 rare case of chemical peritonitis and prolonged fever following laparoscopic salpingo-19 oophorectomy for torsion of a large ovarian dermoid and discuss the management of this patient 20 with prolonged hospital stay, antibiotics and anti-inflammatory use, repeated drainage of the 21 collection as well as re-laparotomy. the occurrence of this rare condition can be extremely 22 distressing for the patient and treating surgeon alike, as the recommendations for management are 23 limited. the management of chemical peritonitis may require one or more surgical procedures 24 along with prolonged anti-inflammatory therapy. 25 keywords: peritonitis, dermoid cyst, laparoscopy 26 27 introduction 28 dermoid cysts are common benign ovarian tumors arising from totipotent germ cells.1,2 the 29 contents are therefore, very diverse and commonly include sebum, hair, teeth, bone, cartilage, and 30 thyroid tissue. the high fat content causes them to float freely in the abdominal cavity, promoting 31 mailto:drriyami@hotmail.com 2 torsion in 15% of dermoid cysts. intraperitoneal rupture of a dermoid cyst may lead to chemical 32 peritonitis. although spillage of cyst contents is fairly common at laparoscopy (66-88%), 3,4 33 chemical peritonitis is very rare (0.2%). 5,6 the occurrence of this rare condition can be extremely 34 distressing for the patient and treating surgeon alike, as the recommendations for management are 35 limited. the management of chemical peritonitis may require one or more surgical procedures 36 along with prolonged anti-inflammatory therapy. 37 38 case report 39 a 31-year-old woman, para1living1, who underwent a caesarean section two and half months 40 before presented to the emergency department at sultan qaboos university hospital, muscat, 41 oman, in 2021 with two days history of abdominal pain, vomiting and diarrhea. on imaging, she 42 was found to have bilateral dermoid cysts measuring 75.07mm x 59.69mm (figure1), with the right 43 ovary showing evidence of torsion. preoperative crp was 4 mg/l. emergency laparoscopy was 44 performed. intraoperatively, the right ovary was 80 mm in size and gangrenous, and left ovary had 45 a smaller dermoid of 40 mm. the large dermoid was punctured with the trocar, to suck out the 46 contents and enable retrieval of the specimen. inadvertent intraperitoneal spillage of contents 47 occurred, and the specimen (right tube and ovary) were retrieved through endobag. left dermoid 48 cystectomy was performed as well. in view of the peritoneal spill, thorough, repeated peritoneal 49 lavage was done using three liters of saline. as the instilled saline was sucked out, no drain was 50 inserted. patient was discharged after 24 hours as there were no immediate complications. 51 histopathology was reported as mature cystic teratoma with hemorrhagic infarction. 52 53 the patient was re-admitted three days later with a history of high-grade fever and diarrhea of 1 54 day duration. on examination, she was dehydrated temperature 38.50c, heart rate of 110 beats/min 55 and blood pressure of 110/70 mm hg. the abdomen was soft, with no clinical signs of peritonitis. 56 septic work revealed, c-reactive protein (crp) of 380mg/l, total white blood cell 57 count16.8x109/l, covid-19 rtpcr negative, no growth on blood and urine cultures. ct 58 abdomen and pelvis revealed evidence of diffuse intraperitoneal inflammation, fat stranding of 59 mesentery and enlarged mesenteric nodes, with no evidence of intraperitoneal or pelvic collection 60 and no pneumoperitoneum to suggest injury of hollow viscous (figure 2). mild bilateral pleural 61 effusion was noted with minimal atelectasis of right lower lobe. it was decided to manage her 62 conservatively with antibiotics (tazocin 4.5 mg iv bid) and intravenous paracetamol only. 63 3 64 the diarrhea subsided over the next week, but high-grade fever persisted. repeat ct abdomen four 65 days after initiating antibiotics revealed a small sub-hepatic collection and slight worsening of the 66 inflammatory process. the sub-hepatic collection was drained under ultrasound guidance, the 67 aspirate was straw colored and sterile. the blood, urine and stool cultures were sterile. 68 inflammatory markers, crp-373mg/l. 69 70 ten days after re admission, patient developed chest pain in addition to persistent high-grade fever. 71 chest x-ray and ct chest revealed moderate pleural effusion with right lobe atelectasis. a pleural 72 tap was done and a covid test was repeated. about 580 ml of straw-colored fluid was drained and 73 a pigtail catheter was left in situ. the pleural fluid was also sterile and negative for acid fast 74 bacilli. fever persisted and she began to complain o f generalized abdominal pain. on 75 examination, a vague tender mass was palpable around the umbilicus. 76 77 a decision was taken for exploratory laparotomy and a thorough peritoneal lavage, after counseling 78 the patient that the procedure may not assure complete resolution of symptoms. she underwent a 79 laparotomy 20 days after admission. intraoperatively, inflamed, thickened omentum was found, 80 dense bowel adhesions were encountered which were separated with difficulty. dermoid contents 81 of hair and sebum were seen between bowel loops. the contents were cleared as much as safely 82 permissible. the upper abdomen could not be accessed due to dense adhesions. during 83 adhesiolysis, a small jejunal injury occurred, which was closed with vicryl no.3-0. entire peritoneal 84 cavity and bowel loops were inflamed and edematous. uterus left tube and ovary were normal. 85 thorough peritoneal lavage was done with six liters of normal saline and intraperitoneal drain was 86 inserted. histopathology showed omentum with fat necrosis, microabscess formation and 87 granulomatous inflammation around the content of dermoid. 88 89 she remained afebrile for 48 hours after the procedure. total parenteral nutrition was started as her 90 serum albumin was low (22gm/l) and her oral intake for the last 3 weeks was minimal. two days 91 post laparotomy, high spikes of fever returned reaching 39°c. repeat imaging of the chest and 92 abdomen showed a slight worsening of the right lower lobe atelectasis. no intra-abdominal 93 collection or pneumoperitoneum was seen. she began tolerating orally and moved her bowel, the 94 surgical wound was well healed, but the fever persisted. systemic anti-inflammatory diclofenac, 95 4 was given for four days post laparotomy as her renal parameters were normal. fever gradually 96 reduced but continued with a maximum temperature of 37.4°c. she was discharged on day 41 of 97 admission, on regular oral paracetamol. 98 99 eight weeks after discharge, she remained afebrile, but complained of nausea and occasional 100 vomiting. she reported a weight loss of 10 kg over the last two months. blood investigations as well 101 as repeat ct abdomen and pelvis was ordered. counts, liver function tests and crp were normal. 102 ct scan revealed multiple nodular deposits in the entire abdomen mesentery, para colic gutters 103 and sub-diaphragm. radiologist suggested that disseminated carcinomatosis has to be ruled out, 104 other possibilities being granulomatous peritonitis (inflammatory response to dermoid contents) or 105 tuberculosis abdomen. ultrasound guided biopsy revealed granulomatous inflammation. systemic 106 steroids were considered in case patient was not better symptomatically but fortunately she did not 107 require it. 108 109 patient consent was obtained for publication purpose. 110 111 discussion 112 dermoid cysts are common benign tumors of the ovary. 15% of dermoid cysts undergo torsion. 113 rupture of dermoids either spontaneous or iatrogenic may occur. the contents of dermoid, sebum 114 and hair can be highly irritant to peritoneum, resulting in chemical peritonitis. hence all attempts 115 must be made to avoid or minimize spillage of contents. this may be difficult with large dermoids 116 especially when laparoscopic retrieval is attempted. studies have been directed to compare the 117 outcomes of laparoscopy versus laparotomy, with regard to avoiding spillage in large dermoids. 118 laparoscopy is associated with a higher incidence of spillage, up to 88% with large dermoids, 4 but 119 chemical peritonitis is rare. 120 121 a lot of factors may influence the development of this rare complication in certain individuals. the 122 more likely ones being an exaggerated inflammatory response to the irritant contents, the volume of 123 spillage and the thoroughness of the peritoneal lavage. despite thorough peritoneal lavage at 124 laparoscopy, after spillage of contents, our patient had a prolonged severe inflammatory response 125 due to the spillage of the large dermoid content and her exaggerated inflammatory response causing 126 dilemmas in management. our initial strategy was to adopt a conservative approach, with broad 127 5 spectrum antibiotics and anti-inflammatory medications. as a thorough lavage was done at primary 128 surgery, imaging not revealing any collection and no clinical signs of peritonitis, on initial 129 presentation with post-operative fever. 130 131 we hoped that the fever would settle, after the paracentesis and pleural tap, but as high-grade fever 132 continued into the 3rd week, and patient started having diffuse abdominal pain, and a tender vague 133 mass became palpable around that umbilicus, laparotomy and thorough peritoneal lavage was 134 considered. as anticipated, entry into the abdomen was extremely challenging and dense 135 inflammatory adhesions were encountered. no intraabdominal collection was found and on 136 separating bowel adhesions with difficulty, some hair and sebum were found between bowel loops. 137 138 post operatively patient was started on diclofenac. she remained afebrile for 48 hours, subsequently 139 it was interesting to know that the spikes of fever would occur just prior to the scheduled time of 140 next dose of diclofenac. this prompted us to continue the drug for 8 days, after which anti-141 inflammatory drug was downgraded to paracetamol, and she gradually improved. systemic steroids 142 were not given since the role is controversial and the patient had pneumonia. 143 144 the case was reviewed by the morbidity committee in the department and agreed that laparoscopy 145 will continue to be the standard of care even for a large dermoid. this case was operated by a 146 skilled consultant with adequate experience. thorough peritoneal lavage was done and the 147 specimen was retrieved by an endo-bag, as is the recommendation. prophylactic single dose of 148 antibiotics and was not continued as the was no evidence of infectious process. the committee 149 suggested an earlier re-laparoscopy and lavage within 48 hours of her presentation could have 150 reduced the duration of her morbidity. why a decision for immediate laparoscopy and lavage was 151 not taken as, it was thought that a thorough lavage was done at primary surgery and going back in 152 might increase morbidity due to adhesions. howevere, in hindsight immediate relaparoscopy and 153 relavage might be a good option before dense adhesions set in. as there is insufficient literature to 154 support or refute early relaparoscopy. 155 156 laparoscopic approach is preferred to laparotomy, considering the overall reduction in operative 157 morbidity, post op pain, analgesic requirement and hospital stay, with satisfactory scar.7,8 to 158 minimize the occurrence of intra operative spillage and ensuing peritonitis, measures recommended 159 6 include puncture of a large dermoid with trocar, retrieval of the specimen via endobag, 9 and 160 thorough peritoneal lavage. abundant saline lavage has been proven to reduce inflammation and 161 adhesions significantly in an experimental study.10 retrieval of specimen via colpotomy also 162 lessens spillage as compared to laparoscopic port site retrieval.11 systemic steroids have also been 163 tried with one group reporting success.12 164 165 conclusion 166 chemical peritonitis following spillage of dermoid contents poses a management dilemma. though 167 fortunately rare, when it does occur it is extremely distressing for the patient and the treating 168 surgeon alike. s epsis was ruled out in our patient, thus conservative management with antibiotics 169 therapy formed was tried and as the patient was not responding, laparomty and thorough peritoneal 170 lavage was resorted too but the procedure was technically challenging. strong multidisciplinary 171 input along with timely surgical intervention as when required, is the key to successful 172 management of this agonizing complication. 173 acute inflammation was the consistent finding both at imaging and at laparotomy. role of powerful 174 anti-inflammatory agents like steroids need to be studied further. 175 176 authors’ contribution 177 mgf wrote the whole manuscript. svk, lm and ss reviewed the manuscript. nar assisted in the 178 writing and revision of the manuscript. all authors approved the final version of the manuscript. 179 180 references 181 1. watrowski r, kostov s, alkatout i. complications in laparoscopic and robotic-assisted 182 surgery: definitions, classifications, incidence and risk factors – an up-to-date review. 183 videosurgery miniinvasive tech. 2021 sep;16(3):501–25. https://doi: 184 10.5114/wiitm.2021.108800. 185 2. shamshirsaz aa, shamshirsaz aa, vibhakar jl, broadwell c, van voorhis bj. laparoscopic 186 management of chemical peritonitis caused by dermoid cyst spillage. jsls. 2011;15(3):403–187 5. https://doi: 10.4293/108680811x13125733356990. 188 3. berg c, berndorff u, diedrich k, malik e. laparoscopic management of ovarian dermoid 189 cysts. a series of 83 cases. arch gynecol obstet. 2002 jul;266(3):126–9. https://doi: 190 10.1007/s004040100228. 191 7 4. zanetta g, ferrari l, mignini-renzini m, vignali m, fadini r. laparoscopic excision of 192 ovarian dermoid cysts with controlled intraoperative spillage. safety and effectiveness. j 193 reprod med. 1999 sep;44(9):815–20. 194 5. nezhat c, kalyoncu s, johnson e, berlands n, nezhat c, nezhat f. laparoscopic management 195 of ovarian dermoid cysts: ten years’ experience. obstet gynecol. 1999 apr;93(4):s76. 196 6. shawki o, soliman i, ebrashy a, sadek me, bahnassy a. laparoscopic management of 197 ovarian dermoid cysts. middle east fertility society journal 2004;9(1):58-65. 198 7. yuen pm, yu km, yip sk, lau wc, rogers ms, chang a. a randomized prospective study 199 of laparoscopy and laparotomy in the management of benign ovarian masses. am j obstet 200 gynecol. 1997 jul;177(1):109–14. https://doi: 10.1016/s0002-9378(97)70447-2. 201 8. milingos s, protopapas a, drakakis p, liapi a, loutradis d, rodolakis a, et al. laparoscopic 202 treatment of ovarian dermoid cysts: eleven years’ experience. j am assoc gynecol 203 laparosc. 2004 nov 1;11(4):478–85. https://doi: 10.1016/s1074-3804(05)60079-5. 204 9. campo s, garcea n. laparoscopic conservative excision of ovarian dermoid cysts with and 205 without an endobag. j am assoc gynecol laparosc. 1998 may;5(2):165–70. https://doi: 206 10.1016/s1074-3804(98)80084-4. 207 10. fiedler ep, guzick ds, guido r, kanbour-shakir a, krasnow js. adhesion formation from 208 release of dermoid contents in the peritoneal cavity and effect of copious lavage: a prospective, 209 randomized, blinded, controlled study in a rabbit model. fertil steril. 1996 apr 1;65(4):852–9. 210 https://doi: 10.1016/s0015-0282(16)58225-9. 211 11. ferrari mm, mezzopane r, bulfoni a, grijuela b, carminati r, ferrazzi e, et al. surgical 212 treatment of ovarian dermoid cysts: a comparison between laparoscopic and vaginal removal. 213 eur j obstet gynecol reprod biol. 2003 jul 1;109(1):88–91. https://doi: 10.1016/s0301-214 2115(02)00510-9. 215 12. tasaka r, tokuyama o, nishimura s, miyama m, kawamura n. successful treatment of 216 severe chemical peritonitis caused by spontaneous rupture of an ovarian mature cystic teratoma 217 using corticosteroids : a case report. adv obstet gynecol. 2013;65(2):153–60. 218 219 8 220 figure 1: preoperative ct-abdomen, showing bilateral dermoids 221 9 222 figure 2: postoperative ct –abdomen with signs of acute inflammation 223 submitted 25 sept 22 1 revision req. 27 oct 22; revision recd. 17 nov 22 2 accepted 18 dec 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.064 5 6 giant mediastinal myxoid pleomorphic liposarcoma 7 *adil h. al kindi,1 faiza a. al kindi,2 marwa al riyami,3 essam khalil1 8 9 1division of cardiothoracic surgery and 3department of pathology, sultan qaboos university 10 hospital, muscat, oman; 2radiology department, royal hospital, muscat, oman. 11 *corresponding author’s e-mail: alkindi2001@gmail.com; adil.h.alkindi@gmail.com 12 13 introduction 14 an 18 years old girl with no past medical history was experiencing progressive shortness of breath 15 for 3 months. at presentation, she was tachypneic, tachycardiac, hypotensive and was not able to 16 lie flat. 17 18 her chest x-ray revealed abnormal contouring of the mediastinum (figure 1a). contrasted ct of 19 the chest showed a large heterogenous mass occupying the anterior mediastinum, right and left 20 hemithorax with posterior displacement of the heart and atelectasis of the lungs. (figure b, c) the 21 patient underwent urgent surgical resection. the mass was exposed thorough a clam shell incision 22 exposing the anterior mediastinum and bilateral pleura (figure 2a). the mass was yellow, 23 encapsulated and lobulated. it was resected en-block with intra-operative frozen section 24 confirming negative margins. the mass weighed 3208 grams and was 22 × 18 × 13 cms. (figure 25 2b) 26 27 post-operatively, the patient did well with complete resolution of her symptoms. the final 28 histopathology proved the mass to be high grade malignant pleomorphic myxoid liposarcoma. 29 (figure 3 & 4). mdm2 and cyclin-dependent kinase 4 were both negative. she received adjuvant 30 chemotherapy and is now on close surveillance by the oncologist. 31 32 consent was taken from the patient for the publication of the case and images. 33 34 comment 35 liposarcoma is a relatively uncommon malignant tumor of adipose tissue that can occur at 36 anybody site. 1 for rare instances it arises primarily in the mediastinum.2 the recent world health 37 organization (who) classification has classified adipocytic tumors into: 1) benign 2) 38 intermediate (locally aggressive) and 3) malignant. malignant tumors include: 1) well 39 differentiated liposarcoma: lipoma-like, sclerosing, inflammatory 2) dedifferentiated liposarcoma 40 3) myxoid liposarcoma 4) pleomorphic liposarcoma 5) myxoid pleomorphic liposarcoma. 3, 2, 4 41 42 myxoid pleomorphic liposarcoma is a new entity in this classification. unlike other liposarcomas, 43 its most common anatomical site is in the mediastinum followed by the limbs and neck. 44 histologically, it shows a mixture of both myxoid and pleomorphic liposarcoma.3 mediastinal 45 liposarcoma may grow to substantial size before causing any symptoms. the most common 46 presentation is incidental finding on chest x-ray. symptomatic patients may have cough, dyspnea, 47 dysphagia, and chest pain.5 48 49 radiologically, the tumor appears inhomogeneous in ct scan with a difficulty to differentiate it 50 from other forms of sarcoma. mri can differentiate lipoma from well differentiated liposarcoma 51 (wdl).6 in lipoma, mri shows high intensity in t1 and t2 weighted images as this represents 52 the uniform structure with fatty tissue. in contrast, high grade liposarcoma show low intensity in 53 t1 images. in addition, liposarcomas tends to be larger and has more thick septa.7,8 as the entity 54 is rare, there are no randomized trials that assess different treatment modalities. current practice 55 is based on case reports and series.4 complete surgical resection remains the mainstay for the 56 treatment of myxoid pleomorphic liposarcoma.8 wide resection with negative margins is the goal. 57 however, anatomical location plays an important role whether this is possible. patients with huge 58 mediastinal mass that present late may pose high risk surgical candidates as the compression of 59 vital structures, such as the heart and the lung, may cause critical hemodynamic issues during 60 surgery.9 61 62 myxoid pleomorphic liposarcoma has an aggressive clinical presentation with high recurrence rate 63 and distant metastasis following surgical resection approximately 40% recur after surgery.8thus, 64 discussion in a multidisciplinary tumor board is recommended to assess the need for adjuvant 65 radiotherapy with or without chemotherapy after surgical resection.9 although 90% of mediastinal 66 wdl show 12q12-15 amplicon that represents amplified oncogenes mdm2 and cdk-4, no 67 genetic aberration has been associated with myxoid pleomorphic liposarcoma.3,9 68 69 in conclusion, primary mediastinal myxoid pleomorphic liposarcoma is a rare entity and tend to 70 present at an advanced stage. recognition of the need for complete surgical resection followed by 71 adjuvant therapy is very important. 72 73 authors’ contribution 74 ahk performed the surgery of this case. ek assisted in the surgery. fak prepared and reported 75 the radiological images. mr prepared the pathology of the patient and reported the pathological 76 images. ahk and ek drafted and edited the manuscript. all authors approved the final version of 77 the manuscript. 78 79 references 80 1. dei tos a. liposarcoma: new entities and evolving concepts. ann diagn pathol. 2000 81 aug;4(4):252–66. doi: 10.1053/adpa.2000.8133 82 2. suster di, suster s. liposarcomas of the mediastinum. mediastinum. 2020 sep;4:27–27. 83 doi:10.21037/med-20-42 84 3. choi jh, ro jy. the 2020 who classification of tumors of soft tissue: selected changes 85 and new entities. adv anat pathol. 2021 jan;28(1):44–58. 86 doi:10.1097/pap.0000000000000284 87 4. sugiura y, hashizume t, fujimoto h, nemoto e. a giant mediastinal liposarcoma weighing 88 3500 g resected with clam shell approach, a case report with review of literature. int j surg 89 case rep. 2017;41:292–5. doi:10.1016/j.ijscr.2017.10.055 90 5. ortega p, suster d, falconieri g, zambrano e, moran ca, morrison c, et al. liposarcomas of 91 the posterior mediastinum: clinicopathologic study of 18 cases. modern pathology. 2015 may 92 5;28(5):721–31. doi:10.1038/modpathol.2014.152 93 6. patnaik s, malempati a, uppin m, susarla r. rare mediastinal masses – imaging review. j 94 cancer res ther. 2021;17(1):13. doi:10.4103/jcrt.jcrt_587_19 95 7. nagano s, yokouchi m, setoguchi t, ishidou y, sasaki h, shimada h, et al. differentiation 96 of lipoma and atypical lipomatous tumor by a scoring system: implication of increased 97 vascularity on pathogenesis of liposarcoma. bmc musculoskelet disord. 2015 dec 98 22;16(1):36. doi:10.1186/s12891-015-0491-8 99 8. mei x, li m, xia y. a huge mediastinal, well-differentiated liposarcoma with heterogenous 100 smooth muscle differentiation: a case report. int j clin exp pathol. 2019;12(7):2763–6. 101 9. nassif na, tseng w, borges c, chen p, eisenberg b. recent advances in the management of 102 liposarcoma. f1000res. 2016 dec 22;5:2907. doi:10.12688/f1000research.10050.1 103 104 figure 1: a: anteroposterior chest radiograph showing an abnormal contouring of the 105 mediastinum with a large lesion in the anterior mediastinum and the left lower hemithorax. hilar 106 overlay sign is noted with both hilar shadows identified through the opacity of the abnormal 107 lesion. b & c: ct-scan images of the chest with iv contrast, (b) axial (c) coronal , showing a 108 large heterogenous mass occupying the anterior mediastinum, right and left hemithorax with 109 posterior displacement of the heart and atelectasis of the lungs . the mass shows areas of low 110 density (*) likely representing fat content and other areas of high density (**) representing 111 calcification. 112 113 114 figure 2: a: clam-shell incision exposing the anterior mediastinum and bilateral pleura. b: the 115 mass was yellow, encapsulated and lobulated measuring was 22 × 18 × 13cms. 116 117 118 figure 3: microscopic examination showed an encapsulated multinodular malignant neoplasm 119 of variable cellularity (a). there were lipomatous areas showing atypical multivacuolated 120 lipoblasts (arrows) (b). other areas showed myxoid stroma containing plump spindle to stellate 121 cells (c). there were highly cellular nodules formed of fascicles of pleomorphic spindle cells 122 with frequent mitotic figures (arrow) (d). 123 124 125 figure 4: areas of geographic coagulative type necrosis were seen (asterisk) (a). the tumor 126 cells in the lipomatous areas were strongly positive for s-100 (b) but this was negative in the 127 cellular pleomorphic areas (c). tumor cells were negative for mdm2 and cdk4. cdk4 is 128 shown here (d). 129 august 2007 vol 7 copy.indd abstract the superior transverse scapular ligament (stsl) bridges the suprascapular notch, converting it into a suprascapular foramen. the suprascapular nerves and the vessels traverse through the suprascapular foramen of the scapula. often the stsl is ossified to produce compression of the suprascapular nerves producing resultant symptoms. the entrapment of the suprascapular nerve by the ossified stsl may result in symptoms like pain in the shoulder region and also result in wasting and weakness of the supraspinatus and infraspinatus muscles. such a condition has to be differentiated from other conditions like rotator cuff tears. often asymptomatic cases make the diagnosis difficult. the present study reports the anomalous ossified stsl detected in a bone specimen, discusses its anatomical and radiological aspects and describes its clinical implications. keywords: scapula; ligament; anomalies; ossification; entrapment; case report. ossification of superior transverse scapular ligament and its clinical implications *srijit das,1 rajesh suri,2 vijay kapur3 السريرية املستعترض ومقتضياته العلوي الكتفي الرباط تعظم كابور فيجي سوري، راجيش داس، سريجيت خالله من والذي متر الكتف، عظم أعلى في ثقب إلى ثلمة ليحولها من تِف الكَ مِ ظْ فَوقَ عَ ةُ الثُّلْمَ املستعرض العلوي الكتفي الرباط امللخص: يجسر إلى مؤدياً واألعصاب ــة هذه األوعي على ضغطا ــبباً ــعترض مس العلوي املس الكتفي يتعظم الرباط ما غالبا ــة العلوية. الكتفي ــاب واألعص ــة األوعي هذه بني التمييز يتوجب وعليه ــوكي. الش الناتئ حتت وعضلة ــوكي الش الناتئ في عضلة فوق وضمور ضعف مع الكتف في منطقة بآالم ــاس اإلحس حالة التقرير هذا ــتعرض يس صعبا. أعراض كهذه يرافقها التي ال احلاالت ــخيص أما تش الكتفية املديرة. العضلة متزق حالة مثل وحاالت أخرى احلالة املمكن التي من ــريرية الس ــعاعية والدالالت والش ــريحية خصائصها التش ــعترض، ويناقش املس العلوي الكتفي الرباط فيها م تعظَ لعينة غير عادية احلالة. استنتاجها في هذه حالة تقرير اخ، خَ انْفِ تعظم، املستعرض، الرباط اللوحي، الكلمات: الكتفي، مفتاح 1department of anatomy, maulana azad medical college, new delhi, india; 2department of anatomy, vardhman mahavir medical college, new delhi, india; 3 department of anatomy, maulana azad medical college, new delhi, india *to whom correspondence should be addressed. email: das_srijit23@rediffmail.com sultan qaboos university medical journal august 2007 vol 7, no. 2, p. 157-160 sultan qaboos university© submitted 13 february 2007 c a s e r e p o r t the suprascapular notch is converted into a foramen by the stsl with the supras-capular nerve passing through the foramen and the suprascapular vessels passing above the stsl.1 the stsl has been reported to be ossified as in conventional anatomy text books.1 past research studies have reported the stsl to be calcified and partially or completely ossified.2 the variations of the suprascapular notch and the stsl have been known to predispose to suprascapular nerve entrapment.3 many past research studies on the ossification of the stsl have described it to be a cause of a suprascapular nerve entrapment syndrome.2-7 thus, the role of stsl in causing suprascapular nerve entrapment is a known fact and better understanding of the topographical anatomy may be helpful for clinicians, surgeons and academicians in day to day practice. while many of the past research studies have described the anatomy and clinical study of ossified stsl, there is a paucity of literature on the anatomico-radiological study of the ossified stsl. the present study aims to report the morphology of ossified stsl and its radiological findings in a bone specimen and to discuss its clinical implications. in conclusion, anatomical and radiological knowledge of the ossified stsl may be helpful in diagnosis and treatment of suprascapular nerve entrapment. s r i j i t d a s , r a j e s h s u r i a n d vi j ay k a p u r 158 c a s e r e p o r t during routine undergraduate osteological teaching for medical students, ossification of stsl was noted only in a scapula. the anomalous bone specimen was studied in detail and the specimen was photographed [figure 1]. a skiagram was also obtained for the bone specimen [figure 2] the scapula showed ossification of the stsl (‘s’ in figure 1). the suprascapular foramen (‘c’ in figure 1) measured 1.2 cm as its maximum vertical height and 0.8 cm as its maximum transverse diameter. the distance of the supracapular foramen from the lateral angle of the scapula measured 5.5 cm, while the distance from the glenoid notch measured 2.7 cm. the stsl measured 2 cm x 0.7 cm. the lateral border of the scapula had a projection in its lower portion. no other deformities were noted in the bone specimen. the x-ray of the specimen (oblique view) revealed a small suprascapular foramen (marked with a lead pin in figure 2) and the completely ossified stsl (marked with an arrow in figure 2). d i s c u s s i o n the suprascapular nerve has a motor supply to the supraspinatus and the infraspinatus muscle, but it does not innervate the skin. in case of irritation of the nerve, the pain is deep and poorly localized and this is perhaps the reason why the cause of the pain and tenderness is difficult to discover in any individual.8 often, by the time the patient approaches the clinician with complaints, the muscle atrophy will have already begun.8 an early and correct diagnosis requires a thorough anatomical knowledge of the course of the nerve and its possible sites of entrapment. the suprascapular nerve entrapment may be due to traumatic or non-traumatic causes. the suprascapular nerve is commonly susceptible to compression mainly at two major sites i.e. at the level of the suprascapular notch and at the base of the scapular spine.9 the suprascapular nerve passes through the suprscapular foramen and there is a possibility that the nerve may be compressed by the stsl, especially if it is ossified. the research reports have defined the shape of the suprascapular notch or the ossification of the stsl to predispose to suprascapular nerve entrapment.2 research reports have described a ‘u’ shaped suprascapular notch in 77% and a ‘v’ shaped notch in 23% of individuals, respectively. 2 in the present bone specimen, we noted a foramen, which had the stsl fully ossified. admittedly, in the absence of any clinical history of the patient, it is difficult to comment on the clinical status, but we presume that in this individual there may have been entrapment of the suprascapular nerve. the ossification of the stsl has been reported to be 18% for the partial and 5% for the complete type.2 past studies have reported a 3.7% 4% incidence of partial ossification of stsl.10, 11 it is thus evident, that the extreme rarity of complete ossification of stsl as figure 1: photograph of the scapula (anterior view) showing: a: acromion process b: coracoid process c: suprascapular foramen d: lateral angle e: inferior angle f : medial border g: glenoid cavity s: ossified superior transverse scapular ligament o s s i f i c at i o n o f s u p e r i o r tr a n s v e r s e s c a p u l a r l i g a m e n t a n d i t s c l i n i c a l i m p l i c at i o n s 159 seen in this case, may be clinically and academically relevant. as anatomists, we think that a study of stsl in a larger sample would definitely be worthwhile. interestingly, entrapment of the suprascaspular nerve at the suprascapular notch was first described by kopell and thompson. according to these authors, the movement of abduction or horizontal adduction of the shoulder resulted in compression of the nerve against the stsl.12 research studies have also defined it as a ‘sling effect’ because there is kinking of the suprascapular nerve against the stsl. 13 involvement of the suprascapular nerve by an ossified stsl may result in pain. the history of such a patient will have to be carefully noted and a thorough physical examination undertaken. usually in these cases of entrapment, the patient complains of pain, which may be present over the postero-lateral aspect of the shoulder. the pain may radiate down the arm and there is weakness with abduction and external rotation of shoulder.14 thus weakness with abduction and external rotation is an important clinical feature to diagnose such an entrapment. however, this pain may also resemble a rotator cuff tear. anatomically, the rotator cuff includes the muscles subscapularis, supraspinatus, infraspinatus and the teres minor. out of these four muscles, only the supraspinatus and infraspinatus muscles are innervated by suprascapular nerve. thus entrapment of the suprascapular nerve would result in loss of action of both the supraspinatus and infraspinatus muscles. external rotation by both infraspinatus and teres minor muscles and just the loss of action of the infraspinatus may be difficult to identify. under such conditions, the patient is asked to adduct the arm across the chest, which tenses the nerve on the stsl and there is a resultant increase in pain.15 the nerve conduction velocity and electromyographic studies may help in proper diagnosis.16 investigations like ct, mri scans and arthrography may help at arriving at a correct diagnosis. interestingly, even atrophy of muscles has been found in mri scans, therefore mri scans may be beneficial for correct diagnosis.17 non-operative treatment has been advised for majority of the cases. 16 a rehabilitation programme with gradual strengthening of the involved muscles is always advised. in extreme cases, surgical decompression of the nerve is advised. the approach is anterior, superior or posterior. the idea is to identify the suprascapular nerve by retracting the suprascapular vessels laterally and then the stsl may be resected to decompress the impinged nerve. 14 in the present case, the complete ossification of the stsl can be easily made out in the radiological study (marked with an arrow in figure 2). we also kept a lead pin in vertical position for the better visualization of the suprascapular foramen, which was complete because of the ossification of the stsl. in the presence of a normal suprascapular foramen with a normal stsl, there would be no distinct bar of bone casting figure 2: skiagram of scapula (oblique view) showing: a: acromion process b: coracoid process c: glenoid cavity d: lateral angle e: lateral border f : inferior angle suprascapular foramen is being shown with small arrow (·) and the ossification of the ligament (l) is shown with lead pin placed vertically while obtaining the skiagram s r i j i t d a s , r a j e s h s u r i a n d vi j ay k a p u r 160 any shadow in the x-ray plate, but one was noticed in the present case (marked with arrow in figure 2). the presence of such an ossified ligament may not be detected unless compression symptoms exist. the presence of an ossified stsl may also pose a challenge during decompression of the suprascapular notch if the condition is not fully appreciated.2 the ossification of the stsl may also alter the attachment of the omohyoid muscle, which has its attachment close to it. the lateral border of the scapula had a projection and it may have distorted the attachment of the omohyoid muscle, thereby altering its actions. c o n c l u s i o n the anatomical and radiological knowledge of the ossification of the stsl may be helpful for clinicians, radiologists and surgeons dealing with suprascapular nerve entrapment conditions. overall, it is an interesting osteological study, which opens the door for further research on the ossification of stsl. r e f e r e n c e s 1. standring s, ellis h, healy j, johnson d, williams a. pectoral girdle, shoulder region and axilla. in: standring s, ed. gray’s anatomy the anatomical basis of clinical practice. new york: elsevier churchill livingstone, 2005. p. 821-822. 2. ticker jb, djurasovic m, strauch rj, april ew, pollock rg, flatow el, bigliani lu. the incidence of ganglion cysts and other variations in anatomy along the course of the suprascapular nerve. j shoulder elbow surg 1998; 7:472-478. 3. osuagwu fc, imosemi io, oladejo ow. sources of cadaver used for dissection at the ibadan medical school, nigeria analysis of a three year data. african j biomed res 2004; 7:93-95. 4. bayramoglu a , demiryurek d , tuccar e , erbil m , aldur mm , tetik o , doral mn.. variations in anatomy at the suprascapular notch possibly causing suprascapular nerve entrapment: an anatomical study. knee surg. sports traumatol arthrosc 2003; 11:393-398. 5. callahan jd, scully tb, shapiro sa, worth rm. suprascapular nerve entrapment. a series of 27 cases. j neurosurg 1991; 74:893-896. 6. post m, grinblat e. suprascapular nerve entrapment; diagnosis and results of treatment. j shoulder elbow surg 1993; 2:190-197. 7. vastamaki m, goransson h. suprascapular nerve entrapment. clin orthop relat res 1993; 297:135-143. 8. thompson wal, kopell hp. peripheral entrapment neuropathies of the upper extremities. n engl j med 1959; 260:1261-1265. 9. mestdagh m, drizenko a, ghestem p. anatomical basis of suprascapular nerve syndrome. anat clin 1981; 3:6771. 10. hrdlicka a. the scapula: visual observations. am j phys anthropol 1942; 2:73-94. 11. rengachary ss, neff jp, singer pa, brackett cf. suprascapular nerve entrapment neuropathy: a clinical, anatomical and comparative study. part 1: clinical study. neurosurgery 1979; 5:441-445. 12. antoniadis g, richter hp, rath s, braun v, moese g. suprascapular nerve entrapment: experience with 28 cases. j neurosurg 1996; 85:1020-1025. 13. rengachary ss, burr d, lucas s, brackett ce. suprascapular entrapment neuropathy: a clinical, anatomical, and comparative study. part 3: comparative study. neurosurgery 1979; 5:452-455. 14. cohen sb, dines dm, moorman ct. familial calcification of the superior transverse scapular ligament causing neuropathy. clin orthop relat res 1997; 334:131135. 15. hama h, ueba y, morinaga t, suzuki k, kuroki h, yamamuro t. a new strategy for treatment of suprascapular entrapment neuropathy in athletes: shaving of the base of the scapular spine. j shoulder elbow surg 1992; 1:253-260. 16. cummins ca, messer tm, nuber gw. suprascapular nerve entrapment. j bone joint surg am 2000; 82:415424. 17. kullmer k, sievers kw, reimers cd, rompe jd, muller-felber w, nagele m, et al. changes of sonographic, magnetic resonance tomographic, electromyographic, and histopathologic findings within a 2-month period of examinations after experimental muscle denervation. arch orthop trauma surg 1998; 117:228-234. march 2007 vol 7 isuue 1 final without suicide .indd sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© 1parasitology department, faculty of medicine, sebha university, sebha, libya 2parasitology department, faculty of medicine, al-fateh university, tripoli, libya. *to whom correspondence should be addressed. email: alfellani@yahoo.co.uk prevalence and clinical features of blastocystis hominis infection among patients in sebha, libya *mohammed a al-fellani1, abdul h khan1, rugaia m al-gazoui1, mabrouk k zaid2, mahmoud a alferjani2 abstract objective: to determine the prevalence and seasonal variation, and to assess the clinical manifestations and treatment of blastocystosis in libyan patients. methods: three thousand six hundred and forty five stool samples were screened for blastocystis hominis using normal saline and iodine solution preparations. the clinical features of 08 patients were described, in whom b. hominis was the only parasite isolated. fifty symptomatic patients were treated with 500 mg metronidazole daily for 7 days and their stools were re-investigated for b. hominis. results: b. hominis was found in 969 (26.58 %) of 3645 stool specimens examined. the infection of b. hominis was significantly more (p < 0.05) in summer than in winter over a three year period. in a prospective study of 08 patients, the most common symptoms with stools positive only for b. hominis were diarrhoea (84.94 %), abdominal pain (66.66 %), flatulence (7.20 %) and vomiting (6.2 %). high concentration of b. hominis cells were found more in symptomatic patients than asymptomatic ones (9.20 cells per 40 x field versus 4.06 respectively) with statistically significant differences (p < 0.00). patients with b. hominis responded to metronidazole and were fully cured after 7 days. conclusion: the occurrence of b. hominis infections in outpatients are probably related to weather conditions, with the suggestion that the hot, dry weather of the sebha region favors the development and transmission of this organism. b. hominis infections might have a role in some pathological conditions, resulting in gastrointestinal symptoms. key words: blastocystis, seasonal variation, culture, diarrhoea. عند السريرية وصفاتها رِيَّة البَشَ يَّةُ الكيسِ ةُ مَ املُتَبَرْعِ عدوى انتشار (ليبيا) سبها في املرضى على الفرجانى ومحمود خليفة زايد مبروك اجلازوى، محمد رقية عبد احلفيظ خان، الفالني، محمد عبد السالم للمرضى والعالجية السريرية احلالة تقييم وكذلك فيها، املوسمي االختالف رِيَّة ومعرفة البَشَ ــيَّةُ الكيسِ ةُ مَ ُتَبَرْعِ امل ــار انتش امللخص: الهدف: حتديد ومحلول نظامي ملحي محلول باستعمال رِيَّة البَشَ يَّةُ الكيسِ ةُ مَ ُتَبَرْعِ حالة امل 3645 لتقصي من براز الطريقة: أخذنا عينات بها. املصابني الليبيني بعقار أعراضا لديهم كانت ممكن مريضا ــني خمس عولج فقط. ــرِيَّة البَشَ ــيَّةُ الكيسِ ةُ مَ ُتَبَرْعِ بامل مصابا 108 مريضا ــريرية ل احلالة الس وصف مت اليود. (26.58%) 969 في رِيَّة البَشَ يَّةُ الكيسِ ةُ مَ ُتَبَرْعِ امل النتائج: وجدت مرة أخرى. فحص البراز أعيد أيام، وبعدها ملدة سبعة (1500 ملجم) امليترونيدازول p=0.05) معتد إحصائي بفارق الثالث ــنوات الس في ــتاء الش في منه الصيف في حدوثا أكثر العدوى كانت .3645 البراز البالغة مجموع عينات من ،(66.66%) البطن ألم ،(84.94%) ــهال اإلس هي املوجب للبراز الفحص مع ــيوعا ش كانت األعراض األكثر 108 مريضا، ــبقة ل مس ــة في دراس .( (9.20 خلية غيرهم عن أعراضا يظهرون الذين املرضى عند أكثر رِيَّة البَشَ يَّةُ الكيسِ ةُ مَ ُتَبَرْعِ امل خاليا عدد كان .(16.12%) والتقيؤ (17.20%) الغازات بعقار ــرِيَّة البَشَ ةُ ــيَّ الكيسِ ةُ مَ ُتَبَرْعِ بامل املصابون املرضى ــفي ش . (p<0.001)معتد إحصائي وبفرق 4.06 لآلخرين)، مقابل 40 مرة التكبير مجال في أن حيث باملناخ، عالقة لها اخلارجية العيادة مراجعي عند رِيَّة يَّةُ البَشَ الكيسِ ةُ مَ ُتَبَرْعِ العدوى بامل تكون : رمبا اسبوع. اخلالصة فترة امليترونيدازول خالل التي املرضية احلاالت دورا في بعض بها تلعب العدوى رمبا والتي ــرِيَّة، البَشَ يَّةُ الكيسِ ةُ مَ ُتَبَرْعِ وانتقال امل تكاثر على ــاعد واجلاف قد يس احلار ــبها س مناخ هضمية. أعراضا تسبب الزرع. اإلسهال، الفصلية، التغيرات يَّة، الكيسِ ةُ مَ ُتَبَرْعِ الكلمات: امل مفتاح c l i n i c a l & b a s i c r e s e a r c h m o h a m m e d a a l f e l l a n i , a b d u l h k h a n , r u g a i a m a l g a z o u i , m a b r o u k k z a i d a n d m a h m o u d a a l f e r j a n i 36 infection by blastocystis hominis occurs all over the world, but is commonly found in de-veloping countries.¹’² practicing physicians and gastroenterologists usually have low awareness of the association of b. hominis with human disease. these infections are overlooked in clinical laboratories. the centre for disease control and prevention also considered it to be a pathogenic protozoan.³ b. hominis is now increasingly recognized as a possible cause of gastrointestinal disorders.4-7 a subgroup of b. hominis could possibly be pathogenic in some patients.8 the specific pathogenic potential of b. hominis has not been defined.9-12 the results of a recent study in sebha, libya, revealed that b. hominis was the most frequent isolate in all stool specimens submitted for analysis,13 but the clinical significance of b. hominis infection in the libyan population has not been documented so far. in the present study, the aim was to investigate the prevalence of b. hominis among patients attending the central laboratory in sebha, libya and to describe the clinical presentations of patients parasitized only with b. hominis infection in libyan communities. m e t h o d s this prospective study was performed in sebha city, fezzan province, south-western libya. this region is characterized by a hot and dry climate. it is an arid and desert area with a population of over one hundred thirty thousand. most people work in agriculture. a total of 3,645 stool samples were collected (from the beginning of january to the end of december 2005) from outpatients attending the central laboratory in sebha, libya, for routine examination of intestinal parasites. soon after the collection of stool specimens, two faecal smears were prepared (normal saline and lugol’s iodine) from each sample. these preparations were examined under both a low power (10 x) and a high power (40 x) of microscope to detect possible b. hominis. the seasonal prevalence of b. hominis was recorded among 8,089 patients, who attended the central laboratory in sebha, over a 3 year period from january 2003 to december 2005. a prospective study on 108 patients parasitized exclusively with b. hominis was performed. clinical information on patients with stools which tested positive for b. hominis was obtained by sending a survey questionnaire to practicing physicians at the al-jadeed clinic in sebha, libya. the numbers of b. hominis cells in faecal materials were counted with a 40 x field microscope. ninety three patients harboured only b. hominis and presented with gastrointestinal symptoms (diarrhoea with or without abdominal pain and flatulence or vomiting) were treated for seven days with metronidazole 500 mg three times per day for 7 days. only fifty patients returned back for a follow up examination. stool samples from these patients were re-examined for b. hominis after completion of the therapy. the positive rate of b.hominis was expressed as a percentage (number, sex, seasonal variation, diarrhoea etc) and statistical analysis was carried out using the independent sample t-test. p-values of < 0.05 and 0.001 were considered statistically significant. r e s u l t s the prevalence of b. hominis was found to be 26.58 % among outpatients at the central laboratory in sebha. of the 3,645 patients examined, 1,925 (52.81 %) were males and 1,720 (47.18 %) were females. a total of 558 (28.98 %) males and 411 (23.89 %) females were harbouring b. hominis. the highest positivity (10.28 %) rate was found in the 21 to 40 age group. the seasonal variation of b. hominis among patients attending the central laboratory in sebha is presented in table 1. the prevalence of b. hominis was found to be significantly more (p<0.05) in summer year summer season* winter season** total investigated no. no. positive no. no. positive no. no. positive*** 2003 2572 458 (17.80) 1855 279 (15.04) 4427 737 (16.64) 2004 2264 497 (21.95) 1398 267 (19.09) 3662 764 (20.86) 2005 2336 640 (27.39) 1309 329 (25.13) 3645 969 (26.58) figures in parentheses indicate percentages. * april to october. ** november to march. *** p < 0.05 versus comparison with summer and winter season. table 1 : seasonal variation of b. hominis among patients attending the central laboratory in sebha 37 p r e va l e n c e a n d c l i n i c a l f e at u r e s o f b l a s t o c y s t i s h o m i n i s i n f e c t i o n a m o n g pat i e n t s i n s e b h a , l i b ya than in winter. the clinical presentations of 93 patients parasitized exclusively with b. hominis are shown in table 2. the most frequent manifestation was diarrhoea (84.94%). sixty-four (68.81%) patients had two or more gastrointestinal complaints. twenty-nine patients (31.18 %) had only one clinical feature (25 had diarrhoea and 4 had cramping abdominal pain). forty-nine patients (52.68 %) had two gastrointestinal complaints (33 had diarrhoea with cramping abdominal pain, 6 had diarrhoea with vomiting, 2 had vomiting with cramping abdominal pain and 8 had cramping abdominal pain with flatulence). fifteen patients (16.12 %) had three clinical symptoms of blastocystosis (7 had diarrhoea with cramping abdominal pain and vomiting, 8 had diarrhoea with cramping abdominal pain and flatulence). the intensity of b. hominis among symptomatic and asymptomatic individuals is presented in table 3. the mean number of b. hominis was significantly higher (p<0.001) in symptomatic patients than in asymptomatic individuals (9.20 ± 2.41 organisms per 40 x field, versus 4.06 ± 1.86 respectively). two infected persons, in whom b. hominis cells were found 10 and 12 per 40 x field, were entirely asymptomatic. b. hominis were not found in stools from patients upon the completion of the 7 day therapeutic course of metronidazole. all fifty patients showed clinical improvement and were fully cured using 1500 mg of metronidazole daily for 7 days. d i s c u s s i o n physicians usually have low awareness that b. hominis is a cause of human disease. the number of infections appears to be high in most populations, however, the frequency is grossly underestimated. asymptomatic shedding of b. hominis provides an appropriate environment for its transmission to other subjects. recently b. hominis has been considered as potential pathogen. 5-7 infections of b. hominis may be an important pubic health problem in libyan communities. 30-32 so far, only one study has been carried out on the prevalence of b. hominis among patients attending the central laboratory in sebha, libya.13 this study was carried out to investigate the prevalence, seasonal variation and the association between the presence of b.hominis and gastrointestinal symptoms among patients. the results of this study show that b. hominis was detected in 26.58 % of stool specimens examined. very similar prevalence have been described in other parts of the world: 25% in jordan,3 32% in pakistan,6 18% in bethesda,14 31% in egypt,20 25.78% in venezuela,24 26.5% in brazil29 and 22.9% in argentina33 [table 4]. however, higher prevalence of b. hominis has been reported in other countries of the world: 36% in tanzania,23 40.7% in philippines,25 36.9% in thailand,26 and 46.9% in venezuela.34 in the present study, the prevalence of b. hominis was higher than previously reported among the same population. this may be due to improvement in detection of b. hominis infection in clinical laboratories, but infections with this organism may have also increased in the population. in the libyan arab jamahiriya, the rapid socio-economic development, agriculture practices and the enormous increase in the number of foreign workers from neighbouring countries may have lead to a substantial increase of intestinal parasites in the country. prior research has shown that immigrants and refugees from clinical symptoms no. of cases diarrhoea 79 (84.94) cramping abdominal pain 62 (66.66) flatulence 16 (17.20) vomiting / nausea 15 (16.12) parasitized exclusively by b. hominis. figures in parentheses indicate percentages. table 2: clinical manifestations of 93 symptomatic patients table 3: intensity of b. hominis infection among blastocystosis patients. category no. of cases and (%) intensity of b. hominis no. of organisms mean of no. ± sd no. of organisms mean of no. ± sd symptoms 93 (86.11) positive for b. hominis with gastrointestinal symptoms more than 7 9.20±2.41** (8 to 30)* symptoms 15 (13.88) positive for b. hominis without trointestinalsymptoms less than 5 4.06±1.86 (2 to 12)* * range of no. of b. hominis cells per 40 x field. ** p < 0.001 versus comparison with number of b. hominis cells among asymptomatic individuals. m o h a m m e d a a l f e l l a n i , a b d u l h k h a n , r u g a i a m a l g a z o u i , m a b r o u k k z a i d a n d m a h m o u d a a l f e r j a n i 38 developing countries have a higher incidence of b. hominis. in the present study, males were more infected (28.98%) with b. hominis than females (23.89%). the difference was significant (p<0.05). several studies have reported significantly higher prevalence in male than female patients.2, 3, 12 the parasitological examination of faecal samples revealed that the incidence of b. hominis is widespread throughout the year with a particular peak in the summer season. the high incidence of b. hominis in the sebha region may be due to the dry climatic conditions that favour the survival and transmission of this organism in the population throughout the year. this is in contrary to other parts of the world, where infections of b. hominis are commonest during the premonsoonal months, spring and winter seasons.16, 20, 27 the most prominent gastrointestinal symptoms in 93 patients parasitized exclusively by b. hominis were diarrhoea (84.94%), cramping abdominal pain (66.66%) and nonspecific gastrointestinal symptoms such as flatulence (17.20%) and nausea or vomiting (16.12%). these symptoms were similar to the one reported previously in patients infected with b. hominis. 2-8, 20 in the present study, the number of b. hominis was significantly higher (p < 0.001) in the stools of symptomatic patients than in asymptomatic individuals (more than seven cells with mean number 9.20 ± 2.41 versus less than five with mean number 4.06 ± 1.86). several studies have reported detecting more than five cells of b. hominis per 40 x field in stool samples from symptomatic patients.3, 7, 20, 35 in addition five or more b. hominis cells per oil immersion field (100 x) have been detected in symptomatic patients.22,36-38 the mean numbers of b. hominis cells in the stools of symptomatic patients were significantly higher than asymptomatic patients.5, 7 several studies reported severe symptoms in patients with high numbers of b. hominis,9, 20 however, this correlation was not found in others.21, 22, 40 in the present study, among asymptomatic subjects (except two cases) the number of b. hominis cells found was less than five per 40 x field. similarly less reference country / locality % of b. hominis wang et al2 community population in china 3.7 nimri3 preschool children in jordan 25.0 yakoob et al6 outpatients in pakistan 32.0 al-fellani et al13 outpatients in libya 18.5 zierdt14 community population in bethesda 18.0 garcia et al.15 outpatients in los angeles 12.0 babock et al.16 population in nepal 10.0 markell and udkow17 outpatients in san francisco 12.0 sheehan et al.18 outpatients in new york 11.0 kain et al.19 outpatients vancouver 13.0 el masry et al.20 outpatients in egypt 31.0 doyle et al.21 outpatients in canada 3.2 martin-sanchez et al.22 primary school children in spain 19.4 gomez morales et al.23 outpatients in tanzania 36.0 requena et al.24 food handlers in venezuela 25.8 eleonor et al.25 children in philippines 40.7 leelayoova et al.26 army personal in thailand 36.9 suresh and smith27 outpatients in united kingdom 3.9 khan and khalife28 food handlers in saudi arabia 8.5 nascimento and moitinho29 community population in brazil 26.5 present study outpatients in libya 26.58 table 4: prevalence of b. hominis in various countries/states of the world. 39 p r e va l e n c e a n d c l i n i c a l f e at u r e s o f b l a s t o c y s t i s h o m i n i s i n f e c t i o n a m o n g pat i e n t s i n s e b h a , l i b ya than five organisms (fewer than three) per 40 x microscopic fields among stool samples of apparently healthy subjects have been reported.3, 24 large numbers of b. hominis were also observed in faeces of some asymptomatic individuals.12, 22, 41 in this prospective study, the physicians of health centre al-jadeed in sebha successfully treated fifty patients infected with b. hominis with metronidazole 500 mg three times per day for 7 days. in all these patients, no other parasites were demonstrated in the faecal specimens. all patients responded to the therapy and symptoms disappeared after 7 to 10 days. moreover, b. hominis was not detected in the stools of patients after 7 days. this suggests that the gastrointestinal symptoms in all these patients (positive only for b. hominis) are probably due to b. hominis infection. metronidazole has been suggested as the first line chemotherapeutic agent for treatment of b. hominis infection.42-44 however, some authors reported that metronidazole did not eradicate the b. hominis completely and was effective only in some individuals.6, 45, 46 in conclusion, we report that b.hominis is a common intestinal protozoa infection in sebha and with higher prevelance in warm and hot seasons of the year. in patients with blastocystosis, gastrointestinal symptoms are more likely to be associated with intensity of b. hominis. further research to evaluate the pathogenic potential of this organism is needed. r e f e r e n c e s 1. stenzel dj, boreham pfl. blastocystis hominis revisited. clin microbiol rev 1996; 9:563-584. 2. wang kx, li cp, wang j, cui yb. epidemiological survey of blastocystis hominis in huainan city, anhui province, china. world j gastroenterol 2002; 8:928932. 3. nimri lf. evidence of an epidemic of blastocystis hominis infections in preschool children in northern jordan. j clin microbiol 1993; 31:2706-2708. 4. zaman v. blastocystis hominis. weatherall dj, ledigham jgg and warrell d. eds. oxford textbook of medicine. third edition. oxford: oxford university press, 1996. p. 887. 5. barahona rl, maguina vc, naquira vc, terashima ia, tello r. human blastocystosis: prospective study symptomatology and associated epidemiological factors. rev gastroenterol peru 2003; 23:29-35. 6. yakoob j, jafri w, jafri n, et al. irritable bowel syndrome: in search of an etiology: role of blastocystis hominis. am j trop med hyg 2004; 70:383-385. 7. el-shazly am, abdel-magied aa, el-beshbishi sn, et al. blastocystis hominis among symptomatic individuals in talkha center, dakahlin governorate, egypt j egypt soc parasitol 2005; 35:653-666. 8. tungtrongchitr a, manatsathit s, kositchaiwt c, et al. blastocystis hominis infection in irritable bowel syndrome patients. southeast asian j trop med public health 2004; 35:705-710. 9. nimri lf, batchoun r. intestinal colonization of symptomatic and asymptomatic schoolchildren with blastocystis hominis. j clin microbiol 1994; 32:2865-2866. 10. taamasri p, mungthin m, raugsin r, tongupprakarn b, areekul w, leelayoova s. transmission of blastocystis related to the quality of drinking water. southeast asian j trop med public health 2002; 31:112-117. 11. te-lichen, che-chang c, hsin-paichen, chang-phone f, chih-peilin wan-leong c, cheng-yiliu. clinical charactesistics and endoscpic findings associated with blastocystis hominis in healthy adults. am j trop med hyg 2003; 69:213-216. 12. leder k, hellard me, sinclair mi, fairley ck, wolfe r. no correlation between clinical symptoms and blastocystis hominis in immunocompetent individuals. j gastroenterol hepatol 2005; 20:1390-1394. 13. al-fellani ma, abdulrahman dm, khan ah, abousaif aa. prevalence of intestinal parasites in sebha, libya. garyounis med j 2005; 22:16-21. 14. zierdt ch. blastocystis hominis, a protozoan parasite and intestinal pathogen of human beings. clin microbiol newsl 1983; 5:57-59. 15. garcia ls, bruckner da, clancy mn. clinical relevance of blastocystis hominis. lancet 1984, i, 1233-1234 (letter). 16. babcock d, houston r, kumaki d, shlim d. blastocystis hominis in kathmandu, nepal. n engl j med 1985; 313: 1419 (letter). 17. markell ek, udkow mp. blastocystis hominis pathogen or fellow traveller? am j trop med hyg 1986; 35:10231026. 18. sheehan dj, raucher bg, mckitrick jc. association of blastocystis hominis with signs and symptoms of human disease. j clin microbiol 1986; 24:548-550. 19. kain kc, noble ma, freeman hj, barteluk rl. epidemiology and clinical features associated with blastocystis hominis infection. diagn microbiol infect dis 1987; 8:235-244. 20. el masry na, bassily s, farid z, aziz ag. potential clinical significance of blastocystis hominis in egypt. trans r soc trop med hyg 1990; 84:695. 21. doyle pw, helgason mm, mathias rg, proctor, em. epidemiology and pathogenicity of blastocystis hominis. j clin microbiol 1990; 28:116-121. m o h a m m e d a a l f e l l a n i , a b d u l h k h a n , r u g a i a m a l g a z o u i , m a b r o u k k z a i d a n d m a h m o u d a a l f e r j a n i 40 22. martin-sanchez am, canut-blasco a, rodriguez-hernandez j, montes-martinez i, garcia-rodriguez ja. epidemiology and clinical significance of blastocystis hominis in different population groups in salamanca (spain). eur j epidemiol 1992; 8:553-559. 23. gomez morales ma, atzori c, ludovisi a, rossi p, scaglia m, pozio e. opportunistic and non-opportunistic parasites in hiv-positive and negative patients with diarrhea in tanzania. trop med parasitol 1995, 46, 109114. 24 requena i, hernandez y, ramsay m, salazar c, devera r. prevalence of blastocystis hominis among food handlers from caroni municipality, bolivar state, vevezuela: cad saude publica 2003; 19:1721-1727. 25. eleonor tb, vicente yb, winifreda ud, hyun hk, dong-ii c. infection status of intestinal parasites in children living in residential institutions in metro malina, the philippines. korean j parasitol 2004; 42:67-70. 26. leelayoova s, rangsin r, taamasri p, naaglor t, thathaisong u, mungthin m. evidence of waterborne transmission of blastocystis hominis. am j trop med hyg 2004; 70:658-662. 27. suresh k, smith h. comparison of methods for detecting blastocystis hominis. eur j microbiol infect dis 2004; 23:509-511. 28. khan za, al-khalife is. prevalence of blastocystis hominis among “healthy” food handlers in dammam, saudi arabia. j egypt soc parasitol 2005; 35:395-401. 29. nascimento sa, moitinho md. blastocystis hominis and other intestinal parasites in a community of pitannga city parana state, brazil. rev inst med trop 2005; 47: 213-217. 30. narkewicz mr, janoff en, sokol rj, levin mj. blastocystis hominis gastroenteritis in a haemophiliac with acquired immune deficiency syndrome. j pediatr gastroenterol nutr 1989; 8:125-128. 31. lee mj. pathogenicity of blastocystis hominis. j clin microbiol 1991; 29:2089 (letter). 32. gugliemetti p, fantoni a, sansoni a, rossolini a. prevalenza e significato clinico di blastocystis hominis in bambini sintomatici e asintomatici autoctoni e provenienti da aree tropicali. rev parassit 1993; 10:15-24. 33. minvielle mc, pezzani bc, cordoba ma, deluca mm, apeztequina mc, basualdo ja. epidemiological survey of giardia spp. and blastocystis hominis in an argentinian rural community. korean j parasitol 2004; 42:121127. 24. velasquez v, caldera r, wong w, et al. blastocystosis: a high prevalence of cases found in patients form health center of soledad, anzoateni state, venezuela. rev soc bras med trop 2005; 38:356-357. 35. zuckerman mj, ho h, hooper l, anderson b, polly sm. frequency of recovery of blastocystis hominis in clinical practice. j gastroenterol 1990; 12:525-532. 36. vannatta jb, adamson bd mullican k. blastocystis hominis infection presenting as recurrent diarrhoea. ann inter med 1985; 102:495-496. 37. zaki m, daoud as, pugh rnh, al-ali f, al-mutairi g, al-saleh q. clinical report of blastocystis hominis infection in children. j trop med hyg 1991; 94:118-122. 38. logar j, andlovic a, poljsak-prijatelj m. incidence of blastocystis hominis in patients with diarrhoea. j infect 1994; 28:151-154. 39. tasova y, sahin b, koltes s, paydas s. clinical significance and frequency of blastocystis hominis in turkish patients with haematological malignancy. acta med okayama 2000; 54:133-136. 40. shilm dr, hoge cw, rajah r, rabold jg, echeverria p. is blastocystis hominis a cause of diarrhoea in travellers? a prospective control study in nepal. clin infect dis 1995; 21:97-101. 41. svenungsson b, lagergren a, ekwall e. enteropathogens in adult patients with diarrhoea and healthy control subjects: a 1-year prospective study in a swedish clinic for infectious diseases. clin infec dis 2000; 30:770-778. 42. stenzel dj, boreham pfl. bacteria-like endosymbionts in blastocystis spp. int j parasitol 1994; 24:147-149. 43. rao k, sekar u, iraivan, kt, abraham g, soundararajan p. blastocystis hominis: an emerging cause of diarrhoea in renal transplant recipients. j assoc physician india 2003; 51:719-721 44. nasirudeen ama, hian ye, singh m, tan ksw. metronidazole induces programmed cell death in the protozoan parasite blastocystis hominis. microbiol 2004;150: 33-43. 45. horiki n, kandera y, maruyama m, fujita y, tachibana h. intestinal blockage by carcinoma and blastocystis hominis infection. am j trop med hyg 1999; 60:400402. 46. moghaddam dd, ghadirian e, azami m. blastocystis hominis and the evaluation of efficacy of metronidazole and trimethopri/ sulfamethoxazole. parasitol res 2005; 96: 273-275. 1 submitted 10 sep 22 1 revision req. 26 oct 22; revision recd. 20 nov 22 2 accepted 22 dec 22 3 online-first: january 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.003 5 6 women’s views on factors that influence utilisation of postnatal follow-7 up in oman 8 a descriptive, qualitative study 9 *amal al hadi,1 jennifer dawson,2 michelle paliwoda,1 karen walker,3 10 karen new1 11 12 1school of nursing, midwifery and social work, university of queensland, brisbane, 13 queensland, australia; 2newborn research centre, the royal women’s hospital, victoria, 14 melbourne, australia; 3faculty of medicine and health, the university of sydney, sydney, 15 new south wales, australia 16 *corresponding author’s e-mail: a.alhadi@uq.net.au 17 18 abstract 19 objective: postnatal follow-up care (pnfc) is important to promote maternal and newborn 20 health and wellbeing. in oman, women’s utilisation of postnatal follow-up services has 21 declined with rates as low as 0.29 (mean visits) in some governorates; well below the 22 recommended postnatal follow up visits at twoand six-weeks for assessment of mother and 23 newborn. the reasons for low utilisation are not well understood. the aim of this study is to 24 explore women’s views and identify factors that influence their utilisation of postnatal 25 follow-up services. methods: purposive sampling and semi-structured telephone interviews 26 with 15 women aged 20 to 39 years at six to eight weeks post childbirth between may 2021 27 to august 2022. data were analysed using erlingsson and brysiewicz content analysis 28 approach. results: six categories were identified as influencing pnfc utilisation: 1) need for 29 information; 2) experiences and expectations; 3) family support, expectations and customs; 4) 30 sociocultural beliefs and practice; 5) impact of covid-19 and 6) the healthcare environment. 31 influencing factors within each category include the need to: empower women, provide 32 individualised care, address family and community expectations, offer alternatives to face-to-33 mailto:a.alhadi@uq.net.au 2 face clinic visits, provide organised, scheduled appointments. conclusion: women in oman 34 identified the need for consistent information from health care providers (hcps), a more 35 organised postnatal follow-up service including scheduled appointments and a woman-36 centred approach to pnfc. 37 keywords: postnatal care; postpartum period; qualitative research. 38 39 advances in knowledge 40  to our knowledge, this is the first study to explore the views of women in oman on 41 factors influencing their utilisation of pnfc. 42  obtaining the perspectives of the end-user of a service is an important step in 43 considering interventions to improve healthcare service utilisation. 44 45 application to patient care 46  the findings of this study will be used to inform the development of a survey that will 47 be sent to a large sample of postnatal women in oman to confirm factors that 48 influence pnfc utilisation. 49  the findings of this study intend to allow further clarification of influences that occur 50 at the individual, family, community, and institutional levels. 51 52 introduction 53 postnatal care is the latter part of the continuum of maternity care and is provided to women 54 and their newborns immediately following, and generally up to 42 days, after birth.1 the 42-55 day period (six weeks) post childbirth is based on universal agreement.1 however, in a 56 number of countries, this period extends to eight weeks post childbirth.2 the postnatal period 57 is classified into three stages: immediate (0–24 hours), early (2–7 days), and late (8–42 58 days).1 the immediate stage is usually spent at the birthing hospital, although with early 59 discharge becoming more common, the immediate care stage may last over only six hours.3 60 early and late postnatal follow-up occurs in the community4 or at the hospital outpatient 61 level. care during the postnatal period is equally important as that provided during the 62 antenatal period, as complications can result in adverse outcomes such as morbidities and 63 mortality for the mother, the newborn or both.1 in addition to physical complications, mental 64 health complications such as postnatal depression can occur in the mother5. these 65 3 complications can have a destructive impact on the whole family if not diagnosed and 66 managed early on and effectively.5 67 68 newborn mortality is highest within the first week of life, caused by perinatal asphyxia, 69 prematurity and congenital malformations mostly.6 while approximately half of all infection-70 related deaths occur in the first week of life, a quarter of them occur between weeks 2 and 4.6 71 therefore, the world health organization (who) emphasises that postnatal follow-up 72 contacts with health professionals play an important role in reducing deaths of newborns, 73 through early detection, referral and management of complications.7 74 75 the number and time of postnatal vary globally. the who8 recommends four postnatal 76 contacts9, while the american college of obstetricians and gynecologists recommend the 77 number and timing of contact be more individualised depending on the need.10 whereas, the 78 sultanate of oman ministry of health guideline recommends postnatal follow-up health 79 centre visits at two and six weeks for both the mother and the newborn.11 80 81 in oman, the number of postnatal follow-up visits has decreased from 1.3 in 2000 to 0.73 in 82 2019.12 in comparison, attendance is high for antenatal visits, with 74% of women attending 83 four or more appointments.12 there are clear differences between antenatal and postnatal 84 care. for example, women are given antenatal appointments to attend the clinic on a specific 85 date and time, with appointment reminders sent via the short message service (sms). in 86 contrast, for pnfc, no formal appointment is arranged, with only hcps informing women 87 that they should visit the health centre when they reach the 14and 42-day mark post birth. 88 low utilisation of postnatal follow-up means there are lost opportunities for health promotion 89 and health monitoring of mothers and their newborns, which may be reflected in the poor 90 exclusive breastfeeding rate at 6 months of only 8.9%12. 91 92 a literature review was undertaken with factors identified that impeded utilisation of 93 postnatal follow-up, including women’s lack of knowledge of postnatal services, beliefs that 94 there is no need for postnatal follow-up and the impact of long queues (waiting time) at 95 health centres.13 of the 17 studies eligible for inclusion in the review, one was conducted in 96 the middle east (jordan), which has cultural similarities to oman but a different healthcare 97 system and delivery of postnatal care. this study reported concerns regarding the unmet 98 learning needs of women in terms of postnatal care, including danger signs post caesarean 99 4 section, breastfeeding and newborn care at the two postnatal contacts, that is, at day 1 and 6–100 8 weeks following birth.14 however, it did not explore the factors contributing to the low 101 utilisation of postnatal service. as no published studies have explored women’s experiences 102 and utilisation of pnfc in oman, this study was undertaken as the first step toward 103 ascertaining why pnfc is poorly utilised in oman. the objective of the study was to explore 104 the factors that influence utilisation of pnfc in oman from the perspective of postnatal 105 women. 106 107 methods 108 design 109 this descriptive qualitative study is a part of a larger exploratory mixed methods project 110 designed to gain more insight into pnfc from women, hospitals and health centre hcps 111 through qualitative interviews. the results from the hcps will be reported elsewhere. the 112 results of study one will inform the development of quantitative measures (survey) of the 113 mixed method study. this will enable an investigation of the pnfc with a larger sample size, 114 thereby facilitating policy change to improve the quality of care.15 purposive sampling was 115 used and semi-structured telephone interviews were conducted in arabic between may and 116 august 2021 by the primary investigator, an omani registered nurse-midwife experienced in 117 conducting interviews. the interview guide (table 3) developed by the researchers was 118 guided by the findings from the literature review.13 ethical approval was granted by the 119 research and ethical review and approval committee, oman ministry of health 120 [moh/csr/20/23647], and the university of queensland 121 [2020002085/moh/csr/20/23647]. 122 123 setting and participants 124 postnatal women were recruited at khoula and ibra hospitals. the sites were selected 125 because of their differences in terms of population density and social, educational and 126 healthcare services.12 women who gave birth at the study site and were fluent in arabic or 127 english were eligible to participate, regardless of nationality. women with any pregnancy 128 complications or history of newborn admission to a neonatal nursery were ineligible. women 129 were recruited by the primary investigator in collaboration with the clinical hospital hcps to 130 identify eligible women. informed consent was obtained from the women following a 131 detailed explanation of the study and participation requirements. the date and time for the 132 telephone interview were scheduled between 6–8 weeks based on mutual agreement. 133 5 data collection 134 interviews were conducted between 6–8 weeks postnatally via telephone due to the covid-19 135 pandemic. further, this allowed women to be interviewed in their home environment. 136 interviewing participants in their own environment in which they are comfortable and 137 familiar can result in more openly expressed opinions.16 the interviews were digitally 138 recorded and lasted on average for 25 min. data collection ended with concept saturation.17 139 140 data analysis 141 interviews were de-identified and transcribed verbatim in arabic and then translated into 142 english by an external experienced bilingual translator. this enabled the native english-143 speaking research team to review the transcripts, thus increasing reliability and minimising 144 inaccuracies when translating between the source language to the target language.18 the 145 primary investigator compared the english transcripts with the arabic transcripts, checking 146 for accuracy, including transliteration where necessary in cases where english counterparts 147 for certain arabic terms and names did not exist. conventional content analysis was 148 performed manually and was guided by the process described by erlingsson and 149 brysiewicz19: familiarisation with the data; dividing the text into meaning units; condensing 150 meaning units; formulating codes; developing categories. conventional content analysis was 151 performed, as no study has been conducted in oman about pnfc. this approach enabled the 152 flow of categories without the restriction of preconceived ideas/categories.20 all condensed 153 meaning units, codes, sub-categories and categories were manually added to microsoft excel 154 version 16.54 to enhance data management. 155 156 the development of meaning units, codes and categories was undertaken by the primary 157 investigator and agreed upon by two co-authors. the categories reflected factors that 158 influenced women’s views, decisions or experiences of utilisation of pnfc. 159 160 results 161 no new information was identified from the 14th interview, and this was empirically 162 confirmed following the completion of the 15th interview. the demographic data of the 163 participants is presented in table 1. 164 165 during the content analysis, initially 246 meaning units were extracted. after reviewing, the 166 units were condensed into 166 units. then the meaning units were coded into 46 codes. the 167 6 codes were further clustered into 18 sub-categories. finally, six clear categories emerged 168 from the data: 1) need for information; 2) experiences and expectations; 3) family support, 169 expectations and customs; 4) sociocultural beliefs and practice; 5) impact of covid-19; 6) the 170 healthcare environment. 171 172 need for information 173 the utilisation of early pnfc at health centres appears to be dependent on hcps providing 174 information to women about the need for pnfc for both themselves and their newborns. the 175 participants reported that appointments were not given or explained well to them: “no one 176 told me about appointments about me, they just gave me an appointment for my child 177 vaccination after two months and it is written in my baby card” (p7) (table 2, quote 1), or 178 that they were told they would be seen by a doctor but not specifically informed why (table 179 2, quote 2). the women felt strongly that they should be informed and empowered by being 180 given information with an explanation of why they should attend (table 2, quote 3). 181 182 the participants reported not visiting for pnfc because they were told by the hcps at the 183 hospitals and health centres that they only needed to attend if they experienced complications 184 (table 2, quote 4). thus, women who did not have any complications did not visit any health 185 centres. 186 187 many women expressed a desire for more information around newborn care (e.g. bathing, 188 feeding, cord care), signs of danger to themselves or their newborns, managing complications 189 for themselves women and their newborns and, in particular, their own mental health (table 190 2, quote 5). additionally, women who had a caesarian section birth or had perineal wounds 191 expressed the need for more information on wound care (table 2, quote 6), and this was 192 highlighted by a postnatal woman who was also a nurse. she stated that she knew how to take 193 care of her wound because of her experience, not because she was given any information by 194 the hcps (table 2, quote 7). women who delivered by caesearean felt they needed an 195 appointment 1 week postnatally for reassurance about their health and well-being (table 2, 196 quote 8). 197 198 the need for increased and more comprehensive breastfeeding information and support was 199 raised by most women, as many reported breastfeeding challenges that they had to try and 200 solve by themselves: “i faced a huge problem with breastfeeding i did not know how to 201 7 breastfeed, maybe the technique was wrong, or i did not have enough milk” (p3) (table 2, 202 quotes 9). otherwise, they opted to artificially feed, as it was easier (table 2, quotes 10 and 203 11). additionally, women reported that the information given to them was not helpful or did 204 not solve their problems (table 2, quotes 12 and 13). 205 206 experiences and expectations 207 previous experience with pnfc influenced the participants’ decisions to attend or not with 208 their newborn. many women reported that the care was not woman-focused or beneficial, nor 209 did it meet their individual needs: “i feel every time i go to the doctor, i only get a verbal 210 advice, which does not benefit me much, it is not practical, they give us their opinion, but the 211 reality is different” (p6) (table 2, quote 14). they also reported that pnfc was focused on 212 the newborn, with little attention to the mothers’ health (table 2, quotes 15 and 16). 213 214 the participants strongly felt that it was very important to have pnfc appointments, as 215 attending with a newborn in a crowded clinic and waiting for long periods without dedicated 216 breastfeeding areas was not ideal (table 2, quotes 17, 18 and 19). not having scheduled 217 appointments led the women to perceive that pnfc is optional and not important. if 218 appointments had been scheduled, they would have attended (table 2, quotes 20 and 21). 219 the women further stressed that the covid-19 pandemic highlighted the need and 220 importance of scheduled appointments: “set scheduled appointments with specific date in an 221 organised manner, so women do not have to wait for long time with their babies especially 222 now corona is here” (p10). also important to women was the need for alternative follow-up 223 options, which they suggested should be more accessible and practical, such as text 224 messaging, telephone calls and home visits. 225 226 family support, expectations and customs 227 some of the participants followed strict customs pertaining to the postnatal period, such as 228 staying in their family home for a few days: “they can ask about the woman by calling and 229 this is very useful way to ensure about her health and the health of the child, and they see 230 what she needs” (p9). another custom is to receive support from their family, which is 231 viewed as an expectation and responsibility of the family (table 2, quotes 22 and 23). 232 however, several others received little support (table 2, quotes 24 and 25). the level of 233 support had an influence on attendance at pnfc, as when the mothers had no one to take 234 them to the health centre or to take care of their other children at home, then they did not visit 235 8 (table 2, quote 26). the influence of family and customs affecting women’s decisions and 236 choices were also revealed: “i gave all my children artificial milk immediately after hospital 237 discharge because of my in-laws’ influence. they told me that i have to give my baby 238 artificial milk or he will lose weight” (p4). 239 240 sociocultural beliefs and practice 241 various social and cultural practices are expected of women during the postnatal period, such 242 as ‘seclusion’, which appear to influence attendance at pnfc. the participants reported that 243 they are expected to stay indoors for 40 days, as seclusion is important to prevent maternal 244 and newborn sickness, to ensure normal growth for the newborn and to avoid embarrassment 245 among family and community members: “i did not leave the house in the 40 days because it 246 is a scandal and people will talk about me…this is our custom, even if we had a normal 247 vaginal birth, we do not go out, we must sit at home except for necessity” (p14) (table 2, 248 quote 27). 249 250 several traditional practices related to food and medicine used after birth also appear to 251 influence women’s decision to visit a health centre. the participants indicated that they 252 believed traditional foods were effective in overcoming postnatal complications, such as 253 insufficient milk production and bleeding and to ‘cleanse the uterus’: “my family cooked for 254 me special food such as fresh meat, omani chicken, fenugreek, and bread made of wheat 255 flour, which very helpful in increasing the milk production, prevent gases formation and 256 make my bones stronger as it was weakened due to pregnancy and delivery” (p15) (table 2, 257 quote 28). similarly, women used and trusted traditional medicines to treat postnatal 258 complications such as wound pain, infection and the newborn’s abdominal cramps (table 2, 259 quotes 29 and 30). 260 261 impact of covid-19 262 the participants stated that they did not utilise pnfc because they were worried about both 263 themselves and their newborn being infected with covid-19 when visiting health centres: “i 264 was afraid to go out during after birth because of corona” (p6) (table 2, quote 31). 265 moreover, these women’s decision to visit health centres was impacted by being discouraged 266 or turned away by hcps due to covid-19 (table 2, quote 32). 267 268 9 healthcare environment 269 the women in this study were reluctant to attend pnfc, as they felt that the physical 270 environment for postnatal care in health centres was not comfortable or suitable for them or 271 for their newborn: “the environment in the health centre is not comfortable it is very cold 272 and the chairs are hard so it causes pain especially with perineal wound…there is no special 273 area for mothers to breastfeed their babies” (p5). with no appointment system, women are 274 expected to sit and wait for their turn. depending on the number of women, some may not be 275 seen and have to return another day. thus, a number of women stated that they chose to be 276 seen in private health facilities (table 2, quote 33). furthermore, women cited the low 277 quality of pnfc provided as a reason for not visiting (table 2, quotes 34 and 35). 278 279 discussion 280 this qualitative study highlights factors influencing postnatal women’s utilisation of pnfc in 281 oman. these occur at four levels: individual, family, community and institutional levels. 282 gaining the perspectives of postnatal women is essential since they are consumers of 283 healthcare services, and they should feel cared for, safe and confident in receiving quality 284 care.21 many countries have developed standards for safe and quality health care in which 285 the importance of involving consumers in their own care and providing clear communication 286 is advocated22 across the continuum of ‘planning, design, delivery, measurement and 287 evaluation of care’.21 involvement of the consumer at the primary care level has the potential 288 to prevent illness before it begins. thus, engaging postnatal women to improve utilisation of 289 pnfc service has the potential to shape and influence policy change for better outcomes.23 290 291 need for information 292 our findings reveal that postnatal women need more information regarding postnatal care. 293 increasing health literacy, including knowledge and awareness, and thereby empowering 294 women in their own healthcare is not unique to oman, having been reported in studies from 295 many countries.14, 24,25 two studies found that postnatal women in indonesia and ethiopia 296 were not provided with adequate information and thus had poor knowledge and awareness of 297 the importance of postnatal care.24,25 engaging and empowering consumers in health care and 298 health promotion appears to remain a challenge despite discussion and policy development 299 over the last few decades. interestingly, the need for more information was not only reported 300 by first-time mothers but also multiparous women, who highlighted their need for more 301 educational support, especially regarding breastfeeding. the women in our study reported 302 10 using artificial formula very early in the postnatal period as a way of overcoming 303 breastfeeding challenges such as attachment or low milk supply, and few women maintained 304 exclusive breastfeeding to 6 months postnatally. data from oman shows that only around a 305 third (31.3%) of women breastfed exclusively at 6 months in 2005, and by 2019, the rate of 306 exclusive breastfeeding declined to just 8.9%.12 in contrast, over the same time period, the 307 use of artificial formula and other foods rather than breastmilk has increased considerably at 308 6 months, from 60.7% in 2005 to 90.7 % in 2019.12 this is a concern, as breastmilk is 309 important for the health and wellbeing of newborns, as it protects from malnutrition, common 310 childhood infections, allergies, metabolic disorders and obesity.1, 26 thus, at the institutional 311 level, it is clear that there is potential for improvement of pnfc by addressing health literacy 312 through policies that support individualised care and making information resources accessible 313 to consumers. 314 315 experiences and expectations 316 the women in this study believed that not having specific appointments for postnatal follow-317 up meant that pnfc was not important. in 2019, the rate of utilisation of postnatal care in 318 oman was shown to be as low as 0.73 postnatal visits per woman.12 this is in contrast to 319 antenatal appointments which are scheduled and, therefore, considered important, with 73.9% 320 of women attending four or more visits in 2019.12 the american college of obstetricians and 321 gynecologists10 recommends scheduling postnatal visits during the prenatal period or prior to 322 hospital discharge as an imperative strategy to promote and ensure women’s utilisation of 323 postnatal follow-up. 324 325 in this study, women expressed that they would like options for postnatal follow-up, 326 including home visits and telephone calls, indicating that a more individualised postnatal 327 follow-up approach was of importance. de sousa et al.27 reported that, to ensure the best 328 health outcomes, there is a need to promote attentive listening to women’s concerns, 329 encourage continuity of care and increase home-based services. furthermore, a cochrane 330 systematic review found that early discharge accompanied by a home visit resulted in reduced 331 newborn readmissions in the weeks following birth, encouraged women to continue exclusive 332 breastfeeding and increased maternal satisfaction with postnatal care. 28 the importance and 333 need for individualised care have been reported by several international organisations and 334 agencies.9, 29 our study has demonstrated that alternative modes of postnatal follow-up are 335 11 wanted by women; thus, future studies should explore alternative options at community and 336 institutional levels. 337 338 family support, expectations and customs 339 in oman, the influence of the family, their expectations, customs and level of support to 340 women in the postnatal period plays a key role in utilisation of health services. this is 341 consistent with a study reporting the influence of families on women’s knowledge, attitudes 342 and practices during the postnatal period.24 therefore, it is important that this is considered at 343 the individual level when designing interventions to improve utilisation of services. 344 educational interventions need to be targeted towards the family and community and not just 345 the women concerned.24 this is particularly important in our study setting, where there is an 346 expectation that the family provides information and physical support and influences 347 decision-making. the impact of family-related factors has been reported to negatively 348 influence postnatal women’s compliance to health advice provided by hcps.24 however, 349 having family support can also impact utilisation positively. for example, family members 350 can assist women to attend postnatal follow-up appointments by caring for other children to 351 allow women time to visit the health centre for appointments. without this type of support, it 352 is often too difficult for women to focus on their health. the women in our study indicated 353 that lack of family assistance with their other children prevented them from utilising postnatal 354 follow-up, which is consistent with the findings from studies conducted in ethiopia.25, 30 355 356 sociocultural beliefs and practice 357 in oman, similar to many arab countries, the postnatal period is culturally perceived as a 358 unique time during which mothers are expected to practice seclusion, eat a special diet and 359 receive congratulatory visits and gifts from family members and friends.31 the practice of 360 seclusion for 40 days is common in middle eastern countries, where the women and their 361 newborns are viewed as being weak and at increased risk of morbidities, mortality and the 362 ‘evil eye’.31 although seclusion did not appear to directly impede the study participants’ 363 utilisation of postnatal follow-up, they still reported that they favoured staying indoors for 40 364 days, with many mentioning that they would only attend the health centre at 40 days for 365 information about birth spacing. thus, offering alternative methods of follow-up could be 366 useful to provide support on breastfeeding and mental health well-being in the early postnatal 367 period. in our study, the women trusted the cultural practices of traditional food and medicine 368 consumption to overcome postnatal complications and were more likely to try these than go 369 12 to a health centre, as reported in previous studies.25, 32 therefore, it is crucial for 370 policymakers, community leaders and hcps to work collaboratively toward increasing 371 community awareness regarding the importance of postnatal follow-up. 372 373 impact of covid-19 374 not surprisingly, concerns were raised regarding the inability to utilise postnatal follow-up 375 due to the covid-19 pandemic. this occurred at the individual level, with many women 376 indicating that they were reluctant to leave the house and go to a health centre where they 377 would be required to sit and wait for an extended period of time because appointments were 378 not scheduled. at the institutional level, women spoke about being discouraged from visiting 379 clinics in person. non-face-to-face methods for providing postnatal follow-up were not 380 initiated by institutions in response to the pandemic. an unintended result of not attending 381 postnatal clinics has been the isolation of new mothers, impacting further their ability to 382 obtain information and support. women raised concerns regarding their mental, physical and 383 emotional well-being, including the risk of postnatal depression. this is concerning, as the 384 findings from a cross-sectional survey indicated that the risk of postpartum depression at one 385 month was higher in women with low support compared to those with higher support.33 386 recommendations have been made regarding the importance of continued care for postnatal 387 women and newborns during the pandemic and the use of different accessible modalities to 388 provide breastfeeding, mental health and parenting support.34 unlike in other countries, 389 institutions in oman have not reviewed or adapted services or policies in response to the 390 pandemic, as women were not offered alternative postnatal follow-up approaches. 391 392 the healthcare environment 393 several environmental factors that played a key role in impeding women’s utilisation of 394 postnatal follow-up have been highlighted in this study. these factors included crowded 395 health centres and long waiting times. the impact of the environment and long waiting 396 queues at health facilities on postnatal follow-up utilisation has previously been reported in 397 the literature.35 thus, for oman, a solution to address these factors may be as simple as 398 scheduling appointments, as it can help to reduce both overcrowding and long waiting times. 399 providing women with alternatives to face-to-face visits, such as phone calls and home visits, 400 might also be successful in improving utilisation. 401 402 strengths and limitations of the study 403 13 to our knowledge, this is the first study exploring the utilisation of pnfc in oman from the 404 perspective of postnatal women. this is important to inform quality care improvements, make 405 pnfc women-centred and amend the national guideline to increase the uptake of pnfc. a 406 limitation of this study is that it was conducted during the covid-19 pandemic, which may 407 have influenced the women’s decision to attend the pnfc visit, although it did not inhibit 408 policymakers from providing alternative ways of contact, such as via telephone calls, text 409 messages and videoconferencing via platforms such as zoom. 410 411 conclusion 412 the women in this study identified key factors that both facilitated and impeded utilisation of 413 pnfc. these are important in the development and implementation of effective strategies to 414 increase utilisation of pnfc, which can provide opportunities for health promotion, support 415 and optimal care of women and newborns. policymakers, community leaders and hcps must 416 work collaboratively to promote the utilisation of pnfc by scheduling appointments, 417 increasing awareness among women, families and the community on the importance of 418 pnfc and providing alternative modes of contact. 419 420 acknowledgements 421 our sincere thanks and appreciation to women for their participation in this study. we also 422 extend our gratitude to the directorates general of khoula hospital and the directorate 423 general of health services at north ash sharqiyah governorate for facilitating the 424 recruitment process. 425 426 authors’ contribution 427 aah contributed to the conceptualization, methodology, formal analysis, project 428 administration, visualisation and writing (original draft). jd contributed to the 429 conceptualization, methodology, visualisation, supervision and writing (review and editing). 430 mp contributed to the conceptualization, methodology, formal analysis, visualisation, 431 supervision and writing (review and editing). kw contributed to the conceptualization, 432 methodology, visualisation, supervision and writing (review and editing). kn contributed to 433 the conceptualization, methodology, formal analysis, visualisation, supervision and writing 434 (review and editing). 435 436 conflicts of interest 437 14 the authors declare no conflict of interests. 438 439 funding 440 funding for aah via a scholarship was provided by the omani 441 government through the omani ministry of higher education, research and innovation 442 (grant number: d.p.s/699/201). 443 444 references 445 1. world health organization. who technical consultation on postpartum and 446 postnatal care. geneva, switzerland: world health organization. who/mps/10.03. 447 pp. 12. 448 2. national institute for health and care excellence. postnatal care up to 8 weeks after 449 birth. london: national institute for health and care excellence. from: 450 https://www.nice.org.uk/guidance/ng194/resources/postnatal-care-pdf-451 66142082148037 accessed: august 2022. 452 3. campbell om, cegolon l, macleod d, benova l. length of stay after childbirth in 453 92 countries and associated factors in 30 low-and middle-income countries: 454 compilation of reported data and a cross-sectional analysis from nationally 455 representative surveys. plos med 2016; 13:e1001972-e1001972. doi: 456 https://doi.org/10.1371/journal.pmed.1001972. 457 4. royal australian college of general practitioners. guidelines for preventive 458 activities in general practice.victoria: royal australian college of general 459 practitioners; 2018. pp. 127-138. 460 5. rai s, pathak a, sharma i. postpartum psychiatric disorders: early diagnosis and 461 management. indian j psychiatry 2015; 57:s216-221. doi: 10.4103/0019-462 5545.161481. 463 6. sankar m, natarajan c, das r, agarwal r, chandrasekaran a, paul v. when do 464 newborns die? a systematic review of timing of overall and cause-specific neonatal 465 deaths in developing countries. j perinatol 2016; 36:s1-s11. doi: 10.1038/jp.2016.27. 466 7. warren c, daly p, toure l, mongi p. postnatal care. in lawn j, kerber k, editors. 467 opportunities for africa’s newborns: practical data, policy and programmatic 468 support for newborn care in africa. geneva, switzerland: world health 469 organization on behalf of the partnership for maternal, newborn and child health; 470 2006. pp. 79-90. 471 https://www.nice.org.uk/guidance/ng194/resources/postnatal-care-pdf-66142082148037 https://www.nice.org.uk/guidance/ng194/resources/postnatal-care-pdf-66142082148037 https://doi.org/10.1371/journal.pmed.1001972 15 8. world health organization, united nations population fund, world bank group and 472 the united nations population division. trends in maternal mortality 2000 to 2017. 473 geneva, switzerland: world health organization; 2019. pp. 59. 474 9. world health organization. who recommendations on postnatal care of the mother 475 and newborn. geneva, switzerland: world health organization; 2013. pp. 3. 476 10. mckinney j, keyser l, clinton s, pagliano c. acog committee opinion no. 736: 477 optimizing postpartum care. obstet gynecol 2018; 132:784-785. doi: 478 10.1097/aog.0000000000002849. 479 11. sultanate of oman ministry of health. pregnancy and childbirth management 480 guidelines. muscat: sultanate of oman ministry of health; 2016. pp. 105-108. 481 12. sultanate of oman ministry of health. annual health report 2019: health status 482 indicators. muscat: sultanate of oman ministry of health; 2019. pp. 1-5. 483 13. al hadi a, paliwoda m, dawson j, walker k, new k. women’s utilisation, 484 experiences and satisfaction with postnatal follow-up care: a systematic literature 485 review. sultan qaboos univ med j 2022; 22:455-471. doi: 486 10.18295/squmj.10.2022.059 . 487 14. almalik mm. understanding maternal postpartum needs: a descriptive survey of 488 current maternal health services. j clin nurs 2017; 26:4654–63. 489 https://doi.org/10.1111/jocn.13812. 490 15. holloway i, galvin k. qualitative research in nursing and healthcare. john wiley & 491 sons 2016:273-283. 492 16. bolderston a. conducting a research interview. j med imaging radiat sci 2012; 493 43:66-76. doi: 10.1016/j.imir.2011.12.002. 494 17. cresweel, j. w., & v. l. (2018). designing and conducting mixed methods research. 495 3rd ed. california: sage publications, 2018. 496 18. al-amer r, ramjan l, glew p, darwish m, salamonson y. language translation 497 challenges with arabic speakers participating in qualitative research studies. int j 498 nurs stud 2016; 54:150-157. doi: 10.1016/j.ijnurstu.2015.04.010. 499 19. erlingsson c, brysiewicz p. a hands-on guide to doing content analysis. afr j emerg 500 med 2017; 7:93-99. doi: 10.1016/j.afjem.2017.08.001. 501 20. hsieh hf, shannon se. three approaches to qualitative content analysis. 502 qualitative health research. 2005;15(9):1277–88 503 https://journals.squ.edu.om/index.php/squmj/article/view/5347 https://doi.org/10.1111/jocn.13812 16 21. australian commission on saftey and quality in health care. national safety and 504 quality health service (nsqhs) standards. sydney: australian commission on 505 saftey and quality in health care; 2021. pp. 36-54. 506 22. nilsen e, myrhaug h, johansen m, oliver s, oxman a. methods of consumer 507 involvement in developing healthcare policy and research, clinical practice guidelines 508 and patient information material. cochrane database syst rev 2006; 509 2006:cd004563. doi: 10.1002/14651858. 510 23. bustreo f. she decides on her health, her future. geneva, switzerland: world health 511 organization; 2017. 512 24. probandari a, arcita a, kothijah k, pamungkasari e. barriers to utilization of 513 postnatal care at village level in klaten district, central java province, indonesia. 514 bmc health serv res 2017; 17:541. doi: 10.1186/s12913-017-2490-y. 515 25. tesfahun f, worku w, mazengiya f, kifle m. knowledge, perception and utilization 516 of postnatal care of mothers in gondar zuria district, ethiopia: a cross-sectional 517 study. matern child health j 2014; 18:2341-51. doi: 10.1007/s10995-014-1474-3. 518 26. eidelman a. breastfeeding and the use of human milk: an analysis of the american 519 academy of pediatrics 2012: breastfeeding policy statement. breastfeed med 2012; 520 7:323-324. doi: 10.1089/bfm.2012.0067. 521 27. de sousa machado t, chur-hansen a, due c. first-time mothers’ perceptions of 522 social support: recommendations for best practice. health psychol open 2020; 523 7:2055102919898611. doi: 10.1177/2055102919898611. 524 28. yonemoto n, dowswell t, nagai s, mori r. schedules for home visits in the early 525 postpartum period. cochrane database syst rev 2017; 8:cd009326. doi: 526 10.1002/14651858.cd009326.pub3. 527 29. public health agency of canada. family‐centred maternity and newborn care: 528 national guidelines. ottawa: public health agency of canada; 2021. pp. 46-53. 529 30. gebrehiwot g, medhanyie aa, gidey g, abrha k. postnatal care utilization among 530 urban women in northern ethiopia: crosssectional survey. bmc womens health 531 2018; 18:78. doi: 10.1186/s12905-018-0557-5. 532 31. hundt gl, beckerleg s, kassem f, jafar ama, belmaker i, abu saad k, et al. 533 women's health custom made: building on the 40 days postpartum for arab women. 534 health care women int 2000; 21:529-42. doi: 10.1080/07399330050130313. 535 32. belihu tm, deressa at. postnatal care within one week and associated factors among 536 women who gave birth in ameya district, oromia regional state, ethiopia, 2018: 537 17 cross sectional study. ethiop j health sci 2020; 30:329-336. doi: 538 10.4314/ejhs.v30i3.3. 539 33. terada s, kinjo k, fukuda y. the relationship between postpartum depression and 540 social support during the covid‐19 pandemic: a cross‐sectional study. j obstet 541 gynaecol res 2021; 47:3524-3531. doi: 10.1111/jog.14929. 542 34. ross-davie m, lambert j, brigante l, et al. guidance for antenatal and postnatal 543 services in the evolving coronavirus (covid-19) pandemic. london: the royal 544 college of obstetricians and gynaecologists; 2020. pp. 8-9. 545 35. woodward bm, zadoroznyj m, benoit c. beyond birth: women's concerns about 546 post-birth care in an australian urban community. women birth 2016; 29:153-9. doi: 547 10.1016/j.wombi.2015.09.006. 548 549 table 1: participants’ demographic data 550 participa nt and hospital age group (years ) educational level birth s (num ber) living arrangements p1-kh 25-29 advanced* 2 living with extended family** p2-kh 30–34 advanced* 1 living with extended family** p3-kh 30-34 advanced* 1 living with husband and children p4-kh 35 -39 secondary*** 4 living with husband and children p5-kh 30-34 secondary*** 3 living with husband and children p6-kh 35-39 advanced* 2 living with husband and children p7-ih 25-29 secondary*** 5 living with husband and children p8-ih 25-29 advanced* 2 living with husband and children p9-ih 20-24 advanced* 1 living with husband, child/children, and one set of parents p10-kh 25-29 advanced* 1 living with husband and children p11-kh 25-29 advanced* 3 living with husband and children p12-kh 20-24 primary**** 5 living with extended family** p13-ih 30-34 preparatory*** ** 3 living with husband and children p14-ih 25-29 advanced* 2 living with extended family** p15-ih 25-29 secondary*** 5 living with husband, child/children, and one set of parents *advanced: completed diploma bachelor, master’s, or phd. **extended family includes 551 others in addition to parents, such as grandparents, brothers, sisters, uncles, aunts and 552 cousins. ***secondary: completed grade 12; ****primary: grade 1–6. *****preparatory: 553 grade 7–9. 554 555 18 table 2: quotes from participants 556 categories verbatim quotation from participants need for information 1. “appointments need to be clearly explained to us, whether they are for mother only or we have to bring our baby with us.” (p1) 2. “they told me that after two weeks, my baby is having appointment and it is written in the pink card, and i should go with baby because the doctor will see me as well.” (p6) 3. “before we [are] discharged from the hospital, they must explain to us in detail about the appointments and give us the numbers of the people we can contact if we need information about postpartum care in general, not only about breastfeeding.” (p6) 4. “i was informed from health centre that no need to followup after birth unless you or newborn have complication.” (p1) 5. “i need someone to teach me about mental health, as sometimes i was feeling bad, depressed and tired, especially when the baby was crying despite that i have fed him and changed his diaper.” (p1) 6. “i wish to know more about how to take care of the wound because i still suffer from pain and infection.” (p5) 7. “from my experience as a nurse, i know how to take care of the wound and know if the wound bleeds or smells or the wound opens, i go to the health center, but no one explained this to me after the birth.” (p14) 8. “women should return to health centre after a week, especially if delivered by is operation, because we want to be reassured our health and wellbeing and to have chance to discuss with them about our concerns on this appointment.” (p8) 9. “i learned everything by myself and through searching the internet. (p6) 10. “i started with artificial milk with all my three children because it was the easiest solution to solve breastfeeding problems.” (p4) 11. “my first and second child, i did not breastfeed them naturally because i did not know how to breastfeed them. 19 my family tried with me, but it did not work, and i gave them artificial milk.” (p7) 12. “the nurse gave me a paper and it was written on it how to store the milk, but my milk flow was not enough for the baby.” (p10) 13. “i was trying to breastfeed her but was having difficulty to attach to the nipple and [she] refused to breastfeed as she did not want me, so i contacted the lactation specialist through instagram, she advised me to stop giving my baby’s pacifier. her advice helped me a little, but the problem did not stop.” (p6) experiences and expectations 14. “for all my five births, i never went to the health centre, neither for the two-week nor for the forty-day appointment because they don’t do anything for me, only they measure the baby weight.” (p12) 15. “i feel frankly that there is no care for me, they only ask about the child if he passed urine, there was nothing else, unless the person asks by himself in order to get reassured.” (p7) 16. “the two-week appointment they do not give us much, they only ask us how are you doing, and if you have any problem, i feel they are more interested in the child than the mother, at least they could do a comprehensive examination for the mother like a child.” (p6) 17. “it is very important to have scheduled appointments with date and time.” (p4) 18. “health centres are crowded and we have a newborn with us.” (p5) 19. “especially women who have undergone surgeries or have stitches, they should pay more attention to them because they suffer from more pain and open wounds.” (p13) 20. “if we have scheduled appointment with date and time, we will care more about it.” (p2) 21. “they must be on time, they are not optional … we don't feel that postnatal care is important.” (p8) 22. “i went to my family’s house for forty days and got psychological support from my mother and sisters who raised my spirits to prevent me from getting postpartum depression, they were also helping me with my first child, 20 since i had operational delivery and i could not move much.” (p8) 23. “my aunt (mother-in-law) and my sisters helped me clean the house and cook for us to eat while i stay in my house because my parents passed away.” (p12) 24. “i was in my sisters’ house and i was sleeping alone with my baby and i was holding her all the night no body helped me.” (p3) 25. “my parents passed away and i have my sisters and brothers, but they have other responsibilities.”(p4) 26. “i could not attend as my husband at work and i didn’t have car and i have 3 more children at home.” (p4) sociocultural beliefs and practices 27. “in our customs, women must stay for forty days in the same place, and we are convinced that this custom is beneficial for the mother and the child.” (p11) 28. “my mother and sisters helped me and they cooked me rice and porridge with fenugreek. this food is useful especially the fenugreek as it increases milk production and cleans the uterus from traces of blood.” (p13) 29. “the operation wound was very painful and i got tired from the pain so my mother advised me to apply luqman oil to it to heal fast.” (p13) 30. “my mother helped me to deal with my baby's abdominal cramps and gave the baby traditional medicine and did some massage to remove gasses from the baby's tummy.” (p1) impact of covid-19 31. “i will not go out because of corona; i am worried about my child.” (p2) 32. “they [hcps] told me, don't come, we don't receive the two-week appointment, come only for vaccination date after two months because of corona, even they didn't check the child, so, i had to go to another private hospital recommended from my workplace to check my baby and to be reassured that everything is fine with her.” (p6) health care environment 33. “we follow-up in private because health centres are overcrowded and only see postnatal women in specific timings.” (p1) 21 34. “the quality of postnatal services provided for mothers and babies need to be improved not only checking baby weight and looking at our faces otherwise i will not waste my time to attend.” (p3) 35. “there is no postnatal care, they only give the child an injection and that’s all.” (p13) 557 558 table 3: interview guide 559 1. when you were getting ready to be discharged from hospital, can you tell me what information the nurse/midwife/doctor gave you about visiting a health centre for postnatal care? 2. when you got home from the hospital, can you tell me about the support your family gave you? 3. thinking about when you first arrived home from the hospital, what were the most challenging things? 4. have you had the opportunity to leave the house since your baby was born? 5. since you were discharged from the hospital, have you visited any health centres for you or your baby? a. if attended – how many times did you visit? who did you see when you visited the health centre a nurse/midwife/doctor? can you tell me about your experience of visiting the health centre? in your opinion are their things that could be done better to improve the visit? b. if did not attend – can you tell me a little about why you did not visit? did anyone else give you information about looking after yourself/your baby? what could be done differently to encourage you to visit? from your point of view, can you think of any other reasons why women may/may not attend postnatal follow-up care at a health centre? 6. in your opinion, what would you like to discuss or be told about at postnatal followup visit? 7. do you have any suggestions or changes that would improve the probability of visiting the health centre for postnatal follow-up care? 8. do you have any other comments to make regarding postnatal follow-up care? 560 2department of haematology, 1college of medicine and health sciences, sultan qaboos university, muscat, oman; 3department of medicine, sultan qaboos university hospital, muscat, oman *corresponding author’s e-mail: khabori@squ.edu.om productivity of clinical trials conducted in the gulf cooperative council region abdullah al-hajri,1 *murtadha al-khabori,2 wasif rasool3 clinical & basic research sultan qaboos university med j, november 2022, vol. 22, iss. 4, pp. 501–507, epub. 7 nov 22 submitted 16 jun 21 revision req. 25 jul 21; revision recd. 11 sep 21 accepted 21 sep 21 https://doi.org/10.18295/squmj.11.2021.144 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. abstract: objectives: this study aimed to assess the productivity of clinical trials in the gulf cooperation council (gcc) region, including oman, saudi arabia, united arab emirates, qatar, bahrain and kuwait and to address the existing research gap. specifically, this paper aimed to estimate the number of clinical trials conducted and estimate the proportion of clinical trials conducted in the gcc countries published in peer-reviewed journals. methods: the clinical trials registry of the us national library of medicine was searched for clinical trials conducted from january 2000 to october 2019. the productivity was assessed by the publication status of the trials in the registry and through the search in medline indexed journals. results: a total of 682 trials were found from the gcc region, with an overall trend of 4.1 trials each year. however, the clinical trial productivity from the region contributes to only 0.37% of the trials globally. when comparing the raw data, saudi arabia showed the highest proportion, contributing 66.6% of the clinical trials from the region (p <0.001), while oman contributed 3.5%. after normalisation to population, qatar was found to be the highest contributor, with 42.78 trials per million. a total of 238 trials were conducted before 2016, of which 46.6% were published. conclusion: saudi arabia is the leading country in clinical trial productivity in the gcc region. countries in the gcc should utilise the triple helix model to form partnerships with the industry and improve their contributions to science. keywords: productivity; clinical trial; publications; oman; gulf cooperation council. advances in knowledge a total of 682 clinical trials were conducted in the gulf cooperative council (gcc) countries. clinical trial productivity from the region was only 0.37% of the trials conducted globally. saudi arabia showed the highest proportion, contributing with 66.6% of the clinical trial from the region. application to patient care clinical trials are essential for patient care. this study will help researchers and policymakers ensure proper future planning and conduct of clinical trials in gcc countries, especially oman. clinical trials are extremely crucial in delivering the best healthcare system. their main goal is to assess the impact of interventions and measure the effectiveness and safety to ensure better healthcare.1 this information is needed for proper future planning of research funding. the contribution to clinical trials from gulf cooperation council (gcc) countries has not been well-studied. nonetheless, a small number of studies have been conducted addressing this question. for instance, a study was conducted to estimate the clinical trials in behavioural sciences in the arab gulf states from 2010 to 2018. it found that the gcc country that contributes the most to this area was saudi arabia. moreover, there were only 16 trials conducted during the study period, which is considered low compared to the geographical location that includes over 93 million people.2 most of the other studies have shown that saudi arabia is the major contributor of research output in the arabian gulf region.3–7 when the publication was normalised for population size, kuwait showed the highest research output with qatar coming second.3,6 whereas, oman shows a significant increase in the publication productivity from 1990 to 2005. still, no information is available after this period.3 overall, the research outcome from the gulf region is increasing throughout the years. the publications registered in pubmed (national library of medicine, bethesda, maryland, usa) doubled between 1988–1997 and 1998–2007.8 nevertheless, the gcc still lags behind other regions, even when publications are normalised for population size and despite being in a high-income rank.7 this study aimed to assess the productivity of clinical trials conducted in gcc countries, including oman, saudi arabia, united arab emirates (uae), qatar, bahrain and kuwait. specifically, this research aimed to estimate the number of clinical trials conducted, classify the stages of clinical trials, assess the trend and estimate the proportion of clinical trials conducted in the gcc countries and published in peer-reviewed journals. https://creativecommons.org/licenses/by-nd/4.0/ productivity of clinical trials conducted in the gulf cooperative council region 502 | squ medical journal, november 2022, volume 22, issue 4 continuous variables were described using means, while categorical variables were described using frequencies and percentages. in addition, a bar chart was used to assess the trend of the trials conducted each year, publication per country per year and the publication trend from each country. the average rate of publication was estimated by dividing the total clinical trials over the study period. the independent t-test was used to compare between two independent groups.10 finally, the t-test was used to compare the number of trials from each year. using statistical package for the social sciences (spss), version 24.0 (ibm corp., armonk, new york, usa), the data retrieved from the search was graphically represented and analysed accordingly using the bar chart. then, the same was done to know how many trials were published from each country. the raw data collected cannot be used to compare gcc countries’ productivity, as it will not serve as a fair comparison unless normalised. after all, countries with different population sizes and expenditures are expected to have different research productivity. normalising the productivity rates to the population size or the expenditure allows comparing these rates between countries. therefore, the data was normalised using population size and gross domestic product (gdp) for each country. the average population size was obtained over the study period from the population division of the department of economic and social affairs of the united nations secretariat. in addition, the average gdp over the study period was obtained from the united nations department of economics and social affairs, statistics division.11 results the search strategy retrieved 752 trials, of which 55 were duplicates and 15 were found to have missing data and thus excluded. therefore, a total of 682 trials were included in this analysis. on the other hand, there were 185,285 trials registered and conducted methods this study is a retrospective bibliometric analysis of all clinical trials conducted in the gcc region from january 2000 to october 2019. the data were collected from the us national library of medicine (nlm) clinical trial registry database.9 productivity was assessed using the publication status of these trials in the registry and searching the publication of these trials in medline-indexed journals. the search was focused on studies conducted in the gcc countries using the clinical trials registered in the nlm. to focus on interventional studies (clinical trials), the search needed to be narrowed-down using the advance search feature. moreover, the study results were assigned to include all trials registered either with or without results. the starting date of ‘01/01/2000’ and an undefined completion date was taken to list all the trials registered at the time of searching, which was october 2019. furthermore, clinical trials were retrieved from each country individually using the ‘on map’ feature. to assess the publication from each country, python software foundation, version 3.0, (python™, wilmington, delaware, usa) was used to automate the search for publications in peer-reviewed journals. after obtaining the ‘national clinical trial (nct)’ number for each trial from the nlm, selenium webdriver was used to search the ‘nct’ number in the medline database with the help of pyautogui (python™), an automated graphical user interface that assists image recognition. moreover, the system was programmed to wait until the results appeared, identify them and then return them to be saved. this process gave a more accurate result and minimised missing data due to slow or interrupted connection. all the trials conducted after 2015 were excluded to provide a reasonable time for the trials to be published. furthermore, a study was considered not published whenever there was a trial run before 2015, and this was not published. figure 1: trend of clinical trials conducted in the gulf cooperative council countries between 2000 and 2019. abdullah al-hajri, murtadha al-khabori and wasif rasool clinical and basic research | 503 worldwide during the same study period. therefore, the contribution from gcc countries represented 0.37% of trials conducted worldwide. furthermore, out of the trials conducted before 2016, there were 111 published, representing 46.6% publication productivity. the overall trend of the trials was increasing over the study period by an average of 4.1 trials each year (0.6%), albeit with some fluctuation [figure 1]. saudi arabia showed the highest proportion among all the gcc countries, contributing 66.6% of the clinical trials, which is statistically different from the other gcc countries (p <0.001). in contrast, bahrain contributed 2.5%, which is the lowest in this region. qatar, uae, kuwait and oman contributed 10.3%, 9.7%, 7.3% and 3.5%, respectively [figure 2]. to avert the bias of population size on the publication from each country, the trials from each country were normalised for the population size [table 1]. after normalisation, qatar was found to be the highest contributing country (42.776 trials per million population [pmp]), followed by kuwait (16.969 pmp) and saudi arabia (16.846 pmp). oman scored the lowest among the gcc countries (7.796 pmp). when normalised for gdp, saudi arabia showed the highest productivity at 0.92 trial per 1 billion usd, followed by bahrain (0.73 per 1 billion usd) and qatar (0.64 per 1 billion usd). the uae showed the lowest productivity when normalised for gdp (0.24 per 1 billion usd). oman scored the second before last with 0.49 trials per 1 billion usd [table 1]. most of the gcc countries had higher than average publication productivity (46.6%), except for saudi arabia and bahrain. in saudi arabia, a total of 154 trials were conducted before 2016. however, the published trials represented 43.5% of the total trials conducted. in addition, the total published trials figure 2: clinical trials from each gulf cooperative council country every year (2000–2020). uae = united arab emirates. figure 3: distribution of clinical trials as per the phase when obtained from the clinical trials registry table 1: clinical trials from each country after normalisation for gross domestic product per one billion and population per one million country average gdp per billion publication per gdp per billion average population size per million publication per million population oman 51.21 0.49 3.21 7.796 bahrain 23.39 0.73 1.117 15.221 kuwait 107.06 0.47 2.95 16.969 saudi arabia 491 0.92 26.95 16.846 qatar 109 0.64 1.64 42.776 united arab emirates 270 0.24 6.924 9.532 gdp = gross domestic product. productivity of clinical trials conducted in the gulf cooperative council region 504 | squ medical journal, november 2022, volume 22, issue 4 from bahrain represented 20% of the trials conducted during the study period. in contrast, the publication productivity from qatar, oman, uae and kuwait represented 57.7%, 60%, 51.7% and 52.9%, respectively. clinical trials from the gcc countries also covered a wide range of specialties. oncology was the most frequently covered subject in this region, contributing towards 15.5% of all the trials. in oman, clinical trials in haematology were the highest, contributing towards almost 50% of the trials conducted in the country [table 2]. clinical trials obtained from the nlm were categorised by phase. with respect to the gcc region, most of the research published focused on trials in phases 3 and 4 [figure 3]. of the 682 trials retrieved from the nlm registry, 49.1% were completed and 22.1% were still recruiting [table 3]. discussion it is essential to conduct clinical trials to enhance and develop the healthcare systems and deliver the best healthcare option to patients. moreover, it is also needed to make evidence-based decisions and create cost-effective interventions suitable for patients.12 as such, when assessing the productivity of clinical trials, it is important to include factors that enable and limit the execution of clinical trials. therefore, this study aimed to evaluate the productivity using the information available in clinical trial registries. the number of clinical trials from gcc countries has been increasing throughout the years, despite some fluctuation in the years 2010 and 2016. however, the region still lags behind other countries with a contribution of only 0.37% to the total clinical trials worldwide. alemayehu et al. studied the barriers to conducting clinical trials in developing countries. they found that common barriers include lack of financial and human capacity, ethical and regulatory system obstacles, lack of research environment, oper ational barriers and competing demands.13 moreover, a bibliometric analysis by swaminathan et al. to study global clinical research by the anaesthesia departments listed the top 34 countries with 20 or more publications and found countries from the gcc region among them.14 while the mean publication in only anaesthesia departments globally was 18.65 pmp over the six-year period, publication in the gcc countries was only 16.6 in all specialties in the past 19 years.14 in this current research’s analysis, saudi arabia had the highest number of clinical trials, with a significant difference compared to the other gcc countries, while bahrain had the lowest. after normalisation of the results to account for population size, qatar had the highest productivity, while oman had the lowest productivity. when the raw productivity was normalised using the gdp, saudi arabia had the highest productivity while the uae had the lowest. furthermore, more than half of the trials have not yet been published in peer-reviewed journals. with respect to the specific subjects, most of the trials in the region were in the field of oncology, while trials in haematology were dominant in oman. there is an overall increasing trend in the number of clinical trials conducted in the gcc countries. this is expected, given the growing gdp of these countries. furthermore, the increased expenditure on research and development (r&d) has likely contributed to this. in addition, an increase in the population size and the number of hospitals and medical colleges in the study period likely influenced the number of clinical trials conducted. this is echoed by al-maawali et al., who found a significant positive correlation between the number of publications and physicians.3 moreover, a study by bredan et al. assessed the visibility of research from arab countries in the world biomedical literature over two decades (1988–1997 and 1998–2007). it table 2: most common subjects in clinical trials conducted in gulf cooperative council countries country n (%) subject oman 12 (48) haematology saudi arabia 90 (19.8) oncology united arab emirates 16 (24.2) endocrinology qatar 12 (17.1) endocrinology bahrain 3 (17.6) genitourinary 3 (17.6) musculoskeletal kuwait 16 (32) endocrinology table 3: status of clinical trials conducted in the gulf cooperative council countries as per the united states national library of medicine status n (%) completed 335 (49.1) active, not recruiting 53 (7.8) enrolling by invitation 6 (0.9) not yet recruiting 22 (3.2) recruiting 151 (22.1) suspended 4 (0.6) terminated 28 (4.1) unknown status 77 (11.3) withdrawn 6 (0.9) total 682 (100) abdullah al-hajri, murtadha al-khabori and wasif rasool clinical and basic research | 505 found that publication from arab countries doubled in the second decade, compared to the first. moreover, the number of publications in pubmed increased by 50% between the two decades.8 as such, there was an overall increasing trend in publication over time. however, the publication trend fluctuated in the years 2010 and 2016. these dips may have resulted from the great recession affecting the global economy, including the gcc countries around 2007–2009, which manifested in the biomedical field as a decline in clinical trials conducted after around two years of the crisis. saudi arabia was the leading country in the total number of clinical trials among the gcc countries. this is expected from a country with a relatively larger population and many medical colleges and hospitals, including many physicians. this finding is echoed by all other studies assessing biomedical research in gcc countries and the middle east or arab countries.3,5,6,8,15 for example, when comparing the productivity of biomedical research in gcc countries, al-maawali et al. found that population size correlated with the number of hospitals, physicians and healthcare expenditure, which are factors associated with clinical research productivity.3 this being said, other factors affect productivity in clinical research, which are discussed later in this discussion. after normalisation for population size, qatar shows the highest productivity in gcc countries. this finding can be explained by qatar’s early investment in building excellent biomedical research infrastructure and collaborating with many institutions with good research experience. for instance, qatar foundation (qf) was established in 1995 and has provided exciting r&d opportunities for the new generation since then. qf provided a link between universities, the government and industries for the advancement of r&d in qatar. li and fang studied the impact of the triple helix model on research and productivity. this model involves universities, the government and industries that have an interactive relationship rather than a linear one to develop innovative systems in a country, including r&d.16 rassi et al., studied the medical research productivity in arab countries in 2007–2016 and showed that qatar had the highest research output pmp, not only among the gcc countries but also of all arab countries.5 this supports this paper’s finding as their study period is similar to that employed in this research and echoed by al-kindi et al. in the field of cardiovascular research.15 oman scored the lowest in the number of clinical trials among the gcc countries. this was similar to findings from other research, even after normalisation for population size.5 the research council in oman was established in 2005 and made a difference in the productivity of research in general and in clinical trials [figure 2]. nonetheless, the number of clinical trials are still considered low compared to the other gcc countries. according to the world bank, this could be due to the lack of infrastructure for clinical trial research and the country’s relatively low funding and expenditure in r&d. in oman, r&d expenditure (% of gdp) was reported to be 0.21961% in 2018.17 as low expenditure in r&d is a persisting issue, researchers and policymakers should collaborate to a greater degree to address this, given its impact on research productivity. when the productivity was normalised to gdp, saudi arabia was the highest among the gcc countries and uae was the lowest. according to the world bank, saudi arabia spent around 0.898% of its gdp on r&d in 2011 and was considered the highest spender on r&d until 2015.18 since then, uae has spent 0.895% of its gdp on r&d and is regarded as the highest spender since. this could explain why saudi arabia was found to be the highest, but it does not explain the finding in the case of uae. to answer this inconsistency, bredan et al. studied the visibility of arab countries in the world biomedical literature. they divided the countries into three economic groups based on their per capita gross national products. it was noticed that publications doubled in the lowerincome group and tripled in the middle-income group, where it increased only slightly in the upper-income group, which is what can be seen in the case of uae.8 less than half (46%) of the registered clinical trials in the gcc region were published in peer-reviewed journals. the number of clinical trials published was expected to be higher as all these articles were completed before 2016; however, this might be explained by the bias toward biomedical research in general in the arabian region.19 oncology was found to be the most covered subject in gcc countries. moreover, this was expected to be influenced by the result from saudi arabia, since they have the highest contribution among all gcc countries. alghamdi et al. studied the oncology research over ten years and found a positive trend in oncology research from saudi arabia due to the increase in the number of cancer centres and practicing centre specialties. in addition, they compared the published papers during 2008–2012 and 2013–2017 and found a significant increase in the number of the publications in the second period (p = 0.004). moreover, the international collaboration increased in the second period (p = 0.001).20 most of the clinical trials retrieved from the nlm were found to be in phases 3 and 4. even though productivity of clinical trials conducted in the gulf cooperative council region 506 | squ medical journal, november 2022, volume 22, issue 4 the region’s contribution to the trials worldwide is low, most of the trials are in their latest phases. a total of 335 trials registered with nlm were completed and only 115 (34%) trials had their result available in the nlm registry. as such, further investigation about the reasons behind such a finding is needed. there are a few limitations to this study. the search was limited to only one database (clinicaltrials.gov). second, the selection of the clinical trials registry of the nlm over the who registry was made for several reasons: (1) the who registry was established after the nlm registry (2006 versus 2000); (2) the nlm is a comprehensive registry containing all important and relevant trials; and (3) the assumption was made that the trend found in studies from the nlm registry would be similar to that of the who registry. there is no reason to expect systematic differences between the two registries and the main focus was the trend and not the absolute numbers. however, information from other registries would improve the accuracy of observations and conclusions. additionally, not all studies are registered and this may also have limited the results retrieved. moreover, only the quantitative aspects of clinical trials in this study were considered rather than the qualitative aspects. nonetheless, to the best of the authors’ knowledge, this paper is the first to address the clinical trial productivity in this period. conclusion healthcare system delivery is strongly related to clinical trials. there is a positive trend in the productivity of clinical trials from the gcc countries. saudi arabia is the leading country in clinical trial productivity among the gcc countries, while oman scored lower than expected. in addition, qatar showed promising results when normalising the raw data for population size. countries in the gcc region should improve research infrastructure to attract more sponsored clinical trials and facilitate investigator-initiated trials. a u t h o r s’ c o n t r i b u t i o n aa-h and ma-k conceptualised and designed the study. ma-k and wr prepared the analysis plan. aa-h collected the data, conducted the data analysis and drafted the manuscript. ma-k and wr reviewed the initial draft. all authors approved the final version of the manuscript. a c k n o w l e d g e m e n t we would like to thank dr sanjay jaju for the review of the statistical analysis and hadi alajmi for his assistance with the data collection. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g no funding was received for this study. references 1. national institute on aging. what are clinical trials and studies? from: https://www.nia.nih.gov/health/what-are-clinical-trialsand-studies#four accessed: sep 2021. 2. saquib n, ibrahim ay, saquib j. behavioral trials in the arab gulf states: a scoping review. sage open med 2019; 7:2050312119846787. https://doi.org/10.1177/2050312119846787. 3. al-maawali a, busadi a al, al-adawi s. biomedical publications profile and trends in gulf cooperation council countries. sultan qaboos univ med j 2012; 12:41–7. 4. tadmouri go, bissar-tadmouri n. biomedical publications in an unstable region: the arab world, 1988-2002. lancet 2003; 362:1766. https://doi.org/10.1016/s0140-6736(03)14868-4. 5. rassi r el, meho li, nahlawi a, salameh js, bazarbachi a, akl ea. medical research productivity in the arab countries: 2007-2016 bibliometric analysis. j glob health 2018; 8:020411. https://doi.org/10.7189/jogh.08.020411. 6. shaban sf, abu-zidan fm. a quantitative analysis of medical publications from arab countries. saudi med j 2003; 24:294–6. 7. benamer hts, bakoush o. arab nations lagging behind other middle eastern countries in biomedical research: a comparative study. bmc med res methodol 2009; 9:26. https://doi.org/10.11 86/1471-2288-9-26. 8. bredan a, benamer hts, bakoush o. world biomedical literature. libyan j med 2011; 6:10–12. https://doi.org/10.3402/ljm.v6i0.6325. 9. us national library of medicine. clinical trial database. from: https://clinicaltrials.gov/ accessed: sep 2021. 10. potochnik a, colombo m, wright c. statistics and probability. in: potochnik a, colombo m, wright c, eds. recipes for science, 1st ed. new york, usa: taylor and francis group, 2018. pp. 167–206. https://doi.org/10.4324/9781315686875-6. 11. united nations. department of economic and social affairs. from: https://www.un.org/development/desa/en/ accessed: sep 2021. 12. mcmichael c, waters e, volmink j. evidence-based public health: what does it offer developing countries? j public health (oxf ) 2005; 27:215–21. https://doi.org/10.1093/pubmed/fdi024. 13. alemayehu c, mitchell g, nikles j. barriers for conducting clinical trials in developing countries-a systematic review. int j equity health 2018; 17:37. https://doi.org/10.1186/s12939-018-0748-6. 14. swaminathan m, phillips-bute bg, grichnik kp. a bibliometric analysis of global clinical research by anesthesia departments. anesth analg 2007; 105:1741–6. https://doi.org/10.1213/01. ane.0000286149.57763.e7. 15. al-kindi s, al-juhaishi t, haddad f, taheri s, khalil ca. cardiovascular disease research activity in the middle east: a bibliometric analysis. ther adv cardiovasc dis 2015; 9:70–6. https://doi.org/10.1177/1753944715578585. 16. li r, fang w. university-industry-government relations of the ministry of industry and information technology (miit) univer sities: the perspective of the mutual information. plos one 2019; 14:e0211939. https://doi.org/10.1371/journal.pone.0211939. 17. al-riyami a. editorial health researchers and policy makers: a need to strengthen relationship. oman med j 2010; 25:251–2. https://doi.org/10.5001/omj.2010.75. https://doi.org/10.1177/2050312119846787 https://doi.org/10.1016/s0140-6736(03)14868-4. https://doi.org/10.7189/jogh.08.020411 https://doi.org/10.1186/1471-2288-9-26. https://doi.org/10.1186/1471-2288-9-26. https://doi.org/10.3402/ljm.v6i0.6325 https://doi.org/10.4324/9781315686875-6 https://doi.org/10.1093/pubmed/fdi024 https://doi.org/10.1186/s12939-018-0748-6 https://doi.org/10.1213/01.ane.0000286149.57763.e7 https://doi.org/10.1213/01.ane.0000286149.57763.e7 https://doi.org/10.1177/1753944715578585 https://doi.org/10.1371/journal.pone.0211939 https://doi.org/10.5001/omj.2010.75 abdullah al-hajri, murtadha al-khabori and wasif rasool clinical and basic research | 507 18. the world bank. gdp (current us$), saudi arabia, oman, qatar, bahrain, kuwait, united arab emirates. from: http s : / / d at a . w o r l d b a n k . o rg / i n d i c ato r / n y. g d p. m k t p. cd?locations=sa-om-qa-bh-kw-ae accessed: sep 2021. 19. al-adawi s, ali b. west is west, east is east the divide in science. saudi med j 2010; 31:1093–4. 20. alghamdi ma, alzahrani ra, alhashemi hh, obaid aa, alghamdi ag, aldokhi ma, et al. oncology research in saudi arabia over a 10-year period: a synopsis. saudi med j 2020; 41:261–6. https://doi.org/10.15537/smj.2020.3.24912. https://doi.org/10.15537/smj.2020.3.24912 2008-issue1.indd abstract this is a case report describing a patient at sultan qaboos university hospital, oman, with recurrent local breast cancer and axillary lymph node metastasis. the cancer was detected with 99tc-m tetrofosmin scintimammography after an equivocal mammography study. keywords: breast scintigraphy, tc-99m tetrofosmin; mammography; breast cancer; case report; oman. tc-99m tetrofosmin scintimammography for the detection of recurrent breast cancer in a patient with equivocal mammography study *samir hussein,1 sukhpal sawhney,1 adil al-jarrah2 sultan qaboos university medical journal march 2008, volume 8, issue 1, p. 79-81 sultan qaboos university© submitted 7th october 2007 accepted 22nd december 2007 departments of 1radiology and molecular imaging, and 2surgery sultan qaboos university hospital, muscat, sultanate of oman *to whom correspondence should be addressed. email: samirs@squ.edu.om الثدي سرطان الكتشاف بالتيتروفوسمن ضانِيّ مَ تصوير الثدي الوَ بِس املُلْتَ يّ عاعِ الشُّ ِ ي الثَّدْ ويرُ تَصْ وجود حالة املريضات قي الراجع عند اجلراح سامر حسني، سكبال سوني، عادل الليمفاوية إلى الغدد واملنتقل الراجع الثدي ــرطان من س تعاني حلالة مريضة قابوس ــلطان الس جامعة ــفى مستش من وصفي امللخص: هذا تقرير . للثدي ملتبس شعاعي تصوير على احلصول بعد ضانِيّ الوَمَ الثدي بتصوير اكتشف السرطان . االبطية عمان. ، تقرير حالة ، الثدي سرطان ، الشعاعي الثدي تصوير ، تيتروفوسمن ، ضانِيّ الثدي الوَمَ الكلمات: تصوير مفتاح breast cancer is becoming a global challenge.1 there is evidence that the inci-dence of breast cancer is rising in developing countries2 where diagnostic facilities have been reported to be rudimentary.3 recent affluence in oman has led to the development of a modern health care infrastructure including radiological facilities for the diagnosis of breast cancer. there are no reports to our knowledge from oman that document the progress of the use of modern radiological techniques. the present discourse is to highlight this in a patient, whose recurrent cancer was detected with tc-99m tetrofosmin scintimammography. c a s e a 42 years old female underwent right breast lumpectomy for breast cancer at a hospital in oman. six months later, she presented to the surgical outpatient department at sultan qaboos university hospital for follow up. her clinical examination, which is not the focus of this report, did not reveal any abnormality except a surgical scar in the right breast. a mammography was performed, which showed an equivocal residual tumour at the lumpectomy site with pathologic right axillary lymph nodes and underlying seroma [fig 1]. a scintimammography was performed using 740 mbq of tc-99m tetrofosmin which was injected in the arm contra-lateral to the mammary lesion. ten minutes later, planar imaging was performed using a rectangular, large field of view, dual-head gamma camera equipped with low-energy, high-resolution, parallelhole collimators. a 10% window and a 140-kev photo peak were selected. planar images were acquired in c a s e r e p o r t s a m i r h u s s e i n , s u k h pa l s aw h n e y, a d i l a l j a r r a h 80 both anterior and lateral views, with a 256 x 256 matrix size, an acquisition time of 600 s per view. first, the anterior planar view was acquired in the supine position; both breasts and the axillae were included in the field of view. the procedure is well described in the european association for nuclear medicine’s guidelines for breast scintigraphy. 4 the scintimammography showed abnormal uptake in the right breast indicating recurrence of breast cancer, and abnormal uptake in the right axilla indicating lymph node metastasis [fig 2]. the patient subsequently underwent right modified radical mastectomy with right axillary lymph node dissection. the histopathological findings were fibrocystic changes and duct ectasia. there were foci of residual high grade ductal carcinoma in situ and axillary lymph nodes positive for tumour metastasis. d i s c u s s i o n mammography combined with clinical examination represents the method of choice both in the screening and in the diagnosis of primary and recurrent breast cancer, demonstrating high sensitivity even in the detection of small non-palpable lesions. however, mammography can also yield false-negative results in some cases; 5 in addition, it is characterized by low specificity and a low positive predictive value.6 scintimammography with the cationic lipophilic oncotropic radiotracers, tc-99m methoxyisobutylisonitrile (mibi) and tc-99m tetrofosmin have proved useful methods for the detection of primary breast cancer and the differentiation of malignant from benign mammary lesions.7-10 two recent meta-analysis studies showed that there is evidence that scintimammography is a robust imaging technique delivering high sensitivities and specificities in patients studied in both single-centre and multi-centre trials and, as such, can be relied on as an adjunctive method for the investigation of primary breast cancer with sensitivity range of 85% 87.8% and specificity range of 83% 86.9%.11, 12 we preferred the use of tetrofosmin to mibi for scintimammography because of its more favourable pharmacokinetics: its faster and greater clearance from the lungs and liver allow a higher target to background ratio.13 the detection of recurrent breast cancer by mammography is a challenging task because architectural changes (mainly fibrosis) and scarring secondary to surgery and radiotherapy, cause difficulties in the infigure 1: right breast mammography showing heterogeneity of parenchyma with spiculations extending towards pectoralis muscle, seen under surgical scar site in supero-lateral quadrant figure 2: tc-99m tetrofosmin showing abnormal uptake in the right breast (grey wide arrow), and abnormal uptake in the right axilla (black dotted arrow) 9 9 tc m te t r o f o s m i n s c i n t i m a m m o g r a p h y f o r t h e d e t e c t i o n o f r e c u r r e n t b r e a s t c a n c e r i n a pat i e n t w i t h e q u i v o c a l m a m m o g r a p h y s t u d y 81 terpretation of mammograms. in a prospective trial14 performed to assess the accuracy of tc-99m-mibi scintimammography in women with suspected recurrent breast cancer in the breast and/or locoregional tissues, the sensitivity was 78% in detecting recurrent disease, compared with 55% for mammography.15 in addition, scintimammography identified 63% of axillary lymph nodes with recurrent tumour. c o n c l u s i o n scintimammography should be performed in patients with recurrent breast cancer and equivocal mammography results. r e f e r e n c e s 1. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin 2005; 55:74-108. 2. al-moundhri m, al-bahrani b, pervez i, ganguly ss, nirmala v, al-madhani a, et al. the outcome of treatment of breast cancer in a developing country oman. breast 2004; 13:139-145. 3. chopra sa, chopra fs. cancer in the africans and arabs of zanzibar. int j cancer 1977; 19: 298-304. 4. breast scintigraphy procedure guidelines for imaging. from http://www.eanm.org/scientific_info/guidelines/ gl_onco_breast.php?navid=54. accessed september 2007. 5. bird re, wallace tw, yankaskas bc. analysis of cancers missed at screening mammography. radiology 1992; 184:613-617. 6. kopans db. the positive predictive value of mammography. ajr 1992; 158:521-526. 7. khalkhali i, cutrone j, mena i, diggles l, venegas r, vargas h, et al. technetium-99m-sestamibi scintimammography of breast lesions: clinical and pathological follow-up. j nucl med 1995; 36:1784-1789. 8. palmedo h, grünwald f, bender h, schomburg a, mallmann p, krebs d, et al. scintimammography with technetium-99m methoxyisobutile: comparison with mammography and magnetic resonance imaging. eur j nucl med 1996; 23:940-946. 9. mansi l, rambaldi pf, procaccini e, di gregorio f, laprovitera a, pecori b, et al. scintimammography with technetium-99m tetrofosmin in the diagnosis of breast cancer and lymph node metastases. eur j nucl med 1996; 23:932-939. 10. fenlon hm, phelan n, tierney s, gorey t, ennis jt. tc-99m tetrofosmin scintigraphy as an adjunct to plainfilm mammography in palpable breast lesions. clin radiol 1998; 53:17-24. 11. liberman m, sampalis f, mulder ds, sampalis js. breast cancer diagnosis by scintimammography: a meta-analysis and review of the literature. breast cancer res treat 2003; 80:115-126. 12. hussain r, buscombe jr. a meta-analysis of scintimammography: an evidence-based approach to its clinical utility. nucl med commun 2006; 27:589-594. 13. higley b, smith fw, gemmel hg, das gupta p, gvozdanovic dv, graham d, et al. technetium-99m1,2-bis [bis(2-ethoxyethyl) phosphino] ethane: human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent. j nucl med 1993; 34:3038. 14. cwikla jb, kolasinska a, buscombe jr, hilson aj. tc99m mibi in suspected recurrent breast cancer. cancer biother radiopharm 2000; 15:367–372. 15. orel sg, troupin rh, patterson ea, fowble bl. breast cancer recurrence after lumpectomy and irradiation: role of mammography in detection. radiology 1992; 183:201-206. 1 submitted 22 nov 22 1 revisions req. 26 jan & 5 mar 23; revisions recd. 16 feb & 19 mar 23 2 accepted 21 mar 23 3 online-first: march 2023 4 doi: https://doi.org/10.18295/squmj.3.2023.020 5 6 ramsay hunt syndrome associated with varicella-zoster virus encephalitis 7 in a child 8 eman y. ahmed,1,2 hatem al rawahi,2 fatema al amrani,2 9 laila al masaoudi,3 *laila al yazidi2 10 11 1school clinic, ahlia school, al qurayya, bahrain; departments of 2child health and 3surgery, 12 sultan qaboos university hospital, muscat, oman 13 *corresponding author’s e-mail: lailay@squ.edu.om 14 15 abstract 16 ramsay hunt syndrome (rhs) is a triad of peri-auricular pain, ipsilateral facial nerve palsy and 17 vesicular rash around the ear pinna. it is caused by reactivation of varicella-zoster virus (vzv) 18 that lies dormant in the geniculate ganglia. it can be complicated by vzv encephalitis rarely. we 19 report the case of an 8-year-old previously healthy boy who presented to a tertiary care hospital 20 in muscat, oman in 2021 with fever, progressive left ear pain, vesicular rash around his ear 21 pinna and left-sided facial nerve palsy. his course was complicated by vzv encephalitis where 22 he was managed with iv acyclovir and iv corticosteroids. he improved significantly and was 23 asymptomatic with a normal neurology examination at the 6-months follow-up. 24 keywords: varicella zoster virus; ramsay hunt syndrome; encephalitis; children. 25 26 introduction 27 ramsay hunt syndrome (rhs), which is also known as geniculate neuralgia, is caused by 28 reactivation of varicella zoster virus (vzv) that lies dormant in the geniculate ganglion after the 29 primary infection with chickenpox.1-3 it was described for the first time by james ramsay hunt, 30 mailto:lailay@squ.edu.om 2 an american neurologist in 1907.3 it tends to be less frequent and less severe in children 31 compared to adults but there is limited data on how to manage pediatric rhs.4 it is responsible 32 for about 16.7% of cases of facial paralysis in children and it can be complicated rarely with 33 encephalitis.1,3,5 rhs has a low incidence in children with a rate of 2.7/100.000 in younger than 34 10 years of age, and is more common in children 6 to 15 years of age.3 35 36 case report 37 an 8-year-old previously healthy boy presented to the emergency department of a tertiary care 38 hospital in muscat, oman, in 2020 with a 3-day history of fever, progressive left ear pain and 39 swelling and vesicular rash around the left ear pinna. in addition, he had poor oral intake but no 40 seizure or behavioral changes. there was no history of a previous chicken pox, recent travel or 41 any sick contacts. no history of recurrent ear infections, ear trauma or swimming in a pool was 42 given. his immunization was up-to-date and he got the varicella vaccine at 12 months of age as 43 per oman’s immunization schedule. 44 45 upon initial examination, his left ear was swollen with redness extended to the pre-auricular and 46 postauricular area. he had vesicular lesions with red base on the outer ear canal, extending to the 47 left side maxillary dermatome, with yellowish discharge as well as tender enlarged left cervical 48 node (2 x 3 cm) figure (1). his throat was clear and the examination of his right ear was 49 unremarkable. 50 51 laboratory investigations showed normal full blood count, c-reactive protein, serum electrolytes 52 and random blood sugar. based on the clinical findings, ramsay hunt syndrome diagnosis was 53 made and acyclovir (450 mg orally every 6 hours) was started. varicella zoster virus (vzv) 54 polymerase chain reaction (pcr) from the ear swab was reported positive while both bacterial 55 culture and herpes simplex pcr were negative. the patient developed lower motor neuron facial 56 nerve palsy on day 2 of admission and later developed dizziness and he was noticed to be more 57 sleepy. on day 3 of admission, he developed vomiting, dysarthria and unsteady gait. no changes 58 in personality, seizures, meningeal signs or motor or sensory deficits were reported. at this stage, 59 acyclovir was switched to intravenous formulation (15 mg/kg/dose 8 hourly) and prednisolone 1 60 mg/kg daily was added. he also underwent an urgent brain magnetic resonance imaging (mri) 61 3 and magnetic resonance venography (mrv) and both were reported to be normal. cerebrospinal 62 fluid was obtained and it showed 10 leukocytes (8 mononuclear cells and 2 polymorphonuclear 63 cells), and 2 red cells with normal protein and glucose. bacterial culture was negative and vzv 64 pcr reported positive from the cerebrospinal fluid. in the following few days, his ear pain, 65 swelling, vomiting and the unsteady gait improved significantly and was asymptomatic on 66 discharge. he received 10 days of intravenous acyclovir and 7 days of predinsolone of 67 1mg/kg/day. eye care and physiotherapy was provided. he remained completely asymptomatic 68 and had a normal mri with no evidence of cerebral arteritis vasculopathies on the 6 months 69 follow-up. paternal consent was obtained for publication purposes. 70 71 72 discussion 73 ramsy hunt syndrome is uncommon in children. our patient had a classic presentation on 74 admission. rhs is characterized by a triad of periauricular pain, ipsilateral peripheral facial 75 nerve palsy and erythematous vesicular rash around the ear pinna and outer ear canal or in the 76 oral mucosa.5 the clinical symptoms begin with otalgia which can last for 1 to 3 days.1,4,5 facial 77 nerve palsy usually develops within 1–2 weeks after the rash appearance.3 rhs can affect both, 78 the facial and vestibulocochlear nerves.5 if the vestibulocochlear nerve gets affected, the patient 79 can develop nausea, vomiting, vertigo, tinnitus, and nystagmus.1,5 hearing loss is reported in 80 24% of children with rhs.3 our patient has normal hearing during his presentation and on 81 follow-up. 82 83 rhs is usually diagnosed clinically.3-5 our patient presented with classic symptoms of rhs so 84 acyclovir was started from the beginning. laboratory and imaging investigations are not 85 necessary to make the diagnosis most of the time and they do not affect the patient’s outcomes.5 86 confirming diagnosis can be done using molecular testing from skin lesions and this can be 87 considered when the diagnosis of rsh is doubtful. the use of serum anti-vzv igg and igm 88 antibody titers is recommended for the routine laboratory diagnosis of pediatric patients with 89 acute peripheral facial paralysis.3,5 90 91 4 childhood immunization with varicella vaccine can reduce the risk of getting rhs.4 although 92 our patient had varicella vaccine at 12 months of age but he still developed rhs. he has no clear 93 history of chickenpox in the past, so rhs either resulted from a reactivation of subclinical 94 infection in the past or because of a vaccine-related strain. 95 96 rhs carry worse prognosis compared to bell’s palsy in children.5 advanced facial paralysis at 97 presentation, audiovestibular findings and delayed treatment are unfavorable prognostic factors.1 98 early treatment with acyclovir and high-dose corticosteroid therapy should be considered in all 99 patients with rhs.3 the combination of acyclovir ( for 7 -10 days) and corticosteroid therapy 100 has been found to be more effective than treatment with acyclovir alone.1,3,5 acyclovir inhibits 101 viral replication and help with rapid healing of lesions and corticosteroids help with reducing 102 edema and pain by reducing the inflammation in peripheral neurons.3 hato et al. and his 103 colleagues examined the recovery of facial nerve function after initiating treatment in the first 104 three days, at 3–7 days, or later than seven-days and found that the recovery was better when 105 acyclovir was started within 3-days of presentation. the recovery rates were 75, 48, and 30%, 106 respectively.6 full recovery from rhs-related facial paralysis has been reported to vary between 107 27 and 70% even with early treatment.5 our patient improved significantly and he was 108 asymptomatic with normal neurology examination at the 6-months follow-up after using the 109 combination of acyclovir and corticosteroids. 110 111 our patient’s course was complicated by vzv encephalitis. he was sleepy, lethargic, and 112 complaining of headache and vomiting. his physical examination showed signs of cerebellar 113 involvement manifested as a wide-base gait with unsteadiness and dysarthria. although some of 114 these symptoms can be explained by vestibular involvement, however, the headache, lethargy, 115 sleepiness, and wide base gait cannot be explained by vestibular involvement alone. the 116 constellation of these symptoms along with the isolation of vzv from cerebrospinal fluid 117 support the diagnosis of encephalitis. although most of the reported patients with ramsy hunt 118 syndrome associated with encephalitis, have abnormal mri-brain, ricigliano et al reported that 119 around 31% of patients with rhs-associated encephalitis have negative mri-brain. therefore, 120 normal mri-brain in the context of rhsassociated varicella encephalitis does not exclude this 121 diagnosis.7 122 5 123 vzv can affect cns disease through 3 mechanisms including acute vzv encephalitis, post-124 vzv cerebellitis and vzv vasculopathy.2,5 development of vzv encephalitis following rhs is 125 extremely rare in an immunocompetent patient, which is the case in our patient.2,3,5,8 the 126 available literature report only 6 adults with rhs complicated by vzv encephalitis and 2 of 127 them are immunocompetent.8-10 we could not find any pediatric cases of rhs complicated by 128 vzv encephalitis. hematogenous spread of vzv to the central nervous system or dissemination 129 through the cerebrospinal fluid pathway has been hypothesized which could be the case in our 130 patient.8 131 132 acyclovir-induced encephalopathy should be considered in the differential diagnosis of our 133 patient encephalopathy. furthermore, this adverse effect is more common in patients with renal 134 insufficiency, which is not the case in our patient.11 the main treatment of this entity is dialysis 135 along with cessation of acyclovir.11 our patient showed improvement of his clinical symptoms 136 without any dosing adjustment, and he improved before the end of the acyclovir course. 137 therefore, it is unlikely for his presentation to be secondary to acyclovir-induced 138 encephalopathy. 139 140 there is limited data on how to manage vzv encephalitis. the association of british 141 neurologists and british paediatric allergy, immunology and infection group recommend 142 giving intravenous acyclovir (500 mg/m2 if 3 months -12 years of age or 10 -15 mg/kg in > 12 143 years of age) for management of vzv encephalitis in children for total of 10 14 days.2 in 144 immunocompromised patients with vzv encephalitis, prolonged course of antivirals may be 145 required.2 if vasculopathy present, then it is recommended to use corticosteroids with or without 146 acyclovir.2 the limitation of this report is that we could not prove that our patient has rhs-147 associated encephalitis because he has a normal mri. the csf pleocytosis can accompany 148 nerve inflammation. the mild clinical syndrome and the normal mri may be secondary to early 149 initiation of antiviral therapy and corticosteroids in our patient. 150 151 conclusion 152 careful examination and early trial of treatment with antiviral therapy and corticosteroids should 153 6 be considered in children with rhs. vzv encephalitis, although uncommon, can complicate 154 rhs in children. 155 156 authors’ contribution 157 dr eman ahmed wrote the first draft which was directly supervised by dr laila al yazidi. all 158 other co-authors helped with the literature review and the manuscript writing and revision. 159 160 references 161 1. derin s, derin h, sahan m, caksen h. a pediatric case of ramsay hunt syndrome. case 162 rep otolaryngol. 2014;2014:469565. https://doi.org/10.1155/2014/469565 163 2. kneen r, michael bd, menson e, mehta b, easton a, hemingway c, et al. 164 management of suspected viral encephalitis in children association of british 165 neurologists and british paediatric allergy, immunology and infection group national 166 guidelines. j infect. 2012 may;64(5):449–77. https://doi.org/10.1016/j.jinf.2011.11.013 167 3. aydoğdu i̇, ataç e, saltürk z, atar y, özdemir e, uyar y, et al. pediatric ramsay hunt 168 syndrome: analysis of three cases. case rep otolaryngol. 2015;2015:1–4. 169 https://doi.org/10.1155/2015/971249 170 4. masukume g, chibwowa s, ndlovu m. full recovery of a 13-year-old boy with pediatric 171 ramsay hunt syndrome using a shorter course of aciclovir and steroid at lower doses: a 172 case report. j med case reports. 2011;5:376. https://doi.org/10.1186/1752-1947-5-376 173 5. çiçek m, kılıç z, mercen y, karaoğlan e, öztarhan k. a rare cause of facial paralysis 174 in children: a case of ramsay hunt syndrome. j pediatr neurol. 2021;19(1):43–175 5.http://doi.org/10.1055/s-0040-1719052. 176 6. hato n, matsumoto s, kisaki h, takahashi h, wakisaka h, honda n, et al. efficacy of 177 early treatment of bell’s palsy with oral acyclovir and prednisolone: otol neurotol. 178 2003;24(6):948–51. 179 7. ricigliano vag, saraceno l, cavalli m, rodegher m, meola g. slowly progressing 180 varicella zoster brainstem encephalitis complicating ramsay hunt syndrome in an 181 immunocompetent patient: case report and review of literature. j. neurovirol. 182 2017;23(6):922-928. doi: 10.1007/s13365-017-0575-3. 183 https://doi.org/10.1016/j.jinf.2011.11.013 https://doi.org/10.1155/2015/971249 http://www.thieme-connect.de/doi/doi?10.1055/s-0040-1719052 http://www.thieme-connect.de/doi/doi?10.1055/s-0040-1719052 http://www.thieme-connect.de/doi/doi?10.1055/s-0040-1719052 7 8. chan tlh, cartagena am, bombassaro am, hosseini-moghaddam sm. ramsay hunt 184 syndrome associated with central nervous system involvement in an adult. can j 185 infect dis med microbiol ;2016:1–4. https://doi.org/10.1155/2016/9859816 186 9. elshereye a, erdinc b, sahni s. disseminated varicella-zoster virus infection 187 complicated by encephalitis and ramsay hunt syndrome in an hiv patient. cureus. 188 2020;12(7):e9235. https://doi.org/10.7759/cureus.9235 189 10. shen yy, dai tm, liu hl, wu w, tu jl. ramsay hunt syndrome complicated by 190 brainstem encephalitis in varicella-zoster virus infection. chin med j (engl). 191 2015.;128(23):3258–9. https://doi.org/10.4103/0366-6999.170275 192 11. sakamoto h, hirano m, nose k, ueno s, oki t, sugimoto k, et al. a case of severe 193 ganciclovir-induced encephalopathy. case rep neurol. 2013;5(3):183-6. doi: 194 10.1159/000355638. 195 196 197 figure 1: shows redness, swelling and crusting of the left ear associated with vesicular rash in 198 the maxillary dermatome. 199 https://doi.org/10.1155/2016/9859816 https://doi.org/10.1155/2016/9859816 https://doi.org/10.4103/0366-6999.170275 january 2007 vol 7 correct a.indd abstract objective: to study the effect of the postnatal administration of ambroxol in the prevention of respiratory distress syndrome in preterm neonates at risk and on the severity of the disease in those neonates already suffering from it. methods: the study was a randomized clinical trial performed on 20 preterm neonates admitted to the neonatal unit of the suez canal university hospital, egypt, with gestational age of 28 to 34 weeks. it was performed in the period from september 200 through march 2003. half of the enrolled neonates received intravenous ambroxol (20 mg/kg/d), while the control group received the routine management of prematurity and a placebo. results: ambroxol decreased the incidence of respiratory distress syndrome (rds), improved the gas exchange, and decreased continious positive airway pressure (cpap) pressure, the length of mechanical ventilation and also the mortality rate. conclusion: the study concluded that ambroxol reduced the incidence of this disease in preterm neonates at risk of developing it, and improved the clinical course of rds. key words: respiratory distress syndrome (rds), prematurity, ambroxol. evaluation of the role of postnatal ambroxol in the prevention and treatment of respiratory distress syndrome in preterm neonates hesham f elsayed1, muhammed i elkhaiouby1 sunia m elsharkawey1, *muna a elnemr2 sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© 1the institution where the research was performed: neonatal intensive care unit, pediatric department, suez canal university hospital, egypt, 2faculty of medicine, university of science and technology, sanaa, yemen *to whom correspondence should be addressed. email: munaabdo@hotmail.com o r i g i n a l s t u d y الضائقة وعالج متالزمة منع في الوالدة بعد دور االمبروكسول تقييم اخلدج عند املواليد التنفسية املواليد اخلدج ــيَّة عند سِ التَّنَفُّ ةِ ائِقَ الضَّ ــةُ تَالَزِمَ ملنع حصول مُ الوالدة ــد بع ــرة مباش املعطى ــول االمبروكس عقار ــة فعالية امللخص: الهدف: دراس 120خديجا دراسة السريرية العشوائية الدراسة هذه في الطريقة: مت . هؤالء املواليد املصابني بها من عند املرض شدة وتقليل ، بها لألصابة املعرضني من سبتمبر استغرقت الدراسة . الوالدة عند 28 – 34 اسبوعا بني أعمارهم تراوحت (مصر) السويس قناة جامعة مبستشفى اخلدج وحدة في أدخلوا 20 ملجم/كجم/يوم) (بجرعة ــول االمبروكس عقار االولى اموعة ، واعطاء مجموعتني الى ــوائيا عش اخلدج ــيم تقس 2003 . مت مارس 2001 الى اخلاصة باخلدج. الرعاية الى اضافة (كاذبا) ال فْ غُ ــارا عق الضابطة) (العينة الثانية اموعة أعطيت بينما ، متوالية أيام ــة خمس وملدة الوريدي ــن باحلق فترة تقليص أدى الى مما ، ــرض للم املصاحبة االعراض تخفيف الى وأدى ، ة ــيَّ سِ ةِ التَّنَفُّ ائِقَ الضَّ ةُ مبُتَالَزِمَ االصابة حدوث ــول االمبروكس ألنتائــج: قلل من يقلل للخدج الوالدة املعطى بعد ــول عقار االمبروكس أن التجربة هذه اخلالصة: اثبتت . الوفيات بينهم معدل وكذلك قلل االصطناعية التنفس . بها املصابني عند لها املصاحبة االعراض حدة من يخفف و ، يَّة سِ ةِ التَّنَفُّ ائِقَ ةُ الضَّ االصابة مبُتَالَزِمَ أمبروكسول. ، اخلداجة ، التنفسية الضائقة املفردات املفتاحية: متالزمة respiratory distress syndrome (rds) is the most common respiratory malfunction oc-curring in preterm newborns.1 it is one of the most important factors determining neonatal morbidity and mortality.2 in egypt, rds was reported to be the most common cause of morbidity (42.5%) among preterm neonates admitted to the neonatal intensive care unit (nicu) of cairo university hospital and is responsible for 70% of the neonatal mortality.3 there are an estimated 40,000 cases of rds annually in the united states, representing about 14% of all low-birth weight infants.4 the role of endogenous pulmonary surfactant in the maintenance of alveolar stability has been reported since 1950.4 the deficiency of surfactant in newborns was attributed to pulmonary atelectasis and hyaline membrane disease, the condition now known as respiratory distress syndrome.5 h e s h a m f e l s ay e d , m u h a m m e d i e l k h a i o u b y, s u n i a m e l s h a r k aw e y, m u n a a e l n e m r 42 although exogenous surfactant therapy has dramatically improved survival in clinical rds, chronic lung disease continues to cause significant mortality and morbidity, thus there is an increasing interest in the potential role of newer therapies that may further decrease lung injury in susceptible premature newborns6,7 and even prevent its occurrence. although glucocorticoids are effective in the prevention of rds and in the treatment of chronic lung disease,8 their action depends on the repetition of the dose every seven days, which leads to a rise in cumulative side effects.9 there are now growing concerns, based on animal and human data, that repeated antenatal doses could lead to growth retardation, decreased fetal brain size and abnormal neuronal development.10 ambroxol, is a relatively new promoter of fetal lung maturity, the data on its efficacy are not yet as numerous as those of corticosteroids, although an increasing number of studies reported its role in the prevention of rds, when given antenatally, with no side effects on the newborn.11,12,13,14 the effectiveness of postnatal intravenous ambroxol in the treatment and the prevention of rds remains an area of concern and needs more research. therefore, this study was conducted to evaluate the role of post-natal intravenous administration of ambroxol in the treatment of rds and its effects on the course and severity of the disease among egyptian neonates. m e t h o d s the sample size of our study was 120 preterm neonates with gestational ages between 28 to 34 weeks, admitted to the neonatal unit of suez canal university hospital between september 2001 and march 2003. the study protocol was approved by the ethical committee of researches in the faculty of medicine in suez canal university in egypt before the launch of the study and an oral consent was taken from every parent before inclusion in the study in which the goal and the nature of the study was explained. the study was funded by university of science and technology, sanaa republic of yemen in 2003. neonates with major congenital malformations or diseases that could cause respiratory distress in the neonates (e.g. congenital diaphragmatic hernia, congenital heart disease, congenital pneumonia, congenital emphysema, etc.) were excluded, as well as those neonates with a history of maternal conditions that are associated with increased risk of rds (e.g. toxemia of pregnancy, diabetes mellitus, placenta previa, etc.). randomisation was done immediately after inclusion. all eligible patients assigned to the study were submitted to an initial assessment regarding gestational age, then a complete clinical examination, with particular attention paid to signs of respiratory distress, chest auscultation and cardiac and radiological examinations. at the time of the study (2003) and, as in many arabic countries, surfactant could not be given as standard treatment (that is given for every case of rds) because it was and still is very expensive. therefore, the standard treatment for the control group was only the usual management of preterms. once rds appeared, table 1: distribution of the enrolled neonates according to their birth weight (gm) ambroxol group control group total t test p value birth weight (gm) mean s.d mean s.d 1547.7 241.3 1590.6 305.1 1.290 >0.05 no % no % no % chi -2 test p value 1100 1400 26 43.4 23 38.3 49 40.83 0.14 >0.05 >1400 2000 34 56.6 37 61.6 71 59.17 total 60 100.0 60 100.0 120 100.00 not statistically significant difference at 0.05 level table 2: distribution of the enrolled neonates according to apgar score at 5 minutes apgar score ambroxol group control group total no % no % no % < 5 2 3.33 0 0.0 2 1.67 ≥ 5 58 96.67 60 100.0 118 98.33 total 60 100 60 100 120 100 statistically not significant difference at 0.05 level fisher exact test (2-tailed) p=0.49 e va l uat i o n o f t h e r o l e o f p o s t n ata l a m b r o xo l i n t h e p r e v e n t i o n a n d tr e at m e n t o f r e s p i r at o r y d i s t r e s s s y n d r o m e i n p r e t e r m n e o n at e s 43 respiratory support was given with either continuous positive airway pressure (cpap) in mild cases or mechanical ventilation if not responding and according to the mentioned indications in the methods. therefore surfactant was not used in both the control and intervention groups and from here comes the importance of using a cheaper product to support such cases as long as surfactants are not available, especially in poor communities. the treatment protocol in our study was as follows: 1. resuscitation and supportive care by giving sufficient inflation pressures through cpap in mild cases, and by endotracheal intubation and mechanical ventilation in severe cases with hypoxia despite cpap 2. blood gas monitoring by taking arterial blood samples. 3. monitoring of blood pressure and adequate circulatory support. 4. other general supportive measures like temperature control and minimal handling. the intervention group received, in addition to the above mentioned protocol, intravenous ambroxol (mucosolvan, boehringer, ingelheim am rhein, germany) in a dose of 10 mg /kg, repeated every 12 hours for a duration of 5 days as infusion over 5 minutes, as early as possible after birth. ambroxol was available in ampoules containing 15 mg diluted in 2 ml saline. the control group received a placebo, which was available as similar indistinguishable ampoules in dose and duration. antenatal steroids were given for every woman with threatened premature labour and in our patients it was given prenatally to all cases of both groups (at least one dose of betamethasone was given) o u tc ome me a sur e me n ts the diagnosis of respiratory distress syndrome was based on clinical, radiological and blood gas examinations according to kimya et al., (1995)11 ie. onset of respiratory distress within the first four hours of life, with a duration of more than 24 hours, tachypnea of more than 60 beats/minute, intercostal retractions, grunting on expiration, cyanosis and/or pao2 less than 60mmhg at room air temperature, reticulogranular pattern and/or air bronchogram on chest x-ray. table 3: vital signs of the enrolled neonates at the initial assessment neonates characteristics ambroxol group control group ttest p value range mean ±sd range mean ±sd respiratory rate 45-80 64.17 7.86 50-80 66.77 6.29 1.555 >0.05 heart rate 110-180 146.33 22.40 120-180 144.50 23.10 0.466 >0.05 temperature 35.5-37 36.44 0.34 35.5-37 36.52 0.39 1.497 >0.05 sao2 88-100% 94.83 4.34 66-95% 94.13 3.80 0.944 >0.05 not significant at 0.05 level sao2: oxygen saturation at room air. table 4: result of assessments after 24 hrs of admission incidence of rds at 24hrs ambroxol group control group chi 2 test p value no % no % yes 20 33.3 29 48.4 2.21 0.049* no 40 66.7 31 51.6 mean ±sd mean ±sd ttest p value pao2 mmhg 94.03 5.24 76.75 16.72 7.971 0.0007* pco2 mmhg 35.57 3.58 42.62 8.44 5.933 0.0003* sao2 % 95.94 3.77 83.25 9.14 9.798 0.008* ph 7.34 0.03 7.31 0.5 0.463 >0.05 *statistically significant difference at p< 0.05. h e s h a m f e l s ay e d , m u h a m m e d i e l k h a i o u b y, s u n i a m e l s h a r k aw e y, m u n a a e l n e m r 44 the severity of the disease was determined by the following indices: 1. the need for continuous positive air way pressure (cpap), defined as the presence of mild respiratory distress requiring a fraction of inspired oxygen (fio2) below 0.40 to maintain a pressure of arterial oxygen of 50-80 mmhg. 2. the need for mechanical ventilation was defined as pao2 ≤ 50 mmhg at oxygen concentration of 70-100% and cpap 8-10 cmh2o, arterial blood pco2 of 60mmhg or more or persistent apnea. 3. the main airway pressure (map) needed during the ventilation to keep pao2 at an adequate limit at the initial settings was calculated by the specific formulas as well as the oxygenation index (oi). r e s u l t s the mean gestational age in the intervention group was 30.23 weeks, while in the control group was 30.63 weeks. the mode of delivery was lower segment cesarean section in 11.67% of the neonates in the intervention group, while 13.33 % of the control group delivered by cesarean section. the distribution of the enrolled neonates according to their birth weight, apgar score at 5 minutes, is shown in the tables 1 and 2 respectively. fisher exact test (2-tailed) p= 0.49 unfortunately, the cause of preterm delivery was not recorded as part of the research. the result of the initial assessment of the enrolled neonates regarding respiratory rate, heart rate, temperature and oxygen saturation percentage are shown in table 3. it shows no significant differences in the two groups of the neonates. the incidence of rds was significantly lower in the ambroxol group (33.3%) compared with the control group (48.4%) as shown in table 4. this table shows also the blood gas analysis to be significantly better in the ambroxol group. the main pressure of cpap needed during the course of the treatment was found to be significantly lower in the ambroxol group [table 5]. the need for and the duration of mechanical ventilation were lower in the ambroxol group. the oxygenation index as an indicator of gas exchange during the mechanical ventilation was lower in the ambroxol group [table 6]. table 5: results of the analysis of cpap settings effect of ambroxol ambroxol control chi 2 test p value no % no % need for cpap yes 9 15.00 27 45 11.47 0.0007* no 51 85.00 33 55 mean ±sd mean ±sd t-test p value pressure of cpap cm h2o 5.78 1.09 7.71 1.45 8.540 0.0006* *statistically significant difference at p< 0.05. table 6: results of the analysis of the need for mechanical ventilation and its settings ambroxol control chi 2 test p value need for m.v no % no % yes 4 6.67 20 33.33 11.72 0.0006* no 56 93.33 40 66.66 mean ±sd mean ±sd t-test p-value oi during m.v 10 0.1 12.42 1.85 8.593 0.0001* map during m.v 9 0.1 10.24 0.97 9.850 0.0001* duration of m.v(hrs) 84 12.70 169.60 32.0 2.923 0.004* * statistically significant difference at p< 0.05. for duration of m.v, two-sample wilcoxon rank-sum for equality of medians was used. m.v: mechanical ventilation. oi: oxygenation index. map: mean airway pressure. e va l uat i o n o f t h e r o l e o f p o s t n ata l a m b r o xo l i n t h e p r e v e n t i o n a n d tr e at m e n t o f r e s p i r at o r y d i s t r e s s s y n d r o m e i n p r e t e r m n e o n at e s 45 the present study shows also that the mortality rate was significantly lower in the ambroxol group (18.3%) compared with the control group (35%) [table 7]. d i s c u s s i o n there are increasing numbers of studies that report the improving effect of ambroxol on lung maturation and on the course of rds in preterms.15 it is possible to increase surface active material in the alveolar spaces either by direct installation of exogenous surfactant or by accelerating endogenous surfactant biosynthesis in the alveolar type 2 cells by ambroxol.16 in this work, the prevalence of rds at 24 hours of administration was significantly lower in the group of neonates who received ambroxol group. this preventive effect coincides with the effect reported by wauer et al.,17 leurti et al.,18 laoag et al.17,18,19 ambroxol generally reduced the severity of rds among the enrolled neonates. the need for cpap was used as an index for severity (morbidity of rds). ambroxol reduced the need for cpap and its mean pressure. moreover ambroxol reduced the need for the initiation of mechanical ventilation during the course of illness and the initial ventilator setting. this coincides with the results of wauer et al.20 ambroxol also reduced the oxygenation index (oi) which reflects a better gas exchange, a lower mean airway pressure (map) and a lower fraction of inspired oxygen (fio2). the map was also lower in the group treated with ambroxol. this reflects a reduced peak inspiratory pressure (pip) and peak expiratory end pressure (peep), as well as reduced inspiratory time. this result goes with those reported by durisova,21 sackdy et al.,12 and schmalisch et al.14 our study showed the overall death rate to be significantly lower in the group treated with ambroxol. this is consistent with the results concluded by duresova in 1992.21 ambroxol efficacy is probably dependent not only on lung pathology, but also on the dose administered and the duration of administration. our choice of 20mg/kg/day was the minimal dose reported in the literature; larger doses could be used safely. the ambroxol used in this study was safe and caused no complications. according to literature no significant complications were attributed to this drug during 30 years of research and it has been used in neonates intravenously for pneumonias to improve table 8: mortality and cause of death among the two studied groups ambroxol group control group chi-2 test p-value no % no % yes 11 18.33 21 35.0 3.261 0.039* no 49 81.66 39 65.0 cause of death hmd 4 36.4 8 38.1 0.01 0.993hypo 1 9.1 2 9.5 sepsis 6 45.5 11 52.4 death at day <14 6 54.5 12 57.1 fe** 1.000 ≥14-28 5 45.5 9 42.9 * statistically significant at p< 0.05 hmd: hyaline membrane disease. hypo: hypotension **fe: fisher exact test (2 tailed) table 7: mortality among the two studied groups death rate ambroxol group control group chi-2 test p value no % no % yes 11 18.33 21 35 3.261 0.039* no 49 81.66 39 65 * statistically significant at p< 0.05. hmd: hyaline membrane disease. hypo: hypotension. **fe: fisher exact test (2 tailed) 46 thick secretions, so we were looking for simple complications such as frothy secretions as well as it is being mucolytic. moreover, its administration is simple in comparison with surfactant administration and is cheaper. c o n c l u s i o n finally, we could conclude that ambroxol administration to preterm neonates at risk of/or suffering from rds improves gas exchange, and decreases the length of mechanical ventilation, as well as the incidence of rds and of mortality. furthermore, ambroxol therapy could be considered as a therapeutic option in cases of at risk neonates for rds and for those neonates with established rds. it is also safe, cheap and easy to administer, so that infants who are managed without intubation can benefit from it, which is a major advantage of ambroxol. r e f e r e n c e s 1. rudriguez rj. management of respiratory distress, an up date. respir care 2003; 48:279-287. 2. hernandez r, navarro-solis e, carreon z. lamellar bodies as a diagnostic test of lung maturity. int j gynecol obstet 2003; 77:217-221. 3. salama ei, sami sm. morbidity and mortality in the neonatal intensive care unit. medical journal of cairo university 1999; 67:781-788. 4. pappoff p, christensen rd, calboun da, juulse e. granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor and neutrophils in the bronchoalveolar lavage fluid of premature infants with respiratory distress syndrome. biol neonate aug 2001; 80:133-134. 5. taeusch hw, avery me. respiratory distress syndrome in avery’s diseases of the newborn. philadelphia, sounders company 200, 289-320, 7th ed. 2000. 6. kinsella j, steven h. abman r, et al. clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. j of pediatrics 2000; 136:717-26. 7. neerhof mg, silver rk, ashwood er, et al. lamellar body counts compared with traditional phospholipids analysis as an assay for evaluating fetal lung maturity. obstet gynecol 2001; 9:305-9. 8. bott rj, van mm, lafeber hn, delemarrevan de. glucocorticoids and lung development in the fetus and preterm infants. pediatr pulmonol 2001; 32:76-91. 9. schmitz t, goffinet f, jarreau ph, morietting h. repetition of corticoid treatment for fetal lung maturation clinical and experimental scientific data. j de gynecologie 2000; 29:458-468. 10. ko y, chang y, park w, et al. comparison of respiratory indices in predicting response to high frequency oscillatory ventilation in very low birth weight infants with respiratory distress syndrome. j. korean med sci 2000; 153-158. 11. kimya s, kucukkomurcu h, ozan gu, et al.: antenatal ambroxol usage in the prevention of infant respiratory distress syndrome. clin exp obst gyn 1995; 22:205211. 12. sackdy s, gadzinowski j, szymankiewie zm, et al. evaluation of ambroxol given prenatally and postnatally on gas exchange in the newborn with respiratory distress syndrome. ginekol pol 1995; 66:409-412. 13. bhutta za, yusuf k, khan ia, et al. is management of neonatal rds feasible in developing countries? pediatr pulmonol 1999, 27:205-211. 14. schmalisch g, wauer r, bohme b. effect of early ambroxol treatment on lung function in mechanically ventilated preterm neoborns who subsequently developed bronchopulmonary dysplasia. respir medicine, 2000; 378-384. 15. fantz cr, powell c, karon b, et al. assessment of the diagnostic accuracy of the tdx-flm to predict fetal lung maturity. clin chem 2002; 48:342-345. 16. stevens t, blennow m, soll rf, et al. early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk of rds. cochrane data base syst rew, (2):cd003063, 2002. 17. wauer rr, schmalisch g. antenatal use of ambroxol to prevent hyaline membrane disease, a controlled double blind study. j biol res preg perinatol 1982; 84-86. 18. leurti m, lazzarin a, corbella e, et al. an alternative to steroids for prevention of respiratory distress syndrome, a multicenter controlled study to compare ambroxol and betamethasone. j perinat med 1987, 15:227-238. 19. laoag jb, fernandez z, maraot j, et al. antenatal use of ambroxol for the prevention of respiratory distress syndrome in infants. gynec research 2000, 26:307-312. 20. wauer rr, schmalisch g, bohme b. randomized double blind trial of ambroxol for the treatment of respiratory distress syndrome. eur j pediatr 1992, 151:357363. h e s h a m e l s ay e d , m e l k h a i o u b y, s e l s h a r k aw e y a n d m e l n e m r july 2008.indd sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 149-156 sultan qaboos university© submitted 27th april 2008 accepted 20th may 2008 medical education units history, functions, and organisation nadia m al-wardy most medical schools have well established independent medical educa-tion units or similar bodies. such units have various titles,1 but the ones in common use are: office, division, department, centre, and unit.2 in this paper, the term ‘medical education unit’ (meu) will be used to refer to such titles. the development of meus has been triggered by several factors such as curriculum reforms, need for faculty training, new methods for student selection, advances in medical informatics, the requirements from quality assurance and accreditation bodies, and education becoming a viable faculty career track. in the uk, in response to the recommendations of tomorrow’s doctors,3 many such units were established and charged with the responsibility for overseeing staff development. these units took on additional roles that were crucial to introducing changes in the curriculum.4, 5 the functions of meus include research, teaching, service and career development of staff and the scope of their activities ranges from undergraduate to postgraduate programmes and from uni-professional to multi-professional audiences. the balance of these activities varies according to the mission and scope of the units; however, the right balance is important for their continuity and stability.6 many meus started as administrative units in the medical school’s dean’s office,2 but then slowly evolved into independent academic units or departments. the medical education unit, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman email: naiwardi@squ.edu.om r e v i e w وحدات التعليم الطبي اإلداري التنظيم و الوظائف و التأريخ الوردي نادية تَلِفةُ وتَعمل خْ مُ عناوينُ لَها هذه الوحداتِ مثل الطبي. التعليم لتحسني شابهها ما أَو طبيةِ تعليم وحداتَ الطبيّةِ أكثر الكليّات ستْ ص: أَسّ امللخّ اخلدمات وتزويد التعليم إلى إضافة تربوية، بحوث راء إجْ ن يَتضمّ املذكورة الوحدات ــاط نش الكلية. عميد مكتبِ إشراف حتت أَو ــتقل مس ــكل بش إما ــتويات املس في اآلخرينِ الصحةِ محترفي لّ كُ ــمل ليش الطبيةِ الكليّةِ ة مَ دْ خِ ــاطاتِها نش مجالُ وقد يتعدى فني. للموظّ األكادمييِ ــتقبل وتطويرَ املس الطبية. الكليات على إيجابي أثر له أن تأسيسها وحداتِ التعليم الطبي ويرى جناحِ تُساهمُ في عوامل ة دّ عِ توجد بعدها. وما اجلامعية عمان. ، واإلدارة التنظيم ، الطبي الكلمات: التعليم مفتاح abstract most medical schools have established a medical education unit (meu) or similar bodies in response to various reforms in medical education. such units have a variety of titles and operate either independently or under the office of the dean. their activities include conducting educational research, teaching and providing service and career development of academic staff. the scope of their activities ranges from serving medical faculty only to all other health professionals at either the undergraduate or postgraduate levels. several factors contribute to the success of meus and their establishment is seen to have a positive effect on their medical school. keywords: education, medical. organisation and administration; oman. n a d i a m a l wa r d y 150 staff of the unit includes a range of expertise and comes from different professional backgrounds including medical and educational with part-time or full-time commitments. several sections can exist in the unit to fulfill its mission. backup and support is important to sustain meus. this support can come from the dean and higher administration. financial support can come from the medical school, university, government, or external sources. the establishment of meus has several positive effects on medical schools. it enhances the quality of medical education7, increases the publication of scholarly articles as well as the productivity of educational research8, 9, leading to the commitment of universities to their continuation.10 the units continue to provide important benefits to the educational mission of their institution and, by supporting the professional identity of medical education scholars, they are essential to the continued development of medical education as a discipline. this review attempts to document the development of such units, the need for their establishment, their functions and organisational structure, thus providing useful information for those intending to establish one. w o r l d w i d e d e v e l o p m e n t o f m e d i c a l e d u c a t i o n u n i t s many medical schools around the world have well established meus. however, the process of their establishment has been slow. from 1958, when the first medical education unit was started, until the 1970’s, there were only 72 meus worldwide.1 from then on, the number of meus steadily increased. in the usa, as of 2001, there were 61 formal meu.2 some of these units started as offices of research in medical education11, 12 while others have started as audiovisual units.13 in canada, the trigger for the establishment of meus was the innovative initiative of problem-based learning14 and in latin america, meus began to be established around 196815 as a result of lack of coordination in activities related to teaching and learning. in the uk, several meus were set up during the 1970s to support the undergraduate curriculum and to act as a national resource in medical education.1 several more were established as a result of financial support that was provided for medical schools to appoint facilitators to help faculty respond to the recommendations of tomorrow’s doctors. these facilitators, and the offices that supported them, were the precursors of many meus in britain.4, 5 now, all new medical schools in the uk have meus to help underpin teaching with a strong research base.16 in other countries in europe, meus were established in the universities of geneva, bern1, the university of maastricht17 and the università campus bio-medico, rome, italy.18 the who played a leading role in creating a system of regional teacher training centres (rttcs) to provide training to future national leaders to establish national centres in their countries. the creation of such a centre in iran in the early 1970s had a remarkable impact on the region.11 in south east asia, rttcs were established at the chulalongkorn university in thailand and the university of sri lanka.11, 19 these played a critical role in the establishment of the first national teacher training centres (nttcs) in philippines, republic of south korea, india, bangladesh, myanmar and other countries in the south east region of the world health organisation (who). in india, however, the withdrawal of funding to these nttcs led to their withering, but not before fostering the development of meus in other medical colleges.20 in china, the first medical education unit was established as a medical education research unit in china’s shanghai first medical university in october 1978. its purpose was to evaluate and promote the quality of medical education.7 later, more research units were established in china’s other medical schools. in south east asia, many medical schools have a medical education unit or a similar structure in place. the majority of these meus were established during or since 1990.21 in japan, only 8 meus were founded in 1995, but by the year 2000, the number of meus reached 20.22 in the african continent, meus were established in several medical schools in response to issues such as deteriorating student performance in medical exams,23 and the growing demands of the countries and the region for qualified medical teachers.24, 25 in australia, the rttc established by the who in sydney (which is also the centre for medical education at the university of new south wales) in the early 1970s, played an important role in creating a critical mass of concerned and informed individuals and in matching training programmes with the identified needs of a regional constituency.11, 26 later, curriculum reforms, with the introduction of gradum e d i c a l e d u c at i o n u n i t s 151 ate-entry programmes and new admission criteria, led to the establishment of several meus in the 1990s.10 now, almost all medical schools in australia have set up similar bodies to lead and support this curriculum reform.16, 27 a survey that was conducted to look at the establishment and role of meus in the gulf cooperation council (gcc) medical schools showed that 10 out of 13 medical schools had such units (unpublished data). meus exist in several medical colleges in saudi arabia, kuwait, bahrain, the united arab emirates and, recently, a medical education unit has been established in the college of medicine and health sciences at sultan qaboos university, oman. t h e n e e d f o r m e d i c a l e d u c a t i o n u n i t s c ur r i c ulum c h a n ge medical curricula around the world are undergoing reform. the introduction of new student selection criteria, integration of basic and clinical sciences, emphasis on relevance, increased attention to personal and professional development, problem-based and self-directed learning, the emphasis on information technology to support learning, community-based initiatives and the introduction of graduate-entry programmes are all major innovations to which medical schools have to respond. as a result, many medical schools have set up these units to lead, support and evaluate curriculum reform, with many being the driving force behind curriculum change.16 a c c r e d i tati o n r e q ui r e me n ts accreditation and quality assurance bodies are demanding greater scrutiny of the education process, the number and qualifications of teachers and teaching/ learning and assessment methods. this has resulted in the design of outcome-based curricula,28 audits of teaching, and appraisal activities that are now normal processes in many medical schools around the world. a medical education unit can provide major support for these initiatives and a home base for staff involved in this process.1 in fact, certain accrediting bodies list the existence of a medical education unit in their criteria for accrediting new medical schools. te a c h e r tr a i n i n g the increasing complexity of the curriculum with its new educational strategies, new assessment tools and the increased use of learning technologies, has led to the recognition that all those who teach require some background and training in education. the general medical council of the uk requires that training in teaching is provided even at undergraduate level.3 many universities conduct faculty development programmes for their teachers and make use of in-house, regional and international medical centre programmes, for this purpose.4 in fact, teaching constitutes a component, if not a major one, of promotion criteria in many medical school.4, 21, 29, 30 teacher training has proved pivotal in stimulating curricular changes and is becoming compulsory for all new staff members in some medical schools.21 in addition, many schools have encouraged their established staff, who have major teaching responsibilities, to undertake training leading to a recognised teaching certificate or diploma. in one medical school, consultants apply to become clinical teachers and are encouraged to undertake a postgraduate qualification in medical education. their teaching practice is reviewed as part of their regular appraisal and consistently poor performance would result in their teaching duties being withdrawn.31 meus can assist in this requirement of teacher training, a function that is provided by many such units around the world. in fact, some of the larger units organise award-bearing medical education programmes up to and including doctoral-level.17, 32, 33 it has been reported that this teacher training had “very much” improved medical education at their schools.34, 35 a dmi n i str ati v e n e e d due recognition is needed for faculty who undertake the responsibility of training staff and who conduct faculty development workshops in their ‘borrowed’ time. meus should create a proper administrative structure with appropriate job descriptions and reward structures leading to the recognition of the efforts of staff undertaking these activities on a part-time basis. f u n c t i o n s o f m e d i c a l e d u c a t i o n u n i t s the functions of meus vary from institution to institution; their scope of activities can include undergraduate and postgraduate education and continuing professional education. these activities could extend not only to medical professionals but also to other healthcare professions such as dentistry, pharmacy, medical technology and nursing. in general, the functions of meus span the areas of research, teaching, service, n a d i a m a l wa r d y 152 workshops, evaluation, consultancies, and the career development of staff.1, 36 r e se a r c h an essential mission of meus across institutions is to conduct research and provide scientifically sound information that advances and promotes medical education.6 the extent and priority of research in different meus depends on many identified factors such as access to research expertise, protected time for scholarship, funding (whether internal or external), the institutional culture of scholarship, educational leadership, the history of medical education innovation, the quality of faculty and the complementary areas of expertise they possess, critical mass of educational scholars, status of the medical education unit, response to accreditation bodies, mentorship, faculty development, access to learners, and growth of opportunities for advanced training in educational scholarship.9, 37-42 the areas of research also vary according to the mission of the unit and the need of the institution. in the faculty of medicine at the university of maastricht, for example, the initial focus of research was on the evaluation of problem-based learning, but this focus widened to include the areas of student and teacher learning, learning environments, and assessment and evaluation of learning and teaching.39 a wide variety of research is undertaken in other places, covering topics considered important to their governments, health system administration, communities and funding bodies.43 the areas include health services research, public health, workforce and career outcomes of medical courses and their relations to student characteristics, admission and selection procedures, curriculum development, and clinical reasoning and problem solving.44 based on a survey of 25 members of the society for directors of research in medical education (sdrme – an international organisation with primarily north american membership),39 the research areas of focus were (in rank order): assessment of competencies, curriculum, student assessment approaches, standardised patients, instructional design, computer-based education applications, patient simulations, institutional research, student selection, clinical decision making, medical informatics, faculty careers, patient education, continuing education, chronic diseases, health economics and disease prevention. meus play an important part in creating a culture of research by innovating, developing new approaches to medical education and publishing their findings. fellows of meus are authors of a substantial number of peer reviewed manuscripts.6, 37, 38 communication concerning research such as running journal clubs, circulating medical education newsletters, and conducting medical education rounds45 are also ways used by the units for promoting this culture. te a c h i n g the major role of the meu in the teaching aspect of their function is to help equip the teaching staff with the necessary abilities to undertake effectively their roles as medical teachers. teaching areas vary according to need. they can range from teaching and learning, medical student assessment and selection, curriculum development and evaluation, course design, research in medical education,1,15 instructional material design, and e-learning.1 again, based on a survey of 25 members of the sdrme39 the teaching areas of meus were (in rank order): research skills, educational methods, statistics, academic skills, test taking/preparation, computer applications, clinical education, medical humanities, clinical decision making, international medical education, enrichment programmes, basic sciences, patient education, health economics/policy, and disease prevention. some meus in gcc medical schools also took responsibility for running continuing medical education (cme) activities, conferences, workshops on evidence-based medicine and running the clinical skills laboratory. types of educational activities were workshops, seminar series, short courses, individual or augmented feedback and site visits. longitudinal programmes (e.g. fellowships, masters and phds) were also offered by some units. target audiences were both practising clinicians and basic scientists from either one or more disciplines34 or a mixture of health professionals. a wide range of instructional methods were used such as lectures, small-group discussions, interactive exercises, role plays and simulations, films and videotape reviews of performance. 34 se rv i c e pr ov i si o n many meus are service providers within an institution. for some, a service responsibility was the main rationale for their establishment.13 the service areas include: service on committees and task forces; consultancies to educational providers; curriculum development, planning and administration, for example, assistance m e d i c a l e d u c at i o n u n i t s 153 in defining objectives and curriculum organisation; assessment and evaluation, for example, curriculum and programme evaluation, test administration and scoring, developing and maintaining examination databanks; educational support services, for example, computer classroom/laboratory administration, computer support, standardised patient programme administration, clinical skills laboratory administration and preparation of teaching material; data analysis and statistical support; undergraduate and graduate student selection and admission to the medical programme;, coordination of clinical elective placements; mentoring and student counselling and other services such as media production, printing, copying, medical illustrations and graphics production. 1, 15, 39, 46 a c a d e mi c d e v e l o pme n t a n d supp o rt an important role of meus is to provide an academic home for and nurture the careers of faculty members wanting to focus on educational scholarship and develop as future medical educationists. by ensuring that these faculty members are given the necessary exposure to the field, and are allowed to develop their studies and publish research in medical education, meus help them to gain academic rewards and recognition for their expertise. o r g a n i s a t i o n a l s t r u c t u r e a dmi n i str ati v e stru c t ur e the structure and organisation of an meu depends on its position within the university’s structure i.e. whether it is within the medical school, within an institute of health sciences, or within the university. the units are usually administrative structures within the medical school dean’s office, but a few are free-standing departments. they are headed by persons who hold titles such as head,45 coordinator,47 director, chair, assistant or associate deans.2, 39 these lead persons report to individuals with 7 different administrative titles, again, depending on the position of the unit within the university. if within the medical school, then the lead person reports to the dean or associate dean; if outside the medical school, then he/she reports to vice-chancellor, vice-president, or vice-provost.39 si z e a n d sta ff pr o fi l e the size of the meu varies from very small to very large depending on its role in the wider institution. in north america, on average, meus employ 5 professional or faculty staff and 3 clerical staff or support staff.6 the degrees held by faculty/professional staff were mostly phd or edd while few were md. around 68% of heads has a phd while only 16% has an md.39 the technical support staff has varied titles: systems analyst, standardized patient coordinator, research scientist/statistician, instructional technology manager, information analyst, and data manager.39 the same author reported that the average number of years of experience of professional staff in medical education was seven and their average annual salary (based on 100% fte) 56,000 u.s. dollars. a mixture of tenure and non-tenure staff with full-time or parttime commitment contribute to the activities of the unit.1, 23, 39, 47 i n te r n a l o r g a n i sati o n different kinds of sections exist within meus depending on their size and mission. examples of these are course administration unit, computer assisted learning unit, clinical skills and simulation unit,46 community based education unit, ethics unit, staff development unit, communication skills unit, international programme unit, graduate studies unit, medical humanities unit, and research unit.1 fi n a n c i a l supp o rt financial support can come from the university, hospital, medical school or government funds.1 in australia, for example, grants from the health department enabled the establishment of meus in 3 universities.10 however, constraints on funding led the consortium of graduate medical schools in australia to create different resources for their programmes.27 in developing countries, the who played a substantial part in setting up meus in several medical schools.11, 20, 26 in the north american context the median budget for each medical education unit was $650,000 with 75% of support coming from ‘hard’ university funds. the remainder of support came from research and training grants, services, and contracts with other institutions and government agencies.6 on average, the level of unit activities supported by external funds accounted for approximately 16% of unit finances in 200239 which is in contrast to 25% in 1998.2 n a d i a m a l wa r d y 154 o p p o r t u n i t i e s a n d c h a l l e n g e s f o r t h e e s t a b l i s h m e n t a n d c o n t i n u a t i o n o f m e d i c a l e d u c a t i o n u n i t s the calls for reform in medical education created opportunities for the establishment of meus and the support came from a variety of sources, one of the key points of their success. financial support whether it is from the university, hospital, external, or from international programmes, is important at least at the early stages of setting up the unit.1 other important factors that contribute to the success and sustainability of the units are: meu leaders able to motivate and provide a role model;48 educational relevance and professional alignment of the activities of the units; diversity of ideas and research methodologies; access to research expertise; focused and collaborative research; a culture of mutual support and mentorship; a clear faculty development initiative; access to learners; and protected time for scholarship.37-42 several challenges are faced when setting up meu such as lack of full-time dedicated faculty, appropriate financial support, and finding the right balance between the research and service functions of the unit. many units employ part-time faculty, but demands on productivity in their own professions might restrict their participation in the activities of the unit. to encourage their involvement, appropriate reward structures need to be set up. appropriate financial support is needed for setting up the unit and a great deal of this comes from ‘hard’ university funds.6 however, at times when institutes are becoming increasingly dependent on research grants there is paucity of funding for medical education research.40, 49 finding the right balance between the research and service functions of the medical education unit is important for its continuity. if the unit concentrates on service at the expense of research, it will reduce its innovative capacity and wither. several units have closed or downsized because the sole responsibility of the unit was service provision.1 on the other hand, if the unit concentrates on research at the expense of service it might come into conflict with the administration of the medical school whose interest lies in solving immediate institutional needs and problems.6 finding the right point on the research-service continuum is a challenge. the units sometimes become entrapped in service provision because of the urgency of institutional needs. a solution for this would be to highlight to the medical school administration the enhanced reputation that the institute receives by being an innovator in educational research. members of the medical education unit can also learn from their service activities and so generate scholarship material relevant beyond the home institution. c o n c l u s i o n meus have been established in response to several contemporary needs. by providing specialised resources for teaching, service and a focus on educational research, they are essential to the continued development of medical education as a discipline. r e f e r e n c e s 1. davis m, karunathilake i, harden r. amee education guide no. 28: the development and role of departments of medical education. med teach 2005; 27:665–675. 2. albanese m, dottl s, nowacek g. offices of research in medical education: accomplishments and added value contributions. teach learn med 2001; 13:258–267. 3. tomorrow’s doctors: recommendations on undergraduate medical education. london: general medical council, 1993. 4. christopher d, harte k, george c. the implementation of tomorrow’s doctors. med educ 2002; 36:282-288. 5. bligh j. tomorrow’s doctors: extending the role of public health medicine in medical education. med educ 2002; 36: 206-207. 6. gruppen l. creating and sustaining centres for medical education research and development. med educ 2008; 42:121-122. 7. gao t, shiwaku k, fukushima t, isobe a,yamane y. medical education in china for the 21st century. med educ 1999; 33:768-773. 8. irby d, hodgson c, muller j. promoting research in medical education at the university of california, san francisco, school of medicine. acad med 2004; 79:981– 984. 9. elam c. medical education research at the university of kentucky college of medicine. acad med 2004; 79:985–989. 10. prideaux d, teubner j, sefton a, field m, gordon j, price d. the consortium of graduate medical schools in australia: formal and informal collaboration in medical education. med educ 2000; 34:449-454. 11. miller g. educating medical teachers. cambridge, ma: harvard university press, 1980. m e d i c a l e d u c at i o n u n i t s 155 12. rosinski e. the society of directors of research in medical education: a brief history. usa: society of directors of research in medical education, 1988. 13. engel c. teaching services in the medical school. who medical education bulletin 1, 2. geneva: who, 1966. 14. regehr g. report to canadian institutes of health research committee: research in medical education fund. ottawa, ca: association of canadian medical colleges, 2001. 15. munoz e. activities and strategy of an office or department of medical education. educ med salud 1976; 10:70-77. 16. pritchard l. changing course. med educ 2004; 38: 582586 . 17. university of maastricht, department of educational development & research. from http://www.educ.unimaas.nl accessed april 2008. 18. binetti p. medical education centres: strategies and purpose. clin ter 1999; 150:359-72. 19. sanusi r. medical education units. health policy educ 1982; 3:183-191. 20. supe a, and burdick w. challenges and issues in medical education in india. acad med 2006; 81:1076-1080. 21. amin z, eng k, gwee m, rhoon k, hoon t. medical education in south east asia: emerging issues, challenges and opportunities. med educ 2005; 39:829-832. 22. onishi h, yoshida i. rapid change in japanese medical education. med teach 2004; 26:403-408. 23. ofoegbu e, ozumba b. establishment of an office of medical education: nigeria. med educ 2007; 41:505. 24. fahal a. medical education in the sudan: its strengths and weaknesses. med teach 2007; 29:910-914. 25. suez canal university-joint master netherlands-egypt. from www.unimaas.nl/default.asp?template=werkveld. htm&id=dj6qr26xn5x4754h55o3&taal=nl 17k accessed april 2008. 26. rundle f. the who regional teacher training centre for the health sciences, sydney. aust fam physician 1976; 5:262. 27. prideaux d, saunders n, schofield k, wing l, gordon j, hays r, et al. country report: australia. med educ 2001; 35:495-504. 28. harden r, crosby j, davis m. an introduction to outcome-based education med teach 1999; 21:7-14. 29. simpson d, hafler j, brown d, wilkerson l. documentation systems for educators seeking academic promotion in us medical schools. acad med 2004; 79:783– 790. 30. simpson d, fincher r, hafler j, irby d, richards b, rosenfeld g et al. advancing educators and education by defining the components and evidence associated with educational scholarship. med educ 2007; 41:10021009. 31. leinster s. medical education in the real world. med educ 2003; 37:397-398. 32. university of dundee centre for medical education. from http://www.dundee.ac.uk/meded/frames/home. html accessed april 2008. 33. monash university centre for medical and health sciences education. from http://www.med.monash.edu. au/cmhse/ accessed april 2008. 34. steinert y, mann k, centeno a, dolmans d, spencer j, gelula m et al. a systematic review of faculty development initiatives designed to improve teaching effectiveness in medical education: beme guide no.8. med teach 2006; 28:497-526. 35. wilson s, denison a, mckenzie h. survey of clinical teaching fellowships. med educ 2008; 42:170-175. 36. gruppen l. report of the 2004 member survey society of directors of research in medical education (sdrme) north american units 2007. from http://www.sdrme. org/ accessed april 2008 37. irby d, cooke m, lowenstein d, richards b. the academy movement: a structural approach to reinvigorating the education mission. acad med 2004; 79:729-736. 38. thomas p, wright s, kern d. educational research at johns hopkins university school of medicine: a grassroots development. acad med 2004; 79:975-980. 39. van der vleuten c, dolmans d, de grave w, van luijk s, muijtjens a, scherpbier a et al. education research at the faculty of medicine, university of maastricht: fostering the interrelationship between professional and education practice. acad med 2004; 79:990-996. 40. gruppen l. the department of medical education at the university of michigan medical school: a case study in medical education research productivity. acad med 2004; 79:997-1002. 41. hodges b. advancing health care education and practice through research: the university of toronto, donald r wilson centre for research in education. acad med 2004; 79:1003-1006. 42. wolf f, schaad d, carline j, and dohner c. medical education research at the university of washington school of medicine: lessons from the past and potential for the future. acad med 2004; 79:1007-11. 43. searle j, prideaux d. medical education research: being strategic. med educ 2005; 39:544-546. 44. grover p et al. activities and trends in offices of research in medical education, 1974-1984. professions education researcher notes 1985; 6:3-6. 45. national university of singapore medical education n a d i a m a l wa r d y 156 unit. from http://www.med.nus.edu.sg/meu/index. shtml accessed february 2008. 46. medical education department, flinders university. from http://som.flinders.edu.au/staff/groups/deptmededuc/default.htm accessed january 2008. 47. continuing professional development at the faculty of medicine and health sciences: role of the medical education unit. from http://66.102.9.104/search?q=cache: ouqqriu2fzij:www.calm.unimas.my/insite9/article3. html accessed april 2008. 48. bordage g, foley r, goldyn s. skills and attributes of directors of educational programmes. med educ 2000; 34:206-210. 49. wartman s, o’sullivan, p. the case for a national center for health professions education research. acad med 1989; 64:295-299. december 2007 vol 8 after meeting.indd sultan qaboos university medical journal december 2007 vol 7, no. 3, p. 193-195 sultan qaboos university© submitted 11th september 2007 accepted 30th september 2007 hiv/aids vaccines how long must humanity wait? ali a al-jabri over forty million people are infected with the human immunodeficiency virus(hiv), the causative agent of acquired immunodeficiency syndrome (aids), and more than 95% of these infected individuals are in the developing countries. the prevalence levels for this virus will continue to rise globally. the hiv/aids pandemic is the most devastating global public health crisis since the great plagues of the middle-ages with approximately fifteen thousand new hiv infections and ten thousand deaths due to aids every day and approximately 3.1 million total deaths due to aids.1 historically, vaccines have proven to be the most effective weapon in our fight against infectious diseases such as small pox, polio, measles and yellow fever. hiv vaccines are our best hope to end the hiv pandemic. although successful vaccines have been developed for the common childhood diseases, the development of a vaccine against the aids virus is a much greater challenge. the best way to stop the spread of the disease and the suffering of aids patients is by the development of successful vaccines to prevent infection with hiv and delay or stop progression to aids. it is now two decades and a half since hiv was first discovered and researchers have spent millions of riyals (omani currency; 1 riyal = 2.6 us$) looking for possible candidates as vaccines, but what is the outcome of this research? it seems the discovery of a licensed and globally accessible hiv/aids vaccine is still years away, the question that arises is: how soon are we going to see a successful hiv/aids vaccine? more realistically, how long are we going to wait for such a vaccine? in this article, i will very briefly touch on the scientific hurdles that have impeded the search for an effective aids vaccine and discuss novel research approaches to accelerate its progress. despite important progression in the understanding of hiv pathogenesis2 and hiv/aids virus compared to any other viral disease, why are we still not able to produce an effective or even partially effective hiv/aids vaccine? the answer to this question lies in understanding how the virus evades the immune system. first, hiv disables the very cells that are responsible for fighting it. second, hiv is able to integrate its viral genome into the chromosome of the infected cells and therefore hide from recognition by the immune response for many years. third, hiv is able to conceal the protein components that can induce protective immune responses and therefore presents itself to the body in a way that makes it difficult for the immune system to respond effectively. fourth, hiv is genetically diverse and rapidly changing, particularly its outer envelope, and this allows the virus to evade most of the natural and protective immune mechanisms that the immune system is able to make. as soon as hiv infection becomes established, hiv continues to mudepartment of microbiology & immunology, college of medicine & health sciences, sultan qaboos university, p.o. box 35, al-khod 123, muscat, sultanate of oman. email: aaljabri@squ.edu.om e d i t o r i a l (االيدز) املناعة املكتسبة نقص ومتالزمة فيروس ضد اللقاحات تنتظر؟ أن البشرية على يجب الوقت من كم اهللا اجلابري عبد بن علي a l i a . a l j a b r i 194 tate genetically and many variants may arise within an infected person. therefore, investigators need to know the significance of strain variation within the individuals and among the populations when developing an effective hiv/aids vaccine. the most logical approach for designing an effective hiv/aids vaccine is to identify which immune responses are most protective against this virus infection and to construct a vaccine that is able to stimulate these protective responses. of the two main types of immune responses, the humoral immune response mainly uses antibodies to protect against a cell-free virus, whereas the cell mediated immune response is essential for body defense when the virus is hidden inside the cells. although earlier vaccine research focused primarily on vaccines that elicited antibodies, it is now generally believed that both arms of the immune response are required in order to control and prevent hiv infection. moreover, much attention has recently been directed towards vaccines that induce good innate (natural) immune responses particularly dendritic cells and toll-like receptors which play an important role in inducing and modulating the adoptive immune responses.3 the most practical goal for an hiv vaccine is to prevent hiv transmission rather than preventing infection with the virus. experts believe a vaccine is the only way to eradicate hiv/aids because the most common modes of transmission, sexual contact, injection drug use and mother-to-child transmission at childbirth or breast-feeding are impossible to eliminate completely. the main characteristics of a desirable hiv vaccine are: safety, simple administration as well as affordable cost, long lasting immunity and effective against all hiv subtypes. to develop such an hiv/aids vaccine there is a need for team work in fundamental basic research; preclinical screening for active candidates and appropriate animal model followed by product development, manufacturing, and clinical research.3 currently, there are more promising vaccine candidates being tested than ever before. vaccine candidates are being constructed based on isolates from different regions of the world, and several research groups are testing a cocktail or a mixture of different viral components from different isolates of hiv. in addition, to optimize the immune responses, new vaccine strategies are being tested [table 1]. the most current hiv vaccine candidates focus on producing cytotoxic cd4+ t cells, which attack hivinfected cells in the body; such vaccines might not prevent an hiv-negative person from contracting the virus, but would delay hiv from progressing to aids and prevent transmission to others. another challenge in vaccine research is that hiv strains vary among people and regions. vaccine trial participants are chosen based on health standards for industrialized nations and many people in developing countries are not healthy enough to participate in such trials.4 vaccineinduced antibodies that interfere with viral entry are the protective correlate of most existing prophylactic vaccines; however, for highly variable viruses such as hiv-1, the ability to elicit broadly neutralizing antibody responses through vaccination has proven to be extremely difficult. the major targets for hiv-1 neutralizing antibodies are the viral envelope glycoprotein trimers on the surface of the virus that mediate receptor binding and virus entry. hiv-1 has evolved many mechanisms on the surface of envelope glycoproteins to evade antibody-mediated neutralization, including subunit vaccines (a structural piece of hiv such as the envelope or a core protein) live vector vaccines (a live bacterium or virus modified to carry genes that encode hiv proteins). peptides (small pieces of hiv proteins). fusion protein vaccines (two proteins merged together). dna vaccines (direct injection of hiv-dna sequences). vaccine combinations such as the prime-boost strategy table 1: examples of hiv vaccine strategies h i v / a i d s va c c i n e s 195 the masking of conserved regions by glycan, quaternary protein interactions and the presence of immunodominant variable elements. the primary challenge in the development of an hiv-1 vaccine that elicits broadly neutralizing antibodies therefore lies in the design of suitable envelope glycoprotein immunogens that circumvent these barriers.5 individuals who are infected with hiv but remain healthy and keep viral replication in check may offer some hope for guiding the design of an effective hiv vaccine.6 some of these long-term survivors make a very small amount of antibody, which, when isolated, can neutralize hiv from patient isolates. further, those antibodies can neutralize viruses from many different patient isolates, which is necessary for an aids vaccine that will be effective against a broad spectrum of hiv strains. unfortunately, even these antibodies may not be the whole answer. tests of cells in culture indicate that the antibodies must be present at surprisingly high concentrations to block hiv entry into cells effectively. many researchers continue to look into developing a live, attenuated hiv vaccine despite safety concerns. because such a vaccine would closely mimic active hiv, it should theoretically be effective at inducing cellular immunity, antibody-based immunity and perhaps-other unknown modes of protection. by systematically deleting genes critical for hiv replication, scientists hope to develop a variant of the virus that can elicit a strong immune response without giving rise to aids.4 it also is hoped that vaccines may give the body an immunological ‘head start’ by priming the immune system to attack hiv as soon as it appears, rather than taking time to initiate a defense from scratch. as the pathogenesis of hiv infection has become better understood, investigators have realized that if the virus can be kept at low concentrations in the blood, an infected person may never progress to aids.7 this insight is encouraging because it suggests that even a partially effective vaccine could be valuable in limiting the amount of virus in patients, thus potentially reducing virus infectiousness and the aids symptoms. the multitude of scientists searching for successful aids vaccines will require appropriate funding and ample time. funding is now improving, but because of the above difficulties we may not see a vaccine in near future.8 governments need to cooperate to break barriers, reduce the stigma associated with hiv/aids, encourage hiv testing, provide support for people with hiv/aids and allocate appropriate funding to institutes that work for the development of hiv/aids vaccines. the development of appropriate antiviral therapy and reconstructing the damaged immune system are two approaches, both of which require significant financial support. for developing countries, educating the public on preventative measures is the first step in preventing and reducing the spread of hiv/aids. treating those infected with hiv or who have aids is also, of course, critical, but the real hope for the future lies in developing a successful vaccine. r e f e r e n c e s 1. who. report on global aids. 2006. 2. sailaja g, skountzou i, quan fs, compans rw, kang sm. human immunodeficiency virus-like particles activate multiple types of immune cells. virology 2007; 362:331-341. 3. kwissa m, villinger f, amara, rr, alkan s, robinson h, jabbar a, et al. harnessing dendritic cells and tlr ligands to enhance the immunogenicity of a plasmid dna/rmva prime boost vaccine against siv in rhesus macaques. 13th international congress of immunology, rio de janerio, brazil, aug 21-25, 2007. ms-71.1. 4. the jordon report. accelerated development of vaccines. national institues of health 2007. nih publication no. 06-6057. http://www.cdc.gov-vaccines-recsacip-downloads-mtg-slides-jun07/37-jordanrpt-curlin. pdf. accessed sept 2007. 5. phogat s, wyatt rt, karlsson hedestam gb. inhibition of hiv-1 entry by antibodies: potential viral and cellular targets. j intern med 2007; 262:26-43. 6. al-jabri aa. mechanisms of host resistance against hiv infection and progression to aids. sultan qaboos university medical journal 2007; 7:13-26. 7. rodríguez b, sethi ak, cheruvu vk, et al. predictive value of plasma hiv rna level on rate of cd4 tcell decline in untreated hiv infection. jama 2006; 296:1498-506. 8. day m. aids expert doubts vaccine will be found in near future. bmj 2007; 334:1133. department of emergency & critical care nursing, school of nursing & midwifery, iran university of medical sciences, tehran, iran *corresponding author’s e-mail: najafi.t@iums.ac.ir abstract: objectives: the family caregivers of patients undergoing coronary artery bypass graft (cabg) surgery experience considerable physical and emotional distress. this study aimed to investigate the effect of an educational support programme on caregiver burden among the family caregivers of patients undergoing cabg surgery in iran. methods: this non-randomised controlled clinical trial was conducted from january to april 2017 at a cardiovascular centre in tehran, iran. a total of 80 family caregivers of patients undergoing cabg surgery were sequentially selected and non-randomly assigned to intervention and control groups. the control group received routine care, whereas the intervention group received additional education sessions at baseline, prior to surgery, the day after surgery and before discharge. caregiver burden was compared at baseline and six weeks post-discharge using the persian-language versions of the caregiver burden inventory (cbi) and katz index of independence in activities of daily living (iadl). results: a significant difference was observed between family caregivers in the control and intervention groups with regards to pre-post differences in mean cbi scores (+1.67 ± 19.23 versus +17.45 ± 9.83; p <0.001), with an effect size of −1.14. in addition, there was a significant increase in mean post-discharge iadl scores among cabg patients in the intervention group compared to the control group (4.42 ± 1.05 versus 3.07 ± 1.09; p <0.001). conclusion: an educational support programme significantly reduced caregiver burden among the family members of patients undergoing cabg surgery in iran. as such, in addition to routine care, healthcare providers should provide educational support to this population to help mitigate caregiver burden. keywords: caregiver burden; coronary artery bypass surgery; patient education as topic; caregivers; education; quality of life; controlled clinical trial; iran. effect of an educational support programme on caregiver burden among the family members of patients undergoing coronary artery bypass graft surgery helen dalirirad, *tahereh najafi, naima seyedfatemi sultan qaboos university med j, may 2021, vol. 21, iss. 2, pp. e266–274, epub. 21 jun 21 submitted 14 may 20 revision req. 18 jun 20; revision recd. 26 jul 20 accepted 19 aug 20 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.2021.21.02.016 clinical & basic research advances in knowledge an educational programme was found to be effective in reducing caregiver burden among the family caregivers of patients undergoing coronary artery bypass graft surgery in iran. application to patient care healthcare providers should seek to decrease caregiver burden using appropriate educational programmes, such as the one described in this study. coronary heart disease is the one of the greatest causes of death worldwide, resulting in approximately 17.5 million deaths annually, of which 80% occur in lowand middleincome countries.1 coronary artery bypass graft (cabg) surgery is a potentially lifesaving treatment for heart disease; however, it can have debilitating physical and mental consequences.2,3 as such, patients often require a considerable degree of care before, during and immediately after surgery as well as during their lengthy recovery period. however, due to advancements in technology and recent changes in the healthcare system which have shortened the duration of hospital stay, patients with long-term and complex care needs are often taken care of at home by their family members.4 in addition, limitations in home care services have increased familial responsibility for providing patient care.5 family caregivers provide care to patients with chronic illnesses over multiple dimensions, including emotional and financial support during periods of hospitalisation, along with physical and organisational tasks related to managing postoperative pain, wound care, the administration of medications and changes in diet and lifestyle.6 these tasks result in increased stress on the part of the caregiver, potentially threatening their health and giving rise to chronic illnesses.7,8 many family caregivers report not feeling prepared for the burden and demands of caregiving for patients undergoing cabg surgery.8,9 although the majority of caregiving for patients undergoing cabg surgery usually falls on family members, most studies focus primarily on the needs of the patients, with few studies evaluating the burden on family caregivers, particularly in the middle east.10,11 a previous qualitative study explored caregiver burden https://creativecommons.org/licenses/by-nd/4.0/ helen dalirirad, tahereh najafi and naima seyedfatemi clinical and basic research | e267 among the family members of patients with heart failure in iran; the researchers identified four themes including lack of care-related knowledge, physical exhaustion, psychosocial exhaustion and lack of support, and emphasised the necessity of providing more effective social, informational and professional support to family caregivers.12 as such, this study aimed to investigate the effect of an educational support programme on caregiver burden among the family caregivers of patients undergoing cabg surgery in an urban area of iran. methods this non-randomised controlled clinical trial was conducted from january to april 2017 at a cardio vascular centre in tehran, iran. this 601-bed centre is one of the largest specialist and subspecialist heart centres in iran. family caregivers of patients undergoing cabg surgery at this centre were selected using a sequential sampling method. the inclusion criteria consisted of family members who had taken on the main role in providing care to the patient for at least two months and who could read, write and communicate in persian.10 individuals with physical and psychosomatic illnesses and those with a previous history of cardiac surgery or of caring for a patient undergoing cardiac surgery were excluded, as were those concurrently providing care to another person with physical or mental illness or employed as healthcare professionals. the necessary sample size was calculated to be 40 patients in each group based on a 95% confidence interval (ci) and type ii error of 0.2, assuming an effect size of 3 of the intervention on caregiver burden, a 10% drop-out rate and a standard deviation of 14.3 and 12.0 in the intervention and control groups, respectively.10 due to the possibility of contamination, sampling for the intervention group was conducted prior to sampling for the control group. in both instances, sampling was continued until the desired sample size was reached. due to the nature of the intervention, blinding of the research subjects was impossible. caregivers in the control group received only routine care including standard postoperative care education provided by a nurse and education pamphlets on the day of discharge from the hospital. in addition to routine care, caregivers in the intervention group underwent four educational sessions lasting 45–60 minutes. these sessions were conducted either in the staff room or the caregivers’ waiting room at four different time points: baseline (i.e. the beginning of the study), before the surgery, the day after the surgery and before discharge from the hospital. caregivers were taught by one of the researchers using various approaches including face-to-face learning, video tutorials, skill demonstrations and interactive discussions. in addition, the caregivers received educational materials in the form of a pamphlet and compact computer disc for perusal at home. at the beginning of each session, the educational content of the previous session were reviewed in terms of changes to the patients’ condition. further details of the educational programme are presented in table 1. subsequently, after the patients had been discharged from hospital, caregivers in the intervention group were contacted by telephone calls on a weekly basis to exchange information and provide support tailored to the subjects’ needs. this method of follow-up was employed since it is often used in clinical practice to support patients after discharge and is an easily accessible mode of communication. the telephone conversations included questions about the patient’s and caregiver’s physical, psychosocial and social health status, educational content, discussions and the provision of solutions to any problems. at the end of each call, an appointment was made to schedule the time and date of the next call. caregivers were also informed that they could contact the researcher in the meantime if they had any questions or faced any problems. conversations varied in length with an average duration of 10 minutes. the researcher also provided digital educational materials to the caregivers via a mobile social networking application. data were collected from the participants using a demographic data form, as well as the caregiver burden inventory (cbi) and the katz index of independence in activities of daily living (iadl).13,14 the demographic data form was developed and completed by the researchers during interviews with the subjects upon entering the study, in conjunction with a review of the patients’ health records. a persian version of the 24-item cbi tool was used to measure five dimensions of caregiver burden including time dependence (five items), evolution (five items), physical burden (four items), social burden (five items) and emotional burden (five items).13,15 responses to each item were measured on a 5-point likert scale in terms of frequency from 0 (never) to 4 (always). total scores ranged from 0–96, with scores of >36 indicative of a high burden on the caregiver.13 all of the individual dimension subscales had total scores ranging from 0–20, expect the third one, which had a total score ranging from 0–16. a previous study reported that the iranian version of the cbi was valid and reliable (cronbach’s alpha coefficient: 0.90).15 the version of effect of an educational support programme on caregiver burden among the family members of patients undergoing coronary artery bypass graft surgery e268 | squ medical journal, february 2020, volume 20, issue 1 the tool used in the current study was also found to have appropriate internal consistency (cronbach’s alpha coefficient: 0.946). a persian version of the six-item iadl was used to measure the functional status of the patients.14,16 this tool includes six questions regarding the individual’ ability to perform everyday activities including going to the bathroom, going to bed, eating, dressing, controlling their bladder/bowels and moving around. each item was scored out of 2, with a score of 1 indicating the patient’s independence in performing the task and a score of 0 indicating dependence on others. total scores ranged from 0–6, with scores of <3, 3–4 and 5–6 indicative of severe functional disability, moderate functional disability and complete independence, respectively.14 the iranian version of the tool has been found to be valid and reliable (cronbach’s alpha coefficient: 0.923).16 in the current study, the tool similarly had high internal consistency (cronbach’s alpha coefficient: 0.950). participants in both groups initially completed the cbi and iadl sections of the questionnaire at baseline, upon entering the study, and for a second time six weeks after discharge from the hospital. this follow-up duration was determined because cabg patients usually require up to a sixweek recovery period before being able to resume their normal daily activities.17 data were analysed using the statistical package for the social sciences (spss), version 13.0 (ibm corp., armonk, new york, usa). a kolmogorovsmirnov test was used to examine the normality of the distribution of the variables. comparisons between the groups were performed using an independent t-test, chi-squared test or fisher’s exact test, as appropriate. effect size was evaluated using cohen’s d method. a p value of <0.050 was considered statistically significant. a lack of participation of the subjects in one education session and patient/caregiver death were considered per-protocol analysis criteria resulting in exclusion of subjects from the study. permission to conduct this trial was granted by the ethics committee of the iran university of medical sciences (ir.iums.rec1395.9313677002). the research protocol was also registered with the iranian registry of clinical trials (irct #2016030526900n1). written informed consent was obtained from all subjects and patients prior to participation in the trial. all data were kept confidential and unique study identifiers were used to assure anonymity. collected data were kept in a locked file to which only the primary investigator had access. after completion of the study, all educational materials from the programme were also supplied to individuals in the control group. results a total of 80 family caregivers took part in the study, with no participants lost to follow-up or attrition. caregivers in the control and intervention groups were homogeneous in terms of all demographic characteristics, except for gender and previous experience receiving educational sessions [table 2]. however, an indep endent t-test confirmed that gender and previous education experience were not confounding variables. in addition, no significant differences were reported between the groups in terms of patient characteristics [table 3]. table 1: details of an educational support intervention for the family caregivers of patients undergoing coronary artery bypass graft surgery time of session content of session educational approach duration of session in minutes baseline • awareness of the hospital and different wards (i.e. open-heart care, postsurgery care, etc.) • anxiety and stress • coping skills and stress management 10 15 35 • face-to-face • skill demonstration • question and answer • pamphlet before the surgery • heart diseases and the cabg surgery • immediate postoperative care 30 15 • face-to-face • question and answer • video clips • pamphlet day after the surgery • medical condition and patient care after surgery • lung physiotherapy • wound care • diet and medication 45 • face-to-face • question and answer • video clips • skill demonstration before discharge from the hospital • home care • diet and medication • wound care • prevention of infection after surgery • readmission for followup visits • cardiac rehabilitation • surgical complications • postoperative activities 30 30 • question and answer • demonstration of skills • video clips • compact computer disc cabg = coronary artery bypass graft. helen dalirirad, tahereh najafi and naima seyedfatemi clinical and basic research | e269 at baseline, patients in both groups were completely independent. however, fewer patients in the control group were completely independent six weeks after discharge compared to those in the intervention group (12.5% versus 45%). nevertheless, the majority of patients in both groups were relatively independent (60% and 50%, respectively) [table 4]. there was a statistically significant difference with regards to mean iadl scores six weeks post-discharge (3.07 ± 1.09 versus 4.42 ± 1.05; t = 5.60; degrees of freedom = 78; p <0.001). at baseline, most caregivers reported a low level of caregiver burden, regardless of allocation to the control or intervention groups (75% and 60%, respectively). six weeks after discharge, the majority (80%) of subjects in the intervention group reported a low burden, whereas most caregivers (72.5%) in the control group reported a high burden [table 5]. table 6 presents a comparison of mean cbi scores for specific dimensions of caregiver burden at baseline and six weeks post-discharge in both groups. no significant difference was observed in mean cbi scores between the intervention and control groups at baseline (31.87 ± 21.45 versus 25.67 ± 14.97; p = 0.138). however, there was a statistically significant difference in mean scores post-discharge (33.55 ± 5.54 versus 43.12 ± 10.51; p <0.001). while the difference in prepost mean cbi scores increased from baseline in table 2: demographic characteristics according to group allocation* of family caregivers of patients undergoing coronary artery bypass graft surgery at a specialist heart centre in tehran, iran (n = 80) characteristic n (%) p value intervention group (n = 40) control group (n = 40) age in years 0.428 mean ± sd 39.20 ± 10.41 41.05 ± 10.35 gender 0.002† male 10 (25) 24 (60) female 30 (75) 16 (40) marital status 0.363 married 35 (87.5) 8 (50) single 5 (12.5) 32 (80.0) employment status 0.551 unemployed 1 (2.5) 3 (7.5) employed 13 (32.5) 15 (37.5) housewife 19 (47.5) 12 (30) self-employed 5 (12.5) 9 (22.5) retired 2 (5) 1 (2.5) education level 0.560 primary 4 (10) 5 (12.5) secondary 7 (17.5) 5 (12.5) diploma 13 (32.5) 18 (45) university 16 (40) 12 (30) self-reported income 0.500 sufficient 18 (45) 23 (57.5) somewhat sufficient 20 (50) 16 (40) insufficient 2 (5) 1 (2.5) person responsible for medical expenses 0.459 patient 27 (67.5) 30 (75) caregiver 13 (32.5) 10 (25) number of children among married participants (n = 35) (n = 32) 0.569 0 4 (11.4) 1 (3.1) 1 6 (17.1) 7 (21.9) 2 16 (45.7) 16 (50) 3 5 (14.3) 4 (12.5) 4 1 (2.9) 4 (12.5) >4 3 (8.6) 0 (0) history of illness‡ heart failure 7 (17.5) 1 (2.5) 0.057 hyperlipidaemia 6 (15) 7 (17.5) 0.762 diabetes 1 (2.5) 6 (15) 0.108 previous experience receiving educational sessions 0.040 yes 4 (10) 0 (0) no 36 (90) 40 (100) primary source of information about surgery 0.417 none 20 (50) 15 (37.5) healthcare personnel 5 (12.5) 7 (17.5) personal research 4 (10) 5 (12.5) media 4 (10) 0 (0) internet 7 (17.5) 6 (15) relatives 0 (0) 7 (17.5) sd = standard deviation. *the control group received normal care, whereas the intervention group received additional education sessions at baseline, prior to surgery, the day after surgery and before discharge. †statistically significant at p <0.050. ‡percentages for this variable do not add up to 100% as some subjects may have had more than one illness or none. effect of an educational support programme on caregiver burden among the family members of patients undergoing coronary artery bypass graft surgery e270 | squ medical journal, february 2020, volume 20, issue 1 both the intervention and control groups, there was a significantly smaller increase in the intervention compared to the control group (+1.67 ± 19.23 versus +17.45 ± 9.83; p <0.001). the effect size of the educational programme in reducing caregiver burden was high (effect size: −1.14; 95% ci: −1.61 to 0.67). with regards to specific dimensions of caregiver burden, there was a significant difference at baseline between the intervention and control groups in terms of mean cbi scores for the time dependence subscale (9.72 ± 5.30 versus 5.17 ± 4.14; p <0.001). no differences were noted between the groups at baseline for the other dimensions of the cbi tool. however, six weeks after discharge, significant differences in mean cbi scores were noted between the groups in terms of time dependence (7.47 ± 2.40 versus 11.22 ± 2.73; p <0.001), physical burden (6.55 ± 1.69 versus 8.15 ± 2.41; p = 0.007), social burden (6.37 ± 1.84 versus 5.62 ± 3.09; table 3: demographic characteristics according to group allocation* of patients undergoing coronary artery bypass graft surgery at a specialist heart centre in tehran, iran (n = 80) characteristic n (%) p value intervention group (n = 40) control group (n = 40) age in years mean ± sd 57.12 ± 9.64 58.15 ± 9.45 0.633 gender 0.459 male 30 (75) 13 (67.5) female 10 (25) 27 (32.5) education level 0.817 illiterate 4 (10) 3 (7.5) primary 14 (35) 15 (37.5) secondary 8 (20) 6 (15) diploma 9 (22.5) 13 (32.5) university 5 (12.5) 3 (7.5) living status 0.326 alone 2 (5) 1 (2.5) with children and spouse 35 (87.5) 38 (95) with children 3 (7.5) 0 (0) with parents 0 (0) 1 (2.5) time from diagnosis to surgery in weeks 0.313 >2 10 (25) 6 (15) 3–8 11 (27.5) 19 (47.5) 9–12 5 (12.5) 2 (5) 13–24 9 (22.5) 7 (17.5) ≥25 5 (12.5) 6 (15) history of illness† kidney failure 3 (7.5) 2 (5) 0.990 high blood pressure 20 (50) 24 (60) 0.369 hyperlipidaemia 21 (52.5) 14 (35) 0.115 diabetes 17 (42.5) 18 (45) 0.822 number of coronary arteries involved 0.833 1 2 (5) 1 (2.5) 2 7 (17.5) 9 (22.5) ≥3 31 (77.5) 30 (75) sd = standard deviation. the control group received normal care, whereas the intervention group received additional education sessions at baseline, prior to surgery, the day after surgery and before discharge. †percentages for this variable do not add up to 100% as some subjects may have had more than one illness or none. table 4: ability to perform activities of daily living* six weeks after discharge according to group allocation† among patients who had received coronary artery bypass graft surgery at a specialist heart centre in tehran, iran (n = 80) level of independence‡ n (%) intervention group (n = 40) control group (n = 40) dependent 2 (5) 11 (27.5) relatively independent 20 (50) 24 (60) completely independent 18 (45) 5 (12.5) *self-assessed using a persian version of the 6-item katz index of independ ence in activities of daily living index.14,16 †the control group received normal care, whereas the intervention group received additional educ ation sessions at baseline, prior to surgery, the day after surgery and before discharge. ‡total sum scores ranged from 0–6, with scores of <3, 3–4 and 5–6 indicative of severe functional disability, moderate functional disability and complete independence, respectively.14 table 5: changes in caregiver burden* at baseline and six weeks post-discharge according to group allocation† among family caregivers of patients undergoing coronary artery bypass graft surgery at a specialist heart centre in tehran, iran (n = 80) level of burden‡ n (%) intervention group (n = 40) control group (n = 40) baseline after 6 weeks baseline after 6 weeks low 24 (60) 32 (80) 30 (75) 11 (27.5) high 16 (40) 8 (20) 10 (25) 29 (72.5) *self-assessed using a persian version of the 24-item caregiver burden index tool.13,15 †the control group received normal care, whereas the intervention group received additional education sessions at baseline, prior to surgery, the day after surgery and before discharge. ‡total sum scores ranged from 0–96, with scores of ≤35 and >36 indicative of a low or high level of burden, respectively.13 helen dalirirad, tahereh najafi and naima seyedfatemi clinical and basic research | e271 p = 0.003) and emotional burden (6.37 ± 2.30 versus 10.32 ± 3.52; p <0.001), but not evolution (6.80 ± 1.91 versus 7.80 ± 2.98; p = 0.199). similarly, significant differences in pre-post mean cbi score changes from baseline were noted for all dimensions, except for social burden. the effect size of the educational programme was high for all dimensions apart from social burden. the relationship between caregiver burden and the patients’ ability to independently perform tasks was found to be nonsignificant using pearson’s correlation coefficient. therefore, patient ability was not considered a confounding variable. discussion family caregivers often experience a great deal of physical and emotional distress and require additional support to alleviate the burden of caregiving.11,18,19 as such, health problems not only impact the affected table 6: changes in specific dimensions of caregiver burden* at baseline and six weeks post-discharge according to group allocation† among family caregivers of patients undergoing coronary artery bypass graft surgery at a specialist heart centre in tehran, iran (n = 80) dimension mean sum cbi score‡ ± sd t value§ p value effect size (95% ci) intervention group (n = 40) control group (n = 40) time dependence baseline 9.72 ± 5.30 5.17 ± 4.14 4.27 <0.001¶ after 6 weeks 7.47 ± 2.40 11.22 ± 2.73 −6.51 <0.001¶ −1.45 (−1.95 to −0.96) change −2.25 ± 4.43 +6.05 ± 3.62 −9.16 <0.001¶ −2.05 (−2.59 to −1.51) evolution baseline 6.10 ± 6.05 4.67 ± 3.30 1.30 0.195 after 6 weeks 6.80 ± 1.91 7.80 ± 2.98 −1.78 0.199 −0.39 (−0.84 to 0.04) change +0.70 ± 6.06 +3.12 ± 2.31 −2.36 0.021¶ −0.52 (−0.97 to −0.08) physical burden baseline 5.72 ± 4.91 5.47 ± 2.90 0.27 0.783 after 6 weeks 6.55 ± 1.69 8.15 ± 2.41 −3.43 0.007¶ −0.76 (−1.22 to −0.31) change +0.82 ± 4.09 +2.67 ± 2.86 −2.34 0.022¶ −0.52 (−0.97 to −0.07) social burden baseline 4.22 ± 4.85 3.80 ± 3.13 0.46 0.643 after 6 weeks 6.37 ± 1.84 5.62 ± 3.09 1.31 0.003¶ −0.29 (−0.14 to 0.73) change +2.15 ± 4.74 +1.82 ± 2.31 0.38 0.698 −0.08 (−0.35 to 0.52) emotional burden baseline 6.10 ± 5.54 6.55 ± 4.78 −0.38 0.698 after 6 weeks 6.37 ± 2.30 10.32 ± 3.52 −5.93 <0.001¶ −1.32 (−1.81 to −0.84) change +0.27 ± 5.18 +3.77 ± 3.72 −3.46 0.001¶ −0.77 (−1.23 to −0.32) overall baseline 31.87 ± 21.45 25.67 ± 14.97 1.50 0.138 after 6 weeks 33.55 ± 5.54 43.12 ± 10.51 −5.1 <0.001¶ −1.14 (−1.61 to 0.67) change +1.67 ± 19.23 +17.45 ± 9.83 4.61 <0.001¶ −1.02 (−1.49 to −0.56) cbi = caregiver burden inventory; sd = standard deviation; df = degrees of freedom; ci = confidence interval. *self-assessed using a persian version of the 24-item cbi tool.13,15 †the control group received normal care, whereas the intervention group received additional education sessions at baseline, prior to surgery, the day after surgery and before discharge. ‡total sum scores for each dimension ranged from 0–20, except for physical burden which ranged from 0–16, with higher scores indicating greater caregiver burden.13 §degrees of freedom = 78. ¶statistically significant at p <0.050. effect of an educational support programme on caregiver burden among the family members of patients undergoing coronary artery bypass graft surgery e272 | squ medical journal, february 2020, volume 20, issue 1 patient, but also the health and quality of life of their family members and caregivers. previous research indicates that support and educational interventions may be effective in reducing caregiver burden and improving the physical and mental wellbeing of both the caregiver and patient.20–22 such interventions usually focus on increasing knowledge of the disease, enabling the caregiver to adapt to the realities of caring for the patient and promoting enhanced communication and problem-solving skills.20,21 robley et al. stressed the importance of alleviating stress among cabg patients and their family care givers by providing accurate and honest information throughout the diagnosis and treatment process, as well as promoting empathy among nurses, arranging routine telephone communications and providing bedside education and support.11 however, most previous studies assessing the effects of educational support programmes have focused on the family caregivers of patients undergoing palliative care and those with stroke, end-stage cancer and heart failure.23–28 moreover, there is a need to evaluate the effect of such interventions in different sociocultural settings, since sociocultural factors have been found to influence care behaviours and family relationships.29 the results of the current study showed that the implementation of an educational programme resulted in a significant reduction in caregiver burden among the family caregivers of patients undergoing cabg surgery in iran, with a substantial effect size. overall, significant differences in mean scores between the intervention and control groups were observed, both for overall summed cbi scores as well as mean scores for most specific dimensions of caregiver burden. these findings could be attributed to greater awareness among family caregivers in the intervention group regarding strategies for coping with and managing problems related to patient care. in addition, the educational support programme could have helped to decrease their anxiety and stress and improve their confidence. this is important as increased levels of stress among family caregivers have been found to have a direct relationship with depression and a negative relationship with self-confidence.30 moieni et al. previously reported that a familybased nursing intervention was effective in reducing caregiver burden among the family caregivers of patients undergoing cabg surgery in iran.10 similarly, etemadifar et al. found that a supportive educational group intervention was successful in reducing caregiver burden among the family caregivers of patients with heart failure in iran.31 however, ågren et al. indicated that a psycho-educational intervention had no effect on caregiver burden among the caregivers of patients with postoperative heart failure in sweden.32 these differences in findings could be related to variations in the research population and intervention protocols, particularly as the latter study was a pilot study involving a small sample.32 in the current study, the intervention and control groups demonstrated significant differences in caregiver burden in terms of time dependence and emotional burden. in particular, family caregivers who took part in the educational support programme had significantly lower mean cbi scores for these dimensions compared to those in the control group. moreover, the effect size of the educational programme in these dimensions was medium to high. ghane et al. previously reported that a supportive educative programme decreased caregiver burden among the family caregivers of haemodialysis patients in iran after six weeks, although effect size was not reported.33 overall, the greatest caregiver burden reported by subjects in the present study was in the time dependence dimension, regardless of group allocation. consistent with these findings, another study reported that the greatest caregiver burden among the caregivers of patients with coronary artery disease lay mainly in demands to the caregiver’s personal time.3 nasrabadi et al. found that implementation of a continuous care model led to a reduction in caregiver burden in the social dimension among the family caregivers of patients undergoing cabg surgery in iran.34 this is consistent with the results of the present study. such findings likely arise because participants receive information regarding patient management, as well as advice regarding coping with stress, thereby helping to improve their mental and emotional health and relieve their anxiety. in addition, baptista marques et al. found that social support was the second most used coping strategy by the family members of haemodialysis patients.35 this study was subject to certain limitations which may have affected the generalisability of the results. the study was conducted in a single centre, albeit one of the largest cardiac referral centres in iran. moreover, the non-randomisation of the group allocation assignments may have affected the results as there were more female caregivers in the intervention group, whereas the opposite was true for the control group. according to chappell et al., the majority of caregivers tend to be women.36 indeed, most family caregivers of elderly patients and those with chronic diseases in iran are female.37 moreover, cultural gender expectations relegate tasks associated with caring for children, patients, individuals with disabilities and older people to women as part of their household duties, along with other chores. helen dalirirad, tahereh najafi and naima seyedfatemi clinical and basic research | e273 conclusion caring for patients can have negative effects on the physical, psychological, emotional and social health of family caregivers. the current study found that an educational support programme was successful in significantly reducing caregiver burden among the family members of patients undergoing cabg surgery in iran. healthcare providers are therefore encouraged to incorporate additional educational support into the routine care of cabg patients in order to support family caregivers. c o n f l i c t o f i n t e r e s t the authors declare no conflicts of interest. f u n d i n g this study was funded by the iran university of medical sciences. references 1. world health organization. global status report on noncommunicable diseases 2014. from: www.who.int/nmh/publica tions/ncd-status-report-2014/en/ accessed: jul 2020. 2. hollis ib, jennings dl, oliphant cs, baker wl, davis em, allender je, et al. key articles and guidelines in the management of patients undergoing cardiac surgery. j pharm pract 2015; 28:67–85. https://doi.org/10.1177/0897190015570566. 3. mochari-greenberger h, mosca m, aggarwal b, umann t, mosca l. caregiver status: a simple marker to identify patients at risk for longer post-operative length of stay, rehospitalization or death. j cardiovasc nurs 2014; 29:12–19. https://doi. org/10.1097/jcn.0b013e318274d19b. 4. mcdonald j, mckinlay e, keeling s, levack w. complex home care: challenges arising from the blurring of boundaries between family and professional care. kōtuitui new zealand j soc sci online 2017; 12:246–55. https://doi.org/10.1080/11770 83x.2017.1373681. 5. theobald k, mcmurray a. coronary artery bypass graft surgery: discharge planning for successful recovery. j adv nurs 2004; 47:483–91. https://doi.org/10.1111/j.1365-2648.2004.03127.x. 6. sautter jm, tulsky ja, johnson ks, olsen mk, burton-chase am, lindquist jh, et al. caregiver experience during advanced chronic illness and last year of life. j am geriatr soc 2014; 62:1082–90. https://doi.org/10.1111/jgs.12841. 7. alzahrani sh, fallata eo, alabdulwahab ma, alsafi wa, bashawri j. assessment of the burden on caregivers of patients with mental disorders in jeddah, saudi arabia. bmc psychiatry 2017; 17:202. https://doi.org/10.1186/s12888-017-1368-1. 8. park eo, yates bc, schumacher kl, meza j, kosloski k, pullen c. caregiving demand and difficulty in older adult spousal care givers after coronary artery bypass surgery. geriatr nurs 2013; 34:383–7. https://doi.org/10.1016/j.gerinurse.2013.05.007. 9. halm ma. age and gender influences on the needs, concerns and strategies of cabg caregivers. heart lung 2017; 46:159–65. https://doi.org/10.1016/j.hrtlng.2017.01.012. 10. moieni m, poorpooneh z, pahlavanzadeh s. investigating the effect of family-focused nursing intervention on caregiver burden of the family members of the patients undergoing coronary bypass surgery in isfahan shahid chamran hospital during 2012. iran j nurs midwifery res 2014; 19:187–92. 11. robley l, ballard n, holtzman d, cooper w. the experience of stress for open heart surgery patients and their caregivers. west j nurs res 2010; 32:794–813. https://doi.org/10.1177/01939459 10361469. 12. bahrami m, etemadifar s, shahriari m, farsani ak. caregiver burden among iranian heart failure family caregivers: a descriptive, exploratory, qualitative study. iran j nurs midwifery res 2014; 19:56–63. 13. novak m, guest c. application of a multidimensional caregiver burden inventory. gerontologist 1989; 29:798–803. https://doi. org/10.1093/geront/29.6.798. 14. katz s, downs td, cash hr, grotz rc. progress in the develop ment of the index of adl. gerontologist 1970; 10:20–30. https://doi.org/10.1093/geront/10.1_part_1.20. 15. abbasi a, shamsizadeh m, asayesh h, rahmani h, hosseini sa, talebi m. [the relationship between caregiver burden with coping strategies in family caregivers of cancer patients]. iran j psychiatr nurs 2013; 1:62–71. 16. khoei ma, akbari me, sharifi f, fakhrzadeh h, larijani b. translation and validation of the activities of daily living scale with iranian elderly cancer patients treated in an oncology unit. asian pac j cancer prev 2013; 14:2731–7. https://doi.org/10.73 14/apjcp.2013.14.5.2731. 17. mendes m. is there a role for cardiac rehabilitation after coronary artery bypass grafting? there is no role for cardiac rehabilitation after coronary artery bypass grafting. circulation 2016; 133:2538–43. https://doi.org/10.1161/circulationaha.115.017800. 18. leigh es. the role of support in the physical and psychological health of coronary artery bypass graft surgery patients and their partners. ph.d. thesis, 2013, university college london, uk. 19. park b, kim sy, shin jy, sanson-fisher rw, shin dw, cho j, et al. prevalence and predictors of anxiety and depression among family caregivers of cancer patients: a nationwide survey of patient-family caregiver dyads in korea. support care cancer 2013; 21:2799–807. https://doi.org/10.1007/s00520-013-1852-1. 20. hudson p, payne s. family caregivers and palliative care: current status and agenda for the future. j palliat med 2011; 14:864–9. https://doi.org/10.1089/jpm.2010.0413. 21. hartmann m, bäzner e, wild b, eisler i, herzog w. effects of interventions involving the family in the treatment of adult patients with chronic physical diseases: a meta-analysis. psychother psychosom 2010; 79:136–48. https://doi.org/10.1159/000286958. 22. myaskovsky l, posluszny dm, schulz r, dimartini af, switzer ge, devito dabbs a, et al. predictors and outcomes of health-related quality of life in caregivers of cardiothoracic transplant recipients. am j transplant 2012; 12:3387–97. https://doi.org/10.1111/j.16 00-6143.2012.04243.x. 23. hafsteinsdóttir tb, vergunst m, lindeman e, schuurmans m. educational needs of patients with a stroke and their caregivers: a systematic review of the literature. patient educ couns 2011; 85:14–25. https://doi.org/10.1016/j.pec.2010.07.046. 24. lee kc, yiin jj, chao yf. effect of integrated caregiver support on caregiver burden for people taking care of people with cancer at the end of life: a cohort and quasi-experimental clinical trial. int j nurs stud 2016; 56:17–26. https://doi.org/10.1016/j. ijnurstu.2016.01.002. 25. hu x, dolansky ma, su y, hu x, qu m, zhou l. effect of a multidisciplinary supportive program for family caregivers of patients with heart failure on caregiver burden, quality of life, and depression: a randomized controlled study. int j nurs stud 2016; 62:11–21. https://doi.org/10.1016/j.ijnurstu.2016.07.006. 26. liljeroos m, ågren s, jaarsma t, årestedt k, strömberg a. long-term effects of a dyadic psycho-educational intervention on caregiver burden and morbidity in partners of patients with heart failure: a randomized controlled trial. qual life res 2017; 26:367–79. https://doi.org/10.1007/s11136-016-1400-9. https://doi.org/10.1177/0897190015570566 https://doi.org/10.1097/jcn.0b013e318274d19b https://doi.org/10.1097/jcn.0b013e318274d19b https://doi.org/10.1080/1177083x.2017.1373681 https://doi.org/10.1080/1177083x.2017.1373681 https://doi.org/10.1111/j.1365-2648.2004.03127.x https://doi.org/10.1111/jgs.12841 https://doi.org/10.1186/s12888-017-1368-1 https://doi.org/10.1016/j.gerinurse.2013.05.007 https://doi.org/10.1016/j.hrtlng.2017.01.012 https://doi.org/10.1177/0193945910361469 https://doi.org/10.1177/0193945910361469 https://doi.org/10.1093/geront/29.6.798 https://doi.org/10.1093/geront/29.6.798 https://doi.org/10.1093/geront/10.1_part_1.20 https://doi.org/10.7314/apjcp.2013.14.5.2731 https://doi.org/10.7314/apjcp.2013.14.5.2731 https://doi.org/10.1161/circulationaha.115.017800 https://doi.org/10.1007/s00520-013-1852-1 https://doi.org/10.1089/jpm.2010.0413 https://doi.org/10.1159/000286958 https://doi.org/10.1111/j.1600-6143.2012.04243.x https://doi.org/10.1111/j.1600-6143.2012.04243.x https://doi.org/10.1016/j.pec.2010.07.046 https://doi.org/10.1016/j.ijnurstu.2016.01.002 https://doi.org/10.1016/j.ijnurstu.2016.01.002 https://doi.org/10.1016/j.ijnurstu.2016.07.006 https://doi.org/10.1007/s11136-016-1400-9 effect of an educational support programme on caregiver burden among the family members of patients undergoing coronary artery bypass graft surgery e274 | squ medical journal, february 2020, volume 20, issue 1 27. holm m, årestedt k, carlander i, fürst cj, wengström y, öhlen j, et al. short-term and long-term effects of a psycho-educational group intervention for family caregivers in palliative home care: results from a randomized control trial. psychooncology 2016; 25:795–802. https://doi.org/10.1002/pon.4004. 28. azizi a, khatiban m, mollai z, mohammadi y. [the effect of informational support on satisfaction of family caregivers of patients with hemiplegic stroke from receiving information]. avicenna j nurs midwifery care 2018; 26:211–18. https://doi. org/10.30699/sjhnmf.26.4.211. 29. dunbar sb, clark pc, quinn c, gary ra, kaslow nj. family influences on heart failure self-care and outcomes. j cardiovasc nurs 2008; 23:258–65. https://doi.org/10.1097/01.jcn.000030 5093.20012.b8. 30. kim d. relationships between caregiving stress, depression, and self-esteem in family caregivers of adults with a disability. occup ther int 2017; 2017:1686143. https://doi.org/10.1155/ 2017/1686143. 31. etemadifar s, bahrami m, shahriari m, farsani ak. the effective ness of a supportive educative group intervention on family caregiver burden of patients with heart failure. iran j nurs midwifery res 2014; 19:217–23. 32. ågren s, strömberg a, jaarsma t, luttik ml. caregiving tasks and caregiver burden: effects of an psycho-educational intervention in partners of patients with post-operative heart failure. heart lung 2015; 44:270–5. https://doi.org/10.1016/j.hrtlng.2015.04.003. 33. ghane g, farahani ma, seyedfatemi n, haghani h. [effectiveness of supportive educative program on the burden in family caregivers of hemodialysis patients]. nurs midwifery j 2017; 14:885–95. 34. nasrabadi t, sharafi s, fallahtafti b, vaezi aa, heidari mr. [investigating the effect of continuous care model on social health status of family caregivers in hospitalized patients undergoing coronary artery bypass graft surgery]. j shahid sadoughi univ med sci 2016; 24:513–23. 35. baptista marques fr, botelho mr, marcon ss, lenzi pupulim js. coping strategies used by family members of individuals receiving hemodialysis. text context nurs 2014; 23:915–24. https://doi.org/10.1590/0104-07072014002220011. 36. chappell nl, dujela c, smith a. caregiver well-being: inter sections of relationship and gender. res aging 2015; 37:623–45. https://doi.org/10.1177/0164027514549258. 37. farahani ma, bahloli s, jamshidiorak r, ghaffari f. investigating the needs of family caregivers of older stroke patients: a long itudinal study in iran. bmc geriat 2020; 20:313. https://doi. org/10.1186/s12877-020-01670-0. https://doi.org/10.1002/pon.4004 https://doi.org/10.30699/sjhnmf.26.4.211 https://doi.org/10.30699/sjhnmf.26.4.211 https://doi.org/10.1097/01.jcn.0000305093.20012.b8 https://doi.org/10.1097/01.jcn.0000305093.20012.b8 https://doi.org/10.1155/2017/1686143 https://doi.org/10.1155/2017/1686143 https://doi.org/10.1016/j.hrtlng.2015.04.003 https://doi.org/10.1590/0104-07072014002220011 https://doi.org/10.1177/0164027514549258 https://doi.org/10.1186/s12877-020-01670-0 https://doi.org/10.1186/s12877-020-01670-0 submitted 30 may 22 1 revision req. 6 jul 22; revision recd. 1 aug 22 2 accepted 31 aug 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.71 5 6 nil intervention is at times the best intervention 7 benign emptying of pneumonectomy space 8 pratap upadhya,1 *muniza bai,2 veeraraghavan gunasekaran,3 dharm p. 9 dwivedi,1 shahana m.p.1 10 11 1department of pulmonary medicine, jawaharlal institute of postgraduate medical education 12 and research (jipmer), puducherry, india; 2department of pulmonary medicine, critical 13 care and sleep medicine, all india institute of medical sciences, new delhi, india; 14 3department of radiodiagnosis, jawaharlal institute of postgraduate medical education and 15 research (jipmer), puducherry, india. 16 *corresponding author’s e-mail: muzuni123@gmail.com 17 18 abstract 19 a sudden drop of air-fluid level in the pneumonectomy space in the absence of a 20 bronchopleural fistula and pleural infection is termed benign emptying of the post 21 pneumonectomy space (beps). we herein report a case of benign emptying of 22 pneumonectomy space, briefly review the literature and enumerate possible mechanisms for 23 the same. it is an extremely rare entity and follows a benign course. patients with beps are 24 clinically stable, afebrile with no fluid expectoration, and have a normal white blood cell 25 count. bronchoscopy reveals an intact bronchial stump and pleural fluid cultures are often 26 sterile. close monitoring and early detection of a bronchopleural fistula is the management. 27 clinicians should keep beps among the differential diagnosis in case of a drop in the air-28 fluid level of the post pneumonectomy space. awareness of this entity is crucial as it helps 29 prevent unnecessary and morbid surgical interventions. 30 keywords: pneumonectomy; beps; bronchopleural fistula; india. 31 32 introduction 33 pneumonectomy, the surgical resection of an entire lung is associated with significant 34 perioperative morbidity and mortality. the understanding of the normal physiology and chest 35 radiography post pneumonectomy is imperative to pick up complications early. immediately 36 following pneumonectomy, air fills the postpneumonectomy space. within 24 hours, the 37 ipsilateral diaphragm becomes slightly elevated, mediastinum gets slightly shifted to the 38 contralateral side and fluid accumulation commences in the postpneumonectomy space. in the 39 early postoperative period, fluid accumulation occurs at the rate of one to two intercostal spaces 40 per day.1 within 2 weeks, 80-90% of the space gets filled with fluid.1 a drop in the air-fluid 41 level should evoke the suspicion of a possible bronchopleural fistula.2 similar radiologic 42 picture in the absence of bronchopleural fistula and associated infection points towards a lesser 43 known entity, benign emptying of pneumonectomy space.3 we herein report a case of benign 44 emptying of pneumonectomy space, briefly review the literature and enumerate possible 45 mechanisms for the same. 46 47 case report 48 a 28-year young woman, a known case of type 1 diabetes mellitus was admitted in view of 49 diabetic ketoacidosis in the month of september 2020. she presented with complaints of 50 multiple episodes of vomiting. she had no history of cough with expectoration, breathlessness, 51 chest pain, or fever. the clinical diagnosis of dka was made in view of elevated plasma 52 glucose, positive urinary ketones and acidosis in arterial blood gas analysis. 53 54 her history revealed that she was diagnosed to have sputum smear-positive pulmonary 55 tuberculosis with left-sided secondary spontaneous pneumothorax in august 2017 (figure1a). 56 left-sided chest tube insertion was done at that time for the pneumothorax. she also received 57 category1 weight-based anti-tuberculosis treatment for 6 months and was declared cured. in 58 view of left lung persistent hydropneumothorax with pleural thickening (a trapped lung) in 59 spite of chest tube in situ (figure1b) and tuberculosis drug treatment she underwent left-sided 60 pneumonectomy in july 2018 through posterolateral thoracotomy. she was discharged on the 61 fifth postoperative day without chest tube or any complications. a chest radiograph taken in 62 her follow up visit two weeks after discharge demonstrated the expected fluid increase in the 63 post pneumonectomy space (figure 1c). 64 65 however, a routine chest radiograph taken during this admission revealed a drop in the air-fluid 66 level in the left hemithorax (figure1d). this incidental finding raised the alarms of a possible 67 bronchopleural fistula. but surprisingly, she had no specific respiratory complaints. her pulse 68 rate was 70 beats per minute, blood pressure 110/70 mmhg, room air oxygen saturation was 69 96%, and respiratory rate 18 breaths per minute. she was afebrile with benign physical 70 examination findings except for decreased air entry on the left side of chest. so, we elected to 71 work up and not hurry up with a chest tube insertion. her total white blood cell count and 72 routine biochemistry were reported normal. in view of recurrent vomiting episodes, an 73 ultrasound abdomen was done and reported normal. pleural fluid diagnostic aspirate was sent 74 for culture which was reported sterile.the patient did not receive any course of antibiotics as 75 she did not have any clinical features suggestive of infection. she was afebrile, no purulent 76 expectoration, normal total leucocyte count and sterile pleural fluid culture report. 77 78 given the ongoing covid pandemic, a virtual bronchoscopy reconstruction was done from 79 high resolution computed tomography of the thorax instead of diagnostic flexible 80 bronchoscopy to rule out bpf (figure 2). it showed linear thin fenestrated membranes partially 81 occluding the lumen of the left main bronchus, beyond which soft density was seen, probably 82 collapsed lung parenchyma or scar tissue with suture material. no obvious bronchopleural 83 fistula was noted. 84 85 these favored a diagnosis of benign emptying of pneumonectomy space. she was 86 conservatively managed and duly discharged once plasma glucose levels were controlled. 87 repeat chest radiograph after two weeks revealed reaccumulation of fluid in the 88 postpneumonectomy space, reinstating our diagnosis (figure 1e). informed written consent 89 was obtained from the patient and attenders to share patient information and radiology images. 90 91 discussion 92 the possible pulmonary complications of pneumonectomy are pulmonary edema, 93 postpneumonectomy syndrome and intraoperative spillage. the extrapulmonary complications 94 include post pneumonectomy empyema, post pneumonectomy syndrome, esophagopleural 95 fistlula, chylothorax, acute hemothorax, contralateral pneumothorax and bronchopleural fistula 96 is one among these. a drop in the air-fluid level within the post pneumonectomy space in an 97 erect chest radiograph is often considered pathognomonic of bronchopleural fistula (bpf). it 98 is a lethal condition and warrants early intervention in the form of prompt and urgent drainage 99 by chest tube insertion. the reported incidence of bpf after pneumonectomy is 0-9% and the 100 associated mortality rate is 16-23%.3 patients with bpf usually have clinical features of cough 101 with fluid expectoration, fever, and breathlessness. some may present with new infiltrates in 102 the contralateral lung due to trans-bronchial spill. other radiographic presentations include 103 persistent or increasing pneumothorax despite adequate drainage via chest tube, progressive 104 mediastinal or subcutaneous emphysema, or mediastinal shift to the contralateral side. a 105 decrease in the height of the fluid column by 1.5cm or more is suggestive of bpf.4a decrease 106 in the fluid level less than 1.5cm can be ignored unless there is an associated mediastinal shift 107 to the contralateral side or features of infection.5 108 109 the confirmation of bpf can be done using bronchoscopy and/or contrast enhanced chest 110 tomography(cect). other methods include contrast bronchography, intrapleural methylene 111 blue administration, and ventilation scintigraphy.6 bronchoscopic examination of the bronchial 112 stump is the most commonly used method to confirm the diagnosis of bpf. to identify bpf, 113 bronchial stump immersed in saline is visualized under positive pressure ventilation or can be 114 done by visualization of continuous air bubbles on lavage. once diagnosed, the fistula needs 115 to be repaired. ct chest with airway virtual reconstruction is an alternative and safer option to 116 confirm or rule out bpf as it is easier to perform, faster and also allows better visualization of 117 the fistula tract. 118 119 a similar drop in the air-fluid level of pneumonectomy space without the existence of bpf is 120 termed benign emptying of pneumonectomy space (beps). it is a rare condition which may be 121 misdiagnosed and mismanaged as a bpf. the calculated incidence of beps is reported as 0.65 122 of pneumonectomies.3 such patients are often asymptomatic, clinically stable, and do not 123 require any urgent intervention. they are often afebrile with normal white blood cell count and 124 sterile pleural fluid culture. bronchoscopy reveals an intact bronchial stump with no fistula. 125 126 the possible mechanism behind beps might be (1) the presence of an occult fistula that heals 127 spontaneously before seeding and the occurrence of infection, (2) the presence of a valve-like 128 fistula of a small caliber that allows the passage of only air and does not allow the fluid to enter 129 the airway or a large number of bacteria to enter the pleural cavity to fuel an infection.3 a 130 transient microscopic and spontaneously healing fistula is the most accepted mechanism. the 131 transit of air into the pleural space causes an increase in the intrapleural pressure forcing the 132 fluid out of the hemithorax into the surrounding cavities or tissues. three potential routes for 133 the pleural fluid to break free from the pleural space are (1) congenital diaphragmatic 134 fenestrations in individuals with porous diaphragm syndrome (2) diaphragm and peritoneal 135 defects formed at the time of extra pleural pneumonectomy and diaphragm reconstruction (3) 136 failure to produce watertight chest wall closure helps pleural fluid to escape into the 137 surrounding soft tissues, often resulting in an entity called woody chest wall.8.9 (1) and (2) 138 allow the egress of pleural fluid into the abdomen. 139 140 in 2011, merritt et al surveyed 28 leading thoracic surgeons across the united states to acquire 141 an estimate of the incidence and varied clinical presentations of beps. based on their 142 observations, a strict clinical and laboratory criterion was described to confidently diagnose 143 beps.3 the criteria include absence of fever, normal white blood cell count, no fluid 144 expectoration, negative bronchoscopy, and negative pleural fluid cultures if performed.3 our 145 patient met the afore-mentioned criteria. it is important to note that a diagnostic pleural tap 146 could have been avoided in this case as she did not have any clinical features suggestive of 147 infection. interestingly, a higher incidence of beps was noted following right lung resections 148 compared to the left, unlike our case. right-sided predisposition can be due to the shorter length 149 and lesser concealment of the right bronchial stump and greater chances of ischemia when 150 blood is supplied by a single bronchial artery. 151 152 beps is managed conservatively, and the pneumonectomy cavity quickly refills over time. 153 watchful waiting is the right approach. such patients should be followed up closely with repeat 154 chest radiographs every 1-2 weeks until pleural fluid reaccumulates.3 patients should be 155 counseled of the red flag signs suggestive of bpf and concomitant infection of the 156 pneumonectomy space. empirical oral antibiotics are not recommended in beps. 157 158 conclusion 159 clinicians should keep beps among the differential diagnosis in case of a drop in the air-fluid 160 level of the post pneumonectomy space. a drop in air fluid level of the post pneumonectomy 161 space is not always a pointer to bronchopleural fistula and does not warrant an intercostal drain 162 placement or a surgical intervention. it can just be a benign emptying of pneumonectomy space 163 which does not require any intervention. a right diagnosis of beps, when clinched early, will 164 avoid unnecessary, costly, and morbid surgical interventions. 165 166 167 authors’ contribution 168 pu and dpd provided care for the patient. vg and smp collected the data. dpd supervised 169 the work. mb and pu drafted the manuscript. all authors critically reviewed the manuscript 170 while mb and smp edited the manuscript. all authors approved the final version of the 171 manuscript. 172 173 acknowledgements 174 we are grateful to dr sivaselvi and dr lakshmi s residents of the department of pulmonary 175 medicine, jipmer for the help rendered in diagnosis, workup and patient care. 176 177 references 178 1. paone g, rose gd, giudice gc, cappelli s. physiology of pleural space after pulmonary 179 resection. journal of xiangya medicine. 2018 mar 14;3(3). 180 2. hollaus ph, lax f, el-nashef bb, hauck hh, lucciarini p, pridun ns. natural history of 181 bronchopleural fistula after pneumonectomy: a review of 96 cases. ann thoracsurg 182 1997;63:1391–1396. 183 3. merritt re, reznik si, dasilva mc, sugarbaker dj, whyte ri, donahue dm, hoang cd, 184 smythe wr, shrager jb. benign emptying of the postpneumonectomy space. ann 185 thoracsurg 2011;92:1076–1081. 186 4. lauckner me, beggs i, armstrong rf. the radiological characteristics of bronchopleural 187 fistula following pneumonectomy. anaesthesia 1983;38: 452– 456. 188 5. wechsler rj, goodman lr. mediastinal position and air-fluid height after 189 pneumonectomy: the effect of the respiratory cycle. ajr am j roentgenol 190 1985;145:1173–1176. 191 6. nielsen kr, blake lm, mark jb, et al localization of bronchopleural fistula using 192 ventilation scintigraphy. j nucl med 1994;35,867–9. 193 7. sarkar p, patel n, chusid j, shah r, talwar a. the role of computed tomography 194 bronchography in the management of bronchopleural fistulas. j thorac imaging. 2010 195 feb;25(1):w10-3. doi: 10.1097/rti.0b013e31819d12f1. pmid: 20160584. 196 8. kirschner pa. porous diaphragm syndromes. chest surg clin n am 1998;8:449–72. 197 9. cerfolio rj, bryant as. efficacy of video-assisted thoracoscopic surgery with talc 198 pleurodesis for porous diaphragm syndrome in patients with refractory hepatic 199 hydrothorax. ann thorac surg 2006;82:457–9. 200 201 202 figure 1: chest radiographs showing a left side pneumothorax with tracheal and mediastinal 203 shift to the right, b – persistent left hydropneumothorax with left chest tube in place, c –totally 204 filled up post pneumonectomy space (july 2018), d – drop in the air fluid level in the 205 pneumonectomy space (september 2020), e – reaccumulation of fluid in the post 206 pneumonectomy space (2 weeks later). 207 208 209 figure 2: image of virtual bronchoscopy reconstruction showing linear thin fenestrated 210 membranes partially occluding the lumen of the left main bronchus and an intact left bronchial 211 stump with no evidence of bronchopleural fistula. 212 march 2007 vol 7 isuue 1 final without suicide .indd sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© department of general surgery and radiology, roya; medical services p o box 849, princess haya hospital, aqaba, jordan. *to whom correspondence should be addressed. email: mazenonline64@yahoo.com the role of computed tomography in blunt abdominal trauma *mazen i hamidi, khalid m aldaoud, izzeddin qtaish abstract objective: to determine the utility of the computed tomography (ct) scan in blunt abdominal trauma and to compare it with operative findings or clinical outcomes. methods: a retrospective analysis based on existing, diagnostic ct scan reports taken during a 5 year period from 245 consecutive patients with blunt abdominal trauma. percentages and types of trauma identified were based on ct scan findings. recorded data included age, sex, type of injuries and scan results. the ct findings were compared and correlated with the operative findings, or clinical follow-up in conservatively managed cases. results: of the total of 245 patients, 3 (46%) underwent surgery. one hundred and thirty two (54%) patients were conservatively managed. there were 2 (4.9%) deaths. hemoperitoneum were detected in 70 patients. all 52 patients with small hemoperitoneum on ct scan were conservatively managed and all 22 patients with large hemoperitoneum required surgical exploration. there were 95 splenic, 63 renal, 48 hepatic and 3 pancreatic injuries. twenty one patients had bowel injuries. five patients had vascular injuries. twenty three patients had multi-organ injuries. organ injuries were graded using the ois (organ injury scale) guidelines. conclusion: in conjunction with close clinical monitoring, ct was reliable in the evaluation of blunt abdominal trauma in a selected group of patients, with overall sensitivity of 97% and specificity of about 95%. positive predictive value 82% and negative predictive value 00%. key words: blunt abdominal trauma, ct scan. عن الكشف في ب) َوسَ احملُ يّ عِ طَ املَقْ رُّسٌ (التَفَ املقطعية االشعة دور ليلَة الكَ البطن اصابات الدين قطيش وعز الداوود خالد احلميدي، مازن بعد ما بنتائج ومقارنتها الكليلة البطن اصابات ــف في كش ب) َوسَ احملُ يّ عِ طَ َقْ امل رُّسٌ (ألتَفَ املقطعية ــعة االش ــتعماالت اس امللخص: الهدف: حتديد البطن الصابات 245 مريضا تعرضوا نتائج مت مقارنة التحليلية ــتعادية ــة االس الدراس الطريقة: في هذه ــريرية. الس التداخالت اجلراحية والفحوص املقطعية، ومت االشعة نتائج على اعتمادا حتديدها مت فقد املئوية ــبتها ونس االصابة نوع اما .(2004 1999الى (من ــنوات س الكليلة خالل فترة خمس العمليات في التي شوهدت تلك املقطعية مع االشعة من عليها حصلنا التي النتائج .قارنا االصابة ونوع واجلنس العمر مثل االخرى املعلومات تسجيل ،(46%) 113 جراحيا معاجلة مت 245 مريضا, مجموع : من النتائج . حتفظيا عوجلت التي للحاالت زبارات املتابعة أو املالحظات السريربة في اجلراحية، ــيمهم تقس 170 مريضا،حيث مت عند جوفي نزف عن ــف مت الكش 12 حالة وفاة. هناك كان . . حتفظية (54% – 132) الباقني معاجلة كانت بينما حتفظيا, معاجلتهم ومت 52 مريضا، في خفيفة االصابة كانت حيث ،( ــديد وش ــط متوس خفيف, ) اجلوفي النزف كمية حيث من مجموعات ثالث الى 63 اصابة , 95 اصابة طحال يلي: كما ــاب املص العضو حيث من االصابات كانت . جراحيا معاجلتهم 22 مريضا ومت في ــديدة ش ــت االصابة كان ــا بينم 23 مريضا. في عضو من ــر أكث في كانت االصابة . جوفية اصابات وعائية ــس خم و معوية 21 اصابة , بنكرياس 13 اصابة , ــد كب ــة 48 اصاب , ــى كل عن ــف الكش في موثوق بها كانت املقطعية ــعة االش نتائج ان تبني التداخالت اجلراحية ونتائج ــريرية الس الفحوصات نتائج مع اخلالصة: باملقارنة %82 والقيمة فكانت املوجبة ــة التنبؤي القيمة أما .95% وصلت الى ــة نوعية %97 ودق الى وصلت ــية بحساس اجلوفية الداخلية االعضاء ــات اصاب .100% التنبؤية السلبية البطن. املقطعية،اصابات االشعة الكلمات: مفتاح c l i n i c a l & b a s i c r e s e a r c h 42 m a z e n i h a m i d i , k h a l i d m a l d a o u d , i z z e d d i n q ta i s h the care of the trauma patient is demanding and requires speed and efficien-cy. evaluating patients who have sustained blunt abdominal trauma (bat) remains one of the most challenging and resource-intensive aspects of acute trauma care. missed intra-abdominal injuries continue to cause preventable deaths. physical examination findings are notoriously unreliable for several reasons; a few examples are the presence of distracting injuries, an altered mental state, and drug and alcohol intoxication in the patient. coordinating trauma resuscitation demands a thorough understanding of the pathophysiology of trauma and shock, excellent clinical and diagnostic acumen, skill with complex procedures, compassion and the ability to think rationally in a chaotic milieu. bat usually results from motor vehicle collisions, assaults, recreational accidents, or falls. men tend to be affected slightly more often than women. the most commonly injured organs are the spleen, liver, retroperitoneum, small bowel, kidneys, bladder, colorectum, diaphragm, and pancreas. the ct scan remains the criterion standard for the detection of solid organ injuries.1 in addition, a ct scan of the abdomen can reveal other associated injuries, notably vertebral and pelvic fractures and injuries in the thoracic cavity. ct scans, unlike direct peritoneal lavage (dpl) or focused assessment with sonography for trauma (fast) examinations, have the capability to determine the source of haemorrhage. in addition, many retroperitoneal injuries go unnoticed with dpl and fast examinations. ct scans provide excellent imaging of the pancreas, duodenum and genitourinary system. the images can help quantitate the amount of blood in the abdomen and can reveal individual organs with precision. the limitations of ct scans include marginal sensitivity for diagnosing diaphragmatic, pancreatic and hollow viscus injuries. also, they are relatively expensive and time consuming and require oral or intravenous contrast, which may cause adverse reactions. 2, 3 m e t h o d s in this retrospective study, over a period of 5 years (from may 1999 to march 2004), we used abdomen ct scan reports available within the clinical charts of 245 patients with bat, who were stable enough to undergo radiological investigation in prince hashem hospital in zarqa, jordan. the patients included 171 (70%) males and 74 (30%) females. the age range was 14 72 years. diagnostic peritoneal tapping was not performed in any of them. patients with a normal ct scan and patients who either did not require admission, or who were discharged after a short, uneventful (max. 3 day) observation period without any further investigation, were excluded from the study. all ct scans were obtained with a hi speed dual helical ct scanner from general electric. a single breath-hold helical scan from the top of the t12 vertebral body to the pubic symphysis was obtained by using 5-mm beam collimation and 8 mm/sec table speed (pitch, 1.6; 120 kvp; 240–270 mas). routine oral (or through nasogastric tube) contrast agents in the form of 1-2% diluted ionic iodinated contrast were given 30-40 minutes before the study. oral contrast was not given to 23 patients with repeated vomiting or when limited information was required before proceeding for prompt laparotomy. all patients received intravenous bolus of iodinated contrast agents. following completion of the examination, the ct images were immediately reviewed by two specialist radiologists. they were in agreement on all the findings. delayed ct scans were also incorporated whenevfigures 1-3: patient with multi organ injury: grade v renal injury and shattered spleen. note: the 3d reformat of ct-angio with complete loss of renal vascularisation (left) 43 th e r o l e o f c o m p u t e d to m o g r a p h y i n b l u n t a b d o m i n a l tr au m a er there was suspicion of kidney or urinary tract injury. follow up ct scans were obtained for 14 patients, as dictated by the clinical course of the patient, but they did not contribute any further information. hemoperitoneum on ct was graded as described by federle and jeffrey et al. 4 [table 1]. individual organ injuries were graded according to the ois (organ injury scale) system.5, 15 the ois classification scheme is fundamentally an anatomic description, scaled from 1 to 5, representing the least to the most severe injury, ie. from simple organic contusion to avascularisation of one organ. ct findings were compared with operative findings in 113 patients, and with the clinical outcome and follow-up in 132 conservatively managed patients. the results were analysed with respect to hemoperitoneum quantification and ois grades. the overall imaging findings were analysed for their role in guiding the therapeutic options, whether conservative or surgical. r e s u l t s of the 245 patients with blunt trauma, road traffic accident was the commonest mode of injury and it was the cause of abdominal trauma in 186 patients. in 40 patients, the injury was caused by fall from height. nineteen patients had blunt injuries from other miscellaneous causes. of the total of 245 patients, 113 (46%) underwent surgery and 132 (54%) patients were conservatively managed without any complications. there were 12 deaths, three of which were related to postoperative complications. the other nine patients died of associated head injuries within 24 hours. no autopsy results were available. hemoperitoneum was detected in (69.4%) patients and they were divided into three groups according to the federle and jeffrey system4 [table 1]. there were 52 ‘small’ patients, 96 ‘moderate’ patients and 22 ‘large’ patients [table 2]. all 52 patients with small fluid hemoperitoneum on ct were conservatively managed and all 22 patients with large hemoperitoneum required surgical exploration. in the moderate fluid group, 50 patients were managed conservatively and the other 46 patients that were either unstable haemodynamically and/or had unexplained abdominal rigidity and/or packed-cell volume (pcv) drop were surgically explored. thus the rate of therapeutic laparotomy in patients with moderate hemoperitoneum shown on the ct scan was 52%. among the solid organ injuries, the spleen was the commonest organ involved. there were 95 (38.8%) splenic, 63 (25.7%) renal, 48 (19.6%) hepatic and 13 (5.3%) pancreatic injuries. twenty one (8.6%) patients had bowel injuries. five (2%) patients had vascular injuries. twenty three patients had multi-organ injuries [figs. 1, 2 & 3]. organ injuries were graded using the ois guidelines.5 among the 95 splenic injuries, 52 had mild injuries (grade ii), 37 had grade iii [fig. 4] and iv [fig. 7] injuries [fig. 1] and 6 had grade v injuries. nineteen of the 43 patients with moderate to severe (grade iii, iv and v) injuries required surgery. sixty three patients had kidney injuries, 51 were unilateral and 12 bilateral. of these 39 patients had grade iii, 20 patients had grade iv and four patients figure 4: grade iii splenic injury figure 5: grade ii liver tear figure 6: retroperitoneal, (right) paraspinal haematoma. note: the associated fracture involving the transverse process of l4 vertebra; it represents an anatomical entity at the level of aortic bifurcation 44 m a z e n i h a m i d i , k h a l i d m a l d a o u d , i z z e d d i n q ta i s h had grade v [fig.2] injuries. only fourteen of the 63 patients with renal injury up to grade iv required surgery. all patients with grade v injury were operated upon as expected. forty eight patients had liver injuries. twenty nine had grade ii and iii [fig. 5], 15 had grade iv and 4 patients had grade v injuries. all grade v and 11 out of 15 grade iv liver injuries required surgery. the rest of the injuries were managed conservatively. similarly, 13 patients had grade ii and iii pancreatic injuries. all these patients were managed conservatively. of the total 245 patients in our study, 219 (89.4%) patients had solid organ injuries (liver, spleen, pancreas or kidneys). ct ois grading in these patients showed that all 62 patients with grade ii injuries were conservatively managed, while 14 patients with grade v injuries were operated. however, the majority, i.e. 143 of these 219 patients, had either grade iii or grade iv injuries and these were either managed conservatively or operated on depending on their assessment on an individual basis [table 3]. hence, in the overall analysis of solid organ injuries, ois grading in isolation did not appear to predict the management protocols in a small proportion of them. after calculations, the sensitivity and specificity were 97% and 95%, respectively. in conjunction with close clinical monitoring, ct was reliable in the evaluation of blunt abdominal trauma in a selected group of patients, with overall sensitivity of 97% and specificity of about 95%. positive predictive value was 82% and negative predictive value 100 %. although sensitivity and specificity were calculated regarding intra abdominal injury in our group of patients, showing an overall sensitivity of about 97% and specificity of about 95%, it should be mentioned that these results were less in cases of bowel, mesenteric or vascular injuries. for solid organ injuries the results were higher for specificity and the same for sensitivity. d i s c u s s i o n several studies have highlighted the inaccuracies of the physical examination in bat,6 however, ct requires a cooperative, haemodynamically stable patient the accuracy of ct in haemodynamically stable blunt trauma patients has been well established. sensitivity between 92% and 97.6% and specificity as high as 98.7% has been reported in patients subjected to emergency ct,7, 8 which is in the range of our study. most authors recommend admission and observation following a negative ct scan.9, 10 in a recent study of 2,774 patients, the authors concluded that the negative predictive value (99.63%) of ct was sufficiently high to permit safe discharge of bat patients following a negative ct scan.11 we found good correlation between the ct quantification of the hemoperitoneum with the management approach. all 52 patients with small fluid were conservatively managed and similarly all 22 patients with large fluid required surgical exploration. approximately half of the patients with moderate fluid were explored. taylor et al. also reported a similar experience.12 ct is notoriously inadequate for the diagnosis of mesenteric injuries and may also miss hollow visceral injuries. in patients at risk for mesenteric or hollow visceral injury, dpl is generally felt to be a more appropriate test.7, 13 a negative ct scan in such a patient cannot reliably exclude intra-abdominal injuries. ct has the unique ability to detect clinically unsuspected figure 4: post operative finding, note grade iv splenic rupture table 1: ct quantification of hemoperitoneum (federle et al.)4 description estimates approximate amount fluid in only one space small 100-200 ml fluid in two or more spaces moderate 250-500 ml fluid in all spaces or pelvic fluid anterior/ superior to urinary bladder large >500 ml location of hemoperitoneum: 1. perisplenic space 2. perihepatic space 3. morrison’s pouch 4. left paracolic gutter 5. cul-de-sac in pelvis. 45 th e r o l e o f c o m p u t e d to m o g r a p h y i n b l u n t a b d o m i n a l tr au m a injuries. in a series of 444 patients, in whom ct was performed to evaluate renal injuries, 525 concomitant abdominal and/or retroperitoneal injuries were diagnosed. another advantage of ct scanning over other diagnostic modalities is its ability to evaluate the retroperitoneal structures8 [fig 6]. kane performed ct in 44 haemodynamically stable blunt trauma patients following dpl. in 16 patients, ct revealed significant intra-abdominal or retroperitoneal injuries not diagnosed by dpl. moreover, the findings from ct resulted in a modification to the original treatment plan in 58% of the patients.14 the ois5, 15 (organ injury scale) system is a relatively new system that is gaining recent acceptance in literature. though its sole purpose is to establish uniformity in different studies and thereby facilitate easy comparison, we found that splenic injury upto grade iii infrequently required surgery. only 5 out of 25 in this category required splenectomy as a part of surgery for multi-organ injury. on the contrary, grade iv or higher grade splenic injuries required surgery more often (11 out of 18 patients). we found no correlation between the grade of kidney injury with the management outcome. although two cases of grade iii kidney injuries required nephrectomies because of persistent hematuria and associated multi-organ injuries respectively, it is quite possible that, in the absence of significant hematuria or multi-organ injuries, isolated renal injury up to and including grade iv can be conservatively managed. the overall likelihood of surgical management increases with higher ois grading of solid organ injury, however ois grading in isolation appears inadequate for predicting management protocol in the relatively small number of patients in our study. c o n c l u s i o n we conclude that the ct scan is accurate, safe and has all the attributes to make it an initial investigation of choice in haemodynamically stable patients with bat. the rate of negative laparotomy is reduced by avoiding surgical intervention in cases that can be managed conservatively. r e f e r e n c e s 1. wing v, federle m, morris j, et al. the clinical impact of ct for blunt abdominal trauma. am j roentgenol 1985; 145:1191-1194. 2. udean j abdominal trauma, blunt (serial online). available from: http://www.emedicine.com/med/topic2804. htm. accessed: 27 feb 2003 3. robert a novelline, m, james t, et al. helical ct in emergency radiology. radiology 1999; 213:321-339. 4. federle m, jeffery r. hemoperitoneum studied by computed tomography. radiology 1983; 148:187-192. 5. moore e, cogbill t, malagoni m, et al. organ injury scaling. surg clin north am 1995; 75:293-303. 6. rodriguez a, dupriest r, shatney c. recognition of intra-abdominal injury in blunt trauma victims. a prospective study comparing physical examination with peritoneal lavage. am surg 1982; 48:457-459 7. peitzman a, makaroun m, slasky b, et al. prospective study of computed tomography in initial management of blunt abdominal trauma. j trauma 1986; 26:585-592. 8. webster v. abdominal trauma: pre-operative assessment and postoperative problems in intensive care. anaesth intensive care 1985; 13:258-262. 9. lang e. intra-abdominal and retroperitoneal organ injuries diagnosed on dynamic computed tomograms obtained for assessment of renal trauma. j trauma 1990; 30: 1161-1168. 10. matsubara t, fong h, burns c. computed tomography of abdomen (cta) in management of blunt abdominal trauma. j trauma 1990; 30:410-414. table 3: ct-ois grading and management in 219 patients with solid organ injuries. ois grade total number of patients number of conservatively managed patients number of operated patients ii 62 62 0 iii 96 85 11 iv 47 27 20 v 14 0 14 *grade of the maximally injured organ in cases of multiorgan injuries. table 2: ct quantification and management in 170 patients with themoperitoneum on ct examination ct quantification of hemoperitoneum total number of patients number of conservatively managed patients number of operated patients small 52 52 0 moderate 96 50 46 large 22 0 22 46 m a z e n i h a m i d i , k h a l i d m a l d a o u d , i z z e d d i n q ta i s h 11. livingston d, lavery r, passannante m, et al. admission or observation is not necessary after a negative abdominal computed tomographic scan in patients with suspected blunt abdominal trauma: results of a prospective, multi-institutional trial. j trauma 1998; 44: 272-282. 12. taylor ga, fallat me, potter bm, et al. the role of computed tomography in blunt abdominal trauma in children. j trauma 1988; 28:1660-1664. 13. nolan b, gabram s, schwartz r, et al. mesenteric injury from blunt abdominal trauma. am surg 1995; 61:501506. 14. kane n, dorfman g, cronan j. efficacy of ct following peritoneal lavage in abdominal trauma. j comp assist tomogr 1987; 11:998-1002 15. moore ee, cogbill th, jurkovich gj, shackford sr, marangoni ma, champion hr. organ injury scaling: spleen and liver (1994 revision). j trauma 1995; 38:323– 324. submitted 9 feb 22 1 revisions req. 9 may & 18 jul 22; revisions recd. 23 jun & 27 sep 22 2 accepted 16 oct 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.065 5 6 the impact of the covid-19 pandemic on the pattern of trauma presenting 7 to a tertiary care trauma center in oman 8 rahma al harthi,1 maram al hinai,1 maather al abri,2 ashjan almaamari,3 9 edwin stephen,4 *hani al qadhi4 10 11 1department of general surgery, oman medical specialty board, muscat, oman; 2department 12 of general surgery, 3sultan qaboos university, muscat, oman; 4department of general 13 surgery, sultan qaboos university hospital, muscat, oman. 14 *corresponding author’s e-mail: halqadhi@squ.edu.om 15 16 abstract 17 objective: we noticed a change in the pattern of presentation of trauma cases at squh, before 18 the pandemic and during the two waves. our study aimed at studying this observation. methods: 19 this retrospective study was from january 2019 to october 2021. data of all trauma patients was 20 collected from the hospital information system after ethics committee approval. the pattern of 21 trauma was divided into pediatric, adult, and geriatric age groups. location of trauma was 22 described as outdoor, home and roads along with the details of mechanism of trauma was 23 collected. patients with incomplete data were excluded. results: based on the inclusion criteria 24 589 records were analyzed. the mean age of presentation was 29 years. majority were male 25 (71%). adults were (54.2%), pediatrics (34%) and geriatric (11.9%). there was a gradual 26 increase in percentage of pediatric trauma during pre-covid, covid wave 1 and covid wave 27 2 (29%, 32%, 51%), respectively. a significant decline in the number of geriatric trauma by 28 almost 50% between pre-covid and covid phase ii. increase in trauma at home during covid 29 phase ii (65.9%) as was an increase in penetrating trauma during covid phase ii (16.5%). icu 30 admissions increased during the first wave of the pandemic (10.5%). conclusion: we noted a 31 true change in the pattern of trauma cases before and during the covid -19 pandemic. 32 observations made could lead to better safety guidelines for the pediatric age groups and take 33 steps to reduce penetrating trauma. 34 keywords: trauma, coronavirus, covid-19, oman, muscat, epidemiology. 35 36 advances in knowledge 37 ● the rate of pediatric trauma increased during the covid19 pandemic. 38 ● the rate of trauma has overall decreased during the pandemic. 39 ● the rate of motor vehicle crashes (mvc) was not affected by the restrictions 40 implemented during the pandemic. 41 42 application to patient care 43 ● public awareness should be raised to prevent trauma during pandemics with special focus 44 on the most vulnerable demographic groups. 45 ● with the overwhelming load of pandemic on the health systems and healthcare workers, 46 understanding trauma patterns during a global pandemic will aid in preparing and 47 planning strategies to deal with such an issue. 48 49 introduction 50 the covid-19 pandemic has had a significant impact on the social, economic, educational and 51 health systems all over the world. many adjustments and restrictions were implemented in an 52 attempt to curb the spread of the virus and minimize the burden of the disease. 53 54 the sultanate of oman is located in the southeastern coast of the arabian peninsula and has a 55 population size of 4.5 million people.1 the first two cases of covid-19 infection in oman were 56 registered in late february 2020.2 the number of cases related to travel gradually increased and 57 community transmission was noted by the end of march the same year. a “supreme committee” 58 [sc] was formed to manage the pandemic and released several directives to control the outbreak 59 at regular intervals, based on the case load, morbidity, and mortality within the nation.3 60 61 during the pandemic tertiary hospitals in the sultanate announced a temporary suspension of all 62 routine non-emergency services such as elective surgeries and procedures, outpatient 63 appointments, etc.4,5 and ours was one such center the sultan qaboos university hospital 64 [squh], located in the capital city of muscat, with a capacity of 600 beds.6 it is considered one 65 of two major trauma centers in muscat that accepts cases from all across the sultanate. 66 67 several studies conducted around the world showed that the pandemic led to significant 68 reductions in trauma case load and changed the pattern injurie.7,8 however, no national level 69 studies were conducted to evaluate this issue. we noticed a change in the pattern of presentation 70 of trauma cases at squh, before the pandemic and during the two waves. the objective of this 71 study is to study the overall trend (increase or decrease) in trauma cases presenting to a major 72 trauma center in the sultanate. moreover, it looks at identifying the groups that are at higher risk 73 of trauma and the most common mechanisms of injuries. this will help in raising public 74 awareness to prevent trauma injuries in such overwhelming situations, as well as providing a 75 baseline data for stakeholders to prepare healthcare services to deal with such problems. 76 77 methods 78 this retrospective, cross-sectional study included all trauma cases that presented to squh from 79 1st of january 2019 until 30th october 2021 and was conducted after ethics committee approval. 80 81 to make the comparison between different time periods, we divided the dates of data collection 82 into three phases: pre-covid (01 jan 2019 29 feb 2020), covid phase i (01 march 2020 28 83 feb 2021) and covid phase ii (01 mar 2021 – 31 oct 2021). age groups were divided as 84 pediatrics (less than or equal to 13 years of age), adults (14 to 64 years of age) and geriatrics 85 (more than or equal to 65 years of age). 86 87 electronic medical records of patients’ were reviewed. data collected included demographics 88 (age and gender), date of presentation to the emergency department (ed), location of trauma, 89 type of trauma (penetrating or blunt), mechanism of trauma, list of injuries, outcomes including 90 disposition from the trauma bay (admission (icu/ward), discharge home, transfer to another 91 hospital or death and length of hospital stay in days. 92 93 statistical analysis was conducted using statistical package for social sciences (spss 21.0). 94 continuous variables were presented as mean, median, and standard deviation. categorical 95 variables were presented as frequency and percentage. association/difference between two 96 categorical variables were assessed by using a chi-square test (fisher's exact/likelihood ratio). 97 appropriate graphs were used to show trends over time. a p-value less than 0.05 was considered 98 statistically significant. all the analyses were carried out in ibm spss statistics version 28.0. 99 100 results 101 we reviewed 594 files and excluded 5 of them as the data was incomplete, leaving a total of 589 102 cases. 103 104 demographic data of our study showed that (table 1) majority of the patients were males 105 (421;71.5%); and median age was 29 years (age range 7 weeks to 96 years). more than half of 106 the cases were adults (54%), a third of the cases were children (34%) and 12% were in the 107 elderly age group. 108 109 phase wise analysis revealed a falling trend in the total number of trauma cases presenting to ed 110 (288; 49%, 210; 36%, 91; 15%) (figure 1) across the adult and geriatric age groups; however, a 111 rising trend was noted for the pediatric age group (29.5%, 32% and 51.6%) which was 112 statistically significant (p <0.05). the gender distribution between the three phases of time was 113 not statistically significant (p 0.061). 114 115 majority of trauma occurred at home (344; 58%), followed by outdoors (184; 31%) and roads 116 (46; 8%). these differences were not statistically significant (p 0.43). only 10 cases occurred at 117 work/school, and these were equally divided between the pre-covid and covid phase i. 118 blunt trauma was significantly higher than penetrating trauma (81% vs 11%) with decreasing 119 frequency during the three phases (87%, 79% and 71%). however, the percentage of penetrating 120 trauma increased (7%, 15% and 17%). this change in trend was statistically significant (p 121 <0.05). 122 123 as for the mechanism of trauma (table 2), falls accounted for 57% of the total number of cases, 124 followed by motor vehicle collision/accidents [mvc] (11%), penetrating trauma and others 125 (8.8% each). lastly, sports related injuries, crush injuries, assault, drowning, and suicide 126 attempts accounted for the remaining cases (4.4%, 3.7%, 3.6%, 1.5% and 0.7% respectively). we 127 noted a decreasing trend in falls and sports related injuries through the three phases. 128 interestingly, penetrating injuries and drowning saw an increase. the rate of mvc remained 129 stable throughout the three-time phases. no particular trend was noted for the remaining 130 mechanism of trauma. 131 132 injuries to the extremities were the most common (38%, lower limbs 23% and upper limbs 133 15%), (table 3). these included bone fracture/dislocation, soft tissue injuries or neurovascular 134 injuries. secondly, head and neck injuries accounted for 26% of cases and included traumatic 135 brain / ophthalmic / soft tissue injuries to the scalp, face and neck, and maxillofacial fractures. 136 this was followed by polytrauma (10%), spinal injuries (5%), thoracic injuries (3%), 137 genitourinary injuries (2%), abdominal injuries (1%) and pelvic injuries (0.3%). in 14% of the 138 cases, which included those with falls with late presentation to the ed and foreign body 139 ingestions, we found no injury acquired. 140 141 ninety five percent of our patients required admission (88% were admitted to the ward, 7% 142 required admission to icu). four percent of the cases were discharged home while 0.3% were 143 transferred to a different hospital. no cases were declared dead in the trauma bay. the admission 144 duration varied between one day to 155 days (median duration 2 days). there was no 145 significant difference in trauma outcome during the three-time phases. 146 147 discussion 148 the covid19 pandemic shook the social and medical realms amongst others. this retrospective 149 study looks at the impact of this pandemic on trauma patterns presenting to a major trauma 150 center (squh) in oman’s capital city of muscat. this was done by comparing all trauma 151 presentations to ed one-year pre-covid, the first and second phase of covid. 152 153 589 cases made it to the final analysis. we noted an overall decrease in the total number of 154 trauma cases presenting to ed. when comparing the three-time phases, the total number of cases 155 dropped by a third between the pre-covid and covid phase i (288; 49% versus 210; 36%) 156 respectively. this trend continued in the second phase, where we observed a further drop of two-157 thirds (91; 15%). the latter could be an overestimation as data was collected until october 2021, 158 which makes it a shorter period of time compared to the two other time phases. several 159 international studies have found a similar trend like a multicentre study by berg et al which 160 found a 32% decrease in the number of trauma cases during the pandemic.7 other studies showed 161 a decrease ranging from 22% to 57%.8,9 these observations can be attributed to the precautions 162 that were implemented during the pandemic. this included closure of all international border for 163 non-residents, restricting inter-governorate travel to absolute essential, a 70% reduction in the 164 number of employees at workplaces [work from home policy], suspension of classes in schools 165 and universities, banning all public gatherings, closing retail outlets, and recommending social 166 distancing. 167 168 the first lockdown in the muscat governorate was implemented on the 10th of april 2020, which 169 was subsequently extended during the holy month of ramadhan and finally lifted on may 170 29th. 10,11 alongside this was a staged lockdown between governorates in june. night curfew [nc] 171 was implemented from march 28th till april 8th, 2021, between the hours of 8pm and 5am. the 172 implementation of a lockdown/curfew led to a significant reduction in public and traffic 173 movement. in our study, we found no significant drop in trauma cases during the first lockdown, 174 in fact, the number of cases has remained stable. on the contrary, a drop was noted in the 175 following year during the partial lockdown /nc. 176 177 as for demographics males predominate with a male to female ratio of 3:1. this male 178 predominance is consistent with trauma epidemiology overall12 and no significant change in the 179 sex distribution was observed during the covid pandemic. this was true for our study and in 180 other international studies.7,13,14 when it comes to age, adults (13 to 64 years) formed the 181 majority of our study population (54%), and this is expected as this age group was the most 182 active. although the number of trauma cases for both adult and geriatric age groups has 183 significantly dropped during the pandemic, the number of pediatric trauma has risen significantly 184 and exceeded the percentage of adult trauma in covid phase ii (52% vs 41%). this finding was 185 contrary to what was found in other studies which showed a drop in overall pediatrics trauma 186 reaching up to one half.15,16 we also expected the rate to decrease considering the shutdown of 187 schools, parks, public playgrounds etc, but home related injuries can explain this rise. this might 188 be due to the increase of stressors to families resulting from a number of new changes such as; 189 working from home, supervising online teaching, lack of professional childcare services as well 190 as restrictions in seeking extended family support. this in turn led to reduced direct and expert 191 supervision and care of children. 192 193 more than a half of trauma occurred at home followed by a third occurring outdoors. there was 194 no statistically significant difference in the distribution of trauma location between pre-covid 195 and the two phases of covid. the proportion of blunt versus penetrating injury, however, 196 changed during the pandemic. a significant decrease in blunt trauma was noted, versus a rise in 197 penetrating trauma. this change was also demonstrated in studies conducted in the united states 198 of america and the united kingdom.8,17,18 the increase in penetrating injuries has reached up to 199 21% in a multicenter retrospective study from south california, usa.19 this was attributed to 200 the socio-economic stress that resulted from the pandemic such as cutting down working staff 201 and a rise in unemployment rate.7,8,19 others have attributed this to the rise in homicide, sales of 202 firearms, self-harm, and domestic violence.19,20 however, we cannot relate these findings to our 203 studied population, as only three cases of penetrating injuries were attributed to assault and all of 204 them were stabbing injuries. another explanation is that more do it yourself (diys) were 205 conducted at homes, which have resulted in those injuries. this rising trend should alert health 206 care professionals to be prepared to deal with penetrating injuries as they are usually more 207 severe. moreover, such injuries are usually associated with more blood loss and often require 208 blood transfusion. there was a shortage in blood supply during the pandemic due to reduction in 209 donation21, the health system should therefore be prepared to overcome such problems in the 210 future. 211 212 different mechanisms of injury were noted in our group, but the majority was due to falls (57%), 213 followed by mvc (11%) and penetrating traumas (8.8%). during the different time periods, we 214 noted a decreasing trend in falls and sports related injuries. other studies have also found a 215 similar trend, which was statistically significant19 and was attributed to social gatherings being 216 banned, and sports centres being shut down during covid phase i and ii. the trend of mvc 217 remained unaffected during the pandemic while we expected it to drop given the implemented 218 restrictions that reduced road travel in general. a no change trend in mvc was also noted in 219 other studies8, however, larger studies showed a significant reduction of mvc.7 a possible 220 explanation for our finding is that less severe mvc related injuries were dealt with in regional or 221 non-trauma centers prior to the covid pandemic. and although the overall trend reduced, the 222 severity of injuries increased during the pandemic and such cases could only be managed in a 223 major trauma center like squh. drowning incidents increased in covid phase ii. this is 224 probably because private properties with swimming pools were more utilized during the 225 pandemic in an attempt to entertain families and lift the pressure associated with the lockdown. 226 227 the distribution of injuries was classified by anatomical location. cumulative upper and lower 228 limbs injuries accounted for 38% of all acquired injuries. head and neck injuries were the second 229 most common and account for a quarter of our cases. these injuries are usually associated with 230 blunt injury which was more common in our cohort. 231 232 we have studied the short-term outcome of our cases and found that 95% required admission and 233 only 4% were safe to be sent home. there was no noted effect of the pandemic on the disposition 234 of the patients from the trauma bay. we had a median length of hospital stay of two days which 235 was also not affected by the pandemic. our median seems to be shorter than that shown in other 236 studies which varied between 4 days17,19 and 5.5 days.18 this might be due to less severe injuries 237 seen in our study population. 238 239 this study aims to look at the trend of trauma patterns before and after the covid pandemic and 240 does not aim to compare particular blocks of time or absolute date. being a retrospective study, 241 there are a number of limitations associated with this type of studies such as recall bias, missed 242 data and mis-documentation. moreover, this is a single center study in the capital of the 243 sultanate which might not reflect the pattern of trauma in other areas of oman before or during 244 the pandemic. also, a number of new implementations have been imposed by the sc to control 245 the pandemic, and the exact direct cause in changing the trauma pattern cannot be specifically 246 identified. 247 248 conclusion 249 the covid-19 pandemic has influenced the frequency and pattern of trauma in oman. there is 250 an overall decrease in the total number of trauma cases presenting to squh, however, the 251 proportion of pediatrics and penetrating injuries showed an increase. despite the limitations of 252 our study, the findings can be taken into consideration when formulating safety guidelines for the 253 pediatric / geriatric age groups with special attention to penetrating trauma, lest there be another 254 phase or pandemic. 255 256 conflicts of interest 257 the authors declare no conflict of interests. 258 259 funding 260 no funding was received for this study. 261 262 author contributions 263 rahma al harthti was involved in data collection, data analysis, literature review and manuscript 264 writing. maram al hinaei was involved in data collection and in drafting out the ethical approval 265 application. maather al abri was involved in data collection. ashjan almaamari was involved 266 in data collection. edwin stephen was involved in study design and supervising the research. dr 267 hani al qadhi was involved in supervising the research. all authors approved the final version 268 of the manuscript. 269 270 references 271 1. population data portal [internet]. [cited 2021 dec 3]. available from: 272 https://data.gov.om/ompop2016/population 273 2. moh registers first two novel coronavirus (covid-2019) in oman media center display 274 page ministry of health [internet]. [cited 2021 nov 22]. available from: 275 https://www.moh.gov.om/en/-/--1226 276 3. statements and updates ministry of health [internet]. [cited 2021 nov 22]. available from: 277 https://www.moh.gov.om/en/-59 278 4. observer o. royal hospital to stop admitting non-emergency cases [internet]. oman observer. 279 2020 [cited 2021 nov 22]. available from: 280 https://www.omanobserver.om/article/14822/main/royal-hospital-to-stop-admitting-non-281 emergency-cases 282 5. observer o. al nahda hospital to suspend outpatient appointments [internet]. oman observer. 283 2020 [cited 2021 nov 22]. available from: 284 https://www.omanobserver.om/article/14247/coronavirus/al-nahda-hospital-to-suspend-285 outpatient-appointments 286 6. about hospital [internet]. [cited 2021 nov 22]. available from: 287 https://www.squ.edu.om/squh/about/about-hospital 288 7. berg gm, wyse rj, morse jl, chipko j, garland jm, slivinski a, et al. decreased adult 289 trauma admission volumes and changing injury patterns during the covid-19 pandemic at 85 290 trauma centers in a multistate healthcare system. trauma surg acute care open. 2021 feb 291 11;6(1):e000642. 292 8. chodos m, sarani b, sparks a, bruns b, gupta s, michetti cp, et al. impact of covid-19 293 pandemic on injury prevalence and pattern in the washington, dc metropolitan region: a 294 multicenter study by the american college of surgeons committee on trauma, washington, 295 dc. trauma surg acute care open. 2021 jan 19;6(1):e000659. 296 9. kamine th, rembisz a, barron rj, baldwin c, kromer m. decrease in trauma admissions 297 with covid-19 pandemic. west j emerg med. 2020 jul;21(4):819–22. 298 10. muscat lockdown from friday, schools suspended until further notice [internet]. [cited 2021 299 nov 22]. available from: 300 https://web.archive.org/web/20200726112845/https://www.omanobserver.om/muscat-301 supreme-commitee/ 302 11. observer o. muscat lockdown extended, ban on all ramadhan gatherings [internet]. oman 303 observer. 2020 [cited 2021 nov 22]. available from: 304 https://www.omanobserver.om/article/13832/coronavirus/muscat-lockdown-extended-305 ban-on-all-ramadhan-gatherings 306 12. sauaia a, moore fa, moore ee, moser ks, brennan r, read ra, et al. epidemiology of 307 trauma deaths: a reassessment. j trauma. 1995 feb;38(2):185–93. 308 13. okoye og, olaomi oo, gwaram ua, apollo kd. the impact of covid-19 lockdown on 309 acute trauma patients seen at the national hospital trauma centre abuja, nigeria. pan afr 310 med j. 2021 apr 30;38:414. 311 14. zsilavecz a, wain h, bruce jl, smith mtd, bekker w, laing gl, et al. trauma patterns 312 during the covid-19 lockdown in south africa expose vulnerability of women. s afr med j. 313 2020 oct 28;110(11):1110–2. 314 15. sanford el, zagory j, blackwell j-m, szmuk p, ryan m, ambardekar a. changes in 315 pediatric trauma during covid-19 stay-at-home epoch at a tertiary pediatric hospital. j 316 pediatr surg. 2021 may;56(5):918–22. 317 16. shi y, kvasnovsky c, khan s, jain s, sargeant d, lamoshi a, et al. impact of the covid-19 318 pandemic on trauma activations at a pediatric level 1 trauma center in new york. pediatr surg 319 int. 2021 jul 15;1–6. 320 17. sheets nw, fawibe os, mahmoud a, chawla-kondal b, ayutyanont n, plurad ds. impact 321 of the covid-19 pandemic on trauma encounters. am surg. 2021 jul 322 4;00031348211029858. 323 18. ghafil c, matsushima k, ding l, henry r, inaba k. trends in trauma admissions during 324 the covid-19 pandemic in los angeles county, california. jama netw open. 2021 feb 325 22;4(2):e211320. 326 19. yeates eo, grigorian a, barrios c, schellenberg m, owattanapanich n, barmparas g, et al. 327 changes in traumatic mechanisms of injury in southern california related to covid-19: 328 penetrating trauma as a second pandemic. j trauma acute care surg. 2021 apr;90(4):714–329 21. 330 20. olding j, zisman s, olding c, fan k. penetrating trauma during a global pandemic: changing 331 patterns in interpersonal violence, self-harm and domestic violence in the covid-19 outbreak. 332 the surgeon. 2021 feb;19(1):e9–13. 333 21. stephen e, al-adawi ssh, abdelhady i, mawali ha, al-wahaibi k. managing vascular 334 surgery emergencies and referrals during the covid-19 pandemic at a tertiary centre in 335 oman. sultan qaboos univ med j squmj. 2021 mar 15;21(1):e116-119. 336 337 338 figure 1: the number of trauma cases presenting to ed from january 2019 till september 2021 339 340 table 1: the demographic data of our studied population. 341 pre-covid (288) covid phase i (210) covid phase ii (91) total number (589) sex male female 193 (67%) 95 (33%) 160 (76%) 50 (24%) 68 (75%) 23 (25%) 421 (71.5%) 168 (28.5%) age groups pediatric adult geriatric 85 (29.5%) 161 (55.9%) 42 (14.6%) 68 (32%) 121 (58%) 21 (10%) 47 (51.6%) 37 (40.7%) 7 (7.7%) 200 (34%) 319 (54%) 70 (12%) 342 table 2: mechanism of injury 343 pre-covid (n 288) covid phase i (n 210) covid phase ii (n 91) total (n 589) fall 175 (61%) 115 (55%) 48 (53%) 338 (57%) mvc 32 (11%) 23 (11%) 10 (11%) 65 (11%) penetrating 14 (5%) 27 (13%) 11 (12%) 52 (8.8%) sports 19 (6.6%) 5 (2%) 2 (2%) 26 (4%) crush 11 (4%) 7 (3%) 4 (4%) 22 (3.7%) assault 10 (3.5%) 9 (4%) 2 (2%) 21 (3.6%) drowning 4 (1%) 1 (0.5%) 4 (4.4%) 9 (1.5%) suicide attempt 2 (0.7%) 1 (0.5%) 1 (1%) 4 (0.7%) others 21 (7%) 22 (10.5%) 9 (10%) 52 (9%) 344 table 3: anatomical location of the injuries 345 pre-covid covid phase i covid phase ii total head and neck 62 (21.5%) 58 (28%) 34 (37%) 154 (26%) lower limbs 80 (28%) 44 (21%) 13 (14%) 137 (23%) upper limbs 49 (17%) 32 (15%) 9 (10%) 90 (15%) polytrauma 26 (9%) 26 (12%) 6 (7%) 58 (10%) spine 13 (4%) 10 (5%) 4 (4%) 27 (5%) thorax 9 (3%) 5 (2%) 2 (2%) 16 (3%) genitourinary 4 (1%) 4 (2%) 2 (2%) 10 (1.7%) abdomen 3 (1%) 3 (1%) 0 (0%) 6 (1%) pelvis 2 (0.7%) 0 (0%) 0 (0%) 2 (0.3%) others 4 (1%) 0 (0%) 0 (0%) 4 (0.7%) note: there are excluded data for patients who had no or minimal injury (36, 28 and 21 patients 346 from the pre-covid, covid phase i and covid phase ii respectively. 347 1 submitted 26 jul 22 1 revision req. 13 sep 22; revision recd. 7 oct 22 2 accepted 24 oct 22 3 online-first: december 2022 4 doi: https://doi.org/10.18295/squmj.12.2022.72 5 6 a rare case of a direct incarcerated inguinal hernia containing an 7 epiploic appendage and a literature review 8 *stella papamichail,1 eleni karlafti,2 petra malliou,1 9 apostolos zatagias,1 aristeidis ioannidis,1 smaro netta,1 10 stavros panidis,1 daniel paramythiotis1 11 12 11st propaedeutic surgical department, university hospital of thessaloniki ahepa, 13 aristotle university of thessaloniki, thessaloniki, greece; 2emergency department, 14 university hospital of thessaloniki ahepa, aristotle university of thessaloniki, 15 thessaloniki, greece. 16 *corresponding author’s e-mail: stellapz@auth.gr 17 18 abstract 19 inguinal hernias are a widespread condition, responsible for a large number of acute 20 abdomen cases. typically, indirect, rather than direct, hernias are the ones leading to 21 complications, as a consequence of their narrower hernial defect. our case concerns a 22 rather rare incidence of a direct incarcerated hernia in a 71-year-old man who presented 23 with acute pain in the left inguinal area. upon clinical examination, an irreducible 24 inguinal mass was palpated. therefore, the existence of a complicated hernia was 25 suspected. the patient underwent an emergency repair, during which it was established 26 that the hernia was direct and incarcerated and that its sac contained an ischemic epiploic 27 appendage. the hernia was successfully repaired with mesh, the patient recovered 28 uneventfully and was discharged five days later. despite the rarity of complicated direct 29 2 inguinal hernias, they should always be included in the differential diagnosis of 30 irreducible groin masses, because they can increase severe complications. 31 keywords: direct inguinal hernia; appendix epiploica. 32 33 introduction 34 inguinal hernias are the most frequent type of hernia and their repair is among the most 35 common procedures general surgeons perform.1 various risk factors can cause a 36 predisposition to the development of hernias, such as male sex, old age, a high body mass 37 index, connective tissue disorders and activity that increases intra-abdominal pressure, 38 like chronic coughing or weight-lifting.2 inguinal hernias are divided into two categories 39 depending on the point of protrusion of the tissue. the hernia is indirect, when the 40 protrusion occurs through the internal inguinal ring, whereas direct hernias arise from the 41 posterior wall of inguinal canal, in the hesselbach triangle.3 due to their wider neck, 42 direct hernias are far less prone to complications.4 an uncomplicated or reducible 43 inguinal hernia typically presents as an inguinal bulge whose contents can return to the 44 abdomen, either spontaneously or by applying pressure.5 complications arise when the 45 content becomes trapped or incarcerated, whereas strangulation involves reduced blood 46 supply and can cause obstruction, bowel necrosis and perforation.6 treatment options 47 include ‘watchful waiting’ or elective repair for asymptomatic patients. reinforcement of 48 the abdominal wall defect through a mesh repair is necessary when complications 49 emerge.7 50 51 in this case report we describe the case of a patient with a complicated direct inguinal 52 hernia who underwent emergency surgery, at the university general hospital. 53 54 case report 55 in 2017, a 71-year-old male presented to the surgical emergency department due to pain, 56 located in the left inguinal region. the pain had started 72 hours before his admission, 57 after lifting weight. clinical examination revealed a moderately distended abdomen, 58 diminished bowel sounds and mild diffuse tenderness, without signs of peritonitis. in the 59 left inguinal region there was a tender hernia. reduction of the hernia was attempted but 60 https://pubmed.ncbi.nlm.nih.gov/31482863/ https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5614933/ https://www.aafp.org/afp/2020/1015/p487.html https://link.springer.com/article/10.1007/bf01207592 https://www.ncbi.nlm.nih.gov/books/nbk555972/ https://www.ncbi.nlm.nih.gov/books/nbk459309/ https://link.springer.com/article/10.1007/s10029-017-1668-x#citeas 3 proved impossible. blood pressure, heart rate, oxygen saturation and body temperature 61 were within normal range. no chronic diseases, past surgeries, allergies of any sort or a 62 history of smoking were mentioned. the laboratory tests were normal except the elevated 63 levels of total white blood cell count (10,56k/μl). 64 65 moreover, the x – ray of the abdomen was clear. ultrasonography revealed a large hernia 66 in the left inguinal area [figure 1]. doppler ultrasonography showed a reduction of blood 67 flow to the hernial content, a finding on which the diagnosis of an incarcerated inguinal 68 hernia was based [figure 2]. 69 70 the patient underwent surgery in order to reduce the hernia and repair the abdominal wall 71 defect. a left sided inguinal skin incision was performed to access the inguinal canal. 72 during surgery it was confirmed that the hernia was direct and its content was found to 73 be an ischemic, yet not necrotic epiploic appendage arising from the sigmoid colon 74 [figure 3]. after the appendage was pushed back into the abdomen and blood flow was 75 restored, the abdominal wall weakening was reinforced using synthetic mesh. 76 postoperative recovery was smooth, the patient was discharged after 5 days and presented 77 no complications during follow up. 78 79 written informed consent has been obtained from the patient to publish this paper. 80 81 discussion 82 inguinal hernias constitute quite a common condition, affecting approximately 27% of 83 men and 3% of women across the world, and are typically classified as either direct or 84 indirect, based on differences in anatomy.2 usually, inguinal hernias are asymptomatic 85 and do not alarm the patient until a straining event, such as lifting weight, raises the 86 intraabdominal pressure, causing soft tissue to protrude through an anatomical defect.6 87 the lifetime risk of dangerous complications following such an event has been found to 88 be rather low, estimated around 1-3%.5 nevertheless, an increased risk has been strongly 89 associated with indirect hernias, whereas the less prevalent direct hernias, are about three 90 times less likely to become complicated which can be attributed to their wider neck.4,8,9 91 https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5614933/ https://www.ncbi.nlm.nih.gov/books/nbk459309/ https://www.ncbi.nlm.nih.gov/books/nbk555972/ https://link.springer.com/article/10.1007/bf01207592 https://pubmed.ncbi.nlm.nih.gov/30031240/ https://pubmed.ncbi.nlm.nih.gov/15008294/ 4 specifically, indirect hernias herniate through the internal inguinal ring, which has 92 narrow diameter, while direct hernias protrude through hesselbach’s triangle, medial to 93 the inferior epigastric vessels.10 however, despite the fact, that the neck of the fascial 94 defect in direct hernias is initially wide and soft, studies have shown that it can become 95 fibrotic and inelastic over time, and the above may multiply the risk of incarceration.4 96 97 regarding diagnosis, the physical examination that involves inspection and palpation, 98 usually suffices to confirm the presence of the inguinal hernia.11 further diagnostic 99 investigation using imaging methods such as ultrasonography, computed tomography 100 (ct), magnetic resonance imaging (mri) or herniography is required only in cases of 101 pain and/ or swelling that suggest the presence of a complication. differentiating between 102 direct and indirect hernias during preoperative care is meaningless and is in fact quite 103 challenging to achieve clinically or even through imaging.12 concerning differential 104 diagnosis, if the initial clinical presentation includes edema, then lymph node 105 enlargement, aneurysm, saphena varix, soft-tissue tumor, abscess or genital anomalies 106 (such as ectopic testis) must be excluded. in case of the presence of pain, then adductor 107 tendonitis, pubic osteitis and hip arthritis should be considered likely.7 108 109 regarding recommended treatment, options depend on the severity of the patient’s 110 symptoms. asymptomatic or mild symptoms cases, can be managed with the ‘watchful 111 waiting’ approach or a scheduled repair, while complicated hernias require emergency 112 surgical repair.7 moreover, the surgical techniques include tissue, open mesh and laparo-113 endoscopic mesh repair techniques, with a mesh-based repair being strongly 114 recommended for the majority of cases.7 115 116 epiploic appendages are located in the large bowel and can be found in inguinal hernia 117 sacs, though this incident is quite rare and few cases have been reported.13 these 118 appendages are outpouchings of fatty tissue, covered by serosa that project into the 119 peritoneal cavity and that are supplied by one or two small arteries. due to the limited 120 arterial blood supply, along with their pedunculated structure that allows increased 121 movement, epiploic appendages are prone to torsion and ischemia or bleeding, which can 122 https://pubmed.ncbi.nlm.nih.gov/34322367/ https://link.springer.com/article/10.1007/bf01207592 https://pubmed.ncbi.nlm.nih.gov/26987468/ https://link.springer.com/article/10.1007/s10029-009-0529-7#citeas https://link.springer.com/article/10.1007/s10029-017-1668-x#citeas https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5809582/ https://link.springer.com/article/10.1007/s10029-017-1668-x#citeas https://www.hindawi.com/journals/cris/2013/890234/ 5 also be caused by the thrombosis of the central vein.14 epiploic appendagitis is also 123 related to diverticulitis because of the local spread of inflammation. ct scans are the 124 preferred imaging method of diagnosing epiploic appendagitis, which when primary does 125 not necessarily require surgical intervention and can be treated with non-steroidal anti-126 inflammatory drugs. however, in cases where the appendages become incarcerated in an 127 irreducible inguinal hernia, an emergency surgery can be called for.15 128 129 despite the unlikelihood of direct hernia complications, there have been a few 130 documented cases of strangulated direct hernias arising in various ways. one such case 131 involved a life threatening bowel perforation, secondary to ischemic necrosis, which 132 required emergent resection of the necrotic bowel.16 in addition, incarcerated direct 133 hernias have also been reported as the cause of acute bowel obstruction.8 moreover, a 134 complicated direct inguinal hernia containing the urinary bladder has led to obstructive 135 uropathy presenting with severe acute kidney failure, requiring emergency surgery and 136 dialysis.17 finally, we describe two cases very similar to ours, one of which concerns an 137 irreducible direct inguinal hernia that was found to contain inflamed and hypertrophic 138 epiploic appendices which had to be resected before the hernia could be repaired.18 the 139 second one is a case of an incarcerated inguinal hernia which during emergent surgical 140 hernia reduction and herniorraphy was revealed to contain not only epiploic appendices, 141 but also part of the sigmoid colon.19 142 143 eventually, after searching for similar cases on international literature, we found few 144 relevant case reports of direct strangulated or incarcerated hernias and even fewer of 145 hernias containing epiploic appendices. our main findings are summarized in table 1. it 146 is important to mention that the majority of reported cases of epiploic appendages being 147 found in inguinal hernias concerned indirect hernias.15 hence this case report is unique in 148 that it describes a direct hernia. 149 150 conclusion 151 strangulation and incarceration occur scarcely among direct inguinal hernias. general 152 surgeons usually do not repair asymptomatic direct hernias and choose to follow the 153 https://insightsimaging.springeropen.com/articles/10.1186/s13244-019-0715-9 https://www.cureus.com/articles/77749-epiploic-appendagitis-in-an-incarcerated-inguinal-hernia-a-case-report-and-literature-review https://pubmed.ncbi.nlm.nih.gov/33489592/ https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6076353/ https://pubmed.ncbi.nlm.nih.gov/32300033/ https://pubmed.ncbi.nlm.nih.gov/19547689/ https://pubmed.ncbi.nlm.nih.gov/35636214/ https://www.cureus.com/articles/77749-epiploic-appendagitis-in-an-incarcerated-inguinal-hernia-a-case-report-and-literature-review 6 ‘watch and wait approach’. however, the risk of complications increases significantly 154 with age and in the presence of certain concomitant diseases. consequently, being aware 155 of the fact that elective surgery for groin hernia is known to be a low-risk procedure, 156 patients suspected for groin hernia, should be considered for hernia repair depending on 157 their age, sex and clinical presentation, in order to avoid severe complications. 158 159 authors’ contributions 160 ek, pm, az, ai, span and dp managed the patient. spap and pm performed the 161 investigation. spap provided the required resources. sn and dp curated the data. sn and 162 dp supervised the work. spap and ek drafted the initial manuscript. ek, az and dp 163 reviewed and edited the manuscript. all authors approved the final version of the 164 manuscript. 165 166 references 167 1. berndsen mr, gudbjartsson t, berndsen fh. laeknabladid. 2019;105(9):385-391. 168 doi:10.17992/lbl.2019.09.247. 169 2. öberg s, andresen k, rosenberg j. etiology of inguinal hernias: a comprehensive 170 review. front surg. 2017;4:52. published 2017 sep 22. 171 doi:10.3389/fsurg.2017.00052 172 3. shakil a, aparicio k, barta e, munez k. inguinal hernias: diagnosis and 173 management. am fam physician. 2020;102(8):487-492. 174 4. kulacoglu h, kulah b, hatipoglu s, coskun f. incarcerated direct inguinal hernias: 175 a three-year series at a large volume teaching hospital. hernia 2000, 4 (3), 145–176 147. https://doi.org/130.1007/bf01207592. 177 5. pastorino a, alshuqayfi aa. strangulated hernia. [updated 2021 dec 28]. in: 178 statpearls [internet]. treasure island (fl): statpearls publishing; 2022 jan-. 179 available from: https://www.ncbi.nlm.nih.gov/books/nbk555972/ 180 6. hassler kr, saxena p, baltazar-ford ks. open inguinal hernia repair. [updated 181 2021 sep 18]. in: statpearls [internet]. treasure island (fl): statpearls publishing; 182 2022 jan-. available from: https://www.ncbi.nlm.nih.gov/books/nbk459309/ 183 7 7. the herniasurge group. international guidelines for groin hernia management. 184 hernia 22, 1–165 (2018). https://doi.org/10.1007/s10029-017-1668-x. 185 8. kamat m, singh n, nattey k. a rare encounter of obstructed direct inguinal hernia of 186 sliding variety. int j surg case rep. 2018;49:209-214. 187 doi:10.1016/j.ijscr.2018.06.025 188 9. ohene-yeboah m. strangulated external hernias in kumasi. west afr j med. 189 2003;22(4):310-313. doi:10.4314/wajm.v22i4.28053 190 10. hori t, yasukawa d. fascinating history of groin hernias: comprehensive 191 recognition of anatomy, classic considerations for herniorrhaphy, and current 192 controversies in hernioplasty. world j methodol. 2021;11(4):160-186. published 193 2021 jul 20. doi:10.5662/wjm.v11.i4.160 194 11. berger d. evidence-based hernia treatment in adults. dtsch arztebl int. 195 2016;113(9):150-158. doi:10.3238/arztebl.2016.0150 196 12. simons mp, aufenacker t, bay-nielsen m, bouillot jl, campanelli g, conze j et al. 197 european hernia society guidelines on the treatment of inguinal hernia in adult 198 patients. hernia. 2009;13(4):343-403. doi:10.1007/s10029-009-0529-7 199 13. shiryajev yn, glebova av, chalenko mv: strangulation and necrosis of an epiploic 200 appendage of the sigmoid colon in a right inguinal hernia. case rep surg. 2013, 201 2013:1-4. 10.1155/2013/890234 https://doi.org/10.1155/2013/890234 202 14. giambelluca d, cannella r, caruana g. et al. ct imaging findings of epiploic 203 appendagitis: an unusual cause of abdominal pain. insights imaging 10, 26 (2019). 204 https://doi.org/10.1186/s13244-019-0715-9 205 15. shiryajev yn, glebova av, chalenko mv: strangulation and necrosis of an epiploic 206 appendage of the sigmoid colon in a right inguinal hernia. case rep surg. 2013, 207 2013:1-4. 10.1155/2013/890234 208 16. monib s, hamad a, habashy hf. small bowel perforation as a consequence of 209 strangulated direct inguinal hernia. cureus. 2020;12(12):e12181. published 2020 210 dec 20. doi:10.7759/cureus.12181https://pubmed.ncbi.nlm.nih.gov/33489592/ 211 17. levi j, chopra k, hussain m, chowdhury s. rare giant inguinal hernia causing end-212 stage dialysis-dependent renal failure. bmj case rep. 2020;13(4):e233140. 213 published 2020 apr 15. doi:10.1136/bcr-2019-233140 214 https://doi.org/10.1186/s13244-019-0715-9 https://pubmed.ncbi.nlm.nih.gov/33489592/ 8 18. jain m, khanna s, sen b, tantia o. irreducible inguinal hernia with appendices 215 epiploicae in the sac. j minim access surg. 2008;4(3):85-87. doi:10.4103/0972-216 9941.43094 217 19. danish a. incarcerated right inguinal hernia containing sigmoid colon: an unusual 218 case report. int j surg case rep. 2022;95:107237. doi:10.1016/j.ijscr.2022.107237 219 220 221 figure 1: ultrasonography of left inguinal region, revealing hernia (white arrow) 222 223 224 figure 2: doppler ultrasonography revealing reduced blood flow of the hernia content. 225 226 9 227 figure 3: direct inguinal hernia containing an ischemic epiploic appendage (white 228 arrow); image taken during surgery. 229 230 table 1: examples of cases of complicated direct inguinal hernias. 231 author content sherif monib et al. 2020 58-year-old man with a direct strangulated hernia, complicated with a small bowel perforation. jacob levi et al. 2020 72-year-old man presenting with hematuria, urinary retention and severe acute kidney failure who was diagnosed with a direct incarcerated hernia containing the urinary bladder. manmohan kamat et al. 2018 83-year-old male with a direct obstructed hernia of sliding type containing congested loops of ileum as well as part of the urinary bladder. mayank jain et al. 2008 52-year-old man whose irreducible direct hernia contained inflamed epiploic appendices. ahmadullah danish 2022 65-year old man with an incarcerated inguinal hernia containing sigmoid colon and epiploic appendices. 232 july 2008.indd regional variation in the prevalence of asthma symptoms among omani school children comparisons from two nationwide cross-sectional surveys six years apart *omar a al-rawas,1 bazdawi m al-riyami,1 hussein al-kindy,2 abdullah a al-maniri,3 asya a al-riyami4 العمانيني املدارس أطفال بني الربو أعراض انتشار في اإلقليمي التباين سنوات ست بينهما مقطعيني مسحني بني مقارنة الريامي آسيا املنيري، اهللا عبد الكندي، بزدوي الريامي، حسني عمر الرواس، مختلف بني الربو انتشار في واسع وجود اختالف (isaac (ايزاك األطفال عند احلساسية للربو وأمراض الدولية الدراسة امللخص: الهدف: أكدت بالسلطنة. املناطق اتلفة املدارس في أطفال وأعراضه بني الربو في مدى انتشار االختالف حتديد إلى هذا البحث ويهدف الدولة. وحتى في نفس الدول الثالثة (املرحلة 2001 عام والثاني ــزاك) من اي األولى (املرحلة 1995 عام مقطعيني: األول ــحني مس بعمل ” ايزاك ” ــة ضمن دراس الطريقــة: قمنا وقد شارك في مناطق السلطنة. مبختلف املدارس طالب من (13-14 سنة) الكبار و ــنوات) (6-7 س الصغار عمريتني ــمالن مرحلتني يش ايزاك) من فئة 3753 من الصغار و 4126 من فئة ) 7879 طالبا ــي الثان وفي فئة الكبار) 3174 من الصغار و ــن فئة (3893 م ــا 7067 طالب األول ــح املس وأعراضه في املرحلتني بالربو لإلصابة معدل أعلى بإظهار ــرقية الش منطقة األولى استمرت ــة الدراس من ــنوات س ــت س النتائج: بعد مرور الكبار). ( % 17.8 13.8 % إلى (من الربو ــخيص في تش 13.8 % ) وكذلك 8.7 % إلى من ) الصدري الصفير ــار انتش معدل في واضح ارتفاع العمريتني مع نسب ظلت فقد املناطق ). أما بالنسبة لبقية % 27.8 %21.6 إلى من ) الكبار في الليلي ــعال الس في واضح ارتفاع ــاف اكتش كما مت الصغار. في فقد ظل الصدري بالصفير املصابني بني األطفال الربو أما تشخيص بعض املناطق. في هبوط طفيف مع وجود املسحني بني ثابتة الربو أعراض انتشار الشديد الصفير الصدري من األطفال ذوي 60 %) فقط ) حيث أن مرتفعة غير املشخص نسبة الربو ظلت كل املناطق بالسلطنة، كما في هو كما املدارس باملناطق بني أطفال وأعراضه الربو انتشار مدى في اختالف وجود الدراسة هذه تؤكد اخلالصة: ــحني. املس كال في لديهم الربو ــخيص بتش أقروا األطفال. هؤالء عند الربو تشخيص نسبة ضعف الدراسة تبني كما الشرقية. منطقة في ارتفاع واضح مع وجود بالسلطنة، اتلفة عمان. ، يافعني أطفال ، انتشار ، الكلمات: الربو ، مفتاح sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 157-164 sultan qaboos university© submitted 23rd january 2008 accepted 2nd february 2008 departments of 1medicine, 2child health, 3family medicine and public health, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; 4department of resarch studies, ministry of health, muscat, sultanate of oman *to whom correspondence should be addressed. email: orawas@squ.edu.om abstract objectives: the international study of asthma and allergies in children (isaac) highlighted the presence of wide variations in asthma prevalence between and within countries. the aim of this study was to determine the changes in the prevalence of asthma and its symptoms across the different regions of oman. methods: two cross-sectional surveys were conducted as part of isaac phases i (995) and iii (200) in two age groups (6-7 and 3-4 years) from nation-wide samples of omani school children, with 7,067 participants in 995 (3,893 young and 3,74 older group) and 7,879 participants in 200 (4,26 young and 3,753 older group). results: over the period of six years, the sharqiya (eastern) region continued to have the highest prevalence of self-reported asthma diagnosis and all asthma symptoms in both age groups, with a significant increase in the prevalence of wheeze in the past 2 months (from 8.7% to 3.8%; p=0.002) and asthma diagnosis (from 3.8% to 7.8 %; p=0.046) in the young group, and a significant increase in night cough (from 2.6% to 27.8%; p=0.039) in the older group. all other regions had lower prevalence rates in 995 in both age groups, and showed either no significant change or a decline in one or two of the self-reported asthma symptoms. the prevalence of asthma diagnosis among wheezy children remained unchanged across all regions. in addition, asthma under-diagnosis remains a problem with only 60% of children with severe wheeze reporting asthma diagnosis in both surveys. conclusion: the geographic variation in the prevalence of self-reported of asthma symptoms among omani school children persists with further increase in the sharqiya region. the findings also suggest under-diagnosis and/or poor recognition of asthma which had not improved over time. key words: asthma, prevalence; children; adolescents; oman. c l i n i c a l a n d b a s i c r e s e a r c h o m a r a a l r awa s , b a z d aw i m a l r i ya m i , h u s s i e n a l k i n d y, a b d u l l a h a a l m a n i r i a n d a s i ya a a l r i ya m i 158 asthma is one of the most common chronic conditions in children and is a major global health problem.1, 2 it is also perceived to be one of the most common chronic conditions in oman. studies from many different countries showed that the prevalence of asthma has been increasing over the last three decades and the results of the international study of asthma and allergies in childhood (isaac) confirmed the wide international variation in the prevalence of asthma diagnosis and symptoms.3, 4 asthma management has many components; the first of which is surveillance, which determines how much asthma exists in the population, how severe it is and how well it is being detected and controlled. such data enable healthcare providers to make evidencebased decisions in the development of asthma control programs.2 our participation in isaac phase i (conducted in 1995), yielded the first epidemiological survey into symptoms of asthma in oman, and revealed that asthma diagnosis and symptoms in omani children are not only common, but also associated with a relatively high prevalence of symptoms indicative of severe or uncontrolled asthma (sleep-disturbing wheeze, speech-limiting wheeze and frequent attacks of wheeze).5, 6 in addition, these results suggested under-diagnosis and/or undertreatment of asthma in these children. we also found a wide variation in the prevalence of asthma diagnosis and symptoms among the different geographical regions of the country with the sharqiya (eastern) region scoring the highest prevalence rates of self-reported asthma diagnosis and all asthma symptoms in both age groups.5 the aim of this study was to evaluate the changes in the prevalence of asthma symptoms and severity among omani schoolchildren across the different geographic regions of oman by comparing the data from isaac phases i (1995) and iii (2001). m e t h o d s the details of study design and methods have been previously described.5, 6 the study used the data collected in two isaac surveys 6 years apart (phase i in 1995 and phase iii in 2001) using identical isaac protocols during the same month of the year (april).7, 8 in both surveys, the total national target samples were randomly selected from the ten administrative (representing the eight geographical) regions of oman using the proportion allocation method. the total number of distributed questionnaires (arabic version) was 7,625 (4,079 aged 6–7 years and 3,546 aged 13–14 years) in 1995 and 8,080 questionnaires (4,235 aged 6–7 years and 3,853 aged 13–14 years) in 2001. the study design and data quality assurance followed the isaac protocol in all aspects, including the double entry of data and translation guidelines. in phase iii, in addition to the written questionnaire, 13-14 year old children completed the isaac asthma video questionnaire.8 the international version of the isaac video shows young adults from a variety of ethnic backgrounds manifesting different symptoms of asthma during a set of five different short sequences as follows: wheezing at rest, wheezing after exercise, waking at night by wheezing, night cough, advances in knowledge: the isaac project in oman provided the first insight into the prevalence of asthma and its symptoms in omani school children and this isaac phase iii survey reveals the following: • asthma symptoms in omani children are not only common, but also associated with a relatively high frequency of severe symptoms such as frequent wheeze and speech limiting wheeze. • there is also a significant difference in the prevalence of asthma and symptoms between the different regions of oman, the cause of which is unclear and merits further evaluation. • there was worrisome under-diagnosis of asthma in children all over oman and this had not improved between the two surveys. application to patients care: • alerts healthcare providers to the burden of asthma and its symptoms • highlights the need to consider asthma in children with respiratory symptoms so that appropriate treatment can be initiated promptly. r e g i o n a l va r i at i o n i n t h e p r e va l e n c e o f a s t h m a s y m p t o m s a m o n g o m a n i s c h o o l c h i l d r e n 159 and severe wheeze. after each scene, the children ticked the answer whether or not they experienced the same problems with breathing as the person in the video ever in life and if yes, whether in the past 12 months. the terms asthma and wheezing were not mentioned in the video questionnaire in order to avoid language problems. the primary outcome measure was the changes in the prevalence of wheeze in the past 12 months, “current wheeze” and self-reported asthma diagnosis. secondary outcome measures included the prevalence of exercise induced wheeze, night cough and symptoms suggestive of severe asthma. for the purpose of this analysis severe asthma was defined as the presence (positive response to the written questionnaire) of one or more of any of the following during the past 12 months: frequent wheeze (four or more wheezing attacks), frequents sleep disturbance (one night or more 6-7 year age group 13-14 year age group region isaac phase i number (% of total sample) isaac phase iii n (%) isaac phase i n (%) isaac phase iii n (%) muscat 518 (13.7) 639 (16.0) 507 (16.5) 636 (17.3) batinah 1167 (30.9) 1519 (38) 975 (31.7) 1291 (35.2) dakhiliya 550 (14.6) 434 (10.9) 485 (15.7) 551 (15) sharqiya 665 (17.6) 730 (18.3) 384 (12.5) 507 (13.8) dhahirah 384 (10.2) 355 (8.9) 353 (11.5) 340 (9.3) dhofar 493 (13.1) 319 (8) 376 (12.2) 345 (9.4) total national sample 3777 (100) 3996 (100) 3080 (100) 3670 (100) table 1: regional distribution of the two age groups in two surveys isaac phases i (1995) & iii (2001) 12 month prevalence of any wheeze exercise wheeze night cough severe asthma symptoms ever had asthma region phase i phase iii phase i phase iii phase i phase iii phase i phase iii phase i phase iii muscat 5.4 7.2 5.6 4.4 17.8 16.6 4.2 3.3 9.5 9.7 batinah 7.4 7.5 6.4 5.7 18.1 15.0* 6.3 4.8 9.4 8.8 dakhiliya 7.5 5.8 7.5 5.3 20.7 13.4 * 7.6 3.5* 12.2 7.8* sharqiya 8.7 13.8 9.0 10.3 25.6 27.3 7.4 8.6 13.8 17.3 * dhahirah 6.3 7.0 6.8 7.0 20.6 16.6 5.2 4.8 6.8 9.9 dhofar 6.3 6.6 7.1 5.6 16.2 22.6* 4.9 3.4 11.8 11.6 total sample 7.2 8.3 * 7.0 6.4 19.8 18.1 * 6.1 5.0* 10.6 10.7 *significant change in prevalence (p < 0.05) between the two surveys adjusted for sex table 2: regional difference in the prevalence (%) of asthma symptoms and diagnosis in 6-7 year age group: comparison between isaac phases i (1995) and iii (2001) o m a r a a l r awa s , b a z d aw i m a l r i ya m i , h u s s i e n a l k i n d y, a b d u l l a h a a l m a n i r i a n d a s i ya a a l r i ya m i 160 per week) and/or speech limiting wheeze.6 ethical approval of the study protocol was obtained from both the ministry of health and the ministry of education. data were collected and entered according to the isaac protocol and were analysed using the statistical package for the social sciences (spss) package for windows, version 13 (spss inc., chicago, il, usa). prevalence estimates were calculated by dividing the number of positive responses to each question by the total number of completed questionnaires. as the changes in males and females were very similar (both in the direction and magnitude of change), the findings were presented for both sexes combined adjusted for sex. comparisons between the two surveys were performed using the pearson chi-square test and results were adjusted for sex using logistic regression analysis. a p value of <0.05 was considered statistically significant. r e s u l t s the sex distribution in the total national sample as well as regional samples was nearly equal for both groups and both surveys. because of the small sample size of the musandam and wusta regions, the observed changes between the two surveys in these two regions may not be reliable and therefore were not included in the trend analysis. table 1 shows the regional distribution of the two age groups for both surveys (phase i in 1995 and phase iii in 2001). table 2 shows the changes in the prevalence of asthma diagnosis and its symptoms in the 6 to 7 year old age group. there was no significant change over the 6 year period in the nationwide prevalence of self-reported asthma or any of the listed asthma symptoms except for wheeze in the last 12 months which had slightly increased from 7.2% to 8.3% (p = 0.041). this was mainly driven by the high increase in the sharqiya region from 8.7% to 13.8 % (p = 0.002). the sharqiya region had the highest prevalence of parent-reported asthma diagnosis and symptoms in both surveys with a significant increase in self-reported asthma from 13.8% in 1995 to 17.8 % in 2001 (p = 0.046). on the other hand, the dakhiliya (interior) region had a significant drop in the prevalence of asthma diagnosis (from 12.2 % to 7.8 %; p = 0.016), night cough (from 20.7% to 13.4%; p = 0.003) and symptoms of severe asthma (from 7.6% to 3.5%; p = 0.005). there were no significant changes in asthma diagnosis and symptoms in any of the remaining regions (muscat, batinah, dhahirah and dhofar), except for night cough which increased in dhofar (from 16.2% to 22.6%; p = 0.025); and decreased in batinah (18.1% to 15%; p = 0.039). table 3 shows the changes in the prevalence of asthma diagnosis and symptoms between phase i and phase iii surveys in the13-14 year old age group. again, the sharqiya region had the highest prevalence of asthma diagnosis and all asthma symptoms in both phases with significant increase in the prevalence of night cough (from 21.6% to 27.8 %; p = 0.039). in batinah region, there was a significant drop in self-reported asthma diagnosis (from 24.5 % to 19.3 %; p = 0.003) and in symptoms of severe asthma (from 8.8 % to 6.4 %; p = 0.02) with no significant change in other 12 month prevalence of any wheeze exercise wheeze night cough severe asthma symptoms ever had asthma region phase i phase iii phase i phase iii phase i phase iii phase i phase iii phase i phase iii batinah 11.9 10.6 23.1 20.8 21.7 19.1 8.8 6.4 * 24.5 19.3* dakhiliya 5. 8 5.6 16.9 20.9 19.2 17.8 3.3 4.2 20.2 24.7 sharqiya 11.2 12.6 25.0 21.9 21.6 27.8* 7.8 7.5 28.6 28.8 dhahirah 7.9 11.5 17.8 17.4 19.0 20.0 5.4 7.4 15.0 15.0 dhofar 7.7 4.3 17.6 13.9 21.8 16.5 5.6 3.5 13.8 12.5 total sample 9.0 8.5 19.4 18.7 20.9 20.1 6.4 5.4 * 21.1 20.0 *significant change (p< 0.05) in prevalence adjusted for sex table 3: regional difference in the prevalence (%) of asthma symptoms and diagnosis in 13-14 year age group: comparison between isaac phases i (1995) and iii (2001) r e g i o n a l va r i at i o n i n t h e p r e va l e n c e o f a s t h m a s y m p t o m s a m o n g o m a n i s c h o o l c h i l d r e n 161 symptoms. the only change in the muscat region was in the prevalence of severe asthma symptoms which declined from 4.9% to 2.7% (p = 0.048). there was no significant change in asthma diagnosis or in any of the reported asthma symptoms in the remaining regions (dakhiliya, dhahirah and dhofar) in this age group. figure 1 shows the prevalence rates of wheeze in the past 12 months calculated from the written and video questionnaire responses for each region in the 13-14 years old age group of phase iii. in the total national sample, the frequency of positive responses to the video questionnaire was significantly lower than written questionnaire (7.0% versus 8.4%; p <0.001) with good correlation between the two responses (r = 0.60, p <0.001). the ranking of the regions by responses to both questionnaires was similar, with the sharqiya region recording the highest prevalence rate of wheeze in both questionnaires, with good correlation between the two responses in all regions (r values ranged from 0.48 in dhofar to 0.67 in batinah). the responses to the video and written questionnaires were similar in regions with relatively low prevalence of wheeze (dakhiliya, dhofar and muscat), whereas the responses to the video were lower than that of the written questionnaire in the regions with higher prevalence of wheeze (batinah, sharqiya, dhahirah). figure 2 shows the changes in the prevalence of self-reported asthma diagnosis among children (both age groups combined) who reported symptoms of severe asthma by region. in the nationwide sample, as well as in most regions, approximately 60% (ranging from 48.7% in dhahirah to 76.3% in muscat) of all children with severe asthma symptoms reported the diagnosis of asthma with no significant change in either the national average or any of the regions over the 6 year period. d i s c u s s i o n this study was a follow up on isaac phase i which took place in 1995 and was the first study ever done in oman on the prevalence of asthma in omani schoolchildren.5, 6, 9 the results of phase i highlighted two striking features of asthma in omani schoolchildren: the first was the relatively high prevalence of severe asthma symptoms compared to regional and international prevalence rates, and the second was the significant variation in asthma diagnosis and symptoms between the different regions of oman.5, 6 participation in the isaac phase iii survey in 2001 has provided us with an opportunity to analyse the changes in the prevalence of asthma diagnosis and symptoms over a period of 6 years (between 1995 and 2001) in the different regions of oman. the results of this study revealed that over a period of six years the sharqiya region continued to have the highest prevalence of self-reported asthma diagnosis and all symptoms of asthma in both age groups with a significant increase in the prevalence of current figure 1: the prevalence rates of wheeze in the past 12 months calculated from the written and video questionnaire for each region in the 13-14 years old age group in isaac phase iii (n = 3,679) o m a r a a l r awa s , b a z d aw i m a l r i ya m i , h u s s i e n a l k i n d y, a b d u l l a h a a l m a n i r i a n d a s i ya a a l r i ya m i 162 wheeze and asthma diagnosis in the 6 to 7 year old age group and a significant increase in night cough in the older group. all other regions had lower prevalence rates in 1995 in both age groups, and showed either no change or a decline in one or two of the asthma symptoms. in general, the prevalence of asthma symptoms in the different regions of oman in phase iii resembled phase i results. the regional variation in the prevalence of asthma symptoms within oman is similar to reports from other countries and is consistent with isaac findings.9-11 the cause of the higher and increasing prevalence of asthma symptoms in the eastern (sharqiya) region compared to other regions of oman is not clear, and in the absence of previous information, all the possible factors of high asthma prevalence need to be considered and evaluated.12-15 thus the observed regional difference may be explained by differences in one or more of the following factors: interpretation of the written questionnaire, recognition of asthma diagnosis and symptoms, healthcare utilization and prevalence of genetic and environmental risk factors.13 although the possibility of regional differences in the interpretation of the written questionnaire can not be completely excluded, our analysis suggests that it is unlikely to be a significant factor.16 the arabic version of the written questionnaire had been previously validated,17 and the arabic translation of the english term “wheeze” used descriptive words/phrases common to all regions of oman. in addition, the pattern of difference in the prevalence of cough, a symptom with more uniform interpretation, mirrored that of wheeze. furthermore, the ranking of the regions for the prevalence of wheeze in the past 12 months was similar in both the written and the video questionnaires (sharqiya region had the highest rates in both questionnaires). by showing, rather than describing, symptoms of asthma, the isaac video questionnaire was developed to minimise the effect of language, culture, and literacy.18, 19 like most centres, the frequency of positive responses of our children to question on wheezing in the last 12 months on the video questionnaire was lower than the written questionnaire.9, 20 it has been suggested that the visible and audible scenes on a video are likely to represent more severe symptoms than the full spectrum from mild to severe asthma covered by the written questionnaire.21 another possible factor to be considered is poor recognition and/or under-diagnosis of asthma. children and parents who are more alert to asthma and its symptoms are more likely to report it, and physicians who are more alert to a particular condition, tend to diagnose more cases.22-25 in addition, under-diagnosis and/or under-treatment of asthma is associated with higher prevalence of severe asthma symptoms.26, 27 in our study, only 60% of children with severe asthma figure 2: the changes in the prevalence of self-reported asthma diagnosis among children (both age groups combined) who reported symptoms of severe asthma by region. r e g i o n a l va r i at i o n i n t h e p r e va l e n c e o f a s t h m a s y m p t o m s a m o n g o m a n i s c h o o l c h i l d r e n 163 symptoms reported asthma diagnosis, with no significant difference between sharqiya and other regions. although this suggests poor recognition and/or under-diagnosis of asthma across the country, which has not improved over time and merits attention, it does not explain the observed differences between regions. since this study did not investigate the pattern of asthma management or the health seeking behaviour among asthmatics, it is not possible to determine if there were regional differences in the use of effective treatment, especially inhaled corticosteroids which could reduce the prevalence of severe asthma symptom.28-31 it is possible that the observed decline in the prevalence of severe asthma symptoms in most regions was due to improved use of effective treatment. however, the use of effective treatment is unlikely to affect the prevalence of asthma diagnosis, and is therefore unlikely to explain the regional difference in prevalence of asthma. although there is no information available on the prevalence of ‘established’ asthma risk factors in oman, the observed regional difference in asthma symptoms may be due to differences in the prevalence of genetic and/or environmental risk factors.2 potential factors include family history of atopy, sensitisation to aeroallergens such as house dust mite, respiratory infections, dietary habits, parental smoking, and residence in urban areas. these factors may influence the pathogenesis and severity of asthma and require investigation. the finding of the regional difference in the prevalence of asthma symptoms in both age groups, suggest that the causes of this difference exert their effect early in childhood.10 c o n c l u s i o n in conclusion, this study demonstrated a relatively high prevalence of asthma in omani schoolchildren with significant variations between its regions. it alerts healthcare planners and providers to the particularly high and rising prevalence of asthma symptoms in the sharqiya region and to the need to investigate the possible causes and prioritise resources for asthma control. a c k n ow l e d ge me n ts this study was supported by a grant from sultan qaboos university research fund, sultanate of oman. we thank all children and parents of children who participated in the study. we also thank the school health physicians of the ministry of health for distributing and retrieving the questionnaires. r e f e r e n c e s 1. smyth rl. asthma: a major pediatric health issue. respir res 2002; 3:s3-s7. 2. eder w, ege mj, von mutius e. the asthma epidemic. n engl j med 2006; 355:2226-2235. 3. asher i. isaac international study of asthma and allergies in childhood. pediatr pulmonol 2007; 42:100. 4. asher mi, montefort s, bjorksten b, lai ck, strachan dp, weiland sk, et al. worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: isaac phases one and three repeat multicountry cross-sectional surveys. lancet 2006; 368:733-743. 5. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. prevalence of asthma symptoms in omani schoolchildren. squ journal for scientific research medical sciences 2001; 3:21-27. 6. al-riyami bm, al-rawas oa, al-riyami aa, jasim lg, mohammed aj. a relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the sultanate of oman. respirology 2003; 8:69-76. 7. asher mi, keil u, anderson hr, beasley r, crane j, martinez f, et al. international study of asthma and allergies in childhood (isaac): rationale and methods. eur respir j 1995; 8:483-491. 8. ellwood p, asher mi, beasley r, clayton to, stewart aw. the international study of asthma and allergies in childhood (isaac): phase three rationale and methods. int j tuberc lung dis 2005; 9:10-16. 9. worldwide variations in the prevalence of asthma symptoms: the international study of asthma and allergies in childhood (isaac). eur respir j 1998; 12:315-335. 10. carvajal-uruena i, garcia-marcos l, busquets-monge r, morales-suarez-varela m, garcia de andoin n, batlles-garrido j, et al. geographic variation in the prevalence of asthma symptoms in spanish children and adolescents. international study of asthma and allergies in childhood (isaac) phase 3, spain. arch bronconeumol 2005; 41:659-666. 11. bener a, al-jawadi tq, ozkaragoz f, anderson ja. prevalence of asthma and wheeze in two different climatic areas of saudi arabia. indian j chest dis allied sci 1993; 35:9-15. 12. nolte h, backer v, porsbjerg c. environmental factors as a cause for the increase in allergic disease. ann allergy asthma immunol 2001; 87:7-11. 13. pearce n, douwes j. the global epidemiology of asthma in children. int j tuberc lung dis 2006; 10:125-132. 14. wong gw, chow cm. childhood asthma epidemiology: insights from comparative studies of rural and uro m a r a a l r awa s , b a z d aw i m a l r i ya m i , h u s s i e n a l k i n d y, a b d u l l a h a a l m a n i r i a n d a s i ya a a l r i ya m i 164 ban populations. pediatr pulmonol 2008; 43:107-116. 15. wong gw, von mutius e, douwes j, pearce n. environmental determinants associated with the development of asthma in childhood. int j tuberc lung dis 2006; 10:242-251. 16. kemp t, pearce n, crane j, beasley r. problems of measuring asthma prevalence respirology 1996; 1:183-188. 17. miller cj, joseph j, safa w, flood pe, dunn ev, shaheen hm. accuracy of arabic versions of three asthma symptoms questionnaires against the clinical diagnosis of asthma. j asthma 2007; 44:29-34. 18. beasley r, lai ck, crane j, pearce n. the video questionnaire: one approach to the identification of the asthmatic phenotype. clin exp allergy 1998; 28:8-12. 19. pekkanen j, pearce n. defining asthma in epidemiological studies. eur respir j 1999; 14:951-957. 20. pearce n, aït-khaled n, beasley r, mallol j, keil u, mitchell e, et al. worldwide trends in the prevalence of asthma symptoms: phase iii of the international study of asthma and allergies in childhood (isaac). thorax 2007; 62:758-766. 21. crane j, mallol j, beasley r, stewart a, asher mi. agreement between written and video questions for comparing asthma symptoms in isaac. eur respir j 2003; 21:455-461. 22. van sd. perceptions of asthma among physicians: an exploratory study with the isaac video. eur respir j 2005; 26:829-834. 23. chew ft, goh dy, lee bw. under-recognition of childhood asthma in singapore: evidence from a questionnaire survey. ann trop paediatr 1999; 19:83-91. 24. al-shadli am, bener a, brebner j, dunn ev. asthma diagnosis and management in adults: is the risk of underdiagnosis and under treatment related to patients’ education levels? j asthma 2001; 38:121-126. 25. grech v, agius-muscat h, montefort s, lenicker h. recognition of asthmatic symptoms in the pediatric age group. pediatr allergy immunol 2001; 12:49-53. 26. yeatts k, shy c, sotir m, music s, herget c. health consequences for children with undiagnosed asthma-like symptoms. arch pediatr adolesc med 2003; 157:540544. 27. van gent r, van essen le, rovers mm, kimpen jl, van der ent ck, de meer g. quality of life in children with undiagnosed and diagnosed asthma. eur j pediatr 2007; 166:843-848. 28. aït-khaled n, auregan g, bencharif n, camara lm, dagli e, djankine k, et al. affordability of inhaled corticosteroids as a potential barrier to treatment of asthma in some developing countries. int j tuberc lung dis 2000; 4:268-271. 29. mommers m, swaen gm, weishoff-houben m, dott w, van schayck cp. differences in asthma diagnosis and medication use in children living in germany and the netherlands. prim care respir j 2005; 14:31-37. 30. butland bk, strachan dp, crawley-boevey ee, anderson hr. childhood asthma in south london: trends in prevalence and use of medical services 1991-2002 thorax 2006; 61:383-387. 31. beasley r. unmet need in inadequately controlled asthma. respirology 2007; 12 suppl 3:s18-s21. march 2007 vol 7 isuue 1 final without suicide .indd abstract objective: the objective of this study was to evaluate the efficacy of unfractionated heparin, warfarin and low molecular weight heparins (lmwh) used for the prevention of venous thromboembolism in arthroplastic surgery of the knee joint. methods: in this prospective study from august 2002 to november 2004, 60 patients were included and divided into three groups with equal numbers, with each group receiving different treatment protocol. postoperatively, the occurrence of symptomatic deep vein thrombosis (dvt) or pulmonary embolism (pe) was recorded during the first 30 days after surgery and at a routine follow-up visit. results: a significantly lower prevalence of dvt and pe was found in patients using warfarin and lmwh as prophylaxis in comparison with patients using unfractionated heparin. conclusion: warfarin and low molecular weight heparins are more beneficial and effective than unfractionated heparin for dvt and pe prophylaxis in arthroplastic knee surgeries. keywords: arthroplasty, deep vein thrombosis (dvt), prophylaxis, low molecular weight heparin, warfarin. pharmacologic prophylaxis and treatment of venous thromboembolism after knee arthroplasty *jamal s shawabkeh, malek m ghnaimat, ammar m hijazi sultan qaboos university medical journal april 2007 vol 7, no. 1 sultan qaboos university© orthopedic department, royal jordanian medical services, p o box 517, amman 11118, jordan *to whom correspondence should be addressed. email: drjamalss@yahoo.com c l i n i c a l & b a s i c r e s e a r c h مفصل رأب بعد الوريدي اخلثاري االنصمام ومعاجلة الوقاية الدوائية الركبة حجازي وعمار غنيمات مالك الشوابكة، جمال اخلثاري االنصمام من استخدامها للوقاية عند املنخفض، اجلزيئي الوزن ذو والهيبارين والوارفيرين ازأ الهيبارين غير فعالية امللخص: الهدف: تقييم جلراحة رأب مفصل خضعوا مريضا ــتني أجريت على س ــتقبلية) (املس ــتِبَاقِيَّة االِسْ ــة الدراس الركبة. الطريقة: هذه مفصل جراحة رأب الوريدي في كل ــاوية، متس ثالث مجاميع وبأعداد ــيمهم إلى تقس 2004 ، ومت ــر عام نوفمب 2002 وحتى عام ــطس أغس من املمتدة الفترة ــالل خ ــى األول ــة الركب يوما ثالثني خالل أول العرضي الرئوي االنصمام أو العرضي العميق الوريدي اخلثار حاالت تسجيل مت عن اآلخرين. مختلف بنظام معني عوجلت مجموعة الرئوي االنصمام و العميق الوريدي اخلثار في حاالت نقص الفت ــكل بش ــة الدراس الروتينية. النتائج: أظهرت املتابعة زيارات خالل ومن اجلراحة بعد غير الهيبارين يستخدمون الذين مع املرضى باملقارنة وقائي بشكل املنخفض اجلزيئي الوزن ذو الوارفيرين والهيبارين يستخدمون املرضى الذين عند العميق الوريدي اخلثار غير ازأ في حاالت الهيبارين من وفعالية فائدة اكثر املنخفض اجلزيئي ــوزن ال ذو الهيبارين و ــزأ. اخلالصــة: يعد الوارفيرين ا اجلراحية. الركبة رأب مفصل في حاالت الرئوي واالنصمام املنخفض. اجلزيئي الهيبارين ذو الوزن ، الوارفيرين الوقاية، ، العميق الوريدي اخلثار من الوقاية ، الكلمات: رأب املفصل مفتاح patients having primary or revision total knee arthroplasty have an increased risk of the de-velopment of thromboembolism. without prophylaxis, the overall prevalence of thromboembolism has been reported to range from 40% to 84%, with proximal thrombi in 9% to 24% of patients.1 symptomatic pulmonary embolism (pe) has been reported to occur in up to 7% of patients having total knee arthroplasty without prophylaxis, being fatal in 2% of them.2 most surgeons recommend routine prophylaxis against thromboembolism, but there is controversy about the optimal method. m e t h o d s this is a study of three consecutive anti-thromboembolism regimens after total knee arthroplasty conducted in the farah royal rehabilitation centre, jordan, during the period august 2002 to november 2004. a total of sixty patients were included in the study. after the purpose of the study and the possible complications j a m a l s . s h awa b k e h , m a l e k m . g h n a i m at a n d a m m a r m . h i j a z i 48 were explained to the patients, permission was taken. this study has been also authorized by the scientific and research committee of the royal jordanian medical services. three prophylactic methods were used and the patients were classified into three groups, group a (n=20), who received unfractionated heparin in a fixed dose of 5000 iu, beginning at the night of surgery, twice daily subcutaneous; group b (n=20), who received warfarin 10 mg daily two days prior to surgery, the dose being titrated according to inr (international normalized ratio) level; and group c (n=20), who received lmwh at the night of surgery in a dose of 20 mg daily one day prior to surgery. all the surgeries were done under general anaesthesia. patients with a previous history of deep vein thrombosis (dvt), chronic venous insufficiency, stroke, varicose veins, malignancy, renal insufficiency, recent myocardial infarction, heart failure, and those taking oral contraceptives, or steroidal/hormonal/anticoagulant drugs for any medical condition, were excluded from the study. no mechanical devices were used in dvt prophylaxis in the study. all the patients were mobilized from bed on the first day post-operatively. post-operative assessment for dvt was done in all patients on both the lower limbs by color doppler ultrasonography including an examination of bilateral common femoral, superficial femoral, popliteal, anterior tibial, and posterior tibial veins. they were assessed for flow, visualized thrombus, compressibility, and augmentation. a diagnosis of dvt was made where there was visualization of thrombosis, absence of flow, lack of compressibility, or lack of augmentation. a spiral ct scan was used for the diagnosis of pe. patients on lmwh were discharged from the hospital after two weeks with a weekly follow up for two weeks. those on heparin and warfarin were discharged after ptt (partial thromboplastin time) and inr levels were adjusted and followed up in weekly visits. no complications of the drugs used were encountered. thrombi were classified as proximal if the popliteal or femoral veins were involved and distal if only the veins of the calf were involved. if the duplex scan showed a calf vein thrombus and the patient was asymptomatic, the prophylaxis was continued and the scan was repeated in one week. in the asymptomatic patient with a popliteal or femoral vein thrombus, the prophylaxis was considered to have failed and anticoagulation was started with lmwh. oral anticoagulation, with a goal of a prothrombin time of 15 to 18 seconds, was continued for 12 weeks. the symptomatic patients with a calf thrombus were treated according to the surgeon’s judgment, but the symptomatic patients with popliteal or femoral thrombi routinely were given heparin followed by warfarin for 6 months. r e s u l t s postoperatively, occurrence of symptomatic dvt or pe was recorded during the first 30 days after surgery and at a routine follow-up visit. in group a, symptomatic dvt was diagnosed in 4 patients (20%) of which two patients had proximal dvt, while pe occurred in two patients (10%). patients in group b showed a lower incidence of symptomatic dvt (5%) than those patients in group c (10%), with no recorded cases of pe in both groups b and c, as shown in table 1. d i s c u s s i o n several studies have evaluated the efficacy of lmwh and warfarin for prophylaxis against thromboembolism after total knee arthroplasty.3, 4-9 there is no clinically significant difference between warfarin and enoxaparin prophylaxis in terms of efficacy (venographic or clinical events) and safety for hip arthroplasty patients.7 there is no significant difference in terms of clinical events between warfarin and lmwh prophylaxis in knee arthroplasty patients.9 there are fewer venographic events with lmwh. the safety seems comparable, but lmwh should be started the day after surgery in knee patients. warfarin is one of the most commonly used prophylactic agents against thromboembolic disease in groups incidence of deep vein thrombosis (dvt) incidence of pulmonary embolism (pe) a 20% 10% b 5% 0% c 10% 0% table 1: incidence of dv t or pe in groups a, b & c p h a r m a c o l o g i c p r o p h y l a x i s a n d tr e at m e n t o f ve n o u s th r o m b o e m b o l i s m a f t e r k n e e a r t h r o p l a s t y 49 hip arthroplasty patients. for four decades, low-dose warfarin has been used successfully for prophylaxis against deep vein thrombosis following total knee replacement, and its efficacy has been proven both in both studies and well-designed clinical trials.16, 17 the reported venographic rates for overall dvt are between 10% and 20% and between 5% and 10% for proximal dvt. major bleeds occur in 1% to 3% of the cases and minor bleeds in 2% to 5%. warfarin interferes with vitamin k metabolism in the liver and prevents the formation of functional clotting factors ii, vii, ix, and x. it takes at least 36 hours to have a measurable effect, and 4 to 5 days to reach effective anticoagulation. dose response to warfarin, especially in surgical patients, is highly variable, and prothrombin time (pt) monitoring is necessary. the anticoagulant effect is expressed in the inr value, which corrects for the variability in sensitivity of the different reagents used in various institutions to measure prothrombin time (pt). high-molecular-weight heparin fractions, however, have a strong affinity for platelets where they inhibit the aggregation. they also inhibit platelet function and vascular smooth-muscle cell proliferation. these fractions delay hypersensitivity reactions and increase the permeability of vessel walls. finally, they have been implicated in the regulation of angiogenesis commercial heparin is a heterogeneous mixture of sulfated polysaccharide chains of molecular weights ranging from 3,000 to 30,000 daltons (mean 15,000). one-third of the heparin, mostly low-molecular-weight fractions, binds to antithrombin iii and is responsible for most of the anticoagulant activity at therapeutic levels. at the molecular level, heparin acts on antithrombin iii by inducing a conformational change which unmasks an arginine center, which in turn inhibits the active serine center of thrombin and other coagulation enzymes. after doing so, heparin dissociates from antithrombin iii and can be reused. lmwh is not a homogenous drug, but it contains only polysaccharide chains of less than 8000 daltons. there are many commercially available lmwhs which are prepared by various processes. these preparations are pharmacologically different from each other and, therefore, may not be clinically identical. compared to standard heparin, lmwh fragments have a better bioavailability, a longer half-life, a lesser platelet inhibitory effect.10 clinical studies have reported a 60% to 80% overall radiographic dvt risk reduction in hip arthroplasty patients with lmwh when compared to a placebo. no significant increase in major bleeding complications was found, but a significant increase in minor bleeds (mostly subcutaneous hematomas) has been noted.11 the potential advantages of lmwh compared to unfractionated regular heparin are more predictable dose response, longer half-life and less hemorrhagic effect for a given antithrombotic effect. recent studies have demonstrated the efficacy and safety of outpatient treatment of acute proximal dvt using lmwh.12,13 in these randomized trials, intravenous heparin was compared with outpatient lmwh, given twice-daily in a weight-adjusted dose regimen. warfarin therapy was started on the first day of treatment in both study groups. during follow-up, there were no significant differences in the incidence of recurrent venous thromboembolism or bleeding complications.14 outpatient treatment of acute dvt is a promising and more versatile approach than conventional, in-hospital treatment and is likely to be more cost-effective. outpatient treatment of dvt with the combination of lmwh and warfarin should be employed by centres experienced in the treatment of thromboembolic disorders. an ideal prophylactic regimen has not been identified and the selection of an appropriate agent is usually a balance between efficacy and the risk of bleeding. the most effective prophylactic agents for these patients include low-molecular-weight heparin, warfarin, and fondaparinux,15 as we found in our study. we suggest the usage of lmwh or warfarin in the prophylaxis of dvt and pe for a thirty day period. more prolonged prophylaxis should be considered following total joint arthroplasties in patients who are at higher risk, including those with a history of venous thromboembolic disease, limited mobilisation, obesity, and cancer.18, 19 c o n c l u s i o n the usage of lmwh and warfarin is a more beneficial and effective method for the prophylaxis of deep vein thrombosis and pulmonary embolism after knee arthroplasty than unfractionated heparin. this finding corroborates other studies in the literature. r e f e r e n c e s 1. francis cw, pellegrini vd, stulberg bn, et al. prevention of venous thrombosis after total knee arthroplasty. j bone joint surg am 1990; 72:976-982. j a m a l s . s h awa b k e h , m a l e k m . g h n a i m at a n d a m m a r m . h i j a z i 50 2. khaw fm, moran im, smith sr: the incidence of fatal pulmonary embolism after knee replacement with no prophylactic anticoagulation. j bone joint surg br 1993; 75:940-941. 3. fitzgerald rh: preventing dvt following total knee replacement: a review of recent clinical trials. orthopedics 1995; 18 (suppl):10-11. 4. pulmonary embolism prevention (pep) trial collaborative group: prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: pulmonary embolism prevention (pep) trial. lancet 2000; 355:1295-1302. 5. colwell cw, spiro te, trowbridge aa, et al. efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep venous thrombosis after elective knee arthroplasty. clin orthop 1995; 321:19-27. 6. hull rd, raskob ge. current concepts review. prophylaxis of venous thromboembolic disease following hip and knee surgery. j bone joint surg am 1986; 68:146150. 7. leclerc jr, geerts wh, desjardins l, et al. prevention of deep vein thrombosis after major knee surgery, a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo. thromb haemost 1992; 67:417-423. 8. rd heparin arthroplasty group: heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. j bone joint surg am 1994; 76:1174-1185. 9. spiro te, fitzgerald rh, trowbridge aa, et al. enoxaparin (a low molecular weight heparin) and warfarin for the prevention of venous thromboembolic disease after elective knee replacement surgery. blood 1994; 84 (suppl 1):246a 10. carter c, kelton j, hirsh j, et al. the relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. blood 1982; 59:1239-1245 11. colwell cw, spiro te, trowbridge aa, et al. use of enoxaparin, a low molecular weight heparin, and unfractionated heparin for the prevention of deep vein thrombosis after total hip replacement. j bone joint surg am 1994; 76:3-14. 12. levine mn, gent m, hirsh, et al. a comparison of low molecular weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. new engl j med 1996; 334:677-681. 13. koopman mmw, prandoni p, piovella p, et al. treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared to subcutaneous low molecular weight heparin administered at home. new engl j med 1996; 334:682-687 14. o’reilly rf, burgess ia, zicat b. prevalence of venous thromboembolism after hip and knee replacement surgery, med j aust 2005; 182:154-159. 15. lieberman jr, wellington kh. prevention of venous thromboembolic disease after total hip and knee arthroplasty, j bone joint surg am 2005; 87:2097-2112. 16. fitzgerald rh jr, spiro te, trowbridge aa, et al. prevention of venous thromboembolic disease following primary total knee arthroplasty. j bone joint surg am 2001; 83:900-906 17. heit ja, elliott cg, et al. ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. ann intern med 2000; 132:853-861. 18. geerts wh, pineo gp, heit ja, et al. prevention of venous thromboembolism: the seventh accp conference on antithrombotic and thrombolytic therapy. chest 2004; 126 (suppl 3):338s-400s. 19. kearon c. duration of venous thromboembolism prophylaxis after surgery. chest 2003; 124(suppl 6):386s -392s. january 2007 vol 7 correct a.indd abstract objective: little published research exists in the area of fetal thigh biometry, specifically in the use of the anteriorposterior fetal thigh diameter (aptd). a continuing review of existing practices needs to be coupled with evaluation of alternate or additional methodology. this study evaluated the usefulness and direct correlation of a simple, new method of predicting fetal age by measurement of the anterior-posterior thigh diameter (aptd) in a normal 8-to 28 week pregnancies using two-dimensional sonography. methods: this was a quantitative prospective study of 55 patients in the high level general hospital, alberta, canada. anterior-posterior thigh diameters (aptd) were sonographically measured and the normal range for each week of pregnancy was determined five times for reliability. results: significant correlation was found between (aptd) and fetal age from simple line regression analysis, with >99.9% confidence intervals at each week from 8 to 28 weeks gestation. there was a correlation of  mm aptd per  week of fetal age. the standard error of estimation was very low at (0.08664) in edition (r>0.9993) and (p < than 0.000). the residual scatter plots confirmed the aptd validity. conclusion: aptd is a reliable and valid method for assessing fetal age in a normal pregnancy and may be particularly useful when other parameters are unable accurately to predict fetal age. an accurate linear measurement of multiple fetal parameters allows a more complete profile of fetal growth and estimated date of delivery (edd). aptd may also be useful in identifying fetal growth problems. all of the values of fetal age lie directly on the “best-fit” regression line. since the coefficient of determination (rsq) is very high, this model is very effective. keywords: fetal age, aptd, anterior-posterior thigh diameter, parameters anterior-posterior thigh diameter measured by twodimensional sonography indicator of fetal age at 8 to 28 weeks gestation ? saad r i al-kubaisi there is no existing literature comparing fetal thigh diameter with fetal age and estimated dates of delivery (edd). however, femur length in the 18 to 38 weeks fetus has been shown to have a relationship to subsequent blood pressure in childhood.1 there are many parameters ultrasound supervisor, high level general hospital, nwhc, alberta, canada, p.o.box 1462 high level, ab, t0h 120 email: saa3d@hotmail.com التصواتي التخطيط اخللفي بواسطة جهاز االمامي الفخذ قطر قياس ؟ 28-18 اسبوعا من احلمل بني عمر اجلنني عمر مؤشر احلمل الطبيعي أثناء اجلنني وعمر ذلك بني املباشرة ، والعالقة اخللفي – االمامي اجلنني فخذ قطر قياس من االستفادة مدى امللخص: الهدف: تقييم دراسة استباقية ألطريقة: هذه ثنائي البعد. وتية) فَوقَ الصَّ وَاجِ باألَمْ طيطٌ (تَخْ وَاتِيِّ التَصْ طيطٌ التَخْ جهاز استعمال بواسطة ،28 – 18 االسبوع بني وَاتِيِّ ، التَصْ طيطٌ التَخْ ــاز ــطة حه بواس للفخذ اخللفي االمامي القطر قياس مت . (كندا) ــي البيرتا ف عام متطور ــفى مستش في 55 مريضة ــملت ش الفخذ قطر بني ترابط كبير هناك أن لوحظ النتائج: . (االعتمادية) وَّلِيَّة ُعَ امل من للتأكد مرات خمس حسابه مت احلمل من اسبوع الطبيعي لكل واملدى ترابط %99 . هناك بنسبة ةِ الثِّقَ دُّ حَ مع وُّف) التّحَ لُ عامِ (مُ االحصائي التحليل حسب 18 – 28 اسبوعا) عمر (بني اجلنني وعمر اخللفي – االمامي (االحتمالية االحصائية الناحية من جدا متدنيا كان للحساب املعياري اخلطأ . احلمل من اسبوع لكل للفخذ اخللفي – االمامي القطر من 1 ملم بني اخللفي للفخذ – االمامي القطر قياس أن البحث هذا اخلالصة: أثبت . املتبقي االنتشار احصائيا برسم دوقِيَّة ايضا َصْ امل وأكدت .(0.0001 أقل من مختلف جمع ميكن كما . االخرى القياسات على احلصول يتعذر حني خاصة وبصورة ، الطبيعي احلمل أثناء عمر اجلنني في قياس وْق دُ صْ ومَ عليه وَّل عَ مُ هذه .تعتبر اجلنني عند النمو ــاكل مش معرفة ميكن كذلك املذكور الفخذ وبقياس . الوالدة ملوعد أدق ــد ولتحدي ملعرفة منوه باجلنني ــة اخلاص ــات القياس . لها الداللة االحصائية لقوة وذلك جدا فعالة الطريقة قياسات اخللفي، – االمامي الفخذ قطر اجلنني، : عمر املفتاحية املفردات sultan qaboos university medical journal december 2006 vol 6, no. 2 sultan qaboos university© o r i g i n a l s t u d y s a a d r i a l k u b a i s i 48 that can be tested by sonography, including biparietal diameter (bpd), abdominal circumference (ac), head circumference (hc) and femur length (fl). it is important to find a new parameter for measuring fetal growth that correlates with fetal age so that fetuses that are not growing well can be identified and treated. the taner et al.2 study has shown that there is a relationship between femur length (fl) and fetal age, however the measurement of femur length has a potential technical error factor involving the non-visible epiphyses, which is often not considered.2 multiple factors may influence the fetal biometry including, for example, pathological factors that affect the fetal head meauserments.3 fetal organ sizes remains small during early pregnancy, followed by a period of rapid growth with rate and time vary for individual organs.4 barker’s5,6 studies have shown that this critical period of growth can be affected by external and internal factors. fe ta l m a l nu tr i ti o n there is evidence that poor nutrition can reduce the number of beta cells in the pancreas causing glucose intolerance.7 kurmanvicius’8 studies have shown fetal biometric accuracy in predicting suspected fetal malnutrition to be overestimated. many factors contribute to fetal weight differences: maternal factors (race, stature), environmental factors (altitude, nutrition, and smoking), physiological factors (glucose metabolism), pathological factors (hypertension, uterine pathology), and complications of pregnancy (diabetes mellitus, pre-eclampsia).9-16 most published methods for fetal weight assessment are significantly subject to predictive errors.17, 18 i n tr au te r i n e gr ow th r e str i c ti o n ( iu gr at a simplistic level, intrauterine growth restriction is a problem caused by restricted oxygen and nutrient delivery to the fetus, leading to a failure of normal intrauterine growth.19, 20 among the many factors that can influence iugr are maternal disease (eg, hypertension), poor maternal nutrition (eg, smoking, substance abuse), anatomical factors (eg, placental site and function) and fetal disorders (eg, genetic disorders). 19, 21, & 22 th e r e l i a bi l i t y o f multi pl e pa r a me te r s yoshida et al.23 studies have supported the use of multiple parameters to improve the accuracy of fetal age and weight estimation. a birth weight of less than 2500g, or greater than 4,700g, are risk factors for fetal and delivery complications.24 taylor et al.25 studies have provided a logical explanation of why it is necessary to measure the fetal leg. it suggested that some times measuring the fetal head is impossible, for example when it is too low in the pelvic cavity, and therefore alternate methods must be used. taylor et al.’s 25 formula of femur length, multiplied by the square root of the cross sectional area of thigh, has shown a significant correlation with fetal weight. the validity of estimated fetal weight is reported to be either below or above the normal limits by using fetal biometry formulas as described in cheng et al.’s method.26 ratanasiri et al.’s27 formulas of fetal weight showed more accuracy than other fetal weight formulas. the nahum et al.28 study has indicated that there is no substantial correlation between maternal obesity and fetal weight gain at term pregnancy and it is reported clinically insignificant. fetal thigh calf circumference ratios showed excellent results in evaluating fetal growth in high-risk patients in late pregnancy, with unknown due dates.29 zelop et al.’s 30 studies have shown that race and ethnicity do not affect the regression line of long bones and fetal head biometries. jeanty et al.’s 31 studies have indicated that using more than one fetal biometry parameter can increase the reliability and accuracy in determining fetal age and the estimated date of delivery, especially when using long bone biometry from 12 to 40 weeks gestation. jeanty et al.’s32 study has found limb volume to be a reliable predictor of intrauterine growth restriction and correlates strongly with fetal age. flanagan et al.’s 39 study has indicated that there is no relationship between birth size and insulin sensitivity or insulin secretion in women. chitkara et al.’s 33 studies have shown that a short fetal ear length is indicative of high-risk figure 1: label a is showing the wrong way to measure fetal thigh (coronal) and label b is showing the correct way to measure the anteriorposterior thigh diameter (aptd) in the sagittal plane (profile). a n t e r i o r p o s t e r i o r th i g h d i a m e t e r m e a s u r e d b y tw o d i m e n s i o n a l s o n o g r a p h y 49 chromosomal abnormality. fetal alcohol syndrome is a threat to the fetus, caused by the mother drinking alcohol during pregnancy, and may cause the fetus to have a lower body weight and smaller body size.34 fe ta l path o l o g y a n d bi ome try with the use of fetal measurements, wide ranges of pathological conditions can be discovered.35 among these are chromosomal abnormalities (trisomy 21, fetal nasal pathology).35 the ratio of femur to foot length has proven a useful parameter in assessing dysplastic limb reduction and fetal growth.36, 37, 38 goldstein, et al.’s 39 studies have shown that there is significant correlation between femur length (fl) and orbital diameter (od) and this may aid in future research regarding fetal orbital abnormalities. konje et al.’s40 studies have shown that the fetal kidney length, in the 24 to 38 weeks gestational period, is a more accurate fetal biometry than biparietal diameter (bpd) and head circumference (hc). mercer et al.’s41 studies have shown that fetal hand and foot lengths as predictors of fetal age are reliable parameters to use. chen et al.’s26 studies have shown that biparietal diameter (bpd), head circumference (hc) and femur length (fl), if used as a single parameter, are not as specific when compared to abdominal circumference (ac), which has been shown to be the best single parameter in predicting macrosomia. chen et al.’s 26 studies have indicated that a combination of more than one parameter should be used to increase the reliability, sensitivity, and accuracy of fetal biometry. fetal growth accuracy is extremely important, especially when using fetal long bone biometry to predict the risk for trisomy 21 in the second trimester and to determine the need for genetic amniocentesis.42 congenital and hereditary bone disorders can affect the bone length and in turn will affect fetal biometry.43 m ate r n a l a ge , ge n e ti c d i s o r d e r s , a n d oth e r fa c to r s difficulty in conception increases after age 35 years but can be treated successfully.44 women over the age of 35 years were excluded from the study of normal fetal biometry because salihu et al.’s45 studies have shown that maternal age may increase the risk of genetic disorders. pregnant teenagers are at greater risk for fetal death, anaemia, premature labour, still birth, and high blood pressure, especially in those who neglect prenatal medical care.46 overgrowth in the fetus (large for dates, macrosomia) can be caused by diabetes mellitus.47 poor fetal weight increase may program the fetus and cause chronic disease later in life by lessening the lean body mass and increasing the risk of obesity.49, 50 since 1950, maternal smoking has been recognized as a risk factor for fetal growth restriction and reduced birth weight.51, 52 murphy et al.’s53 studies have found that maternal smoking affects the fetal biparietal diameter (bpd) and can cause a reduction in birth weight. studies on twin pregnancies have shown lower infant birth weights in maternal smokers than in single pregnancies.54 accurate measurement of fetal age is the most useful contribution ultrasound has made to obstetric practice.2 so far crown rump length (crl), biparietal diameter (bpd) and femur length (fl) are considered the measurements of choice.55 all these measurements were acquired before 1985 and in some cases before electronic calipers were available, resulting in a need to update these procedures by using new sonographic equipment. l i mi tati o n s before a new parameter can be used, it must be shown to correlate with fetal age in normal pregnancies. robinson et al.’s 55 study has indicated that the major limitation on crown rump length (crl) is that it can only be used effectively in the first trimester. many pregnancies are not referred for ultrasound assessment until the second trimester, and so any new measurements will be a welcome addition to the biparietal diameter (bpd) and femur length (fl).56 neilson et al.’s56 studies have indicated that the limitations of bpd were found in the measurement of macrencephalic heads. confusion may also exist in expressing gestational age. figure 2: the white arrow is showing the double line of the fetal thigh. the correct measurement of the anterior-posterior thigh diameter would be the second line marked by the number (1) arrow in the real anterior wall of the fetal thigh, as this is the true skin line. the second line marked by number (2) arrow is part of the thigh tissue as the sound waves travels through the convex area, and can be corrected by scanning in a good sagittal plane. s a a d r i a l k u b a i s i 50 yagel et al.’s 57 studies have shown that radiologists and physicians round the measurements up or down to the nearest week; for example, a fetal age of 18 weeks and 5 days is reported as 19 weeks and this can lead to a systematic half-week difference between otherwise identical curves. some fetal positions can reduce the ability to measure specific areas of the fetal body; for example in the occipital anterior or occipital posterior position, it will not be possible to obtain a biparietal diameter (bpd). serial measurements of biparietal diameter and or head circumference alone are of no value because of the “brain sparing” effect.58, 59 benson et al.’s 60 study has indicated that the reliability of the ratio of head circumference to abdominal circumference to predict intrauterine growth restriction is limited.60 there are situations, for example pre-term labour, diabetes, breech presentation or previous caesarean section, when it is important for the attending physician to have a single estimate of the fetal size or weight at one point in time. all formulas of fetal biometry tend to overestimate the weight of the small fetus and underestimate the weight of the large fetus; this is clearly undesirable.61, 62 gestational diabetes mellitus (gdm) can be associated with high birth weight and therefore can effect overall fetal measurements.63 femur length (fl) is a reliable measurement, but it can be affected by skeletal dysplasias and it is best measured after 14 weeks.64 studies have indicated that the use of multiple predictors of fetal biometry improve the accuracy of fetal age estimation, and reduces the potential for error if only a single fetal biometry had been used.65, 66 m e t h o d s fifty-five uncomplicated pregnancies were studied prospectively and quantitatively in the high level general hospital (north-western health centre), alberta, between march 21 2005 and may 10, 2005. the author’s data and tables agreed favourably with the dr. hadlock’s tables for femur length.67, 68 the growth of the fetal anterior-posterior thigh diameter (aptd), outer to outer skin surface was sonographically measured at the middle point of the fetal femur in sagittal section and compared with the fetal age from 18 to 28 weeks gestation. the selection of the second trimester period was chosen because soft tissue accretion of the fetal thigh begins to accelerate towards the end of this period. the inclusion criteria for this study were: singleton uncomplicated pregnancies with a normal fetus and an informed consent form, read and signed by the patients and approved by the hospital and the charles sturt university ethical committee. the patients’ ages ranged between 18 and 35 years, with a mean age of 26.5. the study population was a mix of different ethnic groups (eg, caucasians, germans, native indians, mennonites, irish, hispanics, ukrainians and east indians). the radiologists reported major congenital malformations, chromosomal abnormalities and maternal complications, such as gestational diabetes, drug, and tobacco user. the author did not release any pathological information to the patients and patients were asked to obtain their reports from their physicians. routine transabdominal sonography was done, including femur length (fl), biparietal diameter (bpd), abdominal circumference (ac), and head circumference (hc). in addition, the author measured the fetal anterior-posterior thigh diameter (aptd), from the middle point of the fetal femur in sagittal section of the fetal thigh using the femur length as a landmark. the anterior-posterior thigh diameter (aptd) measurements were analyzed and compared with fetal age using the hadlock’s tables for femur length.67, 68 the equipment use in this study was atl and philips. the fetal age of each patient was determined by using figure 3: the sagittal section of the fetal thigh is showing the measurement of the femur length. the arrow is showing the fetal knee. magnification can be a helpful tool figure 4: sagittal plane of the fetal thigh show the femur length with one of the calipers in the mid point of the femur length a n t e r i o r p o s t e r i o r th i g h d i a m e t e r m e a s u r e d b y tw o d i m e n s i o n a l s o n o g r a p h y 51 dr. hadlock’s measurements of the femur length (fl). 67, 68 the comparison was made between the anterior posterior thigh diameter and the fetal age. the correct diameter of the fetal thigh was measured in the same portion of fetal thigh every time by measuring the mid point of the femur. eleven groups were studied, each group having 5 patients with all 5 patients in the same gestational period, from 18 to 28 weeks. te c h n i q ue starting with the transducer at the fetal abdominal circumference 1. move transducer inferiorly to transect the fetal bladder. 2. rotate transducer 30 degrees to view the fetal femur. 3. rotate transducer until a sagittal view of the fetal thigh be obtained [figure 1]. 4. exclude the distal femoral epiphyses (usually present after 32 weeks gestation). 5. the tibia is at times mistaken for the femur (make sure to identify the fetal knee). 6. if a double line is seen in the fetal thigh, measure the inner line or repeat the scan until a smooth (sagittal) line of the fetal thigh is obtained [figure 2]. this double line can be corrected by obtaining a perfect sagittal view of the fetal thigh. otherwise the curve of the thigh adds an extra false line to the real outer skin surface of the fetal thigh in the lateral or medial section. the thigh is convex in the anterior part and concave in the posterior part, so geometrically we are dealing with a cylinder and not a flat surface. 7. use real-time sonographic equipment with 3.0, 3.5, and 5.0 mhz transducers frequencies to obtain the images. 8. freeze-frame and electronic calipers are more sensitive tools to provide accurate measurements of the fetal thigh. 9. using the zoom capability to outline the fetal thigh (outer skin surface) will increase sensitivity of this measurement 10. using dr. hadlock’s tables for femur length,67, 68 to compare with anterior-posterior thigh diameter (aptd) or posterior-anterior thigh diameter (patd). me a sur e me n ts 1. scan the femur length (fl) at the sagittal view [figure 1& 2]. 2. measure the femur length, then bring the first caliper to the exact middle point of the fetal femur; for example, if the femur length was 2.4 cm (24mm), then bring the first caliper until the measurement reads 1.2 cm (12 mm), [figure 3] and [figure 4]. 3. carefully move the first caliper to the outer surface of the fetal anterior thigh [figure 5]. measure the real skin surface and not the extra double line created by the sound waves travelling through the convex part of the thigh in parasagittal planes. scanning the fetal thigh in the sagittal plane can make a correction and smooth the skin surface of the fetal thigh. 4. move the second caliper to the outer posterior surface of the fetal thigh, then enter and log the measurement. c a l c ul ati o n s each one millimetre (1mm) of the anterior-posterior thigh diameter (aptd), or the posterior-anterior thigh diameter (patd) measurements, will be equal to one-week (1 w); for example, 1.90 cm (19 mm) will be equal to 19 weeks gestation, and 2.80 cm (28 mm) will be equal to 28 weeks gestation. 1.428 will multiply any fraction of a millimetre, 1.428 obtained from (10 mm divided by 7 days), for example, aptd of 2.68 cm equal to (26.8 mm) calculates to 26 weeks plus (0.8 x figure 5: the first caliper is moved to the real outer skin of the anterior wall of the fetal thigh figure 6: the second caliper is moved to the posterior wall of the fetal thigh. enter and log the measurement of the anterior posterior thigh diameter (aptd) s a a d r i a l k u b a i s i 52 1.428) = 0.1424 day, this will be added to the 26 weeks equalling 27.0 weeks and 1.4 day. the anterior-posterior thigh measurement (aptd) was found to be relatively constant, one mm equal to one week. serial measurements should be obtained. the measurements should be repeated with zooming capability and electronic calipers; the serial measurements range should be less than 1 mm. if these measurements don’t match the fetal age obtained by using the hadlcok’s tables for femur length67, 68 a follow-up scan is recommended. stati sti c a l a n a ly si s regression – aptd (cm) and fetal age (weeks) the standard error of estimation (see) is very low at (0.08664.) this indicates the good ‘fit’ of this model. the ‘spread’ of values for the dependent variable (fetal age) around the mean value of the independent variable is very narrow. about 70% of the values of fetal age will lie+/0.08664 from the mean of aptd. femur length (cm) from hadlock table67, 68 fetal age (wk) using hadlock table aptd (cm) aptd (wk/days) femur length (cm) from hadlock table 67,68 fetal age (wk) using hadlock table aptd (cm) aptd (wk/days) 2.70 18.0 1.80 18.0 4.38 2.37 2.37 23.9 2.73 18.0 1.82 18.2 4.40 24.1 2.42 24.2 2.76 18.1 1.81 18.1 4.50 24.5 2.45 24.6 2.80 18.2 1.82 18.2 4.55 24.7 2.47 24.9 2.90 18.6 1.86 18.8 4.60 24.9 2.47 24.9 3.00 19.0 1.90 19.0 4.60 24.9 2.47 24.9 3.10 19.2 1.92 19.2 4.68 25.0 2.50 25.0 3.16 19.2 1.93 19.4 4.70 25.3 2.53 25.4 3.20 19.6 1.96 19.8 4.80 25.7 2.55 25.6 3.30 19.9 1.97 19.9 4.82 25.7 2.56 25.8 3.36 20.0 2.00 20.0 4.84 25.8 2.56 25.8 3.40 20.3 2.03 20.4 4.90 26.1 2.63 26.4 3.43 20.4 2.04 20.5 4.92 26.1 2.63 26.4 3.45 20.5 2.05 20.6 4.94 26.2 2.64 26.5 3.50 20.7 2.06 20.8 5.00 26.5 2.65 26.6 3.60 21.0 2.10 21.0 5.04 26.6 2.66 26.8 3.70 21.4 2.13 21.4 5.10 27.0 2.71 27.1 3.76 21.5 2.14 21.5 5.20 27.4 2.75 27.6 3.80 21.8 2.16 21.8 5.26 27.6 2.77 27.9 3.80 21.8 2.17 21.9 5.30 27.8 2.77 27.9 3.90 22.1 2.22 22.2 5.36 27.9 2.77 27.9 3.94 22.1 2.22 22.2 5.40 28.2 2.83 28.4 3.96 22.3 2.23 22.4 5.45 28.4 2.83 28.4 4.00 22.5 2.26 22.8 5.46 28.5 2.86 28.8 4.10 22.9 2.27 22.9 5.48 28.6 2.86 28.8 4.20 23.3 2.33 23.4 5.50 28.7 2.87 28.9 4.30 23.7 2.35 23.6 4.31 23.7 2.36 23.8 4.35 23.8 2.36 23.8 table 1: the correlation between anterior-posterior thigh diameter (aptd-cm) and fetal age (ga-wk) 50th percentile values for fetal femur length are shown below, (n=55). a n t e r i o r p o s t e r i o r th i g h d i a m e t e r m e a s u r e d b y tw o d i m e n s i o n a l s o n o g r a p h y 53 anovab model sum of squares df mean square f p value 1 regressions residual total 559.954 3.146 560.099 1 53 54 556.954 0.059 9383.824 0.000a a. predictors: (constant). aptdcm b. dependent variable: gestational age (weeks) coefficientsa model sum of squares df mean square f p value 1 regressions residual total 559.954 3.146 560.099 1 53 54 556.954 0.059 9383.824 0.000a a. dependent variable: gestational age (weeks) graph 1:the regression line for aptd s a a d r i a l k u b a i s i 54 anovab model sum of squares df mean square f p value 1 regressions residual total 559.954 3.146 560.099 1 53 54 556.954 0.059 9383.824 0.000a a. predictors: femur from hadlock table b. dependent variable: gestational age (weeks) coefficientsa model unstandardized coefficients standardized coefficients t p value b standard errors beta 44.387 96.870 0.000 0.0001 regressions residual total 559.701 0.398 560.099 0.168 0.039 0.997 a. dependent variable: gestational age (weeks) graph 3: the residual (error), scatter plot and validity of the (aptd) graph 4:the residual (error) scatter plot – femur length from dr. hadlock table 67 a n t e r i o r p o s t e r i o r th i g h d i a m e t e r m e a s u r e d b y tw o d i m e n s i o n a l s o n o g r a p h y 55 r e s u l t s measurements of femur lengths from the 55 patients who met the criteria were correlated with the anterior-posterior thigh diameter (aptd) and used to construct tables and graphs. there was significant correlation between the anterior-posterior thigh diameter (aptd) and fetal age. using a simple linear regression for this study, more than 99.993 % confidence intervals were found at each week of the eleven groups from 18 to 28 weeks gestation (rsq > 0.9993), and (p less than 0.0001). the anterior-posterior thigh diameter was positively correlated with fetal age [table 1] and [graphs 1, 2, 3 & 4]. eleven gestational periods from 18 to 28 weeks were analyzed, each period including 5 different measurements of the femur lengths compared to the fetal age and to the anterior-posterior thigh diameter with mean +/-2sd. femur length measured from 2.70 centimetre (cm) to 5.50 cm over all gestational periods, the mean being 4.31-4.35. fetal weight ranged between 310 grams and 1400 grams, the mean being 629 grams. the anterior-posterior thigh diameter (aptd) ranged between 1.80 to 2.87 cm, with the mean at 2.36 cm. linear growth was obtained in each gestational period from 18 to 28 weeks, and compared favourably with the dr. hadlock’s tables.67, 68 in addition, linear growth of fetal weight was observed. the anterior-posterior thigh diameter, converted to millimetres and compared with the fetal age, was found to be a consistent and valid measurement by using the scatter plots [graph 2 & 3]. the standard errors of estimates using anterior-posterior thigh diameter (aptd) were significantly lower (at 0.08664) than that using femur length at 0.2436. the variability estimates from dr. hadlock et al.’s 67 table for femur length versus fetal age from 18 to 30 weeks have indicated ± 1.8 weeks to 2.4 weeks. the aptd table in this study shows ± 3 days variability. the adjusted r square (variance) was >.99 for both models. d i s c u s s i o n the simplicity of the application found by this study is really its greatest advantage. accuracy of fetal age, weight and estimated delivery date (edd) will be improved if multiple predictors are used,27, 31, 57 especially when it is difficult to obtain fetal head biometry (for example, when the head is too low in the pelvis or there is hydrocephalus, anencephaly, or fetal renal disease). reliable methods for estimating fetal body weight and fetal age without head measurement are therefore required. reliable new methods of fetal biometry can be very beneficial in reducing overall fetal biometry errors and increasing the reliability of the fetal biometry.30, 37, 44 the results of this study show that anterior-posterior thigh diameter (aptd) predicts second trimester growth with high validity and reliability. the very simple correlation in this study of 1 mm aptd per week of fetal age is new and useful information. taylor et al.’s 25 study has shown that measuring the thigh parameter can be a convenient method for determining fetal growth in the second trimester. the aptd may have a role in quality control of second trimester ultrasound examinations and may help in the diagnosis of fetal growth abnormalities. the accuracy of fetal biometry is extremely important, especially when using fetal long bone biometry.56 studies have shown that there are relationships between intrauterine growth restriction (iugr), smaller fetal biometry, and smaller thigh circumference.10, 11 the aptd may be used as an indicator of fetal biometric disturbance, thus enabling the physician to manage the pregnancy better. diabetes mellitus is one cause of intrauterine growth restriction (iugr) 51, 52 and may affect the femur length (fl). 51, 52 diabetes mellitus may also affect the fetal body mass and consequently the abdominal circumference and fetal thigh 13-19, 21 hence, the anterior-posterior thigh diameter may be used not only as indictor for fetal age but also to detect iugr. renal pathology, such as hydronephrosis or congenital renal malformation, can affect the fetal abdominal circumference, making this measurement unreliable as an indicator of fetal age. the use of combined parameters may be superior to the use of each measurement alone as a marker of trisomy 21.42 in addition, it can be difficult in practice to obtain a good fetal thigh circumference, or fetal hands, feet and ears to obtain fetal biometry. this study shows that the fetal aptd provides an accurate linear measurement of the fetus, thus generating a more complete profile of the fetus. significant correlations of aptd with fetal age indicate that this is a reliable method and is particularly useful when other fetal parameters may not accurately predict fetal age or if they are difficult to obtain. if the age predicted from the aptd does not match the age using the femur length, other factors such as intrauterine growth restriction or maternal and fetal nutrition deficits should be considered. the soft tissue accretion of the fetal thigh also depends on the generalized nutritional status of the infant, but such an increase in s a a d r i a l k u b a i s i 56 soft tissue is usually more marked after 30th weeks gestation. the aptd measurements that were obtained from the 11 groups correlated perfectly with the fetal age. they were repeated five times for each gestational group between 18 and 28 weeks. racial differences in the population should not be neglected. the variability estimates from dr. hadlock et al.’s 67,68 tables for femur length versus gestational age from 18 to 30 weeks were ± 1.8 to ± 2.4 weeks, while the variability estimates in the aptd table was ± 3 days. researchers should check this measurement with different racial groups, to produce a universally applicable measurement. both models predict the fetal age very well, but compared to fl, using aptd produces a model with better ‘fit’ based on differences in the see between the two of them on the analysis of both models. the ‘spread’ of values for the dependent variable is narrower around the mean of the independent variable in the aptd model and wider in the fl model. the standard error of estimates (see) of 0.2436 obtained for fl versus gestational age is higher than that obtained in the analysis with aptd. this indicates a weaker ‘fit’ of this model. the ‘spread’ of values for the dependent variable around the mean value of the independent variable is wider. 68% of the values of fetal age will lie +/ 0.2436 from the mean of aptd. model statistics (f, t, and standardized beta) are significant for both models. beta (aptd)=10.0 (see=0.037), beta (fl)=3.79 (se=0. 039). t=273.07 for ga x aptd model=96.87 for ga x fl model. c o n c l u s i o n aptd was found to be a valid and reliable index for estimating fetal age. further research to study the relationship between aptd versus fetal weight and iugr is needed. a c k n ow l e d ge me n ts i would like to thank dr. s desilva, dr. p hughes, dr. boutha , dr. k hofmann and gary katchur for all their help and assistance with this study r e f e r e n c e s 1. blake kv , gurrin lc, beilin lj, et al. prenatal ultrasound biometry related to subsequent blood pressure in childhood. journal of epidemiol community health 2002; 56:713-718. 2. taner z, khalil am. an assessment of femur growth parameters and their relationship to fetal age. turk journal of med sic. 2003; 33:27-32. 3. jensen sl, ramussen s, sollien r, kiserud t. fetal age assessment based on ultrasound head biometry and the effect of maternal and fetal factors. acta obstetricia and gynecol scand 2004; 83,716. 4. widdowson e.m, mcance r.a. the determination of growth and form. proc. royal soc. lond 1974; 185:117. 5. barker d j p. the fetal origins of adult disease. proc. royal soc. lond.1994; 262:37-43. 6. barker d j p. mothers, babies, and disease in later life. london: b.m.j publishing, 1994. 7. hales c.n, and barker d j p: type 2-(non-insulin dependent) diabetes mellitus: the thrifty phenotype hypothesis. diabetologia 1992; 35:1019-1022. 8. kurmanvicius j: ultrasonographic fetal weight estimation: accuracy of formulas and accuracy of examiners by birth weight from 500 to 5000 grams. j perinat med 2004; 32(2004) 155-161. 9. cheng mc, chew pg, ratnams s. birth weight distribution of singapore, chinese, malay, and indian infants from 34 to 42 weeks gestation. j obstet gynaecol, br common w 1972; 149-153. 10. freman mg, cliver sp, cutter gr, hoffman hj. indigent black and caucasian birth weight-fetal age tables. pediatrics 1970; 46:9-15. 11. goldenberg rl, cliver sp, gutter gr. black-white differences in newborn anthropometrics measurements. obstet gynecol 1991; 78:782-788. 12. jansen gm, moore lg. the effect of high altitude and other risk factors on birth weight: independent or interactive effects. a m j public health 1997; 87:1003-1007. 13. berkus md, langer o. glucose tolerance tests: degree of glucose abnormality correlates with neonatal outcome. obstet gynecol, 1993; 81: 344-348. 14. haelterman e, breart g, paris-liado j, dramaix m, techoboutsky c. effect of uncomplicated chronic hypertension on the risk of small for fetal age birth. am j epidemiol 1997; 15:689695. 15. horta bl, vicora cg, menezes am, halpern r, barros fc. low, birth weight, pre term births, and iugr in relation to maternal smoking. paediatric perinat epidemiol 1997; 11:140-51. 16. shiono ph, klebanoff ma, graubard bi, berendes hw, rhoads gg. birth weight among women of different ethnic groups. jama 1986; 255:48-52. 17. hanretty kp, neilson jp, fleming jee. re-evaluation of clinical estimation of fetal weight; a comparison with ultrasound. j obstet gynaecol 1990; 10:199-201. 18. ott wj, doyle s, flamm s, wittman j. accurate ultrasonic estimation of fetal weight prospective analysis of new ultrasonic formulas. am j perinatol 1986; 3:30710. a n t e r i o r p o s t e r i o r th i g h d i a m e t e r m e a s u r e d b y tw o d i m e n s i o n a l s o n o g r a p h y 57 19. baschat aa, hecher k. fetal growth restriction due to placental disease. semin, perinatol 2004; 28:67-80 20. chien pf, owen p, khan ks. validity of ultrasound estimation of fetal weight: obstet gynecol 2002; 95:856860. 21. battaglia c, artinin pg, d’ambrogio g, bencini s, galli pa, genazzani ar. maternal hyper oxygenation in the treatment of intrauterine growth retardation. amj obstet gynecol 1992; 167: 430-435. 22. neerhof mg. causes of intrauterine growth restriction. clin perinatol 1995; 22:375-385. 23. yoshida s, nuno n, and kageawa h. prenatal detection of high-risk group for intrauterine growth restriction based on sonographic fetal biometry. int j gynaecol obstet 2000; 68:225-232. 24. wikstrom i, bergstorm r, bakketeig l, jacobsen g, lindmark g. gynecol/obstet invest 1993; 35:27-33. 25. isobe t: approach for estimating fetal body weight using two-dimensional ultrasound. j matern fetal neonatal medicine, parthenon publishing, 2004; 15:225-231. 26. chen cp, chang fm, chang ch, lin ys, chou cy and ko hc. prediction of fetal macrosomia by single ultrasonic fetal biometry. j formos med assoc 1993; 92: 2428. 27. ratanasiri t, jirapornkul s, somboon por w, seejorn k, patumnakul p. comparison of the accuracy of ultrasonic fetal weight estimation by using the various equations. j med assoc thai 2002; 85:962-967. 28. nahum gg, stanislaw h, huffaker bj. fetal weight gain at term; linear with minimal dependence on maternal obesity: am j obstet gynecol 1995; 172:1387-1394. 29. vintzielos am, neckless, campbell wa, kaplan bm, andreoli jw, nochimson dj. ultrasound fetal thigh calf circumference and fetal age-independent fetal ratios in normal pregnancy: j ultrasound med 1985; 4:287-292. 30. zelop cm, borgida. af, james fx. variation of fetal humeral length in 2nd trimester fetuses according to race and ethnicity. j ultrasound med 2003; 22:691-693. 31. jeanty p, rodesch f, delbeke d, dumont je. estimation of fetal age from measurement of fetal long bones. j ultrasound med, 1984; 3:75-79, and. jeanty p, et al. fetal limb volume: a new parameter to assess fetal growth and nutrition ultrasound med 1985; 4:273-282. 32. flanagan de, moore vm, godsland if, cokington ra, robinson s, phillips diw. fetal growth and the physiological control of glucose tolerance in adults: a minimal model analysis. am j physiol endocrinal metab. 2002; 278:e700-706. 33. chitkara u, lee l, oehlert jw, bloch da, holbrook rh, yy eh-sayed, dunzin ml. fetal ear length measurement: a useful predictor of aneuploidy. ultrasound obstetr gynecol, 2002; 19:131-135. 34. abel, ernest, sokol. r: alcoholism: clinical and experimental research. missouri: department of health, state center for health statistic and its economic impact 1992. 35. bunduki v, ruano r, miguelez j, yoshizaki ct, kahhale s, zngaib.m. fetal nasal bone length: reference range and clinical application in ultrasound screening for trisomy 21: ultrasound obstetr and gynecol 2003; 21:160. 36. campbell j, henderson a, campbell s. the fetal femur /foot length ratio: a new parameter to assess dysplastic limb reduction: obstetrics and gynaecology 1988; 72:181-184. 37. streeter gl. weight, sitting height, head size, foot length, and menstrual age for the human embryo cantrib embryol 1920; 55:156. 38. chatterg h s, adhate a. ultrasonic imaging of fetal foot for evaluation of fetal age: proceeding of the wfump 1986; 206:14-19. 39. goldstein a. tamir e.z, itskovitz j. growth of the fetal orbit and lens in normal pregnancies: world federation of ultrasound in medicine, biology, obstetr gynecol 1998; 12:175. 40. konje j c, abrams k.r., bell s c & taylor d j. determination of fetal age after 24th weeks of gestation, from fetal kidney length measurements; ultrasound obstetr & gynecol 2002; 19:592-597. 41. mercer pm, sklar s, shariatmadar a, gillieson ms and d’alton me. fetal foot length as a predictor of fetal age; am j gynecol 1987; 156:350-355. 42. vintzileos am, neckles s, campbell wa, kaplan bm. adjusting the risk for trisomy 21 by a simple ultrasound method using fetal long-bone biometry? obstet gynecol 1996; 87:953-958. 43. rousseau f, saugier p, merrer m le, munnich a, delezoid al, maroteauv p. mutation in he gene encoding fibroblast grpwth factor receptor-3 in achondroplasia: nature 1994; 371:252-254. 44. pregnancy after 35 from www.marchofdimes.com ,accessed september, 2004. 45. salihu hm, shumpert mn, slay m, kirby rs, alexander gr. child bearing beyond maternal age 50 and fetal outcomes in the united states: obstet gynecol 2003; 102:1006-1014. 46. special concerns of pregnant teens from www.kidhealth. org, accessed september, 2004. 47. moses s. fetal macrosomia: family practice notebook, llc 2000; 4466. 48. science blog. new study provides first linkage of fetal alcohol exposure and enlarged heart from www.scineceblog.com, accessed sept, 2004. 49. desai m, crowther n, lucas and hales, cm: adult glus a a d r i a l k u b a i s i 58 cose and lipid metabolism may be programmed med during fetal life. biochem soc transact 1985; 23:331335 50. singhal a, wells j, cole tj, fewtrell m, lucas a. programming of lean body mass: a link between birth weight, obesity, and cardiovascular disease, am j clin nutr 2003; 77:726-730. 51. cliver sp, goldenberg rl, gutter gr, hoffman hj, davis ro, nelson kg. the effect of cigarette smoking on neonatal anthropometrics measurements. ob gyn 1995; 85:625-630. 52. kramer ms. determinants of low birth weight: methodological assessment and meta-analysis. who 1987; 65:663-737. 53. murphy jf, drumm je, mulcaby r, daly l. the effect of maternal cigarette smoking on fetal weight and on growth of the fetal biparietal diameter. bjog 1980; 87:462-466. 54. williams s, poulton r. twins and maternal smoking: ordeals for the fetal origins hypothesis? a cohort study. bmj 1991; 318:897. 55. robinson hp, fleming je. a critical evolution of sonar crown-rump length measurements. bjog 1975; 82:702710. 56. neilson jp, munjaja sp, whitfield cr. screening for small for dates fetuses: a controlled trial. bmj (clinic res ed) 1984; 289:1179-1182. 57. yagel s, adoni a, oman s, wax y, hochner cd. a statistical examination of the accuracy of combining fenoral length and biparietel diameteras an index of fetal age. bj obstet gynecol 1986; 93:109-115. 58. duck fa, dyson m, evans ja, terhaar g, williams ar. bmus ultrasonic fetal measurement survey, part 4. br med ultrasound bull 1989; 52:4-10. 59. deter rl, harrist rb, hadlock fp, carpenter rj. fetal head and abdominal circumferences: a critical re-evaluation of the relationship to menstrual age. j clinical ultrasound, 1982; 10: 365-372. 60. benson cb, doubilet pm, saltzman dh. intravterine growth of ultrasound criteria for antenatal diagnosis. radiology1986; 160:415-417. 61. campbell s. et al. abdomen circumference in the estimation of fetal weight. bjog 1975; 82:689-697. 62. hadlock fp, harrist rb, sharman rs, deter rl, park sk. estimation of fetal weight by ultrasound. ajog 1985; 151:333-337. 63. gillman mw, shiman sr, berkey cs, field ae, colditz ga. pediatrics viii 2003; 3:221-226. 64. ultrasound of fetal biometric and growth, creighton university school of medicine from www.radiology. creighton.edu/ultraoffetalbiomet.html, accessed oct, 2004. 65. degani s. fetal biometry: clinical, pathological, and technical consideration. obstet gynecol survey. 2001; 56:159-167. 66. thomas c. et al. cerebella and frontal lobe hypoplasia in fetuses with trisomy 21: usefulness as combined us markers. radiology 2000; 214:533-538. 67. hadlock fp, deter rl, harrist rb, and park sk. fetal femur length as a predictor of estimating fetal age: computer-assisted analysis of multiple fetal growth parameters. radiology 1984; 152:497-501. 68. hadlock fp, deter rl, harrist rb, park sk. fetal femur length as a predictor of menstrual age: sonographically measured. amer j roentgenol 1982; 138:875. july 2008.indd sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 165-169 sultan qaboos university© submitted 19th january 2008 accepted 22nd april 2008 1department of medicine, college of medicine & health sciences, sultan qaboos university, muscat, sultanate of oman; 2department of medicine, sultan qaboos university hospital, muscat, sultanate of oman; 3department of medicine, mubarek al-kabeer hospital, kuwait *to whom correspondence should be addressed. email: omayma0@hotmail.com familial mineralocorticoid induced hypertension in the sultanate of oman nicholas jy woodhouse,1 *omayma t elshafie,2 fatma ben abid,2 suhail a doi3 objectives: in oman, many hypertensive patients with a family history of the disease respond to treatment with spironolactone, a mineralocorticoid receptor (mc-r) blocking agent thus suggesting a high prevalence of mineralocorticoid (mc) induced disease. the aim of this study was to document the prevalence of mc induced disease in patients with a positive family history of hypertension (htn). methods: serum calcium, potassium, creatinine, aldosterone and renin levels were measured under standard conditions in all patients together with an abdominal ultrasound scan and an adrenal computed tomography (ct) scan in four patients. results: in this small study, we show that 8 of the 27 patients (66%) had undetectable (suppressed) renin levels with usually normal aldosterone values (4 patients) and respond to treatment with spironoactone. conclusion: we suggest that mc induced hypertension is likely to be common in the middle east. in evolutionary terms, this makes sense as the ability to conserve salt in hot climates might be expected to confer a definite survival advantage. key words: hypertension, familial; mineralocorticoids; high prevalence; oman في نِيَّة دِ املَعْ رانِيَّات شْ القِ عن الناجت الوراثي الدم ضغط �ارتفاع عمان سلطنة دوا سهيل عابد، بن فاطمة الشفيع، اميمة وودهاوز، نيكوالس لعقار ــتجابوا اس والذين ــي الدم الوراث ضغط ــاع بارتف ــني املصابني العماني ــن املرضى م كبيرا ــددا ع ــابقة س ــة ــص: الهــدف: وجدنا في دراس امللخ عن الناجت ضغط الدم ــار انتش ارتفاع على يدل وهذا ، الكلى فوق املوجودة نِيَّة دِ َعْ امل ــرانِيَّاتُ شْ القِ ــتلمات مس وظيفة يبطل ، وهو عقار ــبايرونوالكتون س لذلك موجب عائلي تأريخ لديهم الذين العمانيني عند العالي الدم ضغط من النوع هذا نسبة ارتفاع إثبات البحث هذا نريد في املعدنية. القشرانيات إلى باإلضافة ، املرضى كل عند وااللدوستيرون الرينني هرموني وكذلك ، والكرياتنني والبوتاسيوم الكالسيوم أمالح قياس مستويات مت املرض. الطريقة: هذه في النتائج: وجدنا 4 مرضى. ــب في وسَ حَ مُ يٌّ عِ طَ قْ مَ ويرٌ تَصْ وعمل املرضى والكلى في كل للغدة الكظرية الصوت فائقة بطنية ــة تفريس عمل لهرمون طبيعي مستوى مع (منخفض) محسوس غير رنني (66 %) لديهم مستوى 27 مجموع 18 من املرضى من الصغيرة نسبة عالية الدراسة في الوراثي الدم نتوقع كثرة انتشار ارتفاع نسبة ضغط ــة الدراس اخلالصة: من هذه سبايرونوالكتون. لعقار ــتجابوا واس (14 مريضا) ــتيرون الدوس البقاء. أجل من نوعية ميزة رمبا يعطي احلار اجلو في امللح على احلفاظ على القدرة ، وأن األوسط الشرق عمان. انتشار عالي، نِيَّة، دِ َعْ امل رانِيَّاتُ شْ القِ العائلي، الدم، ضغط ارتفاع الكلمات: مفتاح c l i n i c a l a n d b a s i c r e s e a r c h advances in knowledge • this is the first study uniquely selecting patients with familial hypertension • mineralocorticoid induced hypertension is reported in 10% or more of the general hypertensive population. we have only studied patients with a positive familial history of the disease and found a much higher prevalence (66%) with mineralocorticoid (mc) induced disease application to patient care • patients with a positive family history of hypertension should undergo a short one month trial of a mineralocorticoid blocking drug such as spironolactone. 166 n i c h o l a s j y wo o d h o u s e , o m ay m a t e l s h a f i e , fat m a b e n a b i d a n d s u h a i l a d o i it has generally been recommended1-2 that screening for hyperaldosteronism be considered at least for hypertensive patients with spontaneous hypokalemia (k <3.5 mmol/l), or with marked diuretic-induced hypokalemia (k <3.0 mmol/l), with hypertension refractory to treatment with three or more drugs or those found to have an incidental adrenal adenoma. previously, primary hyperaldosteronism (pal) was not believed to be familial and thought to account for less than 1% of hypertensive patients and hypokalemia was considered a prerequisite for pursuing diagnostic tests2. recent studies with screening of both hypokalemic and normokalemic hypertensives have reported now a much higher prevalence of this disease, with primary hyperaldosteronism accounting for up to 12% of hypertensive patients most of them being normokalemic.3-4 furthermore, in 1991, a second form of familial hyperaldosteronism (fh-ii) that was not glucocorticoid remediable was first reported. there were six patients, four with aldosterone-producing adenoma (apa) and two with bilateral adrenal hyperplasia (bah)) among three families.5 till 2001, a total of 68 patients among 27 families have been described, making fh-ii more common than fh-i (34 patients among five families).6 to date, two familial forms of hyperaldosteronism have been identified: glucocorticoid suppressible, familial hypertension type 1 (fh1) and glucocorticoid non-suppressible disease, (fh2).6-7 we recently reported a potentially high prevalence of familial mineralocorticoid (mc) induced hypertension (htn) in patients attending our general endocrine clinics8 and found that in 39 of 45 patients (80 %) their blood pressure could be controlled using spironolactone alone. we therefore concluded that the prevalence of mc induced disease in oman might prove to be quite high8. in the uk, a recent study of more than 800 hypertensive patients in a general practice setting, who were without a positive family history, revealed that 14% responded to spironolactone with a fall in bp of 26/11 mmhg. all of them had suppressed renin levels, but as in our study, the aldosterone levels were only occasionally raised.9 only 1 of these patients had conn’s syndrome. we are now providing a more detailed account of 27 additional subjects with familial disease, but in addition their circulating renin and aldosterone levels were measured before starting treatment with spironolactone. m e t h o d s these 27 hypertensive patients were from different families having one or more affected parents and siblings, twenty four were omanis and three sudanese. they had been randomly selected from our general endocrine clinics if they had a positive family history of hypertension. serum calcium, potassium, creatinine, aldosterone (n. 28-440 pmol/l) and renin (n. 2.4-21.9 ng/l) levels were measured after lying supine for 6 hours and after stopping β-blockers under supervision for 4 days.10 renal ultrasounds were obtained in all patients, as well as a contrast adrenal computed tomography (ct) scan, with 2-3mm slices, in those with documented hyperaldosteronism and suppressed renin levels. the patients with suppressed renin levels were given a 1 month course of spironolactone 50-100 mg daily alone to four newly diagnosed patients, or in addition to other antihypertensives in the remainder. these were on a minimum of two drugs (16 patients) or ≥ three drugs (7 patients). the usual combination of medications was angiotensin-converting enzyme (ace) inhibitors, angiotensin ii (at2) receptor blockers, diuretics or beta-blockers (4 patients). no patients were taking methyldopa or clonidine. if the blood pressure (bp) was controlled (<140/80), after 2-4 weeks the other medications were sequentially withdrawn at weekly intervals until the patient was taking spironolactone alone for at least one month. renin was measured using a renin immunoradiometric assay (irma) kit (dsl-25100) from diagnostic systems laboratories inc. and aldosterone was measured via radioimmunoassay (ria) kit from dia sorin inc. the normal ranges used are from the north american data provided by the relevant companies. formal suppression tests of aldosterone secretion were not performed. fully informed consent was obtained from all patients. there was no conflict of interest financial or otherwise. r e s u l t s of the 27 patients studied, renin levels were suppressed in 18 (66%), but aldosterone values were normal in 13, elevated in 4 and undetectable in one case. the remaining 9 patients had normal values of aldosterone, but renin levels were low in 3 of them [table 1]. of the 18 patients with suppressed renin levels, 14 were available for follow up whilst taking spironolactone and in 1 other case taking moduretic. their final median bp was 130/70 with a range of 140/70-100/70. 167 fa m i l i a l m i n e r a l o c o r t i c o i d i n d u c e d h y p e r t e n s i o n i n t h e s u lta n at e o f o m a n serum calcium and potassium levels were normal in every patient. serum creatinine levels were mildly elevated in two cases at 129 and 147 µmol/l [table 1]. there were 5 patients in consanguineous marriages in this group. d i s c u s s i o n the results of this study further support our original suggestion8 that there is a high prevalence of mc induced htn in patients who have a strong family history of the disease. two thirds of our patients in this study had suppressed renin levels with autonomous patient no age sex renin ng/l aldosterone pmol/l final bp 1 45 f <0.5 380 125/70 2 49 m <0.5 140 125/70 3 56 f <0.5 57 130/70 4 44 f <0.5 112 130/70 5 55 m <0.5 168 ltfu 6 45 m <0.5 225 ltfu 7 44 f <0.5 70 125/70 8 58 m <0.5 108 100/70 9 42 f <0.5 227 ltfu 10 58 f <0.5 220 135/85 11 51 f <0.5 40 ltfu 12 46 f <0.5 136 135/70 13 42 m <0.5 351 130/80 14 44 f <0.5 <20 130/75 15 56 f <0.5 575 140/70 16 42 f <0.5 508 120/70 17 69 f <0.5 543 130/80 18 49 m <0.5 500 120/70 19 48 f 2.3 407 ltfu 20 42 f 0.5 321 130/70 21 38 f 1.3 323 110/75 22 36 m 2.7 79 150/85 23 39 f 2.5 140 145/85 24 54 m 4.7 383 155/90 25 45 m 3.1 381 150/80 26 42 m 2.6 300 140/80 27 50 f 20 448 145/80 normal range supine > 6 hrs 2.4-21.9 28-440 table 1: data from 27 patients with familial hypertension. the median basal blood pressure of the 4 patients not on medication was 155/105, with a range of 170/95 – 150/110 (patients 1, 3, 10, 17). basal blood pressure values of patients already on treatment are not shown as they were only slightly elevated. 168 n i c h o l a s j y wo o d h o u s e , o m ay m a t e l s h a f i e , fat m a b e n a b i d a n d s u h a i l a d o i aldosterone production, and their bp was controlled using spironolactone a known mc receptor blocking agent. it is now recognized that primary aldosteronism occurs in more than 10 percent of the general hypertensive population and that hypokalaemia is an uncommon presenting feature.3-9 in fact, of the 72 patients with familial disease we have studied so far, only 6 were hypokalaemic at presentation including the one patient with conn’s syndrome.8 we did not carry out dexamathasone suppression tests in these patients, but suspect that the majority have fh2 as we earlier found only one responsive family in 15 that were tested. the pathophysiology of fh2 is not known with certainty, but presumably results from one or more activating mutations in the renin/angiotensin/ aldosterone pathway. of interest is the one patient who had suppressed renin and aldosterone levels. this combination occurs in liddle’s syndrome and apparent mineralocorticoid excess (ame). both result from excessive renal tubular reabsorption of sodium; the former caused by activating mutations of the epithelial sodium channels (enac) and the latter activation of the type i mc-receptor. in ame there is an inherited or acquired deficiency of the renal isoform of 11-b-oh steroid dehydrogenase (11-b-oh sd). normally this enzyme converts cortisol to inactive cortisone. in its absence, tissue cortisol levels increase activating the mc-receptor. our patient does not have liddle’s syndrome, however, as this disorder does not respond to a mc-receptor blocking drug. ame is also unlikely as there is no history of childhood ill health hypokalemia or ingestion of compounds known to inactivate 11-b-oh sd such as liquorice or chewing tobacco. we are currently exploring the possibility that she might be secreting another mc-receptor stimulating compound. figure 3: shows aldosterone values in patients with supressed (•) normal renin (•) levels 169 fa m i l i a l m i n e r a l o c o r t i c o i d i n d u c e d h y p e r t e n s i o n i n t h e s u lta n at e o f o m a n the brisbane group has suggested that fh-ii (familial hypertension type 2) has an autosomal dominant mode of transmission with linkage to 7p22 and gender distribution that is roughly equal.6-11 however, apart from being familial, fh-ii has no specific clinical, biochemical or morphological hallmarks that permit distinction from apparently non-familial pal, with the two groups demonstrating similar mean ages, gender distributions, hypokalaemic percentages, mean upright plasma aldosterone and pra levels, with these and the use of other investigative techniques.10 this suggests that the genetic defects that underlie the development of fh-ii may also be operative in many patients with apparently non-familial pal and may be picked up earlier by family screening. indeed, it has been suggested that pal passes through four phases in its evolution: low renin normotension, normokalemic primary aldosteronism and finally hypokalemic primary aldosteronism.12 c o n c l u s i o n mc induced disease seems to be common in oman. in evolutionary terms this makes sense as the ability to conserve salt in hot climates might be expected to confer a definite survival advantage. we recommend that all patients with a positive family history of htn should be screened for mc induced disease or at least receive a short therapeutic trial of spironolactone to avoid unnecessary complications. to our knowledge there have been no previous reports documenting mc induced disease in patients screened using a positive family history only. r e f e r e n c e s 1. hemmelgarn br, mcallister fa, myers mg, mckay dw, bolli p, et al. the 2005 canadian hypertension education program recommendations for the management of hypertension: part 1blood pressure measurement, diagnosis and assessment of risk. can j cardiol 2005; 21:645-656. 2. ganguly a. primary aldosteronism. n engl j med 1998; 339:1828-1834. 3. gordon rd, ziesak md, tunny tj, stowasser m, klemm sa. evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. clin exp pharmacol physiol 1993; 20:296-298. 4. mulatero p, rabbia f, milan a, paglieri c, morello f, chiandussi l, et al. drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. hypertension 2002; 40:897-902. 5. gordon rd, stowasser m, tunny tj, klemm sa, finn wl, krek al. clinical and pathological diversity of primary aldosteronism, including a new familial variety. clin exp pharmacol physiol 1991; 18:283-286. 6. stowasser m, gunasekera tg, gordon rd. familial varieties of primary aldosteronism. clin exp pharmacol physiol 2001; 28:1087-1090. 7. stewart pm. dexamethasone-suppressible hypertension. lancet 2000; 356:697-699. 8. woodhouse nj, elshafie ot, mehar a, johnston wj, al-kaabi jm. spironolactone responsive familial hypertension. a potentially high prevalence of mineralocorticoid disease in oman. saudi med j 2003; 24:229-231. 9. hood s, cannon j, foo r, brown m. prevalence of primary hyperaldosteronism assessed by aldosterone/ renin ratio and spironolactone testing. clin med 2005; 5:55-60. 10. seifarth c, trenkel s, schobel h, hahn eg, hensen j. influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism. clin endocrinol (oxf ) 2002; 57:457-465. 11. so a, duffy dl, gordon rd, jeske yw, lin-su k, new mi, et al. familial hyperaldosteronism type ii is linked to the chromosome 7p22 region but also shows predicted heterogeneity. j hypertens 2005; 23:1477-1484. 12. grim ce. evolution of diagnostic criteria for primary aldosteronism: why is it more common in “drug-resistant” hypertension today? curr hypertens rep 2004; 6:485-492. submitted 28 dec 22 1 revision req. 31 jan 23; revision recd. 15 mar 23 2 accepted 11 apr 23 3 online-first: may 2023 4 doi: https://doi.org/10.18295/squmj.5.2023.021 5 6 papilliferous keratoameloblastoma 7 a systematic review 8 *sanpreet s. sachdev, tabita j. chettiankandy, yogita b. adhane, manisha 9 a. sardar, akshay trimukhe, riya jain 10 11 department of oral pathology and microbiology, government dental college and hospital, 12 mumbai, india 13 *corresponding author’s e-mail: sunpreetss@yahoo.in 14 15 abstract 16 papilliferous keratoameloblastoma (pka) is a rare entity and not much is known about its 17 clinicodemographic features or biological nature. our review aimed to provide clarity with respect 18 to the characterization of demographic, clinical, radiological, and histopathological features of 19 pka. case reports of pka were identified by means of a systematic search across multiple 20 databases. the search yielded a total of 10 cases, half of which were of indian origin. all the cases 21 invariably occurred in the mandibular posterior region and involved the right side, except for one 22 case which primarily involved the left side of the mandible. pka should be considered as a variant 23 of conventional ameloblastoma but towards the more aggressive end of the spectrum. it tends to 24 occur in older individuals (fifth decade or older), with a marked propensity to occur in the right 25 mandibular posterior region. surgical resection with diligent follow-up is warranted in the 26 treatment of pka. 27 keywords: odontogenic tumors; ameloblastoma; keratin; odontogenic keratocyst 28 29 30 introduction 31 an array of metaplastic changes can occur in the epithelial component of ameloblastoma (am) 32 that are attributable to the potentiality of odontogenic epithelium. the epithelial cells within 33 ameloblastic follicles or plexuses may exhibit squamous, basaloid cell, granular cell, clear cell or 34 even mucous metaplasia. these metaplastic changes give rise to a polymorphic histopathological 35 picture in am. consequently, numerous corresponding variants of am such as acanthomatous, 36 basaloid, granular, clear cell have been recognized [1]. 37 38 squamous metaplasia in the central stellate reticulum-like cells of am is the hallmark of 39 acanthomatous ameloblastoma (aa). the terminal fate of squamous cells is to form keratin and 40 desquamate. as a result, extensive keratinization to the extent of keratin pearl formation may occur 41 in am. four types of histopathological pictures have been reported in line with the spectrum of 42 keratinizing ams. these include1) simple histology: ameloblastomatous follicles filled with 43 orthoor parakeratin centrally, 2) simple histology along with features of conventional 44 odontogenic keratocyst (okc), 3) complex histology: extrusion of keratin masses into the stroma 45 along with features of simple histology with or without hard tissue formation, 4) papilliferous 46 histology: papillary projections of the odontogenic epithelium into the cystic lumen or microcystic 47 spaces [2]. 48 49 the world health organization in 1992, recognized such am with extensive keratinization as 50 keratoameloblastoma (ka). while some authors consider ka as a subset of aa, others have 51 reported it as a distinct variant of am [2,3]. the centrally desquamated cells lead to the formation 52 of microcystic areas within the ameloblastomatous follicles. the presence of papillary ingrowths 53 of odontogenic epithelium within these microcysts or in the primary cystic lumen is an even rarer 54 phenomenon. the first such case was described by pindborg and weinmann as a subset of am 55 and the term ‘papilliferous keratoameloblastoma’ (pka) was suggested [4]. while an ample 56 number of cases of ka displaying either simple or complex histology have been identified, the 57 pka variant is exceedingly rare [3,5]. as a result, not much is known about the clinicodemographic 58 characterization and biological nature of pka. 59 60 the question whether pka differs from other variants of am in its biological behavior or it 61 belongs to spectrum of aa without any clinical significance is not yet answered. the present 62 systematic review aims to gain a better understanding of the rare entity by identifying and 63 analyzing all the reported cases of pka in scientific literature. the objectives of our review are to 64 describe the demographic, clinical, and histopathological characteristics of pka. 65 66 methods 67 case reports of pka were retrieved by a systematic search of the databases: medline (ovid), 68 pubmed, pubmed central, web of science citation index expanded, (sciexpanded), and 69 google scholar. a systematic search with keywords ((ameloblastoma) and (papillae)) or 70 (papilliferous ameloblastoma). an additional search with keywords((ameloblastoma) and 71 (keratin)) or (keratoameloblastoma) or (keratinizing ameloblastoma), was performed and 72 screened for potential presence of papilliferous areas in the microscopic picture. the cross 73 references cited in the retrieved literature were also screened for identification of possible cases of 74 pka, in case if any were missed by the search strategy. 75 76 full text articles of all the cases belonging to the spectrum of keratinizing ams were scrutinized 77 for histopathological features of pka. the quality of case reports was evaluated by means of jbi 78 critical appraisal tool for case reports [6]. to further minimize bias in quality assessment, the 79 authors were divided into two groups (ss and tc; ms and ya) which independently evaluated 80 the case reports for their inclusion in the present review (figure 1). 81 82 the criterion for inclusion of the cases was the histopathological presence of papilliferous 83 proliferations of odontogenic epithelium into the primary cystic lumen or microcysts formed 84 within the ameloblastoma follicles along with the formation of keratin (figure 2). for a better 85 understanding of the histopathological features, photomicrographs (figure 3) were obtained from 86 the case reported by bedi et al.[2] cases with an ambiguous description or unclear histopathological 87 demonstration of a papilliferous component or keratin formation were excluded from the review. 88 the presence or absence of additional histopathological features besides papilliferous patterns such 89 as budding of cells, dentinoid formation, calcifications, ghost cells or okc-like features, were also 90 recorded. however, these additional features were not considered definitive criteria for diagnosis 91 of pka as they represent variations that can occur in the odontogenic neoplasm. 92 data extraction: 93 the demographic, clinical, radiological, and histopathological features of all the cases was 94 extracted. additional investigations such as special stains, immunohistochemistry (ihc) or gene 95 expression was also elicited. the treatment performed in all the cases, number of recurrences, 96 period between the recurrences and time with no evidence of disease after treatment was recorded. 97 the quality of articles included in the review was also assessed using the grade approach [7]. 98 the extracted data was entered and tabulated in into worksheets (microsoft office excel 2016, 99 redmond, washington, usa). 100 101 the review title and search protocol are registered in the international prospective register of 102 systematic reviews prospero under the registration number: crd42021282930. 103 104 results and discussion 105 a total of 10 reported cases of pka were found in scientific literature available in english [2-5,8-13]. 106 half of the patients (n=5, 50%) in these reported cases were of indian origin [2,5,11-13]. the 107 clinicodemographic data extracted from all the cases of pka are tabulated in table 1. the age of 108 patients ranged from 18 to 76 years with a mean age of 49.7 years (s.d = +20.95). bedi et al., in 109 their review, reported a slightly lower mean age of 40 years for ka exhibiting papilliferous 110 features [2]. conventional am shows a peak of occurrence in the third and fourth decades [1,14]. 111 however, the cases of pka were evenly distributed amongst all the decades with majority of cases 112 occurring in fifth decade or later (n=7, 70%). only three cases occurred in patients of age less than 113 30 years, while no case of pka occurring in the fourth decade has yet been reported. these 114 findings indicate that pka may occur at any age, but commonly occurs in patients of older age 115 groups. 116 117 there was a slight male predilection observed with 60% of the cases occurring in males (n=6) and 118 40% in females (n=4). the male-to-female ratio was found to be 1.5: 1. data from a recent 119 systematic review of the global profile of am has suggested that conventional am also exhibits a 120 slight male predilection in africa, north america and asia [15]. a higher male predilection with 121 two-thirds of cases occurring in males was reported by konda et al., and a ratio as high as 3:1 was 122 found by bedi et al. in their respective reviews of pka [2,12]. on the contrary, an equal sex 123 distribution (1:1) in reported cases of pka was reported by rathore et al [13]. however, the 124 omission of certain cases or reports of additional cases after the reviews conducted by these authors 125 has led to a variation in the sex distribution of pka. 126 127 all the patients (n=9, unknown for one case) complained of swelling of duration ranging from 3 128 months to 5 years. the swelling was asymptomatic in most of the cases (n=6, 60%), which is a 129 common mode of presentation of am. pain was present in 3 cases, while mobility of teeth was 130 present in one case. pain is an uncommon feature in am, and is usually noted in lesions of larger 131 size that tend to impinge on adjacent or involved nerves or due to secondary infection [16]. 132 infiltration of the lesions within the bony trabeculae and subsequent resorption could account for 133 the occasional mobility of teeth noted in conventional am or its variants such as pka. difficulty 134 in mandibular movement was present in the case reported by collini et al., which was attributable 135 to the involvement of condylar process by the lesion [10]. 136 137 all the cases invariably involved the posterior region of the mandibular jaw (n=10, 100%) and 138 none of the reported cases of pka to date has occurred primarily in the maxilla or in the anterior 139 region of the mandible. this propensity of pka to occur in the mandible is similar to that displayed 140 by conventional am, wherein 90% of cases involve the mandibular jaw [17]. the lesion exhibited 141 a marked predilection to occur on the right side (n=9, 90%), while only one case primarily 142 involving the left side of the mandible was noted. this finding was in contrast to conventional 143 am, which involves both sides almost equally [1]. in one case, the lesion was extensive enough to 144 involve the entire right side of the mandible, cross the midline and involve the anterior region of 145 the left side. 146 147 the lesion was described radiologically as a radiolucency (n=9, 90%), which was unilocular in 2 148 cases and multilocular in 7 cases. the radiolucency was well-defined in 5 cases and ill-defined in 149 3 cases. in one case, it was described as an osteolytic lesion with irregular calcifications [10]. the 150 radiological features demonstrated by pka are not pathognomonic and are shared by several other 151 entities [18]. therefore, odontogenic keratocyst, various benign and malignant odontogenic tumors, 152 benign fibrosseous lesions and central giant cell granuloma constitute the clinicoradiological 153 differential diagnosis of pka. the extensively destructive nature of pka was evident in 154 radiographs of all the cases wherein the majority of the cases involved the body, angle and ramus 155 of the mandible (n=7, 50%). out of these, 2 cases exhibited extended involvement up to the 156 sigmoid notch and condylar process. 157 158 additionally, all the cases that reported findings of computed tomography, found that the buccal 159 and lingual cortical plates exhibited expansion as well as perforation. am displays a tendency to 160 cause extensive bone destruction and aggressively invade local structures. increased motility of 161 neoplastic cells due to loss of syndecan-1 coupled with increased expression of matrix 162 metalloproteinases (mmps) and receptor activator of nuclear factor-kappa b ligand (rankl) has 163 been suggested as the possible reasons for the aggressive biological nature of am [19,20]. however, 164 none of the authors has investigated the expression of these markers or genes involved in the 165 reported cases of pka. expression of similar markers needs to be studied in cases of pka, to 166 further elucidate the reasons for its aggressive nature. 167 168 histopathologically, all the lesions exhibited an am component with keratinization and 169 papilliferous areas. the histopathological features of pka described by various authors in their 170 respective cases are tabulated in table 2. when considering the am component, the follicular 171 pattern of ameloblastoma was observed most commonly (n=5). the plexiform pattern of am was 172 predominant in the case reported by konda et al., which also exhibited areas of desmoplastic 173 changes within the stroma. two cases exhibited an admixture of the follicular and plexiform 174 pattern [12]. in one case, the papilliferous proliferations were present in the primary lumen of a 175 unicystic ameloblastoma (uam) [13]. in the case reported by collini et al., the architecture of 176 tumor cells was described as nests, tubules, islands and even single-file pattern, which simulated 177 the appearance of a salivary gland neoplasm [10]. 178 179 ameloblast-like cells were present in the majority of lesions wherein low to tall columnar 180 ameloblast-like cells exhibiting nuclear hyperchromatism and reversal of polarity were present in 181 almost all the cases (n=8, 80%). these cells were present peripherally in the tumor follicles or 182 plexuses. of these 7 cases exhibited stellate reticulum-like cells, while one case had granular cells 183 towards the centre. besides ameloblastomatous follicles, some of the follicles were lined by only 184 squamous cells with or without keratin formation. 185 one case of am exhibiting papilliferous proliferations reported by adeyemi et al. had basaloid 186 metaplasia within the centre of the follicles [21]. we believe that their case represents a basaloid 187 variant of am exhibiting papilliferous changes or possibly a hybrid odontogenic tumor. however, 188 since there was no keratin formation within the tumor islands, it did not fulfil the criteria for 189 diagnosis of pka. the earliest cases of pka reported by pindborg and altini et al. did not exhibit 190 ameloblast-like cells lining the follicles [4,8]. instead, single to multiple layers of parakeratotic 191 squamous epithelial cells were observed, half of which formed tumor islands while the other 192 demonstrated papilliferous epithelium within a central cystic lumen. similar parakeratotic 193 stratified squamous cells were noted in the tumor islands of cases reported by kuberappa et al. and 194 rathore et al., but with the presence of am-like features in some follicles [5,13]. 195 196 the majority of the cases exhibited cystic degeneration centrally within the ameloblastic follicles 197 or plexuses (n=8, 80%) in which necrotic cell debris were present. it has been suggested that these 198 acantholytic cells separate from the viable epithelial cells in the follicle which continue 199 proliferating. this differential rate of proliferation and necrosis gives rise to pseudopapillary 200 structures projecting into the microcystic lumen [8]. such phenomena are noted occasionally in 201 am, but are common in odontogenic carcinomas. this suggests a closer histopathological 202 resemblance of pka to the more aggressive end of the spectrum of odontogenic neoplasms. 203 204 it has also been postulated that pka is ka in which extensive acantholysis results in 205 pseudopapillary projections [22]. however, true papillae consisting of ameloblastoma-like 206 epithelium with fibrovascular core were also present proliferating in the primary cystic lumen or 207 those formed within the follicles. the center of tumor follicles, islands, plexuses and nests were 208 packed with stacks of paraor orthokeratin. in three cases, the stacks of keratin were extruded 209 into the connective tissue stroma and illustrated a pacinian corpuscle-like architecture [3,9,12]. 210 211 classically, am has been defined as an odontogenic neoplasm of ameloblast-like cells in which 212 the cells do not undergo differentiation to the point of hard tissue formation [1]. even so, formation 213 of hard tissues is a frequent finding in ka and was also noted in three cases of pka. it has been 214 suggested that the extruded stacks of keratin undergo mineralization, ultimately leading to hard 215 tissue formation. necrotic tissues may undergo a transition to bone with or without dystrophic 216 calcification; a process termed ‘pathologic ossification’. takeda et al. described the hard tissue 217 formation as a result of pathological ossification producing cellular cementum or woven bone-like 218 material [9]. the transition between the keratin accumulated in the stroma and the forming hard 219 tissue was also evident microscopically in their case. dystrophic calcifications in the stroma were 220 demonstrated in the case reported by norval et al [3]. 221 222 another entity associated with am that comprises hard tissue formation is adenoid ameloblastoma 223 with dentinoid. this dentinoid-producing tumor exhibits characteristic histopathological features 224 of am and adenomatoid odontogenic tumor (aot), but is not yet recognized as an official entity 225 by the who. our recent review of literature found about 30 cases of aad reported to date [23]. 226 similarly, it would be possible for dentinoid formation to occur in pka which was also described 227 in one case by bedi et al. even so, the mechanism of dentinoid formation would be different for 228 aad (epithelial-mesenchymal induction) and pka (pathologic ossification), considering the 229 different pathogenesis of both entities. the term ‘kerato-odontoameloblastoma’ was suggested for 230 such ka with odontogenic hard tissue formation [2]. 231 232 while okc-like features are commonly noted in ka, they were absent in all the cases of pka [24]. 233 it has been suggested that okc may occasionally serve as a source of epithelium for ka to develop 234 since it shares a common phenotype and genetic profile, to some extent, with the cells of 235 ameloblastic lineage [25]. development of mural islands of am from the lining epithelium of okc 236 was demonstrated by brannon et al. cases exhibiting combined histopathological features have 237 been reported as ‘hybrid’ lesions by some authors while others have considered them within the 238 spectrum of ka [24,26]. there is yet lack of evidence linking okc with pka. 239 240 additional histopathological features such as foreign body giant cells, cholesterol clefts, ghost 241 cells, duct-like structures and rosette-like structures were also described across the reported cases 242 of pka by various authors [2,5,10]. the presence of foreign body giant cells and cholesterol clefts is 243 not surprising, and they represent the normal host tissue inflammatory response or constitute a part 244 of the secondary infection of the tumor. the presence of abundant keratin bodies with faint nuclear 245 outlines was implicated as the reason for the resemblance to ghost cells [5]. the follicles with cystic 246 degeneration are occasionally lined by a single layer of epithelium adherent to the basement 247 membrane that imparted a hobnail appearance [8]. a cross-section of such follicles was suggested 248 to be the reason for the apparent duct-like structures [8,21]. the presence of acantholytic cells within 249 such follicles would also impart a rosette-like appearance, leading to misinterpretation of the lesion 250 as aot. a highly vascularized stroma was present in the case reported by kuberappa et al. that 251 resembled hemangiomatous am [8]. trauma or stimulation of vessels closely associated with the 252 dental follicle has been suggested as the reason for the highly vascular transition of the stroma in 253 am [27]. 254 255 while the tumor cells in most of the cases had a benign morphology, a high mitotic rate of 3 256 mitoses/ high power field was reported by collini et al. recurrences occurred after 39 and 58 257 months, respectively, in their case [10]. the patient ultimately succumbed to non-hodgkin’s 258 lymphoma (nhl) after 6 years. they proposed that pka should be renamed as “papillary 259 ameloblastic carcinoma” considering its clinically aggressive nature, the microscopic abundance 260 of necrosis and recurrence. such cases may closely resemble ameloblastic carcinoma, well-261 differentiated oral squamous cell carcinoma or primary intraosseous carcinoma. generally, pka 262 lacks cellular pleomorphism, vascular and neural invasion, and abnormal mitoses. the presence 263 of these features can aid in distinguishing pka from these other malignant epithelial or 264 odontogenic neoplasms. 265 266 investigation of the biological chemistry of the tissue by special stains and biomarkers by means 267 of ihc has not been extensively studied in cases of pka. the case reported by collini et al. 268 resembled a salivary gland tumor owing to the presence of tubules and duct-like structures [10]. the 269 authors investigated mucin production by alcian blue which resulted in negative staining. the 270 salivary gland origin of the tumor was ruled out by negative immunostaining for high-molecular-271 weight cytokeratins, smooth muscle α-actin, maspin, gfap, and cd45. they found positive 272 immunoexpression of low-molecular-weight cytokeratins in the epithelial cells, and vimentin in 273 the stroma along with focal and weak expression of s100. rathore et al. found intense 274 immunoexpression of ck19 in the basal and suprabasal layers of the lining epithelium, which was 275 indicative of its odontogenic origin [28]. ki-67 was intensely expressed in the basal and suprabasal 276 layers along with infrequent positivity in the superficial cells, which was indicative of the high 277 proliferative potential of the cells. they also found that p53 was strongly expressed in the basal 278 and suprabasal layers, suggestive of mutation in the tumor suppressor gene. the ihc findings of 279 collini et al. and rathore et al. provided further evidence for the aggressive biological potential of 280 the neoplastic odontogenic cells in pka [10,13]. 281 282 various authors have dealt with pka through different approaches such as wide excision (n=4, 283 40%), segmental resection (n=2, 20%), hemimandibulectomy (n=2, 20%). considering the 284 extensive clinical involvement, presence of atypical cytological features and recurrence, collini et 285 al. performed modified neck dissection along with the hemimandibulectomy procedure in their 286 case [10]. the lesion recurred 39 months after the treatment procedure, after which, no treatment 287 was performed for the recurrent tumor owing to presence of concomitant nhl. another recurrence 288 was reported in the case reported by bedi et al., which occurred three years after en bloc resection 289 [2]. the remainder of cases showed no evidence of disease for a varying follow-up period of 2 290 months to 1 year. however, considering the recurrences in the case of collini et al. and bedi et al. 291 after three years of treatment, the follow-up period provided by the other authors may not be 292 sufficient to declare a successful outcome. 293 294 except for luminal and intraluminal uam, there is no difference in the treatment of different 295 variants of am [1]. marx and stern stated that classifying am according to all the different types 296 of histopathological features would only serve to complicate the classification system, ultimately 297 confusing the clinicians [29]. even so, the different histopathological types have academic 298 importance and are of interest to pathologists. therefore, as long as there is no significant 299 difference in the biological behavior, including different histopathological types of an entity as 300 variants seems the most rational approach. reports of more cases in future with extensive long-301 term follow-up of the outcome would shed more light on the subject of whether pka is just a 302 variant of am or a distinct entity. in view of the current evidence, we believe that pka should be 303 considered as a variant of am within the spectrum of keratinizing ams 304 305 conclusion 306 pka is a rare entity with only 10 reported cases to date, all of which have involved the mandibular 307 posterior region. the clinicodemographic and radiological characteristics of pka are much similar 308 to am except that it occurs more commonly in older individuals and shows a marked predilection 309 to occur on the right side. the lesion is locally aggressive exhibiting extensive clinical involvement 310 of the mandible and adjacent structures. the radiological features of pka are not pathognomonic 311 and resemble other odontogenic neoplasms. histopathological presence of papilliferous 312 proliferations of the odontogenic epithelium, along with extensive keratin production which may 313 even occur in the stroma are characteristic of pka. based on the presence of necrotic areas, the 314 high proliferating potential of cells, and possible recurrence, we recommend it to be considered 315 within the spectrum of keratinizing ams, towards the more aggressive end. further studies 316 pertaining to biomarkers in pka such as syndecan—1, mmps and rankl, will aid in elucidating 317 the biological potential of the lesion. with an increasing number of reported cases, more insights 318 could be gained with respect to the possible links between the pathogenesis of okc, aa, ka, and 319 pka. 320 321 authors’ contribution 322 ss and tc conceptualised the idea and designed the review. all the authors were responsible for 323 data collection, analysis and resolution of any issues. ss, ya and tc prepared the manuscript 324 while the content was critically reviewed and edited by ms, at and rj. all authors approved the 325 final version of the manuscript. 326 327 references 328 1. takata t, slootweg pj. odontogenic and maxillofacial bone tumours.in: el naggar ak, 329 chan jk, grandis jr, takata t, slootweg pj. who classification of head and neck 330 tumours, 4th ed, iarc, lyon, 2017:pp203-232. 331 2. bedi rs, sah k, singh a, chandra s, raj v. keratoameloblastoma or kerato-332 odontoameloblastoma: report of its soft tissue recurrence with literature review. 333 quantitative imaging in medicine and surgery. 2015 dec;5(6):898-908. 334 doi: 10.3978/j.issn.2223-4292.2015.09.01. pmid: 26807371; pmcid: pmc4700246. 335 https://dx.doi.org/10.3978%2fj.issn.2223-4292.2015.09.01 https://www.ncbi.nlm.nih.gov/pubmed/26807371 3. norval ej, thompson io, van wyk cw. an unusual variant of keratoameloblastoma. j 336 oral pathol med. 1994 nov;23(10):465-7. doi: 10.1111/j.1600-0714.1994.tb00446.x. 337 pmid: 7532221. 338 4. pindborg jj, weinmann jp. squamous cell metaplasia with calcification in 339 ameloblastomas. acta pathol microbiol scand. 1958;44(3):247-52. doi: 10.1111/j.1699-340 0463.1958.tb01074.x. pmid: 13605784. 341 5. kuberappa ph, anuradha a, kiresur ma, bagalad bs. papilliferous 342 keratoameloblastoma–a rare entity: a case report with a review of literature. j oral 343 maxillofac pathol. 2020 feb;24(suppl 1):s2-6. doi: 10.4103/jomfp.jomfp_42_17. 344 pmid: 32189894; pmcid: pmc7069145. 345 6. aromataris e, munn z (editors). jbi manual for evidence synthesis. jbi, 2020. available 346 from https://synthesismanual.jbi.global. https://doi.org/10.46658/jbimes-20-01 347 7. granholm a, alhazzani w, møller mh. use of the grade approach in systematic 348 reviews and guidelines. british journal of anaesthesia. 2019 nov 1;123(5):554-349 9. doi: 10.1016/j.bja.2019.08.015. pmid: 31558313. 350 8. altini m, dev slabbert h, johnston t. papilliferous keratoameloblastoma. j oral pathol 351 med. 1991 jan;20(1):46-8. doi: https://10.1111/j.1600-0714.1991.tb00887.x. 352 pmid: 1705984. 353 9. takeda y, satoh m, nakamura si, ohya t. keratoameloblastoma with unique histological 354 architecture: an undescribed variation of ameloblastoma. virchows arch. 2001 355 oct;439(4):593-6. doi: 10.1007/s004280100489. pmid: 11710648. 356 10. collini p, zucchini n, vessecchia g, guzzo m. papilliferous keratoameloblastoma of 357 mandible: a papillary ameloblastic carcinoma: report of a case with a 6-year follow-up and 358 review of the literature. int j surg pathol. 2002 apr;10(2):149-55. 359 doi: 10.1177/106689690201000210. pmid: 12075410 360 11. mohanty n, rastogi v, misra sr, mohanty s. papilliferous keratoameloblastoma: an 361 extremely rare case report. case rep dent. 2013 jun 3;2013:epub. 362 doi: 10.1155/2013/706128. pmid: 23862079; pmcid: pmc3686074. 363 12. konda p, bavle rm, muniswamappa s, makarla s, venugopal r. papilliferous 364 keratoameloblastoma of the mandible-a rare case report. j clin diagn res. 2016 365 https://doi.org/10.1111/j.1600-0714.1994.tb00446.x https://doi.org/10.1111/j.1699-0463.1958.tb01074.x https://doi.org/10.1111/j.1699-0463.1958.tb01074.x https://dx.doi.org/10.4103%2fjomfp.jomfp_42_17 https://www.ncbi.nlm.nih.gov/pubmed/32189894 https://synthesismanual.jbi.global/ https://doi.org/10.46658/jbimes-20-01 https://doi.org/10.1016/j.bja.2019.08.015 https://10.0.4.87/j.1600-0714.1991.tb00887.x https://doi.org/10.1007/s004280100489 https://doi.org/10.1177/106689690201000210 https://doi.org/10.1155/2013/706128 http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3686074/ aug;10(8):zd08-11. doi: 10.7860/jcdr/2016/18862.8232. pmid: 27656576; 366 pmcid: pmc5028498. 367 13. rathore as, juneja s, khurana n, shetty dc. papilliferous keratoameloblastoma: a rare 368 case report. int j appl basic med res. 2017 apr-jun; 7(2): 139–142. 369 doi: 10.4103/ijabmr.ijabmr_136_16. pmid: 28584748; pmcid: pmc5441264. 370 14. reichart pa, philipsen hp, sonner s. ameloblastoma: biological profile of 3677 cases. 371 eur j cancer b oral oncol. 1995 mar;31b(2):86-99. doi: 10.1016/0964-1955(94)00037-372 5. pmid: 7633291. 373 15. hendra fn, van cann em, helder mn, ruslin m, de visscher jg, forouzanfar t, de vet 374 hc. global incidence and profile of ameloblastoma: a systematic review and meta‐375 analysis. oral diseases. 2020 jan;26(1):12-21. 376 16. ueno s, nakamura s, mushimoto k, shirasu r. a clinicopathologic study of 377 ameloblastoma. j oral maxillofac surg. 1986 may 1;44(5):361-5. doi: 10.1016/s0278-378 2391(86)80031-3. pmid: 3457915. 379 17. jing w, xuan m, lin y, wu l, liu l, zheng x et al. odontogenic tumours: a retrospective 380 study of 1642 cases in a chinese population. int j oral maxillofac surg. 2007;36(1):20-5. 381 18. avril l, lombardi t, ailianou a, burkhardt k, varoquaux a, scolozzi p, becker m. 382 radiolucent lesions of the mandible: a pattern-based approach to diagnosis. insights 383 imaging. 2014 feb;5(1):85-101. doi: 10.1007/s13244-013-0298-9. pmid: 24323536 384 pmcid: pmc3948901. 385 19. brito-mendoza, l., bologna-molina, r., irigoyen-camacho, m.e., martinez, g., sánchez-386 romero, c. and mosqueda-taylor, a., 2018. a comparison of ki67, syndecan-1 (cd138), 387 and molecular rank, rankl, and opg triad expression in odontogenic keratocyts, 388 unicystic ameloblastoma, and dentigerous cysts. dis markers. 2018 jul 29;2018:7048531. 389 doi: 10.1155/2018/7048531. pmid: 30151060; pmcid: pmc6087607. 390 20. siar, c.h., tsujigiwa, h., ishak, i., hussin, n.m., nagatsuka, h. and ng, k.h., 2015. 391 rank, rankl, and opg in recurrent solid/multicystic ameloblastoma: their distribution 392 patterns and biologic significance. oral surg oral med oral pathol oral radiol. 2015 393 jan;119(1):83-91. doi: 10.1016/j.oooo.2014.09.017. pmid: 25446507. 394 https://dx.doi.org/10.7860%2fjcdr%2f2016%2f18862.8232 https://www.ncbi.nlm.nih.gov/pubmed/27656576 https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5441264/ https://dx.doi.org/10.4103%2fijabmr.ijabmr_136_16 https://www.ncbi.nlm.nih.gov/pubmed/28584748 https://doi.org/10.1016/0964-1955(94)00037-5 https://doi.org/10.1016/0964-1955(94)00037-5 https://doi.org/10.1016/s0278-2391(86)80031-3 https://doi.org/10.1016/s0278-2391(86)80031-3 https://dx.doi.org/10.1007%2fs13244-013-0298-9 https://www.ncbi.nlm.nih.gov/pubmed/24323536 https://doi.org/10.1155/2018/7048531 http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6087607/ https://doi.org/10.1016/j.oooo.2014.09.017 21. adeyemi bf, adisa ao, fasola ao, akang ee. keratoameloblastoma of the mandible. 395 journal of oral and maxillofacial pathology: jomfp. 2010 jul;14(2):77-9. doi: 396 10.4103/0973-029x.72507. 397 22. ketabi ma, dehghani n, sadeghi hm, shams mg, mohajerani h, azarsina m, azizi a. 398 keratoameloblastoma, a very rare variant of ameloblastoma. j craniofac surg. 2013 nov 399 1;24(6):2182-6. doi: 10.1097/scs.0b013e3182a28be3. pmid: 24220437. 400 23. sachdev ss, chettiankandy tj, sardar ma, adhane yb, shah am, grace ae. adenoid 401 ameloblastoma with dentinoid: a systematic review. sultan qaboos univ med j 402 2021;1(1). https://doi.org/10.18295/squmj.9.2021.127 [online-first version]. 403 24. siar ch, ng kh. combined ameloblastoma and odontogenic keratocyst’or ‘keratinising 404 ameloblastoma. br j oral maxillofac surg. 1993 jun;31(3):183-6. doi: 10.1016/0266-405 4356(93)90122-d. pmid: 7685634. 406 25. ren c, amm hm, devilliers p, wu y, deatherage jr, liu z, macdougall m. targeting 407 the sonic hedgehog pathway in keratocystic odontogenic tumor. j biol chem. 2012 aug 408 3;287(32):27117-25. doi: 10.1074/jbc.m112.367680. pmid: 22679015; 409 pmcid: pmc3411054. 410 26. brannon rb. the odontogenic keratocyst: a clinicopathologic study of 312 cases. part i. 411 clinical features. oral surgery, oral medicine, oral pathology. 1976 jul 1;42(1):54-72. 412 doi: 10.1016/0030-4220(76)90031-1. pmid: 1065842. 413 27. venigalla a, bojji m, pinisetti s, babburi s. hemangiomatous ameloblastoma: case report 414 with a brief review. j oral maxillofac pathol. 2018 jan; 22(suppl 1): s24–s28. 415 doi: 10.4103/jomfp.jomfp_28_16. pmid: 29491600; pmcid: pmc5824512. 416 28. kawai s, ito e, yamaguchi a, eishi y, okada n. immunohistochemical characteristics of 417 odontogenic carcinomas: their use in diagnosing and elucidating histogenesis. oral med 418 pathol. 2009;13(2):55-63.doi: 10.3353/omp.13.55. 419 29. marx r, stern d: oral and maxillofacial pathology. hanover park, il, quintessence 420 publishing, 2003:pp.646. 421 422 423 https://doi.org/10.1097/scs.0b013e3182a28be3 https://doi.org/10.18295/squmj.9.2021.127 https://doi.org/10.1016/0266-4356(93)90122-d https://doi.org/10.1016/0266-4356(93)90122-d https://doi.org/10.1074/jbc.m112.367680 http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3411054/ https://doi.org/10.1016/0030-4220(76)90031-1 https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5824512/ https://dx.doi.org/10.4103%2fjomfp.jomfp_28_16 https://www.ncbi.nlm.nih.gov/pubmed/29491600 424 figure 1: prisma flow chart indicating selection process of articles for final qualitative 425 synthesis of the present systematic review. 426 427 428 429 figure 2: line diagram illustrating histopathological features of pka. ameloblast-like cells (1), 430 stacks of keratin within cystic degeneration in the follicle (2), papillary projections into the follicle 431 (3), acantholytic cells (4), keratin extruded into the stroma (5), necrotic material within the 432 follicle (6), micropapillary structures in a follicle lined by squamous epithelial cells (7), normal 433 ameloblastoma-like follicle with central stellate reticulum-like cells (8) 434 435 436 figure 3: “(a) photomicrograph exhibiting proliferating odontogenic epithelium lining the cystic 437 lumen (h&e, ×40); (b) odontogenic epithelium proliferating in plexiform pattern of odontogenic 438 epithelium (h&e, ×100); (c) papillary projections from odontogenic epithelium (h&e, ×100); 439 (d) papillary proliferation of odontogenic epithelium within a collagenous connective tissue stoma 440 (h&e, ×40); (e) extensive squamous metaplasia with in odontogenic islands lined by tall columnar 441 ameloblast-like cells (h&e, ×100); (f) squamous metaplasia with keratin pearl formation (h&e, 442 ×100); (g) “keratin filled cystic spaces” with keratin production in the stroma (h&e, ×100); (h) 443 “keratin filled cystic spaces” with keratin production in the stroma (krebergs stain, ×100); (i) 444 “curvilinear ribbons” of odontogenic epithelium within collagenized stroma, which is extruding a 445 “lamellar stack of keratin” into the stroma without foreign body response (h&e, ×100); (j) 446 “pacinian-like” stack of keratin (h&e, ×100); (k) parakeratin packed elongated epithelial follicles 447 showing lamellar arrangement of keratin forming “hair-like structures” (h&e, ×100); (l) 448 formation of dentinoid-like material adjacent to odontogenic epithelium (h&e, ×100); (m) 449 dentinoid-like material (h&e, ×1,000); (n) dentinoid-like material with tubular structures (h&e, 450 ×1,000); (o) granuloma with cholesterol cleft formation (h&e, ×100).” (picture obtained from 451 the case reported by bedi et al.[2]) 452 table 1: summary of demographic, clinical, radiological features and management of cases of pka by various authors 453 sr. no . author yea r age years se x race durati on ja w side regio n extent sympto ms radiogra phic features final diagnosis treatment and follow-up grad e system 1 pindbor g et al. 197 0 57 f unkno wn unkno wn m n righ t posteri or body, angle, ramus unknow n ml rl pka unknown low 2 altini et al. 199 1 76 f south african 12 months m n righ t posteri or pm to sigmoi d notch swelling wd ml rl pka hemimandibulect omy 1 year, ned modera te 3 norval et al. 199 4 26 f south african 60 months m n righ t posteri or pm to 3m swelling , pain wd ml rl unusual variant of ka segmental resection + iliac crest graft high 4 takeda et al. 200 1 76 m japanes e several months m n left posteri or c to 2m, body swelling wd ml rl ka surgical resection high 5 collini et al. 200 2 62 m italian 3 months m n righ t posteri or ramus and condyl e swelling , difficult y in mandibu lar moveme nt osteolyti c lesion with irregular calcificati ons pka hemimandibulect omy + modified neck dissection recurrence after 39 months resection recurrence after 18 died after 6 years due to concurrent lymphoma high 6 mohant y et al 201 3 46 m indian 12 months m n righ t posteri or c to ramus swelling id ml rl pka unknown modera te 7 bedi et al. 201 5 27 f indian 7 months m n righ t posteri or 2pm to sigmoi d notch swelling id ml rl ka complex histology wide excision recurred once after 3 years of en bloc resection high 8 konda et al. 201 6 44 m indian 6 months m n righ t posteri or c to 1m swelling , intermitt ent pain, mobility of teeth wd ul rl papilliferou s keratinizin g variant of solid multicystic ameloblast oma in toto excision 1 year, ned high 9 kuberap pa et al. 201 7 65 m indian 4 months m n righ t antero posteri or 31 to 47 swelling , pain id ml rl pka wide excision 2 months, ned high 10 rathore et al. 201 7 18 m indian 3 months m n righ t posteri or c to 3m swelling wd ul rl pka wide excision 2 years, ned high 454 legends for table 1: 455 m = male, f = female; mn = mandible 456 c = canine, pm = premolar, m = molar 457 wd = well-defined, id = ill-defined, ml = multi-locular, ul = unilocular, rl = radiolucency 458 pka = papilliferous keratoameloblastoma, ka = keratoameloblastoma 459 ned = no evidence of disease 460 461 462 table 2: summary of histopathological features observed in cases of pka reported by various authors 463 464 author epithelial component connective tissue component type cystic degeneration necrotic material desquamated keratin papillary projections ameloblastlike features stratified squamous lining in follicles extruded keratin hard tissue formation pindborg et al. follicles/islands present present present present present present absent absent altini et al. follicles present present present present absent present absent absent norval et al. follicles present present present present present questionabl e present dystrophic calcification takeda et al. follicles absent absent present present present present present cellular cementum / woven bonelike collini et al. nests, tubules, islands, indian file present minimal present present present absent absent absent mohanty et al. follicles present present present present present absent absent absent bedi et al. follicles, nests, chords, plexuses present present present present present absent absent dentinoid material konda et al. plexiform absent absent present present present absent present absent kuberappa et al. follicle, plexiform present present present present present present absent absent rathore et al. uam with mural islands present present present present present present absent absent 1 submitted 11 oct 22 2 revision req. 2 jan 22; revisions recd. 1 feb 22 3 accepted 23 mar 23 4 online-first: may 2023 5 doi: https://doi.org/10.18295/squmj.5.2023.022 6 7 preoperative diagnosis of xanthogranulomatous cholecystitis 8 asma s. alhatmi, atheel kamoona, *ishaq s. al salmi 9 10 radiology department, the royal hospital, muscat, oman 11 *corresponding author’s email: ishaqalsalmi85@gmail.com 12 13 introduction 14 a sixty-one years old man, known case of hypertension presented to the hepatobiliary surgery 15 clinic, royal hospital, muscat, oman, in december 2020 with a history of right upper quadrant 16 pain associated with nausea, vomiting, loss of appetite and jaundice for the past two months. on 17 examination, tenderness and fullness were present over the right upper quadrant. laboratory 18 investigations showed deranged liver function test with elevated liver enzymes and bilirubin 19 level. the total count of white blood cells and neutrophils were normal. cancer antigen 19-9 20 (ca 19-9) was elevated reaching 2364 u/ml and carcinoembryonic antigen (cea) was 21 negative. computerized tomography (ct) and magnetic resonance imaging (mri) of abdomen 22 were performed. ct revealed irregular diffuse mural wall thickening of the gallbladder along 23 with few hypoattenuating mural nodules, multiple hyperdense calculi and pericholecystic fluid 24 collection. poor fat plane to the adjacent liver parenchyma was seen and common bile duct 25 (cbd) was mildly dilated with multiple calculi noted within it. mri showed a diffusely 26 thickened gallbladder along with few non enhancing mural nodules within the thickened wall 27 which showed isoto slightly hypointense signal on both t1 and t2-wieghted images and some 28 of them demonstrated reduced signal in opposed images (op) denoting microscopic fat 29 depositions of xanthogranuloma in post contrast images, smooth luminal surface enhancement 30 along with focal area of early enhancement of adjacent liver parenchyma were noted. the 31 mailto:asmaalhatmi1989@gmail.com mailto:atheel88@gmail.com javascript:if(intformhaschanged%20==%200)%7bpopupreviewerinfoemdetails(16219,%209079,'squmj',%200)%7delse%7bpopupreviewerinfoemdetails(16219,%209079,'squmj',%201)%7d mailto:ishaqalsalmi85@gmail.com diagnosis of xanthogranulomatous cholecystitis (xgc) was raised. endoscopic retrograde 32 cholangiopancreatography (ercp) was performed for biliary decompression and cbd stone 33 extraction and stent insertion. later, total radical cholecystectomy with resection of segment 34 4b/5 of liver and portahepatis and celiac lymph node dissection were done and showed a 35 gallbladder mass with surrounding greater omental adhesions extending to adjacent liver 36 parenchyma and hepatic flexure with no evidence of liver or peritoneal metastasis. the 37 postoperative period was uneventful. the histopathology report revealed xgc with no evidence 38 of malignancy. xgc is uncommon inflammatory condition of the gallbladder in which the 39 diagnosis can be challenging on both imaging and histopathology due to overlapping features 40 with other serious conditions like carcinoma of the gallbladder. we report the ct and mri 41 findings of xgc with a literature review. 42 43 informed patient consent of publication was obtained. 44 45 comment 46 xgc is a rare type of chronic cholecystitis that was first reported by christensen et al in 1970.1 47 the underlying pathophysiology is still unclear, although many hypotheses attributed this 48 condition to a bile leak into the gallbladder wall which occurs secondary to rokitansky sinuses 49 rupture or mucosal injury in long standing high intraluminal pressure of the gallbladder due to 50 obstructing stones. subsequently, this leads to an inflammatory reaction that will attract more 51 foamy cells and macrophages resulting in chronic infiltrative granulomatous inflammation and 52 fibrosis which may extend to involve the adjacent structures.1,2 the histopathology reveals an ill-53 defined infiltrative yellow mass of thickened gallbladder wall.2 half of the xgc cases are 54 associated with pericholecystic fat infiltration and hepatic extension. 36% of the cases are 55 associated with biliary obstruction and reactive lymphadenopathy.2,3,4 microscopically, xgc 56 shows a mixture of xanthogranuloma with foamy histiocytes, macrophages and fibroblasts.2 57 xgc is an uncommon disease with estimated prevalence rate of 0.7-10%.1 it is predominantly 58 seen among elderly women in their sixth to eighth decades of life.1,2 80% of xgc cases are 59 associated with gallbladder calculi. the association between xgc and gallbladder carcinoma is 60 doubtful, although some studies in the literature reported gallbladder carcinoma in 8.5% to 61 30.5% of xgc cases.1 accompanying bacterial infections can also be identified and commonly 62 isolated organisms are escherichia coli, klebsiella and enterococcus.2 one third of xgc cases 63 are associated with complications such as perforation, abscess and fistula formation, 64 inflammatory infiltration to adjacent structures including the liver, colon and abdominal wall.1,2 65 the clinical presentation of xgc is variable and non-specific.1 majority of the patients present 66 with right upper quadrant pain and features of chronic cholecystitis. on examination, right upper 67 quadrant tenderness and palpable mass can be seen. no specific laboratory test is available for 68 xgc.2 elevated leukocytes level is usually present. some xgc cases may show elevated tumor 69 marker levels like ca 19-9 and cea.2,4 70 71 radiological images play a key role in the diagnosis of xgc, although sometimes the 72 radiological diagnosis of xgc can be difficult due to overlapping features with other 73 conditions.2,4 ultrasound (us) examination may show significant focal or diffuse gallbladder 74 wall thickening with associated calculi or sludge.1,3 presence of hypoechoic nodules within 75 thickened wall is a typical finding which favors the diagnosis of xgc.1 rana et al studied 76 features of gb wall thickening in us which help to differentiate between xgc and gall bladder 77 carcinoma. presence of focal wall thickening, wall disruption and indistinct liver margin favors 78 underlying neoplastic process compared to diffuse wall thickening or intramural features 79 including echogenic foci and hypoechoic nodules which favors benign process like xgc.8 the 80 most common ct finding of xgc is diffuse gallbladder wall thickening with presence of 81 intramural hypodense nodules or bands and luminal surface enhancement with continuous 82 mucosal line.3,4,5 goshima et al found that five ct findings improve the sensitivity and 83 diagnostic accuracy for xgc which help to differentiate it from gallbladder carcinoma.5 those 84 include the above-mentioned ct findings in addition to absence of intrahepatic bile duct 85 dilatation and hepatic invasion.1,5 kobayashi et al developed a scoring system of five ct 86 components to improve the diagnostic sensitivity and specificity of xgc. it includes diffuse wall 87 thickening of gallbladder, presence of intramural nodules or bands, absence of polypoid lesions, 88 pericholecystic infiltration and pericholecystic abscess. they concluded that presence of three or 89 more findings have high specificity of 94% and sensitivity of 77% for the diagnosis of xgc.4 90 ct may also show associated findings like cholelithiasis and choledocholithiasis along witwall h 91 possible associated previously mentioned complications.3,4,6 ct findings of the current patient ( 92 figure 1) show comparable findings including irregular diffuse gallbladder mural thickening 93 along with few hypoattenuating mural nodules, multiple hyperdense calculi, pericholecystic fluid 94 collection and choledocholithiasis. poor fat planes to the adjacent liver parenchyma is also noted. 95 96 mri usually demonstrates findings similar to the ct scan.1 signal drop-out in in-phase and 97 opposed-phase chemical shift imaging denoting the presence of microscopic fat within the 98 thickened gallbladder wall is considered a characteristic finding of xgc.3 diffusion weighted 99 imaging has an additive value which helps to further discriminate between xgc and gallbladder 100 carcinoma. majority of gallbladder carcinomas show diffusion restriction compared to only 7% 101 of xgc cases.3,5,7 mri of the current patient ( figure 2) shows a diffusely thickened gallbladder 102 wall along with few mural nodules within the thickened wall some of which demonstrate signal 103 drop-out in opposed-phase images (op) denoting microscopic fat depositions of 104 xanthogranuloma. in postcontrast images, smooth luminal surface enhancement and focal area of 105 early enhancement of adjacent liver parenchyma is noted. no evidence of diffusion restriction 106 was seen. 107 108 carcinoma of the gallbladder and gallbladder actinomycosis are the most challenging differential 109 diagnosis for xgc and the radiological diagnosis can be difficult due to overlapping features.1,2 110 fine needle aspiration cytology (fnac) or biopsy can be helpful preoperatively for further 111 differentiation.2 the systemic review shows that fnac was an efficient and safe method for 112 diagnosis of gallbladder carcinoma with high sensitivity, specifity and low complication rate. 113 percutaneous biopsy is un common minimally invasive procedure which can be helpful to 114 diagnose the unresectable cases, however it can be rarely associated with such complications like 115 hemorrhage, bacteremia, bile leakage and peritonitis and tumor seeding. false negative results 116 can occurred especially in small sized lesion.1,2 adenomyomatosis is another differential 117 diagnosis which is characterized by intramural foci of cholesterol crystals with characteristic 118 reverberation comet tail artefacts on us and “pearl necklace sign” on t2-weighted images.1,3 119 120 cholecystectomy is the treatment of choice for xgc.2 however, complete removal can be 121 challenging due to extensive adhesions and local inflammatory infiltration.1 a recently published 122 systemic review showed that half of xgc cases required open cholecystectomy and conversion 123 rate was reaching 35%. although majority of these surgeries were complex, the mortality and 124 complication rates were low and found to be 0.3% and 2-6% respectively.9 125 126 xgc is a rare variant of chronic cholecystitis and the diagnosis can be suspected on pre-127 operative imaging in the presence of typical characteristic imaging findings. however, some 128 cases can be misleading due to overlapping features with other conditions. sometimes, fnac is 129 helpful in pre-operative diagnosis. 130 131 authors’ contribution 132 ah collected the clinical and radiological data, reviewed literature and drafted the manuscript. is 133 supervised the work, selected the representative images and reviewed the manuscript. ak 134 created the idea and reviewed the manuscript. all authors approved the final version of the 135 manuscript. 136 137 references 138 1. singh vp, rajesh s, bihari c, desai sn, pargewar ss, arora a. xanthogranulomatous 139 cholecystitis: what every radiologist should know. world j radiol. 2016;8(2):183-191. 140 doi:10.4329/wjr.v8.i2.183 141 2. rammohan a, cherukuri sd, sathyanesan j, palaniappan r, govindan m. 142 xanthogranulomatous cholecystitis masquerading as gallbladder cancer: can it be 143 diagnosed preoperatively?. gastroenterol res pract. 2014;2014:253645. 144 doi:10.1155/2014/253645 145 3. zhao f, lu px, yan sx, wang gf, yuan j, zhang sz, wang yx. ct and mr features 146 of xanthogranulomatous cholecystitis: an analysis of consecutive 49 cases. eur j radiol. 147 2013;82(9):1391-1397. doi:10.1016/j.ejrad.2013.04.026 148 4. r, kobayashi t, ogasawara g, kono y, mori k, kawasaki s. a scoring system based on 149 computed tomography for the correct diagnosis of xanthogranulomatous cholecystitis. 150 (2020) acta radiologica open. 9 151 (4):2058460120918237. doi:10.1177/2058460120918237 152 https://doi.org/10.1177/2058460120918237 5. goshima s, chang s, wang jh, kanematsu m, bae kt, federle mp. 153 xanthogranulomatous cholecystitis: diagnostic performance of ct to differentiate from 154 gallbladder cancer. eur j radiol. 2010;74(3):e79-e83. doi:10.1016/j.ejrad.2009.04.017 155 6. bo x, chen e, wang j, et al. diagnostic accuracy of imaging modalities in differentiating 156 xanthogranulomatous cholecystitis from gallbladder cancer. ann transl med. 157 2019;7(22):627. doi:10.21037/atm.2019.11.35 158 7. feng l, you z, gou j, liao e, chen l. xanthogranulomatous cholecystitis: experience in 159 100 cases. ann transl med. 2020;8(17):1089. doi:10.21037/atm-20-5836 160 8. rana p, gupta p, kalage d, soundararajan r, kumar-m p, dutta u. grayscale 161 ultrasonography findings for characterization of gallbladder wall thickening in non-acute 162 setting: a systematic review and meta-analysis. expert rev gastroenterol hepatol. 163 2022;16(1):59-71. doi:10.1080/17474124.2021.2011210 164 9. frountzas m, schizas d, liatsou e, et al. presentation and surgical management of 165 xanthogranulomatous cholecystitis. hepatobiliary pancreat dis int. 2021;20(2):117-127. 166 doi:10.1016/j.hbpd.2021.01.002 167 168 169 170 figure 1: contrast enhanced computed tomography (ct) scans of the abdomen in axial and 171 coronal views from (a–c) demonstrate irregular diffuse gallbladder mural thickening (red arrows) 172 along with few hypoattenuating mural nodules (white head arrows). multiple hyperdense calculi 173 (white arrows) and pericholecystic fluid collection (yellow arrows) are seen. poor fat planes to the 174 adjacent liver parenchyma is noted (blue arrows). 175 176 a c 177 178 figure 2: magnetic resonance imaging (mri) of the abdomen from (a–d) including t2w image 179 (a), in-phase (ip) (b), opposed-phase (op) chemical shift imaging (c), t1wi post contrast 180 images in axial (d) show a diffusely thickened gallbladder wall along with few non enhancing 181 mural nodules within the thickened wall which showed isoto slightly hypointense signal on both 182 t1 and t2-wieghted images and (white head arrows) some of which demonstrate reduced signal 183 in opposed images (op) denoting microscopic fat depositions of xanthogranuloma (red arrows). 184 minimal pericholecystic fluid. smooth luminal surface enhancement is noted in post contrast 185 images (blue arrows). focal area of early enhancement of adjacent liver parenchyma is seen (green 186 arrows). 187 b d submitted 20 sept 22 1 revision req. 31 oct 22; revision recd. 24 nov 22 2 accepted 29 dec 22 3 online-first: january 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.004 5 6 knowledge, attitude, and practice among palestinian healthcare workers in 7 the gaza strip towards hepatitis b 8 a cross-sectional survey 9 abd al-karim sammour, younis elijla, muath alsarafandi, *belal 10 aldabbour, loay kanou, fahmy almaidana, moataz el egla, samah harara, 11 seham oda, nour albardaweel, adnan skaik 12 13 faculty of medicine, islamic university of gaza, gaza, state of palestine. 14 *corresponding author’s e-mail: belal90md@gmail.com 15 16 abstract 17 objectives: healthcare workers are at a high potential risk of hepatitis b virus infection (hbv). 18 this survey aims to identify gaps and strengths in the knowledge, cultural perceptions, and 19 practices of healthcare workers towards hbv in order to drive appropriate health interventions. 20 methods: this cross-sectional study was conducted between march and april 2022. we 21 surveyed a convenience sample of three at-risk healthcare providers from the major health 22 facilities in gaza. a 40-item, self-administered questionnaire was used. statistical data analysis 23 was conducted using spss version 25 to obtain descriptive and inferential statistics via various 24 nonparametric, correlation, and regression tests (with p<0.05). results: 447 healthcare workers 25 participated in the study. overall, 105 (23.5%) demonstrated poor knowledge (under 14\20 26 points), 284 (63.5%) had moderate knowledge (14-17 points), and 58 (13%) showed good 27 knowledge about hbv. the majority (367, 82.1%) expressed an excellent attitude. finally, 287 28 (64.2%) demonstrated a good level of practice toward hbv infection. a history of needle stick 29 injury was reported by 233 (52.1%) participants, of whom 170 (73.3%) reported taking 30 appropriate preventive actions after exposure. conclusion: the majority of participants 31 demonstrated overall good knowledge regarding hbv infection. nonetheless, significant gaps 32 remain in the different aspects of the kap construct, which require appropriate awareness 33 campaigns to further limit the spread of this preventable viral infection. 34 keywords: health knowledge, attitudes, practice; attitude of health personnel; hepatitis b; 35 epidemiology; prevention and control; health personnel; cross-sectional studies. 36 37 advances in knowledge: 38  the overall knowledge about hbv infection among hcws in gaza strip is good. 39  there were significant gaps in knowledge, such as modes of transmission and hbv 40 therapy. 41 application to patient care: 42  assessing the knowledge, attitude, and practice among hcws will help pinpoint gaps in 43 the hbv prevention protocols and practices, ultimately helping health policy-makers 44 protect both at-risk hcws and their patients. 45 46 introduction 47 hepatitis b virus (hbv) is a vaccine-preventable viral infection of the liver with serious potential 48 complications such as liver cirrhosis and hepatocellular carcinoma. it is bloodborne and may be 49 transmitted through blood transfusion, sexual activity, or perinatally from the infected mother.1 50 the global burden of hbv was estimated at 316 million cases in 2019 (all-age prevalence of 51 4.1%), with more than half a million hbv-related deaths globally during the same year.2 52 53 the middle east is an area of low-intermediate hbv endemicity (2% 4.9%).3 palestine is 54 considered a moderately endemic area for hbv infection.4 the hbv incidence and carrier rates 55 in the country were 0.37 and 7.9/100,000 population, respectively, in 2020. in the gaza strip, the 56 rates were 0.15 and 5.6/100,000 populations, respectively, during the same year.5 this represented 57 a significant decline from an incidence rate of 11-15/100,000 between 1990–1994 in palestine, 58 which has been attributed to adapting the hbv vaccine into the national vaccination schedule since 59 1992.6 the hbv vaccine is a reliable and cost-effective preventive tool with over 90% 60 effectiveness against chronic hbv infection and nearly 70% protection against hbv-related 61 hepatocellular carcinoma (hcc).7,8 62 63 risk factors for hbv transmission in palestine include undergoing blood transfusion or dental 64 procedures, sharing contaminated sharp objects such as shaving blades and hejamat tools, and 65 intravenous drug use.4 hemodialysis patients and patients who receive treatment in neighboring 66 countries also are at increased risk.9 hcws are at a several-fold higher risk of contracting hbv 67 infection compared to the general population,10-12 and the hazard is higher for professions that 68 include performing invasive procedures or handling human blood and specimens (e.g., surgeons, 69 nurses, dentists).13,14 therefore, besides hbv vaccination, additional preventive measures are 70 necessary to protect hcws against hbv infection, including the use of personal protective 71 equipment (ppe), proper sterilization of medical equipment, disinfection of health facilities, and 72 post-exposure prophylaxis after accidental exposure to contaminated blood or body fluids.15 73 74 needle stick injuries (nsis) represent a particularly preventable hazard that can be avoided with 75 appropriate staff training and safety protocols.16 a study in 2004 found a 2.8% prevalence of 76 hepatitis b surface antigen (hbsag) among 399 tested healthcare workers, and needle stick 77 injuries demonstrated a highly significant association as the leading risk factor for infection. also, 78 unvaccinated healthcare workers showed higher rates of infection with approximately twice the 79 rate among vaccinated participants (4.1% vs. 2.0%).17 another study in 2021 demonstrated that 80 289 of 538 healthcare workers in gaza (54%) had had at least one nsi, with nurses and cleaners 81 at the highest risk.18 82 83 implementing effective preventive plans for hbv infection necessitates that hcws demonstrate 84 an adequate understanding of the disease, reflected in their knowledge, attitude, and practice 85 (kap). kap studies have been used widely in measuring public health levels, assessing the 86 fundamental understanding, perspectives, and activities commonly shared by a certain population 87 on a particular topic. this is the first study to examine the kap of hcws in the gaza strip towards 88 hbv infection. 89 methods 90 study design, settings, and population 91 this descriptive, institution-based, cross-sectional study was conducted at seven governmental 92 hospitals (al-shifa medical complex, nasser medical complex, european gaza hospital, 93 indonesian hospital, rantissi pediatric complex, al durra pediatric hospital, palestinian-turkish 94 friendship hospital), one major governmental primary health center (sabha al harazin primary 95 healthcare center), and two private hospitals (al-quds specialized hospital and al-sahaba 96 medical complex). these institutions represented the major hospitals and health centers providing 97 healthcare services across the gaza strip from north to south. the study was conducted between 98 march and april 2022. the convenience sampling method was used to survey 447 medical doctors, 99 nurses, and laboratory technicians who worked in the above-mentioned facilities, as those 100 professions were considered to be at the highest risk for exposure to patients and their blood 101 products. the study included hcws from the three professions who worked in these hospitals 102 during the study period and consented to fill out the questionnaire. we excluded hcws from other 103 disciplines, those who were absent during the data collection period, and those who refused to 104 participate. 105 106 data collection 107 the study team constructed a questionnaire based on a literature review of previous similar 108 studies.19-23 the final version of the questionnaire included 40 items divided into four sections; the 109 first section included the sociodemographic data of participants, the second section (20 questions) 110 assessed participants’ knowledge, the third section (9 questions) assessed participants’ attitudes, 111 and the fourth section (11 questions) assessed participants’ practice towards hbv. the validity 112 and reliability of the referenced questionnaires were established by the referenced studies. experts 113 from the public health department at the islamic university of gaza evaluated our questionnaire's 114 face, substance, and convergent validity and ensured that the questionnaire appropriately covered 115 the relevant questions pertaining to the study within the local context. the questionnaire was then 116 piloted for acceptability and consistency with 20 respondents who shared similar demographic 117 characteristics with the actual study population. only a few linguistic modifications were required 118 after the pilot testing, and data from the pilot study were not included in the final analysis. 119 scoring system 120 hcws who scored 18 or more correct answers out of 20 questions in the second section were 121 considered to have high knowledge about hbv; scores between 14 and 17 were regarded as 122 moderate knowledge, while scores below 14 were regarded as having insufficient knowledge. in 123 terms of attitude, scores of six and above reflected a good attitude. meanwhile, scoring six or seven 124 out of seven items reflected a good level of practice. these measurements resulted from the 125 normality characteristics of data distribution, either 25-75 quartiles or the median. 126 127 data analysis 128 data were analyzed using the statistical package for social sciences (spss) version 25 (spss inc., 129 chicago, il, usa). data analysis provided frequency tables for variables. the kolmogorov-130 smirnov test was used to assess the sample distribution's normality. kruskal-wallis and mann-131 whitney tests were used to determine the relationship between the dependent variables 132 (knowledge, attitude, and practice) and the independent categorical variables of the 133 sociodemographic data. the multinomial logistic regression was used to predict the relationship 134 between the cohort characteristics and kap domains. statistical significance was set at p-values 135 of less than 0.05. 136 137 ethical consideration 138 before conducting the study, written ethical approval was obtained from the human resource at 139 the ministry of health, and administrative approvals were obtained from the directorate of each 140 facility. verbal consent was obtained from participants upon answering the questionnaire. each 141 questionnaire was deidentified and assigned a code number throughout data entry and data analysis 142 in order to maintain anonymity and confidentiality for all participants. 143 144 results 145 sociodemographic characteristics of the cohort 146 a total of 447 hcws working in ten governmental and private health centers participated in our 147 study (table 1). the response rate was 100%. most participants were recruited from governmental 148 hospitals (95.3%). the largest age group was 24-30 years (41.4%), and the majority had more than 149 two years of work experience (table 1). 150 knowledge about hbv and its associated factors 151 the majority of participants in our study demonstrated a moderate level of knowledge about hbv 152 infection (284 hcws; 63.5%). on the other hand, ten participants (2.2%) denied that hbv 153 infection is caused by a virus, and 125 (28%) failed to acknowledge sexual transmission as a 154 common hbv transmission mode. also, 179 (40%) participants believed that sharing dishes with 155 hbv-positive patients can transmit the disease, while 110 (24.6%) participants did not recognize 156 the association between hbv infection and liver cancer. meanwhile, 278 (56.2%) of participants 157 believed that the human body could not spontaneously cure an hbv infection, while 32 (7.2%) 158 were oblivious to the presence of a vaccine against hbv (table 2). the kruskal-wallis test 159 demonstrated a significant difference in knowledge levels among the different professions (p < 160 .001). still, no significant associations were found between knowledge levels and age, affiliation, 161 or experience years (table 5). 162 163 attitude about hbv and its relations 164 most participants demonstrated a good attitude (367 participants, 82.1%) (table 3). fear and 165 sadness were the most common expected reactions to receiving a diagnosis of hbv infection, 166 reported by 202 (45.2%) and 150 (33.6%) participants, respectively. the majority (344, 77%) said 167 they would first inform the physician about their illness, while friends came last. most participants 168 (365, 81.7%) would visit a health facility if they had symptoms of hbv infection as soon as they 169 realized them, while 35 (7.8%) said they would seek traditional healers. the majority believed that 170 instrument sterilization, wearing gloves, and vaccination could prevent transmission, but 86 171 (19.2%) did not recommend post-exposure prophylaxis for those exposed to hbv. there was a 172 statistically significant difference in attitude depending on affiliation (p < 0.001), specialty (p < 173 0.001), and experience years (p = 0.02) but not age (table 5). 174 175 practical measures for hbv and needle stick injuries 176 of 447 participants, 296 (66.2%) have been screened previously for hbv infection. there was a 177 statistically significant difference in screening for hbv among health specialties, with the highest 178 screening rate among medical laboratory technicians (p = 0.005). of the sample, 45 (11.1%) said 179 they would not ask for blood screening for hbv before receiving a potential blood transfusion. 180 most, however, ask for a new syringe before use (405, 90.6%) and apply safety equipment for ear 181 or nose piercing (376, 84.1%) (table 4). nearly half (233, 52.1%) the participants reported having 182 needle stick injuries before. of those, most followed preventive and health guidelines to prevent 183 infection with hbv (table 4). practical measures were statistically different according to age 184 groups (p < 0.001), affiliation (p = 0.006), and years of experience (p < 0.001), but not specialty 185 (table 5). 186 187 predictors of kap performance among participants 188 the multinomial logistic regression revealed that nurses were more susceptible to having lower 189 knowledge levels with an odds ratio of 0.161 (p= 0.000) (table 6). also, being a governmental 190 employee or a medical doctor was associated with having higher levels of good attitude, with an 191 odds ratio of 8.505 and 8.599 (p= 0.000) (table 6). additionally, having less than two years of 192 work experience was associated with low levels of both attitude and practice, with an odds ratio 193 of 0.292 and 0.485, respectively (p= 0.001 and 0.011) (tables 6). finally, the three domains 194 (knowledge, attitude, and practice) demonstrated a positive correlation with each other, with the 195 knowledge-attitude correlation coefficient (.275), knowledge-practice correlation coefficient 196 (.202), attitude-practice correlation coefficient (.295), (p<0.01). 197 198 discussion 199 this study evaluated the kap of palestinian hcws in the gaza strip towards hbv. there is a 200 dearth of literature on this topic in palestine. our literature review did not identify previous similar 201 local studies. the ministry of health (moh) is the major provider of primary and secondary 202 healthcare services in palestine.24 also, due to poor economic conditions in gaza, many private-203 sector hcws are also government employees working two jobs. therefore, government-employed 204 hcws represented the majority of our cohort. 205 206 we found that 76.5% of participants demonstrated moderate or excellent knowledge regarding 207 hbv. this result falls within the range revealed by other recent studies done between 2013-2019 208 from ethiopia, afghanistan, and nigeria, where 73% to 86% of surveyed hcws demonstrated 209 good knowledge about hbv. it is also higher than other studies from cameroon and sudan, where 210 only 47% and 58% of participants, respectively, had an adequate knowledge.20,21,25-27 the different 211 results reflect variations in knowledge among the hcws in these countries, but they may also be 212 partly attributed to variations in the professions representing each study’s population. knowledge 213 levels among nurses were lower than doctors and laboratory technicians in our study, and similar 214 observations were made in the studies from afghanistan and ethiopia.20,26 overall, hcws 215 surveyed in our study fall closer to the better-educated end of the knowledge spectrum revealed in 216 those studies and other studies in the literature. 217 218 also, in terms of knowledge, 94%, 96.6%, and 82.8% of participants answered correctly that hbv 219 could be transmitted via contaminated sharps, blood transfusion, and from mother to fetus (i.e., 220 vertical transmission), which approximately correlates with the results of the afghanistan study.20 221 however, the results diverge where it concerns the transmission of hbv through unprotected sex 222 (72.0% vs. 89.64) and whether hbv has a definitive cure (43.8% vs. 82.86%). additionally, the 223 fact that nearly one-third of participants in our study wrongfully answered other questions related 224 to hbv modes of transmission (questions 3, 4, 8, and 10) reveals a significant gap in knowledge 225 and cultural beliefs about hbv and indicates the need for more awareness campaigns regarding 226 primary prevention of hbv in the gaza strip. 227 228 about 82.1% of the participants showed an overall favorable attitude toward hbv, which is 229 similar to the sudanese study in which 86.4% of participants had a favorable attitude, and higher 230 than the afghan and cameroonian studies (44% and 46%, respectively).20,21,25 the authors of the 231 latter study attributed the inadequate attitude to the insufficient knowledge of the participants, 232 which further stresses the importance of disease awareness among hcws. meanwhile, medical 233 doctors in the afghan study had more unfavorable attitudes toward hbv compared to the other 234 professions. in contrast, doctors in our cohort performed much better in terms of healthy attitudes 235 (or 8.599) compared to the remaining participants. doctors receive longer and more extensive 236 education compared to the other health professions, which could explain this observation, 237 especially in the context of the correlation between knowledge and attitude that was demonstrated 238 in our analysis (table 7). 239 240 the finding that 77% of participants chose the physician as the first go-to person to inform about 241 their illness and 88.6% would visit a health facility if they had symptoms of hbv infection reflects 242 a positive cultural behavior shared among the different hcws in our study. we also found that 243 93.3%, 97.8%, and 80.8% of participants acknowledge the importance of wearing gloves, 244 instrument sterilization, and post-exposure prophylaxis. these results are better than those in 245 the sudanese study (72.7%, 64.5%, and 52.7%, respectively). again, this difference may be partly 246 related to the different representations of healthcare professions among the cohorts. it may also be 247 explained by the better knowledge scores of our study. 248 249 the prevalence of nsis among hcws was 52.1%, which replicates the findings of another recent 250 local study where the prevalence was 54%.18 the numbers are also similar to those reported in the 251 sudanese study (51.8%) (21). these alarming results warrant advocating for the widespread 252 application of well-established safety and needlestick prevention guidelines.28 of the hcws who 253 suffered nsis, 91.0%, 88,8%, and 82.4% showed appropriate practice responses after the injury, 254 such as washing hands with water and soap, sterilizing the wound site, and checking if the patient 255 has a blood-borne disease. 256 257 overall, 85.2% of participants in our cohort reported being vaccinated against hbv. in a recent 258 study from the west bank, the prevalence of hbv vaccination among 265 dentists was 74.5%.29 259 in contrast, the prevalence of hbv vaccination was 56.37% in the afghan study, under 50% in 260 the sudanese study, and even lower in the cameroon (19%).20,21,25 it is estimated that hbv 261 vaccines saved an estimated $130 billion in direct and indirect costs between 2001 and 2020 in 73 262 lowand-middle income countries.30 adopting the hbv vaccine in the palestinian national 263 vaccination schedule is also credited for the declining incidence of hbv in the country.6 hbv 264 vaccine is available to the population free of charge. also, hbv screening is a mandatory part of 265 the pre-employment health examination, which may play a role in enhancing the percentage of 266 vaccinated people in palestine. 267 268 in our study, we demonstrated a positive correlation between the different study domains 269 (knowledge, attitude, and practice), which has also been reported in studies from ghana and 270 pakistan.31,23 this finding emphasizes that having good knowledge is essential in order to modify 271 false beliefs and preconceptions and help hcws develop healthy attitudes and practices. 272 stigmatization of hbv is an important barrier to appropriate practices and it has been shown to 273 exert substantial influence on the health behavior of individuals with or at risk for hbv.33 future 274 research is invited to assess public perceptions and prejudices toward people living with hbv 275 infection. this study has several limitations, including the use of the convenience sampling method 276 and the relative underrepresentation of private-sector employees. the study was also limited to 277 hcws in the gaza strip due to the political and geographical separation from the west bank. 278 these limitations might limit the generalization of the results, so further studies are still needed. 279 finally, kap surveys are inherently reliant on self-reported responses, therefore the results might 280 partly reflect participant assumptions rather than reality. 281 282 conclusion 283 the overall knowledge about hbv infection among hcws in gaza strip is good. however, 284 significant gaps remain, such as regarding modes of transmission and hbv therapy, requiring the 285 attention of health prevention authorities. these gaps may be addressed through awareness lectures 286 and campaigns. most hcws' attitudes and practices are within a reasonable range, and knowledge, 287 attitude, and practice demonstrated a positive correlation. the study showed a high prevalence of 288 nsis among hcws in the gaza strip, which could be minimized by providing targeted 289 interventions and training to improve risk awareness. fortunately, though, the vaccination 290 coverage among hcws is high, which should help averse against some of the risks and maintain 291 the trend of the declining incidence of hbv in palestine. 292 293 authors’ contribution 294 aks, ye, ma and ba contributed to the literature review, study design, data analysis and drafting 295 of the manuscript. all authors contributed to data collection, data entry and data curation. all 296 authors revised and approved the final version of the manuscript. 297 298 conflict of interest 299 the authors declare no conflicts of interest. 300 301 funding 302 no funding was received for this study. 303 304 references 305 1. kwon sy, lee ch. epidemiology and prevention of hepatitis b virus infection. korean j 306 hepatol. 2011;17(2):87-95. https://doi.org/10.3350/kjhep.2011.17.2.87 307 2. sharma r, abbasi-kangevari m, abd-rabu r, abidi h, abu-gharbieh e, manuel acuna 308 j, et al. global, regional, and national burden of colorectal cancer and its risk factors, 309 1990-2019: a systematic analysis for the global burden of disease study 2019. lancet 310 gastroenterol hepatol. 2022;7(7):627-47. https://doi.org/10.1016/s2468-1253(22)00044-311 9 312 3. akyildiz m, ahiskali e, zeybel m, yurdaydin c. regional epidemiology, burden, and 313 management of hepatitis b virus in the middle east. clin liver dis (hoboken). 314 2019;14(6):212-4. https://doi.org/10.1002/cld.887 315 4. nazzal z, sobuh i. risk factors of hepatitis b transmission in northern palestine: a case 316 control study. bmc res notes. 2014;7:190. https://doi.org/10.1186/1756-0500-7-190 317 5. palestinian ministry of health. health annual report 2020, from: 318 www.site.moh.ps/content/books/mv2fio4xvf1tberz9cwytakowkasrfsllobnuomj319 7opsajow2fvoci_dqyaixdf2i8gcmphbcsav29dihqw26gzu9qjdiw2qsifzt6frds320 4h2.pdf , accessed: august 23rd 2022. 321 6. al-amleh s. prevalence of hepatitis b virus among children of hbsag-positive mothers 322 in hebron district, palestine. transl gastroenterol hepatol. 2020;5:34. 323 https://doi.org/10.21037/tgh.2019.11.06 324 7. chang mh, chen ds. prevention of hepatitis b. cold spring harb perspect med. 325 2015;5(3):a021493. https://doi.org/10.1101/cshperspect.a021493 326 8. flores je, thompson aj, ryan m, howell j. the global impact of hepatitis b vaccination 327 on hepatocellular carcinoma. vaccines (basel). 2022;10(5). 328 https://doi.org/10.3390/vaccines10050793 329 9. el-kader ye-oa, elmanama aa, ayesh bm. prevalence and risk factors of hepatitis b 330 and c viruses among haemodialysis patients in gaza strip, palestine. virol j. 2010;7:210. 331 https://doi.org/10.1186/1743-422x-7-210 332 10. dannetun e, tegnell a, torner a, giesecke j. coverage of hepatitis b vaccination in 333 swedish healthcare workers. j hosp infect. 2006;63(2):201-4. 334 https://doi.org/10.1016/j.jhin.2006.01.014 335 https://doi.org/10.3350/kjhep.2011.17.2.87 https://doi.org/10.1016/s2468-1253(22)00044-9 https://doi.org/10.1016/s2468-1253(22)00044-9 https://doi.org/10.1002/cld.887 https://doi.org/10.1186/1756-0500-7-190 https://doi.org/10.21037/tgh.2019.11.06 https://doi.org/10.1101/cshperspect.a021493 https://doi.org/10.3390/vaccines10050793 https://doi.org/10.1186/1743-422x-7-210 https://doi.org/10.1016/j.jhin.2006.01.014 11. carvalho p, schinoni mi, andrade j, vasconcelos rego ma, marques p, meyer r, et al. 336 hepatitis b virus prevalence and vaccination response in health care workers and students 337 at the federal university of bahia, brazil. ann hepatol. 2012;11(3):330-7. 338 https://doi.org/10.1016/s1665-2681(19)30928-7 339 12. ziglam h, el-hattab m, shingheer n, zorgani a, elahmer o. hepatitis b vaccination 340 status among healthcare workers in a tertiary care hospital in tripoli, libya. j infect public 341 health. 2013;6(4):246-51. https://doi.org/10.1016/j.jiph.2013.02.001 342 13. bhat m, ghali p, deschenes m, wong p. hepatitis b and the infected health care worker: 343 public safety at what cost? can j gastroenterol. 2012;26(5):257-60. 344 https://doi.org/10.1155/2012/348240 345 14. ziraba ak, bwogi j, namale a, wainaina cw, mayanja-kizza h. sero-prevalence and 346 risk factors for hepatitis b virus infection among health care workers in a tertiary hospital 347 in uganda. bmc infect dis. 2010;10:191. https://doi.org/10.1186/1471-2334-10-191 348 15. askarian m, yadollahi m, kuochak f, danaei m, vakili v, momeni m. precautions for 349 health care workers to avoid hepatitis b and c virus infection. int j occup environ med. 350 2011;2(4):191-8. 351 16. adefolalu a. needle stick injuries and health workers: a preventable menace. ann med 352 health sci res. 2014;4(suppl 2):s159-60. https://doi.org/10.4103/2141-9248.138046 353 17. el-astal z. hepatitis b and c among governmental health providers in southern gaza 354 strip, palestine. sahel medical journal. 2004;6. 355 18. alwali a, shaheen a, ahmed m, mansour z, kanou l, alqanoa b, et al. awareness and 356 prevalence of needle stick injuries among cleaners and health-care providers in gaza strip 357 hospitals: a cross-sectional study. lancet. 2021;398 suppl 1:s12. 358 https://doi.org/10.1016/s0140-6736(21)01498-7 359 19. althobaiti s, alhumaidi g, alwagdani w, almaroani k, altowairqi b, alhaddad m, et al. 360 assessment of knowledge, attitude, and practice among saudi residents regarding 361 hepatitis e virus. am j trop med hyg. 2021;106. https://doi.org/10.4269/ajtmh.21-0841 362 20. roien r, mousavi sh, ozaki a, baqeri sa, hosseini smr, ahmad s, et al. assessment 363 of knowledge, attitude, and practice of health-care workers towards hepatitis b virus 364 prevention in kabul, afghanistan. j multidiscip healthc. 2021;14:3177-86. 365 https://doi.org/10.2147/jmdh.s334438 366 https://doi.org/10.1016/s1665-2681(19)30928-7 https://doi.org/10.1016/j.jiph.2013.02.001 https://doi.org/10.1155/2012/348240 https://doi.org/10.1186/1471-2334-10-191 https://doi.org/10.4103/2141-9248.138046 https://doi.org/10.1016/s0140-6736(21)01498-7 https://doi.org/10.4269/ajtmh.21-0841 https://doi.org/10.2147/jmdh.s334438 21. mohammed-elbager s, mohamed s. knowledge, attitude, and practice towards hepatitis 367 b infection among nurses and midwives in two maternity hospitals in khartoum, sudan. 368 bmc public health. 2019;19. https://doi.org/10.1186/s12889-019-7982-8 369 22. abdela a, woldu b, haile k, tebeje b, deressa t. assessment of knowledge, attitudes 370 and practices toward prevention of hepatitis b virus infection among students of medicine 371 and health sciences in northwest ethiopia. bmc res notes. 2016;9. 372 https://doi.org/10.1186/s13104-016-2216-y 373 23. haq n, hassali m, shafie a, saleem f, farooqui m, haseeb a, et al. a cross-sectional 374 assessment of knowledge, attitude and practice among hepatitis-b patients in quetta, 375 pakistan. bmc public health. 2013;13:448. https://doi.org/10.1186/1471-2458-13-448 376 24. jebril m, deakin s. the political economy of health in the gaza strip: reversing de-377 development. j glob health. 2022;12:03014. https://doi.org/10.7189/jogh.12.03014 378 25. tatsilong ho, noubiap jj, nansseu jr, aminde ln, bigna jj, ndze vn, et al. hepatitis 379 b infection awareness, vaccine perceptions and uptake, and serological profile of a group 380 of health care workers in yaounde, cameroon. bmc public health. 2016;15:706. 381 https://doi.org/10.1186/s12889-016-3388-z 382 26. ayalew mb, horssa ba, getachew n, amare s, getnet a. knowledge and attitude of 383 health care professionals regarding hepatitis b virus infection and its vaccination, 384 university of gondar hospital, ethiopia. hepat med. 2016;8:135-42. 385 https://doi.org/10.2147/hmer.s120477 386 27. hassan m, awosan k, nasir s, tunau k, burodo a, yakubu a, et al. knowledge, risk 387 perception and hepatitis b vaccination status of healthcare workers in usmanu danfodiyo 388 university teaching hospital, sokoto, nigeria. j public health epidemiol. 2016;8:53-9. 389 https://doi.org/10.5897/jphe2015.0795 390 28. king kc, strony r. needlestick. statpearls. treasure island (fl)2022. 391 29. menawi w, sabbah a, kharraz l. cross-infection and infection control in dental clinics in 392 nablus and tulkarm districts. bmc microbiol. 2021;21(1):352. 393 https://doi.org/10.1186/s12866-021-02382-0 394 30. ozawa s, clark s, portnoy a, grewal s, stack ml, sinha a, et al. estimated economic 395 impact of vaccinations in 73 lowand middle-income countries, 2001-2020. bull world 396 health organ. 2017;95(9):629-38. https://doi.org/10.2471/blt.16.178475 397 https://doi.org/10.1186/s12889-019-7982-8 https://doi.org/10.1186/s13104-016-2216-y https://doi.org/10.1186/1471-2458-13-448 https://doi.org/10.7189/jogh.12.03014 https://doi.org/10.1186/s12889-016-3388-z https://doi.org/10.2147/hmer.s120477 https://doi.org/10.5897/jphe2015.0795 https://doi.org/10.1186/s12866-021-02382-0 https://doi.org/10.2471/blt.16.178475 31. afihene m, duduyemi b, a-tetteh h-l, khatib a. knowledge, attitude and practices 398 concerning hepatitis b infection, among healthcare workers in bantama, ghana: a cross 399 sectional study. int j community med public health. 2015:244-53. 400 https://dx.doi.org/10.18203/2394-6040.ijcmph20150477 401 32. ul haq n, hassali ma, shafie aa, saleem f, farooqui m, aljadhey h. a cross sectional 402 assessment of knowledge, attitude and practice towards hepatitis b among healthy 403 population of quetta, pakistan. bmc public health. 2012;12:692. 404 https://doi.org/10.1186/1471-2458-12-692 405 33. li d, tang t, patterson m, ho m, heathcote j, shah h. the impact of hepatitis b 406 knowledge and stigma on screening in canadian chinese persons. can j gastroenterol. 407 2012;26(9):597-602. https://doi.org/10.1155/2012/705094 408 409 table 1: demographic characteristics of the participants. 410 demographic characteristics n percent age 24-30 185 41.4% 31-40 142 31.8% 41-50 75 16.8% older than 50 45 10.0% experience years less than 2 years 111 24.8% more than 2 years 336 75.2% affiliation governmental hospitals medical doctor 143 32% nurse 195 43.6% laboratory technician 88 19.7%) private hospitals medical doctor 3 0.7% nurse 18 4% laboratory technician 0 0% total 447 100.0% 411 https://dx.doi.org/10.18203/2394-6040.ijcmph20150477 https://doi.org/10.1186/1471-2458-12-692 https://doi.org/10.1155/2012/705094 table 2: participant’s responses to knowledge on hbv infection. 412 hbv knowledge items ‡ total medical doctor† nurse† laboratory technician† p-value * hbv infection is caused by a virus organism 437 (97.8%) 143 (97.9%) 206 (96.7%) 88 (100.0%) .211 hbv infection can be transmitted from mother to fetus 370 (82.8%) 134 (91.8%) 159 (74.6%) 77 (87.5%) .000 hbv infection cannot be transmitted to the infants through breast milk 309 (69.1%) 97 (66.4%) 152 (71.4%) 60 (68.2%) .598 hbv infection cannot be spread through close contact (such as kissing) 281 (62.9%) 101 (69.2%) 126 (59.2%) 54 (61.4%) .147 sexual transmission is a common way through which hbv infection can be transmitted 322 (72.0%) 104 (71.2%) 156 (73.2%) 62 (70.5%) .857 hbv infection can spread through blood transfusion 432 (96.6%) 144 (98.6%) 201 (94.4%) 87 (98.9%) .038 hbv infection can spread through sharps such as needles, blades and operation tools 420 (94.0%) 142 (97.3%) 194 (91.1%) 84 (95.5%) .044 hbv infection can spread by using shared blades at the barber, or shared ear and nose piercing tools 291 (65.1%) 107 (73.3%) 131 (61.5%) 53 (60.2%) .040 undergoing medical and/or surgical procedures increases the chance of hbv infection 411 (91.9%) 134 (91.8%) 192 (90.1%) 85 (96.6%) .173 hbv infection cannot spread through sharing dishes with an hbv positive patient 268 (60.0%) 100 (68.5%) 101 (47.4%) 67 (76.1%) .000 symptoms of hbv infection do not appear immediately after the entrance of hvb into the body 368 (82.3%) 127 (87.0%) 161 (75.6%) 80 (90.9%) .001 hbv infection can lead to liver cirrhosis 380 (85.0%) 123 (84.2%) 182 (85.4%) 75 (85.2%) .950 hbv infection is associated with an increased risk of liver cancer 337 (75.4%) 117 (80.1%) 149 (70.0%) 71 (80.7%) .039 an infected individual can have hbv infection without symptoms 359 (80.3%) 126 (86.3%) 159 (74.6%) 74 (84.1%) .015 jaundice is one of the common symptoms of hbv infection 349 (78.1%) 105 (71.9%) 172 (80.8%) 72 (81.8%) .089 nausea, vomiting, and loss of appetite are common symptoms of hbv infection 338 (75.6%) 115 (78.8%) 169 (79.3%) 54 (61.4%) .002 413 414 hbv infection is not curable 241 (53.9%) 80 (54.8%) 129 (60.6%) 32 (36.4%) .001 hbv infection can be self-cured by the body 196 (43.8%) 64 (43.8%) 80 (37.6%) 52 (59.1%) .003 there is vaccine available for hbv infection 415 (92.8%) 137 (93.8%) 195 (91.5%) 83 (94.3%) .594 no specific diet is required during the treatment of hbv infection 215 (48.1%) 79 (54.1%) 79 (37.1%) 57 (64.8%) .000 * chi-square tests, † percentage from each specialty, ‡ correct answers table 3: participant’s responses on attitude towards hbv infection. 415 hbv attitude items total medical doctor† nurse† laboratory technician† p-value * what would be your reaction if you found out that you have hbv infection? ‡ fear 202 (45.2%) 75 (51.4%) 103 (48.4%) 24 (27.3%) .001 shame 40 (8.9%) 3 )2.1%) 30 )14.1%) 7 )8.0%) .000 surprise 70 (15.7%) 20 )13.7%) 36 )16.9%) 14 )15.9%) .713 sadness 150 (33.6%) 54 )37.0%) 50 )23.5%) 46 )52.3%) .000 whom would you inform about your illness? ‡ physician 344 (77.0%) 116 )79.5%) 158 )74.2%) 70 )79.5%) .412 spouse 54 (12.1%) 21 )14.4%) 24 )11.3%) 9 )10.2%) .564 children 26 (5.8%) 5 )3.4%) 14 )6.6%) 7 )8.0%) .289 other relatives 39 (8.7%) 9 )6.2%) 23 )10.8%) 7 )8.0%) .299 friends 29 (6.5%) 13 )8.9%) 15 )7.0%) 1 )1.1%) .059 when do you think you will visit health facility if you have symptoms of hbv infection? own treatment fails 45 (10.1% 8 )5.5%) 26 )12.2%) 11 )12.5%) .007 soon as i realized the symptoms§ 365 (81.7%) 133 )91.1%) 162 )76.1%) 70 )79.5%) .007 will not go to the health facility 37 (8.3%) 5 )3.4%) 25 )11.7%) 7 )8.0%) .007 what would worry you the most if you are diagnosed with hbv infection? ‡ fear of death 97 (21.7%) 37 )25.3%) 45 )21.1%) 15 )17.0%) .316 fear of disease spread to family 277 (62.0%) 95 )65.1%) 120 )56.3%) 62 )70.5%) .046 cost of treatment 36 (8.1%) 9 )6.2%) 17 )8.0%) 10 )11.4%) .367 416 417 isolation from community 60 (13.4%) 11 )7.5%) 39 )18.3%) 10 )11.4%) .011 what would you do if you think you have symptoms of hbv infection? go to pharmacy 16 (3.6%) 1 )0.7%) 13 )6.1%) 2 )2.3%) .000 go to traditional healers 35 (7.8%) 3 )2.1%) 25 )11.7%) 7 )8.0%) .000 go to health facility§ 396(88.6%) 142 )97.3%) 175 )82.2%) 79 )89.8%) .000 do you believe that instrument sterilization is important to prevent transmission? yes§ 437 (97.8%) 142 )97.3%) 210 )98.6%) 85 )96.6%) .499 no 10 (2.2%) 4 )2.7%) 3 )1.4%) 3 )3.4%) .499 do you believe that wearing gloves is important to prevent transmission? yes§ 417 (93.3%) 139 )95.2%) 201 )94.4%) 77 )87.5%) .051 no 30 (6.7%) 7 )4.8%) 12 )5.6%) 11 )12.5%) .051 do you believe that vaccination could prevent transmission? yes§ 404 (90.4%) 134 )91.8%) 192 )90.1%) 78 )88.6%) .722 no 43 (9.6%) 12 )8.2%) 21 )9.9%) 10 )11.4%) .722 do you recommend post exposure prophylaxis for those who had been exposed to hbv? yes§ 361 (80.8%) 132 )90.4%) 168 )78.9%) 61 )69.3%) .000 no 86 (19.2%) 14 )9.6%) 45 )21.1%) 27 )30.7%) .000 * chi-square tests, † percentage from each specialty, ‡can apply more than one, § favorable attitude table 4: participant’s responses on practice toward hbv infection. 418 419 hbv practice items total medical doctor† nurse† laboratory technician† p-value * have you been screened for hbv infection? 296 (66.2) 86 (58.9%) 140 (65.7%) 70 (79.5%) .005 have you got yourself vaccinated? 381 (85.2) 119 (81.5%) 183 (85.9%) 79 (89.8%) .209 do you ask for new syringe before use? 405 (90.6) 132 (90.4%) 191 (89.7%) 82 (93.2%) .634 do you ask your barber to change blade/or safe equipment for ear or nose piercing? 376 (84.1) 128 (87.7%) 181 (85.0%) 67 (76.1%) .058 do you ask for blood screening before transfusion? 402 (89.9) 118 (80.8%) 203 (95.3%) 81 (92.0%) .000 in case you are diagnosed with hbv infection, would you go for further investigation? 401 (89.7) 137 (93.8%) 188 (88.3%) 76 (86.4%) .120 do you avoid meeting a patient with hbv infection? 302 (67.6) 110 (75.3%) 129 (60.6%) 63 (71.6%) .009 have you had a needle stick injury before? 233 (52.1) 66 (45.2%) 124 (58.2%) 43 (48.9%) .042 washing hands with water and soap after a needle stick injury‡ 212 (91.0) 56 (84.8%) 117 (94.4%) 39 (90.7%) .093 clean the wound site after a needle stick injury‡ 207 (88.8) 57 (86.4%) 112 (90.3%) 38 (88.4%) .707 check if the patient has a blood-borne disease after a needle stick injury‡ 192 (82.4) 44 (66.7%) 110 (88.7%) 38 (88.4%) .000 * chi-square tests, † percentage from each specialty, ‡ from hcws who had a history of needle stick injury table 5: interaction between cohort characteristics and kap domains. 420 demographic characteristics n knowledge score mean (sd) p-value attitude score mean (sd) p-value practice score mean (sd) p-value age * 0.166 0.113 0.00 24-30 185 15.10 (2.041) 5.22 (.955) 5.42 (1.244) 31-40 142 14.86 (1.915) 5.33 (.928) 5.95 (1.163) 41-50 75 15.15 (2.276) 5.49 (.844) 6.12 (1.026) more than 50 45 15.56 (2.292) 5.44 (.785) 5.71 (1.160) affiliation ** 0.463 0.00 0.006 governmental 426 15.09 (2.071) 5.36 (.906) 5.77 (1.198) private 21 14.81 (14.81) 4.52 (.750) 5.05 (1.203) specialty * 0.00 0.00 0.503 medical doctor 146 15.61 (2.141) 5.63 (.654) 5.68 (1.219) nurse 213 14.52 (1.985) 5.20 (.967) 5.70 (1.241) laboratory technician 88 15.15 (1.825) 5.11 (1.033) 5.89 (1.098) experience years ** .866 0.02 0.00 less than 2 years 111 15.10 (2.013) 5.07 (1.042) 5.23 (1.291) more than 2 years 336 15.07 (2.094) 5.41 (.855) 5.90 (1.130) * kruskal wallis test, ** mann-whitney test, p<0.05 421 422 table 6: predictors of demonstrating a good knowledge, attitude and practice levels about hbv. 423 424 item demographic characteristics n p value odds ratio ci 95 (lowe bond) ci 95 (upper bond) p re d ic to rs o f d e m o n st ra ti n g a g o o d k n o w le d g e l e v e l a b o u t h b v age 24-30 185 .056 .292 .082 1.034 31-40 142 .102 .369 .112 1.219 41-50 75 .154 .408 .119 1.398 more than 50 45 ref ref ref ref affiliation governmental 426 .959 .955 .160 5.691 private 21 ref ref ref ref specialty medical doctor 146 .600 1.283 .505 3.260 nurse 213 000 .161 .058 .445 laboratory technician 88 ref ref ref ref experience years less than 2 years 111 .483 1.434 .523 3.932 more than 2 years 336 ref ref ref ref p re d ic to rs o f d e m o n st ra ti n g a g o o d a tt it u d e l e v e l a b o u t h b v age 24-30 185 .508 .662 .196 2.240 31-40 142 .158 .441 .141 1.374 41-50 75 .667 .750 .202 2.788 more than 50 45 ref ref ref ref affiliation governmental 426 .000 8.505 2.912 24.840 private 21 ref ref ref ref specialty medical doctor 146 .000 8.599 3.493 21.168 nurse 213 .130 1.619 .868 3.018 laboratory technician 88 ref ref ref ref experience years less than 2 years 111 .001 .292 .138 .617 more than 2 years 336 ref ref ref ref p re d ic to rs o f d e m o n st ra ti n g a g o o d p ra c ti c e l e v e l a b o u t h b v age 24-30 185 .918 1.041 .487 2.222 31-40 142 .382 1.381 .670 2.846 41-50 75 .248 1.612 .717 3.624 more than 50 45 ref ref ref ref affiliation governmental 426 .055 2.544 .978 6.616 private 21 ref ref ref ref specialty medical doctor 146 .561 .844 .476 1.496 nurse 213 .826 1.064 .612 1.850 laboratory technician 88 ref ref ref ref experience years less than 2 years 111 .011 .485 .277 .849 more than 2 years 336 ref ref ref ref july 2008.indd extended-spectrum β-lactamase (esbl) in omani children study of prevalence, risk factors and clinical outcomes at sultan qaboos university hospital, sultanate of oman zakariya al muharrmi,1 *akbar m rafay,1 abdullah balkhair,2 salem al-tamemi,3 ali al mawali,4 hilal al sadiri4 في (esbl) املديد الطيف ذي البيتاالكتاميز التي تفرز البكتيريا األطفال العمانيني جامعة مستشفى في السريرية والنتائج تِطار لُ االِخْ وامِ وعَ االنتشار دراسة عمان سلطنة قابوس، السلطان السديري هالل ، علي املعولي ، التميمي سالم بلخير ، عبداهللا ، رافع أكبر احملرّمي، زكريا الى تهدف ــة الدراس هذه . ــب املناس اختيار املضاد احليوي في صعوبات ، وهذا يضع العالم في ــكلة متنامية مش البكتريا مقاومة امللخص: الهدف: شهر إلى شهر يناير من قابوس السلطان جامعة مبستشفى في قسم األطفال (esbl) املديد الطيف البيتاالكتاميز ذي تفرز التي تقييم البكتيريا عند االختطار عوامل مت حتليل . قسم األطفال في الراقدين األطفال البكتيريا عند تلك ــة ودراس مت حتديد ــهرا 12 ش الطريقة: خالل .2005 ــمبر ديس الطيف ذي البيتاالكتاميز تفرز الرئوية الكليبسيال 16.6 %) من و( املعوية االشريشيا من (13.3% ): النتائج . البكتريا بتلك أصيبوا الذين املرضى استخدام هو البكتيريا بهذه اإلصابة إلى أدت التي االختطار عوامل وأهم .(42.6% ) الدم ومن ، البول من (46.2 %) جاءت هذه البكتريا غالبية . املديد ــية حساس كانت .(84.6% ) أنثى املريض وكون ،(92.3% ) ــديد واملرض الش ــفى املستش في الطويل من الترقيد %100)، وكال ) ــة احليوي ــادات املض لم ــبورين. سيفالوس أماينوــياألوكس ضد (100 %) مقاومة ــا أبدى جميعها (92 %) ، بينم ــني لألميكاس و ، (100% ) ــم للكاربابين ــا البكتري النايتروفرونتوين. اجلنتاميسني مع النايتروفرونتوين، مع أميكاسني تازوباكتم، البيبراسيلنيمع التالية: األميكاسني ضد التوليفات مناعة أية تسجل للمضادات ــبق املس وأن التعرض ، املرضى العمانيني األطفال ــكلة كبيرة عند مش املديد الطيف ذي البيتاالكتاميز تفرز البكتيريا التي متثل اخلالصة: االستعاضة وميكن ، الكاربابينم هو البكتريا لهذه األمثل العالج البكتيريا. هذه انتشار لتقليل بها التحكم ميكن هي عوامل الطويل والترقيد احليوية النايتروفرونتوين. اجلنتاميسني مع النايتروفرونتوين، مع أميكاسني تازوباكتم، البيبراسيلنيمع التالية: األميكاسني بالتوليفات عنه عمان. احليوية، املضادات االختطار، عوامل الرئوية، الكليبسيال ، املعوية االشريشيا املديد، الطيف ذي الكلمات: البيتاالكتاميز مفتاح departments of 1microbiology & immunology, 2medicine, 3child health, sultan qaboos university hospital, muscat, oman; 4medical student, college of medicine & health sciences, sultan qaboos university, muscat, oman *to whom correspondence should be addressed. email: akbarrafay@hotmail.com sultan qaboos university medical journal july 2008, volume 8, issue 2, p. 171-177 sultan qaboos university© submitted 3rd october 2007 accepted 31st march 2008 abstract objectives: antimicrobial resistance is a growing problem worldwide, which imposes difficulties in the selection of appropriate empirical antimicrobial therapy. this study evaluated extended-spectrum β-lactamase (esbl) isolates in 2005 in the department of child health at sultan qaboos university hospital (squh), oman. methods: during the 2 month period from january 2005 to december 2005, esbl isolates from paediatrics inpatients were identified and analysed. risk factors for the patients who grew esbls were analysed. results: 3.3% of e. coli and 6.6% of klebsiella pneumoniae isolated were esbl producers. most of the esbls were from urine (46.2%) and blood (42.6%). the main risk factors for esbl in these children were previous exposure to antimicrobials (00%), prolonged hospital stay, severe illness (92.3%) and female gender (84.6%). sensitivity of 00% was observed to carbapenems whereas 92% of the isolates were susceptible to amikacin. the oximino-cephalosporins were 00% resistant. klebsiella pneumoniae were 00% resistant to piperacillin-tazobactam and nitrofurantoin. e. coli was 00% resistant to trimethoprim-sulfamethoxazole and ciprofloxacin. no resistance was recorded for the following combinations: amikacin plus piperacillin-tazobactam, amikacin plus nitrofurantoin and gentamicin plus nitrofurantoin. conclusion: esbl-producing organisms are becoming a major problem in omani children. exposure to antimicrobials and long admissions are modifiable risk factors that should be targeted for better control. carbapenems are the most sensitive and reliable treatment options for infections caused by esbls. amikacin plus piperacillin-tazobactam or nitrofurantoin are good alternatives. keywords: extended-spectrum β-lactamase; escherichia coli; klebsiella pneumonia; anti-infective agents; risk factors; oman. c l i n i c a l a n d b a s i c r e s e a r c h z a k a r i ya a l m u h a r r m i , a k b a r m r a fay, a b d u l l a h b a l k h a i r , s a l e m a l -ta m e m i , a l i a l m awa l i a n d h i l a l a l s a d i r i 172 antimicrobial resistance is a growing problem worldwide, which imposes difficul-ties in the selection of appropriate empirical antimicrobial therapy. since the first extended-spectrum β-lactamase (esbl) producing klebsiella pneumoniae were discovered in western europe in the mid-1980s, the esbl producing enterobacteriacea became the focus of many scientific research studies and investigations.1-5 esbl are enzymes belonging to either class a or class d β-lactamases. class a esbls belong to three types: shv with more than 50 varieties currently recognized on the basis of unique combinations of aminoacid replacements; tem with more than 130 tem enzymes currently recognized; and ctx-m with more than 40 ctx-m enzymes currently known.6 other uncommon class a esbls are bes-1, ges-1, ges-2, ibc-1, ibc-2, per-1, sfo-1, tla-1, veb-1 and veb-2.6 there are also at least twelve esbls belonging to the oxa type (class d).6 esbls are plasmid-mediated, and their potential for transfer makes it increasingly difficult to control and treat these organisms effectively.7 as of 25 january 2005, there were 138 tem(tem-1 to tem-139) and 62 shv-types (shv-1 to shv-63) of β-lactamases, mostly found in k. pneumoniae and e. coli strains.8 these mutant enzymes were termed ‘extended-spectrum β-lactamase’ by philippon et al9 in 1989. esbls hydrolyse extended spectrum cephalosporins with an oxyimino side chain.10 these cephalosporins include cefotaxime, ceftriaxone and ceftazidime, as well as the oxyimino-monobactam aztreonam. in addition, esblproducing organisms are frequently resistant to many other classes of antibiotics, including fluoroquinolones, the monobactam aztreonam, while resistance to trimethoprim–sulfamethoxazole and aminoglycosides is frequently co-transferred on the same plasmid.9, 1114 esbls are sensitive to cephamycins (cefoxitin, cefotetan) and carbapenems. esbl-producing organisms are poorly responsive to treatment with wide spectrum cephalosporins such as ceftazidime and cefepime.7, 15 esbl-producing organisms are difficult to differentiate from ampc β-lactamase-producing enterobacteriacea; however, most esbl producers are generally susceptible to cephamycins (e.g. cefoxitin) in vitro. esbls are plasmid-mediated while ampc βlactamase enzymes are located on the chromosomes of enterobacter sp, citrobacter freundii, morganella morganii, serratia marcescens, and pseudomonas aeruginosa. the appearance of similar plasmid-mediated β-lactamases in k. pneumoniae and e. coli raises concerns over the spread of resistance, 7 which will further increase the difficulties of phenotypically identifying ß-lactamases.16-21 there are many precipitating factors for selection of esbl producing organisms. these include the increasing use of oxyimino-β-lactams such as ceftazidime, cefotaxime and ceftriaxone. other risk factors for the acquisition of esbls include presence of intravascular catheters; emergency intra-abdominal surgery; a gastrostomy or jejunostomy tube; gastrointestinal colonisation; length of hospital or intensive care unit stay; prior antibiotics (including third-generation cephalosporins); prior nursing home stay; severity of illness; presence of a urinary catheter and ventilator assistance.22 the problem of esbl production is still relatively unappreciated by most clinicians.23, 24 this may be due in part to difficulty in laboratory identification of esbls and misreporting them as sensitive organisms.15, 25-27 many esbl-producing isolates are not always phenotypically resistant to all oximino-cephalosporins; however, patients suffering from infections caused by esbl-producing organisms are at risk of treatment failure if treated with one of the oximinocephalosporins.9, 28, 29 therefore, it is imperative for the clinical microbiology laboratory to identify isolates that possess increased minimum inhibitory concentrations (mics) (≥ 2 µg ⁄ ml) to oximino-cephalosporins, even though they may be equal to or below the susceptibility breakpoint (mic ≤ 8 µg ⁄ ml).9 the rate of esbl varies from country to country. the prevalence of esbls in the uk in 2002 was 7.4%.30 in europe, the prevalence of esbl producing e.coli is 10.8% while k. pneumoniae is 13.6%.31 in the usa, the prevalence of esbl producing e.coli is 1.4% while k. pneumoniae is 4.4% 31. the prevalence of esbl at sultan qaboos university hospital, (squh), oman is not yet known. we have analysed the sensitivity and distribution of some esbl isolates in squh previously32 without studying the prevalence rate of esbl in squh as a whole, or in individual departments. in this article, we are reporting the prevalence of esbl isolates in paediatric patients admitted to squh with an analysis of the risk factors and clinical outcomes of esbls infections. e x t e n d e d s p e c t r u m β l a c ta m a s e ( e s b l ) i n o m a n i c h i l d r e n 173 m e t h o d s squh is a 500-bed tertiary and teaching hospital covering all major medical specialties. it is located on the campus of sultan qaboos university in muscat, oman. the department of child health occupies three different wards. each ward accommodates 24 beds of which 4 beds are for isolation. all specimens received from department of child health from january-december 2005 were properly processed to identify esbls. initially, the isolates were screened by a commercial system (phoenix identification and susceptibility system from becton dickinson) for esbl production. the positive results were further confirmed using the clinical and laboratory standards institute (clsi) approved double-disk diffusion method14, which is based on a synergistic increase of inhibition zone of ceftazidime and cefotaxime when they are combined with clavulanate. the test is considered positive when the increase of the inhibition zone is (>/= 5 mm).9, 33, 34 susceptibility results were recorded for the following antimicrobials using the phoenix identification and susceptibility system: gentamicin, amikacin, imipenem, meropenem, cefotaxime, ceftazidime, cefepime, ciprofloxacin, piperacillin-tazobactam, trimethoprim/sulfamethoxazole and nitrofurantoin. there was no resistance recorded for the following combinations: amikacin plus piperacillin-tazobactam, amikacin plus nitrofurantoin and gentamicin plus nitrofurantoin [table 5]. r e s u l t s a total of 87 isolates of e. coli and klebsiella pneumoniae were isolated from patients admitted to paediatric wards in squh in 2005. out of these 13 (14.9 %) were esbl producers, out of which 6 (46.2%) were e. coli and 7 (53.8%) were klebsiella pneumoniae [table 1]. the percentage of e. coli producing esbl from the total number of e. coli isolated in 2005 was 13.3% [table 1]. while the percentage of klebsiella pneumoniae producing esbl from the total number of klebsiella pneumoniae isolated in 2005 was 16.6% [table 1]. most of the esbls isolates were from urine (46.2%) and blood (42.6%) [table 2]. a total of 85.7% of esbl producing klebsiella pneumoniae were isolated from urine samples, while 83.3% of esbl producing e. coli were from blood [table 1]. no esbl were isolated from wound and pus swabs. the main risk factors for esbl in these children were the previous exposure to antimicrobials (100%) [table 3], hospital stays of more than 5 days (92.3%) and female sex (84.6%). malignancies, admission to the intensive care unit and the use of a urinary catheter were each (38.5%) associated with esbl. only one patient (1/13) was ventilated. abdominal surgery and obstructive disease of the urinary tract were not found to be risk factors in our patients. the carbapenems (imipenem and meropenem) were the most active antibiotics against the esbls tested, with no resistance recorded [table 4], followed by amikacin with 8% resistance. all the esbls were resistant to oximino-cephalosporins. all esbl producing klebsiella pneumoniae were sensitive to gentamycin and amikacin [table 4], whereas all e. coli were resistant to gentamycin and but only 18% were resistant to amikacin. all klebsiella pneumoniae were resistant to piperacillin-tazobactam and nitrofurantoin, whereas no resistance was seen in e. coli to nitrofurantoin and only 16% were resistant to piperacillin-tazobactam. all e. coli were resistant to ciprofloxacin and trimethoprim/ sulfamethoxazole, while 14% of klebsiella pneumoniae isolates total esbls esbl (%) e.coli 45 6 13.3 k. pneumoniae 42 7 16.6 total 87 13 14.9 table 1: percentage of esbls among e.coli and k. pneumoniae in sultan qaboos university hospital, oman, paediatrics wards in 2005 isolates blood respiratory swabs urine klebsiella pnemoniae 1 0 0 6 e. coli 5 1 0 0 total 6 1 0 6 table 2: source of esbl isolates from paediatric wards z a k a r i ya a l m u h a r r m i , a k b a r m r a fay, a b d u l l a h b a l k h a i r , s a l e m a l -ta m e m i , a l i a l m awa l i a n d h i l a l a l s a d i r i 174 were resistant to ciprofloxacin and 28% were resistant to trimethoprim/sulfamethoxazole [table 4]. no resistance was recorded for the following combinations: amikacin plus piperacillin-tazobactam, amikacin plus nitrofurantoin and gentamicin plus nitrofurantoin [table 5]. klebsiella pneumoniae isolates were sensitive to all combinations containing gentamicin and amikacin [table 5]. e. coli isolates were sensitive to all combination containing nitrofurantoin [table 5]. all patients (100%) were isolated in a single room and nursed using gloves. they were all treated with a carbapenem (imipenem or meropenem). all patients (100%) cleared the infection. d i s c u s s i o n the percentage of esbl producing e. coli and klebsiella pneumoniae in children admitted at squh was low compared to other squh wards. the prevalence of esbls in medical wards was 28.3% (unpublished data); however, the prevalence rate of esbls among e. coli and klebsiella pneumoniae isolated from paediatrics patients was significantly high (13.3% and 16.6% respectively) compared to the prevalence of esbls in the usa in 2004 (1.4% for e. coli and 4.4% klebsiella pneumoniae) 31 and europe (10.8% for e. coli and 13.6% for klebsiella pneumoniae).31 the rate of esbl among e. coli (13.3%) was lower than that for klebsiella pneumoniae (16.6%). this was the same as the prevalence in usa (1.4% for e. coli versus 4.4% for klebsiella pneumoniae) and europe (10.8% for e. coli versus 13.6% for klebsiella pneumoniae).31 urine (70.8%) was the main source of esbls from all patients, followed by blood (15%). the high rate of esbls in urine samples is not striking if we consider the high prevalence of esbls in the gut as shown in hong kong where the faecal carriage rates of esbl is 19% in general outpatients, 19.3% in hospitalized patients, 22.5% in healthy inmates, and 33.3% in convalescent patients.35 in one middle east country, 1.25% of all gram-negative organisms causing community acquired urinary tract infections during 1999 were reported as esbl producers.22, 36 previous exposure to antimicrobials, female sex, risk factors case 1 case 2 case 3 case 4 case 5 case 6 case 7 case 8 case 9 case 10 case 11 case 12 case 13 total sex m f f m f f f f f f f f f f=11 m=2 previous use of antibiotics y y y y y y y y y y y y y 13/13 hospital stay > 5 days y y y n y y y y y y y y y 12/13 malignancies n y n n n y y n y n n y n 5/13 use of urinary catheter n n y n n n n y n y y n y 5/13 admission to intensive care unit y n n n n y y n y n n y n 5/13 ventilatory assistance y n n n n n n n n n n n n 1/13 abdominal surgery n n n n n n n n n n n n n 0 obstructive disease of urinary tract n n n n n n n n n n n n n 0 table 3: esbl risk factors in a group of sultan qaboos university hospital paediatric patients e x t e n d e d s p e c t r u m β l a c ta m a s e ( e s b l ) i n o m a n i c h i l d r e n 175 prolonged hospital stays of more than 5 days, malignancies, admission to the intensive care unit and the use of a urinary catheter were all found to be risk factors for esbl acquisition. exposure to antimicrobials was present in 100% of cases, which supports the need for antimicrobial control. 84.6% of cases were female, this might be explained by the increased frequency of urinary tract infections (uti) in females. all the esbl isolates in squh were susceptible to carbapenems (100%). the susceptibility rate is similar to esbls in the usa where they were 100% susceptible to meropenem and imipenem.31 meropenem and imipenem activity against esbl producing e. coli and klebsiella spp. collected in europe during 1997–2004 was between 96.9–100.0%, which was lower than the susceptibility of esbls in squh and the usa.31 susceptibility of esbls from squh to amikacin was very high (95.9% for e. coli and 90% for klebsiella pneumoniae). kizirgila et al have shown similar susceptibility patterns to amikacin for esbls in turkey (94.5 for e. coli and 83.3% for klebsiella pneumoniae), 37 which makes amikacin a good antibiotic in treatment of esbls especially in combination therapy. on the contrary, gentamicin had very low activity against esbls at squh. gentamicin had only (28.8%) activity against e. coli compared to europe and usa where the e. coli susceptibility to gentamicin was 66.7% and 80% respectively in 2004.31 gentamicin had only 25% activity against klebsiella pneumoniae which is similar to the usa (26.3%), which are lower rates than those (47.5%) reported in europe in 2004.31 esbls at squh had low susceptibility against piperacillin/tazobactam (50.7% e. coli and 32.5% klebsiella pneumoniae). this level was lower than that reported in europe (72.5% e. coli and 38.6% klebsiella pneumoniae)31 and the usa (80.0% for e. coli and 42.1% for klebsiella pneumoniae)31, which does not make piperacillin/tazobactam a good empirical choice if suspicion of esbl is high. ciprofloxacin had very low activity against esbls in squh. it was only 16.4% active against e. coli which is similar to europe (20.2%) and the usa (20%) in 2004, 31 whereas higher activity against klebsiella pneumoniae (32.5%) was recorded. this higher activity compared to e. coli has also been demonstrated in europe (57.5%) and the usa (36.8%) in 2004.31 the opposite situation has been detected in turkey where ciprofloxacin was more active against e. coli (33.3%) compared to klebsiella pneumoniae (25.9%).37 the best non-carbapenem containing combinations were amikacin plus piperacillin-tazobactam, amikacin plus nitrofurantoin and gentamycin plus nitrofurantoin. so if esbl is expected in a severely ill patient the best empirical combination therapy would be amikacin plus piperacillin-tazobactam. if klebsiella pneumoniae were cultured and a suspension of esbl was present, the empirical combination therapy should include either gentamycin or amikacin. if e. coli was isolated from a urine culture of a stable patient nitrofurantoin would be the drug of choice. all patients underwent a good infection control procedure of isolation and barrier nursing according to accepted standards. all patients made a full clinical recovery with microbiologic eradication of esbls on carbapenem. overall prevalence of esbl-producing isolates in omani children was high compared to other countries. prevention and good infection control practices should be our priority because these organisms have very limited treatment options. modification of risk factors and control of antimicrobials should be considered. carbapenem should be the drug of choice in treatment of esbls, which theoretically may lead to increase in carbapenem-resistant acinetobacter sp and carbapenem-resistant p. aeruginosa. however, robert g et al have not seen any increase in carbapenem isolates cn ak imi mem ctx caz cefi cip taz sxt f klebsiella pnemoniae 0 0 0 0 7 7 7 1 7 2 7 e. coli 6 1 0 0 6 6 6 6 1 6 0 total 6 (46) 1 (8) 0 0 13 (100) 13 (100) 13 (100) 7 (54) 8 (62) 8 (62) 7 (54) cn = gentamicin, ak = amikacin, imi = imipenem, mem = meropenem ctx = cefotaxime, caz = ceftazidime, cefi = cefepime, cip = ciprofloxacin, taz = tazocin, sxt = cotrimoxazole, f = nitrofurantoin. table 4: esbl isolates from paediatric wards: frequency and (%) z a k a r i ya a l m u h a r r m i , a k b a r m r a fay, a b d u l l a h b a l k h a i r , s a l e m a l -ta m e m i , a l i a l m awa l i a n d h i l a l a l s a d i r i 176 resistance despite continued use of meropenem and imipenem.30 other options would be amikacin plus piperacillin-tazobactam or nitrofurantoin. wong-beringer suggested the use of piperacillin–tazobactam in the case of a non-outbreak situation, to preserve the therapeutic value of carbapenem.38 c o n c l u s i o n esbl-producing organisms are becoming a major problem in omani children. exposure to antimicrobials and long admissions are modifiable risk factors that should be targeted for better control. carbapenems are the most sensitive and reliable treatment options for infections caused by esbls. amikacin plus piperacillin-tazobactam or nitrofurantoin are good alternatives. r e f e r e n c e s 1. winokur pl, canton r, casellas jm, legakis n. variations in the prevalence of strains expressing an extended spectrum b-lactamase phenotype and characterisation of isolates from europe, the americas and the western pacific region. clin microbiol dis 2001; 32:s94–s103. 2. bradford pa. extended-spectrum b-lactamases in the 21st century: characterisation, epidemiology, and detection of this important resistance threat. clin microbiol rev 2001; 14:933–951. 3. quinn jp, miyashiro d, sahm d, flamm r, bush k. novel plasmid-mediated ß-lactamase (tem-10) conferring selective resistance to ceftazidime and aztreonam in clinical isolates of klebsiella pneumoniae. antimicrob agents chemother 1989; 33:1451-1456. 4. knothe a, shah p, kremery v, antal m, mitsuhashi s. transferable resistance to cefotaxime, cefoxitin, cefamandole and cefuroxime and in clinical isolates of klebsiella pneumoniae and serratia marcescens. infection 1983; 11:315-317. 5. jacoby ga, medeiros aa, o’brien tf, pinto me, jiang j. broad-spectrum transmissible β-lactamases. n engl j med 1989; 319:723-724. 6. jacoby ga, munoz-price ls. the new β-lactamases. n engl j med 2005; 352:380-391. 7. kaye ks, engemann jj, fraimow hs, abrutyn e. pathogens resistant to antimicrobial agents: epidemiology, molecular mechanisms, and clinical management. infect dis clin north am 2004; 18:467– 511. 8. giamarellou h. multidrug resistance in gram-negative bacteria that produce extended-spectrum b-lactamases (esbls). clin microbiol & infection 2005; 11:1-16 9. philippon a, labia r, jacoby g. extended-spectrum b-lactamases. antimicrob agents chemother 1989; 33:1131–1136. 10. patterson je. extended-spectrum beta-lactamases. semin respir infect 2000; 15:299-307. 11. itokazu gs, quinn jp, bell-dixon c, kahan fm, weinstein ra. antimicrobial resistance rates among aerobic gram-negative bacilli recovered from patients in intensive care units: evaluation of a national postmarketing surveillance program. clin infect dis 1996; 23:779-784. 12. jacoby ga, sutton l. properties of plasmids responsible for production of extended-spectrum ß-lactamases. antimicrob agents chemother 1991; 35:164. 13. jacoby ga. genetics of extended-spectrum ß-lactamases. eur j clin infect dis 1994; 13:2-11. 14. rice lb, willey sh, papanicolaou ga, medeiros aa, eliopoulos gm, moellering rc jr, et al. outbreak of ceftazidime resistance caused by extended-spectrum b-lactamases at a massachusetts chronic-care facility. antimicrob agents chemother 1990; 11:2193–2199. 15. paterson dl, ko wc, von gottberg a, casellas jm, mulazimoglu l, klugman kp, et al. outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum b-lactamases: implications for the clini isolates cn + cep cn + taz cn + cip cn + f ak + cep ak + taz ak + cip ak+ f cip + taz cip + cep cip + f f + taz f + cep klebsiella pneumoniae 0 0 0 0 0 0 0 0 1 1 1 7 7 e. coli 6 1 6 0 1 0 1 0 1 6 0 0 0 total 6 (46) 1 (8) 6 (46) 0 1 (8) 0 1 (8) 0 2 (16) 7 (54) 1 (8) 7 (54) 7 (54) cn + cep = gentamicin+ cefepime, cn + taz =gentamicin+ tazocin, cn + cip = gentamicin+ ciprofloxacin, cn + f = gentamicin + nitrofurantoin ak + cep = amikacin + cefepime, ak + taz = amikacin + tazocin, ak + cip = amikacin + ciprofloxacin, ak + f = amikacin + nitrofurantoin, cip + taz = ciprofloxacin + tazocin, cip + cep = ciprofloxacin + cefepime, cip + f = ciprofloxacin + nitrofurantoin, f + taz = nitrofurantoin + tazocin, f + cep = nitrofurantoin + cefepime table 5: esbl resistance to combination therapy of sultan qaboos university hospital paediatric patients e x t e n d e d s p e c t r u m β l a c ta m a s e ( e s b l ) i n o m a n i c h i l d r e n 177 cal microbiology laboratory. j clin microbiol 2001; 39:2206–2212. 16. coudron pe, moland es, thomson ks. occurrence and detection of ampc ß-lactamases among escherichia coli, klebsiella pneumoniae, and proteus mirabilis isolates at a veteran’s medical center. j clin microbiol 2000; 38:1791-1796. 17. bauernfeind a, wagner s, jungwirth r, schneider i, meyer d. a novel class c ß-lactamase (fox-2) in escherichia coli conferring resistance to cephamycins. antimicrob agents chemother 1997; 41:2041-2046. 18. bou g, oliver a, ojeda m, monzon c, martinez-beltran j. molecular characterization of fox-4, a new ampc-type plasmid-mediated ß-lactamase from an escherichia coli strain isolated in spain. antimicrob agents chemother 2000; 44:2549-2553. 19. gazouli m, tzouvelekis ls, vatopoulos ac, tzelepi e. transferrable class c ß-lactamases in escherichia coli strains isolated in greek hospitals and characterization of two enzyme variants (lat-3 and lat-4) closely related to citrobacter freundii ampc ß-lactamase. j antimicrob chemother 1998; 42:419-425. 20. fortineau n, poirel l, nordmann p. plasmid-mediated and inducible cephalosporinase dha-2 from klebsiella pneumoniae. j antimicrob chemother 2001; 47:207210. 21. queenan am, jenkins s, bush k. cloning and biochemical characterization of fox-5, an ampc-type plasmidencoded ß-lactamase from a new york city klebsiella pneumoniae clinical isolate. antimicrob agents chemother 2001; 45:3189-3194. 22. colodner r, extended-spectrum b-lactamases: a challenge for clinical microbiologists and infection control specialists. am j infection control 2005; 2:104-107. 23. paterson dl, yu vl. extended-spectrum beta-lactamases: a call for improved detection and control. clin infect dis 1999; 29:1419-1422. 24. goossens h. the problem of esbl producers a worldwide survey into physician awareness and perception. program and abstracts of the 42nd interscience conference on antimicrobial agents and chemotherapy, san diego, california, usa, 27-30 september 2002. 25. steward cd, rasheed jk, hubert sk, biddle jw, raney pm, anderson gj, et al. characterization of clinical isolates of klebsiella pneumoniae from 19 laboratories using the national committee for clinical laboratory standards extended-spectrum beta-lactamase detection methods. j clin microbiol 2001; 39:2864-2872. 26. tenover fc. esbl testing, interpretation, and reporting. program and abstracts of the 42nd interscience conference on antimicrobial agents and chemotherapy, san diego, california, usa, 27-30 september 2002. 27. document m100-s14. clinical and laboratory standards institute, formerly national committee for clinical laboratory standards. wayne, pa: nccls, 2004. 28. paterson dl, singh n, gayowski t, marino ir. fatal infection due to extended-spectrum beta-lactamaseproducing escherichia coli: implications for antibiotic choice for spontaneous bacterial peritonitis. clin infect dis 1999; 28:683–684. 29. karas ja, pillay dg, muckart d, sturm aw. treatment failure due to extended spectrum b-lactamase. j antimicrob chemother 1996; 37:203–204. 30. robert g. masterton, philip j. turner. trends in antimicrobial susceptibility in uk centres: the mystic programme (1997–2002). int j antimicrob agents 2006; 27:69–72. 31. goossens h, grabein b. prevalence and antimicrobial susceptibility data for extended-spectrum β-lactamase– and ampc-producing enterobacteriaceae from the mystic program in europe and the united states (1997–2004). diagn microbiol infect dis 2005; 53:257– 264. 32. rafay am, almuharrmi z, toki r. prevalence of extended–spectrum beta-lactamases-producing isolates over a one-year period at a university hospital in oman. saudi med j 2007; 28: 22-27. 33. carter mw, oakton kj, warner m, livermore dm. detection of extended-spectrum b-lactamases in klebsiella with the oxoid combination disk method. j clin microbiol 2000; 38:4228–4232. 34. m’zali fh, chanawong a, kerr kg, birkenhead d, hawkey pm. detection of extended-spectrum b-lactamases in members of the family enterobacteriaceae: comparison of the mast dd test, the double disc and the etest esbl. j antimicrob chemother 2000; 45:881– 885. 35. boost m, tsang kl, kam km. esbl-producing strains of e. coli in hong kong. int j antimicrob agents 2005; 26s:s65s112. 36. colodner r, keness y, chazan b, raz r. antimicrobial susceptibility of community acquired uropathogens in northern israel. int j antimicrob agents 2001; 18:18992. 37. kizirgila a, demirdagb k, ozdenb m, buluta y, yakupogullaria y, toramana za. in vitro activity of three different antimicrobial agents against esbl producing escherichia coli and klebsiella pneumoniae blood isolates. microbiol res 2005; 160:135-140. 38. wong-beringer a, hindler j, loeloff m, queenan am, lee n, pegues da, et al. molecular correlation for the treatment outcomes in bloodstream infections caused by escherichia coli and klebsiella pneumoniae with reduced susceptibility to ceftazidime. clin infect dis 2002; 34:135-46. submitted 2 aug 22 1 revision req. 25 oct 22; revision recd. 18 dec 22 2 accepted 17 jan 23 3 online-first: february 2023 4 doi: https://doi.org/10.18295/squmj.1.2023.011 5 6 hepatic vascular variants in hereditary haemorrhagic telangiectasia 7 imaging findings 8 *alamelu alagappan,1 biswajit sahoo,1 jain h. prakash,2 manas k. 9 panigrahi,2 taraprasad tripathy1 10 11 departments of 1radiodiagnosis and 2gastroenterology, all india institute of medical sciences, 12 bhubaneswar, odisha, india. 13 *corresponding author’s e-mail: sornavallialagappan@gmail.com 14 15 abstract 16 hereditary haemorrhagic telangiectasia (hht) is an autosomal dominant disorder characterized 17 by vascular dysplasia. hepatic vascular malformations (vms) range from small telangiectases to 18 significant vascular shunting. here we report two cases of hht. case 1 had diffuse ectasia of the 19 hepatic artery along its intrahepatic and extrahepatic course with a hepatic arterial aneurysm. 20 case 2 presented with ileal and hepatic telangiectases. knowledge of these vascular variants is 21 indispensable for clinicians and radiologists in aiding diagnosis and surgical and interventional 22 management. 23 keywords: vascular malformations, hht, arteriovenous malformation, ileal telangiectasis. 24 25 introduction 26 hereditary haemorrhagic telangiectasia (hht), also known as osler weber rendu syndrome, is 27 a multi-system autosomal dominant vascular disorder, with an incidence of one in 5000 to 8000 28 individuals.1 it was initially recognized as a mucocutaneous vascular disorder presenting with 29 epistaxis, gastrointestinal haemorrhage, and iron deficiency anaemia. however, with the 30 increasing use of imaging modalities, many patients come to attention with incidentally detected 31 visceral vascular malformations (vms). recent studies have demonstrated the frequent 32 occurrence of pulmonary, hepatic and cerebral vascular malformations, with an estimate that at 33 least 30% of hht has hepatic involvement.2,3 with such high prevalence, it is fundamental for 34 all radiologists, physicians and hepatologists to be acquainted with hepatic vascular involvement 35 in hht. gastric and small bowel telangiectases are rare manifestations of hht, most commonly 36 involving the stomach, duodenum and jejunum. the ileum is less commonly affected.4 this case 37 report presents two cases of hht with hepatic vascular variants and one with ileal 38 telangiectases. 39 40 case reports 41 case one 42 a 35-year-old gentleman presented with a complaint of recurrent epistaxis for many years. he 43 had a vague upper abdominal discomfort for 2 years for which he underwent a screening 44 ultrasound abdomen which revealed the presence of hepatic arterio-portal shunting. on detailed 45 physical examination, there were multiple small reddish-purple lesions over both ear lobes, 46 fingertips and multiple oral telangiectases (figure 1a, 1b). in presence of epistaxis with multiple 47 mucocutaneous telangiectases, the possibility of hereditary hemorrhagic telangiectasia (hht) 48 was considered. however, there was no family member affected by hht. 49 50 after a preliminary examination, he was referred to the radiodiagnosis department for dedicated 51 ultrasonography (usg) and contrast-enhanced computer tomography (cect) abdomen scan. 52 53 on usg, multiple dilated and tortuous vessels were seen in the liver, which showed arterial 54 waveform with peak systolic velocity in the range of 140 to 155cm/s. the portal vein, hepatic 55 vein, and inferior vena cava were usual with typical waveform. the liver showed normal 56 echotexture with smooth margins. (figure 1c, 1d) 57 58 triple phase cect scan was acquired with arterial, portal, and venous phases after bolus 59 injection of contrast. on cect arterial phase (figure 2), variant hepatic arterial anatomy was 60 seen, with the left hepatic artery arising directly from the coeliac axis and common hepatic artery 61 arising from the coeliac axis giving rise to the middle hepatic artery and gastroduodenal artery 62 (gda). the right hepatic artery was seen arising from the superior mesenteric artery (sma). all 63 three hepatic arteries were tortuous and dilated (~12 mm) throughout their intrahepatic and 64 extrahepatic course. gda, left gastric artery and splenic artery were normal in course and 65 calibre. the coeliac artery and sma were dilated. an intrahepatic saccular aneurysm was seen 66 from a branch of the left hepatic artery. the portal vein and all three hepatic veins showed 67 normal contrast uptake. there was opacification of the peripheral portal branches in the arterial 68 phase, consistent with the presence of arterioportal shunting. cranial magnetic resonance 69 imaging and computed tomography (ct) of the chest were normal. 70 71 these dilated and tortuous patterns of hepatic arteries with high peak systolic velocities led to 72 radiological suspicion of hht. based on curaçao criteria [table 1],2 a diagnosis of hht was 73 established. 74 75 case two 76 a 56-year-old gentleman with hht who had been followed up for 3 years got admitted owing to 77 multiple episodes of blood in his stools, primarily dark red. there was no history of fever, loose 78 stools, abdominal pain, or distension. his vitals were stable on admission (pulse rate – 70 bpm, 79 blood pressure – 120/70 mmhg, temperature – 99f, spo2 – 98% in room air). per rectal 80 examination was unremarkable. haemoglobin profile showed moderate anaemia (9 g/dl), with 81 normocytic normochromic anaemia. on cect enterography (figure 3), multiple arterial-82 enhancing ileal lesions were seen. incidental multiple arterial enhancing lesions were also found 83 in the liver. on enteroscopy, the stomach and proximal small bowel appeared unremarkable. 84 multiple blood clots were evident within the bowel loops with coffee brown-coloured fluid. 85 multiple punctate lesions with pulsatile bleeding were seen in the terminal ileum (type 2a – 86 yano yamamoto classification),5 confirming the radiological diagnosis (figure 3c). 87 88 written consent was obtained from both patients for publication purposes. 89 90 91 92 discussion 93 hht is an autosomal dominant disorder characterized by vascular malformations. nearly 80% of 94 hht patients have identifiable mutations, most commonly eng (endoglin, hht1 genotype), 95 acvrl1 (activin a, hht2 genotype) and madh4 mutations.6 these causative genes are 96 involved in the tgf-β/bmp cell signalling pathway, which has a role in vascular 97 remodelling.7 mutations in these genes lead to altered tgf-β/bmp signalling pathways 98 disrupting the endothelial response, smooth muscle differentiation, and vascular integrity 99 resulting in small, fragile vessels.8 100 101 diagnosis of hht is based on four criteria recurrent epistaxis, mucocutaneous telangiectases, 102 visceral vascular lesions and an affected first-degree relative (the curaçao criteria) [table 1].2 103 according to these criteria, diagnosis of hht is “definite” when three criteria are satisfied and 104 “possible” when two criteria are present. vascular manifestations in hht include telangiectasis, 105 aneurysms, and shunting. common visceral vascular lesions include vascular malformations in 106 gastrointestinal, pulmonary, hepatic and central nervous system circulation. 107 108 most hepatic vascular malformations in hht are asymptomatic, with less than 10% of patients 109 having symptoms related to these lesions. clinical manifestations are related to either high-110 output heart failure or portal hypertension due to arterioportal shunting. arteriovenous shunting 111 causes high-output cardiac failure due to reduced systemic vascular resistance which in turn 112 leads to activation of the renin-angiotensin-aldosterone system, causing water and salt retention. 113 portal hypertension occurs when the portal flow or vascular resistance is increased. arterioportal 114 shunt is an uncommon cause of presinusoidal portal hypertension and is believed to be the result 115 of increased blood flow in the portal system. hepatomegaly, ascites, bleeding episodes, and 116 splenomegaly can all be symptoms of portal hypertension. these clinical manifestations result 117 from deviations from starling's law, where the force maintaining fluid in the vascular space is 118 less powerful than the force removing fluid from the vascular space.9 119 120 follow-up of liver vascular malformations has shown up to 5% mortality and 25% morbidity 121 over a median follow-up period of 44 months.10 with the advent of cross-sectional imaging 122 modalities, visceral vascular manifestations are frequently detected. a recent study using 123 multidetector computed tomography (ct) has demonstrated hepatic involvement of around 74 124 – 79%.11,12 125 126 hepatic involvement in hht ranges from tiny telangiectasis to large confluent vascular masses. 127 telangiectases are the most common vascular lesions seen in the liver in hht.13 one of our 128 cases saw an incidental finding of telangiectasia in the liver (case 2). maximum intensity 129 projection (mip) imaging helps appreciate these inconspicuous lesions from the hepatic 130 parenchyma as in our case. these telangiectasias can progress to form more complex vascular 131 malformations. hence the patient has to be monitored for long-term follow-up. 132 133 hepatic arteries are dilated and tortuous in hht. doppler study helps differentiate between the 134 dilated biliary radicles and tortuous hepatic arteries in hht. in our case (case 1), the hepatic 135 arterial velocity was similar to that of the mean velocity 153+/-65.2cm/s illustrated by nagamuna 136 et al. in their study.14 137 138 viyannan et al., in their case report, demonstrated that their patient had hepatic arterio-portal 139 shunting which was also seen in our case (case 2).15 proper phased protocol (arterial, portal, and 140 venous phase) helps in identifying inconspicuous shunting.13 141 142 in addition to dilated and tortuous hepatic arteries, a saccular aneurysm of the left hepatic artery 143 was found in our first case. however, very few cases of hepatic artery aneurysms have been 144 reported in the literature.16,17 there is still a paucity of qualitative research on the role of 145 intervention in the management of aneurysms in hht. 146 147 complications of vascular malformations (vms) include recurrent endothelial damage and 148 micro-vascular thrombosis may eventually cause improper hepatocyte proliferation and fibrosis. 149 cirrhosis development may ultimately result from chronic micro-vascular ischemia.18 150 hepatic arterial insufficiency results in numerous types of ischemic biliary damage (ischemic 151 cholangiopathies). several clinicopathological categories, including bile duct necrosis, bile leak 152 and biloma, biliary strictures, and biliary casts, make up ischemic cholangiopathies.19 153 154 management of symptomatic hepatic vms is mostly conservative. patients manifesting with high 155 output cardiac failure are treated with salt restriction, diuretics, beta-blockers, ace inhibitors, 156 digoxin, antiarrhythmic agents, cardioversion and radiofrequency ablation. patients presenting 157 with complications of portal hypertension are treated with vasopressors, variceal ligation (for 158 variceal bleeding), diuretics (for ascites), lactulose and rifaximin (for encephalopathy). this is 159 accompanied by iron administration for anaemia along with definitive treatment for bleeding 160 sources. with this therapy, around 63% of patients show complete and another 21% show partial 161 response.10 162 163 in patients not responding to initial medical management, invasive options can be considered 164 including peripheral, staged trans arterial embolization of liver vms.20 165 166 liver transplantation is the only definitive curative option, indicated for intractable high-output 167 heart failure, complicated portal hypertension and ischemic biliary necrosis.21,22 bevacizumab 168 was shown to reduce cardiac index in patients with severe liver vms with high output cardiac 169 failure.23 asymptomatic liver vms at high risk of poor outcomes (grade 4) can be targeted for 170 prophylactic therapy.1 sufficient data on the natural history and management of liver vms are 171 lacking and there are no clear recommendations to prefer one treatment option over another. 172 173 gastrointestinal telangiectases are rare manifestations of hht. it generally affects the caecum or 174 colon and rarely the small intestine.24 an extensive literature search in pubmed, embase and 175 cochrane, ct angiographic manifestations of gastrointestinal telangiectases is less reported. 176 only one case of jejunal telangiectasis is reported.24 this article thus describes the ct 177 angiographic manifestations of ileal telangiectasis. 178 179 conclusion 180 a cluster of findings led to high-end radiological suspicion, which unveiled the diagnosis of 181 hht in one of our cases. screening for hepatic vms is recommended in asymptomatic 182 individuals suspected to have hht as this leads to confirmation of diagnosis and better 183 management of these patients with doppler ultrasound being proposed as a first-line 184 investigation. ileal telangiectases should be considered in patients of hht with gastrointestinal 185 bleeding. 186 187 authors’ contribution 188 aa and jhp drafted the manuscript. bs and mkp supervised the work. tt critically reviewed 189 and edited the manuscript. all authors approved the final version of the manuscript. 190 191 references 192 1. begbie me, wallace gm, shovlin cl. hereditary haemorrhagic telangiectasia (osler-193 weber-rendu syndrome): a view from the 21st century. postgrad med j. 2003 194 jan;79(927):18-24. doi: 10.1136/pmj.79.927.18. pmid: 12566546; pmcid: pmc1742589. 195 2. piantanida m, buscarini e, dellavecchia c, minelli a, rossi a, buscarini l, et al. hereditary 196 haemorrhagic telangiectasia with extensive liver involvement is not caused by either hht1 197 or hht2. j med genet. 1996 jun 1;33(6):441-3. 198 3. mcdonald je, miller fj, hallam se, nelson l, marchuk da, ward kj. clinical 199 manifestations in a large hereditary hemorrhagic telangiectasia (hht) type 2 kindred. am j 200 med genet. 2000 aug 14;93(4):320-7. 201 4. canzonieri c, centenara l, ornati f, pagella f, matti e, alvisi c, et al. endoscopic 202 evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and 203 correlation with their genotypes. genet med. 2014 jan;16(1):3-10. doi: 10.1038/gim.2013.62. 204 epub 2013 may 30. pmid: 23722869. 205 5. yano t, yamamoto h. vascular, polypoid, and other lesions of the small bowel. best pract 206 res clin gastroenterol. 2009 feb 1;23(1):61-74. 207 6. abdalla sa, letarte m. hereditary hemorrhagic telangiectasia: current views on genetics 208 and mechanisms of disease. j med genet. 2006; 43(2):97-110. 209 7. shovlin cl. hereditary hemorrhagic telangiectasia: pathophysiology, diagnosis and 210 treatment. blood rev. 2010; 24(6):203-219. 211 8. fernández-l a, sanz-rodriguez f, blanco fj, bernabéu c, botella lm. hereditary 212 hemorrhagic telangiectasia, a vascular dysplasia affecting the tgfsignalling pathway. 213 clin med res. 2006; 4(1):66-78. 214 9. zhang dy, weng sq, dong l, shen xz, qu xd. portal hypertension induced by congenital 215 hepatic arterioportal fistula: report of four clinical cases and review of the literature. world j 216 gastroenterol. 2015 feb 2;21(7):2229. doi: 10.3748/wjg.v21.i7.2229. pmid: 25717263; 217 pmcid: pmc4326165. 218 10. buscarini e, leandro g, conte d, danesino c, daina e, manfredi g, et al. natural history 219 and outcome of hepatic vascular malformations in a large cohort of patients with hereditary 220 hemorrhagic telangiectasia. dig dis sci. 2011 jul;56(7):2166-78. 221 11. ianora aa, memeo m, sabba c, cirulli a, rotondo a, angelelli g. hereditary hemorrhagic 222 telangiectasia: multi-detector row helical ct assessment of hepatic involvement. radiology. 223 2004 jan;230(1):250-9. 224 12. memeo m, stabile ianora aa, scardapane a, buonamico p, sabba c, angelelli g. hepatic 225 involvement in hereditary hemorrhagic telangiectasia. abdom imaging. 2004 mar;29(2):211-226 20. 227 13. siddiki h, doherty mg, fletcher jg, stanson aw, vrtiska tj, hough dm, et al. abdominal 228 findings in hereditary hemorrhagic telangiectasia: pictorial essay on 2d and 3d findings with 229 isotropic multiphase ct. radiographics. 2008 jan;28(1):171-83. 230 14. naganuma h, ishida h, niizawa m, igarashi k, shioya t, masamune o. hepatic 231 involvement in osler-weber-rendu disease: findings on pulsed and color doppler 232 sonography. ajr am j roentgenology. 1995 dec;165(6):1421-5. doi: 233 10.2214/ajr.165.6.7484577. 234 15. viyannan m, balalakshmoji d, leelakrishnan v. hereditary hemorrhagic telangiectasia of 235 liver: pathophysiology with role of radiology in diagnosis and treatment. indian j radiol 236 imaging. 2020 jan-mar;30(1):98-101. doi: 10.4103/ijri.ijri_367_19. epub 2020 mar 30. 237 pmid: 32476760; pmcid: pmc7240902. 238 16. miyabe k, akita s, kitajima y, hirai m, naitoh i, hayashi k, et al. rupture of hepatic 239 aneurysm complicating hereditary hemorrhagic telangiectasia (osler–weber–rendu disease) 240 for which hepatic arterial coil embolization was effective. journal of gastroenterology and 241 hepatology. 2007 dec;22(12):2352-7. doi: 10.1111/j.1440-1746.2006.03456.x. 242 17. milot l, dumortier j, boillot o, pilleul f. giant aneurysm of the main hepatic artery 243 secondary to hereditary hemorrhagic telangiectasia: 3d contrast-enhanced mr angiography 244 features. gastroenterol clin biol. 2007 mar;31(3):297-9. doi: 10.1016/s0399-245 8320(07)89377-8. pmid: 17396089. 246 18. mancuso a. the ischemic liver cirrhosis theory and its clinical implications. med 247 hypotheses. 2016 sep;94:4-6. doi: 10.1016/j.mehy.2016.06.008. epub 2016 jun 9. 248 pmid:27515188. 249 19. kobayashi s, nakanuma y, matsui o. intrahepatic peribiliary vascular plexus in various 250 hepatobiliary diseases: a histological survey. hum pathol. 1994;25(9):940–6. 251 20. chavan a, luthe l, gabel m, barg-hock h, seifert h, raab r, et al. complications and 252 clinical outcome of hepatic artery embolization in patients with hereditary haemorrhagic 253 telangiectasia. eur radiol 2013;23:951–957. 254 21. buscarini e, plauchu h, garcia tsao g, white ri jr, sabbà c, miller f, et al. liver 255 involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. liver 256 int. 2006 nov;26(9):1040-6. doi: 10.1111/j.1478-3231.2006.01340.x. pmid: 17032403. 257 22. faughnan me, palda va, garcia-tsao g, geisthoff uw, mcdonald j, proctor dd, et al. 258 international guidelines for the diagnosis and management of hereditary haemorrhagic 259 telangiectasia. j med genet. 2011 feb;48(2):73-87. doi: 10.1136/jmg.2009.069013. epub 260 2009 jun 23. pmid: 19553198. 261 23. dupuis-girod s, ginon i, saurin jc, marion d, guillot e, decullier e, et al. bevacizumab in 262 patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular 263 malformations and high cardiac output. jama. 2012 mar 7;307(9):948-55.doi: 264 10.1001/jama.2012.250. pmid: 22396517. 265 24. zhang wj, huang ys, zhu zm, luo hl. a case report of unexplained jejunal telangiectasia 266 complicated with bleeding. int j surg case rep. 2020;67:219-222. doi: 267 10.1016/j.ijscr.2020.01.062. pmid: 32066112; pmcid: pmc7025968. 268 269 270 https://www.google.com/search?newwindow=1&sxsrf=apq-wbv-6nypu4jvc_sfemjb-9nc6scefq:1649917607557&q=chavan+a,+luthe+l,+gabel+m,+barg-hock+h,+seifert+h,+raab+r,+et+al.+complications+and+clinical+outcome+of+hepatic+artery+embolization+in+patients+with+hereditary+haemorrhagic+telangiectasia.+eur+radiol+2013;23:951%e2%80%93957.&spell=1&sa=x&ved=2ahukewius6ch9pl3ahvzr2wghsw4b94qbsgaegqiaraz https://www.google.com/search?newwindow=1&sxsrf=apq-wbv-6nypu4jvc_sfemjb-9nc6scefq:1649917607557&q=chavan+a,+luthe+l,+gabel+m,+barg-hock+h,+seifert+h,+raab+r,+et+al.+complications+and+clinical+outcome+of+hepatic+artery+embolization+in+patients+with+hereditary+haemorrhagic+telangiectasia.+eur+radiol+2013;23:951%e2%80%93957.&spell=1&sa=x&ved=2ahukewius6ch9pl3ahvzr2wghsw4b94qbsgaegqiaraz https://www.google.com/search?newwindow=1&sxsrf=apq-wbv-6nypu4jvc_sfemjb-9nc6scefq:1649917607557&q=chavan+a,+luthe+l,+gabel+m,+barg-hock+h,+seifert+h,+raab+r,+et+al.+complications+and+clinical+outcome+of+hepatic+artery+embolization+in+patients+with+hereditary+haemorrhagic+telangiectasia.+eur+radiol+2013;23:951%e2%80%93957.&spell=1&sa=x&ved=2ahukewius6ch9pl3ahvzr2wghsw4b94qbsgaegqiaraz 271 figure 1: case 1 (a and b) showing telangiectatic foci in pinna and hand (black arrows) (c) 272 gray scale ultrasound image of the left lobe of the liver showing tortuous and dilated left hepatic 273 artery (white arrow) with corkscrew appearance; (d) duplex doppler image of left hepatic artery 274 shows normal waveform with markedly elevated peak systolic velocity (152 cm/s); (c and d) 275 276 277 figure 2: case 1 cect arterial phase axial images (a, b) showing dilated and tortuous left 278 (lha) and middle (mha) hepatic arteries with evidence of arterio-portal shunting. lha was 279 directly arising from the celiac trunk. mha was seen as a direct continuation of the common 280 hepatic artery arising from the celiac trunk. a pseudoaneurysm (pa) is noted in the left lobe of 281 the liver arising from a branch of lha. liver contour is normal. arterial phase coronal image (c) 282 showing dilated and tortuous right hepatic artery (rha) arising from the superior mesenteric 283 artery (replaced rha). 284 285 286 figure 3: case 2 cect arterial phase axial image (a) showing mural enhancement in the 287 ileum (white arrow). arterial phase axial images (b) showing multiple arterially enhancing 288 telangiectatic foci (black arrows) in both lobes of the liver. the hepatic artery is seen of normal 289 calibre with no arterio-portal shunting (c) enteroscopic image showing multiple punctate 290 telangiectases in ileum (black arrows). 291 a b c departments of 1surgery & preventive and 2social medicine, jawaharlal institute of postgraduate medical education and research, pondicherry, india *corresponding author’s e-mail: drvikramkate@gmail.com comparison of short-course and conventional antimicrobial duration in mild and moderate complicated intra-abdominal infections a randomised controlled trial p. vinodhini,1 sathasivam sureshkumar,1 balakrishnan gurushankari,1 thulasingam mahalakshmy,2 *vikram kate1 sultan qaboos university med j, may 2023, vol. 23, iss. 2, pp. 212–219, epub. 31 may 23 submitted 1 feb 22 revisions req. 19 may & 8 aug 22; revisions recd. 10 jun & 17 aug 22 accepted 27 aug 22 this work is licensed under a creative commons attribution-noderivatives 4.0 international license. https://doi.org/10.18295/squmj.1.2023.006 clinical & basic research abstract: objectives: studies have shown the feasibility of short-course antimicrobials in complicated intraabdominal infection (ciai) following source control procedure (scp). this study aimed to compare postoperative complication rates in short-course (5 days) and conventional (7–10 days) duration groups after antimicrobial therapy. methods: this was a single-centre, open-labelled, randomised controlled trial conducted in jawaharlal institute of postgraduate medical education and research, pondicherry, india, from july 2017 to december 2019 on patients with ciai. patients who were haemodynamically unstable, pregnant and had non-perforated, non-gangrenous appendicitis or cholecystitis were excluded. primary endpoints were surgical site infection (ssi), recurrent intraabdominal infection (iai) and mortality. secondary endpoints included time till occurrence of composite primary outcomes, duration of antimicrobial therapy, the length of hospital stays, antimicrobial-free interval, hospital-free days at 30 day intervals and the presence of extra-abdominal infections. results: overall, 140 patients were included whose demographic and clinico-pathological details were comparable in both groups. there was no difference in ssi (37% versus 35.6%) and recurrent iai (5.7% versus 2.8%; p = 0.76); no mortality was observed in either groups. the composite primary outcome (37% versus 35.7%) was also similar in both groups. secondary outcomes included the duration of antimicrobial therapy (5 versus 8 days; p <0.001) and length of hospitalisation (5 versus 7 days; p = 0.014) were significant. times till occurrence of ssi and recurrent iai, incidence of extra-abdominal infection and resistant pathogens were comparable. conclusion: short-course antimicrobial therapy for 5 days following scp for mild and moderate ciai was comparable to conventional duration antimicrobial therapy, indicating similar efficacy. keywords: abdominal abscess; antibiotic prophylaxis; antimicrobial stewardship; appendicitis, perforated; drug resistance, microbial; intra-abdominal infection; peritonitis; surgical wound infection, india. advances in knowledge the use of short-course antimicrobials in complicated intra-abdominal infections is safe and efficacious. short-course antimicrobial therapy leads to a reduced length of hospital stay. short-course antimicrobial therapy has a comparable postoperative outcome to conventional antimicrobial therapy. applications to patient care short-course antimicrobials help reduce the development of antibiotic resistances, which is considered a major concern across the globe. it also helps in early discharge of patients and for maintaining a better cost-benefit ratio in the hospitals. complicated intra-abdominal infection (ciai) is one of the most frequent cases encountered by a surgeon in an emergency scenario. ciai is usually defined as abscess formation or peritonitis beyond the origin of the perforation of a hollow viscus in the peritoneal cavity, which requires an invasive procedure for source control.1–3 the three pillars of management are fluid resuscitation, source control procedure (scp) and the usage of antibiotics to eliminate residual organisms.1–3 patients undergoing major abdominal surgery, in which infective postoperative complications are anticipated, require perioperative antibiotic cover. this necessity is more pronounced in the subset of patients who undergo emergency abdominal surgery, especially when the patient has associated abdominal or generalised sepsis. traditionally, in such cases, antibiotic coverage is stopped two days after the resolution of systemic inflammatory response syndrome as documented by the normalisation of total leukocyte counts and resolution of fever.2 conventionally, the recommended duration of the use of antibiotics in these conditions is between 10–14 days.3,4 however, recent evidence indicates that not all postoperative febrile episodes are due to active abdominal infection.2–5 the surviving sepsis campaign guidelines recommend that relevant cultures should be obtained and antibiotic therapy should be modified accordingly.6 recent reports imply that the duration of antibiotics can be shortened after a proper scp p. vinodhini, sathasivam sureshkumar, balakrishnan gurushankari, thulasingam mahalakshmy and vikram kate clinical and basic research | 213 is followed to control the sepsis and that there is no need for antibiotics to be continued for an extended period after an scp.3 studies have shown the utility and efficacy of short-course antibiotic usage after scp in complicated iais both in open and laparoscopic procedures.2–5 however, despite this, many surgeons are still apprehensive in implementing the same. this trepidation is mostly attributed to the possibility of postoperative iais developing in patients, as well as multiple nosocomial infections that patients are exposed to in the hospital.7 however, the decrease in the duration of antibiotics helps in shortening the length of hospital stay, and it has been shown to have comparable results in terms of postoperative complications.6 management of a complicated iai requires vigilant and timely intervention in order to contain the sepsis, which includes fluid and electrolyte correction, an effective scp and judicious use of antimicrobials. all these three measures should be carried out expediently in order to achieve a good outcome. the duration of antibiotics is crucial as undertreatment and overtreatment can be detrimental to the patient. however, the optimum duration for the course of antibiotics is still debatable. recent reports have shown that the use of a short course of antimicrobials after an effective scp may be satisfactory for the control of infection, the rationale being that the scp helps in eliminating a major portion of the sepsis, and thereafter, since the load of bacteria is expected to be largely reduced, the duration of antimicrobials can be safely truncated.8 though studies have shown that short-course antimicrobial therapy is safe and effective compared with conventional long-course therapy, it is to be noted that a majority of these studies were carried out in western countries, where the antibiotic usage is well regulated and antibiotic resistance is low. however, in the developing countries, with varying patient profile, poor nutritional status, delayed presentation, diverse aetiology of intra-abdominal infection, unrestricted antimicrobial usage with higher resistance pattern, the efficacy of short-course antimicrobial therapy needs to be studied to assess their effectiveness in these populations. hence, this study aimed to compare the rates of postoperative complications in patients with complicated iais after conventional duration and short-course antimicrobial therapy. methods this was a randomised controlled trial, which was single-centred, non-inferior and open-labelled, conducted in the surgery department in jawaharlal institute of postgraduate medical education and research, pondicherry, india, from july 2017 to december 2019. the study was registered at the clinical trials registry in india (registration number: ctri/2018/03/012682). this work has been reported in accordance with the consolidated standards of reporting trials (consort) guidelines. patients aged >18 years who presented to the emergency surgical unit and were diagnosed with complicated iais such as perforated/gangrenous appendicitis/cholecystitis, bowel gangrene/ perforation and gastric/duodenal perforation with peritonitis were enrolled and assessed for eligibility. the diagnosis was confirmed by clinical examination and relevant laboratory and radiological investigations. patients who were haemodynamically unstable, who were pregnant and who had non-perforated, nongangrenous appendicitis or cholecystitis, infected necrotising pancreatitis, primary spontaneous bacterial peritonitis and infection associated with indwelling peritoneal dialysis catheter were excluded. patients who received antimicrobial therapy for either 5 days or of a conventional duration of 7–10 days were randomly assigned in a 1:1 ratio. a computer programme was used for block randomisation with block sizes of four and six selected randomly. the technique called ‘serially numbered opaque sealed envelope’ (snose) was used for concealment during allocation. a person independent of the investigators had prepared these sealed envelopes. the nurse opened the envelope at the time of decision of surgery and group allocation was done. before the operation, all patients were stabilised by fluid resuscitation according to conventional guidelines and were started on intravenous (iv) empirical antibiotics.9 standard preoperative care was provided as per the routine protocol. patients were admitted in the emergency surgical ward and laboratory investigations and imaging, including contrast enhanced computed tomography, were carried out for the diagnosis. placement of a nasogastric tube at admission, urinary catheterisation and administration of crystalloids for fluid replacement were done. patients received iv empirical antibiotic therapy with ceftriaxone and metronidazole or piperacillin–tazobactam depending on the possible grade of infection and iv acid reducing therapy with pantoprazole.9,10 all patients underwent open laparotomy and received standard scp as per the primary diagnosis, which included omental patch closure for gastric or duodenal perforation, primary resection anastomosis or stoma for bowel gangrene, appendectomy and comparison of short-course and conventional antimicrobial duration in mild and moderate complicated intra-abdominal infections a randomised controlled trial 214 | squ medical journal, may 2023, volume 23, issue 2 peritoneal lavage for gangrenous or perforated appendix, etc. intraoperative fluid or specimen was sent for aerobic culture. patients in the shortcourse group and in the conventional duration group received antimicrobial therapy for 5 days and for 7–10 days, respectively.2 in both the groups, the antibiotics that were given were ceftriaxone with metronidazole or piperacillin–tazobactam based on a mild or moderate infection, which was diagnosed taking into account the total and differential leukocyte count, fever, respiratory rate and the possible organ involved based on the radiological investigation. these antibiotics were administered based on the antibiotic guidelines of the authors’ institute, which is based not only on the sensitivity and resistance pattern of their hospital but also based on the standard guidelines of the international society.3,10 in cases where the intraoperative pus/fluid culture showed a resistance pattern to the ongoing antibiotics, a sensitive antibiotic was given as per the culture and sensitivity report within 48 hours of starting the initial antibiotics. subsequent occurrence of recurrent intra-abdominal infection and surgical site infection (ssi) were treated as per the standard protocol and with antibiotics based on the culture report. patients were monitored till the time of discharge for the presence of ssi, recurrent iai or death due to any cause. in case of development of ssi or recurrent abdominal infection, a wound swab or percutaneously/ surgically drained fluid was sent for culture and sensitivity. patients were followed-up till the time of discharge and on days 15 and 30 postoperatively for occurrence of any of the primary outcomes and complications, for re-admission and for mortality. the primary endpoints in the two groups were development of ssi, recurrent iai and mortality. the primary outcome was assessed as a composite endpoint comprising any one, two or three of the primary endpoints. the secondary outcome included the time of the occurrence of composite primary outcomes, duration of antimicrobial therapy, the length of hospital stays, antimicrobial-free interval, hospital-free days at 30 days’ interval and the presence of extra-abdominal infections. the composite primary outcomes were used for power analysis. the sample size was calculated using nmaster software, version 2.0 (christian medical college, tamil nadu, india). assuming the proportion of composite primary outcome in the conventional duration group to be 30–40% and a non-inferiority margin of 10%, the sample size was calculated as 70 in each arm (total = 140), with a power of 80%, an alpha error of 5% and estimated loss to follow-up of 10%.2 data were collected as per the specified proforma prepared by the investigators. different demographic variables such as age, gender, address, organ of infection and scp were collected and analysed. statistical analysis was done using the statistical package for the social sciences (spss), version 20.0 (ibm corporation, armonk, new york, usa). continuous variables such as time till the occurrence of composite primary outcome and duration of antimicrobial therapy were expressed as mean ± standard deviation or median (interquartile range) depending upon the normality of distribution. categorical variables such as parameters of primary outcomes were expressed as proportions. the chisquared test was used to compare the proportions of figure 1: flowchart for the study. p. vinodhini, sathasivam sureshkumar, balakrishnan gurushankari, thulasingam mahalakshmy and vikram kate clinical and basic research | 215 primary endpoints and composite primary outcome in the two groups. secondary outcomes such as the time till the occurrence of primary endpoints and composite primary outcomes, duration of antimicrobial therapy, the length of hospital stay, antimicrobial-free interval and hospital-free days at 30 days’ interval were compared using the mann-whitney u test. fisher’s test was used to compare the incidence of extra-abdominal infections and organisms of aerobic infection in the two groups. all results were interpreted as intentionto-treat analysis. a p value below 0.05 was considered as statistically significant. the study was approved by the institute ethics committee (jip/iec/2017/0239) and written informed consent was taken from all the participants. results a total of 164 patients with complicated iai were assessed for eligibility from july 2017 to may 2019. a total of 24 patients were excluded [figure 1]. the remaining 140 patients were randomised, with 70 in the short-course group and 70 in the conventional duration group. there was no loss to follow-up. the two groups were comparable in terms of all demographic and clinico-pathological characteristics [table 1]. the incidence of superficial incisional ssi was 31.4% and 32.8%, deep incisional ssi was 2.8% and 1.4% and organ space infection was 2.8% and 1.4% in the short-course and the conventional duration antimicrobial therapy groups, respectively (p = 0.764) [table 2]. four and two patients developed recurrent iai in the short-course group and in the conventional duration group, respectively, while two and one patients developed deep organ space infection in the shortcourse group and the conventional duration group, respectively. except one patient in the short-course group who had postoperative leak after the initial adequate source control by omental patch closure for duodenal perforation (upper gastrointestinal tract), which resulted in recurrent iai, the rest of the patients in both the groups had a small bowel or appendix (lower gastrointestinal tract) aetiology as a source of ciai. the incidence of recurrent iai was similar at 5.7% and 2.8% in the short-course and conventional duration antimicrobial therapy groups, respectively (p = 0.764). there was no mortality in both the groups. the composite primary outcome was 37% and 35.7% in the short-course and conventional duration groups, which was also similar (p = 0.726). there was a significant reduction in the length of hospital stay by 2 days in the short-course and conventional duration antimicrobial therapy groups (p = 0.014) [table 3]. there was a significant reduction in the duration of antimicrobial therapy by 3 days in the table 1: baseline demographic and clinical characteristics in the short-course and conventional duration groups (n = 140) variables n (%) p value short-course group (n = 70) conventional duration group (n = 70) mean age in years ± sd 40 ± 15.5 43 ± 15.8 0.11 male patients 54 (77.1) 51 (72.8) 0.55 organ of origin appendix 32 (45.7) 34 (48.5) small bowel 23 (32.8) 27 (38.5) stomach 11 (15.7) 6 (8.6) 0.465 large bowel 3 (4.3) 2 (2.9) gall bladder 1 (1.4) 1 (1.4) source control procedure appendectomy 32 (45.7) 34 (48.5) omental patch closure 21 (30.0) 18 (25.7) resection and anastomosis 8 (11.4) 7(10.0) 0.764 resection and stoma 8 (11.4) 10(14.3) pigtail 1 (1.4) 1 (1.4) sd = standard deviation; scp = source control procedure. table 2: comparison of primary endpoints and composite primary outcomes in the short-course and conventional duration groups (n = 140) surgical site infection n (%) p value* short-course group (n = 70) conventional duration group (n = 70) superficial incisional ssi 22 (31.4) 23 (32.8) deep incisional ssi 2 (2.8) 1 (1.4) 0.764 organ space infection 2 (2.8) 1 (1.4) recurrent intraabdominal infection 4 (5.7) 2 (2.8) composite primary outcomes 27 (37)† 25 (35.7)† ssi = surgical site infection. *using chi-squared test. †patients with composite outcome (having any one of more than one type of ssi mentioned above). comparison of short-course and conventional antimicrobial duration in mild and moderate complicated intra-abdominal infections a randomised controlled trial 216 | squ medical journal, may 2023, volume 23, issue 2 short-course and conventional duration antimicrobial therapy groups (p <0.001). the time till the occurrence of ssi was 3.8 ± 0.7 and 4.2 ± 1.2 days (p = 0.77) and recurrent iai was 7 ± 1.8 and 5.3 ± 0.5 days (p = 0.195) in the short-duration and conventional duration groups, respectively. the time till the occurrence of composite primary outcome was 4.1 ± 1.6 and 4.5 ± 1.3 days in both the groups, which was similar (p = 0.256) [table 4]. the incidence of extra-abdominal infections such as urinary tract infection (2.8% versus 2.8%), bloodstream infection (4.2% versus 2.8%), pulmonary infection (4.2% versus 5.6%) and vascular catheterassociated infection (1.4% versus 0.0%) were similar in the two groups (p = 0.582). escherichia coli (55.1% versus 49.7%) was the most common organism isolated from the culture specimen followed by enterococcus (2.9% versus 7.6%), klebsiella (2.9% versus 2.5%), pseudomonas (2.9% versus 2.5%) and acinetobacter (2.9% versus 2.5%) in the short-course and conventional duration groups, respectively [table 5]. nearly 33.3% of the shortcourse group and 35.2% of the conventional duration group showed poly-microbial growth. based on the intraoperative culture and sensitivity report, 9.2% of the study population required a change of antibiotics due to resistance of the primary antibiotics that were given perioperatively. culture-sensitive antibiotics such as third-generation cephalosporins with metronidazole, piperacillin– tazobactam, meropenem or imipenem–cilastatin with metronidazole were used for ssi and recurrent intraabdominal infection in the study population. discussion this study showed that short-course antimicrobial therapy for 5 days following scp for complicated iai had similar outcomes to antimicrobial therapy for a conventional duration. a significant reduction in the length of hospitalisation in patients undergoing shortcourse antimicrobial therapy was also observed. the times till the occurrence of ssi and recurrence of iai were comparable between the two groups. also, the times till the occurrence of composite primary outcome were similar among the two groups. the incidences of extra-abdominal infections such as urinary tract infection, bloodstream infection, pulmonary infection and vascular catheter-associated infection were similar in the two groups. e. coli was the most common table 3: comparison of secondary outcomes in shortcourse and conventional duration groups (n = 140) secondary outcomes duration in days (range) p value* short-course group (n = 70) conventional duration group (n = 70) antimicrobial therapy 5† 8 (7–10) <0.001 antimicrobialfree days at 30 days’ interval 25† 22 (20–23) <0.001 hospitalisation after index procedure 5† 7 (7–10) 0.014 hospital free days at 30 days’ interval 25 (23–25) 23 (20–23) 0.012 *using mann-whitney u test. †the duration of antibiotics was fixed at five days in all the patients in short course group. table 4: comparison of the time till occurrence of the primary endpoints and composite primary outcomes in short-course and conventional duration groups (n = 140) time to event duration in days p value* short-course group (n = 70) conventional duration group (n = 70) surgical site infections 3.8 ± 0.7 4.2 ± 1.2 0.770 recurrent intraabdominal infection 7.0 ± 1.8 5.3 ± 0.5 0.195 composite primary outcomes 4.1 ± 1.6 4.5 ± 1.3 0.256 *using mann-whitney u test. table 5: comparison of organisms of aerobic infection in short-course and conventional duration groups (n = 140) organisms of aerobic infection n (%) p value* short-course group (n = 70) conventional duration group (n = 70) aerobic infection 34 (48.5) 39 (55.7) 0.397 anaerobic infection 2 (2.8) 2 (2.8) 0.97 e. coli 27 (38.5) 28 (40.0) 0.706 enterococcus 10 (14.2) 10 (14.2) klebsiella 5 (7.1) 8 (11.4) pseudomonas 6 (8.5) 7 (10.0) acinetobacter 1 (1.4) 3 (4.2) more than one organism 11 (15.7) 14 (20.0) *using fisher exact. p. vinodhini, sathasivam sureshkumar, balakrishnan gurushankari, thulasingam mahalakshmy and vikram kate clinical and basic research | 217 organism isolated from the culture specimens in both the groups, followed by enterococcus, klebsiella, pseudomonas and acinetobacter. only a few reports have been published on the use of antimicrobials for a shorter duration in complicated iai.2 although recent guidelines and a few studies in this aspect have shown a similar outcome as short-course antimicrobial therapy, surgeons are still apprehensive in implementing the same in clinical practice, due to the life-threatening consequences of potential undertreatment.3 in this study, the primary outcomes such as ssis and recurrent iais were comparable in the short-course and conventional duration antimicrobial groups. in this study, appendicular perforation was the commonest cause of complicated intra-abdominal infections. though a significant number of patients had small and large bowel perforations, they could not be included in the study as they were haemodynamically unstable and required inotropes support at the time of presentation. this was consistent with the study conducted by lopez et al., in which appendicular perforation was the most common cause of peritonitis.11 in this study, the most common organism isolated was e. coli, which was similar to a report from italy.1 in this report, after e. coli, enterococcus was the next organism isolated in a very small number of cases while the cultures of many patients showed the growth of more than one aerobic organism. in a small subset of patients, anaerobic organisms such as bacteroides fragilis were found growing in their culture. as per the surgical infection society-infectious diseases society of america guidelines, third-generation cephalosporins with metronidazole are recommended in patients with complicated iais who are at low risk, while in patients at high risk, piperacillin-tazobactam, meropenem or imipenem–cilastatin with metronidazole can be used.12 addition of metronidazole to the antibiotic therapy has been shown to reduce the postoperative complications as b. fragilis are obligate anaerobes in the distal small bowel and large bowel.13 in this study, third-generation cephalosporins and metronidazole were given to most patients, while patients at high risk received piperacillin-tazobactam. antimicrobials and its use in the complicated iai are based on the susceptibility of the organisms.14 the antibiotics in this study were used according to the hospital guidelines and policy. similar to this study, another report administered 4 ± 1 days of antibiotics in the short-course group and the conventional duration group received antibiotics till the fever resolved and white cell counts were normalised.2 schein et al. also reported the use of 3–5 days of antibiotics in patients with complicated iai following scp.15 in this study, the short-course group and the conventional duration group received 5 and 7–10 days of antibiotics, respectively. in both the groups, a few patients received antibiotics for a longer time than the stipulated duration, when they had organ space infection, recurrent iai and extraabdominal infection. in a study from the united states and canada, 10% of the patients had received antibiotics for a prolonged duration owing to the occurrence of wound infections and extra-abdominal infection.2 in the short-course group of that study, four patients had re-exploration and two patients had organ space infection, which required a longer duration of antibiotics. among the four patients, in one of the patients a postoperative leak occurred after the initial adequate source control by omental patch closure, which resulted in recurrent iai. two patients had anastomotic leak, which required reexploration, and one other patient had an iatrogenic perforation, which was detected in the postoperative period. though the majority of the studies advocate short-course antimicrobial therapy after adequate source control for mild to moderate iai, a longer duration of therapy may be required for patients with severe iai and showing features of severe sepsis. these patients may have an unpredictable clinical course that require a more complex and individualised approach for the diagnosis of ongoing sepsis, the reason for antimicrobial failure and continuous monitoring of inflammatory markers.16 in that study, patients in the short-course and the conventional duration groups developed extra-abdominal infection at the rate of 12.6% and 11.2%, respectively. pulmonary infection accounted for the majority of infections. in the rct by sawyer et al., the recurrent intraabdominal infection rate was considerably high with 36 (13.8%) in the control group versus 40 (15.6%) in the experimental group with (p = 0.67).2 this was significantly lower in the current study with 4 (5.7%) in the short-course group versus 2 (2.8%) in the conventional duration group. considering the lesser number of events in both the groups in the current study, the difference was not observed. in the study by sawyer et al., the short-course group had 40.2% of infectious complications and the conventional duration group had 38.4% out of which ssis accounted for a majority of cases, superficial incisional ssi being the most common. there was no mortality in both the groups. in another report, the rate of infectious complications were more than 20% in both the groups; however, the majority of the cases were recurrent iais.2 there were two deaths in the study group and three deaths in the experimental group. antibiotics such as ertapenem had been given for only 3 days to comparison of short-course and conventional antimicrobial duration in mild and moderate complicated intra-abdominal infections a randomised controlled trial 218 | squ medical journal, may 2023, volume 23, issue 2 patients with mild to moderate iais with a successful outcome.17 the times taken till the occurrence of ssis and recurrent iais were similar in the two groups. the time till the occurrence of the composite primary outcome was 4.1 days in the short-course group. this led to early detection and timely intervention, thus avoiding the need for readmissions. in the current study, the antimicrobial-free days at the 30 day interval was 3 days less in the short-course group with comparable postoperative complications. the hospitalisation duration after the index procedure was 2 days less in the short-course group and was costeffective. there were certain limitations in this study. firstly, in the majority of patients the source of iai was from the appendix or the small bowel with mild to moderate severity. severe iai and colon as a source were found only in a limited number of patients. hence, the results of this study are predominantly applicable to mild to moderate iai. secondly, the ssi rate in this study is high compared with the published literature from the western population. as the authors’ hospital is a public sector institute in a developing country, the patient population is usually from a low socioeconomic status, with poor knowledge of personal hygiene and selfcare. the patients also mostly present late following the onset of symptoms, which could possibly lead to higher incidence of ssi. previous published studies by the authors’ institute on ssi have also shown a similar rate, indicating the possible role of patient population in the higher rate of ssi.18,19 conclusion this study showed that short-course antimicrobial therapy when compared with conventional duration therapy has comparable incidences of ssi and recurrent iai in patients with mild and moderate complicated iai. the time till the occurrence of composite primary outcomes and the presence of extra-abdominal infections were similar in both groups. there was a significant reduction in the duration of antimicrobial therapy and the length of hospital stays. future studies are recommended to include critically ill patients to assess the efficacy of short-term antimicrobial therapy following scp in severe ciai. a u t h o r s’ c o n t r i b u t i o n vk and ss conceptualised and bg contributed to the designed the study. pv collected the data and performed the investigation. pv, bg, tm and vk performed the data analysis. ss, tm and vk supervised the work. pv and bg drafted the manuscript. ss, bg, tm and vk reviewed and edited the manuscript. all authors approved the final version of the manuscript. c o n f l i c t o f i n t e r e s t the authors declare no conflict of interest. f u n d i n g no funding was received for this study. a c k n o w l e d g e m e n t s the authors would like to thank dr rohith gorrepati and dr evangeline mary kiruba samuel, senior residents, department of surgery, and dr arivarasan, former junior resident, department of preventive and social medicine, jawaharlal institute of post graduate medical education and research (jipmer), pondicherry, india, for their support in conducting the study and for helping in the statistical analysis. parts of this manuscript results have been published as an abstract at the 61st annual meeting of the society for surgery of the alimentary tract, usa (2020) under the title ‘comparison of short course antimicrobial therapy vs. conventional antimicrobial therapy in patients with complicated intra-abdominal infections: a randomised controlled trial.’ the same is available at https://meetings.ssat. com/abstracts/2020/180.cgi. references 1. sartelli m. a focus on intra-abdominal infections. world j emerg surg 2010; 5:9. https://doi.org/10.1186/1749-7922-5-9. 2. sawyer rg, claridge ja, nathens ab, rotstein od, duane tm, evans hl, et al. trial of short course antimicrobial therapy for intra-abdominal infections. n engl j med 2015; 372:1996–2005. https://doi.org/10.1056/nejmoa1411162. 3. solomkin js, mazuski je, bradley js, rodvold ka, goldstein ejc, baron ej, et al. diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the surgical infection society and the infectious diseases society of america. clin infect dis 2010; 50:133–64. https:// doi.org/10.1086/649554. 4. solomkin js, mazuski je, baron ej, sawyer rg, nathens ab, dipiro jt, et al. guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. clin infect dis 2003; 37:997–1005. https://doi.org/10.1086/378702. 5. van rossem cc, schreinemacher mh, van geloven aa, bemelman wa. snapshot appendicitis collaborative study group: antibiotic duration after laparoscopic appendectomy for acute complicated appendicitis. jama surg 2016; 151:323–9. https://doi.org/10.1001/jamasurg.2015.4236. 6. levy mm, evans le, rhodes a. the surviving sepsis campaign bundle. intensive care med 2018; 44:925–8. https://doi. org/10.1007/s00134-018-5085-0. 7. inui t, haridas m, claridge ja, malangoni ma. mortality for intra-abdominal infection is associated with intrinsic risk factors rather than the source of infection. surgery 2009; 146:654–61. https://doi.org/10.1016/j.surg.2009.06.051. p. vinodhini, sathasivam sureshkumar, balakrishnan gurushankari, thulasingam mahalakshmy and vikram kate clinical and basic research | 219 8. jimenez mf, marshall jc. source control in the management of sepsis. intensive care med 2001; 27:s49–62. https://doi. org/10.1007/pl00003797. 9. dellinger rp, levy mm, carlet jm, bion j, parker mm, jaeschke r, et al. surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. intensive care med 2008; 34:17–60. https://doi.org/10.1007/s00134-007-0934-2. 10. nathens ab, rotstein od. therapeutic options in peritonitis. surg clin north am 1994; 74:677–92. 11. lopez n, kobayashi l, coimbra r. a comprehensive review of abdominal infections. world j emerg surg 2011; 6:7. https:// doi.org/10.1186/1749-7922-6-7. 12. mazuski je, sawyer rg, nathens ab, dipiro jt, schein m, kudsk ka, et al. the surgical infection society guidelines on antimicrobial therapy for intraabdominal infections: an executive summary. surg infect (larchmt) 2002; 3:161–73. https://doi.org/10.1089/109629602761624171. 13. jamalov fh, agayev rm, achundov it, huseynov sg, jamalova tp. antibacterial prophylaxis in emergency surgery of abdominal infection. euroasian j hepatogastroenterol 2018; 8:116–20. https://doi.org/10.5005/jp-journals-10018-1276. 14. haddad n, kanj ss, awad ls, abdallah di, moghnieh ra. the 2018 lebanese society of infectious diseases and clinical microbiology guidelines for the use of antimicrobial therapy in complicated intra-abdominal infections in the era of anti microbial resistance. bmc infect dis 2019; 19:293. https://doi. org/10.1186/s12879-019-3829-2. 15. schein m, assalia a, bachus h. minimal antibiotic therapy after emergency abdominal surgery: a prospective study. br j surg 1994; 81:989–91. https://doi.org/10.1002/bjs.1800810720. 16. sartelli m, catena f, ansaloni l, coccolini f, di saverio s, griffiths ea. duration of antimicrobial therapy in treating compl icated intra-abdominal infections: a comprehensive review. surg infect (larchmt) 2016; 17:9–12. https://doi.org/10.1089/ sur.2015.130. 17. basoli a, chirletti p, cirino e, d’ovidio ng, doglietto gb, giglio d, et al. a prospective, double-blind, multicenter, randomized trial comparing ertapenem 3 vs. ≥5 days in communityacquired intraabdominal infection. j gastrointest surg 2008; 12:592–600. https://doi.org/10.1007/s11605-007-0277-x. 18. pranavi ar, sureshkumar s, mahalakshmy t, kundra p, kate v. adapted eras pathway versus standard care in patients undergoing emergency surgery for perforation peritonitis: a randomized controlled trial. j gastrointest surg 2022; 26:39–49. https://doi.org/10.1007/s11605-021-05184-x. 19. mayank m, mohsina s, sureshkumar s, kundra p, kate v. effect of perioperative high oxygen concentration on postoperative ssi in elective colorectal surgery: a randomized controlled trial. j gastrointest surg 2019; 23:145–52. https://doi.org/10.1007/ s11605-018-3996-2.